PMID- 28334939 TI - Association between tau deposition and antecedent amyloid-beta accumulation rates in normal and early symptomatic individuals. AB - See Vandenberghe and Schaeverbeke (doi:10.1093/awx065) for a scientific commentary on this article. A long-term goal of our field is to determine the sequence of pathological events, which ultimately lead to cognitive decline and dementia. In this study, we first assessed the patterns of brain tau tangle accumulation (measured with the positron emission tomography tracer 18F-AV-1451) associated with well-established Alzheimer's disease factors in a cohort including cognitively healthy elderly individuals and individuals at early symptomatic stages of Alzheimer's disease. We then explored highly associated patterns of greater 18F-AV-1451 binding and increased annualized change in cortical amyloid-beta plaques measured as florbetapir positron emission tomography binding antecedent to 18F-AV-1451 positron emission tomography scans, and to what extent these multimodal pattern associations explained the variance in cognitive performance and clinical outcome measures, independently and jointly. We found that: (i) 18F-AV-1451 positron emission tomography retention was differentially associated with age, and cross-sectional florbetapir positron emission tomography retention, but not with years of education, gender, or APOE genotype; (ii) increased annualized change in florbetapir retention, antecedent to 18F-AV-1451 positron emission tomography scans, in the parieto-temporal and precuneus brain regions was associated with greater 18F-AV-1451 PET retention most prominently in the inferior temporal and inferior parietal regions in the full cohort, with florbetapir positive/negative-associated variability; and (iii) this 18F-AV-1451 positron emission tomography retention pattern significantly explained the variance in cognitive performance and clinical outcome measures, independent of the associated antecedent increased annualized change in florbetapir positron emission tomography retention. These findings are in agreement with the pathology literature, which suggests that tau tangles but not amyloid-beta plaques correlate with cognition and clinical symptoms. Furthermore, non-local associations linking increased amyloid-beta accumulation rates with increased tau deposition are of great interest and support the idea that the amyloid-beta pathology might have remote effects in disease pathology spread potentially via the brain's intrinsic connectivity networks. PMID- 28334940 TI - AAV9 delivered bispecific nanobody attenuates amyloid burden in the gelsolin amyloidosis mouse model. AB - Gelsolin amyloidosis is a dominantly inherited, incurable type of amyloidosis. A single point mutation in the gelsolin gene (G654A is most common) results in the loss of a Ca2+ binding site in the second gelsolin domain. Consequently, this domain partly unfolds and exposes an otherwise buried furin cleavage site at the surface. During secretion of mutant plasma gelsolin consecutive cleavage by furin and MT1-MMP results in the production of 8 and 5 kDa amyloidogenic peptides. Nanobodies that are able to (partly) inhibit furin or MT1-MMP proteolysis have previously been reported. In this study, the nanobodies have been combined into a single bispecific format able to simultaneously shield mutant plasma gelsolin from intracellular furin and extracellular MT1-MMP activity. We report the successful in vivo expression of this bispecific nanobody following adeno associated virus serotype 9 gene therapy in gelsolin amyloidosis mice. Using SPECT/CT and immunohistochemistry, a reduction in gelsolin amyloid burden was detected which translated into improved muscle contractile properties. We conclude that a nanobody-based gene therapy using adeno-associated viruses shows great potential as a novel strategy in gelsolin amyloidosis and potentially other amyloid diseases. PMID- 28334941 TI - RNA-protein interactions govern antiviral specificity and encapsidation of broad spectrum anti-HIV reverse transcriptase aptamers. AB - RNA aptamers that bind HIV-1 reverse transcriptase (RT) inhibit HIV-1 replication, but little is known about potential aptamer-specific viral resistance. During replication, RT interacts with diverse nucleic acids. Thus, the genetic threshold for eliciting resistance may be high for aptamers that make numerous contacts with RT. To evaluate the impact of RT-aptamer binding specificity on replication, we engineered proviral plasmids encoding diverse RTs within the backbone of HIV-1 strain NL4-3. Viruses inhibited by pseudoknot aptamers were rendered insensitive by a naturally occurring R277K variant, providing the first demonstration of aptamer-specific resistance in cell culture. Naturally occurring, pseudoknot-insensitive viruses were rendered sensitive by the inverse K277R mutation, establishing RT as the genetic locus for aptamer mediated HIV-1 inhibition. Non-pseudoknot RNA aptamers exhibited broad-spectrum inhibition. Inhibition was observed only when virus was produced in aptamer expressing cells, indicating that encapsidation is required. HIV-1 suppression magnitude correlated with the number of encapsidated aptamer transcripts per virion, with saturation occurring around 1:1 stoichiometry with packaged RT. Encapsidation specificity suggests that aptamers may encounter dimerized GagPol in the cytosol during viral assembly. This study provides new insights into HIV 1's capacity to escape aptamer-mediated inhibition, the potential utility of broad-spectrum aptamers to overcome resistance, and molecular interactions that occur during viral assembly. PMID- 28334942 TI - Epidemiological analysis of childhood cancer in Japan based on population-based cancer registries, 1993-2009. AB - Background: There are few recent data on trends in childhood cancer incidence using population-based cancer registries in Japan. Methods: This study comprised 6110 reported cases of patients aged 0-14 years who were diagnosed as having primary cancer between 1993 and 2009. We chose cancer registries of seven prefectures, according to the international cancer registry standard of fewer than 10% death certificate only cases among cancer registries in Japan. We analyzed population-based cancer registration data in the seven prefectures between 1993 and 2009. We calculated childhood cancer incidence, age-specific incidence, crude incidence rate, age-adjusted incidence rate, confidence intervals and annual change for each prefecture and classified the data into 12 diagnostic groups, according to the International Classification of Childhood Cancer (ICCC). Results: According to sex-specific incidence, males accounted for slightly more cases than females. Children 0-3 years old accounted for 41.1% of patients. Leukemia accounted for 36.0% of cancers, followed by central nervous system tumors with 15.0%, according to the ICCC. The crude incidence rate did not change substantially, remaining at an average 8-11 per 100 000 population. In addition, the age-adjusted incidence rate remained constant with an average 2 per 100 000 population. Conclusions: Using population-based cancer registry data, age specific incidence and 12 diagnostic groups according to the ICCC showed characteristics of childhood cancers. The incidence rate of childhood cancers has been nearly stable in Japan over the past 15 years. PMID- 28334944 TI - Recent Trends in Body Mass Index and Waist Circumference among Children and Adolescents in Shandong China. AB - Background: The present study examined the recent trends in body mass index (BMI) and waist circumference (WC), and the prevalence of general and abdominal obesity among children and adolescents in Shandong, China. Methods: Data for this study were obtained from two cross-sectional surveys of schoolchildren carried out in 2010 and 2014 in Shandong Province, China. A total of 72 755 students aged 7-18 years were included in this study. The BMI cutoff points recommended by the International Obesity Task Force were used to define overweight and general obesity. Abdominal obesity was defined as waist-to-height ratio (WHtR) >= 0.5. Both BMI and WHtR were used to define three types of obesity as follows: general obesity only, abdominal obesity only and combined obesity. Results: For both boys and girls, an increasing trend in BMI and WC was observed between 2010 and 2014 ( p < 0.01), WC has increased faster than BMI. The sum of the prevalence of the three types of obesity increased from 16.63% (boys) and 8.13% (girls) in 2010 to 20.37% (boys) and 11.61% (girls) in 2014 ( p < 0.01). Conclusion: WC and abdominal obesity increased faster than BMI and general obesity among children and adolescents between 2010 and 2014. This study also suggested that distinguishing the types of obesity and examining the prevalence of various types of obesity are useful in practice. PMID- 28334943 TI - Effects of prefrontal cortex damage on emotion understanding: EEG and behavioural evidence. AB - Humans are highly social beings that interact with each other on a daily basis. In these complex interactions, we get along by being able to identify others' actions and infer their intentions, thoughts and feelings. One of the major theories accounting for this critical ability assumes that the understanding of social signals is based on a primordial tendency to simulate observed actions by activating a mirror neuron system. If mirror neuron regions are important for action and emotion recognition, damage to regions in this network should lead to deficits in these domains. In the current behavioural and EEG study, we focused on the lateral prefrontal cortex including dorsal and ventral prefrontal cortex and utilized a series of task paradigms, each measuring a different aspect of recognizing others' actions or emotions from body cues. We examined 17 patients with lesions including (n = 8) or not including (n = 9) the inferior frontal gyrus, a core mirror neuron system region, and compared their performance to matched healthy control subjects (n = 18), in behavioural tasks and in an EEG observation-execution task measuring mu suppression. Our results provide support for the role of the lateral prefrontal cortex in understanding others' emotions, by showing that even unilateral lesions result in deficits in both accuracy and reaction time in tasks involving the recognition of others' emotions. In tasks involving the recognition of actions, patients showed a general increase in reaction time, but not a reduction in accuracy. Deficits in emotion recognition can be seen by either direct damage to the inferior frontal gyrus, or via damage to dorsal lateral prefrontal cortex regions, resulting in deteriorated performance and less EEG mu suppression over sensorimotor cortex. PMID- 28334945 TI - Ubiquitin-related network underlain by (CAG)n loci modulate age at onset in Machado-Joseph disease. PMID- 28334946 TI - Mutations affecting the transmembrane domain of the LDL receptor: impact of charged residues on the membrane insertion. AB - Familial hypercholesterolemia (FH) is caused by mutations in the low density lipoprotein receptor (LDLR) gene. To study the impact of mutations affecting the hydrophobic transmembrane domain of the LDLR, each of the 22 amino acids of the transmembrane domain was individually mutated to arginine. The more centrally in the transmembrane domain an arginine was located, the lower amounts of the 120 kDa precursor LDLR in the endoplasmic reticulum were observed. This led to lower amounts of the 160 kDa mature LDLR on the cell surface. For the mutants V797R LDLR, L798R-LDLR and L799R-LDLR a proportion of full-length receptors including the transmembrane and cytoplasmic domains, was secreted into the endoplasmic reticulum lumen to appear in the culture medium. When the transmembrane domain of the epidermal growth factor receptor (EGFR) was replaced by that of the mutant L799R-LDLR, similar effects were observed for the EGFR as for L799R-LDLR. Introducing arginines in the transmembrane domain of the LDLR also affected metalloproteinase cleavage of the ectodomain and gamma-secretase cleavage within the transmembrane domain. The most likely explanation for the low amounts of the 120 kDa precursor is that a basic residue in the hydrophobic transmembrane domain prevents the mutant LDLR from being inserted in the endoplasmic reticulum membrane from the Sec61 translocon complex. As a consequence, quality control systems could be activated. However, our data indicate that proteasomal degradation, lysosomal degradation, autophagy or ectodomain cleavage were not the underlying mechanism for degradation of these mutant LDLRs. PMID- 28334949 TI - Mycoplasma hominis, Ureaplasma urealyticum and Chlamydia trachomatis Respiratory Colonization in Malaysian Preterm Infants. AB - This prospective observational study aims to determine the incidence, predictors and clinical features of Mycoplasma hominis (MH), Ureaplasma urealyticum (UU) and Chlamydia trachomatis (CT) respiratory colonization in infants <37 weeks of gestation. A total of 200 preterm newborns admitted to a tertiary center in Malaysia between 2013 and 2015 for increased breathing effort had their respiratory secretions tested for these bacteria by polymerase chain reaction. Fifteen of the 200 (7.5%) infants were detected to have these organisms in their respiratory tracts. Preterm prelabor rupture of membrane was associated with positive detection (odds ratio: 3.7; 95% confidence interval: 1.2-11.3). Seventy three of the 200 (36.5%) infants were given macrolide for presumed infection but only 4.1% (3 of 73) were positive for these organisms. The incidence of UU respiratory colonization among preterm infants in our center is lower than other published reports, while the frequency of MH and CT isolation is comparable with many studies. There should be judicious use of empirical antibiotics for presumed UU, MH and CT infection in preterm infants. PMID- 28334947 TI - Protocadherin 19 (PCDH19) interacts with paraspeckle protein NONO to co-regulate gene expression with estrogen receptor alpha (ERalpha). AB - De novo and inherited mutations of X-chromosome cell adhesion molecule protocadherin 19 (PCDH19) cause frequent, highly variable epilepsy, autism, cognitive decline and behavioural problems syndrome. Intriguingly, hemizygous null males are not affected while heterozygous females are, contradicting established X-chromosome inheritance. The disease mechanism is not known. Cellular mosaicism is the likely driver. We have identified p54nrb/NONO, a multifunctional nuclear paraspeckle protein with known roles in nuclear hormone receptor gene regulation, as a PCDH19 protein interacting partner. Using breast cancer cells we show that PCDH19-NONO complex is a positive co-regulator of ERalpha-mediated gene expression. Expression of mutant PCDH19 affects at least a subset of known ERalpha-regulated genes. These data are consistent with our findings that genes regulated by nuclear hormone receptors and those involved in the metabolism of neurosteroids in particular are dysregulated in PCDH19-epilepsy girls and affected mosaic males. Overall we define and characterize a novel mechanism of gene regulation driven by PCDH19, which is mediated by paraspeckle constituent NONO and is ERalpha-dependent. This PCDH19-NONO-ERalpha axis is of relevance not only to PCDH19-epilepsy and its comorbidities but likely also to ERalpha and generally nuclear hormone receptor-associated cancers. PMID- 28334948 TI - A Phase I/II trial of continuous hepatic intra-arterial infusion of 5 fluorouracil, mitoxantrone and cisplatin for advanced hepatocellular carcinoma. AB - Background: The aim of this study was to investigate the dose-limiting toxicities (DLTs) and determine the recommended doses in the Phase I part of the study, and to evaluate the efficacy and toxicity in the Phase II part, of continuous hepatic intra-arterial infusion therapy with 5-fluorouracil, mitoxantrone and cisplatin (FMP therapy) in patients with advanced hepatocellular carcinoma (HCC). Methods: Forty-five patients with advanced HCC were enrolled. The therapy consisted of continuous intra-arterial infusion of 5-fluorouracil from Day 1 through Day 5, and intra-arterial administration of mitoxantrone and cisplatin on Day 1 [5 fluorouracil/mitoxantrone/cisplatin (mg/m2): Level 1; 400/4/60, Level 2; 400/6/60, Level 3; 500/6/60]. Results: In the Phase I part of the study, one of the six patients at Level 1 developed DLTs, including Grade 3 pulmonary embolism, while none of the patients at either Level 2 or Level 3 exhibited any DLTs. In the Phase II part, at Level 3, 36 patients were enrolled. Nine patients (25%) showed partial response, representing a response rate of 25% (95% confidence interval: 12-42%). The overall median survival time, 1-year survival rate and median progression-free survival time were 11.3 months, 46.9% and 7.0 months, respectively. The main Grade 3 or 4 hematological and non-hematological toxicities were leukopenia (36%), neutropenia (39%), thrombocytopenia (19%), and elevated serum aspartate aminotransferase (22%), elevated serum alanine aminotransferase (14%) and occlusion of hepatic artery (22%), respectively. Conclusion: Hepatic intra-arterial infusion therapy of FMP could not demonstrate a favorable tumor response and overall survival in patients with advanced HCC. PMID- 28334950 TI - Downstream targets of GWAS-detected genes for breast, lung, and prostate and colon cancer converge to G1/S transition pathway. AB - Genome-wide association studies (GWASs) identified over 500 single nucleotide polymorphisms (SNPs) influencing cancer risk. It is logical to expect the cancer associated genes to cluster in pathways directly involved in carcinogenesis, e.g. cell cycle. Nevertheless, analyses of the GWAS-detected cancer risk genes usually show no or weak enrichment by known cancer genes.We hypothesized that GWAS detected cancer risk-associated genes function as upstream regulators of the genes directly involved in carcinogenesis. We have analyzed four common cancers: breast, colon, lung, and prostate. To identify downstream targets of GWAS detected cancer risk genes we used MedScan, which is a text mining tool offered by PathwayStudio. We also used data on protein/protein interactions reported by BioGRID database. Among all identified targets we have selected common downstream targets. A gene was considered a common downstream target if it was a downstream target for at least three GWAS-detected genes for a given cancer type. Common downstream targets were identified separately for each cancer type. We found that common downstream targets for all four cancer types were enriched by cell cycle genes, more specifically, the genes involved in G1/S transition. Common downstream targets for bipolar disorder, Crohn's disease, and type 2 diabetes did not show G1/S transition enrichment.The results of this analysis suggest that many cancer risk genes function as upstream regulators of the genes directly involved in G1/S transition and exert their risk effects by reducing threshold for G1/S transition, elevating the background level of cell proliferation and cancer risk. PMID- 28334951 TI - Community participation in research from resource-constrained countries: a scoping review. AB - Participatory health research (PHR) involves equitable community participation in all aspects of the research process. It is a potentially beneficial approach to research in resource-constrained countries. Measuring participation in specific activities and aspects is necessary for understanding the community and research related benefits of PHR. The aims of this scoping review were to: develop a measure of lay-community participation in aspects and activities of PHR in resource-constrained countries; and use the measure to assess the nature and extent of reported participation. Directed content analysis was used to identify aspects and activities reported in peer-reviewed articles identified through a systematic search, develop the Comprehensive Community Participation in Research Framework (CCPRF) and use it to measure participation. Total and aspect participation scores, which considered both the nature and extent of participation, were calculated for articles reporting extensive participation. Eighty-five articles detailing 66 studies were included. Nine aspects and 49 activities of research were included in the CCPRF. Community participation was reported in a median of 5/9 (range 1-9) aspects and 8/49 (range 1-35) activities. The review provided diverse examples, and enabled development of a more comprehensive measure, of participation. It highlighted limited lay-community participation is reported in research labelled participatory from resource constrained countries. As participation in all aspects of PHR is rarely achieved, strategic planning of more limited participation is imperative. More detailed and systematic planning, assessment and reporting of participation, guided by a comprehensive measure like the CCPRF, is required to develop evidence regarding the benefits of participation in various research activities. PMID- 28334952 TI - DNMT1 mutations found in HSANIE patients affect interaction with UHRF1 and neuronal differentiation. AB - DNMT1 is recruited to substrate sites by PCNA and UHRF1 to maintain DNA methylation after replication. The cell cycle dependent recruitment of DNMT1 is mediated by the PCNA-binding domain (PBD) and the targeting sequence (TS) within the N-terminal regulatory domain. The TS domain was found to be mutated in patients suffering from hereditary sensory and autonomic neuropathies with dementia and hearing loss (HSANIE) and autosomal dominant cerebellar ataxia deafness and narcolepsy (ADCA-DN) and is associated with global hypomethylation and site specific hypermethylation. With functional complementation assays in mouse embryonic stem cells, we showed that DNMT1 mutations P496Y and Y500C identified in HSANIE patients not only impair DNMT1 heterochromatin association, but also UHRF1 interaction resulting in hypomethylation. Similar DNA methylation defects were observed when DNMT1 interacting domains in UHRF1, the UBL and the SRA domain, were deleted. With cell-based assays, we could show that HSANIE associated mutations perturb DNMT1 heterochromatin association and catalytic complex formation at methylation sites and decrease protein stability in late S and G2 phase. To investigate the neuronal phenotype of HSANIE mutations, we performed DNMT1 rescue assays and could show that cells expressing mutated DNMT1 were prone to apoptosis and failed to differentiate into neuronal lineage. Our results provide insights into the molecular basis of DNMT1 dysfunction in HSANIE patients and emphasize the importance of the TS domain in the regulation of DNA methylation in pluripotent and differentiating cells. PMID- 28334954 TI - The Science and Politics of Naming: Reforming Anatomical Nomenclature, ca. 1886 1955. AB - Anatomical nomenclature is medicine's official language. Early in their medical studies, students are expected to memorize not only the bodily geography but also the names for all the structures that, by consensus, constitute the anatomical body. The making and uses of visual maps of the body have received considerable historiographical attention, yet the history of production, communication, and reception of anatomical names-a history as long as the history of anatomy itself has been studied far less. My essay examines the reforms of anatomical naming between the first modern nomenclature, the 1895 Basel Nomina Anatomica (BNA), and the 1955 Nomina Anatomica Parisiensia (NAP, also known as PNA), which is the basis for current anatomical terminology. I focus on the controversial and ultimately failed attempt to reform anatomical nomenclature, known as Jena Nomina Anatomica (INA), of 1935. Discussions around nomenclature reveal not only how anatomical names are made and communicated, but also the relationship of anatomy with the clinic; disciplinary controversies within anatomy; national traditions in science; and the interplay between international and scientific disciplinary politics. I show how the current anatomical nomenclature, a successor to the NAP, is an outcome of both political and disciplinary tensions that reached their peak before 1945. PMID- 28334953 TI - Early motor phenotype detection in a female mouse model of Rett syndrome is improved by cross-fostering. AB - Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the gene encoding methyl CpG binding protein 2 (MeCP2) that occur sporadically in 1:10,000 female births. RTT is characterized by a period of largely normal development followed by regression in language and motor skills at 6-18 months of age. Mecp2 mutant mice recapitulate many of the clinical features of RTT, but the majority of behavioral assessments have been conducted in male Mecp2 hemizygous null mice as offspring of heterozygous dams. Given that RTT patients are predominantly female, we conducted a systematic analysis of developmental milestones, sensory abilities, and motor deficits, following the longitudinal decline of function from early postnatal to adult ages in female Mecp2 heterozygotes of the conventional Bird line (Mecp2tm1.1bird-/+), as compared to their female wildtype littermate controls. Further, we assessed the impact of postnatal maternal environment on developmental milestones and behavioral phenotypes. Cross-fostering to CD1 dams accelerated several developmental milestones independent of genotype, and induced earlier onset of weight gain in adult female Mecp2tm1.1bird-/+ mice. Cross-fostering improved the sensitivity of a number of motor behaviors that resulted in observable deficits in Mecp2tm1.1bird-/+ mice at much earlier (6-7 weeks) ages than were previously reported (6-9 months). Our findings indicate that female Mecp2tm1.1bird-/+ mice recapitulate many of the motor aspects of RTT syndrome earlier than previously appreciated. In addition, rearing conditions may impact the phenotypic severity and improve the ability to detect genotype differences in female Mecp2 mutant mice. PMID- 28334957 TI - QuEChERS-Based Method for Pesticides Analysis in Adipose Tissue Associated with Rat Ovaries. AB - The concomitant exposure to low doses of various pesticides is one of the most relevant issues in human toxicology today. An experimental toxicology study was developed to evaluate the effects of this type of exposure on the reproductive capacity of females of three species of rats that were exposed to mixtures of dicofol, dieldrin, endosulfan and permethrin at low doses (LOAEL and NOAEL). In this context, we have developed a method for determining pesticides in adipose tissue (0.5 g, 49% lipid) associated with the ovaries, based on the QuEChERS (quick, easy, cheap, effective, rugged and safe) strategy. The method quantification limit (LOQ) was 0.5 mg/kg for dicofol and permethrin, 0.05 mg/kg for endosulfan and dieldrin and 0.2 mg/kg for diclorobenzophenone. Mean recoveries ranged from 75% to 93% with a relative standard deviation <13%. The unspecific selectivity (matrix effect) indicates the mandatory use of analytical curves constructed on the matrix extract. All the analyzed samples (53 adipose tissue associated to ovaries) showed residues of dichlorobenzophenone + dicofol, dieldrin and cis-permethrin while trans-permethrin were detected in 40% of the samples but were below the LOQ. The data indicated the bioaccumulation characteristics of these substances. PMID- 28334958 TI - Self-help materials for smoking relapse prevention: a process evaluation of the SHARPISH randomized controlled trial. AB - Background: UK Stop Smoking Services are effective at assisting smokers to quit. However, smoking relapse rates are high, representing a significant public health problem. No effective interventions are currently available. This embedded qualitative process evaluation, within a randomized controlled trial of a self help smoking relapse prevention intervention, aimed to understand patient perspectives in explaining the null trial finding, and to make recommendations for intervention development. Methods: The intervention was a British version of the 'Forever Free' self-help booklets (SHARPISH-ISRCTN 36980856). The qualitative evaluation purposefully sampled 43 interview participants, triangulated with the views of 10 participants and 12 health professionals in focus groups. Data were thematically analysed. Results: Analysis revealed important variation in individual engagement with the self-help booklets. Variation was interpreted by the meta-themes of 'motivation for cessation', and 'positioning on information provision', interacting with the theme of 'mechanisms for information provision'. Conclusions: Targeting self-help information towards those most motivated to engage may be beneficial, considering the social and cultural realities of individual's lives. Individual preferences for the mechanisms of information delivery should be appraised when designing future interventions. Long-term personalized follow-up may be a simple step in improving smoking relapse rates. PMID- 28334959 TI - Clinical utility of a self-administered questionnaire for assessment of hereditary gynecologic cancer. PMID- 28334956 TI - PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment. AB - PRUNE is a member of the DHH (Asp-His-His) phosphoesterase protein superfamily of molecules important for cell motility, and implicated in cancer progression. Here we investigated multiple families from Oman, India, Iran and Italy with individuals affected by a new autosomal recessive neurodevelopmental and degenerative disorder in which the cardinal features include primary microcephaly and profound global developmental delay. Our genetic studies identified biallelic mutations of PRUNE1 as responsible. Our functional assays of disease-associated variant alleles revealed impaired microtubule polymerization, as well as cell migration and proliferation properties, of mutant PRUNE. Additionally, our studies also highlight a potential new role for PRUNE during microtubule polymerization, which is essential for the cytoskeletal rearrangements that occur during cellular division and proliferation. Together these studies define PRUNE as a molecule fundamental for normal human cortical development and define cellular and clinical consequences associated with PRUNE mutation. PMID- 28334960 TI - Neural mechanisms of reinforcement learning in unmedicated patients with major depressive disorder. AB - According to current concepts, major depressive disorder is strongly related to dysfunctional neural processing of motivational information, entailing impairments in reinforcement learning. While computational modelling can reveal the precise nature of neural learning signals, it has not been used to study learning-related neural dysfunctions in unmedicated patients with major depressive disorder so far. We thus aimed at comparing the neural coding of reward and punishment prediction errors, representing indicators of neural learning-related processes, between unmedicated patients with major depressive disorder and healthy participants. To this end, a group of unmedicated patients with major depressive disorder (n = 28) and a group of age- and sex-matched healthy control participants (n = 30) completed an instrumental learning task involving monetary gains and losses during functional magnetic resonance imaging. The two groups did not differ in their learning performance. Patients and control participants showed the same level of prediction error-related activity in the ventral striatum and the anterior insula. In contrast, neural coding of reward prediction errors in the medial orbitofrontal cortex was reduced in patients. Moreover, neural reward prediction error signals in the medial orbitofrontal cortex and ventral striatum showed negative correlations with anhedonia severity. Using a standard instrumental learning paradigm we found no evidence for an overall impairment of reinforcement learning in medication-free patients with major depressive disorder. Importantly, however, the attenuated neural coding of reward in the medial orbitofrontal cortex and the relation between anhedonia and reduced reward prediction error-signalling in the medial orbitofrontal cortex and ventral striatum likely reflect an impairment in experiencing pleasure from rewarding events as a key mechanism of anhedonia in major depressive disorder. PMID- 28334955 TI - The Schizosaccharomyces pombe PPR protein Ppr10 associates with a novel protein Mpa1 and acts as a mitochondrial translational activator. AB - The pentatricopeptide repeat (PPR) proteins characterized by tandem repeats of a degenerate 35-amino-acid motif function in all aspects of organellar RNA metabolism, many of which are essential for organellar gene expression. In this study, we report the characterization of a fission yeast Schizosaccharomyces pombe PPR protein, Ppr10 and a novel Ppr10-associated protein, designated Mpa1. The ppr10 deletion mutant exhibits growth defects in respiratory media, and is dramatically impaired for viability during the late-stationary phase. Deletion of ppr10 affects the accumulation of specific mitochondrial mRNAs. Furthermore, deletion of ppr10 severely impairs mitochondrial protein synthesis, suggesting that Ppr10 plays a general role in mitochondrial protein synthesis. Ppr10 interacts with Mpa1 in vivo and in vitro and the two proteins colocalize in the mitochondrial matrix. The ppr10 and mpa1 deletion mutants exhibit very similar phenotypes. One of Mpa1's functions is to maintain the normal protein level of Ppr10 protein by protecting it from degradation by the mitochondrial matrix protease Lon1. Our findings suggest that Ppr10 functions as a general mitochondrial translational activator, likely through interaction with mitochondrial mRNAs and mitochondrial translation initiation factor Mti2, and that Ppr10 requires Mpa1 association for stability and function. PMID- 28334961 TI - High intra-familiar clinical variability in MORC2 mutated CMT2 patients. PMID- 28334962 TI - Exposure to fictional medical television and health: a systematic review. AB - Fictional medical television programs have long been a staple of television programming, and they remain popular today. We aimed to examine published literature assessing the influence of medical television programs on health outcomes. We conducted systematic literature searches in PubMed, PsychINFO and CINAHL. Selected studies had to be scholarly research, to involve exposure to fictionalized medical television programming, and to assess associations between exposures and outcomes. Of 3541 unique studies identified, nineteen met selection criteria. The most commonly studied programs were ER (73%), Grey's Anatomy (58%) and House M.D. (37%). Outcomes included knowledge, perceptions and behaviors related to topics as diverse as organ donation, cancer screening, sexually transmitted infections, and heart disease. Viewing fictional medical television programs had a negative influence on viewers' health-related knowledge, perceptions and/or behavior in 11% of studies, a positive influence in 32% of studies, and mixed influence in 58%. While most studies (58%) were characterized as having fair quality in terms of rigor of study design, 21% were classified as good and 21% were classified as poor. As such, medical television can affect health education and outcomes. Future work should utilize randomization, more longitudinal assessments, and more direct assessments of health education and behavioral outcomes. PMID- 28334964 TI - Mutations in the leukemia inhibitory factor receptor (LIFR) gene and Lifr deficiency cause urinary tract malformations. AB - Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. As CAKUT is a genetically heterogeneous disorder and most cases are genetically unexplained, we aimed to identify new CAKUT causing genes. Using whole-exome sequencing and trio-based de novo analysis, we identified a novel heterozygous de novo frameshift variant in the leukemia inhibitory factor receptor (LIFR) gene causing instability of the mRNA in a patient presenting with bilateral CAKUT and requiring kidney transplantation at one year of age. LIFR encodes a transmembrane receptor utilized by IL-6 family cytokines, mainly by the leukemia inhibitory factor (LIF). Mutational analysis of 121 further patients with severe CAKUT yielded two rare heterozygous LIFR missense variants predicted to be pathogenic in three unrelated patients. LIFR mutants showed decreased half-life and cell membrane localization resulting in reduced LIF-stimulated STAT3 phosphorylation. LIFR showed high expression in human fetal kidney and the human ureter, and was also expressed in the developing murine urogenital system. Lifr knockout mice displayed urinary tract malformations including hydronephrosis, hydroureter, ureter ectopia, and, consistently, reduced ureteral lumen and muscular hypertrophy, similar to the phenotypes observed in patients carrying LIFR variants. Additionally, a form of cryptorchidism was detected in all Lifr-/- mice and the patient carrying the LIFR frameshift mutation. Altogether, we demonstrate heterozygous novel or rare LIFR mutations in 3.3% of CAKUT patients, and provide evidence that Lifr deficiency and deactivating LIFR mutations cause highly similar anomalies of the urogenital tract in mice and humans. PMID- 28334963 TI - Three- and four-dimensional mapping of speech and language in patients with epilepsy. AB - We have provided 3-D and 4D mapping of speech and language function based upon the results of direct cortical stimulation and event-related modulation of electrocorticography signals. Patients estimated to have right-hemispheric language dominance were excluded. Thus, 100 patients who underwent two-stage epilepsy surgery with chronic electrocorticography recording were studied. An older group consisted of 84 patients at least 10 years of age (7367 artefact-free non-epileptic electrodes), whereas a younger group included 16 children younger than age 10 (1438 electrodes). The probability of symptoms transiently induced by electrical stimulation was delineated on a 3D average surface image. The electrocorticography amplitude changes of high-gamma (70-110 Hz) and beta (15-30 Hz) activities during an auditory-naming task were animated on the average surface image in a 4D manner. Thereby, high-gamma augmentation and beta attenuation were treated as summary measures of cortical activation. Stimulation data indicated the causal relationship between (i) superior-temporal gyrus of either hemisphere and auditory hallucination; (ii) left superior-/middle-temporal gyri and receptive aphasia; (iii) widespread temporal/frontal lobe regions of the left hemisphere and expressive aphasia; and (iv) bilateral precentral/left posterior superior-frontal regions and speech arrest. On electrocorticography analysis, high-gamma augmentation involved the bilateral superior-temporal and precentral gyri immediately following question onset; at the same time, high gamma activity was attenuated in the left orbitofrontal gyrus. High-gamma activity was augmented in the left temporal/frontal lobe regions, as well as left inferior-parietal and cingulate regions, maximally around question offset, with high-gamma augmentation in the left pars orbitalis inferior-frontal, middle frontal, and inferior-parietal regions preceded by high-gamma attenuation in the contralateral homotopic regions. Immediately before verbal response, high-gamma augmentation involved the posterior superior-frontal and pre/postcentral regions, bilaterally. Beta-attenuation was spatially and temporally correlated with high gamma augmentation in general but with exceptions. The younger and older groups shared similar spatial-temporal profiles of high-gamma and beta modulation; except, the younger group failed to show left-dominant activation in the rostral middle-frontal and pars orbitalis inferior-frontal regions around stimulus offset. The human brain may rapidly and alternately activate and deactivate cortical areas advantageous or obtrusive to function directed toward speech and language at a given moment. Increased left-dominant activation in the anterior frontal structures in the older age group may reflect developmental consolidation of the language system. The results of our functional mapping may be useful in predicting, across not only space but also time and patient age, sites specific to language function for presurgical evaluation of focal epilepsy. PMID- 28334967 TI - The difference between compensation, and mechanism-specific spatial recovery. PMID- 28334968 TI - Postoperative Stridor following Repair of Tracheoesophageal Fistula: A Case Report. AB - We report a case of prolonged post-operative stridor in a full-term neonate who was operated for tracheoesophageal fistula. Initial evaluation including an endoscopy and contrast-enhanced computed tomography scan was normal. Repeat endoscopic evaluation under anesthesia revealed tight aryepiglottic folds. Aryepiglottic split was performed and stridor improved dramatically. Tight aryepiglottic folds should be kept in differential diagnosis in a case of postoperative stridor in an infant. PMID- 28334965 TI - Photosensitive epilepsy is associated with reduced inhibition of alpha rhythm generating networks. AB - See Hamandi (doi:10.1093/awx049) for a scientific commentary on this article.Photosensitivity is a condition in which lights induce epileptiform activities. This abnormal electroencephalographic response has been associated with hyperexcitability of the visuo-motor system. Here, we evaluate if intrinsic dysfunction of this network is present in brain activity at rest, independently of any stimulus and of any paroxysmal electroencephalographic activity. To address this issue, we investigated the haemodynamic correlates of the spontaneous alpha rhythm, which is considered the hallmark of the brain resting state, in photosensitive patients and in people without photosensitivity. Second, we evaluated the whole-brain functional connectivity of the visual thalamic nuclei in the various populations of subjects under investigation. Forty-four patients with epilepsy and 16 healthy control subjects underwent an electroencephalography-correlated functional magnetic resonance imaging study, during an eyes-closed condition. The following patient groups were included: (i) genetic generalized epilepsy with photosensitivity, 16 subjects (mean age 25 +/- 10 years); (ii) genetic generalized epilepsy without photosensitivity, 13 patients (mean age 25 +/- 11 years); (iii) focal epilepsy, 15 patients (mean age 25 +/- 9 years). For each subject, the posterior alpha power variations were convolved with the standard haemodynamic response function and used as a regressor. Within- and between-groups second level analyses were performed. Whole brain functional connectivity was evaluated for two thalamic regions of interest, based on the haemodynamic findings, which included the posterior thalamus (pulvinar) and the medio-dorsal thalamic nuclei. Genetic generalized epilepsy with photosensitivity demonstrated significantly greater mean alpha-power with respect to controls and other epilepsy groups. In photosensitive epilepsy, alpha related blood oxygen level-dependent signal changes demonstrated lower decreases relative to all other groups in the occipital, sensory-motor, anterior cingulate and supplementary motor cortices. Coherently, the same brain regions demonstrated abnormal connectivity with the visual thalamus only in epilepsy patients with photosensitivity. As predicted, our findings indicate that the cortical subcortical network generating the alpha oscillation at rest is different in people with epilepsy and visual sensitivity. This difference consists of a decreased alpha-related inhibition of the visual cortex and sensory-motor networks at rest. These findings represent the substrate of the clinical manifestations (i.e. myoclonus) of the photoparoxysmal response. Moreover, our results provide the first evidence of the existence of a functional link between the circuits that trigger the visual sensitivity phenomenon and those that generate the posterior alpha rhythm. PMID- 28334966 TI - Structural and mechanistic insights into regulation of HBO1 histone acetyltransferase activity by BRPF2. AB - HBO1, a member of the MYST family of histone acetyltransferases (HATs), is required for global acetylation of histone H3K14 and embryonic development. It functions as a catalytic subunit in multisubunit complexes comprising a BRPF1/2/3 or JADE1/2/3 scaffold protein, and two accessory proteins. BRPF2 has been shown to be important for the HAT activity of HBO1 toward H3K14. Here we demonstrated that BRPF2 can regulate the HAT activity of HBO1 toward free H3 and H4, and nucleosomal H3. Particularly, a short N-terminal region of BRPF2 is sufficient for binding to HBO1 and can potentiate its activity toward H3K14. The crystal structure of the HBO1 MYST domain in complex with this segment of BRPF2 together with the biochemical and cell biological data revealed the key residues responsible for the HBO1-BRPF2 interaction. Our structural and functional data together indicate that the N-terminal region of BRPF2 plays an important role in the binding of HBO1 and a minor role in the binding of nucleosomes, which provide new mechanistic insights into the regulation of the HAT activity of HBO1 by BRPF2. PMID- 28334969 TI - A single miR390 targeting event is sufficient for triggering TAS3-tasiRNA biogenesis in Arabidopsis. AB - In plants, tasiRNAs form a class of endogenous secondary siRNAs produced through the action of RNA-DEPENDENT-RNA-POLYMERASE-6 (RDR6) upon microRNA-mediated cleavage of non-coding TAS RNAs. In Arabidopsis thaliana, TAS1, TAS2 and TAS4 tasiRNA production proceeds via a single cleavage event mediated by 22nt-long or/and asymmetric miRNAs in an ARGONAUTE-1 (AGO1)-dependent manner. By contrast, tasiRNA production from TAS3 seems to follow the so-called 'two-hit' process, where dual targeting of TAS3, specifically mediated by the 21nt-long, symmetric miR390, initiates AGO7-dependent tasiRNA production. Interestingly, features for TAS3 tasiRNA production differ in other plant species and we show here that such features also enable TAS3 tasiRNA biogenesis in Arabidopsis, and that a single miR390 targeting event is, in fact, sufficient for this process, suggesting that the 'one-hit' model underpins all the necessary rudiments of secondary siRNA biogenesis from plant TAS transcripts. Further results suggest that the two-hit configuration likely enhances the fidelity of tasiRNA production and, hence, the accuracy of downstream gene regulation. Finally, we show that a 'non-cleavable one-hit' process allows tasiRNA production from both TAS1 and TAS3 transcripts, indicating that RDR6 recruitment does not require miRNA cleavage, nor does the recruitment, as we further show, of SUPRRESSOR-OF-GENE-SILENCING-3, indispensable for tasiRNA generation. PMID- 28334970 TI - Expenditure tracking and review of reproductive maternal, newborn and child health policy in Pakistan. AB - Since 2001 substantial resources have been allocated to the reproductive, maternal, newborn and child health sector (RMNCH) in Pakistan. Many new programmes have been started and coverage of some existing programmes has been extended to un-served and rural areas. Despite these efforts the Millennium Development Goals (MDGs) 4 and 5 were not achieved (2000-15). Maternal Mortality Ratio was reduced to 170 per 100 000 live births (target 100) by 2013 at an annual reduction rate of 3.6% (1990-2013). Against the target of 46 per 1000 live births, the Under Five Mortality Rate was reduced to 81 per 1000 live births by 2015 at an annual reduction rate of 2.1% (1990-2015). We evaluated the comparative expenditures for the RMNCH sector and analysed impact of public expenditures on the use of the public facilities for the RMNCH services. Expenditure on RMNCH increased by 181% (2000-10), reaching PKR 628.79 billion (US$9.67 billion). The Share of the RMNCH expenditure in the total health expenditure increased from 16 to 21% (2005-10). The share of official development assistance for the RMNCH increased from 36 to 51% (2003-10). Equity was modestly achieved with a greater proportion of the poor using public facilities for the childhood diarrhoea (Concentration Index -0.06 in 2001-02 to - 0.11 in 2010-11) and reduction in the proportion of the rich using the public health facilities for institutional births (Concentration Index 0.30 in 2001-02 to 0.25 in 2010 11). Overall the RMNCH disease control programmes focused on vertical primary health approach and targeted the district health system in the un-served areas. Our findings confirm that diseconomies of scale, donor dependence and supply side perspective could only result in a modest progress towards achieving the MDGs. We call for urgent attention of the policy makers for the integration of the vertical and the routine primary health care and reliance on indigenous sustainable healthcare financing. We also recommend acknowledging economic perspective on health policy and health programmes. PMID- 28334971 TI - Expanding glycosaminoglycan chemical space: towards the creation of sulfated analogs, novel polymers and chimeric constructs. AB - Glycosaminoglycans (GAGs) have therapeutic potential in areas ranging from angiogenesis, inflammation, hemostasis and cancer. GAG bioactivity is conferred by intrinsic structural features, such as disaccharide composition, glycosidic linkages and sulfation pattern. Unfortunately, the in vitro enzymatic synthesis of defined GAGs is quite restricted by a limited understanding of current GAG synthases and modifying enzymes. Our work provides insights into GAG-active enzymes through the creation of sulfated oligosaccharides, a new polysaccharide and chimeric polymers. We show that a C6-sulfonated uridine diphospho (UDP) glucose (Glc) derivative, sulfoquinovose, can be used as an uronic acid donor, but not as a hexosamine donor, to cap hyaluronan (HA) chains by the HA synthase from the microbe Pasteurella multocida. However, the two heparosan (HEP) synthases from the same species, PmHS1 and PmHS2, could not employ the UDP sulfoquinovose under similar conditions. Serendipitously, we found that PmHS2 co polymerized Glc with glucuronic acid (GlcA), creating a novel HEP-like polymer we named hepbiuronic acid [-4-GlcAbeta1-4-Glcalpha1-]n. In addition, we created chimeric block polymers composed of both HA and HEP segments; in these reactions GlcA-, but not N-acetylglucosamine-(GlcNAc), terminated GAG acceptors were recognized by their noncognate synthase for further extension, likely due to the common beta-linkage connecting GlcA to GlcNAc in both of these GAGs. Overall, these GAG constructs provide new tools for studying biology and offer potential for future sugar-based therapeutics. PMID- 28334972 TI - Enrichment methods provide a feasible approach to comprehensive and adequately powered investigations of the brain methylome. AB - Methylome-wide association studies are typically performed using microarray technologies that only assay a very small fraction of the CG methylome and entirely miss two forms of methylation that are common in brain and likely of particular relevance for neuroscience and psychiatric disorders. The alternative is to use whole genome bisulfite (WGB) sequencing but this approach is not yet practically feasible with sample sizes required for adequate statistical power. We argue for revisiting methylation enrichment methods that, provided optimal protocols are used, enable comprehensive, adequately powered and cost-effective genome-wide investigations of the brain methylome. To support our claim we use data showing that enrichment methods approximate the sensitivity obtained with WGB methods and with slightly better specificity. However, this performance is achieved at <5% of the reagent costs. Furthermore, because many more samples can be sequenced simultaneously, projects can be completed about 15 times faster. Currently the only viable option available for comprehensive brain methylome studies, enrichment methods may be critical for moving the field forward. PMID- 28334973 TI - Analysis of dropout across the continuum of maternal health care in Tanzania: findings from a cross-sectional household survey. AB - The 'continuum of care' is proposed as a key framework for the delivery of maternal, neonatal and child health services. This study examined the extent of dropout as well as factors associated with retention across the MNCH continuum from antenatal care (ANC), through skilled birth attendance (SBA), to postnatal care (PNC).We analyzed data from 1931 women who delivered in the preceding 2-14 months, from a two-stage cluster sampling household survey in four districts of Tanzania's Morogoro region. The survey was conducted in 2011 as a part of a baseline for an independent evaluation of a maternal health program. Using the Anderson model of health care seeking, we fitted logistic models for three transition stages in the continuum.Only 10% of women received the 'recommended' care package (4+ ANC visits, SBA, and 1+ PNC visit), while 1% reported not having care at any stage. Receipt of four ANC visits was positively associated with women being older in age (age 20-34 years-OR: 1.77, 95%CI: 1.22-2.56; age 35-49 years-2.03, 1.29-3.2), and knowledge of danger signs (1.75, 1.39 -2.1). A pro rich bias was observed in facility-based deliveries (proxy for SBA), with women from the fourth (1.66, 1.12-2.47) and highest quintiles of household wealth (3.4, 2.04-5.66) and the top tertile of communities by wealth (2.9, 1.14-7.4). Higher rates of facility deliveries were also reported with antenatal complications (1.37, 1.05-1.79), and 4+ ANC visits (1.55, 1.14-2.09). Returning for PNC was highest among the wealthiest communities (2.25, 1.21-4.44); catchment areas of a new PNC program (1.89, 1.03-3.45); knowledge of danger signs (1.78, 1.13-2.83); community health worker counselling (4.22, 1.97-9.05); complicated delivery (3.25, 1.84-5.73); and previous health provider counselling on family planning (2.39, 1.71-3.35).Dropout from maternal care continuum is high, especially for the poorest, in rural Tanzania. Interactions with formal health system and perceived need for future services appear to be important factors for retention. PMID- 28334974 TI - Efficacy and safety of sequential use of everolimus in Japanese patients with advanced renal cell carcinoma after failure of first-line treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitor: a multicenter phase II clinical trial. AB - Objective: Many studies have shown the efficacy of everolimus after pretreatment with vascular endothelial growth factor receptor-tyrosine kinase inhibitors. We investigated the efficacy and safety of everolimus as a second-line treatment after the failure of vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy in Japanese patients with advanced renal cell carcinoma. Methods: This was an open-label, multicenter, phase II trial conducted in Japan through the central registration system. A total of 57 patients were enrolled. Patients were administered 10 mg of everolimus q.d. orally. The primary efficacy endpoint was progression-free survival achieved by administration of everolimus. Results: The median progression-free survival of patients administered everolimus was 5.03 months (95% confidence interval: 3.70-6.20). The median overall survival was not reached. The objective response rate was 9.4% (95% confidence interval: 3.1-20.7). The progression-free survival in the group of <100% relative dose intensity was 6.70 months (95% confidence interval: 4.13-11.60), and that in the group of 100% relative dose intensity was 3.77 months (hazard ratio: 2.79, 95% confidence interval: 2.77-5.63). The commonly observed adverse events and laboratory abnormalities were stomatitis (49.1%), hypertriglyceridemia (26.4%), interstitial lung disease (26.4%), anemia (22.6%) and hypercholesterolemia (22.6%). Conclusion: The median progression-free survival was almost similar to that recorded in the RECORD-1 study, whereas prolongation of overall survival was observed in the present study compared with the RECORD-1 study. The treatment outcomes of first-line vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy and second-line everolimus treatment in Japanese patients were successfully established in the present study. PMID- 28334975 TI - APRICOT: an integrated computational pipeline for the sequence-based identification and characterization of RNA-binding proteins. AB - RNA-binding proteins (RBPs) have been established as core components of several post-transcriptional gene regulation mechanisms. Experimental techniques such as cross-linking and co-immunoprecipitation have enabled the identification of RBPs, RNA-binding domains (RBDs) and their regulatory roles in the eukaryotic species such as human and yeast in large-scale. In contrast, our knowledge of the number and potential diversity of RBPs in bacteria is poorer due to the technical challenges associated with the existing global screening approaches. We introduce APRICOT, a computational pipeline for the sequence-based identification and characterization of proteins using RBDs known from experimental studies. The pipeline identifies functional motifs in protein sequences using position specific scoring matrices and Hidden Markov Models of the functional domains and statistically scores them based on a series of sequence-based features. Subsequently, APRICOT identifies putative RBPs and characterizes them by several biological properties. Here we demonstrate the application and adaptability of the pipeline on large-scale protein sets, including the bacterial proteome of Escherichia coli. APRICOT showed better performance on various datasets compared to other existing tools for the sequence-based prediction of RBPs by achieving an average sensitivity and specificity of 0.90 and 0.91 respectively. The command line tool and its documentation are available at https://pypi.python.org/pypi/bio apricot. PMID- 28334976 TI - A sensitivity analysis of RNA folding nearest neighbor parameters identifies a subset of free energy parameters with the greatest impact on RNA secondary structure prediction. AB - Nearest neighbor parameters for estimating the folding energy changes of RNA secondary structures are used in structure prediction and analysis. Despite their widespread application, a comprehensive analysis of the impact of each parameter on the precision of calculations had not been conducted. To identify the parameters with greatest impact, a sensitivity analysis was performed on the 291 parameters that compose the 2004 version of the free energy nearest neighbor rules. Perturbed parameter sets were generated by perturbing each parameter independently. Then the effect of each individual parameter change on predicted base-pair probabilities and secondary structures as compared to the standard parameter set was observed for a set of sequences including structured ncRNA, mRNA and randomized sequences. The results identify for the first time the parameters with the greatest impact on secondary structure prediction, and the subset which should be prioritized for further study in order to improve the precision of structure prediction. In particular, bulge loop initiation, multibranch loop initiation, AU/GU internal loop closure and AU/GU helix end parameters were particularly important. An analysis of parameter usage during folding free energy calculations of stochastic samples of secondary structures revealed a correlation between parameter usage and impact on structure prediction precision. PMID- 28334977 TI - sCLIP-an integrated platform to study RNA-protein interactomes in biomedical research: identification of CSTF2tau in alternative processing of small nuclear RNAs. AB - RNA-binding proteins (RBPs) are central for gene expression by controlling the RNA fate from birth to decay. Various disorders arising from perturbations of RNA protein interactions document their critical function. However, deciphering their function is complex, limiting the general functional elucidation of this growing class of proteins and their contribution to (patho)physiology. Here, we present sCLIP, a simplified and robust platform for genome-wide interrogation of RNA protein interactomes based on crosslinking-immunoprecipitation and high throughput sequencing. sCLIP exploits linear amplification of the immunoprecipitated RNA improving the complexity of the sequencing-library despite significantly reducing the amount of input material and omitting several purification steps. Additionally, it permits a radiolabel-free visualization of immunoprecipitated RNA. In a proof of concept, we identify that CSTF2tau binds many previously not recognized RNAs including histone, snoRNA and snRNAs. CSTF2tau-binding is associated with internal oligoadenylation resulting in shortened snRNA isoforms subjected to rapid degradation. We provide evidence for a new mechanism whereby CSTF2tau controls the abundance of snRNAs resulting in alternative splicing of several RNAs including ANK2 with critical roles in tumorigenesis and cardiac function. Combined with a bioinformatic pipeline sCLIP thus uncovers new functions for established RBPs and fosters the illumination of RBP-protein interaction landscapes in health and disease. PMID- 28334978 TI - Therapeutic window of dopamine D2/3 receptor occupancy to treat psychosis in Alzheimer's disease. AB - See Caravaggio and Graff-Guerrero (doi:10.1093/awx023) for a scientific commentary on this article.Antipsychotic drugs, originally developed to treat schizophrenia, are used to treat psychosis, agitation and aggression in Alzheimer's disease. In the absence of dopamine D2/3 receptor occupancy data to inform antipsychotic prescribing for psychosis in Alzheimer's disease, the mechanisms underpinning antipsychotic efficacy and side effects are poorly understood. This study used a population approach to investigate the relationship between amisulpride blood concentration and central D2/3 occupancy in older people with Alzheimer's disease by combining: (i) pharmacokinetic data (280 venous samples) from a phase I single (50 mg) dose study in healthy older people (n = 20, 65-79 years); (ii) pharmacokinetic, 18F-fallypride D2/3 receptor imaging and clinical outcome data on patients with Alzheimer's disease who were prescribed amisulpride (25-75 mg daily) to treat psychosis as part of an open study (n = 28; 69-92 years; 41 blood samples, five pretreatment scans, 19 post treatment scans); and (iii) 18F-fallypride imaging of an antipsychotic free Alzheimer's disease control group (n = 10, 78-92 years), to provide additional pretreatment data. Non-linear mixed effects modelling was used to describe pharmacokinetic-occupancy curves in caudate, putamen and thalamus. Model outputs were used to estimate threshold steady state blood concentration and occupancy required to elicit a clinically relevant response (>25% reduction in scores on delusions, hallucinations and agitation domains of the Neuropsychiatric Inventory) and extrapyramidal side effects (Simpson Angus Scale scores > 3). Average steady state blood levels were low (71 +/- 30 ng/ml), and associated with high D2/3 occupancies (65 +/- 8%, caudate; 67 +/- 11%, thalamus; 52 +/- 11%, putamen). Antipsychotic clinical response occurred at a threshold concentration of 20 ng/ml and D2/3 occupancies of 43% (caudate), 25% (putamen), 43% (thalamus). Extrapyramidal side effects (n = 7) emerged at a threshold concentration of 60 ng/ml, and D2/3 occupancies of 61% (caudate), 49% (putamen) and 69% (thalamus). This study has established that, as in schizophrenia, there is a therapeutic window of D2/3 receptor occupancy for optimal treatment of psychosis in Alzheimer's disease. We have also shown that occupancies within and beyond this window are achieved at very low amisulpride doses in Alzheimer's disease due to higher than anticipated occupancies for a given blood drug concentration. Our findings support a central pharmacokinetic contribution to antipsychotic sensitivity in Alzheimer's disease and implicate the blood-brain barrier, which controls central drug access. Whether high D2/3 receptor occupancies are primarily accounted for by age- or disease-specific blood-brain barrier disruption is unclear, and this is an important future area of future investigation, as it has implications beyond antipsychotic prescribing. PMID- 28334979 TI - The effectiveness of optimised clinical medication reviews for geriatric patients: Opti-Med a cluster randomised controlled trial. AB - Background: Inappropriate drug use is a frequent problem in older patients and associated with adverse clinical outcomes and an important determinant of geriatric problems. Clinical medication reviews (CMR) may reduce inappropriate drug use. Objective: The aim of this study is to investigate the effectiveness of CMR on quality of life (QoL) and geriatric problems in comparison with usual care in older patients with geriatric problems in the general practice. Methods: We performed a cluster randomised controlled trial in 22 Dutch general practices. Patients of >=65 years were eligible if they newly presented with pre-specified geriatric symptoms in general practice and the chronic use of >=1 prescribed drug. The intervention consisted of CMRs which were prepared by an independent expert team and discussed with the patient by the general practitioner. Primary outcomes: QoL and the presence of self-reported geriatric problems after a follow up period of 6 months. Results: 518 patients were included. No significant differences between the intervention and control group and over time were found for QoL, geriatric problems, satisfaction with medication and self-reported medication adherence. After 6 months the percentage of solved Drug Related Problems (DRPs) was significantly higher in the intervention group compared to the control group [B 22.6 (95%CI 14.1-31.1), P < 0.001]. Conclusion: The study intervention did not influence QoL and geriatric problems. The higher percentage of solved DRPs in the intervention group did not result in effects on the patient's health. CMRs on a large scale seem not meaningful and should be reconsidered. PMID- 28334980 TI - Public health implications of 4 decades of neoliberal policy: a qualitative case study from post-industrial west central Scotland. AB - Background: The UK has long had a strong commitment to neoliberal policy, the risks of which for population health are well researched. Within Europe, Scotland demonstrates especially poor health outcomes, much of which is driven by high levels of deprivation, wide inequalities and the persistent impacts of deindustrialisation. The processes through which neoliberalism has contributed to this poor health record are the subject of significant research interest. Methods: Qualitative case study of a post-industrial town in west central Scotland. Primary data were collected using photovoice (11) and oral history (9) interviews, supplemented by qualitative and quantitative secondary source data. Results: For those who fared poorly after the initial introduction of neoliberal policy in the 1970s, subsequent policy decisions have served to deepen and entrench negative impacts on the determinants of health. Neoliberalism has constituted a suite of rapidly and concurrently implemented policies, cross cutting a variety of domains, which have reached into every part of people's lives. Conclusions: In formerly industrial parts of west central Scotland, policy developments since the 1970s have generated multiple and sustained forms of deprivation. This case study suggests that a turn away from neoliberal policy is required to improve quality of life and health. PMID- 28334981 TI - Computer models to inform epilepsy surgery strategies: prediction of postoperative outcome. PMID- 28334982 TI - Use it or lose it: citations predict the continued online availability of published bioinformatics resources. AB - Scientific Data Analysis Resources (SDARs) such as bioinformatics programs, web servers and databases are integral to modern science, but previous studies have shown that the Uniform Resource Locators (URLs) linking to them decay in a time dependent manner, with ~27% decayed to date. Because SDARs are overrepresented among science's most cited papers over the past 20 years, loss of widely used SDARs could be particularly disruptive to scientific research. We identified URLs in MEDLINE abstracts and used crowdsourcing to identify which reported the creation of SDARs. We used the Internet Archive's Wayback Machine to approximate 'death dates' and calculate citations/year over each SDAR's lifespan. At first glance, decayed SDARs did not significantly differ from available SDARs in their average citations per year over their lifespan or journal impact factor (JIF). But the most cited SDARs were 94% likely to be relocated to another URL versus only 34% of uncited ones. Taking relocation into account, we find that citations are the strongest predictors of current online availability after time since publication, and JIF modestly predictive. This suggests that URL decay is a general, persistent phenomenon affecting all URLs, but the most useful/recognized SDARs are more likely to persist. PMID- 28334983 TI - GWAS-linked PPARGC1A variant in Asian patients with essential tremor. PMID- 28334984 TI - Interdisciplinary working in public health research: a proposed good practice checklist. AB - Background: Guidance on how different disciplines from the natural, behavioural and social sciences can collaborate to resolve complex public health problems is lacking. This article presents a checklist to support researchers and principle investigators to develop and implement interdisciplinary collaborations. Methods: Fourteen individuals, representing 10 disciplines, participated in in-depth interviews to explore the strengths and challenges of working together on an interdisciplinary project to identify the determinants of substance use and gambling disorders, and to make recommendations for future interdisciplinary teams. Data were analysed thematically and a checklist was derived from insights offered by participants during interview and discussion among the authors on the implications of findings. Results: Participants identified 18 scientific, interactional and structural strengths and challenges of interdisciplinary research. These findings were used to develop an 18-item BASICS checklist to support future interdisciplinary collaborations. The five domains of the checklist are: (i) Blueprint, (ii) Attitudes, (iii) Staffing, (iv) Interactions and (v) Core Science. Conclusion: Interdisciplinary work has the potential to advance public health science but the numerous challenges should not be underestimated. Use of a checklist, such as BASICS, when planning and managing projects may help future collaborations to avoid some of the common pitfalls of interdisciplinary research. PMID- 28334986 TI - Addressing London's modern urban health challenges: learning from other global cities. AB - Around 150 cities have emerged as notable at a global scale. With a global population of fewer than 12%, they generate 46% of world gross domestic product. There is growing interest in how cities can accelerate health improvements through wider social and economic collaboration. A team led by Public Health England in London visited counterparts in New York City and Paris to examine how city health leaders addressed public health challenges. The three cities have similar health challenges but different legal, political and fiscal resources for promoting and protecting health. Consequently, there is no single model that every city could adopt. Organizational structures, interpersonal relationships and individual skills can play an important part in effective delivery of better city health. Lack of access to published evidence on how practice has been influenced by city health policies hampers learning between cities. There is little easily comparable data to guide those interested in such learning. Municipal governments are ideally situated to join researchers to fill this gap in the literature. PMID- 28334985 TI - Multicriteria Optimization Methodology in Stability-Indicating Method Development of Cilazapril and Hydrochlorothiazide. AB - Multicriteria optimization methodology was applied in development of UHPLC-UV-MS method for separation of cilazapril, hydrochlorothiazide and their degradation products. This method is also applicable for analysis of cilazapril, hydrochlorothiazide and their degradation products in combined tablet formulation. Prior to method optimization forced degradation studies were conducted. Cilazapril and hydrochlorothiazide were subjected to acidic (0.1, 0.5 and 1.0 M HCl), basic (0.1, 0.5 and 1.0 M NaOH), thermal (70 degrees C), oxidative (3-30% H2O2) degradation and photodegradation (day light). Cilazapril appeared to be unstable toward acid and base and resulted in formation of cilazaprilat. Hydrochlorothiazide significantly degraded after acid, base and thermal hydrolysis and formed degradation product was 4-amino-6-chlorobenzene-1.3 disulfonamide. For both substances, after oxidative degradation unknown products have arisen. Initial percentage of acetonitrile in mobile phase, final percentage of acetonitrile in mobile phase, time of gradient elution and column temperature were defined as variables to be optimized toward two chromatographic responses by means of central composite design and Derringer's desirability function. The satisfactory chromatographic analysis was achieved on Kinetex C18 (2.6 um, 50 * 2.1 mm) column with temperature set at 25 degrees C. The final mobile phase consisted of acetonitrile and 20 mM ammonium formate buffer (pH adjusted to 8.5). The flow rate of the mobile phase was 400 MUL min-1 and it was pumped in a gradient elution mode. PMID- 28334987 TI - Magnetic Solid-Phase Extraction of N,N-Diethyl-m-Toluamide From Baby Toilet Water Prior to its HPLC-UV Detection. AB - Fe3O4@MIL-100 (MIL, Material Institut Lavoisier) core-shell magnetic microspheres were prepared and applied as the sorbent for the magnetic solid phase extraction (MSPE) of N,N-diethyl-m-toluamide (DEET) in baby toilet water for the first time. The synthesized magnetic metal-organic frameworks were characterized by transmission electron microscope, infrared spectroscopy and thermogravimetric analysis. The functionalized magnetic microparticles showed excellent dispersibility in aqueous solution. The MSPE conditions were investigated in detail. Under the optimized conditions, an MSPE-high performance liquid chromatography method for the determination of DEET was developed. The method was linear in the concentration range from 5 to 500 MUg L-1 for DEET in baby toilet water and good linearity (r2 > 0.9998) was obtained for the calibration curve. The limit of detection was 1.5 MUg L-1. Both the intra-day and inter-day precisions (relative standard deviations) were <3%. PMID- 28334988 TI - Attitudes and lifestyle changes following Jog your Mind: results from a multi factorial community-based program promoting cognitive vitality among seniors. AB - This study examined the effects on attitudes and lifestyle behavior of Jog your Mind, a multi-factorial community-based program promoting cognitive vitality among seniors with no known cognitive impairment. A quasi-experimental study was conducted. Twenty-three community organizations were assigned either to the experimental group (offering the program) or to the control group (creating a waiting list). They recruited 294 community-dwelling seniors. The aims of the study were to verify the effects of the program on attitudes and behaviors related to cognitive vitality and to explore its effects on cognitive vitality. Data was collected at baseline and after the program. Regression analyses revealed that, following their participation in the program, experimental group participants reported: (i) in terms of attitudes, having a greater feeling of control concerning their cognitive capacities, (ii) in terms of behaviors, using significantly more memory strategies and practicing more physical activity and stimulating activities than control group participants. However, the program had no significant effects on measures of cognitive vitality. This study supports the fact that a multi-factorial community-based program can have significant effects on seniors' attitudes and lifestyle behaviors related to cognitive vitality but at short term, no effects on cognitive vitality it-self were found. PMID- 28334989 TI - Impaired fetal muscle development and JAK-STAT activation mark disease onset and progression in a mouse model for merosin-deficient congenital muscular dystrophy. AB - Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is a dramatic neuromuscular disease in which crippling muscle weakness is evident from birth. Here, we use the dyW mouse model for human MDC1A to trace the onset of the disease during development in utero. We find that myotomal and primary myogenesis proceed normally in homozygous dyW-/- embryos. Fetal dyW-/- muscles display the same number of myofibers as wildtype (WT) muscles, but by E18.5 dyW-/- muscles are significantly smaller and muscle size is not recovered post-natally. These results suggest that fetal dyW-/- myofibers fail to grow at the same rate as WT myofibers. Consistent with this hypothesis between E17.5 and E18.5 dyW-/- muscles display a dramatic drop in the number of Pax7- and myogenin-positive cells relative to WT muscles, suggesting that dyW-/- muscles fail to generate enough muscle cells to sustain fetal myofiber growth. Gene expression analysis of dyW-/- E17.5 muscles identified a significant increase in the expression of the JAK-STAT target gene Pim1 and muscles from 2-day and 3-week old dyW-/- mice demonstrate a dramatic increase in pSTAT3 relative to WT muscles. Interestingly, myotubes lacking integrin alpha7beta1, a laminin-receptor, also show a significant increase in pSTAT3 levels compared with WT myotubes, indicating that alpha7beta1 can act as a negative regulator of STAT3 activity. Our data reveal for the first time that dyW-/- mice exhibit a myogenesis defect already in utero. We propose that overactivation of JAK-STAT signaling is part of the mechanism underlying disease onset and progression in dyW-/- mice. PMID- 28334991 TI - Frameworks to assess health systems governance: a systematic review. AB - Governance of the health system is a relatively new concept and there are gaps in understanding what health system governance is and how it could be assessed. We conducted a systematic review of the literature to describe the concept of governance and the theories underpinning as applied to health systems; and to identify which frameworks are available and have been applied to assess health systems governance. Frameworks were reviewed to understand how the principles of governance might be operationalized at different levels of a health system. Electronic databases and web portals of international institutions concerned with governance were searched for publications in English for the period January 1994 to February 2016. Sixteen frameworks developed to assess governance in the health system were identified and are described. Of these, six frameworks were developed based on theories from new institutional economics; three are primarily informed by political science and public management disciplines; three arise from the development literature and four use multidisciplinary approaches. Only five of the identified frameworks have been applied. These used the principal-agent theory, theory of common pool resources, North's institutional analysis and the cybernetics theory. Governance is a practice, dependent on arrangements set at political or national level, but which needs to be operationalized by individuals at lower levels in the health system; multi-level frameworks acknowledge this. Three frameworks were used to assess governance at all levels of the health system. Health system governance is complex and difficult to assess; the concept of governance originates from different disciplines and is multidimensional. There is a need to validate and apply existing frameworks and share lessons learnt regarding which frameworks work well in which settings. A comprehensive assessment of governance could enable policy makers to prioritize solutions for problems identified as well as replicate and scale-up examples of good practice. PMID- 28334992 TI - Utility of chromogranin B compared with chromogranin A as a biomarker in Japanese patients with pancreatic neuroendocrine tumors. AB - Objective: Currently, serum chromogranin A is a well-established biomarker for pancreatic neuroendocrine tumors; however, other pancreatic diseases, oral use of a proton pump inhibitor and renal impairment can affect chromogranin A. Meanwhile, chromogranin B, belonging to the same granin family as chromogranin A, is not fully examined in these conditions. The present study aimed to evaluate the utility of chromogranin B as a pancreatic neuroendocrine tumor biomarker. Methods: Serum chromogranin B levels were determined by radioimmunoassay and serum chromogranin A levels by enzyme-linked immunosorbent assay in pancreatic neuroendocrine tumor (n = 91) and other pancreatic conditions, and in healthy people (n = 104), to assess the relationships with clinical features. Results: The diagnostic ability of chromogranin B was as good as chromogranin A. The area under the curve was 0.79 for chromogranin B (sensitivity/specificity: 72%/77%), and 0.78 for chromogranin A (sensitivity/specificity: 79%/64%). Chromogranin B was not affected by proton pump inhibitor use and age, which affected chromogranin A. The number of cases without liver metastases was larger in pancreatic neuroendocrine tumor patients with positive chromogranin B and negative chromogranin A. Though chromogranin A significantly elevated cases with proton pump inhibitor treatment and had positive correlation with age, chromogranin B did not have the tendencies. However, both chromogranin B and chromogranin A elevated in the case with renal impairment. In addition, the logistic regression analysis showed that chromogranin B was superior to chromogranin A in differentiation of pancreatic neuroendocrine tumor from other pancreatic diseases. Conclusions: Compared with chromogranin A, chromogranin B may be more useful during proton pump inhibitor treatment and can detect tumors without liver metastases. In addition, chromogranin B may be an excellent biomarker when differentiation of pancreatic neuroendocrine tumor from other pancreatic diseases is required. PMID- 28334990 TI - Insulin resistance and exendin-4 treatment for multiple system atrophy. AB - See Stayte and Vissel (doi:10.1093/awx064) for a scientific commentary on this article. Multiple system atrophy is a fatal sporadic adult-onset neurodegenerative disorder with no symptomatic or disease-modifying treatment available. The cytopathological hallmark of multiple system atrophy is the accumulation of alpha-synuclein aggregates in oligodendrocytes, forming glial cytoplasmic inclusions. Impaired insulin/insulin-like growth factor-1 signalling (IGF-1) and insulin resistance (i.e. decreased insulin/IGF-1) have been reported in other neurodegenerative disorders such as Alzheimer's disease. Increasing evidence also suggests impaired insulin/IGF-1 signalling in multiple system atrophy, as corroborated by increased insulin and IGF-1 plasma concentrations in multiple system atrophy patients and reduced IGF-1 brain levels in a transgenic mouse model of multiple system atrophy. We here tested the hypothesis that multiple system atrophy is associated with brain insulin resistance and showed increased expression of the key downstream messenger insulin receptor substrate-1 phosphorylated at serine residue 312 in neurons and oligodendrocytes in the putamen of patients with multiple system atrophy. Furthermore, the expression of insulin receptor substrate 1 (IRS-1) phosphorylated at serine residue 312 was more apparent in inclusion bearing oligodendrocytes in the putamen. By contrast, it was not different between both groups in the temporal cortex, a less vulnerable structure compared to the putamen. These findings suggest that insulin resistance may occur in multiple system atrophy in regions where the neurodegenerative process is most severe and point to a possible relation between alpha-synuclein aggregates and insulin resistance. We also observed insulin resistance in the striatum of transgenic multiple system atrophy mice and further demonstrate that the glucagon-like peptide-1 analogue exendin-4, a well-tolerated and Federal Drug Agency-approved antidiabetic drug, has positive effects on insulin resistance and monomeric alpha-synuclein load in the striatum, as well as survival of nigral dopamine neurons. Additionally, plasma levels of exosomal neural-derived IRS-1 phosphorylated at serine residue 307 (corresponding to serine residue 312 in humans) negatively correlated with survival of nigral dopamine neurons in multiple system atrophy mice treated with exendin-4. This finding suggests the potential for developing this peripheral biomarker candidate as an objective outcome measure of target engagement for clinical trials with glucagon-like peptide-1 analogues in multiple system atrophy. In conclusion, our observation of brain insulin resistance in multiple system atrophy patients and transgenic mice together with the beneficial effects of the glucagon-like peptide 1 agonist exendin-4 in transgenic mice paves the way for translating this innovative treatment into a clinical trial. PMID- 28334994 TI - Rural retention of new medical graduates from the Collaborative Project to Increase Production of Rural Doctors (CPIRD): a 12-year retrospective study. AB - Physician scarcity in rural areas is a major obstacle to healthcare access, leading to health inequity worldwide. In Thailand, a special recruitment program of medical education [Collaborative Project to Increase Production of Rural Doctors (CPIRD)] was initiated with four different medical training tracks. No previous research has examined the rural retention of new medical graduates across the CPIRD tracks, compared with those receiving conventional medical education (Normal track). This study examines the public retention of rural physicians from different tracks of entry. A retrospective study was conducted in new medical graduates who entered Ministry of Public Health (MoPH) hospitals from January 2003 to October 2014, and followed up until June 2015, using administrative data from the Personnel Administration Division, MoPH. The CPIRD registry database was used to identify physicians' tracks of entry. Survival analyses and multiple logistic regression analyses were applied to compare the annual retention and the probability of 3-year retention of rural physicians. Results clearly demonstrated a high rural retention of CPIRD medical graduates, compared with their Normal track peers, regarding both lower annual resignation (HR 0.456, P < 0.001) and higher 3-year retention (OR 2.441, CI: 2.192, 2.719). Some variations of rural retention were revealed across the different CPIRD tracks. Evidence from this study can be used as part of the information to reshape the physician production policy to reduce health inequity in rural areas. PMID- 28334995 TI - Reply: Clinical approach to delayed-onset cerebellar impairment following deep brain stimulation for tremor. PMID- 28334993 TI - The mechanism of the glycosylase reaction with hOGG1 base-excision repair enzyme: concerted effect of Lys249 and Asp268 during excision of 8-oxoguanine. AB - The excision of 8-oxoguanine (oxoG) by the human 8-oxoguanine DNA glycosylase 1 (hOGG1) base-excision repair enzyme was studied by using the QM/MM (M06-2X/6 31G(d,p):OPLS2005) calculation method and nuclear magnetic resonance (NMR) spectroscopy. The calculated glycosylase reaction included excision of the oxoG base, formation of Lys249-ribose enzyme-substrate covalent adduct and formation of a Schiff base. The formation of a Schiff base with DeltaG# = 17.7 kcal/mol was the rate-limiting step of the reaction. The excision of the oxoG base with DeltaG# = 16.1 kcal/mol proceeded via substitution of the C1?-N9 N-glycosidic bond with an H-N9 bond where the negative charge on the oxoG base and the positive charge on the ribose were compensated in a concerted manner by NH3+(Lys249) and CO2-(Asp268), respectively. The effect of Asp268 on the oxoG excision was demonstrated with 1H NMR for WT hOGG1 and the hOGG1(D268N) mutant: the excision of oxoG was notably suppressed when Asp268 was mutated to Asn. The loss of the base-excision function was rationalized with QM/MM calculations and Asp268 was confirmed as the electrostatic stabilizer of ribose oxocarbenium through the initial base-excision step of DNA repair. The NMR experiments and QM/MM calculations consistently illustrated the base-excision reaction operated by hOGG1. PMID- 28334997 TI - Self-efficacy and comfort with partner-assisted skin examination in patients receiving follow-up care for melanoma. AB - The objective of this study was to examine the role of interpersonal variables on melanoma survivors' self-efficacy for performing skin self-examinations (SSEs) during melanoma follow-up care. Specifically, the impact of comfort with partner assistance for SSE, SSE support received from one's partner, general partner support, relationship satisfaction, as well as partner attendance at a SSE education session, were examined. One hundred and thirty-seven patients with melanoma between the ages of 18 and 70 years, who also reported being involved in a romantic relationship, received a standardized education on SSE, and completed self-report questionnaires. Results indicate that SSE support and SSE comfort predicted patients' SSE self-efficacy. Partner attendance at the SSE education moderated the relationship between SSE comfort and SSE self-efficacy. In other words, SSE self-efficacy was found to be affected by partner attendance at the SSE education only in cases where the patient reported lower levels of comfort having his or her partner assist with SSE. Results highlight the importance of partner involvement in SSE education, as well as patient comfort with a partner's assistance during skin examinations. Findings inform potential modifications to the follow-up care provided to melanoma survivors by demonstrating the importance of partner involvement in SSE education. PMID- 28334996 TI - Amelogenesis imperfecta caused by N-terminal enamelin point mutations in mice and men is driven by endoplasmic reticulum stress. AB - 'Amelogenesis imperfecta' (AI) describes a group of inherited diseases of dental enamel that have major clinical impact. Here, we identify the aetiology driving AI in mice carrying a p.S55I mutation in enamelin; one of the most commonly mutated proteins underlying AI in humans. Our data indicate that the mutation inhibits the ameloblast secretory pathway leading to ER stress and an activated unfolded protein response (UPR). Initially, with the support of the UPR acting in pro-survival mode, Enamp.S55I heterozygous mice secreted structurally normal enamel. However, enamel secreted thereafter was structurally abnormal; presumably due to the UPR modulating ameloblast behaviour and function in an attempt to relieve ER stress. Homozygous mutant mice failed to produce enamel. We also identified a novel heterozygous ENAMp.L31R mutation causing AI in humans. We hypothesize that ER stress is the aetiological factor in this case of human AI as it shared the characteristic phenotype described above for the Enamp.S55I mouse. We previously demonstrated that AI in mice carrying the Amelxp.Y64H mutation is a proteinopathy. The current data indicate that AI in Enamp.S55I mice is also a proteinopathy, and based on comparative phenotypic analysis, we suggest that human AI resulting from the ENAMp.L31R mutation is another proteinopathic disease. Identifying a common aetiology for AI resulting from mutations in two different genes opens the way for developing pharmaceutical interventions designed to relieve ER stress or modulate the UPR during enamel development to ameliorate the clinical phenotype. PMID- 28334998 TI - Spatiotemporal mapping of epileptic spikes using simultaneous EEG-functional MRI. AB - Epileptic spikes occur on the sub-second timescale and are known to involve not only epileptic foci but also large-scale distributed brain networks. There is likely to be a sequence of neural activity in multiple brain regions that occurs within the duration of a single spike, but standard electroencephalography functional magnetic resonance imaging analyses, which use only the timing of the spikes to model the functional magnetic resonance imaging data, cannot determine the sequence of these activations. Our aim in this study is to temporally resolve these spatial activations to observe the spatiotemporal dynamics of the spike related neural activity at a sub-second timescale. We studied eight focal epilepsy patients (age 11-42 years, six female) and used amplitude features of the electroencephalogram specific to different spike components (early and late peaks and troughs) to encode temporal information into our functional magnetic resonance imaging models. This enables us to associate each activation with a specific model of each of the spike components to infer the temporal order of these spike-related spatial activations. In seven of eight patients the distributed networks were associated with the late spike component. The focal activations were more variably coupled with time epochs, but tended to precede the distributed network effects. We also found that incorporating electroencephalogram features into the models increased sensitivity and in six patients revealed additional regions unseen in the standard analysis result. This included strong bilateral thalamus activation in two patients. We demonstrate the clinical utility of this approach in a patient who recently underwent a successful surgical resection of the region where we saw enhanced activation using electroencephalogram amplitude information specific to the early spike component. This focal cluster of activation was larger and more precisely tracked the anatomy compared to what was seen using the standard timing-based analysis. Our novel electroencephalography-functional magnetic resonance imaging data fusion approach, which utilizes information based on the single spike variability across all electroencephalogram channels, has the potential to help us better understand epileptic networks and aid in the interpretation of functional magnetic resonance imaging activation maps during treatment planning. PMID- 28334999 TI - Rewiring the primary somatosensory cortex in carpal tunnel syndrome with acupuncture. AB - Carpal tunnel syndrome is the most common entrapment neuropathy, affecting the median nerve at the wrist. Acupuncture is a minimally-invasive and conservative therapeutic option, and while rooted in a complex practice ritual, acupuncture overlaps significantly with many conventional peripherally-focused neuromodulatory therapies. However, the neurophysiological mechanisms by which acupuncture impacts accepted subjective/psychological and objective/physiological outcomes are not well understood. Eligible patients (n = 80, 65 female, age: 49.3 +/- 8.6 years) were enrolled and randomized into three intervention arms: (i) verum electro-acupuncture 'local' to the more affected hand; (ii) verum electro acupuncture at 'distal' body sites, near the ankle contralesional to the more affected hand; and (iii) local sham electro-acupuncture using non-penetrating placebo needles. Acupuncture therapy was provided for 16 sessions over 8 weeks. Boston Carpal Tunnel Syndrome Questionnaire assessed pain and paraesthesia symptoms at baseline, following therapy and at 3-month follow-up. Nerve conduction studies assessing median nerve sensory latency and brain imaging data were acquired at baseline and following therapy. Functional magnetic resonance imaging assessed somatotopy in the primary somatosensory cortex using vibrotactile stimulation over three digits (2, 3 and 5). While all three acupuncture interventions reduced symptom severity, verum (local and distal) acupuncture was superior to sham in producing improvements in neurophysiological outcomes, both local to the wrist (i.e. median sensory nerve conduction latency) and in the brain (i.e. digit 2/3 cortical separation distance). Moreover, greater improvement in second/third interdigit cortical separation distance following verum acupuncture predicted sustained improvements in symptom severity at 3-month follow-up. We further explored potential differential mechanisms of local versus distal acupuncture using diffusion tensor imaging of white matter microstructure adjacent to the primary somatosensory cortex. Compared to healthy adults (n = 34, 28 female, 49.7 +/- 9.9 years old), patients with carpal tunnel syndrome demonstrated increased fractional anisotropy in several regions and, for these regions we found that improvement in median nerve latency was associated with reduction of fractional anisotropy near (i) contralesional hand area following verum, but not sham, acupuncture; (ii) ipsilesional hand area following local, but not distal or sham, acupuncture; and (iii) ipsilesional leg area following distal, but not local or sham, acupuncture. As these primary somatosensory cortex subregions are distinctly targeted by local versus distal acupuncture electrostimulation, acupuncture at local versus distal sites may improve median nerve function at the wrist by somatotopically distinct neuroplasticity in the primary somatosensory cortex following therapy. Our study further suggests that improvements in primary somatosensory cortex somatotopy can predict long-term clinical outcomes for carpal tunnel syndrome. PMID- 28335000 TI - Better than sham? A double-blind placebo-controlled neurofeedback study in primary insomnia. AB - See Thibault et al. (doi:10.1093/awx033) for a scientific commentary on this article.Neurofeedback training builds upon the simple concept of instrumental conditioning, i.e. behaviour that is rewarded is more likely to reoccur, an effect Thorndike referred to as the 'law of effect'. In the case of neurofeedback, information about specific electroencephalographic activity is fed back to the participant who is rewarded whenever the desired electroencephalography pattern is generated. If some kind of hyperarousal needs to be addressed, the neurofeedback community considers sensorimotor rhythm neurofeedback as the gold standard. Earlier treatment approaches using sensorimotor-rhythm neurofeedback indicated that training to increase 12-15 Hz sensorimotor rhythm over the sensorimotor cortex during wakefulness could reduce attention-deficit/hyperactivity disorder and epilepsy symptoms and even improve sleep quality by enhancing sleep spindle activity (lying in the same frequency range). In the present study we sought to critically test whether earlier findings on the positive effect of sensorimotor rhythm neurofeedback on sleep quality and memory could also be replicated in a double-blind placebo-controlled study on 25 patients with insomnia. Patients spent nine polysomnography nights and 12 sessions of neurofeedback and 12 sessions of placebo-feedback training (sham) in our laboratory. Crucially, we found both neurofeedback and placebo feedback to be equally effective as reflected in subjective measures of sleep complaints suggesting that the observed improvements were due to unspecific factors such as experiencing trust and receiving care and empathy from experimenters. In addition, these improvements were not reflected in objective electroencephalographic-derived measures of sleep quality. Furthermore, objective electroencephalographic measures that potentially reflected mechanisms underlying the efficacy of neurofeedback such as spectral electroencephalographic measures and sleep spindle parameters remained unchanged following 12 training sessions. A stratification into 'true' insomnia patients and 'insomnia misperceivers' (subjective, but no objective sleep problems) did not alter the results. Based on this comprehensive and well-controlled study, we conclude that for the treatment of primary insomnia, neurofeedback does not have a specific efficacy beyond unspecific placebo effects. Importantly, we do not find an advantage of neurofeedback over placebo feedback, therefore it cannot be recommended as an alternative to cognitive behavioural therapy for insomnia, the current (non pharmacological) standard-of-care treatment. In addition, our study may foster a critical discussion that generally questions the effectiveness of neurofeedback, and emphasizes the importance of demonstrating neurofeedback efficacy in other study samples and disorders using truly placebo and double-blind controlled trials. PMID- 28335001 TI - FASTKD1 and FASTKD4 have opposite effects on expression of specific mitochondrial RNAs, depending upon their endonuclease-like RAP domain. AB - FASTK family proteins have been identified as regulators of mitochondrial RNA homeostasis linked to mitochondrial diseases, but much remains unknown about these proteins. We show that CRISPR-mediated disruption of FASTKD1 increases ND3 mRNA level, while disruption of FASTKD4 reduces the level of ND3 and of other mature mRNAs including ND5 and CYB, and causes accumulation of ND5-CYB precursor RNA. Disrupting both FASTKD1 and FASTKD4 in the same cell results in decreased ND3 mRNA similar to the effect of depleting FASTKD4 alone, indicating that FASTKD4 loss is epistatic. Interestingly, very low levels of FASTKD4 are sufficient to prevent ND3 loss and ND5-CYB precursor accumulation, suggesting that FASTKD4 may act catalytically. Furthermore, structural modeling predicts that each RAP domain of FASTK proteins contains a nuclease fold with a conserved aspartate residue at the putative active site. Accordingly, mutation of this residue in FASTKD4 abolishes its function. Experiments with FASTK chimeras indicate that the RAP domain is essential for the function of the FASTK proteins, while the region upstream determines RNA targeting and protein localization. In conclusion, this paper identifies new aspects of FASTK protein biology and suggests that the RAP domain function depends on an intrinsic nucleolytic activity. PMID- 28335002 TI - Handcuffing reversal is facilitated by proteases and replication initiator monomers. AB - Specific nucleoprotein complexes are formed strictly to prevent over-initiation of DNA replication. An example of those is the so-called handcuff complex, in which two plasmid molecules are coupled together with plasmid-encoded replication initiation protein (Rep). In this work, we elucidate the mechanism of the handcuff complex disruption. In vitro tests, including dissociation progress analysis, demonstrate that the dimeric variants of plasmid RK2 replication initiation protein TrfA are involved in assembling the plasmid handcuff complex which, as we found, reveals high stability. Particular proteases, namely Lon and ClpAP, disrupt the handcuff by degrading TrfA, thus affecting plasmid stability. Moreover, our data demonstrate that TrfA monomers are able to dissociate handcuffed plasmid molecules. Those monomers displace TrfA molecules, which are involved in handcuff formation, and through interaction with the uncoupled plasmid replication origins they re-initiate DNA synthesis. We discuss the relevance of both Rep monomers and host proteases for plasmid maintenance under vegetative and stress conditions. PMID- 28335004 TI - Barriers and facilitators for institutional delivery among poor Mesoamerican women: a cross-sectional study. AB - Professional skilled care has shown to be one of the most promising strategies to reduce maternal mortality, and in-facility deliveries are a cost-effective way to ensure safe births. Countries in Mesoamerica have emphasized in-facility delivery care by professionally skilled attendants, but access to good-quality delivery care is still lacking for many women. We examined the characteristics of women who had a delivery in a health facility and determinants of the decision to bypass a closer facility and travel to a distant one. We used baseline information from the Salud Mesoamerica Initiative (SMI). Data were collected from a large household and facilities sample in the poorest quintile of the population in Guatemala, Honduras and Nicaragua. The analysis included 1592 deliveries. After controlling for characteristics of women and health facilities, being primiparous (RR = 1.15, 95% CI 1.10, 1.21), being literate (RR = 1.24, 95% CI 1.04, 1.48), having antenatal care (RR = 1.68, 95% CI 1.24, 2.27), being informed of the need for having a C-section (RR = 1.07, 95% CI 1.02, 1.11) and travel time to the closest facility totaling 1-2 h vs under 30 min (RR = 0.88, 95% CI 0.77, 0.99) were associated with in-health facility deliveries. In Guatemala, increased availability of medications and equipment at a distant facility was strongly associated with bypassing the closest facility in favor of a distant one for delivery (RR = 2.10, 95% CI 1.08, 4.07). Our study showed a strong correlation between well-equipped facilities and delivery attendance in poor areas of Mesoamerica. Indeed, women were more likely to travel to more distant facilities if the facilities were of higher level, which scored higher on our capacity score. Our findings call for improving the capacity of health facilities, quality of care and addressing cultural and accessibility barriers to increase institutional delivery among the poor population in Mesoamerica. PMID- 28335003 TI - Identification of genetic variants affecting vitamin D receptor binding and associations with autoimmune disease. AB - Large numbers of statistically significant associations between sentinel SNPs and case-control status have been replicated by genome-wide association studies. Nevertheless, few underlying molecular mechanisms of complex disease are currently known. We investigated whether variation in binding of a transcription factor, the vitamin D receptor (VDR), whose activating ligand vitamin D has been proposed as a modifiable factor in multiple disorders, could explain any of these associations. VDR modifies gene expression by binding DNA as a heterodimer with the Retinoid X receptor (RXR). We identified 43,332 genetic variants significantly associated with altered VDR binding affinity (VDR-BVs) using a high resolution (ChIP-exo) genome-wide analysis of 27 HapMap lymphoblastoid cell lines. VDR-BVs are enriched in consensus RXR::VDR binding motifs, yet most fell outside of these motifs, implying that genetic variation often affects the binding affinity only indirectly. Finally, we compared 341 VDR-BVs replicating by position in multiple individuals against background sets of variants lying within VDR-binding regions that had been matched in allele frequency and were independent with respect to linkage disequilibrium. In this stringent test, these replicated VDR-BVs were significantly (q < 0.1) and substantially (>2-fold) enriched in genomic intervals associated with autoimmune and other diseases, including inflammatory bowel disease, Crohn's disease and rheumatoid arthritis. The approach's validity is underscored by RXR::VDR motif sequence being predictive of binding strength and being evolutionarily constrained. Our findings are consistent with altered RXR::VDR binding contributing to immunity-related diseases. Replicated VDR-BVs associated with these disorders could represent causal disease risk alleles whose effect may be modifiable by vitamin D levels. PMID- 28335005 TI - TDP-43 suppresses tau expression via promoting its mRNA instability. AB - In the brains of individuals with Alzheimer's disease (AD) and chronic traumatic encephalopathy, tau pathology is accompanied usually by intracellular aggregation of transactive response DNA-binding protein 43 (TDP-43). However, the role of TDP 43 in tau pathogenesis is not understood. Here, we investigated the role of TDP 43 in tau expression in vitro and in vivo. We found that TDP-43 suppressed tau expression by promoting its mRNA instability through the UG repeats of its 3? untranslated region (3?-UTR). The C-terminal region of TDP-43 was required for this function. Neurodegenerative diseases-causing TDP-43 mutations affected tau mRNA instability differentially, in that some promoted and others did not significantly affect tau mRNA instability. The expression levels of tau and TDP 43 were inverse in the frontal cortex and the cerebellum. Accompanied with cytoplasmic accumulation of TDP-43, tau expression was elevated in TDP-43M337V transgenic mouse brains. The level of TDP-43, which is decreased in AD brains, was found to correlate negatively with the tau level in human brain. Our findings indicate that TDP-43 suppresses tau expression by promoting the instability of its mRNA. Down-regulation of TDP-43 may be involved in the tau pathology in AD and related neurodegenerative disorders. PMID- 28335006 TI - A platform for functional assessment of large variant libraries in mammalian cells. AB - Sequencing-based, massively parallel genetic assays have revolutionized our ability to quantify the relationship between many genotypes and a phenotype of interest. Unfortunately, variant library expression platforms in mammalian cells are far from ideal, hindering the study of human gene variants in their physiologically relevant cellular contexts. Here, we describe a platform for phenotyping variant libraries in transfectable mammalian cell lines in two steps. First, a landing pad cell line with a genomically integrated, Tet-inducible cassette containing a Bxb1 recombination site is created. Second, a single variant from a library of transfected, promoter-less plasmids is recombined into the landing pad in each cell. Thus, every cell in the recombined pool expresses a single variant, allowing for parallel, sequencing-based assessment of variant effect. We describe a method for incorporating a single landing pad into a defined site of a cell line of interest, and show that our approach can be used generate more than 20 000 recombinant cells in a single experiment. Finally, we use our platform in combination with a sequencing-based assay to explore the N end rule by simultaneously measuring the effects of all possible N-terminal amino acids on protein expression. PMID- 28335008 TI - Corrigendum. PMID- 28335007 TI - A class of circadian long non-coding RNAs mark enhancers modulating long-range circadian gene regulation. AB - Circadian rhythm exerts its influence on animal physiology and behavior by regulating gene expression at various levels. Here we systematically explored circadian long non-coding RNAs (lncRNAs) in mouse liver and examined their circadian regulation. We found that a significant proportion of circadian lncRNAs are expressed at enhancer regions, mostly bound by two key circadian transcription factors, BMAL1 and REV-ERBalpha. These circadian lncRNAs showed similar circadian phases with their nearby genes. The extent of their nuclear localization is higher than protein coding genes but less than enhancer RNAs. The association between enhancer and circadian lncRNAs is also observed in tissues other than liver. Comparative analysis between mouse and rat circadian liver transcriptomes showed that circadian transcription at lncRNA loci tends to be conserved despite of low sequence conservation of lncRNAs. One such circadian lncRNA termed lnc-Crot led us to identify a super-enhancer region interacting with a cluster of genes involved in circadian regulation of metabolism through long-range interactions. Further experiments showed that lnc-Crot locus has enhancer function independent of lnc-Crot's transcription. Our results suggest that the enhancer-associated circadian lncRNAs mark the genomic loci modulating long-range circadian gene regulation and shed new lights on the evolutionary origin of lncRNAs. PMID- 28335010 TI - Schistosomiasis in Scottish travellers: public health importance of laboratory testing and the need for enhanced surveillance. AB - Background: Imported schistosomiasis is of significant public health importance and is likely to be underestimated since infection is often asymptomatic. We describe data from travellers residing in Scotland which includes a subset of group travellers from one of the largest Health Boards in Scotland. Methods: Clotted bloods were obtained during the period 2001-15 from a total of 8163 Scottish travellers. This included seven groups comprising of 182 travellers. Sera were examined for the presence of Schistosome species antibody at the Scottish Parasite Diagnostic and Reference Laboratory (SPDRL). Results: Of all, 25% (n = 1623) tested positive with 40% (n = 651) of those patients aged between 20 and 24 years. Although 62% (n = 1006) of those who tested positive reported travel to Africa, important information on the specific region visited was lacking in almost one-third of samples received. Overall, 62 (34%) of group travellers tested positive and 95% (n = 59) reporting travel to Africa. Conclusions: Globalization, affordable air travel and improved awareness, are likely to contribute towards the increasing number of imported schistosomiasis cases. Therefore, enhanced surveillance capturing detailed travel history and fresh water exposures will improve risk stratification, pre-travel advice and optimize testing and treatment regimes for this increasingly important parasitic disease. PMID- 28335011 TI - Understanding public perception of the need for major change in Latin American healthcare systems. AB - The opinions and experiences of the public regarding health services are valuable insights into identifying opportunities to improve healthcare systems. We analyzed the 2012-2013 Public Opinion Health Policy Survey carried out in Brazil (n = 1486), Colombia (n = 1485), El Salvador (n = 1460), Jamaica (n = 1480), Mexico (n = 1492) and Panama (n = 1475). In these countries between 82 and 96% of participants perceived that their health systems needed fundamental changes. The most frequent barrier to access to healthcare was lack of the primary medical home, difficulties in obtaining medical care during the weekends and financial barriers. Type of health insurance and challenges in obtaining medical care during the weekends were associated with an increased opinion for the need for fundamental changes in healthcare systems, whereas having a primary medical home showed a protective effect. Focusing on tackling organizational and financial barriers and ensuring access to a primary medical home should be placed on the agenda of Latin American countries. PMID- 28335009 TI - Open chromatin profiling of human postmortem brain infers functional roles for non-coding schizophrenia loci. AB - Open chromatin provides access to DNA-binding proteins for the correct spatiotemporal regulation of gene expression. Mapping chromatin accessibility has been widely used to identify the location of cis regulatory elements (CREs) including promoters and enhancers. CREs show tissue- and cell-type specificity and disease-associated variants are often enriched for CREs in the tissues and cells that pertain to a given disease. To better understand the role of CREs in neuropsychiatric disorders we applied the Assay for Transposase Accessible Chromatin followed by sequencing (ATAC-seq) to neuronal and non-neuronal nuclei isolated from frozen postmortem human brain by fluorescence-activated nuclear sorting (FANS). Most of the identified open chromatin regions (OCRs) are differentially accessible between neurons and non-neurons, and show enrichment with known cell type markers, promoters and enhancers. Relative to those of non neurons, neuronal OCRs are more evolutionarily conserved and are enriched in distal regulatory elements. Transcription factor (TF) footprinting analysis identifies differences in the regulome between neuronal and non-neuronal cells and ascribes putative functional roles to a number of non-coding schizophrenia (SCZ) risk variants. Among the identified variants is a Single Nucleotide Polymorphism (SNP) proximal to the gene encoding SNX19. In vitro experiments reveal that this SNP leads to an increase in transcriptional activity. As elevated expression of SNX19 has been associated with SCZ, our data provide evidence that the identified SNP contributes to disease. These results represent the first analysis of OCRs and TF-binding sites in distinct populations of postmortem human brain cells and further our understanding of the regulome and the impact of neuropsychiatric disease-associated genetic risk variants. PMID- 28335012 TI - Improving working memory performance in brain-injured patients using hypnotic suggestion. AB - Working memory impairment is prevalent in brain injured patients across lesion aetiologies and severities. Unfortunately, rehabilitation efforts for this impairment have hitherto yielded small or no effects. Here we show in a randomized actively controlled trial that working memory performance can be effectively restored by suggesting to hypnotized patients that they have regained their pre-injury level of working memory functioning. Following four 1-h sessions, 27 patients had a medium-sized improvement relative to 22 active controls (Bayes factors of 342 and 37.5 on the two aggregate outcome measures) and a very large improvement relative to 19 passive controls (Bayes factor = 1.7 * 1013). This was a long-term effect as revealed by no deterioration following a 6.7 week no-contact period (Bayes factors = 7.1 and 1.3 in favour of no change). To control for participant-specific effects, the active control group was crossed over to the working memory suggestion and showed superior improvement. By the end of the study, both groups reached a performance level at or above the healthy population mean with standardized mean differences between 1.55 and 2.03 relative to the passive control group. We conclude that, if framed correctly, hypnotic suggestion can effectively improve working memory following acquired brain injury. The speed and consistency with which this improvement occurred, indicate that there may be a residual capacity for normal information processing in the injured brain. PMID- 28335013 TI - Lifetime and 1-year prevalence of homelessness in the US population: results from the National Epidemiologic Survey on Alcohol and Related Conditions-III. AB - Background: Homelessness remains a major public health problem in the USA but there have been few recent epidemiological studies in the general population. Methods: Using data from structured interviews with a nationally representative sample of 36 299 US adults from the 2012-13 Wave 3 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC-III), this study examined the lifetime and 1-year prevalence of homelessness, and its correlates. Results: Lifetime and 1-year prevalence of homelessness in the US population was found to be 4.2 and 1.5%, respectively. Low income, debt, borderline personality disorder (PD), past-year tobacco use disorder, any history of suicidal attempts and being a victim of crime in the past year were all independently strongly associated with past-year homelessness (all OR > 1.5). Low income, debt, history of incarceration, antisocial PD and any history of suicidal attempts were all independently strongly associated with lifetime homelessness (all OR > 1.5). Conclusions: These findings provide an update to the original NESARC, suggesting a possible increase in lifetime homelessness (2.7-4.2%) in the past decade. Along with known economic and behavioral health conditions, special attention should be paid to PDs in efforts to prevent and end homelessness. PMID- 28335014 TI - Impact of high-intensity polio eradication activities on children's routine immunization status in Northern India. AB - The objective of this article is to analyse and quantify the side effects of the Polio Eradication Initiative on routine immunization performance in India. Past studies have faced methodological challenges in assessing these side effects. This article offers a methodological alternative for health policy analysts. The research uses secondary household survey data from the Indian District-Level Household and Facility Survey (DLHS), focusing on children aged 10-30 months in the Northern Indian states of Uttar Pradesh (n = 34 327) and Bihar (n = 20 525). Covering the years 2002-08, this is the latest large-scale data from India that enables the matching technique used in this article. District-level programme intensity data of the Polio Eradication Initiative in India were reconstructed using publicly available resources. The methodological innovation compared with previous studies consists of matching each child in the DLHS data set with a child-specific value of programme exposure depending on its district of residence, its birth date, and the date of the survey interview. Average and age specific associations between polio programme exposure and children's full immunization status were assessed using logistic regression, controlling for other determinants of immunization. The regression results show that the link is negative in Uttar Pradesh and positive in Bihar. Age-specific analysis shows that the positive association diminishes for older children in Bihar and that a negative association emerges and becomes increasingly pronounced for older children in Uttar Pradesh. This indicates that heterogeneous results emerge across two neighbouring states with similar programme intensity and suggests that the catch-up of unvaccinated older children may be a channel through which negative effects accrue. The method described in this article, based on an analytical focus on individual-level programme exposure, can therefore help health policy implementers and evaluators to illuminate positive or negative interactions between a health intervention and a health system. PMID- 28335015 TI - The synaptic function of parkin. AB - Loss of function mutations in the gene PARK2, which encodes the protein parkin, cause autosomal recessive juvenile parkinsonism, a neurodegenerative disease characterized by degeneration of the dopaminergic neurons localized in the substantia nigra pars compacta. No therapy is effective in slowing disease progression mostly because the pathogenesis of the disease is yet to be understood. From accruing evidence suggesting that the protein parkin directly regulates synapses it can be hypothesized that PARK2 gene mutations lead to early synaptic damage that results in dopaminergic neuron loss over time. We review evidence that supports the role of parkin in modulating excitatory and dopaminergic synapse functions. We also discuss how these findings underpin the concept that autosomal recessive juvenile parkinsonism can be primarily a synaptopathy. Investigation into the molecular interactions between parkin and synaptic proteins may yield novel targets for pharmacologic interventions. PMID- 28335017 TI - The Medical Battery in The United States (1870-1920): Electrotherapy at Home and in the Clinic. AB - This paper focuses on the history of a portable shock-producing electrotherapeutic device known as the medical battery (1870-1920), which provided both direct and alternating current and was thought to cure a wide variety of ailments. The product occupied a unique space at the nexus of medicine, consumerism and quackery: it was simultaneously considered a legitimate device by medical professionals who practiced electrotherapeutics, yet identical versions were sold directly to consumers, often via newspaper advertisements and with cure-all marketing language. Indeed, as I show in this paper, the line between what was considered a medical device and a consumer product was often blurred. Even though medical textbooks and journals never mentioned (much less promoted) the home use of electricity, every reputable electrotherapy instrument manufacturer sold a "family battery" for patients to use on themselves at home. While a handful of physicians spoke out against the use of electricity by the laity-as they felt it undermined the image of electrotherapy as a skilled medical procedure-existing evidence suggests that many physicians were likely recommending the home use of medical electricity to their patients. Taken together, this paper shows how the professional ideals of electrotherapeutics were not always aligned with physicians' actual practices. PMID- 28335016 TI - tRNA-derived small RNAs target transposable element transcripts. AB - tRNA-derived RNA fragments (tRFs) are 18-26 nucleotide small RNAs that are not random degradation products, but are rather specifically cleaved from mature tRNA transcripts. Abundant in stressed or viral-infected cells, the function and potential targets of tRFs are not known. We identified that in the unstressed wild-type male gamete containing pollen of flowering plants, and analogous reproductive structure in non-flowering plant species, tRFs accumulate to high levels. In the reference plant Arabidopsis thaliana, tRFs are processed by Dicer like 1 and incorporated into Argonaute1 (AGO1), akin to a microRNA. We utilized the fact that many plant small RNAs direct cleavage of their target transcripts to demonstrate that the tRF-AGO1 complex acts to specifically target and cleave endogenous transposable element (TE) mRNAs produced from transcriptionally active TEs. The data presented here demonstrate that tRFs are bona-fide regulatory microRNA-like small RNAs involved in the regulation of genome stability through the targeting of TE transcripts. PMID- 28335019 TI - Clinical approach to delayed-onset cerebellar impairment following deep brain stimulation for tremor. PMID- 28335018 TI - Dissecting gamma frequency activity during human memory processing. AB - Gamma frequency activity (30-150 Hz) is induced in cognitive tasks and is thought to reflect underlying neural processes. Gamma frequency activity can be recorded directly from the human brain using intracranial electrodes implanted in patients undergoing treatment for drug-resistant epilepsy. Previous studies have independently explored narrowband oscillations in the local field potential and broadband power increases. It is not clear, however, which processes contribute to human brain gamma frequency activity, or their dynamics and roles during memory processing. Here a large dataset of intracranial recordings obtained during encoding of words from 101 patients was used to detect, characterize and compare induced gamma frequency activity events. Individual bursts of gamma frequency activity were isolated in the time-frequency domain to determine their spectral features, including peak frequency, amplitude, frequency span, and duration. We found two distinct types of gamma frequency activity events that showed either narrowband or broadband frequency spans revealing characteristic spectral properties. Narrowband events, the predominant type, were induced by word presentations following an initial induction of broadband events, which were temporally separated and selectively correlated with evoked response potentials, suggesting that they reflect different neural activities and play different roles during memory encoding. The two gamma frequency activity types were differentially modulated during encoding of subsequently recalled and forgotten words. In conclusion, we found evidence for two distinct activity types induced in the gamma frequency range during cognitive processing. Separating these two gamma frequency activity components contributes to the current understanding of electrophysiological biomarkers, and may prove useful for emerging neurotechnologies targeting, mapping and modulating distinct neurophysiological processes in normal and epileptogenic brain. PMID- 28335020 TI - ZNHIT3 is defective in PEHO syndrome, a severe encephalopathy with cerebellar granule neuron loss. AB - Progressive encephalopathy with oedema, hypsarrhythmia, and optic atrophy (PEHO) syndrome is an early childhood onset, severe autosomal recessive encephalopathy characterized by extreme cerebellar atrophy due to almost total granule neuron loss. By combining homozygosity mapping in Finnish families with Sanger sequencing of positional candidate genes and with exome sequencing a homozygous missense substitution of leucine for serine at codon 31 in ZNHIT3 was identified as the primary cause of PEHO syndrome. ZNHIT3 encodes a nuclear zinc finger protein previously implicated in transcriptional regulation and in small nucleolar ribonucleoprotein particle assembly and thus possibly to pre-ribosomal RNA processing. The identified mutation affects a highly conserved amino acid residue in the zinc finger domain of ZNHIT3. Both knockdown and genome editing of znhit3 in zebrafish embryos recapitulate the patients' cerebellar defects, microcephaly and oedema. These phenotypes are rescued by wild-type, but not mutant human ZNHIT3 mRNA, suggesting that the patient missense substitution causes disease through a loss-of-function mechanism. Transfection of cell lines with ZNHIT3 expression vectors showed that the PEHO syndrome mutant protein is unstable. Immunohistochemical analysis of mouse cerebellar tissue demonstrated ZNHIT3 to be expressed in proliferating granule cell precursors, in proliferating and post-mitotic granule cells, and in Purkinje cells. Knockdown of Znhit3 in cultured mouse granule neurons and ex vivo cerebellar slices indicate that ZNHIT3 is indispensable for granule neuron survival and migration, consistent with the zebrafish findings and patient neuropathology. These results suggest that loss-of function of a nuclear regulator protein underlies PEHO syndrome and imply that establishment of its spatiotemporal interaction targets will be the basis for developing therapeutic approaches and for improved understanding of cerebellar development. PMID- 28335021 TI - MRI-visible perivascular space location is associated with Alzheimer's disease independently of amyloid burden. AB - Perivascular spaces that are visible on magnetic resonance imaging (MRI) are a neuroimaging marker of cerebral small vessel disease. Their location may relate to the type of underlying small vessel pathology: those in the white matter centrum semi-ovale have been associated with cerebral amyloid angiopathy, while those in the basal ganglia have been associated with deep perforating artery arteriolosclerosis. As cerebral amyloid angiopathy is an almost invariable pathological finding in Alzheimer's disease, we hypothesized that MRI-visible perivascular spaces in the centrum semi-ovale would be associated with a clinical diagnosis of Alzheimer's disease, whereas those in the basal ganglia would be associated with subcortical vascular cognitive impairment. We also hypothesized that MRI-visible perivascular spaces in the centrum semi-ovale would be associated with brain amyloid burden, as detected by amyloid positron emission tomography using 11C-Pittsburgh B compound (PiB-PET). Two hundred and twenty-six patients (Alzheimer's disease n = 110; subcortical vascular cognitive impairment n = 116) with standardized MRI and PiB-PET imaging were included. MRI-visible perivascular spaces were rated using a validated 4-point visual rating scale, and then categorized by severity ('none/mild', 'moderate' or 'frequent/severe'). Univariable and multivariable regression analyses were performed. Those with Alzheimer's disease-related cognitive impairment were younger, more likely to have a positive PiB-PET scan and carry at least one apolipoprotein E E4 allele; those with subcortical vascular cognitive impairment were more likely to have hypertension, diabetes mellitus, hyperlipidaemia, prior stroke, lacunes, deep microbleeds, and carry the apolipoprotein E E3 allele. In adjusted analyses, the severity of MRI-visible perivascular spaces in the centrum semi-ovale was independently associated with clinically diagnosed Alzheimer's disease (frequent/severe grade odds ratio 6.26, 95% confidence interval 1.66-23.58; P = 0.017, compared with none/mild grade), whereas the severity of MRI-visible perivascular spaces in the basal ganglia was associated with clinically diagnosed subcortical vascular cognitive impairment and negatively predicted Alzheimer's disease (frequent/severe grade odds ratio 0.03, 95% confidence interval 0.00 0.44; P = 0.009, compared with none/mild grade). MRI-visible perivascular space severity in either location did not predict PiB-PET. These findings provide further evidence that the anatomical distribution of MRI-visible perivascular spaces may reflect the underlying cerebral small vessel disease. Using MRI visible perivascular space location and severity together with other imaging markers may improve the diagnostic value of neuroimaging in memory clinic populations, in particular in differentiating between clinically diagnosed Alzheimer's and subcortical vascular cognitive impairment. PMID- 28335022 TI - Towards local implementation of Dutch health policy guidelines: a concept-mapping approach. AB - To develop a targeted implementation strategy for a municipal health policy guideline, implementation targets of two guideline users [Regional Health Services (RHSs)] and guideline developers of leading national health institutes were made explicit. Therefore, characteristics of successful implementation of the guideline were identified. Differences and similarities in perceptions of these characteristics between RHSs and developers were explored. Separate concept mapping procedures were executed in two RHSs, one with representatives from partner local health organizations and municipalities, the second with RHS members only. A third map was conducted with the developers of the guideline. All mapping procedures followed the same design of generating statements up to interpretation of results with participants. Concept mapping, as a practical implementation tool, will be discussed in the context of international research literature on guideline implementation in public health. Guideline developers consider implementation successful when substantive components (health issues) of the guidelines, content are visible in local policy practice. RHSs, local organizations and municipalities view the implementation process itself within and between organizations as more relevant, and state that usability of the guideline for municipal policy and commitment by officials and municipal managers are critical targets for successful implementation. Between the RHSs, differences in implementation targets were smaller than between RHSs and guideline developers. For successful implementation, RHSs tend to focus on process targets while developers focus more on the thematic contents of the guideline. Implications of these different orientations for implementation strategies are dealt with in the discussion. PMID- 28335023 TI - QbD-Driven Development and Validation of Liquid Chromatography Tandem Mass Spectrometric Method for the Quantitation of Sildenafil in Human Plasma. AB - The present work was employing the Quality by Design approach for the development and validation of a LC-MS-MS method to support the clinical advancement in determination of sildenafil in human plasma using lorazepam as an internal standard. Sample preparation involved solid phase extraction and calibration range observed between 3 and 1,700 ng/mL. The method was systematically optimized by employing Box-Behnken design and used mobile phase flow rate, pH and composition of mobile phase as the critical factors, and assessing the design for retention time and peak area as the responses. A substantial decrease in the variability associated with the method variables was shown in optimization studies and confirmed enhanced method robustness. The present studies revealed that developed method achieves all the regulatory requirements for linearity, accuracy, precision, selectivity, sensitivity and stability for the determination of sildenafil in human plasma. There was not any significant change in the stability of the drug shown by stability studies, performed in human plasma through freeze-thaw cycles, bench-top stability, short-term stability, long-term stability and auto sampler stability. In short, this method shows satisfactory results for the analysis of sildenafil in human plasma and possesses high degree of utility in pharmacokinetic and bioequivalence studies. PMID- 28335024 TI - Impaired dual tasking in Parkinson's disease is associated with reduced focusing of cortico-striatal activity. AB - See Bell et al. (doi:10.1093/awx063) for a scientific commentary on this article. Impaired dual tasking, namely the inability to concurrently perform a cognitive and a motor task (e.g. 'stops walking while talking'), is a largely unexplained and frequent symptom of Parkinson's disease. Here we consider two circuit-level accounts of how striatal dopamine depletion might lead to impaired dual tasking in patients with Parkinson's disease. First, the loss of segregation between striatal territories induced by dopamine depletion may lead to dysfunctional overlaps between the motor and cognitive processes usually implemented in parallel cortico-striatal circuits. Second, the known dorso-posterior to ventro anterior gradient of dopamine depletion in patients with Parkinson's disease may cause a funnelling of motor and cognitive processes into the relatively spared ventro-anterior putamen, causing a neural bottleneck. Using functional magnetic resonance imaging, we measured brain activity in 19 patients with Parkinson's disease and 26 control subjects during performance of a motor task (auditory-cued ankle movements), a cognitive task (implementing a switch-stay rule), and both tasks simultaneously (dual task). The distribution of task-related activity respected the known segregation between motor and cognitive territories of the putamen in both groups, with motor-related responses in the dorso-posterior putamen and task switch-related responses in the ventro-anterior putamen. During dual task performance, patients made more motor and cognitive errors than control subjects. They recruited a striatal territory (ventro-posterior putamen) not engaged during either the cognitive or the motor task, nor used by controls. Relatively higher ventro-posterior putamen activity in controls was associated with worse dual task performance. These observations suggest that dual task impairments in Parkinson's disease are related to reduced spatial focusing of striatal activity. This pattern of striatal activity may be explained by a loss of functional segregation between neighbouring striatal territories that occurs specifically in a dual task context. PMID- 28335025 TI - A Novel LC-MS-MS Method With an Effective Antioxidant for the Determination of Edaravone, a Free-Radical Scavenger in Dog Plasma and its Application to a Pharmacokinetic Study. AB - The objective of this study was to investigate the stability of edaravone in dog plasma by using an added antioxidant stabilizer, with an ultimate goal of developing and validating a sensitive, reliable and robust LC-MS-MS method for determination of edaravone in plasma samples. Edaravone was unstable in plasma, but it presented a good stability performance in the plasma with sodium metabisulfite (SMB), an effective antioxidant. The blood sample was collected in the heparinized eppendorf tube containing SMB and plasma sample was deproteinized using acetonitrile containing 20 ng/mL of phenacetin (Internal standard). The chromatographic separation was performed on a Zorbax Extend-C18 analytical column (2.1 mm * 150 mm I.D., particle size 3.5 um, Agilent Technologies, USA). The mobile phase consisted of 0.1% formic acid in water (v/v) and methanol, and gradient elution was used. The analyte detection was performed on a triple quadrupole tandem mass spectrometer equipped with positive-ion electrospray ionization by multiple reaction ion monitoring mode of the transitions at m/z [M + H]+ 175.1 -> 77.1 for edaravone, and m/z [M + H]+ 180.2 -> 110.0 for phenacetin. The linearity of this method was within the concentration range of 10 1000 ng/mL for edaravone in dog plasma. The lower limit of quantification was 10 ng/mL. The relative standard deviations of intra- and inter-precision were <10%. This method was successfully employed in the pharmacokinetics evaluation of edaravone in beagle dogs after intravenous administration. PMID- 28335026 TI - Melting temperature highlights functionally important RNA structure and sequence elements in yeast mRNA coding regions. AB - Secondary structure elements in the coding regions of mRNAs play an important role in gene expression and regulation, but distinguishing functional from non functional structures remains challenging. Here we investigate the dependence of sequence-structure relationships in the coding regions on temperature based on the recent PARTE data by Wan et al. Our main finding is that the regions with high and low thermostability (high Tm and low Tm regions) are under evolutionary pressure to preserve RNA secondary structure and primary sequence, respectively. Sequences of low Tm regions display a higher degree of evolutionary conservation compared to high Tm regions. Low Tm regions are under strong synonymous constraint, while high Tm regions are not. These findings imply that high Tm regions contain thermo-stable functionally important RNA structures, which impose relaxed evolutionary constraint on sequence as long as the base-pairing patterns remain intact. By contrast, low thermostability regions contain single-stranded functionally important conserved RNA sequence elements accessible for binding by other molecules. We also find that theoretically predicted structures of paralogous mRNA pairs become more similar with growing temperature, while experimentally measured structures tend to diverge, which implies that the melting pathways of RNA structures cannot be fully captured by current computational approaches. PMID- 28335027 TI - A transposon-derived small RNA regulates gene expression in Salmonella Typhimurium. AB - Bacterial sRNAs play an important role in regulating many cellular processes including metabolism, outer membrane homeostasis and virulence. Although sRNAs were initially found in intergenic regions, there is emerging evidence that protein coding regions of the genome are a rich reservoir of sRNAs. Here we report that the 5?UTR of IS200 transposase mRNA (tnpA) is processed to produce regulatory RNAs that affect expression of over 70 genes in Salmonella Typhimurium. We provide evidence that the tnpA derived sRNA base-pairs with invF mRNA to repress expression. As InvF is a transcriptional activator of SPI-1 encoded and other effector proteins, tnpA indirectly represses these genes. We show that deletion of IS200 elements in S. Typhimurium increases invasion in vitro and reduces growth rate, while over-expression of tnpA suppresses invasion. Our work indicates that tnpA acts as an sRNA 'sponge' that sets a threshold for activation of Salmonella pathogenicity island (SPI)-1 effector proteins and identifies a new class of 'passenger gene' for bacterial transposons, providing the first example of a bacterial transposon producing a regulatory RNA that controls host gene expression. PMID- 28335029 TI - The Challenge of Assessing Microcephaly in the Context of the Zika Virus Epidemic. AB - The present article examines the impact of the current limitations of the microcephaly definition in the context of the Zika virus outbreak. It highlights its dependence on the method used for determining gestational age and other anthropometric parameters, and includes original results of prevalence of microcephaly in four countries from two different continents (Mozambique, Brazil, Guatemala and Colombia). Alternative definitions of microcephaly are proposed to allow the identification of true cases of microcephaly in a more accurate manner. PMID- 28335028 TI - Defining the 5? and 3? landscape of the Drosophila transcriptome with Exo-seq and RNaseH-seq. AB - Cells regulate biological responses in part through changes in transcription start sites (TSS) or cleavage and polyadenylation sites (PAS). To fully understand gene regulatory networks, it is therefore critical to accurately annotate cell type-specific TSS and PAS. Here we present a simple and straightforward approach for genome-wide annotation of 5?- and 3?-RNA ends. Our approach reliably discerns bona fide PAS from false PAS that arise due to internal poly(A) tracts, a common problem with current PAS annotation methods. We applied our methodology to study the impact of temperature on the Drosophila melanogaster head transcriptome. We found hundreds of previously unidentified TSS and PAS which revealed two interesting phenomena: first, genes with multiple PASs tend to harbor a motif near the most proximal PAS, which likely represents a new cleavage and polyadenylation signal. Second, motif analysis of promoters of genes affected by temperature suggested that boundary element association factor of 32 kDa (BEAF-32) and DREF mediates a transcriptional program at warm temperatures, a result we validated in a fly line where beaf-32 is downregulated. These results demonstrate the utility of a high-throughput platform for complete experimental and computational analysis of mRNA-ends to improve gene annotation. PMID- 28335030 TI - Urinary Kinetics of Heroin Metabolites in Pigs Shortly After Intake. AB - In previous experimental studies on heroin metabolites excretion in urine, the first sample was often collected a few hours after intake. In forensic cases, it is sometimes questioned if a positive urine result is expected e.g., 30 min after intake. The aim of this study was to investigate urinary excretion of heroin metabolites (morphine, 6-monoacetylmorphine (6-MAM) and morphine-3-glucuronide (M3G)) every 30 min until 330 min after injection of a 20 mg heroin dose in six pigs. Samples were analyzed using a previously published, fully validated liquid chromatography-tandem mass spectrometry method. All metabolites were detected after 30 min in all pigs. The time to maximum concentration (Tmax) median (range) for 6-MAM and morphine was 30 min (first sample) (30-120), and 90 min (30-330) for M3G. In four of the six pigs, the Tmax of 6-MAM and morphine was reached within 30 min. All analytes were still detectable at the end of study. This study showed that positive results in urine are expected to be seen shortly after use of heroin in pigs. Detection times were longer than previously indicated, especially for 6-MAM, but previous studies used lower doses. As the physiology of these animals resembles that of the humans, transferability to man is expected. PMID- 28335031 TI - Ethics of health policy and systems research: a scoping review of the literature. AB - Health policy and systems research (HPSR) is increasingly funded and undertaken as part of health system strengthening efforts worldwide. HPSR ethics is also a relatively new and emerging field, with numerous normative and descriptive questions that have largely not been considered. Normative questions include what ethical principles and values should guide HPSR. Descriptive questions include what ethical concerns arise when conducting HPSR. A small but growing body of scholarly work characterizes the various ethics issues inherent in HPSR. Towards informing the future development of ethics guidance for HPSR, a scoping review was undertaken to: (1) identify the range of ethics issues relevant to the conduct of HPSR-with a deliberate (though not exclusive) focus on low- and middle income country settings and (2) describe existing guidance on key ethics issues relevant to HPSR. Using the Cochrane methods as a basis, the review identified formal and informal literature on HPSR ethics by searching the following databases: PubMed's Medline, Embase, Global Health, Scopus, WHO Global Health Regional Libraries, LILACs, OpenDOAR and Bielefeld Academic Search Engine. In total, 11 062 documents were identified from the formal (10 519) and informal (543) literature. One hundred and seven of these documents (formal 99 and informal 8) met at least one inclusion criterion and underwent thematic analysis. Ethical issues in four main categories were identified: upholding autonomy, identifying and balancing risks and benefits, justice and determination of ethical review requirements. The review indicated that the ethical values behind HPSR place an emphasis on its contributing to the reduction of health disparities. Unsurprisingly then, numerous ethical concerns relating to justice arise in HPSR. However, the majority of existing guidance focuses on obtaining or waiving informed consent and, thus, appears to be insufficient for HPSR. A list of priority ethics issues in HPSR in need of guidance development is provided. PMID- 28335032 TI - Allele-specific ablation rescues electrophysiological abnormalities in a human iPS cell model of long-QT syndrome with a CALM2 mutation. AB - Calmodulin is a ubiquitous Ca2+ sensor molecule encoded by three distinct calmodulin genes, CALM1-3. Recently, mutations in CALM1-3 have been reported to be associated with severe early-onset long-QT syndrome (LQTS). However, the underlying mechanism through which heterozygous calmodulin mutations lead to severe LQTS remains unknown, particularly in human cardiomyocytes. We aimed to establish an LQTS disease model associated with a CALM2 mutation (LQT15) using human induced pluripotent stem cells (hiPSCs) and to assess mutant allele specific ablation by genome editing for the treatment of LQT15. We generated LQT15-hiPSCs from a 12-year-old boy with LQTS carrying a CALM2-N98S mutation and differentiated these hiPSCs into cardiomyocytes (LQT15-hiPSC-CMs). Action potentials (APs) and L-type Ca2+ channel (LTCC) currents in hiPSC-CMs were analyzed by the patch-clamp technique and compared with those of healthy controls. Furthermore, we performed mutant allele-specific knockout using a CRISPR-Cas9 system and analyzed electrophysiological properties. Electrophysiological analyses revealed that LQT15-hiPSC-CMs exhibited significantly lower beating rates, prolonged AP durations, and impaired inactivation of LTCC currents compared with control cells, consistent with clinical phenotypes. Notably, ablation of the mutant allele rescued the electrophysiological abnormalities of LQT15-hiPSC-CMs, indicating that the mutant allele caused dominant-negative suppression of LTCC inactivation, resulting in prolonged AP duration. We successfully recapitulated the disease phenotypes of LQT15 and revealed that inactivation of LTCC currents was impaired in CALM2-N98S hiPSC model. Additionally, allele-specific ablation using the latest genome editing technology provided important insights into a promising therapeutic approach for inherited cardiac diseases. PMID- 28335033 TI - Lingual-Alveolar Contact Pressure During Speech in Amyotrophic Lateral Sclerosis: Preliminary Findings. AB - Purpose: This preliminary study on lingual-alveolar contact pressures (LACP) in people with amyotrophic lateral sclerosis (ALS) had several aims: (a) to evaluate whether the protocol induced fatigue, (b) to compare LACP during speech (LACP-Sp) and during maximum isometric pressing (LACP-Max) in people with ALS (PALS) versus healthy controls, (c) to compare the percentage of LACP-Max utilized during speech (%Max) for PALS versus controls, and (d) to evaluate relationships between LACP-Sp and LACP-Max with word intelligibility. Method: Thirteen PALS and 12 healthy volunteers produced /t, d, s, z, l, n/ sounds while LACP-Sp was recorded. LACP-Max was obtained before and after the speech protocol. Word intelligibility was obtained from auditory-perceptual judgments. Results: LACP-Max values measured before and after completion of the speech protocol did not differ. LACP Sp and LACP-Max were statistically lower in the ALS bulbar group compared with controls and PALS with only spinal symptoms. There was no statistical difference between groups for %Max. LACP-Sp and LACP-Max were correlated with word intelligibility. Conclusions: It was feasible to obtain LACP-Sp measures without inducing fatigue. Reductions in LACP-Sp and LACP-Max for bulbar speakers might reflect tongue weakness. Although confirmation of results is needed, the data indicate that individuals with high word intelligibility maintained LACP-Sp at or above 2 kPa and LACP-Max at or above 50 kPa. PMID- 28335034 TI - Reply: The difference between compensation, and mechanism-specific spatial recovery. PMID- 28335036 TI - Validated Method for the Screening and Quantification of Baclofen, Gabapentin and Pregabalin in Human Post-Mortem Whole Blood Using Protein Precipitation and Liquid Chromatography-Tandem Mass Spectrometry. AB - There has been a rapid increase in the number of prescriptions for baclofen (BLF), gabapentin (GBP) and pregabalin (PGL) in the UK since their introduction to therapy. Recent studies across the European Union and USA have shown the illicit abuse potential of these drugs and deaths have been observed. A simple, reliable and fully validated method was developed for the screening and quantification of BLF, GBP and PGL in human post-mortem (PM) blood. The analytes and their deuterated analogs as internal standard were extracted from blood using a single addition acetonitrile protein precipitation reaction followed by analysis using liquid chromatography-tandem mass spectrometry (LC-MS-MS) with triggered dynamic multiple reaction monitoring mode for simultaneous confirmation and quantification. The assay was linear from 0.05 to 1.00 ug/mL for BLF and 0.5 to 50.0 ug/mL for GBP and PGL, respectively with r2 > 0.999 (n = 9) for all analytes. Intra-day and inter-day imprecisions (n = 80) were calculated using one way ANOVA; no significant difference (P > 0.99) was observed for all analytes over 8 non-consecutive days. The average recovery for all analytes was >98.9%. The limits of detection and quantification were both 0.05 ug/mL for BLF, and 0.5 ug/mL for GBP and PGL. The method was highly selective with no interference from endogenous compounds or from 54 drugs commonly encountered in PM toxicology. To prove method applicability, 17 PM blood samples submitted for analysis were successfully analyzed. The concentration range observed in PM blood for BLF was 0.08-102.00 ug/mL (median = 0.25 ug/mL), for GBP 1.0-134.0 ug/mL (median = 49.0 ug/mL) and 2.0-540.0 ug/mL (median = 42.0 ug/mL) for PGL. PMID- 28335035 TI - A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca2+ homeostasis and ER-mitochondria interactions. AB - Wolfram syndrome (WS) is a progressive neurodegenerative disease characterized by early-onset optic atrophy and diabetes mellitus, which can be associated with more extensive central nervous system and endocrine complications. The majority of patients harbour pathogenic WFS1 mutations, but recessive mutations in a second gene, CISD2, have been described in a small number of families with Wolfram syndrome type 2 (WFS2). The defining diagnostic criteria for WFS2 also consist of optic atrophy and diabetes mellitus, but unlike WFS1, this phenotypic subgroup has been associated with peptic ulcer disease and an increased bleeding tendency. Here, we report on a novel homozygous CISD2 mutation (c.215A > G; p.Asn72Ser) in a Moroccan patient with an overlapping phenotype suggesting that Wolfram syndrome type 1 and type 2 form a continuous clinical spectrum with genetic heterogeneity. The present study provides strong evidence that this particular CISD2 mutation disturbs cellular Ca2+ homeostasis with enhanced Ca2+ flux from the ER to mitochondria and cytosolic Ca2+ abnormalities in patient derived fibroblasts. This Ca2+ dysregulation was associated with increased ER mitochondria contact, a swollen ER lumen and a hyperfused mitochondrial network in the absence of overt ER stress. Although there was no marked alteration in mitochondrial bioenergetics under basal conditions, culture of patient-derived fibroblasts in glucose-free galactose medium revealed a respiratory chain defect in complexes I and II, and a trend towards decreased ATP levels. Our results provide important novel insight into the potential disease mechanisms underlying the neurodegenerative consequences of CISD2 mutations and the subsequent development of multisystemic disease. PMID- 28335037 TI - LRSAM1-mediated ubiquitylation is disrupted in axonal Charcot-Marie-Tooth disease 2P. AB - Charcot-Marie-Tooth (CMT) disease type 2 is a genetically heterogeneous group of inherited neuropathies characterized by motor and sensory deficits as a result of peripheral axonal degeneration. We recently reported a frameshift (FS) mutation in the Really Interesting New Gene finger (RING) domain of LRSAM1 (c.2121_2122dup, p.Leu708Argfs) that encodes an E3 ubiquitin ligase, as the cause of axonal-type CMT (CMT2P). However, the frequency of LRSAM1 mutations in CMT2 and the functional basis for their association with disease remains unknown. In this study, we evaluated LRSAM1 mutations in two large Dutch cohorts. In the first cohort (n = 107), we sequenced the full LRSAM1 coding exons in an unbiased fashion, and, in the second cohort (n = 468), we specifically sequenced the last, RING-encoding exon in individuals where other CMT-associated genes had been ruled out. We identified a novel LRSAM1 missense mutation (c.2120C > T, p.Pro707Leu) mapping to the RING domain. Based on our genetic analysis, the occurrence of pathogenic LRSAM1 mutations is estimated to be rare. Functional characterization of the FS, the identified missense mutation, as well as of another recently reported pathogenic missense mutation (c.2081G > A, p.Cys694Tyr), revealed that in vitro ubiquitylation activity was largely abrogated. We demonstrate that loss of the E2-E3 interaction that is an essential prerequisite for supporting ubiquitylation of target substrates, underlies this reduced ubiquitylation capacity. In contrast, LRSAM1 dimerization and interaction with the bona fide target TSG101 were not disrupted. In conclusion, our study provides further support for the role of LRSAM1 in CMT and identifies LRSAM1-mediated ubiquitylation as a common determinant of disease-associated LRSAM1 mutations. PMID- 28335038 TI - A comparative effectiveness education trial for lifestyle health behavior change in African Americans. AB - Obesity and excess weight are significant clinical and public health issues that disproportionately affect African Americans because of physical inactivity and unhealthy eating. We compared the effects of alternate behavioral interventions on obesity-related health behaviors. We conducted a comparative effectiveness education trial in a community-based sample of 530 adult African Americans. Outcomes variables were physical activity (PA) and fruit and vegetable intake. Outcomes were evaluated at baseline and 1-month following interventions about shared risk factors for cancer and cardiovascular disease (CVD) (integrated, INT) or CVD only (disease-specific). Significant increases were found in the proportion of participants who met PA guidelines from baseline (47.4%) to follow up (52.4%) (P = 0.005). In the stratified analysis that were conducted to examine interaction between education and intervention group assignment, this effect was most apparent among participants who had <=high school education and were randomized to INT (OR = 2.28, 95% CI = 1.04, 5.00, P = 0.04). Completing the intervention was associated with a 1.78 odds of meeting PA guidelines (95% CI = 1.02, 3.10, P = 0.04). Education about risk factors for chronic disease and evidence-based strategies for health behavior change may be useful for addressing obesity-related behaviors among African Americans. PMID- 28335039 TI - Brain temporal complexity in explaining the therapeutic and cognitive effects of seizure therapy. AB - Over 350 million people worldwide suffer from depression, a third of whom are medication-resistant. Seizure therapy remains the most effective treatment in depression, even when many treatments fail. The utility of seizure therapy is limited due to its cognitive side effects and stigma. The biological targets of seizure therapy remain unknown, hindering design of new treatments with comparable efficacy. Seizures impact the brains temporal dynamicity observed through electroencephalography. This dynamicity reflects richness of information processing across distributed brain networks subserving affective and cognitive processes. We investigated the hypothesis that seizure therapy impacts mood (depressive symptoms) and cognition by modulating brain temporal dynamicity. We obtained resting-state electroencephalography from 34 patients (age = 46.0 +/- 14.0, 21 females) receiving two types of seizure treatments-electroconvulsive therapy or magnetic seizure therapy. We used multi-scale entropy to quantify the complexity of the brain's temporal dynamics before and after seizure therapy. We discovered that reduction of complexity in fine timescales underlined successful therapeutic response to both seizure treatments. Greater reduction in complexity of fine timescales in parieto-occipital and central brain regions was significantly linked with greater improvement in depressive symptoms. Greater increase in complexity of coarse timescales was associated with greater decline in cognition including the autobiographical memory. These findings were region and timescale specific. That is, change in complexity in occipital regions (e.g. O2 electrode or right occipital pole) at fine timescales was only associated with change in depressive symptoms, and not change in cognition, and change in complexity in parieto-central regions (e.g. Pz electrode or intra and transparietal sulcus) at coarser timescale was only associated with change in cognition, and not depressive symptoms. Finally, region and timescale specific changes in complexity classified both antidepressant and cognitive response to seizure therapy with good (80%) and excellent (95%) accuracy, respectively. In this study, we discovered a novel biological target of seizure therapy: complexity of the brain resting state dynamics. Region and timescale dependent changes in complexity of the brain resting state dynamics is a novel mechanistic marker of response to seizure therapy that explains both the antidepressant response and cognitive changes associated with this treatment. This marker has tremendous potential to guide design of the new generation of antidepressant treatments. PMID- 28335041 TI - The Cerebellum and Its Wrapping Meninge: Developmental Interplay between Two Major Structures. AB - Meninges have long been considered as a protective and supportive tissue for the central nervous system. Nevertheless, new developmental roles are now attributed to them. The meninges that surround the cerebellum come from the cephalic mesoderm. They are essential for the cerebellum to develop normally. They induce and maintain the basal lamina and glia limitans. In the absence of these structures, the external granular cells of the cerebellum migrate aberrantly and penetrate the subarachnoid space. The molecules involved in the recognition between the cerebellar primordium and the basal lamina belong to two groups in humans: dystroglycan and laminin on the one hand, and GPR56 and collagen III on the other. Finally, molecules secreted by the meninges and acting on the cerebellum begin to be demonstrated; such is the case of SDF1 secreted under the action of FOXC1. PMID- 28335040 TI - [New Ways of Diagnosing ADHD in Adults]. AB - Objective Diagnosing Attention-Deficit-Hyperactivity Disorder (ADHD) in adults requires that ADHD has already been present in childhood. However, recall of ADHD symptoms in childhood is fallible, for example influenced by mood. Furthermore, diagnostics need a procedure to handle oblivion and judgment biases. The Essen Interview-for-school-days-related-biography (EIS-B) addresses these problems and offers a tool for retrospectively diagnosing childhood ADHD in adults. Method 36 patients with ADHD, 27 patients with depression or adjustment disorders and 39 healthy controls were included in the pilot study. All participants were comparable regarding age and gender. Results Internal consistency varied between alpha = 0.58 and alpha = 0.97, split-half-reliability was r = 0.98, inter-rater reliability yielded kappa = 0.66. Retest-reliability varied between r = 0.40 and r = 0.88. Sensitivity was 82 %. Specificity yielded 100 %. Discussion The results indicate that EIS-B is a reliable and valid interview to retrospectively elucidate symptoms of childhood ADHD in adult patients. Further studies should aim for replication of our results using a larger sample size. PMID- 28335042 TI - Acute Sensory Neuronopathy following Enterovirus Infection in a 3-Year-Old Girl. AB - Acute sensory neuronopathy (SNN) is a rapidly developing peripheral nervous system disease that primarily affects sensory neurons in the dorsal root ganglion or trigeminal ganglion, leading to the impairment of sensory axons. SNN is notably uncommon in childhood; only three cases of childhood or adolescent SNN have been reported to date. Moreover, SSN has never been reported in association with enterovirus infection. Here, we report the case of a 3-year-old girl who was initially diagnosed with enterovirus infection based on the presentation of fevers, rashes on all extremities, and ulceration over the posterior pharynx. Nine days later, she presented with ataxic and wide-based gait and dysmetria affecting the extremities, with an absence of sensory nerve action potentials in the upper and lower limbs. The patient was diagnosed with acute SNN based on the criteria developed by Camdessanche et al in 2009. To our knowledge, this is the youngest case of SNN reported to date. In addition, this case reveals that enterovirus infection can be associated with acute SNN in children in rare cases. Accurate diagnosis relies on clinical suspicion, comprehensive knowledge of the patient's history, and careful characterization of abnormal findings in electrodiagnostic studies. PMID- 28335043 TI - Platelet-Derived NO in Subjects Affected by Type 2 Diabetes with and without Complications: Is there any Relationship with their Offspring? AB - Macro- and microvascular complications are currently the principal causes of morbidity and mortality in patients with diabetes mellitus. Aim of this study was to determine if type 2 diabetic patients with nephropathy and coronary artery disease showed altered platelet-derived nitric oxide (NO) production, compared with diabetic subjects without complications, and if this alteration is also present in their diabetic offspring. In this case-control observational study, platelet NO and peroxynitrite content was determined on plasma from 60 male adult type 2 diabetic patients and 60 male offspring type 2 diabetic patients. Plasmatic levels of homocysteine were also determined in the same individuals. Moreover, Western blot analysis of platelet lysates was performed with specific monoclonal antibody for endothelial (eNOS) and inducible (iNOS) nitric oxide synthase. Our study showed a lower piastrinic production of NO in the group of parents without complications (ADH), compared with the group of offspring without complications (YDH) and with the groups of parents with complications. Furthermore, we observed a lower synthesis of peroxynitrite in platelets from the ADH group than in the groups of patients with complications, and in the YDH group compared with all other groups. Subjects from YDH group also showed lower iNOS expression, compared with all other groups. Our data suggest that alterations in nitric oxide metabolism may represent potential risk factors in type 2 diabetes complications, such as nephropathy and cardiovascular diseases, leading to development of new therapeutic strategies in order to delay and prevent the onset of such complications. PMID- 28335044 TI - Semi-automated De-identification of German Content Sensitive Reports for Big Data Analytics. AB - Purpose Projects involving collaborations between different institutions require data security via selective de-identification of words or phrases. A semi automated de-identification tool was developed and evaluated on different types of medical reports natively and after adapting the algorithm to the text structure. Materials and Methods A semi-automated de-identification tool was developed and evaluated for its sensitivity and specificity in detecting sensitive content in written reports. Data from 4671 pathology reports (4105 + 566 in two different formats), 2804 medical reports, 1008 operation reports, and 6223 radiology reports of 1167 patients suffering from breast cancer were de identified. The content was itemized into four categories: direct identifiers (name, address), indirect identifiers (date of birth/operation, medical ID, etc.), medical terms, and filler words. The software was tested natively (without training) in order to establish a baseline. The reports were manually edited and the model re-trained for the next test set. After manually editing 25, 50, 100, 250, 500 and if applicable 1000 reports of each type re-training was applied. Results In the native test, 61.3 % of direct and 80.8 % of the indirect identifiers were detected. The performance (P) increased to 91.4 % (P25), 96.7 % (P50), 99.5 % (P100), 99.6 % (P250), 99.7 % (P500) and 100 % (P1000) for direct identifiers and to 93.2 % (P25), 97.9 % (P50), 97.2 % (P100), 98.9 % (P250), 99.0 % (P500) and 99.3 % (P1000) for indirect identifiers. Without training, 5.3 % of medical terms were falsely flagged as critical data. The performance increased, after training, to 4.0 % (P25), 3.6 % (P50), 4.0 % (P100), 3.7 % (P250), 4.3 % (P500), and 3.1 % (P1000). Roughly 0.1 % of filler words were falsely flagged. Conclusion Training of the developed de-identification tool continuously improved its performance. Training with roughly 100 edited reports enables reliable detection and labeling of sensitive data in different types of medical reports. Key Points: . Collaborations between different institutions require de identification of patients' data. . Software-based de-identification of content sensitive reports grows in importance as a result of 'Big data'. . A de identification software was developed and tested natively and after training. . The proposed de-identification software worked quite reliably, following training with roughly 100 edited reports. . A final check of the texts by an authorized person remains necessary. Citation Format . Seuss H, Dankerl P, Ihle M et al. Semi-automated De-identification of German Content Sensitive Reports for Big Data Analytics. Fortschr Rontgenstr 2017; 189: 661 - 671. PMID- 28335045 TI - [Imaging of Metastastic Renal Cell Carcinoma under Therapy with Immune Checkpoint Inhibitors]. PMID- 28335057 TI - White Paper: Curriculum in Interventional Radiology. AB - Purpose Scope and clinical importance of interventional radiology markedly evolved over the last decades. Consequently it was acknowledged as independent subspecialty by the "European Union of Medical Specialists" (UEMS). Based on radiological imaging techniques Interventional Radiology is an integral part of Radiology. Materials und Methods In 2009 the German Society for Interventional Radiology and minimally-invasive therapy (DeGIR) developed a structured training in Interventional Radiology. In cooperation with the German Society of Neuroradiology (DGNR) this training was extended to also cover Interventional Neuroradiology in 2012. Tailored for this training in Interventional Radiology a structured curriculum was developed, covering the scope of this modular training. Results The curriculum is based on the DeGIR/DGNR modular training concept in Interventional Radiology. There is also an European Curriculum and Syllabus for Interventional Radiology developed by the "Cardiovascular and Interventional Radiological Society of Europe" (CIRSE). The presented curriculum in Interventional Radiology is designed to provide a uniform base for the training in Interventional Radiology in Germany, based on the competencies obtained during residency. Conclusion This curriculum can be used as a basis for training in Interventional Radiology by all training sites. Key Points: . Interventional Radiology is an integral part of clinical radiology. . The German Society for Interventional Radiology and minimally-invasive therapy (DeGIR) developed a curriculum in Interventional Radiology. . This curriculum is an integrative basis for the training in interventional. Citation Format . Mahnken AH, Bucker A, Hohl C et al. White Paper: Curriculum in Interventional Radiology. Fortschr Rontgenstr 2017; 189: 309 - 311. PMID- 28335058 TI - Instructions for Radiological Case Reports. AB - Purpose This paper explains the purpose and structure of a radiological case report and provides guidance for radiologists with respect to the writing of a well-structured patient case report. Materials and Methods The current literature and the author's experience as a writer were used to create a manual that describes steps for preparing a radiological case report containing all of the important ingredients for effective communication. Results Case reports are the first line of evidence in documenting clinical observations in the literature. A case report should be written succinctly and consists of four structured main sections: introduction, description of the case, discussion and conclusion. Its structure follows the structure of an original research article, whereby the description of the case of the case report corresponds to the materials and methods section of the research article. The introduction provides the subject and merit of the case report with respect to the published literature. The case description presents the case in detail and chronological order to allow for plausibility. The discussion compares the case with the published literature and summarizes the essential features. A case report, like an original article, must provide a justified conclusion. The conclusion should be brief and be applicable to clinical practice. Conclusion The unique quality of the case, proper preparation and a clear conclusion are essential for a case report to be published. Key Points: . Case reports are the first line of evidence in documenting clinical observations in the literature. . The structure of a case report structure follows the structure of an original research article. . The unique quality of the case, proper preparation and a clear conclusion are essential for a case report to be published.. Citation Format . Bannas P. Anleitung zum Schreiben eines radiologischen Fallberichts. Fortschr Rontgenstr 2017; 189: 333 - 337. PMID- 28335059 TI - Retrospective Evaluation of Percutaneous Access for TEVAR and EVAR: Time to Make it the Standard Approach? AB - Introduction To evaluate the safety of percutaneous endovascular aortic repair and the relationship of access site characteristics to complications Materials and Methods All patients undergoing percutaneous TEVAR, EVAR and FEVAR procedures from January 2010 to May 2016 were retrospectively analysed for incidence of complications and their relationship to various access site characteristics like access artery size, degree of vessel calcification, skin to artery distance and sheath to artery ratio. Hemostasis occurring within 15 min after suture closure with or without manual compression was defined as primary hemostasis. Results 92 patients with 142 femoral access sites were included in the study. Median follow up was 28.13 months (range 2.5 - 76.7 months, Mean 32.39, SD - 21.66 months). Introducer system size ranged from 12F to 25F. Primary haemostasis was achieved in 97.1 % (138/142) of the total femoral access sites. Four access sites (2.8 %) had to be closed surgically; in all 4 cases the introducer systems was >= 18F. Two of these access sites had been operated upon previously. Late complications including inguinal hematoma (n = 7), wound infection (n = 1), scrotal hematoma (n = 1), pseudoaneurysm (n = 4) and late bleeding (n = 4) occurred in 17 access sites (11.9 %), of which 13 were managed conservatively. On account of the low complication rate, no correlation between the evaluated variables and observed complications could be established. Conclusion Percutaneous endovascular aortic repair is feasible and safe irrespective of the size of the introducer sheath and the nature of aorto-iliac pathology. The technical success rate is high and the incidence of complications is low. Early complications are most often associated with sheath sizes >= 18 F. The majority of the late complications can be treated conservatively. Key points: . Percutaneous endovascular aortic repair is feasible and safe.. . Technical success rate is high and complication rate is low.. . Vascular closure device failure in the occasional patient may necessitate surgical intervention.. Citation Format . Thomas RP, Kowald T, Schmuck B et al. Retrospective Evaluation of Percutaneous Access for TEVAR and EVAR: Time to Make it the Standard Approach?. Fortschr Rontgenstr 2017; 189: 347 - 355. PMID- 28335060 TI - ? PMID- 28335064 TI - ? PMID- 28335073 TI - Clinical characteristics and whole exome/transcriptome sequencing of coexisting chronic myeloid leukemia and myelofibrosis. AB - Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell (HSC) disorders that can be classified on the basis of genetic, clinical, phenotypic features. Genetic lesions such as JAK2 mutations and BCR-ABL translocation are often mutually exclusive in MPN patients and lead to essential thrombocythemia, polycythemia vera, or myelofibrosis or chronic myeloid leukemia, respectively. Nevertheless, coexistence of these genetic aberrations in the same patient has been reported. Whether these aberrations occur in the same stem cell or a different cell is unclear, but an unstable genome in the HSCs seems to be the common antecedent. In an effort to characterize the underlying genetic events that might contribute to the appearance of more than one MPN in a patient, we studied neoplastic cells from patients with dual MPNs by next-generation sequencing. We observed that most patients with two MPNs harbored mutations in genes known to contribute to clonal hematopoiesis through altered epigenetic regulation such as TET2, ASXL1/2, SRSF2, and IDH2 at varying frequencies (1% 47%). In addition, we found that some patients also harbored oncogenic mutations in N/KRAS, TP53, BRAF, EZH2, and GNAS at low frequencies, which probably represent clonal evolution. These findings support the hypothesis that hematopoietic cells from MPN patients harbor multiple genetic aberrations, some of which can contribute to clonal dominance. Acquiring mutations in JAK2/CALR/MPL or the BCR-ABL translocation probably drive the oncogenic phenotype towards a specific MPN. Further, we propose that the acquisition of BCR-ABL in these patients is frequently a secondary event resulting from an unstable genome. PMID- 28335074 TI - A comment on improving transcranial Doppler ultrasonography screening in children with sickle cell anemia. PMID- 28335075 TI - Breastmilk with a high omega-6 to omega-3 fatty acid ratio induced cellular events similar to insulin resistance and obesity in 3T3-L1 adipocytes. AB - BACKGROUND: An imbalance of omega (n)-3 and n-6 polyunsaturated fatty acids (PUFA) during critical periods of development may have adverse effects on the health of the newborn in later life. OBJECTIVES: We hypothesized that breastmilk with higher n-6 to n-3 PUFA ratio will have higher inflammatory cytokines and initiate cellular events similar to insulin resistance and obesity. METHODS: Breastmilk was collected from healthy women who gave natural birth at full term. Breastmilk fatty acids were measured using gas chromatography; samples were pooled based on the n-6 to n-3 PUFA ratio (high, medium and low), and soluble cytokines were measured. Pooled samples were used to treat 3T3-L1 cells; mRNA expression of diacylglycerol acyltransferase2, stearoyl-CoA desaturase-1, leptin and RPLPO was measured. RESULTS: Breastmilk with a higher ratio of n-6 to n-3 PUFA showed higher pro-inflammatory cytokines; there was a direct correlation between n-6 PUFA and pro-inflammatory cytokines. Breastmilk with a higher ratio of n-6 to n-3 PUFA increased the expression of genes involved in lipogenesis. CONCLUSIONS: Pro-inflammatory cytokines in breastmilk are associated with higher levels of n-6 PUFA in breastmilk and has the capacity to alter adipose tissue metabolism to likely predispose the newborn to a higher risk of obesity in later life. PMID- 28335076 TI - Fine mapping of chromosome 5p15.33 identifies novel lung cancer susceptibility loci in Han Chinese. AB - Genome-wide association studies in European and Asian populations have consistently identified chromosome 5p15.33 as a lung cancer susceptibility region. To investigate further the genetic architecture of common variants in this region, we conducted a two-stage fine-mapping analysis discovered by targeted resequencing of 200 cases and 300 controls individually, and validated in multiethnic lung cancer Genome wide association studies (GWASs) with 12,843 cases and 12,639 controls. Two independent variants were identified in approximate conditional analysis with GCTA and consistently validated in lung cancer GWASs in both Asian and European populations. These were rs10054203 in TERT (resequencing: OR = 1.69, p = 2.70 * 10-4 ; validation: OR = 1.34, p = 2.10 * 10-23 for Asian, and OR = 1.09, p = 6.00 * 10-3 for European), and rs397640 in CLPTM1L (resequencing: OR = 0.37, p = 1.19 * 10-4 ; validation: OR = 0.75, p = 5.89 * 10-8 for Asian, and OR = 0.90, p = 2.40 * 10-2 for European). Expression quantitative trait loci analysis showed the risk allele (C) of rs10054203 was significantly associated with lower mRNA expression of CTD-2245Ef15.3 (p = 0.019) and Tubulin Polymerization-Promoting Protein (TPPP, p = 0.031) in 167 lung tissues. In conclusion, in this largest and first resequencing-based fine-mapping analysis of 5p15.33 region in Han Chinese, we identified two novel variants associated with lung cancer susceptibility. Further validation studies and functional work is required to confirm the roles of the newly discovered variants. PMID- 28335078 TI - Dairy intake and prostate cancer survival. PMID- 28335077 TI - Introduction to the Critical Balance - Residual Kidney Function and Incremental Transition to Dialysis. PMID- 28335079 TI - Cutaneous septic emboli from Candida glabrata in a haematological patient. PMID- 28335080 TI - Comparisons among MRI signs, apparent diffusion coefficient, and fractional anisotropy in dogs with a solitary intracranial meningioma or histiocytic sarcoma. AB - Although MRI has become widely used in small animal practice, little is known about the validity of advanced MRI techniques such as diffusion-weighted imaging and diffusion tensor imaging. The aim of this retrospective analytical observational study was to investigate the characteristics of diffusion parameters, that is the apparent diffusion coefficient and fractional anisotropy, in dogs with a solitary intracranial meningioma or histiocytic sarcoma. Dogs were included based on the performance of diffusion MRI and histological confirmation. Statistical analyses were performed to compare apparent diffusion coefficient and fractional anisotropy for the two types of tumor in the intra- and peritumoral regions. Eleven cases with meningioma and six with histiocytic sarcoma satisfied the inclusion criteria. Significant differences in apparent diffusion coefficient value (* 10-3 mm2 /s) between meningioma vs. histiocytic sarcoma were recognized in intratumoral small (1.07 vs. 0.76) and large (1.04 vs. 0.77) regions of interest, in the peritumoral margin (0.93 vs. 1.08), and in the T2 high region (1.21 vs. 1.41). Significant differences in fractional anisotropy values were found in the peritumoral margin (0.29 vs. 0.24) and the T2 high region (0.24 vs. 0.17). The current study identified differences in measurements of apparent diffusion coefficient and fractional anisotropy for meningioma and histiocytic sarcoma in a small sample of dogs. In addition, we observed that all cases of intracranial histiocytic sarcoma showed leptomeningeal enhancement and/or mass formation invading into the sulci in the contrast study. Future studies are needed to determine the sensitivity of these imaging characteristics for differentiating between these tumor types. PMID- 28335081 TI - The impact of body mass index and nuclear beta-catenin on survival in locally advanced rectal cancer treated with preoperative radiochemotherapy. AB - BACKGROUND AND OBJECTIVE: We examined the prognostic value of obesity and nuclear beta-catenin in patients with locally advanced rectal cancer. METHODS: We prospectively recruited a total of 98 eligible patients with locally advanced cancer for preoperative radiochemotherapy followed by total mesorectal excision. Patients' height and weight were reaorded before radiochemotherapy, and the immunohistochemical expression of nuclear beta-catenin was analyzed. Disease-free survival (DFS) was analyzed using the Kaplan-Meier method and a Cox regression model was employed for the multivariate analysis. RESULTS: Obese patients were associated with a lower number of recurrences (3.6% vs. 34.3%, P = 0.001), and a higher DFS (95% vs. 53%; HR, 0.09; 95%CI, 0.01-0.64; P = 0.005) than non-obese patients. In the multivariate analysis, body mass index, nuclear beta-catenin expression, and the absence of lymph node metastases showed a significant increase in DFS. CONCLUSIONS: Obesity and nuclear beta-catenin are independent favorable prognostic factors for DFS in locally advanced cancer treated with preoperative radiochemotherapy. J. Surg. Oncol. 2017;115:301-306. (c) 2017 Wiley Periodicals, Inc. PMID- 28335082 TI - Reporting of mitotic rate in cutaneous melanoma: A study using the national cancer data base. AB - BACKGROUND: The seventh edition of the American Joint Commission on Cancer staging manual (AJCC7, published 2009), updated thin cutaneous melanoma staging protocols with the incorporation of mitotic rate (MR). In these patients, higher MR is associated with decreased survival. This study utilizes the National Cancer Data Base (NCDB) to evaluate MR reporting since AJCC7. METHODS: The NCDB was queried for patients with primary cutaneous melanoma from 1998 to 2013. Because MR reporting was infrequent prior to implementing AJCC7, records from 2010 to 2013 were analyzed. Categorical variables were compared with chi-square tests; univariate and multivariate logistic regression models were constructed to determine the effects of covariates on MR reporting. RESULTS: A total of 107,134 patients met inclusion criteria. From 2010 to 2013, MR reporting increased dramatically (64.3-80.9%). On multivariate analysis, factors significantly related to increased MR reporting include later diagnosis year, T-classification (T1a and b vs. T1), facility type (academic vs. other specified types of cancer programs), facility volume, patient income, level of education, and county population (metropolitan vs. urban and rural). CONCLUSIONS: MR reporting increased dramatically after the introduction of AJCC7; however, disparities in reporting remain across facility types. Further investigation of procedures performed in academic settings that may influence reporting of MR is warranted. J. Surg. Oncol. 2017;115:281-286. (c) 2017 Wiley Periodicals, Inc. PMID- 28335084 TI - Identification of new BMP6 pro-peptide mutations in patients with iron overload. AB - Hereditary Hemochromatosis (HH) is a genetically heterogeneous disorder caused by mutations in at least five different genes (HFE, HJV, TFR2, SLC40A1, HAMP) involved in the production or activity of the liver hormone hepcidin, a key regulator of systemic iron homeostasis. Nevertheless, patients with an HH-like phenotype that remains completely/partially unexplained despite extensive sequencing of known genes are not infrequently seen at referral centers, suggesting a role of still unknown genetic factors. A compelling candidate is Bone Morphogenetic Protein 6 (BMP6), which acts as a major activator of the BMP SMAD signaling pathway, ultimately leading to the upregulation of hepcidin gene transcription. A recent seminal study by French authors has described three heterozygous missense mutations in BMP6 associated with mild to moderate late onset iron overload (IO). Using an updated next-generation sequencing (NGS)-based genetic test in IO patients negative for the classical HFE p.Cys282Tyr mutation, we found three BMP6 heterozygous missense mutations in four patients from three different families. One mutation (p.Leu96Pro) has already been described and proven to be functional. The other two (p.Glu112Gln, p.Arg257His) were novel, and both were located in the pro-peptide domain known to be crucial for appropriate BMP6 processing and secretion. In silico modeling also showed results consistent with their pathogenetic role. The patients' clinical phenotypes were similar to that of other patients with BMP6-related IO recently described. Our results independently add further evidence to the role of BMP6 mutations as likely contributing factors to late-onset moderate IO unrelated to mutations in the established five HH genes. PMID- 28335083 TI - Down-regulation of DAB2IP promotes colorectal cancer invasion and metastasis by translocating hnRNPK into nucleus to enhance the transcription of MMP2. AB - DOC-2/DAB2 interacting protein (DAB2IP) is a RasGAP protein that shows a suppressive effect on cancer progression. Our previous study showed the involvement of transcription regulation of DAB2IP in metastasis of colorectal cancer (CRC). However, the molecular mechanisms of DAB2IP in regulating the progression of CRC need to be further explored. Here, we identified heterogeneous nuclear ribonucleoprotein K (hnRNPK) and matrix metalloproteinase 2 (MMP2) as vital downstream targets of DAB2IP in CRC cells by two-dimensional fluorescence difference gel electrophoresis and cDNA microassay, respectively. Mechanistically, down-regulation of DAB2IP increased the level of hnRNPK through MAPK/ERK signaling pathway. Subsequently, translocation of hnRNPK into nucleus enhanced the transcription activity of MMP2, and therefore promoted invasion and metastasis of CRC. Down-regulation of DAB2IP correlated negatively with hnRNPK and MMP2 expressions in CRC tissues. In conclusion, our study elucidates a novel mechanism of the DAB2IP/hnRNPK/MMP2 axis in the regulation of CRC invasion and metastasis, which may be a potential therapeutic target. PMID- 28335086 TI - Neonatal anemia: Revisiting the enigmatic pyknocyte. PMID- 28335085 TI - Modifications in dietary and alcohol intakes between before and after cancer diagnosis: Results from the prospective population-based NutriNet-Sante cohort. AB - Postdiagnosis diet and alcohol consumption may be associated with cancer prognosis, recurrence and mortality. Our aim was to investigate food, nutrient and alcohol intake variations between before and after cancer diagnosis and their determinants in a prospective cohort. Subjects (n = 696) were incident cancer cases diagnosed in the NutriNet-Sante cohort between 2009 and 2016. Food, nutrient and alcohol intakes were prospectively collected using repeated nonconsecutive 24-hr dietary records since subjects' inclusion (i.e. an average of 2 y before diagnosis). Mean number of dietary records per subject was 5.9 before and 8.1 after diagnosis. All dietary data before and after diagnosis were compared by mixed models. Factors associated with the main dietary changes observed were also investigated using multivariable logistic regressions. We observed a decrease in intakes of vegetables (mean decrease in intake in patients who decreased their intake=-102.4 +/- 79.8 g/d), dairy products (-93.9 +/- 82.8 g/d), meat/offal (-35.5 +/- 27.8/d), soy products (-85.8 +/- 104.1 g/d), sweetened soft drinks (-77.9 +/- 95.4 g/d), and alcoholic drinks (-92.9 +/- 119.9 g/d), and an increase in broths (42.1 +/- 34.9 g/d) and fats/sauces (18.0 +/- 13.4 g/d). We observed a decrease in energy intake (-377.2 +/- 243.5 kcal/d) and in intakes of alcohol (-7.6 +/- 9.4 g/d) proteins (-17.4 +/- 12.5 g/d), and several vitamins (p < 0.05) and micronutrients (p < 0.05). Conversely, lipid (19.4 +/- 14.6 g/d), SFA (9.3 +/- 7.0 g/d), MUFA (8.3 +/- 6.3 g/d) and vitamin E (3.9 +/- 3.3 mg/d) intakes increased after diagnosis. This large prospective study suggests that cancer diagnosis is a key period for nutritional changes. It highlights some healthy behaviors such as a decrease in alcohol and sweetened drink consumption, but also less favorable trends, such as a decrease in vegetable consumption and in many vitamin and mineral intakes. These results provide insights to identify and target recommendations to put forward for better nutritional care of cancer survivors. PMID- 28335087 TI - Ursolic acid and mechanisms of actions on adipose and muscle tissue: a systematic review. AB - This systematic review aimed at addressing the ursolic acid actions as an adjunctive treatment of the obesity-mediated metabolic abnormalities. To explore our aims, we used the literature search including clinical and animal studies using the Medline and Google Scholar (up to December 2015). Out of 63 screened studies, 17 presented eligibility criteria, such as the use of ursolic acid on adiposity, energy expenditure and skeletal muscle mass in mice and humans. In the literature, we found that several physiological and molecular mechanisms are implicated in the effects of ursolic acid on obesity, energy expenditure, hepatic steatosis, skeletal muscle mass loss and physical fitness, such as (1) increase of thermogenesis by modulation adipocyte transcription factors, activation of 5' adenosine monophosphate-activated protein kinase and overexpression of the uncoupling protein 1 thermogenic marker; (2) enhancement of skeletal muscle mass by activation in bloodstream growth hormone and insulin-like growth factor-1 concentrations secretion, as well as in the activation of mammalian target of rapamycin and inhibition of ring-finger protein-1; and (3) improvement of physical fitness by skeletal muscle proliferator-activated receptor gamma co activator alpha and sirtuin 1 expression. Therefore, supplementation with ursolic acid may be an adjunctive therapy for prevention and treatment of obesity mediated and muscle mass-mediated metabolic consequences. PMID- 28335088 TI - Further characterization of computed tomographic and clinical features for staging and prognosis of idiopathic pulmonary fibrosis in West Highland white terriers. AB - Idiopathic pulmonary fibrosis is an interstitial lung disease of unknown etiology resulting in progressive interstitial fibrosis, with a known predilection in West Highland white terriers. In humans, computed tomography (CT) is a standard method for providing diagnostic and prognostic information, and plays a major role in the idiopathic pulmonary fibrosis staging process. Objectives of this retrospective, analytical, cross-sectional study were to establish descriptive criteria for reporting CT findings and test correlations among CT, clinical findings and survival time in West Highland white terriers with idiopathic pulmonary fibrosis. Inclusion criteria for affected West Highland white terriers were a diagnosis of idiopathic pulmonary fibrosis and available CT, bronchoscopy, bronchoalveolar lavage, echocardiography, and routine blood analysis findings. Clinically normal West Highland white terriers were recruited for the control group. Survival times were recorded for affected dogs. The main CT lung pattern and clinical data were blindly and separately graded as mild, moderate, or severe. Twenty-one West Highland white terriers with idiopathic pulmonary fibrosis and 11 control West Highland white terriers were included. The severity of pulmonary CT findings was positively correlated with severity of clinical signs (rho = 0.48, P = 0.029) and negatively associated with survival time after diagnosis (rho = -0.56, P = 0.025). Affected dogs had higher lung attenuation (median: -563 Hounsfield Units (HU)) than control dogs (median: -761 HU), (P < 0.001). The most common CT characteristics were ground-glass pattern (16/21) considered as a mild degree of severity, and focal reticular and mosaic ground glass patterns (10/21) considered as a moderate degree of severity. Findings supported the use of thoracic CT as a method for characterizing idiopathic pulmonary fibrosis in West Highland white terriers and providing prognostic information for owners. PMID- 28335089 TI - Variance components estimation for farrowing traits of three purebred pigs in Korea. AB - OBJECTIVE: This study was conducted to estimate breed-specific variance components for total number born (TNB), number born alive (NBA) and mortality rate from birth through weaning including stillbirths (MORT) of three main swine breeds in Korea. In addition, the importance of including maternal genetic and service sire effects in estimation models was evaluated. METHODS: Records of farrowing traits from 6,412 Duroc, 18,020 Landrace, and 54,254 Yorkshire sows collected from January 2001 to September 2016 from different farms in Korea were used in the analysis. Animal models and the restricted maximum likelihood method were used to estimate variances in animal genetic, permanent environmental, maternal genetic, service sire and residuals. RESULTS: The heritability estimates ranged from 0.072 to 0.102, 0.090 to 0.099, and 0.109 to 0.121 for TNB; 0.087 to 0.110, 0.088 to 0.100, and 0.099 to 0.107 for NBA; and 0.027 to 0.031, 0.050 to 0.053, and 0.073 to 0.081 for MORT in the Duroc, Landrace and Yorkshire breeds, respectively. The proportion of the total variation due to permanent environmental effects, maternal genetic effects, and service sire effects ranged from 0.042 to 0.088, 0.001 to 0.031, and 0.001 to 0.021, respectively. Spearman rank correlations among models ranged from 0.98 to 0.99, demonstrating that the maternal genetic and service sire effects have small effects on the precision of the breeding value. CONCLUSION: Models that include additive genetic and permanent environmental effects are suitable for farrowing traits in Duroc, Landrace, and Yorkshire populations in Korea. This breed-specific variance components estimates for litter traits can be utilized for pig improvement programs in Korea. PMID- 28335090 TI - In ovo vaccination using Eimeria profilin and Clostridium perfringens NetB proteins in Montanide IMS adjuvant increases protective immunity against experimentally-induced necrotic enteritis. AB - OBJECTIVE: The effects of vaccinating 18-day-old chicken embryos with the combination of recombinant Eimeria profilin plus Clostridium perfringens (C. perfringens) NetB proteins mixed in the Montanide IMS adjuvant on the chicken immune response to necrotic enteritis (NE) were investigated using an Eimeria maxima (E. maxima)/C. perfringens co-infection NE disease model that we previously developed. METHODS: Eighteen-day-old broiler embryos were injected with 100 MUL of phosphate-buffered saline, profilin, profilin plus necrotic enteritis B-like (NetB), profilin plus NetB/Montanide adjuvant (IMS 106), and profilin plus Net-B/Montanide adjuvant (IMS 101). After post-hatch birds were challenged with our NE experimental disease model, body weights, intestinal lesions, serum antibody levels to NetB, and proinflammatory cytokine and chemokine mRNA levels in intestinal intraepithelial lymphocytes were measured. RESULTS: Chickens in ovo vaccinated with recombinant profilin plus NetB proteins/IMS106 and recombinant profilin plus NetB proteins/IMS101 showed significantly increased body weight gains and reduced gut damages compared with the profilin-only group, respectively. Greater antibody response to NetB toxin were observed in the profilin plus NetB/IMS 106, and profilin plus NetB/IMS 101 groups compared with the other three vaccine/adjuvant groups. Finally, diminished levels of transcripts encoding for proinflammatory cytokines such as lipopolysaccharide-induced tumor necrosis factor-alpha factor, tumor necrosis factor superfamily 15, and interleukin-8 were observed in the intestinal lymphocytes of chickens in ovo injected with profilin plus NetB toxin in combination with IMS 106, and profilin plus NetB toxin in combination with IMS 101 compared with profilin protein alone bird. CONCLUSION: These results suggest that the Montanide IMS adjuvants potentiate host immunity to experimentally induced avian NE when administered in ovo in conjunction with the profilin and NetB proteins, and may reduce disease pathology by attenuating the expression of proinflammatory cytokines and chemokines implicated in disease pathogenesis. PMID- 28335091 TI - Assessment of genetic diversity and phylogenetic relationships of Korean native chicken breeds using microsatellite markers. AB - OBJECTIVE: This study was conducted to investigate the basic information on genetic structure and characteristics of Korean Native chickens (NC) and foreign breeds through the analysis of the pure chicken populations and commercial chicken lines of the Hanhyup Company which are popular in the NC market, using the 20 microsatellite markers. METHODS: In this study, the genetic diversity and phylogenetic relationships of 445 NC from five different breeds (NC, Leghorn [LH], Cornish [CS], Rhode Island Red [RIR], and Hanhyup [HH] commercial line) were investigated by performing genotyping using 20 microsatellite markers. RESULTS: The highest genetic distance was observed between RIR and LH (18.9%), whereas the lowest genetic distance was observed between HH and NC (2.7%). In the principal coordinates analysis (PCoA) illustrated by the first component, LH was clearly separated from the other groups. The correspondence analysis showed close relationship among individuals belonging to the NC, CS, and HH lines. From the STRUCTURE program, the presence of 5 clusters was detected and it was found that the proportion of membership in the different clusters was almost comparable among the breeds with the exception of one breed (HH), although it was highest in LH (0.987) and lowest in CS (0.578). For the cluster 1 it was high in HH (0.582) and in CS (0.368), while for the cluster 4 it was relatively higher in HH (0.392) than other breeds. CONCLUSION: Our study showed useful genetic diversity and phylogenetic relationship data that can be utilized for NC breeding and development by the commercial chicken industry to meet consumer demands. PMID- 28335092 TI - Effect of energy density and virginiamycin supplementation in diets on growth performance and digestive function of finishing steers. AB - OBJECTIVE: This study was determined the influence of virginiamycin supplementation on growth-performance and characteristics of digestion of cattle with decreasing dietary net energy value of the diet for maintenance (NEm) from 2.22 to 2.10 Mcal/kg. METHODS: Eighty crossbred beef steers (298.2+/-6.3 kg) were used in a 152-d performance evaluation consisting of a 28-d adaptation period followed by a 124-d growing-finishing period. During the 124-d period steers were fed either a lesser energy dense (LED, 2.10 Mcal/kg NEm) or higher energy dense (HED, 2.22 Mcal/kg NEm) diet. Diets were fed with or without 28 mg/kg (dry matter [DM] basis) virginiamycin in a 2*2 factorial arrangement. Four Holstein steers (170.4+/-5.6 kg) with cannulas in the rumen (3.8 cm internal diameter) and proximal duodenum were used in 4*4 Latin square experiment to study treatment effects on characteristics of digestion. RESULTS: Neither diet energy density nor virginiamycin affected average daily gain (p>0.10). As expected, dry matter intake and gain efficiency were greater (p<0.01) for LED- than for HED-fed steers. Virginiamycin did not affect estimated net energy value of the LED diet. Virginiamycin increased estimated NE of the HED diet. During daylight hours when the temperature humidity index averaged 81.3+/-2.7, virginiamycin decreased (p<0.05) ruminal temperature. Virginiamycin did not influence (p>0.10) ruminal or total tract digestion. Ruminal (p = 0.02) and total tract digestion (p<0.01) of organic matter, and digestible energy (p<0.01) were greater for HED vs LED. Ruminal microbial efficiency was lower (p<0.01) for HED vs LED diets. CONCLUSION: The positive effect of virginiamycin on growth performance of cattle is due to increased efficiency of energy utilization, as effects of virginiamycin on characteristics of digestion were not appreciable. Under conditions of high ambient temperature virginiamycin may reduce body temperature. PMID- 28335093 TI - Carbohydrate and lipid spectroscopic molecular structures of different alfalfa hay and their relationship with nutrient availability in ruminants. AB - OBJECTIVE: This study was conducted to determine molecular structures related to carbohydrates and lipid in alfalfa hay cut at early bud, late bud and early flower and in the afternoon and next morning using Fourier transform infrared spectroscopy (FT/IR) and to determine their relationship with alfalfa hay nutrient profile and availability in ruminants. METHODS: Chemical composition analysis, carbohydrate fractionation, in situ ruminal degradability, and DVE/OEB model were used to measure nutrient profile and availability of alfalfa hay. Univariate analysis, hierarchical cluster analysis (CLA) and principal components analysis (PCA) were conducted to identify FT/IR spectra differences. RESULTS: The FT/IR non-structural carbohydrate (NSCHO) to total carbohydrates and NSCHO to structural carbohydrate ratios decreased (p<0.05), while lignin to NSCHO and lipid CH3 symmetric to CH2 symmetric ratios increased with advancing maturity (p<0.05). The FT/IR spectra related to structural carbohydrates, lignin and lipids were distinguished for alfalfa hay at three maturities by PCA and CLA, while FT/IR molecular structures related to carbohydrates and lipids were similar between alfalfa hay cut in the morning and afternoon when analyzed by PCA and CLA analysis. Positive correlations were found for FT/IR NSCHO to total carbohydrate and NSCHO to structural carbohydrate ratios with non-fiber carbohydrate (by wet chemistry), ruminal fast and intermediately degradable carbohydrate fractions and total ruminal degradability of carbohydrates and predicted intestinal nutrient availability in dairy cows (r>=0.60; p<0.05) whereas FT/IR lignin to NSCHO and CH3 to CH2 symmetric stretching ratio had negative correlation with predicted ruminal and intestinal nutrient availability of alfalfa hay in dairy cows (r>= 0.60; p<0.05). CONCLUSION: FT/IR carbohydrate and lipid molecular structures in alfalfa hay changed with advancing maturity from early bud to early flower, but not during the day, and these molecular structures correlated with predicted nutrient supply of alfalfa hay in ruminants. PMID- 28335094 TI - Growth and physiological responses of broiler chickens to diets containing raw, full-fat soybean and supplemented with a high-impact microbial protease. AB - OBJECTIVE: This study evaluated the change and function of the pancreas, and small intestine in relation to growth performance of broilers on diets supplemented with raw soybean meal (RSBM) and protease. Samples of test ingredients and diets, after mixing and prior to being used were also assessed on contents of anti-nutritional factors. METHODS: A 3*3 factorial study was used, with three levels of RSBM (commercial soybean meal [SBM] was replaced by RSBM at 0, 10%, or 20%) and protease (0.1, 0.2, or 0.3 g/kg). Each treatment was replicated six times with nine birds per replicate. Birds were housed in cages, in climate-controlled room and fed starter, grower and finisher diets. RESULTS: Levels of trypsin inhibitors in the diets, containing varying levels of RSBM ranged between 1,730.5 and 9,913.2 trypsin inhibitor units/g DM. Neither RSBM nor protease supplementation in diets significantly affected (p>0.05) the body weight of broilers in the entire periods (0 to 35-d). Increasing the level of RSBM in diets increased the weight of the pancreas at d 10 (p<0.000), d 24 (p<0.001), and d 35 (p<0.05). Increasing levels of RSBM in the diets reduced the apparent ileal digestibility of crude protein (CP), and amino acid (AA) at d 24. Increasing level of RSBM in the diets decreased (p<0.01) pancreatic protein content, but this was increased (p<0.05) when protease was added to the diets (0 to 10-d). Increasing the level of protease improved the pancreatic digestive enzymes, including trypsin (p<0.05), chymotrypsin (p<0.01), and general proteolytic enzymes (p<0.05). CONCLUSION: The commercial SBM could be replaced at up to 20% by RSBM for broilers. Although protease supplementation slightly improved the digestive enzymes, and the ileal digestibilities of CP and AA, the CP and AA were negatively affected by increasing RSBM. PMID- 28335095 TI - Genetic correlation between live body measurements and beef cutability traits in Hanwoo steers. AB - OBJECTIVE: The growth, carcass and retail cut yield records on 1,428 Hanwoo steers obtained through progeny testing were analyzed in this study, and their heritability and genetic relationships among the traits were estimated using animal models. METHODS: Two different models were compared in this study. Each model was fitted for different fixed class effects, date of slaughter for carcass traits and batch of progeny test live measurement traits, and a choice of covariates (carcass weight in Model 1 or backfat thickness in Model 2) for carcass traits. RESULTS: The differences in body composition among individuals were deemed being unaffected by their age at slaughter, except for carcass weight and backfat thickness. Heritability estimates of body size measurements were 0.21 to 0.36. Heritability estimates of retail cut percentage were high (0.56 from Model 1 and 0.47 from Model 2). And the heritability estimates for loin muscle percentage were 0.36 from Model 1 and 0.42 from Model 2, which were high enough to consider direct selection on carcass cutability traits as effective. The genetic correlations between body size measurements and retail cut ratio (RCR) were close to zero. But, some negative genetic correlations were found with chest girths measured at yearling (Model 1) or at 24 months of age or with chest widths. Loin muscle ratio (LMR) was genetically negatively correlated with body weights or body size measurements, in general in Model 1. These relationships were low close to zero but positive in Model 2. Phenotypic correlation between cutability traits (RCR, LMR) and live body size measurements were moderate and negative in Model 1 while those in Model 2 were all close to zero. CONCLUSION: Therefore, the body weights or linear body measurements at an earlier age may not be the most desirable selection traits for exploitation of correlated responses to improve loin muscle or lean meat yield. PMID- 28335096 TI - Estimation of methane emissions from local and crossbreed beef cattle in Daklak province of Vietnam. AB - OBJECTIVE: This study was aimed at evaluating effects of cattle breed resources and alternative mixed-feeding practices on meat productivity and emission intensities from household farming systems (HFS) in Daklak Province, Vietnam. METHODS: Records from Local Yellow*Red Sindhi (Bos indicus; Lai Sind) and 1/2 Limousin, 1/2 Drought Master, and 1/2 Red Angus cattle during the growth (0 to 21 months) and fattening (22 to 25 months) periods were used to better understand variations on meat productivity and enteric methane emissions. Parameters were determined by the ruminant model. Four scenarios were developed: (HFS1) grazing from birth to slaughter on native grasses for approximately 10 h plus 1.5 kg dry matter/d (0.8% live weight [LW]) of a mixture of guinea grass (19%), cassava (43%) powder, cotton (23%) seed, and rice (15%) straw; (HFS2) growth period fed with elephant grass (1% of LW) plus supplementation (1.5% of LW) of rice bran (36%), maize (33%), and cassava (31%) meals; and HFS3 and HFS4 computed elephant grass, but concentrate supplementation reaching 2% and 1% of LW, respectively. RESULTS: Results show that compared to HFS1, emissions (72.3+/-0.96 kg CH4/animal/life; least squares means+/- standard error of the mean) were 15%, 6%, and 23% lower (p<0.01) for the HFS2, HFS3, and HFS4, respectively. The predicted methane efficiencies (CO2eq) per kg of LW at slaughter (4.3+/-0.15), carcass weight (8.8+/-0.25 kg) and kg of edible protein (44.1+/-1.29) were also lower (p<0.05) in the HFS4. In particular, irrespective of the HSF, feed supply and ratio changes had a more positive impact on emission intensities when crossbred 1/2 Red Angus cattle were fed than in their crossbred counterparts. CONCLUSION: Modest improvements on feeding practices and integrated modelling frameworks may offer potential trade-offs to respond to climate change in Vietnam. PMID- 28335097 TI - Effects of dietary forage-to-concentrate ratio on nutrient digestibility and enteric methane production in growing goats (Capra hircus hircus) and Sika deer (Cervus nippon hortulorum). AB - OBJECTIVE: Two experiments were conducted to determine the effects of forage-to concentrate (F:C) ratio on the nutrient digestibility and enteric methane (CH4) emission in growing goats and Sika deer. METHODS: Three male growing goats (body weight [BW] = 19.0+/-0.7 kg) and three male growing deer (BW = 19.3+/-1.2 kg) were respectively allotted to a 3*3 Latin square design with an adaptation period of 7 d and a data collection period of 3 d. Respiration-metabolism chambers were used for measuring the enteric CH4 emission. Treatments of low (25:75), moderate (50:50), and high (73:27) F:C ratios were given to both goats and Sika deer. RESULTS: Dry matter (DM) and organic matter (OM) digestibility decreased linearly with increasing F:C ratio in both goats and Sika deer. In both goats and Sika deer, the CH4 emissions expressed as g/d, g/kg BW0.75, % of gross energy intake, g/kg DM intake (DMI), and g/kg OM intake (OMI) decreased linearly as the F:C ratio increased, however, the CH4 emissions expressed as g/kg digested DMI and OMI were not affected by the F:C ratio. Eight equations were derived for predicting the enteric CH4 emission from goats and Sika deer. For goat, equation 1 was found to be of the highest accuracy: CH4 (g/d) = 3.36+4.71*DMI (kg/d) 0.0036*neutral detergent fiber concentrate (NDFC, g/kg)+0.01563*dry matter digestibility (DMD, g/kg)-0.0108*neutral detergent fiber digestibility (NDFD, g/kg). For Sika deer, equation 5 was found to be of the highest accuracy: CH4 (g/d) = 66.3+27.7*DMI (kg/d)-5.91*NDFC (g/kg)-7.11* DMD (g/kg)+0.0809*NDFD (g/kg). CONCLUSION: Digested nutrient intake could be considered when determining the CH4 generation factor in goats and Sika deer. Finally, the enteric CH4 prediction model for goats and Sika deer were estimated. PMID- 28335098 TI - Endoscopic Submucosal Tunnel Dissection for Upper Gastrointestinal Submucosal Tumors Originating from the Muscularis Propria Layer: A Single-Center Study. AB - Background/Aims: In recent years, endoscopic submucosal tunnel dissection (ESTD) has gained popularity worldwide. The aim of this study was to evaluate the safety and efficacy of ESTD in treating upper gastrointestinal submucosal tumors (SMTs) in a large-volume endoscopic center. Methods: Patients with SMTs were enrolled in this study between January 2012 and January 2015. Demographic data, clinical data, and treatment outcome were collected and analyzed. Results: Seventy SMTs originating from the muscularis propria (MP) layer were identified in 69 patients. All patients successfully underwent the ESTD procedure. The mean procedure time was 49.0+/-29.5 minutes, and the mean tumor size was 18.7+/-7.2 mm. Among all lesions, the majority (70.0%) were located in the esophagus, 12.9% in the cardia, and 17.1% in the stomach. Complete resection was achieved in 67 lesions (95.7%). Perforation occurred in three patients (4.3%), who were treated by endoclips. Pneumothorax occurred in two patients (2.9%) and was successfully managed by thoracic drainage. During a median follow-up of 18.1 months, patients were free of local recurrence or distant metastasis. Conclusions: Our results demonstrated the feasibility and safety of ESTD in treating upper gastrointestinal SMTs originating from the MP layer. Large-scale comparative studies with other treatment methods should be conducted in the future. PMID- 28335099 TI - Endoscopic Treatment of Diverse Complications Caused by Laparoscopic Adjustable Gastric Banding: A Study in Eastern Asia. AB - Background/Aims: The use of laparoscopic adjustable gastric banding (LAGB) is increasing proportionally with the obesity epidemic. However, some postoperative complications have been highlighted as major problems associated with LAGB. There is no consensus concerning the endoscopic management of these adverse events. The aim of this study was to retrospectively review the feasibility and effectiveness of endoscopic treatment for LAGB complications. Methods: We retrospectively evaluated 352 patients who underwent LAGB between 2011 and 2015. LAGB-associated complications developed in 26 patients (7.4%). This study involved six patients (1.7%) who received endoscopic treatment. Results: Types of LAGB-induced complications in our series included intragastric migration (n=3), gastric leaks (n=2), and gastric fistulas (n=1). The endoscopic treatment of these complications was successful in four of the six patients. Endoscopic band removal was successful in two patients. All gastric leaks were successfully closed via an endoscopic procedure. In two cases (intragastric migration and gastric fistula), endoscopic treatment was not sufficient, and surgery was performed. Conclusions: Endoscopic procedures afforded acceptable treatment of band migration and gastric leaks after LAGB. However, the results were poor in patients with gastric fistula. PMID- 28335100 TI - Is the Reinitiation of Antiplatelet Agents Safe at 1 Week after Gastric Endoscopic Submucosal Dissection? Assessment of Bleeding Risk Using the Forrest Classification. AB - Background/Aims: Delayed bleeding after gastric endoscopic submucosal dissection (ESD) commonly occurs within 3 days, but it may also occur after 1 week following ESD, especially in antiplatelet agent users. We evaluated the risk of delayed bleeding in post-ESD ulcers using the Forrest classification. Methods: Registry data on the Forrest classification of post-ESD ulcers (n=371) at 1 week or 2 weeks after ESD were retrospectively evaluated. The Forrest classification was categorized into two groups: increased risk (Forrest Ia to IIc) or low risk (Forrest III). The odds ratios (ORs) were calculated using logistic regression analysis. Results: Among 371 post-ESD ulcers, one ulcer (0.3%) was classified as Forrest Ib, two (0.5%) as Forrest IIa, 17 (4.6%) as Forrest IIb, 172 (46.4%) as Forrest IIc, and 179 (48.2%) as Forrest III. The proportion of increased-risk ulcers was 72.2% (140/194) at 1 week after ESD, which decreased to 29.4% (52/177) at 2 weeks after ESD (p<0.001). In the multivariate analysis, a post-ESD ulcer at 1 week after ESD (OR, 7.54), younger age (OR, 2.17), and upper/middle ulcer location (OR, 2.05) were associated with increased-risk ulcers. Conclusions: One week after ESD, ulcers still have an increased risk of bleeding when assessed using the Forrest classification. This risk should be considered when resuming antiplatelet therapy. PMID- 28335101 TI - Prevalence and Incidence of Depression during Interferon-Based Antiviral Therapy in Chronic Hepatitis C Patients in the Republic of Korea. AB - Background/Aims: The association between depression and chronic hepatitis C virus (HCV) infection or pegylated interferon alpha and ribavirin therapy (PR therapy) has not been extensively studied in Korea. We aimed to clarify the prevalence of depression and its incidence during PR therapy in chronic hepatitis C (CHC) patients. Methods: In this prospective, multicenter study, 114 CHC patients were screened for depression using two self-reported scales, the Beck Depression Inventory-I (BDI-I) and the Hospital Anxiety and Depression scale (HADS). The incidence of depression during PR therapy was evaluated in 62 patients who underwent PR therapy during the study period. Results: The prevalence of baseline depression was 17.5% according to the BDI-I score >=10 criterion and 4.4% according to the HADS-D score >=8 criterion in the 114 CHC patients, and it was significantly associated with an unmarried state. During PR therapy, depression developed in 34.6% according to the BDI-I scale and 29.5% according to the HADS D, which negatively affected sustained virologic response (SVR). Conclusions: The prevalence of depression in Korean CHC patients appears to be low compared to that in Western patients; however, its incidence during PR therapy (approximately 30%) was similar to that of other populations, which led to a lower SVR rate. Active screening and multidisciplinary management of depression during PR therapy is warranted. PMID- 28335102 TI - Efficacy of a Multiplex Paclitaxel Emission Stent Using a Pluronic(r) Mixture Membrane versus a Covered Metal Stent in Malignant Biliary Obstruction: A Prospective Randomized Comparative Study. AB - Background/Aims: A drug-eluting stent for unresectable malignant biliary obstruction was developed to increase stent patency by preventing tumor ingrowth. The safety and efficacy of a new generation of metallic stents covered with a paclitaxel-incorporated membrane using a Pluronic(r) mixture (MSCPM-II) were compared prospectively with those of covered metal stents (CMSs) in patients with malignant biliary obstructions. Methods: This study was initially designed as a prospective randomized trial but was closed early because of a high incidence of early occlusion. Therefore, the data were analyzed using the intent-to-treat method. A total of 72 patients with unresectable distal malignant biliary obstructions were prospectively enrolled. Results: The two groups did not differ significantly in basic characteristics and mean follow-up period (MSCPM-II 194 days vs CMS 277 days, p=0.063). Stent occlusion occurred in 14 patients (35%) who received MSCPM-II and in seven patients (21.9%) who received CMSs. Stent patency and survival time did not significantly differ between the two groups (p=0.355 and p=0.570). The complications were mild and resolved by conservative management in both groups. Conclusions: There were no significant differences in stent patency or patient survival in MSCPM-II and CMS patients with malignant biliary obstructions. PMID- 28335183 TI - Numerical Study of Complementary Nanostructures for Light Trapping in Colloidal Quantum Dot Solar Cells. AB - We have investigated two complementary nanostructures, nanocavity and nanopillar arrays, for light absorption enhancement in depleted heterojunction colloidal quantum dot (CQD) solar cells. A facile complementary fabrication process is demonstrated for patterning these nanostructures over the large area required for light trapping in photovoltaic devices. The simulation results show that both proposed periodic nanostructures can effectively increase the light absorption in CQD layer of the solar cell throughout the near-infrared region where CQD solar cells typically exhibit weak light absorption. The complementary fabrication process for implementation of these nanostructures can pave the way for large area, inexpensive light trapping implementation in nanostructured solar cells. PMID- 28335103 TI - Correlation Between Gastric Emptying and Gastric Adaptive Relaxation Influenced by Amino Acids. AB - Background/Aims: Amino acids have many physiological activities. We report the correlation between gastric emptying and gastric adaptive relaxation using tryptophan and amino acids with a straight alkyl chain, hydroxylated chain, and branched chain. Here we sought to further clarify the correlation between gastric emptying and gastric adaptive relaxation by using other amino acids. Methods: In Sprague-Dawley rats, gastric emptying was evaluated by a breath test using [1 13C] acetic acid. The expired 13CO2 pattern, Tmax, Cmax, and AUC120min values were used as evaluation items. Gastric adaptive relaxation was evaluated in a barostat experiment. Individual amino acids (1 g/kg) were administered orally 30 minutes before each breath test or barostat test. Results: L-phenylalanine and L tyrosine did not influence gastric emptying. All other amino acids, ie, L proline, L-histidine, L-cysteine, L-methionine, L-aspartic acid, L-glutamic acid, L-asparagine, L-arginine, L-glutamine, and L-lysine significantly delayed and inhibited gastric emptying. L-Cysteine and L-aspartic acid significantly enhanced and L-methionine and L-glutamine significantly inhibited gastric adaptive relaxation. L-Phenylalanine moved the balloon toward the antrum, suggesting strong contraction of the fundus. Tmax showed a significant positive correlation (r = 0.709), and Cmax and AUC120min each showed negative correlations (r = 0.613 and 0.667, respectively) with gastric adaptive relaxation. Conclusion: From the above findings, it was found that a close correlation exists between gastric emptying and adaptive relaxation, suggesting that enhanced gastric adaptive relaxation inhibits gastric emptying. PMID- 28335185 TI - Nanomaterials for Biosensing Applications. AB - Nanomaterials have shown tremendous potentials to impact the broad field of biological sensing. Nanomaterials, with extremely small sizes and appropriate surface modifications, allow intimate interaction with target biomolecules. [...]. PMID- 28335184 TI - Selective Labeling of Proteins on Living Cell Membranes Using Fluorescent Nanodiamond Probes. AB - The impeccable photostability of fluorescent nanodiamonds (FNDs) is an ideal property for use in fluorescence imaging of proteins in living cells. However, such an application requires highly specific labeling of the target proteins with FNDs. Furthermore, the surface of unmodified FNDs tends to adsorb biomolecules nonspecifically, which hinders the reliable targeting of proteins with FNDs. Here, we combined hyperbranched polyglycerol modification of FNDs with the beta lactamase-tag system to develop a strategy for selective imaging of the protein of interest in cells. The combination of these techniques enabled site-specific labeling of Interleukin-18 receptor alpha chain, a membrane receptor, with FNDs, which eventually enabled tracking of the diffusion trajectory of FND-labeled proteins on the membrane surface. PMID- 28335187 TI - Nickel Decorated on Phosphorous-Doped Carbon Nitride as an Efficient Photocatalyst for Reduction of Nitrobenzenes. AB - Nickel nanoparticle-decorated phosphorous-doped graphitic carbon nitride (Ni@g PC3N4) was synthesized and used as an efficient photoactive catalyst for the reduction of various nitrobenzenes under visible light irradiation. Hydrazine monohydrate was used as the source of protons and electrons for the intended reaction. The developed photocatalyst was found to be highly active and afforded excellent product yields under mild experimental conditions. In addition, the photocatalyst could easily be recovered and reused for several runs without any detectable leaching during the reaction. PMID- 28335186 TI - Ex-Vivo Tissues Engineering Modeling for Reconstructive Surgery Using Human Adult Adipose Stem Cells and Polymeric Nanostructured Matrix. AB - The major challenge for stem cell translation regenerative medicine is the regeneration of damaged tissues by creating biological substitutes capable of recapitulating the missing function in the recipient host. Therefore, the current paradigm of tissue engineering strategies is the combination of a selected stem cell type, based on their capability to differentiate toward committed cell lineages, and a biomaterial, that, due to own characteristics (e.g., chemical, electric, mechanical property, nano-topography, and nanostructured molecular components), could serve as active scaffold to generate a bio-hybrid tissue/organ. Thus, effort has been made on the generation of in vitro tissue engineering modeling. Here, we present an in vitro model where human adipose stem cells isolated from lipoaspirate adipose tissue and breast adipose tissue, cultured on polymeric INTEGRA(r) Meshed Bilayer Wound Matrix (selected based on conventional clinical applications) are evaluated for their potential application for reconstructive surgery toward bone and adipose tissue. We demonstrated that human adipose stem cells isolated from lipoaspirate and breast tissue have similar stemness properties and are suitable for tissue engineering applications. Finally, the overall results highlighted lipoaspirate adipose tissue as a good source for the generation of adult adipose stem cells. PMID- 28335188 TI - Synthesis of Lithium Metal Oxide Nanoparticles by Induction Thermal Plasmas. AB - Lithium metal oxide nanoparticles were synthesized by induction thermal plasma. Four different systems-Li-Mn, Li-Cr, Li-Co, and Li-Ni-were compared to understand formation mechanism of Li-Me oxide nanoparticles in thermal plasma process. Analyses of X-ray diffractometry and electron microscopy showed that Li-Me oxide nanoparticles were successfully synthesized in Li-Mn, Li-Cr, and Li-Co systems. Spinel structured LiMn2O4 with truncated octahedral shape was formed. Layer structured LiCrO2 or LiCoO2 nanoparticles with polyhedral shapes were also synthesized in Li-Cr or Li-Co systems. By contrast, Li-Ni oxide nanoparticles were not synthesized in the Li-Ni system. Nucleation temperatures of each metal in the considered system were evaluated. The relationship between the nucleation temperature and melting and boiling points suggests that the melting points of metal oxides have a strong influence on the formation of lithium metal oxide nanoparticles. A lower melting temperature leads to a longer reaction time, resulting in a higher fraction of the lithium metal oxide nanoparticles in the prepared nanoparticles. PMID- 28335190 TI - Erratum: Tsai, S.-L.; et al. The Coupled Photothermal Reaction and Transport in a Laser Additive Metal Nanolayer Simultaneous Synthesis and Pattering for Flexible Electronics. Nanomaterials 2016, 6, 12. AB - Due to an error during production, the Figure 7b in the published paper [1] was incorrect. The correct figure is as follows:[...]. PMID- 28335189 TI - Synergistic Antibacterial Effects of Nanoparticles Encapsulated with Scutellaria baicalensis and Pure Chlorhexidine on Oral Bacterial Biofilms. AB - Scutellariabaicalensis (SB) is a traditional Chinese medicine for treating infectious and inflammatory diseases. Our recent study shows potent antibacterial effects of nanoparticle-encapsulated chlorhexidine (Nano-CHX). Herein, we explored the synergistic effects of the nanoparticle-encapsulated SB (Nano-SB) and Nano-CHX on oral bacterial biofilms. Loading efficiency of Nano-SB was determined by thermogravimetric analysis, and its releasing profile was assessed by high-performance liquid chromatographyusing baicalin (a flavonoid compound of SB) as the marker. The mucosal diffusion assay on Nano-SB was undertaken in a porcine model. The antibacterial effects of the mixed nanoparticles (Nano-MIX) of Nano-SB and Nano-CHX at 9:1 (w/w) ratio were analyzed in both planktonic and biofilm modes of representative oral bacteria. The Nano-MIX was effective on the mono-species biofilms of Streptococcus (S.) mutans, S. sobrinus, Fusobacterium (F.) nucleatum, and Aggregatibacter (A.) actinomycetemcomitans (MIC 50 MUg/mL) at 24 h, and exhibited an enhanced effect against the multi-species biofilms such as S. mutans, F. nucleatum, A. actinomycetemcomitans, and Porphyromonas (P.) gingivalis (MIC 12.5 MUg/mL) at 24 h that was supported by the findings of both scanning electron microscopy (SEM) and confocal scanning laser microscopy (CLSM). This study shows enhanced synergistic antibacterial effects of the Nano-MIX on common oral bacterial biofilms, which could be potentially developed as a novel antimicrobial agent for clinical oral/periodontal care. PMID- 28335191 TI - Nanostructured Materials for Li-Ion Batteries and Beyond. AB - This Special Issue "Nanostructured Materials for Li-Ion Batteries and Beyond" of Nanomaterials is focused on advancements in the synthesis, optimization, and characterization of nanostructured materials, with an emphasis on the application of nanomaterials for building high performance Li-ion batteries (LIBs) and future systems.[...]. PMID- 28335192 TI - Morphology-Controlled High-Efficiency Small Molecule Organic Solar Cells without Additive Solvent Treatment. AB - This paper focuses on nano-morphology-controlled small-molecule organic solar cells without solvent treatment for high power-conversion efficiencies (PCEs). The maximum high PCE reaches up to 7.22% with a bulk-heterojunction (BHJ) thickness of 320 nm. This high efficiency was obtained by eliminating solvent additives such as 1,8-diiodooctane (DIO) to find an alternative way to control the domain sizes in the BHJ layer. Furthermore, the generalized transfer matrix method (GTMM) analysis has been applied to confirm the effects of applying a different thickness of BHJs for organic solar cells from 100 to 320 nm, respectively. Finally, the study showed an alternative way to achieve high PCE organic solar cells without additive solvent treatments to control the morphology of the bulk-heterojunction. PMID- 28335193 TI - Facile Synthesis of Gd-Functionalized Gold Nanoclusters as Potential MRI/CT Contrast Agents. AB - Multi-modal imaging plays a key role in the earlier detection of disease. In this work, a facile bioinspired method was developed to synthesize Gd-functionalized gold nanoclusters (Gd-Au NCs). The Gd-Au NCs exhibit a uniform size, with an average size of 5.6 nm in dynamic light scattering (DLS), which is a bit bigger than gold clusters (3.74 nm, DLS), while the fluorescent properties of Gd-Au NCs are almost the same as that of Au NCs. Moreover, the Gd-Au NCs exhibit a high longitudinal relaxivity value (r1) of 22.111 s-1 per mM of Gd in phosphate buffered saline (PBS), which is six times higher than that of commercial Magnevist (A complex of gadolinium with a chelating agent, diethylenetriamine penta-acetic acid, Gd-DTPA, r1 = 3.56 mM-1.s-1). Besides, as evaluated by nano single photon emission computed tomography (SPECT) and computed tomography (CT) the Gd-Au NCs have a potential application as CT contrast agents because of the Au element. Finally, the Gd-Au NCs show little cytotoxicity, even when the Au concentration is up to 250 MUM. Thus, the Gd-Au NCs can act as multi-modal imaging contrast agents. PMID- 28335194 TI - Automatic Echographic Detection of Halloysite Clay Nanotubes in a Low Concentration Range. AB - Aim of this work was to investigate the automatic echographic detection of an experimental drug delivery agent, halloysite clay nanotubes (HNTs), by employing an innovative method based on advanced spectral analysis of the corresponding "raw" radiofrequency backscatter signals. Different HNT concentrations in a low range (5.5-66 * 1010 part/mL, equivalent to 0.25-3.00 mg/mL) were dispersed in custom-designed tissue-mimicking phantoms and imaged through a clinically available echographic device at a conventional ultrasound diagnostic frequency (10 MHz). The most effective response (sensitivity = 60%, specificity = 95%), was found at a concentration of 33 * 1010 part/mL (1.5 mg/mL), representing a kind of best compromise between the need of enough particles to introduce detectable spectral modifications in the backscattered signal and the necessity to avoid the losses of spectral peculiarity associated to higher HNT concentrations. Based on theoretical considerations and quantitative comparisons with literature-available results, this concentration could also represent an optimal concentration level for the automatic echographic detection of different solid nanoparticles when employing a similar ultrasound frequency. Future dedicated studies will assess the actual clinical usefulness of the proposed approach and the potential of HNTs for effective theranostic applications. PMID- 28335195 TI - PMN-PT/PVDF Nanocomposite for High Output Nanogenerator Applications. AB - The 0.7Pb(Mg1/3Nb2/3)O3-0.3PbTiO3(0.7PMN-0.3PT) nanorods were obtained via hydrothermal method with high yield (over 78%). Then, new piezoelectric nanocomposites based on (1-x)Pb(Mg1/3Nb2/3)O3-xPbTiO3 (PMN-PT) nanorods were fabricated by dispersing the 0.7PMN-0.3PT nanorods into piezoelectric poly(vinylidene fluoride) (PVDF) polymer. The mechanical behaviors of the nanocomposites were investigated. The voltage and current generation of PMN PT/PVDF nanocomposites were also measured. The results showed that the tensile strength, yield strength, and Young's modulus of nanocomposites were enhanced as compared to that of the pure PVDF. The largest Young's modulus of 1.71 GPa was found in the samples with 20 wt % nanorod content. The maximum output voltage of 10.3 V and output current of 46 nA were obtained in the samples with 20 wt % nanorod content, which was able to provide a 13-fold larger output voltage and a 4.5-fold larger output current than that of pure PVDF piezoelectric polymer. The current density of PMN-PT/PVDF nanocomposites is 20 nA/cm2. The PMN-PT/PVDF nanocomposites exhibited great potential for flexible self-powered sensing applications. PMID- 28335196 TI - Gold Nanomaterial Uptake from Soil Is Not Increased by Arbuscular Mycorrhizal Colonization of Solanum Lycopersicum (Tomato). AB - Bioaccumulation of engineered nanomaterials (ENMs) by plants has been demonstrated in numerous studies over the past 5-10 years. However, the overwhelming majority of these studies were conducted using hydroponic systems and the degree to which the addition of the biological and chemical components present in the soil might fundamentally alter the potential of plant bioaccumulation of ENMs is unclear. Here, we used two genotypes of Solanum lycopersicum (tomato), reduced mycorrhizal colonization (rmc), a mutant which does not allow arbuscular mycorrhizal fungi (AMF) colonization, and its progenitor, 76R, to examine how colonization by AMF alters trends of gold ENM bioaccumulation from a natural soil. Gold was taken up and bioaccumulated by plants of both genotypes. Gold concentrations were significantly higher in the rmc treatment although this was likely attributable to the large differences in biomass between the 76R and rmc plants. Regardless, there was little evidence that AMF played a significant role in trafficking Au ENMs into the plants. Furthermore, despite very low NH4NO3 extractable Au concentrations, Au accumulated at the root-soil interface. Although this observation would seem to suggest that ENMs may have potential to influence this particularly biologically active and important soil compartment, we observed no evidence of this here, as the 76R plants developed a robust AMF symbiosis despite accumulation of Au ENMs at the rhizoplane. PMID- 28335197 TI - Cationic Nanoparticles Assembled from Natural-Based Steroid Lipid for Improved Intracellular Transport of siRNA and pDNA. AB - Developing new functional biomaterials from biocompatible natural-based resources for gene/drug delivery has attracted increasing attention in recent years. In this work, we prepared a series of cationic nanoparticles (Diosarg-DOPE NPs) by assembly of a natural steroid diosgenin-based cationic lipid (Diosarg) with commercially-available helper lipid 1,2-dioleoyl-sn-glycero-3 phosphorethanolamine (DOPE). These cationic Diosarg-DOPE NPs were able to efficiently bind siRNA and plasmid DNA (pDNA) via electrostatic interactions to form stable, nano-sized cationic lipid nanoparticles instead of lamellar vesicles in aqueous solution. The average particle size, zeta potentials and morphologies of the siRNA and pDNA complexes of the Diosarg-DOPE NPs were examined. The in vitro cytotoxicity of NPs depends on the dose and assembly ratio of the Diosarg and DOPE. Notably, the intracellular transportation efficacy of the exogenesis siRNA and pDNA could be greatly improved by using the Diosarg-DOPE NPs as the cargoes in H1299 cell line. The results demonstrated that the self-assembled Diosarg-DOPE NPs could achieve much higher intracellular transport efficiency for siRNA or pDNA than the cationic lipid Diosarg, indicating that the synergetic effect of different functional lipid components may benefit the development of high efficiency nano-scaled gene carriers. Moreover, it could be noted that the traditional "lysosome localization" involved in the intracellular trafficking of the Diosarg and Diosarg-DOPE NPs, indicating the co-assembly of helper lipid DOPE, might not significantly affect the intracellular localization features of the cationic lipids. PMID- 28335198 TI - Gold Nanoparticles: An Efficient Antimicrobial Agent against Enteric Bacterial Human Pathogen. AB - Enteric bacterial human pathogens, i.e., Escherichia coli, Staphylococcus aureus, Bacillus subtilis and Klebsiella pneumoniae, are the major cause of diarrheal infections in children and adults. Their structure badly affects the human immune system. It is important to explore new antibacterial agents instead of antibiotics for treatment. This project is an attempt to explain how gold nanoparticles affect these bacteria. We investigated the important role of the mean particle size, and the inhibition of a bacterium is dose-dependent. Ultra Violet (UV)-visible spectroscopy revealed the size of chemically synthesized gold nanoparticle as 6-40 nm. Atomic force microscopy (AFM) analysis confirmed the size and X-ray diffractometry (XRD) analysis determined the polycrystalline nature of gold nanoparticles. The present findings explained how gold nanoparticles lyse Gram-negative and Gram-positive bacteria. PMID- 28335199 TI - Highly-Efficient Plasmon-Enhanced Dye-Sensitized Solar Cells Created by Means of Dry Plasma Reduction. AB - Plasmon-assisted energy conversion is investigated in a comparative study of dye sensitized solar cells (DSCs) equipped with photo-anodes, which are fabricated by forming gold (Au) and silver (Ag) nanoparticles (NPs) on an fluorine-doped tin oxide (FTO) glass surface by means of dry plasma reduction (DPR) and coating TiO2 paste onto the modified FTO glass through a screen printing method. As a result, the FTO/Ag-NPs/TiO2 photo-anode showed an enhancement of its photocurrent, whereas the FTO/Au-NPs/TiO2 photo-anode showed less photocurrent than even a standard photo-anode fabricated by simply coating TiO2 paste onto the modified FTO glass through screen printing. This result stems from the small size and high areal number density of Au-NPs on FTO glass, which prevent the incident light from reaching the TiO2 layer. PMID- 28335200 TI - Structural and Magnetic Response in Bimetallic Core/Shell Magnetic Nanoparticles. AB - Bimagnetic monodisperse CoFe2O4/Fe3O4 core/shell nanoparticles have been prepared by solution evaporation route. To demonstrate preferential coating of iron oxide onto the surface of ferrite nanoparticles X-ray diffraction (XRD), High resolution transmission electron microscope (HR-TEM) and Raman spectroscopy have been performed. XRD analysis using Rietveld refinement technique confirms single phase nanoparticles with average seed size of about 18 nm and thickness of shell is 3 nm, which corroborates with transmission electron microscopy (TEM) analysis. Low temperature magnetic hysteresis loops showed interesting behavior. We have observed large coercivity 15.8 kOe at T = 5 K, whereas maximum saturation magnetization (125 emu/g) is attained at T = 100 K for CoFe2O4/Fe3O4 core/shell nanoparticles. Saturation magnetization decreases due to structural distortions at the surface of shell below 100 K. Zero field cooled (ZFC) and Field cooled (FC) plots show that synthesized nanoparticles are ferromagnetic till room temperature and it has been noticed that core/shell sample possess high blocking temperature than Cobalt Ferrite. Results indicate that presence of iron oxide shell significantly increases magnetic parameters as compared to the simple cobalt ferrite. PMID- 28335201 TI - Size- and Shape-Dependent Antibacterial Studies of Silver Nanoparticles Synthesized by Wet Chemical Routes. AB - Silver nanoparticles (AgNPs) of different shapes and sizes were prepared by solution-based chemical reduction routes. Silver nitrate was used as a precursor, tri-sodium citrate (TSC) and sodium borohydride as reducing agents, while polyvinylpyrrolidone (PVP) was used as a stabilizing agent. The morphology, size, and structural properties of obtained nanoparticles were characterized by scanning electron microscopy (SEM), UV-visible spectroscopy (UV-VIS), and X-ray diffraction (XRD) techniques. Spherical AgNPs, as depicted by SEM, were found to have diameters in the range of 15 to 90 nm while lengths of the edges of the triangular particles were about 150 nm. The characteristic surface plasmon resonance (SPR) peaks of different spherical silver colloids occurring in the wavelength range of 397 to 504 nm, whereas triangular particles showed two peaks, first at 392 nm and second at 789 nm as measured by UV-VIS. The XRD spectra of the prepared samples indicated the face-centered cubic crystalline structure of metallic AgNPs. The in vitro antibacterial properties of all synthesized AgNPs against two types of Gram-negative bacteria, Pseudomonas aeruginosa and Escherichia coli were examined by Kirby-Bauer disk diffusion susceptibility method. It was noticed that the smallest-sized spherical AgNPs demonstrated a better antibacterial activity against both bacterial strains as compared to the triangular and larger spherical shaped AgNPs. PMID- 28335202 TI - Versatile Production of Poly(Epsilon-Caprolactone) Fibers by Electrospinning Using Benign Solvents. AB - The electrospinning technique is widely used for the fabrication of micro- and nanofibrous structures. Recent studies have focused on the use of less toxic and harmful solvents (benign solvents) for electrospinning, even if those solvents usually require an accurate and longer process of optimization. The aim of the present work is to demonstrate the versatility of the use of benign solvents, like acetic acid and formic acid, for the fabrication of microfibrous and nanofibrous electrospun poly(epsilon-caprolactone) mats. The solvent systems were also shown to be suitable for the fabrication of electrospun structures with macroporosity, as well as for the fabrication of composite electrospun mats, fabricated by the addition of bioactive glass (45S5 composition) particles in the polymeric solution. PMID- 28335203 TI - Temperature-Dependent Magnetic Response of Antiferromagnetic Doping in Cobalt Ferrite Nanostructures. AB - In this work MnxCo1-xFe2O4 nanoparticles (NPs) were synthesized using a chemical co-precipitation method. Phase purity and structural analyses of synthesized NPs were performed by X-ray diffractometer (XRD). Transmission electron microscopy (TEM) reveals the presence of highly crystalline and narrowly-dispersed NPs with average diameter of 14 nm. The Fourier transform infrared (FTIR) spectrum was measured in the range of 400-4000 cm-1 which confirmed the formation of vibrational frequency bands associated with the entire spinel structure. Temperature-dependent magnetic properties in anti-ferromagnet (AFM) and ferromagnet (FM) structure were investigated with the aid of a physical property measurement system (PPMS). It was observed that magnetic interactions between the AFM (Mn) and FM (CoFe2O4) material arise below the Neel temperature of the dopant. Furthermore, hysteresis response was clearly pronounced for the enhancement in magnetic parameters by varying temperature towards absolute zero. It is shown that magnetic properties have been tuned as a function of temperature and an externally-applied field. PMID- 28335206 TI - Cytotoxic Induction and Photoacoustic Imaging of Breast Cancer Cells Using Astaxanthin-Reduced Gold Nanoparticles. AB - Astaxanthin, a kind of photosynthetic pigment, was employed for gold nanoparticle formation. Nanoparticles were characterized using Ulteraviolet-Visible (UV-Vis) spectroscopy, transmission electron microscopy, and X-ray diffraction, and the possible presence of astaxanthin functional groups were analyzed by Fourier transform infrared spectroscopy (FTIR). The cytotoxic effect of synthesized nanoparticles was evaluated against MDA-MB-231 (human breast cancer cells) using a tetrazolium-based assay, and synthesized nanoparticles exhibited dose-dependent toxicity. The morphology upon cell death was differentiated through fluorescent microscopy using different stains that predicted apoptosis. The synthesized nanoparticles were applied in ultrasound-coupled photoacoustic imaging to obtain good images of treated cells. Astaxanthin-reduced gold nanoparticle has the potential to act as a promising agent in the field of photo-based diagnosis and therapy. PMID- 28335207 TI - Synergistic Effect of Functionalized Nanokaolin Decorated MWCNTs on the Performance of Cellulose Acetate (CA) Membranes Spectacular. AB - In order to enhance salt rejection level and high pressure mechanical integrity, functionalized nanokaolin decorated multiwall carbon nanotubes (FNKM, 0-5 wt % loading) were incorporated into a cellulose acetate (CA) matrix using high temperature solution mixing methodology. Scanning electron microscopy (SEM), X ray diffraction technique (XRD), thermo-gravimetric analyzer (TGA) and Fourier transform infrared spectrometer (FTIR) were used to characterize the prepared membranes. The obtained results revealed that with increasing FNKM concentration in the host polymeric matrix, composite membrane's structural, functional, thermal, water permeation/flux and salt rejection characteristics were also modified accordingly. Percent enhancement in salt rejection was increased around threefold by adding 5 wt % FNKM in CA. PMID- 28335205 TI - Photosensitizer-Embedded Polyacrylonitrile Nanofibers as Antimicrobial Non-Woven Textile. AB - Toward the objective of developing platform technologies for anti-infective materials based upon photodynamic inactivation, we employed electrospinning to prepare a non-woven textile comprised of polyacrylonitrile nanofibers embedded with a porphyrin-based cationic photosensitizer; termed PAN-Por(+). Photosensitizer loading was determined to be 34.8 nmol/mg material; with thermostability to 300 degrees C. Antibacterial efficacy was evaluated against four bacteria belonging to the ESKAPE family of pathogens (Staphylococcus aureus; vancomycin-resistant Enterococcus faecium; Acinetobacter baumannii; and Klebsiella pneumonia), as well as Escherichia coli. Our results demonstrated broad photodynamic inactivation of all bacterial strains studied upon illumination (30 min; 65 +/- 5 mW/cm2; 400-700 nm) by a minimum of 99.9996+% (5.8 log units) regardless of taxonomic classification. PAN-Por(+) also inactivated human adenovirus-5 (~99.8% reduction in PFU/mL) and vesicular stomatitis virus (>7 log units reduction in PFU/mL). When compared to cellulose-based materials employing this same photosensitizer; the higher levels of photodynamic inactivation achieved here with PAN-Por(+) are likely due to the combined effects of higher photosensitizer loading and a greater surface area imparted by the use of nanofibers. These results demonstrate the potential of photosensitizer embedded polyacrylonitrile nanofibers to serve as scalable scaffolds for anti infective or self-sterilizing materials against both bacteria and viruses when employing a photodynamic inactivation mode of action. PMID- 28335204 TI - Multifunctional Inorganic Nanoparticles: Recent Progress in Thermal Therapy and Imaging. AB - Nanotechnology has enabled the development of many alternative anti-cancer approaches, such as thermal therapies, which cause minimal damage to healthy cells. Current challenges in cancer treatment are the identification of the diseased area and its efficient treatment without generating many side effects. Image-guided therapies can be a useful tool to diagnose and treat the diseased tissue and they offer therapy and imaging using a single nanostructure. The present review mainly focuses on recent advances in the field of thermal therapy and imaging integrated with multifunctional inorganic nanoparticles. The main heating sources for heat-induced therapies are the surface plasmon resonance (SPR) in the near infrared region and alternating magnetic fields (AMFs). The different families of inorganic nanoparticles employed for SPR- and AMF-based thermal therapies and imaging are described. Furthermore, inorganic nanomaterials developed for multimodal therapies with different and multi-imaging modalities are presented in detail. Finally, relevant clinical perspectives and the future scope of inorganic nanoparticles in image-guided therapies are discussed. PMID- 28335208 TI - The Influence of Fluorination on Nano-Scale Phase Separation and Photovoltaic Performance of Small Molecular/PC71BM Blends. AB - To investigate the fluorination influence on the photovoltaic performance of small molecular based organic solar cells (OSCs), six small molecules based on 2,1,3-benzothiadiazole (BT), and diketopyrrolopyrrole (DPP) as core and fluorinated phenyl (DFP) and triphenyl amine (TPA) as different terminal units (DFP-BT-DFP, DFP-BT-TPA, TPA-BT-TPA, DFP-DPP-DFP, DFP-DPP-TPA, and TPA-DPP-TPA) were synthesized. With one or two fluorinated phenyl as the end group(s), HOMO level of BT and DPP based small molecular donors were gradually decreased, inducing high open circuit voltage for fluorinated phenyl based OSCs. DFP-BT-TPA and DFP-DPP-TPA based blend films both displayed stronger nano-scale aggregation in comparison to TPA-BT-TPA and TPA-DPP-TPA, respectively, which would also lead to higher hole motilities in devices. Ultimately, improved power conversion efficiency (PCE) of 2.17% and 1.22% was acquired for DFP-BT-TPA and DFP-DPP-TPA based devices, respectively. These results demonstrated that the nano-scale aggregation size of small molecules in photovoltaic devices could be significantly enhanced by introducing a fluorine atom at the donor unit of small molecules, which will provide understanding about the relationship of chemical structure and nano-scale phase separation in OSCs. PMID- 28335209 TI - Dye-Doped Fluorescent Silica Nanoparticles for Live Cell and In Vivo Bioimaging. AB - The need for novel design strategies for fluorescent nanomaterials to improve our understanding of biological activities at the molecular level is increasing rapidly. Dye-doped fluorescent silica nanoparticles (SiNPs) emerge with great potential for developing fluorescence imaging techniques as a novel and ideal platform for the monitoring of living cells and the whole body. Organic dye containing fluorescent SiNPs exhibit many advantages: they have excellent biocompatibility, are non-toxic, highly hydrophilic, optically transparent, size tunable and easily modified with various biomolecules. The outer silica shell matrix protects fluorophores from outside chemical reaction factors and provides a hydrophilic shell for the insoluble nanoparticles, which enhances the photo stability and biocompatibility of the organic fluorescent dyes. Here, we give a summary of the synthesis, characteristics and applications of fluorescent SiNPs for non-invasive fluorescence bioimaging in live cells and in vivo. Additionally, the challenges and perspectives of SiNPs are also discussed. We prospect that the further development of these nanoparticles will lead to an exciting breakthrough in the understanding of biological processes. PMID- 28335210 TI - Application of L-Aspartic Acid-Capped ZnS:Mn Colloidal Nanocrystals as a Photosensor for the Detection of Copper (II) Ions in Aqueous Solution. AB - Water-dispersible ZnS:Mn nanocrystals (NCs) were synthesized by capping the surface with polar L-aspartic acid (Asp) molecules. The obtained ZnS:Mn-Asp NC product was optically and physically characterized using the corresponding spectroscopic methods. The ultra violet-visible (UV-VIS) absorption spectrum and photoluminescence (PL) emission spectrum of the NCs showed broad peaks at 320 and 590 nm, respectively. The average particle size measured from the obtained high resolution-transmission electron microscopy (HR-TEM) image was 5.25 nm, which was also in accordance with the Debye-Scherrer calculations using the X-ray diffraction (XRD) data. Moreover, the surface charge and degree of aggregation of the ZnS:Mn-Asp NCs were determined by electrophoretic and hydrodynamic light scattering methods, respectively. These results indicated the formation of agglomerates in water with an average size of 19.8 nm, and a negative surface charge (-4.58 mV) in water at ambient temperature. The negatively-charged NCs were applied as a photosensor for the detection of specific cations in aqueous solution. Accordingly, the ZnS:Mn-Asp NCs showed an exclusive luminescence quenching upon addition of copper (II) cations. The kinetic mechanism study on the luminescence quenching of the NCs by the addition of the Cu2+ ions proposed an energy transfer through the ionic binding between the two oppositely-charged ZnS:Mn-Asp NCs and Cu2+ ions. PMID- 28335211 TI - Noise Removal with Maintained Spatial Resolution in Raman Images of Cells Exposed to Submicron Polystyrene Particles. AB - The biodistribution of 300 nm polystyrene particles in A549 lung epithelial cells has been studied with confocal Raman spectroscopy. This is a label-free method in which particles and cells can be imaged without using dyes or fluorescent labels. The main drawback with Raman imaging is the comparatively low spatial resolution, which is aggravated in heterogeneous systems such as biological samples, which in addition often require long measurement times because of their weak Raman signal. Long measurement times may however induce laser-induced damage. In this study we use a super-resolution algorithm with Tikhonov regularization, intended to improve the image quality without demanding an increased number of collected pixels. Images of cells exposed to polystyrene particles have been acquired with two different step lengths, i.e., the distance between pixels, and compared to each other and to corresponding images treated with the super-resolution algorithm. It is shown that the resolution after application of super-resolution algorithms is not significantly improved compared to the theoretical limit for optical microscopy. However, to reduce noise and artefacts in the hyperspectral Raman images while maintaining the spatial resolution, we show that it is advantageous to use short mapping step lengths and super-resolution algorithms with appropriate regularization. The proposed methodology should be generally applicable for Raman imaging of biological samples and other photo-sensitive samples. PMID- 28335212 TI - Rapid Nanoparticle Synthesis by Magnetic and Microwave Heating. AB - Traditional hot-injection (HI) syntheses of colloidal nanoparticles (NPs) allows good separation of the nucleation and growth stages of the reaction, a key limitation in obtaining monodisperse NPs, but with limited scalability. Here, two methods are presented for obtaining NPs via rapid heating: magnetic and microwave assisted. Both of these techniques provide improved engineering control over the separation of nucleation and growth stages of nanomaterial synthesis when the reaction is initiated from room temperature. The advantages of these techniques with preliminary data are presented in this prospective article. It is shown here that microwave assisted heating could possibly provide some selectivity in activating the nanomaterial precursor materials, while magnetic heating can produce very tiny particles in a very short time (even on the millisecond timescale), which is important for scalability. The fast magnetic heating also allows for synthesizing larger particles with improved size distribution, therefore impacting, not only the quantity, but the quality of the nanomaterials. PMID- 28335213 TI - Biosynthesis of Metal Nanoparticles: Novel Efficient Heterogeneous Nanocatalysts. AB - This review compiles the most recent advances described in literature on the preparation of noble metal nanoparticles induced by biological entities. The use of different free or substituted carbohydrates, peptides, proteins, microorganisms or plants have been successfully applied as a new green concept in the development of innovative strategies to prepare these nanoparticles as different nanostructures with different forms and sizes. As a second part of this review, the application of their synthetic ability as new heterogonous catalysts has been described in C-C bond-forming reactions (as Suzuki, Heck, cycloaddition or multicomponent), oxidations and dynamic kinetic resolutions. PMID- 28335214 TI - Graphene FETs with Low-Resistance Hybrid Contacts for Improved High Frequency Performance. AB - This work proposes a novel geometry field effect transistor with graphene as a channel-graphene field-effect transistor (GFET), having a hybrid contact that consists of an ohmic source/drain and its extended part towards the gate, which is capacitively coupled to the channel. The ohmic contacts are used for direct current (DC) biasing, whereas their capacitive extension reduces access region length and provides the radio frequency (RF) signal a low impedance path. Minimization of the access region length, along with the paralleling of ohmic contact's resistance and resistive part of capacitively coupled contact's impedance, lower the overall source/drain resistance, which results in an increase in current gain cut-off frequency, fT. The DC and high-frequency characteristics of the two chosen conventional baseline GFETs, and their modified versions with proposed hybrid contacts, have been extensively studied, compared, and analyzed using numerical and analytical techniques. PMID- 28335216 TI - Investigation of the Structural, Electrical, and Optical Properties of the Nano Scale GZO Thin Films on Glass and Flexible Polyimide Substrates. AB - In this study, Ga2O3-doped ZnO (GZO) thin films were deposited on glass and flexible polyimide (PI) substrates at room temperature (300 K), 373 K, and 473 K by the radio frequency (RF) magnetron sputtering method. After finding the deposition rate, all the GZO thin films with a nano-scale thickness of about 150 +/- 10 nm were controlled by the deposition time. X-ray diffraction patterns indicated that the GZO thin films were not amorphous and all exhibited the (002) peak, and field emission scanning electron microscopy showed that only nano-scale particles were observed. The dependences of the structural, electrical, and optical properties of the GZO thin films on different deposition temperatures and substrates were investigated. X-ray photoemission spectroscopy (XPS) was used to measure the elemental composition at the chemical and electronic states of the GZO thin films deposited on different substrates, which could be used to clarify the mechanism of difference in electrical properties of the GZO thin films. In this study, the XPS binding energy spectra of Ga2p3/2 and Ga2p1/2 peaks, Zn2p3/2 and Zn2p1/2 peaks, the Ga3d peak, and O1s peaks for GZO thin films on glass and PI substrates were well compared. PMID- 28335215 TI - Rapamycin Loaded Solid Lipid Nanoparticles as a New Tool to Deliver mTOR Inhibitors: Formulation and in Vitro Characterization. AB - Recently, the use of mammalian target of rapamycin (mTOR) inhibitors, in particular rapamycin (Rp), has been suggested to improve the treatment of neurodegenerative diseases. However, as Rp is a strong immunosuppressant, specific delivery to the brain has been postulated to avoid systemic exposure. In this work, we fabricated new Rp loaded solid lipid nanoparticles (Rp-SLN) stabilized with polysorbate 80 (PS80), comparing two different methods and lipids. The formulations were characterized by differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), wide angle X-ray scattering (WAXS), cryo transmission electron microscopy (cryo-TEM), dynamic light scattering (DLS) and particle tracking. In vitro release and short-term stability were assessed. Biological behavior of Rp-SLN was tested in SH-SY5Y neuroblastoma cells. The inhibition of mTOR complex 1 (mTORC1) was evaluated over time by a pulse-chase study compared to free Rp and Rp nanocrystals. Compritol Rp-SLN resulted more stable and possessing proper size and surface properties with respect to cetyl palmitate Rp-SLN. Rapamycin was entrapped in an amorphous form in the solid lipid matrix that showed partial crystallinity with stable Lbeta, sub-Lalpha and Lbeta' arrangements. PS80 was stably anchored on particle surface. No drug release was observed over 24 h and Rp-SLN had a higher cell uptake and a more sustained effect over a week. The mTORC1 inhibition was higher with Rp-SLN. Overall, compritol Rp-SLN show suitable characteristics and stability to be considered for further investigation as Rp brain delivery system. PMID- 28335217 TI - Modification of the Interfacial Interaction between Carbon Fiber and Epoxy with Carbon Hybrid Materials. AB - The mechanical properties of the hybrid materials and epoxy and carbon fiber (CF) composites were improved significantly as compared to the CF composites made from unmodified epoxy. The reasons could be attributed to the strong interfacial interaction between the CF and the epoxy composites for the existence of carbon nanomaterials. The microstructure and dispersion of carbon nanomaterials were characterized by transmission electron microscopy (TEM) and optical microscopy (OM). The results showed that the dispersion of the hybrid materials in the polymer was superior to other carbon nanomaterials. The high viscosity and shear stress characterized by a rheometer and the high interfacial friction and damping behavior characterized by dynamic mechanical analysis (DMA) indicated that the strong interfacial interaction was greatly improved between fibers and epoxy composites. Remarkably, the tensile tests presented that the CF composites with hybrid materials and epoxy composites have a better reinforcing and toughening effect on CF, which further verified the strong interfacial interaction between epoxy and CF for special structural hybrid materials. PMID- 28335218 TI - Aggregation and Colloidal Stability of Commercially Available Al2O3 Nanoparticles in Aqueous Environments. AB - The aggregation and colloidal stability of three, commercially-available, gamma aluminum oxide nanoparticles (gamma-Al2O3 NPs) (nominally 5, 10, and 20-30 nm) were systematically examined as a function of pH, ionic strength, humic acid (HA) or clay minerals (e.g., montmorillonite) concentration using dynamic light scattering and transmission electron microscopy techniques. NPs possess pH dependent surface charges, with a point of zero charge (PZC) of pH 7.5 to 8. When pH < PZC, gamma-Al2O3 NPs are colloidally stable up to 100 mM NaCl and 30 mM CaCl2. However, significant aggregation of NPs is pronounced in both electrolytes at high ionic strength. In mixed systems, both HA and montmorillonite enhance NP colloidal stability through electrostatic interactions and steric hindrance when pH <= PZC, whereas their surface interactions are quite limited when pH > PZC. Even when pH approximates PZC, NPs became stable at a HA concentration of 1 mg.L 1. The magnitude of interactions and dominant sites of interaction (basal planes versus edge sites) are significantly dependent on pH because both NPs and montmorillonite have pH-dependent (conditional) surface charges. Thus, solution pH, ionic strength, and the presence of natural colloids greatly modify the surface conditions of commercial gamma-Al2O3 NPs, affecting aggregation and colloidal stability significantly in the aqueous environment. PMID- 28335219 TI - Post-Plasma SiOx Coatings of Metal and Metal Oxide Nanoparticles for Enhanced Thermal Stability and Tunable Photoactivity Applications. AB - The plasma-based aerosol process developed for the direct coating of particles in gases with silicon oxide in a continuous chemical vapor deposition (CVD) process is presented. It is shown that non-thermal plasma filaments induced in a dielectric barrier discharge (DBD) at atmospheric pressure trigger post-DBD gas phase reactions. DBD operating conditions are first scanned to produce ozone and dinitrogen pentoxide. In the selected conditions, these plasma species react with gaseous tetraethyl orthosilicate (TEOS) precursor downstream of the DBD. The gaseous intermediates then condense on the surface of nanoparticles and self reactions lead to homogeneous solid SiOx coatings, with thickness from nanometer to micrometer. This confirms the interest of post-DBD injection of the organo silicon precursor to achieve stable production of actives species with subsequent controlled thickness of SiOx coatings. SiOx coatings of spherical and agglomerated metal and metal oxide nanoparticles (Pt, CuO, TiO2) are achieved. In the selected DBD operating conditions, the thickness of homogeneous nanometer sized coatings of spherical nanoparticles depends on the reaction duration and on the precursor concentration. For agglomerates, operating conditions can be tuned to cover preferentially the interparticle contact zones between primary particles, shifting the sintering of platinum agglomerates to much higher temperatures than the usual sintering temperature. Potential applications for enhanced thermal stability and tunable photoactivity of coated agglomerates are presented. PMID- 28335220 TI - PDE5 Inhibitors-Loaded Nanovesicles: Physico-Chemical Properties and In Vitro Antiproliferative Activity. AB - Novel therapeutic approaches are required for the less differentiated thyroid cancers which are non-responsive to the current treatment. In this study we tested an innovative formulation of nanoliposomes containing sildenafil citrate or tadalafil, phosphodiesterase-5 inhibitors, on two human thyroid cancer cell lines (TPC-1 and BCPAP). Nanoliposomes were prepared by the thin layer evaporation and extrusion methods, solubilizing the hydrophilic compound sildenafil citrate in the aqueous phase during the hydration step and dissolving the lipophilic tadalafil in the organic phase. Nanoliposomes, made up of 1,2 dipalmitoyl-sn-glycero-3-phosphatidylcholine monohydrate (DPPC), cholesterol, and N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-3 phosphoethanolamine (DSPE-mPEG2000) (6:3:1 molar ratio), were characterized by a mean diameter of ~100 nm, a very low polydispersity index (~0.1) and a negative surface charge. The drugs did not influence the physico-chemical properties of the systems and were efficiently retained in the colloidal structure. By using cell count and MTT assay, we found a significant reduction of the viability in both cell lines following 24 h treatment with both nanoliposomal-encapsulated drugs, notably greater than the effect of the free drugs. Our findings demonstrate that nanoliposomes increase the antiproliferative activity of phosphodiesterase-5 inhibitors, providing a useful novel formulation for the treatment of thyroid carcinoma. PMID- 28335221 TI - Mechanochemical Synthesis of TiO2 Nanocomposites as Photocatalysts for Benzyl Alcohol Photo-Oxidation. AB - TiO2 (anatase phase) has excellent photocatalytic performance and different methods have been reported to overcome its main limitation of high band gap energy. In this work, TiO2-magnetically-separable nanocomposites (MAGSNC) photocatalysts with different TiO2 loading were synthesized using a simple one pot mechanochemical method. Photocatalysts were characterized by a number of techniques and their photocatalytic activity was tested in the selective oxidation of benzyl alcohol to benzaldehyde. Extension of light absorption into the visible region was achieved upon titania incorporation. Results indicated that the photocatalytic activity increased with TiO2 loading on the catalysts, with moderate conversion (20%) at high benzaldehyde selectivity (84%) achieved for 5% TiO2-MAGSNC. These findings pointed out a potential strategy for the valorization of lignocellulosic-based biomass under visible light irradiation using designer photocatalytic nanomaterials. PMID- 28335222 TI - Effects of Atomization Injection on Nanoparticle Processing in Suspension Plasma Spray. AB - Liquid atomization is applied in nanostructure dense coating technology to inject suspended nano-size powder materials into a suspension plasma spray (SPS) torch. This paper presents the effects of the atomization parameters on the nanoparticle processing. A numerical model was developed to simulate the dynamic behaviors of the suspension droplets, the solid nanoparticles or agglomerates, as well as the interactions between them and the plasma gas. The plasma gas was calculated as compressible, multi-component, turbulent jet flow in Eulerian scheme. The droplets and the solid particles were calculated as discrete Lagrangian entities, being tracked through the spray process. The motion and thermal histories of the particles were given in this paper and their release and melting status were observed. The key parameters of atomization, including droplet size, injection angle and velocity were also analyzed. The study revealed that the nanoparticle processing in SPS preferred small droplets with better atomization and less aggregation from suspension preparation. The injection angle and velocity influenced the nanoparticle release percentage. Small angle and low initial velocity might have more nanoparticles released. Besides, the melting percentage of nanoparticles and agglomerates were studied, and the critical droplet diameter to ensure solid melting was drawn. Results showed that most released nanoparticles were well melted, but the agglomerates might be totally melted, partially melted, or even not melted at all, mainly depending on the agglomerate size. For better coating quality, the suspension droplet size should be limited to a critical droplet diameter, which was inversely proportional to the cubic root of weight content, for given critical agglomerate diameter of being totally melted. PMID- 28335223 TI - Ultraviolet Plasmonic Aluminium Nanoparticles for Highly Efficient Light Incoupling on Silicon Solar Cells. AB - Plasmonic metal nanoparticles supporting localized surface plasmon resonances have attracted a great deal of interest in boosting the light absorption in solar cells. Among the various plasmonic materials, the aluminium nanoparticles recently have become a rising star due to their unique ultraviolet plasmonic resonances, low cost, earth-abundance and high compatibility with the complementary metal-oxide semiconductor (CMOS) manufacturing process. Here, we report some key factors that determine the light incoupling of aluminium nanoparticles located on the front side of silicon solar cells. We first numerically study the scattering and absorption properties of the aluminium nanoparticles and the influence of the nanoparticle shape, size, surface coverage and the spacing layer on the light incoupling using the finite difference time domain method. Then, we experimentally integrate 100-nm aluminium nanoparticles on the front side of silicon solar cells with varying silicon nitride thicknesses. This study provides the fundamental insights for designing aluminium nanoparticle-based light trapping on solar cells. PMID- 28335224 TI - Structural Changes Induced in Grapevine (Vitis vinifera L.) DNA by Femtosecond IR Laser Pulses: A Surface-Enhanced Raman Spectroscopic Study. AB - In this work, surface-enhanced Raman spectra of ten genomic DNAs extracted from leaf tissues of different grapevine (Vitis vinifera L.) varieties, respectively, are analyzed in the wavenumber range 300-1800 cm-1. Furthermore, structural changes induced in grapevine genomic nucleic acids upon femtosecond (170 fs) infrared (IR) laser pulse irradiation (lambda = 1100 nm) are discussed in detail for seven genomic DNAs, respectively. Surface-enhanced Raman spectroscopy (SERS) signatures, vibrational band assignments and structural characterization of genomic DNAs are reported for each case. As a general observation, the wavenumber range between 1500 and 1660 cm-1 of the spectra seems to be modified upon laser treatment. This finding could reflect changes in the base-stacking interactions in DNA. Spectral shifts are mainly attributed to purines (dA, dG) and deoxyribose. Pyrimidine residues seem to be less affected by IR femtosecond laser pulse irradiation. Furthermore, changes in the conformational properties of nucleic acid segments are observed after laser treatment. We have found that DNA isolated from Feteasca Neagra grapevine leaf tissues is the most structurally responsive system to the femtosecond IR laser irradiation process. In addition, using unbiased computational resources by means of principal component analysis (PCA), eight different grapevine varieties were discriminated. PMID- 28335225 TI - Enhancing the Photocurrent of Top-Cell by Ellipsoidal Silver Nanoparticles: Towards Current-Matched GaInP/GaInAs/Ge Triple-Junction Solar Cells. AB - A way to increase the photocurrent of top-cell is crucial for current-matched and highly-efficient GaInP/GaInAs/Ge triple-junction solar cells. Herein, we demonstrate that ellipsoidal silver nanoparticles (Ag NPs) with better extinction performance and lower fabrication temperature can enhance the light harvest of GaInP/GaInAs/Ge solar cells compared with that of spherical Ag NPs. In this method, appropriate thermal treatment parameters for Ag NPs without inducing the dopant diffusion of the tunnel-junction plays a decisive role. Our experimental and theoretical results confirm the ellipsoidal Ag NPs annealed at 350 degrees C show a better extinction performance than the spherical Ag NPs annealed at 400 degrees C. The photovoltaic conversion efficiency of the device with ellipsoidal Ag NPs reaches 31.02%, with a nearly 5% relative improvement in comparison with the device without Ag NPs (29.54%). This function of plasmonic NPs has the potential to solve the conflict of sufficient light absorption and efficient carrier collection in GaInP top-cell devices. PMID- 28335227 TI - Synthesis of Ball-Like Ag Nanorod Aggregates for Surface-Enhanced Raman Scattering and Catalytic Reduction. AB - In this work, ball-like Ag nanorod aggregates have been synthesized via a simple seed-mediated method. These Ag mesostructures were characterized by scanning electron microscope (SEM), transmission electron microscopy (TEM), ultraviolet visible spectroscopy (UV-Vis), and X-ray diffraction (XRD). Adding a certain amount of polyvinyl pyrrolidone (PVP) can prolong its coagulation time. These Ag nanorod aggregates exhibit effective SERS effect, evaluated by Rhodamine 6G (R6G) and doxorubicin (DOX) as probe molecules. The limit of detection (LOD) for R6G and DOX are as low as 5 * 10-9 M and 5 * 10-6 M, respectively. Moreover, these Ag nanorod aggregates were found to be potential catalysts for the reduction of 4 nitrophenol (4-NP) in the presence of NaBH4. PMID- 28335226 TI - Improving the Photocurrent in Quantum-Dot-Sensitized Solar Cells by Employing Alloy PbxCd1-xS Quantum Dots as Photosensitizers. AB - Ternary alloy PbxCd1-xS quantum dots (QDs) were explored as photosensitizers for quantum-dot-sensitized solar cells (QDSCs). Alloy PbxCd1-xS QDs (Pb0.54Cd0.46S, Pb0.31Cd0.69S, and Pb0.24Cd0.76S) were found to substantially improve the photocurrent of the solar cells compared to the single CdS or PbS QDs. Moreover, it was found that the photocurrent increases and the photovoltage decreases when the ratio of Pb in PbxCd1-xS is increased. Without surface protecting layer deposition, the highest short-circuit current density reaches 20 mA/cm2 under simulated AM 1.5 illumination (100 mW/cm2). After an additional CdS coating layer was deposited onto the PbxCd1-xS electrode, the photovoltaic performance further improved, with a photocurrent of 22.6 mA/cm2 and an efficiency of 3.2%. PMID- 28335229 TI - TiAl3-TiN Composite Nanoparticles Produced by Hydrogen Plasma-Metal Reaction: Synthesis, Passivation, and Characterization. AB - TiAl3 and TiN composite nanoparticles were continuously synthesized from Ti-48Al master alloy by hydrogen plasma-metal reaction in a N2, H2 and Ar atmosphere. The phase, morphology, and size of the nanoparticles were studied by X-ray diffraction (XRD) and transmission electronic microscopy (TEM). X-ray photoelectron spectroscopy (XPS) and evolved gas analysis (EGA) were used to analyze the surface phase constitution and oxygen content of the nanoparticles. The as-synthesized nanopowders were mainly composed of nearly spherical TiAl3 and tetragonal TiN phases, with a mean diameter of ~42 nm and mass fractions of 49.1% and 24.3%, respectively. Passivation in the atmosphere of Ar and O2 for 24 h at room temperature led to the formation of amorphous Al2O3 shells on the TiAl3 particle surface, with a mean thickness of ~5.0 nm and a mass fraction of ~23.5%, as well as TiO2 with a mass fraction of ~3.2%. PMID- 28335228 TI - Fabricating Water Dispersible Superparamagnetic Iron Oxide Nanoparticles for Biomedical Applications through Ligand Exchange and Direct Conjugation. AB - Stable superparamagnetic iron oxide nanoparticles (SPIONs), which can be easily dispersed in an aqueous medium and exhibit high magnetic relaxivities, are ideal candidates for biomedical applications including contrast agents for magnetic resonance imaging. We describe a versatile methodology to render water dispersibility to SPIONs using tetraethylene glycol (TEG)-based phosphonate ligands, which are easily introduced onto SPIONs by either a ligand exchange process of surface-anchored oleic-acid (OA) molecules or via direct conjugation. Both protocols confer good colloidal stability to SPIONs at different NaCl concentrations. A detailed characterization of functionalized SPIONs suggests that the ligand exchange method leads to nanoparticles with better magnetic properties but higher toxicity and cell death, than the direct conjugation methodology. PMID- 28335230 TI - Fluorescent Nanocomposite of Embedded Ceria Nanoparticles in Crosslinked PVA Electrospun Nanofibers. AB - This paper introduces a new fluorescent nanocomposite of electrospun biodegradable nanofibers embedded with optical nanoparticles. In detail, this work introduces the fluorescence properties of PVA nanofibers generated by the electrospinning technique with embedded cerium oxide (ceria) nanoparticles. Under near-ultra violet excitation, the synthesized nanocomposite generates a visible fluorescent emission at 520 nm, varying its intensity peak according to the concentration of in situ embedded ceria nanoparticles. This is due to the fact that the embedded ceria nanoparticles have optical tri-valiant cerium ions, associated with formed oxygen vacancies, with a direct allowed bandgap around 3.5 eV. In addition, the impact of chemical crosslinking of the PVA on the fluorescence emission is studied in both cases of adding ceria nanoparticles in situ or of a post-synthesis addition via a spin-coating mechanism. Other optical and structural characteristics such as absorbance dispersion, direct bandgap, FTIR spectroscopy, and SEM analysis are presented. The synthesized optical nanocomposite could be helpful in different applications such as environmental monitoring and bioimaging. PMID- 28335231 TI - Enhanced Activity of Supported Ni Catalysts Promoted by Pt for Rapid Reduction of Aromatic Nitro Compounds. AB - To improve the activities of non-noble metal catalysts is highly desirable and valuable to the reduced use of noble metal resources. In this work, the supported nickel (Ni) and nickel-platinum (NiPt) nanocatalysts were derived from a layered double hydroxide/carbon composite precursor. The catalysts were characterized and the role of Pt was analysed using X-ray diffraction (XRD), high-resolution transmission electron microscopy (HRTEM), energy dispersive X-ray spectroscopy (EDS) mapping, and X-ray photoelectron spectroscopy (XPS) techniques. The Ni2+ was reduced to metallic Ni0 via a self-reduction way utilizing the carbon as a reducing agent. The average sizes of the Ni particles in the NiPt catalysts were smaller than that in the supported Ni catalyst. The electronic structure of Ni was affected by the incorporation of Pt. The optimal NiPt catalysts exhibited remarkably improved activity toward the reduction of nitrophenol, which has an apparent rate constant (Ka) of 18.82 * 10-3 s-1, 6.2 times larger than that of Ni catalyst and also larger than most of the reported values of noble-metal and bimetallic catalysts. The enhanced activity could be ascribed to the modification to the electronic structure of Ni by Pt and the effect of exposed crystal planes. PMID- 28335232 TI - The Influence of Modified Silica Nanomaterials on Adult Stem Cell Culture. AB - The preparation of tailored nanomaterials able to support cell growth and viability is mandatory for tissue engineering applications. In the present work, silica nanoparticles were prepared by a sol-gel procedure and were then functionalized by condensation of amino groups and by adsorption of silver nanoparticles. Transmission electron microscopy (TEM) imaging was used to establish the morphology and the average dimensions of about 130 nm, which were not affected by the functionalization. The three silica samples were deposited (1 mg/mL) on cover glasses, which were used as a substrate to culture adult human bone marrow-mesenchymal stem cells (hBM-MSCs) and human adipose-derived stem cells (hASCs). The good cell viability over the different silica surfaces was evaluated by monitoring the mitochondrial dehydrogenase activity. The analysis of the morphological parameters (aspect ratio, cell length, and nuclear shape Index) yielded information about the interactions of stem cells with the surface of three different nanoparticles. The data are discussed in terms of chemical properties of the surface of silica nanoparticles. PMID- 28335233 TI - Nanoparticles in Bioimaging. AB - This Special Issue of Nanomaterials is dedicated to the application of nanoparticulate materials in biological imaging.[...]. PMID- 28335234 TI - Fe3+-Doped TiO2 Nanotube Arrays on Ti-Fe Alloys for Enhanced Photoelectrocatalytic Activity. AB - Highly ordered, vertically oriented Fe3+-doped TiO2 nanotube arrays (Fe-TNTs) were prepared on Ti-Fe alloy substrates with different Fe contents by the electrochemical anodization method. The as-prepared Fe-TNTs were characterized by scanning electron microscope (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and related electrochemical techniques. XPS results demonstrated that Fe3+ ions were successfully doped into TiO2 nanotubes. The photoelectrochemical activity of Fe TNTs was compared with that of pure TiO2 nanotube arrays (TNTs). The results showed that Fe-TNTs grown on low concentration (0.5 wt %-1 wt % Fe) Ti-Fe alloys possessed higher photocurrent density than TNTs. The Fe-TNTs grown on Ti-Fe alloy containing 0.8 wt % Fe exhibited the highest photoelectrochemical activity and the photoelectrocatalytic degradation rate of methylene blue (MB) aqueous solution was significantly higher than that of TNTs. PMID- 28335235 TI - Engineered Nanomaterials in the Environment. AB - This Special Issue of Nanomaterials, "Engineered Nanomaterials in the Environment", is comprised of one communication and five research articles.[...]. PMID- 28335236 TI - Complex-Morphology Metal-Based Nanostructures: Fabrication, Characterization, and Applications. AB - Due to their peculiar qualities, metal-based nanostructures have been extensively used in applications such as catalysis, electronics, photography, and information storage, among others. New applications for metals in areas such as photonics, sensing, imaging, and medicine are also being developed. Significantly, most of these applications require the use of metals in the form of nanostructures with specific controlled properties. The properties of nanoscale metals are determined by a set of physical parameters that include size, shape, composition, and structure. In recent years, many research fields have focused on the synthesis of nanoscale-sized metallic materials with complex shape and composition in order to optimize the optical and electrical response of devices containing metallic nanostructures. The present paper aims to overview the most recent results-in terms of fabrication methodologies, characterization of the physico-chemical properties and applications-of complex-morphology metal-based nanostructures. The paper strongly focuses on the correlation between the complex morphology and the structures' properties, showing how the morphological complexity (and its nanoscale control) can often give access to a wide range of innovative properties exploitable for innovative functional device production. We begin with an overview of the basic concepts on the correlation between structural and optical parameters of nanoscale metallic materials with complex shape and composition, and the possible solutions offered by nanotechnology in a large range of applications (catalysis, electronics, photonics, sensing). The aim is to assess the state of the art, and then show the innovative contributions that can be proposed in this research field. We subsequently report on innovative, versatile and low-cost synthesis techniques, suitable for providing a good control on the size, surface density, composition and geometry of the metallic nanostructures. The main purpose of this study is the fabrication of functional nanoscale-sized materials, whose properties can be tailored (in a wide range) simply by controlling the structural characteristics. The modulation of the structural parameters is required to tune the plasmonic properties of the nanostructures for applications such as biosensors, opto-electronic or photovoltaic devices and surface-enhanced Raman scattering (SERS) substrates. The structural characterization of the obtained nanoscale materials is employed in order to define how the synthesis parameters affect the structural characteristics of the resulting metallic nanostructures. Then, macroscopic measurements are used to probe their electrical and optical properties. Phenomenological growth models are drafted to explain the processes involved in the growth and evolution of such composite systems. After the synthesis and characterization of the metallic nanostructures, we study the effects of the incorporation of the complex morphologies on the optical and electrical responses of each specific device. PMID- 28335237 TI - DNA Sequencing by Hexagonal Boron Nitride Nanopore: A Computational Study. AB - The single molecule detection associated with DNA sequencing has motivated intensive efforts to identify single DNA bases. However, little research has been reported utilizing single-layer hexagonal boron nitride (hBN) for DNA sequencing. Here we employ molecular dynamics simulations to explore pathways for single strand DNA (ssDNA) sequencing by nanopore on the hBN sheet. We first investigate the adhesive strength between nucleobases and the hBN sheet, which provides the foundation for the hBN-base interaction and nanopore sequencing mechanism. Simulation results show that the purine base has a more remarkable energy profile and affinity than the pyrimidine base on the hBN sheet. The threading of ssDNA through the hBN nanopore can be clearly identified due to their different energy profiles and conformations with circular nanopores on the hBN sheet. The sequencing process is orientation dependent when the shape of the hBN nanopore deviates from the circle. Our results open up a promising avenue to explore the capability of DNA sequencing by hBN nanopore. PMID- 28335238 TI - Selective Plasma Etching of Polymeric Substrates for Advanced Applications. AB - In today's nanoworld, there is a strong need to manipulate and process materials on an atom-by-atom scale with new tools such as reactive plasma, which in some states enables high selectivity of interaction between plasma species and materials. These interactions first involve preferential interactions with precise bonds in materials and later cause etching. This typically occurs based on material stability, which leads to preferential etching of one material over other. This process is especially interesting for polymeric substrates with increasing complexity and a "zoo" of bonds, which are used in numerous applications. In this comprehensive summary, we encompass the complete selective etching of polymers and polymer matrix micro-/nanocomposites with plasma and unravel the mechanisms behind the scenes, which ultimately leads to the enhancement of surface properties and device performance. PMID- 28335239 TI - A Flexible 360-Degree Thermal Sound Source Based on Laser Induced Graphene. AB - A flexible sound source is essential in a whole flexible system. It's hard to integrate a conventional sound source based on a piezoelectric part into a whole flexible system. Moreover, the sound pressure from the back side of a sound source is usually weaker than that from the front side. With the help of direct laser writing (DLW) technology, the fabrication of a flexible 360-degree thermal sound source becomes possible. A 650-nm low-power laser was used to reduce the graphene oxide (GO). The stripped laser induced graphene thermal sound source was then attached to the surface of a cylindrical bottle so that it could emit sound in a 360-degree direction. The sound pressure level and directivity of the sound source were tested, and the results were in good agreement with the theoretical results. Because of its 360-degree sound field, high flexibility, high efficiency, low cost, and good reliability, the 360-degree thermal acoustic sound source will be widely applied in consumer electronics, multi-media systems, and ultrasonic detection and imaging. PMID- 28335240 TI - Gd-Si Oxide Nanoparticles as Contrast Agents in Magnetic Resonance Imaging. AB - We describe the synthesis, characterization and application as contrast agents in magnetic resonance imaging of a novel type of magnetic nanoparticle based on Gd Si oxide, which presents high Gd3+ atom density. For this purpose, we have used a Prussian Blue analogue as the sacrificial template by reacting with soluble silicate, obtaining particles with nanorod morphology and of small size (75 nm). These nanoparticles present good biocompatibility and higher longitudinal and transversal relaxivity values than commercial Gd3+ solutions, which significantly improves the sensitivity of in vivo magnetic resonance images. PMID- 28335241 TI - Erratum: Mustafa, R.; Luo, Y.; Wu, Y.; Guo, R.; Shi, X. Dendrimer-Functionalized Laponite(r) Nanodisks as a Platform for Anticancer Drug Delivery. Nanomaterials 2015, 5, 1716-1731. AB - It has been brought to our attention that Laponite(r) is a trademark of BYK Additives, however the trademark symbol is missing in [1].[...]. PMID- 28335242 TI - Targeting and Photodynamic Killing of Cancer Cell by Nitrogen-Doped Titanium Dioxide Coupled with Folic Acid. AB - Titanium dioxide (TiO2) has attracted wide attention as a potential photosensitizer (PS) in photodynamic therapy (PDT). However, bare TiO2 can only be excited by ultraviolet illumination, and it lacks specific targeting ligands, which largely impede its application. In our study, we produced nitrogen-doped TiO2 and linked it with an effective cancer cell targeting agent, folic acid (FA), to obtain N-TiO2-FA nanoconjugates. Characterization of N-TiO2-FA included Zeta potential, absorption spectra and thermogravimetric analysis. The results showed that N-TiO2-FA was successfully produced and it possessed better dispersibility in aqueous solution than unmodified TiO2. The N-TiO2-FA was incubated with human nasopharyngeal carcinoma (KB) and human pulmonary adenocarcinoma (A549) cells. The KB cells that overexpress folate receptors (FR) on cell membranes were used as FR-positive cancer cells, while A549 cells were used as FR-negative cells. Laser scanning confocal microscopy results showed that KB cells had a higher uptake efficiency of N-TiO2-FA, which was about twice that of A549 cells. Finally, N-TiO2-FA is of no cytotoxicity, and has a better photokilling effect on KB cells under visible light irradiation. In conclusion, N TiO2-FA can be as high-value as a PS in cancer targeting PDT. PMID- 28335243 TI - Correlation between CdSe QD Synthesis, Post-Synthetic Treatment, and BHJ Hybrid Solar Cell Performance. AB - In this publication we show that the procedure to synthesize nanocrystals and the post-synthetic nanocrystal ligand sphere treatment have a great influence not only on the immediate performance of hybrid bulk heterojunction solar cells, but also on their thermal, long-term, and air stability. We herein demonstrate this for the particular case of spherical CdSe nanocrystals, post-synthetically treated with a hexanoic acid based treatment. We observe an influence from the duration of this post-synthetic treatment on the nanocrystal ligand sphere size, and also on the solar cell performance. By tuning the post-synthetic treatment to a certain degree, optimal device performance can be achieved. Moreover, we show how to effectively adapt the post-synthetic nanocrystal treatment protocol to different nanocrystal synthesis batches, hence increasing the reproducibility of hybrid nanocrystal:polymer bulk-heterojunction solar cells, which usually suffers due to the fluctuations in nanocrystal quality of different synthesis batches and synthesis procedures. PMID- 28335245 TI - Ag Nanoparticle-Functionalized Open-Ended Freestanding TiO2 Nanotube Arrays with a Scattering Layer for Improved Energy Conversion Efficiency in Dye-Sensitized Solar Cells. AB - Dye-sensitized solar cells (DSSCs) were fabricated using open-ended freestanding TiO2 nanotube arrays functionalized with Ag nanoparticles (NPs) in the channel to create a plasmonic effect, and then coated with large TiO2 NPs to create a scattering effect in order to improve energy conversion efficiency. Compared to closed-ended freestanding TiO2 nanotube array-based DSSCs without Ag or large TiO2 NPs, the energy conversion efficiency of closed-ended DSSCs improved by 9.21% (actual efficiency, from 5.86% to 6.40%) with Ag NPs, 6.48% (actual efficiency, from 5.86% to 6.24%) with TiO2 NPs, and 14.50% (actual efficiency, from 5.86% to 6.71%) with both Ag NPs and TiO2 NPs. By introducing Ag NPs and/or large TiO2 NPs to open-ended freestanding TiO2 nanotube array-based DSSCs, the energy conversion efficiency was improved by 9.15% (actual efficiency, from 6.12% to 6.68%) with Ag NPs and 8.17% (actual efficiency, from 6.12% to 6.62%) with TiO2 NPs, and by 15.20% (actual efficiency, from 6.12% to 7.05%) with both Ag NPs and TiO2 NPs. Moreover, compared to closed-ended freestanding TiO2 nanotube arrays, the energy conversion efficiency of open-ended freestanding TiO2 nanotube arrays increased from 6.71% to 7.05%. We demonstrate that each component-Ag NPs, TiO2 NPs, and open-ended freestanding TiO2 nanotube arrays-enhanced the energy conversion efficiency, and the use of a combination of all components in DSSCs resulted in the highest energy conversion efficiency. PMID- 28335244 TI - Human Serum Albumin Nanoparticles for Use in Cancer Drug Delivery: Process Optimization and In Vitro Characterization. AB - Human serum albumin nanoparticles (HSA-NPs) are widely-used drug delivery systems with applications in various diseases, like cancer. For intravenous administration of HSA-NPs, the particle size, surface charge, drug loading and in vitro release kinetics are important parameters for consideration. This study focuses on the development of stable HSA-NPs containing the anti-cancer drug paclitaxel (PTX) via the emulsion-solvent evaporation method using a high pressure homogenizer. The key parameters for the preparation of PTX-HSA-NPs are: the starting concentrations of HSA, PTX and the organic solvent, including the homogenization pressure and its number cycles, were optimized. Results indicate a size of 143.4 +/- 0.7 nm and 170.2 +/- 1.4 nm with a surface charge of -5.6 +/- 0.8 mV and -17.4 +/- 0.5 mV for HSA-NPs and PTX-HSA-NPs (0.5 mg/mL of PTX), respectively. The yield of the PTX-HSA-NPs was ~93% with an encapsulation efficiency of ~82%. To investigate the safety and effectiveness of the PTX-HSA NPs, an in vitro drug release and cytotoxicity assay was performed on human breast cancer cell line (MCF-7). The PTX-HSA-NPs showed dose-dependent toxicity on cells of 52%, 39.3% and 22.6% with increasing concentrations of PTX at 8, 20.2 and 31.4 MUg/mL, respectively. In summary, all parameters involved in HSA-NPs' preparation, its anticancer efficacy and scale-up are outlined in this research article. PMID- 28335246 TI - Quaternized Carboxymethyl Chitosan-Based Silver Nanoparticles Hybrid: Microwave Assisted Synthesis, Characterization and Antibacterial Activity. AB - A facile, efficient, and eco-friendly approach for the preparation of uniform silver nanoparticles (Ag NPs) was developed. The synthesis was conducted in an aqueous medium exposed to microwave irradiation for 8 min, using laboratory prepared, water-soluble quaternized carboxymethyl chitosan (QCMC) as a chemical reducer and stabilizer and silver nitrate as the silver source. The structure of the prepared QCMC was characterized using Fourier transform infrared (FT-IR) and 1H nuclear magnetic resonance (NMR). The formation, size distribution, and dispersion of the Ag NPs in the QCMC matrix were determined using X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), ultraviolet-visible (UV-Vis), transmission electron microscopy (TEM), and field emission scanning electron microscope (FESEM) analysis, and the thermal stability and antibacterial properties of the synthesized QCMC-based Ag NPs composite (QCMC-Ag) were also explored. The results revealed that (1) QCMC was successfully prepared by grafting quaternary ammonium groups onto carboxymethyl chitosan (CMC) chains under microwave irradiation in water for 90 min and this substitution appeared to have occurred at -NH2 sites on C2 position of the pyranoid ring; (2) uniform and stable spherical Ag NPs could be synthesized when QCMC was used as the reducing and stabilizing agent; (3) Ag NPs were well dispersed in the QCMC matrix with a narrow size distribiution in the range of 17-31 nm without aggregation; and (4) due to the presence of Ag NPs, the thermal stability and antibacterial activity of QCMC-Ag were dramatically improved relative to QCMC. PMID- 28335247 TI - Hydrothermal Fabrication of Silver Nanowires-Silver Nanoparticles-Graphene Nanosheets Composites in Enhancing Electrical Conductive Performance of Electrically Conductive Adhesives. AB - Silver nanowires-silver nanoparticles-graphene nanosheets (AgNWs-AgNPs-GN) hybrid nanomaterials were fabricated through a hydrothermal method by using glucose as a green reducing agent. The charge carriers of AgNWs-AgNPs-GN passed through defect regions in the GNs rapidly with the aid of the AgNW and AgNP building blocks, leading to high electrical conductivity of electrically conductive adhesives (ECA) filled with AgNWs-AgNPs-GN. The morphologies of synthesized AgNWs-AgNPs-GN hybrid nanomaterials were characterized by field emission scanning electron microscope (FESEM), and high resolution transmission electron microscopy (HRTEM). X-ray diffraction (XRD) and laser confocal micro-Raman spectroscopy were used to investigate the structure of AgNWs-AgNPs-GN. The resistance of cured ECAs was investigated by the four-probe method. The results indicated AgNWs-AgNPs-GN hybrid nanomaterials exhibited excellent electrical properties for decreasing the resistivity of electrically conductive adhesives (ECA). The resistivity of ECA was 3.01 * 10-4 Omega.cm when the content of the AgNWs-AgNPs-GN hybrid nanomaterial was 0.8 wt %. PMID- 28335248 TI - A Fast Response Ammonia Sensor Based on Coaxial PPy-PAN Nanofiber Yarn. AB - Highly orientated polypyrrole (PPy)-coated polyacrylonitrile (PAN) (PPy-PAN) nanofiber yarn was prepared with an electrospinning technique and in-situ chemical polymerization. The morphology and chemical structure of PPy-PAN nanofiber yarn was characterized by scanning electron microscopy (SEM), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), and fourier transform infrared spectroscopy (FTIR), which indicated that the PPy as the shell layer was homogeneously and uniformly polymerized on the surface of PAN nanofiber. The effects of different concentration of doping acid on the responses of PPy-PAN nanofiber yarn sensor were investigated. The electrical responses of the gas sensor based on the PPy-PAN nanofiber yarn to ammonia were investigated at room temperature. The nanoyarn sensor composed of uniaxially aligned PPy-PAN nanofibers with a one-dimensional structure exhibited a transient response, and the response time was less than 1 s. The excellent sensing properties mentioned above give rise to good potential application prospects in the field of ammonia sensor. PMID- 28335249 TI - Plasma Nanoengineering and Nanofabrication. AB - With the recent advances in nanotechnology, plasma nanofabrication has become an exciting new niche because plasma-based approaches can deliver unique structures at the nanoscale that cannot be achieved by other techniques and/or in a more economical and environmentally friendly manner.[...]. PMID- 28335250 TI - Nanoparticles for Catalysis. AB - Nanoscience emerged in the last decades of the 20th century with the general aim to determine those properties that appear when small particles of nanometric dimensions are prepared and stabilized.[...]. PMID- 28335251 TI - Nanostructured TiO2 Surfaces Promote Human Bone Marrow Mesenchymal Stem Cells Differentiation to Osteoblasts. AB - Micro- and nano-patterning/modification are emerging strategies to improve surfaces properties that may influence critically cells adherence and differentiation. Aim of this work was to study the in vitro biological reactivity of human bone marrow mesenchymal stem cells (hBMSCs) to a nanostructured titanium dioxide (TiO2) surface in comparison to a coverglass (Glass) in two different culture conditions: with (osteogenic medium (OM)) and without (proliferative medium (PM)) osteogenic factors. To evaluate cell adhesion, hBMSCs phosphorylated focal adhesion kinase (pFAK) foci were analyzed by confocal laser scanning microscopy (CLSM) at 24 h: the TiO2 surface showed a higher number of pFAK foci with respect to Glass. The hBMSCs differentiation to osteoblasts was evaluated in both PM and OM culture conditions by enzyme-linked immunosorbent assay (ELISA), CLSM and real-time quantitative reverse transcription PCR (qRT-PCR) at 28 days. In comparison with Glass, TiO2 surface in combination with OM conditions increased the content of extracellular bone proteins, calcium deposition and alkaline phosphatase activity. The qRT-PCR analysis revealed, both in PM and OM, that TiO2 surface increased at seven and 28 days the expression of osteogenic genes. All together, these results demonstrate the capability of TiO2 nanostructured surface to promote hBMSCs osteoblast differentiation and its potentiality in biomedical applications. PMID- 28335252 TI - Stress Waves and Characteristics of Zigzag and Armchair Silicene Nanoribbons. AB - The mechanical properties of silicene nanostructures subject to tensile loading were studied via a molecular dynamics (MD) simulation. The effects of temperature on Young's modulus and the fracture strain of silicene with armchair and zigzag types were examined. The maximum in-plane stress and the corresponding critical strain of the armchair and the zigzag silicene sheets at 300 K were 8.85 and 10.62, and 0.187 and 0.244 N/m, respectively. The in-plane stresses of the silicene sheet in the armchair direction at the temperatures of 300, 400, 500, and 600 K were 8.85, 8.50, 8.26, and 7.79 N/m, respectively. The in-plane stresses of the silicene sheet in the zigzag direction at the temperatures of 300, 400, 500, and 600 K were 10.62, 9.92, 9.64, and 9.27 N/m, respectively. The improved mechanical properties can be calculated in a silicene sheet yielded in the zigzag direction compared with the tensile loading in the armchair direction. The wrinklons and waves were observed at the shear band across the center zone of the silicene sheet. These results provide useful information about the mechanical and fracture behaviors of silicene for engineering applications. PMID- 28335254 TI - Quaternized Chitosan-Capped Mesoporous Silica Nanoparticles as Nanocarriers for Controlled Pesticide Release. AB - Nanotechnology-based pesticide formulations would ensure effective utilization of agricultural inputs. In the present work, mesoporous silica nanoparticles (MSNs) with particle diameters of ~110 nm and pore sizes of ~3.7 nm were synthesized via a liquid crystal templating mechanism. A water-soluble chitosan (CS) derivative (N-(2-hydroxyl)propyl-3-trimethyl ammonium CS chloride, HTCC) was successfully capped on the surface of pyraclostrobin-loaded MSNs. The physicochemical and structural analyses showed that the electrostatic interactions and hydrogen bonding were the major forces responsible for the formation of HTCC-capped MSNs. HTCC coating greatly improved the loading efficiency (LC) (to 40.3%) compared to using bare MSNs as a single encapsulant (26.7%). The microstructure of the nanoparticles was revealed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The pyraclostrobin-loaded nanoparticles showed an initial burst and subsequent sustained release behavior. HTCC-capped MSNs released faster than bare MSNs in the initial stage. Pyraclostrobin-loaded HTCC capped MSNs with half doses of pyraclostrobin technical demonstrated almost the same fungicidal activity against Phomopsis asparagi (Sacc.), which obviously reduced the applied pesticide and enhanced the utilization efficiency. Therefore, HTCC-decorated MSNs demonstrated great potential as nanocarriers in agrochemical applications. PMID- 28335253 TI - Soft Interaction in Liposome Nanocarriers for Therapeutic Drug Delivery. AB - The development of smart nanocarriers for the delivery of therapeutic drugs has experienced considerable expansion in recent decades, with the development of new medicines devoted to cancer treatment. In this respect a wide range of strategies can be developed by employing liposome nanocarriers with desired physico-chemical properties that, by exploiting a combination of a number of suitable soft interactions, can facilitate the transit through the biological barriers from the point of administration up to the site of drug action. As a result, the materials engineer has generated through the bottom up approach a variety of supramolecular nanocarriers for the encapsulation and controlled delivery of therapeutics which have revealed beneficial developments for stabilizing drug compounds, overcoming impediments to cellular and tissue uptake, and improving biodistribution of therapeutic compounds to target sites. Herein we present recent advances in liposome drug delivery by analyzing the main structural features of liposome nanocarriers which strongly influence their interaction in solution. More specifically, we will focus on the analysis of the relevant soft interactions involved in drug delivery processes which are responsible of main behaviour of soft nanocarriers in complex physiological fluids. Investigation of the interaction between liposomes at the molecular level can be considered an important platform for the modeling of the molecular recognition processes occurring between cells. Some relevant strategies to overcome the biological barriers during the drug delivery of the nanocarriers are presented which outline the main structure-properties relationships as well as their advantages (and drawbacks) in therapeutic and biomedical applications. PMID- 28335255 TI - A Gallium Oxide-Graphene Oxide Hybrid Composite for Enhanced Photocatalytic Reaction. AB - Hybrid composites (HCs) made up of gallium oxide (GaO) and graphene oxide (GO) were investigated with the intent of enhancing a photocatalytic reaction under ultraviolet (UV) radiation. The material properties of both GaO and GO were preserved, even after the formation of the HCs. The incorporation of the GO into the GaO significantly enhanced the photocatalytic reaction, as indicated by the amount of methylene blue (MB) degradation. The improvements in the reaction were discussed in terms of increased surface area and the retarded recombination of generated charged carriers. PMID- 28335257 TI - Characteristic Evaluation of Graphene Oxide for Bisphenol A Adsorption in Aqueous Solution. AB - This paper investigates the characteristics of graphene oxide (GO) for Bisphenol A (BPA) adsorption in water. Batch experiments on the influence of significant parameters were performed. While an improvement of the adsorption capacity of BPA was obtained by the increment of contact time and the initial BPA concentration, the increment of pH above 8, GO dosage, and temperature showed the reverse results. The thermodynamic study suggested that BPA adsorption on GO was an exothermic and spontaneous process. The kinetics was explained by the pseudo second-order model which covers all steps of adsorption. The fit of the results with the Langmuir isotherm indicated the monolayer adsorption. At 298 K, the adsorption reached equilibrium within 30 min with the maximum adsorption capacity of 49.26 mg/g. The low BPA adsorption capacity of GO can be interpreted by the occurrence of oxygen-containing functional groups (OCFGs) that are able to form hydrogen bonds with the surrounding OCFGs and water molecules. This effect inhibited the role of pi-pi interactions that are mainly responsible for the adsorption of BPA. PMID- 28335256 TI - Electrospinning of Nanofibers for Energy Applications. AB - With global concerns about the shortage of fossil fuels and environmental issues, the development of efficient and clean energy storage devices has been drastically accelerated. Nanofibers are used widely for energy storage devices due to their high surface areas and porosities. Electrospinning is a versatile and efficient fabrication method for nanofibers. In this review, we mainly focus on the application of electrospun nanofibers on energy storage, such as lithium batteries, fuel cells, dye-sensitized solar cells and supercapacitors. The structure and properties of nanofibers are also summarized systematically. The special morphology of nanofibers prepared by electrospinning is significant to the functional materials for energy storage. PMID- 28335258 TI - Nanostructures Derived from Starch and Chitosan for Fluorescence Bio-Imaging. AB - Fluorescent nanostructures (NSs) derived from polysaccharides have drawn great attention as novel fluorescent probes for potential bio-imaging applications. Herein, we reported a facile alkali-assisted hydrothermal method to fabricate polysaccharide NSs using starch and chitosan as raw materials. Transmission electron microscopy (TEM) demonstrated that the average particle sizes are 14 nm and 75 nm for starch and chitosan NSs, respectively. Fourier transform infrared (FT-IR) spectroscopy analysis showed that there are a large number of hydroxyl or amino groups on the surface of these polysaccharide-based NSs. Strong fluorescence with an excitation-dependent emission behaviour was observed under ultraviolet excitation. Interestingly, the photostability of the NSs was found to be superior to fluorescein and rhodamine B. The quantum yield of starch NSs could reach 11.12% under the excitation of 360 nm. The oxidative metal ions including Cu(II), Hg(II)and Fe(III) exhibited a quench effect on the fluorescence intensity of the prepared NSs. Both of the two kinds of the multicoloured NSs showed a maximum fluorescence intensity at pH 7, while the fluorescence intensity decreased dramatically when they were put in an either acidic or basic environment (at pH 3 or 11). The cytotoxicity study of starch NSs showed that low cell cytotoxicity and 80% viability was found after 24 h incubation, when their concentration was less than 10 mg/mL. The study also showed the possibility of using the multicoloured starch NSs for mouse melanoma cells and guppy fish imaging. PMID- 28335260 TI - A Label-Free Microelectrode Array Based on One-Step Synthesis of Chitosan-Multi Walled Carbon Nanotube-Thionine for Ultrasensitive Detection of Carcinoembryonic Antigen. AB - Carcinoembryonic antigen (CEA) has been an extensively used tumor marker responsible for clinical early diagnosis of cervical carcinomas, and pancreatic, colorectal, gastric and lung cancer. Combined with micro-electro mechanical system (MEMS) technology, it is important to develop a novel immune microelectrode array (MEA) not only for rapid analysis of serum samples, but also for cell detection in vitro and in vivo. In this work, we depict a simple approach to modify chitosan-multi-walled carbon nanotubes-thionine (CS-MWCNTs THI) hybrid film through one-step electrochemical deposition and the CS-MWCNTs THI hybrid films are successfully employed to immobilize anti-CEA for fabricating simple, label-free, and highly sensitive electro-chemical immune MEAs. The detection principle of immune MEA was based on the fact that the increasing formation of the antigen-antibody immunocomplex resulted in the decreased response currents and the relationship between the current reductions with the corresponding CEA concentrations was directly proportional. Experimental results indicated that the label-free MEA had good selectivity and the limit of detection for CEA is 0.5 pg/mL signal to noise ratio (SNR) = 3. A linear calibration plot for the detection of CEA was obtained in a wide concentration range from 1 pg/mL to 100 ng/mL (r = 0.996). This novel MEA has potential applications for detecting CEA for the research on cancer cells and cancer tissue slices as well as for effective early diagnosis. PMID- 28335259 TI - Lipid Nanovectors to Deliver RNA Oligonucleotides in Cancer. AB - The growing knowledge on the mechanisms of gene silencing and gene regulation by non-coding RNAs (ncRNA), mainly small interfering RNA (siRNA) and microRNA (miRNA), is providing a significant boost to the development of new therapeutic strategies for the treatment of cancer. However, the design of RNA-based therapeutics is hampered by biopharmaceutical issues, thus requiring the use of suitable delivery strategies. In this regards, lipid nanovectors have been successfully investigated to deliver RNA in different forms of cancer. Compared to other biomaterials, lipids offer advantages such as biocompatibility, biodegradability, easy production, low cost, limited toxicity and immunogenicity. The possibility to formulate these materials in the form of nanovectors allows overcoming biopharmaceutical issues associated to the therapeutic use of RNA, with the possibility to target tumors. This review takes stock of the main lipid nanovectors proposed to deliver ncRNA. For each considered delivery strategy, the rational design and the most meaningful in vitro and in vivo results are reported and discussed. PMID- 28335261 TI - Nanomaterials for Cardiac Myocyte Tissue Engineering. AB - Since their synthesizing introduction to the research community, nanomaterials have infiltrated almost every corner of science and engineering. Over the last decade, one such field has begun to look at using nanomaterials for beneficial applications in tissue engineering, specifically, cardiac tissue engineering. During a myocardial infarction, part of the cardiac muscle, or myocardium, is deprived of blood. Therefore, the lack of oxygen destroys cardiomyocytes, leaving dead tissue and possibly resulting in the development of arrhythmia, ventricular remodeling, and eventual heart failure. Scarred cardiac muscle results in heart failure for millions of heart attack survivors worldwide. Modern cardiac tissue engineering research has developed nanomaterial applications to combat heart failure, preserve normal heart tissue, and grow healthy myocardium around the infarcted area. This review will discuss the recent progress of nanomaterials for cardiovascular tissue engineering applications through three main nanomaterial approaches: scaffold designs, patches, and injectable materials. PMID- 28335263 TI - Enhanced Deposition Uniformity via an Auxiliary Electrode in Massive Electrospinning. AB - Uniform deposition of nanofibers in the massive electrospinning process is critical in the industrial applications of nanofibers. Tip-Induced Electrospinning (TIE) is a cost-effective large-scale nanofiber-manufacturing method, but it has poor deposition uniformity. An auxiliary conductive electrode connected to the emitting electrode was introduced to improve the deposition uniformity of the nanofibers. The effects of the auxiliary electrode shape, the tilted angles and the position of the boat-like electrode on the electric field distribution, the diameter of the nanofibers, the jet control and the deposition uniformity were explored by using finite element analysis of the electric field and experiments. Experiments showed that the boat-like electrode at 20 mm above the reservoir bottom with a 5 degrees tilted angle helped to decrease the relative deposition error of nanofibers in the greatest extent to about 5.66%, indicating such an auxiliary electrode is a good candidate method to greatly improve the deposition uniformity of nanofibers in massive electrospinning. PMID- 28335264 TI - Antimicrobial Properties of Biofunctionalized Silver Nanoparticles on Clinical Isolates of Streptococcus mutans and Its Serotypes. AB - (1) Background: Streptococcus mutans (S. mutans) is the principal pathogen involved in the formation of dental caries. Other systemic diseases have also been associated with specific S. mutans serotypes (c, e, f, and k). Silver nanoparticles (SNP) have been demonstrated to have good antibacterial effects against S. mutans; therefore, limited studies have evaluated the antimicrobial activity of biofunctionalized SNP on S. mutans serotypes. The purpose of this work was to prepare and characterize coated SNP using two different organic components and to evaluate the antimicrobial activity of SNP in clinical isolates of S. mutans strains and serotypes; (2) Methods: SNP with bovine serum albumin (BSA) or chitosan (CS) coatings were prepared and the physical, chemical and microbiological properties of SNP were evaluated; (3) Results: Both types of coated SNP showed antimicrobial activity against S. mutans bacteria and serotypes. Better inhibition was associated with smaller particles and BSA coatings; however, no significant differences were found between the different serotypes, indicating a similar sensitivity to the coated SNP; (4) Conclusion: This study concludes that BSA and CS coated SNP had good antimicrobial activity against S. mutans strains and the four serotypes, and this study suggest the widespread use of SNP as an antimicrobial agent for the inhibition of S. mutans bacteria. PMID- 28335265 TI - Green Synthesis of Hierarchically Structured Silver-Polymer Nanocomposites with Antibacterial Activity. AB - The in situ formation of silver nanoparticles (AgNPs) aided by chondroitin sulfate and the preparation of a hierarchically structured silver-polymer nanocomposite with antimicrobial activity is shown. Green synthesis of AgNPs is carried out by thermal treatment (80 and 90 degrees C) or UV irradiation of a chondroitin sulfate solution containing AgNO3 without using any further reducing agents or stabilizers. Best control of the AgNPs size and polydispersity was achieved by UV irradiation. The ice-segregation-induced self-assembly (ISISA) process, in which the polymer solution containing the AgNPs is frozen unidirectionally, and successively freeze-drying were employed to produce the chondroitin sulfate 3D scaffolds. The scaffolds were further crosslinked with hexamethylene diisocyanate vapors to avoid water solubility of the 3D structures in aqueous environments. The antimicrobial activity of the scaffolds was tested against Escherichia coli. The minimum inhibitory concentration (MIC) found for AgNPs-CS (chondroitin sulfate) scaffolds was ca. 6 ppm. PMID- 28335266 TI - Synthesis of p-Co3O4/n-TiO2 Nanoparticles for Overall Water Splitting under Visible Light Irradiation. AB - p-Co3O4/n-TiO2 nanoparticles (~400 nm) for photocatalysis were prepared via carbon assisted method and sol-gel method in this work. The paper also studied the application of visible light illuminated p-Co3O4/n-TiO2 nanocomposites cocatalyst to the overall pure water splitting into H2 and O2. In addition, the H2 evolution rate of the p-Co3O4/n-TiO2 nanocomposites is 25% higher than that of the pure Co3O4 nanoparticles. Besides, according to the results of the characterizations, the scheme of visible light photocatalytic water splitting is proposed, the Co3O4 of the nanocomposites is excited by visible light, and the photo-generated electrons and holes existing on the conduction band of Co3O4 and valence band of TiO2 have endowed the photocatalytic evolution of H2 and O2 with higher efficiency. The optimal evolution rate of H2 and O2 is 8.16 MUmol/h.g and 4.0 MUmol/h.g, respectively. PMID- 28335262 TI - Nanomaterials for Tissue Engineering In Dentistry. AB - The tissue engineering (TE) of dental oral tissue is facing significant changes in clinical treatments in dentistry. TE is based on a stem cell, signaling molecule, and scaffold triad that must be known and calibrated with attention to specific sectors in dentistry. This review article shows a summary of micro- and nanomorphological characteristics of dental tissues, of stem cells available in the oral region, of signaling molecules usable in TE, and of scaffolds available to guide partial or total reconstruction of hard, soft, periodontal, and bone tissues. Some scaffoldless techniques used in TE are also presented. Then actual and future roles of nanotechnologies about TE in dentistry are presented. PMID- 28335268 TI - Optoelectronic and Electrochemical Properties of Vanadium Pentoxide Nanowires Synthesized by Vapor-Solid Process. AB - Substantial synthetic vanadium pentoxide (V2O5) nanowires were successfully produced by a vapor-solid (VS) method of thermal evaporation without using precursors as nucleation sites for single crystalline V2O5 nanowires with a (110) growth plane. The micromorphology and microstructure of V2O5 nanowires were analyzed by scanning electron microscope (SEM), energy-dispersive X-ray spectroscope (EDS), transmission electron microscope (TEM) and X-ray diffraction (XRD). The spiral growth mechanism of V2O5 nanowires in the VS process is proved by a TEM image. The photo-luminescence (PL) spectrum of V2O5 nanowires shows intrinsic (410 nm and 560 nm) and defect-related (710 nm) emissions, which are ascribable to the bound of inter-band transitions (V 3d conduction band to O 2p valence band). The electrical resistivity could be evaluated as 64.62 Omega.cm via four-point probe method. The potential differences between oxidation peak and reduction peak are 0.861 V and 0.470 V for the first and 10th cycle, respectively. PMID- 28335267 TI - DNA-Based Enzyme Reactors and Systems. AB - During recent years, the possibility to create custom biocompatible nanoshapes using DNA as a building material has rapidly emerged. Further, these rationally designed DNA structures could be exploited in positioning pivotal molecules, such as enzymes, with nanometer-level precision. This feature could be used in the fabrication of artificial biochemical machinery that is able to mimic the complex reactions found in living cells. Currently, DNA-enzyme hybrids can be used to control (multi-enzyme) cascade reactions and to regulate the enzyme functions and the reaction pathways. Moreover, sophisticated DNA structures can be utilized in encapsulating active enzymes and delivering the molecular cargo into cells. In this review, we focus on the latest enzyme systems based on novel DNA nanostructures: enzyme reactors, regulatory devices and carriers that can find uses in various biotechnological and nanomedical applications. PMID- 28335269 TI - Galactosylated Liposomes for Targeted Co-Delivery of Doxorubicin/Vimentin siRNA to Hepatocellular Carcinoma. AB - The combination of therapeutic nucleic acids and chemotherapeutic drugs has shown great promise for cancer therapy. In this study, asialoglycoprotein receptors (ASGPR) targeting-ligand-based liposomes were tested to determine whether they can co-deliver vimentin siRNA and doxorubicin to hepatocellular carcinoma (HCC) selectively. To achieve this goal, we developed an ASGPR receptor targeted co delivery system called gal-doxorubicin/vimentin siRNA liposome (Gal-DOX/siRNA-L). The Gal-DOX/siRNA-L was created via electrostatic interaction of galactose linked cationic liposomal doxorubicin (Gal-DOX-L) on vimentin siRNA. Previous studies have shown that Gal-DOX/siRNA-L inhibited tumor growth by combined effect of DOX and vimentin siRNA than single delivery of either DOX or vimentin siRNA. These Gal-DOX/siRNA-Ls showed stronger affinity to human hepatocellular carcinoma cells (Huh7) than other cells (lung epithelial carcinoma, A549). These liposomes also have demonstrated that novel hepatic drug/gene delivery systems composed of cationic lipid (DMKE: O,O'-dimyristyl-N-lysyl glutamate), cholesterol, galactosylated ceramide, POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine), and PEG2000-DSPE (distearoyl phosphatidyl ethanolamine) at 2:1:1:1:0.2 (moral ratios) can be used as an effective drug/gene carrier specifically targeting the liver in vivo. These results suggest that Gal-DOX-siRNA-L could effectively target tumor cells, enhance transfection efficacy and subsequently achieve the co delivery of DOX and siRNA, demonstrating great potential for synergistic anti tumor therapy. PMID- 28335270 TI - Review of Recent Developments on Using an Off-Lattice Monte Carlo Approach to Predict the Effective Thermal Conductivity of Composite Systems with Complex Structures. AB - Here, we present a review of recent developments for an off-lattice Monte Carlo approach used to investigate the thermal transport properties of multiphase composites with complex structure. The thermal energy was quantified by a large number of randomly moving thermal walkers. Different modes of heat conduction were modeled in appropriate ways. The diffusive heat conduction in the polymer matrix was modeled with random Brownian motion of thermal walkers within the polymer, and the ballistic heat transfer within the carbon nanotubes (CNTs) was modeled by assigning infinite speed of thermal walkers in the CNTs. Three case studies were conducted to validate the developed approach, including three-phase single-walled CNTs/tungsten disulfide (WS2)/(poly(ether ether ketone) (PEEK) composites, single-walled CNT/WS2/PEEK composites with the CNTs clustered in bundles, and complex graphene/poly(methyl methacrylate) (PMMA) composites. In all cases, resistance to heat transfer due to nanoscale phenomena was also modeled. By quantitatively studying the influencing factors on the thermal transport properties of the multiphase composites, it was found that the orientation, aggregation and morphology of fillers, as well as the interfacial thermal resistance at filler-matrix interfaces would limit the transfer of heat in the composites. These quantitative findings may be applied in the design and synthesis of multiphase composites with specific thermal transport properties. PMID- 28335272 TI - Silicon Nanowire Photocathodes for Photoelectrochemical Hydrogen Production. AB - The performance of silicon for water oxidation and hydrogen production can be improved by exploiting the antireflective properties of nanostructured silicon substrates. In this work, silicon nanowires were fabricated by metal-assisted electroless etching of silicon. An enhanced photocurrent density of -17 mA/cm2 was observed for the silicon nanowires coated with an iron sulphur carbonyl catalyst when compared to bare silicon nanowires (-5 mA/cm2). A substantial amount of 315 umol/h hydrogen gas was produced at low bias potentials for the silicon nanowires coated with an iron sulphur carbonyl catalyst. PMID- 28335271 TI - Distribution of Iron Oxide Core-Titanium Dioxide Shell Nanoparticles in VX2 Tumor Bearing Rabbits Introduced by Two Different Delivery Modalities. AB - This work compares intravenous (IV) versus fluoroscopy-guided transarterial intra catheter (IC) delivery of iron oxide core-titanium dioxide shell nanoparticles (NPs) in vivo in VX2 model of liver cancer in rabbits. NPs coated with glucose and decorated with a peptide sequence from cortactin were administered to animals with developed VX2 liver cancer. Two hours after NPs delivery tumors, normal liver, kidney, lung and spleen tissues were harvested and used for a series on histological and elemental analysis tests. Quantification of NPs in tissues was done both by bulk inductively coupled plasma mass spectrometry (ICP-MS) analysis and by hard X-ray fluorescence microscopy. Both IV and IC NPs injection are feasible modalities for delivering NPs to VX2 liver tumors with comparable tumor accumulation. It is possible that this is an outcome of the fact that VX2 tumors are highly vascularized and hemorrhagic, and therefore enhanced permeability and retention (EPR) plays the most significant role in accumulation of nanoparticles in tumor tissue. It is, however, interesting to note that IV delivery led to increased sequestration of NPs by spleen and normal liver tissue, while IC delivery lead to more NP positive Kupffer cells. This difference is most likely a direct outcome of blood flow dynamics. Armed with this knowledge about nanoparticle delivery, we plan to test them as radiosensitizers in the future. PMID- 28335273 TI - Nanostructured Solar Cells. AB - We are glad to announce the Special Issue "Nanostructured Solar Cells", published in Nanomaterials. This issue consists of eight articles, two communications, and one review paper, covering major important aspects of nanostructured solar cells of varying types. From fundamental physicochemical investigations to technological advances, and from single junction solar cells (silicon solar cell, dye sensitized solar cell, quantum dots sensitized solar cell, and small molecule organic solar cell) to tandem multi-junction solar cells, all aspects are included and discussed in this issue to advance the use of nanotechnology to improve the performance of solar cells with reduced fabrication costs. PMID- 28335274 TI - Metallic Nanostructures Based on DNA Nanoshapes. AB - Metallic nanostructures have inspired extensive research over several decades, particularly within the field of nanoelectronics and increasingly in plasmonics. Due to the limitations of conventional lithography methods, the development of bottom-up fabricated metallic nanostructures has become more and more in demand. The remarkable development of DNA-based nanostructures has provided many successful methods and realizations for these needs, such as chemical DNA metallization via seeding or ionization, as well as DNA-guided lithography and casting of metallic nanoparticles by DNA molds. These methods offer high resolution, versatility and throughput and could enable the fabrication of arbitrarily-shaped structures with a 10-nm feature size, thus bringing novel applications into view. In this review, we cover the evolution of DNA-based metallic nanostructures, starting from the metallized double-stranded DNA for electronics and progress to sophisticated plasmonic structures based on DNA origami objects. PMID- 28335275 TI - Methanol-Tolerant Platinum-Palladium Catalyst Supported on Nitrogen-Doped Carbon Nanofiber for High Concentration Direct Methanol Fuel Cells. AB - Pt-Pd catalyst supported on nitrogen-doped carbon nanofiber (N-CNF) was prepared and evaluated as a cathode electrode of the direct methanol fuel cell (DMFC). The N-CNF, which was directly synthesized by the catalytic chemical vapor deposition from acetonitrile at 640 degrees C, was verified as having a change of electrochemical surface properties such as oxygen reduction reaction (ORR) activities and the electrochemical double layer compared with common carbon black (CB). To attain the competitive oxygen reduction reaction activity with methanol tolerance, the Pt and Pd metals were supported on the CB or the N-CNF. The physical and electrochemical characteristics of the N-CNF-supported Pt-Pd catalyst were examined and compared with catalyst supported on the CB. In addition, DMFC single cells using these catalysts as the cathode electrode were applied to obtain I-V polarization curves and constant current operating performances with high-concentration methanol as the fuel. Pt-Pd catalysts had obvious ORR activity even in the presence of methanol. The higher power density was obtained at all the methanol concentrations when it applied to the membrane electrode assembly (MEA) of the DMFC. When the N-CNF is used as the catalyst support material, a better performance with high-concentration methanol is expected. PMID- 28335276 TI - Flexible Textile-Based Organic Transistors Using Graphene/Ag Nanoparticle Electrode. AB - Highly flexible and electrically-conductive multifunctional textiles are desirable for use in wearable electronic applications. In this study, we fabricated multifunctional textile composites by vacuum filtration and wet transfer of graphene oxide films on a flexible polyethylene terephthalate (PET) textile in association with embedding Ag nanoparticles (AgNPs) to improve the electrical conductivity. A flexible organic transistor can be developed by direct transfer of a dielectric/semiconducting double layer on the graphene/AgNP textile composite, where the textile composite was used as both flexible substrate and conductive gate electrode. The thermal treatment of a textile-based transistor enhanced the electrical performance (mobility = 7.2 cm2.V-1.s-1, on/off current ratio = 4 * 105, and threshold voltage = -1.1 V) due to the improvement of interfacial properties between the conductive textile electrode and the ion-gel dielectric layer. Furthermore, the textile transistors exhibited highly stable device performance under extended bending conditions (with a bending radius down to 3 mm and repeated tests over 1000 cycles). We believe that our simple methods for the fabrication of graphene/AgNP textile composite for use in textile-type transistors can potentially be applied to the development of flexible large-area electronic clothes. PMID- 28335277 TI - Receptor-Meditated Endocytosis by Hyaluronic Acid@Superparamagnetic Nanovetor for Targeting of CD44-Overexpressing Tumor Cells. AB - The present report proposes a more rational hyaluronic acid (HA) conjugation protocol that can be used to modify the surface of the superparamagnetic iron oxide nanoparticles (SPIONs) by covalently binding the targeting molecules (HA) with glutamic acid as a molecular linker on peripheral surface of SPIONs. The synthesis of HA-Glutamic Acid (GA)@SPIONs was included oxidization of nanoparticle's surface with H2O2 followed by activation of hydroxyl group and reacting glutamic acid as an intermediate molecule demonstrating transfection of lung cancer cells. Fourier transform infrared (FTIR) and zeta-potential studies confirmed the chemical bonding between amino acid linker and polysaccharides. 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay showed that HA-SPIONs-treated cells remained 82.9% +/- 2.7% alive at high particle dosage (200 ug/mL iron concentration), whereas GA-SPIONs and bare SPIONs (B-SPIONs) treated cells had only 59.3% +/- 13.4% and 26.5% +/- 3.1% survival rate at the same conditions, respectively. Confocal microscopy analysis showed increased cellular internalization of HA-SPIONs compared to non-interacting agarose coated SPIONs (AgA-SPIONs). PMID- 28335278 TI - Recent Prospects in the Inline Monitoring of Nanocomposites and Nanocoatings by Optical Technologies. AB - Nanostructured materials have emerged as a key research field in order to confer materials with unique or enhanced properties. The performance of nanocomposites depends on a number of parameters, but the suitable dispersion of nanoparticles remains the key in order to obtain the full nanocomposites' potential in terms of, e.g., flame retardance, mechanical, barrier, thermal properties, etc. Likewise, the performance of nanocoatings to obtain, for example, tailored surface affinity with selected liquids (e.g., for self-cleaning ability or anti fog properties), protective effects against flame propagation, ultra violet (UV) radiation or gas permeation, is highly dependent on the nanocoating's thickness and homogeneity. In terms of recent advances in the monitoring of nanocomposites and nanocoatings, this review discusses commonly-used offline characterization approaches, as well as promising inline systems. All in all, having good control over both the dispersion and thickness of these materials would help with reaching optimal and consistent properties to allow nanocomposites to extend their use. PMID- 28335279 TI - A Novel Polyvinylidene Fluoride Tree-Like Nanofiber Membrane for Microfiltration. AB - A novel polyvinylidene fluoride (PVDF) tree-like nanofiber membrane (PVDF-TLNM) was fabricated by adding tetrabutylammonium chloride (TBAC) into a PVDF spinning solution via one-step electrospinning. The structure of the prepared membranes was characterized by field emission scanning electron microscopy (FE-SEM), Fourier transform infrared spectroscopy (FT-IR) and pore size analysis, and the hydrophilic property and microfiltration performance were also evaluated. The results showed that the tree-like nanofiber was composed of trunk fibers and branch fibers with diameters of 100-500 nm and 5-100 nm, respectively. The pore size of PVDF-TLNM (0.36 MUm) was smaller than that of a common nanofiber membrane (3.52 MUm), and the hydrophilic properties of the membranes were improved significantly. The PVDF-TLNM with a thickness of 30 +/- 2 MUm showed a satisfactory retention ratio of 99.9% against 0.3 MUm polystyrene (PS) particles and a high pure water flux of 2.88 * 104 L.m-2.h-1 under the pressure of 25 psi. This study highlights the potential benefits of this novel PVDF tree-like nanofiber membrane in the membrane field, which can achieve high flux rates at low pressure. PMID- 28335280 TI - Pregnancy Vaccination with Gold Glyco-Nanoparticles Carrying Listeria monocytogenes Peptides Protects against Listeriosis and Brain- and Cutaneous Associated Morbidities. AB - Listeriosis is a fatal infection for fetuses and newborns with two clinical main morbidities in the neonatal period, meningitis and diffused cutaneous lesions. In this study, we vaccinated pregnant females with two gold glyconanoparticles (GNP) loaded with two peptides, listeriolysin peptide 91-99 (LLO91-99) or glyceraldehyde-3-phosphate dehydrogenase 1-22 peptide (GAPDH1-22). Neonates born to vaccinated mothers were free of bacteria and healthy, while non-vaccinated mice presented clear brain affections and cutaneous diminishment of melanocytes. Therefore, these nanoparticle vaccines are effective measures to offer pregnant mothers at high risk of listeriosis interesting therapies that cross the placenta. PMID- 28335282 TI - Inverter Circuits Using ZnO Nanoparticle Based Thin-Film Transistors for Flexible Electronic Applications. AB - Innovative systems exploring the flexibility and the transparency of modern semiconducting materials are being widely researched by the scientific community and by several companies. For a low-cost production and large surface area applications, thin-film transistors (TFTs) are the key elements driving the system currents. In order to maintain a cost efficient integration process, solution based materials are used as they show an outstanding tradeoff between cost and system complexity. In this paper, we discuss the integration process of ZnO nanoparticle TFTs using a high-k resin as gate dielectric. The performance in dependence on the transistor structure has been investigated, and inverted staggered setups depict an improved performance over the coplanar device increasing both the field-effect mobility and the ION/IOFF ratio. Aiming at the evaluation of the TFT characteristics for digital circuit applications, inverter circuits using a load TFT in the pull-up network and an active TFT in the pull down network were integrated. The inverters show reasonable switching characteristics and V/V gains. Conjointly, the influence of the geometry ratio and the supply voltage on the devices have been analyzed. Moreover, as all integration steps are suitable to polymeric templates, the fabrication process is fully compatible to flexible substrates. PMID- 28335281 TI - Study on Utilization of Carboxyl Group Decorated Carbon Nanotubes and Carbonation Reaction for Improving Strengths and Microstructures of Cement Paste. AB - Carbon nanotubes (CNTs) have excellent mechanical properties and can be used to reinforce cement-based materials. On the other hand, the reaction product of carbonation with hydroxides in hydrated cement paste can reduce the porosity of cement-based materials. In this study, a novel method to improve the strength of cement paste was developed through a synergy of carbon nanotubes decorated with carboxyl group and carbonation reactions. The experimental results showed that the carboxyl group (-COOH) of decorated carbon nanotubes and the surfactant can control the morphology of the calcium carbonate crystal of carbonation products in hydrated cement paste. The spindle-like calcium carbonate crystals showed great morphological differences from those observed in the conventional carbonation of cement paste. The spindle-like calcium carbonate crystals can serve as fiber-like reinforcements to reinforce the cement paste. By the synergy of the carbon nanotubes and carbonation reactions, the compressive and flexural strengths of cement paste were significantly improved and increased by 14% and 55%, respectively, when compared to those of plain cement paste. PMID- 28335283 TI - Electrically Tunable Absorption Enhancement with Spectral and Polarization Selectivity through Graphene Plasmonic Light Trapping. AB - In this paper, anisotropic graphene plasmonic structures are explored for light trapping and absorption enhancement in surrounding media. It is shown that electrically tunable and versatile spectral and polarization selectivity can be realized. Particularly, it is possible to control absorption of the incident light's polarization component at a specific wavelength by varying the Fermi energy with suitable geometric designs. It may find applications for new types of infrared and THz photodetectors and will promote the research of other novel polarization devices. PMID- 28335284 TI - Graphene-Enabled Electrodes for Electrocardiogram Monitoring. AB - The unique parameters of graphene (GN)-notably its considerable electron mobility, high surface area, and electrical conductivity-are bringing extensive attention into the wearable technologies. This work presents a novel graphene based electrode for acquisition of electrocardiogram (ECG). The proposed electrode was fabricated by coating GN on top of a metallic layer of a Ag/AgCl electrode using a chemical vapour deposition (CVD) technique. To investigate the performance of the fabricated GN-based electrode, two types of electrodes were fabricated with different sizes to conduct the signal qualities and the skin electrode contact impedance measurements. Performances of the GN-enabled electrodes were compared to the conventional Ag/AgCl electrodes in terms of ECG signal quality, skin-electrode contact impedance, signal-to-noise ratio (SNR), and response time. Experimental results showed the proposed GN-based electrodes produced better ECG signals, higher SNR (improved by 8%), and lower contact impedance (improved by 78%) values than conventional ECG electrodes. PMID- 28335285 TI - Graphene and Carbon Quantum Dot-Based Materials in Photovoltaic Devices: From Synthesis to Applications. AB - Graphene and carbon quantum dots have extraordinary optical and electrical features because of their quantum confinement properties. This makes them attractive materials for applications in photovoltaic devices (PV). Their versatility has led to their being used as light harvesting materials or selective contacts, either for holes or electrons, in silicon quantum dot, polymer or dye-sensitized solar cells. In this review, we summarize the most common uses of both types of semiconducting materials and highlight the significant advances made in recent years due to the influence that synthetic materials have on final performance. PMID- 28335286 TI - Enhanced End-Contacts by Helium Ion Bombardment to Improve Graphene-Metal Contacts. AB - Low contact resistance between graphene and metals is of paramount importance to fabricate high performance graphene-based devices. In this paper, the impact of both defects induced by helium ion (He+) bombardment and annealing on the contact resistance between graphene and various metals (Ag, Pd, and Pt) were systematically explored. It is found that the contact resistances between all metals and graphene are remarkably reduced after annealing, indicating that not only chemically adsorbed metal (Pd) but also physically adsorbed metals (Ag and Pt) readily form end-contacts at intrinsic defect locations in graphene. In order to further improve the contact properties between Ag, Pd, and Pt metals and graphene, a novel method in which self-aligned He+ bombardment to induce exotic defects in graphene and subsequent thermal annealing to form end-contacts was proposed. By using this method, the contact resistance is reduced significantly by 15.1% and 40.1% for Ag/graphene and Pd/graphene contacts with He+ bombardment compared to their counterparts without He+ bombardment. For the Pt/graphene contact, the contact resistance is, however, not reduced as anticipated with He+ bombardment and this might be ascribed to either inappropriate He+ bombardment dose, or inapplicable method of He+ bombardment in reducing contact resistance for Pt/graphene contact. The joint efforts of as-formed end-contacts and excess created defects in graphene are discussed as the cause responsible for the reduction of contact resistance. PMID- 28335287 TI - Non-Enzymatic Glucose Biosensor Based on CuO-Decorated CeO2 Nanoparticles. AB - Copper oxide (CuO)-decorated cerium oxide (CeO2) nanoparticles were synthesized and used to detect glucose non-enzymatically. The morphological characteristics and structure of the nanoparticles were characterized through transmission electron microscopy, X-ray photoelectron spectroscopy, and X-ray diffraction. The sensor responses of electrodes to glucose were investigated via an electrochemical method. The CuO/CeO2 nanocomposite exhibited a reasonably good sensitivity of 2.77 MUA mM-1cm-2, an estimated detection limit of 10 MUA, and a good anti-interference ability. The sensor was also fairly stable under ambient conditions. PMID- 28335288 TI - Biosynthesis of Silver Nanoparticles Using Taxus yunnanensis Callus and Their Antibacterial Activity and Cytotoxicity in Human Cancer Cells. AB - Plant constituents could act as chelating/reducing or capping agents for synthesis of silver nanoparticles (AgNPs). The green synthesis of AgNPs has been considered as an environmental friendly and cost-effective alternative to other fabrication methods. The present work described the biosynthesis of AgNPs using callus extracts from Taxus yunnanensis and evaluated their antibacterial activities in vitro and potential cytotoxicity in cancer cells. Callus extracts were able to reduce silver nitrate at 1 mM in 10 min. Transmission electron microscope (TEM) indicated the synthesized AgNPs were spherical with the size range from 6.4 to 27.2 nm. X-ray diffraction (XRD) confirmed the AgNPs were in the form of nanocrystals. Fourier transform infrared spectroscopy (FTIR) suggested phytochemicals in callus extracts were possible reducing and capping agents. The AgNPs exhibited effective inhibitory activity against all tested human pathogen bacteria and the inhibition against Gram-positive bacteria was stronger than that of Gram-negative bacteria. Furthermore, they exhibited stronger cytotoxic activity against human hepatoma SMMC-7721 cells and induced noticeable apoptosis in SMMC-7721 cells, but showed lower cytotoxic against normal human liver cells (HL-7702). Our results suggested that biosynthesized AgNPs could be an alternative measure in the field of antibacterial and anticancer therapeutics. PMID- 28335289 TI - Copper Micro-Labyrinth with Graphene Skin: New Transparent Flexible Electrodes with Ultimate Low Sheet Resistivity and Superior Stability. AB - We have developed self-assembled copper (Cu) micro-labyrinth (ML) with graphene skin for transparent flexible electrodes of optoelectronic devices. The Cu ML is simply formed by heating a thin Cu film with a 100-nm thickness on a SiO2/Si substrate at 950 degrees C under hydrogen ambient to block the oxidation. Moreover, the Cu ML can have graphene skin at the surface by inserting carbo hydroxyl molecules (CxHy) during heating due to the catalytic decomposition of C H bonds on the Cu surface. The Cu ML with graphene skin (Cu ML-G) has superior sheet resistivity below 5 Omega/sq and mechanical flexibility without cracks at the bending radius of 0.1 cm. Although the transmittance of Cu ML-G is a little lower (70%~80%) than that of conventional metallic nanowires electrodes (such as Ag, ~90% at the visible wavelength), it has good thermal stability in conductivity without any damage at 200 degrees C due to a micro-sized pattern and graphene skin which prohibits the surface migration of Cu atoms. PMID- 28335290 TI - The Effect of Viscous Air Damping on an Optically Actuated Multilayer MoS2 Nanomechanical Resonator Using Fabry-Perot Interference. AB - We demonstrated a multilayer molybdenum disulfide (MoS2) nanomechanical resonator by using optical Fabry-Perot (F-P) interferometric excitation and detection. The thin circular MoS2 nanomembrane with an approximate 8-nm thickness was transferred onto the endface of a ferrule with an inner diameter of 125 MUm, which created a low finesse F-P interferometer with a cavity length of 39.92 MUm. The effects of temperature and viscous air damping on resonance behavior of the resonator were investigated in the range of -10-80 degrees C. Along with the optomechanical behavior of the resonator in air, the measured resonance frequencies ranged from 36 kHz to 73 kHz with an extremely low inflection point at 20 degrees C, which conformed reasonably to those solved by previously obtained thermal expansion coefficients of MoS2. Further, a maximum quality (Q) factor of 1.35 for the resonator was observed at 0 degrees C due to viscous dissipation, in relation to the lower Knudsen number of 0.0025~0.0034 in the tested temperature range. Moreover, measurements of Q factor revealed little dependence of Q on resonance frequency and temperature. These measurements shed light on the mechanisms behind viscous air damping in MoS2, graphene, and other 2D resonators. PMID- 28335291 TI - Multispectral Emissions of Lanthanide-Doped Gadolinium Oxide Nanophosphors for Cathodoluminescence and Near-Infrared Upconversion/Downconversion Imaging. AB - Comprehensive imaging of a biological individual can be achieved by utilizing the variation in spatial resolution, the scale of cathodoluminescence (CL), and near infrared (NIR), as favored by imaging probe Gd2O3 co-doped lanthanide nanophosphors (NPPs). A series of Gd2O3:Ln3+/Yb3+ (Ln3+: Tm3+, Ho3+, Er3+) NPPs with multispectral emission are prepared by the sol-gel method. The NPPs show a wide range of emissions spanning from the visible to the NIR region under 980 nm excitation. The dependence of the upconverting (UC)/downconverting (DC) emission intensity on the dopant ratio is investigated. The optimum ratios of dopants obtained for emissions in the NIR regions at 810 nm, 1200 nm, and 1530 nm are applied to produce nanoparticles by the homogeneous precipitation (HP) method. The nanoparticles produced from the HP method are used to investigate the dual NIR and CL imaging modalities. The results indicate the possibility of using Gd2O3 co-doped Ln3+/Yb3+ (Ln3+: Tm3+, Ho3+, Er3+) in correlation with NIR and CL imaging. The use of Gd2O3 promises an extension of the object dimension to the whole-body level by employing magnetic resonance imaging (MRI). PMID- 28335292 TI - A Tunable Photoluminescent Composite of Cellulose Nanofibrils and CdS Quantum Dots. AB - The preparation of fluorescent nanocomposite materials with tunable emission wavelengths by combining cellulose nanofibrils (CNFs) with inorganic nanoparticles is important for promoting CNFs applications. A CNF/CdS nanocomposite was prepared via in situ compositing at room temperature on oxidized CNFs with CdS quantum dots. By controlling the -COOH/Cd2+ ratio on the CNF, the feeding time of Na2S and the ultrasonic maturing time, the size of the CdS quantum dots on the CNF surface could be adjusted so that to obtain the CNF/CdS nanocomposite material with different fluorescent colors. The results indicated that the CdS particles quantized were evenly distributed on the CNF. The maximum average size of the CdS nanoparticles glowed red under the excitation of UV light was 5.34 nm, which could be obtained with a -COOH/Cd2+ ratio of 1.0, a Na2S feeding time of 20 min, and an ultrasonic maturing time of 60 min. A series of CNF/CdS nanocomposite materials were obtained with CdS nanoparticle sizes varying from 3.44 nm to 5.34 nm, the emission wavelength of which varied from 546 nm to 655 nm, and their fluorescence color changed from green to yellow to red. This is the first time the fluorescence-tunable effect of the CNF/CdS nanocomposite has been realized. PMID- 28335293 TI - Cholesterol-Modified Amino-Pullulan Nanoparticles as a Drug Carrier: Comparative Study of Cholesterol-Modified Carboxyethyl Pullulan and Pullulan Nanoparticles. AB - To search for nano-drug preparations with high efficiency in tumor treatment, we evaluated the drug-loading capacity and cell-uptake toxicity of three kinds of nanoparticles (NPs). Pullulan was grafted with ethylenediamine and hydrophobic groups to form hydrophobic cholesterol-modified amino-pullulan (CHAP) conjugates. Fourier transform infrared spectroscopy and nuclear magnetic resonance were used to identify the CHAP structure and calculate the degree of substitution of the cholesterol group. We compared three types of NPs with close cholesterol hydrophobic properties: CHAP, cholesterol-modified pullulan (CHP), and cholesterol-modified carboxylethylpullulan (CHCP), with the degree of substitution of cholesterol of 2.92%, 3.11%, and 3.46%, respectively. As compared with the two other NPs, CHAP NPs were larger, 263.9 nm, and had a positive surface charge of 7.22 mV by dynamic light-scattering measurement. CHAP NPs showed low drug-loading capacity, 12.3%, and encapsulation efficiency of 70.8%, which depended on NP hydrophobicity and was affected by surface charge. The drug release amounts of all NPs increased in the acid media, with CHAP NPs showing drug-release sensitivity with acid change. Cytotoxicity of HeLa cells was highest with mitoxantrone-loaded CHAP NPs on MTT assay. CHAP NPs may have potential as a high-efficiency drug carrier for tumor treatment. PMID- 28335294 TI - Preparation, Characterization and Manipulation of Conjugates between Gold Nanoparticles and DNA. AB - Here we described the preparation and characterization by atomic force microscopy of dumbbell-shaped conjugates between 450 bp double-stranded DNA polymer, poly(dG)-poly(dC), and 5 nm gold nanoparticles (GNPs). We have demonstrated that the size of the nanoparticles in the conjugates can be increased in a controlled fashion. Application of the conjugates for measuring the electrical conductivity of DNA is discussed. PMID- 28335296 TI - Controlled Mechanical Cracking of Metal Films Deposited on Polydimethylsiloxane (PDMS). AB - Stretchable large area electronics conform to arbitrarily-shaped 3D surfaces and enables comfortable contact to the human skin and other biological tissue. There are approaches allowing for large area thin films to be stretched by tens of percent without cracking. The approach presented here does not prevent cracking, rather it aims to precisely control the crack positions and their orientation. For this purpose, the polydimethylsiloxane (PDMS) is hardened by exposure to ultraviolet radiation (172 nm) through an exposure mask. Only well-defined patterns are kept untreated. With these soft islands cracks at the hardened surface can be controlled in terms of starting position, direction and end position. This approach is first investigated at the hardened PDMS surface itself. It is then applied to conductive silver films deposited from the liquid phase. It is found that statistical (uncontrolled) cracking of the silver films can be avoided at strain below 35%. This enables metal interconnects to be integrated into stretchable networks. The combination of controlled cracks with wrinkling enables interconnects that are stretchable in arbitrary and changing directions. The deposition and patterning does not involve vacuum processing, photolithography, or solvents. PMID- 28335295 TI - Investigation of the Band Structure of Graphene-Based Plasmonic Photonic Crystals. AB - In this paper, one-dimensional (1D) and two-dimensional (2D) graphene-based plasmonic photonic crystals (PhCs) are proposed. The band structures and density of states (DOS) have been numerically investigated. Photonic band gaps (PBGs) are found in both 1D and 2D PhCs. Meanwhile, graphene-based plasmonic PhC nanocavity with resonant frequency around 175 THz, is realized by introducing point defect, where the chemical potential is from 0.085 to 0.25 eV, in a 2D PhC. Also, the bending wvaguide and the beam splitter are realized by introducing the line defect into the 2D PhC. PMID- 28335297 TI - Rotation of Magnetization Derived from Brownian Relaxation in Magnetic Fluids of Different Viscosity Evaluated by Dynamic Hysteresis Measurements over a Wide Frequency Range. AB - The dependence of magnetic relaxation on particle parameters, such as the size and anisotropy, has been conventionally discussed. In addition, the influences of external conditions, such as the intensity and frequency of the applied field, the surrounding viscosity, and the temperature on the magnetic relaxation have been researched. According to one of the basic theories regarding magnetic relaxation, the faster type of relaxation dominates the process. However, in this study, we reveal that Brownian and Neel relaxations coexist and that Brownian relaxation can occur after Neel relaxation despite having a longer relaxation time. To understand the mechanisms of Brownian rotation, alternating current (AC) hysteresis loops were measured in magnetic fluids of different viscosities. These loops conveyed the amplitude and phase delay of the magnetization. In addition, the intrinsic loss power (ILP) was calculated using the area of the AC hysteresis loops. The ILP also showed the magnetization response regarding the magnetic relaxation over a wide frequency range. To develop biomedical applications of magnetic nanoparticles, such as hyperthermia and magnetic particle imaging, it is necessary to understand the mechanisms of magnetic relaxation. PMID- 28335298 TI - Monitoring Damage Propagation in Glass Fiber Composites Using Carbon Nanofibers. AB - In this work, we report the potential use of novel carbon nanofibers (CNFs), dispersed during fabrication of glass fiber composites to monitor damage propagation under static loading. The use of CNFs enables a transformation of the typically non-conductive glass fiber composites into new fiber composites with appreciable electrical conductivity. The percolation limit of CNFs/epoxy nanocomposites was first quantified. The electromechanical responses of glass fiber composites fabricated using CNFs/epoxy nanocomposite were examined under static tension loads. The experimental observations showed a nonlinear change of electrical conductivity of glass fiber composites incorporating CNFs versus the stress level under static load. Microstructural investigations proved the ability of CNFs to alter the polymer matrix and to produce a new polymer nanocomposite with a connected nanofiber network with improved electrical properties and different mechanical properties compared with the neat epoxy. It is concluded that incorporating CNFs during fabrication of glass fiber composites can provide an innovative means of self-sensing that will allow damage propagation to be monitored in glass fiber composites. PMID- 28335299 TI - Synthesis of SiC/Ag/Cellulose Nanocomposite and Its Antibacterial Activity by Reactive Oxygen Species Generation. AB - We describe the synthesis of nanocomposites, based on nanofibers of silicon carbide, silver nanoparticles, and cellulose. Silver nanoparticle synthesis was achieved with chemical reduction using hydrazine by adding two different surfactants to obtain a nanocomposite with silver nanoparticles of different diameters. Determination of antibacterial activity was based on respiration tests. Enzymatic analysis indicates oxidative stress, and viability testing was conducted using an epifluorescence microscope. Strong bactericidal activity of nanocomposites was found against bacteria Escherichia coli and Bacillus cereus, which were used in the study as typical Gram-negative and Gram-positive bacteria, respectively. It is assumed that reactive oxygen species generation was responsible for the observed antibacterial effect of the investigated materials. Due to the properties of silicon carbide nanofiber, the obtained nanocomposite may have potential use in technology related to water and air purification. Cellulose addition prevented silver nanoparticle release and probably enhanced bacterial adsorption onto aggregates of the nanocomposite material. PMID- 28335300 TI - Effect of Particle Size on the Magnetic Properties of Ni Nanoparticles Synthesized with Trioctylphosphine as the Capping Agent. AB - Magnetic cores of passive components are required to have low hysteresis loss, which is dependent on the coercive force. Since it is well known that the coercive force becomes zero at the superparamagnetic regime below a certain critical size, we attempted to synthesize Ni nanoparticles in a size-controlled fashion and investigated the effect of particle size on the magnetic properties. Ni nanoparticles were synthesized by the reduction of Ni acetylacetonate in oleylamine at 220 degrees C with trioctylphosphine (TOP) as the capping agent. An increase in the TOP/Ni ratio resulted in the size decrease. We succeeded in synthesizing superparamagnetic Ni nanoparticles with almost zero coercive force at particle size below 20 nm by the TOP/Ni ratio of 0.8. However, the saturation magnetization values became smaller with decrease in the size. The saturation magnetizations of the Ni nanoparticles without capping layers were calculated based on the assumption that the interior atoms of the nanoparticles were magnetic, whereas the surface-oxidized atoms were non-magnetic. The measured and calculated saturation magnetization values decreased in approximately the same fashion as the TOP/Ni ratio increased, indicating that the decrease could be mainly attributed to increases in the amounts of capping layer and oxidized surface atoms. PMID- 28335302 TI - Effect of Graphene-Graphene Oxide Modified Anode on the Performance of Microbial Fuel Cell. AB - The inferior hydrophilicity of graphene is an adverse factor to the performance of the graphene modified anodes (G anodes) in microbial fuel cells (MFCs). In this paper, different amounts of hydrophilic graphene oxide (GO) were doped into the modification layers to elevate the hydrophilicity of the G anodes so as to further improve their performance. Increasing the GO doped ratio from 0.15 mg.mg 1 to 0.2 mg.mg-1 and 0.25 mg.mg-1, the static water contact angle (thetac) of the G-GO anodes decreased from 74.2 +/- 0.52 degrees to 64.6 +/- 2.75 degrees and 41.7 +/- 3.69 degrees , respectively. The G-GO0.2 anode with GO doped ratio of 0.2 mg.mg-1 exhibited the optimal performance and the maximum power density (Pmax) of the corresponding MFC was 1100.18 mW.m-2, 1.51 times higher than that of the MFC with the G anode. PMID- 28335301 TI - Facile Synthesis of g-C3N4 Nanosheets/ZnO Nanocomposites with Enhanced Photocatalytic Activity in Reduction of Aqueous Chromium(VI) under Visible Light. AB - Graphitic-C3N4 nanosheets (CN)/ZnO photocatalysts (CN/ZnO) with different CN loadings were successfully prepared via a simple precipitation-calcination in the presence of exfoliated C3N4 nanosheets. Their morphology and structure were thoroughly characterized by powder X-ray diffraction (XRD), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), X-ray photoelectron spectroscopy (XPS), UV-Vis diffuse reflectance spectroscopy (DRS) and photoluminescence spectra (PL). The results showed that hexagonal wurzite phase ZnO nanoparticles were randomly distributed onto the CN nanosheets with a well-bonded interface between the two components in the CN/ZnO composites. The performance of the photocatalytic Cr(VI) reduction indicated that CN/ZnO exhibited better photocatalytic activity than pure ZnO under visible-light irradiation and the photocatalyst composite with a lower loading of CN sheets eventually displayed higher activity. The enhanced performance of CN/ZnO photocatalysts could be ascribed to the increased absorption of the visible light and the effective transfer and separation of the photogenerated charge carriers. PMID- 28335303 TI - Detection of Prohibited Fish Drugs Using Silver Nanowires as Substrate for Surface-Enhanced Raman Scattering. AB - Surface-enhanced Raman scattering or surface-enhanced Raman spectroscopy (SERS) is a promising detection technology, and has captured increasing attention. Silver nanowires were synthesized using a rapid polyol method and optimized through adjustment of the molar ratio of poly(vinyl pyrrolidone) and silver nitrate in a glycerol system. Ultraviolet-visible spectrometry, X-ray diffraction, and transmission electron microscopy were used to characterize the silver nanowires. The optimal silver nanowires were used as a SERS substrate to detect prohibited fish drugs, including malachite green, crystal violet, furazolidone, and chloramphenicol. The SERS spectra of crystal violet could be clearly identified at concentrations as low as 0.01 ng/mL. The minimum detectable concentration for malachite green was 0.05 ng/mL, and for both furazolidone and chloramphenicol were 0.1 MUg/mL. The results showed that the as-prepared Ag nanowires SERS substrate exhibits high sensitivity and activity. PMID- 28335305 TI - Simultaneous Detection of Dopamine and Uric Acid Using a Poly(l-lysine)/Graphene Oxide Modified Electrode. AB - A novel, simple and selective electrochemical method was investigated for the simultaneous detection of dopamine (DA) and uric acid (UA) on a poly(l lysine)/graphene oxide (GO) modified glassy carbon electrode (PLL/GO/GCE) by differential pulse voltammetry (DPV). The electrochemically prepared PLL/GO sensory platform toward the oxidation of UA and DA exhibited several advantages, including high effective surface area, more active sites and enhanced electrochemical activity. Compared to the PLL-modified GCE (PLL/GCE), GO-modified GCE and bare GCE, the PLL/GO/GCE exhibited an increase in the anodic potential difference and a remarkable enhancement in the current responses for both UA and DA. For the simultaneous detection of DA and UA, the detection limits of 0.021 and 0.074 MUM were obtained, while 0.031 and 0.018 MUM were obtained as the detection limits for the selective detection of UA and DA, using DPV in the linear concentration ranges of 0.5 to 20.0 and 0.5 to 35 MUM, respectively. In addition, the PLL/GO/GCE demonstrated good reproducibility, long-term stability, excellent selectivity and negligible interference of ascorbic acid (AA). The proposed modified electrode was successfully implemented in the simultaneous detection of DA and UA in human blood serum, urine and dopamine hydrochloride injection with satisfactory results. PMID- 28335304 TI - Silver Nanoparticle-Embedded Thin Silica-Coated Graphene Oxide as an SERS Substrate. AB - A hybrid of Ag nanoparticle (NP)-embedded thin silica-coated graphene oxide (GO@SiO2@Ag NPs) was prepared as a surface-enhanced Raman scattering (SERS) substrate. A 6 nm layer of silica was successfully coated on the surface of GO by the physical adsorption of sodium silicate, followed by the hydrolysis of 3 mercaptopropyl trimethoxysilane. Ag NPs were introduced onto the thin silica coated graphene oxide by the reduction of Ag+ to prepare GO@SiO2@Ag NPs. The GO@SiO2@Ag NPs exhibited a 1.8-fold enhanced Raman signal compared to GO without a silica coating. The GO@SiO2@Ag NPs showed a detection limit of 4 mercaptobenzoic acid (4-MBA) at 0.74 MUM. PMID- 28335306 TI - Ionic Adsorption and Desorption of CNT Nanoropes. AB - A nanorope is comprised of several carbon nanotubes (CNTs) with different chiralities. A molecular dynamic model is built to investigate the ionic adsorption and desorption of the CNT nanoropes. The charge distribution on the nanorope is obtained by using a modified gradient method based on classical electrostatic theory. The electrostatic interactions among charged carbon atoms are calculated by using the Coulomb law. It was found here that the charged nanorope can adsorb heavy metal ions, and the adsorption and desorption can be realized by controlling the strength of applied electric field. The distance between the ions and the nanorope as well as the amount of ions have an effect on the adsorption capacity of the nanorope. The desorption process takes less time than that of adsorption. The study indicates that the CNT nanorope can be used as a core element of devices for sewage treatment. PMID- 28335307 TI - Zinc Oxide Nanorods-Decorated Graphene Nanoplatelets: A Promising Antimicrobial Agent against the Cariogenic Bacterium Streptococcus mutans. AB - Nanomaterials are revolutionizing the field of medicine to improve the quality of life due to the myriad of applications stemming from their unique properties, including the antimicrobial activity against pathogens. In this study, the antimicrobial and antibiofilm properties of a novel nanomaterial composed by zinc oxide nanorods-decorated graphene nanoplatelets (ZNGs) are investigated. ZNGs were produced by hydrothermal method and characterized through field-emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy (EDX) and X-ray diffraction (XRD) techniques. The antimicrobial activity of ZNGs was evaluated against Streptococcus mutans, the main bacteriological agent in the etiology of dental caries. Cell viability assay demonstrated that ZNGs exerted a strikingly high killing effect on S. mutans cells in a dose-dependent manner. Moreover, FE-SEM analysis revealed relevant mechanical damages exerted by ZNGs at the cell surface of this dental pathogen rather than reactive oxygen species (ROS) generation. In addition, inductively coupled plasma mass spectrometry (ICP MS) measurements showed negligible zinc dissolution, demonstrating that zinc ion release in the suspension is not associated with the high cell mortality rate. Finally, our data indicated that also S. mutans biofilm formation was affected by the presence of graphene-zinc oxide (ZnO) based material, as witnessed by the safranin staining and growth curve analysis. Therefore, ZNGs can be a remarkable nanobactericide against one of the main dental pathogens. The potential applications in dental care and therapy are very promising. PMID- 28335309 TI - Separation of Bacteria, Protozoa and Carbon Nanotubes by Density Gradient Centrifugation. AB - Sustainable production and use of carbon nanotube (CNT)-enabled materials require efficient assessment of CNT environmental hazards, including the potential for CNT bioaccumulation and biomagnification in environmental receptors. Microbes, as abundant organisms responsible for nutrient cycling in soil and water, are important ecological receptors for studying the effects of CNTs. Quantification of CNT association with microbial cells requires efficient separation of CNT associated cells from individually dispersed CNTs and CNT agglomerates. Here, we designed, optimized, and demonstrated procedures for separating bacteria (Pseudomonas aeruginosa) from unbound multiwall carbon nanotubes (MWCNTs) and MWCNT agglomerates using sucrose density gradient centrifugation. We demonstrate separation of protozoa (Tetrahymena thermophila) from MWCNTs, bacterial agglomerates, and protozoan fecal pellets by centrifugation in an iodixanol solution. The presence of MWCNTs in the density gradients after centrifugation was determined by quantification of 14C-labeled MWCNTs; the recovery of microbes from the density gradient media was confirmed by optical microscopy. Protozoan intracellular contents of MWCNTs and of bacteria were also unaffected by the designed separation process. The optimized methods contribute to improved efficiency and accuracy in quantifying MWCNT association with bacteria and MWCNT accumulation in protozoan cells, thus supporting improved assessment of CNT bioaccumulation. PMID- 28335308 TI - Probe Microscopic Studies of DNA Molecules on Carbon Nanotubes. AB - Hybrids of DNA and carbon nanotubes (CNTs) are promising nanobioconjugates for nanobiosensors, carriers for drug delivery, and other biological applications. In this review, nanoscopic characterization of DNA-CNT hybrids, in particular, characterization by scanning probe microscopy (SPM), is summarized. In many studies, topographical imaging by atomic force microscopy has been performed. However, some researchers have demonstrated advanced SPM operations in order to maximize its unique and valuable functions. Such sophisticated approaches are attractive and will have a significant impact on future studies of DNA-CNT hybrids. PMID- 28335310 TI - Effect of Continuous Multi-Walled Carbon Nanotubes on Thermal and Mechanical Properties of Flexible Composite Film. AB - To investigate the effect of continuous multi-walled carbon nanotubes (MWCNTs) on the thermal and mechanical properties of composites, we propose a fabrication method for a buckypaper-filled flexible composite film prepared by a two-step process involving buckypaper fabrication using vacuum filtration of MWCNTs, and composite film fabrication using the dipping method. The thermal conductivity and tensile strength of the composite film filled with the buckypaper exhibited improved results, respectively 76% and 275% greater than those of the individual MWCNT-filled composite film. It was confirmed that forming continuous MWCNT fillers is an important factor which determines the physical characteristics of the composite film. In light of the study findings, composite films using buckypaper as a filler and polydimethylsiloxane (PDMS) as a flexible matrix have sufficient potential to be applied as a heat-dissipating material, and as a flexible film with high thermal conductivity and excellent mechanical properties. PMID- 28335311 TI - A Study of Inverted-Type Perovskite Solar Cells with Various Composition Ratios of (FAPbI3)1-x(MAPbBr3)x. AB - : This work presents mixed (FAPbI3)1-x(MAPbBr3)x perovskite films with various composition ratios, x (x = 0-1), which are formed using the spin coating method. The structural, optical, and electronic behaviors of the mixed (FAPbI3)1 x(MAPbBr3)x perovskite films are discussed. A device with structure glass/indium tin oxide (ITO)/poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS)/mixed perovskite/C60/BCP/Ag was fabricated. The mixed perovskite film was an active light-harvesting layer. PEDOT: PSS was a hole transporting layer between the ITO and perovskite. Both C60 and bathocuproine (BCP) were electron transporting layers. MAPbBr3 was added to FAPbI3 with a composition ratio of x = 0.2, stabilizing the perovskite phase, which exhibited a uniform and dense morphology. The optimal device exhibited band matching with C60, resulting in a low series resistance (Rsh) and a high fill factor (FF). Therefore, the device with composition (FAPbI3)1-x(MAPbBr3)x and x = 0.2 exhibited outstanding performance. PMID- 28335312 TI - Correction: Yan, X., et al. Study on Utilization of Carboxyl Group Decorated Carbon Nanotubes and Carbonation Reaction for Improving Strengths and Microstructures of Cement Paste. Nanomaterials 2016, 6, 153. AB - The authors wish to make the following correction to this paper [1].[...]. PMID- 28335313 TI - Triboelectric Hydrogen Gas Sensor with Pd Functionalized Surface. AB - Palladium (Pd)-based hydrogen (H2) gas sensors have been widely investigated thanks to its fast reaction and high sensitivity to hydrogen. Various sensing mechanisms have been adopted for H2 gas sensors; however, all the sensors must be powered through an external battery. We report here an H2 gas sensor that can detect H2 by measuring the output voltages generated during contact electrification between two friction surfaces. When the H2 sensor, composed of Pd coated ITO (indium tin oxide) and PET (polyethylene Terephthalate) film, is exposed to H2, its output voltage is varied in proportion to H2 concentration because the work function (WF) of Pd-coated surface changes, altering triboelectric charging behavior. Specifically, the output voltage of the sensor is gradually increased as exposing H2 concentration increases. Reproducible and sensitive sensor response was observed up 1% H2 exposure. The approach introduced here can easily be adopted to development of triboelectric gas sensors detecting other gas species. PMID- 28335314 TI - Effects of G-Quadruplex Topology on Electronic Transfer Integrals. AB - G-quadruplex is a quadruple helical form of nucleic acids that can appear in guanine-rich parts of the genome. The basic unit is the G-tetrad, a planar assembly of four guanines connected by eight hydrogen bonds. Its rich topology and its possible relevance as a drug target for a number of diseases have stimulated several structural studies. The superior stiffness and electronic pi pi overlap between consecutive G-tetrads suggest exploitation for nanotechnologies. Here we inspect the intimate link between the structure and the electronic properties, with focus on charge transfer parameters. We show that the electronic couplings between stacked G-tetrads strongly depend on the three dimensional atomic structure. Furthermore, we reveal a remarkable correlation with the topology: a topology characterized by the absence of syn-anti G-G sequences can better support electronic charge transfer. On the other hand, there is no obvious correlation of the electronic coupling with usual descriptors of the helix shape. We establish a procedure to maximize the correlation with a global helix shape descriptor. PMID- 28335315 TI - Oxidation of CO and Methanol on Pd-Ni Catalysts Supported on Different Chemically Treated Carbon Nanofibers. AB - In this work, palladium-nickel nanoparticles supported on carbon nanofibers were synthesized, with metal contents close to 25 wt % and Pd:Ni atomic ratios near to 1:2. These catalysts were previously studied in order to determine their activity toward the oxygen reduction reaction. Before the deposition of metals, the carbon nanofibers were chemically treated in order to generate oxygen and nitrogen groups on their surface. Transmission electron microscopy analysis (TEM) images revealed particle diameters between 3 and 4 nm, overcoming the sizes observed for the nanoparticles supported on carbon black (catalyst Pd-Ni CB 1:2). From the CO oxidation at different temperatures, the activation energy Eact for this reaction was determined. These values indicated a high tolerance of the catalysts toward the CO poisoning, especially in the case of the catalysts supported on the non chemically treated carbon nanofibers. On the other hand, apparent activation energy Eap for the methanol oxidation was also determined finding-as a rate determining step-the COads diffusion to the OHads for the catalysts supported on carbon nanofibers. The results here presented showed that the surface functional groups only play a role in the obtaining of lower particle sizes, which is an important factor in the obtaining of low CO oxidation activation energies. PMID- 28335316 TI - Polymer Nanocomposite Film with Metal Rich Surface Prepared by In Situ Single Step Formation of Palladium Nanoparticles: An Interesting Way to Combine Specific Functional Properties. AB - This paper presents a continuous single-step route that permits preparation of a thermostable polymer/metal nanocomposite film and to combine different functional properties in a unique material. More precisely, palladium nanoparticles are in situ generated in a polyimide matrix thanks to a designed curing cycle which is applied to a polyamic acid/metal precursor solution cast on a glass plate. A metal-rich surface layer which is strongly bonded to the bulk film is formed in addition to homogeneously dispersed metal nanoparticles. This specific morphology leads to obtaining an optically reflective film. The metal nanoparticles act as gas diffusion barriers for helium, oxygen, and carbon dioxide; they induce a tortuosity effect which allows dividing the gas permeation coefficients by a factor near to 2 with respect to the neat polyimide matrix. Moreover, the ability of the in situ synthesized palladium nanoparticles to entrap hydrogen is evidenced. The nanocomposite film properties can be modulated as a function of the location of the film metal-rich surface with respect to the hydrogen feed. The synthesized nanocomposite could represent a major interest for a wide variety of applications, from specific coatings for aerospace or automotive industry, to catalysis applications or sensors. PMID- 28335317 TI - Cytotoxicity of Silver Nanoparticle and Chitin-Nanofiber Sheet Composites Caused by Oxidative Stress. AB - Size-controlled spherical silver nanoparticles (<10 nm) and chitin-nanofiber sheet composites (Ag NPs/CNFS) have previously been reported to have strong antimicrobial activity in vitro. Although Ag NPs/CNFS have strong antimicrobial activity, their cytotoxicity has not been investigated. This study was performed to evaluate the effects of Ag NPs/CNFS on cytotoxicity for fibroblasts in vitro and healing delay of wound repair in vivo, focused on oxidative stress. Cytotoxic activities of Ag NPs/CNFS were investigated using a fibroblast cell proliferation assay, nitric oxide/nitrogen dioxide (NO/NO2) measurement of the cell lysates in vitro, inhibitory effects of Ag NPs/CNFS on healing-impaired wound repair using diabetic mice in vivo, 8-hydroxy-2'-deoxyguanosine (8-OHdG) immunohistochemical staining of the skin sections, and generation of carbonyl protein in the wound was performed to evaluate cytotoxicity with oxidative stress. Ag NPs/CNFS exhibited cytotoxicity for fibroblasts and a significant increase of total NO/NO2 levels in the cell lysates in vitro and increased levels of 8-OHdG and carbonyl proteins in vivo. Although wound repair in the continuously Ag NPs/CNFS-treated group was delayed, it could be mitigated by washing the covered wound with saline. Thus, Ag NPs/CNFS may become accepted as an anti-infectious wound dressing. PMID- 28335318 TI - A Label-Free and Sensitive Fluorescent Qualitative Assay for Bisphenol A Based on Rolling Circle Amplification/Exonuclease III-Combined Cascade Amplification. AB - Bisphenol A (BPA) detection in drinking water and food packaging materials has attracted much attention since the discovery that BPA can interfere with normal physiological processes and cause adverse health effects. Here, we constructed a label-free aptamer fluorescent assay for selective and sensitive detection of BPA based on the rolling circle amplification (RCA)/Exonuclease III (Exo III) combined cascade amplification strategy. First, the duplex DNA probe (RP) with anti-BPA aptamer and trigger sequence was designed for BPA recognition and signal amplification. Next, under the action of BPA, the trigger probe was liberated from RP to initiate RCA reaction as primary amplification. Subsequently, the RCA products were used to trigger Exo III assisted secondary amplification with the help of hairpin probes, producing plenty of "G-quadruplex" in lantern-like structures. Finally, the continuously enriched "G-quadruplex lanterns" were lightened by zinc(II)-protoporphyrin IX (ZnPPIX) generating enhanced fluorescence signals. By integrating the primary RCA and secondary Exo III mediated cascade amplification strategy, this method displayed an excellent sensitivity with the detection limits of 5.4 * 10-17 M. In addition, the anti-BPA aptamer exhibits high recognition ability with BPA, guaranteeing the specificity of detection. The reporter signal probe (G-quadruplex with ZnPPIX) provides a label-free fluorescence signals readout without complicated labeling procedures, making the method simple in design and cost-effective in operation. Moreover, environmental samples analysis was also performed, suggesting that our strategy was reliable and had a great potential application in environmental monitoring. PMID- 28335319 TI - Influence of Quantum Dot Concentration on Carrier Transport in ZnO:TiO2 Nano Hybrid Photoanodes for Quantum Dot-Sensitized Solar Cells. AB - Zinc oxide nanowire and titanium dioxide nanoparticle (ZnO:TiO2 NW/NP) hybrid films were utilized as the photoanode layer in quantum dot-sensitized solar cells (QDSSCs). CdSe quantum dots (QDs) with a ZnS passivation layer were deposited on the ZnO:TiO2 NW/NP layer as a photosensitizer by successive ion layer adsorption and reaction (SILAR). Cells were fabricated using a solid-state polymer electrolyte and intensity-modulated photovoltage and photocurrent spectroscopy (IMVS/PS) was carried out to study the electron transport properties of the cell. Increasing the SILAR coating number enhanced the total charge collection efficiency of the cell. The electron transport time constant and diffusion length were found to decrease as more QD layers were added. PMID- 28335320 TI - Cellular Interactions and Formation of an Epithelial "Nanocoating-Like Barrier" with Mesoporous Silica Nanoparticles. AB - Oral mucosa as the front-line barrier in the mouth is constantly exposed to a complex microenvironment with multitudinous microbes. In this study, the interactions of mesoporous silica nanoparticles (MSNs) with primary human gingival epithelial cells were analyzed for up to 72 h, and their diffusion capacity in the reconstructed human gingival epithelia (RHGE) and porcine ear skin models was further assessed at 24 h. It was found that the synthesized fluorescent mesoporous silica nanoparticles (RITC-NPs) with low cytotoxicity could be uptaken, degraded, and/or excreted by the human gingival epithelial cells. Moreover, the RITC-NPs penetrated into the stratum corneum of RHGE in a time-dependent manner, while they were unable to get across the barrier of stratum corneum in the porcine ear skins. Consequently, the penetration and accumulation of RITC-NPs at the corneum layers of epithelia could form a "nanocoating-like barrier". This preliminary proof-of-concept study suggests the feasibility of developing nanoparticle-based antimicrobial and anti-inflammatory agents through topical application for oral healthcare. PMID- 28335322 TI - Black Phosphorus: Critical Review and Potential for Water Splitting Photocatalyst. AB - A century after its first synthesis in 1914, black phosphorus has been attracting significant attention as a promising two-dimensional material in recent years due to its unique properties. Nowadays, with the development of its exfoliation method, there are extensive applications of black phosphorus in transistors, batteries and optoelectronics. Though, because of its hardship in mass production and stability problems, the potential of the black phosphorus in various fields is left unexplored. Here, we provide a comprehensive review of crystal structure, electronic, optical properties and synthesis of black phosphorus. Recent research works about the applications of black phosphorus is summarized. Among them, the possibility of black phosphorous as a solar water splitting photocatalyst is mainly discussed and the feasible novel structure of photocatalysts based on black phosphorous is proposed. PMID- 28335323 TI - Morphology Controlled Fabrication of InN Nanowires on Brass Substrates. AB - Growth of semiconductor nanowires on cheap metal substrates could pave the way to the large-scale manufacture of low-cost nanowire-based devices. In this work, we demonstrated that high density InN nanowires can be directly grown on brass substrates by metal-organic chemical vapor deposition. It was found that Zn from the brass substrates is the key factor in the formation of nanowires by restricting the lateral growth of InN. The nanowire morphology is highly dependent on the growth temperature. While at a lower growth temperature, the nanowires and the In droplets have large diameters. At the elevated growth temperature, the lateral sizes of the nanowires and the In droplets are much smaller. Moreover, the nanowire diameter can be controlled in situ by varying the temperature in the growth process. This method is very instructive to the diameter-controlled growth of nanowires of other materials. PMID- 28335321 TI - Two-Dimensional Semiconductor Optoelectronics Based on van der Waals Heterostructures. AB - Two-dimensional (2D) semiconductors such as transition metal dichalcogenides (TMDCs) and black phosphorous have drawn tremendous attention as an emerging optical material due to their unique and remarkable optical properties. In addition, the ability to create the atomically-controlled van der Waals (vdW) heterostructures enables realizing novel optoelectronic devices that are distinct from conventional bulk counterparts. In this short review, we first present the atomic and electronic structures of 2D semiconducting TMDCs and their exceptional optical properties, and further discuss the fabrication and distinctive features of vdW heterostructures assembled from different kinds of 2D materials with various physical properties. We then focus on reviewing the recent progress on the fabrication of 2D semiconductor optoelectronic devices based on vdW heterostructures including photodetectors, solar cells, and light-emitting devices. Finally, we highlight the perspectives and challenges of optoelectronics based on 2D semiconductor heterostructures. PMID- 28335324 TI - DNA Origami Reorganizes upon Interaction with Graphite: Implications for High Resolution DNA Directed Protein Patterning. AB - Although there is a long history of the study of the interaction of DNA with carbon surfaces, limited information exists regarding the interaction of complex DNA-based nanostructures with the important material graphite, which is closely related to graphene. In view of the capacity of DNA to direct the assembly of proteins and optical and electronic nanoparticles, the potential for combining DNA-based materials with graphite, which is an ultra-flat, conductive carbon substrate, requires evaluation. A series of imaging studies utilizing Atomic Force Microscopy has been applied in order to provide a unified picture of this important interaction of structured DNA and graphite. For the test structure examined, we observe a rapid destabilization of the complex DNA origami structure, consistent with a strong interaction of single-stranded DNA with the carbon surface. This destabilizing interaction can be obscured by an intentional or unintentional primary intervening layer of single-stranded DNA. Because the interaction of origami with graphite is not completely dissociative, and because the frustrated, expanded structure is relatively stable over time in solution, it is demonstrated that organized structures of pairs of the model protein streptavidin can be produced on carbon surfaces using DNA origami as the directing material. PMID- 28335325 TI - Nanoscale Electric Characteristics and Oriented Assembly of Halobacterium salinarum Membrane Revealed by Electric Force Microscopy. AB - Purple membranes (PM) of the bacteria Halobacterium salinarum are a unique natural membrane where bacteriorhodopsin (BR) can convert photon energy and pump protons. Elucidating the electronic properties of biomembranes is critical for revealing biological mechanisms and developing new devices. We report here the electric properties of PMs studied by using multi-functional electric force microscopy (EFM) at the nanoscale. The topography, surface potential, and dielectric capacity of PMs were imaged and quantitatively measured in parallel. Two orientations of PMs were identified by EFM because of its high resolution in differentiating electrical characteristics. The extracellular (EC) sides were more negative than the cytoplasmic (CP) side by 8 mV. The direction of potential difference may facilitate movement of protons across the membrane and thus play important roles in proton pumping. Unlike the side-dependent surface potentials observed in PM, the EFM capacitive response was independent of the side and was measured to be at a dC/dz value of ~5.25 nF/m. Furthermore, by modification of PM with de novo peptides based on peptide-protein interaction, directional oriented PM assembly on silicon substrate was obtained for technical devices. This work develops a new method for studying membrane nanoelectronics and exploring the bioelectric application at the nanoscale. PMID- 28335327 TI - Targeting at the Nanoscale: A Novel S-Layer Fusion Protein Enabling Controlled Immobilization of Biotinylated Molecules. AB - With the aim of constructing an S-layer fusion protein that combines both excellent self-assembly and specific ligand i.e., biotin binding ability, streptavidin (aa 16-133) was fused to the S-layer protein of Sporosarcina ureae ATCC 13881 (SslA) devoid of its N-terminal 341 and C-terminal 172 amino acids. The genetically engineered chimeric protein could be successfully produced in E. coli, isolated, and purified via Ni affinity chromatography. In vitro recrystallisation experiments performed with the purified chimeric protein in solution and on a silicon wafer have demonstrated that fusion of the streptavidin domain does not interfere with the self-assembling properties of the S-layer part. The chimeric protein self-assembled into multilayers. More importantly, the streptavidin domain retained its full biotin-binding ability, a fact evidenced by experiments in which biotinylated quantum dots were coupled to the fusion protein monomers and adsorbed onto the in vitro recrystallised fusion protein template. In this way, this S-layer fusion protein can serve as a functional template for the controlled immobilization of biotinylated and biologically active molecules. PMID- 28335326 TI - Tuning the Emission Energy of Chemically Doped Graphene Quantum Dots. AB - Tuning the emission energy of graphene quantum dots (GQDs) and understanding the reason of tunability is essential for the GOD function in optoelectronic devices. Besides material-based challenges, the way to realize chemical doping and band gap tuning also pose a serious challenge. In this study, we tuned the emission energy of GQDs by substitutional doping using chlorine, nitrogen, boron, sodium, and potassium dopants in solution form. Photoluminescence data obtained from (Cl- and N-doped) GQDs and (B-, Na-, and K-doped) GQDs, respectively exhibited red- and blue-shift with respect to the photoluminescence of the undoped GQDs. X-ray photoemission spectroscopy (XPS) revealed that oxygen functional groups were attached to GQDs. We qualitatively correlate red-shift of the photoluminescence with the oxygen functional groups using literature references which demonstrates that more oxygen containing groups leads to the formation of more defect states and is the reason of observed red-shift of luminescence in GQDs. Further on, time resolved photoluminescence measurements of Cl- and N-GQDs demonstrated that Cl substitution in GQDs has effective role in radiative transition whereas in N-GQDs leads to photoluminescence (PL) quenching with non-radiative transition to ground state. Presumably oxidation or reduction processes cause a change of effective size and the bandgap. PMID- 28335328 TI - Investigation of the Mechanical Properties and Microstructure of Graphene Nanoplatelet-Cement Composite. AB - In this work, graphene nanoplatelets (GNPs) were dispersed uniformly in aqueous solution using methylcellulose (MC) as a dispersing agent via ultrasonic processing. Homogenous GNP suspensions were incorporated into the cement matrix to investigate the effect of GNPs on the mechanical behavior of cement paste. The optimum concentration ratio of GNPs to MC was confirmed as 1:7 by ultraviolet visible spectroscopy (UV-Vis), and the optical microscope and transmission electron microscopy (TEM) images displayed remarkable dispersing performance. The GNP-cement composite exhibited better mechanical properties with the help of surface-modified GNPs. The flexural strength of cement paste increased up to 15% 24% with 0.05 wt % GNPs (by weight of cement). Meanwhile, the compressive strength of the GNP-cement composite increased up to 3%-8%. The X-ray diffraction (XRD) and thermal analysis (TG/DTG) demonstrated that the GNPs could accelerate the degree of hydration and increase the amount of hydration products, especially at an early age. Meanwhile, the lower porosity and finer pore size distribution of GNP-cement composite were detected by mercury intrusion porosimetry (MIP). In addition, scanning electron microscope (SEM) analysis showed the introduction of GNPs could impede the development of cracks and preserve the completeness of the matrix through the plicate morphology and tortuous behavior of GNPs. PMID- 28335329 TI - Nanoparticle-Based Delivery of Anaplasma marginale Membrane Proteins; VirB9-1 and VirB10 Produced in the Pichia pastoris Expression System. AB - Bovine anaplasmosis or cattle-tick fever is a tick-borne haemolytic disease caused by the rickettsial haemoparasite Anaplasma marginale in tropical and subtropical areas of the world. While difficult to express, the proteins VirB9-1 and VirB10 are immunogenic components of the outer membrane type IV secretion system that have been identified as candidate antigens for vaccines targeting of A. marginale. Soluble VirB9-1 and VirB10 were successfully expressed using Pichia pastoris. When formulated with the self-adjuvanting silica vesicles, SV-100 (diameter: 50 nm, and pore entrance size: 6 nm), 200 ug of VirB9-1 and VirB10 were adsorbed per milligram of nanoparticle. The VirB9-1 and VirB10, SV-100 formulations were shown to induce higher antibody responses in mice compared to the QuilA formulations. Moreover, intracellular staining of selected cytokines demonstrated that both VirB9-1 and VirB10 formulations induced cell-mediated immune responses in mice. Importantly, the SV-100 VirB9-1 and VirB10 complexes were shown to specifically stimulate bovine T-cell linages derived from calves immunised with A. marginale outer membrane fractions, suggesting formulations will be useful for bovine immunisation and protection studies. Overall this study demonstrates the potential of self-adjuvanting silica vesicle formulations to address current deficiencies in vaccine delivery applications. PMID- 28335330 TI - Carbon Nanotube (CNT) Honeycomb Cell Area-Dependent Optical Reflectance. AB - The relationship between the physical structure of carbon nanotube (CNT) honeycomb structures and their total, diffuse, and specular reflectance is investigated for the first time. It is found that CNT honeycomb structures with average cell areas of smaller than 30 MUm2 show a higher total reflectance. Particularly, a thinner, highly packed CNT (buckypaper) film, along with a larger wall height and higher ratio of wall height to cell area, markedly increase the total reflectance for cell areas smaller than 30 MUm2, which means that a higher total area of buckypapers in CNT walls and bottom areas increases the total reflectance, including the diffuse reflectance. It is also found that the total reflection of non-absorbed light in CNT honeycomb structures consists primarily of diffuse reflectance. PMID- 28335331 TI - The Use of Spray-Dried Mn3O4/C Composites as Electrocatalysts for Li-O2 Batteries. AB - The electrocatalytic activities of Mn3O4/C composites are studied in lithium oxygen (Li-O2) batteries as cathode catalysts. The Mn3O4/C composites are fabricated using ultrasonic spray pyrolysis (USP) with organic surfactants as the carbon sources. The physical and electrochemical performance of the composites is characterized by X-ray diffraction, scanning electron microscopy, particle size analysis, Brunauer-Emmett-Teller (BET) measurements, elemental analysis, galvanostatic charge-discharge methods and rotating ring-disk electrode (RRDE) measurements. The electrochemical tests demonstrate that the Mn3O4/C composite that is prepared using Trition X-114 (TX114) surfactant has higher activity as a bi-functional catalyst and delivers better oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) catalytic performance in Li-O2 batteries because there is a larger surface area and particles are homogeneous with a meso/macro porous structure. The rate constant (kf) for the production of superoxide radical (O2*-) and the propylene carbonate (PC)-electrolyte decomposition rate constant (k) for M3O4/C and Super P electrodes are measured using RRDE experiments and analysis in the 0.1 M tetrabutylammonium hexafluorophosphate (TBAPF6)/PC electrolyte. The results show that TX114 has higher electrocatalytic activity for the first step of ORR to generate O2*- and produces a faster PC-electrolyte decomposition rate. PMID- 28335332 TI - Micromechanical Properties of Nanostructured Clay-Oxide Multilayers Synthesized by Layer-by-Layer Self-Assembly. AB - Clay-based nanostructured multilayers, such as clay-polymer multilayers and clay oxide multilayers, have attracted growing attention owing to their remarkable mechanical properties and promising application in various fields. In this paper, synthesis of a new kind of nanostructured clay-oxide multilayers by layer-by layer self-assembly was explored. Nano-mechanical characterization of 18 clay based multilayer samples, prepared under as-deposited (i.e., air-dried) and annealing conditions at 400 degrees C/600 degrees C with different precursor cations and multilayer structure, were carried out using nanoindentation testing, atomic force microscopy (AFM), and X-ray diffraction (XRD). The influencing factors, including as-deposited and annealing conditions and clay concentrations on the mechanical properties were analyzed. Results show that all of the multilayers exhibit high bonding strength between interlayers. Higher modulus and hardness of clay-based multilayers were obtained with lower clay concentrations than that with higher clay concentrations. Different relationships between the modulus and hardness and the annealing temperature exist for a specific type of clay-oxide multilayer. This work offers the basic and essential knowledge on design of clay-based nanostructured multilayers by layer-by-layer self-assembly. PMID- 28335333 TI - Plant Mediated Green Synthesis of CuO Nanoparticles: Comparison of Toxicity of Engineered and Plant Mediated CuO Nanoparticles towards Daphnia magna. AB - Research on green production methods for metal oxide nanoparticles (NPs) is growing, with the objective to overcome the potential hazards of these chemicals for a safer environment. In this study, facile, ecofriendly synthesis of copper oxide (CuO) nanoparticles was successfully achieved using aqueous extract of Pterospermum acerifolium leaves. P. acerifolium-fabricated CuO nanoparticles were further characterized by UV-Visible spectroscopy, field emission scanning electron microscopy (FE-SEM), energy dispersive X-ray (EDX), Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS) and dynamic light scattering (DLS). Plant-mediated CuO nanoparticles were found to be oval shaped and well dispersed in suspension. XPS confirmed the elemental composition of P. acerifolium-mediated copper nanoparticles as comprised purely of copper and oxygen. DLS measurements and ion release profile showed that P. acerifolium mediated copper nanoparticles were more stable than the engineered CuO NPs. Copper oxide nanoparticles are used in many applications; therefore, their potential toxicity cannot be ignored. A comparative study was performed to investigate the bio-toxic impacts of plant-synthesized and engineered CuO nanoparticles on water flea Daphnia. Experiments were conducted to investigate the 48-h acute toxicity of engineered CuO NPs and plant-synthesized nanoparticles. Lower EC50 value 0.102 +/- 0.019 mg/L was observed for engineered CuO NPs, while 0.69 +/- 0.226 mg/L was observed for plant-synthesized CuO NPs. Additionally, ion release from CuO nanoparticles and 48-h accumulation of these nano CuOs in daphnids were also calculated. Our findings thus suggest that the contribution of released ions from nanoparticles and particles/ions accumulation in Daphnia needs to be interpreted with care. PMID- 28335334 TI - Hybrid Nanostructures Containing Sulfadiazine Modified Chitosan as Antimicrobial Drug Carriers. AB - Chitosan (CH) nanofibrous structures containing sulfadiazine (SDZ) or sulfadiazine modified chitosan (SCH) in the form of functional nanoparticles attached to nanofibers (hybrid nanostructures) were obtained by mono-axial and coaxial electrospinning. The mono-axial design consisted of a SDZ/CH mixture solution fed through a single nozzle while the coaxial design consisted of SCH and CH solutions separately supplied to the inner and outer nozzle (or in reverse order). The CH ability to form nanofibers assured the formation of a nanofiber mesh, while SDZ and SCH, both in form of suspensions in the electrospun solution, assured the formation of active nanoparticles which remained attached to the CH nanofiber mesh after the electrospinning process. The obtained nanostructures were morphologically characterized by scanning electron microscopy (SEM) and atomic force microscopy (AFM). The SDZ release profiles and kinetics were analyzed. The SDZ or SCH nanoparticles loosely attached at the surface of the nanofibers, provide a burst release in the first 20 min, which is important to stop the possible initial infection in a wound, while the SDZ and SCH from the nanoparticles which are better confined (or even encapsulated) into the CH nanofibers would be slowly released with the erosion/disruption of the CH nanofiber mesh. PMID- 28335335 TI - Contact Resistance and Channel Conductance of Graphene Field-Effect Transistors under Low-Energy Electron Irradiation. AB - We studied the effects of low-energy electron beam irradiation up to 10 keV on graphene-based field effect transistors. We fabricated metallic bilayer electrodes to contact mono- and bi-layer graphene flakes on SiO2, obtaining specific contact resistivity rho c ~ 19 k Omega . u m 2 and carrier mobility as high as 4000 cm2.V-1.s-1. By using a highly doped p-Si/SiO2 substrate as the back gate, we analyzed the transport properties of the device and the dependence on the pressure and on the electron bombardment. We demonstrate herein that low energy irradiation is detrimental to the transistor current capability, resulting in an increase in contact resistance and a reduction in carrier mobility, even at electron doses as low as 30 e-/nm2. We also show that irradiated devices recover their pristine state after few repeated electrical measurements. PMID- 28335336 TI - Oral Toxicity and Intestinal Transport Mechanism of Colloidal Gold Nanoparticle Treated Red Ginseng. AB - (1) Background: Application of nanotechnology or nanomaterials in agricultural food crops has attracted increasing attention with regard to improving crop production, quality, and nutrient utilization. Gold nanoparticles (Au-NPs) have been reported to enhance seed yield, germination rate, and anti-oxidant potential in food crops, raising concerns about their toxicity potential. In this study, we evaluated the oral toxicity of red ginseng exposed to colloidal Au-NPs during cultivation (G-red ginseng) in rats and their intestinal transport mechanism. (2) Methods: 14-day repeated oral administration of G-red ginseng extract to rats was performed, and body weight, hematological, serum biochemical, and histopathological values were analyzed. An in vitro model of human intestinal follicle-associated epithelium (FAE) and an intestinal epithelial monolayer system were used for intestinal transport mechanistic study. (3) Results: No remarkable oral toxicity of G-red ginseng extract in rats was found, and Au-NPs did not accumulate in any organ, although Au-NP transfer to G-red ginseng and some increased saponin levels were confirmed. Au-NPs were transcytozed by microfold (M) cells, but not by a paracellular pathway in the intestinal epithelium. (4) Conclusion: These findings suggest great potential of Au-NPs for agricultural food crops at safe levels. Further study is required to elucidate the functional effects of Au-NPs on ginseng and long-term toxicity. PMID- 28335337 TI - Effect of Crystal Orientation on Self-Assembly Nanocones Formed on Tungsten Surface Induced by Helium Ion Irradiation and Annealing. AB - The self-assembly nanocone structures on the surface of polycrystalline tungsten were created by He+ ion irradiation and then annealing, and the resulting topography and morphology were characterized using atomic force microscopy and scanning electron microscopy. The cross-sectional samples of the self-assembly nanocones were prepared using an in situ-focused ion beam and then observed using transmission electron microscopy. The self-assembly nanocones were induced by the combined effect of He+ ion irradiation, the annealing process and the chromium impurity. The distribution characteristics, density and morphology of the nanocones exhibited a distinct difference relating to the crystal orientations. The highest density of the nanocones was observed on the grain surface with a (1 1 1) orientation, with the opposite for that with a (0 0 1) orientation and a medium value on the (1 0 1)-oriented grain. The size of the self-assembly nanocones increased with increasing the annealing time which met a power-law relationship. Irradiation-induced defects acted as the nucleation locations of the protrusions which attracted the migration of the tiny amount of chromium atoms. Under the action of temperature, the protrusions finally evolved into the nanocones. PMID- 28335338 TI - Green Synthesis of Iron Nanoparticles and Their Environmental Applications and Implications. AB - Recent advances in nanoscience and nanotechnology have also led to the development of novel nanomaterials, which ultimately increase potential health and environmental hazards. Interest in developing environmentally benign procedures for the synthesis of metallic nanoparticles has been increased. The purpose is to minimize the negative impacts of synthetic procedures, their accompanying chemicals and derivative compounds. The exploitation of different biomaterials for the synthesis of nanoparticles is considered a valuable approach in green nanotechnology. Biological resources such as bacteria, algae fungi and plants have been used for the production of low-cost, energy-efficient, and nontoxic environmental friendly metallic nanoparticles. This review provides an overview of various reports of green synthesised zero valent metallic iron (ZVMI) and iron oxide (Fe2O3/Fe3O4) nanoparticles (NPs) and highlights their substantial applications in environmental pollution control. This review also summarizes the ecotoxicological impacts of green synthesised iron nanoparticles opposed to non green synthesised iron nanoparticles. PMID- 28335339 TI - Electrochemical and Capacitive Properties of Carbon Dots/Reduced Graphene Oxide Supercapacitors. AB - There is much recent interest in graphene-based composite electrode materials because of their excellent mechanical strengths, high electron mobilities, and large specific surface areas. These materials are good candidates for applications in supercapacitors. In this work, a new graphene-based electrode material for supercapacitors was fabricated by anchoring carbon dots (CDs) on reduced graphene oxide (rGO). The capacitive properties of electrodes in aqueous electrolytes were systematically studied by galvanostatic charge-discharge measurements, cyclic voltammetry, and electrochemical impedance spectroscopy. The capacitance of rGO was improved when an appropriate amount of CDs were added to the material. The CD/rGO electrode exhibited a good reversibility, excellent rate capability, fast charge transfer, and high specific capacitance in 1 M H2SO4. Its capacitance was as high as 211.9 F/g at a current density of 0.5 A/g. This capacitance was 74.3% higher than that of a pristine rGO electrode (121.6 F/g), and the capacitance of the CD/rGO electrode retained 92.8% of its original value after 1000 cycles at a CDs-to-rGO ratio of 5:1. PMID- 28335340 TI - Recent Advances in Chiral Nematic Structure and Iridescent Color of Cellulose Nanocrystal Films. AB - One unique property of cellulose nanocrystals (CNC) is their property of forming suspensions with chiral nematic order. This order can be preserved in films cast from the suspensions, raising the possibility of applications as photonic materials and templates. However, it has proved difficult to generate uniform, well-ordered chiral nematic materials from CNC. Recently, the importance of kinetic arrest due to gel formation in the later stages of evaporation has been recognized as a key step in film formation. In this brief review, recent developments regarding the structure of chiral nematic suspensions and films as monitored by polarized light microscopy are outlined, and attention is drawn to the importance of shear forces on the self-organization process. PMID- 28335341 TI - Design and Electrochemical Study of Platinum-Based Nanomaterials for Sensitive Detection of Nitric Oxide in Biomedical Applications. AB - The extensive physiological and regulatory roles of nitric oxide (NO) have spurred the development of NO sensors, which are of critical importance in neuroscience and various medical applications. The development of electrochemical NO sensors is of significant importance, and has garnered a tremendous amount of attention due to their high sensitivity and selectivity, rapid response, low cost, miniaturization, and the possibility of real-time monitoring. Nanostructured platinum (Pt)-based materials have attracted considerable interest regarding their use in the design of electrochemical sensors for the detection of NO, due to their unique properties and the potential for new and innovative applications. This review focuses primarily on advances and insights into the utilization of nanostructured Pt-based electrode materials, such as nanoporous Pt, Pt and PtAu nanoparticles, PtAu nanoparticle/reduced graphene oxide (rGO), and PtW nanoparticle/rGO-ionic liquid (IL) nanocomposites, for the detection of NO. The design, fabrication, characterization, and integration of electrochemical NO sensing performance, selectivity, and durability are addressed. The attractive electrochemical properties of Pt-based nanomaterials have great potential for increasing the competitiveness of these new sensors and open up new opportunities in the creation of novel NO-sensing technologies for biological and medical applications. PMID- 28335342 TI - Innovative Self-Cleaning and Biocompatible Polyester Textiles Nano-Decorated with Fe-N-Doped Titanium Dioxide. AB - The development of innovative technologies to modify natural textiles holds an important impact for medical applications, including the prevention of contamination with microorganisms, particularly in the hospital environment. In our study, Fe and N co-doped TiO2 nanoparticles have been obtained via the hydrothermal route, at moderate temperature, followed by short thermal annealing at 400 degrees C. These particles were used to impregnate polyester (PES) materials which have been evaluated for their morphology, photocatalytic performance, antimicrobial activity against bacterial reference strains, and in vitro biocompatibility on human skin fibroblasts. Microscopic examination and quantitative assays have been used to evaluate the cellular morphology and viability, cell membrane integrity, and inflammatory response. All treated PES materials specifically inhibited the growth of Gram-negative bacilli strains after 15 min of contact, being particularly active against Pseudomonas aeruginosa. PES fabrics treated with photocatalysts did not affect cell membrane integrity nor induce inflammatory processes, proving good biocompatibility. These results demonstrate that the treatment of PES materials with TiO2-1% Fe-N particles could provide novel biocompatible fabrics with short term protection against microbial colonization, demonstrating their potential for the development of innovative textiles that could be used in biomedical applications for preventing patients' accidental contamination with microorganisms from the hospital environment. PMID- 28335343 TI - Photoelectrochemical Performance Observed in Mn-Doped BiFeO3 Heterostructured Thin Films. AB - Pure BiFeO3 and heterostructured BiFeO3/BiFe0.95Mn0.05O3 (5% Mn-doped BiFeO3) thin films have been prepared by a chemical deposition method. The band structures and photosensitive properties of these films have been investigated elaborately. Pure BiFeO3 films showed stable and strong response to photo illumination (open circuit potential kept -0.18 V, short circuit photocurrent density was -0.023 mA.cm-2). By Mn doping, the energy band positions shifted, resulting in a smaller band gap of BiFe0.95Mn0.05O3 layer and an internal field being built in the BiFeO3/BiFe0.95Mn0.05O3 interface. BiFeO3/BiFe0.95Mn0.05O3 and BiFe0.95Mn0.05O3 thin films demonstrated poor photo activity compared with pure BiFeO3 films, which can be explained by the fact that Mn doping brought in a large amount of defects in the BiFe0.95Mn0.05O3 layers, causing higher carrier combination and correspondingly suppressing the photo response, and this negative influence was more considerable than the positive effects provided by the band modulation. PMID- 28335344 TI - A Targeted Nanoprobe Based on Carbon Nanotubes-Natural Biopolymer Chitosan Composites. AB - A novel targeting theranostic nanoprobe based on single-walled carbon nanotubes (SWCNTs)-natural biopolymer chitosan composites was developed for cancer cell targeting imaging and fluorescence imaging-guided photodynamic therapy. First, chitosan was respectively conjugated with a tumor-homing molecule folic acid, or a photosensitizing drug pyropheophorbide a using a water-soluble carbodiimide coupling chemistry. Chitosan was fluorescently labeled by fluorescein isothiocyanate via the covalently linkage of the isothiocyanate group with the amino group. Second, SWCNTs were sonicated in the functional chitosan aqueous solution for 6 h at room temperature in order to obtain the nanoprobe (PPa/FITC SWCNT-FA). The as-prepared nanoprobe has been characterized with transmission electron microscope, confocal microscopy, and cell cytotoxicity tests. Chitosan was decorated onto SWCNTs resulting in the water-dispersible PPa/FITC-SWCNT-FA, and can be selectively transported inside folate receptor-positive tumor cell with good targeting imaging. PPa/FITC-SWCNT-FA exhibited low dark toxicity about 7%-13%, and high phototoxicity about 60%-74% against HeLa cells upon a 635 nm laser irradiation, indicating satisfying biocompatibility and antitumor activity. These results suggest the study could offer a feasible alternative to presently available nanoparticle-based theranostic agents. PMID- 28335345 TI - Electrostatic Self-Assembly of Diamond Nanoparticles onto Al- and N-Polar Sputtered Aluminum Nitride Surfaces. AB - Electrostatic self-assembly of diamond nanoparticles (DNPs) onto substrate surfaces (so-called nanodiamond seeding) is a notable technique, enabling chemical vapor deposition (CVD) of nanocrystalline diamond thin films on non diamond substrates. In this study, we examine this technique onto differently polarized (either Al- or N-polar) c-axis oriented sputtered aluminum nitride (AlN) film surfaces. This investigation shows that Al-polar films, as compared to N-polar ones, obtain DNPs with higher density and more homogeneously on their surfaces. The origin of these differences in density and homogeneity is discussed based on the hydrolysis behavior of AlN surfaces in aqueous suspensions. PMID- 28335346 TI - A Facile Method to In-Situ Synthesize Porous Ni2GeO4 Nano-Sheets on Nickel Foam as Advanced Anode Electrodes for Li-Ion Batteries. AB - A strategy for growth of porous Ni2GeO4 nanosheets on conductive nickel (Ni) foam with robust adhesion as a high-performance electrode for Li-ion batteries is proposed and realized, through a facile two-step method. It involves the low temperature hydro-thermal synthesis of bimetallic (Ni, Ge) hydroxide nanosheets precursor on Ni foam substrates and subsequent thermal transformation to porous Ni2GeO4 nanosheets. The as-prepared Ni2GeO4 nanosheets possess many interparticle mesopores with a size range from 5 to 15 nm. The hierarchical structure of porous Ni2GeO4 nanosheets supported by Ni foam promises fast electron and ion transport, large electroactive surface area, and excellent structural stability. The efficacy of the specially designed structure is demonstrated by the superior electrochemical performance of the generated Ni2GeO4 nanosheets including a high capacity of 1.8 mA.h.cm-2 at a current density of 50 MUA.cm-2, good cycle stability, and high power capability at room temperature. Because of simple conditions, this fabrication strategy may be easily extended to other mixed metal oxides (MxGeOy). PMID- 28335347 TI - The Dispersion State of Tangled Multi-Walled Carbon Nanotubes Affects Their Cytotoxicity. AB - The medical applications of carbon nanotubes (CNTs) have garnered much attention. However, evaluating the safety of CNTs remains difficult, and no consensus has been reached. Moreover, assessing the biosafety of multi-walled CNTs (MWCNTs), which can become tangled during manufacturing, is challenging because they do not readily disperse. We studied how the dispersion state of tangled MWCNTs affects their cytotoxicity, using three sonicators. Flotube 9110 (FT9110), tangled MWCNTs, were dispersed in two dispersants (fetal bovine serum and polysorbate 80) using a new type of sonicator (PR-1) and two conventional sonicators. The size and cytotoxicity of the dispersed FT9110 were measured using the BEAS-2B human bronchial epithelial cell line. The PR-1 dispersed the FT9110 to agglomerates <200 nm in diameter; FT9110 dispersed with the PR-1 did not show cytotoxicity regardless of dispersant. The other sonicators dispersed the FT9110 to particles >1000 nm in diameter, and cytotoxicity depended on the dispersant. We found that excluding cells adhered to agglomerated FT9110 before evaluating cytotoxicity can lead to false-positive results. The PR-1 sonicator dispersed tangled FT9110 to many single fibers, which showed lower cytotoxicity than conventionally-sonicated MWCNTs. We suggest that dispersion state should be accounted for when evaluating the cytotoxicity of MWCNTs. PMID- 28335348 TI - Electrochemical Synthesis of Polypyrrole, Reduced Graphene Oxide, and Gold Nanoparticles Composite and Its Application to Hydrogen Peroxide Biosensor. AB - Here we report a facile eco-friendly one-step electrochemical approach for the fabrication of a polypyrrole (PPy), reduced graphene oxide (RGO), and gold nanoparticles (nanoAu) biocomposite on a glassy carbon electrode (GCE). The electrochemical behaviors of PPy-RGO-nanoAu and its application to electrochemical detection of hydrogen peroxide were investigated by cyclic voltammetry. Graphene oxide and pyrrole monomer were first mixed and casted on the surface of a cleaned GCE. After an electrochemical processing consisting of the electrooxidation of pyrrole monomer and simultaneous electroreduction of graphene oxide and auric ions (Au3+) in aqueous solution, a PPy-RGO-nanoAu biocomposite was synthesized on GCE. Each component of PPy-RGO-nanoAu is electroactive without non-electroactive substance. The obtained PPy-RGO nanoAu/GCE exhibited high electrocatalytic activity toward hydrogen peroxide, which allows the detection of hydrogen peroxide at a negative potential of about 0.62 V vs. SCE. The amperometric responses of the biosensor displayed a sensitivity of 40 uA/mM, a linear range of 32 uM-2 mM, and a detection limit of 2.7 uM (signal-to-noise ratio = 3) with good stability and acceptable reproducibility and selectivity. The results clearly demonstrate the potential of the as-prepared PPy-RGO-nanoAu biocomposite for use as a highly electroactive matrix for an amperometric biosensor. PMID- 28335350 TI - Shape and Charge of Gold Nanomaterials Influence Survivorship, Oxidative Stress and Moulting of Daphnia magna. AB - Engineered nanomaterials (ENMs) are materials with at least one dimension between 1-100 nm. The small size of ENMs results in a large surface area to volume ratio, giving ENMs novel characteristics that are not traditionally exhibited by larger bulk materials. Coupled with large surface area is an enormous capacity for surface functionalization of ENMs, e.g., with different ligands or surface changes, leading to an almost infinite array of variability of ENMs. Here we explore the effects of various shaped (spheres, rods) and charged (negative, positive) gold ENMs on Daphnia magna (D. magna) in terms of survival, ENM uptake and production of reactive oxygen species (ROS), a key factor in oxidative stress responses. We also investigate the effects of gold ENMs binding to the carapace of D. magna and how this may induce moulting inhibition in addition to toxicity and stress. The findings suggest that ENM shape and surface charge play an important role in determining ENM uptake and toxicity. PMID- 28335349 TI - Exchange Bias Effects in Iron Oxide-Based Nanoparticle Systems. AB - The exploration of exchange bias (EB) on the nanoscale provides a novel approach to improving the anisotropic properties of magnetic nanoparticles for prospective applications in nanospintronics and nanomedicine. However, the physical origin of EB is not fully understood. Recent advances in chemical synthesis provide a unique opportunity to explore EB in a variety of iron oxide-based nanostructures ranging from core/shell to hollow and hybrid composite nanoparticles. Experimental and atomistic Monte Carlo studies have shed light on the roles of interface and surface spins in these nanosystems. This review paper aims to provide a thorough understanding of the EB and related phenomena in iron oxide based nanoparticle systems, knowledge of which is essential to tune the anisotropic magnetic properties of exchange-coupled nanoparticle systems for potential applications. PMID- 28335351 TI - Modified Nanoemulsions with Iron Oxide for Magnetic Resonance Imaging. AB - A nanoemulsion (NE) is a surfactant-based, oil-in-water, nanoscale, high-energy emulsion with a mean droplet diameter of 400-600 nm. When mixed with antigen and applied nasally, a NE acts as a mucosal adjuvant and induces mucosal immune responses. One possible mechanism for the adjuvant effect of this material is that it augments antigen uptake and distribution to lymphoid tissues, where the immune response is generated. Biocompatible iron oxide nanoparticles have been used as a unique imaging approach to study the dynamics of cells or molecular migration. To study the uptake of NEs and track them in vivo, iron oxide nanoparticles were synthesized and dispersed in soybean oil to make iron oxide modified NEs. Our results show that iron oxide nanoparticles can be stabilized in the oil phase of the nanoemulsion at a concentration of 30 ug/MUL and the iron oxide-modified NEs have a mean diameter of 521 nm. In vitro experiments demonstrated that iron oxide-modified NEs can affect uptake by TC-1 cells (a murine epithelial cell line) and reduce the intensity of magnetic resonance (MR) images by shortening the T2 time. Most importantly, in vivo studies demonstrated that iron oxide-modified NE could be detected in mouse nasal septum by both transmission electron microscopy and MR imaging. Altogether these experiments demonstrate that iron oxide-modified NE is a unique tool that can be used to study uptake and distribution of NEs after nasal application. PMID- 28335352 TI - Nano-Biosensor for Monitoring the Neural Differentiation of Stem Cells. AB - In tissue engineering and regenerative medicine, monitoring the status of stem cell differentiation is crucial to verify therapeutic efficacy and optimize treatment procedures. However, traditional methods, such as cell staining and sorting, are labor-intensive and may damage the cells. Therefore, the development of noninvasive methods to monitor the differentiation status in situ is highly desirable and can be of great benefit to stem cell-based therapies. Toward this end, nanotechnology has been applied to develop highly-sensitive biosensors to noninvasively monitor the neural differentiation of stem cells. Herein, this article reviews the development of noninvasive nano-biosensor systems to monitor the neural differentiation of stem cells, mainly focusing on optical (plasmonic) and eletrochemical methods. The findings in this review suggest that novel nano biosensors capable of monitoring stem cell differentiation are a promising type of technology that can accelerate the development of stem cell therapies, including regenerative medicine. PMID- 28335353 TI - The Chemical Deposition Method for the Decoration of Palladium Particles on Carbon Nanofibers with Rapid Conductivity Changes. AB - Palladium (Pd) metal is well-known for hydrogen sensing material due to its high sensitivity and selectivity toward hydrogen, and is able to detect hydrogen at near room temperature. In this work, palladium-doped carbon nanofibers (Pd/CNFs) were successfully produced in a facile manner via electrospinning. Well-organized and uniformly distributed Pd was observed in microscopic images of the resultant nanofibers. Hydrogen causes an increment in the volume of Pd due to the ability of hydrogen atoms to occupy the octahedral interstitial positions within its face centered cubic lattice structure, resulting in the resistance transition of Pd/CNFs. The resistance variation was around 400%, and it responded rapidly within 1 min, even in 5% hydrogen atmosphere conditions at room temperature. This fibrous hybrid material platform will open a new and practical route and stimulate further researches on the development of hydrogen sensing materials with rapid response, even to low concentrations of hydrogen in an atmosphere. PMID- 28335354 TI - Titanium Dioxide Nanoparticle-Biomolecule Interactions Influence Oral Absorption. AB - Titanium dioxide (TiO2) nanoparticles (NPs) have been widely applied in various industrial fields, such as electronics, packaging, food, and cosmetics. Accordingly, concerns about the potential toxicity of TiO2 NPs have increased. In order to comprehend their in vivo behavior and potential toxicity, we must evaluate the interactions between TiO2 NPs and biomolecules, which can alter the physicochemical properties and the fate of NPs under physiological conditions. In the present study, in vivo solubility, oral absorption, tissue distribution, and excretion kinetics of food grade TiO2 (f-TiO2) NPs were evaluated following a single-dose oral administration to rats and were compared to those of general grade TiO2 (g-TiO2) NPs. The effect of the interactions between the TiO2 NPs and biomolecules, such as glucose and albumin, on oral absorption was also investigated, with the aim of determining the surface interactions between them. The intestinal transport pathway was also assessed using 3-dimensional culture systems. The results demonstrate that slightly higher oral absorption of f-TiO2 NPs compared to g-TiO2 NPs could be related to their intestinal transport mechanism by microfold (M) cells, however, most of the NPs were eliminated through the feces. Moreover, the biokinetics of f-TiO2 NPs was highly dependent on their interaction with biomolecules, and the dispersibility was affected by modified surface chemistry. PMID- 28335355 TI - Influence of External Gaseous Environments on the Electrical Properties of ZnO Nanostructures Obtained by a Hydrothermal Method. AB - This paper deals with experimental investigations of ZnO nanostructures, consisting of a mixture of nanoparticles and nanowires, obtained by the chemical (hydrothermal) method. The influences of both oxidizing (NO2) and reducing gases (H2, NH3), as well as relative humidity (RH) on the physical and chemical properties of ZnO nanostructures were tested. Carrier gas effect on the structure interaction with gases was also tested; experiments were conducted in air and nitrogen (N2) atmospheres. The effect of investigated gases on the resistance of the ZnO nanostructures was tested over a wide range of concentrations at room temperature (RT) and at 200 degrees C. The impact of near- ultraviolet (UV) excitation (lambda = 390 nm) at RT was also studied. These investigations indicated a high response of ZnO nanostructures to small concentrations of NO2. The structure responses to 1 ppm of NO2 amounted to about: 600% in N2/230% in air at 200 degrees C (in dark conditions) and 430% in N2/340% in air at RT (with UV excitation). The response of the structure to the effect of NO2 at 200 degrees C is more than 105 times greater than the response to NH3, and more than 106 times greater than that to H2 in the relation of 1 ppm. Thus the selectivity of the structure for NO2 is very good. What is more, the selectivity to NO2 at RT with UV excitation increases in comparison at elevated temperature. This paper presents a great potential for practical applications of ZnO nanostructures (including nanoparticles) in resistive NO2 sensors. PMID- 28335356 TI - Refinement of Magnetite Nanoparticles by Coating with Organic Stabilizers. AB - Magnetite nanoparticles are of great importance in nanotechnology and nanomedicine and have found manifold applications. Here, the effect of coating of magnetite nanoparticles with organic stabilizers, such as O-phosphoryl ethanolamine, glycerol phosphate, phospho-l-ascorbic acid, phospho-d,l-serine, glycolic acid, lactic acid, d,l-malic acid, and d,l-mandelic acid was studied. Remarkably, this procedure led to an improvement of saturation magnetization in three cases rather than to an unfavorable decrease as usually observed. Detailed X-ray powder diffraction investigations revealed that changes in the average crystallite occurred in the coating process. Surprisingly, changes of the average crystallite sizes in either direction were further observed, when the exposure time to the stabilizer was increased. These results imply a new mechanism for the well-known coating of magnetite nanoparticles with stabilizers. Instead of the hitherto accepted simple anchoring of the stabilizers to the magnetite nanoparticle surfaces, a more complex recrystallization mechanism is likely, wherein partial re-dispersion of magnetite moieties from the nanoparticles and re deposition are involved. The results can help producers and users of magnetite nanoparticles to obtain optimal results in the production of core shell magnetite nanoparticles. PMID- 28335357 TI - The Assembly of DNA Amphiphiles at Liquid Crystal-Aqueous Interface. AB - In this article, we synthesized a type of DNA amphiphiles (called DNA-lipids) and systematically studied its assembly behavior at the liquid crystal (LC)-aqueous interface. It turned out that the pure DNA-lipids at various concentrations cannot trigger the optical transition of liquid crystals from planar anchoring to homeotropic anchoring at the liquid crystal-aqueous interface. The co-assembly of DNA-lipid and l-dilauroyl phosphatidylcholine (l-DLPC) indicated that the DLPC assembled all over the LC-aqueous interface, and DNA-lipids prefer to couple with LC in certain areas, particularly in polarized and fluorescent image, forming micron sized net-like structures. The addition of DNA complementary to DNA-lipids forming double stranded DNA-lipids caused de-assembly of DNA-lipids from LC aqueous interface, resulting in the disappearance of net-like structures, which can be visualized through polarized microscope. The optical changes combined with DNA unique designable property and specific interaction with wide range of target molecules, the DNA-lipids decorated LC-aqueous interface would provide a new platform for biological sensing and diagnosis. PMID- 28335358 TI - Optimum Conditions for the Fabrication of Zein/Ag Composite Nanoparticles from Ethanol/H2O Co-Solvents Using Electrospinning. AB - The optimum conditions for the fabrication of zein/Ag composite nanoparticles from ethanol/H2O cosolvents using electrospinning and the properties of the composite were investigated. The zein/Ag nanoparticles were characterized using field-emission scanning electron microscopy, transmission electron microscopy (TEM), X-ray diffraction (XRD), and thermogravimetric analysis. The antibacterial activity of the zein/Ag composite nanoparticles was also investigated. The XRD patterns and TEM images indicate the coexistence of a zein matrix and well distributed Ag nanoparticles. PMID- 28335360 TI - Super-Hydrophobic/Icephobic Coatings Based on Silica Nanoparticles Modified by Self-Assembled Monolayers. AB - A super-hydrophobic surface has been obtained from nanocomposite materials based on silica nanoparticles and self-assembled monolayers of 1H,1H,2H,2H perfluorooctyltriethoxysilane (POTS) using spin coating and chemical vapor deposition methods. Scanning electron microscope images reveal the porous structure of the silica nanoparticles, which can trap small-scale air pockets. An average water contact angle of 163 degrees and bouncing off of incoming water droplets suggest that a super-hydrophobic surface has been obtained based on the silica nanoparticles and POTS coating. The monitored water droplet icing test results show that icing is significantly delayed by silica-based nano-coatings compared with bare substrates and commercial icephobic products. Ice adhesion test results show that the ice adhesion strength is reduced remarkably by silica based nano-coatings. The bouncing phenomenon of water droplets, the icing delay performance and the lower ice adhesion strength suggest that the super hydrophobic coatings based on a combination of silica and POTS also show icephobicity. An erosion test rig based on pressurized pneumatic water impinging impact was used to evaluate the durability of the super-hydrophobic/icephobic coatings. The results show that durable coatings have been obtained, although improvement will be needed in future work aiming for applications in aerospace. PMID- 28335359 TI - Temperature- and Angle-Dependent Magnetic Properties of Ni Nanotube Arrays Fabricated by Electrodeposition in Polycarbonate Templates. AB - Parallel arrays of Ni nanotubes with an external diameter of 150 nm, a wall thickness of 15 nm, and a length of 1.2 +/- 0.3 um were successfully fabricated in ion-track etched polycarbonate (PC) templates by electrochemical deposition. The morphology and crystal structure of the nanotubes were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), and X ray diffraction (XRD). Structural analyses indicate that Ni nanotubes have a polycrystalline structure with no preferred orientation. Angle dependent hysteresis studies at room temperature carried out by using a vibrating sample magnetometer (VSM) demonstrate a transition of magnetization between the two different magnetization reversal modes: curling rotation for small angles and coherent rotation for large angles. Furthermore, temperature dependent magnetic analyses performed with a superconducting quantum interference device (SQUID) magnetometer indicate that magnetization of the nanotubes follows modified Bloch's law in the range 60-300 K, while the deviation of the experimental curve from this law below 60 K can be attributed to the finite size effects in the nanotubes. Finally, it was found that coercivity measured at different temperatures follows Kneller's law within the premises of Stoner-Wohlfarth model for ferromagnetic nanostructures. PMID- 28335361 TI - Preparation and Characterization of Zirconia-Coated Nanodiamonds as a Pt Catalyst Support for Methanol Electro-Oxidation. AB - Zirconia-coated nanodiamond (ZrO2/ND) electrode material was successfully prepared by one-step isothermal hydrolyzing from ND-dispersed ZrOCl2.8H2O aqueous solution. High-resolution transmission electron microscopy reveals that a highly conformal and uniform ZrO2 shell was deposited on NDs by this simple method. The coating obtained at 90 degrees C without further calcination was mainly composed of monoclinic nanocrystalline ZrO2 rather than common amorphous Zr(OH)4 clusters. The ZrO2/NDs and pristine ND powder were decorated with platinum (Pt) nanoparticles by electrodeposition from 5 mM chloroplatinic acid solution. The electrochemical studies indicate that Pt/ZrO2/ND catalysts have higher electrocatalytic activity and better stability for methanol oxidation than Pt/ND catalysts in acid. PMID- 28335362 TI - The Change of Electronic Transport Behaviors by P and B Doping in Nano Crystalline Silicon Films with Very High Conductivities. AB - Nano-crystalline Si films with high conductivities are highly desired in order to develop the new generation of nano-devices. Here, we first demonstrate that the grain boundaries played an important role in the carrier transport process in un doped nano-crystalline Si films as revealed by the temperature-dependent Hall measurements. The potential barrier height can be well estimated from the experimental results, which is in good agreement with the proposed model. Then, by introducing P and B doping, it is found that the scattering of grain boundaries can be significantly suppressed and the Hall mobility is monotonously decreased with the temperature both in P- and B-doped nano-crystalline Si films, which can be attributed to the trapping of P and B dopants in the grain boundary regions to reduce the barriers. Consequently, a room temperature conductivity as high as 1.58 * 103 S/cm and 4 * 102 S/cm is achieved for the P-doped and B-doped samples, respectively. PMID- 28335363 TI - Antimicrobial, Antioxidant, and Anticancer Activities of Biosynthesized Silver Nanoparticles Using Marine Algae Ecklonia cava. AB - Green synthesis of silver nanoparticles (AgNPs) has gained great interest as a simple and eco-friendly alternative to conventional chemical methods. In this study, AgNPs were synthesized by using extracts of marine algae Ecklonia cava as reducing and capping agents. The formation of AgNPs using aqueous extract of Ecklonia cava was confirmed visually by color change and their surface plasmon resonance peak at 418 nm, measured by UV-visible spectroscopy. The size, shape, and morphology of the biosynthesized AgNPs were observed by transmission electron microscopy and dynamic light scattering analysis. The biosynthesized AgNPs were nearly spherical in shape with an average size around 43 nm. Fourier transform infrared spectroscopy (FTIR) analysis confirmed the presence of phenolic compounds in the aqueous extract of Ecklonia cava as reducing and capping agents. X-ray diffraction (XRD) analysis was also carried out to demonstrate the crystalline nature of the biosynthesized AgNPs. Antimicrobial results determined by an agar well diffusion assay demonstrated a significant antibacterial activity of the AgNPs against Escherichia coli and Staphylococcus aureus. Antioxidant results determined by 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging assay revealed an efficient antioxidant activity of the biosynthesized AgNPs. The biosynthesized AgNPs also exhibited a strong apoptotic anticancer activity against human cervical cancer cells. Our findings demonstrate that aqueous extract of Ecklonia cava is an effective reducing agent for green synthesis of AgNPs with efficient antimicrobial, antioxidant, and anticancer activities. PMID- 28335364 TI - Nickel Based Electrospun Materials with Tuned Morphology and Composition. AB - Nickel is set to play a crucial role to substitute the less-abundant platinum in clean electrochemical energy conversion and storage devices and catalysis. The controlled design of Ni nanomaterials is essential to fine-tune their properties to match these applications. A systematic study of electrospinning and thermal post-treatment parameters has been performed to synthesize Ni materials and tune their morphology (fibers, ribbons, and sponge-like structures) and composition (metallic Ni, NiO, Ni/C, Ni3N and their combinations). The obtained Ni-based spun materials have been characterized by scanning and transmission electron microscopy, X-ray diffraction and thermogravimetric analysis. The possibility of upscaling and the versatility of electrospinning open the way to large-scale production of Ni nanostructures, as well as bi- and multi-metal systems for widened applications. PMID- 28335366 TI - Nano Copper Oxide-Modified Carbon Cloth as Cathode for a Two-Chamber Microbial Fuel Cell. AB - In this work, Cu2O nanoparticles were deposited on a carbon cloth cathode using a facile electrochemical method. The morphology of the modified cathode, which was characterized by scanning electron microscopy (SEM) and Brunauer-Emmett-Teller (BET) tests, showed that the porosity and specific surface area of the cathode improved with longer deposition times. X-ray photoelectron spectroscopy (XPS) and cyclic voltammetry (CV) results showed that cupric oxide and cuprous oxide coexisted on the carbon cloth, which improved the electrochemical activity of cathode. The cathode with a deposition time of 100 s showed the best performance, with a power density twice that of bare carbon cloth. Linear sweep voltammetry (LSV) and electrochemical impedance spectroscopy (EIS) results revealed that moderate deposition of nano copper oxide on carbon cloth could dramatically reduce the charge transfer resistance, which contributed to the enhanced electrochemical performance. The mediation mechanism of copper oxide nanocatalyst was illustrated by the fact that the recycled conversion between cupric oxide and cuprous oxide accelerated the electron transfer efficiency on the cathode. PMID- 28335365 TI - Antibacterial Properties of Visible-Light-Responsive Carbon-Containing Titanium Dioxide Photocatalytic Nanoparticles against Anthrax. AB - The bactericidal activity of conventional titanium dioxide (TiO2) photocatalyst is effective only on irradiation by ultraviolet light, which restricts the applications of TiO2 for use in living environments. Recently, carbon-containing TiO2 nanoparticles [TiO2(C) NP] were found to be a visible-light-responsive photocatalyst (VLRP), which displayed significantly enhanced antibacterial properties under visible light illumination. However, whether TiO2(C) NPs exert antibacterial properties against Bacillus anthracis remains elusive. Here, we evaluated these VLRP NPs in the reduction of anthrax-induced pathogenesis. Bacteria-killing experiments indicated that a significantly higher proportion (40%-60%) of all tested Bacillus species, including B. subtilis, B. cereus, B. thuringiensis, and B. anthracis, were considerably eliminated by TiO2(C) NPs. Toxin inactivation analysis further suggested that the TiO2(C) NPs efficiently detoxify approximately 90% of tested anthrax lethal toxin, a major virulence factor of anthrax. Notably, macrophage clearance experiments further suggested that, even under suboptimal conditions without considerable bacterial killing, the TiO2(C) NP-mediated photocatalysis still exhibited antibacterial properties through the reduction of bacterial resistance against macrophage killing. Our results collectively suggested that TiO2(C) NP is a conceptually feasible anti anthrax material, and the relevant technologies described herein may be useful in the development of new strategies against anthrax. PMID- 28335368 TI - Shape Evolution of Hierarchical W18O49 Nanostructures: A Systematic Investigation of the Growth Mechanism, Properties and Morphology-Dependent Photocatalytic Activities. AB - Hierarchical tungsten oxide assemblies such as spindle-like structures, flowers with sharp petals, nanowires and regular hexagonal structures are successfully synthesized via a solvothermal reduction method by simply adjusting the reaction conditions. On the basis of the experimental results, it is determined that the reaction time significantly influences the phase transition, microstructure and photocatalytic activity of the prepared samples. The possible mechanisms for the morphology evolution process have been systematically proposed. Moreover, the as prepared products exhibit significant morphology-dependent photocatalytic activity. The flower-like W18O49 prepared at 6 h possesses a large specific surface area (150.1 m2?g-1), improved separation efficiency of electron-hole pairs and decreased electron-transfer resistance according to the photoelectrochemical measurements. As a result, the flower-like W18O49 prepared at 6 h exhibits the highest photocatalytic activity for the degradation of Methyl orange aqueous solution. The radical trap experiments showed that the degradation of MO was driven mainly by the participation of h+ and *O2- radicals. PMID- 28335367 TI - Investigating Polymer-Metal Interfaces by Grazing Incidence Small-Angle X-Ray Scattering from Gradients to Real-Time Studies. AB - Tailoring the polymer-metal interface is crucial for advanced material design. Vacuum deposition methods for metal layer coating are widely used in industry and research. They allow for installing a variety of nanostructures, often making use of the selective interaction of the metal atoms with the underlying polymer thin film. The polymer thin film may eventually be nanostructured, too, in order to create a hierarchy in length scales. Grazing incidence X-ray scattering is an advanced method to characterize and investigate polymer-metal interfaces. Being non-destructive and yielding statistically relevant results, it allows for deducing the detailed polymer-metal interaction. We review the use of grazing incidence X-ray scattering to elucidate the polymer-metal interface, making use of the modern synchrotron radiation facilities, allowing for very local studies via in situ (so-called "stop-sputter") experiments as well as studies observing the nanostructured metal nanoparticle layer growth in real time. PMID- 28335369 TI - Effect of Nano-SiO2 on the Hydration and Microstructure of Portland Cement. AB - This paper systematically studied the modification of cement-based materials by nano-SiO2 particles with an average diameter of about 20 nm. In order to obtain the effect of nano-SiO2 particles on the mechanical properties, hydration, and pore structure of cement-based materials, adding 1%, 3%, and 5% content of nano SiO2 in cement paste, respectively. The results showed that the reaction of nano SiO2 particles with Ca(OH)2 (crystal powder) started within 1 h, and formed C-S-H gel. The reaction speed was faster after aging for three days. The mechanical properties of cement-based materials were improved with the addition of 3% nano SiO2, and the early strength enhancement of test pieces was obvious. Three-day compressive strength increased 33.2%, and 28-day compressive strength increased 18.5%. The exothermic peak of hydration heat of cement increased significantly after the addition of nano-SiO2. Appearance time of the exothermic peak was advanced and the total heat release increased. Thermogravimetric-differential scanning calorimetry (TG-DSC) analysis showed that nano-SiO2 promoted the formation of C-S-H gel. The results of mercury intrusion porosimetry (MIP) showed that the total porosity of cement paste with 3% nano-SiO2 was reduced by 5.51% and 5.4% at three days and 28 days, respectively, compared with the pure cement paste. At the same time, the pore structure of cement paste was optimized, and much-detrimental pores and detrimental pores decreased, while less harmful pores and innocuous pores increased. PMID- 28335370 TI - Vibration of Piezoelectric ZnO-SWCNT Nanowires. AB - A hybrid nanowire (HNW) was constructed by coating a single-wall carbon nanotube (SWCNT) with piezoelectric zinc oxide (ZnO). The two components of the HNW interact with each other via the van der Waals (vdW) force. This paper aims to study the effect of the piezoelectricity in the ZnO layer and the inter-phase vdW interaction on the fundamental vibration of the HNWs. In doing this, a new model was developed where the two components of the HNWs were modeled as Euler beams coupled via the interphase vdW interaction. Based on the model, the dependence of the frequency on an applied electrical voltage was calculated for HNWs of different geometric sizes to reveal the voltage effect. The results were then compared with those calculated without considering the inter-phase vdW interaction. It was found that the interphase vdW interaction can substantially decrease the structural stiffness, leading to a greatly enhanced piezoelectric effect but a lower frequency for the vibration of the HNWs. PMID- 28335371 TI - Synthesis of Antifungal Agents from Xanthene and Thiazine Dyes and Analysis of Their Effects. AB - Indoor fungi growth is an increasing home health problem as our homes are more tightly sealed. One thing that limits durability of the antifungal agents is the scarcity of reactive sites on many surfaces to attach these agents. In order to increase graft yield of photosensitizers to the fabrics, poly(acrylic acid-co styrene sulfonic acid-co-vinyl benzyl rose bengal or phloxine B) were polymerized and then grafted to electrospun fabrics. In an alternative process, azure A or toluidine blue O were grafted to poly(acrylic acid), which was subsequently grafted to nanofiber-based and microfiber-based fabrics. The fabrics grafted with photosensitizers induced antifungal effects on all seven types of fungi in the order of rose bengal > phloxine B > toluidine blue O > azure A, which follows the quantum yield production of singlet oxygen for these photoactive dyes. Their inhibition rates for inactivating fungal spores decreased in the order of P. cinnamomi, T. viride, A. niger, A. fumigatus, C. globosum, P. funiculosum, and M. grisea, which is associated with lipid composition in membrane and the morphology of fungal spores. The antifungal activity was also correlated with the surface area of fabric types which grafted the photosensitizer covalently on the surface as determined by the bound color strength. PMID- 28335372 TI - Graphene Oxide Bionanocomposite Coatings with High Oxygen Barrier Properties. AB - In this work, we present the development of bionanocomposite coatings on poly(ethylene terephthalate) (PET) with outstanding oxygen barrier properties. Pullulan and graphene oxide (GO) were used as main polymer phase and nanobuilding block (NBB), respectively. The oxygen barrier performance was investigated at different filler volume fractions (phi) and as a function of different relative humidity (RH) values. Noticeably, the impermeable nature of GO was reflected under dry conditions, in which an oxygen transmission rate (OTR, mL.m-2.24 h-1) value below the detection limit of the instrument (0.01 mL.m-2.24 h-1) was recorded, even for phi as low as 0.0004. A dramatic increase of the OTR values occurred in humid conditions, such that the barrier performance was totally lost at 90% RH (the OTR of coated PET films was equal to the OTR of bare PET films). Modelling of the experimental OTR data by Cussler's model suggested that the spatial ordering of GO sheets within the main pullulan phase was perturbed because of RH fluctuations. In spite of the presence of the filler, all the formulations allowed the obtainment of final materials with haze values below 3%, the only exception being the formulation with the highest loading of GO (phi ~ 0.03). The mechanisms underlying the experimental observations are discussed. PMID- 28335373 TI - Dietary Patterns and Insomnia Symptoms in Chinese Adults: The China Kadoorie Biobank. AB - Limited attention has been paid to the effect of dietary patterns on sleep problems. In the present study, we analyzed the cross-sectional data of 481,242 adults aged 30-79 years from the China Kadoorie Biobank. A laptop-based questionnaire was administered to collect information on food intakes and insomnia symptoms. Logistic regression was used to estimate the odds ratios of each insomnia symptom according to quartiles of each dietary pattern, with adjustment for potential confounders. Two major dietary patterns were derived by factor analysis. The traditional northern dietary pattern was characterized by high intakes of wheat and other staple food, whereas the modern dietary pattern was characterized by high intakes of meat, poultry, fish, eggs, fresh fruit, and dairy products. Both dietary patterns were associated with a decreased prevalence of insomnia symptoms (p for trend < 0.001); after adjustment for potential confounders, individuals who had the highest quartile score of traditional northern dietary pattern were 12%-19% less likely to have insomnia symptoms compared to those in the lowest quartile (odds ratio: 0.81-0.88), and the corresponding values for the modern dietary pattern were 0.89-1.01. Furthermore, interactions of these two dietary patterns on insomnia symptoms were observed. Further prospective studies are needed to elucidate the relationship between diet and insomnia. PMID- 28335374 TI - Beverage Consumption among U.S. Children Aged 0-24 Months: National Health and Nutrition Examination Survey (NHANES). AB - Data on beverage consumption patterns in early life are limited. The aim of this study was to describe beverage consumption by sociodemographic characteristics, along with water intake and sources of water among U.S. children aged 0-24 months. Data from 2740 children in the 2005-2012 NHANES were analysed. Food intake was determined via one 24-h dietary recall. Beverages were categorised according to What We Eat In America groups. Poverty-Income ratio was used to define household income. During infancy (0-5.9 months and 6-11.9 months) infant formulas were the most commonly consumed beverage, 74.1% and 78.6% of children consuming, respectively. Comparatively fewer children, 41.6% and 24.3%, consumed breast milk. In toddlers (12-24 months), the most commonly consumed beverages were plain milk (83.6% of children consuming), water (68.6%), 100% fruit juice (51.8%) and sweetened beverages (31.2%). Non-Hispanic black and Mexican-American children were more likely to consume sweetened beverages, 100% fruit juice and infant formula than Non-Hispanic white children. Children from lower income households were more likely to consume sweetened beverages and 100% fruit juice and less likely to consume breast milk than children from higher income households. Total water intake increased with age and the contribution of water from food and beverage sources was ~20% and ~80% for all children, respectively. Disparities in beverage consumption by race/ethnicity and income level are apparent in early life. PMID- 28335375 TI - Assessing the Spectral Properties of Sunlit and Shaded Components in Rice Canopies with Near-Ground Imaging Spectroscopy Data. AB - Monitoring the components of crop canopies with remote sensing can help us understand the within-canopy variation in spectral properties and resolve the sources of uncertainties in the spectroscopic estimation of crop foliar chemistry. To date, the spectral properties of leaves and panicles in crop canopies and the shadow effects on their spectral variation remain poorly understood due to the insufficient spatial resolution of traditional spectroscopy data. To address this issue, we used a near-ground imaging spectroscopy system with high spatial and spectral resolutions to examine the spectral properties of rice leaves and panicles in sunlit and shaded portions of canopies and evaluate the effect of shadows on the relationships between spectral indices of leaves and foliar chlorophyll content. The results demonstrated that the shaded components exhibited lower reflectance amplitude but stronger absorption features than their sunlit counterparts. Specifically, the reflectance spectra of panicles had unique double-peak absorption features in the blue region. Among the examined vegetation indices (VIs), significant differences were found in the photochemical reflectance index (PRI) between leaves and panicles and further differences in the transformed chlorophyll absorption reflectance index (TCARI) between sunlit and shaded components. After an image-level separation of canopy components with these two indices, statistical analyses revealed much higher correlations between canopy chlorophyll content and both PRI and TCARI of shaded leaves than for those of sunlit leaves. In contrast, the red edge chlorophyll index (CIRed-edge) exhibited the strongest correlations with canopy chlorophyll content among all vegetation indices examined regardless of shadows on leaves. These findings represent significant advances in the understanding of rice leaf and panicle spectral properties under natural light conditions and demonstrate the significance of commonly overlooked shaded leaves in the canopy when correlated to canopy chlorophyll content. PMID- 28335377 TI - Cooperative Position Aware Mobility Pattern of AUVs for Avoiding Void Zones in Underwater WSNs. AB - In this paper, we propose two schemes; position-aware mobility pattern (PAMP) and cooperative PAMP (Co PAMP). The first one is an optimization scheme that avoids void hole occurrence and minimizes the uncertainty in the position estimation of glider's. The second one is a cooperative routing scheme that reduces the packet drop ratio by using the relay cooperation. Both techniques use gliders that stay at sojourn positions for a predefined time, at sojourn position self-confidence (s-confidence) and neighbor-confidence (n-confidence) regions that are estimated for balanced energy consumption. The transmission power of a glider is adjusted according to those confidence regions. Simulation results show that our proposed schemes outperform the compared existing one in terms of packet delivery ratio, void zones and energy consumption. PMID- 28335376 TI - Genetic Polymorphisms Contribute to the Individual Variations of Imatinib Mesylate Plasma Levels and Adverse Reactions in Chinese GIST Patients. AB - Imatinib mesylate (IM) has dramatically improved the outcomes of gastrointestinal stromal tumor (GIST) patients. However, the clinical responses of IM may considerably vary among single individuals. This study aimed to investigate the influences of genetic polymorphisms of drug-metabolizing enzyme (CYP3A4), transporters (ABCB1, ABCG2), and nuclear receptor (Pregnane X Receptor (PXR, encoded by NR1I2)) on IM plasma levels and related adverse reactions in Chinese GIST patients. A total of 68 Chinese GIST patients who have received IM 300-600 mg/day were genotyped for six single nucleotide polymorphisms (SNPs) (CYP3A4 rs2242480; ABCB1 rs1045642; ABCG2 rs2231137; NRI12 rs3814055, rs6785049, rs2276706), and the steady-state IM trough plasma concentrations were measured by a validated HPLC method. There were statistically significant variances in the steady-state IM trough plasma concentrations (from 272.22 to 4365.96 ng/mL). Subjects of GG in rs2242480, T allele carriers in rs1045642 and CC in rs3814055 had significantly higher steady-state IM dose-adjusted trough plasma concentrations. Subjects of CC in rs3814055 had significantly higher incidence rate of edema. The genetic polymorphisms of rs2242480, rs1045642, rs3814055 were significantly associated with IM plasma levels, and the genetic variations of rs3814055 were significantly associated with the incidence rate of edema in Chinese GIST patients. The current results may serve as valuable fundamental knowledge for IM therapy in Chinese GIST patients. PMID- 28335378 TI - Bioavailability of Microencapsulated Iron from Fortified Bread Assessed Using Piglet Model. AB - The aim of this study was to investigate the influence of oral iron supplementation, in the form of fortified breads, on the growth performance, health, iron status parameters, and fecal metabolome of anemic piglets. A study was conducted on 24 hybrid (Large White * Landrace * Duroc) piglets. From day 44, the post-natal 12 piglets were supplemented with 100 g of one of two experimental breads, each fortified with 21 mg of ferrous sulphate, either encapsulated or not. After one week of oral supplementation, hematological parameters (hematocrit value, hemoglobin, and red blood cells) showed statistically significant differences (p <= 0.05). Piglets fed with the fortified breads had higher iron concentrations in the heart, liver, and intestinal mucosa compared to anemic piglets fed with control bread. Gene expression of hepcidin, iron exporter ferroportin (IREG1), and divalent metal transporter 1 (DMT1), together with concentrations of plasma ferritin, showed no significant statistical differences between groups. Both fortified breads could be used as sources of bioavailable iron. The seven-day intervention trial showed microencapsulation to have only a mild effect on the effectiveness of iron supplementation in the form of fortified bread. PMID- 28335380 TI - Vitamin E Nicotinate. AB - Vitamin E refers to a family of compounds that function as lipid-soluble antioxidants capable of preventing lipid peroxidation. Naturally occurring forms of vitamin E include tocopherols and tocotrienols. Vitamin E in dietary supplements and fortified foods is often an esterified form of alpha-tocopherol, the most common esters being acetate and succinate. The vitamin E esters are hydrolyzed and converted into free alpha-tocopherol prior to absorption in the intestinal tract. Because its functions are relevant to many chronic diseases, vitamin E has been extensively studied in respect to a variety of diseases as well as cosmetic applications. The forms of vitamin E most studied are natural alpha-tocopherol and the esters alpha-tocopheryl acetate and alpha-tocopheryl succinate. A small number of studies include or focus on another ester form, alpha-tocopheryl nicotinate, an ester of vitamin E and niacin. Some of these studies raise the possibility of differences in metabolism and in efficacy between vitamin E nicotinate and other forms of vitamin E. Recently, through metabolomics studies, we identified that alpha-tocopheryl nicotinate occurs endogenously in the heart and that its level is dramatically decreased in heart failure, indicating the possible biological importance of this vitamin E ester. Since knowledge about vitamin E nicotinate is not readily available in the literature, the purpose of this review is to summarize and evaluate published reports, specifically with respect to alpha-tocopheryl nicotinate with an emphasis on the differences from natural alpha-tocopherol or alpha-tocopheryl acetate. PMID- 28335381 TI - Computational Prediction of the Protonation Sites of Ac-Lys-(Ala)n-Lys-NH2 Peptides through Conceptual DFT Descriptors. AB - Six density functionals (M11, M11L, MN12L, MN12SX, N12, and N12SX) in connection with the Def2TZVP basis set and the SMD solvation model (water as a solvent) have been assessed for the calculation of the molecular structure and properties of several peptides with the general formulaAc-Lys-(Ala)n-Lys-NH2,withn=0to5 [...]. PMID- 28335379 TI - The Role of Adenosine Signaling in Headache: A Review. AB - Migraine is the third most prevalent disease on the planet, yet our understanding of its mechanisms and pathophysiology is surprisingly incomplete. Recent studies have built upon decades of evidence that adenosine, a purine nucleoside that can act as a neuromodulator, is involved in pain transmission and sensitization. Clinical evidence and rodent studies have suggested that adenosine signaling also plays a critical role in migraine headache. This is further supported by the widespread use of caffeine, an adenosine receptor antagonist, in several headache treatments. In this review, we highlight evidence that supports the involvement of adenosine signaling in different forms of headache, headache triggers, and basic headache physiology. This evidence supports adenosine A2A receptors as a critical adenosine receptor subtype involved in headache pain. Adenosine A2A receptor signaling may contribute to headache via the modulation of intracellular Cyclic adenosine monophosphate (cAMP) production or 5' AMP-activated protein kinase (AMPK) activity in neurons and glia to affect glutamatergic synaptic transmission within the brainstem. This evidence supports the further study of adenosine signaling in headache and potentially illuminates it as a novel therapeutic target for migraine. PMID- 28335382 TI - Feasibility of Assessing Diet with a Mobile Food Record for Adolescents and Young Adults with Down Syndrome. AB - Technology-based methods for assessing diet in those with disability remains largely unexplored. The aim was to assess the feasibility of assessing diet with an image-based mobile food record application (mFR) in 51 adolescents and young adults with Down syndrome (PANDs). Adherence was also assessed with the instruction to include a fiducial marker object in the before and after eating images. The PANDs sample completed a four-day mFR and results were compared with a sample of young adults from the Connecting Health and Technology study (CHAT, n = 244). Compared to the CHAT sample, PANDs participants reported more fruit (2.2 +/- 1.8 versus 1.0 +/- 0.9 serves respectively) and vegetables (2.4 +/- 1.3 versus 1.9 +/- 1.0 serves, respectively), but no differences in energy-dense nutrient-poor (EDNP) foods and beverages were observed. Compared to CHAT, PANDs participants captured fewer images with the mFR (4.9 +/- 2.3 versus 4.0 +/- 1.5 images, respectively). Adherence to the instruction to include the fiducial marker in images was lower for PANDs compared with the CHAT sample (90.3% versus 96.5%). Due to the quality of information captured in images and the high acceptability of the fiducial marker, the mFR shows great promise as a feasible method of assessing diet in adolescents and young adults with Down syndrome. PMID- 28335383 TI - A Biomedical Investigation of the Hepatoprotective Effect of Radix salviae miltiorrhizae and Network Pharmacology-Based Prediction of the Active Compounds and Molecular Targets. AB - Radix salviae miltiorrhizae (Danshen in Chinese), a classic traditional Chinese medicine (TCM) herb, has been used for centuries to treat liver diseases. In this study, the preventive and curative potential of Danshen aqueous extract on acute/chronic alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) was studied. The in vivo results indicated that Danshen could alleviate hepatic inflammation, fatty degeneration, and haptic fibrogenesis in ALD and NAFLD models. In the aspect of mechanism of action, the significant reduction in MDA levels in both ALD and NAFLD models implies the decreased levels of oxidative stress by Danshen. However, Danshen treatment could not activate the internal enzymatic antioxidant system in ALD and NAFLD models. To further explore the hepatoprotective mechanism of Danshen, an in silico-based network pharmacology approach was employed in the present study. The pharmacological network analysis result revealed that six potential active ingredients such as tanshinone iia, salvianolic acid b, and Danshensu may contribute to the hepatoprotective effects of Danshen on ALD and NAFLD. The action mechanism may relate with regulating the intracellular molecular targets such as PPARalpha, CYP1A2, and MMP2 for regulation of lipid metabolism, antioxidant and anti-fibrogenesis by these potential active ingredients. Our studies suggest that the combination of network pharmacology strategy with in vivo experimental study may provide a forceful tool for exploring the mechanism of action of traditional Chinese medicine (TCM) herb and developing novel bioactive ingredients. PMID- 28335384 TI - Localization and Tracking of Implantable Biomedical Sensors. AB - Implantable sensor systems are effective tools for biomedical diagnosis, visualization and treatment of various health conditions, attracting the interest of researchers, as well as healthcare practitioners. These systems efficiently and conveniently provide essential data of the body part being diagnosed, such as gastrointestinal (temperature, pH, pressure) parameter values, blood glucose and pressure levels and electrocardiogram data. Such data are first transmitted from the implantable sensor units to an external receiver node or network and then to a central monitoring and control (computer) unit for analysis, diagnosis and/or treatment. Implantable sensor units are typically in the form of mobile microrobotic capsules or implanted stationary (body-fixed) units. In particular, capsule-based systems have attracted significant research interest recently, with a variety of applications, including endoscopy, microsurgery, drug delivery and biopsy. In such implantable sensor systems, one of the most challenging problems is the accurate localization and tracking of the microrobotic sensor unit (e.g., robotic capsule) inside the human body. This article presents a literature review of the existing localization and tracking techniques for robotic implantable sensor systems with their merits and limitations and possible solutions of the proposed localization methods. The article also provides a brief discussion on the connection and cooperation of such techniques with wearable biomedical sensor systems. PMID- 28335385 TI - Patient Posture Monitoring System Based on Flexible Sensors. AB - Monitoring patients using vision cameras can cause privacy intrusion problems. In this paper, we propose a patient position monitoring system based on a patient cloth with unobtrusive sensors. We use flexible sensors based on polyvinylidene fluoride, which is a flexible piezoelectric material. Theflexiblesensorsareinsertedintopartsclosetothekneeandhipoftheloosepatientcloth. We measure electrical signals from the sensors caused by the piezoelectric effect when the knee and hip in the cloth are bent. The measured sensor outputs are transferred to a computer via Bluetooth. We use a custom-made program to detect the position of the patient through a rule-based algorithm and the sensor outputs. The detectable postures are based on six human motions in and around a bed. The proposed system can detect the patient positions with a success rate over 88 percent for three patients. PMID- 28335386 TI - Revisiting the Metabolism and Bioactivation of Ketoconazole in Human and Mouse Using Liquid Chromatography-Mass Spectrometry-Based Metabolomics. AB - Although ketoconazole (KCZ) has been used worldwide for 30 years, its metabolic characteristics are poorly described. Moreover, the hepatotoxicity of KCZ limits its therapeutic use. In this study, we used liquid chromatography-mass spectrometry-based metabolomics to evaluate the metabolic profile of KCZ in mouse and human and identify the mechanisms underlying its hepatotoxicity. A total of 28 metabolites of KCZ, 11 of which were novel, were identified in this study. Newly identified metabolites were classified into three categories according to the metabolic positions of a piperazine ring, imidazole ring, and N-acetyl moiety. The metabolic characteristics of KCZ in human were comparable to those in mouse. Moreover, three cyanide adducts of KCZ were identified in mouse and human liver microsomal incubates as "flags" to trigger additional toxicity study. The oxidation of piperazine into iminium ion is suggested as a biotransformation responsible for bioactivation. In summary, the metabolic characteristics of KCZ, including reactive metabolites, were comprehensively understood using a metabolomics approach. PMID- 28335387 TI - Dectin-1-Mediated Pathway Contributes to Fusarium proliferatum-Induced CXCL-8 Release from Human Respiratory Epithelial Cells. AB - Fusarium species are causative agents of human respiratory disorders and are distributed widely in our environment. Little is known of their interaction with human respiratory epithelial cells, which may contribute to allergic airway responses. In this study, we report on the release of C-X-C motif chemokine ligand 8 (CXCL-8) from human bronchial epithelial BEAS-2B cells upon stimulation with Fusarium proliferatum extracts. F. proliferatum-induced cytokine release from BEAS-2B cells was determined by cytokine array and CXCL-8 enzyme-linked immunosorbent assay (ELISA) kits. Blocking antibodies and signaling pathway inhibitors were employed to delineate cell surface receptors and signaling pathways participating in CXCL-8 release. F. proliferatum extracts induced the release of CXCL-8 in a time-dependent manner. The dectin-1 receptor ligands, curdlan and laminarin, reduced CXCL-8 release. Cells pre-treated with anti-Dectin 1 antibodies (2 ug/mL) decreased CXCL-8 release by 24%. Furthermore, F. proliferatum-stimulated CXCL-8 release was reduced by 32%, 53%-81%, 40% and 26% after BEAS-2B cells were pretreated with activation inhibitors of spleen tyrosine kinase (Syk)-piceatannol-, mitogen-activated protein kinases (MAPKs)-PD98059, U0126, SB202190, SP600125-, phosphatidylinositol-3-kinase (PI3K)-LY294002-and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) BAY117082-, respectively. These results suggest that Dectin-1-mediated activation of the Syk, MAPKs, PI3K and NF-kappaB signaling pathways contributes to F. proliferatum-stimulated CXCL-8 release from BEAS-2B cells and provides an important basis for developing novel therapeutic strategies in clinical allergy. PMID- 28335389 TI - Characteristics and Lethality of a Novel Recombinant Dermonecrotic Venom Phospholipase D from Hemiscorpius lepturus. AB - Hemoscorpius lepturus is the most medically important scorpion in Iran. The clinical signs of H. lepturus envenomation are remarkably similar to those reported for brown spiders, including dermonecrosis, hematuria, renal failure and even death. The lethality and toxicity of brown spiders' venom have been attributed to its phospholipase D activity. This study aims to identify a phospholipase D with possible lethality and dermonecrotic activity in H. lepturus venom. In this study, a cDNA library of the venom glands was generated by Illumina RNA sequencing. Phospholipase D (PLD) from H. lepturus was characterized according to its significant similarity with PLDs from brown spiders. The main chain designated as Hl-RecPLD1 (the first recombinant isoform of H. lepturus PLD) was cloned, expressed and purified. Sphingomyelinase, dermonecrotic and lethal activities were examined. Hl-PLD1 showed remarkable sequence similarity and structural homology with PLDs of brown spiders. The conformation of Hl-PLD1 was predicted as a "TIM beta/alpha-barrel". The lethal dose 50 (LD50) and dermonecrotic activities of Hl-RecPLD1 were determined as 3.1 MUg/mouse and 0.7 cm2 at 1 MUg respectively. It is the first report indicating that a similar molecular evolutionary mechanism has occurred in both American brown spiders and this Iranian scorpion. In conclusion, Hl-RecPLD1 is a highly active phospholipase D, which would be considered as the lethal dermonecrotic toxin in H. lepturus venom. PMID- 28335390 TI - A Simple Metallothionein-Based Biosensor for Enhanced Detection of Arsenic and Mercury. AB - Metallothioneins (MTs) are a family of cysteine-rich proteins whose biological roles include the regulation of essential metal ions and protection against the harmful effects of toxic metals. Due to its high affinity for many toxic, soft metals, recombinant human MT isoform 1a was incorporated into an electrochemical based biosensor for the detection of As3+ and Hg2+. A simple design was chosen to maximize its potential in environmental monitoring and MT was physically adsorbed onto paper discs placed on screen-printed carbon electrodes (SPCEs). This system was tested with concentrations of arsenic and mercury typical of contaminated water sources ranging from 5 to 1000 ppb. The analytical performance of the MT adsorbed paper discs on SPCEs demonstrated a greater than three-fold signal enhancement and a lower detection limit compared to blank SPCEs, 13 ppb for As3+ and 45 ppb for Hg2+. While not being as low as some of the recommended drinking water limits, the sensitivity of the simple MT-biosensor would be potentially useful in monitoring of areas of concern with a known contamination problem. This paper describes the ability of the metal binding protein metallothionein to enhance the effectiveness of a simple, low-cost electrochemical sensor. PMID- 28335388 TI - A Combination of Flaxseed Oil and Astaxanthin Improves Hepatic Lipid Accumulation and Reduces Oxidative Stress in High Fat-Diet Fed Rats. AB - Hepatic lipid accumulation and oxidative stress are crucial pathophysiological mechanisms for non-alcoholic fatty liver disease (NAFLD). Thus, we examined the effect of a combination of flaxseed oil (FO) and astaxanthin (ASX) on hepatic lipid accumulation and oxidative stress in rats fed a high-fat diet. ASX was dissolved in flaxseed oil (1 g/kg; FO + ASX). Animals were fed diets containing 20% fat, where the source was lard, or 75% lard and 25% FO + ASX, or 50% lard and 50% FO + ASX, or FO + ASX, for 10 weeks. Substitution of lard with FO + ASX reduced steatosis and reduced hepatic triacylglycerol and cholesterol. The combination of FO and ASX significantly decreased hepatic sterol regulatory element-binding transcription factor 1 and 3-hydroxy-3-methylglutaryl-CoA reductase but increased peroxisome proliferator activated receptor expression. FO + ASX significantly suppressed fatty acid synthase and acetyl CoA carboxylase but induced carnitine palmitoyl transferase-1 and acyl CoA oxidase expression. FO + ASX also significantly elevated hepatic SOD, CAT and GPx activity and GSH, and markedly reduced hepatic lipid peroxidation. Thus, FO and ASX may reduce NAFLD by reversing hepatic steatosis and reducing lipid accumulation and oxidative stress. PMID- 28335391 TI - New Metabolites and Bioactive Chlorinated Benzophenone Derivatives Produced by a Marine-Derived Fungus Pestalotiopsis heterocornis. AB - Four new compounds, including two isocoumarins, pestaloisocoumarins A and B (1, 2), one sesquiterpenoid degradation, isopolisin B (4), and one furan derivative, pestalotiol A (5), together with one known isocoumarin, gamahorin (3), and three chlorinated benzophenone derivatives, pestalachloride B (6), pestalachloride E (7) and a mixture of pestalalactone atropisomers (8a/8b), were isolated from a culture of the fungus Pestalotiopsis heterocornis associated with sponge Phakellia fusca. These new chemical structures were established using NMR and MS spectroscopic data, as well as single-crystal X-ray crystallographic analysis and CD Cotton effects. All of the isolated compounds were evaluated for their antimicrobial and cytotoxic activities. Isocoumarins 1-3, showed antibacterial activities against Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis with MIC values ranging from 25 to 100 MUg/mL and weak antifungal activities. Chlorinated benzophenone derivatives 6-8 exhibited antibacterial activities against S. aureus and B. subtilis with MIC values ranging from 3.0 to 50 MUg/mL and cytotoxicities against four human cancer cell lines with IC50 values of 6.8-87.8 MUM. PMID- 28335392 TI - Conscientious Objection to Animal Experimentation in Italian Universities. AB - In Italy, Law 413/1993 states that public and private Italian Institutions, including academic faculties, are obliged to fully inform workers and students about their right to conscientious objection to scientific or educational activities involving animals, hereafter written as "animal CO". However, little monitoring on the faculties' compliance with this law has been performed either by the government or other institutional bodies. Based on this premise, the authors have critically reviewed the existing data and compared them with those emerging from their own investigation to discuss limitations and inconsistencies. The results of this investigation revealed that less than half of Italian academic faculties comply with their duty to inform on animal CO. Non-compliance may substantially affect the right of students to make ethical choices in the field of animal ethics and undermines the fundamental right to express their own freedom of thought. The Italian Ministry of Education, Universities and Research, ethics committees and animal welfare bodies should cooperate to make faculties respect this law. Further research is needed to better understand the reasons for the current trend, as well as to promote the enforcement of Law 413/1993 with particular regard to information on animal CO. PMID- 28335393 TI - Solvent Retention Capacities of Oat Flour. AB - This study measured the solvent retention capacities (SRCs) of flours from eight oat varieties and one wheat variety against different solvents to explore the swelling volume of oat flour with different solvents, and thus provide a theoretical basis for quick beta-glucan analysis. The SRC profile consists of water SRC (WSRC), 50% sucrose SRC (SSRC), 5% lactic acid SRC (LASRC), 5% Na2CO3 SRC (SCASRC), NaCl SRC (SCSRC), CaCl2 SRC (CCSRC), FeCl3 SRC (FCSRC), sodium cholate SRC (SCHSRC), NaOH (pH 10) SRC (SHSRC), Na2CO3 (pH 10) SRC (SCABSRC) and SDS (pH 10) SRC (SDSSRC) values, and a Chopin SRC kit was used to measure the SRC value. SRCs of the oat flours increased when the solvents turned from neutral (water and NaCl) to acidic (5% lactic acid) or alkaline (5% Na2CO3, CaCl2, FeCl3, NaOH and pH 10 Na2CO3), and rose as the metal ion valencies of the metal salts (NaCl, CaCl2 and FeCl3) increased. The beta-glucan contents were significantly positively correlated with the SCSRC (0.83**), CCSRC (0.82**), SCHSRC (0.80**) and FCSRC (0.78*). SRC measurements of beta-glucan in oat flours revealed that the CCSRC values were related with beta-glucan (0.64*) but not related with protein and starch. CaCl2 could therefore potentially be exploited as a reagent for beta-glucan assay. PMID- 28335394 TI - Motor Function Evaluation of Hemiplegic Upper-Extremities Using Data Fusion from Wearable Inertial and Surface EMG Sensors. AB - Quantitative evaluation of motor function is of great demand for monitoring clinical outcome of applied interventions and further guiding the establishment of therapeutic protocol. This study proposes a novel framework for evaluating upper limb motor function based on data fusion from inertial measurement units (IMUs) and surface electromyography (EMG) sensors. With wearable sensors worn on the tested upper limbs, subjects were asked to perform eleven straightforward, specifically designed canonical upper-limb functional tasks. A series of machine learning algorithms were applied to the recorded motion data to produce evaluation indicators, which is able to reflect the level of upper-limb motor function abnormality. Sixteen healthy subjects and eighteen stroke subjects with substantial hemiparesis were recruited in the experiment. The combined IMU and EMG data yielded superior performance over the IMU data alone and the EMG data alone, in terms of decreased normal data variation rate (NDVR) and improved determination coefficient (DC) from a regression analysis between the derived indicator and routine clinical assessment score. Three common unsupervised learning algorithms achieved comparable performance with NDVR around 10% and strong DC around 0.85. By contrast, the use of a supervised algorithm was able to dramatically decrease the NDVR to 6.55%. With the proposed framework, all the produced indicators demonstrated high agreement with the routine clinical assessment scale, indicating their capability of assessing upper-limb motor functions. This study offers a feasible solution to motor function assessment in an objective and quantitative manner, especially suitable for home and community use. PMID- 28335395 TI - Essential Oil Composition and Bioactivities of Waldheimia glabra (Asteraceae) from Qinghai-Tibet Plateau. AB - Waldheimia glabra is traditionally used as incense and as an anti-influenza drug by Tibetans in China. Here, we collected W. glabra from the Gangs Rinpoche mountain at an altitude of 5200 m, and analyzed its essential oil by gas chromatography-mass spectrometry (GC-MS) combined with the retention indices (RI). Twenty-seven compounds, representing 72.4% of the total essential oil, were identified, including alpha-bisabolol (20.2%), valeranone (11.8%), chamazulene (9.9%), spathulenol (8.2%), beta-caryophyllene (6.1%), and caryophyllene oxide (5.2%). Bioactivity evaluation of the essential oil revealed that it exhibited potent anti-influenza effect on viruses H3N2 and anti-inflammatory effect by inhibiting the lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages, but no anti-complementary activity. PMID- 28335398 TI - Tunable Plasmonic Band-Pass Filter with Dual Side-Coupled Circular Ring Resonators. AB - A wavelength band-pass filter with asymmetric dual circular ring resonators in a metal-insulator-metal (MIM) structure is proposed and numerically simulated. For the interaction of the local discrete state and the continuous spectrum caused by the side-coupled resonators and the baffle, respectively, the transmission spectrum exhibits a sharp and asymmetric profile. By adjusting the radius and material imbedded in one ring cavity, the off-to-on plasmon-induced absorption (PIA) optical response can be tunable achieved. In addition, the structure can be easily extended to other similar compact structures to realize the filtering task. Our structures have important potential applications for filters and sensors at visible and near-infrared regions. PMID- 28335396 TI - Optimization of Conditions for Cyanidin-3-OGlucoside (C3G) Nanoliposome Production by Response Surface Methodology and Cellular Uptake Studies in Caco-2 Cells. AB - We aimed to optimize the formulation of C3G nanoliposomes using response surface methodology. Additionally, we evaluated the stability, particle change, and encapsulation efficiency (EE) of C3G nanoliposomes under different temperatures and storage durations, as well as in simulated gastrointestinal juice (SGF) and simulated intestinal fluid. The morphology of C3G nanoliposomes was observed by transmission electron microscope. The ability of C3G nanoliposomes to affect cancer cell morphology and inhibit cancer cell proliferation was studied with Caco-2 cells. Reverse-phase evaporation method is a simple and efficient method for liposome preparation. The optimal preparation conditions for this method were as follows: C3G concentration of 0.17 mg/mL, phosphatidylcholine/cholesterol ratio of 2.87, and rotary evaporation temperature of 41.41 degrees C. At optimal conditions, the particle size and EE of the C3G nanoliposomes were 165.78 +/- 4.3 nm and 70.43% +/- 1.95%, respectively. The C3G nanoliposomes showed an acceptable stability in SGF at 37 degrees C for 4 h, but were unstable under extended storage durations and high temperatures. Moreover, our results showed that different concentrations of C3G nanoliposomes affected the morphology and inhibited the proliferation of Caco-2 cells. PMID- 28335399 TI - An Eddy Current Testing Platform System for Pipe Defect Inspection Based on an Optimized Eddy Current Technique Probe Design. AB - The use of the eddy current technique (ECT) for the non-destructive testing of conducting materials has become increasingly important in the past few years. The use of the non-destructive ECT plays a key role in the ensuring the safety and integrity of the large industrial structures such as oil and gas pipelines. This paper introduce a novel ECT probe design integrated with the distributed ECT inspection system (DSECT) use for crack inspection on inner ferromagnetic pipes. The system consists of an array of giant magneto-resistive (GMR) sensors, a pneumatic system, a rotating magnetic field excitation source and a host PC acting as the data analysis center. Probe design parameters, namely probe diameter, an excitation coil and the number of GMR sensors in the array sensor is optimized using numerical optimization based on the desirability approach. The main benefits of DSECT can be seen in terms of its modularity and flexibility for the use of different types of magnetic transducers/sensors, and signals of a different nature with either digital or analog outputs, making it suited for the ECT probe design using an array of GMR magnetic sensors. A real-time application of the DSECT distributed system for ECT inspection can be exploited for the inspection of 70 mm carbon steel pipe. In order to predict the axial and circumference defect detection, a mathematical model is developed based on the technique known as response surface methodology (RSM). The inspection results of a carbon steel pipe sample with artificial defects indicate that the system design is highly efficient. PMID- 28335397 TI - Emerging Anti-Mitotic Activities and Other Bioactivities of Sesquiterpene Compounds upon Human Cells. AB - We review the bio-activities of natural product sesquiterpenes and present the first description of their effects upon mitosis. This type of biological effect upon cells is unexpected because sesquiterpenes are believed to inactivate proteins through Michael-type additions that cause non-specific cytotoxicity. Yet, certain types of sesquiterpenes can arrest cells in mitosis as measured by cell biology, biochemical and imaging techniques. We have listed the sesquiterpenes that arrest cells in mitosis and analyzed the biological data that support those observations. In view of the biochemical complexity of mitosis, we propose that a subset of sesquiterpenes have a unique chemical structure that can target a precise protein(s) required for mitosis. Since the process of mitotic arrest precedes that of cell death, it is possible that some sesquiterpenes that are currently classified as cytotoxic might also induce a mitotic arrest. Our analysis provides a new perspective of sesquiterpene chemical biology. PMID- 28335400 TI - Online Classification of Contaminants Based on Multi-Classification Support Vector Machine Using Conventional Water Quality Sensors. AB - Water quality early warning system is mainly used to detect deliberate or accidental water pollution events in water distribution systems. Identifying the types of pollutants is necessary after detecting the presence of pollutants to provide warning information about pollutant characteristics and emergency solutions. Thus, a real-time contaminant classification methodology, which uses the multi-classification support vector machine (SVM), is proposed in this study to obtain the probability for contaminants belonging to a category. The SVM-based model selected samples with indistinct feature, which were mostly low concentration samples as the support vectors, thereby reducing the influence of the concentration of contaminants in the building process of a pattern library. The new sample points were classified into corresponding regions after constructing the classification boundaries with the support vector. Experimental results show that the multi-classification SVM-based approach is less affected by the concentration of contaminants when establishing a pattern library compared with the cosine distance classification method. Moreover, the proposed approach avoids making a single decision when classification features are unclear in the initial phase of injecting contaminants. PMID- 28335403 TI - Comparison of Faunal Scavenging of Submerged Carrion in Two Seasons at a Depth of 170 m, in the Strait of Georgia, British Columbia. AB - The taphonomy of carcasses submerged in the ocean is little understood, yet it is extremely important ecologically and forensically. The objectives of this study were to determine the fate of pig carcasses as human proxies in the Strait of Georgia at 170 m in spring and fall. Using Ocean Networks Canada's Victoria Experimental Network Underseas (VENUS) observatory, two carcasses per season were placed under a cabled platform hosting a webcam and instruments measuring water chemistry. Two minutes of video were recorded every 15 min. In spring, Lyssianassidae amphipods and Pandalus platyceros were immediately attracted and fed on the carcasses, the amphipods removed the bulk of the soft tissue from the inside whilst the shrimp shredded the skin and tissue. The carcasses were skeletonized on Days 8 and 10. In fall, Metacarcinus magister was the major scavenger, removing most of the soft tissue from one carcass. Amphipods did not arrive in large numbers until Day 15, when they skeletonized the scavenged carcass by Day 22 and the less scavenged carcass by Day 24. Amphipods remained for some days after skeletonization. This skeletonization was very different from previous experiments at different depths and habitats. Such data are very valuable for predicting preservation, planning recoveries, and managing family expectations. PMID- 28335402 TI - 2-Hydroxymelatonin, a Predominant Hydroxylated Melatonin Metabolite in Plants, Shows Antitumor Activity against Human Colorectal Cancer Cells. AB - 2-Hydroxymelatonin is a predominant hydroxylated melatonin metabolite in plants. To investigate whether it has potent cytotoxic effects on colorectal cancer cells, four colorectal cancer cell lines, Caco2, HCT116, DLD1, and CT26, were treated with 2-hydroxymelatonin and melatonin. 2-Hydroxymelatonin had a much lower IC50 value than melatonin in the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. The cytotoxic effect of 2 hydroxymelatonin was much stronger than that of melatonin at high concentrations (1000 or 2000 MUM) in HCT116, DLD1, and CT26 cells, but only at intermediate concentrations (250 or 500 MUM) in Caco2 cells. The cytotoxicity of 2 hydroxymelatonin was induced through activation of the apoptotic signaling pathway, as confirmed by Hoechst staining and Annexin V-FITC/propidium iodide double labeling of cells treated with a lethal dose (1 mM). However, sub-lethal doses of 2-hydroxymelatonin inhibited the invasive ability of Caco2 cells. Epithelial-mesenchymal transition (EMT) markers were significantly regulated by 2 hydroxymelatonin. Overall, the anti-cancer activity of 2-hydroxymelatonin is more potent than that of melatonin. Taken together, 2-hydroxymelatonin exhibits potent anti-cancer activity against human colorectal cancer cells via induction of apoptosis and inhibition of EMT. PMID- 28335401 TI - The Vital Dye CDr10b Labels the Zebrafish Mid-Intestine and Lumen. AB - We describe the use of the fluorescent reporter compound CDr10b to label mid intestinal structures in zebrafish larvae after simple immersion. CDr10b is deposited into the gut where it initially fills the lumen and is excreted. Using laser-mediated injury of the intestine, we show that CDr10b provides a useful readout of the integrity and repair of the epithelial cell barrier. In addition, CDr10b specifically labels the absorptive mid-intestine segment that is analogous to the mammalian small intestine. By perturbing retinoic acid signaling, which regulates the size of the mid-intestine segment, we show that CDr10b is a valuable tool to rapidly assess developmental malformations of the intestine in live animals. PMID- 28335404 TI - Perceptions of Health Co-Benefits in Relation to Greenhouse Gas Emission Reductions: A Survey among Urban Residents in Three Chinese Cities. AB - Limited information is available on the perceptions of stakeholders concerning the health co-benefits of greenhouse gas (GHG) emission reductions. The purpose of this study was to investigate the perceptions of urban residents on the health co-benefits involving GHG abatement and related influencing factors in three cities in China. Beijing, Ningbo and Guangzhou were selected for this survey. Participants were recruited from randomly chosen committees, following quotas for gender and age in proportion to the respective population shares. Chi-square or Fisher's exact tests were employed to examine the associations between socio demographic variables and individuals' perceptions of the health co-benefits related to GHG mitigation. Unconditional logistic regression analysis was performed to investigate the influencing factors of respondents' awareness about the health co-benefits. A total of 1159 participants were included in the final analysis, of which 15.9% reported that they were familiar with the health co benefits of GHG emission reductions. Those who were younger, more educated, with higher family income, and with registered urban residence, were more likely to be aware of health co-benefits. Age, attitudes toward air pollution and governmental efforts to improve air quality, suffering from respiratory diseases, and following low carbon lifestyles are significant predictors of respondents' perceptions on the health co-benefits. These findings may not only provide information to policy-makers to develop and implement public welcome policies of GHG mitigation, but also help to bridge the gap between GHG mitigation measures and public engagement as well as willingness to change health-related behaviors. PMID- 28335405 TI - Association of Short-Term Exposure to Ambient Fine Particulate Matter with Skin Symptoms in Schoolchildren: A Panel Study in a Rural Area of Western Japan. AB - Numerous studies have unmasked the deleterious effects of particulate matter less than 2.5 MUm (PM2.5) on health. However, epidemiologic evidence focusing on the effects of PM2.5 on skin health remains limited. An important aspect of Asian dust (AD) in relationship to health is the amount of PM2.5 contained therein. Several studies have demonstrated that AD can aggravate skin symptoms. The current study aimed to investigate the effects of short-term exposure to PM2.5 and AD particles on skin symptoms in schoolchildren. A total of 339 children recorded daily skin symptom scores during February 2015. Light detection and ranging were used to calculate AD particle size. Generalized estimating equation logistic regression analyses were used to estimate the associations among skin symptoms and the daily levels of PM2.5 and AD particles. Increases in the levels of PM2.5 and AD particles were not related to an increased risk of skin symptom events, with increases of 10.1 MUg/m3 in PM2.5 and 0.01 km-1 in AD particles changing odds ratios by 1.03 and 0.99, respectively. These results suggest that short-term exposure to PM2.5 and AD does not impact skin symptoms in schoolchildren. PMID- 28335406 TI - Factors That Negatively Affect the Prognosis of Pediatric Community-Acquired Pneumonia in District Hospital in Tanzania. AB - Community-acquired pneumonia (CAP) is still the most important cause of death in countries with scarce resources. All children (33 months +/- 35 DS) discharged from the Pediatric Unit of Itigi Hospital, Tanzania, with a diagnosis of CAP from August 2014 to April 2015 were enrolled. Clinical data were gathered. Dried blood spot (DBS) samples for quantitative real-time polymerase chain reaction (PCR) for bacterial detection were collected in all 100 children included. Twenty-four percent of patients were identified with severe CAP and 11% died. Surprisingly, 54% of patients were admitted with a wrong diagnosis, which increased complications, the need for antibiotics and chest X-rays, and the length of hospitalization. Comorbidity, found in 32% of children, significantly increased severity, complications, deaths, need for chest X-rays, and oxygen therapy. Malnourished children (29%) required more antibiotics. Microbiologically, Streptococcus pneumonia (S. p.), Haemophilus influenza type b (Hib) and Staphylococcus aureus (S. a.) were the bacteria more frequently isolated. Seventy five percent of patients had mono-infection. Etiology was not correlated with severity, complications, deaths, oxygen demand, or duration of hospitalization. Our study highlights that difficult diagnoses and comorbidities negatively affect clinical evolution. S. p. and Hib still play a large role; thus, implementation of current vaccine strategies is needed. DBS is a simple and efficient diagnostic method for bacterial identification in countries with scarce resources. PMID- 28335407 TI - Bovine Colostrum Whey Protein Hydrolysate Inhibits Cell DNA Damage and LDL Oxidation In Vitro. AB - Whey protein isolated from bovine colostrums collected on the second day postpartum was two-stage hydrolyzed by alcalase and flavourzyme [...]. PMID- 28335408 TI - n-Hexane Insoluble Fraction of Plantago lanceolata Exerts Anti-Inflammatory Activity in Mice by Inhibiting Cyclooxygenase-2 and Reducing Chemokines Levels. AB - Inflammation is involved in the progression of many disorders, such as tumors, arthritis, gastritis, and atherosclerosis. Thus, the development of new agents targeting inflammation is still challenging. Medicinal plants have been used traditionally to treat various diseases including inflammation. A previous study has indicated that dichloromethane extract of P. lanceolata leaves exerts anti inflammatory activity in an in vitro model. Here, we examined the in vivo anti inflammatory activities of a n-hexane insoluble fraction of P. lanceolata leaves dichloromethane extract (HIFPL). We first evaluated its potency to reduce paw edema induced by carrageenan, and the expression of the proinflammatory enzyme, cyclooxygenase (COX)-2, in mice. The efficacy of HIFPL to inhibit COX-2 was also evaluated in an in vitro enzymatic assay. We further studied the effect of HIFPL on leukocytes migration in mice induced by thioglycollate. The level of chemokines facilitating the migration of leukocytes was also measured. We found that HIFPL (40, 80, 160 mg/kg) demonstrated anti-inflammatory activities in mice. The HIFPL reduced the volume of paw edema and COX-2 expression. However, HIFPL acts as an unselective COX-2 inhibitor as it inhibited COX-1 with a slightly higher potency. Interestingly, HIFPL strongly inhibited leukocyte migration by reducing the level of chemokines, Interleukine-8 (IL-8) and Monocyte chemoattractant protein-1 (MCP-1). PMID- 28335410 TI - Non-Canonical Roles of Dengue Virus Non-Structural Proteins. AB - The Flaviviridae family comprises a number of human pathogens, which, although sharing structural and functional features, cause diseases with very different outcomes. This can be explained by the plurality of functions exerted by the few proteins coded by viral genomes, with some of these functions shared among members of a same family, but others being unique for each virus species. These non-canonical functions probably have evolved independently and may serve as the base to the development of specific therapies for each of those diseases. Here it is discussed what is currently known about the non-canonical roles of dengue virus (DENV) non-structural proteins (NSPs), which may account for some of the effects specifically observed in DENV infection, but not in other members of the Flaviviridae family. This review explores how DENV NSPs contributes to the physiopathology of dengue, evasion from host immunity, metabolic changes, and redistribution of cellular components during infection. PMID- 28335412 TI - Ameliorative Effects of Neutral Electrolyzed Water on Growth Performance, Biochemical Constituents, and Histopathological Changes in Turkey Poults during Aflatoxicosis. AB - Different in vitro and in silico approaches from our research group have demonstrated that neutral electrolyzed water (NEW) can be used to detoxify aflatoxins. The objective of this investigation was to evaluate the ability of NEW to detoxify B-aflatoxins (AFB1 and AFB2) in contaminated maize and to confirm detoxification in an in vivo experimental model. Batches of aflatoxin contaminated maize were detoxified with NEW and mixed in commercial feed. A total of 240 6-day-old female large white Nicholas-700 turkey poults were randomly divided into four treatments of six replicates each (10 turkeys per replicate), which were fed ad libitum for two weeks with the following dietary treatments: (1) control feed containing aflatoxin-free maize (CONTROL); (2) feed containing the aflatoxin-contaminated maize (AF); (3) feed containing the aflatoxin contaminated maize detoxified with NEW (AF + NEW); and (4) control feed containing aflatoxin-free maize treated with NEW (NEW). Compared to the control groups, turkey poults of the AF group significantly reduced body weight gain and increased feed conversion ratio and mortality rate; whereas turkey poults of the AF + NEW group did not present significant differences on productive parameters. In addition, alterations in serum biochemical constituents, enzyme activities, relative organ weight, gross morphological changes and histopathological studies were significantly mitigated by the aflatoxin-detoxification procedure. From these results, it is concluded that the treatment of aflatoxin-contaminated maize with NEW provided reasonable protection against the effects caused by aflatoxins in young turkey poults. PMID- 28335409 TI - The Formyl Peptide Receptors: Diversity of Ligands and Mechanism for Recognition. AB - The formyl peptide receptors (FPRs) are G protein-coupled receptors that transduce chemotactic signals in phagocytes and mediate host-defense as well as inflammatory responses including cell adhesion, directed migration, granule release and superoxide production. In recent years, the cellular distribution and biological functions of FPRs have expanded to include additional roles in homeostasis of organ functions and modulation of inflammation. In a prototype, FPRs recognize peptides containing N-formylated methionine such as those produced in bacteria and mitochondria, thereby serving as pattern recognition receptors. The repertoire of FPR ligands, however, has expanded rapidly to include not only N-formyl peptides from microbes but also non-formyl peptides of microbial and host origins, synthetic small molecules and an eicosanoid. How these chemically diverse ligands are recognized by the three human FPRs (FPR1, FPR2 and FPR3) and their murine equivalents is largely unclear. In the absence of crystal structures for the FPRs, site-directed mutagenesis, computer-aided ligand docking and structural simulation have led to the identification of amino acids within FPR1 and FPR2 that interact with several formyl peptides. This review article summarizes the progress made in the understanding of FPR ligand diversity as well as ligand recognition mechanisms used by these receptors. PMID- 28335411 TI - How the Cobra Got Its Flesh-Eating Venom: Cytotoxicity as a Defensive Innovation and Its Co-Evolution with Hooding, Aposematic Marking, and Spitting. AB - The cytotoxicity of the venom of 25 species of Old World elapid snake was tested and compared with the morphological and behavioural adaptations of hooding and spitting. We determined that, contrary to previous assumptions, the venoms of spitting species are not consistently more cytotoxic than those of closely related non-spitting species. While this correlation between spitting and non spitting was found among African cobras, it was not present among Asian cobras. On the other hand, a consistent positive correlation was observed between cytotoxicity and utilisation of the defensive hooding display that cobras are famous for. Hooding and spitting are widely regarded as defensive adaptations, but it has hitherto been uncertain whether cytotoxicity serves a defensive purpose or is somehow useful in prey subjugation. The results of this study suggest that cytotoxicity evolved primarily as a defensive innovation and that it has co-evolved twice alongside hooding behavior: once in the Hemachatus + Naja and again independently in the king cobras (Ophiophagus). There was a significant increase of cytotoxicity in the Asian Naja linked to the evolution of bold aposematic hood markings, reinforcing the link between hooding and the evolution of defensive cytotoxic venoms. In parallel, lineages with increased cytotoxicity but lacking bold hood patterns evolved aposematic markers in the form of high contrast body banding. The results also indicate that, secondary to the evolution of venom rich in cytotoxins, spitting has evolved three times independently: once within the African Naja, once within the Asian Naja, and once in the Hemachatus genus. The evolution of cytotoxic venom thus appears to facilitate the evolution of defensive spitting behaviour. In contrast, a secondary loss of cytotoxicity and reduction of the hood occurred in the water cobra Naja annulata, which possesses streamlined neurotoxic venom similar to that of other aquatic elapid snakes (e.g., hydrophiine sea snakes). The results of this study make an important contribution to our growing understanding of the selection pressures shaping the evolution of snake venom and its constituent toxins. The data also aid in elucidating the relationship between these selection pressures and the medical impact of human snakebite in the developing world, as cytotoxic cobras cause considerable morbidity including loss-of-function injuries that result in economic and social burdens in the tropics of Asia and sub-Saharan Africa. PMID- 28335414 TI - Inhibition of Listeria monocytogenes on Ready-to-Eat Meats Using Bacteriocin Mixtures Based on Mode-of-Action. AB - : Bacteriocin-producing (Bac+) lactic acid bacteria (LAB) comprising selected strains of Lactobacillus curvatus, Lactococcus lactis, Pediococcus acidilactici, and Enterococcus faecium and thailandicus were examined for inhibition of Listeria monocytogenes during hotdog challenge studies. The Bac+ strains, or their cell-free supernatants (CFS), were grouped according to mode-of-action (MOA) as determined from prior studies. Making a mixture of as many MOAs as possible is a practical way to obtain a potent natural antimicrobial mixture to address L. monocytogenes contamination of RTE meat products (i.e., hotdogs). The heat resistance of the bacteriocins allowed the use of pasteurization to eliminate residual producer cells for use as post-process surface application or their inclusion into hotdog meat emulsion during cooking. The use of Bac+ LAB comprising 3* MOAs directly as co-inoculants on hotdogs was not effective at inhibiting L. monocytogenes. However, the use of multiple MOA Bac+ CFS mixtures in a variety of trials demonstrated the effectiveness of this approach by showing a >2-log decrease of L. monocytogenes in treatment samples and 6-7 log difference vs. CONTROLS: These data suggest that surface application of multiple mode-of action bacteriocin mixtures can provide for an Alternative 2, and possibly Alternative 1, process category as specified by USDA-FSIS for control of L. monocytogenes on RTE meat products. PMID- 28335413 TI - Chitin Oligosaccharide (COS) Reduces Antibiotics Dose and Prevents Antibiotics Caused Side Effects in Adolescent Idiopathic Scoliosis (AIS) Patients with Spinal Fusion Surgery. AB - Antibiotics are always considered for surgical site infection (SSI) in adolescent idiopathic scoliosis (AIS) surgery. However, the use of antibiotics often causes the antibiotic resistance of pathogens and side effects. Thus, it is necessary to explore natural products as drug candidates. Chitin Oligosaccharide (COS) has anti-inflammation and anti-bacteria functions. The effects of COS on surgical infection in AIS surgery were investigated. A total of 312 AIS patients were evenly and randomly assigned into control group (CG, each patient took one-gram alternative Azithromycin/Erythromycin/Cloxacillin/Aztreonam/Ceftazidime or combined daily), experiment group (EG, each patient took 20 mg COS and half-dose antibiotics daily), and placebo group (PG, each patient took 20 mg placebo and half-dose antibiotics daily). The average follow-up was one month, and infection severity and side effects were analyzed. The effects of COS on isolated pathogens were analyzed. SSI rates were 2%, 3% and 8% for spine wounds and 1%, 2% and 7% for iliac wound in CG, EG and PG (p < 0.05), respectively. COS reduces the side effects caused by antibiotics (p < 0.05). COS improved biochemical indexes and reduced the levels of interleukin (IL)-6 and tumor necrosis factor (TNF) alpha. COS reduced the antibiotics dose and antibiotics-caused side effects in AIS patients with spinal fusion surgery by improving antioxidant and anti inflammatory activities. COS should be developed as potential adjuvant for antibiotics therapies. PMID- 28335415 TI - Time Modulated Arrays: From their Origin to Their Utilization in Wireless Communication Systems. AB - Time-modulated arrays (TMAs) are electromagnetic systems whose radiated power pattern is controlled by the application of variable-width periodical pulses to the individual elements. The nonlinear nature of the array operation causes the appearance of radiation patterns at the harmonic frequencies of such periodic pulses. The technique can be used for improving the side-lobe level (SLL) topology of the radiation pattern at the central frequency and/or to profitably exploit the harmonic patterns in order to supply smart antenna capabilities. Among the latter features, the TMA harmonic beamforming takes on special importance due to its attractive trade-off performance-hardware complexity. From this perspective, TMAs are sensors capable of transforming the spatial diversity of a communication channel into frequency diversity, thus improving the performance of a wireless communication. In addition to a walk through the origins of the concept, and a brief analysis of the mathematical fundamentals, this paper organizes the prolific state of the art of TMAs in two major thematic blocks: (1) TMA design from an antenna perspective; and (2) TMA design from a signal processing perspective. PMID- 28335417 TI - DNA Sequencing Sensors: An Overview. AB - The first sequencing of a complete genome was published forty years ago by the double Nobel Prize in Chemistry winner Frederick Sanger. That corresponded to the small sized genome of a bacteriophage, but since then there have been many complex organisms whose DNA have been sequenced. This was possible thanks to continuous advances in the fields of biochemistry and molecular genetics, but also in other areas such as nanotechnology and computing. Nowadays, sequencing sensors based on genetic material have little to do with those used by Sanger. The emergence of mass sequencing sensors, or new generation sequencing (NGS) meant a quantitative leap both in the volume of genetic material that was able to be sequenced in each trial, as well as in the time per run and its cost. One can envisage that incoming technologies, already known as fourth generation sequencing, will continue to cheapen the trials by increasing DNA reading lengths in each run. All of this would be impossible without sensors and detection systems becoming smaller and more precise. This article provides a comprehensive overview on sensors for DNA sequencing developed within the last 40 years. PMID- 28335419 TI - Anti-Allergic Compounds from the Deep-Sea-Derived Actinomycete Nesterenkonia flava MCCC 1K00610. AB - A novel cyclic ether, nesterenkoniane (1), was isolated from the deep-sea-derived actinomycete Nesterenkonia flava MCCC 1K00610, together with 12 known compounds, including two macrolides (2, 3), two diketopiperazines (4, 5), two nucleosides (6, 7), two indoles (8, 9), three phenolics (10-12), and one butanol derivate (13). Their structures were established mainly on detailed analysis of the NMR and MS spectroscopic data. All 13 compounds were tested for anti-allergic activities using immunoglobulin E (IgE) mediated rat mast RBL-2H3 cell model. Under the concentration of 20 MUg/mL, 1 exhibited moderate anti-allergic activity with inhibition rate of 9.86%, compared to that of 37.41% of the positive control, loratadine. While cyclo(d)-Pro-(d)-Leu (4) and indol-3-carbaldehyde (8) showed the most potent effects with the IC50 values of 69.95 and 57.12 MUg/mL, respectively, which was comparable to that of loratadine (IC50 = 35.01 MUg/mL). To the best of our knowledge, it is the first report on secondary metabolites from the genus of Nesterenkonia. PMID- 28335418 TI - Food Insecurity, Poor Diet Quality, and Suboptimal Intakes of Folate and Iron Are Independently Associated with Perceived Mental Health in Canadian Adults. AB - BACKGROUND: To address nutrition-related population mental health data gaps, we examined relationships among food insecurity, diet quality, and perceived mental health. METHODS: Stratified and logistic regression analyses of respondents aged 19-70 years from the Canadian Community Health Survey, Cycle 2.2 were conducted (n = 15,546). Measures included the Household Food Security Survey Module, diet quality (i.e., comparisons to the Dietary Reference Intakes, Healthy Eating Index), perceived mental health (poor versus good), sociodemographics, and smoking. RESULTS: In this sample, 6.9% were food insecure and 4.5% reported poor mental health. Stratified analysis of food security and mental health status by age/gender found associations for poor diet quality, protein, fat, fibre, and several micronutrients (p-values < 0.05); those who were food insecure tended to have higher suboptimal intakes (p-values < 0.05). After adjustment for covariates, associations in relation to mental health emerged for food insecurity (OR = 1.60, 95% CI 1.45-1.71), poor diet quality (1.61, 95% CI 1.34-1.81), and suboptimal intakes of folate (OR = 1.58, 95% CI 1.17-1.90) and iron (OR = 1.45, 95% CI 1.23-1.88). CONCLUSIONS: Population approaches that improve food security and intakes of high quality diets may protect people from poor mental health. PMID- 28335421 TI - PAMAM Dendrimers Cross the Blood-Brain Barrier When Administered through the Carotid Artery in C57BL/6J Mice. AB - Drug delivery into the central nervous system (CNS) is challenging due to the blood-brain barrier (BBB) and drug delivery into the brain overcoming the BBB can be achieved using nanoparticles such as dendrimers. The conventional cationic dendrimers used are highly toxic. Therefore, the present study investigates the role of novel mixed surface dendrimers, which have potentially less toxicity and can cross the BBB when administered through the carotid artery in mice. In vitro experiments investigated the uptake of amine dendrimers (G1-NH2 and G4-NH2) and novel dendrimers (G1-90/10 and G4-90/10) by primary cortical cultures. In vivo experiments involved transplantation of G4-90/10 into mice through (1) invasive intracranial injections into the striatum; and (2) less invasive carotid injections. The animals were sacrificed 24-h and 1-week post-transplantations and their brains were analyzed. In vivo experiments proved that the G4-90/10 can cross the BBB when injected through the carotid artery and localize within neurons and glial cells. The dendrimers were found to migrate through the corpus callosum 1-week post intracranial injection. Immunohistochemistry showed that the migrating cells are the dendrimer-infected glial cells. Overall, our results suggest that poly-amidoamine (PAMAM) dendrimers may be used as a minimally invasive means to deliver biomolecules for treating neurological diseases or disorders. PMID- 28335420 TI - Efforts and Challenges in Engineering the Genetic Code. AB - This year marks the 48th anniversary of Francis Crick's seminal work on the origin of the genetic code, in which he first proposed the "frozen accident" hypothesis to describe evolutionary selection against changes to the genetic code that cause devastating global proteome modification. However, numerous efforts have demonstrated the viability of both natural and artificial genetic code variations. Recent advances in genetic engineering allow the creation of synthetic organisms that incorporate noncanonical, or even unnatural, amino acids into the proteome. Currently, successful genetic code engineering is mainly achieved by creating orthogonal aminoacyl-tRNA/synthetase pairs to repurpose stop and rare codons or to induce quadruplet codons. In this review, we summarize the current progress in genetic code engineering and discuss the challenges, current understanding, and future perspectives regarding genetic code modification. PMID- 28335424 TI - An Alternative Wearable Tracking System Based on a Low-Power Wide-Area Network. AB - This work presents an alternative wearable tracking system based on a low-power wide area network. A complete GPS receiver was integrated with a textile substrate, and the latitude and longitude coordinates were sent to the cloud by means of the SIM-less SIGFOX network. To send the coordinates over SIGFOX protocol, a specific codification algorithm was used and a customized UHF antenna on jeans fabric was designed, simulated and tested. Moreover, to guarantee the compliance to international regulations for human body exposure to electromagnetic radiation, the electromagnetic specific absorption rate of this antenna was analyzed. A specific remote server was developed to decode the latitude and longitude coordinates. Once the coordinates have been decoded, the remote server sends this information to the open source data viewer SENTILO to show the location of the sensor node in a map. The functionality of this system has been demonstrated experimentally. The results guarantee the utility and wearability of the proposed tracking system for the development of sensor nodes and point out that it can be a low cost alternative to other commercial products based on GSM networks. PMID- 28335425 TI - Linear Mathematical Model for Seam Tracking with an Arc Sensor in P-GMAW Processes. AB - Arc sensors have been used in seam tracking and widely studied since the 80s and commercial arc sensing products for T and V shaped grooves have been developed. However, it is difficult to use these arc sensors in narrow gap welding because the arc stability and sensing accuracy are not satisfactory. Pulse gas melting arc welding (P-GMAW) has been successfully applied in narrow gap welding and all position welding processes, so it is worthwhile to research P-GMAW arc sensing technology. In this paper, we derived a linear mathematical P-GMAW model for arc sensing, and the assumptions for the model are verified through experiments and finite element methods. Finally, the linear characteristics of the mathematical model were investigated. In torch height changing experiments, uphill experiments, and groove angle changing experiments the P-GMAW arc signals all satisfied the linear rules. In addition, the faster the welding speed, the higher the arc signal sensitivities; the smaller the groove angle, the greater the arc sensitivities. The arc signal variation rate needs to be modified according to the welding power, groove angles, and weaving or rotate speed. PMID- 28335423 TI - Treatment with 17beta-Estradiol Reduced Body Weight and the Risk of Cardiovascular Disease in a High-Fat Diet-Induced Animal Model of Obesity. AB - Estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) play important roles in cardiovascular disease (CVD) prevention. Recently, these estrogen receptors were reconsidered as an important treatment target of obesity leading to CVD. In this study, 17beta-estradiol (17beta-E) replacement therapy applied to high-fat diet-induced obese C57B male mice and ovariectomized (OVX) rats were evaluated, and the protective effects against high-fat diet-induced obesity were assessed in C57B mouse hearts. The results showed that 17beta-E treatment activated both ERalpha and ERbeta, and ERbeta levels increased in a dose-dependent manner in high-fat diet C57B mouse cardiomyocytes following 17beta E treatment. Notably, an almost 16% reduction in body weight was observed in the 17beta-E-treated (12 MUg/kg/day for 60 days) high-fat diet-induced obese C57B male mice. These results suggested that 17beta-E supplements may reduce CVD risk due to obesity. PMID- 28335416 TI - Supplementation with Phycocyanobilin, Citrulline, Taurine, and Supranutritional Doses of Folic Acid and Biotin-Potential for Preventing or Slowing the Progression of Diabetic Complications. AB - Oxidative stress, the resulting uncoupling of endothelial nitric oxide synthase (eNOS), and loss of nitric oxide (NO) bioactivity, are key mediators of the vascular and microvascular complications of diabetes. Much of this oxidative stress arises from up-regulated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Phycocyanobilin (PhyCB), the light-harvesting chromophore in edible cyanobacteria such as spirulina, is a biliverdin derivative that shares the ability of free bilirubin to inhibit certain isoforms of NADPH oxidase. Epidemiological studies reveal that diabetics with relatively elevated serum bilirubin are less likely to develop coronary disease or microvascular complications; this may reflect the ability of bilirubin to ward off these complications via inhibition of NADPH oxidase. Oral PhyCB may likewise have potential in this regard, and has been shown to protect diabetic mice from glomerulosclerosis. With respect to oxidant-mediated uncoupling of eNOS, high dose folate can help to reverse this by modulating the oxidation status of the eNOS cofactor tetrahydrobiopterin (BH4). Oxidation of BH4 yields dihydrobiopterin (BH2), which competes with BH4 for binding to eNOS and promotes its uncoupling. The reduced intracellular metabolites of folate have versatile oxidant-scavenging activity that can prevent oxidation of BH4; concurrently, these metabolites promote induction of dihydrofolate reductase, which functions to reconvert BH2 to BH4, and hence alleviate the uncoupling of eNOS. The arginine metabolite asymmetric dimethylarginine (ADMA), typically elevated in diabetics, also uncouples eNOS by competitively inhibiting binding of arginine to eNOS; this effect is exacerbated by the increased expression of arginase that accompanies diabetes. These effects can be countered via supplementation with citrulline, which efficiently enhances tissue levels of arginine. With respect to the loss of NO bioactivity that contributes to diabetic complications, high dose biotin has the potential to "pinch hit" for diminished NO by direct activation of soluble guanylate cyclase (sGC). High-dose biotin also may aid glycemic control via modulatory effects on enzyme induction in hepatocytes and pancreatic beta cells. Taurine, which suppresses diabetic complications in rodents, has the potential to reverse the inactivating impact of oxidative stress on sGC by boosting synthesis of hydrogen sulfide. Hence, it is proposed that concurrent administration of PhyCB, citrulline, taurine, and supranutritional doses of folate and biotin may have considerable potential for prevention and control of diabetic complications. Such a regimen could also be complemented with antioxidants such as lipoic acid, N-acetylcysteine, and melatonin-that boost cellular expression of antioxidant enzymes and glutathione-as well as astaxanthin, zinc, and glycine. The development of appropriate functional foods might make it feasible for patients to use complex nutraceutical regimens of the sort suggested here. PMID- 28335422 TI - Association between Coffee Consumption and Its Polyphenols with Cardiovascular Risk Factors: A Population-Based Study. AB - Epidemiological studies have examined the effect of coffee intake on cardiovascular disease, but the benefits and risks for the cardiovascular system remain controversial. Our objective was to evaluate the association between coffee consumption and its polyphenols on cardiovascular risk factors. Data came from the "Health Survey of Sao Paulo (ISA-Capital)" among 557 individuals, in Sao Paulo, Brazil. Diet was assessed by two 24-h dietary recalls. Coffee consumption was categorized into <1, 1-3, and >=3 cups/day. Polyphenol intake was calculated by matching food consumption data with the Phenol-Explorer database. Multiple logistic regression models were used to assess the associations between cardiovascular risk factors (blood pressure, total cholesterol, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), triglycerides, fasting glucose, and homocysteine) and usual coffee intake. The odds were lower among individuals who drank 1-3 cups of coffee/day to elevated systolic blood pressure (SBP) (Odds Ratio (OR) = 0.45; 95% Confidence Interval (95% CI): 0.26, 0.78), elevated diastolic blood pressure (DBP) (OR = 0.44; 95% CI: 0.20, 0.98), and hyperhomocysteinemia (OR = 0.32; 95% CI: 0.11, 0.93). Furthermore, significant inverse associations were also observed between moderate intake of coffee polyphenols and elevated SBP (OR = 0.46; 95% CI: 0.24, 0.87), elevated DBP (OR = 0.51; 95% CI: 0.26, 0.98), and hyperhomocysteinemia (OR = 0.29; 95% CI: 0.11, 0.78). In conclusion, coffee intake of 1-3 cups/day and its polyphenols were associated with lower odds of elevated SBP, DBP, and hyperhomocysteinemia. Thus, the moderate consumption of coffee, a polyphenol-rich beverage, could exert a protective effect against some cardiovascular risk factors. PMID- 28335426 TI - Elevated Serum Hepcidin Levels during an Intensified Training Period in Well Trained Female Long-Distance Runners. AB - Iron is essential for providing oxygen to working muscles during exercise, and iron deficiency leads to decreased exercise capacity during endurance events. However, the mechanism of iron deficiency among endurance athletes remains unclear. In this study, we compared iron status between two periods involving different training regimens. Sixteen female long-distance runners participated. Over a seven-month period, fasting blood samples were collected during their regular training period (LOW; middle of February) and during an intensified training period (INT; late of August) to determine blood hematological, iron, and inflammatory parameters. Three-day food diaries were also assessed. Body weight and lean body mass did not differ significantly between LOW and INT, while body fat and body fat percentage were significantly lower in INT (p < 0.05). Blood hemoglobin, serum ferritin, total protein, and iron levels, total iron-binding capacity, and transferrin saturation did not differ significantly between the two periods. Serum hepcidin levels were significantly higher during INT than LOW (p < 0.05). Carbohydrate and iron intakes from the daily diet were significantly higher during INT than LOW (p < 0.05). In conclusion, an elevated hepcidin level was observed during an intensified training period in long-distance runners, despite an apparently adequate daily intake of iron. PMID- 28335427 TI - Laxative Effects of Total Diterpenoids Extracted from the Roots of Euphorbia pekinensis Are Attributable to Alterations of Aquaporins in the Colon. AB - This study was designed to evaluate the toxic effects of total diterpenoids extracted from the roots of Euphorbia pekinensis (TDEP) on the mouse colon and to clarify the mechanism. Dried powdered roots of E. pekinensis were extracted with chloroform, and then the extract (6.7 g) was subjected to column chromatography and preparative TLC, giving TDEP. Using the HPLC-DAD method, the purity of TDEP was determined as 85.26%. Mice were orally administered with TDEP (3.942, 19.71 and 39.42 mg/kg), after which fecal water content and colon water content were examined. Both of them increased over time after TDEP administration, accompanied by severe diarrhea. Three hours after TDEP administration, the animals were sacrificed to obtain their colons. The mRNA and protein expression levels of aquaporin 1 (AQP1), AQP3 and AQP4 in the colon were measured using real-time RT PCR and Western blotting, respectively. TDEP significantly increased the levels of AQP3 and AQP4, but decreased that of AQP1 in dose-dependent manners. Similarly, Pekinenin C, a casbane diterpenoid, significantly increased AQP3 protein and mRNA expressions in human intestinal epithelial cells (HT-29). Histopathological examination revealed that the colon was not significantly damaged. The laxative effects of E. pekinensis were associated with the alterations of AQPs in the colon by TDEP. PMID- 28335429 TI - The Adverse Effect of Hypertension in the Treatment of Thyroid Cancer with Multi Kinase Inhibitors. AB - The treatment of thyroid cancer has promising prospects, mostly through the use of surgical or radioactive iodine therapy. However, some thyroid cancers, such as progressive radioactive iodine-refractory differentiated thyroid carcinoma, are not remediable with conventional types of treatment. In these cases, a treatment regimen with multi-kinase inhibitors is advisable. Unfortunately, clinical trials have shown a large number of patients, treated with multi-kinase inhibitors, being adversely affected by hypertension. This means that treatment of thyroid cancer with multi-kinase inhibitors prolongs progression-free and overall survival of patients, but a large number of patients experience hypertension as an adverse effect of the treatment. Whether the prolonged lifetime is sufficient to develop sequelae from hypertension is unclear, but late-stage cancer patients often have additional diseases, which can be complicated by the presence of hypertension. Since the exact mechanisms of the rise of hypertension in these patients are still unknown, the only available strategy is treating the symptoms. More studies determining the pathogenesis of hypertension as a side effect to cancer treatment as well as outcomes of dose management of cancer drugs are necessary to improve future therapy options for hypertension as an adverse effect to cancer therapy with multi-kinase inhibitors. PMID- 28335431 TI - Building a Relationship between Robot Characteristics and Teleoperation User Interfaces. AB - The Robot Operating System (ROS) provides roboticists with a standardized and distributed framework for real-time communication between robotic systems using a microkernel environment. This paper looks at how ROS metadata, Unified Robot Description Format (URDF), Semantic Robot Description Format (SRDF), and its message description language, can be used to identify key robot characteristics to inform User Interface (UI) design for the teleoperation of heterogeneous robot teams. Logical relationships between UI components and robot characteristics are defined by a set of relationship rules created using relevant and available information including developer expertise and ROS metadata. This provides a significant opportunity to move towards a rule-driven approach for generating the designs of teleoperation UIs; in particular the reduction of the number of different UI configurations required to teleoperate each individual robot within a heterogeneous robot team. This approach is based on using an underlying rule set identifying robots that can be teleoperated using the same UI configuration due to having the same or similar robot characteristics. Aside from reducing the number of different UI configurations an operator needs to be familiar with, this approach also supports consistency in UI configurations when a teleoperator is periodically switching between different robots. To achieve this aim, a Matlab toolbox is developed providing users with the ability to define rules specifying the relationship between robot characteristics and UI components. Once rules are defined, selections that best describe the characteristics of the robot type within a particular heterogeneous robot team can be made. A main advantage of this approach is that rather than specifying discrete robots comprising the team, the user can specify characteristics of the team more generally allowing the system to deal with slight variations that may occur in the future. In fact, by using the defined relationship rules and characteristic selections, the toolbox can automatically identify a reduced set of UI configurations required to control possible robot team configurations, as opposed to the traditional ad-hoc approach to teleoperation UI design. In the results section, three test cases are presented to demonstrate how the selection of different robot characteristics builds a number of robot characteristic combinations, and how the relationship rules are used to determine a reduced set of required UI configurations needed to control each individual robot in the robot team. PMID- 28335430 TI - A Review on Ubiquitination of Neurotrophin Receptors: Facts and Perspectives. AB - Ubiquitination is a reversible post-translational modification involved in a plethora of different physiological functions. Among the substrates that are ubiquitinated, neurotrophin receptors (TrkA, TrkB, TrkC, and p75NTR) have been studied recently. TrkA is the most studied receptor in terms of its ubiquitination, and different E3 ubiquitin ligases and deubiquitinases have been implicated in its ubiquitination, whereas not much is known about the other neurotrophin receptors aside from their ubiquitination. Additional studies are needed that focus on the ubiquitination of TrkB, TrkC, and p75NTR in order to further understand the role of ubiquitination in their physiological and pathological functions. Here we review what is currently known regarding the ubiquitination of neurotrophin receptors and its physiological and pathological relevance. PMID- 28335428 TI - An Updated Review of Ciguatera Fish Poisoning: Clinical, Epidemiological, Environmental, and Public Health Management. AB - Ciguatera Fish Poisoning (CFP) is the most frequently reported seafood-toxin illness in the world. It causes substantial human health, social, and economic impacts. The illness produces a complex array of gastrointestinal, neurological and neuropsychological, and cardiovascular symptoms, which may last days, weeks, or months. This paper is a general review of CFP including the human health effects of exposure to ciguatoxins (CTXs), diagnosis, human pathophysiology of CFP, treatment, detection of CTXs in fish, epidemiology of the illness, global dimensions, prevention, future directions, and recommendations for clinicians and patients. It updates and expands upon the previous review of CFP published by Friedman et al. (2008) and addresses new insights and relevant emerging global themes such as climate and environmental change, international market issues, and socioeconomic impacts of CFP. It also provides a proposed universal case definition for CFP designed to account for the variability in symptom presentation across different geographic regions. Information that is important but unchanged since the previous review has been reiterated. This article is intended for a broad audience, including resource and fishery managers, commercial and recreational fishers, public health officials, medical professionals, and other interested parties. PMID- 28335432 TI - Marine Lectins DlFBL and HddSBL Fused with Soluble Coxsackie-Adenovirus Receptor Facilitate Adenovirus Infection in Cancer Cells BUT Have Different Effects on Cell Survival. AB - Cancer development and progression are usually associated with glycosylation change, providing prognostic and diagnostic biomarkers, as well as therapeutic targets, for various cancers. In this work, Dicentrarchus labrax fucose binding lectin (DlFBL) and Haliotis discus discus sialic acid binding lectin (HddSBL) were genetically fused with soluble coxsackie-adenovirus receptor (sCAR), and produced through a bacterial expression system. Results showed that recombinant sCAR-DlFBL not only facilitated adenovirus Ad-EGFP infection in K562/ADR and U87MG cells, but also enhanced the cytotoxicity of adenovirus harboring gene encoding Pinellia pedatisecta agglutinin (PPA) or DlFBL (Ad-PPA or Ad-DlFBL) on U87MG cells through inducing apoptosis. Recombinant sCAR-HddSBL facilitated Ad EGFP infection, but dramatically counteracted the cytotoxicity of both Ad-PPA and Ad-DlFBL in U87MG cells. Further analysis revealed that sCAR-HddSBL, but not sCAR DlFBL, significantly upregulated transcription factor E2F1 levels in U87MG cells, which might be responsible for the adverse effect of sCAR-HddSBL on Ad-PPA and Ad DlFBL. Taken together, our data suggested that sCAR-DlFBL could be further developed to redirect therapeutic adenoviruses to infect cancer cells such as U87MG, and the sCAR-lectin fusion proteins for adenoviral retargeting should be carefully examined for possible survival signaling induced by lectins, such as HddSBL. PMID- 28335433 TI - Evaluation and Adaptation of a Laboratory-Based cDNA Library Preparation Protocol for Retrospective Sequencing of Archived MicroRNAs from up to 35-Year-Old Clinical FFPE Specimens. AB - Formalin-fixed paraffin-embedded (FFPE) specimens, when used in conjunction with patient clinical data history, represent an invaluable resource for molecular studies of cancer. Even though nucleic acids extracted from archived FFPE tissues are degraded, their molecular analysis has become possible. In this study, we optimized a laboratory-based next-generation sequencing barcoded cDNA library preparation protocol for analysis of small RNAs recovered from archived FFPE tissues. Using matched fresh and FFPE specimens, we evaluated the robustness and reproducibility of our optimized approach, as well as its applicability to archived clinical specimens stored for up to 35 years. We then evaluated this cDNA library preparation protocol by performing a miRNA expression analysis of archived breast ductal carcinoma in situ (DCIS) specimens, selected for their relation to the risk of subsequent breast cancer development and obtained from six different institutions. Our analyses identified six miRNAs (miR-29a, miR-221, miR-375, miR-184, miR-363, miR-455-5p) differentially expressed between DCIS lesions from women who subsequently developed an invasive breast cancer (cases) and women who did not develop invasive breast cancer within the same time interval (control). Our thorough evaluation and application of this laboratory based miRNA sequencing analysis indicates that the preparation of small RNA cDNA libraries can reliably be performed on older, archived, clinically-classified specimens. PMID- 28335434 TI - Induction of G2M Arrest by Flavokawain A, a Kava Chalcone, Increases the Responsiveness of HER2-Overexpressing Breast Cancer Cells to Herceptin. AB - HER2/neu positive breast tumors predict a high mortality and comprise 25%-30% of breast cancer. We have shown that Flavokawain A (FKA) preferentially reduces the viabilities of HER2-overexpressing breast cancer cell lines (i.e., SKBR3 and MCF7/HER2) versus those with less HER2 expression (i.e., MCF7 and MDA-MB-468). FKA at cytotoxic concentrations to breast cancer cell lines also has a minimal effect on the growth of non-malignant breast epithelial MCF10A cells. FKA induces G2M arrest in cell cycle progression of HER2-overexpressing breast cancer cell lines through inhibition of Cdc2 and Cdc25C phosphorylation and downregulation of expression of Myt1 and Wee1 leading to increased Cdc2 kinase activities. In addition, FKA induces apoptosis in SKBR3 cells by increasing the protein expression of Bim and BAX and decreasing expression of Bcl2, BclX/L, XIAP, and survivin. FKA also downregulates the protein expression of HER-2 and inhibits AKT phosphorylation. Herceptin plus FKA treatment leads to an enhanced growth inhibitory effect on HER-2 overexpressing breast cancer cell lines through downregulation of Myt1, Wee1, Skp2, survivin, and XIAP. Our results suggest FKA as a promising and novel apoptosis inducer and G2 blocking agent that, in combination with Herceptin, enhances for the treatment of HER2-overexpressing breast cancer. PMID- 28335435 TI - Spirobifluorene Core-Based Novel Hole Transporting Materials for Red Phosphorescence OLEDs. AB - Two new hole transporting materials, named HTM 1A and HTM 1B, were designed and synthesized in significant yields using the well-known Buchwald Hartwig and Suzuki cross- coupling reactions. Both materials showed higher decomposition temperatures (over 450 degrees C) at 5% weight reduction and HTM 1B exhibited a higher glass transition temperature of 180 degrees C. Red phosphorescence-based OLED devices were fabricated to analyze the device performances compared to Spiro NPB and NPB as reference hole transporting materials. Devices consist of hole transporting material as HTM 1B showed better maximum current and power efficiencies of 16.16 cd/A and 11.17 lm/W, at the same time it revealed an improved external quantum efficiency of 13.64%. This efficiency is considerably higher than that of Spiro-NPB and NPB-based reference devices. PMID- 28335436 TI - Photonic Low Cost Micro-Sensor for in-Line Wear Particle Detection in Flowing Lube Oils. AB - The presence of microscopic particles in suspension in industrial fluids is often an early warning of latent or imminent failures in the equipment or processes where they are being used. This manuscript describes work undertaken to integrate different photonic principles with a micro- mechanical fluidic structure and an embedded processor to develop a fully autonomous wear debris sensor for in-line monitoring of industrial fluids. Lens-less microscopy, stroboscopic illumination, a CMOS imager and embedded machine vision technologies have been merged to develop a sensor solution that is able to detect and quantify the number and size of micrometric particles suspended in a continuous flow of a fluid. A laboratory test-bench has been arranged for setting up the configuration of the optical components targeting a static oil sample and then a sensor prototype has been developed for migrating the measurement principles to real conditions in terms of operating pressure and flow rate of the oil. Imaging performance is quantified using micro calibrated samples, as well as by measuring real used lubricated oils. Sampling a large fluid volume with a decent 2D spatial resolution, this photonic micro sensor offers a powerful tool at very low cost and compacted size for in-line wear debris monitoring. PMID- 28335437 TI - Effect of Clozapine on DNA Methylation in Peripheral Leukocytes from Patients with Treatment-Resistant Schizophrenia. AB - Clozapine is an atypical antipsychotic, that is established as the treatment of choice for treatment-resistant schizophrenia (SCZ). To date, no study investigating comprehensive DNA methylation changes in SCZ patients treated with chronic clozapine has been reported. The purpose of the present study is to reveal the effects of clozapine on DNA methylation in treatment-resistant SCZ. We conducted a genome-wide DNA methylation profiling in peripheral leukocytes (485,764 CpG dinucleotides) from treatment-resistant SCZ patients treated with clozapine (n = 21) in a longitudinal study. Significant changes in DNA methylation were observed at 29,134 sites after one year of treatment with clozapine, and these genes were enriched for "cell substrate adhesion" and "cell matrix adhesion" gene ontology (GO) terms. Furthermore, DNA methylation changes in the CREBBP (CREB binding protein) gene were significantly correlated with the clinical improvements. Our findings provide insights into the action of clozapine in treatment-resistant SCZ. PMID- 28335439 TI - Mercury Levels in Human Hair and Farmed Fish near Artisanal and Small-Scale Gold Mining Communities in the Madre de Dios River Basin, Peru. AB - Artisanal and small-scale gold mining (ASGM) has been an important source of income for communities in the Madre de Dios River Basin in Peru for hundreds of years. However, in recent decades, the scale of ASGM activities in the region has increased dramatically, and exposures to a variety of occupational and environmental hazards related to ASGM, including mercury, are becoming more widespread. The aims of our study were to: (1) examine patterns in the total hair mercury level of human participants in several communities in the region and compare these results to the 2.2 ug/g total hair mercury level equivalent to the World Health Organization (WHO) Expert Committee of Food Additives (JECFA)'s Provisional Tolerable Weekly Intake (PTWI); and (2), to measure the mercury levels of paco (Piaractus brachypomus) fish raised in local aquaculture ponds, in order to compare these levels to the EPA Fish Tissue Residue Criterion of 0.3 ug Hg/g fish (wet weight). We collected hair samples from 80 participants in four communities (one control and three where ASGM activities occurred) in the region, and collected 111 samples from fish raised in 24 local aquaculture farms. We then analyzed the samples for total mercury. Total mercury levels in hair were statistically significantly higher in the mining communities than in the control community, and increased with increasing geodesic distance from the Madre de Dios headwaters, did not differ by sex, and frequently exceeded the reference level. Regression analyses indicated that higher hair mercury levels were associated with residence in ASGM communities. The analysis of paco fish samples found no samples that exceeded the EPA tissue residue criterion. Collectively, these results align with other recent studies showing that ASGM activities are associated with elevated human mercury exposure. The fish farmed through the relatively new process of aquaculture in ASGM areas appeared to have little potential to contribute to human mercury exposure. More research is needed on human health risks associated with ASGM to discern occupational, residential, and nutritional exposure, especially through tracking temporal changes in mercury levels as fish ponds age, and assessing levels in different farmed fish species. Additionally, research is needed to definitively determine that elevated mercury levels in humans and fish result from the elemental mercury from mining, rather than from a different source, such as the mercury released from soil erosion during deforestation events from mining or other activities. PMID- 28335440 TI - Profile of Polyphenol Compounds of Five Muscadine Grapes Cultivated in the United States and in Newly Adapted Locations in China. AB - Polyphenol compositions and concentrations in skins and seeds of five muscadine grapes (cv. "Noble", "Alachua", "Carlos", "Fry", and "Granny Val") cultivated in the United States (Tallahassee-Florida, TA-FL) and South China (Nanning-Guangxi, NN-GX and Pu'er-Yunnan, PE-YN) were investigated, using ultra performance liquid chromatography tandem triple quadrupole time-of-flight mass spectrometry (UPLC Triple TOF MS/MS). Fourteen ellagitannins were newly identified in these muscadine grapes. The grapes grown in NN-GX accumulated higher levels of ellagic acid, methyl brevifolin carboxylate, and ellagic acid glucoside in skins, and penta-O-galloyl-glucose in seeds. In PE-YN, more flavonols were detected in skins, and higher contents of flavan-3-ols, ellagic acid, and methyl gallate were identified in seeds. Abundant seed gallic acid and flavonols were found among the grapes grown in TA-FL. Based on principal component analysis (PCA) of 54 evaluation parameters, various cultivars grown in different locations could be grouped together and vice versa for the same cultivar cultivated in different regions. This is the result of the interaction between genotype and environmental conditions, which apparently influences the polyphenol synthesis and accumulation. PMID- 28335438 TI - The Food Production Environment and the Development of Antimicrobial Resistance in Human Pathogens of Animal Origin. AB - Food-borne pathogens are a serious human health concern worldwide, and the emergence of antibiotic-resistant food pathogens has further confounded this problem. Once-highly-efficacious antibiotics are gradually becoming ineffective against many important pathogens, resulting in severe treatment crises. Among several reasons for the development and spread of antimicrobial resistance, their overuse in animal food production systems for purposes other than treatment of infections is prominent. Many pathogens of animals are zoonotic, and therefore any development of resistance in pathogens associated with food animals can spread to humans through the food chain. Human infections by antibiotic-resistant pathogens such as Campylobacter spp., Salmonella spp., Escherichia coli and Staphylococcus aureus are increasing. Considering the human health risk due to emerging antibiotic resistance in food animal-associated bacteria, many countries have banned the use of antibiotic growth promoters and the application in animals of antibiotics critically important in human medicine. Concerted global efforts are necessary to minimize the use of antimicrobials in food animals in order to control the development of antibiotic resistance in these systems and their spread to humans via food and water. PMID- 28335442 TI - In Vitro and In Vivo Effects of Gracilaria verrucosa Extracts on Osteoclast Differentiation. AB - Bone remodeling, a physiological process characterized by bone formation by osteoblasts and bone resorption by osteoclasts, is important for the maintenance of healthy bone in adult humans. Osteoclasts play a critical role in bone erosion and osteoporosis and are bone-specific multinucleated cells generated through differentiation of monocyte/macrophage lineage precursors. Receptor activator of NF-kappaB ligand (RANKL) has been reported to induce osteoclast differentiation. In this study, we explored whether Gracilaria verrucosa extracts (GE) could affect RANKL-mediated osteoclast differentiation. GE significantly inhibited RANKL-activated osteoclast differentiation by inhibiting protein expression of c fos and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), vital factors in RANKL-mediated osteoclastogenesis. In addition, GE attenuated ovariectomy-induced bone loss in mice. In summary, GE can prevent osteoclastogenesis and hormone-related bone loss via blockage of c-fos-NFATc1 signaling. Our results suggest that GE may have therapeutic potential in the treatment of postmenopausal osteoporosis. PMID- 28335441 TI - Dietary Intake of Individual (Free and Intrinsic) Sugars and Food Sources in the Spanish Population: Findings from the ANIBES Study. AB - The consumption of total and individual sugars is controversial and little is known about consumption and dietary sources in Spain. The purpose was to examine free and intrinsic sugar intake and food and beverage sources. The ANIBES Study (Anthropometry, Intake and Energy Balance in Spain), a cross-sectional study of a representative sample of the Spanish population (9-75 years old; n = 2009) carried out in 2013, was used. Food and beverage records were obtained by a three day dietary record by using a tablet device. The median total sugar intake was 71.5 g/day (17% Total Energy, TE), the intrinsic sugar intake was 38.3 g/day (9.6% TE), and the free sugar was 28.8 g/day (7.3% TE). Total sugar intake (free and intrinsic) was higher in men than in women for all age groups, although in terms of the contribution to total energy intake, the opposite was observed. Differences were observed for free sugar consumption dependent on age and marked differences (up to two-fold) were observed when considering the percent TE, which was much higher in children and adolescents. For the intrinsic sugar, however, a higher contribution to TE was observed in the elderly. The major sources of intrinsic sugars were fruits (31.8%), milks (19.6%), juices and nectars (11.1%), vegetables (9.89%), yogurt and fermented milk (7.18%), low-alcohol-content beverages (4,94%), bread (2.91%), and sugar soft drinks (2.24%), greater than 90% from diet contribution. As for free sugars, sources were sugar soft drinks (25.5%), sugar (17.8%), bakery and pastry items (15.2%), chocolates (11.4%), yogurt and fermented milk (6.44%), other dairy products (5.99%), jams (3.58%), juices and nectars (2.91%), and breakfast cereals and cereal bars (2.78%), summing up to 90% of the contribution. The present study demonstrates that only a moderate percentage of the Spanish population adhered to the present recommendations for total sugar intake, and urgent efforts are needed to improve diet quality in the youngest populations. PMID- 28335444 TI - HIV Education and Welfare Services in Primary Care: An Empirical Model of Integration in Brazil's Unified Health System. AB - Integration of health education and welfare services in primary care systems is a key strategy to solve the multiple determinants of chronic diseases, such as Human Immunodeficiency Virus Infection and Acquired Immune Deficiency Syndrome (HIV/AIDS). However, there is a scarcity of conceptual models from which to build integration strategies. We provide a model based on cross-sectional data from 168 Community Health Agents, 62 nurses, and 32 physicians in two municipalities in Brazil's Unified Health System (UHS). The outcome, service integration, comprised HIV education, community activities (e.g., health walks and workshops), and documentation services (e.g., obtainment of working papers and birth certificates). Predictors included individual factors (provider confidence, knowledge/skills, perseverance, efficacy); job characteristics (interprofessional collaboration, work-autonomy, decision-making autonomy, skill variety); and organizational factors (work conditions and work resources). Structural equation modeling was used to identify factors associated with service integration. Knowledge and skills, skill variety, confidence, and perseverance predicted greater integration of HIV education alongside community activities and documentation services. Job characteristics and organizational factors did not predict integration. Our study offers an explanatory model that can be adapted to examine other variables that may influence integration of different services in global primary healthcare systems. Findings suggest that practitioner trainings to improve integration should focus on cognitive constructs-confidence, perseverance, knowledge, and skills. PMID- 28335445 TI - Deciphering Egyptian Hieroglyphs: Towards a New Strategy for Navigation in Museums. AB - This work presents a novel strategy to decipher fragments of Egyptian cartouches identifying the hieroglyphs of which they are composed. A cartouche is a drawing, usually inside an oval, that encloses a group of hieroglyphs representing the name of a monarch. Aiming to identify these drawings, the proposed method is based on several techniques frequently used in computer vision and consists of three main stages: first, a picture of the cartouche is taken as input and its contour is localized. In the second stage, each hieroglyph is individually extracted and identified. Finally, the cartouche is interpreted: the sequence of the hieroglyphs is established according to a previously generated benchmark. This sequence corresponds to the name of the king. Although this method was initially conceived to deal with both high and low relief writing in stone, it can be also applied to painted hieroglyphs. This approach is not affected by variable lighting conditions, or the intensity and the completeness of the objects. This proposal has been tested on images obtained from the Abydos King List and other Egyptian monuments and archaeological excavations. The promising results give new possibilities to recognize hieroglyphs, opening a new way to decipher longer texts and inscriptions, being particularly useful in museums and Egyptian environments. Additionally, devices used for acquiring visual information from cartouches (i.e., smartphones), can be part of a navigation system for museums where users are located in indoor environments by means of the combination of WiFi Positioning Systems (WPS) and depth cameras, as unveiled at the end of the document. PMID- 28335443 TI - Pharmacokinetic and Pharmacodynamic Responses to Clopidogrel: Evidences and Perspectives. AB - Clopidogrel has significantly reduced the incidence of recurrent atherothrombotic events in patients with acute coronary syndrome (ACS) and in those undergoing percutaneous coronary intervention (PCI). However, recurrence events still remain, which may be partly due to inadequate platelet inhibition by standard clopidogrel therapy. Genetic polymorphisms involved in clopidogrel's absorption, metabolism, and the P2Y12 receptor may interfere with its antiplatelet activity. Recent evidence indicated that epigenetic modification may also affect clopidogrel response. In addition, non-genetic factors such as demographics, disease complications, and drug-drug interactions can impair the antiplatelet effect of clopidogrel. The identification of factors contributing to the variation in clopidogrel response is needed to improve platelet inhibition and to reduce risk for cardiovascular events. This review encompasses the most recent updates on factors influencing pharmacokinetic and pharmacodynamic responses to clopidogrel. PMID- 28335446 TI - Knowledge, Self-Confidence and Attitudes towards Suicidal Patients at Emergency and Psychiatric Departments: A Randomised Controlled Trial of the Effects of an Educational Poster Campaign. AB - Educational posters are used to enhance knowledge, attitudes and self-confidence of patients. Little is known on their effectiveness for educating health care professionals. As these professionals may play an important role in suicide prevention, the effects of a poster and accompanying evaluation and triage guide on knowledge, self-confidence and attitudes regarding suicidal thoughts and behaviours, were studied in a multicentre cluster randomised controlled trial, involving staff from 39 emergency and 38 psychiatric departments throughout Flanders (n = 1171). Structured self-report questionnaires assessed the knowledge, confidence and beliefs regarding suicidal behaviour management, and attitudes. Data were analysed through a Solomon four-group design, with random assignment to the different conditions. Baseline scores for knowledge and provider confidence were high. The poster and accompanying evaluation and triage guide did not have an effect on knowledge about suicide and self-confidence in suicidal behaviour management. However, the poster campaign appeared to be beneficial for attitudes towards suicidal patients, but only among staff from mental health departments that were assigned to the un-pretested condition. Given the limited effects of the poster campaign in the studied population with a relatively high baseline knowledge, the evaluation of this poster as part of a multimodal educational programme in a more heterogeneous sample of health care professionals is recommended. PMID- 28335447 TI - Transcriptomic Complexity of Aspergillus terreus Velvet Gene Family under the Influence of Butyrolactone I. AB - Filamentous fungi of the Ascomycota phylum are known to contain a family of conserved conidiation regulating proteins with distinctive velvet domains. In Aspergilli, this velvet family includes four proteins, VeA, VelB, VelC and VosA, and is involved in conidiation and secondary metabolism along with a global regulator LaeA. In A. terreus, the overexpression of LaeA has been observed to increase the biogenesis of the pharmaceutically-important secondary metabolite, lovastatin, while the role of the velvet family has not been studied. The secondary metabolism and conidiation of A. terreus have also been observed to be increased by butyrolactone I in a quorum-sensing manner. An enlightenment of the interplay of these regulators will give potential advancement to the industrial use of this fungus, as well as in resolving the pathogenic features. In this study, the Aspergillus terreus MUCL 38669 transcriptome was strand-specifically sequenced to enable an in-depth gene expression analysis to further investigate the transcriptional role of butyrolactone I in these processes. The sequenced transcriptome revealed intriguing properties of the velvet family transcripts, including the regulator laeA, and uncovered the velC gene in A. terreus. The reliability refining microarray gene expression analysis disclosed a positive regulatory role for butyrolactone I in laeA expression, as well as an influence on the expression of the canonical conidiation-regulating genes under submerged culture. All of this supports the suggested regulative role of butyrolactone I in A. terreus secondary metabolism, as well as conidiation. PMID- 28335449 TI - The Relation between Frequency of E-Cigarette Use and Frequency and Intensity of Cigarette Smoking among South Korean Adolescents. AB - INTRODUCTION: The prevalence of adolescent electronic cigarette (e-cigarette) use has increased in most countries. This study aims to determine the relation between the frequency of e-cigarette use and the frequency and intensity of cigarette smoking. Additionally, the study evaluates the association between the reasons for e-cigarette use and the frequency of its use. MATERIALS AND METHODS: Using the 2015 Korean Youth Risk Behavior Web-Based Survey, we included 6655 adolescents with an experience of e-cigarette use who were middle and high school students aged 13-18 years. We compared smoking experience, the frequency and intensity of cigarette smoking, and the relation between the reasons for e cigarette uses and the frequency of e-cigarette use. RESULTS: The prevalence of e cigarette ever and current (past 30 days) users were 10.1% and 3.9%, respectively. Of the ever users, approximately 60% used e-cigarettes not within 1 month. On the other hand, 8.1% used e-cigarettes daily. The frequent and intensive cigarette smoking was associated with frequent e-cigarette uses. The percentage of frequent e-cigarette users (>=10 days/month) was 3.5% in adolescents who did not smoke within a month, but 28.7% among daily smokers. Additionally, it was 9.1% in smokers who smoked less than 1 cigarette/month, but 55.1% in smokers who smoked >=20 cigarettes/day. The most common reason for e cigarette use was curiosity (22.9%), followed by the belief that they are less harmful than conventional cigarettes (18.9%), the desire to quit smoking (13.1%), and the capacity for indoor use (10.7%). Curiosity was the most common reason among less frequent e-cigarette users; however, the desire to quit smoking and the capacity for indoor use were the most common reasons among more frequent users. CONCLUSIONS: Results showed a positive relation between frequency or intensity of conventional cigarette smoking and the frequency of e-cigarette use among Korean adolescents, and frequency of e-cigarette use differed according to the reason for the use of e-cigarettes. PMID- 28335448 TI - A Community Multi-Omics Approach towards the Assessment of Surface Water Quality in an Urban River System. AB - A multi-omics approach was applied to an urban river system (the Brisbane River (BR), Queensland, Australia) in order to investigate surface water quality and characterize the bacterial population with respect to water contaminants. To do this, bacterial metagenomic amplicon-sequencing using Illumina next-generation sequencing (NGS) of the V5-V6 hypervariable regions of the 16S rRNA gene and untargeted community metabolomics using gas chromatography coupled with mass spectrometry (GC-MS) were utilized. The multi-omics data, in combination with fecal indicator bacteria (FIB) counts, trace metal concentrations (by inductively coupled plasma mass spectrometry (ICP-MS)) and in-situ water quality measurements collected from various locations along the BR were then used to assess the health of the river ecosystem. Sites sampled represented the transition from less affected (upstream) to polluted (downstream) environments along the BR. Chemometric analysis of the combined datasets indicated a clear separation between the sampled environments. Burkholderiales and Cyanobacteria were common key factors for differentiation of pristine waters. Increased sugar alcohol and short-chain fatty acid production was observed by Actinomycetales and Rhodospirillaceae that are known to form biofilms in urban polluted and brackish waters. Results from this study indicate that a multi-omics approach enables a deep understanding of the health of an aquatic ecosystem, providing insight into the bacterial diversity present and the metabolic output of the population when exposed to environmental contaminants. PMID- 28335450 TI - Assessment of Radioactive Materials and Heavy Metals in the Surface Soil around the Bayanwula Prospective Uranium Mining Area in China. AB - The present work is the first systematic and large scale study on radioactive materials and heavy metals in surface soil around the Bayanwula prospective uranium mining area in China. In this work, both natural and anthropogenic radionuclides and heavy metals in 48 surface soil samples were analyzed using High Purity Germanium (HPGe) gamma spectrometry and inductively coupled plasma mass spectrometry (ICP-MS). The obtained mean activity concentrations of 238U, 226Ra, 232Th, 40K, and 137Cs were 25.81 +/- 9.58, 24.85 +/- 2.77, 29.40 +/- 3.14, 923.0 +/- 47.2, and 5.64 +/- 4.56 Bq/kg, respectively. The estimated average absorbed dose rate and annual effective dose rate were 76.7 +/- 3.1 nGy/h and 83.1 +/- 3.8 MUSv, respectively. The radium equivalent activity, external hazard index, and internal hazard index were also calculated, and their mean values were within the acceptable limits. The estimated lifetime cancer risk was 3.2 * 10 4/Sv. The heavy metal contents of Cr, Ni, Cu, Zn, As, Cd, and Pb from the surface soil samples were measured and their health risks were then assessed. The concentrations of all heavy metals were much lower than the average backgrounds in China except for lead which was about three times higher than that of China's mean. The non-cancer and cancer risks from the heavy metals were estimated, which are all within the acceptable ranges. In addition, the correlations between the radionuclides and the heavy metals in surface soil samples were determined by the Pearson linear coefficient. Strong positive correlations between radionuclides and the heavy metals at the 0.01 significance level were found. In conclusion, the contents of radionuclides and heavy metals in surface soil around the Bayanwula prospective uranium mining area are at a normal level. PMID- 28335452 TI - Fabrication and Water Treatment Application of Carbon Nanotubes (CNTs)-Based Composite Membranes: A Review. AB - Membrane separation technology is widely explored for various applications, such as water desalination and wastewater treatment, which can alleviate the global issue of fresh water scarcity. Specifically, carbon nanotubes (CNTs)-based composite membranes are increasingly of interest due to the combined merits of CNTs and membrane separation, offering enhanced membrane properties. This article first briefly discusses fabrication and growth mechanisms, characterization and functionalization techniques of CNTs, and then reviews the fabrication methods for CNTs-based composite membranes in detail. The applications of CNTs-based composite membranes in water treatment are comprehensively reviewed, including seawater or brine desalination, oil-water separation, removal of heavy metal ions and emerging pollutants as well as membrane separation coupled with assistant techniques. Furthermore, the future direction and perspective for CNTs-based composite membranes are also briefly outlined. PMID- 28335451 TI - A Review of Phage Therapy against Bacterial Pathogens of Aquatic and Terrestrial Organisms. AB - Since the discovery of bacteriophage in the early 1900s, there have been numerous attempts to exploit their innate ability to kill bacteria. The purpose of this report is to review current findings and new developments in phage therapy with an emphasis on bacterial diseases of marine organisms, humans, and plants. The body of evidence includes data from studies investigating bacteriophage in marine and land environments as modern antimicrobial agents against harmful bacteria. The goal of this paper is to present an overview of the topic of phage therapy, the use of phage-derived protein therapy, and the hosts that bacteriophage are currently being used against, with an emphasis on the uses of bacteriophage against marine, human, animal and plant pathogens. PMID- 28335453 TI - A Spatially Offset Raman Spectroscopy Method for Non-Destructive Detection of Gelatin-Encapsulated Powders. AB - Non-destructive subsurface detection of encapsulated, coated, or seal-packaged foods and pharmaceuticals can help prevent distribution and consumption of counterfeit or hazardous products. This study used a Spatially Offset Raman Spectroscopy (SORS) method to detect and identify urea, ibuprofen, and acetaminophen powders contained within one or more (up to eight) layers of gelatin capsules to demonstrate subsurface chemical detection and identification. A 785-nm point-scan Raman spectroscopy system was used to acquire spatially offset Raman spectra for an offset range of 0 to 10 mm from the surfaces of 24 encapsulated samples, using a step size of 0.1 mm to obtain 101 spectral measurements per sample. As the offset distance was increased, the spectral contribution from the subsurface powder gradually outweighed that of the surface capsule layers, allowing for detection of the encapsulated powders. Containing mixed contributions from the powder and capsule, the SORS spectra for each sample were resolved into pure component spectra using self-modeling mixture analysis (SMA) and the corresponding components were identified using spectral information divergence values. As demonstrated here for detecting chemicals contained inside thick capsule layers, this SORS measurement technique coupled with SMA has the potential to be a reliable non-destructive method for subsurface inspection and authentication of foods, health supplements, and pharmaceutical products that are prepared or packaged with semi-transparent materials. PMID- 28335456 TI - Mosquito Traps: An Innovative, Environmentally Friendly Technique to Control Mosquitoes. AB - We tested the use of mosquito traps as an alternative to spraying insecticide in Camargue (France) following the significant impacts observed on the non-target fauna through Bti persistence and trophic perturbations. In a village of 600 inhabitants, 16 Techno Bam traps emitting CO2 and using octenol lures were set from April to November 2016. Trap performance was estimated at 70% overall based on mosquitoes landing on human bait in areas with and without traps. The reduction of Ochlerotatus caspius and Oc. detritus, the two species targeted by Bti spraying, was, respectively, 74% and 98%. Traps were less efficient against Anopheles hyrcanus (46%), which was more attracted by lactic acid than octenol lures based on previous tests. Nearly 300,000 mosquitoes from nine species were captured, with large variations among traps, emphasizing that trap performance is also influenced by surrounding factors. Environmental impact, based on the proportion of non-target insects captured, was mostly limited to small chironomids attracted by street lights. The breeding success of a house martin colony was not significantly affected by trap use, in contrast to Bti spraying. Our experiment confirms that the deployment of mosquito traps can offer a cost effective alternative to Bti spraying for protecting local populations from mosquito nuisance in sensitive natural areas. PMID- 28335455 TI - Viral Protein Kinetics of Piscine Orthoreovirus Infection in Atlantic Salmon Blood Cells. AB - Piscine orthoreovirus (PRV) is ubiquitous in farmed Atlantic salmon (Salmo salar) and the cause of heart and skeletal muscle inflammation. Erythrocytes are important target cells for PRV. We have investigated the kinetics of PRV infection in salmon blood cells. The findings indicate that PRV causes an acute infection of blood cells lasting 1-2 weeks, before it subsides into persistence. A high production of viral proteins occurred initially in the acute phase which significantly correlated with antiviral gene transcription. Globular viral factories organized by the non-structural protein uNS were also observed initially, but were not evident at later stages. Interactions between uNS and the PRV structural proteins lambda1, u1, sigma1 and sigma3 were demonstrated. Different size variants of uNS and the outer capsid protein u1 appeared at specific time points during infection. Maximal viral protein load was observed five weeks post cohabitant challenge and was undetectable from seven weeks post challenge. In contrast, viral RNA at a high level could be detected throughout the eight-week trial. A proteolytic cleavage fragment of the u1 protein was the only viral protein detectable after seven weeks post challenge, indicating that this u1 fragment may be involved in the mechanisms of persistent infection. PMID- 28335459 TI - Estimation of Image Sensor Fill Factor Using a Single Arbitrary Image. AB - Achieving a high fill factor is a bottleneck problem for capturing high-quality images. There are hardware and software solutions to overcome this problem. In the solutions, the fill factor is known. However, this is an industrial secrecy by most image sensor manufacturers due to its direct effect on the assessment of the sensor quality. In this paper, we propose a method to estimate the fill factor of a camera sensor from an arbitrary single image. The virtual response function of the imaging process and sensor irradiance are estimated from the generation of virtual images. Then the global intensity values of the virtual images are obtained, which are the result of fusing the virtual images into a single, high dynamic range radiance map. A non-linear function is inferred from the original and global intensity values of the virtual images. The fill factor is estimated by the conditional minimum of the inferred function. The method is verified using images of two datasets. The results show that our method estimates the fill factor correctly with significant stability and accuracy from one single arbitrary image according to the low standard deviation of the estimated fill factors from each of images and for each camera. PMID- 28335458 TI - In Vitro Antioxidant Activity and In Vivo Anti-Fatigue Effect of Sea Horse (Hippocampus) Peptides. AB - This study investigated changes the in vitro antioxidant activity of Hippocampus polypeptides during enzymatic hydrolysis, including the effects of enzyme species, enzyme concentration, material-liquid ratio, hydrolysis time, pH, and temperature of the reaction system. Its in vivo anti-fatigue activity was also studied. Hippocampus peptide prepared by papain digestion exhibited the highest 1,1-diphenyl-2-picryl-hydrazyl free radical scavenging rate (71.89% +/- 1.50%) and strong hydroxyl radical scavenging rate (75.53% +/- 0.98%), compared to those prepared by five other commonly used enzymes (i.e., trypsin, neutral protease, compound protease, flavorzyme, and alkaline protease). Additionally, maximum antioxidant activity of Hippocampus polypeptide prepared by papain digestion was reached after hydrolysis for 40 min at pH 6.0 and 60 degrees C of the reaction system by using 2000 U/g enzyme and a material-liquid ratio of 1:15. Moreover, compared with the control group, Hippocampus peptide prolonged the swimming time by 33%-40%, stabilized the blood glucose concentration, increased liver glycogen levels, and decreased blood lactate levels and blood urea nitrogen levels in mice (p < 0.01). In conclusion, these results indicated that Hippocampus polypeptide prepared by papain digestion under optimal conditions exhibited high degrees of antioxidant and anti-fatigue activity. PMID- 28335454 TI - Porcine Rotaviruses: Epidemiology, Immune Responses and Control Strategies. AB - Rotaviruses (RVs) are a major cause of acute viral gastroenteritis in young animals and children worldwide. Immunocompetent adults of different species become resistant to clinical disease due to post-infection immunity, immune system maturation and gut physiological changes. Of the 9 RV genogroups (A-I), RV A, B, and C (RVA, RVB, and RVC, respectively) are associated with diarrhea in piglets. Although discovered decades ago, porcine genogroup E RVs (RVE) are uncommon and their pathogenesis is not studied well. The presence of porcine RV H (RVH), a newly defined distinct genogroup, was recently confirmed in diarrheic pigs in Japan, Brazil, and the US. The complex epidemiology, pathogenicity and high genetic diversity of porcine RVAs are widely recognized and well-studied. More recent data show a significant genetic diversity based on the VP7 gene analysis of RVB and C strains in pigs. In this review, we will summarize previous and recent research to provide insights on historic and current prevalence and genetic diversity of porcine RVs in different geographic regions and production systems. We will also provide a brief overview of immune responses to porcine RVs, available control strategies and zoonotic potential of different RV genotypes. An improved understanding of the above parameters may lead to the development of more optimal strategies to manage RV diarrheal disease in swine and humans. PMID- 28335457 TI - The Epigenetic Link between Prenatal Adverse Environments and Neurodevelopmental Disorders. AB - Prenatal adverse environments, such as maternal stress, toxicological exposures, and viral infections, can disrupt normal brain development and contribute to neurodevelopmental disorders, including schizophrenia, depression, and autism. Increasing evidence shows that these short- and long-term effects of prenatal exposures on brain structure and function are mediated by epigenetic mechanisms. Animal studies demonstrate that prenatal exposure to stress, toxins, viral mimetics, and drugs induces lasting epigenetic changes in the brain, including genes encoding glucocorticoid receptor (Nr3c1) and brain-derived neurotrophic factor (Bdnf). These epigenetic changes have been linked to changes in brain gene expression, stress reactivity, and behavior, and often times, these effects are shown to be dependent on the gestational window of exposure, sex, and exposure level. Although evidence from human studies is more limited, gestational exposure to environmental risks in humans is associated with epigenetic changes in peripheral tissues, and future studies are required to understand whether we can use peripheral biomarkers to predict neurobehavioral outcomes. An extensive research effort combining well-designed human and animal studies, with comprehensive epigenomic analyses of peripheral and brain tissues over time, will be necessary to improve our understanding of the epigenetic basis of neurodevelopmental disorders. PMID- 28335460 TI - Neuropsychology of Aesthetic Judgment of Ambiguous and Non-Ambiguous Artworks. AB - Several affective and cognitive processes have been found to be pivotal in affecting aesthetic experience of artworks and both neuropsychological as well as psychiatric symptoms have been found to affect artistic production. However, there is a paucity of studies directly investigating effects of brain lesions on aesthetic judgment. Here, we assessed the effects of unilateral brain damage on aesthetic judgment of artworks showing part/whole ambiguity. We asked 19 unilaterally brain-damaged patients (10 left and 9 right brain damaged patients, respectively LBDP and RBDP) and 20 age- and education-matched healthy individuals (controls, C) to rate 10 Arcimboldo's ambiguous portraits (AP), 10 realistic Renaissance portraits (RP), 10 still life paintings (SL), and 10 Arcimboldo's modified portraits where only objects/parts are detectable (AO). They were also administered a Navon task, a facial recognition test, and evaluated on visuo perceptual and visuo-constructional abilities. Patients included in the study did not show any deficits that could affect the capability to explore and enjoy artworks. SL and RP was not affected by brain damage regardless of its laterality. On the other hand, we found that RBDP liked AP more than the C participants. Furthermore, we found a positive correlation between aesthetic judgment of AP and visuo-perceptual skills even if the single case analyses failed to find a systematic association between neuropsychological deficits and aesthetic judgment of AP. On the whole, the present data suggest that a right hemisphere lesion may affect aesthetic judgment of ambiguous artworks, even in the absence of exploration or constructional deficits. PMID- 28335461 TI - Design and Validation of a Low-Cost Portable Device to Quantify Postural Stability. AB - Measurement of the displacement of the center-of-pressure (COP) is an important tool used in biomechanics to assess postural stability and human balance. The goal of this research was to design and validate a low-cost portable device that can offer a quick indication of the state of postural stability and human balance related conditions. Approximate entropy (ApEn) values reflecting the amount of irregularity hiding in COP oscillations were used to calculate the index. The prototype adopted a portable design using the measurements of the load cells located at the four corners of a low-cost force platform. The test subject was asked to stand on the device in a quiet, normal, upright stance for 30 s with eyes open and subsequently for 30 s with eyes closed. Based on the COP displacement signals, the ApEn values were calculated. The results indicated that the prototype device was capable of capturing the increase in regularity of postural control in the visual-deprivation conditions. It was also able to decipher the subtle postural control differences along anterior-posterior and medial-lateral directions. The data analysis demonstrated that the prototype would enable the quantification of postural stability and thus provide a low-cost portable device to assess many conditions related to postural stability and human balance such as aging and pathologies. PMID- 28335464 TI - A Geographic Information-Assisted Temporal Mixture Analysis for Addressing the Issue of Endmember Class and Endmember Spectra Variability. AB - Spectral mixture analysis (SMA) is a common approach for parameterizing biophysical fractions of urban environment and widely applied in many fields. For successful SMA, the selection of endmember class and corresponding spectra has been assumed as the most important step. Thanks to the spatial heterogeneity of natural and urban landscapes, the variability of endmember class and corresponding spectra has been widely considered as the profound error source in SMA. To address the challenging problems, we proposed a geographic information assisted temporal mixture analysis (GATMA). Specifically, a logistic regression analysis was applied to analyze the relationship between land use/land covers and surrounding socio-economic factors, and a classification tree method was used to identify the present status of endmember classes throughout the whole study area. Furthermore, an ordinary kriging analysis was employed to generate a spatially varying endmember spectra at all pixels in the remote sensing image. As a consequence, a fully constrained temporal mixture analysis was conducted for examining the fractional land use land covers. Results show that the proposed GATMA achieved a promising accuracy with an RMSE of 6.81%, SE of 1.29% and MAE of 2.6%. In addition, comparative analysis result illustrates that a significant accuracy improvement has been found in the whole study area and both developed and less developed areas, and this demonstrates that the variability of endmember class and endmember spectra is essential for unmixing analysis. PMID- 28335462 TI - Therapeutic Potentials of Microalgae in the Treatment of Alzheimer's Disease. AB - Current research is geared towards the discovery of new compounds with strong neuroprotective potential and few or no side effects compared to synthetic drugs. This review focuses on the potentials of extracts and biologically active compounds derived from microalgal biomass for the treatment and management of Alzheimer's disease (AD). Microalgal research has gained much attention recently due to its contribution to the production of renewable fuels and the ability of alga cells to produce several secondary metabolites such as carotenoids, polyphenols, sterols, polyunsaturated fatty acids and polysaccharides. These compounds exhibit several pharmacological activities and possess neuroprotective potential. The pathogenesis of Alzheimer's disease (AD) involves complex mechanisms that are associated with oxidative stress, cholinergic dysfunction, neuronal damage, protein misfolding and aggregation. The antioxidant, anticholinesterase activities as well as the inhibitory effects of some bioactive compounds from microalgae extracts on beta-amyloid aggregation and neuronal death are discussed extensively. Phytochemical compounds from microalgae are used as pharmaceuticals, nutraceuticals and food supplements, and may possess neuroprotective potentials that are relevant to the management and/or treatment of AD. PMID- 28335465 TI - Schrodinger's Cheshire Cat: Are Haploid Emiliania huxleyi Cells Resistant to Viral Infection or Not? AB - Emiliania huxleyi is the main calcite producer on Earth and is routinely infected by a virus (EhV); a double stranded DNA (dsDNA) virus belonging to the family Phycodnaviridae. E. huxleyi exhibits a haplodiploid life cycle; the calcified diploid stage is non-motile and forms extensive blooms. The haploid phase is a non-calcified biflagellated cell bearing organic scales. Haploid cells are thought to resist infection, through a process deemed the "Cheshire Cat" escape strategy; however, a recent study detected the presence of viral lipids in the same haploid strain. Here we report on the application of an E. huxleyi CCMP1516 EhV-86 combined tiling array (TA) that further confirms an EhV infection in the RCC1217 haploid strain, which grew without any signs of cell lysis. Reverse transcription polymerase chain reaction (RT-PCR) and PCR verified the presence of viral RNA in the haploid cells, yet indicated an absence of viral DNA, respectively. These infected cells are an alternative stage of the virus life cycle deemed the haplococcolithovirocell. In this instance, the host is both resistant to and infected by EhV, i.e., the viral transcriptome is present in haploid cells whilst there is no evidence of viral lysis. This superimposed state is reminiscent of Schrodinger's cat; of being simultaneously both dead and alive. PMID- 28335467 TI - Through the Kinesthetic Lens: Observation of Social Attunement in Autism Spectrum Disorders. AB - : This paper will present a movement-informed perspective to social attunement in Autism Spectrum Disorders (ASD). BACKGROUND: Dance movement therapy (DMT) is a psychotherapeutic intervention that is used with participants with ASD in various settings. Regular clinical outcome monitoring in an outpatient setting in the Netherlands had shown positive effects on social attunement capacities in young people with ASD. However, a systematic study of the development of social attunement movement behaviors of participants with ASD throughout a DMT intervention was not yet available. METHODS: A series of individual cases of DMT with young people with ASD (mean age 12.2 years.) were analyzed for changes in interpersonal movement behaviors employing video-based retrospective observation. RESULTS: The findings were summarized in an observation scale for interpersonal movement behaviors. This scale was then tested for its applicability for the monitoring of social attunement behaviors throughout therapy. DISCUSSION: A movement-informed perspective may be helpful to inventory changes in social attunement behaviors in participants with ASD. The relevance of a movement informed perspective for the concept of social attunement in ASD will be discussed. PMID- 28335466 TI - A Specific Mixture of Nutrients Suppresses Ovarian Cancer A-2780 Tumor Incidence, Growth, and Metastasis to Lungs. AB - Ovarian cancer is the deadliest gynecological malignancy in women, and fifth leading cause of death. Despite advances made in chemotherapy and surgery, the average time of clinical remission is approximately 2 years and the 5-year survival rate is 45%. Thus, there is an urgent need for the development of a novel therapeutic approach to ovarian cancer treatment. We investigated the effect of a specific nutrient mixture (EPQ) containing ascorbic acid, lysine, proline, green tea extract, and quercetin on human ovarian cancer cell A-2780 in vivo and in vitro. Athymic female nude mice (n = 12) were all inoculated intraperitoneally (IP) with 2 * 106 cells in 0.1 mL of phosphate buffered saline (PBS) and randomly divided into two groups. Upon injection, the Control group (n = 6) was fed a regular diet and the EPQ group (n = 6) a regular diet supplemented with 0.5% EPQ. Four weeks later, the mice were sacrificed and tumors that developed in the ovary were excised, weighed, and processed for histology. Lungs were inspected for metastasis. In vitro, A-2780 cells were cultured in Dulbecco modified Eagle medium supplemented with 10% FBS and antibiotics. At near confluence, cells were treated with EPQ in triplicate at concentrations between 0 and 1000 MUg/mL. Cell proliferation was measured via MTT assay, MMP-9 secretion via gelatinase zymography, invasion through Matrigel and morphology via hematoxylin and eosin (H & E) staining. All Control mice developed large ovarian tumors, whereas 5 out of 6 mice in the EPQ group developed no tumors, and one, a small tumor. Control mice also showed lung metastasis in 6 out of 6 mice, while no lung metastasis was evident in EPQ mice. Zymography demonstrated only MMP-9 expression, which EPQ inhibited in a dose-dependent fashion, with virtual total block at 250 MUg/mL concentration. EPQ significantly inhibited invasion through Matrigel with total block at 250 MUg/mL concentration. MTT showed dose-dependent inhibition of cell proliferation with EPQ, and H & E staining showed no morphological changes below 500 MUg/mL EPQ. These results suggest that EPQ has therapeutic potential in the treatment of ovarian cancer by significantly suppressing ovarian tumor incidence and growth and lung metastasis, and by inhibiting MMP-9 secretion and invasion of A-2780 ovarian cancer cells. PMID- 28335463 TI - Dysfunctional mTORC1 Signaling: A Convergent Mechanism between Syndromic and Nonsyndromic Forms of Autism Spectrum Disorder? AB - Whereas autism spectrum disorder (ASD) exhibits striking heterogeneity in genetics and clinical presentation, dysfunction of mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway has been identified as a molecular feature common to several well-characterized syndromes with high prevalence of ASD. Additionally, recent findings have also implicated mTORC1 signaling abnormalities in a subset of nonsyndromic ASD, suggesting that defective mTORC1 pathway may be a potential converging mechanism in ASD pathology across different etiologies. However, the mechanistic evidence for a causal link between aberrant mTORC1 pathway activity and ASD neurobehavioral features varies depending on the ASD form involved. In this review, we first discuss six monogenic ASD-related syndromes, including both classical and potentially novel mTORopathies, highlighting their contribution to our understanding of the neurobiological mechanisms underlying ASD, and then we discuss existing evidence suggesting that aberrant mTORC1 signaling may also play a role in nonsyndromic ASD. PMID- 28335468 TI - Differential Degradation and Detoxification of an Aromatic Pollutant by Two Different Peroxidases. AB - Enzymatic degradation of organic pollutants is a new and promising remediation approach. Peroxidases are one of the most commonly used classes of enzymes to degrade organic pollutants. However, it is generally assumed that all peroxidases behave similarly and produce similar degradation products. In this study, we conducted detailed studies of the degradation of a model aromatic pollutant, Sulforhodamine B dye (SRB dye), using two peroxidases-soybean peroxidase (SBP) and chloroperoxidase (CPO). Our results show that these two related enzymes had different optimum conditions (pH, temperature, H2O2 concentration, etc.) for efficiently degrading SRB dye. High-performance liquid chromatography and liquid chromatography -mass spectrometry analyses confirmed that both SBP and CPO transformed the SRB dye into low molecular weight intermediates. While most of the intermediates produced by the two enzymes were the same, the CPO treatment produced at least one different intermediate. Furthermore, toxicological evaluation using lettuce (Lactuca sativa) seeds demonstrated that the SBP-based treatment was able to eliminate the phytotoxicity of SRB dye, but the CPO-based treatment did not. Our results show, for the first time, that while both of these related enzymes can be used to efficiently degrade organic pollutants, they have different optimum reaction conditions and may not be equally efficient in detoxification of organic pollutants. PMID- 28335471 TI - Mobile Phonocardiogram Diagnosis in Newborns Using Support Vector Machine. AB - Phonocardiogram (PCG) monitoring on newborns is one of the most important and challenging tasks in the heart assessment in the early ages of life. In this paper, we present a novel approach for cardiac monitoring applied in PCG data. This basic system coupled with denoising, segmentation, cardiac cycle selection and classification of heart sound can be used widely for a large number of the data. This paper describes the problems and additional advantages of the PCG method including the possibility of recording heart sound at home, removing unwanted noises and data reduction on a mobile device, and an intelligent system to diagnose heart diseases on the cloud server. A wide range of physiological features from various analysis domains, including modeling, time/frequency domain analysis, an algorithm, etc., is proposed in order to extract features which will be considered as inputs for the classifier. In order to record the PCG data set from multiple subjects over one year, an electronic stethoscope was used for collecting data that was connected to a mobile device. In this study, we used different types of classifiers in order to distinguish between healthy and pathological heart sounds, and a comparison on the performances revealed that support vector machine (SVM) provides 92.2% accuracy and AUC = 0.98 in a time of 1.14 seconds for training, on a dataset of 116 samples. PMID- 28335470 TI - Design of New Benzo[h]chromene Derivatives: Antitumor Activities and Structure Activity Relationships of the 2,3-Positions and Fused Rings at the 2,3-Positions. AB - A series of novel 4H-benzo[h]chromenes 4, 6-11, 13, 14; 7H-benzo[h]chromeno[2,3 d]pyrimidines 15-18, 20, and 14H-benzo[h]chromeno[3,2-e][1,2,4]triazolo[1,5 c]pyrimidine derivatives 19a-e, 24 was prepared. The structures of the synthesized compounds were characterized on the basis of their spectral data. Some of the target compounds were examined for their antiproliferative activity against three cell lines; breast carcinoma (MCF-7), human colon carcinoma (HCT 116) and hepatocellular carcinoma (HepG-2). The cytotoxic behavior has been tested using MTT assay and the inhibitory activity was referenced to three standard anticancer drugs: vinblastine, colchicine and doxorubicin. The bioassays demonstrated that some of the new compounds exerted remarkable inhibitory effects as compared to the standard drugs on the growth of the three tested human tumor cell lines. The structure-activity relationships (SAR) study highlights that the antitumor activity of the target compounds was significantly affected by the lipophilicity of the substituent at 2- or 3- and fused rings at the 2,3 positions. PMID- 28335472 TI - Detecting Breast Cancer with a Dual-Modality Device. AB - Although mammography has been the gold standard for the early detection of breast cancer, if a woman has dense breast tissue, a false negative diagnosis may occur. Breast ultrasound, whether hand-held or automated, is a useful adjunct to mammography but adds extra time and cost. The primary aim was to demonstrate that our second-generation Aceso system, which combines full-field digital mammography (FFDM) and automated breast ultrasound (ABUS) in a single platform, is able to produce improved quality images that provide clinically meaningful results. Aceso was first tested using two industry standards: a Contrast Detail Mammography (CDMAM) phantom to assess the FFDM images, and the CIRS 054GS phantom to evaluate the ABUS images. In addition, 25 women participated in a clinical trial: 14 were healthy volunteers, while 11 were patients referred by the breast clinic at Groote Schuur Hospital. The CDMAM phantom results showed the FFDM results were better than the European Reference (EUREF) standard of "acceptable" and were approaching "achievable". The ABUS results showed a lateral and axial spatial resolution of 0.5 mm and an adequate depth penetration of 80 mm. Our second generation Aceso system, with its improved quality of clinical FFDM and ABUS images, has demonstrated its potential for the early detection of breast cancer in a busy clinic. PMID- 28335469 TI - Comparison of the Pharmacokinetic Properties of Hemoglobin-Based Oxygen Carriers. AB - Hemoglobin (Hb) is an ideal material for use in the development of an oxygen carrier in view of its innate biological properties. However, the vascular retention of free Hb is too short to permit a full therapeutic effect because Hb is rapidly cleared from the kidney via glomerular filtration or from the liver via the haptogloblin-CD 163 pathway when free Hb is administered in the blood circulation. Attempts have been made to develop alternate acellular and cellular types of Hb based oxygen carriers (HBOCs), in which Hb is processed via various routes in order to regulate its pharmacokinetic properties. These HBOCs have been demonstrated to have superior pharmacokinetic properties including a longer half life than the Hb molecule in preclinical and clinical trials. The present review summarizes and compares the pharmacokinetic properties of acellular and cellular type HBOCs that have been developed through different approaches, such as polymerization, PEGylation, cross-linking, and encapsulation. PMID- 28335473 TI - Assessment of Antioxidant and Cytoprotective Potential of Jatropha (Jatropha curcas) Grown in Southern Italy. AB - Jatropha (Jatropha curcas L.) is a plant native of Central and South America, but widely distributed in the wild or semi-cultivated areas in Africa, India, and South East Asia. Although studies are available in literature on the polyphenolic content and bioactivity of Jatropha curcas L., no information is currently available on plants grown in pedoclimatic and soil conditions different from the autochthon regions. The aim of the present work was to characterize the antioxidant system developed by the plant under a new growing condition and to evaluate the polyphenol amount in a methanolic extract of leaves. Along with these analyses we have also tested the antioxidant and cytoprotective activities on lymphocytes. RP-HPLC-DAD analysis of flavonoids revealed a chromatographic profile dominated by the presence of flavone C-glucosydes. Vitexin is the most abundant identified compound followed by vicenin-2, stellarin-2, rhoifolin, and traces of isovitexin and isorhoifolin. Methanolic extract had high scavenging activity in all antioxidant assays tested and cytoprotective activity on lymphocytes exposed to tertz-buthylhydroperoxide. The results highlighted a well defined mechanism of adaptation of the plant and a significant content of secondary metabolites with antioxidant properties, which are of interest for their potential uses, especially as a rich source of biologically active products. PMID- 28335475 TI - Mobile Health Applications to Promote Active and Healthy Ageing. AB - The European population is ageing, and there is a need for health solutions that keep older adults independent longer. With increasing access to mobile technology, such as smartphones and smartwatches, the development and use of mobile health applications is rapidly growing. To meet the societal challenge of changing demography, mobile health solutions are warranted that support older adults to stay healthy and active and that can prevent or delay functional decline. This paper reviews the literature on mobile technology, in particular wearable technology, such as smartphones, smartwatches, and wristbands, presenting new ideas on how this technology can be used to encourage an active lifestyle, and discusses the way forward in order further to advance development and practice in the field of mobile technology for active, healthy ageing. PMID- 28335474 TI - Coccolithoviruses: A Review of Cross-Kingdom Genomic Thievery and Metabolic Thuggery. AB - Coccolithoviruses (Phycodnaviridae) infect and lyse the most ubiquitous and successful coccolithophorid in modern oceans, Emiliania huxleyi. So far, the genomes of 13 of these giant lytic viruses (i.e., Emiliania huxleyi viruses-EhVs) have been sequenced, assembled, and annotated. Here, we performed an in-depth comparison of their genomes to try and contextualize the ecological and evolutionary traits of these viruses. The genomes of these EhVs have from 444 to 548 coding sequences (CDSs). Presence/absence analysis of CDSs identified putative genes with particular ecological significance, namely sialidase, phosphate permease, and sphingolipid biosynthesis. The viruses clustered into distinct clades, based on their DNA polymerase gene as well as full genome comparisons. We discuss the use of such clustering and suggest that a gene-by gene investigation approach may be more useful when the goal is to reveal differences related to functionally important genes. A multi domain "Best BLAST hit" analysis revealed that 84% of the EhV genes have closer similarities to the domain Eukarya. However, 16% of the EhV CDSs were very similar to bacterial genes, contributing to the idea that a significant portion of the gene flow in the planktonic world inter-crosses the domains of life. PMID- 28335476 TI - Inhibition of Neoplastic Transformation and Chemically-Induced Skin Hyperplasia in Mice by Traditional Chinese Medicinal Formula Si-Wu-Tang. AB - Exploring traditional medicines may lead to the development of low-cost and non toxic cancer preventive agents. Si-Wu-Tang (SWT), comprising the combination of four herbs, Rehmanniae, Angelica, Chuanxiong, and Paeoniae, is one of the most popular traditional Chinese medicines for women's diseases. In our previous studies, the antioxidant Nrf2 pathways were strongly induced by SWT in vitro and in vivo. Since Nrf2 activation has been associated with anticarcinogenic effects, the purpose of this study is to evaluate SWT's activity of cancer prevention. In the Ames test, SWT demonstrated an antimutagenic activity against mutagenicity induced by the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). In JB6 P+ cells, a non-cancerous murine epidermal model for studying tumor promotion, SWT inhibited epidermal growth factor (EGF)-induced neoplastic transformation. The luciferase reporter gene assays demonstrated that SWT suppressed EGF-induced AP-1 and TNF-alpha-induced NF-kappaB activation, which are essential factors involved in skin carcinogenesis. In a DMBA-induced skin hyperplasia assay in 'Sensitivity to Carcinogenesis' (SENCAR) mice, both topical and oral SWT inhibited DMBA-induced epidermal hyperplasia, expression of the proliferation marker Proliferating cell nuclear antigen (PCNA), and H-ras mutations. These findings demonstrate, for the first time, that SWT prevents tumor promoter and chemical-induced carcinogenesis in vitro and in vivo, partly by inhibiting DNA damage and blocking the activation of AP-1 and NF-kappaB. PMID- 28335477 TI - Association between Circulating Vitamin D Level and Urolithiasis: A Systematic Review and Meta-Analysis. AB - Many studies compared the serum/plasma 1,25 dihydroxyvitamin D3 (1,25(OH)2D) and 25 hydroxyvitamin D3 (25(OH)D) between people with and without nephrolithiasis, and their results were conflicting. After systematically searching PubMed, Web of Science, The Cochrane Library, CNKI, and the Wanfang Database, we conducted a meta-analysis. Thirty-two observational studies involving 23,228 participants were included. Meta-analysis of these studies showed that of stone formers (SFs), calcium SFs had significantly higher concentrations of 1,25(OH)2D (weighted mean difference (WMD), 10.19 pg/mL; 95% confidence interval (CI), 4.31-16.07; p = 0.0007 and WMD, 11.28 pg/mL; 95% CI, 4.07-18.50; p = 0.002, respectively) than non-stone formers, while the levels of 25(OH)D (WMD, 0.88 ng/mL; 95% CI, -1.04 2.80; p = 0.37 and WMD, -0.63 ng/mL; 95% CI, -2.72-1.47; p = 0.56, respectively) are similar. Compared with controls and normocalciuria SFs, hypercalciuria SFs had increased circulating 1,25(OH)2D (WMD, 9.41 pg/mL; 95% CI, 0.15-18.67; p = 0.05 and WMD, 2.75 pg/mL; 95% CI, -0.20-5.69; p = 0.07, respectively) and markedly higher 25(OH)D (WMD, 5.02 ng/mL; 95% CI, 0.99-9.06; p = 0.01 and WMD, 5.02 ng/mL; 95% CI, 2.14-7.90; p = 0.0006, respectively). Normocalciuria SFs had elevated 1,25(OH)2D level (WMD, 6.85 pg/mL; 95% CI, -5.00-18.71; p = 0.26) and comparable 25(OH)D (WMD, 0.94 ng/mL; 95% CI, -3.55-5.43; p = 0.68). Sensitivity analysis generated similar results. Current evidence suggests that increased circulating 1,25(OH)2D is associated with urinary stones and a higher level of circulating 25(OH)D is significantly associated with hypercalciuria urolithiasis. Further studies are still needed to reconfirm and clarify the role of vitamin D in the pathogenesis of stones. PMID- 28335478 TI - Lactational Stage of Pasteurized Human Donor Milk Contributes to Nutrient Limitations for Infants. AB - BACKGROUND: Mother's own milk is the first choice for feeding preterm infants, but when not available, pasteurized human donor milk (PDM) is often used. Infants fed PDM have difficulties maintaining appropriate growth velocities. To assess the most basic elements of nutrition, we tested the hypotheses that fatty acid and amino acid composition of PDM is highly variable and standard pooling practices attenuate variability; however, total nutrients may be limiting without supplementation due to late lactational stage of the milk. METHODS: A prospective cross-sectional sampling of milk was obtained from five donor milk banks located in Ohio, Michigan, Colorado, Texas-Ft Worth, and California. Milk samples were collected after Institutional Review Board (#07-0035) approval and informed consent. Fatty acid and amino acid contents were measured in milk from individual donors and donor pools (pooled per Human Milk Banking Association of North America guidelines). Statistical comparisons were performed using Kruskal-Wallis, Spearman's, or Multivariate Regression analyses with center as the fixed factor and lactational stage as co-variate. RESULTS: Ten of the fourteen fatty acids and seventeen of the nineteen amino acids analyzed differed across Banks in the individual milk samples. Pooling minimized these differences in amino acid and fatty acid contents. Concentrations of lysine and docosahexaenoic acid (DHA) were not different across Banks, but concentrations were low compared to recommended levels. CONCLUSIONS: Individual donor milk fatty acid and amino acid contents are highly variable. Standardized pooling practice reduces this variability. Lysine and DHA concentrations were consistently low across geographic regions in North America due to lactational stage of the milk, and thus not adequately addressed by pooling. Targeted supplementation is needed to optimize PDM, especially for the preterm or volume restricted infant. PMID- 28335479 TI - Phakellistatins: An Underwater Unsolved Puzzle. AB - A critical summary on the discovery of the nineteen members of the phakellistatin family (phakellistatin 1-19), cytotoxic proline-rich cyclopeptides of marine origin, is reported. Isolation, structural elucidation, and biological properties of the various-sized natural macrocycles are described, along with the total syntheses and the enigmatic issues of the cytotoxic activity reproducibility. PMID- 28335480 TI - Weighted Kernel Entropy Component Analysis for Fault Diagnosis of Rolling Bearings. AB - This paper presents a supervised feature extraction method called weighted kernel entropy component analysis (WKECA) for fault diagnosis of rolling bearings. The method is developed based on kernel entropy component analysis (KECA) which attempts to preserve the Renyi entropy of the data set after dimension reduction. It makes full use of the labeled information and introduces a weight strategy in the feature extraction. The class-related weights are introduced to denote differences among the samples from different patterns, and genetic algorithm (GA) is implemented to seek out appropriate weights for optimizing the classification results. The features based on wavelet packet decomposition are derived from the original signals. Then the intrinsic geometric features extracted by WKECA are fed into the support vector machine (SVM) classifier to recognize different operating conditions of bearings, and we obtain the overall accuracy (97%) for the experimental samples. The experimental results demonstrated the feasibility and effectiveness of the proposed method. PMID- 28335482 TI - Improved Wallis Dodging Algorithm for Large-Scale Super-Resolution Reconstruction Remote Sensing Images. AB - A sub-block algorithm is usually applied in the super-resolution (SR) reconstruction of images because of limitations in computer memory. However, the sub-block SR images can hardly achieve a seamless image mosaicking because of the uneven distribution of brightness and contrast among these sub-blocks. An effectively improved weighted Wallis dodging algorithm is proposed, aiming at the characteristic that SR reconstructed images are gray images with the same size and overlapping region. This algorithm can achieve consistency of image brightness and contrast. Meanwhile, a weighted adjustment sequence is presented to avoid the spatial propagation and accumulation of errors and the loss of image information caused by excessive computation. A seam line elimination method can share the partial dislocation in the seam line to the entire overlapping region with a smooth transition effect. Subsequently, the improved method is employed to remove the uneven illumination for 900 SR reconstructed images of ZY-3. Then, the overlapping image mosaic method is adopted to accomplish a seamless image mosaic based on the optimal seam line. PMID- 28335483 TI - Land Use for Edible Protein of Animal Origin-A Review. AB - The present period is characterized by a growing world population and a higher demand for more and better quality food, as well as other products for an improved standard of living. In the future, there will be increasingly strong competition for arable land and non-renewable resources such as fossil carbon sources, water, and some minerals, as well as between food, feed, fuel, fiber, flowers, and fun (6 F's). Proteins of animal origin like milk, meat, fish, eggs and, probably, insects are very valuable sources of essential amino acids, minerals and vitamins, but their production consumes some non-renewable resources including arable land and causes considerable emissions. Therefore, this study's objective was to calculate some examples of the land use (arable land and grassland) for production of edible animal protein taking into consideration important animal species/categories, levels of plant and animal yields, the latter estimated with and without co-products from agriculture, and the food/biofuel industry in animal feeding. There are large differences between animal species/categories and their potential to produce edible protein depending on many influencing variables. The highest amounts per kilogram body weight are produced by growing broiler chicken followed by laying hens and dairy cows; the lowest yields in edible protein and the highest land need were observed for beef cattle. This review clearly indicates that the production of food of animal origin is a very complex process, and selective considerations, i.e., focusing on single factors, do not provide an assessment that reflects the complexity of the subject. PMID- 28335481 TI - Genetic Variants Contributing to Colistin Cytotoxicity: Identification of TGIF1 and HOXD10 Using a Population Genomics Approach. AB - Colistin sulfate (polymixin E) is an antibiotic prescribed with increasing frequency for severe Gram-negative bacterial infections. As nephrotoxicity is a common side effect, the discovery of pharmacogenomic markers associated with toxicity would benefit the utility of this drug. Our objective was to identify genetic markers of colistin cytotoxicity that were also associated with expression of key proteins using an unbiased, whole genome approach and further evaluate the functional significance in renal cell lines. To this end, we employed International HapMap lymphoblastoid cell lines (LCLs) of Yoruban ancestry with known genetic information to perform a genome-wide association study (GWAS) with cellular sensitivity to colistin. Further association studies revealed that single nucleotide polymorphisms (SNPs) associated with gene expression and protein expression were significantly enriched in SNPs associated with cytotoxicity (p <= 0.001 for gene and p = 0.015 for protein expression). The most highly associated SNP, chr18:3417240 (p = 6.49 * 10-8), was nominally a cis expression quantitative trait locus (eQTL) of the gene TGIF1 (transforming growth factor beta (TGFbeta)-induced factor-1; p = 0.021) and was associated with expression of the protein HOXD10 (homeobox protein D10; p = 7.17 * 10-5). To demonstrate functional relevance in a murine colistin nephrotoxicity model, HOXD10 immunohistochemistry revealed upregulated protein expression independent of mRNA expression in response to colistin administration. Knockdown of TGIF1 resulted in decreased protein expression of HOXD10 and increased resistance to colistin cytotoxicity. Furthermore, knockdown of HOXD10 in renal cells also resulted in increased resistance to colistin cytotoxicity, supporting the physiological relevance of the initial genomic associations. PMID- 28335484 TI - Energy of Intramolecular Hydrogen Bonding in ortho-Hydroxybenzaldehydes, Phenones and Quinones. Transfer of Aromaticity from ipso-Benzene Ring to the Enol System(s). AB - Intramolecular hydrogen bonding (HB) is one of the most studied noncovalent interactions of molecules. Many physical, spectral, and topological properties of compounds are under the influence of HB, and there are many parameters used to notice and to describe these changes. Hitherto, no general method of measurement of the energy of intramolecular hydrogen bond (EHB) has been put into effect. We propose the molecular tailoring approach (MTA) for EHB calculation, modified to apply it to Ar-O-H???O=C systems. The method, based on quantum calculations, was checked earlier for hydroxycarbonyl-saturated compounds, and for structures with resonance-assisted hydrogen bonding (RAHB). For phenolic compounds, the accuracy, repeatability, and applicability of the method is now confirmed for nearly 140 structures. For each structure its aromaticity HOMA indices were calculated for the central (ipso) ring and for the quasiaromatic rings given by intramolecular HB. The comparison of calculated HB energies and values of estimated aromaticity indices allowed us to observe, in some substituted phenols and quinones, the phenomenon of transfer of aromaticity from the ipso-ring to the H-bonded ring via the effect of electron delocalization. PMID- 28335486 TI - Implicit Regularization for Reconstructing 3D Building Rooftop Models Using Airborne LiDAR Data. AB - With rapid urbanization, highly accurate and semantically rich virtualization of building assets in 3D become more critical for supporting various applications, including urban planning, emergency response and location-based services. Many research efforts have been conducted to automatically reconstruct building models at city-scale from remotely sensed data. However, developing a fully-automated photogrammetric computer vision system enabling the massive generation of highly accurate building models still remains a challenging task. One the most challenging task for 3D building model reconstruction is to regularize the noises introduced in the boundary of building object retrieved from a raw data with lack of knowledge on its true shape. This paper proposes a data-driven modeling approach to reconstruct 3D rooftop models at city-scale from airborne laser scanning (ALS) data. The focus of the proposed method is to implicitly derive the shape regularity of 3D building rooftops from given noisy information of building boundary in a progressive manner. This study covers a full chain of 3D building modeling from low level processing to realistic 3D building rooftop modeling. In the element clustering step, building-labeled point clouds are clustered into homogeneous groups by applying height similarity and plane similarity. Based on segmented clusters, linear modeling cues including outer boundaries, intersection lines, and step lines are extracted. Topology elements among the modeling cues are recovered by the Binary Space Partitioning (BSP) technique. The regularity of the building rooftop model is achieved by an implicit regularization process in the framework of Minimum Description Length (MDL) combined with Hypothesize and Test (HAT). The parameters governing the MDL optimization are automatically estimated based on Min-Max optimization and Entropy-based weighting method. The performance of the proposed method is tested over the International Society for Photogrammetry and Remote Sensing (ISPRS) benchmark datasets. The results show that the proposed method can robustly produce accurate regularized 3D building rooftop models. PMID- 28335485 TI - Intra Amniotic Administration of Raffinose and Stachyose Affects the Intestinal Brush Border Functionality and Alters Gut Microflora Populations. AB - This study investigates the effectiveness of two types of prebiotics-stachyose and raffinose-which are present in staple food crops that are widely consumed in regions where dietary Fe deficiency is a health concern. The hypothesis is that these prebiotics will improve Fe status, intestinal functionality, and increase health-promoting bacterial populations in vivo (Gallus gallus). By using the intra-amniotic administration procedure, prebiotic treatment solutions were injected in ovo (day 17 of embryonic incubation) with varying concentrations of a 1.0 mL pure raffinose or stachyose in 18 MOmega H2O. Four treatment groups (50, 100 mg.mL-1 raffinose or stachyose) and two controls (18 MOmega H2O and non injected) were utilized. At hatch the cecum, small intestine, liver, and blood were collected for assessment of the relative abundance of the gut microflora, relative expression of Fe-related genes and brush border membrane functional genes, hepatic ferritin levels, and hemoglobin levels, respectively. The prebiotic treatments increased the relative expression of brush border membrane functionality proteins (p < 0.05), decreased the relative expression of Fe related proteins (p < 0.05), and increased villus surface area. Raffinose and stachyose increased the relative abundance of probiotics (p < 0.05), and decreased that of pathogenic bacteria. Raffinose and stachyose beneficially affected the gut microflora, Fe bioavailability, and brush border membrane functionality. Our investigations have led to a greater understanding of these prebiotics' effects on intestinal health and mineral metabolism. PMID- 28335487 TI - Electromagnetic Vortex-Based Radar Imaging Using a Single Receiving Antenna: Theory and Experimental Results. AB - Radar imaging based on electromagnetic vortex can achieve azimuth resolution without relative motion. The present paper investigates this imaging technique with the use of a single receiving antenna through theoretical analysis and experimental results. Compared with the use of multiple receiving antennas, the echoes from a single receiver cannot be used directly for image reconstruction using Fourier method. The reason is revealed by using the point spread function. An additional phase is compensated for each mode before imaging process based on the array parameters and the elevation of the targets. A proof-of-concept imaging system based on a circular phased array is created, and imaging experiments of corner-reflector targets are performed in an anechoic chamber. The azimuthal image is reconstructed by the use of Fourier transform and spectral estimation methods. The azimuth resolution of the two methods is analyzed and compared through experimental data. The experimental results verify the principle of azimuth resolution and the proposed phase compensation method. PMID- 28335488 TI - Italian Registry of Congenital Bleeding Disorders. AB - In Italy, the surveillance of people with bleeding disorders is based on the National Registry of Congenital Coagulopathies (NRCC) managed by the Italian National Institute of Health (Istituto Superiore di Sanita). The NRCC collects epidemiological and therapeutic data from the 54 Hemophilia Treatment Centers, members of the Italian Association of Hemophilia Centres (AICE). The number of people identified with bleeding disorders has increased over the years, with the number rising from approx. 7000 in 2000 to over 11,000 in 2015. The NRCC includes 4020 patients with hemophilia A and 859 patients with hemophilia B. The prevalence of the rare type 3 vWD is 0.20/100,000 inhabitants. Less common congenital bleeding disorders include the following deficiencies: Factor I (fibrinogen), Factor II (prothrombin), Factor V, Factor VII, Factor X, Factor XI and Factor XIII, which affect 1953 patients. Hepatitis C Virus (HCV) infection affects 1561 patients, more than 200 of whom have two infections (HCV + HIV). Estimated hemophilia-related drug consumption in 2015 was approx. 550 million IU of FVIII for hemophilia A patients and approx. 70 million IU of FIX for hemophilia B patients. The NRCC, with its bleeding disorder data set, is a tool that can provide answers to fundamental questions in public health, monitoring care provision and drug treatment, as well as facilitating clinical and epidemiological research. PMID- 28335489 TI - Effects of the Mediterranean Diet before and after Weight Loss on Eating Behavioral Traits in Men with Metabolic Syndrome. AB - The objective of this study was to investigate the impact of the Mediterranean diet (MedDiet) consumed before and after weight loss on eating behavioral traits as measured by the Three-Factor Eating Questionnaire (TFEQ) in men with metabolic syndrome (MetS). In this fixed sequence study, 19 men with MetS (National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) criteria), aged between 24 and 62 years, first consumed a five-week standardized North American control diet followed by a five-week MedDiet, both under weight maintaining controlled-feeding conditions. This was followed by a 20-week caloric restriction weight loss period in free-living conditions, without specific recommendations towards adhering to the principles of the MedDiet. Participants were finally subjected to a final five-week MedDiet phase under isoenergetic controlled-feeding conditions. The MedDiet before weight loss had no impact on eating behavioral traits. Body weight reduction by caloric restriction (-10.2% of initial weight) was associated with increased cognitive restraint (p < 0.0001) and with reduced disinhibition (p = 0.02) and susceptibility to hunger (p = 0.01). Feeding the MedDiet for five weeks under isoenergetic conditions after the weight loss phase had no further impact on eating behavioral traits. Results of this controlled-feeding study suggest that consumption of the MedDiet per se has no effect on eating behavioral traits as measured by TFEQ, unless it is combined with significant weight loss. PMID- 28335490 TI - Monitoring of Selected Health Indicators in Children Living in a Copper Mine Development Area in Northwestern Zambia. AB - The epidemiology of malaria, anaemia and malnutrition in children is potentially altered in mining development areas. In a copper extraction project in northwestern Zambia, a health impact assessment (HIA) was commissioned to predict, manage and monitor health impacts. Two cross-sectional surveys were conducted: at baseline prior to project development (2011) and at four years into development (2015). Prevalence of Plasmodium falciparum, anaemia and stunting were assessed in under-five-year-old children, while hookworm infection was assessed in children aged 9-14 years in communities impacted and comparison communities not impacted by the project. P. falciparum prevalence was significantly higher in 2015 compared to 2011 in both impacted and comparison communities (odds ratio (OR) = 2.51 and OR = 6.97, respectively). Stunting was significantly lower in 2015 in impacted communities only (OR = 0.63). Anaemia was slightly lower in 2015 compared to baseline in both impacted and comparison communities. Resettlement due to the project and migration background (i.e., moving into the area within the past five years) were generally associated with better health outcomes in 2015. We conclude that repeated cross-sectional surveys to monitor health in communities impacted by projects should become an integral part of HIA to deepen the understanding of changing patterns of health and support implementation of setting-specific public health measures. PMID- 28335491 TI - Health and Wellbeing of Occupants in Highly Energy Efficient Buildings: A Field Study. AB - Passive houses and other highly energy-efficient buildings need mechanical ventilation. However, ventilation systems in such houses are regarded with a certain degree of skepticism by parts of the public due to alleged negative health effects. Within a quasi-experimental field study, we investigated if occupants of two types of buildings (mechanical vs. natural ventilation) experience different health, wellbeing and housing satisfaction outcomes and if associations with indoor air quality exist. We investigated 123 modern homes (test group: with mechanical ventilation; control group: naturally ventilated) built in the years 2010 to 2012 in the same geographic area and price range. Interviews of occupants based on standardized questionnaires and measurements of indoor air quality parameters were conducted twice (three months after moving in and one year later). In total, 575 interviews were performed (respondents' mean age 37.9 +/- 9 years in the test group, 37.7 +/- 9 years in the control group). Occupants of the test group rated their overall health status and that of their children not significantly higher than occupants of the control group at both time points. Adult occupants of the test group reported dry eyes statistically significantly more frequently compared to the control group (19.4% vs. 12.5%). Inhabitants of energy-efficient, mechanically ventilated homes rated the quality of indoor air and climate significantly higher. Self-reported health improved more frequently in the mechanically ventilated new homes (p = 0.005). Almost no other significant differences between housing types and measuring time points were observed concerning health and wellbeing or housing satisfaction. Associations between vegetative symptoms (dizziness, nausea, headaches) and formaldehyde concentrations as well as between CO2 levels and perceived stale air were observed. However, both associations were independent of the type of ventilation. In summary, occupants of the mechanically ventilated homes rated their health status slightly higher and their health improved significantly more frequently than in occupants of the control group. As humidity in homes with mechanical ventilation was lower, it seems plausible that the inhabitants reported dry eyes more frequently. PMID- 28335492 TI - Novel Approach for the Recognition and Prediction of Multi-Function Radar Behaviours Based on Predictive State Representations. AB - The extensive applications of multi-function radars (MFRs) have presented a great challenge to the technologies of radar countermeasures (RCMs) and electronic intelligence (ELINT). The recently proposed cognitive electronic warfare (CEW) provides a good solution, whose crux is to perceive present and future MFR behaviours, including the operating modes, waveform parameters, scheduling schemes, etc. Due to the variety and complexity of MFR waveforms, the existing approaches have the drawbacks of inefficiency and weak practicability in prediction. A novel method for MFR behaviour recognition and prediction is proposed based on predictive state representation (PSR). With the proposed approach, operating modes of MFR are recognized by accumulating the predictive states, instead of using fixed transition probabilities that are unavailable in the battlefield. It helps to reduce the dependence of MFR on prior information. And MFR signals can be quickly predicted by iteratively using the predicted observation, avoiding the very large computation brought by the uncertainty of future observations. Simulations with a hypothetical MFR signal sequence in a typical scenario are presented, showing that the proposed methods perform well and efficiently, which attests to their validity. PMID- 28335494 TI - Cooperative Opportunistic Pressure Based Routing for Underwater Wireless Sensor Networks. AB - In this paper, three opportunistic pressure based routing techniques for underwater wireless sensor networks (UWSNs) are proposed. The first one is the cooperative opportunistic pressure based routing protocol (Co-Hydrocast), second technique is the improved Hydrocast (improved-Hydrocast), and third one is the cooperative improved Hydrocast (Co-improved Hydrocast). In order to minimize lengthy routing paths between the source and the destination and to avoid void holes at the sparse networks, sensor nodes are deployed at different strategic locations. The deployment of sensor nodes at strategic locations assure the maximum monitoring of the network field. To conserve the energy consumption and minimize the number of hops, greedy algorithm is used to transmit data packets from the source to the destination. Moreover, the opportunistic routing is also exploited to avoid void regions by making backward transmissions to find reliable path towards the destination in the network. The relay cooperation mechanism is used for reliable data packet delivery, when signal to noise ratio (SNR) of the received signal is not within the predefined threshold then the maximal ratio combining (MRC) is used as a diversity technique to improve the SNR of the received signals at the destination. Extensive simulations validate that our schemes perform better in terms of packet delivery ratio and energy consumption than the existing technique; Hydrocast. PMID- 28335493 TI - Melatonin MT1 and MT2 Receptors in the Ram Reproductive Tract. AB - Some melatonin functions in mammals are exerted through MT1 and MT2 receptors. However, there are no reports of their presence in the reproductive tract of the ram, a seasonal species. Thus, we have investigated their existence in the ram testis, epididymis, accessory glands and ductus deferens. Real-time polymerase chain reaction (qPCR) revealed higher levels of m-RNA for both receptors in the testis, ampulla, seminal vesicles, and vas deferens, than in the other organs of the reproductive tract (p < 0.05). Western blot analyses showed protein bands compatible with the MT1 in the testis and cauda epididymis, and for the MT2 in the cauda epididymis and deferent duct. Immunohistochemistry analyses revealed the presence of MT1 receptors in spermatogonias, spermatocytes, and spermatids, and MT2 receptors in the newly-formed spermatozoa in the testis, whereas both receptors were located in the epithelial cells of the ampulla, seminal vesicles, and ductus deferens. Indirect immunofluorescence showed significant differences in the immunolocation of both receptors in spermatozoa during their transit in the epididymis. In conclusion, it was demonstrated that melatonin receptors are present in the ram reproductive tract. These results open the way for new studies on the molecular mechanism of melatonin and the biological significance of its receptors. PMID- 28335495 TI - Brain-Derived Neurotrophic Factor Loaded PS80 PBCA Nanocarrier for In Vitro Neural Differentiation of Mouse Induced Pluripotent Stem Cells. AB - Brain derived neurotrophic factor (BDNF) can induce neural differentiation in stem cells and has the potential for repair of the nervous system. In this study, a polysorbate 80-coated polybutylcyanoacrylate nanocarrier (PS80 PBCA NC) was constructed to deliver plasmid DNAs (pDNAs) containing BDNF gene attached to a hypoxia-responsive element (HRE-cmvBDNF). The hypoxia-sensing mechanism of BDNF expression and inductiveness of the nano-formulation on mouse induced pluripotent stem cells (iPSCs) to differentiate into neurons following hypoxia was tested in vitro with immunofluorescent staining and Western blotting. The HRE-cmvBDNF appeared to adsorb onto the surface of PS80 PBCA NC, with a resultant mean diameter of 92.6 +/- 1.0 nm and zeta potential of -14.1 +/- 1.1 mV. HIF-1alpha level in iPSCs was significantly higher in hypoxia, which resulted in a 51% greater BDNF expression when transfected with PS80 PBCA NC/HRE-cmvBDNF than those without hypoxia. TrkB and phospho-Akt were also elevated which correlated with neural differentiation. The findings suggest that PS80 PBCA NC too can be endocytosed to serve as an efficient vector for genes coupled to the HRE in hypoxia-sensitive cells, and activation of the PI3/Akt pathway in iPSCs by BDNF is capable of neural lineage specification. PMID- 28335498 TI - On the Prediction of Flickr Image Popularity by Analyzing Heterogeneous Social Sensory Data. AB - The increase in the popularity of social media has shattered the gap between the physical and virtual worlds. The content generated by people or social sensors on social media provides information about users and their living surroundings, which allows us to access a user's preferences, opinions, and interactions. This provides an opportunity for us to understand human behavior and enhance the services provided for both the real and virtual worlds. In this paper, we will focus on the popularity prediction of social images on Flickr, a popular social photo-sharing site, and promote the research on utilizing social sensory data in the context of assisting people to improve their life on the Web. Social data are different from the data collected from physical sensors; in the fact that they exhibit special characteristics that pose new challenges. In addition to their huge quantity, social data are noisy, unstructured, and heterogeneous. Moreover, they involve human semantics and contextual data that require analysis and interpretation based on human behavior. Accordingly, we address the problem of popularity prediction for an image by exploiting three main factors that are important for making an image popular. In particular, we investigate the impact of the image's visual content, where the semantic and sentiment information extracted from the image show an impact on its popularity, as well as the textual information associated with the image, which has a fundamental role in boosting the visibility of the image in the keyword search results. Additionally, we explore social context, such as an image owner's popularity and how it positively influences the image popularity. With a comprehensive study on the effect of the three aspects, we further propose to jointly consider the heterogeneous social sensory data. Experimental results obtained from real-world data demonstrate that the three factors utilized complement each other in obtaining promising results in the prediction of image popularity on social photo-sharing site. PMID- 28335496 TI - Quantitative Analysis of the KSHV Transcriptome Following Primary Infection of Blood and Lymphatic Endothelial Cells. AB - The transcriptome of the Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) after primary latent infection of human blood (BEC), lymphatic (LEC) and immortalized (TIME) endothelial cells was analyzed using RNAseq, and compared to long-term latency in BCBL-1 lymphoma cells. Naturally expressed transcripts were obtained without artificial induction, and a comprehensive annotation of the KSHV genome was determined. A set of unique coding sequence (UCDS) features and a process to resolve overlapping transcripts were developed to accurately quantitate transcript levels from specific promoters. Similar patterns of KSHV expression were detected in BCBL-1 cells undergoing long-term latent infections and in primary latent infections of both BEC and LEC cultures. High expression levels of poly-adenylated nuclear (PAN) RNA and spliced and unspliced transcripts encoding the K12 Kaposin B/C complex and associated microRNA region were detected, with an elevated expression of a large set of lytic genes in all latently infected cultures. Quantitation of non-overlapping regions of transcripts across the complete KSHV genome enabled for the first time accurate evaluation of the KSHV transcriptome associated with viral latency in different cell types. Hierarchical clustering applied to a gene correlation matrix identified modules of co-regulated genes with similar correlation profiles, which corresponded with biological and functional similarities of the encoded gene products. Gene modules were differentially upregulated during latency in specific cell types indicating a role for cellular factors associated with differentiated and/or proliferative states of the host cell to influence viral gene expression. PMID- 28335497 TI - Ginsenoside PPD's Antitumor Effect via Down-Regulation of mTOR Revealed by Super Resolution Imaging. AB - Derived from Panax ginseng, the natural product 20(S)-Protopanaxadiol (PPD) has been reported for its cytotoxicity against several cancer cell lines. The molecular mechanism is, however, not well understood. Here we show that PPD significantly inhibits proliferation, induces apoptosis and causes G2/M cell cycle arrest in human laryngeal carcinoma cells (Hep-2 cells). PPD also decreases the levels of proteins related to cell proliferation. Moreover, PPD-induced apoptosis is characterized by a dose-dependent down-regulation of Bcl-2 expression and up-regulation of Bax, and is accompanied by the activation of Caspase-3 as well. Further molecular mechanism is revealed by direct stochastic optical reconstruction microscopy (dSTORM)-a novel high-precision localization microscopy which enables effective resolution down to the order of 10 nm. It shows the expression and spatial arrangement of mTOR and its downstream effectors, demonstrating that this ginsenoside exerts its excellent anticancer effects via down-regulation of mTOR signaling pathway in Hep-2 cells. Taken together, our findings elucidate that the antitumor effect of PPD is associated with its regulation of mTOR expression and distribution, which encourages further studies of PPD as a promising therapeutic agent against laryngeal carcinoma. PMID- 28335499 TI - Synthesis of Substituted alpha-Trifluoromethyl Piperidinic Derivatives. AB - A comprehensive survey of pathways leading to the generation of alpha trifluoromethyl monocyclic piperidinic derivatives is provided (65 references). These compounds have been synthesized either from 6-membered rings e.g., pipecolic acid or lactam derivatives by introduction a trifluoromethyl group, from pyridine or pyridinone derivatives by reduction, and from 5-membered rings e.g., prolinol derivatives by ring expansion, from linear amines by cyclization or from dienes/dienophiles by [4 + 2]-cycloaddition. PMID- 28335500 TI - Comparison of Two Types of Overoxidized PEDOT Films and Their Application in Sensor Fabrication. AB - Poly(3,4-ethylenedioxythiophene) (PEDOT) films were prepared by electro-oxidation on Au microelectrodes in an aqueous solution. Electrolyte solutions and polymerization parameters were optimized prior to overoxidation. The effect of overoxidation time has been optimized by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), which results in the film overoxidized for 45 s at 1.35 V presenting a strong adsorption. The other one step overoxidation film prepared by direct CV ranging from -0.6 V to 1.35 V was polymerized for comparison. Scanning electron microscope (SEM) analysis and Fourier transform infrared (FTIR) spectroscopy were used for monitoring morphological changes and the evolution of functional groups. Both of them indicate increased abundant oxygen functional groups and roughness, yet the products exhibit dendritic morphology and piles of spherical protrusions, respectively. Moreover, double-step overoxidized film showed better electrochemical performance toward lead ion sensing. These characterizations highlight some novel properties that may be beneficial for specific sensing applications. PMID- 28335501 TI - Communication Matters: Exploring the Intersection of Family and Practitioner End of Life Communication. AB - After establishing a baseline understanding of some of the factors that influence and shape family end of life communication, empirical research centered on the communication tendencies of nationally-recognized palliative care clinicians is presented. Because death is no longer confined to the bedroom and individuals are increasingly turning to hospitals and health care institutes to assist with end of life, the role of palliative care practitioners is vital. To that end, common communication-rooted issues that may transpire among various medical personnel are explored. Focus on a shared underlying tension-care vs. cure-links the findings between family and palliative care clinician communication regarding end of life. Practical communication solutions and suggestions are offered to facilitate productive and mindful end of life communication between and among family members and health care practitioners. PMID- 28335503 TI - Synthesis of Randomly Substituted Anionic Cyclodextrins in Ball Milling. AB - A number of influencing factors mean that the random substitution of cyclodextrins (CD) in solution is difficult to reproduce. Reaction assembly in mechanochemistry reduces the number of these factors. However, lack of water can improve the reaction outcomes by minimizing the reagent's hydrolysis. High-energy ball milling is an efficient, green and simple method for one-step reactions and usually reduces degradation and byproduct formation. Anionic CD derivatives have successfully been synthesized in the solid state, using a planetary ball mill. Comparison with solution reactions, the solvent-free conditions strongly reduced the reagent hydrolysis and resulted in products of higher degree of substitution (DS) with more homogeneous DS distribution. The synthesis of anionic CD derivatives can be effectively performed under mechanochemical activation without significant changes to the substitution pattern but the DS distributions were considerably different from the products of solution syntheses. PMID- 28335504 TI - Diagnosis of Breast Cancer Tissues Using 785 nm Miniature Raman Spectrometer and Pattern Regression. AB - For achieving the development of a portable, low-cost and in vivo cancer diagnosis instrument, a laser 785 nm miniature Raman spectrometer was used to acquire the Raman spectra for breast cancer detection in this paper. However, because of the low spectral signal-to-noise ratio, it is difficult to achieve high discrimination accuracy by using the miniature Raman spectrometer. Therefore, a pattern recognition method of the adaptive net analyte signal (NAS) weight k-local hyperplane (ANWKH) is proposed to increase the classification accuracy. ANWKH is an extension and improvement of K-local hyperplane distance nearest-neighbor (HKNN), and combines the advantages of the adaptive weight k local hyperplane (AWKH) and the net analyte signal (NAS). In this algorithm, NAS was first used to eliminate the influence caused by other non-target factors. Then, the distance between the test set samples and hyperplane was calculated with consideration of the feature weights. The HKNN only works well for small values of the nearest-neighbor. However, the accuracy decreases with increasing values of the nearest-neighbor. The method presented in this paper can resolve the basic shortcoming by using the feature weights. The original spectra are projected into the vertical subspace without the objective factors. NAS was employed to obtain the spectra without irrelevant information. NAS can improve the classification accuracy, sensitivity, and specificity of breast cancer early diagnosis. Experimental results of Raman spectra detection in vitro of breast tissues showed that the proposed algorithm can obtain high classification accuracy, sensitivity, and specificity. This paper demonstrates that the ANWKH algorithm is feasible for early clinical diagnosis of breast cancer in the future. PMID- 28335502 TI - Catechins and Their Therapeutic Benefits to Inflammatory Bowel Disease. AB - Catechins are natural polyphenolic phytochemicals that exist in food and medicinal plants, such as tea, legume and rubiaceae. An increasing number of studies have associated the intake of catechins-rich foods with the prevention and treatment of chronic diseases in humans, such as inflammatory bowel disease (IBD). Some studies have demonstrated that catechins could significantly inhibit the excessive oxidative stress through direct or indirect antioxidant effects and promote the activation of the antioxidative substances such as glutathione peroxidases (GPO) and glutathione (GSH), reducing the oxidative damages to the colon. In addition, catechins can also regulate the infiltration and proliferation of immune related-cells, such as neutrophils, colonic epithelial cells, macrophages, and T lymphocytes, helping reduce the inflammatory relations and provide benefits to IBD. Perhaps catechins can further inhibit the deterioration of intestinal lesions through regulating the cell gap junctions. Furthermore, catechins can exert their significant anti-inflammatory properties by regulating the activation or deactivation of inflammation-related oxidative stress-related cell signaling pathways, such as nuclear factor-kappa B (NF kappaB), mitogen activated protein kinases (MAPKs), transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2), signal transducer and the activator of transcription 1/3 (STAT1/3) pathways. Finally, catechins can also stabilize the structure of the gastrointestinal micro-ecological environment via promoting the proliferation of beneficial intestinal bacteria and regulating the balance of intestinal flora, so as to relieve the IBD. Furthermore, catechins may regulate the tight junctions (TJ) in the epithelium. This paper elaborates the currently known possible molecular mechanisms of catechins in favor of IBD. PMID- 28335506 TI - A Colorimetric Sensor for the Highly Selective Detection of Sulfide and 1,4 Dithiothreitol Based on the In Situ Formation of Silver Nanoparticles Using Dopamine. AB - Hydrogen sulfide (H2S) has attracted attention in biochemical research because it plays an important role in biosystems and has emerged as the third endogenous gaseous signaling compound along with nitric oxide (NO) and carbon monoxide (CO). Since H2S is a kind of gaseous molecule, conventional approaches for H2S detection are mostly based on the detection of sulfide (S2-) for indirectly reflecting H2S levels. Hence, there is a need for an accurate and reliable assay capable of determining sulfide in physiological systems. We report here a colorimetric, economic, and green method for sulfide anion detection using in situ formation of silver nanoparticles (AgNPs) using dopamine as a reducing and protecting agent. The changes in the AgNPs absorption response depend linearly on the concentration of Na2S in the range from 2 to 15 MUM, with a detection limit of 0.03 MUM. Meanwhile, the morphological changes in AgNPs in the presence of S2- and thiol compounds were characterized by transmission electron microscopy (TEM). The as-synthetized AgNPs demonstrate high selectivity, free from interference, especially by other thiol compounds such as cysteine and glutathione. Furthermore, the colorimetric sensor developed was applied to the analysis of sulfide in fetal bovine serum and spiked serum samples with good recovery. PMID- 28335505 TI - Porcine Epidemic Diarrhea Virus Induces Autophagy to Benefit Its Replication. AB - The new porcine epidemic diarrhea (PED) has caused devastating economic losses to the swine industry worldwide. Despite extensive research on the relationship between autophagy and virus infection, the concrete role of autophagy in porcine epidemic diarrhea virus (PEDV) infection has not been reported. In this study, autophagy was demonstrated to be triggered by the effective replication of PEDV through transmission electron microscopy, confocal microscopy, and Western blot analysis. Moreover, autophagy was confirmed to benefit PEDV replication by using autophagy regulators and RNA interference. Furthermore, autophagy might be associated with the expression of inflammatory cytokines and have a positive feedback loop with the NF-kappaB signaling pathway during PEDV infection. This work is the first attempt to explore the complex interplay between autophagy and PEDV infection. Our findings might accelerate our understanding of the pathogenesis of PEDV infection and provide new insights into the development of effective therapeutic strategies. PMID- 28335508 TI - Detrimental Effect Elimination of Laser Frequency Instability in Brillouin Optical Time Domain Reflectometer by Using Self-Heterodyne Detection. AB - A useful method for eliminating the detrimental effect of laser frequency instability on Brillouin signals by employing the self-heterodyne detection of Rayleigh and Brillouin scattering is presented. From the analysis of Brillouin scattering spectra from fibers with different lengths measured by heterodyne detection, the maximum usable pulse width immune to laser frequency instability is obtained to be about 4 us in a self-heterodyne detection Brillouin optical time domain reflectometer (BOTDR) system using a broad-band laser with low frequency stability. Applying the self-heterodyne detection of Rayleigh and Brillouin scattering in BOTDR system, we successfully demonstrate that the detrimental effect of laser frequency instability on Brillouin signals can be eliminated effectively. Employing the broad-band laser modulated by a 130-ns wide pulse driven electro-optic modulator, the observed maximum errors in temperatures measured by the local heterodyne and self-heterodyne detection BOTDR systems are 7.9 degrees C and 1.2 degrees C, respectively. PMID- 28335510 TI - Gender Recognition from Human-Body Images Using Visible-Light and Thermal Camera Videos Based on a Convolutional Neural Network for Image Feature Extraction. AB - Extracting powerful image features plays an important role in computer vision systems. Many methods have previously been proposed to extract image features for various computer vision applications, such as the scale-invariant feature transform (SIFT), speed-up robust feature (SURF), local binary patterns (LBP), histogram of oriented gradients (HOG), and weighted HOG. Recently, the convolutional neural network (CNN) method for image feature extraction and classification in computer vision has been used in various applications. In this research, we propose a new gender recognition method for recognizing males and females in observation scenes of surveillance systems based on feature extraction from visible-light and thermal camera videos through CNN. Experimental results confirm the superiority of our proposed method over state-of-the-art recognition methods for the gender recognition problem using human body images. PMID- 28335509 TI - Novel Diagnostic and Predictive Biomarkers in Pancreatic Adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease for a multitude of reasons including very late diagnosis. This in part is due to the lack of understanding of the biological behavior of PDAC and the ineffective screening for this disease. Significant efforts have been dedicated to finding the appropriate serum and imaging biomarkers to help early detection and predict response to treatment of PDAC. Carbohydrate antigen 19-9 (CA 19-9) has been the most validated serum marker and has the highest positive predictive value as a stand-alone marker. When combined with carcinoembryonic antigen (CEA) and carbohydrate antigen 125 (CA 125), CA 19-9 can help predict the outcome of patients to surgery and chemotherapy. A slew of novel serum markers including multimarker panels as well as genetic and epigenetic materials have potential for early detection of pancreatic cancer, although these remain to be validated in larger trials. Imaging studies may not correlate with elevated serum markers. Critical features for determining PDAC include the presence of a mass, dilated pancreatic duct, and a duct cut-off sign. Features that are indicative of early metastasis includes neurovascular bundle involvement, duodenal invasion, and greater post contrast enhancement. 18-F-fluorodeoxyglucose (18-FDG) radiotracer uptake and changes following treatment may predict patient overall survival following treatment. Similarly, pretreatment apparent diffusion coefficient (ADC) values may predict prognosis with lower ADC lesions having worse outcome. Although these markers have provided significant improvement in the care of pancreatic cancer patients, further advancements can be made with perhaps better combination of markers or discovery of unique marker(s) to pancreatic cancer. PMID- 28335507 TI - Hydroxytyrosol in the Prevention of the Metabolic Syndrome and Related Disorders. AB - Virgin olive oil (VOO) constitutes the main source of fat in the Mediterranean diet. VOO is rich in oleic acid, displaying health-promoting properties, but also contains minor bioactive components, especially phenolic compounds. Hydroxytyrosol (HT), the main polyphenol of olive oil, has been reported to be the most bioactive component. This review aims to compile the results of clinical, animal and cell culture studies evaluating the effects of HT on the features of Metabolic Syndrome (MetS) (body weight/adiposity, dyslipidemia, hypertension, and hyperglycemia/insulin resistance) and associated complications (oxidative stress and inflammation). HT was able to improve the lipid profile, glycaemia, and insulin sensitivity, and counteract oxidative and inflammatory processes. Experimental studies identified multiple molecular targets for HT conferring its beneficial effect on health in spite of its low bioavailability. However, rodent experiments and clinical trials with pure HT at biologically relevant concentrations are still lacking. Moreover, the roles of intestine and its gut microbiota have not been elucidated. PMID- 28335511 TI - 1st Workshop of the Canadian Society for Virology. AB - The 1st Workshop of the Canadian Society for Virology (CSV2016) was a Special Workshop of the 35th Annual Meeting for the American Society for Virology, held on 18 June 2016 on the beautiful Virginia Tech campus in Blacksburg, Virginia. The workshop provided a forum for discussion of recent advances in the field, in an informal setting conducive to interaction with colleagues. CSV2016 featured two internationally-renowned Canadian keynote speakers who discussed translational virology research; American Society for Virology President Grant McFadden (then from University of Florida, now relocated to Arizona State University) who presented his studies of oncolytic poxviruses, while Matthew Miller (McMaster University) reviewed the prospects for a universal influenza vaccine. The workshop also featured a variety of trainee oral and poster presentations, and a panel discussion on the topic of the future of the CSV and virus research in Canada. PMID- 28335512 TI - Symptoms Relevant to Surveillance for Ovarian Cancer. AB - To examine how frequently and confidently healthy women report symptoms during surveillance for ovarian cancer. A symptoms questionnaire was administered to 24,526 women over multiple visits accounting for 70,734 reports. A query of reported confidence was included as a confidence score (CS). Chi square, McNemars test, ANOVA and multivariate analyses were performed. 17,623 women completed the symptoms questionnaire more than one time and >9500 women completed it more than one four times for >43,000 serially completed questionnaires. Reporting ovarian cancer symptoms was ~245 higher than ovarian cancer incidence. The positive predictive value (0.073%) for identifying ovarian cancer based on symptoms alone would predict one malignancy for 1368 cases taken to surgery due to reported symptoms. Confidence on the first questionnaire (83.3%) decreased to 74% when more than five questionnaires were completed. Age-related decreases in confidence were significant (p < 0.0001). Women reporting at least one symptom expressed more confidence (41,984/52,379 = 80.2%) than women reporting no symptoms (11,882/18,355 = 64.7%), p < 0.0001. Confidence was unrelated to history of hormone replacement therapy or abnormal ultrasound findings (p = 0.30 and 0.89). The frequency of symptoms relevant to ovarian cancer was much higher than the occurrence of ovarian cancer. Approximately 80.1% of women expressed confidence in what they reported. PMID- 28335513 TI - Bioactive Potential of Marine Macroalgae from the Central Red Sea (Saudi Arabia) Assessed by High-Throughput Imaging-Based Phenotypic Profiling. AB - Marine algae represent an important source of novel natural products. While their bioactive potential has been studied to some extent, limited information is available on marine algae from the Red Sea. This study aimed at the broad discovery of new bioactivities from a collection of twelve macroalgal species from the Central Red Sea. We used imaging-based High-Content Screening (HCS) with a diverse spectrum of cellular markers for detailed cytological profiling of fractionated algal extracts. The cytological profiles for 3 out of 60 algal fractions clustered closely to reference inhibitors and showed strong inhibitory activities on the HIV-1 reverse transcriptase in a single-enzyme biochemical assay, validating the suggested biological target. Subsequent chemical profiling of the active fractions of two brown algal species by ultra-high resolution mass spectrometry (FT-ICR-MS) revealed possible candidate molecules. A database query of these molecules led us to groups of compounds with structural similarities, which are suggested to be responsible for the observed activity. Our work demonstrates the versatility and power of cytological profiling for the bioprospecting of unknown biological resources and highlights Red Sea algae as a source of bioactives that may serve as a starting point for further studies. PMID- 28335514 TI - The Association between Vitamin D Deficiency and Diabetic Retinopathy in Type 2 Diabetes: A Meta-Analysis of Observational Studies. AB - Emerging evidence from in vivo and in vitro studies have shown that vitamin D may play an important role in the development of diabetic retinopathy (DR), but individually published studies showed inconclusive results. The aim of this study was to quantitatively summarize the association between vitamin D and the risk of diabetic retinopathy. We conducted a systematic literature search of Pubmed, Medline, and EMBASE updated in September 2016 with the following keywords: "vitamin D" or "cholecalciferol" or "25-hydroxyvitamin D" or "25(OH)D" in combination with "diabetic retinopathy" or "DR". Fifteen observational studies involving 17,664 subjects were included. In this meta-analysis, type 2 diabetes patients with vitamin D deficiency (serum 25(OH)D levels <20 ng/mL) experienced a significantly increased risk of DR (odds ratio (OR) = 2.03, 95% confidence intervals (CI): 1.07, 3.86), and an obvious decrease of 1.7 ng/mL (95% CI: -2.72, -0.66) in serum vitamin D was demonstrated in the patients with diabetic retinopathy. Sensitivity analysis showed that exclusion of any single study did not materially alter the overall combined effect. In conclusion, the evidence from this meta-analysis indicates an association between vitamin D deficiency and an increased risk of diabetic retinopathy in type 2 diabetes patients. PMID- 28335515 TI - Dehydroepiandrosterone (DHEA) Feeding Protects Liver Steatosis in Obese Breast Cancer Rat Model. AB - Obesity is a major health problem in the US and globally. Obesity is associated with the risk of cardiovascular disease, type 2 diabetes, cancers, hyperlipidemia, and liver steatosis development. Dehydroepiandrosterone (DHEA) is a dietary supplement used as an anti-obesity supplement. Previously, we reported that DHEA feeding protects 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors. The objectives of this study were to investigate the effects of obesity and DHEA feeding on liver steatosis, body weight gain, and serum DHEA, DHEA sulfate (DHEA-S), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-3 (IGFBP-3) levels. Female Zucker rats were randomly assigned to either a control diet or a control diet with DHEA supplementation for 155 days. Livers were collected for histological examination. Serum was collected to measure DHEA, DHEA-S, IGF-1, and IGFBP-3. Our results show that DHEA-fed rats had significantly less liver steatosis (p < 0.001) than control-fed rats and gained less weight (p < 0.001). DHEA feeding caused significant decreases (p < 0.001) in the serum levels of IGF-1 and IGFBP-3 and significantly increased (p < 0.001) serum levels of DHEA and DHEA-S. Our results suggest that DHEA feeding can protect against liver steatosis by reducing body weight gain and modulating serum IGF-1 and IGFBP-3 levels in an obese breast cancer rat model. PMID- 28335516 TI - Marine Diterpenes: Molecular Modeling of Thrombin Inhibitors with Potential Biotechnological Application as an Antithrombotic. AB - Thrombosis related diseases are among the main causes of death and incapacity in the world. Despite the existence of antithrombotic agents available for therapy, they still present adverse effects like hemorrhagic risks which justify the search for new options. Recently, pachydictyol A, isopachydictyol A, and dichotomanol, three diterpenes isolated from Brazilian marine brown alga Dictyota menstrualis were identified as potent antithrombotic molecules through inhibition of thrombin, a key enzyme of coagulation cascade and a platelet agonist. Due to the biotechnological potential of these marine metabolites, in this work we evaluated their binding mode to thrombin in silico and identified structural features related to the activity in order to characterize their molecular mechanism. According to our theoretical studies including structure-activity relationship and molecular docking analysis, the highest dipole moment, polar surface area, and lowest electronic density of dichotomanol are probably involved in its higher inhibition percentage towards thrombin catalytic activity compared to pachydictyol A and isopachydictyol A. Interestingly, the molecular docking studies also revealed a good shape complementarity of pachydictyol A and isopachydictyol A and interactions with important residues and regions (e.g., H57, S195, W215, G216, and loop-60), which probably justify their thrombin inhibitor effects demonstrated in vitro. Finally, this study explored the structural features and binding mode of these three diterpenes in thrombin which reinforced their potential to be further explored and may help in the design of new antithrombotic agents. PMID- 28335518 TI - New Chiral Ebselen Analogues with Antioxidant and Cytotoxic Potential. AB - New chiral camphane-derived benzisoselenazol-3(2H)-ones and corresponding diselenides have been synthetized using a convenient one-pot procedure. Se-N bond was efficiently converted to an Se-Se bond, which could also be easily re oxidized to the initial benzisoselenazolone moiety. The antioxidant activity of camphor derivatives was evaluated and compared to the reactivity of a series of N amino acid benzisoselenazol-3(2H)-ones obtained by a modified procedure involving the improved synthesis and isolation of the diseleno bis(dibenzoic) acid. The most efficient peroxide scavengers, N-bornyl and N-leucine methyl ester benzisoselenazol-3(2H)-ones, were further evaluated as cytotoxic agents on four cancer cell lines (MCF-7, HEP G2, HL 6, and DU 145) and normal cell line PNT1A. The highest antiproliferative potential was evaluated for two compounds bearing a 3-methylbutyl carbon chain, N-leucine methyl ester and N-3-methylbutyl benzisoselenazol-3(2H)-ones. PMID- 28335517 TI - State of the Art on Functional Virgin Olive Oils Enriched with Bioactive Compounds and Their Properties. AB - Virgin olive oil, the main fat of the Mediterranean diet, is per se considered as a functional food-as stated by the European Food Safety Authority (EFSA)-due to its content in healthy compounds. The daily intake of endogenous bioactive phenolics from virgin olive oil is variable due to the influence of multiple agronomic and technological factors. Thus, a good strategy to ensure an optimal intake of polyphenols through habitual diet would be to produce enriched virgin olive oil with well-known bioactive polyphenols. Different sources of natural biological active substances can be potentially used to enrich virgin olive oil (e.g., raw materials derived from the same olive tree, mainly olive leaves and pomaces, and/or other compounds from plants and vegetables, mainly herbs and spices). The development of these functional olive oils may help in prevention of chronic diseases (such as cardiovascular diseases, immune frailty, ageing disorders and degenerative diseases) and improving the quality of life for many consumers reducing health care costs. In the present review, the most relevant scientific information related to the development of enriched virgin olive oil and their positive human health effects has been collected and discussed. PMID- 28335519 TI - Translating Developmental Origins: Improving the Health of Women and Their Children Using a Sustainable Approach to Behaviour Change. AB - Theories of the developmental origins of health and disease imply that optimising the growth and development of babies is an essential route to improving the health of populations. A key factor in the growth of babies is the nutritional status of their mothers. Since women from more disadvantaged backgrounds have poorer quality diets and the worst pregnancy outcomes, they need to be a particular focus. The behavioural sciences have made a substantial contribution to the development of interventions to support dietary changes in disadvantaged women. Translation of such interventions into routine practice is an ideal that is rarely achieved, however. This paper illustrates how re-orientating health and social care services towards an empowerment approach to behaviour change might underpin a new developmental focus to improving long-term health, using learning from a community-based intervention to improve the diets and lifestyles of disadvantaged women. The Southampton Initiative for Health aimed to improve the diets and lifestyles of women of child-bearing age through training health and social care practitioners in skills to support behaviour change. Analysis illustrates the necessary steps in mounting such an intervention: building trust; matching agendas and changing culture. The Southampton Initiative for Health demonstrates that developing sustainable; workable interventions and effective community partnerships; requires commitment beginning long before intervention delivery but is key to the translation of developmental origins research into improvements in human health. PMID- 28335521 TI - Gene-Transformation-Induced Changes in Chemical Functional Group Features and Molecular Structure Conformation in Alfalfa Plants Co-Expressing Lc-bHLH and C1 MYB Transcriptive Flavanoid Regulatory Genes: Effects of Single-Gene and Two-Gene Insertion. AB - Alfalfa (Medicago sativa L.) genotypes transformed with Lc-bHLH and Lc transcription genes were developed with the intention of stimulating proanthocyanidin synthesis in the aerial parts of the plant. To our knowledge, there are no studies on the effect of single-gene and two-gene transformation on chemical functional groups and molecular structure changes in these plants. The objective of this study was to use advanced molecular spectroscopy with multivariate chemometrics to determine chemical functional group intensity and molecular structure changes in alfalfa plants when co-expressing Lc-bHLH and C1 MYB transcriptive flavanoid regulatory genes in comparison with non-transgenic (NT) and AC Grazeland (ACGL) genotypes. The results showed that compared to NT genotype, the presence of double genes (Lc and C1) increased ratios of both the area and peak height of protein structural Amide I/II and the height ratio of alpha-helix to beta-sheet. In carbohydrate-related spectral analysis, the double gene-transformed alfalfa genotypes exhibited lower peak heights at 1370, 1240, 1153, and 1020 cm-1 compared to the NT genotype. Furthermore, the effect of double gene transformation on carbohydrate molecular structure was clearly revealed in the principal component analysis of the spectra. In conclusion, single or double transformation of Lc and C1 genes resulted in changing functional groups and molecular structure related to proteins and carbohydrates compared to the NT alfalfa genotype. The current study provided molecular structural information on the transgenic alfalfa plants and provided an insight into the impact of transgenes on protein and carbohydrate properties and their molecular structure's changes. PMID- 28335520 TI - Endoplasmic Reticulum Stress and Unfolded Protein Response in Cartilage Pathophysiology; Contributing Factors to Apoptosis and Osteoarthritis. AB - Chondrocytes of the growth plate undergo apoptosis during the process of endochondral ossification, as well as during the progression of osteoarthritis. Although the regulation of this process is not completely understood, alterations in the precisely orchestrated programmed cell death during development can have catastrophic results, as exemplified by several chondrodystrophies which are frequently accompanied by early onset osteoarthritis. Understanding the mechanisms that underlie chondrocyte apoptosis during endochondral ossification in the growth plate has the potential to impact the development of therapeutic applications for chondrodystrophies and associated early onset osteoarthritis. In recent years, several chondrodysplasias and collagenopathies have been recognized as protein-folding diseases that lead to endoplasmic reticulum stress, endoplasmic reticulum associated degradation, and the unfolded protein response. Under conditions of prolonged endoplasmic reticulum stress in which the protein folding load outweighs the folding capacity of the endoplasmic reticulum, cellular dysfunction and death often occur. However, unfolded protein response (UPR) signaling is also required for the normal maturation of chondrocytes and osteoblasts. Understanding how UPR signaling may contribute to cartilage pathophysiology is an essential step toward therapeutic modulation of skeletal disorders that lead to osteoarthritis. PMID- 28335523 TI - [2 + 2] Photodimerization of Naphthylvinylpyridines through Cation-pi Interactions in Acidic Solution. AB - Irradiation of (E)-4-(2-(2-naphthyl)vinyl)pyridine (1a) and (E)-4-(2-(1 naphthyl)vinyl)pyridine (1b) with a 250 W high-pressure mercury lamp in acidic solution afforded synHT dimers in high stereoselectivities. Similar results were obtained by visible light irradiation. On the other hand, when the reactions were carried out under neutral conditions, the stereoselectivities were very low, and the yields were decreased by visible light irradiation. Comparison of the UV-vis spectra between the acidic and the neutral conditions elucidated that the red shift was observed in acidic solutions. These results show that HCl plays essential roles not only in the preorientation of substrates through cation-pi interactions, but also in the changes in the absorption properties of substrates that enable visible light reactions. PMID- 28335522 TI - Extracellular Vesicles Deliver Host and Virus RNA and Regulate Innate Immune Response. AB - The innate immune system plays a crucial role in controlling viral infection. Pattern recognition receptors (PRRs), such as Toll-like receptors and RIG-I-like receptors, sense viral components called pathogen-associated molecular patterns (PAMPs) and trigger signals to induce innate immune responses. Extracellular vesicles (EVs), including exosomes and microvesicles, deliver functional RNA and mediate intercellular communications. Recent studies have revealed that EVs released from virus-infected cells deliver viral RNA to dendritic cells and macrophages, thereby activating PRRs in recipient cells, which results in the expression of type I interferon and pro-inflammatory cytokines. On the other hand, EVs transfer not only viral RNA but also host microRNAs to recipient cells. Recently, infection of hepatocytes with hepatitis B virus (HBV) was shown to affect microRNA levels in EVs released from virus-infected cells, leading to attenuation of host innate immune response. This suggests that the virus utilizes the EVs and host microRNAs to counteract the antiviral innate immune responses. In this review, we summarize recent findings related to the role of EVs in antiviral innate immune responses. PMID- 28335524 TI - Roles of CDK and DDK in Genome Duplication and Maintenance: Meiotic Singularities. AB - Cells reproduce using two types of divisions: mitosis, which generates two daughter cells each with the same genomic content as the mother cell, and meiosis, which reduces the number of chromosomes of the parent cell by half and gives rise to four gametes. The mechanisms that promote the proper progression of the mitotic and meiotic cycles are highly conserved and controlled. They require the activities of two types of serine-threonine kinases, the cyclin-dependent kinases (CDKs) and the Dbf4-dependent kinase (DDK). CDK and DDK are essential for genome duplication and maintenance in both mitotic and meiotic divisions. In this review, we aim to highlight how these kinases cooperate to orchestrate diverse processes during cellular reproduction, focusing on meiosis-specific adaptions of their regulation and functions in DNA metabolism. PMID- 28335525 TI - The History of Clotting Factor Concentrates Pharmacokinetics. AB - Clotting factor concentrates (CFCs) underwent tremendous modifications during the last forty years. Plasma-derived concentrates made the replacement therapy feasible not only in the hospital but also at patients' home by on-demand or prophylactic regimen. Virucidal methods, implemented soon after hepatitis and AIDS outbreak, and purification by Mabs made the plasma-derived concentrates safer and purer. CFCs were considered equivalent to the other drugs and general rules and methods of pharmacokinetics (PK) were applied to their study. After the first attempts by graphical methods and calculation of In Vivo Recovery, compartment and non-compartment methods were applied also to the study of PK of CFCs. The bioequivalence of the new concentrates produced by means of recombinant DNA biotechnology was evaluated in head-to-head PK studies. Since the beginning, the large inter-patient variability of dose/response of replacement therapy was realized. PK allowed tailoring haemophilia therapy and PK driven prophylaxis resulted more cost effective. Unfortunately, the need of several blood samples and logistic difficulties made the PK studies very demanding. Recently, population PK (PopPK) has been applied to the prediction of CFCs dosing by Bayesian methodology. By PopPK also sparse data may allow evaluating the appropriateness of replacement therapy. PMID- 28335526 TI - Oral Cyanocobalamin is Effective in the Treatment of Vitamin B12 Deficiency in Crohn's Disease. AB - Cobalamin deficiency is common in patients with Crohn's disease (CD). Intramuscular cobalamin continues to be the standard therapy for the deficiency and maintenance treatment in these patients, although oral route has been demonstrated to be effective in other pathologies with impaired absorption. Our aims were to evaluate the efficacy of oral therapy in the treatment of cobalamin deficiency and in long-term maintenance in patients with Crohn's disease. We performed a multicenter retrospective cohort study that included 94 patients with Crohn's disease and cobalamin deficiency. Seventy-six patients had B12 deficiency and 94.7% of them normalized their cobalamin levels with oral treatment. The most used dose was 1 mg/day, but there were no significant differences in treatment effectiveness depending on the dose used (>=1 mg/24 h vs. <1 mg/24 h). Eighty-two patients had previous documented B12 deficiency and were treated with oral B12 to maintain their correct cobalamin levels. After a mean follow-up of 3 years, the oral route was effective as maintenance treatment in 81.7% of patients. A lack of treatment adherence was admitted by 46.6% of patients in who the oral route failed. In conclusion, our study shows that oral cyanocobalamin provides effective acute and maintenance treatment for vitamin B12 deficiency caused by CD with or without ileum resection. PMID- 28335527 TI - Metabolic Disorder in Chronic Obstructive Pulmonary Disease (COPD) Patients: Towards a Personalized Approach Using Marine Drug Derivatives. AB - Metabolic disorder has been frequently observed in chronic obstructive pulmonary disease (COPD) patients. However, the exact correlation between obesity, which is a complex metabolic disorder, and COPD remains controversial. The current study summarizes a variety of drugs from marine sources that have anti-obesity effects and proposed potential mechanisms by which lung function can be modulated with the anti-obesity activity. Considering the similar mechanism, such as inflammation, shared between obesity and COPD, the study suggests that marine derivatives that act on the adipose tissues to reduce inflammation may provide beneficial therapeutic effects in COPD subjects with high body mass index (BMI). PMID- 28335528 TI - Pretreatment of Lignocellulosic Biomass with Ionic Liquids and Ionic Liquid-Based Solvent Systems. AB - Pretreatment is very important for the efficient production of value-added products from lignocellulosic biomass. However, traditional pretreatment methods have several disadvantages, including low efficiency and high pollution. This article gives an overview on the applications of ionic liquids (ILs) and IL-based solvent systems in the pretreatment of lignocellulosic biomass. It is divided into three parts: the first deals with the dissolution of biomass in ILs and IL based solvent systems; the second focuses on the fractionation of biomass using ILs and IL-based solvent systems as solvents; the third emphasizes the enzymatic saccharification of biomass after pretreatment with ILs and IL-based solvent systems. PMID- 28335529 TI - Effects of Momordica charantia (Bitter Melon) on Ischemic Diabetic Myocardium. AB - Objective: A rat model is here used to test a hypothesis that Momordica charantia (Bitter melon (BM)) extract favorably alters processes in cardiovascular tissue and is systemically relevant to the pathophysiology of type 2 diabetes (T2DM) and related cardiovascular disease. Methods: Male Lean and Zucker Obese (ZO) rats were gavage-treated for six weeks with 400 mg/kg body weight bitter melon (BM) extract suspended in mucin-water vehicle, or with vehicle (Control). Animals were segregated into four treatment groups, 10 animals in each group, according to strain (Lean or ZO) and treatment (Control or BM). Following six-week treatment periods, peripheral blood was collected from selected animals, followed by sacrifice, thoracotomy and mounting of isolated working heart setup. Results: Body mass of both Lean and ZO rats was unaffected by treatment, likewise, peripheral blood fasting glucose levels showed no significant treatment-related effects. However, some BM treatment-related improvement was noted in postischemic cardiac functions when Lean, BM-treated animals were compared to vehicle treated Lean control rats. Treatment of Lean, but not ZO, rats significantly reduced the magnitude of infarcted zone in isolated hearts subjected to 30 min of ischemia followed by 2 h of working mode reperfusion. Immunohistochemical demonstration of caspase-3 expression by isolated heart tissues subjected to 30 min of ischemia followed by 2 h of reperfusion, revealed significant correlation between BM treatment and reduced expression of this enzyme in hearts obtained from both Lean and ZO animals. The hierarchy and order of caspase-3 expression from highest to lowest was as follows: ZO rats receiving vehicle > ZO rats receiving BM extract > Lean rats treated receiving vehicle > Lean rats administered BM extract. Outcomes of analyses of peripheral blood content of cardiac-related analytics: with particular relevance to clinical application was a significant elevation in blood of ZO and ZO BM-treated, versus Lean rats of total cholesterol (high density lipoprotein HDL-c + low density lipoprotein LDL-c), with an inferred increase in HDL-c/LDL-c ratio-an outcome associated with decreased risk of atherosclerotic disease. Conclusions: BM extract failed to positively affect T2DM- and cardiovascular-related outcomes at a level suggesting use as a standalone treatment. Nevertheless, the encouraging effects of BM in enhancement of cardiac function, suppression of post-ischemic/reperfused infarct size extent and capacity to modulate serum cholesterol, will likely make it useful as an adjuvant therapy for the management of T2DM and related cardiovascular diseases. PMID- 28335530 TI - Risk of Suicide and Dysfunctional Patterns of Personality among Bereaved Substance Users. AB - Background: Research has shown that suicide is a phenomenon highly present among the drug dependent population. Different studies have demonstrated an upraised level of comorbidity between personality disorders (PD) and substance use disorders (SUD). This study aimed to describe which PDs are more frequent among those patients with a risk of suicide. Methods: The study was based on a consecutive non-probabilistic convenience sample of 196 bereaved patients attended to in a Public Addiction Center in Girona (Spain). Sociodemographic data, as well as suicide and drug related characteristics were recorded. The risk of suicide was assessed with the Spanish version of "Risk of suicide". Personality disorders were measured with the Spanish version of Millon Multiaxial Clinical Inventory. Results: The PDs more associated with the presence of risk of suicide were depressive, avoidant, schizotypal and borderline disorders. However, the histrionic, narcissistic and compulsive PDs are inversely associated with risk of suicide even though the narcissistic scale had no statistical correlation. Conclusions: The risk of suicide is a significant factor to take into account related to patients with SUD and especially with the presence of specific PDs. These findings underline the importance of diagnosing and treating rigorously patients with SUD. PMID- 28335532 TI - Separation of Alkyne Enantiomers by Chiral Column HPLC Analysis of Their Cobalt Complexes. AB - Separation of the enantiomers of new chiral alkynes in strategic syntheses and bioorthogonal studies is always problematic. The chiral column high-performance liquid chromatography (HPLC) method in general could not be directly used to resolve such substrates, since the differentiation of the alkyne segment with the other alkane/alkene segment is not significant in the stationary phase, and the alkyne group is not a good UV chromophore. Usually, a pre-column derivatization reaction with a tedious workup procedure is needed. Making use of easily-prepared stable alkyne-cobalt-complexes, we developed a simple and general method by analyzing the in situ generated cobalt-complex of chiral alkynes using chiral column HPLC. This new method is especially suitable for the alkynes without chromophores and other derivable groups. PMID- 28335531 TI - Associations among Substance Use, Mental Health Disorders, and Self-Harm in a Prison Population: Examining Group Risk for Suicide Attempt. AB - Substance use disorders (SUD) and mental health disorders are significant public health issues that co-occur and are associated with high risk for suicide attempts. SUD and mental health disorders are more prevalent among offenders (i.e., prisoners or inmates) than the non-imprisoned population, raising concerns about the risk of self-harm. This cross-sectional study examined the population of a state prison system (10,988 out of 13,079) to identify associations among SUD (alcohol, cannabis, intravenous drugs, narcotics, and tobacco smoking), mental health disorders (anxiety, bipolar, depression, and psychotic disorders), and suicide attempts. The primary aim was to determine which groups (SUD, mental health disorders, and co-occurrences) were strongly association with suicide attempts. Groups with a documented SUD or mental health disorders compared to peers without these issues had 2.0 and 9.2 greater odds, respectively, for attempting suicide, which was significant at p < 0.0001 for both conditions. There were also significant differences within SUD and mental health disorders groups in regard to suicide attempts. Groups with the greatest odds for suicide attempts were offenders with comorbid bipolar comorbid and anxiety, alcohol combined with depression, and cannabis co-occurring with depression. Documentation of suicide attempts during imprisonment indicates awareness, but also suggest a need to continue enhancing screening and evaluating environmental settings. PMID- 28335534 TI - A Networked Sensor System for the Analysis of Plot-Scale Hydrology. AB - This study presents the latest updates to the Audubon Society of Western Pennsylvania (ASWP) testbed, a $50,000 USD, 104-node outdoor multi-hop wireless sensor network (WSN). The network collects environmental data from over 240 sensors, including the EC-5, MPS-1 and MPS-2 soil moisture and soil water potential sensors and self-made sap flow sensors, across a heterogeneous deployment comprised of MICAz, IRIS and TelosB wireless motes. A low-cost sensor board and software driver was developed for communicating with the analog and digital sensors. Innovative techniques (e.g., balanced energy efficient routing and heterogeneous over-the-air mote reprogramming) maintained high success rates (>96%) and enabled effective software updating, throughout the large-scale heterogeneous WSN. The edaphic properties monitored by the network showed strong agreement with data logger measurements and were fitted to pedotransfer functions for estimating local soil hydraulic properties. Furthermore, sap flow measurements, scaled to tree stand transpiration, were found to be at or below potential evapotranspiration estimates. While outdoor WSNs still present numerous challenges, the ASWP testbed proves to be an effective and (relatively) low-cost environmental monitoring solution and represents a step towards developing a platform for monitoring and quantifying statistically relevant environmental parameters from large-scale network deployments. PMID- 28335533 TI - Exploring Impacts of Taxes and Hospitality Bans on Cigarette Prices and Smoking Prevalence Using a Large Dataset of Cigarette Prices at Stores 2001-2011, USA. AB - In the USA, little is known about local variation in retail cigarette prices; price variation explained by taxes, bans, and area-level socio-demographics, and whether taxes and hospitality bans have synergistic effects on smoking prevalence. Cigarette prices 2001-2011 from chain supermarkets and drug stores (n = 2973) were linked to state taxes (n = 41), state and county bar/restaurant smoking bans, and census block group socio-demographics. Hierarchical models explored effects of taxes and bans on retail cigarette prices as well as county smoking prevalence (daily, non-daily). There was wide variation in store-level cigarette prices in part due to differences in state excise taxes. Excise taxes were only partially passed onto consumers (after adjustment, $1 tax associated with $0.90 increase in price, p < 0.0001) and the pass-through was slightly higher in areas that had bans but did not differ by area-level socio demographics. Bans were associated with a slight increase in cigarette price (after adjustment, $0.09 per-pack, p < 0.0001). Taxes and bans were associated with reduction in smoking prevalence and taxes had a stronger association when combined with bans, suggesting a synergistic effect. Given wide variation in store-level prices, and uneven state/county implementation of taxes and bans, more federal policies should be considered. PMID- 28335535 TI - Enterovirus 71 Neutralizing Antibodies Seroepidemiological Research among Children in Guangzhou, China between 2014 and 2015: A Cross-Sectional Study. AB - A hand-foot-mouth disease outbreak occurred in 2014 around Guangdong. The purpose of this study was investigating the status and susceptibility of infectious neutralizing antibodies to enterovirus 71 among children so as to provide scientific evidence for the population immunity level of hand-foot-mouth disease and prepare for enterovirus 71 vaccination implementation. Serum specimens were collected from children in communities from January 2014 to March 2015 in Guangzhou. A total of 197 serum samples from children 1-5 years old were collected for this cross-sectional study via non-probabilistic sampling from the database of Chinese National Science and Technique Major Project. Neutralization activity was measured via micro neutralization test in vitro. The positive rate of enterovirus 71 neutralizing antibodies was 59.4%, whereas the geometric mean titre was 1:12.7. A statistically significant difference in true positive rates was found between different age groups but not between different genders. Being the most susceptible population of hand-foot-mouth disease, children under 3 years of age are more likely to be infected with enterovirus 71, and the immunity of children increases with increasing age. Further cohort studies should be conducted, and measures for prevention and vaccination should be taken. PMID- 28335536 TI - DOA Estimation Based on Real-Valued Cross Correlation Matrix of Coprime Arrays. AB - A fast direction of arrival (DOA) estimation method using a real-valued cross correlation matrix (CCM) of coprime subarrays is proposed. Firstly, real-valued CCM with extended aperture is constructed to obtain the signal subspaces corresponding to the two subarrays. By analysing the relationship between the two subspaces, DOA estimations from the two subarrays are simultaneously obtained with automatic pairing. Finally, unique DOA is determined based on the common results from the two subarrays. Compared to partial spectral search (PSS) method and estimation of signal parameter via rotational invariance (ESPRIT) based method for coprime arrays, the proposed algorithm has lower complexity but achieves better DOA estimation performance and handles more sources. Simulation results verify the effectiveness of the approach. PMID- 28335537 TI - An Effective and Robust Decentralized Target Tracking Scheme in Wireless Camera Sensor Networks. AB - In this paper, we propose an effective and robust decentralized tracking scheme based on the square root cubature information filter (SRCIF) to balance the energy consumption and tracking accuracy in wireless camera sensor networks (WCNs). More specifically, regarding the characteristics and constraints of camera nodes in WCNs, some special mechanisms are put forward and integrated in this tracking scheme. First, a decentralized tracking approach is adopted so that the tracking can be implemented energy-efficiently and steadily. Subsequently, task cluster nodes are dynamically selected by adopting a greedy on-line decision approach based on the defined contribution decision (CD) considering the limited energy of camera nodes. Additionally, we design an efficient cluster head (CH) selection mechanism that casts such selection problem as an optimization problem based on the remaining energy and distance-to-target. Finally, we also perform analysis on the target detection probability when selecting the task cluster nodes and their CH, owing to the directional sensing and observation limitations in field of view (FOV) of camera nodes in WCNs. From simulation results, the proposed tracking scheme shows an obvious improvement in balancing the energy consumption and tracking accuracy over the existing methods. PMID- 28335538 TI - Precise Orbit Solution for Swarm Using Space-Borne GPS Data and Optimized Pseudo Stochastic Pulses. AB - Swarm is a European Space Agency (ESA) project that was launched on 22 November 2013, which consists of three Swarm satellites. Swarm precise orbits are essential to the success of the above project. This study investigates how well Swarm zero-differenced (ZD) reduced-dynamic orbit solutions can be determined using space-borne GPS data and optimized pseudo-stochastic pulses under high ionospheric activity. We choose Swarm space-borne GPS data from 1-25 October 2014, and Swarm reduced-dynamic orbits are obtained. Orbit quality is assessed by GPS phase observation residuals and compared with Precise Science Orbits (PSOs) released by ESA. Results show that pseudo-stochastic pulses with a time interval of 6 min and a priori standard deviation (STD) of 10-2 mm/s in radial (R), along track (T) and cross-track (N) directions are optimized to Swarm ZD reduced dynamic precise orbit determination (POD). During high ionospheric activity, the mean Root Mean Square (RMS) of Swarm GPS phase residuals is at 9-11 mm, Swarm orbit solutions are also compared with Swarm PSOs released by ESA and the accuracy of Swarm orbits can reach 2-4 cm in R, T and N directions. Independent Satellite Laser Ranging (SLR) validation indicates that Swarm reduced-dynamic orbits have an accuracy of 2-4 cm. Swarm-B orbit quality is better than those of Swarm-A and Swarm-C. The Swarm orbits can be applied to the geomagnetic, geoelectric and gravity field recovery. PMID- 28335539 TI - Abundance of Pathogenic Escherichia coli Virulence-Associated Genes in Well and Borehole Water Used for Domestic Purposes in a Peri-Urban Community of South Africa. AB - In the absence of pipe-borne water, many people in Africa, especially in rural communities, depend on alternative water sources such as wells, boreholes and rivers for household and personal hygiene. Poor maintenance and nearby pit latrines, however, lead to microbial pollution of these sources. We evaluated the abundance of Escherichia coli and the prevalence of pathogenic E. coli virulence genes in water from wells, boreholes and a river in a South African peri-urban community. Monthly samples were collected between August 2015 and November 2016. In all, 144 water samples were analysed for E. coli using the Colilert 18 system. Virulence genes (eagg, eaeA, stx1, stx2, flichH7, ST, ipaH, ibeA) were investigated using real-time polymerase chain reaction. Mean E. coli counts ranged between 0 and 443.1 Most Probable Number (MPN)/100 mL of water sample. Overall, 99.3% of samples were positive for at least one virulence gene studied, with flicH7 being the most detected gene (81/140; 57.6%) and the stx2 gene the least detected gene (8/140; 5.7%). Both intestinal and extraintestinal pathogenic E. coli genes were detected. The detection of virulence genes in these water sources suggests the presence of potentially pathogenic E. coli strains and is a public health concern. PMID- 28335540 TI - A Vehicle Steering Recognition System Based on Low-Cost Smartphone Sensors. AB - Recognizing how a vehicle is steered and then alerting drivers in real time is of utmost importance to the vehicle and driver's safety, since fatal accidents are often caused by dangerous vehicle maneuvers, such as rapid turns, fast lane changes, etc. Existing solutions using video or in-vehicle sensors have been employed to identify dangerous vehicle maneuvers, but these methods are subject to the effects of the environmental elements or the hardware is very costly. In the mobile computing era, smartphones have become key tools to develop innovative mobile context-aware systems. In this paper, we present a recognition system for dangerous vehicle steering based on the low-cost sensors found in a smartphone: i.e., the gyroscope and the accelerometer. To identify vehicle steering maneuvers, we focus on the vehicle's angular velocity, which is characterized by gyroscope data from a smartphone mounted in the vehicle. Three steering maneuvers including turns, lane-changes and U-turns are defined, and a vehicle angular velocity matching algorithm based on Fast Dynamic Time Warping (FastDTW) is adopted to recognize the vehicle steering. The results of extensive experiments show that the average accuracy rate of the presented recognition reaches 95%, which implies that the proposed smartphone-based method is suitable for recognizing dangerous vehicle steering maneuvers. PMID- 28335542 TI - The Impact of Bending Stress on the Performance of Giant Magneto-Impedance (GMI) Magnetic Sensors. AB - The flexibility of amorphous Giant Magneto-Impedance (GMI) micro wires makes them easy to use in several magnetic field sensing applications, such as electrical current sensing, where they need to be deformed in order to be aligned with the measured field. The present paper deals with the bending impact, as a parameter of influence of the sensor, on the GMI effect in 100 um Co-rich amorphous wires. Changes in the values of key parameters associated with the GMI effect have been investigated under bending stress. These parameters included the GMI ratio, the intrinsic sensitivity, and the offset at a given bias field. The experimental results have shown that bending the wire resulted in a reduction of GMI ratio and sensitivity. The bending also induced a net change in the offset for the considered bending curvature and the set of used excitation parameters (1 MHz, 1 mA). Furthermore, the field of the maximum impedance, which is generally related to the anisotropy field of the wire, was increased. The reversibility and the repeatability of the bending effect were also evaluated by applying repetitive bending stresses. The observations have actually shown that the behavior of the wire under the bending stress was roughly reversible and repetitive. PMID- 28335541 TI - Effects of Forest Therapy on Depressive Symptoms among Adults: A Systematic Review. AB - This study systematically reviewed forest therapy programs designed to decrease the level of depression among adults and assessed the methodological rigor and scientific evidence quality of existing research studies to guide future studies. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The authors independently screened full-text articles from various databases using the following criteria: (1) intervention studies assessing the effects of forest therapy on depressive symptoms in adults aged 18 years and older; (2) studies including at least one control group or condition; (3) peer-reviewed studies; and (4) been published either in English or Korean before July 2016. The Scottish Intercollegiate Guideline Network measurement tool was used to assess the risk of bias in each trial. In the final sample, 28 articles (English: 13, Korean: 15) were included in the systematic review. We concluded that forest therapy is an emerging and effective intervention for decreasing adults' depression levels. However, the included studies lacked methodological rigor. Future studies assessing the long-term effect of forest therapy on depression using rigorous study designs are needed. PMID- 28335543 TI - Influence of Transportation Noise and Noise Sensitivity on Annoyance: A Cross Sectional Study in South Korea. AB - Environmental noise is known to cause noise annoyance. Since noise annoyance is a subjective indicator, other mediators-such as noise sensitivity-may influence its perception. However, few studies have thus far been conducted on noise annoyance in South Korea that consider noise sensitivity and noise level simultaneously. The aim of this study was to evaluate the correlations between noise sensitivity or noise level and noise annoyance on a large scale in South Korea. This study estimated the level of noise exposure based on a noise map created in 2014; identified and surveyed 1836 subjects using a questionnaire; and assessed the impact of transportation noise and noise sensitivity on noise annoyance. The result showed that noise exposure level and noise sensitivity simultaneously affect noise annoyance, and noise sensitivity has a relatively larger impact on noise annoyance. In conclusion, when study subjects were exposed to a similar level of noise, the level of noise annoyance differed depending on the noise sensitivity of the individual. PMID- 28335544 TI - Combination Effect of Antituberculosis Drugs and Ethanolic Extract of Selected Medicinal Plants against Multi-Drug Resistant Mycobacterium tuberculosis Isolates. AB - Adverse drug reaction and resistance to antituberculosis drugs remain the causes of tuberculosis therapeutic failure. This research aimed to find the combination effect of standard antituberculosis drugs with Hibiscus sabdariffa L., Kaempferia galanga L., and Piper crocatum N.E. Br against multi-drug resistant (MDR) Mycobacterium tuberculosis isolates. Two MDR strains (i.e., isoniazid/ethambutol resistant and rifampicin/streptomycin resistant) of M. tuberculosis were inoculated in Lowenstein-Jensen medium containing a combination of standard antituberculosis drugs and ethanolic extracts of H. sabdariffa calyces, K. galanga rhizomes, and P. crocatum leaves using various concentration combinations of drug and extract. The colony numbers were observed for 8 weeks. The effect of the combination was analyzed using the proportion method which was calculated by the mean percentage of inhibition reduction in a number of colonies on drug extract containing medium compared to extract-free control medium. The results showed that all three plant extracts achieved good combination effects with rifampicin against the rifampicin/streptomycin resistant strain. Antagonistic effects were, however, observed with streptomycin, ethambutol and isoniazid, therefore calling for caution when using these plants in combination with antituberculosis treatment. PMID- 28335545 TI - Reference Values of 14 Serum Trace Elements for Pregnant Chinese Women: A Cross Sectional Study in the China Nutrition and Health Survey 2010-2012. AB - The development of reference values of trace elements is recognized as a fundamental prerequisite for the assessment of trace element nutritional status and health risks. In this study, a total of 1400 pregnant women aged 27.0 +/- 4.5 years were randomly selected from the China Nutrition and Health Survey 2010-2012 (CNHS 2010-2012). The concentrations of 14 serum trace elements were determined by high-resolution inductively coupled plasma mass spectrometry. Reference values were calculated covering the central 95% reference intervals (P2.5-P97.5) after excluding outliers by Dixon's test. The overall reference values of serum trace elements were 131.5 (55.8-265.0 MUg/dL for iron (Fe), 195.5 (107.0-362.4) MUg/dL for copper (Cu), 74.0 (51.8-111.3) MUg/dL for zinc (Zn), 22.3 (14.0-62.0) MUg/dL for rubidium (Rb), 72.2 (39.9-111.6) MUg/L for selenium (Se), 45.9 (23.8-104.3) MUg/L for strontium (Sr), 1.8 (1.2-3.6) MUg/L for molybdenum (Mo), 2.4 (1.2-8.4) MUg/L for manganese (Mn), 1.9 (0.6-9.0) ng/L for lead (Pb), 1.1 (0.3-5.6) ng/L for arsenic (As), 835.6 (219.8-4287.7) ng/L for chromium (Cr), 337.9 (57.0 1130.0) ng/L for cobalt (Co), 193.2 (23.6-2323.1) ng/L for vanadium (V), and 133.7 (72.1-595.1) ng/L for cadmium (Cd). Furthermore, some significant differences in serum trace element reference values were observed between different groupings of age intervals, residences, anthropometric status, and duration of pregnancy. We found that serum Fe, Zn, and Se concentrations significantly decreased, whereas serum Cu, Sr, and Co concentrations elevated progressively compared with reference values of 14 serum trace elements in pregnant Chinese women. The reference values of serum trace elements established could play a key role in the following nutritional status and health risk assessment. PMID- 28335547 TI - Genomic Loads and Genotypes of Respiratory Syncytial Virus: Viral Factors during Lower Respiratory Tract Infection in Chilean Hospitalized Infants. AB - The clinical impact of viral factors (types and viral loads) during respiratory syncytial virus (RSV) infection is still controversial, especially regarding newly described genotypes. In this study, infants with RSV bronchiolitis were recruited to describe the association of these viral factors with severity of infection. RSV antigenic types, genotypes, and viral loads were determined from hospitalized patients at Hospital Roberto del Rio, Santiago, Chile. Cases were characterized by demographic and clinical information, including days of lower respiratory symptoms and severity. A total of 86 patients were included: 49 moderate and 37 severe cases. During 2013, RSV-A was dominant (86%). RSV-B predominated in 2014 (92%). Phylogenetic analyses revealed circulation of GA2, Buenos Aires (BA), and Ontario (ON) genotypes. No association was observed between severity of infection and RSV group (p = 0.69) or genotype (p = 0.87). After a clinical categorization of duration of illness, higher RSV genomic loads were detected in infants evaluated earlier in their disease (p < 0.001) and also in infants evaluated later, but coursing a more severe infection (p = 0.04). Although types and genotypes did not associate with severity in our children, higher RSV genomic loads and delayed viral clearance in severe patients define a group that might benefit from new antiviral therapies. PMID- 28335546 TI - Dietary Protein and Amino Acid Supplementation in Inflammatory Bowel Disease Course: What Impact on the Colonic Mucosa? AB - Inflammatory bowel diseases (IBD), after disease onset, typically progress in two cyclically repeated phases, namely inflammatory flare and remission, with possible nutritional status impairment. Some evidence, either from epidemiological, clinical, and experimental studies indicate that the quantity and the quality of dietary protein consumption and amino acid supplementation may differently influence the IBD course according to the disease phases. For instance, although the dietary protein needs for mucosal healing after an inflammatory episode remain undetermined, there is evidence that amino acids derived from dietary proteins display beneficial effects on this process, serving as building blocks for macromolecule synthesis in the wounded mucosal area, energy substrates, and/or precursors of bioactive metabolites. However, an excessive amount of dietary proteins may result in an increased intestinal production of potentially deleterious bacterial metabolites. This could possibly affect epithelial repair as several of these bacterial metabolites are known to inhibit colonic epithelial cell respiration, cell proliferation, and/or to affect barrier function. In this review, we present the available evidence about the impact of the amount of dietary proteins and supplementary amino acids on IBD onset and progression, with a focus on the effects reported in the colon. PMID- 28335549 TI - Understanding the Fresh Produce Safety Challenges. AB - Consumption of fresh fruits and vegetables is important for a balanced diet and healthy life-style. [...]. PMID- 28335548 TI - Study of Different Variants of Mo Enzyme crARC and the Interaction with Its Partners crCytb5-R and crCytb5-1. AB - The mARC (mitochondrial Amidoxime Reducing Component) proteins are recently discovered molybdenum (Mo) Cofactor containing enzymes. They are involved in the reduction of several N-hydroxylated compounds (NHC) and nitrite. Some NHC are prodrugs containing an amidoxime structure or mutagens such as 6 hydroxylaminopurine (HAP). We have studied this protein in the green alga Chlamydomonas reinhardtii (crARC). Interestingly, all the ARC proteins need the reducing power supplied by other proteins. It is known that crARC requires a cytochrome b5 (crCytb5-1) and a cytochrome b5 reductase (crCytb5-R) that form an electron transport chain from NADH to the substrates. Here, we have investigated NHC reduction by crARC, the interaction with its partners and the function of important conserved amino acids. Interactions among crARC, crCytb5-1 and crCytb5 R have been studied by size-exclusion chromatography. A protein complex between crARC, crCytb5-1 and crCytb5-R was identified. Twelve conserved crARC amino acids have been substituted by alanine by in vitro mutagenesis. We have determined that the amino acids D182, F210 and R276 are essential for NHC reduction activity, R276 is important and F210 is critical for the Mo Cofactor chelation. Finally, the crARC C-termini were shown to be involved in protein aggregation or oligomerization. PMID- 28335550 TI - Preparation of Biodegradable and Elastic Poly(epsilon-caprolactone-co-lactide) Copolymers and Evaluation as a Localized and Sustained Drug Delivery Carrier. AB - To develop a biodegradable polymer possessing elasticity and flexibility, we synthesized MPEG-b-(PCL-co-PLA) copolymers (PCxLyA), which display specific rates of flexibility and elasticity. We synthesize the PCxLyA copolymers by ring opening polymerization of epsilon-caprolactone and l-lactide. PCxLyA copolymers of various compositions were synthesized with 500,000 molecular weight. The PCxLyA copolymers mechanical properties were dependent on the mole ratio of the epsilon-caprolactone and l-lactide components. Cyclic tensile tests were carried out to investigate the resistance to creep of PCxLyA specimens after up to 20 deformation cycles to 50% elongation. After in vivo implantation, the PCxLyA implants exhibited biocompatibility, and gradually biodegraded over an eight-week experimental period. Immunohistochemical characterization showed that the PCxLyA implants provoked in vivo inflammation, which gradually decreased over time. The copolymer was used as a drug carrier for locally implantable drugs, the hydrophobic drug dexamethasone (Dex), and the water-soluble drug dexamethasone 21 phosphate disodium salt (Dex(p)). We monitored drug-loaded PCxLyA films for in vitro and in vivo drug release over 40 days and observed real-time sustained release of near-infrared (NIR) fluorescence over an extended period from hydrophobic IR-780- and hydrophilic IR-783-loaded PCxLyA implanted in live animals. Finally, we confirmed that PCxLyA films are usable as biodegradable, elastic drug carriers. PMID- 28335552 TI - Virological Surveillance of Influenza A Subtypes Isolated in 2014 from Clinical Outbreaks in Canadian Swine. AB - Influenza A viruses (IAVs) are respiratory pathogens associated with an acute respiratory disease that occurs year-round in swine production. It is currently one of the most important pathogens in swine populations, with the potential to infect other host species including humans. Ongoing research indicates that the three major subtypes of IAV-H1N1, H1N2, and H3N2-continue to expand in their genetic and antigenic diversity. In this study, we conducted a comprehensive genomic analysis of 16 IAVs isolated from different clinical outbreaks in Alberta, Manitoba, Ontario, and Saskatchewan in 2014. We also examined the genetic basis for probable antigenic differences among sequenced viruses. On the basis of phylogenetic analysis, all 13 Canadian H3N2 viruses belonged to cluster IV, eight H3N2 viruses were part of the IV-C cluster, and one virus belonged to the IV-B and one to the IV-D cluster. Based on standards used in this study, three H3N2 viruses could not be clearly classified into any currently established group within cluster IV (A to F). Three H1N2 viruses were part of the H1alpha cluster. PMID- 28335551 TI - Molecular Basis for Modulation of Metabotropic Glutamate Receptors and Their Drug Actions by Extracellular Ca2. AB - Metabotropic glutamate receptors (mGluRs) associated with the slow phase of the glutamatergic signaling pathway in neurons of the central nervous system have gained importance as drug targets for chronic neurodegenerative diseases. While extracellular Ca2+ was reported to exhibit direct activation and modulation via an allosteric site, the identification of those binding sites was challenged by weak binding. Herein, we review the discovery of extracellular Ca2+ in regulation of mGluRs, summarize the recent developments in probing Ca2+ binding and its co regulation of the receptor based on structural and biochemical analysis, and discuss the molecular basis for Ca2+ to regulate various classes of drug action as well as its importance as an allosteric modulator in mGluRs. PMID- 28335553 TI - Biosynthesis of Polyunsaturated Fatty Acids in Octopus vulgaris: Molecular Cloning and Functional Characterisation of a Stearoyl-CoA Desaturase and an Elongation of Very Long-Chain Fatty Acid 4 Protein. AB - Polyunsaturated fatty acids (PUFAs) have been acknowledged as essential nutrients for cephalopods but the specific PUFAs that satisfy the physiological requirements are unknown. To expand our previous investigations on characterisation of desaturases and elongases involved in the biosynthesis of PUFAs and hence determine the dietary PUFA requirements in cephalopods, this study aimed to investigate the roles that a stearoyl-CoA desaturase (Scd) and an elongation of very long-chain fatty acid 4 (Elovl4) protein play in the biosynthesis of essential fatty acids (FAs). Our results confirmed the Octopus vulgaris Scd is a ?9 desaturase with relatively high affinity towards saturated FAs with >= C18 chain lengths. Scd was unable to desaturate 20:1n-15 (?520:1) suggesting that its role in the biosynthesis of non-methylene interrupted FAs (NMI FAs) is limited to the introduction of the first unsaturation at ?9 position. Interestingly, the previously characterised ?5 fatty acyl desaturase was indeed able to convert 20:1n-9 (?1120:1) to ?5,1120:2, an NMI FA previously detected in octopus nephridium. Additionally, Elovl4 was able to mediate the production of 24:5n-3 and thus can contribute to docosahexaenoic acid (DHA) biosynthesis through the Sprecher pathway. Moreover, the octopus Elovl4 was confirmed to play a key role in the biosynthesis of very long-chain (>C24) PUFAs. PMID- 28335555 TI - Activity Recognition and Semantic Description for Indoor Mobile Localization. AB - As a result of the rapid development of smartphone-based indoor localization technology, location-based services in indoor spaces have become a topic of interest. However, to date, the rich data resulting from indoor localization and navigation applications have not been fully exploited, which is significant for trajectory correction and advanced indoor map information extraction. In this paper, an integrated location acquisition method utilizing activity recognition and semantic information extraction is proposed for indoor mobile localization. The location acquisition method combines pedestrian dead reckoning (PDR), human activity recognition (HAR) and landmarks to acquire accurate indoor localization information. Considering the problem of initial position determination, a hidden Markov model (HMM) is utilized to infer the user's initial position. To provide an improved service for further applications, the landmarks are further assigned semantic descriptions by detecting the user's activities. The experiments conducted in this study confirm that a high degree of accuracy for a user's indoor location can be obtained. Furthermore, the semantic information of a user's trajectories can be extracted, which is extremely useful for further research into indoor location applications. PMID- 28335554 TI - Complete and Incomplete Hepatitis B Virus Particles: Formation, Function, and Application. AB - Hepatitis B virus (HBV) is a para-retrovirus or retroid virus that contains a double-stranded DNA genome and replicates this DNA via reverse transcription of a RNA pregenome. Viral reverse transcription takes place within a capsid upon packaging of the RNA and the viral reverse transcriptase. A major characteristic of HBV replication is the selection of capsids containing the double-stranded DNA, but not those containing the RNA or the single-stranded DNA replication intermediate, for envelopment during virion secretion. The complete HBV virion particles thus contain an outer envelope, studded with viral envelope proteins, that encloses the capsid, which, in turn, encapsidates the double-stranded DNA genome. Furthermore, HBV morphogenesis is characterized by the release of subviral particles that are several orders of magnitude more abundant than the complete virions. One class of subviral particles are the classical surface antigen particles (Australian antigen) that contain only the viral envelope proteins, whereas the more recently discovered genome-free (empty) virions contain both the envelope and capsid but no genome. In addition, recent evidence suggests that low levels of RNA-containing particles may be released, after all. We will summarize what is currently known about how the complete and incomplete HBV particles are assembled. We will discuss briefly the functions of the subviral particles, which remain largely unknown. Finally, we will explore the utility of the subviral particles, particularly, the potential of empty virions and putative RNA virions as diagnostic markers and the potential of empty virons as a vaccine candidate. PMID- 28335556 TI - Trm5 and TrmD: Two Enzymes from Distinct Origins Catalyze the Identical tRNA Modification, m1G37. AB - The N1-atom of guanosine at position 37 in transfer RNA (tRNA) is methylated by tRNA methyltransferase 5 (Trm5) in eukaryotes and archaea, and by tRNA methyltransferase D (TrmD) in bacteria. The resultant modified nucleotide m1G37 positively regulates the aminoacylation of the tRNA, and simultaneously functions to prevent the +1 frameshift on the ribosome. Interestingly, Trm5 and TrmD have completely distinct origins, and therefore bear different tertiary folds. In this review, we describe the different strategies utilized by Trm5 and TrmD to recognize their substrate tRNAs, mainly based on their crystal structures complexed with substrate tRNAs. PMID- 28335557 TI - ROS Production and ERK Activity Are Involved in the Effects of d-beta Hydroxybutyrate and Metformin in a Glucose Deficient Condition. AB - Hypoglycemia, a complication of insulin or sulfonylurea therapy in diabetic patients, leads to brain damage. Furthermore, glucose replenishment following hypoglycemic coma induces neuronal cell death. In this study, we investigated the molecular mechanism underlying glucose deficiency-induced cytotoxicity and the protective effect of d-beta-hydroxybutyrate (D-BHB) using SH-SY5Y cells. The cytotoxic mechanism of metformin under glucose deficiency was also examined. Cell viability under 1 mM glucose (glucose deficiency) was significantly decreased which was accompanied by increased production of reactive oxygen species (ROS) and decreased phosphorylation of extracellular signal-regulated kinase (ERK) and glycogen synthase 3 (GSK3beta). ROS inhibitor reversed the glucose deficiency induced cytotoxicity and restored the reduced phosphorylation of ERK and GSK3beta. While metformin did not alter cell viability in normal glucose media, it further increased cell death and ROS production under glucose deficiency. However, D-BHB reversed cytotoxicity, ROS production, and the decrease in phosphorylation of ERK and GSK3beta induced by the glucose deficiency. ERK inhibitor reversed the D-BHB-induced increase in cell viability under glucose deficiency, whereas GSK3beta inhibitor did not restore glucose deficiency-induced cytotoxicity. Finally, the protective effect of D-BHB against glucose deficiency was confirmed in primary neuronal cells. We demonstrate that glucose deficiency induced cytotoxicity is mediated by ERK inhibition through ROS production, which is attenuated by D-BHB and intensified by metformin. PMID- 28335558 TI - Modeling the Development of Audiovisual Cue Integration in Speech Perception. AB - Adult speech perception is generally enhanced when information is provided from multiple modalities. In contrast, infants do not appear to benefit from combining auditory and visual speech information early in development. This is true despite the fact that both modalities are important to speech comprehension even at early stages of language acquisition. How then do listeners learn how to process auditory and visual information as part of a unified signal? In the auditory domain, statistical learning processes provide an excellent mechanism for acquiring phonological categories. Is this also true for the more complex problem of acquiring audiovisual correspondences, which require the learner to integrate information from multiple modalities? In this paper, we present simulations using Gaussian mixture models (GMMs) that learn cue weights and combine cues on the basis of their distributional statistics. First, we simulate the developmental process of acquiring phonological categories from auditory and visual cues, asking whether simple statistical learning approaches are sufficient for learning multi-modal representations. Second, we use this time course information to explain audiovisual speech perception in adult perceivers, including cases where auditory and visual input are mismatched. Overall, we find that domain-general statistical learning techniques allow us to model the developmental trajectory of audiovisual cue integration in speech, and in turn, allow us to better understand the mechanisms that give rise to unified percepts based on multiple cues. PMID- 28335559 TI - The Optimization and Characterization of an RNA-Cleaving Fluorogenic DNAzyme Probe for MDA-MB-231 Cell Detection. AB - Breast cancer is one of the most frequently diagnosed cancers in females worldwide and lacks specific biomarkers for early detection. In a previous study, we obtained a selective RNA-cleaving Fluorogenic DNAzyme (RFD) probe against MDA MB-231 cells, typical breast cancer cells, through the systematic evolution of ligands by exponential process (SELEX). To improve the performance of this probe for actual application, we carried out a series of optimization experiments on the pH value of a reaction buffer, the type and concentration of cofactor ions, and sequence minimization. The length of the active domain of the probe reduced to 25 nt from 40 nt after optimization, which was synthesized more easily and economically. The detection limit of the optimized assay system was 2000 MDA-MB 231 cells in 30 min, which is more sensitive than the previous one (almost 5000 cells). The DNAzyme probe was also capable of distinguishing MDA-MB-231 cell specifically from 3 normal cells and 10 other tumor cells. This probe with high sensitivity, selectivity, and economic efficiency enhances the feasibility for further clinical application in breast cancer diagnosis. Herein, we developed an optimization system to produce a general strategy to establish an easy-to-use DNAzyme-based assay for other targets. PMID- 28335561 TI - Optimal Power Allocation of Relay Sensor Node Capable of Energy Harvesting in Cooperative Cognitive Radio Network. AB - A cooperative cognitive radio scheme exploiting primary signals for energy harvesting is proposed. The relay sensor node denoted as the secondary transmitter (ST) harvests energy from the primary signal transmitted from the primary transmitter, and then uses it to transmit power superposed codes of the secrecy signal of the secondary network (SN) and of the primary signal of the primary network (PN). The harvested energy is split into two parts according to a power splitting ratio, one for decoding the primary signal and the other for charging the battery. In power superposition coding, the amount of fractional power allocated to the primary signal is determined by another power allocation parameter (e.g., the power sharing coefficient). Our main concern is to investigate the impact of the two power parameters on the performances of the PN and the SN. Analytical or mathematical expressions of the outage probabilities of the PN and the SN are derived in terms of the power parameters, location of the ST, channel gain, and other system related parameters. A jointly optimal power splitting ratio and power sharing coefficient for achieving target outage probabilities of the PN and the SN, are found using these expressions and validated by simulations. PMID- 28335560 TI - Serum Amyloid A Production Is Triggered by Sleep Deprivation in Mice and Humans: Is That the Link between Sleep Loss and Associated Comorbidities? AB - Serum amyloid A (SAA) was recently associated with metabolic endotoxemia, obesity and insulin resistance. Concurrently, insufficient sleep adversely affects metabolic health and is an independent predisposing factor for obesity and insulin resistance. In this study we investigated whether sleep loss modulates SAA production. The serum SAA concentration increased in C57BL/6 mice subjected to sleep restriction (SR) for 15 days or to paradoxical sleep deprivation (PSD) for 72 h. Sleep restriction also induced the upregulation of Saa1.1/Saa2.1 mRNA levels in the liver and Saa3 mRNA levels in adipose tissue. SAA levels returned to the basal range after 24 h in paradoxical sleep rebound (PSR). Metabolic endotoxemia was also a finding in SR. Increased plasma levels of SAA were also observed in healthy human volunteers subjected to two nights of total sleep deprivation (Total SD), returning to basal levels after one night of recovery. The observed increase in SAA levels may be part of the initial biochemical alterations caused by sleep deprivation, with potential to drive deleterious conditions such as metabolic endotoxemia and weight gain. PMID- 28335562 TI - Virus-Bacteria Interactions: An Emerging Topic in Human Infection. AB - Bacteria and viruses often occupy the same niches, however, interest in their potential collaboration in promoting wellness or disease states has only recently gained traction. While the interaction of some bacteria and viruses is well characterized (e.g., influenza virus), researchers are typically more interested in the location of the infection than the manner of cooperation. There are two overarching types of bacterial-virus disease causing interactions: direct interactions that in some way aid the viruses, and indirect interactions aiding bacteria. The virus-promoting direct interactions occur when the virus exploits a bacterial component to facilitate penetration into the host cell. Conversely, indirect interactions result in increased bacterial pathogenesis as a consequence of viral infection. Enteric viruses mainly utilize the direct pathway, while respiratory viruses largely affect bacteria in an indirect fashion. This review focuses on some key examples of how virus-bacteria interactions impact the infection process across the two organ systems, and provides evidence supporting this as an emerging theme in infectious disease. PMID- 28335563 TI - The Effects of Sweet Foods on the Pharmacokinetics of Glycyrrhizic Acid by icELISA. AB - The effect of sweet foods, such as honey, was investigated from the perspective of pharmacokinetics on the absorption of glycyrrhizic acid (GA). Due to the unique properties of indirect competitive enzyme-linked immunosorbent assay (icELISA), namely, its: specificity, sensitivity, repeatability, simple pretreatment of samples, fast and simple operation, and because it is economic and non-polluting, it has received increased attention. In this study, we used the advantages of this method to see how honey affected the pharmacokinetics of GA. The effects of honey on the pharmacokinetics of GA by ELISA were investigated for the first time. The results indicate that honey can postpone the peak concentration of GA in mouse blood, and this effect correlates well with fructose. As a representative of sweet foods, the result provides the valuable information that honey, or fructose, may act as sustained-releasing drugs in clinical scenarios; and that sweet foods may have some influences on drugs when taken together. PMID- 28335565 TI - An Eco-Safety Assessment of Glyoxal-Containing Cellulose Ether on Freeze-Dried Microbial Strain, Cyanobacteria, Daphnia, and Zebrafish. AB - The objective of this study was to investigate the aquatic-toxic effects of glyoxal-containing cellulose ether with four different glyoxal concentrations (0%, 1.4%, 2.3%, and 6.3%) in response to global chemical regulations, e.g., European Union Classification, Labeling and Packaging (EU CLP). Toxicity tests of glyoxal-containing cellulose ether on 11 different microbial strains, Microcystis aeruginosa, Daphnia magna, and zebrafish embryos were designed as an initial stage of toxicity screening and performed in accordance with standardized toxicity test guidelines. Glyoxal-containing cellulose ether showed no significant toxic effects in the toxicity tests of the 11 freeze-dried microbial strains, Daphnia magna, and zebrafish embryos. Alternatively, 6.3% glyoxal containing cellulose ether led to a more than 60% reduction in Microcystis aeruginosa growth after 7 days of exposure. Approximately 10% of the developmental abnormalities (e.g., bent spine) in zebrafish embryos were also observed in the group exposed to 6.3% glyoxal-containing cellulose ether after 6 days of exposure. These results show that 6.3% less glyoxal-containing cellulose ether has no acute toxic effects on aquatic organisms. However, 6.3% less glyoxal containing cellulose ether may affect the health of aquatic organisms with long term exposure. In order to better evaluate the eco-safety of cellulosic products containing glyoxal, further studies regarding the toxic effects of glyoxal containing cellulose ether with long-term exposure are required. The results from this study allow us to evaluate the aquatic-toxic effects of glyoxal-containing cellulosic products, under EU chemical regulations, on the health of aquatic organisms. PMID- 28335564 TI - Passage through the Ocular Barriers and Beneficial Effects in Retinal Ischemia of Topical Application of PACAP1-38 in Rodents. AB - The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) has two active forms, PACAP1-27 and PACAP1-38. Among the well-established actions are PACAP's neurotrophic and neuroprotective effects, which have also been proven in models of different retinopathies. The route of delivery is usually intravitreal in studies proving PACAP's retinoprotective effects. Recently, we have shown that PACAP1-27 delivered as eye drops in benzalkonium-chloride was able to cross the ocular barriers and exert retinoprotection in ischemia. Since PACAP1-38 is the dominant form of the naturally occurring PACAP, our aim was to investigate whether the longer form is also able to cross the barriers and exert protective effects in permanent bilateral common carotid artery occlusion (BCCAO), a model of retinal hypoperfusion. Our results show that radioactive PACAP1-38 eye drops could effectively pass through the ocular barriers to reach the retina. Routine histological analysis and immunohistochemical evaluation of the Muller glial cells revealed that PACAP1-38 exerted retinoprotective effects. PACAP1-38 attenuated the damage caused by hypoperfusion, apparent in almost all retinal layers, and it decreased the glial cell overactivation. Overall, our results confirm that PACAP1-38 given in the form of eye drops is a novel protective therapeutic approach to treat retinal diseases. PMID- 28335566 TI - Profiling and Preparation of Metabolites from Pyragrel in Human Urine by Online Solid-Phase Extraction Coupled with High Performance Liquid Chromatography Tandem Mass Spectrometry Followed by a Macroporous Resin-Based Purification Approach. AB - Pyragrel, a new anticoagulant drug, is derived from the molecular combination of ligustrazine and ferulic acid. Pyragrel showed significant inhibitory activity against platelet aggregation induced by adenosine diphosphate (ADP), and had been approved for a phase I clinical trial by CFDA. To characterize the metabolites of Pyragrel in human urine after intravenous administration, a reliable online solid phase extraction couple with high performance liquid chromatography tandem mass spectrometry (online SPE-HPLC-MSn) method was conceived and applied. Five metabolites were detected and tentatively identified, which suggested that the major metabolic pathways of Pyragrel in human were double-bond reduction, double bond oxidation, and then followed by glucuronide conjugation. Two main metabolites were then prepared using beta-glucuronide hydrolysis and macroporous resin purification approach followed by preparative high-performance liquid chromatography (PHPLC) method, with their structures confirmed on the basis of nuclear magnetic resonance (NMR) data. This study provided information for the further study of the metabolism and excretion of Pyragrel. PMID- 28335568 TI - An Electricity Price-Aware Open-Source Smart Socket for the Internet of Energy. AB - The Internet of Energy (IoE) represents a novel paradigm where electrical power systems work cooperatively with smart devices to increase the visibility of energy consumption and create safer, cleaner and sustainable energy systems. The implementation of IoE services involves the use of multiple components, like embedded systems, power electronics or sensors, which are an essential part of the infrastructure dedicated to the generation and distribution energy and the one required by the final consumer. This article focuses on the latter and presents a smart socket system that collects the information about energy price and makes use of sensors and actuators to optimize home energy consumption according to the user preferences. Specifically, this article provides three main novel contributions. First, what to our knowledge is the first hardware prototype that manages in a practical real-world scenario the price values obtained from a public electricity operator is presented. The second contribution is related to the definition of a novel wireless sensor network communications protocol based on Wi-Fi that allows for creating an easy-to-deploy smart plug system that self organizes and auto-configures to collect the sensed data, minimizing user intervention. Third, it is provided a thorough description of the design of one of the few open-source smart plug systems, including its communications architecture, the protocols implemented, the main sensing and actuation components and the most relevant pieces of the software. Moreover, with the aim of illustrating the capabilities of the smart plug system, the results of different experiments performed are shown. Such experiments evaluate in real world scenarios the system's ease of use, its communications range and its performance when using HTTPS. Finally, the economic savings are estimated for different appliances, concluding that, in the practical situation proposed, the smart plug system allows certain energy-demanding appliances to save almost ?70 per year. PMID- 28335569 TI - A Quantitative Risk Assessment Model Involving Frequency and Threat Degree under Line-of-Business Services for Infrastructure of Emerging Sensor Networks. AB - The prospect of Line-of-Business Services (LoBSs) for infrastructure of Emerging Sensor Networks (ESNs) is exciting. Access control remains a top challenge in this scenario as the service provider's server contains a lot of valuable resources. LoBSs' users are very diverse as they may come from a wide range of locations with vastly different characteristics. Cost of joining could be low and in many cases, intruders are eligible users conducting malicious actions. As a result, user access should be adjusted dynamically. Assessing LoBSs' risk dynamically based on both frequency and threat degree of malicious operations is therefore necessary. In this paper, we proposed a Quantitative Risk Assessment Model (QRAM) involving frequency and threat degree based on value at risk. To quantify the threat degree as an elementary intrusion effort, we amend the influence coefficient of risk indexes in the network security situation assessment model. To quantify threat frequency as intrusion trace effort, we make use of multiple behavior information fusion. Under the influence of intrusion trace, we adapt the historical simulation method of value at risk to dynamically access LoBSs' risk. Simulation based on existing data is used to select appropriate parameters for QRAM. Our simulation results show that the duration influence on elementary intrusion effort is reasonable when the normalized parameter is 1000. Likewise, the time window of intrusion trace and the weight between objective risk and subjective risk can be set to 10 s and 0.5, respectively. While our focus is to develop QRAM for assessing the risk of LoBSs for infrastructure of ESNs dynamically involving frequency and threat degree, we believe it is also appropriate for other scenarios in cloud computing. PMID- 28335570 TI - An Improved Multi-Sensor Fusion Navigation Algorithm Based on the Factor Graph. AB - An integrated navigation system coupled with additional sensors can be used in the Micro Unmanned Aerial Vehicle (MUAV) applications because the multi-sensor information is redundant and complementary, which can markedly improve the system accuracy. How to deal with the information gathered from different sensors efficiently is an important problem. The fact that different sensors provide measurements asynchronously may complicate the processing of these measurements. In addition, the output signals of some sensors appear to have a non-linear character. In order to incorporate these measurements and calculate a navigation solution in real time, the multi-sensor fusion algorithm based on factor graph is proposed. The global optimum solution is factorized according to the chain structure of the factor graph, which allows for a more general form of the conditional probability density. It can convert the fusion matter into connecting factors defined by these measurements to the graph without considering the relationship between the sensor update frequency and the fusion period. An experimental MUAV system has been built and some experiments have been performed to prove the effectiveness of the proposed method. PMID- 28335567 TI - Cross-Regulation between Transposable Elements and Host DNA Replication. AB - Transposable elements subvert host cellular functions to ensure their survival. Their interaction with the host DNA replication machinery indicates that selective pressures lead them to develop ancestral and convergent evolutionary adaptations aimed at conserved features of this fundamental process. These interactions can shape the co-evolution of the transposons and their hosts. PMID- 28335571 TI - 3-Substituted N-Benzylpyrazine-2-carboxamide Derivatives: Synthesis, Antimycobacterial and Antibacterial Evaluation. AB - A series of substituted N-benzyl-3-chloropyrazine-2-carboxamides were prepared as positional isomers of 5-chloro and 6-chloro derivatives, prepared previously. During the aminolysis of the acyl chloride, the simultaneous substitution of chlorine with benzylamino moiety gave rise to N-benzyl-3-(benzylamino)pyrazine-2 carboxamides as side products, in some cases. Although not initially planned, the reaction conditions were modified to populate this double substituted series. The final compounds were tested against four mycobacterial strains. N-(2 methylbenzyl)-3-((2-methylbenzyl)amino)pyrazine-2-carboxamide (1a) and N-(3,4 dichlorobenzyl)-3-((3,4-dichlorobenzyl)amino)pyrazine-2-carboxamide (9a) proved to be the most effective against Mycobacterium tuberculosis H37Rv, with MIC = 12.5 MUg.mL-1. Compounds were screened for antibacterial activity. The most active compound was 3-chloro-N-(2-chlorobenzyl)pyrazine-2-carboxamide (5) against Staphylococcus aureus with MIC = 7.81 MUM, and Staphylococcus epidermidis with MIC = 15.62 MUM. HepG2 in vitro cytotoxicity was evaluated for the most active compounds; however, no significant toxicity was detected. Compound 9a was docked to several conformations of the enoyl-ACP-reductase of Mycobacterium tuberculosis. In some cases, it was capable of H-bond interactions, typical for most of the known inhibitors. PMID- 28335572 TI - Efficient and Security Enhanced Anonymous Authentication with Key Agreement Scheme in Wireless Sensor Networks. AB - At present, users can utilize an authenticated key agreement protocol in a Wireless Sensor Network (WSN) to securely obtain desired information, and numerous studies have investigated authentication techniques to construct efficient, robust WSNs. Chang et al. recently presented an authenticated key agreement mechanism for WSNs and claimed that their authentication mechanism can both prevent various types of attacks, as well as preserve security properties. However, we have discovered that Chang et al's method possesses some security weaknesses. First, their mechanism cannot guarantee protection against a password guessing attack, user impersonation attack or session key compromise. Second, the mechanism results in a high load on the gateway node because the gateway node should always maintain the verifier tables. Third, there is no session key verification process in the authentication phase. To this end, we describe how the previously-stated weaknesses occur and propose a security-enhanced version for WSNs. We present a detailed analysis of the security and performance of our authenticated key agreement mechanism, which not only enhances security compared to that of related schemes, but also takes efficiency into consideration. PMID- 28335573 TI - Ultratrace Detection of Histamine Using a Molecularly-Imprinted Polymer-Based Voltammetric Sensor. AB - Rapid and cost-effective analysis of histamine, in food, environmental, and diagnostics research has been of interest recently. However, for certain applications, the already-existing biological receptor-based sensing methods have usage limits in terms of stability and costs. As a result, robust and cost effective imprinted polymeric receptors can be the best alternative. In the present work, molecularly-imprinted polymers (MIPs) for histamine were synthesized using methacrylic acid in chloroform and acetonitrile as two different porogens. The binding affinity of the MIPs with histamine was evaluated in aqueous media. MIPs synthesized in chloroform displayed better imprinting properties for histamine. We demonstrate here histamine MIPs incorporated into a carbon paste (CP) electrode as a MIP-CP electrode sensor platforms for detection of histamine. This simple sensor format allows accurate determination of histamine in the sub-nanomolar range using an electrochemical method. The sensor exhibited two distinct linear response ranges of 1 * 10-10-7 * 10-9 M and 7 * 10 9-4 * 10-7 M. The detection limit of the sensor was calculated equal to 7.4 * 10 11 M. The specificity of the proposed electrode for histamine is demonstrated by using the analogous molecules and other neurotransmitters such as serotonin, dopamine, etc. The MIP sensor was investigated with success on spiked serum samples. The easy preparation, simple procedure, and low production cost make the MIP sensor attractive for selective and sensitive detection of analytes, even in less-equipped laboratories with minimal training. PMID- 28335574 TI - Proof of Concept: Development of Snow Liquid Water Content Profiler Using CS650 Reflectometers at Caribou, ME, USA. AB - The quantity of liquid water in the snowpack defines its wetness. The temporal evolution of snow wetness's plays a significant role in wet-snow avalanche prediction, meltwater release, and water availability estimations and assessments within a river basin. However, it remains a difficult task and a demanding issue to measure the snowpack's liquid water content (LWC) and its temporal evolution with conventional in situ techniques. We propose an approach based on the use of time-domain reflectometry (TDR) and CS650 soil water content reflectometers to measure the snowpack's LWC and temperature profiles. For this purpose, we created an easily-applicable, low-cost, automated, and continuous LWC profiling instrument using reflectometers at the Cooperative Remote Sensing Science and Technology Center-Snow Analysis and Field Experiment (CREST-SAFE) in Caribou, ME, USA, and tested it during the snow melt period (February-April) immediately after installation in 2014. Snow Thermal Model (SNTHERM) LWC simulations forced with CREST-SAFE meteorological data were used to evaluate the accuracy of the instrument. Results showed overall good agreement, but clearly indicated inaccuracy under wet snow conditions. For this reason, we present two (for dry and wet snow) statistical relationships between snow LWC and dielectric permittivity similar to Topp's equation for the LWC of mineral soils. These equations were validated using CREST-SAFE in situ data from winter 2015. Results displayed high agreement when compared to LWC estimates obtained using empirical formulas developed in previous studies, and minor improvement over wet snow LWC estimates. Additionally, the equations seemed to be able to capture the snowpack state (i.e., onset of melt, medium, and maximum saturation). Lastly, field test results show advantages, such as: automated, continuous measurements, the temperature profiling of the snowpack, and the possible categorization of its state. However, future work should focus on improving the instrument's capability to measure the snowpack's LWC profile by properly calibrating it with in situ LWC measurements. Acceptable validation agreement indicates that the developed snow LWC, temperature, and wetness profiler offers a promising new tool for snow hydrology research. PMID- 28335575 TI - Public Preferences for the Use of Taxation and Labelling Policy Measures to Combat Obesity in Young Children in Australia. AB - Objective: Childhood obesity is a serious concern for developed and developing countries. This study aimed to assess the level of support in Australia for regulation and to assess whether systematic differences occur between individuals who support increased regulation and individuals who oppose it. Methods: An online survey (n = 563) was used to assess parental/caregiver preferences for taxation policy options and nutrition labelling designed to address the incidence of childhood obesity. Participants were parents or caregivers of young children (3 to 7 years) who were actively enrolled in an existing birth cohort study in South-East Queensland, Australia. Results: The majority of the parents (over 80%) strongly agreed or agreed with labelling food and drink with traffic light or teaspoon labelling. Support for taxation was more variable with around one third strongly supporting and a further 40% of participants equivocal about using taxation; however, a quarter strongly rejected this policy. Cluster analysis did not detect any socio-demographic differences between those who strongly supported taxation and those who did not. Conclusions: Better food labelling would be welcomed by parents to enhance food choices for their children. Taxation for health reasons would not be opposed by most parents. Implications for Public Health: Governments should consider taxation of unhealthy drinks and improved labelling to encourage healthy food purchasing. PMID- 28335577 TI - GC-MS Metabolomic Analysis to Reveal the Metabolites and Biological Pathways Involved in the Developmental Stages and Tissue Response of Panax ginseng. AB - Ginsenosides, the major compounds present in ginseng, are known to have numerous physiological and pharmacological effects. The physiological processes, enzymes and genes involved in ginsenoside synthesis in P. ginseng have been well characterized. However, relatively little information is known about the dynamic metabolic changes that occur during ginsenoside accumulation in ginseng. To explore this topic, we isolated metabolites from different tissues at different growth stages, and identified and characterized them by using gas chromatography coupled with mass spectrometry (GC-MS). The results showed that a total of 30, 16, 20, 36 and 31 metabolites were identified and involved in different developmental stages in leaf, stem, petiole, lateral root and main root, respectively. To investigate the contribution of tissue to the biosynthesis of ginsenosides, we examined the metabolic changes of leaf, stem, petiole, lateral root and main root during five development stages: 1-, 2-, 3-, 4- and 5-years. The score plots of partial least squares-discriminate analysis (PLS-DA) showed clear discrimination between growth stages and tissue samples. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis in the same tissue at different growth stages indicated profound biochemical changes in several pathways, including carbohydrate metabolism and pentose phosphate metabolism, in addition, the tissues displayed significant variations in amino acid metabolism, sugar metabolism and energy metabolism. These results should facilitate further dissection of the metabolic flux regulation of ginsenoside accumulation in different developmental stages or different tissues of ginseng. PMID- 28335576 TI - Genome-Wide Identification and Evolutionary Analysis of Sarcocystis neurona Protein Kinases. AB - The apicomplexan parasite Sarcocystis neurona causes equine protozoal myeloencephalitis (EPM), a degenerative neurological disease of horses. Due to its host range expansion, S. neurona is an emerging threat that requires close monitoring. In apicomplexans, protein kinases (PKs) have been implicated in a myriad of critical functions, such as host cell invasion, cell cycle progression and host immune response evasion. Here, we used various bioinformatics methods to define the kinome of S. neurona and phylogenetic relatedness of its PKs to other apicomplexans. We identified 97 putative PKs clustering within the various eukaryotic kinase groups. Although containing the universally-conserved PKA (AGC group), S. neurona kinome was devoid of PKB and PKC. Moreover, the kinome contains the six-conserved apicomplexan CDPKs (CAMK group). Several OPK atypical kinases, including ROPKs 19A, 27, 30, 33, 35 and 37 were identified. Notably, S. neurona is devoid of the virulence-associated ROPKs 5, 6, 18 and 38, as well as the Alpha and RIO kinases. Two out of the three S. neurona CK1 enzymes had high sequence similarities to Toxoplasma gondii TgCK1-alpha and TgCK1-beta and the Plasmodium PfCK1. Further experimental studies on the S. neurona putative PKs identified in this study are required to validate the functional roles of the PKs and to understand their involvement in mechanisms that regulate various cellular processes and host-parasite interactions. Given the essentiality of apicomplexan PKs in the survival of apicomplexans, the current study offers a platform for future development of novel therapeutics for EPM, for instance via application of PK inhibitors to block parasite invasion and development in their host. PMID- 28335579 TI - Application of a MEMS-Based TRNG in a Chaotic Stream Cipher. AB - In this work, we used a sensor-based True Random Number Generator in order to generate keys for a stream cipher based on a recently published hybrid algorithm mixing Skew Tent Map and a Linear Feedback Shift Register. The stream cipher was implemented and tested in a Field Programmable Gate Array (FPGA) and was able to generate 8-bit width data streams at a clock frequency of 134 MHz, which is fast enough for Gigabit Ethernet applications. An exhaustive cryptanalysis was completed, allowing us to conclude that the system is secure. The stream cipher was compared with other chaotic stream ciphers implemented on similar platforms in terms of area, power consumption, and throughput. PMID- 28335578 TI - Exploring the Antitumor Mechanism of High-Dose Cytarabine through the Metabolic Perturbations of Ribonucleotide and Deoxyribonucleotide in Human Promyelocytic Leukemia HL-60 Cells. AB - Despite the apparent clinical benefits of high-dose cytarabine (Ara-C) over lower dose Ara-C in acute myeloid leukemia (AML) therapy, the mechanism behind high dose Ara-C therapy remains uncertain. In this study, a LC-MS-based method was carried out to investigate the metabolic alteration of ribonucleotide and deoxyribonucleotide in human promyelocytic leukemia cells (HL-60) after treatment with Ara-C to reveal its antitumor mechanism. The metabolic results revealed that four nucleotides (ATP, ADP, CDP, and dCTP) could be used as potential biomarkers indicating the benefit of high-dose Ara-C over lower dose Ara-C treatment. Combining metabolic perturbation and cell cycle analysis, we conjectured that, apart from the acknowledged mechanism of Ara-C on tumor inhibition, high-dose Ara C could present a specific action pathway. It was suggested that the pronounced rise in AMP/ATP ratio induced by high-dose Ara-C can trigger AMP-activated protein kinase (AMPK) and subsequently Forkhead Box, class O (FoxO), to promote cell cycle arrest. Moreover, the significant decrease in CDP pool induced by high dose Ara-C might further accelerate the reduction of dCTP, which then aggravates DNA synthesis disturbance. As a result, all of these alterations led to heightened tumor inhibition. This study provides new insight in the investigation of potential mechanisms in the clinical benefits of high-dose Ara-C in therapy for AML. PMID- 28335580 TI - The Development of Psychiatric Services Providing an Alternative to Full-Time Hospitalization Is Associated with Shorter Length of Stay in French Public Psychiatry. AB - International recommendations for mental health care have advocated for a reduction in the length of stay (LOS) in full-time hospitalization and the development of alternatives to full-time hospitalizations (AFTH) could facilitate alignment with those recommendations. Our objective was therefore to assess whether the development of AFTH in French psychiatric sectors was associated with a reduction in the LOS in full-time hospitalization. Using data from the French national discharge database of psychiatric care, we computed the LOS of patients admitted for full-time hospitalization. The level of development of AFTH was estimated by the share of human resources allocated to those alternatives in the hospital enrolling the staff of each sector. Multi-level modelling was carried out to adjust the analysis on other factors potentially associated with the LOS (patients', psychiatric sectors' and environmental characteristics). We observed considerable variations in the LOS between sectors. Although the majority of these variations resulted from patients' characteristics, a significant negative association was found between the LOS and the development of AFTH, after adjusting for other factors. Our results provide first evidence of the impact of the development of AFTH on mental health care and will provide a lever for policy makers to further develop these alternatives. PMID- 28335581 TI - Biosynthesis of Oligomeric Anthocyanins from Grape Skin Extracts. AB - We synthesized oligomeric anthocyanins from grape skin-derived monomeric anthocyanins such as anthocyanidin and proanthocyanidin by a fermentation technique using Aspergillus niger, crude enzymes and glucosidase. The biosyntheses of the oligomeric anthocyanins carried out by the conventional method using Aspergillus niger and crude enzymes were confirmed by ESI-MS. The molecular weight of the synthesized anthocyanin oligomers was determined using MALDI-MS. The yield of anthocyanin oligomers using crude enzymes was higher than that of the synthesis using Aspergillus fermentation. Several studies have been demonstrated that oligomeric anthocyanins have higher antioxidant activity than monomeric anthocyanins. Fermentation-based synthesis of oligomeric anthocyanins is an alternative way of producing useful anthocyanins that could support the food industry. PMID- 28335582 TI - Nonradiative Relaxation Mechanisms of UV Excited Phenylalanine Residues: A Comparative Computational Study. AB - The present work is directed toward understanding the mechanisms of excited state deactivation in three neutral model peptides containing the phenylalanine residue. The excited state dynamics of thegammaL(g+)folded form of N acetylphenylalaninylamide (NAPA B) and its amide-N-methylated derivative (NAPMA B) is reviewed and compared to the dynamics of the monohydrated structure of NAPA (NAPAH). The goal is to unravel how the environment, and in particular solvation, impacts the photodynamics of peptides. The systems are investigated using reaction path calculations and surface hopping nonadiabatic dynamics based on the coupled cluster doubles (CC2) method and time-dependent density functional theory. The work emphasizes the role that excitation transfer from the phenylpipi*to amidenpi*state plays in the deactivation of the three systems and shows how the ease of out-of-plane distortions of the amide group determines the rate of population transfer between the two electronic states. The subsequent dynamics on thenpi*state is barrierless along several pathways and leads to fast deactivation to the ground electronic state. PMID- 28335583 TI - Is Accessibility to Dental Care Facilities in Rural Areas Associated with Number of Teeth in Elderly Residents? AB - Given that public transportation networks are less developed in rural than in urban areas, a lack of accessibility to dental care facilities could be a barrier to routine dental checkups. Thus, we hypothesized that the distance to the dental care facilities is a risk factor for tooth loss. The aim of this study was to test whether there is an association between the distance to dental care facilities, estimated by geographic information systems, and number of teeth, assessed by an oral examination, among elderly residents of a rural area in Japan. Data were collected in 2016 from a cross-sectional study conducted in Shimane prefecture, Japan. After excluding participants with missing data (n = 21), we analyzed data from 710 participants. Of them, 40.6% were male and the mean (standard deviation) age was 67.4 (7.4) years. Further, 68.0% (n = 483) had at least 20 teeth. We found that the distance to dental care facilities was significantly associated with the number of teeth (less than 20) (odds ratio = 1.07, 95% confidence interval = 1.01-1.12) after adjustment for potential confounders. This result suggested that individuals without easy access to dental care facilities may be important targets for dental care. PMID- 28335586 TI - Can Characteristic Mri Brain Substitute Invasive Lumbar Puncture Search For 14-3 3 Immunoassay For Creutzfeldt Jakob Disease? Suggestions From A Case Study PMID- 28335585 TI - Anisotropic Magnetoresistance of Nano-conductive Filament in Co/HfO2/Pt Resistive Switching Memory. AB - Conductive bridge random access memory (CBRAM) has been extensively studied as a next-generation non-volatile memory. The conductive filament (CF) shows rich physical effects such as conductance quantization and magnetic effect. But so far, the study of filaments is not very sufficient. In this work, Co/HfO2/Pt CBRAM device with magnetic CF was designed and fabricated. By electrical manipulation with a partial-RESET method, we controlled the size of ferromagnetic metal filament. The resistance-temperature characteristics of the ON-state after various partial-RESET behaviors have been studied. Using two kinds of magnetic measurement methods, we measured the anisotropic magnetoresistance (AMR) of the CF at different temperatures to reflect the magnetic structure characteristics. By rotating the direction of the magnetic field and by sweeping the magnitude, we obtained the spatial direction as well as the easy-axis of the CF. The results indicate that the easy-axis of the CF is along the direction perpendicular to the top electrode plane. The maximum magnetoresistance was found to appear when the angle between the direction of magnetic field and that of the electric current in the CF is about 30 degrees , and this angle varies slightly with temperature, indicating that the current is tilted. PMID- 28335584 TI - ATRAP Expression in Brown Adipose Tissue Does Not Influence the Development of Diet-Induced Metabolic Disorders in Mice. AB - Activation of tissue renin-angiotensin system (RAS), mainly mediated by an angiotensin II (Ang II) type 1 receptor (AT1R), plays an important role in the development of obesity-related metabolic disorders. We have shown that AT1R associated protein (ATRAP), a specific binding protein of AT1R, functions as an endogenous inhibitor to prevent excessive activation of tissue RAS. In the present study, we newly generated ATRAP/Agtrap-floxed (ATRAPfl/fl) mice and adipose tissue-specific ATRAP downregulated (ATRAPadipoq) mice by the Cre/loxP system using Adipoq-Cre. Using these mice, we examined the functional role of adipose ATRAP in the pathogenesis of obesity-related metabolic disorders. Compared with ATRAPfl/fl mice, ATRAPadipoq mice exhibited a decreased ATRAP expression in visceral white adipose tissue (WAT) and brown adipose tissue (BAT) by approximately 30% and 85%, respectively. When mice were fed a high-fat diet, ATRAPfl/fl mice showed decreased endogenous ATRAP expression in WAT that was equivalent to ATRAPadipoq mice, and there was no difference in the exacerbation of dietary obesity and glucose and lipid metabolism. These results indicate that ATRAP in BAT does not influence the pathogenesis of dietary obesity or metabolic disorders. Future studies that modulate ATRAP in WAT are necessary to assess its in vivo functions in the development of obesity-related metabolic disorders. PMID- 28335587 TI - Neuronatin Is Associated with an Anti-Inflammatory Role in the White Adipose Tissue. AB - Neuronatin (NNAT) is known to regulate ion channels during brain development and plays a role in maintaining the structure of the nervous system. A previous in silico analysis showed that Nnat was overexpressed in the adipose tissue of an obese rodent model relative to the wild type. Therefore, the aim of the present study was to investigate the function of Nnat in the adipose tissue. Because obesity is known to systemically induce low-grade inflammation, the Nnat expression level was examined in the adipose tissue obtained from C57BL/6 mice administered lipopolysaccharide (LPS). Unexpectedly, the Nnat expression level decreased in the white adipose tissue after LPS administration. To determine the role of NNAT in inflammation, 3T3-L1 cells overexpressing Nnat were treated with LPS. The level of the p65 subunit of nuclear factor-kappa B (NF-kappaB) and the activity of NF-kappaB luciferase decreased following LPS treatment. These results indicate that NNAT plays an anti-inflammatory role in the adipose tissue. PMID- 28335588 TI - Recovery of NK(CD56+CD3-) Cells after One Year of Tenofovir Therapy for Chronic Hepatitis B Infection. AB - Natural killer (NK) cells have been reported to be dysfunctional in chronic hepatitis B (CHB) infection. However, the functional recovery of NK cells under antiviral therapeutic agents in CHB was not clearly understood. In this study, we investigated the phenotypic changes of NK(CD56+CD3-) cells in terms of their functional markers (CD16, NKG2A, NKG2D) during tenofovir therapy in CHB. The frequency of NK(CD56+CD3-) cells in CHB patients was significantly increased after 12 months of tenofovir therapy when compared with baseline. The expression levels of CD16+/CD56+CD3- and NKG2A+/CD56+CD3- cells were also affected by tenofovir treatment. In addition, there was a positive correlation between the proportion of NK(CD56+CD3-) cells and HBV DNA (log copies/ml) in CHB patients. PMID- 28335589 TI - Global Functional Analysis of Butanol-Sensitive Escherichia coli and Its Evolved Butanol-Tolerant Strain. AB - Butanol is a promising alternative to ethanol and is desirable for use in transportation fuels and additives to gasoline and diesel fuels. Microbial production of butanol is challenging primarily because of its toxicity and low titer of production. Herein, we compared the transcriptome and phenome of wild type Escherichia coli and its butanol-tolerant evolved strain to understand the global cellular physiology and metabolism responsible for butanol tolerance. When the ancestral butanol-sensitive E. coli was exposed to butanol, gene activities involved in respiratory mechanisms and oxidative stress were highly perturbed. Intriguingly, the evolved butanol-tolerant strain behaved similarly in both the absence and presence of butanol. Among the mutations occurring in the evolved strain, cis-regulatory mutations may be the cause of butanol tolerance. This study provides a foundation for the rational design of the metabolic and regulatory pathways for enhanced biofuel production. PMID- 28335590 TI - Roles of Budding Yeast Hrr25 in Recombination and Sporulation. AB - Hrr25, a casein kinase 1 delta/epsilon homolog in budding yeast, is essential to set up mono-orientation of sister kinetochores during meiosis. Hrr25 kinase activity coordinates sister chromatid cohesion via cohesin phosphorylation. Here, we investigated the prophase role of Hrr25 using the auxin-inducible degron system and by ectopic expression of Hrr25 during yeast meiosis. Hrr25 mediates nuclear division in meiosis I but does not affect DNA replication. We also found that initiation of meiotic double-strand breaks as well as joint molecule formation were normal in HRR25-deficient cells. Thus, Hrr25 is essential for termination of meiotic division but not homologous recombination. PMID- 28335591 TI - Heteroatom-Doped Perihexacene from a Double Helicene Precursor: On-Surface Synthesis and Properties. AB - We report on the surface-assisted synthesis and spectroscopic characterization of the hitherto longest periacene analogue with oxygen-boron-oxygen (OBO) segments along the zigzag edges, that is, a heteroatom-doped perihexacene 1. Surface catalyzed cyclodehydrogenation successfully transformed the double helicene precursor 2, i.e., 12a,26a-dibora-12,13,26,27-tetraoxa-benzo[1,2,3-hi:4,5,6 h'i']dihexacene, into the planar perihexacene analogue 1, which was visualized by scanning tunneling microscopy and noncontact atomic force microscopy. X-ray photoelectron spectroscopy, Raman spectroscopy, together with theoretical modeling, on both precursor 2 and product 1, provided further insights into the cyclodehydrogenation process. Moreover, the nonplanar precursor 2 underwent a conformational change upon adsorption on surfaces, and one-dimensional self assembled superstructures were observed for both 2 and 1 due to the presence of OBO units along the zigzag edges. PMID- 28335592 TI - Air- and Light-Stable P4 and As4 within an Anion-Coordination-Based Tetrahedral Cage. AB - In contrast to the stable dinitrogen molecule, white phosphorus (P4) and yellow arsenic (As4) are very reactive allotropic modifications of these two heavier pnictogen elements, which has greatly hampered the study of their properties and applications. Thus, the safe storage and transport of them is imperative. Supramolecular caged structures are one of the most efficient approaches for the encapsulation and stabilization of reactive species; however, their use in the P4 and As4 chemistry is very rare. In the current work, we demonstrate a new design strategy for constructing finite cages and including guests based on anion coordination chemistry. The phosphate-coordination-based tetrahedral cages can readily accommodate the tetrahedral guests P4 and As4, which is facilitated by the shape and size complementarity as well as favorable sigma-pi and lone-pair-pi interactions. Moreover, the latter case represents the first example of As4 inclusion in a well-defined tetrahedral cage. PMID- 28335593 TI - Simultaneous Single-Cell Analysis of Na+, K+, Ca2+, and Mg2+ in Neuron-Like PC-12 Cells in a Microfluidic System. AB - Various intracellular metal ions have closely related functional roles in the nervous system. An excess or deficiency of essential metal ions can contribute to neurodegenerative diseases. Thus, the detection of various metal ions in neurons is important for diagnosing and monitoring these diseases. In particular, single cell analysis of multiple metal ions allows us to not only understand the cellular heterogeneity and differentiation but also determine the actual relationships among multiple metal ions in each individual cell. Aiming at the low efficient single-cell manipulation and interference of complex biological matrices within cells in the existing method for single-cell metal ion detection, in this manuscript, we present a convenient, sensitive, and reliable method to simultaneously identify and quantify multiple metal ions at the single-cell level using a microfluidic system. Using the combination of on-chip electrophoresis separation and multicolor fluorescence detection, we achieved the simultaneous analysis of Na+, K+, Ca2+, and Mg2+ in single PC-12 cells and studied changes in these four metal ions in Abeta25-35-treated PC-12 cells, which is a model of Alzheimer's disease (AD). The data showed that metal ions imbalances in neuron like cells may be associated with AD induced by Abeta25-35. This method paves the way for multiple metal ion detection in single neuron-like cells, and the results provide insights regarding synergistic function of multiple metal ions in regulation of neurological diseases at the single-cell level. PMID- 28335595 TI - Ligand-Exchange Dynamics on Gold Nanocrystals: Direct Monitoring of Nanoscale Polyvinylpyrrolidone-Thiol Domain Surface Morphology. AB - We report direct high-resolution monitoring of an evolving mixed nanodomain surface morphology during thiol adsorption on polyvinylpyrrolidone (PVP) stabilized single crystal gold nanocrystals. The thiol adsorption and replacement dynamics are much more complex than a simple complete substitution of the initial polymer ligand. We observed that during ligand exchange with linear thiol, the nanocrystal surface evolved from an initial 1 nm uniform PVP coating into a remarkably stable network of globular PVP domains 20-100 nm in size and ~4 nm in height surrounded by thiol self-assembled monolayers. The final stability of such a mixed thiol-PVP surface morphology can possibly be attributed to the interfacial energy reduction from partially solvophilic surfaces and the entropic gain from mixed ligand surface layers. The ligand-exchange dynamics and the unusual equilibrium morphology revealed here provide important insights into both displacement dynamics of surface-bound molecules and the nanoscale peculiarities of surface functionalization of colloidal metal substrates. PMID- 28335594 TI - Skeletal Transformation of a Classical Fullerene C88 into a Nonclassical Fullerene Chloride C84Cl30 Bearing Quaternary Sequentially Fused Pentagons. AB - A classical fullerene is composed of hexagons and pentagons only, and its stability is generally determined by the Isolated-Pentagon-Rule (IPR). Herein, high-temperature chlorination of a mixture containing a classical IPR-obeying fullerene C88 resulted in isolation and X-ray crystallographic characterization of non-IPR, nonclassical (NC) fullerene chloride C84(NC2)Cl30 (1) containing two heptagons. The carbon cage in C84(NC2)Cl30 contains 14 pentagons, 12 of which form two pairs of fused pentagons and two groups of quaternary sequentially fused pentagons, which have never been observed in reported carbon cages. All 30 Cl atoms form an unprecedented single chain of ortho attachments on the C84 cage. A reconstruction of the pathway of the chlorination-promoted skeletal transformation revealed that the previously unknown IPR isomer C88(3) is converted into 1 by two losses of C2 fragments followed by two Stone-Wales rearrangements, resulting in the formation of very stable chloride with rather short C-Cl bonds. PMID- 28335596 TI - Fast Fabrication of a Stable Perovskite Solar Cell with an Ultrathin Effective Novel Inorganic Hole Transport Layer. AB - With the aim of fabricating simple, reproducible, and scalable perovskite solar cells (PSCs) with least time consumption, a novel CoOx hole transport layer (HTL) was first proposed and introduced in this work. The CoOx HTL thickness was minimized to about 10 nm with complete coverage on the FTO substrate (F-doped SnO2) by direct current magnetron sputtering. The ultrathin HTL could minimize the incident light loss caused by cobalt ion absorption and reduce the carrier transport loss by shortening the transport path. Copper was incorporated into the CoOx lattice to address the low conductivity of the CoOx film and the energy level mismatch between CoOx and the perovskite material. On the basis of cobalt copper binary oxide (Co1-yCuyOx), the highest power conversion efficiency (PCE) of about 10% was achieved, which was acceptable for mass production. Moreover, the deposition of such Co1-yCuyOx films takes only 2 min without size limitation of substrates. A well-functioned device based on the Co1-yCuyOx HTL could hence be fabricated within 100 min. Excellent stability was demonstrated as well, with over 90% of the initial PCE remaining after being stored in a dark and humid environment (relative humidity 60%) for 12 days. PMID- 28335597 TI - Enantioselective Conjunctive Cross-Coupling of Bis(alkenyl)borates: A General Synthesis of Chiral Allylboron Reagents. AB - Palladium-catalyzed conjunctive cross-coupling is used for the synthesis of enantioenriched allylboron reagents. This reaction employs nonsymmetric bis(alkenyl)borates as substrates and appears to occur by a mechanism that involves selective activation of the less substituted alkene followed by migration of the more substituted alkene during the course of a Pd-induced metalate rearrangement. PMID- 28335598 TI - Predicting the Rate of Skin Penetration Using an Aggregated Conformal Prediction Framework. AB - Skin serves as a drug administration route, and skin permeability of chemicals is of significant interest in the pharmaceutical and cosmetic industries. An aggregated conformal prediction (ACP) framework was used to build models for predicting the permeation rate (log Kp) of chemical compounds through human skin. The conformal prediction method gives as an output the prediction range at a given level of confidence for each compound, which enables the user to make a more informed decision when, for example, suggesting the next compound to prepare. Predictive models were built using both the random forest and the support vector machine methods and were based on experimentally derived permeability data on 211 diverse compounds. The derived models were of similar predictive quality as compared to earlier published models but have the extra advantage of not only presenting a single predicted value for each compound but also a reliable, individually assigned prediction range. The models use calculated descriptors and can quickly predict the skin permeation rate of new compounds. PMID- 28335599 TI - Cl2 Elimination in 248 nm Photolysis of (COCl)2 Probed with Cavity Ring-Down Absorption Spectroscopy. AB - Cavity ring-down absorption spectroscopy (CRDS) is employed to investigate one photon dissociation of (COCl)2 at 248 nm obtaining a primary Cl2 elimination channel. A ratio of vibrational population is estimated to be 1:(0.12 +/- 0.03):(0.011 +/- 0.003) for the v = 0, 1, and 2 levels. The quantum yield of Cl2 molecular channel is obtained to be 0.8 +/- 0.4 initiated from the X 1Ag ground state surface (COCl)2 via internal conversion. The obtained total quantum yield is attributed to both primary ((COCl)2 + hnu -> 2CO + Cl2) and secondary reactions (dominated by Cl + COCl -> Cl2 + CO). The former is estimated to share a yield of >0.14, while the latter contributes up to 0.66. The photodissociation pathway to the molecular products is calculated to proceed via a four-center transition state (TS) from which Cl2 is eliminated synchronously. Installation of the mirrors with reflectivity of 99.995% in the CRDS apparatus prolongs the ring down time to 70 MUs, thus allowing for the contribution from 17% up to 66% of the total Cl2 yield from secondary reaction depending on the reaction temperature. Despite uncertainty in determining the product yield, the primary Cl2 dissociation channel eliminated from (COCl)2 is observed for the first time. PMID- 28335601 TI - Cu-Mediated Rearrangements of Allenylcyclopropanols to Cyclopentenones: Two Divergent Pathways. AB - Two CuCN-mediated rearrangement reactions of allenylcyclopropanols to cyclopentenones have been achieved by means of Et2Zn/CuCN.2LiCl or CuCN.2LiCl to afford 5-alkyl or 4-alkyl cyclopentenone regioisomers: the former conditions afford 5-alkyl substituted cyclopentenones via beta-carbon elimination, whereas the latter result in the 4-alkyl substituted regioisomers with concomitant oxidation at the gamma-position, via a free radical mechanism. PMID- 28335600 TI - Redox Potential-Sensitive N-Acetyl Cysteine-Prodrug Nanoparticles Inhibit the Activation of Microglia and Improve Neuronal Survival. AB - One hallmark of neuroinflammation is the activation of microglia, which triggers the production and release of reactive oxygen species (ROS), nitrate, nitrite, and cytokines. N-Acetyl cysteine (NAC) is a free radical scavenger that is involved in the intracellular and extracellular detoxification of reactive oxygen species in the brain. However, the clinical application of NAC is limited by its low bioavailability and short half-life. Herein, NAC was conjugated to a polymer through a disulfide bond to form a NAC-prodrug nanoparticle (NAC-NP). Dynamic light scattering found that the NAC-NP has a size of around 50 nm. In vitro studies revealed that the release of NAC from NAC-NP is responsive to its environmental redox potential. For mimicking neuroinflammation in vitro, microglial cells were stimulated by a lipopolysaccharide (LPS), and the effect of NAC-NP on activated microglia was investigated. The study found that the morphology as well as the expression of microgliosis marker Iba-1 of the cells treated with NAC-NPs and LPS were close to those of control cells, indicating that NAC-NPs can inhibit the activation of microglia stimulated by LPS. Compared with free NAC, the production of ROS, NO3-, NO2-, tumor necrosis factor-alpha (TNF-alpha), and interleukin (IL)-1beta from the LPS-stimulated microglia was considerably decreased when the cells were pretreated with NAC-NPs. Furthermore, LPS-induced microglial phagocytocis of neurons was inhibited in the presence of NAC-NPs. These results indicated that NAC-NPs are more effective than free NAC for reversing the effect of LPS on microglia and subsequently protecting neurons. PMID- 28335602 TI - Local Structure and Dynamics of Water Absorbed in Poly(ether imide): A Hydrogen Bonding Anatomy. AB - Hydrogen bonding (HB) interactions play a major role in determining the behavior of macromolecular systems absorbing water. In fact, functional and structural properties of polymer-water mixtures are affected by the amount and type of these interactions. This contribution aims at a molecular level understanding of the interactional scenario for the technologically relevant case of the poly(ether imide)-water system. The problem has been tackled by combining different experimental and theoretical approaches which, taken together, provide a comprehensive physical picture. Relevant experimental data were gathered by in situ FTIR spectroscopy, while molecular dynamics (MD) and statistical thermodynamics approaches were used as modeling theoretical tools. It was found that, among the possible configurations, some are strongly prevailing. In particular, water molecules preferentially establish water bridges with two carbonyl groups of the same PEI repeating unit. Water self-interactions were also detected, giving rise to a "second shell" species in the prevalent form of dimers. The population of the different water species was evaluated spectroscopically, and a remarkable agreement with theoretical predictions was found. PMID- 28335603 TI - Molecular Dynamics Simulation of Water Transport Mechanisms through Nanoporous Boron Nitride and Graphene Multilayers. AB - In this study, molecular dynamics simulations are used to investigate water transport mechanisms through hourglass-shaped pore structure in nanoporous boron nitride (BN) and graphene multilayers. An increase in water flux is evidenced as the gap between the layers increases, reaching a maximum of 41 and 43 ns-1 at d = 6 A in BN and graphene multilayers, respectively. Moreover, the BN multilayer exhibits less flux compared to graphene due to large friction force and energy barrier. In BN, the friction force dramatically increases when the layers are strongly stacked (d = 3.5 A), whereas it would be independent of the layer separation when the layers are sufficiently spaced (d >= 5 A). In contrast, it was shown that the friction force is independent of the layer spacing in graphene. On the other hand, water molecules across the BN exhibits larger energy barriers compared to graphene when the layers are highly spaced at d = 8 A. Consistent with the result reported for the flux, the axial diffusion coefficient of water molecules in graphene increases with layer spacing, reaching a maximum of 6.8 * 10-5 cm2/s when the layers are spaced at d = 6 A. PMID- 28335604 TI - Prioritizing Natural Product Diversity in a Collection of 146 Bacterial Strains Based on Growth and Extraction Protocols. AB - In order to expedite the rapid and efficient discovery and isolation of novel specialized metabolites, while minimizing the waste of resources on rediscovery of known compounds, it is crucial to develop efficient approaches for strain prioritization, rapid dereplication, and the assessment of favored cultivation and extraction conditions. Herein we interrogated bacterial strains by systematically evaluating cultivation and extraction parameters with LC-MS/MS analysis and subsequent dereplication through the Global Natural Product Social Molecular Networking (GNPS) platform. The developed method is fast, requiring minimal time and sample material, and is compatible with high-throughput extract analysis, thereby streamlining strain prioritization and evaluation of culturing parameters. With this approach, we analyzed 146 marine Salinispora and Streptomyces strains that were grown and extracted using multiple different protocols. In total, 603 samples were analyzed, generating approximately 1.8 million mass spectra. We constructed a comprehensive molecular network and identified 15 molecular families of diverse natural products and their analogues. The size and breadth of this network shows statistically supported trends in molecular diversity when comparing growth and extraction conditions. The network provides an extensive survey of the biosynthetic capacity of the strain collection and a method to compare strains based on the variety and novelty of their metabolites. This approach allows us to quickly identify patterns in metabolite production that can be linked to taxonomy, culture conditions, and extraction methods, as well as informing the most valuable growth and extraction conditions. PMID- 28335607 TI - Special Issue in Honor of Professor Phil Crews. PMID- 28335606 TI - Isolation and Identification of the Novel Tubulin Polymerization Inhibitor Bifidenone. AB - The pursuit of structurally novel compounds has led to the isolation of a series of neolignans (2-6), for which the structures have been determined from microgram quantities using microcryoprobe NMR technology. Compounds 2-6 provided some unexpectedly clear structure-activity relationship data, with compound 2 demonstrating significantly more potency in the in vitro cytotoxicity assay than the other analogues. Further screening found that compound 2 induces apoptosis with activation of caspase 3/7. The NCI Compare algorithm suggested that compound 2 acts through the inhibition of tubulin/microtubule dynamics. Compound 2 was confirmed to be a tubulin polymerization inhibitor that binds directly to tubulin. PMID- 28335608 TI - Superhydrophobic Breakdown of Nanostructured Surfaces Characterized in Situ Using ATR-FTIR. AB - In situ characterization of the underwater stability of superhydrophobic micro- and nanostructured surfaces is important for the development of self-cleaning and antifouling materials. In this work, we demonstrate a novel attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy-based method for large-area wetting characterization of silicon nanopillars. When air is present in between the structures, as is characteristic of the Cassie-Baxter state, the relative intensities of the water bands in the absorption spectrum change because of the wavelength-dependent attenuation of the evanescent wave. This phenomenon enables unambiguous identification of the wetting state and assessment of liquid impalement. Using mixtures of isopropanol and water with different concentrations, the breakdown of superhydrophobic states and the wetting hysteresis effects are systematically studied on uniform arrays of silicon nanopillars. A transition from the Cassie-Baxter to Wenzel state is observed when the isopropanol concentration exceeds 2.8 mol %, corresponding to a critical surface tension of 39 mN/m. Spontaneous dewetting does not occur upon decreasing the isopropanol concentration, and pure water can be obtained in a stable Wenzel state on the originally superhydrophobic substrates. The developed ATR-FTIR method can be promising for real-time monitoring of the wetting kinetics on nanostructured surfaces. PMID- 28335605 TI - Opportunistic Sampling of Roadkill as an Entry Point to Accessing Natural Products Assembled by Bacteria Associated with Non-anthropoidal Mammalian Microbiomes. AB - Few secondary metabolites have been reported from mammalian microbiome bacteria despite the large numbers of diverse taxa that inhabit warm-blooded higher vertebrates. As a means to investigate natural products from these microorganisms, an opportunistic sampling protocol was developed, which focused on exploring bacteria isolated from roadkill mammals. This initiative was made possible through the establishment of a newly created discovery pipeline, which couples laser ablation electrospray ionization mass spectrometry (LAESIMS) with bioassay testing, to target biologically active metabolites from microbiome associated bacteria. To illustrate this process, this report focuses on samples obtained from the ear of a roadkill opossum (Dideiphis virginiana) as the source of two bacterial isolates (Pseudomonas sp. and Serratia sp.) that produced several new and known cyclic lipodepsipeptides (viscosin and serrawettins, respectively). These natural products inhibited biofilm formation by the human pathogenic yeast Candida albicans at concentrations well below those required to inhibit yeast viability. Phylogenetic analysis of 16S rRNA gene sequence libraries revealed the presence of diverse microbial communities associated with different sites throughout the opossum carcass. A putative biosynthetic pathway responsible for the production of the new serrawettin analogues was identified by sequencing the genome of the Serratia sp. isolate. This study provides a functional roadmap to carrying out the systematic investigation of the genomic, microbiological, and chemical parameters related to the production of natural products made by bacteria associated with non-anthropoidal mammalian microbiomes. Discoveries emerging from these studies are anticipated to provide a working framework for efforts aimed at augmenting microbiomes to deliver beneficial natural products to a host. PMID- 28335610 TI - Rheumatoid Forefoot Reconstruction in the Nonrheumatoid Patient. AB - BACKGROUND: Recurrent pain and deformity following forefoot surgery can cause significant patient disability. In patients with rheumatoid arthritis, first metatarsophalangeal (MTP) joint arthrodesis with lesser metatarsal head resections-termed the rheumatoid forefoot reconstruction-has been shown to be a reliable operation for pain relief and deformity correction. Limited data, however, have been published on outcomes of the same forefoot reconstruction operation in the nonrheumatoid patient. Here, we describe our experience with this procedure in patients without rheumatoid disease, hypothesizing improved clinical and radiographic outcomes following surgery. METHODS: Following chart review and reviewing billing codes, we retrospectively identified patients without a diagnosis of rheumatoid arthritis who underwent first MTP arthrodesis with lesser metatarsal head resections. Phone surveys were conducted to assess clinical outcomes including pain and patient satisfaction. Preoperative and postoperative radiographs were reviewed for 1, 2 intermetatarsal angle (IMA), hallux valgus angle (HVA), second MTP angle (MTP-2), and lesser MTP alignment (in both sagittal and axial planes). Postoperative radiographs were assessed for radiographic union. We identified 14 nonrheumatoid patients (16 feet) who underwent forefoot reconstruction. Of those, 13 patients (15 feet) were successfully contacted via follow-up phone survey at an average of 44.3 months postoperatively (range: 20-76 months). RESULTS: Mean postoperative satisfaction scores were 9.0 (out of 10). No patients required reoperation at final phone follow-up. Pain scores significantly decreased from 6.2 preoperatively to 1.9 postoperatively ( P <.001). Radiographic parameters (1,2 IMA, HVA, MTP-2, and lesser MTP alignment in the sagittal plane) improved with surgery ( P <.05), and all 16 feet achieved union of the first MTP arthrodesis. CONCLUSION: With decreased pain, high satisfaction rates, and improved radiographic parameters, first MTP arthrodesis coupled with lesser metatarsal head resection was a viable option for nonrheumatoid patients who failed prior attempts at forefoot reconstruction or have chronic forefoot pain with deformity. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 28335609 TI - Early and Delayed Antiretroviral Therapy Results in Comparable Reductions in CD8+ T Cell Exhaustion Marker Expression. AB - In untreated HIV infection, CD8+ T cell exhaustion (i.e., decreased proliferative and effector capacity) is associated with high levels of expression of coinhibitory receptors, including PD-1, T cell immunoreceptor with Ig and ITIM domains (TIGIT), CD160, and 2B4. This is evident for both HIV-specific and non HIV-specific CD8+ T cells. Antiretroviral therapy (ART) initiated during chronic infection decreases but may not completely normalize the expression of such "exhaustion markers." Compared to initiation of ART later in the course of disease, initiation soon after infection reduces some parameters of chronic inflammation and adaptive immune dysfunction. However, it is not known if Early ART (e.g., initiated within the first 6 months after HIV infection) versus Delayed ART (e.g., initiated during chronic infection) preferentially reduces expression of exhaustion markers. We evaluated exhaustion marker expression on subsets of circulating effector and memory CD8+ T cells at longitudinal pre- and post-ART (2 and 5 years on ART) time points from n = 19 (Early ART) and n = 23 (Delayed ART) individuals. Before ART, TIGIT and CD160 were expressed on a statistically significantly higher proportion of effector and transitional memory cells from individuals in the Delayed ART group: the timing of ART initiation, however, did not consistently affect the expression of the exhaustion markers once viral suppression was achieved. Understanding which factors do and do not regulate aspects of CD8+ T cell exhaustion, including the expression of exhaustion markers, is critical to inform the rational design of CD8+ T cell based therapies to treat HIV, for which CD8+ T cell exhaustion remains an important barrier to efficacy. PMID- 28335611 TI - Evaluation of thioesterases from Acinetobacter baylyi for production of free fatty acids. AB - Acinetobacter baylyi is one of few Gram-negative bacteria capable of accumulating storage lipids in the form of triacylglycerides and wax esters, which makes it an attractive candidate for production of lipophilic products, including biofuel precursors. Thioesterases play a significant dual role in the triacylglyceride and wax ester biosynthesis by either providing or removing acyl-CoA from this pathway. Therefore, 4 different thioesterase genes were cloned from Acinetobacter baylyi ADP1 and expressed in Escherichia coli to investigate their contribution to free fatty acids (FFAs) accumulation. Overexpression of the genes tesA' (a leaderless form of the gene tesA) and tesC resulted in increased accumulation of FFAs when compared with the host E. coli strain. Overexpression of tesA' showed a 1.87-fold increase in production of long-chain fatty acids (C16 to C18) over the host strain. Unlike TesC and the other investigated thioesterases, the TesA' thioesterase also produced shorter chain FFAs (e.g., myristic acid) and unsaturated FFAs (e.g., cis-vaccenic acid (18:1Delta11)). A comparison of the remaining 3 A. baylyi ADP1 thioesterases (encoded by the tesB, tesC, and tesD genes) revealed that only the strain containing the tesC gene produced statistically higher levels of FFAs over the control, suggesting that it possesses the acyl-ACP thioesterase activity. Both E. coli strains containing the tesB and tesD genes produced levels of FFAs similar to those of the plasmid-free control E. coli strain, which indicates that TesB and TesD lack the acyl-ACP thioesterase activity. PMID- 28335612 TI - Thrombin Generation in Patients With Suspected Venous Thromboembolism. AB - Increasing number of patients with clinically suspected venous thromboembolism is referred to radiological departments for definitive diagnosis. A simple assay to exclude the diagnosis and avoid radiological examinations is needed. We have reported correlations between D-dimer and prothrombin fragment 1 + 2 measured in plasma and urine. To further develop an analysis based on urine, more understanding of thrombin generation in these patients is needed. The aim of this study was to compare ex vivo thrombin generation with in vivo markers in plasma and urine in patients with and without venous thromboembolism. Urine and blood samples were collected from patients with suspected venous thromboembolism. Commercially available enzyme-linked immunosorbent assay (ELISA) kits were used to analyze the samples for in vivo thrombin generation. The ex vivo thrombogram parameters were measured by the calibrated automated thrombogram assay. Venous thromboembolism was verified with compression ultrasound of the lower extremity deep veins or with computer tomography of the pulmonary arteries. Venous thromboembolism was diagnosed in 117 of 591 patients, and they had significantly higher levels of urine and plasma prothromin fragment 1 + 2, D-dimer, lag time, time to peak, and endogenous thrombin potential when adjusted for covariates. The pattern of ex vivo and in vivo thrombin generation in patients with suspected venous thromboembolism was comparable when adjusted for covariates. Prothrombin fragment 1 + 2 in plasma and urine reflects thrombin generation ex vivo in the same manner. This indicates that urine may be an alternative substrate to quantify a procoagulant state. PMID- 28335613 TI - Tightly bound soil water introduces isotopic memory effects on mobile and extractable soil water pools. AB - Cryogenic vacuum extraction is the well-established method of extracting water from soil for isotopic analyses of waters moving through the soil-plant atmosphere continuum. We investigate if soils can alter the isotopic composition of water through isotope memory effects, and determined which mechanisms are responsible for it. Soils with differing physicochemical properties were re wetted with reference water and subsequently extracted by cryogenic water distillation. Results suggest some reference waters bind tightly to the soil and not all of this tightly bound water is removed during cryogenic vacuum extraction. Kinetic isotopic fractionation occurring when reference water binds to the soil is likely responsible for the 18O-depletion of re-extracted reference water, suggesting an enrichment of the tightly bound soil water pool. Further re wetting of cryogenically extracted soils indicates an isotopic memory effect of tightly bound soil water on water added to the soil. The data suggest tightly bound soil water can influence the isotopic composition of mobile soil water. Findings show that soils influence the isotope composition of soil water by (i) kinetic fractionation when water is bound to the soil and (ii) equilibrium fractionation between different soil water pools. These findings could be relevant for plant water uptake investigations and complicate ecohydrological and paleohydrological studies. PMID- 28335615 TI - Personality and sexuality in older adults. AB - OBJECTIVE: This study explored cross-time associations between personality and multiple components of sexual functioning and behaviour in a large cohort of older adults (n = 5745). DESIGN: Participants (Mage = 65.57 +/- 8.28 years) completed questionnaires in 2010 and 2012. MAIN OUTCOME MEASURES: Outcomes explored included sexual attitudes, sexual activity, sexual satisfaction, lifetime sexual partners, sexual orientation and sexual dysfunction. RESULTS: We found that higher levels of openness and lower levels of agreeableness were related to more liberal attitudes toward sex, a greater number of sexual partners, a higher sex drive, more frequent sexual activity, lower levels of sexual dysfunction and (for women) a greater tendency towards homosexuality. Higher levels of conscientiousness were also related to more conservative attitudes towards sex, lower levels of sexual dysfunction and a greater tendency towards heterosexuality. For sexually active older adults, higher levels of extraversion and lower levels of neuroticism were related to greater sexual satisfaction. Higher levels of extraversion and lower levels of conscientiousness were also related to a greater number of sexual partners in men but not women. CONCLUSION: These findings provide evidence that personality is an important correlate of sexual functioning and behaviour in older adults. PMID- 28335614 TI - Therapeutic Targeting of Protein Kinase CK2 Gene Expression in Feline Oral Squamous Cell Carcinoma: A Naturally Occurring Large-Animal Model of Head and Neck Cancer. AB - Protein kinase CK2 (CK2) is a highly promising target for cancer therapy, and anti-CK2 gene expression therapy has shown effectiveness in rodent models of human head and neck cancer (HNC). To date, there has been no large-animal model of cancer in which to further explore anti-CK2 therapies. Feline oral squamous cell carcinoma (FOSCC) has been proposed as a large-animal model for human HNC, and we have previously shown that CK2 is a rational target in FOSCC. Here we have tested the hypothesis that a novel tenfibgen-coated tumor-specific nanocapsule carrying RNA interference (RNAi) oligonucleotides targeting feline CK2alpha and CK2alpha' (TBG-RNAi-fCK2alphaalpha') would be safe in cats with FOSCC; assessment of target inhibition and tumor response were secondary aims. Nine cats were enrolled and treated at two dose levels in a 3+3 escalation. Cats received a total of six treatments with TBG-RNAi-fCK2alphaalpha'. Pre- and posttreatment, tumor and normal oral mucosa biopsies were collected to assess CK2 expression, using immunohistochemistry (IHC) preparations evaluated by light microscopy. Toxicity and tumor response were assessed on the basis of standard criteria. The most common adverse events were grade 1 or 2 weight loss and anorexia. Grade 3 tissue necrosis was seen in association with tumor response in one cat, asymptomatic grade 4 elevations in aspartate transaminase and creatine phosphokinase in one cat, and asymptomatic grade 3 hypokalemia in one cat. Of six cats with evaluable biopsies, two had a reduction in CK2 IHC score in tumors after treatment. Four cats had progressive disease during the study period, three had stable disease, one had partial response, and response could not be evaluated in one cat. We conclude that the drug appeared safe and that there is some evidence of efficacy in FOSCC. Further investigation regarding dosing, schedule, target modulation, toxicity, and efficacy in a larger group of cats is warranted and may inform future clinical studies in human head and neck cancer. PMID- 28335616 TI - Predictors of CD4 health and viral suppression outcomes for formerly homeless people living with HIV/AIDS in scattered site supportive housing. AB - Stable housing is key to improving health outcomes for people living with HIV/AIDS. Though many formerly homeless HIV positive individuals reside in supportive housing, little research has examined biometric HIV health outcomes for residents of these programs. Through a community-based research partnership, this study analyzed secondary data from a Shelter Plus Care supportive housing program in Cincinnati, Ohio to examine the likelihood of participants achieving a healthy CD4 count (>500 cells/mm3) and viral suppression (viral load <200 copies/mL) while in supportive housing and to identify participant characteristics associated with these outcomes. The study sample was 86 participants who entered the program between 2008 and 2016, including 50 current residents and 36 exited participants. Participants' average length of stay in Shelter Plus Care was 35.2 months (range 3.2-108.1 months) during the study period. Bivariate analysis indicated statistically significant improvements on both outcome variables, with 45% of participants achieving a healthy CD4 count and 79% achieving viral suppression by program exit or most recent time point. Participants who had health insurance at intake and who had never been incarcerated were more likely to achieve viral suppression, and longer length of stay in the program was also positively associated with viral suppression. These results add to the literature on the relationship between housing conditions and HIV health outcomes by demonstrating that residence in supportive housing is associated with improvements in CD4 count and viral load for a sample of formerly homeless persons living with HIV/AIDS, two-thirds of whom had co-occurring physical health, mental health, or substance abuse problems. Further research collaborations should expand on these findings to examine the service packages that are associated with optimal HIV health outcomes for supportive housing residents. PMID- 28335617 TI - Operative Treatment of Traumatic Hallux Valgus in Elite Athletes. AB - BACKGROUND: Traumatic hallux valgus is an increasingly common injury in the athletic population and represents a unique variant of turf toe. Failure to appropriately recognize and treat these injuries can lead to continued pain, decreased performance, progressive deformities, and ultimately degeneration of the hallux metatarsophalangeal joint. Limited literature currently exists to assist in the diagnosis, management, and operative treatment. METHODS: Nineteen patients were reviewed in this series, including 12 National Football League, 6 college, and 1 high school player who was a college prospect. The average age for all patients at the time of surgery was 24.4 years (range, 19-33 years). Return to play and complications were evaluated. RESULTS: Overall, good operative results were obtained, with 74% of patients returning to their preinjury level of play at an average recovery time of 3.4 months. CONCLUSION: Traumatic hallux valgus is an increasingly common injury in the athletic population and represents a unique variant of turf toe. The impact of this injury cannot be overstated, as one-quarter of players were unable to return to play. LEVEL OF EVIDENCE: Level IV, case series. PMID- 28335618 TI - AAV: An Overview of Unanswered Questions. AB - AAV has been studied for 55 years and has been developed as a vector for about 35 years. By now, there is a fairly good idea of the dimensions of what would be useful to know to employ AAV optimally as a vector, but there are still many unanswered questions within the system. As with all biological systems, each good experiment raises further questions to answer. This article provides an overview of those areas in which unknown information can be identified and of those questions that have not yet been recognized. Some of these are touched on in the six review articles in this issue of Human Gene Therapy. PMID- 28335620 TI - A novel mutation of BICD2 gene associated with juvenile amyotrophic lateral sclerosis. PMID- 28335619 TI - Overexpression of the X-Linked Inhibitor of Apoptosis Protects Against Retinal Degeneration in a Feline Model of Retinal Detachment. AB - Retinal detachment is an acute disorder in humans that is caused by trauma or disease, and it can often lead to permanent visual deficits that result from the death of photoreceptors in the retina. The final pathway for photoreceptor cell death is apoptosis and necroptosis. The X-linked inhibitor of apoptosis (XIAP) has been shown to block both of these cell death pathways. This study tested the effects of XIAP on photoreceptor survival in a feline model of retinal detachment. The study was performed in 12 cats, divided into two experimental groups. Six animals received a subretinal injection of adeno-associated virus (AAV) carrying XIAP, and six animals received AAV carrying green fluorescent protein (GFP) as a control. Three weeks after viral delivery, retinas were detached by injecting C3F8 gas into the subretinal space. Optical coherence tomography revealed that the retinal detachments resolved within 3-6 weeks as the gas was slowly resorbed. Analysis of histological sections through the plane of the detachment showed significant preservation of the photoreceptor layer in AAV XIAP-treated animals compared to AAV-GFP-treated animals at 9 weeks after the detachment. XIAP-treated detached retinas were similar to intact controls. These studies support the potential for XIAP therapy in the treatment of human retinal detachment. PMID- 28335621 TI - Re: Srivastava A, Carter BJ; AAV Infection: Protection from Cancer; Hum Gene Ther 2017;28:323-327; DOI: 10.1089/hum.2016.147. PMID- 28335625 TI - Is ICU Safety Threatened by the Straight Corridor? PMID- 28335622 TI - Functional Connectivity of the Subcallosal Cingulate Cortex And Differential Outcomes to Treatment With Cognitive-Behavioral Therapy or Antidepressant Medication for Major Depressive Disorder. AB - OBJECTIVE: The purpose of this article was to inform the first-line treatment choice between cognitive-behavioral therapy (CBT) or an antidepressant medication for treatment-naive adults with major depressive disorder by defining a neuroimaging biomarker that differentially identifies the outcomes of remission and treatment failure to these interventions. METHOD: Functional MRI resting state functional connectivity analyses using a bilateral subcallosal cingulate cortex (SCC) seed was applied to 122 patients from the Prediction of Remission to Individual and Combined Treatments (PReDICT) study who completed 12 weeks of randomized treatment with CBT or antidepressant medication. Of the 122 participants, 58 achieved remission (Hamilton Depression Rating Scale [HAM-D] score <=7 at weeks 10 and 12), and 24 had treatment failure (<30% decrease from baseline in HAM-D score). A 2*2 analysis of variance using voxel-wise subsampling permutation tests compared the interaction of treatment and outcome. Receiver operating characteristic curves constructed using brain connectivity measures were used to determine possible classification rates for differential treatment outcomes. RESULTS: The resting-state functional connectivity of the following three regions with the SCC was differentially associated with outcomes of remission and treatment failure to CBT and antidepressant medication and survived application of the subsample permutation tests: the left anterior ventrolateral prefrontal cortex/insula, the dorsal midbrain, and the left ventromedial prefrontal cortex. Using the summed SCC functional connectivity scores for these three regions, overall classification rates of 72%-78% for remission and 75%-89% for treatment failure was demonstrated. Positive summed functional connectivity was associated with remission with CBT and treatment failure with medication, whereas negative summed functional connectivity scores were associated with remission to medication and treatment failure with CBT. CONCLUSIONS: Imaging based depression subtypes defined using resting-state functional connectivity differentially identified an individual's probability of remission or treatment failure with first-line treatment options for major depression. This biomarker should be explored in future research through prospective testing and as a component of multivariate treatment prediction models. PMID- 28335623 TI - Genetic Heterogeneity in Depressive Symptoms Following the Death of a Spouse: Polygenic Score Analysis of the U.S. Health and Retirement Study. AB - OBJECTIVE: Experience of stressful life events is associated with risk of depression. Yet many exposed individuals do not become depressed. A controversial hypothesis is that genetic factors influence vulnerability to depression following stress. This hypothesis is often tested with a "diathesis-stress" model, in which genes confer excess vulnerability. The authors tested an alternative formulation of this model: genes may buffer against depressogenic effects of life stress. METHOD: The hypothesized genetic buffer was measured using a polygenic score derived from a published genome-wide association study of subjective well-being. The authors tested whether married older adults who had higher polygenic scores were less vulnerable to depressive symptoms following the death of their spouse compared with age-matched peers who had also lost their spouse and who had lower polygenic scores. Data were analyzed from 8,588 non Hispanic white adults in the Health and Retirement Study (HRS), a population representative longitudinal study of older adults in the United States. RESULTS: HRS adults with higher well-being polygenic scores experienced fewer depressive symptoms during follow-up. Those who survived the death of their spouses (N=1,647) experienced a sharp increase in depressive symptoms following the death and returned toward baseline over the following 2 years. Having a higher well being polygenic score buffered against increased depressive symptoms following a spouse's death. CONCLUSIONS: The effects were small, and the clinical relevance is uncertain, although polygenic score analyses may provide clues to behavioral pathways that can serve as therapeutic targets. Future studies of gene environment interplay in depression may benefit from focus on genetics discovered for putative protective factors. PMID- 28335624 TI - Effects of Patient Preferences on Outcomes in the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) Study. AB - OBJECTIVE: The Predictors of Remission in Depression to Individual and Combined Treatments [PReDICT] study aimed to identify clinical and biological factors predictive of treatment outcomes in major depressive disorder among treatment naive adults. The authors evaluated the efficacy of cognitive-behavioral therapy (CBT) and two antidepressant medications (escitalopram and duloxetine) in patients with major depression and examined the moderating effect of patients' treatment preferences on outcomes. METHOD: Adults aged 18-65 with treatment-naive major depression were randomly assigned with equal likelihood to 12 weeks of treatment with escitalopram (10-20 mg/day), duloxetine (30-60 mg/day), or CBT (16 50-minute sessions). Prior to randomization, patients indicated whether they preferred medication or CBT or had no preference. The primary outcome was change in the 17-item Hamilton Depression Rating Scale (HAM-D), administered by raters blinded to treatment. RESULTS: A total of 344 patients were randomly assigned, with a mean baseline HAM-D score of 19.8 (SD=3.8). The mean estimated overall decreases in HAM-D score did not significantly differ between treatments (CBT: 10.2, escitalopram: 11.1, duloxetine: 11.2). Last observation carried forward remission rates did not significantly differ between treatments (CBT: 41.9%, escitalopram: 46.7%, duloxetine: 54.7%). Patients matched to their preferred treatment were more likely to complete the trial but not more likely to achieve remission. CONCLUSIONS: Treatment guidelines that recommend either an evidence based psychotherapy or antidepressant medication for nonpsychotic major depression can be extended to treatment-naive patients. Treatment preferences among patients without prior treatment exposure do not significantly moderate symptomatic outcomes. PMID- 28335627 TI - State of the Science in Healthcare Design. PMID- 28335629 TI - Executive Summary of Key Concepts. PMID- 28335628 TI - Letter to the Editors and Response. PMID- 28335630 TI - The Design, Prototyping, and Formative Evaluation of an Assistive Robotic Table (ART) for Stroke Patients. AB - OBJECTIVE: This article presents the results of an exploratory study in which 14 healthcare subject matter experts (H-SMEs) in addition to four research and design subject matter experts (RD-SMEs) at a regional rehabilitation hospital engaged in a series of complementary, participatory activities in order to design an assistive robotic table (ART). BACKGROUND: As designers, human factor experts, and healthcare professionals continue to work to integrate assistive human-robot technologies in healthcare, it is imperative to understand how the technology affects patient care from clinicians' perspectives. METHOD: Fourteen clinical H SMEs rated a subset of conceptual ART design ideas; participated in the iterative design process of ART; and evaluated a final cardboard prototype, the rehabilitation hospital's current over-the-bed table (OBT), an ART built with true materials, and two therapy surface prototypes. Four RD-SMEs conducted a heuristic evaluation on the ART built with true materials. Data were analyzed by frequency and content analysis. RESULTS: The results include a design and prototype for the next generation ART and a pneumatically controlled therapy surface, a broadened list of specifications for the future design and implementation of assistive robotic furniture, and final observations. CONCLUSION: When compared to the rehabilitation hospital's current OBT, the developed ART in this study was successful. Designing novel features is dependent upon ensuring patient safety. The inclusion of clinicians in the participatory iterative design and evaluation process and the use of personas provided a broadened list of specifications for the successful implementation of assistive robotic furniture. PMID- 28335632 TI - Executive Summary of Key Concepts. PMID- 28335631 TI - Demystifying the Peer-Review Process for HERD. PMID- 28335633 TI - If A, Then B. PMID- 28335634 TI - Applying Lean Methods to Healthcare Design. PMID- 28335636 TI - Utility values associated with advanced or metastatic non-small cell lung cancer: data needs for economic modeling. AB - INTRODUCTION: Cost-effectiveness analyses often inform healthcare reimbursement decisions. The preferred measure of effectiveness is the quality adjusted life year (QALY) gained, where the quality of life adjustment is measured in terms of utility. Areas covered: We assessed the availability and variation of utility values for health states associated with advanced or metastatic non-small cell lung cancer (NSCLC) to identify values appropriate for cost-effectiveness models assessing alternative treatments. Our systematic search of six electronic databases (January 2000 to August 2015) found the current literature to be sparse in terms of utility values associated with NSCLC, identifying 27 studies. Utility values were most frequently reported over time and by treatment type, and less frequently by disease response, stage of disease, adverse events or disease comorbidities. Expert commentary: In response to rising healthcare costs, payers increasingly consider the cost-effectiveness of novel treatments in reimbursement decisions, especially in oncology. As the number of therapies available to treat NSCLC increases, cost-effectiveness analyses will play a key role in reimbursement decisions in this area. Quantifying the relationship between health and quality of life for NSCLC patients via utility values is an important component of assessing the cost effectiveness of novel treatments. PMID- 28335637 TI - Reversing the anticoagulation effects of dabigatran. AB - The standard of care for oral anticoagulation therapy has primarily been warfarin, which is limited by its indirect mechanism-of-action, variable kinetics, tolerability, and routine monitoring concerns. The direct-acting oral anticoagulants (DOACs) have predictable pharmacokinetics and pharmacodynamics, and improved safety and efficacy compared to warfarin for the prevention of stroke in patients with nonvalvular atrial fibrillation and prevention or management of venous thromboembolism. Consequential bleeding is a concern with all anticoagulants. Vitamin K is not a rapid reversal agent for warfarin; rather it facilitates synthesis of new vitamin K-dependent clotting factors, which can take longer than 24 h. Other nonspecific agents, including recombinant activated factor VII, three- and four-factor prothrombin complex concentrates (PCC), and activated PCC or Factor Eight Inhibitor Bypassing Activity (FEIBA(r)), are options based on clinical need. Specific agents to quickly reverse the effects of DOACs have been under development, and idarucizumab, a monoclonal antibody fragment that rapidly binds dabigatran, has been approved for clinical use in cases of dabigatran-related life-threatening bleeding, or if a dabigatran-treated patient needs emergency surgery or an invasive procedure. Idarucizumab specifically and rapidly reverses dabigatran-induced anticoagulation as measured by established coagulation assays. However, this does not guarantee complete hemostasis, especially if a patient has underlying comorbidities such as renal or liver disease, or has experienced recent trauma that requires urgent surgery. In these cases, concomitant supportive therapy and/or administration of concentrated clotting factors may be considered. Emerging data from ongoing trials and clinical experience will further inform providers regarding optimal approaches for anticoagulation reversal. PMID- 28335638 TI - Incidence and clinical predictors of subsequent atrial fibrillation requiring additional ablation after cavotricuspid isthmus ablation for typical atrial flutter. AB - OBJECTIVES: We sought to investigate the incidence of atrial fibrillation after catheter ablation for typical atrial flutter and to determine the predictors for symptomatic atrial fibrillation that required a further additional dedicated ablation procedure. DESIGN: 127 patients underwent elective cavotricuspid isthmus ablation with the indication of symptomatic, typical atrial flutter. The occurrence of atrial flutter, atrial fibrillation, cerebrovascular events and the need for additional ablation procedures for symptomatic atrial fibrillation was assessed during long-term follow-up. RESULTS: The majority of patients (70%) manifested atrial fibrillation during a follow-up period of 68 +/- 24 months, and a significant proportion (42%) underwent one or multiple atrial fibrillation ablation procedures after an average of 26 months from the index procedure. Recurrence of typical atrial flutter was rare. Ten patients (8%) suffered cerebrovascular events. Earlier documentation of atrial fibrillation (OR 3.53), previous use of flecainide (OR 3.33) and left atrial diameter (OR 2.96) independently predicted occurrence of atrial fibrillation during the follow-up. A combination of pre- and intra-procedural documentation of atrial fibrillation (OR 3.81) and previous use of flecainide (OR 2.43) independently predicted additional atrial fibrillation ablation. DISCUSSION: Atrial fibrillation occurred in the majority of patients after ablation for typical atrial flutter and 42% of them required an additional dedicated ablation procedure. Pre- and intraprocedural documentation of atrial fibrillation together with previous use of flecainide independently predicted atrial fibrillation occurrence and a need for additional ablation. Anticoagulation treatment should be continued in high-risk patients in spite of clinical disappearance of atrial flutter. PMID- 28335639 TI - A teachers' training program accompanying the "School Fruit Scheme" fruit distribution improves children's adherence to the Mediterranean diet: an Italian trial. AB - The effects of a nutrition education program, led by trained teachers within the Italian School Fruit Scheme, were evaluated. Pre-post intervention children's adherence to the Mediterranean diet (MD) was assessed by the KIDMED test. A representative cluster sample of 494 fourth grade students from thirteen Italian schools in the three areas of low (North), medium (Centre) and high (South) prevalence of overweight and obesity was investigated. Within the same schools, the intervention group (n = 395) received the program, the control group (n = 99) did not. In the intervention group, the proportion of children with high adherence to the MD significantly increased in the total sample, females and South in the post-intervention; no significant changes in levels of adherence related to ponderal status were detected. A significant increase was found, particularly, in the proportion of children who improved their frequency of consumption of fruit and vegetables (FV) daily, especially in the South. PMID- 28335640 TI - Nebivolol attenuates cerebral vasospasm both by increasing endothelial nitric oxide and by decreasing oxidative stress in an experimental subarachnoid haemorrhage. AB - OBJECTIVE: Evidence suggests that reduction of nitric oxide (NO) bioavailability due to oxidative stress plays a central role in the pathophysiology of cerebral vasospasm after subarachnoid haemorrhage (SAH). To prevent SAH-induced cerebral vasospasm, therefore we used nebivolol hydrochloride as a NO-mediated vasodilator and an antioxidant drug in an experimental rat model of SAH. MATERIALS AND METHODS: Forty female Wistar rats were divided into control, SAH, SAH plus placebo, and SAH plus nebivolol groups. Starting six hours after inducing SAH, 5 mg/kg of nebivolol hydrochloride and of pharmaceutical excipients of nebivolol was given orally once daily for five days to SAH plus nebivolol and SAH plus placebo groups, respectively. The lumen diameter and vessel wall thickness of the basilar artery were measured in brain sections. The serum and brain supernatant levels of nitric oxide (NO) were analysed. The brain supernatant levels of intrinsic antioxidants superoxide dismutase (SOD) and glutathione peroxidase (GSH Px) were measured as markers of the antioxidant status. RESULTS: Nebivolol administration attenuated cerebral vasospasm both by increasing NO levels and by decreasing oxidative stress. Our study also demonstrated that nebivolol administration reverses SAH created imbalance between SOD and GSH-Px by increasing GSH-Px activity relative to SOD. CONCLUSIONS: Nebivolol attenuates the cerebral vasospasm after SAH both increasing NO levels and decreasing oxidative stress. Therefore, it may promise to prevent SAH-induced cerebral vasospasm as an anti-spasmodic and anti-oxidant agent. PMID- 28335641 TI - Corrigendum. PMID- 28335642 TI - Voriconazole for prophylaxis of invasive fungal infections after allogeneic hematopoietic stem cell transplantation. AB - INTRODUCTION: Invasive fungal infections (IFIs) following allogeneic hematopoietic stem cell transplantation (alloHSCT) are associated with a high mortality, and accordingly most alloHSCT recipients receive prophylaxis with antifungal agents. Despite some improvement in outcomes of IFIs over time, they continue to represent substantial clinical risk, mortality, and financial burden. Areas covered: We review the main pathogens responsible for IFIs in recipients of alloHSCT, current treatment recommendations, and discuss clinical and economic considerations associated with voriconazole prophylaxis of IFIs in these patients. Expert commentary: The clinical efficacy of voriconazole appears to be at least equivalent to other antifungal treatments, and generally well tolerated. Overall, benefit-risk balance is favorable, and findings from cost-effectiveness analyses support the use of voriconazole prophylaxis of IFIs in recipients of alloHSCT. PMID- 28335643 TI - Prospects and progress of atezolizumab in non-small cell lung cancer. AB - INTRODUCTION: Immunotherapy has recently come to the forefront of oncology treatment as a potential means of combating cancer by restoring the body's adaptive cancer-immunity cycle. Atezolizumab is a monoclonal antibody agent that specifically targets programmed death ligand 1 (PD-L1), a key molecule in the cancer-immunity pathway, to block binding to its receptors PD-1 and B7.1. Areas covered: This review covers the role of atezolizumab in the treatment of non small-cell lung cancer (NSCLC). Several studies have reported promising efficacy in this indication. The phase II FIR and BIRCH studies evaluated atezolizumab monotherapy across different lines of therapy in NSCLC selected by PD-L1 expression status. The randomized POPLAR and OAK trials of atezolizumab versus docetaxel in previously treated NSCLC reported improved efficacy in the atezolizumab arm. Several ongoing studies yet to report data are also described and treatment-related adverse events are discussed. Expert opinion: Clinical trials have shown that atezolizumab has a favorable risk-benefit ratio compared with standard chemotherapy in second-line treatment of non-oncogene-driven advanced NSCLC. Promising response rates and survival over 2 years has been reported in the first-line setting; however, more research is needed in this setting and in evaluating combinatorial strategies to treat NSCLC. PMID- 28335645 TI - Treatment of sleep disorders in youth with ADHD: what is the evidence from randomised controlled trials and how should the field move forward? PMID- 28335644 TI - Heart rate and dyssynchrony in patients with cardiac resynchronization therapy: a pilot study. AB - OBJECTIVES: The objective of this pilot study was to describe the impact of paced heart rate on left ventricular (LV) mechanical dyssynchrony in synchronous compared to dyssynchronous pacing modes in patients with heart failure. METHODS: Echocardiography was performed in 14 cardiac resynchronization therapy (CRT) patients at paced heart rates of 70 and 90 bpm in synchronous- (CRT), and dyssynchronous (atrial pacing + wide QRS activation) pacing modes. LV dyssynchrony was quantified using the 12-segment standard deviation model (Ts-SD) derived from Tissue Doppler Imaging. In addition, cardiac cycle intervals were assessed using cardiac state diagrams and stroke volume (SV) and filling pressure were estimated. RESULTS: Ts-SD decreased significantly with CRT at 90 bpm (25 +/- 12 ms) compared to 70 bpm (35 +/- 15 ms, p = .01), but remained unchanged with atrial pacing at different paced heart rates (p = .96). The paced heart rate dependent reduction in Ts-SD was consistent when Ts-SD was indexed to average Ts and systolic time interval. Cardiac state diagram derived analysis of cardiac cycle intervals demonstrated a significant reduction of the pre-ejection interval and an increase in diastole with CRT compared to atrial pacing. SV was maintained at the higher paced heart rate with CRT pacing but decreased with atrial pacing. DISCUSSION: Due to the small sample size in this pilot study general and firm conclusions are difficult to render. However, the data suggest that pacing at higher heart rates acutely reduces remaining LV dyssynchrony during CRT, but not during atrial pacing with dyssynchronous ventricular activation. These results need confirmation in a larger patient cohort. PMID- 28335646 TI - Synthesis of an acridine orange sulfonamide derivative with potent carbonic anhydrase IX inhibitory action. AB - Acridine orange (AO) a fluorescent cationic dye used for the management of human musculoskeletal sarcomas, due to its strong tumoricidal action and accumulation in the acidic environment typical of hypoxic tumors, was used for the preparation of a primary sulfonamide derivative. The rationale behind the drug design is the fact that hypoxic, acidic tumors overexpress carbonic anhydrase (CA, EC 4.2.1.1) isoforms, such as CA IX, which is involved in pH regulation, proliferation, cell migration and invasion, and this enzyme is strongly inhibited by primary sulfonamides. The AO-sulfonamide derivative was indeed a potent, low nanomolar CA IX inhibitor whereas its inhibition of the cytosolic isoforms CA I and II was in the micromolar range. A second transmembrane, tumor-associated isoform, CA XII, was also effectively inhibited by the AO-sulfonamide derivative, making this compound an interesting theranostic agent for the management of hypoxic tumors. PMID- 28335647 TI - Sorafenib for the treatment of breast cancer. AB - INTRODUCTION: Breast cancer treatment includes many options depending on the tumor clinicopathological profile, which groups breast cancer into various subtypes. Bevacizumab is currently the only drug capable of targeting angiogenesis in breast cancer. Sorafenib has also been studied in combination with other agents. Areas covered: Pharmacological aspects of sorafenib, including results from preclinical studies on breast cancer cells; findings about clinical efficacy and safety in both single-arm and randomized clinical trials; ongoing trials. Expert opinion: Since sorafenib as a single agent has shown limited efficacy in breast cancer, its combination with other drugs is under investigation. Dose reduction is the main challenge when sorafenib is combined with chemotherapy or endocrine therapy. Although randomized phase-II trials on sorafenib plus chemotherapy versus chemotherapy alone have shown potential benefits in progression-free survival, preliminary results from a phase-III study in combination with capecitabine are negative. The definitive results of this trial and results from other ongoing phase-II trials will determine further developments of sorafenib in breast cancer. Although these additional data could help determine the most appropriate dose, drug combination and patient settings, a confirmation of the preliminary negative results reported in the phase-III trial are likely to discourage further use of sorafenib in breast cancer, given its non-negligible toxicity, lack of predicting markers, and the number of more promising drugs for breast cancer. PMID- 28335648 TI - Inflammation and pharmacokinetics: potential implications for HIV-infection. AB - INTRODUCTION: The physiological changes accompanying inflammation may alter the pharmacokinetics (PK) of certain medications. Individuals infected with HIV have chronically elevated inflammatory markers despite viral suppression following effective antiretroviral therapy (ART), as well as age-related inflammation. Understanding the potential clinical implications of inflammation on the PK of medications is important for understanding dose-response relationships and necessitates future research. Areas covered: An extensive literature search was carried out using PubMed and associated bibliographies to summarize the current state of knowledge regarding altered PK in response to inflammation and its application to the field of HIV. Expert opinion: Preclinical and clinical studies show that inflammation leads to a downregulation of certain drug metabolizing enzymes and both up and down regulation of transporters depending on the transporter and cell type. Decreased gastric acidity, fluid shifts, and plasma protein alterations also occur with inflammation, leading to potential absorption, distribution, and clearance changes. More research is needed including controlled PK studies to address the clinical relevance of these observations, especially in the aging HIV-infected population. Results from future studies will enable us to better predict drug concentrations in individuals with inflammation, in line with efforts to provide personalized pharmacotherapy in our healthcare system. PMID- 28335649 TI - Plasma growth arrest-specific 6 levels in term and preterm newborns. AB - OBJECTIVE: Growth Arrest-Specific 6 (GAS6) is a vitamin K-dependent protein. Despite a similar structure to Protein S, it has no anticoagulant activity. An association between GAS6 and some diseases for adults has been reported. In the absence of prospective clinical studies of GAS6 in neonates, so far, the objective of this study is to obtain, for the first time, plasma GAS6 levels before and after vitamin K1 prophylaxis in full-term and pre-term newborns. METHODS: 80 newborns (40 term and 40 preterm) were recruited for this study. Cord blood samples and peripheral blood samples 48 h after vitamin K1 injection were collected into EDTA-tubes. GAS6 levels were measured in platelet-poor plasma by ELISA. RESULTS: Cord blood plasma GAS6 levels in preterm and term newborns were 9.07 +/- 5.30 ng/mL and 9.75 +/- 4.34 ng/mL, respectively. In response to vitamin K1 injection, GAS6 levels increased in preterm newborns (10.50 +/- 5.28 ng/mL) (p < .05), but not in term newborns (9.12 +/- 3.42 ng/mL, p > .05). CONCLUSION: This pilot study provided, to the best of our knowledge, the first report that GAS6 levels increased significantly after vitamin K1 prophylaxis in preterm newborns but not in term infants. This study may serve as a first step toward more extensive studies in neonates. PMID- 28335650 TI - Are we nearing the end in the fight against hepatitis C? PMID- 28335651 TI - From mystery to mechanism: can proteomics build systems-level understanding of our gut microbes? PMID- 28335652 TI - Positive vaginal culture at rescue cerclage predicts subsequent preterm delivery. AB - PURPOSE: This retrospective case-control study is aimed to extract predictors of preterm delivery after rescue cerclage. MATERIALS AND METHODS: We collected the data from all the pregnant women who underwent rescue cerclage before 26+0 gestational weeks at our facility between July 2006 and July 2016. These women were divided into "delivery at <34 weeks" group (n = 12) and "delivery at >=34 weeks" group (n = 12). Multiple factors that had been detected at the time of cerclage were compared between these two groups. RESULTS: "Gestational weeks at cerclage >=23" and "positive vaginal culture at cerclage" were significantly more prevalent in the "delivery at <34 weeks" group than in the "delivery at >=34 weeks" group. "Prolapsed membranes at cerclage" tended to be more prevalent in the "delivery at <34 weeks" group than in the "delivery at >=34 weeks" group. "Positive vaginal culture at cerclage" was the only independent risk factor associated with eventual preterm delivery before 34 gestational weeks. CONCLUSIONS: Simple aerobic bacterial culture of the vaginal swab sampled at the time of cerclage could be used as a reliable test to predict subsequent preterm delivery before 34 gestational weeks. PMID- 28335653 TI - Anesthesia management of complete versus incomplete placenta previa: a retrospective cohort study. AB - PURPOSE: Placenta previa (PP) is a major cause of obstetric hemorrhage. Clinical diagnosis of complete versus incomplete PP has a significant impact on the peripartum outcome. Our study objective is to examine whether distinction between PP classifications effect anesthetic management. METHODS AND MATERIALS: This multi-center, retrospective, cohort study was performed in two tertiary university-affiliated medical centers between the years 2005 and 2013. Electronic delivery databases were reviewed for demographic, anesthetic, obstetric hemorrhage, and postoperative outcomes for all cases. RESULTS: Throughout the study period 452 cases of PP were documented. We found 134 women (29.6%) had a complete PP and 318 (70.4%) had incomplete PP. Our main findings were that women with complete PP intraoperatively had higher incidence of general anesthesia (p = .017), higher mean estimated blood loss (p < .001), increased blood components transfusions (p < .001), and significant increase in cesarean hysterectomy rate (p < .001) than women with incomplete PP. Additionally, complete PP was associated with more postoperative complications: higher incidence of admission to the intensive care unit (ICU) (p < .001), more mechanical ventilation (p = .02), a longer median postoperative care unit (PACU) (p = .02), ICU (p = .002), and overall length of stay in the hospital (p < .001). CONCLUSIONS: Complete PP is associated with increased risk of hemorrhage compared with incomplete PP. Therefore distinction between classifications should be factored into anesthetic management protocols. PMID- 28335654 TI - Gestational weight gain among nutritionally treated GDM patients. AB - OBJECTIVE: We aimed to evaluate pregnancy outcome in diet-treated gestational diabetes mellitus (GDM) patients according to the 2009 Institute of Medicine (IOM) guidelines concerning gestational weight gain (GWG). DESIGN AND PATIENTS: This was a retrospective cohort study, limited to women with singleton pregnancies and diet-treated GDM. Women with preexisting diabetes or women with pharmaceutical treatment were excluded. We compared patients with adequate GWG with patients with excess GWG according to the 2009 IOM guidelines. RESULTS: Overall, 142 women were evaluated, of which 99 (69.7%) had adequate GWG and 43 (30.3%) had excess GWG. All demonstrated good glycemic control. Patients in the excess GWG group had higher mean pre-pregnancy weight and body mass index (BMI). No other obstetrical or perinatal statistically significant differences were demonstrated, although there was a trend for higher birth weight percentile and higher rate of respiratory distress among the excess GWG group. CONCLUSIONS: Higher pre-pregnancy BMI is a risk factor for failing to comply with the 2009 IOM GWG guidelines. However, it seems that in pregnancies complicated by diet-treated GDM, GWG is not a reliable marker for adverse pregnancy outcome if glycemic control is adequate. PMID- 28335655 TI - The therapeutic potential of targeting ABC transporters to combat multi-drug resistance. AB - INTRODUCTION: Most disseminated cancers remain fatal despite the availability of a variety of conventional and novel treatments including surgery, chemotherapy, radiotherapy, immunotherapy, and biologically targeted therapy. A major factor responsible for the failure of chemotherapy in the treatment of cancer is the development of multidrug resistance (MDR). The overexpression of various ABC transporters in cancer cells can efficiently remove the anticancer drug from the cell, thus causing the drug to lose its effect. Areas covered: In this review, we summarised the ongoing research related to the mechanism, function, and regulation of ABC transporters. We integrated our current knowledge at different levels from molecular biology to clinical trials. We also discussed potential therapeutic strategies of targeting ABC transporters to reverse MDR in cancer cells. Expert opinion: Involvement of various ABC transporters to cancer MDR lays the foundation for developing tailored therapies that can overcome MDR. An ideal MDR reversal agent should have broad-spectrum ABC-transporter inhibitory activity, be potent, have good pharmacokinetics, have no trans-stimulation effects, and have low or no toxicity. Alternatively, nanotechnology-based drug delivery systems containing both the cytotoxic drug and reversing agent may represent a useful approach to reversing MDR with minimal off-target toxicity. PMID- 28335656 TI - Response to letter to the editor "Mean platelet volume may have not a predictive value for placental invasion anomalies". PMID- 28335657 TI - Molecular characteristics of uterine sarcomas. AB - INTRODUCTION: Uterine sarcomas are rare cancers, of which the most common entities are leiomyosarcoma and endometrial stromal sarcoma. These two tumors may have overlapping clinical presentation, morphology and immunohistochemical profile, but are increasingly recognized to be two molecularly distinct entities. Endometrial stromal sarcomas are further currently divided into a low-grade and high-grade group based on molecular characteristics. Area covered: This review discusses recent data which shed light on the molecular profile of these two cancers and may aid in understanding their evolution and progression, in the aim of improving their diagnosis and management. Search was through PubMed, with focus on studies published in the last 5 years. Expert commentary: The literature presented and discussed documents rapidly expanding knowledge of the genetic characteristics of leiomyosarcoma and endometrial stromal sarcoma, with an array of molecules and pathways implicated in the biology of these cancers. Several of these molecules are potential therapeutic targets. Assessment of their predictive and prognostic role awaits larger studies. PMID- 28335658 TI - Dopamine antagonists for treatment resistance in autism spectrum disorders: review and focus on BDNF stimulators loxapine and amitriptyline. AB - INTRODUCTION: Drug development and repurposing are urgently needed for individuals with autism spectrum disorders (ASD) and psychiatric comorbidity, which often presents as aggression and self-injury. Areas covered: We review dopamine antagonists, including classical and atypical, as well as unconventional antipsychotics in ASD. The older antipsychotic loxapine is discussed in terms of preliminary albeit limited evidence in ASD. Emerging promise of amitriptyline in ASD is discussed, together with promising BDNF effects of loxapine and amitriptyline. Expert opinion: In ASD, pharmacotherapy and specifically dopamine antagonist drugs are often prescribed for challenging behaviors including aggression. The novel antipsychotics risperidone and aripiprazole have received most study in ASD and are FDA-approved for irritability in children with ASD over age 5 years; individuals with ASD are prone to weight gain, Type II diabetes and associated side effects. Low dose loxapine has properties of classical and novel antipsychotics but importantly appears more weight neutral, and with promising use in adolescents and adults with ASD. Amitriptyline appears effective in ASD for irritability, aggression, gastrointestinal problems, and insomnia, in children, adolescents and adults however our adult data on amitriptyline in ASD is still in preparation for publication. Both loxapine and amitriptyline may stimulate BDNF; further studies are warranted. PMID- 28335660 TI - Recommendation of the WFITN regarding simulation in neurointerventional training. PMID- 28335659 TI - Factors associated with weight gain among adult patients initiating antiretroviral therapy in Port Harcourt, Nigeria: a retrospective cohort study. PMID- 28335661 TI - Safety and efficacy of balloon angioplasty of the anterior cerebral artery for vasospasm treatment after subarachnoid hemorrhage. AB - Balloon angioplasty is often performed for symptomatic vasospasm following aneurysmal subarachnoid hemorrhage. Angioplasty of the anterior cerebral artery (ACA), however, is perceived to be a challenging endeavor and not routinely performed due to technical and safety concerns. Here, we evaluate the safety and efficacy of balloon angioplasty of the anterior cerebral artery for vasospasm treatment. Patients with vasospasm following subarachnoid hemorrhage who underwent balloon angioplasty at our institution between 2011 and 2016 were retrospectively reviewed. All ACA angioplasty segments were analyzed for pre- and post-angioplasty radiographic measurements. The degree of vasospasm was categorized as mild (<25%), moderate (25-50%), or severe (>50%), and relative change in caliber was measured following treatment. Clinical outcomes following treatment were also assessed. Among 17 patients, 82 total vessel segments and 35 ACA segments were treated with balloon angioplasty. Following angioplasty, 94% of segments had increased caliber. Neurological improvement was noted in 75% of awake patients. There were no intra-procedural complications, but two patients developed ACA territory infarction, despite angioplasty treatment. We demonstrate that balloon angioplasty of the ACA for vasospasm treatment is safe and effective. Thus, ACA angioplasty should be considered to treat vasospasm in symptomatic patients recalcitrant to vasodilation infusion therapy. PMID- 28335662 TI - Performance of computed tomography angiography to determine anterograde and collateral blood flow status in patients with symptomatic middle cerebral artery stenosis. AB - Background The purpose of this study was to determine the performance of computed tomography angiography (CTA) by using a scoring system to predict anterograde and collateral blood flow status in patients with symptomatic middle cerebral artery (MCA) stenosis with use of conventional angiography as standard reference. Methods We retrospectively identified all consecutive patients with unilateral symptomatic MCA stenosis in our center who underwent conventional angiography and CTA within 1 month. The anterograde and collateral blood flow (AnCo) scoring system consisted of anterograde score (AnS) and collateral score (CoS). Evaluation of the CTA images was done independently by two readers, based on the AnCo scoring system. The conventional angiography was assessed by using the Thrombolysis in Cerebral Infarction (TICI) and American Society of Interventional and Therapeutic Neuroradiology (ASITN/SIR) scoring system to determine the status of anterograde and collateral blood flow. Diagnostic performance of AnCo was evaluated by using the area under the receiver operating characteristic (ROC) curve. Results A total of 61 patients were included in the analysis with mean age of 53.4 +/- 11.0 years. AnS demonstrated a strong correlation with TICI with statistical significance ( r = 0.786; p < 0.001). CoS had a modest yet statistically significant correlation with ASITN/SIR ( r = 0.574; p < 0.001). The ROC curve analysis for AnS demonstrated an area under the curve (AUC) of 0.894 ( p < 0.001) and the ROC curve analysis for CoS showed an AUC of 0.824 ( p < 0.001). Conclusions CTA was a potential method to evaluate anterograde and collateral blood flow status in patients with symptomatic unilateral MCA stenosis. PMID- 28335663 TI - Universal and particular in morphological processing: Evidence from Hebrew. AB - Do properties of individual languages shape the mechanisms by which they are processed? By virtue of their non-concatenative morphological structure, the recognition of complex words in Semitic languages has been argued to rely strongly on morphological information and on decomposition into root and pattern constituents. Here, we report results from a masked priming experiment in Hebrew in which we contrasted verb forms belonging to two morphological classes, Paal and Piel, which display similar properties, but crucially differ on whether they are extended to novel verbs. Verbs from the open-class Piel elicited familiar root priming effects, but verbs from the closed-class Paal did not. Our findings indicate that, similarly to other (e.g., Indo-European) languages, down-to-the root decomposition in Hebrew does not apply to stems of non-productive verbal classes. We conclude that the Semitic word processor is less unique than previously thought: Although it operates on morphological units that are combined in a non-linear way, it engages the same universal mechanisms of storage and computation as those seen in other languages. PMID- 28335664 TI - Cognitive Behavioral Intervention Compared to Telephone Counseling Early after Mild Traumatic Brain Injury: A Randomized Trial. AB - Many patients do not return to work (RTW) after mild traumatic brain injury (mTBI) because of persistent complaints that are often resistant to therapy in the chronic phase. Recent studies suggest that psychological interventions should be implemented early post-injury to prevent patients from developing chronic complaints. This study is a randomized, controlled trial that examines the effectiveness of a newly developed cognitive behavioral therapy (CBT) intervention (CBTi) compared to telephonic counseling (TC) in at-risk mTBI patients (patients with high reports of early complaints). Patients underwent either five sessions of CBT treatment or five phone conversations starting 4-6 weeks post-trauma. The main outcome measure was RTW 6 and 12 months post-trauma. Secondary measures comprised functional outcome at 6 and 12 months, and depression, anxiety, and reported post-traumatic complaints at 3, 6, and 12 months post-injury. After excluding dropouts, CBTi consisted of 39 patients and TC of 45 patients. No significant differences were found with regard to RTW, with 65% of CBTi patients and 67% of TC patients reporting a RTW at previous level. However, TC patients reported fewer complaints at 3 (8 vs. 6; p = 0.010) and 12 months post-injury (9 vs. 5; p = 0.006), and more patients in the TC group showed a full recovery 12 months post-injury compared to the CBTi group (62% vs. 39%). The results of this study suggest that early follow-up of at-risk patients can have a positive influence on patients' well-being, and that a low-intensive, low cost telephonic intervention might be more effective than a CBT intervention at improving outcome in at-risk patients. PMID- 28335666 TI - Control of dental-derived induced pluripotent stem cells through modified surfaces for dental application. AB - OBJECTIVE: The aim of this study is to investigate the behaviour of iPSc derived from dental stem cells in terms of initial adhesion, differentiation potential on differently surface-treated titanium disc. MATERIALS AND METHODS: iPSc derived from human gingival fibroblasts (hGFs) were established using 4-reprogramming factors transduction with Sendai virus. The hGF-iPSc established in this study exhibited the morphology and growth properties similar to human embryonic stem (ES) cells and expressed pluripotency makers. Alkaline Phosphatase (AP) staining, Embryoid Body (EB) formation and in vitro differentiation and karyotyping further confirmed pluripotency of hGF-iPSc. Then, hGF-iPSc were cultured on machined- and Sandblasted and acid etched (SLA)-treated titanium discs with osteogenic induction medium and their morphological as well as quantitative changes according to different surface types were investigated using Alizrin Red S staining, Scanning electron microscopy (SEM), Flow cytometry and RT-PCR. RESULTS: Time-dependent and surface-dependent morphological changes as well as quantitative change in osteogenic differentiation of hGF-iPSc were identified and osteogenic gene expression of hGF-iPSc cultured on SLA-treated titanium disc found to be greater than machined titanium disc, suggesting the fate of hGF-iPSc may be determined by the characteristics of surface to which hGF-iPSc first adhere. CONCLUSIONS: iPSc derived from dental stem cell can be one of the most promising and practical cell sources for personalized regenerative dentistry and their morphological change as well as quantitative change in osteogenic differentiation according to different surface types may be further utilized for future clinical application incorporated with dental implant. PMID- 28335665 TI - Calcium oxalate crystals induces tight junction disruption in distal renal tubular epithelial cells by activating ROS/Akt/p38 MAPK signaling pathway. AB - Tight junction plays important roles in regulating paracellular transports and maintaining cell polarity. Calcium oxalate monohydrate (COM) crystals, the major crystalline composition of kidney stones, have been demonstrated to be able to cause tight junction disruption to accelerate renal cell injury. However, the cellular signaling involved in COM crystal-induced tight junction disruption remains largely to be investigated. In the present study, we proved that COM crystals induced tight junction disruption by activating ROS/Akt/p38 MAPK pathway. Treating Madin-Darby canine kidney (MDCK) cells with COM crystals induced a substantial increasing of ROS generation and activation of Akt that triggered subsequential activation of ASK1 and p38 mitogen-activated protein kinase (MAPK). Western blot revealed a significantly decreased expression of ZO-1 and occludin, two important structural proteins of tight junction. Besides, redistribution and dissociation of ZO-1 were observed by COM crystals treatment. Inhibition of ROS by N-acetyl-l-cysteine (NAC) attenuated the activation of Akt, ASK1, p38 MAPK, and down-regulation of ZO-1 and occludin. The redistribution and dissociation of ZO-1 were also alleviated by NAC treatment. These results indicated that ROS were involved in the regulation of tight junction disruption induced by COM crystals. In addition, the down-regulation of ZO-1 and occludin, the phosphorylation of ASK1 and p38 MAPK were also attenuated by MK-2206, an inhibitor of Akt kinase, implying Akt was involved in the disruption of tight junction upstream of p38 MAPK. Thus, these results suggested that ROS-Akt-p38 MAPK signaling pathway was activated in COM crystal-induced disruption of tight junction in MDCK cells. PMID- 28335668 TI - Directions for use of intracranial pressure monitoring in treatment of severe traumatic brain injury using data from the Japan Neurotrauma Data Bank. AB - Neuromonitoring can be used to observe intracranial pathological conditions in neurointensive care, but use of intracranial pressure (ICP) monitoring is low in Japan. In this study, we retrospectively investigated the effects of ICP monitoring in treatment of severe traumatic brain injury (TBI) using data from the Japan Neurotrauma Data Bank (JNTDB). The study was conducted in 1,091 subjects enrolled in the JNTDB (Project 2009) from July 2009 to June 2011. The subjects were divided into those treated with and without ICP monitoring in intensive care for severe TBI. Age at admission, sex, level of consciousness (Glasgow Coma Scale (GCS)), pupillary findings, findings on head CT, treatment, and outcome were compared between these groups. The subjects were also classified into two groups based on the outcome. Relationships between patient background factors, including ICP, and clinical outcome were evaluated. The rate of ICP monitoring in treatment of severe TBI was 28%. Therapies were performed aggressively in the ICP monitoring group and this group had a significant reduction in mortality, but no increase in the favorable outcome rate. In multivariate analysis, age, GCS, pupillary abnormalities, perimesencephalic cistern disappearance or compression, and ICP were associated with a favorable outcome, but the therapeutic method did not affect outcome. We conclude that ICP monitoring and management of ICP are both important for management and care of severe TBI. However, current therapies do not control ICP sufficiently and more effective therapies are needed. PMID- 28335669 TI - The experience of modified sequential selective laser photocoagulation of communicating vessels technique for twin-twin transfusion syndrome. AB - OBJECTIVE: Fetoscopic laser photocoagulation of vascular anastomoses (FLP) is the essential choice in twin-twin transfusion syndrome (TTTS). We proposed that the modified sequential selective laser photocoagulation of communicating vessels (modified SQLPCV) to clarify the perinatal outcomes in TTTS. METHODS: The modified SQLPCV was designed with the following order: 1, artery-to-artery anastomoses; 2, venous-to-venous anastomoses; 3, artery-to-venous anastomoses from donor to recipient; and 4, artery-to-venous anastomoses from recipient to donor. The perinatal outcomes were present in TTTS patients who underwent the modified SQLPCV. RESULTS: A total of 203 women underwent modified SQLPCV. The mean pregnancy prolongation period was 83 days, and the mean gestational age at delivery was 33 weeks (range 23-40 weeks). There was a significantly lower rate of recipient fetal demise than donor fetal demise (4% vs. 13%; p < .01). The survival rate of zero and one were respectively 6% (13/203) and 19% (39/203). Two survivors were seen in 74% (151/203), and at least one survivor in 94% (190/203). Univariate and multivariate analysis showed that abnormal fetal Doppler measurements in donor were correlated with donor demise after surgery. CONCLUSIONS: The modified SQLPCV represents satisfactory outcomes for fetuses complicating with TTTS. PMID- 28335670 TI - Different lengths, copies and expression levels of the mitochondrial atp6 gene in male sterile and fertile lines of carrot (Daucus carota L.). AB - The male-sterile carrot is an effective material for carrot breeding. The atp6 gene is involved in carrot fertility. However, the differences in lengths, copies, and expression profiles of the atp6 gene in fertile and male-sterile lines of carrot are unclear. In this study, one copy atp6 gene was found in the mtDNAs of 'Kuroda' (fertility, 954 bp) and 'Wuye-BY' (male sterility, 819 bp) carrot lines, while two copies atp6 genes (Wuye-L and Wuye-D, 954 bp and 819 bp, respectively) were found in the mtDNA of 'Wuye' (fertility). Two putative conserved domains have been detected in the carrot atp6 protein. Evolutionary analysis showed that the atp6 protein sequences of Wuye-L and Kuroda were clustered in the same branch, while Wuye-D and Wuye-BY were clustered in the same branch. The atp6 gene was higher expressed in the flowers of 'Kuroda' and 'Wuye' (Wuye-L), while lower expressed in 'Wuye-BY' and 'Wuye' (Wuye-D). PMID- 28335672 TI - Effect of Severe Vitamin D Deficiency at Admission on Shock Reversal in Children With Septic Shock. AB - OBJECTIVES: To evaluate the association of severe vitamin D deficiency with clinically important outcomes in children with septic shock. METHODS: We enrolled children <=17 years with septic shock prospectively over a period of 6 months. We estimated 25-hydroxyvitamin D [25 (OH) D] levels at admission and 72 hours. Severe deficiency was defined as serum 25 (OH) <10 ng/mL. We performed univariate and multivariate analysis to evaluate association with clinically important outcomes. RESULTS: Forty-three children were enrolled in the study. The prevalence of severe vitamin D deficiency was 72% and 69% at admission and 72 hours, respectively. On univariate analysis, severe vitamin D deficiency at admission was associated with lower rates of shock reversal, 74% (23) versus 25% (3); relative risk (95% confidence interval [CI]): 2.9 (1.09-8.08), at 24 hours and greater need for fluid boluses (75 vs 59 mL/kg). On multivariate analysis, nonresolution of shock at 24 hours was significantly associated with severe vitamin D deficiency after adjusting for other key baseline and clinical variables, adjusted odds ratio (95% CI): 12 (2.01-87.01); 0.01. CONCLUSION: The prevalence of severe vitamin D deficiency is high in children with septic shock admitted to pediatric intensive care unit. Severe vitamin D deficiency at admission seems to be associated with lower rates of shock reversal at 24 hours of ICU stay. Our study provides preliminary data for planning interventional studies in children with septic shock and severe vitamin D deficiency. PMID- 28335671 TI - The relationship between survival rate and intradialytic blood pressure changes in maintenance hemodialysis patients. AB - OBJECTIVE: The objective of this study is to investigate the relationship between blood pressure changes and all-cause mortality, and between blood pressure changes and cardiovascular mortality, for maintenance hemodialysis (MHD) patients during dialysis. METHODS: Data regarding general condition, biochemical indices, and survival prognosis of MHD patients who were treated at the Shanghai Jiao Tong University School of Medicine-affiliated Renji Hospital from July 2007 to December 2012 were collected, in order to evaluate the relationship between patients' blood pressure changes during hemodialysis and mortality. RESULTS: Among 364 patients, with an average age of 63.07 +/- 13.93 years, an average dialysis vintage of 76.00 (range, 42.25-134.00) months, and a follow-up time of 54.86 +/- 19.84 months, there were 85 cases (23.4%) of all-cause death and 46 cases (14.2%) of cardiovascular death. All-cause mortality and cardiovascular mortality were lowest (OR, 0.324 and 0.335; 95% CI, 0.152-0.692 and 0.123-0.911; p value, .004 and .032, respectively) in patients whose systolic blood pressure difference (DeltaSBP) before and after dialysis was between 7.09 and 14.25 mmHg. Kaplan-Meier analysis indicated that both all-cause mortality and cardiovascular mortality were markedly increased for patients with DeltaSBPless than -0.25 mmHg (p value, .001 and .044, respectively). Cox regression analysis showed that DeltaSBP< -0.25 mmHg, hemoglobin concentration, Kt/v and albumin were independent risk factors for all-cause mortality in MHD patients. CONCLUSIONS: MHD patients whose blood pressure increased significantly after hemodialysis had a higher risk of dying; DeltaSBP, hemoglobin concentration, Kt/v and albumin were independent risk factors for all-cause mortality in MHD patients. PMID- 28335673 TI - Modifiable Risk Factors for Delirium in Critically Ill Trauma Patients. AB - OBJECTIVE: Intensive care unit (ICU)-acquired delirium has been associated with increased morbidity and mortality. Prevention strategies including modification of delirium risk factors are emphasized by practice guidelines. No study has specifically evaluated modifiable delirium risk factors in trauma ICU patients. Our goal was to evaluate modifiable risk factors for delirium among trauma patients admitted to the ICU. DESIGN: Prospective observational study. SETTING: Two level 1 trauma ICU centers. PATIENTS: Patients 18 years of age or older admitted for trauma including mild to moderate traumatic brain injury were eligible for the study. INTERVENTIONS AND MEASUREMENTS: Delirium was assessed daily using the confusion assessment method for the ICU (CAM-ICU). The effect of modifiable risk factors was assessed using multivariate Cox regression analysis adjusting for severity of illness and significant nonmodifiable risk factors. MAIN RESULTS: A total of 58 of 150 recruited patients (38.7%; 95% confidence interval [CI] 30.9-46.5) screened positive for delirium during ICU stay. When adjusting for significant nonmodifiable risk factors, physical restraints (hazard ratio [HR]: 2.13; 95% CI: 1.07-4.24) and active infection or sepsis (HR: 2.12; 95% CI: 1.18-3.81) significantly increased the risk of delirium, whereas opioids (HR: 0.35; 95% CI: 0.13-0.98), episodes of hypoxia (HR: 0.55; 95% CI: 0.31-0.95), access to a television/radio in the room (HR: 0.26; 95% CI: 0.11-0.62), and number of hours mobilized per day (HR: 0.77; 95% CI: 0.68-0.88) were associated with significantly less risk of delirium. CONCLUSION: We have identified modifiable risk factors for delirium. Future studies should aim at implementing strategies to modify these risk factors and evaluate their impact on the risk of delirium. PMID- 28335674 TI - An unexpected cause of transient diarrhea. AB - Migration of percutaneous endoscopic gastrostomy (PEG) tube to colon with gastro colonic-cutaneous fistula formation is a rare complication of the procedure. Transient episodic diarrhea following each PEG tube feeding is typical of this complication. We present a 72-year-old man with cerebrovascular disease and scoliosis who encountered episodes of transient diarrhea after each PEG tube feeding. His diarrhea was refractory to medications. Colonoscopy demonstrated a mal-positioned PEG in the transverse colon. Computed tomogram (CT) of abdomen further confirmed the finding. After removal of the migrated PEG, his diarrhea had ceased completely. The gastro-colonic-cutaneous fistula was further managed with endoscopic clipping method with no complications encountered during follow up. PMID- 28335675 TI - Development and Application of an Indirect Enzyme-Linked Immunosorbent Assay Using Recombinant Mag1 for Serodiagnosis of Toxoplasma gondii In Dogs. AB - Serologic tests are widely accepted and applied as means to detect anti- Toxoplasma gondii immunoglobulin G antibodies. In this study, recombinant matrix antigen (rMAG1) was induced by isopropyl-beta-d-thiogalactoside and purified by nickel-nitrilotriacetic acid purification system. We then developed and optimized an indirect enzyme-linked immunosorbent assay (ELISA) through checkerboard assays using serial dilutions of antigens and sera to assess the potential use of rMAG1 in serologic detection of T. gondii infection in dogs. Serum samples from 93 domestic dogs were analyzed by western blot and rMAG1-ELISA. The results were compared with those obtained from an ELISA with the soluble Toxoplasma lysate antigens (TLA). We found that although yielding an excellent agreement (96.7%) with western blot data (kappa = 0.9659), rMAG1-ELISA produced higher sensitivity (93.9% vs. 87.8%) and specificity (98.3% vs. 96.7%) than TLA-ELISA. In addition, receiver operating characteristic analysis also revealed that rMAG1-ELISA is in more agreement with western blot (area under the curve [AUC] = 0.985) relative to TLA-ELISA (AUC = 0.955). These results indicated that the rMAG1-ELISA established in this study provides a promising and reliable tool for serologic detection of T. gondii infection in dogs. PMID- 28335677 TI - Comparison of anti-pertussis toxin ELISA and agglutination assays to assess immune responses to pertussis. AB - BACKGROUND: The goal of our study was to compare the following two methods of assessment of pertussis post-vaccination immunity: bacterial agglutination test and pertussis toxin enzyme-linked immunosorbent assay (ELISA). METHODS: The study was carried out in Perm Region, Russia. We measured pertussis immunity using two serological methods: ELISA of IgG to pertussis toxin (PT) and the agglutination test (AT) among 135 children, in the age range from 2 months to 17 years old. The immunization schedule included four doses of DTwP: at 3, 4.5 and 6 months of age and a booster at 18 months. All participants were divided into six age groups. RESULTS: The percentage of samples with IgG level less than the detection limit in vaccinated children was 52.2%. The total seropositivity rate (the percent of children with agglutinin titres >=1:160) in vaccinated children was 47.8%. Only a weak association was observed between agglutinin and anti-PT IgG titres (R = .3). Neither the primary nor the booster vaccination with DTwP influenced the IgG levels in children. Agglutinin titres significantly increased after vaccination and declined 5 years after the booster dose. Significant growth of IgG concentration was observed in 11-year-olds, indicating the presence of B. pertussis circulation in the childhood population. CONCLUSIONS: Based on the obtained results and the results of other authors, we summarize that anti-PT ELISA should be carefully used to assess the population immunity to pertussis. Currently, there is neither a serological test that accurately determines the protection against pertussis nor a distinctive criterion of protection that can be applied in seroepidemiological studies. PMID- 28335676 TI - Physiopathological approach to infective endocarditis in chronic hemodialysis patients: left heart versus right heart involvement. AB - Infectious endocarditis (IE), a complication that is both cardiac and infectious, occurs frequently and is associated with a heavy burden of morbidity and mortality in chronic hemodialysis patients (CHD). About 2-6% of chronic hemodialysis patients develop IE and the incidence is 50-60 times higher among CHD patients than in the general population. The left heart is the most frequent location of IE in CHD and the different published series report a prevalence of left valve involvement varying from 80% to 100%. Valvular and perivalvular abnormalities, alteration of the immune system, and bacteremia associated with repeated manipulation of the vascular access, particularly central venous catheters, comprise the main factors explaining the left heart IE in CHD patients. While left-sided IE develops in altered valves in a high-pressure system, right-sided IE on the contrary, generally develops in healthy valves in a low-pressure system. Right-sided IE is rare, with its incidence varying from 0% to 26% depending on the study, and the tricuspid valve is the main location. Might the massive influx of pathogenic and virulent germs via the central venous catheter to the right heart, with the tricuspid being the first contact valve, have a role in the physiopathology of IE in CHD, thus facilitating bacterial adhesion? While the physiopathology of left-sided IE entails multiple and convincing mechanisms, it is not the case for right-sided IE, for which the physiopathological mechanism is only partially understood and remains shrouded in mystery. PMID- 28335678 TI - Computational study on transfer of L-ascorbic acid by UlaA through Escherichia coli membrane. AB - In this study, the transfer of L-ascorbic acid by UlaA through Escherichia coli (E. coli) membrane was evaluated using density functional theory (DFT), molecular docking, and molecular dynamics (MD) simulation methods. DFT calculations at the B3lyp/6[Formula: see text]311[Formula: see text]G(p,d) level were performed to investigate the interaction properties and molecular descriptors. The physical properties, such as chemical potential, chemical hardness, and chemical electrophilicity of all studied molecules, were investigated. Natural population analysis was employed to describe the state of charge transfer between interactions using the natural bond orbital (NBO). The atoms in molecules (AIM) theory was used to examine the properties of the bond critical points such as their electron densities and Laplacians. Molecular docking studies showed that L ascorbic acid was bounded to the internal cavity of UlaA. It was found that there were some hydrogen bond interactions between L-ascorbic acid and active sites of UlaA. The results of the MD simulation showed that the root mean square deviation (RMSD) of UlaA and L-ascorbic acid bound-UlaA reached equilibrium after 3.7[Formula: see text]ns. An evaluation of the radius of gyration ([Formula: see text]) revealed that UlaA and L-ascorbic acid bound-UlaA were stabilized around 10,000[Formula: see text]ns. Finally, analysis of the RMS fluctuations suggested that the structure of the L-ascorbic acid binding site remained approximately rigid during simulation. All obtained results shed light on the special manner of L-ascorbic acid transfer through E. coli membrane, and confirmed the results of previous studies on this issue. PMID- 28335681 TI - Is action video gaming related to sustained attention of adolescents? AB - Over the past few years, an increasing number of studies have shown that playing action video games can have positive effects on tasks that involve attention and visuo-spatial cognition (e.g., visual search, enumeration tasks, tracking multiple objects). Although playing action video games can improve several cognitive functions, the intensive interaction with the exciting, challenging, intrinsically stimulating and perceptually appealing game environments may adversely affect other functions, including the ability to maintain attention when the level of stimulation is not as intense. This study investigated whether a relationship existed between action video gaming and sustained attention performance in a sample of 45 Italian teenagers. After completing a questionnaire about their video game habits, participants were divided into Action Video Game Player (AVGP) and Non-Action Video Game Player (NAVGP) groups and underwent cognitive tests. The results confirm previous findings of studies of AVGPs as they had significantly enhanced performance for instantly enumerating a set of items. Nevertheless, we found that the drop in performance over time, typical of a sustained attention task, was significantly greater in the AVGP compared with the NAVGP group. This result is consistent with our hypothesis and demonstrates a negative effect of playing action video games. PMID- 28335680 TI - AMPK Knockdown in Placental Labyrinthine Progenitor Cells Results in Restriction of Critical Energy Resources and Terminal Differentiation Failure. AB - Placental abnormalities can cause Pregnancy-Associated Disorders, including preeclampsia, intrauterine growth restriction, and placental insufficiency, resulting in complications for both the mother and fetus. Trophoblast cells within the labyrinthine layer of the placenta facilitate the exchange of nutrients, gases, and waste between mother and fetus; therefore, the development of this cell layer is critical for fetal development. As trophoblast cells differentiate, it is assumed their metabolism changes with their energy requirements. We hypothesize that proper regulation of trophoblast metabolism is a key component of normal placental development; therefore, we examined the role of AMP-activated kinase (AMPK, PRKAA1/2), a sensor of cellular energy status. Our previous studies have shown that AMPK knockdown alters both trophoblast differentiation and nutrient transport. In this study, AMPKalpha1/2 shRNA was used to investigate the metabolic effects of AMPK knockdown on SM10 placental labyrinthine progenitor cells before and after differentiation. Extracellular flux analysis confirmed that AMPK knockdown was sufficient to reduce trophoblast glycolysis, mitochondrial respiration, and ATP coupling efficiency. A reduction in AMPK in differentiated trophoblasts also resulted in increased mitochondrial volume. These data indicate that a reduction in AMPK disrupts cellular metabolism in both progenitors and differentiated placental trophoblasts. This disruption correlates to abortive trophoblast differentiation that may contribute to the development of Pregnancy-Associated Disorders. PMID- 28335682 TI - Effect of lipophilicity of amylamine and amylglycine ligands on biological activity of new anticancer cisplatin analog. AB - Investigation of side effects and solubility of anticancer drugs is a major challenge in chemotherapy science. Thus, design and synthesis of cisplatin analogs with higher lipophilicity as novel water-soluble anticancer drugs is valuable. In this work, two new Pt(II) complexes were synthesized with formula cis-[Pt(NH3)2(amylgly)]NO3 and cis-[Pt(amylamine)2(amylgly)]NO3, where gly is penthyl glycine as an amino acid. The new compounds were synthesized and extensively characterized using analytical techniques; spectroscopic methods, and conductivity measurement. The anticancer activity of synthesized complexes was investigated against colon cancer cell line HCT116 using MTT assay and results showed excellent anticancer activity with Cc50 values of 36 and 270 M after 24-h incubation time for cis-[Pt(NH3)2(amylgly)]NO3 and cis-[Pt(NH2 amyl)2(amylgly)]NO3, respectively; which is lower than that for cisplatin. These complexes were also interacted with highly polymerized calf thymus DNA and the binding mode of the complexes to CT-DNA was evaluated by fluorescence, circular dichroism, and UV spectroscopy. The calculation of binding and thermodynamic of Pt(II) complexes with CT-DNA can provide deeper insight into mechanism of the action of these types of complexes with nucleic acids. So, thermodynamic parameters were also determined according to isothermal titration. In comparison with cis-[Pt(NH3)2(amylgly)]NO3 in DNA interaction, the result show that cis [Pt(NH2-amyl)2(amylgly)]NO3 has higher affinity with binding constant Kf = 8.72 mM to CT-DNA. The results indicate that cis-[Pt(amylamine)2(amylgly)]NO3 with large and bulky aliphatic group bind to CT-DNA by different modes and covalent and groove bindings were preferred mode of interaction with DNA. PMID- 28335679 TI - Puerarin attenuates renal fibrosis by reducing oxidative stress induced epithelial cell apoptosis via MAPK signal pathways in vivo and in vitro. AB - Puerarin (PR) is an isoflavonoid isolated from the root of the plant Pueraria lobata and has been widely used in traditional Chinese herbal medicine for the treatment of various diseases. Oxidative stress and epithelial cell apoptosis play important roles in the renal fibrotic process. The present study aimed to determine whether or not PR inhibits renal fibrosis by reducing oxidative stress induced-epithelial cell apoptosis. In vivo, unilateral ureteral obstruction (UUO) induced renal fibrosis, and epithelial cell apoptosis. A total of 24 mice were randomly assigned to four experimental groups: sham, UUO alone, UUO +50 mg/kg PR, and UUO +100 mg/kg PR. In vitro, 200 MUM hydrogen peroxide (H2O2) induced epithelial cell apoptosis. The experiments were dived into four groups: control, H2O2 alone, H2O2+50 MUM PR, and H2O2+100 MUM PR. Tubular injury was measured in the renal cortex of the mice through periodic acid-Schiff (PAS) staining, and the extracellular matrix (ECM) was measured through Sirius red (SR), immunohistochemistry (IHC) staining, and Western blot. Renal epithelial cell apoptosis was measured through terminal deoxynucleotidyl transferase-mediated dUTP Nick-End labeling (TUNEL), flow cytometry (FCM), and Hoechst assays. The protein expression of NOX4, caspase3, ERK, P38, and JNK was assessed through Western blot. PAS staining showed that PR decreased renal tubular injury in UUO mice. SR and IHC staining demonstrated that PR decreased the accumulation of ECM. PR treatment significantly inhibited epithelial cell apoptosis according to the results of TUNEL, FCM, Hoechst, and Western blot. Furthermore, NOX4 increased in UUO mice and decreased with PR treatment. H2O2-derived oxidative stress activated epithelial apoptosis and mitogen-activated protein kinases (MAPK), and PR treatment significantly reversed it. These results suggest that PR treatment ameliorates renal fibrosis by inhibiting oxidative stress induced-epithelial cell apoptosis through MAPK signaling. PMID- 28335683 TI - Redescription of Pallisentis (Brevitritospinus) Indica (Acanthocephala: Quadrigyridae) from Channa punctatus Bloch & Schneider (Channidae) in Aligarh, India with New Understandings of Old Structures. AB - Pallisentis indica Mital and Lal, 1976 was originally described from Channa gachua Hamilton (Channidae) in Kali Nadi River, Aligarh, India. The parasite was later placed in the subgenus Brevitritospinus Amin, Heckmann, Ha, Luc, and Doanh, 2000 . Our collection from the spotted snakehead Channa punctatus Bloch & Schneider in another locality of the same stream in Aligarh produced many specimens with variable traits, revealing new structures that have never before been described in the Acanthocephala, especially relating to the ducted trunk spines. The proboscis has 4 circles of 10 hooks each, with hooks in the anterior 2 circles being considerably larger than those in the posterior 2 circles. Y shaped trunk spines are ducted in 2 regions separated by a spineless zone. The anterior collar spines are in complete rings of 9-17 circles of crowded spines and the larger posterior trunk spines are in 1 (posterior) to 41 (anterior) circles extending to level of cement glands in males posteriorly. Considerable variations from the original description and new structures are reported for the first time. PMID- 28335684 TI - Bone-Marrow-Derived Endothelial Progenitor Cell Treatment in a Model of Lateral Fluid Percussion Injury in Rats: Evaluation of Acute and Subacute Outcome Measures. AB - Traumatic brain injury (TBI) continues to be a serious health care issue while therapies to treat TBI remain elusive. Promising results from the use of endothelial progenitor cells (EPCs) in numerous disease states highlight the pleiotropic capacity of this cell type. We have previously demonstrated that EPC conditioned media reduces axonal degeneration subsequent to in vitro oxygen glucose deprivation insult and concurrently improves white matter and microvascular outcome in vivo after mid-line fluid percussion injury. In the current study, we evaluated the effectiveness of allogeneic endothelial cells derived from rat bone marrow on microvascular recovery and neuronal sparing after lateral fluid percussion injury. We observed reduced expression of activated caspase-3 and poly (ADP-ribose) polymerase cleavage at 72 h post-injury. Subacute injury assessments at 30 days post-injury using immunohistochemistry indicated nonsignificant effects on microvascular outcome and neuronal cell density in the hippocampus. Behavioral testing using the Morris Water Maze and rotarod demonstrated significant improvement in locomotor function, as measured by the rotarod task, but no significant differences in spatial memory ability. The data suggest that EPCs contribute to improvements in the early phase of secondary injury through inhibition of apoptosis whereas the effects on longer-term recovery were less clearly defined. There is potential in the use of EPCs to treat secondary injury post-TBI; however, optimization of their effects through increased duration or homing capacities remains to be examined. PMID- 28335685 TI - Preterm Delivery as a Unique Pathophysiologic State Characterized by Maternal Soluble FMS-Like Tyrosine Kinase 1 and Uterine Artery Resistance During Pregnancy: A Longitudinal Cohort Study. AB - BACKGROUND: Preterm delivery (PTD) may be characterized by altered interrelationships among angiogenic factors and measures of placental function. We analyzed the longitudinal relationship between maternal serum concentrations of soluble fms-like tyrosine kinase 1 (sFlt1), an important antiangiogenic factor, and uterine artery resistance in pregnancies resulting in preterm and term deliveries. METHODS: Data were collected in a longitudinal cohort study involving 278 women monitored at 6 to 10, 10 to 14, 16 to 20, 22 to 26, and 32 to 36 weeks of gestation. Concentrations of maternal serum sFlt1 were determined using solid-phase enzyme-linked immunosorbent assay, and uterine artery resistance indices (RI) were measured by Doppler velocimetry at each interval. Preterm delivery was defined as birth before 37-weeks completed gestation. Data analyses used multivariable repeated measures regression models. RESULTS: Uterine artery RI decreased across gestation. As pregnancy progressed, RI trajectories diverged for term and preterm deliveries; the mean RI was significantly higher in third trimester for pregnancies resulting in PTD ( P = .08). sFlt1 was stable through 21 3/7 weeks of gestation and then increased rapidly; women who delivered preterm had significantly higher sFlt1 levels in the third trimester ( P = .04). The relationship between uterine artery RI and sFlt1 from the prior visit was significantly different between the groups ( P < .0001). For term deliveries, higher sFlt1 concentrations were associated with a smaller RI at the subsequent visit (beta = -.08, 95% confidence interval [CI]: -0.14 to -0.02). For PTD, higher sFlt1 concentrations were associated with a larger uterine artery RI (beta = .14, 95% CI: 0.06 to 0.22). CONCLUSION: PTD is characterized by altered relationships between angiogenic factors and placental vascular blood flow starting in early pregnancy. PMID- 28335686 TI - Grammatical-gender effects in noun-noun compound production: Evidence from German. AB - We examined how noun-noun compounds and their syntactic properties are lexically stored and processed in speech production. Using gender-marked determiner primes ( dermasc, diefem, dasneut [the]) in a picture naming task, we tested for specific effects from determiners congruent with either the modifier or the head of the compound target (e.g., Teemasckannefem [teapot]) to examine whether the constituents are processed independently at the syntactic level. Experiment 1 assessed effects of auditory gender-marked determiner primes in bare noun picture naming, and Experiment 2 assessed effects of visual gender-marked determiner primes in determiner-noun picture naming. Three prime conditions were implemented: (a) head-congruent determiner (e.g., diefem), (b) modifier-congruent determiner (e.g., dermasc), and (c) incongruent determiner (e.g., dasneuter). We observed a facilitation effect of head congruency but no effect of modifier congruency. In Experiment 3, participants produced novel noun-noun compounds in response to two pictures, demanding independent processing of head and modifier at the syntactic level. Now, head and modifier congruency effects were obtained, demonstrating the general sensitivity of our task. Our data support the notion of a single-lemma representation of lexically stored compound nouns in the German production lexicon. PMID- 28335687 TI - Isolated HAGL lesion after arthroscopic Bankart repair in a professional soccer player. AB - Post-traumatic anterior shoulder instability commonly occurs following an avulsion of capsulolabral complex from glenoid (Bankart lesion) or rarely after humeral avulsion of the glenohumeral ligaments (HAGL lesion). Arthroscopic Bankart repair offers high success rates of healing. However, trauma following the treatment may cause implant failure or re-avulsion of the treated tissue. We aim to present the diagnosis and treatment of an isolated HAGL lesion in a professional soccer player who had previously undergone arthroscopic Bankart repair. PMID- 28335688 TI - Predictors of Resourcefulness in Preadolescent Children. AB - Resourcefulness is a set of cognitive-behavioral self-control skills for coping with stress to maintain quality of life. However, research examining precursors in the development of resourcefulness in preadolescents is scant. A cross sectional approach was used to investigate hypothesized predicting effects of intrinsic contextual factors (children's age, gender, and school performance), extrinsic contextual factors (parents' age, gender, education, income, and resourcefulness), and process regulators (academic stress and dispositional optimism) in a convenience sample of 361 preadolescent-parent dyads. Results show that preadolescents' process regulators, academic stress, and dispositional optimism were significant predictors of resourcefulness. The findings suggest that preadolescents' resourcefulness was greatly influenced by process regulators, which are cognitive perceptions intervening the use of resourcefulness. Further research with various study designs is needed to examine additional factors that may influence resourcefulness in large and more diverse child-parent samples. PMID- 28335689 TI - Trends in occupational hygiene in Finland. AB - The aim of this work is to evaluate and describe the current status of, and prospects for, the future of occupational hygiene in Finland. The main sources of information include a seminar held in the annual meeting of Finnish Occupational Hygiene Society and interviews with different stakeholders. Nanotechnology and other new materials, changing work environments, circular economy including green jobs, new medical methods and advances of construction methods were recognized as future challenges. Future work opportunities for occupational hygiene experts included exposure assessments in indoor air surveys, private consulting and entrepreneurship in general, international activities and product safety issues. Unclear topics needing more attention in the future were thought to be in new exposures, sensitive persons, combined effects, skin exposures and applicability of personal protective equipment. Occupational hygiene should broaden its view; occupational hygienists should have to cooperate with other specialists and grasp new challenges. PMID- 28335690 TI - Promoting physical activity after stroke via self-management: a feasibility study. AB - BACKGROUND: Many people with mild disability after stroke are physically inactive despite the risk of recurrent stroke. A self-management program may be one strategy to increase physical activity in stroke survivors. OBJECTIVES: To investigate the feasibility of a self-management program, and determine whether self-management can increase daily physical activity levels and self-efficacy for exercise, decrease cardiovascular risk, and improve walking ability, participation, and quality of life in people with mild disability after stroke. METHOD: A Phase I, single-group, pre-post intervention study was carried out with twenty stroke survivors who had mild disability and were discharged directly home from acute stroke units. A self-management program was delivered via five home based sessions over 3 months, incorporating: education, goal setting, barrier identification, self-monitoring, and feedback. Feasibility of the intervention was determined by examining adherence, duration, usefulness, and safety. Clinical outcomes were amount of physical activity (duration of moderate physical activity in min/day and counts of physical activity in steps/day), self-efficacy, cardiovascular risk, walking ability, participation, and quality of life. RESULTS: The intervention was feasible with 96% of sessions being delivered, each taking less than an hour (41 min, SD 12). Participants perceived the self management program to be useful and there were few adverse events. At 3 months, participants completed 27 min/day (95% CI 4-49) more moderate physical activity than at baseline and 16 min/day (95% CI -10 to 42) at 6 months. CONCLUSION: Self management appears to be feasible and has the potential to increase physical activity in people with mild disability after stroke. A Phase II randomized trial is warranted. PMID- 28335691 TI - Cases of drug-induced Torsade de Pointes: a review of Belgian cases in the EudraVigilance database. AB - OBJECTIVES: Post-marketing surveillance is very important, especially for rare adverse drug reactions like QTc-prolongation and Torsade de Pointes (TdP). The objective of this study was to investigate the characteristics of Belgian cases of drug-related TdP reported in the EudraVigilance database. METHODS: The EudraVigilance database was searched for Belgian post-marketing cases of TdP reported between December 2001-April 2015. These cases were identified with MedDRA preferred terms. Duplicate reports were excluded. Each included case report was reviewed to collect data about age, gender, seriousness, suspected drug, concomitant drugs, causality, and other known risk factors for QTc prolongation. RESULTS: Between 2001 and 2015, only 31 cases coded as TdP were identified; 16 cases were also coded as 'prolonged QT' and 2 patients died. In total, 21 suspected drugs were implicated and most of them (N = 11) were part of list 1 of CredibleMeds. The most common suspected drugs were citalopram (N = 4) and amiodarone (N = 3). In 18 cases, a pharmacodynamic drug-drug interaction with risk of QTc-prolongation was present. Most patients (N = 25) had >=2 other risk factors for QTc-prolongation. CONCLUSION: Over 15 years, only a low number of Belgian cases of TdP were identified in the EudraVigilance database. In most case reports, multiple risk factors for QTc-prolongation could be detected. This illustrates that there is a clear underreporting of QTc-prolongation and TdP in Belgium. Initiatives are needed to improve the awareness and knowledge of health care professionals regarding the risk of QTc-prolongation and TdP, both to prevent cases of TdP and to stimulate the reporting of these cases. PMID- 28335693 TI - Erratum. PMID- 28335692 TI - Liposomal amphotericin B (AmBisome(r)) at beginning of its third decade of clinical use. AB - Haematologists have been using liposomal amphotericin-B (L-AMB) since 1993 and despite the introduction of several novel antifungal agents over the past decade, their propensity to prescribe L-AMB remains unchanged. Although antifungal guidelines strongly recommend voriconazole as the drug of choice in the treatment of probable and proven invasive fungal disease (IFD), L-AMB is widely used in the real life because of its several advantages in terms of wide anti-mould spectrum, tolerability and efficacy. Furthermore, the concept that L-AMB is endowed with immune-modulating effects, which may have a role in fighting IFD, represent another reason for its use in patients who do not tolerate an excess of inflammation. Finally, given its tolerability and safety, L-AMB is an ideal partner for combining therapy, particularly with echinocandins with which shares the immunological properties that result in a synergistic effect. PMID- 28335694 TI - Construction of Three-Dimensional Dermo-Epidermal Skin Equivalents Using Cell Coating Technology and Their Utilization as Alternative Skin for Permeation Studies and Skin Irritation Tests. AB - In vitro generated human skin equivalents are generating interest as promising tools in basic study, as alternatives to animal testing, and for clinical applications in regenerative medicine. For prediction of skin irritation and corrosion, three-dimensional human skin equivalents consisting of differentiated human keratinocytes (KCs) have been developed and some models have been internationally accepted. However, more delicate assessments using full-thickness skin models, such as skin sensitization tests, cannot be performed due to the lack of a dermis containing fibroblasts or appendages. In a previous study, we developed dermo-epidermal human skin equivalents (DESEs) using a cell coating technique, which employs cell surface coating by layer-by-layer assembled extracellular matrix (ECM) films. The DESEs with dermis consisting of normal human dermal fibroblasts (NHDFs) and epidermis consisting of human KCs were easily fabricated by using this technology. In this study, the constructed DESEs were evaluated as an alternative skin for skin permeation and irritation tests. A good relationship of permeability coefficient of chemicals was observed between the DESEs and human skin data. We investigated whether the DESEs, a new in vitro skin model, are capable of identifying skin irritant and nonirritant substances among 20 reference chemicals. It was confirmed that the DESEs are applicable to skin irritation testing as defined in the European Centre for the Validation of Alternative Methods (ECVAM) Performance Standard (OECD Test Guideline 439). We further studied the construction of DESEs with density-controlled blood capillary networks using human umbilical vein endothelial cells (HUVECs). The results suggest that DESEs allowing incorporation of skin appendages are more promising alternatives to animal testing and can be applied to the design of physiologically relevant in vitro skin models. PMID- 28335695 TI - Impact of cognition and noise reduction on speech perception in adults with unilateral cochlear implants. AB - OBJECTIVES: The purpose of this study was to investigate the impact of cognition and noise reduction (NR) technology in cochlear implants (CIs) on speech perception and listening effort. METHODS: Thirteen adults fitted with unilateral CIs (Nucleus(r) 6, CP900) participated in this study. Participants performed: (I) cognitive tests of working memory and processing speed, (II) speech perception in noise tests, and (III) an auditory-visual dual-task paradigm to quantify listening effort, as a part of the three-phase experimental study. Both the participant and the tester, performing the outcome measures, were blinded to the NR settings (ON/OFF) of the CI for phases II and III. RESULTS: Speech intelligibility significantly improved with the NR activated, but was independent of individual differences in cognitive abilities. Listening effort did not significantly change with NR setting; however, there was a trend for participants with good working memory to have better speech perception scores with NR activated during the effortful listening task (dual-task paradigm). CONCLUSION: Future studies are warranted to explore the interaction between cognition and CI NR algorithms during an effortful listening task. PMID- 28335696 TI - Development and initial evaluation of a lateral flow dipstick test for antigen detection of Entamoeba histolytica in stool sample. AB - Entamoeba histolytica infection remains a public health concern in developing countries. Early diagnosis of amoebiasis can avoid disease complications, thus this study was aimed at developing a test that can rapidly detect the parasite antigens in stool samples. Rabbits were individually immunized with recombinant pyruvate phosphate dikinase (rPPDK) and E. histolytica excretory-secretory antigens to produce polyclonal antibodies. A rapid dipstick test was produced using anti-rPPDK PAb lined on the dipstick as capture reagent and anti-EhESA PAb conjugated to colloidal gold as the detector reagent. Using E. histolytica-spiked in stool sample of a healthy individual, the detection limit of the dipstick test was found to be 1000 cells ml-1. Meanwhile when rPPDK was spiked in the stool sample, the minimum concentration detected by the dipstick test was 0.1 MUg ml-1. The performances of the dipstick, commercial Techlab E. histolytica II enzyme linked immunosorbent assays (ELISA) and real-time PCR were compared using 70 stool samples from patients infected with Entamoeba species (n = 45) and other intestinal pathogens (n = 25). When compared to real-time PCR, the diagnostic sensitivity of the dipstick for detection of E. histolytica was 65.4% (n = 17/26); while the diagnostic specificity when tested with stool samples containing other intestinal pathogens was 92% (23/25). In contrast, Techlab E. histolytica II ELISA detected 19.2% (5/26) of the E. histolytica-positive samples as compared to real-time PCR. The lateral flow dipstick test produced in this study enabled rapid detection of E. histolytica, thus it showed good potential to be further developed into a diagnostic tool for intestinal amoebiasis. PMID- 28335697 TI - Investigation of a Lifestyle Intervention in Women at High Risk of Breast Cancer. AB - One fourth of breast cancer can be attributed to sedentary lifestyles and being overweight or obese. This pilot study was conducted to explore whether a 6-month lifestyle intervention affected body composition and obesity-related biomarkers among women at high risk of breast cancer. Overweight/obese women at high risk of breast cancer were randomized to the control group or to the intervention. The intervention was an individually tailored, cognitive-behavioral therapy program that assists women in identifying strategies to improve their nutrition and physical activity habits with the goal of reduced adiposity. We compared changes in body composition and plasma biomarkers from baseline to 6 months. Body weight, adiposity, leptin, insulin resistance, and C-reactive protein were significantly reduced in the intervention group versus controls. No significant differences were observed in adiponectin, insulin, glucose, or interleukin-6. Our findings suggest that this intervention improves the metabolic and inflammatory profiles of overweight/obese women at risk of breast cancer. PMID- 28335699 TI - Approaches to paraspinal tumours - a technical note. AB - Neurogenic tumours of the paraspinal space can occur in all age groups. It is common in adult population and relatively rare in elderly group. Usually they are benign, but in children, arising from the autonomic system, tends to be malignant in nature. Usually in adults, they arise from peripheral nerve sheath and are labelled as schwannomas. For a given tumour, determination of a correct surgical approach is mandatory to achieve a successful surgical outcome. Several factors like tumour size, histology, involvement of the bony spinal canal, etc. are some of the deciding factors for a correct surgical approach. Since many such tumours are benign, total excision is possible with a correct surgical approach. If the tumour involves the integrity of the spine then additionally a stabilization procedure may have to be carried out. Unfortunately, there are still no guidelines regarding the choice of surgical approach for the excision of such tumors. Presented here is a series of five patients managed by us over a period of 10 years. Four patients were adults and one female child was three years old. Four patients were operated upon successfully and the fifth one is waiting for surgery. PMID- 28335698 TI - Person-Centered Communication for Nursing Home Residents With Dementia: Four Communication Analysis Methods. AB - Person-centered communication recognizes the individual as a person and responds to the individual's feelings, preferences, and needs. This secondary analysis tested four interdisciplinary strategies to measure changes in person-centered communication used by nursing home staff following an intervention. Thirty-nine nursing assistants were recruited from 11 nursing homes and participated in the three-session Changing Talk communication training. Video recordings were collected at baseline, immediately postintervention, and at 3-month follow-up. Staff communication was analyzed using behavioral, psycholinguistic, and emotional tone coding of elderspeak communication and content analysis of communication topics. Sign rank test was used to compare postintervention changes for each measure of communication. Postintervention improvements in communication occurred for each measure; however, the changes were statistically significant only for behavioral and psycholinguistic measures. Methods and results for each communication measure were compared. Implications for future research and use of measures of person-centered communication as a tool to improve care are discussed. PMID- 28335701 TI - The effect of a whole-body vibration therapy on the sitting balance of subacute stroke patients: a randomized controlled trial. AB - BACKGROUND: The use of a whole-body vibration (WBV) therapy has recently been applied and investigated as a rehabilitation method for subacute stroke patients. OBJECTIVE: To evaluate the effects of a WBV therapy on recovery of balance in subacute stroke patients who were unable to gain sitting balance. METHODS: The conventional rehabilitation group (CG) received conventional physical therapy, including sitting balance training by a physical therapist, for 30 min a one session, for twice a day for five days a week for two weeks. The whole-body vibration group (VG) received one session of conventional physical therapy, and received WBV therapy instead of conventional physical therapy for 30 min a day for five days a week for two weeks. RESULTS: There were 15 patients in the CG and 15 patients in the VG who completed the two-week therapy. After the two-week therapy, both groups showed functional improvement. Patients in the VG improved functional ambulation categories, Berg balance scale, trunk impairment scale scores. But, no statistically significant correlations between the therapeutic methods and outcomes were observed in either group. CONCLUSION: Our results suggest that WBV therapy led to improvement of the recovery in balance recovery for subacute stroke patients. Because the WBV therapy was as effective as conventional physical therapy, we can consider a WBV therapy as a clinical method to improve the sitting balance of subacute stoke patients. PMID- 28335700 TI - Cochlear implants in the management of hearing loss in Neurofibromatosis Type 2. AB - OBJECTIVE: Review of cochlear implant (CI) outcomes in patients with Neurofibromatosis Type 2 (NF2), implanted in the presence of an ipsilateral vestibular schwannoma (VS). Hearing restoration was combined in some cases with a Bevacizumab regime. METHOD: Retrospective review of 12 patients, managed over the period 2009-2016, at a tertiary referral multidisciplinary NF2 clinic. The patients are grouped by hearing outcomes to explore likely protective factors, and to generate a proposed decision-making tool for the selection of either CI or Auditory Brainstem Implant (ABI). RESULTS: Four of the 12 patients achieved speech discrimination without lip-reading. In these individuals there is reason to think that the mechanism of their hearing loss was cochlear dysfunction. A further four patients received benefit to lip-reading and awareness of environmental sound. For such patients their hearing loss may have been due to both cochlear and neural dysfunction. Two patients gained access to environmental sound only from their CI. Two patients derived no benefit from their CIs, which were subsequently explanted. Both these latter patients had had prior ipsilateral tumour surgery, one just before the CI insertion. CONCLUSION: Cochlear implantation can lead to open set speech discrimination in patients with NF2 in the presence of a stable VS. Use of promontory stimulation and intraoperative electrically evoked auditory brainstem response testing, along with case history, can inform the decision whether to implant an ABI or CI. PMID- 28335703 TI - Corrigendum. AB - Holden A, Merrilees S, Buckley B, et al. First-in-human experience with the Gore balloon-expandable covered endoprosthesis in iliac artery occlusive disease. J Endovasc Ther. 2017;24:11-18. doi: 10.1177/1526602816680570 . PMID- 28335702 TI - A Benign but Unusual Radiological Sign During EVAS Follow-up. AB - PURPOSE: To report a heretofore undescribed complication seen on imaging after endovascular aortic sealing (EVAS). CASE REPORT: A 77-year-old woman was treated with the Nellix EVAS device for an infrarenal aortic aneurysm. After a normal computed tomography (CT) scan at 15 days, the 6-month CT showed the onset of perianeurysmal inflammatory tissue. The patient was asymptomatic, and blood tests were normal. Imaging suggested a nonaggressive inflammatory process, so a conservative approach was adopted with close follow-up. The periaortic tissue remitted without any treatment after a further 9 months (16 months after EVAS). CONCLUSION: The cause of this nonacute complication is unclear. Some clues suggest that interaction between the endobags and aneurysm wall could be involved. Imaging and clinical data led to a successful conservative strategy. PMID- 28335704 TI - Edward B. Diethrich, MD (1935-2017). PMID- 28335705 TI - Commentary: Outcome of Fenestrated Stent-Graft Repair for Abdominal Aortic Aneurysms. PMID- 28335707 TI - History of Proximal Carotid Protection and Flow Reversal. PMID- 28335706 TI - Transcarotid Artery Revascularization With Flow Reversal. AB - PURPOSE: To report a study evaluating the safety and efficacy of stenting via direct carotid access with flow reversal using the ENROUTE Transcarotid Neuroprotection System. METHODS: Between March 2009 and June 2012, 75 patients (mean age 72.6 years; 45 men) underwent carotid artery stenting with the ENROUTE System; the majority of patients (63, 84%) were asymptomatic. The primary safety endpoint was the composite of major stroke, myocardial infarction, or death at 30 days. Efficacy outcomes included acute device success, procedure success, and tolerance to flow reversal. Fifty-six (74.7%) patients underwent diffusion weighted magnetic resonance imaging (DW-MRI) before and after the procedure to assess the development of new ischemic brain lesions. RESULTS: Acute device and procedure success were achieved in 68 (90.6%) patients. The reverse flow circuit was established in 71 (94.6%) patients; only 5 patients demonstrated transient intolerance to flow reversal that did not interfere with completion of the procedure. The mean time on flow reversal was 19.1 minutes. In the DW-MRI substudy, 10 (17.9%) of 56 patients had ipsilateral new white lesions with a mean volume of 0.17 mL. At 30 days, no major stroke, myocardial infarction, or death occurred; 1 patient had experienced a minor stroke that was adjudicated as not related to either the device or procedure. CONCLUSION: Results of the PROOF study demonstrate the safety and efficacy of transcarotid revascularization with the ENROUTE Transcarotid Neuroprotection System. PMID- 28335708 TI - Will Carotid Artery Stenting Become a Safer Procedure Than Carotid Endarterectomy? PMID- 28335709 TI - Another Possible Pattern of Chimney EVAR-Related Type I Endoleak. PMID- 28335710 TI - Treatment of Posterior Circulation Symptomatic Disease: A Reappraisal May Be Needed. PMID- 28335711 TI - Peer Group and Text Message-Based Weight-Loss and Management Intervention for African American Women. AB - About 80% of African American (AA) women are overweight or obese. Accessible and effective weight management programs targeting weight loss, weight maintenance and the prevention of weight regain are needed to improve health of AA women. A feasibility study was conducted to examine the feasibility, acceptability, and potential efficacy of a 16-week intervention protocol for weight loss and management that combined daily text messages and biweekly peer group sessions. Modest but statistically significant reductions were detected in weight and body mass index from baseline to 16 weeks. At baseline, 36% of participants were in action and maintenance stages in measures of the stages of change for weight loss and management; this percent increased to 82% at 16 weeks. Findings of this feasibility study provide preliminary evidence of an educational intervention that could motivate women and lead to successful behavior change, and successful weight loss and management for AA women. PMID- 28335713 TI - Erratum to: An integrative Bayesian Dirichlet-multinomial regression model for the analysis of taxonomic abundances in microbiome data. PMID- 28335712 TI - Exploring the evolutionary origin of floral organs of Erycina pusilla, an emerging orchid model system. AB - BACKGROUND: Thousands of flowering plant species attract pollinators without offering rewards, but the evolution of this deceit is poorly understood. Rewardless flowers of the orchid Erycina pusilla have an enlarged median sepal and incised median petal ('lip') to attract oil-collecting bees. These bees also forage on similar looking but rewarding Malpighiaceae flowers that have five unequally sized petals and gland-carrying sepals. The lip of E. pusilla has a 'callus' that, together with winged 'stelidia', mimics these glands. Different hypotheses exist about the evolutionary origin of the median sepal, callus and stelidia of orchid flowers. RESULTS: The evolutionary origin of these organs was investigated using a combination of morphological, molecular and phylogenetic techniques to a developmental series of floral buds of E. pusilla. The vascular bundle of the median sepal indicates it is a first whorl organ but its convex epidermal cells reflect convergence of petaloid features. Expression of AGL6 EpMADS4 and APETALA3 EpMADS14 is low in the median sepal, possibly correlating with its petaloid appearance. A vascular bundle indicating second whorl derivation leads to the lip. AGL6 EpMADS5 and APETALA3 EpMADS13 are most highly expressed in lip and callus, consistent with current models for lip identity. Six vascular bundles, indicating a stamen-derived origin, lead to the callus, stelidia and stamen. AGAMOUS is not expressed in the callus, consistent with its sterilization. Out of three copies of AGAMOUS and four copies of SEPALLATA, EpMADS22 and EpMADS6 are most highly expressed in the stamen. Another copy of AGAMOUS, EpMADS20, and the single copy of SEEDSTICK, EpMADS23, are most highly expressed in the stelidia, suggesting EpMADS22 may be required for fertile stamens. CONCLUSIONS: The median sepal, callus and stelidia of E. pusilla appear to be derived from a sepal, a stamen that gained petal identity, and stamens, respectively. Duplications, diversifying selection and changes in spatial expression of different MADS-box genes shaped these organs, enabling the rewardless flowers of E. pusilla to mimic an unrelated rewarding flower for pollinator attraction. These genetic changes are not incorporated in current models and urge for a rethinking of the evolution of deceptive flowers. PMID- 28335715 TI - Cytotype coexistence in the field cannot be explained by inter-cytotype hybridization alone: linking experiments and computer simulations in the sexual species Pilosella echioides (Asteraceae). AB - BACKGROUND: Processes driving ploidal diversity at the population level are virtually unknown. Their identification should use a combination of large-scale screening of ploidy levels in the field, pairwise crossing experiments and mathematical modelling linking these two types of data. We applied this approach to determine the drivers of frequencies of coexisting cytotypes in mixed-ploidy field populations of the fully sexual plant species Pilosella echioides. We examined fecundity and ploidal diversity in seeds from all possible pairwise crosses among 2x, 3x and 4x plants. Using these data, we simulated the dynamics of theoretical panmictic populations of individuals whose progeny structure is identical to that determined by the hybridization experiment. RESULTS: The seed set differed significantly between the crossing treatments, being highest in crosses between diploids and tetraploids and lowest in triploid-triploid crosses. The number of progeny classes (with respect to embryo and endosperm ploidy) ranged from three in the 2x-2x cross to eleven in the 3x-3x cross. Our simulations demonstrate that, provided there is no difference in clonal growth and/or survival between cytotypes, it is a clear case of minority cytotype exclusion depending on the initial conditions with two stable states, neither of which corresponds to the ploidal structure in the field: (i) with prevalent diploids and lower proportions of other ploidies, and (ii) with prevalent tetraploids and 9% of hexaploids. By contrast, if clonal growth differs between cytotypes, minority cytotype exclusion occurs only if the role of sexual reproduction is high; otherwise differences in clonal growth are sufficient to maintain triploid prevalence (as observed in the field) independently of initial conditions. CONCLUSIONS: The projections of our model suggest that the ploidal structure observed in the field can only be reached via a relatively high capacity for clonal growth (and proportionally lower sexual reproduction) in all cytotypes combined with higher clonal growth in the prevailing cytotype (3x). PMID- 28335714 TI - Testis-specific ATP synthase peripheral stalk subunits required for tissue specific mitochondrial morphogenesis in Drosophila. AB - BACKGROUND: In Drosophila early post-meiotic spermatids, mitochondria undergo dramatic shaping into the Nebenkern, a spherical body with complex internal structure that contains two interwrapped giant mitochondrial derivatives. The purpose of this study was to elucidate genetic and molecular mechanisms underlying the shaping of this structure. RESULTS: The knotted onions (knon) gene encodes an unconventionally large testis-specific paralog of ATP synthase subunit d and is required for internal structure of the Nebenkern as well as its subsequent disassembly and elongation. Knon localizes to spermatid mitochondria and, when exogenously expressed in flight muscle, alters the ratio of ATP synthase complex dimers to monomers. By RNAi knockdown we uncovered mitochondrial shaping roles for other testis-expressed ATP synthase subunits. CONCLUSIONS: We demonstrate the first known instance of a tissue-specific ATP synthase subunit affecting tissue-specific mitochondrial morphogenesis. Since ATP synthase dimerization is known to affect the degree of inner mitochondrial membrane curvature in other systems, the effect of Knon and other testis-specific paralogs of ATP synthase subunits may be to mediate differential membrane curvature within the Nebenkern. PMID- 28335716 TI - Human MFAP1 is a cryptic ortholog of the Saccharomyces cerevisiae Spp381 splicing factor. AB - BACKGROUND: Pre-mRNA splicing involves the stepwise assembly of a pre-catalytic spliceosome, followed by its catalytic activation, splicing catalysis and disassembly. Formation of the pre-catalytic spliceosomal B complex involves the incorporation of the U4/U6.U5 tri-snRNP and of a group of non-snRNP B-specific proteins. While in Saccharomyces cerevisiae the Prp38 and Snu23 proteins are recruited as components of the tri-snRNP, metazoan orthologs of Prp38 and Snu23 associate independently of the tri-snRNP as members of the B-specific proteins. The human spliceosome contains about 80 proteins that lack obvious orthologs in yeast, including most of the B-specific proteins apart from Prp38 and Snu23. Conversely, the tri-snRNP protein Spp381 is one of only five S. cerevisiae splicing factors without a known human ortholog. RESULTS: Using InParanoid, a state-of-the-art method for ortholog inference between pairs of species, and systematic BLAST searches we identified the human B-specific protein MFAP1 as a putative ortholog of the S. cerevisiae tri-snRNP protein Spp381. Bioinformatics revealed that MFAP1 and Spp381 share characteristic structural features, including intrinsic disorder, an elongated shape, solvent exposure of most residues and a trend to adopt alpha-helical structures. In vitro binding studies showed that human MFAP1 and yeast Spp381 bind their respective Prp38 proteins via equivalent interfaces and that they cross-interact with the Prp38 proteins of the respective other species. Furthermore, MFAP1 and Spp381 both form higher-order complexes that additionally include Snu23, suggesting that they are parts of equivalent spliceosomal sub-complexes. Finally, similar to yeast Spp381, human MFAP1 partially rescued a growth defect of the temperature-sensitive mutant yeast strain prp38-1. CONCLUSIONS: Human B-specific protein MFAP1 structurally and functionally resembles the yeast tri-snRNP-specific protein Spp381 and thus qualifies as its so far missing ortholog. Our study indicates that the yeast Snu23-Prp38-Spp381 triple complex was evolutionarily reprogrammed from a tri snRNP-specific module in yeast to the B-specific Snu23-Prp38-MFAP1 module in metazoa, affording higher flexibility in spliceosome assembly and thus, presumably, in splicing regulation. PMID- 28335717 TI - Genomic regions underlying susceptibility to bovine tuberculosis in Holstein Friesian cattle. AB - BACKGROUND: The significant social and economic loss as a result of bovine tuberculosis (bTB) presents a continuous challenge to cattle industries in the UK and worldwide. However, host genetic variation in cattle susceptibility to bTB provides an opportunity to select for resistant animals and further understand the genetic mechanisms underlying disease dynamics. METHODS: The present study identified genomic regions associated with susceptibility to bTB using genome wide association (GWA), regional heritability mapping (RHM) and chromosome association approaches. Phenotypes comprised de-regressed estimated breeding values of 804 Holstein-Friesian sires and pertained to three bTB indicator traits: i) positive reactors to the skin test with positive post-mortem examination results (phenotype 1); ii) positive reactors to the skin test regardless of post-mortem examination results (phenotype 2) and iii) as in (ii) plus non-reactors and inconclusive reactors to the skin tests with positive post mortem examination results (phenotype 3). Genotypes based on the 50 K SNP DNA array were available and a total of 34,874 SNPs remained per animal after quality control. RESULTS: The estimated polygenic heritability for susceptibility to bTB was 0.26, 0.37 and 0.34 for phenotypes 1, 2 and 3, respectively. GWA analysis identified a putative SNP on Bos taurus autosomes (BTA) 2 associated with phenotype 1, and another on BTA 23 associated with phenotype 2. Genomic regions encompassing these SNPs were found to harbour potentially relevant annotated genes. RHM confirmed the effect of these genomic regions and identified new regions on BTA 18 for phenotype 1 and BTA 3 for phenotypes 2 and 3. Heritabilities of the genomic regions ranged between 0.05 and 0.08 across the three phenotypes. Chromosome association analysis indicated a major role of BTA 23 on susceptibility to bTB. CONCLUSION: Genomic regions and candidate genes identified in the present study provide an opportunity to further understand pathways critical to cattle susceptibility to bTB and enhance genetic improvement programmes aiming at controlling and eradicating the disease. PMID- 28335718 TI - rNAV 2.0: a visualization tool for bacterial sRNA-mediated regulatory networks mining. AB - BACKGROUND: Bacterial sRNA-mediated regulatory networks has been introduced as a powerful way to analyze the fast rewiring capabilities of a bacteria in response to changing environmental conditions. The identification of mRNA targets of bacterial sRNAs is essential to investigate their functional activities. However, this step remains challenging with the lack of knowledge of the topological and biological constraints behind the formation of sRNA-mRNA duplexes. Even with the most sophisticated bioinformatics target prediction tools, the large proportion of false predictions may be prohibitive for further analyses. To deal with this issue, sRNA target analyses can be carried out from the resulting gene lists given by RNA-SEQ experiments when available. However, the number of resulting target candidates may be still huge and cannot be easily interpreted by domain experts who need to confront various biological features to prioritize the target candidates. Therefore, novel strategies have to be carried out to improve the specificity of computational prediction results, before proposing new candidates for an expensive experimental validation stage. RESULT: To address this issue, we propose a new visualization tool rNAV 2.0, for detecting and filtering bacterial sRNA targets for regulatory networks. rNAV is designed to cope with a variety of biological constraints, including the gene annotations, the conserved regions of interaction or specific patterns of regulation. Depending on the application, these constraints can be variously combined to analyze the target candidates, prioritized for instance by a known conserved interaction region, or because of a common function. CONCLUSION: The standalone application implements a set of known algorithms and interaction techniques, and applies them to the new problem of identifying reasonable sRNA target candidates. PMID- 28335719 TI - Enhanced construction of gene regulatory networks using hub gene information. AB - BACKGROUND: Gene regulatory networks reveal how genes work together to carry out their biological functions. Reconstructions of gene networks from gene expression data greatly facilitate our understanding of underlying biological mechanisms and provide new opportunities for biomarker and drug discoveries. In gene networks, a gene that has many interactions with other genes is called a hub gene, which usually plays an essential role in gene regulation and biological processes. In this study, we developed a method for reconstructing gene networks using a partial correlation-based approach that incorporates prior information about hub genes. Through simulation studies and two real-data examples, we compare the performance in estimating the network structures between the existing methods and the proposed method. RESULTS: In simulation studies, we show that the proposed strategy reduces errors in estimating network structures compared to the existing methods. When applied to Escherichia coli, the regulation network constructed by our proposed ESPACE method is more consistent with current biological knowledge than the SPACE method. Furthermore, application of the proposed method in lung cancer has identified hub genes whose mRNA expression predicts cancer progress and patient response to treatment. CONCLUSIONS: We have demonstrated that incorporating hub gene information in estimating network structures can improve the performance of the existing methods. PMID- 28335720 TI - Widespread promoter methylation of synaptic plasticity genes in long-term potentiation in the adult brain in vivo. AB - BACKGROUND: DNA methylation is a key modulator of gene expression in mammalian development and cellular differentiation, including neurons. To date, the role of DNA modifications in long-term potentiation (LTP) has not been explored. RESULTS: To investigate the occurrence of DNA methylation changes in LTP, we undertook the first detailed study to describe the methylation status of all known LTP associated genes during LTP induction in the dentate gyrus of live rats. Using a methylated DNA immunoprecipitation (MeDIP)-array, together with previously published matched RNA-seq and public histone modification data, we discover widespread changes in methylation status of LTP-genes. We further show that the expression of many LTP-genes is correlated with their methylation status. We show that these correlated genes are enriched for RNA-processing, active histone marks, and specific transcription factors. These data reveal that the synaptic activity-evoked methylation changes correlates with pre-existing activation of the chromatin landscape. Finally, we show that methylation of Brain-derived neurotrophic factor (Bdnf) CpG-islands correlates with isoform switching from transcripts containing exon IV to exon I. CONCLUSIONS: Together, these data provide the first evidence of widespread regulation of methylation status in LTP associated genes. PMID- 28335722 TI - Generalizing cell segmentation and quantification. AB - BACKGROUND: In recent years, the microscopy technology for imaging cells has developed greatly and rapidly. The accompanying requirements for automatic segmentation and quantification of the imaged cells are becoming more and more. After studied widely in both scientific research and industrial applications for many decades, cell segmentation has achieved great progress, especially in segmenting some specific types of cells, e.g. muscle cells. However, it lacks a framework to address the cell segmentation problems generally. On the contrary, different segmentation methods were proposed to address the different types of cells, which makes the research work divergent. In addition, most of the popular segmentation and quantification tools usually require a great part of manual work. RESULTS: To make the cell segmentation work more convergent, we propose a framework that is able to segment different kinds of cells automatically and robustly in this paper. This framework evolves the previously proposed method in segmenting the muscle cells and generalizes it to be suitable for segmenting and quantifying a variety of cell images by adding more union cases. Compared to the previous methods, the segmentation and quantification accuracy of the proposed framework is also improved by three novel procedures: (1) a simplified calibration method is proposed and added for the threshold selection process; (2) a noise blob filter is proposed to get rid of the noise blobs. (3) a boundary smoothing filter is proposed to reduce the false seeds produced by the iterative erosion. As it turned out, the quantification accuracy of the proposed framework increases from 93.4 to 96.8% compared to the previous method. In addition, the accuracy of the proposed framework is also better in quantifying the muscle cells than two available state-of-the-art methods. CONCLUSIONS: The proposed framework is able to automatically segment and quantify more types of cells than state-of the-art methods. PMID- 28335721 TI - Transcriptomic insights into the genetic basis of mammalian limb diversity. AB - BACKGROUND: From bat wings to whale flippers, limb diversification has been crucial to the evolutionary success of mammals. We performed the first transcriptome-wide study of limb development in multiple species to explore the hypothesis that mammalian limb diversification has proceeded through the differential expression of conserved shared genes, rather than by major changes to limb patterning. Specifically, we investigated the manner in which the expression of shared genes has evolved within and among mammalian species. RESULTS: We assembled and compared transcriptomes of bat, mouse, opossum, and pig fore- and hind limbs at the ridge, bud, and paddle stages of development. Results suggest that gene expression patterns exhibit larger variation among species during later than earlier stages of limb development, while within species results are more mixed. Consistent with the former, results also suggest that genes expressed at later developmental stages tend to have a younger evolutionary age than genes expressed at earlier stages. A suite of key limb-patterning genes was identified as being differentially expressed among the homologous limbs of all species. However, only a small subset of shared genes is differentially expressed in the fore- and hind limbs of all examined species. Similarly, a small subset of shared genes is differentially expressed within the fore- and hind limb of a single species and among the forelimbs of different species. CONCLUSIONS: Taken together, results of this study do not support the existence of a phylotypic period of limb development ending at chondrogenesis, but do support the hypothesis that the hierarchical nature of development translates into increasing variation among species as development progresses. PMID- 28335723 TI - Erratum to: Unity in defence: honeybee workers exhibit conserved molecular responses to diverse pathogens. PMID- 28335725 TI - Surface layer proteins from virulent Clostridium difficile ribotypes exhibit signatures of positive selection with consequences for innate immune response. AB - BACKGROUND: Clostridium difficile is a nosocomial pathogen prevalent in hospitals worldwide and increasingly common in the community. Sequence differences have been shown to be present in the Surface Layer Proteins (SLPs) from different C. difficile ribotypes (RT) however whether these differences influence severity of infection is still not clear. RESULTS: We used a molecular evolutionary approach to analyse SLPs from twenty-six C. difficile RTs representing different slpA sequences. We demonstrate that SLPs from RT 027 and 078 exhibit evidence of positive selection (PS). We compared the effect of these SLPs to those purified from RT 001 and 014, which did not exhibit PS, and demonstrate that the presence of sites under positive selection correlates with ability to activate macrophages. SLPs from RTs 027 and 078 induced a more potent response in macrophages, with increased levels of IL-6, IL-12p40, IL-10, MIP-1alpha, MIP-2 production relative to RT 001 and 014. Furthermore, RTs 027 and 078 induced higher expression of CD40, CD80 and MHC II on macrophages with decreased ability to phagocytose relative to LPS. CONCLUSIONS: These results tightly link sequence differences in C. difficile SLPs to disease susceptibility and severity, and suggest that positively selected sites in the SLPs may play a role in driving the emergence of hyper-virulent strains. PMID- 28335724 TI - A genetic chronology for the Indian Subcontinent points to heavily sex-biased dispersals. AB - BACKGROUND: India is a patchwork of tribal and non-tribal populations that speak many different languages from various language families. Indo-European, spoken across northern and central India, and also in Pakistan and Bangladesh, has been frequently connected to the so-called "Indo-Aryan invasions" from Central Asia ~3.5 ka and the establishment of the caste system, but the extent of immigration at this time remains extremely controversial. South India, on the other hand, is dominated by Dravidian languages. India displays a high level of endogamy due to its strict social boundaries, and high genetic drift as a result of long-term isolation which, together with a very complex history, makes the genetic study of Indian populations challenging. RESULTS: We have combined a detailed, high resolution mitogenome analysis with summaries of autosomal data and Y-chromosome lineages to establish a settlement chronology for the Indian Subcontinent. Maternal lineages document the earliest settlement ~55-65 ka (thousand years ago), and major population shifts in the later Pleistocene that explain previous dating discrepancies and neutrality violation. Whilst current genome-wide analyses conflate all dispersals from Southwest and Central Asia, we were able to tease out from the mitogenome data distinct dispersal episodes dating from between the Last Glacial Maximum to the Bronze Age. Moreover, we found an extremely marked sex bias by comparing the different genetic systems. CONCLUSIONS: Maternal lineages primarily reflect earlier, pre-Holocene processes, and paternal lineages predominantly episodes within the last 10 ka. In particular, genetic influx from Central Asia in the Bronze Age was strongly male driven, consistent with the patriarchal, patrilocal and patrilineal social structure attributed to the inferred pastoralist early Indo-European society. This was part of a much wider process of Indo-European expansion, with an ultimate source in the Pontic-Caspian region, which carried closely related Y chromosome lineages, a smaller fraction of autosomal genome-wide variation and an even smaller fraction of mitogenomes across a vast swathe of Eurasia between 5 and 3.5 ka. PMID- 28335727 TI - Overexpression of snapdragon Delila (Del) gene in tobacco enhances anthocyanin accumulation and abiotic stress tolerance. AB - BACKGROUND: Rosea1 (Ros1) and Delila (Del) co-expression controls anthocyanin accumulation in snapdragon flowers, while their overexpression in tomato strongly induces anthocyanin accumulation. However, little data exist on how Del expression alone influences anthocyanin accumulation. RESULTS: In tobacco (Nicotiana tabacum 'Xanthi'), Del expression enhanced leaf and flower anthocyanin production through regulating NtCHS, NtCHI, NtF3H, NtDFR, and NtANS transcript levels. Transgenic lines displayed different anthocyanin colors (e.g., pale red: T0-P, red: T0-R, and strong red: T0-S), resulting from varying levels of biosynthetic gene transcripts. Under salt stress, the T2 generation had higher total polyphenol content, radical (DPPH, ABTS) scavenging activities, antioxidant related gene expression, as well as overall greater salt and drought tolerance than wild type (WT). CONCLUSION: We propose that Del overexpression elevates transcript levels of anthocyanin biosynthetic and antioxidant-related genes, leading to enhanced anthocyanin production and antioxidant activity. The resultant increase of anthocyanin and antioxidant activity improves abiotic stress tolerance. PMID- 28335726 TI - Analysis of hepatic transcript profile and plasma lipid profile in early lactating dairy cows fed grape seed and grape marc meal extract. AB - BACKGROUND: It was recently reported that dairy cows fed a polyphenol-rich grape seed and grape marc meal extract (GSGME) during the transition period had an increased milk yield, but the underlying reasons remained unclear. As polyphenols exert a broad spectrum of metabolic effects, we hypothesized that feeding of GSGME influences metabolic pathways in the liver which could account for the positive effects of GSGME in dairy cows. In order to identify these pathways, we performed genome-wide transcript profiling in the liver and lipid profiling in plasma of dairy cows fed GSGME during the transition period at 1 week postpartum. RESULTS: Transcriptomic analysis of the liver revealed 207 differentially expressed transcripts, from which 156 were up- and 51 were down-regulated, between cows fed GSGME and control cows. Gene set enrichment analysis of the 155 up-regulated mRNAs showed that the most enriched gene ontology (GO) biological process terms were dealing with cell cycle regulation and the most enriched Kyoto Encyclopedia of Genes and Genomes pathways were p53 signaling and cell cycle. Functional analysis of the 43 down-regulated mRNAs revealed that a great part of these genes are involved in endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) and inflammatory processes. Accordingly, protein folding, response to unfolded protein, unfolded protein binding, chemokine activity and heat shock protein binding were identified as one of the most enriched GO biological process and molecular function terms assigned to the down-regulated genes. In line with the transcriptomics data the plasma concentrations of the acute phase proteins serum amyloid A (SAA) and haptoglobin were reduced in cows fed GSGME compared to control cows. Lipidomic analysis of plasma revealed no differences in the concentrations of individual species of major and minor lipid classes between cows fed GSGME and control cows. CONCLUSIONS: Analysis of hepatic transcript profile in cows fed GSGME during the transition period at 1 week postpartum indicates that polyphenol-rich feed components are able to inhibit ER stress-induced UPR and inflammatory processes, both of which are considered to contribute to liver-associated diseases and to impair milk performance in dairy cows, in the liver of dairy cows during early lactation. PMID- 28335728 TI - Allelic incompatibility can explain female biased sex ratios in dioecious plants. AB - BACKGROUND: Biased sex ratios are common among dioecious plant species despite the theoretical prediction of selective advantage of even sex ratios. Albeit the high prevalence of deviations from even sex ratios, the genetic causes to sex biases are rarely known outside of a few model species. Here we present a mechanism underlying the female biased sex ratio in the dioecious willow species Salix viminalis. RESULTS: We compared the segregation pattern of genome-wide single nucleotide polymorphism markers in two contrasting bi-parental pedigree populations, the S3 with even sex ratio and the S5 with a female biased sex ratio. With the segregation analysis and comparison between the two populations, we were able to demonstrate that sex determination and sex ratio distortion are controlled by different genetic mechanisms. We furthermore located the sex ratio distorter locus to a Z/W-gametologous region on chromosome 15, which was in close linkage with the sex determination locus. Interestingly, all males in the population with biased sex ratio have in this sex ratio distorter locus the same genotype, meaning that males with the Z1/Z3-genotype were missing from the population, thereby creating the 2:1 female biased sex ratio. CONCLUSIONS: We attribute the absence of Z1/Z3 males to an allelic incompatibility between maternally and paternally inherited alleles in this sex ratio distorter locus. Due to the tight linkage with the sex determination locus only male individuals are purged from the population at an early age, presumably before or during seed development. We showed that such allelic incompatibility could be stably maintained over evolutionary times through a system of overdominant or pseudooverdominant alleles. Thus, it is possible that the same mechanism generates the female biased sex ratio in natural willow populations. PMID- 28335729 TI - Study protocol for the SOFIA project: Swallowing function, Oral health, and Food Intake in old Age: a descriptive study with a cluster randomized trial. AB - BACKGROUND: Extensive studies have shown that older people are negatively impacted by impaired eating and nutrition. The abilities to eat, enjoy food, and participate in social activities associated with meals are important aspects of health-related quality of life (HRQoL) and recovery after illness. This project aims to (i) describe and analyze relationships between oral health and oral HRQoL, swallowing ability, eating ability, and nutritional risk among older individuals admitted to short-term care; (ii) compare the perceptions that older individuals and staff report on care quality related to oral hygiene and eating; and (iii) study the feasibility and effects of a training program for people with impaired swallowing (i.e., dysphagia). METHODS/DESIGN: This project consists of two parts, which will be performed in five Swedish counties. It will include approximately 400 older individuals and 200 healthcare professionals. Part 1 is a cross-sectional, descriptive study of older people admitted to short-term care. Subjects will be assessed by trained professionals regarding oral health status, oral HRQoL, eating and nutritional risk, and swallowing ability. Swallowing ability will be measured with a teaspoon test and a swallowing capacity test (SCT). Furthermore, subjects and staff will complete a questionnaire regarding their perceptions of care quality. Part 2 is a cluster randomized intervention trial with controls. Older participants with dysphagia (i.e., SCT <10 ml/s, measured in part 1) will be recruited consecutively to either the intervention or control group, depending on where they were admitted for short-term care. At baseline, all subjects will be assessed for oral health status, oral HRQoL, eating and nutritional risk, swallowing ability, and swallowing-related QoL. Then, the intervention group will receive 5 weeks of training with an oral screen for neuromuscular training focused on orofacial and pharyngeal muscles. After completing the intervention, and at six months post-intervention, all assessments will be repeated in both study groups. DISCUSSION: The results will make important contributions to rehabilitation knowledge, including approaches for improving swallowing function, oral health, and food intake and for improving the quality of oral care for older people. TRIAL REGISTRATION: This trial was retrospectively registered at ClinicalTrials.gov, on July 4, 2016, identifier: NCT02825927 . PMID- 28335730 TI - Auscultatory versus oscillometric blood pressure measurement in patients with atrial fibrillation and arterial hypertension. AB - BACKGROUND: The aim of our study was to investigate the reliability of automated oscillometric blood pressure (BP) monitoring in the presence and absence of atrial fibrillation (AF) in hypertensive patients. METHODS: BP was measured and compared in 71 randomly selected patients with AF and arterial hypertension diagnosis, 4 times each by auscultatory and oscillometric (Microlife BP A6 PC with AF detection system) methods. RESULTS: Study included 71 patients: 36 males (mean age 67.4 years) and 35 females (70.2 years). At the time of BP measuring procedure, 36 patients were in sinus rhythm (SR) and 35 in AF. In SR patients mean systolic blood pressure (SBP) was 132 +/- 17.9 mmHg with auscultatory method (AM), 137.4 +/- 19.4 mmHg with oscillometric method (OM); mean diastolic BP was 77.1 +/- 10.9 mmHg (AM), 78.5 +/- 12.2 mmHg (OM), in AF patients mean SBP was 127.5 +/- 15.1 mmHg (AM), 133.6 +/- 17.4 mmHg (OM); mean diastolic BP was 81.4 +/ 9.9 mmHg (AM), 83.5 +/- 11.8 mmHg (OM), p = 0.037. The averages of differences for SBP and DBP in sinus rhythm group were (-5.3 mmHg (95% limits of agreement 27.2 - 16.6)) and (-1.4 mmHg (95% limits of agreement -12.8 - 10.0)), respectively. In patients with AF the averages of differences for SBP and DBP were (-6.1 mmHg (95% limits of agreement -23.9 - 11.7)) and (-2.1 mmHg (95% limits of agreement -12.9 - 8.7)), respectively. CONCLUSIONS: The oscillometric device validated for patients with AF on average gives 5.3 mmHg higher systolic BP values for patients with SR and 6.3 mmHg higher BP values for patients with AF. However, the limits of agreement between two methods reveal wide range of random error rates which is a questionable topic in clinical practice, as it could possibly affect the treatment of arterial hypertension in patients with AF. PMID- 28335731 TI - Highly diverse population of Picornaviridae and other members of the Picornavirales, in Cameroonian fruit bats. AB - BACKGROUND: The order Picornavirales represents a diverse group of positive stranded RNA viruses with small non-enveloped icosahedral virions. Recently, bats have been identified as an important reservoir of several highly pathogenic human viruses. Since many members of the Picornaviridae family cause a wide range of diseases in humans and animals, this study aimed to characterize members of the order Picornavirales in fruit bat populations located in the Southwest region of Cameroon. These bat populations are frequently in close contact with humans due to hunting, selling and eating practices, which provides ample opportunity for interspecies transmissions. RESULTS: Fecal samples from 87 fruit bats (Eidolon helvum and Epomophorus gambianus), were combined into 25 pools and analyzed using viral metagenomics. In total, Picornavirales reads were found in 19 pools, and (near) complete genomes of 11 picorna-like viruses were obtained from 7 of these pools. The picorna-like viruses possessed varied genomic organizations (monocistronic or dicistronic), and arrangements of gene cassettes. Some of the viruses belonged to established families, including the Picornaviridae, whereas others clustered distantly from known viruses and most likely represent novel genera and families. Phylogenetic and nucleotide composition analyses suggested that mammals were the likely host species of bat sapelovirus, bat kunsagivirus and bat crohivirus, whereas the remaining viruses (named bat iflavirus, bat posalivirus, bat fisalivirus, bat cripavirus, bat felisavirus, bat dicibavirus and bat badiciviruses 1 and 2) were most likely diet-derived. CONCLUSION: The existence of a vast genetic variability of picorna-like viruses in fruit bats may increase the probability of spillover infections to humans especially when humans and bats have direct contact as the case in this study site. However, further screening for these viruses in humans will fully indicate their zoonotic potential. PMID- 28335732 TI - Lung function associated gene Integrator Complex subunit 12 regulates protein synthesis pathways. AB - BACKGROUND: Genetic studies of human lung function and Chronic Obstructive Pulmonary Disease have identified a highly significant and reproducible signal on 4q24. It remains unclear which of the two candidate genes within this locus may regulate lung function: GSTCD, a gene with unknown function, and/or INTS12, a member of the Integrator Complex which is currently thought to mediate 3'end processing of small nuclear RNAs. RESULTS: We found that, in lung tissue, 4q24 polymorphisms associated with lung function correlate with INTS12 but not neighbouring GSTCD expression. In contrast to the previous reports in other species, we only observed a minor alteration of snRNA processing following INTS12 depletion. RNAseq analysis of knockdown cells instead revealed dysregulation of a core subset of genes relevant to airway biology and a robust downregulation of protein synthesis pathways. Consistent with this, protein translation was decreased in INTS12 knockdown cells. In addition, ChIPseq experiments demonstrated INTS12 binding throughout the genome, which was enriched in transcriptionally active regions. Finally, we defined the INTS12 regulome which includes genes belonging to the protein synthesis pathways. CONCLUSION: INTS12 has functions beyond the canonical snRNA processing. We show that it regulates translation by regulating the expression of genes belonging to protein synthesis pathways. This study provides a detailed analysis of INTS12 activities on a genome-wide scale and contributes to the biology behind the genetic association for lung function at 4q24. PMID- 28335733 TI - Effects of short-term hyperoxia on erythropoietin levels and microcirculation in critically Ill patients: a prospective observational pilot study. AB - BACKGROUND: The normobaric oxygen paradox states that a short exposure to normobaric hyperoxia followed by rapid return to normoxia creates a condition of 'relative hypoxia' which stimulates erythropoietin (EPO) production. Alterations in glutathione and reactive oxygen species (ROS) may be involved in this process. We tested the effects of short-term hyperoxia on EPO levels and the microcirculation in critically ill patients. METHODS: In this prospective, observational study, 20 hemodynamically stable, mechanically ventilated patients with inspired oxygen concentration (FiO2) <=0.5 and PaO2/FiO2 >= 200 mmHg underwent a 2-hour exposure to hyperoxia (FiO2 1.0). A further 20 patients acted as controls. Serum EPO was measured at baseline, 24 h and 48 h. Serum glutathione (antioxidant) and ROS levels were assessed at baseline (t0), after 2 h of hyperoxia (t1) and 2 h after returning to their baseline FiO2 (t2). The microvascular response to hyperoxia was assessed using sublingual sidestream dark field videomicroscopy and thenar near-infrared spectroscopy with a vascular occlusion test. RESULTS: EPO increased within 48 h in patients exposed to hyperoxia from 16.1 [7.4-20.2] to 22.9 [14.1-37.2] IU/L (p = 0.022). Serum ROS transiently increased at t1, and glutathione increased at t2. Early reductions in microvascular density and perfusion were seen during hyperoxia (perfused small vessel density: 85% [95% confidence interval 79-90] of baseline). The response after 2 h of hyperoxia exposure was heterogeneous. Microvascular perfusion/density normalized upon returning to baseline FiO2. CONCLUSIONS: A two hour exposure to hyperoxia in critically ill patients was associated with a slight increase in EPO levels within 48 h. Adequately controlled studies are needed to confirm the effect of short-term hyperoxia on erythropoiesis. TRIAL REGISTRATION: ClinicalTrials.gov ( www.clinicaltrials.gov ), NCT02481843 , registered 15th June 2015, retrospectively registered. PMID- 28335734 TI - Evaluation of AMSTAR to assess the methodological quality of systematic reviews in overviews of reviews of healthcare interventions. AB - BACKGROUND: Overviews of reviews (overviews) compile information from multiple systematic reviews (SRs) to provide a single synthesis of relevant evidence for decision-making. It is recommended that authors assess and report the methodological quality of SRs in overviews-for example, using A MeaSurement Tool to Assess systematic Reviews (AMSTAR). Currently, there is variation in whether and how overview authors assess and report SR quality, and limited guidance is available. Our objectives were to: examine methodological considerations involved in using AMSTAR to assess the quality of Cochrane and non-Cochrane SRs in overviews of healthcare interventions; identify challenges (and develop potential decision rules) when using AMSTAR in overviews; and examine the potential impact of considering methodological quality when making inclusion decisions in overviews. METHODS: We selected seven overviews of healthcare interventions and included all SRs meeting each overview's inclusion criteria. For each SR, two reviewers independently conducted AMSTAR assessments with consensus and discussed challenges encountered. We also examined the correlation between AMSTAR assessments and SR results/conclusions. RESULTS: Ninety-five SRs were included (30 Cochrane, 65 non-Cochrane). Mean AMSTAR assessments (9.6/11 vs. 5.5/11; p < 0.001) and inter-rater reliability (AC1 statistic: 0.84 vs. 0.69; "almost perfect" vs. "substantial" using the Landis & Koch criteria) were higher for Cochrane compared to non-Cochrane SRs. Four challenges were identified when applying AMSTAR in overviews: the scope of the SRs and overviews often differed; SRs examining similar topics sometimes made different methodological decisions; reporting of non-Cochrane SRs was sometimes poor; and some non-Cochrane SRs included other SRs as well as primary studies. Decision rules were developed to address each challenge. We found no evidence that AMSTAR assessments were correlated with SR results/conclusions. CONCLUSIONS: Results indicate that the AMSTAR tool can be used successfully in overviews that include Cochrane and non Cochrane SRs, though decision rules may be useful to circumvent common challenges. Findings support existing recommendations that quality assessments of SRs in overviews be conducted independently, in duplicate, with a process for consensus. Results also suggest that using methodological quality to guide inclusion decisions (e.g., to exclude poorly conducted and reported SRs) may not introduce bias into the overview process. PMID- 28335735 TI - Population diversity of the genetically determined TTR expression in human tissues and its implications in TTR amyloidosis. AB - BACKGROUND: Transthyretin (TTR) amyloidosis is a hereditary disease with a complex genotype-phenotype correlation. We conducted a literature survey to define the clinical landscape of TTR amyloidosis across populations worldwide. Then, we investigated whether the genetically determined TTR expression differs among human populations, contributing to the differences observed in patients. Polygenic scores for genetically determined TTR expression in 14 clinically relevant tissues were constructed using data from the GTEx (Genotype-Tissue Expression) project and tested in the samples from the 1,000 Genomes Project. RESULTS: We observed differences among the ancestral groups and, to a lesser extent, among the investigated populations within the ancestry groups. Scandinavian populations differed in their genetically determined TTR expression of skeletal muscle tissue with respect to Southern Europeans (p = 6.79*10-6). This is in line with epidemiological data related to Swedish and Portuguese TTR Val30Met endemic areas. Familial amyloidotic cardiomyopathy (TTR deposits occur primarily in heart tissues) presents clinical variability among human populations, a finding that agrees with the among-ancestry diversity of genetically determined TTR expression in heart tissues (i.e., Atrial Appendage p = 4.55*10-28; Left Ventricle p = 6.54*10-35). CONCLUSIONS: Genetically determined TTR expression varied across human populations. This might contribute to the genotype-phenotype correlation of TTR amyloidosis. PMID- 28335736 TI - The association of Emergency Department presentations in pregnancy with hospital admissions for postnatal depression (PND): a cohort study based on linked population data. AB - BACKGROUND: To investigate the impact of presenting to an Emergency Department (ED) during pregnancy on postnatal depression (PND) in women in New South Wales (NSW), Australia. METHOD: An epidemiological population-based study using linked data from the NSW Emergency Department Data Collection (EDDC), the NSW Perinatal Data Collection (PDC) and the NSW Admitted Patients Data Collection (APDC) was conducted. Women who gave birth to their first child in NSW between 1 January 2006 and 31 December 2010 were followed up from pregnancy to the end of the first year after birth. RESULTS: The study population includes 154,328 women who gave birth to their first child in NSW between 2006 and 2010. Of these, 31,764 women (20.58%) presented to ED during pregnancy (95%CI = 20.38-20.78). Women who presented to ED during pregnancy were more likely to be admitted to hospital for the diagnosis of unipolar depression (the adjusted relative risk (RR) =1.86, 95%CI = 1.49-2.31) and the diagnosis of mild mental and behavioural disorders associated with the puerperium (the adjusted RR = 1.55, 95%CI = 1.29-1.87) than those without ED presentation. CONCLUSION: Women's hospital admissions for postnatal depression were associated with frequent ED presentations during pregnancy. PMID- 28335737 TI - Cytomegalovirus infection in HIV-infected versus non-infected infants and HIV disease progression in Cytomegalovirus infected versus non infected infants early treated with cART in the ANRS 12140-Pediacam study in Cameroon. AB - BACKGROUND: The outcome of CMV/HIV co-infection in infants treated early with combined antiretroviral therapy (cART) in resource-limited settings has not been described. We aimed to estimate the prevalence and identify factors associated with early CMV infection in HIV-infected and non-infected infants included in a study in Cameroon, and to compare HIV disease progression and survival after 1 year of early cART, following infants' CMV status. METHODS: HIV-infected infants followed from birth or from HIV diagnosis before 7 months old and HIV-uninfected infants born to HIV-infected or uninfected mothers were tested for CMV at a median age of 4.0 months [Interquartile range (IQR): 3.4-4.9]. Multivariable logistic regression was performed to identify factors associated with CMV infection. Early cART was offered to HIV-infected infants: mortality, immunological and virological outcomes were assessed. RESULTS: Three hundred and sixty-nine infants were tested. The proportion of infants infected with CMV at baseline was significantly higher in HIV-infected than in HIV-uninfected groups (58.9% (86/146) vs 30.0% (67/223), p < 0.001). At baseline, median CMV viral load was higher in HIV-infected (3.7 log copies/ml [IQR; 3.1-4.3]) than in HIV uninfected infants (2.8 log copies [IQR; 2.1-3.4], p < 0.001). cART was initiated in 90% of HIV-infected infants (132/146) at a median age of 4.0 months (IQR; 3.2 5.9); in this sub-group CMV infection was independently associated with being followed from the time of HIV diagnosis rather than from birth (aOR = 3.1, 95%CI [1.2-8.0]), born to a non-single mother (aOR = 3.4[1.4-8.1]), and breastfeeding (aOR = 7.3 [2.7-19.4]). HIV-infected infants were retested after a median of 7.1 months [4.8-9.5]: CMV was undetectable in 37 of the 61 (60.7%) initially CMV infected cases and became detectable in 8 of the 38 (21.1%) initially CMV negative cases. After 1 year of cART, the probability of death (0.185 vs 0.203; p = 0.75), the proportion of cases with HIV RNA viral load <400 copies/ml (75.5% vs 61.5%; p = 0.17) and the mean CD4 percentage increase (10.97% vs 6.88%; p = 0.15) did not differ between CMV+ and CMV- infants. CONCLUSIONS: We observed a high prevalence of CMV infection among HIV-infected infants. Early initiation of cART may have limited the negative impact of CMV even in the absence of specific anti CMV treatment. PMID- 28335738 TI - Genome-wide expression profiling establishes novel modulatory roles of vitamin C in THP-1 human monocytic cell line. AB - BACKGROUND: Vitamin C (vit C) is an essential dietary nutrient, which is a potent antioxidant, a free radical scavenger and functions as a cofactor in many enzymatic reactions. Vit C is also considered to enhance the immune effector function of macrophages, which are regarded to be the first line of defence in response to any pathogen. The THP-1 cell line is widely used for studying macrophage functions and for analyzing host cell-pathogen interactions. RESULTS: We performed a genome-wide temporal gene expression and functional enrichment analysis of THP-1 cells treated with 100 MUM of vit C, a physiologically relevant concentration of the vitamin. Modulatory effects of vitamin C on THP-1 cells were revealed by differential expression of genes starting from 8 h onwards. The number of differentially expressed genes peaked at the earliest time-point i.e. 8 h followed by temporal decline till 96 h. Further, functional enrichment analysis based on statistically stringent criteria revealed a gamut of functional responses, namely, 'Regulation of gene expression', 'Signal transduction', 'Cell cycle', 'Immune system process', 'cAMP metabolic process', 'Cholesterol transport' and 'Ion homeostasis'. A comparative analysis of vit C-mediated modulation of gene expression data in THP-1cells and human skin fibroblasts disclosed an overlap in certain functional processes such as 'Regulation of transcription', 'Cell cycle' and 'Extracellular matrix organization', and THP-1 specific responses, namely, 'Regulation of gene expression' and 'Ion homeostasis'. It was noteworthy that vit C modulated the 'Immune system' process throughout the time-course. CONCLUSIONS: This study reveals the genome-wide effects of physiological levels of vit C on THP-1 gene expression. The multitude of effects impacted by vit C in macrophages highlights its role in maintaining homeostasis of several cellular functions. This study provides a rational basis for the use of the Vitamin C- THP-1 cell model, to study biochemical and cellular responses to stresses, including infection with M. tuberculosis and other intracellular pathogens. PMID- 28335739 TI - Identification of long non-coding transcripts with feature selection: a comparative study. AB - BACKGROUND: The unveiling of long non-coding RNAs as important gene regulators in many biological contexts has increased the demand for efficient and robust computational methods to identify novel long non-coding RNAs from transcripts assembled with high throughput RNA-seq data. Several classes of sequence-based features have been proposed to distinguish between coding and non-coding transcripts. Among them, open reading frame, conservation scores, nucleotide arrangements, and RNA secondary structure have been used with success in literature to recognize intergenic long non-coding RNAs, a particular subclass of non-coding RNAs. RESULTS: In this paper we perform a systematic assessment of a wide collection of features extracted from sequence data. We use most of the features proposed in the literature, and we include, as a novel set of features, the occurrence of repeats contained in transposable elements. The aim is to detect signatures (groups of features) able to distinguish long non-coding transcripts from other classes, both protein-coding and non-coding. We evaluate different feature selection algorithms, test for signature stability, and evaluate the prediction ability of a signature with a machine learning algorithm. The study reveals different signatures in human, mouse, and zebrafish, highlighting that some features are shared among species, while others tend to be species-specific. Compared to coding potential tools and similar supervised approaches, including novel signatures, such as those identified here, in a machine learning algorithm improves the prediction performance, in terms of area under precision and recall curve, by 1 to 24%, depending on the species and on the signature. CONCLUSIONS: Understanding which features are best suited for the prediction of long non-coding RNAs allows for the development of more effective automatic annotation pipelines especially relevant for poorly annotated genomes, such as zebrafish. We provide a web tool that recognizes novel long non-coding RNAs with the obtained signatures from fasta and gtf formats. The tool is available at the following url: http://www.bioinformatics-sannio.org/software/ . PMID- 28335740 TI - miR-21 enhances cardiac fibrotic remodeling and fibroblast proliferation via CADM1/STAT3 pathway. AB - BACKGROUND: Cardiac fibrosis play a key role in the atrial fibrillation pathogenesis but the underlying potential molecular mechanism is still understood. However, potential mechanisms for miR-21 upregulation and its role in cardiac fibrosis remain unclear. The controls cell proliferation and processes fundamental to disease progression. METHODS: In this study, immunohistochemistry, real-time RT-PCR, cell transfection, cell cycle, cell proliferation and Western blot were used, respectively. RESULTS: Here we have been demonstrated that the tumor suppressor cell adhesion molecule 1 (CADM1) is the potential target of miR 21. Our study revealed that miR-21 regulation of CADM1 expression, which was decreased in cardiac fibroblasts and fibrosis tissue. The cardiac fibroblasts transfected with miR-21 mimic promoted miR-21 overexpression enhanced STAT3 expression and decreased CADM1 expression. Nevertheless, the cardiac fibroblasts transfected with miR-21 inhibitor obtained the opposite expression result. Furthermore, downexpression of miR-21 suppressed cardiac fibroblast proliferation. CONCLUSIONS: These results suggested that miR-21 overexpression promotes cardiac fibrosis via STAT3 signaling pathway by decrease CADM1 expression, indicating miR-21 as an important signaling molecule for cardiac fibrotic remodeling and AF. PMID- 28335741 TI - High-throughput sequencing of pituitary and hypothalamic microRNA transcriptome associated with high rate of egg production. AB - BACKGROUND: MicroRNAs exist widely in viruses, plants and animals. As endogenous small non-coding RNAs, miRNAs regulate a variety of biological processes. Tissue miRNA expression studies have discovered numerous functions for miRNAs in various tissues of chicken, but the regulation of miRNAs in chicken pituitary and hypothalamic development related to high and low egg-laying performance has remained unclear. RESULTS: In this study, using high-throughput sequencing technology, we sequenced two tissues (pituitary and hypothalamus) in 3 high- and 3 low-rate egg production Luhua chickens at the age of 300 days. By comparing low and high-rate egg production chickens, 46 known miRNAs and 27 novel miRNAs were identified as differentially expressed (P < 0.05). Six differentially expressed known miRNAs, which are expressed in both tissues, were used in RT-qPCR validation and SNP detection. Among them, seven SNPs in two miRNA precursors (gga miR-1684a and gga-miR-1434) were found that might enhance or reduce the production of the mature miRNAs. In addition, 124 and 30 reciprocally expressed miRNA-target pairs were identified by RNA-seq in pituitary and hypothalamic tissues, respectively and randomly selected candidate miRNA and miRNA-target pairs were validated by RT-qPCR in Jiuyuan black fowl. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation illustrated that a large number of egg laying-related pathways were enriched in the high-rate egg production chickens, including ovarian steroidogenesis and steroid hormone biosynthesis. CONCLUSIONS: These differentially expressed miRNAs and their predicted target genes, especially identified reciprocally expressed miRNA-target pairs, advance the study of miRNA function and egg production associated miRNA identification. The analysis of the miRNA-related SNPs and their effects provided insights into the effects of SNPs on miRNA biogenesis and function. The data generated in this study will further our understanding of miRNA regulation mechanisms in the chicken egg-laying process. PMID- 28335743 TI - Reasons for discontinuation of subcutaneous interferon beta-1a three times a week among patients with multiple sclerosis: a real-world cohort study. AB - BACKGROUND: Continuation of interferon (IFN) beta-based therapies is important for maximum treatment effectiveness in patients with multiple sclerosis (MS); however, few real-world data are available on discontinuation from IFN beta. The aim of this cohort analysis was to estimate real-world discontinuation rates up to 3 years among MS patients in the United States taking subcutaneous (sc) IFN beta-1a three times a week (tiw) and to identify whether the factors associated with discontinuation change over time. METHODS: Patient data were pooled from the MarketScan(c) Commercial and Medicare Supplemental healthcare claims databases. Patients with >=1 multiple sclerosis diagnosis who were sc IFN beta-1a tiw naive, had >=1 year of continuous eligibility before treatment, and >=1 prescription were followed from first prescription (index date) until date of discontinuation, switch, or end of observation. Treatment status was analysed at exactly 1, 2 or 3 years after index. Multivariable models were used to identify drivers of discontinuation. RESULTS: Data from 5956 patients were included; 2862 patients (48.1%) discontinued therapy. Discontinuation rates were 36.9% (1 year), 49.5% (2 years) and 55.8% (3 years). A greater proportion of discontinuing patients had poor adherence (<80% [94.0%] versus >=80% [51.7%]) or were taking additional medication at follow-up versus the overall population. Factors independently associated with discontinuation irrespective of time on therapy were increasing number of magnetic resonance imaging scans (1 year adjusted odds ratio 1.45, 95% confidence interval 1.26-1.67; 2 years 1.18, 1.06-1.32; 3 years 1.20, 1.07-1.34) and adherence <80% versus >=80% (1 year 180.95, 135.84-241.03; 2 years 135.80, 100.10-184.23; 3 years 174.89, 115.27-265.38). Factors associated only with early discontinuation (at 1 year) were >=3 sets of laboratory investigations versus none (2.54, 1.20-5.38), and anxiolytic use at follow-up (1.40, 1.06-1.82). Factors associated only with later discontinuation (at 2 years and/or at 3 years) were antidepressant use at follow-up (2 years 1.46, 1.10-1.94) and greater number of relapses (2 years 1.60, 1.11-2.30; 3 years 2.31, 1.27-4.22). CONCLUSIONS: Potential drivers of discontinuation change over time. Improved awareness of the drivers of discontinuation could lead to targeted interventions to improve adherence. PMID- 28335742 TI - Characteristics of early-onset hematotoxicity of sunitinib in Japanese patients with renal cell carcinoma. AB - BACKGROUND: A high incidence of severe hematological adverse events during sunitinib treatment complicates decision making on dose and treatment cycle. We identified the characteristics of early-onset hematotoxicity of sunitinib in Japanese patients with renal cell carcinoma (RCC). METHODS: Seventy-nine patients were treated with sunitinib as 6-week cycles of "4-week on 2-week off" schedule. To evaluate early-onset hematotoxicity, we compared patients with dose reduction during the first cycle (dose-reduced group, n = 57) and those who maintained the initial dose (dose-maintained group, n = 22). ABCG2 and FLT3 genotypes were analyzed for association between hematotoxicity and reported gene polymorphisms. RESULTS: Mean relative dose intensity (RDI) was similar in the two groups during the first 2 weeks of dosing in the first cycle, but was significantly lower in the dose-reduced group during the last 2 weeks. Lymphocytopenia and thrombocytopenia were observed in the dose-reduced group within the first 2 weeks. Genetic analysis indicated a significantly higher frequency of FLT3 738 T/C polymorphism in the dose-reduced group, but no significant difference in the ABCG2 421 C/A polymorphism. CONCLUSIONS: This study showed a high incidence of sunitinib-induced hematotoxicity in Japanese patients with RCC, many of whom need dose adjustment during the first cycle. Further studies should verify whether dose adjustment based on early-onset thrombocytopenia prolongs sunitinib treatment. PMID- 28335744 TI - A systematic review of prognostic factors at the end of life for people with a hematological malignancy. AB - BACKGROUND: Accurate prognosticating is needed when patients are nearing the end of life to ensure appropriate treatment decisions, and facilitate palliative care provision and transitioning to terminal care. People with a hematological malignancy characteristically experience a fluctuating illness trajectory leading to difficulties with prognosticating. The aim of this review was to identify current knowledge regarding 'bedside' prognostic factors in the final 3 months of life for people with a hematological malignancy associated with increased risk of mortality. METHODS: A systematic review of the literature was performed across: PubMed; CINAHL; PsycINFO; and Cochrane with set inclusion criteria: 1) prognostic cohort studies; 2) published 2004-2014; 3) sample >= 18 years; 4) >50% sample had a hematological malignancy; 5) reported 'bedside' prognostic factors; 6) median survival of <3 months; and 7) English language. Quality appraisal was performed using the Quality In Prognostic Studies (QUIPS) tool. Results are reported in line with PRISMA guidelines. RESULTS: The search returned 4860 studies of which 28 met inclusion criteria. Twenty-four studies were rated moderate quality, three were high quality and one study was deemed to be of low quality. Most studies were set in the ICU (n = 24/28) and were retrospective (n = 25/28). Forty 'bedside' prognostic factors were identified as associated with increased risk of mortality encompassing the following broad categories: 1) demographics; 2) physiological complications or conditions; 3) disease characteristics; 4) laboratory blood values; and 5) interventions. CONCLUSIONS: The literature on prognosticating in the final months of life was predominantly focused on people who had experienced acute physiological deterioration and were being treated aggressively in the in-patient setting. A significant gap in the literature exists for people who are treated less aggressively or are on a palliative trajectory. Findings did not report on, or confirm the significance of, many of the key prognostic factors associated with increased risk of mortality at the end of life in the solid tumour population, demonstrating key differences in the two populations. TRIAL REGISTRATION: This systematic review was not registered. PMID- 28335745 TI - Ipsilateral and contralateral sensory changes in healthy subjects after experimentally induced concomitant sensitization and hypoesthesia. AB - BACKGROUND: In unilateral neuropathic pain. e.g. after peripheral nerve injury, both positive and negative sensory signs occur often, accompanied by minor but equally directed contralateral sensory changes. To mimic this feature, we experimentally aimed to induce concomitant c-fibre sensitization and block in healthy subjects and analyzed the bilateral sensory changes by quantitative sensory testing (QST) using the protocol of the German Research Network on Neuropathic Pain. METHODS: Twenty eight healthy subjects were firstly randomized in 2 groups to receive either topical capsaicin (0.6%, 12 cm2, application duration: 15 min.) or a lidocaine/prilocaine patch (25/25 mg, 10 cm2, application duration: 60 min.) on the right volar forearm. Secondly, 7-14 days later in the same area either at first capsaicin (for 15 min.) and immediately afterwards local anesthetics (for 60 min.) was applied (Cap/LA), or in inversed order with the same application duration (LA/Cap). Before, after each application and 7-14 days later a QST was performed bilaterally. STATISTICS: Wilcoxon-test, ANOVA, p < 0.05. RESULTS: Single application of 0,6% capsaicin induced thermal hypoesthesia, cold hypoalgesia, heat hyperalgesia and tactile allodynia. Lidocaine/prilocaine alone induced thermal and tactile hypoesthesia as well as mechanical and cold hypoalgesia, and a heat hyperalgesia (to a smaller extent). Ipsilaterally both co applications induced a combination of the above mentioned changes. Significant contralateral sensory changes occurred only after the co-application with concomitant sensitization and hypoesthesia and comprised increased cold (Cap/LA, LA/Cap) and mechanical detection as well as cold pain threshold (LA/Cap). CONCLUSION: The present experimental model using combined application of capsaicin and LA imitates partly the complex sensory changes observed in patients with unilateral neuropathic pain and might be used as an additional surrogate model. Only the concomitant use both agents in the same area induces both positive and negative sensory signs ipsilaterally as well as parallel contralateral sensory changes (to a lesser extent). TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01540877 , registered on 23 February 2012. PMID- 28335746 TI - Does continuous trusted adult support in childhood impart life-course resilience against adverse childhood experiences - a retrospective study on adult health harming behaviours and mental well-being. AB - BACKGROUND: Adverse childhood experiences (ACEs) including child abuse and household problems (e.g. domestic violence) increase risks of poor health and mental well-being in adulthood. Factors such as having access to a trusted adult as a child may impart resilience against developing such negative outcomes. How much childhood adversity is mitigated by such resilience is poorly quantified. Here we test if access to a trusted adult in childhood is associated with reduced impacts of ACEs on adoption of health-harming behaviours and lower mental well being in adults. METHODS: Cross-sectional, face-to-face household surveys (aged 18-69 years, February-September 2015) examining ACEs suffered, always available adult (AAA) support from someone you trust in childhood and current diet, smoking, alcohol consumption and mental well-being were undertaken in four UK regions. Sampling used stratified random probability methods (n = 7,047). Analyses used chi squared, binary and multinomial logistic regression. RESULTS: Adult prevalence of poor diet, daily smoking and heavier alcohol consumption increased with ACE count and decreased with AAA support in childhood. Prevalence of having any two such behaviours increased from 1.8% (0 ACEs, AAA support, most affluent quintile of residence) to 21.5% (>=4 ACEs, lacking AAA support, most deprived quintile). However, the increase was reduced to 7.1% with AAA support (>=4 ACEs, most deprived quintile). Lower mental well-being was 3.27 (95% CIs, 2.16-4.96) times more likely with >=4 ACEs and AAA support from someone you trust in childhood (vs. 0 ACE, with AAA support) increasing to 8.32 (95% CIs, 6.53 10.61) times more likely with >=4 ACEs but without AAA support in childhood. Multiple health-harming behaviours combined with lower mental well-being rose dramatically with ACE count and lack of AAA support in childhood (adjusted odds ratio 32.01, 95% CIs 18.31-55.98, >=4 ACEs, without AAA support vs. 0 ACEs, with AAA support). CONCLUSIONS: Adverse childhood experiences negatively impact mental and physical health across the life-course. Such impacts may be substantively mitigated by always having support from an adult you trust in childhood. Developing resilience in children as well as reducing childhood adversity are critical if low mental well-being, health-harming behaviours and their combined contribution to non-communicable disease are to be reduced. PMID- 28335747 TI - Effects of diurnal, lighting, and angle-of-incidence variation on anterior segment optical coherence tomography (AS-OCT) angle metrics. AB - BACKGROUND: First reported study to assess the effect of diurnal variation on anterior chamber angle measurements, as well as, to re-test the effects of lighting and angle-of-incidence variation on anterior chamber angle (ACA) measurements acquired by time-domain anterior segment optical coherence tomography (AS-OCT). METHODS: A total of 30 eyes from 15 healthy, normal subjects underwent anterior chamber imaging using a Visante time-domain AS-OCT according to an IRB-approved protocol. For each eye, the inferior angle was imaged twice in the morning (8 am - 10 am) and then again in the afternoon (3 pm - 5 pm), under light meter-controlled conditions with ambient room lighting 'ON' and lights 'OFF', and at 5 degrees angle of incidence increments. The ACA metrics measured for each eye were: angle opening distance (AOD, measured 500 and 750 MUm anterior from scleral spur), the trabecular-iris-space area (TISA, measured 500 and 750 MUm anterior from scleral spur), and scleral spur angle. Measurements were performed by masked, certified Reading Center graders using the Visante's Internal Measurement Tool. Differences in measurements between morning and afternoon, lighting variations, and angle of incidence were compared. RESULTS: Mean age of the participants was 31.2 years (range 23-58). Anterior chamber angle metrics did not differ significantly from morning to afternoon imaging, or when the angle of incidence was offset by 5 degrees in either direction away from the inferior angle 6 o'clock position. (p-value 0.13-0.93). Angle metrics at the inferior corneal limbus, 6 o'clock position (IC270), with room lighting 'OFF', showed a significant decrease (p < 0.05) compared to room lighting 'ON'. CONCLUSIONS: There does not appear to be significant diurnal variation in AS-OCT parameters in normal individuals, but lighting conditions need to be strictly controlled since variation in lighting led to significant variability in AS-OCT parameters. No changes in ACA parameters were noted by varying the angle-of incidence, which gives confidence in being able to perform longitudinal studies in approximately the same area (plus/minus 5 degrees of original scan location). PMID- 28335748 TI - Steroid-resistant nephrotic syndrome as the initial presentation of nail-patella syndrome: a case of a de novo LMX1B mutation. AB - BACKGROUND: Nail-patella syndrome (NPS) is an autosomal dominant disorder caused by mutations in the LMX1B gene and is characterized by nail dysplasia, skeletal abnormalities, and nephropathy. We herein report a case of steroid-resistant nephrotic syndrome (SRNS) prior to overt orthopedic symptoms in a patient with NPS. CASE PRESENTATION: A 24-year-old woman presented to our hospital with knee pain. She had poorly developed nails, hypoplastic patellas, dislocation of the elbows, and iliac horns in the pelvis. At the age of 7, she developed nephrotic syndrome and was diagnosed with primary focal segmental glomerulosclerosis by renal biopsy. She received long-term corticosteroid therapy with no obvious response. Her clinical course and orthopedic manifestations indicated NPS, and a genetic analysis showed a de novo mutation in the LMX1B gene (c.819 + 1G > A). Nephropathy in this case was considered to be associated with NPS. Therefore, we discontinued corticosteroids without the exacerbation of nephrotic syndrome. CONCLUSIONS: Patients with NPS may develop nephrotic syndrome prior to overt orthopedic symptoms and only show non-specific findings in renal biopsy at an early stage of NPS nephropathy. Hereditary nephrotic syndrome, often presenting as childhood-onset SRNS, may also be difficult to diagnose in patients with the following conditions: renal symptoms prior to overt extrarenal symptoms, de novo mutations, and non-specific findings in renal biopsy. Therefore, in the management of SRNS in children, we need to reconsider the possibility of hereditary diseases such as NPS even without a family history. PMID- 28335749 TI - Women's perceptions of discussions about gestational weight gain with health care providers during pregnancy and postpartum: a qualitative study. AB - BACKGROUND: Maternal body weight is an indicator of the health of a mother and her developing fetus. Risks of poor maternal and fetal health issues increase when women gain too little or too much weight during pregnancy. A study of 600 women from Alberta, Canada, reported approximately 30, 46, 80, and 80% of underweight, healthy weight, overweight, and obese women, respectively, gained in excess of Health Canada gestational weight gain guidelines. Behavioural interventions during pregnancy have shown to be effective at supporting women achieve gestational weight gain (GWG) recommendations and return to their pre pregnancy weight postpartum, yet few women are counseled about weight gain during pregnancy. A discrepancy exists between health care providers' (HCP) reported counseling behaviours and women's perceptions of counseling by HCPs; most HCPs report counseling women about GWG; conversely, most women report not receiving counseling about GWG. This study explored women's experiences with GWG and their perceptions of discussions about GWG with HCPs during pregnancy and postpartum. This will help to identify gaps in service delivery and highlight areas for improvement that may better support women to achieve GWG recommendations leading to better health outcomes for women and children. METHODS: Five focus groups (n = 26) were conducted with women up to 1 year postpartum across the five Alberta health zones. Focus groups were transcribed verbatim and analyzed using qualitative content analysis. RESULTS: GWG is important to women, for their health and for the health of their baby. In-depth conversations with HCPs about GWG or weight loss do not occur; however, women want the opportunity to discuss weight gain/loss with HCPs. Women would like discussions about gestational weight gain/loss to become part of standard care and offered to all women. CONCLUSIONS: Women suggested that discussions about GWG should occur with all women, and that HCPs should initiate these discussions by asking women how they feel about discussing weight. Conversations should begin early on in pregnancy and continue through to the postpartum period. Interventions assessing discussions about GWG should be implemented and evaluated as this has been identified as a gap in prenatal service delivery. PMID- 28335750 TI - Novel compound heterozygous mutations in the OTOF Gene identified by whole-exome sequencing in auditory neuropathy spectrum disorder. AB - BACKGROUND: Many hearing-loss diseases are demonstrated to have Mendelian inheritance caused by mutations in single gene. However, many deaf individuals have diseases that remain genetically unexplained. Auditory neuropathy is a sensorineural deafness in which sounds are able to be transferred into the inner ear normally but the transmission of the signals from inner ear to auditory nerve and brain is injured, also known as auditory neuropathy spectrum disorder (ANSD). The pathogenic mutations of the genes responsible for the Chinese ANSD population remain poorly understood. METHODS: A total of 127 patients with non-syndromic hearing loss (NSHL) were enrolled in Guangxi Zhuang Autonomous Region. A hereditary deafness gene mutation screening was performed to identify the mutation sites in four deafness-related genes (GJB2, GJB3, 12S rRNA, and SLC26A4). In addition, whole-exome sequencing (WES) was applied to explore unappreciated mutation sites in the cases with the singularity of its phenotype. RESULTS: Well-characterized mutations were found in only 8.7% (11/127) of the patients. Interestingly, two mutations in the OTOF gene were identified in two affected siblings with ANSD from a Chinese family, including one nonsense mutation c.1273C > T (p.R425X) and one missense mutation c.4994 T > C (p.L1665P). Furthermore, we employed Sanger sequencing to confirm the mutations in each subject. Two compound heterozygous mutations in the OTOF gene were observed in the two affected siblings, whereas the two parents and unaffected sister were heterozygous carriers of c.1273C > T (father and sister) and c.4994 T > C (mother). The nonsense mutation p.R425X, contributes to a premature stop codon, may result in a truncated polypeptide, which strongly suggests its pathogenicity for ANSD. The missense mutation p.L1665P results in a single amino acid substitution in a highly conserved region. CONCLUSIONS: Two mutations in the OTOF gene in the Chinese deaf population were recognized for the first time. These findings not only extend the OTOF gene mutation spectrum for ANSD but also indicate that whole-exome sequencing is an effective approach to clarify the genetic characteristics in non-syndromic ANSD patients. PMID- 28335751 TI - Exploring community participation in project design: application of the community conversation approach to improve maternal and newborn health in Zambia. AB - BACKGROUND: The United Nations Development Programme (UNDP) has adopted an approach entitled Community Conversation (CC) to improve community engagement in addressing health challenges. CCs are based on Paulo Freire's transformative communication approach, in which communities pose problems and critically examine their everyday life experiences through discussion. We adopted this approach to engage communities in maternal and newborn health discussions in three rural districts of Zambia, with the aim of developing community-generated interventions. METHODS: Sixty (60) CCs were held in three target districts, covering a total of 20 health facilities. Communities were purposively selected in each district to capture a range of rural and peri-urban areas at varying distances from health facilities. Conversations were held four times in each community between May and September 2014. All conversations were digitally recorded and later transcribed. NVivo version 10 was used for data analysis. RESULTS AND DISCUSSION: The major barriers to accessing maternal health services included geography, limited infrastructure, lack of knowledge, shortage of human resources and essential commodities, and insufficient involvement of male partners. From the demand side, a lack of information and misconceptions, and, from the supply side, inadequately trained health workers with poor attitudes, negatively affected access to maternal health services in target districts either directly or indirectly. At least 17 of 20 communities suggested solutions to these challenges, including targeted community sensitisation on the importance of safe motherhood, family planning and prevention of teenage pregnancy. Community members and key stakeholders committed time and resources to address these challenges with minimal external support. CONCLUSION: We successfully applied the CC approach to explore maternal health challenges in three rural districts of Zambia. CCs functioned as an advocacy platform to facilitate direct engagement with key decision makers within the community and to align priorities while incorporating community views. There was a general lack of knowledge about safe motherhood and family planning in all three districts. However, other problems were unique to health facilities, demonstrating the need for tailored interventions. PMID- 28335752 TI - Development of a rapid loop-mediated isothermal amplification assay for diagnosis and assessment of cure of Leishmania infection. AB - BACKGROUND: Leishmaniasis is a spectrum of diseases with great relevance to public health. Conventional diagnostic methods are time consuming, needing trained personnel. A robust, rapid and cost effective diagnostic test is warranted for on-time diagnosis and field application. METHODS: We have developed a loop mediated isothermal amplification (LAMP) assay with primers (n = 6) based on Leishmania donovani kDNA for detection of Leishmania infection, using a closed tube to prevent cross-contamination. The assay was used to detect Leishmania infection in biological samples obtained from patients of visceral leishmaniasis (VL), post kala-azar dermal leishmaniasis (PKDL) and cutaneous leishmaniasis (CL). RESULTS: The assay was positive for L. donovani, L. tropica and L. major parasites, with the highest sensitivity towards L. donovani (1 fg DNA). The high sensitivity of the assay for detection of L. donovani was reflected in its ability to detect parasite DNA within 30 min of amplification time with a threshold detection limit of >=25 copies per reaction. The assay detected parasite in 64 of 66 VL blood samples (sensitivity, 96.9%; 95% CI: 89.6-99.2%), 15 of 15 VL bone marrow aspirate samples (sensitivity, 100%; 95% CI:79.6-100%), 65 of 67 PKDL tissue biopsy samples (sensitivity, 97%; 95% CI:89.7-99.2%). The assay was evaluated in a few cases of CL wherein it was found positive in 8 of 10 tissue biopsies (sensitivity, 80%; 95% CI: 49-94.3%). The assay was negative in all control blood (n = 76) and tissue biopsy (n = 24) samples (specificity, 100%; 95% CI: 96.3-100%). Further, the assay was evaluated for its utility in assessment of cure in treated VL and PKDL patients. The assay detected parasite DNA in 2 of 20VL blood samples and 2 of 21 PKDL tissue samples. Out of 4 cases that were positive for parasite DNA at post treatment stage, 2 patients (1VL and 1 PKDL) returned with relapse. CONCLUSIONS: The study demonstrated a Leishmania genus specific closed tube LAMP assay for reliable and rapid molecular diagnosis of VL and PKDL with potential for application in assessment of cure. PMID- 28335753 TI - Leuconostoc mesenteroides periprosthetic knee infection, an unusual fastidious Gram-positive bacteria: a case report. AB - BACKGROUND: Periprosthetic joint infections are mainly caused by Gram-positive cocci. Leuconostoc mesenteroides is a rare microorganism mainly causing bloodstream infections. At times, it might be confused with another type of cocci and give rise to misdiagnosed infections. Molecular diagnosis and biofilm production comprise important techniques to guide antibiotic treatment. CASE PRESENTATION: A 68-year-old Hispanic female with a previous history of bilateral knee arthroplasty presented with acute right-knee inflammation and gait impairment. Blood tests showed inflammatory response and knee x-ray revealed no prosthesis loosening. Irrigation and debridement was performed. Gram-positive cocci were obtained from cultures, and then biochemical and molecular identification revealed L. mesenteroides. Susceptibility and biofilm production were performed. The patient was treated with IntraVenous (IV) Ceftriaxone for ten days and was then switched to Amoxicillin-Clavulanate for 3 months with clinical and laboratory success. CONCLUSIONS: Microbiology diagnosis of fastidious microorganisms is mandatory to treat periprosthetic joint infections adequately. L. mesenteroides may infect non-immunocompromised persons; however, treatment guidelines are lacking. PMID- 28335754 TI - The structural and health policy environment for delivering integrated HIV and substance use disorder treatments in Puerto Rico. AB - BACKGROUND: HIV prevalence in Puerto Rico is nearly twice that of the mainland United States, a level that was substantially fueled by injection drug use. Puerto Rico has a longstanding history of health provision by the public sector that directly affects how HIV and substance use disorder (SUD) treatment services are provided and funded. As part of pre-implementation research for a randomized trial of a community-level intervention to enhance HIV care access for substance users in San Juan, Puerto Rico, we sought to understand the structural and health policy environment for providing HIV and SUD treatments. METHODS: We conducted semi-structured qualitative interviews (n = 8) with government and program administrators in English and Spanish. Data were analyzed to identify dominant and recurrent themes. RESULTS: Participants discussed how lack of integration among medical and mental health service providers, lack of public transportation, and turnover in appointed government officials were barriers to integrated HIV and SUD treatment. Federal funding for support services for HIV patients was a facilitator. The Affordable Care Act has limited impact in Puerto Rico because provisions related to health insurance reform do not apply to U.S. territories. DISCUSSION AND CONCLUSIONS: Implications for intervention design include the need to provide care coordination for services from multiple providers, who are often physically separated and working in different reimbursement systems, and the potential for mobile and patient transportation services to bridge these gaps. Continuous interaction with political leaders is needed to maintain current facilitators. These findings are relevant as the current economic crisis in Puerto Rico affects funding, and may be relevant for other settings with substance use-driven epidemics. PMID- 28335755 TI - The incidence of diabetes mellitus and diabetic retinopathy in a population-based cohort study of people age 50 years and over in Nakuru, Kenya. AB - BACKGROUND: The epidemic rise of diabetes carries major negative public health and economic consequences particularly for low and middle-income countries. The highest predicted percentage growth in diabetes is in the sub-Saharan Africa (SSA) region where to date there has been no data on the incidence of diabetic retinopathy from population-based cohort studies and minimal data on incident diabetes. The primary aims of this study were to estimate the cumulative six-year incidence of Diabetes Mellitus (DM) and DR (Diabetic Retinopathy), respectively, among people aged >=50 years in Kenya. METHODS: Random cluster sampling with probability proportionate to size were used to select a representative cross sectional sample of adults aged >=50 years in 2007-8 in Nakuru District, Kenya. A six-year follow-up was undertaken in 2013-14. On both occasions a comprehensive ophthalmic examination was performed including LogMAR visual acuity, digital retinal photography and independent grading of images. Data were collected on general health and risk factors. The primary outcomes were the incidence of diabetes mellitus and the incidence of diabetic retinopathy, which were calculated by dividing the number of events identified at 6-year follow-up by the number of people at risk at the beginning of follow-up. Age-adjusted risk ratios of the outcomes (DM and DR respectively) were estimated for each covariate using a Poisson regression model with robust error variance to allow for the clustered design and including inverse-probability weighting. RESULTS: At baseline, 4414 participants aged >=50 years underwent complete examination. Of the 4104 non diabetic participants, 2059 were followed-up at six-years (50 . 2%). The cumulative incidence of DM was estimated at 61 . 0 per 1000 (95% CI: 50 . 3-73 . 7) in people aged >=50 years. The cumulative incidence of DR in the sample population was estimated at 15 . 8 per 1000 (95% CI: 9 . 5-26 . 3) among those without DM at baseline, and 224 . 7 per 1000 (116.9-388.2) among participants with known DM at baseline. A multivariable risk factor analysis demonstrated increasing age and higher body mass index to be associated with incident DM. DR incidence was strongly associated with increasing age, and with higher BMI, urban dwelling and higher socioeconomic status. CONCLUSIONS: Diabetes Mellitus is a growing public health concern with a major complication of diabetic retinopathy. In a population of 1 . 6 million, of whom 150,000 are >=50 years, we estimated that 1650 people aged >=50 develop DM per year, and 450 develop DR. Strengthening of health systems is necessary to reduce incident diabetes and its complications in this and similar settings. PMID- 28335756 TI - Acupuncture and moxibustion for chronic fatigue syndrome in traditional Chinese medicine: a systematic review and meta-analysis. AB - BACKGROUND: As the etiology of chronic fatigue syndrome (CFS) is unclear and the treatment is still a big issue. There exists a wide range of literature about acupuncture and moxibustion (AM) for CFS in traditional Chinese medicine (TCM). But there are certain doubts as well in the effectiveness of its treatment due to the lack of a comprehensive and evidence-based medical proof to dispel the misgivings. Current study evaluated systematically the effectiveness of acupuncture and moxibustion treatments on CFS, and clarified the difference among them and Chinese herbal medicine, western medicine and sham-acupuncture. METHODS: We comprehensively reviewed literature including PubMed, EMBASE, Cochrane library, CBM (Chinese Biomedical Literature Database) and CNKI (China National Knowledge Infrastructure) up to May 2016, for RCT clinical research on CFS treated by acupuncture and moxibustion. Traditional direct meta-analysis was adopted to analyze the difference between AM and other treatments. Analysis was performed based on the treatment in experiment and control groups. Network meta analysis was adopted to make comprehensive comparisons between any two kinds of treatments. The primary outcome was total effective rate, while relative risks (RR) and 95% confidence intervals (CI) were used as the final pooled statistics. RESULTS: A total of 31 randomized controlled trials (RCTs) were enrolled in analyses. In traditional direct meta-analysis, we found that in comparison to Chinese herbal medicine, CbAM (combined acupuncture and moxibustion, which meant two or more types of acupuncture and moxibustion were adopted) had a higher total effective rate (RR (95% CI), 1.17 (1.09 ~ 1.25)). Compared with Chinese herbal medicine, western medicine and sham-acupuncture, SAM (single acupuncture or single moxibustion) had a higher total effective rate, with RR (95% CI) of 1.22 (1.14 ~ 1.30), 1.51 (1.31-1.74), 5.90 (3.64-9.56). In addition, compared with SAM, CbAM had a higher total effective rate (RR (95% CI), 1.23 (1.12 ~ 1.36)). In network meta-analyses, similar results were recorded. Subsequently, we ranked all treatments from high to low effective rate and the order was CbAM, SAM, Chinese herbal medicine, western medicine and sham-acupuncture. CONCLUSIONS: In the treatment of CFS, CbAM and SAM may have better effect than other treatments. However, the included trials have relatively poor quality, hence high quality studies are needed to confirm our finding. PMID- 28335757 TI - Sophorae Flos extract inhibits RANKL-induced osteoclast differentiation by suppressing the NF-kappaB/NFATc1 pathway in mouse bone marrow cells. AB - BACKGROUND: Sophorae Flos (SF) is a composite of flowers and buds of Styphnolobium japonicum (L.) Schott and has been used in traditional Korean and Chinese medicine for the treatment of hemostasis and inflammation. Previous studies reported that SF possesses anti-obesity properties, as well as anti allergic, anti-proliferative, and anti-inflammatory activities. However, the effect of SF in bone resorption has not been studies. In this study, we examined the potential of SF extract (SFE) to inhibit receptor activator of NF-kappaB ligand (RANKL) -induced osteoclast differentiation in cultured mouse-derived bone marrow macrophages (BMMs). METHODS: BMMs, that act as osteoclast precursors, were cultured with M-CSF (50 ng/ml) and RANKL (100 ng/ml) for 4 days to generate osteoclasts. Osteoclast differentiation was measured by tartrate-resistant acidic phosphatase (TRAP) staining and the TRAP solution assay. Osteoclast differentiation marker genes were analyzed by the quantitative real-time polymerase chain reaction analysis. RANKLs signaling pathways were confirmed through western blotting. RESULTS: SFE significantly decreased osteoclast differentiation in a dose-dependent manner. SFE inhibited RANKL-induced osteoclastogenesis by suppressing NF-kappaB activation. By contrast, SFE did not affect phospholipase C gamma 2 or subsequent cAMP response element binding activation. SFE inhibited the RANKL-induced expression of nuclear factor of activated T cells c1 (NFATc1). CONCLUSIONS: SFE attenuated the RANKL-mediated induction of NF-kappaB through inhibition of IkappaBalpha phosphorylation, which contributed to inhibiting of RANKL-induced osteoclast differentiation through downregulation of NFATc1. PMID- 28335759 TI - Mobile radiography services in nursing homes: a systematic review of residents' and societal outcomes. AB - BACKGROUND: Demographic changes are leading to an ageing population in Europe, and predict an increase in the number of nursing home residents over the next 30 years. Nursing home residents need specialised healthcare services such as radiology due to both chronic and acute illnesses. Mobile radiography, x-ray examinations performed in the nursing homes, may be a good way of providing services to this population. The aim of this systematic review was to identify the outcomes of mobile radiography services for nursing home residents and society. METHODS: A systematic review based on searches in the Medline, Cochrane, PubMed, Embase and Svemed + databases was performed. Titles and abstracts were screened according to a predefined set of inclusion criteria: empirical studies in the geriatric population, and reports of mobile radiography services in a clinical setting. All publications were quality appraised using MMAT or CASP appraisal tools. Data were extracted using a summary table and results were narratively synthesised. RESULTS: Ten publications were included. Three overarching outcomes were identified: 1) reduced number of hospitalisations and outpatient examinations or treatments, 2) reduced number of transfers between nursing homes and hospitals and 3) increased access to x-ray examinations. These outcomes were interlinked with the more specific outcomes for residents and society reported in the literature. For residents there was a reduction in burdensome transfers and waiting time and adequate treatment and care increased. For society, released resources could be used more efficiently, and overall costs were reduced substantially. CONCLUSIONS: This review indicates that mobile radiography services for nursing home residents in the western world are of comparable quality to hospital-based examinations and have clear potential benefits. Mobile radiography reduced transfers to and from hospital, increased the number of examinations carried out and facilitated timely diagnosis and access to treatments. Further research is needed to formally evaluate potential improvements in care quality and cost-effectiveness. PMID- 28335758 TI - What's wrong with John? a randomised controlled trial of Mental Health First Aid (MHFA) training with nursing students. AB - BACKGROUND: The prevalence of mental health problems have been found to be higher among university students compared to their non-student peers. Nursing students in particular face a range of additional stressors which may impact their undergraduate performance and their careers. Mental Health First Aid (MHFA) aims to increase mental health literacy and to reduce stigma and may positively impact on the student population. This paper describes a MHFA randomised controlled trial targeting nursing students at a large Australian university. This study aimed to measure the impact of the MHFA course on mental health literacy, mental health first aid intentions, confidence in helping someone with a mental health problem and stigmatising attitudes including social distance. METHODS: Participants were first year nursing students (n = 181) randomly allocated to the intervention (n = 92) or control (n = 89) group. Intervention group participants received the standardised MHFA course for nursing students. Online self-report questionnaires were completed at three time intervals: baseline (one week prior to the intervention: T1) (n = 140), post intervention (T2) (n = 120), and two months post intervention (T3) (n = 109). Measures included demographics, mental health knowledge, recognition of depression, confidence in helping, mental health first aid intentions and stigmatising attitudes including social distance. Repeated measures ANOVA was computed to measure if the impact of time (T1, T2, T3) and group (intervention and control) on the outcome variables. RESULTS: There was a significant improvement among intervention compared to control group participants across the three time periods for knowledge scores (p < 0.001), confidence in helping (p < 0.001), mental health first aid intentions (p < 0.001), total personal stigma (p < 0.05), personal dangerous/unpredictable stigma (p < 0.05) and social distance (p < 0.05) scores. CONCLUSION: MHFA is useful training to embed in university courses and has the potential to enhance mental health literacy and reduce stigmatising attitudes and social distance. While this course has particular salience for nursing and other health science students, there are broader benefits to the general university population that should be considered and opportunities accordingly explored for all students to complete the course. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12614000861651 . Retrospectively registered 11 August 2014. PMID- 28335760 TI - Midkine is a potential novel marker for malignant mesothelioma with different prognostic and diagnostic values from mesothelin. AB - BACKGROUND: We evaluated possible diagnostic and prognostic values of serum midkine in malignant pleural mesothelioma in comparison with those of serum mesothelin, a well-established diagnostic biomarker. METHODS: Serum mesothelin and midkine levels were determined with an enzyme-linked immunosorbent assay. We examined specimens from 95 Turkish cases with malignant pleural mesothelioma, 56 metastatic cancers to pleura, 27 other types of benign pleural diseases and 20 benign asbestos pleurisy. The cut-off values were 1.5 nmol/L for mesothelin and 421 pg/mL for midkine. RESULTS: Sensitivity and specificity of mesothelin were 51.6 and 71.4%, 51.6 and 85.2%, and 51.6 and 85% for differentiating mesothelioma from metastatic cancers to pleura, other benign pleural diseases and benign asbestos pleurisy, respectively. Sensitivity and specificity of midkine were 61.1 and 41.1%, 61.1 and 48.1%, and 61.1 and 75% to distinguish mesothelioma from metastatic cancers to pleura, other benign pleural diseases and benign asbestos pleurisy, respectively. Combination of both biomarkers did not improve the differential diagnostic efficacy. Mesothelin levels were elevated in the epitheloid type and in the advanced cases, but were not related to the prognosis. In contrast, elevated baseline levels of midkine were independently associated with a poor prognosis of mesothelioma patients after adjusting for the stage, the histological subtypes and treatment schedules (HR = 1.84; 95% CI: 1.09-3.09) (p = 0.022). CONCLUSIONS: Serum mesothelin showed moderate sensitivity and high specificity to differentiate malignant pleural mesothelioma from metastatic malignancy to pleura and from benign pleural diseases. In contrast, midkine was a useful marker for predicting prognosis of mesothelioma patients. PMID- 28335761 TI - The effects of Jiao-Tai-Wan on sleep, inflammation and insulin resistance in obesity-resistant rats with chronic partial sleep deprivation. AB - BACKGROUND: Jiao-Tai-Wan (JTW), composed of Rhizome Coptidis and Cortex Cinnamomi, is a classical traditional Chinese prescription for treating insomnia. Several in vivo studies have concluded that JTW could exert its therapeutical effect in insomnia rats. However, the specific mechanism is still unclear. The present study aimed to explore the effect of JTW on sleep in obesity-resistant (OR) rats with chronic partial sleep deprivation (PSD) and to clarify its possible mechanism. METHODS: JTW was prepared and the main components contained in the granules were identified by 3D-High Performance Liquid Chromatography (3D HPLC) assay. The Male Sprague-Dawley (SD) rats underwent 4 h PSD by environmental noise and the treatment with low and high doses of JTW orally for 4 weeks, respectively. Then sleep structure was analyzed by electroencephalographic (EEG). Inflammation markers including high-sensitivity C reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels were examined in the rat plasma. Meanwhile, metabolic parameters as body weight increase rate, fasting plasma glucose (FPG), fasting insulin (FINS) levels and insulin resistance index (HOMA-IR) were measured. The expressions of clock gene cryptochromes (Cry1 and Cry2) and inflammation gene nuclear factor-kappaB (NF kappaB) in peripheral blood monocyte cells (PBMC) were also determined. RESULTS: The result showed that the administration of JTW significantly increased total sleep time and total slow wave sleep (SWS) time in OR rats with PSD. Furthermore, the treatment with JTW reversed the increase in the markers of systemic inflammation and insulin resistance caused by sleep loss. These changes were also associated with the up-regulation of Cry1 mRNA and Cry 2 mRNA and the down regulation of NF-kappaB mRNA expression in PBMC. CONCLUSIONS: This study suggests that JTW has the beneficial effects of improving sleep, inflammation and insulin sensitivity. The mechanism appears to be related to the modulation of circadian clock and inflammation genes expressions in PBMC. PMID- 28335762 TI - Oral Cancer Awareness Among Dental Patients in Omdurman, Sudan: a cross-sectional Study. AB - BACKGROUND: Oral cancer is a preventable disease. Its occurrence is mostly due to lifestyle. In Sudan, the use of smokeless tobacco (Toombak) has long been linked to oral cancer. Knowledge of the signs and symptoms of oral cancer may well aid in early diagnosis and treatment. This is bound to result in increasing survival rates, as well as reducing the oral cancer burden on the society. This study aimed to assess oral cancer awareness regarding knowledge of signs, symptoms, risk factors and sources of the information. Furthermore, it attempts to evaluate attitudes towards oral cancer screening and any previous experience of screening, amongst dental patients attending University of Science and Technology (UST) Dental Teaching Hospital. Omdurman, Sudan. METHODS: A hospital based cross sectional study, interviewer-administered questionnaire was conducted amongst 500 adult patients attending the UST Dental Hospital during 2015. RESULTS: A total of 57.7% (286) of the individuals demonstrated good knowledge of signs and symptoms, whereas 49% (139) expressed good knowledge of risk factors of oral cancer. For the majority of the individuals 66.1% (290), the most common source of information about oral cancer was from the media, while 33.9% individuals (149), obtained knowledge from direct contact of health workers. The overwhelming majority, 93.2% (466) never screened for oral cancer despite their positive attitude towards it 66.4% (332). Knowledge of risk factors associated significantly with those reported positive attitude towards oral cancer screening and those reported direct contact with health workers as a source of information, (p <= 0.001). Moreover, females and those living in urban districts scores higher than their counterpart in knowledge of risk factor of oral cancer. In addition, those employed 58.6% (280) and 62.8% (164) with correct believes about oral cancer showed significant association with positive knowledge of signs and symptoms (p <= 0.05). CONCLUSIONS: Awareness levels, knowledge of risk factors and identifying early signs and symptoms of oral cancer necessitate the need for more structured preventive programs using media. Dentists and health workers should do more because they have a pivotal role in early diagnosis by performing oral cancer screening, raising levels of knowledge and in rectifying misconceptions about oral cancer. This would entail a reduction in high rates of morbidity and mortality associated with oral cancer. PMID- 28335763 TI - Identification of drug combinations administered by continuous subcutaneous infusion that require analysis for compatibility and stability. AB - BACKGROUND: A continuous subcutaneous infusion (CSCI) delivered via syringe pump is a method of drug administration used to maintain symptom control when a patient is no longer able to tolerate oral medication. Several classes of drugs, such as opioids, antiemetics, anticholinergics, antipsychotics and benzodiazepines are routinely administered by CSCI alone or in combinations. Previous studies attempting to identify the most-common CSCI combinations are now several years old and no longer reflect current clinical practice. The aim of this work was to review current clinical practice and identify CSCI drug combinations requiring analysis for chemical compatibility and stability. METHODS: UK pharmacy professionals involved in the delivery of care to palliative patients in hospitals and hospices were invited to enter CSCI combinations comprised of two or more drugs onto an electronic database over a 12-month period. In addition, a separate Delphi study with a panel of 15 expert healthcare professionals was completed to identify a maximum of five combinations of drugs used to treat more complex, but less commonly encountered symptoms unlikely to be identified by the national survey. RESULTS: A total of 57 individuals representing 33 separate palliative care services entered 1,945 drug combinations suitable for analysis, with 278 discrete combinations identified. The top 40 drug combinations represented nearly two-thirds of combinations recorded. A total of 23 different drugs were administered in combination and the median number of drugs in a combination was three. The Delphi study identified five combinations for the relief of complex or refractory symptoms. CONCLUSION: This study represents the first step towards developing authoritative national guidance on the administration of drugs by CSCI. Further work will ensure healthcare practitioners have the knowledge and confidence that a prescribed combination will be both safe and efficacious. PMID- 28335764 TI - Health care cost associated with the use of enzyme-inducing and non-enzyme-active antiepileptic drugs in the UK: a long-term retrospective matched cohort study. AB - BACKGROUND: Some antiepileptic drugs (AEDs) induce expression of hepatic enzymes. This can contribute to comorbidities via interference with metabolic pathways and concomitant drug metabolization, thereby increasing the likelihood of health care interventions. Using medical records, we compared the direct health care cost in patients initiating epilepsy therapy with enzyme-inducing AEDs (EIAEDs) vs non enzyme-active AEDs (nEAAEDs) over up to 12 years. METHODS: Patients with untreated epilepsy were indexed in the UK Clinical Practice Research Datalink and Hospital Episode Statistics database when prescribed a new EIAED or nEAAED between January 2001 and December 2010. Propensity score matching reduced confounding factors between cohorts. Patients were followed until cohort treatment failure or data cut-off. The primary outcome was the median standardized monthly direct health care cost during follow-up in 2014 LGBP, calculated using published reference costs and compared using a Mann-Whitney U test. RESULTS: The unmatched EIAED cohort (n = 2752) was older (54 vs 46 years), more likely to be male, had more comorbidities, and higher health care resource use/cost during the 1-year pre-index period (median L3014 vs L2516) than the nEAAED cohort (n = 2,137). The most common index EIAED and nEAAED were carbamazepine (63.3%) and lamotrigine (58.0%), respectively. After matching, cohorts had similar features (n = 951 each). Over up to 12 years of follow-up, the median standardized monthly direct health care cost was L229 for the EIAED and L188 for the nEAAED cohorts (p = 0.0091). The median cost was higher for the EIAED cohort in every year of follow-up. In the two cohorts, 25.1% and 20.1% of total mean cost during follow-up was epilepsy-related, with approximately 4.6% and 3.0% for AED acquisition, respectively. The median time to cohort treatment failure was shorter in the matched EIAED cohort (468 vs 1194 days). CONCLUSIONS: Patients in the UK who initiated epilepsy therapy with an EIAED appeared to be at higher risk of complications associated with enzyme induction. In long-term matched cohort analyses, the median total direct health care cost associated with EIAED therapy was higher than with nEAAEDs. Changing current treatment practices could potentially improve patient outcomes and reduce costs. PMID- 28335765 TI - A structural model of treatment program and individual counselor leadership in innovation transfer. AB - BACKGROUND: A number of program-level and counselor-level factors are known to impact the adoption of treatment innovations. While program leadership is considered a primary factor, the importance of leadership among clinical staff to innovation transfer is less known. Objectives included explore (1) the influence of two leadership roles, program director and individual counselor, on recent training activity and (2) the relationship of counselor attributes on training endorsement. METHODS: The sample included 301 clinical staff in 49 treatment programs. A structural equation model was evaluated for key hypothesized relationships between exogenous and endogenous variables related to the two leadership roles. RESULTS: The importance of organizational leadership, climate, and counselor attributes (particularly counseling innovation interest and influence) to recent training activity was supported. In a subset of 68 counselors who attended a developer-led training on a new intervention, it was found that training endorsement was higher among those with high innovation interest and influence. CONCLUSIONS: The findings suggest that each leadership level impacts the organization in different ways, yet both can promote or impede technology transfer. PMID- 28335766 TI - Barriers to the conduct and application of research in complementary and alternative medicine: a systematic review. AB - BACKGROUND: The popularity of Complementary and alternative medicine (CAM) has grown considerably over the past few decades. This has been accompanied by increasing public pressure for CAM to be evidence-based. Notwithstanding, the conduct and application of research in CAM faces a number of obstacles. No systematic review has mapped these barriers to date. Therefore, this systematic literature review aimed to explore, identify and map the barriers to the conduct and application of research in CAM. METHODS: Systematic searching of MEDLINE, Embase, AMED, CINAHL, The Cochrane library, Google scholar and Google was conducted between February and June 2016 for pertinent publications. Pearling (secondary searching) of retrieved publications was also undertaken. Literature published only in English were included; however, no year limit was placed for searching. Two critical appraisal tools were used to critically appraise descriptive studies and opinion publications. RESULTS: A total of 21 eligible publications were included in this review; this comprised of eight primary research articles and thirteen opinion publications. A critical appraisal process found two categories of good quality publications while recognising their limitations in terms of descriptive and opinion publications. The synthesised data from the selected publications about the barriers to the conduct and application of research within CAM were captured within two broad components, namely capacity and culture. Capacity encompassed elements such as access, competency, bias, incentives and time. Encompassed within culture were elements relating to the values and complex system of CAM. CONCLUSIONS: Multiple barriers exist for the conduct and application of research in CAM. Given the growing popularity of these therapies, it is essential that the evidence base underpinning CAM also continues to expand. Without overt recognition of these barriers, enabling strategies cannot be applied. By addressing these barriers, CAM professions will be able to develop a critical mass and a well-coordinated research effort to assist the integration of evidence - based practice in CAM. PMID- 28335767 TI - Feasibility, acceptability and efficacy of a web-based computer-tailored physical activity intervention for pregnant women - the Fit4Two randomised controlled trial. AB - BACKGROUND: Physical activity (PA) during pregnancy is associated with a variety of health benefits including a reduced risk of pregnancy related conditions such as pre-eclampsia and pregnancy-induced hypertension and leads to greater control over gestational weight gain. Despite these associated health benefits, very few pregnant women are sufficiently active. In an attempt to increase health outcomes, it is important to explore innovative ways to increase PA among pregnant women. Therefore, the aim of this study was to assess the feasibility, acceptability and efficacy of a four week web-based computer-tailored PA intervention among pregnant women. METHODS: Seventy-seven participants were randomised into either: (1) an intervention group that received tailored PA advice and access to a resource library of articles relating to PA during pregnancy; or (2) a standard information group that only received access to the resources library. Objective moderate-to-vigorous physical activity (MVPA) was assessed at baseline and immediately post-intervention. Recruitment, attrition, intervention adherence, and website engagement were assessed. Questions on usability and satisfaction were administered post-intervention. RESULTS: Feasibility was demonstrated through acceptable recruitment (8.5 participants recruited and randomised/month), and attrition (25%). Acceptability among intervention group participants was positive with high intervention adherence (96% of 4 modules completed). High website engagement (participants logged in 1.6 times/week although only required to log in once per week), usability (75/100), and satisfaction outcomes were reported in both groups. However, participants in the intervention group viewed significantly more pages on the website (p < 0.05), reported that the website felt more personally relevant (p < 0.05), and significantly increased their MVPA from baseline to post-intervention (mean difference = 35.87 min), compared to the control group (mean difference = 9.83 min) (p < 0.05), suggesting efficacy. CONCLUSIONS: The delivery of a computer tailored web-based intervention designed to increase PA in pregnant women is feasible, well accepted and associated with increases in short-term MVPA. Findings suggest the use of computer-tailored information leads to greater website engagement, satisfaction and greater PA levels among pregnant women compared to a generic information only website. TRIAL REGISTRATION: The trial was 'retrospectively registered' with the Australian New Zealand Clinical Trials Registry ( ACTRN12614001105639 ) on 17th October, 2014. PMID- 28335768 TI - Leisure sedentary time is differentially associated with hypertension, diabetes mellitus, and hyperlipidemia depending on occupation. AB - BACKGROUND: Sedentary behavior is considered an independent cause of cardio metabolic diseases, regardless of physical activity level and obesity. Few studies have reported the association between leisure sedentary time and cardio vascular diseases in terms of occupation. METHODS: We performed a cross-sectional study using data from the Korean Community Health Survey (KCHS) for 240,086 participants assessed in 2011 and 2013. Occupation was categorized into four groups: farmer or fisherman, laborer, and soldier (Group I); service worker, salesperson, technician, mechanic, production worker, and engineer (Group II); manager, expert, specialist, and clerk (Group III); and unemployed (Group IV). Leisure sedentary time was divided into five groups: 0 h, 1 h, 2 h, 3 h, and 4+ h. The association between leisure sedentary time on weekdays and hypertension/diabetes mellitus/hyperlipidemia for different occupations was analyzed using simple and multiple logistic regression analyses with complex sampling. RESULTS: In Groups I, II and III, no length of sedentary time was associated with hypertension, and only 3 h or 4+ h of sedentary time was associated with diabetes mellitus and hyperlipidemia. Group IV showed a significant association with hypertension and diabetes mellitus for the 2 h, 3 h, and 4+ h sedentary times. CONCLUSIONS: The unemployed are more susceptible than other occupation groups to cardio-metabolic diseases when leisure time is sedentary. PMID- 28335769 TI - Cost-effectiveness of CRAG-LFA screening for cryptococcal meningitis among people living with HIV in Uganda. AB - BACKGROUND: Cryptococcal meningitis (CM) constitutes a significant source of mortality in resource-limited regions. Cryptococcal antigen (CRAG) can be detected in the blood before onset of meningitis. We sought to determine the cost effectiveness of implementing CRAG screening using the recently developed CRAG lateral flow assay in Uganda compared to current practice without screening. METHODS: A decision-analytic model was constructed to compare two strategies for cryptococcal prevention among people living with HIV with CD4 < 100 in Uganda: No cryptococcal screening vs. CRAG screening with WHO-recommended preemptive treatment for CRAG-positive patients. The model was constructed to reflect primary HIV clinics in Uganda, with a cohort of HIV-infected patients with CD4 < 100 cells/uL. Primary outcomes were expected costs, DALYs, and incremental cost effectiveness ratios (ICERs). We evaluated varying levels of programmatic implementation in secondary analysis. RESULTS: CRAG screening was considered highly cost-effective and was associated with an ICER of $6.14 per DALY averted compared to no screening (95% uncertainty range: $-20.32 to $36.47). Overall, implementation of CRAG screening was projected to cost $1.52 more per person, and was projected to result in a 40% relative reduction in cryptococcal-associated mortality. In probabilistic sensitivity analysis, CRAG screening was cost effective in 100% of scenarios and cost saving (ie cheaper and more effective than no screening) in 30% of scenarios. Secondary analysis projected a total cost of $651,454 for 100% implementation of screening nationally, while averting 1228 deaths compared to no screening. CONCLUSION: CRAG screening for PLWH with low CD4 represents excellent value for money with the potential to prevent cryptococcal morbidity and mortality in Uganda. PMID- 28335770 TI - A model of influences on the clinical learning environment: the case for change at one U.S. medical school. AB - BACKGROUND: The learning environment within a school of medicine influences medical students' values and their professional development. Despite national requirements to monitor the learning environment, mistreatment of medical students persists. METHODS: We designed a program called WE SMILE: We can Eradicate Student Mistreatment In the Learning Environment with a vision to enhance trainee and faculty awareness and ultimately eliminate medical student mistreatment. We provide a description of our program and early outcomes. RESULTS: The program has enhanced student awareness of what constitutes mistreatment and how to report it. Faculty members are also aware of the formal processes and procedures for review of such incidents. Our proposed model of influences on the learning environment and the clinical workforce informs the quality of trainee education and safety of patient care. Institutional leadership and culture play a prominent role in this model. Our integrated institutional response to learning environment concerns is offered as a strategy to improve policy awareness, reporting and management of student mistreatment concerns. CONCLUSIONS: Our WE SMILE program was developed to enhance education and awareness of what constitutes mistreatment and to provide multiple pathways for student reporting, with clear responsibilities for review, adjudication and enforcement. The program is demonstrating several signs of early success and is offered as a strategy for other schools to adopt or adapt. We have recognized a delicate balance between preserving student anonymity and informing them of specific actions taken. Providing students and other stakeholders with clear evidence of institutional response and accountability remains a key challenge. Multiple methods of reporting have been advantageous in eliciting information on learning environment infringements. These routes and types of reporting have enhanced our understanding of student perceptions and the specific contexts in which mistreatment occurs, allowing for targeted interventions. A common platform across the healthcare professions to report and review concerns has afforded us opportunities to deal with interprofessional issues in a respectful and trustworthy manner. We offer a model of learning environment influences with leadership and institutional culture at the helm, as a way to frame a comprehensive perspective on this challenging and complex concern. PMID- 28335771 TI - Understanding the motivations of health-care providers in performing female genital mutilation: an integrative review of the literature. AB - BACKGROUND: Female genital mutilation (FGM) is a traditional harmful practice that can cause severe physical and psychological damages to girls and women. Increasingly, trained health-care providers carry out the practice at the request of families. It is important to understand the motivations of providers in order to reduce the medicalization of FGM. This integrative review identifies, appraises and summarizes qualitative and quantitative literature exploring the factors that are associated with the medicalization of FGM and/or re infibulation. METHODS: Literature searches were conducted in PubMed, CINAHL and grey literature databases. Hand searches of identified studies were also examined. The "CASP Qualitative Research Checklist" and the "STROBE Statement" were used to assess the methodological quality of the qualitative and quantitative studies respectively. A total of 354 articles were reviewed for inclusion. RESULTS: Fourteen (14) studies, conducted in countries where FGM is largely practiced as well as in countries hosting migrants from these regions, were included. The main findings about the motivations of health-care providers to practice FGM were: (1) the belief that performing FGM would be less harmful for girls or women than the procedure being performed by a traditional practitioner (the so-called "harm reduction" perspective); (2) the belief that the practice was justified for cultural reasons; (3) the financial gains of performing the procedure; (4) responding to requests of the community or feeling pressured by the community to perform FGM. The main reasons given by health-care providers for not performing FGM were that they (1) are concerned about the risks that FGM can cause for girls' and women's health; (2) are preoccupied by the legal sanctions that might result from performing FGM; and (3) consider FGM to be a "bad practice". CONCLUSION: The findings of this review can inform public health program planners, policy makers and researchers to adapt or create strategies to end medicalization of FGM in countries with high prevalence of this practice, as well as in countries hosting immigrants from these regions. Given the methodological limitations in the included studies, it is clear that more robust in-depth qualitative studies are needed, in order to better tackle the complexity of this phenomenon and contribute to eradicating FGM throughout the world. PMID- 28335772 TI - Production of (S)-2-aminobutyric acid and (S)-2-aminobutanol in Saccharomyces cerevisiae. AB - BACKGROUND: Saccharomyces cerevisiae (baker's yeast) has great potential as a whole-cell biocatalyst for multistep synthesis of various organic molecules. To date, however, few examples exist in the literature of the successful biosynthetic production of chemical compounds, in yeast, that do not exist in nature. Considering that more than 30% of all drugs on the market are purely chemical compounds, often produced by harsh synthetic chemistry or with very low yields, novel and environmentally sound production routes are highly desirable. Here, we explore the biosynthetic production of enantiomeric precursors of the anti-tuberculosis and anti-epilepsy drugs ethambutol, brivaracetam, and levetiracetam. To this end, we have generated heterologous biosynthetic pathways leading to the production of (S)-2-aminobutyric acid (ABA) and (S)-2-aminobutanol in baker's yeast. RESULTS: We first designed a two-step heterologous pathway, starting with the endogenous amino acid L-threonine and leading to the production of enantiopure (S)-2-aminobutyric acid. The combination of Bacillus subtilis threonine deaminase and a mutated Escherichia coli glutamate dehydrogenase resulted in the intracellular accumulation of 0.40 mg/L of (S)-2-aminobutyric acid. The combination of a threonine deaminase from Solanum lycopersicum (tomato) with two copies of mutated glutamate dehydrogenase from E. coli resulted in the accumulation of comparable amounts of (S)-2-aminobutyric acid. Additional L threonine feeding elevated (S)-2-aminobutyric acid production to more than 1.70 mg/L. Removing feedback inhibition of aspartate kinase HOM3, an enzyme involved in threonine biosynthesis in yeast, elevated (S)-2-aminobutyric acid biosynthesis to above 0.49 mg/L in cultures not receiving additional L-threonine. We ultimately extended the pathway from (S)-2-aminobutyric acid to (S)-2 aminobutanol by introducing two reductases and a phosphopantetheinyl transferase. The engineered strains produced up to 1.10 mg/L (S)-2-aminobutanol. CONCLUSIONS: Our results demonstrate the biosynthesis of (S)-2-aminobutyric acid and (S)-2 aminobutanol in yeast. To our knowledge this is the first time that the purely synthetic compound (S)-2-aminobutanol has been produced in vivo. This work paves the way to greener and more sustainable production of chemical entities hitherto inaccessible to synthetic biology. PMID- 28335773 TI - Oral administration of propionic acid during lactation enhances the colonic barrier function. AB - BACKGROUND: Propionic acid is a three-carbon short chain fatty acid (SCFA) that has various effects on colonic functions. Although several studies have shown the effects of propionic acid on intestinal mucosal barrier function, studies of the promotion effect during pre-weaning are rare in the literature as far as we know. METHODS: Pre-weaning male Sprague-Dawley rats 7 days after birth were given an oral 0.2 mL/10 g of 200 mM propionic acid solution in the propionic acid group or normal saline solution in the control group by gavage twice a day for ten days. The proximal colonic contents were used for extraction and determination of propionic acid by gas chromatographic analysis; the transepithelial electrical resistance (TER) of colonic tissue was detected by an Ussing chamber; the alterations of ZO-1, Claudin-1, Claudin-8 and Occludin proteins were analyzed by Western blot and immunohistochemistry; and The activity of ERK and p38 MAPK was determined by the phosphorylation status of ERK1/2 and p38 with Western blot. RESULTS: Our results suggested a higher concentration (23.5 +/- 1.9 mmol/kg) of propionic acid compared to the physiological concentration (18.1 +/- 0.9 mmol/kg) in colonic contents after oral administration increased the value of TER and the expression of ZO-1, Claudin-1, Claudin-8 and Occludin compared to the control group. Furthermore, the expression levels of phosphorylated ERK1/2 and p38 MAPK were increased in propionic acid group. CONCLUSIONS: We concluded that continuous oral administration of propionic acid during lactation may increase its concentration in the proximal colon and promote epithelial barrier function of proximal colon by enhancing the expression of ZO-1, Claudin-8, Claudin-1 and Occludin via increases in the expression of ERK1/2 and p38 MAPK. PMID- 28335775 TI - Evaluation of biomarker canine-prostate specific arginine esterase (CPSE) for the diagnosis of benign prostatic hyperplasia. AB - BACKGROUND: Benign prostatic hyperplasia (BPH) is the most common canine prostatic disorder. Although most or even all intact male dogs may develop BPH by 5-8 years of age, many show no clinical signs. Taking into account the non specific character of clinical and ultrasonographic findings, a new diagnostic approach has recently been proposed based on the augmentation of blood canine prostate-specific arginine esterase (CPSE) in hyperplasic dogs. The aim of the present study was to verify CPSE levels in negative controls and hyperplasic dogs, considering cytological findings as the reference method and taking into account the fact that controls were middle-aged intact dogs (median of 5.0 years), contrarily to previous studies carried out with very young control dogs. RESULTS: Significant differences of median CPSE levels were found between controls and hyperplasic dogs (29.1 versus 160.7 ng/mL, respectively); and significant positive correlations were found between median CPSE levels and age or prostatic volume (r = 0.549 and 0.448, respectively; p < 0.001). Sensitivity, specificity, positive and negative likelihood ratios put into evidence the good performance of the test. The agreement between methods was found to be very high, notably between CPSE levels and cytological results (Cohen's kappa coefficients above 0.8). CONCLUSIONS: Considering the results all together, measurement of CPSE is confirmed as a useful and accurate method and should be considered as an alternative or complementary tool to conventional methods for the diagnosis of BPH in middle-aged dogs. PMID- 28335776 TI - Challenges and strategies to improve the availability and geographic accessibility of physicians in Portugal. AB - BACKGROUND: Shortages of physicians in remote, rural and other underserved areas and lack of general practitioners limit access to health services. The aims of this article are to identify the challenges faced by policy and decision-makers in Portugal to guarantee the availability and geographic accessibility to physicians in the National Health Service and to describe and analyse their causes, the strategies to tackle them and their results. We also raise the issue of whether research evidence was used or not in the process of policy development. METHODS: We analysed policy and technical documents, peer-reviewed papers and newspaper articles from 1995 to 2015 through a structured search of government websites, Portuguese online newspapers and PubMed and Virtual Health Library (Biblioteca Virtual em Saude (BVS)) databases; key informants were consulted to validate and complement the documentary search. RESULTS: The challenges faced by decision-makers to ensure access to physicians were identified as a forecasted shortage of physicians, geographical imbalances and maldistribution of physicians by level of care. To date, no human resources for health policy has been formulated, in spite of most documents reviewed stating that it is needed. On the other hand, various isolated and ad hoc strategies have been adopted, such as incentives to choose family health as a specialty or to work in an underserved region and recruitment of foreign physicians through bilateral agreements. CONCLUSIONS: Health workforce research in Portugal is scarce, and therefore, policy decisions regarding the availability and accessibility of physicians are not based on evidence. The policy interventions described in this paper should be evaluated, which would be a good starting point to inform health workforce policy development. PMID- 28335774 TI - How does the multifaceted plant hormone salicylic acid combat disease in plants and are similar mechanisms utilized in humans? AB - Salicylic acid (SA) is an important plant hormone that regulates many aspects of plant growth and development, as well as resistance to (a)biotic stress. Efforts to identify SA effector proteins have revealed that SA binds to and alters the activity of multiple plant proteins-this represents a shift from the paradigm that hormones mediate their functions via one or a few receptors. SA and its derivatives also have multiple targets in animals; some of these proteins, like their plant counterparts, are associated with pathological processes. Together, these findings suggest that SA exerts its defense-associated effects in both kingdoms via a large number of targets. PMID- 28335777 TI - The reasons why Pakistan might be at high risk of Crimean Congo haemorrhagic fever epidemic; a scoping review of the literature. AB - Pakistan has faced a number of significant healthcare challenges over the past decade. In 2000, one of these events - a deadly epidemic of Crimean Congo Haemorrhagic Fever (CCHF) - struck Pakistan. The people of Pakistan are at a very high risk of acquiring CCHF, due to a number of factors which emerge from a scoping review of the literature. First, the underdeveloped healthcare system of the country is currently not prepared to cope with challenges of this nature. Healthcare professionals and medical institutes are not sufficiently equipped to properly diagnose, manage and prevent CCHF. Second, a large percentage of the general public is unaware of the spread and control of the vector. The agricultural sector of Pakistan is vast and thus many people are involved in animal husbandry and the handling of livestock which can lead to the transmission of the CCHF virus. Even in urban areas the risk of transmission is significantly higher around the time of Eid-ul-Azha, when Muslims slaughter animals. Finally, the political upheavals faced by the country have also increased Pakistan's vulnerability because a large number of refugees from Afghanistan, a CCHF endemic country, have migrated to Pakistan as a result of the Afghan war. Most of the refugees and their animals settle in Baluchistan and Khyber Pakhtunkhwa provinces, which consequently have a higher prevalence of CCHF. This scoping review of the literature highlights the potential causes of high risk CCHF and draws conclusions and makes recommendations that policy-makers in Pakistan may wish to consider in-order to improve on the current situation. PMID- 28335778 TI - Radiation dose escalation based on FDG-PET driven dose painting by numbers in oropharyngeal squamous cell carcinoma: a dosimetric comparison between TomoTherapy-HA and RapidArc. AB - PURPOSE: Validation of dose escalation through FDG-PET dose painting (DP) for oropharyngeal squamous cell carcinoma (SCC) requires randomized clinical trials with large sample size, potentially involving different treatment planning and delivery systems. As a first step of a joint clinical study of DP, a planning comparison was performed between Tomotherapy HiArt(r) (HT) and Varian RapidArc(r) (RA). METHODS: The planning study was conducted on five patients with oropharyngeal SCC. Elective and therapeutic CTVs were delineated based on anatomic information, and the respective PTVs (CTVs + 4 mm) were prescribed a dose of 56 (PTV56) and 70 Gy (PTV70). A gradient-based method was used to delineate automatically the external contours of the FDG-PET volume (GTVPET). Variation of the FDG uptake within the GTVPET was linearly converted into a prescription between 70 and 86 Gy. A dilation of the voxel-by-voxel prescription of 2.5 mm was applied to account for geometric errors in dose delivery (PTVPET). The study was divided in two planning phases aiming at maximizing target coverage (phase I) and lowering doses to OAR (phase II). A Quality-Volume Histogram (QVH) assessed conformity with the DP prescription inside the PTVPET. RESULTS: In phase I, for both HT and RA, all plans achieved comparable target coverage for PTV56 and PTV70, respecting the planning objectives. A median value of 99.9 and 97.2% of all voxels in the PTVPET received at least 95% of the prescribed dose for RA and HT, respectively. A median value of 0.0% and 3.7% of the voxels in the PTVPET received 105% or more of prescribed dose for RA and HT, respectively. In phase II, no significant differences were found in OAR sparing. Median treatment times were 13.7 min for HT and 5 min for RA. CONCLUSIONS: Both HT and RA can generate similar dose distributions for FDG-PET based dose escalation and dose painting in oropharyngeal SCC patients. PMID- 28335779 TI - Activity of AMP2041 against human and animal multidrug resistant Pseudomonas aeruginosa clinical isolates. AB - BACKGROUND: Antimicrobial resistance is a growing threat to public health. Pseudomonas aeruginosa is a relevant pathogen causing human and animal infections, frequently displaying high levels of resistance to commonly used antimicrobials. The increasing difficulty to develop new effective antibiotics have discouraged investment in this area and only a few new antibiotics are currently under development. An approach to overcome antibiotic resistance could be based on antimicrobial peptides since they offer advantages over currently used microbicides. METHODS: The antimicrobial activity of the synthetic peptide AMP2041 was evaluated against 49 P. aeruginosa clinical strains with high levels of antimicrobial resistance, isolated from humans (n = 19) and animals (n = 30). In vitro activity was evaluated by a microdilution assay for lethal dose 90% (LD90), while the activity over time was performed by time-kill assay with 12.5 ug/ml of AMP2014. Evidences for a direct membrane damage were investigated on P. aeruginosa ATCC 27853 reference strain, on animal isolate PA-VET 38 and on human isolate PA-H 24 by propidium iodide and on P. aeruginosa ATCC 27853 by scanning electron microscopy. RESULTS: AMP2041 showed a dose-dependent activity, with a mean (SEM) LD90 of 1.69 and 3.3 ug/ml for animal and human strains, respectively. AMP2041 showed microbicidal activity on P. aeruginosa isolates from a patient with cystic fibrosis (CF) and resistance increased from first infection isolate (LD90 = 0.3 MUg/ml) to the mucoid phenotype (LD90 = 10.4 MUg/ml). The time-kill assay showed a time-dependent bactericidal effect of AMP2041 and LD90 was reached within 20 min for all the strains. The stain-dead assay showed an increasing of membrane permeabilization and SEM analysis revealed holes, dents and bursts throughout bacterial cell wall after 30 min of incubation with AMP2041. CONCLUSIONS: The obtained results assessed for the first time the good antimicrobial activity of AMP2041 on P. aeruginosa strains of human origin, including those deriving from a CF patient. We confirmed the excellent antimicrobial activity of AMP2041 on P. aeruginosa strains derived from dog otitis. We also assessed that AMP2041 antimicrobial activity is linked to changes of the P. aeruginosa cell wall morphology and to the increasing of membrane permeability. PMID- 28335780 TI - Considerable interobserver variation in delineation of pancreatic cancer on 3DCT and 4DCT: a multi-institutional study. AB - BACKGROUND: The delineation of pancreatic tumors on CT is challenging. In this study, we quantified the interobserver variation for pancreatic tumor delineation on 3DCT as well as on 4DCT. METHODS: Eight observers (radiation oncologists) from six institutions delineated pancreatic tumors of four patients with (borderline) resectable pancreatic cancer. The study consisted of two stages. In the 3DCT stage, the gross tumor volume (GTV) was delineated on a contrast-enhanced scan. In the 4DCT-stage, the internal GTV (iGTV) was delineated, accounting for the respiratory motion. We calculated the volumes of the (i)GTV, the overlap of the delineated volumes (expressed as generalized conformity index: CIgen), the local observer variation (local standard deviation: SD) and the overall observer variation (overall SD). We compared these results between GTVs and iGTVs. Additionally, observers were asked to fill out a questionnaire concerning the difficulty of the delineation and their experience in delineating pancreatic tumors. RESULTS: The ratios of the largest to the smallest delineated GTV and iGTV within the same patient were 6.8 and 16.5, respectively. As the iGTV incorporates the GTV during all respiratory phases, the mean volumes of the iGTV (40.07 cm3) were larger than those of the GTV (29.91 cm3). For all patients, CIgen was larger for the iGTV than for the GTV. The mean overall observer variation (root-mean-square of all local SDs over four patients) was 0.63 cm and 0.80 cm for GTV and iGTV, respectively. The largest local observer variations were seen close to biliary stents and suspicious pathological enlarged lymph nodes, as some observers included them and some did not. This variation was more pronounced for the iGTV than for the GTV. The observers rated the 3DCT-stage and 4DCT-stage equally difficult and treated on average three to four pancreatic cancer patients per year. CONCLUSIONS: A considerable interobserver variation in delineation of pancreatic tumors was observed. This variation was larger for 4D than for 3D delineation. The largest local observer variation was found around biliary stents and suspicious pathological enlarged lymph nodes. PMID- 28335781 TI - Tailored design of NKT-stimulatory glycolipids for polarization of immune responses. AB - Natural killer T (NKT) cell is a distinct population of T lymphocytes that can rapidly release massive amount of Th1 and Th2 cytokines upon the engagement of their T cell receptor with glycolipids presented by CD1d. The secreted cytokines can promote cell-mediated immunity to kill tumor cells and intracellular pathogens, or suppress autoreactive immune cells in autoimmune diseases. Thus, NKT cell is an attractive target for developing new therapeutics to manipulate immune system. The best-known glycolipid to activate NKT cells is alpha galactosylceramide (alpha-GalCer), which has been used as a prototype for designing new NKT stimulatory glycolipids. Many analogues have been generated by modification of the galactosyl moiety, the acyl chain or the phytosphingosine chain of alpha-GalCer. Some of the analogues showed greater abilities than alpha GalCer in polarizing immune responses toward Th1 or Th2 dominance. Among them, several analogues containing phenyl groups in the lipid tails were more potent in inducing Th1-skewed cytokines and exhibited greater anticancer efficacy than alpha-GalCer. Analyses of the correlation between structure and activity of various alpha-GalCer analogues on the activation of iNKT cell revealed that CD1d glycolipid complexes interacted with the same population of iNKT cell expressing similar T-cell receptor Vbeta as alpha-GalCer. On the other hand, those phenyl glycolipids with propensity for Th1 dominant responses showed greater binding avidity and stability than alpha-GalCer for iNKT T-cell receptor when complexed with CD1d. Thus, it is the avidity and stability of the ternary complexes of CD1d glycolipid-iNKT TCR that dictate the polarity and potency of immune responses. These findings provide a key to the rationale design of immune modulating glycolipids with desirable Th1/Th2 polarity for clinical application. In addition, elucidation of alpha-GalCer-induced anergy, liver damage and accumulation of myeloid derived suppressor cells has offered explanation for its lacklustre anti-cancer activities in clinical trials. On other hand, the lack of such drawbacks in glycolipid analogues containing phenyl groups in the lipid tails of alpha-GalCer coupled with the greater binding avidity and stability of CD1d-glycolipid complex for iNKT T-cell receptor, account for their superior anti cancer efficacy in tumor bearing mice. Further clinical development of these phenyl glycolipids is warranted. PMID- 28335783 TI - SVR Rates of HCV-infected population under PEG-IFN-alpha/R treatment in Northwest China. AB - BACKGROUND: Chronic HCV Patients taking PEG-IFN-alpha/R from different ethnic groups have different probabilities of reaching a sustained viral response (SVR). There are many influence factors, such as HCV genotype, IL-28B single-nucleotide polymorphisms (SNP), Fibrosis 4 index (FIB-4), and aspartate aminotransferase-to platelet ratio index (APRI) score. But the baseline factors in relation to treatment outcome was still not much clear. METHODS: We evaluated data from 231 chronic HCV patients with or without liver fibrosis and their antiviral efficacy after treatment with pegylated interferon plus ribavirin (PEG-IFN-alpha/R) for 24 48 weeks. IL-28B SNP and HCV genotypes were analyzed with genome sequencing using pyrosequencing. RESULTS: Sustained viral response (SVR) rates of patients with HCV 1b and 2a genotypes were 52.25% (58/111) and 75.28% (67/89) (P < 0.01). SVR rates of patients with IL-28B rs8099917 TT, rs12979860 CC and rs12980275 AA were 92.41% (25/27), 92.86% (26/28) and 88.89% (24/27) separately. We found that SVR rates in HCV 1b and 2a patients were only 31.0 and 39.4% if their FIB-4 > 3.25. In addition, when their APRI > 2, only 30.3% of HCV 1b patients and 50.2% of HCV 2a patients could obtain SVR. CONCLUSIONS: There were high proportion of HCV genotype 1b and 2a in Northwest China. In both HCV 1b and 2a genotypes, patients with protective-genotype of IL-28B were more likely to obtain SVR. However, those with significant fibrosis or cirrhosis were less likely, no matter their genotype. Combined factors of HCV genotype, IL-28B genotype, FIB-4 and ARPI may indicate high prediction and clinical value regarding treatment with PEG-IFN alpha/R and prognostic evaluation of chronic hepatitis C patients. PMID- 28335784 TI - The benefit of adjuvant radiotherapy after breast conserving surgery in older patients with low risk breast cancer- a meta-analysis of randomized trials. AB - PURPOSE/OBJECTIVE(S): It is currently unclear whether patients with low risk breast cancer receiving adjuvant endocrine therapy need adjuvant radiation therapy after breast conserving surgery. The data of randomized trials are available. MATERIALS/METHODS: In a database search 5 randomized trials including in total 3766 mostly elderly patients with early stage breast cancer tr eated either with adjuvant endocrine therapy or with endocrine therapy and additional whole breast radiation after breast conserving surgery were identified. Published hazard ratios for time to local recurrence were the basis of our meta-analysis. Meta-analysis of the effect sizes on local recurrence was performed using a random effects model based on parameter estimates of log hazard ratios in Cox models and their standard errors. Furthermore, overall survival was examined. RESULTS: Adjuvant hormone therapy alone in mostly older patients with low risk breast cancer resulted in significantly shorter time to local relapse compared to radiation therapy combined with hormone therapy (Hazard Ratio: 6.8, 95% CI: 4.23 10.93, p < 0.0001) . There was no significant difference for overall survival. CONCLUSION: Additional radiation therapy to hormone therapy did improve local relapse in breast cancer patients but did not show significant impact on overall survival. PMID- 28335785 TI - We need to include bystander first aid in trauma research. AB - BACKGROUND: The chain of trauma survival is a concept that originated in the area of out-of-hospital cardiac arrest (OHCA) and was adapted to the treatment of trauma. In out-of-hospital cardiac arrest research into bystander first aid has resulted in improved outcome. Whereas, in trauma research the first link of the chain of survival is almost ignored. METHODS: In OHCA, cardiopulmonary resuscitation (CPR) from bystanders has been subject of a vast amount of research, as well as measures and programs to raise the rate of bystander CPR to cardiac arrest victims. These efforts have resulted in improved survival. The research effort has been well grounded in the research community, as demonstrated by its natural inclusion in the uniform reporting template (Utstein) for the treatment of OHCA. In trauma the bystander may contribute by providing an open airway, staunch bleedings, or prevent hypothermia. In trauma however, while the chain of survival has been adopted along with it distinct links, including bystander first aid, the consensus-based uniform reporting template for trauma (the Utstein template) does not include the bystander first aid efforts. There is extremely little research on what first aid measures bystanders provide to trauma victims, and on what impact such measures have on outcome. An important step to improve research on bystander first aid in trauma would be to include this as part of the uniform reporting template for trauma CONCLUSION: The lack of research on bystander first aid makes the first link in the trauma chain of survival the weakest link. We, the trauma research community, should either improve our research and knowledge in this area, or remove the link from the chain of survival. PMID- 28335786 TI - Matching safety to access: global actors and pharmacogovernance in Kenya- a case study. AB - BACKGROUND: The Kenyan government has sought to address inadequacies in its National Pharmaceutical Policy and the Pharmacy and Poisons Board's (PPB) medicines governance by engaging with global actors (e.g. the World Health Organization). Policy actors have influenced the way pharmacovigilance is defined, how challenges are understood and which norms are requisite to address drug safety issues. In this paper, we investigate the relationship between specific modes of engagement among global (exogenous) and domestic actors at the national and sub-national level to identify the positive or negative effect on pharmacovigilance and pharmacogovernance in Kenya. Pharmacogovernance is defined as the manner in which governing structures; policy instruments; institutional authority (e.g., ability to act, implement and enforce norms, policies and processes) and resources are managed to promote societal interests for patient safety and protection from adverse drug reactions (ADRs). Qualitative research methods that included key informant interviews and document analysis, were employed to investigate the relationship between global actors' patterns of engagement with national actors and pharmacogovernance in Kenya. RESULTS: Global actors' influence on pharmacogovernance and pharmacovigilance priorities in Kenya (e.g., legislation and adverse drug reaction surveillance) was positively perceived by key informants. We found that global actors' engagement with state actors produced positive and negative outcomes. Engagement with the PPB and Ministry of Health (MOH) that was characterized as dependent (advocacy, empowerment, delegated) or interdependent (collaborative, cooperative, consultative) was mostly associated with positive outcomes e.g., capacity building; strengthening legislation and stakeholder coordination. Fragmentation (independent engagement) hindered risk communication between public, private, and NGO health programs. CONCLUSION: A framework for assessing pharmacogovernance would support policy makers' evidence-based decision making regarding investments to strengthen capacity for pharmacovigilance and guide policies regarding the state and exogenous actor relationship pertaining to pharmacogovernance. Ideally, dependency on exogenous actors should be reduced while retaining consultative, collaborative, and cooperative engagement when inter-dependency is appropriate. The use of global actors to address Kenya's pharmacovigilance inadequacies leaves the country vulnerable to 1) ad hoc drug surveillance; 2) pharmacovigilance fragmentation; 3) shifting priorities; and 4) cross purpose interests. PMID- 28335782 TI - The HIV-1 transmission bottleneck. AB - It is well established that most new systemic infections of HIV-1 can be traced back to one or a limited number of founder viruses. Usually, these founders are more closely related to minor HIV-1 populations in the blood of the presumed donor than to more abundant lineages. This has led to the widely accepted idea that transmission selects for viral characteristics that facilitate crossing the mucosal barrier of the recipient's genital tract, although the specific selective forces or advantages are not completely defined. However, there are other steps along the way to becoming a founder virus at which selection may occur. These steps include the transition from the donor's general circulation to the genital tract compartment, survival within the transmission fluid, and establishment of a nascent stable local infection in the recipient's genital tract. Finally, there is the possibility that important narrowing events may also occur during establishment of systemic infection. This is suggested by the surprising observation that the number of founder viruses detected after transmission in intravenous drug users is also limited. Although some of these steps may be heavily selective, others may result mostly in a stochastic narrowing of the available founder pool. Collectively, they shape the initial infection in each recipient. PMID- 28335787 TI - Risk factors of atherosclerotic tissue types in single-vessel and intermediate coronary lesions: a cross-sectional study. AB - BACKGROUND: Few data exist that correlate lesion-related risk factors such as conventional cardiovascular risks or lipoprotein-associated phospholipase A2 (Lp PLA2) with tissue types within atherosclerotic plaques in patients with single vessel and intermediate coronary lesions. METHODS: One hundred and ninety-two patients with single-vessel and intermediate coronary lesions were enrolled in a cross-sectional study and divided into two groups: stable angina pectoris (SAP) and acute coronary syndrome (ACS) groups. Data regarding clinical characteristics and Lp-PLA2 mass were collected. Using iMAP-IVUS, lumen areas were manually traced to determine the minimum lumen area (MLA) at 1-mm intervals in diseased segments. At the minimum lumen lesion, areas of different types of atherosclerotic tissue [i.e., areas of fibrous plaque tissue (FP), fibro-fatty tissue (FF), dense calcium (DC) and necrotic core (NC)], vascular external elastic membrane (EEMCSA) and plaque and media (P&MCSA) were calculated using the built-in iMap algorithm. Plaque burden was computed as P&MCSA divided by EEMCSA. RESULTS: In a univariate analysis, glycosylated hemoglobin A1C (GHbA1C), low density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), hypertension, Lp-PLA2 and a history of taking statins predicted the degree of FP and NC area, as well as plaque burden, but were not significant predictors of FF or DC area. In a multivariate analysis, Lp-PLA2 and HbA1c remained independent predictors of plaque burden, FP and NC area. However, the results of the regression analyses were not identical when the SAP and ACS groups were analyzed separately. Lp-PLA2, diabetes and NC area were significant predictors of acute coronary lesions, and the predictive value of Lp-PLA2 was confirmed by the finding of a high area-under-the-curve in a ROC analysis (0.837, 95% CI:0.778-0.895, P = 0.000), as well as by the reasonable sensitivity and specificity of cut-off values. CONCLUSIONS: GHbA1C and Lp-PLA2 were strong independent predictors of plaque burden and FP and NC area at the minimum lumen lesion in patients with single-vessel and intermediate coronary lesions. Furthermore, Lp-PLA2 has a certain predictive value for acute coronary lesions. PMID- 28335788 TI - Accuracy of left ventricular ejection fraction by contemporary multiple gated acquisition scanning in patients with cancer: comparison with cardiovascular magnetic resonance. AB - BACKGROUND: Multiple gated acquisition scanning (MUGA) is a common imaging modality for baseline and serial assessment of left ventricular ejection fraction (LVEF) for cardiotoxicity risk assessment prior to, surveillance during, and surveillance after administration of potentially cardiotoxic cancer treatment. The objective of this study was to compare the accuracy of left ventricular ejection fractions (LVEF) obtained by contemporary clinical multiple gated acquisition scans (MUGA) with reference LVEFs from cardiovascular magnetic resonance (CMR) in consecutive patients with cancer. METHODS: In a cross sectional study, we compared MUGA clinical and CMR reference LVEFs in 75 patients with cancer who had both studies within 30 days. Misclassification was assessed using the two most common thresholds of LVEF used in cardiotoxicity clinical studies and practice: 50 and 55%. RESULTS: Compared to CMR reference LVEFs, MUGA clinical LVEFs were only lower by a mean of 1.5% (48.5% vs. 50.0%, p = 0.17). However, the limits of agreement between MUGA clinical and CMR reference LVEFs were wide at -19.4 to 16.5%. At LVEF thresholds of 50 and 55%, there was misclassification of 35 and 20% of cancer patients, respectively. CONCLUSIONS: MUGA clinical LVEFs are only modestly accurate when compared with CMR reference LVEFs. These data have significant implications on clinical research and patient care of a population with, or at risk for, cardiotoxicity. PMID- 28335789 TI - Sex-determining region Y-box protein 3 induces epithelial-mesenchymal transition in osteosarcoma cells via transcriptional activation of Snail1. AB - BACKGROUND: The transcription factor sex-determining region Y-box protein 3 (SOX3) plays important roles in various types of cancer. However, its expression and function have not yet been elucidated in osteosarcoma (OS). METHODS: The expression levels of SOX3 in OS tissues and OS cell lines were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. The effects of SOX3 expression on OS cell biological traits were investigated by overexpressing and downregulating SOX3 protein. The expression of epithelial-mesenchymal transition (EMT) markers and transcription factors associated with EMT (EMT-TFs), were detected simultaneously. The mechanism underlying SOX3-mediated Snail1 expression was further investigated. RESULTS: SOX3 was upregulated in human OS tissues. SOX3 overexpression promoted the EMT, migration and invasion in OS cells. The downregulation of SOX3 resulted in opposing effects. Furthermore, SOX3 upregulation enhanced the expression of the transcriptional repressor Snail1 by binding to its promoter region. Additionally, a positive correlation among the expression of SOX3, Snail1, and E-cadherin was demonstrated in human OS tissues. CONCLUSIONS: SOX3 promotes migration, invasiveness, and EMT in OS cells via transcriptional activation of Snail1 expression, suggesting that SOX3 is a novel regulator of EMT in OS and may serve as a therapeutic target for the treatment of OS metastasis. PMID- 28335790 TI - Physical mechanism and modeling of heat generation and transfer in magnetic fluid hyperthermia through Neelian and Brownian relaxation: a review. AB - Current clinically accepted technologies for cancer treatment still have limitations which lead to the exploration of new therapeutic methods. Since the past few decades, the hyperthermia treatment has attracted the attention of investigators owing to its strong biological rationales in applying hyperthermia as a cancer treatment modality. Advancement of nanotechnology offers a potential new heating method for hyperthermia by using nanoparticles which is termed as magnetic fluid hyperthermia (MFH). In MFH, superparamagnetic nanoparticles dissipate heat through Neelian and Brownian relaxation in the presence of an alternating magnetic field. The heating power of these particles is dependent on particle properties and treatment settings. A number of pre-clinical and clinical trials were performed to test the feasibility of this novel treatment modality. There are still issues yet to be solved for the successful transition of this technology from bench to bedside. These issues include the planning, execution, monitoring and optimization of treatment. The modeling and simulation play crucial roles in solving some of these issues. Thus, this review paper provides a basic understanding of the fundamental and rationales of hyperthermia and recent development in the modeling and simulation applied to depict the heat generation and transfer phenomena in the MFH. PMID- 28335791 TI - Fischer's Plants in folk beliefs and customs: a previously unknown contribution to the ethnobotany of the Polish-Lithuanian-Belarusian borderland. AB - BACKGROUND: Historical ethnobotanical studies are useful starting points for further diachronic analysis. The aim of this contribution is to present archival data from the Polish-Lithuanian-Belarusian borderland, which were collected by Adam Fischer, a Polish ethnographer from Lviv, in the 1930s. These data were originally gathered for publication in the first part of the Lexicon of Slavic beliefs and customs, dedicated to plant uses in traditional Slavonic culture. It was intended to be a joint international enterprise, but was never actually fulfilled. METHODS: In this article we used information from historical Lithuania (the Great Duchy of Lithuania), nowadays a border region between Poland, Lithuania and Belarus. We applied cultural importance indices such as Use Value, Relative Importance value and Sorensen similarity coefficient, in order to compare our data with a western Ukraine data set from the same research framework. RESULTS: In total, 153 plant taxa were registered as used in peasant culture in the Polish-Lithuanian-Belarusian borderland in the 1930s. The species which achieved the highest Use Values were: Calendula officinalis, Cyanus segetum, Helichrysum arenarium, Betula sp., Prunella vulgaris, and Nuphar lutea or Lilium sp. The most salient use categories were medicinal, followed by food and home garden plants. The overall similarity to plants recorded in western Ukraine within the same project of Fischer's is quite low (46%), which may be explained by the partly different flora found in the regions, and a cultural discontinuity, revealed by the difference in species with the highest UV. Moreover, the field collaborators were different in the two regions and may have paid attention to different cultural spheres of use. CONCLUSIONS: The presented ethnobotanical data are a valuable contribution to the ethnobotany of Eastern Europe as a whole. In particular, the presented list of plants may be a rich source for future studies on the ethnobotany of the Polish diaspora in Lithuania, and diachronic studies in north-east Poland and Belarus. PMID- 28335792 TI - Can incontinence be cured? A systematic review of cure rates. AB - BACKGROUND: Incontinence constitutes a major health problem affecting millions of people worldwide. The present study aims to assess cure rates from treating urinary (UI) or fecal incontinence (FI) and the number of people who may remain dependent on containment strategies. METHODS: Medline, Embase, PsycINFO, Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL, and PEDro were searched from January 2005 to June 2015. Supplementary searches included conference abstracts and trials registers (2013-2015). Included studies had patients >= 18 years with UI or FI, reported treatment cure or success rates, had >= 50 patients treated with any intervention recognized in international guideline algorithms, a follow-up >= 3 months, and were published from 2005 onwards. Title and abstract screening, full paper screening, data extraction and risk-of-bias assessment were performed independently by two reviewers. Disagreements were resolved through discussion or referral to a third reviewer where necessary. A narrative summary of included studies is presented. RESULTS: Most evidence was found for UI: Surgical interventions for stress UI showed a median cure rate of 82.3% (interquartile range (IQR), 72-89.5%); people with urgency UI were mostly treated using medications (median cure rate for antimuscarinics = 49%; IQR, 35.6-58%). Pelvic floor muscle training and bulking agents showed lower cure rates for UI. Sacral neuromodulation for FI had a median cure rate of 38.6% (IQR, 35.6-40.6%). CONCLUSIONS: Many individuals were not cured and hence may continue to rely on containment. No studies were found assessing success of containment strategies. There was a lack of data in the disabled and in those with neurological diseases, in the elderly and those with cognitive impairment. Surgical interventions were effective for stress UI. Other interventions for UI and FI showed lower cure rates. Many individuals are likely to be reliant on containment strategies. PROSPERO REGISTRATION: PROSPERO registration number: CRD42015023763 . PMID- 28335794 TI - Tumor motion changes in stereotactic body radiotherapy for liver tumors: an evaluation based on four-dimensional cone-beam computed tomography and fiducial markers. AB - BACKGROUND: For stereotactic body radiation therapy (SBRT) of liver tumors, tumor motion induced by respiration must be taken into account in planning and treatment. We evaluated whether liver tumor motion at the planning simulation represents liver tumor motion during SBRT, and estimated inter- and intrafractional tumor motion changes in patients undergoing liver SBRT. METHODS: Ten patients underwent four-dimensional cone-beam computed tomography (4D-CBCT) image-guided liver SBRT with abdominal compression (AC) and fiducial markers. 4D CBCT was performed to evaluate liver tumor motion at the planning simulation, pre , and post-SBRT. The translational distances at the center position of the fiducial markers from all 10 phases on the 4D-CBCT images were measured as the extent of the liver tumor motion in the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions. Pearson correlation coefficients were calculated to evaluate the correlation between liver tumor motion of the planning simulation and the mean liver tumor motion of the pre-SBRT. Inter- and intrafractional liver tumor motion changes were measured based on the 4D-CBCT of planning simulation, pre-, and post-SBRT. Significant inter- and intrafractional changes in liver tumor motion were defined as a change of >3 mm. RESULTS: The mean (+/- SD) liver tumor motion of the planning simulation 4D-CBCT was 1.7 +/- 0.8 mm, 2.4 +/- 2.2 mm, and 5.3 +/- 3.3 mm, in the LR, AP, and SI directions, respectively. Those of the pre-SBRT 4D-CBCT were 1.2 +/- 0.7 mm, 2.3 +/- 2.3 mm, and 4.5 +/- 3.8 mm, in the LR, AP, and SI directions, respectively. There was a strong significant correlation between liver tumor motion of the planning simulation and pre-SBRT in the LR (R = 0.7, P < 0.01), AP (R = 0.9, P < 0.01), and SI (R = 0.9, P < 0.01) directions. Significant inter- and intrafractional liver tumor motion changes occurred in 10 and 2% of treatment fractions, respectively. CONCLUSIONS: Liver tumor motion at the planning simulation represents liver tumor motion during SBRT. Inter- and intrafractional liver tumor motion changes were small in patients with AC. PMID- 28335795 TI - Gemella morbillorum endocarditis of pulmonary valve:a case report. AB - BACKGROUND: Pulmonary valve infective endocarditis is a rare finding for endocarditis. Infective endocarditis caused by Gemella morbillorum remains a scanty occurrence. CASE PRESENTATION: This is a case reported of a 28-year-old Chinese male with endocarditis caused by pulmonary valve infection of Gemella morbillorum associated with congenital ventricular septal defect, atrial septal defect and double-chambered right ventricle. The patient presented with fever, shortness of breath, progressively worsening exertional fatigue, dyspnea and weight loss for 3 months. The diagnosis was made with transthoracic echocardiogram, blood cultures, and post-operative pathology. The patient developed congestive heart failure and was managed with aggressive antibiotic therapy followed by surgery. He underwent replacement of the pulmonary valve with an aortic bioprosthetic valve, repair of ventricular septal defect and atrial septal defect, reconstruction of the right ventricular outlflow tract, and excision of vegetations. His postoperative recovery was uneventful. No bacteria were isolated from the excised tissues. He was asymptomatic without recurrence at 3-month follow-up. CONCLUSIONS: The rare pathogen such as Gemella morbillorum can be the cause of infective endocarditis and timely surgical repair is necessary if the infection is refractory or there is progression of congestive heart failure under antibiotic cover. PMID- 28335793 TI - Thrombus leukocytes exhibit more endothelial cell-specific angiogenic markers than peripheral blood leukocytes do in acute coronary syndrome patients, suggesting a possibility of trans-differentiation: a comprehensive database mining study. AB - BACKGROUND: Current angiogenic therapies for cancers and cardiovascular diseases have not yet achieved expected benefits, which reflects the need for improved understanding of angiogenesis. In this study, we focused on solving the problem of whether tissues have different angiogenic potentials (APs) in physiological conditions and how angiogenesis is regulated in various disease conditions. METHODS: In healthy and diseased human and mouse tissues, we profiled the expression of 163 angiogenic genes, including transcription regulators (TRs), growth factors and receptors (GF/Rs), cytokines and chemokines (C/Cs), and proteases and inhibitors (P/Is). TRs were categorized as inflammatory, homeostatic, and endothelial cell-specific TRs, and C/Cs were categorized as pro angiogenic, anti-angiogenic, and bi-functional C/Cs. RESULTS: We made the following findings: (1) the human heart, muscle, eye, pancreas, and lymph node are among the tissues with the highest APs; (2) tissues with high APs have more active angiogenic pathways and angiogenic C/C responses; (3) inflammatory TRs dominate regulation of all angiogenic C/Cs; homeostatic TRs regulate all to a lower extent, while endothelial cell-specific TRs mainly regulate pro-angiogenic and bi-functional C/Cs; (4) tissue AP is positively correlated with the expression of oxygen sensors PHD2 and HIF1B, VEGF pathway gene VEGFB, and stem cell gene SOX2; (5) cancers of the digestive system tend to have increased angiogenesis dominated by endothelial cell-specific pro-angiogenic pathways, while lung cancer and prostate cancer have significantly decreased angiogenesis; and (6) endothelial cell-specific pro-angiogenic pathways are significantly increased in thrombus-derived leukocytes in patients with acute coronary artery disease. CONCLUSIONS: Our results demonstrate that thrombus-derived leukocytes express more endothelial cell-specific angiogenic markers to directly promote angiogenesis after myocardial infarction and that certain solid tumors may be more sensitive to anti-angiogenic therapies than others. PMID- 28335796 TI - Predicting dementia using socio-demographic characteristics and the Free and Cued Selective Reminding Test in the general population. AB - BACKGROUND: Our study aimed to determine whether the consideration of socio demographic features improves the prediction of Alzheimer's dementia (AD) at 5 years when using the Free and Cued Selective Reminding Test (FCSRT) in the general older population. METHODS: Our analyses focused on 2558 subjects from the prospective Three-City Study, a cohort of community-dwelling individuals aged 65 years and over, with FCSRT scores. Four "residual scores" and "risk scores" were built that included the FCSRT scores and socio-demographic variables. The predictive performance of crude, residual and risk scores was analyzed by comparing the areas under the ROC curve (AUC). RESULTS: In total, 1750 subjects were seen 5 years after completing the FCSRT. AD was diagnosed in 116 of them. Compared with the crude free-recall score, the predictive performances of the residual score and of the risk score were not significantly improved (AUC: 0.83 vs 0.82 and 0.88 vs 0.89 respectively). CONCLUSION: Using socio-demographic features in addition to the FCSRT does not improve its predictive performance for dementia or AD. PMID- 28335797 TI - Poor prognostic factors guiding treatment decisions in rheumatoid arthritis patients: a review of data from randomized clinical trials and cohort studies. AB - Prognostic factors are used for treatment decisions in rheumatoid arthritis (RA). High disease activity, the early presence of erosions, and autoantibody positivity are the most frequently used poor prognostic factors but other features, such as functional disability, extraarticular disease, or multibiomarkers, are also assessed. Prognostic factors are incorporated in current treatment recommendations for the management of RA and are used as inclusion criteria in randomized controlled trials. They are defined heterogeneously and the relevance of a single or combined presence of poor prognostic factors remains unclear. This review summarizes the current definitions of poor prognostic factors and their use in clinical research. Perspectives on future research are also outlined. PMID- 28335798 TI - Treatment of mucocutaneous manifestations in Behcet's disease with anakinra: a pilot open-label study. AB - BACKGROUND: The effect of IL-1 blocking therapy on mucocutaneous manifestations of Behcet's disease is incompletely understood. METHODS: Six patients with Behcet's disease and ongoing oral/genital ulcers for >=1 month were enrolled into an adaptive, two-phase clinical trial and included in the analysis. Study duration was 6 months with extension up to 16 months. All were treated non blinded with anakinra 100 mg subcutaneous daily with the option to escalate the dose to 200 mg in partial responders after 1 month and 300 mg after 6 months. Patients recorded the number and severity of ulcers in daily diaries. The primary outcome was remission defined as no ulcers on physical exam for two consecutive monthly visits between months 3 and 6. Secondary outcomes included the number and severity of patient-reported ulcers, patient/physician global scores, and standardized disease activity scores. RESULTS: Two of six patients achieved the primary outcome. Five of six patients had improvement in the number and severity of ulcers. Non-statistically significant improvements were seen in secondary outcomes. Over the entire study, patients reported >=1 oral and >=1 genital ulcer on 665 (66%) and 139 (14%) days, respectively. On anakinra 200 mg vs 100 mg, patients reported fewer days with oral ulcers (65% vs 74% of days, p = 0.01) and genital ulcers (10% vs 22% of days, p < 0.001) and milder oral ulcer severity (p < 0.001). Increase of anakinra to 300 mg did not result in further improvements. Adverse events were notable for mild infections. CONCLUSION: Anakinra at an optimal dose of 200 mg daily had an acceptable safety profile and was partially effective in the treatment of resistant oral and genital ulcers in Behcet's disease. TRIAL REGISTRATION: Clinicaltrials.gov. NCT01441076 . Registered on 24 September 2011. PMID- 28335799 TI - Convergent and sequential synthesis designs: implications for conducting and reporting systematic reviews of qualitative and quantitative evidence. AB - BACKGROUND: Systematic reviews of qualitative and quantitative evidence can provide a rich understanding of complex phenomena. This type of review is increasingly popular, has been used to provide a landscape of existing knowledge, and addresses the types of questions not usually covered in reviews relying solely on either quantitative or qualitative evidence. Although several typologies of synthesis designs have been developed, none have been tested on a large sample of reviews. The aim of this review of reviews was to identify and develop a typology of synthesis designs and methods that have been used and to propose strategies for synthesizing qualitative and quantitative evidence. METHODS: A review of systematic reviews combining qualitative and quantitative evidence was performed. Six databases were searched from inception to December 2014. Reviews were included if they were systematic reviews combining qualitative and quantitative evidence. The included reviews were analyzed according to three concepts of synthesis processes: (a) synthesis methods, (b) sequence of data synthesis, and (c) integration of data and synthesis results. RESULTS: A total of 459 reviews were included. The analysis of this literature highlighted a lack of transparency in reporting how evidence was synthesized and a lack of consistency in the terminology used. Two main types of synthesis designs were identified: convergent and sequential synthesis designs. Within the convergent synthesis design, three subtypes were found: (a) data-based convergent synthesis design, where qualitative and quantitative evidence is analyzed together using the same synthesis method, (b) results-based convergent synthesis design, where qualitative and quantitative evidence is analyzed separately using different synthesis methods and results of both syntheses are integrated during a final synthesis, and (c) parallel-results convergent synthesis design consisting of independent syntheses of qualitative and quantitative evidence and an interpretation of the results in the discussion. CONCLUSIONS: Performing systematic reviews of qualitative and quantitative evidence is challenging because of the multiple synthesis options. The findings provide guidance on how to combine qualitative and quantitative evidence. Also, recommendations are made to improve the conducting and reporting of this type of review. PMID- 28335800 TI - A new method for in vitro feeding of Rhipicephalus australis (formerly Rhipicephalus microplus) larvae: a valuable tool for tick vaccine development. AB - BACKGROUND: Rhipicephalus microplus is a hard tick that has a major impact on cattle health in tropical and subtropical regions because it feeds on cattle and is implicated in the transmission of pathogens that cause diseases such as bovine anaplasmosis and babesiosis. Presently, acaricides are used to control tick infestation but this is becoming increasingly less effective due to the emergence of tick strains that are resistant to one or more classes of acaricides. Anti tick vaccines are a promising alternative to control tick infestation in cattle. The life-cycle and host preference of R. microplus, however, makes vaccine research in cattle costly and would therefore greatly benefit from an in vitro screening system. METHODS: To this aim, a stacked 24-well in vitro feeding system was designed in which the blood meal was administered in a chamber on top of the compartment containing the ticks, exploiting their anti-gravitational tendency. Both compartments were separated by a special feeding membrane, which was made by applying a silicone mixture to a gold beater's skin (baudruche membrane) with a paint roller to create a slightly uneven surface of 17-40 MUm variable thickness. To further stimulate feeding, the membrane was treated with bovine hair extract and the unit was placed at 37 degrees C with 90% RH and 5% CO2. RESULTS: Using this set-up with Rhipicephalus australis (formerly Rhipicephalus microplus), a larval engorgement rate of up to 71% could be achieved. The larvae could successfully feed on blood, but also on serum. The latter allows easy screening of the effect of sera that are raised against tick proteins on feeding. As an example, serum from cattle that were vaccinated with the Bm86 midgut protein of R. microplus significantly reduced larval engorgement rates by 42%. CONCLUSION: The in vitro feeding system's high throughput design and its ability to measure statistically significant anti-tick effects in sera from immunized cattle enables screening of multiple vaccine candidates in a cost-effective manner. PMID- 28335801 TI - Different challenges, different approaches and related expenditures of community based tuberculosis activities by international non-governmental organizations in Myanmar. AB - BACKGROUND: International non-governmental organizations (INGOs) have been implementing community-based tuberculosis (TB) care (CBTBC) in Myanmar since 2011. Although the National TB Programme (NTP) ultimately plans to take over CBTBC, there have been no evaluations of the models of care or of the costs of providing CBTBC in Myanmar by INGOs. METHODS: This was a descriptive study using routinely-collected programmatic and financial data from four INGOs during 2013 and 2014, adjusted for inflation. Data analysis was performed from the provider perspective. Costs for sputum examination were not included as it was provided free of charge by NTP. We calculated the average cost per year of each programme and cost per patient completing treatment. RESULTS: Four INGOs assisted the NTP by providing CBTBC in areas where access to TB services was challenging. Each INGO faced different issues in their contexts and responded with a diversity of strategies. The total costs ranged from US$ 140 754 to US$ 550 221 during the study period. The cost per patient completing treatment ranged from US$ 215 to US$ 1 076 for new cases and US$ 354 to US$ 1 215 for retreatment cases, depending on the targeted area and the package of services offered. One INGO appeared less costly, more sustainable and patient oriented than others. CONCLUSIONS: This study revealed a wide variety of models of care and associated costs for implementing CBTBC in diverse and challenging populations and contexts in Myanmar. Consequently, we recommend a more comprehensive evaluation, including development of a cost model, to estimate the costs of scaling up CBTBC country wide, and cost-effectiveness studies, to best inform the NTP as it prepares to takeover CBTBC activities from INGOs. While awaiting evidence from these studies, model of CBTBC that have higher sustainability potential and allocate more resources to patient-centered care should be given priority support. PMID- 28335802 TI - Use of low-dose computed tomography to assess pulmonary tuberculosis among healthcare workers in a tuberculosis hospital. AB - BACKGROUND: According to the World Health Organization, China is one of 22 countries with serious tuberculosis (TB) infections and one of the 27 countries with serious multidrug-resistant TB strains. Despite the decline of tuberculosis in the overall population, healthcare workers (HCWs) are still at a high risk of infection. Compared with high-income countries, the TB prevalence among HCWs is higher in low- and middle-income countries. Low-dose computed tomography (LDCT) is becoming more popular due to its superior sensitivity and lower radiation dose. However, there have been no reports about active pulmonary tuberculosis (PTB) among HCWs as assessed with LDCT. The purposes of this study were to examine PTB statuses in HCWs in hospitals specializing in TB treatment and explore the significance of the application of LDCT to these workers. METHODS: This study retrospectively analysed the physical examination data of healthcare workers in the Beijing Chest Hospital from September 2012 to December 2015. Low dose lung CT examinations were performed in all cases. The comparisons between active and inactive PTB according to the CT findings were made using the Pearson chi-square test or the Fisher's exact test. Comparisons between the incidences of active PTB in high-risk areas and non-high-risk areas were performed using the Pearson chi-square test. Analyses of active PTB were performed according to different ages, numbers of years on the job, and the risks of the working areas. Active PTB as diagnosed by the LDCT examinations alone was compared with the final comprehensive diagnoses, and the sensitivity and positive predictive value were calculated. RESULTS: A total of 1 012 participants were included in this study. During the 4-year period of medical examinations, active PTB was found in 19 cases, and inactive PTB was found in 109 cases. The prevalence of active PTB in the participants was 1.24%, 0.67%, 0.81%, and 0.53% for years 2012 to 2015. The corresponding incidences of active PTB among the tuberculosis hospital participants were 0.86%, 0.41%, 0.54%, and 0.26%. Most HCWs with active TB (78.9%, 15/19) worked in the high-risk areas of the hospital. There was a significant difference in the incidences of active PTB between the HCWs who worked in the high-risk and non-high-risk areas (odds ratio [OR], 14.415; 95% confidence interval (CI): 4.733 - 43.896). Comparisons of the CT signs between the active and inactive groups via chi-square tests revealed that the tree-in bud, cavity, fibrous shadow, and calcification signs exhibited significant differences (P = 0.000, 0.021, 0.001, and 0.024, respectively). Tree-in-bud and cavity opacities suggest active pulmonary tuberculosis, whereas fibrous shadow and calcification opacities are the main features of inactive pulmonary tuberculosis. Comparison with the final comprehensive diagnoses revealed that the sensitivity and positive predictive value of the diagnoses of active PTB based on LDCT alone were 100% and 86.4%, respectively. CONCLUSIONS: Healthcare workers in tuberculosis hospitals are a high-risk group for active PTB. Yearly LDCT examinations of such high-risk groups are feasible and necessary. PMID- 28335805 TI - Erratum to: Cognitive rehabiliation for Parkinson's disease dementia: a study protocol for a pilot randomised controlled trial. PMID- 28335804 TI - Symbolic time series analysis of electroencephalographic (EEG) epileptic seizure and brain dynamics with eye-open and eye-closed subjects during resting states. AB - OBJECTIVE: Epilepsy is a neuronal disorder for which the electrical discharge in the brain is synchronized, abnormal and excessive. To detect the epileptic seizures and to analyse brain activities during different mental states, various methods in non-linear dynamics have been proposed. This study is an attempt to quantify the complexity of control and epileptic subject with and without seizure as well as to distinguish eye-open (EO) and eye-closed (EC) conditions using threshold-based symbolic entropy. METHODS: The threshold-dependent symbolic entropy was applied to distinguish the healthy and epileptic subjects with seizure and seizure-free intervals (i.e. interictal and ictal) as well as to distinguish EO and EC conditions. The original time series data was converted into symbol sequences using quantization level, and word series of symbol sequences was generated using a word length of three or more. Then, normalized corrected Shannon entropy (NCSE) was computed to quantify the complexity. The NCSE values were not following the normal distribution, and the non-parametric Mann-Whitney-Wilcoxon (MWW) test was used to find significant differences among various groups at 0.05 significance level. The values of NCSE were presented in a form of topographic maps to show significant brain regions during EC and EO conditions. The results of the study were compared to those of the multiscale entropy (MSE). RESULTS: The results indicated that the dynamics of healthy subjects are more complex compared to epileptic subjects (during seizure and seizure-free intervals) in both EO and EC conditions. The comparison of the dynamics of epileptic subjects revealed that seizure-free intervals are more complex than seizure intervals. The dynamics of healthy subjects during EO conditions are more complex compared to those during EC conditions. Further, the results clearly demonstrated that threshold-dependent symbolic entropy outperform MSE in distinguishing different physiological and pathological conditions. CONCLUSION: The threshold symbolic entropy has provided improved accuracy in quantifying the dynamics of healthy and epileptic subjects during EC an EO conditions for each electrode compared to the MSE. PMID- 28335803 TI - Spatial-temporal analysis of pulmonary tuberculosis in the northeast of the Yunnan province, People's Republic of China. AB - BACKGROUND: The number of pulmonary tuberculosis (PTB) cases in China ranks third in the world. A continuous increase in cases has recently been recorded in Zhaotong prefecture-level city, which is located in the northeastern part of Yunnan province. This study explored the space-time dynamics of PTB cases in Zhaotong to provide useful information that will help guide policymakers to formulate effective regional prevention and control strategies. METHODS: The data on PTB cases were extracted from the nationwide tuberculosis online registration system. Time series and spatial cluster analyses were applied to detect PTB temporal trends and spatial patterns at the town level between 2011 and 2015 in Zhaotong. Three indicators of PTB treatment registration history were used: initial treatment registration rate, re-treatment registration rate, and total PTB registration rate. RESULTS: Seasonal trends were detected with an apparent symptom onset peak during the winter season and a registration peak during the spring season. A most likely cluster and six secondary clusters were identified for the total PTB registration rate, one most likely cluster and five secondary clusters for the initial treatment registration rate, and one most likely cluster for the re-treatment registration rate. The most likely cluster of the three indicators had a similar spatial distribution and size in Zhenxiong County, which is characterised by a poor socio-economic level and the largest population in Yunnan. CONCLUSION: This study identified temporal and spatial distribution of PTB in a high PTB burden area using existing health data. The results of the study provide useful information on the prevailing epidemiological situation of PTB in Zhaotong and could be used to develop strategies for more effective PTB control at the town level. The cluster that overlapped the three PTB indicators falls within the geographic areas where PTB control efforts should be prioritised. PMID- 28335806 TI - Effectiveness of early interventions for parental sensitivity following preterm birth: a systematic review protocol. AB - BACKGROUND: Parental sensitivity is the interaction process by which parents (a) recognize cues from their infant, (b) interpret these cues adequately, (c) identify an appropriate response and (d) apply this response in an appropriate time frame. In the neonatal intensive care unit, parents of preterm infants often encounter factors hampering the establishment of their parental sensitivity. Parents report the need to be in proximity to and to participate in their preterm infant's care in order to develop their sensitivity to their newborn infant. To do so, the effectiveness of interventions promoting their parental sensitivity has been evaluated with randomized controlled trials. The purpose of this systematic review is to evaluate the effectiveness of early interventions promoting parental sensitivity of preterm infants' parents. METHODS/DESIGN: A search will be done in the following databases: CINAHL, PubMed in addition to Medline, Embase, PsycInfo, Web of Science, Scopus and ProQuest. No restriction for the years of publication will be considered. Two experts will be conducting independently each step of the review. All studies of randomized controlled trials of early interventions, for parents of preterm infants, implemented in the neonatal intensive care unit before the infant has reached 37 weeks of corrected gestational age, will be considered eligible. Primary outcome is parental sensitivity. Depending on the availability and quality of data, a meta-analysis will be done. Alternatively, a qualitative synthesis of data is planned. The systematic review follows the PRISMA recommendations. Finally, risk of bias and quality of the evidence of included studies will be assessed. DISCUSSION: To our knowledge, this will be the first systematic review to examine the effect of early interventions that promote parental sensitivity of parents of preterm infants in the neonatal intensive care unit. The results of this review will guide development of best practice guidelines and recommendations for further research and will have implications for neonatal clinical practice. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016047083. PMID- 28335808 TI - Potential for hydrogen-oxidizing chemolithoautotrophic and diazotrophic populations to initiate biofilm formation in oligotrophic, deep terrestrial subsurface waters. AB - BACKGROUND: Deep terrestrial biosphere waters are separated from the light-driven surface by the time required to percolate to the subsurface. Despite biofilms being the dominant form of microbial life in many natural environments, they have received little attention in the oligotrophic and anaerobic waters found in deep bedrock fractures. This study is the first to use community DNA sequencing to describe biofilm formation under in situ conditions in the deep terrestrial biosphere. RESULTS: In this study, flow cells were attached to boreholes containing either "modern marine" or "old saline" waters of different origin and degree of isolation from the light-driven surface of the earth. Using 16S rRNA gene sequencing, we showed that planktonic and attached populations were dissimilar while gene frequencies in the metagenomes suggested that hydrogen-fed, carbon dioxide- and nitrogen-fixing populations were responsible for biofilm formation across the two aquifers. Metagenome analyses further suggested that only a subset of the populations were able to attach and produce an extracellular polysaccharide matrix. Initial biofilm formation is thus likely to be mediated by a few bacterial populations which were similar to Epsilonproteobacteria, Deltaproteobacteria, Betaproteobacteria, Verrucomicrobia, and unclassified bacteria. CONCLUSIONS: Populations potentially capable of attaching to a surface and to produce extracellular polysaccharide matrix for attachment were identified in the terrestrial deep biosphere. Our results suggest that the biofilm populations were taxonomically distinct from the planktonic community and were enriched in populations with a chemolithoautotrophic and diazotrophic metabolism coupling hydrogen oxidation to energy conservation under oligotrophic conditions. PMID- 28335809 TI - Poor uptake of an online intervention in a cluster randomised controlled trial of online diabetes education for rural general practitioners. AB - BACKGROUND: In Australia, rural and remote communities have high rates of diabetes-related death and hospitalisation. General practitioners (GPs) play a major role in diabetes detection and management. Education of GPs could optimise diabetes management and improve patient outcomes at a population level. The study aimed to describe the uptake of a continuing medical education intervention for rural GPs and its impact on the viability of a cluster randomised controlled trial of the effects of continuing medical education on whole-town diabetes monitoring and control. METHOD: Trial design: the cluster randomised controlled trial involved towns as the unit of allocation and analysis with outcomes assessed by de-identified pathology data (not reported here). The intervention programme consisted of an online active learning module, direct electronic access to specialist advice and performance feedback. Multiple rounds of invitation were used to engage GPs with the online intervention content. Evidence-based strategies (e.g. pre-notification, rewards, incentives) were incorporated into the invitations to enrol in the programme. Recruitment to the programme was electronically monitored through the hosting software package during the study intervention period. RESULTS: Eleven matched pairs of towns were included in the study. There were 146 GPs in the 11 intervention towns, of whom 34 (23.3%) enrolled in the programme, and 8 (5.5%) completed the online learning module. No town had more than 10% of the resident GPs complete the learning module. There were no contacts made by GPs regarding requests for specialist advice. Consequently, the trial was discontinued. CONCLUSION: There is an ongoing need to engage primary care physicians in improving diabetes monitoring and management in rural areas. Online training options, while notionally attractive and accessible, are not likely to have high levels of uptake, even when evidence-based recruitment strategies are implemented. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, identifier: ACTRN12611000553976 . Retrospectively registered on 31 May 2011. PMID- 28335807 TI - Time-dependent association of glucocorticoids with adverse outcome in community acquired pneumonia: a 6-year prospective cohort study. AB - BACKGROUND: The hypothalamic-pituitary-adrenal stress axis plays a crucial role in community-acquired pneumonia (CAP), with high cortisol being associated with disease severity and corticosteroid treatment resulting in earlier time to recovery. Our aim in the present study was to compare different glucocorticoid hormones, including cortisol, 11-deoxycortisol, cortisone, and corticosterone, regarding their association with short- and long-term adverse outcomes in a well defined CAP cohort. METHODS: We prospectively followed 285 patients with CAP from a previous Swiss multicenter trial for a median of 6.1 years and measured different admission glucocorticoid serum levels by liquid chromatography coupled with tandem mass spectrometry. We used adjusted Cox regression models to investigate associations between admission hormone levels and all-cause mortality at different time points. RESULTS: Mortality was 5.3% after 30 days and increased to 47.3% after 6 years. High admission cortisol was associated with adverse outcome after 30 days (adjusted OR 3.85, 95% CI 1.10-13.49, p = 0.035). In the long term (i.e.,), however, high admission cortisol was associated with better survival (adjusted HR after 3 years 0.53, 95% CI 0.32-0.89, p = 0.017; adjusted HR after 6 years 0.57, 95% CI 0.36-0.90, p = 0.015). Compared with 11 deoxycortisol, cortisone, and corticosterone, cortisol showed the highest association with mortality. CONCLUSIONS: Among different glucocorticoid hormones, cortisol showed the highest association with mortality in CAP. Whereas a more pronounced glucocorticoid stress response on hospital admission was associated with higher short-term adverse outcome, long-term outcome was favorable in these patients. These data should support the correct interpretation of glucocorticoid blood data. PMID- 28335810 TI - Structured relearning of activities of daily living in dementia: the randomized controlled REDALI-DEM trial on errorless learning. AB - BACKGROUND: Errorless learning (EL) is a method for optimizing learning, which uses feed-forward instructions in order to prevent people from making mistakes during the learning process. The majority of previous studies on EL taught patients with dementia artificial tasks of little or no relevance for their daily lives. Furthermore, only a few controlled studies on EL have so far been performed and just a handful of studies have examined the long-term effects of EL. Tasks were not always trained in the patients' natural or home environment, limiting the external validity of these studies. This multicenter parallel randomized controlled trial examines the effects of EL compared with trial and error learning (TEL) on the performance of activities of daily living in persons with Alzheimer's or mixed-type dementia living at home. METHODS: Patients received nine 1-hour task training sessions over eight weeks using EL or TEL. Task performance was measured using video observations at week 16. Secondary outcome measures were task performance measured at week 26, satisfaction with treatment, need for assistance, challenging behavior, adverse events, resource utilization and treatment costs. RESULTS: A total of 161 participants were randomized, of whom 71 completed the EL and 74 the TEL arm at week 11. Sixty-nine EL patients and 71 TEL patients were assessed at the 16-week follow-up (the primary measurement endpoint). Intention-to-treat analysis showed a significantly improved task performance in both groups. No significant differences between the treatment groups were found for primary or secondary outcomes. CONCLUSIONS: Structured relearning improved the performance of activities of daily living. Improvements were maintained for 6 months. EL had no additional effect over TEL. TRIAL REGISTRATION: German Register of Clinical Trials DRKS00003117 . Registered 31 May 2011. PMID- 28335811 TI - Three patients presenting with severe macrosomia and congenital hypertrophic cardiomyopathy: a case series. AB - BACKGROUND: Macrosomia and hypertrophic cardiomyopathy are two features often associated in neonates of diabetic mothers. We report the cases of three patients with severe macrosomia and critical hypertrophic cardiomyopathy without severely unbalanced maternal diabetes. Only three patients with those two features and no uncontrolled maternal diabetes have been previously reported. CASE PRESENTATION: The first patient was a 39-week-old girl, the second patient was a 39-week-old girl, and the third patient was a 41-week-old boy. The two French girls and the French boy had severe macrosomia and hypertrophic cardiomyopathy, leading to the death of the boy. The outcome of the two girls was favorable, with a standardization of growth curves and ventricular hypertrophy. Their mothers presented with high body mass index but no severe documented maternal diabetes; glycemic imbalance was only suspected on postnatal analyses. There was no hydramnios during pregnancy and no other environmental factor, especially toxic exposure. Their parents are from Mayotte, Guadeloupe, and Guinea-Conakry. The usual genetics causes, Beckwith-Wiedemann syndrome, and chromosomal copy number variation, were also excluded. CONCLUSIONS: This report suggests the implication of other factors in addition to glycemic disorders, including genetic factors, in the occurrence of macrosomia and severe hypertrophic cardiomyopathy in neonates. These three original observations indicate that gynecologists and neonatologists should pay attention to neonates from mothers with a high body mass index and when maternal diabetes is not documented. PMID- 28335812 TI - CancerLocator: non-invasive cancer diagnosis and tissue-of-origin prediction using methylation profiles of cell-free DNA. AB - We propose a probabilistic method, CancerLocator, which exploits the diagnostic potential of cell-free DNA by determining not only the presence but also the location of tumors. CancerLocator simultaneously infers the proportions and the tissue-of-origin of tumor-derived cell-free DNA in a blood sample using genome wide DNA methylation data. CancerLocator outperforms two established multi-class classification methods on simulations and real data, even with the low proportion of tumor-derived DNA in the cell-free DNA scenarios. CancerLocator also achieves promising results on patient plasma samples with low DNA methylation sequencing coverage. PMID- 28335813 TI - Tumor lysis syndrome in an extraskeletal osteosarcoma: a case report and review of the literature. AB - BACKGROUND: This case report describes a spontaneous tumor lysis syndrome due to a rare solid tumor. CASE PRESENTATION: A 65-year-old white woman had tumor lysis syndrome, which represent a dangerous oncological emergency. This syndrome occurs usually with a hematological tumor, but in this case our patient had a solid tumor, which was a rare extraskeletal osteosarcoma, localized in her pelvic region. She also had lung metastases and bilateral hydronephrosis. After spontaneous tumor lysis syndrome, she had acute renal insufficiency, which was treated with hemodialysis and successively with rasburicase, Kayexalate (sodium polystyrene sulfonate), and febuxostat. CONCLUSION: Tumor lysis syndrome represents an oncological emergency, which must be suspected and treated as soon as possible. PMID- 28335814 TI - Symbiosis and microbiome flexibility in calcifying benthic foraminifera of the Great Barrier Reef. AB - BACKGROUND: Symbiosis is a phenomenon that allows organisms to colonise a wide range of environments and occupy a variety of ecological niches in marine environments. Large benthic foraminifera (LBF) are crucial marine calcifiers that rely on photo-endosymbionts for growth and calcification, yet the influence of environmental conditions in shaping their interactions with prokaryotic and eukaryotic associates is poorly known. RESULTS: Here, we used next-generation sequencing to identify eukaryotic photosynthesizing and prokaryotic microbes associated with the common LBF Amphistegina lobifera across a physio-chemical gradient on the Great Barrier Reef (GBR). We collected samples from three reef sites located in the inner-, mid- and outer-shelf regions of the northern section of the GBR. Results showed the consistent presence of Bacillaryophyta as the main eukaryotic taxa associated with A. lobifera across all reef sites analysed; however, the abundance and the diversity of prokaryotic organisms varied among reef sites. Inner-shelf specimens showed the highest diversity of prokaryote associates, with a total of 231 genotypes in their core microbiome. A total of 30 taxa were identified in the core microbiome across all reef sites. Within these taxa, Proteobacteria was the most abundant bacteria present. The presence of groups such as Actinobacteria was significantly correlated with inner-shelf populations, whereas the abundance of Bacteroidetes and Firmicutes was associated with A. lobifera collected from mid- and outer-shelf reef sites. CONCLUSIONS: We found that benthic foraminifera form stable and persistent symbiosis with eukaryotic partners, but flexible and site-specific associations with prokaryotic microbes that likely influence the ecological success of these crucial calcifying organisms on the GBR. PMID- 28335815 TI - Skin snips have no role in programmatic evaluations for onchocerciasis elimination: a reply to Bottomley et al. AB - A critique of the recommendation that skin snips be used for post-MDA surveillance of formerly endemic onchocerciasis areas is provided. After considering several fundamental aspects of the use of this methodology within the context of prolonged mass distribution of ivermectin, we argue that skin-snipping has no value for monitoring onchocerciasis elimination programs. PMID- 28335816 TI - Diagnostic delay and associated factors among patients with pulmonary tuberculosis in Dar es Salaam, Tanzania. AB - BACKGROUND: Tanzania is among the 30 countries with the highest tuberculosis (TB) burdens. Because TB has a long infectious period, early diagnosis is not only important for reducing transmission, but also for improving treatment outcomes. We assessed diagnostic delay and associated factors among infectious TB patients. METHODS: We interviewed new smear-positive adult pulmonary TB patients enrolled in an ongoing TB cohort study in Dar es Salaam, Tanzania, between November 2013 and June 2015. TB patients were interviewed to collect information on socio demographics, socio-economic status, health-seeking behaviour, and residential geocodes. We categorized diagnostic delay into <= 3 or > 3 weeks. We used logistic regression models to identify risk factors for diagnostic delay, presented as crude (OR) and adjusted Odds Ratios (aOR). We also assessed association between geographical distance (incremental increase of 500 meters between household and the nearest pharmacy) with binary outcomes. RESULTS: We analysed 513 patients with a median age of 34 years (interquartile range 27-41); 353 (69%) were men. Overall, 444 (87%) reported seeking care from health care providers prior to TB diagnosis, of whom 211 (48%) sought care > 2 times. Only six (1%) visited traditional healers before TB diagnosis. Diagnostic delay was positively associated with absence of chest pain (aOR = 7.97, 95% confidence intervals [CI]: 3.15-20.19; P < 0.001), and presence of hemoptysis (aOR = 25.37, 95% CI: 11.15-57.74; P < 0.001) and negatively associated with use of medication prior to TB diagnosis (aOR = 0.31, 95% CI: 0.14-0.71; P = 0.01). Age, sex, HIV status, education level, household income, and visiting health care facilities (HCFs) were not associated with diagnostic delay. Patients living far from pharmacies were less likely to visit a HCF (incremental increase of distance versus visit to any facility: OR = 0.51, 95% CI: 0.28-0.96; P = 0.037). CONCLUSIONS: TB diagnostic delay was common in Dar es Salaam, and was more likely among patients without prior use of medication and presenting with hemoptysis. Geographical distance to HCFs may have an impact on health-seeking behaviour. Increasing community awareness of TB signs and symptoms could further reduce diagnostic delays and interrupt TB transmission. PMID- 28335817 TI - Gene expression differences between PAXgene and Tempus blood RNA tubes are highly reproducible between independent samples and biobanks. AB - BACKGROUND: Gene expression profiling from blood is sensitive to technology choices. For example, the main blood RNA collection systems-the PAXgene and Tempus tubes-differently influence RNA expression signatures. The aim of this study was to establish a common RNA isolation protocol for these two systems and investigate if it could reduce the differences in gene expression between them. RESULTS: We collected identical blood samples on the PAXgene and Tempus systems and retrieved blood samples from two independent biobanks-NOWAC and HUNT3-which are based on PAXgene and Tempus, respectively. High-quality RNA was extracted from both sampling systems by using their original protocols and our common modified protocol, and were profiled on Illumina microarrays. Regardless of the protocol used, we found most of the measured transcripts to be differently affected by the two sampling systems. However, our modified protocol reduced the number of transcripts that were significantly differentially expressed between PAXgene and Tempus by approximately 50%. Expression differences between PAXgene and Tempus were highly reproducible both between protocols and between different independent sample sets (Pearson correlation 0.563-0.854 across 47323 probes). Moreover, the modified protocol increased the microRNA output of the system with lowest microRNA yield, the PAXgene system. CONCLUSIONS: Most transcripts are affected by the choice of sampling system, but these effects are highly reproducible between independent samples. We propose that by running a control experiment with samples on both systems in parallel with biologically relevant samples, researchers may adjust for technical differences between the sampling systems. PMID- 28335818 TI - Genotype distribution characteristics of multiple human papillomavirus in women from the Taihu River Basin, on the coast of eastern China. AB - BACKGROUND: There is limited data on the genotype distribution of human papillomavirus (HPV) in the Taihu River Basin, home to 1.29 million people on the coast of eastern China. This study evaluated the prevalence and genotypes among different female age groups in this region. METHODS: Twenty-six HPV strains (low risk HPV 6, 11, 40, 42, 44, 61, 73 and high-risk HPV 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 55, 56, 58, 59, 66, 68, 82, and 83) were detected using TellgenplexTM HPV technology in samples obtained from three clinical hospitals located in different regions of the Taihu Lake Basin. RESULTS: The results showed that 1855 samples (20.97% of all samples) were found to be HPV-positive. Of these, 1375 samples (15.55% of all samples) were found to have a single HPV infection. Age-specific prevalence showed two peaks, one that corresponded to the group of 21-30 year-old women and the other peak that corresponded to the group of women over 51 years old. The three most prevalent genotypes were HPV52 (19.95%, 370/1855), HPV16 (13.48%, 150/1855), and HPV58 (11.32%, 210/1855). Mixed strains HPV58 + HPV33 and HPV58 + HPV52 were most commonly found in females infected with multiple HPV types. CONCLUSIONS: This investigation reveals that HPV infection in the Taihu River Basin varied significantly among different age groups. The most prevalent genotypes are included in the nonavalent vaccine, V503, however this vaccine is not licensed for use in mainland China. The most frequently occurring genotypes should be considered in the development of next generation HPV vaccines for optimal protection of public health. PMID- 28335819 TI - Concordance analysis of microarray studies identifies representative gene expression changes in Parkinson's disease: a comparison of 33 human and animal studies. AB - BACKGROUND: As the popularity of transcriptomic analysis has grown, the reported lack of concordance between different studies of the same condition has become a growing concern, raising questions as to the representativeness of different study types, such as non-human disease models or studies of surrogate tissues, to gene expression in the human condition. METHODS: In a comparison of 33 microarray studies of Parkinson's disease, correlation and clustering analyses were used to determine the factors influencing concordance between studies, including agreement between different tissue types, different microarray platforms, and between neurotoxic and genetic disease models and human Parkinson's disease. RESULTS: Concordance over all studies is low, with correlation of only 0.05 between differential gene expression signatures on average, but increases within human patients and studies of the same tissue type, rising to 0.38 for studies of human substantia nigra. Agreement of animal models, however, is dependent on model type. Studies of brain tissue from Parkinson's disease patients (specifically the substantia nigra) form a distinct group, showing patterns of differential gene expression noticeably different from that in non-brain tissues and animal models of Parkinson's disease; while comparison with other brain diseases (Alzheimer's disease and brain cancer) suggests that the mixed study types display a general signal of neurodegenerative disease. A meta-analysis of these 33 microarray studies demonstrates the greater ability of studies in humans and highly-affected tissues to identify genes previously known to be associated with Parkinson's disease. CONCLUSIONS: The observed clustering and concordance results suggest the existence of a 'characteristic' signal of Parkinson's disease found in significantly affected human tissues in humans. These results help to account for the consistency (or lack thereof) so far observed in microarray studies of Parkinson's disease, and act as a guide to the selection of transcriptomic studies most representative of the underlying gene expression changes in the human disease. PMID- 28335820 TI - Exploring the tensions of being and becoming a medical educator. AB - BACKGROUND: Previous studies have identified tensions medical faculty encounter in their roles but not specifically those with a qualification in medical education. It is likely that those with postgraduate qualifications may face additional tensions (i.e., internal or external conflicts or concerns) from differentiation by others, greater responsibilities and translational work against the status quo. This study explores the complex and multi-faceted tensions of educators with qualifications in medical education at various stages in their career. METHODS: The data described were collected in 2013-14 as part of a larger, three-phase mixed-methods research study employing a constructivist grounded theory analytic approach to understand identity formation among medical educators. The over-arching theoretical framework for the study was Communities of Practice. Thirty-six educators who had undertaken or were undertaking a postgraduate qualification in medical education took part in semi-structured interviews. RESULTS: Participants expressed multiple tensions associated with both becoming and being a healthcare educator. Educational roles had to be juggled with clinical work, challenging their work-life balance. Medical education was regarded as having lower prestige, and therefore pay, than other healthcare career tracks. Medical education is a vast speciality, making it difficult as a generalist to keep up-to-date in all its areas. Interestingly, the graduates with extensive experience in education reported no fears, rather asserting that the qualification gave them job variety. CONCLUSION: This is the first detailed study exploring the tensions of educators with postgraduate qualifications in medical education. It complements and extends the findings of the previous studies by identifying tensions common as well as specific to active students and graduates. These tensions may lead to detachment, cynicism and a weak sense of identity among healthcare educators. Postgraduate programmes in medical education can help their students identify these tensions in becoming and develop coping strategies. Separate career routes, specific job descriptions and academic workload models for medical educators are recommended to further the professionalisation of medical education. (Tensions, Fears, Healthcare Educators, Medical Education, Postgraduate Programmes, Identity, Career Choice, Faculty Development, Communities of Practice). PMID- 28335822 TI - Erratum to: Transcriptome profile analysis reflects rat liver and kidney damage following chronic ultra-low dose Roundup exposure. PMID- 28335821 TI - Differential gene expression profiling of endometrium during the mid-luteal phase of the estrous cycle between a repeat breeder (RB) and non-RB cows. AB - BACKGROUND: Repeat breeding directly affects reproductive efficiency in cattle due to an increase in services per conception and calving interval. This study aimed to investigate whether changes in endometrial gene expression profile are involved in repeat breeding in cows. Differential gene expression profiles of the endometrium were investigated during the mid-luteal phase of the estrous cycle between repeat breeder (RB) and non-RB cows using microarray analysis. METHODS: The caruncular (CAR) and intercaruncular (ICAR) endometrium of both ipsilateral and contralateral uterine horns to the corpus luteum were collected from RB (inseminated at least three times but not pregnant) and non-RB cows on Day 15 of the estrous cycle (4 cows/group). Global gene expression profiles of these endometrial samples were analyzed with a 15 K custom-made oligo-microarray for cattle. Immunohistochemistry was performed to investigate the cellular localization of proteins of three identified transcripts in the endometrium. RESULTS: Microarray analysis revealed that 405 and 397 genes were differentially expressed in the CAR and ICAR of the ipsilateral uterine horn of RB, respectively when compared with non-RB cows. In the contralateral uterine horn, 443 and 257 differentially expressed genes were identified in the CAR and ICAR of RB, respectively when compared with non-RB cows. Gene ontology analysis revealed that genes involved in development and morphogenesis were mainly up-regulated in the CAR of RB cows. In the ICAR of both the ipsilateral and contralateral uterine horns, genes related to the metabolic process were predominantly enriched in the RB cows when compared with non-RB cows. In the analysis of the whole uterus (combining the data above four endometrial compartments), RB cows showed up regulation of 37 genes including PRSS2, GSTA3 and PIPOX and down-regulation of 39 genes including CHGA, KRT35 and THBS4 when compared with non-RB cows. Immunohistochemistry revealed that CHGA, GSTA3 and PRSS2 proteins were localized in luminal and glandular epithelial cells and stroma of the endometrium. CONCLUSION: The present study showed that endometrial gene expression profiles are different between RB and non-RB cows. The identified candidate endometrial genes and functions in each endometrial compartment may contribute to bovine reproductive performance. PMID- 28335824 TI - The biomechanical and histological effects of posterior cruciate ligament rupture on the medial tibial plateau. AB - BACKGROUND: The objective of this study was to investigate the biomechanical and histological effects of the posterior cruciate ligament (PCL) on the medial tibial plateau. METHODS: A total of 12 cadaveric human knee specimens were collected and grouped as follows: the PCL intact group (n = 12), the anterolateral bundle rupture group (n = 6), the postmedial bundle rupture group (n = 6), and the PCL rupture group (n = 12). The strain on the anterior, middle, and posterior parts of the medial tibial plateau with an axial loading force at different flexion angles was measured and analyzed, respectively. Forty-eight rabbits were chosen for animal study: surgery was performed on the one side of each rabbit randomly (experimental group), while the other side was taken as control (control group). Every 12 rabbits were culled at each of the four selected time points to collect the medial tibial plateau for morphological and histological observation. RESULTS: The PCL rupture, either partial or complete, may generate an abnormal load on all the parts of the medial tibial plateau with axial loading at all positions. Noticeable time-dependent degenerative histological changes of the medial tibial plateau were observed in the rabbit models of PCL rupture. Compared with the control group, all the PCL rupture groups exhibited a higher expression of the matrix metalloproteinase-7 (MMP-7) and the tissue inhibitors of metalloproteinase-1 (TIMP-1) at all the time points. CONCLUSIONS: Either partial or complete PCL rupture may generate an abnormal load on all the parts of the medial tibial plateau with axial loading at all the positions and may cause cartilage degeneration on the medial tibial plateau. PMID- 28335823 TI - The FORGE AHEAD clinical readiness consultation tool: a validated tool to assess clinical readiness for chronic disease care mobilization in Canada's First Nations. AB - BACKGROUND: Given the astounding rates of diabetes and related complications, and the barriers to providing care present in Indigenous communities in Canada, intervention strategies that take into account contextual factors such as readiness to mobilize are needed to maximize improvements and increase the likelihood of success and sustainment. As part of the national FORGE AHEAD Program, we sought to develop, test and validate a clinical readiness consultation tool aimed at assessing the readiness of clinical teams working on reserve in First Nations communities to participate in quality improvement (QI) to enhance diabetes care in Canada. METHODS: A literature review was conducted to identify existing readiness tools. The ABCD - SAT was adapted using a consensus approach that emphasized a community-based participatory approach and prioritized the knowledge and wisdom held by community members. The tool was piloted with a group of 16 people from 7 provinces and 11 partnering communities to assess language use, clarity, relevance, format, and ease of completion using examples. Internal reliability analysis and convergence validity were conducted with data from 53 clinical team members from 11 First Nations communities (3-5 per community) who have participated in the FORGE AHEAD program. RESULTS: The 27-page Clinical Readiness Consultation Tool (CRCT) consists of five main components, 21 sub-components, and 74 items that are aligned with the Expanded Chronic Care Model. Five-point Likert scale feedback from the pilot ranged from 3.25 to 4.5. Length of the tool was reported as a drawback but respondents noted that all the items were needed to provide a comprehensive picture of the healthcare system. Results for internal consistency showed that all sub-components except for two were within acceptable ranges (0.77-0.93). The Team Structure and Function sub component scale had a moderately significant positive correlation with the validated Team Climate Inventory, r = 0.45, p < 0.05. CONCLUSIONS: The testing and validation of the FORGE AHEAD CRCT demonstrated that the tool is acceptable, valid and reliable. The CRCT has been successfully used to support the implementation of the FORGE AHEAD Program and the health services changes that partnering First Nations communities have designed and undertaken to improve diabetes care. TRIAL REGISTRATION NUMBER: Current ClinicalTrial.gov protocol ID NCT02234973 . Date of Registration: July 30, 2014. PMID- 28335825 TI - Canine tick-borne diseases in pet dogs from Romania. AB - BACKGROUND: Tick-borne diseases are of substantial concern worldwide for animals as well as humans. Dogs have been a human companion for millennia, and their significant impact on human life renders disease in dogs to be of great concern. Tick-borne diseases in dogs represent a substantial diagnostic challenge for veterinarians in that clinical signs are often diffuse and overlapping. In addition, co-infections with two or more pathogens enhance this problem further. Molecular methods are useful to disentangle co-infections and to accurately describe prevalence and geographical distribution of tick-borne diseases. At this point, this information is lacking in many areas worldwide. Romania is one such area, where prevalence and distribution of several important pathogens need to be further investigated. To address this, we screened blood samples from 96 sick dogs with molecular methods for eight different pathogens including Babesia spp., Theileria spp., Hepatozoon spp., Anaplasma spp., Ehrlichia spp., "Candidatus Neoehrlichia mikurensis", Mycoplasma spp., and Borrelia spp. RESULTS: As many as 45% (43/96) of the dogs in the study were infected with protozoan parasites. Babesia canis was the most frequent of these (28 infected dogs), whereas Hepatozoon canis was detected in 15% (14/96) and Babesia gibsoni was found in a single sample. Bacterial infection with Mycoplasma spp. occurred in 18% (17/96) of the sampled dogs. Obtained bacterial sequences revealed the occurrence of two species: Mycoplasma canis and "Candidatus Mycoplasma haematoparvum". In several cases co-infection with protozoan parasites and Mycoplasma sp. were detected. All dogs were negative for Anaplasma spp., Ehrlichia spp., "Ca. Neoehrlichia mikurensis", and for Borrelia spp. CONCLUSIONS: The results from the present study reinforce the notion that Babesia canis is an important pathogen in the Romanian dog population. However, more surprisingly, another protozoan species, H. canis, seems to be infecting dogs to a larger extent than previously recognized in Romania. Well-known tick-borne bacterial disease agents such as Anaplasma spp. and Borrelia spp. were not detected. In contrast, less well studied bacteria such as hemotropic Mycoplasma spp. were detected frequently. Moreover, co-infection might aggravate disease and complicate diagnosis and should be further studied in dogs. PMID- 28335826 TI - First establishment of microsatellite markers in clausiliid snails (Mollusca: Gastropoda: Clausiliidae). AB - BACKGROUND: Clausiliidae (door snails) are gastropods with a very high diversity concerning shell morphology, especially of their complex closing apparatus, which provides the most important diagnostic traits for classification of taxa. Due to the high variability, a high number of taxa has been described, though their systematics and taxonomy is partially controversially discussed. Montenegrina is the second most speciose door snail genus in Europe. It is an obligate rock dwelling land snail and has, compared to its complex systematics, a rather small distribution range in the western parts of the Balkan Peninsula. The different taxa themselves show a very narrow and patchy distribution range. As Montenegrina is comprehensively sampled over the whole distribution range, it is a perfect study system for general questions on speciation and morphological differentiation in land snails. To study the amount of gene flow between geographically close or co-occurring populations, highly polymorphic markers are needed. RESULTS: Thirteen microsatellite loci with a tetranucleotid repeat were isolated and tested in three geographically close Montenegrina populations (two populations of M. dofleini prespaensis from the Prespa Lake, n = 35 and one population from M. stankovici from the Ohrid Lake, n = 20). The number of alleles per locus ranged from 2 to 27. No significant linkage disequilibria between the same two loci were found in all three tested populations. The deviation from Hardy-Weinberg equilibrium reveal only for two loci a significant deviation from HWE in more than one population (Mont_5483 and Mont_4477). CONCLUSION: The 13 newly established genetic markers will help to gain better insights to the population genetic structure of Montenegrina and might reveal new results about speciation processes in co-occurring taxa. Furthermore, these microsatellite loci could also be tested in other clausiliid species. PMID- 28335829 TI - Comparison of nasopharyngeal and guttural pouch specimens to determine the optimal sampling site to detect Streptococcus equi subsp equi carriers by DNA amplification. AB - BACKGROUND: Streptococcus equi subsp equi (S. equi) is the cause of "equine strangles" which is a highly infectious upper respiratory disease. Detection of S. equi is influenced by site of specimen collection, method of sampling, and type of diagnostic test that is performed. We hypothesized i) that a loop mediated isothermal amplification (LAMP) assay that targets the S. equi-specific eqbE gene would be more sensitive than a realtime PCR assay that targets the S. equi-specific seeI gene and ii) that LAMP of specimens obtained by guttural pouch lavage (GPL) would be more sensitive than LAMP of nasopharyngeal specimens to identify S. equi carriers. METHODS: A nasopharyngeal flocked swab, nasopharyngeal wash, and GPL specimen was collected from 44 convalescent horses and the eqbE LAMP assay was performed. The seeI realtime PCR assay and aerobic culture were also performed on the GPL specimen. Logistic regression was performed to compare sampling sites and test methods (P-values <=0.05 were considered significant). RESULTS: One of 41 nasopharyngeal flocked swabs, 6/38 nasopharyngeal wash and 24/44 GPL specimens were positive by eqbE LAMP. 18/44 GPL specimens were positive by seeI PCR and S. equi was isolated from 4/44 of these specimens. Detection of S. equi DNA was 51 times more likely from the GPL samples than nasopharyngeal samples (OR 51.0, P < 0.0001). When eqbE LAMP GPL samples were positive, it was eight times more likely that the guttural pouch had any abnormality on endoscopy (OR 8.2, P <= 0.005), almost 20 times more likely that mild empyema was found (OR 19.7, P <= 0.002), and eight times more likely that the SeeI PCR was positive for S. equi DNA (OR 8.1, P <= 0.006). CONCLUSION: This study demonstrates that guttural pouch lavage specimens should be used to detect S. equi and that the eqbE LAMP assay was comparable to the seeI PCR. PMID- 28335828 TI - DHA brain uptake and APOE4 status: a PET study with [1-11C]-DHA. AB - BACKGROUND: The apolipoprotein E E4 (APOE4) allele is the strongest genetic risk factor identified for developing Alzheimer's disease (AD). Among brain lipids, alteration in the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) homeostasis is implicated in AD pathogenesis. APOE4 may influence both brain DHA metabolism and cognitive outcomes. METHODS: Using positron emission tomography, regional incorporation coefficients (k*), rates of DHA incorporation from plasma into the brain using [1-11C]-DHA (J in), and regional cerebral blood flow using [15O]-water were measured in 22 middle-aged healthy adults (mean age 35 years, range 19-65 years). Data were partially volume error-corrected for brain atrophy. APOE4 phenotype was determined by protein expression, and unesterified DHA concentrations were quantified in plasma. An exploratory post hoc analysis of the effect of APOE4 on DHA brain kinetics was performed. RESULTS: The mean global gray matter DHA incorporation coefficient, k*, was significantly higher (16%) among APOE4 carriers (n = 9) than among noncarriers (n = 13, p = 0.046). Higher DHA incorporation coefficients were observed in several brain regions, particularly in the entorhinal subregion, an area affected early in AD pathogenesis. Cerebral blood flow, unesterified plasma DHA, and whole brain DHA incorporation rate (J in) did not differ significantly between the APOE groups. CONCLUSIONS: Our findings suggest an increase in the DHA incorporation coefficient in several brain regions in APOE4 carriers. These findings may contribute to understanding how APOE4 genotypes affect AD risk. PMID- 28335831 TI - Matrix Biology Highlights. PMID- 28335830 TI - International non-governmental organizations' provision of community-based tuberculosis care for hard-to-reach populations in Myanmar, 2013-2014. AB - BACKGROUND: National tuberculosis (TB) programs increasingly engage with international non-governmental organizations (INGOs), especially to provide TB care in complex settings where community involvement might be required. In Myanmar, however, there is limited data on how such INGO community-based programs are organized and how effective they are. In this study, we describe four INGO strategies for providing community-based TB care to hard-to-reach populations in Myanmar, and assess their contribution to TB case detection. METHODS: We conducted a descriptive study using program data from four INGOs and the National TB Program (NTP) in 2013-2014. For each INGO, we extracted information on its approach and key activities, the number of presumptive TB cases referred and undergoing TB testing, and the number of patients diagnosed with TB and their treatment outcomes. The contribution of INGOs to TB diagnosis in their selected townships was calculated as the proportion of INGO-diagnosed new TB cases out of the total NTP-diagnosed new TB cases in the same townships. RESULTS: All four INGOs implemented community-based TB care in challenging contexts, targeting migrants, post-conflict areas, the urban poor, and other vulnerable populations. Two recruited community volunteers via existing community health volunteers or health structures, one via existing community leaderships, and one directly involved TB infected/affected individuals. Two INGOs compensated volunteers via performance-based financing, and two provided financial and in-kind initiatives. All relied on NTP laboratories for diagnosis and TB drugs, but provided direct observation treatment support and treatment follow-up. A total of 21 995 presumptive TB cases were referred for TB diagnosis, with 7 383 (34%) new TB cases diagnosed and almost all (98%) successfully treated. The four INGOs contributed to the detection of, on average, 36% (7 383/20 663) of the total new TB cases in their respective townships (range: 15-52%). CONCLUSION: Community based TB care supported by INGOs successfully achieved TB case detection in hard to-reach and vulnerable populations. This is vital to achieving the World Health Organization End TB Strategy targets. Strategies to ensure sustainability of the programs should be explored, including the need for longer-term commitment of INGOs. PMID- 28335827 TI - Management of acute respiratory diseases in the pediatric population: the role of oral corticosteroids. AB - Respiratory diseases account for about 25% of all pediatric consultations, and 10% of these are for asthma. The other main pediatric respiratory diseases, in terms of incidence, are bronchiolitis, acute bronchitis and respiratory infections. Oral corticosteroids, in particular prednisolone, are often used to treat acute respiratory diseases given their anti-inflammatory effects. However, the efficacy of treatment with oral corticosteroids differs among the various types of pediatric respiratory diseases. Notably, also the adverse effects of corticosteroid treatment can differ depending on dosage, duration of treatment and type of corticosteroid administered - a case in point being growth retardation in long-course treatment. A large body of data has accumulated on this topic. In this article, we have reviewed the data and guidelines related to the role of oral corticosteroids in the treatment and management of pediatric bronchiolitis, wheezing, asthma and croup in the attempt to provide guidance for physicians. Also included is a section on the management of acute respiratory failure in children. PMID- 28335832 TI - Development of 126Sn separation method by means of anion exchange resin and gamma spectroscopy. AB - This paper describes a method employing anion exchange resin for determination of 126Sn in radioactive waste. The method is suitable for the separation of 126Sn isotope from hydrochloric and hydrofluoric acid solution. The separation is based on precipitation of tin with ammonium sulfide in 0.5molL-1 HCl, dissolution of the precipitate in concentrated HCl, loading in 2molL-1 HCl onto anion exchange resin column and elution with 2molL-1 HNO3. 126Sn was measured by gamma spectrometry. PMID- 28335833 TI - Association Between Cardiovascular Risk Factors and Aortic Stenosis: The CANHEART Aortic Stenosis Study. AB - BACKGROUND: Few longitudinal studies have delineated the association between traditional cardiovascular risk factors and development of aortic stenosis (AS). OBJECTIVES: The authors examined the association between traditional cardiovascular risk factors and incident severe AS in a large, unselected elderly population. METHODS: This observational cohort study used multiple linked health care population-based databases of individuals older than 65 years on April 1, 2002, without prior valvular disease, coronary artery disease, heart failure, cardiac arrhythmia, cerebrovascular disease, congenital heart disease, or admissions with cardiac symptoms. The relationship between hypertension (HTN), diabetes, dyslipidemia, and incident severe AS requiring hospitalization or surgical or interventional treatment was examined. RESULTS: Among 1.12 million individuals followed for a median of 13 years, 20,995 subjects developed severe AS. Overall absolute incidence was 144 per 100,000 person-years (169 and 127 per 100,000 person-years in men and women, respectively). In cause-specific hazard models, HTN (adjusted hazard ratio [HR]: 1.71; 95% confidence interval [CI]: 1.66 to 1.76), diabetes (HR: 1.49; 95% CI: 1.44 to 1.54), and dyslipidemia (HR: 1.17; 95% CI: 1.14 to 1.21) were all significantly associated with increased risk of developing severe AS (all p < 0.001). There was a positive dose-response relationship between the number and duration of cardiac risk factors and risk of AS. In the Fine-Gray model, all 3 risk factors were independently associated with a higher incidence of AS. The population-attributable risk of AS associated with 3 cardiac risk factors was 34.4% (95% CI: 32.8 to 36.0). CONCLUSIONS: HTN, diabetes, and dyslipidemia have independent and dose-response associations with incident AS in an unselected population of older individuals, and together accounted for approximately one-third of the incidence of severe AS. PMID- 28335834 TI - Aortic Stenosis: Moving From Treatment to Prevention. PMID- 28335836 TI - PEITHO Long-Term Outcomes Study: Data Disrupt Dogma. PMID- 28335835 TI - Impact of Thrombolytic Therapy on the Long-Term Outcome of Intermediate-Risk Pulmonary Embolism. AB - BACKGROUND: The long-term effect of thrombolytic treatment of pulmonary embolism (PE) is unknown. OBJECTIVES: This study investigated the long-term prognosis of patients with intermediate-risk PE and the effect of thrombolytic treatment on the persistence of symptoms or the development of late complications. METHODS: The PEITHO (Pulmonary Embolism Thrombolysis) trial was a randomized (1:1) comparison of thrombolysis with tenecteplase versus placebo in normotensive patients with acute PE, right ventricular (RV) dysfunction on imaging, and a positive cardiac troponin test result. Both treatment arms received standard anticoagulation. Long-term follow-up was included in the third protocol amendment; 28 sites randomizing 709 of the 1,006 patients participated. RESULTS: Long-term (median 37.8 months) survival was assessed in 353 of 359 (98.3%) patients in the thrombolysis arm and in 343 of 350 (98.0%) in the placebo arm. Overall mortality rates were 20.3% and 18.0%, respectively (p = 0.43). Between day 30 and long-term follow-up, 65 deaths occurred in the thrombolysis arm and 53 occurred in the placebo arm. At follow-up examination of survivors, persistent dyspnea (mostly mild) or functional limitation was reported by 36.0% versus 30.1% of the patients (p = 0.23). Echocardiography (performed in 144 and 146 patients randomized to thrombolysis and placebo, respectively) did not reveal significant differences in residual pulmonary hypertension or RV dysfunction. Chronic thromboembolic pulmonary hypertension (CTEPH) was confirmed in 4 (2.1%) versus 6 (3.2%) cases (p = 0.79). CONCLUSIONS: Approximately 33% of patients report some degree of persistent functional limitation after intermediate-risk PE, but CTEPH is infrequent. Thrombolytic treatment did not affect long-term mortality rates, and it did not appear to reduce residual dyspnea or RV dysfunction in these patients. (Pulmonary Embolism Thrombolysis study [PEITHO]; NCT00639743). PMID- 28335838 TI - Do Women Really Respond Differently to Antiplatelet Therapies?: The Evidence Just Doesn't Add Up. PMID- 28335837 TI - Potent P2Y12 Inhibitors in Men Versus Women: A Collaborative Meta-Analysis of Randomized Trials. AB - BACKGROUND: Sex-specific differences in response to antiplatelet therapies have been described. Whether women and men derive comparable benefit from intensification of antiplatelet therapy remains uncertain. OBJECTIVES: The study investigated the efficacy and safety of the potent P2Y12 inhibitors in patients with coronary artery disease. METHODS: A collaborative sex-specific meta-analysis was conducted of phase III or IV randomized trials of potent P2Y12 inhibitors, including prasugrel, ticagrelor, and intravenous cangrelor. Seven trials were included that enrolled a total of 24,494 women and 63,346 men. Major adverse cardiovascular events (MACE) were defined as the primary endpoint for each trial. RESULTS: Potent P2Y12 inhibitors significantly reduced the risk of MACE by 14% in women (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.78 to 0.94) and by 15% in men (HR: 0.85; 95% CI: 0.80 to 0.90; p interaction = 0.93). Treatment reduced the risk of myocardial infarction by 13% in women (HR: 0.87; 95% CI: 0.78 to 0.96) and 16% in men (HR: 0.84; 95% CI: 0.77 to 0.91; p interaction = 0.65), and the risk of stent thrombosis by 51% in women (HR: 0.49; 95% CI: 0.37 to 0.65) and 41% in men (HR: 0.59; 95% CI: 0.42 to 0.84; p interaction = 0.85). Directional consistency was seen for cardiovascular death in women (HR: 0.87; 95% CI: 0.76 to 1.01) and men (HR: 0.85; 95% CI: 0.77 to 0.95; p interaction = 0.86). The potent P2Y12 inhibitors increased major bleeding in women (HR: 1.28; 95% CI: 0.87 to 1.88) and men (HR: 1.52; 95% CI: 1.12 to 2.07; p interaction = 0.62). CONCLUSIONS: In randomized trials, the efficacy and safety of the potent P2Y12 inhibitors were comparable between men and women. Given these data, sex should not influence patient selection for the administration of potent P2Y12 inhibitors. PMID- 28335840 TI - Apolipoproteins and Blood Pressure: A Story of Evolution in Biomarker Analysis. PMID- 28335842 TI - Central Sleep Apnea in Heart Failure: Sleeping With the Wrong Enemy? PMID- 28335839 TI - Apolipoprotein L1 Variants and Blood Pressure Traits in African Americans. AB - BACKGROUND: African Americans (AA) are disproportionately affected by hypertension-related health disparities. Apolipoprotein L1 (APOL1) risk variants are associated with kidney disease in hypertensive AAs. OBJECTIVES: This study assessed the APOL1 risk alleles' association with blood pressure traits in AAs. METHODS: The discovery cohort included 5,204 AA participants from Mount Sinai's BioMe biobank. Replication cohorts included additional BioMe (n = 1,623), Vanderbilt BioVU (n = 1,809), and Northwestern NUgene (n = 567) AA biobank participants. Single nucleotide polymorphisms determining APOL1 G1 and G2 risk alleles were genotyped in BioMe and imputed in BioVU/NUgene participants. APOL1 risk alleles' association with blood pressure-related traits was tested in the discovery cohort, a meta-analysis of replication cohorts, and a combined meta analysis under recessive and additive models after adjusting for age, sex, body mass index, and estimated glomerular filtration rate. RESULTS: There were 14% to 16% of APOL1 variant allele homozygotes (2 copies of G1/G2) across cohorts. APOL1 risk alleles were associated under an additive model with systolic blood pressure (SBP) and age at diagnosis of hypertension, which was 2 to 5 years younger in the APOL1 variant allele homozygotes (Cox proportional hazards analysis, p value for combined meta-analysis [pcom] = 1.9 * 10-5). APOL1 risk alleles were associated with overall SBP (pcom = 7.0 * 10-8) and diastolic blood pressure (pcom = 2.8 * 10-4). After adjustment for all covariates, those in the 20- to 29-year age range showed an increase in SBP of 0.94 +/- 0.44 mm Hg (pcom = 0.01) per risk variant copy. APOL1-associated estimated glomerular filtration rate decline was observed starting a decade later in life in the 30- to 39-year age range. CONCLUSIONS: APOL1 risk alleles are associated with higher SBP and earlier hypertension diagnoses in young AAs; this relationship appears to follow an additive model. PMID- 28335841 TI - Cardiovascular Outcomes With Minute Ventilation-Targeted Adaptive Servo Ventilation Therapy in Heart Failure: The CAT-HF Trial. AB - BACKGROUND: Sleep apnea is common in hospitalized heart failure (HF) patients and is associated with increased morbidity and mortality. OBJECTIVES: The CAT-HF (Cardiovascular Improvements With MV-ASV Therapy in Heart Failure) trial investigated whether minute ventilation (MV) adaptive servo-ventilation (ASV) improved cardiovascular outcomes in hospitalized HF patients with moderate-to severe sleep apnea. METHODS: Eligible patients hospitalized with HF and moderate to-severe sleep apnea were randomized to ASV plus optimized medical therapy (OMT) or OMT alone (control). The primary endpoint was a composite global rank score (hierarchy of death, cardiovascular hospitalizations, and percent changes in 6 min walk distance) at 6 months. RESULTS: 126 of 215 planned patients were randomized; enrollment was stopped early following release of the SERVE-HF (Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure) trial results. Average device usage was 2.7 h/night. Mean number of events measured by the apnea-hypopnea index decreased from 35.7/h to 2.1/h at 6 months in the ASV group versus 35.1/h to 19.0/h in the control group (p < 0.0001). The primary endpoint did not differ significantly between the ASV and control groups (p = 0.92 Wilcoxon). Changes in composite endpoint components were not significantly different between ASV and control. There was no significant interaction between treatment and ejection fraction (p = 0.10 Cox model); however, pre-specified subgroup analysis suggested a positive effect of ASV in patients with HF with preserved ejection fraction (p = 0.036). CONCLUSIONS: In hospitalized HF patients with moderate-to-severe sleep apnea, adding ASV to OMT did not improve 6-month cardiovascular outcomes. Study power was limited for detection of safety signals and identifying differential effects of ASV in patients with HF with preserved ejection fraction, but additional studies are warranted in this population. (Cardiovascular Improvements With MV ASV Therapy in Heart Failure [CAT-HF]; NCT01953874). PMID- 28335843 TI - Anomalous Aortic Origin of a Coronary Artery From the Inappropriate Sinus of Valsalva. AB - Anomalous aortic origin of a coronary artery (AAOCA) from the inappropriate sinus of Valsalva is increasingly recognized by cardiac imaging. Although most AAOCA subtypes are benign, autopsy studies report an associated risk of sudden death with interarterial anomalous left coronary artery (ALCA) and anomalous right coronary artery (ARCA). Despite efforts to identify high-risk ALCA and ARCA patients who may benefit from surgical repair, debate remains regarding their classification, prevalence, risk stratification, and management. We comprehensively reviewed 77 studies reporting the prevalence of AAOCA among >1 million patients, and 20 studies examining outcomes of interarterial ALCA/ARCA patients. Observational data suggests that interarterial ALCA is rare (weighted prevalence = 0.03%; 95% confidence interval [CI]: 0.01% to 0.04%) compared with interarterial ARCA (weighted prevalence = 0.23%; 95% CI: 0.17% to 0.31%). Recognizing the challenges in managing these patients, we review cardiac tests used to examine AAOCA and knowledge gaps in management. PMID- 28335845 TI - Recognizing Inevitable Change and Responding Responsibly. PMID- 28335846 TI - The Proliferation of Scoring Systems: Trying to Keep Our Heads Out of The Clouds. PMID- 28335844 TI - Heart Failure-Induced Brain Injury. AB - Heart failure (HF) is a systemic illness with grave implications for bodily functions. The brain, among other vital organs, often suffers insults as a result of HF, and both anatomic and functional brain abnormalities were found in the HF population. This injury was demonstrated across a wide range of clinical conditions and cardiac functions and was shown to affect patients' outcomes. Although reduced cardiac output and high burden of cardiovascular risk factors are the prevailing explanations for these findings, there are data showing the involvement of neurohormonal, nutritional, and inflammatory mechanisms in this complex process. Here, the authors review the suggested pathophysiology behind brain injury in HF, describe its effect on patients' outcomes, offer a diagnostic approach, and discuss possible therapeutic options. PMID- 28335847 TI - Familial Catecholamine-Induced QT Prolongation in Unexplained Sudden Cardiac Death. PMID- 28335848 TI - Sudden Cardiac Death in Pre-Excitation and Wolff-Parkinson-White: Demographic and Clinical Features. PMID- 28335849 TI - Diastolic Blood Pressure and Myocardial Damage: What About Coronary Perfusion Time? PMID- 28335850 TI - Diastolic Hypotension and Myocardial Ischemia: A Reason to Remember Cuff Artifact in Blood Pressure Measurement. PMID- 28335851 TI - The Role of Heart Rate in Diastolic Coronary Perfusion and Subclinical Myocardial Ischemia. PMID- 28335852 TI - In the Treatment of Hypertension, Lowering of Diastolic Pressure to <70 mm Hg Is Often Unavoidable. PMID- 28335853 TI - Reply: Diastolic Blood Pressure: Myocardial Damage and Coronary Ischemic Events. PMID- 28335854 TI - Valve Thrombosis After Transcatheter Aortic Valve Replacement. PMID- 28335855 TI - Correction. PMID- 28335856 TI - Correction. PMID- 28335857 TI - Modeling Syndromic Congenital Heart Defects in Zebrafish. AB - Cardiac development is a dynamic process regulated by spatial and temporal cues that are integrated to effect molecular, cellular, and tissue-level events that form the adult heart. Disruption of these highly orchestrated events can be devastating for cardiac form and function. Aberrations in heart development result in congenital heart defects (CHDs), which affect 1 in 100 infants in the United States each year. Zebrafish have proven informative as a model organism to understand both heart development and the mechanisms associated with CHDs due to the similarities in heart morphogenesis among vertebrates, as well as their genetic tractability and amenability to live imaging. In this review, we discuss the mechanisms of zebrafish heart development and the utility of zebrafish for understanding syndromic CHDs, those cardiac abnormalities that occur in the context of multisystem disorders. We conclude with avenues of zebrafish research that will potentially inform future therapeutic approaches for the treatment of CHDs. PMID- 28335858 TI - Netting Novel Regulators of Hematopoiesis and Hematologic Malignancies in Zebrafish. AB - Zebrafish are one of the preeminent model systems for the study of blood development (hematopoiesis), hematopoietic stem and progenitor cell (HSPC) biology, and hematopathology. The zebrafish hematopoietic system shares strong similarities in functional populations, genetic regulators, and niche interactions with its mammalian counterparts. These evolutionarily conserved characteristics, together with emerging technologies in live imaging, compound screening, and genetic manipulation, have been employed to successfully identify and interrogate novel regulatory mechanisms and molecular pathways that guide hematopoiesis. Significantly, perturbations in many of the key developmental signals controlling hematopoiesis are associated with hematological disorders and disease, including anemia, bone marrow failure syndromes, and leukemia. Thus, understanding the regulatory pathways controlling HSPC production and function has important clinical implications. In this review, we describe how the blood system forms and is maintained in zebrafish, with particular focus on new insights into vertebrate hematological regulation gained using this model. The interplay of factors controlling development and disease in the hematopoietic system combined with the unique attributes of the zebrafish make this a powerful platform to discover novel targets for the treatment of hematological disease. PMID- 28335859 TI - Making It New Again: Insight Into Liver Development, Regeneration, and Disease From Zebrafish Research. AB - The adult liver of most vertebrates is predominantly comprised of hepatocytes. However, these cells must work in concert with biliary, stellate, vascular, and immune cells to accomplish the vast array of hepatic functions required for physiological homeostasis. Our understanding of liver development was accelerated as zebrafish emerged as an ideal vertebrate system to study embryogenesis. Through work in zebrafish and other models, it is now clear that the cells in the liver develop in a coordinated fashion during embryogenesis through a complex yet incompletely understood set of molecular guidelines. Zebrafish research has uncovered many key players that govern the acquisition of hepatic potential, cell fate, and plasticity. Although rare, some hepatobiliary diseases-especially biliary atresia-are caused by developmental defects; we discuss how research using zebrafish to study liver development has informed our understanding of and approaches to liver disease. The liver can be injured in response to an array of stressors including viral, mechanical/surgical, toxin-induced, immune-mediated, or inborn defects in metabolism. The liver has thus evolved the capacity to efficiently repair and regenerate. We discuss the emerging field of using zebrafish to study liver regeneration and highlight recent advances where zebrafish genetics and imaging approaches have provided novel insights into how cell plasticity contributes to liver regeneration. PMID- 28335860 TI - "Muscling" Throughout Life: Integrating Studies of Muscle Development, Homeostasis, and Disease in Zebrafish. AB - The proper development and function of skeletal muscle is vital for health throughout the lifespan. Skeletal muscle function enables posture, breathing, and locomotion; and also impacts systemic processes-such as metabolism, thermoregulation, and immunity. Diseases of skeletal muscle (myopathies, muscular dystrophies) and even some neurological, age-related, and metabolic diseases compromise muscle function and negatively affect health span and quality of life. There have been numerous, recent examples of studies on skeletal muscle development with exciting, therapeutic implications for muscle diseases. The zebrafish (Danio rerio) is a vertebrate model organism well accepted for developmental biology and biomedical research and thus an ideal system in which to elucidate the translational implications of mechanisms regulating skeletal muscle development and homeostasis. Muscle fiber types (slow- vs fast-twitch) are spatially segregated in zebrafish allowing for the opportunity to identify distinct mechanisms regulating fiber type specification during development as well as observe fiber type-specific effects in zebrafish models of muscle diseases. Accessible genetics coupled with transparent zebrafish embryos has enabled in vivo cell biology experiments allowing for the visualization and understanding of never-before-seen cellular processes occurring in muscle development, regeneration, and disease. In addition, high-throughput drug screening provides a platform for efficient drug discovery. The purpose of this chapter is to review the studies in zebrafish that significantly contributed to our understanding of cellular and molecular mechanisms regulating skeletal muscle development, homeostasis, or disease in vertebrates, with a particular emphasis on the basic developmental biology studies with promising therapeutic implications. PMID- 28335861 TI - Zebrafish Pancreas Development and Regeneration: Fishing for Diabetes Therapies. AB - The zebrafish pancreas shares its basic organization and cell types with the mammalian pancreas. In addition, the developmental pathways that lead to the establishment of the pancreatic islets of Langherhans are generally conserved from fish to mammals. Zebrafish provides a powerful tool to probe the mechanisms controlling establishment of the pancreatic endocrine cell types from early embryonic progenitor cells, as well as the regeneration of endocrine cells after damage. This knowledge is, in turn, applicable to refining protocols to generate renewable sources of human pancreatic islet cells that are critical for regulation of blood sugar levels. Here, we review how previous and ongoing studies in zebrafish and beyond are influencing the understanding of molecular mechanisms underlying various forms of diabetes and efforts to develop cell-based approaches to cure this increasingly widespread disease. PMID- 28335862 TI - Modeling Infectious Diseases in the Context of a Developing Immune System. AB - Zebrafish has been used for over a decade to study the mechanisms of a wide variety of inflammatory disorders and infections, with models ranging from bacterial, viral, to fungal pathogens. Zebrafish has been especially relevant to study the differentiation, specialization, and polarization of the two main innate immune cell types, the macrophages and the neutrophils. The optical accessibility and the early appearance of myeloid cells that can be tracked with fluorescent labels in zebrafish embryos and the ability to use genetics to selectively ablate or expand immune cell populations have permitted studying the interaction between infection, development, and metabolism. Additionally, zebrafish embryos are readily colonized by a commensal flora, which facilitated studies that emphasize the requirement for immune training by the natural microbiota to properly respond to pathogens. The remarkable conservation of core mechanisms required for the recognition of microbial and danger signals and for the activation of the immune defenses illustrates the high potential of the zebrafish model for biomedical research. This review will highlight recent insight that the developing zebrafish has contributed to our understanding of host responses to invading microbes and the involvement of the microbiome in several physiological processes. These studies are providing a mechanistic basis for developing novel therapeutic approaches to control infectious diseases. PMID- 28335864 TI - Using Zebrafish to Study Kidney Development and Disease. AB - The kidneys are a crucial pair of organs that are responsible for filtering the blood to remove waste, maintain electrolyte and water homeostasis, and regulate blood pressure. There are a number of factors, both genetic and environmental, that can impair the function of the kidneys resulting in significant morbidity and mortality for millions of people affected by kidney disease worldwide. The zebrafish, Danio rerio, has emerged as an attractive vertebrate model in the study of kidney development and disease and has proven to be a powerful tool in the advancement of how kidney development occurs in vertebrates and how the kidney repairs itself after injury. Zebrafish share significant similarities in kidney development and composition of nephrons, the functional unit of the kidney. This makes the zebrafish a very promising model to study the mechanisms by which renal developmental defects occur. Furthermore, zebrafish are ideally suited for the study of how vertebrate kidneys respond to injury and have provided researchers with invaluable information on repair processes after kidney injury. Importantly, zebrafish have profound potential for discovering treatment modalities and, in fact, studies in zebrafish models have provided leads for therapeutics for human patients suffering from kidney disease and kidney injury. Here, we discuss the similarities and differences in zebrafish and mammalian kidney models, and highlight some of the major contributions the zebrafish has made in the understanding of kidney development and disease. PMID- 28335866 TI - Preface. PMID- 28335865 TI - Zebrafish Developmental Models of Skeletal Diseases. AB - The zebrafish skeleton shares many similarities with human and other vertebrate skeletons. Over the past years, work in zebrafish has provided an extensive understanding of the basic developmental mechanisms and cellular pathways directing skeletal development and homeostasis. This review will focus on the cell biology of cartilage and bone and how the basic cellular processes within chondrocytes and osteocytes function to assemble the structural frame of a vertebrate body. We will discuss fundamental functions of skeletal cells in production and secretion of extracellular matrix and cellular activities leading to differentiation of progenitors to mature cells that make up the skeleton. We highlight important examples where findings in zebrafish provided direction for the search for genes causing human skeletal defects and also how zebrafish research has proven important for validating candidate human disease genes. The work we cover here illustrates utility of zebrafish in unraveling molecular mechanisms of cellular functions necessary to form and maintain a healthy skeleton. PMID- 28335867 TI - Here/In This Issue and There/Abstract Thinking: Some Identification, Please. PMID- 28335863 TI - Zebrafish in Toxicology and Environmental Health. AB - As manufacturing processes and development of new synthetic compounds increase to keep pace with the expanding global demand, environmental health, and the effects of toxicant exposure are emerging as critical public health concerns. Additionally, chemicals that naturally occur in the environment, such as metals, have profound effects on human and animal health. Many of these compounds are in the news: lead, arsenic, and endocrine disruptors such as bisphenol A have all been widely publicized as causing disease or damage to humans and wildlife in recent years. Despite the widespread appreciation that environmental toxins can be harmful, there is limited understanding of how many toxins cause disease. Zebrafish are at the forefront of toxicology research; this system has been widely used as a tool to detect toxins in water samples and to investigate the mechanisms of action of environmental toxins and their related diseases. The benefits of zebrafish for studying vertebrate development are equally useful for studying teratogens. Here, we review how zebrafish are being used both to detect the presence of some toxins as well as to identify how environmental exposures affect human health and disease. We focus on areas where zebrafish have been most effectively used in ecotoxicology and in environmental health, including investigation of exposures to endocrine disruptors, industrial waste byproducts, and arsenic. PMID- 28335869 TI - How Environmental Factors Can Get Under the Skin: Epigenetics in Attention Deficit/Hyperactivity Disorder. PMID- 28335868 TI - Ten Things Transgender and Gender Nonconforming Youth Want Their Doctors to Know. PMID- 28335871 TI - Early Identification of Autism Spectrum Disorder: Is Diagnosis by Age 3 a Reasonable Goal? PMID- 28335870 TI - Persistent Tics, Tourette Syndrome, and Psychopathology: Where Are We Now, and Where Are We Going? PMID- 28335872 TI - Cognitive Impairment in Euthymic Pediatric Bipolar Disorder: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To perform a systematic review and meta-analysis of studies investigating neurocognition in euthymic youths with bipolar disorder (BD) compared to healthy controls (HCs). METHOD: A systematic literature search was conducted in the PubMed/MEDLINE, PsycINFO, and EMBASE databases from inception up until March 23, 2016, for original peer-reviewed articles that investigated neurocognition in euthymic youths with BD compared to HCs. Effect sizes (ES) for individual tests were extracted. In addition, results were grouped according to cognitive domain. This review complied with the PRISMA statement guidelines. RESULTS: A total of 24 studies met inclusion criteria (N = 1,146; 510 with BD). Overall, euthymic youths with BD were significantly impaired in verbal learning, verbal memory, working memory, visual learning, and visual memory, with moderate to large ESs (Hedge's g 0.76-0.99); significant impairments were not observed for attention/vigilance, reasoning and problem solving, and/or processing speed. Heterogeneity was moderate to large (I2 >= 50%) for most ES estimates. Differences in the definition of euthymia across studies explained the heterogeneity in the ES estimate for verbal learning and memory. We also found evidence for other potential sources of heterogeneity in several ES estimates including co-occurring attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders, and the use of medications. In addition, the use of different neuropsychological tests appeared to contribute to heterogeneity of some estimates (e.g., attention/vigilance domain). CONCLUSION: Euthymic youths with BD exhibit significant cognitive dysfunction encompassing verbal learning and memory, working memory, and/or visual learning and memory domains. These data indicate that for a subset of individuals with BD, neurodevelopmental factors may contribute to cognitive dysfunction. PMID- 28335873 TI - Parental Psychopathology and Tourette Syndrome/Chronic Tic Disorder in Offspring: A Nationwide Case-Control Study. AB - OBJECTIVE: To determine the associations between maternal and paternal psychiatric diagnoses and Tourette syndrome (TS)/chronic tic disorder (CT) in a nationwide study. METHOD: This nested case-control study linked data derived from three national registers. All singletons born and diagnosed with TS/CT in Finland between January 1991 and December 2010 were identified (n = 1,120) and matched to four controls (n = 4,299). Conditional logistic regression was used to examine the associations between parental psychopathology and TS/CT. RESULTS: Altogether, 24.9% of patients with TS/CT and 12.0% of controls had a mother with a psychiatric diagnosis. Similarly, 17.9% and 12.9% had a father with a psychiatric diagnosis. Any maternal and any paternal psychiatric diagnosis was associated with offspring TS/CT (odds ratio [OR] 2.3; 95% CI 1.9-2.7 and OR 1.2; 95% CI 1.01 1.5, respectively). The association between maternal psychiatric diagnosis and TS/CT was stronger than that between paternal psychiatric diagnosis and TS/CT (p < .001). Maternal personality disorders (OR 3.1, 95% CI 1.9-5.1), anxiety disorders (OR 2.6, 95% CI 1.9-3.5), affective disorders (OR 2.3, 95% CI 1.8-2.9), psychotic disorders (OR 2.0, 95% CI 1.2-3.3), and addiction disorders (OR 1.8, 95% CI 1.1-2.8) were associated with TS/CT. Paternal OCD (OR 6.5, 95% CI 1.1 39.5) and anxiety disorders (OR 1.5, 95% CI 1.1-2.3) were associated with TS/CT. CONCLUSION: Parental psychiatric diagnoses (especially in the mother) are associated with diagnosed offspring TS/CT. Further studies are required before the results can be generalized to all children with TS/CT. The associations between maternal psychiatric disorders and TS may reflect both maternal specific environmental and/or genetic influences. PMID- 28335874 TI - Course of Tourette Syndrome and Comorbidities in a Large Prospective Clinical Study. AB - OBJECTIVE: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder characterized by tics and frequent comorbidities. Although tics often improve during adolescence, recent studies suggest that comorbid obsessive compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) tend to persist. This large prospective follow-up study describes the clinical course of tics and comorbidities during adolescence and the prevalence of coexisting psychopathologies. METHOD: The clinical cohort was recruited at the Danish National Tourette Clinic, and data were collected at baseline (n = 314, age range 5-19 years) and at follow-up 6 years later (n = 227) to establish the persistence and severity of tics and comorbidities. During follow-up, the Development and Well-Being Assessment (DAWBA) was used to diagnose coexisting psychopathologies. Repeated measures of severity scores were modeled using mixed effects models. RESULTS: Tic severity declined yearly (0.8 points, CI: 0.58-1.01, on the Yale Global Tic Severity Scale [YGTSS]) during adolescence; 17.7% of participants above age 16 years had no tics, whereas 59.5% had minimal or mild tics, and 22.8% had moderate or severe tics. Similarly, significant yearly declines in severity of both OCD (0.24, CI: 0.09-0.39, on the Yale-Brown Obsessive Compulsive Scale for Adults [Y-BOCS] and Yale-Brown Obsessive Compulsive Scale for Children [CY-BOCS]) and ADHD (0.42, CI: 0.32-0.52, DSM-IV) were recorded. At follow-up, 63.0% of participants had comorbidities or coexistent psychopathologies, whereas 37.0% had pure TS. CONCLUSION: Severity of tics, OCD, and ADHD were significantly associated with age and declined during adolescence. However, considerable comorbidities and coexisting psychopathologies persist throughout adolescence and require monitoring by clinicians. PMID- 28335875 TI - Age at First Identification of Autism Spectrum Disorder: An Analysis of Two US Surveys. AB - OBJECTIVE: Evidence regarding the age at which autism spectrum disorder (ASD) is identified is essential for improving early detection, yet many extant studies have not applied time-to-event analyses, which account for statistical biases that arise from sampling in cross-sectional surveys by adjusting for child age at time of parental report. Our objective was to estimate age distributions for first identification of ASD in national parent surveys using time-to-event analyses. METHOD: We conducted time-to-event analyses of responses to identical questions in the 2011 to 2012 National Survey of Children's Health (n = 95,677) and the 2009 to 2010 National Survey of Children with Special Health Care Needs (n = 371,617). RESULTS: Parents in both surveys reported that a minority of ASD cases were identified before age 3 years, and that one-third to one-half of cases were identified after 6 years. In both surveys, a majority of parents described their child's ASD severity as mild, and these parents reported the oldest age at identification (mean, 5.6 and 8.6 years). In contrast, parents who described their child's ASD as severe reported earlier age at identification (mean, 3.7 and 4.5 years). Time-to-event analyses yielded older estimates of age at identification than analyses based on raw distributions. CONCLUSION: In two national surveys, a majority of parents of children with ASD reported identification after 3 years, when eligibility for early intervention services expires, and many reported identification of ASD after school age. Later identification of children with milder symptoms highlights the need for early screening that is sensitive to all forms of ASD, regardless of severity. PMID- 28335876 TI - Child Abuse, Neural Structure, and Adolescent Psychopathology: A Longitudinal Study. AB - OBJECTIVE: Child abuse exerts a deleterious impact on a broad array of mental health outcomes. However, the neurobiological mechanisms that mediate this association remain poorly characterized. Here, we use a longitudinal design to prospectively identify neural mediators of the association between child abuse and psychiatric disorders in a community sample of adolescents. METHOD: Structural magnetic resonance imaging (MRI) data and assessments of mental health were acquired for 51 adolescents (aged 13-20; M=16.96; SD=1.51), 19 of whom were exposed to physical or sexual abuse. Participants were assessed for abuse exposure (time 1), participated in MRI scanning and a diagnostic structured interview (time 2), and 2 years later were followed-up to assess psychopathology (time 3). We examined associations between child abuse and neural structure, and identified whether abuse-related differences in neural structure prospectively predicted psychiatric symptoms. RESULTS: Abuse was associated with reduced cortical thickness in medial and lateral prefrontal and temporal lobe regions. Thickness of the left and right parahippocampal gyrus predicted antisocial behavior symptoms, and thickness of the middle temporal gyrus predicted symptoms of generalized anxiety disorder. Thickness of the left parahippocampal gyrus mediated the longitudinal association of abuse with antisocial behavior. CONCLUSION: Child abuse is associated with widespread disruptions in cortical structure, and these disruptions are selectively associated with increased vulnerability to internalizing and externalizing psychopathology. Identifying predictive biomarkers of vulnerability following childhood maltreatment may uncover neurodevelopmental mechanisms linking environmental experience with the onset of psychopathology. PMID- 28335877 TI - Cognitive-Behavioral and Psychodynamic Therapy in Female Adolescents With Bulimia Nervosa: A Randomized Controlled Trial. AB - OBJECTIVE: The authors compared cognitive-behavioral therapy (CBT) and psychodynamic therapy (PDT) for the treatment of bulimia nervosa (BN) in female adolescents. METHOD: In this randomized controlled trial, 81 female adolescents with BN or partial BN according to the DSM-IV received a mean of 36.6 sessions of manualized disorder-oriented PDT or CBT. Trained psychologists blinded to treatment condition administered the outcome measures at baseline, during treatment, at the end of treatment, and 12 months after treatment. The primary outcome was the rate of remission, defined as a lack of DSM-IV diagnosis for BN or partial BN at the end of therapy. Several secondary outcome measures were evaluated. RESULTS: The remission rates for CBT and PDT were 33.3% and 31.0%, respectively, with no significant differences between them (odds ratio [OR] = 0.90, 95% CI = 0.35-2.28, p = .82). The within-group effect sizes were h = 1.22 for CBT and h = 1.18 for PDT. Significant improvements in all secondary outcome measures were found for both CBT (d = 0.51-0.82) and PDT (d = 0.24-1.10). The improvements remained stable at the 12-month follow-up in both groups. There were small between-group effect sizes for binge eating (d = 0.23) and purging (d = 0.26) in favor of CBT and for eating concern (d = -0.35) in favor of PDT. CONCLUSION: CBT and PDT were effective in promoting recovery from BN in female adolescents. The rates of remission for both therapies were similar to those in other studies evaluating CBT. This trial identified differences with small effects in binge eating, purging, and eating concern. Clinical trial registration information-Treating Bulimia Nervosa in Female Adolescents With Either Cognitive Behavioral Therapy (CBT) or Psychodynamic Therapy (PDT). http://isrctn.com/; ISRCTN14806095. PMID- 28335880 TI - Ketamine as a Treatment for Adolescent Depression: A Case Report. PMID- 28335878 TI - Psychotic Symptoms in Attention-Deficit/Hyperactivity Disorder: An Analysis of the MTA Database. AB - OBJECTIVE: To assess the prevalence of psychotic symptoms among youths (14-25 years of age) with a childhood diagnosis of attention-deficit/hyperactivity disorder (ADHD) combined type. METHOD: Participants in the Multimodal Treatment Study of Children with ADHD (MTA) and a local normative comparison group (LNCG) were systematically assessed 6, 8, 10, 12, 14, and 16 years after the original enrollment at a mean age of 8.5 years. Trained research assistants administered a psychosis screener, and positive screens were referred to study clinicians to confirm or exclude psychosis. Possible associations between screening positive and alcohol or substance use were assessed. RESULTS: Data were available from 509 MTA participants (88% of original MTA sample; mean age 25.1 years) and 276 LNCG participants (96% of original sample; mean age 24.6 years) at year 16. Twenty-six MTA participants (5%; 95% CI 3-7) and 11 LNCG participants (4%; 95% CI 2-6) screened positive for at least 1 psychotic symptom (p = .60). Most psychotic symptoms were transient. The prevalence of clinician-confirmed psychotic symptoms was 1.1% (95% CI 0.2-2.1) in the MTA group and 0.7% (0-1.7) in the LNCG (p = .72). Greater cannabis use was reported by those who screened positive (p < .05) and were confirmed positive (p < .01). CONCLUSION: There was no evidence that ADHD increased the risk for psychotic symptoms. In the ADHD and normative comparison groups, more frequent cannabis use was associated with a greater likelihood of experiencing psychotic symptoms, thus supporting the recommendation that youth should not use cannabis. PMID- 28335881 TI - Measurement of Autism Symptomatology in Children With Neurodevelopmental Impairment. PMID- 28335879 TI - Are Social and Communication Difficulties a Risk Factor for the Development of Social Anxiety? AB - OBJECTIVE: Social anxiety (SA) is a common condition associated with social and communication (SC) difficulties in typically developing young people, as well as those with autism spectrum disorder (ASD). Whether SC difficulties place children at risk for developing SA is unclear. Using a longitudinal design, the present study aimed to disentangle the relationship between SA symptoms and SC difficulties using a population-based sample of 9,491 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). METHOD: Parent-reported data on SC difficulties and SA symptoms were collected at ages 7, 10, and 13 years. A cross-lagged panel model was used to investigate the longitudinal stability and directional relationship between latent SC difficulties and SA constructs over time. RESULTS: More SC difficulties were associated with greater SA symptoms at all ages. Earlier SC difficulties predicted a small but significant amount of variance in later SA symptoms. The reverse relationship from SA to SC difficulties was not observed. The relationship from SC difficulties to SA was strongest from age 7 to 10 years. No sex differences were observed. CONCLUSION: The evidence suggests that SC difficulties may be an important risk factor for the development of SA. These findings suggest the potential usefulness of incorporating social skills training alongside effective interventions to prevent or alleviate symptoms of SA in childhood. PMID- 28335882 TI - In Reply. PMID- 28335883 TI - Power. PMID- 28335884 TI - Prognostic factors and survival according to tumour subtype in women presenting with breast cancer brain metastases at initial diagnosis. AB - BACKGROUND: The presence of brain metastases at the time of initial breast cancer diagnosis (BMIBCD) is uncommon. Hence, the prognostic assessment and management of these patients is very challenging. The aim of this study was to analyse the influence of tumour subtype compared with other prognostic factors in the survival of patients with BMIBCD. METHODS: We evaluated women with BMIBCD, reported to Surveillance, Epidemiology and End Results program from 2010 to 2013. Patients with other primary malignancy were excluded. Univariate and multivariate analyses were performed to determine the effects of each variable on overall survival (OS). RESULTS: We included 740 patients. Median OS for the whole population was 10 months, and 20.7% of patients were alive at 36 months. Tumour subtype distribution was: 46.6% hormone receptor (HR)+/HER2-, 17% HR+/HER2+, 14.1% HR-/HER2+ and 22.3% triple-negative. Univariate analysis showed that the presence of liver metastases, lung metastases and triple-negative patients (median OS 6 months) had worse prognosis. The HR+/HER2+ subtype had the longest OS with a median of 22 months. In multivariate analysis, older age (hazard ratio 1.8), lobular histology (hazard ratio 2.08), triple-negative subtype (hazard ratio 2.25), liver metastases (hazard ratio 1.6) and unmarried patients (hazard ratio 1.39) had significantly shorter OS. CONCLUSIONS: Although the prognosis of patients with BMIBCD is generally poor, 20.7% were still alive 3 years after the diagnosis. There were substantial differences in OS according to tumour subtype. In addition to tumour subtype, other independent predictors of OS are age at diagnosis, marital status, histology and liver metastases. PMID- 28335885 TI - Policy and priorities for national cancer control planning in low- and middle income countries: Lessons from the Association of Southeast Asian Nations (ASEAN) Costs in Oncology prospective cohort study. AB - BACKGROUND: Evidence to guide policymakers in developing affordable and equitable cancer control plans are scarce in low- and middle-income countries (LMIC). METHODS: The 2012-2014 ASEAN Costs in Oncology Study prospectively followed-up 9513 newly diagnosed cancer patients from eight LMIC in Southeast Asia for 12 months. Overall and country-specific incidence of financial catastrophe (out-of pocket health costs >= 30% of annual household income), economic hardship (inability to make necessary household payments), poverty (living below national poverty line), and all-cause mortality were determined. Stepwise multinomial regression was used to estimate the extent to which health insurance, cancer stage and treatment explained these outcomes. RESULTS: The one-year incidence of mortality (12% in Malaysia to 45% in Myanmar) and financial catastrophe (24% in Thailand to 68% in Vietnam) were high. Economic hardship was reported by a third of families, including inability to pay for medicines (45%), mortgages (18%) and utilities (12%), with 28% taking personal loans, and 20% selling assets (not mutually exclusive). Out of households that initially reported incomes above the national poverty levels, 4.9% were pushed into poverty at one year. The adverse economic outcomes in this study were mainly attributed to medical costs for inpatient/outpatient care, and purchase of drugs and medical supplies. In all the countries, cancer stage largely explained the risk of adverse outcomes. Stage stratified analysis however showed that low-income patients remained vulnerable to adverse outcomes even when diagnosed with earlier cancer stages. CONCLUSION: The LMIC need to realign their focus on early detection of cancer and provision of affordable cancer care, while ensuring adequate financial risk protection, particularly for the poor. PMID- 28335887 TI - Trastuzumab in combination with weekly paclitaxel and carboplatin as neo-adjuvant treatment for HER2-positive breast cancer: The TRAIN-study. AB - AIM: To determine the efficacy and safety of an anthracycline-free neo-adjuvant regimen consisting of weekly paclitaxel, carboplatin and trastuzumab in HER2 positive breast cancer. PATIENTS AND METHODS: Patients with stage II or III HER2 positive breast cancer received weekly paclitaxel ([P], 70 mg/m2), trastuzumab ([T], 2 mg/kg, loading dose 4 mg/kg) and carboplatin ([C], AUC = 3 mg ml-1 min) for 24 weeks. In weeks 7, 8, 15, 16, 23 and 24, trastuzumab was administered without chemotherapy. The primary end-point was pathologic complete response in the surgical resection specimen, defined as the absence of invasive tumour cells in breast and axilla. RESULTS: One hundred and eleven patients were included in the study, and 108 were evaluable for the primary end-point. The pathologic complete response rate was 43% (95% confidence interval [CI]: 33-52). Median follow-up was 52 months, and the 3-year event-free survival was 88% (95% CI: 82 94), and the 3-year overall survival was 92% (95% CI: 88-98). The most common grade 3-4 adverse events were neutropenia (67%) and thrombocytopenia (43%). Less than five percent of patients experienced febrile neutropenia. No symptomatic left ventricular systolic dysfunction was observed during neo-adjuvant treatment. CONCLUSION: An anthracycline-free neo-adjuvant regimen of weekly paclitaxel, trastuzumab and carboplatin is highly effective in HER2-positive breast cancer with manageable toxicity. PMID- 28335888 TI - Second- and third-generation drugs for immuno-oncology treatment-The more the better? AB - Recent success in cancer immunotherapy (anti-CTLA-4, anti-PD1/PD-L1) has confirmed the hypothesis that the immune system can control many cancers across various histologies, in some cases producing durable responses in a way not seen with many small-molecule drugs. However, only less than 25% of all patients do respond to immuno-oncology drugs and several resistance mechanisms have been identified (e.g. T-cell exhaustion, overexpression of caspase-8 and beta-catenin, PD-1/PD-L1 gene amplification, MHC-I/II mutations). To improve response rates and to overcome resistance, novel second- and third-generation immuno-oncology drugs are currently evaluated in ongoing phase I/II trials (either alone or in combination) including novel inhibitory compounds (e.g. TIM-3, VISTA, LAG-3, IDO, KIR) and newly developed co-stimulatory antibodies (e.g. CD40, GITR, OX40, CD137, ICOS). It is important to note that co-stimulatory agents strikingly differ in their proposed mechanism of action compared with monoclonal antibodies that accomplish immune activation by blocking negative checkpoint molecules such as CTLA-4 or PD-1/PD-1 or others. Indeed, the prospect of combining agonistic with antagonistic agents is enticing and represents a real immunologic opportunity to 'step on the gas' while 'cutting the brakes', although this strategy as a novel cancer therapy has not been universally endorsed so far. Concerns include the prospect of triggering cytokine-release syndromes, autoimmune reactions and hyper immune stimulation leading to activation-induced cell death or tolerance, however, toxicity has not been a major issue in the clinical trials reported so far. Although initial phase I/II clinical trials of agonistic and novel antagonistic drugs have shown highly promising results in the absence of disabling toxicity, both in single-agent studies and in combination with chemotherapy or other immune system targeting drugs; however, numerous questions remain about dose, schedule, route of administration and formulation as well as identifying the appropriate patient populations. In our view, with such a wealth of potential mechanisms of action and with the ability to fine-tune monoclonal antibody structure and function to suit particular requirements, the second and third wave of immuno-oncology drugs are likely to provide rapid advances with new combinations of novel immunotherapy (especially co-stimulatory antibodies). Here, we will review the mechanisms of action and the clinical data of these new antibodies and discuss the major issues facing this rapidly evolving field. PMID- 28335886 TI - NEOSCOPE: A randomised phase II study of induction chemotherapy followed by oxaliplatin/capecitabine or carboplatin/paclitaxel based pre-operative chemoradiation for resectable oesophageal adenocarcinoma. AB - BACKGROUND: Oxaliplatin-capecitabine (OxCap) and carboplatin-paclitaxel (CarPac) based neo-adjuvant chemoradiotherapy (nCRT) have shown promising activity in localised, resectable oesophageal cancer. PATIENTS AND METHODS: A non-blinded, randomised (1:1 via a centralised computer system), 'pick a winner' phase II trial. Patients with resectable oesophageal adenocarcinoma >= cT3 and/or >= cN1 were randomised to OxCapRT (oxaliplatin 85 mg/m2 day 1, 15, 29; capecitabine 625 mg/m2 bd on days of radiotherapy) or CarPacRT (carboplatin AUC2; paclitaxel 50 mg/m2 day 1, 8, 15, 22, 29). Radiotherapy dose was 45 Gy/25 fractions/5 weeks. Both arms received induction OxCap chemotherapy (2 * 3 week cycles of oxaliplatin 130 mg/m2 day 1, capecitabine 625 mg/m2 bd days 1-21). Surgery was performed 6-8 weeks after nCRT. Primary end-point was pathological complete response (pCR). Secondary end-points included toxicity, surgical morbidity/mortality, resection rate and overall survival. STATISTICS: Based on pCR <= 15% not warranting future investigation, but pCR >= 35% would, 76 patients (38/arm) gave 90% power (one sided alpha 10%), implying that arm(s) having >=10 pCR out of first 38 patients could be considered for phase III trials. ClinicalTrials.gov: NCT01843829. Funder: Cancer Research UK (C44694/A14614). RESULTS: Eighty five patients were randomised between October 2013 and February 2015 from 17 UK centres. Three of 85 (3.5%) died during induction chemotherapy. Seventy-seven patients (OxCapRT = 36; CarPacRT = 41) underwent surgery. The 30-d post-operative mortality was 2/77 (2.6%). Grade III/IV toxicity was comparable between arms, although neutropenia was higher in the CarPacRT arm (21.4% versus 2.6%, p = 0.01). Twelve of 41 (29.3%) (10 of first 38 patients) and 4/36 (11.1%) achieved pCR in the CarPacRT and OxcapRT arms, respectively. Corresponding R0 resection rates were 33/41 (80.5%) and 26/36 (72.2%), respectively. CONCLUSION: Both regimens were well tolerated. Only CarPacRT passed the predefined pCR criteria for further investigation. PMID- 28335889 TI - Human papillomavirus as prognostic marker with rising prevalence in neck squamous cell carcinoma of unknown primary: A retrospective multicentre study. AB - Patients with neck squamous cell carcinomas of unknown primary tumour (NSCCUP) present with lymph node metastasis without evidence for a primary tumour. Most patients undergo an aggressive multimodal treatment, which induces severe, potentially unnecessary toxicity. Primary tumours of NSCCUP can be hidden in the oropharynx. Human papillomavirus (HPV) is causally involved in a subgroup of oropharyngeal squamous cell carcinomas (OPSCC) associated with early lymph node metastasis and good prognosis. Detection of markers for HPV transformation in NSCCUP could allow focussing on the oropharynx in primary tumour search and could be of value for choice and extent of treatment. In a retrospective multicentre study (Germany, Italy and Spain), we analysed metastatic lymph nodes from 180 NSCCUP patients for the presence of HPV DNA, HPV E6*I mRNA and cellular p16INK4a overexpression, a surrogate marker for HPV-induced transformation. HPV status, defined as positivity for viral mRNA with at least one additional marker, was correlated with clinical parameters and survival outcome. A substantial proportion (16%) of NSCCUP were HPV-driven, mainly by HPV16 (89%). HPV prevalence increased with year of diagnosis from 9% during 1998-2004 to 23% during 2005-2014 (p = 0.007). HPV-driven NSCCUP had significantly better overall and progression free survival rates (p <= 0.008). Based on this survival benefit, it is contended that HPV RNA status should be included in NSCCUP diagnosis and in therapeutic decision-making. Deintensification of radiation in patients with HPV-driven NSCCUP, while concurrently concentrating on the oropharynx appears to be a promising therapeutic strategy, the efficacy of which should be assessed in prospective trials. To our knowledge, this is the largest study on HPV in NSCCUP. PMID- 28335890 TI - Cervical cancer incidence in elderly women-biology or screening history? AB - AIM: In many countries, the age-specific pattern of cervical cancer incidence is currently bipolar with peaks at for instance 45 and 65 years of age. Consequently, a large proportion of cervical cancer cases are presently diagnosed in women above the screening age. The purpose of the study was to determine whether this bipolar pattern in age-specific incidence of cervical cancer reflects underlying biology or can be explained by the fact that the data come from birth cohorts with different screening histories. METHODS: Combination of historical data on cervical screening and population-based cancer incidence data from Denmark 1943-2013, Finland and Norway 1953-2013, and Sweden 1958-2013. RESULTS: Since the implementation of screening, the incidence of cervical cancer has decreased for each successive birth cohort. All birth cohorts showed a unipolar age-specific pattern. In unscreened women in Denmark and Sweden, the incidence peaked around the age of 50; the peak was less marked in Finland; while peak age for unscreened women could not be determined for Norway due to widespread opportunistic screening. The current old-age peak in the incidence of cervical cancer represents residuals from unscreened or underscreened birth cohorts. CONCLUSION: The current bipolar pattern in age-specific incidence of cervical cancer can largely be explained by the different screening histories of successive birth cohorts. While it is reasonable to offer screening to elderly women today, birth cohort trends in disease burden should be carefully monitored to justify permanent changes in upper screening age. PMID- 28335891 TI - The majority of patients with metastatic melanoma are not represented in pivotal phase III immunotherapy trials. AB - BACKGROUND: Recent randomised phase III trials have led to the approval of several immune checkpoint inhibitors for unresectable or metastatic melanoma (MM). These trials all employed strict patient selection criteria, and it is currently unknown how large proportion of 'real-world' patients diagnosed with MM is not represented in these trials. PATIENTS AND METHODS: The Danish MM Database contains data on the entire, unselected population of MM within a nationwide geographical area. A total of 276 unselected cases of MM (ocular melanoma excluded), referred for first oncological evaluation in 2014, were included in the analysis. Seven pre-defined eligibility criteria, all used to select patients for enrolment in five recent randomised phase III immunotherapy trials, were analysed. RESULTS: Fifty-five percent of the total population with MM did not meet one or more eligibility criteria ('not eligible' group) at first evaluation. PS >= 2 or active/untreated known brain metastases accounted alone for 74% of non eligibility cases. Median overall survival in the 'not eligible' group was 5.43 months versus 18.3 months for the eligible (p < 0.0001, hazard ratio (HR) 2.44), reflected by significantly worse baseline prognostic features. However, patients treated with immunotherapy had similar survival outcomes regardless of eligibility. CONCLUSION: Over half of the patients evaluated for systemic treatment of MM are not represented in phase III registration immunotherapy trials. The data reveal a huge knowledge gap regarding the usefulness of new immunotherapies in the 'real-world' patient population, and urge additional testing of known regimens in selected poor prognosis cohorts. PMID- 28335892 TI - Hybrid Percutaneous Coronary Intervention With Bioresorbable Vascular Scaffolds in Combination With Drug-Eluting Stents or Drug-Coated Balloons for Complex Coronary Lesions. AB - Bioresorbable vascular scaffolds (BVS) have become an attractive option in the percutaneous coronary intervention field due to the potential advantages associated with the complete resorption process that occurs within a few years. However, current-generation BVS have several limitations including thicker struts, reduced radial strength, and limited expansion capability when compared with drug-eluting stents (DES). As a result, complex coronary disease often contains BVS-inappropriate/unfavorable segments. This does not necessarily mean that BVS use must be completely avoided, and minimizing the length of permanent metallic caging may still be advantageous. Operators should fully understand the limitations of current BVS, and when to consider a hybrid strategy of BVS in combination with DES or drug-coated balloons. PMID- 28335894 TI - Proximal Left Anterior Descending Coronary Artery PCI: Is it No Longer the Last Lesion Standing? PMID- 28335893 TI - Long-Term Outcomes of Stenting the Proximal Left Anterior Descending Artery in the PROTECT Trial. AB - OBJECTIVES: This study sought to compare the outcomes of patients undergoing drug eluting stent implantation according to lesion location within or outside the proximal left anterior descending (LAD) artery. BACKGROUND: Proximal LAD artery involvement is considered uniquely in revascularization guidelines. The impact of LAD lesion location on long-term outcomes after revascularization is poorly understood in context of current percutaneous coronary intervention and medical therapy. METHODS: Among 8,709 patients enrolled in PROTECT (Patient Related Outcomes with Endeavor Versus Cypher Stenting Trial), a multicenter percutaneous coronary intervention trial, we compared the outcomes of 2,534 patients (29.1%) (3,871 lesions [31.5%]) with stents implanted in the proximal LAD to 6,172 patients (70.9%) (8,419 lesions [68.5%]) with stents implanted outside the proximal LAD. RESULTS: At the 4-year follow-up, death rates were the same (5.8% vs. 5.8%; p > 0.999), but more myocardial infarctions occurred in the proximal LAD group (6.2% vs. 4.9%; p = 0.015). The rate of clinically driven target vessel failure (TVF) (14.8% vs. 13.5%; p = 0.109), major adverse cardiac event(s) (MACE) (15.0% vs. 13.7%; hazard ratio: 1.1; 95% confidence interval: 0.97 to 1.31; p = 0.139), and stent thrombosis (2.1% vs. 2.0%; p = 0.800) were similar. Drug eluting stent type had no interaction with MACE or TVF. In multivariate analysis, the proximal LAD was a predictor of myocardial infarction (p = 0.038) but not of TVF (p = 0.149) or MACE (p = 0.069). CONCLUSIONS: In this study of contemporary percutaneous coronary intervention, proximal LAD location was associated with higher rates of myocardial infarction during the long-term follow-up, but there were no differences in stent thrombosis, death, TVF, or overall MACE. This finding may suggest that, in the drug-eluting stent era, proximal LAD no longer confers a different prognosis than other lesion sites. (Randomized Study Comparing Endeavor With Cypher Stents [PROTECT]; NCT00476957). PMID- 28335896 TI - Collateral Damage: Sufficient Coronary Collaterals Provide Important, Yet Limited, Protection in Chronic Total Occlusions. PMID- 28335895 TI - Coronary Collaterals Function and Clinical Outcome Between Patients With Acute and Chronic Total Occlusion. AB - OBJECTIVES: This study sought to demonstrate how changes in the collateral function and its clinical significance before and after percutaneous coronary interventions (PCIs) are compared between patients with acute coronary syndrome and total or nearly total occlusions (ATOs) and chronic total occlusions (CTOs). BACKGROUND: The functional relevance of the collateral circulation in patients with ATOs and CTOs has not been fully investigated. METHODS: The pressure-derived collateral pressure index (CPI), myocardial fractional flow reserve (FFRmyo), and coronary fractional flow reserve (FFRcor) at maximum hyperemia induced by intravenous adenosine were evaluated in occluded vessels at baseline, after the PCI, and at 1 year in 23 ATO and 74 CTO patients. RESULTS: The FFRmyo and FFRcor were significantly lower, but the CPI was significantly higher in the CTO than ATO patients at baseline and after the PCI. There were significant increases in the FFRmyo (p < 0.001) and FFRcor (p < 0.001), whereas there was no significant change in the CPI immediately after the PCI in both ATO and CTO patients. In the CTO patients, a post-PCI FFRmyo <0.90 (p = 0.01) and post-PCI CPI <0.25 (p = 0.033) were independent predictors of the clinical outcome. Patients with a high post-PCI CPI had better clinical outcomes in CTO patients with a low post-PCI FFRmyo (log-rank p = 0.009), but not a high post-PCI FFRmyo (log-rank p = 0.492). CONCLUSIONS: Recruitable coronary collateral flow did not regress completely immediately after the PCI both in patients with ATOs and CTOs. Despite good collaterals in CTO patients, aggressive efforts to reduce the ischemic burden might improve the clinical outcome. PMID- 28335898 TI - Mitral Loop Cerclage: Encircling Functional Mitral Regurgitation. PMID- 28335897 TI - Mitral Loop Cerclage Annuloplasty for Secondary Mitral Regurgitation: First Human Results. AB - OBJECTIVES: This is an early feasibility clinical test of mitral loop cerclage annuloplasty to treat secondary mitral valve regurgitation. BACKGROUND: Secondary mitral regurgitation is characterized by cardiomyopathy, mitral annular enlargement, and leaflet traction contributing to malcoaptation. Transcatheter mitral loop cerclage applies circumferential compression to the mitral annulus by creating a loop through the coronary sinus across the interventricular septum, protecting entrapped coronary arteries from compression, and interactive annular reduction under echocardiographic guidance. This is the first human test of mitral loop annuloplasty. METHODS: Five subjects with severe symptomatic secondary mitral regurgitation underwent mitral loop cerclage, with echocardiographic and computed tomography follow-up over 6 months. RESULTS: Mitral loop cerclage was successful in 4 of 5 subjects and aborted in 1 of the 5 because of unsuitable septal coronary vein anatomy. Immediately and over 6 months, measures of both mitral valve regurgitation (effective orifice area and regurgitation fraction) and chamber dimensions (left atrial and left ventricular volumes) were reduced progressively and ejection fractions increased. Two with persistent and permanent atrial fibrillation spontaneously reverted to sinus rhythm during follow-up. One subject experienced a small myocardial infarction from an unrecognized small branch coronary occlusion. Another, experiencing cardiogenic shock at baseline, died of intractable heart failure after 6 weeks. CONCLUSIONS: In this first human test, mitral loop cerclage annuloplasty was successful in 4 of 5 attempts, caused reverse remodeling (reduction in secondary mitral regurgitation and heart chamber volumes), and suggested electrical remodeling (reversion of atrial fibrillation). Further evaluation is warranted. PMID- 28335901 TI - Feasibility of Early Mechanical Support During Mechanical Reperfusion of Acute Myocardial Infarct Cardiogenic Shock. PMID- 28335899 TI - Percutaneous Plug-Based Arteriotomy Closure Device for Large-Bore Access: A Multicenter Prospective Study. AB - OBJECTIVES: The authors sought to study the safety and efficacy of the MANTA Vascular Closure Device (VCD), a novel collagen-based technology dedicated to closure of large-bore arteriotomies. BACKGROUND: Novel transfemoral therapeutic interventions requiring large-bore catheters have become valid minimally invasive options but have inherent access management challenges. To date, no dedicated vascular closure devices exist for large arteriotomies. METHODS: A prospective, single-arm clinical investigation enrolling patients who underwent elective percutaneous interventions with large-bore catheters and planned percutaneous arteriotomy closure in 3 European institutions. RESULTS: A total of 50 patients with a mean age of 79.5 +/- 8.3 years underwent high-risk percutaneous coronary intervention, balloon aortic valvuloplasty, or transcatheter aortic valve replacement with large-bore catheters sized 12-F to 19-F. MANTA closure was performed by 9 different operators. The 14-F MANTA VCD was deployed in one-third of the overall cohort (16 of 50, 32%), and the 18-F MANTA VCD in the remainder. The MANTA VCD was deployed successfully in all patients. The mean time to hemostasis was 2 min, 23 s. One patient had a major vascular and major bleeding complication with prolonged femoral bleeding that was successfully treated with a covered stent and eventual surgical repair. There were no other access site related complications. CONCLUSIONS: This first multicenter experience demonstrates rapid and reliable hemostasis and low complication rates with the use of the plug-based MANTA VCD for large-bore arteriotomy closure. PMID- 28335900 TI - Percutaneous Tricuspid Valve Annuloplasty Under Conscious Sedation (With Only Fluoroscopic and Intracardiac Echocardiography Monitoring). PMID- 28335902 TI - Very Late Scaffold Thrombosis in Absorb BVS: Association With DAPT Termination? PMID- 28335903 TI - High Radiation Exposure of the Imaging Specialist During Structural Heart Interventions With Echocardiographic Guidance. PMID- 28335904 TI - Percutaneous Rescue of an Embolized Valve After Transcatheter Mitral Valve Replacement. PMID- 28335905 TI - The Effect of Survivor Bias on Observational Analyses of Staged PCI in STEMI Patients. PMID- 28335906 TI - Reply: The Effect of Survivor Bias on Observational Analyses of Staged PCI in STEMI Patients. PMID- 28335907 TI - Stop and Smell the Plumeria. PMID- 28335908 TI - Predicting Psychosis with Accuracy. PMID- 28335909 TI - Erratum to "2016 SCCT/STR guidelines for coronary artery calcium scoring of noncontrast noncardiac chest CT scans a report of the society of Cardiovascular Computed Tomography and Society of Thoracic Radiology" [J. Cardiovasc. Comput. Tomogr. 11 (2017) 74-84]. PMID- 28335911 TI - Adolescent Male With Right Shoulder Pain After Football Injury. PMID- 28335910 TI - Management Strategies for CLN2 Disease. AB - CLN2 disease (neuronal ceroid lipofuscinosis type 2) is a rare, autosomal recessive, pediatric-onset, rapidly progressive neurodegenerative lysosomal storage disorder caused by tripeptidyl peptidase 1 (TPP1) enzyme deficiency, and is characterized by language delay, seizures, rapid cognitive and motor decline, blindness, and early death. No management guidelines exist and there is a paucity of published disease-specific evidence to inform clinical practice, which currently draws upon experience from the field of childhood neurodisability. Twenty-four disease experts were surveyed on CLN2 disease management and a subset met to discuss current practice. Management goals and strategies are consistent among experts globally and are guided by the principles of pediatric palliative care. Goals and interventions evolve as the disease progresses, with a shift in focus from maintenance of function early in the disease to maintenance of quality of life. A multidisciplinary approach is critical for optimal patient care. This work represents an initial step toward the development of consensus-based management guidelines for CLN2 disease. PMID- 28335912 TI - A Middle-aged Female with Dyspnea. PMID- 28335914 TI - Bluey. PMID- 28335915 TI - Yet Another. PMID- 28335913 TI - Clinical Policy: Critical Issues in the Diagnosis and Management of the Adult Psychiatric Patient in the Emergency Department. PMID- 28335916 TI - Yet Another Cut. PMID- 28335917 TI - Stepwise. PMID- 28335918 TI - One and Done: Steroids for Adult Asthma: Answers to the November 2016 Journal Club Questions. PMID- 28335919 TI - A Man With Severe Back Pain. PMID- 28335920 TI - Man With Throat Pain. PMID- 28335921 TI - Boy With Fever and Abdominal Pain. PMID- 28335922 TI - Just How Good Are Handheld Metal Detectors for Ingested Foreign Bodies? PMID- 28335923 TI - Woman With Left Shoulder Bumps. PMID- 28335924 TI - In-Flight Emergency. PMID- 28335925 TI - In reply. PMID- 28335926 TI - Sedating the Agitated Patient: A Moving Target? PMID- 28335927 TI - Should Kidney Stone Patients With Diagnosis by Ultrasonography Be Prescribed Tamsulosin? PMID- 28335928 TI - In reply. PMID- 28335929 TI - Clarification: Editorial Oversight of Results Reported in Annals. PMID- 28335930 TI - Young Woman With Epigastric Pain. PMID- 28335931 TI - An irregular pulse in a 72-year-old woman. PMID- 28335932 TI - Predictive Medicine in Ophthalmology. PMID- 28335933 TI - Screening for Diabetic Retinopathy in Youth-Onset Diabetes. PMID- 28335934 TI - Optical Coherence Tomography Angiography of Conjunctival Racemose Hemangioma. PMID- 28335935 TI - Fluorescein Angiography in Persistent Fetal Vasculature. PMID- 28335937 TI - Paracentral Acute Middle Maculopathy After Cardiac Arrest. PMID- 28335936 TI - Traumatic Maculopathy with Macular Hole. PMID- 28335938 TI - Malignant Orbital Melanoma Associated with Oculodermal Melanocytosis. PMID- 28335939 TI - Subretinal Hemorrhage Associated with Astrocytic Hamartoma. PMID- 28335940 TI - Combined Central Retinal Vein Occlusion and Central Retinal Arterial Obstruction with Cilioretinal Artery Sparing. PMID- 28335941 TI - Association of Carotid-Cavernous Fistula with Central Retinal Vein Occlusion. PMID- 28335942 TI - Reply. PMID- 28335943 TI - Re: Narayanaswamy et al.: Argon laser peripheral iridoplasty for primary angle closure glaucoma: a randomized controlled trial (Ophthalmology. 2016;123:514 521). PMID- 28335944 TI - Re: Kontadakis et al.: Long-term comparison of simultaneous topography-guided photorefractive keratectomy followed by corneal cross-linking versus corneal cross-linking alone (Ophthalmology. 2016;123:974-983). PMID- 28335945 TI - Reply. PMID- 28335946 TI - Re: Mayer et al.: Pupillary reconstruction and outcome after artificial iris implantation (Ophthalmology. 2016;123:1011-1018). PMID- 28335947 TI - Reply. PMID- 28335948 TI - Re: Wells et al.: Aflibercept, Bevacizumab, or Ranibizumab for diabetic macular edema: two year results from a comparative effectiveness randomized clinical trial (Ophthalmology. 2016;123:1351-1359). PMID- 28335949 TI - Reply. PMID- 28335950 TI - Re: Yu et al.: Risk of visual field progression in glaucoma patients with progressive retinal nerve fiber layer thinning (Ophthalmology. 2016;123:1201 1210). PMID- 28335951 TI - Re: Price et al.: Three-year longitudinal survey comparing visual satisfaction with LASIK and contact lenses (Ophthalmology. 2016;123:1659-1666). PMID- 28335952 TI - Reply. PMID- 28335953 TI - Re: Floud et al.: Risk factors for cataracts treated surgically in postmenopausal women (Ophthalmology. 2016;123:1704-1710). PMID- 28335954 TI - Reply. PMID- 28335955 TI - Reply. PMID- 28335956 TI - Re: Schwartz et al.: Intracameral antibiotics and cataract surgery: endophthalmitis rates, cost, and stewardship (Ophthalmology. 2016;123:1411-1413). PMID- 28335957 TI - Reply. PMID- 28335958 TI - Re: Alfawaz et al.: Corneal endothelium in patients with anterior uveitis (Ophthalmology. 2016;123:1637-1645). PMID- 28335959 TI - Reply. PMID- 28335960 TI - Reply. PMID- 28335961 TI - Re: Jaffe et al.: Injectable fluocinolone acetonide long-acting implant for noninfectious intermediate uveitis, posterior uveitis, and panuveitis: two-year results (Ophthalmology. 2016;123:1940-1948). PMID- 28335962 TI - Combining ANOVA-PCA with POCHEMON to analyse micro-organism development in a polymicrobial environment. AB - Revealing the biochemistry associated to micro-organismal interspecies interactions is highly relevant for many purposes. Each pathogen has a characteristic metabolic fingerprint that allows identification based on their unique multivariate biochemistry. When pathogen species come into mutual contact, their co-culture will display a chemistry that may be attributed both to mixing of the characteristic chemistries of the mono-cultures and to competition between the pathogens. Therefore, investigating pathogen development in a polymicrobial environment requires dedicated chemometric methods to untangle and focus upon these sources of variation. The multivariate data analysis method Projected Orthogonalised Chemical Encounter Monitoring (POCHEMON) is dedicated to highlight metabolites characteristic for the interaction of two micro-organisms in co culture. However, this approach is currently limited to a single time-point, while development of polymicrobial interactions may be highly dynamic. A well known multivariate implementation of Analysis of Variance (ANOVA) uses Principal Component Analysis (ANOVA-PCA). This allows the overall dynamics to be separated from the pathogen-specific chemistry to analyse the contributions of both aspects separately. For this reason, we propose to integrate ANOVA-PCA with the POCHEMON approach to disentangle the pathogen dynamics and the specific biochemistry in interspecies interactions. Two complementary case studies show great potential for both liquid and gas chromatography - mass spectrometry to reveal novel information on chemistry specific to interspecies interaction during pathogen development. PMID- 28335963 TI - Copper chromogenic reaction based colorimetric immunoassay for rapid and sensitive detection of a tumor biomarker. AB - A new colorimetric immunoassay method was developed for the rapid and sensitive detection of a tumor biomarker of carcinoembryonic antigen (CEA) by combination of a magnetic bead (MB)-based sandwich immunoassay and a copper chromogenic reaction. The magnetic immunoassay platform was constructed through the covalent immobilization of the capture antibody on the surface of carboxylated magnetic beads. After immuno-recognition of CEA, signal antibody-functionalized copper oxide nanoparticle (CuO NP) probes were applied for sandwich immunoreaction to form an immunocomplex. The CuO NP labels quantitatively captured onto the immunocomplex were then dissolved in acid solution to release high-content copper ions. Based on the coordination of these ions with the newly synthesized chromogenic agent of 1,2-diphenyl-2-(2-(pyridin-2-yl)hydrazono)ethanone, a red complex was produced for the colorimetric signal readout, resulting in the successful construction of a sensitive immunoassay method for CEA detection. Under the optimum conditions, this method showed a wide linear range over three orders of magnitude and a low detection limit of 26 pg/mL. Besides, this method showed excellent performance with low cost, rapid and convenient operation as well as satisfactory reproducibility, stability and accuracy, thus providing great potentials for practical applications. PMID- 28335964 TI - Highly sensitive colorimetric immunosensor for influenza virus H5N1 based on enzyme-encapsulated liposome. AB - Development of simple but sensitive biosensor for influenza detection is highly important in immediate and effective clinical treatment. In this study, a sensitive colorimetric immunosensor which combines the advantages of high selectivity of immunoassay and simplicity of colorimetric detection has been developed to detect influenza virus H5N1 based on enzyme-encapsulated liposome. Biotin-tagged liposome encapsulated with large amount of horseradish peroxidase (HRP) was firstly synthesized. In the presence of H5N1, H5N1 co-bound with the capture antibody and the biotinylated detection antibody to form sandwich immunocomplex. Subsequently, the HRP-encapsulated liposome was introduced to conjugate with the detection antibody through biotin-avidin-biotin linkage. Upon the addition of substrate (mixture of 3,3',5,5'-tetramethylbenzidine (TMB) and H2O2), the liposome was directly lysed to release large amount of HRP by TMB. The released HRP catalyzed the H2O2-mediated oxidation of TMB, resulting in color change of the system, which was observed by naked eyes or UV-vis spectra. The result showed that the absorption intensity enhanced with the increase of H5N1 concentration ranging from 0.1 to 4.0 ng/mL, and the detection limit was calculated to be 0.04 ng/mL. The sensitivity of the proposed biosensor is much higher than that of conventional enzyme-linked immunosorbent assay method. The proposed immunosensor is relatively simple, low-cost, sensitive, and selective without using any sophisticated instruments, therefore it may have a promising prospect for detecting targets in clinical medicine, food safety analysis, and environmental monitoring. PMID- 28335965 TI - "Turn-off" fluorescent sensor for highly sensitive and specific simultaneous recognition of 29 famous green teas based on quantum dots combined with chemometrics. AB - Fluorescent "turn-off" sensors based on water-soluble quantum dots (QDs) have drawn increasing attention owing to their unique properties such as high fluorescence quantum yields, chemical stability and low toxicity. In this work, a novel method based on the fluorescence "turn-off" model with water-soluble CdTe QDs as the fluorescent probes for differentiation of 29 different famous green teas is established. The fluorescence of the QDs can be quenched in different degrees in light of positions and intensities of the fluorescent peaks for the green teas. Subsequently, with aid of classic partial least square discriminant analysis (PLSDA), all the green teas can be discriminated with high sensitivity, specificity and a satisfactory recognition rate of 100% for training set and 98.3% for prediction set, respectively. Especially, the "turn-off" fluorescence PLSDA model based on second-order derivatives (2nd der) with reduced least complexity (LVs = 3) was the most effective one for modeling. Most importantly, we further demonstrated the established "turn-off" fluorescent sensor mode has several significant advantages and appealing properties over the conventional fluorescent method for large-class-number classification (LCNC) of green teas. This work is, to the best of our knowledge, the first report on the rapid and effective identification of so many kinds of famous green teas based on the "turn off" model of QDs combined with chemometrics, which also implies other potential applications on complex LCNC classification system with weak fluorescence or even without fluorescence to achieve higher detective response and specificity. PMID- 28335966 TI - A concentration-dependent multicolor conversion strategy for ultrasensitive colorimetric immunoassay with the naked eye. AB - Colorimetric immunoassays have been attracting more attention for use in practical applications, especially in point-of-care diagnostics. In comparison with a single color immunoassay, the dose-dependent multicolor strategy greatly improves the detection resolution and accuracy of visual inspection. In the current study, a concentration-dependent multicolor conversion strategy was developed based on gold nanoparticle (AuNP)-mediated copper deposition for signal amplification and Prussian blue for color generation. Under optimal conditions, a dose-dependent multicolor from yellow through green to blue were successfully achieved, which was easier to be differentiated from each other by the naked eyes. With rabbit IgG and prostate specific antigen (PSA) as model analytes, semi quantitative evaluations were demonstrated in lab buffer and serum by direct readout with the naked eyes. Quantitative detections were also accomplished by measurement of absorbance of Prussian blue with a common UV-Vis spectrophotometer. A limit of detection (LOD) down to sub-picogram per milliliter was determined. In addition, this newly developed colorimetric assay method can be easily adapted for the detection of other biomolecules by simply changing the recognition pairs. PMID- 28335967 TI - An innovative monolithic zwitterionic stationary phase for the separation of phenolic acids in coffee bean extracts by capillary electrochromatography. AB - A methacrylate based monolith, containing the innovative zwitterionic monomer (3 allyl-1-imidazol)propane sulfonate, was prepared in 100 MUm I.D. silica capillaries by UV initiated photo-polymerization. Composition of the porogen, i.e. a mixture of 1-propanol, 1,4 butanediol and water, was of great importance to obtain a homogeneous monolith with satisfactory permeability and good electrochromatographic performance. Morphology of the stationary phase was studied in Scanning Electron Microscopy and IR experiments, which revealed a good attachment to the capillary wall, flowthrough-pores in the range of 0.5-2 MUm, and a continuous monolithic structure. The developed material was well suited for the analysis of six common phenolic acids (salicylic, cinnamic, syringic, rosmarinic, caffeic and chlorogenic acid) by CEC. Their separation was possible in less than 8 min with a mobile phase comprising a 12 mM aqueous ammonium acetate solution with pH 8.5 and acetonitrile, at an applied voltage of - 20 kV. The developed method was validated (R2 >= 0.995; LOD <= 3.9 MUg mL-1, except for salicylic acid; recovery rates from 94 to 104%) and successfully used for the determination of phenolic acids in Coffea arabica samples. All of them contained cinnamic, syringic and caffeic acid, however only in unroasted coffee beans chlorogenic acid (0.06%) was found. The quantitative results were in good agreement to reported literature data. PMID- 28335968 TI - Dipentaerythritol penta-/hexa-acrylate based-highly cross-linked hybrid monolithic column: Preparation and its applications for ultrahigh efficiency separation of proteins. AB - In this study, multi-acrylate based dipentaerythritol penta-/hexa-acrylate (DPEPA) was exploited for fabrication of highly cross-linked hybrid monolithic column by copolymerization with polyhedral oligomeric silsesquioxane methacryl substituted (POSS-MA) via a "one-pot" method. The new DPEPA-POSS hybrid monolithic column was respectively characterized by Fourier transform infrared spectrometry, thermogravimetric analysis, scanning electron microscopy and nitrogen adsorption/desorption measurement. When it was used for the separation of amides, thioureas and positional isomers of phenols, ultrahigh column efficiency separation (up to 511,000 N m-1) was achieved with excellent selectivity. Moreover, intact protein standards could be efficiently separated with minimum tailing peaks, outperforming the commercially available silica-based C8 column. Furthermore, successful separation of complex egg white proteins and expressed BARD1 BRCT domains protein sample was also achieved with good chromatographic performance. In the future work, the DPEPA-POSS hybrid monolithic column will be further exploited and applied in capillary electrochromatography as well as the top-down based proteome research. PMID- 28335969 TI - Design, synthesis and application of a new class of stimuli-responsive separation materials. AB - A new class of efficient stationary phase has been investigated for use in the liquid chromatographic separation of low molecular weight analytes and high molecular weight biomolecules, based on the application of immobilised stimuli responsive polymers (SRPs). To this end, two polymeric units, namely poly(2 dimethylaminoethyl methacrylate) (PDMAEMA) and poly(acrylic acid) (PAA) were tethered to a triazine core. The derived poly(2-dimethyl-aminoethyl methacrylate) block-poly(acrylic acid) (PDMAEMA-b-PAA), as a diblock co-polymer, was then immobilised onto the surface of porous silica particles. The performance of this microparticulate adsorbent was evaluated under various temperature, ionic strength and/or pH conditions in packed columns in a high-performance liquid chromatography (HPLC) format. Baseline separations of a variety of low molecular weight analytes were achieved at different temperatures with this SRP-based adsorbent using 10 mM sodium phosphate buffer, pH 6.0, as the mobile phase. Moreover, when the ionic strength of the mobile phase was increased to 40 mM sodium phosphate buffer, pH 6.0, similar temperature changes resulted in further increases in resolution for the hydrophobic analytes. In addition, changes in the pH of the mobile phase from pH 6.0 to pH 8.0 led to significant changes in selectivity of the analytes, including reversal in their elution orders. Upon increasing the temperature, the retention times of all analytes decreased but without loss of resolution. These findings can be attributed to the consequence of the immobilised copolymer undergoing a phase transition at its lower critical solution temperature (LCST), which leads to changes in its solvated structure, including how the electrostatic, hydrophilic and hydrophobic regions/domains of the copolymer are exposed to the bulk mobile phase. Thermodynamic data were indicative of a temperature-related re-organisation of the structure of the immobilised PDMAEMA-b-PAA stationary phase with exothermic binding of the analytes occurring at temperatures below the lower critical solution temperature (LCST). In this manner; changes in the system temperature could directly be used to manipulate the adsorption and desorption behaviour of these analytes with this stimuli-responsive, polymer-modified porous silica stationary phase. Additional studies with several proteins further documented the versatility of these stimuli responsive separation materials. The results indicated that these separations could be tuned by variation of the temperature with fully aqueous mobile phases at specific ionic strength and pH values, without the need to use an organic solvent as a component in the mobile phase. PMID- 28335970 TI - Quinine bonded to superficially porous particles for high-efficiency and ultrafast liquid and supercritical fluid chromatography. AB - Two new anion-exchange columns were prepared by bonding tert-butyl carbamoylated quinine to 2.7 MUm superficially porous particle (SPP) silica to create chiral stationary phases for high-efficiency and ultrafast chromatography. Performance and retention parameters of these new columns are compared with an analogous 5 MUm fully porous particle (FPP) based Chiralpak QNAX column and a 3-4 fold increase in efficiency was observed. Ultrafast separations ranging from 12 s down to sub-second are shown using 2.7 MUm SPPs bonded via hydrosilation to the selector. Potential benefits of 2.7 MUm SPP based columns for increased LC-MS compatibility were investigated. A van Deemter plot comparison showed 2.7 MUm SPP based columns provided a lower reduced plate height and a higher optimal linear velocity compared to the 5 MUm FPP based column. With geometry-independent kinetic plots, 2.7 MUm SPP and 5 MUm FPP based columns were assessed for their kinetic performance and the maximal number of plates each column can generate in a given analysis time. The 2.7 MUm SPP based column showed remarkable performance improvements in speed and efficiency as indicated by the kinetic plots. PMID- 28335971 TI - Ultrasensitive immunosensor for prostate specific antigen using biomimetic polydopamine nanospheres as an electrochemiluminescence superquencher and antibody carriers. AB - In this work, biomimetic polydopamine nanospheres (PDANSs) were easily prepared and were firstly exploited as an electrochemiluminescence (ECL) nanoquencher for the development of a sandwich type immunosensor. The PDANSs with abundant active functional groups can facilely label the detection antibody and show remarkable quenching effect towards the ECL of the tris-(2,2'-bipyridine)ruthenium (Ru(bpy)32+). The amino-modified multiwall carbon nanotubes/Nafion (MWCNTs-NH2@N) composite-film was adopted as a matrix to incorporate the luminophor Ru(bpy)32+ and immobilize the capture antibody. The prominent decrease of ECL signal intensity was obtained on account of the unique quenching ability of the labeled PDANSs. The quenching mechanism is believed that the excited states of Ru(bpy)32+ can be annihilated by quinone units in PDANSs via energy transfer. The ECL quenching efficiency was logarithmically related to the concentration of the prostate specific antigen (PSA) in the range from 0.1 pg mL-1 to 20 ng mL-1 with a detection limit of 35 fg mL-1. Furthermore, the proposed ECL immunosensor presented good stability, repeatability and selectivity. PMID- 28335972 TI - Ultrasound-assisted ionic liquid-based micellar extraction combined with microcrystalline cellulose as sorbent in dispersive microextraction for the determination of phenolic compounds in propolis. AB - An ionic liquid-(IL) based micellar extraction combined with microcrystalline cellulose- (MCC) assisted dispersive micro solid-phase extraction method was developed to extract phenolic compounds from propolis. A total of 20 target compounds were identified by ultra-high- performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. The main extraction parameters were optimized and included the ultrasonic power, ultrasonic time, sample pH, type of IL, the concentration of [C12mim]Br, extraction time, concentration of MCC, type of sorbent and type of elution solvents. Under the optimum conditions, the proposed method exhibited good linearities (r2 >= 0.999) for all plant phenolic compounds with the lower limits of detection in the range of 0.21-0.41 ng/mL. The recoveries ranged from 82.74% to 97.88% for pinocembrin, chrysin and galangin. Compared with conventional solvent extraction, the present method was simpler and more efficient and required less organic solvent and a shorter extraction time. Finally, the methodology was successfully used for the extraction and enrichment of phenolic compounds in propolis. PMID- 28335973 TI - Papain-functionalized gold nanoparticles as heterogeneous biocatalyst for bioanalysis and biopharmaceuticals analysis. AB - Surface-modified gold nanoparticles (GNPs) were synthesized via layer-by-layer process with alternating cationic polyallylamine and anionic poly(acrylic acid) polyelectrolyte layers leading to a highly hydrophilic biocompatible shell supporting colloidal stability. Afterwards, papain was covalently immobilized on the modified GNPs via amide coupling between the amino groups on papain and the terminal carboxylic groups of the modified GNPs by using N-(3 dimethylaminopropyl)-N'-ethylcarbodiimide and N-hydroxysulfosuccinimide sodium as coupling agents. The resultant papain-functionalized gold nanoparticles were characterized by surface plasmon resonance, dynamic light scattering and zeta potential measurements. The new technology resonant mass measurement was applied for determining the average number of papain molecules immobilized per GNP by measurement of the single nanoparticle buoyant mass in the range of femtograms. The activity of the immobilized enzyme was estimated by determination of the kinetic parameters (Km, Vmax and kcat) with the standard chromogenic substrate Nalpha-benzoyl-dl-arginine-4-nitroanilide hydrochloride. It was found that Km of immobilized and free enzyme are in the same order of magnitude. On contrary, turnover numbers kcat were significantly higher for GNP-conjugated papain. Further, the gold nanobiocatalyst was applied for digestion of polyclonal human immunoglobulin G to yield protein fragments. The resultant fragment mixture was further analyzed by high-performance liquid chromatography-microelectrospray ionization-quadrupole-time-of-flight mass spectrometry, which demonstrated the applicability of the bioreactor based on papain functionalized GNPs. The immobilized papain not only has higher catalytic activity and better stability, but also can be easily isolated from the reaction medium by straightforward centrifugation steps for reuse. PMID- 28335974 TI - Selective solid phase extraction of lanthanides from tap and river waters with ion imprinted polymers. AB - For the first time, an ion imprinted polymer (IIP) able to selectively extract simultaneously all the lanthanide ions was successfully synthesized in acetonitrile using Nd3+ as a template ion, methacrylic acid as a complexing monomer, and ethylene glycol dimethacrylate as a cross-linker. A non-imprinted polymer (NIP) was synthesized under the same conditions as those of the IIP, but in the absence of the template ion. After the removal of the template ions, grounding and sieving, the IIP particles were packed in solid phase extraction (SPE) cartridges. The selectivity of the IIP was evaluated by comparing its behavior with the one of the NIP. Each SPE step (percolation, washing, and elution) was optimized in order to find the best compromise between the selectivity and the extraction recoveries. Using the optimized SPE conditions, the extraction recoveries of eight lanthanide ions representative of the lanthanide family were higher than 77% with an average value of 83% with the IIP, whereas, in the case of the NIP, they ranged between 14 and 36% and they were below 3% for the interfering ions from alkali, transition, and post-transition metal families with the IIP. A first evaluation of the reproducibility of the SPE profiles was carried out by performing statistical tests on the data obtained with several cartridges filled with particles obtained from two different IIP and NIP syntheses. Promising results were obtained. The specific capacity, i. e. the adsorption capacity of Nd3+ ions by the specific cavities of the imprinted polymer, was about 9 mg of Nd3+ per gram of IIP (60 MUmol g-1), which is more than enough for the extraction of the lanthanide ions at trace levels. The breakthrough volume was about 1 mL per mg of IIP, leading to an enrichment factor of 15, which allows not only to selectively extract the lanthanides but also to concentrate them. Finally, the imprinted polymer was successfully used to selectively extract lanthanides from tap and river waters spiked at 1 MUg L-1. PMID- 28335975 TI - In-field determination of trace dissolved manganese in estuarine and coastal waters with automatic on-line preconcentration and flame atomic fluorescence spectrometry. AB - An automatic on-line preconcentration and detection system for analysis of trace dissolved manganese (Mn) in estuarine and coastal waters was established, using preconcentration with IDA chelating resin and detection with flame atomic fluorescence spectrometer (FAFS). The rinse (pre-eluent) solution was optimized, for removing the interference ions while retaining the target element. It was found that the interference ions affected the chelating efficiency of Mn, causing variation of the detection blank and sensitivity. This effect varied when sample volume presented as preconcentration time changed. The influence at preconcentration times of 120 s, 30 s and 10 s were carefully investigated and reported. Ten folds of the foreign trace metals Zn, Cu, Ni, Fe, and Al did not show obvious interference on Mn preconcentration and detection. The method detection limit was 0.9 nmol L-1 (n = 7, preconcentration time 120 s). The linear detection range could be adjusted with designed preconcentration time. In addition to high precision and accuracy, the proposed analytical system had the advantages of high integration, and required normal site preparation, low energy supply and simple auxiliary equipment, which was appropriate for in-field operation. Compared with other common in-field applied molecular spectrometry instruments, the inherent high selectivity and multi-element applicability of FAFS highlighted the superiority and potential of the proposed analytical system. It was successfully applied to in-field vehicle-board determination of dissolved Mn in coastal waters around Xiamen, Fujian, China, and it was also used to analyze natural water samples collected from the Jiulongjiang Estuary, Fujian, China. PMID- 28335976 TI - Quantitative determination of trace hydrogen peroxide in the presence of sulfide using the Amplex Red/horseradish peroxidase assay. AB - The Amplex Red/horseradish peroxidase (AR/HRP) assay for H2O2 is one of the most sensitive and simple approaches for H2O2 quantification, which is effected by measuring the highly-fluorescent resorufin formed from oxidation of AR by the oxidizing intermediates generated by reaction of HRP and H2O2. The direct reactions of S(-II) with both H2O2 and resorufin are too slow to be of relevance on analytical timescales, however, the reaction between S(-II) and the HRP/H2O2 oxidizing intermediates is rapid enough to compete with the desired reaction of these oxidizing intermediates with AR, suppressing formation of the resorufin analyte. As this mode of interference can be considered simply a competition between the AR reagent and S(-II) for the intermediate oxidizing species, a simple equation is derived in this work enabling one to correct for this interference and obtain a good estimate of the true H2O2 concentration after measuring the apparent H2O2 concentration and the S(-II) concentration. This mode of interference is general to any compound that can act as a HRP substrate even if not directly reactive with H2O2. As such, the approach described is widely applicable to many potential reducing interferents and opens up the use of the AR/HRP assay to a much wider range of conditions, as well as demonstrating the utility of explicitly considering the mechanism of the analytical process. PMID- 28335977 TI - Simultaneous determination of ethanol's four types of non-oxidative metabolites in human whole blood by liquid chromatography tandem mass spectrometry. AB - The importance of ethanol non-oxidative metabolites as the specific biomarkers of alcohol consumption in clinical and forensic settings is increasingly acknowledged. Simultaneous determination of these metabolites can provide a wealth of information like drinking habit and history, but it was difficult to achieve because of their wide range of polarity. This work describes development and validation of a simple liquid chromatography tandem mass spectrometry (LC MS/MS) assay for 4 types of ethanol non-oxidative metabolites (ethyl glucuronide, ethyl sulfate, fatty acid ethyl esters and phosphatidylethanols) in 50 MUL of human whole blood. Pretreatment method, column and MS conditions were optimized. For the first time, the four types of ethanol non-oxidative metabolites with enormous discrepancies of property were simultaneously extracted and analyzed in one run within 40 min. The limits of detections (LODs) were among 0.1-10 ng/mL, and good linearity was obtained. Deviations in precision and accuracy were all lower than 15% at three QC levels. This method was then applied to two forensic samples, resulting in information on drinking habits and drinking time which were very useful for the interpretation of the blood alcohol results. PMID- 28335978 TI - Systematic assessment of surfactants for matrix-assisted laser desorption/ionization mass spectrometry imaging. AB - A systematic method for evaluation of MALDI profiling and imaging was developed and applied to the use of three surfactants, sodium dodecyl sulfate (SDS), Triton X-100, and Tween 20, on rat brain tissue. For profiling studies, mass spectra were acquired from regular arrays of spots with manually deposited surfactant and matrix. The studies recorded the total number of peaks in the mass spectra from 2 to 20 kDa and compared the number of peaks and peak intensities with and without surfactant. It was found that SDS decreases the total number of peaks at all concentrations but does lead to an increase in the number of peaks below 5 kDa. Triton X-100 at 0.05% concentration yielded the highest number of peaks and highest number of new peaks, with the best results above 5 kDa. Correlation of the increase in signal with the estimated hydrophobicity suggests that Triton X 100 improves mass spectrometry quality through an increase in the intensity of hydrophobic protein peaks. Tween 20 provided good performance at 0.05% concentration across all mass ranges. For imaging studies, multiple images were obtained and the integrated intensity ratio for images obtained with and without surfactant was compared for 10 selected peaks. It was found that SDS tends to degrade imaging performance whereas Triton X-100 and Tween 20 improved performance compared to no surfactant, especially above 7 kDa. PMID- 28335980 TI - Paper-polymer composite devices with minimal fluorescence background. AB - Polymer film incorporated paper-based devices show advantages in simplicity and rugged backing. However, their applications are restricted by the high fluorescence background interference of conventional laminating pouches. Herein, we report a straightforward approach for minimal fluorescence background device fabrication, in which filter paper was shaped and laminated in between two biaxially oriented polypropylene (OPP) and polyvinyl butyral (PVB) composite films. This composite film provides mechanical strength for enhanced device durability, protection from environmental contamination, and prevents reagent degradation. This approach was tested by the determination of copper ions with a fluorescent probe, while the detection of glucose was used to illustrate the improved device durability. Our results show that lamination by the polymer composite lengthens device lifetime, while allowing for fluorescence detection methods combination with greatly reduced fluorescent background widely present in commercially available lamination pouches. By the combination of rapid device prototyping with low cost materials, we believe that this composite design would further expand the potential of paper-based devices. PMID- 28335979 TI - Microfluidic immunosensor based on mesoporous silica platform and CMK-3/poly acrylamide-co-methacrylate of dihydrolipoic acid modified gold electrode for cancer biomarker detection. AB - We report a hybrid glass-poly (dimethylsiloxane) microfluidic immunosensor for epidermal growth factor receptor (EGFR) determination, based on the covalent immobilization of anti-EGFR antibody (anti-EGFR) on amino-functionalized mesoporous silica (AMS) retained in the central channel of a microfluidic device. The synthetized AMS was characterized by N2 adsorption-desorption isotherm, scanning electron microscopy (SEM), energy dispersive spectrometry (EDS) and infrared spectroscopy. The cancer biomarker was quantified in human serum samples by a direct sandwich immunoassay measuring through a horseradish peroxidase conjugated anti-EGFR. The enzymatic product was detected at -100 mV by amperometry on a sputtering gold electrode, modified with an ordered mesoporous carbon (CMK-3) in a matrix of poly-acrylamide-co-methacrylate of dihydrolipoic acid (poly(AC-co-MDHLA)) through in situ copolymerization. CMK-3/poly(AC-co MDHLA)/gold was characterized by cyclic voltammetry, EDS and SEM. The measured current was directly proportional to the level of EGFR in human serum samples. The linear range was from 0.01 ng mL-1 to 50 ng mL-1. The detection limit was 3.03 pg mL-1, and the within- and between-assay coefficients of variation were below 5.20%. The microfluidic immunosensor is a very promising device for the diagnosis of several kinds of epithelial origin carcinomas. PMID- 28335981 TI - External cavity-quantum cascade laser (EC-QCL) spectroscopy for protein analysis in bovine milk. AB - The analytical determination of bovine milk proteins is important in food and non food industrial applications and yet, rather labour-intensive wet-chemical, low throughput methods have been employed since decades. This work proposes the use of external cavity-quantum cascade laser (EC-QCL) spectroscopy for the simultaneous quantification of the most abundant bovine milk proteins and the total protein content based on the chemical information contained in mid-infrared (IR) spectral features of the amide I band. Mid-IR spectra of protein standard mixtures were used for building partial least squares (PLS) regression models. Protein concentrations in commercial bovine milk samples were calculated after chemometric compensation of the matrix contribution employing science-based calibration (SBC) without sample pre-processing. The use of EC-QCL spectroscopy together with advanced multivariate data analysis allowed the determination of casein, alpha-lactalbumin, beta-lactoglobulin and total protein content within several minutes. PMID- 28335984 TI - Tumor Necrosis Factor Inhibitors, Antinuclear Antibodies, and Autoimmunity in Patients With Psoriasis. PMID- 28335982 TI - Comparison of Displacement Encoding With Stimulated Echoes to Magnetic Resonance Feature Tracking for the Assessment of Myocardial Strain in Patients With Acute Myocardial Infarction. AB - The aim of this study was to compare myocardial strain by cardiovascular magnetic resonance feature tracking (CMR-FT) to those derived from displacement encoding with stimulated echoes (DENSE) in patients with acute myocardial infarction (AMI). Twenty patients (65 pa13 years) with AMI underwent cine, DENSE, black blood T2-weighted and late gadolinium enhancement CMR at 1.5 T. Global and segmental strain was determined by CMR-FT analysis and DENSE on matched 3 short axis planes. Global circumferential strain by CMR-FT showed a good agreement with that by DENSE (r = 0.85, p <0.001; bias 0.02, limits of agreement -0.03 to 0.06). For segmental circumferential strain, r coefficient between CMR-FT and DENSE was 0.61 (p <0.001) with bias of 0.02, limits of agreement of -0.07 to 0.11. Regional circumferential strain determined by CMR-FT in infarct segments (-0.08 +/- 0.05) was significantly altered compared with that in remote normal segments (-0.15 +/- 0.05, p <0.001). CMR-FT measurement of regional and global circumferential strain showed good agreement with DENSE in patients with AMI. PMID- 28335983 TI - Ideal Guiding Catheter Position During Bilaterally Engaged Percutaneous Coronary Intervention. AB - Using a novel combined angiography computed tomography (CT) system, we evaluated the impact of the intra-aortic root position of a right coronary artery (RCA) catheter on its coaxiality. We retrospectively enrolled 19 patients who underwent CT scans during bilaterally engaged percutaneous coronary intervention. Coaxiality was defined as the angle between the RCA and the RCA catheter. The coaxiality was better when the RCA catheter was placed anterior to the left main coronary artery catheter (median 27.0 degrees vs 53.7 degrees , p = 0.02). The position of the RCA catheter had a significant impact on the coaxiality of it, with a coaxiality improvement ratio of 0.506 (95% confidence interval 0.294 to 0.871, p = 0.017). Three-dimensional reconstructed CT images of the right anterior oblique projection could determine the position of catheters in all cases. In conclusion, the RCA catheter should be placed anterior, rather than posterior, to the left main coronary artery catheter for better coaxiality during bilaterally engaged percutaneous coronary intervention. The right anterior oblique projection is useful for determining the catheter position. PMID- 28335985 TI - Aqueous-phase synthesis of iron oxide nanoparticles and composites for cancer diagnosis and therapy. AB - The design and development of multifunctional nanoplatforms for biomedical applications still remains to be challenging. This review reports the recent advances in aqueous-phase synthesis of iron oxide nanoparticles (Fe3O4 NPs) and their composites for magnetic resonance (MR) imaging and photothermal therapy of cancer. Water dispersible and colloidally stable Fe3O4 NPs synthesized via controlled coprecipitation route, hydrothermal route and mild reduction route are introduced. Some of key strategies to improve the r2 relaxivity of Fe3O4 NPs and to enhance their uptake by cancer cells are discussed in detail. These aqueous phase synthetic methods can also be applied to prepare Fe3O4 NP-based composites for dual-mode molecular imaging applications. More interestingly, aqueous-phase synthesized Fe3O4 NPs are able to be fabricated as multifunctional theranostic agents for multi-mode imaging and photothermal therapy of cancer. This review will provide some meaningful information for the design and development of various Fe3O4 NP-based multifunctional nanoplatforms for cancer diagnosis and therapy. PMID- 28335988 TI - Omitting adjuvant chemotherapy in patients with rectal cancer who received neoadjuvant chemoradiation followed by total mesorectal excision and achieved a pathological complete response. PMID- 28335986 TI - On the formation and role of reactive oxygen species in light-driven LPMO oxidation of phosphoric acid swollen cellulose. AB - Light-driven activation of lytic polysaccharide monooxygenases (LPMOs) has been attributed to the transfer of high redox potential electrons from excited photopigments to the enzyme. However, due to the formation of reactive oxygen species (ROS) in such a system, not only electrons from the pigments but also ROS could be part of the enzyme mechanism. This work investigates the role of ROS in the oxidation of phosphoric acid swollen cellulose (PASC) by a light-driven LPMO system. Our results clearly show that the addition of superoxide dismutase or catalase to remove ROS did not attenuate the capacity of the light-driven LPMO system to oxidize PASC, as measured by formation of oxidized oligosaccharides. We conclude that ROS are not part of the light-driven LPMO activation; hence, transfer of high redox potential electrons from the excited photopigment to the LPMO remains the most likely mechanism under the conditions tested in this study. PMID- 28335987 TI - Community health indicators associated with outcomes of pancreatectomy. AB - PURPOSE: This study evaluates the association of environmental, social and health risk factors in relation to outcomes of pancreatic surgery. METHODS: Patients who underwent pancreatectomy with a 30 day postoperative follow up in Florida, New York and Washington states were identified using the State Inpatient Databases (SID) from 2010 to 2011. This data was merged with community health indicators complied from the County Health Ranking database. Fourteen community health indicators were used to determine higher risk communities. Communities were then divided into low and high risk communities based on a scoring system using accumulative community risk. RESULTS: Among 3494 patients included recipients in high-risk communities were more likely African American (p < 0.001), younger (age 40-59; p = 0.001), and had Medicaid as primary insurance (p = 0.001). Management of patients in high-risk communities was associated with increased risk of postoperative complications (p < 0.001), ICU admissions (p < 0.001), increased length of stay (p < 0.001). CONCLUSION: Health indicators from patients' communities are predictors of increased risk of perioperative complications for individuals undergoing pancreas surgery. PMID- 28335989 TI - Sentinel lymph node biopsy in low risk settings. AB - BACKGROUND: Sentinel lymph node biopsy (SLNB) should be performed in patients with ductal carcinoma in situ (DCIS) undergoing mastectomy. Yet, the same logic is controversial in the setting of prophylactic mastectomy. METHODS: Surgeons were surveyed as to their practices. Statistical analyses were performed to identify associated factors. RESULTS: 238 surgeons responded to the survey. 73.1% of respondents stated they would always perform SLNB in the setting of mastectomy for DCIS, but only 6.6% would always do so in the prophylactic setting. While generally perceived that the rate of SLN positivity in the setting of pure DCIS and prophylactic mastectomy was <5% (96.9% and 99.5%, respectively), 61.8% of surgeons who reported "always" performing SLNB in the setting of DCIS treated with mastectomy stated they "never" performed a SLNB for prophylactic mastectomy. CONCLUSION: SLNB practice patterns for these low risk settings are disparate. Consensus is required to rationalize practice. PMID- 28335990 TI - Trial type mixing substantially reduces the response set effect in the Stroop task. AB - The response set effect refers to the finding that an irrelevant incongruent colour-word produces greater interference when it is one of the response options (referred to as a response set trial), compared to when it is not (a non-response set trial). Despite being a key effect for models of selective attention, the magnitude of the effect varies considerably across studies. We report two within subjects experiments that tested the hypothesis that presentation format modulates the magnitude of the response set effect. Trial types (e.g. response set, non-response set, neutral) were either presented in separate blocks (pure) or in blocks containing trials from all conditions presented randomly (mixed). In the first experiment we show that the response set effect is substantially reduced in the mixed block context as a result of a decrease in RTs to response set trials. By demonstrating the modulation of the response set effect under conditions of trial type mixing we present evidence that is difficult for models of the effect based on strategic, top-down biasing of attention to explain. In a second experiment we tested a stimulus-driven account of the response set effect by manipulating the number of colour-words that make up the non-response set of distractors. The results show that the greater the number of non-response set colour concepts, the smaller the response set effect. Alternative accounts of the data and its implications for research debating the automaticity of reading are discussed. PMID- 28335991 TI - Corrigendum to: "Saliva initiates the formation of pro-inflammatory macrophages in vitro" [Arch. Oral Biol. 73 (January) (2017) 295-301]. PMID- 28335993 TI - Biomaterials innovation for next generation ex vivo immune tissue engineering. AB - Primary and secondary lymphoid organs are tissues that facilitate differentiation of B and T cells, leading to the induction of adaptive immune responses. These organs are present in the body from birth and are also recognized as locations where self-reactive B and T cells can be eliminated during the natural selection process. Many insights into the mechanisms that control the process of immune cell development and maturation in response to infection come from the analysis of various gene-deficient mice that lack some or all hallmark features of lymphoid tissues. The complexity of such animal models limits our ability to modulate the parameters that control the process of immune cell development, differentiation, and immunomodulation. Engineering functional, living immune tissues using biomaterials can grant researchers the ability to reproduce immunological events with tunable parameters for more rapid development of immunotherapeutics, cell-based therapy, and enhancing our understanding of fundamental biology as well as improving efforts in regenerative medicine. Here the author provides his review and perspective on the bioengineering of primary and secondary lymphoid tissues, and biomaterials innovation needed for the construction of these immune organs in tissue culture plates and on-chip. PMID- 28335994 TI - Differential expression of serpins may selectively licence distinct granzyme B functions including antigen cross-presentation. PMID- 28335992 TI - Varicella zoster virus vasculopathy: The expanding clinical spectrum and pathogenesis. AB - Varicella zoster virus (VZV) is a ubiquitous, human alphaherpesvirus that produces varicella on primary infection then becomes latent in ganglionic neurons along the entire neuraxis. In elderly and immunocompromised individuals, VZV reactivates and travels along nerve fibers peripherally resulting in zoster. However, VZV can also spread centrally and infect cerebral and extracranial arteries (VZV vasculopathy) to produce transient ischemic attacks, stroke, aneurysm, sinus thrombosis and giant cell arteritis, as well as granulomatous aortitis. The mechanisms of virus-induced pathological vascular remodeling are not fully elucidated; however, recent studies suggest that inflammation and dysregulation of programmed death ligand-1 play a significant role. PMID- 28335995 TI - Assessment of dietary exposure to organohalogen contaminants, legacy and emerging flame retardants in a Norwegian cohort. AB - Polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), emerging halogenated flame retardants (EHFRs) and organophosphate flame retardants (PFRs) were detected in 24h duplicate diet samples from a Norwegian cohort (n=61), with concentrations ranging from = daily cannabis use did not predict lower odds of ART care (Adjusted Odds Ratio [AOR]: 1.02, 95% confidence interval [CI]: 0.77-1.36) or VL non-detectability among ART-exposed (AOR: 0.96, 95% CI: 0.75-1.21). Upon testing for potential interactions, >= daily cannabis use was found to be negatively associated with ART engagement during periods of binge alcohol use (p<0.05). CONCLUSION: With the exception of frequent cannabis use during periods of binge alcohol use, our results showed no statistically significant impact of daily cannabis use on the likelihood of ART care or VL non-detectability among ART-exposed HIV-positive PWUD. These findings are reassuring in light of the impending legalization of cannabis in Canada and ongoing efforts to expand TasP initiatives. PMID- 28336002 TI - World TB Day 2017: Strengthening the fight against TB. PMID- 28336004 TI - [Postnatal diagnosis of gastric volvulus revealing congenital diaphragmatic hernia]. AB - Postnatally diagnosed congenital diaphragmatic hernias (CDH) are rare and have a better prognosis than those diagnosed prenatally. Postnatal symptoms can be respiratory, digestive, or mixed. Gastric volvulus can reveal CDH. Symptoms are pain, abdominal distension, and/or vomiting. Upper gastrointestinal barium X-ray radiography provides the diagnosis. Prognosis is related to early surgical management in complicated forms with intestinal occlusion or sub-occlusion. We report on an infant who presented with vomiting, which revealed gastric volvulus associated with a CDH. Progression was favorable after surgical treatment. PMID- 28336003 TI - Efficacy of a titanium dioxide nanoparticles - based indoor anti-odor product as assessed by electronic nose and gaschromatography-mass spectrometry. AB - Indoor air pollutants and odorants may have psychological and physical impact on exposed individuals and the unpleasant room air is considered as one of the factors associated with sick building syndrome comprising general symptoms such as headache and lethargy. Approaches for improving the quality of indoor air are thus important as support for human health and well-being. Photo-oxidation catalyzed by titanium dioxide (TiO2), is one of the methods used for elimination of volatile organic compounds, which are the cause of odor nuisance in indoor and outdoor air. In the present investigation, the efficacy of an experimental anti odor air freshener based on TiO2 nanoparticles was estimated by testing its ability in removing from a small air chamber (200mL) the odor of triethylamine solutions (50MUL at concentrations between 0.700 to 700mM), used as a model volatile molecule for simulating fish-like unpleasant indoor environment. The evaluation was performed by electronic nose which provided a holistic and objective data on the efficacy of the product, demonstrating that the effects of triethylamine even at the highest tested concentrations can be completely removed by application of 3.0g of the product at 25% TiO2 nanoparticles concentration. The obtained results were confirmed by gaschromatography-mass spectrometry (GC MS) analysis addressed to the quantitative determination of residual triethylamine in the environment after treatment by the anti-odor product. PMID- 28336005 TI - [Need for an overall reflexion on personalized medicine in pediatric oncology]. PMID- 28336007 TI - Diagnostic Performance of Automated Breast Volume Scanning (ABVS) Compared to Handheld Ultrasonography With Breast MRI as the Gold Standard. AB - RATIONALE AND OBJECTIVES: This study aimed to compare the diagnostic value of automated breast volume scanning (ABVS) to that of handheld ultrasonography (HHUS) using breast magnetic resonance imaging (MRI) as the gold standard. MATERIALS AND METHODS: Twenty-eight patients with 39 examined breasts with at least one lesion visible in breast MRI underwent HHUS and ABVS. Detection rate, localization, maximum diameter, and Breast Imaging Reporting and Data System classification were compared. Sensitivity, specificity, diagnostic accuracy, positive predictive value, and negative predictive value were calculated for HHUS and ABVS. Lesion localization and maximum diameters based on HHUS and ABVS were compared to size measurement in MRI. Breast Imaging Reporting and Data System categories based on each method were compared to the MRI diagnosis (malignant or benign) or, if available (21 cases), with the histologic diagnosis. RESULTS: MRI detected 72 lesions, ABVS 59 lesions, and HHUS 54 lesions. Malignancy was proven histopathologically in 15 cases. There was no significant difference between ABVS and HHUS in terms of sensitivity (93.3% vs. 100%), specificity (83.3% vs. 83.3%), diagnostic accuracy (87.2% vs. 89.7%), positive predictive value (77.8% vs. 78.9%), and negative predictive value (95.2% vs. 100%). Agreement regarding lesion localization (same quadrant) was 94.3% for ABVS and MRI and 91.2% for HHUS and MRI. Lesion size compared to MRI lesion size was assessed correctly (+/- 3 mm) in 79.4% (HHUS) and 80% (ABVS). The correlation of size measurement was slightly higher for ABVS-MRI (r = 0.89) than for HHUS-MRI (r = 0.82) with P < .001. CONCLUSIONS: ABVS can be used as an alternative to HHUS. ABVS has the advantage of operator independence and better reproducibility although it is limited in evaluating axillary lymph nodes and lacks Doppler or elastrography capabilities, which sometimes provide important supplementary information in HHUS. PMID- 28336006 TI - Influence of the Integral Quality Monitor transmission detector on high energy photon beams: A multi-centre study. AB - PURPOSE: The influence of the Integral Quality Monitor (IQM) transmission detector on photon beam properties was evaluated in a preclinical phase, using data from nine participating centres: (i) the change of beam quality (beam hardening), (ii) the influence on surface dose, and (iii) the attenuation of the IQM detector. METHODS: For 6 different nominal photon energies (4 standard, 2 FFF) and square field sizes from 1*1cm2 to 20*20cm2, the effect of IQM on beam quality was assessed from the PDD20,10 values obtained from the percentage dose depth (PDD) curves, measured with and without IQM in the beam path. The change in surface dose with/without IQM was assessed for all available energies and field sizes from 4*4cm2 to 20*20cm2. The transmission factor was calculated by means of measured absorbed dose at 10cm depth for all available energies and field sizes. RESULTS: (i) A small (0.11-0.53%) yet statistically significant beam hardening effect was observed, depending on photon beam energy. (ii) The increase in surface dose correlated with field size (p<0.01) for all photon energies except for 18MV. The change in surface dose was smaller than 3.3% in all cases except for the 20*20cm2 field and 10MV FFF beam, where it reached 8.1%. (iii) For standard beams, transmission of the IQM showed a weak dependence on the field size, and a pronounced dependence on the beam energy (0.9412 for 6MV to 0.9578 for 18MV and 0.9440 for 6MV FFF; 0.9533 for 10MV FFF). CONCLUSIONS: The effects of the IQM detector on photon beam properties were found to be small yet statistically significant. The magnitudes of changes which were found justify treating IQM either as tray factors within the treatment planning system (TPS) for a particular energy or alternatively as modified outputs for specific beam energy of linear accelerators, which eases the introduction of the IQM into clinical practice. PMID- 28336009 TI - Case Study in Critical Care Transport: A 51-Year-Old Male With Ludwig Angina. PMID- 28336010 TI - Looking Forward. PMID- 28336011 TI - Winner, Winner, Chicken Dinner. PMID- 28336014 TI - Clinical Significance of Fibrinogen Degradation Product Among Traumatized Patients. AB - OBJECTIVE: We retrospectively analyzed trauma patients who were transported by a physician-staffed helicopter (doctor helicopter) to investigate the clinical significance of the fibrinogen degradation product (FDP) level on arrival. METHODS: From February 2011 to July 2016, a medical chart review was retrospectively performed for all patients with trauma who were transported by the doctor helicopter. The subjects were divided into 2 groups: a survival group and a fatal group. RESULTS: There were 135 patients in the survival group and 16 in the fatal group. The ratio of head injury, value of Injury Severity Score (ISS), and level of FDP in the fatal group were significantly greater than in the survival group. The average Glasgow Coma Scale and systolic blood pressure in the fatal group were significantly smaller than in the survival group. The FDP level at arrival was positively associated with the ISS (R = 0.74, P < .0001). After excluding subjects with shock, unconsciousness, and head injury, the FDP level was still positively associated with the ISS (R = 0.60, P < .0001). CONCLUSION: Therefore, the FDP level may be a useful biochemical parameter for the initial evaluation of the severity of trauma, even in blunt trauma patients without head injury or with stable vital signs. PMID- 28336015 TI - Ten Years of En Route Critical Care Training. AB - OBJECTIVE: The French Military Health Service (FMHS) has developed a training program for medical evacuation (MEDEVAC) of critical care patients on fixed wing aircraft. METHODS: We conducted a 10-year retrospective analysis (2006-2015) of the data from the FMHS Academy. The number of trainees was listed according to the different courses and medical specialties. The number of MEDEVACs recorded during the period was described. RESULTS: Since 2006, the FMHS has developed training courses designed for MEDEVAC of critical care patients. Forty-five collective strategic MEDEVAC courses were delivered to 91 intensivists, 130 anesthetic nurses, 79 flight surgeons, 55 flight nurses, and 89 nurses. Five sessions of tactical MEDEVAC courses were performed for 14 flight surgeons, 6 flight nurses, and 17 other nurses. Ten sessions of individual strategic MEDEVAC courses were delivered to 17 intensivists, 10 flight surgeons, 21 flight nurses, and 7 other nurses. Between 2006 and 2015, 818 (+/- 68) individual strategic MEDEVACs were performed per year. Thirty-three (+/- 19) concerned critical care patients. Five missions of collective strategic MEDEVAC were performed for 56 patients. CONCLUSION: The FMHS has developed specific courses for the MEDEVAC of critical care patients, allowing the training of numerous MEDEVAC teams. PMID- 28336016 TI - Review of Issues and Challenges of Practicing Emergency Medicine Above 30,000 Feet Altitude: 2 Anonymized Cases. AB - We present 2 anonymized cases to identify issues and challenges associated with long-haul in-flight medical emergencies. The first case involved a middle-aged man with a history of carditis on a systemic steroid who developed vomiting and rigor. Four physicians, including a pediatric intensivist, responded to the emergency call. In the second case, a pediatric trainee who was the only onboard medical personnel was summoned for help when a middle-aged man developed acute shortness of breath while traveling on a commercial flight. The cases illustrate the challenges and issues on the critical decisions of diagnosis, resuscitation, and whether the flight had to be returned or diverted. An extensive literature search is made to summarize the evidence available for these decisions and challenges. Epidemiology and outcomes associated with these medical emergencies are reviewed. In-flight medical emergencies are not rare. Physicians of all disciplines should be prepared to deal with these emergencies and make sensible decisions when equipment and resources are likely to be limited. PMID- 28336017 TI - Weather Webcam System for the Safety of Helicopter Emergency Medical Services in Miyazaki, Japan. AB - OBJECTIVE: In Japan, the helicopter emergency medical services (HEMS) system was initiated in 2001 and introduced to Miyazaki Prefecture in 2012. Mountainous areas occupy 88% of Miyazaki's land area, and HEMS flights can be subject to the effects of weather. Therefore, ensuring safety in changing weather conditions is a necessity for HEMS. METHODS: The weather webcam system (WWS) was established to observe the meteorological conditions in 29 locations. Assessments of the probability of a flight based on conventional data including a weather chart provided by the Japan Meteorological Agency and meteorological reports provided by the Miyazaki Airport were compared with the assessment based on the combination of the information obtained from the WWS and the conventional data. RESULTS: The results showed that the probability of a flight by HEMS increased when using the WSS, leading to an increased transportation opportunity for patients in the mountains who rely on HEMS. In addition, the results indicate that the WWS may prevent flights in unfavorable weather conditions. CONCLUSION: The WWS used in conjunction with conventional weather data within Miyazaki HEMS increased the pilot's awareness of current weather conditions throughout the Prefecture, increasing the probability of accepting a flight. PMID- 28336018 TI - Air Medical Transport Residency Program for Flight Nurses and Paramedics. PMID- 28336020 TI - Embrace Action: Mind, Body, and Spirit. PMID- 28336019 TI - Endotracheal Cuff Pressure Changes During Helicopter Transport: A Systematic Review. AB - OBJECTIVE: Cuff pressures are important in ventilated patients undergoing helicopter transport. An altitude-related increase in endotracheal tube (ETT) intracuff pressure has been shown in simulated hypobaric environments, model tracheas, and animal studies and may not accurately reflect in vivo pressures. The aim of this study was to determine if ETT intracuff pressure increases above the critical perfusion pressure of the trachea in ventilated patients during helicopter transport. METHODS: Ovid Medline, CINAHL, Embase, Scopus, and the Cochrane Library were searched from their commencement to January 29, 2016. Google Scholar was searched, and reference lists of relevant articles were examined to identify additional studies. Articles were included if they reported on ETT intracuff pressure in ventilated patients during helicopter emergency medical service transport. RESULTS: A total of 330 articles were identified; only 2 prospective observational studies met the inclusion criteria. The studies reported a mean cuff pressure increase of 23 cm H2O and 33.9 cm H2O. Both studies reported ETT intracuff pressure to frequently exceed the critical perfusion pressure of the tracheal mucosa during helicopter transport. CONCLUSION: Further research with longitudinal follow-up is required to confirm these findings to determine if the effects of transient increased ETT intracuff pressure are clinically significant. PMID- 28336021 TI - Leading Learning in the Internet Age. PMID- 28336022 TI - Author response. PMID- 28336023 TI - Expectations of Perioperative Nurse and Surgeon Behavior in the OR. PMID- 28336024 TI - Postoperative Pain Self-Management Behavior in Patients Who Underwent Total Knee or Hip Arthroplasty. AB - The self-management of acute postoperative pain is not well researched. This cross-sectional study investigates postoperative pain and pain self-management behavior. We recruited 127 patients who underwent total knee or total hip arthroplasty in an acute care hospital. We measured postoperative pain intensity and pain self-management behavior for three postoperative days. The results showed that the participants experienced mild and moderate pain intensity and perceived moderate to severe pain interference, which influenced their mood, sleep patterns, ability to walk, and performance of general activities and rehabilitation exercises. Female participants reported significantly higher pain intensity and lower pain self-management behavior; highly educated participants reported significantly lower pain intensity and higher self-management behavior. Pain intensity scores had a significant negative correlation with the total self management behavior score (r = -0.719, P < .01). Health care professionals must consider patients' demographic characteristics when providing education and support regarding pain self-management for postoperative pain control. PMID- 28336025 TI - Service Dogs in the Perioperative Setting. AB - Service dogs are critical for the independence of individuals with disabilities because they assist with daily living activities and help these individuals navigate society. Perioperative nurses need a working knowledge of disability laws pertaining to service dogs to provide patient-centered care for individuals using service dogs. This article provides information on the Americans With Disabilities Act regulations regarding service dogs, makes recommendations for the care of patients with service dogs across the perioperative continuum, and offers policy directives to ensure that safe, high-quality care is delivered to patients using service dogs. PMID- 28336026 TI - Viscoelastic Studies: Effective Tools for Trauma and Surgical Resuscitation Efforts. AB - Trauma-induced coagulopathy (TIC) is an abrupt disruption of all hemostatic components of coagulation resulting from severe tissue injury and hypoperfusion. The effective management of TIC has remained elusive to clinicians using traditional laboratory methods, challenging efforts to improve outcomes related to uncontrolled bleeding. Recent initiatives have aimed to reduce TIC-associated morbidity and mortality, further invoking trauma experts to explore innovative modalities in the field of viscoelastic studies, such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM). These tests are able to guide proper blood product administration more effectively during trauma and surgical resuscitation compared with conventional laboratory tests. Although TEG and ROTEM are similar tests, inherent differences in their features produce variation in output results. This article calls on the perioperative clinician to evaluate TEG and ROTEM tests and consider their implementation based on the benefits of their application to clinical practice. PMID- 28336027 TI - Reducing Surgery Cancellations at a Pediatric Ambulatory Surgery Center. AB - Surgery cancellations are costly and can be frustrating for patients, their families, and the surgical team. Because of the inherent nature of an ambulatory surgery center, which only performs scheduled elective procedures, surgical cancellations typically result in wasted time and resources. Pediatric surgery cancellations can be mitigated with proper preoperative screening and communication between nurses and patients' guardians. To reduce the rate of cancellation at our pediatric ambulatory surgery center, we implemented a Nurse Patient Preoperative Call Log. Preoperative nurses called patients or their guardians on two separate occasions during the two weeks before surgery to review health history and instructions and answer questions about the upcoming surgery. Three months after implementing the call log, surgery cancellation rates significantly decreased from 16.8% to 8.8% (P < .05). Nurses used the call log for all patients, with 85.6% of patients receiving two calls in the two weeks before their surgery. PMID- 28336028 TI - Guideline Implementation: Energy-Generating Devices, Part 2-Lasers. AB - Lasers have been used in the OR for many years and are essential tools in many different types of procedures. However, laser beams that come into contact with unintended targets directly or via reflection can cause injury to patients or personnel or pose other hazards, such as fires. The new AORN "Guideline for safe use of energy-generating devices" provides guidance on the use of all energy generating devices in the OR. This article focuses on key points of the guideline that address the safe use of lasers. These include the components of the laser safety program, the responsibilities of the personnel in roles specific to use of a laser, laser safety measures, and documentation of laser use. Perioperative RNs should review the complete guideline for additional information and for guidance when writing and updating policies and procedures. PMID- 28336029 TI - Guideline Summary: Energy-Generating Devices, Part 2-Lasers. PMID- 28336030 TI - Applying Human-Centered Design Thinking to Enhance Safety in the OR. PMID- 28336031 TI - Clinical Issues-April 2017. AB - Patient involvement in hand hygiene Key words: patient engagement, hand hygiene, hand washing stations, hand hygiene promotion. Alcohol-based surgical hand rubs in the OR Key words: hand hygiene, hand rub, dispenser. Personal hand hygiene dispensers Key words: hand hygiene, hand rub, hand rub dispenser, personal dispenser. Hand soap Key words: soap, hand hygiene, hand wash, plain soap, triclosan. Disposal of water used for plaster application in scrub sinks Key words: plaster, pour, sink, scrub sink. Multiple hand hygiene indications Key words: hand hygiene, hand wash, hand rub. PMID- 28336032 TI - Evidence appraisal of Koh BTH, Tan JH, Ramruttun AK, Wang W. Effect of storage temperature and equilibration time on polymethyl methacrylate (PMMA) bone cement polymerization in joint replacement surgery.: J Orthop Surg Res. 2015;10(1):178. doi:10.1186/s13018-015-0320-7. PMID- 28336034 TI - A Fumbled Handoff to Inpatient Rehab. PMID- 28336033 TI - Guideline at a Glance: Environmental Cleaning. PMID- 28336035 TI - Effect of Tranexamic Acid on Transfusion Rates Following Total Joint Arthroplasty: A Cost and Comparative Effectiveness Analysis. AB - Tranexamic acid (TXA) is used to reduce blood loss in orthopedic total joint arthroplasty (TJA). This study evaluates the effectiveness of TXA in reducing transfusions and hospital cost in TJA. Participants undergoing elective TJA were stratified into 2 cohorts: those not receiving and those receiving intravenous TXA. TXA decreased total hip arthroplasty (THA) transfusions from 22.7% to 11.9%, and total knee arthroplasty (TKA) from 19.4% to 7.0%. The average direct hospital cost reduction for THA and TKA was $3083 and $2582, respectively. Implementation of a TJA TXA protocol significantly reduced transfusions in a safe and cost effective manner. PMID- 28336036 TI - Physical Function and Physical Activity in Obese Adults After Total Knee Arthroplasty. AB - Obese patients are more likely to have osteoarthritis and total knee arthroplasty (TKA). This investigation sought to evaluate physical function, activity level, and quality of life (QOL). Obese participants near 1-year postsurgical follow-up appointment were recruited. Evaluation included QOL and activity questionnaire, medical histories, anthropometrics, strength, and aerobic capacity. Sixty participants completed assessments. Obese TKA patients have physical performance limitations and low physical activity levels 1 year after surgery and completion of postoperative rehabilitation. PMID- 28336037 TI - Deep Vein Thrombosis and Pulmonary Embolism Considerations in Orthopedic Surgery. AB - Patients undergoing orthopedic surgery have an increased risk for deep venous thrombosis (DVT) and pulmonary embolism (PE). These complications are considered detrimental, as they cause major postoperative morbidity and mortality and lead to a substantial health care burden. Because of the high incidence and serious nature of these complications, it is essential for orthopedic surgeons to have a comprehensive knowledge of the risk factors, diagnosis, and treatment of acute DVT and PE. Perioperative management of orthopedic patients to prevent postoperative DVT and PE and optimize postoperative outcomes is also discussed in this review. PMID- 28336038 TI - Role of Systemic and Local Antibiotics in the Treatment of Open Fractures. AB - The orthopedic community has learned much about the treatment of open fractures from the tremendous work of Ramon Gustilo, Michael Patzakis, and others; however, open fractures continue to be very difficult challenges. Type III open fractures continue to be associated with high infection rates. Some combination of systemic and local antibiotics may be most appropriate in these high-grade open fractures. Further research is still necessary in determining optimal systemic antibiotic regimens as well as the role of local antibiotics. Any new discoveries related to novel systemic antibiotics or local antibiotic carriers will need to be evaluated related to cost. PMID- 28336039 TI - The Antibiotic Nail in the Treatment of Long Bone Infection: Technique and Results. AB - Antibiotic cement nails provide a useful and relatively simple technique to treat intramedullary osteomyelitis of the long bones. These devices provide stability as well as local, targeted antibiotics, which are both critical aspects of osteomyelitis management. Additionally, the use of a threaded core is a critical component of successful cement nail assembly. With adherence to the simple principles outlined in this review, surgeons can expect reliably good results using these drug-delivery implants. PMID- 28336040 TI - The Impact of Negative Pressure Wound Therapy on Orthopaedic Infection. AB - By hastening the resolution of edema and improving local microcirculation, topical negative pressure wound therapy (TNP) aids the establishment of early wound coverage. Its use in the setting of type III open fractures is reviewed. The author's initial use of TNP for closed surgical incisions and how it morphed its way into being applied to closed surgical wounds with heightened likelihood for infection is presented. Several case studies are presented to illustrate the role and the technique for management of acute or subacute infections involving bone and implant. PMID- 28336041 TI - Double-Edged Sword: Musculoskeletal Infection Provoked Acute Phase Response in Children. AB - The acute phase response has a crucial role in mounting the body's response to tissue injury. Excessive activation of the acute phase response is responsible for many complications that occur in orthopedic patients. Given that infection may be considered continuous tissue injury that persistently activates the acute phase response, children with musculoskeletal infections are at markedly increased risk for serious complications. Future strategies that modulate the acute phase response have the potential to improve treatment and prevent complications associated with musculoskeletal infection. PMID- 28336042 TI - Acute Hematogenous Osteomyelitis in Children: Pathogenesis, Diagnosis, and Treatment. AB - Acute hematogenous osteomyelitis (AHO) in children is an ideal condition to study due to its representation of a wide spectrum of disorders that comprise pediatric musculoskeletal infection. Proper care for children with AHO is multidisciplinary and collaborative. AHO continues to present a significant clinical challenge due to evolving epidemiology and complex pathogenesis. A guideline-driven, multidisciplinary approach has been introduced and shown to effectively reduce hospital stay, improve the timing and selection of empirical antibiotic administration, reduce delay to initial MRI, reduce the rate of readmission, and shorten antibiotic duration. PMID- 28336043 TI - Pediatric Septic Arthritis. AB - Acute septic arthritis is a condition with the potential for joint destruction, physeal damage, and osteonecrosis, which warrants urgent identification and treatment. The organism most frequently responsible is Staphylococcus aureus; however, our understanding of pathogens continues to evolve as detection methods continue to improve. MRI has improved our ability to detect concurrent infections and is a useful clinical tool where available. The treatment course involves intravenous antibiotics followed by transition to oral antibiotics when clinically appropriate. The recommended surgical treatment of septic arthritis is open arthrotomy with decompression of the joint, irrigation, and debridement and treatment of concurrent infections. PMID- 28336044 TI - Flexor Tenosynovitis. AB - For patients with suspected flexor tenosynovitis, the mainstay of diagnosis is a thorough history and physical examination. The examination is guided by evaluating the patient for Kanavel's four cardinal signs. Empiric antibiotics should be started immediately on diagnosis covering skin flora and gram-negative bacteria. Typically, surgery is required. Appropriate exposure is required for adequate treatment and incisions should be tailored to preserve areas of skin compromised from draining sinuses and abscess pressure. Diabetes mellitus and peripheral vascular disease place patients at higher risk of poor outcomes including stiffness and amputation; early administration of antibiotics is the intervention that correlates most closely with good outcomes. PMID- 28336045 TI - Atypical Hand Infections. AB - Atypical infections of the hand are caused by organisms such as Mycobacterium, fungi, and viruses, and often do not respond to conventional management. They exist within a wide spectrum of presentations, ranging from cutaneous lesions to deep infections such as tenosynovitis and osteomyelitis. Having a high clinical suspicion for atypical hand infections is vital because diagnosis often requires special tests and/or cultures. Obtaining a detailed medical, work, and travel history is extremely important. An indolent clinical course, late diagnosis, and delayed treatment are common. In addition to medical therapies, surgical debridement is often required to effectively treat these infections. PMID- 28336046 TI - Charcot Arthropathy Versus Osteomyelitis: Evaluation and Management. AB - Charcot arthropathy of the foot and ankle is a severe complication of peripheral neuropathy and is most commonly seen in the developed world in association with diabetes mellitus. Correct diagnosis and differentiation from osteomyelitis of the foot and ankle are critical to guide treatment. It can exist concomitantly with osteomyelitis, typically in the setting of an advanced midfoot ulcer. Simple plain radiographs and contrasted MRI studies often yield inconclusive or confusing data. Correct use of imaging studies and a clinical algorithm can be effective tools to help make accurate and early diagnoses and guide clinical interventions for these conditions. PMID- 28336047 TI - Posttraumatic Reconstruction of the Foot and Ankle in the Face of Active Infection. AB - Posttraumatic infection of the foot and ankle is a challenging issue for orthopedic surgeons. Making the diagnosis often requires combining laboratory and radiologic testing, patient examination, and history. Patient comorbidities should be identified and optimized whenever possible. Treatment must combine effective antibiotic therapy with thorough debridement of the infected zone. Reconstruction often requires a 2-staged approach using antibiotic spacers and temporary external fixation, with the goal of obtaining a functional, pain-free limb that is free of infection. PMID- 28336048 TI - Infection. PMID- 28336049 TI - Hypothyroidism. AB - Hypothyroidism is a common condition of thyroid hormone deficiency, which is readily diagnosed and managed but potentially fatal in severe cases if untreated. The definition of hypothyroidism is based on statistical reference ranges of the relevant biochemical parameters and is increasingly a matter of debate. Clinical manifestations of hypothyroidism range from life threatening to no signs or symptoms. The most common symptoms in adults are fatigue, lethargy, cold intolerance, weight gain, constipation, change in voice, and dry skin, but clinical presentation can differ with age and sex, among other factors. The standard treatment is thyroid hormone replacement therapy with levothyroxine. However, a substantial proportion of patients who reach biochemical treatment targets have persistent complaints. In this Seminar, we discuss the epidemiology, causes, and symptoms of hypothyroidism; summarise evidence on diagnosis, long term risk, treatment, and management; and highlight future directions for research. PMID- 28336051 TI - Optimising care for children with kidney disease. PMID- 28336050 TI - Mortality risk disparities in children receiving chronic renal replacement therapy for the treatment of end-stage renal disease across Europe: an ESPN ERA/EDTA registry analysis. AB - BACKGROUND: We explored the variation in country mortality rates in the paediatric population receiving renal replacement therapy across Europe, and estimated how much of this variation could be explained by patient-level and country-level factors. METHODS: In this registry analysis, we extracted patient data from the European Society for Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association (ESPN/ERA-EDTA) Registry for 32 European countries. We included incident patients younger than 19 years receiving renal replacement therapy. Adjusted hazard ratios (aHR) and the explained variation were modelled for patient-level and country-level factors with multilevel Cox regression. The primary outcome studied was all-cause mortality while on renal replacement therapy. FINDINGS: Between Jan 1, 2000, and Dec 31, 2013, the overall 5 year renal replacement therapy mortality rate was 15.8 deaths per 1000 patient-years (IQR 6.4-16.4). France had a mortality rate (9.2) of more than 3 SDs better, and Russia (35.2), Poland (39.9), Romania (47.4), and Bulgaria (68.6) had mortality rates more than 3 SDs worse than the European average. Public health expenditure was inversely associated with mortality risk (per SD increase, aHR 0.69, 95% CI 0.52-0.91) and explained 67% of the variation in renal replacement therapy mortality rates between countries. Child mortality rates showed a significant association with renal replacement therapy mortality, albeit mediated by macroeconomics (eg, neonatal mortality reduced from 1.31 [95% CI 1.13-1.53], p=0.0005, to 1.21 [0.97-1.51], p=0.10). After accounting for country distributions of patient age, the variation in renal replacement therapy mortality rates between countries increased by 21%. INTERPRETATION: Substantial international variation exists in paediatric renal replacement therapy mortality rates across Europe, most of which was explained by disparities in public health expenditure, which seems to limit the availability and quality of paediatric renal care. Differences between countries in their ability to accept and treat the youngest patients, who are the most complex and costly to treat, form an important source of disparity within this population. Our findings can be used by policy makers and health-care providers to explore potential strategies to help reduce these health disparities. FUNDING: ERA-EDTA and ESPN. PMID- 28336052 TI - Does reef structure affect oyster food resources? A stable isotope assessment. AB - As ecosystem engineers, oysters create and maintain structured habitat and can influence trophodynamics and benthic-pelagic coupling in the surrounding landscape. The physical reef structure and associated biotic parameters can affect the availability of food resources for oysters. Oysters and potential composite food sources - suspended particulate organic matter (SPOM) and surface sediment organic matter (SSOM) - were assessed using a dual stable isotope (delta13C, delta15N) approach at three reef types (natural, restored, and unconsolidated) seasonally for two years to determine if changes in physical and/or biotic parameters affected the relative availability and/or use of food resources by oysters. SPOM was more depleted in 13C (-24.2 +/- 0.60/00, mean +/- SD) than SSOM (-21.2 +/- 0.80/00). SPOM composition is likely dominated by autochthonous phytoplankton production, while SSOM includes trapped phytoplankton and benthic microalgae. SSOM was used by oysters in increasing proportions relative to SPOM over time at all reef types. This temporal trend is likely due to increased oyster biomass over time, promoting enhanced microphytobenthos growth through feedback effects related to oyster biodeposits. Structural differences between reef types observed in this study had no effect on food resource availability and use by oysters, indicating strong bentho-pelagic coupling likely due to shallow depths as well as strong and consistent winds. This study provides insights for restoration of oyster reefs as it highlights that food resources used by oysters remain similar among reef types despite changes in abiotic and biotic parameters among habitats and over time. PMID- 28336053 TI - Non-indigenous predators threaten ecosystem engineers: Interactive effects of green crab and oyster size on American oyster mortality. AB - Non-indigenous green crabs (Carcinus maenas) are emerging as important predators of autogenic engineers like American oysters (Crassostrea virginica) throughout the eastern seaboard of Canada and the United States. To document the spreading distribution of green crabs, we carried out surveys in seven sites of Prince Edward Island during three fall seasons. To assess the potential impact of green crabs on oyster mortality in relation to predator and prey size, we conducted multiple predator-prey manipulations in the field and laboratory. The surveys confirmed an ongoing green crab spread into new productive oyster habitats while rapidly increasing in numbers in areas where crabs had established already. The experiments measured mortality rates on four sizes of oysters exposed to three sizes of crab, and lasted 3-5 days. The outcomes of experiments conducted in Vexar(r) bags, laboratory tanks and field cages were consistent and were heavily dependent on both crab size and oyster size: while little predation occurred on large oysters, large and medium green crabs preyed heavily on small sizes. Oysters reached a refuge within the 35-55 mm shell length range; below that range, oysters suffered high mortality due to green crab predation and thus require management measures to enhance their survival. These results are most directly applicable to aquaculture operations and restoration initiatives but have implications for oyster sustainability. PMID- 28336054 TI - Atypical Mesenteric Revascularisation. PMID- 28336055 TI - Shamanic Healing for Veterans with PTSD: A Case Series. AB - CONTEXT: Posttraumatic stress disorder (PTSD) is a serious health concern. Current evidence-based treatments for PTSD are efficacious; however, they are not appropriate or tolerated by everyone who needs them. Alternative treatment approaches are needed. Shamanic healing is one such therapy that may potentially be beneficial but no systematic research has been conducted on it for PTSD. OBJECTIVE: The objectives of the case series are to (1) develop a structured replicable shamanic treatment plan for veterans with posttraumatic stress disorder (PTSD); (2) collect preliminary data on PTSD-related outcomes, and (3) explore the feasibility and potential for adverse events of the plan. DESIGN: Case series. SETTING: Clinical. PATIENTS OR OTHER PARTICIPANTS: Veterans with PTSD. INTERVENTION: Shamanic healing. MAIN OUTCOME MEASURE(S): PTSD symptoms, quality of life, and piritual wellness. RESULTS: A semi-structured shamanic healing protocol was created with the following components: rapport building, power animal retrieval, extraction, compassionate spirit release, curse unraveling, soul retrieval, forgiveness/cord-cutting, aspect maturing/soul rematrixing, and divination. Six veterans enrolled in the study (mean age = 49.3 +/- 13.1). Qualitative descriptions of the participants, their histories, and effects from the intervention are reported. Preliminary data was collected on PTSD-related outcomes. The protocol was found feasible and acceptable and recommendations for its future use are suggested. Future research is warranted and needed to evaluate the efficacy of shamanic healing as a potential therapy for veterans with PTSD. PMID- 28336056 TI - Persistent Hemoptysis in an Elderly Patient with Pseudoallescheria boydii Mycetoma. PMID- 28336058 TI - Large (9 mm) Deep Anterior Lamellar Keratoplasty with Clearance of a 6-mm Optical Zone Optimizes Outcomes of Keratoconus Surgery. AB - PURPOSE: To evaluate the outcomes of a 9-mm deep anterior lamellar keratoplasty (DALK) with removal of the deep stroma limited to the central 6-mm optical zone. DESIGN: Prospective, noncomparative, interventional case series. PARTICIPANTS: A total of 80 consecutive keratoconic eyes without deep stromal scarring, with at least 1 postoperative examination 1 month after complete suture removal. INTERVENTION: A standardized DALK was performed, including (1) deep trephination of the recipient bed 450 to 550 MUm in depth and 9 mm in diameter; (2) pneumatic dissection; (3) debulking of approximately 80% of the anterior stroma; (4) removal of the deep stroma (bubble roof) from a central 6-mm optical zone; and (5) transplantation of a 9-mm anterior corneal lamella cut by microkeratome assisted dissection (400-MUm head) and sutured with a double running 10-0 nylon suture. MAIN OUTCOME MEASURES: Success rate and type of pneumatic dissection obtained; best spectacle-corrected visual acuity (BSCVA), refractive astigmatism (RA), and topographic astigmatism (TA), central corneal thickness (CCT) and endothelial cell density 12 months postoperatively; and intraoperative and postoperative complications. RESULTS: Pneumatic dissection created a "big bubble" in 67 of 80 eyes (83.7%), all of them but 1 (1.5%) being of type 1 according to the classification by Dua et al. After complete suture removal, BSCVA averaged 0.09+/-0.72 logarithm of the minimum angle of resolution (logMAR) and was >=20/20 in 28 eyes (35%), >=20/25 in 54 eyes (67.5%), and >=20/40 in 76 eyes (95%); RA averaged 3.10+/-1.30 diopters (D), with 73 eyes (91%) within 4.5 D and none above 6 D; regular TA was detected in 72 eyes (90%); mean CCT was 492+/-62.10 MUm; postoperative endothelial cell density averaged 2026+/-397cells/mm2 with a mean cell loss of 11.2%. Intraoperative complications included loss of suction (n = 1) and perforation (n = 4). No conversion to penetrating keratoplasty was necessary. After surgery, double anterior chamber was observed in 2 cases (2.5%), both managed successfully by air filling of the anterior chamber. Stromal rejection was observed in 6 eyes (7.5%) and was reversed with topical steroids in all cases. CONCLUSIONS: In keratoconic eyes without deep stromal scars, the combination of a graft larger than conventional ones with limited removal of deep stroma can improve visual and refractive outcomes of DALK, while minimizing the rate of complications. PMID- 28336057 TI - Hemorrhage and/or Microaneurysm Severity and Count in Ultrawide Field Images and Early Treatment Diabetic Retinopathy Study Photography. AB - OBJECTIVE: To evaluate detection of hemorrhage and/or microaneurysm (H/Ma) using ultrawide field (UWF) retinal imaging as compared with standard Early Treatment Diabetic Retinopathy Study (ETDRS) 7-field photographs (ETDRS photos). DESIGN: Single-site comparative study of UWF images and ETDRS photos. PARTICIPANTS: One hundred twenty-six eyes of 69 patients with no diabetic retinopathy (DR) or mild or moderate nonproliferative DR (NPDR). METHODS: Stereoscopic 200 degrees UWF images and stereoscopic 35mm 30 degrees 7-field color photographs were acquired on the same visit. Images were graded for severity and distribution of H/Ma. H/Mas were counted in ETDRS fields 2 to 7 in both ETDRS photos and UWF images. H/Mas in the UWF peripheral fields were also counted. MAIN OUTCOME MEASURES: Kappa (kappa) and weighted kappa statistics for agreement. Number of H/Ma within and outside ETDRS fields identified in UWF images and ETDRS photos. RESULTS: Distribution of DR severity by ETDRS photos was 24 (19.0%) no DR, 48 (38.1%) mild NPDR, and 54 (42.9%) moderate NPDR. A total of 748 of 756 fields (98.9%) were gradable for H/Mas on ETDRS photos and UWF images. Simple kappa/weighted kappa statistics for severity of H/Ma: all fields 0.61/0.69, field 2 0.70/0.77, field 3 0.62/0.73, field 4 0.50/0.62, field 5 0.54/0.65, field 6 0.64/0.70, and field 7 0.58/0.63 with overall exact agreement in 81.3% and within 1 step in 97.9% of fields. A greater proportion of fields was graded a more severe H/Ma level in UWF images than in the corresponding ETDRS photos (UWF: 12.7% vs. ETDRS: 6.5%). Evaluating comparable areas in UWF images and ETDRS photos (fields 2-7), a mean of 42.8 H/Mas were identified using ETDRS photos and 48.8 in UWF images (P = 0.10). An additional mean of 21.3 H/Mas (49.8% increase, P < 0.0001) were identified in the peripheral fields of the UWF images. CONCLUSIONS: There is good to excellent agreement between UWF images and ETDRS photos in determining H/Ma severity, with excellent correlation of H/Ma counts within ETDRS photo fields. UWF peripheral fields identified 49.8% more H/Ma, suggesting a more severe H/Ma in 12.7% of eyes. Given the additional lesions detected in peripheral fields and the known risks associated with H/Ma and peripheral lesions, quantification of H/Ma using UWF images may provide a more accurate representation of DR disease activity and potential greater accuracy in predicting DR progression. PMID- 28336060 TI - Recent Advances in Development of Genetically Encoded Fluorescent Sensors. AB - Genetically encoded fluorescent sensors are essential tools in modern biological research, and recent advances in fluorescent proteins (FPs) have expanded the scope of sensor design and implementation. In this review we compare different sensor platforms, including Forster resonance energy transfer (FRET) sensors, fluorescence-modulated single FP-based sensors, translocation sensors, complementation sensors, and dimerization-based sensors. We discuss elements of sensor design and engineering for each platform, including the incorporation of new types of FPs and sensor screening techniques. Finally, we summarize the wide range of sensors in the literature, exploring creative new sensor architectures suitable for different applications. PMID- 28336059 TI - Progression of Near Vision Loss and Incidence of Near Vision Impairment in an Adult Chinese Population. AB - PURPOSE: To investigate the progression of near vision loss and the cumulative incidence of near vision impairment (NVI) 6 years after initial examination of an urban Chinese cohort. DESIGN: Population-based, prospective cohort study. PARTICIPANTS: People aged >=35 years examined at baseline in the Yuexiu District of Guangzhou, China. METHODS: Participants examined at baseline were invited for 2-year and 6-year follow-up examinations in 2010 and 2014, respectively. Examinations included noncycloplegic autorefraction and binocular near visual acuity (NVA) with and without current near correction measured at 40 cm using a LogMAR ETDRS near vision tumbling E chart. Those with uncorrected binocular NVA (UCNVA) <=20/40 underwent subjective refraction to obtain best-corrected binocular NVA (BCNVA). MAIN OUTCOME MEASURES: Change in UCNVA between baseline and 2014 follow-up examinations and the 6-year cumulative incidence of vision impairment based on 3 definitions: NVA <=20/40, <=20/50, and <=20/63. RESULTS: Among the 1817 baseline participants, 1595 (87.8%) were reexamined in 2010 and 1427 (78.5%) in 2014. Mean vision loss between baseline and the 2014 follow-up was 1.54 (+/-1.74) lines of UCNVA. Vision loss was associated with age 80 years or older, less education, and better baseline UCNVA. The 6-year cumulative incidence of uncorrected binocular NVI (UCNVI) across the 3 vision impairment definitions was 55.2% (95% confidence interval [CI], 46.1%-64.3%), 51.3% (95% CI, 44.0%-58.7%), and 42.4% (95% CI, 35.5%-49.3%), respectively. With best-corrected binocular NVI (BCNVI), incidence was 6.89% (95% CI, 4.28%-9.50%), 5.17% (95% CI, 2.89%-7.44%), and 2.62% (95% CI, 1.11%-4.12%), respectively. A higher incidence of UCNVI was associated with worse baseline UCNVA for all 3 impairment definitions. Similarly, incidence of BCNVI was associated with worse baseline BCNVA, but also with older age and education at the primary level or less. Gender was not significant for either UCNVI or BCNVI. CONCLUSIONS: Approximately half of those aged 35 years or older develop UCNVI in 6 years, the overwhelming majority of whom can be corrected with spectacles. Cost-effective strategies to provide spectacles to this at-risk population remains an issue requiring further study. PMID- 28336061 TI - Enzymes as Sensors. AB - Over the last few decades the development of new technologies, the fabrication of new materials, and the introduction of nanotechnologies created new trends in a series of advances that produced innovations in biological sensing devices with a wide range of application from health, security, defense, food, and medicine, to the environment. Specificity, low cost, rapidity, sensitivity, and multiplicity are some of the reasons for their growth, and their commercial success is expected to increase in the next future. Biosensors are devices in which the recognition part of the target molecule is accomplished by biological macromolecules such as proteins, enzymes, antibodies, aptamers, etc. These biomolecules are able to bind to the target molecules with high selectivity and specificity. The interaction between the target molecule and the specific biomolecule is reflected as a change of the biomolecule structural features. The extent of this change is strictly related to the biosensor response. Fluorescence spectroscopy, due to its sensitivity, is often used as the principal technique to monitor biological interactions, and thus the biosensor response as well. Both the intrinsic ultraviolet fluorescence of protein, arising from aromatic amino acids (tryptophan, tyrosine, and phenylalanine), and extrinsic fluorescent labels emitting in the visible region of the spectrum together allow for very flexible transduction of the analyte recognition, suitable for many different applications. This chapter focuses special attention on enzymes as practically unmatched recognition elements for biosensors and emphasizes the potential advantages of customized biosensor devices using apo- or holo forms of enzymes also isolated from thermophile sources. PMID- 28336064 TI - Novel Fluorescence-Based Biosensors Incorporating Unnatural Amino Acids. AB - Fluorescent proteins of different colors are useful probes to study protein structure and function, and to investigate cellular events and conditions. Large efforts have focused on engineering new properties into fluorescent proteins via rational design and directed evolution. In addition to applications in imaging of protein expression level and subcellular localization, fluorescent proteins have been increasingly engineered to act as biosensors to track concentrations of small-molecule metabolites, enzyme activities, and protein conformational changes in living cells. Unlike small-molecule fluorescence biosensors, fluorescent proteins are genetically encodable, and thus can be expressed inside living cells. Attachment of organelle-specific signals to the proteins allows their localization to be specified. Recently, a new class of fluorescent protein biosensors has been developed to include unnatural amino acids as the sensing element. The unique chemical and physical properties of the unnatural amino acids enable sensor designs that cannot be realized by using the standard genetic code with the 20 canonical amino acids. In this chapter, we detail the general procedure for the genetic incorporation of unnatural amino acids. We further present two protocols for the in vitro and in vivo detection of hydrogen peroxide (H2O2) using a fluorescent protein biosensor that contains an unnatural amino acid, p-boronophenylalanine. PMID- 28336063 TI - Probing Cdc42 Polarization Dynamics in Budding Yeast Using a Biosensor. AB - Cdc42 is a small guanosine triphosphatase (GTPase) that plays a central role in polarity development in diverse cell types. Since the activity of Cdc42 is dynamically controlled in time and space, it is required to develop a biosensor to monitor its activation in vivo. In this chapter, we describe the construction and usage of a simple and robust biosensor for monitoring active Cdc42 in budding yeast. This affinity-based biosensor uses a red fluorescent protein fused to a Cdc42- and Rac-interactive binding motif from one of the Cdc42 effector proteins. Because it binds specifically to the GTP-bound Cdc42, this biosensor can be used to monitor Cdc42 activation in vivo. This or similar biosensors can be widely used for studying GTPase signaling in other cell types because of the conserved CRIB motif present among GTPase targets. PMID- 28336062 TI - Integrated Strategies to Gain a Systems-Level View of Dynamic Signaling Networks. AB - In order to survive and function properly in the face of an ever changing environment, cells must be able to sense changes in their surroundings and respond accordingly. Cells process information about their environment through complex signaling networks composed of many discrete signaling molecules. Individual pathways within these networks are often tightly integrated and highly dynamic, allowing cells to respond to a given stimulus (or, as is typically the case under physiological conditions, a combination of stimuli) in a specific and appropriate manner. However, due to the size and complexity of many cellular signaling networks, it is often difficult to predict how cellular signaling networks will respond under a particular set of conditions. Indeed, crosstalk between individual signaling pathways may lead to responses that are nonintuitive (or even counterintuitive) based on examination of the individual pathways in isolation. Therefore, to gain a more comprehensive view of cell signaling processes, it is important to understand how signaling networks behave at the systems level. This requires integrated strategies that combine quantitative experimental data with computational models. In this chapter, we first examine some of the progress that has recently been made toward understanding the systems level regulation of cellular signaling networks, with a particular emphasis on phosphorylation-dependent signaling networks. We then discuss how genetically targetable fluorescent biosensors are being used together with computational models to gain unique insights into the spatiotemporal regulation of signaling networks within single, living cells. PMID- 28336065 TI - Folding- and Dynamics-Based Electrochemical DNA Sensors. AB - A number of electrochemical DNA sensors based on the target-induced change in the conformation and/or flexibility of surface-bound oligonucleotides have been developed in recent years. These sensors, which are often termed E-DNA sensors, are comprised of an oligonucleotide probe modified with a redox label (e.g., methylene blue) at one terminus and attached to a gold electrode via a thiol-gold bond at the other. Binding of the target to the DNA probe changes its structure and dynamics, which, in turn, influences the efficiency of electron transfer to the interrogating electrode. Since electrochemically active contaminants are less common, these sensors are resistant to false-positive signals arising from the nonspecific adsorption of contaminants and perform well even when employed directly in serum, whole blood, and other realistically complex sample matrices. Moreover, because all of the sensor components are chemisorbed to the electrode, the E-DNA sensors are essentially label-free and readily reusable. To date, these sensors have achieved state-of-the-art sensitivity, while offering the unprecedented selectivity, reusability, and the operational convenience of direct electrochemical detection. This chapter reviews the recent advances in the development of both "signal-off" and "signal-on" E-DNA sensors. Critical aspects that dictate the stability and performance of these sensors are also addressed so as to provide a realistic overview of this oligonucleotide detection platform. PMID- 28336066 TI - Construction of Protein-Based Biosensors Using Ligand-Directed Chemistry for Detecting Analyte Binding. AB - Protein-based fluorescent biosensors are powerful tools for quantitative detection of biomolecules or drugs with high sensitivity under physiological conditions. However, conventional methods for construction of biosensors require structural data with high resolution or amino acid sequence information in most cases, which hampers applicability of this method to structurally complicated receptor proteins. To sidestep such limitations, we recently developed a new method that employs ligand-directed chemistry coupled with a bimolecular fluorescence quenching and recovery system, which enabled the conversion of various kinds of membrane-bound receptors to "turn-on" type fluorescent sensors. Here, we describe a protocol for construction of "turn-on" type fluorescent biosensors based on the GABAA receptor which permits quantitative analysis of the ligand affinity. PMID- 28336067 TI - Measuring and Imaging Metal Ions With Fluorescence-Based Biosensors: Speciation, Selectivity, Kinetics, and Other Issues. AB - Fluorescence-based biosensors have shown themselves to be a powerful tool for the study of a variety of chemical species in biological systems, notably including metal ions. This chapter provides an overview of several important issues in using such sensors to study metallobiochemistry. These issues include selectivity for the analyte over potential interferents, including those that do not themselves induce a signal, the different forms in which metal ions are found (speciation), the utility of metal ion buffers, and the importance of kinetics in studying metal ion binding reactions. Finally, the chapter briefly discusses some of the issues in understanding whole-organism distribution of metal ions and its control. PMID- 28336068 TI - Bioapplications of Electrochemical Sensors and Biosensors. AB - Recent progress in the electrochemical field enabled development of miniaturized sensing devices that can be used in biological settings to obtain fundamental and practical biochemically relevant information on physiology, metabolism, and disease states in living systems. Electrochemical sensors and biosensors have demonstrated potential for rapid, real-time measurements of biologically relevant molecules. This chapter provides an overview of the most recent advances in the development of miniaturized sensors for biological investigations in living systems, with focus on the detection of neurotransmitters and oxidative stress markers. The design of electrochemical (bio)sensors, including their detection mechanism and functionality in biological systems, is described as well as their advantages and limitations. Application of these sensors to studies in live cells, embryonic development, and rodent models is discussed. PMID- 28336069 TI - A Highly Sensitive Biosensor for ATP Using a Chimeric Firefly Luciferase. AB - Firefly luciferases, which emit visible light in a highly specific ATP-dependent process, have been adapted for a variety of applications based on the detection of the enzymes or using the proteins to measure ATP levels. Based on studies of chimeric luciferases, we engineered a novel luciferase called PLG2 that has enhanced specific activity, and thermal and pH stability compared to the commonly used Photinus pyralis luciferase. We present here protocols for preparing a single assay mixture containing PLG2 that can be used to readily detect femtomole levels of ATP. Our methodology can be used with a variety of samples, including human and bacterial cells, where measurements of ATP can be used as a biosensor for the detection of viable cells. PMID- 28336070 TI - Highly Modular Bioluminescent Sensors for Small Molecules and Proteins. AB - Obtaining patient-specific information through the quantification of small molecules and proteins in bodily fluids is essential for personalized therapies. Point-of-care (POC) diagnostic devices hold the promise of delivering such benefit to a wide range of patients. However, there is a lack of enabling technology, as the majority of newly developed POC devices focus on the same underlying core technologies. Here we provide an overview of a new technology based on highly modular bioluminescent sensors that enables the quantification of small molecules and proteins at the POC with low-cost devices. PMID- 28336071 TI - Sensitive Protein Detection and Quantification in Paper-Based Microfluidics for the Point of Care. AB - The design of appropriate diagnostic assays for the point of care requires development of suitable biosensors, detection methods, and diagnostic platforms for sensitive, quantitative detection of biological analytes. Protein targets in particular are especially challenging to detect quantitatively and sensitively due to the lack of amplification strategies akin to nucleic acid amplification. However, recent advances in transducer and biosensor design, new detection labels, and paper-based microfluidics may realize the goal of sensitive, fast, portable, and low-cost protein detection. In this review, we discuss the biochemistry, optics, and engineering advances that may be leveraged to design such a sensitive protein diagnostic assay. The binding kinetics, mechanisms of binding in porous networks, and potential transducers are explained in detail. We discuss the relative merits of various optical detection strategies, potential detection labels, optical readout approaches, and image-processing techniques that are amenable to point-of-care use. To conclude, we present a systematic analysis of potential approaches to enhance the sensitivity of paper-based assays. The assay development framework presented here provides bioassay developers a strategy to methodically enhance the sensitivity and point-of-care suitability of protein diagnostics. PMID- 28336072 TI - Microneedle Enzyme Sensor Arrays for Continuous In Vivo Monitoring. AB - Microneedle enzyme sensors by virtue of their minimally invasive and hence pain free penetration of skin allow for the measurement of metabolites, biomarkers, and drugs in the interstitial fluid that bathes the dermal tissue. Such devices if they are to be adopted widely into clinical practice need to be capable of delivering reliable measurements over extended periods of time (days) and to be fabricated by low-cost, scalable methods. Using injection molding of the base structures in polycarbonate, metal film deposition by sputtering and enzyme immobilization by electrodeposition can meet these requirements. The workflow to produce devices for clinical evaluation is then completed by sterilization and packaging. In vitro evaluation of the sensors' response to varying analyte concentrations and their mechanical testing establish performance and safety characteristics. While most of the work is focused on glucose sensing, reflecting the significance of the global diabetes "epidemic," the microneedles can also be used to measure lactate (another metabolite) and theophylline (a therapeutic drug). PMID- 28336074 TI - Engineering Rugged Field Assays to Detect Hazardous Chemicals Using Spore-Based Bacterial Biosensors. AB - Bacterial whole cell-based biosensors have been genetically engineered to achieve selective and reliable detection of a wide range of hazardous chemicals. Although whole-cell biosensors demonstrate many advantages for field-based detection of target analytes, there are still some challenges that need to be addressed. Most notably, their often modest shelf life and need for special handling and storage make them challenging to use in situations where access to reagents, instrumentation, and expertise are limited. These problems can be circumvented by developing biosensors in Bacillus spores, which can be engineered to address all of these concerns. In its sporulated state, a whole cell-based biosensor has a remarkably long life span and is exceptionally resistant to environmental insult. When these spores are germinated for use in analytical techniques, they show no loss in performance, even after long periods of storage under harsh conditions. In this chapter, we will discuss the development and use of whole cell-based sensors, their adaptation to spore-based biosensors, their current applications, and future directions in the field. PMID- 28336073 TI - Visualization of the Genomic Loci That Are Bound by Specific Multiprotein Complexes by Bimolecular Fluorescence Complementation Analysis on Drosophila Polytene Chromosomes. AB - We have developed a procedure that enables visualization of the genomic loci that are bound by complexes formed by a specific combination of chromatin-binding proteins. This procedure is based on imaging bimolecular fluorescence complementation (BiFC) complexes on Drosophila polytene chromosomes. BiFC complexes are formed by the facilitated association of two fluorescent protein fragments that are fused to proteins that interact with, or are in close proximity to, each other. The intensity of BiFC complex fluorescence at individual genomic loci is greatly enhanced by the parallel alignment of hundreds of chromatids within the polytene chromosomes. The loci that are bound by the complexes are mapped by comparing the locations of BiFC complex fluorescence with the stereotypical banding patterns of the chromosomes. We describe strategies for the design, expression, and validation of fusion proteins for the analysis of BiFC complex binding on polytene chromosomes. We detail protocols for the preparation of polytene chromosome spreads that have been optimized for the purpose of BiFC complex visualization. Finally, we provide guidance for the interpretation of results from studies of BiFC complex binding on polytene chromosomes and for comparison of the genomic loci that are bound by BiFC complexes with those that are bound by subunits of the corresponding endogenous complexes. The visualization of BiFC complex binding on polytene chromosomes provides a unique method to visualize multiprotein complex binding at specific loci, throughout the genome, in individual cells. PMID- 28336076 TI - Preface. PMID- 28336075 TI - Engineering BRET-Sensor Proteins. AB - FRET-sensors have become important tools for intracellular imaging, but their dependence on external illumination presents some limitations, such as photobleaching and phototoxicity, which limit measurements over extended periods of time. Fluorescence measurements also suffer from autofluorescence and light scattering, which hampers in vivo imaging and measurements in strongly absorbing and scattering media such as blood. In principle, these issues can be resolved by using sensors based on bioluminescence resonance energy transfer (BRET). The recent development of brighter and more stable luciferases and the concomitant improvement in luciferase substrates have substantially decreased the sensitivity gap between fluorescence and bioluminescence. As a result, the application of BRET-sensors is no longer restricted to measurements on cell populations, but they can also be used for imaging of single living cells, and BRET has started to emerge as an attractive sensor format for point-of-care diagnostics. The aim of this chapter is to first provide a brief overview of the basic design principles for BRET-sensors. Next, important design considerations will be discussed in more detail by describing the development of three different classes of BRET-sensors, both from our own work and that of others. These examples are all based on the NanoLuc luciferase, a bright and very stable blue light-emitting luciferase developed by Promega that has quickly risen to prominence in the bioluminescence field. PMID- 28336077 TI - Out-of-hospital cardiac arrest: Concise review of strategies to improve outcome. AB - Despite decades of research, cardiac arrest remains a major cause of morbidity and mortality, with frustratingly poor survival rates of approximately 10% to hospital discharge. Various strategies have been shown to improve survival, but differing degrees of implementation have led to a disparity in survival rates. These improvements, however, are balanced against the increasing age of patients presenting with out of hospital cardiac arrest and decreasing incidence of ventricular fibrillation, the rhythm with the best outcome. In this review, we will summarize the most up-to-date literature on key questions in the management pathway and recommend evidence based strategies to improve care. PMID- 28336078 TI - What Is the Negative Predictive Value of Multiparametric Magnetic Resonance Imaging in Excluding Prostate Cancer at Biopsy? A Systematic Review and Meta analysis from the European Association of Urology Prostate Cancer Guidelines Panel. AB - CONTEXT: It remains unclear whether patients with a suspicion of prostate cancer (PCa) and negative multiparametric magnetic resonance imaging (mpMRI) can safely obviate prostate biopsy. OBJECTIVE: To systematically review the literature assessing the negative predictive value (NPV) of mpMRI in patients with a suspicion of PCa. EVIDENCE ACQUISITION: The Embase, Medline, and Cochrane databases were searched up to February 2016. Studies reporting prebiopsy mpMRI results using transrectal or transperineal biopsy as a reference standard were included. We further selected for meta-analysis studies with at least 10-core biopsies as the reference standard, mpMRI comprising at least T2-weighted and diffusion-weighted imaging, positive mpMRI defined as a Prostate Imaging Reporting Data System/Likert score of >=3/5 or >=4/5, and results reported at patient level for the detection of overall PCa or clinically significant PCa (csPCa) defined as Gleason >=7 cancer. EVIDENCE SYNTHESIS: A total of 48 studies (9613 patients) were eligible for inclusion. At patient level, the median prevalence was 50.4% (interquartile range [IQR], 36.4-57.7%) for overall cancer and 32.9% (IQR, 28.1-37.2%) for csPCa. The median mpMRI NPV was 82.4% (IQR, 69.0 92.4%) for overall cancer and 88.1% (IQR, 85.7-92.3) for csPCa. NPV significantly decreased when cancer prevalence increased, for overall cancer (r=-0.64, p<0.0001) and csPCa (r=-0.75, p=0.032). Eight studies fulfilled the inclusion criteria for meta-analysis. Seven reported results for overall PCa. When the overall PCa prevalence increased from 30% to 60%, the combined NPV estimates decreased from 88% (95% confidence interval [95% CI], 77-99%) to 67% (95% CI, 56 79%) for a cut-off score of 3/5. Only one study selected for meta-analysis reported results for Gleason >=7 cancers, with a positive biopsy rate of 29.3%. The corresponding NPV for a cut-off score of >=3/5 was 87.9%. CONCLUSIONS: The NPV of mpMRI varied greatly depending on study design, cancer prevalence, and definitions of positive mpMRI and csPCa. As cancer prevalence was highly variable among series, risk stratification of patients should be the initial step before considering prebiopsy mpMRI and defining those in whom biopsy may be omitted when the mpMRI is negative. PATIENT SUMMARY: This systematic review examined if multiparametric magnetic resonance imaging (MRI) scan can be used to reliably predict the absence of prostate cancer in patients suspected of having prostate cancer, thereby avoiding a prostate biopsy. The results suggest that whilst it is a promising tool, it is not accurate enough to replace prostate biopsy in such patients, mainly because its accuracy is variable and influenced by the prostate cancer risk. However, its performance can be enhanced if there were more accurate ways of determining the risk of having prostate cancer. When such tools are available, it should be possible to use an MRI scan to avoid biopsy in patients at a low risk of prostate cancer. PMID- 28336079 TI - Re: Radiation With or Without Antiandrogen Therapy in Recurrent Prostate Cancer. PMID- 28336080 TI - Re: Mid-term Outcomes After AdvanceXP Male Sling Implantation. PMID- 28336081 TI - Depression screening and treatment recall in male and female coronary artery disease inpatients: Association with symptoms one year later. AB - BACKGROUND: This study examined whether cardiac inpatients recall depression screening and how it is related to depressive symptoms and treatment one year later. METHODS: 2635 cardiac inpatients from 11 hospitals completed a survey and were mailed a follow-up survey one year later; both surveys included the BDI-II. RESULTS: Of the 1809 (68.7%) retained participants, 513 (30.0%) recalled depression screening. Recall was not significantly related to depressive symptoms at either time point (P > 0.05). Participants who were recommended antidepressants had higher BDI-II scores than those who were not, both as inpatients (P < 0.01) and one year later (P < 0.05). There was no significant change in depressive symptoms over time in patients who received any type of therapy. CONCLUSION: Less than one-third of cardiac inpatients recalled being screened for depression. Recall of screening was not significantly related to depressive symptoms, and use of treatment was related to greater symptoms. PMID- 28336082 TI - [Social and health resources in Catalonia. Current situation]. AB - The network of social and health care has advanced since its inception. Furthermore, news services have been created and some resources have been adapted within the framework of respective health plans. This article presents the current situation of the different social and health resources in Catalonia, as well as the main changes that have occurred in recent years, more specifically in the period of the Health Plan 2011-2015. This period is characterised by an adaptation of the social and health network within the context of chronic care, for which the development of intermediate care resources has become the most relevant aspect. There is also a need to create a single long-term care sector in which the health care quality is guaranteed. Moreover, in this period, integral and cross-care level is promoted in the health system through a greater coordination between all different levels of care. The social and health network, due to its trajectory and expertise, plays a key role in the quality of care for people with social and medical needs. PMID- 28336083 TI - Surviving the Intensive Care Units looking through the family's eyes. PMID- 28336084 TI - Propofol-induced non-convulsive epileptic crisis. PMID- 28336085 TI - The dual effect of vegetation green-up date and strong wind on the return period of spring dust storms. AB - Vegetation phenology changes have been widely applied in the disaster risk assessments of the spring dust storms, and vegetation green-up date shifts have a strong influence on dust storms. However, the effect of earlier vegetation green up dates due to climate warming on the evaluation of dust storms return periods remains an important, but poorly understood issue. In this study, we evaluate the spring dust storm return period (February to June) in Inner Mongolia, Northern China, using 165 observations of severe spring dust storm events from 16 weather stations, and regional vegetation green-up dates as an integrated factor from NDVI (Normalized Difference Vegetation Index), covering a period from 1982 to 2007, by building the bivariate Copula model. We found that the joint return period showed better fitting results than without considering the integrated factor when the actual dust storm return period is longer than 2years. Also, for extremely severe dust storm events, the gap between simulation result and actual return period can be narrowed up to 0.4888years by using integrated factor. Furthermore, the risk map based on the return period results shows that the Mandula, Zhurihe, Sunitezuoqi, Narenbaolige stations are identified as high risk areas. In this study area, land surface is extensively covered by grasses and shrubs, vegetation green-up date can play a significant role in restraining spring dust storm outbreaks. Therefore, we suggest that Copula method can become a useful tool for joint return period evaluation and risk analysis of severe dust storms. PMID- 28336086 TI - Incretin hormones regulate microglia oxidative stress, survival and expression of trophic factors. AB - The incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are primarily known for their metabolic function in the periphery. GLP-1 and GIP are secreted by intestinal endocrine cells in response to ingested nutrients. Both GLP-1 and GIP stimulate the production and release of insulin from pancreatic beta cells as well as exhibit several growth regulating effects on peripheral tissues. GLP-1 and GIP are also present in the brain, where they provide modulatory and anti-apoptotic signals to neurons. However, very limited information is available regarding the effects of these hormones on glia, the immune and supporting cells of the brain. Therefore, we set out to resolve whether primary human microglia and astrocytes, two subtypes of glial cells, express the GLP-1 receptor (GLP-1R) and GIP receptor (GIPR), which are necessary to detect and respond to GLP-1 and GIP, respectively. We further tested whether these hormones, similar to their effects on neuronal cells, have growth-regulating, antioxidant and anti-apoptotic effects on microglia. We show for the first time expression of the GLP-1R and the GIPR by primary human microglia and astrocytes. We demonstrate that GLP-1 and GIP reduce apoptotic death of murine BV-2 microglia through the binding and activation of the GLP-1R and GIPR, respectively, with subsequent activation of the protein kinase A (PKA) pathway. Moreover, we reveal that incretins upregulate BV-2 microglia expression of brain derived neurotrophic factor (BDNF), glial cell-line derived neurotrophic factor (GDNF) and nerve growth factor (NGF) in a phosphoinositide 3-kinase (PI3K) and PKA-dependent manner. We also show that incretins reduce oxidative stress in BV-2 microglia by inhibiting the accumulation of intracellular reactive oxygen species (ROS) and release of nitric oxide (NO), as well as by increasing the expression of the antioxidant glutathione peroxidase 1 (GPx1) and superoxide dismutase 1 (SOD1). We confirm these results by demonstrating that GLP-1 and GIP also inhibit apoptosis of primary murine microglia, and upregulate expression of BDNF by primary murine microglia. These results indicate that GLP-1 and GIP affect several critical homeostatic functions of microglia, and could therefore be tested as a novel therapeutic treatment option for brain disorders that are characterized by increased oxidative stress and microglial degeneration. PMID- 28336088 TI - Trends in ADHD medication use in children and adolescents in five western countries, 2005-2012. AB - Over the last two decades, the use of ADHD medication in US youth has markedly increased. However, less is known about ADHD medication use among European children and adolescents. A repeated cross-sectional design was applied to national or regional data extracts from Denmark, Germany, the Netherlands, the United Kingdom (UK) and the United States (US) for calendar years 2005/2006-2012. The prevalence of ADHD medication use was assessed, stratified by age and sex. Furthermore, the most commonly prescribed ADHD medications were assessed. ADHD medication use prevalence increased from 1.8% to 3.9% in the Netherlands cohort (relative increase: +111.9%), from 3.3% to 3.7% in the US cohort (+10.7%), from 1.3% to 2.2% in the German cohort (+62.4%), from 0.4% to 1.5% in the Danish cohort (+302.7%), and from 0.3% to 0.5% in the UK cohort (+56.6%). ADHD medication use was highest in 10-14-year olds, peaking in the Netherlands (7.1%) and the US (8.8%). Methylphenidate use predominated in Europe, whereas in the US amphetamines were nearly as common as methylphenidate. Although there was a substantially greater use of ADHD medications in the US cohort, there was a relatively greater increase in ADHD medication use in youth in the four European countries. ADHD medication use patterns in the US differed markedly from those in western European countries. PMID- 28336087 TI - Dermatopontin augments angiogenesis and modulates the expression of transforming growth factor beta 1 and integrin alpha 3 beta 1 in endothelial cells. AB - Dermatopontin (DPT) is a matricellular protein with cardinal roles in cutaneous wound healing. The protein is also reported to be altered in various anomalies including cancer. The present study is aimed to unravel the role of DPT in angiogenesis which is imperative in many physiological and pathological processes. DPT's capabilities on promoting angiogenesis were assessed using various in vitro and ex vivo systems. The results indicated that DPT enhances cell motility and induces lamellipodia formation in endothelial cells. Additionally, we noticed that DPT stimulates tube formation in endothelial cells when plated on a matrigel substrate. However, it was observed that DPT had no effect on the proliferation of endothelial cells even at higher concentrations and prolonged treatment periods. Additional experiments on CAM and aortic arch assays apparently depicted that DPT promotes neovascularisation and tube sprouting, thus unraveling its prominent role in angiogenesis. Further, PCR analysis revealed that endothelial cells are devoid of DPT expression, but when exogenously supplied, modulates the expression of transforming growth factor beta1 and integrin alpha3beta1 which are reported to have crucial roles in endothelial cell behaviour during angiogenesis. In conclusion, DPT possess vital pro-angiogenic properties and thus retains promising therapeutic values in managing chronic wounds and cancer. PMID- 28336089 TI - Cold Lake Blend diluted bitumen toxicity to the early development of Japanese medaka. AB - Diluted bitumen (dilbit) from Alberta oil sands (Canada) is transported across major continental watersheds, yet little is known about its toxicity to fish if spilled into aquatic environments. The toxicity of Cold Lake (CLB) dilbit was assessed for medaka embryos (Oryzias latipes) exposed to water accommodated fractions (WAF) and chemically-enhanced WAF (CEWAF) using Corexit(r)EC9500A as dispersant. The effects of CLB toxicity were similar to conventional crude oils and Access Western Blend (AWB) dilbit. The prevalence of malformations and cyp1a mRNA synthesis in hatched fish increased monotonically with concentration during WAF and CEWAF treatments and provided a novel indicator of dilbit PAH toxicity. Apart from nfe2 (an antioxidant transcription factor), there were no statistically significant monotonic exposure-responses of ahr, arnt2, cat, sod, gpx, gst, gsr, g6pdh, p53, and hsp70 transcripts at total polycyclic aromatic hydrocarbons (TPAH) concentrations bracketing EC50s for embryotoxicity (WAF ? 3 MUg/L; CEWAF ? 0.1 MUg/L TPAH). Based on measured TPAH concentrations in exposure test solutions, CLB dilbit was 6-10 fold more toxic to medaka than AWB during chronic exposures. Lack of direct monotonic gene transcription responses to increasing oil concentrations during exposures that were embryotoxic suggests that the capacity of the oxidative stress response is limited in earlier lifestages or that differences exist among species in mechanisms of toxicity. This study provides a comparative framework for identifying suitable biomarkers and toxicity methods for those fish species in sensitive lifestages at highest risk of Canadian oil sands dilbit exposure following a spill in the freshwater environment. PMID- 28336090 TI - Trace metal behavior in sediments of Jiulong River Estuary and implication for benthic exchange fluxes. AB - Severe metal pollution due to industrial effluents releases has been documented in Jiulong River estuary, Southern China. However, integrated understanding of trace metal behavior in the sediment is lacking. In the present study, DGT (diffusive gradients in thin films) technique was employed together with sediment cores to study the porewater dynamics of trace metals as well as the benthic exchange fluxes from four sampling sites over three different months. The sedimentary environment showed distinct spatial and temporal variations due to effluent discharge and biological activities. Metal behavior was controlled by early diagenetic reactions below the interface, in suboxic layer and in deeper sediment. Precipitation as sulfides and adsorption onto Mn/Fe (hydr)oxides were important in scavenging trace metals. Estimated exchange fluxes at sediment-water interface in this estuary indicated that the overlying water was a major source for trace metals, whereas sediments could also be the source if surface remobilization (Mn/Fe reduction) dominated. Our results highlighted the impacts of both natural and anthropogenic processes on the source, fate and transformation of trace metals in this dynamic system. PMID- 28336091 TI - Altered cellular metabolism of HepG2 cells caused by microcystin-LR. AB - This study aimed to evaluate the possible effects of microcystin-LR (MC-LR) exposure on the metabolism and drug resistance of human hepatocellular carcinoma (HepG2) cells. For this purpose, we first conducted an experiment to make sure that MC-LR could penetrate the HepG2 cell membrane effectively. The transcriptional levels of phase I (such as CYP2E1, CYP3A4, and CYP26B1) and phase II (such as EPHX1, SULTs, and GSTM) enzymes and export pump genes (such as MRP1 and MDR1) were altered by MC-LR-exposure for 24 h, indicating that MC-LR treatment may destabilize the metabolism of HepG2 cells. Further research showed that the CYP inducers omeprazole, ethanol, and rifampicin inhibited cell viability, in particular, ethanol, a CYP2E1 inducer, induced ROS generation, lipid peroxidation, and apoptosis in HepG2 cells treated with MC-LR. The CYP2E1 inhibitor chlormethiazole inhibited ROS generation, mitochondrial membrane potential loss, caspase-3 activity, and cytotoxicity caused by MC-LR. Meanwhile, the results also showed that co-incubation with the ROS scavenger l-ascorbic acid and MC-LR decreased ROS levels and effectively prevented apoptosis. These findings provide an interesting mechanistic explanation of cellular metabolism associated with MC-LR, i.e., MC-LR-exposure exerted toxicity on HepG2 cells and induced apoptosis of HepG2 cells via promoting CYP2E1 expression and inducing excessive ROS in HepG2 cells. PMID- 28336092 TI - Physiological and biochemical responses of Salix integra Thunb. under copper stress as affected by soil flooding. AB - To explore the joint effect of copper (Cu) and flooding on Salix integra Thunb. (S. integra), the physiological and biochemical parameters of the seedlings grown in Cu amended soil (50, 150, 450 mg kg-1) with or without the flooding for 60 days were evaluated. The results suggested that the flooding significantly inhibited the root growth in terms of root length and root tips. The Cu exposures of 50 and 150 mg kg-1 notably enhanced the root growth as compared to the control. Majority of Cu was accumulated in S. integra roots, while flooding significantly reduced the Cu content, except the 150 mg kg-1 Cu treatment, but the iron (Fe) and manganese (Mn) content on the root surface were both markedly increased relative to non-flooded control. The malonaldehyde (MDA) and glutathione (GSH) contents in leaves showed a dose-response upon Cu exposure. Soil flooding enhanced the GSH level, which displayed 4.50-49.59% increases compared to its respective non-flooded treatment, while no difference was evident on MDA contents between the flooding and the non-flooded treatments. Both superoxide dismutase (SOD) and peroxidase (POD) activities were boosted while the catalase (CAT) was suppressed with increasing Cu exposure dose, and soil flooding reduced the POD and CAT activities. The elevated Cu level caused the evident increases of root calcium (Ca), potassium (K), and sulfur (S) concentrations and decreases of root phosphorus (P), sodium (Na), and zinc (Zn) concentrations. Soil flooding increased the concentrations of Fe, S, Na, Ca, and magnesium (Mg) in S. integra root. Taken together, our results suggested S. integra has high tolerance to the joint stress from Cu and flooding. PMID- 28336093 TI - Concurrent methylation and demethylation of arsenic by fungi and their differential expression in the protoplasm proteome. AB - Microbial methylation and demethylation are central to arsenic's (As) biogeochemical cycling. Here, the transformations of monomethylarsonic acid (MMA(V)) (50 mg L-1) for 15 days in cells of As-methylating fungi, Fusarium oxysporum CZ-8F1, Penicillium janthinellum SM-12F4, and Trichoderma asperellum SM 12F1, were evaluated, and trace concentrations of As(III) and As(V) were observed in fungal cell extracts. Trace amounts of DMA(V) were also detected in MMA(V) and P. janthinellum SM-12F4 incubations. In situ X-ray absorption near edge structure (XANES) indicated that after exposure to MMA(V) (500 mg L-1) for 15 days, 28.6 48.6% of accumulated As in fungal cells was DMA(V), followed by 18.4-30.3% from As(V), 0-28.1% from As(III), and 4.8-28.9% from MMA(V). The concurrent methylation and demethylation of As occurs in fungal cells. Furthermore, a majority of proteins involved in metabolism, transport, ATP activity, biosynthesis, signal transduction, DNA activity, translation, and oxidative stress were upregulated in T. asperellum SM-12F1 cells after MMA(V) exposure compared to As(III), As(V), and DMA(V). The detoxification process of T. asperellum SM-12F1 was As species-specific. Methylenetetrahydrofolate reductase (R7YMH0) donation of a methyl group for S-adenosylmethionine (SAM) generation significantly increased following MMA(V) exposure. PMID- 28336094 TI - Distinct succession patterns of abundant and rare bacteria in temporal microcosms with pollutants. AB - Elucidating the driving forces behind the temporal dynamics of abundant and rare microbes is essential for understanding the assembly and succession of microbial communities. Here, we explored the successional trajectories and mechanisms of abundant and rare bacteria via soil-enrichment subcultures in response to various pollutants (phenanthrene, n-octadecane, and CdCl2) using time-series Illumina sequencing datasets. The results reveal different successional patterns of abundant and rare sub-communities in eighty pollutant-degrading consortia and two original soil samples. A temporal decrease in alpha-diversity and high turnover rate for beta-diversity indicate that deterministic processes are the main drivers of the succession of the abundant sub-community; however, the high cumulative species richness indicates that stochastic processes drive the succession of the rare sub-community. A functional prediction showed that abundant bacteria contribute primary functions to the pollutant-degrading consortia, such as amino acid metabolism, cellular responses to stress, and hydrocarbon degradation. Meanwhile, rare bacteria contribute a substantial fraction of auxiliary functions, such as carbohydrate-active enzymes, fermentation, and homoacetogenesis, which indicates their roles as a source of functional diversity. Our study suggests that the temporal succession of microbes in polluted microcosms is mainly associated with abundant bacteria rather than the high proportion of rare taxa. The major forces (i.e., stochastic or deterministic processes) driving microbial succession could be dependent on the low- or high-abundance community members in temporal microcosms with pollutants. PMID- 28336096 TI - Multigenerational effects of two glucocorticoids (prednisolone and dexamethasone) on life-history parameters of crustacean Ceriodaphnia dubia (Cladocera). AB - Synthetic glucocorticoids (GCs) such as dexamethasone (DEX) and prednisolone (PDS) have been used since the 1940s to cure inflammatory and auto-immune disorders. Their use has been linked to a host of deleterious effects in aquatic ecosystems such as osteoporosis in vertebrates, developmental impairments in molluscs and reduced fecundity and growth in cladocerans. Apart from these handful of studies, the effects of GCs on aquatic biota are largely unknown. The present study is a first of its kind aiming to assess the multi-generational exposure effects of DEX and PDS on the life history parameters of Ceriodaphnia dubia (C. dubia). Multigenerational studies have proved to be an advantage in assessing the cumulative damage caused by aquatic toxicants at the population level of the exposed organisms over a period of successive generations using multiple biological endpoints. Test results demonstrated that C. dubia exhibited varied sensitivities towards both the studied chemicals however were more sensitive to DEX with 48-h EC50 (95% confidence interval) of 0.75 mg/L (CI: 0.59 0.92) in comparison to PDS [19 mg/L (CI: 15-23)]. EC10 values for F0 in a multigenerational chronic bioassays were 48 MUg/L (CI: 37.4-61) for DEX and 460 MUg/L (CI: 341-606) for PDS and in F3 were 2.2 MUg/L (CI: 1.6-3.1) for DEX and 31 MUg/L (CI: 19.4-46) for PDS. There was a positive trend of increased toxicity followed by reduced life history traits such as fecundity, brood size and time to first brood and intrinsic rate of population increase and body growth (length and area) of C. dubia in the case of both studied chemicals. The results from the current work highlighted the importance of multigenerational studies in identifying the evolutionary responses of stressed non-target aquatic organisms, and data obtained can be further used in developing water quality guidelines. PMID- 28336095 TI - Chlorinated pesticides and natural brominated anisoles in air at three northern Baltic stations. AB - Polyurethane foam (PUF) disk passive samplers were deployed at one inland and two island locations in the Bothnian Bay region of the northern Baltic Sea. Uptake was linear over 81-147 d and a temperature range of -2.6 to 14.2 degrees C for organochlorine pesticides (OCPs) and current-use pesticides (CUPs) having log KOA >=9 at ambient temperatures. Partial saturation of the PUF disks occurred for the more volatile OCPs hexachlorocyclohexanes (HCHs) and hexachlorobenzene (HCB), and for bromoanisoles (BAs), which are products of bromophenols released by natural and anthropogenic sources. Correction for nonlinear uptake of these was made using experimentally measured PUF-air partition coefficients. Passive-derived air concentrations of pesticides were uniform over the bay and agreed within a factor of 2 or better with levels determined by active (pumped) sampling at one of the island stations. Levels of OCPs were similar to those reported at background sites in the European and Canadian Arctic and at monitoring stations in the central Baltic and southern Scandinavia, indicating long-range transport. The insecticide chlorpyrifos was 10 times lower at bay stations than in the Canadian Arctic. Insight to sources and processes was gained by examining compound profiles. Fractions Falpha = alpha-HCH/(alpha-HCH + gamma-HCH) and FTC = trans chlordane/(trans-chlordane + cis-chlordane) at bay stations were higher than in the Norwegian and Finnish Arctic and similar to those at the southern monitoring stations. Volatilization of chlordanes from Baltic seawater may also modify FTC. Higher FTriBA = 2,4,6-TriBA/(2,4,6-TriBA + 2,4-DiBA) distinguished local volatilization from the Baltic Sea versus lower FTriBA found at the inland site and reported in air on the Norwegian coast, suggesting westerly transport from the Atlantic across Norway and Sweden. PMID- 28336097 TI - Ranking current and prospective NO2 pollution mitigation strategies: An environmental and economic modelling investigation in Oxford Street, London. AB - Air pollution continues to be a problem in the urban environment. A range of different pollutant mitigation strategies that promote dispersion and deposition exist, but there is little evidence with respect to their comparative performance from both an environmental and economic perspective. This paper focuses on examining different NO2 mitigation strategies such as trees, buildings facades coated with photocatalytic paint and solid barriers in Oxford Street in London. The case study findings will support ranking the environmental and economic impacts of these different strategies to improve personal exposure conditions on the footpath and on the road in a real urban street canyon. CFD simulations of airflow and NO2 dispersion in Oxford Street in London were undertaken using the OpenFOAM software platform with the k-epsilon model, taking into account local prevailing wind conditions. Trees are shown to be the most cost-effective strategy, with a small reduction in NO2 concentrations of up to 0.7% on the road. However, solid barriers with and without the application of photocatalytic paint and an innovative material (20 times more expensive than trees) can improve air quality on the footpaths more substantially, up to 7.4%, yet this has a significant detrimental impact on NO2 concentrations (<=23.8%) on the road. Photocatalytic paint on building surfaces presented a minimal environmental reductions (1.2%) and economic (>100 times more expensive than trees) mitigation strategy. The findings recognised the differences between footpath and road concentrations occurred and that a focused examination of three pollution hotspots can provide more cost effective pollution mitigation. This study considers how a number of pollutant mitigation measures can be applied in a single street canyon and demonstrates the strengths and weaknesses of these strategies from economic and environmental perspectives. Further research is required to extrapolate the findings presented here to different street geometries. PMID- 28336098 TI - Complications of volar locking plating of distal radius fractures in 576 patients with 3.2 years follow-up. AB - BACKGROUND: Volar plating of unstable distal radius fractures (DRF) has become the favoured treatment. The complication rates vary from 3 to 36%. The purpose of the study was to estimate the complication rate of volar plating of DRF and its association with AO/OTA fracture type, surgeon experience and type of volar plate. METHODS: Retrospectively, all patients treated with volar plating of a DRF between February 2009 and June 2013 at Aarhus University Hospital, Denmark were included. AO/OTA fracture type, surgeon experience (1st year, 2nd-5th year resident or consultant), type of plate (VariAx(r), Acu-Loc(r)) and complications were extracted from the electronic medical records. Complications were categorized as carpal tunnel syndrome, other sensibility issues, tendon complications including irritation and rupture, deep infections, complex regional pain syndrome and unidentified DRUJ or scapholunar problems. Reoperations including hardware removal were also charted. RESULTS: 576 patients with a median age of 63 years (min: 15; max: 87) were included. 78% were female and the mean observation time was 3.2 years (min: 2.0; max: 5.4). 78% (n=451) of the patients were treated with VariAx(r) and 22% (n=125) with Acu-Loc(r). The overall complication rate was 14.6% (95% CI 11.8-17.7) including carpal tunnel syndrome or change in sensibility in 5.2% and tendon complications in 4.7%. Five flexor tendon ruptures and 12 extensor tendon ruptures were observed. The reoperation rate was 10.4% including 41 cases of hardware removal. A statistically significant association between AO/OTA fracture type C and complications was found. No statistically significant association between complication rate and surgeon experience and type of plate was observed. CONCLUSION: The majority of DRF patients treated with a volar plate suffer no complications. However, the overall complication rate of 14.6% is substantial. Intra-articular fractures, e.g. AO/OTA-type 23C1-3, had significantly higher complication rates. Neither surgeon experience, nor type of volar plate was able to predict complications. PMID- 28336099 TI - Direct fixation of fractures of the posterior pilon via a posteromedial approach. AB - The treatment of fractures of the posterior pilon is a timely issue. Restoration of the integrity of the incisura fibularis and subsequent anatomic reduction of the fibula are essential for reconstruction of the ankle mortise after trauma, and syndesmotic stability. Inappropriate treatment ultimately will lead to a poor functional outcome and quality of life. Open reduction and direct internal fixation through a posterolateral or posteromedial approach are increasingly preferred over indirect reduction and anteroposterior screw fixation. The posteromedial approach, although elegant, straightforward, and offering an excellent exposure of the fracture site, is used less frequently than the posterolateral approach. In this technical note we describe the posteromedial approach for the treatment of posterior pilon fractures in a step-by-step fashion. We will discuss the indications, its benefits and limitations. PMID- 28336100 TI - In vivo evaluation of the hippocampal glutamate, GABA and the BDNF levels associated with spatial memory performance in a rodent model of neuropathic pain. AB - BACKGROUND: Patients with chronic pain usually suffer from learning and memory impairment which may significantly decrease their quality of life. Despite laboratory and clinical studies, the mechanism underlying this memory impairment remains elusive. We evaluated the effect of chronic pain on the glutamate and GABA levels and BDNF expression in the CA1 region of hippocampus as a possible explanation for memory impairment related to neuropathic pain. METHODS: In this respect, 30 male rats were randomly allocated to 3 groups as control, sham and neuropathic. Neuropathic pain was induced by a chronic constriction injury of the sciatic nerve (CCI) and mechanical allodynia and the spatial memory was assessed using the Von Frey filaments and Morris water maze respectively. To determine the potential mechanisms, the in vivo extracellular levels of glutamate and gamma aminobutyric acid (GABA) were measured by microdialysis and the brain-derived neurotrophic factor (BDNF) expression was determined by using western blots technique in the hippocampus on days 14 and 21 post-CCI. RESULTS: We showed that CCI impaired spatial learning and memory in Morris water maze (MWM) task. BDNF expression level and glutamate concentration significantly decreased in rats with chronic constriction injury of the sciatic nerve (P<0.001, F=7.3, F=23.23). In addition, GABA increased in hippocampal CA1 region (P<0.001, F=39.2) when the pain threshold was minimum. Nevertheless, these changes reversed while pain was relieved spontaneously. CONCLUSION: Chronic pain induced by constriction of the sciatic nerve impairs the spatial learning and memory function in rats. This effect exerts through the increase in GABA concentration and decrease in the glutamate and BDNF levels in the CA1 region of the hippocampus. PMID- 28336101 TI - Metabolic syndrome, hepatic steatosis, and cardiovascular risk in children. AB - OBJECTIVES: Pediatric metabolic syndrome (MetS) is a well-recognized entity; however, there is no consensus on its exact value in predicting long-term cardiovascular (CV) risk. Hepatic steatosis (HS) is another emerging condition associated with pediatric obesity, and data have been reported suggesting a possible role of HS in CV risk linked to MetS. The aim of the present study was to evaluate the usefulness of HS and MetS cluster in predicting CV risk linked to pediatric obesity. METHODS: We studied 803 overweight and obese children (395 girls and 408 boys, mean age 9.4 +/- 2.5 y, body mass index z-score 2.2 +/- 0.53) with complete clinical and biological assessment. MetS was defined using the modified criteria of the American Heart Association. The diagnosis and severity of the HS was based on ultrasound. To assess CV risk, all patients underwent ultrasonography to measure carotid intima-media thickness (cIMT)-a validated marker of subclinical vascular disease. RESULTS: The overall prevalence of MetS was 13.07%; HS was significantly higher in patients with MetS (40.9 versus 18.5%; P < 0.001; odds ratio, 3.059; 95% confidence interval, 1.98-4.7). Spearman's correlation between HS grade and the number of MetS criteria met by each patient was significant (r = 0.285; P < 0.001). No statistical difference was recorded in cIMT and cIMT z-scores between patients with or without MetS, until inclusion of HS as an additional criterion for the diagnosis of MetS. In this case, there was a significant difference in cIMT z-scores between the two groups. In multiple linear regression analysis, the cIMT z-score value was better predicted with HS grade and the MetS cluster (adjusted R2 = 2.6%; P = 0.002) than when using the MetS cluster only. CONCLUSIONS: HS could be used as additional criterion in detecting pediatric MetS phenotype at higher risk for long-term CV morbidity. PMID- 28336102 TI - Influence of gestational diabetes mellitus on fatty acid concentrations in human colostrum. AB - OBJECTIVE: The aim of this study was to examine differences in fatty acid concentrations in colostrum of women with and without gestational diabetes mellitus (GDM). The effect of GDM on fatty acid composition of colostrum is not fully understood, although rates of GDM are increasing globally. METHODS: A prospective case-control study was conducted of postpartum women with and without GDM. Gas chromatographic analysis was conducted to examine differences in colostral fatty acids of the colostrum samples of 29 women with and 34 without GDM. RESULTS: Analyses of the fatty acid composition revealed significantly higher concentrations of four essential omega-6 polyunsaturated fatty acids-gamma linolenic, eicosatrienoic, arachidonic, and docosatetraenoic-in the colostrum of GDM women compared with non-GDM women. Timing of collection influenced saturated medium chain fatty acid and monounsaturated fatty acid levels. CONCLUSIONS: Differences in concentrations of omega-6 fatty acids but not in dietary linoleic fatty acid or omega-3 fatty acids suggest that altered concentrations are attributed to changes in specific endogenous metabolic pathways. Implications of higher concentrations of omega-6 fatty acids in the colostrum of women with GDM have yet to be determined. Timing of colostrum collection is critical in determining colostral fatty acid and metabolite concentrations. PMID- 28336104 TI - Serum 25-hydroxyvitamin D and metabolic syndrome in a Japanese working population: The Furukawa Nutrition and Health Study. AB - OBJECTIVE: Increasing evidence has suggested a protective role of vitamin D on metabolic syndrome (MetS). However, studies addressing this issue are limited in Asia and it remains unclear whether calcium could modify the association. We examined the association of serum 25-hydroxyvitamin D (25(OH)D) status with MetS, and the potential effect modification by calcium intake in a Japanese working population. METHODS: Study subjects were 1790 workers, ages 18 to 69 y, who participated in a health survey at the time of periodic checkup. MetS was defined according to the joint interim statement. Serum 25(OH)D was measured by a protein binding assay. Multilevel logistic regression was used to estimate the odds ratio (OR) with adjustment for potential confounding variables. RESULTS: An inverse trend was observed between 25(OH)D and MetS. Compared with those with a 25(OH)D of <20 ng/mL, multivariable adjusted OR (95% confidence interval) for MetS was 0.79 (0.55-1.15) and 0.52 (0.25-1.04) for those with a 25(OH)D of 20 to 29 ng/mL and >=30 ng/mL, respectively (P for trend = 0.051). Similar association was observed in the analysis using quartile categories of 25(OH)D; the OR in the highest quartile of 25(OH)D compared with the lowest quartile was 0.61 (0.36 1.01) (P for trend = 0.046). This association was noted only in older subjects (>=44 y). The inverse association between serum 25(OH)D and MetS was more pronounced in subjects with high calcium intake. The inverse association between 25(OH)D and MetS appears to be linear according to restricted cubic spline regression. There was inverse, but statistically nonsignificant, associations between 25(OH)D and each component of MetS. CONCLUSION: Our results suggest that higher circulating vitamin D is associated with decreased likelihood of having MetS among Japanese adults. PMID- 28336103 TI - 25-hydroxyvitamin D is differentially associated with calcium intakes of Northern, Central, and Southern European adolescents: Results from the HELENA study. AB - OBJECTIVES: Adolescents in the European Union (EU) exhibit a higher prevalence of vitamin D (VitD) deficiency than other age groups. The degree to which sunlight exposure 25-hydroxyvitamin D [25(OH)D] concentrations depends on a variety of factors, including diet. Nevertheless, the relationship between calcium and VitD intake and 25(OH)D concentrations has not been previously studied among adolescents living in different EU countries and consequently in different latitudes. Therefore, the aim of this study was to examine whether calcium and VitD intakes are differentially associated with 25(OH)D in adolescents from northern, central and southern EU countries. METHODS: The present analysis included 178 adolescents from northern EU countries, 251 from central EU countries, and 212 from southern EU countries (ages 12.5-17.5 y). Mixed model linear regression analyses stratified by geographic location were used to verify associations between calcium and VitD intake and 25(OH)D concentrations. Age, Tanner stage, seasonality, energy intake, and supplement use were entered as covariates. RESULTS: Only the calcium intake of central EU adolescents was positively associated with 25(OH)D (alpha = 0.005; 95% confidence interval, 0.007 0.028). CONCLUSIONS: Further longitudinal studies should confirm these observations, as this could be important for future public health interventions aiming to increase 25(OH)D concentrations in adolescents. PMID- 28336105 TI - Tolerance and efficacy of a polyamine-deficient diet for the treatment of perioperative pain. AB - BACKGROUND: Polyamines have been identified as pain agonists and interact with N methyl-D-aspartate receptors. A prospective, randomized, multicenter, and blinded phase II clinical trial was conducted to evaluate a polyamine-deficient diet for the treatment of perioperative pain in patients during spinal surgery. METHODS: All analyses followed the intention-to-treat principle. The trial was designed to evaluate the dose-ranging effect of a low polyamine diet with respect to a total (group 1) or partial (group 2) polyamine diet on perioperative pain (7 d before and 5 d after surgery). Pain (numerical scale at rest and motion), quality of life questionnaires (Brief Pain Inventory, EIFEL questionnaire, and Short Form-12 acute questionnaire), and tolerance of and compliance with the nutritional program were measured. RESULTS: Compliance (preoperatively: 100% in group 1 and 83% in group 2; postoperatively: 83% in group 1 and 71% in group 2) and tolerance were good. After 7 d following the diet before surgery, decreased pain was observed in group 1 whereas no effect was observed in group 2 (P = 0.144). This analgesic effect became significant in group 1 in the subgroup of patients with initial high levels of pain (NS >= 4) at rest (P = 0.03) and during motion (P = 0.011). Quality of life was significantly improved in group 1 (P = 0.0465). In the postoperative period, pain was significantly decreased in group 1 compared to group 2 at rest (P = 0.022) and during motion (P = 0.029). The effect was significantly better on patients with higher initial pain both at rest (P = 0.013) and during motion (P = 0.005) in group 1 compared to group 2. CONCLUSION: Suppression of polyamines from the diet offers a nutrition-based treatment option for perioperative pain reduction independent of and complementary to typical analgesic approaches. PMID- 28336106 TI - Nomogram for predicting oral feeding intolerance in patients with acute pancreatitis. AB - OBJECTIVES: Oral feeding intolerance (OFI) is a common complication of acute pancreatitis that leads to prolonged hospitalization, increased use of hospital resources, and impaired quality of life. However, there are no clinically useful predictors of OFI. The aims of this study were to determine whether gastrointestinal dysmotility is associated with the development of OFI, and whether the gastroparesis cardinal symptom index (GCSI) can be used as a predictive tool in a clinical setting. METHODS: This was a prospective cohort study. The primary outcome was the development of OFI. Daily GCSI total score and subscores (nausea/vomiting, early satiety, and bloating) were recorded. Univariate and multivariate binary logistic regression analyses were conducted, adjusting for age, etiology of pancreatitis, severity, diabetes status, and time from symptom onset to hospital admission. RESULTS: The study included 217 consecutive adult patients with acute pancreatitis. Multivariate analyses showed significant associations between OFI occurrence and the total GCSI score on day 2 of hospital admission (odds ratio [OR], 1.42; 95% confidence interval [CI], 1.02 2.00), the highest total GCSI score (OR, 1.38; 95% CI, 1.03-1.86), the day 2 nausea/vomiting subscore (OR, 1.40; 95% CI, 1.04-1.89), the day 2 bloating subscore (OR, 1.25; 95% CI, 1.01-1.54), and the highest bloating subscore (OR, 1.32; 95% CI, 1.08-1.63). CONCLUSIONS: Gastrointestinal dysmotility is associated with the development of OFI and the GCSI has potential as a clinically useful predictive tool in the setting of acute pancreatitis. The developed nomogram holds promise but needs to be validated externally. PMID- 28336107 TI - Enriched enteral nutrition may improve short-term survival in stage IV gastric cancer patients: A randomized, controlled trial. AB - OBJECTIVE: The aim of the study was to determine whether the postoperative use of enteral nutrition enriched with arginine, glutamine, and omega-3 fatty acids influences survival in patients diagnosed with stomach cancer. For the purpose of the study, the second wave of the trial performed in 2003 to 2009 was done. METHODS: Ninety-nine patients who underwent surgery for gastric cancer (27 F, 72 M, mean age: 62.9 y) met the inclusion criteria. Of those, 54 were randomized to standard and 45 to enriched enteral nutrition (EEN). In all patients, short- and long-term (5 y) survival was analyzed. RESULTS: Analysis of the overall survival time did not reveal differences between groups (P = 0.663). Until the end of the third month, however, there were nine deaths in the standard enteral nutrition group and no deaths in the EEN group (16.7% versus 0.0%, P = 0.004). The univariate analyses suggested that the EEN group may have lower risk, especially during the first year after intervention. A significant reduction in the risk of death was seen during the early period after surgery (first 6 mo) in the EEN group in stage IV patients (hazard ratio = 0.25, P = 0.049). The use of enriched enteral diet did not influence, however, the risk of dying when patients were analyzed together. CONCLUSIONS: The study does not support the beneficial effect of enriched enteral nutrition in long-term survival; however, the positive impact on the stage IV patients suggests the need for further, more detailed studies. PMID- 28336108 TI - Vitamin D increases PPARgamma expression and promotes beneficial effects of physical activity in metabolic syndrome. AB - OBJECTIVES: Peroxisome proliferator-activated receptor (PPAR) and vitamin D signaling pathways regulate a multitude of genes involved in different physiological functions. The aim of the present study was to examine the effects of vitamin D supplementation and aerobic training on metabolic syndrome and PPARgamma expression. METHODS: Forty female ovariectomized rats were divided into five groups of aerobic training with high (OVX + Exe + HD), moderate (OVX + Exe + MD), and low dose of vitamin D (OVX + Exe + LD), aerobic training receving vehicle (sesame oil; OVX + Exe + oil), and sham-operated control (sham) groups. After 2 mo of treatment, serum insulin, vitamin D, glucose, lipid profile, visceral fat, and liver PPARgamma gene expression were measured. RESULTS: The combination of exercise and high doses of vitamin D significantly reduced insulin (P = 0.039), blood glucose (P = 0.024), and homeostatic model assessment for insulin resistance (P = 0.011), and elevated PPARgamma gene expression (P = 0.032). Also, treatment with aerobic training and either high or moderate vitamin D, ameliorated overall metabolic syndrome Z scores (P = 0.001). CONCLUSION: Findings from the present study suggested that a sedentary lifestyle and vitamin D deficiency accelerated the occurrence of metabolic syndrome probably by decreasing the expression of nuclear receptor PPARgamma. Additionally, adequate levels of plasma vitamin D are necessary to achieve the beneficial metabolic effects of physical activity. PMID- 28336109 TI - Multivitamin/mineral supplements: Rationale and safety. AB - Multivitamin/mineral supplements (MVMs) are widely used in many populations. MVMs, together with iron and folic acid, are recommended for pregnant women to improve birth outcome and to reduce low-birthweight and rates of miscarriage. However, MVM use is common in the general population as well. The aim of the present review was to evaluate the safety of long-term use of these supplements. To examine the safety of MVM use, we performed a literature search for randomized controlled studies involving supplementation with a combination of at least nine vitamins and three minerals at a maximum concentration of 100% of the Recommended Dietary Allowance. We found nine studies evaluating the use and efficacy of MVMs in pregnant women and healthy adults and six studies in the elderly where adverse effects were explicitly addressed. Only minor adverse events (e.g., unspecific gastrointestinal symptoms) were reported in all studies. In particular, there were no significant differences between treatment and placebo groups. MVM use within the range of the Dietary Reference Intake will not result in excess intake, even when including the effect of food and fortified food, and does not increase mortality. Taken together, these findings indicate that MVMs can be safe for long-term use (>10 y). PMID- 28336110 TI - Patient-Generated Subjective Global Assessment as a prognosis tool in patients with multiple myeloma. AB - OBJECTIVE: Disease-related weight loss is relatively common in patients with newly diagnosed multiple myeloma (MM), but limited data exist regarding the effects of nutritional status on survival. The aim of this study was to assess the relationship between malnutrition (as measured by Patient-Generated Subjective Global Assessment [PG-SGA]) and clinical characteristics of patients with MM, and to investigate the association between the PG-SGA score before chemotherapy and overall survival in MM patients. METHODS: Using the PG-SGA score, we retrospectively explored the effect of malnutrition on the survival of Asian patients with MM. RESULTS: We divided 216 patients with MM into three groups based on their PG-SGA scores. Of these patients 23% (n = 50) had PG-SGA scores >=9, indicating severe malnutrition requiring specialist nutrition intervention. Body mass index and serum hemoglobin were independently associated with PG-SGA scores (P < 0.05). The median survival time was not reached in nourished patients with PG-SGA scores of 0 to 3, 58.7 mo in moderately malnourished patients with PG-SGA scores of 4 to 8, and 35 mo in severely malnourished patients with PG-SGA scores >=9 (P = 0.001). Multivariate analysis revealed that PG-SGA scores >=9 compared with PG-SGA scores of 0 to 3 (hazard ratio [HR], 2.347; 95% confidence interval [CI], 1.271-4.334; P = 0.006), International Staging System (ISS) stage III compared with ISS stage I (HR, 2.360; 95% CI, 1.271-4.379; P = 0.007), and autologous stem cell transplantation (HR, 0.388; 95% CI, 0.248-0.606; P < 0.001) were associated with overall survival. CONCLUSIONS: A higher PG-SGA score before chemotherapy was associated with reduced survival among patients with MM. Nutritional evaluation should be an integral part of the clinical assessment of MM patients, and the PG-SGA score would be an appropriate tool to evaluate nutritional status. PMID- 28336111 TI - Hepatoprotective effects of curcumin in rats after bile duct ligation via downregulation of Rac1 and NOX1. AB - OBJECTIVES: New evidence has proven the hepatoprotective activity of curcumin; however, its underlying mechanisms remain to be elucidated. The aim of this study was to investigate the protective effect of curcumin on hepatic damage by measuring the antioxidant capacity and expression level of Rho-related C3 botulinum toxin substrate (Rac1), Rac1-Guanosine triphosphate (Rac1-GTP), and NADPH oxidase 1(NOX1) in biliary duct-ligated (BDL)-fibrotic rat model. METHODS: Wistar rats weighing 200 to 250 g were divided into four groups (n = 8 for each): sham group, sham+Cur group (received curcumin 100 mg/kg daily), BDL+Cur group, and BDL group. The mRNA and protein expression levels of Rac1, Rac1-GTP, and NOX1 were measured by real-time polymerase chain reaction and Western blotting, respectively. RESULTS: Curcumin treatment of BDL rats reduced liver injury, as verified by improvement of hepatic cell histologic alterations, and by reduction of hepatic enzymes. Moreover, the increase in the expression of Rac1, Rac1-GTP, and NOX1 observed in BDL rats was precluded and reversed back toward normalcy by curcumin treatment (P < 0.05). We also observed an escalation of protein thiol groups, increased enzyme activity of serum antioxidant markers (e.g., superoxide dismutase) and a decrease of carbonylation in curcumin-treated BDL rats compared with BDL rats (P < 0.05). CONCLUSIONS: Curcumin attenuated liver damage through the downregulation of Rac1, Rac1-GTP, and NOX1 as well as reduced oxidative stress in the serum and liver tissue of BDL rats. PMID- 28336112 TI - Evaluation of daily ginger consumption for the prevention of chronic diseases in adults: A cross-sectional study. AB - OBJECTIVES: The aim of this study was to assess daily ginger consumption and explore its correlation with chronic diseases among adults and to analyze further how different levels of ginger intake affect the prevalence of chronic diseases. METHODS: We examined the prevalence rate of chronic diseases (diabetes, hypertension, coronary heart disease [CHD], hyperlipidemia, cerebrovascular disease, fatty liver, anemia, and tumor), as well as the daily ginger intake in a large cross-sectional study. In all, 4628 participants (1823 men and 2805 women) ages 18 to 77 y completed face-to-face dietary and health questionnaires. We extracted diagnoses and investigation results from the participants' health records. The association between the level of ginger intake (0-2 g/d, 2-4 g/d, and 4-6 g/d) and the prevalence of chronic diseases was analyzed by using chi2 statistical test and unconditional logistic model. RESULTS: Overall, daily ginger consumption was associated with decreased risk for hypertension (odds ratio [OR], 0.92; 95% confidence interval [CI], 0.86-0.98) and CHD (OR, 0.87; 95% CI, 0.78 0.96) in adults ages >=18 y. Differences were also observed in adults ages >=40 y: hypertension (OR, 0.92; 95% CI, 0.87-0.99), CHD (OR, 0.87; 95% CI, 0.78-0.97). However, after 20 y, no association was seen for hypertension but there was still a difference between ginger consumption and CHD in adults ages >=60 y (OR, 0.84; 95% CI, 0.73-0.96). Again, the probability of illness (hypertension or CHD) decreased when the level of daily ginger intake increased. CONCLUSIONS: These data indicate that ginger has a potential preventive property against some chronic diseases, especially hypertension and CHD, as well as its ability to reduce the probability of illness. PMID- 28336114 TI - Paradoxical aortic stenosis: A systematic review. AB - Aortic stenosis (AS) is a complex systemic valvular and vascular disease with a high prevalence in developed countries. The new entity "paradoxical low-flow, low gradient aortic stenosis" refers to cases in which patients have severe AS based on assessment of aortic valve area (AVA) (<=1 cm2) or indexed AVA (<=0.6 cm2/m2), but paradoxically have a low mean transvalvular gradient (<40 mmHg) and a low stroke volume index (<=35 ml/m2), despite preserved left ventricular ejection fraction (>=50%). A search was carried out in the PubMed database on paradoxical AS for the period 2007-2014. A total of 57 articles were included for this review. The prevalence of paradoxical AS ranged from 3% to 35% of the population with severe degenerative AS. It was more frequent in females and in older patients. Paradoxical AS was associated with characteristic left ventricular remodeling as well as an increase in systemic arterial stiffness. It was noted that there may be errors and inaccuracies in the calculation of AVA by the continuity equation, which could erroneously suggest the paradoxical phenotype. There are new diagnostic methods to facilitate the study of AS, such as aortic valve calcium score, valvuloarterial impedance and the longitudinal mechanics of the left ventricle. With regard to its natural history, it is not clear whether paradoxical AS corresponds to an advance stage of the disease or if paradoxical AS patients have a distinct phenotype with specific characteristics. Valve replacement, either surgical or percutaneous, may be indicated in patients with severe and symptomatic paradoxical AS. PMID- 28336113 TI - Effect of branched-chain amino acid ratio on the proliferation, differentiation, and expression levels of key regulators involved in protein metabolism of myocytes. AB - OBJECTIVES: Branched-chain amino acids (BCAAs), including leucine (Leu), isoleucine (Ile), and valine (Val), are key regulators of protein synthesis in muscle. The aim of this study was to investigate the effect of different BCAA ratios (Leu:Ile:Val) on the proliferation, differentiation, and expression levels of the regulators related to protein metabolism of C2 C12 myocytes. METHODS: Studies were conducted in C2C12 myocytes exposed to different BCAA ratios (Leu: Ile: Val = 0, 1:0.25:0.25, 1:1:1). RESULTS: The ratio of 1:0.25:0.25 increased cell viability and promoted cell cycle progression from G0/G1 phase to S phase, which was an indicator of proliferation enhancement (P < 0.05). Moreover, this optimal ratio (1:0.25:0.25) promoted the differentiation of myocytes into myotubes by upregulating myogenin and interleukin-15 gene expression, and differently regulated the expression of L-type amino acid transporter 1 and 4 and system ASC amino acid transporters 2. Furthermore, the ratio stimulated mTOR expression at the mRNA and phosphorylated protein levels, as well as ribosomal protein S6 kinase and regulatory-associated protein of mTOR (raptor). In contrast, the optimal ratio decreased the amount of ubiquitin ligase muscle specific RING finger 1 and muscle atrophy F-box during proliferation and differentiation (P < 0.05). No change was observed in the expression of key genes related to energy metabolism except for uncoupling protein 3 (P > 0.05). CONCLUSIONS: The results suggested that appropriate BCAA ratios could enhance proliferation and differentiation of the C2 C12 myocytes, also mediate the key regulators related to protein metabolism including the mTORC1 pathway. A proper utilization of balanced BCAA ratio in food would be beneficial to human and animal nutrition. PMID- 28336115 TI - Anomalous pulmonary venous connection: An underestimated entity. PMID- 28336117 TI - Moraxella catarrhalis meningitis during certolizumab pegol treatment. PMID- 28336116 TI - Purulent pericarditis by Staphylococcus Panton-Valentine secondary to hair implants. PMID- 28336119 TI - Intestinal obstruction due to olive. PMID- 28336118 TI - Anticoagulation quality control in Primary Care with vitamin K antagonists. PMID- 28336120 TI - Spontaneous severe hemoperitoneum in peritoneal dialysis patients. PMID- 28336121 TI - Septic arthritis due to Klebsiella oxytoca. PMID- 28336122 TI - Familial acute necrotizing encephalopathy with RANBP2 mutation: The first report in Northeast Asia. AB - BACKGROUND: Acute necrotizing encephalopathy (ANE) is a rare but rapidly progressing encephalopathy following a febrile illness, commonly a viral infection. It is characterized by the features of acute encephalopathy such as seizure, alteration of consciousness, and symmetric involvement of the bilateral thalamus on neuroimaging tests. Although most ANE cases have occurred sporadically, familial or recurrent ANE has been reported in Caucasian patients, with genetic susceptibility to ANE noted in some patients due to a RANBP2 mutation. We report the cases of two Korean siblings with typical ANE and RANBP2 mutation. CASE REPORT: A 2year-old Korean girl presented with prolonged seizures and encephalopathy after two days of febrile illness. Brain computed tomography (CT) showed diffuse brain swelling and low attenuation in the bilateral thalamus. Two months later, her younger sister presented with lethargy and flurries of seizures after a Mycoplasma pneumoniae infection. Brain magnetic resonance imaging scan (MRI) showed a characteristic involvement of the bilateral thalamus, suggesting ANE. Although they received intravenous steroids and immunoglobulin, the older child died; her sister remained in a coma. Both were diagnosed with familial ANE after identifying a common missense mutation in RANBP2 (c.1754C>T: p.Thr585Met) in the younger sister and their father. CONCLUSIONS: This report is the first case of familial ANE in Northeast Asia identifying a RANBP2 mutation with poor outcome. Due to rapidly deterioration and recurrent nature of familial ANE, genetic test of RANBP2 mutation should be considered for early diagnosis. Further studies are needed to elucidate the nature of ANE. PMID- 28336123 TI - Yellow fever outbreak in Brazil, 2017. PMID- 28336124 TI - Ultraviolet B inhibition of DNMT1 activity via AhR activation dependent SIRT1 suppression in CD4+ T cells from systemic lupus erythematosus patients. AB - BACKGROUND: Previous studies have reported that ultraviolet B (UVB) inhibits DNA methyltransferase1 (DNMT1) activity in CD4+ T cells from systemic lupus erythematosus (SLE) patients. Silent mating type information regulation 2 homolog 1 (SIRT1) is a type of Class III histone deacetylases (HDACs), and has been reported to play roles in the pathogenesis of different autoimmune diseases and can modulate DNMT1 activity. Moreover, aryl hydrocarbon receptor (AhR) has been reported to link UVB with SLE. However, the exact mechanisms by which DNMT1 activity is inhibited by UVB in lupus CD4+ T cells remain largely unknown. OBJECTIVE: To elucidate the exact mechanisms by which DNMT1 activity is inhibited by UVB in lupus CD4+ T cells. METHODS: Twenty-two newly diagnosed active SLE patients and 30 healthy controls were enrolled in the study. CD4+ T cells were isolated, cultured and treated. DNMT1 activity assay, quantitative real-time PCR (qRT-PCR), Western blotting, RNA interference using small interfering RNA and Chromatin Immunoprecipitation (ChIP) assay were employed. RESULTS: DNMT1 activity was inhibited in si-SIRT1-transfected CD4+ T cells, and increased by the established SIRT1 activator, SRT1720. Moreover, the mRNA and protein expression of SIRT1 were suppressed by UVB exposure in lupus CD4+ T cells. UVB-inhibited DNMT1 activity was reversed by SRT1720 in si-control-transfected lupus CD4+ T cells, but not in si-SIRT1-transfected lupus CD4 + T cells. Furthermore, AhR activation by VAF347 reduced the mRNA and protein expression of SIRT1. ChIP using an antibody against AhR in normal CD4+ T cells revealed a 16-fold stronger signal at the site about 1.6kb upstream from the translation start site of the SIRT1 promoter. Finally, UVB could activate AhR and inhibit the mRNA and protein expression of SIRT1. AhR knockdown abrogated the inhibition of UVB-mediated SIRT1 mRNA and protein expression and DNMT1 activity in lupus CD4+ T cells. CONCLUSION: UVB suppressed SIRT1 expression via activating AhR, and subsequently inhibited DNMT1 activity in CD4+ T cells from SLE patients. PMID- 28336125 TI - Differences in short and long-term survival between males and females with new onset heart failure: A retrospective cohort study. PMID- 28336126 TI - Epidemiology of cystic fibrosis-related diabetes in Madrid (Spain) and frequency of hospitalization. PMID- 28336127 TI - Commitment to life and the right to die. PMID- 28336128 TI - Retinal pigment epithelium tears: Classification, pathogenesis, predictors, and management. AB - Various eye conditions cause tears in the retinal pigment epithelium (RPE). The most common cause of a RPE tear is vascularized retinal pigment epithelial detachment (PED) in patients with exudative age-related macular degeneration. Although RPE tears can develop spontaneously in vascularized PEDs, most recent cases have been associated with anti-vascular endothelial growth factor (VEGF) injections. The subretinal fluid within the PED applies hydrostatic pressure to the RPE and stretches it. The PED enlarges as the hydrostatic pressure increases. Contraction of the choroidal neovascular membrane adds tractional forces to the RPE monolayer. Especially in larger PEDs, the risk of a RPE tear increases after anti-VEGF therapy owing to increasing contraction of the choroidal neovascular membrane. The risk factors and predictors defined by retinal imaging can contribute to prevention of RPE tears, and modified therapies can be used for patients at most risk; however, there is no proven method for prevention of RPE tears. After tear formation, in the presence of an active choroidal neovascular membrane, anti-VEGF should be repeated until the underlying disease has been suppressed. When the subretinal fluid is present for more than 6 months, the denuded area is covered with thickened fibrotic tissue. We review the literature to describe the classification, epidemiology, mechanisms of development, and repair of RPE tears, diagnosis, risk factors and predictors, prevention, and management. PMID- 28336129 TI - Labile iron potentiates ascorbate-dependent reduction and mobilization of ferritin iron. AB - Ascorbate mobilizes iron from equine spleen ferritin by two separate processes. Ascorbate alone mobilizes ferritin iron with an apparent Km (ascorbate) ~1.5mM. Labile iron >2MUM, complexed with citrate (10mM), synergises ascorbate-dependent iron mobilization by decreasing the apparent Km (ascorbate) to ~270MUM and raising maximal mobilization rate by ~5-fold. Catalase reduces the apparent Km(ascorbate) for both ascorbate and ascorbate+iron dependent mobilization by ~80%. Iron mobilization by ascorbate alone has a higher activation energy (Ea=45.0+/-5.5kJ/mole) than when mediated by ascorbate with labile iron (10MUM) (Ea=13.7+/-2.2kJ/mole); also mobilization by iron-ascorbate has a three-fold higher pH sensitivity (pH range 6.0-8.0) than with ascorbate alone. Hydrogen peroxide inhibits ascorbate's iron mobilizing action. EPR and autochemiluminescence studies show that ascorbate and labile iron within ferritin enhances radical formation, whereas ascorbate alone produces negligible radicals. These findings suggest that iron catalysed single electron transfer reactions from ascorbate, involving ascorbate or superoxide and possibly ferroxidase tyrosine radicals, accelerate iron mobilization from the ferroxidase centre more than EPR silent, bi-dentate two-electron transfers. These differing modes of electron transference from ascorbate mirror the known mono and bidentate oxidation reactions of dioxygen and hydrogen peroxide with di-ferrous iron at the ferroxidase centre. This study implies that labile iron, at physiological pH, complexed with citrate, synergises iron mobilization from ferritin by ascorbate (50-4000MUM). This autocatalytic process can exacerbate oxidative stress in ferritin-containing inflamed tissue. PMID- 28336130 TI - Organizers and activators: Cytosolic Nox proteins impacting on vascular function. AB - NADPH oxidases of the Nox family are important enzymatic sources of reactive oxygen species (ROS) in the cardiovascular system. Of the 7 members of the Nox family, at least three depend for their activation on specific cytosolic proteins. These are p47phox and its homologue NoxO1 and p67phox and its homologue NoxA1. Also the Rho-GTPase Rac is important but as this protein has many additional functions, it will not be covered here. The Nox1 enzyme is preferentially activated by the combination of NoxO1 with NoxA1, whereas Nox2 gains highest activity with p47phox together with p67phox. As p47phox, different to NoxO1 contains an auto inhibitory region it has to be phosphorylated prior to complex formation. In the cardio-vascular system, all cytosolic Nox proteins are expressed but the evidence for their contribution to ROS production is not well established. Most data have been collected for p47phox, whereas NoxA1 has basically not yet been studied. In this article the specific aspects of cytosolic Nox proteins in the cardiovascular system with respect to Nox activation, their expression and their importance will be reviewed. Finally, it will be discussed whether cytosolic Nox proteins are suitable pharmacological targets to tamper with vascular ROS production. PMID- 28336131 TI - Modulating the DNA Damage Response to Improve Treatment Response in Cervical Cancer. AB - Cervical cancer is the fourth most common cause of cancer-related death in women worldwide and new therapeutic approaches are needed to improve clinical outcomes for this group of patients. Current treatment protocols for locally advanced and metastatic disease consist of ionising radiation and chemotherapy. Chemoradiation induces cytotoxic levels of DNA double-strand breaks, which activates programmed cell death via the DNA damage response (DDR). Cervical cancers are unique given an almost exclusive association with human papillomavirus (HPV) infection; a potent manipulator of the DDR, with the potential to alter tumour sensitivity to DNA-damaging agents and influence treatment response. This review highlights the wide range of therapeutic strategies in development that have the potential to modulate DDR and sensitise cervical tumours to DNA-damaging agents in the context of HPV oncogenesis. PMID- 28336132 TI - Complete genome sequence of sequential Pandoraea apista isolates from the same cystic fibrosis patient supports a model of chronic colonization with in vivo strain evolution over time. AB - Pandoraea apista in the family Burkholderiaceae is an emerging opportunistic pathogen in cystic fibrosis patients. Here, we describe a case from which 3 separate isolates of P. apista were recovered over a 1-year period. Using a combination of first-, second-, and third-generation sequencing technologies, we sequenced and de novo assembled the complete genomes of these 3 P. apista isolates. The genome of P. apista TF81F4 sequenced in this study was 5.58 Mb with a GC% of 62.3%, differed in sequence from other Pandoraea species by >20%, and included a number of previously undescribed loci. Three P. apista isolates cultured over a 12-month period were >99.999% identical by nucleotide, consistent with a model of chronic colonization by a single strain. Over time, the isolates accumulated point mutations, deletions, and insertions in a stepwise fashion, indicating in vivo strain evolution within the cystic fibrosis lung niche. PMID- 28336133 TI - Comparison of Cobas(r) HPV and AnyplexTM II HPV28 assays for detecting and genotyping human papillomavirus. AB - Persistent infection with high-risk human papillomavirus (HPV-HR) is a recognized cause of cervical cancer. The aim of this study was to compare analytical and clinical performances of the Cobas(r) HPV and AnyplexTM II HPV28 assays for HPV detection and genotyping. A total of 94 cervical samples were tested. For HPV-HR, the results agreed very well (94.68%), with 100% agreement when detecting CIN2+. The AnyplexTM II HPV28 assay detected more genotypes than the Cobas(r) HPV Test, but their clinical performances were similar. PMID- 28336134 TI - Evaluation of matrix-assisted laser desorption/ionization time-of-fight mass spectrometry for identification of 345 clinical isolates of Aspergillus species from 11 Korean hospitals: comparison with molecular identification. AB - We evaluated the ability of the Filamentous Fungi Library 1.0 of the MALDI-TOF MS Biotyper system to identify 345 clinical Aspergillus isolates from 11 Korean hospitals. Compared with results of the internal transcribed spacer region sequencing, the frequencies of correct identification at the species-complex level were 94.5% and 98.8% with cutoff values of 2.0 and 1.7, respectively. Compared with results of beta-tubulin gene sequencing, the frequencies of correct identification at the species level were 96.0% (cutoff 2.0) and 100% (cutoff 1.7) for 303 Aspergillus isolates of five common, non-cryptic species, but only 4.8% (cutoff 1.7) and 0% (cutoff 2.0) for 42 Aspergillus isolates of six cryptic species (identifiable by beta-tubulin or calmodulin sequencing). These results show that the MALDI Biotyper using the Filamentous Fungi Library version 1.0 enables reliable identification of the majority of common clinical Aspergillus isolates, although the database should be expanded to facilitate identification of cryptic species. PMID- 28336135 TI - High prevalence of non-clonal imipenem-nonsusceptible Enterobacter spp. isolates in Korea and their association with porin down-regulation. AB - We investigated the prevalence and clonal distribution of imipenem-nonsusceptible Enterobacter clinical isolates from hospitals in Korea and the contributions of various mechanisms to imipenem nonsusceptibility. The in vitro antimicrobial susceptibility to imipenem of 357 non-duplicated Enterobacter isolates obtained from eight geographically distant tertiary care hospitals in Korea was evaluated. Imipenem-nonsusceptible Enterobacter isolates were genotyped. Additionally, beta lactamase genes were screened using PCR, and the expression of efflux pump and porin genes was investigated using quantitative RT-PCR. A total of 31 isolates (8.7%) were not susceptible to imipenem. Clonal diversity of 17 imipenem nonsusceptible E. cloacae isolates was demonstrated by multilocus sequence typing. Fourteen imipenem-nonsusceptible E. aerogenes isolates were found to be distantly genetically related by an ERIC-PCR analysis. Expression levels of porin ompD and ompK35 genes were decreased in all imipenem-nonsusceptible E. cloacae and E. aerogenes isolates. However, only two isolates were found positive for blaIMP and blaVIM genes, and expression of the efflux pump gene, acrB, was not associated with reduced imipenem susceptibility. Imipenem resistance seems to have occurred independently in most of the imipenem-nonsusceptible isolates in this study, and decreased porin expression was found to be the main mechanism underlying this reduced susceptibility to imipenem. PMID- 28336136 TI - Antimicrobial susceptibility of 2906 Pseudomonasaeruginosa clinical isolates obtained from patients in Canadian hospitals over a period of 8 years: Results of the Canadian Ward surveillance study (CANWARD), 2008-2015. AB - Pseudomonas aeruginosa is an important nosocomial pathogen. The purpose of this study was to evaluate the antimicrobial susceptibility profile of P. aeruginosa clinical isolates obtained from inpatients and outpatients at hospitals across Canada from January 2008 to December 2015 (CANWARD Study). Susceptibility testing was performed using broth microdilution, as described by the Clinical and Laboratory Standards Institute. In total, 2906 P. aeruginosa isolates were evaluated. The percentage of isolates susceptible to common antipseudomonal antimicrobials was: colistin 94.9%, amikacin 93.2%, piperacillin-tazobactam 84.3%, ceftazidime 83.1%, gentamicin 82.7%, meropenem 80.5%, ciprofloxacin 76.5%. In general, susceptibility to the antipseudomonal antimicrobials tested remained fairly stable or slightly improved (ciprofloxacin, gentamicin, colistin) over the 8year study period. Multidrug-resistant (MDR = non-susceptible to at least one antimicrobial from >=3 classes) and extensively drug-resistant (XDR = non susceptible to at least one antimicrobial from 5 classes) P. aeruginosa accounted for 14.5% and 2.6% of the isolates, respectively. Colistin remained active against 92.9% of MDR and 88.3% of XDR P. aeruginosa. PMID- 28336137 TI - An ultra-sensitive method for the analysis of perfluorinated alkyl acids in drinking water using a column switching high-performance liquid chromatography tandem mass spectrometry. AB - In epidemiological research, it has become increasingly important to assess subjects' exposure to different classes of chemicals in multiple environmental media. It is a common practice to aliquot limited volumes of samples into smaller quantities for specific trace level chemical analyses. A novel method was developed for the determination of 14 perfluorinated alkyl acids (PFAAs) in small volumes (10mL) of drinking water using off-line solid phase extraction (SPE) pre treatment followed by on-line pre-concentration on a WAX column before analysis on column-switching high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). In general, large volumes (100-1000mL) have been used for the analysis of PFAAs in drinking water. The current method requires approximately 10mL of drinking water concentrated by using an SPE cartridge and eluted with methanol. A large volume injection of the extract was introduced on to a column-switching HPLC-MS/MS using a mix-mode SPE column for the trace level analysis of PFAAs in water. The recoveries for most of the analytes in the fortified laboratory blanks ranged from 73+/-14% to 128+/-5%. The lowest concentration minimum reporting levels (LCMRL) for the 14 PFAAs ranged from 0.59 to 3.4ng/L. The optimized method was applied to a pilot-scale analysis of a subset of drinking water samples from an epidemiological study. These samples were collected directly from the taps in the households of Ohio and Northern Kentucky, United States and the sources of drinking water samples are both surface water and ground water, and supplied by different water distribution facilities. Only five PFAAs, perfluoro-1-butanesulfonic acid (PFBS), perfluoro-1- -hexanesulfonic acid (PFHxS), perfluoro-1-octanesulfonic acid (PFOS), perfluoro-n heptanoic acid (PFHpA) and perfluoro-n-octanoic acid (PFOA) are detected above the LCMRL values. The median concentrations of these five PFAAs detected in the samples was <=4.1ng/L with PFOS at 7.6ng/L and PFOA at 10ng/L. Concentrations of perfluoro-1-decanesulfonic acid, PFDS and other perfluoroalkyl carboxylic acids were below the LCMRL values. PMID- 28336138 TI - Preparation of an epitope-imprinted polymer with antibody-like selectivity for beta2-microglobulin and application in serum sample analysis with a facile method of on-line solid-phase extraction coupling with high performance liquid chromatography. AB - Molecularly imprinted polymers (MIPs) for protein recognition have great application potential in the biological analysis. However, preparation of protein imprinted polymer is still facing challenge. Beta2-microglobulin (beta2m) is a protein biomarker that can be used in diagnosis of different diseases. In this research, a novel MIP with ability of beta2m recognition has been developed by epitope and surface-confined imprinting approaches. A peptide with sequence of MIQRTPKIQ was selected as template. A strategy of combination of hierarchical imprinting and template immobilization was employed in the beta2m-MIP synthesis. Imprinted binding sites with open-entrance have been created that have good accessibility for beta2m and facilitated fast reversible binding kinetics. The experimental results demonstrated that the MIP has good selectivity. It can differentiate the template from peptide with different sequence and distinguish the beta2m from other proteins with similar size and pI values. After binding property study of the beta2m-MIP, a method of beta2m determination in serum was established in which beta2m was on-line extracted by MIP and analyzed by HPLC process. The recoveries for spiked serum was >=83% with RSD <1.1%, indicating that the method has good accuracy and precisions. The LOD and LOQ were 0.058 and 0.195mgL-1 respectively, which meet the requirements of the beta2m analysis. The successful application of the beta2m-MIP demonstrated that beta2m has reversible binding on the MIP with a kinetics that can meet the requirements of the HPLC analysis. It also indicated that the beta2m-MIP has good mechanical strength and reusability that can be applied reliably in the practical analysis. As a synthetic antibody, beta2m-MIP is advantageous compared to the biological molecules. PMID- 28336139 TI - Separation of phytochemicals from Helichrysum italicum: An analysis of different isolation techniques and biological activity of prepared extracts. AB - Helichrysum italicum presents a valuable source of natural bioactive compounds. In this work, a literature review of terpenes, phenolic compounds, and other less common phytochemicals from H. italicum with regard to application of different separation methods is presented. Data including extraction/separation methods and experimental conditions applied, obtained yields, number of identified compounds, content of different compound groups, and analytical techniques applied are shown as corresponding tables. Numerous biological activities of both isolates and individual compounds are emphasized. In addition, the data reported are discussed, and the directions for further investigations are proposed. PMID- 28336140 TI - Corrigendum to "Synthesis and preliminary pharmacological evaluation of N-2-(4-(4 (2-substitutedthiazol-4-yl) piperazin-1-yl)-2-oxoethyl)acetamides as novel atypical antipsychotic agents" [Bioorg. Med. Chem. Lett. 18 (2008) 6054-6057]. PMID- 28336143 TI - Reply. PMID- 28336142 TI - Novel 11-norbetaenone isolated from an entomopathogenic fungus Lecanicillium antillanum. AB - A novel nor-betaenone compound, 11-norbetaenone (1), was isolated from the culture broth of an entomopathogenic fungus Lecanicillium antillanum. The structure was determined on the basis of 1D and 2D NMR spectroscopic data. The absolute stereochemistry of 1 was further confirmed by X-ray single crystallography analysis. It is the first secondary metabolite reported from the species Lecanicillium antillanum. And it is also the first time that a betaenone type compound was isolated from the genus Lecanicillium. Furthermore, 11 norbetaenone (1) displayed significant anti-angiogenic effect by suppressing tube formation. PMID- 28336141 TI - The discovery of potent and selective kynurenine 3-monooxygenase inhibitors for the treatment of acute pancreatitis. AB - A series of potent, competitive and highly selective kynurenine monooxygenase inhibitors have been discovered via a substrate-based approach for the treatment of acute pancreatitis. The lead compound demonstrated good cellular potency and clear pharmacodynamic activity in vivo. PMID- 28336144 TI - Complications of endoscopic retrograde cholangiopancreatography in children with chronic pancreatitis depends on center experience. PMID- 28336145 TI - Legionella pneumophila Pneumonia in Two Infants Treated with Adrenocorticotropic Hormone. AB - Patients with infantile spasms, an intractable epileptic disorder, often are treated with adrenocorticotropic hormone. Legionella pneumophila is a rare cause of pneumonia in children. We describe 2 infants with Legionella pneumonia whose infection occurred within 1 month after starting adrenocorticotropic hormone. PMID- 28336146 TI - An Investigation of Connections between Birth Defects and Cancers Arising in Adolescence and Very Young Adulthood. AB - This study investigated the relationship between birth defects and cancer in adolescents and very young adults using California's population-based registries. Although overall cancer risk was elevated among individuals with chromosomal birth defects, this was not observed in those with nonchromosomal birth defects, as was demonstrated previously in younger children. PMID- 28336147 TI - Overcoming Diagnostic Errors in Medical Practice. PMID- 28336150 TI - Effects of foot rotation positions on knee valgus during single-leg drop landing: Implications for ACL injury risk reduction. AB - BACKGROUND: Non-contact anterior cruciate ligament (ACL) injuries commonly occur when athletes land in high risk positions such as knee valgus. The position of the foot at landing may influence the transmission of forces from the ankle to the knee. Using an experimental approach to manipulate foot rotation positions, this study aimed to provide new insights on how knee valgus during single-leg landing may be influenced by foot positions. METHODS: Eleven male recreational basketball players performed single-leg drop landings from a 30-cm high platform in three foot rotation positions (toe-in, toe-forward and toe-out) at initial contact. A motion capture system and a force plate were used to measure lower extremity kinematics and kinetics. Knee valgus angles at initial contact (KVA) and maximum knee valgus moments (KVM), which were known risk factors associated with ACL injury, were measured. A one-way repeated measures Analysis of Variance was conducted (alpha=0.05) to compare among the three foot positions. RESULTS: Foot rotation positions were found to have a significant effect on KVA (p<0.001, eta2=0.66) but the difference between conditions (about 1 degrees ) was small and not clinically meaningful. There was a significant effect of foot position on KVM (p<0.001, eta2=0.55), with increased moment observed in the toe-out position as compared to toe-forward (p=0.012) or toe-in positions (p=0.002). CONCLUSIONS: When landing with one leg, athletes should avoid extreme toe-out foot rotation positions to minimise undesirable knee valgus loading associated with non-contact ACL injury risks. PMID- 28336149 TI - The ACL injury response: A collagen-based analysis. AB - BACKGROUND: Anterior cruciate ligament (ACL) injuries do not effectively heal. Tendon graft tissue after reconstruction shows rapid tissue turnover and 'ligamentization.' It is unknown whether native torn ACL tissue undergoes significant collagen turnover after injury or is arrested by the intraarticular environment. It is also unknown whether injury mechanism or chronicity affect torn ligament tissue turnover. METHODS: Thirty-three mid-substance ACL biopsies were obtained during primary arthroscopic ACL reconstruction (n=31; nine contact injuries, 22 non-contact injuries, 22 males, 11 females; mean age 28.5 years; median injury to surgery time 12 weeks), or from cadavers as uninjured ACL (n=2). As a marker for collagen turnover, immature collagen cross-link content was determined by ninhydrin reagent assays. The immature cross-link content was assessed against injury mechanism, patient age, and injury to surgery time. Histochemical analysis was conducted on two uninjured ACL cadaveric controls, a four-week-old ACL tear, and a four-year-old ACL tear. RESULTS: Contact and non contact groups were not demographically different with respect to sex, patient age, injury to surgery time, and activity involvement prior to injury, which ranged from basketball to logging. Collagen crosslink content was very low across all samples, suggesting high tissue turnover between injury and surgery regardless of injury mechanism (non-contact: 1.68ng/mol, CI 0.48-2.89; contact: 1.50ng/mol, CI 0.14-2.86; p=0.842). CONCLUSION: Collagen turnover occurs rapidly after ACL injury regardless of contact or non-contact mechanism. Robust tissue turnover starts within the first several weeks after injury and persists to some extent throughout the life of the torn ACL. PMID- 28336148 TI - Preoperative body mass index and physical function are associated with length of stay and facility discharge after total knee arthroplasty. AB - BACKGROUND: Hospital length of stay (LOS) and facility discharge are primary drivers of the cost of total knee arthroplasty (TKA). We sought to identify modifiable patient factors that were associated with increased LOS and facility discharge after TKA. METHODS: Prospective data were reviewed from 716 consecutive, primary TKA procedures performed by two arthroplasty surgeons between 2006 and 2012 at a single institution. Preoperative body mass index (BMI), Veterans RAND-12 (VR-12) physical component score (PCS), and hemoglobin level were collected in addition to other adjusters. Multivariate linear and logistic models were constructed to predict LOS and facility discharge, respectively. RESULTS: After adjustment, higher BMI was associated with increased LOS in a dose-response effect: Compared to normal weight (BMI <25) overweight (25 29.9) was associated with longer LOS by 0.32days (P=0.038), class-I obesity (30 34.9) by 0.33days (P=0.024), class-II obesity (35-39.9) by 0.67days (P=0.012) and class-III obesity (>40) by 1.15days (P<0.001). Class-III obesity was associated with facility discharge (odds ratio=2.08, P=0.008). Poor PCS was associated with increasing LOS: compared to PCS>=50, PCS 20-29 was associated with a LOS increase of 0.40days (P=0.014) and PCS<20 with a LOS increase of 0.64days (P=0.031). CONCLUSION: Patient BMI has a dose-response effect in increasing LOS. Poor PCS was associated similarly with increased LOS. These associations for of BMI and PCS suggest that improvement preoperatively, by any amount, may potentially translate to decreased LOS and perhaps lower the cost associated with TKA. PMID- 28336151 TI - Corrigendum to "A wearable multisensing patch for continuous sweat monitoring" [Biosens. Bioelectron. (2016)]. PMID- 28336153 TI - Quantification and comparison of the mechanical properties of four human cardiac valves. AB - OBJECTIVE: Although having the same ability to permit unidirectional flow within the heart, the four main valves-the mitral valve (MV), aortic (AV), tricuspid (TV) and pulmonary (PV) valves-experience different loading conditions; thus, they exhibit different structural integrity from one another. Most research on heart valve mechanics have been conducted mainly on MV and AV or an individual valve, but none quantify and compare the mechanical and structural properties among the four valves from the same aged patient population whose death was unrelated to cardiovascular disease. METHODS: A total of 114 valve leaflet samples were excised from 12 human cadavers whose death was unrelated to cardiovascular disease (70.1+/-3.7years old). Tissue mechanical and structural properties were characterized by planar biaxial mechanical testing and histological methods. The experimental data were then fitted with a Fung-type constitutive model. RESULTS: The four valves differed substantially in thickness, degree of anisotropy, and stiffness. The leaflets of the left heart (the AV leaflets and the anterior mitral leaflets, AML) were significantly stiffer and less compliant than their counterparts in the right heart. TV leaflets were the most extensible and isotropic, while AML and AV leaflets were the least extensible and the most anisotropic. Age plays a significant role in the reduction of leaflet stiffness and extensibility with nearly straightened collagen fibers observed in the leaflet samples from elderly groups (65years and older). CONCLUSIONS: Results from 114 human leaflet samples not only provided a baseline quantification of the mechanical properties of aged human cardiac valves, but also offered a better understanding of the age-dependent differences among the four valves. It is hoped that the experimental data collected and the associated constitutive models in this study can facilitate future studies of valve diseases, treatments and the development of interventional devices. STATEMENT OF SIGNIFICANCE: Most research on heart valve mechanics have been conducted mainly on mitral and aortic valves or an individual valve, but none quantify and compare the mechanical and structural properties among the four valves from the same relatively healthy elderly patient population. In this study, the mechanical and microstructural properties of 114 leaflets of aortic, mitral, pulmonary and tricuspid valves from 12 human cadaver hearts were mechanically tested, analyzed and compared. Our results not only provided a baseline quantification of the mechanical properties of aged human valves, but a age range between patients (51-87years) also offers a better understanding of the age-dependent differences among the four valves. It is hoped that the obtained experimental data and associated constitutive parameters can facilitate studies of valve diseases, treatments and the development of interventional devices. PMID- 28336152 TI - Development of hypomelanotic macules is associated with constitutive activated mTORC1 in tuberous sclerosis complex. AB - TSC1 and TSC2 are genes mutated in the syndrome TSC (tuberous sclerosis complex). We describe a 3-generation family with 17 affected members, all presenting classic TSC features except renal manifestations. The disease segregates with a silent substitution in TSC2, c.4149C>T, p.(Ser1838Ser), which leads to the formation of an active donor splice site, resulting in three shorter alternatively spliced transcripts with premature stop codons. However a small amount of normal spliced transcript is apparently produced from the mutated allele, which might explain the milder phenotype. The gene products of TSC1/2 form a complex which at energy limiting states, down-regulates the activity of the regulator of protein synthesis, the mammalian target of rapamycin complex1 (mTORC1). As expected, in contrast to cultured control fibroblasts, starvation of cultured patient fibroblasts obtained from a hypomelanotic macule did not lead to repression of mTORC1, whereas partial repression was observed in patient fibroblasts obtained from non-lesional skin. The findings indicate that the development of hypomelanotic macules is associated with constitutive activated mTORC1, whereas mild deregulation of mTORC1 allows the maintenance of normal skin. Furthermore, the finding establishes the pathogenic effect of the "silent" c.4149C>T substitution and emphasizes the need for awareness when interpreting silent substitutions in general. PMID- 28336155 TI - Emergency nurses' perceptions of emergency department preparedness for an ebola outbreak: A qualitative descriptive study. AB - BACKGROUND: Ebola Virus Disease is highly contagious and has high mortality. In 2014, when the outbreak in West Africa was declared a public health emergency, emergency departments in Australia commenced preparation and vigilance for people presenting with ebola like symptoms, to limit spread of the disease. RESEARCH AIM: To examine Australian emergency nurses' perceptions regarding their own and their emergency departments' preparedness to manage an ebola outbreak. METHOD: A qualitative descriptive design was used to collect and analyse data in one metropolitan emergency department in Victoria, Australia. Four focus groups were conducted with 13 emergency nurses. Data were thematically analysed. RESULTS: Major themes emerged from the data: organisational, personal and future preparedness. Participants' believed that both the organisation and themselves had achieved desirable and appropriate preparedness for ebola in their emergency setting. CONCLUSION: Participants trusted their organisation to prepare and protect them for ebola. Appropriate policies, procedures, and equipment infrastructure were reportedly in place. Nurses' decisions to care for a patient with ebola were informed by professional commitment, and personal responsibilities. Participants were concerned about transmitting ebola to their families, and suggested that more regular training in personal protective equipment would increase confidence and skill in self-protection. PMID- 28336156 TI - Pediatric arterial ischemic stroke: Epidemiology, risk factors, and management. AB - Pediatric arterial ischemic stroke (AIS) is an uncommon but important cause of neurologic morbidity in neonates and children, with consequences including hemiparesis, intellectual disabilities, and epilepsy. The causes of pediatric AIS are unique to those typically associated with stroke in adults. Familiarity with the risk factors for AIS in children will help with efficient diagnosis, which is unfortunately frequently delayed. Here we review the epidemiology and risk factors for AIS in neonates and children. We also outline consensus-based practices in the evaluation and management of pediatric AIS. Finally we discuss the outcomes observed in this population. While much has been learned in recent decades, many uncertainties sill persist in regard to pediatric AIS. The ongoing development of specialized centers and investigators dedicated to pediatric stroke will continue to answer such questions and improve our ability to effectively care for these patients. PMID- 28336157 TI - [Prescription of acetaminophen in five French hospitals: What are the practices?] AB - AIM: Acetaminophen is widely used in hospital settings and often considered as nontoxic. We conducted a multicentric study in order to evaluate its proper use. METHOD: Prescriptions from five general hospitals were analyzed, according to dose adjustments required in renal or liver failure, weight or chronic alcoholism, determined using a literature review. Other criteria have been assessed: indication for parenteral access, accuracy of administration time and pain assessment. RESULTS: Among the 1256 analyzed prescriptions, 21% are non compliants. The main causes of non-compliance (NC) are adjustments to weight and renal failure. Higher NC rates concern chronic alcoholism and liver failure. CONCLUSION: Misuse of acetaminophen seems related to a lack of official recommendations concerning dose adjustments. Hospital pharmacists have an important role to play in the promotion of proper use of acetaminophen. Therefore we established a prescribing aid. PMID- 28336158 TI - [Acetaminophen: Knowledge, use and overdose risk in urban patients consulting their general practitioner. A prospective, descriptive and transversal study]. AB - INTRODUCTION: Acetaminophen is the most involved active substance in both unintentional and intentional drug poisoning. However, its availability outside community pharmacies is being debated in France. METHODS: We made, via a self administered questionnaire, a prospective assessment of knowledge, use and acetaminophen overdose risk in patients consulting their general practitioner, in the Metz Metropole urban area, between May 2015 and February 2016. We estimated the prevalence of potential unintentional overdosage by capture-recapture method. RESULTS: Among 819 responding patients, only 17.9 % had a sufficient knowledge and 20.3 % were at risk for potential unintentional overdose. The risk was higher for patients aged over 55 years or belonging to socioprofessional categories of laborers and inactive. A good knowledge score was a protective factor for overdose risk (P<0.0001). The liver toxicity of acetaminophen was particularly unknown. The prevalence of potential unintentional acetaminophen overdose was estimated at 1 to2 % of the population. CONCLUSION: Proposing acetaminophen outside of pharmacies cannot be recommended in France in such conditions. Information campaigns are needed to limit the risk of unintentional overdose and its consequences on liver toxicity. PMID- 28336159 TI - The anticholinergic impregnation scale: Towards the elaboration of a scale adapted to prescriptions in French psychiatric settings. AB - PURPOSE: Some drugs have anticholinergic activity and can cause peripheral or central side effects. Several scales exist to evaluate the potential anticholinergic effect of prescribed drugs but: (i) they are validated in the elderly and mainly assess the cognitive side effect of treatments; (ii) they do not concern some of the drugs frequently used in clinical psychiatry in France. The aim of our study is to develop a new scale, the anticholinergic impregnation scale (AIS), with drugs used in France and based on an assessment of the drugs used against peripheral anticholinergic adverse effects. METHODS: We assigned a score, ranging from 1 to 3, to a list of 128 drugs with a consensus approach obtained via literature data and expert opinions. We collected data from 7278 prescriptions in 34 French psychiatric facilities: age, sex, atropinic drugs, laxatives and treatments of xerophthalmia and xerostomia, in order to evaluate the association between AIS score and the prescription of drugs aiming to reduce peripheral anticholinergic side effects. RESULTS: The most frequently prescribed drugs were cyamemazine (n=1429; 20%) and tropatepine (n=1403; 19%), two drugs marketed almost exclusively in France and with a score of 3. The frequency of patients with a high AIS score, greater than 5, was significantly higher in patients who received laxatives and treatments of xerostomia. AIS score represents the first validated solution to evaluate anticholinergic load in psychiatry settings in France. CONCLUSION: The anticholinergic problem remains underevaluated in mental health settings. In order to rule out the confounding factor of mental disease, assessment of peripheral side effects can be considered more objective than the evaluation of cognitive function in psychiatric patients. Building scales appropriate for each state also appear essential to obtain an useful and effective tool in clinical practice. PMID- 28336160 TI - Unexpected drug-induced Raynaud phenomenon: Analysis from the French national pharmacovigilance database. AB - OBJECTIVE: To estimate the association between exposure to medicinal products and Raynaud phenomenon. METHODS: The study used the data of all adverse drug reactions notified to the French national pharmacovigilance database. All cases reported between 1st January 1995 and 10th December 2012 were selected. A case/non-case method was used to measure disproportionality of the association between drug exposure and Raynaud phenomenon. The cases concerned all observations involving Raynaud phenomenon. Non-cases comprised all other reports of adverse drug reactions over the same period. RESULTS/DISCUSSION: Among the 307,128 adverse drug reaction reports selected from the French national pharmacovigilance database, 175 involved Raynaud phenomenon, most of them affecting women (61.1%). The mean age was 50.1 years, and 8% had a past medical history of Raynaud phenomenon. According to the summaries of product characteristics, 42.3% of these cases were exposed to drugs known to induce Raynaud phenomenon. Unexpected Raynaud phenomenons (unlisted in the summaries of product characteristics) were associated with exposure to drugs for which Raynaud phenomenons are published (interferons, ribavirin, gemcitabine) or for which Raynaud phenomenons are not published (hepatitis B vaccine, isotretinoin, leflunomide, hydroxycarbamide, rofecoxib, telmisartan, zolmitriptan). CONCLUSION: The case/non-case method is usually used to generate signals. Further epidemiological studies are now necessary to confirm these findings. PMID- 28336162 TI - Meiotic segregation analyses of reciprocal translocations in spermatozoa and embryos: no support for predictive value regarding PGD outcome. AB - Translocation heterozygotes have an increased risk of producing gametes with unbalanced chromosome content. This often leads to reproductive problems such as infertility, repeated miscarriages or birth of an affected child. To increase the chances of having a healthy live-born child, translocation heterozygotes often opt for preimplantation genetic diagnosis (PGD). The aim of this study was to investigate whether there is a correlation between chromosome segregation in spermatozoa from translocation heterozygotes and the number of balanced embryos produced during PGD that may be used to predict the PGD outcome. Ten male reciprocal translocation heterozygotes that went through PGD at a Stockholm PGD centre were included. We analysed 1000 spermatozoa from each patient and between 3 and 29 embryos from the total of PGD cycles that the couples went through. Fluorescence in-situ hybridization (FISH) analysis of spermatozoa and embryos was performed with the same DNA probes. We found that the proportion of balanced spermatozoa was much higher than the proportion of balanced embryos during PGD. Our results indicate that a sperm FISH analysis prior to PGD is not a reliable predictor of the PGD outcome. PGD is a valuable reproductive alternative for translocation heterozygotes with reproductive problems and should be offered to these couples. PMID- 28336161 TI - [Hemorrhage treatment: Evaluation of the proper use of fibrinogen concentrate]. AB - An increase in fibrinogen concentrate prescriptions was noticed in 2015 after several guidelines regarding their use were published. We tried to evaluate if they were used appropriately. To evaluate the conformity of the prescriptions to these guidelines, we searched for each prescription if a dosage of blood fibrinogen was made, if its result was below the limit recommended to prescribe fibrinogen concentrate, and if the posology was in line with the recommendations. Effect and security of the treatment was also evaluated. We analyzed 202 prescriptions for 117 patients. The indications are respected except for one prescription for which we could not find it. The blood fibrinogen is measured for 76% of the prescriptions, 59% of the results are below the limit recommended to prescribe. The posology is conforming to the guidelines for 73% of the prescriptions, it is below the dose recommended for 20%. Patients who were prescribed low doses seemed less at risk than the others which questions the necessity of the prescriptions. The guidelines respect depends on the emergency of the prescription situation. It would be interesting to conduct a prospective study to better explain why doses below those recommended are prescribed. PMID- 28336163 TI - A meta-analysis of the impact of human leukocyte antigen-G on the outcomes of IVF/ICSI. AB - This analysis was performed to determine whether the presence of soluble human leukocyte antigen-G (sHLA-G) in embryo culture medium is predictive of clinical outcomes in IVF treatment. The outcomes of implantation, clinical pregnancy, multiple pregnancy and miscarriage, between groups with and without sHLA-G in embryo culture media, were analysed. Fifteen studies with a total of 6170 cases were included. Ten of them were prospective studies while five were retrospective studies. Embryo culture media with sHLA-G were associated with significantly higher implantation rate and clinical pregnancy rate when compared with those without; the odd ratios (ORs) were 2.66 [95% confidence interval (CI): 1.75-4.06, P < 0.00001], 3.79 (95% CI: 2.69-5.33, P < 0.00001), respectively. There was no significant difference in the rate of multiple pregnancy (OR: 1.87, 95% CI: 0.55 6.31) and miscarriage (OR: 0.77, 95% CI: 0.52-1.16). The results suggested that the presence of sHLA-G in the embryo culture medium favoured higher implantation rate and pregnancy rate. However, the conclusion needs to be consolidated by further clinical studies using a more precise method of determination of sHLA-G and research on the physiological and molecular mechanisms of the beneficial effect of sHLA-G on early embryo development and implantation. PMID- 28336164 TI - Expression of unusual immunohistochemical markers in mucinous breast carcinoma. AB - BACKGROUND: Mucinous breast carcinoma is characterized by the production of variable amounts of mucin. Some studies have addressed immunohistochemical characterization of mucinous breast carcinoma using a limited set of antibodies. However, the purpose of the present study was to investigate a larger panel of markers not widely used in daily practice and to determine their pathological implications. METHODS: Forty patients diagnosed with mucinous breast carcinoma were enrolled. An immunohistochemical study was performed on whole sections of paraffin embedded tissue, using antibodies for the following markers: estrogen receptor alpha and beta, progesterone receptor, androgen receptor, HER2, EGFR, Ki 67, E-cadherin, beta-catenin, p53, chromogranin, synaptophysin, GCDFP15, mammaglobin, and CDX2. RESULTS: The pure mucinous type was more prevalent in older patients and more frequently expressed GCDFP15. Capella type B presented more frequently with a high Ki-67 index and neuroendocrine differentiation. Although there was a lower frequency of vascular invasion and lymph node metastases in the pure type, the difference was not statistically significant. No case expressed CDX2 (a marker for gastrointestinal tumors), while 85% of the cases expressed at least one of the two typical breast markers (GCDFP15 and mammaglobin), suggesting that these markers may be reliably used for differential diagnosis. Expression of estrogen receptor beta was related to the presence of mucin cell producing lymph node metastasis, with potential prognostic and predictive value. CONCLUSION: our findings support the immunohistochemical homogeneity of mucinous breast carcinomas because only minor differences were found when subgrouping them into Capella types A and B or into types pure and mixed. PMID- 28336165 TI - Suspicious outbreak of ventilator-associated pneumonia caused by Burkholderia cepacia in a surgical intensive care unit. AB - BACKGROUND: We reviewed Burkholderia cepacia infections in a hospital from 2013 2016 to report a suspicious outbreak that occurred in a surgical intensive care unit in 2015, and to outline the infection control measures adopted thereafter. METHODS: Review of the health care-associated infection data regarding B cepacia via the surveillance system, hospital information system, electronic medical records, and laboratory information system together with the outbreak investigation was managed by the health care-associated infection control team. RESULTS: During June 1-14, 2015, 4 cases of ventilator-associated pneumonia (VAP) were identified; B cepacia was isolated from endotracheal aspirate samples. On June 16, 120 environmental samples were collected and analyzed for microbiologic differentiation. Thirteen strains of B cepacia were prominently found in the expiratory blocks of ventilators, revealing the biocontamination source. After chemical disinfection without damaging ventilator components, repeat microbiologic testing of random ventilator samples yielded negative results until July 30, 2015. Retrospective data showed that isolation rates of B cepacia strains had increased since 2014. Although the resistance phenotype of these strains varied slightly, they exhibited similar patterns of antibiotic susceptibility. CONCLUSIONS: Routine cleaning and disinfection of ventilators, in addition to an intervention bundle, should form part of an integrated VAP prevention and management approach. PMID- 28336166 TI - Methodological issues in determination of low muscle mass reference cut-off values: Reply to Comment on "Cut-off points to identify sarcopenia according to European Working Group on Sarcopenia in Older People (EWGSOP) definition". PMID- 28336167 TI - Biologically-Inspired Biomarkers for Mental Disorders. PMID- 28336168 TI - [Pseudo-tumoral invasive fungus infection of the maxillary sinus in Abidjan]. AB - INTRODUCTION: The invasive fungal infection of the maxillary sinus is a rare and serious disease generally favored by immunosuppression. We report an exceptional case of pseudotumoral invasive fungal infection of the maxillary sinus in an immunocompetent patient. OBSERVATION: A 32-year-old patient consulted for labial and left temporal swelling associated with proptosis and chemosis that has been developing for 18 months. The scanner objectified a filling of the left maxillary sinus, and the ipsilateral orbital cavity, and the surrounding muscles. Histological examination of the surgical specimen revealed invasive fungal infection of the left maxillary sinus. The relevant antifungal therapy, namely voriconazole, could not be administered due to the unavailability of the medicine. However, the patient has received 200mg of itraconazole every 12hours for three weeks. The change proved disappointing with recurrence and significant sequelae, sort of sagging of the right hemifacial, severe limitation of mouth opening and functional loss of the right eye. CONCLUSION: The invasive fungus infections of the maxillary sinus and the orbit are exceptional in immunocompetent patient. Healing is based on early diagnosis and administration of the reference antifungal to face the risk of recurrence. PMID- 28336170 TI - [Drug syrups: Errors in drug labels with possible consequences in patients with heritary fructose intolerance]. PMID- 28336169 TI - [Evaluation of school menu food balance in the Autonomous Community of Valencia (Spain) by means of a questionnaire]. AB - OBJECTIVE: To evaluate school menu food balance in the Autonomous Community of Valencia (Spain) by means of a questionnaire. METHOD: Observational cross-section study. For convenience it shows of 255 monthly school menus (20 days each). INDEPENDENT VARIABLES: size of the city the school is in, province, location (coast vs. inland), ownership (public vs. private), design of the menu (company vs. school) and month (May vs. October). The 17-item EQ-MEs questionnaire was used as a tool to measure balance. Differences in the balance of the menus and the average of monthly servings were compared, taking into account the different levels of the independent variables. RESULTS: The average of the balance index obtained was 9.19 points (range: 0-17). Approximately 78.4% of menus were designed by companies. Approximately 60.4% were classified as suitable and 0.8% as balanced. The menus designed by companies obtained a higher score (9.49) than those designed by schools (8.13). Menus in Castellon (10.35) achieved a higher score than those in Alicante (9.43) and Valencia (8.86). Only 3.1% of the studied menus met serving recommendations in terms of meat, 37.6% met pulses serving recommendations, 49.4% met fish serving recommendations and 37% met fruit serving recommendations. CONCLUSION: With the EQ-MEs questionnaire, most of the menus offered in the Autonomous Community of Valencia are suitable for children. To improve them, they should reduce fried potato, rice, pasta, meat, fried food and dairy product servings, while increasing pulses, fish, oily fish and fruit servings. PMID- 28336171 TI - [Virus and wheezing in infants. Certainties or doubts?] PMID- 28336172 TI - Curcuma longa Linn. extract and curcumin protect CYP 2E1 enzymatic activity against mercuric chloride-induced hepatotoxicity and oxidative stress: A protective approach. AB - The present investigation has been conducted to evaluate the therapeutic potential of Curcuma longa (200mgkg-1, po) and curcumin (80mgkg-1, po) for their hepatoprotective efficacy against mercuric chloride (HgCl2: 12MUmolkg-1, ip; once only) hepatotoxicity. The HgCl2 administration altered various biochemical parameters, including transaminases, alkaline phosphatase, lactate dehydrogenase, bilirubin, gamma-glutamyl transferase, triglycerides and cholesterol contents with a concomitant decline in protein and albumin concentration in serum which were restored towards control by therapy of Curcuma longa or curcumin. On the other hand, both treatments showed a protective effect on drug metabolizing enzymes viz. aniline hydroxylase (AH) and amidopyrine-N-demethylase (AND), hexobarbitone induced sleep time and BSP retention. Choleretic, 1,1-diphenyl-2 picryl-hydrazil (DPPH)-free radical scavenging activities and histological studies also supported the biochemical findings. The present study concludes that Curcuma longa extract or curcumin has the ability to alleviate the hepatotoxic effects caused by HgCl2 in rats. PMID- 28336173 TI - Effects of Artesunate on some biochemical parameters in pregnant albino Wistar rats challenged with lethal strain Plasmodium berghei NK65: Appreciating the activities of artemisinin drugs on key pregnancy hormone balance. AB - In humans, malaria in pregnancy can cause serious maternal and foetal morbidity and in extreme untreated cases, foetal mortality occurs. The therapeutic approach to curbing this malaise is the administration of an effective and/or combinations of anti-malaria medicaments. Acute or chronic administration of some of these drugs, however, gives rise to some adverse medical conditions including reproductive dysfunction, especially in pregnancy. Studies aimed at the hormonal interplays following administration of these drugs in pregnancy have been limited due to too few appropriate animal models. In this experiment, pregnant albino rats were infected with rodent parasite, Plasmodium berghei on the 5th day of gestation, following which biochemical changes, specific for pregnancy maintenance were monitored in the blood of test rats. We observed that infecting the pregnant rats with P. berghei negatively impacted the measured biological parameters (hormones) compared to unchallenged controls. The observed effect was however retreated following oral administration of 3mg/kg body weight, qDay of Artesunate until the 17th day of gestation. Findings, therefore, suggest that Artesunate is an effective therapeutic agent in pregnancy, demonstrated by the restoration of the hormonal changes occasioned by the parasitic infection. PMID- 28336175 TI - The academic-industrial complex: navigating the translational and cultural divide. AB - In general, the fruits of academic discoveries can only be realized through joint efforts with industry. However, the poor reproducibility of much academic research has damaged credibility and jeopardized translational efforts that could benefit patients. Meanwhile, journals are rife with articles bemoaning the limited productivity and increasing costs of the biopharmaceutical industry and its resultant predilection for mergers and reorganizations while decreasing internal research efforts. The ensuing disarray and uncertainty has created tremendous opportunities for academia and industry to form even closer ties, and to embrace new operational and financial models to their joint benefit. This review article offers a personal perspective on the opportunities, models and approaches that harness the increased interface and growing interdependency between biomedical research institutes, the biopharmaceutical industry and the technological world. PMID- 28336174 TI - The exposure to formaldehyde causes renal dysfunction, inflammation and redox imbalance in rats. AB - Twenty-eight Fischer male rats were divided into four groups: control group (CG), exposed to the ambient air, and groups exposed to formaldehyde (FA) at concentrations of 1% (FA1%), 5% (FA5%) and 10% (FA10%). Kidney function was assessed by dosage of uric acid, creatinine and urea. Morphometry was performed on the thickness of the lumen of Bowman's capsule and diameter of the lumen of the renal tubules. We evaluated the redox imbalance through the catalase and superoxide dismutase activity as well as oxidative damage by lipid peroxidation. Inflammatory chemokines CCL2, CCL3 and CCL5 were analyzed by enzyme immunoassays. There was an increase in the concentration of urea in FA10% compared with CG and FA1%. The levels of creatinine, renal lumen and lipid peroxidation increased in all FA-treated groups compared with CG. The concentration of uric acid in FA10% was lower compared with all other groups. There was an increase in the space of Bowman's capsule in FA5% and FA10% compared with CG and FA1%. However, the superoxide dismutase activity was higher in FA5% compared with other groups while CCL5 was higher in FA1% compared with CG. The exposure to formaldehyde in a short period of time leads to changes in the kidney function, inflammation and morphology, as well as promoted the increase of superoxide dismutase activity and oxidative damage. PMID- 28336178 TI - Symbiont Acquisition and Replacement as a Source of Ecological Innovation. AB - Nutritional symbionts play a major role in the ecology and evolution of insects. The recent accumulation of knowledge on the identity, function, genomics, and phylogenetic relationships of insect-bacteria symbioses provides the opportunity to assess the effects of symbiont acquisitions and replacements on the shift into novel ecological niches and subsequent lineage diversification. The megadiverse insect order Hemiptera presents a particularly large diversity of symbiotic associations that has frequently undergone shifts in symbiont localization and identity, which have contributed to the exploitation of nutritionally imbalanced diets such as plant saps or vertebrate blood. Here we review the known ecological and evolutionary implications of symbiont gains, switches, and replacements, and identify future research directions that can contribute to a more comprehensive understanding of symbiosis as a major driving force of ecological adaptation. PMID- 28336179 TI - Control of DNA end resection by yeast Hmo1p affects efficiency of DNA end joining. AB - The primary pathways for DNA double strand break (DSB) repair are homologous recombination (HR) and non-homologous end-joining (NHEJ). The choice between HR and NHEJ is influenced by the extent of DNA end resection, as extensive resection is required for HR but repressive to NHEJ. Conversely, association of the DNA end binding protein Ku, which is integral to classical NHEJ, inhibits resection. In absence of key NHEJ components, a third repair pathway is exposed; this alternative-end joining (A-EJ) is a highly error-prone process that uses micro homologies at the breakpoints and is initiated by DNA end resection. In Saccharomyces cerevisiae, the high mobility group protein Hmo1p has been implicated in controlling DNA end resection, suggesting its potential role in repair pathway choice. Using a plasmid end-joining assay, we show here that absence of Hmo1p results in reduced repair efficiency and accuracy, indicating that Hmo1p promotes end-joining; this effect is only observed on DNA with protruding ends. Notably, inhibition of DNA end resection in an hmo1Delta strain restores repair efficiency to the levels observed in wild-type cells. In absence of Ku, HMO1 deletion also reduces repair efficiency further, while inhibition of resection restores repair efficiency to the levels observed in kuDelta. We suggest that Hmo1p functions to control DNA end resection, thereby preventing error-prone A-EJ repair and directing repairs towards classical NHEJ. The very low efficiency of DSB repair in kuDeltahmo1Delta cells further suggests that excessive DNA resection is inhibitory for A-EJ. PMID- 28336180 TI - An important intestinal transporter that regulates the enterohepatic circulation of bile acids and cholesterol homeostasis: The apical sodium-dependent bile acid transporter (SLC10A2/ASBT). AB - The enterohepatic circulation of bile acids (BAs) is governed by specific transporters expressed in the liver and the intestine and plays a critical role in the digestion of fats and oils. During this process, the majority of the BAs secreted from the liver is reabsorbed in intestinal epithelial cells via the apical sodium-dependent bile acid transporter (ASBT/SLC10A2) and then transported into the portal vein. Previous studies revealed that regulation of the ASBT involves BAs and cholesterol. In addition, abnormal ASBT expression and function might lead to some diseases associated with disorders in the enterohepatic circulation of BAs and cholesterol homeostasis, such as diarrhoea and gallstones. However, decreasing cholesterol or BAs by partly inhibiting ASBT-mediated transport might be used for treatments of hypercholesterolemia, cholestasis and diabetes. This review mainly discusses the regulation of the ASBT by BAs and cholesterol and its relevance to diseases and treatment. PMID- 28336181 TI - Experimental comparison of the bioaccumulation of anthropogenic radionuclides by egg and juvenile life stages of a small shark. AB - This study compared the bioaccumulation of anthropogenic nuclides (65Zn, 134Cs, 60Co and 241Am) between the egg and juvenile life stages of a small shark (Scyliorhinus canicula), based on previously published experimental data. Rates of accumulation over 15 days were derived and summed for the transfer pathways which were specific to these two life stages. Radionuclide transfers to the egg and its embryo & yolk were quantified for i) the maternal pathway following her uptake of radionuclides via food and seawater and ii) from seawater following its oviposition. For the juvenile, the transfer of radionuclides were measured for aqueous & dietary pathways. The results show that, compared to juveniles, eggs have equivalent rates of accumulation of 65Zn and 134Cs but enhanced accumulation of 241Am by a factor of five and of 60Co by two orders of magnitude. The radiological exposure of the embryo due to radionuclides maternally transferred to the embryo & yolk is also enhanced for the alpha-emitting 241Am. This enhanced accumulation of 241Am and 60Co, as well as the equivalent accumulation of 65Zn and 134Cs, suggest greater likely vulnerability to radiation damage in eggs as compared to juveniles. Radiological dose assessment confirmed highest doses to the egg which is predominantly due to accumulated 241Am. PMID- 28336182 TI - Light chain amyloidosis: Where are the light chains from and how they play their pathogenic role? AB - Amyloid light-chain (AL) amyloidosis is a plasma-cell dyscrasia, as well as the most common type of systematic amyloidosis. Pathogenic plasma cells that have distinct cytogenetic and molecular properties secrete an excess amount of amyloidogenic light chains. Assisted by post-translational modifications, matrix components, and other environmental factors, these light chains undergo a conformational change that triggers the formation of amyloid fibrils that overrides the extracellular protein quality control system. Moreover, the amyloidogenic light-chain itself is cytotoxic. As a consequence, organ dysfunction is caused by both organ architecture disruption and the direct cytotoxic effect of amyloidogenic light chains. Here, we reviewed the molecular mechanisms underlying this sequence of events that ultimately leads to AL amyloidosis and also discuss current in vitro and in vivo models, as well as relevant novel therapeutic approaches. PMID- 28336183 TI - Evosystem Services: Rapid Evolution and the Provision of Ecosystem Services. AB - Evolution is recognized as the source of all organisms, and hence many ecosystem services. However, the role that contemporary evolution might play in maintaining and enhancing specific ecosystem services has largely been overlooked. Recent advances at the interface of ecology and evolution have demonstrated how contemporary evolution can shape ecological communities and ecosystem functions. We propose a definition and quantitative criteria to study how rapid evolution affects ecosystem services (here termed contemporary evosystem services) and present plausible scenarios where such services might exist. We advocate for the direct measurement of contemporary evosystem services to improve understanding of how changing environments will alter resource availability and human well-being, and highlight the potential utility of managing rapid evolution for future ecosystem services. PMID- 28336184 TI - Atrial fibrillation management in a breeding stallion. AB - A 20-year-old warmblood breeding stallion presented to a University practice for semen collection and evaluation was incidentally diagnosed with atrial fibrillation (AF). Electrocardiogram recordings during breeding revealed inappropriately rapid tachycardia and occasional ventricular premature depolarizations/aberrant ventricular conduction. Transvenous electrical cardioversion was performed. After successful cardioversion the horse displayed supraventricular ectopy and atrial contractile dysfunction and was administered sotalol hydrochloride in an attempt to decrease the risk of AF recurrence. Supraventricular ectopy and echocardiographic evidence of atrial dysfunction gradually improved and normalized over 6 months. No direct adverse effects of the chronic anti-arrhythmic treatment were observed and libido and semen quality were unaffected. AF recurred 6 months after cardioversion and sotalol therapy was continued to control the ventricular ectopy/aberrant ventricular conduction during semen collection. Considerations regarding pathologic arrhythmias and inappropriately high heart rates in breeding stallions with AF may be similar to those in riding horses. Sotalol hydrochloride was a safe anti-arrhythmic drug in the management of this case. PMID- 28336185 TI - Self-expanding metallic stent as a bridge to surgery in the treatment of left colon cancer obstruction: Cost-benefit analysis and oncologic results. AB - INTRODUCTION: The use of a self-expanding metallic stent as a bridge to surgery in acute malignant left colonic obstruction has been suggested as an alternative treatment to emergency surgery. The aim of the present study was to compare the morbi-mortality, cost-benefit and long-term oncological outcomes of both therapeutic options. METHODS: This is a prospective, comparative, controlled, non randomized study (2005-2010) performed in a specialized unit. The study included 82 patients with left colon cancer obstruction treated by stent as a bridge to surgery (n=27) or emergency surgery (n=55) operated with local curative intention. The main outcome measures (postoperative morbi-mortaliy, cost-benefit, stoma rate and long-term oncological outcomes) were compared based on an "intention-to-treat" analysis. RESULTS: There were no significant statistical differences between the two groups in terms of preoperative data and tumor characteristics. The technically successful stenting rate was 88.9% (11.1% perforation during stent placement) and clinical success was 81.4%. No difference was observed in postoperative morbi-mortality rates. The primary anastomosis rate was higher in the bridge to surgery group compared to the emergency surgery group (77.8% vs. 56.4%; P=.05). The mean costs in the emergency surgery group resulted to be ?1,391.9 more expensive per patient than in the bridge to surgery group. There was no significant statistical difference in oncological long-term outcomes. CONCLUSIONS: The use of self-expanding metalllic stents as a bridge to surgery is a safe option in the urgent treatment of obstructive left colon cancer, with similar short and long-term results compared to direct surgery, inferior mean costs and a higher rate of primary anastomosis. PMID- 28336187 TI - The chaotic characteristic of the carbon-monoxide utilization ratio in the blast furnace. AB - In this paper, carbon monoxide utilization ratio (CMUR) is served as a real-time index to evaluate the energy consumption of blast furnace (BF), and the chaotic analysis method is also presented to study the characteristic of CMUR. Firstly, the time series data measured from two representative BFs are adopted as the sample to investigate the characteristics of CMUR. Secondly, the phase space model of CMUR is reconstructed, and two key related parameters of the model are derived as well. Finally, the value of the chaotic attractor's saturated correlative dimensions in the reconstructed phase space of CMUR is obtained. The result shows that the sample time series of these two BFs have chaos property. Furthermore, the development process of CMUR is also proved to be the chaotic process. It provides a solid foundation for us to further study the chaotic predication and control of CMUR, which helps us to better master the variational tendency of CMUR and provides the effective operation guidance for the BF on the spot to reduce the energy consumption in BF. PMID- 28336186 TI - Variation in head and neck cancer care in the Netherlands: A retrospective cohort evaluation of incidence, treatment and outcome. AB - BACKGROUND: To explore variation in numbers and treatment between hospitals that treat head and neck cancer (HNC) in the Netherlands. MATERIAL AND METHODS: Patient, tumor and treatment characteristics were collected from the Netherlands Cancer Registry, while histopathological features were obtained by linkage to the national pathology record register PALGA. Inter-hospital variation in volume, stage, treatment, pathologically confirmed loco-regional recurrence and overall survival rate was evaluated by tumor site. RESULTS: In total, 2094 newly diagnosed patients were included, ranging from 65 to 417 patients in participating hospitals treating HNC in 2008. Oral cavity cancer was mainly treated by surgery only, ranging from 46 to 82% per hospital, while the proportion of surgery with (chemo)radiotherapy ranged from 18 to 40%. Increasing age, male sex, and high stage were associated with a higher hazard of dying. In oropharynx cancer, the use of (chemo)radiotherapy varied from 31 to 82% between hospitals. We found an indication that higher volume was associated with a lower overall hazard of dying for the total group, but not by subsite. Low numbers, e.g. for salivary gland, nasopharynx, nasal cavity and paranasal sinus, did not permit all desired analyses. CONCLUSION: This study revealed significant interhospital variation in numbers and treatment of especially oropharyngeal and oral cavity cancer. This study is limited because we had to rely on data recorded in the past for a different purpose. To understand whether this variation is unwanted, future research should be based on prospectively collected data, including detailed information on recurrences, additional case-mix information and cause of death. PMID- 28336189 TI - 3D CAD/reverse engineering technique for assessment of Thai morphology: Proximal femur and acetabulum. AB - PURPOSE: To assess morphological parameters of proximal femur and acetabulum in Thai population with three-dimensional measurement technique, and to analysis of collateral side symmetric, gender difference, and correlation between morphometric parameters. METHODS: Investigation was performed in 240 femurs. All three-dimensional femur models were acquitted from 64-slice spiral CT scanner. Morphometric parameters under consideration included acetabular diameter, femoral head diameter, shaft isthmus location, intramedullary canal diameter, diaphyseal diameter, femoral head height, femoral neck isthmus, femoral neck length, neck shaft angle, bow angle, and anteversion angle. All parameters were measured based on functions and least-square regression function in CAD software. Obtained measured data were then used for analysis of collateral side symmetric, gender difference, correlation between morphometric parameters, and compared with other populations. RESULTS: Female had a smaller dimension compared with male in most of the parameters. No significant difference was observed between left and right femurs. High correlation pairs of morphometric parameters included femoral head diameter-acetabular diameter, femoral head diameter-neck isthmus diameter, femoral head diameter-diaphyseal diameter at shaft isthmus level, acetabular diameter-neck isthmus diameter, neck isthmus diameter-diaphyseal diameter at shaft isthmus level, and acetabular diameter-diaphyseal diameter at shaft isthmus level. Some morphometric parameters of Thai are smaller than other Caucasian, and some Asian nation, i.e. femoral head diameter, femoral neck length, and femoral head height. CONCLUSIONS: This study provides essential morphometric data for various orthopedic implant designs relating to proximal femur region. PMID- 28336188 TI - Identification, characterization and modulation of ferritin-H in the sub Antarctic Notothenioid Eleginops maclovinus challenged with Piscirickettsia salmonis. AB - Ferritin is a major iron storage protein essential not only in the infectious process, but also in any circumstance generating oxidative stress. In this study, the cDNA coding sequence of ferritin-H was obtained from the sub-Antarctic Notothenioid fish Eleginops maclovinus through transcriptomic analysis of the head kidney. This sequence contained a 534 bp open reading frame that coded for a 177 amino acid protein with a molecular weight of 20,786.2 Da and a theoretical pI of 5.56. The protein displayed a region of iron putative response elements in the 5'UTR, two putative ferritin iron-binding region signatures, and seven characteristic amino acids with ferroxidase functions. Phylogenetic analysis related this sequence to ferritin-H sequences of other Antarctic Notothenioid fish, sharing 96.61% similarity. Constitutive gene expression analysis in different organs revealed increased ferritin-H gene expression in the gills, spleen, muscle, and liver. After infection with two bacterial strains of Piscirickettsia salmonis (LF-89 and Austral-005), ferritin-H was differentially expressed depending on bacterial strain and tissue. This study provides relevant information towards understanding the iron metabolism of a sub-Antarctic Notothenioid fish. PMID- 28336190 TI - Clinical and radiological outcomes of midfoot derotational osteotomy for midfoot forefoot varus deformity. AB - BACKGROUND: Moderate to severe midfoot-forefoot varus deformities are commonly found in several conditions. However, few techniques are available to correct these deformities. So, we evaluated the clinical and radiological outcomes of patients who underwent midfoot derotational osteotomy to achieve plantigrade foot. METHODS: From 2006 to 2014, 6 patients (7 feet) underwent midfoot derotational osteotomy. A visual analog scale (VAS) pain and the American Orthopedic Foot & Ankle Society (AOFAS) functional score were evaluated. Radiographic parameters, including tibiocalcaneal angle (TCA) and navicular height (NH), were assessed. RESULTS: The mean patient age at surgery was 48.0 years (37-58). From before the operation to the final follow-up, the mean VAS score decreased from 6.5 (2-9) to 1.3 (0-4) and the mean AOFAS score improved from 42.7 (34-58) to 77 (68-87). All patients were satisfied with outcomes. The mean TCA significantly improved from 33.8 degrees (9.9-66.7) to 12.7 (5.1-27.6) (p = 0.018)and the mean NH decreased from 46.7 mm (32.8-67) to42.6 (30.1-60.8) (p = 0.018). CONCLUSION: Severe midfoot-forefoot varus deformities can be efficiently corrected by midfoot derotational osteotomy resulting in favorable clinical and radiological outcomes and high patient satisfaction. LEVEL OF EVIDENCE: IV, case series. PMID- 28336191 TI - Implantation of the anterior atlantoaxial lateral mass intervertebral cage using the transoral approach. AB - BACKGROUND: The purpose of this study was to evaluate the possibility of implanting the anterior atlantoaxial lateral mass intervertebral cage, a new type of fixation, by the transoral approach. METHOD: This study examined the possibility of implantation in vivo by the quantitative measurement on the dry atlantoaxial bone and implantation of the anterior atlantoaxial lateral mass intervertebral cage in specimens. Anterior atlantoaxial lateral mass intervertebral cages were implanted in 10 atlantoaxial joint specimens using the transoral approach. Eight anatomical parameters (width, the thickness, ordinates, abscissas, and declination angles of the mass) from each of the 30 dry atlas and axis bone specimens were measured. These parameters determined the size and the design of the cage and the way of implantation. RESULTS: The course of the vertebral artery forms the safe boundary for transoral surgery. The shape of the area of work exposure was an inverted trapezoid. In specimens, the anterior atlantoaxial lateral mass intervertebral cages could be successfully implanted using the transoral approach. The parameters of the human atlantoaxial lateral masses exposed anteriorly showed that there was enough space, for the safe anterior implantation of the cage. The surgery using the transoral atlantoaxial reduction and plate makes possible the implantation of the anterior cage. CONCLUSION: The implantation of anterior atlantoaxial lateral mass intervertebral cage through transoral approach is possible. PMID- 28336192 TI - Radiological morphology variances of transient osteoporosis of the hip. AB - BACKGROUND: Although several morphological abnormalities or variances of the hip joint have been proposed to be associated with hip joint degeneration, few studies have investigated any radiological features in patients with transient osteoporosis of the hip (TOH). The purpose of this study is to evaluate the morphological variances of the hip joint in TOH patients radiographically. METHODS: The TOH group consisted of 31 hips in 31 patients. Age- and gender matched asymptomatic hips in patients with unilateral osteonecrosis of the femoral head were served as controls. Radiographs and MRI were utilized to examine the following parameters: acetabular dysplasia, acetabular overcoverage, acetabular retroversion, and asphericity of the femoral head-neck junction. Also, localization of the main bone marrow edema (BME) lesion was investigated. RESULTS: TOH patients had a significantly higher incidence of acetabular retroversion (52% with a positive cross-over sign and 29% with posterior wall deficiency) than the controls (13%, P = 0.0023; 6%, P = 0.043, respectively), which was also confirmed by smaller acetabular anteversion angles on axial MRI. In addition, TOH patients tended to show asphericity of the anterior femoral head neck junction compared to controls (39% vs. 13%, P = 0.040). In 90% of the TOH patients, the main BME lesion was located in the subchondral area of the superior portion of the femoral head, and 77% of the lesion were recognized as a band-like pattern in MRI. CONCLUSIONS: Acetabular retroversion and asphericity of the femoral head-neck junction were more commonly observed in TOH patients compared to controls. The main BME lesion was most frequently located in the superior portion of the femoral head. PMID- 28336193 TI - Insights into Chronic Functional Movement Disorders: The Value of Qualitative Psychiatric Interviews. PMID- 28336194 TI - Screening Medical Patients for Depression: Lessons From a National Program in Cancer Clinics. AB - BACKGROUND: Screening has been recommended to improve the identification of depression in medical patients. There is, therefore, a need for useful practical information on how to successfully implement large-scale depression screening in medical clinics. OBJECTIVE: To describe the practical lessons learned from our experience of implementing a large-scale depression screening program in cancer clinics throughout Scotland, UK. METHOD: Reflective review based on the experience of the screening team and records of the iterative development of the program. FINDINGS: Systematic screening for depression in patients with medical illnesses can be delivered in clinics as long as the program is well designed. Design issues include ensuring the engagement of staff and patients, implementing efficient 2-stage screening processes and effectively managing workflow and quality assurance. DISCUSSION: Screening has the potential to offer a solution to the well-documented problem of missed depression and other psychiatric diagnoses, thereby improving patient care if closely linked to treatment provision. PMID- 28336195 TI - Cognitive correlates of visual neural plasticity in schizophrenia. AB - Neuroplasticity may be an important treatment target to improve the cognitive deficits in schizophrenia (SZ). Yet, it is poorly understood and difficult to assess. Recently, a visual high-frequency stimulation (HFS) paradigm that potentiates electroencephalography (EEG)-based visual evoked potentials (VEP) has been developed to assess neural plasticity in the visual cortex. Using this paradigm, we examined visual plasticity in SZ patients (N=64) and its correlations with clinical symptoms, neurocognition, functional capacity, and community functioning. VEPs were assessed prior to (baseline), and 2-, 4-, and 20 min after (Post-1, Post-2, and Post-3, respectively) 2min of visual HFS. Cluster based permutation tests were conducted to identify time points and electrodes at which VEP amplitudes were significantly different after HFS. Compared to baseline, there was increased negativity between 140 and 227ms for the early post HFS block (average of Post-1 and Post-2), and increased positivity between 180 and 281ms for the late post-HFS block (Post-3), at parieto-occipital and occipital electrodes. The increased negativity in the early post-HFS block did not correlate with any of the measures, whereas increased positivity in the late post-HFS block correlated with better neurocognitive performance. Results suggest that SZ patients exhibit both short- and long-term plasticity. The long-term plasticity effect, which was present 22min after HFS, was evident relatively late in the VEP, suggesting that neuroplastic changes in higher-order visual association areas, rather than earlier short-term changes in primary and secondary visual cortex, may be particularly important for the maintenance of neurocognitive function in SZ. PMID- 28336196 TI - New strategy of closed suction drainage after primary total hip arthroplasty. AB - OBJECTIVE: The purpose of this study was to evaluate the effect of late applied negative pressure on postoperative drain output after primary total hip arthroplasty (THA). PATIENTS AND METHODS: 100 patients (100 hips) were treated by closed suction drainage applying negative pressure immediately after THA (group I). The remaining 100 patients (100 hips) were treated by the same drainage system, but the negative pressure was not applied in the first 24 h after THA and then negative pressure was applied (group II). RESULTS: The mean total drain output was different between the two groups (group I: 597 +/- 200.1 mL, group II: 403 +/- 204.1 mL; p < 0.05). Reported drain output from immediate postoperative to postoperative day one was 369 +/- 125.5 ml in group I and 221 +/- 141.3 ml in group II (p < 0.05). The change of hemoglobin from immediate postoperative to 24 h after THA was lower in group II (group I: 1.5 +/- 0.62 g/dL, group II: 1.1 +/- 0.73 g/dL; p = 0.004). The mean unit number of blood transfusions was 1.0 (range, 0.0-5.0) in group I and 0.3 (range, 0.0-2.0) in group II (p < 0.05). There was no difference in Harris hip score between the two groups at postoperative 1 year or last follow-up (p = 0.073). CONCLUSION: The minor change in drain system management can reduce postoperative blood loss after primary THA and the need for transfusion. LEVEL OF EVIDENCE: Level III, Therapeutic study. PMID- 28336197 TI - Determination of specific IgE in pericardial fluid. PMID- 28336198 TI - Augmented oxidative stress in infertile women with persistent chlamydial infection. AB - There is established association between oxidative stress, infections of genital tract and fertility. Genital tract infections may provoke increased production of free radicals and generate oxidative stress that can be involved in pathophysiology of a number of reproductive diseases and complications during pregnancy. The aim of this study was to determine connection between oxidative stress and infertility associated with persistent chlamydial infection. Serum samples of infertile women with tubal factor infertility (TFI), women with multiple spontaneous abortions (MSA) and fertile women was screened for C. trachomatis MOMP specific IgG and IgA antibodies and cHSP60 specific igG antibodies using ELISA. The levels of superoxide anion radical, nitric oxide and reduced glutathione were determined spectrophotometricaly. Serum levels of testosterone, luteinizing hormone and follicle stimulating hormone were determined by enzyme-linked fluorescent immunoassay method. Our results showed that persistent infection was more prevalent in TFI than in MSA group, whereas seropositivity was higher in MSA than in TFI group of patients. We also found that superoxide anion was significantly lower, while LH was markedly higher in TFI and MSA group of patients. However, when our results were analyzed according to the serological status of chlamydial infection, we found that parameters of oxidative stress, superoxide anion and index of oxidative stress, defined as relative ratio between superoxide anion and nitrites sum and glutathione ((O2 +NO2-)/GSH) were significantly elevated in infertile patients with persistent chlamydial infection compared to seropositive and seronegative patients. Our findings point to the possible impact of Chlamydia trachomatis infection on prooxidative-antioxidative balance that can influence fertility potential in women with persistent chlamydial infection. PMID- 28336199 TI - Primary care physician decision making regarding referral for bariatric surgery: a national survey. AB - BACKGROUND: Bariatric surgery is the most effective treatment for severe obesity. It results in significant and sustained weight loss and reduces obesity-related co-morbidities. Despite an increasing prevalence of severe obesity, the number of bariatric operations performed in Denmark has decreased during the past years. This is only partly explained by changes in the national guidelines for bariatric surgery. The purpose of the cross-sectional study is to investigate referral patterns and possible reservations regarding bariatric surgery among Danish primary care physicians (PCPs). SETTING: Primary care physicians in Denmark METHODS: A total of 300 Danish PCPs were invited to participate in a questionnaire survey regarding experiences with bariatric surgery, reservations about bariatric surgery, attitudes to specific patient cases, and the future treatment of severe obesity. Most questions required a response on a 5-point Likert scale (strongly disagree, disagree, neither agree nor disagree, agree, and strongly agree) and frequency distributions were calculated. RESULTS: 133 completed questionnaires (44%) were returned. Most physicians found that they had good knowledge about the national referral criteria for bariatric surgery. With respect to the specific patient cases, a remarkably smaller part of physicians would refer patients on their own initiative, compared with the patient's initiative. Fear of postoperative surgical complications and medical complications both influenced markedly the decision to refer patients for surgery. Only 9% of the respondents indicated that bariatric surgery should be the primary treatment option for severe obesity in the future. CONCLUSION: Danish PCPs express severe concerns about surgical and medical complications following bariatric surgery. This might, in part, result in a low rate of referral to bariatric surgery. PMID- 28336200 TI - Systematic review of transgastric ERCP in Roux-en-Y gastric bypass patients. AB - Balloon-assisted endoscopic retrograde cholangiopancreatoscopy (ERCP) in Roux-en Y gastric bypass (RYGB) patients is technically challenging due to anatomic and accessory constraints, thus success rates are modest. Transgastric ERCP (TG-ERCP) offers a viable alternative. We aimed to systematically review the literature on TG-ERCP in RYGB patients to better define the technical approaches, success rates, and adverse events of this procedure. A computer-assisted search of the Embase and PubMed databases was performed to identify studies that focused on the techniques and clinical outcomes of TG-ERCP. Two investigators independently identified studies and abstracted relevant data. The literature search yielded 26 eligible studies comprising 509 TG-ERCP cases. Access to the excluded stomach to facilitate ERCP was achieved laparoscopically in 58% of reported cases, via open surgery (6% of reported cases), by antecedent placement of a percutaneous gastrostomy tube (33%), or with endoscopic ultrasound assistance (3%). Successful gastric access was reported in 100% of cases and successful ductal cannulation in 98.5%. Adverse events were reported in 14% of cases; 80% of these were related to gastrostomy creation and the rest were attributable to ERCP. Wound infections (n = 19, 3.7%) were the most common gastrostomy-related adverse event, and post-ERCP pancreatitis (n = 7, 1.4%) was the most common ERCP-related adverse event. No deaths were reported. Based on existing observational studies, TG-ERCP appears to be a safe and highly effective approach in patients with RYGB anatomy. Additional research and clinical experience are needed to more precisely define the risk benefit ratio and optimal technique of TG-ERCP. PMID- 28336201 TI - A facile method for isolation of recombinant human apolipoprotein A-I from E. coli. AB - Apolipoprotein (apo) A-I is the major protein component of high-density lipoprotein (HDL) and plays key roles in the Reverse Cholesterol Transport pathway. In the past decade, reconstituted HDL (rHDL) has been employed as a therapeutic agent for treatment of atherosclerosis. The ability of rHDL to promote cholesterol efflux from peripheral cells has been documented to reduce the size of atherosclerotic plaque lesions. However, development of apoA-I rHDL based therapeutics for human use requires a cost effective process to generate an apoA-I product that meets "Good Manufacturing Practice" standards. Methods available for production and isolation of unmodified recombinant human apoA-I at scale are cumbersome, laborious and complex. To overcome this obstacle, a streamlined two-step procedure has been devised for isolation of recombinant untagged human apoA-I from E. coli that takes advantage of its ability to re-fold to a native conformation following denaturation. Heat treatment of a sonicated E. coli supernatant fraction induced precipitation of a large proportion of host cell proteins (HCP), yielding apoA-I as the major soluble protein. Reversed-phase HPLC of this material permitted recovery of apoA-I largely free of HCP and endotoxin. Purified apoA-I possessed alpha-helix secondary structure, formed rHDL upon incubation with phospholipid and efficiently promoted cholesterol efflux from cholesterol loaded J774 macrophages. PMID- 28336202 TI - Medical-surgical activity and the current state of training of urology residents in Spain: Results of a national survey. AB - OBJECTIVES: To determine the actual state of medical-surgical activity and training for urology residents in Spain. MATERIAL AND METHOD: We designed 2 anonymous surveys, which were uploaded with the Google Docs(c) tool so that the respondents could answer the surveys online. The online collection period was September 2015 to January 2016. The collected data were processing using the statistical programme IBM SPSS for Windows, Version 21.0 and the programme R version 3.2.3. RESULTS: The total number of responders was 163. In reference to the number of physically present on-call residents, the majority conducted between 4 and 6 shifts a month. Eighty-four of those surveyed indicated that they were in the operating room less than 20hours a week, and 43 of these even less than 10hours. Thirty percent of those surveyed had not performed any transurethral resection. The majority had performed at least one prostatic adenomectomy, but had not performed any major oncologic procedure, either laparoscopically or openly. In the questions concerning training and training courses, we found that most of the residents trained in laparoscopy at the hospital or at home. The overall satisfaction for the residence was assessed at 2.6. Based on this score, the overall satisfaction could be considered moderate. CONCLUSIONS: Efforts should be directed towards standardising the acquisition of surgical and nonsurgical skills, ensuring access to training courses, establishing a minimum of required operations per year and achieving an objective assessment of the specialty. PMID- 28336203 TI - Is extracorporeal shock wave lithotripsy a current treatment for urolithiasis? A systematic review. AB - INTRODUCTION: Technological advances have prompted a change in the management of urolithiasis. Endourological techniques are gaining importance because they are highly effective treatments. The aim of this study was to answer the question of whether extracorporeal shock wave lithotripsy (ESWL) is still a competitive alternative compared with other therapeutic modalities. ACQUISITION OF EVIDENCE: We conducted a literature search of articles published in the past 5 years. We identified 12 randomized and comparative studies and assessed the methodology and results of the study variables. We performed a narrative synthesis of the included studies. To summarise the variables, we used the mean and standard deviation for continuous variables and absolute numbers and percentages for the qualitative variables. ANALYSIS OF THE EVIDENCE: Of the studies reviewed, 7 evaluated the various treatments for nephrolithiasis and 5 evaluated the treatments for ureteral lithiasis. At the renal level, a stone-free rate of 33.33 91.5% at 3 months was reached with ESWL, while a rate of 90.4-100% was achieved with the other endourological techniques, without finding statistically significant differences in the studies. At the ureteral level, a stone-free rate of 73.5-82.2% at 3 months was reached with ESWL, while a rate of 79-94.1% was achieved with the other endourological techniques, without finding statistically significant differences in the studies. CONCLUSION: There is a lack of homogeneity among the published studies. ESWL is a minimally invasive treatment that with an appropriate technique and patient selection achieves high effectiveness, thus maintaining an important role at this time. PMID- 28336204 TI - N-terminal pro-brain natriuretic peptide is related with coronary flow velocity reserve and diastolic dysfunction in patients with asymmetric hypertrophic cardiomyopathy. AB - BACKGROUND: The relations of elevated N-terminal pro-brain natriuretic peptide (NT-pro-BNP) and cardiac ischemia in hypertrophic cardiomyopathy (HCM) patients is uncertain. Therefore we designed the study with the following aims: (1) to analyze plasma concentrations of NT-pro-BNP in various subsets of HCM patients; (2) to reveal the correlations of NT-pro-BNP, myocardial ischemia, and diastolic dysfunction; (3) to assess predictors of the elevated plasma levels of NT-pro BNP. METHODS AND RESULTS: In 61 patients (mean age 48.9+/-16.3 years; 26 male) with asymmetric HCM plasma levels of NT-pro-BNP were obtained. Standard transthoracic examination, tissue Doppler echocardiography with measurement of transthoracic coronary flow velocity reserve (CFVR) in left anterior descending artery (LAD) was done. Mean natural logarithm value of NT-pro-BNP was 7.11+/ 0.95pg/ml [median value 1133 (interquartile range 561-2442)pg/ml]. NT-pro-BNP was significantly higher in patients with higher NYHA class, in obstructive HCM, more severe mitral regurgitation, increased left atrial volume index (LAVI), presence of calcified mitral annulus, elevated left ventricular (LV) filling pressure and in decreased CFVR. Levels of NT-pro-BNP significantly correlated with the ratio of E/e' (r=0.534, p<0.001), LV outflow tract gradient (r=0.503, p=0.024), LAVI (r=0.443, p<0.001), while inversely correlated with CFVR LAD (r=-0.569, p<0.001). When multivariate analysis was done only CFVR LAD and E/e' emerged as independent predictors of NT-pro-BNP. CONCLUSION: Plasma levels of NT-pro-BNP were significantly higher in HCM patients with more advanced disease. Elevated NT-pro BNP not only reflects the diastolic impairment of the LV, but it might also be the result of cardiac ischemia in patients with HCM. PMID- 28336206 TI - Toxic metal pollution in the Yellow Sea and Bohai Sea, China: distribution, controlling factors and potential risk. AB - The Bohai Sea (BS) and Yellow Sea (YS), which are adjacent to the most urbanized and industrialized areas in China, are facing a variety of environmental problems. Two cruises were conducted to investigate the pollution status of toxic metals in BS and YS sediments. They generally presented a decreasing trend from near shore to offshore. In addition, two high concentration areas were observed in the central south YS and north of the Shandong Peninsula. The results of multiple regression analyses suggest that Hg is mainly controlled by anthropogenic loading, whereas for Cr, Cu, Ni, Pb and Zn, sediment properties, especially the Fe oxides content, play a more important role. For As and Cd, the contribution of anthropogenic loading and sediment properties are comparable. The risk assessment indicates that Hg, As, Cd and Ni should be listed as the primary contaminant metals in the BS and YS. PMID- 28336205 TI - Andersen-Tawil syndrome: Clinical presentation and predictors of symptomatic arrhythmias - Possible role of polymorphisms K897T in KCNH2 and H558R in SCN5A gene. AB - BACKGROUND: Andersen-Tawil syndrome (ATS) is rare channelopathy caused by KCNJ2 mutation and probably KCNJ5. It is characterized by arrhythmias, neurological symptoms, and dysmorphic features. The present study retrospectively examined the characteristics of 11 unrelated families with ATS. METHODS: This study consisted of 11 probands positive for KCNJ2 variants and 33 family members (mean age 30.0+/ 17.3 years, female n=31). Additional genetic screening of 3 LQTS genes (KCNQ1, KCNH2, SCN5A) was performed in 9 families. Predictors of arrhythmias [premature ventricular beats>2000/24h, biventricular and polymorphic ventricular tachycardia (VT)], syncope, and/or cardiac arrest (CA) were evaluated. RESULTS: In KCNJ2 mutation carriers vs non-carriers (n=25 vs n=19) significant differences were observed in U-wave manifestations in V2-V4, Tpeak-Tend duration, QTUc duration (p<0.0001), dysmorphic features, and neurological symptoms. Compared to asymptomatic carriers (n=9), in those with arrhythmias and/or syncope and/or CA (n=16) micrognathia (p=0.004), periodic paralysis (p=0.019), palpitation (p=0.005), U-wave n V2-V4 (p=0.049) were more frequent; QTU (p=0.045) and Tpeak Tend (p=0.014) were also longer (n=9). In the subgroup of carriers with syncope and/or cardiac arrest (n=10, 90% women), K897T-KCNH2 polymorphism (p=0.02), periodic paralysis (p=0.004), muscle weakness (p=0.04), palpitations (p=0.04), arrhythmias (biventricular VT, p=0.003; polymorphic VT, p=0.009) were observed more frequently. Tpeak-Tend duration was longer (p=0.007) and the percentage of patients with premature ventricular contraction >2000/24h was higher (p=0.005). CONCLUSION: A higher risk of arrhythmia, syncope, and/or CA is associated with the presence of micrognathia, periodic paralysis, and prolonged Tpeak-Tend time. Our findings suggest that K897T may contribute to the occurrence of syncope. PMID- 28336207 TI - Heavy metal concentrations in some gastropods and bivalves collected from the fishing zone of South India. AB - The present study investigates heavy metal concentrations in gastropods and bivalves collected from major fishing centers in South India. Three gastropods, Bursa spinosa, Tibia curta, and Murex trapa, and two bivalves, Perna viridis and Villoritta cyprinoids, were collected for the analysis of heavy metals. The metals in the present study followed the order Mg>Ca>Zn>Fe>Cu>Mn>Cr>Pb>Ni>Co>Cd. Trace metal concentrations in the soft tissue of the molluscs varied as follows: for Cd: 0.04-5.33, Co: 0.09-0.87, Cr: 2.18-7.59, Cu: 9.54-37.02, Mn: 1.30-8.50, Ni: 0.94-3.21, Pb: 1.16-2.64 and Zn: 68.16-113.64mgkg-1. Metal concentrations in all the species were below the limits proposed by the World Health Organization, except for Pb and Cd. This baseline study suggests that the levels of toxic metals in M. trapa, T. curta, and B. spinosa should be continuously monitored to assess the fate and effects of these metals in this fragile ecosystem. PMID- 28336208 TI - Reducing the marine debris of recreational hoop nets in south-eastern Australia. AB - Alternative configurations of Australian recreational portunid hoop nets were investigated to address debris and selectivity issues. Four treatment nets (all comprising 152-mm polyamide-PA mesh) were assessed that differed in their twine (conventional multifilament vs new multi-monofilament) and fishing configuration (conventional conical vs inverted shapes). The conical multifilament design lost means (+/-SEs) of 130.6+/-23.1 and 5.3+/-1.2mm of twine 3-h soak-1 when used to target Scylla serrata and Portunus pelagicus. Inverting this hoop net significantly reduced legal-sized catches (by up to 70%) and with greater twine loss (*5) when targeting P. pelagicus. Conversely, both multi-monofilament configurations maintained legal catches of S. serrata and P. pelagicus, but lost 78 and 95% less twine than the conical multifilament design. Using multi monofilament hoop nets could reduce PA debris by thousands of m p.a. in south eastern Australia, without affecting targeted catches. Further, a lower fishing height of inverted multi-monofilament nets might reduce non-portunid bycatch. PMID- 28336209 TI - Transboundary movement of marine litter in an estuarine gradient: Evaluating sources and sinks using hydrodynamic modelling and ground truthing estimates. AB - Marine debris' transboundary nature and new strategies to identify sources and sinks in coastal areas were investigated along the Paranagua estuarine gradient (southern Brazil), through integration of hydrodynamic modelling, ground truthing estimates and regressive vector analysis. The simulated release of virtual particles in different parts of the inner estuary suggests a residence time shorter than 5days before being exported through the estuary mouth (intermediate compartment) to the open ocean. Stranded litter supported this pathway, with beaches in the internal compartment presenting proportionally more items from domestic sources, while fragmented items with unknown sources were proportionally more abundant in the oceanic beaches. Regressive vector analysis reinforced the inner estuarine origin of the stranded litter in both estuarine and oceanic beaches. These results support the applicability of simple hydrodynamic models to address marine debris' transboundary issues in the land-sea transition zone, thus supporting an ecosystem transboundary (and not territorial) management approach. PMID- 28336210 TI - Burkholderia pseudomallei and Burkholderia mallei vaccines: Are we close to clinical trials? AB - B. pseudomallei is the cause of melioidosis, a serious an often fatal disease of humans and animals. The closely related bacterium B. mallei, which cases glanders, is considered to be a clonal derivative of B. pseudomallei. Both B. pseudomallei and B. mallei were evaluated by the United States and the former USSR as potential bioweapons. Much of the effort to devise biodefence vaccines in the past decade has been directed towards the identification and formulation of sub-unit vaccines which could protect against both melioidosis and glanders. A wide range of proteins and polysaccharides have been identified which protective immunity in mice. In this review we highlight the significant progress that has been made in developing glycoconjugates as sub-unit vaccines. We also consider some of the important the criteria for licensing, including the suitability of the "animal rule" for assessing vaccine efficacy, the protection required from a vaccine and the how correlates of protection will be identified. Vaccines developed for biodefence purposes could also be used in regions of the world where naturally occurring disease is endemic. PMID- 28336211 TI - The state of midwifery in small island Pacific nations. AB - BACKGROUND: Strengthening midwifery is a global priority. Recently, global evidence has provided momentum toward developing the midwifery workforce. In 2014, the State of the World's Midwifery 2014 Report explored midwifery services in 73 low to middle income countries. In the South Pacific region, only Papua New Guinea and the Solomon Islands were included. This means that there is little known on the state of midwifery in the small island countries in the South Pacific. AIM: To explore the current situation of the education, regulation and association of midwives in 12 small island nations of the South Pacific and determine the gaps in these areas. METHODS: A descriptive study was undertaken. Data were collected through a survey completed by key representatives (usually the Chief Nursing and Midwifery Officer) from each of the 12 countries. Ethical approval was received from the relevant Human Research Ethics Committee. FINDINGS: Many of the countries had few midwives, in some instances, only two midwives for the whole country. Midwifery education programs included post graduate diploma, certificates and bachelor degrees. Midwives were required to be registered nurses in all countries. Regulation and licensing also varied - most countries did not have a separate licensing system for midwives. Only three countries have a specific professional association for midwives. CONCLUSION: The variation and the small number of midwives poses challenges for workforce planning. Consideration could be given to developing regional standards and potentially a shared curriculum framework. Ongoing collaboration and networking between countries is a critical part of future developments. PMID- 28336212 TI - Impact of a continuing professional development intervention on midwifery academics' awareness of cultural safety. AB - BACKGROUND: Cultural safety in higher education learning and teaching environments is paramount to positive educational outcomes for Aboriginal and/or Torres Strait Islander (hereafter called First Peoples) students. There is a lack of research evaluating the impact of continuing professional development on midwifery academics' awareness of cultural safety. AIM: To implement and evaluate a continuing professional development intervention to improve midwifery academics' awareness of cultural safety in supporting First Peoples midwifery students success. METHODS: A pre-post intervention mixed methods design was used. Academics (n=13) teaching into a Bachelor of Midwifery program agreed to participate. The intervention consisted of two workshops and five yarning circles across a semester. Data included the Awareness of Cultural Safety Scale, self assessment on cultural safety and perceptions of racism, evaluation of the intervention, participants' journal entries, and researcher's reflections. FINDINGS: Responses on the Awareness of Cultural Safety Scale revealed significant improvement in participants' awareness of cultural safety. There was an upward trend in self-assessment ratings. Participants reported high levels of satisfaction with the intervention or workshops and yarning circles. Participants' journal entries revealed themes willingness to participate and learn, confidence as well as anger and distress. CONCLUSION: Increased awareness of cultural safety can be transformative for midwifery academics. Workshops and yarning circles can support academics in moving beyond a 'sense of paralysis' and engage in challenging conversations to transform their learning and teaching and in turn foster a culturally safe learning and teaching environment for First Peoples midwifery students towards success. PMID- 28336213 TI - Transient and permanent changes in DNA methylation patterns in inorganic arsenic mediated epithelial-to-mesenchymal transition. AB - Chronic low dose inorganic arsenic exposure causes cells to take on an epithelial to-mesenchymal phenotype, which is a crucial process in carcinogenesis. Inorganic arsenic is not a mutagen and thus epigenetic alterations have been implicated in this process. Indeed, during the epithelial-to-mesenchymal transition, morphologic changes to cells correlate with changes in chromatin structure and gene expression, ultimately driving this process. However, studies on the effects of inorganic arsenic exposure/withdrawal on the epithelial-to-mesenchymal transition and the impact of epigenetic alterations in this process are limited. In this study we used high-resolution microarray analysis to measure the changes in DNA methylation in cells undergoing inorganic arsenic-induced epithelial-to mesenchymal transition, and on the reversal of this process, after removal of the inorganic arsenic exposure. We found that cells exposed to chronic, low-dose inorganic arsenic exposure showed 30,530 sites were differentially methylated, and with inorganic arsenic withdrawal several differential methylated sites were reversed, albeit not completely. Furthermore, these changes in DNA methylation mainly correlated with changes in gene expression at most sites tested but not at all. This study suggests that DNA methylation changes on gene expression are not clear-cut and provide a platform to begin to uncover the relationship between DNA methylation and gene expression, specifically within the context of inorganic arsenic treatment. PMID- 28336215 TI - Association of increased levels of MCP-1 and cathepsin-D in young onset type 2 diabetes patients (T2DM-Y) with severity of diabetic retinopathy. AB - AIM: Young onset type 2 diabetes patients (T2DM-Y) have been shown to possess an increased risk of developing microvascular complications particularly diabetic retinopathy. However, the molecular mechanisms are not clearly understood. In this study, we investigated the serum levels of monocyte chemotactic protein 1 (MCP-1) and cathepsin-D in patients with T2DM-Y without and with diabetic retinopathy. METHODS: In this case-control study, participants comprised individuals with normal glucose tolerance (NGT=40), patients with type 2 diabetes mellitus (T2DM=35), non-proliferative diabetic retinopathy (NPDR=35) and proliferative diabetic retinopathy (PDR=35). Clinical characterization of the study subjects was done by standard procedures and MCP-1 and cathepsin-D were measured by ELISA. RESULTS: Compared to control individuals, patients with T2DM Y, NPDR and PDR exhibited significantly (p<0.001) higher levels of MCP-1. Cathepsin-D levels were also significantly (p<0.001) higher in patients with T2DM Y without and with diabetic retinopathy. Correlation analysis revealed a positive association (p<0.001) between MCP-1 and cathepsin-D levels. There was also a significant negative correlation of MCP1/cathepsin-D with C-peptide levels. The association of increased levels of MCP-1/cathepsin-D in patients with DR persisted even after adjusting for all the confounding factors. CONCLUSION: As both MCP-1 and cathepsin-D are molecular signatures of cellular senescence, we suggest that these biomarkers might be useful to predict the development of retinopathy in T2DM-Y patients. PMID- 28336216 TI - Leptin is associated with cardiopulmonary fitness independent of body-mass index and insulin sensitivity in adolescents with type 1 diabetes: a brief report from the EMERALD study. AB - Cardiopulmonary fitness is decreased in type 1 diabetes for reasons that are incompletely understood. In this study, leptin was associated with exercise capacity independent of insulin sensitivity (IS) and body mass index (BMI), suggesting that leptin may relate to cardiopulmonary fitness by mechanisms beyond IS and/or obesity. PMID- 28336214 TI - Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl hydrocarbon receptor. AB - Indoleamine 2,3-dioxygenase 1 (IDO1) plays a key role in the immune system by regulating tryptophan levels and T cell differentiation. Several tumor types overexpress IDO1 to avoid immune surveillance making IDO1 of interest as a target for therapeutic intervention. As a result, several IDO1 inhibitors are currently being tested in clinical trials for cancer treatment as well as several other diseases. Many of the IDO1 inhibitors in clinical trials naturally bear structural similarities to the IDO1 substrate tryptophan, as such, they fulfill many of the structural and functional criteria as potential AHR ligands. Using mouse and human cell-based luciferase gene reporter assays, qPCR confirmation experiments, and CYP1A1 enzyme activity assays, we report that some of the promising clinical IDO1 inhibitors also act as agonists for the aryl hydrocarbon receptor (AHR), best known for its roles in xenobiotic metabolism and as another key regulator of the immune response. The dual role as IDO antagonist and AHR agonist for many of these IDO target drugs should be considered for full interrogation of their biological mechanisms and clinical outcomes. PMID- 28336217 TI - Pathogenic Mechanisms of Cryptosporidium and Giardia. AB - Intestinal protozoa are important etiological agents of diarrhea, particularly in children, yet the public health risk they pose is often neglected. Results from the Global Enteric Multicenter Study (GEMS) showed that Cryptosporidium is among the leading causes of moderate to severe diarrhea in children under 2 years. Likewise, Giardia infects approximately 200 million individuals worldwide, and causes acute diarrhea in children under 5 years. Despite this recognized role as pathogens, the question is why and how these parasites cause disease in some individuals but not in others. This review focuses on known pathogenic mechanisms of Cryptosporidium and Giardia, and infection progress towards disease. PMID- 28336218 TI - Malaria Altering Host Attractiveness and Mosquito Feeding. AB - Several studies have suggested that malaria parasites stack the odds of transmission in their favour by manipulating the attraction profiles of their hosts. A recent study provides evidence that a specific parasite factor, (E)-4 hydroxy-3-methyl-but-2-enyl pyrophosphate, may increase both the attractiveness of infected vertebrates and the susceptibility of mosquitoes to infection. PMID- 28336219 TI - Comparison of the mesophilic and thermophilic anaerobic digestion of spent cow bedding in leach-bed reactors. AB - Anaerobic digestion of spent cow bedding in batch leach-bed reactors (LBRs) was compared in mesophilic and thermophilic conditions for the first time. Results show that the use of thermophilic conditions enhanced only the degradation kinetics of easily-degradable matter during the first days of the digestion, whereas similar methane yields (80% of the Biomethane Potential) were reached after 42days at both temperatures. Therefore, the anaerobic digestion in LBRs of spent cow bedding, a substrate rich in slowly-degradable compounds, was not improved in term of methane production considering the overall digestion time. Moreover, the high initial biogas production rate in thermophilic reactors was found to significantly reduce the energetic performance of the cogeneration unit at industrial scale, leading to a 5.9% decrease in the annual electricity production when compared to a mesophilic one. PMID- 28336220 TI - Ureteroscopy and laser stone fragmentation (URSL) for large (>=1 cm) paediatric stones: Outcomes from a university teaching hospital. AB - INTRODUCTION: The treatment of large renal stones (>=1 cm) in paediatric patients is challenging. The usual treatment options include percutaneous nephrolithotomy (PCNL) or shockwave lithotripsy (SWL). There is a rise in the use of ureteroscopy and laser stone fragmentation (URSL) for paediatric stones; however, outcomes of treatment for large renal stones in this age group are still largely unknown. OBJECTIVE: To investigate the outcome of URSL for large paediatric renal stones >=1 cm treated at the present institution over the last 5 years. METHODS: A retrospective review was performed of outcomes from the prospectively maintained stone database. Only paediatric patients undergoing ureteroscopic (rigid or flexible ureteroscopy (URS)) procedures for stones >=1 cm were included. Patient demographics, operative details, stone burden, hospital stay, complications and stone clearance were recorded and analysed. RESULTS: From April 2010 to June 2015, 18 paediatric patients with a mean age of 10.4 years (range 3.6-15) underwent 35 ureteroscopic procedures for large stones (>=1 cm). The stone location was in the kidney (n = 14), ureter (n = 1), and in both the kidney and ureter for the remaining three patients. Nine patients had multiple stones. There was a preceding history of PCNL in four patients, with one patient having URS combined with a PCNL. The mean follow-up was 2.7 years (range 0-5). A postoperative stent was inserted in 21 (60%) patients. The overall stone-free rate (SFR) was 89% for a mean of 1.8 procedures per patient (range 1-4) - see Summary Table below. There was an inability to access stone within a lower pole calyx in one patient, despite maximum deflection of the ureteroscope. No intra- or post-operative complications were noted, and mean hospital stay was 1.1 days (range 0-5). DISCUSSION: Published papers in adult literature have shown that ureteroscopy and laser fragmentation (URSL) is a viable alternative to PCNL. Newer equipment and improved techniques have resulted in SFRs being comparable with PCNL. A recent systematic review reported an SFR of 91% for large adult stones (>2 cm) for a mean 1.45 procedures per patient, and an overall complication rate of 8.6%. The present study has also demonstrated excellent outcomes in the use of ureteroscopy and laser fragmentation for the management of large paediatric stones with no complications. CONCLUSION: The results show that paediatric URSL for large stones achieves a good SFR with minimal morbidity and is a good treatment option in established endourological units. PMID- 28336221 TI - The use of contact lens telescopic systems in low vision rehabilitation. AB - Refracting telescopes are afocal compound optical systems consisting of two lenses that produce an apparent magnification of the retinal image. They are routinely used in visual rehabilitation in the form of monocular or binocular hand held low vision aids, and head or spectacle-mounted devices to improve distance visual acuity, and with slight modifications, to enhance acuity for near and intermediate tasks. Since the advent of ground glass haptic lenses in the 1930's, contact lenses have been employed as a useful refracting element of telescopic systems; primarily as a mobile ocular lens (the eyepiece), that moves with the eye. Telescopes which incorporate a contact lens eyepiece significantly improve the weight, comesis, and field of view compared to traditional spectacle mounted telescopes, in addition to potential related psycho-social benefits. This review summarises the underlying optics and use of contact lenses to provide telescopic magnification from the era of Descartes, to Dallos, and the present day. The limitations and clinical challenges associated with such devices are discussed, along with the potential future use of reflecting telescopes incorporated within scleral lenses and tactile contact lens systems in low vision rehabilitation. PMID- 28336222 TI - Evaluation of the shifting of the line of sight and higher order aberrations of eyes with keratoconus after corneal cross-linking. AB - AIM: To evaluate changes in the coordinates of the line of sight (LoS) and higher order aberrations (HOAs) of eyes with keratoconus, following corneal cross linking (CXL). METHODS: All patients (93 eyes) underwent detailed ophthalmologic examination and Pentacam HR measurements at baseline and at 3, 6, and 12 months after corneal CXL. LoS coordinates on the horizontal (x) and vertical (y) axes, vertical coma, vertical trefoil, spherical aberration, total root-mean square (RMS), and HOA-RMS values were recorded along with visual acuity and topographical parameters. RESULTS: LoS significantly shifted to the nasal region after corneal CXL in both right and left eyes (p=0.003 and p=0.01, respectively). Horizontal axis values of both eyes significantly shifted to the temporal region at postoperative 6th months compared to the baseline measurements (p=0.02 and p=0.02, respectively) and remained the same between postoperative 6th months and 12th months (p=1.00 and p=0.97, respectively). Total-RMS, HOA-RMS, vertical coma, and spherical aberration values significantly improved after corneal CXL (p<0.001, p=0.02, p=0.04, and p<0.001, respectively). The improvements in HOAs were significant at postoperative 6th months compared to the baseline measurements (p=0.003, p=0.02, p<0.001, and p=0.003, respectively) while remained the same between postoperative 6th months and 12th months (p>0.05 for all values). The changes in horizontal-axis coordinates in left eyes were significantly correlated with anterior elevation, anterior astigmatism, total-RMS and HOA-RMS changes (r2=0.20, p=0.03; r2=0.35, p<0.01; r2=0.50, p<0.001 and r2=0.35, p=0.004; respectively). CONCLUSIONS: LoS significantly shifted to the nasal region and HOAs improved after corneal CXL and these changes stabilized 6th months after corneal CXL. It would be more better to perform refractive surgery in crosslinked corneas at least 6th months after corneal CXL. PMID- 28336223 TI - Paediatric idiopathic limbal stem cell deficiency. AB - Acquired limbal stem cell deficiency (LSCD) describes a condition in which the corneal limbal stem cells are altered or destroyed, typically due to ocular trauma, chronic allergy or inflammation. Idiopathic LSCD is a term used to describe limbal stem cell failure in the absence of any identifiable causative factor. While several cases of adult-onset LSCD have been identified previously, this case report describes a rare presentation of bilateral asymmetric idiopathic paediatric limbal stem cell deficiency in a sixteen-year-old male with an otherwise unremarkable ocular history. PMID- 28336224 TI - Surface coverage with single vs. multiple gaze surface topography to fit scleral lenses. AB - OBJECTIVES: To determine surface coverage of measurements using the sMap3D(r) corneo-scleral topographer in patients presenting for scleral lens fitting. METHODS: Twenty-five eyes of 23 scleral lens patients were examined. Up-gaze, straight-gaze, and down-gaze positions of each eye were "stitched" into a single map. The percentage surface coverage between 10mm and 20mm diameter circles from corneal center was compared between the straight-gaze and stitched images. Scleral toricity magnitude was calculated at 100% coverage and at the same diameter after 50% of the data was removed. RESULTS: At a 10mm diameter from corneal center, the straight-gaze and stitched images both had 100% coverage. At the 14, 15, 16, 18 and 20mm diameters, the straight-gaze image only covered 68%, 53%, 39%, 18%, and 6% of the ocular surface diameters while the stitched image covered 98%, 96%, 93%, 75%, and 32% respectively. In the case showing the most scleral coverage at 16mm (straight-gaze), there was only 75% coverage (straight gaze) compared to 100% (stitched image); the case with the least coverage had 7% (straight gaze) and 92% (stitched image). The 95% limits of agreement between the 50% and 100% coverage scleral toricity was between -1.4D (50% coverage value larger) and 1.2D (100% coverage larger), a 2.6D spread. The absolute difference between 50% to 100% coverage scleral toricity was >=0.50D in 28% and >=1.0D in 16% of cases. CONCLUSIONS: It appears that a single straight-gaze image would introduce significant measurement inaccuracy in fitting scleral lenses using the sMap3D while a 3-gaze stitched image would not. PMID- 28336226 TI - Systematic review of the clinical significance of lymph node micrometastases of pancreatic adenocarcinoma following surgical resection. AB - OBJECTIVES: The aim of this study is to perform a systematic review of the clinical impact of lymph node micrometastasis in pancreatic adenocarcinoma following surgical resection. METHODS: A systematic review was conducted and published literature were searched using "pancreas or pancreatic" and "cancer or carcinoma or neoplasm", and "micrometastasis or micrometastses" in the PubMed, EMBAE, and Web of Science. RESULTS: Thirteen publications with 726 patients and 3701 lymph nodes were included in this systematic review. The detection method was immunohistochemical stains or polymerase chain reaction. The pooled proportion of patients with positive lymph node micrometastasis was 43.1% (95% Confidence interval (CI) 0.254-0.628). The pooled proportion of positive lymph node micrometastasis (number of positive lymph node micrometastasis/total number of lymph nodes examined) was 10.8% (95% CI 4.8-22.6). Among the conventional H &E negative patients, the reported 5-year survival rates of the patients without lymph node micrometastases vs. those with lymph node micrometastases in the ranged from 50% to 61% and from 0% to 36%, respectively Patients with lymph node micrometastasis showed poorer survival (Hazard ratio 4.29, 95% CI 1.27-14.41). CONCLUSIONS: The presence of lymph node micrometastasis is associated with poorer survival. Lymph node micrometastasis is applicable to stratify the risk of recurrence and the need for adjuvant therapy of post-resection patients with pancreatic adenocarcinoma in the conventional H & E lymph node negative patients. PMID- 28336225 TI - Abdominal contamination with Candida albicans after pancreaticoduodenectomy is related to hemorrhage associated with pancreatic fistulas. AB - BACKGROUND/OBJECTIVES: Pancreatic fistulas are one of the most frequent morbidities after pancreaticoduodenectomy. Several reports have suggested a relationship between bacterial infections and postoperative pancreatic fistulas, although details of the mechanisms involved in hemorrhage in association with the fistulas have not been elucidated. This study retrospectively examined the relationship between positive drainage culture and hemorrhage associated with pancreatic fistulas after pancreaticoduodenectomy. METHODS: From January 2012 to December 2015, 142 consecutive patients underwent pancreaticoduodenectomy at our institution. We retrospectively reviewed the patients' demographic data, perioperative laboratory data, and drainage culture results. RESULTS: Twenty-four (17%) patients had clinically relevant postoperative pancreatic fistulas, whereas thirty-four (24%) patients experienced positive drainage culture. Multivariable analysis revealed that positive drainage culture was independently associated with clinically relevant postoperative pancreatic fistulas (odds ratio, 18.1; 95% confidence interval, 5.5-72.2; P < 0.001). Additionally, the prevalence of Candida albicans in the lavage of eight patients significantly correlated with hemorrhage associated with pancreatic fistulas (odds ratio, 43.5; 95% confidence interval, 6.2-513.3; P < 0.001). Seventy-five percent (6/8) of these patients suffered potentially lethal hemorrhagic complications and needed intervention. CONCLUSIONS: A positive abdominal drainage culture is associated with the development of pancreatic fistulas. Moreover, the presence of Candida albicans in drainage fluid may be a risk factor for hemorrhagic complications. PMID- 28336227 TI - Aqueous calyxes extract of Roselle or Hibiscus sabdariffa Linn supplementation improves liver morphology in streptozotocin induced diabetic rats. AB - BACKGROUND AND STUDY AIMS: The complex series of deleterious events among diabetes patients leads to multiple organ failure. Therefore, a holistic approach of treatment is urgently required to prevent worsening of complications. The present investigation was carried out to study the possible protective effects of Roselle or Hibiscus sabdariffa Linn (HSL) calyxes aqueous extract, as an antidiabetic and antioxidant agent against oxidative liver injury in streptozotocin-induced diabetic rats. MATERIAL AND METHODS: A single dose of streptozotocin (45mg/kg body weight, iv) was used to induced diabetes in male Sprague Dawley rats which were then divided into two groups: Diabetic control (DC) and HSL-treated diabetic (DR) group. Normal rats were divided into normal control (NC), HSL-treated control (NR). Aqueous calyxes extract of HSL (100mg/kg/day, orally) was given for 28 consecutive days in the treated group. Weight, biochemical and histopathological (light and electron microscopic) parameters were compared in all groups. RESULTS: Supplementation of HSL significantly lowered the level of fasting blood glucose and increased plasma insulin level in DR group compared to DC group (p<0.05). Alanine aminotransaminases and aspartate aminotransferase enzymes level were found to be significantly reduced in DR compared to DC. Microscopic examination demonstrated destruction of the liver architecture, cytoplasmic vacuolation of the hepatocytes and signs of necrosis in diabetic rats. Moreover, dilatation and congestion of blood vessels with leucocytes adherence were detected. Ultrastructural study using electron microscope showed homogeneous substance accumulation in nuclear chromatin, a decrease of organelles and mitochondrial degeneration in the diabetic rats. CONCLUSION: Administration of HSL in diabetic rats causes significant decrease in hepatocyte destruction and prevented the changes associated with the diabetic condition. Thus, our findings provide a scientific rationale for the use of HSL as promising agent in preventing liver injury in diabetes. PMID- 28336228 TI - Ultrasound guided serratus plane block for management of acute thoracic herpes zoster. PMID- 28336229 TI - Arthroscopic in Situ Repair of Partial Bursal Rotator Cuff Tears Without Acromioplasty. AB - PURPOSE: To evaluate functional outcomes and complications in a consecutive group of patients with partial bursal rotator cuff tears (PBRCTs) treated with insitu repair without acromioplasty. METHODS: Seventy-four patients who had undergone an arthroscopic single row in situ repair for bursal-sided rotator cuff tears were evaluated. Clinical assessment consisted of glenohumeral range of motion measurement, the American Shoulder and Elbow Surgeons score, and the University of California at Los Angeles score. Pain was recorded using a visual analog scale. Postoperative complications were also assessed. RESULTS: Mean age was 55.2 years (+/-6.3) with a minimum of 2-year follow-up. After arthroscopic repair, all active range of motion parameters improved significantly (P < .0001). The American Shoulder and Elbow Surgeons scores improved from 42.5 to 86.1; the University of California at Los Angeles scores improved from 15.8 to 31.4, and the visual analog scale scores improved from 6.6 to 0.7 (P < .0001). Only 3 patients developed a postoperative adhesive capsulitis that responded to physical therapy. CONCLUSIONS: In the midterm follow-up (42 months), arthroscopic in situ repair of PBRCTs without acromioplasty is a reliable procedure that produces significant functional improvements and pain relief. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 28336230 TI - The Effect of Concomitant Biceps Tenodesis on Reoperation Rates After Rotator Cuff Repair: A Review of a Large Private-Payer Database From 2007 to 2014. AB - PURPOSE: To determine if reoperation rates are higher for patients who underwent isolated rotator cuff repair (RCR) than those who underwent RCR with concomitant biceps tenodesis using a large private-payer database. METHODS: A national insurance database was queried for patients who underwent arthroscopic RCR between the years 2007 and 2014 (PearlDiver, Warsaw, IN). The Current Procedural Terminology (CPT) 29,827 (arthroscopy, shoulder, surgical; with RCR) identified RCR patients who were subdivided into 3 groups-group 1: RCR without biceps tenodesis; group 2: RCR with concomitant arthroscopic biceps tenodesis (CPT 29827 and 29,828); group 3: RCR with concomitant open biceps tenodesis (CPT 29827 and 23,430). Reoperation rates (revision RCR, subsequent biceps surgeries) and complications at 30 days, 90 days, 6 months, and 1 year were analyzed. Multivariate logistic regression was used to compare reoperations and complications between groups. Rotator cuff tear size, whether the biceps was ruptured and whether a biceps tenotomy was performed, was not available. RESULTS: Group 1: 27,178 patients. Group 2: 4,810 patients. Group 3: 1,493 patients. More patients underwent concomitant arthroscopic than concomitant open tenodesis (P < .001). A total of 2,509 patients underwent a reoperation for RCR or biceps tenodesis within 1 year after RCR. When adjusted for age, sex, and comorbidities, no significant differences in reoperation rates at 30 days or 90 days among the 3 groups, but significantly more patients who had a tenodesis, required a reoperation compared with those who did not have a tenodesis at 6 months and 1 year (both P < .001). Urinary tract infections were more common in patients who did not have a tenodesis, whereas dislocation, nerve injury, and surgical site infection were more common in tenodesis patients. CONCLUSIONS: Higher reoperation rates at 1 year were seen in patients who had concomitant biceps tenodesis. LEVEL OF EVIDENCE: Level III, case-control database review study. PMID- 28336231 TI - TNF-alpha inhibits the migration of oral squamous cancer cells mediated by miR 765-EMP3-p66Shc axis. AB - Whereas TNF-alpha can facilitate the metastasis of oral squamous cancer cells (OSCC), whether it inhibits the metastasis is not clear so far. In this study, we demonstrated that high dose TNF-alpha at 100ng/mL could in vitro significantly inhibit the migration of two OSCC cell lines, CAL-27 and SCC-25. To explore the related mechanisms, we focused on the involvement of the microRNAs and found that TNF-alpha increased the expression of miR-765. The upregulation of miR-765 was attributed to the inhibition of the migration. We showed that miR-765 directly targeted EMP3 and suppressed its expression. We also found that the expression of EMP3 was much higher in human oral squamous cancer in compare with the surrounding normal tissue. Interestingly, p66Shc, a downstream molecule in the EMP3-related signaling pathway, was increased by TNF-alpha. We found that the overexpression of p66Shc could suppress the migration through the enhanced E cadherin and ZO-1 signals. Either silencing the expression of EMP3 or enhancing the expression of miR-765 could upregulate the expression of p66Shc. Together, our results demonstrated that TNF-alpha inhibited the metastasis of oral squamous cancer cell through the miR-765-EMP3-p66Shc axis, which may provide new insights for the therapy of oral squamous cancer. PMID- 28336233 TI - Roles for RACK1 in cancer cell migration and invasion. AB - Migration and invasion of cancer cells into surrounding tissue and vasculature is an important initial step in cancer metastasis. Metastasis is the leading cause of cancer related death and thus it is crucial that we improve our understanding of the mechanisms that promote this life-threatening phenomenon. Cell migration involves a complex, multistep process that leads to the actin-driven movement of cells on or through the tissues of the body. The multifunctional scaffolding protein RACK1 plays important roles in nucleating cell signalling hubs, anchoring proteins at specific subcellular locations and regulating protein activity. It is essential for cell migration and accumulating evidence now demonstrates multiple roles for RACK1 in regulating migration and invasion of tumour cells. The possibility of designing drugs that block the migratory and invasive capabilities of cancer cells represents an attractive therapeutic strategy for treating malignant disease with RACK1 being a potential target. In this review we summarize this evidence and examine the mechanisms that underlie the contribution of RACK1 to the various stages of cell migration and invasion. PMID- 28336232 TI - TGFbeta1 induces endometrial cancer cell adhesion and migration by up-regulating integrin alphavbeta3 via SMAD-independent MEK-ERK1/2 signaling. AB - Endometrial cancer is the most common, and second most lethal, gynecological malignancy, and its rates of incidence and death are growing. This is likely attributable to increased numbers of high-risk type II endometrial cancers which account for ~30% of cases but ~75% of deaths due to their aggressive and metastatic behaviour. Histopathological and in vitro functional studies suggest that aberrant TGFbeta1 signaling may contribute to endometrial cancer development and the acquisition of invasive/metastatic characteristics. However, little is known about the cellular and molecular mechanisms of TGFbeta1 in high-risk endometrial cancers. In the present study, we examined the roles and mechanisms of TGFbeta1 on cell adhesion and motility in type II endometrial cancer cell lines, KLE and HEC-1B. We show that treatment with TGFbeta1 increases cell adhesion to vitronectin and transwell cell migration. We also demonstrate that TGFbeta1 treatment increases integrin beta3 and alphav mRNA and protein levels via SMAD-independent MEK-ERK1/2 signaling. Importantly, siRNA depletion or antibody-mediated blocking of integrin alphavbeta3 reversed the effects of TGFbeta1 on cell adhesion and migration. Our results suggest that TGFbeta1-MEK ERK1/2-integrin alphavbeta3 signaling could contribute to the invasive behaviour of high-risk endometrial cancer by promoting cell adhesion and migration. PMID- 28336234 TI - Ubiquitin-specific protease 4 (USP4) suppresses myoblast differentiation by down regulating MyoD activity in a catalytic-independent manner. AB - For myotube formation, proliferation and differentiation of myoblasts must be tightly regulated by various myogenic regulatory factors (MRFs) such as MyoD, myogenic factor 5 (Myf5), myogenin, and muscle-specific regulatory factor 4 (MRF4). However, it is not clear how the expression or activity of these MRFs is controlled during myogenesis. In this study, we identified ubiquitin-specific protease 4 (USP4), one of deubiquitinating enzymes, as a suppressor of MRFs by demonstrating that a knockdown of USP4 enhances myogenesis by controlling MyoD and the level of myogenesis marker proteins in C2C12 cells. However, it was revealed that the effect of USP4 on myogenesis is independent of its deubiquitinase activity because the catalytic-site mutant has the same inhibitory effects as the wild-type USP4 on myogenesis. We observed that the activity and protein levels of both HDAC1 and HDAC4 are decreased when myoblast differentiation is promoted by the USP4 knockdown. We also found that the role of USP4 in muscle differentiation is correlated with two major signaling pathways in myogenesis, AKT and the p38 mitogen-activated protein kinase pathways. According to these results, we propose that USP4 is a key player in myogenic differentiation; it controls myogenic regulatory factors in a catalytic independent manner. PMID- 28336235 TI - Tyrosine phosphorylation of Rab7 by Src kinase. AB - The small molecular weight GTPase Rab7 is a key regulator for late endosomal/lysosomal membrane trafficking, it was known that Rab7 is phosphorylated, but the corresponding kinase and the functional regulation of Rab7 phosphorylation remain unclear. We provide evidence here that Rab7 is a substrate of Src kinase, and is tyrosine-phosphorylated by Src, withY183 residue of Rab7 being the optimal phosphorylation site for Src. Further investigations demonstrated that the tyrosine phosphorylation of Rab7 depends on the guanine nucleotide binding activity of Rab7 and the activity of Src kinase. The tyrosine phosphorylation of Rab7 is physiologically induced by EGF, and impairs the interaction of Rab7 with RILP, consequently inhibiting EGFR degradation and sustaining Akt signaling. These results suggest that the tyrosine phosphorylation of Rab7 may be involved in coordinating membrane trafficking and cell signaling. PMID- 28336237 TI - Point-of-Care Ultrasound: Sonographic Posterior Fat Pad Sign: A Case Report and Brief Literature Review. AB - BACKGROUND: Diagnosis of elbow fracture can sometimes be difficult with plain radiography due to overlapping bones, growth plates, and maturing bones in the pediatric population. The radiographic posterior fat pad (PFP) sign is one of the frequently referenced indirect signs of an occult elbow fracture. This sign can be falsely negative if the sign is subtle, and can be falsely positive when the position of the elbow is not flexed at 90 degrees. CASE REPORT: We discuss a case in which sonographic PFP sign helped to diagnose an elbow fracture. A 57-year-old female presented to the emergency department (ED) after a fall on an outstretched hand. The point-of-care ultrasound (POCUS) was completed identifying an elevated PFP and an anechoic joint fluid collection with innumerous floating hyperechogenic spicules visualized in the olecranon fossa. Diagnosis of a radial head fracture was later confirmed by plain radiograph. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The increase in use and availability of POCUS in the ED makes this a very practical application. Our ability to rapidly perform the ultrasound of the elbow may allow us a more rapid diagnosis of pathology, as well as provide a way to further triage our patients. With time, it may even allow us to avoid routine use of plain radiography. PMID- 28336236 TI - Non-invasive measurement of peripheral, central and 24-hour blood pressure in patients with continuous-flow left ventricular assist device. PMID- 28336238 TI - Hydropneumothorax Due to Esophageal Rupture. AB - BACKGROUND: A brief review of the historical aspects of esophageal rupture is presented along with a case and current recommendations for diagnostic evaluation and treatment. CASE REPORT: A 97-year-old woman complained of acute dyspnea without prior vomiting. Chest x-ray study showed a large right pneumothorax with associated effusion. A thoracostomy tube was placed with return of > 1 L turbid fluid with polymicrobial culture and elevated pleural fluid amylase level. Chest computed tomography (CT) scan demonstrated overt leakage of oral contrast into the right pleural space. She was treated with ongoing pleural evacuation, antibiotics, antifungals, and total parenteral nutrition. The patient and family declined surgical resection as well as endoscopic stent placement. In 1724, Boerhaave described spontaneous rupture of the esophagus postmortem; Boerhaave syndrome remains the name for complete disruption of the esophageal wall in the absence of pre-existing pathology typically occurring after vomiting. It most commonly occurs in the distal left posterolateral thoracic esophagus. Contrast esophagram is considered the "gold standard" for diagnosing esophageal rupture although CT esophagography also shows good diagnostic performance. Treatment includes nil per os status, broad-spectrum antibiotics, and drainage of the pleural space. Surgical repair of the esophageal perforation should be done early if the patient is deemed a good candidate, and esophageal stenting is also an option. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Esophageal perforation should be suspected in patients with new pleural effusion, often with overt pneumothorax, that is polymicrobial with elevated amylase. PMID- 28336239 TI - Penile Gangrene by Calciphylaxis: An Unusual Clinical Presentation in a Patient with Diabetic Nephropathy on Hemodialysis. PMID- 28336240 TI - What's the Evidence: Self-Assessment Implications for Life-Long Learning in Emergency Medicine. AB - BACKGROUND: The 2012 Academic Emergency Medicine Consensus Conference, "Education Research in Emergency Medicine: Opportunities, Challenges, and Strategies for Success" noted that emergency medicine (EM) educators often rely on theory and tradition when molding their approaches to teaching and learning, and called on the EM education community to advance the teaching of our specialty through the performance and application of research in teaching and assessment methods, cognitive function, and the effects of education interventions. OBJECTIVE: The purpose of this article was to review the research-based evidence for the effectiveness of self-assessment and to provide suggestions for its use in clinical teaching and practice in EM. DISCUSSION: This article reviews hypothesis testing research related to self-assessment behaviors and learning. Evidence indicates that self-assessment is inherently flawed when used in isolation. We review a multi-dimensional approach to informed self-assessment that can serve as the basis for life-long learning and development. CONCLUSIONS: Advancing EM education will require that high-quality education research results be translated into actual curricular, pedagogical, assessment, and professional development changes. The informed self-assessment framework is a method that is applicable to teaching and practice in EM. PMID- 28336241 TI - Intracardiac Venous Stent Migration: Emergency Department Presentation of a Catastrophic Complication. AB - BACKGROUND: Venous stents are commonly placed to ensure patency in patients with chronic peripheral venous insufficiency. Although serious complications are uncommon, peripheral venous stent placement can have some potentially life threatening complications. One of the most feared, and certainly the most dramatic, complication is stent migration. CASE REPORT: We report on a 55-year old woman with transvenous migration of an infrarenal inferior vena cava stent into the right atrium and through the intra-atrial septum. The patient expired in the emergency department (ED). WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: There are several potentially life-threatening post-surgical complications after an endovascular procedure, some of which occur shortly after the patient is discharged from the recovery unit. Frequently, these patients present to the ED for initial evaluation. Although details of the procedure performed and the surgical intervention might not be available immediately, emergency physicians should consider stent migration when a patient presents in extremis shortly after an endovascular procedure. PMID- 28336243 TI - Hand-arm vibration syndrome: Workers' experience with functional impairment and disability. AB - STUDY DESIGN: Qualitative and descriptive study. INTRODUCTION: Hand-arm vibration syndrome (HAVS) is a prevalent disease in Canada. There is little work on the perspectives of HAVS patients. PURPOSE OF THE STUDY: Explore perceptions of disability and functional compromise in patients with HAVS. METHODS: Semi structured telephone interviews were conducted with HAVS patients and analysed using content analysis. RESULTS: The 11 participants reported numbness, pain, and reduced dexterity, strength, and sensation. Participants noted that HAVS was an inevitable aspect of their work. They indicated frustration with their condition and viewed it as a disability. To overcome impairments risky strategies are often used. Participants reported lack of support to manage symptoms and overcome work disability. DISCUSSION: HAVS related impairment is disabling. Workers require improved resources and support to address symptom management and safe strategies to minimize work disability. CONCLUSION: HAVS patients experience functional, social, emotional, and psychological disability. LEVEL OF EVIDENCE: Not applicable. PMID- 28336242 TI - Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial. AB - BACKGROUND: Available therapies for myelofibrosis can exacerbate cytopenias and are not indicated for patients with severe thrombocytopenia. Pacritinib, which inhibits both JAK2 and FLT3, induced spleen responses with limited myelosuppression in phase 1/2 trials. We aimed to assess the efficacy and safety of pacritinib versus best available therapy in patients with myelofibrosis irrespective of baseline cytopenias. METHODS: This international, multicentre, randomised, phase 3 trial (PERSIST-1) was done at 67 sites in 12 countries. Patients with higher-risk myelofibrosis (with no exclusions for baseline anaemia or thrombocytopenia) were randomly assigned (2:1) to receive oral pacritinib 400 mg once daily or best available therapy (BAT) excluding JAK2 inhibitors until disease progression or unacceptable toxicity. Randomisation was stratified by risk category, platelet count, and region. Treatment assignments were known to investigators, site personnel, patients, clinical monitors, and pharmacovigilance personnel. The primary endpoint was spleen volume reduction (SVR) of 35% or more from baseline to week 24 in the intention-to-treat population as assessed by blinded, centrally reviewed MRI or CT. We did safety analyses in all randomised patients who received either treatment. Here we present the final data. This trial is registered with ClinicalTrials.gov, number NCT01773187. FINDINGS: Between Jan 8, 2013, and Aug 1, 2014, 327 patients were randomly assigned to pacritinib (n=220) or BAT (n=107). Median follow-up was 23.2 months (IQR 14.8 28.7). At week 24, the primary endpoint of SVR of 35% or more was achieved by 42 (19%) patients in the pacritinib group versus five (5%) patients in the BAT group (p=0.0003). 90 patients in the BAT group crossed over to receive pacritinib at a median of 6.3 months (IQR 5.8-6.7). The most common grade 3-4 adverse events through week 24 were anaemia (n=37 [17%]), thrombocytopenia (n=26 [12%]), and diarrhoea (n=11 [5%]) in the pacritinib group, and anaemia (n=16 [15%]), thrombocytopenia (n=12 [11%]), dyspnoea (n=3 [3%]), and hypotension (n=3 [3%]) in the BAT group. The most common serious adverse events that occurred through week 24 were anaemia (10 [5%]), cardiac failure (5 [2%]), pyrexia (4 [2%]), and pneumonia (4 [2%]) with pacritinib, and anaemia (5 [5%]), sepsis (2 [2%]), and dyspnoea (2 [2%]) with BAT. Deaths due to adverse events were observed in 27 (12%) patients in the pacritinib group and 14 (13%) patients in the BAT group throughout the duration of the study. INTERPRETATION: Pacritinib therapy was well tolerated and induced significant and sustained SVR and symptom reduction, even in patients with severe baseline cytopenias. Pacritinib could be a treatment option for patients with myelofibrosis, including those with baseline cytopenias for whom options are particularly limited. FUNDING: CTI BioPharma Corp. PMID- 28336244 TI - [Commitment in plasmapheresis donation: A study of determinants among regular donors in plasmapheresis]. AB - The purpose of this study, based on the Theory of planned behavior, is to identify and ultimately better understand what determines the fidelity and the regularity of donors committed in plasmapheresis donation. This qualitative study is a primary stage to establish a classification of donors in a French socio cultural context. For this reason, we have carried out a survey among 16 regular plasmapheresis donors, by way of semi-structured individual interviews at the Etablissement francais du sang - Brittany. The level of commitment of these regular donors is considered as a level of appropriation. If subjective norms have initially influenced their decision to donate blood, no specific motivation has been highlighted for them to donate plasma except a generally favourable attitude towards the voluntary donation process. The perception of control over their environment is a variable which played a decisive role in the donor's intention to give, with little cost associated to plasmapheresis donation and recourse to internal causal explanations. A better comprehension of the plasmapheresis donors' determinants should lead us to a more efficient awareness of new potential donors, thereby enhancing recruitment and retention. Due to the increasing need for plasma-derived products, this study's ultimate issue is closely correlated both with ethical and socio-economic aspects. Following which, after analysing the results, a certain number of recommendations will be made. PMID- 28336245 TI - Does the Timing of Chemotherapy Affect Post-Mastectomy Breast Reconstruction Complications? AB - INTRODUCTION: In this study we evaluated how the timing of chemotherapy for breast cancer affects post-reconstruction complications to determine whether there is an optimal time for breast reconstruction after chemotherapy. PATIENTS AND METHODS: A retrospective review identified 344 breast cancer patients who underwent chemotherapy with mastectomy and autologous/prosthetic reconstruction from 2011 to 2014. A control group of 127 breast cancer patients who underwent mastectomy and autologous/prosthetic reconstruction without chemotherapy was also identified from the same period. The 2 groups were compared and analyzed for differences in demographic characteristics, treatment, and postoperative complication rates. The chemotherapy group was subsequently stratified into 3 subgroups on the basis of the number of days between chemotherapy treatment and reconstructive surgery (<= 30 days, 30-60 days, > 60 days) for further analysis. RESULTS: Patients who received chemotherapy were followed for an average of 803.4 days (26.4 months) from the time of initial reconstruction (mean time to complication, 43.3 +/- 82.7 days), and experienced an overall greater complication rate compared with control subjects (32.8% vs. 24.4%; P = .078). When complications were divided into minor, major, and reconstructive failure categories, analysis revealed that the chemotherapy group experienced more minor complications than the control group (18% vs. 11%; P = .067). However, there were no statistically significant differences in major complication rates (10.5% vs. 9.4%) and reconstructive failure complication rates (3.8% vs. 2.4%) between the chemotherapy group and control group. Sixty-eight patients (19.8%) underwent surgery within 30 days of chemotherapy, 210 patients (61%) within 30 to 60 days, and 66 patients (19.2%) after 60 days. Of note, patients in the <= 30 days group underwent surgery at a mean time of 24.8 days with 2 patients who underwent surgery in < 15 days. The 3 groups did not differ with respect to demographic factors or breast reconstructive modality, and there were no significant differences in overall complication rates (33.8% for <= 30 days, 31.4% for 30-60 days, and 36.4% for > 60 days), time to complication, complication severity, or complication type. Whereas patients who underwent surgery 30 to 60 days from the time of chemotherapy had lower rates of skin necrosis (3.8%) and infection (15.7%) compared with the <= 30 days and 60 to 90 days groups, this finding was not statistically significant. CONCLUSION: Results of this study suggest that chemotherapy does increase overall breast reconstruction complications, however, a decreased time between chemotherapy and surgical reconstruction does not predispose patients to postoperative complications. Consequently, surgery might be feasible in close temporal proximity to chemotherapy administration. PMID- 28336246 TI - Does Hip Arthroscopy Have a Role in the Treatment of Developmental Hip Dysplasia? AB - BACKGROUND: Indications for hip arthroscopy in mildly dysplastic patients with a symptomatic hip remain controversial. METHODS: This article provides a concise review of the available literature evaluating the role of hip arthroscopy in treating symptomatic dysplasia. Potential indications for hip arthroscopy in isolation are reviewed. Emerging evidence on the role of hip arthroscopy based on patient-specific pathomorphology is highlighted. RESULTS: Hip arthroscopy in isolation may be helpful for select dysplastic patients with dynamic impingement or microinstability. Isolated arthroscopic treatment of intra-articular pathology resulting from static overload is unlikely to be successful in the long term and may be detrimental. CONCLUSION: Arthroscopic procedures for individuals with mild dysplasia in the absence of frank instability may be effective; however, great caution should be exercised when approaching dysplastic patients with symptomatic hips. PMID- 28336247 TI - Surgical Case Order Has an Effect on the Risk of Subsequent Periprosthetic Joint Infection. AB - BACKGROUND: Periprosthetic joint infection (PJI) after total joint arthroplasty (TJA) is a serious complication with multiple etiologies. Prior spine literature has shown that later cases in the day were more likely to develop surgical site infection. However, the effect of case order on PJI after TJA is unknown. This study aims to determine the influence of case order, prior infected case, and terminal cleaning on the risk for a subsequent PJI. METHODS: A retrospective, single-institution study was conducted on 31,499 TJAs performed from 2000 to 2014. Case order was determined by case start times per date within the same operating room. PJI was defined by the Musculoskeletal Infection Society criteria. Logistic regression was used to determine risk factors for a subsequent PJI. RESULTS: Noninfected cases followed an infected case in 92 of 31,499 cases (0.29%) and were more likely to develop PJI (adjusted odds ratio [OR], 2.43; P = .029). However, terminal cleaning after infected cases did not affect the risk for PJI in cases the following morning (OR, 1.42; P = .066). Case order had an OR of 0.98 (P = .655), implying that later cases did not have a higher likelihood of infection. CONCLUSION: Although surgical case order is not an independent risk factor for subsequent PJI, TJA cases following an infected case in the same room on the same day have a higher infection risk. Despite improved sterile technique and clean air operating rooms, the risk of contaminating a TJA with pathogens from a prior infected case appears to be high. Terminal cleaning appears to be effective in reducing the bioburden in the operating room. PMID- 28336248 TI - Numbness Around the Total Knee Arthroplasty Surgical Scar: Prevalence and Effect on Functional Outcome. AB - BACKGROUND: Numbness around the surgical scar can be a source of discomfort or dissatisfaction in a proportion of patients undergoing total knee arthroplasty (TKA). Literature reports wide variation in its prevalence and the consequence of numbness on the outcome of TKA is not clear. We investigated the prevalence of numbness, along with contributing factors, and assessed its effect on the functional outcome of TKA. METHODS: In total, 258 knees were included in this prospective patient-reported outcome measure case-control study. Demographic details, type and length of incision, pre-operative and 1-year post-operative Knee Society Scores were recorded and compared. RESULTS: The prevalence of numbness at 1 year was 53%, with a female preponderance. Patients older than 70 years were less affected. Discomfort due to numbness was recorded in 8.7% of the patients, 75% of which were female. The length of the incision correlated positively with the presence of numbness. The Knee Society Scores did not correlate with the presence or area of numbness. CONCLUSION: Our findings indicate a high prevalence of numbness after TKA. Nevertheless, numbness does not affect the functional outcome. PMID- 28336249 TI - Current Epidemiology of Revision Total Hip Arthroplasty in the United States: National Inpatient Sample 2009 to 2013. AB - BACKGROUND: Despite the excellent outcomes associated with primary total hip arthroplasty (THA), implant failure and revision continues to burden the healthcare system. THA failure has evolved and displays variability throughout the literature. In order to understand how THAs are failing and how to reduce this burden, it is essential to assess modes of implant failure on a large scale. Thus, we report: (1) etiologies for revision THA; (2) frequencies of revision THA procedures; (3) patient demographics, payor type, and US Census region of revision THA patients; and (4) the length of stay and total costs based on the type of revision THA procedure. METHODS: We queried the National Inpatient Sample database for all revision THA procedures performed between January 1, 2009 and December 31, 2013. This yielded 258,461 revision THAs. Patients specific demographics were identified in order to determine the prevalence of revision procedure performed. RESULTS: Dislocation was the main indication for revision THA (17.3%), followed by mechanical loosening (16.8%). All-component revision was the most common procedure performed (41.8%). Patients were most commonly white (77.4%), aged 75 years and older (31.6%), and resided in the South US Census region (37.0%). The average length of stay for all procedures was 5.29 days. The mean total charge for revision THA procedures was $77,851.24. CONCLUSION: Dislocation and mechanical loosening is the predominant indication for revision THA in the United States. With the frequency of revision THAs projected to double in the next decade, orthopedists must take steps to mitigate this potentially devastating complication. PMID- 28336250 TI - Response to Letter to the Editor on 'The Prevalence of Positive Findings on Metal Artifact Reduction Sequence Magnetic Resonance Imaging in Metal-on-Metal Total Hip Arthroplasty'. PMID- 28336251 TI - Distal Extension of the Anterior Approach to the Hip Using the Femoral Interbundle Technique: Surgical Technique and Case Series. AB - BACKGROUND: The direct anterior approach (DAA) is becoming more popular as the standard surgical approach for primary total hip arthroplasty. However, it has been associated with an increased incidence of intraoperative femoral fractures in particular during the learning curve. Distal extension of the approach may be needed in case of intraoperative complications. The aim of the present study is to describe the distal extension of the DAA using the femoral interbundle technique. METHODS: A stepwise approach based on a cadaveric study to extend the DAA distally is presented. The interval between the neurovascular bundles running to the vastus lateralis is used to gain access to the femur. Clinical and electromyography results of 5 patients undergoing a revision of the femoral component through an extended anterior approach are reported. RESULTS: In 2 cases, the proximal bundle was exposed whereas in 3 cases the interval between the proximal and distal bundle was developed and cerclage wires were applied around the isthmus of the femur. All fractures had healed at 6 months of follow up. Four cases had a normal electromyography, and 1 case demonstrated a neuropraxia of a branch to the vastus lateralis. All cases had a 5/5 extension power of the quadriceps muscle clinically. CONCLUSION: The interbundle technique is an alternative way to gain additional exposure of the femur during the DAA and is based on precise knowledge of the periarticular neurovascular structures. This approach can be helpful to safely deal with intraoperative complications such as fractures requiring proximal femoral cerclage wiring during the anterior approach. PMID- 28336252 TI - Trends in cervical cancer brachytherapy volume suggest case volume is not the primary driver of poor compliance rates with brachytherapy delivery for locally advanced cervical cancer. AB - PURPOSE: The aim of this study was to evaluate temporal trends in the volume of cervical cancer brachytherapy cases available to trainees as a potential contributing factor to national trends toward decreased utilization of brachytherapy for locally advanced cervical cancer. METHODS AND MATERIALS: The National Cancer Database was queried to identify a cohort of women diagnosed with locally advanced cervical cancer during 2004-2013 who received primary radiation therapy. We identified academic facilities that reported radiation therapy and brachytherapy delivery the study period, categorized facilities based on annual number of cases, and evaluated temporal trends. RESULTS: A total of 6290 patients treated at 220 facilities were evaluated. During the study period, the proportion of facilities with higher brachytherapy volume remained stable. The trend of each grouping was not significant (p > 0.05) with the exception of centers treating one case per year, which demonstrated a decrease over time (p = 0.022). CONCLUSIONS: Our analysis suggests that cervical cancer case volume at academic institutions, available for resident training, was stable throughout the study period. These findings suggest that targeting resident educational programs should not be the highest priority for interventions to improve rates of appropriate brachytherapy utilization for cervical cancer. PMID- 28336253 TI - Mitochondrial matters: Mitochondrial bottlenecks, self-assembling structures, and entrapment in the female germline. AB - Mitochondrial replacement therapy, a procedure to generate embryos with the nuclear genome of a donor mother and the healthy mitochondria of a recipient egg, has recently emerged as a promising strategy to prevent transmission of devastating mitochondrial DNA diseases and infertility. The procedure may produce an embryo that is free of diseased mitochondria. A recent study addresses important fundamental questions about the mechanisms underlying maternal inheritance and translational questions regarding the transgenerational effectiveness of this promising therapeutic strategy. This review considers recent advances in our understanding of maternal inheritance of mitochondria, implications for fertility and mitochondrial disease, and potential roles for the Balbiani body, an ancient oocyte structure, in mitochondrial selection in oocytes, with emphasis on therapies to remedy mitochondrial disorders. PMID- 28336254 TI - Effectiveness of training patients using DVD in the accurate use of inhalers for the treatment of bronchial asthma. AB - BACKGROUND: Inhalants are the standard treatment for patients with bronchial asthma. Inaccurate inhaler use leads to inadequate therapeutic effects and unnecessary dosage increases. However, it is a challenge for practitioners to master the various devices available and train patients on the accurate use of inhalers. Thus, establishing a system to instruct patients on how to accurately use inhalers is essential. We prepared a DVD and accompanying user manual explaining the operation of each inhaler device used in Japan. This pilot study aimed to examine the efficacy of these materials. METHODS: The subjects were 33 outpatients with bronchial asthma who received treatment in our facility for asthma and had already received conventional inhalant training. The oral medication and inhalants used by the patients were not changed. The patients were randomly assigned to a DVD viewing group or non-viewing group; various parameters were comparatively examined after 4 weeks. RESULTS: Significant improvements in Asthma Control Test scores, inhalation technique, forced vital capacity, forced expiratory volume in 1 s, impulse oscillometry resonant frequency, and induced sputum eosinophil count were observed in the DVD viewing group at 4 weeks post training. CONCLUSIONS: Pulmonary function and inflammatory parameters improved significantly in the DVD viewing group. These findings suggest that unnecessary step-up of asthma treatment can be avoided, leading to treatment cost reduction. Training patients with asthma in accurate inhaler use improves quality of life and therefore has great clinical significance. Hence, this method should be used more extensively in Japan and worldwide. PMID- 28336255 TI - Homelessness following disability-related discharges from active duty military service in Afghanistan and Iraq. AB - BACKGROUND: Many dynamics in the relationship among military service-related disabilities, health care benefits, mental health disorders, and post-deployment homelessness among US Veterans are not well understood. OBJECTIVES: Determine whether Veterans with a disability-related discharge from military service are at higher risk for homelessness, whether Veterans Health Administration (VHA) service-connected disability benefits mitigates that risk, and whether risks associated with discharge type, service-connected disability, or the interaction between them vary as a function of mental health disorders. METHODS: Retrospective cohort study of 364,997 Veterans with a disability-related or routine discharge and initial VHA encounter between 2005 and 2013. Logistic regression and survival analyses were used to estimate homelessness risk as a function of discharge status, mental health disorders, and receipt of VHA disability benefits. RESULTS: Disability-discharged Veterans had higher rates of homelessness compared to routine discharges (15.1 verses 9.1 per 1000 person years at risk). At the time of the first VHA encounter, mental health disorders were associated with differentially greater risk for homelessness among Veterans with a disability discharge relative to those with a routine discharge. During the first year of VHA service usage, higher levels of disability benefits were protective against homelessness among routinely-discharged Veterans, but not among disability-discharged Veterans. By 5-years, disability discharge was a risk factor for homelessness (AOR = 1.30). CONCLUSIONS: In the long-term, disability discharge is an independent risk factor for homelessness. While VHA disability benefits help mitigate homelessness risk among routinely-discharged Veterans during the early reintegration period, they may not offer sufficient protection for disability-discharged Veterans. PMID- 28336256 TI - Nose burns: 4-dimensional analysis. AB - The nose is the central organ of the face. It has two essential roles, aesthetic and breathing. It is often seriously damaged in the context of facial burns, causing grotesque facial disfigurement. As this disfigurement is visible on frontal and profile views, the patient suffers both socially and psychologically. The nose is a three-dimensional organ. Reconstruction is therefore more difficult and needs to be more precise than in other parts of the face. Maintaining symmetry, contour and function are essential for successful nasal reconstruction. Multiple factors determine the optimal method of reconstruction, including the size of the defect, its depth and its site. Satisfactory social life is recovered only after multiple surgical procedures and long-term rehabilitation and physiotherapy. PMID- 28336258 TI - A comparison of combined intravenous and topical administration of tranexamic acid with intravenous tranexamic acid alone for blood loss reduction after total hip arthroplasty: A meta-analysis. AB - BACKGROUND: The optimal dose and protocol of tranexamic acid (TXA) for reducing blood loss in total hip arthroplasty (THA) is controversial. Intravenous TXA (IV TXA) and combined IV-TXA with topical TXA are the two common protocol after THA. A meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of combined IV and topical TXA with IV-TXA alone in reducing blood loss after THA. METHODS: PubMed, Medline, Embase, Web of Science, the Cochrane Library, China Wanfang database and Google database were searched from the inception to February 2017 to identify RCTs that comparing combined IV and topical TXA with IV-TXA alone for patients prepared for primary THA. Total blood loss, hidden blood loss, transfusion rate, hemoglobin drop, length of hospital stay and the occurrence of deep venous thrombosis (DVT) were pooled to comprehensive analyses the efficacy and safety of combined IV and topical TXA with IV-TXA alone. Software Stata 12.0 was used to calculated relevant data. RESULTS: Six RCTs involving 747 patients were finally included in the meta analysis. Combined TXA decrease the volume of total blood loss and hidden blood loss by 250.37 ml (MD = -250.37; 95% CI: -376.43 to -124.31, P = 0.000) and 117.23 ml respectively (MD = -117.23; 95% CI: 228.38 to -6.07, P = 0.091). Meanwhile, combined TXA can also decrease the transfusion rate by 9.1% (RR = 0.32; 95% CI: 0.17 to 0.63; P = 0.001). No significant differences were seen in hemoglobin drop, the length of hospital stay and the occurrence of DVT between the two groups (P > 0.05). CONCLUSIONS: Our meta-analysis suggests that the combined application of IV and topical TXA for patients undergoing THA may reduce the total blood loss compared with IV use alone without increasing the risk of postoperative complications. However, due to the quality and number of included studies, more studies were need to further identify the optimal dose for combine IV-TXA. PMID- 28336257 TI - A novel pyrazole-containing indolizine derivative suppresses NF-kappaB activation and protects against TNBS-induced colitis via a PPAR-gamma-dependent pathway. AB - The nuclear factor-kappaB (NF-kappaB)-mediated activation of macrophages plays a key role in mucosal immune responses in Crohn's disease (CD). Moreover, increasing evidence shows that the activation of peroxisome proliferator activated receptor-gamma (PPAR-gamma) exerts satisfactory anti-inflammatory effects in experimental colitis models, mostly by suppressing NF-kappaB-mediated macrophage activation. Therefore, exploring therapeutic strategies to activate PPAR-gamma and inhibit the NF-kappaB pathway in colonic macrophages holds great promise for the treatment of CD. In this study, five novel pyrazole-containing indolizine derivatives (B1, B2, B3, B4 and B5) were successfully synthesized and characterized, and their anti-inflammatory activities for CD treatment were also investigated. Among the five compounds, compound B4 effectively decreased the NF kappaB-mediated production of the pro-inflammatory cytokine TNF-alpha in LPS stimulated peritoneal macrophages. Moreover, compound B4 significantly ameliorated 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced mouse colitis symptoms, including body weight loss, colonic pathological damage and inflammatory cell infiltration. The results of western blotting and luciferase reporter assays indicated that compound B4 activated PPAR-gamma and subsequently suppressed NF-kappaB activation. Conversely, the addition of the PPAR-gamma antagonist GW9662 abrogated the anti-inflammatory effects of compound B4 both in vitro and in vivo. In summary, compound B4 activated the PPAR-gamma pathway to inhibit downstream NF-kappaB signaling, which alleviated experimental colitis. Thus, this compound may serve as a potential therapeutic agent for patients with CD. PMID- 28336261 TI - Methane rescues retinal ganglion cells and limits retinal mitochondrial dysfunction following optic nerve crush. AB - Secondary degeneration is a common event in traumatic central nervous system disorders, which involves neuronal apoptosis and mitochondrial dysfunction. Exogenous methane exerts the therapeutic effects in many organ injury. Our study aims to investigate the potential neuroprotection of methane in a rat model of optic nerve crush (ONC). Adult male Sprague-Dawley rats were subjected to ONC and administrated intraperitoneally with methane-saturated or normal saline (10 ml/kg) once per day for one week after ONC. The retinal ganglion cells (RGCs) density was assessed by hematoxylin and eosin staining and Fluoro-Gold retrogradely labeling. Visual function was evaluated by flash visual evoked potentials (FVEP). The retinal apoptosis was measured by terminal-deoxy transferase-mediated dUTP nick end labeling (TUNEL) assay and the expression of apoptosis-related factors, such as phosphorylated Bcl-2-associated death promoter (pBAD), phosphorylated glycogen synthase kinase-3beta (pGSK-3beta), Bcl-2 associated X protein (Bax) and Bcl-2 extra large (Bcl-xL). Retinal mitochondrial function was assessed by the mRNA expressions of peroxisome proliferator activated receptor gamma coactivator-1alpha (PGC-1alpha), nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), the mitochondrial DNA (mtDNA) copy number, citrate synthase activity and ATP content. Methane treatment significantly improved the RGC loss and visual dysfunction following ONC. As expected, methane also remarkably inhibited the retinal neural apoptosis, such as the fewer TUNEL-positive cells in ganglion cell layer, accompanied by the up-regulations of anti-apoptotic factors (pGSK-3beta, pBAD, Bcl-xL) and the down-regulation of pro-apoptotic factor (Bax). Furthermore, methane treatment suppressed up-regulations of critical mitochondrial components (PGC-1alpha, NRF1 and TFAM) mRNA and mtDNA copy number, as well as improved the reduction of functional mitochondria markers, including citrate synthase activity and ATP content, in retinas with ONC. Taken together, methane treatment promotes RGC survival and limits retinal mitochondrial dysfunction against ONC insult. Methane can be a potential neuroprotective agent for traumatic and glaucomatous neurodegeneration. PMID- 28336260 TI - The analysis of human conjunctival epithelium proteome in ocular surface diseases using impression cytology and 2D-DIGE. AB - Conjunctival impression cytology samples from patients with meibomian gland dysfunction (MGD), dry eye (DE), and healthy subjects (CT) were collected for determination of the degree of squamous metaplasia (SM) by PAS-hematoxylin staining and for comparative proteomic analyses by 2D-DIGE. The protein spots with discriminant expression were identified by MALDI-TOF/TOF mass spectrometry. Three independent statistical studies were conducted: i). Analysis of differential protein expression between study groups: We observed increased expression of proteins S100A4, S100A8, retinal dehydrogenase-1, peroxiredoxin-1, annexin-A1, annexin-A2, alpha-enolase, and glutathione S-transferase-P in DE, whereas the highest expression of peroxiredoxin-6, actin cytoplasmic-1, peroxiredoxin-2, and heat shock protein HSP-90-alpha was observed in MGD; ii). Correlation between changes in the proteome profile and the grade of SM: The expression of 5 different cytokeratins (KRT1, KRT4, KRT8, KRT10, and KRT13) correlated with the degree of SM; iii). Proteome profile differences between pathological and CT groups: An overall proteome analysis revealed upregulation of 9 proteins in the pathological groups (Annexin-A1, alpha-enolase, Annexin-A2, S100A8, cytokeratin-1, Peroxiredoxin-2 and Leukocyte elastase inhibitor) and downregulation of 2 proteins (Galectin-3 and Lipocalin-1). In conclusion, a sensitive proteomic approach to study conjunctival tissue collected from minimally invasive impression cytology was implemented. Differential proteomics analyses showed that in comparison with the MGD, the DE patients presented higher overexpression of proteins related to antimicrobial defense, tissue-damage response, and regulation of body fluid secretions. Changes in MGD proteome were associated with oxidative stress and anti-apoptotic processes. We found a correlation between the grade of SM and expression of proteins associated with cytoskeleton and keratinization. The studied pathological groups shared elements related to the defense and inflammatory responses. Dot blot assays of proteins ANXA1, S100A8, and S100A4 validated the proteomic results obtained from 2D-DIGE experiments and confirmed the correlation between the expression of these proteins and the clinical parameters. PMID- 28336259 TI - The role of pili in Bacillus cereus intraocular infection. AB - Bacterial endophthalmitis is a potentially blinding intraocular infection. The bacterium Bacillus cereus causes a devastating form of this disease which progresses rapidly, resulting in significant inflammation and loss of vision within a few days. The outer surface of B. cereus incites the intraocular inflammatory response, likely through interactions with innate immune receptors such as TLRs. This study analyzed the role of B. cereus pili, adhesion appendages located on the bacterial surface, in experimental endophthalmitis. To test the hypothesis that the presence of pili contributed to intraocular inflammation and virulence, we analyzed the progress of experimental endophthalmitis in mouse eyes infected with wild type B. cereus (ATCC 14579) or its isogenic pilus-deficient mutant (DeltabcpA-srtD-bcpB or DeltaPil). One hundred CFU were injected into the mid-vitreous of one eye of each mouse. Infections were analyzed by quantifying intraocular bacilli and retinal function loss, and by histology from 0 to 12 h postinfection. In vitro growth and hemolytic phenotypes of the infecting strains were also compared. There was no difference in hemolytic activity (1:8 titer), motility, or in vitro growth (p > 0.05, every 2 h, 0-18 h) between wild type B. cereus and the DeltaPil mutant. However, infected eyes contained greater numbers of wild type B. cereus than DeltaPil during the infection course (p <= 0.05, 3-12 h). Eyes infected with wild type B. cereus experienced greater losses in retinal function than eyes infected with the DeltaPil mutant, but the differences were not always significant. Eyes infected with DeltaPil or wild type B. cereus achieved similar degrees of severe inflammation. The results indicated that the intraocular growth of pilus-deficient B. cereus may have been better controlled, leading to a trend of greater retinal function in eyes infected with the pilus deficient strain. Although this difference was not enough to significantly alter the severity of the inflammatory response, these results suggest a potential role for pili in protecting B. cereus from clearance during the early stages of endophthalmitis, which is a newly described virulence mechanism for this organism and this infection. PMID- 28336262 TI - Increased susceptibility to fundus camera-delivered light-induced retinal degeneration in mice deficient in oxidative stress response proteins. AB - Oxidative stress is an important contributor to the pathogenesis of many retinal diseases including age-related macular degeneration and retinal dystrophies. Light-induced retinal degeneration (LIRD) can serve as a model in which to study the response of the retina to stress. Of note, many genetic mutant mice are in a C57BL/6 J background and are thus resistant to the usual LIRD models. We recently developed a new model of fundus camera-delivered light-induced retinal degeneration (FCD-LIRD) which is effective in strains of mice expressing the light-resistant variant of RPE65 (450Met), including C57BL/6 J. In this work we investigated whether FCD-LIRD would be useful as a model in which to test the effect of genetic mutations on the response of the retina to stress. Furthermore, we tested whether oxidative stress plays an important role in the setting of this new FCD-LIRD model. FCD-LIRD was applied to C57BL/6 J mice and to mice simultaneously deficient in three proteins that are important in the response of the retina to oxidative stress (SOD1, DJ-1 and Parkin). Using fundus photography, we found that retinal damage was dramatically increased in the SOD1/DJ-1/Parkin deficient mice compared to C57BL/6 J. Outer retinal OCT volume and RPE cell morphology analysis in ZO-1-stained flat mounts added support to these findings. Gene expression analysis confirmed a strong oxidative stress response after FCD LIRD, which was differentially altered in the SOD1/DJ1/Parkin deficient mice. We conclude that FCD-LIRD is useful to study the effect of genetic mutations on the response of the retina to light stress in light-resistant strains of mice. Furthermore, oxidative stress seems to be an important component of FCD-LIRD. Finally, we have established protocols to quantify the effect of FCD-LIRD on the retina and RPE which will be useful for future studies. Further dissection of the mechanisms by which the retina responds to light-induced oxidative stress may result in new strategies to modulate this response, which could lead to a reduction in retinal and RPE damage. PMID- 28336263 TI - Environmental radioactivity study of Austrian and Bavarian forest ecosystems: Long-term behaviour of contamination of soil, vegetation and wild boar and its radioecological coherences. AB - 137Cs and 40K in soil, vegetation and flesh of wild boar samples from Austrian and Bavarian regions were investigated by gamma-ray spectrometry and 90Sr in bones of wild boar with Liquid Scintillation Counting (LSC) after radiochemical separation. The soil core profiles revealed that 70-97% of the soil caesium content is still accumulated in the 0-10cm soil depth. From all vegetation samples the mushrooms, particularly the bay boletus showed the highest 137Cs contamination. The activity concentration of 137Cs in muscle tissue of boar ranged from 14.9+/-1.5Bq/kg (Bavaria) to 4711+/-377Bq/kg (Lower Austria). In the bones of wild boars, 90Sr activity concentration ranged from 1.4+/-0.2Bq/kg (Bavaria) to 70.3+/-10.5Bq/kg (Upper Austria). PMID- 28336264 TI - Genomic imbalances in syndromic congenital heart disease. AB - OBJECTIVE: To identify pathogenic genomic imbalances in patients presenting congenital heart disease (CHD) with extra cardiac anomalies and exclusion of 22q11.2 deletion syndrome (22q11.2 DS). METHODS: 78 patients negative for the 22q11.2 deletion, previously screened by fluorescence in situ hybridization (FISH) and/or multiplex ligation probe amplification (MLPA) were tested by chromosomal microarray analysis (CMA). RESULTS: Clinically significant copy number variations (CNVs >=300kb) were identified in 10% (8/78) of cases. In addition, potentially relevant CNVs were detected in two cases (993kb duplication in 15q21.1 and 706kb duplication in 2p22.3). Genes inside the CNV regions found in this study, such as IRX4, BMPR1A, SORBS2, ID2, ROCK2, E2F6, GATA4, SOX7, SEMAD6D, FBN1, and LTPB1 are known to participate in cardiac development and could be candidate genes for CHD. CONCLUSION: These data showed that patients presenting CHD with extra cardiac anomalies and exclusion of 22q11.2 DS should be investigated by CMA. The present study emphasizes the possible role of CNVs in CHD. PMID- 28336266 TI - Progesterone and estradiol profiles in different reproductive stages of captive collared peccary (Pecari tajacu) females assessed by fecal metabolites. AB - The study determined the fecal progesterone and estradiol profiles in different reproductive stages of captive collared peccary (Pecari tajacu) females from eastern Mexico. Fifteen adult females were included. At the start of the study the females were either pregnant (early, mid, or late pregnancy), lactating, or non-lactating of unknown pregnancy status. Feces from each female were collected once a week during nine consecutive months to determine concentrations of fecal progesterone and estradiol metabolites using ELISA. Progesterone was similar in early (2048+/-285ng/g), mid (2254+/-274ng/g), and late pregnancy (2491+/ 374ng/g), and in early-pregnant and non-lactating females (1154+/-274ng/g). Progesterone in lactating females (442+/-255ng/g) was lower than in females at any stage of pregnancy, but was similar to non-lactating females. Overall progesterone in pregnant females (2229+/-173ng/g) was higher than in lactating and non-lactating females together (772+/-189ng/g). Estradiol was similar in early (66+/-8ng/g), mid (83+/-9ng/g), late pregnant (109+/-15ng/g), and non lactating females (64+/-9ng/g). Estradiol in lactating females (34+/-8ng/g) was similar to estradiol in early-pregnant and non-lactating females, but was lower than in females in late and mid pregnancy. Overall estradiol in pregnant females (79+/-6ng/g) was similar to non-lactating females, but higher than in lactating females. The progesterone and estradiol profiles of captive collared peccary females at different reproductive stages were determined by assessing concentrations of fecal hormone metabolites. PMID- 28336267 TI - Association analysis of polymorphism in KiSS1 gene with reproductive traits in goats. AB - Understanding the genetic information of related genes is helpful for the selection and breeding course through marker assisted selection. The aim of the current study was to detect polymorphisms of the KiSS1 gene in 137 animals, including Baladi, Zaraibi and Damascus goat breeds by PCR-RFLP, and DNA sequencing and to investigate the association between these variants and reproductive traits. Comparison of the nucleotide sequence indicated the substitution of T with A at position 121 (T121A) in the intron 1 of the KiSS1 gene in all goat breeds. This substitution distorts the restriction site of the XmnI restriction enzyme and consequently two genotypes were detected (TA and TT). The T121A SNP is associated significantly with litter size in Damascus and Zaribi breeds (p=0.025 and 0.001, respectively). The animals with the TT genotype in Damascus and Zaribi breeds had a significantly higher estradiol17beta level than that recorded in TA genotype at estrus phase (p=0.013 and 0.028, respectively) and late-luteal phase (p=0.067 and 0.041, respectively) of the estrus cycle. Furthermore, animals with the TT genotype in Damascus and Zaribi breeds had significant higher progesterone level at mid-luteal (p=0.037 and 0.045, respectively) phase. Meanwhile, there were no significant differences in progesterone level in late-luteal phase between both genotypes in Zaribi breed (p=0.267). The current trial indicated that the prolific TT genotype in both Damascus and Zaribi breeds had superior estradiol17beta level at estrus phase and an eminent progesterone level at both early and mid-luteal phases of the estrous cycle. PMID- 28336268 TI - Malaria incidence during early childhood in rural Burkina Faso: Analysis of a birth cohort protected with insecticide-treated mosquito nets. AB - BACKGROUND: Even in the high transmission areas of sub-Saharan Africa (SSA), the incidence of falciparum malaria varies greatly depending on factors such as age, rainfall pattern, distance to breeding places, quality of houses, and existing vector control measures. Insecticide-treated mosquito nets (ITN) have now become the vector control standard in nearly all of SSA. This study aims to describe and analyse the incidence of malaria in a cohort of young children protected with ITN in rural West Africa. METHODS: Data of a subsample from a large community trial in rural north-western Burkina Faso consisting of 420 children were analysed. The main aim of the trial was to evaluate the long-term effects of ITNs in two groups of new-borns; Group A was protected with ITN from birth onwards while Group B was protected only from month six onwards. The primary objective of this study was to describe malaria incidence in detail with an analysis of the impact of potentially relevant determinants of malaria incidence, in particular age, sex, ITN protection, village, month and season as secondary objective. Bivariate negative binomial regression analysis was used to calculate incidence rate ratios of malaria incidence. Moreover, relevant variables were included in a multivariate negative binomial regression model to examine possible risk factors for malaria. RESULTS: Out of the 420 study children 387 (92.1%) developed a total of 1822 falciparum malaria episodes; the malaria incidence rate was 7.6 per 1000 child days. Group A children had lower malaria incidence rates compared to group B, but only in early infancy. Malaria incidence varied significantly between villages and increased with age, but no sex-specific differences were observed; these findings were confirmed in the multi-variate analysis. Malaria incidence peaked sharply towards the end of the rainy season in September but there were no differences in the seasonal pattern by study group. CONCLUSIONS: The study, carried out in a high-transmission West African area, shows that malaria incidence remains high in spite of maximum ITN coverage. PMID- 28336265 TI - Brain Structural Markers and Caregiving Characteristics as Interacting Correlates of Caregiving Strain. AB - OBJECTIVE: To evaluate the association between brain structural markers and caregiving strain among older informal caregivers. DESIGN: A secondary data analysis combining data from the Caregiver Health Effects Study (1993-1994) and the Cardiovascular Health Study MRI examination (1992-1994). SETTING: Four United States communities. PARTICIPANTS: Co-residing spousal caregivers (N = 237; mean age: 76.2 years, SD: 2.2 years). MEASUREMENTS: Visually rated ventricular and white matter (WM) grades from magnetic resonance imaging, caregiving strain defined as "emotional or physical strain associated with providing care" for any of 12 activities of daily living (ADLs) and instrumental activities of daily living (IADLs), plus measures of caregiving characteristics and caregiver's health. RESULTS: Overall, 56% of caregivers reported strain. We detected an interaction where strain was very common (>82%) among caregivers who helped with four or more IADLs, regardless of WM grades, and among caregivers with the worst WM grades (WM grades >=4), regardless of the number of IADLs they helped with. Among caregivers helping with fewer than four IADLs, having WM grade 4 or greater was associated with a 55% higher prevalence ratio for reporting strain. This association remained statistically significant but was most markedly attenuated by adjustments for: care recipient's memory and behavioral problems, caregiver's depression symptoms, and caregiver's ADL impairment. CONCLUSIONS: Caregiving strain is very common among older informal caregivers who provide help with many IADLs, and among caregivers who help with fewer IADLs, but have manifest signs of white matter pathology. Modern quantitative-neuroimaging studies are needed to evaluate whether more subtle variability in brain structure confers caregiving strain and the related health consequences. PMID- 28336269 TI - Epidemiology of polyparasitism with Taenia solium, schistosomes and soil transmitted helminths in the co-endemic village of Malanga, Democratic Republic of Congo. AB - Helminth co-infections are common in sub-Saharan Africa. However, little is known about the distribution and determinants of co-infections with Taenia solium taeniasis/cysticercosis. Building on a previous community-based study on human cysticercosis in Malanga village, we investigated co-infections with Taenia solium, soil-transmitted helminths (STHs) and Schistosoma spp and associated risk factors in a random subsample of 330 participants. Real time PCR assays were used to detect DNA of soil-transmitted helminths (STHs), T. solium and Schistosoma in stool samples and Schistosoma DNA in urine samples. Serum samples were tested for T. solium cysticercosis using the B158/B60 monoclonal antibody-based antigen ELISA. Bivariate analysis and logistic regression were applied to assess associations of single and co-infections with common risk factors (age, sex, area, hygiene) as well as pair wise associations between helminth species. Overall, 240 (72.7%) participants were infected with at least one helminth species; 128 (38.8%) harbored at least two helminth species (16.1% with STHs Schistosoma, 14.5% with STHs-T. solium taeniasis/cysticercosis and 8.2% with Schistosoma-T. solium taeniasis/cysticercosis co-infections). No significant associations were found between Schistosoma-T. solium taeniasis/cysticercosis co infection and any of the risk factors studied. Males (OR=2 (95%CI=1.1-5), p=0.03) and open defecation behavior (OR=3.8 (95%CI=1.1-6.5), p=0.04) were associated with higher odds of STHs-T. solium taeniasis/cysticercosis co-infection. Village districts that were found at high risk of T. solium taeniasis/cysticercosis were also at high risk of co-infection with STHs and T. solium taeniasis/cysticercosis (OR=3.2 (95%CI=1.1-7.8), p=0.03). Significant pair-wise associations were found between T. solium cysticerci and Necator americanus (OR=2.2 (95%CI=1.2-3.8), p<0.01) as well as Strongyloides stercoralis (OR=2.7 (95%CI=1.1-6.5), p=0.02). These findings show that co-infections with T. solium are common in this polyparasitic community in DRC. Our results on risk factors of helminth co infections and specific associations between helminths may contribute to a better integration of control within programmes that target more than one NTD. PMID- 28336270 TI - The natural history of cystic echinococcosis in untreated and albendazole-treated patients. AB - The World Health Organization (WHO) treatment protocols for cystic echinococcosis (CE) are based on the standardized ultrasound (US) classification. This study examined whether the classification reflected the natural history of CE in untreated and albendazole-treated patients. Data were collected during mass US screenings in CE endemic regions among transhumant populations, the Turkana and Berber peoples of Kenya and Morocco. Cysts were classified using the WHO classification. Patient records occurring prior to treatment, and after albendazole administration, were selected. 852 paired before/after observations of 360 cysts from 257 patients were analyzed. A McNemar-Bowker chi2 test for symmetry was significant (p<0.0001). 744 observations (87.3%) maintained the same class, and 101 (11.9%) progressed, consistent with the classification. Regression to CE3B occurred in seven of 116 CE4 cyst observations (6.0%). A McNemar-Bowker chi2 test of 1414 paired before/after observations of 288 cysts from 157 albendazole-treated patients was significant (p<0.0001). 1236 observations (87.4%) maintained the same class, and 149 (10.5%) progressed, consistent with the classification. Regression to CE3B occurred in 29 of 206 CE4 observations (14.1%). Significant asymmetry confirms the WHO classification's applicability to the natural history of CE and albendazole-induced changes. Regressions may reflect the stability of CE3B cysts. PMID- 28336271 TI - Helminth secretomes reflect different lifestyles and parasitized hosts. AB - Helminths cause a number of medical and agricultural problems and are a major cause of parasitic infections in humans, animals and plants. Comparative analysis of helminth genes and genomes are important to understand the genomic biodiversity and evolution of parasites and their hosts in terms of different selective pressures in their habitats. The interactions between the infective organisms and their hosts are mediated in large part by secreted proteins, known collectively as the "secretome". Proteins secreted by parasites are able to modify a host's environment and modulate their immune system. The composition and function of this set of proteins varies depending on the ecology, lifestyle and environment of an organism. The present study aimed to predict, in silico, the secretome in 44 helminth species including Nematoda (31 species) and Platyhelminthes (13 species) and, understand the diversity and evolution of secretomes. Secretomes from plant helminths range from 7.6% (943 proteins) to 13.9% (2,077 proteins) of the filtered proteome with an average of 10.2% (1,412 proteins) and from free-living helminths range from 4.4% (870 proteins) to 13% (3,121 proteins) with an average of 9.8% (2,126 proteins), respectively, and thus are considerably larger secretomes in relation to animal helminth secretomes which range from 4.2% (431 proteins) to 11.8% (2,419 proteins) of the proteomes, with an average of 7.1% (804 proteins). Across 44 secretomes in different helminth species, we found five conserved domains: (i) PF00014 (Kunitz/Bovine pancreatic trypsin inhibitor domain), (ii) PF00046 (Homeobox domain), (iii) PF00188 (cysteine-rich secretory proteins, antigen 5, and pathogenesis-related 1 proteins), (iv) PF00085 (Thioredoxin) and (v) PF07679 (Immunoglobulin I-set domain). Our results detected secreted proteins associated with invasion, infection, adhesion and immunoregulation processes as protease inhibitors and cytokines, among other functions. In summary, this study will contribute towards the understanding of host-parasite interactions and possibly identify new molecular targets for the treatment or diagnosis of helminthiases. PMID- 28336273 TI - Soft palate fistula after radiofrequency ablation for primary snoring: a case report and literature review. PMID- 28336272 TI - Apigenin-7-diglucuronide protects retinas against bright light-induced photoreceptor degeneration through the inhibition of retinal oxidative stress and inflammation. AB - Vision impairment in retinal degenerative diseases such as age-related macular degeneration is primarily associated with photoreceptor degeneration, in which oxidative stress and inflammatory responses are mechanistically involved as central players. Therapies with photoreceptor protective properties remain to be developed. Apigenin-7-diglucuronide (A7DG), a flavonoid glycoside, is present in an assortment of medicinal plants with anti-inflammatory or ant-oxidant activities. However, the pharmacological significance of A7DG remains unknown in vivo. The current study isolated A7DG from Glechoma longituba (Nakai) Kuprian and investigated the retinal protective effect A7DG in mice characterized by bright light-induced photoreceptor degeneration. The results showed that A7DG treatment led to remarkable photoreceptor protection in bright light-exposed BALB/c mice. Moreover, A7DG treatment alleviated photoreceptor apoptosis, mitigated oxidative stress, suppressed reactive gliosis and microglial activation and attenuated the expression of proinflammatory genes in bright light-exposed retinas. The results demonstrated for the first time remarkable photoreceptor protective activities of A7DG in vivo. Inhibition of bright light-induced retinal oxidative stress and retinal inflammatory responses was associated with the retinal protection conferred by A7DG. The work here warrants further evaluation of A7DG as a pharmacological candidate for the treatment of vision-threatening retinal degenerative disorders. Moreover, given the general implication of oxidative stress and inflammation in the pathogenesis of neurodegeneration, A7DG could be further tested for the treatment of other neurodegenerative disorders. PMID- 28336274 TI - Characterization, molecular docking, dynamics simulation and metadynamics of kisspeptin receptor with kisspeptin. AB - We report molecular characterization of the kisspeptin receptor (kiss1r), an essential gatekeeper for reproduction and onset of puberty in vertebrates. The full-length cDNA sequence of kiss1r is 1786bp which consist of 5' UTR (untranslated region) 261bp, 3' UTR of 424bp and open reading frame of 1101 encoding a putative protein of 366 amino acids. Basal tissue expression pattern of kiss1r mRNA revealed that it is mainly expressed in the brain and testis. We also report the structure of the kiss1r, along with plausible activation mechanism of this receptor by kisspeptin using computational modelling and dynamic simulation approach of multiple 100ns of timescale. A present modelling and simulations studies shed light on the molecular level of interaction, suggesting that direct hydrogen bonds between ASN4, SER5, GLY7, ARG9 and PHE10 of kisspeptin and TRP7, ASN8, GLU11, ILE17, ASN19 and TYR183 of kiss1r could be crucial role players in initial binding of receptor and the kisspeptin towards allosteric modulatory effects of kisspeptin on the receptor. To the best our knowledge, this is the first report on computational modelling and molecular dynamic simulations of kiss1r in animals shedding light on its possible mode of activation. PMID- 28336275 TI - Structural characterization of purine nucleoside phosphorylase from human pathogen Helicobacter pylori. AB - Microaerophilic bacterium Helicobacer pylori is a well known human pathogen involved in the development of many diseases. Due to the evergrowing infection rate and increase of H. pylori antibiotic resistence, it is of utmost importance to find a new way to attack and eradicate H. pylori. The purine metabolism in H. pylori is solely dependant on the salvage pathway and one of the key enzymes in this pathway is purine nucleoside phosphorylase (PNP). In this timely context, we report here the basic biochemical and structural characterization of recombinant PNP from the H. pylori clinical isolate expressed in Escherichia coli. Structure of H. pylori PNP is typical for high molecular mass PNPs. However, its activity towards adenosine is very low, thus resembling more that of low molecular mass PNPs. Understanding the molecular mechanism of this key enzyme may lead to the development of new drug strategies and help in the eradication of H. pylori. PMID- 28336276 TI - Chitin extraction from blue crab (Portunus segnis) and shrimp (Penaeus kerathurus) shells using digestive alkaline proteases from P. segnis viscera. AB - Since chitin is closely associated with proteins, deproteinization is a crucial step in the process of extracting chitin. Thus, this research aimed to extract chitin from Portunus segnis and Penaeus kerathurus shells by means of crude digestive alkaline proteases from the viscera of P. segnis, regarding deproteinization step, as an alternative to chemical treatment. Casein zymography revealed that five caseinolytic proteases bands exist, suggesting the presence of at least five different major proteases. The optimum pH and temperature for protease activity were pH 8.0 and 60 degrees C, respectively, using casein as a substrate. The crude enzymes extract was highly stable at low temperatures and over a wide range of pH from 6.0 to 12.0. The crude alkaline protease extract was found to be effective in the deproteinization of blue crab and shrimp shells, to produce chitin. The best efficiency in deproteinization (84.69+/-0.65% for blue crab shells and 91.06+/-1.40% for shrimp shells) was achieved with an E/S ratio of 5U/mg of proteins after 3h incubation at 50 degrees C. These results suggest that enzymatic deproteinization of crab and shrimp wastes by fish endogenous alkaline proteases could be a potential alternative in the chitin production process. PMID- 28336278 TI - Thermoplastic starch composites with TiO2 particles: Preparation, morphology, rheology and mechanical properties. AB - Composites of thermoplastic starch (TPS) with titanium dioxide particles (mTiO2; average size 0.1MUm) with very homogeneous matrix and well-dispersed filler were prepared by a two-step method, including solution casting (SC) followed by melt mixing (MM). Light and scanning electron microscopy confirmed that only the two step procedure (SC+MM) resulted in ideally homogeneous TPS/mTiO2 systems. The composites prepared by single-step MM contained non-plasticized starch granules and the composites prepared by single-step SC suffered from mTiO2 agglomeration. Dynamic mechanical measurements showed an increase modulus with increasing filler concentration. In TPS containing 3wt.% of mTiO2 the stiffness was enhanced by >40%. Further experiments revealed that the recommended addition of chitosan or the exchange of mTiO2 for anisometric titanate nanotubes with high aspect ratio did not improve the properties of the composites. PMID- 28336277 TI - Structure characteristics of an acidic polysaccharide purified from banana (Musa nana Lour.) pulp and its enzymatic degradation. AB - Banana is one of the most important fruits over the world. The chemical composition is critical for the organoleptic properties and health benefits. As one of the leading bioactive components in banana pulp, the polysaccharides may contribute to the beneficial health effects. However, their precise structure information remains unknown. A leading acidic polysaccharide (ABPP) of banana pulp was purified and identified by nuclear magnetic resonnance spectroscopy (NMR) and gas chromatography-mass spectrometry (GC-MS). ->4-alpha-d-GalpA-1-> and ->4-alpha-d-GalpAMe-1-> constituted the backbone. No branch chains were detected. The molecular weight was determined to be 8.9kDa by gel permeation chromatography, which was smaller than previously reported fruit-derived polygalacturonic acids. The precise structure was identified as below. Digestion by enzyme would lead to production of oligogalacturonic acids and quick accumulation of 5000-7000Da fraction. PMID- 28336279 TI - [Brimonidine and acute anterior granulomatous uveitis: A case report and literature review]. PMID- 28336280 TI - [Intraocular pressure decrease after manual small incision cataract surgery]. AB - PURPOSE: We decided to evaluate the decrease in intraocular pressure six months after cataract surgery. MATERIALS AND METHODS: We evaluated patients' IOP using an applanation tonometer. The patients then underwent cataract surgery. Six months after cataract surgery, we reevaluated the IOP by the same method, and we determined the post-operative change. RESULTS: Among the 147 operated eyes, 123 eyes or 83.67% exhibited a decrease in IOP. The mean preoperative IOP for the operative eye was 15.61+/-4.5mmHg; the mean post-operative IOP was 12.57+/ 3.5mmHg; the mean IOP decrease after surgery was 3.16+/-4mmHg, for a mean decrease of 20%. This decrease is statistically significant, P<001. The decrease in IOP varies proportionally to the initial IOP. In glaucomatous patients, the mean preoperative IOP was 23.16+/-5.68mmHg and mean post-operative IOP was 14.5+/ 2.7mmHg, a decrease of 37.39%. CONCLUSION: The decrease in IOP after cataract surgery was generally moderate. However, this IOP decreased proportionally to the initial IOP, thus giving significant decreases for higher IOPs. This decrease in IOP, well known after phacoemulsification, was also obtained after Manual Small Incision Cataract Surgery, a surgical technique which is increasingly employed in developing countries. PMID- 28336281 TI - [Optic disc changes by optical coherence tomography in optic disc edema in Lome]. AB - OBJECTIVE: To study the influence of optic disc edema (ODE) on the dimensions of the disc and the thickness of the retinal nerve fiber layer (RNFL) by optical coherence tomography (OCT) in Lome. PATIENTS AND METHODS: This was a retrospective study which took place in a general ophthalmology office in the city. Twenty-six eyes were examined for ODE (cases) between January 2013 and May 2015, and 26 healthy eyes (control group) were considered in this study. The control group was recruited taking age into account with a variation not exceeding 5 years compared to the ODE cases. Topcon 3D-OCT 2000 software was used to analyze the disc and to measure the thickness of the peripapillary RNFL. The results were compared with software integrated into the OCT device, to the normal range of databases (normative basis) of RNFL thickness. The variables studied were age, gender, etiology of the edema, disc dimensions (optic disc surface area, vertical cup to disc ratio [CDR]), and the thickness of the peripapillary RNFL. Chi2 tests were used for comparison of proportions with a significance level less than or equal to 0.05. RESULTS: Twenty-six eyes of 16 patients with ODE (mean age 25.88+/-14.35years) and 26 eyes of 16 control group patients (mean age 25.73+/-15.90 years) were recruited. The ODE was caused by inflammatory optic neuropathies in 10 cases, malignant hypertension in 8 cases and intracranial hypertension in 8 cases. The surface area of the disc was 3.77+/-1.82mm2 for the ODE group vs. 2.74+/-0.57mm2 for the control group (P=0.009). The vertical CDR was 0.11+/-0.15 for the ODE group vs. 0.50+/-0.15 for the control group (P=0). The mean RNFL thickness was 117.12+/-18.30MUm for the ODE group vs. 95.77+/ 2.52MUm for the control group (P=0.006). This study reveals an increase in RNFL in all quadrants (superior, P=0.027; inferior, P=0.007; nasal, P=0.026; temporal, P=0.032). Of the 26 ODE cases, we noted an increase beyond the normative base; superiorly (in 9 cases), inferiorly (in 12 cases), nasally (in 10 cases) and temporally (in 11 cases). CONCLUSION: The study of papillary changes with OCT in ODE has allowed us to note an increase in the surface area of the disc, a reduction of the vertical CDR, and an increase in the thickness of the average RNF in all quadrants. PMID- 28336282 TI - [Management of upper eyelid retraction associated with dysthyroid orbitopathy during the acute inflammatory phase with botulinum toxin type A]. AB - PURPOSE: To evaluate the efficacy of transconjunctival botulinum toxin type A (BTX-A) in the treatment of upper eyelid retraction in the active inflammatory phase of dysthyroid orbitopathy, establish the ideal dose, and evaluate side effects. METHODS: This is a comparative, prospective study in patients with thyroid orbitopathy, conducted at the Conde Ophthalmology Institute in Valenciana, Mexico. The patients included had dysthyroid orbitopathy in the inflammatory phase, and they were treated with subconjunctival injection of botulinum toxin type A (BTX-A) in the upper eyelid. Five units (group 1) and ten units (group 2) of BTX-A, in a single subconjunctival dose were applied to the non-dominant eye. We evaluated visual acuity, margin-to-reflex distance (RPM1), crease height, ocular motility, diplopia and keratitis, before and after administration of the toxin. The patients were followed at one, 4 and 16 weeks, with the Student t-test as a statistical analysis. RESULTS: At week 4, 15 patients (100%) showed a reduced margin to reflex distance. The mean result for group 1 was -1.75mm (range -1 to -2.5mm) and group 2 was -2mm (range -1 to -4mm). Statistically significant differences were seen between pre-treatment and week 4 in both groups, but no differences between doses. Complete improvement of keratitis and lagophthalmos was observed in 5 and 2 patients, respectively. Visual acuity, ocular motility and crease height did not change in 93% of the patients. One patient (group 1) exhibited complete ptosis and vertical diplopia, which resolved spontaneously at week 6. CONCLUSION: Transconjunctival BTX-A application is safe and effective for the treatment of eyelid retraction in dysthyroid orbitopathy. No difference was found between doses. No severe side effects were reported. PMID- 28336283 TI - [Early efficacy of dexamethasone implant (OZURDEX(r)) in diabetic macular edema: Real life study]. AB - PURPOSE: To assess early efficacy of dexamethasone intravitreal implant 0.7mg (OZURDEX(r)) at the time of peak efficacy (2 months after injection) in patients with decreased visual acuity secondary to diabetic macular edema (DME). MATERIALS AND METHODS: Retrospective monocentric study. Inclusion criteria were best corrected visual acuity (BCVA)<=70 letters (20/40) due to DME and central retinal thickness (CRT)>=300 microns (Cirrus 2, Carl Zeiss Meditec, Inc, Dublin). Enrolled patients could be treatment naive or not (after failure of laser photocoagulation and/or anti-VEGF therapy). Follow-up was at least 6 months. Our primary endpoint was BCVA gain at M2 after injection. Secondary endpoints were best-corrected visual acuity at 2 and 4 months, central retinal thickness at 2 and 4 months, mean interval between 2 injections, and adverse events. RESULT: Nineteen eyes of 19 patients were included in this study. The mean age was 67.45 years, sex ratio was 2.17 men/women, and the patients were all type 2 diabetics. Three of 19 patients were treatment naive for anti-VEGF intravitreal injection, and 52.3% were pseudophakic (10/19 patients). The mean gain of BCVA at M2 was +7.7 letters. The mean BCVA was 51.1 ETDRS letters at baseline and 58.8 at M2. Mean CRT was 568.9MUm at baseline and 291.2MUm at M2. Treatment with dexamethasone implant was mainly a second-line treatment after failure of other treatments (macular laser photocoagulation and/or intravitreal injection of anti VEGF). Three patients were naive of anti-VEGF treatment. Intraocular pressure>=25mmHg was found in 2 patients, and controlled medically. No glaucoma surgery was performed. CONCLUSION: The dexamethasone implant (OZURDEX(r)) allows an anatomical and functional improvement in patients suffering from vision loss due to DME. In this series, the implant was well tolerated. PMID- 28336285 TI - [Response to aflibercept in patients with fibrovascular pigment epithelial detachment refractory to ranibizumab in exudative age-related macular degeneration]. PMID- 28336284 TI - Macular pigment density variation after supplementation of lutein and zeaxanthin using the Visucam(r) 200 pigment module: Impact of age-related macular degeneration and lens status. AB - PURPOSE: To assess the evolution of macular pigment optical density (MPOD) following supplementation with various macular formulations obtained with the Visucam(r) 200, and to study the factors affecting MPOD measurements. MATERIALS AND METHODS: In this prospective, randomized, double-masked multicenter study, patients were divided into 2 groups: group A (patients without retinal pathology who underwent cataract surgery 1 month previously) and group B (patients with neovascular age-related macular degeneration [AMD] in one eye). In each group, half of the patients were randomly assigned to receive a food supplementation either with or without carotenoids (5mg of Lutein and 1mg of Zeaxanthin). Outcome measures included MPOD responses obtained with the Visucam(r) 200 for one year. RESULTS: In total, 126 subjects (52 men, 74 women) with a mean age of 75.3+/-7.61 years were enrolled. Mean MPOD values at the time of inclusion were statistically lower in group A (0.088 density unit [DU]) compared to group B (0.163 DU, P<0.05). No statistically significant increase in MPOD was noted in either group, even after discontinuation of the supplementation. By multiple regression analysis, age, female gender, lens status and the presence of AMD seemed to significantly affect MPOD measurements. CONCLUSION: No significant improvement in MPOD seems to be detected with the Visucam(r) 200 after carotenoid supplementation. The MPOD measurement seems to be highly affected by cataract extraction and the presence of AMD. PMID- 28336286 TI - Robotic Surgery in Uro-oncology: A Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - Robotic surgery represents a new horizon in minimally invasive urologic surgery. This systematic review of the literature and meta-analysis examines the effectiveness of robotic surgery compared with laparoscopic or open surgery for major uro-oncological procedures. Twenty-five articles reported findings from 8 trials of prostatectomy (4 trials) and cystectomy (4 trials) including 1033 participants. Robotic surgery is comparable with laparoscopic or open surgery for oncological outcomes and overall complications, and provides somewhat better functional outcome when compared with laparoscopic and open surgery. PMID- 28336287 TI - A Unique Case of Pentaorchidism. AB - Polyorchidism is a rare congenital anomaly with less than 200 case reports in literature. Triorchidism, the condition of having 3 testicles, is the most common presentation. We present an unusual case of a patient who was diagnosed with 5 testicles by magnetic resonance imaging. To the best of our knowledge, this rare presentation has not previously been reported in the medical literature. PMID- 28336288 TI - Incidental Malignancies Identified During Staging for Prostate Cancer With 68Ga Prostate-specific Membrane Antigen HBED-CC Positron Emission Tomography Imaging. AB - The rapid uptake of 68Ga prostate-specific membrane antigen HBED-CC positron emission tomography (PSMA PET) imaging for prostate cancer staging has led to concerns regarding its specificity, with uptake in both malignant and nonmalignant tissues. We describe 3 separate malignancies identified on PSMA PET imaging. The misnomer "prostate-specific membrane antigen" is demonstrated by this case and highlights the importance of continued investigation of the potential role of PSMA PET in other malignancies. PMID- 28336289 TI - Prospective Case-crossover Study Investigating the Possible Association Between Nonarteritic Anterior Ischemic Optic Neuropathy and Phosphodiesterase Type 5 Inhibitor Exposure. AB - OBJECTIVE: To evaluate the association between intermittent phosphodiesterase type 5 inhibitor (PDE5i) exposure and risk of acute nonarteritic anterior ischemic optic neuropathy (NAION) using a case-crossover design. METHODS: Male adults with suspected NAION were enrolled at 41 US ophthalmology sites from 2010 to 2015 and were interviewed regarding risk factors for NAION, medical history, and PDE5i use before NAION onset (index date of onset [IDO]). An adjudication committee confirmed the NAION cases. The primary analysis, using the person-time method, examined the rate of PDE5i exposure within 5 half-lives of NAION onset relative to PDE5i exposure over a 30-day study period preceding the IDO in men exposed to PDE5i intermittently as a measure of NAION risk associated with PDE5i exposure. Rate ratios were estimated using the Mantel-Haenszel estimator. Secondary analyses included person-time analyses over the 12-months preceding the IDO and matched-interval analyses over 42 days preceding the IDO. RESULTS: Of 279 men with confirmed NAION, 22 were exposed to PDE5i intermittently within 30 days of IDO. The Mantel-Haenszel rate ratio for risk of NAION associated with PDE5i exposure within 5 half-lives of IDO was 2.27 (95% confidence interval [CI]: 0.99 5.20) over the 30-day period (n = 22) and 3.52 (95% CI: 1.59-7.79) over the 12 month period (n = 26). Sensitivity analyses showed similar results and were statistically significant. The matched-interval method found no association (hazard ratio = 1.64 [95% CI: 0.60-4.51]). CONCLUSION: Overall, the study suggests an increased risk of NAION associated with PDE5i use. Patients and health-care providers should continue to weigh the risks and benefits of PDE5i use, including the potential for NAION. PMID- 28336290 TI - Serum microRNA Expression Profiling: Potential Diagnostic Implications of a Panel of Serum microRNAs for Clear Cell Renal Cell Cancer. AB - OBJECTIVE: To study the expression profiles of 5 microRNAs in tissue and serum of patients with clear cell renal cell cancer (ccRCC) and evaluate their diagnostic and prognostic potential. MATERIALS AND METHODS: We prospectively analyzed 30 patients of histologically proven ccRCC and collected 3 mL of serum preoperatively and small pieces of tumor and adjacent non-tumor renal tissue intraoperatively. Control serum samples were obtained from 15 patients of non renal benign diseases. We analyzed 5 miRNAs-miR-34a, miR-141, miR-200c, miR-1233, and miR-21-2. Freshly collected samples were immediately frozen in liquid nitrogen and total RNA was extracted. cDNA was synthesized by reverse transcription, and quantitative polymerase chain reaction was performed to determine relative miRNA expression. RESULTS: In the renal tissue and serum samples, 3 out of 5 miRNAs were differentially expressed; that is, the expression levels of miR-34a and miR-141 were significantly decreased, whereas that of miR 1233 was significantly increased. Serum miR-34a, miR-141, and miR-1233 were able to diagnose ccRCC with a sensitivity of 80.76%, 75%, and 93.33%, and specificity of 80%, 73.33%, and 100%, respectively, as compared to histopathology. Using a panel of 2 serum miRNAs (miR-141 and miR-1233) ccRCC can be diagnosed with 100% sensitivity and 73.3% specificity. CONCLUSION: miRNAs are differentially expressed in serum of patients with ccRCC and can be used to diagnose ccRCC with high sensitivity and specificity. Diagnostic sensitivity can be further improved by using a panel of miRNAs and has the potential to serve as novel diagnostic markers of ccRCC. PMID- 28336291 TI - Reply by the Authors. PMID- 28336294 TI - Palmitate mediated diacylglycerol accumulation causes endoplasmic reticulum stress, Plin2 degradation, and cell death in H9C2 cardiomyoblasts. AB - We have previously shown that palmitate causes ER stress in primary cardiomyocytes and this was associated with a diffuse lipid staining histology. In contrast, oleate, which was non-toxic, led to the formation of abundant, clearly delineated lipid droplets. The aberrant lipid histology in palmitate treated cells led us to hypothesize that perhaps there was an impairment in lipid droplet formation, which could lead to accumulation of lipids in the ER and consequent ER stress. To test this hypothesis we treated H9C2s (a cardiomyoblast cell line) with either 300uM oleate or palmitate for 8h. We found that palmitate resulted in significantly less lipid droplet abundance despite elevated intracellular lipid accumulation. Next we showed that palmitate was packaged primarily as diacylglycerol (DAG), in contrast oleate formed primarily triacylglycerol (TAG). Furthermore, the palmitate induced DAG accumulated mostly in the ER, while oleate treatment resulted in accumulation of TAG primarily in lipid droplets. The palmitate-induced accumulation of lipid in the ER was associated with a strong ER stress response. Interestingly, we found that ER stress induced by either palmitate, tunicamycin, or thapsigargin led to the degradation of Plin2, an important lipid droplet binding protein. In contrast palmitate had little effect on either Plin3 or Plin5. Furthermore, we found that acute MG132 administration significantly attenuated palmitate mediated ER stress and cell death. This protection was associated with a moderate attenuation of Plin2 degradation. PMID- 28336295 TI - Botryococcus braunii strains compared for biomass productivity, hydrocarbon and carbohydrate content. AB - Botryococcus braunii can produce both long-chain hydrocarbons as well as carbohydrates in large quantities, and is therefore a promising industrial organism for the production of biopolymer building blocks. Many studies describe the use of different strains of Botryococcus braunii but differences in handling and cultivation conditions make the comparison between strains difficult. In this study, 16 B. braunii strains obtained from six culture collections were compared for their biomass productivity and hydrocarbon and carbohydrate content. Biomass productivity was highest for AC768 strain with 1.8gL-1day-1, while hydrocarbon production ranged from none to up to 42% per gram biomass dry weight, with Showa showing the highest hydrocarbon content followed by AC761. The total carbohydrate content varied from 20% to 76% per gram of the biomass dry weight, with CCALA777 as the highest producer. Glucose and galactose are the main monosaccharides in most strains and fucose content reached 463mgL-1 in CCALA778. PMID- 28336292 TI - Structural elucidation and physiologic functions of specialized pro-resolving mediators and their receptors. AB - The acute inflammatory response is host-protective to contain foreign invaders. Many of today's pharmacopeia that block pro-inflammatory chemical mediators can cause serious unwanted side effects such as immune suppression. Uncontrolled inflammation is now considered a pathophysiologic basis associated with many widely occurring diseases such as cardiovascular disease, neurodegenerative diseases, diabetes, obesity and asthma, as well as the classic inflammatory diseases, e.g. arthritis, periodontal diseases. The inflammatory response is designated to be a self-limited process that produces a superfamily of chemical mediators that stimulate resolution of inflammatory responses. Specialized proresolving mediators (SPM) uncovered in recent years are endogenous mediators that include omega-3-derived families resolvins, protectins and maresins, as well as arachidonic acid-derived (n-6) lipoxins that stimulate and promote resolution of inflammation, clearance of microbes, reduce pain and promote tissue regeneration via novel mechanisms. Here, we review recent evidence from human and preclinical animal studies, together with the structural and functional elucidation of SPM indicating the SPM as physiologic mediators and pharmacologic agonists that stimulate resolution of inflammation and infection. These results suggest that it is time to develop immunoresolvents as agonists for testing resolution pharmacology in nutrition and health as well as in human diseases and during surgery. PMID- 28336297 TI - Home-based telerehabilitation is not inferior to a centre-based program in patients with chronic heart failure: a randomised trial. AB - QUESTION: Is a 12-week, home-based telerehabilitation program conducted in small groups non-inferior to a traditional centre-based program in terms of the change in 6-minute walk distance? Is the telerehabilitation program also non-inferior to a centre-based program in terms of functional capacity, muscle strength, quality of life, urinary incontinence, patient satisfaction, attendance rates, and adverse events? DESIGN: Randomised, parallel, non-inferiority trial with concealed allocation, intention-to-treat analysis and assessor blinding. PARTICIPANTS: Patients with stable chronic heart failure (including heart failure with reduced or preserved ejection fraction) were recruited from two tertiary hospitals in Brisbane, Australia. INTERVENTION: The experimental group received a 12-week, real-time exercise and education intervention delivered into the participant's home twice weekly, using online videoconferencing software. The control group received a traditional hospital outpatient-based program of the same duration and frequency. Both groups received similar exercise prescription. OUTCOME MEASURES: Participants were assessed by independent assessors at baseline (Week 0), at the end of the intervention (Week 12) and at follow-up (Week 24). The primary outcome was a between-group comparison of the change in 6-minute walk distance, with a non-inferiority margin of 28m. Secondary outcomes included other functional measures, quality of life, patient satisfaction, program attendance rates and adverse events. RESULTS: In 53 participants (mean age 67 years, 75% males), there were no significant between-group differences on 6-minute walk distance gains, with a mean difference of 15m (95% CI -28 to 59) at Week 12. The confidence intervals were within the predetermined non-inferiority range. The secondary outcomes indicated that the experimental intervention was at least as effective as traditional rehabilitation. Significantly higher attendance rates were observed in the telerehabilitation group. CONCLUSION: Telerehabilitation was not inferior to a hospital outpatient-based rehabilitation program in patients with chronic heart failure. Telerehabilitation appears to be an appropriate alternative because it promotes greater attendance at the rehabilitation sessions. TRIAL REGISTRATION: ACTRN12613000390785. [Hwang R, Bruning J, Morris NR, Mandrusiak A, Russell T (2017) Home-based telerehabilitation is not inferior to a centre-based program in patients with chronic heart failure: a randomised trial. Journal of Physiotherapy 63: 101-107]. PMID- 28336293 TI - A compendium of proteins that interact with HIF-1alpha. AB - Hypoxia-inducible factor 1 (HIF-1) is the founding member of a family of transcription factors that function as master regulators of oxygen homeostasis. HIF-1 is composed of an O2-regulated HIF-1alpha subunit and a constitutively expressed HIF-1beta subunit. This review provides a compendium of proteins that interact with the HIF-1alpha subunit, many of which regulate HIF-1 activity in either an O2-dependent or O2-independent manner. PMID- 28336298 TI - Working Alliance Inventory-Short Form Revised. PMID- 28336299 TI - Inhibitory Effect of Crizotinib on Creatinine Uptake by Renal Secretory Transporter OCT2. AB - Crizotinib, a tyrosine kinase inhibitor, exhibits some cases of an increase in serum creatinine levels. Creatinine is excreted by not only glomerular filtration but also active secretion by organic cation transporters such as organic cation transporter 2 (OCT2). In the present study, we evaluated in vitro inhibitory effect of crizotinib on OCT2 by directly measuring creatinine uptake by OCT2. Coincubation of crizotinib reduced uptake of [14C]creatinine by cultured HEK293 cells expressing OCT2 (HEK293/OCT2) in a concentration-dependent manner with IC50 values of 1.58 +/- 0.24 MUM. Preincubation or both preincubation and coincubation (preincubation/coincubation) with crizotinib showed stronger inhibitory effect on [14C]creatinine uptake compared with that in coincubation alone with IC50 values of 0.499 +/- 0.076 and 0.347 +/- 0.040 MUM, respectively. These IC50 values of crizotinib on [3H]N-methyl-4-phenylpyridinium acetate uptake by OCT2 were 10-20 times higher than those of [14C]creatinine uptake. Furthermore, preincubation of crizotinib inhibited creatinine uptake by OCT2 in an apparently competitive manner. In conclusion, crizotinib at a clinically relevant concentration has the potential to inhibit creatinine transport by OCT2, suggesting an increase of serum creatinine levels in clinical use. PMID- 28336296 TI - Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies. AB - BACKGROUND: People with Parkinson's disease can show premotor neurochemical changes in the dopaminergic and non-dopaminergic systems. Using PET, we assessed whether dopaminergic and serotonin transporter changes are similar in LRRK2 mutation carriers with Parkinson's disease and individuals with sporadic Parkinson's disease, and whether LRRK2 mutation carriers without motor symptoms show PET changes. METHODS: We did two cross-sectional PET studies at the Pacific Parkinson's Research Centre in Vancouver, BC, Canada. We included LRRK2 mutation carriers with or without manifest Parkinson's disease, people with sporadic Parkinson's disease, and age-matched healthy controls, all aged 18 years or older. People with Parkinson's disease were diagnosed by a neurologist with movement disorder training, in accordance with the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. In the first study, LRRK2 mutation carriers with or without manifest Parkinson's disease who were referred for investigation between July, 1999, and January, 2012, were scanned with PET tracers for the membrane dopamine transporter, and dopamine synthesis and storage (18F-6-fluoro-L-dopa; 18F-FDOPA). We compared findings with those in people with sporadic Parkinson's disease and age-matched healthy controls. In the second study, distinct groups of LRRK2 mutation carriers, individuals with sporadic Parkinson's disease, and age-matched healthy controls seen from November, 2012, to May, 2016, were studied with tracers for the serotonin transporter and vesicular monoamine transporter 2 (VMAT2). Striatal dopamine transporter binding, VMAT2 binding, 18F-FDOPA uptake, and serotonin transporter binding in multiple brain regions were compared by ANCOVA, adjusted for age. FINDINGS: Between January, 1997, and January, 2012, we obtained data for our first study from 40 LRRK2 mutation carriers, 63 individuals with sporadic Parkinson's disease, and 35 healthy controls. We identified significant group differences in striatal dopamine transporter binding (all age ranges in caudate and putamen, p<0.0001) and 18F-FDOPA uptake (in caudate: age <=50 years, p=0.0002; all other age ranges, p<0.0001; in putamen: all age ranges, p<0.0001). LRRK2 mutation carriers with manifest Parkinson's disease (n=15) had reduced striatal dopamine transporter binding and 18F-FDOPA uptake, comparable with amounts seen in individuals with sporadic Parkinson's disease of similar duration. LRRK2 mutation carriers without manifest Parkinson's disease (n=25) had greater 18F-FDOPA uptake and dopamine transporter binding than did individuals with sporadic Parkinson's disease, with 18F-FDOPA uptake comparable with controls and dopamine transporter binding lower than in controls. Between November, 2012, and May, 2016, we obtained data for our second study from 16 LRRK2 mutation carriers, 13 individuals with sporadic Parkinson's disease, and nine healthy controls. Nine LRRK2 mutation carriers without manifest Parkinson's disease had significantly elevated serotonin transporter binding in the hypothalamus (compared with controls, individuals with LRRK2 Parkinson's disease, and people with sporadic Parkinson's disease, p<0.0001), striatum (compared with people with sporadic Parkinson's disease, p=0.02), and brainstem (compared with LRRK2 mutation carriers with manifest Parkinson's disease, p=0.01), after adjustment for age. Serotonin transporter binding in the cortex did not differ significantly between groups after age adjustment. Striatal VMAT2 binding was reduced in all individuals with manifest Parkinson's disease and reduced asymmetrically in one LRRK2 mutation carrier without manifest disease. INTERPRETATION: Dopaminergic and serotonergic changes progress in a similar fashion in LRRK2 mutation carriers with manifest Parkinson's disease and individuals with sporadic Parkinson's disease, but LRRK2 mutation carriers without manifest Parkinson's disease show increased serotonin transporter binding in the striatum, brainstem, and hypothalamus, possibly reflecting compensatory changes in serotonergic innervation preceding the motor onset of Parkinson's disease. Increased serotonergic innervation might contribute to clinical differences in LRRK2 Parkinson's disease, including the emergence of non-motor symptoms and, potentially, differences in the long-term response to levodopa. FUNDING: Canada Research Chairs, Michael J Fox Foundation, National Institutes of Health, Pacific Alzheimer Research Foundation, Pacific Parkinson's Research Institute, National Research Council of Canada. PMID- 28336301 TI - Big cats as a model system for the study of the evolution of intelligence. AB - Currently, carnivores, and felids in particular, are vastly underrepresented in cognitive literature, despite being an ideal model system for tests of social and ecological intelligence hypotheses. Within Felidae, big cats (Panthera) are uniquely suited to studies investigating the evolutionary links between social, ecological, and cognitive complexity. Intelligence likely did not evolve in a unitary way but instead evolved as the result of mutually reinforcing feedback loops within the physical and social environments. The domain-specific social intelligence hypothesis proposes that social complexity drives only the evolution of cognitive abilities adapted only to social domains. The domain-general hypothesis proposes that the unique demands of social life serve as a bootstrap for the evolution of superior general cognition. Big cats are one of the few systems in which we can directly address conflicting predictions of the domain general and domain-specific hypothesis by comparing cognition among closely related species that face roughly equivalent ecological complexity but vary considerably in social complexity. PMID- 28336300 TI - Development of Topical Delivery Systems for Flightless Neutralizing Antibody. AB - Flightless I (Flii) is an actin remodeling protein important for cytoskeletal regulation and cellular processes including migration, proliferation, and adhesion. Previous studies have clearly identified Flii as a novel therapeutical target for improved wound repair and have demonstrated Flii regulation using Flii neutralizing antibodies (FnAb) in different models of wound healing in vivo. Here we describe the development of an optimized topical delivery system that can neutralize Flii activity in the epidermis. Topical delivery of FnAb is an attractive approach as it provides a convenient application, sustained release, localized effect, and reduced dosage. Three successful formulations were developed, and their physical and chemical stability examined. The in vitro release revealed prolonged and sustained release of FnAb in all the tested formulations. Additionally, penetration studies using intact porcine skin showed that FnAb penetrated the epidermis and upper papillary dermis. The penetrated FnAb significantly reduced Flii expression compared to dosed matched IgG controls. This study has successfully developed a topical delivery system for FnAb that could serve as a potential platform for future localized wound treatments. PMID- 28336302 TI - [Vasopressors and inotropes: use in paediatrics]. AB - The cardiovascular system is a dynamic system, which is required to ensure adequate delivery of oxygen, nutrients, and hormones to the tissues that are necessary for cell metabolism. It also synthesises and modifies the vasoactive components that regulate vascular tone and myocardial function. These vasoactive components have demonstrated their beneficial effects in the management of paediatric patients in a critical condition with heart failure and shock. However, their use and abuse brings harmful effects, increases mortality, and is associated with arrhythmias. An increase in myocardial oxygen consumption favours the presence of ischaemia, therefore it is necessary to know the mechanism of action and indications of these drugs to minimise their harmful effects. The purpose of this review is to describe the pharmacology and clinical applications of inotropic and vasopressor agents in the paediatric patient in acritical condition. PMID- 28336303 TI - Rituximab maintenance improves overall survival of patients with follicular lymphoma-Individual patient data meta-analysis. AB - BACKGROUND: Randomised trials of rituximab maintenance (MR) for patients with follicular lymphoma support improved progression-free survival (PFS), but the effect on overall survival has been inconclusive. To evaluate the effect of MR on overall survival according to patient and disease characteristics, and to explore certain adverse events, we performed an individual patient data (IPD) meta analysis. METHODS: All investigators of randomised controlled trials that compared MR therapy with observation or treatment only at relapse (no MR) for patients with follicular lymphoma were invited to participate in an IPD meta analysis. We obtained baseline patient and disease characteristics and time to progression and death for each patient. All analyses took into account the trial and original randomised treatment group. We analysed data in two ways: a two stage analysis and a multivariate model including patient and disease characteristics. FINDINGS: Seven trials including 2315 patients were analysed. Overall survival of patients improved with MR compared with no MR (hazard ratio [HR] 0.79, 95% CI 0.66-0.96). We could not detect any patient or disease characteristics that were associated with a survival benefit with MR. In all of the models, MR had a beneficial effect on overall survival compared with observation for all types of patients, which was not shown in a particular subgroup in which the patient had already received rituximab in the induction phase and received first-line therapy. MR improved PFS compared with observation (HR 0.57, 95% CI 0.51-0.64). The risk of adverse events was higher with MR, specifically infection of any grade and grade 3-4 infections. INTERPRETATION: Based on IPD from randomised controlled trials, MR improves overall survival consistently in all patients, regardless of patient and disease characteristics when compared with observation, and should be prescribed after a successful induction with R-CVP or R-CHOP for patients with follicular lymphoma. It is still uncertain if that holds when the patient has already received rituximab in his/hers first induction. The effect of MR after bendamustine-rituximab induction compared with rituximab at progression should be further explored. PMID- 28336304 TI - Management of adult infectious encephalitis in metropolitan France. AB - Infectious encephalitis is a severe disease leading to a high mortality and morbidity. The most frequent causes include Herpes simplex virus, Varicella Zoster virus, Listeria monocytogenes, and Mycobacterium tuberculosis. Urgent treatment is required (anti-infective therapy and nonspecific supportive care). The aim of this study was to define treatment strategy, empirical and after microbiological documentation at 48hours, through a systematic literature review. PMID- 28336306 TI - Efficacy of Acellular Nerve Allografts in Trigeminal Nerve Reconstruction. AB - PURPOSE: During trigeminal nerve repair, a gap is sometimes encountered that prevents the tension-free apposition of nerve endings. The use of a processed acellular nerve allograft is a novel technique that shows promise in overcoming this problem. The goal of the present study was to support the slowly evolving body of evidence that acellular processed nerve allografts (Avance; Axogen, Alachua, FL) are a viable alternative to autogenous nerve grafting and the use of conduits for reconstructing defects of the trigeminal nerve. PATIENTS AND METHODS: The study design consisted of a retrospective review of the medical records of patients referred to Rutgers School of Dental Medicine for management of trigeminal nerve injuries from July 2008 to August 2014. Sixteen patients met the inclusion criteria for the present study. All patients underwent nerve grafting using a processed nerve allograft. All operations were performed by the same surgeon (V.Z.). Serial neurosensory testing was performed by 1 clinician (V.Z.) in a standardized fashion. The primary outcome variable was the interval to functional sensory recovery as defined by the Medical Research Council Scale. RESULTS: The participants ranged in age from 16 to 62 years (mean 32). Of the 16 patients, 12 were female (75%) and 4 were male (25%), and 3 were smokers (18.75%) and 13 were nonsmokers (81.25%). One half of the patients (n = 8; 50%) underwent surgery on the inferior alveolar nerve, and 8 (50%) underwent surgery on the lingual nerve. The most common mechanism of injury was impacted third molar removal (n = 9; 56.25%) Of the 16 patients, 15 (93.75%) achieved functional sensory recovery during the study period. CONCLUSIONS: The results of the present study support the hypothesis that processed nerve allografts are effective in reconstructing small (<2-cm) trigeminal nerve defects. PMID- 28336305 TI - From point process observations to collective neural dynamics: Nonlinear Hawkes process GLMs, low-dimensional dynamics and coarse graining. AB - This review presents a perspective on capturing collective dynamics in recorded neuronal ensembles based on multivariate point process models, inference of low dimensional dynamics and coarse graining of spatiotemporal measurements. A general probabilistic framework for continuous time point processes reviewed, with an emphasis on multivariate nonlinear Hawkes processes with exogenous inputs. A point process generalized linear model (PP-GLM) framework for the estimation of discrete time multivariate nonlinear Hawkes processes is described. The approach is illustrated with the modeling of collective dynamics in neocortical neuronal ensembles recorded in human and non-human primates, and prediction of single-neuron spiking. A complementary approach to capture collective dynamics based on low-dimensional dynamics ("order parameters") inferred via latent state-space models with point process observations is presented. The approach is illustrated by inferring and decoding low-dimensional dynamics in primate motor cortex during naturalistic reach and grasp movements. Finally, we briefly review hypothesis tests based on conditional inference and spatiotemporal coarse graining for assessing collective dynamics in recorded neuronal ensembles. PMID- 28336308 TI - Robotic Intracorporeal Continent Cutaneous Diversion. AB - PURPOSE: Robotic intracorporeal urinary diversion has mostly been done for ileal conduit or orthotopic neobladder diversion. We present what is to our knowledge the initial series, detailed technique and outcomes of the robotic intracorporeal Indiana pouch with a minimum 1-year followup. MATERIALS AND METHODS: Ten patients underwent robotic radical cystectomy, pelvic lymphadenectomy and intracorporeal Indiana pouch urinary diversion for cancer in 9 and benign disease in 1. Data were collected prospectively. Baseline demographics, pathology data, and 1-year complication rates and functional outcomes were assessed. RESULTS: All 10 cases were successfully completed intracorporeally without open conversion. Median total operative time was 6 hours, including 3.5 hours for pouch creation. Median blood loss was 200 cc and median hospital stay was 10 days. Four Clavien grade 1 2 and 3 Clavien 3-5 complications occurred. None of the patients had a bowel leak. One noncompliant patient requested undiversion to an ileal conduit. The remaining 9 patients successfully catheterized the ileal channel and were completely continent at the last followup at a median of 13.7 months (range 12.3 to 15.2). Study limitations include small sample size and short followup. CONCLUSIONS: We present what is to our knowledge the initial series of robotic completely intracorporeal Indiana pouch diversion. Early perioperative data indicate acceptable operative efficiency and complication rates. Longer followup is required to assess the functional outcomes of this less commonly performed diversion. PMID- 28336307 TI - Measuring RNA structure transcriptome-wide with icSHAPE. AB - RNA molecules can be found at the heart of nearly every aspect of gene regulation: from gene expression to protein translation. The ability of RNA molecules to fold into intricate structures guides their function. Chemical methods to measure RNA structure have been part of the RNA biologists toolkit for several decades. These methods, although often cumbersome and difficult to perform on large RNAs, are notable for their accuracy and precision of structural measurements. Recent extension of these methods to transcriptome-wide analyses has opened the door to interrogating the structure of complete RNA molecules inside cells. Within this manuscript we describe the biochemical basis for the methodology behind a novel technology, icSHAPE, which measures RNA flexibility and single-strandedness in RNA. Novel methods such as icSHAPE have greatly expanded our understanding of RNA function and have paved the way to expansive analyses of large groups of RNA structures as they function inside the native environment of the cell. PMID- 28336309 TI - Usefulness of the ElliPro epitope predictor program in defining the repertoire of HLA-ABC eplets. AB - HLA matching at the epitope level offers new opportunities to identify suitable donors for transplant patients. The International HLA Epitope Registry (www.Epregistry.com.br) describes for the various HLA loci, repertoires of eplets including those that correspond to epitopes experimentally verified with specific antibodies. There are also many eplets which have remained as theoretical entities because no informative antibodies have been found. Which of them have immunogenic potential or conversely, might be considered as non-epitopes that cannot elicit specific antibody responses? This question is important for the application of epitope-based HLA matching in clinical transplantation. Correct predictions of B-cell epitopes on antigenic proteins are essential to the effective design of microbial vaccines and the development of specific antibodies used in immunotherapy and immunodiagnostics but prediction programs based on structural and physiochemical properties of amino acid residues are generally ineffective. Recent prediction programs based on three-dimensional structures of antigen-antibody complexes are more promising. One such program is called ElliPro developed by Ponomarenko. This report describes studies demonstrating that ElliPro can predict alloantibody responses to HLA-ABC eplets. Antibody-verified eplets have amino acid residues with much higher ElliPro scores than eplets for which no specific antibodies have been found. The latter group includes residues with very low ElliPro scores; they appear to represent eplets that might be classified as non-epitopes. In conclusion, ElliPro offers a new approach to characterize epitope repertoires that are clinically relevant in HLA matching. PMID- 28336310 TI - Regulatory role of CCL5 (rs2280789) and CXCL10 (rs56061981) gene polymorphisms on intracellular CCL5 and CXCL10 expression in pulmonary tuberculosis. AB - Genetic variations in chemokine genes influence the chemoattractive properties of T cells which may be associated with outcome of infections. In present study, we have investigated the regulatory role played by In1.1T/C (rs2280789) polymorphism of CCL5 and -135G/A (rs56061981) polymorphism of CXCL10 gene on intracellular CCL5 and CXCL10 expression in T cells. Whole blood cell cultures were stimulated with culture filtrate antigen (CFA) and infected with live M. tuberculosis were used for intracellular CCL5 and CXCL10 expression using flow cytometry. Genotyping was performed using polymerase chain reaction based restriction fragment length polymorphism (PCR-RFLP). Significantly higher expression of CCL5 expressing CD3+ and CD3+ CD8+ T cells were observed in HCs with In1.1TT genotype compared to C allele carrier (TT+TC) under unstimulated and CFA induced cultures (p<0.05). In -135G/A (rs56061981) polymorphism, PTB patients with GG genotype showed a significantly decreased expression of CD3+ CXCL10+ and CD3+ CD4+ CXCL10+ T cells compared to A allele carrier (GA+AA) under unstimulated, CFA induced and M. tuberculosis infected cultures (P<0.05). The present study suggest that TT genotype of CCL5 In1.1T/C (rs2280789) polymorphism play an important role to increased CCL5 expression in T cell which may enhanced Th1 immunity and help in protection against tuberculosis. The study also suggests GG genotype of CXCL10 135G/A (rs56061981) polymorphism decreased CXCL10 expression in T cells which may have defective recruitment of mononuclear cells at the site of infection as well granuloma formation and in turn contribute to progression of TB. PMID- 28336311 TI - Polyclonal dissemination of KPC-2 in Serratia marcescens, including a clone with epidemic behaviour in the nosocomial niche. PMID- 28336312 TI - Old antibiotics for emerging multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB). AB - Recently, multidrug-resistant tuberculosis (MDR-TB) has become a therapeutic challenge. In addition to drug resistance, drug adverse events, intravenous delivery, cost and availability of some antibiotics in low-income countries have led to a look back to old drugs, especially those efficient against closely related organisms such as Mycobacterium leprae. Here we review the available drugs that respect the conditions above and could be upgraded to first-line therapy for treating MDR-TB and extensively drug-resistant tuberculosis (XDR-TB). PMID- 28336313 TI - Vancomycin-resistant enterococci colonisation, risk factors and risk for infection among hospitalised paediatric patients: a systematic review and meta analysis. AB - The objective of this study was to estimate the rate and significance of colonisation with vancomycin-resistant enterococci (VRE) among hospitalised children. The PubMed and EMBASE databases were systematically searched (last accessed on 29 May 2016) to identify studies evaluating VRE colonisation of the gastrointestinal tract of hospitalised children in non-outbreak periods. Of 945 non-duplicate citations, 19 studies enrolling 20 234 children were included. The overall and paediatric intensive care unit (PICU) rate of VRE colonisation were both 5% [95% confidence interval (CI) 3-8% overall and 95% CI 2-9% in the PICU] but was 23% in haematology/oncology units (95% CI 18-29%). Studies that were exclusively performed in haematology/oncology units reported significantly higher rates compared with all other studies in the univariate and multivariate analyses (P = 0.001). Previous vancomycin [risk ratio (RR) = 4.34, 95% CI 2.77-6.82] or ceftazidime (RR = 4.15, 95% CI 2.69-6.40) use was a risk factor for VRE colonisation. Importantly, VRE colonisation increased the risk of subsequent VRE infection (RR = 8.75, 95% CI 3.19-23.97). In conclusion, a high rate of VRE colonisation was found among hospitalised children in institutions that performed targeted screening. Importantly, colonised children were almost 9 times more likely to develop subsequent VRE infection. Judicious use of specific antibiotics along with intensification of infection control measures should be considered in high-prevalence institutions. Also, the high incidence of VRE colonisation among children with haematological/oncological diseases identifies a high-risk population. PMID- 28336314 TI - Non-linear van't Hoff behavior in pulmonary surfactant model membranes. AB - Pulmonary surfactant exhibits phase coexistence over a wide range of surface pressure and temperature. Less is known about the effect of temperature on pulmonary surfactant models. Given the lack of studies on this issue, we used electron paramagnetic resonance (EPR) and nonlinear least-squares (NLLS) simulations to investigate the thermotropic phase behavior of the matrix that mimics the pulmonary surfactant lipid complex, i.e., the lipid mixture composed of dipalmitoyl phosphatidylcholine (DPPC), palmitoyl-oleoyl phosphatidylcholine (POPC) and palmitoyl-oleoyl phosphatidylglycerol (POPG). Irrespective of pH, the EPR spectra recorded from 5 degrees C to 25 degrees C in the DPPC/POPC/POPG (4:3:1) model membrane contain two spectral components corresponding to lipids in gel-like and fluid-like phases, indicating a coexistence of two domains in that range. The temperature dependence of the distribution of spin labels between the domains yielded nonlinear van't Hoff plots. The thermodynamic parameters evaluated were markedly different for DPPC and for the ternary DPPC/POPC/POPG (4:3:1) membranes and exhibited a dependence on chemical environment. While enthalpy and entropy changes for DPPC were always positive and presented a quadratic behavior with temperature, those of the ternary mixture were linearly dependent on temperature and changed from negative to positive values. Despite that, enthalpy-entropy compensation takes place in the two systems. The thermotropic process associated with the coexistence of the two domains is entropically-driven in DPPC and either entropically- or enthalpically-driven in the pulmonary surfactant membrane depending on the pH, ionic strength and temperature. The significance of these results to the structure and function of the pulmonary surfactant lipid matrix is discussed. PMID- 28336318 TI - Concentric muscle involvement in POLG-related distal myopathy. PMID- 28336316 TI - Effects of age and soybean isoflavones on hepatic cholesterol metabolism and thyroid hormone availability in acyclic female rats. AB - Soy-food and its isoflavones, genistein (G) and daidzein (D), were reported to exert mild cholesterol-lowering effect, but the underlying mechanism is still unclear. In this research, first we studied age-related alterations in hepatic cholesterol metabolism of acyclic middle-aged (MA) female rats. Then we tested if purified isoflavones may prevent or reverse these changes, and whether putative changes in hepatic thyroid hormone availability may be associated with this effect. Serum and hepatic total cholesterol (TChol), bile acid and cholesterol precursors, as well as serum TSH and T4 concentrations, hepatic deiodinase (Dio) 1 enzyme activity and MCT8 protein expression were determined by comparing data obtained for MA with young adult (YA) intact (IC) females. Effects of subcutaneously administered G or D (35mg/kg) to MA rats were evaluated versus vehicle-treated MA females. MA IC females were characterized by: higher (p<0.05) serum TChol, lower (p<0.05) hepatic TChol and its biosynthetic precursors, lower (p<0.05) hepatic 7alpha-hydroxycholesterol but elevated (p<0.05) 27- and 24 hydroxycholesterol in comparison to YA IC. Both isoflavone treatments decreased (p<0.05) hepatic 27-hydroxycholesterol, G being more effective than D, without affecting any other parameter of Chol metabolism. Only G elevated hepatic Dio1 activity (p<0.05). In conclusion, age-related hypercholesteremia was associated with lower hepatic Chol synthesis and shift from main neutral (lower 7alpha hydroxycholesterol) to alternative acidic pathway (higher 27-hydroxycholesterol) of Chol degradation to bile acid. Both isoflavones lowered hepatic 27 hydroxycholesterol, which may be considered beneficial. Only G treatment increased hepatic Dio1 activity, thus indicating local increase in thyroid hormones, obviously insufficient to induce prominent cholesterol-lowering effect. PMID- 28336315 TI - Cardiolipin and mitochondrial cristae organization. AB - A fundamental question in cell biology, under investigation for over six decades, is the structural organization of mitochondrial cristae. Long known to harbor electron transport chain proteins, crista membrane integrity is key to establishment of the proton gradient that drives oxidative phosphorylation. Visualization of cristae morphology by electron microscopy/tomography has provided evidence that cristae are tube-like extensions of the mitochondrial inner membrane (IM) that project into the matrix space. Reconciling ultrastructural data with the lipid composition of the IM provides support for a continuously curved cylindrical bilayer capped by a dome-shaped tip. Strain imposed by the degree of curvature is relieved by an asymmetric distribution of phospholipids in monolayer leaflets that comprise cristae membranes. The signature mitochondrial lipid, cardiolipin (~18% of IM phospholipid mass), and phosphatidylethanolamine (34%) segregate to the negatively curved monolayer leaflet facing the crista lumen while the opposing, positively curved, matrix facing monolayer leaflet contains predominantly phosphatidylcholine. Associated with cristae are numerous proteins that function in distinctive ways to establish and/or maintain their lipid repertoire and structural integrity. By combining unique lipid components with a set of protein modulators, crista membranes adopt and maintain their characteristic morphological and functional properties. Once established, cristae ultrastructure has a direct impact on oxidative phosphorylation, apoptosis, fusion/fission as well as diseases of compromised energy metabolism. PMID- 28336317 TI - Lethal multiple pterygium syndrome: A severe phenotype associated with a novel mutation in the nebulin gene. AB - Fetal akinesia deformation sequence is a clinically and genetically heterogeneous disorder characterized by a variable combination of fetal akinesia, intrauterine growth restriction, developmental abnormalities such as cystic hygroma, hydrops fetalis, pulmonary hypoplasia, occasional arthrogryposis, and pterygia. The pathogenetic mechanisms of fetal akinesia deformation sequence include neuropathy, muscular disorders, neuromuscular junction disorders, maternal myasthenia gravis, restrictive dermopathy and others. We here report an Egyptian family presenting with recurrent lethal multiple pterygium syndrome. The diagnosis was based on antenatal sonographic demonstration of complete fetal akinesia and a large cystic hygroma with severe limb contractures evident on postmortem examination. Next generation sequencing performed on the second affected fetus identified a novel homozygous essential splice-site variant in the nebulin gene. In conclusion, our report adds further evidence for the involvement of the nebulin gene in the etiology of fetal akinesia deformation sequence/lethal multiple pterygium syndrome. PMID- 28336320 TI - Preliminary research on DNA methylation changes during murine palatogenesis induced by TCDD. AB - 2,3,7,8-Tetrachlrodibenzo-p-dioxin (TCDD) has been shown to induce cleft palate through growth factor and receptor expression changes during palatogenesis. DNA methylation is an important epigenetic modification that can regulate gene expressions and may be involved in TCDD-induced cleft palate. In this study, we investigated the effects of TCDD on the global and CpG DNA methylation status and the expression levels of DNA methyltransferases (Dnmts) in palate tissue of fetal mice. Pregnant C57BL/6J mice were administered with corn oil or TCDD 28 MUg/kg at gestation day 10.5(GD10.5), and sacrificed at GD13.5, 14.5, 15.5. Fetal palates were collected for molecular analysis. Global DNA methylation status was detected by MethylampTM Global DNA Methylation Quantification Ultra Kit. The expression of DNA methyltransferases were examined by quantitative real-time PCR(q-PCR). Methylation Specific PCR (MSP) was performed to analyze CpG methylation status of Dnmts. We found that the global DNA methylation level and the expression of Dnmt3a were higher at GD13.5 in the TCDD group. The methylation level of CpG site 2 in the promoter region of Dnmt3a in the control group was higher than that of the TCDD group at GD13.5. The low CpG methylation level of Dnmt3a at GD13.5 which causes the up-expression of Dnmt3a may induce global hypermethylation in fetal palate tissue. The aberrant global methylation status at GD13.5 may be the cause of palate malformation in fetal mice induced by TCDD. PMID- 28336319 TI - Influence of gender of the teaching staff on students' acceptance of a virtual implant planning course. AB - Acceptance of new technology is influenced by a number of situational and social factors. So far, only limited data are available on the influence of the teaching staff's gender on the acceptance of virtual dental implant planning by students. This study aimed at assessing the influence of the teaching staff's gender on the acceptance of a virtual implant planning course by male and female undergraduate dental students and their general attitude toward implantology. Two groups of third-year dental students (group 1, 9 males, 22 females; group 2, 12 males, 20 females) attended a virtual dental implant planning course. For the first group the teaching staff was all-male, while the teaching staff was all-female for the second group. After completion of the course the students filled in a technology acceptance questionnaire. An all-female teaching staff led to a degree of technology acceptance that did not differ significantly for male and female students. When the teaching staff was all-male, significant differences for technology acceptance occurred between male and female students. However, male as well as female students attributed the practice of implantology to both genders of dentists, equally, without statistically significant difference independent of the gender of the teaching staff. The more evenly distributed degree of technology acceptance of students of both genders being taught by a female staff is a favorable effect which may be explained by the more egalitarian style of women. Therefore, while feminization in dentistry proceeds, adequate measures should be taken to increase the number of female teachers. PMID- 28336321 TI - The histological and histomorphometric changes in the mandible after radiotherapy: An animal model. AB - PURPOSE: Approximately 5% of irradiated head and neck cancer patients develop osteoradionecrosis of the mandible. The current non-surgical treatment options for osteoradionecrosis have limited effects and are based on a small number of studies. Therefore, we aimed to enhance the understanding of the pathophysiology of osteoradionecrosis by investigating changes induced by external irradiation in mini-pigs. METHODS: Sixteen Gottingen mini-pigs were divided into four groups for the application in two fractions with total equivalent radiation dosages of 25, 50, 70 Gray, and one group served as control. Thirteen weeks after irradiation, the left lateral teeth the mandible were removed and implants were placed. The pigs were sacrificed twenty-six weeks after irradiation, and the bone samples were stained with Masson's trichrome. RESULTS: The amount of fibrosis, resorption lacunae, necrosis, and the woven/lamellar bone ratios were increased after higher radiation dosages. The diameter of the lumen of the inferior alveolar artery was reduced depending on the irradiation dosages. The rate of bone remodeling decreased after irradiation. CONCLUSION: Both surgery and increasing irradiation dosages cause architectural bone changes and damage the vascularization. This might result in a chronic hypoxic state of the mandibular bone. In general, the bone formation rate was markedly decreased after radiotherapy. PMID- 28336322 TI - A novel semi-automatic segmentation protocol for volumetric assessment of alveolar cleft grafting procedures. AB - A novel protocol for volumetric assessment of alveolar cleft grafting procedures is presented. Eleven cone-beam computed tomography (CBCT) datasets of patients who underwent secondary alveolar cleft reconstructive surgery for a unilateral alveolar cleft were evaluated by two investigators. Residual bone volumes 1 year after surgery were analysed using a semi-automated technique in which preoperative CBCT datasets were superimposed on the postoperative scans using voxel-based registration. To define the correct boundaries of the alveolar cleft defect in the preoperative CBCT dataset, a mirror image of the preoperative CBCT dataset was superimposed on the preoperative CBCT dataset. For the difference in residual bone volume between the two observers, an intraclass correlation of 0.98 and a Dice coefficient of 0.89 were found. This study describes a reliable segmentation protocol for volumetric analysis of the alveolar cleft defect in patients with a unilateral alveolar cleft. PMID- 28336324 TI - First detection of Klebsiella pneumoniae producing OXA-48 in fresh vegetables from Bejaia city, Algeria. PMID- 28336325 TI - Allogeneic Hematopoietic Stem Cell Transplantation Is Underutilized in Older Patients with Myelodysplastic Syndromes. AB - Allogeneic hematopoietic stem cell transplantation (HCT) is the only curative treatment for myelodysplastic syndrome (MDS). The proportion of MDS patients referred for transplantation evaluation, those undergoing transplantation, and the reasons for not undergoing transplantation are unknown. In this retrospective analysis, predefined HCT eligibility and indications criteria were applied to 362 unselected patients with newly diagnosed MDS seen by leukemia faculty between 2008 and 2015 at Memorial Sloan Kettering Cancer Center. Two hundred ninety-four patients (81%) were deemed eligible for transplantation and among these, transplantation was considered indicated in 244 (83%). Of these, 158 of 244 (65%) were referred for transplantation evaluation at a median of 3.9 months from diagnosis. Overall 120 of 362 (33%) underwent transplantation at a median of 7.7 months from diagnosis. Metastatic solid-organ malignancy was the major reason for transplantation ineligibility (54%), and death due to MDS, which occurred in 41% of candidates who did not undergo transplantation, was the major reason for not undergoing transplantation. Factors associated with a lower likelihood of referral for transplantation evaluation included age >=65 (P < .001), >=2 comorbidities (P = .008), intermediate-1/low risk MDS (P < .001), <5% blasts at diagnosis (overall P < .001), having Medicare/Medicaid health insurance (P < .001), not being married (P = .017), and diagnosis between 2008 and 2011 (P = .035). On multivariate analysis adjusting for all of the previous factors, diagnosis between 2008 and 2011 (P < .001), age >=65 (P = .001), and <5% blasts at diagnosis (overall P = .031) were associated with a lower likelihood of referral for transplantation evaluation. Factors associated with a lower likelihood of undergoing transplantation included age >=65 (P < .001), >=2 comorbidities (P = .003), intermediate-1/low risk MDS (P < .001), <5% blasts (overall P < .001), very low/low/intermediate risk International Prognostic Scoring System-revised karyotype (P = .018), and having Medicare/Medicaid health insurance (P < .001). In multivariate analysis adjusting for all of the previous factors, age >=65 (P = .021), presence of >=2 comorbidities (P = .018), and <5% blasts (overall P = .011) were associated with a lower likelihood of undergoing transplantation. The results highlight that transplantation for MDS remains underutilized, particularly for candidates over the age of 65. PMID- 28336323 TI - M1 muscarinic activation induces long-lasting increase in intrinsic excitability of striatal projection neurons. AB - The dorsolateral striatum is critically involved in movement control and motor learning. Striatal function is regulated by a variety of neuromodulators including acetylcholine. Previous studies have shown that cholinergic activation excites striatal principal projection neurons, medium spiny neurons (MSNs), and this action is mediated by muscarinic acetylcholine subtype 1 receptors (M1) through modulating multiple potassium channels. In the present study, we used electrophysiology techniques in conjunction with optogenetic and pharmacological tools to determine the long-term effects of striatal cholinergic activation on MSN intrinsic excitability. A transient increase in acetylcholine release in the striatum by optogenetic stimulation resulted in a long-lasting increase in excitability of MSNs, which was associated with hyperpolarizing shift of action potential threshold and decrease in afterhyperpolarization (AHP) amplitude, leading to an increase in probability of EPSP-action potential coupling. The M1 selective antagonist VU0255035 prevented, while the M1 selective positive allosteric modulator (PAM) VU0453595 potentiated the cholinergic activation induced persistent increase in MSN intrinsic excitability, suggesting that M1 receptors are critically involved in the induction of this long-lasting response. This M1 receptor-dependent long-lasting change in MSN intrinsic excitability could have significant impact on striatal processing and might provide a novel mechanism underlying cholinergic regulation of the striatum-dependent motor learning and cognitive function. Consistent with this, behavioral studies indicate that potentiation of M1 receptor signaling by VU0453595 enhanced performance of mice in cue-dependent water-based T-maze, a dorsolateral striatum dependent learning task. PMID- 28336326 TI - Oxidative stress and genes regulation of cerebral malaria upon Zizyphus spina christi treatment in a murine model. AB - The development and spread of multidrug-resistant strains of malarial parasites have led to an overwhelming increase in the resistance to current antimalarial drugs. The urgent need for alternative antimalarial drugs has directed some of the current studies toward folkloric medicine approaches. Interestingly, the Zizyphus spina Cristi leaf extract (ZLE) has been found to exhibit antiplasmodial activity. This study evaluated the protective effect of ZLE against Plasmodium berghei-induced cerebral tissue injuries in mice. Male C57Bl/6 mice received an injection of P. berghei-infected red blood cells. Mice were divided into three groups (control, infected, and ZLE-treated), and were subjected to histological, biochemical, and molecular analyses. Murine malaria infections induced significant weight loss; however, upon ZLE treatment, the weight of mice was markedly restored. Additionally, infected mice showed brain histopathological changes and induction of oxidative damage. Significantly, ZLE treatment restored the levels of oxidative markers and antioxidant enzyme to the normal ranges. The mRNA expression of several genes in the brain of mice including Cacnb4, Adam23, Glrb, Vdac3, and Cabp1 was significantly upregulated during P. berghei infection. In contrast, ZLE markedly reduced the mRNA expression of these genes. To conclude, the results indicate that ZLE could play an important role in reducing the destructive effect of P. berghei-induced cerebral malaria owing to its antiplasmodial and antioxidant activities. PMID- 28336327 TI - Galectin-1-driven upregulation of SDF-1 in pancreatic stellate cells promotes pancreatic cancer metastasis. AB - Galectin-1, mainly expressed in activated pancreatic stellate cells (PSCs), is involved in many important cancer-related processes. However, very little is known how Galectin-1 modulates PSCs and subsequently impacts pancreatic cancer cells (PCCs). Our chemokine antibody array and in vitro studies demonstrates that Galectin-1 induces secretion of stromal cell-derived factor-1(SDF-1) in PSCs by activating NF-kappaB signaling. The secreted SDF-1 increases migration and invasion of PCCs. Knockdown of Galectin-1 and inhibitor-mediated blockade of SDF 1 as well as its ligand CXCR4 and NF-kappaB verifies the findings. In vivo experiment by knockdown of Galectin-1 in PSCs further demonstrates the conclusion. Collectively, the present studies demonstrate that Galectin-1-driven production of SDF-1 in PSCs through activation of NF-kappaB promotes metastasis in PDAC, offering a potential target in the treatment of pancreatic cancer. PMID- 28336328 TI - Bone healing is achievable despite extensive wound dehiscence and wide plate and screws exposure in children. AB - BACKGROUND: Extensive wound dehiscence and wide plate and screw exposure in the early weeks following orthopaedic surgery in children is usually managed either by extensive debridement, lavage and secondary closure or hardware removal and external fixation. PATIENTS: Three children with LCP plate and screws exposure were managed by simple repetitive debridement and local wound care without any IV antibiotics, nor secondary closure or hardware removal. All three cases occurred in the tibia, one following tibial osteotomy in lateral hemimelia with a long history of previous surgeries, one following wide excision of a tibial Ewing sarcoma with chemo- and radiotherapy, and the third following wide excision of a 12cm necrotic tibial segment due to chronic osteomyelitis. Bone healing was uneventful in 2 cases and was in progress in the case with the Ewing sarcoma. Plate and screws were removed in all cases, following an obvious bone healing in 2 cases, and forced by the need for chemotherapy due to the presence of lung metastases in the third case. Spontaneous soft tissue healing occurred thereafter. CONCLUSION: A stable fixation may lead to a good bone healing despite an extensive wound dehiscence and a wide plate and screws exposure with just a proper local wound care and without any major additional surgery. LEVEL OF EVIDENCE: Level IV. PMID- 28336329 TI - An aromatic amino acid within intracellular loop 2 of the prostaglandin EP2 receptor is a prerequisite for selective association and activation of Galphas. AB - We previously demonstrated that the aromatic moiety of Tyr143 within the intracellular loop 2 (ICL2) region of the prostaglandin EP2 receptor plays a crucial role in Gs coupling. Here we investigated whether the ICL2 of the EP2 receptor directly binds to Galphas and whether an aromatic moiety affects this interaction. In Chinese hamster ovary cells, mutations of Tyr143 reduced the ability of the EP2 receptor to interact with G proteins as demonstrated by GTPgammaS sensitivity, as well as the ability of agonist-induced cAMP formation, with the rank order of Phe>Tyr (wild-type)=Trp>Leu>Ala (=0). We found that the wild-type ICL2 peptide (i2Y) and its mutant with Phe at Tyr143 (i2F) inhibited receptor-G protein complex formation of wild-type EP2 in membranes, whereas the Ala-substituted mutant (i2A) did not. Specific interactions between these peptides and the Galphas protein were detected by surface plasmon resonance, but Galphas showed different association rates, with a rank order of i2F>i2Y?i2A, with similar dissociation rates. Moreover, i2F and i2Y, but not i2A activated membrane adenylyl cyclase. These results indicate that the ICL2 region of the EP2 receptor is its potential interaction site with Galphas, and that the aromatic side chain moiety at position 143 is a determinant for the accessibility of the ICL2 to the Galphas protein. PMID- 28336330 TI - Requirement of cytosolic phospholipase A2 gamma in lipid droplet formation. AB - Lipid droplet (LD) accumulation in hepatocytes is a typical character of steatosis. Hepatitis C virus (HCV) infection, one of the risk factors related to steatosis, induced LD accumulation in cultured cells. However, the mechanisms of which HCV induce LD formation are not fully revealed. Previously we identified cytosolic phospholipase A2 gamma (PLA2G4C) as a host factor upregulated by HCV infection and involved in HCV replication. Here we further revealed that PLA2G4C plays an important role in LD biogenesis and refined the functional analysis of PLA2G4C in LD biogenesis and HCV assembly. LD formation upon fatty acid and HCV stimulation in PLA2G4C knockdown cells was impaired and could not be restored by complementation with PLA2G4A. PLA2G4C was tightly associated in the membrane with the domain around the amino acid residues 260-292, normally in ER but relocated into LDs upon oleate stimulation. Mutant PLA2G4C without enzymatic activity was not able to restore LD formation in PLA2G4C knockdown cells. Thus, both the membrane attachment and the enzymatic activity of PLA2G4C were required for its function in LD formation. The participation of PLA2G4C in LD formation is correlated with its involvement in HCV assembly. Finally, PLA2G4C overexpression itself led to LD formation in hepatic cells and enhanced LD accumulation in the liver of high-fat diet (HFD)-fed mice, suggesting its potential role in fatty liver disease. PMID- 28336331 TI - Are neutral loss and internal product ions useful for top-down protein identification? AB - : Neutral loss and internal product ions have been found to be significant in both peptide and protein tandem mass spectra and they have been proposed to be included in database search and for protein identification. In addition to common canonical b/y ions in collision-based dissociation or c/z ions in electron-based dissociation, inclusion of neutral loss and internal product ions would certainly make better use of tandem mass spectra data; however, their ultimate utility for protein identification with false discovery rate control remains unclear. Here we report our proteome-level utility benchmarking of neutral loss and internal product ions with tandem mass spectra of intact E. coli proteome. Utility of internal product ions was further evaluated at the protein level using selected tandem mass spectra of individual E. coli proteins. We found that both neutral loss and internal products ions do not have direct utility for protein identification when they were used for scoring of P Score; but they do have indirect utility for provision of more canonical b/y ions when they are included in the database search and overlapping ions between different ion types are resolved. BIOLOGICAL SIGNIFICANCE: Tandem mass spectrometry has evolved to be a state-of-the-art method for characterization of protein primary structures (including amino acid sequence, post-translational modifications (PTMs) as well as their site location), where full study and utilization tandem mass spectra and product ions are indispensable. This primary structure information is essential for higher order structure and eventual function study of proteins. PMID- 28336333 TI - Lithium recycling and cathode material regeneration from acid leach liquor of spent lithium-ion battery via facile co-extraction and co-precipitation processes. AB - A novel process for extracting transition metals, recovering lithium and regenerating cathode materials based on facile co-extraction and co-precipitation processes has been developed. 100% manganese, 99% cobalt and 85% nickel are co extracted and separated from lithium by D2EHPA in kerosene. Then, Li is recovered from the raffinate as Li2CO3 with the purity of 99.2% by precipitation method. Finally, organic load phase is stripped with 0.5M H2SO4, and the cathode material LiNi1/3Co1/3Mn1/3O2 is directly regenerated from stripping liquor without separating metal individually by co-precipitation method. The regenerative cathode material LiNi1/3Co1/3Mn1/3O2 is miro spherical morphology without any impurities, which can meet with LiNi1/3Co1/3Mn1/3O2 production standard of China and exhibits good electrochemical performance. Moreover, a waste battery management model is introduced to guarantee the material supply for spent battery recycling. PMID- 28336332 TI - How to use and integrate bioinformatics tools to compare proteomic data from distinct conditions? A tutorial using the pathological similarities between Aortic Valve Stenosis and Coronary Artery Disease as a case-study. AB - : Nowadays we are surrounded by a plethora of bioinformatics tools, powerful enough to deal with the large amounts of data arising from proteomic studies, but whose application is sometimes hard to find. Therefore, we used a specific clinical problem - to discriminate pathophysiology and potential biomarkers between two similar cardiovascular diseases, aortic valve stenosis (AVS) and coronary artery disease (CAD) - to make a step-by-step guide through four bioinformatics tools: STRING, DisGeNET, Cytoscape and ClueGO. Proteome data was collected from articles available on PubMed centered on proteomic studies enrolling subjects with AVS or CAD. Through the analysis of gene ontology provided by STRING and ClueGO we could find specific biological phenomena associated with AVS, such as down-regulation of elastic fiber assembly, and with CAD, such as up-regulation of plasminogen activation. Moreover, through Cytoscape and DisGeNET we could pinpoint surrogate markers either for AVS (e.g. popeye domain containing protein 2 and 28S ribosomal protein S36, mitochondrial) or for CAD (e.g. ankyrin repeat and SOCS box protein 7) which deserve future validation. Data recycling and integration as well as research orientation are among the main advantages of resorting to bioinformatics analysis, hence these tutorials can be of great convenience for proteomics investigators. BIOLOGICAL SIGNIFICANCE: As we saw for aortic valve stenosis and coronary artery disease, it can be of great relevance to perform preliminary bioinformatics analysis with already published proteomics data. It not only saves us time in the lab (avoiding work duplication) as it points out new hypothesis to explain the phenotypical presentation of the diseases as well as new surrogate markers with clinical relevance, deserving future scrutiny. These essential steps can be easily overcome if one follows the steps proposed in our tutorial for STRING, DisGeNET, Cytoscape and ClueGO utilization. PMID- 28336334 TI - Agricultural utilization of biosolids: A review on potential effects on soil and plant grown. AB - Environmental and economic implications linked with the proper ecofriendly disposal of modern day wastes, has made it essential to come up with alternative waste management practices that reduce the environmental pressures resulting from unwise disposal of such wastes. Urban wastes like biosolids are loaded with essential plant nutrients. In this view, agricultural use of biosolids would enable recycling of these nutrients and could be a sustainable approach towards management of this hugely generated waste. Therefore biosolids i.e. sewage sludge can serve as an important resource for agricultural utilization. Biosolids are characterized by the occurrence of beneficial plant nutrients (essential elements and micro and macronutrients) which can make help them to work as an effective soil amendment, thereby minimizing the reliance on chemical fertilizers. However, biosolids might contain toxic heavy metals that may limit its usage in the cropland. Heavy metals at higher concentration than the permissible limits may lead to food chain contamination and have fatal consequences. Biosolids amendment in soil can improve physical and nutrient property of soil depending on the quantity and portion of the mixture. Hence, biosolids can be a promising soil ameliorating supplement to increase plant productivity, reduce bioavailability of heavy metals and also lead to effective waste management. PMID- 28336335 TI - Management of spent shea waste: An instrumental characterization and valorization in clay bricks construction. AB - This work studies the reuse of spent shea waste as an economic construction material in improving fired clay bricks manufacture aside providing a novel approach to ecofriendly managing its excessive generated from the shea agroindustry. For this purpose, the influence of spent shea waste addition on the chemical, mineralogical, molecular bonding and technological properties (i.e. compressive strength and water absorption) of the fired clay bricks were extensively investigated. The results indicated that the chemical, mineralogical, phase transformations, molecular bonding and thermal behavior of the produced bricks were practically unaffected by the addition of spent shea waste. However, spent shea waste addition increased the compressive strengths and water absorptions of the brick products. Potential performance benefits of reusing spent shea waste was improved fluxing agents, energy-contribution reaction, excellent porosifying effect, reduced thermal conductivity and enhanced compressive strengths of the brick products. This research has therefore provided compelling evidence that could create newfound route for the synergistic ecofriendly reuse of spent shea waste to enhance clay brick construction aside being a potential mainstream disposal option. PMID- 28336336 TI - Sunbed use among 64,000 Danish students and the associations with demographic factors, health-related behaviours, and appearance-related factors. AB - Sunbed use is associated with an increased risk for skin cancer and is particularly dangerous for younger persons. The objective of this study was to assess how demographic factors, health-related behaviours and appearance-related factors are associated with sunbed use. Cross-sectional data from the Danish National Youth Study collected by the National Institute of Public Health during 2014 was used. A total of 64,382 students aged 15-25years were included in the present study. Multilevel logistic regression analyses were used to determine associations. Sunbed use during the past 12months was reported by 22% of students, with a higher proportion among females (29%) than males (12%). Factors associated with sunbed use were older age, studying at a vocational college or a higher preparatory examination school compared to upper secondary school, and lower parental education. Furthermore, being a smoker, been binge-drinking, longer duration of exercise and been dieting were also associated with sunbed use. For females, poor dietary habits were also associated with sunbed use. Feeling overweight was associated with lower odds for sunbed use for males, but with higher odds for females. Lower body satisfaction was associated with higher odds of sunbed use, except for overweight males. Students who were underweight had lower odds for sunbed use, than normal weight students. Conclusively, we found evidence of associations between demographic factors, health-related behaviours and appearance-related factors and sunbed use. Understanding these relations could help to identify high-risk groups and guide preventive strategies for sunbed use and skin cancer prevention. PMID- 28336337 TI - Mismatch negativity as a potential neurobiological marker of early-stage Alzheimer disease and vascular dementia. AB - Alzheimer's disease (AD) and vascular dementia (VD) are serious, irreversible forms of cognitive impairment, which means that an early diagnosis is essential to slow down their progression. One potential neurophysiological biomarker of these diseases is the mismatch negativity (MMN) event-related potentials (ERP) component, which reflects an automatic detection mechanism at the pre-attentive stages of information processing. We evaluated the auditory MMN response in individuals from two patient groups: those in the prodromal stages of AD (P-AD) and those in the prodromal stages of VD (P-VD). Thirty patients (15 P-AD patients and 15 P-VD patients) and 30 age-matched controls were recruited to undergo electrophysiological recordings during the presentation of an auditory deviant standard-reverse oddball paradigm that was used to elicit genuine MMN responses. We show that over the frontal-central area, the mean amplitude of the MMN was significantly reduced in both the P-AD (p=0.017) and P-VD groups (p=0.013) compared with controls. The MMN peak latency in P-VD patients was significantly shorter than in controls (p=0.027). No MMN response differences between the P-AD and P-VD were found in either the frontal-central or the temporal areas. These results indicate that P-AD and P-VD patients exhibit impaired pre-attentive information processing mechanisms as revealed by the frontal-central area MMN response, which is associated with sensory memory and cognitive deficits. PMID- 28336338 TI - Knockdown of APPL mimics transgenic Abeta induced neurodegenerative phenotypes in Drosophila. AB - A variety of Drosophila mutant lines have been established as potential disease models to study various disease mechanisms including human neurodegenerative diseases like Alzheimer's disease (AD), Huntington's disease (HD) and Parkinson's disease (PD). The evolutionary conservation of APP (Amyloid Precursor Protein) and APPL (Amyloid Precursor Protein-Like) and the comparable detrimental effects caused by their metabolic products strongly implies the conservation of their normal physiological functions. In view of this milieu, a comparative analysis on the pattern of neurodegenerative phenotypes between Drosophila APPL-RNAi line and transgenic Drosophila line expressing eye tissue specific human Abeta (Amyloid beta) was undertaken. Our results clearly show that Drosophila APPL-RNAi largely mimics transgenic Abeta in various phenotypes which include eye degeneration, reduced longevity and motor neuron deficit functions, etc. The ultra-structural morphological pattern of eye degeneration was confirmed by scanning electron microscopy. Further, a comparative study on longevity and motor behaviour between Abeta expressing and APPL knockdown lines revealed similar kind of behavioural deficit and longevity phenotypes. Therefore, it is suggested that APPL-knockdown approach can be used as an alternative approach to study neurodegenerative diseases in the fly model. To the best of our knowledge this is the first report showing comparable phenotypes between APPL and Abeta in AD model of Drosophila. PMID- 28336339 TI - Optimal feature selection from fNIRS signals using genetic algorithms for BCI. AB - In this paper, a novel technique for determination of the optimal feature combinations and, thereby, acquisition of the maximum classification performance for a functional near-infrared spectroscopy (fNIRS)-based brain-computer interface (BCI), is proposed. After obtaining motor-imagery and rest signals from the motor cortex, filtering is applied to remove the physiological noises. Six features (signal slope, signal mean, signal variance, signal peak, signal kurtosis and signal skewness) are then extracted from the oxygenated hemoglobin (HbO). Afterwards, the hybrid genetic algorithm (GA)-support vector machine (SVM) is applied in order to determine and classify 2- and 3-feature combinations across all subjects. The SVM classifier is applied to classify motor imagery versus rest. Moreover, four time windows (0-20s, 0-10s, 11-20s and 6-15s) are selected, and the hybrid GA-SVM is applied in order to extract the optimal 2- and 3-feature combinations. In the present study, the 11-20s time window showed significantly higher classification accuracies - the minimum accuracy was 91% - than did the other time windows (p<0.05). The proposed hybrid GA-SVM technique, by selecting optimal feature combinations for an fNIRS-based BCI, shows positive classification-performance-enhancing results. PMID- 28336340 TI - Basal prolactin levels in rat plasma correlates with response to antidepressant treatment in animal model of depression. AB - Prolactin (PRL) has been shown to be altered by psychotropic drugs, including antidepressant drugs (ADs). Many studies have focused on the response to antidepressant treatment (especially related to the serotonergic system) using the fenfluramine test (PRF), however some data suggest lack of correlation between PRF and prediction of clinical response to ADs. In our study we have investigated the hypothesis that basal plasma level of prolactin is a better predictor of antidepressant treatment. We have used Chronic Mild Stress (CMS) - the animal model of depression. Rats are exposed to CMS in combination with imipramine (IMI) treatment for 5 consecutive weeks. Blood samples were collected from the rat tail vein three times: before the CMS procedure, after 2 weeks of stress and after the complete CMS procedure (after 5 weeks of stress and IMI treatment). The PRL level in plasma was determined using the commercially available ELISA kit. In CMS, anhedonia in rats is manifested by reduced consumption of sucrose solution while administration of antidepressant drugs reverses anhedonia. Some animals (ca.30%) did not respond to antidepressant therapy and were considered treatment-resistant. There was no correlation between basal PRL levels and stress response, however, from the results obtained by Spearman Rank Correlation analysis we have observed a significant negative correlation between basal PRL levels before the CMS procedure and behavioral response to IMI administration. The obtained results indicate that the basal PRL level in rat plasma correlates with a good response to treatment in the animal model of depression. PMID- 28336341 TI - Visuospatial information processing load and the ratio between parietal cue and target P3 amplitudes in the Attentional Network Test. AB - In ERP studies of cognitive processes during attentional tasks, the cue signals containing information about the target can increase the amplitude of the parietal cue P3 in relation to the 'neutral' temporal cue, and reduce the subsequent target P3 when this information is valid, i.e. corresponds to the target's attributes. The present study compared the cue-to-target P3 ratios in neutral and visuospatial cueing, in order to estimate the contribution of valid visuospatial information from the cue to target stages of the task performance, in terms of cognitive load. The P3 characteristics were also correlated with the results of individuals' performance of the visuospatial tasks, in order to estimate the relationship of the observed ERP with spatial reasoning. In 20 typically developing boys, aged 10-13 years (11.3+/-0.86), the intelligence quotient (I.Q.) was estimated by the Block Design and Vocabulary subtests from the WISC-III. The subjects performed the Attentional Network Test (ANT) accompanied by EEG recording. The cued two-choice task had three equiprobable cue conditions: No cue, with no information about the target; Neutral (temporal) cue, with an asterisk in the center of the visual field, predicting the target onset; and Spatial cues, with an asterisk in the upper or lower hemifield, predicting the onset and corresponding location of the target. The ERPs were estimated for the mid-frontal (Fz) and mid-parietal (Pz) scalp derivations. In the Pz, the Neutral cue P3 had a lower amplitude than the Spatial cue P3; whereas for the target ERPs, the P3 of the Neutral cue condition was larger than that of the Spatial cue condition. However, the sums of the magnitudes of the cue and target P3 were equal in the spatial and neutral cueing, probably indicating that in both cases the equivalent information processing load is included in either the cue or the target reaction, respectively. Meantime, in the Fz, the analog ERP components for both the cue and target stimuli did not depend on the cue condition. The results show that, in the parietal site, the spatial cue P3 reflects the processing of visuospatial information regarding the target position. This contributes to the subsequent "decision-making", thus reducing the information processing load on the target response, which is probably reflected in the lower P3. This finding is consistent with the positive correlation of parietal cue P3 with the individual's ability to perform spatial tasks as scored by the Block Design subtest. PMID- 28336342 TI - Pharmacological assessments of potent A2A receptor antagonist IDPU (1-(7-imino-3 propyl-2,3-dihydrothiazolo[4,5-d]pyrimidin-6(7H)-yl)urea) in rodent model of haloperidol induced Parkinson like symptoms. AB - A2A receptor antagonists emerged as potential candidate for management of Parkinson's disease. Earlier we had reported the therapeutic potential of 1-(7 imino-3-propyl-2,3-dihydrothiazolo[4,5-d]pyrimidin-6(7H)-yl) urea (IDPU) as A2A receptor antagonist. Herein, we have investigated the effect of IDPU in attenuation of haloperidol induced Parkinson like symptoms in rats. It has successfully restored hypo-locomotion induced by haloperidol and NECA. IDPU also displayed protective effect against oxidative stress induced by chronic haloperidol treatment in rats. The antidepressant activity of IDPU was determined in mice showed that it imperatively reduced depression like symptoms in well established depression models viz. TST and FST. Additionally, IDPU was found to be a safe and non-toxic chemical entity in acute, sub-acute and neurotoxicity studies. In silico study of IDPU showed acceptable physicochemical parameters and in vitro screening exhibited satisfactory metabolic stability. This study clearly indicates that A2A receptor antagonist IDPU is able to ameliorate Parkinsonian symptoms without exerting any significant toxicity. PMID- 28336343 TI - Viral delivered gene therapy to treat catecholaminergic polymorphic ventricular tachycardia (CPVT2) in mouse models. AB - BACKGROUND: The recessive form of catecholaminergic polymorphic ventricular tachycardia 2 (CPVT2) is caused by mutations in cardiac calsequestrin (CASQ2), leading to protein deficiency. OBJECTIVES: The aims of this study were to develop a viral-delivered gene therapy for CPVT2 and to determine the relationship between CASQ2 expression and antiarrhythmic efficacy in a murine model. METHODS: We used a murine model of CPVT2 caused by the D307H human mutation (CASQ2D307H) or CASQ2 knockout (CASQ2Delta/Delta). Adeno-associated virus (AAV) particles containing the CASQ2 gene (AAVCASQ2) were injected into the heart or intraperitoneally to 12-week-old mice. A telemetry device was implanted, and mice underwent provocation testing 7-8 weeks after gene therapy. RESULTS: CASQ2Delta/Delta mice injected intracardiacally with AAVCASQ2 expressed 40% +/- 25% of the normal CASQ2 protein level, which was increased compared to untreated CASQ2Delta/Delta mice (n = 10; P < .05). Intraperitoneal therapy led to a significantly elevated expression of the CASQ2 protein, which was comparable in CASQ2D307H (n = 12) and CASQ2Delta/Delta (n = 4) mice. All control mice with CPVT2 had nonsustained ventricular tachycardia (VT) and 8 of 13 had sustained VT on provocation. Expressing >=33% of the normal CASQ2 level was needed to protect from nonsustained VT as well as stress-induced premature ventricular contractions. Lower levels of expression prevented sustained VT in AAVCASQ2 treated mice (0 of 26; P < .001 vs controls). CONCLUSION: AAVCASQ2 displays a long-lasting capacity to attenuate and potentially cure CPVT2. Systemic delivery is feasible and convenient, reproducibly providing adequate levels of transgene expression. Antiarrhythmic efficacy depends on the CASQ2 level: >=33% of the normal CASQ2 level is needed to prevent arrhythmia. However, even lower levels of protein protect from sustained VT, thereby potentially reducing the risk of sudden death. PMID- 28336344 TI - Participation Restriction in People With Multiple Sclerosis: Prevalence and Correlations With Cognitive, Walking, Balance, and Upper Limb Impairments. AB - OBJECTIVES: To calculate the percentage of participation restrictions according to disability level in multiple sclerosis (MS), and to assess the relationship between participation restrictions and cognitive, gait, balance, and upper limb deficits. DESIGN: Cross-sectional study. SETTING: Rehabilitation unit. PARTICIPANTS: Participants (N=125) consisted of people with MS (n=105) and healthy subjects (HS; n=20). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The Community integration Questionnaire was used to assess participation in home, social, and productive activities. Percentages of people with MS having Community Integration Questionnaire scores lower than the 10th percentile of those of HS were calculated for each subscale to categorize the persons with participation restrictions. Cognitive deficits (Symbol Digit Modalities Test), walking disability (25-ft walking test/Expanded Disability Status Scale [EDSS]), balance disorders (Bohannon Standing Balance Test), and manual dexterity (Nine Hole Peg Test) were recorded. RESULTS: Seventy-seven percent of participants showed participation restrictions, which increased with higher EDSS scores from 40% (EDSS<4) to 82% (EDSS>5.5). Social participation was more restricted than home integration, with <20% of participants shopping for groceries alone. Cognitive deficits were more highly associated (r=.60) with participation restrictions than balance (r=.47), gait (r=-.45), and hand dexterity (r=.45) limitations. CONCLUSIONS: Participation restrictions are present in MS and increase with disability level. However, the results also show that MS does not restrict participation in all domains. Participation restrictions at home are less restricted compared with social participation. Cognitive disorders are more associated with participation restrictions than physical limitations. PMID- 28336345 TI - Dancing for Parkinson Disease: A Randomized Trial of Irish Set Dancing Compared With Usual Care. AB - OBJECTIVE: To examine the feasibility of a randomized controlled study design and to explore the benefits of a set dancing intervention compared with usual care. DESIGN: Randomized controlled design, with participants randomized to Irish set dance classes or a usual care group. SETTING: Community based. PARTICIPANTS: Individuals with idiopathic Parkinson disease (PD) (N=90). INTERVENTIONS: The dance group attended a 1.5-hour dancing class each week for 10 weeks and undertook a home dance program for 20 minutes, 3 times per week. The usual care group continued with their usual care and daily activities. MAIN OUTCOME MEASURES: The primary outcome was feasibility, determined by recruitment rates, success of randomization and allocation procedures, attrition, adherence, safety, willingness of participants to be randomized, resource availability, and cost. Secondary outcomes were motor function (motor section of the Unified Parkinson's Disease Rating Scale), quality of life (Parkinson's Disease Questionnaire-39), functional endurance (6-min walk test), and balance (mini-BESTest). RESULTS: Ninety participants were randomized (45 per group). There were no adverse effects or resource constraints. Although adherence to the dancing program was 93.5%, there was >40% attrition in each group. Postintervention, the dance group had greater nonsignificant gains in quality of life than the usual care group. There was a meaningful deterioration in endurance in the usual care group. There were no meaningful changes in other outcomes. The exit questionnaire showed participants enjoyed the classes and would like to continue participation. CONCLUSIONS: For people with mild to moderately severe PD, set dancing is feasible and enjoyable and may improve quality of life. PMID- 28336346 TI - Antiviral activity of the adenosine analogue BCX4430 against West Nile virus and tick-borne flaviviruses. AB - There are currently no approved antiviral therapies against medically important human flaviviruses. The imino-C-nucleoside BCX4430 shows broad-spectrum antiviral activity against a wide range of RNA viruses. Here, we demonstrate that BCX4430 inhibits tick-borne species of the genus Flavivirus; however, the antiviral effect varies against individual species. Micro-molar BCX4430 levels inhibited tick-borne encephalitis virus (TBEV); while, approximately 3-8-fold higher concentrations were needed to inhibit louping ill virus and Kyasanur Forest disease virus. Moreover, the compound strongly inhibited in vitro replication of West Nile virus, a typical mosquito-transmitted flavivirus. Two chemical forms of the compound, i.e. BCX4430 and BCX4430 hydrochloride, were compared and both exerted similar inhibitory profiles in our in vitro antiviral assay systems and no or negligible cytotoxicity in porcine kidney stable and Vero cells. The obtained data indicate that, in addition to mosquito-borne flaviviruses, the compound has strong antiviral activity against members of the TBEV serocomplex. PMID- 28336347 TI - Solution conformations of a linked construct of the Zika virus NS2B-NS3 protease. AB - The Zika virus presents a serious risk for global health. Crystal structures of different constructs of the Zika virus NS2B-NS3 protease (NS2B-NS3pro) have been determined with the aim to provide a basis for rational drug discovery. In these structures, the C-terminal beta-hairpin of NS2B, NS2Bc, was observed to be either disordered (open conformation) or bound to NS3pro complementing the substrate binding site (closed conformation). Enzymatically active constructs of flaviviral NS2B-NS3 proteases commonly used for inhibitor testing contain a covalent peptide linker between NS2B and NS3pro. Using a linked construct of Zika virus NS2B NS3pro, we studied the location of NS2Bc relative to NS3pro in solution by pseudocontact shifts generated by a paramagnetic lanthanide tag attached to NS3pro. Both closed and open conformations were observed with different inhibitors. As the NS2B co-factor is involved in substrate binding of flaviviral NS2B-NS3 proteases, the destabilization of the closed conformation in the linked construct makes it an attractive tool to search for inhibitors that interfere with the formation of the enzymatically active, closed conformation. PMID- 28336348 TI - Neurovascular uncoupling after rapid glycemic control as a trigger of the diabetic-uremic striatopallidal syndrome. PMID- 28336349 TI - Decisional capacity for advanced care directives in Parkinson's disease with cognitive concerns. AB - INTRODUCTION: Physician Orders for Life Sustaining Therapies (POLST) or Goals of Care (GOC) are legal documents to guide intensity of interventions (ICU, resuscitation, hospitalization or comfort care) completed by healthcare professionals following counseling of patients or their designated medical decision makers. Capacity (understanding, appreciation, reasoning and expressing a choice) to consent to POLST or GOC has not been determined among Parkinson's disease (PD) patients. We sought to assess GOC PD decisional capacity for those with cognitive complaints but not dementia. METHODS: Fifty consecutive PD patients were recruited from the Movement Disorders Program. Mini Mental Status Examination (MMSE), Montreal Cognitive Assessment (MoCA) and the MacArthur Competency Assessment Test (MacCAT) for GOC were administered. RESULTS: Mean MMSE and MOCA was 27.76 and 24.5 respectively. Twenty subjects had impaired executive function. MacCAT correlated with MoCA and MMSE (p < 0.001, 0.001) but despite impaired understanding, appreciation and reasoning among some subjects, all subjects expressed a choice. CONCLUSIONS: This exploratory study demonstrates PD with cognitive concerns had a range in decisional capacity with lower MoCA and MMSE scores predicting impaired MacCAT subscores. Clinicians should be aware that cognitive complaints without dementia may impact capacity. Despite impairments in understanding, appreciation or reasoning, patients may still express a choice. Hence, a choice in this setting may not represent their true values and goals. GOC discussions require explicit determination of the domains of capacity. Discussions regarding GOC should occur early in the course of PD. PMID- 28336350 TI - Smoking as a Risk Factor for the Occurrence of Atrial Fibrillation in Men Versus Women: A Meta-Analysis of Prospective Cohort Studies. AB - BACKGROUND: Although smoking is known to be associated with cardiovascular diseases, the number of large-scale cohort studies on the association between smoking and atrial fibrillation (AF) is limited and the results obtained are also inconsistent, and even fewer studies have addressed the difference between the male and female genders. The present study was intended to clarify and quantify the association between smoking and the risk of AF in men versus women. METHODS: Using AF- and smoking-related keywords, a comprehensive literature search on PubMed, Embase and Web of Science was conducted with a time limit until December 2016, which was followed by manual screening, quality assessment and data extraction. The pooled relative risk (RR) of the included studies was estimated by using the random-effects model. Subgroup, heterogeneity and sensitivity analyses were also conducted. RESULTS: A total of 14 prospective studies and 222,159 individuals were included in this meta-analysis, and the pooled RR of the 14 studies was 1.24 (95% CI, 1.12-1.36; p<0.0001) for the occurrence of AF in smoking populations. The pooled RR in men was 1.38 (95% CI, 1.21-1.57 p<0.0001) versus 1.28 in women (95% CI, 0.93-1.76; p=0.1356). The male-to-female ratio of relative risk (RRR) was 1.17 (95% CI, 0.84-1.63; p=0.3418) of smoking versus non smoking individuals. CONCLUSION: Smoking is a risk factor for the occurrence of AF. Compared with women, male smokers are more likely to develop AF. PMID- 28336351 TI - Proposed Medicare Coverage for Diabetes Prevention: Strengths, Limitations, and Recommendations for Improvement. PMID- 28336352 TI - Accessibility and Affordability of Supermarkets: Associations With the DASH Diet. AB - INTRODUCTION: It is unknown whether there is an interplay of affordability (economic accessibility) and proximity (geographic accessibility) of supermarkets in relation to having a Dietary Approaches to Stop Hypertension (DASH)-accordant diet. METHODS: Data (collected: 2005-2015, analyzed: 2016) were from the cross sectional, population-based Fenland Study cohort: 9,274 adults aged 29-64 years, living in Cambridgeshire, United Kingdom. Dietary quality was evaluated using an index of DASH dietary accordance, based on recorded consumption of foods and beverages in a validated 130-item, semi-quantitative food frequency questionnaire. DASH accordance was defined as a DASH score in the top quintile. Dietary costs (L/day) were estimated by attributing a food price variable to the foods consumed according to the questionnaire. Individuals were classified as having low-, medium-, or high-cost diets. Supermarket affordability was determined based on the cost of a 101-item market basket. Distances between home address to the nearest supermarket (geographic accessibility) and nearest economically-appropriate supermarket (economic accessibility) were divided into tertiles. RESULTS: Higher-cost diets were more likely to be DASH-accordant. After adjustment for key demographics and exposure to other food outlets, individuals with lowest economic accessibility to supermarkets had lower odds of being DASH accordant (OR=0.59, 95% CI=0.52, 0.68) than individuals with greatest economic accessibility. This association was stronger than with geographic accessibility alone (OR=0.85, 95% CI=0.74, 0.98). CONCLUSIONS: Results suggest that geographic and economic access to food should be taken into account when considering approaches to promote adherence to healthy diets for the prevention of cardiovascular diseases and other chronic disease. PMID- 28336354 TI - Educational Disparities in Mortality Between Adults Aged 50-64 and 66-79 Years, U.S. AB - INTRODUCTION: This study estimated differences in educational disparities in mortality between ages 50-64 and 66-79 years in the U.S. and explored factors contributing to the differences. METHODS: Based on the follow-up of a nationally representative cohort in the National Longitudinal Mortality Study 2002-2011, relative differences in educational disparities (relative index of inequality) between people aged 50-64 and 66-79 years were calculated for deaths from all causes, cancer, cardiovascular disease, injuries, and other causes by sex and race/ethnicity. Analyses were conducted in 2016. RESULTS: In all racial/ethnic-, sex-, and age-specific groups, death rates were higher among the least educated than the most educated groups for all causes combined and most specific causes except for injuries in non-Hispanic blacks. Among non-Hispanic whites, the relative index of inequality for all causes combined among the younger and older age groups was 5.6 (95% CI=4.9, 6.5) and 2.8 (95% CI=2.6, 3.0), respectively. Among non-Hispanic blacks, corresponding index values were 4.1 (95% CI=3.6, 4.6) and 1.7 (95% CI=1.6, 1.8). Larger disparities in the younger age group were also observed for cardiovascular disease, cancer, and other causes among non-Hispanic whites, non-Hispanic blacks, and all races combined. CONCLUSIONS: Educational disparities in mortality among non-Hispanic whites and blacks were 41%-61% lower in people aged 66-79 years than in those aged 50-64 years. Various factors may contribute to diminished disparities in the elderly, including differences in access to care, health perception, stress level, lifestyle, and health behaviors with advancing age and retirement. PMID- 28336353 TI - Effectiveness of Switching Smoking-Cessation Medications Following Relapse. AB - INTRODUCTION: Nicotine dependence is a chronic disorder often characterized by multiple failed quit attempts (QAs). Yet, little is known about the sequence of methods used across multiple QAs or how this may impact future ability to abstain from smoking. This prospective cohort study examines the effectiveness of switching smoking-cessation medications (SCMs) across multiple QAs. METHODS: Adult smokers (aged >=18 years) participating in International Tobacco Control surveys in the United Kingdom, U.S., Canada, and Australia (N=795) who: (1) completed two consecutive surveys between 2006 and 2011; (2) initiated a QA at least 1 month before each survey; and (3) provided data for the primary predictor (SCM use during most recent QA), outcome (1-month point prevalence abstinence), and relevant covariates. Analyses were conducted in 2016. RESULTS: Five SCM user classifications were identified: (1) non-users (43.5%); (2) early users (SCM used for initial, but not subsequent QA; 11.4%); (3) later users (SCM used for subsequent, but not initial QA; 18.4%); (4) repeaters (same SCM used for both QAs; 10.7%); and (5) switchers (different SCM used for each QA; 14.2%). Abstinence rates were lower for non-users (15.9%, OR=0.48, p=0.002), early users (16.6%, OR=0.27, p=0.03), and repeaters (12.4%, OR=0.36, p=0.004) relative to switchers (28.5%). CONCLUSIONS: Findings suggest smokers will be more successful if they use a SCM in QAs and vary the SCM they use across time. That smokers can increase their odds of quitting by switching SCMs is an important message that could be communicated to smokers. PMID- 28336355 TI - Estimated HIV Inter-test Interval Among People at High Risk for HIV Infection in the U.S. AB - INTRODUCTION: Knowing the HIV testing frequency and its temporal changes are central to evaluate public adherence to HIV testing recommendations and performance of HIV prevention programs. This study intended to estimate the mean HIV inter-test interval (ITI) and monitor its trends among men who have sex with men (MSM); people who inject drugs (PWID); and high-risk heterosexuals (HRH). METHODS: Using National HIV Behavioral Surveillance data collected during 2008 2015, this analysis estimated the mean HIV ITI for each year by race/ethnicity and age among MSM, PWID, and HRH who reported the most recent HIV test date. Separate statistical models based on renewal process theory were fit using PROC NLIN with Newton-Raphson method. Estimated mean HIV ITI lengths were compared using the z-test. RESULTS: Estimated HIV ITI generally decreased in the past decade among MSM, PWID, and HRH who reported the most recent HIV test date. In most recent study years, estimated HIV ITI (in months) ranged from 5.8 to 12.5 among MSM, from 9.0 to 13.1 among PWID, and from 15.3 to 26.7 among HRH. Within each risk group, estimated HIV ITI was shortest among blacks and individuals aged 18-24 years. CONCLUSIONS: People at high risk for HIV infection who ever tested for HIV tested more frequently in the past decade. Most recently, MSM and PWID largely adhered to the Centers for Disease Control and Prevention's HIV testing recommendations, but HRH tested less frequently. Identifying factors associated with infrequent testing among HRH may provide information for future HIV testing initiatives. PMID- 28336356 TI - Primary Enforcement of Mandatory Seat Belt Laws and Motor Vehicle Crash Deaths. AB - INTRODUCTION: Policies that allow directly citing motorists for seat belt non-use (primary enforcement) have been shown to reduce motor vehicle crash deaths relative to secondary enforcement, but the evidence base is dated and does not account for recent improvements in vehicle designs and road safety. The purpose of this study was to test whether recent upgrades to primary enforcement still reduce motor vehicle crash deaths. METHODS: In 2016, researchers used motor vehicle crash death data from the Fatal Analysis Reporting System for 2000-2014 and calculated rates using both person- and exposure-based denominators. Researchers used a difference-in-differences design to estimate the effect of primary enforcement on death rates, and estimated negative binomial regression models, controlling for age, substance use involvement, fixed state characteristics, secular trends, state median household income, and other state level traffic safety policies. RESULTS: Models adjusted only for crash characteristics and state-level covariates models showed a protective effect of primary enforcement (rate ratio, 0.88, 95% CI=0.77, 0.98; rate difference, -1.47 deaths per 100,000 population, 95% CI= -2.75, -0.19). After adjustment for fixed state characteristics and secular trends, there was no evidence of an effect of upgrading from secondary to primary enforcement in the whole population (rate ratio, 0.98, 95% CI=0.92, 1.04; rate difference, -0.22, 95% CI= -0.90, 0.46) or for any age group. CONCLUSIONS: Upgrading to primary enforcement no longer appears protective for motor vehicle crash death rates. PMID- 28336357 TI - Assessment of vestibulo-ocular function without measuring eye movements. AB - BACKGROUND: The vestibulo-ocular reflex (VOR) maintains stable gaze during head motion. Deficiencies lead to apparent world motion due to incomplete stabilization of eyes in space. VOR measurement requires specialized apparatus, trained operators, and significant setup time. NEW METHOD: We present a system (VON: vestibulo-ocular nulling) for rapid vestibulo-ocular assessment without measuring eye movements per se. VON uses a head-mounted motion sensor, laptop computer with user input control, and laser target whose position is controlled by the computer. As the head moves, the target is made to move in the same manner with a gain set by the subject. When the subject sets the gain so the target appears stationary in space, it is stationary on the retinas. One can determine from this gain the extent to which the eyes move in space when the head moves, which is the amount by which the VOR is deficient. From this the gain of the compensatory eye movements is derived. RESULTS: VON was compared with conventional video-based VOR measures. Both methods track expected changes in gain over 20min of adaptation to minifying spectacles. VON measures are more consistent across subjects, and pre-adaptation values are closer to compensatory. COMPARISON WITH EXISTING METHOD: VON is a rapid means to assess vestibulo-ocular performance. As a functional perceptual measure, it accounts for gaze-stabilizing contributions that are not apparent in the standard VOR, such as pursuit and perceptual tolerance. CONCLUSIONS: VON assesses functional VOR performance. Future implementations will make VOR assessment widely available to investigators and clinicians. PMID- 28336358 TI - Assessing hemispheric specialization for processing arithmetic skills in adults: A functional transcranial doppler ultrasonography (fTCD) study. AB - BACKGROUND: A major model of the cerebral circuits that underpin arithmetic calculation is the triple-code model of numerical processing. This model proposes that the lateralization of mathematical operations is organized across three circuits: a left-hemispheric dominant verbal code; a bilateral magnitude representation of numbers and a bilateral Arabic number code. NEW METHOD: This study simultaneously measured the blood flow of both middle cerebral arteries using functional transcranial Doppler ultrasonography to assess hemispheric specialization during the performance of both language and arithmetic tasks. The propositions of the triple-code model were assessed in a non-clinical adult group by measuring cerebral blood flow during the performance of multiplication and subtraction problems. Participants were 17 adults aged between 18-27 years. We obtained laterality indices for each type of mathematical operation and compared these in participants with left-hemispheric language dominance. It was hypothesized that blood flow would lateralize to the left hemisphere during the performance of multiplication operations, but would not lateralize during the performance of subtraction operations. RESULTS: Hemispheric blood flow was significantly left lateralized during the multiplication task, but was not lateralized during the subtraction task. COMPARISON WITH EXISTING METHOD(S): Compared to high spatial resolution neuroimaging techniques previously used to measure cerebral lateralization, functional transcranial Doppler ultrasonography is a cost-effective measure that provides a superior temporal representation of arithmetic cognition. CONCLUSIONS: These results provide support for the triple code model of arithmetic processing and offer complementary evidence that multiplication operations are processed differently in the adult brain compared to subtraction operations. PMID- 28336359 TI - Enrichment and isolation of neurons from adult mouse brain for ex vivo analysis. AB - BACKGROUND: Isolation of neurons from the adult mouse CNS is important in order to study their gene expression during development or the course of different diseases. NEW METHODS: Here we present two different methods for the enrichment or isolation of neurons from adult mouse CNS. These methods: are either based on flow cytometry sorting of eYFP expressing neurons, or by depletion of non neuronal cells by sorting with magnetic-beads. RESULTS: Enrichment by FACS sorting of eYFP positive neurons results in a population of 62.4% NeuN positive living neurons. qPCR data shows a 3-5fold upregulation of neuronal markers. The isolation of neurons based on depletion of non-neuronal cells using the Miltenyi Neuron Isolation Kit, reaches a purity of up to 86.5%. qPCR data of these isolated neurons shows an increase in neuronal markers and an absence of glial markers, proving pure neuronal RNA isolation. COMPARISON WITH EXISTING METHODS: Former data related to neuronal gene expression are mainly based on histology, which does not allow for high-throughput transcriptome analysis to examine differential gene expression. CONCLUSION: These protocols can be used to study cell type specific gene expression of neurons to unravel their function in the process of damage to the CNS. PMID- 28336362 TI - Broad Ligament Ectopic Pregnancy after Bilateral Tubal Ligation. PMID- 28336360 TI - GAIN: A graphical method to automatically analyze individual neurite outgrowth. AB - BACKGROUND: Neurite outgrowth is a metric widely used to assess the success of in vitro neural stem cell differentiation or neuron reprogramming protocols and to evaluate high-content screening assays for neural regenerative drug discovery. However, neurite measurements are tedious to perform manually, and there is a paucity of freely available, fully automated software to determine neurite measurements and neuron counting. To provide such a tool to the neurobiology, stem cell, cell engineering, and neuroregenerative communities, we developed an algorithm for performing high-throughput neurite analysis in immunofluorescent images. NEW METHOD: Given an input of paired neuronal nuclear and cytoskeletal microscopy images, the GAIN algorithm calculates neurite length statistics linked to individual cells or clusters of cells. It also provides an estimate of the number of nuclei in clusters of overlapping cells, thereby increasing the accuracy of neurite length statistics for higher confluency cultures. GAIN combines image processing for neuronal cell bodies and neurites with an algorithm for resolving neurite junctions. RESULTS: GAIN produces a table of neurite lengths from cell body to neurite tip per cell cluster in an image along with a count of cells per cluster. COMPARISON WITH EXISTING METHODS: GAIN's performance compares favorably with the popular ImageJ plugin NeuriteTracer for counting neurons, and provides the added benefit of assigning neurites to their respective cell bodies. CONCLUSIONS: In summary, GAIN provides a new tool to improve the robust assessment of neural cells by image-based analysis. PMID- 28336361 TI - A novel multiplex PCR assay for simultaneous detection of nine clinically significant bacterial pathogens associated with bovine mastitis. AB - For rapid and simultaneous detection of nine bovine mastitic pathogens, a sensitive and specific multiplex PCR assay was developed. The assay was standardized using reference strains and validated on mastitic milk cultures which were identified to species level based on 16S rRNA sequencing. Multiplex PCR assay also efficiently detected the target bacterial strains directly from milk. The detection limit of the assay was up to 50 pg for DNA isolated from pure cultures and 104 CFU/ml for spiked milk samples. As estimated by latent class analysis, the assay was sensitive up to 88% and specific up to 98% for targeted mastitic pathogens, compared with the bacterial culture method and the 16S rRNA sequence analysis. This novel molecular assay could be useful for monitoring and maintaining the bovine udder health, ensuring the bacteriological safety of milk, and conducting epidemiological studies. PMID- 28336364 TI - Mechanisms and roles by which IRF-3 mediates the regulation of ORMDL3 transcription in respiratory syncytial virus infection. AB - Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis in infancy, which is a major risk factor for recurrent wheezing and asthma. Orosomucoid 1-like protein 3 (ORMDL3) has been reported to associate with virus triggered recurrent wheezing and asthma in children. However, little is known about how ORMDL3 is involved into RSV infection. In this study, we showed that the mRNA expression of ORMDL3 is significantly increased in the peripheral blood lymphocytes of infants with RSV-induced bronchiolitis compared with uninfected controls, also increased in bronchial epithelial cells and lung fibroblasts following RSV infection in vitro. To investigate the underlying mechanisms of RSV induced ORMDL3 expression, we performed in silico analysis of the binding sites of several transcription factors in the ORMDL3 promoter. The proximal interferon regulatory factor-3 (IRF-3) binding site positively regulated ORMDL3 transcription following exposure to RSV, as determined through mutational analysis. Overexpression and RNA interference experiments targeting IRF-3 showed that it regulates the expression of ORMDL3 following RSV exposure. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay showed that IRF-3 binds directly to the promoter of the ORMDL3 gene. Furthermore, we confirmed that expression of IRF-3 is significantly increased and shows a strong linear correlation with increased ORMDL3 in the peripheral blood lymphocytes from infants with RSV-induced bronchiolitis. Our results indicate that IRF-3 is an important regulator of ORMDL3 induction following RSV infection by binding directly to the promoter of ORMDL3, which may be implicated in the inflammatory and immune reactions involved in bronchiolitis and wheezing diseases. PMID- 28336365 TI - Breast cancer cells: Focus on the consequences of epithelial-to-mesenchymal transition. AB - Breast cancers are highly heterogeneous and successful treatment of those subtypes with a high frequency of metastases and resistance to clinically available therapies remains a challenge. An understanding of mechanisms which may contribute to this heterogeneity and generation of more resilient cancer cells is therefore essential. Epithelial-to-mesenchymal transition (EMT) is a dynamic two way process that occurs during embryonic development and wound healing whereby epithelial cells can gain plasticity and switch to a mesenchymal-like phenotype. EMT has received interest from cancer researchers due to its potential role in processes important in cancer progression and metastasis. Recent evidence has revealed a clear association between EMT and resistance to therapeutics. Targeting of EMT and/or the mesenchymal-like phenotype may be a promising avenue for future therapeutic intervention. This review provides a brief summary of the functional consequences of EMT in breast cancer, with a focus on the mesenchymal like phenotype. PMID- 28336363 TI - Does Surgical Teaching Take Time? Resident Participation in Minimally Invasive Hysterectomy for Endometrial Cancer. AB - STUDY OBJECTIVE: To determine the association between resident involvement and operative time for minimally invasive surgery (MIS) for endometrial cancer. DESIGN: A retrospective cohort study (Canadian Task Force classification II-2). SETTING: An integrated health care system in Northern California. PATIENTS: A total of 1433 women who underwent MIS for endometrial cancer and endometrial intraepithelial neoplasia from January 2009 to January 2014. INTERVENTIONS: Resident participation in 430 of 688 laparoscopic cases (62%) and 341 of 745 robotic cases (46%). MEASUREMENTS AND MAIN RESULTS: The primary outcome was the impact of resident involvement on surgical time. When residents were involved in laparoscopic and robotic surgery, there was an increase of 61 minutes (median operative time, 186 vs 125 minutes; p < .001) and 31 minutes (median operative time, 165 vs 134 minutes; p < .001), respectively. Resident participation was associated with increased operative times in all levels of surgical complexity from hysterectomy alone to hysterectomy with pelvic and para-aortic lymph node dissection. Resident participation was also associated with increased major intraoperative complications (3.4% vs 1.8%, p = .02) as well as major postoperative complications (6.4% vs 3.8%, p = .003). CONCLUSION: The presence of a resident was associated with a 32% increase in operative time for minimally invasive cases in gynecologic oncology for endometrial cancer. Because of the retrospective nature, we cannot infer causality of operative outcomes because residents were also involved in more high-risk patients and complex cases. For health care systems using surgical metrics, there may be a need to allocate more time for resident involvement. PMID- 28336366 TI - [Foruncular myiasis; presentation of an imported case]. PMID- 28336368 TI - Novel strategies in the oral delivery of antidiabetic peptide drugs - Insulin, GLP 1 and its analogs. AB - As diabetes is a complex disorder being a major cause of mortality and morbidity in epidemic rates, continuous research has been done on new drug types and administration routes. Up to now, a large number of therapeutic peptides have been produced to treat diabetes including insulin, glucagon-like peptide-1 (GLP 1) and its analogs. The most common route of administration of these antidiabetic peptides is parenteral. Due to several drawbacks associated with this invasive route, delivery of these antidiabetic peptides by the oral route has been a goal of pharmaceutical technology for many decades. Dosage form development should focus on overcoming the limitations facing oral peptides delivery as degradation by proteolytic enzymes and poor absorption in the gastrointestinal tract (GIT). This review focuses on currently developed strategies to improve oral bioavailability of these peptide based drugs; evaluating their advantages and limitations in addition to discussing future perspectives on oral peptides delivery. Depending on the previous reports and papers, the area of nanocarriers systems including polymeric nanoparticles, solid lipid nanoparticles, liposomes and micelles seem to be the most promising strategy that could be applied for successful oral peptides delivery; but still further potential attempts are required to be able to achieve the FDA approved oral antidiabetic peptide delivery system. PMID- 28336367 TI - New real time and conventional RT-PCRs for updated molecular diagnosis of infectious bronchitis virus infection (IBV) in chickens in Egypt associated with frequent co-infections with avian influenza and Newcastle Disease viruses. AB - In Egypt, currently two geographically restricted genotypes of the infectious bronchitis coronavirus (IBV) are circulating with detrimental effects for poultry industry. A sensitive real-time RT-PCR assay targeting the IBV nucleocapsid gene (N) was developed to screen clinical samples for presence of IBV. Conventional RT PCRs amplifying hypervariable regions (HVRs 1-2 and 3) of the IBV S1 gene were developed and amplificates used for nucleotide sequence-based typing of IBV field strains in Egyptian chickens directly from clinical samples. PMID- 28336369 TI - RETRACTED: Pre-exposures to taro (Colocasia esculenta) leaf volatiles enhance the reproductive behaviors in Spodoptera litura. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal).This article has been retracted at the request of the authors of the paper.Some of the data of the work published was work of a different researcher (the principal investigator), and published without their permission. Furthermore, it has been realised that the analysis and calculation methods used for the gene expressions and some other results in this paper need to be tested further before publication. PMID- 28336370 TI - Purinergic P2Y6 receptors: A new therapeutic target of age-dependent hypertension. AB - Aging has a remarkable effect on cardiovascular homeostasis and it is known as the major non-modifiable risk factor in the development of hypertension. Medications targeting sympathetic nerve system and/or renin-angiotensin aldosterone system are widely accepted as a powerful therapeutic strategy to improve hypertension, although the control rates remain unsatisfactory especially in the elder patients with hypertension. Purinergic receptors, activated by adenine, uridine nucleotides and nucleotide sugars, play pivotal roles in many biological processes, including platelet aggregation, neurotransmission and hormone release, and regulation of cardiovascular contractility. Since clopidogrel, a selective inhibitor of G protein-coupled purinergic P2Y12 receptor (P2Y12R), achieved clinical success as an anti-platelet drug, P2YRs has been attracted more attention as new therapeutic targets of cardiovascular diseases. We have revealed that UDP-responsive P2Y6R promoted angiotensin type 1 receptor (AT1R)-stimulated vascular remodeling in mice, in an age-dependent manner. Moreover, the age-related formation of heterodimer between AT1R and P2Y6R was disrupted by MRS2578, a P2Y6R-selective inhibitor. These findings suggest that P2Y6R is a therapeutic target to prevent age-related hypertension. PMID- 28336372 TI - Doxorubicin targets multiple players: A new view of an old problem. AB - Anthracycline cardiotoxicity remains a serious problem in paediatric and adult cancer survivors, and the advancement of cardio-oncology is a necessary step for an effective care of the patients that experience adverse cardiovascular effects. In this review, we discuss the multiple instruments used by clinicians that constitute the current strategies for primary and secondary prevention aiming at contrasting the onset of early and late doxorubicin-induced cardiotoxic events. The importance of early detection of cardiotoxicity and the following pharmacological therapy has been acknowledged with the emphasis put on impaired diastolic function, an increasingly recognized precocious sign of doxorubicin cardiotoxicity with an emerging scientific and clinical interest. We highlight the involvement of progenitor cells of cardiac and extra-cardiac origin as well as multiple cardiac cell types (fibroblasts and vasculature cells), focusing on molecular signals involved in cellular injury and response. Oxidative stress, DNA damage, senescence and cell death are established mechanisms driving anthracycline toxicity, but the comprehension of their relative weight on affecting specific cell type behaviour remains to be consolidated. The contribution of these crucial stressors and the emerging tools for preserving cell function are discussed. PMID- 28336373 TI - Gender differences in liver disease and the drug-dose gender gap. AB - Although gender-based medicine is a relatively recent concept, it is now emerging as an important field of research, supported by the finding that many diseases manifest differently in men and women and therefore, might require a different treatment. Sex-related differences regarding the epidemiology, progression and treatment strategies of certain liver diseases have long been known, but most of the epidemiological and clinical trials still report results only about one sex, with consequent different rate of response and adverse reactions to treatment between men and women in clinical practice. This review reports the data found in the literature concerning the gender-related differences for the most representative hepatic diseases. PMID- 28336371 TI - Novel adaptive and innate immunity targets in hypertension. AB - Hypertension is a worldwide epidemic and global health concern as it is a major risk factor for the development of cardiovascular diseases. A relationship between the immune system and its contributing role to the pathogenesis of hypertension has been long established, but substantial advancements within the last few years have dissected specific causal molecular mechanisms. This review will briefly examine these recent studies exploring the involvement of either innate or adaptive immunity pathways. Such pathways to be discussed include innate immunity factors such as antigen presenting cells and pattern recognition receptors, adaptive immune elements including T and B lymphocytes, and more specifically, the emerging role of T regulatory cells, as well as the potential of cytokines and chemokines to serve as signaling messengers connecting innate and adaptive immunity. Together, we summarize these studies to provide new perspective for what will hopefully lead to more targeted approaches to manipulate the immune system as hypertensive therapy. PMID- 28336374 TI - Developments and future clinical outlook of taxane nanomedicines. AB - Taxanes are highly valuable drugs for cancer treatment. Low water-solubility however puts a major challenge in obtaining formulations that are stable and easy to-use in clinical practice. Initially, solubilization and lowering toxicity of taxanes has been the main research focus. However, emerging passive and active targeting strategies, especially in the field of nanomedicine, have been capital incentives to further broaden therapeutic index by improving efficacy. This review provides an up-to-date clinical track record of taxane nanomedicines in view of the current state-of-the-art in anti-cancer drug delivery. Additionally, the clinical status of taxane nanomedicines is discussed and considerations are provided for improving future clinical translation. PMID- 28336375 TI - Tumortropic adipose-derived stem cells carrying smart nanotherapeutics for targeted delivery and dual-modality therapy of orthotopic glioblastoma. AB - Chemotherapy is typically used to treat malignant brain tumors, especially for the tumors in surgically inaccessible areas. However, owing to the existence of blood-brain barrier (BBB), the tumor accumulation and therapeutic efficacy of clinical therapeutics is still of great concerns. To this end, we present herein a prominent therapeutic strategy adopting adipose-derived stem cells (ADSCs) capable of carrying nanotherapeutic payloads selectively toward brain tumors for thermo/chemotherapy. The nanoparticle (NP) payload was obtained from co-assembly of poly(gamma-glutamic acid-co-distearyl gamma-glutamate) with poly(lactic-co glycolic acid), paclitaxel (PTX), and oleic acid-coated superparamagnetic iron oxide NPs in aqueous solution. The particle size and drug loading content were ca 110nm and 8.4wt%, respectively. After being engulfed by ADSCs, the nanotherapeutics was found rather harmless to cellular hosts at a PTX concentration of 30MUM over 48h in the absence of pertinent stimulus. Nevertheless, the ADSC-based approach combined with high frequency magnetic field exhibits a sound therapeutic performance with a 4-fold increase in therapeutic index on brain astrocytoma (ALTS1C1)-bearing mice (C57BL/6J) as compared to the typical chemotherapy using a current first-line chemodrug, temozolomide. Immunohistochemical examination of brain tumor sections confirms the successful cellular transport and pronounced cytotoxic action of therapeutics against tumor cells in vivo. This work demonstrates the promise of ADSC-mediated chemo/thermal therapy against brain tumors. PMID- 28336376 TI - Effect of anesthetics on microglial activation and nanoparticle uptake: Implications for drug delivery in traumatic brain injury. AB - Traumatic brain injury (TBI) is a serious public health problem, often with devastating consequences for patients and their families. Affordable and timely therapies can have a substantial impact on outcomes in severe TBI. Despite the common use of sedatives and anesthetics in the acute phase of TBI management, their effect on glial cells is not well understood. We investigated the effect of a commonly used sedative, pentobarbital, on glial cells and their uptake of nanoparticles. First, we studied how pentobarbital affects BV2 mouse microglial cells in culture. The cell morphology was imaged by confocal microscopy and analyzed. Our results suggest that microglia change to a more swollen, 'activated' shape with pentobarbital (cell area increased by approximately 20%, p<0.001). Such glial activation may have negative implications for the ability of the injured brain to clear edema. Second, we investigated how pentobarbital treatment affected nanoparticle uptake. BV-2 mouse microglial cells in the presence and absence of pentobarbital were treated with fluorescently-labeled, hydroxyl-functionalized poly(amidoamine) dendrimer nanoparticles (Dendrimer-Cy5). We demonstrated that the presence of pentobarbital increased the dendrimer nanoparticle uptake significantly (~2-fold both 2 and 6h following treatment). This semi-quantitative fluorescence assessment was broadly consistent among confocal image analysis, flow cytometry, and fluorescence quantification of cell extracted dendrimer-Cy5. Although anesthetics appear to activate microglia, the increased uptake of dendrimer nanoparticles in their presence can be exploited to deliver drug-loaded nanoparticles directly to microglia after TBI. These drugs could restore glial and glymphatic function, enabling efficient drainage of waste and fluid from the brain and effectively improving recovery after TBI. A key future direction is to validate these findings in TBI models. PMID- 28336377 TI - Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. AB - Boron neutron capture therapy is a promising tumor treatment method, though its wide application has been limited due to the poor tumor selectivity and intracellular delivery of 10B-compounds. Here, block copolymer-boron cluster conjugate based on the clinically used sodium borocaptate (BSH) and poly(ethylene glycol)-b-poly(glutamic acid) copolymer have been developed for effectively penetrating tumor tissues and homogeneously delivering the boron clusters into cancer cells towards safe and efficient boron neutron capture therapy. The PEGylated block copolymer-boron cluster (BSH) conjugate has demonstrated significant higher cellular uptake and tumor accumulation when compared to the non-PEGylated formulations and BSH. Moreover, the enhanced delivery to tumors of the conjugates, as well as their superior intratumoral penetration, which facilitated reaching the intracellular space of most cells in tumors, allowed the effective ablation of tumors after neutron irradiation. PMID- 28336378 TI - Optimized biodegradable polymeric reservoir-mediated local and sustained co delivery of dendritic cells and oncolytic adenovirus co-expressing IL-12 and GM CSF for cancer immunotherapy. AB - Administration of dendritic cells (DCs) combined with oncolytic adenovirus (Ad) expressing antitumor cytokines induces a potent antitumor effect and antitumor immunity by ameliorating the immunosuppressive tumor microenvironment. However, this combination therapy has significant limitations due to rapid dissemination and inactivation of the therapeutics at the tumor site, necessitating multiple injections of both therapeutics. To overcome these limitations, we have utilized gelatin-based hydrogel to co-deliver oncolytic Ad co-expressing interleukin (IL) 12 and granulocyte-macrophage colony-stimulating factor (GM-CSF) (oAd) and DCs for sustained release of both therapeutics. The injectable and biodegradable hydrogels were prepared by mixing the polymer solutions containing horseradish peroxidase and hydrogen peroxide. Gel matrix enabled sustained release of both oAd and DCs while preserving their biological activity over a considerable time period, leading to efficient retention of both therapeutics in tumor tissue. Further, tumors treated with oAd- and DC-loaded gel (oAd+DC/gel) showed a significantly greater expression level of IL-12, GM-CSF, and interferon-gamma (IFN-gamma) than either single treatment (oAd or DC) or oAd in combination with DC (oAd+DC), resulting in efficient activation of both endogenous and exogenous DCs, migration of DCs to draining lymph nodes, and tumor infiltration of CD4+ and CD8+ T cells. Moreover, oAd+DC/gel resulted in a significantly higher number of tumor-specific IFN-gamma-secreting immune cells compared with oAd+DC. Lastly, oAd+DC/gel significantly attenuated tumor-mediated thymic atrophy, which is associated with immunosuppression in the tumor microenvironment, compared with oAd+DC. Taken together, these results demonstrate that gelatin gel-mediated co delivery of oncolytic Ad and DCs might be a promising strategy to efficiently retain both therapeutics in tumor tissue and induce a potent antitumor immune response for an extended time period via a single administration. PMID- 28336380 TI - Risk Prediction Models for Incident Heart Failure: A Systematic Review of Methodology and Model Performance. AB - BACKGROUND: Numerous models predicting the risk of incident heart failure (HF) have been developed; however, evidence of their methodological rigor and reporting remains unclear. This study critically appraises the methods underpinning incident HF risk prediction models. METHODS AND RESULTS: EMBASE and PubMed were searched for articles published between 1990 and June 2016 that reported at least 1 multivariable model for prediction of HF. Model development information, including study design, variable coding, missing data, and predictor selection, was extracted. Nineteen studies reporting 40 risk prediction models were included. Existing models have acceptable discriminative ability (C statistics > 0.70), although only 6 models were externally validated. Candidate variable selection was based on statistical significance from a univariate screening in 11 models, whereas it was unclear in 12 models. Continuous predictors were retained in 16 models, whereas it was unclear how continuous variables were handled in 16 models. Missing values were excluded in 19 of 23 models that reported missing data, and the number of events per variable was < 10 in 13 models. Only 2 models presented recommended regression equations. There was significant heterogeneity in discriminative ability of models with respect to age (P < .001) and sample size (P = .007). CONCLUSIONS: There is an abundance of HF risk prediction models that had sufficient discriminative ability, although few are externally validated. Methods not recommended for the conduct and reporting of risk prediction modeling were frequently used, and resulting algorithms should be applied with caution. PMID- 28336381 TI - Stop the Next Readmission for Heart Failure With Gap Time and a Natriuretic Peptide? PMID- 28336382 TI - Migration and infectious diseases. AB - BACKGROUND: Infectious diseases still represent an important cause of morbidity and mortality among foreign-born individuals. The rising migration flows towards Europe throughout the last few years are raising renewed concerns about management issues and the potential associated risk for the native population. AIMS: To discuss the health implications and challenges related to the four phases of migration, from first arrival to stable resettlement. SOURCES: Scientific literature and relevant statistical reports. CONTENT: Although infectious diseases are not a health priority at first arrival, a syndromic screening to identify the most common communicable conditions (pulmonary tuberculosis above all) should be promptly conducted. Reception centres where asylum seekers are gathered after arrival may be crowded, so favouring epidemic outbreaks, sometimes caused by incomplete vaccine coverage for preventable diseases. After resettlement, the prevalence of some chronic infections such as human immunodeficiency virus, viral hepatitis or tuberculosis largely reflects the epidemiological pattern in the country of origin, with poor living conditions being an additional driver. Once resettled, migrants usually travel back to their country of origin without seeking pre-travel advice, which results in a high incidence of malaria and other infections. IMPLICATIONS: Although infectious diseases among migrants are known to have a negligible impact on European epidemiology, screening programmes need to be implemented and adapted to the different stages of the migratory process to better understand the trends and set priorities for action. Appropriate access to care regardless of the legal status is crucial to improve the health status and prevent the spread of contagious conditions. PMID- 28336379 TI - Synthetic nanovaccines for immunotherapy. AB - Although vaccination is historically one of the most successful strategies for the prevention of infectious diseases, development of vaccines for cancer and many chronic infections, such as HIV, malaria, and tuberculosis, has remained a challenge. Strong and long-lasting antigen-specific T cell responses are critical for therapy of these diseases. A major challenge in achieving a robust CD8+ T cell response is the requirement of spatio-temporal orchestration of antigen cross-presentation in antigen-presenting cells with innate stimulation. Here, we discuss the development of nanoparticle vaccine (nanovaccine) that modulates the innate immune system and enhances adaptive immunity with reduced toxicity. We address how nanovaccines can integrate multiple functions, such as lymph node targeting, antigen presentation, and stimulation of innate immunity, to achieve a robust T cell response for immunotherapy. PMID- 28336383 TI - The ability of Group A streptococcus to adhere to immortalized human skin versus throat cell lines does not reflect their predicted tissue tropism. AB - OBJECTIVES: To determine if emm pattern-inferred tissue tropisms of Group A streptococcus strains is reflected in their ability to adhere to immortalized human HaCat (keratinocyte) and Detroit 562 (pharyngeal) cell lines. METHODS: Human epithelial cell line monolayers were inoculated with Group A streptococcus, and the percentage of adhered bacteria after a 1-h incubation period was calculated. RESULTS: Of the 21/69 inferred-skin-tropic, and the 25/69 inferred throat-tropic isolates no preferential adherence was observed to a particular cell line. The 23/69 strains classified as 'generalists', however, showed an overall greater ability to adhere to both cell lines. CONCLUSIONS: Predicted tissue-tropism based on emm patterns is not reflected by preferential adherence to a specific cell line, suggesting that early adhesion events may not be as important in establishing infection at a particular ecological niche than originally expected. PMID- 28336384 TI - Predictors for individual patient antibiotic treatment effect in hospitalized community-acquired pneumonia patients. AB - OBJECTIVE: Our objective was to identify clinical predictors of antibiotic treatment effects in hospitalized patients with community-acquired pneumonia (CAP) who were not in the intensive care unit (ICU). METHODS: Post-hoc analysis of three prospective cohorts (from the Netherlands and Spain) of adult patients with CAP admitted to a non-ICU ward having received either beta-lactam monotherapy, beta-lactam + macrolide, or a fluoroquinolone-based therapy as empirical antibiotic treatment. We evaluated candidate clinical predictors of treatment effects in multiple mixed-effects models by including interactions of the predictors with empirical antibiotic choice and using 30-day mortality, ICU admission and length of hospital stay as outcomes. RESULTS: Among 8562 patients, empirical treatment was beta-lactam in 4399 (51.4%), fluoroquinolone in 3373 (39.4%), and beta-lactam + macrolide in 790 (9.2%). Older age (interaction OR 1.67, 95% CI 1.23-2.29, p 0.034) and current smoking (interaction OR 2.36, 95% CI 1.34-4.17, p 0.046) were associated with lower effectiveness of fluoroquinolone on 30-day mortality. Older age was also associated with lower effectiveness of beta-lactam + macrolide on length of hospital stay (interaction effect ratio 1.14, 95% CI 1.06-1.22, p 0.008). CONCLUSIONS: Older age and smoking could influence the response to specific antibiotic regimens. The effect modification of age and smoking should be considered hypothesis generating to be evaluated in future trials. PMID- 28336385 TI - Frequency and pattern of chronic complications of diabetes and their association with glycemic control. AB - BACKGROUND: The study was conducted in diabetes care centers to explore association of chronic complications of diabetes with glycemic status along with their frequency and pattern among adult patients with type 2 diabetes. METHODS: A cross-sectional study was conducted at outpatient departments of eight diabetes care centers in Dhaka. Data were collected by face to face interview by trained research physicians. Disease related information was recorded in the checklist from diabetes guide books of the patients. Chronic complications of diabetes were recorded from the records of expert consultation. RESULTS: Records of 5215 patients with type diabetes (59.4% males) were analyzed. Mean age of the male and female subjects was 52.7 and 50.6 years, respectively. Hypertriglyceridemia [OR 1.74, 95% CI (1.18-2.57)], increased LDL [OR 1.27, 95% CI (0.78-2.07)] and decreased HDL [OR 0.81, 95% CI (0.43-1.53)] and diabetic foot ulcers [OR 2.32, 95% CI (1.14-4.01)] were significantly associated with poor glycemic control, whereas hypertriglyceridemia [OR 2.39, 95% CI (1.42-4.03)] diabetic foot ulcer [OR 2.32, 95% CI (1.14-4.01)], hypetension [OR 1.65, 95% CI (1.15-2.43)] and coronary artery diasease [OR 1.23, 95% CI (0.77-2.13) were significantly associated with poor glycemic control according to FPG. CONCLUSION: The study finds association of chronic complications of diabetes with glycemic control among type 2 diabetes patients in Bangladesh. PMID- 28336386 TI - The WHF Roadmap for Reducing CV Morbidity and Mortality Through Prevention and Control of RHD. AB - Rheumatic heart disease (RHD) is a preventable non-communicable condition that disproportionately affects the world's poorest and most vulnerable. The World Heart Federation Roadmap for improved RHD control is a resource designed to help a variety of stakeholders raise the profile of RHD nationally and globally, and provide a framework to guide and support the strengthening of national, regional and global RHD control efforts. The Roadmap identifies the barriers that limit access to and uptake of proven interventions for the prevention and control of RHD. It also highlights a variety of established and promising solutions that may be used to overcome these barriers. As a general guide, the Roadmap is meant to serve as the foundation for the development of tailored plans of action to improve RHD control in specific contexts. PMID- 28336387 TI - The World Heart Federation Roadmap for Nonvalvular Atrial Fibrillation. AB - BACKGROUND: The World Heart Federation has undertaken an initiative to develop a series of Roadmaps to promote development of national policies and health systems approaches, and to identify potential roadblocks on the road to effective prevention, detection, and management of cardiovascular disease in low-and middle income countries (LMICs) and develop strategies for overcoming these. This Roadmap focuses on atrial fibrillation (AF). AF is the most common, clinically significant arrhythmia and, among other clinical outcomes, is associated with increased risk of stroke. METHODS: Development of this Roadmap included a review of published guidelines and research papers, and consultation with an expert committee comprising experts in clinical management of AF and health systems research in LMICs. The Roadmap identifies 1) key interventions for detection, diagnosis, and management of AF; 2) gaps in implementation of these interventions (knowledge-practice gaps); 3) health system roadblocks to implementation of AF interventions in LMICs; and 4) potential strategies for overcoming these. RESULTS: More research is needed on determinants and primary prevention of AF. Knowledge-practice gaps for detection, diagnosis, and management of AF are present worldwide, but may be more prominent in LMICs. Potential barriers to implementation of AF interventions include long distances to health facilities, shortage of health care professionals with training in AF, including interpretation of ECG, unaffordability of oral anticoagulants for patient households, reluctance on the part of physicians to initiate oral anticoagulant (OAC) therapy, and lack of awareness of the importance of persistent adherence to OAC therapy. Potential solutions include training of nonphysician health workers and pharmacists in pulse-taking, use of telemedicine technologies to transmit electrocardiogram results, engagement of nonphysician health workers in OAC therapy adherence support, and country-specific support and education programs for noncardiologist health care professionals. CONCLUSIONS: AF affects millions of people worldwide and, left untreated, increases the risk and severity of stroke and heart failure. Although guidelines for the detection, diagnosis, and management of AF exist, there are gaps in implementation of these guidelines globally, and in particular in LMICs. This Roadmap identifies some potential solutions that may improve AF outcomes in LMICs but require further evaluation in these settings. PMID- 28336388 TI - The Importance of Conducting Stroke Genomics Research in African Ancestry Populations. PMID- 28336390 TI - Is parasternal intercostal EMG an accurate surrogate of respiratory neural drive and biomarker of dyspnea during cycle exercise testing? AB - Recent evidence suggests that surface electromyography of the parasternal intercostals (EMGpara) can be a non-invasive alternative to diaphragmatic EMG (EMGdi) for estimating neural respiratory drive (NRD) during cardiopulmonary exercise testing (CPET). The purpose of this study was to determine if non respiratory muscles influence EMGpara by having subjects place their hands on (Hon) and off (Hoff) the handlebars during cycling-based CPET. Ten healthy adults performed an incremental cycling test until volitional exhaustion. Participants were instrumented with an esophageal electrode catheter to measure EMGdi, and surface electrodes on the 2nd intercostal space to measure EMGpara. Subjects alternated between 30s of Hon and 30s Hoff during each exercise stage. There were no differences in EMGdi across all exercise intensities. However, EMGpara was significantly greater during the Hon vs. Hoff condition at all exercise intensities (p<0.05). These results suggest that EMGpara may not be an appropriate surrogate of NRD during cycle exercise testing due to co-activation of adjacent skeletal muscles. PMID- 28336389 TI - Metformin Ameliorates Uterine Defects in a Rat Model of Polycystic Ovary Syndrome. AB - Adult rats treated concomitantly with insulin and human chorionic gonadotropin exhibit endocrine, metabolic, and reproductive abnormalities that are very similar to those observed in polycystic ovary syndrome (PCOS) patients. In this study, we used this rat model to assess the effects of metformin on PCOS-related uterine dysfunction. In addition to reducing androgen levels, improving insulin sensitivity, and correcting the reproductive cycle, metformin treatment induced morphological changes in the PCOS-like uterus. At the molecular and cellular levels, metformin normalized the androgen receptor-mediated transcriptional program and restored epithelial-stromal interactions. In contrast to glucose transport, uterine inflammatory gene expression was suppressed through the PI3K Akt-NFkappaB network, but without affecting apoptosis. These effects appeared to be independent of AMPK subunit and autophagy-related protein regulation. We found that when metformin treatment partially restored implantation, several implantation-related genes were normalized in the PCOS-like rat uterus. These results improve our understanding of how metformin rescues the disruption of the implantation process due to the uterine defects that result from hyperandrogenism and insulin resistance. Our data provide insights into the molecular and functional clues that might help explain, at least in part, the potential therapeutic options of metformin in PCOS patients with uterine dysfunction. PMID- 28336391 TI - Serum high C reactive protein concentrations are related to the intake of dietary macronutrients and fiber: Findings from a large representative Persian population sample. AB - OBJECTIVE: Serum high-sensitivity CRP is a marker of inflammation and an independent predictor of chronic diseases. However, the effect of diet on serum hs-CRP is unclear. The aim of this study was to investigate the relationship between dietary macronutrient intake and serum hs-CRP. DESIGN AND METHODS: We recruited 9778 adults, aged 35-65years as part of the MASHAD study. Dietary intake was determined using 24-hour dietary recall and several biochemical parameters including serum hs-CRP were measured. Analysis of covariance was used for assessment of crude and energy-adjusted nutrients across quartiles of serum hs-CRP. To find the association of dietary nutrients intake and serum hs-CRP level, we used logistic regression in different model. RESULTS: Unadjusted and adjusted multivariate analyses indicate that there was a significant positive association between dietary protein and sodium intake and serum hs-CRP concentrations. There was also a positive association with dietary fat and cholesterol and serum hs-CRP in the adjusted models. There was a significant inverse association between dietary carbohydrate and fiber consumption and serum hs-CRP in both crude and adjusted models. CONCLUSION: We have found a significant positive association between the dietary intake of fat, protein, cholesterol and sodium and hs-CRP level, and an inverse correlation between dietary carbohydrate and fiber and serum hs-CRP in a large representative Iranian population. PMID- 28336392 TI - Diagnostic laboratories in Asia Pacific region: Investigation on quality characteristics and time of reporting. AB - This is the result of a Survey of various aspects of quality, cost and speed in a large sample of diagnostic laboratories in the Asia Pacific region. It is the first of its type to be published and represents a snapshot of the current performance in a large number of diagnostic laboratories in a broad range of countries in the Asia Pacific region. This demonstrates that there are common issues facing all the laboratories surveyed but also common solutions using a Quality Systems approach which involves Accreditation, Customer responsiveness, greater use of IT, automation and Lean principles. The Survey provides data on some quality characteristics such as Turnaround Time (TAT) and quality improvement activities. It has been the case that some of the KPIs have improved over the course of the Surveys for example a reduction in the average TAT, and it might be that this occurred as a result of participation. Most laboratories have a target of 46-60min for STAT (Short Turnaround Time) on Clinical Chemistry and Immunoassay samples. PMID- 28336393 TI - Contributions of beta-tubulin to cellular morphology, sporulation and virulence in the insect-fungal pathogen, Metarhizium acridum. AB - beta-tubulin is an elementary subunit of microtubules that form the cytoskeleton, participating in a wide range of cellular processes. The contributions of the single beta-tubulin gene in affecting cell morphology, sporulation and virulence were examined in the entomopathogenic fungus Metarhizium acridum. Targeted gene knockout of beta-tubulin resulted in resistance to benomyl but impaired proper nuclear segregation, lipid droplet transport, and deposition of chitin to the cell wall. M. acridum beta-tubulin mutants displayed wavy hyphal growth and densely packed, wrinkled colonies. Decreases in the rate of phialides formation and conidial yield were observed for the beta-tubulin mutant, which was also impaired in virulence towards locust hosts as compared to wild type and complemented strains. Morphological analyses of infection structures revealed development of bifurcated germ tubes, with reduced appressoria formation seen in the beta-tubulin mutant. M. acridum beta-tubulin mutant appressoria were aberrant in morphology and displayed decreased turgor pressure. The ability of the M. acridum beta-tubulin mutant to proliferate in the insect hemolymph both in vitro and in vivo was also significantly reduced. Our results indicate that in M. acridum, beta-tubulin is not essential for survival but that it contributes to cellular transport of organelles and cell wall materials, impacting growth, appressorial differentiation, virulence, and sporulation. PMID- 28336394 TI - Ts1Cje Down syndrome model mice exhibit environmental stimuli-triggered locomotor hyperactivity and sociability concurrent with increased flux through central dopamine and serotonin metabolism. AB - Ts1Cje mice have a segmental trisomy of chromosome 16 that is orthologous to human chromosome 21 and display Down syndrome-like cognitive impairments. Despite the occurrence of affective and emotional impairments in patients with Down syndrome, these parameters are poorly documented in Down syndrome mouse models, including Ts1Cje mice. Here, we conducted comprehensive behavioral analyses, including anxiety-, sociability-, and depression-related tasks, and biochemical analyses of monoamines and their metabolites in Ts1Cje mice. Ts1Cje mice showed enhanced locomotor activity in novel environments and increased social contact with unfamiliar partners when compared with wild-type littermates, but a significantly lower activity in familiar environments. Ts1Cje mice also exhibited some signs of decreased depression like-behavior. Furthermore, Ts1Cje mice showed monoamine abnormalities, including increased extracellular dopamine and serotonin, and enhanced catabolism in the striatum and ventral forebrain. This study constitutes the first report of deviated monoamine metabolism that may help explain the basis for abnormal behaviors, including the environmental stimuli triggered hyperactivity, increased sociability and decreased depression-like behavior in Ts1Cje mice. PMID- 28336396 TI - Tumor Control Index as a new tool to assess tumor growth in experimental animals. AB - Measurement of tumor diameters, tumor volumes, or area under the curve has been traditionally used to quantitate and compare tumor growth curves in immune competent as well as immune-compromised mice and rats. Here, using tumor growth data from a large number of mice challenged with live tumor cells, we describe the use of a new composite parameter, Tumor Control Index (TCI) as an alternative method to do the same. This index, comprised of three distinct values, the Tumor Inhibition Score, Tumor Rejection Score, and Tumor Stability Score, provides a complete picture of nearly every aspect of tumor growth in large numbers of animals, can be deduced automatically from tumor diameter or volume data, and can be used to compare several groups of animals in different experiments. This automatically derivable index also corresponds neatly to the use of complete and partial responses and tumor stability data generated in human tumors, and can be used to assess the efficacy of interventions to be used in clinical studies. PMID- 28336395 TI - Human immune compartment comparisons: Optimization of proliferative assays for blood and gut T lymphocytes. AB - The accumulation of peripheral blood late-differentiated memory CD8 T cells with features of replicative (cellular) senescence, including inability to proliferate in vitro, has been extensively studied. Importantly, the abundance of these cells is directly correlated with increased morbidity and mortality in older persons. Of note, peripheral blood contains only 2% of the total body lymphocyte population. By contrast, the gut-associated lymphoid tissue (GALT) is the most extensive lymphoid organ, housing up to 60% of total body lymphocytes, but has never been assessed with respect to senescence profiles. We report here the development of a method for measuring and comparing proliferative capacity of peripheral blood and gut colorectal mucosa-derived CD8 T cells. The protocol involves a 5-day culture of mononuclear leukocyte populations, from blood and gut colorectal mucosa respectively, labeled with 5-(and 6)-carboxyfluorescein diacetate succinimidyl ester (CFSE) and 5-bromo-2'-deoxyuridine (BrdU) and stimulated with anti-CD2/3/28-linked microbeads. Variables tested and optimized as part of the protocol development include: mode of T cell stimulation, CFSE concentration, inclusion of a second proliferation marker, BrdU, culture duration, initial culture concentration, and inclusion of autologous irradiated feeder cells. Moving forward, this protocol demonstrates a significant advance in the ability of researchers to study compartment-specific differences of in vitro proliferative dynamics of CD8 T cells, as an indicator of replicative senescence and immunological aging. The study's two main novel contributions are (1) Optimization and adaptation of standard proliferative dynamics blood T cell protocols for T cells within the mucosal immune system. (2) Introduction of the novel technique of combining CFSE and BrdU staining to do so. PMID- 28336397 TI - Soluble endoglin modulates the pro-inflammatory mediators NF-kappaB and IL-6 in cultured human endothelial cells. AB - AIMS: Endoglin is a transmembrane glycoprotein, that plays an important role in regulating endothelium. Proteolytic cleavage of membrane endoglin releases soluble endoglin (sEng), whose increased plasma levels have been detected in diseases related to the cardiovascular system. It was proposed that sEng might damage vascular endothelium, but detailed information about the potential mechanisms involved is not available. Thus, we hypothesized that sEng contributes to endothelial dysfunction, leading to a pro-inflammatory phenotype by a possible modulation of the TGF-beta and/or inflammatory pathways. MAIN METHODS: Human umbilical vein endothelial cells (HUVECs) and Human embryonic kidney cell line (HEK293T) were treated with different sEng concentration and time in order to reveal possible effect on biomarkers of inflammation and TGF-beta signaling. IL6 and NFkappaB reporter luciferase assays, quantitative real-time PCR analysis, Western blot analysis and immunofluorescence flow cytometry were used. KEY FINDINGS: sEng treatment results in activation of NF-kappaB/IL-6 expression, increased expression of membrane endoglin and reduced expression of Id-1. On the other hand, no significant effects on other markers of endothelial dysfunction and inflammation, including eNOS, peNOSS1177, VCAM-1, COX-1, COX-2 and ICAM-1 were detected. SIGNIFICANCE: As a conclusion, sEng treatment resulted in an activation of NF-kappaB, IL-6, suggesting activation of pro-inflammatory phenotype in endothelial cells. The precise mechanism of this activation and its consequence remains to be elucidated. A combined treatment of sEng with other cardiovascular risk factors will be necessary in order to reveal whether sEng is not only a biomarker of cardiovascular diseases, but also a protagonist of endothelial dysfunction. PMID- 28336398 TI - Modulation of mammary tumor vascularization by mast cells: Ultrasonographic and histopathological approaches. AB - AIMS: The inhibition of mast cells' degranulation may be an approach to prevent the formation of new vessels during the mammary carcinogenesis. MATERIALS AND METHODS: Female Sprague-Dawley rats were randomly divided into five experimental groups. Mammary tumors were induced by intraperitoneal injection of N-methyl-N nitrosourea (MNU). Animals from group II were treated with ketotifen for 18weeks immediately after the MNU administration, while animals from group III only received the ketotifen after the development of the first mammary tumor. Mammary tumors vascularization was assessed by ultrasonography (Doppler, B Flow and contrast-enhanced ultrasound) and immunohistochemistry (vascular endothelial growth factor-A). KEY FINDINGS AND SIGNIFICANCE: Similar to what occurs in women with breast cancer, the majority of MNU-induced mammary tumors exhibited a centripetal enhancement order of the contrast agent, clear margin and heterogeneous enhancement. Ultrasonographic and immunohistochemical data suggest that the inhibition of mast cells' degranulation did not change the mammary tumors vascularization. PMID- 28336399 TI - Synthetic matrix of polyether-polyurethane as a biological platform for pancreatic regeneration. AB - AIMS: Several alternative cellular approaches using biomaterials to host insulin producing cells derived from stem cells have been developed to overcome the limitations of type 1 diabetes treatment (exogenous insulin injection). However, none seem to fulfill all requirements needed to induce pancreatic cells successful colonization of the scaffolds. Here, we report a polymeric platform adherent to the native mice pancreas filled with human adipose stem cells (hASCs) that was able to induce growth of pancreatic parenchyma. MAIN METHODS: Synthetic polyether-polyurethane discs were placed adjacent to pancreas of normoglycemic and streptozotocin-induced diabetic mice. At day 4 post implantation, 1*106 hASCs were injected intra-implant in groups of normoglycemic and diabetic mice. Immunohistochemistry analysis of the implants was performed to identify insulin positive cells in the newly formed tissue. In addition, metabolic, inflammatory and angiogenic parameters were carried out in those mice. KEY FINDINGS: This study provides evidence of the ability of a biohybrid device to induce the growth of differentiated pancreas parenchyma in both normoglycemic and streptozotocin induced diabetic mice as detected by histological analysis. Glucose metabolism and body weight of hyperglycemic mice bearing hASCs implants improved. SIGNIFICANCE: The synthetic porous scaffold bearing hASC cells placed adjacent to the native animal pancreas exhibits the potential to be exploited in future cell based type 1 diabetes therapies. PMID- 28336400 TI - Mechanistic characterization of S 38093, a novel inverse agonist at histamine H3 receptors. AB - Histaminergic H3 inverse agonists, by stimulating central histamine release, represent attractive drug candidates to treat cognitive disorders. The present studies aimed to describe the mechanistic profile of S 38093 a novel H3 receptors inverse agonist. S 38093 displays a moderate affinity for rat, mouse and human H3 receptors (Ki=8.8, 1.44 and 1.2uM, respectively) with no affinity for other histaminergic receptors. In cellular models, the compound was able to antagonize mice H3 receptors (KB=0.65uM) and to suppress cAMP decrease induced by an H3 agonist via human H3 receptors (KB=0.11uM). The antagonism properties of the compound were confirmed by electrophysiological studies on rat hippocampal slices (from 0.1MUM). In cells expressing a high H3 density, S 38093 behaved as a moderate inverse agonist at rat and human H3 receptors (EC50=9 and 1.7uM, respectively). S 38093 was rapidly absorbed in mouse and rat (Tmax=0.25-0.5h), slowly in monkey (2h), with a bioavailability ranging from 20% to 60% and t1/2 ranging from 1.5 to 7.4h. The compound was widely distributed with a moderate volume of distribution and low protein binding. The brain distribution of S 38093 was rapid and high. In mice, S 38093 significantly increased ex vivo N-tele Methylhistamine cerebral levels from 3mg/kg p.o. and antagonized R-alpha Methylhistamine-induced dipsogenia from 10mg/kg i.p. Taken together, these data suggest that S 38093, a novel H3 inverse agonist, is a good candidate for further in vivo evaluations, in particular in animal models of cognition. PMID- 28336401 TI - Performance of the Spot Vision Screener in Children Younger Than 3 Years of Age. AB - PURPOSE: To evaluate the use of the Spot Vision Screener (Spot; Welch Allyn, Skaneateles Falls, New York, USA) for detection of amblyopia risk factors in children aged 6 months to 3 years, as defined by the 2013 guidelines of the American Association for Pediatric Ophthalmology and Strabismus. DESIGN: Reliability analysis. METHODS: In this study, children seen from June 1, 2012, to April 30, 2016 were tested with the Spot during a routine visit. Enrolled children underwent a comprehensive eye examination including cycloplegic refraction and sensorimotor testing within 6 months of the testing date by a pediatric ophthalmologist masked to the Spot results. RESULTS: A total of 184 children were included. The Spot successfully obtained readings in 89.7% of patients. Compared with the ophthalmologist's examination, the Spot had an overall sensitivity of 89.8% and a specificity of 70.4%. CONCLUSION: The Spot achieved good sensitivity and specificity for detection of amblyopia risk factors in this young cohort, particularly in the older subgroup. Our data offer support for automated vision screening in young children. PMID- 28336402 TI - Postoperative Efficacy, Predictability, Safety, and Visual Quality of Laser Corneal Refractive Surgery: A Network Meta-analysis. AB - PURPOSE: To compare the postoperative efficacy, predictability, safety, and visual quality of all major forms of laser corneal refractive surgeries for correcting myopia. DESIGN: Systematic review and network meta-analysis. METHODS: Search of MEDLINE, EMBASE, Cochrane Library, and the US trial registry was conducted up to November 2015. Randomized controlled trials (RCT) reporting in accordance with the eligibility criteria were included in this review. We performed a Bayesian random-effects network meta-analysis. RESULTS: Forty-eight RCTs were identified. For efficacy (uncorrected visual acuity [UCVA]), there were no statistically significant differences between any pair of treatments analyzed. The SUCRA (surface under the cumulative ranking curve) ranking (from best to worst) was femtosecond-based laser in situ keratomileusis (FS-LASIK), LASIK, small-incision lenticule extraction, femtosecond lenticule extraction (FLEx), photorefractive keratectomy (PRK), laser epithelial keratomileusis (LASEK), epipolis (Epi)-LASIK, transepithelial PRK (T-PRK). For predictability (refractive spherical equivalent [SE]), a statistically significant difference was found when FS-LASIK was compared with LASIK (odds ratio [OR] 2.29, 95% credible interval [CrI] 1.20-4.14), PRK (OR 2.16, 95% CrI 1.15-4.03), LASEK (OR 2.09, 95% CrI 1.08 4.55), and Epi-LASIK (OR 2.74, 95% CrI 1.11-6.20). The SUCRA ranking (from best to worst) was FS-LASIK, T-PRK, LASEK, PRK, LASIK, Epi-LASIK. There were no statistically significant differences in the safety (best spectacle-corrected visual acuity) comparisons. For both postoperative higher-order aberrations (HOAs) and contrast sensitivity (CS), there were no statistically significant differences between any pair of treatments analyzed. The SUCRA ranking results show that some corneal surface ablation techniques (PRK and LASEK) rank highest. CONCLUSIONS: This network meta-analysis shows that there were no statistically significant differences in either visual outcomes (efficacy and safety) or visual quality (HOAs and CS). FS-LASIK behaved better in predictability than any other type of surgeries. PMID- 28336404 TI - Mapping Region of Human Restriction Factor APOBEC3H Critical for Interaction with HIV-1 Vif. AB - The APOBEC3 (A3) family of cellular cytidine deaminases comprises seven members (A, B, C, D, F, G, and H) that potently inhibit retroviral replication. Human immunodeficiency virus type 1 (HIV-1) Vif is a small pleiotropic protein that specifically inactivates these enzymes, targeting them for ubiquitin-mediated proteasomal degradation. A3 Vif-interaction sites are presumed to fall into three distinct types: A3C/D/F, A3G, and A3H. To date, two types of A3G and A3C/D/F sites have been well characterized, whereas the A3H Vif-binding site remains poorly defined. Here, we explore the residues critical for the A3H-type Vif interaction. To avoid technical difficulties in performing experiments with human A3H haplotype II (hapII), which is relatively resistant to HIV-1 Vif, we employed its ortholog chimpanzee A3H (cA3H), which displays high Vif sensitivity, for a comparison of sensitivity with that of A3H hapII. The Vif susceptibility of A3H hapII-cA3H chimeras and their substitution mutants revealed a single residue at position 97 as a major determinant for the difference in their Vif sensitivities. We further surveyed critical residues by structure-guided mutagenesis using an A3H structural model and thus identified eight additional residues important for Vif sensitivity, which mapped to the alpha3 and alpha4 helices of A3H. Interestingly, this area is located on a surface adjacent to the A3G and A3C/D/F interfaces and is composed of negatively charged and hydrophobic patches. These findings suggest that HIV-1 Vif has evolved to utilize three dispersed surfaces for recognizing three types of interfaces on A3 proteins under certain structural constraints. PMID- 28336403 TI - Broad Analysis of Vicinal Disulfides: Occurrences, Conformations with Cis or with Trans Peptides, and Functional Roles Including Sugar Binding. AB - Vicinal disulfides between sequence-adjacent cysteine residues are very rare and rather startling structural features which play a variety of functional roles. Typically discussed as an isolated curiosity, they have never received a general treatment covering both cis and trans forms. Enabled by the growing database of high-resolution structures, required deposition of diffraction data, and improved methods for discriminating reliable from dubious cases, we identify and describe distinct protein families with reliably genuine examples of cis or trans vicinal disulfides and discuss their conformations, conservation, and functions. No cis trans interconversions and only one case of catalytic redox function are seen. Some vicinal disulfides are essential to large, functionally coupled motions, whereas most form the centers of tightly packed internal regions. Their most widespread biological role is providing a rigid hydrophobic contact surface under the undecorated side of a sugar or multiring ligand, contributing an important aspect of binding specificity. PMID- 28336405 TI - Photoactivation Mechanism of a Bacterial Light-Regulated Adenylyl Cyclase. AB - Light-regulated enzymes enable organisms to quickly respond to changing light conditions. We characterize a photoactivatable adenylyl cyclase (AC) from Beggiatoa sp. (bPAC) that translates a blue light signal into the production of the second messenger cyclic AMP. bPAC contains a BLUF photoreceptor domain that senses blue light using a flavin chromophore, linked to an AC domain. We present a dark state crystal structure of bPAC that closely resembles the recently published structure of the homologous OaPAC from Oscillatoria acuminata. To elucidate the structural mechanism of light-dependent AC activation by the BLUF domain, we determined the crystal structures of illuminated bPAC and of a pseudo lit state variant. We use hydrogen-deuterium exchange measurements of secondary structure dynamics and hypothesis-driven point mutations to trace the activation pathway from the chromophore in the BLUF domain to the active site of the cyclase. The structural changes are relayed from the residues interacting with the excited chromophore through a conserved kink of the BLUF beta-sheet to a tongue-like extrusion of the AC domain that regulates active site opening and repositions catalytic residues. Our findings not only show the specific molecular pathway of photoactivation in BLUF-regulated ACs but also have implications for the general understanding of signaling in BLUF domains and of the activation of ACs. PMID- 28336406 TI - Reagent-free continuous thermal tert-butyl ester deprotection. AB - Continuous processing enables the use of non-standard reaction conditions such as high temperatures and pressures while in the liquid phase. This expands the chemist's toolbox and can enable previously unthinkable chemistry to proceed with ease. For a series of amphoteric amino acid derivatives, we have demonstrated the ability to hydrolyze the tert-butyl ester functionality in protic solvent systems. Using a continuous plug flow reactor at 120-240 degrees C and 15-40min reaction times, no pH modification or additional reagents are needed to achieve the desired transformation. The method was then expanded to encompass a variety of more challenging substrates to test selectivity and racemization potential. The acid products were generally isolated as crystalline solids by simple solvent exchange after the deprotection reaction in good to high yield and purity. PMID- 28336407 TI - Development of N-hydroxycinnamamide-based HDAC inhibitors with improved HDAC inhibitory activity and in vitro antitumor activity. AB - Histone deacetylase inhibitors (HDACIs) are promising in the treatment of various diseases, among which cancer treatment has achieved the most success. We have previously developed series of HDACIs combining N-hydroxycinnamamide bioactive fragment and indole bioactive fragment, which showed moderate to potent antitumor activities. Herein, further structural derivatization based on our previous structure-activity relationship (SAR) got 25 novel compounds. Most compounds showed much more potent histone deacetylases (HDACs) inhibitory activity than their parent compound 1 and even the positive control SAHA. What's more, compared with the approved HDACs inhibitor SAHA, compounds 6i, 6k, 6q and 6t displayed better in vitro antiproliferation against multiple tumor cell lines. It is worth noting that though the 4-hydroxycinnamic acid-based compound 2 showed HDAC1/3 dual selectivity, its 4-hydroxy-3-methoxycinnamic acid-based analog 6t turned out to be a pan-HDACs inhibitor as SAHA, indicating that the 3-methoxy group on the N hydroxycinnamamide fragment could dramatically influence the HDACs isoform selectivity of this series of compounds. PMID- 28336408 TI - Synthesis, properties, antitumor and antibacterial activity of new Pt(II) and Pd(II) complexes with 2,2'-dithiobis(benzothiazole) ligand. AB - Mono- and binuclear Pt(II) and Pd(II) complexes with 2,2' dithiobis(benzothiazole) (DTBTA) ligand are reported. [Pt(DTBTA)(DMSO)Cl]Cl?CHCl3 (1) and [Pd2(u-Cl)2(DTBTA)2]Cl2 (2) have been synthesized and structurally characterized by elemental analysis, IR, 1H and 13C NMR spectroscopy, MS spectrometry and the content of platinum and palladium was determined using a flame atomic spectrometer. Two different coordination modes of 1 and 2 complexes were found; in both complexes, the coordination of Pt(II) and Pd(II) ions involves the N(3) atoms of the ligand but the binuclear complex 2, is a cis chloro-bridged palladium complex. Evaluation of their in vitro antitumor activity against two human tumor cell lines human breast cancer (MCF-7) and hepatocellular carcinoma (HepG2); and their antimicrobial activity against Escherichia coli and Kokuria rhizophila was performed. Only complex 1 showed a dose- and time dependent cytotoxic activity against the two tumor cell lines, associated to apoptosis and accumulation of treated cells in G0/G1 phase of cell cycle, while both 1 and 2 exhibited antimicrobial activity with complex 1 much more potent. The study on intracellular uptake in both MCF-7 and HepG2 cell lines revealed that only platinum of complex 1 is present inside the cells, suggesting a different mode of action of the two compounds. This was also in agreement with the results obtained for the antitumor and antibacterial activity. PMID- 28336409 TI - Development and crystallographic evaluation of histone H3 peptide with N-terminal serine substitution as a potent inhibitor of lysine-specific demethylase 1. AB - Lysine-specific demethylase 1 (LSD1/KDM1A) is a flavoenzyme demethylase, which removes mono- and dimethyl groups from histone H3 Lys4 (H3K4) or Lys9 (H3K9) in complexes with several nuclear proteins. Since LSD1 is implicated in the tumorigenesis and progression of various cancers, LSD1-specific inhibitors are considered as potential anti-cancer agents. A modified H3 peptide with substitution of Lys4 to Met [H3K4M] is already known to be a potent competitive inhibitor of LSD1. In this study, we synthesized a series of H3K4M peptide derivatives and evaluated their LSD1-inhibitory activities in vitro. We found that substitutions of the N-terminal amino acid with amino acids having a larger side chain were generally not tolerated, but substitution of Ala1 to Ser unexpectedly resulted in more potent inhibitory activity toward LSD1. X-ray crystallographic analysis of H3K4M derivatives bound to the LSD1.CoREST complex revealed the presence of additional hydrogen bonding between the N-terminal Ser residue of the H3 peptide derivative and LSD1. The present structural and biochemical findings will be helpful for obtaining more potent peptidic inhibitors of LSD1. PMID- 28336410 TI - The spatial-temporal interaction in the LTP induction between layer IV to layer II/III and layer II/III to layer II/III connections in rats' visual cortex during the development. AB - During the early developmental period, long-term potentiation (LTP) can be induced in both vertical and horizontal connections in the rat visual cortex. However, the temporal difference in LTP change between the two pathways during animal development remains unclear. In this study, LTP in vertical (from layer IV to layer II/III) and horizontal (from layer II/III to layer II/III) synaptic connections were recorded in brain slices from the same rats, and the developmental changes of LTP in both directions were compared within the animals' eye-opening period. The results showed that the LTP amplitudes declined to unobservable levels on P16 in the horizontal connections and on P20 in the vertical synaptic connections. Meanwhile, V-LTP (LTP induced in the vertical direction) was always stronger than H-LTP (LTP induced in the horizontal direction) under the same conditions of pairing stimulus (PS). Next, H-LTP and V LTP were induced from the same neuron in layer II/III to determine the spatiotemporal interactions between layer II/III horizontal inputs and ascending synaptic inputs during the maturation of rat visual cortex. The data show that the weak PS, which failed to induce H-LTP alone, was able to induce H-LTP effectively while V-LTP was performed on P10. Our results suggest that V-LTP can strengthen H-LTP induction in the visual cortex during the early developmental period. In contrast, the regulatory effect of H-LTP on V-LTP was much weaker. PMID- 28336411 TI - Exogenous hydrogen sulfide eliminates spatial memory retrieval impairment and hippocampal CA1 LTD enhancement caused by acute stress via promoting glutamate uptake. AB - Acute stress impairs the hippocampus-dependent spatial memory retrieval, and its synaptic mechanisms are associated with hippocampal CA1 long-term depression (LTD) enhancement in the adult rats. Endogenous hydrogen sulfide (H2S) is recognized as a novel gasotransmitter and has the neural protective roles. However, very little attention has been paid to understanding the effects of H2S on spatial memory retrieval impairment. We observed the protective effects of NaHS (a donor of H2S) against spatial memory retrieval impairment caused by acute stress and its synaptic mechanisms. Our results showed that NaHS abolished spatial memory retrieval impairment and hippocampal CA1 LTD enhancement caused by acute stress, but not by glutamate transporter inhibitor l-trans-pyrrolidine-2,4 dicarboxylic (tPDC), indicating that the activation of glutamate transporters is necessary for exogenous H2S to exert its roles. Moreover, NaHS restored the decreased glutamate uptake in the hippocampal CA1 synaptosomal fraction caused by acute stress. Dithiothreitol (DTT, a disulfide reducing agent) abolished a decrease in the glutamate uptake caused by acute stress, and NaHS eradicated the decreased glutamate uptake caused by 5,5'-dithio-bis(2-nitrobenzoic)acid (DTNB, a thiol oxidizing agent), collectively, revealing that exogenous H2S increases glutamate uptake by reducing disulfide bonds of the glutamate transporters. Additionally, NaHS inhibited the increased expression level of phosphorylated c Jun-N-terminal kinase (JNK) in the hippocampal CA1 region caused by acute stress. The JNK inhibitor SP600125 eliminated spatial memory retrieval impairment, hippocampal CA1 LTD enhancement and the decreased glutamate uptake caused by acute stress, indicating that exogenous H2S exerts these roles by inhibiting the activation of JNK signaling pathway. PMID- 28336412 TI - A pilot, prospective, randomized trial of video versus direct laryngoscopy for paramedic endotracheal intubation. AB - BACKGROUND: Prehospital intubation poses several unique challenges. Video assisted laryngoscopy has been shown to help increase intubation success in the hospital setting; however, little prospective data have examined video assisted laryngoscopy in traditional ground ambulance agencies. METHODS: We performed a randomized, cross-over, non-blinded trial in ground ambulances comparing first attempt success and overall intubation success between video assisted laryngoscopy using the King Video Laryngoscope (KVL) and direct laryngoscopy (DL). We collected patient and provider demographics along with intubation details. Success rates were compared on a per-protocol and an intention-to-treat analysis. RESULTS: Over 34 months, a total of 82 intubations were performed with 42 DL and 40 KVL based on the intention-to-treat analysis. First attempt success (28/42, 66.7% vs 25/40, 62.5%, p=0.69) and overall success (34/42, 81% vs 29/40, 72.5%, p=0.37) were similar between DL and KVL. Cormack-Lehane view and percentage of glottic opening were similar between devices. These results were consistent in the per-protocol analysis. CONCLUSIONS: In our study utilizing two ground EMS agencies, video assisted laryngoscopy with the KVL had similar first attempt success rates to direct laryngoscopy. PMID- 28336413 TI - Stent thrombosis in patients undergoing coronary stenting after return of spontaneous circulation. Does the choice of antiplatelet drug matter? PMID- 28336414 TI - CCR6+ Th cells in the cerebrospinal fluid of persons with multiple sclerosis are dominated by pathogenic non-classic Th1 cells and GM-CSF-only-secreting Th cells. AB - Considerable attention has been given to CCR6+ IL-17-secreting CD4+ T cells (Th17) in the pathology of a number of autoimmune diseases including multiple sclerosis (MS). However, other Th subsets also play important pathogenic roles, including those that secrete IFNgamma and GM-CSF. CCR6 expression by Th17 cells allows their migration across the choroid plexus into the cerebrospinal fluid (CSF), where they are involved in the early phase of experimental autoimmune encephalomyelitis (EAE), and in MS these cells are elevated in the CSF during relapses and contain high frequencies of autoreactive cells. However, the relatively low frequency of Th17 cells suggests they cannot by themselves account for the high percentage of CCR6+ cells in MS CSF. Here we identify the dominant CCR6+ T cell subsets in both the blood and CSF as non-classic Th1 cells, including many that secrete GM-CSF, a key encephalitogenic cytokine. In addition, we show that Th cells secreting GM-CSF but not IFNgamma or IL-17, a subset termed GM-CSF-only-secreting Th cells, also accumulate in the CSF. Importantly, in MS the proportion of IFNgamma- and GM-CSF-secreting T cells expressing CCR6 was significantly enriched in the CSF, and was elevated in MS, suggesting these cells play a pathogenic role in this disease. PMID- 28336415 TI - sNCAM as a specific marker of peripheral demyelination. AB - Adhesion molecules are involved in nerve growth, synaptic plasticity and myelin formation and maintenance process. Neural cell adhesion molecule (CD56 or NCAM) seems to play a crucial role in all the above-mentioned events. Having found poly sialylated NCAM increased re-expression on demyelinated axons within multiple sclerosis plaques we assessed soluble NCAM (sNCAM) in sera of patients with various types of peripheral nerve affections - demyelinating, axonal "inflammatory", axonal metabolic polyneuropathies and healthy controls. These data were compared with the clinical state using Overall Neuropathy Limitations Scale (ONLS) and nerve conduction studies. We found significantly increased sNCAM concentration in demyelinating polyneuropathies in comparison to axonal group and healthy controls as well as significantly increased sNCAM level in axonal group in comparison to healthy subjects. We also found high positive correlation between sNCAM and ONLS and strong negative correlation between sNCAM level and the lowest conduction velocity (Vmin) found in a patient. We conclude that sNCAM might be thought as a specific marker of peripheral nerve demyelination and as a sensitive marker of peripheral nerve injuries. PMID- 28336416 TI - Repression of the DCL2 and DCL4 genes in Nicotiana benthamiana plants for the transient expression of recombinant proteins. AB - The production of recombinant proteins in plants has many advantages, including safety and reduced costs. However, this technology still faces several issues, including low levels of production. The repression of RNA silencing seems to be particularly important for improving recombinant protein production because RNA silencing effectively degrades transgene-derived mRNAs in plant cells. Therefore, to overcome this, we used RNA interference technology to develop DCL2- and DCL4 repressed transgenic Nicotiana benthamiana plants (DeltaD2, DeltaD4, and DeltaD2DeltaD4 plants), which had much lower levels of NbDCL2 and/or NbDCL4 mRNAs than wild-type plants. A transient gene expression assay showed that the DeltaD2DeltaD4 plants accumulated larger amounts of green fluorescent protein (GFP) and human acidic fibroblast growth factor (aFGF) than DeltaD2, DeltaD4, and wild-type plants. Furthermore, the levels of GFP and aFGF mRNAs were also higher in DeltaD2DeltaD4 plants than in DeltaD2, DeltaD4, and wild-type plants. These findings demonstrate that DeltaD2DeltaD4 plants express larger amounts of recombinant proteins than wild-type plants, and so would be useful for recombinant protein production. PMID- 28336417 TI - Demonstrating the value and importance of combining DNA barcodes and discriminant morphological characters for polystome taxonomy (Platyhelminthes, Monogenea). AB - Polystomes are monogenean parasites that infest mainly semi aquatic vertebrates, such as amphibians and chelonians. Owing to the lack of discriminative morphological characters and because polystomes are considered to be strictly host- and site-specific, host identity is often used as an additional character for parasite identification. Recent genetic studies, however, showed that polystomes infecting freshwater turtles in outdoor turtle enclosures and natural environments, were not strictly host-specific. Therefore, we proposed a new procedure for turtle polystome taxonomy based on the combination of Cytochrome c Oxydase I sequences and two discriminant morphological characters, namely the number of genital spines and the testis shape. We tested the validity of this procedure with Polystomoides oris, which was collected from the pharyngeal cavity of the American painted turtle Chrysemys picta and two undescribed species, both collected from the pharyngeal cavity of the American slider Trachemys scripta and two other European turtles, namely the European pond turtle Emys orbicularis and the Mediterranean turtle Mauremys leprosa. A Principal Component Analysis based on both morphological characters allowed the separation of all specimens in three morphological groups, which matched well with the molecular data. As a result, we describe two new polystome species, i.e., Polystomoides soredensis n. sp. and Polystomoides scriptanus n. sp. PMID- 28336418 TI - Treatment of cerebrospinal fluid leak after spine surgery. AB - Owing to the complexity of spinal surgery, there is a great prevalence of dural tear causing cerebrospinal fluid (CSF) leakage. Many studies focused on suture repair for dural tear to stop CSF leak. Now some new treatment strategies have shown a promising effect that is listed as follows: 1) creating watertight dural closure to stop CSF leak with the help of dural substitute material; and 2) retarding CSF leak by changing pressure difference, including reducing the subarachnoid fluid pressure, increasing the epidural space pressure and both. In fact several methods mentioned above are usually combined to treat CSF leak. However, no update review summarized the relevant studies implemented in recent years. In this review, the authors would compare the effects of different dural closure techniques, and introduce the latest treatment methods and mechanisms. PMID- 28336419 TI - Scarf-related injuries at a major trauma center in northern India. AB - PURPOSE: Scarf is a long loose piece of cloth worn around the neck and shoulder. Despite cultural association of this apparel, it is part of numerous injury episodes of varying enormity. Entanglement of loose scarf in spoke wheels of bike, tricycle, belt driven machines like sugarcane juice machine, thresher, grinding machines, etc is observed both in social and industrial milieu. This study aims to investigate the scarf-related injuries at a major trauma center in northern India. METHODS: From June 2013 to May 2015, a hospital-based prospective observational study was done in patients who presented to a level 1 trauma center in northern India with the mode of injury involving scarf around the neck. Demographic profile, mode of trauma, contributing factors, injury pattern, and the early management as well as early complications were recorded. RESULTS: There were 76 injuries directly related from scarf with the mean age of patients being 32.4 years. The most common primary factor involved was rotating wheel of motorbike/tricycle (46.1%), followed by belt driven machines (28.9%). The spectrum of injuries was diverse, including minor abrasions or lacerations (53.9%), large lacerations (15.8%), fractures and spine trauma (18.4%), mangled extremity and amputations (7.9%) and death (3.9%). More severe injury patterns were noted with belt driven machines. CONCLUSION: Scarf-related injuries constitute a sizable proportion of trauma, with varying degrees of severity. Devastating consequences in significant proportion of cases dictate the call for a prevention plan comprising both educational and legislative measures. Urgent preventive measures targeting scarf-related injuries will help reduce mortality and morbidity. PMID- 28336421 TI - Percutaneous planter fasciitis release under local anesthesia: A prospective study. AB - PURPOSE: Plantar fasciitis is the most common cause of pain on the bottom of the heel. It occurs when the strong band of the tissue supporting the arch of foot becomes irritated and inflamed. The majority of patients can be treated conservatively but some resistant cases need surgery eventually. This study aims to evaluate the outcome results of percutaneous planter fascia release under local anesthesia for chronic planter fasciitis. METHODS: This prospective study was conducted in the Department of Orthopaedic Surgery in the School of Medical Science and Research, Sharda University, India from December 2010 to December 2013. Totally 78 patients with planter fasciitis for more than 6-12 months were recruited from the outpatient department. All patients were operated on under local anesthesia and followed up for a year. RESULTS: The clinical results were evaluated in terms of pain, activity level and patient satisfaction. Pain relief was achieved averagely at eight weeks after surgery. The results were excellent in 88.46% (69/78) patients and good in 6.41% (9/78) patients. Neither complications of lateral column instability, sinus tarsitis and metatarsalgia nor wound-related complications were encountered. On subjective evaluations, 88.46% (69/78) patients reported full satisfaction and 6.41% (9/78) reported partial satisfaction after treatment. CONCLUSION: Percutaneous planter fasciitis release under local anesthesia is a minimally invasive procedure that can be performed in the outpatient setting. It is easy, quick, effective and moreover with few complications. PMID- 28336420 TI - Injury prevention, performance and return to sport: How can science help? PMID- 28336422 TI - Nomenclatural stability does not justify recognition of paraphyletic taxa: A response to Scherz et al. (2016). AB - Peloso et al. (2015: PELOSO) published a comprehensive phylogenetic study of the frog family Microhylidae, which resulted in the discovery that several taxa were not monophyletic. To remedy this, a series of nomenclatural changes were proposed (several generic synonymies and two new subfamilies named). A recent study published in this journal by Scherz et al. (2016: SCHERZ), provided a novel phylogeny for the Malagasy subfamily Cophylinae. SCHERZ dispute the analyses and taxonomic conclusions of PELOSO. Their study is, however, based on substantial reduction of data from the PELOSO study, limited addition of new data, and different analytical methods. In spite of the fact that their own results are consistent with the taxonomy of PELOSO, SCHERZ reject that conservative taxonomy and suggest the revalidation of Platypelis (from the synonymy of Cophyla), the revalidation of Stumpffia (from the synonymies of Rhombophryne), and the creation of at least two new genera (only one named therein). In doing so, SCHERZ accept the recognition of likely paraphyletic taxa, with Stumpffia paraphyletic in their parsimony analysis. Herein, we provide a response to several points raised in SCHERZ: (1) we discuss issues with their interpretation (and selective use) of available phylogenetic and phenotypic evidence; (2) and provide a new phylogenetic analysis of all the data in PELOSO and SCHERZ combined. In the new analysis Stumpffia is paraphyletic with respect to Rhombophryne, whereas Cophyla and Platypelis are both monophyletic and sister taxa. We provide a case for the use of the taxonomy suggested in PELOSO. PMID- 28336423 TI - Comparative analysis of complete genome sequences of European subtype tick-borne encephalitis virus strains isolated from Ixodes persulcatus ticks, long-tailed ground squirrel (Spermophilus undulatus), and human blood in the Asian part of Russia. AB - Tick-borne encephalitis virus (TBEV) is divided into three subtypes: European (TBEV-Eu), Siberian (TBEV-Sib), and Far Eastern (TBEV-FE) subtypes. The geographical range of TBEV-Eu dominates in Europe, but this subtype is present focally across the whole non-tropical forested Eurasian belt, through Russia to South Korea. However, the TBEV-Eu strains isolated outside Europe remain poorly characterized. In this study, full-genome sequences of eight TBEV-Eu isolates were determined. These strains were isolated from Ixodes persulcatus ticks, long tailed ground squirrel (Spermophilus undulatus), and human blood in the natural foci of Western and Eastern Siberia, Russia. A phylogenetic analysis of all available TBEV-Eu genomic sequences revealed that strains from Siberia were closely related to other strains from Europe and South Korea. The closest relation was identified between the Siberian strains and strains from Zmeinogorsk (Western Siberia, Russia) and strain Absettarov (Karelia, Russia), and were most divergent from strains from the Czech Republic and Norway. TBEV-Eu strains isolated in Eastern Siberia were more closely related phylogenetically to strains from South Korea, but strains from Western Siberia grouped together with the strains from Europe, suggesting two genetic TBEV-Eu lineages present in Siberia. PMID- 28336425 TI - Characterizing object- and position-dependent response profiles to uni- and bilateral stimulus configurations in human higher visual cortex: a 7T fMRI study. AB - Visual scenes are initially processed via segregated neural pathways dedicated to either of the two visual hemifields. Although higher-order visual areas are generally believed to utilize invariant object representations (abstracted away from features such as stimulus position), recent findings suggest they retain more spatial information than previously thought. Here, we assessed the nature of such higher-order object representations in human cortex using high-resolution fMRI at 7T, supported by corroborative 3T data. We show that multi-voxel activation patterns in both the contra- and ipsilateral hemisphere can be exploited to successfully classify the object category of unilaterally presented stimuli. Moreover, robustly identified rank order-based response profiles demonstrated a strong contralateral bias which frequently outweighed object category preferences. Finally, we contrasted different combinatorial operations to predict the responses during bilateral stimulation conditions based on responses to their constituent unilateral elements. Results favored a max operation predominantly reflecting the contralateral stimuli. The current findings extend previous work by showing that configuration-dependent modulations in higher-order visual cortex responses as observed in single unit activity have a counterpart in human neural population coding. They furthermore corroborate the emerging view that position coding is a fundamental functional characteristic of ventral visual stream processing. PMID- 28336426 TI - SAR Simulations & Safety. AB - At ultra-high fields, the assessment of radiofrequency (RF) safety presents several new challenges compared to low-field systems. Multi-channel RF transmit coils in combination with parallel transmit techniques produce time-dependent and spatially varying power loss densities in the tissue. Further, in ultra-high field systems, localized field effects can be more pronounced due to a transition from the quasi stationary to the electromagnetic field regime. Consequently, local information on the RF field is required for reliable RF safety assessment as well as for monitoring of RF exposure during MR examinations. Numerical RF and thermal simulations for realistic exposure scenarios with anatomical body models are currently the only practical way to obtain the requisite local information on magnetic and electric field distributions as well as tissue temperature. In this article, safety regulations and the fundamental characteristics of RF field distributions in ultra-high-field systems are reviewed. Numerical methods for computation of RF fields as well as typical requirements for the analysis of realistic multi-channel RF exposure scenarios including anatomical body models are highlighted. In recent years, computation of the local tissue temperature has become of increasing interest, since a more accurate safety assessment is expected because temperature is directly related to tissue damage. Regarding thermal simulation, bio-heat transfer models and approaches for taking into account the physiological response of the human body to RF exposure are discussed. In addition, suitable methods are presented to validate calculated RF and thermal results with measurements. Finally, the concept of generalized simulation-based specific absorption rate (SAR) matrix models is discussed. These models can be incorporated into local SAR monitoring in multi-channel MR systems and allow the design of RF pulses under constraints for local SAR. PMID- 28336428 TI - Emergence of norovirus GII.2 and its novel recombination during the gastroenteritis outbreak in Japanese children in mid-2016. AB - In mid-2016, norovirus GII.2 emerged as a major cause of gastroenteritis outbreak in Japan with overall detection rate of 56.3% of norovirus cases. The differences in ORF1 and ORF2 of some norovirus GII were observed. Inter-subtype recombinants GII.Pe/GII.2, GII.P16/GII.2 and GII.P17/GII.2 were detected. Three amino acid substitutions were noted at P2 antigenic site of GII.P16/GII.2 recombinants. Furthermore, this study revealed that the current immunochromatographic kit available in Japan could be used effectively for the detection of recent GII.2 genotype. PMID- 28336427 TI - High resolution anatomical and quantitative MRI of the entire human occipital lobe ex vivo at 9.4T. AB - Several magnetic resonance imaging (MRI) contrasts are sensitive to myelin content in gray matter in vivo which has ignited ambitions of MRI-based in vivo cortical histology. Ultra-high field (UHF) MRI, at fields of 7T and beyond, is crucial to provide the resolution and contrast needed to sample contrasts over the depth of the cortex and get closer to layer resolved imaging. Ex vivo MRI of human post mortem samples is an important stepping stone to investigate MRI contrast in the cortex, validate it against histology techniques applied in situ to the same tissue, and investigate the resolutions needed to translate ex vivo findings to in vivo UHF MRI. Here, we investigate key technology to extend such UHF studies to large human brain samples while maintaining high resolution, which allows investigation of the layered architecture of several cortical areas over their entire 3D extent and their complete borders where architecture changes. A 16 channel cylindrical phased array radiofrequency (RF) receive coil was constructed to image a large post mortem occipital lobe sample (~80*80*80mm3) in a wide-bore 9.4T human scanner with the aim of achieving high-resolution anatomical and quantitative MR images. Compared with a human head coil at 9.4T, the maximum Signal-to-Noise ratio (SNR) was increased by a factor of about five in the peripheral cortex. Although the transmit profile with a circularly polarized transmit mode at 9.4T is relatively inhomogeneous over the large sample, this challenge was successfully resolved with parallel transmit using the kT-points method. Using this setup, we achieved 60MUm anatomical images for the entire occipital lobe showing increased spatial definition of cortical details compared to lower resolutions. In addition, we were able to achieve sufficient control over SNR, B0 and B1 homogeneity and multi-contrast sampling to perform quantitative T2* mapping over the same volume at 200MUm. Markov Chain Monte Carlo sampling provided maximum posterior estimates of quantitative T2* and their uncertainty, allowing delineation of the stria of Gennari over the entire length and width of the calcarine sulcus. We discuss how custom RF receive coil arrays built to specific large post mortem sample sizes can provide a platform for UHF cortical layer-specific quantitative MRI over large fields of view. PMID- 28336429 TI - Insight into stereochemistry of a new IMP allelic variant (IMP-55) metallo-beta lactamase identified in a clinical strain of Acinetobacter baumannii. AB - Metallo-beta-lactamases (MBLs) such as IMPs are broad-spectrum beta-lactamases that inactivate virtually all beta-lactam antibiotics including carbapenems. In this study, we investigated the hydrolytic activity, phylogenetic relationship, three dimensional (3D) structure including zinc binding motif of a new IMP variant (IMP-55) identified in a clinical strain of Acinetobacter baumannii (AB). AB strain 56 was isolated from an adult ICU of a teaching hospital in Kerman, Iran. It exhibited MIC 32MUg/ml to imipenem and showed MBL activity. Hydrolytic property of the MBL enzyme was measured phenotypically. Presence of blaIMP gene encoded by class 1 integrons was detected by PCR-sequencing. Phylogenetic tree of IMP protein was constructed using the Unweighted Pair Group Method with Arithmetic Mean (UPGMA) and 3D model including zinc binding motif was predicted by bioinformatics softwares. Analysis of IMP sequence led to the identification of a novel IMP-type designated as IMP-55 (GenBank: KU299753.1; UniprotKB: A0A0S2MTX2). Impact in term of hydrolytic activity compared to the closest variants suggested efficient imipenem hydrolysis by this enzyme. Evolutionary distance matrix assessment indicated that IMP-55 protein is not closely related to other A. baumannii IMPs, however, shared 98% homology with Escherichia coli IMP-30 (UniprotKB: A0A0C5PJR0) and Pseudomonas aeruginosa IMP-1 (UniprotKB: Q19KT1). It consisted of five alpha-helices, ten beta-sheets and six loops. A monovalent zinc ion attached to core of enzyme via His95, His97, His157 and Cys176. Multiple amino acid sequence alignments and mutational trajectory with reported IMPs showed 4 amino acid substitutions at positions 12(Phe->Ile), 31(Asp >Glu), 172(Leu->Phe) and 185(Asn->Lys). We suggest that the pleiotropic effect of mutations due to frequent administration of imipenem is responsible for emergence of new IMP variant in our hospitals. PMID- 28336430 TI - Female Physicians Are Underrepresented in Recognition Awards from the American Academy of Physical Medicine and Rehabilitation. AB - BACKGROUND: Medical specialty societies are important resources for physicians in advancing their careers. There is a gap in the literature regarding gender disparities within these societies. This study assesses one area where disparities may exist: recognition awards. OBJECTIVE: To determine whether female physicians are underrepresented among recognition award recipients by the American Academy of Physical Medicine and Rehabilitation (AAPM&R). DESIGN: Surveillance study. SETTING AND METHODS: A published online list of national award recipients from the AAPM&R was analyzed. Forty-eight years of data were included, as the list contained all major recognition award recipients from 1968 to 2015. All awards that were given exclusively to physicians were included. There were eight award categories listed online; seven met this criterion, with a total of 264 individual awards presented. One award category was excluded because it focused on distinguished public service and included both physician and nonphysician (eg, public official) recipients. Awards that were not published online were also excluded. MAIN OUTCOME MEASURES: Total awards given to female versus male physicians from 1968 to 2015, with awards given over the past decade (2006-2015) assessed independently. Lectureships were also analyzed as a set. For awards given to groups of physician recipients, analysis included gender composition of the group (eg, male only versus female only versus mixed-gender physician groups). To assess the proportion of female versus male physiatrists over time, physician gender and specialty data from 3 sources were used: the American Medical Association (AMA), the Association of American Medical Colleges (AAMC), and the AAPM&R. RESULTS: Over the past 48 years, the AAPM&R presented 264 recognition awards to physicians. Award recipients were overwhelmingly male (n = 222; 84.1%). Females received 15.9% (n = 42) of the total awards, although there was an upward trend in female physician recipients to 26.8% (n = 26) from 2006 to 2015. Lectureships were given to 8 female physicians (n = 8 of 77, 10.4%). These results were lower than the proportion of female physicians in the field of physiatry (35% in 2013). Female physicians were more likely to receive awards if they were part of a group and less likely to be recognized if the award was given to only 1 recipient each year or involved a lectureship with a speaking opportunity at a national meeting. CONCLUSIONS: To our knowledge, this is the first study in medicine to assess whether female physicians are underrepresented among recipients of recognition awards presented by a national medical society. For nearly half a century, female physicians have been underrepresented in awards presented by the AAPM&R. Although it is encouraging that the proportion of female physicians receiving awards is increasing, further research is needed to understand why underrepresentation remains. LEVEL OF EVIDENCE: Not applicable. PMID- 28336424 TI - The impact of oxidative stress and inflammation on RPE degeneration in non neovascular AMD. AB - The retinal pigment epithelium (RPE) is a highly specialized, unique epithelial cell that interacts with photoreceptors on its apical side and with Bruch's membrane and the choriocapillaris on its basal side. Due to vital functions that keep photoreceptors healthy, the RPE is essential for maintaining vision. With aging and the accumulated effects of environmental stresses, the RPE can become dysfunctional and die. This degeneration plays a central role in age-related macular degeneration (AMD) pathobiology, the leading cause of blindness among the elderly in western societies. Oxidative stress and inflammation have both physiological and potentially pathological roles in RPE degeneration. Given the central role of the RPE, this review will focus on the impact of oxidative stress and inflammation on the RPE with AMD pathobiology. Physiological sources of oxidative stress as well as unique sources from photo-oxidative stress, the phagocytosis of photoreceptor outer segments, and modifiable factors such as cigarette smoking and high fat diet ingestion that can convert oxidative stress into a pathological role, and the negative impact of impairing the cytoprotective roles of mitochondrial dynamics and the Nrf2 signaling system on RPE health in AMD will be discussed. Likewise, the response by the innate immune system to an inciting trigger, and the potential role of local RPE production of inflammation, as well as a potential role for damage by inflammation with chronicity if the inciting trigger is not neutralized, will be debated. PMID- 28336431 TI - Calcium-sensing receptor antagonist NPS2390 attenuates neuronal apoptosis though intrinsic pathway following traumatic brain injury in rats. AB - Traumatic brain injury (TBI) initiates a complex cascade of neurochemical and signaling changes that leads to neuronal apoptosis, which contributes to poor outcomes for patients with TBI. Previous study indicates that calcium-sensing receptor (CaSR) activation contributes to neuron death in focal cerebral ischemia reperfusion mice, however, its role in neuronal apoptosis after TBI is not well established. Using a controlled cortical impact model in rats, the present study was designed to determine the effect of CaSR inhibitor NPS2390 upon neuronal apoptosis after TBI. Rats were randomly distributed into three groups undergoing the sham surgery or TBI procedure, and NPS2390 (1.5 mg/kg) was infused subcutaneously at 30 min and 120 min after TBI. All rats were sacrificed at 24 h after TBI. Our data indicated that NPS2390 significantly reduced the brain edema and improved the neurological function after TBI. In addition, NPS2390 decreased caspase-3 levels and the number of apoptotic neurons. Furthermore, NPS2390 up regulated anti-apoptotic protein Bcl-2 expression and down-regulated pro apoptotic protein Bax, and reduced subsequent release of cytochrome c into the cytosol. In summary, this study indicated that inhibition of CaSR by NPS2390 attenuates neuronal apoptosis after TBI, in part, through modulating intrinsic apoptotic pathway. PMID- 28336432 TI - Behavioral abnormalities and reduced norepinephrine in EP4 receptor-associated protein (EPRAP)-deficient mice. AB - EP4 receptor-associated protein (EPRAP) is a newly identified molecule that regulates macrophage activation. We recently demonstrated the presence of EPRAP in the mice brain; however, little is known about the function of EPRAP in this tissue. Therefore, we investigated the role of EPRAP in behavior and emotion using behavioral analysis in mice. In this study, we subjected EPRAP-deficient (KO) mice and wild-type C57BL/6 (WT) mice to a battery of behavioral tests. EPRAP KO mice tended to have shorter latencies to fall in the wire hang test, but had normal neuromuscular strength. EPRAP-KO mice exhibited elevated startle responses and reduced pre-pulse inhibition. Compared with WT mice, EPRAP-KO mice increased depression-like behavior in the forced swim test. These abnormal behaviors partially mimic symptoms of depression, attention deficit hyperactivity disorder (ADHD) and schizophrenia. Methylphenidate administration increased locomotor activity less in EPRAP-KO mice than in WT mice. Finally, levels of norepinephrine were reduced in the EPRAP-KO mouse brain. These behavioral abnormalities in EPRAP KO mice may result from the dysfunction of monoamines, in particular, norepinephrine. Our results suggest that EPRAP participates in the pathogenesis of various behavioral disorders. PMID- 28336433 TI - Early-stage reduction of the dendritic complexity in basolateral amygdala of a transgenic mouse model of Alzheimer's disease. AB - Alzheimer's disease is a representative age-related neurodegenerative disease that could result in loss of memory and cognitive deficiency. However, the precise onset time of Alzheimer's disease affecting neuronal circuits and the mechanisms underlying the changes are not clearly known. To address the neuroanatomical changes during the early pathologic developing process, we acquired the neuronal morphological characterization of AD in APP/PS1 double transgenic mice using the Micro-Optical Sectioning Tomography system. We reconstructed the neurons in 3D datasets with a resolution of 0.32 * 0.32 * 1 MUm and used the Sholl method to analyze the anatomical characterization of the dendritic branches. The results showed that, similar to the progressive change in amyloid plaques, the number of dendritic branches were significantly decreased in 9-month-old mice. In addition, a distinct reduction of dendritic complexity occurred in third and fourth-order dendritic branches of 9-month-old mice, while no significant changes were identified in these parameters in 6-month-old mice. At the branch-level, the density distribution of dendritic arbors in the radial direction decreased in the range of 40-90 MUm from the neuron soma in 6-month-old mice. These changes in the dendritic complexity suggest that these reductions contribute to the progressive cognitive impairment seen in APP/PS1 mice. This work may yield insights into the early changes in dendritic abnormality and its relevance to dysfunctional mechanisms of learning, memory and emotion in Alzheimer's disease. PMID- 28336434 TI - Vav1 expression is increased in esophageal squamous cell carcinoma and indicates poor prognosis. AB - Recently, Vav1 has been suggested to play an essential role in the progression of human cancers. However, the correlation between Vav1 expression and prognosis of esophageal squamous cell carcinoma (ESCC) is still unknown. The aim of this study was to investigate Vav1 expression and its prognostic value in ESCC. The expression of Vav1 was detected by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting in ESCC tissues and matched nontumorous tissues. Immunohistochemistry (IHC) was carried out to detect Vav1 expression in paraffin samples from 112 primary ESCC patients. Survival analysis was performed using Kaplan-Meier method. Univariate and multivariate Cox regression analyses were performed to evaluate the correlation of Vav1 expression with prognosis of ESCC patients. The expression levels of Vav1 mRNA and protein in ESCC tissues were both significantly higher than those in adjacent nontumorous tissues. High Vav1 expression was significantly correlated with larger tumor size (P = 0.015), depth of tumor invasion (P = 0.023), lymph node metastasis (P = 0.008) and TNM stage (P < 0.001). The rate of overall survival (OS) was significantly lower in patients with high Vav1 expression than those with low Vav1 expression (P = 0.014). Multivariate Cox analysis indicated that Vav1 expression is an independent prognostic factor for OS (HR = 1.660, 95%CI = 1.058 2.607, P = 0.028). In summary, our findings demonstrate that Vav1 may be a candidate molecular prognostic marker for patients with ESCC. PMID- 28336435 TI - In vitro model of cerebral ischemia by using brain microvascular endothelial cells derived from human induced pluripotent stem cells. AB - Brain-derived microvascular endothelial cells (BMECs), which play a central role in blood brain barrier (BBB), can be used for the evaluation of drug transport into the brain. Although human BMEC cell lines have already been reported, they lack original properties such as barrier integrity. Pluripotent stem cells (PSCs) can be used for various applications such as regenerative therapy, drug screening, and pathological study. In the recent study, an induction method of BMECs from PSCs has been established, making it possible to more precisely study the in vitro human BBB function. Here, using induced pluripotent stem (iPS) cell derived BMECs, we examined the effects of oxygen-glucose deprivation (OGD) and OGD/reoxygenation (OGD/R) on BBB permeability. OGD disrupted the barrier function, and the dysfunction was rapidly restored by re-supply of the oxygen and glucose. Interestingly, TNF-alpha, which is known to be secreted from astrocytes and microglia in the cerebral ischemia, prevented the restoration of OGD-induced barrier dysfunction in an apoptosis-independent manner. Thus, we could establish the in vitro BBB disease model that mimics the cerebral ischemia by using iPS cell-derived BMECs. PMID- 28336436 TI - Induction of dopamine D1 and D5 receptors in R28 cells by light exposures. AB - Dopamine is known to play an important role in the pathophysiological process of myopia development relevant to the ambient lighting, but it is still poorly understood about how lighting regulates dopamine and its interaction with dopamine receptors to mediate the pathogenic signal transduction leading to alterations of ocular globe and the pathogenesis of myopia. Many studies have highlighted changes of ocular dopamine amount in response to different lighting conditions, but little attention has been paid to the dopamine receptors during these processes. Here we examined the effects of different lighting exposures on the expression of dopamine receptors in rat R28 retinal precursor cells. R28 cells normally grown in dark were exposed to a low (10 lux) or high (500 lux) intensity of a source of LED white light (5000 K-6000 K) for 12 h and total RNA was isolated either immediately or after certain time continuous growing in dark. Both conventional and real-time RT-PCR were performed to determine the expression of all five different dopamine receptors in cells after treatments. While the transcripts of dopamine D2, D3, and D4 receptors were not detected in the total RNA preparations of all the cells, those of D1 and D5 receptors (DRD1 and DRD5) were induced by lighting in contrast to the dark control. Elevated levels of DRD1 and DRD5 mRNA returned back close to the original levels once the cells were maintained in dark after light exposures. Immunofluorescence microscopy using a specific antibody confirmed an increase in the immunoreactivity of DRD1 in the cells exposed to 500 lux lighting versus dark control. Notably, treatments of R28 cells with nanomolar dosages of dopamine (0-500 nM) directly downregulated expression of both DRD1 and DRD5, whereas haloperidol (0-50 nM), a DRD2 antagonist, significantly induced expression of DRD1. These results suggest that dopamine receptors in the retinal cells might actively respond to the environmental lighting to act as an important player in the activation of the dopaminergic system in the ocular structures relevant to the lighting-induced pathogenic development of myopia. PMID- 28336437 TI - Overexpression of TACC3 is correlated with tumor aggressiveness and poor prognosis in prostate cancer. AB - Transforming acidic coiled-coil (TACC3), a member of the TACC family, has been shown to be deregulated in various cancers and involved in tumor progression. However, its biological role and molecular mechanism in prostate cancer (PCa) have not been elucidated. Herein, we reported that TACC3 was markedly upregulated in metastatic PCa. The upregulation of TACC3 was significantly associated with the metastasis status, tumor stage, total prostate-specific antigen (PSA) level, and Gleason score in patients with PCa. Moreover, a Kaplan-Meier survival analysis showed that patients with PCa who had high TACC3 expression experienced shorter disease-free survival than patients with a low TACC3 expression. In addition, the knockdown of TACC3 dramatically reduced the migratory speed and invasiveness of PCa cells. Furthermore, silencing TACC3 markedly suppressed the Wnt/beta-catenin signaling pathway. Taken together, these findings uncover a supportive role for TACC3 in PCa metastasis, which is mediated by the activation of the Wnt/beta-catenin signaling pathway, suggesting that TACC3 may serve as a prognostic marker in patients with metastatic PCa. PMID- 28336439 TI - Reproductive toxicity provoked by titanium dioxide nanoparticles and the ameliorative role of Tiron in adult male rats. AB - Titanium dioxide nanoparticles (TDN) are widely used in paints, plastics, ceramics, cosmetics, printing ink, rubber and paper. Tiron is a water soluble metal chelator and antioxidant. This study was designed to investigate the reproductive toxicity of TDN in male albino rats and the ameliorative role of Tiron to minimize such toxic effects. Eighty adult male albino rats were assigned into 4 equal groups, group 1: control; group 2: received TDN at 100 mg/kg/day orally for 8 weeks; group 3: received Tiron at 470 mg/kg/day intraperitoneally for 2 weeks (the last 2 weeks of the experimental period); group 4: received both TDN and Tiron by the same previously mentioned dose, route and duration. The results revealed that TDN provoked reproductive toxicity which was proved by the deteriorated spermogram picture, high incidence of micronucleated RBCs, elevated oxidative stress parameters and up regulation of Testin gene. Whereas, Tiron co treatment ameliorated most of these toxic alterations. Our findings highlighted the protective role of tiron against TDN intoxication. PMID- 28336438 TI - KLF15 protects against isoproterenol-induced cardiac hypertrophy via regulation of cell death and inhibition of Akt/mTOR signaling. AB - Increasing evidence indicate that the Kruppel-like factor KLF15, a member of Cys2/His2 zinc-finger DNA-binding proteins, attenuates cardiac hypertrophy. However, the role of KLF15 in cardiovascular system is largely unknown and the exact molecular mechanism of its protective function is not fully elucidated. In the present study, we established a mouse model of cardiac hypertrophy and found that KLF15 expression was down-regulated in hypertrophic hearts. To evaluate the roles of KLF15 in cardiac hypertrophy, we generated transgenic mice overexpressing KLF15 of KLF15 knockdown mice and subsequently induced cardiac hypertrophy. The results indicated that KLF15 overexpression protects mice from ISO-induced cardiac hypertrophy, with reduced ratios of heart weight (HW)/body weight (BW) and cross-sectional area. We also observed that KLF15 overexpression attenuated cardiac fibrosis, inhibited apoptosis and induced autophagy in cardiomyocytes compared with KLF15 knockdown mice. More importantly, we found that the KLF15 overexpression inhibited the Akt/mTOR signaling pathway. Taken together, our findings imply that KLF15 possesses potential anti-hypertrophic and anti-fibrotic functions, possibly via regulation of cell death pathways and the inhibition of Akt/mTOR axis. KLF15 may constitute an efficient candidate drug for the treatment of heart failure and other cardiovascular diseases. PMID- 28336440 TI - Astroglial Ca2+ signaling is generated by the coordination of IP3R and store operated Ca2+ channels. AB - Astrocytes play key roles in the central nervous system and regulate local blood flow and synaptic transmission via intracellular calcium (Ca2+) signaling. Astrocytic Ca2+ signals are generated by multiple pathways: Ca2+ release from the endoplasmic reticulum (ER) via the inositol 1, 4, 5-trisphosphate receptor (IP3R) and Ca2+ influx through various Ca2+ channels on the plasma membrane. However, the Ca2+ channels involved in astrocytic Ca2+ homeostasis or signaling have not been fully characterized. Here, we demonstrate that spontaneous astrocytic Ca2+ transients in cultured hippocampal astrocytes were induced by cooperation between the Ca2+ release from the ER and the Ca2+ influx through store-operated calcium channels (SOCCs) on the plasma membrane. Ca2+ imaging with plasma membrane targeted GCaMP6f revealed that spontaneous astroglial Ca2+ transients were impaired by pharmacological blockade of not only Ca2+ release through IP3Rs, but also Ca2+ influx through SOCCs. Loss of SOCC activity resulted in the depletion of ER Ca2+, suggesting that SOCCs are activated without store depletion in hippocampal astrocytes. Our findings indicate that sustained SOCC activity, together with that of the sarco-endoplasmic reticulum Ca2+-ATPase, contribute to the maintenance of astrocytic Ca2+ store levels, ultimately enabling astrocytic Ca2+ signaling. PMID- 28336442 TI - Total coliform and E. coli in public water systems using undisinfected ground water in the United States. AB - Public water systems (PWSs) in the United States generate total coliform (TC) and Escherichia coli (EC) monitoring data, as required by the Total Coliform Rule (TCR). We analyzed data generated in 2011 by approximately 38,000 small (serving fewer than 4101 individuals) undisinfected public water systems (PWSs). We used statistical modeling to characterize a distribution of TC detection probabilities for each of nine groupings of PWSs based on system type (community, non-transient non-community, and transient non-community) and population served (less than 101, 101-1000 and 1001-4100 people). We found that among PWS types sampled in 2011, on average, undisinfected transient PWSs test positive for TC 4.3% of the time as compared with 3% for undisinfected non-transient PWSs and 2.5% for undisinfected community PWSs. Within each type of PWS, the smaller systems have higher median TC detection than the larger systems. All TC-positive samples were assayed for EC. Among TC-positive samples from small undisinfected PWSs, EC is detected in about 5% of samples, regardless of PWS type or size. We evaluated the upper tail of the TC detection probability distributions and found that significant percentages of some system types have high TC detection probabilities. For example, assuming the systems providing data are nationally-representative, then 5.0% of the ~50,000 small undisinfected transient PWSs in the U.S. have TC detection probabilities of 20% or more. Communities with such high TC detection probabilities may have elevated risk of acute gastrointestinal (AGI) illness - perhaps as great or greater than the attributable risk to drinking water (6-22%) calculated for 14 Wisconsin community PWSs with much lower TC detection probabilities (about 2.3%, Borchardt et al., 2012). PMID- 28336441 TI - Chronic stress-induced dendritic reorganization and abundance of synaptosomal PKA dependent CP-AMPA receptor in the basolateral amygdala in a mouse model of depression. AB - Chronic stress is a precipitating factor for disorders including depression. The basolateral amygdala (BLA) is a critical substrate that interconnects with stress modulated neural networks to generate emotion- and mood-related behaviors. The current study shows that 3 h per day of restraint stress for 14 days caused mice to exhibit long-term depressive behaviors, manifested by disrupted sociality and despair levels, which were rescued by fluoxetine. These behavioral changes corresponded with morphological and molecular changes in BLA neurons, including chronic stress-elicited increases in arborization, dendritic length, and spine density of BLA principal neurons. At the molecular level, calcium-permeable alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (CP-AMPARs) within the synaptosome exhibited an increased GluR1:GluR2 subunit ratio. We also observed increased GluR1 phosphorylation at Ser 845 and enhanced cyclic AMP dependent protein kinase (PKA) activity in the BLA. These molecular changes reverted to the basal state post-treatment with fluoxetine. The expression of synaptophysin (SYP) and postsynaptic density protein 95 (PSD-95) at BLA neuronal synapses was also enhanced by chronic stress, which was reversed post-treatment. Finally, chronic stress-provoked depressive behavior was overcome by local blockage of CP-AMPARs in the BLA via stereotaxic injection (IEM-1460). Chronic stress-elicited depressive behavior may be due to hypertrophy of BLA neuronal dendrites and increased of PKA-dependent CP-AMPAR levels in BLA neurons. Furthermore, fluoxetine can reverse chronic stress-triggered cytoarchitectural and functional changes of BLA neurons. These findings provide insights into depression-linked structural and functional changes in BLA neurons. PMID- 28336443 TI - Predicting Academic Career Placement: Neurosurgery's Quest for the Holy Grail. PMID- 28336444 TI - Tool-Tissue Interaction Forces in Brain Arteriovenous Malformation Surgery. AB - OBJECTIVE: Surgical resection of a brain arteriovenous malformation (AVM) poses a technical challenge because of the fragility and number of small feeding and draining vessels around the nidus. Acquiring knowledge of the optimal force applied to such tissue is important in surgical performance and education. METHODS: A force-sensing bipolar forceps was developed through installation of strain gauge sensors, and force profiles were obtained from 2 AVM surgeries. The force data associated with vessel injury, unsuccessful trial, was compared with that from successful trials. Receiver operating curve analysis was used for determining optimal force threshold and evaluating the discriminative accuracy of measurement. RESULTS: Force data from 519 trials was collected, of which 16 (3.1%) were unsuccessful. The mean and maximum forces in successful trials were 0.23 +/- 0.06 N and 0.35 +/- 0.11 N compared with unsuccessful trials of 0.33 +/- 0.05 N and 0.53 +/- 0.11 N, respectively (P < 0.001). There was a strong association of mean and maximum force peaks with unsuccessful trials as reflected by the area under the curve of 0.91 and 0.87, respectively. Threshold analysis showed that the rate of unsuccessful trials and error forces tended to increase with surgical time. CONCLUSIONS: Excessive force at the tool tip may result in injury to fragile vessels during AVM surgery. A quantifiable metric through force sensing instruments can detect and predict the occurrence of such injury. Such an instrument may be ideal for resident training and evaluation. PMID- 28336446 TI - Ethical Obligations in Attempting to Do Good in a Surgical Mission: Reflections on the Neurosurgical Mission to Mongolia. PMID- 28336445 TI - Mortality-Associated Characteristics of Patients with Traumatic Brain Injury at the University Teaching Hospital of Kigali, Rwanda. AB - OBJECTIVE: Traumatic brain injury (TBI) is a leading cause of death and disability. Patients with TBI in low and middle-income countries have worse outcomes than patients in high-income countries. We evaluated important clinical indicators associated with mortality for patients with TBI at University Teaching Hospital of Kigali, Kigali, Rwanda. METHODS: A prospective consecutive sampling of patients with TBI presenting to University Teaching Hospital of Kigali Accident and Emergency Department was screened for inclusion criteria: reported head trauma, alteration in consciousness, headache, and visible head trauma. Exclusion criteria were age <10 years, >48 hours after injury, and repeat visit. Data were assessed for association with death using logistic regression. Significant variables were included in a multivariate logistic regression model and refined via backward elimination. RESULTS: Between October 7, 2013, and April 6, 2014, 684 patients were enrolled; 14 (2%) were excluded because of incomplete data. Of patients, 81% were male with mean age of 31 years (range, 10-89 years; SD 11.8). Most patients (80%) had mild TBI (Glasgow Coma Scale [GCS] score 13 15); 10% had moderate (GCS score 9-12) and 10% had severe (GCS score 3-8) TBI. Multivariate logistic regression determined that GCS score <13, hypoxia, bradycardia, tachycardia, and age >50 years were significantly associated with death. CONCLUSIONS: GCS score <13, hypoxia, bradycardia, tachycardia, and age >50 years were associated with mortality. These findings inform future research that may guide clinicians in prioritizing care for patients at highest risk of mortality. PMID- 28336448 TI - Permanent implants for lip augmentation: Results from a retrospective study and presentation of tips and tricks. AB - BACKGROUND: Requests for lip augmentation are increasing because of expanding media exposure and consumer needs. Temporary effects can be obtained by several techniques, but a recent procedure consisting of lip prosthesis implantation, offering a permanent result, is emerging. Accordingly, the implantation of solid lip prosthesis represents an innovation in the field of esthetic medicine and surgery. METHODS: A total of 100 women with atrophic or hypoplastic lips were treated with lip implants. The treatment was performed in a single session, and controls were scheduled at fixed time intervals. A standard digital photo was used for measurement and analysis. Data concerning patient satisfaction and complications of the technique were collected and analyzed. Variations to the original technique were also discussed. RESULTS: Patient evaluation revealed that a permanent and natural result without discomfort for the patient and/or the partner was reached with the implantation of silicone prosthesis in the upper and/or lower lip. Swelling, bruising, and malpositions were the most frequent adverse events. A case of severe edema was reported. Practical tricks acquired through experience were discussed to prevent complications. CONCLUSIONS: One of the most widespreading methods for lip remodeling is hyaluronic acid injections. Nevertheless, hyaluronic acid has a variable duration, and it is not always the first choice. This context allowed for the development of other techniques such as the implantation of silicone prosthesis. The advantages of this prosthesis are as follows: safety, definitive result, and reversibility considering the possibility to remove the implanted prosthesis in the case of a request. PMID- 28336447 TI - Anatomical reconstruction of the fourth brachymetatarsia with one-stage iliac bone and cartilage cap grafting. AB - BACKGROUND: We present a one-stage procedure for lengthening the fourth brachymetatarsia with autogenous iliac bone and cartilage cap grafting for the anatomical reconstruction of the metatarsophalangeal (MTP) joint METHODS: During the last 8 years, 56 feet in 41 patients with congenital brachymetatarsia of the fourth toe were corrected with a one-stage operation to reposition the articular cartilage cap to the distal part of interpositional iliac bone graft at the metatarsal epiphysis. RESULTS: The length of the harvested iliac bone graft was 22.9 mm on average. The mean fixation period was 58.5 days, and the mean gain in length and percentage increase was 20.9 mm and 39%, respectively. MRI showed a stable MTP joint over viable cartilage cap in 83.3% of the cases. Mean postoperative American Orthopedic Foot and Ankle Society lesser MTP interphalangeal score was 82.0. Neither neurovascular impairment nor recurrence of brachymetatarsia occurred in the mean follow-up period of 43.6 months. All patients were satisfied with the postoperative cosmetic results. Thirteen patients (23.2%) complained of limited active dorsiflexion of the fourth toe, and extensor adhesion was released by extensor tenolysis in only one patient. In a single case of nonunion at the bone graft site, additional surgery was not necessary. CONCLUSIONS: Anatomical reconstruction of the fourth brachymetatarsia with one-stage interpositional iliac bone and cartilage cap grafting resulted in excellent cosmetic results and a physiologic MTP joint, providing the benefits of one-stage lengthening with a low complication rate. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28336449 TI - Objective sensory and functional outcomes at the donor site following endoscopic assisted sural nerve harvest. AB - BACKGROUND: The sural nerve is a common choice for a nerve graft. Understanding the potential morbidity associated with its harvest is important. In this study, we describe the objective sensory and functional outcomes associated with endoscopic sural nerve harvest from a combined paediatric and adult population. METHODS: Data were collected prospectively from patients attending for follow-up between August 2015 and January 2016, who had previously undergone an endoscopic sural nerve graft harvest. Sensory loss was evaluated using a 5.07 Semmes Weinstein monofilament. The lower extremity functional scale was used to evaluate the patients' lower limb function. Statistical comparison was made using the Student's t-test. RESULTS: The outcomes from 46 sural nerve grafts were evaluated. The mean age of the patients was 18.1 years (range 4-45 years old). The mean time since surgery was 4.3 years. Those aged <=18 years had a significantly smaller area of sensory loss (p = 0.003), which was not related to a difference in foot size. Those who had undergone surgery >6 months previously had a significantly smaller area of sensory loss than those who had undergone surgery <6 months ago (p = 0.0002). The mean lower extremity functional scale score was 78.7/80. CONCLUSION: We demonstrated a significantly reduced post harvest sensory deficit among a paediatric population compared to that seen in adults. Furthermore, sensory loss reduces with time. Despite the sensory loss resulting from sural nerve graft harvest, there is minimal loss of function. As such, the sural nerve continues to be an excellent donor for a nerve graft procedure. PMID- 28336450 TI - Commentary on the Furlow paper. PMID- 28336451 TI - Effect of soybean phosphatidylcholine on lipid profile of bovine oocytes matured in vitro. AB - The phospholipid (PL) composition of embryo and oocyte membranes affects thermal phase behavior and several physicochemical properties such as fluidity and permeability. The characterization of PL profiles and the development of suitable in vitro maturation (IVM) protocols, that are able to modify membrane's composition, may result in significant improvements in oocyte developmental potential and cryotolerance. Using soybean phosphatidylcholine (PC) as a model supplement, we evaluated the effect of PL supplementation during IVM on bovine cumulus-oocyte-complex (COC). Substantial changes in the lipid profiles of oocyte membrane were observed and associated with pre-implantation data. The propensity of the PC supplement to become soluble in the maturation medium and/or diffuse into mineral oil was also assessed. Oocytes were matured in TCM without supplementation, i.e. control, (n=922) or supplemented with 50 or 100MUM PC (n=994). The maturation media and mineral oil pre- and post- IVM, along with control and PC-treated oocytes were then analyzed using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), and the lipid profiles were compared via principal component analysis (PCA). Soybean PCs are bioavailable and stable in IVM medium; further, PCs did not diffuse to the mineral oil, which also remained unaltered by the metabolism of treated oocytes. PC supplementation at 100MUM resulted in substantially greater relative abundances of polyunsatured PL, namely PC (32:1), PC (34:2), PC (36:6), PC (36:4), and PC (38:6), in oocyte membrane. These differences indicated that short-term exposure to the PC supplement could indeed modify the lipid composition of IVM-oocytes in a dose dependent manner. Membrane incorporation of polyunsaturated molecular species of PC was favored, and does so without compromising the viability of the subsequent embryo in regards to cleavage, blastocyst development and hatching rate. The reported approach will allow for the development of novel strategies to modulate oocyte membrane dynamics and structure. PMID- 28336452 TI - The relationship of bone properties using high resolution peripheral quantitative computed tomography to radiographic components of hip osteoarthritis. AB - OBJECTIVE: Positive associations between radiographic osteoarthritis (OA) and areal bone mineral density (BMD) have been demonstrated and appear strongest when bony features of OA are considered. To date, these associations have not been assessed using HRpQCT. DESIGN: A total of 318 participants (170 men and 148 women), aged 72.1-81.4 years from a non-selected cohort, underwent HRpQCT of the distal radius and tibia along with hip radiography. Differences in bone microarchitecture were assessed between those with and without osteophytes, sclerosis or joint space narrowing (JSN) in either hip. RESULTS: Men with osteophytes alone had significantly higher radial trabecular volumetric BMD (Tb.vBMD) and radial and tibial trabecular thickness (Tb.Th). Men with both sclerosis and osteophytes had significantly higher cortical volumetric BMD (Ct.vBMD) and cortical thickness (Ct.Th) at the distal tibia than those with osteophytes alone (P < 0.05). These relationships were maintained after adjustment for age and Body Mass Index (BMI), and were not replicated in women. Bone microarchitecture did not differ significantly in those with JSN from those without it in men or women. CONCLUSIONS: Our findings suggest higher Tb.vBMD and Tb.Th in men with osteophytosis but higher tibial Ct.vBMD and Ct.Th in men with hip joint sclerosis. These results do however require replication in other cohorts. PMID- 28336453 TI - A bioinformatic analysis of microRNAs role in osteoarthritis. AB - OBJECTIVE: To evaluate the underlying function of microRNAs (miRNAs) in osteoarthritis (OA). DESIGN: A bioinformatic analysis of miRNAs-OA studies was completed in multiple databases. All identified articles were assessed using specific inclusion and exclusion criteria (Eligible case-control studies for the present study included those which investigated miRNAs differential expression in cartilage tissues and cells of OA and controls. Abstracts, case reports, conference presentations, editorials, and expert opinions were excluded.). We performed bioinformatic analysis and assessed which miRNAs are commonly elevated or decreased in cartilage of OA, and assessed putative targets of these miRNAs using TargetScan, Database for Annotation, Visualization and Integrated Discovery (DAVID), FunRich and String. RESULTS: Fifty seven studies were included in this study. Our current review has identified 46 differentially expressed miRNAs involved in autophagy, inflammation, chondrocyte apoptosis, chondrocyte differentiation & homeostasis, chondrocyte metabolism and degradation of the extracellular matrix (ECM). Additionally, our literature search identified a wide range of miRNAs that have been shown to be differentially expressed in OA. The function of up-regulated miRNAs primarily target nucleus, whereas the function of down-regulated miRNAs primarily target transcription. CONCLUSIONS: Comprehensive analysis of all miRNAs studies reveals cooperation in miRNA signatures and suggests that there may be two biologically synergic classes of miRNAs that are associated with OA. This finding suggests that miRNAs may be useful as diagnostic biomarkers and/or may provide new therapeutic targets in OA. Furthermore, a better understanding of the targets of these miRNAs will accelerate biomedical discoveries and improve clinical care based on new knowledge of OA-related disease mechanisms. PMID- 28336454 TI - Cryoneurolysis to treat the pain and symptoms of knee osteoarthritis: a multicenter, randomized, double-blind, sham-controlled trial. AB - OBJECTIVE: Evaluate the efficacy and safety/tolerability of cryoneurolysis for reduction of pain and symptoms associated with knee osteoarthritis (OA). DESIGN: Randomized, double-blind, sham-controlled, multicenter trial with a 6-month follow-up in patients with mild-to-moderate knee OA. Patients were randomized 2:1 to cryoneurolysis targeting the infrapatellar branch of the saphenous nerve (IPBSN) or sham treatment. The primary endpoint was the change from baseline to Day 30 in the Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain score adjusted by the baseline score and site. Secondary endpoints, including visual analogue scale (VAS) pain score and total WOMAC score, were tested in a pre-defined order. RESULTS: The intent-to-treat (ITT) population consisted of 180 patients (n = 121 active treatment, n = 59 sham treatment). Compared to the sham group, patients who received active treatment had a statistically significant greater change from baseline in the WOMAC pain subscale score at Day 30 (P = 0.0004), Day 60 (P = 0.0176), and Day 90 (P = 0.0061). Patients deemed WOMAC pain responders at Day 120 continued to experience a statistically significant treatment effect at Day 150. Most expected side effects were mild in severity and resolved within 30 days. The incidence of device- or procedure-related adverse events was similar in the two treatment groups with no occurrence of serious or unanticipated adverse device effects (ADE). CONCLUSIONS: Cryoneurolysis of the IPBSN resulted in statistically significant decreased knee pain and improved symptoms compared to sham treatment for up to 150 days, and appeared safe and well tolerated. PMID- 28336455 TI - Targeted delivery of epirubicin to tumor-associated macrophages by sialic acid cholesterol conjugate modified liposomes with improved antitumor activity. AB - With the knowledge that the receptors of sialic acid are overexpressed on the surface of tumor-associated macrophages (TAMs), which play a crucial role in the tumor's progression and metastasis, a sialic acid-cholesterol conjugate (SA-CH) was synthesized and modified on the surface of epirubicin (EPI)-loaded liposomes (EPI-SAL) to improve the delivery of EPI to the TAMs. The liposomes were developed using remote loading technology via a pH gradient. The liposomes were evaluated for particle size, encapsulation efficiency, in vitro release, stability, in vitro cytotoxicity and pharmacokinetics. And the in vitro and in vivo cellular uptake studies demonstrated EPI-SAL achieved enhanced accumulation of EPI into TAMs. The antitumor studies indicated that EPI-SAL provided the strongest antitumor activity compared with the other formulations (EPI-S, EPI-CL and EPI-PL represent EPI solution, conventional liposomal EPI, PEGylated liposomal EPI, respectively), and the survival percent of tumor-bearing mice was 83.3%. The superior antitumor efficacy was probably attributed to the killing of TAMs by EPI-SAL, and modulating the tumor microenvironment with the depletion of TAMs. These findings suggested that SA-CH decorated EPI-loaded liposomes may present an effective strategy to eradicate TAMs, which may be a promising approach for cancer therapy. PMID- 28336456 TI - Small nanosized poly(vinyl benzyl trimethylammonium chloride) based polyplexes for siRNA delivery. AB - The success of siRNA gene therapy requires the availability of safe and efficient delivery systems. In the present study, we investigated poly(vinyl benzyl trimethylammonium chloride) (PVTC) and its block copolymer with poly(oligo(ethyleneglycol) methacrylate) (POEGMA) as delivery vector for siRNA. Small polyplexes ranging from 8 to 25nm in diameter were formed in aqueous solution by spontaneous self-assembly of both the homopolymer and block copolymer with siRNA and the formed particles were stable at physiological ionic strength. It was shown that when human ovarian adenocarcinoma cells were transfected, siRNA polyplexes based on PVTC (40kDa) and PVTC-POEGMA-4 (PP4, 34kDa) efficiently induced luciferase gene silencing to the same extent as the formulation based on a commercial lipid (Lipofectamine(r)) (~80%), and showed higher gene silencing than the linear polyethylenimine formulation linear polyethylenimine (~35%). Importantly, the POEGMA block polymers displayed a significantly lower cytotoxicity as compared to L-pEI. siRNA polyplexes based on the block polymers displayed high cellular uptake resulting in ~50% silencing of luciferase expression also in the presence of serum. These results demonstrate that PVTC based polymers are promising siRNA delivery vectors. PMID- 28336457 TI - Synergistic inhibition of migration and invasion of breast cancer cells by dual docetaxel/quercetin-loaded nanoparticles via Akt/MMP-9 pathway. AB - Metastasis impedes the successful chemotherapy for breast cancer. In this study, an Akt inhibitor (quercetin, Qu) was co-delivered with a chemotherapeutic agent (docetaxel, DTX) by using hyaluronic acid (HA)-modified nanoparticles (NPs) as vectors to block metastasis. Dual DTX/Qu-loaded HA/polylactic-co-glycolic acid polyethyleneimine NPs (PP-HA/NPs) were prepared through a modified emulsion solvent evaporation technique. The particle size of PP-HA/NPs with narrow polydispersity was 209.8+/-10.8nm. Wound healing assay revealed that Qu co delivery and HA modification elicited synergistic inhibitory effects on cell motility. The downregulation of p-Akt and matrix metalloproteinase-9 (MMP-9) expression contributed to the significant inhibition of cell migration and invasion with inhibition rates of 95.6% and 99.3%, respectively. Further studies indicated that PP-HA/NPs could be efficiently uptaken by 4T1 breast cancer cells and could further induce cytotoxicity, decrease colony formation and promote cell apoptosis. Biodistribution assay demonstrated PP-HA/NPs also enhanced drug accumulation in the tumor and lungs and predicted that PP-HA/NPs could be employed as an effective therapy for primary tumor and pulmonary metastasis. Therefore, PP-HA/NPs could be a promising delivery system to treat metastatic breast cancer effectively. PMID- 28336458 TI - Nile red nanosuspensions as investigative model to study the follicular targeting of drug nanocrystals. AB - The strategy of formulating poorly soluble actives as nanosuspension has been explored by more than a thousand research papers, with some medicinal products for oral and intravenous use having reached the market or advanced clinical trials. Interestingly, there is a limited number of reports of nanosuspensions formulated for dermal and transdermal drug delivery. In the present work, a nanocrystals suspension of the fluorescent, water-insoluble dye Nile Red, is prepared through a media milling technique and exploited to characterize the fate of the nanosuspended drug when applied on the skin. More in detail, the accumulation of Nile Red nanocrystals inside the hair follicles is evidenced by scanning electron microscopy, and the diffusion of drug molecules in the different skin layers is evaluated by confocal microscopy and skin permeation studies. Overall, the combination of the analytical techniques provide a description of the mechanisms underlying dermal accumulation, and transdermal penetration of a drug formulated as a nanosuspension. PMID- 28336459 TI - Correlation between calculated molecular descriptors of excipient amino acids and experimentally observed thermal stability of lysozyme. AB - A quantitative structure-property relationship (QSPR) between protein stability and the physicochemical properties of excipients was investigated to enable a more rational choice of stabilizing excipients than prior knowledge. The thermal transition temperature and aggregation time were determined for lysozyme in combination with 13 different amino acids using high throughput fluorescence spectroscopy and kinetic static light scattering measurements. On the theoretical side, around 200 2D and 3D molecular descriptors were calculated based on the amino acids' chemical structure. Multivariate data analysis was applied to correlate the descriptors with the experimental results. It was possible to identify descriptors, i.e. amino acids properties, with a positive influence on either transition temperature or aggregation onset time, or both. A high number of hydrogen bond acceptor moieties was the most prominent stabilizing factor for both responses, whereas hydrophilic surface properties and high molecular mass density mostly had a positive influence on the unfolding temperature. A high partition coefficient (logP(o/w)) was identified as the most prominent destabilizing factor for both responses. The QSPR shows good correlation between calculated molecular descriptors and the measured stabilizing effect of amino acids on lysozyme. PMID- 28336460 TI - Nanoincorporation of bioactive compounds from red grape pomaces: In vitro and ex vivo evaluation of antioxidant activity. AB - In this study, the active components of grape pomaces were first extracted by maceration in ethanol and propylene glycol, then in extra virgin olive oil. The main components of the hydrophilic extractive solutions were flavonoids, while monounsaturated fatty acids were the most abundant constituents of the extractive oil, with high levels of oleic acid, which were identified by HPLC/DAD and GC/MS, respectively. The hydrophilic extractive solutions and the lipophilic extractive oil were used to prepare phospholipid vesicles, avoiding the energetically and economically expensive steps required to obtain solid matrixes or pure compounds. The obtained grape bioactive enriched penetration enhancer containing vesicles (PEVs) were multilamellar, around 200nm in size, and more viscous than the corresponding solutions. The antioxidant activity, evaluated by the Folin Ciocalteu and DPPH assays, was potentiated when the extractive solutions were loaded in PEVs. Further, the grape enriched PEVs were able to ensure an optimal protection against oxidative stress in an ex vivo human erythrocytes-based model. PMID- 28336461 TI - Chloroform-free permeabilization for improved detection of beta-galactosidase activity in Vibrio cholerae. AB - LacZ (beta-galactosidase) is used to monitor the transcription of genes in reporter strains carrying the lacZ gene under the control of a promotor of interest. This protocol for LacZ activity determinations in Vibrio cholerae following detergent lysis results in 2.5-fold increase of LacZ activities compared to lysis with chloroform. PMID- 28336462 TI - The molecular mechanisms of androgen receptor in nephrolithiasis. AB - OBJECTIVES: This study aimed to investigate the molecular mechanisms of androgen receptor (AR) in nephrolithiasis. METHODS: Human kidney 2(HK-2) cells were transfected with Lentiviruses expressing AR (DEC-AR), shRNA targeting AR (sh-AR) or the empty vector control using the pLEX lentiviral vector system. The expression levels of AR were measured by qRT-PCR at 72h postinfection, and cells under different treatments were collected for microarray analysis. Differentially expressed genes (DEGs) were identified using Student's t-test. The protein protein interaction (PPI) network was constructed for negatively correlated DEGs using GeneMANIA. Then, functional and pathway enrichment analysis were performed for the genes in the PPI network. RESULTS: The qRT-PCR revealed that expression level of AR in DEC-AR cells was obviously increased and decreased in sh-AR cells at 72h postinfection (p<0.05). Totally, 64 negatively correlated DEGs showed lower expressions and 63 negatively correlated DEGs were up-regulated in the DEC AR HK2 cells. Negatively correlated DEGs were significantly related to cell differentiation, response to stimulus, multicellular organismal process and multicellular organismal development. Pathway enrichment analysis revealed that DEGs mainly participated in the rheumatoid arthritis (CCL2, CSF1, IL11, LTB and MMP1), gematopoietic cell lineage (CD33, CD44, CSF1 and IL11) and TNF signaling pathway (CCL2, CSF1, MMP9 and VCAM1). Meanwhile, CD44, LAMC2 and THBS2 were significantly enriched in ECM-receptor interaction. CONCLUSION: The negatively correlated DEGs, especially CCL2, CD44, MMP1 and MMP9, might play critical roles in nephrolithiasis. PMID- 28336463 TI - Identification of a de novo microdeletion 1q44 in a patient with hypogenesis of the corpus callosum, seizures and microcephaly - A case report. AB - Microdeletion 1q44 on the long arm of chromosome 1 leads to a phenotype that includes microcephaly, seizure, agenesis or hypogenesis of the corpus callosum, polydactyly, congenital heart defects and severe developmental delay along with characteristic facial dysmorphic signs. Until today, the distinct genetic causes for the different symptoms remain unclear. We here report a 1.2Mb de novo microdeletion 1q44 identified by performing a SNP array analysis. The female patient presented with microcephaly, seizure, hypogenesis of corpus callosum, postaxial hexadactyly, an atrial septal defect, a ventricular septal defect, hypertelorism, a long and smooth philtrum, thin vermilion borders, and micrognathia, all common features of microdeletion 1q44. An additionally performed chromosome analysis excluded any chromosomal rearrangements. The deleted region included the genes ZBTB18 as well as HNRNPU amongst others. Both are possibly candidate genes for the dysgenesis of the corpus callosum. AKT3, another candidate gene, was not affected by the deletion in this patient. Thus, the genetic findings in this case report spotlight ZBTB18 and HNRNPU in the genesis of the typical microdeletion 1q44 symptoms, especially concerning the dysgenesis of the corpus callosum, and therefore could help to unveil more of the genetic background of this syndrome. PMID- 28336464 TI - New insights into the codon usage patterns of the bactericidal/permeability increasing (BPI) gene across nine species. AB - Bactericidal/permeability-increasing (BPI) protein is a member of a new generation of proteins known as super-antibiotics that are implicated as endotoxin neutralising agents. Non-uniform usage of synonymous codons for a specific amino acid during translation of a protein is known as codon usage bias (CUB). Analysis of CUB and compositional dynamics of coding sequences could contribute to a better understanding of the molecular mechanism and the evolution of a particular gene. In this study, we performed CUB analysis of the complete coding sequences of the BPI gene from nine different species. The codon usage patterns of BPI across different species were found to be influenced by GC bias, particularly GC3s, with a moderate bias in the codon usage of BPI. We found significant similarities in the codon usage patterns in BPI gene among closely related species, such as Sus_scrofa and Bos_taurus. Moreover, we observed evolutionary conservation of the most over-represented codon CUG for the amino acid leucine in the BPI gene across all species. In conclusion, our analysis provides a novel insight into the codon usage patterns of BPI. This information facilitates an improved understanding of the structural, functional and evolutionary significance of BPI gene among species, and provides a theoretical reference for developing antiseptic drug proteins with high efficiency across species. PMID- 28336466 TI - Global trends and predictions in hepatocellular carcinoma mortality. AB - BACKGROUND & AIMS: Trends in hepatocellular carcinoma (HCC) mortality rates have increased over recent decades in most countries. It is also the third cause of cancer death worldwide. The aim of this study is to update global trends in HCC mortality to 2014, and predict trends in rates in the EU, USA and Japan to 2020. METHODS: Death certification data for HCC over the 1990-2014 period from the World Health Organization database were analyzed. Sixteen European, five American countries, and six other countries worldwide were included, as well as the EU as a whole. RESULTS: In European men, mortality rates were stable during the last decade (3.5/100,000). HCC mortality increased in Northern and Central Europe, and decreased in Southern Europe. In the USA, HCC mortality increased by 35% between 2002 and 2012, reaching 3.1/100,000 men in 2012; it is predicted to remain stable to 2020. Reduced mortality rates were observed in East Asia, although they remained around 10-24/100,000 men. In Japan, HCC mortality is predicted to decrease (5.4/100,000 men in 2020). Trends were favorable in the young, but unfavorable in middle aged, except in East Asia. Mortality rates were 3- to 5 fold lower in women than men in most regions, but trends were similar. CONCLUSIONS: Control of hepatitis B (HBV) and hepatitis C virus (HCV) infections has contributed to the decrease in HCC-related mortality in East Asia and Southern Europe. Unfavorable trends in other regions can be attributed to HCV (and HBV) epidemics in the 1960s and 1980s, alcohol consumption, increased overweight/obesity, and diabetes. Better management of cirrhosis, HCC diagnosis and treatment are also influencing the mortality trends worldwide. LAY SUMMARY: Mortality rates due to HCC have increased in many countries over recent decades. In this study, we updated worldwide mortality trends for HCC from 1990 to 2014, and predicted trends for some countries to 2020. We observed unfavorable trends in Northern and Central Europe, North and Latin America. East Asia showed an improvement, however mortality rates in this region were 2- to 5-fold higher than in most European countries and the Americas. Steady declines to 2020 are predicted for East Asia but not for Europe and the Americas. PMID- 28336465 TI - Smoking and the risk of type 2 diabetes. AB - Despite accumulating evidence demonstrating strong epidemiologic and mechanistic associations between cigarette smoking, hyperglycemia, and the development of type 2 diabetes, tobacco abuse has not been uniformly recognized as a modifiable risk factor in diabetes prevention or screening strategies. In this review, we highlight population-based studies that have linked cigarette smoking with an increased risk of type 2 diabetes and summarize clinical and preclinical studies offering insight into mechanisms through which cigarette smoking and nicotine exposure impact body composition, insulin sensitivity, and pancreatic beta cell function. Key questions for future studies are identified and strategies for smoking cessation as a means to decrease diabetes risk are discussed. PMID- 28336467 TI - An evaluation of portion size estimation aids: Consumer perspectives on their effectiveness. AB - OBJECTIVE: This qualitative study aimed to investigate consumer opinions on the usefulness of portion size estimation aids (PSEA); consumer preferences in terms of format and context for use; and the level of detail of guidance considered necessary for the effective application of PSEA. DESIGN: Six focus groups (three to eight participants per group) were conducted to elicit views on PSEA. The discussions were recorded, transcribed verbatim and analysed by two independent researchers using a template approach. SETTING: The focus groups were conducted in 2013 by an experienced moderator in various sites across the island of Ireland (three in the Republic of Ireland and three in Northern Ireland) including local leisure, community and resource centres; the home environment; and a university meeting room. PARTICIPANTS: General population, males (n = 17) and females (n = 15) aged 18-64 years old. Participants were recruited from both urban and rural locations representing a range of socio-economic groups. RESULTS: The majority of participants deemed the coloured portion pots and disposable plastic cup (household measures) to be useful particularly for the estimation of amorphous cereal products (e.g. breakfast cereals). Preferences were evident for "visual" PSEA (reference objects, household measures and food packaging) rather than 'quantities and measures' such as weighing in grams or ounces. Participants stated that PS education should be concise, consistent, from a reputable source, initiated at school age and communicated innovatively e.g. mobile app or TV advertisement. Guidance in relation to gender, age and activity level was favoured over a "one size fits all" approach. CONCLUSIONS: This study identified consumer preferences and acceptance of "visual" PSEA such as portion pots/cups to estimate appropriate PS of amorphous grain foods such as breakfast cereals, pasta and rice. Concise information from a reputable source in relation to gender, age and activity level should accompany PSEA. PMID- 28336468 TI - The effect of a change to healthy vending in a major Australian health service on sales of healthy and unhealthy food and beverages. PMID- 28336469 TI - A review of the ethnopharmacology, phytochemistry and pharmacology of Notopterygium incisum. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Notopterygium incisum Ting ex H.T. Chang, known in Chinese as 'Qianghuo' is a traditional Chinese medicinal herb with the rhizome and roots associated with meridians of the kidney and urinary bladder. It is pungent, bitter and warm in nature. It has been used over the years to disperse cold, prevent painful obstructions from wind, damp and warm pain. It has also been used with other herbs to treat wind-cold exterior syndrome and wind-cold damp bi-syndromes and has been known to grow well in regions of high altitude such as Gansu, Tibet etc. THE AIM OF THE REVIEW: This systematic review focuses on the ethnopharmacological uses of this herb, including recent advances on the phytochemical and pharmacological study of N. incisum. Recent analytical methods developed for the quantitative and qualitative determination of constituents in this herb have also been reviewed. Additionally, future trends and prospects in the study of this herb have been proposed. MATERIALS AND METHOD: Various literature and electronic databases such as Pubmed, Science Direct, Springer, Wiley etc were searched and data obtained. Other online academic libraries such as Google Scholar and ethnopharmacological literature were searched systematically for more information on the herb. RESULTS: This review focuses on the ethnopharmacological uses of N. incisum and also the various chemical constituents present in the herb and their various therapeutic effects such as analgesic, anti-inflammatory, anti-cancer and antioxidants effects. Analytical methods developed for the quantitative and qualitative determination of various compounds in this herb were further reviewed. CONCLUSION: In this paper, we have reviewed various researches conducted on N. incisum especially in areas of its ethnopharmacological use, phytochemicals, pharmacology and developed analytical methods. This herb has been used over the years in treating headache, rheumatoid arthritis, cold, diaphoretic etc, prompting many types of research into identifying which compounds are responsible for these activities and their mechanism of action. More research is needed in the area of pharmacokinetics and toxicology to give further information on the clinical use and control the quality of the herb. PMID- 28336470 TI - Bioassay-guided isolation of active principles from Nigerian medicinal plants identifies new trypanocides with low toxicity and no cross-resistance to diamidines and arsenicals. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Leaves from the plant species studied herein are traditionally used in northern Nigeria against various protozoan infections. However, none of these herbal preparations have been standardized, nor have their toxicity to mammalian cells been investigated. In search of improved and non toxic active antiprotozoal principles that are not cross-resistant with current anti-parasitics, we here report the results of the in vitro screening of extracts from seven selected medicinal plant species (Centrosema pubescens, Moringa oleifera, Tridax procumbens, Polyalthia longifolia, Newbouldia laevis, Eucalyptus maculate, Jathropha tanjorensis), used traditionally to treat kinetoplastid infections in Nigeria, and the isolation of their bioactive principles. AIM OF THE STUDY: To investigate the efficacies of medicinal plant extracts, and of compounds isolated therefrom, against kinetoplastid parasites, assess cross resistance to existing chemotherapy, and assay their toxicity against mammalian cells in vitro. MATERIAL AND METHODS: Plants were extracted with hexane, ethyl acetate and methanol. Active principles were isolated by bioassay-led fractionation, testing for trypanocidal activity, and identified using NMR and mass spectrometry. EC50 values for their activity against wild-type and multi drug resistant Trypanosoma brucei were obtained using the viability indicator dye resazurin. RESULTS: Seven medicinal plants were evaluated for activity against selected kinetoplastid parasites. The result shows that crude extracts and isolated active compounds from Polyalthia longifolia and Eucalyptus maculata, in particular, display promising activity against drug-sensitive and multi-drug resistant Trypanosoma brucei. The EC50 value of a clerodane (16alpha-hydroxy cleroda-3,13(14)-Z-dien-15,16-olide) isolated from Polyalthia longifolia was as low as 0.38ug/mL, while a triterpenoid (3beta,13beta-dihydroxy-urs-11-en-28-oic acid) isolated from Eucalyptus maculata displayed an EC50 of 1.58ug/mL. None of the isolated compounds displayed toxicity towards Human Embryonic Kidney cells at concentrations up to 400ug/mL. In addition, the isolated compounds were active against Leishmania mexicana, as well as against T. congolense. CONCLUSION: We have isolated a clerodane compound from Polyalthia longifolia that shows low toxicity, no cross-resistance with current treatments, and promising activity against both human-infective and veterinary Trypanosoma species. PMID- 28336471 TI - Cutaneous myiasis. PMID- 28336473 TI - Unravelling the complexities of vascular smooth muscle ion channels: Fine tuning of activity by ancillary subunits. AB - Which ion channel is the most important for regulating vascular tone? Which one is responsible for controlling the resting membrane potential or repolarization? Which channels are recruited by different intracellular signalling pathways or change in certain vascular diseases? Many different ion channels have been identified in the vasculature over the years and claimed as future therapeutic targets. Unfortunately, several of these ion channels are not just found in the vasculature, with many of them also found to have prominent functional roles in different organs of the body, which then leads to off-target effects. As cardiovascular diseases are expected to increase worldwide to epidemic proportions, ion channel research and the hunt for the next major therapeutic target to treat different vascular diseases has never been more important. However, I believe that the question we should now be asking is: which ancillary subunits are involved in regulating specific ion channels in the vasculature and do they have the potential to be new therapeutic targets? PMID- 28336474 TI - The evolution of heart failure with reduced ejection fraction pharmacotherapy: What do we have and where are we going? AB - Cardiovascular diseases represent a leading cause of mortality and increased healthcare expenditure worldwide. Heart failure, which simply describes an inability of the heart to meet the body's needs, is the end point for many other cardiovascular conditions. The last three decades have witnessed significant efforts aiming at the discovery of treatments to improve the survival and quality of life of patients with heart failure; many were successful, while others failed. Given that most of the successes in treating heart failure were achieved in patients with reduced left ventricular ejection fraction (HFrEF), we constructed this review to look at the recent evolution of HFrEF pharmacotherapy. We also explore some of the ongoing clinical trials for new drugs, and investigate potential treatment targets and pathways that might play a role in treating HFrEF in the future. PMID- 28336472 TI - Comparison of strategies for grading retinal images of premature infants for referral warranted retinopathy of prematurity. AB - PURPOSE: To determine the accuracy of identifying referral-warranted retinopathy of prematurity (RW-ROP, defined as any zone I ROP, stage 3 or worse, or plus disease) from retinal image sets using three grading protocols: a single optic disk-centered image, a set of 3 horizontal images, and a 5-image set. METHODS: In this secondary analysis of images from the e-ROP study, a weighted sample of 250 image sets from 250 infants (125 with RW-ROP and 125 without RW-ROP) was randomly selected. The sensitivities and specificities for detecting RW-ROP and its components from a single disk center image, along with nasal and temporal retinal images, were calculated and compared with the e-ROP grading of RW-ROP of all 5 retinal images (disk center and nasal, temporal, superior, and inferior retinal images). RESULTS: RW-ROP was identified with a sensitivity of 11.2% (95% CI, 6.79%-17.9%) using a single disk center image, with a sensitivity of 70.4% (95% CI, 61.9%-77.9%) using 3 horizontal images, and a statistically higher sensitivity of 82.4% (95% CI, 75.0%-89.0%) using all 5 images (P = 0.002). The specificities were 100%, 86.4%, and 90.4%, respectively. For grading using 3 horizontal images, sensitivity was 14.3% for plus disease, 25% for zone I ROP, and 71.2% for stage 3 or worse compared to 40.8%, 50%, and 79.8% for grading using 5-image sets, respectively. CONCLUSIONS: Both a single, disk-centered, posterior pole image and 3 horizontal images were less effective than a 5-image set in determining the presence of RW-ROP on qualitative grading by trained readers. PMID- 28336476 TI - Associations of water balance and thermal sensitivity of toads with macroclimatic characteristics of geographical distribution. AB - Interspecific variation in patterns of geographical distribution of phylogenetically related species of amphibians might be related to physiological adaptation to different climatic conditions. In this way, a comparative study of resistance to evaporative water loss, rehydration rates and sensitivity of locomotor performance to variations on hydration level and temperature was performed for five species of Bufonidae toads (Rhinella granulosa, R. jimi, R. ornata, R. schneideri and R. icterica) inhabiting different Brazilian biomes. The hypotheses tested were that, when compared to species inhabiting mesic environments, species living at hot and dry areas would show: (1) greater resistance to evaporative water loss, (2) higher rates of water uptake, (3) lower sensitivity of locomotor performance to dehydration and (4) lower sensitivity of locomotor performance at higher temperatures and higher sensitivity of locomotor performance at lower temperatures. This comparative analysis showed relations between body mass and interspecific variation in rehydration rates and resistance to evaporative water loss in opposite directions. These results might represent a functional compensation associated with relatively lower absorption areas in larger toads and higher evaporative areas in smaller ones. Moreover, species from the semi-arid Caatinga showed locomotor performance less sensitive to dehydration but highly affected by lower temperatures, as well greater resistance to evaporative water loss, when compared to the other species from the mesic Atlantic Forest and the savannah-like area called Cerrado. These results suggest adaptation patterns to environmental conditions. PMID- 28336475 TI - Intraoperative Rupture of Ovarian Dermoid Cysts in the Pediatric and Adolescent Population: Should This Change Your Surgical Management? AB - STUDY OBJECTIVE: (1) To determine the incidence of chemical peritonitis after cystectomy for ovarian dermoid cysts with intraoperative cyst rupture in the pediatric and adolescent population; and (2) to examine the intraoperative and postoperative outcomes of cystectomies performed for ovarian dermoid cysts using laparoscopy and laparotomy, especially those with intraoperative cyst rupture. DESIGN: A retrospective cohort study of female patients who underwent ovarian cystectomy with proven ovarian dermoid pathology between July 2007 and July 2015. SETTING: Texas Children's Hospital, Houston, Texas. PARTICIPANTS: One hundred forty-four patients between the ages of 1 and 21 years who underwent an ovarian cystectomy with proven benign ovarian dermoid histology on the basis of pathology reports. INTERVENTIONS AND MAIN OUTCOME MEASURES: Occurrence of spill of cyst contents, chemical peritonitis, postoperative complications, and hospital readmissions. RESULTS: One hundred forty-four female patients underwent cystectomy (38 laparotomy and 106 laparoscopy) resulting in benign ovarian dermoid histology. Their mean age was 12.4 +/- 4.1 years (range, 1-21), mean cyst size was 9.2 +/- 6.4 cm (range, 1-30 cm), no patients had elevated tumor markers, 42 (29.1%) presented with torsion, 73 (50.7%) had cyst fluid spill, and there were no cases of chemical peritonitis. Few significant differences were found between cases performed via laparoscopy and laparotomy and those with and without intraoperative cyst rupture resulting in spill of contents. Laparotomy cases were found to have larger mean cyst size (P < .001), estimated blood loss (P = .003), and presence of bilateral cysts (P = .017) compared with laparoscopic cases. Cyst fluid spill occurred in more laparoscopic cases ([67/106] 63.2% vs [6/38] 15.8%; P < .001), and risk increased with cyst size greater than 5 cm (P < .001). In the laparoscopy group, cyst size greater than 5 cm was more likely to present with torsion (P < .001). There was no significant difference in the repeat cystectomy rate between the laparoscopy and laparotomy groups even with cyst rupture (P = .394). Only 5 cases presented to the emergency room postoperatively and 2 were admitted postoperatively for umbilical port site dehiscence and pyelonephritis. CONCLUSION: Laparoscopic cystectomy of ovarian dermoid cysts is associated with greater intraoperative cyst rupture. However, cyst rupture is rarely associated with complications, therefore minimally invasive surgical management of ovarian dermoid cysts is a reasonable surgical approach. PMID- 28336477 TI - A novel semantic representation for eligibility criteria in clinical trials. AB - Eligibility Criteria (EC) comprise an important part of a clinical study, being determinant of its cost, duration and overall success. Their formal, computer processable description can significantly improve clinical trial design and conduction by enabling their intelligent processing, replicability and linkability with other data. For EC representation purposes, related standards were investigated, along with published literature. Moreover, a considerable number of clinicaltrials.gov studies was analyzed in collaboration with clinical experts for the determination and classification of parameters of clinical research importance. The outcome of this process was the EC Representation; a CDISC-compliant schema for organizing criteria along with a patient-centric model for their formal expression, properly linked with international classifications and codifications. Its evaluation against 200 randomly selected EC indicated that it can adequately serve its purpose, while it can be also combined with existing tools and components developed for both EC specification and especially application to Electronic Health Records. PMID- 28336478 TI - An extended protocol for usability validation of medical devices: Research design and reference model. AB - This paper proposes and demonstrates an extended protocol for usability validation testing of medical devices. A review of currently used methods for the usability evaluation of medical devices revealed two main shortcomings. Firstly, the lack of methods to closely trace the interaction sequences and derive performance measures. Secondly, a prevailing focus on cross-sectional validation studies, ignoring the issues of learnability and training. The U.S. Federal Drug and Food Administration's recent proposal for a validation testing protocol for medical devices is then extended to address these shortcomings: (1) a novel process measure 'normative path deviations' is introduced that is useful for both quantitative and qualitative usability studies and (2) a longitudinal, completely within-subject study design is presented that assesses learnability, training effects and allows analysis of diversity of users. A reference regression model is introduced to analyze data from this and similar studies, drawing upon generalized linear mixed-effects models and a Bayesian estimation approach. The extended protocol is implemented and demonstrated in a study comparing a novel syringe infusion pump prototype to an existing design with a sample of 25 healthcare professionals. Strong performance differences between designs were observed with a variety of usability measures, as well as varying training-on-the job effects. We discuss our findings with regard to validation testing guidelines, reflect on the extensions and discuss the perspectives they add to the validation process. PMID- 28336479 TI - Radiosurgical target distance from the root entry zone in the treatment of trigeminal neuralgia. AB - PURPOSE: Stereotactic radiosurgery (SRS) provides a noninvasive treatment modality for patients with medically refractory trigeminal neuralgia. The root entry zone (REZ) has been proposed to be an ideal stereotactic target because it is partially composed of centrally produced myelin, conferring a theoretical increased sensitivity to irradiation as well as increased susceptibility to neurovascular conflict, making it the site in which nociceptive signals likely arise. The aim of this study is to determine if there is a statistically and clinically significant difference in pain relief or facial hypesthesia following SRS based on distance of the stereotactic isocenter from REZ. METHODS AND MATERIALS: Patients undergoing Novalis radiosurgery for the treatment of trigeminal neuralgia with at least 3 months' follow-up were included in this study. Postoperative outcomes were stratified by Barrow Neurological Institute (BNI) score for pain relief and BNI facial numbness score for facial hypesthesia. RESULTS: Sixty-seven patients met inclusion criteria and were included in this study. BNI score of I-IIIa was attained in 82% of patients at 3 months and 65% at 1 year following SRS. Distance from isocenter to REZ varied from 0 to 8.6 mm, with a mean of 1.94 +/- 1.62 mm. Logistic regression of target-REZ distance against pain relief outcome (patients with score I-IIIa and IIIb-V) was insignificant at 3 months (P = .988), 6 months (P = .925), 9 months (P = .845), and 12 months (P = .547) postoperatively. Furthermore, no significant correlation was found with logistic regression of target-REZ distance with pain relief outcome (patients with score I and score II-IV) (P = .544). CONCLUSIONS: The current analysis suggests that distance from REZ does not correlate with degree of postoperative pain relief or facial hypesthesia; thus, targeting specific regions within the trigeminal nerve in relation to these anatomical characteristics may not afford any advantage from this perspective. PMID- 28336480 TI - Can a commercially available EPID dosimetry system detect small daily patient setup errors for cranial IMRT/SRS? AB - PURPOSE: The purpose of this study was to determine if the Sun Nuclear PerFRACTION electronic portal imager device dosimetry software would be able to detect setup errors in a clinical setting and would be able to correctly identify the direction in which the setup error was introduced. METHODS AND MATERIALS: A 7 field intensity modulated radiation therapy (IMRT) treatment plan for a centrally located tumor was developed for 1 phantom and 5 canine cadaver heads. Systematic setup errors were introduced by manually moving the treatment couch by 1, 3, and 5 mm in each translational direction to assess stereotactic radiation surgery (SRS), IMRT, and 3-dimensional (3D) treatment tolerances after the initial alignment was performed. An angular setup error of 5 degrees yaw was also assessed. The delivered treatment fluence was automatically imported in the PerFRACTION software and compared with the baseline fluence. RESULTS: In the canine phantom, a 5-mm shift was undetected by gamma analysis, and up to a 2-cm shift had to be introduced for the gamma pass rate of 3%/3 mm to fall below a 95% pass rate criterion. The same 5-mm shift using 3% difference caused the pass rates for 2 fields to drop below the 95% tolerance. For each respective translational shift, the affected beam angles were consistent across the cadaver heads and correlated with the direction of translational shift. The best field pass rate, worst field pass rate, and average pass rate across all 7 fields was analyzed to develop clinical guidance on parameter settings for SRS, IMRT, and 3D tolerances. CONCLUSIONS: PerFRACTION 2-dimensional mode successfully detected setup errors outside the systematic error tolerance for SRS, IMRT, and 3D when an appropriate analysis metric and pass/fail criteria was implemented. Our data confirm that percent difference may be more sensitive in detecting plan failure than gamma analysis. PMID- 28336481 TI - Irinotecan-induced radiation-recall myositis in a patient with metastatic breast cancer: A case report. PMID- 28336482 TI - Surgical treatment of lumbar disc herniation in different ages-evaluation of 11,237 patients. AB - BACKGROUND CONTEXT: Surgical treatment of lumbar disc herniation (LDH) may lead to different outcomes in young, middle-aged, and elderly patients. However, no study has, by the same data ascertainment, evaluated referral pattern, improvement, and outcome in different age strata. PURPOSE: This study aimed to evaluate referral pattern and outcome in patients of different ages surgically treated because of LDH. STUDY DESIGN: This is a register study of prospectively collected data. PATIENT SAMPLE: In SweSpine, the national Swedish register for spinal surgery, we identified 11,237 patients who between 2000 and 2010 had their outcome of LDH surgery registered in pre-, per-, and 1-year postoperative evaluations. OUTCOME MEASURES: The data collected included age, gender, smoking habits, walking distance, preoperative duration and degree of back and leg pain, consumption of analgesics, quality of life in the patient-reported outcome measure (PROM) Short-Form 36 (SF-36) and EuroQol 5 dimensions (EQ5D), disability in the Oswestry Disability Index, operated level, type of surgery, and complications. METHODS: We compared the outcome in patients within different 10 year age strata. IBM SPSS Statistics 22 was used in the statistical calculations. No funding was obtained for this study. The authors have no conflicts of interest to declare. RESULTS: Patients in all ages referred to surgery had inferior PROM data compared with published normative age-matched PROM data. Referral to LDH surgery demanded of each 10-year strata statistically significantly more pain, lower quality of life, and more disability (all p<.001). Surgery markedly improved quality of life and reduced disability in all age groups (all p<.001), but with statistically significantly less PROM improvement with each older 10 year strata (all p<.001). This resulted in statistically significantly inferior PROM values for pain, quality of life, and disability postoperatively for each 10 year strata (all p<.001). There were also more complications (p<.001) with each 10-year older strata. CONCLUSIONS: In general, older patients referred to LDH surgery have statistically significantly inferior PROM scores, improve less, and reach inferior PROM scores postoperatively. The clinical relevance must however be questioned because most patients reach, independent of age group, the defined level for a successful outcome, and the patient satisfaction rate is high. PMID- 28336483 TI - "Text neck": an epidemic of the modern era of cell phones? PMID- 28336484 TI - Lumbar magnetic resonance imaging findings in patients with and without Waddell Signs. AB - BACKGROUND CONTEXT: Waddell Signs (WS), introduced as a method to establish patients with substantial psychosocial components to their low back pain, carry a negative association despite no literature evaluating whether physical disease is associated with them. PURPOSE: To compare lumbar magnetic resonance imaging (MRI) findings between the patients with and without WS. STUDY DESIGN: Retrospective cohort study based on prospectively collected data. PATIENT SAMPLE: Thirty patients aged 35 to 55 years with an Oswestry Disability Index (ODI) score >50 randomly selected such that there was an even distribution of patients based on the number of WS. OUTCOME MEASURES: ODI and Short Form-12 scores, number of WS, presence and severity of spinal pathology. METHODS: MRIs were reviewed by three spine specialists blinded to clinical exam findings, number of WS, and patient identity. Type and severity of pathology and presence of surgical and non surgical lesions were assessed, and findings were rank ordered based on the overall impression of the pathology. There was no external funding or potential conflicts of interest for this study. RESULTS: There were significantly more individual pathologic findings in patients without WS (p=.02). However, there was no difference in the severity of pathology based on WS (p=.46). Furthermore, the rank ordering based on overall impression of severity showed no difference between the patients with and without WS (p=.20). Although 100% of the patients without WS showed pathologic findings on MRI, 70% of WS patients also had significant pathology on MRI. The prevalence of spondylolisthesis, stenosis, and disc herniation was similar (p=.41, p=.22, and p=.43, respectively). The prevalence and mean number of lesion amenable to surgery did not differ based on presence of WS (p=.21 and p=.18, respectively). CONCLUSIONS: Patients with WS present a difficult diagnostic challenge for the physician as their organic symptoms are often coexistent with emotional fear avoidance behavior. Although there is more overall pathology in patients without WS, a significant number of these patients appear to have comparable spinal pathology with equivalent severity, which may be contributing to patients' symptoms and disability. Presence of these non-organic symptoms often makes us doubt these patients. However, as part of effective treatment, physicians should better understand both the physical and psychological components of patient disability. PMID- 28336485 TI - Low-Dose CT Scan for Lung Cancer Screening: Clinical and Coding Considerations. AB - Lung cancer screening with low-dose CT (LDCT) scan was shown to reduce lung cancer mortality in the National Lung Screening Trial, a large randomized controlled trial of high-risk current and former smokers. Despite ongoing uncertainty over the effectiveness of LDCT scan in the real-world setting, the Centers for Medicare and Medicaid Services (CMS) decided to cover LDCT scan as a preventive service. As part of its National Coverage Determination, CMS set forth a series of requirements for reimbursement of LDCT scan, including a counseling and shared decision-making visit prior to a LDCT scan being ordered. During this visit, providers must determine patient eligibility, engage in shared decision making around LDCT scan, discuss the importance of adherence to screening, and provide smoking cessation counseling (if applicable). Two new billing codes were introduced for the counseling and shared decision-making visit and subsequent LDCT scan. In this review, we summarize the evidence around lung cancer screening and describe practical aspects of the counseling and shared decision-making, including billing considerations. We conclude with a discussion of the greater implications of CMS National Coverage Determination, especially as it pertains to quality assurance around new screening tests. PMID- 28336487 TI - Phylogeny and expression analysis of C-reactive protein (CRP) and serum amyloid-P (SAP) like genes reveal two distinct groups in fish. AB - The acute phase response (APR) is an early innate immune function that is initiated by inflammatory signals, leading to the release of acute phase proteins to the bloodstream to re-establish homeostasis following microbial infection. In this study we analysed the Atlantic salmon (Salmo salar) whole-genome database and identified five C-reactive protein (CRP)/serum amyloid P component (SAP) like molecules namely CRP/SAP-1a, CRP/SAP-1b, CRP/SAP-1c, CRP/SAP-2 and CRP/SAP-3. These CRP/SAP genes formed two distinct sub-families, a universal group (group I) present in all vertebrates and a fish/amphibian specific group (group II). Salmon CRP/SAP-1a, CRP/SAP-1b and CRP/SAP-1c and CRP/SAP-2 belong to the group I family whilst salmon CRP/SAP-3 is a member of group II. Gene expression analysis showed that the salmon CRP/SAP-1a as well as serum amyloid A-5 (SAA-5), one of the major acute phase proteins, were significantly up-regulated by recombinant cytokines (rIL-1beta and rIFNgamma) in primary head kidney cells whilst the other four CRP/SAPs remained refractory. Furthermore, SAA-5 was produced as the main acute phase protein (APP) in Atlantic salmon challenged with Aeromonas salmonicida (aroA(-) strain) whilst salmon CRP/SAPs remained unaltered. Overall, these data illustrate the potential different functions of expanded salmon CRP/SAPs to their mammalian homologues. PMID- 28336488 TI - Isolation and characterization of two glutathione S-transferases from freshwater bivalve Anodonta woodiana: Chronic effects of pentachlorophenol on gene expression profiles. AB - Glutathione S-transferases (GST) play a prominent role in protecting cells against oxidative stress. Our previous study showed that the reactive oxygen species (ROS) generated from pentachlorophenol (PCP) could cause an acute impact on freshwater bivalve Anodonta Woodiana, but its chronic toxicity remain unclear. In order to investigate the chronic effect of PCP, clams A. Woodiana were randomly grouped into PCP treated group in which animals were administrated with 13.9 MUg/L concentrations of PCP, and control group those with similar volume dimethyl sulfoxide. In addition, two complete GST sequences were isolated from A. Woodianaa and respectively named AwGST1 and AwGST2. The full-length cDNA of AwGST1 was consisted of a 5' untranslated region (UTR) of 132 bp, a 3' UTR of 80 bp and an open reading frame (ORF) of 609 bp encoding a polypeptide of 203 amino acids. The full-length cDNA of AwGST2 contained a 5' UTR of 57 bp, a 3' UTR of 291 bp and an ORF of 678 bp encoding a polypeptide of 226 amino acids. The constitutive expression levels of AwGST1 and AwGST2 were examined in different tissues including foot, mantle, adductor muscle, heart, hepatopancreas, hemocytes and gill. Administration of PCP could result in a significant increase of AwGST1 and AwGST2 expression in the hepatopancreas, gill and hemocytes. In the hepatopancreas, AwGST1 mRNA levels of PCP treated group increased more than 28.73% at day 1, then 70.37% (P < 0.05) at day 3, reach to 6.64 times (P < 0.01) at day 15 in contrasted with that of control group. AwGST2 increased more 18.18%, 82.88% (P < 0.05) and 2.43 times (P < 0.01) at day 1, 3 and 15, respectively. In the gill, AwGST1 expression showed a significant up-regulation in the PCP treated group during experiment observed compared with that of control group, mRNA level of AwGST2 increased more than 1.44 times (P < 0.05). In addition, expressions of AwGST1 and AwGST2 were significantly induced after PCP treatment in the hemocytes. These results indicated that up-regulations of AwGST1 and AwGST2 expression in bivalve A. woodiana are contribute to against oxidative stress derived from PCP treatment during experiment observed. PMID- 28336486 TI - Mitochondrial Dysfunction in Airway Disease. AB - There is increasing appreciation that mitochondria serve cellular functions beyond oxygen sensing and energy production. Accordingly, it has become important to explore noncanonical roles of mitochondria in normal and pathophysiological processes that influence airway structure and function in the context of diseases such as asthma and COPD. Mitochondria can sense upstream processes such as inflammation, infection, tobacco smoke, and environmental insults important in these diseases and in turn can respond to such stimuli through altered mitochondrial protein expression, structure, and resultant dysfunction. Conversely, mitochondrial dysfunction has downstream influences on cytosolic and mitochondrial calcium regulation, airway contractility, gene and protein housekeeping, responses to oxidative stress, proliferation, apoptosis, fibrosis, and certainly metabolism, which are all key aspects of airway disease pathophysiology. Indeed, mitochondrial dysfunction is thought to play a role even in normal processes such as aging and senescence and in conditions such as obesity, which impact airway diseases. Thus, understanding how mitochondrial structure and function play central roles in airway disease may be critical for the development of novel therapeutic avenues targeting dysfunctional mitochondria. In this case, it is likely that mitochondria of airway epithelium, smooth muscle, and fibroblasts play differential roles, consistent with their contributions to disease biology, underlining the challenge of targeting a ubiquitous cellular element of existential importance. This translational review summarizes the current state of understanding of mitochondrial processes that play a role in airway disease pathophysiology and identifying areas of unmet research need and opportunities for novel therapeutic strategies. PMID- 28336489 TI - Current applications, selection, and possible mechanisms of actions of synbiotics in improving the growth and health status in aquaculture: A review. AB - Synbiotics, a conjunction between prebiotics and probiotics, have been used in aquaculture for over 10 years. However, the mechanisms of how synbiotics work as growth and immunity promoters are far from being unraveled. Here, we show that a prebiotic as part of a synbiotic is hydrolyzed to mono- or disaccharides as the sole carbon source with diverse mechanisms, thereby increasing biomass and colonization that is established by specific crosstalk between probiotic bacteria and the surface of intestinal epithelial cells of the host. Synbiotics may indirectly and directly promote the growth of aquatic animals through releasing extracellular bacterial enzymes and bioactive products from synbiotic metabolic processes. These compounds may activate precursors of digestive enzymes of the host and augment the nutritional absorptive ability that contributes to the efficacy of food utilization. In fish immune systems, synbiotics cause intestinal epithelial cells to secrete cytokines which modulate immune functional cells as of dendritic cells, T cells, and B cells, and induce the ability of lipopolysaccharides to trigger tumor necrosis factor-alpha and Toll-like receptor 2 gene transcription leading to increased respiratory burst activity, phagocytosis, and nitric oxide production. In shellfish, synbiotics stimulate the proliferation and degranulation of hemocytes of shrimp due to the presence of bacterial cell walls. Pathogen-associated molecular patterns are subsequently recognized and bound by specific pattern-recognition proteins, triggering melanization and phagocytosis processes. PMID- 28336491 TI - Neurobehavioral effects of lithium in the rat: Investigation of the effect/concentration relationships and the contribution of the poisoning pattern. AB - Severity of lithium poisoning depends on the ingested dose, previous treatment duration and renal function. No animal study has investigated neurobehavioral differences in relation to the lithium poisoning pattern observed in humans, while differences in lithium pharmacokinetics have been reported in lithium pretreated rats mimicking chronic poisonings with enhanced brain accumulation in rats with renal failure. Our objectives were: 1)-to investigate lithium-related effects in overdose on locomotor activity, anxiety-like behavior, spatial recognition memory and anhedonia in the rat; 2)-to model the relationships between lithium-induced effects on locomotion and plasma, erythrocyte, cerebrospinal fluid and brain concentrations previously obtained according to the poisoning pattern. Open-field, elevated plus-maze, Y-maze and sucrose consumption tests were used. In acutely lithium-poisoned rats, we observed horizontal (p<0.001) and vertical hypolocomotion (p<0.0001), increased anxiety-like behavior (p<0.05) and impaired memory (p<0.01) but no altered hedonic status. Horizontal (p<0.01) and vertical (p<0.001) hypolocomotion peaked more markedly 24h after lithium injection and was more prolonged in acute-on-chronically vs. acutely lithium-poisoned rats. Hypolocomotion in chronically lithium-poisoned rats with impaired renal function did not differ from acutely poisoned rats 24h after the last injection. Interestingly, hypolocomotion/concentration relationships best fitted a sigmoidal Emax model in acute poisoning and a linear regression model linked to brain lithium in acute-on-chronic poisoning. In conclusion, lithium overdose alters rat behavior and consistently induces hypolocomotion which is more marked and prolonged in repeatedly lithium-treated rats. Our data suggest that differences between poisoning patterns regarding lithium-induced hypolocomotion are better explained by the duration of lithium exposure than by its brain accumulation. PMID- 28336492 TI - Looking into the brain through the retinal ganglion cells in psychiatric disorders: A review of evidences. AB - Psychiatry and neuroscience research need novel approaches to indirectly investigate brain function. As the retina is an anatomical and developmental extension of the central nervous system (CNS), changes in retinal function may reflect neurological dysfunctions in psychiatric disorders. The last and most integrated retinal relay before visual information transfer to the brain is the ganglion cell layer. Here, based on collected arguments, we argue that these cells offer a crucial site for indirectly investigating brain function. We describe the anatomical and physiological properties of these cells together with measurements of their functional properties named pattern electroretinogram (PERG). Based on ganglion cell dysfunctions measured with PERG in neurological disorders, we argue for the relevance of studying ganglion cell function in psychiatric research. We review studies that have evaluated ganglion cell function in psychiatric and addictive disorders and discuss how changes in PERG measurements could be functional markers of pathophysiological mechanisms of psychiatric disorders. PMID- 28336490 TI - Novel therapeutic interventions for pseudoachondroplasia. AB - Pseudoachondroplasia (PSACH), a severe short-limbed dwarfing condition, is associated with life-long joint pain and early onset osteoarthritis. PSACH is caused by mutations in cartilage oligomeric matrix protein (COMP), a pentameric matricellular protein expressed primarily in cartilage and other musculoskeletal tissues. Mutations in COMP diminish calcium binding and as a result perturb protein folding and export to the extracellular matrix. Mutant COMP is retained in the endoplasmic reticulum (ER) of growth plate chondrocytes resulting in massive intracellular COMP retention. COMP trapped in the ER builds an intracellular matrix network that may prevent the normal cellular clearance mechanisms. We have shown that accumulation of intracellular matrix in mutant COMP (MT-COMP) mice stimulates intense unrelenting ER stress, inflammation and oxidative stress. This cytotoxic stress triggers premature death of growth plate chondrocytes limiting long-bone growth. Here, we review the mutant COMP pathologic mechanisms and anti-inflammatory/antioxidant therapeutic approaches to reduce ER stress. In MT-COMP mice, aspirin and resveratrol both dampen the mutant COMP chondrocyte phenotype by decreasing intracellular accumulation, chondrocyte death and inflammatory marker expression. This reduction in chondrocyte stress translates into an improvement in long-bone growth in the MT-COMP mice. Our efforts now move to translational studies targeted at reducing the clinical consequences of MT-COMP and painful sequelae associated with PSACH. PMID- 28336493 TI - The central mechanism of risperidone-induced hyperprolactinemia. AB - Risperidone is known to increase prolactin secretion in treating mental illness patients. This side-effect is thought to be mediated via central signaling pathway. However, the exact pathway involved between risperidone and hyperprolactinemia are still unknown. Therefore, we have treated mice with risperidone and investigated the central mechanisms. The present study showed that in risperidone treated group, the level of the serum prolactin significantly increased, which was consistent with increased positive prolactin staining in pituitary gland. Elevated c-fos expression was observed in the arcuate hypothalamic nucleus (Arc) where we found 65% c-fos positive neurons co-localised with neuropeptide Y (NPY) in mice treated with risperidone. In addition, the results from in situ hybridization showed that the NPY mRNA in the Arc was significantly increased, whereas the tyrosine hydroxylase (TH) mRNA dramatically decreased compared with control group in the paraventricular hypothalamic nucleus (PVN). These findings revealed that risperidone may mediate the transcriptional regulation of Arc NPY and TH in the PVN. Furthermore, risperidone induced a decreased dopamine synthesis in the PVN and thus reduced the dopamine-induced inhibition of prolactin release, ultimately lead to hyperprolactinemia. Therefore, insights into these neuronal mechanisms open up potential new ways to treat schizophrenia patients in order to ameliorate hyperprolactinemia. PMID- 28336494 TI - Minocycline reduces inflammatory parameters in the brain structures and serum and reverses memory impairment caused by the administration of amyloid beta (1-42) in mice. AB - Alzheimer's disease (AD) is a neurodegenerative disorder and the most common type of age-related dementia. Cognitive decline, beta-amyloid (Abeta) accumulation, neurofibrillary tangles, and neuroinflammation are the main pathophysiological characteristics of AD. Minocycline is a tetracycline derivative with anti inflammatory properties that has a neuroprotective effect. The aim of this study was to evaluate the effect of minocycline on memory, neurotrophins and neuroinflammation in an animal model of AD induced by the administration of Abeta (1-42) oligomer. Male BALB/c mice were treated with minocycline (50mg/kg) via the oral route for a total of 17days, 24h after intracerebroventricular administration of Abeta (1-42) oligomer. At the end of this period, was performed the radial maze test, and 24h after the last minocycline administration, serum was collected and the cortex and hippocampus were dissected for biochemical analysis. The administration of minocycline reversed the memory impairment caused by Abeta (1-42). In the hippocampus, minocycline reversed the increases in the levels of interleukin (IL-1beta), Tumor Necrosis Factor- alpha (TNF-alpha) and, IL-10 caused by Abeta (1-42). In the cortex, AD-like model increase the levels of IL-1beta, TNF-alpha and, IL-4. Minocycline treatment reversed this. In the serum, Abeta (1-42) increased the levels of IL-1beta and IL-4, and minocycline was able to reverse this action, but not to reverse the decrease of IL-10 levels. Minocycline also reversed the increase in the levels of Brain-derived neurotrophic factor (BDNF) in the hippocampus caused by Abeta (1-42), and reduced Nerve Growth Factor (NGF) increases in the total cortex. Therefore, our results indicate that minocycline causes improvements in the spatial memory, and cytokine levels were correlated with this effect in the brain it. Besides this, minocycline reduced BDNF and NGF levels, highlighting the promising effects of minocycline in treating AD-like dementia. PMID- 28336495 TI - Genetic variation and epigenetic modification of the prodynorphin gene in peripheral blood cells in alcoholism. AB - Dynorphins are critically involved in the development, maintenance and relapse of alcoholism. Alcohol-induced changes in the prodynorphin gene expression may be influenced by both gene polymorphisms and epigenetic modifications. The present study of human alcoholics aims to evaluate DNA methylation patterns in the prodynorphin gene (PDYN) promoter and to identify single nucleotide polymorphisms (SNPs) associated with alcohol dependence and with altered DNA methylation. Genomic DNA was isolated from peripheral blood cells of alcoholics and healthy controls, and DNA methylation was studied in the PDYN promoter by bisulfite pyrosequencing. In alcoholics, DNA methylation increased in three of the seven CpG sites investigated, as well as in the average of the seven CpG sites. Data stratification showed lower increase in DNA methylation levels in individuals reporting craving and with higher levels of alcohol consumption. Association with alcoholism was observed for rs2235751 and the presence of the minor allele G was associated with reduced DNA methylation at PDYN promoter in females and younger subjects. Genetic and epigenetic factors within PDYN are related to risk for alcoholism, providing further evidence of its involvement on ethanol effects. These results might be of relevance for developing new biomarkers to predict disease trajectories and therapeutic outcome. PMID- 28336496 TI - Functional EEG network analysis in schizophrenia: Evidence of larger segregation and deficit of modulation. AB - OBJECTIVE: Higher mental functions depend on global cerebral functional coordination. Our aim was to study fast modulation of functional networks in schizophrenia that has not been previously assessed. METHODS: Graph-theory was used to analyze the electroencephalographic (EEG) activity during an odd-ball task in 57 schizophrenia patients (18 first episode patients, FEPs) and 59 healthy controls. Clustering coefficient (CLC), characteristic path length (PL) and small-worldness (SW) were computed at baseline ([-300 0] ms prior to stimulus delivery) and response ([150 450] ms post-stimulus) windows. Clinical and cognitive assessments were performed. RESULTS: CLC, PL and SW showed a significant modulation between baseline and response in controls but not in patients. Patients obtained higher CLC and SW at baseline, lower CLC and higher PL at response, and diminished modulation of CLC and SW as compared to controls. In patients, CLC and SW modulation were inversely associated to cognitive performance in executive tasks and directly associated to working memory. Similar patterns were observed in FEPs. CLC and SW during the baseline were inversely associated to their respective modulation magnitudes. CONCLUSIONS: Our results are coherent with a hyper-segregated network at baseline (higher CLC) and a decreased modulation of the functional connectivity during cognition in schizophrenia. PMID- 28336497 TI - Intrinsic disruption of white matter microarchitecture in first-episode, drug naive major depressive disorder: A voxel-based meta-analysis of diffusion tensor imaging. AB - Previous studies have demonstrated the influences of episodes and antidepressant drugs on white matter (WM) in patients with major depressive disorder (MDD). However, most diffusion tensor imaging (DTI) studies included highly heterogeneous individuals with different numbers of depressive episodes or medication status. To exclude the confounding effects of multiple episodes or medication, we conducted a quantitative voxel-based meta-analysis of fractional anisotropy (FA) in patients with first-episode, drug-naive MDD to identify the intrinsic WM alterations involved in the pathogenesis of MDD. The pooled meta analysis revealed significant FA reductions in the body of the corpus callosum (CC), bilateral anterior limb of the internal capsule (ALIC), right inferior temporal gyrus (ITG) and right superior frontal gyrus (SFG) in MDD patients relative to healthy controls. Meta-regression analyses revealed that FA reduction in the right ALIC and right SFG was negatively correlated with symptom severity and duration of depression, respectively. Our findings provide robust evidence that the WM impairments in the interhemispheric connections and frontal subcortical neuronal circuits may play an important role in MDD pathogenesis. PMID- 28336498 TI - Pregnancy does not affect fecal calprotectin concentration in healthy women. AB - BACKGROUND/AIMS: Noninvasive activity markers are extremely important in conditions, such as pregnancy, when endoscopy is not recommended. The aim of this prospective study was to determine fecal calprotectin (FC) concentrations in healthy non-pregnant and pregnant women and in patients with inflammatory bowel disease (IBD). MATERIALS AND METHODS: Healthy pregnant and non-pregnant women and patients with active and inactive IBD were prospectively enrolled in this study. Demographic and clinical parameters and clinical disease activity scores in patients with IBD were recorded. Blood and stool samples of every patient were obtained to determine C-reactive protein and FC levels. FC levels were measured with a quantitative lateral flow assay. RESULTS: One hundred and thirty-five subjects were enrolled in the study (24 non-pregnant and 48 pregnant healthy women, 40 non-pregnant patients with active IBD and 23 non-pregnant patients with inactive IBD). FC was significantly higher in active IBD patients than in pregnant (p<0.001) and non-pregnant healthy women (p<0.001). No difference could be detected in FC concentrations between pregnant and non-pregnant healthy women. CONCLUSION: Since FC levels remained unchanged during pregnancy, it may be a useful noninvasive diagnostic tool in pregnancy for monitoring mucosal inflammation. PMID- 28336499 TI - Radical resection of the pancreas should not always be necessary in the surgical management of pancreatic solid pseudopapillary tumor in children. AB - BACKGROUND/AIMS: Pancreatic solid pseudopapillary tumor (SPT) is a rare neoplasm in children. In this study, we aimed to present our surgical strategy based on minimal resection by enucleation or limited resection in localized pancreatic SPT. MATERIALS AND METHODS: We retrospectively analyzed the medical records of children who underwent surgical resection between October 2011 and September 2016. RESULTS: Five female patients with a median age of 15 years (range, 14-17 years) were operated. Tumors were located in the pancreatic head (n=4) or tail (n=1). The median greatest tumor diameter was 9 cm (range, 5-13 cm). All the patients were investigated with MRI before the resection to demonstrate the relationship between the tumor and the main pancreatic duct. Patients underwent enucleation (n=4) for head localization or local distal resection without splenectomy (n=1) at the pancreatic tail. At postoperative follow-up, major pancreatic leakage was observed in two patients and endoscopically treated. Surgical margins were negative in all patients. The median follow-up period was 44 months (range, 2-59 months) and no local recurrence or distant metastasis was observed in the postoperative period. CONCLUSION: An optimal surgical strategy is still controversial in pancreatic SPT in children. Radical resections such as pancreaticoduodenoctomy or distal pancreatectomy with splenectomy result in loss of pancreatic tissue for endocrine and exocrine functions. Minimal resections such as enucleation or limited pancreatic resection with negative surgical margins should be performed in selected patients with no invasion to the main pancreatic duct or adjacent organs. PMID- 28336500 TI - Stump Appendicitis: Result of an Incomplete Surgery. PMID- 28336501 TI - Extraordinary biliary variant. PMID- 28336502 TI - A new accurate model for predicting mortality up to 12 months after ERCP. PMID- 28336503 TI - Tweet for Behavior Change: Using Social Media for the Dissemination of Public Health Messages. AB - BACKGROUND: Social media public health campaigns have the advantage of tailored messaging at low cost and large reach, but little is known about what would determine their feasibility as tools for inducing attitude and behavior change. OBJECTIVE: The aim of this study was to test the feasibility of designing, implementing, and evaluating a social media-enabled intervention for skin cancer prevention. METHODS: A quasi-experimental feasibility study used social media (Twitter) to disseminate different message "frames" related to care in the sun and cancer prevention. Phase 1 utilized the Northern Ireland cancer charity's Twitter platform (May 1 to July 14, 2015). Following a 2-week "washout" period, Phase 2 commenced (August 1 to September 30, 2015) using a bespoke Twitter platform. Phase 2 also included a Thunderclap, whereby users allowed their social media accounts to automatically post a bespoke message on their behalf. Message frames were categorized into 5 broad categories: humor, shock or disgust, informative, personal stories, and opportunistic. Seed users with a notable following were contacted to be "influencers" in retweeting campaign content. A pre- and postintervention Web-based survey recorded skin cancer prevention knowledge and attitudes in Northern Ireland (population 1.8 million). RESULTS: There were a total of 417,678 tweet impressions, 11,213 engagements, and 1211 retweets related to our campaign. Shocking messages generated the greatest impressions (shock, n=2369; informative, n=2258; humorous, n=1458; story, n=1680), whereas humorous messages generated greater engagement (humorous, n=148; shock, n=147; story, n=117; informative, n=100) and greater engagement rates compared with story tweets. Informative messages, resulted in the greatest number of shares (informative, n=17; humorous, n=10; shock, n=9; story, n=7). The study findings included improved knowledge of skin cancer severity in a pre- and postintervention Web-based survey, with greater awareness that skin cancer is the most common form of cancer (preintervention: 28.4% [95/335] vs postintervention: 39.3% [168/428] answered "True") and that melanoma is most serious (49.1% [165/336] vs 55.5% [238/429]). The results also show improved attitudes toward ultraviolet (UV) exposure and skin cancer with a reduction in agreement that respondents "like to tan" (60.5% [202/334] vs 55.6% [238/428]). CONCLUSIONS: Social media-disseminated public health messages reached more than 23% of the Northern Ireland population. A Web-based survey suggested that the campaign might have contributed to improved knowledge and attitudes toward skin cancer among the target population. Findings suggested that shocking and humorous messages generated greatest impressions and engagement, but information-based messages were likely to be shared most. The extent of behavioral change as a result of the campaign remains to be explored, however, the change of attitudes and knowledge is promising. Social media is an inexpensive, effective method for delivering public health messages. However, existing and traditional process evaluation methods may not be suitable for social media. PMID- 28336504 TI - mHealth for Clinical Decision-Making in Sub-Saharan Africa: A Scoping Review. AB - BACKGROUND: In a bid to deliver quality health services in resource-poor settings, mobile health (mHealth) is increasingly being adopted. The role of mHealth in facilitating evidence-based clinical decision-making through data collection, decision algorithms, and evidence-based guidelines, for example, is established in resource-rich settings. However, the extent to which mobile clinical decision support systems (mCDSS) have been adopted specifically in resource-poor settings such as Africa and the lessons learned about their use in such settings are yet to be established. OBJECTIVE: The aim of this study was to synthesize evidence on the use of mHealth for point-of-care decision support and improved quality of care by health care workers in Africa. METHODS: A scoping review of 4 peer-reviewed and 1 grey literature databases was conducted. No date limits were applied, but only articles in English language were selected. Using pre-established criteria, 2 reviewers screened articles and extracted data. Articles were analyzed using Microsoft Excel and MAXQDA. RESULTS: We retained 22 articles representing 11 different studies in 7 sub-Saharan African countries. Interventions were mainly in the domain of maternal health and ranged from simple text messaging (short message service, SMS) to complex multicomponent interventions. Although health workers are generally supportive of mCDSS and perceive them as useful, concerns about increased workload and altered workflow hinder sustainability. Facilitators and barriers to use of mCDSS include technical and infrastructural support, ownership, health system challenges, and training. CONCLUSIONS: The use of mCDSS in sub-Saharan Africa is an indication of progress in mHealth, although their effect on quality of service delivery is yet to be fully explored. Lessons learned are useful for informing future research, policy, and practice for technologically supported health care delivery, especially in resource-poor settings. PMID- 28336505 TI - Internet-based Self-Management Support for Patients With Well-Controlled Type 2 Diabetes: A Real-Life Study. AB - BACKGROUND: Little attention has been paid to self-management support of patients with well-controlled type 2 diabetes mellitus (T2DM). Most studies evaluated the addition of self-management support to regular diabetes care, but self-management as an alternative for part of regular diabetes care has hardly been studied. In this study, we offered patients with well-controlled T2DM the opportunity to perform the 3 quarterly monitoring sessions at home using an Internet-based self management program, resulting in online personalized advice. OBJECTIVE: The aim of our study was to assess the reach and feasibility of an Internet-based diabetes self-management support program for patients with well-controlled T2DM, addressing both primary care providers' (PCPs) opinions and patients' willingness to participate in such a support program. METHODS: PCPs assessed patients' eligibility for Internet-based self-management, and patients were offered the opportunity to participate. Characteristics of eligible and ineligible patients were compared, as well as those of participants and nonparticipants, also with regard to quality of life, treatment satisfaction, and illness perceptions. Multivariate logistic regression models were performed and odds ratios (ORs) calculated with 95% CIs. RESULTS: Almost half (128/282, 45.4%) of the patients with well-controlled T2DM were considered ineligible by their PCPs mainly because of cognitive impairment and language barriers (8.2% and 8.9%). Older patients (OR for each year 1.06, 95% CI 1.03-1.09, P<.001), non-Western European patients (OR 3.64, 95% CI 1.67-7.92, P=.001), and patients with a longer diabetes duration (OR for each year 1.56, 95% CI 1.04-2.34, P=.03) were more often regarded as ineligible. Of the 154 patients considered eligible, 57 (37.0%) consented to participate and 30 (10.6%) started the program. Of 57 participants, 45 returned the 3 questionnaires; 21 of 97 nonparticipants returned the questionnaires. Nonparticipants less often thought that their disease would last their entire life (median 8.0 vs 10.0, P=.03) and they were more satisfied with their current treatment than participants (DTSQ total score 44.0 vs 40.0, P=.05). There was no significant difference in quality of life between the 2 groups. CONCLUSIONS: PCPs considered half of their patients with well-controlled T2DM incapable of Internet based self-management mainly because of cognitive impairment and language barriers; of the selected patients, about 1 out of 3 was willing to participate. Older patients, non-Western European patients, and patients with a higher BMI were less likely to participate. Predominantly, practical issues (such as Internet problems) hindered implementation of the Internet-based self-management program. PMID- 28336506 TI - Using eHealth Technologies: Interests, Preferences, and Concerns of Older Adults. AB - BACKGROUND: The Internet and eHealth technologies represent new opportunities for managing health. Age, sex, socioeconomic status, and current technology use are some of the known factors that influence individuals' uptake of eHealth; however, relatively little is known about facilitators and barriers to eHealth uptake specific to older adults, particularly as they relate to their experiences in accessing health care. OBJECTIVE: The aim of our study was to explore the interests, preferences, and concerns of older adults in using the Internet and eHealth technologies for managing their health in relation to their experiences with the current health care system. METHODS: Two focus groups (n=15) were conducted with adults aged 50+ years. Pragmatic thematic analysis using an inductive approach was conducted to identify the interests, preferences, and concerns of using the Internet and eHealth technologies. RESULTS: Five themes emerged that include (1) Difficulty in identifying credible and relevant sources of information on the Web; (2) Ownership, access, and responsibility for medical information; (3) Peer communication and support; (4) Opportunities to enhance health care interactions; and (5) Privacy concerns. These findings support the potential value older adults perceive in eHealth technologies, particularly in their ability to provide access to personal health information and facilitate communication between providers and peers living with similar conditions. However, in order to foster acceptance, these technologies will need to provide personal and general health information that is secure, readily accessible, and easily understood. CONCLUSIONS: Older adults have diverse needs and preferences that, in part, are driven by their experiences and frustrations with the health care system. Results can help inform the design and implementation of technologies to address gaps in care and access to health information for older adults with chronic conditions who may benefit the most from this approach. PMID- 28336507 TI - Planking or the "Lying-Down Game:" Two Case Reports. AB - BACKGROUND: The monitoring and management of risks regarding children and young people admitted to the emergency department as a result of dangerous behaviors distributed via the Internet should be based on clinical reasoning and knowledge about these social media-related phenomena. Here we examine 2 cases of teenagers who reported severe injuries while performing the "planking" craze, a challenge that consists in lying face-down stiffly like a board on any kind of surface. OBJECTIVE: Our objective is to examine and describe the Internet craze called planking, also known as the "lying-down game," through 2 case reports from our experience, enriching this study with information gained through discussions with secondary school teenagers. METHODS: Details of the 2 case reports were taken from electronic medical records giving information on care support processes, care management, and the costs of traumatic episodes. Demographic data, hemoglobin and serum lactate values, and Injury Severity Scores were evaluated. The study took place in secondary schools of our city from 2013 to 2014 during medical education courses, with the aim of analyzing the influence of social media on teenagers' activities and behaviors. RESULTS: Both patients suffered multiple trauma injuries and needed high-level health assistance. The first patient underwent a splenectomy and the second one a nephrectomy; both of them required a long hospital stay (14 and 20 days, respectively), and the costs for their management have been estimated at US $27,000 and US $37,000, respectively. Their decision to perform the planking in dangerous locations was due to their ambition to gain peers' acclaim through shared videos and pictures. CONCLUSIONS: Reporting and understanding these cases may potentially help prevent future events occurring in similar circumstances: the scientific community cannot leave this problem unaddressed. There is also a role of education resources for health care professionals; for this, we must identify and follow up strange or misleading information found on websites. A key element of this research study was to report physicians' misperceptions concerning planking and, with these cases used for teaching purposes, improve knowledge of the clinical and forensic aspects of this emerging problem. PMID- 28336508 TI - Using Web-Based Search Data to Study the Public's Reactions to Societal Events: The Case of the Sandy Hook Shooting. AB - BACKGROUND: Internet search is the most common activity on the World Wide Web and generates a vast amount of user-reported data regarding their information-seeking preferences and behavior. Although this data has been successfully used to examine outbreaks, health care utilization, and outcomes related to quality of care, its value in informing public health policy remains unclear. OBJECTIVE: The aim of this study was to evaluate the role of Internet search query data in health policy development. To do so, we studied the public's reaction to a major societal event in the context of the 2012 Sandy Hook School shooting incident. METHODS: Query data from the Yahoo! search engine regarding firearm-related searches was analyzed to examine changes in user-selected search terms and subsequent websites visited for a period of 14 days before and after the shooting incident. RESULTS: A total of 5,653,588 firearm-related search queries were analyzed. In the after period, queries increased for search terms related to "guns" (+50.06%), "shooting incident" (+333.71%), "ammunition" (+155.14%), and "gun-related laws" (+535.47%). The highest increase (+1054.37%) in Web traffic was seen by news websites following "shooting incident" queries whereas searches for "guns" (+61.02%) and "ammunition" (+173.15%) resulted in notable increases in visits to retail websites. Firearm-related queries generally returned to baseline levels after approximately 10 days. CONCLUSIONS: Search engine queries present a viable infodemiology metric on public reactions and subsequent behaviors to major societal events and could be used by policymakers to inform policy development. PMID- 28336511 TI - New negligence claims service aims to resolve cases more quickly. PMID- 28336510 TI - David Oliver: Getting real about care closer to home. PMID- 28336509 TI - Decriminalisation of abortion. PMID- 28336512 TI - An easily mistaken pulmonary opacity. PMID- 28336513 TI - Promises, promises. PMID- 28336514 TI - Doctors at India's top hospital call for new inquiry into woman's death after resident is sacked. PMID- 28336515 TI - The motor activity of DNA2 functions as an ssDNA translocase to promote DNA end resection. AB - DNA2 nuclease-helicase functions in DNA replication and recombination. This requires the nuclease of DNA2, while, in contrast, the role of the helicase activity has been unclear. We now show that the motor activity of both recombinant yeast and human DNA2 promotes efficient degradation of long stretches of ssDNA, particularly in the presence of the replication protein A. This degradation is further stimulated by a direct interaction with a cognate RecQ family helicase, which functions with DNA2 in DNA end resection to initiate homologous recombination. Consequently, helicase-deficient yeast dna2 K1080E cells display reduced resection speed of HO-induced DNA double-strand breaks. These results support a model of DNA2 and the RecQ family helicase partner forming a bidirectional motor machine, where the RecQ family helicase is the lead helicase, and the motor of DNA2 functions as a ssDNA translocase to promote degradation of 5'-terminated DNA. PMID- 28336517 TI - Gender-specific outcomes of cardiac resynchronisation therapy with or without defibrillator. PMID- 28336516 TI - A novel role of the Dna2 translocase function in DNA break resection. AB - DNA double-strand break repair by homologous recombination entails nucleolytic resection of the 5' strand at break ends. Dna2, a flap endonuclease with 5'-3' helicase activity, is involved in the resection process. The Dna2 helicase activity has been implicated in Okazaki fragment processing during DNA replication but is thought to be dispensable for DNA end resection. Unexpectedly, we found a requirement for the helicase function of Dna2 in end resection in budding yeast cells lacking exonuclease 1. Biochemical analysis reveals that ATP hydrolysis-fueled translocation of Dna2 on ssDNA facilitates 5' flap cleavage near a single-strand-double strand junction while attenuating 3' flap incision. Accordingly, the ATP hydrolysis-defective dna2-K1080E mutant is less able to generate long products in a reconstituted resection system. Our study thus reveals a previously unrecognized role of the Dna2 translocase activity in DNA break end resection and in the imposition of the 5' strand specificity of end resection. PMID- 28336520 TI - Surge in child emergency admissions prompts new care standards. PMID- 28336518 TI - BMP-9 interferes with liver regeneration and promotes liver fibrosis. AB - OBJECTIVE: Bone morphogenetic protein (BMP)-9, a member of the transforming growth factor-beta family of cytokines, is constitutively produced in the liver. Systemic levels act on many organs and tissues including bone and endothelium, but little is known about its hepatic functions in health and disease. DESIGN: Levels of BMP-9 and its receptors were analysed in primary liver cells. Direct effects of BMP-9 on hepatic stellate cells (HSCs) and hepatocytes were studied in vitro, and the role of BMP-9 was examined in acute and chronic liver injury models in mice. RESULTS: Quiescent and activated HSCs were identified as major BMP-9 producing liver cell type. BMP-9 stimulation of cultured hepatocytes inhibited proliferation, epithelial to mesenchymal transition and preserved expression of important metabolic enzymes such as cytochrome P450. Acute liver injury caused by partial hepatectomy or single injections of carbon tetrachloride (CCl4) or lipopolysaccharide (LPS) into mice resulted in transient downregulation of hepatic BMP-9 mRNA expression. Correspondingly, LPS stimulation led to downregulation of BMP-9 expression in cultured HSCs. Application of BMP-9 after partial hepatectomy significantly enhanced liver damage and disturbed the proliferative response. Chronic liver damage in BMP-9-deficient mice or in mice adenovirally overexpressing the selective BMP-9 antagonist activin-like kinase 1 Fc resulted in reduced deposition of collagen and subsequent fibrosis. CONCLUSIONS: Constitutive expression of low levels of BMP-9 stabilises hepatocyte function in the healthy liver. Upon HSC activation, endogenous BMP-9 levels increase in vitro and in vivo and high levels of BMP-9 cause enhanced damage upon acute or chronic injury. PMID- 28336519 TI - Anticollagen type II antibodies are associated with an acute onset rheumatoid arthritis phenotype and prognosticate lower degree of inflammation during 5 years follow-up. AB - OBJECTIVE: Antifibrillar collagen type II (anti-CII) antibody-positive patients with rheumatoid arthritis (RA) have early but not late signs of increased inflammation and joint erosions. We wanted to replicate this in a large RA cohort, and to relate to human leukocyte antigen (HLA)-DRB1* alleles. METHODS: Anti-CII and anti-cyclic citrullinated peptide (CCP)2 were measured at baseline in 773 patients with RA from the Swedish Epidemiological Investigation in Rheumatoid Arthritis (EIRA) study with clinical follow-up data from the Swedish Rheumatology Quality Register (SRQ) registry, and 1476 with HLA-DRB1* information. Comparisons were done concerning C reactive protein (CRP), erythrocyte sedimentation rate (ESR), tender joint count (TJC), swollen joint count (SJC), Disease Activity Score encompassing 28 joints based on ESR (DAS28), DAS28CRP, pain-Visual Analogue Scale (VAS), global-VAS and Health Assessment Questionnaire Score (HAQ) at eight occasions during 5 years, and association with HLA-DRB1* alleles. RESULTS: Anti-CII associated with elevated CRP, ESR, SJC, DAS28 and DAS28CRP at diagnosis and up to 6 months, whereas anti-CCP2 associated with SJC and DAS28 from 6 months to 5 years, but not earlier. The anti-CII associated phenotype was strong, and predominated in anti-CII/anti-CCP2 double positive patients. Anti-CII was associated with improvements in CRP, ESR, SJC, TJC and DAS28, whereas anti-CCP2 was associated with deteriorations in SJC and DAS28 over time. Anti-CII-positive patients achieved European League Against Rheumatism good or moderate response more often than negative patients. Anti-CII was positively associated with HLA-DRB1*01 and HLA-DRB1*03, with significant interaction, and double-positive individuals had >14 times higher mean anti-CII levels than HLA double negatives. Whereas smoking was associated with elevated anti-CCP2 levels, smokers had lower anti-CII levels. CONCLUSIONS: Anti-CII seropositive RA represents a distinct phenotype, in many respects representing the converse to the clinical, genetic and smoking associations described for anticitrullinated protein peptide autoantibodies. Although not diagnostically useful, early anti-CII determinations predict favourable inflammatory outcome in RA. PMID- 28336521 TI - Defending strong tobacco packaging and labelling regulations in Uruguay: transnational tobacco control network versus Philip Morris International. AB - OBJECTIVE: Describe the process of enacting and defending strong tobacco packaging and labelling regulations in Uruguay amid Philip Morris International's (PMI) legal threats and challenges. METHODS: Triangulated government legislation, news sources and interviews with policy-makers and health advocates in Uruguay. RESULTS: In 2008 and 2009, the Uruguayan government enacted at the time the world's largest pictorial health warning labels (80% of front and back of package) and prohibited different packaging or presentations for cigarettes sold under a given brand. PMI threatened to sue Uruguay in international courts if these policies were implemented. The Vazquez administration maintained the regulations, but a week prior to President Vazquez's successor, President Mujica, took office on 1 March 2010 PMI announced its intention to file an investment arbitration dispute against Uruguay in the International Centre for the Settlement of Investment Disputes. Initially, the Mujica administration announced it would weaken the regulations to avoid litigation. In response, local public health groups in Uruguay enlisted former President Vazquez and international health groups and served as brokers to develop a collaboration with the Mujica administration to defend the regulations. This united front between the Uruguayan government and the transnational tobacco control network paid off when Uruguay defeated PMI's investment dispute in July 2016. CONCLUSION: To replicate Uruguay's success, other countries need to recognise that strong political support, an actively engaged local civil society and financial and technical support are important factors in overcoming tobacco industry's legal threats to defend strong public health regulations. PMID- 28336524 TI - Dual roles for bone marrow-derived Sca-1 cells in cardiac function. AB - Recruitment of stem cells from the bone marrow (BM) is an important aspect of cardiac healing that becomes inefficient with age. We investigated the role of young stem cell antigen 1 (Sca-1)-positive BM cells on the aged heart by microarray analysis after BM reconstitution. Sca-1+ and Sca-1- BM cells from young green fluorescent protein (GFP)-positive mice were used to reconstitute the BM of aged mice. Myocardial infarction (MI) was induced 3 mo later. GFP+ cells were more abundant in the BM, blood, and heart of Sca-1+ mice, which corresponded to preserved cardiac function after MI. At baseline, Sca-1+ BM reconstitution increased cardiac expression of serum response factor, vascular endothelial growth factor A, and myogenic genes, but reduced the expression of Il-1beta. After MI, inflammation was identified as a key difference between Sca-1- and Sca 1+ groups, as cytokine expression and cell surface markers associated with inflammatory cells were up-regulated with Sca-1+ reconstitution. Mac-3 and F4/80 staining showed that the postinfarction heart was composed of a mixture of GFP+ (donor) macrophages, GFP- (host) macrophages, and GFP+ cells that did not contribute to the macrophage population. This study demonstrates that Sca-1+ BM cells regulate cardiac healing though an acute inflammatory response and also before injury by stimulating formation of a beneficial cardiac niche.-Tobin, S. W., Li, S.-H., Li, J., Wu, J., Yeganeh, A., Yu, P., Weisel, R. D., Li, R.-K. Dual roles for bone marrow-derived Sca-1 cells in cardiac function. PMID- 28336525 TI - Extracellular TDP-43 aggregates target MAPK/MAK/MRK overlapping kinase (MOK) and trigger caspase-3/IL-18 signaling in microglia. AB - Dysregulated microglial responses are central in neurodegenerative proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar disease (FTLD). Pathologic TDP-43, which is typically found in intracellular inclusions, is a misfolding protein with emerging roles in ALS and FTLD. Recently, TDP-43 species have been found in extracellular fluids of patients; however, the overall implications of TDP-43-mediated signaling linked to neuroinflammation are poorly understood. Our work-the first, to our knowledge, to focus on innate immunity responses to TDP-43 aggregates-shows that such species are internalized by microglia and cause abnormal mobilization of endogenous TDP-43. Exposure to TDP-43 aggregates elicited not only IL-1beta, but also NLRP3-dependent and noncanonical IL-18 processing. Moreover, we report a link between TDP-43 and neuronal loss via the apoptosis-independent emerging roles of caspase-3 in neurotoxic inflammation. Our results further support the view of noncell autonomous neurodegenerative mechanisms in ALS. Remarkably, we demonstrate that TDP-43 aggregates bind to and colocalize with MAPK/MAK/MRK overlapping kinase (MOK) and show that its phosphorylation status is disrupted. Finally, we show that this TDP-43-caused activation state can be altered by exogenous Hsp27 and Hsp70 chaperones. Our study provides new insight into the immune phenotype, mechanisms, and signaling pathways that operate in microglial neurotoxic activation in ALS.-Leal-Lasarte, M. M., Franco, J. M., Labrador Garrido, A., Pozo, D., Roodveldt, C. Extracellular TDP-43 aggregates target MAPK/MAK/MRK overlapping kinase (MOK) and trigger caspase-3/IL-18 signaling in microglia. PMID- 28336526 TI - Identification of unipotent megakaryocyte progenitors in human hematopoiesis. AB - The developmental pathway for human megakaryocytes remains unclear, and the definition of pure unipotent megakaryocyte progenitor is still controversial. Using single-cell transcriptome analysis, we have identified a cluster of cells within immature hematopoietic stem- and progenitor-cell populations that specifically expresses genes related to the megakaryocyte lineage. We used CD41 as a positive marker to identify these cells within the CD34+CD38+IL 3RalphadimCD45RA- common myeloid progenitor (CMP) population. These cells lacked erythroid and granulocyte-macrophage potential but exhibited robust differentiation into the megakaryocyte lineage at a high frequency, both in vivo and in vitro. The efficiency and expansion potential of these cells exceeded those of conventional bipotent megakaryocyte/erythrocyte progenitors. Accordingly, the CD41+ CMP was defined as a unipotent megakaryocyte progenitor (MegP) that is likely to represent the major pathway for human megakaryopoiesis, independent of canonical megakaryocyte-erythroid lineage bifurcation. In the bone marrow of patients with essential thrombocythemia, the MegP population was significantly expanded in the context of a high burden of Janus kinase 2 mutations. Thus, the prospectively isolatable and functionally homogeneous human MegP will be useful for the elucidation of the mechanisms underlying normal and malignant human hematopoiesis. PMID- 28336529 TI - TOE imaging of a large aortic mass: an unusual cause of systemic embolization in a septic patient. PMID- 28336528 TI - Platelet CD36 promotes thrombosis by activating redox sensor ERK5 in hyperlipidemic conditions. AB - Atherothrombosis is a process mediated by dysregulated platelet activation that can cause life-threatening complications and is the leading cause of death by cardiovascular disease. Platelet reactivity in hyperlipidemic conditions is enhanced when platelet scavenger receptor CD36 recognizes oxidized lipids in oxidized low-density lipoprotein (oxLDL) particles, a process that induces an overt prothrombotic phenotype. The mechanisms by which CD36 promotes platelet activation and thrombosis remain incompletely defined. In this study, we identify a mechanism for CD36 to promote thrombosis by increasing activation of MAPK extracellular signal-regulated kinase 5 (ERK5), a protein kinase known to be exquisitely sensitive to redox stress, through a signaling pathway requiring Src kinases, NADPH oxidase, superoxide radical anion, and hydrogen peroxide. Pharmacologic inhibitors of ERK5 blunted platelet activation and aggregation in response to oxLDL and targeted genetic deletion of ERK5 in murine platelets prevented oxLDL-induced platelet deposition on immobilized collagen in response to arterial shear. Importantly, in vivo thrombosis experiments after bone marrow transplantation from platelet-specific ERK5 null mice into hyperlipidemic apolipoprotein E null mice showed decreased platelet accumulation and increased thrombosis times compared with mice transplanted with ERK5 expressing control bone marrows. These findings suggest that atherogenic conditions critically regulate platelet CD36 signaling by increasing superoxide radical anion and hydrogen peroxide through a mechanism that promotes activation of MAPK ERK5. PMID- 28336530 TI - Using chiral tactoids as optical probes to study the aggregation behavior of chromonics. AB - Tactoids are nuclei of an orientationally ordered nematic phase that emerge upon cooling the isotropic phase. In addition to providing a natural setting for exploring chromonics under confinement, we show that tactoids can also serve as optical probes to delineate the role of temperature and concentration in the aggregation behavior of chromonics. For high concentrations, we observe the commonly reported elongated bipolar tactoids. As the concentration is lowered, breaking of achiral symmetry in the director configuration is observed with a predominance of twisted bipolar tactoids. On further reduction of concentration, a remarkable transformation of the director configuration occurs, wherein it conforms to a unique splay-minimizing configuration. Based on a simple model, we arrive at an interesting result that lower concentrations have longer aggregates at the same reduced temperature. Hence, the splay deformation that scales linearly with the aggregate length becomes prohibitive for lower concentrations and is relieved via twist and bend deformations in this unique configuration. Raman scattering measurements of the order parameters independently verify the trend in aggregate lengths and provide a physical picture of the nematic-biphasic transition. PMID- 28336527 TI - A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia. AB - Selinexor is a novel, first-in-class, selective inhibitor of nuclear export compound, which blocks exportin 1 (XPO1) function, leads to nuclear accumulation of tumor suppressor proteins, and induces cancer cell death. A phase 1 dose escalation study was initiated to examine the safety and efficacy of selinexor in patients with advanced hematological malignancies. Ninety-five patients with relapsed or refractory acute myeloid leukemia (AML) were enrolled between January 2013 and June 2014 to receive 4, 8, or 10 doses of selinexor in a 21- or 28-day cycle. The most frequently reported adverse events (AEs) in patients with AML were grade 1 or 2 constitutional and gastrointestinal toxicities, which were generally manageable with supportive care. The only nonhematological grade 3/4 AE, occurring in >5% of the patient population, was fatigue (14%). There were no reported dose-limiting toxicities or evidence of cumulative toxicity. The recommended phase 2 dose was established at 60 mg (~35 mg/m2) given twice weekly in a 4-week cycle based on the totality of safety and efficacy data. Overall, 14% of the 81 evaluable patients achieved an objective response (OR) and 31% percent showed >=50% decrease in bone marrow blasts from baseline. Patients achieving an OR had a significant improvement in median progression-free survival (PFS) (5.1 vs 1.3 months; P = .008; hazard ratio [HR], 3.1) and overall survival (9.7 vs 2.7 months; P = .01; HR, 3.1) compared with nonresponders. These findings suggest that selinexor is safe as a monotherapy in patients with relapsed or refractory AML and have informed subsequent phase 2 clinical development. This trial was registered at www.clinicaltrials.gov as #NCT01607892. PMID- 28336531 TI - Vasopressin-induced serine 269 phosphorylation reduces Sipa1l1 (signal-induced proliferation-associated 1 like 1)-mediated aquaporin-2 endocytosis. AB - The abundance of integral membrane proteins in the plasma membrane is determined by a dynamic balance between exocytosis and endocytosis, which can often be regulated by physiological stimuli. Here, we describe a mechanism that accounts for the ability of the peptide hormone vasopressin to regulate water excretion via a phosphorylation-dependent modulation of the PDZ domain-ligand interaction involving the water channel protein aquaporin-2. We discovered that the PDZ domain-containing protein Sipa1l1 (signal-induced proliferation-associated 1 like 1) binds to the cytoplasmic PDZ-ligand motif of aquaporin-2 and accelerates its endocytosis in the absence of vasopressin. Vasopressin-induced aquaporin-2 phosphorylation within the type I PDZ-ligand motif disrupted the interaction, in association with reduced aquaporin-2 endocytosis and prolonged plasma membrane aquaporin-2 retention. This phosphorylation-dependent alteration in the PDZ domain-ligand interaction was explained by 3D structural models, which showed a hormone-regulated mechanism that controls osmotic water transport and systemic water balance in mammals. PMID- 28336534 TI - Muscle length-dependent contribution of motoneuron Cav1.3 channels to force production in model slow motor unit. AB - Persistent inward current (PIC)-generating Cav1.3 channels in spinal motoneuron dendrites are thought to be actively recruited during normal behaviors. However, whether and how the activation of PIC channels influences force output of motor unit remains elusive. Here, building a physiologically realistic model of slow motor unit I demonstrated that force production induced by the PIC activation is much smaller for short than lengthened muscles during the regular firing of the motoneuron that transitions from the quiescent state by either a brief current pulse at the soma or a brief synaptic excitation at the dendrites. By contrast, the PIC-induced force potentiation was maximal for short muscles when the motoneuron switched from a stable low-frequency firing state to a stable high frequency firing state by the current pulse at the soma. Under the synaptic excitation at the dendrites, however, the force could not be potentiated by the transitioning of the motoneuron from a low- to a high-frequency firing state due to the simultaneous onset of PIC at the dendrites and firing at the soma. The strong dependency of the input-output relationship of the motor unit on the neuromodulation and Ia afferent inputs for the PIC channels was further shown under static variations in muscle length. Taken together, these findings suggest that the PIC activation in the motoneuron dendrites may differentially affect the force production of the motor unit, depending not only on the firing state history of the motoneuron and the variation in muscle length but also on the mode of motor activity.NEW & NOTEWORTHY Cav1.3 channels in motoneuron dendrites are actively involved during normal motor activities. To investigate the effects of the activation of motoneuron Cav1.3 channels on force production, a model motor unit was built based on best-available data. The simulation results suggest that force potentiation induced by Cav1.3 channel activation is strongly modulated not only by firing history of the motoneuron but also by length variation of the muscle as well as neuromodulation inputs from the brainstem. PMID- 28336532 TI - MOAG-4 promotes the aggregation of alpha-synuclein by competing with self protective electrostatic interactions. AB - Aberrant protein aggregation underlies a variety of age-related neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Little is known, however, about the molecular mechanisms that modulate the aggregation process in the cellular environment. Recently, MOAG-4/SERF has been identified as a class of evolutionarily conserved proteins that positively regulates aggregate formation. Here, by using nuclear magnetic resonance (NMR) spectroscopy, we examine the mechanism of action of MOAG-4 by characterizing its interaction with alpha synuclein (alpha-Syn). NMR chemical shift perturbations demonstrate that a positively charged segment of MOAG-4 forms a transiently populated alpha-helix that interacts with the negatively charged C terminus of alpha-Syn. This process interferes with the intramolecular interactions between the N- and C-terminal regions of alpha-Syn, resulting in the protein populating less compact forms and aggregating more readily. These results provide a compelling example of the complex competition between molecular and cellular factors that protect against protein aggregation and those that promote it. PMID- 28336533 TI - Critical residues and motifs for homodimerization of the first transmembrane domain of the plasma membrane glycoprotein CD36. AB - The plasma transmembrane (TM) glycoprotein CD36 is critically involved in many essential signaling processes, especially the binding/uptake of long-chain fatty acids and oxidized low-density lipoproteins. The association of CD36 potentially activates cytosolic protein tyrosine kinases that are thought to associate with the C-terminal cytoplasmic tail of CD36. To understand the mechanisms by which CD36 mediates ligand binding and signal transduction, we have characterized the homo-oligomeric interaction of CD36 TM domains in membrane environments and with molecular dynamics (MD) simulations. Analysis of pyrene- and coumarin-labeled TM1 peptides in SDS by FRET confirmed the homodimerization of the CD36 TM1 peptide. Homodimerization assays of CD36 TM domains with the TOXCAT technique showed that its first TM (TM1) domain, but not the second TM (TM2) domain, could homodimerize in a cell membrane. Small-residue, site-specific mutation scanning revealed that the CD36 TM1 dimerization is mediated by the conserved small residues Gly12, Gly16, Ala20, and Gly23 Furthermore, molecular dynamics (MD) simulation studies demonstrated that CD36 TM1 exhibited a switching dimerization with two right handed packing modes driven by the 12GXXXGXXXA20 and 20AXXG23 motifs, and the mutational effect of G16I and G23I revealed these representative conformations of CD36 TM1. This packing switch pattern of CD36 TM1 homodimer was further examined and confirmed by FRET analysis of monobromobimane (mBBr)-labeled CD36 TM1 peptides. Overall, this work provides a structural basis for understanding the role of TM association in regulating signal transduction via CD36. PMID- 28336535 TI - The effects of short work vs. longer work periods within intermittent exercise on Vo2p kinetics, muscle deoxygenation, and energy system contribution. AB - We examined the effects of inserting 3-s recovery periods during high-intensity cycling exercise at 25-s and 10-s intervals on pulmonary oxygen uptake (Vo2p), muscle deoxygenation [deoxyhemoglobin (HHb)], their associated kinetics (tau), and energy system contributions. Eleven men (24 +/- 3 yr) completed two trials of three cycling protocols: an 8-min continuous protocol (CONT) and two 8-min intermittent exercise protocols with work-to-rest periods of 25 s to 3 s (25INT) and 10 s to 3 s (10INT). Each protocol began with a step-transition from a 20-W baseline to a power output (PO) of 60% between lactate threshold and maximal Vo2p (Delta60). This PO was maintained for 8 min in CONT, whereas 3-s periods of 20-W cycling were inserted every 10 s and 25 s after the transition to Delta60 in 10INT and 25INT, respectively. Breath-by-breath gas exchange measured by mass spectrometry and turbine and vastus lateralis [HHb] measured by near-infrared spectroscopy were recorded throughout. Arterialized-capillary lactate concentration ([Lac-]) was obtained before and 2 min postexercise. The tauVo2p was lowest (P < 0.05) for 10INT (24 +/- 4 s) and 25INT (23 +/- 5 s) compared with CONT (28 +/- 4 s), whereas HHb kinetics did not differ (P > 0.05) between conditions. Postexercise [Lac-] was lowest (P < 0.05) for 10INT (7.0 +/- 1.7 mM), was higher for 25INT (10.3 +/- 1.9 mM), and was greatest in CONT (14.3 +/- 3.1 mM). Inserting 3-s recovery periods during heavy-intensity exercise speeded Vo2p kinetics and reduced overall Vo2p, suggesting an increased reliance on PCr derived phosphorylation during the work period of INT compared with an identical PO performed continuously.NEW & NOTEWORTHY We report novel observations on the effects of differing heavy-intensity work durations between 3-s recovery periods on pulmonary oxygen uptake (Vo2p) kinetics, muscle deoxygenation, and energy system contributions. Relative to continuous exercise, Vo2p kinetics are faster in intermittent exercise, and increased frequency of 3-s recovery periods improves microvascular O2 delivery and reduces Vo2p and arterialized-capillary lactate concentration. The metabolic burden of identical intensity work is altered when performed intermittently vs. continuously. PMID- 28336536 TI - The effect of aging and cardiorespiratory fitness on the lung diffusing capacity response to exercise in healthy humans. AB - Aging is associated with deterioration in the structure and function of the pulmonary circulation. We characterized the lung diffusing capacity for carbon monoxide (DLCO), alveolar-capillary membrane conductance (DmCO), and pulmonary capillary blood volume (Vc) response to discontinuous incremental exercise at 25, 50, 75, and 90% of peak work (Wpeak) in four groups: 1) Young [27 +/- 3 yr, maximal oxygen consumption (Vo2max): 110 +/- 18% age predicted]; 2) Young Highly Fit (27 +/- 3 yr, Vo2max: 147 +/- 8% age predicted); 3) Old (69 +/- 5 yr, Vo2max: 116 +/- 13% age predicted); and 4) Old Highly Fit (65 +/- 5 yr, Vo2max: 162 +/- 18% age predicted). At rest and at 90% Wpeak, DLCO, DmCO, and Vc were decreased with age. At 90% Wpeak, DLCO, DmCO, and Vc were greater in Old Highly Fit vs. Old adults. The slope of the DLCO-cardiac output (Q) relationship from rest to end exercise at 90% Wpeak was not different between Young, Young Highly Fit, Old, and Old Highly Fit (1.35 vs. 1.44 vs. 1.10 vs. 1.35 mlCO.mmHg-1.liter blood-1, P = 0.388), with no evidence of a plateau in this relationship during exercise; this was also true for DmCO-Q and Vc-Q. Vo2max was positively correlated with 1) DLCO, DmCO, and Vc at rest; and 2) the rest to end exercise change in DLCO, DmCO, and Vc. In conclusion, these data suggest that despite the age-associated deterioration in the structure and function of the pulmonary circulation, expansion of the pulmonary capillary network does not become limited during exercise in healthy individuals regardless of age or cardiorespiratory fitness level.NEW & NOTEWORTHY Healthy aging is a crucial area of research. This article details how differences in age and cardiorespiratory fitness level affect lung diffusing capacity, particularly during high-intensity exercise. We conclude that highly fit older adults do not experience a limit in lung diffusing capacity during high-intensity exercise. Interestingly, however, we found that highly fit older individuals demonstrate greater values of lung diffusing capacity during high-intensity exercise than their less fit age-matched counterparts. PMID- 28336539 TI - The influence of gravity on regional lung blood flow in humans: SPECT in the upright and head-down posture. AB - Previous studies in humans have shown that gravity has little influence on the distribution of lung blood flow while changing posture from supine to prone. This study aimed to evaluate the maximal influence of posture by comparison of regional lung blood flow in the upright and head-down posture in 8 healthy volunteers, using a tilt table. Regional lung blood flow was marked by intravenous injection of macroaggregates of human albumin labeled with 99mTc or 113mIn, in the upright and head-down posture, respectively, during tidal breathing. Both radiotracers remain fixed in the lung after administration. The distribution of radioactivity was mapped using quantitative single photon emission computed tomography (SPECT) corrected for attenuation and scatter. All images were obtained supine during tidal breathing. A shift from upright to the head-down posture caused a clear redistribution of blood flow from basal to apical regions. We conclude that posture plays a role for the distribution of lung blood flow in upright humans, and that the influence of posture, and thereby gravity, is much greater in the upright and head-down posture than in horizontal postures. However, the results of the study demonstrate that lung structure is the main determinant of regional blood flow and gravity is a secondary contributor to the distribution of lung blood flow in the upright and head-down positions.NEW & NOTEWORTHY Using a dual-isotope quantitative SPECT method, we demonstrated that although a shift in posture redistributes blood flow in the direction of gravity, the results are also consistent with lung structure being a greater determinant of regional blood flow than gravity. To our knowledge, this is the first study to use modern imaging methods to quantify the shift in regional lung blood flow in humans at a change between the upright and head-down postures. PMID- 28336537 TI - Muscle-specific and age-related changes in protein synthesis and protein degradation in response to hindlimb unloading in rats. AB - Disuse is a potent inducer of muscle atrophy, but the molecular mechanisms driving this loss of muscle mass are highly debated. In particular, the extent to which disuse triggers decreases in protein synthesis or increases in protein degradation, and whether these changes are uniform across muscles or influenced by age, is unclear. We aimed to determine the impact of disuse on protein synthesis and protein degradation in lower limb muscles of varied function and fiber type in adult and old rats. Alterations in protein synthesis and degradation were measured in the soleus, medial gastrocnemius, and tibialis anterior (TA) muscles of adult and old rats subjected to hindlimb unloading (HU) for 3, 7, or 14 days. Loss of muscle mass was progressive during the unloading period, but highly variable (-9 to -38%) across muscle types and between ages. Protein synthesis decreased significantly in all muscles, except for the old TA. Atrophy-associated gene expression was only loosely associated with protein degradation as muscle RING finger-1, muscle atrophy F-box (MAFbx), and Forkhead box O1 expression significantly increased in all muscles, but an increase in proteasome activity was only observed in the adult soleus. MAFbx protein levels were significantly higher in the old muscles compared with adult muscles, despite the old having higher expression of microRNA-23a. These results indicate that adult and old muscles respond similarly to HU, and the greatest loss in muscle mass occurs in predominantly slow-twitch extensor muscles due to a concomitant decrease in protein synthesis and increase in protein degradation.NEW & NOTEWORTHY In this study, we showed that age did not intensify the atrophy response to unloading in rats, but rather that the degree of atrophy was highly variable across muscles, indicating that changes in protein synthesis and protein degradation occur in a muscle-specific manner. Our data emphasize the importance of studying muscles of varying fiber-type and physiological function at multiple time points to fully understand the molecular mechanisms responsible for disuse atrophy. PMID- 28336538 TI - Effects of dobutamine on intestinal microvascular blood flow heterogeneity and O2 extraction during septic shock. AB - Derangements of microvascular blood flow distribution might contribute to disturbing O2 extraction by peripheral tissues. We evaluated the dynamic relationships between the mesenteric O2 extraction ratio ([Formula: see text]) and the heterogeneity of microvascular blood flow at the gut and sublingual mucosa during the development and resuscitation of septic shock in a swine model of fecal peritonitis. Jejunal-villi and sublingual microcirculation were evaluated using a portable intravital-microscopy technique. Simultaneously, we obtained arterial, mixed-venous, and mesenteric blood gases, and jejunal tonometric measurements. During resuscitation, pigs were randomly allocated to a fixed dose of dobutamine (5 ug.kg-1.min-1) or placebo while three sham models with identical monitoring served as controls. At the time of shock, we observed a significant decreased proportion of perfused intestinal-villi (villi-PPV) and sublingual percentage of perfused small vessels (SL-PPV), paralleling an increase in [Formula: see text] in both dobutamine and placebo groups. After starting resuscitation, villi-PPV and SL-PPV significantly increased in the dobutamine group with subsequent improvement of functional capillary density, whereas [Formula: see text] exhibited a corresponding significant decrease (repeated measures ANOVA, P = 0.02 and P = 0.04 for time * group interactions and intergroup differences for villi-PPV and [Formula: see text], respectively). Variations in villi-PPV were paralleled by variations in [Formula: see text] (R2 = 0.88, P < 0.001) and these, in turn, by mesenteric lactate changes (R2 = 0.86, P < 0.001). There were no significant differences in cardiac output and systemic O2 delivery throughout the experiment. In conclusion, dynamic changes in microvascular blood flow heterogeneity at jejunal mucosa are closely related to the mesenteric O2 extraction ratio, suggesting a crucial role for microvascular blood flow distribution on O2 uptake during development and resuscitation from septic shock.NEW & NOTEWORTHY Our observations suggest that dynamic changes in the heterogeneity of microvascular blood flow at the gut mucosa are closely related to mesenteric O2 extraction, thus supporting the role of decreasing functional capillary density and increased intercapillary distances on alterations of O2 uptake during development and resuscitation from septic shock. Addition of a low-fixed dose of dobutamine might reverse such flow heterogeneity, improving microcirculatory flow distribution and tissue O2 consumption. PMID- 28336540 TI - Effects of midline sagittal location on bone-conducted cervical and ocular vestibular evoked myogenic potentials. AB - We have investigated the effectiveness of two bone-conducted (BC) stimuli in producing vestibular evoked myogenic potentials (VEMPs) following stimulation along midsagittal skull sites. Twenty subjects (mean age 24 yr, range: 18-34 yr; 6 men; 14 women) were studied using a smoothed impulse and a 500-Hz tone burst applied to Nz, Fpz, AFz, Fz, FCz, and Cz with both compressive and rarefactive onset phases. Cervical (cVEMPs) and ocular VEMPs (oVEMPs) were recorded as well as linear acceleration in three axes. cVEMPs evoked by 500 Hz showed no change in response polarity to either stimulus location or phase. cVEMPs evoked by the impulsive stimulus showed larger initial peak amplitudes at AFz and Fz using compressive stimuli and differences in initial peak latency between the two phases. In contrast, amplitude, latency, and response polarity for oVEMPs were markedly affected by stimulus location and phase, which were similar for both BC stimuli, with little correlation with induced acceleration of the head. Latencies were earliest at AFz and Fz where compressive onset stimuli evoked an initial negativity (average latency 8.6-11.0 ms). At other sites compressive onset stimuli usually evoked oVEMPs with an initial positivity. We conclude that both 500 Hz and impulsive stimuli are effective means of evoking cVEMPs and oVEMPs from mid sagittal skull sites. The effects depend upon both location and phase and differ for oVEMPs and cVEMPs. Initial negativities for oVEMPs following compressive stimuli were most consistently obtained using the AFz and Fz sites.NEW & NOTEWORTHY We investigated the effect of stimulus location and phase (compressive and rarefactive) in the midsagittal plane for the cVEMP and oVEMP evoked by bone-conducted (BC) 500 Hz and BC impulsive stimuli. For cVEMPs, location effects were limited but were observed for BC impulses. For oVEMPs, both stimuli affected amplitude, latency, and polarity, depending on stimulus location and phase. Compressive stimuli at Fz and AFz evoked early negative oVEMPs most reliably. PMID- 28336541 TI - Unilateral nasal obstruction affects motor representation development within the face primary motor cortex in growing rats. AB - Postnatal growth is influenced by genetic and environmental factors. Nasal obstruction during growth alters the electromyographic activity of orofacial muscles. The facial primary motor area represents muscles of the tongue and jaw, which are essential in regulating orofacial motor functions, including chewing and jaw opening. This study aimed to evaluate the effect of chronic unilateral nasal obstruction during growth on the motor representations within the face primary motor cortex (M1). Seventy-two 6-day-old male Wistar rats were randomly divided into control (n = 36) and experimental (n = 36) groups. Rats in the experimental group underwent unilateral nasal obstruction after cauterization of the external nostril at 8 days of age. Intracortical microstimulation (ICMS) mapping was performed when the rats were 5, 7, 9, and 11 wk old in control and experimental groups (n = 9 per group per time point). Repeated-measures multivariate ANOVA was used for intergroup and intragroup statistical comparisons. In the control and experimental groups, the total number of positive ICMS sites for the genioglossus and anterior digastric muscles was significantly higher at 5, 7, and 9 wk, but there was no significant difference between 9 and 11 wk of age. Moreover, the total number of positive ICMS sites was significantly smaller in the experimental group than in the control at each age. It is possible that nasal obstruction induced the initial changes in orofacial motor behavior in response to the altered respiratory pattern, which eventually contributed to face M1 neuroplasticity.NEW & NOTEWORTHY Unilateral nasal obstruction in rats during growth periods induced changes in arterial oxygen saturation (SpO2) and altered development of the motor representation within the face primary cortex. Unilateral nasal obstruction occurring during growth periods may greatly affect not only respiratory function but also craniofacial function in rats. Nasal obstruction should be treated as soon as possible to avoid adverse effects on normal growth, development, and physiological functions. PMID- 28336542 TI - Seten: a tool for systematic identification and comparison of processes, phenotypes, and diseases associated with RNA-binding proteins from condition specific CLIP-seq profiles. AB - RNA-binding proteins (RBPs) control the regulation of gene expression in eukaryotic genomes at post-transcriptional level by binding to their cognate RNAs. Although several variants of CLIP (crosslinking and immunoprecipitation) protocols are currently available to study the global protein-RNA interaction landscape at single-nucleotide resolution in a cell, currently there are very few tools that can facilitate understanding and dissecting the functional associations of RBPs from the resulting binding maps. Here, we present Seten, a web-based and command line tool, which can identify and compare processes, phenotypes, and diseases associated with RBPs from condition-specific CLIP-seq profiles. Seten uses BED files resulting from most peak calling algorithms, which include scores reflecting the extent of binding of an RBP on the target transcript, to provide both traditional functional enrichment as well as gene set enrichment results for a number of gene set collections including BioCarta, KEGG, Reactome, Gene Ontology (GO), Human Phenotype Ontology (HPO), and MalaCards Disease Ontology for several organisms including fruit fly, human, mouse, rat, worm, and yeast. It also provides an option to dynamically compare the associated gene sets across data sets as bubble charts, to facilitate comparative analysis. Benchmarking of Seten using eCLIP data for IGF2BP1, SRSF7, and PTBP1 against their corresponding CRISPR RNA-seq in K562 cells as well as randomized negative controls, demonstrated that its gene set enrichment method outperforms functional enrichment, with scores significantly contributing to the discovery of true annotations. Comparative performance analysis using these CRISPR control data sets revealed significantly higher precision and comparable recall to that observed using ChIP-Enrich. Seten's web interface currently provides precomputed results for about 200 CLIP-seq data sets and both command line as well as web interfaces can be used to analyze CLIP-seq data sets. We highlight several examples to show the utility of Seten for rapid profiling of various CLIP-seq data sets. Seten is available on http://www.iupui.edu/~sysbio/seten/. PMID- 28336543 TI - In vivo binding of PRDM9 reveals interactions with noncanonical genomic sites. AB - In mouse and human meiosis, DNA double-strand breaks (DSBs) initiate homologous recombination and occur at specific sites called hotspots. The localization of these sites is determined by the sequence-specific DNA binding domain of the PRDM9 histone methyl transferase. Here, we performed an extensive analysis of PRDM9 binding in mouse spermatocytes. Unexpectedly, we identified a noncanonical recruitment of PRDM9 to sites that lack recombination activity and the PRDM9 binding consensus motif. These sites include gene promoters, where PRDM9 is recruited in a DSB-dependent manner. Another subset reveals DSB-independent interactions between PRDM9 and genomic sites, such as the binding sites for the insulator protein CTCF. We propose that these DSB-independent sites result from interactions between hotspot-bound PRDM9 and genomic sequences located on the chromosome axis. PMID- 28336544 TI - High-resolution anatomic correlation of cyclic motor patterns in the human colon: Evidence of a rectosigmoid brake. AB - Colonic cyclic motor patterns (CMPs) have been hypothesized to act as a brake to limit rectal filling. However, the spatiotemporal profile of CMPs, including anatomic origins and distributions, remains unclear. This study characterized colonic CMPs using high-resolution (HR) manometry (72 sensors, 1-cm resolution) and their relationship with proximal antegrade propagating events. Nine healthy volunteers were recruited. Recordings were performed over 4 h, with a 700-kcal meal given after 2 h. Propagating events were visually identified and analyzed by pattern, origin, amplitude, extent of propagation, velocity, and duration. Manometric data were normalized using anatomic landmarks identified on abdominal radiographs. These were mapped over a three-dimensional anatomic model. CMPs comprised a majority of detected propagating events. Most occurred postprandially and were retrograde propagating events (84.9 +/- 26.0 retrograde vs. 14.3 +/- 11.8 antegrade events/2 h, P = 0.004). The dominant sites of initiation for retrograde CMPs were in the rectosigmoid region, with patterns proximally propagating by a mean distance of 12.4 +/- 0.3 cm. There were significant differences in the characteristics of CMPs depending on the direction of travel and site of initiation. Association analysis showed that proximal antegrade propagating events occurred independently of CMPs. This study accurately characterized CMPs with anatomic correlation. CMPs were unlikely to be triggered by proximal antegrade propagating events in our study context. However, the distal origin and prominence of retrograde CMPs could still act as a mechanism to limit rectal filling and support the theory of a "rectosigmoid brake."NEW & NOTEWORTHY Retrograde cyclic motor patterns (CMPs) are the dominant motor patterns in a healthy prepared human colon. The major sites of initiation are in the rectosigmoid region, with retrograde propagation, supporting the idea of a "rectosigmoid brake." A significant increase in the number of CMPs is seen after a meal. In our study context, the majority of CMPs occurred independent of proximal propagating events, suggesting that CMPs are primarily controlled by external innervation. PMID- 28336545 TI - Changes in intestinal microbiota composition and metabolism coincide with increased intestinal permeability in young adults under prolonged physiological stress. AB - The magnitude, temporal dynamics, and physiological effects of intestinal microbiome responses to physiological stress are poorly characterized. This study used a systems biology approach and a multiple-stressor military training environment to determine the effects of physiological stress on intestinal microbiota composition and metabolic activity, as well as intestinal permeability (IP). Soldiers (n = 73) were provided three rations per day with or without protein- or carbohydrate-based supplements during a 4-day cross-country ski-march (STRESS). IP was measured before and during STRESS. Blood and stool samples were collected before and after STRESS to measure inflammation, stool microbiota, and stool and plasma global metabolite profiles. IP increased 62 +/- 57% (mean +/- SD, P < 0.001) during STRESS independent of diet group and was associated with increased inflammation. Intestinal microbiota responses were characterized by increased alpha-diversity and changes in the relative abundance of >50% of identified genera, including increased abundance of less dominant taxa at the expense of more dominant taxa such as Bacteroides Changes in intestinal microbiota composition were linked to 23% of metabolites that were significantly altered in stool after STRESS. Together, pre-STRESS Actinobacteria relative abundance and changes in serum IL-6 and stool cysteine concentrations accounted for 84% of the variability in the change in IP. Findings demonstrate that a multiple-stressor military training environment induced increases in IP that were associated with alterations in markers of inflammation and with intestinal microbiota composition and metabolism. Associations between IP, the pre-STRESS microbiota, and microbiota metabolites suggest that targeting the intestinal microbiota could provide novel strategies for preserving IP during physiological stress.NEW & NOTEWORTHY Military training, a unique model for studying temporal dynamics of intestinal barrier and intestinal microbiota responses to stress, resulted in increased intestinal permeability concomitant with changes in intestinal microbiota composition and metabolism. Prestress intestinal microbiota composition and changes in fecal concentrations of metabolites linked to the microbiota were associated with increased intestinal permeability. Findings suggest that targeting the intestinal microbiota could provide novel strategies for mitigating increases in intestinal permeability during stress. PMID- 28336546 TI - Barrett's metaplasia develops from cellular reprograming of esophageal squamous epithelium due to gastroesophageal reflux. AB - Gastroesophageal reflux disease (GERD) clinically predisposes to columnar Barrett's metaplasia (BM) in the distal esophagus. We demonstrate evidence supporting the cellular origin of BM from reprograming or transcommitment of resident normal esophageal squamous (NES) epithelial cells in response to acid and bile (A + B) exposure using an in vitro cell culture model. The hTERT immortalized NES cell line NES-B10T was exposed 5 min/day to an A + B mixture for 30 wk. Morphological changes, mRNA, and protein expression levels for the inflammatory marker cyclooxygenase-2; the lineage-determining transcription factors TAp63 (squamous), CDX2, and SOX9 (both columnar); and the columnar lineage markers Villin, Muc-2, CK8, and mAb Das-1 (incomplete phenotype of intestinal metaplasia) were assessed every 10 wk. Markers of columnar lineage and inflammation increased progressively, while squamous lineage-determining transcriptional factors were significantly decreased both at the mRNA and/or protein level in the NES-B10T cells at/after A + B treatment for 30 wk. Distinct modifications in morphological features were only observed at/after 30 wk of A + B exposure. These changes acquired by the NES-B10T 30-wk cells were retained even after cessation of A + B exposure for at least 3 wk. This study provides evidence that chronic exposure to the physiological components of gastric refluxate leads to repression of the discernable squamous transcriptional factors and activation of latent columnar transcriptional factors. This reflects the alteration in lineage commitment of the precursor-like biphenotypic, NES-B10T cells in response to A + B exposure as the possible origin of BM from the resident NES cells.NEW & NOTEWORTHY This study provides evidence of the origins of Barrett's metaplasia from lineage transcommitment of resident esophageal cells after chronic exposure to gastroesophageal refluxate. The preterminal progenitor-like squamous cells alter their differentiation and develop biphenotypic characteristics, expressing markers of incomplete-type columnar metaplasia. Development of these biphenotypic precursors in vitro is a unique model to study pathogenesis of Barrett's metaplasia and esophageal adenocarcinoma. PMID- 28336547 TI - Glycans in the intestinal peptide transporter PEPT1 contribute to function and protect from proteolysis. AB - Despite the fact that many membrane proteins carry extracellular glycans, little is known about whether the glycan chains also affect protein function. We recently demonstrated that the proton-coupled oligopeptide transporter 1 (PEPT1) in the intestine is glycosylated at six asparagine residues (N50, N406, N439, N510, N515, and N532). Mutagenesis-induced disruption of the individual N glycosylation site N50, which is highly conserved among mammals, was detected to significantly enhance the PEPT1-mediated inward transport of peptides. Here, we show that for the murine protein the inhibition of glycosylation at sequon N50 by substituting N50 with glutamine, lysine, or cysteine or by replacing S52 with alanine equally altered PEPT1 transport kinetics in oocytes. Furthermore, we provide evidence that the uptake of [14C]glycyl-sarcosine in immortalized murine small intestinal (MODE-K) or colonic epithelial (PTK-6) cells stably expressing the PEPT1 transporter N50Q is also significantly increased relative to the wild type protein. By using electrophysiological recordings and tracer flux studies, we further demonstrate that the rise in transport velocity observed for PEPT1 N50Q is bidirectional. In line with these findings, we show that attachment of biotin derivatives, comparable in weight with two to four monosaccharides, to the PEPT1 N50C transporter slows down the transport velocity. In addition, our experiments provide strong evidence that glycosylation of PEPT1 confers resistance against proteolytic cleavage by proteinase K, whereas a remarkable intrinsic stability against trypsin, even in the absence of N-linked glycans, was detected.NEW & NOTEWORTHY This study highlights the role of N50-linked glycans in modulating the bidirectional transport activity of the murine peptide transporter PEPT1. Electrophysiological and tracer flux measurements in Xenopus oocytes have shown that removal of the N50 glycans increases the maximal peptide transport rate in the inward and outward directions. This effect could be largely reversed by replacement of N50 glycans with structurally dissimilar biotin derivatives. In addition, N-glycans were detected to stabilize PEPT1 against proteolytic cleavage. PMID- 28336548 TI - Nutrient sensing by absorptive and secretory progenies of small intestinal stem cells. AB - Nutrient sensing triggers responses by the gut-brain axis modulating hormone release, feeding behavior and metabolism that become dysregulated in metabolic syndrome and some cancers. Except for absorptive enterocytes and secretory enteroendocrine cells, the ability of many intestinal cell types to sense nutrients is still unknown; hence we hypothesized that progenitor stem cells (intestinal stem cells, ISC) possess nutrient sensing ability inherited by progenies during differentiation. We directed via modulators of Wnt and Notch signaling differentiation of precursor mouse intestinal crypts into specialized organoids each containing ISC, enterocyte, goblet, or Paneth cells at relative proportions much higher than in situ as determined by mRNA expression and immunocytochemistry of cell type biomarkers. We identified nutrient sensing cell type(s) by increased expression of fructolytic genes in response to a fructose challenge. Organoids comprised primarily of enterocytes, Paneth, or goblet, but not ISC, cells responded specifically to fructose without affecting nonfructolytic genes. Sensing was independent of Wnt and Notch modulators and of glucose concentrations in the medium but required fructose absorption and metabolism. More mature enterocyte- and goblet-enriched organoids exhibited stronger fructose responses. Remarkably, enterocyte organoids, upon forced dedifferentiation to reacquire ISC characteristics, exhibited a markedly extended lifespan and retained fructose sensing ability, mimicking responses of some dedifferentiated cancer cells. Using an innovative approach, we discovered that nutrient sensing is likely repressed in progenitor ISCs then irreversibly derepressed during specification into sensing-competent absorptive or secretory lineages, the surprising capacity of Paneth and goblet cells to detect fructose, and the important role of differentiation in modulating nutrient sensing.NEW & NOTEWORTHY Small intestinal stem cells differentiate into several cell types transiently populating the villi. We used specialized organoid cultures each comprised of a single cell type to demonstrate that 1) differentiation seems required for nutrient sensing, 2) secretory goblet and Paneth cells along with enterocytes sense fructose, suggesting that sensing is acquired after differentiation is triggered but before divergence between absorptive and secretory lineages, and 3) forcibly dedifferentiated enterocytes exhibit fructose sensing and lifespan extension. PMID- 28336549 TI - EAVK segment "c" sequence confers Ca2+-dependent changes to the kinetics of full length human Ano1. AB - Anoctamin1 (Ano1 and TMEM16A) is a calcium-activated chloride channel specifically expressed in the interstitial cells of Cajal (ICC) of the gastrointestinal tract muscularis propria. Ano1 is necessary for normal electrical slow waves and ICC proliferation. The full-length human Ano1 sequence includes an additional exon, exon "0," at the NH2 terminus. Ano1 with exon 0 [Ano1(0)] had a lower EC50 for intracellular calcium ([Ca2+]i) and faster chloride current (ICl) kinetics. The Ano1 alternative splice variant with segment "c" encoding exon 13 expresses on the first intracellular loop four additional amino acid residues, EAVK, which alter ICl at low [Ca2+]i Exon 13 is expressed in 75-100% of Ano1 transcripts in most human tissues but only 25% in the human stomach. Our aim was to determine the effect of EAVK deletion on Ano1(0)ICl parameters. By voltage-clamp electrophysiology, we examined ICl in HEK293 cells transiently expressing Ano1(0) with or without the EAVK sequence [Ano1(0)DeltaEAVK]. The EC50 values of activating and deactivating ICl for [Ca2+]i were 438 +/- 7 and 493 +/- 9 nM for Ano1(0) but higher for Ano1(0)DeltaEAVK at 746 +/- 47 and 761 +/- 26 nM, respectively. Meanwhile, the EC50 values for the ratio of instantaneous to steady-state ICl were not different between variants. Congruently, the time constant of activation was slower for Ano1(0)DeltaEAVK than Ano1(0) currents at intermediate [Ca2+]i These results suggest that EAVK decreases the calcium sensitivity of Ano1(0) current activation and deactivation by slowing activation kinetics. Differential expression of EAVK in the human stomach may function as a switch to increase sensitivity to [Ca2+]i via faster gating of Ano1.NEW & NOTEWORTHY Calcium-activated chloride channel anoctamin1 (Ano1) is necessary for normal slow waves in the gastrointestinal interstitial cells of Cajal. Exon 0 encodes the NH2 terminus of full-length human Ano1 [Ano1(0)], while exon 13 encodes residues EAVK on its first intracellular loop. Splice variants lack EAVK more often in the stomach than other tissues. Ano1(0) without EAVK [Ano1(0)DeltaEAVK] has reduced sensitivity for intracellular calcium, attributable to slower kinetics. Differential expression of EAVK may function as a calcium-sensitive switch in the human stomach. PMID- 28336551 TI - Gut Microbes May Up PD-1 Inhibitor Response. AB - Confirming the results of animal studies, new research shows that the composition of patients' microbiome influences their response to checkpoint inhibitors. Patients with melanoma who benefit from PD-1 inhibitors carry a greater variety of species and higher numbers of microbes in the Clostridiales group. Increased abundance of certain bacteria in this group also correlated with higher numbers of CD8+ T cells in patients' tumors. PMID- 28336550 TI - The effect of intravenous corticotropin-releasing hormone administration on esophageal sensitivity and motility in health. AB - Esophageal hypersensitivity is important in gastroesophageal reflux disease (GERD) patients who are refractory to acid-suppressive therapy. Stress affects visceral sensitivity and exacerbates heartburn in GERD. Peripheral CRH is a key mediator of the gut stress response. We hypothesize that CRH increases esophageal sensitivity and alters esophageal motility in health. Esophageal sensitivity to thermal, mechanical, electrical, and chemical stimuli was assessed in 14 healthy subjects after administration of placebo or CRH (100 MUg iv). Perception scores were assessed for first perception, pain perception threshold (PPT), and pain tolerance threshold (PTT). Esophageal motility was investigated by high resolution impedance manometry, before and after CRH and evaluated by distal contractile integral (DCI) and intrabolus pressure (IBP). Pressure flow analysis assessed bolus clearance (impedance ratio), degree of pressurization needed to propel bolus onward (IBP slope), and pressure flow (pressure flow index, PFI). Stress and mood were assessed during the study. Sensitivity to mechanical distention was increased after CRH compared with placebo (PPT: P = 0.0023; PTT: P = 0.0253). CRH had no influence on the other stimulations. DCI was increased for all boluses (liquid, P = 0.0012; semisolid, P = 0.0017; solid, P = 0.0107). Impedance ratio for liquid (P < 0.0001) and semisolid swallows (P = 0.0327) decreased after CRH. IBP slope increased after CRH for semisolid (P = 0.0041) and solid (P = 0.0003) swallows. PFI increased for semisolid (P = 0.0017) and solid swallows (P = 0.0031). CRH increased esophageal sensitivity to mechanical distention, not to the other stimulation modalities. CRH increased esophageal contractility and tone, decreased LES relaxation, increased esophageal bolus pressurization, improved esophageal bolus clearance, and increased pressure flow.NEW & NOTEWORTHY This is the first study to address the effect of corticotropin-releasing hormone (CRH) on esophageal sensitivity and alterations in motility in health. CRH administration increased esophageal sensitivity to mechanical distention. This effect is accompanied by an increase in esophageal contractility and tone and a decrease in lower esophageal sphincter relaxation. CRH increased esophageal bolus pressurization, improved esophageal bolus clearance, and increased pressure flow. The changes in esophageal contractile properties may underlie the increased sensitivity to mechanical distention after CRH. PMID- 28336554 TI - Depersonalisation and derealisation: assessment and management. PMID- 28336552 TI - Prospective Comprehensive Molecular Characterization of Lung Adenocarcinomas for Efficient Patient Matching to Approved and Emerging Therapies. AB - Tumor genetic testing is standard of care for patients with advanced lung adenocarcinoma, but the fraction of patients who derive clinical benefit remains undefined. Here, we report the experience of 860 patients with metastatic lung adenocarcinoma analyzed prospectively for mutations in >300 cancer-associated genes. Potentially actionable genetic events were stratified into one of four levels based upon published clinical or laboratory evidence that the mutation in question confers increased sensitivity to standard or investigational therapies. Overall, 37.1% (319/860) of patients received a matched therapy guided by their tumor molecular profile. Excluding alterations associated with standard-of-care therapy, 14.4% (69/478) received matched therapy, with a clinical benefit of 52%. Use of matched therapy was strongly influenced by the level of preexistent clinical evidence that the mutation identified predicts for drug response. Analysis of genes mutated significantly more often in tumors without known actionable mutations nominated STK11 and KEAP1 as possible targetable mitogenic drivers.Significance: An increasing number of therapies that target molecular alterations required for tumor maintenance and progression have demonstrated clinical activity in patients with lung adenocarcinoma. The data reported here suggest that broader, early testing for molecular alterations that have not yet been recognized as standard-of-care predictive biomarkers of drug response could accelerate the development of targeted agents for rare mutational events and could result in improved clinical outcomes. Cancer Discov; 7(6); 596-609. (c)2017 AACR.See related commentary by Liu et al., p. 555This article is highlighted in the In This Issue feature, p. 539. PMID- 28336553 TI - TLR2 knockout protects against diabetes-mediated changes in cerebral perfusion and cognitive deficits. AB - The risk of cognitive decline in diabetes (Type 1 and Type 2) is significantly greater compared with normoglycemic patients, and the risk of developing dementia in diabetic patients is doubled. The etiology for this is likely multifactorial, but one mechanism that has gained increasing attention is decreased cerebral perfusion as a result of cerebrovascular dysfunction. The innate immune system has been shown to play a role in diabetic vascular complications, notably through the Toll-like receptor (TLR)-stimulated release of proinflammatory cytokines and chemokines that lead to vascular damage. TLR2 has been implicated in playing a crucial role in the development of diabetic microvascular complications, such as nephropathy, and thus, we hypothesized that TLR2-mediated cerebrovascular dysfunction leads to decreased cerebral blood flow (CBF) and cognitive impairment in diabetes. Knockout of TLR2 conferred protection from impaired CBF in early stage diabetes and from hyperperfusion in long-term diabetes, prevented the development of endothelium-dependent vascular dysfunction in diabetes, created a hyperactive and anxiolytic phenotype, and protected against diabetes-induced impairment of long-term hippocampal and prefrontal cortex-mediated fear learning. In conclusion, these findings support the involvement of TLR2 in the pathogenesis of diabetic vascular disease and cognitive impairment. PMID- 28336556 TI - Human MicroRNA-548p Decreases Hepatic Apolipoprotein B Secretion and Lipid Synthesis. AB - OBJECTIVE: MicroRNAs (miRs) play important regulatory roles in lipid metabolism. Apolipoprotein B (ApoB), as the only essential scaffolding protein in the assembly of very-low-density lipoproteins, is a target to treat hyperlipidemia and atherosclerosis. We aimed to find out miRs that reduce apoB expression. APPROACH AND RESULTS: Bioinformatic analyses predicted that hsa-miR-548p can interact with apoB mRNA. MiR-548p or control miR was transfected in human and mouse liver cells to test its role in regulating apoB secretion and mRNA expression levels. Site-directed mutagenesis was used to identify the interacting site of miR-548p in human apoB 3'-untranslated region. Fatty acid oxidation and lipid syntheses were examined in miR-548p overexpressing cells to investigate its function in lipid metabolism. We observed that miR-548p significantly reduces apoB secretion from human hepatoma cells and primary hepatocytes. Mechanistic studies showed that miR-548p interacts with the 3'-untranslated region of human apoB mRNA to enhance post-transcriptional degradation. Bioinformatic algorithms suggested 2 potential binding sites of miR-548p on human apoB mRNA. Site-directed mutagenesis studies revealed that miR-548p targets site I involving both seed and supplementary sequences. MiR-548p had no effect on fatty acid oxidation but significantly decreased lipid synthesis in human hepatoma cells by reducing HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) and ACSL4 (Acyl-CoA synthetase long-chain family member 4) enzymes involved in cholesterol and fatty acid synthesis. In summary, miR-548p reduces lipoprotein production and lipid synthesis by reducing expression of different genes in human liver cells. CONCLUSIONS: These studies suggest that miR-548p regulates apoB secretion by targeting mRNA. It is likely that it could be useful in treating atherosclerosis, hyperlipidemia, and hepatosteatosis. PMID- 28336557 TI - Catechins as Potential Mediators of Cardiovascular Health. AB - The impact of diet on cardiovascular disease has become an increasingly relevant topic as ongoing epidemiological evidence continues to demonstrate clear associations with disease burden and mortality. Certain diets, such as those high in sodium and saturated fat, are associated with cardiovascular disease states, while other diets can be cardioprotective. However, there is limited knowledge on how the micro- and macronutrients within such cardioprotective diets afford their benefits. One such micronutrient is the catechin class, which are naturally occurring compounds in plant foods, such as teas, cocoa, wine, pears, and apples. Recent evidence reveals that catechins may be a key mediator in cardiovascular health via mechanisms of blood pressure reduction, flow-mediated vasodilation, and atherosclerosis attenuation. This review evaluates the current literature on the interplay between catechins and cardiovascular disease, which may have important implications for nutrition counseling and pharmaceutical drug development. PMID- 28336558 TI - Remnant Cholesterol Elicits Arterial Wall Inflammation and a Multilevel Cellular Immune Response in Humans. AB - OBJECTIVE: Mendelian randomization studies revealed a causal role for remnant cholesterol in cardiovascular disease. Remnant particles accumulate in the arterial wall, potentially propagating local and systemic inflammation. We evaluated the impact of remnant cholesterol on arterial wall inflammation, circulating monocytes, and bone marrow in patients with familial dysbetalipoproteinemia (FD). APPROACH AND RESULTS: Arterial wall inflammation and bone marrow activity were measured using 18F-FDG PET/CT. Monocyte phenotype was assessed with flow cytometry. The correlation between remnant levels and hematopoietic activity was validated in the CGPS (Copenhagen General Population Study). We found a 1.2-fold increase of 18F-FDG uptake in the arterial wall in patients with FD (n=17, age 60+/-8 years, remnant cholesterol: 3.26 [2.07-5.71]) compared with controls (n=17, age 61+/-8 years, remnant cholesterol 0.29 [0.27 0.40]; P<0.001). Monocytes from patients with FD showed increased lipid accumulation (lipid-positive monocytes: Patients with FD 92% [86-95], controls 76% [66-81], P=0.001, with an increase in lipid droplets per monocyte), and a higher expression of surface integrins (CD11b, CD11c, and CD18). Patients with FD also exhibited monocytosis and leukocytosis, accompanied by a 1.2-fold increase of 18F-FDG uptake in bone marrow. In addition, we found a strong correlation between remnant levels and leukocyte counts in the CGPS (n=103 953, P for trend 5*10-276). In vitro experiments substantiated that remnant cholesterol accumulates in human hematopoietic stem and progenitor cells coinciding with myeloid skewing. CONCLUSIONS: Patients with FD have increased arterial wall and cellular inflammation. These findings imply an important inflammatory component to the atherogenicity of remnant cholesterol, contributing to the increased cardiovascular disease risk in patients with FD. PMID- 28336559 TI - Microvascular Endothelial Dysfunction in Obesity Is Driven by Macrophage Dependent Hydrogen Sulfide Depletion. AB - OBJECTIVE: The function of perivascular adipose tissue as an anticontractile mediator in the microvasculature is lost during obesity. Obesity results in inflammation and recruitment of proinflammatory macrophages to the perivascular adipose tissue that is paralleled by depletion of the vasorelaxant signaling molecule hydrogen sulfide (H2S) in the vessel. The current objective was to assess the role of macrophages in determining vascular [H2S] and defining how this impinged on vasodilation. APPROACH AND RESULTS: Contractility and [H2S] were measured in mesenteric resistance arterioles from lean and obese mice by using pressure myography and confocal microscopy, respectively. Vasodilation was impaired and smooth muscle and endothelial [H2S] decreased in vessels from obese mice compared with those from lean controls. Coculturing vessels from lean mice with macrophages from obese mice, or macrophage-conditioned media, recapitulated obese phenotypes in vessels. These effects were mediated by low molecular weight species and dependent on macrophage inducible nitric oxide synthase activity. CONCLUSIONS: The inducible nitric oxide synthase activity of perivascular adipose tissue-resident proinflammatory macrophages promotes microvascular endothelial dysfunction by reducing the bioavailability of H2S in the vessel. These findings support a model in which vascular H2S depletion underpins the loss of perivascular adipose tissue anticontractile function in obesity. PMID- 28336561 TI - Mice Lacking the Inhibitory Collagen Receptor LAIR-1 Exhibit a Mild Thrombocytosis and Hyperactive Platelets. AB - OBJECTIVE: Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is a collagen receptor that belongs to the inhibitory immunoreceptor tyrosine-based inhibition motif-containing receptor family. It is an inhibitor of signaling via the immunoreceptor tyrosine-based activation motif-containing collagen receptor complex, glycoprotein VI-FcRgamma-chain. It is expressed on hematopoietic cells, including immature megakaryocytes, but is not detectable on platelets. Although the inhibitory function of LAIR-1 has been described in leukocytes, its physiological role in megakaryocytes and in particular in platelet formation has not been explored. In this study, we investigate the role of LAIR-1 in megakaryocyte development and platelet production by generating LAIR-1-deficient mice. APPROACH AND RESULTS: Mice lacking LAIR-1 exhibit a significant increase in platelet counts, a prolonged platelet half-life in vivo, and increased proplatelet formation in vitro. Interestingly, platelets from LAIR-1-deficient mice exhibit an enhanced reactivity to collagen and the glycoprotein VI-specific agonist collagen-related peptide despite not expressing LAIR-1, and mice showed enhanced thrombus formation in the carotid artery after ferric chloride injury. Targeted deletion of LAIR-1 in mice results in an increase in signaling downstream of the glycoprotein VI-FcRgamma-chain and integrin alphaIIbbeta3 in megakaryocytes because of enhanced Src family kinase activity. CONCLUSIONS: Findings from this study demonstrate that ablation of LAIR-1 in megakaryocytes leads to increased Src family kinase activity and downstream signaling in response to collagen that is transmitted to platelets, rendering them hyper reactive specifically to agonists that signal through Syk tyrosine kinases, but not to G-protein-coupled receptors. PMID- 28336560 TI - Lipoprotein(a) and HIV: Allele-Specific Apolipoprotein(a) Levels Predict Carotid Intima-Media Thickness in HIV-Infected Young Women in the Women's Interagency HIV Study. AB - OBJECTIVE: In the general population, lipoprotein(a) [Lp(a)] has been established as an independent causal risk factor for cardiovascular disease. Lp(a) levels are to a major extent regulated by a size polymorphism in the apolipoprotein(a) [apo(a)] gene. The roles of Lp(a)/apo(a) in human immunodeficiency virus (HIV) related elevated cardiovascular disease risk remain unclear. APPROACH AND RESULTS: The associations between total plasma Lp(a) level, allele-specific apo(a) level, an Lp(a) level carried by individual apo(a) alleles, and common carotid artery intima-media thickness were assessed in 150 HIV-infected and 100 HIV-uninfected women in the WIHS (Women's Interagency HIV Study). Linear regression analyses with and without adjustments were used. The cohort was young (mean age, ~31 years), with the majority being Blacks (~70%). The prevalence of a small size apo(a) (<=22 Kringle repeats) or a high Lp(a) level (>=30 mg/dL) was similar by HIV status. Total plasma Lp(a) level (P=0.029) and allele-specific apo(a) level carried by the smaller apo(a) sizes (P=0.022) were significantly associated with carotid artery intima-media thickness in the HIV-infected women only. After accounting for confounders (age, race, smoking, body mass index, blood pressure, hepatitis C virus coinfection, menopause, plasma lipids, treatment status, CD4+ T cell count, and HIV/RNA viral load), the association remained significant for both Lp(a) (P=0.035) and allele-specific apo(a) level carried by the smaller apo(a) sizes (P=0.010) in the HIV-infected women. Notably, none of the other lipids/lipoproteins was associated with carotid artery intima media thickness. CONCLUSIONS: Lp(a) and allele-specific apo(a) levels predict carotid artery intima-media thickness in HIV-infected young women. Further research is needed to identify underlying mechanisms of an increased Lp(a) atherogenicity in HIV infection. PMID- 28336562 TI - De novo assembly of the Aedes aegypti genome using Hi-C yields chromosome-length scaffolds. AB - The Zika outbreak, spread by the Aedes aegypti mosquito, highlights the need to create high-quality assemblies of large genomes in a rapid and cost-effective way. Here we combine Hi-C data with existing draft assemblies to generate chromosome-length scaffolds. We validate this method by assembling a human genome, de novo, from short reads alone (67* coverage). We then combine our method with draft sequences to create genome assemblies of the mosquito disease vectors Aeaegypti and Culex quinquefasciatus, each consisting of three scaffolds corresponding to the three chromosomes in each species. These assemblies indicate that almost all genomic rearrangements among these species occur within, rather than between, chromosome arms. The genome assembly procedure we describe is fast, inexpensive, and accurate, and can be applied to many species. PMID- 28336565 TI - Rare lymphoma is linked to breast implants, US officials conclude. PMID- 28336564 TI - Identification of a Novel SYK/c-MYC/MALAT1 Signaling Pathway and Its Potential Therapeutic Value in Ewing Sarcoma. AB - Purpose: Ewing sarcoma (EWS) is a devastating soft tissue sarcoma affecting predominantly young individuals. Tyrosine kinases (TK) and associated pathways are continuously activated in many malignancies, including EWS; these enzymes provide candidate therapeutic targets.Experimental Design: Two high-throughput screens (a siRNA library and a small-molecule inhibitor library) were performed in EWS cells to establish candidate targets. Spleen tyrosine kinase (SYK) phosphorylation was assessed in EWS patients and cell lines. SYK was inhibited by a variety of genetic and pharmacological approaches, and SYK-regulated pathways were investigated by cDNA microarrays. The transcriptional regulation of MALAT1 was examined by ChIP-qPCR, luciferase reporter, and qRT-PCR assays.Results: SYK was identified as a candidate actionable target through both high-throughput screens. SYK was highly phosphorylated in the majority of EWS cells, and SYK inhibition by a variety of genetic and pharmacologic approaches markedly inhibited EWS cells both in vitro and in vivo Ectopic expression of SYK rescued the cytotoxicity triggered by SYK-depletion associated with the reactivation of both AKT and c-MYC. A long noncoding RNA, MALAT1, was identified to be dependent on SYK-mediated signaling. Moreover, c-MYC, a SYK-promoted gene, bound to the promoter of MALAT1 and transcriptionally activated MALAT1, which further promoted the proliferation of EWS cells.Conclusions: This study identifies a novel signaling involving SYK/c-MYC/MALAT1 as a promising therapeutic target for the treatment of EWS. Clin Cancer Res; 23(15); 4376-87. (c)2017 AACR. PMID- 28336563 TI - Complex multifault rupture during the 2016 Mw 7.8 Kaikoura earthquake, New Zealand. AB - On 14 November 2016, northeastern South Island of New Zealand was struck by a major moment magnitude (Mw) 7.8 earthquake. Field observations, in conjunction with interferometric synthetic aperture radar, Global Positioning System, and seismology data, reveal this to be one of the most complex earthquakes ever recorded. The rupture propagated northward for more than 170 kilometers along both mapped and unmapped faults before continuing offshore at the island's northeastern extent. Geodetic and field observations reveal surface ruptures along at least 12 major faults, including possible slip along the southern Hikurangi subduction interface; extensive uplift along much of the coastline; and widespread anelastic deformation, including the ~8-meter uplift of a fault bounded block. This complex earthquake defies many conventional assumptions about the degree to which earthquake ruptures are controlled by fault segmentation and should motivate reevaluation of these issues in seismic hazard models. PMID- 28336567 TI - SOX9 Is an Astrocyte-Specific Nuclear Marker in the Adult Brain Outside the Neurogenic Regions. AB - Astrocytes have in recent years become the focus of intense experimental interest, yet markers for their definitive identification remain both scarce and imperfect. Astrocytes may be recognized as such by their expression of glial fibrillary acidic protein, glutamine synthetase, glutamate transporter 1 (GLT1), aquaporin-4, aldehyde dehydrogenase 1 family member L1, and other proteins. However, these proteins may all be regulated both developmentally and functionally, restricting their utility. To identify a nuclear marker pathognomonic of astrocytic phenotype, we assessed differential RNA expression by FACS-purified adult astrocytes and, on that basis, evaluated the expression of the transcription factor SOX9 in both mouse and human brain. We found that SOX9 is almost exclusively expressed by astrocytes in the adult brain except for ependymal cells and in the neurogenic regions, where SOX9 is also expressed by neural progenitor cells. Transcriptome comparisons of SOX9+ cells with GLT1+ cells showed that the two populations of cells exhibit largely overlapping gene expression. Expression of SOX9 did not decrease during aging and was instead upregulated by reactive astrocytes in a number of settings, including a murine model of amyotrophic lateral sclerosis (SOD1G93A), middle cerebral artery occlusion, and multiple mini-strokes. We quantified the relative number of astrocytes using the isotropic fractionator technique in combination with SOX9 immunolabeling. The analysis showed that SOX9+ astrocytes constitute ~10-20% of the total cell number in most CNS regions, a smaller fraction of total cell number than previously estimated in the normal adult brain.SIGNIFICANCE STATEMENT Astrocytes are traditionally identified immunohistochemically by antibodies that target cell-specific antigens in the cytosol or plasma membrane. We show here that SOX9 is an astrocyte-specific nuclear marker in all major areas of the CNS outside of the neurogenic regions. Based on SOX9 immunolabeling, we document that astrocytes constitute a smaller fraction of total cell number than previously estimated in the normal adult mouse brain. PMID- 28336569 TI - Cued Memory Retrieval Exhibits Reinstatement of High Gamma Power on a Faster Timescale in the Left Temporal Lobe and Prefrontal Cortex. AB - Converging evidence suggests that reinstatement of neural activity underlies our ability to successfully retrieve memories. However, the temporal dynamics of reinstatement in the human cortex remain poorly understood. One possibility is that neural activity during memory retrieval, like replay of spiking neurons in the hippocampus, occurs at a faster timescale than during encoding. We tested this hypothesis in 34 participants who performed a verbal episodic memory task while we recorded high gamma (62-100 Hz) activity from subdural electrodes implanted for seizure monitoring. We show that reinstatement of distributed patterns of high gamma activity occurs faster than during encoding. Using a time warping algorithm, we quantify the timescale of the reinstatement and identify brain regions that show significant timescale differences between encoding and retrieval. Our data suggest that temporally compressed reinstatement of cortical activity is a feature of cued memory retrieval.SIGNIFICANCE STATEMENT We show that cued memory retrieval reinstates neural activity on a faster timescale than was present during encoding. Our data therefore provide a link between reinstatement of neural activity in the cortex and spontaneous replay of cortical and hippocampal spiking activity, which also exhibits temporal compression, and suggest that temporal compression may be a universal feature of memory retrieval. PMID- 28336570 TI - Task-Dependent Behavioral Dynamics Make the Case for Temporal Integration in Multiple Strategies during Odor Processing. AB - Differing results in olfactory-based decision-making research regarding the amount of time that rats and mice use to identify odors have led to some disagreements about odor-processing mechanics, including whether or not rodents use temporal integration (i.e., sniffing longer to identify odors better). Reported differences in behavioral strategies may be due to the different types of tasks used in different laboratories. Some researchers have reported that animals performing two-alternative choice (TAC) tasks need only 1-2 sniffs and do not increase performance with longer sampling. Others have reported that animals performing go/no-go (GNG) tasks increase sampling times and performance for difficult discriminations, arguing for temporal integration. We present results from four experiments comparing GNG and TAC tasks over several behavioral variables (e.g., performance, sampling duration). When rats know only one task, they perform better in GNG than in TAC. However, performance was not statistically different when rats learned and were tested in both tasks. Rats sample odors longer in GNG than in TAC, even when they know both tasks and perform them in the same or different sessions. Longer sampling is associated with better performance for both tasks in difficult discriminations, which supports the case for temporal integration over >=2-6 sniffs in both tasks. These results illustrate that generalizations from a single task about behavioral or cognitive abilities (e.g., processing, perception) do not capture the full range of complexity and can significantly impact inferences about general abilities in sensory perception.SIGNIFICANCE STATEMENT Behavioral tasks and training and testing history affect measured outcomes in cognitive tests. Rats sample odors longer in a go/no-go (GNG) than in a two-alternative choice (TAC) task, performing better in GNG unless they know both tasks. Odor-sampling time is extended in both tasks when the odors to be discriminated are very similar. Rats may extend sampling time to integrate odor information up to ~0.5 s (2-6 sniffs). Such factors as task, task parameters, and training history affect decision times and performance, making it important to use multiple tasks when making inferences about sensory or cognitive processing. PMID- 28336568 TI - Cholinergic, But Not Dopaminergic or Noradrenergic, Enhancement Sharpens Visual Spatial Perception in Humans. AB - The neuromodulator acetylcholine modulates spatial integration in visual cortex by altering the balance of inputs that generate neuronal receptive fields. These cholinergic effects may provide a neurobiological mechanism underlying the modulation of visual representations by visual spatial attention. However, the consequences of cholinergic enhancement on visuospatial perception in humans are unknown. We conducted two experiments to test whether enhancing cholinergic signaling selectively alters perceptual measures of visuospatial interactions in human subjects. In Experiment 1, a double-blind placebo-controlled pharmacology study, we measured how flanking distractors influenced detection of a small contrast decrement of a peripheral target, as a function of target-flanker distance. We found that cholinergic enhancement with the cholinesterase inhibitor donepezil improved target detection, and modeling suggested that this was mainly due to a narrowing of the extent of facilitatory perceptual spatial interactions. In Experiment 2, we tested whether these effects were selective to the cholinergic system or would also be observed following enhancements of related neuromodulators dopamine or norepinephrine. Unlike cholinergic enhancement, dopamine (bromocriptine) and norepinephrine (guanfacine) manipulations did not improve performance or systematically alter the spatial profile of perceptual interactions between targets and distractors. These findings reveal mechanisms by which cholinergic signaling influences visual spatial interactions in perception and improves processing of a visual target among distractors, effects that are notably similar to those of spatial selective attention.SIGNIFICANCE STATEMENT Acetylcholine influences how visual cortical neurons integrate signals across space, perhaps providing a neurobiological mechanism for the effects of visual selective attention. However, the influence of cholinergic enhancement on visuospatial perception remains unknown. Here we demonstrate that cholinergic enhancement improves detection of a target flanked by distractors, consistent with sharpened visuospatial perceptual representations. Furthermore, whereas most pharmacological studies focus on a single neurotransmitter, many neuromodulators can have related effects on cognition and perception. Thus, we also demonstrate that enhancing noradrenergic and dopaminergic systems does not systematically improve visuospatial perception or alter its tuning. Our results link visuospatial tuning effects of acetylcholine at the neuronal and perceptual levels and provide insights into the connection between cholinergic signaling and visual attention. PMID- 28336571 TI - Regulation of Alcohol Extinction and Cue-Induced Reinstatement by Specific Projections among Medial Prefrontal Cortex, Nucleus Accumbens, and Basolateral Amygdala. AB - The ability to inhibit drinking is a significant challenge for recovering alcoholics, especially in the presence of alcohol-associated cues. Previous studies have demonstrated that the regulation of cue-guided alcohol seeking is mediated by the basolateral amygdala (BLA), nucleus accumbens (NAc), and medial prefrontal cortex (mPFC). However, given the high interconnectivity between these structures, it is unclear how mPFC projections to each subcortical structure, as well as projections between BLA and NAc, mediate alcohol-seeking behaviors. Here, we evaluate how cortico-striatal, cortico-amygdalar, and amygdalo-striatal projections control extinction and relapse in a rat model of alcohol seeking. Specifically, we used a combinatorial viral technique to express diphtheria toxin receptors in specific neuron populations based on their projection targets. We then used this strategy to create directionally selective ablations of three distinct pathways after acquisition of ethanol self-administration but before extinction and reinstatement. We demonstrate that ablation of mPFC neurons projecting to NAc, but not BLA, blocks cue-induced reinstatement of alcohol seeking and neither pathway is necessary for extinction of responding. Further, we show that ablating BLA neurons that project to NAc disrupts extinction of alcohol approach behaviors and attenuates reinstatement. Together, these data provide evidence that the mPFC->NAc pathway is necessary for cue-induced reinstatement of alcohol seeking, expand our understanding of how the BLA->NAc pathway regulates alcohol behavior, and introduce a new methodology for the manipulation of target-specific neural projections.SIGNIFICANCE STATEMENT The vast majority of recovering alcoholics will relapse at least once and understanding how the brain regulates relapse will be key to developing more effective behavior and pharmacological therapies for alcoholism. Given the high interconnectivity of cortical, striatal, and limbic structures that regulate alcohol intake, it has been difficult to disentangle how separate projections between them may control different aspects of these complex behaviors. Here, we demonstrate a new approach for noninvasively ablating each of these pathways and testing their necessity for both extinction and relapse. We show that inputs to the nucleus accumbens from medial prefrontal cortex and amygdala regulate alcohol seeking behaviors differentially, adding to our understanding of the neural control of alcoholism. PMID- 28336572 TI - The Computational and Neural Basis of Rhythmic Timing in Medial Premotor Cortex. AB - The neural underpinnings of rhythmic behavior, including music and dance, have been studied using the synchronization-continuation task (SCT), where subjects initially tap in synchrony with an isochronous metronome and then keep tapping at a similar rate via an internal beat mechanism. Here, we provide behavioral and neural evidence that supports a resetting drift-diffusion model (DDM) during SCT. Behaviorally, we show the model replicates the linear relation between the mean and standard-deviation of the intervals produced by monkeys in SCT. We then show that neural populations in the medial premotor cortex (MPC) contain an accurate trial-by-trial representation of elapsed-time between taps. Interestingly, the autocorrelation structure of the elapsed-time representation is consistent with a DDM. These results indicate that MPC has an orderly representation of time with features characteristic of concatenated DDMs and that this population signal can be used to orchestrate the rhythmic structure of the internally timed elements of SCT.SIGNIFICANCE STATEMENT The present study used behavioral data, ensemble recordings from medial premotor cortex (MPC) in macaque monkeys, and computational modeling, to establish evidence in favor of a class of drift diffusion models of rhythmic timing during a synchronization-continuation tapping task (SCT). The linear relation between the mean and standard-deviation of the intervals produced by monkeys in SCT is replicated by the model. Populations of MPC cells faithfully represent the elapsed time between taps, and there is significant trial-by-trial relation between decoded times and the timing behavior of the monkeys. Notably, the neural decoding properties, including its autocorrelation structure are consistent with a set of drift-diffusion models that are arranged sequentially and that are resetting in each SCT tap. PMID- 28336573 TI - A randomised cross-over study of methods of acquiring ECG heart rate in newborns. PMID- 28336575 TI - Pharmacologic Profile of Naloxegol, a Peripherally Acting u-Opioid Receptor Antagonist, for the Treatment of Opioid-Induced Constipation. AB - Opioid-induced constipation (OIC) is a common side effect of opioid pharmacotherapy for the management of pain because opioid agonists bind to u opioid receptors in the enteric nervous system (ENS). Naloxegol, a polyethylene glycol derivative of naloxol, which is a derivative of naloxone and a peripherally acting u-opioid receptor antagonist, targets the physiologic mechanisms that cause OIC. Pharmacologic measures of opioid activity and pharmacokinetic measures of central nervous system (CNS) penetration were employed to characterize the mechanism of action of naloxegol. At the human u opioid receptor in vitro, naloxegol was a potent inhibitor of binding (Ki = 7.42 nM) and a neutral competitive antagonist (pA2 - 7.95); agonist effects were <10% up to 30 MUM and identical to those of naloxone. The oral doses achieving 50% of the maximal effect in the rat for antagonism of morphine-induced inhibition of gastrointestinal transit and morphine-induced antinociception in the hot plate assay were 23.1 and 55.4 mg/kg for naloxegol and 0.69 and 1.14 mg/kg by for naloxone, respectively. In the human colon adenocarcinoma cell transport assay, naloxegol was a substrate for the P-glycoprotein transporter, with low apparent permeability in the apical to basolateral direction, and penetrated the CNS 15 fold slower than naloxone in a rat brain perfusion model. Naloxegol-derived radioactivity was poorly distributed throughout the rat CNS and was eliminated from most tissues within 24 hours. These findings corroborate phase 3 clinical studies demonstrating that naloxegol relieves OIC-associated symptoms in patients with chronic noncancer pain by antagonizing the u-opioid receptor in the ENS while preserving CNS-mediated analgesia. PMID- 28336574 TI - Switching head group selectivity in mammalian sphingolipid biosynthesis by active site-engineering of sphingomyelin synthases. AB - SM is a fundamental component of mammalian cell membranes that contributes to mechanical stability, signaling, and sorting. Its production involves the transfer of phosphocholine from phosphatidylcholine onto ceramide, a reaction catalyzed by SM synthase (SMS)1 in the Golgi and SMS2 at the plasma membrane. Mammalian cells also synthesize trace amounts of the SM analog, ceramide phosphoethanolamine (CPE), but the physiological relevance of CPE production is unclear. Previous work revealed that SMS2 is a bifunctional enzyme producing both SM and CPE, whereas a closely related enzyme, SMS-related protein (SMSr)/SAMD8, acts as a monofunctional CPE synthase in the endoplasmic reticulum. Using domain swapping and site-directed mutagenesis on enzymes expressed in defined lipid environments, we here identified structural determinants that mediate the head group selectivity of SMS family members. Notably, a single residue adjacent to the catalytic histidine in the third exoplasmic loop profoundly influenced enzyme specificity, with Glu permitting SMS-catalyzed CPE production and Asp confining the enzyme to produce SM. An exchange of exoplasmic residues with SMSr proved sufficient to convert SMS1 into a bulk CPE synthase. This allowed us to establish mammalian cells that produce CPE rather than SM as the principal phosphosphingolipid and provide a model of the molecular interactions that impart catalytic specificity among SMS enzymes. PMID- 28336577 TI - Fruit Juice and Child Health. PMID- 28336576 TI - Fruit Juice and Change in BMI: A Meta-analysis. AB - CONTEXT: Whether 100% fruit juice consumption causes weight gain in children remains controversial. OBJECTIVE: To determine the association between 100% fruit juice consumption and change in BMI or BMI z score in children. DATA SOURCES: PubMed, Embase, CINAHL, and Cochrane databases. STUDY SELECTION: Longitudinal studies examining the association of 100% fruit juice and change in BMI measures were included. DATA EXTRACTION: Two independent reviewers extracted data using a predesigned data collection form. RESULTS: Of the 4657 articles screened, 8 prospective cohort studies (n = 34 470 individual children) met the inclusion criteria. Controlling for total energy intake, 1 daily 6- to 8-oz serving increment of 100% fruit juice was associated with a 0.003 (95% CI: 0.001 to 0.004) unit increase in BMI z score over 1 year in children of all ages (0% increase in BMI percentile). In children ages 1 to 6 years, 1 serving increment was associated with a 0.087 (95% confidence interval: 0.008 to 0.167) unit increase in BMI z score (4% increase in BMI percentile). 100% fruit juice consumption was not associated with BMI z score increase in children ages 7 to 18 years. LIMITATIONS: All observational studies; studies differed in exposure assessment and covariate adjustment. CONCLUSIONS: Consumption of 100% fruit juice is associated with a small amount of weight gain in children ages 1 to 6 years that is not clinically significant, and is not associated with weight gain in children ages 7 to 18 years. More studies are needed in children ages 1 to 6 years. PMID- 28336578 TI - Quantitative Prediction of CYP3A4 Induction: Impact of Measured, Free, and Intracellular Perpetrator Concentrations from Human Hepatocyte Induction Studies on Drug-Drug Interaction Predictions. AB - Typically, concentration-response curves are based upon nominal inducer concentrations for in-vitro-to-in-vivo extrapolation of CYP3A4 induction. The limitation of this practice is that it assumes the hepatocyte culture model is a static system. We assessed whether correcting for: 1) changes in perpetrator concentration in the induction medium during the incubation period, 2) perpetrator binding to proteins in the induction medium, and 3) nonspecific binding of perpetrator can improve the accuracy of CYP3A4 induction predictions. Of the seven compounds used in this evaluation, significant parent loss and nonspecific binding were observed for rifampicin (29.3-38.3%), pioglitazone (64.3 78.6%), and rosiglitazone (57.1-75.5%). As a result, the free measured EC50 values (EC50u) of pioglitazone, rosiglitazone, and rifampicin were significantly lower than the nominal EC50 values. In general, the accuracy of the induction predictions, using multiple static models, improved when corrections were made for measured medium concentrations, medium protein binding, and nonspecific binding of the perpetrator, as evidenced by 18-29% reductions in the root mean square error. The relative induction score model performed better than the basic static and mechanistic static models, resulting in lower prediction error and no false-positive or false-negative predictions. However, even when the EC50u value was used, the induction prediction for bosentan, which is a substrate of organic anion transporter proteins, was overpredicted by approximately 2-fold. Accounting for the ratio of unbound intracellular concentrations to unbound medium concentrations (Kpuu,in vitro) (0.5-7.5) and the predicted multiple-dose Kpuu,in vivo (0.6) for bosentan resulted in induction predictions within 35% of the observed interaction. PMID- 28336579 TI - Implementation of a Modified WHO Pediatric Procedural Sedation Safety Checklist and Its Impact on Risk Reduction. AB - BACKGROUND AND OBJECTIVES: Major adverse events (AEs) related to pediatric deep sedation occur at a low frequency but can be of high acuity. The high volume of deep sedations performed by 3 departments at our institution provided an opportunity to reduce variability and increase safety through implementation of a procedural sedation safety checklist. We hypothesized that implementation of a checklist would improve compliance of critical safety elements (CSEs) (primary outcome variable) and reduce the sedation-related AE rate (secondary outcome variable). METHODS: This process improvement project was divided into 5 phases: a retrospective analysis to assess variability in capture of CSE within 3 departments that perform deep sedation and the association between noncapture of CSE and AE occurrence (phase 1), design of the checklist and trial in simulation (phase 2), provider education (phase 3), implementation and interim analysis of checklist completion (phase 4), and final analysis of completion and impact on outcome (phase 5). RESULTS: We demonstrated interdepartmental variability in compliance with CSE completion prechecklist implementation, and we identified elements associated with AEs. Completion of provider education was 100% in all 3 departments. Final analysis showed a checklist completion rate of 75%, and its use significantly improved capture of several critical safety elements. Its use did not significantly reduce AEs (P = .105). CONCLUSIONS: This study demonstrates that the implementation of a sedation checklist improved process adherence and capture of critical safety elements; however, it failed to show a significant reduction in sedation-related AEs. PMID- 28336583 TI - Bruising and abnormal leucocytes on a blood film--a haematological emergency. PMID- 28336582 TI - High Mammographic Density in Long-Term Night-Shift Workers: DDM-Spain/Var-DDM. AB - Background: Night-shift work (NSW) has been suggested as a possible cause of breast cancer, and its association with mammographic density (MD), one of the strongest risk factors for breast cancer, has been scarcely addressed. This study examined NSW and MD in Spanish women.Methods: The study covered 2,752 women aged 45-68 years recruited in 2007-2008 in 7 population-based public breast cancer screening centers, which included 243 women who had performed NSW for at least one year. Occupational data and information on potential confounders were collected by personal interview. Two trained radiologist estimated the percentage of MD assisted by a validated semiautomatic computer tool (DM-scan). Multivariable mixed linear regression models with random screening center specific intercepts were fitted using log-transformed percentage of MD as the dependent variable and adjusting by known confounding variables.Results: Having ever worked in NSW was not associated with MD [Formula: see text]:0.96; 95% confidence interval (CI), 0.86-1.06]. However, the adjusted geometric mean of the percentage of MD in women with NSW for more than 15 years was 25% higher than that of those without NSW history (MD>15 years:20.7% vs. MDnever:16.5%;[Formula: see text]:1.25; 95% CI,1.01-1.54). This association was mainly observed in postmenopausal participants ([Formula: see text]:1.28; 95% CI, 1.00-1.64). Among NSW-exposed women, those with <=2 night-shifts per week had higher MD than those with 5 to 7 nightshifts per week ([Formula: see text]:1.42; 95% CI, 1.10 1.84).Conclusions: Performing NSW was associated with higher MD only in women with more than 15 years of cumulated exposure. These findings warrant replication in futures studies.Impact: Our findings suggest that MD could play a role in the pathway between long-term NSW and breast cancer. Cancer Epidemiol Biomarkers Prev; 26(6); 905-13. (c)2017 AACR. PMID- 28336584 TI - Complete Genome Sequences of Six Copper-Resistant Xanthomonas citri pv. citri Strains Causing Asiatic Citrus Canker, Obtained Using Long-Read Technology. AB - The gammaproteobacterium Xanthomonas citri pv. citri causes Asiatic citrus canker. Pathotype A strains have a broad host range, which includes most commercial citrus species, and they cause important economic losses worldwide. Control often relies on frequent copper sprays. We present here the complete genomes of six X. citri pv. citri copper-resistant strains. PMID- 28336581 TI - Differential Impact of Symptom Prevalence and Chronic Conditions on Quality of Life in Cancer Survivors and Non-Cancer Individuals: A Population Study. AB - Background: To compare associations of symptom prevalence, chronic conditions, and health-related quality of life (HRQOL) between cancer survivors and non cancer individuals using the U.S. National Health Interview Survey.Methods: Study samples comprised 604 survivors and 6,166 non-cancer individuals. Symptoms included sensation abnormality, pain, fatigue, cognitive disturbance, depression, and anxiety. Physical and mental HRQOL was measured by the Patient-Reported Outcomes Measurement Information System.Results: Compared with non-cancer individuals, survivors had higher prevalence in sensation abnormality (OR = 2.4; 95% CI = 1.9 to 3.0), pain (OR = 2.1; 95% CI = 1.7 to 2.6), fatigue (OR = 1.4; 95% CI = 1.1 to 1.8), and decremented physical HRQOL (difference = -3.7; 95% CI = -4.7 to -2.6). The prevalence of individual symptoms was significantly associated with decremented physical HRQOL [range = -5.9 (anxiety) to -8.9 (pain)] and mental HRQOL [range = -4.7 (sensation) to -8.4 (depression)]. The association between cancer experience and physical and mental HRQOL was chiefly explained by the prevalence of six symptoms and presence of chronic conditions. Pain (beta = 4.0; 95% CI = -4.5 to -3.6) and >=2 chronic conditions (beta = -9.2; 95% CI = 10.2 to -8.2) significantly decremented physical HRQOL. Depression (beta = -5.2; 95% CI = -5.8 to -4.6) and >=2 chronic conditions (beta = -3.3; 95% CI = -4.4 to 2.3) significantly decremented mental HRQOL.Conclusions: Cancer survivors experience more symptom burden than non-cancer individuals, which is associated with more chronic conditions and impaired HRQOL.Impacts: Interventions to manage symptom prevalence especially for older cancer survivors and survivors with more chronic conditions may improve their HRQOL outcomes. Cancer Epidemiol Biomarkers Prev; 26(7); 1124-32. (c)2017 AACR. PMID- 28336585 TI - Genome Sequence of Deinococcus marmoris PAMC 26562 Isolated from Antarctic Lichen. AB - Deinococcus marmoris strain PAMC 26562 was isolated from Usnea sp., a lichen collected from King George Island, Antarctica. We report here the draft genome sequence of strain PAMC 26562, which has xanthorhodopsin and carbon monoxide dehydrogenase genes in addition to major metabolic pathways presented in deinococcal genomes. PMID- 28336586 TI - Draft Genome Sequence of Tannerella forsythia Clinical Isolate 9610. AB - We present here the draft genome sequence of Tannerella forsythia 9610, a clinical isolate obtained from a periodontitis patient. The genome is composed of 79 scaffolds with 82 contigs, for a length of 3,201,941 bp and a G+C of 47.3%. PMID- 28336587 TI - Draft Genome Sequence of Propionibacterium avidum Strain UCD-PD2 Isolated from a Feline Anal Sac. AB - Here, we present the draft genome sequence of Propionibacterium (Cutibacterium) avidum strain UCD-PD2. The assembly contains 2,667,287 bp in 51 contigs. The strain was isolated from anal sac secretion samples collected from a feral domestic cat (Felis catus) as part of a larger project to study the microbiology of cats. PMID- 28336589 TI - First Complete Genome Sequence of Cucumber green mottle mosaic virus Isolated from Australia. AB - We present here the first complete genome sequence of the tobamovirus Cucumber green mottle mosaic virus (CGMMV) from Australia, obtained from an infected cucumber plant. Compared with other CGMMV genomes, its closest nucleotide identities were 99.6% to KP772568, 99.3% to KF155229, and 99.1% to DQ767631 from Canada, Israel, and India, respectively. PMID- 28336588 TI - Draft Genome Sequences of Three Nontypeable Strains of Haemophilus influenzae, C188, R535, and 1200, Isolated from Different Types of Disease. AB - Nontypeable Haemophilus influenzae is a persistent human respiratory pathogen known to be involved in a range of acute and chronic respiratory diseases. Here, we report the genome sequences of three H. influenzae strains isolated from sputum, otitis media, and blood. Comparative analyses revealed significant differences in the gene contents including the presence of genes mediating antibiotic resistance. PMID- 28336590 TI - First Insights into the Genome Sequence of the Strictly Anaerobic Homoacetogenic Sporomusa sphaeroides Strain E (DSM 2875). AB - Here, we report the draft genome sequence of Sporomusa sphaeroides strain E (DSM 2875), a strict anaerobic homoacetogenic bacterium. It is able to grow autotrophically on different one-carbon compounds. The strain possesses several genes of the Wood-Ljungdahl pathway. The genome consists of a single chromosome (4.98 Mb). PMID- 28336591 TI - Draft Genome Sequence of Corynebacterium pseudotuberculosis Strain PA07 Biovar ovis, Isolated from a Sheep Udder in Amazonia. AB - In this work, we present the draft genome sequence of Corynebacterium pseudotuberculosis strain PA07 biovar ovis, isolated from a caseous secretion from a sheep udder in Para, Brazil. The genome contains 2,320,235 bp, 52.2% G+C content, 2,191 coding sequences (CDSs), five pseudogenes, 48 tRNAs, and three rRNAs. PMID- 28336592 TI - Complete Coding Sequence of Usutu Virus Strain Gracula religiosa/U1609393/Belgium/2016 Obtained from the Brain Tissue of an Infected Captive Common Hill Myna (Gracula religiosa). AB - The complete and annotated coding sequence and partial noncoding sequence of an Usutu virus genome were sequenced from RNA extracted from a clinical brain tissue sample obtained from a common hill myna (Gracula religiosa), demonstrating close homology with Usutu viruses circulating in Europe. PMID- 28336593 TI - Complete Genome Sequence of the Plasmid-Bearing Lactobacillus fermentum Strain SNUV175, a Probiotic for Women's Health Isolated from the Vagina of a Healthy South Korean Woman. AB - Lactobacillus fermentum SNUV175 has been identified as a probiotic strain that inhibits pathogenic microorganisms related to women's health. We present the complete genomic sequence of the strain L. fermentum SNUV175 isolated from the vagina of a South Korean woman. This genomic information may provide insight into the functional activity of this strain. PMID- 28336594 TI - First Report on the Complete Genome Sequence of Lactobacillus crustorum MN047, a Potent Probiotic Strain Isolated from Koumiss in China. AB - The complete genome sequence of Lactobacillus crustorum deciphered by PacBio RS II and Illumina HiSeq 4000 sequencing was first reported with one chromosome and two plasmids. Sequence analysis of L. crustorum MN047 showed probiotic characteristics. PMID- 28336595 TI - Genome Sequence of Creatinine-Fermenting Tissierella creatinophila Strain KRE 4T (DSM 6911). AB - Tissierella creatinophila strain KRE 4T (DSM 6911) is a strictly anaerobic, creatinine-fermenting, and creatine-fermenting organism, which has been isolated from sewage sludge. The draft genome consists of one circular chromosome (2.5 Mb) and harbors 2,533 predicted protein-encoding genes. PMID- 28336596 TI - Whole-Genome Shotgun Sequence of Escherichia coli Strain MN067 from India, a Commensal Bacterium with Potent Pathogenic Ability. AB - Escherichia coli is one of the most frequently prevalent pathogens, causing infections in health care settings throughout the world. Here, we report the whole-genome sequence of MN067, a commensal bacterium with a pathogenic potential. PMID- 28336597 TI - Draft Genome Sequence of Providencia stuartii PS71, a Multidrug-Resistant Strain Associated with Nosocomial Infections in Greece. AB - Providencia stuartii is frequently associated with nosocomial outbreaks and displays intrinsic resistance to many commonly used antimicrobials. We report here the draft genome sequence of a P. stuartii strain carrying acquired resistance genes conferring panresistance to cephalosporins (blaSHV-5 and blaVEB 1), carbapenems (blaVIM-1), and aminoglycosides (rmtB) involved in an outbreak in Greek hospitals. PMID- 28336598 TI - Draft Genome Sequence of the Mycoparasitic Oomycete Pythium periplocum Strain CBS 532.74. AB - The oomycete Pythium periplocum is an aggressive mycoparasite of a number of plant pathogenic fungi and oomycetes and therefore has potential as a biological control agent. Here, we report the first draft genome sequence of P. periplocum, which comprises 35.89 Mb. It contains 1,043 scaffolds and 14,399 predicted protein-coding genes. PMID- 28336599 TI - Complete Genome Sequence and Methylome Analysis of Acinetobacter calcoaceticus 65. AB - Acinetobacter calcoaceticus 65 is the original source strain for the restriction enzyme Acc65I. Its complete sequence and full methylome were determined using single-molecule real-time (SMRT) sequencing. PMID- 28336600 TI - Complete Genome Sequences, before and after Mammalian Cell Culture, of Zika Virus Isolated from the Serum of a Symptomatic Male Patient from Oaxaca, Mexico. AB - Zika virus (ZIKV) is an emerging arthropod-borne flavivirus associated with severe congenital malformations and neurological complications. Although the ZIKV genome is well characterized, there is limited information regarding changes after cell isolation and culture adaptation. We isolated, and passaged in Vero cells, ZIKV from the serum of a symptomatic male patient and compared the viral genomes before and after culture. Single nucleotide polymorphisms were characteristic among serum-circulating genomes, while such diversity decreased after cell culture. PMID- 28336601 TI - Draft Genome Sequence of the Murine Bacterial Isolate Lactobacillus murinus EF-1. AB - Screening for lysogenic lactobacilli in rat fecal samples has identified Lactobacillus murinus EF-1. Whole-genome sequencing revealed a 2.30-Mb draft genome with 39.6% G+C content and 2,196 open reading frames. PHAST analysis identified three intact prophages of 26.1 kb, 25.4 kb, and 49.6 kb in size. PMID- 28336602 TI - Complete Genome Sequences of Pseudomonas fluorescens Bacteriophages Isolated from Freshwater Samples in Omaha, Nebraska. AB - The complete genome sequences of four Pseudomonas fluorescens bacteriophages, UNO SLW1 to UNO-SLW4, isolated from freshwater samples, are 39,092 to 39,215 bp long. The genomes are highly similar (identity, >0.995) but dissimilar from that of Pseudomonas phage Pf-10 (the closest relative, 0.685 to 0.686 identity), with 48 to 49 protein-coding genes and 66 regulatory sites predicted. PMID- 28336604 TI - Draft Genome Sequence of Chromobacterium pseudoviolaceum LMG 3953T, an Enigmatic Member of the Genus Chromobacterium. AB - Chromobacterium pseudoviolaceum LMG 3953T was separated from Chromobacterium violaceum in 2009, but little is known of its origin or environmental role. Here, the genome of LMG 3953T was sequenced to understand the evolution of the genus Chromobacterium It is not clear from this sequence that C. pseudoviolaceum is taxonomically distinct from C. violaceum. PMID- 28336603 TI - High-Quality Draft Genome Sequence of Francisella tularensis subsp. holarctica Strain 08T0073 Isolated from a Wild European Hare. AB - Here, we report a high-quality draft genome sequence of Francisella tularensis subsp. holarctica strain 08T0073, isolated from the cadaver of a wild European hare (Lepus europaeus) found near Helmstedt, Lower Saxony, Germany, in 2007. In Germany, infected hares are a major source of tularemia in humans. PMID- 28336605 TI - Draft Genome Sequence of Chromobacterium subtsugae MWU12-2387 Isolated from a Wild Cranberry Bog in Truro, Massachusetts. AB - Chromobacterium subtsugae MWU12-2387 was isolated from the rhizosphere of cranberry plants. While it is unknown what environmental role these bacteria play in bog soils, they hold potential as biological control agents against nematodes and insect pests. Potential virulence genes were identified, including the violacein synthesis pathway, siderophores, and several chitinases. PMID- 28336606 TI - Draft Genome Sequence of Chromobacterium aquaticum CC-SEYA-1, a Nonpigmented Member of the Genus Chromobacterium. AB - Chromobacterium aquaticum CC-SEYA-1T, isolated from a spring in Taiwan, shares many characteristics with other members of the genus but also contains auxin biosynthesis genes and does not produce the pigment violacein. Chromobacterium sp. 49, isolated from Brazil, is identified here as C. aquaticum, indicating that this is a cosmopolitan species. PMID- 28336607 TI - Genome Sequence of Human Rhinovirus A22, Strain Lancaster/2015. AB - The genome of human rhinovirus A22 (HRV-A22) was assembled by deep sequencing RNA samples from nasopharyngeal swabs. The assembled genome is 8.7% divergent from the HRV-A22 reference strain over its full length, and it is only the second full length genome sequence for HRV-A22. The new strain is designated strain HRV A22/Lancaster/2015. PMID- 28336608 TI - Draft Genome Sequence of Klebsiella pneumoniae subsp. pneumoniae ATCC 9621. AB - We present here the 5.561-Mbp assembled draft genome sequence of Klebsiella pneumoniae subsp. pneumoniae ATCC 9621, a phosphite- and organophosphonate assimilating Gammaproteobacterium. The genome harbors 5,179 predicted protein coding genes. PMID- 28336609 TI - Transition from turbulent to coherent flows in confined three-dimensional active fluids. AB - Transport of fluid through a pipe is essential for the operation of macroscale machines and microfluidic devices. Conventional fluids only flow in response to external pressure. We demonstrate that an active isotropic fluid, composed of microtubules and molecular motors, autonomously flows through meter-long three dimensional channels. We establish control over the magnitude, velocity profile, and direction of the self-organized flows and correlate these to the structure of the extensile microtubule bundles. The inherently three-dimensional transition from bulk-turbulent to confined-coherent flows occurs concomitantly with a transition in the bundle orientational order near the surface and is controlled by a scale-invariant criterion related to the channel profile. The nonequilibrium transition of confined isotropic active fluids can be used to engineer self organized soft machines. PMID- 28336610 TI - Vertically extensive and unstable magmatic systems: A unified view of igneous processes. AB - Volcanoes are an expression of their underlying magmatic systems. Over the past three decades, the classical focus on upper crustal magma chambers has expanded to consider magmatic processes throughout the crust. A transcrustal perspective must balance slow (plate tectonic) rates of melt generation and segregation in the lower crust with new evidence for rapid melt accumulation in the upper crust before many volcanic eruptions. Reconciling these observations is engendering active debate about the physical state, spatial distribution, and longevity of melt in the crust. Here we review evidence for transcrustal magmatic systems and highlight physical processes that might affect the growth and stability of melt rich layers, focusing particularly on conditions that cause them to destabilize, ascend, and accumulate in voluminous but ephemeral shallow magma chambers. PMID- 28336612 TI - UK science, post-Brexit. PMID- 28336611 TI - Self-assembly of genetically encoded DNA-protein hybrid nanoscale shapes. AB - We describe an approach to bottom-up fabrication that allows integration of the functional diversity of proteins into designed three-dimensional structural frameworks. A set of custom staple proteins based on transcription activator-like effector proteins folds a double-stranded DNA template into a user-defined shape. Each staple protein is designed to recognize and closely link two distinct double helical DNA sequences at separate positions on the template. We present design rules for constructing megadalton-scale DNA-protein hybrid shapes; introduce various structural motifs, such as custom curvature, corners, and vertices; and describe principles for creating multilayer DNA-protein objects with enhanced rigidity. We demonstrate self-assembly of our hybrid nanostructures in one-pot mixtures that include the genetic information for the designed proteins, the template DNA, RNA polymerase, ribosomes, and cofactors for transcription and translation. PMID- 28336613 TI - News at a glance. PMID- 28336614 TI - Trump's 2018 budget proposal 'devalues' science. PMID- 28336615 TI - Can flu shots help women get pregnant? PMID- 28336616 TI - Ma, where did they put T. rex? PMID- 28336618 TI - In search for unseen matter, physicists turn to dark sector. PMID- 28336617 TI - New Zealand temblor points to threat of compound quakes. PMID- 28336619 TI - Tweak makes U.S. nukes more precise-and deadlier. PMID- 28336620 TI - Fishy business. PMID- 28336621 TI - Macrophage, a long-distance middleman. PMID- 28336622 TI - Powering up perovskite photoresponse. PMID- 28336623 TI - Bringing proteins into the fold. PMID- 28336624 TI - From chaos to order in active fluids. PMID- 28336625 TI - Using fire to promote biodiversity. PMID- 28336626 TI - Genes, environment, and "bad luck". PMID- 28336627 TI - Hans Rosling (1948-2017). PMID- 28336629 TI - Rain check. PMID- 28336628 TI - A roadmap for rapid decarbonization. PMID- 28336630 TI - Stranger than fiction. PMID- 28336631 TI - Patent pools for CRISPR technology. PMID- 28336632 TI - Patent pools for CRISPR technology-Response. PMID- 28336633 TI - Specimen collection crucial to taxonomy. PMID- 28336635 TI - Cell projections set up pigment pattern. PMID- 28336634 TI - Identifying the hosts of quasar absorbers. PMID- 28336636 TI - Nanograined metals avoid going soft. PMID- 28336638 TI - Using "you" to generalize from me to others. PMID- 28336637 TI - Metal-oxide synergy. PMID- 28336639 TI - Estimating transmission chains for dengue. PMID- 28336640 TI - Helping T cells feel at home in the liver. PMID- 28336641 TI - Why pain and stress lead to depression. PMID- 28336642 TI - Cancer and the unavoidable R factor. PMID- 28336643 TI - Making magma chambers from mush. PMID- 28336645 TI - Added complexity in an asymmetric receptor. PMID- 28336646 TI - Protein-folded DNA nanostructures. PMID- 28336644 TI - Dendrites are more active than expected. PMID- 28336647 TI - Go with the changing flow. PMID- 28336649 TI - Chromatin state dictates drug response. PMID- 28336648 TI - How perovskites have the edge. PMID- 28336650 TI - Lysosomal cholesterol activates mTORC1. PMID- 28336651 TI - NAD+ binding modulates protein interactions. PMID- 28336652 TI - Tugging on Notch receptor tunes signaling. PMID- 28336653 TI - Fire management, made to measure. PMID- 28336654 TI - Influenz-ing IFN responses in dendritic cells. PMID- 28336655 TI - It's easier to see green. PMID- 28336656 TI - A new angle on streams. PMID- 28336657 TI - Turning toys into tools. PMID- 28336658 TI - Stronger pancreas through starvation. PMID- 28336659 TI - The evolution of edited RNA transcripts. PMID- 28336661 TI - Notch1 promotes cancer spread. PMID- 28336660 TI - Recovering galaxy images from noisy data. PMID- 28336662 TI - Dirac cones in a boron monolayer. PMID- 28336663 TI - [C ii] 158-MUm emission from the host galaxies of damped Lyman-alpha systems. AB - Gas surrounding high-redshift galaxies has been studied through observations of absorption line systems toward background quasars for decades. However, it has proven difficult to identify and characterize the galaxies associated with these absorbers due to the intrinsic faintness of the galaxies compared with the quasars at optical wavelengths. Using the Atacama Large Millimeter/Submillimeter Array, we report on detections of [C ii] 158-MUm line and dust-continuum emission from two galaxies associated with two such absorbers at a redshift of z ~ 4. Our results indicate that the hosts of these high-metallicity absorbers have physical properties similar to massive star-forming galaxies and are embedded in enriched neutral hydrogen gas reservoirs that extend well beyond the star-forming interstellar medium of these galaxies. PMID- 28336664 TI - Grain boundary stability governs hardening and softening in extremely fine nanograined metals. AB - Conventional metals become harder with decreasing grain sizes, following the classical Hall-Petch relationship. However, this relationship fails and softening occurs at some grain sizes in the nanometer regime for some alloys. In this study, we discovered that plastic deformation mechanism of extremely fine nanograined metals and their hardness are adjustable through tailoring grain boundary (GB) stability. The electrodeposited nanograined nickel-molybdenum (Ni Mo) samples become softened for grain sizes below 10 nanometers because of GB mediated processes. With GB stabilization through relaxation and Mo segregation, ultrahigh hardness is achieved in the nanograined samples with a plastic deformation mechanism dominated by generation of extended partial dislocations. Grain boundary stability provides an alternative dimension, in addition to grain size, for producing novel nanograined metals with extraordinary properties. PMID- 28336665 TI - Active sites for CO2 hydrogenation to methanol on Cu/ZnO catalysts. AB - The active sites over commercial copper/zinc oxide/aluminum oxide (Cu/ZnO/Al2O3) catalysts for carbon dioxide (CO2) hydrogenation to methanol, the Zn-Cu bimetallic sites or ZnO-Cu interfacial sites, have recently been the subject of intense debate. We report a direct comparison between the activity of ZnCu and ZnO/Cu model catalysts for methanol synthesis. By combining x-ray photoemission spectroscopy, density functional theory, and kinetic Monte Carlo simulations, we can identify and characterize the reactivity of each catalyst. Both experimental and theoretical results agree that ZnCu undergoes surface oxidation under the reaction conditions so that surface Zn transforms into ZnO and allows ZnCu to reach the activity of ZnO/Cu with the same Zn coverage. Our results highlight a synergy of Cu and ZnO at the interface that facilitates methanol synthesis via formate intermediates. PMID- 28336666 TI - How "you" makes meaning. AB - "You" is one of the most common words in the English language. Although it typically refers to the person addressed ("How are you?"), "you" is also used to make timeless statements about people in general ("You win some, you lose some."). Here, we demonstrate that this ubiquitous but understudied linguistic device, known as "generic-you," has important implications for how people derive meaning from experience. Across six experiments, we found that generic-you is used to express norms in both ordinary and emotional contexts and that producing generic-you when reflecting on negative experiences allows people to "normalize" their experience by extending it beyond the self. In this way, a simple linguistic device serves a powerful meaning-making function. PMID- 28336667 TI - Dengue diversity across spatial and temporal scales: Local structure and the effect of host population size. AB - A fundamental mystery for dengue and other infectious pathogens is how observed patterns of cases relate to actual chains of individual transmission events. These pathways are intimately tied to the mechanisms by which strains interact and compete across spatial scales. Phylogeographic methods have been used to characterize pathogen dispersal at global and regional scales but have yielded few insights into the local spatiotemporal structure of endemic transmission. Using geolocated genotype (800 cases) and serotype (17,291 cases) data, we show that in Bangkok, Thailand, 60% of dengue cases living <200 meters apart come from the same transmission chain, as opposed to 3% of cases separated by 1 to 5 kilometers. At distances <200 meters from a case (encompassing an average of 1300 people in Bangkok), the effective number of chains is 1.7. This number rises by a factor of 7 for each 10-fold increase in the population of the "enclosed" region. This trend is observed regardless of whether population density or area increases, though increases in density over 7000 people per square kilometer do not lead to additional chains. Within Thailand these chains quickly mix, and by the next dengue season viral lineages are no longer highly spatially structured within the country. In contrast, viral flow to neighboring countries is limited. These findings are consistent with local, density-dependent transmission and implicate densely populated communities as key sources of viral diversity, with home location the focal point of transmission. These findings have important implications for targeted vector control and active surveillance. PMID- 28336669 TI - A conserved NAD+ binding pocket that regulates protein-protein interactions during aging. AB - DNA repair is essential for life, yet its efficiency declines with age for reasons that are unclear. Numerous proteins possess Nudix homology domains (NHDs) that have no known function. We show that NHDs are NAD+ (oxidized form of nicotinamide adenine dinucleotide) binding domains that regulate protein-protein interactions. The binding of NAD+ to the NHD domain of DBC1 (deleted in breast cancer 1) prevents it from inhibiting PARP1 [poly(adenosine diphosphate-ribose) polymerase], a critical DNA repair protein. As mice age and NAD+ concentrations decline, DBC1 is increasingly bound to PARP1, causing DNA damage to accumulate, a process rapidly reversed by restoring the abundance of NAD+ Thus, NAD+ directly regulates protein-protein interactions, the modulation of which may protect against cancer, radiation, and aging. PMID- 28336668 TI - Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex. AB - The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that becomes activated at the lysosome in response to nutrient cues. Here, we identify cholesterol, an essential building block for cellular growth, as a nutrient input that drives mTORC1 recruitment and activation at the lysosomal surface. The lysosomal transmembrane protein, SLC38A9, is required for mTORC1 activation by cholesterol through conserved cholesterol-responsive motifs. Moreover, SLC38A9 enables mTORC1 activation by cholesterol independently from its arginine-sensing function. Conversely, the Niemann-Pick C1 (NPC1) protein, which regulates cholesterol export from the lysosome, binds to SLC38A9 and inhibits mTORC1 signaling through its sterol transport function. Thus, lysosomal cholesterol drives mTORC1 activation and growth signaling through the SLC38A9 NPC1 complex. PMID- 28336673 TI - Learning from rejections. PMID- 28336670 TI - PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D. AB - Activating mutations in PIK3CA, the gene encoding phosphoinositide-(3)-kinase alpha (PI3Kalpha), are frequently found in estrogen receptor (ER)-positive breast cancer. PI3Kalpha inhibitors, now in late-stage clinical development, elicit a robust compensatory increase in ER-dependent transcription that limits therapeutic efficacy. We investigated the chromatin-based mechanisms leading to the activation of ER upon PI3Kalpha inhibition. We found that PI3Kalpha inhibition mediates an open chromatin state at the ER target loci in breast cancer models and clinical samples. KMT2D, a histone H3 lysine 4 methyltransferase, is required for FOXA1, PBX1, and ER recruitment and activation. AKT binds and phosphorylates KMT2D, attenuating methyltransferase activity and ER function, whereas PI3Kalpha inhibition enhances KMT2D activity. These findings uncover a mechanism that controls the activation of ER by the posttranslational modification of epigenetic regulators, providing a rationale for epigenetic therapy in ER-positive breast cancer. PMID- 28336671 TI - Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. AB - Cancers are caused by mutations that may be inherited, induced by environmental factors, or result from DNA replication errors (R). We studied the relationship between the number of normal stem cell divisions and the risk of 17 cancer types in 69 countries throughout the world. The data revealed a strong correlation (median = 0.80) between cancer incidence and normal stem cell divisions in all countries, regardless of their environment. The major role of R mutations in cancer etiology was supported by an independent approach, based solely on cancer genome sequencing and epidemiological data, which suggested that R mutations are responsible for two-thirds of the mutations in human cancers. All of these results are consistent with epidemiological estimates of the fraction of cancers that can be prevented by changes in the environment. Moreover, they accentuate the importance of early detection and intervention to reduce deaths from the many cancers arising from unavoidable R mutations. PMID- 28336676 TI - Assessment of current practices for developing "preceptors in training". PMID- 28336675 TI - Evolving risk factors and antibiotic sensitivity patterns for microbial keratitis at a large county hospital. AB - : Purpose: To identify the risk factors, causative organisms, antimicrobial susceptibility and outcomes of microbial keratitis in a large county hospital in Houston, Texas.Design: Case series. METHODS: Setting: A large county hospital in Houston, Texas. STUDY POPULATION: Patients with known diagnosis of microbial keratitis from January 2011 to May 2015. OBSERVATION PROCEDURE: Retrospective chart review. MAIN OUTCOMES: Epidemiology, risk factors, outcomes and antibiotic susceptibility of microbial keratitis. RESULTS: The most commonly identified risk factors were contact lens use (34.4%), ocular trauma (26.3%), diabetes mellitus (16.7%), ocular surgery (13.5%), ocular surface diseases (11.5%), previous keratitis (10.4%), glaucoma (6.3%), cocaine use (5.2%) and HIV-positive status (4.2%). Eyes with positive cultures (61.5%) were associated with worse visual outcomes (p=0.019) and a higher number of follow-up visits (p=0.007) than eyes with negative cultures (38.5%). Corneal perforation was the most common complication (11.5%). Gram-negative organisms (21.9%) were all susceptible to ceftazidime, tobramycin and fluoroquinolones. Gram-positive organisms (33.3%) had worse outcomes than Gram-negative organisms (21.9%) and exhibited a wide spectrum of antibiotic resistance, but all were susceptible to vancomycin. Twenty-seven per cent of the coagulase-negative Staphylococci were resistant to fluoroquinolones. CONCLUSION: This study identified a recent shift in risk factors and antibiotic resistance patterns in microbial keratitis at a County Hospital in Houston, Texas. In our patient population, fluoroquinolone monotherapy is not recommended for severe corneal ulcers. On the basis of these results, vancomycin and tobramycin should be used for empirical therapy until microbial identity and sensitivity results are available. PMID- 28336677 TI - The ongoing threat of rising drug prices: ASHP's work goes on. PMID- 28336674 TI - Interchangeability and reliability of macular perfusion parameter measurements using optical coherence tomography angiography. AB - AIM: The aim of the study was to investigate the interchangeability and reliability of macular perfusion measurements using optical coherence tomography angiography. METHODS: A prospective cross-sectional observational study. Healthy adult Chinese subjects were recruited. Macular perfusion parameters were automatically analysed by software included in a spectral-domain optical coherence tomography system. The vessel density (VD) of the whole, parafovea, superior-hemi, inferior-hemi, fovea, temporal, superior, nasal and inferior quadrants as well as the foveal avascular zone (FAZ) and choroidal capillary VD (CCVD) were quantified. RESULTS: A total of 51 eyes in 27 subjects were included (8 men and 19 women, mean age 24+/-4 years). Significant differences in VD of all quadrants (all p<0.001) was detected between the 3*3 mm and 6*6 mm macular scan size. The biggest difference of VD between the two scan size was 5.14+/-4.03, which was not clinically meaningful. No statistically significant differences were found in FAZ or CCVD between the two different scan sizes. The mean intraclass correlation coefficient (ICC) between two measurements from the inter rater of 20 eyes was from 0.560 to 0.893 for VD and 0.845 for FAZ. The mean ICC between two measurements from the intrarater of 20 eyes was from 0.497 to 0.870 for VD and 0.780 for FAZ. CONCLUSIONS: FAZ and CCVD are interchangeable between the 3*3 mm and 6*6 mm macular scan sizes. The VD differences between the two different scan sizes are not clinically meaningful. The macular perfusion parameters presented good but not perfect reliability, which should be acknowledged in clinical practice. PMID- 28336680 TI - Stroke Diagnosis in the Pediatric Emergency Department: An Ongoing Challenge. PMID- 28336678 TI - Neutrophils regulate the lung inflammatory response via gammadelta T cell infiltration in an experimental mouse model of human metapneumovirus infection. AB - Neutrophils are the most abundant leukocytes in human circulation. They are the first immune cell population recruited to the sites of infection. However, the role of neutrophils to regulate host immune responses during respiratory viral infections is largely unknown. To elucidate the role of neutrophils in respiratory antiviral defense, we used an experimental mouse model of human metapneumovirus (HMPV) infection. HMPV, a member of the Paramyxoviridae family, is a leading respiratory pathogen causing severe symptoms, such as bronchiolitis and pneumonia, in young, elderly, and immunocompromised patients. We demonstrate that neutrophils are the predominant population of immune cells recruited into the lungs after HMPV infection. This led us to hypothesize that neutrophils represent a key player of the immune response during HMPV infection, thereby regulating HMPV-induced lung pathogenesis. Specific depletion of neutrophils in vivo using a mAb and simultaneous infection with HMPV exhibited higher levels of inflammatory cytokines, pulmonary inflammation, and severe clinical disease compared with HMPV-infected, competent mice. Interestingly, the lack of neutrophils altered gammadelta T cell accumulation in the lung. The absence of gammadelta T cells during HMPV infection led to reduced pulmonary inflammation. These novel findings demonstrate that neutrophils play a critical role in controlling HMPV-induced inflammatory responses by regulating gammadelta T cell infiltration to the site of infection. PMID- 28336679 TI - Transfer to High-Volume Centers Associated With Reduced Mortality After Endovascular Treatment of Acute Stroke. AB - BACKGROUND AND PURPOSE: Some have argued that it may be beneficial to expand the availability of endovascular revascularization services to lower-volume hospitals to minimize the morbidity associated with transfer to larger endovascular centers. We compared the outcomes after revascularization of patients directly admitted to a low-volume center and those transferred to a high-volume center. METHODS: We searched a national database of hospital-reported outcomes for patients who underwent endovascular revascularization for acute ischemic stroke. Hospitals were categorized as low, medium, or high procedural volume hospitals. Outcomes of inpatient admissions were collected and compared on the basis of admission source and hospital procedural volume. RESULTS: A total of 118 institutions with 8533 patients were included. Mortality rate (14.9% versus 18.6%; P=0.049) and mortality index (1.1 versus 1.6; P=0.048) were significantly lower among directly admitted relative to transferred patients. For all patients, there were significant differences in institutional mortality rate (low: 19.7%, medium: 14.9%, high: 9.8%; P=0.003) and mortality index (low: 1.5, medium: 1.1, high: 0.8; P=0.004) between low-, medium-, and high-volume hospitals. For transferred patients to high-volume centers, both mortality rate (high: 10.0% versus low: 20.4%; P=0.005) and mortality index (high: 0.8 versus low: 1.5; P=0.034) were significantly lower than that observed for directly admitted patients to low-volume hospitals. CONCLUSIONS: We report a beneficial effect of treatment at high-volume hospitals in spite of the detrimental effects of transfer. These findings argue for the centralization of care. PMID- 28336681 TI - Accuracy and Reliability of Stroke Diagnosis in the Pediatric Emergency Department. AB - BACKGROUND AND PURPOSE: Access to acute stroke interventions in the emergency department (ED) relies on correct clinical diagnosis. Our aims were to determine the accuracy and reliability of pediatric ED physician diagnosis of childhood stroke and other conditions presenting with brain attack symptoms. METHODS: Prospective study of consecutive children aged 1 month to 18 years presenting to the ED from June 2009 to December 2010 with focal neurological deficits. Accuracy (sensitivity, specificity, and receiver operator characteristic curves [ROCs]) and interrater agreement (kappa) were determined, between ED physician diagnoses, as recorded in the electronic hospital administrative software system, and final neurological diagnosis, after completion of diagnostic work-up. RESULTS: Two hundred eighty-seven children with 301 consecutive presentations were recruited. The most common final brain attack diagnoses included migraine in 84 children, first seizure in 48, Bell's palsy in 29, stroke in 21, and conversion disorders in 18 children. Sensitivity of ED physician stroke diagnosis was 62%, and specificity was 98% (ROC, 0.8). Inter-rater agreement for ED physician and final stroke diagnosis was substantial (kappa=0.61). ED physician diagnostic accuracy and reliability was highest for Bell's palsy (ROC=0.98; kappa=0.96), and lowest for central nervous system demyelination (ROC=0.5; kappa=-0.01) and cerebellitis (ROC=0.50; kappa=0.50). CONCLUSIONS: ED physician diagnostic accuracy and reliability varies considerably across disorders presenting with brain attack symptoms. Clinical recognition tools are required to assist pediatric ED physicians with diagnosis of stroke and other serious neurological disorders. PMID- 28336686 TI - It's now time to curb advertising using flat-faced dogs, say vets. PMID- 28336692 TI - Sharing expertise on all aspects of small ruminant dairying. AB - Delegates from across the UK, Europe and the USA gathered in Bristol last month to hear world leaders in the field of small ruminant dairy medicine and production discuss matters such as milk quality, disease control and feeding at the second annual Dairy Sheep and Goat Conference. Anthony Wilkinson, one of the conference organisers, gives a flavour of proceedings. PMID- 28336683 TI - let-7 regulates radial migration of new-born neurons through positive regulation of autophagy. AB - During adult neurogenesis, newly formed olfactory bulb (OB) interneurons migrate radially to integrate into specific layers of the OB Despite the importance of this process, the intracellular mechanisms that regulate radial migration remain poorly understood. Here, we find that microRNA (miRNA) let-7 regulates radial migration by modulating autophagy in new-born neurons. Using Argonaute2 immunoprecipitation, we performed global profiling of miRNAs in adult-born OB neurons and identified let-7 as a highly abundant miRNA family. Knockdown of let 7 in migrating neuroblasts prevented radial migration and led to an immature morphology of newly formed interneurons. This phenotype was accompanied by a decrease in autophagic activity. Overexpression of Beclin-1 or TFEB in new-born neurons lacking let-7 resulted in re-activation of autophagy and restored radial migration. Thus, these results reveal a miRNA-dependent link between autophagy and adult neurogenesis with implications for neurodegenerative diseases where these processes are impaired. PMID- 28336695 TI - Equine disease surveillance: quarterly summary. AB - of surveillance testing, October to December 2016International disease occurrence in the fourth quarter of 2016These are among matters discussed in the most recent quarterly equine disease surveillance report, prepared by Defra, the Animal Health Trust and the British Equine Veterinary Association. PMID- 28336682 TI - Molecular mechanism of mRNA repression in trans by a ProQ-dependent small RNA. AB - Research into post-transcriptional control of mRNAs by small noncoding RNAs (sRNAs) in the model bacteria Escherichia coli and Salmonella enterica has mainly focused on sRNAs that associate with the RNA chaperone Hfq. However, the recent discovery of the protein ProQ as a common binding partner that stabilizes a distinct large class of structured sRNAs suggests that additional RNA regulons exist in these organisms. The cellular functions and molecular mechanisms of these new ProQ-dependent sRNAs are largely unknown. Here, we report in Salmonella Typhimurium the mode-of-action of RaiZ, a ProQ-dependent sRNA that is made from the 3' end of the mRNA encoding ribosome-inactivating protein RaiA. We show that RaiZ is a base-pairing sRNA that represses in trans the mRNA of histone-like protein HU-alpha. RaiZ forms an RNA duplex with the ribosome-binding site of hupA mRNA, facilitated by ProQ, to prevent 30S ribosome loading and protein synthesis of HU-alpha. Similarities and differences between ProQ- and Hfq-mediated regulation will be discussed. PMID- 28336696 TI - Time to standardise dry cow therapy terminology. PMID- 28336700 TI - Correction. PMID- 28336704 TI - Leptospira vaccine in dogs. PMID- 28336705 TI - Improving pedigree dog health. PMID- 28336706 TI - Improving pedigree dog health. PMID- 28336707 TI - Study on the impact of liver fluke infection on the welfare of horses. PMID- 28336714 TI - My life with elephants. AB - Born and raised in western Nepal, Sarad Paudel saw his first elephant at Chitwan National Park, southern Nepal, and resolved to build his career around them. PMID- 28336716 TI - Correction to 'Differential effects of food availability on minimum and maximum rates of metabolism'. PMID- 28336717 TI - Publisher's Expression of Concern: Lactobacillus bulgaricus Prevents Intestinal Epithelial Cell Injury Caused by Enterobacter sakazakii-Induced Nitric Oxide both In Vitro and in the Newborn Rat Model of Necrotizing Enterocolitis. PMID- 28336715 TI - Monitoring Cell-surface N-Glycoproteome Dynamics by Quantitative Proteomics Reveals Mechanistic Insights into Macrophage Differentiation. AB - The plasma membrane proteome plays a crucial role in inter- and intracellular signaling, cell survival, and cell identity. As such, it is a prominent target for pharmacological intervention. The relatively low abundance of this subproteome in conjunction with challenging extractability and solubility still hampers its comprehensive analysis. Here, we combined a chemical glycoprotein tagging strategy with mass spectrometry to enable comprehensive analysis of the cell-surface glycoproteome. To benchmark this workflow and to provide guidance for cell line selection for functional experiments, we generated an inventory of the N-linked cell-surface glycoproteomes of 15 standard laboratory human cell lines and three primary lymphocytic cell types. On average, about 900 plasma membrane and secreted proteins were identified per experiment, including more than 300 transporters and ion channels. Primary cells displayed distinct expression of surface markers and transporters underpinning the importance of carefully validating model cell lines selected for the study of cell surface mediated processes. To monitor dynamic changes of the cell-surface proteome in a highly multiplexed experiment, we employed an isobaric mass tag-based chemical labeling strategy. This enabled the time-resolved analysis of plasma membrane protein presentation during differentiation of the monocytic suspension cell line THP-1 into macrophage-like adherent cells. Time-dependent changes observed in membrane protein presentation reflect functional remodeling during the phenotypic transition in three distinct phases: rapid surface presentation and secretion of proteins from intracellular pools concurrent with rapid internalization of no longer needed proteins and finally delayed presentation of newly synthesized macrophage markers. Perturbation of this process using marketed receptor tyrosine kinase inhibitors revealed dasatinib to severely compromise macrophage differentiation due to an off-target activity. This finding suggests that dynamic processes can be highly vulnerable to drug treatment and should be monitored more rigorously to identify adverse drug effects. PMID- 28336720 TI - Preventing the Progression of AKI to CKD: The Role of Mitochondria. PMID- 28336719 TI - Colon Cancer Screening among Patients Receiving Dialysis in the United States: Are We Choosing Wisely? AB - The American Society of Nephrology recommends against routine cancer screening among asymptomatic patients receiving maintenance dialysis on the basis of limited survival benefit. To determine the frequency of colorectal cancer screening among patients on dialysis and the extent to which screening tests were targeted toward patients at lower risk of death and higher likelihood of receiving a kidney transplant, we performed a cohort study of 469,574 Medicare beneficiaries ages >=50 years old who received dialysis between January 1, 2007 and September 30, 2012. We examined colorectal cancer screening tests according to quartiles of risk of mortality and kidney transplant on the basis of multivariable Cox modeling. Over a median follow-up of 1.5 years, 11.6% of patients received a colon cancer screening test (57.9 tests per 1000 person years). Incidence rates of colonoscopy, flexible sigmoidoscopy, and fecal occult blood test were 27.9, 0.6, and 29.5 per 1000 person-years, respectively. Patients in the lowest quartile of mortality risk were more likely to be screened than those in the highest quartile (hazard ratio, 1.53; 95% confidence interval, 1.49 to 1.57; 65.1 versus 46.4 tests per 1000 person-years, respectively), amounting to a 33% higher rate of testing. Additionally, compared with patients least likely to receive a transplant, patients most likely to receive a transplant were more likely to be screened (hazard ratio, 1.68; 95% confidence interval, 1.64 to 1.73). Colon cancer screening is being targeted toward patients on dialysis at lowest risk of mortality and highest likelihood of transplantation, but absolute rates are high, suggesting overscreening. PMID- 28336722 TI - Kim Harmon #SayNoToSuddenCardiacDeath #SuperEverything. PMID- 28336723 TI - Ewa Roos #MorningRun #InspirationalLeadership. PMID- 28336721 TI - Tubule-Derived Wnts Are Required for Fibroblast Activation and Kidney Fibrosis. AB - Cell-cell communication via Wnt ligands is necessary in regulating embryonic development and has been implicated in CKD. Because Wnt ligands are ubiquitously expressed, the exact cellular source of the Wnts involved in CKD remains undefined. To address this issue, we generated two conditional knockout mouse lines in which Wntless (Wls), a dedicated cargo receptor that is obligatory for Wnt secretion, was selectively ablated in tubular epithelial cells or interstitial fibroblasts. Blockade of Wnt secretion by genetic deletion of Wls in renal tubules markedly inhibited myofibroblast activation and reduced renal fibrosis after unilateral ureteral obstruction. This effect associated with decreased activation of beta-catenin and downstream gene expression and preserved tubular epithelial integrity. In contrast, fibroblast-specific deletion of Wls exhibited little effect on the severity of renal fibrosis after obstructive or ischemia-reperfusion injury. In vitro, incubation of normal rat kidney fibroblasts with tubule-derived Wnts promoted fibroblast proliferation and activation. Furthermore, compared with kidney specimens from patients without CKD, biopsy specimens from patients with CKD also displayed increased expression of multiple Wnt proteins, predominantly in renal tubular epithelium. These results illustrate that tubule-derived Wnts have an essential role in promoting fibroblast activation and kidney fibrosis via epithelial-mesenchymal communication. PMID- 28336724 TI - Quantitative Age-specific Variability of Plasma Proteins in Healthy Neonates, Children and Adults. AB - Human blood plasma is a complex biological fluid containing soluble proteins, sugars, hormones, electrolytes, and dissolved gasses. As plasma interacts with a wide array of bodily systems, changes in protein expression, or the presence or absence of specific proteins are regularly used in the clinic as a molecular biomarker tool. A large body of literature exists detailing proteomic changes in pathologic contexts, however little research has been conducted on the quantitation of the plasma proteome in age-specific, healthy subjects, especially in pediatrics. In this study, we utilized SWATH-MS to identify and quantify proteins in the blood plasma of healthy neonates, infants under 1 year of age, children between 1-5 years, and adults. We identified more than 100 proteins that showed significant differential expression levels across these age groups, and we analyzed variation in protein expression across the age spectrum. The plasma proteomic profiles of neonates were strikingly dissimilar to the older children and adults. By extracting the SWATH data against a large human spectral library we increased protein identification more than 6-fold (940 proteins) and confirmed the concentrations of several of these using ELISA. The results of this study map the variation in expression of proteins and pathways often implicated in disease, and so have significant clinical implication. PMID- 28336725 TI - Quantitative Shotgun Proteomics Unveils Candidate Novel Esophageal Adenocarcinoma (EAC)-specific Proteins. AB - Esophageal cancer is the eighth most common cancer worldwide and the majority of patients have systemic disease at presentation. Esophageal adenocarcinoma (OAC), the predominant subtype in western countries, is largely resistant to current chemotherapy regimens. Selective markers are needed to enhance clinical staging and to allow targeted therapies yet there are minimal proteomic data on this cancer type. After histological review, lysates from OAC and matched normal esophageal and gastric samples from seven patients were subjected to LC MS/MS after tandem mass tag labeling and OFFGEL fractionation. Patient matched samples of OAC, normal esophagus, normal stomach, lymph node metastases and uninvolved lymph nodes were used from an additional 115 patients for verification of expression by immunohistochemistry (IHC).Over six thousand proteins were identified and quantified across samples. Quantitative reproducibility was excellent between technical replicates and a moderate correlation was seen across samples with the same histology. The quantitative accuracy was verified across the dynamic range for seven proteins by immunohistochemistry (IHC) on the originating tissues. Multiple novel tumor-specific candidates are proposed and EPCAM was verified by IHC.This shotgun proteomic study of OAC used a comparative quantitative approach to reveal proteins highly expressed in specific tissue types. Novel tumor-specific proteins are proposed and EPCAM was demonstrated to be specifically overexpressed in primary tumors and lymph node metastases compared with surrounding normal tissues. This candidate and others proposed in this study could be developed as tumor-specific targets for novel clinical staging and therapeutic approaches. PMID- 28336727 TI - Multicentric Castleman disease: consensus at last? PMID- 28336726 TI - Proteomic Signature of Acute Liver Failure: From Discovery and Verification in a Pig Model to Confirmation in Humans. AB - Acute liver failure (ALF) is a fatal condition hallmarked by rapid development. The present study aimed to describe the dynamic alterations of serum proteins associated with ALF development, and to seek for novel biomarkers of ALF. Miniature pigs (n = 38) were employed to establish ALF models by infusing d galactosamine (GALN, 1.3 g/kg). A total of 1310 serum proteins were compared in pooled serum samples (n = 10) before and 36 h after GALN administration through label-free quantitation (LFQ) based shotgun proteomics. Functional analysis suggested a significant enrichment of ALF-related proteins involved in energy metabolism. Temporal changes of 20 energy metabolism related proteins were investigated in individual pigs (n = 8) via parallel reaction monitoring (PRM) based targeted proteomics. In addition, mitochondrion degeneration and gene expression alteration of aerobic metabolism genes were confirmed in GALN-insulted pig liver. In clinical validation study enrolled 34 ALF patients and 40 healthy controls, fructose-1,6-bisphosphatase 1 (FBP1) showed a prognostic value for short-term survival (30 days) equal to that of the Model of End-stage Liver Disease score (ROC-AUC = 0.778). Survival analysis suggested significantly higher death-related hazard in ALF patients with higher FBP1 levels (>16.89 MUg/dL) than in those with lower FBP1 levels (p = 0.002). Additionally, serum retinol binding protein 4 (RBP4) level was found decreased prior to ALT elevation in GALN insulted pig model. We also confirmed that serum level of RBP4 is significantly lower in ALF patients (p < 0.001) as compared with healthy controls. In summary, this translational study, displayed by multistaged proteomics techniques, unveiled underlying functional changes related to the development of ALF and facilitated the discovery of novel ALF markers. PMID- 28336728 TI - Unraveling Castleman: progress in a complex process. PMID- 28336729 TI - Platelets: killers of parasites or patients? PMID- 28336730 TI - Is CMV in utero the first event in pediatric ALL? PMID- 28336731 TI - Platelet granules in vascular integrity. PMID- 28336732 TI - Platelet polyphosphate: the long and the short of it. PMID- 28336733 TI - A case of bad Carma! PMID- 28336734 TI - Time to publication for publicly funded clinical trials in Australia: an observational study. AB - OBJECTIVE: To examine the length of time between receiving funding and publishing the protocol and main paper for randomised controlled trials. DESIGN: An observational study using survival analysis. SETTING: Publicly funded health and medical research in Australia. PARTICIPANTS: Randomised controlled trials funded by the National Health and Medical Research Council of Australia between 2008 and 2010. MAIN OUTCOME MEASURES: Time from funding to the protocol paper and main results paper. Multiple variable survival models examining whether study characteristics predicted publication times. RESULTS: We found 77 studies with a total funding of $A59 million. The median time to publication of the protocol paper was 6.4 years after funding (95% CI 4.1 to 8.1). The proportion with a published protocol paper 8 years after funding was 0.61 (95% CI 0.48 to 0.74). The median time to publication of the main results paper was 7.1 years after funding (95% CI 6.3 to 7.6). The proportion with a published main results paper 8 years after funding was 0.72 (95% CI 0.56 to 0.87). The HRs for how study characteristics might influence timing were generally close to one with narrow CIs, the notable exception was that a longer study length lengthened the time to the main paper (HR=0.62 per extra study year, 95% CI 0.43 to 0.89). CONCLUSIONS: Despite the widespread registration of clinical trials, there remain serious concerns of trial results not being published or being published with a long delay. We have found that these same concerns apply to protocol papers, which should be publishable soon after funding. Funding agencies could set a target of publishing the protocol paper within 18 months of funding. PMID- 28336737 TI - Comparative effectiveness of different wound dressings for patients with partial thickness burns: study protocol of a systematic review and a Bayesian framework network meta-analysis. AB - INTRODUCTION: Selecting a suitable wound dressing for patients with partial thickness burns (PTBs) is important in wound care. However, the comparative effectiveness of different dressings has not been studied. We report the protocol of a network meta-analysis designed to combine direct and indirect evidence of wound dressings in the management of PTB. METHODS AND ANALYSIS: We will search for randomised controlled trials (RCTs) evaluating the wound-healing effect of a wound dressing in the management of PTB. Searches will be conducted in MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Wounds Group Specialised Register and CINAHL. A comprehensive search strategy is developed to retrieve articles reporting potentially eligible RCTs. Besides, we will contact the experts in the field and review the conference proceedings to locate non-published studies. The reference lists of articles will be reviewed for any candidate studies. Two independent reviewers will screen titles and abstracts of the candidate articles. All eligible RCTs will be obtained in full text to perform a review. Disagreement on eligibility of an RCT will be solved by group discussion. The information of participants, interventions, comparisons and outcomes from included RCTs will be recorded and summarised. The primary outcome is time to complete wound healing. Secondary outcomes include the proportion of burns completely healed at the end of treatment, change in wound surface area at the end of treatment, incidence of adverse events, etc. ETHICS AND DISSEMINATION: The result of this review will provide evidence for the comparative effectiveness of different wound dressings in the management of PTB. It will also facilitate decision-making in choosing a suitable wound dressing. We will disseminate the review through a peer-review journal and conference abstracts or posters. TRIAL REGISTRATION NUMBER: PROSPERO CRD42016041574; Pre-results. PMID- 28336735 TI - Risk of tuberculosis in patients treated with TNF-alpha antagonists: a systematic review and meta-analysis of randomised controlled trials. AB - OBJECTIVES: An increased risk of tuberculosis (TB) has been reported in patients treated with TNF-alpha antagonists, an issue that has been highlighted in a WHO black box warning. This review aimed to assess the risk of TB in patients undergoing TNF-alpha antagonists treatment. METHODS: A systematic literature search for randomised controlled trials (RCTs) was performed in MEDLINE, Embase and Cochrane library and studies selected for inclusion according to predefined criteria. ORs with 95% CIs were calculated using the random-effect model. Subgroup analyses considered the effects of drug type, disease and TB endemicity. The quality of evidence was assessed using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. RESULTS: 29 RCTs involving 11 879 patients were included (14 for infliximab, 9 for adalimumab, 2 for golimumab, 1 for etanercept and 3 for certolizumab pegol). Of 7912 patients allocated to TNF-alpha antagonists, 45 (0.57%) developed TB, while only 3 cases occurred in 3967 patients allocated to control groups, resulting in an OR of 1.94 (95% CI 1.10 to 3.44, p=0.02). Subgroup analyses indicated that patients of rheumatoid arthritis (RA) had a higher increased risk of TB when treated with TNF alpha antagonists (OR 2.29 (1.09 to 4.78), p=0.03). The level of the evidence was recommended as 'low' by the GRADE system. CONCLUSIONS: Findings from our meta analysis indicate that the risk of TB may be significantly increased in patients treated with TNF-alpha antagonists. However, further studies are needed to reveal the biological mechanism of the increased TB risk caused by TNF-alpha antagonists treatment. PMID- 28336736 TI - Identifying possible reasons why female street sex workers have poor drug treatment outcomes: a qualitative study. AB - AIMS: To explore street sex workers (SSWs) views and experiences of drug treatment, in order to understand why this population tend to experience poor drug treatment outcomes. DESIGN: In-depth interviews. SETTING: Bristol, UK. PARTICIPANTS: 24 current and exited SSWs with current or previous experience of problematic use of heroin and/or crack cocaine. FINDINGS: Participants described how feeling unable to discuss their sex work in drug treatment groups undermined their engagement in the treatment process. They outlined how disclosure of sex work resulted in stigma from male and female service users as well as adverse interactions with male service users. Participants highlighted that non disclosure meant they could not discuss unresolved trauma issues which were common and which emerged or increased when they reduced their drug use. As trauma experiences had usually involved men as perpetrators participants said it was not appropriate to discuss them in mixed treatment groups. SSWs in recovery described how persistent trauma-related symptoms still affected their lives many years after stopping sex work and drug use. Participants suggested SSW-only services and female staff as essential to effective care and highlighted that recent service changes were resulting in loss of trusted staff and SSW-only treatment services. This was reported to be reducing the likelihood of SSWs engaging in drug services, with the resultant loss of continuity of care and reduced time with staff acting as barriers to an effective therapeutic relationship. CONCLUSIONS: SSWs face many barriers to effective drug treatment. SSW-only treatment groups, continuity of care with treatment staff and contact with female staff, particularly individuals who have had similar lived experience, could improve the extent to which SSWs engage and benefit from drug treatment services. Service engagement and outcomes may also be improved by drug services that include identification and treatment of trauma-related symptoms. PMID- 28336738 TI - Single-stage osseointegrated reconstruction and rehabilitation of lower limb amputees: the Osseointegration Group of Australia Accelerated Protocol-2 (OGAAP 2) for a prospective cohort study. AB - INTRODUCTION: Lower limb amputations have detrimental influences on the quality of life, function and body image of the affected patients. Following amputation, prolonged rehabilitation is required for patients to be fitted with traditional socket prostheses, and many patients experience symptomatic socket-residuum interface problems which lead to reduced prosthetic use and quality of life. Osseointegration has recently emerged as a novel approach for the reconstruction of amputated limbs, which overcomes many of the socket-related problems by directly attaching the prosthesis to the skeletal residuum. To date, the vast majority of osseointegration procedures worldwide have been performed in 2 stages, which require at least 4 months and up to 18 months for the completion of reconstruction and rehabilitation from the time of the initial surgery. The current prospective cohort study evaluates the safety and efficacy of a single stage osseointegration procedure performed under the Osseointegration Group of Australia Accelerated Protocol-2 (OGAAP-2), which dramatically reduces the time of recovery to ~3-6 weeks. METHODS AND ANALYSIS: The inclusion criteria for osseointegrated reconstruction under the OGAAP-2 procedure are age over 18 years, unilateral transfemoral amputation and experiencing problems or difficulties in using socket prostheses. All patients receive osseointegrated implants which are press-fitted into the residual bone. Functional and quality-of-life outcome measures are recorded preoperatively and at defined postoperative follow-up intervals up to 2 years. Postoperative adverse events are also recorded. The preoperative and postoperative values are compared for each outcome measure, and the benefits and harms of the single-stage OGAAP-2 procedure will be compared with the results obtained using a previously employed 2-stage procedure. ETHICS AND DISSEMINATION: This study has received ethics approval from the University of Notre Dame, Sydney, Australia (014153S). The study outcomes will be disseminated by publications in peer-reviewed academic journals and presentations at relevant clinical and orthopaedic conferences. PMID- 28336739 TI - Disparities between research attention and burden in liver diseases: implications on uneven advances in pharmacological therapies in Europe and the USA. AB - OBJECTIVES: Effective oral therapies for hepatitis B and C have recently been developed, while there are no approved pharmacological therapies for alcoholic and non-alcoholic fatty liver diseases (ALD and NAFLD). We hypothesise that fewer advances in fatty liver diseases could be related to disparities in research attention. METHODS: We developed the Attention-to-Burden Index (ABI) that compares the research activities during 2010-2014, and an estimate of disease burden of these 4 major liver diseases. The resulting ratio reflects either overattention (positive value) or inadequate attention (negative value) compared with disease burden. The mean research attention and disease burden were calculated from 5 and 6 different parameters, respectively. The efficacy rate of current pharmacological therapies was assessed from published clinical trials. FINDINGS: The mean research attention for hepatitis B and C was 31% and 47%, respectively, while NAFLD and ALD received 17% and 5%. The overall burden was 5% and 28% for hepatitis B and C, and 17% and 50% for NAFLD and ALD. The calculated ABI for hepatitis B and C revealed a +6.7-fold and +1.7-fold overattention, respectively. NAFLD received an appropriate attention compared with its burden, while ALD received marked inadequate attention of -9.7-fold. The efficacy rate of current pharmacological agents was 72% for hepatitis B, 89% for hepatitis C, 25% for non-alcoholic steatohepatitis and 13% for alcoholic hepatitis. Importantly, we found a positive correlation between the mean attention and the efficacy rate of current therapies in these 4 major liver diseases. INTERPRETATION: There are important disparities between research attention and disease burden among the major liver diseases. While viral hepatitis has received considerable attention, there is a marked inadequate attention to ALD. There is a critical need to increase awareness of ALD in the liver research community. PMID- 28336741 TI - Differences between determinants of in-hospital mortality and hospitalisation costs for patients with acute heart failure: a nationwide observational study from Japan. AB - OBJECTIVES: Although current case-mix classifications in prospective payment systems were developed to estimate patient resource usage, whether these classifications reflect clinical outcomes remains unknown. The efficient management of acute heart failure (AHF) with high mortality is becoming more important in many countries as its prevalence and associated costs are rapidly increasing. Here, we investigate the determinants of in-hospital mortality and hospitalisation costs to clarify the impact of severity factors on these outcomes in patients with AHF, and examine the level of agreement between the predicted values of mortality and costs. DESIGN: Cross-sectional observational study. SETTING AND PARTICIPANTS: A total of 19 926 patients with AHF from 261 acute care hospitals in Japan were analysed using administrative claims data. MAIN OUTCOME MEASURES: Multivariable logistic regression analysis and linear regression analysis were performed to examine the determinants of in-hospital mortality and hospitalisation costs, respectively. The independent variables were grouped into patient condition on admission, postadmission procedures indicating disease severity (eg, intra-aortic balloon pumping) and other high-cost procedures (eg, single-photon emission CT). These groups of independent variables were cumulatively added to the models, and their effects on the models' abilities to predict the respective outcomes were examined. The level of agreement between the quartiles of predicted mortality and predicted costs was analysed using Cohen's kappa coefficient. RESULTS: In-hospital mortality was associated with patient's condition on admission and severity-indicating procedures (C-statistics 0.870), whereas hospitalisation costs were associated with severity-indicating procedures and high-cost procedures (R2 0.32). There were substantial differences in determinants between the outcomes. In addition, there was no consistent relationship observed (kappa=0.016, p<0.0001) between the quartiles of in hospital mortality and hospitalisation costs. CONCLUSIONS: The determinants of mortality and costs for hospitalised patients with AHF were generally different. Our results indicate that the same case-mix classifications should not be used to predict both these outcomes. PMID- 28336740 TI - Towards personalised intra-arterial treatment of patients with acute ischaemic stroke: a study protocol for development and validation of a clinical decision aid. AB - INTRODUCTION: Overall, intra-arterial treatment (IAT) proved to be beneficial in patients with acute ischaemic stroke due to a proximal occlusion in the anterior circulation. However, heterogeneity in treatment benefit may be relevant for personalised clinical decision-making. Our aim is to improve selection of patients for IAT by predicting individual treatment benefit or harm. METHODS AND ANALYSIS: We will use data collected in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) trial to analyse the effect of baseline characteristics on outcome and treatment effect. A multivariable proportional odds model with interaction terms will be developed to predict the outcome for each individual patient, both with and without IAT. Model performance will be expressed as discrimination and calibration, after bootstrap resampling and shrinkage of regression coefficients, to correct for optimism. External validation will be conducted on data of patients in the Interventional Management of Stroke III trial (IMS III). Primary outcome will be the modified Rankin Scale (mRS) at 90 days after stroke. ETHICS AND DISSEMINATION: The proposed study will provide an internationally applicable clinical decision aid for IAT. Findings will be disseminated widely through peer reviewed publications, conference presentations and in an online web application tool. Formal ethical approval was not required as primary data were already collected. TRIAL REGISTRATION NUMBERS: ISRCTN10888758; Post-results and NCT00359424; Post-resultsc. PMID- 28336742 TI - Current and potential providers of blood pressure self-screening: a mixed methods study in Oxfordshire. AB - OBJECTIVES: To (1) establish the extent of opportunities for members of the public to check their own blood pressure (BP) outside of healthcare consultations (BP self-screening), (2) investigate the reasons for and against hosting such a service and (3) ascertain how BP self-screening data are used in primary care. DESIGN: A mixed methods, cross-sectional study. SETTING: Primary care and community locations in Oxfordshire, UK. PARTICIPANTS: 325 sites were surveyed to identify where and in what form BP self-screening services were available. 23 semistructured interviews were then completed with current and potential hosts of BP self-screening services. RESULTS: 18/82 (22%) general practices offered BP self-screening and 68/110 (62%) pharmacies offered professional-led BP screening. There was no evidence of permanent BP self-screening activities in other community settings.Healthcare professionals, managers, community workers and leaders were interviewed. Those in primary care generally felt that practice based BP self-screening was a beneficial activity that increased the attainment of performance targets although there was variation in its perceived usefulness for patient care. The pharmacists interviewed provided BP checking as a service to the community but were unable to develop self-screening services without a clear business plan. Among potential hosts, barriers to providing a BP self screening service included a perceived lack of healthcare commissioner and public demand, and a weak-if any-link to their core objectives as an organisation. CONCLUSIONS: BP self-screening currently occurs in a minority of general practices. Any future development of community BP self-screening programmes will require (1) public promotion and (2) careful consideration of how best to support and reward-the community hosts who currently perceive little if any benefit. PMID- 28336743 TI - Is socioeconomic position associated with risk of attempted suicide in rural Sri Lanka? A cross-sectional study of 165 000 individuals. AB - BACKGROUND: Lower socioeconomic position (SEP) is associated with an increased risk of suicidal behaviour in high-income countries, but this association is unclear in low-income and middle-income countries. METHODS: We investigated the association of SEP with attempted suicide in a cross-sectional survey of 165 233 Sri Lankans. SEP data were collected at the household (assets, social standing (highest occupation of a household member), foreign employment and young (<=40 years) female-headed households) and individual level (education and occupation). Respondent-reported data on suicide attempts in the past year were recorded. Random-effects logistic regression models, accounting for clustering, were used to investigate the association of SEP with attempted suicide. RESULTS: Households reported 398 attempted suicides in the preceding year (239 per 100 000). Fewer assets (OR 3.2, 95% CI 2.4 to 4.4) and having a daily wage labourer (ie, insecure/low-income job; OR 2.3, 95% CI 1.6 to 3.2) as the highest occupation increased the risk of an attempted suicide within households. At an individual level, daily wage labourers were at an increased risk of attempted suicide compared with farmers. The strongest associations were with low levels of education (OR 4.6, 95% CI 2.5 to 8.4), with a stronger association in men than women. CONCLUSIONS: We found that indicators of lower SEP are associated with increased risk of attempted suicide in rural Sri Lanka. Longitudinal studies with objective measures of suicide attempts are needed to confirm this association. TRIAL REGISTRATION NUMBER: NCT01146496; Pre-results. PMID- 28336744 TI - Association of respiratory symptoms and asthma with occupational exposures: findings from a population-based cross-sectional survey in Telemark, Norway. AB - OBJECTIVES: The aim of this study was to estimate the prevalence of respiratory symptoms and physician-diagnosed asthma and assess the impact of current occupational exposure. DESIGN: Cross-sectional analyses of the prevalence of self reported respiratory health and association with current occupational exposure in a random sample of the general population in Telemark County, Norway. SETTINGS: In 2013, a self-administered questionnaire was mailed to a random sample of the general population, aged 16-50, in Telemark, Norway. The overall response rate was 33%, comprising 16 099 responders. OUTCOME MEASURES: The prevalence for respiratory symptoms and asthma, and OR of respiratory symptoms and asthma for occupational groups and exposures were calculated. Occupational exposures were assessed using self-reported exposure and an asthma-specific job-exposure matrix (JEM). RESULTS: The prevalence of physician-diagnosed asthma was 11.5%. For the occupational groups, the category with agriculture/fishery workers and craft/related trade workers was associated with wheezing and asthma attack in the past 12 months, showing OR 1.3 (1.1 to 1.6) and 1.9 (1.2 to 2.8), respectively. The group including technicians and associated professionals was also associated with wheezing OR 1.2 (1.0 to 1.3) and asthma attack OR 1.4 (1.1 to 1.9). The JEM data show that exposure to flour was associated with wheezing OR 3.2 (1.4 to 7.3) and woken with dyspnoea OR 3.5 (1.3 to 9.5), whereas exposures to diisocyanates, welding/soldering fumes and exposure to vehicle/motor exhaust were associated with dyspnoea OR 2.9 (1.5 to 5.7), 3.2 (1.6 to 6.4) and 1.4 (1.0 to 1.8), respectively. CONCLUSIONS: The observed prevalence of physician-diagnosed asthma was 11.5%. The 'manual' occupations were associated with respiratory symptoms. Occupational exposure to flour, diisocyanates, welding/soldering fumes and vehicle/motor exhaust was associated with respiratory symptoms in the past 12 months and use of asthma medication. However, prospective data are needed to confirm the observed associations. PMID- 28336745 TI - Sport and scholastic factors in relation to smoking and smoking initiation in older adolescents: a prospective cohort study in Bosnia and Herzegovina. AB - OBJECTIVE: Sport and scholastic factors are known to be associated with cigarette smoking in adolescence, but little is known about the causality of this association. The aim of this study was to prospectively explore the relationships of different sport and scholastic factors with smoking prevalence initiation in older adolescents from Bosnia and Herzegovina. METHODS: In this 2-year prospective cohort study, there were 872 adolescent participants (16 years at baseline; 46% females). The study consisted of baseline tests at the beginning of the third year (September 2013) and follow-up at the end of the fourth year of high school (late May to early June 2015). The independent variables were scholastic and sport-related factors. The dependent variables were (1) smoking at baseline, (2) smoking at follow-up and (3) smoking initiation over the course of the study. Logistic regressions controlling for age, gender and socioeconomic status were applied to define the relationships between independent and dependent variables. RESULTS: School absence at the baseline study was a significant predictor of smoking initiation during the course of the study (OR 1.4, 95% CI 1.1 to 1.8). Those who reported quitting sports at baseline showed an increased risk of smoking at the end of the study (OR 1.4, 95% CI 1.1 to 2.0) and of smoking initiation (OR 1.8, 95% CI 1.3 to 2.0). Adolescents who reported lower competitive achievements in sport were at a higher risk of (1) smoking at baseline (OR 1.5, 95% CI 1.1 to 2.1), (2) smoking at follow-up (OR 1.5, 95% CI 1.1 to 2.1) and (3) smoking initiation (OR 1.6, 95% CI 1.1 to 2.6). CONCLUSIONS: In developing accurate antismoking public health policies for older adolescents, the most vulnerable groups should be targeted. The results showed that most participants initiated smoking before 16 years of age. Therefore, further investigations should evaluate the predictors of smoking in younger ages. PMID- 28336746 TI - Understanding Dutch practice nurses' adherence to evidence-based smoking cessation guidelines and their needs for web-based adherence support: results from semistructured interviews. AB - OBJECTIVES: Practice nurses in general practices suboptimally adhere to smoking cessation guidelines. Since the effectiveness of their smoking cessation support is greatest when full adherence to these guidelines is achieved, interventions need to be developed to improve practice nurses' guideline adherence, for example, by tailoring their content to adherence determinants. However, the sociocognitive determinants explaining adherence have not yet been investigated. Therefore, this qualitative needs assessment aimed to explore practice nurses' current counselling practices, as well as their sociocognitive beliefs related to their smoking cessation guideline adherence and their needs regarding web-based adherence support. SETTING: Primary care; general practices in the Netherlands. PARTICIPANTS: 19 practice nurses, actively involved in smoking cessation counselling. METHODS: Semistructured individual interviews, based on the I-Change Model and the Diffusion of Innovations Theory, were conducted from May to September 2014. Data were systematically analysed using the Framework Method and considered reliable (kappa 0.77; % agreement 99%). RESULTS: Respondents felt able to be empathic and collaborative during smoking cessation consultations. They also reported psychological (eg, low self-efficacy to increase patient motivation and arranging adequate follow-up consultations) and practical barriers (eg, outdated information on quit support compensation and a perceived lack of high quality trainings for practice nurses) to smoking cessation guideline adherence. Most respondents were interested in web-based adherence support to overcome these barriers. CONCLUSIONS: Sociocognitive determinants influence practice nurses' smoking cessation guideline adherence. To improve their adherence, web-based tailored adherence support can provide practice nurses with personally relevant feedback tailored to individually perceived barriers to smoking cessation guideline adherence. More specifically, low self-efficacy levels can be increased by peer modelling (eg, presenting narratives of colleagues) and up-to-date information can be presented online, enabling practice nurses to use it during patient consultations, resulting in more effective communication with their smoking patients. TRIAL REGISTRATION NUMBER: NTR4436; Pre-results. PMID- 28336749 TI - FDA outlines conditions for pharmacies to repackage drug products. PMID- 28336748 TI - The sweet side of AMPK signaling: regulation of GFAT1. AB - Maintaining a steady balance between nutrient supply and energy demand is essential for all living organisms and is achieved through the dynamic control of metabolic processes that produce and consume adenosine-5'-triphosphate (ATP), the universal currency of energy in all cells. A key sensor of cellular energy is the adenosine-5'-monophosphate (AMP)-activated protein kinase (AMPK), which is the core component of a signaling network that regulates energy and nutrient metabolism. AMPK is activated by metabolic stresses that decrease cellular ATP, and functions to restore energy balance by orchestrating a switch in metabolism away from anabolic pathways toward energy-generating catabolic processes. A new study published in a recent issue of Biochemical Journal by Zibrova et al. shows that glutamine:fructose-6-phosphate amidotransferase-1 (GFAT1), the rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP), is a physiological substrate of AMPK. The HBP is an offshoot of the glycolytic pathway that drives the synthesis of uridine-5'-diphospho-N-acetylglucosamine, the requisite donor metabolite needed for dynamic beta-N-acetylglucosamine (O-GlcNAc) modification (O GlcNAcylation) of cellular proteins. O-GlcNAcylation is a nutrient-sensitive post translational modification that, like phosphorylation, regulates numerous intracellular processes. Zibrova et al. show that inhibitory phosphorylation of the GFAT1 residue Ser243 by AMPK in response to physiological or small-molecule activators leads to a reduction in cellular protein O-GlcNAcylation. Further work revealed that AMPK-dependent phosphorylation of GFAT1 promotes angiogenesis in endothelial cells. This elegant study demonstrates that the AMPK-GFAT1 signaling axis serves as an important communication point between two nutrient-sensitive signaling pathways and is likely to play a significant role in controlling physiological processes in many other tissues. PMID- 28336750 TI - New drugs and dosage forms. PMID- 28336751 TI - Maine pharmacists eye legislation to end drug plans' retroactive fees. PMID- 28336752 TI - Alabama pharmacists push for state collaborative therapy law. PMID- 28336747 TI - Cross-sectional associations between dietary intake and carotid intima media thickness in type 2 diabetes: baseline data from a randomised trial. AB - OBJECTIVE: To assess associations between dietary intake and carotid intima media thickness (CIMT) by carotid ultrasound (CUS), a surrogate marker of cardiovascular disease (CVD) risk, in those with type 2 diabetes. DESIGN: Cross sectional analysis of baseline data from 325 participants from three randomised controlled trials collected in the same way. SETTING: Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Canada. PARTICIPANTS: 325 participants with type 2 diabetes, taking oral antidiabetic agents, with an HbA1c between 6.5% and 8.0% at screening, without a recent cardiovascular event. MAIN OUTCOME MEASURES: CIMT by CUS and associations with dietary intake from 7-day food records, as well as anthropometric measures and fasting serum samples. RESULTS: CIMT was significantly inversely associated with dietary pulse intake (beta= 0.019, p=0.009), available carbohydrate (beta=-0.004, p=0.008), glycaemic load (beta=-0.001, p=0.007) and starch (beta=-0.126, p=0.010), and directly associated with total (beta=0.004, p=0.028) and saturated (beta=0.012, p=0.006) fat intake in multivariate regression models adjusted for age, smoking, previous CVD event, blood pressure medication, antidiabetic medication and ultrasonographer. CONCLUSIONS: Lower CIMT was significantly associated with greater consumption of dietary pulses and carbohydrates and lower total and saturated fat intake, suggesting a potential role for diet in CVD risk management in type 2 diabetes. Randomised controlled trials are anticipated to explore these associations further. TRIAL REGISTRATION NUMBER: NCT01063374. PMID- 28336755 TI - Standardizing i.v. infusion concentrations: The time has come. PMID- 28336753 TI - Correction. PMID- 28336756 TI - Empirical gentamicin dosing based on serum creatinine levels in premature and term neonates. AB - PURPOSE: Empirical gentamicin dosing based on serum creatinine (SCr) levels in premature and term neonates was evaluated. METHODS: This single-center, retrospective cohort study was conducted in a standalone children's hospital with a level IIIB, 44-bed neonatal intensive care unit (NICU). Data were abstracted and collected for all neonates admitted to the NICU from March 5, 2012, through March 5, 2014. Patients were included in the study if gentamicin was administered within the first 7 days of life, a trough gentamicin level was measured, and the neonate had a baseline SCr level measured within the first 24 hours of life. A series of logistic regressions was conducted to determine if gentamicin trough levels were influenced by gestational age (<=29 weeks [group 1], 30 weeks to 34 weeks and 6 days [group 2], and >=35 weeks [group 3]) and SCr level (0.81-0.99 mg/dL [mildly elevated] and >=1 mg/dL [elevated]). RESULTS: Of the 577 neonates reviewed during the study period, 507 met the inclusion criteria. Mildly elevated and elevated SCr levels were significantly associated with the presence of an elevated gentamicin trough (p < 0.001). When the effect of gestational age was evaluated, the data suggested that SCr is a strong predictor of elevated gentamicin troughs. CONCLUSION: Neonates with a gestational age of >=30 weeks who had an SCr level of >=1 mg/dL within the first 12-24 hours of life were more likely to have an elevated gentamicin trough level than their counterparts with normal SCr levels. PMID- 28336757 TI - Development of a bedside scoring system for predicting a first recurrence of Clostridium difficile-associated diarrhea. AB - PURPOSE: A scoring system for identifying patients at high or low risk for recurrent Clostridium difficile-associated diarrhea (CDAD) is described. METHODS: A retrospective cohort study was performed using data on adults with CDAD admitted to a 3-hospital system from 2009 to 2014. The primary endpoint was the rate of recurrent CDAD within 60 days of clinical cure of CDAD. Risk factors for CDAD recurrence were identified, and a risk prediction tool was developed using multivariate logistic regression. RESULTS: The CDAD cure rate in the study cohort (n = 340) was 92.3%; the 60-day recurrence rate was 16.9%. Five factors were significantly associated with high recurrence risk: presence of CDAD at admission, body temperature of >37.8 degrees C at admission, leukocytosis, nosocomial CDAD, and abdominal distention on CDAD presentation. From that information a risk prediction tool, the CDAD "recurrence score," was developed (1 point is assigned for each factor present, for a maximum score of 5). Validation testing of the recurrence score indicated an area under the receiver operating characteristic curve of 0.72 (95% confidence interval, 0.65-0.80). A score of >=2 had a negative predictive value of 91%, while a score of >=4 had a positive predictive value of 70%. CONCLUSION: If externally validated in future studies, a tool for predicting the risk of recurrent CDAD using data readily available at the time of presentation could allow clinicians to identify patients at high risk for recurrence, address modifiable risk factors, and select tailored treatments to improve patient outcomes. PMID- 28336758 TI - Evaluation of a pharmacist-led outpatient direct oral anticoagulant service. AB - PURPOSE: The impact of a pharmacist-led direct oral anticoagulant (DOAC) service on prescription appropriateness and patient adherence was simultaneously evaluated. METHODS: In this retrospective analysis, patients age 18 years or older for whom a DOAC was prescribed from September 20, 2013, through December 31, 2014, were identified through electronic medical record review of all DOAC prescriptions within the University of Michigan Health System. Patients had their DOAC therapy managed by a pharmacist-led DOAC service or by their physician (usual care). Primary endpoints included the percentage of patients who had appropriate DOAC therapy prescribed at baseline and at follow-up appointments at 3-6 months. Secondary endpoints included mean medication possession ratios (MPRs). RESULTS: A total of 258 patients were included in the study, with 129 in each group. Patients in the pharmacist-led DOAC service were significantly more likely to have an appropriate combination of DOAC and dosage prescribed for their indication at baseline compared with the usual care group (p = 0.009), a finding that persisted at follow up (p = 0.016). There was no significant difference between groups in the number of patients determined to have an appropriate DOAC prescribed for an approved indication (independent of dose) in the pharmacist-led service (95.3%) versus usual care (93.0%) at baseline. Patients in the pharmacist led service had a greater mean adjusted MPR compared with the usual care group (p = 0.0014) over a median follow-up period of 248 days. CONCLUSION: A pharmacist led DOAC service increased appropriate dosing of DOACs at baseline and follow up as well as patient adherence to therapy. PMID- 28336759 TI - Standardizing concentrations of adult drug infusions in Indiana. AB - PURPOSE: A multidisciplinary, consensus-driven initiative to promote the use of standardized medication concentrations for adult drug infusions across the state of Indiana is described. METHODS: To accomplish development of the Indiana Standard Concentrations of Adult Drug Infusions List ("the Indiana List"), several available lists of i.v. concentrations were compiled, consolidated, and compared. Lists of adult standardized i.v. concentrations were primarily drawn from Indiana regional patient safety coalitions, published literature, and publicly available lists of recommended i.v. concentrations. The standardization project, which expanded initial work completed by the Indianapolis Coalition for Patient Safety, was conducted in conjunction with Purdue University's Center for Medication Safety Advancement, the Indiana Hospital Association, and the 11 regional patient safety coalitions across the state. RESULTS: After a review of 9 existing lists of standard i.v. concentrations, an initial list of 69 concentrations representing a total of 37 medications was derived; 34 of those concentrations were represented on at least 1 of the 3 evaluated Indiana regional patient safety coalition lists. A statewide interdisciplinary work group of representatives of regional patient safety coalitions and 9 health systems representing a total of 81 hospitals ranging from academic medical centers to critical access hospitals assembled to develop consensus on a final list of standard medication concentrations for adult i.v. infusions. CONCLUSION: A final list of 28 concentrations of 26 medications was identified for the recommended Indiana List by an interdisciplinary work group. A checklist of considerations for implementation was also developed. PMID- 28336760 TI - Analysis of variations in the display of drug names in computerized prescriber order-entry systems. AB - PURPOSE: The variations in how drug names are displayed in computerized prescriber-order-entry (CPOE) systems were analyzed to determine their contribution to potential medication errors. METHODS: A diverse set of 10 inpatient and outpatient CPOE system vendors and self-developed CPOE systems in 6 U.S. healthcare institutions was evaluated. A team of pharmacists, physicians, patient-safety experts, and informatics experts created a CPOE assessment tool to standardize the assessment of CPOE features across the systems studied. Hypothetical scenarios were conducted with test patients to study the medication ordering workflow and ways in which medications were displayed in each system. Brand versus generic drug name ordering was studied at 1 large outpatient system to understand why prescribers ordered both brand and generic forms of the same drug. RESULTS: Widespread variations in the display of drug names were observed both within and across the 6 study sites and 10 systems, including the inconsistent display of brand and generic names. Some displayed drugs differently even on the same screen. Combination products were often displayed inconsistently, and some systems required prescribers to know the first drug listed in the combination in order for the correct product to appear in a search. It also appeared that prescribers may have prescribed both brand and generic forms of the same medication, creating the potential for drug duplication errors. CONCLUSION: A review of 10 CPOE systems revealed that medication names were displayed inconsistently, which can result in confusion or errors in reviewing, selecting, and ordering medications. PMID- 28336761 TI - Impact of an antimicrobial stewardship initiative on time to administration of empirical antibiotic therapy in hospitalized patients with bacteremia. AB - PURPOSE: The impact of an antimicrobial stewardship initiative on time to first antibiotic dose and clinical outcomes in bacteremic patients was evaluated. METHODS: A single-center, retrospective study was conducted for adult inpatients who received antibiotics before and after implementation of a rapid administration of antimicrobials by an infectious diseases specialist (RAIDS) protocol. Patients admitted to an inpatient service from June to October 2011 (pre-RAIDS protocol) and from December 2011 to February 2012 (post-RAIDS protocol) were eligible for inclusion if (1) they were age 18 years or older, (2) their infection occurred two or more days after hospital admission, and (3) they had a blood culture growing an organism other than common skin contaminants (i.e., coagulase-negative staphylococci, Bacillus species). The primary outcome was the time to the first antibiotic dose (TFAD), defined as the time that elapsed from a positive blood culture result to administration of the first empirical antimicrobial dose. RESULTS: A total of 111 bacteremic patients were included in the analysis. Implementation of the RAIDS protocol led to significantly faster antibiotic order entry, verification, and administration of empirical antibiotics in patients with bacteremia. The median TFAD was approximately 8 hours faster in the post-RAIDS group than in the pre-RAIDS group (9:09 hr:min versus 1:23 hr:min, p < 0.001). Patients in the post-RAIDS group had a significant reduction in infection-related mortality (p = 0.047), though all cause 30-day mortality was similar. CONCLUSION: Early notification of an infectious diseases pharmacist about positive blood cultures using the RAIDS protocol led to increased appropriateness of empirical drug selection and a dramatic reduction in the administration of antibiotics and was associated with decreased infection-related mortality. PMID- 28336762 TI - Automated detection of look-alike/sound-alike medication errors. AB - PURPOSE: The development and evaluation of an algorithm for detecting potential medication errors due to look-alike/sound-alike (LASA) drug names are described. SUMMARY: A computer algorithm that detects potential LASA errors by analyzing medication orders and diagnostic claims data was developed. The algorithm flags a potential error when (1) a medication order is not justified by a diagnosis documented in the patient's record, (2) another medication whose orthographic similarity to the index drug exceeds a specified threshold exists, and (3) the latter drug has an indication that matches an active documented diagnosis. A review of medication orders and diagnostic claims at a large health system identified cases in which cycloserine was ordered but cyclosporine was the intended treatment. Subsequent review of all cycloserine orders over a 7-year period indicated that 11 of 16 orders were erroneous, prompting placement of an alert regarding the potential for LASA errors involving cycloserine and cyclosporine in the electronic order-entry system. Automated detection and confirmation of LASA errors via chart review can be used retrospectively to identify problematic pairs of drug names and to assess associated error rates within a healthcare system. The same techniques can be used to prevent errors in real time through indication alerts if accurate diagnostic information is available at the time of order entry. CONCLUSION: Automated methods involving the use of medication orders, diagnostic claims, and indications can be used to detect and prevent LASA errors. PMID- 28336763 TI - Improving patients' pain experience in a large rural hospital. PMID- 28336764 TI - Anti-hyperglycaemic activity of Moringa oleifera is partly mediated by carbohydrase inhibition and glucose-fibre binding. AB - Moringa oleifera has potential anti-hyperglycaemic effects that have been reported earlier by different scientific groups using animal models of diabetes. We aimed to explore the possible mechanisms of action of M. oleifera extract through different methods. Primarily, we measured fasting blood glucose and performed glucose tolerance test, in Type 2 diabetic rats. Further, we studied the effects of extracts on pancreatic insulin concentration. Extracts' effect on carbohydrate breakdown was assayed using alpha-amylase inhibition assays and assay of six different segments of gastrointestinal (GI) tracts. An in situ intestinal perfusion model and a glucose fibre assay were performed to see the potentiality of M. oleifera on glucose absorption. M. oleifera showed no significant change in insulin secretion in vivo Additionally, substantial effect of the extract was seen on retarded glucose absorption and in the in situ perfusion study of rat intestinal model. alpha-amylase action was inhibited by the extract, yet again, these findings were further confirmed via the Six Segment assay, where sucrose digestion was found to be inhibited throughout the length of the GI tract. A combined in vitro, in vivo and in situ tests justified the potential of anti-hyperglycaemic activity of M. oleifera and its tissue level mechanism is also justified. PMID- 28336765 TI - miR-330-5p suppresses glioblastoma cell proliferation and invasiveness through targeting ITGA5. AB - The present study intended to investigate the biological effects of miR-330-5p on glioblastoma (GBM) cell proliferation and invasiveness by targeting integrin alpha5 (ITGA5). The expressions of miR-330-5p and ITGA5 mRNA in GBM cell lines (U87, U251, and U373) and normal brain glial cell line (HEB) were detected using RT-qPCR. Protein expression of ITGA5 was examined using Western blot. The present study used MTT assay, colony formation assay, Transwell assay, wound healing assay, and flow cytometry analysis in order to determine the biological functions of GBM cells (including cell proliferation, invasion, migration, apoptosis, and cell cycle). The present study applied dual-luciferase reporter gene assay to identify the target relationship between miR-330-5p and ITGA5. miR-330-5p was low expressed in GBM cell lines while ITGA5 was high-expressed compared with HEB. miR 330-5p could directly target ITGA5 as well as suppress its expression in GBM cells. Up-regulation of miR-330-5p and down-regulation of ITGA5 both have an inhibitory effect on cell proliferation, invasion, and migration. Meanwhile, they could also promote GBM cell apoptosis. miR-330-5p could suppress proliferation and invasion of GBM cells through targeting ITGA5. PMID- 28336766 TI - Abdominal obesity and gastroesophageal cancer risk: systematic review and meta analysis of prospective studies. AB - To systematically and quantitatively review the relation of abdominal obesity, as measured by waist circumference (WC) and waist to hip ratio (WHR), to total gastroesophageal cancer, gastric cancer (GC), and esophageal cancer. PubMed and Web of Science databases were searched for studies assessing the association between abdominal obesity and gastroesophageal cancer (GC and/or esophageal cancer) up to August 2016. A random-effect model was used to calculate the summary relative risks (RRs) and 95% confidence intervals (CIs). Seven prospective cohort studies - one publication included two separate cohorts - from six publications were included in the final analysis. A total of 2130 gastroesophageal cancer cases diagnosed amongst 913182 participants. Higher WC and WHR were significantly associated with increased risk of total gastroesophageal cancer (WC: RR 1.68, 95% CI: 1.38, 2.04; WHR: RR 1.49, 95% CI: 1.19, 1.88), GC (WC: RR 1.48, 95% CI: 1.24, 1.78; WHR: 1.33, 95% CI: 1.04, 1.70), and esophageal cancer (WC: RR 2.06, 95% CI: 1.30, 3.24; WHR: RR 1.99, 95% CI: 1.05, 3.75).Findings from our subgroup analyses showed non-significant positive associations between gastric non-cardia adenocarcinoma (GNCA) and both measures of abdominal adiposity, while gastric cardia adenocarcinoma (GCA) was positively associated with WC but not with WHR. On analysis restricted to studies that adjusted for body mass index (BMI), WC was positively associated with GC and esophageal cancer, whereas WHR was positively associated with risk of GC only. Although limited, the findings from our meta-analysis suggest the potential role of abdominal obesity in the etiology of gastric and esophageal cancers. PMID- 28336769 TI - Health workers are vital to sustainable development goals and universal health coverage. PMID- 28336767 TI - Correlations between ACE single nucleotide polymorphisms and prognosis of patients with septic shock. AB - The aim of the present study is to investigate association between septic shock (SS) and angiotensin I-converting enzyme (ACE) single nucleotide polymorphisms (SNPs). From October 2009 to December 2016, 238 SS patients and 242 healthy individuals were selected for our study. ACE activity was detected, ACE rs4291 and rs4646994 polymorphisms were detected using PCR-restriction fragment length polymorphism (PCR-RFLP). The Kaplan-Meier survival curve was employed to evaluate the association between ACE SNPs and patients' survival and univariate and multivariate analyses to estimate risk factors for SS. ACE activity in the case group was increased in comparison with the control group. Allele and genotype frequencies of rs4291 and rs4646994 were different between the case and control groups. The TT genotype frequency of the rs4291 polymorphisms and the DD genotype of the rs4646994 polymorphisms of the case group were higher than those in the control group. The AT and TT genotypes indicated a significant elevation of ACE activity than the AA genotype, while a significant decline was found in the DI and II genotypes in comparison with the DI genotype. Patients with TT or DD genotypes had increased fatality rate within 7 and 30 days when compared with those with non-TT or non-DD genotypes. Lower sepsis-related organ failure assessment (SOFA) scores, rs4291, serum ACE and rs4646994 were all considered as risky factors for SS patients. The study demonstrates that TT genotype of rs4291 or DD genotype of rs4646994 may be indicative of a higher risk of SS and a poorer prognosis in SS patients. PMID- 28336768 TI - Care of girls and women with Turner syndrome: beyond growth and hormones. AB - Turner syndrome (TS), although considered a rare disease, is the most common sex chromosome abnormality in women, with an incident of 1 in 2500 female births. TS is characterized by distinctive physical features such as short stature, ovarian dysgenesis, an increased risk for heart and renal defects as well as a specific cognitive and psychosocial phenotype. Given the complexity of the condition, patients face manifold difficulties which increase over the lifespan. Furthermore, failures during the transitional phase to adult care result in moderate health outcomes and decreased quality of life. Guidelines on the optimal screening procedures and medical treatment are easy to find. However, recommendations for the treatment of the incriminating psychosocial aspects in TS are scarce. In this work, we first reviewed the literature on the cognitive and psychosocial development of girls with TS compared with normal development, from disclosure to young adulthood, and then introduce a psychosocial approach to counseling and treating patients with TS, including recommendations for age appropriate psychological diagnostics. With this work, we aim to facilitate the integration of emphasized psychosocial care in state-of-the-art treatment for girls and women with TS. PMID- 28336770 TI - pTAC10, a Key Subunit of Plastid-Encoded RNA Polymerase, Promotes Chloroplast Development. AB - Regulation of photosynthetic gene expression by plastid-encoded RNA polymerase (PEP) is essential for chloroplast development. The activity of PEP largely relies on at least 12 PEP-associated proteins (PAPs) encoded in the nuclear genome of plant cells. A recent model proposed that these PAPs regulate the establishment of the PEP complex through broad PAP-PEP or PAP-PAP interactions. In this study, we identified the Arabidopsis (Arabidopsis thaliana) seedling lethal mutant ptac10-1, which has defects in chloroplast development, and found that the mutant phenotype is caused by the suppression of PLASTID S1 RNA-BINDING DOMAIN PROTEIN (pTAC10/PAP3). Analysis of the heterozygous mutant and pTAC10 overexpressing transgenic plants indicated that the expression level of pTAC10 is tightly linked to chloroplast development. Characterization of the interaction of pTAC10 with PAPs revealed that pTAC10 interacts with other PAPs, such as FSD2, FSD3, TrxZ, pTAC7, and pTAC14, but it does not interact with PEP core enzymes, such as rpoA and rpoB. Analysis of pTAC10 interactions using truncated pTAC10 proteins showed that the pTAC10 carboxyl-terminal region downstream of the S1 domain is involved in the pTAC10-PAP interaction. Furthermore, overexpression of truncated pTAC10s lacking the C-terminal regions downstream of the S1 domain could not rescue the ptac10-1 mutant phenotype and induced an abnormal whitening phenotype in Columbia-0 plants. Our observations suggested that these pTAC10-PAP interactions are essential for the formation of the PEP complex and chloroplast development. PMID- 28336771 TI - Dimerization in LBD16 and LBD18 Transcription Factors Is Critical for Lateral Root Formation. AB - LATERAL ORGAN BOUNDARIES DOMAIN/ASYMMETRIC LEAVES2-LIKEs (hereafter referred to as LBD) are plant-specific transcription factors that play important roles in a plethora of plant growth and development. The leucine (Leu) zipper-like coiled coil motif in the lateral organ boundaries domain of the class I LBD proteins has been proposed to mediate protein dimerization, but it has not been experimentally assessed yet. LBD16 and LBD18 have been well characterized to play important roles in lateral root development in Arabidopsis (Arabidopsis thaliana). Here, we investigated the role of the coiled-coil motif in the dimerization of LBD16 and LBD18 and in transcriptional regulation and biological function. We built the molecular models of the coiled coil of LBD16 and LBD18, providing the probable Leu zipper models of the helix dimer. Using a variety of molecular techniques, such as bimolecular fluorescence complementation, luciferase complementation imaging, GST pull down, and coimmunoprecipitation assays, we showed that the conserved Leu or valine residues in the coiled-coil motif are critical for the dimerization of LBD16 or LBD18. Using transgenic Arabidopsis plants that overexpress HA:LBD16 or HA:LBD16Q in lbd16 or HA:LBD18 or HA:LBD18Q in lbd18, we demonstrated that the homodimerization of LBD18 mediated by the coiled-coil motif is crucial for transcriptional regulation via promoter binding and for lateral root formation. In addition, we found that the carboxyl-terminal region beyond the coiled-coil motif in LBD18 acts as an additional dimerization domain. These results provide a molecular basis for homodimerization and heterodimerization among the 42 Arabidopsis LBD family members for displaying their biological functions. PMID- 28336773 TI - ELKS1 helps neuronal synapses diversify. AB - Study reveals how neurons vary the properties of individual synapses by recruiting different Munc13 proteins to presynaptic active zones. PMID- 28336772 TI - GmILPA1, Encoding an APC8-like Protein, Controls Leaf Petiole Angle in Soybean. AB - Leaf petiole angle (LPA) is an important plant architectural trait that affects canopy coverage, photosynthetic efficiency, and ultimately productivity in many legume crops. However, the genetic basis underlying this trait remains unclear. Here, we report the identification, isolation, and functional characterization of Glycine max Increased Leaf Petiole Angle1 (GmILPA1), a gene encoding an APC8-like protein, which is a subunit of the anaphase-promoting complex/cyclosome in soybean (Glycine max). A gamma ray-induced deletion of a fragment involving the fourth exon of GmILPA1 and its flanking sequences led to extension of the third exon and formation of, to our knowledge, a novel 3'UTR from intronic and intergenic sequences. Such changes are responsible for enlarged LPAs that are associated with reduced motor cell proliferation in the Gmilpa1 mutant. GmILPA1 is mainly expressed in the basal cells of leaf primordia and appears to function by promoting cell growth and division of the pulvinus that is critical for its establishment. GmILPA1 directly interacts with GmAPC13a as part of the putative anaphase-promoting complex. GmILPA1 exhibits variable expression levels among varieties with different degrees of LPAs, and expression levels are correlated with the degrees of the LPAs. Together, these observations revealed a genetic mechanism modulating the plant petiole angle that could pave the way for modifying soybean plant architecture with optimized petiole angles for enhanced yield potential. PMID- 28336774 TI - In situ structure of the Legionella Dot/Icm type IV secretion system by electron cryotomography. AB - Type IV secretion systems (T4SSs) are large macromolecular machines that translocate protein and DNA and are involved in the pathogenesis of multiple human diseases. Here, using electron cryotomography (ECT), we report the in situ structure of the Dot/Icm type IVB secretion system (T4BSS) utilized by the human pathogen Legionella pneumophila This is the first structure of a type IVB secretion system, and also the first structure of any T4SS in situ While the Dot/Icm system shares almost no sequence similarity with type IVA secretion systems (T4ASSs), its overall structure is seen here to be remarkably similar to previously reported T4ASS structures (those encoded by the R388 plasmid in Escherichia coli and the cag pathogenicity island in Helicobacter pylori). This structural similarity suggests shared aspects of mechanism. However, compared to the negative-stain reconstruction of the purified T4ASS from the R388 plasmid, the L. pneumophila Dot/Icm system is approximately twice as long and wide and exhibits several additional large densities, reflecting type-specific elaborations and potentially better structural preservation in situ. PMID- 28336775 TI - NELF-E is recruited to DNA double-strand break sites to promote transcriptional repression and repair. AB - Double-strand breaks (DSBs) trigger rapid and transient transcription pause to prevent collisions between repair and transcription machineries at damage sites. Little is known about the mechanisms that ensure transcriptional block after DNA damage. Here, we reveal a novel role of the negative elongation factor NELF in blocking transcription activity nearby DSBs. We show that NELF-E and NELF-A are rapidly recruited to DSB sites. Furthermore, NELF-E recruitment and its repressive activity are both required for switching off transcription at DSBs. Remarkably, using I-SceI endonuclease and CRISPR-Cas9 systems, we observe that NELF-E is preferentially recruited, in a PARP1-dependent manner, to DSBs induced upstream of transcriptionally active rather than inactive genes. Moreover, the presence of RNA polymerase II is a prerequisite for the preferential recruitment of NELF-E to DNA break sites. Additionally, we demonstrate that NELF-E is required for intact repair of DSBs. Altogether, our data identify the NELF complex as a new component in the DNA damage response. PMID- 28336777 TI - Switching genes to silent mode near DNA double-strand breaks. PMID- 28336778 TI - The Predictive Value of Early In-Treatment 18F-FDG PET/CT Response to Chemotherapy in Combination with Bevacizumab in Advanced Nonsquamous Non-Small Cell Lung Cancer. AB - 18F-FDG PET/CT is potentially applicable to predict response to chemotherapy in combination with bevacizumab in patients with advanced non-small cell lung cancer (NSCLC). Methods: In 25 patients with advanced nonsquamous NSCLC, 18F-FDG PET/CT was performed before treatment and after 2 wk, at the end of the second week of first cycle carboplatin-paclitaxel and bevacizumab (CPB) treatment. Patients received up to a total of 4 cycles of CPB treatment. Maintenance treatment with bevacizumab monotherapy was continued until progressive disease without significant treatment-related toxicities of first-line treatment. In the case of progressive disease, bevacizumab was combined with erlotinib. SUV corrected for lean body mass (SUL and SULpeak) were obtained. PERCIST were used for response evaluation. These semiquantitative parameters were correlated with progression free survival and overall survival (OS). Results: Metabolic response, defined by a significant reduction in SULpeak of 30% or more after 2 wk of CPB, was predictive of progression-free survival and OS. For partial metabolic responders (n = 19), the median OS was 22.8 mo. One-year and 2-y OS were 79% and 47%, respectively. Nonmetabolic responders (n = 6) (stable metabolic disease or progressive disease) showed a median OS of 4.4 mo (1-y and 2-y OS was 33% and 0%, respectively) (P < 0.001). Conclusion:18F-FDG PET/CT after 1 treatment cycle is predictive of outcome to first-line chemotherapy with bevacizumab in patients with advanced nonsquamous NSCLC. This enables identification of patients at risk of treatment failure, permitting treatment alternatives such as early switch to a different therapy. PMID- 28336776 TI - Apoptosis inhibitor 5 is an endogenous inhibitor of caspase-2. AB - Caspases are key enzymes responsible for mediating apoptotic cell death. Across species, caspase-2 is the most conserved caspase and stands out due to unique features. Apart from cell death, caspase-2 also regulates autophagy, genomic stability and ageing. Caspase-2 requires dimerization for its activation which is primarily accomplished by recruitment to high molecular weight protein complexes in cells. Here, we demonstrate that apoptosis inhibitor 5 (API5/AAC11) is an endogenous and direct inhibitor of caspase-2. API5 protein directly binds to the caspase recruitment domain (CARD) of caspase-2 and impedes dimerization and activation of caspase-2. Interestingly, recombinant API5 directly inhibits full length but not processed caspase-2. Depletion of endogenous API5 leads to an increase in caspase-2 dimerization and activation. Consistently, loss of API5 sensitizes cells to caspase-2-dependent apoptotic cell death. These results establish API5/AAC-11 as a direct inhibitor of caspase-2 and shed further light onto mechanisms driving the activation of this poorly understood caspase. PMID- 28336779 TI - Validation of the Semiquantitative Static SUVR Method for 18F-AV45 PET by Pharmacokinetic Modeling with an Arterial Input Function. AB - Increased brain uptake of 18F-AV45 visualized by PET is a key biomarker for Alzheimer disease (AD). The SUV ratio (SUVR) is widely used for quantification, but is subject to variability based on choice of reference region and changes in cerebral blood flow. Here we validate the SUVR method against the gold standard volume of distribution (VT) to assess cross-sectional differences in plaque load. Methods: Dynamic 60-min 18F-AV45 (291 +/- 67 MBq) and 1-min 15O-H2O (370 MBq) scans were obtained in 35 age-matched elderly subjects, including 10 probable AD, 15 amnestic mild cognitive impairment (aMCI), and 10 cognitively healthy controls (HCs). 18F-AV45 VT was determined from 2-tissue-compartment modeling using a metabolite-corrected plasma input function. Static SUVR was calculated at 50-60 min after injection, using either cerebellar gray matter (SUVRCB) or whole subcortical white matter (SUVRWM) as the reference. Additionally, whole cerebellum, pons, centrum semiovale, and a composite region were examined as alternative references. Blood flow was quantified by 15O-H2O SUV. Data are presented as mean +/- SEM. Results: There was rapid metabolization of 18F-AV45, with only 35% of unchanged parent remaining at 10 min. Compared with VT, differences in cortical Abeta load between aMCI and AD were overestimated by SUVRWM (+4% +/- 2%) and underestimated by SUVRCB (-10% +/- 2%). VT correlated better with SUVRWM (Pearson r: from 0.63 for posterior cingulate to 0.89 for precuneus, P < 0.0001) than with SUVRCB (Pearson r: from 0.51 for temporal lobe [P = 0.002] to 0.82 for precuneus [P < 0.0001]) in all tested regions. Correlation results for the alternative references were in between those for CB and WM. 15O-H2O data showed that blood flow was decreased in AD compared with aMCI in cortical regions (-5% +/- 1%) and in the reference regions (CB, -9% +/- 8%; WM, -8% +/- 8%). Conclusion: Increased brain uptake of 18F-AV45 assessed by the simplified static SUVR protocol does not truly reflect Abeta load. However, SUVRWM is better correlated with VT and more closely reflects VT differences between aMCI and AD than SUVRCB. PMID- 28336781 TI - Quantitative Evaluation of 2 Scatter-Correction Techniques for 18F-FDG Brain PET/MRI in Regard to MR-Based Attenuation Correction. AB - In PET, corrections for photon scatter and attenuation are essential for visual and quantitative consistency. MR attenuation correction (MRAC) is generally conducted by image segmentation and assignment of discrete attenuation coefficients, which offer limited accuracy compared with CT attenuation correction. Potential inaccuracies in MRAC may affect scatter correction, because the attenuation image (MU-map) is used in single scatter simulation (SSS) to calculate the scatter estimate. We assessed the impact of MRAC to scatter correction using 2 scatter-correction techniques and 3 MU-maps for MRAC. Methods: The tail-fitted SSS (TF-SSS) and a Monte Carlo-based single scatter simulation (MC-SSS) algorithm implementations on the Philips Ingenuity TF PET/MR were used with 1 CT-based and 2 MR-based MU-maps. Data from 7 subjects were used in the clinical evaluation, and a phantom study using an anatomic brain phantom was conducted. Scatter-correction sinograms were evaluated for each scatter correction method and MU-map. Absolute image quantification was investigated with the phantom data. Quantitative assessment of PET images was performed by volume of-interest and ratio image analysis. Results: MRAC did not result in large differences in scatter algorithm performance, especially with TF-SSS. Scatter sinograms and scatter fractions did not reveal large differences regardless of the MU-map used. TF-SSS showed slightly higher absolute quantification. The differences in volume-of-interest analysis between TF-SSS and MC-SSS were 3% at maximum in the phantom and 4% in the patient study. Both algorithms showed excellent correlation with each other with no visual differences between PET images. MC-SSS showed a slight dependency on the MU-map used, with a difference of 2% on average and 4% at maximum when a MU-map without bone was used. Conclusion: The effect of different MR-based MU-maps on the performance of scatter correction was minimal in non-time-of-flight 18F-FDG PET/MR brain imaging. The SSS algorithm was not affected significantly by MRAC. The performance of the MC-SSS algorithm is comparable but not superior to TF-SSS, warranting further investigations of algorithm optimization and performance with different radiotracers and time-of-flight imaging. PMID- 28336780 TI - Biodistribution and Radiation Dosimetry for the Tau Tracer 18F-THK-5351 in Healthy Human Subjects. AB - 18F-THK-5351 is a novel radiotracer that demonstrates high binding selectivity and affinity for tau pathology and exhibits better pharmacokinetics in the living brain than previous THK tau probes. The aim of the present study was to estimate the radiation dose of 18F-THK-5351 in humans and to compare the clinical radiation dosimetry results to estimations published previously with preclinical data. Methods: Serial whole-body PET/CT imaging was performed for 240 min on 12 healthy volunteers after injecting 18F-THK-5351 (mean administered activity, 377.8 +/- 14.0 MBq; range, 340-397 MBq). The bladder and gallbladder were delineated on PET images, and the other organs were delineated on CT images. Voided urine activity was recorded. The decay-corrected and normalized 18F-THK 5351 activity of 15 source-organ regions as a function of time was entered into the OLINDA/EXM software to calculate the effective dose for each subject following the medical internal radiation dosimetry schema. Results: Overall, the 18F-THK-5351 injection was well tolerated. The highest mean initial uptake at 10 min after injection was in the liver (11.4% +/- 2.0%), lung (5.7% +/- 2.1%), intestine (3.4% +/- 0.8%), and kidney (1.4% +/- 0.3%). The highest mean absorbed dose of radiation was in the gallbladder wall (242.2 +/- 105.2 MUGy/MBq), upper large intestine (90.0 +/- 15.8 MUGy/MBq), small intestine (79.5 +/- 13.8 MUGy/MBq), and liver (55.8 +/- 6.1 MUGy/MBq). The resultant whole-body effective dose was 22.7 +/- 1.3 MUSv/MBq. Conclusion: Our results suggest that a routine injection of 370 MBq of 18F-THK-5351 would lead to an estimated effective dose of 8.4 mSv; hence, 18F-THK-5351 has a radiation burden similar to that of other commonly used clinical tracers. Our findings in humans were compatible with recently published preclinical dosimetry data extrapolated from mice. PMID- 28336783 TI - Three-Dimensional Dosimetry for Radiation Safety Estimates from Intrathecal Administration. AB - Intrathecal administration is of growing interest for drug delivery, and its utility is being increasingly investigated through imaging. In this work, the 3 dimensional Voxel-Based Internal Dosimetry Application (VIDA) and 4D Extended Cardiac Torso Phantom (XCAT) were extended to provide radiation safety estimates specific to intrathecal administration. Methods: The 3-dimensional VIDA dosimetry application Monte Carlo simulation was run using a modified XCAT phantom with additional and edited cerebrospinal fluid (CSF) regions to produce voxel-level absorbed dose per unit cumulated activity maps for 9 selected source regions. Simulation validation was performed to compare absorbed dose estimates for common organs in a preexisting dosimetry tool (OLINDA/EXM). Dynamic planar imaging data were acquired in 6 healthy subjects using administered volumes of 5 or 15 mL (n = 3 each) of 185 MBq of 99mTc-diethylenetriaminepentaacetic acid. Absorbed dose was estimated for each subject using the intrathecal-specific dosimetry application. Results: Simulation results were within 6% of OLINDA estimates for common organs. Absorbed dose estimates were highest (0.3-0.8 mGy/MBq) in the lumbar CSF space. A whole-body effective dose estimate of 0.003 mSv/MBq was observed. An administered volume dependency was observed with a 15-mL volume, resulting in lower absorbed dose estimates for several intrathecal and nonintrathecal regions. Conclusion: The intrathecal-specific VIDA implementation enables tailored dosimetry estimation for regions most relevant in intrathecal administration. Absorbed doses are highly localized to CSF and spinal regions and should be taken into consideration when designing intrathecal imaging studies. A potentially interesting relationship was observed between absorbed dose and administered volume, which merits further investigation. PMID- 28336782 TI - Functional Imaging Signature of Patients Presenting with Polycythemia/Paraganglioma Syndromes. AB - Pheochromocytoma/paraganglioma (PPGL) syndromes associated with polycythemia have previously been described in association with mutations in the von Hippel-Lindau gene. Recently, mutations in the prolyl hydroxylase gene (PHD) 1 and 2 and in the hypoxia-inducible factor 2 alpha (HIF2A) were also found to be associated with multiple and recurrent PPGL. Such patients also presented with PPGL and polycythemia, and later on, some presented with duodenal somatostatinoma. In additional patients presenting with PPGL and polycythemia, no further mutations have been discovered. Because the functional imaging signature of patients with PPGL-polycythemia syndromes is still unknown, and because these tumors (in most patients) are multiple, recurrent, and metastatic, the goal of our study was to assess the optimal imaging approach using 4 different PET radiopharmaceuticals and CT/MRI in these patients. Methods: Fourteen patients (10 women, 4 men) with confirmed PPGL and polycythemia prospectively underwent 68Ga-DOTATATE (13 patients), 18F-FDG (13 patients), 18F-fluorodihydroxyphenylalanine (18F-FDOPA) (14 patients), 18F-fluorodopamine (18F-FDA) (11 patients), and CT/MRI (14 patients). Detection rates of PPGL lesions were compared between all imaging studies and stratified between the underlying mutations. Results:18F-FDOPA and 18F-FDA PET/CT showed similar combined lesion-based detection rates of 98.7% (95% confidence interval [CI], 92.7%-99.8%) and 98.3% (95% CI, 90.9%-99.7%), respectively. The detection rates for 68Ga-DOTATATE (35.3%; 95% CI, 25.0%-47.2%), 18F-FDG (42.3; 95% CI, 29.9%-55.8%), and CT/MRI (60.3%; 95% CI, 48.8%-70.7%) were significantly lower (P < 0.01), irrespective of the mutation status. Conclusion:18F-FDOPA and 18F-FDA are superior to 18F-FDG, 68Ga-DOTATATE, and CT/MRI and should be the radiopharmaceuticals of choice in this rare group of patients. PMID- 28336785 TI - Thyroid Cancer: A Comprehensive Guide to Clinical Management. PMID- 28336784 TI - Evaluation of the Effect of Fingolimod Treatment on Microglial Activation Using Serial PET Imaging in Multiple Sclerosis. AB - Traditionally, multiple sclerosis (MS) has been considered a white matter disease with focal inflammatory lesions. It is, however, becoming clear that significant pathology, such as microglial activation, also takes place outside the plaque areas, that is, in areas of normal-appearing white matter (NAWM) and gray matter (GM). Microglial activation can be detected in vivo using 18-kDa translocator protein (TSPO)-binding radioligands and PET. It is unknown whether fingolimod affects microglial activation in MS. The aim of this study was to investigate whether serial PET can be used to evaluate the effect of fingolimod treatment on microglial activation. Methods: Ten relapsing-remitting MS patients were studied using the TSPO radioligand 11C-(R)-PK11195. Imaging was performed at baseline and after 8 and 24 wk of fingolimod treatment. Eight healthy individuals were imaged for comparison. Microglial activation was evaluated as distribution volume ratio of 11C-(R)-PK11195. Results: The patients had MS for an average of 7.9 +/- 4.3 y (mean +/- SD), their total relapses averaged 4 +/- 2.4, and their Expanded Disability Status Scale was 2.7 +/- 0.5. The patients were switched to fingolimod because of safety reasons or therapy escalation. The mean washout period before the initiation of fingolimod was 2.3 +/- 1.1 mo. The patients were clinically stable on fingolimod. At baseline, microglial activation was significantly higher in the combined NAWM and GM areas of MS patients than in healthy controls (P = 0.021). 11C-(R)-PK11195 binding was reduced (-12.31%) within the combined T2 lesion area after 6 mo of fingolimod treatment (P = 0.040) but not in the areas of NAWM or GM. Conclusion: Fingolimod treatment reduced microglial/macrophage activation at the site of focal inflammatory lesions, presumably by preventing leukocyte trafficking from the periphery. It did not affect the widespread, diffuse microglial activation in the NAWM and GM. The study opens new vistas for designing future therapeutic studies in MS that use the evaluation of microglial activation as an imaging outcome measure. PMID- 28336786 TI - 18F-FDG PET/CT Optimizes Treatment in Staphylococcus Aureus Bacteremia and Is Associated with Reduced Mortality. AB - Metastatic infection is an important complication of Staphylococcus aureus bacteremia (SAB). Early diagnosis of metastatic infection is crucial, because specific treatment is required. However, metastatic infection can be asymptomatic and difficult to detect. In this study, we investigated the role of 18F-FDG PET/CT in patients with SAB for detection of metastatic infection and its consequences for treatment and outcome. Methods: All patients with SAB at Radboud University Medical Center were included between January 2013 and April 2016. Clinical data and results of 18F-FDG PET/CT and other imaging techniques, including echocardiography, were collected. Primary outcomes were newly diagnosed metastatic infection by 18F-FDG PET/CT, subsequent treatment modifications, and patient outcome. Results: A total of 184 patients were included, and 18F-FDG PET/CT was performed in 105 patients, of whom 99 had a high-risk bacteremia. 18F FDG PET/CT detected metastatic infectious foci in 73.7% of these high-risk patients. In 71.2% of patients with metastatic infection, no signs and symptoms suggesting metastatic complications were present before 18F-FDG PET/CT was performed. 18F-FDG PET/CT led to a total of 104 treatment modifications in 74 patients. Three-month mortality was higher in high-risk bacteremia patients without 18F-FDG PET/CT performed than in those in whom 18F-FDG PET/CT was performed (32.7% vs. 12.4%, P = 0.003). In multivariate analysis, 18F-FDG PET/CT was the only factor independently associated with reduced mortality (P = 0.005; odds ratio, 0.204; 95% confidence interval, 0.066-0.624). A higher comorbidity score was independently associated with increased mortality (P = 0.003; odds ratio, 1.254; 95% confidence interval, 1.078-1.457). Conclusion:18F-FDG PET/CT is a valuable technique for early detection of metastatic infectious foci, often leading to treatment modification. Performing 18F-FDG PET/CT is associated with significantly reduced 3-mo mortality. PMID- 28336789 TI - Percutaneous Therapy for Tricuspid Regurgitation: A New Frontier for Interventional Cardiology. PMID- 28336787 TI - Probabilistic divergence time estimation without branch lengths: dating the origins of dinosaurs, avian flight and crown birds. AB - Branch lengths-measured in character changes-are an essential requirement of clock-based divergence estimation, regardless of whether the fossil calibrations used represent nodes or tips. However, a separate set of divergence time approaches are typically used to date palaeontological trees, which may lack such branch lengths. Among these methods, sophisticated probabilistic approaches have recently emerged, in contrast with simpler algorithms relying on minimum node ages. Here, using a novel phylogenetic hypothesis for Mesozoic dinosaurs, we apply two such approaches to estimate divergence times for: (i) Dinosauria, (ii) Avialae (the earliest birds) and (iii) Neornithes (crown birds). We find: (i) the plausibility of a Permian origin for dinosaurs to be dependent on whether Nyasasaurus is the oldest dinosaur, (ii) a Middle to Late Jurassic origin of avian flight regardless of whether Archaeopteryx or Aurornis is considered the first bird and (iii) a Late Cretaceous origin for Neornithes that is broadly congruent with other node- and tip-dating estimates. Demonstrating the feasibility of probabilistic time-scaling further opens up divergence estimation to the rich histories of extinct biodiversity in the fossil record, even in the absence of detailed character data. PMID- 28336788 TI - Transcatheter Treatment of Severe Tricuspid Regurgitation With the Edge-to-Edge MitraClip Technique. AB - BACKGROUND: Current surgical and medical treatment options for severe tricuspid regurgitation (TR) are limited, and additional interventional approaches are required. In the present observational study, the safety and feasibility of transcatheter repair of chronic severe TR with the MitraClip system were evaluated. In addition, the effects on clinical symptoms were assessed. METHODS: Patients with heart failure symptoms and severe TR on optimal medical treatment were treated with the MitraClip system. Safety, defined as periprocedural adverse events such as death, myocardial infarction, stroke, or cardiac tamponade, and feasibility, defined as successful implantation of 1 or more MitraClip devices and reduction of TR by at least 1 grade, were evaluated before discharge and after 30 days. In addition, functional outcome, defined as changes in New York Heart Assocation class and 6-minute walking distance, were assessed. RESULTS: We included 64 consecutive patients (mean age 76.6+/-10 years) deemed unsuitable for surgery who underwent MitraClip treatment for chronic, severe TR for compassionate use. Functional TR was present in 88%; in addition, 22 patients were also treated with the MitraClip system for mitral regurgitation as a combined procedure. The degree of TR was severe or massive in 88% of patients before the procedure. The MitraClip device was successfully implanted in the tricuspid valve in 97% of the cases. After the procedure, TR was reduced by at least 1 grade in 91% of the patients, thereof 4% that were reduced from massive to severe. In 13% of patients, TR remained severe after the procedure. Significant reductions in effective regurgitant orifice area (0.9+/-0.3cm2 versus 0.4+/-0.2cm2; P<0.001), vena contracta width (1.1+/-0.5 cm versus 0.6+/-0.3 cm; P=0.001), and regurgitant volume (57.2+/-12.8 mL/beat versus 30.8+/-6.9 mL/beat; P<0.001) were observed. No intraprocedural deaths, cardiac tamponade, emergency surgery, stroke, myocardial infarction, or major vascular complications occurred. Three (5%) in-hospital deaths occurred. New York Heart Association class was significantly improved (P<0.001), and 6-minute walking distance increased significantly (165.9+/-102.5 m versus 193.5+/-115.9 m; P=0.007). CONCLUSIONS: Transcatheter treatment of TR with the MitraClip system seems to be safe and feasible in this cohort of preselected patients. Initial efficacy analysis showed encouraging reduction of TR, which may potentially result in improved clinical outcomes. PMID- 28336790 TI - Prioritizing Functional Capacity as a Principal End Point for Therapies Oriented to Older Adults With Cardiovascular Disease: A Scientific Statement for Healthcare Professionals From the American Heart Association. AB - Adults are living longer, and cardiovascular disease is endemic in the growing population of older adults who are surviving into old age. Functional capacity is a key metric in this population, both for the perspective it provides on aggregate health and as a vital goal of care. Whereas cardiorespiratory function has long been applied by cardiologists as a measure of function that depended primarily on cardiac physiology, multiple other factors also contribute, usually with increasing bearing as age advances. Comorbidity, inflammation, mitochondrial metabolism, cognition, balance, and sleep are among the constellation of factors that bear on cardiorespiratory function and that become intricately entwined with cardiovascular health in old age. This statement reviews the essential physiology underlying functional capacity on systemic, organ, and cellular levels, as well as critical clinical skills to measure multiple realms of function (eg, aerobic, strength, balance, and even cognition) that are particularly relevant for older patients. Clinical therapeutic perspectives and patient perspectives are enumerated to clarify challenges and opportunities across the caregiving spectrum, including patients who are hospitalized, those managed in routine office settings, and those in skilled nursing facilities. Overall, this scientific statement provides practical recommendations and vital conceptual insights. PMID- 28336791 TI - Faultless responsibility: on the nature and allocation of moral responsibility for distributed moral actions. AB - The concept of distributed moral responsibility (DMR) has a long history. When it is understood as being entirely reducible to the sum of (some) human, individual and already morally loaded actions, then the allocation of DMR, and hence of praise and reward or blame and punishment, may be pragmatically difficult, but not conceptually problematic. However, in distributed environments, it is increasingly possible that a network of agents, some human, some artificial (e.g. a program) and some hybrid (e.g. a group of people working as a team thanks to a software platform), may cause distributed moral actions (DMAs). These are morally good or evil (i.e. morally loaded) actions caused by local interactions that are in themselves neither good nor evil (morally neutral). In this article, I analyse DMRs that are due to DMAs, and argue in favour of the allocation, by default and overridably, of full moral responsibility (faultless responsibility) to all the nodes/agents in the network causally relevant for bringing about the DMA in question, independently of intentionality. The mechanism proposed is inspired by, and adapts, three concepts: back propagation from network theory, strict liability from jurisprudence and common knowledge from epistemic logic.This article is part of the themed issue 'The ethical impact of data science'. PMID- 28336792 TI - Data philanthropy and the design of the infraethics for information societies. AB - In mature information societies, sharing data is increasingly recognized as a crucial means to foster their development. However, competing tensions on data control and ownership, limited technical understanding, and the lack of an adequate governance framework pose serious challenges to attempts to share data among different actors. Data philanthropy, understood as the donation of data from both individuals and private companies, has been proposed as means to meet these challenges. While at first sight data philanthropy may seem an uncontroversial phenomenon, a closer analysis reveals a bewildering network of problems. In this article, I analyse the role of data philanthropy in contemporary societies and the moral problems that it yields. I argue that the solution to these problems rests on the understanding of the infraethical nature of data philanthropy and on the design of an ethical framework encompassing the right infraethics and the right ethics. This is a framework able to address the changes brought about by the information revolution and to harness the opportunities that these pose for the prosperity of current and future information societies.This article is part of the themed issue 'The ethical impact of data science'. PMID- 28336793 TI - Compelling truth: legal protection of the infosphere against big data spills. AB - The paper explores whether legal and ethical concepts that have been used to protect the natural environment can also be leveraged to protect the 'infosphere', a neologism used by Luciano Floridi to characterize the totality of the informational environment. We focus, in particular, on the interaction between allocation of (intellectual) property rights and 'communication duties', in particular, data breach notification duties.This article is part of the themed issue 'The ethical impact of data science'. PMID- 28336795 TI - The opportunities and ethics of big data: practical priorities for a national Council of Data Ethics. AB - In order to generate the gains that can come from analysing and linking big datasets, data holders need to consider the ethical frameworks, principles and applications that help to maintain public trust. In the USA, the National Science Foundation helped to set up a Council for Big Data, Ethics and Society, of which there is no equivalent in the UK. In November 2015, the Royal Statistical Society convened a workshop of 28 participants from government, academia and the private sector, and discussed the practical priorities that might be assisted by a new Council of Data Ethics in the UK. This article draws together the views from that meeting. Priorities for policy-makers and others include seeking a public mandate and informing the terms of the social contract for use of data; building professional competence and due diligence on data protection; appointment of champions who are competent to address public concerns; and transparency, across all dimensions. For government data, further priorities include improvements to data access, and development of data infrastructure. In conclusion, we support the establishment of a national Data Ethics Council, alongside wider and deeper engagement of the public to address data ethics dilemmas.This article is part of the themed issue 'The ethical impact of data science'. PMID- 28336794 TI - The ethics of smart cities and urban science. AB - Software-enabled technologies and urban big data have become essential to the functioning of cities. Consequently, urban operational governance and city services are becoming highly responsive to a form of data-driven urbanism that is the key mode of production for smart cities. At the heart of data-driven urbanism is a computational understanding of city systems that reduces urban life to logic and calculative rules and procedures, which is underpinned by an instrumental rationality and realist epistemology. This rationality and epistemology are informed by and sustains urban science and urban informatics, which seek to make cities more knowable and controllable. This paper examines the forms, practices and ethics of smart cities and urban science, paying particular attention to: instrumental rationality and realist epistemology; privacy, datafication, dataveillance and geosurveillance; and data uses, such as social sorting and anticipatory governance. It argues that smart city initiatives and urban science need to be re-cast in three ways: a re-orientation in how cities are conceived; a reconfiguring of the underlying epistemology to openly recognize the contingent and relational nature of urban systems, processes and science; and the adoption of ethical principles designed to realize benefits of smart cities and urban science while reducing pernicious effects.This article is part of the themed issue 'The ethical impact of data science'. PMID- 28336796 TI - The ethics of data and of data science: an economist's perspective. AB - Data collection and modelling are increasingly important in social science and science-based policy, but threaten to crowd out other ways of thinking. Economists recognize that markets embody and shed light on human sentiments. However, their ethical consequences have been difficult to interpret, let alone manage. Although economic mechanisms are changed by data intensity, they can be redesigned to restore their benefits. We conclude with four cautions: if data are good, more may not be better; scientifically desirable data properties may not help policy; consent is a double-edged tool; and data exist only because someone thought to capture and codify them.This article is part of the themed issue 'The ethical impact of data science'. PMID- 28336797 TI - Privacy is an essentially contested concept: a multi-dimensional analytic for mapping privacy. AB - The meaning of privacy has been much disputed throughout its history in response to wave after wave of new technological capabilities and social configurations. The current round of disputes over privacy fuelled by data science has been a cause of despair for many commentators and a death knell for privacy itself for others. We argue that privacy's disputes are neither an accidental feature of the concept nor a lamentable condition of its applicability. Privacy is essentially contested. Because it is, privacy is transformable according to changing technological and social conditions. To make productive use of privacy's essential contestability, we argue for a new approach to privacy research and practical design, focused on the development of conceptual analytics that facilitate dissecting privacy's multiple uses across multiple contexts.This article is part of the themed issue 'The ethical impact of data science'. PMID- 28336798 TI - Data science ethics in government. AB - Data science can offer huge opportunities for government. With the ability to process larger and more complex datasets than ever before, it can provide better insights for policymakers and make services more tailored and efficient. As with all new technologies, there is a risk that we do not take up its opportunities and miss out on its enormous potential. We want people to feel confident to innovate with data. So, over the past 18 months, the Government Data Science Partnership has taken an open, evidence-based and user-centred approach to creating an ethical framework. It is a practical document that brings all the legal guidance together in one place, and is written in the context of new data science capabilities. As part of its development, we ran a public dialogue on data science ethics, including deliberative workshops, an experimental conjoint survey and an online engagement tool. The research supported the principles set out in the framework as well as provided useful insight into how we need to communicate about data science. It found that people had a low awareness of the term 'data science', but that showing data science examples can increase broad support for government exploring innovative uses of data. But people's support is highly context driven. People consider acceptability on a case-by-case basis, first thinking about the overall policy goals and likely intended outcome, and then weighing up privacy and unintended consequences. The ethical framework is a crucial start, but it does not solve all the challenges it highlights, particularly as technology is creating new challenges and opportunities every day. Continued research is needed into data minimization and anonymization, robust data models, algorithmic accountability, and transparency and data security. It also has revealed the need to set out a renewed deal between the citizen and state on data, to maintain and solidify trust in how we use people's data for social good.This article is part of the themed issue 'The ethical impact of data science'. PMID- 28336799 TI - Locating ethics in data science: responsibility and accountability in global and distributed knowledge production systems. AB - The distributed and global nature of data science creates challenges for evaluating the quality, import and potential impact of the data and knowledge claims being produced. This has significant consequences for the management and oversight of responsibilities and accountabilities in data science. In particular, it makes it difficult to determine who is responsible for what output, and how such responsibilities relate to each other; what 'participation' means and which accountabilities it involves, with regard to data ownership, donation and sharing as well as data analysis, re-use and authorship; and whether the trust placed on automated tools for data mining and interpretation is warranted (especially as data processing strategies and tools are often developed separately from the situations of data use where ethical concerns typically emerge). To address these challenges, this paper advocates a participative, reflexive management of data practices. Regulatory structures should encourage data scientists to examine the historical lineages and ethical implications of their work at regular intervals. They should also foster awareness of the multitude of skills and perspectives involved in data science, highlighting how each perspective is partial and in need of confrontation with others. This approach has the potential to improve not only the ethical oversight for data science initiatives, but also the quality and reliability of research outputs.This article is part of the themed issue 'The ethical impact of data science'. PMID- 28336801 TI - What's the good of a science platform? PMID- 28336800 TI - The ethics of big data as a public good: which public? Whose good? AB - International development and humanitarian organizations are increasingly calling for digital data to be treated as a public good because of its value in supplementing scarce national statistics and informing interventions, including in emergencies. In response to this claim, a 'responsible data' movement has evolved to discuss guidelines and frameworks that will establish ethical principles for data sharing. However, this movement is not gaining traction with those who hold the highest-value data, particularly mobile network operators who are proving reluctant to make data collected in low- and middle-income countries accessible through intermediaries. This paper evaluates how the argument for 'data as a public good' fits with the corporate reality of big data, exploring existing models for data sharing. I draw on the idea of corporate data as an ecosystem involving often conflicting rights, duties and claims, in comparison to the utilitarian claim that data's humanitarian value makes it imperative to share them. I assess the power dynamics implied by the idea of data as a public good, and how differing incentives lead actors to adopt particular ethical positions with regard to the use of data.This article is part of the themed issue 'The ethical impact of data science'. PMID- 28336802 TI - The dynamics of big data and human rights: the case of scientific research. AB - In this paper, we address the complex relationship between big data and human rights. Because this is a vast terrain, we restrict our focus in two main ways. First, we concentrate on big data applications in scientific research, mostly health-related research. And, second, we concentrate on two human rights: the familiar right to privacy and the less well-known right to science. Our contention is that human rights interact in potentially complex ways with big data, not only constraining it, but also enabling it in various ways; and that such rights are dynamic in character, rather than fixed once and for all, changing in their implications over time in line with changes in the context we inhabit, and also as they interact among themselves in jointly responding to the opportunities and risks thrown up by a changing world. Understanding this dynamic interaction of human rights is crucial for formulating an ethic tailored to the realities-the new capabilities and risks-of the rapidly evolving digital environment.This article is part of the themed issue 'The ethical impact of data science'. PMID- 28336804 TI - Beyond privacy and exposure: ethical issues within citizen-facing analytics. AB - We discuss the governing forces for analytics, especially concerning citizens' behaviours and their transactions, that depend on which of three spheres of operation an institution is in (corporate, public sector/government and academic). We argue that aspirations and missions also differ by sphere even as digital spaces have drawn these spheres ever closer together. We propose that citizens' expectations and implicit permissions for any exploitation of their data require the perception of a fair balance of benefits, which should be transparent (accessible to citizens) and justifiable. We point out that within the corporate sphere most analytics does not concern identity, targeted marketing nor any direct interference with individual citizens; but instead it supports strategic decision-making, where the data are effectively anonymous. With the three spheres we discuss the nature of models deployed in analytics, including 'black-box' modelling uncheckable by a human mind, and the need to track the provenance and workings or models. We also examine the recent evolution of personal data, where some behaviours, or tokens, identifying individuals (unique and yet non-random) are partially and jointly owned by other individuals that are themselves connected. We consider the ability of heavily and lightly regulated sectors to increase access or to stifle innovation. We also call for clear and inclusive definitions of 'data science and analytics', avoiding the narrow claims of those in technical sub-sectors or sub-themes. Finally, we examine some examples of unethical and abusive practices. We argue for an ethical responsibility to be placed upon professional data scientists to avoid abuses in the future.This article is part of the themed issue 'The ethical impact of data science'. PMID- 28336803 TI - Facilitating the ethical use of health data for the benefit of society: electronic health records, consent and the duty of easy rescue. AB - Advances in data science allow for sophisticated analysis of increasingly large datasets. In the medical context, large volumes of data collected for healthcare purposes are contained in electronic health records (EHRs). The real-life character and sheer amount of data contained in them make EHRs an attractive resource for public health and biomedical research. However, medical records contain sensitive information that could be misused by third parties. Medical confidentiality and respect for patients' privacy and autonomy protect patient data, barring access to health records unless consent is given by the data subject. This creates a situation in which much of the beneficial records-based research is prevented from being used or is seriously undermined, because the refusal of consent by some patients introduces a systematic deviation, known as selection bias, from a representative sample of the general population, thus distorting research findings. Although research exemptions for the requirement of informed consent exist, they are rarely used in practice due to concerns over liability and a general culture of caution. In this paper, we argue that the problem of research access to sensitive data can be understood as a tension between the medical duties of confidentiality and beneficence. We attempt to show that the requirement of informed consent is not appropriate for all kinds of records-based research by distinguishing studies involving minimal risk from those that feature moderate or greater risks. We argue that the duty of easy rescue-the principle that persons should benefit others when this can be done at no or minimal risk to themselves-grounds the removal of consent requirements for minimally risky records-based research. Drawing on this discussion, we propose a risk-adapted framework for the facilitation of ethical uses of health data for the benefit of society.This article is part of the themed issue 'The ethical impact of data science'. PMID- 28336805 TI - What is data ethics? AB - This theme issue has the founding ambition of landscaping data ethics as a new branch of ethics that studies and evaluates moral problems related to data (including generation, recording, curation, processing, dissemination, sharing and use), algorithms (including artificial intelligence, artificial agents, machine learning and robots) and corresponding practices (including responsible innovation, programming, hacking and professional codes), in order to formulate and support morally good solutions (e.g. right conducts or right values). Data ethics builds on the foundation provided by computer and information ethics but, at the same time, it refines the approach endorsed so far in this research field, by shifting the level of abstraction of ethical enquiries, from being information centric to being data-centric. This shift brings into focus the different moral dimensions of all kinds of data, even data that never translate directly into information but can be used to support actions or generate behaviours, for example. It highlights the need for ethical analyses to concentrate on the content and nature of computational operations-the interactions among hardware, software and data-rather than on the variety of digital technologies that enable them. And it emphasizes the complexity of the ethical challenges posed by data science. Because of such complexity, data ethics should be developed from the start as a macroethics, that is, as an overall framework that avoids narrow, ad hoc approaches and addresses the ethical impact and implications of data science and its applications within a consistent, holistic and inclusive framework. Only as a macroethics will data ethics provide solutions that can maximize the value of data science for our societies, for all of us and for our environments.This article is part of the themed issue 'The ethical impact of data science'. PMID- 28336807 TI - PMP22 Regulates Self-Renewal and Chemoresistance of Gastric Cancer Cells. AB - Cancer stem cells possess self-renewal and chemoresistance activities. However, the manner in which these features are maintained remains obscure. We sought to identify cell surface protein(s) that mark self-renewing and chemoresistant gastric cancer cells using the explorer antibody microarray. We identified PMP22, a target gene of the Wnt/beta-catenin pathway, as the most upregulated cell surface protein in gastric cancer xenografts exposed to cisplatin (DDP). PMP22 expression was markedly upregulated in tumorspheric cells and declined with differentiation. Infecting gastric cancer cells with lentivirus expressing PMP22 shRNAs reduced proliferation, tumorsphere formation, and chemoresistance to cisplatin in vitro and in NOD/SCID mice. When combined with bortezomib, a PMP22 inhibitor, the chemotherapeutic sensitivity to cisplatin treatment was dramatically increased by inducing cell apoptosis in cultured cells and xenograft mouse models. Finally, mRNA expression levels of PMP22 were detected in 38 tumor specimens from patients who received six cycles of perioperative chemotherapy. A strong correlation between PMP22 level and tumor recurrence was revealed, thus showing a pivotal role of PMP22 in the clinical chemoresistance of gastric cancer. Our study is the first to show the role of PMP22 in gastric cancer stemness and chemoresistance and reveals a potential new target for the diagnosis and treatment of recurrent gastric cancer. Mol Cancer Ther; 16(6); 1187-98. (c)2017 AACR. PMID- 28336806 TI - Fluorouracil Enhances Photodynamic Therapy of Squamous Cell Carcinoma via a p53 Independent Mechanism that Increases Protoporphyrin IX levels and Tumor Cell Death. AB - Photodynamic therapy (PDT), using 5-aminolevulinic acid (ALA) to drive synthesis of protoporphryin IX (PpIX) is a promising, scar-free alternative to surgery for skin cancers, including squamous cell carcinoma (SCC) and SCC precursors called actinic keratoses. In the United States, PDT is only FDA approved for treatment of actinic keratoses; this narrow range of indications could be broadened if PDT efficacy were improved. Toward that goal, we developed a mechanism-based combination approach using 5-fluorouracil (5-FU) as a neoadjuvant for ALA-based PDT. In mouse models of SCC (orthotopic UV-induced lesions, and subcutaneous A431 and 4T1 tumors), pretreatment with 5-FU for 3 days followed by ALA for 4 hours led to large, tumor-selective increases in PpIX levels, and enhanced cell death upon illumination. Several mechanisms were identified that might explain the relatively improved therapeutic response. First, the expression of key enzymes in the heme synthesis pathway was altered, including upregulated coproporphyrinogen oxidase and downregulated ferrochelatase. Second, a 3- to 6-fold induction of p53 in 5-FU-pretreated tumors was noted. The fact that A431 contains a mutant form p53 did not prevent the development of a neoadjuvantal 5-FU effect. Furthermore, 5-FU pretreatment of 4T1 tumors (cells that completely lack p53), still led to significant beneficial inductions, that is, 2.5-fold for both PpIX and PDT induced cell death. Thus, neoadjuvantal 5-FU combined with PDT represents a new therapeutic approach that appears useful even for p53-mutant and p53-null tumors. Mol Cancer Ther; 16(6); 1092-101. (c)2017 AACR. PMID- 28336809 TI - Lectin, Galactoside-Binding Soluble 3 Binding Protein Promotes 17-N-Allylamino-17 demethoxygeldanamycin Resistance through PI3K/Akt Pathway in Lung Cancer Cell Line. AB - Heat shock protein 90 (HSP90) stabilizing oncoproteins has been an attractive target in cancer therapy. 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG), an HSP90 inhibitor, was tested in phase II/III clinical trials, but due to lack of efficacy, clinical evaluation of 17-AAG has achieved limited success, which led to resistance to 17-AAG. However, the mechanism of 17-AAG resistance has not clearly been identified. Here, we identified LGALS3BP (Lectin, galactoside binding soluble 3 binding protein), a secretory glycoprotein, as a 17-AAG resistance factor. In the clinical reports, it was suggested that LGALS3BP was associated with low survival rate, development of cancer progression, and enhancement of metastasis in human cancers. As we confirmed that the LGALS3BP level was increased in 17-AAG-resistant cells (H1299_17R) compared with that of the parental cell line (H1299_17P), knockdown of LGALS3BP expression increased sensitivity to 17-AAG in H1299_17R cells. Overexpression of LGALS3BP also augmented PI3K/Akt and ERK signaling pathways. Furthermore, we determined that the PI3K/Akt signaling pathway was involved in LGALS3BP-mediated 17-AAG resistance in vitro and in vivo, demonstrating that LGALS3BP mediates the resistance against 17-AAG through PI3K/Akt activation rather than ERK activation. These findings suggest that LGALS3BP would be a target to overcome resistance to 17-AAG in lung cancer. For example, the combination of 17-AAG and PI3K/Akt inhibitor would effectively suppress acquired resistance to 17-AAG. In conclusion, targeting of LGALS3BP-mediated-specific survival signaling pathway in resistant cells may provide a novel therapeutic model for the cancer therapy. Mol Cancer Ther; 16(7); 1355-65. (c)2017 AACR. PMID- 28336811 TI - The circadian protein BMAL1 in myeloid cells is a negative regulator of allergic asthma. AB - Our body clock drives rhythms in the expression of genes that have a 24-h periodicity. The transcription factor BMAL1 is a crucial component of the molecular clock. A number of physiological processes, including immune function, are modulated by the circadian clock. Asthma, a disease with very strong clinical evidence demonstrating regulation by circadian variation, is of particular relevance to circadian control of immunity. Airway hypersensitivity and asthma attacks are more common at night in humans. The molecular basis for this is unknown, and there is no model of asthma in animals with genetic distortion of the molecular clock. We used mice lacking BMAL1 in myeloid cells (BMAL1-LysM-/-) to determine the role of BMAL1 in allergic asthma. Using the ovalbumin model of allergic asthma, we demonstrated markedly increased asthma features, such as increased lung inflammation, demonstrated by drastically higher numbers of eosinophils and increased IL-5 levels in the lung and serum, in BMAL1-LysM-/- mice. In vitro studies demonstrated increased proinflammatory chemokine and mannose receptor expression in IL-4- as well as LPS-treated macrophages from BMAL1-LysM-/- mice compared with wild-type controls. This suggests that Bmal1 is a potent negative regulator in myeloid cells in the context of allergic asthma. Our findings might explain the increase in asthma incidents during the night, when BMAL1 expression is low. PMID- 28336808 TI - Potent Dual BET Bromodomain-Kinase Inhibitors as Value-Added Multitargeted Chemical Probes and Cancer Therapeutics. AB - Synergistic action of kinase and BET bromodomain inhibitors in cell killing has been reported for a variety of cancers. Using the chemical scaffold of the JAK2 inhibitor TG101348, we developed and characterized single agents which potently and simultaneously inhibit BRD4 and a specific set of oncogenic tyrosine kinases including JAK2, FLT3, RET, and ROS1. Lead compounds showed on-target inhibition in several blood cancer cell lines and were highly efficacious at inhibiting the growth of hematopoietic progenitor cells from patients with myeloproliferative neoplasm. Screening across 931 cancer cell lines revealed differential growth inhibitory potential with highest activity against bone and blood cancers and greatly enhanced activity over the single BET inhibitor JQ1. Gene drug sensitivity analyses and drug combination studies indicate synergism of BRD4 and kinase inhibition as a plausible reason for the superior potency in cell killing. Combined, our findings indicate promising potential of these agents as novel chemical probes and cancer therapeutics. Mol Cancer Ther; 16(6); 1054-67. (c)2017 AACR. PMID- 28336810 TI - Role of transient receptor potential vanilloid 1 in the modulation of airway smooth muscle tone and calcium handling. AB - Asthma is a common disorder characterized, in part, by airway smooth muscle (ASM) hyperresponsiveness. Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel expressed on airway nerve fibers that modulates afferent signals, resulting in cough, and potentially bronchoconstriction. In the present study, the TRPV1 transcript was detected by RT-PCR in primary cultured human ASM cells, and the TRPV1 protein was detected in ASM of human trachea by immunohistochemistry. Proximity ligation assays suggest that TRPV1 is expressed in the sarcoplasmic reticulum membrane of human ASM cells in close association with sarco/endoplasmic reticulum Ca2+-ATPase-2. In guinea pig tracheal ring organ bath experiments, the TRPV1 agonist capsaicin led to ASM contraction, but this contraction was significantly attenuated by the sodium channel inhibitor bupivacaine (n = 4, P < 0.05) and the neurokinin-2 receptor antagonist GR-159897 (n = 4, P < 0.05), suggesting that this contraction is neutrally mediated. However, pretreatment of guinea pig and human ASM in organ bath experiments with the TRPV1 antagonist capsazepine inhibited the maintenance phase of an acetylcholine-induced contraction (n = 4, P < 0.01 for both species). Similarly, capsazepine inhibited methacholine-induced contraction of peripheral airways in mouse precision-cut lung slice (PCLS) experiments (n = 4-5, P < 0.05). Although capsazepine did not inhibit store-operated calcium entry in mouse ASM cells in PCLS (n = 4-7, P = nonsignificant), it did inhibit calcium oscillations (n = 3, P < 0.001). These studies suggest that TRPV1 is expressed on ASM, including the SR, but that ASM TRPV1 activation does not play a significant role in initiation of ASM contraction. However, capsazepine does inhibit maintenance of contraction, likely by inhibiting calcium oscillations. PMID- 28336812 TI - TGF-beta1 stimulates HDAC4 nucleus-to-cytoplasm translocation and NADPH oxidase 4 derived reactive oxygen species in normal human lung fibroblasts. AB - Myofibroblasts are important mediators of fibrogenesis; thus blocking fibroblast to-myofibroblast differentiation (FMD) may be an effective strategy to treat pulmonary fibrosis (PF). Previously, we reported that histone deacetylase 4 (HDAC4) activity is necessary for transforming growth factor-beta1 (TGF-beta1) induced human lung FMD. Here, we show that TGF-beta1 increases NADPH oxidase 4 (NOX4) mRNA and protein expression in normal human lung fibroblasts (NHLFs) and causes nuclear export of HDAC4. Application of the NOX family inhibitor diphenyleneiodonium chloride reduces TGF-beta1-induced HDAC4 nuclear export, expression of the myofibroblast marker alpha-smooth muscle actin (alpha-SMA), and alpha-SMA fiber formation. Inhibition of HDAC4 nucleus-to-cytoplasm translocation using leptomycin B (LMB) had little effect on alpha-SMA expression but blocked alpha-SMA fiber formation. A coimmunoprecipitation assay showed that HDAC4 associates with alpha-SMA. Moreover, LMB abolishes TGF-beta1-induced alpha-SMA fiber formation and cell contraction. Relevant to human pulmonary fibrosis, idiopathic PF specimens showed significantly higher NOX4 RNA expression and scant HDAC4 staining within nuclei of fibroblast foci myofibroblasts. Taken together, these results indicate that reactive oxygen species promote TGF-beta1-mediated myofibroblast differentiation and HDAC4 nuclear export. The physical association of HDAC4 with alpha-SMA suggests that HDAC4 has a role in regulating the alpha SMA cytoskeleton arrangement. PMID- 28336813 TI - The innate immune response in fetal lung mesenchymal cells targets VEGFR2 expression and activity. AB - In preterm infants, soluble inflammatory mediators target lung mesenchymal cells, disrupting airway and alveolar morphogenesis. However, how mesenchymal cells respond directly to microbial stimuli remains poorly characterized. Our objective was to measure the genome-wide innate immune response in fetal lung mesenchymal cells exposed to the bacterial endotoxin lipopolysaccharide (LPS). With the use of Affymetrix MoGene 1.0st arrays, we showed that LPS induced expression of unique innate immune transcripts heavily weighted toward CC and CXC family chemokines. The transcriptional response was different between cells from E11, E15, and E18 mouse lungs. In all cells tested, LPS inhibited expression of a small core group of genes including the VEGF receptor Vegfr2 Although best characterized in vascular endothelial populations, we demonstrated here that fetal mouse lung mesenchymal cells express Vegfr2 and respond to VEGF-A stimulation. In mesenchymal cells, VEGF-A increased cell migration, activated the ERK/AKT pathway, and promoted FOXO3A nuclear exclusion. With the use of an experimental coculture model of epithelial-mesenchymal interactions, we also showed that VEGFR2 inhibition prevented formation of three-dimensional structures. Both LPS and tyrosine kinase inhibition reduced three-dimensional structure formation. Our data suggest a novel mechanism for inflammation-mediated defects in lung development involving reduced VEGF signaling in lung mesenchyme. PMID- 28336814 TI - Airway smooth muscle dysfunction in Pompe (Gaa-/- ) mice. AB - Pompe disease is an autosomal recessive disorder caused by a deficiency of acid alpha-glucosidase (GAA), an enzyme responsible for hydrolyzing lysosomal glycogen. Deficiency of GAA leads to systemic glycogen accumulation in the lysosomes of skeletal muscle, motor neurons, and smooth muscle. Skeletal muscle and motor neuron pathology are known to contribute to respiratory insufficiency in Pompe disease, but the role of airway pathology has not been evaluated. Here we propose that GAA enzyme deficiency disrupts the function of the trachea and bronchi and this lower airway pathology contributes to respiratory insufficiency in Pompe disease. Using an established mouse model of Pompe disease, the Gaa-/- mouse, we compared histology, pulmonary mechanics, airway smooth muscle (ASM) function, and calcium signaling between Gaa-/- and age-matched wild-type (WT) mice. Lysosomal glycogen accumulation was observed in the smooth muscle of both the bronchi and the trachea in Gaa-/- but not WT mice. Furthermore, Gaa-/- mice had hyporesponsive airway resistance and bronchial ring contraction to the bronchoconstrictive agents methacholine (MCh) and potassium chloride (KCl) and to a bronchodilator (albuterol). Finally, calcium signaling during bronchiolar smooth muscle contraction was impaired in Gaa-/- mice indicating impaired extracellular calcium influx. We conclude that GAA enzyme deficiency leads to glycogen accumulation in the trachea and bronchi and impairs the ability of lower ASM to regulate calcium and respond appropriately to bronchodilator or constrictors. Accordingly, ASM dysfunction may contribute to respiratory impairments in Pompe disease. PMID- 28336815 TI - Can Renal Biopsy Be Used to Estimate Total Nephron Number? PMID- 28336816 TI - Glomerular Density and Volume in Renal Biopsy Specimens of Children with Proteinuria Relative to Preterm Birth and Gestational Age. AB - BACKGROUND AND OBJECTIVES: A low total nephron number, which is associated with low birth weight (LBW), may indicate increased susceptibility to early-onset renal diseases in children. However, few studies have assessed renal biopsy findings in LBW children. We examined the relationship between LBW and glomerular density (GD) and/or glomerular volume (GV) in renal biopsy samples as a surrogate for total nephron number. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Renal biopsy findings of children of LBW were compared with those of age-matched control subjects of normal birth weight (NBW) who were histopathologically diagnosed with FSGS or minimal change nephrotic syndrome (MCNS) from 1995 to 2011. The GD and GV were estimated on the basis of measurements obtained by computerized image analysis. RESULTS: A total of 31 subjects (mean age 11 years; eight with low birth weight-FSGS [LBW-FSGS], 10 with normal birth weight-FSGS [NBW-FSGS], and 13 with normal birth weight-minimal change nephrotic syndrome [NBW-MCNS]) were analyzed. The mean birth weight of each group was 777 g (629 1000), 3110 g (2888-3358), and 3120 g (2748-3398), respectively (median [25th 75th percentile]). Age, body mass index, BP, and degrees of globally sclerotic glomeruli at biopsy were comparable between the groups. The GD was lower (LBW FSGS, 1.4+/-0.6/mm2; NBW-FSGS, 3.3+/-1.2/mm2; and NBW-MCNS, 3.6+/-1.1/mm2; P<0.05) and the GV was greater (LBW-FSGS, 4.1 [3.1-5.1]*106um3; NBW-FSGS, 1.6 [1.5-2.1]*106um3; and NBW-MCNS, 1.3 [1.1-1.8]*106um3 [median, (25th-75th percentile)]; P<0.05) in patients with LBW-FSGS than in the other patient groups. The GD showed close positive correlations with birth weight (r=0.48) and gestational age (r=0.54), independent of renal function and degree of global glomerular sclerosis. CONCLUSIONS: A low GD together with marked glomerular enlargement characterizes renal biopsy samples of children born with a LBW at an early stage of gestation. PMID- 28336817 TI - Slow Rise in Serum Creatinine Level in a Kidney Transplant Recipient 3 Years Post Transplant. PMID- 28336818 TI - Increased exposure to sodium during pregnancy and lactation changes basal and induced behavioral and neuroendocrine responses in adult male offspring. AB - Excessive sodium (Na+) intake in modern society has been associated with several chronic disorders such as hypertension. Several studies suggest that early life events can program physiological systems and lead to functional changes in adulthood. Therefore, we investigated behavioral and neuroendocrine responses under basal conditions and after 48 h of water deprivation in adult (60-day-old Wistar rats) male, Wistar rats originating from dams were offered only water or 0.15 mol/L NaCl during pregnancy and lactation. Early life salt exposure induced kidney damage, as shown by a higher number of ED-1 positive cells (macrophages/monocytes), increased daily urinary volume and Na+ excretion, blunted basal water intake and plasma oxytocin levels, and increased plasma corticosterone secretion. When challenged with water deprivation, animals exposed to 0.15 mol/L NaCl during early life showed impaired water intake, reduced salt preference ratio, and vasopressin (AVP) secretion. In summary, our data demonstrate that the perinatal exposure to excessive Na+ intake can induce kidney injury in adult offspring and significantly affect the key mechanisms regulating water balance, fluid intake, and AVP release in response to water deprivation. Collectively, these novel results highlight the impact of perinatal programming on the homeostatic mechanisms regulating fluid and electrolyte balance during exposure to an environmental stress (i.e. dehydration) in later life. PMID- 28336819 TI - Fundamental hemodynamic mechanisms mediating the response to myocardial ischemia in conscious paraplegic mice: cardiac output versus peripheral resistance. AB - Autonomic dysfunction, a relative sedentary lifestyle, a reduced muscle mass and increased adiposity leads to metabolic abnormalities that accelerate the development of coronary artery disease (CAD) in individuals living with spinal cord injury (SCI). An untoward cardiac incident is related to the degree of CAD, suggesting that the occurrence of a significant cardiac event is significantly higher for individuals with SCI Thus, understanding the fundamental hemodynamic mechanisms mediating the response to myocardial ischemia has the potential to positively impact individuals and families living with SCI Accordingly, we systematically investigated if thoracic level 5 spinal cord transection (T5X; paraplegia) alters the arterial blood pressure response to coronary artery occlusion and if the different arterial blood pressure responses to coronary artery occlusion between intact and paraplegic mice are mediated by changes in cardiac output and or systemic peripheral resistance and whether differences in cardiac output are caused by changes in heart rate and or stroke volume. To achieve this goal, the tolerance to 3 min of coronary artery occlusion was determined in conscious intact and paraplegic mice. Paraplegic mice had an impaired ability to maintain arterial blood pressure during coronary artery occlusion as arterial pressure fell to near lethal levels by 1.38 +/- 0.64 min. The lower arterial pressure was mediated by a lower cardiac output as systemic peripheral resistance was elevated in paraplegic mice. The lower cardiac output was mediated by a reduced heart rate and stroke volume. These results indicate that in paraplegic mice, the arterial pressure response to coronary artery occlusion is hemodynamically mediated primarily by cardiac output which is determined by heart rate and stroke volume. PMID- 28336822 TI - Erratum. PMID- 28336821 TI - Hyperbaric oxygen therapy reduces renal lactate production. AB - Intrarenal hypoxia is an acknowledged factor contributing to the development of diabetic nephropathy. Hyperbaric oxygen (HBO) therapy is a well-known adjuvant treatment for several medical conditions, such as decompression sickness, infections, and wound healing. The underlying metabolic response of HBO is largely unknown. In this study, we investigated the effect of HBO on the intrarenal metabolic alteration in diabetes. Hyperpolarized [1-13C]pyruvate MRI was performed to assess intrarenal energy metabolism in normoglycemic controls and short-term (2 weeks) streptozotocin-induced diabetic rats with and without HBO for five consecutive days. HBO therapy blunted intrarenal lactate production, 3 days after the therapy, in both normoglycemic controls and diabetic rats without affecting either lactate dehydrogenase mRNA expression or activity. HBO therapy reduced lactate formation in both normoglycemic and hyperglycemic rats. These findings support hyperpolarized [1-13C]pyruvate MRI as a novel method for monitoring HBO therapy via the pyruvate to lactate conversion. PMID- 28336820 TI - An advanced glycation endproduct (AGE)-rich diet promotes accumulation of AGEs in Achilles tendon. AB - Advanced Glycation Endproducts (AGEs) accumulate in long-lived tissue proteins like collagen in bone and tendon causing modification of the biomechanical properties. This has been hypothesized to raise the risk of orthopedic injury such as bone fractures and tendon ruptures. We evaluated the relationship between AGE content in the diet and accumulation of AGEs in weight-bearing animal Achilles tendon. Two groups of mice (C57BL/6Ntac) were fed with either high-fat diet low in AGEs high-fat diet (HFD) (n = 14) or normal diet high in AGEs (ND) (n = 11). AGE content in ND was six to 50-fold higher than HFD The mice were sacrificed at week 40 and Achilles and tail tendons were carefully excised to compare weight and nonweight-bearing tendons. The amount of the AGEs carboxymethyllysine (CML), methylglyoxal-derived hydroimidazolone (MG-H1) and carboxyethyllysine (CEL) in Achilles and tail tendon was measured using ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) and pentosidine with high-pressure liquid chromatography (HPLC) with fluorescent detection. AGEs in Achilles tendon were higher than in tail tendon for CML (P < 0.0001), CEL (P < 0.0001), MG-H1 and pentosidine (for both ND and HFD) (P < 0.0001). The AGE-rich diet (ND) resulted in an increase in CML (P < 0.0001), MG H1 (P < 0.001) and pentosidine (P < 0.0001) but not CEL, in Achilles and tail tendon. This is the first study to provide evidence for AGE accumulation in injury-prone, weight-bearing Achilles tendon associated with intake of an AGE rich diet. This indicates that food-derived AGEs may alter tendon properties and the development of tendon injuries. PMID- 28336823 TI - [Regulatory mechanism of calcium metabolism.] AB - It is often difficult for terrestrial animals to take enough calcium. To maintain serum or extracellular calcium levels is very important for muscle and nerve function. Two major regulators to increase the serum calcium levels are parathyroid hormone(PTH)and vitamin D. PTH binds to the G protein coupling receptor, PTH1R, and increases intracellular cAMP levels. Impirement in the PTH signalling causes many diseases such as pseudohypoparathyroidism and acrodysostosis with hormone resistance. Vitamin D is activated to 1,25 dihydroxyvitamin D[1,25(OH)2D]by two steps of hydroxylation which occurs in the Liver and Kidney. Then, 1,25(OH)2D binds to vitamin D receptor(VDR), which works as a ligand-dependent transcription factor. Hypocalcemia and hypercalcemia are caused by various disorders including abnormal regulation of PTH and vitamin D production and their signal transduction. PMID- 28336824 TI - [The functions of calcium-sensing receptor in regulating mineral metabolism.] AB - Calcium-sensing receptor(CaSR)which belongs to a G protein-coupled receptor family is one of the key elements in regulating calcium homeostasis. CaSR has been identified as a receptor to control parathyroid hormone(PTH)secretion in parathyroid glands according to serum calcium ion(Ca2+)levels. It has also been shown that CaSR controls reabsorption of water and several cations including Ca2+and magnesium ion(Mg2+)in renal tubular cells. This review summarizes the functions and roles of CaSR in mineral metabolism that are exerted in parathyroid glands, kidney, and intestine. PMID- 28336825 TI - [Divergent functions of the calcium-sensing receptor other than regulation ofmineral metabolism.] AB - The calcium-sensing receptor(CaSR)is a G protein-coupled membrane receptor that binds extracellular Ca2+and other cations as a ligand. CaSR is expressed in parathyroid glands at the highest level and plays a critical role in the regulation of extracellular calcium. CaSR is also expressed by a wide variety of tissues other than calcium metabolic organs. In this overview, divergent roles of CaSR in inflammasome as well as various tissues including intestines, lungs, neurons and endocrine pancreas will be briefly summarized. PMID- 28336827 TI - [Pathophysiology of secondary hyperparathyroidism.] AB - Secondary hyperparathyroidism(SHPT)is the result of a compensatory response of the calcium phosphate homeostatic mechanism. Vitamin D deficiency and chronic kidney disease, both representative pathophysiological causes of SHPT, have been related not only to skeletal disorders but also cardiovascular diseases, ADL and QOL. This relates the importance of SHPT as a pathological cause or marker of such states. PMID- 28336826 TI - [Etiology and pathogenesis of primary hyperparathyroidism.] AB - Primary hyperparathyroidism(pHPT)is a frequent endocrine disease in which abnormal calcium(Ca)regulation leads to hypercalcemia. The most frequent cause of pHPT in more than 80% of patients is an adenoma, followed by hyperplasia in about 15%, and cancer in 1~5%. Although most cases of pHPT are sporadic, a few are familial(hereditary), and this is known as familial hyperparathyroidism(FHPT). Gene abnormalities that affect cyclin D1 signaling(CCND1, CDC73, CDKN1B), Wnt/beta-catenin signaling(MEN1), and calcium-sensing receptor signaling(CaSR, GNA11, AP2S1)play a role in the etiology and pathogenesis of pHPT. Vitamin D insufficiency/deficiency and CaSR dysfunction also play a role in pHPT severity. Continued elucidation of the etiology and pathogenesis of pHPT may lead to development of new treatments for pHPT as well as further understanding of Ca regulation. PMID- 28336828 TI - [Disorders Caused by Mutations in Calcium-Sensing Receptor and Related Diseases.] AB - Sensing of extracellular calcium(Ca2+)levels involves the Ca-sensing receptor(CaSR), its downstream signaling molecule Galpha11, and the adaptor related protein complex 2(AP2)that plays a role in clathrin-dependent endocytosis of CaSR. Inactivating mutations in CaSR cause familial hypocalciuric hypercalcemia type 1(FHH1)and neonatal severe hyperparathyroidism(NSHPT), while activating mutations lead to autosomal dominant hypocalcemia type 1(ADH1)and Bartter syndrome type V. Recent studies have identified that inactivating mutations in Galpha11 and sigma-subunit of AP2(AP2sigma)also cause FHH, and these conditions have been classified as FHH2 and FHH3, respectively. In addition, it has been revealed that activating mutations in Galpha11 are responsible for ADH(ADH2). Calcimimetics and calcilytics may be beneficial in the treatment of these disorders. PMID- 28336829 TI - [The effect of oral calcimimetics on cardiovascular events.] AB - The Evolve Trial showed no significant benefit of cinacalcet on the primary composite outcome(death or first non-fatal myocardial infarction, hospitalization for unstable angina, heart failure, or peripheral vascular event)but significantly reduced the incidence of heart failure in an intention-to treat(ITT)analysis. In an adjusted ITT analysis and lag-censoring analysis, the effect of cinacalcet on the primary outcome was significant. The reduced incidence of cardiovascular events in the cinacalcet arm could by predicted by a >=30% reduction in FGF23 levels at week 20. In a post-hoc analysis stratified by age, cinacalcet reduced the primary outcome only in elderly patients(>=65 years). In Japanese MBD-5D cohort study, cinacalcet administration was associated with significantly lower mortality in patients with baseline iPTH >500 pg/mL and lower risk of death or hospitalization due to cardiovascular events in patients with iPTH >300 pg/mL, respectively. PMID- 28336830 TI - [The Discovery, Research and Development of Etelcalcetide Hydrochloride, the World 1st Intravenous Calcimimetics.] AB - Etelcalcetide hydrochloride is the first intravenous calcimimetics agent for secondary hyperparathyroidism (SHPT). Etelcalcetide hydrochloride is to be administered through dialysis circuit by physician or medical staff upon completion of dialysis and such administration is expected to reduce the burden of medication in patients. From the nonclinical study results, etelcalcetide functions as an allosteric activator of calcium-sensing receptor(CaSR). Etelcalcetide suppressed PTH secretion both in vitro and in vivo. In a rat model of chronic renal insufficiency, etelcalcetide suppressed SHPT disorders, such as parathyroid gland hypertrophy, bone disorder, and ectopic calcification. In conclusion, etelcalcetide hydrochloride is expected to exhibit therapeutic effect against each SHPT condition by decreasing blood PTH concentrations via CaSR agonist activity in the clinical situation. PMID- 28336831 TI - [Calcilytic drugs:Feature and future.] AB - Calcium-sensing receptor(CaSR)is highly expressed in parathyroid, kidney, bone, and small and large intestines to regulate Ca homeostasis. Calcilytics are allosteric antagonists of CaSR, and stimulate endogenous PTH release. Several calcilytics have been evaluated as anabolic therapies for postmenopausal osteoporosis but clinical development of all of them has been abandoned because the lacked clinical efficacy. Calcilytics might be repurposed for new indications like autosomal dominant hypocalcemia or other disorders. PMID- 28336832 TI - [Surgical and non-surgical management of primary hyperparathyroidism:How do calcimimetics work?] AB - Primary hyperparathyroidism is a common endocrine disease. The first line therapy for the disease is surgical removal of affected parathyroid gland(s). Other therapeutic options with medication are needed to be established, because many of patients with primary hyperparathyroidism have few or no symptoms and are expected to have a long life expectancy without surgery. Cinacalcet as a calcimimetic, bisphosphonates and denosumab are promising candidates for medical management of the disease. Effectiveness and efficiency of these drugs for patients with primary hyperparathyroidism is to be evaluated in comparison with surgical treatment. PMID- 28336833 TI - [Oral calcimimetics on secondary hyperparathyroidism of uremia.] AB - Secondary hyperparathyroidism of uremia is associated with poor health outcomes, including all-cause mortality, cardiovascular mortality, and fractures. Standard therapy for secondary hyperparathyroidism includes vitamin D receptor activators, and phosphate binders. Persistently elevated parathyroid hormone(PTH)levels may require the addition of calcimimetics which sensitizes calcium-sensing receptors on the parathyroid glands. PMID- 28336834 TI - [Parenteral calcimimetics for the treatment of secondary hyperparathyroidism.] AB - The oral calcimimetics, cinacalcet, is reported to be effective on secondary hyperparathyroidism resistant to classical treatment like phosphate binders or vitamin D receptor activator. The problem that gastrointestinal adverse events cause poor adherence, drug discontinuation, and insufficient dose escalation remains unsolved. The novel injectable calcimimetic, etelcalcetide, is recently developed and is expected to reduce such adverse events and improve the therapeutic effects on moderate to severe secondary hyperparathyroidism. Further studies are needed to demonstrate the potential benefits of etelcalcetide compared to cinacalcet. PMID- 28336835 TI - Improving Powder Magnetic Core Properties via Application of Thin, Insulating Silica-Nanosheet Layers on Iron Powder Particles. AB - A thin, insulating layer with high electrical resistivity is vital to achieving high performance of powder magnetic cores. Using layer-by-layer deposition of silica nanosheets or colloidal silica over insulating layers composed of strontium phosphate and boron oxide, we succeeded in fabricating insulating layers with high electrical resistivity on iron powder particles, which were subsequently used to prepare toroidal cores. The compact density of these cores decreased after coating with colloidal silica due to the substantial increase in the volume, causing the magnetic flux density to deteriorate. Coating with silica nanosheets, on the other hand, resulted in a higher electrical resistivity and a good balance between high magnetic flux density and low iron loss due to the thinner silica layers. Transmission electron microscopy images showed that the thickness of the colloidal silica coating was about 700 nm, while that of the silica nanosheet coating was 30 nm. There was one drawback to using silica nanosheets, namely a deterioration in the core mechanical strength. Nevertheless, the silica nanosheet coating resulted in nanoscale-thick silica layers that are favorable for enhancing the electrical resistivity. PMID- 28336836 TI - Visible Light-Responsive Platinum-Containing Titania Nanoparticle-Mediated Photocatalysis Induces Nucleotide Insertion, Deletion and Substitution Mutations. AB - Conventional photocatalysts are primarily stimulated using ultraviolet (UV) light to elicit reactive oxygen species and have wide applications in environmental and energy fields, including self-cleaning surfaces and sterilization. Because UV illumination is hazardous to humans, visible light-responsive photocatalysts (VLRPs) were discovered and are now applied to increase photocatalysis. However, fundamental questions regarding the ability of VLRPs to trigger DNA mutations and the mutation types it elicits remain elusive. Here, through plasmid transformation and beta-galactosidase alpha-complementation analyses, we observed that visible light-responsive platinum-containing titania (TiO2) nanoparticle (NP)-mediated photocatalysis considerably reduces the number of Escherichia coli transformants. This suggests that such photocatalytic reactions cause DNA damage. DNA sequencing results demonstrated that the DNA damage comprises three mutation types, namely nucleotide insertion, deletion and substitution; this is the first study to report the types of mutations occurring after photocatalysis by TiO2 VLRPs. Our results may facilitate the development and appropriate use of new generation TiO2 NPs for biomedical applications. PMID- 28336837 TI - Pnma-BN: Another Boron Nitride Polymorph with Interesting Physical Properties. AB - Structural, mechanical, electronic properties, and stability of boron nitride (BN) in Pnma structure were studied using first-principles calculations by Cambridge Serial Total Energy Package (CASTEP) plane-wave code, and the calculations were performed with the local density approximation and generalized gradient approximation in the form of Perdew-Burke-Ernzerhof. This BN, called Pnma-BN, contains four boron atoms and four nitrogen atoms buckled through sp3 hybridized bonds in an orthorhombic symmetry unit cell with Space group of Pnma. Pnma-BN is energetically stable, mechanically stable, and dynamically stable at ambient pressure and high pressure. The calculated Pugh ratio and Poisson's ratio revealed that Pnma-BN is brittle, and Pnma-BN is found to turn brittle to ductile (~94 GPa) in this pressure range. It shows a higher mechanical anisotropy in Poisson's ratio, shear modulus, Young's modulus, and the universal elastic anisotropy index AU. Band structure calculations indicate that Pnma-BN is an insulator with indirect band gap of 7.18 eV. The most extraordinary thing is that the band gap increases first and then decreases with the increase of pressure from 0 to 60 GPa, and from 60 to 100 GPa, the band gap increases first and then decreases again. PMID- 28336838 TI - On the Use of the Electrospinning Coating Technique to Produce Antimicrobial Polyhydroxyalkanoate Materials Containing In Situ-Stabilized Silver Nanoparticles. AB - Electro-hydrodynamic processing, comprising electrospraying and electrospinning techniques, has emerged as a versatile technology to produce nanostructured fiber based and particle-based materials. In this work, an antimicrobial active multilayer system comprising a commercial polyhydroxyalkanoate substrate (PHA) and an electrospun PHA coating containing in situ-stabilized silver nanoparticles (AgNPs) was successfully developed and characterized in terms of morphology, thermal, mechanical, and barrier properties. The obtained materials reduced the bacterial population of Salmonella enterica below the detection limits at very low silver loading of 0.002 +/- 0.0005 wt %. As a result, this study provides an innovative route to generate fully renewable and biodegradable materials that could prevent microbial outbreaks in food packages and food contact surfaces. PMID- 28336839 TI - Synthesis of Polyhydroxybutyrate Particles with Micro-to-Nanosized Structures and Application as Protective Coating for Packaging Papers. AB - This study reports on the development of bio-based hydrophobic coatings for packaging papers through deposition of polyhydroxybutyrate (PHB) particles in combination with nanofibrillated cellulose (NFC) and plant wax. In the first approach, PHB particles in the micrometer range (PHB-MP) were prepared through a phase-separation technique providing internally-nanosized structures. The particles were transferred as a coating by dip-coating filter papers in the particle suspension, followed by sizing with a carnauba wax solution. This approach allowed partial to almost full surface coverage of PHB-MP over the paper surface, resulting in static water contact angles of 105 degrees -122 degrees and 129 degrees -144 degrees after additional wax coating. In the second approach, PHB particles with submicron sizes (PHB-SP) were synthesized by an oil in-water emulsion (o/w) solvent evaporation method and mixed in aqueous suspensions with 0-7 wt % NFC. After dip-coating filter papers in PHB-SP/NFC suspensions and sizing with a carnauba wax solution, static water contact angles of 112 degrees -152 degrees were obtained. The intrinsic properties of the particles were analyzed by scanning electron microscopy, thermal analysis and infrared spectroscopy, indicating higher crystallinity for PHB-SP than PHB-MP. The chemical interactions between the more amorphous PHB-MP particles and paper fibers were identified as an esterification reaction, while the morphology of the NFC fibrillar network was playing a key role as the binding agent in the retention of more crystalline PHB-SP at the paper surface, hence contributing to higher hydrophobicity. PMID- 28336841 TI - Bulk Surfaces Coated with Triangular Silver Nanoplates: Antibacterial Action Based on Silver Release and Photo-Thermal Effect. AB - A layer of silver nanoplates, specifically synthesized with the desired localized surface plasmon resonance (LSPR) features, was grafted on amino-functionalized bulk glass surfaces to impart a double antibacterial action: (i) the well-known, long-term antibacterial effect based on the release of Ag+; (ii) an "on demand" action which can be switched on by the use of photo-thermal properties of silver nano-objects. Irradiation of these samples with a laser having a wavelength falling into the so called "therapeutic window" of the near infrared region allows the reinforcement, in the timescale of minutes, of the classical antibacterial effect of silver nanoparticles. We demonstrate how using the two actions allows for almost complete elimination of the population of two bacterial strains of representative Gram-positive and Gram-negative bacteria. PMID- 28336840 TI - Spectroscopic Characterization of Copper-Chitosan Nanoantimicrobials Prepared by Laser Ablation Synthesis in Aqueous Solutions. AB - Copper-chitosan (Cu-CS) nanoantimicrobials are a novel class of bioactive agents, providing enhanced and synergistic efficiency in the prevention of biocontamination in several application fields, from food packaging to biomedical. Femtosecond laser pulses were here exploited to disrupt a Cu solid target immersed into aqueous acidic solutions containing different CS concentrations. After preparation, Cu-CS colloids were obtained by tuning both Cu/CS molar ratios and laser operating conditions. As prepared Cu-CS colloids were characterized by Fourier transform infrared spectroscopy (FTIR), to study copper complexation with the biopolymer. X-ray photoelectron spectroscopy (XPS) was used to elucidate the nanomaterials' surface chemical composition and chemical speciation of the most representative elements. Transmission electron microscopy was used to characterize nanocolloids morphology. For all samples, xi potential measurements showed highly positive potentials, which could be correlated with the XPS information. The spectroscopic and morphological characterization herein presented outlines the characteristics of a technologically-relevant nanomaterial and provides evidence about the optimal synthesis parameters to produce almost monodisperse and properly-capped Cu nanophases, which combine in the same core-shell structure two renowned antibacterial agents. PMID- 28336842 TI - SERS-Based Flavonoid Detection Using Ethylenediamine-beta-Cyclodextrin as a Capturing Ligand. AB - Ethylenediamine-modified beta-cyclodextrin (Et-beta-CD) was immobilized on aggregated silver nanoparticle (NP)-embedded silica NPs (SiO2@Ag@Et-beta-CD NPs) for the effective detection of flavonoids. Silica NPs were used as the template for embedding silver NPs to create hot spots and enhance surface-enhanced Raman scattering (SERS) signals. Et-beta-CD was immobilized on Ag NPs to capture flavonoids via host-guest inclusion complex formation, as indicated by enhanced ultraviolet absorption spectra. The resulting SiO2@Ag@Et-beta-CD NPs were used as the SERS substrate for detecting flavonoids, such as hesperetin, naringenin, quercetin, and luteolin. In particular, luteolin was detected more strongly in the linear range 10-7 to 10-3 M than various organic molecules, namely ethylene glycol, beta-estradiol, isopropyl alcohol, naphthalene, and toluene. In addition, the SERS signal for luteolin captured by the SiO2@Ag@Et-beta-CD NPs remained even after repeated washing. These results indicated that the SiO2@Ag@Et-beta-CD NPs can be used as a rapid, sensitive, and selective sensor for flavonoids. PMID- 28336843 TI - Synthesis of Vertically-Aligned Zinc Oxide Nanowires and Their Application as a Photocatalyst. AB - Vertically aligned zinc oxide (ZnO) nanowires were hydrothermally synthesized on a glass substrate with the assistance of a pre-coated ZnO seeding layer. The crystalline structure, morphology and transmission spectrum of the as-synthesized sample were characterized by X-ray diffraction (XRD), field-emission scanning electron microscopy (FE-SEM), and ultraviolet-visible (UV-Vis) spectrophotometry, respectively, indicating a wurzite ZnO material of approximately 100 nm wire diameter and absorbance at 425 nm and lower wavelengths. The photocatalytic activity of the sample was tested via the degradation of methyl orange in aqueous solution under UV-A irradiation. The synthesized nanowires showed a high photocatalytic activity, which increased up to 90% degradation in 2 h as pH was increased to 12. It was shown that the photocatalytic activity of the nanowires was proportional to the length to diameter ratio of the nanowires, which was in turn controlled by the growth time and grain size of the seed layer. Estimates suggest that diffusion into the regions between nanowires may be significantly hindered. Finally, the reusability of the prepared ZnO nanowire samples was also investigated, with results showing that the nanowires still showed 97% of its original photoactivity after ten cycles of use. PMID- 28336844 TI - Gold Nanobeacons for Tracking Gene Silencing in Zebrafish. AB - The use of gold nanoparticles for effective gene silencing has demonstrated its potential as a tool for gene expression experiments and for the treatment of several diseases. Here, we used a gold nanobeacon designed to specifically silence the enhanced green fluorescence protein (EGFP) mRNA in embryos of a fli EGFP transgenic zebrafish line, while simultaneously allowing the tracking and localization of the silencing events via the beacon's emission. Fluorescence imaging measurements demonstrated a decrease of the EGFP emission with a concomitant increase in the fluorescence of the Au-nanobeacon. Furthermore, microinjection of the Au-nanobeacon led to a negligible difference in mortality and malformations in comparison to the free oligonucleotide, indicating that this system is a biocompatible platform for the administration of gene silencing moieties. Together, these data illustrate the potential of Au-nanobeacons as tools for in vivo zebrafish gene modulation with low toxicity which may be used towards any gene of interest. PMID- 28336845 TI - Parametrically Optimized Carbon Nanotube-Coated Cold Cathode Spindt Arrays. AB - Here, we investigate, through parametrically optimized macroscale simulations, the field electron emission from arrays of carbon nanotube (CNT)-coated Spindts towards the development of an emerging class of novel vacuum electron devices. The present study builds on empirical data gleaned from our recent experimental findings on the room temperature electron emission from large area CNT electron sources. We determine the field emission current of the present microstructures directly using particle in cell (PIC) software and present a new CNT cold cathode array variant which has been geometrically optimized to provide maximal emission current density, with current densities of up to 11.5 A/cm2 at low operational electric fields of 5.0 V/MUm. PMID- 28336846 TI - Preparation of g-C3N4/Graphene Composite for Detecting NO2 at Room Temperature. AB - Graphitic carbon nitride (g-C3N4) nanosheets were exfoliated from bulk g-C3N4 and utilized to improve the sensing performance of a pure graphene sensor for the first time. The role of hydrochloric acid treatment on the exfoliation result was carefully examined. The exfoliated products were characterized by X-ray diffraction (XRD) patterns, scanning electron microscopy (SEM), atomic force microscopy (AFM), and UV-Vis spectroscopy. The exfoliated g-C3N4 nanosheets exhibited a uniform thickness of about 3-5 nm and a lateral size of about 1-2 um. A g-C3N4/graphene nanocomposite was prepared via a self-assembly process and was demonstrated to be a promising sensing material for detecting nitrogen dioxide gas at room temperature. The nanocomposite sensor exhibited better recovery as well as two-times the response compared to pure graphene sensor. The detailed sensing mechanism was then proposed. PMID- 28336848 TI - Effects of Iodine Doping on Optoelectronic and Chemical Properties of Polyterpenol Thin Films. AB - Owing to their amorphous, highly cross-liked nature, most plasma polymers display dielectric properties. This study investigates iodine doping as the means to tune optoelectronic properties of plasma polymer derived from a low-cost, renewable resource, i.e., Melaleuca alternifolia oil. In situ exposure of polyterpenol to vapors of electron-accepting dopant reduced the optical band gap to 1.5 eV and increased the conductivity from 5.05 * 10-8 S/cm to 1.20 * 10-6 S/cm. The increased conductivity may, in part, be attributed to the formation of charge transfer complexes between the polymer chain and halogen, which act as a cation and anion, respectively. Higher levels of doping notably increased the refractive index, from 1.54 to 1.70 (at 500 nm), and significantly reduced the transparency of films. PMID- 28336849 TI - Modification of the Surface Topography and Composition of Ultrafine and Coarse Grained Titanium by Chemical Etching. AB - In this study, we present the detailed investigation of the influence of the etching medium (acidic or basic Piranha solutions) and the etching time on the morphology and surface relief of ultrafine grained (UFG) and coarse grained (CG) titanium. The surface relief and morphology have been studied by means of scanning electron microscopy (SEM), atomic force microscopy (AFM), and the spectral ellipsometry. The composition of the samples has been determined by X ray fluorescence analysis (XRF) and X-ray Photoelectron Spectroscopy (XPS). Significant difference in the etching behavior of UFG and CG titanium has been found. UFG titanium exhibits higher etching activity independently of the etching medium. Formed structures possess higher homogeneity. The variation of the etching medium and time leads to micro-, nano-, or hierarchical micro/nanostructures on the surface. Significant difference has been found between surface composition for UFG titanium etched in basic and acidic Piranha solution. Based on the experimental data, the possible reasons and mechanisms are considered for the formation of nano- and microstructures. The prospects of etched UFG titanium as the material for implants are discussed. PMID- 28336850 TI - Influence of Solution Properties and Process Parameters on the Formation and Morphology of YSZ and NiO Ceramic Nanofibers by Electrospinning. AB - The fabrication process of ceramic yttria-stabilized zirconia (YSZ) and nickel oxide nanofibers by electrospinning is reported. The preparation of hollow YSZ nanofibers and aligned nanofiber arrays is also demonstrated. The influence of the process parameters of the electrospinning process, the physicochemical properties of the spinning solutions, and the thermal treatment procedure on spinnability and final microstructure of the ceramic fibers was determined. The fiber diameter can be varied from hundreds of nanometers to more than a micrometer by controlling the solution properties of the electrospinning process, while the grain size and surface roughness of the resulting fibers are mainly controlled via the final thermal annealing process. Although most observed phenomena are in qualitative agreement with previous studies on the electrospinning of polymeric nanofibers, one of the main differences is the high ionic strength of ceramic precursor solutions, which may hamper the spinnability. A strategy to control the effective ionic strength of precursor solutions is also presented. PMID- 28336851 TI - Nano-Photonic Structures for Light Trapping in Ultra-Thin Crystalline Silicon Solar Cells. AB - Thick wafer-silicon is the dominant solar cell technology. It is of great interest to develop ultra-thin solar cells that can reduce materials usage, but still achieve acceptable performance and high solar absorption. Accordingly, we developed a highly absorbing ultra-thin crystalline Si based solar cell architecture using periodically patterned front and rear dielectric nanocone arrays which provide enhanced light trapping. The rear nanocones are embedded in a silver back reflector. In contrast to previous approaches, we utilize dielectric photonic crystals with a completely flat silicon absorber layer, providing expected high electronic quality and low carrier recombination. This architecture creates a dense mesh of wave-guided modes at near-infrared wavelengths in the absorber layer, generating enhanced absorption. For thin silicon (<2 MUm) and 750 nm pitch arrays, scattering matrix simulations predict enhancements exceeding 90%. Absorption approaches the Lambertian limit at small thicknesses (<10 MUm) and is slightly lower (by ~5%) at wafer-scale thicknesses. Parasitic losses are ~25% for ultra-thin (2 MUm) silicon and just 1%-2% for thicker (>100 MUm) cells. There is potential for 20 MUm thick cells to provide 30 mA/cm2 photo-current and >20% efficiency. This architecture has great promise for ultra-thin silicon solar panels with reduced material utilization and enhanced light-trapping. PMID- 28336853 TI - Enhanced Photocatalytic Performance under Visible and Near-Infrared Irradiation of Cu1.8Se/Cu3Se2 Composite via a Phase Junction. AB - A novel Cu1.8Se/Cu3Se2 composite photocatalyst was prepared by the simple precipitation method. This composite possesses a wide photoabsorption until the range of near-infrared light, and exhibits significantly enhanced photocatalytic activity for methyl orange degradation under visible and near-infrared light irradiation compared with bare Cu1.8Se and Cu3Se2. The mechanism of this outstanding photocatalytic behavior can be explained by the calculated energy band positions. The efficient charge separation via a phase junction of Cu1.8Se/Cu3Se2 composite would make a great contribution to its much-enhanced photocatalytic efficiency. PMID- 28336852 TI - Amorphous Silica Particles Relevant in Food Industry Influence Cellular Growth and Associated Signaling Pathways in Human Gastric Carcinoma Cells. AB - Nanostructured silica particles are commonly used in biomedical and biotechnical fields, as well as, in cosmetics and food industry. Thus, their environmental and health impacts are of great interest and effects after oral uptake are only rarely investigated. In the present study, the toxicological effects of commercially available nano-scaled silica with a nominal primary diameter of 12 nm were investigated on the human gastric carcinoma cell line GXF251L. Besides the analysis of cytotoxic and proliferative effects and the comparison with effects of particles with a nominal primary diameter of 200 nm, emphasis was also given to their influence on the cellular epidermal growth factor receptor (EGFR) and mitogen-activated protein kinases (MAPK) signaling pathways-both of them deeply involved in the regulation of cellular processes like cell cycle progression, differentiation or proliferation. The investigated silica nanoparticles (NPs) were found to stimulate cell proliferation as measured by microscopy and the sulforhodamine B assay. In accordance, the nuclear level of the proliferation marker Ki-67 was enhanced in a concentration-dependent manner. At high particle concentrations also necrosis was induced. Finally, silica NPs affected the EGFR and MAPK pathways at various levels dependent on concentration and time. However, classical activation of the EGFR, to be reflected by enhanced levels of phosphorylation, could be excluded as major trigger of the proliferative stimulus. After 45 min of incubation the level of phosphorylated EGFR did not increase, whereas enhanced levels of total EGFR protein were observed. These results indicate interference with the complex homeostasis of the EGFR protein, whereby up to 24 h no impact on the transcription level was detected. In addition, downstream on the level of the MAP kinases ERK1/2 short term incubation appeared to affect total protein levels without clear increase in phosphorylation. Depending on the concentration range, enhanced levels of ERK1/2 phosphorylation were only observed after 24 h of incubation. Taken together, the present study demonstrates the potential of the tested silica particles to enhance the growth of gastric carcinoma cells. Although interference with the EGFR/MAPK cascade is observed, additional mechanisms are likely to be involved in the onset of the proliferative stimulus. PMID- 28336854 TI - Enhanced Visible Light Photocatalytic Activity of ZnO Nanowires Doped with Mn2+ and Co2+ Ions. AB - In this research, ZnO nanowires doped with Mn2+ and Co2+ ions were synthesized through a facile and inexpensive hydrothermal approach, in which Mn2+ and Co2+ ions successfully substituted Zn2+ in the ZnO crystal lattice without changing the morphology and crystalline structure of ZnO. The atomic percentages of Mn and Co were 6.29% and 1.68%, respectively, in the doped ZnO nanowires. The photocatalytic results showed that Mn-doped and Co-doped ZnO nanowires both exhibited higher photocatalytic activities than undoped ZnO nanowires. Among the doped ZnO nanowires, Co-doped ZnO, which owns a twice active visible-light photocatalytic performance compared to pure ZnO, is considered a more efficient photocatalyst material. The enhancement of its photocatalytic performance originates from the doped metal ions, which enhance the light absorption ability and inhibit the recombination of photo-generated electron-hole pairs as well. The effect of the doped ion types on the morphology, crystal lattice and other properties of ZnO was also investigated. PMID- 28336856 TI - A Novel Heterostructure of BiOI Nanosheets Anchored onto MWCNTs with Excellent Visible-Light Photocatalytic Activity. AB - Developing efficient visible-light-driven (VLD) photocatalysts for environmental decontamination has drawn significant attention in recent years. Herein, we have reported a novel heterostructure of multiwalled carbon nanotubes (MWCNTs) coated with BiOI nanosheets as an efficient VLD photocatalyst, which was prepared via a simple solvothermal method. The morphology and structure were characterized by powder X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), UV-Vis diffuse reflectance spectroscopy (DRS), and specific surface area measurements. The results showed that BiOI nanosheets were well deposited on MWCNTs. The MWCNTs/BiOI composites exhibited remarkably enhanced photocatalytic activity for the degradation of rhodamine B (RhB), methyl orange (MO), and para-chlorophenol (4-CP) under visible-light, compared with pure BiOI. When the MWCNTs content is 3 wt %, the MWCNTs/BiOI composite (3%M-Bi) achieves the highest activity, which is even higher than that of a mechanical mixture (3 wt % MWCNTs + 97 wt % BiOI). The superior photocatalytic activity is predominantly due to the strong coupling interface between MWCNTs and BiOI, which significantly promotes the efficient electron-hole separation. The photo-induced holes (h+) and superoxide radicals (O2-) mainly contribute to the photocatalytic degradation of RhB over 3%M-Bi. Therefore, the MWCNTs/BiOI composite is expected to be an efficient VLD photocatalyst for environmental purification. PMID- 28336857 TI - Linear and Nonlinear Rheology Combined with Dielectric Spectroscopy of Hybrid Polymer Nanocomposites for Semiconductive Applications. AB - The linear and nonlinear oscillatory shear, extensional and combined rheology dielectric spectroscopy of hybrid polymer nanocomposites for semiconductive applications were investigated in this study. The main focus was the influence of processing conditions on percolated poly(ethylene-butyl acrylate) (EBA) nanocomposite hybrids containing graphite nanoplatelets (GnP) and carbon black (CB). The rheological response of the samples was interpreted in terms of dispersion properties, filler distortion from processing, filler percolation, as well as the filler orientation and distribution dynamics inside the matrix. Evidence of the influence of dispersion properties was found in linear viscoelastic dynamic frequency sweeps, while the percolation of the nanocomposites was detected in nonlinearities developed in dynamic strain sweeps. Using extensional rheology, hybrid samples with better dispersion properties lead to a more pronounced strain hardening behavior, while samples with a higher volume percentage of fillers caused a drastic reduction in strain hardening. The rheo-dielectric time-dependent response showed that in the case of nanocomposites containing only GnP, the orientation dynamics leads to non-conductive samples. However, in the case of hybrids, the orientation of the GnP could be offset by the dispersing of the CB to bridge the nanoplatelets. The results were interpreted in the framework of a dual PE-BA model, where the fillers would be concentrated mainly in the BA regions. Furthermore, better dispersed hybrids obtained using mixing screws at the expense of filler distortion via extrusion processing history were emphasized through the rheo-dielectric tests. PMID- 28336858 TI - One-Step Reduction and Surface Modification of Graphene Oxide by 3-Hydroxy-2 Naphthoic Acid Hydrazide and Its Polypropylene Nanocomposites. AB - 3-Hydroxy-2-naphthoic acid hydrazide (HNH), a new reductant and modifier, was applied to reduce and modify graphene oxide (GO) in a one-step process. The obtained HNH reduced graphene oxide (HNH-rGO) was characterized by X-ray diffraction (XRD), scanning electron microscope (SEM), Raman spectroscopy, X-ray photoelectron spectroscopic (XPS) and Fourier transform infrared spectra (FTIR). The results demonstrated that GO was successfully reduced to graphene and the surface of HNH-rGO was grafted with HNH. The interlayer space was increased from 0.751 nm to 1.921 nm, and its agglomeration was much more attenuated compared with GO. HNH-rGO/polypropylene and graphene/polypropylene composites were synthesized through melt-blending method. The viscosity was enhanced with increased addition of graphene and surface modified graphene demonstrated stronger rheological behavior improving effect than the untreated graphene. PMID- 28336859 TI - Design and Synthesis of TiO2 Hollow Spheres with Spatially Separated Dual Cocatalysts for Efficient Photocatalytic Hydrogen Production. AB - TiO2 hollow spheres modified with spatially separated Ag species and RuO2 cocatalysts have been prepared via an alkoxide hydrolysis-precipitation method and a facile impregnation method. High-resolution transmission electron microscopy studies indicate that Ag species and RuO2 co-located on the inner and outer surface of TiO2 hollow spheres, respectively. The resultant catalysts show significantly enhanced activity in photocatalytic hydrogen production under simulated sunlight attributed to spatially separated Ag species and RuO2 cocatalysts on TiO2 hollow spheres, which results in the efficient separation and transportation of photogenerated charge carriers. PMID- 28336860 TI - Light Emission Intensities of Luminescent Y2O3:Eu and Gd2O3:Eu Particles of Various Sizes. AB - There is great technological interest in elucidating the effect of particle size on the luminescence efficiency of doped rare earth oxides. This study demonstrates unambiguously that there is a size effect and that it is not dependent on the calcination temperature. The Y2O3:Eu and Gd2O3:Eu particles used in this study were synthesized using wet chemistry to produce particles ranging in size between 7 nm and 326 nm and a commercially available phosphor. These particles were characterized using three excitation methods: UV light at 250 nm wavelength, electron beam at 10 kV, and X-rays generated at 100 kV. Regardless of the excitation source, it was found that with increasing particle diameter there is an increase in emitted light. Furthermore, dense particles emit more light than porous particles. These results can be explained by considering the larger surface area to volume ratio of the smallest particles and increased internal surface area of the pores found in the large particles. For the small particles, the additional surface area hosts adsorbates that lead to non-radiative recombination, and in the porous particles, the pore walls can quench fluorescence. This trend is valid across calcination temperatures and is evident when comparing particles from the same calcination temperature. PMID- 28336861 TI - Modified Continuum Mechanics Modeling on Size-Dependent Properties of Piezoelectric Nanomaterials: A Review. AB - Piezoelectric nanomaterials (PNs) are attractive for applications including sensing, actuating, energy harvesting, among others in nano-electro-mechanical systems (NEMS) because of their excellent electromechanical coupling, mechanical and physical properties. However, the properties of PNs do not coincide with their bulk counterparts and depend on the particular size. A large amount of efforts have been devoted to studying the size-dependent properties of PNs by using experimental characterization, atomistic simulation and continuum mechanics modeling with the consideration of the scale features of the nanomaterials. This paper reviews the recent progresses and achievements in the research on the continuum mechanics modeling of the size-dependent mechanical and physical properties of PNs. We start from the fundamentals of the modified continuum mechanics models for PNs, including the theories of surface piezoelectricity, flexoelectricity and non-local piezoelectricity, with the introduction of the modified piezoelectric beam and plate models particularly for nanostructured piezoelectric materials with certain configurations. Then, we give a review on the investigation of the size-dependent properties of PNs by using the modified continuum mechanics models, such as the electromechanical coupling, bending, vibration, buckling, wave propagation and dynamic characteristics. Finally, analytical modeling and analysis of nanoscale actuators and energy harvesters based on piezoelectric nanostructures are presented. PMID- 28336855 TI - Behavior and Potential Impacts of Metal-Based Engineered Nanoparticles in Aquatic Environments. AB - The specific properties of metal-based nanoparticles (NPs) have not only led to rapidly increasing applications in various industrial and commercial products, but also caused environmental concerns due to the inevitable release of NPs and their unpredictable biological/ecological impacts. This review discusses the environmental behavior of metal-based NPs with an in-depth analysis of the mechanisms and kinetics. The focus is on knowledge gaps in the interaction of NPs with aquatic organisms, which can influence the fate, transport and toxicity of NPs in the aquatic environment. Aggregation transforms NPs into micrometer-sized clusters in the aqueous environment, whereas dissolution also alters the size distribution and surface reactivity of metal-based NPs. A unique toxicity mechanism of metal-based NPs is related to the generation of reactive oxygen species (ROS) and the subsequent ROS-induced oxidative stress. Furthermore, aggregation, dissolution and ROS generation could influence each other and also be influenced by many factors, including the sizes, shapes and surface charge of NPs, as well as the pH, ionic strength, natural organic matter and experimental conditions. Bioaccumulation of NPs in single organism species, such as aquatic plants, zooplankton, fish and benthos, is summarized and compared. Moreover, the trophic transfer and/or biomagnification of metal-based NPs in an aquatic ecosystem are discussed. In addition, genetic effects could result from direct or indirect interactions between DNA and NPs. Finally, several challenges facing us are put forward in the review. PMID- 28336862 TI - Oscillating Magnet Array-Based Nanomagnetic Gene Transfection: A Valuable Tool for Molecular Neurobiology Studies. AB - To develop treatments for neurodegenerative disorders, it is critical to understand the biology and function of neurons in both normal and diseased states. Molecular studies of neurons involve the delivery of small biomolecules into cultured neurons via transfection to study genetic variants. However, as cultured primary neurons are sensitive to temperature change, stress, and shifts in pH, these factors make biomolecule delivery difficult, particularly non-viral delivery. Herein we used oscillating nanomagnetic gene transfection to successfully transfect SH-SY5Y cells as well as primary hippocampal and cortical neurons on different days in vitro. This novel technique has been used to effectively deliver genetic material into various cell types, resulting in high transfection efficiency and viability. From these observations and other related studies, we suggest that oscillating nanomagnetic gene transfection is an effective method for gene delivery into hard-to-transfect neuronal cell types. PMID- 28336863 TI - A High Power, Frequency Tunable Colloidal Quantum Dot (CdSe/ZnS) Laser. AB - Tunable lasers are essential for medical, engineering and basic science research studies. Most conventional solid-state lasers are capable of producing a few million laser shots, but limited to specific wavelengths, which are bulky and very expensive. Dye lasers are continuously tunable, but exhibit very poor chemical stability. As new tunable, efficient lasers are always in demand, one such laser is designed with various sized CdSe/ZnS quantum dots. They were used as a colloid in tetrahydrofuran to produce a fluorescent broadband emission from 520 nm to 630 nm. The second (532 nm) and/or third harmonic (355 nm) of the Nd:YAG laser (10 ns, 10 Hz) were used together as the pump source. In this study, different sized quantum dots were independently optically pumped to produce amplified spontaneous emission (ASE) with 4 nm to 7 nm of full width at half maximum (FWHM), when the pump power and focusing were carefully optimized. The beam was directional with a 7 mrad divergence. Subsequently, these quantum dots were combined together, and the solution was placed in a resonator cavity to obtain a laser with a spectral width of 1 nm and tunable from 510 to 630 nm, with a conversion efficiency of about 0.1%. PMID- 28336864 TI - Formation of Platinum Catalyst on Carbon Black Using an In-Liquid Plasma Method for Fuel Cells. AB - Platinum (Pt) catalyst was formed on the surface of carbon black using an in liquid plasma method. The formed Pt catalyst showed the average particle size of 4.1 nm. This Pt catalyst was applied to a polymer electrolyte membrane fuel cell (PEMFC). The PEMFC showed an open voltage of 0.85 V and a maximum output power density of 216 mW/cm2. PMID- 28336865 TI - Synthesis, Optical and Structural Properties of Copper Sulfide Nanocrystals from Single Molecule Precursors. AB - We report the synthesis and structural studies of copper sulfide nanocrystals from copper (II) dithiocarbamate single molecule precursors. The precursors were thermolysed in hexadecylamine (HDA) to prepare HDA-capped CuS nanocrystals. The optical properties of the nanocrystals studied using UV-visible and photoluminescence spectroscopy showed absorption band edges at 287 nm that are blue shifted, and the photoluminescence spectra show emission curves that are red shifted with respect to the absorption band edges. These shifts are as a result of the small crystallite sizes of the nanoparticles leading to quantum size effects. The structural studies were carried out using powder X-ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), and atomic force microscopy. The XRD patterns indicates that the CuS nanocrystals are in hexagonal covellite crystalline phases with estimated particles sizes of 17.3-18.6 nm. The TEM images showed particles with almost spherical or rod shapes, with average crystallite sizes of 3-9.8 nm. SEM images showed morphology with ball-like microspheres on the surfaces, and EDS spectra confirmed the presence of CuS nanoparticles. PMID- 28336866 TI - {Ni4O4} Cluster Complex to Enhance the Reductive Photocurrent Response on Silicon Nanowire Photocathodes. AB - Metal organic {Ni4O4} clusters, known oxidation catalysts, have been shown to provide a valuable route in increasing the photocurrent response on silicon nanowire (SiNW) photocathodes. {Ni4O4} clusters have been paired with SiNWs to form a new photocathode composite for water splitting. Under AM1.5 conditions, the combination of {Ni4O4} clusters with SiNWs gave a current density of -16 mA/cm2, which corresponds to an increase in current density of 60% when compared to bare SiNWs. The composite electrode was fully characterised and shown to be an efficient and stable photocathode for water splitting. PMID- 28336867 TI - Synthesis of Multicolor Core/Shell NaLuF4:Yb3+/Ln3+@CaF2 Upconversion Nanocrystals. AB - The ability to synthesize high-quality hierarchical core/shell nanocrystals from an efficient host lattice is important to realize efficacious photon upconversion for applications ranging from bioimaging to solar cells. Here, we describe a strategy to fabricate multicolor core @ shell alpha-NaLuF4:Yb3+/Ln3+@CaF2 (Ln = Er, Ho, Tm) upconversion nanocrystals (UCNCs) based on the newly established host lattice of sodium lutetium fluoride (NaLuF4). We exploited the liquid-solid solution method to synthesize the NaLuF4 core of pure cubic phase and the thermal decomposition approach to expitaxially grow the calcium fluoride (CaF2) shell onto the core UCNCs, yielding cubic core/shell nanocrystals with a size of 15.6 +/- 1.2 nm (the core ~9 +/- 0.9 nm, the shell ~3.3 +/- 0.3 nm). We showed that those core/shell UCNCs could emit activator-defined multicolor emissions up to about 772 times more efficient than the core nanocrystals due to effective suppression of surface-related quenching effects. Our results provide a new paradigm on heterogeneous core/shell structure for enhanced multicolor upconversion photoluminescence from colloidal nanocrystals. PMID- 28336869 TI - Non-Enzymatic Glucose Sensor Composed of Carbon-Coated Nano-Zinc Oxide. AB - Nowadays glucose detection is of great importance in the fields of biological, environmental, and clinical analyzes. In this research, we report a zinc oxide (ZnO) nanorod powder surface-coated with carbon material for non-enzymatic glucose sensor applications through a hydrothermal process and chemical vapor deposition method. A series of tests, including crystallinity analysis, microstructure observation, and electrochemical property investigations were carried out. For the cyclic voltammetric (CV) glucose detection, the low detection limit of 1 mM with a linear range from 0.1 mM to 10 mM was attained. The sensitivity was 2.97 MUA/cm2mM, which is the most optimized ever reported. With such good analytical performance from a simple process, it is believed that the nanocomposites composed of ZnO nanorod powder surface-coated with carbon material are promising for the development of cost-effective non-enzymatic electrochemical glucose biosensors with high sensitivity. PMID- 28336868 TI - Eu, Gd-Codoped Yttria Nanoprobes for Optical and T1-Weighted Magnetic Resonance Imaging. AB - Nanoprobes with multimodal functionality have attracted significant interest recently because of their potential applications in nanomedicine. This paper reports the successful development of lanthanide-doped Y2O3 nanoprobes for potential applications in optical and magnetic resonance (MR) imaging. The morphology, structural, and optical properties of these nanoprobes were characterized by transmission electron microscope (TEM), field emission scanning electron microscope (FESEM), X-ray diffraction (XRD), energy-dispersive X-ray (EDX), and photoluminescence (PL). The cytotoxicity test showed that the prepared lanthanide-doped Y2O3 nanoprobes have good biocompatibility. The obvious contrast enhancement in the T1-weighted MR images suggested that these nanoprobes can be used as a positive contrast agent in MRI. In addition, the clear fluorescence images of the L-929 cells incubated with the nanoprobes highlight their potential for optical imaging. Overall, these results suggest that prepared lanthanide doped Y2O3 nanoprobes can be used for simultaneous optical and MR imaging. PMID- 28336870 TI - Evidence of Protein Adsorption in Pegylated Liposomes: Influence of Liposomal Decoration. AB - In order to contribute to a better knowledge of the events involved in the formation of the protein corona when nanoparticles (NPs) come in contact with proteins, we report a study about the changes on the physicochemical properties of pristine, PEGylated and Cyclic Arginine-Glycine-Aspartate peptide (RGD) functionalized large unilamelar liposomes (LUVs) or magnetoliposomes (MLs) upon incubation with Bovine Serum Albumin (BSA). The main phospholipid component of both LUVs and MLs was l-alpha-phosphatydylcholine (PC) or 1,2-dimyristoyl-sn glycero-3-phosphocholine (DMPC) with 20% of cholesterol. The most obvious indication of the interaction of BSA-nanosystems is given by changes in the hydrodynamic diameter of the particles but other evidence is needed to corroborate the process. Our findings indicate that size modification is a process that is accomplished in few hours and that is strongly dependent not only on the surface decoration but also of the lipid composition of both LUVs and MLs. Fluorescence quenching experiments as well as cryogenic transmission electron microscopy (Cryo-TEM) images assessed these changes and confirmed that although each system has to be studied in a particular way, we can establish three distinctive features that turn into more reactive systems: (a) compositions containing PC compared with their DMPC counterparts; (b) the presence of PEG and/or RGD compared to the pristine counterparts; and (c) the presence of SPIONs: MLs show higher interaction than LUVs of the same lipid composition. Consequently, PEGylation (that is supposed to make stealth NPs) actually fails in preventing complete protein binding. PMID- 28336872 TI - An Enzymatic Glucose Sensor Composed of Carbon-Coated Nano Tin Sulfide. AB - In this study, a biosensor, based on a glucose oxidase (GOx) immobilized, carbon coated tin sulfide (SnS) assembled on a glass carbon electrode (GCE) was developed, and its direct electrochemistry was investigated. The carbon coated SnS (C-SnS) nanoparticle was prepared through a simple two-step process, using hydrothermal and chemical vapor deposition methods. The large reactive surface area and unique electrical potential of C-SnS could offer a favorable microenvironment for facilitating electron transfer between enzymes and the electrode surface. The structure and sensor ability of the proposed GOx/C-SnS electrode were characterized using scanning electron microscopy (SEM), X-ray diffraction (XRD), Raman spectroscopy, UV-vis spectroscopy, Fourier transform infrared spectroscopy (FTIR), and cyclic voltammetry study (CV). PMID- 28336871 TI - Magnetic Nanovectors for the Development of DNA Blood-Stage Malaria Vaccines. AB - DNA vaccines offer cost, flexibility, and stability advantages, but administered alone have limited immunogenicity. Previously, we identified optimal configurations of magnetic vectors comprising superparamagnetic iron oxide nanoparticles (SPIONs), polyethylenimine (PEI), and hyaluronic acid (HA) to deliver malaria DNA encoding Plasmodium yoelii (Py) merozoite surface protein MSP119 (SPIONs/PEI/DNA + HA gene complex) to dendritic cells and transfect them with high efficiency in vitro. Herein, we evaluate their immunogenicity in vivo by administering these potential vaccine complexes into BALB/c mice. The complexes induced antibodies against PyMSP119, with higher responses induced intraperitoneally than intramuscularly, and antibody levels further enhanced by applying an external magnetic field. The predominant IgG subclasses induced were IgG2a followed by IgG1 and IgG2b. The complexes further elicited high levels of interferon gamma (IFN-gamma), and moderate levels of interleukin (IL)-4 and IL-17 antigen-specific splenocytes, indicating induction of T helper 1 (Th1), Th2, and Th17 cell mediated immunity. The ability of such DNA/nanoparticle complexes to induce cytophilic antibodies together with broad spectrum cellular immunity may benefit malaria vaccines. PMID- 28336873 TI - Synthesis, Characterization, and Biological Evaluation of Nanostructured Hydroxyapatite with Different Dimensions. AB - Nanosized hydroxyapatite (HA) is a promising candidate for a substitute for apatite in bone in biomedical applications. Furthermore, due to its excellent bone bioactivity, nanosized strontium-substituted HA (SrHA) has aroused intensive interest. However, the size effects of these nanoparticles on cellular bioactivity should be considered. In this study, nanosized HA and SrHA with different dimensions and crystallization were synthesized by hydrothermal methods. The phase, crystallization and chemical composition were analyzed by X ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR), respectively. The morphology was observed under field emission scanning electron microscopy (FE-SEM) and transmission electron microscopy (TEM). The degradation behaviors of the samples were monitored by determining the ions release profile with inductively coupled plasma mass spectrometry (ICP-MS). The releasing behavior of Ca2+ and Sr2+ showed that the degradation rate was proportional to the specific surface area and inversely proportional to crystallization. The in vitro experiment evaluated by MG63 cells showed that SrHA nanorods with a length greater than 100 nm had the best biological performance both in cell proliferation and differentiation (* p < 0.05 compared with HA-1 and SrHA-1; * p < 0.01 compared with HA-2). In addition, HA nanoparticles with a lower aspect ratio had better bioactivity than higher ones (* p < 0.05). This study demonstrated that nanosized HA and SrHA with subtle differences (including dimensions, crystallization, specific surface area, and degradation rate) could affect the cellular growth and thus might have an impact on bone growth in vivo. This work provides a view of the role of nano-HAs as ideal biocompatible materials in future clinical applications. PMID- 28336875 TI - NiCo2O4-Based Supercapacitor Nanomaterials. AB - In recent years, the research on supercapacitors has ushered in an explosive growth, which mainly focuses on seeking nano-/micro-materials with high energy and power densities. Herein, this review will be arranged from three aspects. We will summarize the controllable architectures of spinel NiCo2O4 fabricated by various approaches. Then, we introduce their performances as supercapacitors due to their excellent electrochemical performance, including superior electronic conductivity and electrochemical activity, together with the low cost and environmental friendliness. Finally, the review will be concluded with the perspectives on the future development of spinel NiCo2O4 utilized as the supercapacitor electrodes. PMID- 28336874 TI - Electrospun Nanofibres Containing Antimicrobial Plant Extracts. AB - Over the last 10 years great research interest has been directed toward nanofibrous architectures produced by electrospinning bioactive plant extracts. The resulting structures possess antimicrobial, anti-inflammatory, and anti oxidant activity, which are attractive for biomedical applications and food industry. This review describes the diverse approaches that have been developed to produce electrospun nanofibres that are able to deliver naturally-derived chemical compounds in a controlled way and to prevent their degradation. The efficacy of those composite nanofibres as wound dressings, scaffolds for tissue engineering, and active food packaging systems will be discussed. PMID- 28336876 TI - Recent Advances in Research on the Synthetic Fiber Based Silica Aerogel Nanocomposites. AB - The presented paper contains a brief review on the synthesis and characterization of silica aerogels and its nanocomposites with nanofibers and fibers based on a literature study over the past twenty years and my own research. Particular attention is focused on carbon fiber-based silica aerogel nanocomposites. Silica aerogel is brittle in nature, therefore, it is necessary to improve this drawback, e.g., by polymer modification or fiber additives. Nevertheless, there are very few articles in the literature devoted to the synthesis of silica aerogel/fiber nanocomposites, especially those focusing on carbon fibers and nanofibers. Carbon fibers are very interesting materials, namely due to their special properties: high conductivity, high mechanical properties in relation to very low bulk densities, high thermal stability, and chemical resistance in the silica aerogel matrix, which can help enhance silica aerogel applications in the future. PMID- 28336877 TI - Lipoic Acid Gold Nanoparticles Functionalized with Organic Compounds as Bioactive Materials. AB - Water soluble gold nanoparticles protected by lipoic acid were obtained and further functionalized by standard coupling reaction with 1-naphtylamine, 4 aminoantipyrine, and 4'-aminobenzo-15-crown-5 ether. Derivatives of lipoic acid with 1-naphtylamine, 4-aminoantipyrine, and 4'-aminobenzo-15-crown-5 ether were also obtained and characterized. All these were tested for their antimicrobial activity, as well as for their influence on mammalian cell viability and cellular cycle. In all cases a decreased antimicrobial activity of the obtained bioactive nanoparticles was observed as compared with the organic compounds, proving that a possible inactivation of the bioactive groups could occur during functionalization. However, both the gold nanoparticles as well as the functionalized bioactive nanosystems proved to be biocompatible at concentrations lower than 50 ug/mL, as revealed by the cellular viability and cell cycle assay, demonstrating their potential for the development of novel antimicrobial agents. PMID- 28336878 TI - Ag Nanoparticles-Modified 3D Graphene Foam for Binder-Free Electrodes of Electrochemical Sensors. AB - Ag nanoparticles-modified 3D graphene foam was synthesized through a one-step in situ approach and then directly applied as the electrode of an electrochemical sensor. The composite foam electrode exhibited electrocatalytic activity towards Hg(II) oxidation with high limit of detection and sensitivity of 0.11 MUM and 8.0 MUA/MUM, respectively. Moreover, the composite foam electrode for the sensor exhibited high cycling stability, long-term durability and reproducibility. These results were attributed to the unique porous structure of the composite foam electrode, which enabled the surface of Ag nanoparticles modified reduced graphene oxide (Ag NPs modified rGO) foam to become highly accessible to the metal ion and provided more void volume for the reaction with metal ion. This work not only proved that the composite foam has great potential application in heavy metal ions sensors, but also provided a facile method of gram scale synthesis 3D electrode materials based on rGO foam and other electrical active materials for various applications. PMID- 28336880 TI - Synthesis of Carbon Nanotubes in Thermal Plasma Reactor at Atmospheric Pressure. AB - In this paper, a novel approach to the synthesis of the carbon nanotubes (CNTs) in reactors operating at atmospheric pressure is presented. Based on the literature and our own research results, the most effective methods of CNT synthesis are investigated. Then, careful selection of reagents for the synthesis process is shown. Thanks to the performed calculations, an optimum composition of gases and the temperature for successful CNT synthesis in the CVD (chemical vapor deposition) process can be chosen. The results, having practical significance, may lead to an improvement of nanomaterials synthesis technology. The study can be used to produce CNTs for electrical and electronic equipment (i.e., supercapacitors or cooling radiators). There is also a possibility of using them in medicine for cancer diagnostics and therapy. PMID- 28336879 TI - In Vitro and In Vivo Evaluation of a Three-Dimensional Porous Multi-Walled Carbon Nanotube Scaffold for Bone Regeneration. AB - Carbon nanotubes (CNTs) have attracted a great deal of attention for the biological and medical science fields because of their characteristic physical and biological properties. In this study, we investigated the capacity of the 3D porous CNT scaffold (CNT porous block; CNTp) for bone regenerative medicine. Surface observations using a scanning electron microscope (SEM), crystal depositions on the surface of CNTps immersed in simulated body fluid (SBF), and evaluations of protein adsorption and controlled releasing were conducted to assess physical properties. The cell proliferation and cell morphology were observed using SEM and fluorescent microscopy. CNTps were implanted into critical size mouse calvarial defects and evaluated for their osteoconductive ability and in vivo controlled release of recombinant human BMP-2 (rhBMP-2). Interconnected porous HA ceramics (IP-CHAs) were used for comparison. CNTps have multiporous structures with interporous connections with networks of multiwalled CNTs. Crystals containing calcium and phosphate were deposited in CNTps and on the surface of the CNT networks by immersing CNTps in SBF. CNTps adsorbed more significantly and released protein more gradually than IP-CHAs. Preosteoblasts seeded onto CNTps filled pores with stretched actin filaments and filopodia. Compared with IP-CHAs, CNTps showed significantly higher cell proliferation, better osteoconduction, and more bone generation with rhBMP-2. In this study, CNTps demonstrated good osteoconductive ability, cell attachment and proliferation capacity, and growth factor retaining ability. CNTps have the potential not only as artificial bones for the treatment of bone defects, but also as scaffolds for regenerative medicine using tissue engineering approaches. PMID- 28336881 TI - The Influence of New Hydrophobic Silica Nanoparticles on the Surface Properties of the Films Obtained from Bilayer Hybrids. AB - Ultra-hydrophobic bilayer coatings on a glass surface were fabricated by sol-gel process using hexadecyltrimethoxysilane (C16TMS) and tetramethoxysilane (TMOS) (1:4 molar ratio) as precursors. After coating, silica nanoparticles (SiO2 NPs) functionalized with different mono-alkoxy derivatives (methoxytrimethylsilane, TMeMS; ethoxydimethylvinylsilane, DMeVES; ethoxydimethylphenylsilane, DMePhES; and methoxydimethyloctylsilane, DMeC8MS) were added, assuring the microscale roughness on the glass surface. Influences of the functionalized SiO2 NPs and surface morphology on the hydrophobicity of the hybrid films were discussed. The successful functionalization of SiO2 NPs with hydrophobic alkyl groups were confirmed by Fourier transform infrared spectroscopy (FTIR). The thermal stability of hydrophobic SiO2 NPs showed that the degradation of the alkyl groups takes place in the 200-400 degrees C range. Bilayer coating with C16TMS/TMOS and SiO2 NPs modified with alkoxysilane substituted with C8 alkyl chain (SiO2 NP-C8) has micro/nano structure. Hydrophobicity of functionalized SiO2 NPs-C8 and its higher degree of nanometer-scale roughness gave rise to ultra-hydrophobicity performance for bilayer coating C16TMS/TMOS + SiO2 NPs-C8 (145 degrees ), compared to other similar hybrid structures. Our synthesis method for the functionalization of SiO2 NPs is useful for the modification of surface polarity and roughness. PMID- 28336884 TI - Influence of Plasma Jet Temperature Profiles in Arc Discharge Methods of Carbon Nanotubes Synthesis. AB - One of the most common methods of carbon nanotubes (CNTs) synthesis is application of an electric-arc plasma. However, the final product in the form of cathode deposit is composed of carbon nanotubes and a variety of carbon impurities. An assay of carbon nanotubes produced in arc discharge systems available on the market shows that commercial cathode deposits contain about 10% CNTs. Given that the quality of the final product depends on carbon-plasma jet parameters, it is possible to increase the yield of the synthesis by plasma jet control. Most of the carbon nanotubes are multiwall carbon nanotubes (MWCNTs). It was observed that the addition of catalysts significantly changes the plasma composition, effective ionization potential, the arc channel conductance, and in effect temperature of the arc and carbon elements flux. This paper focuses on the influence of metal components on plasma-jet forming containing carbon nanotubes cathode deposit. The plasma jet temperature control system is presented. PMID- 28336883 TI - Evaluating Adverse Effects of Inhaled Nanoparticles by Realistic In Vitro Technology. AB - The number of daily products containing nanoparticles (NP) is rapidly increasing. NP in powders, dispersions, or sprays are a yet unknown risk for incidental exposure, especially at workplaces during NP production and processing, and for consumers of any health status and age using NP containing sprays. We developed the nano aerosol chamber for in vitro toxicity (NACIVT), a portable instrument for realistic safety testing of inhaled NP in vitro and evaluated effects of silver (Ag) and carbon (C) NP-which belong to the most widely used nanomaterials on normal and compromised airway epithelia. We review the development, physical performance, and suitability of NACIVT for short and long-term exposures with air liquid interface (ALI) cell cultures in regard to the prerequisites of a realistic in vitro test system for inhalation toxicology and in comparison to other commercially available, well characterized systems. We also review doses applied to cell cultures in vitro and acknowledge that a single exposure to realistic doses of spark generated 20-nm Ag- or CNP results in small, similar cellular responses to both NP types and that cytokine release generally increased with increasing NP dose. PMID- 28336885 TI - Preparation and Characterization of Cellulose Nanocrystals from the Bio-ethanol Residuals. AB - This study was to explore the conversion of low-cost bio-residuals into high value-added cellulose nanocrystals. Two enzymatic hydrolyzed residuals (i.e., HRMMW and HRSPW) were collected from two different bio-ethanol producing processes-hydrolyzing medium-milled wood (MMW) and hydrolyzing acid sulfite pretreated wood (SPW), respectively. The results showed that both residuals contained over 20 wt % glucan with a crystallinity of about 30%, confirming the existence of cellulose in a well-organized structure in two bio-residuals. The cellulose nanocrystals (CNCs) were successfully extracted by first bleaching the hydrolyzed residuals to remove lignin and then hydrolyzing them with sulfuric acid. The resulting CNCs displayed the flow birefringence under two crossed polarizers. Compared with CNCs from microfibrillated cellulose (CNCMCC), HRMMW and its resulted CNC present the smallest particle size and aspect ratio. CNCMCC had the larger particle size, aspect ratio, and higher z-potential value, CNCSPW presented a similar morphology to CNCMCC, and had the largest aspect ratio. The CNCMCC enhanced its high crystallinity to 85.5%. However, CNCMMW and CNCSPW had a better thermal stability and higher activation energy as well as onset temperature and maximum decomposition temperature. As a result, the CNCs from bio ethanol residuals are valued and promising cellulose nanoparticle resources. PMID- 28336882 TI - Antimicrobial Polymers in the Nano-World. AB - Infections are one of the main concerns of our era due to antibiotic-resistant infections and the increasing costs in the health-care sector. Within this context, antimicrobial polymers present a great alternative to combat these problems since their mechanisms of action differ from those of antibiotics. Therefore, the microorganisms' resistance to these polymeric materials is avoided. Antimicrobial polymers are not only applied in the health-care sector, they are also used in many other areas. This review presents different strategies that combine nanoscience and nanotechnology in the polymer world to combat contaminations from bacteria, fungi or algae. It focuses on the most relevant areas of application of these materials, viz. health, food, agriculture, and textiles. PMID- 28336887 TI - SiO2/ZnO Composite Hollow Sub-Micron Fibers: Fabrication from Facile Single Capillary Electrospinning and Their Photoluminescence Properties. AB - In this work, SiO2/ZnO composite hollow sub-micron fibers were fabricated by a facile single capillary electrospinning technique followed by calcination, using tetraethyl orthosilicate (TEOS), polyvinylpyrrolidone (PVP) and ZnO nanoparticles as raw materials. The characterization results of the scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR) spectra indicated that the asprepared composite hollow fibers consisted of amorphous SiO2 and hexagonal wurtzite ZnO. The products revealed uniform tubular structure with outer diameters of 400-500 nm and wall thickness of 50-60 nm. The gases generated and the directional escaped mechanism was proposed to illustrate the formation of SiO2/ZnO composite hollow sub-micron fibers. Furthermore, a broad blue emission band was observed in the photoluminescence (PL) of SiO2/ZnO composite hollow sub micron fibers, exhibiting great potential applications as blue light-emitting candidate materials. PMID- 28336886 TI - Preparation and Electrochemical Properties of Li3V2(PO4)3-xBrx/Carbon Composites as Cathode Materials for Lithium-Ion Batteries. AB - Li3V2(PO4)3-xBrx/carbon (x = 0.08, 0.14, 0.20, and 0.26) composites as cathode materials for lithium-ion batteries were prepared through partially substituting PO43- with Br-, via a rheological phase reaction method. The crystal structure and morphology of the as-prepared composites were characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM), and electrochemical properties were evaluated by charge/discharge cycling and electrochemical impedance spectroscopy (EIS). XRD results reveal that the Li3V2(PO4)3-xBrx/carbon composites with solid solution phase are well crystallized and have the same monoclinic structure as the pristine Li3V2(PO4)3/carbon composite. It is indicated by SEM images that the Li3V2(PO4)3-xBrx/carbon composites possess large and irregular particles, with an increasing Br- content. Among the Li3V2(PO4)3 xBrx/carbon composites, the Li3V2(PO4)2.86Br0.14/carbon composite shows the highest initial discharge capacity of 178.33 mAh.g-1 at the current rate of 30 mA.g-1 in the voltage range of 4.8-3.0 V, and the discharge capacity of 139.66 mAh.g-1 remains after 100 charge/discharge cycles. Even if operated at the current rate of 90 mA.g-1, Li3V2(PO4)2.86Br0.14/carbon composite still releases the initial discharge capacity of 156.57 mAh.g-1, and the discharge capacity of 123.3 mAh.g-1 can be maintained after the same number of cycles, which is beyond the discharge capacity and cycleability of the pristine Li3V2(PO4)3/carbon composite. EIS results imply that the Li3V2(PO4)2.86Br0.14/carbon composite demonstrates a decreased charge transfer resistance and preserves a good interfacial compatibility between solid electrode and electrolyte solution, compared with the pristine Li3V2(PO4)3/carbon composite upon cycling. PMID- 28336888 TI - Microwave-Hydrothermal Synthesis of SnO2-CNTs Hybrid Nanocomposites with Visible Light Photocatalytic Activity. AB - SnO2 nanoparticles coated on carbon nanotubes (CNTs) were prepared via a simple microwave-hydrothermal route. The as-obtained SnO2-CNTs composites were characterized using X-ray powder diffraction, Raman spectroscopy, and transmission electron microscopy. The photocatalytic activity of as-prepared SnO2 CNTs for degradation of Rhodamine B under visible light irradiation was investigated. The results show that SnO2-CNTs nanocomposites have a higher photocatalytic activity than pure SnO2 due to the rapid transferring of electrons and the effective separation of holes and electrons on SnO2-CNTs. PMID- 28336889 TI - Self-propagating Combustion Triggered Synthesis of 3D Lamellar Graphene/BaFe12O19 Composite and Its Electromagnetic Wave Absorption Properties. AB - The synthesis of 3D lamellar graphene/BaFe12O19 composites was performed by oxidizing graphite and sequentially self-propagating combustion triggered process. The 3D lamellar graphene structures were formed due to the synergistic effect of the tremendous heat induced gasification as well as huge volume expansion. The 3D lamellar graphene/BaFe12O19 composites bearing 30 wt % graphene present the reflection loss peak at -27.23 dB as well as the frequency bandwidth at 2.28 GHz (< -10 dB). The 3D lamellar graphene structures could consume the incident waves through multiple Reflection and scattering within the layered structures, Prolonging the propagation path of electromagnetic waves in the absorbers. PMID- 28336890 TI - In Vitro Comparative Skin Irritation Induced by Nano and Non-Nano Zinc Oxide. AB - This study was designed to determine whether nano-sized ZnO has the potential to cause acute cutaneous irritation using cultured HaCaT keratinocytes and a human skin equivalent as in vitro models, compared to non-nanomaterials. Commercial nano ZnO with different sizes (50 nm and 100 nm) was characterized by dynamic light scattering (DLS) and microscopy (SEM) in different media. Nano ZnO reduced the cell viability of HaCaT in a dose-dependent and time-dependent manner, in a similar way to macro ZnO. However, the 3D-epidermis model revealed no irritation at 1 mg/mL after 24 h of exposure. In conclusion, nano-sized ZnO does not irritate skin, in a similar manner to non-nano ZnO. PMID- 28336891 TI - Nanocellulose-Based Materials for Water Purification. AB - Nanocellulose is a renewable material that combines a high surface area with high strength, chemical inertness, and versatile surface chemistry. In this review, we will briefly describe how nanocellulose is produced, and present-in particular, how nanocellulose and its surface modified versions affects the adsorption behavior of important water pollutants, e.g., heavy metal species, dyes, microbes, and organic molecules. The processing of nanocellulose-based membranes and filters for water purification will be described in detail, and the uptake capacity, selectivity, and removal efficiency will also be discussed. The processing and performance of nanocellulose-based membranes, which combine a high removal efficiency with anti-fouling properties, will be highlighted. PMID- 28336892 TI - Effect of the Polymeric Stabilizer in the Aqueous Phase Fischer-Tropsch Synthesis Catalyzed by Colloidal Cobalt Nanocatalysts. AB - A series of small and well defined cobalt nanoparticles were synthesized by the chemical reduction of cobalt salts in water using NaBH4 as a reducing agent and using various polymeric stabilizers. The obtained nanocatalysts of similar mean diameters (ca. 2.6 nm) were fully characterized and tested in the aqueous phase Fischer-Tropsch Synthesis (AFTS). Interestingly, the nature and structure of the stabilizers used during the synthesis of the CoNPs affected the reduction degree of cobalt and the B-doping of these NPs and consequently, influenced the performance of these nanocatalysts in AFTS. PMID- 28336894 TI - Fabrication of Functional Polyurethane/Rare Earth Nanocomposite Membranes by Electrospinning and Its VOCs Absorption Capacity from Air. AB - Volatile organic compounds (VOCs) are a source of air pollution and are harmful to both human health and the environment. In this study, we fabricated polyurethane/rare earth (PU/RE) composite nanofibrous membranes via electrospinning with the aim of removing VOCs from air. The morphological structure of PU/RE nanofibrous mats was investigated using field emission scanning electron microscopy (FE-SEM), fourier transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD) experimental analyses. A certain amount of RE (up to 50 wt. % compared to PU pellets) nanoparticles (NPs) could be loaded on/into PU fibers. The tensile strength of PU/RE nanofibrous membranes decreased slightly with the increasing RE powder content. The PU nanofiber containing 50 wt. % RE powder had the smallest fiber diameter of 356 nm; it also showed the highest VOC absorption capacity compared with other composite membranes, having an absorption capacity about three times greater than pure PU nanofibers. In addition, all of the PU/RE nanofibrous membranes readily absorbed styrene the most, followed by xylene, toluene, benzene and chloroform. Therefore, the PU/RE nanofibrous membrane can play an important role in removing VOCs from the air, and its development prospects are impressive because they are emerging materials. PMID- 28336893 TI - Chitosan-Functionalized Graphene Oxide as a Potential Immunoadjuvant. AB - The application of graphene oxide (GO) as a potential vaccine adjuvant has recently attracted considerable attention. However, appropriate surface functionalization of GO is crucial to improve its biocompatibility and enhance its adjuvant activity. In this study, we developed a simple method to prepare chitosan (CS)-functionalized GO (GO-CS) and further investigated its potential as a nanoadjuvant. Compared with GO, GO-CS possessed considerably smaller size, positive surface charge, and better thermal stability. The functionalization of GO with CS was effective in decreasing the non-specific protein adsorption and improving its biocompatibility. Furthermore, GO-CS significantly activated RAW264.7 cells and stimulated more cytokines for mediating cellular immune response, which was mainly due to the synergistic immunostimulatory effect of both GO and CS. GO-CS exhibits strong potential as a safe nanoadjuvant for vaccines and immunotherapy. PMID- 28336895 TI - Exchange Bias Optimization by Controlled Oxidation of Cobalt Nanoparticle Films Prepared by Sputter Gas Aggregation. AB - Porous films of cobalt nanoparticles have been obtained by sputter gas aggregation and controllably oxidized by air annealing at 100 degrees C for progressively longer times (up to more than 1400 h). The magnetic properties of the samples were monitored during the process, with a focus on the exchange bias field. Air annealing proves to be a convenient way to control the Co/CoO ratio in the samples, allowing the optimization of the exchange bias field to a value above 6 kOe at 5 K. The occurrence of the maximum in the exchange bias field is understood in terms of the density of CoO uncompensated spins and their degree of pinning, with the former reducing and the latter increasing upon the growth of a progressively thicker CoO shell. Vertical shifts exhibited in the magnetization loops are found to correlate qualitatively with the peak in the exchange bias field, while an increase in vertical shift observed for longer oxidation times may be explained by a growing fraction of almost completely oxidized particles. The presence of a hummingbird-like form in magnetization loops can be understood in terms of a combination of hard (biased) and soft (unbiased) components; however, the precise origin of the soft phase is as yet unresolved. PMID- 28336896 TI - Nanofibrous Silver-Coated Polymeric Scaffolds with Tunable Electrical Properties. AB - Electrospun micro- and nanofibrous poly(glycerol sebacate)-poly(epsilon caprolactone) (PGS-PCL) substrates have been extensively used as scaffolds for engineered tissues due to their desirable mechanical properties and their tunable degradability. In this study, we fabricated micro/nanofibrous scaffolds from a PGS-PCL composite using a standard electrospinning approach and then coated them with silver (Ag) using a custom radio frequency (RF) sputtering method. The Ag coating formed an electrically conductive layer around the fibers and decreased the pore size. The thickness of the Ag coating could be controlled, thereby tailoring the conductivity of the substrate. The flexible, stretchable patches formed excellent conformal contact with surrounding tissues and possessed excellent pattern-substrate fidelity. In vitro studies confirmed the platform's biocompatibility and biodegradability. Finally, the potential controlled release of the Ag coating from the composite fibrous scaffolds could be beneficial for many clinical applications. PMID- 28336897 TI - Three-Dimensional BiOI/BiOX (X = Cl or Br) Nanohybrids for Enhanced Visible-Light Photocatalytic Activity. AB - Three-dimensional flower-like BiOI/BiOX (X = Br or Cl) hybrids were synthesized via a facile one-pot solvothermal approach. With systematic characterizations by X-ray diffraction (XRD), scanning electron microscopy (SEM), Transmission electron microscopy (TEM), the Brunauer-Emmett-Teller (BET)specific surface area, X-ray photoelectron spectroscopy (XPS), and the UV-Vis diffuse reflectance spectra (DRS), the BiOI/BiOCl composites showed a fluffy and porous 3-D architecture with a large specific surface area (SSA) and high capability for light absorption. Among all the BiOX (X = Cl, Br, I) and BiOI/BiOX (X = Cl or Br) composites, BiOI/BiOCl stands out as the most efficient photocatalyst under both visible and UV light irradiations for methyl orange (MO) oxidation. The reaction rate of MO degradation on BiOI/BiOCl was 2.1 times higher than that on pure BiOI under visible light. Moreover, BiOI/BiOCl exhibited enhanced water oxidation efficiency for O2 evolution which was 1.5 times higher than BiOI. The enhancement of photocatalytic activity could be attributed to the formation of a heterojunction between BiOI and BiOCl, with a nanoporous structure, a larger SSA, and a stronger light absorbance capacity especially in the visible-light region. The in situ electron paramagnetic resonance (EPR) revealed that BiOI/BiOCl composites could effectively evolve superoxide radicals and hydroxyl radicals for photodegradation, and the superoxide radicals are the dominant reactive species. The superb photocatalytic activity of BiOI/BiOCl could be utilized for the degradation of various industrial dyes under natural sunlight irradiation which is of high significance for the remediation of industrial wastewater in the future. PMID- 28336898 TI - 2D Transition Metal Dichalcogenides and Graphene-Based Ternary Composites for Photocatalytic Hydrogen Evolution and Pollutants Degradation. AB - Photocatalysis have attracted great attention due to their useful applications for sustainable hydrogen evolution and pollutants degradation. Transition metal dichalcogenides (TMDs) such as MoS2 and WS2 have exhibited great potential as cocatalysts to increase the photo-activity of some semiconductors. By combination with graphene (GR), enhanced cocatalysts of TMD/GR hybrids could be synthesized. GR here can act as a conductive electron channel for the transport of the photogenerated electrons, while the TMDs nanosheets in the hybrids can collect electrons and act as active sites for photocatalytic reactions. This mini review will focus on the application of TMD/GR hybrids as cocatalysts for semiconductors in photocatalytic reactions, by which we hope to provide enriched information of TMD/GR as a platform to develop more efficient photocatalysts for solar energy utilization. PMID- 28336900 TI - Improvement of Scratch and Wear Resistance of Polymers by Fillers Including Nanofillers. AB - Polymers have lower resistance to scratching and wear than metals. Liquid lubricants work well for metals but not for polymers nor for polymer-based composites (PBCs). We review approaches for improvement of tribological properties of polymers based on inclusion of fillers. The fillers can be metallic or ceramic-with obvious consequences for electrical resistivity of the composites. Distinctions between effectiveness of micro- versus nano-particles are analyzed. For example, aluminum nanoparticles as filler are more effective for property improvement than microparticles at the same overall volumetric concentration. Prevention of local agglomeration of filler particles is discussed along with a technique to verify the prevention. PMID- 28336899 TI - Nanoemulsified D-Limonene Reduces the Heat Resistance of Salmonella Senftenberg over 50 Times. AB - Salmonella Senftenberg is a pathogen agent causative of foodborne disease and it is considered the most heat-resistant serovar within this genus. Food industries use heat treatment and chemical antimicrobials in order to eliminate this microorganism in food, but consumers prefer natural antimicrobials as essential oils and their components. This study evaluates the combined effect of thermal treatments and different concentrations of D-limonene nanoemulsion on the inactivation of Salmonella (S.) Senftenberg. The results showed an important effect of the nanoemulsified D-limonene on the heat resistance of S. Senftenberg. The delta50 degrees C value was reduced by 85%, 96% and 98% when 0.1, 0.5 and 1 mM of nanoemulsified D-limonene was added to the heating medium. The effect was kept along all the heating temperatures researched and the shape of the survival curves did not change with the addition of the antimicrobial. The results obtained in this research could be very useful for food industries for optimizing or improving heat treatments applied to food. PMID- 28336901 TI - An Optical Sensor with Polyaniline-Gold Hybrid Nanostructures for Monitoring pH in Saliva. AB - Saliva contains important personal physiological information that is related to some diseases, and it is a valuable source of biochemical information that can be collected rapidly, frequently, and without stress. In this article, we reported a new and simple localized surface plasmon resonance (LSPR) substrate composed of polyaniline (PANI)-gold hybrid nanostructures as an optical sensor for monitoring the pH of saliva samples. The overall appearance and topography of the substrates, the composition, and the wettability of the LSPR surfaces were characterized by optical and scanning electron microscope (SEM) images, infrared spectra, and contact angles measurement, respectively. The PANI-gold hybrid substrate readily responded to the pH. The response time was very short, which was 3.5 s when the pH switched from 2 to 7, and 4.5 s from 7 to 2. The changes of visible-near-infrared (NIR) spectra of this sensor upon varying pH in solution showed that-for the absorption at given wavelengths of 665 nm and 785 nm-the sensitivities were 0.0299 a.u./pH (a.u. = arbitrary unit) with a linear range of pH = 5-8 and 0.0234 a.u./pH with linear range of pH = 2-8, respectively. By using this new sensor, the pH of a real saliva sample was monitored and was consistent with the parallel measurements with a standard laboratory method. The results suggest that this novel LSPR sensor shows great potential in the field of mobile healthcare and home medical devices, and could also be modified by different sensitive materials to detect various molecules or ions in the future. PMID- 28336902 TI - Magnetic Hybrid Nanosorbents for the Uptake of Paraquat from Water. AB - Although paraquat has been banned in European countries, this herbicide is still used all over the world, thanks to its low-cost, high-efficiency, and fast action. Because paraquat is highly toxic to humans and animals, there is interest in mitigating the consequences of its use, namely by implementing removal procedures capable of curbing its environmental and health risks. This research describes new magnetic nanosorbents composed of magnetite cores functionalized with bio-hybrid siliceous shells, that can be used to uptake paraquat from water using magnetically-assisted procedures. The biopolymers kappa-carrageenan and starch were introduced into the siliceous shells, resulting in two hybrid materials, Fe3O4@SiO2/SiCRG and Fe3O4@SiO2/SiStarch, respectively, that exhibit a distinct surface chemistry. The Fe3O4@SiO2/SiCRG biosorbents displayed a superior paraquat removal performance, with a good fitting to the Langmuir and Toth isotherm models. The maximum adsorption capacity of paraquat for Fe3O4@SiO2/SiCRG biosorbents was 257 mg.g-1, which places this sorbent among the best systems for the removal of this herbicide from water. The interesting performance of the kappa-carrageenan hybrid, along with its magnetic properties and good regeneration capacity, presents a very efficient way for the remediation of water contaminated with paraquat. PMID- 28336903 TI - Melanin-Associated Synthesis of SERS-Active Nanostructures and the Application for Monitoring of Intracellular Melanogenesis. AB - Melanin plays an indispensable role in the human body. It serves as a biological reducer for the green synthesis of precious metal nanoparticles. Melanin-Ag nanocomposites were successfully produced which exhibited very strong surface enhanced Raman scattering (SERS) effect because of the reducibility property of melanin. A melanin-Ag composite structure was synthesized in situ in melanin cells, and SERS technique was performed for the rapid imaging and quantitative assay of intracellular melanin. This imaging technique was also used to successfully trace the formation and secretion of intracellular melanin after stimulation with melanin-stimulating hormones. Based on the self-reducing property of melanin, the proposed SERS imaging method can provide potentially powerful analytical detection tools to study the biological functions of melanin and to prevent and cure melanin-related diseases. PMID- 28336904 TI - Optoelectronic Properties of Van Der Waals Hybrid Structures: Fullerenes on Graphene Nanoribbons. AB - The search for new optical materials capable of absorbing light in the frequency range from visible to near infrared is of great importance for applications in optoelectronic devices. In this paper, we report a theoretical study of the electronic and optical properties of hybrid structures composed of fullerenes adsorbed on graphene and on graphene nanoribbons. The calculations are performed in the framework of the density functional theory including the van der Waals dispersive interactions. We found that the adsorption of the C 60 fullerenes on a graphene layer does not modify its low energy states, but it has strong consequences for its optical spectrum, introducing new absorption peaks in the visible energy region. The optical absorption of fullerenes and graphene nanoribbon composites shows a strong dependence on photon polarization and geometrical characteristics of the hybrid systems, covering a broad range of energies. We show that an external electric field across the nanoribbon edges can be used to tune different optical transitions coming from nanoribbon-fullerene hybridized states, which yields a very rich electro-absorption spectrum for longitudinally polarized photons. We have carried out a qualitative analysis on the potential of these hybrids as possible donor-acceptor systems in photovoltaic cells. PMID- 28336905 TI - A Nanostructured Matrices Assessment to Study Drug Distribution in Solid Tumor Tissues by Mass Spectrometry Imaging. AB - The imaging of drugs inside tissues is pivotal in oncology to assess whether a drug reaches all cells in an adequate enough concentration to eradicate the tumor. Matrix-Assisted Laser Desorption Ionization Mass Spectrometry Imaging (MALDI-MSI) is one of the most promising imaging techniques that enables the simultaneous visualization of multiple compounds inside tissues. The choice of a suitable matrix constitutes a critical aspect during the development of a MALDI MSI protocol since the matrix ionization efficiency changes depending on the analyte structure and its physico-chemical properties. The objective of this study is the improvement of the MALDI-MSI technique in the field of pharmacology; developing specifically designed nanostructured surfaces that allow the imaging of different drugs with high sensitivity and reproducibility. Among several nanomaterials, we tested the behavior of gold and titanium nanoparticles, and halloysites and carbon nanotubes as possible matrices. All nanomaterials were firstly screened by co-spotting them with drugs on a MALDI plate, evaluating the drug signal intensity and the signal-to-noise ratio. The best performing matrices were tested on control tumor slices, and were spotted with drugs to check the ion suppression effect of the biological matrix. Finally; the best nanomaterials were employed in a preliminary drug distribution study inside tumors from treated mice. PMID- 28336907 TI - New Task Force Criteria Provide Evolution in Diagnosis of Arrhythmogenic Cardiomyopathy in Patients without Typical Progression of the Disease. AB - BACKGROUND The original Task Force Criteria from 1994 for the clinical diagnosis of ARVC were highly specific and based on structural, histological, EKG, and familial features of disease. However, recommendations for clinical diagnosis and management of ARVC are sparse and lacked sensitivity for early disease. CASE REPORT Ventricular electrical instability and sudden cardiac death are the hallmarks of ARVC, and are often present before structural abnormalities. In this case report, we describe a patient who had detectable electrical abnormalities and structural changes that remained unchanged for over 10 years. CONCLUSIONS The disease progression in this case was defined as the development of a new 2010 TFC, which was absent at enrolment in 1994 and in 2008. PMID- 28336906 TI - Identification and Evaluation of New Immunoregulatory Genes in Mesenchymal Stromal Cells of Different Origins: Comparison of Normal and Inflammatory Conditions. AB - BACKGROUND Mesenchymal stromal cells (MSCs) possess potent immunomodulatory properties that increase their value as a cell-based therapeutic tool for managing various immune-based disorders. Over the past years, accumulated results from trials using MSCs-based therapy have shown substantial contradictions. Although the reasons underlying these discrepancies are still not completely understood, it is well known that the immunomodulatory activities mediated by distinct MSCs differ in a manner dependent on their tissue origin and adequate response to inflammation priming. Thus, characterization of new molecular pathway(s) through which distinct MSC populations can exert their immunomodulatory effects, particularly during inflammation, will undoubtedly enhance their therapeutic potential. MATERIAL AND METHODS After confirming their compliance with ISCT criteria, quantitative real time-PCR (qRT-PCR) was used to screen new immunoregulatory genes in MSCs, derived from adipose tissue, foreskin, Wharton's jelly or the bone-marrow, after being cultivated under normal and inflammatory conditions. RESULTS FGL2, GAL, SEMA4D, SEMA7A, and IDO1 genes appeared to be differentially transcribed in the different MSC populations. Moreover, these genes were not similarly modulated following MSCs-exposure to inflammatory signals. CONCLUSIONS Our observations suggest that these identified immunoregulatory genes may be considered as potential candidates to be targeted in order to enhance the immunomodulatory properties of MSCs towards more efficient clinical use. PMID- 28336908 TI - Early Chimerism After Liver Transplantation Reflects the Clinical Course of Recurrent Hepatitis C. AB - BACKGROUND Human leukocyte antigen (HLA) mismatch is a characteristic feature of post-orthotopic liver transplantation (OLT) hepatitis C. To investigate the importance of donor HLA-restricted immune cells in post-OLT hepatitis C recurrence, we analyzed the frequency of donor chimerism and the clinical course of post-OLT hepatitis C. MATERIAL AND METHODS We analyzed peripheral blood chimerism in 11 HCV-reinfected patients with post-HLA mismatched OLT. Patients were divided into 2 groups: the OLT chronic hepatitis C (CHC) group (n=8), exhibiting active hepatitis C recurrence; and the OLT-persistently normal ALT (PNALT) group (n=3), without active hepatitis. Chimerism was analyzed by flow cytometry using donor-specific anti-HLA antibodies in peripheral blood mononuclear cells from 1-100 days after OLT. Kidney (n=7) and lung (n=7) transplant recipients were also analyzed for comparison. As immune cells from the donor liver might contribute to post-OLT chimerism, the characteristics of perfusates from donor livers (n=10) were analyzed and defined. RESULTS Donor derived cells were frequently observed in liver and lung transplant recipients. The frequency of donor-derived cells from the B cell subset was significantly higher in peripheral blood from OLT-CHC group than in that of the OLT-PNALT group. B cells, however, were not the predominant subset in the perfusates, indicating that inflow of donor-derived cells alone did not cause the chimerism. CONCLUSIONS Chimerism of B cells is frequent in liver transplant patients with early recurrence of hepatitis C. We propose that monitoring of early chimerism could facilitate early detection of chronic hepatitis C recurrence, although we need more cases to investigate. PMID- 28336909 TI - Stair-Climbing Test Predicts Postoperative Cardiopulmonary Complications and Hospital Stay in Patients with Non-Small Cell Lung Cancer. AB - BACKGROUND There is currently no reliable method to predict major postoperative cardiopulmonary complications for patients with non-small cell lung cancer (NSCLC). In this study, we hypothesized that exercise oxygen desaturation (EOD) and heart rate change results in a stair-climbing test (SCT) would predict postoperative cardiopulmonary complications for patients with NSCLC. MATERIAL AND METHODS We examined 171 patients (41 females and 130 males) with NSCLC by preoperative SCT from January 2010 to July 2015. Among them, 27 underwent wedge resection, 122 underwent lobectomy, and 22 underwent pneumonectomy. The correlation between postoperative cardiopulmonary complications and parameters of SCT and pulmonary function test (PFT) parameters were analyzed retrospectively. RESULTS The overall 30-day postoperative morbidity of the patients was 46/171 (26.9%), with death occurring in 3/171(1.8%). The age, FEV1%, MVV, height of climbing, EOD, and heart rate change were found to be significantly different between the group with postoperative cardiopulmonary complications and those without. Binary logistic regression analysis showed that EOD and heart rate change were independently correlated with postoperative cardiopulmonary complications. In addition, a model predicting the probability of postoperative cardiopulmonary complication based on logistic regression for multivariable analysis was used to confirm our findings. CONCLUSIONS A symptom-limited SCT with oxygen saturation monitoring is a safe, simple, and low-cost method to evaluate cardiopulmonary function preoperatively. PMID- 28336911 TI - 2D hybrid analysis: Approach for building three-dimensional atomic model by electron microscopy image matching. AB - In this study, we develop an approach termed "2D hybrid analysis" for building atomic models by image matching from electron microscopy (EM) images of biological molecules. The key advantage is that it is applicable to flexible molecules, which are difficult to analyze by 3DEM approach. In the proposed approach, first, a lot of atomic models with different conformations are built by computer simulation. Then, simulated EM images are built from each atomic model. Finally, they are compared with the experimental EM image. Two kinds of models are used as simulated EM images: the negative stain model and the simple projection model. Although the former is more realistic, the latter is adopted to perform faster computations. The use of the negative stain model enables decomposition of the averaged EM images into multiple projection images, each of which originated from a different conformation or orientation. We apply this approach to the EM images of integrin to obtain the distribution of the conformations, from which the pathway of the conformational change of the protein is deduced. PMID- 28336910 TI - Populus trichocarpa encodes small, effector-like secreted proteins that are highly induced during mutualistic symbiosis. AB - During symbiosis, organisms use a range of metabolic and protein-based signals to communicate. Of these protein signals, one class is defined as 'effectors', i.e., small secreted proteins (SSPs) that cause phenotypical and physiological changes in another organism. To date, protein-based effectors have been described in aphids, nematodes, fungi and bacteria. Using RNA sequencing of Populus trichocarpa roots in mutualistic symbiosis with the ectomycorrhizal fungus Laccaria bicolor, we sought to determine if host plants also contain genes encoding effector-like proteins. We identified 417 plant-encoded putative SSPs that were significantly regulated during this interaction, including 161 SSPs specific to P. trichocarpa and 15 SSPs exhibiting expansion in Populus and closely related lineages. We demonstrate that a subset of these SSPs can enter L. bicolor hyphae, localize to the nucleus and affect hyphal growth and morphology. We conclude that plants encode proteins that appear to function as effector proteins that may regulate symbiotic associations. PMID- 28336912 TI - Fgf21 regulates T-cell development in the neonatal and juvenile thymus. AB - We have previously shown that Fibroblast growth factor 21 (Fgf21) is expressed in the thymus as well as in the liver. In line with this expression profile, Fgf21 was recently reported to protect against ageing-related thymic senescence by improving the function of thymic epithelial cells (TECs). However, the function of Fgf21 in the juvenile thymus remained to be elucidated. We investigated the physiological roles of Fgf21 in the juvenile thymus and found that young Fgf21 knockout mice, but not beta-Klotho knockout mice nor adult Fgf21 knockout mice, showed a significant reduction in the percentage of single-positive CD4+ and CD8+ thymocytes without obvious alteration in TECs. Furthermore, treatment with recombinant FGF21 protein rescued the impairment in fetal thymus organ culture (FTOC) of Fgf21 knockout mice. Annexin V staining revealed FGF21 protein enhanced apoptosis of immature thymocytes undergoing selection process in FTOC, suggesting that FGF21 may facilitate the selection of developing T cells. Endocrine Fgf21 from the liver induced by metabolic stimulation did not affect juvenile thymocyte development. Our data suggest that Fgf21 acts as one of intrathymic cytokines in the neonatal and juvenile thymus, involving thymocyte development in a beta Klotho-independent manner. PMID- 28336913 TI - Fission-fusion dynamics over large distances in raven non-breeders. AB - The influence of fission-fusion dynamics, i.e., temporal variation in group size and composition, on social complexity has been studied in large-brained mammals that rely on social bonds. Little is known about birds, even though some species like ravens have recently received attention for their socio-cognitive skills and use of social bonds. While raven breeders defend territories year-round, non breeders roam through large areas and form groups at food sources or night roosts. We here examined the fission-fusion patterns of non-breeding ravens over years, investigating whether birds meet repeatedly either at the same or at different locations. We combined four large datasets: presence-absence observations from two study sites (Austria, Italy) and GPS-tracking of ravens across two study areas (Austria, France). As expected, we found a highly dynamic system in which individuals with long phases of temporary settlement had a high probability of meeting others. Although GPS-tagged ravens spread out over thousands of square kilometres, we found repeated associations between almost half of the possible combinations at different locations. Such a system makes repeated interactions between individuals at different sites possible and likely. High fission-fusion dynamics may thus not hinder but shape the social complexity of ravens and, possibly, other long-term bonded birds. PMID- 28336915 TI - A Novel Method of Evaluating Knee Joint Stability of Patients with Knee Osteoarthritis: Multiscale Entropy Analysis with A Knee-Aiming Task. AB - Deteriorating knee stability is a local risk factor that reflects the occurrence and aggregative of osteoarthritis (OA). Despite the many biomechanics-based methods for assessing the structural stability of knee joints in clinics, these methods have many limitations. The stability of the knee joint relies on not only biomechanical factors, but also proprioception and the central nervous system. In this study, we attempt to depict the stability of knee joint from a holistic viewpoint, and a novel index of knee joint stability (IKJS) was thus extracted. We compared the differences of IKJS in 57 healthy volunteers and 55 patients with OA before and after total knee replacement (TKR). Analysis of Variance results demonstrated that there existed significant differences in IKJS among the three participating groups (<0.0001). Also, the IKJS of the operated leg in patients with knee OA increased remarkably after TKR (p < 0.0001). Furthermore, the results of the experiment suggested that the IKJS has sufficient reproducibility (ICC = 0.80). In conclusion, the proposed IKJS that employs the knee-aiming task is feasible for quantitatively determining knee stability. It can provide a potentially valuable and convenient tool to evaluate the effect of postoperative rehabilitation for patients with knee OA. PMID- 28336914 TI - Inhibition of serum and glucocorticoid regulated kinase-1 as novel therapy for cardiac arrhythmia disorders. AB - Alterations in sodium flux (INa) play an important role in the pathogenesis of cardiac arrhythmias and may also contribute to the development of cardiomyopathies. We have recently demonstrated a critical role for the regulation of the voltage-gated sodium channel NaV1.5 in the heart by the serum and glucocorticoid regulated kinase-1 (SGK1). Activation of SGK1 in the heart causes a marked increase in both the peak and late sodium currents leading to prolongation of the action potential duration and an increased propensity to arrhythmia. Here we show that SGK1 directly regulates NaV1.5 channel function, and genetic inhibition of SGK1 in a zebrafish model of inherited long QT syndrome rescues the long QT phenotype. Using computer-aided drug discovery coupled with in vitro kinase assays, we identified a novel class of SGK1 inhibitors. Our lead SGK1 inhibitor (5377051) selectively inhibits SGK1 in cultured cardiomyocytes, and inhibits phosphorylation of an SGK1-specific target as well as proliferation in the prostate cancer cell line, LNCaP. Finally, 5377051 can reverse SGK1's effects on NaV1.5 and shorten the action potential duration in induced pluripotent stem cell (iPSC)-derived cardiomyocytes from a patient with a gain-of function mutation in Nav 1.5 (Long QT3 syndrome). Our data suggests that SGK1 inhibitors warrant further investigation in the treatment of cardiac arrhythmias. PMID- 28336916 TI - Evaluation of the effects of irrigation and fertilization on tomato fruit yield and quality: a principal component analysis. AB - Irrigation and fertilization are key practices for improving the fruit quality and yield of vegetables grown in greenhouses. We carried out an experiment in a solar greenhouse spanning three consecutive growing seasons to evaluate the effects of irrigation and fertilization on the fruit yield and quality, water use efficiency (WUE) and fertilizer partial factor productivity (PFP) of tomatoes. Interactions between irrigation and fertilization treatments and individual factors of irrigation and fertilization significantly (p < 0.01) affected fruit yield, WUE and PFP. WUE and fruit yield and quality were more sensitive to changes in irrigation than to changes in fertilizer, but PFP showed the opposite trend. Interestingly, the treatment with moderate irrigation (W2: 75% ET 0 ) and high fertilizer level (F1: 240N-120P2O5-150K2O kg ha-1) was twice ranked first after a combinational evaluation. In conclusion, the proper application of drip fertigation (W2F1) may be a good compromise for solar greenhouse-grown tomatoes with regard to fruit yield and quality, WUE, and PFP. The present study sheds light on the contributions of these practices, clarifies their impacts, and provides a basis for evaluating and selecting better management practices for growing greenhouse vegetables. PMID- 28336917 TI - Acclimation of a low iron adapted Ostreococcus strain to iron limitation through cell biomass lowering. AB - Iron is an essential micronutrient involved in many biological processes and is often limiting for primary production in large regions of the World Ocean. Metagenomic and physiological studies have identified clades or ecotypes of marine phytoplankton that are specialized in iron depleted ecological niches. Although less studied, eukaryotic picophytoplankton does contribute significantly to primary production and carbon transfer to higher trophic levels. In particular, metagenomic studies of the green picoalga Ostreococcus have revealed the occurrence of two main clades distributed along coast-offshore gradients, suggesting niche partitioning in different nutrient regimes. Here, we present a study of the response to iron limitation of four Ostreococcus strains isolated from contrasted environments. Whereas the strains isolated in nutrient-rich waters showed high iron requirements, the oceanic strains could cope with lower iron concentrations. The RCC802 strain, in particular, was able to maintain high growth rate at low iron levels. Together physiological and transcriptomic data indicate that the competitiveness of RCC802 under iron limitation is related to a lowering of iron needs though a reduction of the photosynthetic machinery and of protein content, rather than to cell size reduction. Our results overall suggest that iron is one of the factors driving the differentiation of physiologically specialized Ostreococcus strains in the ocean. PMID- 28336918 TI - Clinically applicable GABA receptor positive allosteric modulators promote beta cell replication. AB - A key goal of diabetes research is to develop treatments to safely promote human beta-cell replication. It has recently become appreciated that activation of gamma-aminobutyric acid receptors (GABA-Rs) on beta-cells can promote their survival and replication. A number of positive allosteric modulators (PAMs) that enhance GABA's actions on neuronal GABAA-Rs are in clinical use. Repurposing these GABAA-R PAMs to help treat diabetes is theoretically appealing because of their safety and potential to enhance the ability of GABA, secreted from beta cells, or exogenously administered, to promote beta-cell replication and survival. Here, we show that clinically applicable GABAA-R PAMs can increase significantly INS-1 beta-cell replication, which is enhanced by exogenous GABA application. Furthermore, a GABAA-R PAM promoted human islet cell replication in vitro. This effect was abrogated by a GABAA-R antagonist. The combination of a PAM and low levels of exogenous GABA further increased human islet cell replication. These findings suggest that PAMs may potentiate the actions of GABA secreted by islet beta-cells on GABAA-Rs and provide a new class of drugs for diabetes treatment. Finally, our findings may explain a past clinical observation of a GABAA-R PAM reducing HbA1c levels in diabetic patients. PMID- 28336919 TI - Altered spontaneous brain activity in chronic smokers revealed by fractional ramplitude of low-frequency fluctuation analysis: a preliminary study. AB - Although a substantial body of previous functional magnetic resonance imaging (fMRI) studies have revealed different brain responses to external stimuli in chronic cigarette smokers compared with nonsmokers, only a few studies assessed brain spontaneous activity in the resting state in chronic smokers. The aim of this study was to investigate alterations of brain activity during the resting state in chronic smokers using fractional amplitude of low-frequency fluctuation (fALFF). In the present study, 55 smokers and 49 healthy nonsmokers were included. All the subjects underwent resting-state fMRI scans and the data were analyzed by the fALFF approach. The smokers showed significantly decreased fALFF in the left precuneus, right inferior temporal and occipital gyrus(ITG/IOG), while significantly increased fALFF in the right caudate. Subsequent correlation analysis revealed that the fALFF values of the left precuneus and right ITG/IOG were positively correlated with years of smoking across the smokers. This resting state fMRI study suggests that the changed spontaneous neuronal activity, as reflected by the fALFF, in these regions may be implicated in the underlying the pathophysiology of smoking. PMID- 28336921 TI - Different antiviral effects of IFNalpha subtypes in a mouse model of HBV infection. AB - Interferon alpha (IFNalpha) is commonly used for the treatment of chronic hepatitis B (CHB) patients. There are 13 different IFNalpha subtypes in humans, but only the subtype IFNalpha2 is used for clinical treatment. The antiviral activities of all other IFNalpha subtypes against HBV have not been studied. To obtain basic knowledge about the direct antiviral as well as the immunomodulatory effects of IFNalpha subtypes, we used the HBV hydrodynamic injection (HI) mouse model. Application of most IFNalpha subtype proteins inhibited HBV replication in vivo, with IFNalpha4 and IFNalpha5 being the most effective subtypes. Decreased viral loads after therapeutic application of IFNalpha4 and IFNalpha5 correlated with expanded effector cell populations of NK cells and T cells in both liver and spleen. Hydrodynamic injection of plasmids encoding for the effective IFNalpha subtypes (pIFNalpha) was even more potent against HBV than injecting IFNalpha proteins. The combination of pIFNalpha4 and pIFNalpha5 showed a synergistic antiviral effect on HBV replication, with a strong increase in NK cell and T cell activity. The results demonstrate distinct anti-HBV effects of different IFNalpha subtypes against HBV in the mouse model, which may be relevant for new therapeutic approaches. PMID- 28336920 TI - Xiaoyaosan exerts anxiolytic-like effects by down-regulating the TNF-alpha/JAK2 STAT3 pathway in the rat hippocampus. AB - Although the anxiolytic-like effects of Xiaoyaosan, a Chinese herbal formula, have been described in many previous studies, its underlying mechanism remains undefined. The cytokine tumour necrosis factor-alpha (TNF-alpha) and its closely associated janus kinase 2 (JAK2)-signal transducer and activator of transcription (STAT3) signalling pathway regulate the neuro-inflammatory response in the brain, thus participating in the development of anxiety. Our purpose was to investigate whether the anxiolytic-like effects of Xiaoyaosan are related to the TNF alpha/JAK2-STAT3 pathway in the hippocampus. We examined the effects of Xiaoyaosan on behaviours exhibited in the elevated plus maze test, open field test and novelty-suppressed feeding test as well as hippocampal neuron damage and changes in the TNF-alpha/JAK2-STAT3 pathway in a rat model of chronic immobilization stress (CIS)-induced anxiety. Xiaoyaosan exerts anxiolytic-like effects on CIS-induced anxiety, with a significant alleviation of anxiety-like behaviours, an attenuation of hippocampal neuron damage, and a reversal of the activation of the TNF-alpha/JAK2-STAT3 pathway in the hippocampus that are similar to the effects of the JAK2 antagonist AG490. However, Xiaoyaosan and AG490 failed to effectively regulate apoptosis-related factors, including Bax and Caspase-3. These results suggest that Xiaoyaosan attenuates stress-induced anxiety behaviours by down-regulating the TNF-alpha/JAK2-STAT3 pathway in the rat hippocampus. PMID- 28336922 TI - Novel and traditional lipid-related biomarkers and their combinations in predicting coronary severity. AB - We investigated simultaneously traditional and novel lipid indices, alone or in combination, in predicting coronary severity assessed by Gensini score (GS) in 1605 non-lipid-lowering-drug-treated patients undergoing coronary angiography. Firstly, levels of triglycerides (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), non high density lipoprotein cholesterol (non HDL-C), apolipoprotein (apo) B, lipoprotein (a) [Lp(a)], proprotein convertase subtilisin/kexin type 9 (PCSK9), apoC3, small dense LDL (sdLDL) and large HDL were increased, while HDL-C and apoA1 levels were decreased as GS status (all p for trend <0.05). However, gender stratification analyses showed similar associations between lipids and GS in men but not in women. Secondly, multiple logistic regression analyses indicated that the 12 indices were predictive for high GS (>=24) but not for low GS (1-23) compared with normal coronary (GS = 0) except for TG (neither) and apoB (both). Finally, we found that interactions between two indices with mutually exclusive composition were positively associated with GS status except for couples of TC + apoC3, apoB/PCSK9/apoC3 + sdLDL-C. Concordant elevations in the two showed the highest predictive values for high GS (all p for trend <0.05). Therefore, lipid biomarkers were associated with coronary severity and their adverse changes in combination emerged greater risks in men but not in women. PMID- 28336923 TI - Integrative analysis of multi-omics data reveals distinct impacts of DDB1-CUL4 associated factors in human lung adenocarcinomas. AB - Many DDB1-CUL4 associated factors (DCAFs) have been identified and serve as substrate receptors. Although the oncogenic role of CUL4A has been well established, specific DCAFs involved in cancer development remain largely unknown. Here we infer the potential impact of 19 well-defined DCAFs in human lung adenocarcinomas (LuADCs) using integrative omics analyses, and discover that mRNA levels of DTL, DCAF4, 12 and 13 are consistently elevated whereas VBRBP is reduced in LuADCs compared to normal lung tissues. The transcriptional levels of DCAFs are significantly correlated with their gene copy number variations. SKIP2, DTL, DCAF6, 7, 8, 13 and 17 are frequently gained whereas VPRBP, PHIP, DCAF10, 12 and 15 are frequently lost. We find that only transcriptional level of DTL is robustly, significantly and negatively correlated with overall survival across independent datasets. Moreover, DTL-correlated genes are enriched in cell cycle and DNA repair pathways. We also identified that the levels of 25 proteins were significantly associated with DTL overexpression in LuADCs, which include significant decreases in protein level of the tumor supressor genes such as PDCD4, NKX2-1 and PRKAA1. Our results suggest that different CUL4-DCAF axis plays the distinct roles in LuADC development with possible relevance for therapeutic target development. PMID- 28336925 TI - Prosocial Orientation Alters Network Dynamics and Fosters Cooperation. AB - Dynamic networks have been shown to increase cooperation, but prior findings are compatible with two different mechanisms for the evolution of cooperation. It may be that dynamic networks promote cooperation even in networks composed entirely of egoists, who strategically cooperate to attract and maintain profitable interaction partners. Alternatively, drawing on recent insights into heterogeneous social preferences, we expect that dynamic networks will increase cooperation only when nodes are occupied by persons with more prosocial preferences, who tend to attract and keep more cooperative partners relative to egoists. Our experiment used a standard procedure to classify participants a priori as egoistic or prosocial and then embedded them in homogeneous networks of all prosocials or all egoists, or in heterogeneous networks (50/50). Participants then interacted in repeated prisoner's dilemma games with alters in both static and dynamic networks. In both heterogeneous and homogeneous networks, we find dynamic networks only promote cooperation among prosocials. Resulting from their greater cooperation, prosocials' relations are more stable, yielding substantially higher fitness compared to egoists in both heterogeneous and homogeneous dynamic networks. Our results suggest that a key to the evolution and stability of cooperation is the ability of those with prosocial preferences to alter their networks. PMID- 28336924 TI - Rtn1a-Mediated Endoplasmic Reticulum Stress in Podocyte Injury and Diabetic Nephropathy. AB - We previously reported a critical role of reticulon (RTN) 1A in mediating endoplasmic reticulum (ER) stress in kidney tubular cells and the expression of RTN1A correlates with the renal function and the severity of kidney injury in patients with diabetic nephropathy (DN). Here, we determined the roles of RTN1A and ER stress in podocyte injury and DN. We used db/db mice with early unilateral nephrectomy (Unx) as a murine model of progressive DN and treated mice with tauroursodeoxycholic acid (TUDCA), a specific inhibitor of ER stress. We found increased expression of RTN1A and ER stress markers in the kidney of db/db-Unx mice. Treatment of TUDCA not only attenuated proteinuria and kidney histological changes, but also ameliorated podocyte and glomeruli injury in diabetic mice, which were associated with reduction of RTN1A and ER stress marker expression in the podocytes of TUDCA-treated mice. In vitro, we showed RTN1A mediates albumin induced ER stress and apoptosis in human podocytes. A positive feedback loop between RTN1A and CHOP was found leading to an enhanced ER stress in podocytes. Our data suggest that ER stress plays a major role in podocyte injury in DN and RTN1A might be a key regulator of ER stress in podocytes. PMID- 28336926 TI - Alleviation of mercury toxicity to a marine copepod under multigenerational exposure by ocean acidification. AB - Ocean acidification (OA) may potentially modify the responses of aquatic organisms to other environmental stressors including metals. In this study, we investigated the effects of near-future OA (pCO2 1000 MUatm) and mercury (Hg) on the development and reproduction of marine copepod Tigriopus japonicus under multigenerational life-cycle exposure. Metal accumulation as well as seven life history traits (survival rate, sex ratio, developmental time from nauplius to copepodite, developmental time from nauplius to adult, number of clutches, number of nauplii/clutch and fecundity) was quantified for each generation. Hg exposure alone evidently suppressed the number of nauplii/clutch, whereas single OA exposure negligibly affected the seven traits of copepods. However, OA exposure significantly alleviated the Hg inhibitory effects on number of nauplii/clutch and fecundity, which could be explained by the reduced Hg accumulation under OA. Such combined exposure also significantly shortened the development time. Thus, in contrast to earlier findings for other toxic metals, this study demonstrated that OA potentially mitigated the Hg toxicity to some important life traits in marine copepods during multigenerational exposure. PMID- 28336927 TI - Combination of Electroencephalography and Near-Infrared Spectroscopy in Evaluation of Mental Concentration during the Mental Focus Task for Wisconsin Card Sorting Test. AB - Near-infrared spectroscopy (NIRS) is a noninvasive neuroimaging tool for measuring evoked functional changes in brain oxygenation. Electroencephalography (EEG) can be used to evaluate the functionality of cortical connections and obtain information on regional cortical activity. Coregistration of EEG-NIRS is a recent technique that has been applied for measuring changes in electrical and hemodynamic activity in the human brain. EEG-NIRS coregistration facilitates the avoidance of misleading interpretations of NIRS, particularly in the diagnosis of neurological disorders. In this study, we investigated an approach for enhancing accuracy of NIRS by using EEG to monitor physiological activity during a mental focus task. Using the Wisconsin Card Sorting Test for the subjects mental focus task, we identified two trend types in the EEG and NIRS signals of normal subjects. These data can assist in understanding brain activation statuses and enable determining subjects' degree of mental concentration. If the data can be standardized for the diagnosis of neurological disorders, they can provide a new index to improve traditional methods (e.g., questionnaires) to assist clinical doctors in diagnosing cognitive disorders. PMID- 28336928 TI - Expression of canine distemper virus receptor nectin-4 in the central nervous system of dogs. AB - Canine distemper virus (CDV) exhibits lymphotropic, epitheliotropic, and neurotropic nature, and causes a severe systemic infection in susceptible animals. Initially, signaling lymphocyte activation molecule (SLAM) expressed on immune cells has been identified as a crucial cellular receptor for CDV. Currently, nectin-4 expressed in epithelia has been shown to be another receptor for CDV. Our previous study demonstrated that neurons express nectin-4 and are infected with CDV. In this study, we investigated the distribution pattern of nectin-4 in various cell types in the canine central nervous system and showed its relation to CDV infection to further clarify the pathology of disease. Histopathological, immunohistochemical and immunofluorescent analyses were done using formalin-fixed paraffin-embedded tissues of CDV-infected dogs. Dual staining of nectin-4 and CDV antigen or nectin-4 and brain cell markers was performed. Nectin-4 was detected in ependymal cells, epithelia of choroid plexus, meningeal cells, neurons, granular cells, and Purkinje's cells. CDV antigens were detected in these nectin-4-positive cells, further suggesting contribution of nectin-4 for the CDV neurovirulence. On the other hand, astrocytes did not express nectin-4, although they were frequently infected with CDV. Since astrocytes are negative for SLAM expression, they must express an unidentified CDV receptor, which also contributes to CDV neurovirulence. PMID- 28336929 TI - Developmental Whole Brain White Matter Alterations in Transgenic Huntington's Disease Monkey. AB - Transgenic Huntington's disease monkey (HD monkey) model provides great opportunity for studying disease progression that could lead to new insight for developing biomarker, early intervention and novel therapeutics. Whole brain white matter integrity of HD-monkeys was examined longitudinally from 6 to 48 months using diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS). Progressive developmental white matter alterations in HD monkeys were widespread and were observed not only in fiber bundles connecting cortical areas to the striatum (e.g. striatal bundle and external capsule), but also in long association fiber pathways, commissural fibers, and subcortical fiber bundle. In all fiber tracts, the data indicate an arrest in white matter development around 23 months followed by slight decline until adulthood in HD monkeys. The microstructural changes parallel the progressive motor, memory and cognitive decline previously reported as HD monkeys aged. The findings revealed the widespread progressive temporal-spatial microstructural changes in HD monkey brains from infancy to adulthood, suggesting differentiated degenerations across different brain areas during brain development. PMID- 28336931 TI - Observation of biexcitonic emission at extremely low power density in tungsten disulfide atomic layers grown on hexagonal boron nitride. AB - Monolayer transition metal dichalcogenides (TMDCs) including WS2, MoS2, WSe2 and WS2, are two-dimensional semiconductors with direct bandgap, providing an excellent field for exploration of many-body effects in 2-dimensions (2D) through optical measurements. To fully explore the physics of TMDCs, the prerequisite is preparation of high-quality samples to observe their intrinsic properties. For this purpose, we have focused on high-quality samples, WS2 grown by chemical vapor deposition method with hexagonal boron nitride as substrates. We observed sharp exciton emissions, whose linewidth is typically 22~23 meV, in photoluminescence spectra at room temperature, which result clearly demonstrates the high-quality of the current samples. We found that biexcitons formed with extremely low-excitation power (240 W/cm2) at 80 K, and this should originate from the minimal amount of localization centers in the present high-quality samples. The results clearly demonstrate that the present samples can provide an excellent field, where one can observe various excitonic states, offering possibility of exploring optical physics in 2D and finding new condensates. PMID- 28336930 TI - TP53 Arg72Pro, mortality after cancer, and all-cause mortality in 105,200 individuals. AB - Rs1042522 (Arg72Pro) is a functional polymorphism of TP53. Pro72 has been associated with lower all-cause mortality and lower mortality after cancer. We hypothesized that TP53 Pro72 is associated with lower mortality after cancer, lower all-cause mortality, and with increased cancer incidence in the general population in a contemporary cohort. We genotyped 105,200 individuals aged 20-100 years from the Copenhagen General Population Study, recruited in 2003-2013, and followed them in Danish health registries. During follow-up 5,531 individuals died and 5,849 developed cancer. Hazard ratios for mortality after cancer were 1.03 (95% confidence interval:0.93-1.15) for Arg/Pro and 0.96 (95% CI:0.79-1.18) for Pro/Pro versus Arg/Arg. Hazard ratios for all-cause mortality were 0.99 (95% CI:0.93-1.04) for Arg/Pro and 1.09 (95% CI:0.98-1.21) for Pro/Pro versus Arg/Arg. Risk of cancer specific mortality, cardiovascular mortality, and respiratory mortality were not associated with Arg72Pro genotype overall; however, in exploratory subgroup analyses, genotype-associated risks of malignant melanoma and diabetes were altered. Considering multiple comparisons the latter findings may represent play of chance. The TP53 Arg72Pro genotype was not associated with mortality after cancer, all-cause mortality, or cancer incidence in the general population in a contemporary cohort. Our main conclusion is therefore a lack of reproducing an effect of TP53 Arg72Pro genotype on mortality. PMID- 28336932 TI - Tmeff2 is expressed in differentiating oligodendrocytes but dispensable for their differentiation in vivo. AB - Myelin elaborated by oligodendrocytes (OLs) in the central nervous system (CNS) is required for saltatory conduction of action potentials along neuronal axons. We found that TMEFF2, a transmembrane protein with EGF-like and two follistatin like domains, is selectively expressed in differentiating/myelinating OLs. Previous studies showed that TMEFF2 is capable of binding to PDGFA, which plays important roles in the proliferation, migration and differentiation of oligodendrocyte progenitor cells (OPCs). However, molecular and genetic analysis revealed that Tmeff2 is a weak binder of PDGFA, and not required for OL differentiation and myelin gene expression in vivo. Together, our data suggested that Tmeff2 is specifically upregulated in OLs, but dispensable for OL differentiation and maturation. PMID- 28336933 TI - Internal valence modulates the speed of object recognition. AB - Brain regions that process affect are strongly connected with visual regions, but the functional consequences of this structural organization have been relatively unexplored. How does the momentary affect of an observer influence perception? We induced either pleasant or unpleasant affect in participants and then recorded their neural activity using magnetoencephalography while they completed an object recognition task. We hypothesized, and found, that affect influenced the speed of object recognition by modulating the speed and amplitude of evoked responses in occipitotemporal cortex and regions important for representing affect. Furthermore, affect modulated functional interactions between affective and perceptual regions early during perceptual processing. These findings indicate that affect can serve as an important contextual influence on object recognition processes. PMID- 28336934 TI - Low-frequency stimulation of the primary focus retards positive transfer of secondary focus. AB - Positive transfer of secondary focus (PTS) refers to new epileptogenesis outside the primary focus and is minimally controlled by existing treatments. Low frequency stimulation (LFS) has benefits on the onset of epilepsy and epileptogenesis. However, it's unclear whether LFS can retard the PTS in epilepsy. Here we found that PTS at both contralateral amygdala and ipsilateral hippocampus were promoted after the primary focus was fully kindled in rat kindling model. The promotion of PTS at the mirror focus started when the primary kindling acquisition reached focal seizures. LFS retarded the promotion of PTS when it was applied at the primary focus during its kindling acquisition, while it only slightly retarded the promotion of PTS when applied after generalized seizures. Meanwhile, we found the expression of potassium chloride cotransporter 2 (KCC2) decreased during PTS, and LFS reversed this. Further, the decreased expression of KCC2 was verified in patients with PTS. These findings suggest that LFS may be a potential therapeutic approach for PTS in epilepsy. PMID- 28336935 TI - Preservation of organic matter in marine sediments by inner-sphere interactions with reactive iron. AB - Interactions between organic matter and mineral matrices are critical to the preservation of soil and sediment organic matter. In addition to clay minerals, Fe(III) oxides particles have recently been shown to be responsible for the protection and burial of a large fraction of sedimentary organic carbon (OC). Through a combination of synchrotron X-ray techniques and high-resolution images of intact sediment particles, we assessed the mechanism of interaction between OC and iron, as well as the composition of organic matter co-localized with ferric iron. We present scanning transmission x-ray microscopy images at the Fe L3 and C K1 edges showing that the organic matter co-localized with Fe(III) consists primarily of C=C, C=O and C-OH functional groups. Coupling the co-localization results to iron K-edge X-ray absorption spectroscopy fitting results allowed to quantify the relative contribution of OC-complexed Fe to the total sediment iron and reactive iron pools, showing that 25-62% of total reactive iron is directly associated to OC through inner-sphere complexation in coastal sediments, as much as four times more than in low OC deep sea sediments. Direct inner-sphere complexation between OC and iron oxides (Fe-O-C) is responsible for transferring a large quantity of reduced OC to the sedimentary sink, which could otherwise be oxidized back to CO2. PMID- 28336936 TI - No evidence for microsatellite instability in acute myeloid leukemia. PMID- 28336938 TI - A PSO-based multi-objective multi-label feature selection method in classification. AB - Feature selection is an important data preprocessing technique in multi-label classification. Although a large number of studies have been proposed to tackle feature selection problem, there are a few cases for multi-label data. This paper studies a multi-label feature selection algorithm using an improved multi objective particle swarm optimization (PSO), with the purpose of searching for a Pareto set of non-dominated solutions (feature subsets). Two new operators are employed to improve the performance of the proposed PSO-based algorithm. One operator is adaptive uniform mutation with action range varying over time, which is used to extend the exploration capability of the swarm; another is a local learning strategy, which is designed to exploit the areas with sparse solutions in the search space. Moreover, the idea of the archive, and the crowding distance are applied to PSO for finding the Pareto set. Finally, experiments verify that the proposed algorithm is a useful approach of feature selection for multi-label classification problem. PMID- 28336937 TI - Results of the randomized phase IIB ARCTIC trial of low-dose rituximab in previously untreated CLL. AB - ARCTIC was a multicenter, randomized-controlled, open, phase IIB non-inferiority trial in previously untreated chronic lymphocytic leukemia (CLL). Conventional frontline therapy in fit patients is fludarabine, cyclophosphamide and rituximab (FCR). The trial hypothesized that including mitoxantrone with low-dose rituximab (FCM-miniR) would be non-inferior to FCR. A total of 200 patients were recruited to assess the primary end point of complete remission (CR) rates according to IWCLL criteria. Secondary end points were progression-free survival (PFS), overall survival (OS), overall response rate, minimal residual disease (MRD) negativity, safety and cost-effectiveness. The trial closed following a pre planned interim analysis. At final analysis, CR rates were 76 FCR vs 55% FCM miniR (adjusted odds ratio: 0.37; 95% confidence interval: 0.19-0.73). MRD negativity rates were 54 FCR vs 44% FCM-miniR. More participants experienced serious adverse reactions with FCM-miniR (49%) compared to FCR (41%). There are no significant differences between the treatment groups for PFS and OS. FCM-miniR is not expected to be cost-effective over a lifetime horizon. In summary, FCM miniR is less well tolerated than FCR with an inferior response and MRD negativity rate and increased toxicity, and will not be taken forward into a confirmatory trial. The trial demonstrated that oral FCR yields high response rates compared to historical series with intravenous chemotherapy. PMID- 28336939 TI - Locating the Human Cardiac Conduction System Using a 3D Model of Its Nutritious Arteries. AB - It is difficult for anatomists to dissect the human cardiac conduction system (CCS) on specimens as well as for cardiovascular clinicians to locate the CCS during cardiac operations. Here, we demonstrate a new method for locating the CCS using a 3D model of its nutritious arteries. First, we perfused the coronary arteries with contrast material and then acquired a set of data of thin computer tomography (CT) scans. Then, we generated a 3D model of the coronary artery and distinguished the arteries that supply the CCS. We then located the CCS on the 3D model via its nutritious arteries and dissected the CCS. Finally, the structures that were dissected were removed for histological and immunofluorescent staining. The results of histological and immunofluorescence examination proved the structure to be the CCS. Thus, we successfully located the CCS using a 3D model of its nutritious arteries. We suggest that with this new method, cardiac surgeons can locate a patient's CCS during cardiac surgeries such as transcatheter aortic valve implantation (TAVI) or radiofrequency catheter ablation (RFCA). PMID- 28336940 TI - Genetic Analysis of the IncX4 Plasmids: Implications for a Unique Pattern in the mcr-1 Acquisition. AB - IncX4 plasmids are associated with the dissemination of the mcr-1 genes in Enterobacteriaceae. We screened IncX4 plasmids among 2,470 isolates of Enterobacteriaceae and determined the mcr-1 positive isolates. Forty-three isolates were observed to carry IncX4 type plasmid, among which 13 were identified to carry mcr-1 gene. Three representative mcr-1-positive IncX4 plasmids were selected for high-throughput sequencing. Comparative genomics showed that the mcr-1-carrying IncX4 plasmids exhibit remarkable similarity in the backbone, and the major distinction lies in the region containing mcr-1. The major variable regions of all the IncX4 plasmids were fully characterized by PCR RFLP. The results revealed that the mcr-1 was located on the Variable Region I of IncX4 plasmids in 11 E. coli isolates. Among them, nine E. coli strains possess an epidemic pCSZ4-like IncX4 plasmid containing mcr-1. ISApl1 was presumably involved in the transposition of the mcr-1 cassette and then was lost. Similar genetic contexts were found in different plasmids, even the E. coli chromosome, implying the acquisition of mcr-1 by a unique common mechanism. PMID- 28336941 TI - Analysis of factors affecting the therapeutic effect of propranolol for infantile haemangioma of the head and neck. AB - Infantile haemangiomas (IHs) are the most common congenital vascular tumours of infancy. Propranolol has been demonstrated to be effective for IHs; however, the factors affecting its therapeutic effect remain unknown. We enrolled 169 infants with IHs of the head and neck region treated with oral propranolol at a dose of 2.0 mg/kg/day. We evaluated the therapeutic responses 6 months after treatment and the end of treatment, which were categorized into four grades. The type and location of the lesions and the infant age at treatment initiation were analysed. The clinical response rate (III + IV) was 91.72% at 6 months after treatment and 97.63% at the end of treatment. The average treatment duration was 9.99 (2-24) months. The group aged 4-6 months exhibited a greater therapeutic response rate (98.48%). The treatment duration was shorter (9.52 months) for mixed-type IHs. Better therapeutic responses were observed for IHs located around the parotid, periorbital, cheek, and neck regions and for multiple IH lesions. Our study indicated that propranolol is effective for IHs affecting the head and neck. The age at treatment initiation and the location of the lesions had a significant effect on the therapeutic response, whereas the lesion type might affect the treatment duration. PMID- 28336942 TI - Selective inhibitor of Wnt/beta-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model. AB - Chronic hepatitis C virus (HCV) infection is one of the major causes of serious liver diseases, including liver cirrhosis. There are no anti-fibrotic drugs with efficacy against liver cirrhosis. Wnt/beta-catenin signaling has been implicated in the pathogenesis of a variety of tissue fibrosis. In the present study, we investigated the effects of a beta-catenin/CBP (cyclic AMP response element binding protein) inhibitor on liver fibrosis. The anti-fibrotic activity of PRI 724, a selective inhibitor of beta-catenin/CBP, was assessed in HCV GT1b transgenic mice at 18 months after HCV genome expression. PRI-724 was injected intraperitoneally or subcutaneously in these mice for 6 weeks. PRI-724 reduced liver fibrosis, which was indicated by silver stain, Sirius Red staining, and hepatic hydroxyproline levels, in HCV mice while attenuating alphaSMA induction. PRI-724 led to increased levels of matrix metalloproteinase (MMP)-8 mRNA in the liver, along with elevated levels of intrahepatic neutrophils and macrophages/monocytes. The induced intrahepatic neutrophils and macrophages/monocytes were identified as the source of MMP-8. In conclusion, PRI 724 ameliorated HCV-induced liver fibrosis in mice. We hypothesize that inhibition of hepatic stellate cells activation and induction of fibrolytic cells expressing MMP-8 contribute to the anti-fibrotic effects of PRI-724. PRI-724 is a drug candidate which possesses anti-fibrotic effect. PMID- 28336943 TI - Altered glutamatergic tone reveals two distinct resting state networks at the cellular level in hippocampal sclerosis. AB - Hippocampal sclerosis (HS), the most common subset of drug-resistant epilepsy (DRE), is associated with large-scale network abnormalities, even under resting state. We studied the excitatory postsynaptic currents (EPSCs) recorded from pyramidal neurons in resected samples under resting conditions from the hippocampal and anterior temporal lobe (ATL) obtained from patients with HS (n = 14) undergoing resective surgery. We observed higher frequency and amplitude of spontaneous EPSCs in both the samples compared to non-seizure control samples. Application of tetrodotoxin (TTX) reduced the frequency of spontaneous EPSCs by 49.6 +/- 4.3% and 61.8 +/- 6.2% in the hippocampal and ATL samples, respectively. The magnitude of reduction caused by TTX with respect to non-seizure controls was significantly higher in the ATL samples than in the hippocampal samples. The magnitude of the change in the expression of the NR2A subunit of the NMDA receptors also varied in these two regions. Thus, the mechanism of hyperexcitabilty mediated by glutamatergic network reorganization in the hippocampal region is different from that in the ATL region of patients with HS, suggesting two independent resting-state networks at the cellular level. Taken together, these findings will improve the understanding of the broadly distributed resting-state networks in HS. PMID- 28336944 TI - Kaposi's sarcoma-associated herpesvirus ORF34 is essential for late gene expression and virus production. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. KSHV establishes a life-long infection in its host and alternates between a latent and lytic infection state. During lytic infection, lytic-related genes are expressed in a temporal manner and categorized as immediate early, early, and late gene transcripts. ORF34 is an early-late gene that interacts with several viral transcription-associated factors, however its physiological importance remains poorly understood. Here, we investigated the role of ORF34 during KSHV infection by generating ORF34-deficient KSHV, using a bacterial artificial chromosome system. Our results reveal that ORF34-deficient KSHV exhibited significantly attenuated late gene expression and viral production but did not affect viral DNA replication. ORF34 interacted with transcription factors ORF18, ORF24, ORF31, and ORF66, and a novel ORF34-interaction partner, ORF23. The C-terminal region of ORF34 was important for interaction with ORF24 and viral production. Our data support a model, in which ORF34 serves as a hub for recruiting a viral transcription complex to ORF24 to promote late viral gene expression. PMID- 28336945 TI - X-ray dark-field radiography facilitates the diagnosis of pulmonary fibrosis in a mouse model. AB - The aim of this study was to evaluate whether diagnosing pulmonary fibrosis with projection radiography can be improved by using X-ray dark-field radiograms. Pulmonary X-ray transmission and dark-field images of C57Bl/6N mice, either treated with bleomycin to induce pulmonary fibrosis or PBS to serve as controls, were acquired with a prototype grating-based small-animal scanner. Two blinded readers, both experienced radiologists and familiar with dark-field imaging, had to assess dark-field and transmission images for the absence or presence of fibrosis. Furthermore readers were asked to grade their stage of diagnostic confidence. Histological evaluation of the lungs served as the standard of reference in this study. Both readers showed a notably higher diagnostic confidence when analyzing the dark-field radiographs (p < 0.001). Diagnostic accuracy improved significantly when evaluating the lungs in dark-field images alone (p = 0.02) or in combination with transmission images (p = 0.01) compared to sole analysis of absorption images. Interreader agreement improved from good when assessing only transmission images to excellent when analyzing dark-field images alone or in combination with transmission images. Adding dark-field images to conventional transmission images in a murine model of pulmonary fibrosis leads to an improved diagnosis of this disease on chest radiographs. PMID- 28336947 TI - An ideal dielectric coat to avoid prosthesis RF-artefacts in Magnetic Resonance Imaging. AB - The number of people submitted to total hip or knee arthroplasty increased in the last years and it is likely to grow further. Hence, the importance of a proper investigation tool that allows to determine and recognize the potential presence of perioperative and/or postoperative diseases becomes clear. Although the Magnetic Resonance Imaging (MRI) technique demonstrated several advantages over the other common tomography tools, it suffers from the arise of image artefacts if it is performed in presence of metallic prostheses. In particular, the so called RF-artefacts are caused by the inhomogeneity in the radiofrequency magnetic field of MRI, due to the electric currents induced on the metal surface by the field itself. In this work, a near-zero permittivity dielectric coat is simulated to reduce those currents and, therefore, the RF-artefacts onset in the final image. Numerical results confirm that the dielectric coat strongly reduces the magnetic field inhomogeneity, suggesting a possible solution to a well-known problem in the MRI field. PMID- 28336946 TI - Real-time observational evidence of changing Asian dust morphology with the mixing of heavy anthropogenic pollution. AB - Natural mineral dust and heavy anthropogenic pollution and its complex interactions cause significant environmental problems in East Asia. Due to restrictions of observing technique, real-time morphological change in Asian dust particles owing to coating process of anthropogenic pollutants is still statistically unclear. Here, we first used a newly developed, single-particle polarization detector and quantitatively investigate the evolution of the polarization property of backscattering light reflected from dust particle as they were mixing with anthropogenic pollutants in North China. The decrease in observed depolarization ratio is mainly attributed to the decrease of aspect ratio of the dust particles as a result of continuous coating processes. Hygroscopic growth of Calcium nitrate (Ca(NO3)2) on the surface of the dust particles played a vital role, particularly when they are stagnant in the polluted region with high RH conditions. Reliable statistics highlight the significant importance of internally mixed, 'quasi-spherical' Asian dust particles, which markedly act as cloud condensation nuclei and exert regional climate change. PMID- 28336948 TI - Plasminogen Activator Inhibitor-1 Protects Mice Against Cardiac Fibrosis by Inhibiting Urokinase-type Plasminogen Activator-mediated Plasminogen Activation. AB - Plasminogen activator inhibitor-1 (PAI-1) is known to protect mice against cardiac fibrosis. It has been speculated that PAI-1 may regulate cardiac fibrosis by inactivating urokinase-type plasminogen activator (uPA) and ultimately plasmin (Pm) generation. However, the in vivo role of PAI-1 in inactivating uPA and limiting the generation of Pm during cardiac fibrosis remains to be established. The objective of this study was to determine if the cardioprotective effect of PAI-1 is mediated through its ability to directly regulate urokinase -mediated activation of plasminogen (Pg). An Angiotensin II (AngII)-aldosterone (Ald) infusion mouse model of hypertension was utilised in this study. Four weeks after AngII-Ald infusion, PAI-1-deficient (PAI-1-/-) mice developed severe cardiac fibrosis. However, a marked reduction in cardiac fibrosis was observed in PAI-1-/ /uPA-/- double knockout mice that was associated with reduced inflammation, lower expression levels of TGF-beta and proteases associated with tissue remodeling, and diminished Smad2 signaling. Moreover, total ablation of cardiac fibrosis was observed in PAI-1-/- mice that express inactive plasmin (Pm) but normal levels of zymogen Pg (PAI-1-/-/PgS743A/S743A). Our findings indicate that PAI-1 protects mice from hypertension-induced cardiac fibrosis by inhibiting the generation of active Pm. PMID- 28336949 TI - Induction of apoptosis and ganoderic acid biosynthesis by cAMP signaling in Ganoderma lucidum. AB - Apoptosis is an essential physiological process that controls many important biological functions. However, apoptosis signaling in relation to secondary metabolite biosynthesis in plants and fungi remains a mystery. The fungus Ganoderma lucidum is a popular herbal medicine worldwide, but the biosynthetic regulation of its active ingredients (ganoderic acids, GAs) is poorly understood. We investigated the role of 3',5'-cyclic adenosine monophosphate (cAMP) signaling in fungal apoptosis and GA biosynthesis in G. lucidum. Two phosphodiesterase inhibitors (caffeine and 3-isobutyl-1-methylxanthine, IBMX) and an adenylate cyclase activator (sodium fluoride, NaF) were used to increase intracellular cAMP levels. Fungal apoptosis was identified by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay and a condensed nuclear morphology. Our results showed that GA production and fungal apoptosis were induced when the mycelium was treated with NaF, caffeine, or cAMP/IBMX. Downregulation of squalene synthase and lanosterol synthase gene expression by cAMP was detected in the presence of these chemicals, which indicates that these two genes are not critical for GA induction. Transcriptome analysis indicated that mitochondria might play an important role in cAMP-induced apoptosis and GA biosynthesis. To the best of our knowledge, this is the first report to reveal that cAMP signaling induces apoptosis and secondary metabolite production in fungi. PMID- 28336952 TI - A DFT Study on the Electronic Structures and Conducting Properties of Rubrene and its Derivatives in Organic Field-Effect Transistors. AB - We systematically studied the electronic structures and conducting properties of rubrene and its derivatives reported recently, and disscussed the influences of electron-withdrawing groups and chemical oxidation on the reorganization energies, crystal packing, electronic couplings, and charge injection barrier of rubrene. Hirshfeld surface analysis and quantum-chemical calculations revealed that the introduction of CF3 groups into rubrene decreases the H...H repulsive interaction and increases intermolecular F...H/H...F attractive interactions, which resulted in the tight packing arrangement and the increase of the electronic couplings, and finally cause the higer intrinsic hole-mobility in bis(trifluoromethyl)-dimethyl-rubrene crystal (MUh = 19.2 cm2 V-1 s-1) than in rubrene crystal (MUh = 15.8 cm2 V-1 s-1). In comparison, chemical oxidation reduces charge-carrier mobility of rubrene crystal by 2~4 orders of magnitude and increased the hole and electron injection barrier, which partly explains the rubrene-based field-effect transistor performance degrades upon exposure to air. Furthermore, we also discussed the influence of structural parameters of carbon nanotube (CNT) electrode on charge injection process, which suggests that the regulation of CNT diameters and increasing in thickness is an effective strategy to optimize CNT work functions and improve n-type OFET performances based on these organic materials. PMID- 28336950 TI - Dual regulation of water retention and cell growth by a stress-associated protein (SAP) gene in Prunus. AB - We have identified a gene (PpSAP1) of Prunus persica coding for a stress associated protein (SAP) containing Zn-finger domains A20 and AN1. SAPs have been described as regulators of the abiotic stress response in plant species, emerging as potential candidates for improvement of stress tolerance in plants. PpSAP1 was highly expressed in leaves and dormant buds, being down-regulated before bud dormancy release. PpSAP1 expression was moderately induced by water stresses and heat in buds. In addition, it was found that PpSAP1 strongly interacts with polyubiquitin proteins in the yeast two-hybrid system. The overexpression of PpSAP1 in transgenic plum plants led to alterations in leaf shape and an increase of water retention under drought stress. Moreover, we established that leaf morphological alterations were concomitant with a reduced cell size and down regulation of genes involved in cell growth, such as GROWTH-REGULATING FACTOR (GRF)1-like, TONOPLAST INTRINSIC PROTEIN (TIP)-like, and TARGET OF RAPAMYCIN (TOR)-like. Especially, the inverse expression pattern of PpSAP1 and TOR-like in transgenic plum and peach buds suggests a role of PpSAP1 in cell expansion through the regulation of TOR pathway. PMID- 28336951 TI - Determination of leaf carbon isotope discrimination in C4 plants under variable N and water supply. AB - Understanding the mechanisms underlying variations in carbon isotope discrimination (Delta) in C4 plants is critical for predicting the C3/C4 ratio in C3/C4 mixed grassland. The value of Delta is determined by bundle sheath leakiness (F) and the ratio of intercellular to ambient CO2 concentration (C i /C a ). Leaf nitrogen concentration (N leaf ) is considered a driver of Delta in C4 plants. However, little is known about how N leaf affects F and C i /C a , and subsequently Delta. Here leaf carbon isotope composition, N leaf , F, and leaf gas exchange were measured in Cleistogenes squarrosa, a dominant C4 species in the Inner Mongolia grassland. Delta remained relatively stable under variable N and water supply. Higher N supply and lower water supply increased N leaf , stimulated photosynthesis and further decreased C i /C a . High N supply increased F, which responded weakly to water supply. N leaf exerted similar effects on C i /C a and on F in the field and pot experiments. Pooling all the data, N leaf explained 73% of the variation in C i /C a . Overall, both F and C i /C a determined Delta; however, the contribution of F was stronger. N leaf influenced Delta primarily though C i /C a , rather than F. F should be considered in estimating Delta of C4 endmember. PMID- 28336954 TI - Special issue on therapeutic antibodies and biopharmaceuticals. PMID- 28336953 TI - Palmitoylethanolamide induces microglia changes associated with increased migration and phagocytic activity: involvement of the CB2 receptor. AB - The endogenous fatty acid amide palmitoylethanolamide (PEA) has been shown to exert anti-inflammatory actions mainly through inhibition of the release of pro inflammatory molecules from mast cells, monocytes and macrophages. Indirect activation of the endocannabinoid (eCB) system is among the several mechanisms of action that have been proposed to underlie the different effects of PEA in vivo. In this study, we used cultured rat microglia and human macrophages to evaluate whether PEA affects eCB signaling. PEA was found to increase CB2 mRNA and protein expression through peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activation. This novel gene regulation mechanism was demonstrated through: (i) pharmacological PPAR-alpha manipulation, (ii) PPAR-alpha mRNA silencing, (iii) chromatin immunoprecipitation. Moreover, exposure to PEA induced morphological changes associated with a reactive microglial phenotype, including increased phagocytosis and migratory activity. Our findings suggest indirect regulation of microglial CB2R expression as a new possible mechanism underlying the effects of PEA. PEA can be explored as a useful tool for preventing/treating the symptoms associated with neuroinflammation in CNS disorders. PMID- 28336955 TI - Progress of antibody-based inhibitors of the HGF-cMET axis in cancer therapy. AB - Dysregulated receptor tyrosine kinase signaling in human cancer cells leads to tumor progression, invasion and metastasis. The receptor tyrosine kinase cMET is frequently overexpressed in cancer tissue, and activation of cMET signaling is related to drug resistance and the processes of carcinogenesis, invasion and metastasis. For that reason, cMET and its ligand, hepatocyte growth factor (HGF), are considered prime targets for the development of anticancer drugs. At least eight anti-cMET and four anti-HGF antibodies have been tested or are being tested in clinical trials. However, to date none of these HGF/cMET inhibitors have shown significant efficacy in clinical trials. Furthermore, no receptor tyrosine kinase inhibitors primarily targeting cMET have been approved. Given that neutralization of HGF or cMET does not cause significant adverse effects, inhibition of the HGF/cMET signaling pathway appears to be safe. In this review, we summarized the completed and ongoing clinical trials testing antibody- or protein-based anticancer drugs targeting cMET and HGF. PMID- 28336956 TI - Preclinical development of a humanized neutralizing antibody targeting HGF. AB - Hepatocyte growth factor (HGF) and its receptor, cMET, play critical roles in cell proliferation, angiogenesis and invasion in a wide variety of cancers. We therefore examined the anti-tumor activity of the humanized monoclonal anti-HGF antibody, YYB-101, in nude mice bearing human glioblastoma xenografts as a single agent or in combination with temozolomide. HGF neutralization, The extracellular signal-related kinases 1 and 2 (ERK1/2) phosphorylation, and HGF-induced scattering were assessed in HGF-expressing cell lines treated with YYB-101. To support clinical development, we also evaluated the preclinical pharmacokinetics and toxicokinetics in cynomolgus monkeys, and human and cynomolgus monkey tissue was stained with YYB-101 to test tissue cross-reactivity. We found that YYB-101 inhibited cMET activation in vitro and suppressed tumor growth in the orthotopic mouse model of human glioblastoma. Combination treatment with YYB-101 and temozolomide decreased tumor growth and increased overall survival compared with the effects of either agent alone. Five cancer-related genes (TMEM119, FST, RSPO3, ROS1 and NBL1) were overexpressed in YYB-101-treated mice that showed tumor regrowth. In the tissue cross-reactivity assay, critical cross-reactivity was not observed. The terminal elimination half-life was 21.7 days. Taken together, the in vitro and in vivo data demonstrated the anti-tumor efficacy of YYB-101, which appeared to be mediated by blocking the HGF/cMET interaction. The preclinical pharmacokinetics, toxicokinetics and tissue cross-reactivity data support the clinical development of YYB-101 for advanced cancer. PMID- 28336957 TI - Next-generation sequencing enables the discovery of more diverse positive clones from a phage-displayed antibody library. AB - Phage display technology provides a powerful tool to screen a library for a binding molecule via an enrichment process. It has been adopted as a critical technology in the development of therapeutic antibodies. However, a major drawback of phage display technology is that because the degree of the enrichment cannot be controlled during the bio-panning process, it frequently results in a limited number of clones. In this study, we applied next-generation sequencing (NGS) to screen clones from a library and determine whether a greater number of clones can be identified using NGS than using conventional methods. Three chicken immune single-chain variable fragment (scFv) libraries were subjected to bio panning on prostate-specific antigen (PSA). Phagemid DNA prepared from the original libraries as well as from the Escherichia coli pool after each round of bio-panning was analyzed using NGS, and the heavy chain complementarity determining region 3 (HCDR3) sequences of the scFv clones were determined. Subsequently, through two-step linker PCR and cloning, the entire scFv gene was retrieved and analyzed for its reactivity to PSA in a phage enzyme immunoassay. After four rounds of bio-panning, the conventional colony screening method was performed for comparison. The scFv clones retrieved from NGS analysis included all clones identified by the conventional colony screening method as well as many additional clones. The enrichment of the HCDR3 sequence throughout the bio panning process was a positive predictive factor for the selection of PSA reactive scFv clones. PMID- 28336959 TI - Affibody molecules as engineered protein drugs. AB - Affibody molecules can be used as tools for molecular recognition in diagnostic and therapeutic applications. There are several preclinical studies reported on diagnostic and therapeutic use of this molecular class of alternative scaffolds, and early clinical evidence is now beginning to accumulate that suggests the Affibody molecules to be efficacious and safe in man. The small size and ease of engineering make Affibody molecules suitable for use in multispecific constructs where AffiMabs is one such that offers the option to potentiate antibodies for use in complex disease. PMID- 28336961 TI - Voltage-induced Interface Reconstruction and Electrical Instability of the Ferromagnet-Semiconductor Device. AB - Using x-ray magnetic spectroscopy with in-situ electrical characterizations, we investigated the effects of external voltage on the spin-electronic and transport properties at the interface of a Fe/ZnO device. Layer-, element-, and spin resolved information of the device was obtained by cross-tuning of the x-ray mode and photon energy, when voltage was applied. At the early stage of the operation, the device exhibited a low-resistance state featuring robust Fe-O bonds. However, the Fe-O bonds were broken with increasing voltage. Breaking of the Fe-O bonds caused the formation of oxygen vacancies and resulted in a high-resistance state. Such interface reconstruction was coupled to a charge-transfer effect via Fe-O hybridization, which suppressed/enhanced the magnetization/coercivity of Fe electronically. Nevertheless, the interface became stabilized with the metallic phase if the device was continuously polarized. During this stage, the spin polarization of Fe was enhanced whereas the coercivity was lowered by voltage, but changes of both characteristics were reversible. This stage is desirable for spintronic device applications, owing to a different voltage-induced electronic transition compared to the first stage. The study enabled a straightforward detection of the spin-electronic state at the ferromagnet-semiconductor interface in relation to the transport and reversal properties during operation process of the device. PMID- 28336962 TI - Optomechanically induced transparency of x-rays via optical control. AB - The search for new control methods over light-matter interactions is one of the engines that advances fundamental physics and applied science alike. A specific class of light-matter interaction interfaces are setups coupling photons of distinct frequencies via matter. Such devices, nontrivial in design, could be endowed with multifunctional tasking. Here we envisage for the first time an optomechanical system that bridges optical and robust, high-frequency x-ray photons, which are otherwise notoriously difficult to control. The x-ray-optical system comprises of an optomechanical cavity and a movable microlever interacting with an optical laser and with x-rays via resonant nuclear scattering. We show that optomechanically induced transparency of a broad range of photons (10 eV-100 keV) is achievable in this setup, allowing to tune nuclear x-ray absorption spectra via optomechanical control. This paves ways for metrology applications, e.g., the detection of the 229Thorium clock transition, and an unprecedentedly precise control of x-rays using optical photons. PMID- 28336958 TI - From rabbit antibody repertoires to rabbit monoclonal antibodies. AB - In this review, we explain why and how rabbit monoclonal antibodies have become outstanding reagents for laboratory research and increasingly for diagnostic and therapeutic applications. Starting with the unique ontogeny of rabbit B cells that affords highly distinctive antibody repertoires rich in in vivo pruned binders of high diversity, affinity and specificity, we describe the generation of rabbit monoclonal antibodies by hybridoma technology, phage display and alternative methods, along with an account of successful humanization strategies. PMID- 28336960 TI - Co-expression of BirA with biotin bait achieves in vivo biotinylation of overexpressed stable N-glycosylated sRAGE in transgenic silkworms. AB - Here, we demonstrated the expression of the N-glycosylated extracellular ligand binding domain of receptor for advanced glycation end products (sRAGE) in middle silk glands (MSGs) of transgenic silkworms using the GAL4/UAS system. Over 1 mg of sRAGE was obtained from one transgenic silkworm. sRAGE purified from the silkworm exhibited good stability and maintained specific ligand-binding ability. In addition, N-glycan analysis of sRAGE revealed that N-glucan completely lacked potentially allergenic fucose. Moreover, co-expression of biotin ligase (BirA) with C-terminal BioEase-tagged sRAGE in MSGs resulted in efficient biotinylation of sRAGE after addition of biotin bait. C-terminal biotinylated sRAGE could be immobilized onto a solid surface in one direction through binding to streptavidin without any loss of ability. The dissociation constant of sRAGE with fructose BSA, a typical RAGE ligand, was 7.25 * 10-7 M, consistent with that on the mammalian cell surface. Thus, we developed a novel, innovative silkworm expression system for efficient expression of recombinant sRAGE, which could serve as a basis for the elucidation of RAGE-ligand interactions and facilitate the search for new ligands and inhibitors. PMID- 28336963 TI - Radiological and Clinical Features associated with Epidermal Growth Factor Receptor Mutation Status of Exon 19 and 21 in Lung Adenocarcinoma. AB - The exon 19 and 21 in Epidermal Growth Factor Receptor (EGFR) mutation are the most common subtype of lung adenocarcinoma, and the strongest predictive biomarker for progression-free survival and tumor response. Although some studies have shown differences in radiological features between cases with and without EFGR mutations, they lacked necessary stratification. This article is to evaluate the association of CT features between the wild type and the subtype (exon 19 and 21) of EGFR mutations in patients with lung adenocarcinoma. Of the 721 finally included patients, 132 were positive for EGFR mutation in exon 19, 140 were positive for EGFR mutation in exon 21, and 449 were EGFR wild type. EGFR mutation in exon 19 was associated with a small-maximum diameter (28.51 +/- 14.07) (p < 0.0001); sex (p < 0.0001); pleural retraction (p = 0.0034); and the absence of fibrosis (p < 0.0001), while spiculated margins (p = 0.0095), subsolid density (p < 0.0001) and no smoking (p < 0.0001) were associated with EGFR mutation in exon 21. Receiver Operating Characteristic (ROC) curves suggested that the maximum Area Under the Curve (AUC) was related to the female gender (AUC = 0.636) and the absence of smoking (AUC = 0.681). This study demonstrated the radiological and clinical features could be used to prognosticate EGFR mutation subtypes in exon 19 and 21. PMID- 28336964 TI - Na-rich layered Na2Ti1-xCrxO3-x/2 (x = 0, 0.06): Na-ion battery cathode materials with high capacity and long cycle life. AB - Rechargeable lithium batteries have been well-known and indispensable for portable electronic devices, and have the potential to be used in electric vehicles and smart grids. However, the growing concerns about the availability of lithium resources for large-scale applications have revived interest in sodium ion batteries. Of many obstacles to commercialization of Na-ion batteries, achieving simultaneously a large reversible capacity and good cycling capability of electrode materials remains a major challenge. Here, we report a new cathode material, Na-rich layered oxide Na2Ti0.94Cr0.06O2.97, that delivers high reversible capacity of 336 mAh g-1 at current density of 18.9 mA g-1 along with promising cycling capability of 74% capacity retention over 1000 cycles at current of 378 mA g-1. The high capacity is associated to the redox reaction of oxygen, which is confirmed here by a combined experimental and theoretical study. The present work therefore shows that materials beyond mainstream layered oxides and polyanion compounds should be considered as candidate high-performance cathodes for Na-ion batteries. PMID- 28336965 TI - Exploring Approaches for Detecting Protein Functional Similarity within an Orthology-based Framework. AB - Protein functional similarity based on gene ontology (GO) annotations serves as a powerful tool when comparing proteins on a functional level in applications such as protein-protein interaction prediction, gene prioritization, and disease gene discovery. Functional similarity (FS) is usually quantified by combining the GO hierarchy with an annotation corpus that links genes and gene products to GO terms. One large group of algorithms involves calculation of GO term semantic similarity (SS) between all the terms annotating the two proteins, followed by a second step, described as "mixing strategy", which involves combining the SS values to yield the final FS value. Due to the variability of protein annotation caused e.g. by annotation bias, this value cannot be reliably compared on an absolute scale. We therefore introduce a similarity z-score that takes into account the FS background distribution of each protein. For a selection of popular SS measures and mixing strategies we demonstrate moderate accuracy improvement when using z-scores in a benchmark that aims to separate orthologous cases from random gene pairs and discuss in this context the impact of annotation corpus choice. The approach has been implemented in Frela, a fast high-throughput public web server for protein FS calculation and interpretation. PMID- 28336966 TI - An Integrated H-G Scheme Identifying Areas for Soil Remediation and Primary Heavy Metal Contributors: A Risk Perspective. AB - Traditional sampling for soil pollution evaluation is cost intensive and has limited representativeness. Therefore, developing methods that can accurately and rapidly identify at-risk areas and the contributing pollutants is imperative for soil remediation. In this study, we propose an innovative integrated H-G scheme combining human health risk assessment and geographical detector methods that was based on geographical information system technology and validated its feasibility in a renewable resource industrial park in mainland China. With a discrete site investigation of cadmium (Cd), arsenic (As), copper (Cu), mercury (Hg) and zinc (Zn) concentrations, the continuous surfaces of carcinogenic risk and non carcinogenic risk caused by these heavy metals were estimated and mapped. Source apportionment analysis using geographical detector methods further revealed that these risks were primarily attributed to As, according to the power of the determinant and its associated synergic actions with other heavy metals. Concentrations of critical As and Cd, and the associated exposed CRs are closed to the safe thresholds after remediating the risk areas identified by the integrated H-G scheme. Therefore, the integrated H-G scheme provides an effective approach to support decision-making for regional contaminated soil remediation at fine spatial resolution with limited sampling data over a large geographical extent. PMID- 28336967 TI - The gene expression profiles in response to 102 traditional Chinese medicine (TCM) components: a general template for research on TCMs. AB - Traditional Chinese medicines (TCMs) have important therapeutic value in long term clinical practice. However, because TCMs contain diverse ingredients and have complex effects on the human body, the molecular mechanisms of TCMs are poorly understood. In this work, we determined the gene expression profiles of cells in response to TCM components to investigate TCM activities at the molecular and cellular levels. MCF7 cells were separately treated with 102 different molecules from TCMs, and their gene expression profiles were compared with the Connectivity Map (CMAP). To demonstrate the reliability and utility of our approach, we used nitidine chloride (NC) from the root of Zanthoxylum nitidum, a topoisomerase I/II inhibitor and alpha-adrenoreceptor antagonist, as an example to study the molecular function of TCMs using CMAP data as references. We successfully applied this approach to the four ingredients in Danshen and analyzed the synergistic mechanism of TCM components. The results demonstrate that our newly generated TCM data and related methods are valuable in the analysis and discovery of the molecular actions of TCM components. This is the first work to establish gene expression profiles for the study of TCM components and serves as a template for general TCM research. PMID- 28336968 TI - New cofactors and inhibitors for a DNA-cleaving DNAzyme: superoxide anion and hydrogen peroxide mediated an oxidative cleavage process. AB - Herein, we investigated the effects of new cofactors and inhibitors on an oxidative cleavage of DNA catalysis, known as a pistol-like DNAzyme (PLDz), to discuss its catalytic mechanism. PLDz performed its catalytic activity in the presence of ascorbic acid (AA), in which Cu2+ promoted, whereas Fe2+ significantly inhibited the catalytic function. Since Fe2+/AA-generated hydroxyl radicals are efficient on DNA damage, implying that oxidative cleavage of PLDz had no relation with hydroxyl radical. Subsequently, we used Fe2+/H2O2 and Cu2+/H2O2 to identify the role of hydroxyl radicals in PLDz catalysis. Data showed that PLDz lost its activity with Fe2+/H2O2, but exhibited significant cleavage with Cu2+/H2O2. Because Fe2+/H2O2 and Cu2+/H2O2 are popular reagents to generate hydroxyl radicals and the latter also produces superoxide anions, we excluded the possibility that hydroxyl radical participated in oxidative cleavage and confirmed that superoxide anion was involved in PLDz catalysis. Moreover, pyrogallol, riboflavin and hypoxanthine/xanthine oxidase with superoxide anion and hydrogen peroxide generation also induced self-cleavage of PLDz, where catalase inhibited but superoxide dismutase promoted the catalysis, suggesting that hydrogen peroxide played an essential role in PLDz catalysis. Therefore, we proposed a catalytic mechanism of PLDz in which superoxide anion and hydrogen peroxide mediated an oxidative cleavage process. PMID- 28336970 TI - A Steep-Slope Transistor Combining Phase-Change and Band-to-Band-Tunneling to Achieve a sub-Unity Body Factor. AB - Steep-slope transistors allow to scale down the supply voltage and the energy per computed bit of information as compared to conventional field-effect transistors (FETs), due to their sub-60 mV/decade subthreshold swing at room temperature. Currently pursued approaches to achieve such a subthermionic subthreshold swing consist in alternative carrier injection mechanisms, like quantum mechanical band to-band tunneling (BTBT) in Tunnel FETs or abrupt phase-change in metal-insulator transition (MIT) devices. The strengths of the BTBT and MIT have been combined in a hybrid device architecture called phase-change tunnel FET (PC-TFET), in which the abrupt MIT in vanadium dioxide (VO2) lowers the subthreshold swing of strained-silicon nanowire TFETs. In this work, we demonstrate that the principle underlying the low swing in the PC-TFET relates to a sub-unity body factor achieved by an internal differential gate voltage amplification. We study the effect of temperature on the switching ratio and the swing of the PC-TFET, reporting values as low as 4.0 mV/decade at 25 degrees C, 7.8 mV/decade at 45 degrees C. We discuss how the unique characteristics of the PC-TFET open new perspectives, beyond FETs and other steep-slope transistors, for low power electronics, analog circuits and neuromorphic computing. PMID- 28336969 TI - Complete genome sequence and comparative genomics of the probiotic yeast Saccharomyces boulardii. AB - The probiotic yeast, Saccharomyces boulardii (Sb) is known to be effective against many gastrointestinal disorders and antibiotic-associated diarrhea. To understand molecular basis of probiotic-properties ascribed to Sb we determined the complete genomes of two strains of Sb i.e. Biocodex and unique28 and the draft genomes for three other Sb strains that are marketed as probiotics in India. We compared these genomes with 145 strains of S. cerevisiae (Sc) to understand genome-level similarities and differences between these yeasts. A distinctive feature of Sb from other Sc is absence of Ty elements Ty1, Ty3, Ty4 and associated LTR. However, we could identify complete Ty2 and Ty5 elements in Sb. The genes for hexose transporters HXT11 and HXT9, and asparagine-utilization are absent in all Sb strains. We find differences in repeat periods and copy numbers of repeats in flocculin genes that are likely related to the differential adhesion of Sb as compared to Sc. Core-proteome based taxonomy places Sb strains along with wine strains of Sc. We find the introgression of five genes from Z. bailii into the chromosome IV of Sb and wine strains of Sc. Intriguingly, genes involved in conferring known probiotic properties to Sb are conserved in most Sc strains. PMID- 28336971 TI - Targeting to the non-genomic activity of retinoic acid receptor-gamma by acacetin in hepatocellular carcinoma. AB - We recently demonstrated that retinoic acid receptor-gamma (RARgamma) is overexpressed and acts as a tumor promoter in hepatocellular carcinoma (HCC). The oncogenic activity of RARgamma is mainly attributed to its physiological interaction with p85alpha regulatory subunit of PI3K leading to constitutive activation of AKT. Here we report RARgamma as a negative regulator of p53 signaling and thus extend the oncogenic potential of RARgamma to a new role in controlling the balance between AKT and p53. A natural flavonoid acacetin is then identified to be capable of modulating RARgamma-dependent AKT-p53 network. It specifically binds to RARgamma and inhibits all-trans retinoic acid (atRA) stimulation of RARgamma transactivation. However, the anticancer action of acacetin is independent on its modulation of RARgamma-driven transcriptional activity. Acacetin induces cancer cell apoptosis through antagonizing the non genomic effect of RARgamma on AKT and p53. When bound to RARgamma, acacetin prevents RARgamma from its activation of AKT followed by recovery of the normal p53 signaling. Given the implication of AKT-p53 dysregulation in most HCC, targeting the non-genomic signaling of RARgamma that switches AKT-p53 from a pro survival to a pro-apoptotic program in cancer cells should be a promising strategy for developing novel anti-HCC drugs. PMID- 28336972 TI - Microsatellite analysis for differentiating the origin of renal angiomyolipoma and involved regional lymph node. AB - Renal angiomyolipoma (AML) with the regional lymph node (LN) involved leads to a question of metastasis versus multicentric origin when their histology are similar. As the genomic instability is a common feature of cancer, we hypothesized that independently arising neoplasms in an individual patient would exhibit measurable genomic variation, facilitating the discrimination of tumor lineage and relatedness. Our study enrolled 12 patients who were diagnosed with nodal-involved renal AML at West China Hospital. Genomic DNA from kidney and lymph node lesion from individuals was analyzed through PCR-based analysis which using six microsatellite markers to identify discordant allelic variation. The results showed all 12 patients underwent surgical treatment and none suffered local recurrence or distant metastasis during the follow-up. Ten patients of the included cases showed a consistent trend that all corresponding to six microsatellite markers were detected in DNA from renal AMLs but were reduced or not observed in DNA from the paired LN. With this technique, a possible lineage relationship cannot be excluded between renal AMLs and LN. Thus when enlarged LN were found in images, active surveillance should be taken into consider; if enlarged LN were found intraoperatively, LN resection might be necessary to demonstrate their pathological nature. PMID- 28336973 TI - Microbial community composition is related to soil biological and chemical properties and bacterial wilt outbreak. AB - Soil microbes play important roles in plant growth and health. Little is known about the differences of soil microbes between healthy and bacterial wilt infected soils with Ralstonia solanacearum. By Illumina-MiSeq sequencing of 16S rRNA and 18S rRNA gene amplicons, we found the soil microbial composition and diversity were distinct between healthy and bacterial wilt infected soils. Soil microbial community varied at different plant growth stages due to changes of root exudates composition and soil pH. Healthy soils exhibited higher microbial diversity than the bacterial wilt infected soils. More abundant beneficial microbes including Bacillus, Agromyces, Micromonospora, Pseudonocardia, Acremonium, Lysobacter, Mesorhizobium, Microvirga, Bradyrhizobium, Acremonium and Chaetomium were found in the healthy soils rather than the bacterial wilt infected soils. Compared to bacterial wilt infected soils, the activities of catalase, invertase and urease, as well as soil pH, available phosphorous and potassium content, were all significantly increased in the healthy soils. In a conclusion, the higher abundance of beneficial microbes are positively related the higher soil quality, including better plant growth, lower disease incidence, and higher nutrient contents, soil enzyme activities and soil pH. PMID- 28336975 TI - Colette Bridgman: 'The two prototype practices in Wales have been a sensational success'. PMID- 28336978 TI - Child dental health: Forty year overview. PMID- 28336979 TI - A dental student's life: 'This is definitely the right profession for me!' PMID- 28336976 TI - The Hall Technique 10 years on: Questions and answers. AB - It is ten years since the first paper on the Hall Technique was published in the British Dental Journal and almost 20 years since the technique first came to notice. Dr Norna Hall a (now retired) general dental practitioner from the north of Scotland had, for many years, been managing carious primary molar teeth by cementing preformed metal crowns over them, with no local anaesthesia, tooth preparation or carious tissue removal. This first report, a retrospective analysis of Dr Hall's treatments, caused controversy. How could simply sealing a carious lesion, with all the associated bacteria and decayed tissues, possibly be clinically successful? Since then, growing understanding that caries is essentially a biofilm driven disease rather than an infectious disease, explains why the Hall Technique, and other 'sealing in' carious lesion techniques, are successful. The intervening ten years has seen robust evidence from several randomised control trials that are either completed or underway. These have found the Hall Technique superior to comparator treatments, with success rates (no pain or infection) of 99% (UK study) and 100% (Germany) at one year, 98% and 93% over two years (UK and Germany) and 97% over five years (UK). The Hall Technique is now regarded as one of several biological management options for carious lesions in primary molars. This paper covers commonly asked questions about the Hall Technique and speculates on what lies ahead. PMID- 28336974 TI - PET Radiomics in NSCLC: state of the art and a proposal for harmonization of methodology. AB - Imaging with positron emission tomography (PET)/computed tomography (CT) is crucial in the management of cancer because of its value in tumor staging, response assessment, restaging, prognosis and treatment responsiveness prediction. In the last years, interest has grown in texture analysis which provides an "in-vivo" lesion characterization, and predictive information in several malignances including NSCLC; however several drawbacks and limitations affect these studies, especially because of lack of standardization in features calculation, definitions and methodology reporting. The present paper provides a comprehensive review of literature describing the state-of-the-art of FDG-PET/CT texture analysis in NSCLC, suggesting a proposal for harmonization of methodology. PMID- 28336982 TI - Taxes on sugar-sweetened beverages (Editorial) Effects of taxing sugar-sweetened beverages on caries and treatment costs. AB - 'The oral health community needs to band with our public health colleagues to support SSB (sugar-sweetened beverages) taxation to improve health.' PMID- 28336983 TI - Dental research: Trainee collaborations. PMID- 28336985 TI - The Hall Technique 10 years on: its effect and influence. AB - Dental caries in early childhood can have a very significant effect not only on the oral health of young children but on their quality of life and that of their families. Added to this are the long-term infective risks to the host of untreated caries in primary teeth but also the risk of damage to successor permanent teeth. Traditional restoration of damaged primary teeth has been shown to have only moderate outcomes depending on the techniques and materials used and the ability of children to cooperate because of age or other factors. The Hall technique has outperformed other techniques in randomised clinical trials. In this Opinion Article I will take a look back at the Innes et al. paper, first published in this Journal in 2006, that introduced the Hall Technique and the subsequent scientific literature which provided us with high quality scientific evidence of the efficacy of the technique. I will evaluate how this new technique has affected the management of early childhood caries and hence its influence on wider oral and general health. PMID- 28336988 TI - Restorative dentistry: Occlusal hypervigilance. PMID- 28336989 TI - Meeting and greeting in the clinical setting - are we doing what patients want? AB - Objective To determine how patients want to be greeted by clinicians on a first encounter in the clinical setting.Setting A UK dental teaching hospital in 2015/16.Materials and methods Data was collected prospectively via 450 patient questionnaires. The results were stratified by generational cohort and compared to assess if there was an association between patient preferences and the generational theory.Results Patients preferred to be greeted informally by their first name and didn't mind how the clinician introduced themselves or preferred them to use their first name also. Patients showed a preference to shake hands with their clinician, particularly in older generational cohorts. The majority of patients believed that it was helpful to know the training grade of the clinician providing treatment but didn't understand what the different grades meant. Patients believed that explaining the different training grades and using colour coded uniforms would be useful.Conclusions Consideration should be given to addressing patients informally by their first name and shaking hands at a first encounter. Clinicians should routinely disclose their training grade when introducing themselves and consideration should be given to providing patients with an explanation of the different training grades and using colour-coded uniforms to avoid confusion. PMID- 28336991 TI - Dental radiography: Vanishing implant. PMID- 28336997 TI - Oral health: Welcome progress. PMID- 28336995 TI - Conference report: Dental Speciality Trainee National Committee Conference. PMID- 28337000 TI - NiHiliStic Dentistry. PMID- 28337001 TI - Outreach teachers essential. PMID- 28336998 TI - Characteristics and treatment of invasive cervical resorption in vital teeth. A narrative review and a report of two cases. AB - Invasive cervical resorption (ICR) is a significant defect of the root surface where the hard dental tissues are undermined and become translucent due to the resorptive granulomatous tissue. It is mainly detected on radiographs. The radiographic appearance of ICR is asymmetrical radiolucency with irregular margins and an unchanged root canal. The purpose of this study is to present a comprehensive review together with the characteristics and the treatment of ICR through two cases which were followed-up for 36 months. In both cases the teeth were vital and the management consisted of raising a flap, granulomatous tissue removal, thorough debridement, restoration of the resorptive defect by placing a suitable filling material and follow-up examinations. Our results indicate that the specific treatment protocol has very positive outcomes. After 36 months pulpal vitality tests revealed a healthy pulp, and clinical and radiographic examination confirmed a stable periodontal condition. PMID- 28337003 TI - Shade of resin-based luting agents and final color of porcelain veneers. AB - All that is required is three shades of luting cement. PMID- 28337002 TI - A case series of trigeminal nerve injuries caused by periapical lesions of mandibular teeth. AB - Aims Periapical lesions have been implicated in mandibular trigeminal sensory neuropathy. This study aimed to report on a case series of consecutive patients presenting with mandibular division trigeminal nerve injuries (TNI) caused by periapical lesions. Common presenting characteristics and possible strategies for management were also investigated.Materials and methods A retrospective study of 22 patients with TNI caused by periapical lesions. Data were extracted from patient records and analysed using Microsoft Excel and SPSS. Factors associated with TNI resolution were assessed using Student's t-Tests and one-way Analysis of Variance (ANOVA), where P <0.05 indicated statistical significance.Results Twenty one patients had inferior alveolar nerve injuries (IANI) and one had a lingual nerve injury (LNI). The most commonly affected teeth were the first molars (11 patients; 50%). TNI symptoms included numbness, pain and/or paraesthesia. IANI resolved completely among five patients within a mean time of 4.7 months (range 1.5-12 months). Patients who showed complete resolution had the affected teeth extracted or primary endodontic treatment with antibiotics.Conclusions Patients with TNI caused by periapical lesions can suffer significantly from combined numbness, pain and paraesthesia. Resolution of these injuries may be maximised upon early diagnosis and treatment of the periapical lesion by tooth extraction or primary endodontic treatment. PMID- 28337004 TI - Adequacy and clarity of information on out-of-hours emergency dental services at Greater Manchester NHS dental practices: a cross-sectional study. AB - Objective To perform an evaluation of the information given to patients seeking emergency dental services during out-of-hours periods in Greater Manchester.Method This is a cross-sectional study. A list of all NHS dental practices in Greater Manchester was obtained from the NHS website. The investigators then accessed websites and voicemails of all practices to assess the information given to patients.Results The study shows that most practices have voicemail, which includes varying information on how to access emergency dental services during out-of-hours periods. Few of those included advice on the management of common dental emergencies. On the other hand, the majority of practices did not have websites. From those who included advice on how to access emergency dental services during out-of-hours periods on how to manage common dental emergencies on their websites, the information was easy to find.Conclusion The current information could be improved by ensuring the inclusion of essential details. Websites would help by including more details. In turn, this could help to reduce the number of inappropriate presentations to A&E departments. PMID- 28337007 TI - Cost-effectiveness of regular versus irregular supportive periodontal therapy or tooth removal. AB - Regular SPT (supportive periodontal treatment) retains teeth longer than irregular SPT but this regimen is not necessarily cheaper; extraction and replacement of teeth was usually the most expensive. PMID- 28337006 TI - Challenges in X-ray diagnosis: a review of referrals for specialist opinion. AB - The aim of this study was to determine the common reasons why a dental professional might request a second opinion on a dental radiograph from a Dental and Maxillofacial (DMF) radiologist. The study was a retrospective analysis of consecutive referrals for an opinion received by post or email by one DMF radiologist based in a UK dental hospital. The study period was from March 2009 to November 2015. Referrals came from a mixture of sources: mainly from general dental practitioners and specialists working in primary care, but with some referrals from hospital-based practitioners. An enormous range in diagnoses were made by the DMF radiologist, but the ten most frequent diagnostic categories contributed 57.5% of the total. Normal anatomy and anatomical variations in normal anatomy made up the largest category. Common dental disease was often diagnosed, but idiopathic osteosclerosis and maxillary antrum pathosis were both frequent reasons for seeking a second opinion. This service evaluation may assist in developing curricula for undergraduates and in designing continuing education courses. It also highlights a service that may avoid unnecessary referrals to hospital specialists but which currently is not commissioned by the NHS. PMID- 28337008 TI - BDA Museum acquires nineteenth century dental mirror. PMID- 28337011 TI - PTFE tape inspiration. PMID- 28337012 TI - Preparedness of undergraduate dental students in the United Kingdom: a national study. AB - Aims To evaluate the self-perceived preparedness of final year dental undergraduate students in the United Kingdom.Methods Dental undergraduate students in their final year were invited by email through the Dental Schools Council (DSC) to provide their responses to an online preparedness assessment scale. The data analysis was carried out using the RUMM2030 software which is specifically designed for Rasch analysis, a measurement model based on item response theory.Results Students felt adequately prepared to carry out simple clinical procedures and communication skills. However, low scores were reported on ability to assess orthodontic treatment needs, treatment planning, crowns, endodontics, research skills, referral for suspected oral cancer and raising concerns regarding inappropriate behaviour of colleagues.Conclusions The scale used in this study explored the self-perceived preparedness on a range of cognitive, clinical and behavioural attributes. The data show that the students felt prepared for the majority of the attributes expected from dentists. However, a number of areas were identified where students may benefit from further training and consolidation. PMID- 28337014 TI - Dental student tackles strict pull-up challenge for charity. PMID- 28337016 TI - Dental education: Oral biology teaching. PMID- 28337015 TI - Natural tooth preservation versus extraction and implant placement: patient preferences and analysis of the willingness to pay. AB - Objectives The aim of this study was to evaluate the patients' willingness to pay (WTP) values and preference for the treatment of a tooth with very poor prognosis, among two options: root canal therapy and crown positioning or tooth extraction, implant insertion and crown positioning.Methods A total of 103 patients were recruited from a private dental clinic and interviewed. A questionnaire measured individuals' preferences among the two alternative treatments for a tooth with poor prognosis and the maximum amount of money they would be willing to pay for their choice with a starting bid of [euro]2,000 in [euro]100 increment/decrement. Demographic data, patient choice, median values and WTP association with socio-demographic factors (Student ttest and one-way ANOVA) and correlation between variables (Pearson chi-square test) were revealed.Results Seventy-six percent of patients expressed a preference for root canal therapy, while the remaining 24% chose the dental surgery. A fair agreement between previous experience and current therapeutic choice was found (P = 0.0001). The WTP median value was [euro]2,000 and 46% of participants would pay an additional sum of money for the therapy (median: [euro]300). The preferred treatment was influenced by previous experience, but no association was found between WTP values and socio-demographic factors.Conclusion Patients tend to prefer a conservative approach for the treatment of a tooth with poor prognosis and are willing to pay an additional fee to receive their treatment choice. PMID- 28337017 TI - Multidisciplinary teamwork: Collaborating on diabetes. PMID- 28337018 TI - Rheumatoid Arthritis Fibroblast-like Synoviocyte Suppression Mediated by PTEN Involves Survivin Gene Silencing. AB - Survivin is a proto-oncogene biomarker known for its anti-apoptotic and cell cycle regulating properties induced by the activation of the phosphoinositide 3 kinase (PI3K)/Akt pathway. In the context of non-cancer pathology, such as rheumatoid arthritis (RA), survivin has emerged as a feature associated with severe joint damage and poor treatment response. Phosphatase and tensin homolog (PTEN) is a phosphatase antagonizing all classes of PI3K. The interplay between survivin oncogenic mechanisms and proliferation suppression networks in RA has remained largely elusive. This study investigated the effect of PTEN on survivin gene expression in rheumatiod arthritis fibroblast-like synoviocyte (RA-FLS). We showed for the first time that the suppression of RA-FLS was mediated by PTEN involving survivin silencing. Considering that survivin suppressants are currently available in clinical trials and clinical use, their effects in RA-FLS support a probably RA therapy to clinical practice. PMID- 28337019 TI - Apigenin-induced lysosomal degradation of beta-catenin in Wnt/beta-catenin signaling. AB - The bioflavonoid apigenin has been shown to possess cancer-preventive and anti cancer activities. In a drug screening, we found that apigenin can inhibit Wnt/beta-catenin signaling, a pathway that participates in pivotal biological functions, which dis-regulation results in various human diseases including cancers. However, the underlying mechanism of apigenin in this pathway and its link to anti-cancer activities remain largely unknown. Here we showed that apigenin reduced the amount of total, cytoplasmic, and nuclear beta-catenin, leading to the suppression in the beta-catenin/TCF-mediated transcriptional activity, the expression of Wnt target genes, and cell proliferation of Wnt stimulated P19 cells and Wnt-driven colorectal cancer cells. Western blotting and immunofluorescent staining analyses further revealed that apigenin could induce autophagy-mediated down-regulation of beta-catenin in treated cells. Treatment with autophagy inhibitors wortmannin and chloroquine compromised this effect, substantiating the involvement of autophagy-lysosomal system on the degradation of beta-catenin during Wnt signaling through inhibition of the AKT/mTOR signaling pathway. Our data not only pointed out a route for the inhibition of canonical Wnt signaling through the induction of autophagy-lysosomal degradation of key player beta-catenin, but also suggested that apigenin or other treatments which can initiate this degradation event are potentially used for the therapy of Wnt related diseases including cancers. PMID- 28337021 TI - Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance. AB - The rapid evolution and dissemination of antibiotic resistance among bacterial pathogens are outpacing the development of new antibiotics, but antivirulence agents provide an alternative. These agents can circumvent antibiotic resistance by disarming pathogens of virulence factors that facilitate human disease while leaving bacterial growth pathways - the target of traditional antibiotics - intact. Either as stand-alone medications or together with antibiotics, these drugs are intended to treat bacterial infections in a largely pathogen-specific manner. Notably, development of antivirulence drugs requires an in-depth understanding of the roles that diverse virulence factors have in disease processes. In this Review, we outline the theory behind antivirulence strategies and provide examples of bacterial features that can be targeted by antivirulence approaches. Furthermore, we discuss the recent successes and failures of this paradigm, and new developments that are in the pipeline. PMID- 28337020 TI - Delivery technologies for genome editing. AB - With the recent development of CRISPR technology, it is becoming increasingly easy to engineer the genome. Genome-editing systems based on CRISPR, as well as transcription activator-like effector nucleases (TALENs) and zinc-finger nucleases (ZFNs), are becoming valuable tools for biomedical research, drug discovery and development, and even gene therapy. However, for each of these systems to effectively enter cells of interest and perform their function, efficient and safe delivery technologies are needed. This Review discusses the principles of biomacromolecule delivery and gene editing, examines recent advances and challenges in non-viral and viral delivery methods, and highlights the status of related clinical trials. PMID- 28337022 TI - Model explanation of the seasonal variation of delta18O in cow (Bos taurus) hair under temperate conditions. AB - Oxygen isotopes (delta18O) in animal and human tissues are expected to be good recorders of geographical origin and migration histories. However, seasonal variation of delta18O may diminish the origin information in the tissues. Here the seasonality of delta18O in tail hair was investigated in a domestic suckler cow (Bos taurus) that underwent different ambient conditions, physiological states, keeping and feeding during five years. A detailed mechanistic model was built to explain this variation. The measured delta18O in hair significantly related (p < 0.05) to the delta18O in meteoric water in a regression analysis. Modelling suggested that this relation was only partly derived from the direct influence of feed moisture. Ambient conditions (temperature, moisture) also affected the animal itself (drinking water demand, transcutaneous vapor etc.). The clear temporal variation thus resulted from complex interactions with multiple influences. The twofold influence of ambient conditions via the feed and via the animal itself is advantageous for tracing the geographic origin because delta18O is then less influenced by variations in moisture uptake; however, it is unfavorable for indicating the production system, e.g. to distinguish between milk produced from fresh grass or from silage. The model is versatile but needs testing under a wider range of conditions. PMID- 28337024 TI - Angiotensin II promotes the anticoagulant effects of rivaroxaban via angiotensin type 2 receptor signaling in mice. AB - Rivaroxaban is an oral direct factor Xa inhibitor approved for the treatment of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation. Despite its efficacy, rivaroxaban therapy results in adverse effects and complications, such as bleeding. Angiotensin II (AngII) is implicated in many cardiovascular conditions, such as hypertension and heart failure. In this study, we investigate whether AngII influences anticoagulant effects of rivaroxaban by using an experimental mouse model with type 2 diabetes mellitus and advanced glycation end product (AGE)-exposed human umbilical vein endothelial cells (HUVECs). We found that AngII promoted the anticoagulant effects of rivaroxaban in KKAy mice. The combination of rivaroxaban and AngII enhanced in vivo tissue factor pathway inhibitor (TFPI) activity and induced TFPI expression and activity in AGE-exposed HUVECs. Angiotensin type 2 receptor (AT2R) and Mas antagonists attenuated the AngII-enhanced anticoagulant action of rivaroxaban in vivo, and abolished the increased endothelial TFPI expression and activity. However, angiotensin type 1 receptor (AT1R) antagonist exerted no effects. Additionally, combination of rivaroxaban and AngII induced aortic AT2R and Mas expression. Our data suggest that the anticoagulant effects of rivaroxaban are promoted by AngII via AT2R and Mas signaling. These findings are significant for the clinical administration of rivaroxaban. PMID- 28337023 TI - Reconstruction of Large-scale Defects with a Novel Hybrid Scaffold Made from Poly(L-lactic acid)/Nanohydroxyapatite/Alendronate-loaded Chitosan Microsphere: in vitro and in vivo Studies. AB - A chitosan-based microsphere delivery system has been fabricated for controlled release of alendronate (AL). The present study aimed to incorporate the chitosan/hydroxyapatite microspheres-loaded with AL (CH/nHA-AL) into poly(L lactic acid)/nanohydroxyapatite (PLLA/nHA) matrix to prepare a novel microspheres scaffold hybrid system (CM-ALs) for drug delivery and bone tissue engineering application. The characteristics of CM-ALs scaffolds containing 10% and 20% CH/nHA-AL were evaluated in vitro, including surface morphology and porosity, mechanical properties, drug release, degradation, and osteogenic differentiation. The in vivo bone repair for large segmental radius defects (1.5 cm) in a rabbit model was evaluated by radiography and histology. In vitro study showed more sustained drug release of CM-AL-containing scaffolds than these of CM/nHA-AL and PLLA/nHA/AL scaffolds, and the mechanical and degradation properties of CM-ALs (10%) scaffolds were comparable to that of PLLA/nHA control. The osteogenic differentiation of adipose-derived stem cells (ASCs) was significantly enhanced as indicated by increased alkaline phosphates (ALP) activity and calcium deposition. In vivo study further showed better performance of CM-ALs (10%) scaffolds with complete repair of large-sized bone defects within 8 weeks. A microspheres-scaffold-based release system containing AL-encapsulated chitosan microspheres was successfully fabricated in this study. Our results suggested the promising application of CM-ALs (10%) scaffolds for drug delivery and bone tissue engineering. PMID- 28337025 TI - Prevalence of obesity and comorbid eating disorder behaviors in South Australia from 1995 to 2015. AB - BACKGROUND: Obesity and eating disorders are often studied and treated separately. While the increases in obesity prevalence are well known, examination of its co-occurrence with eating disorders, a problem also of public health concern, is important because eating disorder behaviors are known to contribute to obesity onset and maintenance, and vice versa. METHODS: Data from large cross sectional representative statewide community samples of people in the years of 1995 (n=3001), 2005 (n=3047) and 2015 (n=3005) were analyzed. Data were collected using a structured, self-report interview that included demographic, health related, weight, height and eating disorder behavior questions. Eating behavior questions assessed binge eating, very strict dieting/fasting and purging, and were derived from the Eating Disorder Examination. Logistic regression analyses were conducted comparing prevalence of obesity, eating disorder behaviors and their co-occurrence. RESULTS: The prevalence of obesity or binge eating, or obesity with comorbid binge eating, each increased significantly from 1995 to 2005 (P<0.001 for each comparison) and continued to increase significantly from 2005 to 2015 (P<0.001 for each comparison). The highest increases from 1995 to 2015 were in the prevalence of obesity with comorbid binge eating (7.3-fold), or obesity with comorbid very strict dieting/fasting (11.5-fold). The prevalence of very strict dieting/fasting also increased significantly from 1995 to 2015 (3.8 fold). The prevalence of purging, or obesity with comorbid purging, did not change significantly from 1995 to 2015. CONCLUSION: There were statewide increases during the 20 years from 1995 to 2015 in the independent prevalence of obesity, binge eating and very strict dieting/fasting, and even higher increases in the prevalence of obesity with comorbid binge eating, and obesity with comorbid very strict dieting/fasting. These findings support the need for more integrated approaches to both the prevention and treatment of obesity and eating disorder behaviors, namely binge eating and very strict dieting/fasting. PMID- 28337026 TI - Increased GLP2R expression in gastric chief cells of patients with severe obesity regardless of diabetes status. AB - Glucagon-like peptide-2 (GLP-2) affects multiple facets of gastrointestinal physiology and have been used to treat patients with short bowel syndrome, but the distribution of its receptor (GLP2R) in human remains poorly understood. Gastric tissue samples of non-obese patients (NOB, n=10) and obese patients without diabetes (OB, n=31) and with diabetes (OWD, n=12) were used to evaluate GLP2R expression and distribution. Immunostaining with a validated antibody, as well as fluorescence in situ hybridization, showed that GLP2R expression was significantly increased in gastric chief cells in OB and OWD patients. PKCzeta expression was also significantly increased. This is the first evidence of increased GLP2R expression in chief cells of patients with severe obesity regardless of diabetes status. PMID- 28337027 TI - Obesity-induced decreases in muscle performance are not reversed by weight loss. AB - BACKGROUND/OBJECTIVES: Obesity can affect muscle phenotypes, and may thereby constrain movement and energy expenditure. Weight loss is a common and intuitive intervention for obesity, but it is not known whether the effects of obesity on muscle function are reversible by weight loss. Here we tested whether obesity induced changes in muscle metabolic and contractile phenotypes are reversible by weight loss. SUBJECTS/METHODS: We used zebrafish (Danio rerio) in a factorial design to compare energy metabolism, locomotor capacity, muscle isometric force and work-loop power output, and myosin heavy chain (MHC) composition between lean fish, diet-induced obese fish, and fish that were obese and then returned to lean body mass following diet restriction. RESULTS: Obesity increased resting metabolic rates (P<0.001) and decreased maximal metabolic rates (P=0.030), but these changes were reversible by weight loss, and were not associated with changes in muscle citrate synthase activity. In contrast, obesity-induced decreases in locomotor performance (P=0.0034), and isolated muscle isometric stress (P=0.01), work-loop power output (P<0.001) and relaxation rates (P=0.012) were not reversed by weight loss. Similarly, obesity-induced decreases in concentrations of fast and slow MHCs, and a shift toward fast MHCs were not reversed by weight loss. CONCLUSION: Obesity-induced changes in locomotor performance and muscle contractile function were not reversible by weight loss. These results show that weight loss alone may not be a sufficient intervention. PMID- 28337028 TI - Modifiable risk factors of maternal postpartum weight retention: an analysis of their combined impact and potential opportunities for prevention. AB - BACKGROUND/OBJECTIVES: Pregnancy triggers a physiological change in weight status. Postpartum weight retention in the childbearing years can substantially alter a woman's weight gain trajectory, with several potential contributing factors identified. Most research has relied on women's recall of pre-pregnancy weight during pregnancy or later, and not considered risk factors in combination. Using measured pre-pregnancy weight, this study aimed to examine the associations of maternal postpartum weight retention with parity, pre-pregnancy BMI, excessive gestational weight gain (GWG), maternal serum vitamin D concentration and dietary Glycaemic Index in early and late pregnancy, and breastfeeding duration, including analysis of the combined impact of potentially modifiable risk factors. SUBJECTS/METHODS: Prospective cohort study of 12 583 non-pregnant women aged 20 34 years in Southampton (UK) who were assessed prior to pregnancy, with those who subsequently became pregnant followed up in early and late gestation, and after delivery (n=2559 in the final sample). Linear regression models examined potential predictors of weight retention in adjusted individual and multivariate analyses, and as a risk factor score. RESULTS: Compared with pre-pregnancy weight, 73% of women retained some weight at 6 months postpartum (mean (s.d.): 3.5 (6.2) kg). In the adjusted multivariate model, women who were primiparous, had a lower pre-pregnancy BMI, excessive GWG, a lower early pregnancy vitamin D concentration and breastfed for <6 months had greater weight retention 6 months postpartum (P<0.05 for all variables). For each additional modifiable risk factor (excessive GWG, low vitamin D concentration in early pregnancy and short breastfeeding duration; scale 0-3), women retained an additional 2.49 kg (95% CI: 2.16, 2.82; P<0.001). CONCLUSIONS: Having a greater number of modifiable risk factors was associated with greater weight retention 6 months postpartum. Initiatives supporting women to target these risk factors in the years prior to, during and after pregnancy could impact on their weight gain trajectory and later risk of adverse weight-related outcomes. PMID- 28337029 TI - The impact of protein quantity during energy restriction on genome-wide gene expression in adipose tissue of obese humans. AB - BACKGROUND: Overweight and obesity is a growing health problem worldwide. The most effective strategy to reduce weight is energy restriction (ER). ER has been shown to be beneficial in disease prevention and it reduces chronic inflammation. Recent studies suggest that reducing the protein quantity of a diet contributes to the beneficial effects by ER. The organ most extensively affected during ER is white adipose tissue (WAT). OBJECTIVE: The first objective was to assess changes in gene expression between a high-protein diet and a normal protein diet during ER. Second, the total effect of ER on changes in gene expression in WAT was assessed. METHODS: In a parallel double-blinded controlled study, overweight older participants adhered to a 25% ER diet, either combined with high-protein intake (HP-ER, 1.7 g kg-1 per day), or with normal protein intake (NP-ER, 0.9 g kg-1 per day) for 12 weeks. From 10 HP-ER participants and 12 NP-ER participants subcutaneous WAT biopsies were collected before and after the diet intervention. Adipose tissue was used to isolate total RNA and to evaluate whole-genome gene expression changes upon a HP-ER and NP-ER diet. RESULTS: A different gene expression response between HP-ER and NP-ER was observed for 530 genes. After NP ER, a downregulation in expression of genes linked to immune cell infiltration, adaptive immune response and inflammasome was found, whereas no such effect was found after HP-ER. HP-ER resulted in upregulation in expression of genes linked to cell cycle, GPCR signalling, olfactory signalling and nitrogen metabolism. Upon 25% ER, gene sets related to energy metabolism and immune response were decreased. CONCLUSIONS: Based on gene expression changes, we concluded that consumption of normal protein quantity compared with high-protein quantity during ER has a more beneficial effect on inflammation-related gene expression in WAT. PMID- 28337031 TI - Multimode fiber tip Fabry-Perot cavity for highly sensitive pressure measurement. AB - We demonstrate an optical Fabry-Perot interferometer fiber tip sensor based on an etched end of multimode fiber filled with ultraviolet adhesive. The fiber device is miniature (with diameter of less than 60 MUm), robust and low cost, in a convenient reflection mode of operation, and has a very high gas pressure sensitivity of -40.94 nm/MPa, a large temperature sensitivity of 213 pm/ degrees C within the range from 55 to 85 degrees C, and a relatively low temperature cross-sensitivity of 5.2 kPa/ degrees C. This device has a high potential in monitoring environment of high pressure. PMID- 28337030 TI - Prenatal steroid administration leads to adult pericardial and hepatic steatosis in male baboons. AB - Developmental programming studies indicate that glucocorticoids modify fetal development. We hypothesized that administration of the synthetic glucocorticoid (sGC) betamethasone to pregnant baboons at doses and stages of fetal life equivalent to human obstetric practice to decrease premature offspring morbidity and mortality, programs lipid metabolism. In 10-year-old male baboons (human equivalent 40) exposed in fetal life to betamethasone or saline, we quantified pericardial fat and hepatic lipid content with magnetic resonance imaging and spectroscopy. sGC offspring delivered at term as do most sGC-exposed human neonates. Pericardial fat thickness (7.7+/-3.6 mm vs 3.1+/-1.1 mm, M+/-s.d.; P=0.022; n=5) and hepatic fatty acids (13.3+/-11.0% vs 2.5+/-2.2%; P=0.046; n=5) increased following sGC without birth weight or current body morphometric differences. Our results indicate that antenatal sGC therapy caused abnormal fat deposition and adult body composition in mid-life primate offspring. The concern raised is that this degree of pericardial and hepatic lipid accumulation can lead to harmful local lipotoxicity. In summary, developmental programing by sGC produces a mid-life metabolically obese but normal weight phenotype. Prior studies show sexually dimorphic responses to some programming challenges thus female studies are necessary. PMID- 28337032 TI - Drosophila dyskerin is required for somatic stem cell homeostasis. AB - Drosophila represents an excellent model to dissect the roles played by the evolutionary conserved family of eukaryotic dyskerins. These multifunctional proteins are involved in the formation of H/ACA snoRNP and telomerase complexes, both involved in essential cellular tasks. Since fly telomere integrity is guaranteed by a different mechanism, we used this organism to investigate the specific role played by dyskerin in somatic stem cell maintenance. To this aim, we focussed on Drosophila midgut, a hierarchically organized and well characterized model for stemness analysis. Surprisingly, the ubiquitous loss of the protein uniquely affects the formation of the larval stem cell niches, without altering other midgut cell types. The number of adult midgut precursor stem cells is dramatically reduced, and this effect is not caused by premature differentiation and is cell-autonomous. Moreover, a few dispersed precursors found in the depleted midguts can maintain stem identity and the ability to divide asymmetrically, nor show cell-growth defects or undergo apoptosis. Instead, their loss is mainly specifically dependent on defective amplification. These studies establish a strict link between dyskerin and somatic stem cell maintenance in a telomerase-lacking organism, indicating that loss of stemness can be regarded as a conserved, telomerase-independent effect of dyskerin dysfunction. PMID- 28337035 TI - Addressing the complex challenge of unmet need: a moral and equity imperative? PMID- 28337034 TI - Exposure to an acute hypoxic stimulus during early life affects the expression of glucose metabolism-related genes at first-feeding in trout. AB - Rainbow trout (Oncorhynchus mykiss) is considered a "glucose-intolerant" species. With the aim of programming trout to improve their metabolic use of dietary carbohydrates, we hypothesised that a hypoxic stimulus applied during embryogenesis could later affect glucose metabolism at the first-feeding stage. An acute hypoxic stimulus (2.5 or 5.0 mg.L-1 O2) was applied for 24 h to non hatched embryos or early hatched alevins followed by a challenge test with a high carbohydrate diet at first-feeding. The effectiveness of the early hypoxic stimulus was confirmed by the induction of oxygen-sensitive markers such as egln3. At first-feeding, trout previously subjected to the 2.5 mg.L-1 O2 hypoxia displayed a strong induction of glycolytic and glucose transport genes, whereas these glucose metabolism-related genes were affected much less in trout subjected to the less severe (5.0 mg.L-1 O2) hypoxia. Our results demonstrate that an acute hypoxic stimulus during early development can affect glucose metabolism in trout at first-feeding. PMID- 28337033 TI - Cortical cells reveal APP as a new player in the regulation of GABAergic neurotransmission. AB - The amyloid precursor protein (APP) modulates synaptic activity, resulting from the fine tuning of excitatory and inhibitory neurotransmission. GABAergic inhibitory neurotransmission is affected by modifications in intracellular chloride concentrations regulated by Na+-K+-2Cl- cotransporter 1 (NKCC1) and neuronal K+-Cl- cotransporter 2 (KCC2), allowing entrance and efflux of chloride, respectively. Modifications in NKCC1 and KCC2 expression during maturation of cortical cells induce a shift in GABAergic signaling. Here, we demonstrated that APP affects this GABA shift. Expression of APP in cortical cells decreased the expression of KCC2, without modifying NKCC1, eliciting a less inhibitory GABA response. Downregulation of KCC2 expression by APP was independent of the APP intracellular domain, but correlated with decreased expression of upstream stimulating factor 1 (USF1), a potent regulator of Slc12a5 gene expression (encoding KCC2). KCC2 was also downregulated in vivo following APP expression in neonatal mouse brain. These results argue for a key role of APP in the regulation of GABAergic neurotransmission. PMID- 28337036 TI - Trends in genital warts diagnoses in New Zealand five years following the quadrivalent human papillomavirus vaccine introduction. AB - AIM: To investigate whether changes in rates of genital warts diagnosis at Auckland Sexual Health Service (ASHS), pre and post the quadrivalent human papillomavirus (4vHPV) vaccine introduction in late 2008, differed between clients vaccine-eligible and not eligible. METHOD: All new clients attending ASHS from 2007 to 2013 were categorised as having genital warts or not. Generalised linear mixed models were used to compare differences in rates of change in diagnoses. RESULTS: Overall, 43,480 were seen with genital warts diagnosed in 13.1%. The difference in rate of change over time in diagnosis pre- to post vaccine differed in females vaccine-eligible to not (p=0.004). The relative risk of diagnosis per year pre-vaccine was 0.98 (0.84, 1.13) and post-vaccine 0.77 (0.74, 0.81) in those eligible compared to 0.87 (0.80, 0.95) and 0.95 (0.91, 0.98), respectively, in those not eligible. This difference in change, between vaccine eligible or not, differed between males and females (p=0.02), with males considered eligible if the same aged female would have been. In males, no difference in rate change pre- to post-vaccine could be shown in those eligible or not (p=0.53). CONCLUSION: In this study a population effect for women of the 4vHPV vaccine was demonstrated. PMID- 28337037 TI - The diagnostic performance of ultrasound in the detection of ectopic pregnancy. AB - BACKGROUND: Accurate diagnosis of ectopic pregnancy is essential in reducing maternal mortality and morbidity. Transvaginal ultrasound (TVUS) is the accepted imaging modality of choice for the diagnosis of ectopic pregnancy (EP). AIMS: To assess the effectiveness of transvaginal ultrasound (TVUS) in the detection of EP in consecutive women presenting for ultrasound to a radiology department with a clinical suspicion of EP. METHODS: Retrospective analysis of 585 women presenting for TVUS over a 2.5-year period was performed. Women were classified as having a confirmed EP on the basis of surgery and histology. Women with a suspected EP who were treated medically or expectantly were also included. RESULTS: Eighty-seven women had a confirmed EP and 29 women had a suspected EP. The sensitivity and specificity of ultrasound for the detection of confirmed EP was 88.5% and 96.5% on the initial TVUS and 93.1% and 95.7% with an additional rescan. CONCLUSION: TVUS in the radiology setting of a tertiary hospital has excellent diagnostic performance for the detection of EP. PMID- 28337038 TI - Pilot study of methods for assessing unmet secondary health care need in New Zealand. AB - AIMS: In this pilot study, the primary aim was to compare four potential methods for undertaking a national survey of unmet secondary healthcare need in New Zealand (one collecting data from GPs, and three from community surveys). The secondary aim was to obtain an estimate of the prevalence of unmet secondary healthcare need, to inform sample size calculations for a national survey. METHODS: An electronic system was set up for GPs in Christchurch (Pegasus PHO) and Auckland (Auckland PHO) to record cases of unmet need as encountered in clinics. For the community surveys, a questionnaire developed by the authors was administered to people from the same electoral wards as the GP clinics. Three modes of questionnaire administration were trialled: online, telephone and face to-face interview. Random population sampling from the Maori and General Electoral Rolls was used to identify eligible survey participants until there were approximately 200 respondents for each method in each city. Data collection took place from November 2015 to February 2016. RESULTS: GP reports: Pegasus PHO: 8/78 eligible practices recorded 28 cases of unmet secondary healthcare need in 10 weeks. Auckland PHO: 3/26 practices participated and recorded no cases in three weeks. Surveys: 1,277 interviews were completed (online 428, telephone 447, face-to-face 402). For primary healthcare, 211/1,277 (16.5%) had missed a GP visit because of cost (online 25.0%, telephone 11.6%, face-to-face 12.9%). For secondary healthcare, 119/1,277 (9.3%) reported unmet healthcare need that had been identified by a health professional (online 11.2%; telephone 9.2%; face-to face 7.5%). Of these, 75/119 (63.0%) required a consultation, and 47/119 (39.5%) required a procedure. Completed interview rates as a percentage of names on the Electoral Roll were low (online 8.8%, telephone 15.4%, face-to-face 13.9%), affected by changed addresses and lack of listed telephone numbers. The response rate for those with valid phone numbers was 47.6%, and for those with valid addresses was 31.5%. CONCLUSIONS: Using the Electoral Rolls to identify respondents is problematic. For a national survey, random population sampling by address, similar to the method employed for the New Zealand Health Survey, but giving respondents a choice between face-to-face and phone interviews, is proposed. Asking GPs to record data on unmet need for secondary care was not successful. Our pilot study suggests there is sufficient unmet secondary healthcare need in New Zealand to merit a national survey. PMID- 28337039 TI - Rationing of hip and knee referrals in the public hospital: the true unmet need. AB - AIM: The aim of this paper is to outline the development of a triage system for elective hip and knee referrals to the Orthopaedic Department of the Canterbury District Health Board (CDHB), and to determine the unmet need within this population for accessing first specialist assessment (FSA). METHODS: Between 1 August 2015 and 31 March 2016 data was collected from all elective hip and knee referrals that underwent triage for a FSA. The number of outpatient appointments available according to the government four-month waiting time is set by the CDHB. Patients were triaged by two consultant surgeons on the basis of their referral letter and radiological imaging into one of five categories: accepted for FSA, insufficient information, no capacity, low priority or direct entry to waiting list (if already seen by a specialist). Those not accepted for an FSA were returned to general practitioner (GP) care. RESULTS: During the study period there were 1,733 referrals (838 hip related referrals and 895 knee related referrals) to the orthopaedic department with a request for FSA. All patients had failed conservative management. Of these referrals 43% of hip and 54% of knee related referrals could not be offered an FSA and were returned, following triage, to general practitioner care unseen. Only 8% and 9% respectively were declined for insufficient information in the referral letter or lack of need. CONCLUSION: This study details the implementation of a triage system for elective hip and knee referrals to the CDHB and with accurate data we have been able to determine the large number of patients unable to access a specialist opinion. These patients represent the unmet need within our community and highlights the degree of rationing taking place within the public hospital. PMID- 28337040 TI - Refining metformin prescribing in New Zealand. AB - Metformin is the mainstay of treatment of type 2 diabetes. However, there has been significant concern on prescribing metformin in patients with renal impairment as a result of metformin-associated lactic acidosis (MALA). Recent studies have cast doubt on the existence of MALA purely related to metformin use. Medsafe recently initiated changes to datasheet so lower doses of metformin could be used in patients with GFR down to 15ml/min. In this paper we outline the context and implications of this change. PMID- 28337041 TI - Getting the foundations right for the measurement of medication safety: the need for a meaningful conceptual frame. AB - A number of initiatives aimed at improving medication safety in and across New Zealand public hospitals have been introduced over recent years. Clinicians, policymakers and patients now want to know whether patients are safer today from medicine use than they have been in the past. The challenge has been determining exactly what should be measured. In this viewpoint, we critically examine the suitability of adverse drug events (ADE) as a primary metric for assessing the progress of medication safety improvement. We provide an overview of contemporary dialogue on medication safety measurement and highlight the emergent challenges. Finally, we reflect on how New Zealand has approached medication safety measurement so far and argue the need for a multi-stakeholder informed conceptual framework with a view to further enhancing meaningful assessment of medication safety. PMID- 28337042 TI - Household transmission of NDM-producing E. coli in New Zealand. AB - This report describes the introduction of an extensively antibiotic-resistant carbapenemase-producing Escherichia coli into a hospital in Auckland, New Zealand, by a patient who was a household contact of recent travellers to the Indian subcontinent. The carbapenemase was identified as New Delhi metallo-beta lactamase (NDM) and reflects probable household transmission in the context of a recent upsurge in NDM-producing Enterobacteriaceae isolation in New Zealand. The observations in this report suggest that hospital screening practices to identify carbapenemase-producing Enterobacteriaceae (CPE) colonised patients may need to be extended to include travellers to high-risk countries who were not hospitalised during their trip, and possibly also their close contacts. PMID- 28337043 TI - Poststreptococcal episcleritis. AB - This report describes the case of a patient presenting with an unusual poststreptococcal syndrome that featured episcleritis as a prominent manifestation. To my knowledge, this is the first time that poststreptococcal episcleritis has been described in the literature. PMID- 28337044 TI - Clostridium difficile infections in patients with inflammatory bowel disease. AB - Case report of a 23-year-old male presenting with a severe flare of Crohn's disease, exacerbated by community-acquired infection with Clostridium difficile. This case outlines the association between C. difficile infection and inflammatory bowel disease, as both a mimic and a precipitant of flares. The discussion concerns the latest literature consensus on assessment and management of Clostridium difficile infection in patients with inflammatory bowel disease. PMID- 28337045 TI - Pick a bogus treatment.... PMID- 28337046 TI - What Skills Can Buy: Transmission of advantage through cognitive and noncognitive skills. AB - Parental income and wealth contribute to children's success but are at least partly endogenous to parents' cognitive and noncognitive skills. We estimate the degree to which mothers' skills measured in early adulthood confound the relationship between their economic resources and their children's postsecondary education outcomes. Analyses of NLSY79 suggest that maternal cognitive and noncognitive skills attenuate half of parental income's association with child baccalaureate college attendance, a fifth of its association with elite college attendance, and a quarter of its association with bachelor's degree completion. Maternal skills likewise attenuate a third of parental wealth's association with children's baccalaureate college attendance, half of its association with elite college attendance, and a fifth of its association with bachelor's degree completion. Observational studies of the relationship between parents' economic resources and children's postsecondary attainments that fail to account for parental skills risk seriously overstating the benefits of parental income and wealth. PMID- 28337047 TI - Enhancing Parenting Practices with Latino/a Immigrants: Integrating Evidence based Knowledge and Culture According to the Voices of Latino/a Parents. PMID- 28337050 TI - Neuropsychology across the Lifespan: Proceedings of the Third Meeting of the Federation of European Societies of Neuropsychology. PMID- 28337048 TI - Validity of a New Kit Measuring Salivary Lactate Dehydrogenase Level for Screening Gingivitis. AB - Aim. The aim of this study was to determine the usefulness of a new kit that can evaluate salivary lactate dehydrogenase (LD) level in real time for screening gingivitis. Materials and Methods. The study included 70 systemic healthy volunteers [29 males and 41 females; mean age +/- SD: 24.1 +/- 2.6 years]. Resting saliva was collected from each participant and LD level was evaluated in real time using the kit (a color-changing sheet with an integer scale ranging from 1 to 10). A dentist measured probing pocket depth, clinical attachment level, and the proportion of sites with bleeding on probing (% BOP) at six sites on all teeth. Gingivitis was diagnosed when the BOP value was >=20%. Results. Salivary LD level was positively correlated with mean % BOP (odds ratio: 1.47, 95% confidence interval: 1.132-1.916, and P < 0.001) in a logistic regression model. The sensitivity and specificity of the kit were 0.89 and 0.98, respectively, at a cut-off value of 8.0 for LD level. Conclusions. The new kit for measurement of salivary LD level may be a useful tool to screen for gingivitis in young adults, which contributes to early detection of future periodontitis. PMID- 28337049 TI - Use of 3D Printed Bone Plate in Novel Technique to Surgically Correct Hallux Valgus Deformities. AB - Three-dimensional (3-D) printing offers many potential advantages in designing and manufacturing plating systems for foot and ankle procedures that involve small, geometrically complex bony anatomy. Here, we describe the design and clinical use of a Ti-6Al-4V ELI bone plate (FastForwardTM Bone Tether Plate, MedShape, Inc., Atlanta, GA) manufactured through 3-D printing processes. The plate protects the second metatarsal when tethering suture tape between the first and second metatarsals and is a part of a new procedure that corrects hallux valgus (bunion) deformities without relying on doing an osteotomy or fusion procedure. The surgical technique and two clinical cases describing the use of this procedure with the 3-D printed bone plate are presented within. PMID- 28337052 TI - An eigenvalue localization set for tensors and its applications. AB - A new eigenvalue localization set for tensors is given and proved to be tighter than those presented by Li et al. (Linear Algebra Appl. 481:36-53, 2015) and Huang et al. (J. Inequal. Appl. 2016:254, 2016). As an application of this set, new bounds for the minimum eigenvalue of [Formula: see text]-tensors are established and proved to be sharper than some known results. Compared with the results obtained by Huang et al., the advantage of our results is that, without considering the selection of nonempty proper subsets S of [Formula: see text], we can obtain a tighter eigenvalue localization set for tensors and sharper bounds for the minimum eigenvalue of [Formula: see text]-tensors. Finally, numerical examples are given to verify the theoretical results. PMID- 28337051 TI - A Novel CD48-Based Analysis of Sepsis-Induced Mouse Myeloid-Derived Suppressor Cell Compartments. AB - Myeloid-derived suppressor cells (MDSCs) are a heterogeneous subset of cells that expands dramatically in many disease states and can suppress T-cell responses. MDSCs mainly include monocytic and granulocytic subpopulations that can be distinguished in mice by the expression of Ly6G and Ly6C cell surface markers. This identification system has been validated in experimental tumor models, but not in models of inflammation-associated conditions such as sepsis. We challenged growth factor independent 1 transcription repressor green fluorescent protein (Gfi1:GFP) knock-in reporter mice with cecal ligation and puncture surgery and found that CD11b+Ly6GlowLy6Chigh MDSCs in this sepsis model comprised both monocytic and granulocytic MDSCs. The evidence that conventional Ly6G/Ly6C marker analysis may not be suited to study of inflammation-induced MDSCs led to the development of a novel strategy of distinguishing granulocytic MDSCs from monocytic MDSCs in septic mice by expression of CD48. Application of this novel model should help achieve a more accurate understanding of the inflammation induced MDSC activity. PMID- 28337053 TI - Adolescents' Behaviors as Moderators for the Link between Parental Self-Efficacy and Parenting Practices. AB - Based on theory that parents with higher levels of self-efficacy (PSE) should find it easier to parent effectively in the face of challenging child behaviors than should parents with lower levels of PSE, this study examines the link between PSE and parenting using children's behaviors as potential moderators. Participants were 130 parents who had an older adolescent (Mage = 17.58) in addition to the target adolescent (Mage = 11.79), and both adolescents' externalizing behaviors were used as moderators for the link between PSE and parenting of the target adolescent. Path analysis in Mplus showed that higher PSE was linked to more promotive parenting but only among parents who had an older adolescent with lower levels of externalizing behaviors. Among parents of adolescents with higher levels of externalizing behaviors, whose promotive parenting was significantly lower than other parents overall, PSE did not predict promotive parenting. The link between PSE and parenting did not differ depending on the target adolescents' behavior. Findings suggest that the link between parents' beliefs and parenting depends on the broader family context. More specifically, how PSE is linked to parenting practices depends at least partly on the experiences that parents bring from parenting an older adolescent to their interactions with a later-born adolescent. From a clinical perspective, parents might need guidance in how to think about their earlier parenting experiences when parenting a younger adolescent. PMID- 28337054 TI - The environmental needs of clinician-scientists in ophthalmology. PMID- 28337055 TI - Diabetic retinopathy: Knowledge, awareness and practices of physicians in primary care centers in Riyadh, Saudi Arabia. AB - PURPOSE: Diabetic retinopathy (DR) is a serious cause of irreversible blindness and is the most common complication of diabetes. Annual fundus examination for diabetics aids in the prevention of blindness and allows intervening at a timely manner. As primary care physicians (PCP) are the main providers for diabetic care in Saudi Arabia, we aim to evaluate the current knowledge and awareness, and to assess practices among PCP regarding DR. METHODS: We conducted a cross-sectional study covering 46 randomly selected primary-care centers in Riyadh during October 2015. A Self-administered questionnaire was distributed to PCP containing 3 sections. The first section covered participants' demographics and professional background. The second section contained multiple-choice questions on knowledge related to diabetes and DR. The third section was to assess physicians' practices. RESULTS: A total of 216 PCPs completed the questionnaire. The mean overall knowledge score was 57 +/- 14 out of 100. There was a significant difference in knowledge score between physicians who had obtained a subspecialty degree in family medicine compared to others (59 +/- 14, 53.3 +/- 14 respectively; P = 0.003). Only 19% of PCPs were aware of anti-vascular endothelial growth factor (VEGF) injections as a modality of treatment. A defect was found in the screening and follow-up of type 1 diabetics, and only 24% of physicians correctly referred patients with type 1 diabetes to an ophthalmologist. CONCLUSION: Our study uncovered areas of defects in knowledge among PCP regarding DR. This needs to be addressed in future seminars and workshops with an emphasis on the proper ophthalmological screening and management of diabetic patients. PMID- 28337056 TI - Normative values and contralateral comparison of anterior chamber parameters measured by Pentacam and its correlation with corneal biomechanical factors. AB - PURPOSE: To evaluate the normative values of anterior chamber parameters measured by Pentacam and corneal hysteresis (CH) and corneal resistance factor (CRF) measured by Ocular Response Analyzer (ORA) and their relationship. METHODS: In an observational cross-sectional study, patients aged 18-35 years were included. Exclusion criteria were history of any intraocular or corneal disease, anomaly or surgery; hyperopic spherical refraction more than +3, and myopic spherical refraction less than -5.00 diopters (D) or cylindrical refraction more than 2.00 D. ORA was used to measure CH and CRF. Corneal volume (CV), anterior and posterior Q value (QA and QP), anterior and posterior elevation (AE and PE), central corneal thickness (CCT), corneal thinnest thickness (CTT), anterior chamber depth (ACD), anterior chamber volume (ACV) and anterior chamber angle (ACA) were measured with Pentacam. RESULTS: This study evaluated 506 eyes of 253 cases (182 females) with a mean age of 28.43 +/- 6.36 years. The average CH and CRF were 10.07 +/- 1.61 and 10.33 +/- 1.68 mmHg. CH and CRF were not correlated with PQ, AQ, AE and PE. CH and CRF were significantly correlated with CCT (r = 0.499, p < 0.0001 and r = 0.591, p < 0.0001 respectively), CTT (r = 0.469, p < 0.0001 and r = 0.593, p < 0.0001 respectively) and CV (r = 0.443, p < 0.0001 and r = 0.526, p < 0.0001 respectively). CONCLUSION: A significant positive correlation was found between CH and CRF, and CCT, CTT and CV. This study also provided data about wide range normative values of corneal parameters. PMID- 28337057 TI - Accelerated corneal collagen cross-linking in pediatric keratoconus: One year study. AB - PURPOSE: To evaluate the safety and effectiveness of accelerated corneal collagen crosslinking (CXL) in pediatric keratoconus. DESIGN: Prospective non-randomized observational study. METHODS: 33 eyes of 25 children with keratoconus were included. The corneal epithelium was mechanically removed. Next, riboflavin/hydroxypropyl methylcellulose solution) was applied for 10 min. Accelerated CXL (10 mW/cm2 for 9 min), was accomplished. Visual acuity, slit lamp examination, refraction, keratometry readings, pachymetry, anterior and posterior elevations, average progression indices, and Q values were recorded. The follow up visits were scheduled on one day, 3 days, 7 days, one month and then on 3, 6, 12 months after the procedure. RESULTS: It was statistically significant improvement of the mean UAVA, AVA, and the mean corneal astigmatism (P < .0001). The mean corneal thickness showed a significant reduction. The preoperative mean K max reading was reduced from 49.12 +/- 3.7 D preoperatively to 47.9 +/- 3.7 D at 12 months. The mean max anterior elevation, average progression index and Q value showed statistically significant improvement. No significant impact on posterior elevation was recorded. Serious complications were not encountered in this study. CONCLUSION: Accelerated CXL shows a stabilization and beneficial clinical outcomes in pediatric keratoconus. It seems an effective and safe procedure in this age group. Effects of accelerated CXL on the posterior corneal surface will need further evaluation. PMID- 28337058 TI - Comparison of microkeratome assisted sub-Bowman keratomileusis with photorefractive keratectomy. AB - PURPOSE: To compare the outcomes of photorefractive keratectomy (PRK) and thin flap Laser-Assisted in Situ Keratomileusis/sub-Bowman keratomileusis (SBK) with intended flap thicknesses of 100 MUm using the One Use-Plus SBK microkeratome. METHODS: Ninety-eight eyes of 52 subjects with myopic manifest refraction spherical equivalent (MRSE) of up to -5 diopters (D), a stable refraction for 1 year and a corrected distance visual acuity (CDVA) of at least 20/20 in each eye which had undergone SBK or PRK were reviewed retrospectively. Primary outcome measures were MRSE, uncorrected distance visual acuity (UDVA), CDVA, pachymetry and higher order aberrations (HOA). All patients were seen at 1 and 3 days, 1 week, and 1, 3, and 6 months after surgery. RESULTS: Both MRSE and UDVA showed a statistically significant improvement at postoperative 1, 3 and 6 months from baseline in both SBK and PRK groups. At postoperative 6 months, 100% of eyes were within +/-0.50 D of attempted correction in both groups. However, SBK group demonstrated better outcomes with 81% of eyes within +/-0.13 D, compared to 70% eyes in the PRK group. Both SBK and PRK group demonstrated similar refractive astigmatism accuracy at postoperative 6 months, with 88% of eyes having cylindrical error ?0.25 D. None of eyes lost any lines of CDVA in the PRK, and 2% eyes lost one line of CDVA in SBK group at postoperative 6 months. CONCLUSION: The visual and refractive outcomes after both PRK and microkeratome assisted SBK are comparable, albeit with a higher complication rate in the SBK group. PMID- 28337059 TI - Cataract surgical rate in Yemen: 2012. AB - OBJECTIVE: To determine cataract surgical rate (CSR) in 2012 (01 January to 31 December 2012) in 22 Governorates of Yemen in order to identify the needs to reduce cataract related blindness. METHODS: A standardized questionnaire was sent to the 184 eye units in governmental, university, military, private and charity clinics and hospitals in Yemen. RESULTS: The response rate to the questionnaire was 80.7%, and the collected data are summarized. During the 12-month period, a total of 62,577 cataract surgeries were performed by 268 ophthalmology specialists and residents. The cataract surgical rate was 2473 cataract operations per million inhabitants per year. Intraocular lens implantation was performed on 98% of the cases. CONCLUSION: CSR has increased in Yemen in the recent years but is still below the target suggested by WHO. There is need to increase the cataract surgical rate in Yemen mainly in rural areas. Inadequate number of eye surgeons, limited accessibility of cataract surgical services in rural areas and the affordability of surgery to large sections of society are major constraints that have to be addressed. The information from this study will help and enable Ministry of Health and other eye care providers to more equitably disperse trained ophthalmic personnel and eye units in Yemeni governorates. PMID- 28337061 TI - An introduction to DARC technology. AB - Glaucoma is a multi-factorial neurodegenerative disorder. The common denominator in all types of glaucomas is retinal ganglion cell death through apoptosis. However, this cellular demise in glaucoma is detected late by structural or functional analyses. There can be a 10-year delay prior to the appearance of visual field defects and pre-perimetric glaucoma is an issue still being addressed. However, a new cutting-edge technology called detection of apoptosing retinal cells (DARC) is being developed. This technique is capable of non invasive, real-time visualization of apoptotic changes at the cellular level. It can detect glaucomatous cell damage at a very early stage, at the moment apoptosis starts, and thus management can be initiated even prior to development of visual field changes. In future, this technique will also be able to provide conclusive evidence of the effectiveness of treatment protocol and the need for any modifications which may be required. This article aims to provide a concise review of DARC technology. PMID- 28337062 TI - Successful treatment of Behcet's uveitis with Tocilizumab. AB - A 33-year-old man with history of lymphoma was misdiagnosed as multiple sclerosis (MS) 18 months previously, developed intermediate uveitis, unresponsive to interferon, and corticosteroids. A diagnosis of Behcet's disease (BD) was made on the basis of recurrent orogenital ulceration, erythema nodosum, and a positive pathergy test. The patient was started on Tocilizumab and experienced an improvement in visual acuity and intraocular inflammation over the following 2 weeks. In patients with BD-related uveitis, Tocilizumab can be an effective alternative to anti-tumor necrosis factor alpha medications. PMID- 28337060 TI - Nutraceuticals in prevention of cataract - An evidence based approach. AB - Cataract is a principal cause of blindness in the world and is characterized by clouding of eye's natural lens. Surgery is the major therapeutic step taken to cure cataract; however, it is having its own limitations and complications such as iris prolapse, raised IOP, infection, cystoid macular edema and posterior capsular opacification (PCO). So world is looking toward more robust and natural ways to prevent cataract. One of the important factors that can play a role in prevention of any and many diseases is diet of the people. The inclusion of certain naturally occurring food and nutraceuticals is coming up as a best alternative for curing cataract because of their presumed safety, potential nutritional and therapeutic effects. Some nutraceuticals can act as an anticataract agent through some or the other molecular mechanism if consumed by normal population deliberately or inadvertently. PMID- 28337064 TI - Canalicular pyocele: A new entity and literature review. AB - Canaliculoceles are rare, and under-recognized lesions of the upper lacrimal drainage system that may present as medial canthal masses or swelling. The current case is that of an 85-year-old female patient presented with a painful right upper lid medial, cystic swelling of 10-day duration involving the punctum and the upper canaliculus. A literature review showed that this is the seventh reported case of a canaliculocele but the first case of acute onset that is associated with inflammatory signs and symptoms and accumulation of purulent material. The term canalicular pyocele is suggested to describe this condition. PMID- 28337063 TI - A novel mutation and in vivo confocal microscopic findings in Fabry disease. AB - Fabry disease is a hereditary, X-linked lysosomal storage disease due to a deficiency of the alpha galactosidase A enzyme. Globotriaosylceramide accumulates in tissues and results in multiorgan dysfunction. The most common ocular finding in Fabry disease is cornea verticillata. Increase in conjunctival vascular tortuosity, and cataract may also be seen. Herein, we demonstrate the in vivo confocal microscopic findings of a genetically proven Fabry disease patient with a novel hemizygous R112L mutation in GLA gene. PMID- 28337065 TI - Acute bacterial endophthalmitis following intravitreal dexamethasone implant: A case report and review of literature. AB - Endophthalmitis following intravitreal dexamethasone (DEX) implant has been rarely reported. This report describes the case of a 70-year-old male who underwent intravitreal DEX implant injection under aseptic conditions, for diabetic macular edema. He developed a clinical picture suggestive of endophthalmitis within 2 weeks of the injection, and vitreous culture grew coagulase negative Staphylococcus. He was treated with intravitreal antibiotics followed by pars plana vitrectomy and removal of the implant. This was followed by resolution of the infection with a favorable final visual outcome. The challenges faced during surgical management of this case are discussed. PMID- 28337066 TI - Paintball related ocular injuries: First case report in Saudi patients. AB - Paintball is a popular recreational sport. This case series describes three Saudi patients exposed to paintball ocular injuries with sever ocular trauma. Two patients developed hyphema and traumatic cataract and one patient had vitreous hemorrhage, choroidal detachment, commotio retinae and retinal tear. All patients require surgical intervention. Final best corrected visual acuity was 20/200, 20/30 and 20/50 respectively. Paintball related ocular injuries can result in severe visual loss and in most of the time requires surgical intervention. Most injuries occur in under-supervised settings and are easily preventable. Our main aim was to increase awareness among local ophthalmologists and eye professionals about this new game. Improved safety measures and appropriate public education could prevent such serious ocular injuries. PMID- 28337067 TI - Late spontaneous resolution of a double anterior chamber post deep anterior lamellar keratoplasty. AB - A 31-year-old healthy male underwent deep anterior lamellar keratoplasty with big bubble technique for treatment of keratoconus in his right eye. One week after surgery, he presented with detachment of the endothelium-Descemet complex with formation of a double anterior chamber, despite the apparent absence of an intraoperative Descemet membrane rupture. A subsequent intervention with the intent to relocate the corneal graft button was not effective, because the detachment appeared again one day later. The authors hypothesized that, at the time of the stromal dissection with big bubble technique, a small amount of air penetrated into the anterior chamber, creating a false pathway through the trabecular meshwork. The aqueous humor then penetrated the graft flowing through the false pathway, causing the endothelium-Descemet detachment. The persistence of that pathway, even after the intervention of graft repositioning, caused the failure of the latter procedure and persistence of the double chamber. We decided to wait and observe. The double anterior chamber spontaneously resolved in approximately three months. PMID- 28337068 TI - Statistical analysis of latent generalized correlation matrix estimation in transelliptical distribution. AB - Correlation matrix plays a key role in many multivariate methods (e.g., graphical model estimation and factor analysis). The current state-of-the-art in estimating large correlation matrices focuses on the use of Pearson's sample correlation matrix. Although Pearson's sample correlation matrix enjoys various good properties under Gaussian models, its not an effective estimator when facing heavy-tail distributions with possible outliers. As a robust alternative, Han and Liu (2013b) advocated the use of a transformed version of the Kendall's tau sample correlation matrix in estimating high dimensional latent generalized correlation matrix under the transelliptical distribution family (or elliptical copula). The transelliptical family assumes that after unspecified marginal monotone transformations, the data follow an elliptical distribution. In this paper, we study the theoretical properties of the Kendall's tau sample correlation matrix and its transformed version proposed in Han and Liu (2013b) for estimating the population Kendall's tau correlation matrix and the latent Pearson's correlation matrix under both spectral and restricted spectral norms. With regard to the spectral norm, we highlight the role of "effective rank" in quantifying the rate of convergence. With regard to the restricted spectral norm, we for the first time present a "sign subgaussian condition" which is sufficient to guarantee that the rank-based correlation matrix estimator attains the optimal rate of convergence. In both cases, we do not need any moment condition. PMID- 28337069 TI - Detection of alien genetic introgressions in bread wheat using dot-blot genomic hybridisation. AB - Simple, reliable methods for the identification of alien genetic introgressions are required in plant breeding programmes. The use of genomic dot-blot hybridisation allows the detection of small Hordeum chilense genomic introgressions in the descendants of genetic crosses between wheat and H. chilense addition or substitution lines in wheat when molecular markers are difficult to use. Based on genomic in situ hybridisation, DNA samples from wheat lines carrying putatively H. chilense introgressions were immobilised on a membrane, blocked with wheat genomic DNA and hybridised with biotin-labelled H. chilense genomic DNA as a probe. This dot-blot screening reduced the number of plants necessary to be analysed by molecular markers or in situ hybridisation, saving time and money. The technique was sensitive enough to detect a minimum of 5 ng of total genomic DNA immobilised on the membrane or about 1/420 dilution of H. chilense genomic DNA in the wheat background. The robustness of the technique was verified by in situ hybridisation. In addition, the detection of other wheat relative species such as Hordeum vulgare, Secale cereale and Agropyron cristatum in the wheat background was also reported. PMID- 28337070 TI - Genomic Methods and Microbiological Technologies for Profiling Novel and Extreme Environments for the Extreme Microbiome Project (XMP). AB - The Extreme Microbiome Project (XMP) is a project launched by the Association of Biomolecular Resource Facilities Metagenomics Research Group (ABRF MGRG) that focuses on whole genome shotgun sequencing of extreme and unique environments using a wide variety of biomolecular techniques. The goals are multifaceted, including development and refinement of new techniques for the following: 1) the detection and characterization of novel microbes, 2) the evaluation of nucleic acid techniques for extremophilic samples, and 3) the identification and implementation of the appropriate bioinformatics pipelines. Here, we highlight the different ongoing projects that we have been working on, as well as details on the various methods we use to characterize the microbiome and metagenome of these complex samples. In particular, we present data of a novel multienzyme extraction protocol that we developed, called Polyzyme or MetaPolyZyme. Presently, the XMP is characterizing sample sites around the world with the intent of discovering new species, genes, and gene clusters. Once a project site is complete, the resulting data will be publically available. Sites include Lake Hillier in Western Australia, the "Door to Hell" crater in Turkmenistan, deep ocean brine lakes of the Gulf of Mexico, deep ocean sediments from Greenland, permafrost tunnels in Alaska, ancient microbial biofilms from Antarctica, Blue Lagoon Iceland, Ethiopian toxic hot springs, and the acidic hypersaline ponds in Western Australia. PMID- 28337071 TI - International Standards for Genomes, Transcriptomes, and Metagenomes. AB - Challenges and biases in preparing, characterizing, and sequencing DNA and RNA can have significant impacts on research in genomics across all kingdoms of life, including experiments in single-cells, RNA profiling, and metagenomics (across multiple genomes). Technical artifacts and contamination can arise at each point of sample manipulation, extraction, sequencing, and analysis. Thus, the measurement and benchmarking of these potential sources of error are of paramount importance as next-generation sequencing (NGS) projects become more global and ubiquitous. Fortunately, a variety of methods, standards, and technologies have recently emerged that improve measurements in genomics and sequencing, from the initial input material to the computational pipelines that process and annotate the data. Here we review current standards and their applications in genomics, including whole genomes, transcriptomes, mixed genomic samples (metagenomes), and the modified bases within each (epigenomes and epitranscriptomes). These standards, tools, and metrics are critical for quantifying the accuracy of NGS methods, which will be essential for robust approaches in clinical genomics and precision medicine. PMID- 28337074 TI - The flare Package for High Dimensional Linear Regression and Precision Matrix Estimation in R. AB - This paper describes an R package named flare, which implements a family of new high dimensional regression methods (LAD Lasso, SQRT Lasso, l q Lasso, and Dantzig selector) and their extensions to sparse precision matrix estimation (TIGER and CLIME). These methods exploit different nonsmooth loss functions to gain modeling exibility, estimation robustness, and tuning insensitiveness. The developed solver is based on the alternating direction method of multipliers (ADMM), which is further accelerated by the multistage screening approach. The package flare is coded in double precision C, and called from R by a user friendly interface. The memory usage is optimized by using the sparse matrix output. The experiments show that flare is efficient and can scale up to large problems. PMID- 28337072 TI - Precision Metagenomics: Rapid Metagenomic Analyses for Infectious Disease Diagnostics and Public Health Surveillance. AB - Next-generation sequencing (NGS) technologies have ushered in the era of precision medicine, transforming the way we treat cancer patients and diagnose disease. Concomitantly, the advent of these technologies has created a surge of microbiome and metagenomic studies over the last decade, many of which are focused on investigating the host-gene-microbial interactions responsible for the development and spread of infectious diseases, as well as delineating their key role in maintaining health. As we continue to discover more information about the etiology of infectious diseases, the translational potential of metagenomic NGS methods for treatment and rapid diagnosis is becoming abundantly clear. Here, we present a robust protocol for the implementation and application of "precision metagenomics" across various sequencing platforms for clinical samples. Such a pipeline integrates DNA/RNA extraction, library preparation, sequencing, and bioinformatics analyses for taxonomic classification, antimicrobial resistance (AMR) marker screening, and functional analysis (biochemical and metabolic pathway abundance). Moreover, the pipeline has 3 tracks: STAT for results within 24 h; Comprehensive that affords a more in-depth analysis and takes between 5 and 7 d, but offers antimicrobial resistance information; and Targeted, which also requires 5-7 d, but with more sensitive analysis for specific pathogens. Finally, we discuss the challenges that need to be addressed before full integration in the clinical setting. PMID- 28337073 TI - Real-Time DNA Sequencing in the Antarctic Dry Valleys Using the Oxford Nanopore Sequencer. AB - The ability to sequence DNA outside of the laboratory setting has enabled novel research questions to be addressed in the field in diverse areas, ranging from environmental microbiology to viral epidemics. Here, we demonstrate the application of offline DNA sequencing of environmental samples using a hand-held nanopore sequencer in a remote field location: the McMurdo Dry Valleys, Antarctica. Sequencing was performed using a MK1B MinION sequencer from Oxford Nanopore Technologies (ONT; Oxford, United Kingdom) that was equipped with software to operate without internet connectivity. One-direction (1D) genomic libraries were prepared using portable field techniques on DNA isolated from desiccated microbial mats. By adequately insulating the sequencer and laptop, it was possible to run the sequencing protocol for up to 21/2 h under arduous conditions. PMID- 28337075 TI - Intranasal Dexmedetomidine as a Sedative for Pediatric Procedural Sedation. AB - OBJECTIVE: This study seeks to evaluate the efficacy and safety of intranasal (IN) dexmedetomidine as a sedative medication for non-invasive procedural sedation. METHODS: Subjects 6 months to 18 years of age undergoing non-invasive elective procedures were included. Dexmedetomidine (3 mcg/kg) was administered IN 40 minutes before the scheduled procedure time. The IN dexmedetomidine cohort was matched and compared to a cohort of 690 subjects who underwent sedation for similar procedures without the use of dexmedetomidine to evaluate for observed events/interventions and procedural times. RESULTS: One hundred (92%) of the 109 included subjects were successfully sedated with IN dexmedetomidine. There were no significant differences in the rate of observed events/interventions in comparison to the non-dexmedetomidine cohort. However, the IN dexmedetomidine group had a longer postprocedure sleep time when compared to the non dexmedetomidine cohort (p < 0.001), which had a significant effect on recovery time (p = 0.024). Also, the dexmedetomidine cohort had longer procedure time and total admit time (p < 0.001 and p = 0.037, respectively). CONCLUSIONS: IN dexmedetomidine may be used for non-invasive pediatric procedural sedation. Subjects receiving IN dexmedetomidine had a similar rate of observed events/interventions as the subjects receiving non-dexmedetomidine sedation, with the exception of sleeping time. Also, patients sedated with IN dexmedetomidine had longer time to discharge, procedure time, and total admit time in comparison to other forms of sedation. PMID- 28337076 TI - Nebulized Gentamicin as an Alternative to Nebulized Tobramycin for Tracheitis in Pediatric Patients. AB - OBJECTIVES: Tracheitis is an infection of the lower respiratory tract and is defined by the US Centers for Disease Control and Prevention (CDC) based on signs and symptoms with no radiographic evidence of pneumonia. One method of treatment involves the use of tobramycin given by nebulizer. The purpose of this study was to compare the safety and efficacy of nebulized gentamicin with nebulized tobramycin. METHODS: This study was conducted in patients under 21 years of age who received greater than or equal to 1 day of gentamicin, 80 mg, or tobramycin, 300 mg, given twice a day by nebulization within the 14-month study period. The primary endpoint was amount of time until the patient no longer met the CDC definition of tracheitis. RESULTS: There were 19 patients who presented with 60 separate encounters. The average age of the patients within the gentamicin group was 7.2 and 5 years old within the tobramycin group. The average duration of time for the gentamicin treatment encounters to be free of the CDC definition of tracheitis was 3.36 days compared to 3.17 days with tobramycin. No adverse effects were observed that were attributable to aminoglycoside nebulization. CONCLUSIONS: No differences were detected between the safety and efficacy of intravenous gentamicin administered twice a day by nebulizer and that of tobramycin inhalation solution given twice daily in children without cystic fibrosis. PMID- 28337077 TI - Antithrombin III Doses Rounded to Available Vial Sizes in Critically Ill Pediatric Patients. AB - OBJECTIVES: Children have decreased levels of antithrombin III (AT III) compared to adults. These levels may be further decreased during acute illness. Administration of exogenous AT III can increase anticoagulant efficacy. The objective of this study was to evaluate AT III doses rounded to available vial sizes compared to partial vial doses in critically ill pediatric patients, including patients receiving extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). METHOD: This retrospective review evaluated pediatric patients 0-18 years of age admitted to a 24-bed medical/surgical pediatric intensive care unit between June 1, 2012, and December 31, 2014, who received plasma-derived AT III. Patients received unfractionated heparin, low-molecular-weight heparin, or no anticoagulation. This review included patients who received ECMO and CRRT. RESULTS: Eighty doses of AT III were administered to 24 patients (38 full vial size doses and 42 partial vial size doses). The AT III level following dose administration was >=80% for 26 full vial doses (70%) and 16 partial vial doses (41%; p = 0.010). For patients who received multiple doses of AT III, the median time between doses was 45 hours following full vial doses, and 23 hours following partial vial doses (p = 0.011). Seven patients (29%) had documentation of new or increased bleeding. The median waste prevented from rounding doses to full vial sizes was 363 units. CONCLUSIONS: After receiving AT III doses rounded to full vial sizes, patients were more likely to have a therapeutic AT III level and a longer interval between administrations. Rounding AT III doses to full vial sizes reduces waste and can result in cost savings. PMID- 28337078 TI - Comparison of the Efficacy and Safety of 2 Acetaminophen Dosing Regimens in Febrile Infants and Children: A Report on 3 Legacy Studies. AB - OBJECTIVE: Compare efficacy and safety of 10 to 15 mg/kg with 20 to 30 mg/kg acetaminophen in febrile children 6 months to <= 11 years from 3 double-blind, randomized, single or multiple dose studies. METHODS: Doses were compared on sum of the temperature differences (SUMDIFF), maximum temperature difference (MAXDIFF), temperature differences at each time point, and dose by time interactions. Alanine aminotransferase (ALT) was evaluated in the 72-hour duration study. RESULTS: A single dose of acetaminophen 20 to 30 mg/kg produced a greater effect on temperature decrement and duration of antipyretic effect over 8 hours than a single dose of 10 to 15 mg/kg. When equivalent total doses (i.e., 2 doses of 10 to 15 mg/kg given at 4-hour intervals and 1 dose of 20 to 30 mg/kg) were given over the initial 8-hour period, there were no significant temperature differences. Over a 72-hour period, 10 to 15 mg/kg acetaminophen administered every 4 hours maintained a more consistent temperature decrement than 20 to 30 mg/kg acetaminophen administered every 8 hours. Following doses of 60 to 90 mg/kg/day for up to 72 hours, no child had a clinically important increase in ALT from baseline. The number of children with reported adverse events was similar between doses. CONCLUSIONS: Data demonstrate the antipyretic effect of acetaminophen is dependent on total dose over a given time interval. These 3 studies provide clinical evidence that the recommended standard acetaminophen dose of 10 to 15 mg/kg is a safe and effective dose for treating fever in pediatric patients when administered as a single dose or as multiple doses for up to 72 hours. PMID- 28337079 TI - Comparison of Amikacin Pharmacokinetics in Neonates Following Implementation of a New Dosage Protocol. AB - OBJECTIVES: The primary aim was to compare attainment of goal serum amikacin concentrations using two dosage regimens in patients admitted to a neonatal intensive care unit. Secondary objectives included comparison of percentages of supratherapeutic trough concentrations, and subtherapeutic and supratherapeutic peak concentrations. METHODS: This was an Institutional Review Board-approved, retrospective study of neonates receiving amikacin during January-December 2013 (group 1) and January-December 2014 (group 2). Group 1 received amikacin dosage consistent with published recommendations, whereas group 2 was dosed using a modified protocol that was based on postmenstrual and postnatal age. Goal serum amikacin peak concentration was defined as 20 to 35 mg/L; hence, subtherapeutic and supratherapeutic peak concentrations were defined as <20 mg/L and >35 mg/L, respectively. Supratherapeutic trough concentrations were >8 mg/L. Between-group analysis was performed using Wilcoxon-Mann-Whitney test, Student t-test or chi2, or Fisher exact analysis as appropriate with a p value <0.05. RESULTS: A total of 278 neonates were included (group 1: n = 144; group 2: n = 134). Most patients were male (60%) and were admitted for prematurity or respiratory distress (77%). The median gestational age in group 1 was 34.4 weeks (range, 30.0-37.9 weeks) versus group 2 at 36.9 weeks (range, 31.4-38.9 weeks), whereas the postnatal age was similar between both groups at 4 days. There was a significant increase in attaining goal peak amikacin concentrations between groups 1 and 2, 34% versus 84%, p < 0.001, and decrease in supratherapeutic peak concentrations, 65% versus 12%, p < 0.001. There was no significant difference in subtherapeutic peak or supratherapeutic trough concentrations. CONCLUSIONS: A modified neonatal amikacin dosage protocol resulted in increased peak amikacin serum concentration compared with published dosage recommendations. Future research should focus on determination of the optimal dosage regimen in neonates. PMID- 28337080 TI - Vancomycin AUC/MIC and Corresponding Troughs in a Pediatric Population. AB - OBJECTIVES: Adult guidelines suggest an area under the curve/minimum inhibitory concentration (AUC/MIC) > 400 corresponds to a vancomycin trough serum concentration of 15 to 20 mg/L for methicillin-resistant Staphylococcus aureus infections, but obtaining these troughs in children are difficult. The primary objective of this study was to assess the likelihood that 15 mg/kg of vancomycin every 6 hours in a child achieves an AUC/MIC > 400. METHODS: This retrospective chart review included pediatric patients >2 months to <18 years with a positive S aureus blood culture and documented MIC who received at least two doses of vancomycin with corresponding trough. Patients were divided into two groups: group 1 initially receiving >=15 mg/kg every 6 hours, and group 2 initially receiving any other dosing ranges or intervals. AUCs were calculated four times using three pharmacokinetic methods. RESULTS: A total of 36 patients with 99 vancomycin trough serum concentrations were assessed. Baseline characteristics were similar between groups. For troughs in group 1 (n = 55), the probability of achieving an AUC/MIC > 400 ranged from 16.4% to 90.9% with a median trough concentration of 11.4 mg/L, while in group 2 (n = 44) the probability of achieving AUC/MIC > 400 ranged from 15.9% to 54.5% with mean trough concentration of 9.2 mg/L. The AUC/MICs were not similar between the different pharmacokinetic methods used; however, a trapezoidal equation (Method A) yielded the highest correlation coefficient (r2 = 0.59). When dosing every 6 hours, an AUC/MIC of 400 correlated to a trough serum concentration of 11 mg/L. CONCLUSIONS: The probability of achieving an AUC/MIC > 400 using only a trough serum concentration and an MIC with patients receiving 15 mg/kg every 6 hours is variable based on the method used to calculate the AUC. An AUC/MIC of 400 in children correlated to a trough concentration of 11 mg/L using a trapezoidal Method to calculate AUC. PMID- 28337081 TI - A Comprehensive List of Items to be Included on a Pediatric Drug Monograph. AB - OBJECTIVES: Children require special considerations for drug prescribing. Drug information summarized in a formulary containing drug monographs is essential for safe and effective prescribing. Currently, little is known about the information needs of those who prescribe and administer medicines to children. Our primary objective was to identify a list of important and relevant items to be included in a pediatric drug monograph. METHODS: Following the establishment of an expert steering committee and an environmental scan of adult and pediatric formulary monograph items, 46 participants from 25 countries were invited to complete a 2 round Delphi survey. Questions regarding source of prescribing information and importance of items were recorded. An international consensus meeting to vote on and finalize the items list with the steering committee followed. RESULTS: Pediatric formularies are most commonly the first resource consulted for information on medication used in children by 31 Delphi participants. After the Delphi rounds, 116 items were identified to be included in a comprehensive pediatric drug monograph, including general information, adverse drug reactions, dosages, precautions, drug-drug interactions, formulation, and drug properties. CONCLUSIONS: Health care providers identified 116 monograph items as important for prescribing medicines for children by an international consensus-based process. This information will assist in setting standards for the creation of new pediatric drug monographs for international application and for those involved in pediatric formulary development. PMID- 28337082 TI - Pharmacokinetics of Peramivir in an Adolescent Patient Receiving Continuous Venovenous Hemodiafiltration. AB - Critically ill patients requiring renal replacement therapy commonly experience pharmacokinetic alterations. This case report describes the pharmacokinetics of peramivir (Rapivab, BioCryst Pharmaceuticals, Inc, Durham, NC), the first US Food and Drug Administration-approved intravenous neuraminidase inhibitor for the treatment of influenza, in an adolescent patient receiving continuous renal replacement therapy (CRRT). A 49.5-kg, 17-year-old Caucasian female presented with fever, cough, and persistent hypoxia. She quickly progressed to acute respiratory and renal failure in the setting of viral septic shock as a result of a severe influenza H1N1 infection. On hospital day 3, therapy was switched from oseltamivir (Tamiflu, Roche Laboratories Inc, Nutley, NJ) to peramivir owing to the concern for inadequate enteral absorption. On the third day of peramivir treatment, at a dose of 200 mg daily, peramivir serum concentrations revealed a smaller peak concentration, larger volumes of distribution, similar 24-hour area under the curve, and a shorter half-life as compared to adult patients with normal renal function. This illustrated the significant differences in pharmacokinetics when administered in the setting of CRRT. The patient had resolution of viral infection as evidenced by negative respiratory viral panel polymerase chain reaction at hospital day 14 and was eventually discharged at her baseline. PMID- 28337083 TI - Continuous-Infusion Etomidate in a Patient Receiving Extracorporeal Membrane Oxygenation. AB - We describe a 16-year-old, 65-kg male deployed on extracorporeal membrane oxygenation (ECMO) for refractory respiratory failure secondary to ingestion of multiple substances. During his ECMO course, standard sedative and analgesic strategies failed and alternative medications were used. The patient received various dosages of fentanyl, morphine, hydromorphone, clonidine patches, dexmedetomidine, lorazepam, methadone, pentobarbital, olanzapine, and propofol. Despite administration of multiple agents, on day 29 of ECMO the patient experienced elevated blood pressures due to agitation, and continuous infusion etomidate was started. At the time of etomidate initiation, the osmolar gap was 8 mOsm/kg. During etomidate therapy, the blood pressure remained normal, sedative agents were slowly weaned, and the patient required few PRN medications. On day 6 of etomidate, the osmolar gap increased to 127 mOsm/kg and etomidate was discontinued. Continuous-infusion ketamine was started, but the blood pressure was not controlled. Metabolic acidosis is a known side effect of etomidate due to inclusion of propylene glycol as a pharmaceutical solvent in the formulation. Despite high-dose etomidate (20 mcg/kg/min) for approximately 6 days, our patient did not experience metabolic acidosis. Absence of this adverse effect caused us to question the role of the ECMO circuit. To our knowledge, this is the first report of the use of continuous-infusion etomidate during ECMO. Etomidate infusion could be considered in difficult-to-manage patients after other alternatives have failed. PMID- 28337084 TI - Therapeutic Drug Monitoring of Continuous Infusion Doripenem in a Pediatric Patient on Continuous Renal Replacement Therapy. AB - An 11-year-old African American male with severe combined immunodeficiency variant, non-cystic fibrosis bronchiectasis, pancreatic insufficiency, chronic mycobacterium avium-intracellulare infection, chronic sinusitis, and malnutrition presented with a 1-week history of fevers. He subsequently developed respiratory decompensation and cefepime was discontinued and doripenem was initiated. Doripenem was the carbapenem used due to a national shortage of meropenem. By day 7 the patient (24.7 kg) had a positive fluid balance of 6925 mL (28% FO), and on days 7 into 8 developed acute kidney injury evidenced by an elevated serum creatinine of 0.68 mg/dL, an increase from the baseline of 0.28 mg/dL. On day 9, the patient was initiated on continuous renal replacement therapy (CRRT) and the doripenem dosing was changed to a continuous infusion of 2.5 mg/kg/hr (60 mg/kg/day). Approximately 12.5 hours after the start of the doripenem a serum concentration was obtained, which was 4.01 mg/L corresponding to a clearance of 10.5 mL/min/kg. The pediatric dosing and pharmacokinetic data available for doripenem suggest a clearance estimate of 4.4 to 4.8 mL/min/kg, and the adult clearance estimate is 2.4 to 3.78 mL/min/kg. The calculated clearance in our patient of 10.5 mL/min/kg is over double the highest clearance estimate in the pediatric literature. This case demonstrates that doripenem clearance is significantly increased with CRRT in comparison with the published pediatric and adult data. An appropriate pharmacodynamic outcome (time that free drug concentration > minimum inhibitory concentration) can be achieved by continuous infusion doripenem with concurrent therapeutic drug monitoring. PMID- 28337085 TI - Duty to Advocate: Human Papillomavirus Vaccination. AB - Despite the excellent benefit-to-risk ratio for human papillomavirus (HPV) vaccination and recommendations for its routine use from the Advisory Committee on Immunization Practices (ACIP), significant controversy surrounding HPV vaccination continues to exist. In light of this controversy and continued low rates of vaccination among U.S. adolescents, the Pediatric Pharmacy Advocacy Group (PPAG) endorses the safety and efficacy of HPV vaccination and agrees with ACIP recommendations for protection of the U.S. population against the potentially severe consequences of HPV. The PPAG recommends that all eligible individuals undergo vaccination. We further recommend that pediatric pharmacists participate in the education of patients and their families and serve as advocates for HPV vaccination. This document serves as an update to the 2008 PPAG position statement.1. PMID- 28337086 TI - Pediatric Antimicrobial Stewardship Programs. AB - The frequent use of antimicrobials in pediatric patients has led to a significant increase in multidrug-resistant bacterial infections among children. Antimicrobial stewardship programs have been created in many hospitals in an effort to curtail and optimize the use of antibiotics. Pediatric-focused programs are necessary because of the differences in antimicrobial need and use among this patient population, unique considerations and dosing, vulnerability for resistance due to a lifetime of antibiotic exposure, and the increased risk of adverse events. This paper serves as a position statement of the Pediatric Pharmacy Advocacy Group (PPAG) who supports the implementation of antimicrobial stewardship programs for all pediatric patients. PPAG also believes that a pediatric pharmacy specialist should be included as part of that program and that services be covered by managed care organizations and government insurance entities. PPAG also recommends that states create legislation similar to that in existence in California and Missouri and that a federal Task Force for Combating Antibiotic-Resistant Bacteria be permanently established. PPAG also supports post doctoral pharmacy training programs in antibiotic stewardship. PMID- 28337087 TI - Medication Dosage in Overweight and Obese Children. AB - Approximately 31.8% of U.S. children ages 2 to 19 years are considered overweight or obese. This creates significant challenges to dosing medications that are primarily weight based (mg/kg) and in predicting pharmacokinetics parameters in pediatric patients. Obese individuals generally have a larger volume of distribution for lipophilic medications. Conversely, the Vd of hydrophilic medications may be increased or decreased due to increased lean body mass, blood volume, and decrease percentage of total body water. They may also experience decreased hepatic clearance secondary to fatty infiltrates of the liver. Hence, obesity may affect loading dose, dosage interval, plasma half-life, and time to reach steady-state concentration for various medications. Weight-based dosing is also a cause for potential medication errors. This position statement of the Pediatric Pharmacy Advocacy Group recommends that weight-based dosing should be used in patients ages < 18 years who are < 40 kg; weight-based dosing should be used in patients >= 40 kg, unless, unless the recommended adult dose for the specific indication is exceeded; clinicians should use pharmacokinetic analysis for adjusting medications in overweight/obese children; and research efforts continue to evaluate dosing of medications in obese/overweight children. PMID- 28337088 TI - THE TREASURE CALLED ANTIBIOTICS. PMID- 28337089 TI - EVALUATION OF THE ENVIRONMENTAL NOISE LEVELS IN ABUJA MUNICIPALITY USING MOBILE PHONES. AB - BACKGROUND: Noise remains a nuisance which impacts negatively on the physical, social and psychological wellbeing of man. It aggravates chronic illnesses like hypertension and other cardiopulmonary diseases. Unfortunately, increased activities from industrialization and technological transfers/drifts have tumultuously led to increased noise pollution in most of our fast growing cities today and hence the need for concerted efforts in monitoring and regulating our environmental noise. OBJECTIVE: To assess the equivalent noise level (Leq) in Abuja municipality and promote a simple method for regular assessment of Leq within our environment. METHOD: This is a cross-sectional community based study of the environmental Leq of Abuja municipality conducted between January 2014 and January 2016. The city was divided into 12 segments including residential, business and market areas via the Abuja Geographic Information System. The major markets were captured separately on a different scale. Measurements were taken with the mobile phone softwares having validated this with Extech 407730 digital sound level meter, serial no Z310135. Leq(A) were measured at different points and hours of the day and night. The average Leq(A) were classified according to localities and compared with WHO standard safety levels. RESULTS: LeqD ranged 71 92dB(A); 42-79dB(A) and 69-90dB(A) in business/ parks, residential and market places respectively. The Night measurements were similar 18dB(A)-56dB(A) and the day-night Leq(A)=77.2dB(A) and 90.4dB(A) for residential and business zones. CONCLUSION: The night noise levels are satisfactory but the day and day-night levels are above the recommended tolerable values by WHO and therefore urgently call for awareness and legislative regulations. PMID- 28337090 TI - IS THE CHILD-TO-CHILD APPROACH USEFUL IN IMPROVING UPTAKE OF EYE CARE SERVICES IN DIFFICULT-TO-REACH RURAL COMMUNITIES? EXPERIENCE FROM SOUTHWEST NIGERIA. AB - BACKGROUND: To determine if primary school pupils aged 9-14 years can be satisfactorily trained, using the child-to- parent approach, to assess vision, refer and motivate people to attend screening eye camps. METHOD: Ninety pupils aged 9-14 years attending two purposively-selected primary schools were selected by simple random sampling. Using the child-to-parent approach and Snellens 6/60 illiterate E-chart, participants had a three-day knowledge and skill-based training followed by 2 days of community-based vision assessment and referral of those assessed. The adequacy and success of the training were assessed by comparing preand post-test scores. RESULTS: Three hundred and thirty-six persons were referred and examined; of these, 142 (42.3%) persons were reviewed. Overall, there was significant improvement in knowledge. The accuracy of assessments was 82.1% for Right Eyes (RE), 83.3% for Left Eyes (LE) and 72.1% for presbyopia. The sensitivities for the RE, LE and presbyopia were 84.8%, 86.1% and 76.3% respectively. Similarly, the specificities were 44.4% for RE, 50.0% for LE and 68.6% for presbyopia. The performances were not significantly influenced by age, sex and locality. CONCLUSION: Children aged 9-14 years in primary schools can be empowered, using the child-to-child approach, to assess vision and motivate members of their communities to utilize available eye care services. PMID- 28337091 TI - A SURVEY OF DISPOSITION OF PHYSICIANS TOWARDS PHYSICAL ACTIVITY PROMOTION AT TWO TERTIARY HOSPITALS IN NORTH-EASTERN NIGERIA. AB - BACKGROUND: A general presumption is that any advice from physicians would likely be taken seriously by patients, and patients are more likely to see their doctors in the event of any health complaints than any other health professionals. The perceptions and practice of Nigerian physicians on their role in physical activity promotion are not well known. This study aimed to determine the knowledge of physical activity message, confidence, role perceptions, barriers and feasibility of physical activity promotion among physicians in two tertiary health institutions in North-Eastern Nigeria. METHOD: A total of 153 (84.5% response) physicians at the University of Maiduguri Teaching Hospital and Federal Medical Center Yola completed a previously developed questionnaire that elicited information on their knowledge, barrier, feasibility, role and confidence in physical activity promotion. RESULTS: Physicians in this study reported fairly good knowledge (mean score=14.7+/-2.2/20), minimal or little barrier to physical activity promotion (mean score=24.4+/-3.5/30), perceived physical activity promotion as their role (mean score=12.9+/-1.6/15), were confident in their ability to discuss and recommend exercises for physical activity promotion (mean score=7.9+/-1.3/ 10) and believed promoting physical activity was feasible for them (mean score=15.0+/-2.5/20). The physicians had good disposition to physical activity promotion (Mean score=78.5+/-6.7/100), but male physicians showed better disposition than their female counterparts. CONCLUSION: Overall these cohorts of physicians are somewhat knowledgeable on physical activity promotion and are positively disposed to promoting physical activity among their patients. These findings can be leveraged upon to optimize outcome of campaigns or interventions to change physical activity behaviour in Nigerian populace. PMID- 28337092 TI - PATRONAGE AND COST OF MALARIA TREATMENT IN PRIVATE HOSPITALS IN IBADAN NORTH L.G.A SOUTH WESTERN, NIGERIA. AB - BACKGROUND: Malaria accounts for about 60% of all clinic attendance in Nigeria. About 300,000 children die of malaria annually while an estimated 4,500 pregnant women are lost annually on account of malaria in Nigeria alone. High cost of treatment is a barrier to the uptake of health services in low resource settings, therefore an exploration of the cost of malaria management will reveal possible components that may benefit from intervention and thus reveal important clues for improving access to malaria treatment. Objective of this study therefore is to describe patronage and cost of malaria treatment in private hospitals in Ibadan. METHOD: This was a descriptive cross sectional study, carried out in private hospitals in Ibadan, South Western Nigeria. A self-administered questionnaire with open and close-ended questions was used to collect data on patronage and cost of treatment in adults, children and pregnant women attending private health facilities in Ibadan, Nigeria. Data were presented using tables of frequencies and proportions while analysis was by descriptive statistics. RESULTS: A total of 40 doctors and hospitals participated in the study. Average patronage for malaria, both complicated and uncomplicated per month was 153 patients per hospital. Malaria cases accounts for 331 (46.2%) of total clinic cases seen in private hospitals in a month. About 121 (78%) of malaria cases seen were uncomplicated while 32 (21%) of cases were complicated malaria. Average amount charged patient for treating uncomplicated malaria in private hospitals was N3,941. Average amount spent on antimalarial drugs was about N2,443 (62%) while N1,064 (27.7%) was spent on laboratory investigation and N406.00 (10.3%) for medical consultation. CONCLUSION: Drugs cost constitute the bulk of expenses on malaria treatment. Policy makers may improve access to malaria treatment by subsidizing the cost of anti-malaria drugs for pregnant women and children, who might not be able to afford treatment. PMID- 28337093 TI - ASSESSMENT OF SOCIOECONOMIC STATUS AND CONTROL OF ASTHMA IN ADULTS. AB - BACKGROUND: Asthma is a chronic disease which places considerable economic, social and public health burdens on the society. Education, occupation and income are the most widely used indicators of socioeconomic status (SES). Studies have shown increased asthma hospital admissions for those who are materially deprived and increased asthma severity in low social class groups. The aim of this study is to determine the impact of socioeconomic status on control of asthma in adults. METHOD: The study was a cross-sectional analytical one, conducted over a year at the Medical Outpatient Clinic of the University College Hospital Ibadan. The study population was composed of 355 randomly selected adults aged between 18years and 55years with an established diagnosis of asthma already on treatment. RESULTS: Respondents with monthly income of 40000 and above had a higher proportion with good asthma control (74.1%) compared to those that earned 10000 to 39999 (69.0%) and less than 10000 (47.8%). This was statistically significant. Respondents in occupational class I/II had a slightly higher proportion with good asthma control (70.9%) compared to those in occupation class III/IV (70.1%) and occupation class V/VI (50.6%). This was statistically significant at p = 0.003. CONCLUSION: Respondents in the higher occupational class had better asthma control than respondents in the lower occupational class. Respondents who were earning 40000 and above as monthly income had better control of asthma than other respondents. After adjusting for other variables, the predictor of good asthma control was monthly income of the respondents. PMID- 28337094 TI - PREVALENCE AND CORRELATES OF JOB STRESS AMONG JUNIOR DOCTORS IN THE UNIVERSITY COLLEGE HOSPITAL, IBADAN. AB - BACKGROUND: Doctors respond differently to their complex work environment, some find it stimulating while others find it stressful. This study aimed to assess the prevalence and correlates of stress among junior doctors in a teaching hospital in Southwest Nigeria. METHOD: A descriptive cross sectional survey of all junior doctors employed at the University College Hospital, Ibadan was carried out. Information was collected with a structured pretested questionnaire from 253 doctors. Descriptive statistics were generated. T-test, chi square and logistic regression analyses were conducted using SPSS version 16. Statistical significance was set at 5%. RESULTS: Mean age of respondents was 29.9 (+/-4.1) years, 61.3% were males, 59% had spent less than 5 years in medical practice, and 34.8% were married. Majority (79.4%) were resident doctors. Prevalence of stress, job dissatisfaction and poor mental health were 31.6%, 15.4% and 9.9% respectively. Age, gender, years of medical practice, religion, ethnicity and marital status were not significantly associated with job stress (p>0.05). Doctors who were stressed were more likely to be dissatisfied with their jobs (OR=2.33; CI=1.08-4.04) and to have poor mental health (OR=3.82; CI=1.47-9.95) than those who were not stressed. CONCLUSION: The prevalence of stress in this study is high, and job dissatisfaction and poor mental health have been implicated as determinants of stress. As such, there should be an improvement in doctors' welfare, health care facilities and delivery. PMID- 28337095 TI - ROUTINE SALINE INFUSION SONOHYSTEROGRAPHY PRIOR TO ASSISTED CONCEPTION: A REVIEW OF OUR INITIAL EXPERIENCE. AB - Saline infusion sonohysterography has been employed to evaluate the uterine cavity prior to commencement of assisted conception.Intra-uterine lesions play an important role in the outcome of assisted conception procedures. A descriptive retrospective study of 760 patients who had saline infusion sonohysterography prior to assisted conception, between January 2008 and December, 2010. Forty-six percent of the patients had intra-uterine pathologies. Submucous fibroids accounted for almost half (48.57%) of the pathologies, followed by adhesions (28.57%) and endometrial polyps (22.86%). Complications arising from the procedure were minor and occurred in 26 patients (3.42%). Abdominal cramps, vaginal bleeding and vaginal discharge occurred in 14 (53.85%), 8 (30.77%) and 4 (15.38%) respectively. The average duration of the procedure was 6 minutes with a range of 4-9 minutes. Saline infusion sonohysterography is a reliable, cost effective and safe diagnostic tool in the evaluation of the uterine cavity prior to assisted conception. PMID- 28337096 TI - MORPHOLOGICAL PATTERN OF ENDOMETRIAL BIOPSIES IN SOUTHWESTERN NIGERIA. AB - BACKGROUND: Endometrium remains the most sensitive indicator of ovarian function and endometrial biopsy is one of the diagnostic procedures in endometrial pathology. The current study was carried out to examine the morphological pattern of endometrial biopsies in Ibadan, South-western Nigeria and compare the results with similar studies. METHOD: A retrospective study was undertaken to review all cases of endometrial biopsies received in the Department of Pathology, University College Hospital, Ibadan between January 1999 and December 2008. The patients' data were retrieved from the surgical pathology daybooks and Histology Request forms. The neoplastic lesions were classified according to 2003 World Health Organization classification for endometrial neoplasms. RESULTS: A total of 2,444 cases of endometrial biopsies were received during the 10-year study period. The functional endometrial changes were the most common histopathological diagnostic category, accounting for 53.8% (1035) of cases. Other pathological diagnoses included endometritis (7.8%), simple endometrial hyperplasia (5.8%), partial hydatidiform mole (2.3%), complete hydatidiform mole (2.1%) and malignant neoplastic lesions (3.9%). Infertility was the most common (57%) indication for endometrial biopsies followed by uterine bleeding (33%) while the least common clinical indication were the menstrual disorders (10%). CONCLUSION: The functional endometrial changes account for the highest morphological patterns while malignant lesions account for the least pattern of the endometrial biopsies evaluated for etiological basis of infertility, uterine bleeding and menstrual disorders in Ibadan. Infertility was the commonest indication for endometrial biopsies while the least common clinical indication was menstrual disorders. PMID- 28337097 TI - NEUROMUSCULAR DISEASE MIMICKING MYASTHENIA GRAVIS IN A NIGERIAN FEMALE ADOLESCENT: COULD THIS BE NEMALINE ROD DISEASE? AB - BACKGROUND: Nemaline rod disease is a congenital myopathy, presentation of which may mimic myasthenia gravis. METHOD: We report a suspected case of nemaline rod disease in a female adolescent who presented with features similar to myasthenia gravis but failed to respond effectively to its conventional management. She had features of respiratory failure and cardiomyopathy. RESULTS: Patient had a turbulent clinical course and finally succumbed to illness on the fifth day of admission. CONCLUSION: This report is meant to sensitize child neurologists and general paediatricians on the need to have a broad spectrum of considerations in the management of suspected myasthenia gravis, especially when response to anticholinesterase is poor. PMID- 28337098 TI - Effect of undifferentiated versus hepatogenic partially differentiated mesenchymal stem cells on hepatic and cognitive functions in liver cirrhosis. AB - Liver cirrhosis is the outcome of chronic liver injury. The current study aimed to investigate the therapeutic effect of undifferentiated mesenchymal stem cells versus in vitro partially differentiated mesenchymal stem cells on liver cirrhosis and hepatic encephalopathy. 50 adult male albino rats constituted the animal model and were divided into the following groups: control, thioacetamide, undifferentiated mesenchymal stem cells and hepatocyte growth factor differentiated mesenchymal stem cells groups. Cognitive assessment was achieved by open field test and Y-maze task. We measured serum alanine aminotransferase, albumin and transforming growth factor-beta1, gene expression of alpha-smooth muscle actin, matrix metalloprotein-2, its tissue inhibitor and apoptotic markers: Bax and Bcl2, brain glial fibrillary acidic protein, synaptophysin, and dopaminergic receptors. PMID- 28337099 TI - Development and validation of instrument for ergonomic evaluation of tablet arm chairs. AB - The purpose of this study was to develop and validate an evaluation instrument for tablet arm chairs based on ergonomic requirements, focused on user perceptions and using Item Response Theory (IRT). This exploratory study involved 1,633 participants (university students and professors) in four steps: a pilot study (n=26), semantic validation (n=430), content validation (n=11) and construct validation (n=1,166). Samejima's graded response model was applied to validate the instrument. The results showed that all the steps (theoretical and practical) of the instrument's development and validation processes were successful and that the group of remaining items (n=45) had a high consistency (0.95). This instrument can be used in the furniture industry by engineers and product designers and in the purchasing process of tablet arm chairs for schools, universities and auditoriums. PMID- 28337100 TI - Effect of prolyl hydroxylase domain 2 haplodeficiency on liver progenitor cell characteristics in early mouse hepatocarcinogenesis. AB - Activation of the hypoxia-inducible factor (HIF)-pathway in hepatocellular carcinoma (HCC) induces therapy resistant tumours, characterized by increased liver progenitor cell (LPCs) characteristics and poor prognosis. We previously reported corresponding results in mice with HCC in which hypoxia was mimicked by prolyl hydroxylase domain (PHD) inhibition. Here, we aimed at investigating whether induction of LPC characteristics occurs during the onset of hepatocarcinogenesis and if this is associated with activation of Notch signalling. Dietheylnitrosamine (DEN) was used to induce hepatic tumours in PHD2 haplodeficient (PHD2+/-) mice which were euthanized at 5, 10, 15 and 17 weeks following DEN during neoplastic transformation, before tumour formation. Neoplasia and mRNA expression of LPC and Notch markers were evaluated by histology and qPCR on isolated livers. PHD2 haplodeficiency resulted in enhanced expression of HIF target genes after 17 weeks of DEN compared to wild type (WT) littermates but had no effect on the onset of neoplastic transformation. The mRNA expression of Afp and Epcam was increased at all time points following DEN whereas CK19, Prom1 and Notch3 were increased after 17 weeks of DEN, without difference between PHD2+/- and WT mice. MDR1 mRNA expression was increased in all DEN treated mice compared to saline control with increased expression in PHD2+/- compared to WT from 15 weeks. These results indicate that the effects of PHD2 haplodeficiency on the expression of LPC and Notch markers manifest during tumour nodule formation and not early on during neoplastic transformation. PMID- 28337102 TI - Peritoneal tuberculosis with elevated CA-125 mimicking ovarian cancer with carcinomatosis peritonei: Crucial CT findings. AB - Preoperative diagnosis of peritoneal tuberculosis is often difficult because of confusion with ovarian cancer. A 56-year-old woman was admitted to our hospital with abdominal fullness. Ascites, prominent bilateral ovaries, and elevated CA 125 were noted. Computed tomography showed thickened peritoneum and strandings in the mesentery and omentum. Exploratory laparotomy was performed under the provisional diagnosis of ovarian cancer, but the final diagnosis was peritoneal tuberculosis. Careful evaluation of bilateral fallopian tubes and ovaries and peritoneum are helpful for correct diagnosis. PMID- 28337101 TI - Anti-cancer activities of Brassica juncea leaves in vitro. AB - Mustard (Brassica juncea) leaves are commonly consumed in different Asian and African countries. Cancer is a major burden of disease worldwide, and the colorectal and lung cancers are the leading cause of morbidity and mortality among cancers. In the current study, we aimed to investigate the effects of ethanol extract of mustard leaf (MLE) on the growth, angiogenic, and metastatic potentials of HCT116 colorectal carcinoma and H1299 non-small cell lung carcinoma cells in vitro. Treatment of HCT116 and H1299 cells with MLE inhibited cell growth in a dose-dependent manner (in the range of 175-700 ug/ml, by 39-86 %) and anchorage-independent colonization (at 700 ug/ml, by 56-86 %). Induction of apoptosis by MLE was evidenced by heterogeneous and condensed nucleus morphology, increased 4',6-diamidino-2-phenylindole dihydrochloride staining intensity, and elevated sub-G1 cell population. In both HCT116 and H1299 cells, treatment with MLE markedly suppressed the secretion of key pro-angiogenic factors, such as vascular endothelial cell growth factor (by >92 %) and basic fibroblast growth factor (by 73-94 %). MLE was also effective in inhibiting critical events during metastasis, such as invasion (by 18-33 % in HCT116 and H1299), migration (45-82 % in H1299), and adhesion (by 17-45 % in HCT116 and H1299). These results indicate that MLE possesses in vitro anti-cancer activities against colon and lung cancers. It needs to be verified whether similar effects are reproduced in vivo. PMID- 28337103 TI - Tiagabine treatment in kainic acid induced cerebellar lesion of dystonia rat model. AB - Dystonia is a neurological disorder characterized by excessive involuntary muscle contractions that lead to twisting movements. The exaggerated movements have been studied and have implicated basal ganglia as the point of origin. In more recent studies, the cerebellum has also been identified as the possible target of dystonia, in the search for alternative treatments. Tiagabine is a selective GABA transporter inhibitor, which blocks the reuptake and recycling of GABA. The study of GABAergic drugs as an alternative treatment for cerebellar induced dystonia has not been reported. In our study, tiagabine was i.p. injected into kainic acid induced, cerebellar dystonic adult rats, and the effects were compared with non tiagabine injected and sham-operated groups. Beam walking apparatus, telemetric electromyography (EMG) recording, and histological verification were performed to confirm dystonic symptoms in the rats on post-surgery treatment. Involuntary dystonic spasm was observed with repetitive rigidity, and twisting movements in the rats were also confirmed by a high score on the dystonic scoring and a high amplitude on the EMG data. The rats with tiagabine treatment were scored based on motor amelioration assessed via beam walking. The result of this study suggests and confirms that low dose of kainic acid microinjection is sufficient to induce dystonia from the cerebellar vermis. In addition, from the results of the EMG recording and the behavioral assessment through beam walking, tiagabine is demonstrated as being effective in reducing dystonic spasm and may be a possible alternative therapeutic drug in the treatment of dystonia. PMID- 28337104 TI - Synthesis and antimalarial potential of some novel quinoline-pyrazolopyridine derivatives. AB - A series of 1-(4-methylquinolin-2-yl)-4,6-diaryl-1H-pyrazolo[3,4-b]pyridin-3 amine derivatives was synthesized by the reaction of 3-cinnamoyl-4-hydroxy-6 methyl-2H-pyran-2-ones with 2-chloro-4,6-diphenylnicotinonitrile analogues in the presence of 2-hydrazino-4-methyl quinoline and ethanol. The newly synthesized compounds were characterized by IR, 1H NMR and mass spectral data. The synthetic series of novel quinoline-pyrazolopyridine hybrids were screened for in vitro schizont maturation assay against chloroquine sensitive 3D7 strain of Plasmodium falciparum, from which the most five active analogues were further evaluated for in vivo 4-day suppressive test in Swiss albino mice. Among the series, 5p (containing 4-Cl substituent attached to both aryl ring) portrayed considerable potent antimalarial activity during in vitro as well as in vivo study. PMID- 28337105 TI - Colorectal cancer in Iran: Epidemiology and morphology trends. AB - Colorectal cancer is one of the most prevalent cancers in different countries, including Iran. No comprehensive study has been done in the country for colorectal cancer, but information on the incidence and trends is essential to planning. This study aimed to evaluate the occurrence and morphology of colorectal cancer and its trend in Iran. This study was conducted using data from the national cancer registry system in Iran from 2003-2008. We used joinpoint regression analysis for assessing incidence time trends and morphology change percentage. Of all cases of colorectal cancer, 61.83 % were colon cancer, 27.54 % rectal cancer, 7.46 % rectosigmoid cancer, and 3.10 anal cancer. The most common histological types with the frequencies of 80.85 % was related to adenocarcinoma, NOS. The Annual percentage changes (APC) in ASIR for colorectal cancer significantly increased in both men and women. APC in ASIR was 13.7 (CI: 10.5 17.1) in women and 16.4 (CI: 12.4-20.5) in men. APC of adenocarcinoma in villous adenoma showed significant declining trend (p<0.05), while APC of adenocarcinoma, NOS had a constant trend. The incidence of the cancer in recent years has increased in Iran because of changes in lifestyle and diet. Therefore, further studies are necessary to detect the cause of this cancer and perform preventive measures. PMID- 28337106 TI - AEG-1 is associated with hypoxia-induced hepatocellular carcinoma chemoresistance via regulating PI3K/AKT/HIF-1alpha/MDR-1 pathway. AB - Hypoxia is a common characteristic of hepatocellular carcinoma (HCC) associated with reduced response to chemotherapy, thus increasing the probability of tumor recurrence. Astrocyte elevated gene-1 (AEG-1) has been involved in a wide array of cancer progression including proliferation, chemoresistance, angiogenesis and metastasis, but its effect on HCC chemoresistance induced by hypoxia is unclear. In this study, expression of AEG-1 and multiple drug resistance (MDR-1) were examined in HCC using immunohistochemical staining and RT-PCR. Furthermore, their expression levels were detected in HCC HepG2 cells in normoxia or hypoxia via RT PCR and Western blot assays. Specific shRNAs were used to silence AEG-1 expression in HepG2 cells. Results showed AEG-1 and MDR-1 expression were higher in HCC tissues than in adjacent normal tissues. Incubation of HepG2 cells in hypoxia increased expression of AEG-1 and MDR-1, compared to incubation in normoxia. Exposure to hypoxia blunted sensitivity of HepG2 cells to Adriamycin, 5 fluorouracil and cis-platinum, as evidenced by modest alterations in cell viability and apoptosis rate, however the sensitivity was elevated with AEG-1 knockdown. PI3K/AKT/HIF-1/MDR-1 pathway was attenuated following AEG-1 knockdown in hypoxia. Based on these data, it was suggested that AEG-1 is associated with hypoxia-induced hepatocellular carcinoma chemoresistance via regulating PI3K/AKT/HIF-1/MDR-1 pathway. This study uncovered a novel potential target for development of an effective therapy against hypoxia-induced HCC chemoresistance. PMID- 28337107 TI - Lupane-type triterpenes and their anti-cancer activities against most common malignant tumors: A review. AB - In recent times, a great deal of interest has been motivated on plant derived compounds known as nutraceuticals. These compounds exert important beneficial activities that improve people's health status when are consumed regularly, and now they appear as a viable option to explore their possible therapeutic effects against diseases like cancer. Particularly, lupane-type triterpenes have shown great ability to modulate multiple cancer-related signaling pathways and processes, including NF-kappaB, Wnt/beta-catenin, PI3K/Akt, apoptosis, and many other routes related to proliferation or cell death, which are uncontrolled in malignant tumors. These investigations have promoted in vitro and in vivo studies, searching their mechanisms of action; although more research is still needed to prove its potential in human clinical trials. This review focuses on the ability of betulin, betulinic acid and lupeol to show benefits against the most common types of malignant tumors, which are considered a major global threat for public health. PMID- 28337108 TI - Bromelain capped gold nanoparticles as the novel drug delivery carriers to aggrandize effect of the antibiotic levofloxacin. AB - To develop bromelain capped gold nanoparticles (BRN capped Au-NPs) as the effective drug delivery carriers of the antibiotic levofloxacin (LvN) and evaluate antibacterial potential of its bioconjugated form compared to pure LvN. BRN capped Au-NPs were synthesized by in vitro method and bioconjugated to LvN using 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide as activator to form Au-BRN LvN-NPs. These were characterized for mean particle size by dynamic light scattering analysis, zeta potential by Zetasizer nanosystem analysis and transmission electron microscopy (TEM) on carbon coated TEM copper grids by TEM respectively. Drug loading efficiency of LvN was calculated using UV-visible spectroscopy by standard curve of pure LvN. Antibacterial efficacy of Au-BRN-LvN NPs and pure LvN was determined by evaluating minimum inhibitory concentration (MIC) against Staphylococcus aureus and Eschereschia coli. Two peaks were observed in Au-BRN-LvN-NPs spectrum one at 307 nm and other at 526 nm while one peak in BRN capped Au-NPs at 522 nm during UV spectroscopy suggesting red shift. The drug loading efficiency of LvN was found to be 84.8 +/- 2.41 %. The diameter of Au-BRN-LvN-NPs and BRN capped Au-NPs were found to be (58.65 +/- 2 nm, 38.11 +/- 2 nm), zeta potential (-9.01 mV, -13.8 mV) and surface morphology (~13.2 nm, 11.4 nm) respectively. The MICs against S. aureus and E. coli were found to be (0.128 ug/mL, 1.10 ug/mL) for Au-BRN-LvN-NPs and (0.547 ug/mL, 1.96 ug/mL) for pure LvN. The results suggested that BRN capped Au-NPs can be used as effective drug delivery carriers of the antibiotic LvN. The Au-BRN-LvN-NPs exhibited enhanced antibacterial activity compared to pure LvN alone. (Graphical abstract see Figure 1(Fig. 1)). PMID- 28337110 TI - The effect of hydroalcoholic extract of Achillea eriophora DC. on blood pressure of anaesthetized male rat. AB - Achillea eriophora (Asteraceae) is a medicinal plant commonly used in Iran. This study was performed to determine the cardiovascular effects of hydroethanolic extract of A. eriophora (HEAE) and the underlying mechanisms in anaesthetized rats. The acute effects of intravenous (i.v.) administration of different doses of HEAE (40, 50, 60, 80 mg/kg), and its probable interaction with cholinergic and nitrergic systems were investigated in the presence of ACh and NOS blocker (L NAME) as well as ethanol (HEAE solvent in sham group). Intravenous administration of different doses of HEAE induced hypotension. HEAE (60 mg/kg) significantly reduced mean arterial blood pressure (MAP), systolic arterial blood pressure (SBP) and diastolic arterial blood pressure (DBP) compared to control rats that treated with ethanol only, but no change in heart rate (HR) was seen in both groups. The results showed significant decrease in MAP, SBP, DBP and increase of HR in the presence of HEAE plus ACh (10 ug/kg) compared to when ACh was injected alone. Finally i.v. administration of HEAE, significantly reduced MAP and DBP in L-NAME (5 mg/kg) treated animals, while bradycardic responses to L-NAME were not significantly changed by HEAE. It can be concluded that Achillea eriophora induced hypotensive effect via lowering total peripheral resistance and cardiac output that may be synergist with cholinergic and independent of nitrergic system. PMID- 28337109 TI - Discovery of novel phthalimide analogs: Synthesis, antimicrobial and antitubercular screening with molecular docking studies. AB - In continuation of our endeavor towards the design and development of potent and effective antimicrobial agents, three series of phthalimide derivatives (4a-i, 5a f, and 6a-c) were synthesized, fully characterized and evaluated for their potential antibacterial, antifungal and antimycobacterial activities. These efforts led to the discovery of nine compounds 4c, 4f, 4g, 4h, 4i, 5c, 5d, 5e, and 6c (MIC range from 0.49 to 31.5 MUg/mL) with potent antibacterial, antifungal, and antimycobacterial activities. Ampicillin, ciprofloxacin, amphotericin B were used as references for antibacterial and antifungal screening respectively, while isoniazid was used as a reference for antimycobacterial testing. Furthermore, molecular modeling studies were done to explore the binding mode of the most active derivatives to M. tuberculosis enoyl reductase (InhA) and DNA gyrase B. Our study showed the importance of both hydrogen bonding and hydrophobic interactions as a key interaction with the target enzymes. PMID- 28337111 TI - Hepato- and nephroprotective effects of bradykinin potentiating factor from scorpion (Buthus occitanus) venom on mercuric chloride-treated rats. AB - Bioactive peptides such as bradykinin potentiating factor (BPF), have, anti oxidative, anti-inflammatory, immunomodulatory and ameliorative effects in chronic diseases and play a potential role in cancer prevention. It is known that the liver and kidney accumulate inorganic mercury upon exposure, which often leads to mercury intoxication in these organs. In this study, we investigated the effect of bradykinin potentiating factor (BPF), a scorpion venom peptide, on mercuric chloride-induced hepatic and renal toxicity in rats. We used 20 adult male Albino rats divided into four equal groups: the first group was injected with saline (control); the second group was administered daily with mercuric chloride (HgCl2) for 2 weeks; the third group was administered with BPF twice weekly for 2 successive weeks, while the fourth group was exposed to BPF followed by HgCl2. We observed that HgCl2 treated rats had a significant increase in serum ALT, AST, ALP, creatinine and urea levels compared to control. Furthermore, HgCl2 treated rats showed a marked decrease in total proteins, albumin and uric acids compared to control. The previously studied parameters were not significantly changed in BPF pretreated rats compared to control. Moreover, a significant decrease in the activities of glutathione perioxidase (GSH), superoxide dismutase (SOD), and catalase (CAT), in addition to a significant increase in the level of malondialdehyde (MDA) were observed in hepatic and renal tissues of rats after HgCl2 treatment. In contrast, the HgCl2/BPF treated rats showed a significant elevation in the activity of GSH, SOD, and CAT accompanied with a significant regression in the level of MDA compared to the HgCl2 exposed rats. We conclude that treatment with BPF is a promising prophylactic approach for the management of mercuric chloride-induced hepato- and nephro-toxicities. PMID- 28337112 TI - The past and present of serum aminotransferases and the future of liver injury biomarkers. AB - Laboratory testing is important in the diagnosis and monitoring of liver injury and disease. Current liver tests include plasma markers of injury (e.g. aminotransferases, gamma-glutamyl transferase, and alkaline phosphatase), markers of function (e.g. prothrombin time, bilirubin), viral hepatitis serologies, and markers of proliferation (e.g. alpha-fetoprotein). Among the injury markers, the alanine and aspartate aminotransferases (ALT and AST, respectively) are the most commonly used. However, interpretation of ALT and AST plasma levels can be complicated. Furthermore, both have poor prognostic utility in acute liver injury and liver failure. New biomarkers of liver injury are rapidly being developed, and the US Food and Drug Administration the European Medicines Agency have recently expressed support for use of some of these biomarkers in drug trials. The purpose of this paper is to review the history of liver biomarkers, to summarize mechanisms and interpretation of ALT and AST elevation in plasma in liver injury (particularly acute liver injury), and to discuss emerging liver injury biomarkers that may complement or even replace ALT and AST in the future. PMID- 28337113 TI - Chemical composition and inhibitory effects of water extract of Henna leaves on reactive oxygen species, DNA scission and proliferation of cancer cells. AB - From the centuries, Lawsonia inermis L. (Henna) is utilized in traditional health care system as a medicinal and cosmetic agent. The present study was intended to assess antiradical, DNA protective and antiproliferative activity of water extract of Lawsonia inermis L. leaves (W-LI). Antioxidant activity was estimated using various in vitro assays such as DPPH, ABTS, superoxide anion radical scavenging, FRAP, deoxyribose degradation and DNA protection assay. Growth inhibitory effects of W-LI were assessed using MTT assay against different cancer cell lines viz. HeLa, MCF-7, A549, C6 and COLO-205. From the results of antioxidant assays, it was found that W-LI quenched DPPH and ABTS cation radicals with IC50 value of 352.77 ug/ml and 380.87 ug/ml respectively. It demonstrated hydroxyl radical scavenging potential of 59.75 % at highest test dose of 1000 ug/ml in deoxyribose degradation assay. The results of FRAP assay showed that W LI also possesses significant reducing activity. Extract inhibited hydroxyl radical induced pBR322 plasmid DNA strand scission, thus conferring DNA protection. Growth inhibition of various cancer cell lines was achieved to the varying extent on treatment with W-LI. Further, it was observed that activity was quite promising against colon cancer COLO-205 cells (GI50 121.03 ug/ml). HPLC profiling of W-LI revealed the presence of different polyphenolic compounds such as ellagic acid, catechin, quercetin, kaempferol etc. which might be contributing towards antioxidant and cytotoxic activity. The present study demonstrated that polyphenols rich W-LI extract from leaves of L. inermis possesses ability to inhibit oxidative radicals and cancer cells proliferation. PMID- 28337114 TI - Precondition of right frontal region with anodal tDCS can restore the fear memory impairment induced by ACPA in male mice. AB - Fear memory and learning cause behavioural patterns such as fight or flight responses, which increase survival probability, but unfit processing of fear memory and learning can lead to maladaptive behaviours and maladies such as phobias, Post-Traumatic Stress Disorder (PTSD) and anxiety disorders. The growing prevalence of these maladies shows the need to quest novel methods for their treatment. We used anodal transcranial direct current stimulation (tDCS) on the right frontal region as a precondition neuromodulator and arachidonylcyclopropylamide (ACPA), a selective CB1 cannabinoid receptor agonist, as a fear memory impairing agent to assess their effects on contextual and auditory fear conditioning (reliable model for fear studies). Right frontal anodal tDCS (0.2 mA for. 20 minutes) 24 hours before the train did not alter contextual and auditory learning and memory in short-term (24 hrs after the training phase). Moreover, intraperitoneal pre-train injection of ACPA (0.1 mg/kg) alone, decreased both contextual and auditory learning and memory in short but not long-term. Right frontal anodal tDCS improved short-term contextual fear memory in subthreshold doses of ACPA. On the other hand, right frontal anodal tDCS in long-term improved (lower doses of ACPA) and restored (higher doses of ACPA) both fear memories. These findings showed that, aforementioned approach could cause durable learning and memory improvements. Also this combined modality could be useful for fear extinction training and maladies which inflict amnesia. PMID- 28337115 TI - HPLC-DAD analysis, antinociceptive and anti-inflammatory properties of the ethanolic extract of Hyptis umbrosa in mice. AB - Hyptis umbrosa (syn. Mesosphaerum sidifolium) (Lamiaceae Family) has been used to treat several conditions such as gastrointestinal disorders, skin infections, nasal congestion, fever and cramps. The objective of this study was to evaluate the chemical composition, analgesic and anti-inflammatory profiles of ethanol extract from leaves of Hyptis umbrosa (EEB). HPLC-DAD was used to determine the fingerprint chromatogram of the extract. Male Swiss mice were orally pretreated with EEB (100, 200 or 400 mg/kg; 60 min before initiating algesic stimulation) and antinociceptive activity was assessed using the acetic acid-induced writhing model, formalin test and hyperalgesia induced by glutamate or capsaicin. Also, peritonitis was induced by the intrathoracic injection of carrageenan to quantify the total number of leukocytes. The presence of phenolic compounds in the extract was confirmed using HPLC-DAD. The treatment with EEB, at all doses, produced a significant analgesic effect against acetic acid-induced antinociceptive activity. In the formalin test, only the 400-mg/kg-dose of EEB had a significant effect in the first phase. However, all doses tested were able to reverse nociception in the second phase. The effect of all doses of EEB also showed a significant antinociceptive effect in the glutamate and capsaicin tests and inhibited the carrageenan-induced leukocyte migration to the peritoneal cavity. The present study suggests that the EEB possesses peripheral analgesic action and showed potential in reducing the spreading of the inflammatory processes. Also, it seems to be related with vanilloid and glutamate receptors. PMID- 28337116 TI - Assessment of usefulness of synchrotron radiation techniques to determine arsenic species in hair and rice grain samples. AB - The arseniasis in Southwest Guizhou, China has been identified as a unique case of endemic arseniasis caused by exposure to indoor combustion of high As-content coal. Present investigation targeted the microdistribution and speciation of the element arsenic in human hair and environmental samples collected in one of the hyper-endemic villages of arseniasis in the area. Analyses were performed by micro-beam X-ray fluorescence (MU-XRF) and X-ray absorption fine structure (XAFS). The total As level in hair samples of diagnosed patients was detected at almost the same level as in their asymptomatic neighbors. Concentrations in the lateral cut of hair samples were high-low-high (from surface to center). XAFS revealed the coexistence of both the As+3 and As+5 states in hair samples. However, the samples from patients displayed a tendency of higher As+3 / As+5 ratio than the asymptomatic fellow villagers. The MU-XRF mapping of rice grains shows that arsenic penetrates the endosperm, the major edible part of the grain, when rice grains were stored over the open fire of high As-content coal. Synchrotron radiation techniques are suitable to determine arsenic species concentrations in different parts of hair and rice grain samples. As arsenic penetrates the endosperm, rinsing the rice grains with water will remain largely ineffective. PMID- 28337118 TI - Toxicological risk at workplace and toxicity as Life Cycle Assessment impact category: Substitution of solvents as an example. AB - Substitution of hazardous substances against less hazardous ones is a central requirement of the European Chemical Regulation REACH (European Regulation 1907/2006/EC). Hazardous substances emitted from products may not only affect the worker; drift off and distribution in the environment may finally result in exposure of the general population. This potential threat to health is covered by the impact category "toxicity" in Life Cycle Assessments. In this paper, we present a case of a substitution of volatile organic compounds in a reactive varnish, and compare the "old" formulation with the "new" formulation against health risk to the worker, and concerning the Life Cycle Assessment impact category "toxicity". The "old" formulation contained Naphtha (petroleum), hydrodesulfurized, heavy and Solvent naphtha (petroleum), light, aromatic. In the new formulation, both naphthas were replaced by n-Butylacetate, 1-Ethoxy-2-propyl acetate and Ethyl-3-ethoxy propionate. In the European Union, the naphthas are classified as mutagens and carcinogens category 1, officially. However, if benzene is below 0.1 %, registrants in the EU proposed to omit this classification, and todays naptha products on the market obviously have benzene contents below 0.1 %. On a first glance, the improvement for workplace safety introduced by the substitution, therefore, is comparatively small, as it is for toxicity in Life Cycle Assessment. However, when background knowledge concerning chemical production processes of naphtha is included, benzene below a content of 0.1 % needs to be taken into consideration, and the benefit of substitution is more obvious. PMID- 28337117 TI - Pharmacological aspects of galantamine for the treatment of Alzheimer's disease. PMID- 28337119 TI - Analysis of the Precision of Variable Flip Angle T1 Mapping with Emphasis on the Noise Propagated from RF Transmit Field Maps. AB - In magnetic resonance imaging, precise measurements of longitudinal relaxation time (T1) is crucial to acquire useful information that is applicable to numerous clinical and neuroscience applications. In this work, we investigated the precision of T1 relaxation time as measured using the variable flip angle method with emphasis on the noise propagated from radiofrequency transmit field ([Formula: see text]) measurements. The analytical solution for T1 precision was derived by standard error propagation methods incorporating the noise from the three input sources: two spoiled gradient echo (SPGR) images and a [Formula: see text] map. Repeated in vivo experiments were performed to estimate the total variance in T1 maps and we compared these experimentally obtained values with the theoretical predictions to validate the established theoretical framework. Both the analytical and experimental results showed that variance in the [Formula: see text] map propagated comparable noise levels into the T1 maps as either of the two SPGR images. Improving precision of the [Formula: see text] measurements significantly reduced the variance in the estimated T1 map. The variance estimated from the repeatedly measured in vivoT1 maps agreed well with the theoretically-calculated variance in T1 estimates, thus validating the analytical framework for realistic in vivo experiments. We concluded that for T1 mapping experiments, the error propagated from the [Formula: see text] map must be considered. Optimizing the SPGR signals while neglecting to improve the precision of the [Formula: see text] map may result in grossly overestimating the precision of the estimated T1 values. PMID- 28337121 TI - Logo Effects on Brand Extension Evaluations from the Electrophysiological Perspective. AB - Brand extension typically has two strategies: brand name extension (BN) and brand logo extension (BL). The current study explored which strategy (BN or BL) better enhanced the success of dissimilar brand extension and product promotion in enterprises. Event-related potentials (ERPs) were used to investigate electrophysiological processes when subjects evaluated their acceptance of the brand extension using a combined picture of S1 and S2. S1 was a famous brand presented by two identity signs (brand name and brand logo). S2 was a picture of an extension product that belonged to a dissimilar product category than S1. The behavior data showed that BL was more acceptable than BN in the dissimilar brand extension. The neurophysiology process was reflected by a less negative N2 component and a larger P300 component in the BL than in the BN. We suggested that N2 reflected a whole conflict between the brand-product combination and the long term memory and that P300 could be regarded as the reflection of the categorization process in the working memory. PMID- 28337120 TI - Antidyskinetic Effects of MEK Inhibitor Are Associated with Multiple Neurochemical Alterations in the Striatum of Hemiparkinsonian Rats. AB - L-DOPA-induced dyskinesia (LID) represents one of the major problems of the long term therapy of patients with Parkinson's disease (PD). Although, the pathophysiologic mechanisms underlying LID are not completely understood, activation of the extracellular signal regulated kinase (ERK) is recognized to play a key role. ERK is phosphorylated by mitogen-activated protein kinase kinase (MEK), and thus MEK inhibitor can prevent ERK activation. Here the effect of the MEK inhibitor PD98059 on LID and the associated molecular changes were examined. Rats with unilateral 6-OHDA lesions of the nigrostriatal pathway received daily L DOPA treatment for 3 weeks, and abnormal involuntary movements (AIMs) were assessed every other day. PD98059 was injected in the lateral ventricle daily for 12 days starting from day 10 of L-DOPA treatment. Striatal molecular markers of LID were analyzed together with gene regulation using microarray. The administration of PD98059 significantly reduced AIMs. In addition, ERK activation and other associated molecular changes including DeltaFosB were reversed in rats treated with the MEK inhibitor. PD98059 induced significant up-regulation of 418 transcripts and down-regulation of 378 transcripts in the striatum. Tyrosine hydroxylase (Th) and aryl hydrocarbon receptor nuclear translocator (Arnt) genes were down-regulated in lesioned animals and up-regulated in L-DOPA-treated animals. Analysis of protein levels showed that PD98059 reduced the striatal TH. These results support the association of p-ERK1/2, DeltaFosB, p-H3 to the regulation of TH and ARNT in the mechanisms of LID, and pinpoint other gene regulatory changes, thus providing clues for identifying new targets for LID therapy. PMID- 28337122 TI - Cerebrospinal Fluid Cortisol Mediates Brain-Derived Neurotrophic Factor Relationships to Mortality after Severe TBI: A Prospective Cohort Study. AB - Distinct regulatory signaling mechanisms exist between cortisol and brain derived neurotrophic factor (BDNF) that may influence secondary injury cascades associated with traumatic brain injury (TBI) and predict outcome. We investigated concurrent CSF BDNF and cortisol relationships in 117 patients sampled days 0-6 after severe TBI while accounting for BDNF genetics and age. We also determined associations between CSF BDNF and cortisol with 6-month mortality. BDNF variants, rs6265 and rs7124442, were used to create a gene risk score (GRS) in reference to previously published hypothesized risk for mortality in "younger patients" (<48 years) and hypothesized BDNF production/secretion capacity with these variants. Group based trajectory analysis (TRAJ) was used to create two cortisol groups (high and low trajectories). A Bayesian estimation approach informed the mediation models. Results show CSF BDNF predicted patient cortisol TRAJ group (P = 0.001). Also, GRS moderated BDNF associations with cortisol TRAJ group. Additionally, cortisol TRAJ predicted 6-month mortality (P = 0.001). In a mediation analysis, BDNF predicted mortality, with cortisol acting as the mediator (P = 0.011), yielding a mediation percentage of 29.92%. Mediation effects increased to 45.45% among younger patients. A BDNF*GRS interaction predicted mortality in younger patients (P = 0.004). Thus, we conclude 6-month mortality after severe TBI can be predicted through a mediation model with CSF cortisol and BDNF, suggesting a regulatory role for cortisol with BDNF's contribution to TBI pathophysiology and mortality, particularly among younger individuals with severe TBI. Based on the literature, cortisol modulated BDNF effects on mortality after TBI may be related to known hormone and neurotrophin relationships to neurological injury severity and autonomic nervous system imbalance. PMID- 28337123 TI - Analysis of the Serotonergic System in a Mouse Model of Rett Syndrome Reveals Unusual Upregulation of Serotonin Receptor 5b. AB - Mutations in the transcription factor methyl-CpG-binding-protein 2 (MeCP2) cause a delayed-onset neurodevelopmental disorder known as Rett syndrome (RTT). Although alteration in serotonin levels have been reported in RTT patients, the molecular mechanisms underlying these defects are not well understood. Therefore, we chose to investigate the serotonergic system in hippocampus and brainstem of male Mecp2-/y knock-out mice in the B6.129P2(C)-Mecp2(tm1.1Bird) mouse model of RTT. The serotonergic system in mouse is comprised of 16 genes, whose mRNA expression profile was analyzed by quantitative RT-PCR. Mecp2-/y mice are an established animal model for RTT displaying most of the cognitive and physical impairments of human patients and the selected areas receive significant modulation through serotonin. Using anatomically and functional characterized areas, we found region-specific differential expression between wild type and Mecp2-/y mice at post-natal day 40. In brainstem, we found five genes to be dysregulated, while in hippocampus, two genes were dysregulated. The one gene dysregulated in both brain regions was dopamine decarboxylase, but of special interest is the serotonin receptor 5b (5-ht5b), which showed 75-fold dysregulation in brainstem of Mecp2-/y mice. This dysregulation was not due to upregulation, but due to failure of down-regulation in Mecp2-/y mice during development. Detailed analysis of 5-ht5b revealed a receptor that localizes to endosomes and interacts with Galphai proteins. PMID- 28337124 TI - Interleukin-4 Protects Dopaminergic Neurons In vitro but Is Dispensable for MPTP Induced Neurodegeneration In vivo. AB - Microglia are involved in physiological as well as neuropathological processes in the central nervous system (CNS). Their functional states are often referred to as M1-like and M2-like activation, and are believed to contribute to neuroinflammation-mediated neurodegeneration or neuroprotection, respectively. Parkinson's disease (PD) is one the most common neurodegenerative disease and is characterized by the progressive loss of midbrain dopaminergic (mDA) neurons in the substantia nigra resulting in bradykinesia, tremor, and rigidity. Interleukin 4 (IL4)-mediated M2-like activation of microglia, which is characterized by upregulation of alternative markers Arginase 1 (Arg1) and Chitinase 3 like 3 (Ym1) has been well studied in vitro but the role of endogenous IL4 during CNS pathologies in vivo is not well understood. Interestingly, microglia activation by IL4 has been described to promote neuroprotective and neurorestorative effects, which might be important to slow the progression of neurodegenerative diseases. In the present study, we addressed the role of endogenous and exogenous IL4 during MPP+-induced degeneration of mDA neurons in vitro and further addressed the impact of IL4-deficiency on neurodegeneration in the 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD in vivo. Our results clearly demonstrate that exogenous IL4 is important to protect mDA neurons in vitro, but endogenous IL4 seems to be dispensable for development and maintenance of the nigrostriatal system as well as MPTP-induced loss of TH+ neurons in vivo. These results underline the importance of IL4 in promoting a neuroprotective microglia activation state and strengthen the therapeutic potential of exogenous IL4 for protection of mDA neurons in PD models. PMID- 28337125 TI - Neuronal Mitophagy in Neurodegenerative Diseases. AB - Neuronal homeostasis depends on the proper functioning of different quality control systems. All intracellular components are subjected to continuous turnover through the coordinated synthesis, degradation and recycling of their constituent elements. Autophagy is the catabolic mechanism by which intracellular cytosolic components, including proteins, organelles, aggregates and any other intracellular materials, are delivered to lysosomes for degradation. Among the different types of selective autophagy described to date, the process of mitophagy involves the selective autophagic degradation of mitochondria. In this way, mitophagy is responsible for basal mitochondrial turnover, but can also be induced under certain physiological or pathogenic conditions to eliminate unwanted or damaged mitochondria. Dysfunctional cellular proteolytic systems have been linked extensively to neurodegenerative diseases (ND) like Alzheimer's disease (AD), Parkinson's disease (PD), or Huntington's disease (HD), with autophagic failure being one of the main factors contributing to neuronal cell death in these diseases. Neurons are particularly vulnerable to autophagic impairment as well as to mitochondrial dysfunction, due mostly to their particular high energy dependence and to their post-mitotic nature. The accurate and proper degradation of dysfunctional mitochondria by mitophagy is essential for maintaining control over mitochondrial quality and quantity in neurons. In this report, I will review the role of mitophagy in neuronal homeostasis and the consequences of its dysfunction in ND. PMID- 28337126 TI - Competition between Persistent Na+ and Muscarine-Sensitive K+ Currents Shapes Perithreshold Resonance and Spike Tuning in CA1 Pyramidal Neurons. AB - Neurons from many brain regions display intrinsic subthreshold theta-resonance, responding preferentially to theta-frequency oscillatory stimuli. Resonance may contribute to selective communication among neurons and to orchestrate brain rhythms. CA1 pyramidal neurons receive theta activity, generating place fields. In these neurons the expression of perithreshold frequency preference is controversial, particularly in the spiking regime, with evidence favoring either non-resonant (integrator-like) or resonant behavior. Perithreshold dynamics depends on the persistent Na+ current INaP developing above -70 mV and the muscarine-sensitive K+ current IM activating above -60 mV. We conducted current and voltage clamp experiments in slices to investigate perithreshold excitability of CA1 neurons under oscillatory stimulation. Around 20% of neurons displayed perithreshold resonance that is expressed in spiking. The remaining neurons (~80%) acted as low-pass filters lacking frequency preference. Paired voltage clamp measurement of INaP and IM showed that perithreshold activation of IM is in general low while INaP is high enough to depolarize neurons toward threshold before resonance expression, explaining the most abundant non-resonant perithreshold behavior. Partial blockade of INaP by pharmacological tools or dynamic clamp changed non-resonant to resonant behavior. Furthermore, shifting IM activation toward hyperpolarized potentials by dynamic clamp also transformed non resonant neurons into resonant ones. We propose that the relative levels of INaP and IM control perithreshold behavior of CA1 neurons constituting a gating mechanism for theta resonance in the spiking regime. Both currents are regulated by intracellular signaling and neuromodulators which may allow dynamic switching of perithreshold behavior between resonant and non-resonant. PMID- 28337128 TI - Connexin36 Expression in the Mammalian Retina: A Multiple-Species Comparison. AB - Much knowledge about interconnection of human retinal neurons is inferred from results on animal models. Likewise, there is a lack of information on human retinal electrical synapses/gap junctions (GJ). Connexin36 (Cx36) forms GJs in both the inner and outer plexiform layers (IPL and OPL) in most species including humans. However, a comparison of Cx36 GJ distribution in retinas of humans and popular animal models has not been presented. To this end a multiple-species comparison was performed in retinas of 12 mammals including humans to survey the Cx36 distribution. Areas of retinal specializations were avoided (e.g., fovea, visual streak, area centralis), thus observed Cx36 distribution differences were not attributed to these species-specific architecture of central retinal areas. Cx36 was expressed in both synaptic layers in all examined retinas. Cx36 plaques displayed an inhomogenous IPL distribution favoring the ON sublamina, however, this feature was more pronounced in the human, swine and guinea pig while it was less obvious in the rabbit, squirrel monkey, and ferret retinas. In contrast to the relative conservative Cx36 distribution in the IPL, the labels in the OPL varied considerably among mammals. In general, OPL plaques were rare and rather small in rod dominant carnivores and rodents, whereas the human and the cone rich guinea pig retinas displayed robust Cx36 labels. This survey presented that the human retina displayed two characteristic features, a pronounced ON dominance of Cx36 plaques in the IPL and prevalent Cx36 plaque conglomerates in the OPL. While many species showed either of these features, only the guinea pig retina shared both. The observed similarities and subtle differences in Cx36 plaque distribution across mammals do not correspond to evolutionary distances but may reflect accomodation to lifestyles of examined species. PMID- 28337129 TI - Novel Neuromodulation Techniques to Assess Interhemispheric Communication in Neural Injury and Neurodegenerative Diseases. AB - Interhemispheric interaction has a major role in various neurobehavioral functions. Its disruption is a major contributor to the pathological changes in the setting of brain injury such as traumatic brain injury, peripheral nerve injury, and stroke, as well as neurodegenerative diseases. Because interhemispheric interaction has a crucial role in functional consequence in these neuropathological states, a review of noninvasive and state-of-the-art molecular based neuromodulation methods that focus on or have the potential to elucidate interhemispheric interaction have been performed. This yielded approximately 170 relevant articles on human subjects or animal models. There has been a recent surge of reports on noninvasive methods such as transcranial magnetic stimulation and transcranial direct current stimulation. Since these are noninvasive techniques with little to no side effects, their widespread use in clinical studies can be easily justified. The overview of novel neuromodulation methods and how they can be applied to study the role of interhemispheric communication in neural injury and neurodegenerative disease is provided. Additionally, the potential of each method in therapeutic use as well as investigating the pathophysiology of interhemispheric interaction in neurodegenerative diseases and brain injury is discussed. New technologies such as transcranial magnetic stimulation or transcranial direct current stimulation could have a great impact in understanding interhemispheric pathophysiology associated with acquired injury and neurodegenerative diseases, as well as designing improved rehabilitation therapies. Also, advances in molecular based neuromodulation techniques such as optogenetics and other chemical, thermal, and magnetic based methods provide new capabilities to stimulate or inhibit a specific brain location and a specific neuronal population. PMID- 28337132 TI - Habituation Training Improves Locomotor Performance in a Forced Running Wheel System in Rats. AB - Increasing evidence supports that physical activity promotes mental health; and regular exercise may confer positive effects in neurological disorders. There is growing number of reports that requires the analysis of the impact of physical activity in animal models. Exercise in rodents can be performed under voluntary or forced conditions. The former presents the disadvantage that the volume and intensity of exercise varies from subject to subject. On the other hand, a major challenge of the forced training protocol is the low level of performance typically achieved within a given session. Thus, the aim of the present study was to evaluate the effectiveness of gradual increasing of the volume and intensity (training habituation protocol) to improve the locomotor performance in a forced running-wheel system in rats. Sprague-Dawley rats were randomly assigned to either a group that received an exercise training habituation protocol, or a control group. The locomotor performance during forced running was assessed by an incremental exercise test. The experimental results reveal that the total running time and the distance covered by habituated rats was significantly higher than in control ones. We conclude that the exercise habituation protocol improves the locomotor performance in forced running wheels. PMID- 28337127 TI - NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies. AB - Neuroinflammation has been identified as a causative factor of multiple neurological diseases. The nucleotide-binding oligomerization domain-, leucine rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome, a subcellular multiprotein complex that is abundantly expressed in the central nervous system (CNS), can sense and be activated by a wide range of exogenous and endogenous stimuli such as microbes, aggregated and misfolded proteins, and adenosine triphosphate, which results in activation of caspase-1. Activated caspase-1 subsequently leads to the processing of interleukin-1beta (IL-1beta) and interleukin-18 (IL-18) pro-inflammatory cytokines and mediates rapid cell death. IL-1beta and IL-18 drive inflammatory responses through diverse downstream signaling pathways, leading to neuronal damage. Thus, the NLRP3 inflammasome is considered a key contributor to the development of neuroinflammation. In this review article, we briefly discuss the structure and activation the NLRP3 inflammasome and address the involvement of the NLRP3 inflammasome in several neurological disorders, such as brain infection, acute brain injury and neurodegenerative diseases. In addition, we review a series of promising therapeutic approaches that target the NLRP3 inflammasome signaling including anti-IL-1 therapy, small molecule NLRP3 inhibitors and other compounds, however, these approaches are still experimental in neurological diseases. At present, it is plausible to generate cell-specific conditional NLRP3 knockout (KO) mice via the Cre system to investigate the role of the NLRP3 inflammasome, which may be instrumental in the development of novel pharmacologic investigations for neuroinflammation-associated diseases. PMID- 28337130 TI - The Brainstem in Emotion: A Review. AB - Emotions depend upon the integrated activity of neural networks that modulate arousal, autonomic function, motor control, and somatosensation. Brainstem nodes play critical roles in each of these networks, but prior studies of the neuroanatomic basis of emotion, particularly in the human neuropsychological literature, have mostly focused on the contributions of cortical rather than subcortical structures. Given the size and complexity of brainstem circuits, elucidating their structural and functional properties involves technical challenges. However, recent advances in neuroimaging have begun to accelerate research into the brainstem's role in emotion. In this review, we provide a conceptual framework for neuroscience, psychology and behavioral science researchers to study brainstem involvement in human emotions. The "emotional brainstem" is comprised of three major networks - Ascending, Descending and Modulatory. The Ascending network is composed chiefly of the spinothalamic tracts and their projections to brainstem nuclei, which transmit sensory information from the body to rostral structures. The Descending motor network is subdivided into medial projections from the reticular formation that modulate the gain of inputs impacting emotional salience, and lateral projections from the periaqueductal gray, hypothalamus and amygdala that activate characteristic emotional behaviors. Finally, the brainstem is home to a group of modulatory neurotransmitter pathways, such as those arising from the raphe nuclei (serotonergic), ventral tegmental area (dopaminergic) and locus coeruleus (noradrenergic), which form a Modulatory network that coordinates interactions between the Ascending and Descending networks. Integration of signaling within these three networks occurs at all levels of the brainstem, with progressively more complex forms of integration occurring in the hypothalamus and thalamus. These intermediary structures, in turn, provide input for the most complex integrations, which occur in the frontal, insular, cingulate and other regions of the cerebral cortex. Phylogenetically older brainstem networks inform the functioning of evolutionarily newer rostral regions, which in turn regulate and modulate the older structures. Via these bidirectional interactions, the human brainstem contributes to the evaluation of sensory information and triggers fixed action pattern responses that together constitute the finely differentiated spectrum of possible emotions. PMID- 28337133 TI - Inferring Master Painters' Esthetic Biases from the Statistics of Portraits. AB - The Processing Fluency Theory posits that the ease of sensory information processing in the brain facilitates esthetic pleasure. Accordingly, the theory would predict that master painters should display biases toward visual properties such as symmetry, balance, and moderate complexity. Have these biases been occurring and if so, have painters been optimizing these properties (fluency variables)? Here, we address these questions with statistics of portrait paintings from the Early Renaissance period. To do this, we first developed different computational measures for each of the aforementioned fluency variables. Then, we measured their statistics in 153 portraits from 26 master painters, in 27 photographs of people in three controlled poses, and in 38 quickly snapped photographs of individual persons. A statistical comparison between Early Renaissance portraits and quickly snapped photographs revealed that painters showed a bias toward balance, symmetry, and moderate complexity. However, a comparison between portraits and controlled-pose photographs showed that painters did not optimize each of these properties. Instead, different painters presented biases toward different, narrow ranges of fluency variables. Further analysis suggested that the painters' individuality stemmed in part from having to resolve the tension between complexity vs. symmetry and balance. We additionally found that constraints on the use of different painting materials by distinct painters modulated these fluency variables systematically. In conclusion, the Processing Fluency Theory of Esthetic Pleasure would need expansion if we were to apply it to the history of visual art since it cannot explain the lack of optimization of each fluency variables. To expand the theory, we propose the existence of a Neuroesthetic Space, which encompasses the possible values that each of the fluency variables can reach in any given art period. We discuss the neural mechanisms of this Space and propose that it has a distributed representation in the human brain. We further propose that different artists reside in different, small sub-regions of the Space. This Neuroesthetic-Space hypothesis raises the question of how painters and their paintings evolve across art periods. PMID- 28337131 TI - Changes in Neuronal Oscillations Accompany the Loss of Hippocampal LTP that Occurs in an Animal Model of Psychosis. AB - The first-episode of psychosis is followed by a transient time-window of ca. 60 days during which therapeutic interventions have a higher likelihood of being effective than interventions that are started with a greater latency. This suggests that, in the immediate time-period after first-episode psychosis, functional changes occur in the brain that render it increasingly resistant to intervention. The precise mechanistic nature of these changes is unclear, but at the cognitive level, sensory and hippocampus-based dysfunctions become increasingly manifest. In an animal model of first-episode psychosis that comprises acute treatment of rats with the irreversible N-methyl-D-aspartate receptor (NMDAR)-antagonist, MK801, acute but also chronic deficits in long-term potentiation (LTP) and spatial memory occur. Neuronal oscillations, especially in the form of information transfer through theta and gamma frequency oscillations are an intrinsic component of normal information processing in the hippocampus. Changes in theta-gamma coupling and power are known to accompany deficits in hippocampal plasticity. Here, we examined whether changes in delta, theta, alpha, beta and gamma oscillations, or theta-gamma coupling accompany the chronic loss of LTP that is observed in the MK801-animal model of psychosis. One and 4 weeks after acute systemic treatment of adult rats with MK801, a potent loss of hippocampal in vivo LTP was evident compared to vehicle-treated controls. Overall, the typical pattern of theta-gamma oscillations that are characteristic for the successful induction of LTP was altered. In particular, theta-power was lower and an uncoupling of theta-gamma oscillations was evident in MK801-treated rats. The alterations in network oscillations that accompany LTP deficits in this animal model may comprise a mechanism through which disturbances in sensory information processing and hippocampal function occur in psychosis. These data suggest that the hippocampus is likely to comprise a very early locus of functional change after instigation of a first-episode psychosis-like state in rodents. PMID- 28337136 TI - Corrigendum: Brain networks of perceptual decision-making: an fMRI ALE meta analysis. AB - [This corrects the article on p. 445 in vol. 8, PMID: 24994979.]. PMID- 28337134 TI - Acoustic Enhancement of Sleep Slow Oscillations and Concomitant Memory Improvement in Older Adults. AB - Acoustic stimulation methods applied during sleep in young adults can increase slow wave activity (SWA) and improve sleep-dependent memory retention. It is unknown whether this approach enhances SWA and memory in older adults, who generally have reduced SWA compared to younger adults. Additionally, older adults are at risk for age-related cognitive impairment and therefore may benefit from non-invasive interventions. The aim of this study was to determine if acoustic stimulation can increase SWA and improve declarative memory in healthy older adults. Thirteen participants 60-84 years old completed one night of acoustic stimulation and one night of sham stimulation in random order. During sleep, a real-time algorithm using an adaptive phase-locked loop modeled the phase of endogenous slow waves in midline frontopolar electroencephalographic recordings. Pulses of pink noise were delivered when the upstate of the slow wave was predicted. Each interval of five pulses ("ON interval") was followed by a pause of approximately equal length ("OFF interval"). SWA during the entire sleep period was similar between stimulation and sham conditions, whereas SWA and spindle activity were increased during ON intervals compared to matched periods during the sham night. The increases in SWA and spindle activity were sustained across almost the entire five-pulse ON interval compared to matched sham periods. Verbal paired-associate memory was tested before and after sleep. Overnight improvement in word recall was significantly greater with acoustic stimulation compared to sham and was correlated with changes in SWA between ON and OFF intervals. Using the phase-locked-loop method to precisely target acoustic stimulation to the upstate of sleep slow oscillations, we were able to enhance SWA and improve sleep-dependent memory storage in older adults, which strengthens the theoretical link between sleep and age-related memory integrity. PMID- 28337135 TI - Deficits in Letter-Speech Sound Associations but Intact Visual Conflict Processing in Dyslexia: Results from a Novel ERP-Paradigm. AB - The reading and spelling deficits characteristic of developmental dyslexia (dyslexia) have been related to problems in phonological processing and in learning associations between letters and speech-sounds. Even when children with dyslexia have learned the letters and their corresponding speech sounds, letter speech sound associations might still be less automatized compared to children with age-adequate literacy skills. In order to examine automaticity in letter speech sound associations and to overcome some of the disadvantages associated with the frequently used visual-auditory oddball paradigm, we developed a novel electrophysiological letter-speech sound interference paradigm. This letter speech sound interference paradigm was applied in a group of 9-year-old children with dyslexia (n = 36) and a group of typically developing (TD) children of similar age (n = 37). Participants had to indicate whether two letters look visually the same. In the incongruent condition (e.g., the letter pair A-a) there was a conflict between the visual information and the automatically activated phonological information; although the visual appearance of the two letters is different, they are both associated with the same speech sound. This conflict resulted in slower response times (RTs) in the incongruent than in the congruent (e.g., the letter pair A-e) condition. Furthermore, in the TD control group, the conflict resulted in fast and strong event-related potential (ERP) effects reflected in less negative N1 amplitudes and more positive conflict slow potentials (cSP) in the incongruent than in the congruent condition. However, the dyslexic group did not show any conflict-related ERP effects, implying that letter-speech sound associations are less automatized in this group. Furthermore, we examined general visual conflict processing in a control visual interference task, using false fonts. The conflict in this experiment was based purely on the visual similarity of the presented objects. Visual conflict resulted in slower RTs, less negative N2 amplitudes and more positive cSP in both groups. Thus, on a general, basic level, visual conflict processing does not seem to be affected in children with dyslexia. PMID- 28337137 TI - An Adaptive Neural Mechanism for Acoustic Motion Perception with Varying Sparsity. AB - Biological motion-sensitive neural circuits are quite adept in perceiving the relative motion of a relevant stimulus. Motion perception is a fundamental ability in neural sensory processing and crucial in target tracking tasks. Tracking a stimulus entails the ability to perceive its motion, i.e., extracting information about its direction and velocity. Here we focus on auditory motion perception of sound stimuli, which is poorly understood as compared to its visual counterpart. In earlier work we have developed a bio-inspired neural learning mechanism for acoustic motion perception. The mechanism extracts directional information via a model of the peripheral auditory system of lizards. The mechanism uses only this directional information obtained via specific motor behaviour to learn the angular velocity of unoccluded sound stimuli in motion. In nature however the stimulus being tracked may be occluded by artefacts in the environment, such as an escaping prey momentarily disappearing behind a cover of trees. This article extends the earlier work by presenting a comparative investigation of auditory motion perception for unoccluded and occluded tonal sound stimuli with a frequency of 2.2 kHz in both simulation and practice. Three instances of each stimulus are employed, differing in their movement velocities 0.5 degrees /time step, 1.0 degrees /time step and 1.5 degrees /time step. To validate the approach in practice, we implement the proposed neural mechanism on a wheeled mobile robot and evaluate its performance in auditory tracking. PMID- 28337138 TI - Motor-Skill Learning in an Insect Inspired Neuro-Computational Control System. AB - In nature, insects show impressive adaptation and learning capabilities. The proposed computational model takes inspiration from specific structures of the insect brain: after proposing key hypotheses on the direct involvement of the mushroom bodies (MBs) and on their neural organization, we developed a new architecture for motor learning to be applied in insect-like walking robots. The proposed model is a nonlinear control system based on spiking neurons. MBs are modeled as a nonlinear recurrent spiking neural network (SNN) with novel characteristics, able to memorize time evolutions of key parameters of the neural motor controller, so that existing motor primitives can be improved. The adopted control scheme enables the structure to efficiently cope with goal-oriented behavioral motor tasks. Here, a six-legged structure, showing a steady-state exponentially stable locomotion pattern, is exposed to the need of learning new motor skills: moving through the environment, the structure is able to modulate motor commands and implements an obstacle climbing procedure. Experimental results on a simulated hexapod robot are reported; they are obtained in a dynamic simulation environment and the robot mimicks the structures of Drosophila melanogaster. PMID- 28337140 TI - Antioxidant and Anti-tyrosinase Activities of Phenolic Extracts from Rape Bee Pollen and Inhibitory Melanogenesis by cAMP/MITF/TYR Pathway in B16 Mouse Melanoma Cells. AB - Rape bee pollen possesses many nutritional and therapeutic properties because of its abundant nutrimental and bioactive components. In this study, free (FPE) and bound (BPE) phenolic extracts of rape bee pollen were obtained, phenolic and flavonoid contents were determined, and composition of phenolic acids was analyzed. In vitro antioxidant and anti-tyrosinase (TYR) activities of FPE and BPE were compared, and inhibitory melanogenesis of FPE was further evaluated. Results showed FPE and BPE contain total phenolic contents of 11.76 and 0.81 mg gallic acid equivalents/g dry weight (DW) and total flavonoid contents of 19.24 and 3.65 mg rutin equivalents/g DW, respectively. Phenolic profiling showed FPE and BPE fractions contained 12 and 9 phenolic acids, respectively. FPE contained the highest rutin content of 774.87 MUg/g. FPE and BPE showed the high antioxidant properties in vitro and high inhibitory activities for mushroom TYR. Higher activities of FPE than those of BPE can be attributed to difference in their phenolic compositions. Inhibitory melanogenesis activities of FPE against B16 were further evaluated. Results showed suppressed intracellular TYR activity, reduced melanin content, and promoted glutathione synthesis (p < 0.05) in FPE treated cells. FPE reduced mRNA expression of TYR, TYR-related protein (TRP)-1 and TRP-2, and significantly suppressed cyclic adenosine monophosphate (cAMP) levels through down-regulation of melanocortin 1 receptor gene expression (p < 0.05). FPE reduced mRNA expression of microphthalmia-associated transcription factor (MITF), significantly inhibiting intracellular melanin synthesis (p < 0.05). Hence, FPE regulates melanogenesis of B16 cells involved in cAMP/MITF/TYR pathway. These results revealed that FPE can be used as pharmaceutical agents and cosmetics to protect cells from abnormal melanogenesis. PMID- 28337139 TI - A Mixed-Methods Trial of Broad Band Noise and Nature Sounds for Tinnitus Therapy: Group and Individual Responses Modeled under the Adaptation Level Theory of Tinnitus. AB - Objectives: A randomized cross-over trial in 18 participants tested the hypothesis that nature sounds, with unpredictable temporal characteristics and high valence would yield greater improvement in tinnitus than constant, emotionally neutral broadband noise. Study Design: The primary outcome measure was the Tinnitus Functional Index (TFI). Secondary measures were: loudness and annoyance ratings, loudness level matches, minimum masking levels, positive and negative emotionality, attention reaction and discrimination time, anxiety, depression and stress. Each sound was administered using MP3 players with earbuds for 8 continuous weeks, with a 3 week wash-out period before crossing over to the other treatment sound. Measurements were undertaken for each arm at sound fitting, 4 and 8 weeks after administration. Qualitative interviews were conducted at each of these appointments. Results: From a baseline TFI score of 41.3, sound therapy resulted in TFI scores at 8 weeks of 35.6; broadband noise resulted in significantly greater reduction (8.2 points) after 8 weeks of sound therapy use than nature sounds (3.2 points). The positive effect of sound on tinnitus was supported by secondary outcome measures of tinnitus, emotion, attention, and psychological state, but not interviews. Tinnitus loudness level match was higher for BBN at 8 weeks; while there was little change in loudness level matches for nature sounds. There was no change in minimum masking levels following sound therapy administration. Self-reported preference for one sound over another did not correlate with changes in tinnitus. Conclusions: Modeled under an adaptation level theory framework of tinnitus perception, the results indicate that the introduction of broadband noise shifts internal adaptation level weighting away from the tinnitus signal, reducing tinnitus magnitude. Nature sounds may modify the affective components of tinnitus via a secondary, residual pathway, but this appears to be less important for sound effectiveness. The different rates of adaptation to broadband noise and nature sound by the auditory system may explain the different tinnitus loudness level matches. In addition to group effects there also appears to be a great deal of individual variation. A sound therapy framework based on adaptation level theory is proposed that accounts for individual variation in preference and response to sound. Clinical Trial Registration: www.anzctr.org.au, identifier #12616000742471. PMID- 28337141 TI - beta-Elemene: Mechanistic Studies on Cancer Cell Interaction and Its Chemosensitization Effect. AB - Over the past decade, screening and identifying novel compounds for their biomedical applications has become an upcoming area of research. Identifying the molecular mechanisms of these compounds has become an integral part of anticancer research. beta-elemene, a sesquiterpene, is renowned for its anticancer activity against a variety of cell lines. Recent studies on beta-elemene have elucidated that it possesses anti-proliferative effect on cancer cells by creating an apoptotic trigger. Interestingly, it also induces protective autophagy in some cancerous cell lines and is less cytotoxic compared to other widely accepted chemotherapeutic agents. This provides an edge with the perception of limited toxicity to normal cells. This mini-review precisely focuses on the studies performed to identify the mechanism of anticancer activity of beta-elemene against cancer cells of multiple origin. In accordance to the evaluation made by the studies mentioned, apoptosis has been identified to be most possible reason behind anticancer activity exerted by beta-elemene against a variety of cancer cell lines. Cell cycle arrest and necrosis have been credited to be possible alternate mechanisms for the anticancer effect of beta-elemene. PMID- 28337142 TI - Icariside II Effectively Reduces Spatial Learning and Memory Impairments in Alzheimer's Disease Model Mice Targeting Beta-Amyloid Production. AB - Icariside II (ICS II) is a broad-spectrum anti-cancer natural compound extracted from Herba Epimedii Maxim. Recently, the role of ICS II has been investigated in central nervous system, especially have a neuroprotective effect in Alzheimer's disease (AD). In this study, we attempted to investigate the effects of ICS II, on cognitive deficits and beta-amyloid (Abeta) production in APPswe/PS1dE9 (APP/PS1) double transgenic mice. It was found that chronic ICS II administrated not only effectively ameliorated cognitive function deficits, but also inhibited neuronal degeneration and reduced the formation of plaque burden. ICS II significantly suppressed Abeta production via promoting non-amyloidogenic APP cleavage process by up-regulating a disintegrin and metalloproteinase domain 10 (ADAM10) expression, inhibited amyloidogenic APP processing pathway by down regulating amyloid precursor protein (APP) and beta-site amyloid precursor protein cleavage enzyme 1 (BACE1) expression in APP/PS1 transgenic mice. Meanwhile, ICS II attenuated peroxisome proliferator-activated receptor-gamma (PPARgamma) degradation as well as inhibition of eukaryotic initiation factor alpha phosphorylation (p-eIF2alpha) and PKR endoplasmic reticulum regulating kinase phosphorylation (p-PERK). Moreover, phosphodiesterase type 5 inhibitors (PDE5-Is) have recently emerged as a possible therapeutic target for cognitive enhancement via inhibiting Abeta levels, and we also found that ICS II markedly decreased phosphodiesterase-5A (PDE5A) expression. In conclusion, the present study demonstrates that ICS II could attenuate spatial learning and memory impairments in APP/PS1 transgenic mice. This protection appears to be due to the increased ADAM10 expression and decreased expression of both APP and BACE1, resulting in inhibition of Abeta production in the hippocampus and cortex. Inhibition of PPARgamma degradation and PERK/eIF2alpha phosphorylation are involved in the course, therefore suggesting that ICS II might be a promising potential compound for the treatment of AD. PMID- 28337143 TI - Anti-adipogenic Effects and Mechanisms of Ginsenoside Rg3 in Pre-adipocytes and Obese Mice. AB - Red or black ginseng has been reported more powerful than white/fresh ginseng in dealing with various diseases/conditions including obesity. The major reason is that heating/steaming, the process of making red or black ginseng, produces large amount of bioactive compounds including ginsenoside Rg3 (Rg3), which are trace in fresh or white ginseng. In the present study, Rg3 was applied both in pre adipocytes and obese mice to investigate the anti-adipogenic effects and relevant mechanisms. Our results show that Rg3 dose-dependently inhibited cell differentiation both in 3T3-L1 cells (30, 50, and 100 MUM) and human primary pre adipocytes (10, 20, and 30 MUM). This inhibitory effect is accompanied by the attenuation of the expressions of adipogenic markers including peroxisome proliferator-activated receptor gamma (PPAR-gamma), CCAAT/enhancer binding protein alpha (C/EBP-alpha), fatty acid synthase (FAS), fatty acid binding protein 4 (FABP4) and perilipin. Although dietary intake of Rg3 (0.1 mg Rg3/kg diet, 8 weeks) did not significantly affect body weight gain, fat pads and food intake as well as of PPAR-gamma expression in fat tissues, we found that hepatic PPAR-gamma and C/EBP-alpha protein expressions and hepatic glutathione reductase and glutathione S-transferase, two major antioxidants molecules were significantly reduced by Rg3. These results suggest that ginsenoside Rg3 may be a potential agent in reducing/preventing obesity. PMID- 28337144 TI - Generation and Characterization of Specific Antibodies to the Murine and Human Ectonucleotidase NTPDase8. AB - The ectonucleotidase nucleoside triphosphate diphosphohydrolase-8 (NTPDase8) is the last member of the Ecto-NTPDase family to be discovered and characterized. It is a transmembrane protein which regulates the concentration of the agonists of P1 and P2 receptors at the cell surface. The functions of the enzyme are still not known partly due to the lack of specific tools such as antibodies. In this work, guinea pig polyclonal antibodies against mouse NTPDase8 and mouse monoclonal antibodies against human NTPDase8 have been generated and characterized. For the production of antibodies against mouse NTPDase8 several techniques have been tried. Several peptide antigens in several hosts (rabbit, rat, hamster, and guinea pig) failed to give a positive reaction suggesting that NTPDase8 is poorly immunogenic. In this study, we describe the successful process that led to anti-mouse NTPDase8, namely the cDNA immunization technique. Monoclonal antibodies to human NTPDase8 were also obtained by cDNA immunization followed by a final injection with transfected human embryonic kidney (HEK 293T) cells expressing human NTPDase8. The specificity of these antibodies was evaluated by Western blot, immunocytochemistry, immunohistochemistry and flow cytometry. In contrast, all commercial antibodies to NTPDase8 peptides that we have tested failed to give a specific positive signal against the expressed NTPDase8 protein when used to probe Western blots. In addition, immunohistochemistry experiments confirmed the presence of NTPDase8 in mouse liver canaliculi. The tools generated in this work will help characterize NTPDase8 localization and function in future studies and its contribution to the modulation of P1 and P2 receptor activation. PMID- 28337146 TI - Corrigendum: Pharmacological Characterization of the Native Store-Operated Calcium Channels of Cortical Neurons from Embryonic Mouse Brain. AB - [This corrects the article on p. 486 in vol. 7, PMID: 28018223.]. PMID- 28337145 TI - Dioscin Protects ANIT-Induced Intrahepatic Cholestasis Through Regulating Transporters, Apoptosis and Oxidative Stress. AB - Intrahepatic cholestasis, a clinical syndrome, is caused by excessive accumulation of bile acids in body and liver. Proper regulation of bile acids in liver cells is critical for liver injury. We previously reported the effects of dioscin against alpha-naphthylisothio- cyanate (ANIT)-induced cholestasis in rats. However, the pharmacological and mechanism data are limited. In our work, the animals of rats and mice, and Sandwich-cultured hepatocytes (SCHs) were caused by ANIT, and dioscin was used for the treatment. The results showed that dioscin markedly altered relative liver weights, restored ALT, AST, ALP, TBIL, GSH, GSH-Px, MDA, SOD levels, and rehabilitated ROS level and cell apoptosis. In mechanism study, dioscin not only significantly regulated the protein levels of Ntcp, OAT1, OCT1, Bsep and Mrp2 to accelerate bile acids excretion, but also regulated the expression levels of Bak, Bcl-xl, Bcl-2, Bax, Caspase 3 and Caspase 9 in vivo and in vitro to improve apoptosis. In addition, dioscin markedly inhibited PI3K/Akt pathway and up-regulated the levels of Nrf2, GCLc, GCLm, NQO1 and HO-1 against oxidative stress (OS) caused by bile acids. These results were further validated by inhibition of PI3K and Akt using the inhibitors of wortmannin and perifosine in SCHs. Our data showed that dioscin had good action against ANIT-caused intrahepatic cholestasis through regulating transporters, apoptosis and OS. This natural product can be considered as one active compound to treat intrahepatic cholestasis in the future. PMID- 28337147 TI - 3D Proximal Tubule Tissues Recapitulate Key Aspects of Renal Physiology to Enable Nephrotoxicity Testing. AB - Due to its exposure to high concentrations of xenobiotics, the kidney proximal tubule is a primary site of nephrotoxicity and resulting attrition in the drug development pipeline. Current pre-clinical methods using 2D cell cultures and animal models are unable to fully recapitulate clinical drug responses due to limited in vitro functional lifespan, or species-specific differences. Using Organovo's proprietary 3D bioprinting platform, we have developed a fully cellular human in vitro model of the proximal tubule interstitial interface comprising renal fibroblasts, endothelial cells, and primary human renal proximal tubule epithelial cells to enable more accurate prediction of tissue-level clinical outcomes. Histological characterization demonstrated formation of extensive microvascular networks supported by endogenous extracellular matrix deposition. The epithelial cells of the 3D proximal tubule tissues demonstrated tight junction formation and expression of renal uptake and efflux transporters; the polarized localization and function of P-gp and SGLT2 were confirmed. Treatment of 3D proximal tubule tissues with the nephrotoxin cisplatin induced loss of tissue viability and epithelial cells in a dose-dependent fashion, and cimetidine rescued these effects, confirming the role of the OCT2 transporter in cisplatin-induced nephrotoxicity. The tissues also demonstrated a fibrotic response to TGFbeta as assessed by an increase in gene expression associated with human fibrosis and histological verification of excess extracellular matrix deposition. Together, these results suggest that the bioprinted 3D proximal tubule model can serve as a test bed for the mechanistic assessment of human nephrotoxicity and the development of pathogenic states involving epithelial interstitial interactions, making them an important adjunct to animal studies. PMID- 28337148 TI - On the Estimation Accuracy of the 3D Body Center of Mass Trajectory during Human Locomotion: Inverse vs. Forward Dynamics. AB - The dynamics of body center of mass (BCoM) 3D trajectory during locomotion is crucial to the mechanical understanding of the different gaits. Forward Dynamics (FD) obtains BCoM motion from ground reaction forces while Inverse Dynamics (ID) estimates BCoM position and speed from motion capture of body segments. These two techniques are widely used by the literature on the estimation of BCoM. Despite the specific pros and cons of both methods, FD is less biased and considered as the golden standard, while ID estimates strongly depend on the segmental model adopted to schematically represent the moving body. In these experiments a single subject walked, ran, (uni- and bi-laterally) skipped, and race-walked at a wide range of speeds on a treadmill with force sensors underneath. In all conditions a simultaneous motion capture (8 cameras, 36 markers) took place. 3D BCoM trajectories computed according to five marker set models of ID have been compared to the one obtained by FD on the same (about 2,700) strides. Such a comparison aims to check the validity of the investigated models to capture the "true" dynamics of gaits in terms of distance between paths, mechanical external work and energy recovery. Results allow to conclude that: (1) among gaits, race walking is the most critical in being described by ID, (2) among the investigated segmental models, those capturing the motion of four limbs and trunk more closely reproduce the subtle temporal and spatial changes of BCoM trajectory within the strides of most gaits, (3) FD-ID discrepancy in external work is speed dependent within a gait in the most unsuccessful models, and (4) the internal work is not affected by the difference in BCoM estimates. PMID- 28337149 TI - Influence of Inspiratory Muscle Training on Ventilatory Efficiency and Cycling Performance in Normoxia and Hypoxia. AB - The aim of this study was to analyse the influence of inspiratory muscle training (IMT) on ventilatory efficiency, in normoxia and hypoxia, and to investigate the relationship between ventilatory efficiency and cycling performance. Sixteen sport students (23.05 +/- 4.7 years; 175.11 +/- 7.1 cm; 67.0 +/- 19.4 kg; 46.4 +/ 8.7 ml.kg-1.min-1) were randomly assigned to an inspiratory muscle training group (IMTG) and a control group (CG). The IMTG performed two training sessions/day [30 inspiratory breaths, 50% peak inspiratory pressure (Pimax), 5 days/week, 6-weeks]. Before and after the training period subjects carried out an incremental exercise test to exhaustion with gas analysis, lung function testing, and a cycling time trial test in hypoxia and normoxia. Simulated hypoxia (FiO2 = 16.45%), significantly altered the ventilatory efficiency response in all subjects (p < 0.05). Pimax increased significantly in the IMTG whereas no changes occurred in the CG (time * group, p < 0.05). Within group analyses showed that the IMTG improved ventilatory efficiency (VE/VCO2 slope; EqCO2VT2) in hypoxia (p < 0.05) and cycling time trial performance [WTTmax (W); WTTmean (W); PTF(W)] (p < 0.05) in hypoxia and normoxia. Significant correlations were not found in hypoxia nor normoxia found between ventilatory efficiency parameters (VE/VCO2 slope; LEqCO2; EqCO2VT2) and time trial performance. On the contrary the oxygen uptake efficiency slope (OUES) was highly correlated with cycling time trial performance (r = 0.89; r = 0.82; p < 0.001) under both conditions. Even though no interaction effect was found, the within group analysis may suggest that IMT reduces the negative effects of hypoxia on ventilatory efficiency. In addition, the data suggest that OUES plays an important role in submaximal cycling performance. PMID- 28337151 TI - A Reduction in Maximal Incremental Exercise Test Duration 48 h Post Downhill Run Is Associated with Muscle Damage Derived Exercise Induced Pain. AB - Purpose: To examine whether exercise induced muscle damage (EIMD) and muscle soreness reduce treadmill maximal incremental exercise (MIE) test duration, and true maximal physiological performance as a consequence of exercise induced pain (EIP) and perceived effort. Methods: Fifty (14 female), apparently healthy participants randomly allocated into a control group (CON, n = 10), or experimental group (EXP, n = 40) visited the laboratory a total of six times: visit 1 (familiarization), visit 2 (pre 1), visit 3 (pre 2), visit 4 (intervention), visit 5 (24 h post) and visit 6 (48 h post). Both groups performed identical testing during all visits, except during visit 4, where only EXP performed a 30 min downhill run and CON performed no exercise. During visits 2, 3, and 6 all participants performed MIE, and the following measurements were obtained: time to exhaustion (TTE), EIP, maximal oxygen consumption [Formula: see text], rate of perceived exertion (RPE), maximum heart rate (HRmax), maximum blood lactate (BLamax), and the contribution of pain to terminating the MIE (assessed using a questionnaire). Additionally during visits 1, 2, 3, 5, and 6 the following markers of EIMD were obtained: muscle soreness, maximum voluntary contraction (MVC), voluntary activation (VA), creatine kinase (CK). Results: There were no significant differences (p >= 0.32) between any trials for any of the measures obtained during MIE for CON. In EXP, TTE decreased by 34 s (3%), from pre 2 to 48 h post (p < 0.001). There was a significant association between group (EXP, CON) and termination of the MIE due to "pain" during 48 h post (chi2 = 14.7, p = 0.002). Conclusion: EIMD resulted in premature termination of a MIE test (decreased TTE), which was associated with EIP, MVC, and VA. The exact mechanisms responsible for this require further investigation. PMID- 28337150 TI - Alteration in Taste Perception in Cancer: Causes and Strategies of Treatment. AB - The sense of taste is responsible for the detection and ingestion of food to cover energetic requirements in health and disease. The change in taste perception might lead to malnutrition that is usually one of the frequent causes of morbidity and mortality in patients with cancer. In this review, we summarize the mechanisms of taste perception and how they are altered in cancer. We also address the question of the implication of inflammation, responsible for the alterations in taste modalities. We highlight the role of radio- and chemotherapy in the modulation of taste physiology. Other several factors like damage to taste progenitor cells and disruption of gut microbiota are also dealt with relation to taste perception in cancer. We further shed light on how to restore taste acuity, by using different preventive methods, dietary modifications and pharmacotherapy in subjects with advanced cancer state. PMID- 28337152 TI - Maintaining the Phenotype Stability of Chondrocytes Derived from MSCs by C-Type Natriuretic Peptide. AB - Mesenchymal stem cells (MSCs) play a critical role in cartilage tissue engineering. However, MSCs-derived chondrocytes or cartilage tissues are not stable and easily lose the cellular and cartilage phenotype during long-term culture in vitro or implantation in vivo. As a result, chondrocytes phenotypic instability can contribute to accelerated ossification. Thus, it is a big challenge to maintain their correct phenotype for engineering hyaline cartilage. As one member of the natriuretic peptide family, C-type natriuretic peptide (CNP) is found to correlate with the development of the cartilage, affect the chondrocytes proliferation and differentiation. Besides, based on its biological effects on protection of extracellular matrix of cartilage and inhibition of mineralization, we hypothesize that CNP may contribute to the stability of chondrocyte phenotype of MSCs-derived chondrocytes. PMID- 28337153 TI - Defense Responses to Short-term Hypoxia and Seawater Acidification in the Thick Shell Mussel Mytilus coruscus. AB - The rising anthropogenic atmospheric CO2 results in the reduction of seawater pH, namely ocean acidification (OA). In East China Sea, the largest coastal hypoxic zone was observed in the world. This region is also strongly impacted by ocean acidification as receiving much nutrient from Changjiang and Qiantangjiang, and organisms can experience great short-term natural variability of DO and pH in this area. In order to evaluate the defense responses of marine mussels under this scenario, the thick shell mussel Mytilus coruscus were exposed to three pH/pCO2 levels (7.3/2800 MUatm, 7.7/1020 MUatm, 8.1/376 MUatm) at two dissolved oxygen concentrations (DO, 2.0, 6.0 mg L-1) for 72 h. Results showed that byssus thread parameters, such as the number, diameter, attachment strength and plaque area were reduced by low DO, and shell-closing strength was significantly weaker under both hypoxia and low pH conditions. Expression patterns of genes related to mussel byssus protein (MBP) were affected by hypoxia. Generally, hypoxia reduced MBP1 and MBP7 expressions, but increased MBP13 expression. In conclusion, both hypoxia and low pH induced negative effects on mussel defense responses, with hypoxia being the main driver of change. In addition, significant interactive effects between pH and DO were observed on shell-closing strength. Therefore, the adverse effects induced by hypoxia on the defense of mussels may be aggravated by low pH in the natural environments. PMID- 28337155 TI - Impact of Different e-Cigarette Generation and Models on Cognitive Performances, Craving and Gesture: A Randomized Cross-Over Trial (CogEcig). AB - : Introduction: Most electronic-cigarettes (e-cigarette) are designed to look like traditional cigarettes and simulate the visual, sensory, and behavioral aspects of smoking traditional cigarettes. This research aimed to explore whether different e-cigarette models and smokers' usual classic cigarettes can impact on cognitive performances, craving and gesture. Methods: The study is randomized cross-over trial designed to compare cognitive performances, craving, and gesture in subjects who used first generation electronic cigarettes, second generation electronic cigarettes with their usual cigarettes. (Trial registration: ClinicalTrials.gov number NCT01735487). Results: Cognitive performance was not affected by "group condition." Within-group repeated measures analyses showed a significant time effect, indicating an increase of participants' current craving measure in group "usual classic cigarettes (group C)," "disposable cigalike electronic cigarette loaded with cartridges with 24 mg nicotine (group H), second generation electronic cigarette, personal vaporizer model Ego C, loaded with liquid nicotine 24 mg (group E). Measures of gesture not differ over the course of the experiment for all the products under investigation Conclusion: All cognitive measures attention, executive function and working memory are not influenced by the different e-cigarette and gender showing that in general electronics cigarettes could become a strong support also from a cognitive point of view for those who decide to quit smoking. It seems that not only craving and other smoke withdrawal symptoms but also cognitive performance is not only linked to the presence of nicotine; this suggests that the reasons behind the dependence and the related difficulty to quit smoking needs to be looked into also other factors like the gesture. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT01735487. PMID- 28337154 TI - The Reciprocal Relationship between Suicidality and Stigma. AB - INTRODUCTION: Although suicidality is frequently the cause of stigma, it is conversely true that stigma may be the cause of suicidality. The present paper focuses on the complex relationships that exist between suicidal behavior and stigmatizing attitudes. METHODS: A narrative review of the topic will be presented on the basis of the relevant literature collected from an electronic search of PubMed, ISI Web of Knowledge, and Scopus databases, using stigma, public stigma, structural stigma, perceived stigma, self-stigma, suicide, attempted suicide, and suicidality as key words. RESULTS: A negative perception is frequently held of suicidal people, labeling them as weak and unable to cope with their problems, or selfish. Individuals who have attempted suicide are subject to similar processes of stigmatization and "social distancing"; insurance policies include an exclusion clause against death by suicide. Subjects with a direct personal experience of depression or suicide strongly endorse a feeling of self-stigma; those who have attempted suicide are often ashamed and embarrassed by their behavior and tend to hide the occurrence as much as possible. Similar processes are observed among family members of subjects who have committed suicide or made a suicide attempt, with a higher perceived stigma present in those bereaved by suicide. Perceived or internalized stigma produced by mental or physical disorders, or through belonging to a minority group, may represent a significant risk factor for suicide, being severely distressing, reducing self esteem and acting as a barrier in help-seeking behaviors. CONCLUSION: With the aim of preventing suicide, greater efforts should be made to combat the persisting stigmatizing attitudes displayed toward mental disorders and suicide itself. Indeed, the role of stigma as a risk factor for suicide should further motivate and spur more concerted efforts to combat public stigma and support those suffering from perceived or internalized stigma. Experts and scientific societies should form an alliance with the media in an effort to promote a marked change in the societal perception of mental health issues and suicide. As stigma may result in severe consequences, specialist care and psychological interventions should be provided to populations submitted to stigma. PMID- 28337156 TI - Lack of Evidence That Neural Empathic Responses Are Blunted in Excessive Users of Violent Video Games: An fMRI Study. AB - The use of violent video games has been often linked to increase of aggressive behavior. According to the General Aggression Model, one of the central mechanisms for this aggressiveness inducing impact is an emotional desensitization process resulting from long lasting repeated violent game playing. This desensitization should evidence itself in a lack of empathy. Recent research has focused primarily on acute, short term impact of violent media use but only little is known about long term effects. In this study 15 excessive users of violent games and control subjects matched for age and education viewed pictures depicting emotional and neutral situations with and without social interaction while fMRI activations were obtained. While the typical pattern of activations for empathy and theory of mind networks was seen, both groups showed no differences in brain responses. We interpret our results as evidence against the desensitization hypothesis and suggest that the impact of violent media on emotional processing may be rather acute and short-lived. PMID- 28337157 TI - Pitch Perception in the First Year of Life, a Comparison of Lexical Tones and Musical Pitch. AB - Pitch variation is pervasive in speech, regardless of the language to which infants are exposed. Lexical tone is influenced by general sensitivity to pitch. We examined whether the development in lexical tone perception may develop in parallel with perception of pitch in other cognitive domains namely music. Using a visual fixation paradigm, 100 and one 4- and 12-month-old Dutch infants were tested on their discrimination of Chinese rising and dipping lexical tones as well as comparable three-note musical pitch contours. The 4-month-old infants failed to show a discrimination effect in either condition, whereas the 12-month old infants succeeded in both conditions. These results suggest that lexical tone perception may reflect and relate to general pitch perception abilities, which may serve as a basis for developing more complex language and musical skills. PMID- 28337158 TI - How Not to Do a Mindset Intervention: Learning from a Mindset Intervention among Students with Good Grades. AB - The present study examined the effectiveness of a Growth Mindset intervention based on Dweck et al.'s (1995) theory in the Hungarian educational context. A cluster randomized controlled trial classroom experiment was carried out within the framework of a train-the-trainer intervention among 55 Hungarian 10th grade students with high Grade Point Average (GPA). The results suggest that students' IQ and personality mindset beliefs were more incremental in the intervention group than in the control group 3 weeks after the intervention. Furthermore, compared to both the baseline measure and the control group, students' amotivation decreased. However, no intrinsic and extrinsic motivation change was found. Students with low grit scores reported lower amotivation following the intervention. However, in the second follow-up measurement-the end of the semester-all positive changes disappeared; and students' GPA did not change compared to the previous semester. These results show that mindset beliefs are temporarily malleable and in given circumstances, they can change back to their pre-intervention state. The potential explanation is discussed in the light of previous mindset intervention studies and recent findings on wise social psychological interventions. PMID- 28337159 TI - Hey Teacher, Don't Leave Them Kids Alone: Action Is Better for Memory than Reading. AB - There is no consensus on how the enactment effect (EE), although it is robust, enhances memory. Researchers are currently investigating the cognitive processes underlying this effect, mostly during adulthood; the link between EE and crucial function identified in adulthood such as episodic memory and binding process remains elusive. Therefore, this study aims to verify the existence of EE in 6-10 years old and assess cognitive functions potentially linked to this effect in order to shed light on the mechanisms underlying the EE during childhood. Thirty five children (15 second graders and 20 fifth graders) were included in this study. They encoded 24 action phrases from a protocol adapted from Hainselin et al. (2014). Encoding occurred under four conditions: Verbal Task, Listening Task, Experimenter-Performed Task, and Subject-Performed Task. Memory performance was assessed for free and cued recall, as well as source memory abilities. ANOVAS were conducted to explore age-related effects on the different scores according to encoding conditions. Correlations between EE scores (Subject-Performed Task/Listening Task) and binding memory scores (short-term binding and episodic memory) were run. Both groups benefited from EE. However, in both groups, performance did not significantly differ between Subject-Performed Task and Experimenter-Performed Task. A positive correlation was found between EE and episodic memory score for second graders and a moderate negative correlation was found between EE and binding scores for fifth graders. Our results confirm the existence of EE in 6 and 10 year olds, but they do not support the multimodal theory (Engelkamp, 2001) or the "glue" theory (Kormi-Nouri and Nilsson, 2001). This suggests instead that episodic memory might not underlie EE during early childhood. PMID- 28337161 TI - Editorial: Learning in Social Context: The Nature and Profit of Living in Groups for Development. PMID- 28337160 TI - The Association between Self-Reported Difficulties in Emotion Regulation and Heart Rate Variability: The Salient Role of Not Accepting Negative Emotions. AB - Difficulties in emotion regulation are associated with development and maintenance of psychopathology. Typically, features of emotion regulation are assessed with self-report questionnaires. Heart rate variability (HRV) is an objective measure proposed as an index of emotional regulation capacity. A limited number of studies have shown that self-reported difficulties in emotion regulation are associated with HRV. However, results from prior studies are inconclusive, and an ecological validation of the association has not yet been tested. Therefore, further exploration of the relation between self-report questionnaires and psychophysiological measures of emotional regulation is needed. The present study investigated the contribution of self-reported emotion regulation difficulties on HRV in a student sample. We expected higher scores on emotion regulation difficulties to be associated with lower vagus-mediated HRV (vmHRV). Sixty-three participants filled out the Difficulties in Emotion Regulation Scale and their resting HRV was assessed. In addition, a subsample of participants provided ambulatory 24-h HRV data, in order to ecologically validate the resting data. Correlation analyses indicated that self-reported difficulties in emotion regulation was negatively associated with vmHRV in both resting HRV and 24-h HRV. Specifically, when exploring the contribution of the different facets of emotion dysregulation, the inability to accept negative emotions showed the strongest association with HRV. The results are discussed and need for future research is described. PMID- 28337163 TI - A New Method of Random Environmental Walking for Assessing Behavioral Preferences for Different Lighting Applications. AB - Accurate assessment of people's preferences for different outdoor lighting applications is increasingly considered important in the development of new urban environments. Here a new method of random environmental walking is proposed to complement current methods of assessing urban lighting applications, such as self report questionnaires. The procedure involves participants repeatedly walking between different lighting applications by random selection of a lighting application and preferred choice or by random selection of a lighting application alone. In this manner, participants are exposed to all lighting applications of interest more than once and participants' preferences for the different lighting applications are reflected in the number of times they walk to each lighting application. On the basis of an initial simulation study, to explore the feasibility of this approach, a comprehensive field test was undertaken. The field test included random environmental walking and collection of participants' subjective ratings of perceived pleasantness (PP), perceived quality, perceived strength, and perceived flicker of four lighting applications. The results indicate that random environmental walking can reveal participants' preferences for different lighting applications that, in the present study, conformed to participants' ratings of PP and perceived quality of the lighting applications. As a complement to subjectively stated environmental preferences, random environmental walking has the potential to expose behavioral preferences for different lighting applications. PMID- 28337162 TI - Time-Order Errors in Duration Judgment Are Independent of Spatial Positioning. AB - Time-order errors (TOEs) occur when the discriminability between two stimuli are affected by the order in which they are presented. While TOEs have been studied since the 1860s, it is unknown whether the spatial properties of a stimulus will affect this temporal phenomenon. In this experiment, we asked whether perceived duration, or duration discrimination, might be influenced by whether two intervals in a standard two-interval method of constants paradigm were spatially overlapping in visual short-term memory. Two circular sinusoidal gratings (one standard and the other a comparison) were shown sequentially and participants judged which of the two was presented for a longer duration. The test stimuli were either spatially overlapping (in different spatial frames) or separate. Stimulus order was randomized between trials. The standard stimulus lasted 600 ms, and the test stimulus had one of seven possible values (between 300 and 900 ms). There were no overall significant differences observed between spatially overlapping and separate stimuli. However, in trials where the standard stimulus was presented second, TOEs were greater, and participants were significantly less sensitive to differences in duration. TOEs were also greater in conditions involving a saccade. This suggests there is an intrinsic memory component to two interval tasks in that the information from the first interval has to be stored; this is more demanding when the standard is presented in the second interval. Overall, this study suggests that while temporal information may be encoded in some spatial form, it is not dependent on visual short-term memory. PMID- 28337164 TI - Implicit Processes, Self-Regulation, and Interventions for Behavior Change. AB - The ability to regulate and subsequently change behavior is influenced by both reflective and implicit processes. Traditional theories have focused on conscious processes by highlighting the beliefs and intentions that influence decision making. However, their success in changing behavior has been modest with a gap between intention and behavior apparent. Dual-process models have been recently applied to health psychology; with numerous models incorporating implicit processes that influence behavior as well as the more common conscious processes. Such implicit processes are theorized to govern behavior non-consciously. The article provides a commentary on motivational and volitional processes and how interventions have combined to attempt an increase in positive health behaviors. Following this, non-conscious processes are discussed in terms of their theoretical underpinning. The article will then highlight how these processes have been measured and will then discuss the different ways that the non conscious and conscious may interact. The development of interventions manipulating both processes may well prove crucial in successfully altering behavior. PMID- 28337165 TI - Motivation Measures in Sport: A Critical Review and Bibliometric Analysis. AB - Motivation is widely-researched, in both sport psychology and other fields. As rigorous measurement is essential to understanding this latent construct, a critical appraisal of measurement instruments is needed. Thus, the purpose of this review was to evaluate the six most highly cited motivation measures in sport. Peer-reviewed articles published prior to August 2016 were searched to identify the six most highly cited motivation questionnaires in sport: Sport Motivation Scale (SMS), Intrinsic Motivation Inventory (IMI), Situational Motivational Scale (SIMS), Perceptions of Success Questionnaire (POSQ), Behavioural Regulation in Sport Questionnaire (BRSQ), and Task and Ego Orientation in Sport Questionnaire (TEOSQ). The questionnaires were then evaluated and discussed in four sections: Development, Reliability, Correlates, and Summary. Bibliometric data were also calculated (average weighted impact factor) and assessed (e.g., citations per year) to evaluate the impact of the use of each questionnaire. Despite some variance in their psychometric properties, conceptualization, structure, and utility, the six questionnaires are psychometrically strong instruments for quantifying motivation that are widely supported in the literature. Bibliometric analyses suggested that the IMI ranks first and the SMS ranks sixth according to the average weighted impact factors of their original publications. Consideration of each questionnaire's psychometric strengths/limitations, and conceptualization of motivation in the context of specific research questions should guide researchers in selecting the most appropriate instrument to measure motivation in sport. The average weighted impact factor of each questionnaire is a useful value to consider as well. With these points in mind, recommendations are provided. PMID- 28337166 TI - Difference between Leisure and Work Contexts: The Roles of Perceived Enjoyment and Perceived Usefulness in Predicting Mobile Video Calling Use Acceptance. AB - There is a rapidly growing body of literature on mobile video calling, which is a promising communication technology; however, little research has focused on user acceptance of mobile video calling, especially in different use contexts. This study explored factors (especially perceived enjoyment) influencing the intention of users to employ video calling in different contexts (a work and a leisure context) by applying the technology acceptance model (TAM) combined with the theory of planned behavior. The revised research model differentiated external factors (subjective norms and personal innovativeness) from internal factors (perceived usefulness, perceived ease of use (PEU), perceived enjoyment, and intention to use mobile video calling). In addition, the current study investigated predictors of perceived enjoyment across these two contexts. With the use of a structured questionnaire, participants were divided in two groups and completed self-report measures related to one context; a total of 386 student respondents' responses were analyzed. The results indicated that users' intentions were directly predicted by their perceived enjoyment of video calling (beta >= 0.35) and the call's perceived usefulness (beta >= 0.27) and PEU (beta = 0.13, only for the leisure context), which jointly explained at least 55.6% of the variance in use intention. In addition to the effects of these predictors on mobile video calling use acceptance, an assessment of the moderating effects of different contexts indicated that perceived enjoyment played a more important role in influencing intention for the leisure context, while perceived usefulness appeared to be more important for the work context. This study's findings are important in that they provide strong support for the necessity of distinguishing among different types of contexts when predicting users' intentions to use video calling. Furthermore, the results showed that perceived enjoyment was most significantly influenced by perceived usefulness (beta >= 0.61), followed by PEU (beta >= 0.13). In summary, the roles of core TAM variables (especially perceived enjoyment and perceived usefulness) and of external factors (subjective norms and personal innovativeness) differed between the leisure and work contexts. The implications of these findings are discussed. PMID- 28337167 TI - Research Recommendations for Improving Measurement of Treatment Effectiveness in Depression. AB - Background: Despite the steadily escalating psychological and economic burden of depression, there is a lack of evidence for the effectiveness of available interventions on functioning areas beyond symptomatology. Therefore, the main objective of this study was to give an insight into the current measurement of treatment effectiveness in depression and to provide recommendations for its improvement. Materials and Methods: The study was based on a multi-informant approach, comparing data from a systematic literature review, an expert survey with representatives from clinical practice (130), and qualitative interviews with patients (11) experiencing depression. Results: Current literature places emphasis on symptomatic outcomes and neglects other domains of functioning, whereas clinicians and depressed patients highlight the importance of both. Interpersonal relationships, recreation and daily activities, communication, social participation, work difficulties were identified as being crucial for recovery. Personal factors, neglected by the literature, such as self-efficacy were introduced by experts and patients. Furthermore, clinicians and patients identified a number of differences regarding the areas improved by psychotherapeutic or pharmacological interventions that were not addressed by the pertinent literature. Conclusion: Creation of a new cross-nationally applicable measure of psychosocial functioning, broader remission criteria, report of domain specific information, and a personalized approach in treatment decision-making are the first crucial steps needed for the improvement of the measurement of treatment effectiveness in depression. A better measurement will facilitate the clinical decision making and answer the escalating burden of depression. PMID- 28337168 TI - Working Memory Capacity as a Factor Influencing the Relationship between Language Outcome and Rehabilitation in Mandarin-Speaking Preschoolers with Congenital Hearing Impairment. AB - Memory processes could account for a significant part of the variance in language performances of hearing-impaired children. However, the circumstance in which the performance of hearing-impaired children can be nearly the same as the performance of hearing children remains relatively little studied. Thus, a group of pre-school children with congenital, bilateral hearing loss and a group of pre school children with normal hearing were invited to participate in this study. In addition, the hearing-impaired participants were divided into two groups according to their working memory span. A language disorder assessment test for Mandarin-speaking preschoolers was used to measure the outcomes of receptive and expressive language of the two groups of children. The results showed that the high-span group performed as good as the hearing group, while the low-span group showed lower accuracy than the hearing group. A linear mixed-effects analysis showed that not only length of rehabilitation but also the memory span affected the measure of language outcome. Furthermore, the rehabilitation length positively correlated with the measure of expressive language only among the participants of the high-span group. The pattern of the results indicates that working memory capacity is one of the factors that could support the children to acquire age-equivalent language skills. PMID- 28337169 TI - Commentary: Can Inner Experience Be Apprehended in High Fidelity? Examining Brain Activation and Experience from Multiple Perspectives. PMID- 28337170 TI - Why Your Body Can Jog Your Mind. PMID- 28337171 TI - The Skull Vibration-Induced Nystagmus Test of Vestibular Function-A Review. AB - A 100-Hz bone-conducted vibration applied to either mastoid induces instantaneously a predominantly horizontal nystagmus, with quick phases beating away from the affected side in patients with a unilateral vestibular loss (UVL). The same stimulus in healthy asymptomatic subjects has little or no effect. This is skull vibration-induced nystagmus (SVIN), and it is a useful, simple, non invasive, robust indicator of asymmetry of vestibular function and the side of the vestibular loss. The nystagmus is precisely stimulus-locked: it starts with stimulation onset and stops at stimulation offset, with no post-stimulation reversal. It is sustained during long stimulus durations; it is reproducible; it beats in the same direction irrespective of which mastoid is stimulated; it shows little or no habituation; and it is permanent-even well-compensated UVL patients show SVIN. A SVIN is observed under Frenzel goggles or videonystagmoscopy and recorded under videonystagmography in absence of visual-fixation and strong sedative drugs. Stimulus frequency, location, and intensity modify the results, and a large variability in skull morphology between people can modify the stimulus. SVIN to 100 Hz mastoid stimulation is a robust response. We describe the optimum method of stimulation on the basis of the literature data and testing more than 18,500 patients. Recent neural evidence clarifies which vestibular receptors are stimulated, how they cause the nystagmus, and why the same vibration in patients with semicircular canal dehiscence (SCD) causes a nystagmus beating toward the affected ear. This review focuses not only on the optimal parameters of the stimulus and response of UVL and SCD patients but also shows how other vestibular dysfunctions affect SVIN. We conclude that the presence of SVIN is a useful indicator of the asymmetry of vestibular function between the two ears, but in order to identify which is the affected ear, other information and careful clinical judgment are needed. PMID- 28337172 TI - Bone Marrow-Derived Cell Accumulation in the Spinal Cord Is Independent of Peripheral Mobilization in a Mouse Model of Amyotrophic Lateral Sclerosis. AB - Bone marrow-derived cells (BMDCs) are capable of migrating across the blood-brain barrier (BBB) and accumulating in the central nervous system (CNS) when transplanted into recipients conditioned with whole-body irradiation or chemotherapy. We used the chemotherapeutic agents busulfan and treosulfan to condition recipient mice for transplantation with bone marrow (BM) cells isolated from donor mice ubiquitously expressing green fluorescent protein. We attempted to increase the accumulation of BMDCs in the CNS by mobilization of BMDCs using either, or both, granulocyte colony-stimulating factor (GCSF) or plerixafor (AMD3100). We also used several concentrations of busulfan. We hypothesized that higher concentrations of busulfan and BMDC mobilization would increase numbers of GFP+ cells in the CNS. The doses of busulfan employed (60-125 mg/kg) all resulted in high levels of sustained chimerism (>85% 1 year post-transplant) in both the blood and BM of wild-type (WT) mice and an amyotrophic lateral sclerosis (ALS) mouse model. Moreover, cells accumulated within the CNS in a dose-, time-, and disease-dependent manner. Conditioning with the hydrophilic busulfan analog treosulfan, which is unable to cross the BBB efficiently, also resulted in a high degree of BM chimerism. However, few GFP+ BMDCs were found within the CNS of WT or ALS mice of treosulfan-conditioned mice. Mobilization of BMDCs into the circulation using GCSF and/or AMD3100 did not lead to increased accumulation of GFP+ BMDCs within the CNS of WT or ALS mice. Weekly analysis of BMDC accumulation revealed that BMDCs accumulated more rapidly and to a greater extent in the CNS of ALS mice conditioned with a high dose (125 mg/kg) of busulfan compared to a lower dose (80 mg/kg). The number of GFP+ BMDCs in the CNS labeling with the proliferation marker Ki67 increased in parallel with BMDC accumulation within the CNS. Our results indicate that establishment of high levels of blood and BM chimerism alone is not sufficient to induce BMDC accumulation within the CNS and that CNS conditioning is a crucial requirement for BMDC accumulation to occur. Moreover, it appears that proliferation of BMDCs that infiltrate the CNS is partly responsible for cell accumulation in busulfan-conditioned ALS mice. PMID- 28337173 TI - Twenty-Year Clinical Progression of Dysferlinopathy in Patients from Dagestan. AB - To date, over 30 genes with mutations causing limb-girdle muscle dystrophy have been described. Dysferlinopathies are a form of limb-girdle muscle dystrophy type 2B with an incidence ranging from 1:1,300 to 1:200,000 in different populations. In 1996, Dr. S. N. Illarioshkin described a family from the Botlikhsky district of Dagestan, where limb-girdle muscle dystrophy type 2B and Miyoshi myopathy were diagnosed in 12 members from three generations of a large Avar family. In 2000, a previously undescribed mutation in the DYSF gene (c.TG573/574AT; p. Val67Asp) was detected in the affected members of this family. Twenty years later, in this work, we re-examine five known and seven newly affected family members previously diagnosed with dysferlinopathy. We observed disease progression in family members who were previously diagnosed and noted obvious clinical polymorphism of the disease. A typical clinical case is provided. PMID- 28337175 TI - Effects of Chronic ACTH Excess on Human Adrenal Cortex. AB - Chronic ACTH excess leads to chronic cortisol excess, without escape phenomenon, resulting in Cushing's syndrome. Excess adrenal androgens also occur: in females, they will overcompensate the gonadotrophic loss, inducing high testosterone; in males, they will not compensate it, inducing low testosterone. Chronic ACTH excess leads to chronic adrenal mineralocorticoid excess and low aldosterone levels: after an acute rise, aldosterone plasma levels resume low values after a few days when ACTH is prolonged. Two other mineralocorticoids in man, cortisol and 11 deoxycorticosterone (DOC), at the zona fasciculata, will not escape the long-term effect of chronic ACTH excess and their secretion rates will remain elevated in parallel. Over all, the concomitant rise in cortisol and 11 DOC will more than compensate the loss of aldosterone, and eventually create a state of chronic mineralocorticoid excess, best evidenced by the accompanying suppression of the renin plasma levels, a further contribution to the suppression of aldosterone secretion. Prolonged in vivo stimulation with ACTH leads to an increase in total adrenal protein and RNA synthesis. Cell proliferation is indicated by an increase in total DNA the resulting adrenocortical hyperplasia participates in the amplified response of the chronically stimulated gland, and the weight of each gland can be greatly increased. The growth-stimulatory effect of ACTH in vivo most likely proceeds through the activation of a local and complex network of autocrine growth factors and their own receptors; a number of compounds, including non-ACTH proopiomelanocortin peptides such as gamma3-MSH, have been shown to exert some adrenocortical growth effect. PMID- 28337176 TI - Osteoporosis Therapy: Bone Modeling during Growth and Aging. PMID- 28337174 TI - Regulation of Mammalian Physiology by Interconnected Circadian and Feeding Rhythms. AB - Circadian clocks are endogenous timekeeping systems that adapt in an anticipatory fashion the physiology and behavior of most living organisms. In mammals, the master pacemaker resides in the suprachiasmatic nucleus and entrains peripheral clocks using a wide range of signals that differentially schedule physiology and gene expression in a tissue-specific manner. The peripheral clocks, such as those found in the liver, are particularly sensitive to rhythmic external cues like feeding behavior, which modulate the phase and amplitude of rhythmic gene expression. Consequently, the liver clock temporally tunes the expression of many genes involved in metabolism and physiology. However, the circadian modulation of cellular functions also relies on multiple layers of posttranscriptional and posttranslational regulation. Strikingly, these additional regulatory events may happen independently of any transcriptional oscillations, showing that complex regulatory networks ultimately drive circadian output functions. These rhythmic events also integrate feeding-related cues and adapt various metabolic processes to food availability schedules. The importance of such temporal regulation of metabolism is illustrated by metabolic dysfunctions and diseases resulting from circadian clock disruption or inappropriate feeding patterns. Therefore, the study of circadian clocks and rhythmic feeding behavior should be of interest to further advance our understanding of the prevention and therapy of metabolic diseases. PMID- 28337177 TI - Diversity and Abundance of Ice Nucleating Strains of Pseudomonas syringae in a Freshwater Lake in Virginia, USA. AB - The bacterium Pseudomonas syringae is found in a variety of terrestrial and aquatic environments. Some strains of P. syringae express an ice nucleation protein (hereafter referred to as Ice+) allowing them to catalyze the heterogeneous freezing of water. Though P. syringae has been sampled intensively from freshwater sources in France, little is known about the genetic diversity of P. syringae in natural aquatic habitats in North America. We collected samples of freshwater from three different depths in Claytor Lake, Virginia, USA between November 2015 and June 2016. Samples were plated on non-selective medium (TSA) and on medium selective for Pseudomonas (KBC) and closely related species to estimate the total number of culturable bacteria and of Pseudomonas, respectively. A droplet freezing assay was used to screen colonies for the Ice+ phenotype. Ice+ colonies were then molecularly identified based on the cts (citrate synthase) gene and the 16S rDNA gene. Phylogenetic analysis of cts sequences showed a surprising diversity of phylogenetic subgroups of P. syringae. Frequencies of Ice+ isolates on P. syringae selective medium ranged from 0 to 15% per sample with the highest frequency being found in spring. Our work shows that freshwater lakes can be a significant reservoir of Ice+ P. syringae. Future work is needed to determine the contribution of P. syringae from freshwater lakes to the P. syringae populations present in the atmosphere and on plants and, in particular, if freshwater lakes could be an inoculum source of P. syringae-caused plant disease outbreaks. PMID- 28337178 TI - Glucose Uptake in Prochlorococcus: Diversity of Kinetics and Effects on the Metabolism. AB - We have previously shown that Prochlorococcus sp. SS120 strain takes up glucose by using a multiphasic transporter encoded by the Pro1404 gene. Here, we studied the glucose uptake kinetics in multiple Prochlorococcus strains from different ecotypes, observing diverse values for the Ks constants (15-126.60 nM) and the uptake rates (0.48-6.36 pmol min-1 mg prot-1). Multiphasic kinetics was observed in all studied strains, except for TAK9803-2. Pro1404 gene expression studies during the 21st Atlantic Meridional Transect cruise showed positive correlation with glucose concentrations in the ocean. This suggests that the Pro1404 transporter has been subjected to diversification along the Prochlorococcus evolution, in a process probably driven by the glucose availabilities at the different niches it inhabits. The glucose uptake mechanism seems to be a primary transporter. Glucose addition induced detectable transcriptomic and proteomic changes in Prochlorococcus SS120, but photosynthetic efficiency was unaffected. Our studies indicate that glucose is actively taken up by Prochlorococcus, but its uptake does not significantly alter the trophic ways of this cyanobacterium, which continues performing photosynthesis. Therefore Prochlorococcus seems to remain acting as a fundamentally phototrophic organism, capable of using glucose as an extra resource of carbon and energy when available in the environment. PMID- 28337179 TI - Characterization of a Novel Nicotine Degradation Gene Cluster ndp in Sphingomonas melonis TY and Its Evolutionary Analysis. AB - Sphingomonas melonis TY utilizes nicotine as a sole source of carbon, nitrogen, and energy through a variant of the pyridine and pyrrolidine pathways (VPP). A 31 kb novel nicotine-degrading gene cluster, ndp, in strain TY exhibited a different genetic organization with the vpp cluster in strains Ochrobactrum rhizosphaerae SJY1 and Agrobacterium tumefaciens S33. Genes in vpp were separated by a 20-kb interval sequence, while genes in ndp were localized together. Half of the homolog genes were in different locus in ndp and vpp. Moreover, there was a gene encoding putative transporter of nicotine or other critical metabolite in ndp. Among the putative nicotine-degrading related genes, the nicotine hydroxylase, 6 hydroxy-L-nicotine oxidase, 6-hydroxypseudooxynicotine oxidase, and 6-hydroxy-3 succinyl-pyridine monooxygenase responsible for catalyzing the transformation of nicotine to 2, 5-dihydropyridine in the initial four steps of the VPP were characterized. Hydroxylation at C6 of the pyridine ring and dehydrogenation at the C2-C3 bond of the pyrrolidine ring were the key common reactions in the VPP, pyrrolidine and pyridine pathways. Besides, VPP and pyrrolidine pathway shared the same latter part of metabolic pathway. After analysis of metabolic genes in the pyridine, pyrrolidine, and VPP pathways, we found that both the evolutionary features and metabolic mechanisms of the VPP were more similar to the pyrrolidine pathway. The linked ndpHFEG genes shared by the VPP and pyrrolidine pathways indicated that these two pathways might share the same origin, but variants were observed in some bacteria. And we speculated that the pyridine pathway was distributed in Gram-positive bacteria and the VPP and pyrrolidine pathways were distributed in Gram-negative bacteria by using comprehensive homologs searching and phylogenetic tree construction. PMID- 28337180 TI - The Effect of Increased Loads of Dissolved Organic Matter on Estuarine Microbial Community Composition and Function. AB - Increased river loads are projected as one of the major consequences of climate change in the northern hemisphere, leading to elevated inputs of riverine dissolved organic matter (DOM) and inorganic nutrients to coastal ecosystems. The objective of this study was to investigate the effects of elevated DOM on a coastal pelagic food web from the coastal northern Baltic Sea, in a 32-day mesocosm experiment. In particular, the study addresses the response of bacterioplankton to differences in character and composition of supplied DOM. The supplied DOM differed in stoichiometry and quality and had pronounced effects on the recipient bacterioplankton, driving compositional changes in response to DOM type. The shifts in bacterioplankton community composition were especially driven by the proliferation of Bacteroidetes, Gemmatimonadetes, Planctomycetes, and Alpha- and Betaproteobacteria populations. The DOM additions stimulated protease activity and a release of inorganic nutrients, suggesting that DOM was actively processed. However, no difference between DOM types was detected in these functions despite different community compositions. Extensive release of re mineralized carbon, nitrogen and phosphorus was associated with the bacterial processing, corresponding to 25-85% of the supplied DOM. The DOM additions had a negative effect on phytoplankton with decreased Chl a and biomass, particularly during the first half of the experiment. However, the accumulating nutrients likely stimulated phytoplankton biomass which was observed to increase towards the end of the experiment. This suggests that the nutrient access partially outweighed the negative effect of increased light attenuation by accumulating DOM. Taken together, our experimental data suggest that parts of the future elevated riverine DOM supply to the Baltic Sea will be efficiently mineralized by microbes. This will have consequences for bacterioplankton and phytoplankton community composition and function, and significantly affect nutrient biogeochemistry. PMID- 28337181 TI - Comparative Genomic Analysis Reveals Ecological Differentiation in the Genus Carnobacterium. AB - Lactic acid bacteria (LAB) differ in their ability to colonize food and animal associated habitats: while some species are specialized and colonize a limited number of habitats, other are generalist and are able to colonize multiple animal linked habitats. In the current study, Carnobacterium was used as a model genus to elucidate the genetic basis of these colonization differences. Analyses of 16S rRNA gene meta-barcoding data showed that C. maltaromaticum followed by C. divergens are the most prevalent species in foods derived from animals (meat, fish, dairy products), and in the gut. According to phylogenetic analyses, these two animal-adapted species belong to one of two deeply branched lineages. The second lineage contains species isolated from habitats where contact with animal is rare. Genome analyses revealed that members of the animal-adapted lineage harbor a larger secretome than members of the other lineage. The predicted cell surface proteome is highly diversified in C. maltaromaticum and C. divergens with genes involved in adaptation to the animal milieu such as those encoding biopolymer hydrolytic enzymes, a heme uptake system, and biopolymer-binding adhesins. These species also exhibit genes for gut adaptation and respiration. In contrast, Carnobacterium species belonging to the second lineage encode a poorly diversified cell-surface proteome, lack genes for gut adaptation and are unable to respire. These results shed light on the important genomics traits required for adaptation to animal-linked habitats in generalist Carnobacterium. PMID- 28337182 TI - New Insights into the Anti-pathogenic Potential of Lactococcus garvieae against Staphylococcus aureus Based on RNA Sequencing Profiling. AB - The bio-preservation potential of Lactococcus garvieae lies in its capacity to inhibit the growth of staphylococci, especially Staphylococcus aureus, in dairy products and in vitro. In vitro, inhibition is modulated by the level of aeration, owing to hydrogen peroxide (H2O2) production by L. garvieae under aeration. The S. aureus response to this inhibition has already been studied. However, the molecular mechanisms of L. garvieae underlying the antagonism against S. aureus have never been explored. This study provides evidence of the presence of another extracellular inhibition effector in vitro. This effector was neither a protein, nor a lipid, nor a polysaccharide, nor related to an L threonine deficiency. To better understand the H2O2-related inhibition mechanism at the transcriptome level and to identify other mechanisms potentially involved, we used RNA sequencing to determine the transcriptome response of L. garvieae to different aeration levels and to the presence or absence of S. aureus. The L. garvieae transcriptome differed radically between different aeration levels mainly in biological processes related to fundamental functions and nutritional adaptation. The transcriptomic response of L. garvieae to aeration level differed according to the presence or absence of S. aureus. The higher concentration of H2O2 with high aeration was not associated with a higher expression of L. garvieae H2O2-synthesis genes (pox, sodA, and spxA1) but rather with a repression of L. garvieae H2O2-degradation genes (trxB1, ahpC, ahpF, and gpx). We showed that L. garvieae displayed an original, previously undiscovered, H2O2 production regulation mechanism among bacteria. In addition to the key factor H2O2, the involvement of another extracellular effector in the antagonism against S. aureus was shown. Future studies should explore the relation between H2O2-metabolism, H2O2-producing LAB and the pathogen they inhibit. The nature of the other extracellular effector should also be determined. PMID- 28337183 TI - Are Oligotypes Meaningful Ecological and Phylogenetic Units? A Case Study of Microcystis in Freshwater Lakes. AB - Oligotyping is a computational method used to increase the resolution of marker gene microbiome studies. Although oligotyping can distinguish highly similar sequence variants, the resulting units are not necessarily phylogenetically and ecologically informative due to limitations of the selected marker gene. In this perspective, we examine how oligotyping data is interpreted in recent literature, and we illustrate some of the method's constraints with a case study of the harmful bloom-forming cyanobacterium Microcystis. We identified three Microcystis oligotypes from a western Lake Erie bacterial community 16S rRNA gene (V4 region) survey that had previously clustered into one OTU. We found the same three oligotypes and two additional sequence variants in 46 Microcystis cultures isolated from Michigan inland lakes spanning a trophic gradient. In Lake Erie, shifts in Microcystis oligotypes corresponded to spatial nutrient gradients and temporal transitions in bloom toxicity. In the cultures, Microcystis oligotypes showed preferential distributions for different trophic states, but genomic data revealed that the oligotypes identified in Lake Erie did not correspond to toxin gene presence. Thus, oligotypes could not be used for inferring toxic ecotypes. Most strikingly, Microcystis oligotypes were not monophyletic. Our study supports the utility of oligotyping for distinguishing sequence types along certain ecological features, while it stresses that 16S rRNA gene sequence types may not reflect ecologically or phylogenetically cohesive populations. Therefore, we recommend that studies employing oligotyping or related tools consider these caveats during data interpretation. PMID- 28337184 TI - The Maternally Inheritable Wolbachia wAlbB Induces Refractoriness to Plasmodium berghei in Anopheles stephensi. AB - The endosymbiont Wolbachia wAlbB induces refractoriness to Plasmodium falciparum in Anopheles stephensi, the primary mosquito vector of human malaria in the Middle East and South Asia. However, it remains unknown whether such refractoriness can be extended to other malaria species. In particular, it was reported that under very specific conditions, wAlbB can enhance Plasmodium infection in some hosts. Here, we measured the impact of wAlbB on the rodent malaria parasite Plasmodium berghei in A. stephensi by comparing the load of oocysts and sporozoites in midguts and salivary glands, respectively, between wAlbB-infected and -uninfected mosquitoes. To investigate whether wAlbB modulated mosquito immune defense against parasites, we compared the expression of the immune genes, which were previously reported to involve in antimalarial response, in both midguts and the remaining carcass tissues of mosquitoes. The stable association of wAlbB with A. stephensi resulted in reduction of parasites by more than half at the oocyst stage, and up to 91.8% at the sporzoite stage. The anti plasmodium immune genes, including TEP1, LRIM1, Toll pathway gene Rel1 and the effector Defensin 1, were induced by wAlbB in different mosquito body tissues. These findings suggest that immune priming is a potential cause of wAlbB-mediated antimalarial response in A. stephensi. More importantly, no evidence was found for any enhancement of Plasmodium infection in A. stephensi stably infected with wAlbB. We discuss these findings with possible implementations of Wolbachia for malaria control in disease endemic areas. PMID- 28337185 TI - Food-Like Growth Conditions Support Production of Active Vitamin B12 by Propionibacterium freudenreichii 2067 without DMBI, the Lower Ligand Base, or Cobalt Supplementation. AB - Propionibacterium freudenreichii is a traditional dairy bacterium and a producer of short chain fatty acids (propionic and acetic acids) as well as vitamin B12. In food applications, it is a promising organism for in situ fortification with B12 vitamin since it is generally recognized as safe (GRAS) and it is able to synthesize biologically active form of the vitamin. In the present study, vitamin B12 and pseudovitamin biosynthesis by P. freudenreichii was monitored by UHPLC as a function of growth in food-like conditions using a medium mimicking cheese environment, without cobalt or 5,6-dimethylbenzimidazole (DMBI) supplementation. Parallel growth experiments were performed in industrial-type medium known to support the biosynthesis of vitamin B12. The production of other key metabolites in the two media were determined by HPLC, while the global protein production was compared by gel-based proteomics to assess the effect of growth conditions on the physiological status of the strain and on the synthesis of different forms of vitamin. The results revealed distinct protein and metabolite production, which reflected the growth conditions and the potential of P. freudenreichii for synthesizing nutritionally relevant amounts of active vitamin B12 regardless of the metabolic state of the cells. PMID- 28337187 TI - Defining and Evaluating a Core Genome Multilocus Sequence Typing Scheme for Whole Genome Sequence-Based Typing of Klebsiella pneumoniae. AB - At present, the most used methods for Klebsiella pneumoniae subtyping are multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE). However, the discriminatory power of MLST could not meet the need for distinguishing outbreak and non-outbreak isolates and the PFGE is time-consuming and labor-intensive. A core genome multilocus sequence typing (cgMLST) scheme for whole-genome sequence-based typing of K. pneumoniae was developed for solving the disadvantages of these traditional molecular subtyping methods. Firstly, we used the complete genome of K. pneumoniae strain HKUOPLC as the reference genome and 907 genomes of K. pneumoniae download from NCBI database as original genome dataset to determine cgMLST target genes. A total of 1,143 genes were retained as cgMLST target genes. Secondly, we used 26 K. pneumoniae strains from a nosocomial infection outbreak to evaluate the cgMLST scheme. cgMLST enabled clustering of outbreak strains with <10 alleles difference and unambiguous separation from unrelated outgroup strains. Moreover, cgMLST revealed that there may be several sub-clones of epidemic ST11 clone. In conclusion, the novel cgMLST scheme not only showed higher discriminatory power compared with PFGE and MLST in outbreak investigations but also showed ability to reveal more population structure characteristics than MLST. PMID- 28337188 TI - Influence of Herbicide Triasulfuron on Soil Microbial Community in an Unamended Soil and a Soil Amended with Organic Residues. AB - The effect of organic amendments and pesticides on a soil microbial community has garnered considerable interest due to the involvement of microorganisms in numerous soil conservation and maintenance reactions. The aim of this work was to assess the influence on a soil microbial community of the simultaneous application of the herbicide triasulfuron at three doses (2, 10, and 50 mg kg-1), with an organic amendment [sewage sludge (SS) or green compost (GC)]. Dissipation kinetics, soil microbial biomass, dehydrogenase activity (DHA) and respiration, and the profile of phospholipid fatty acids (PLFAs) extracted from the soil, were determined in unamended (S) soil and amended (S+SS and S+GC) ones. Triasulfuron dissipation followed the single first-order kinetics model. Half-life (DT50) values were higher in the amended soils than in the unamended one for the 10 and 50 mg kg-1 doses. The dissipation rates were lower in the S+GC soil for the three herbicide doses applied. In general, soil biomass, DHA and respiration values increased in SS- and GC-amended soils compared to the unamended one. DHA values decreased (S and S+SS) or increased (S+GC) with the incubation time of soil with herbicide at the different doses applied. Respiration values increased with the herbicide doses applied and decreased with the incubation time, although maximum values were obtained for soils treated with the highest dose after 70 days of incubation. PLFA analysis indicated different effects of triasulfuron on the soil microbial community structure depending on the organic amendments. While the increasing triasulfuron doses resulted in deeper alterations in the S soil, the time after triasulfuron application was the most important variation in the S+SS and S+GC soils. The overall results indicate that the soil amendment has an effect on herbicide dissipation rate and the soil microbial community. Initially, a high dose of triasulfuron had detrimental effects on the soil microbial community, which is important in the case of the long-term use of this compound. PMID- 28337189 TI - Elizabethkingia anophelis Isolated from Patients with Multiple Organ Dysfunction Syndrome and Lower Respiratory Tract Infection: Report of Two Cases and Literature Review. AB - Elizabethkingia anophelis, originally discovered from Anopheles mosquito gut, is an emerging pathogen, especially in immunocompromised patients. We isolated two strains of E. anophelis from two separate patients with multiple organ dysfunction syndrome and lower respiratory tract infection. In this paper, we reviewed the status of E. anophelis infection and its antibiotics resistance from reported cases. PMID- 28337186 TI - Genotypes Associated with Listeria monocytogenes Isolates Displaying Impaired or Enhanced Tolerances to Cold, Salt, Acid, or Desiccation Stress. AB - The human pathogen Listeria monocytogenes is a large concern in the food industry where its continuous detection in food products has caused a string of recalls in North America and Europe. Most recognized for its ability to grow in foods during refrigerated storage, L. monocytogenes can also tolerate several other food related stresses with some strains possessing higher levels of tolerances than others. The objective of this study was to use a combination of phenotypic analyses and whole genome sequencing to elucidate potential relationships between L. monocytogenes genotypes and food-related stress tolerance phenotypes. To accomplish this, 166 L. monocytogenes isolates were sequenced and evaluated for their ability to grow in cold (4 degrees C), salt (6% NaCl, 25 degrees C), and acid (pH 5, 25 degrees C) stress conditions as well as survive desiccation (33% RH, 20 degrees C). The results revealed that the stress tolerance of L. monocytogenes is associated with serotype, clonal complex (CC), full length inlA profiles, and the presence of a plasmid which was identified in 55% of isolates. Isolates with full length inlA exhibited significantly (p < 0.001) enhanced cold tolerance relative to those harboring a premature stop codon (PMSC) in this gene. Similarly, isolates possessing a plasmid demonstrated significantly (p = 0.013) enhanced acid tolerance. We also identified nine new L. monocytogenes sequence types, a new inlA PMSC, and several connections between CCs and the presence/absence or variations of specific genetic elements. A whole genome single-nucleotide-variants phylogeny revealed sporadic distribution of tolerant isolates and closely related sensitive and tolerant isolates, highlighting that minor genetic differences can influence the stress tolerance of L. monocytogenes. Specifically, a number of cold and desiccation sensitive isolates contained PMSCs in sigmaB regulator genes (rsbS, rsbU, rsbV). Collectively, the results suggest that knowing the sequence type of an isolate in addition to screening for the presence of full-length inlA and a plasmid, could help food processors and food agency investigators determine why certain isolates might be persisting in a food processing environment. Additionally, increased sequencing of L. monocytogenes isolates in combination with stress tolerance profiling, will enhance the ability to identify genetic elements associated with higher risk strains. PMID- 28337190 TI - Epidemiological Characteristics and Environmental Risk Factors of Severe Fever with Thrombocytopenia Syndrome in Hubei Province, China, from 2011 to 2016. AB - Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne viral disease affecting hundreds of people in China each year. To better understand the epidemiological characteristics and environmental risk factors associated with the incidence of SFTS in Hubei Province, China, we conducted a retrospective epidemiological study and risk assessment of SFTS from 2011 to 2016. Although, the incidence and epidemic areas of SFTS are increasing, the fatality rate has decreased. Elderly farmers are the population most commonly infected with SFTS virus between May and July in the northeast Hubei Province, which seems to be consistent with local agricultural activities and the seasonal abundance of ticks. Spatial scanning showed that regions bordering with Xinyang City, Henan Province accounted for most of the SFTS cases in Hubei Province, and there was a significant association of SFTS incidence with temporal changes in the climate within these clusters. Multivariate modeling analysis identified density of cattle, rain-fed cropland, built-up land, temperature, and relative humidity as independent risk factors for the distribution of SFTS. Future epidemiological and serological studies are warranted to elucidate the dynamics and immunity patterns of local SFTS disease and to optimize interventions. PMID- 28337192 TI - Editorial: Bioactive Compounds from Microbes. PMID- 28337191 TI - Toxoplasma gondii Infection in Immunocompromised Patients: A Systematic Review and Meta-Analysis. AB - Toxoplasma gondii has been suggested as an important opportunistic pathogen in immunocompromised patients. We conducted a global meta-analysis to assess the prevalence and odds ratios (ORs) of T. gondii infection in immunocompromised individuals. Electronic databases were reviewed for T. gondii infection in HIV/AIDS patients, cancer patients, and transplant recipients, and meta-analyses were conducted to calculate overall estimated prevalence and ORs using random or fixed-effects models. Totally, 72 eligible studies were included. The estimated pooled prevalence of T. gondii infection in immunocompromised patients and the control was 35.9 and 24.7% (p < 0.001), with an OR of 2.24, i.e., 42.1 and 32.0% for HIV/AIDS patients and the control (p < 0.05), 26.0 and 12.1% for cancer patients and the control (p < 0.001), and 42.1 and 34.5% for transplant recipients and the control (p > 0.05), whose estimated pooled ORs were 1.92 (95% CI, 1.44-2.55), 2.89 (95% CI, 2.36-3.55), and 1.51 (95% CI, 1.16-1.95), respectively. This study is the first to demonstrate that the immunocompromised patients are associated with higher odds of T. gondii infection, and appropriate prevention and control measures are highly recommended for these susceptible populations. PMID- 28337193 TI - Baicalin Protects Mice from Lethal Infection by Enterohemorrhagic Escherichia coli. AB - Shiga-like toxin-producing Escherichia coli (STEC) O157:H7 poses grave challenges to public health by its ability to cause severe colonic diseases and renal failure in both human and animals. Shiga-like toxins are the major pathogenic factor for some highly virulent E. coli expecially Shiga-like toxin 2. Conventional treatments such as antibiotics can facilitate the release of the toxin thus potentially exacerbate the diseases. Small molecule inhibitors and antibodies capable of neutralizing the toxins are the two major venues for the development of therapeutics against enterohemorrhagic serotype E. coli infection. While promising and potentially effective at clinical settings, these approaches need to overcome obstacles such as the limited routes of administration, responses from the host immune system, which are known to differ greatly among individuals. Our previous studies demonstrate that Baicalin (BAI), a flavonoid compound isolated from Scutellaria baicalensis protects against rStx2-induced cell cytotoxicity and also protects mice from lethal rStx2 challenges by inducing Stx2 to form inactive oligomers. In this manuscript, we present some exciting work showing that baicalin is an effective agent for therapeutic treatment of STEC O157:H7 infection. PMID- 28337194 TI - IL-1beta, IL-8, and Matrix Metalloproteinases-1, -2, and -10 Are Enriched upon Monocyte-Breast Cancer Cell Cocultivation in a Matrigel-Based Three-Dimensional System. AB - Breast cancer remains the first cancer-related cause of death in women worldwide, particularly in developing countries in which most cases are diagnosed in late stages. Although most cancer studies are based in the genetic or epigenetic changes of the tumor cells, immune cells within the tumor stroma often cooperate with cancer progression. Particularly, monocytes are attracted to the tumor primary site in which they are differentiated into tumor-associated macrophages that facilitate tumor cell invasion and metastasis. In this study, we used three dimensional cultures to form acini-like structures to analyze the inflammatory secretion profile of tumor cells individually or in co-culture with monocytes. Breast cancer cell lines and primary isolates from eight Mexican patients with breast cancer were used. We found high levels of RANTES/CCL5, MCP-1/CCL2, and G CSF in the breast cancer individual cultures, supporting an important recruitment capacity of monocytes, but also of neutrophils. The co-cultures of the tumor cells and monocytes were significantly enriched with the potent pro-inflammatory cytokines interleukin (IL)-1beta and IL-8, known to support malignant progression. We also found that the interaction of tumor cells with monocytes promoted high levels of matrix metalloproteinases (MMP)-1, MMP-2, and MMP-10. Our study supports that a key event for malignant progression is the recruitment of different immune cell populations, which help to sustain and enhance a chronic inflammatory microenvironment that highly favors tumor malignancy. PMID- 28337196 TI - Salmonella Typhi Porins OmpC and OmpF Are Potent Adjuvants for T-Dependent and T Independent Antigens. AB - Several microbial components, such as bacterial DNA and flagellin, have been used as experimental vaccine adjuvants because of their inherent capacity to efficiently activate innate immune responses. Likewise, our previous work has shown that the major Salmonella Typhi (S. Typhi) outer membrane proteins OmpC and OmpF (porins) are highly immunogenic protective antigens that efficiently stimulate innate and adaptive immune responses in the absence of exogenous adjuvants. Moreover, S. Typhi porins induce the expression of costimulatory molecules on antigen-presenting cells through toll-like receptor canonical signaling pathways. However, the potential of major S. Typhi porins to be used as vaccine adjuvants remains unknown. Here, we evaluated the adjuvant properties of S. Typhi porins against a range of experimental and clinically relevant antigens. Co-immunization of S. Typhi porins with ovalbumin (OVA), an otherwise poorly immunogenic antigen, enhanced anti-OVA IgG titers, antibody class switching, and affinity maturation. This adjuvant effect was dependent on CD4+ T-cell cooperation and was associated with an increase in IFN-gamma, IL-17A, and IL-2 production by OVA-specific CD4+ T cells. Furthermore, co-immunization of S. Typhi porins with an inactivated H1N1 2009 pandemic influenza virus experimental vaccine elicited higher hemagglutinating anti-influenza IgG titers, antibody class switching, and affinity maturation. Unexpectedly, co-administration of S. Typhi porins with purified, unconjugated Vi capsular polysaccharide vaccine (Vi CPS)-a T-independent antigen-induced higher IgG antibody titers and class switching. Together, our results suggest that S. Typhi porins OmpC and OmpF are versatile vaccine adjuvants, which could be used to enhance T-cell immune responses toward a Th1/Th17 profile, while improving antibody responses to otherwise poorly immunogenic T-dependent and T-independent antigens. PMID- 28337197 TI - Hypofractionated Irradiation Has Immune Stimulatory Potential and Induces a Timely Restricted Infiltration of Immune Cells in Colon Cancer Tumors. AB - In addition to locally controlling the tumor, hypofractionated radiotherapy (RT) particularly aims to activate immune cells in the RT-modified microenvironment. Therefore, we examined whether hypofractionated RT can activate dendritic cells (DCs), induce immune cell infiltration in tumors, and how the chronology of immune cell migration into tumors occurs to gain knowledge for future definition of radiation breaks and inclusion of immunotherapy. Colorectal cancer treatments offer only limited survival benefit, and immunobiological principles for additional therapies need to be explored with preclinical models. The impact of hypofractionated RT on CT26 colon cancer tumor cell death, migration of DCs toward supernatants (SN) of tumor cells, and activation of DCs by SN were analyzed. The subcutaneous tumor of a BALB/c-CT26 mouse model was locally irradiated with 2 * 5 Gy, the tumor volume was monitored, and the infiltration of immune cells in the tumor was determined by flow cytometry daily. Hypofractionated RT induced a mixture of apoptotic and necrotic CT26 cells, which is known to be in particular immunogenic. DCs that migrated toward SN of CT26 cells particularly upregulated the activation markers CD80 and CD86 when in contact with SN of irradiated tumor cells. After hypofractionated RT, the tumor outgrowth was significantly retarded and in the irradiated tumors an increased infiltration of macrophages (CD11bhigh/F4-80+) and DCs (MHC-II+), but only between day 5 and 10 after the first irradiation, takes place. While CD4+ T cells migrated into non-irradiated and irradiated tumors, CD8+ T cells were only found in tumors that had been irradiated and they were highly increased at day 8 after the first irradiation. Myeloid-derived suppressor cells and regulatory T cells show regular turnover in irradiated and non-irradiated tumors. Tumor cell specific anti-IgM antibodies were enhanced in the serum of animals with irradiated tumors. We conclude that hypofractionated RT suffices to activate DCs and to induce infiltration of innate and adaptive immune cells into solid colorectal tumors. However, the presence of immune cells in the tumor which are beneficial for antitumor immune responses is timely restricted. These findings should be considered when innovative multimodal tumor treatment protocols of distinct RT with immune therapies are designed and clinically implemented. PMID- 28337195 TI - NK Cells: Uncertain Allies against Malaria. AB - Until recently, studies of natural killer (NK) cells in infection have focused almost entirely on their role in viral infections. However, there is an increasing awareness of the potential for NK cells to contribute to the control of a wider range of pathogens, including intracellular parasites such as Plasmodium spp. Given the high prevalence of parasitic diseases in the developing world and the devastating effects these pathogens have on large numbers of vulnerable people, investigating interactions between NK cells and parasitized host cells presents the opportunity to reveal novel immunological mechanisms with the potential to aid efforts to eradicate these diseases. The capacity of NK cells to produce inflammatory cytokines early after malaria infection, as well as a possible role in direct cytotoxic killing of malaria-infected cells, suggests a beneficial impact of NK cells in this disease. However, NK cells may also contribute to overproduction of pro-inflammatory cytokines and the consequent immunopathology. As comparatively little is known about the role of NK cells later in the course of infection, and growing evidence suggests that heterogeneity in NK cell responses to malaria may be influenced by KIR/HLA interactions, a better understanding of the mechanisms by which NK cells might directly interact with parasitized cells may reveal a new role for these cells in the course of malaria infection. PMID- 28337198 TI - Role of Metallic Nanoparticles in Vaccinology: Implications for Infectious Disease Vaccine Development. AB - Subunit vaccines are safer but less immunogenic than live-attenuated vaccines or whole cell inactivated vaccines. Adjuvants are used to enhance and modulate antigen (Ag) immunogenicity, aiming to induce a protective and long-lasting immune response. Several molecules and formulations have been studied for their adjuvanticity, but only seven have been approved to formulate human vaccines. Metallic nanoparticles (MeNPs), particularly those containing gold and iron oxides, are widely used in medicine for diagnosis and therapy and have been used as carriers for drugs and vaccines. However, little is known about the immune response elicited by MeNPs or about their importance in the development of new vaccines. There is evidence that these particles display adjuvant characteristics, promoting cell recruitment, antigen-presenting cell activation, cytokine production, and inducing a humoral immune response. This review focuses on the characteristics of MeNPs that could facilitate the induction of a cellular immune response, particularly T-helper 1 and T-helper 17, and their potential functions as adjuvants for subunit vaccines. PMID- 28337201 TI - Phenotype and Tissue Residency of Lymphocytes in the Murine Oral Mucosa. AB - The oral mucosa is a critical barrier tissue that harbors a series of distinct immune cell subsets. Immune surveillance in the oral mucosa is important for both local and systemic immunity because the oral cavity is a heavily utilized route of pathogen entry and also serves as site of pathogen propagation. Nonetheless, composition and phenotype of the lymphocyte pool in the oral mucosa have remained poorly characterized. Utilizing a newly established protocol for mucosal immune cell isolation, here, we report that the oral mucosa features a unique cellular composition of immune cells, which differed not only from secondary lymphoid organs but also from mucosal tissues in the gut and lung. We observed profound accumulation of CD11b+Ly6Clo monocytes in the oral mucosa that were maintained independently of T- and B-lymphocytes. Unlike the gut mucosa, the oral mucosa neither contained CD8alphaalpha T cells nor was it enriched for CD103+CD69+ tissue-resident memory CD8 T cells. In fact, a major fraction of T cells circulated and trafficked through the mucosa as revealed by treatment with the S1P1 receptor antagonist, FTY720, a potent inhibitor of lymphocyte migration. Collectively, these results provide a comprehensive picture of immune cells in the oral mucosa as an active site of lymphocyte recruitment and surveillance. PMID- 28337199 TI - Nutrient and Metabolic Sensing in T Cell Responses. AB - T cells play pivotal roles in shaping host immune responses in infectious diseases, autoimmunity, and cancer. The activation of T cells requires immune and growth factor-derived signals. However, alterations in nutrients and metabolic signals tune T cell responses by impinging upon T cell fates and immune functions. In this review, we summarize how key nutrients, including glucose, amino acids, and lipids, and their sensors and transporters shape T cell responses. We also briefly discuss regulation of T cell responses by oxygen and energy sensing mechanisms. PMID- 28337200 TI - Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment. AB - Cytotoxic T lymphocytes and NK cells play an important role in eliminating malignant tumor cells and the number and activity of tumor-infiltrating T cells represent a good marker for tumor prognosis. Based on these findings, immunotherapy, e.g., checkpoint blockade, has received considerable attention during the last couple of years. However, for the majority of patients, immune control of their tumors is gray theory as malignant cells use effective mechanisms to outsmart the immune system. Increasing evidence suggests that changes in tumor metabolism not only ensure an effective energy supply and generation of building blocks for tumor growth but also contribute to inhibition of the antitumor response. Immunosuppression in the tumor microenvironment is often based on the mutual metabolic requirements of immune cells and tumor cells. Cytotoxic T and NK cell activation leads to an increased demand for glucose and amino acids, a well-known feature shown by tumor cells. These close metabolic interdependencies result in metabolic competition, limiting the proliferation, and effector functions of tumor-specific immune cells. Moreover, not only nutrient restriction but also tumor-driven shifts in metabolite abundance and accumulation of metabolic waste products (e.g., lactate) lead to local immunosuppression, thereby facilitating tumor progression and metastasis. In this review, we describe the metabolic interplay between immune cells and tumor cells and discuss tumor cell metabolism as a target structure for cancer therapy. Metabolic (re)education of tumor cells is not only an approach to kill tumor cells directly but could overcome metabolic immunosuppression in the tumor microenvironment and thereby facilitate immunotherapy. PMID- 28337202 TI - Murine Cytomegalovirus Disrupts Splenic Dendritic Cell Subsets via Type I Interferon-Dependent and -Independent Mechanisms. AB - Dendritic cells (DC) are well-known modulators of immunity. This heterogeneous population is composed of defined subsets that exhibit functional specialization and are critical in initiating responses to pathogens. As such, many infectious agents employ strategies to disrupt DC functioning in attempts to evade the immune system. In some instances, this manifests as an outright loss of these cells. Previous work has suggested that, in the absence of an efficient natural killer (NK) cell response, murine cytomegalovirus (MCMV) induces large amounts of interferon (IFN)-I. This heightened IFN-I response is thought to contribute to conventional DC (cDC) loss and delayed development of T cell immunity. However, the precise role of IFN-I in such cDC loss remains unclear. We investigated the effects of licensed NK cells and IFN-I signaling on splenic cDC subsets during MCMV infection and found that a licensed NK cell response partially protects cDC numbers, but does not prevent increases in serum IFN-I. This suggested that high residual IFN-I could contribute to cDC loss. Therefore, we used multiple strategies to modulate IFN-I signaling during MCMV infection including plasmacytoid DC depletion, IFN-I receptor (IFNAR) blockade, and genetic ablation of IFNAR expression. Interestingly, restriction of IFN-I signals did not substantially preserve either CD8+ or CD4+ DC total numbers, but resulted in significant retention and/or accumulation of the splenic CD8- CD4- [double negative (DN)] subset. However, the DN DC effect manifested in a DC-extrinsic manner since IFNAR-deficient cells were not preferentially retained over their IFNAR wild-type counterparts in a mixed-chimera setting. Our results show that IFN-I signaling is not responsible for overt cDC toxicity in the setting of acute MCMV infection and emphasize that additional mechanisms contribute to DC loss and require exploration. PMID- 28337204 TI - Phenol-Soluble Modulin alpha Peptide Toxins from Aggressive Staphylococcus aureus Induce Rapid Formation of Neutrophil Extracellular Traps through a Reactive Oxygen Species-Independent Pathway. AB - Neutrophils have the ability to capture and kill microbes extracellularly through the formation of neutrophil extracellular traps (NETs). These are DNA and protein structures that neutrophils release extracellularly and are believed to function as a defense mechanism against microbes. The classic NET formation process, triggered by, e.g., bacteria, fungi, or by direct stimulation of protein kinase C through phorbol myristate acetate, is an active process that takes several hours and relies on the production of reactive oxygen species (ROS) that are further modified by myeloperoxidase (MPO). We show here that NET-like structures can also be formed by neutrophils after interaction with phenol-soluble modulin alpha (PSMalpha) that are cytotoxic membrane-disturbing peptides, secreted from community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). The PSMalpha-induced NETs contained the typical protein markers and were able to capture microbes. The PSMalpha-induced NET structures were disintegrated upon prolonged exposure to DNase-positive S. aureus but not on exposure to DNase negative Candida albicans. Opposed to classic NETosis, PSMalpha-triggered NET formation occurred very rapidly, independently of ROS or MPO, and was also manifest at 4 degrees C. These data indicate that rapid NETs release may result from cytotoxic membrane disturbance by PSMalpha peptides, a process that may be of importance for CA-MRSA virulence. PMID- 28337205 TI - High Interferon-gamma Uniquely in Vdelta1 T Cells Correlates with Markers of Inflammation and Axonal Damage in Early Multiple Sclerosis. AB - We have identified a population of T lymphocytes in peripheral blood, Vdelta1 TCRgammadelta T lymphocytes, which unexpectedly was uniquely expressing high production of interferon-gamma in newly diagnosed, untreated multiple sclerosis (MS) patients. IFN-gamma production in this population distinctly correlated to parameters of clinical disease activity, inflammation, and neuronal damage. These Vdelta1 T lymphocytes belong to a population of innate T lymphocytes that recognize antigen in the context of CD1d/CD1c and which include reactivity to the myelin glycosphingolipid sulfatide. Importantly, patients treated with natalizumab, blocking leukocyte transmigration to central nervous system, had completely normalized levels of interferon-gamma-producing Vdelta1 T lymphocytes. A biomarker and early sign of demyelinating disease in MS is much warranted and would help identify immunopathogenesis and prognosis of disease as well as monitor success with adequate treatment. The present study identifies the Vdelta1 T lymphocytes as an early marker of MS and a possible link to understanding the disease etiology. PMID- 28337206 TI - Cases of Impaired Oxidative Burst in HIV-Exposed Uninfected Infants' Neutrophils A Pilot Study. AB - An increased risk of serious bacterial infections in HIV-exposed uninfected (HEU) infants has been demonstrated. Although neutrophils are essential for the protection of infants against bacterial infections, no study has investigated their profile in HEU infants to date. In this study, we assessed the function of neutrophils in HEU infants using the nitroblue tetrazolium reduction test. Among 25 HEU infants, 9 (36%) showed a reduced ability of their neutrophils to produce reactive oxygen species upon stimulation with bacteria. No alteration of total neutrophil counts was noted in the blood of HEU infants indicating that the alteration observed in the 36% of HEU infants may only be functional. Conclusively, impaired neutrophil function could be a factor of vulnerability in HEU infants. PMID- 28337203 TI - A Universal Vaccine against Leptospirosis: Are We Going in the Right Direction? AB - Leptospirosis is the most widespread zoonosis in the world and a neglected tropical disease estimated to cause severe infection in more than one million people worldwide every year that can be combated by effective immunization. However, no significant progress has been made on the leptospirosis vaccine since the advent of bacterins over 100 years. Although protective against lethal infection, particularly in animals, bacterin-induced immunity is considered short term, serovar restricted, and the vaccine can cause serious side effects. The urgent need for a new vaccine has motivated several research groups to evaluate the protective immune response induced by recombinant vaccines. Significant protection has been reported with several promising outer membrane proteins, including LipL32 and the leptospiral immunoglobulin-like proteins. However, efficacy was variable and failed to induce a cross-protective response or sterile immunity among vaccinated animals. As hundreds of draft genomes of all known Leptospira species are now available, this should aid novel target discovery through reverse vaccinology (RV) and pangenomic studies. The identification of surface-exposed vaccine candidates that are highly conserved among infectious Leptospira spp. is a requirement for the development of a cross-protective universal vaccine. However, the lack of immune correlates is a major drawback to the application of RV to Leptospira genomes. In addition, as the protective immune response against leptospirosis is not fully understood, the rational use of adjuvants tends to be a process of trial and error. In this perspective, we discuss current advances, the pitfalls, and possible solutions for the development of a universal leptospirosis vaccine. PMID- 28337207 TI - Gastrointestinal Microbiome Dysbiosis in Infant Mice Alters Peripheral CD8+ T Cell Receptor Signaling. AB - We recently reported that maternal antibiotic treatment (MAT) of mice in the last days of pregnancy and during lactation dramatically alters the density and composition of the gastrointestinal microbiota of their infants. MAT infants also exhibited enhanced susceptibility to a systemic viral infection and altered adaptive immune cell activation phenotype and function. CD8+ effector T cells from MAT infants consistently demonstrate an inability to sustain interferon gamma (IFN-gamma) production in vivo following vaccinia virus infection and in vitro upon T cell receptor (TCR) stimulation. We hypothesize that T cells developing in infant mice with gastrointestinal microbiota dysbiosis and insufficient toll-like receptor (TLR) exposure alters immune responsiveness associated with intrinsic T cell defects in the TCR signaling pathway and compromised T cell effector function. To evaluate this, splenic T cells from day of life 15 MAT infant mice were stimulated in vitro with anti-CD3 and anti-CD28 antibodies prior to examining the expression of ZAP-70, phosphorylated ZAP-70, phospho-Erk-1/2, c-Rel, total protein tyrosine phosphorylation, and IFN-gamma production. We determine that MAT infant CD8+ T cells fail to sustain total protein tyrosine phosphorylation and Erk1/2 activation. Lipopolysaccharide treatment in vitro and in vivo, partially restored IFN-gamma production in MAT effector CD8+ T cells and reduced mortality typically observed in MAT mice following systemic viral infection. Our results demonstrate a surprising dependence on the gastrointestinal microbiome and TLR ligand stimulation toward shaping optimal CD8+ T cell function during infancy. PMID- 28337208 TI - Natural Killer Cell Development and Maturation Revisited: Possible Implications of a Novel Distinct Lin-CD34+DNAM-1brightCXCR4+ Cell Progenitor. AB - Since the first description of natural killer (NK) cells, the view on their role in innate immunity has evolved considerably. In addition to first-line defense against transformed and pathogen-infected autologous cells, NK cells contribute to modulate adaptive immune responses and in some cases acquire specialized functions, including exhausted, adaptive, and decidual NK cells. NK cells derive from CD34+ progenitors, in vivo and in vitro; however, it is unclear whether the high phenotype diversity in vivo may be generated from these precursors alone. The recent characterization of a novel CD34+DNAM-1brightCXCR4+ precursor giving rise to apparently licensed and functional maturing NK cells may suggest the possibility for a higher than expected common lymphocyte precursor diversity and a consequently higher peripheral NK cell phenotype variability. Here, we review the evidences on NK cell central and peripheral development from CD34+ precursors and propose a possible updated reading frame based on the characterization of CD34+DNAM-1brightCXCR4+ cell progenies, which favors the possibility of concurrent NK cell maturation from different CD34+ precursors. PMID- 28337209 TI - Transcriptional Responses of Chilean Quinoa (Chenopodium quinoa Willd.) Under Water Deficit Conditions Uncovers ABA-Independent Expression Patterns. AB - HIGHLIGHTS R49 genotype displayed best performance on selected physiological parameters and highest tolerance to drought.R49 drought over-represented transcripts has exhibited 19% of genes (306 contigs) that presented no homology to published databases.Expression pattern for canonical responses to drought such as ABA biosynthesis and other genes induced in response to drought were assessed by qPCR. Global freshwater shortage is one of the biggest challenges of our time, often associated to misuse, increased consumption demands and the effects of climate change, paralleled with the desertification of vast areas. Chenopodium quinoa (Willd.) represents a very promising species, due to both nutritional content and cultivation under water constraint. We characterized drought tolerance of three Chilean genotypes and selected Genotype R49 (Salares ecotype) based upon Relative Water Content (RWC), Electrolyte Leakage (EL) and maximum efficiency of photosystem II (Fv/Fm) after drought treatment, when compared to another two genotypes. Exploratory RNA-Seq of R49 was generated by Illumina paired-ends method comparing drought and control irrigation conditions. We obtained 104.8 million reads, with 54 million reads for control condition and 51 million reads for drought condition. Reads were assembled in 150,952 contigs, were 31,523 contigs have a reading frame of at least 300 nucleotides (100 aminoacids). BLAST2GO annotation showed a 15% of genes without homology to NCBI proteins, but increased to 19% (306 contigs) when focused into drought-induced genes. Expression pattern for canonical drought responses such as ABA biosynthesis and other genes induced were assessed by qPCR, suggesting novelty of R49 drought responses. PMID- 28337210 TI - Assessing Wheat Traits by Spectral Reflectance: Do We Really Need to Focus on Predicted Trait-Values or Directly Identify the Elite Genotypes Group? AB - Phenotyping, via remote and proximal sensing techniques, of the agronomic and physiological traits associated with yield potential and drought adaptation could contribute to improvements in breeding programs. In the present study, 384 genotypes of wheat (Triticum aestivum L.) were tested under fully irrigated (FI) and water stress (WS) conditions. The following traits were evaluated and assessed via spectral reflectance: Grain yield (GY), spikes per square meter (SM2), kernels per spike (KPS), thousand-kernel weight (TKW), chlorophyll content (SPAD), stem water soluble carbohydrate concentration and content (WSC and WSCC, respectively), carbon isotope discrimination (Delta13C), and leaf area index (LAI). The performances of spectral reflectance indices (SRIs), four regression algorithms (PCR, PLSR, ridge regression RR, and SVR), and three classification methods (PCA-LDA, PLS-DA, and kNN) were evaluated for the prediction of each trait. For the classification approaches, two classes were established for each trait: The lower 80% of the trait variability range (Class 1) and the remaining 20% (Class 2 or elite genotypes). Both the SRIs and regression methods performed better when data from FI and WS were combined. The traits that were best estimated by SRIs and regression methods were GY and Delta13C. For most traits and conditions, the estimations provided by RR and SVR were the same, or better than, those provided by the SRIs. PLS-DA showed the best performance among the categorical methods and, unlike the SRI and regression models, most traits were relatively well-classified within a specific hydric condition (FI or WS), proving that classification approach is an effective tool to be explored in future studies related to genotype selection. PMID- 28337211 TI - Nutritional, Biophysical and Physiological Characteristics of Wild Rocket Genotypes As Affected by Soilless Cultivation System, Salinity Level of Nutrient Solution and Growing Period. AB - With the aim of defining the best management of nutrient solution (NS) in a soilless system for obtaining high quality baby-leaf rocket, the present study focuses on two wild rocket genotypes ("Nature" and "Naturelle"), grown in a greenhouse under two Southern Italy growing conditions-autumn-winter (AW) and winter-spring (WS)-using two soilless cultivation systems (SCS)-at two electrical conductivity values (EC) of NS. The SCSs used were the Floating System (FS) and Ebb and Flow System (EFS) and the EC values were 2.5 and 3.5 dS m-1 (EC2.5; EC3.5) for the AW cycle and 3.5 and 4.5 dS m-1 (EC3.5; EC4.5) for the WS cycle. The yield, bio-physical, physiological and nutritional characteristics were evaluated. Higher fresh (FY) (2.25 vs. 1.50 kg m-2) and dry (DY) (230.6 vs. 106.1 g m-2) weight yield, leaf firmness (dry matter, 104.3 vs. 83.2 g kg-1 FW; specific leaf area, 34.8 vs. 24.2 g cm-2) and antioxidant compounds (vitamin C, 239.0 vs. 152.7 mg kg-1 FW; total phenols, 997 vs. 450 mg GAE mg kg-1 FW; total glucosinulates-GLSs, 1,078.8 vs. 405.7 mg kg-1 DW; total antioxidant capacity TAC, 11,534 vs. 8,637 MUmol eq trolox kg-1 FW) and lower nitrates (1,470 vs. 3,460 mg kg-1 FW) were obtained under WS conditions. The seasonal differences were evident on the GLS profile: some aliphatic GLSs (gluconapoleiferin, glucobrassicanapin) and indolic 4-OH-glucobrassicin were only expressed in WS conditions, while indolic glucobrassicin was only detected in the AW period. Compared with EFS, FS improved leaf firmness, visual quality, antioxidant content (TAC, +11.6%) and reduced nitrate leaf accumulation (-37%). "Naturelle" performed better than "Nature" in terms of yield, visual quality and nutritional profile, with differences more evident under less favorable climatic conditions and when the cultivars were grown in FS. Compared to EC2.5, the EC3.5 treatment did not affect DY while enhancing firmness, visual quality, and antioxidant compounds (TAC, +8%), and reducing the nitrate content (-47%). The EC4.5 treatment reduced FY and DY and the antioxidant content. Despite seasonal climatic condition variability, FS and the moderate salinity level of NS (3.5 dS m-1) can be suggested as optimum. PMID- 28337212 TI - Identification of Norway Spruce MYB-bHLH-WDR Transcription Factor Complex Members Linked to Regulation of the Flavonoid Pathway. AB - Transcription factors (TFs) forming MYB-bHLH-WDR complexes are known to regulate the biosynthesis of specialized metabolites in angiosperms through an intricate network. These specialized metabolites participate in a wide range of biological processes including plant growth, development, reproduction as well as in plant immunity. Studying the regulation of their biosynthesis is thus essential. While MYB (TFs) have been previously shown to control specialized metabolism (SM) in gymnosperms, the identity of their partners, in particular bHLH or WDR members, has not yet been revealed. To gain knowledge about MYB-bHLH-WDR transcription factor complexes in gymnosperms and their regulation of SW, we identified two bHLH homologs of AtTT8, six homologs of the MYB transcription factor AtTT2 and one WDR ortholog of AtTTG1 in Norway spruce. We investigated the expression levels of these genes in diverse tissues and upon treatments with various stimuli including methyl-salicylate, methyl-jasmonate, wounding or fungal inoculation. In addition, we also identified protein-protein interactions among different homologs of MYB, bHLH and WDR. Finally, we generated transgenic spruce cell lines overexpressing four of the Norway spruce AtTT2 homologs and observed differential regulation of genes in the flavonoid pathway and flavonoid contents. PMID- 28337213 TI - Root Branching Is a Leading Root Trait of the Plant Economics Spectrum in Temperate Trees. AB - Global vegetation models use conceived relationships between functional traits to simulate ecosystem responses to environmental change. In this context, the concept of the leaf economics spectrum (LES) suggests coordinated leaf trait variation, and separates species which invest resources into short-lived leaves with a high expected energy return rate from species with longer-lived leaves and slower energy return. While it has been assumed that being fast (acquisitive) or slow (conservative) is a general feature for all organ systems, the translation of the LES into a root economics spectrum (RES) for tree species has been hitherto inconclusive. This may be partly due to the assumption that the bulk of tree fine roots have similar uptake functions as leaves, despite the heterogeneity of their environments and resources. In this study we investigated well-established functional leaf and stature traits as well as a high number of fine root traits (14 traits split by different root orders) of 13 dominant or subdominant temperate tree species of Central Europe, representing two phylogenetic groups (gymnosperms and angiosperms) and two mycorrhizal associations (arbuscular and ectomycorrhizal). We found reflected variation in leaf and lower-order root traits in some (surface areas and C:N) but not all (N content and longevity) traits central to the LES. Accordingly, the LES was not mirrored belowground. We identified significant phylogenetic signal in morphological lower-order root traits, i.e., in root tissue density, root diameter, and specific root length. By contrast, root architecture (root branching) was influenced by the mycorrhizal association type which developed independent from phylogeny of the host tree. In structural equation models we show that root branching significantly influences both belowground (direct influence on root C:N) and aboveground (indirect influences on specific leaf area and leaf longevity) traits which relate to resource investment and lifespan. We conclude that branching of lower order roots can be considered a leading root trait of the plant economics spectrum of temperate trees, since it relates to the mycorrhizal association type and belowground resource exploitation; while the dominance of the phylogenetic signal over environmental filtering makes morphological root traits less central for tree economics spectra across different environments. PMID- 28337214 TI - Crystal Structure of the Chloroplastic Oxoene Reductase ceQORH from Arabidopsis thaliana. AB - Enzymatic and non-enzymatic peroxidation of polyunsaturated fatty acids give rise to accumulation of aldehydes, ketones, and alpha,beta-unsaturated carbonyls of various lengths, known as oxylipins. Oxylipins with alpha,beta-unsaturated carbonyls are reactive electrophile species and are toxic. Cells have evolved several mechanisms to scavenge reactive electrophile oxylipins and decrease their reactivity such as by coupling with glutathione, or by reduction using NAD(P)H dependent reductases and dehydrogenases of various substrate specificities. Plant cell chloroplasts produce reactive electrophile oxylipins named gamma-ketols downstream of enzymatic lipid peroxidation. The chloroplast envelope quinone oxidoreductase homolog (ceQORH) from Arabidopsis thaliana was previously shown to reduce the reactive double bond of gamma-ketols. In marked difference with its cytosolic homolog alkenal reductase (AtAER) that displays a high activity toward the ketodiene 13-oxo-9(Z),11(E)-octadecadienoic acid (13-KODE) and the ketotriene 13-oxo-9(Z), 11(E), 15(Z)-octadecatrienoic acid (13-KOTE), ceQORH binds, but does not reduce, 13-KODE and 13-KOTE. Crystal structures of apo-ceQORH and ceQORH bound to 13-KOTE or to NADP+ and 13-KOTE have been solved showing a large ligand binding site, also observed in the structure of the cytosolic alkenal/one reductase. Positioning of the alpha,beta-unsaturated carbonyl of 13-KOTE in ceQORH-NADP+-13-KOTE, far away from the NADP+ nicotinamide ring, provides a rational for the absence of activity with the ketodienes and ketotrienes. ceQORH is a monomeric enzyme in solution whereas other enzymes from the quinone oxidoreductase family are stable dimers and a structural explanation of this difference is proposed. A possible in vivo role of ketodienes and ketotrienes binding to ceQORH is also discussed. PMID- 28337216 TI - Smart Data: Where the Big Data Meets the Semantics. PMID- 28337215 TI - Root Adaptive Responses to Aluminum-Treatment Revealed by RNA-Seq in Two Citrus Species With Different Aluminum-Tolerance. AB - Seedlings of aluminum (Al)-tolerant Citrus sinensis and Al-intolerant Citrus grandis were fertigated daily with nutrient solution containing 0 and 1.0 mM AlCl3?6H2O for 18 weeks. The Al-induced decreases of biomass and root total soluble proteins only occurred in C. grandis, demonstrating that C. sinensis had higher Al-tolerance than C. grandis. Under Al-treatment, C. sinensis roots secreted more citrate and malate than C. grandis ones; less Al was accumulated in C. sinenis than in C. grandis leaves. The Al-induced reduction of phosphorus was lesser in C. sinensis roots and leaves than in C. grandis ones, whereas the Al induced increase of sulfur was greater in C. sinensis roots and leaves. Using RNA seq, we isolated 1905 and 2670 differentially expressed genes (DEGs) from Al treated C. sinensis than C. grandis roots, respectively. Among these DEGs, only 649 DEGs were shared by the two species. Further analysis suggested that the following several aspects conferred C. sinensis higher Al-tolerance: (a) Al treated C. sinensis seedlings had a higher external Al detoxification capacity via enhanced Al-induced secretion of organic acid anions, a higher antioxidant capacity and a more efficient chelation system in roots; (b) Al-treated C. sinensis seedlings displayed a higher level of sulfur in roots and leaves possibly due to increased uptake and decreased export of sulfur and a higher capacity to maintain the cellular phosphorus homeostasis by enhancing phosphorus acquisition and utilization; (c) Cell wall and cytoskeleton metabolism, energy and carbohydrate metabolism and signal transduction displayed higher adaptative responses to Al in C. sinensis than in C. grandis roots; (d) More upregulated than downregulated genes related to fatty acid and amino acid metabolisms were isolated from Al-treated C. sinensis roots, but the reverse was the case for Al treated C. grandis roots. These results provide a platform for further investigating the roles of genes possibly responsible for citrus Al-tolerance. PMID- 28337217 TI - Cost-Effectiveness Analysis of Helicobacter pylori Diagnostic Methods in Patients with Atrophic Gastritis. AB - Background. There are several diagnostic methods for Helicobacter pylori (H. pylori) infection. A cost-effective analysis is needed to decide on the optimal diagnostic method. The aim of this study was to determine a cost-effective diagnostic method in patients with atrophic gastritis (AG). Methods. A decision analysis model including seven diagnostic methods was constructed for patients with AG diagnosed by esophagogastroduodenoscopy. Expected values of cost and effectiveness were calculated for each test. Results. If the prevalence of H. pylori in the patients with AG is 85% and CAM-resistant H. pylori is 30%, histology, stool H. pylori antigen (SHPAg), bacterial culture (BC), and urine H. pylori antibody (UHPAb) were dominated by serum H. pylori IgG antibody (SHPAb), rapid urease test (RUT), and urea breath test (UBT). Among three undominated methods, the incremental cost-effective ratios (ICER) of RUT versus SHPAb and UBT versus RUT were $214 and $1914, respectively. If the prevalence of CAM-sensitive H. pylori was less than 55%, BC was not dominated, but its H. pylori eradication success rate was 0.86. Conclusions. RUT was the most cost-effective at the current prevalence of CAM-resistant H. pylori. BC could not be selected due to its poor effectiveness even if CAM-resistant H. pylori was more than 45%. PMID- 28337218 TI - Effect of Transplantation of Bone Marrow Derived Mesenchymal Stem Cells and Platelets Rich Plasma on Experimental Model of Radiation Induced Oral Mucosal Injury in Albino Rats. AB - Normal tissue damage following radiotherapy is still a major problem in cancer treatment. Therefore, the current work aimed at exploring the possible role of systemically injected bone marrow derived mesenchymal stem cells (BM-MSCs) and/or locally injected platelet rich plasma (PRP) in ameliorating the side effects of ionizing radiation on the rat's tongue. Twelve rats served as control group (N) and 48 rats received a single radiation dose of 13 Gy to the head and neck region; then, they were equally divided into 4 experimental groups: irradiated only (C), irradiated + MSCs (S), irradiated + (PRP) (P), and combined group (PS). Animal scarification occurred in 3 and 7 days after radiation. Then, tongues were dissected and examined histologically and for expression of bcl-2 by RT-PCR. Histological examination of the treated groups (S), (P), and (PS) revealed an obvious improvement in the histological structure of the tongue, compared to group (C), in addition to upregulated expression of bcl-2, indicating decreased apoptotic activity. Conclusion. BM-MSCs and PRP have shown positive effect in minimizing the epithelial atrophy of normal oral mucosa after regional radiotherapy, which was emphasized by decreasing apoptotic activity in these tissues. Nevertheless, combined use of BM-MSCs and PRP did not reveal the assumed synergetic effect in oral tissue protection. PMID- 28337219 TI - Neural Differentiation in HDAC1-Depleted Cells Is Accompanied by Coilin Downregulation and the Accumulation of Cajal Bodies in Nucleoli. AB - Cajal bodies (CBs) are important compartments containing accumulated proteins that preferentially regulate RNA-related nuclear events, including splicing. Here, we studied the nuclear distribution pattern of CBs in neurogenesis. In adult brains, coilin was present at a high density, but CB formation was absent in the nuclei of the choroid plexus of the lateral ventricles. Cells of the adult hippocampus were characterized by a crescent-like morphology of coilin protein. We additionally observed a 70 kDa splice variant of coilin in adult mouse brains, which was different to embryonic brains and mouse pluripotent embryonic stem cells (mESCs), characterized by the 80 kDa standard variant of coilin. Here, we also showed that depletion of coilin is induced during neural differentiation and HDAC1 deficiency in mESCs caused coilin accumulation inside the fibrillarin positive region of the nucleoli. A similar distribution pattern was observed in adult brain hippocampi, characterized by lower levels of both coilin and HDAC1. In summary, we observed that neural differentiation and HDAC1 deficiency lead to coilin depletion and coilin accumulation in body-like structures inside the nucleoli. PMID- 28337220 TI - Paracrine Secreted Frizzled-Related Protein 4 Inhibits Melanocytes Differentiation in Hair Follicle. AB - Wnt signaling plays crucial role in regulating melanocyte stem cells/melanocyte differentiation in the hair follicle. However, how the Wnt signaling is balanced to be overactivated to control follicular melanocytes behavior remains unknown. Here, by using immunofluorescence staining, we showed that secreted frizzled related protein 4 (sFRP4) is preferentially expressed in the skin epidermal cells rather than in melanocytes. By overexpression of sFRP4 in skin cells in vivo and in vitro, we found that sFRP4 attenuates activation of Wnt signaling, resulting in decrease of melanocytes differentiation in the regenerating hair follicle. Our findings unveiled a new regulator that involves modulating melanocytes differentiation through a paracrine mechanism in hair follicle, supplying a hope for potential therapeutic application to treat skin pigmentation disorders. PMID- 28337221 TI - Cancer Stem Cells and Their Microenvironment: Biology and Therapeutic Implications. AB - Tumor consists of heterogeneous cancer cells including cancer stem cells (CSCs) that can terminally differentiate into tumor bulk. Normal stem cells in normal organs regulate self-renewal within a stem cell niche. Likewise, accumulating evidence has also suggested that CSCs are maintained extrinsically within the tumor microenvironment, which includes both cellular and physical factors. Here, we review the significance of stromal cells, immune cells, extracellular matrix, tumor stiffness, and hypoxia in regulation of CSC plasticity and therapeutic resistance. With a better understanding of how CSC interacts with its niche, we are able to identify potential therapeutic targets for the development of more effective treatments against cancer. PMID- 28337222 TI - A Conditioned Medium of Umbilical Cord Mesenchymal Stem Cells Overexpressing Wnt7a Promotes Wound Repair and Regeneration of Hair Follicles in Mice. AB - Mesenchymal stem cells (MSCs) can affect the microenvironment of a wound and thereby accelerate wound healing. Wnt proteins act as key mediators of skin development and participate in the formation of skin appendages such as hair. The mechanisms of action of MSCs and Wnt proteins on skin wounds are largely unknown. Here, we prepared a Wnt7a-containing conditioned medium (Wnt-CM) from the supernatant of cultured human umbilical cord-MSCs (UC-MSCs) overexpressing Wnt7a in order to examine the effects of this CM on cutaneous healing. Our results revealed that Wnt-CM can accelerate wound closure and induce regeneration of hair follicles. Meanwhile, Wnt-CM enhanced expression of extracellular matrix (ECM) components and cell migration of fibroblasts but inhibited the migratory ability and expression of K6 and K16 in keratinocytes by enhancing expression of c-Myc. However, we found that the CM of fibroblasts treated with Wnt-CM (HFWnt-CM-CM) can also promote wound repair and keratinocyte migration; but there was no increase in the number of hair follicles of regeneration. These data indicate that Wnt7a and UC-MSCs have synergistic effects: they can accelerate wound repair and induce hair regeneration via cellular communication in the wound microenvironment. Thus, this study opens up new avenues of research on the mechanisms underlying wound repair. PMID- 28337224 TI - Gut Mesenchymal Stromal Cells in Immunity. AB - Mesenchymal stromal cells (MSCs), first found in bone marrow (BM), are the structural architects of all organs, participating in most biological functions. MSCs possess tissue-specific signatures that allow their discrimination according to their origin and location. Among their multiple functions, MSCs closely interact with immune cells, orchestrating their activity to maintain overall homeostasis. The phenotype of tissue MSCs residing in the bowel overlaps with myofibroblasts, lining the bottom walls of intestinal crypts (pericryptal) or interspersed within intestinal submucosa (intercryptal). In Crohn's disease, intestinal MSCs are tightly stacked in a chronic inflammatory milieu, which causes their enforced expression of Class II major histocompatibility complex (MHC). The absence of Class II MHC is a hallmark for immune-modulator and tolerogenic properties of normal MSCs and, vice versa, the expression of HLA-DR is peculiar to antigen presenting cells, that is, immune-activator cells. Interferon gamma (IFNgamma) is responsible for induction of Class II MHC expression on intestinal MSCs. The reversal of myofibroblasts/MSCs from an immune modulator to an activator phenotype in Crohn's disease results in the formation of a fibrotic tube subverting the intestinal structure. Epithelial metaplastic areas in this context can progress to dysplasia and cancer. PMID- 28337223 TI - Emerging Perspectives in Scaffold for Tissue Engineering in Oral Surgery. AB - Bone regeneration is currently one of the most important and challenging tissue engineering approaches in regenerative medicine. Bone regeneration is a promising approach in dentistry and is considered an ideal clinical strategy in treating diseases, injuries, and defects of the maxillofacial region. Advances in tissue engineering have resulted in the development of innovative scaffold designs, complemented by the progress made in cell-based therapies. In vitro bone regeneration can be achieved by the combination of stem cells, scaffolds, and bioactive factors. The biomimetic approach to create an ideal bone substitute provides strategies for developing combined scaffolds composed of adult stem cells with mesenchymal phenotype and different organic biomaterials (such as collagen and hyaluronic acid derivatives) or inorganic biomaterials such as manufactured polymers (polyglycolic acid (PGA), polylactic acid (PLA), and polycaprolactone). This review focuses on different biomaterials currently used in dentistry as scaffolds for bone regeneration in treating bone defects or in surgical techniques, such as sinus lift, horizontal and vertical bone grafts, or socket preservation. Our review would be of particular interest to medical and surgical researchers at the interface of cell biology, materials science, and tissue engineering, as well as industry-related manufacturers and researchers in healthcare, prosthetics, and 3D printing, too. PMID- 28337225 TI - Bufei Huoxue Capsule Attenuates PM2.5-Induced Pulmonary Inflammation in Mice. AB - Atmospheric fine particulate matter 2.5 (PM 2.5) may carry many toxic substances on its surface and this may pose a public health threat. Epidemiological research indicates that cumulative ambient PM2.5 is correlated to morbidity and mortality due to pulmonary and cardiovascular diseases and cancer. Mitigating the toxic effects of PM2.5 is therefore highly desired. Bufei Huoxue (BFHX) capsules have been used in China to treat pulmonary heart disease (cor pulmonale). Thus, we assessed the effects of BFHX capsules on PM2.5-induced pulmonary inflammation and the underlying mechanisms of action. Using Polysearch and Cytoscape 3.2.1 software, pharmacological targets of BFHX capsules in atmospheric PM2.5-related respiratory disorders were predicted and found to be related to biological pathways of inflammation and immune function. In a mouse model of PM2.5-induced inflammation established with intranasal instillation of PM2.5 suspension, BFHX significantly reduced pathological response and inflammatory mediators including IL-4, IL-6, IL-10, IL-8, TNF-alpha, and IL-1beta. BFHX also reduced keratinocyte growth factor (KGF), secretory immunoglobulin A (sIgA), and collagen fibers deposition in lung and improved lung function. Thus, BFHX reduced pathological responses induced by PM2.5, possibly via regulation of inflammatory mediators in mouse lungs. PMID- 28337226 TI - Tetramethylpyrazine Protects against Early Brain Injury after Experimental Subarachnoid Hemorrhage by Affecting Mitochondrial-Dependent Caspase-3 Apoptotic Pathway. AB - This study was to test the hypothesis that tetramethylpyrazine (TMP) protected against early brain injury after subarachnoid hemorrhage (SAH) by affecting the mitochondrial-dependent caspase-3 apoptotic pathway. TMP was administrated after the rats' prechiasmatic SAH mode. Animal neurobehavioral functions were assessed and the mitochondrial morphology, mitochondrial and cytoplasmic calcium, and mitochondrial membrane potential changes (Deltapsim) of the brain tissues were measured. The expressions of cytoplasmic cytochrome c (cyt c), second mitochondria-derived activator of caspases (Smac), and cleaved caspase-3 B-cell lymphoma 2 (bcl-2) in cells were determined and cellular apoptosis was detected. The treatment of TMP resulted in less apoptotic cells and milder mitochondrial injury and potentially performed better in the neurobehavioral outcome compared to those with saline. Also, TMP ameliorated calcium overload in mitochondria and cytoplasm and alleviated the decrease of Deltapsim. In addition, TMP inhibited the expression of cytoplasmic cyt c, Smac, and cleaved caspase-3, yet it upregulated the expression of bcl-2. These findings suggest that TMP exerts an antiapoptosis property in the SAH rat model and this is probably mediated by the caspase-3 apoptotic pathway triggered by mitochondrial calcium overload. The finding offers a new therapeutic candidate for early brain injury after SAH. PMID- 28337227 TI - Potential Protective Effects of Bioactive Constituents from Chinese Propolis against Acute Oxidative Stress Induced by Hydrogen Peroxide in Cardiac H9c2 Cells. AB - Chinese propolis (CP) is known as a health food but its beneficial effects in protecting cardiomyocytes remain elusive. Here, we investigated the effects of CP and its active compounds on hydrogen peroxide (H2O2) induced rats cardiomyocytes (H9c2) oxidative injury. Cell viability decreases induced by H2O2 were mitigated by different CP extracts using various solvents. From these active fractions, six active compounds were separated and identified. Among tested isolated compound, the cytoprotective activities of three caffeates, caffeic acid phenethyl ester (CAPE), benzyl caffeate (BZC), and cinnamyl caffeate (CNC), exerted stronger effects than chrysin, pinobanksin, and 3,4-dimethoxycinnamic acid (DMCA). These three caffeates also increased H9c2 cellular antioxidant potential, decreased intracellular calcium ion ([Ca2+]i) level, and prevented cell apoptosis. Overall, the cardiovascular protective effects of the CP might be attributed to its caffeates constituents (CAPE, BZC, and CNC) and provide evidence for its usage in complementary and alternative medicine. PMID- 28337228 TI - Evaluation of Efficacy and Safety of Dan'e-Fukang Soft Extract in the Treatment of Endometriosis: A Meta-Analysis of 39 Randomized Controlled Trials Enrolling 5442 Patients. AB - Objective. To systematically evaluate the efficacy and safety of Dan'e-fukang soft extract in endometriosis treatment. Method. PubMed, CNKI, Wanfang Database, VIP, SinoMed, and Cochrane Library were searched. Randomized controlled trials (RCTs) comparing the efficacy of Dan'e-fukang soft extract and conventional western medicines for endometriosis treatment were included. The data were extracted independently by two people and analyzed using RevMan 5.2.0 software. The relative risk (RR) and mean difference (MD) with 95% confidence intervals were considered as effective outcome indicators. Results. Thirty-nine papers including 5442 patients with endometriosis were included in this study. A meta analysis revealed that Dan'e-fukang soft extract was more efficient than gestrinone in the treatment of endometriosis (RR = 1.08, 95% CI = 1.03 to 1.15, I2 = 71%, REM, 18 trials) and its efficacy was comparable to that of danazol and mifepristone. Dan'e-fukang soft extract was also as effective as gestrinone and mifepristone in terms of relapse rate and relieving dysmenorrhea. The incidence of adverse reactions was lower than that of conventional western medicines. Conclusions. The results of this study showed that Dan'e-fukang soft extract offers certain advantages in endometriosis treatment, but rigorously designed, strictly implemented RCTs are needed to further validate its efficacy. PMID- 28337229 TI - Allergic enteritis in children. AB - The gastrointestinal form of food allergy is very common in children. The most frequently observed types are allergic proctitis and proctocolitis. In most cases the symptoms subside within the first 2 months of life. The babies seem healthy, and the only abnormality is a small amount of blood in stool. Symptoms can also include small intestine inflammation and colitis. Patients may present with irritability, abdominal pain, flatulence, colic, postprandial vomiting, chronic diarrhoea, and hindered physical development. The diagnosis of allergic enteritis is based on the clinical examination and the results of additional tests including an endoscopy of the lower digestive tract with histopathological assessment. Cow's milk proteins are the most common nutrition proteins responsible for the development of the symptoms of allergic enteritis. The most essential method of treating allergic enteritis is the elimination diet. The symptoms should subside within 1-2 weeks from the beginning of the diet. PMID- 28337231 TI - Role of endoscopic submucosal dissection in treatment of rectal gastroenteropancreatic neuroendocrine neoplasms. AB - INTRODUCTION: A significant rise in incidence of rectal gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) has been observed in the last decade. Most detected gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are well differentiated and less than 2 cm in diameter. Endoscopic submucosal dissection (ESD) is a new method for endoscopic treatment of such tumors, difficult to resect by conventional endoscopic techniques and thus subject to surgical treatment. AIM: To present the results of the endoscopic treatment of GEP NET tumors in the rectum using ESD in single academic center. MATERIAL AND METHODS: From June 2013 to April 2014, 4 cases of GEP-NET in the rectum were treated by ESD in our center. Effectiveness of dissection, complications and tumor recurrence after 3 months of treatment were then retrospectively investigated. RESULTS: The group contained 2 patients with primary rectal GEP-NET (1 male, 1 female; age range: 48-60 years) and 2 with scars after incomplete polypectomy of rectal GEP-NET (1 male, 1 female; 61-65 years). Primary rectal GEP-NET diameters were 0.6 cm and 1.5 cm. Scar resection specimen diameters were 0.7 cm and 1 cm. Mean resection time was 28 min. The en bloc resection rate was 100% (2 of 2) and the histologically complete resection was confirmed in both cases. No foci of neuroendocrine neoplasia were reported in dissected scars. No complications were observed. After 3 months, 3 patients underwent follow-up colonoscopy - no local recurrence was reported. CONCLUSIONS: Endoscopic submucosal dissection of rectal GEP-NET should be recommended as a treatment of choice when dealing with lesions over 1 cm in diameter without invasion of the muscle layer. Due to technical difficulties, performing this procedure should be reserved for centers with appropriately trained endoscopic staff. PMID- 28337230 TI - Health-related quality of life assessment among patients with inflammatory bowel diseases after surgery - review. AB - Aim of the work was to review systematically the published literature addressing whether quality of life (QoL) and health-related QoL (HRQoL) are influenced by surgery among patients with inflammatory bowel disease (IBD). Electronic databases and published articles were searched to identify relevant studies published in the years 1990-2015. Then, a multistep selection was undertaken to identify articles that met specific selection criteria, such us specific key words (IBD, HRQoL, ulcerative colitis (UC), Crohn's disease (CD), and surgery), and the population was assessed (studies concerning patients < 18 years old were excluded). The review included 27 studies that were evaluated in the context of the influence of surgery on QoL and HRQoL. Concluding, with the increase in the incidence of IBD, monitoring of QoL is an important indicator of the health effects at each stage of the surgical treatment. PMID- 28337233 TI - Diagnostic value of optimised real-time sonoelastography in the assessment of liver fibrosis in chronic hepatitis B and C. AB - AIM: To optimise the method of real-time elastography (RTE) in the assessment of liver fibrosis using an in-house prepared method for elastogram analysis, as well as a semiquantitative analysis based on newly introduced parameters. MATERIAL AND METHODS: Sonoelastography was performed in 94 patients with various degrees of liver fibrosis and also in 25 healthy volunteers. As a reference method for diagnostic efficacy of sonoelastography-based parameters used for the assessment of fibrosis degree in patients with chronic B and C hepatitis, a liver biopsy was used. Patient's elastograms were analysed using in-house prepared software, Pixel Count, calculating two semiquantitative parameters: mean stiffness fraction (MSF%) and intrinsic stiffness ratio (ISR). RESULTS: Statistically significant differences between distributions of the above presented parameters for different degrees of liver fibrosis were revealed. Indices of diagnostic efficacy for detection of significant liver fibrosis (F >= 2) using MSF% amounted to: sensitivity - 76%, specificity - 87% and ISR: 81% and 87%, respectively. Sensitivity of both parameters in detection of cirrhosis (F = 4) was equal to 88% and specificity amounted to: for MSF% - 84% and ISR - 86%. Interobserver reproducibility determined for both of the above parameters was high, intraclass correlation coefficients (ICC) were 0.91 for MSF% and 0.93 for ISR. CONCLUSIONS: Real-time elastography applied in this study, using in-house prepared Pixel Count software, provided good reproducibility and diagnostic efficacy, especially specificity, in the assessment of liver fibrosis degree. PMID- 28337232 TI - Melanosis coli in patients with colon cancer. AB - INTRODUCTION: Melanosis coli is a benign lesion affecting the mucosa of the large intestine. There is a relationship between the presence of melanosis and anthraquinone laxative use. Melanosis coli is also observed in patients with colon cancer, but there is doubt whether these two conditions are related. AIM: To analyze the correlation between melanosis and colon cancer. MATERIAL AND METHODS: We analyzed retrospectively 436 patients undergoing colon cancer surgery. There were 246 women and 190 men. Patients were divided into three age groups: under 50 years, between 51 and 65 years, and over 66 years. We analyzed sections of the cancer and intestinal mucosa from the tumor's proximal (2-5 cm) and distal (8-10 cm) zone. RESULTS: Melanosis coli was present in 52 patients, which represents 11.9% of patients with colon cancer. More often it was present in women. The most common location of melanosis and colon cancer was the terminal part of the large intestine. In patients below 50 years of age in both sexes melanosis coli did not occur. In men, melanosis was more common in the age group over 66 years. Intensity of pigmentation was higher in the tumor's distal zone. CONCLUSIONS: The incidence of melanosis coli increases with age, similar to that of colon cancer. Melanosis was not present inside tumors, in almost half of the cases it was not present in the proximal zone, and the degree of pigmentation increased in distal zone. The cause-effect relationship between melanosis coli and colon cancer remains uncertain. PMID- 28337234 TI - Is computerised tomography better than fibreoptic gastroscopy for early detection of gastric varices? AB - INTRODUCTION: Video endoscopic diagnosis of gastric varices is particularly limited, owing to the deep submucosal or subserosal location of the varices and the normal appearance of the overlying mucosa. AIM: We present and emphasise the value of computerised tomography (CT) examination in the early detection of gastric varices (GVs). MATERIAL AND METHODS: In this retrospective study, a total of 216 consecutive patients with cirrhosis were evaluated at the Turkiye Yuksek Ihtisas Training and Research Hospital between September 2008 and March 2011. RESULTS: One hundred and thirty patients with cirrhosis were enrolled in the study. The mean age of the male (88 cases) patients was 59.45 +/-2.42 years, and the mean age of the female (42 cases) patients was 56.29 +/-1.14 years. Computerised tomography identified oesophageal varices (EVs) in 103/130 patients, and endoscopy identified EVs in 103/130 patients. Computerised tomography identified GVs in 86/130 patients, and endoscopy identified GVs in 26/130 patients. After endoscopic elastic band ligation (EBL), CT identified GVs in 22/26 patients, and endoscopy identified GVs in 7/26 patients. CONCLUSIONS: Gastric varices lie in the submucosa, deeper than EVs, and distinguishing GVs from gastric rugae may be difficult with video endoscopy. This study demonstrated that CT is a sensitive method for early detection of GVs and has been used previously in the evaluation of GVs. PMID- 28337235 TI - The concentration of calprotectin in the stools of children with diagnosed cystic fibrosis. AB - INTRODUCTION: Calprotectin is a protein that plays a regulatory role in inflammatory reactions as an antibacterial and antiproliferative factor. AIM: To assess the concentration of calprotectin in the stools of patients with diagnosed cystic fibrosis. MATERIAL AND METHODS: Forty-one patients were included in the study, 24 boys and 17 girls, aged from 7 weeks to 18 years. The concentration of calprotectin in stools was assessed with the ELISA method. The analysis included clinical symptoms and the results of laboratory tests and the type of mutation. RESULTS: An elevated level of calprotectin in the stool was observed in 4/41 (9.7%) patients, mainly in older children, and mainly delta F508/deltaF508 mutation. The correlation between the concentration of calprotectin and clinical symptoms, age, increased indicators of an inflammatory process, levels of protein and aminotransferases in blood serum and the values of acid steatocrit of the stool was not proven. CONCLUSIONS: High concentrations of calprotectin in the stools of children with diagnosed cystic fibrosis do not correlate with the level of advancement of lesions within the gastrointestinal tract. Elevated concentrations of calprotectin in the stools of patients with cystic fibrosis may indicate inflammation of intestine and should be further scrutinised. PMID- 28337236 TI - Adalimumab for endoscopic and histopathological mucosal healing in paediatric patients with moderate to severe Crohn's disease. AB - INTRODUCTION: Deep remission, defined as clinical remission with mucosal healing (MH), with anti-tumor necrosis factor (TNF)-alpha agents is a new target for therapy in Crohn's disease (CD). Provided that the efficacy of infliximab (IFX) for induction of MH in CD has been demonstrated, there are much less data for adalimumab (ADA), and none concerning MH on histopathological examination. AIM: To assess the impact of biological therapy with ADA on both endoscopic and histopathological MH in paediatric patients with CD. MATERIAL AND METHODS: Twenty three children (10 boys and 13 girls) aged 13.0 +/-9.3 years with moderate to severely active CD diagnosed at the mean age of 5.5 +/-0.83 years were included into the study. Seven (30.4%) patients had been previously treated with infliximab and switched to ADA due to intolerance or loss of response. Colonoscopy and gastroscopy with sample collection were performed in all patients before and after induction treatment with ADA. Clinical activity of the disease was assessed using the Paediatric Crohn's Disease Activity Index (PCDAI), and the endoscopic activity was scored using the Simple Endoscopic Score (SES-CD). Histological changes were evaluated by a self-adapted numerical scoring system. RESULTS: Four (17.4%) patients reached clinical remission (PCDAI <= 10). When comparing data at baseline and at a week after ADA treatment, a significant decrease was observed in median PCDAI and in SES-CD score between the initial and control colonoscopies. We reported a decrease in histological scale, which was not statistically significant. A correlation was found between PCDAI and SES-CD score. CONCLUSIONS: Biological therapy with ADA has a positive impact on endoscopic mucosal healing in paediatric patients with CD, which is not associated with histological evidence of suppression of inflammation. Endoscopic MH correlates better than microscopic one with clinical remission. PMID- 28337238 TI - Body composition as an indicator of the nutritional status in children with newly diagnosed ulcerative colitis and Crohn's disease - a prospective study. AB - INTRODUCTION: The prevalence of nutritional status disorders in children with ulcerative colitis (UC) is much lower than in the case of Crohn's disease (CD). The largest variability in the components of body composition occurs at the time of a new diagnosis and in periods of disease exacerbation. AIM: Assessment of body composition in children with UC and CD. MATERIAL AND METHODS: The preliminary study included 59 children with inflammatory bowel disease (IBD) (34 children with UC vs. 25 children with CD) aged 4-18 years. The final analysis included 26 newly diagnosed children (16 children with UC vs. 10 children with CD). The evaluation of body composition was conducted by means of BIA-101 bioimpedance analyser. RESULTS: Decreased values of lean mass were found in children with newly diagnosed IBD (UC: 41.13 kg vs. control group: 42.06 kg; CD: 35.50 kg vs. control group: 45.50 kg). After a year interval, an increase in fat (UC 1: 7.67 kg vs. UC 2: 10.33 kg; CD 1: 7.36 kg vs. CD 2: 9.47 kg) as well as lean body mass (UC 1: 35.22 kg vs. UC 2: 39.00 kg; CD 1: 35.99 kg vs. CD 2: 42.41 kg) was found in children. CONCLUSIONS: Children with newly diagnosed IBD were highly vulnerable to nutritional status disturbances. The increase in fat and lean body mass in an annual interval may be due to the treatment regime and control of the children. PMID- 28337237 TI - Relationship between Helicobacter pylori infection and celiac disease: a cross sectional study and a brief review of the literature. AB - INTRODUCTION: Whether Helicobacter pylori triggers celiac disease (CD) or protects against CD is currently the subject of research. In the literature, there are epidemiologic studies that have reported conflicting results regarding the association between H. pylori and CD. AIM: To compare the prevalence of CD autoantibody positivity and the levels of CD autoantibodies between H. pylori positive and H. pylori-negative subjects. MATERIAL AND METHODS: This study was prospectively designed and included 240 dyspeptic patients who underwent upper gastrointestinal endoscopy with gastric and duodenal biopsies. The patients were divided into two groups according to presence of H. pylori infection. The serum levels of immunoglobulin (Ig) A, tissue transglutaminase antibodies (tTGA; IgA and IgG classes), and anti-endomysial antibodies (EMA; IgA and IgG classes) were measured for all participants by a blinded biochemistry expert. RESULTS: There were no significant differences in the serum levels of CD autoantibodies or IgA between the two groups. There were also no significant differences in the percentages of subjects with positive CD serologies or subjects with IgA deficiencies between the groups. CONCLUSIONS: Helicobacter pylori remains one of the bacterial species that is most likely to trigger autoimmunity. However, studies have failed to reveal a relationship between H. pylori and CD; thus, additional basic work on the immunological aspects of the microbial-host interactions and longitudinal studies enrolling patients at very early stages of the disease may help us to address this issue. PMID- 28337239 TI - Disease activity, quality of life, and indirect costs of ulcerative colitis in Poland. AB - INTRODUCTION: Ulcerative colitis (UC) require expensive, lifelong treatment, which generates huge direct costs and has a significant impact on the quality of life, especially in the active state of the disease. AIM: To assess the indirect costs, health-related quality of life, and clinical characteristics of patients with UC in Poland. Additionally, we investigated the association between activity of UC and productivity loss of patients in a Polish setting. MATERIAL AND METHODS: A questionnaire survey was conducted using the Patient Simple Clinical Colitis Activity Index (P-SCCAI) to assess disease activity, as well as the modified Work Productivity and Activity Impairment Questionnaire to assess productivity loss. The quality of life was presented as utility calculated with the EQ-5D-3L questionnaire. Indirect costs were assessed with the Human Capital Approach and were expressed in Polish zlotys (PLN) as well as in euros (?). Correlations were presented using the Spearman coefficient. RESULTS: We performed our analysis based on 202 full questionnaires collected. Mean patient age and age at disease onset were 33.14 years (standard deviation (SD): 9.90) and 26.35 years (SD: 8.89), respectively. The mean P-SCCAI score in the analysed group of patients was 8.26, and the mean utility was 0.8651. Average and median annual indirect costs per working person were ?2043 and ?1389 (8543 PLN and 5808 PLN), respectively, calculated using the gross domestic product, as well as ?4791 and ?3257 (20,026 PLN and 13,615 PLN), respectively, calculated using the gross value added. Total productivity loss was significantly correlated with the disease activity. CONCLUSIONS: Ulcerative colitis causes a decrease in the quality of life as well as patients' productivity loss associated with both absenteeism and with presenteeism. PMID- 28337240 TI - Autoimmune pancreatitis as a component of autoimmune polyglandular syndrome. PMID- 28337241 TI - Rotavirus gastroenteritis and a rare case accompanying acute pancreatitis. PMID- 28337242 TI - Mucosal gastric calcinosis in a hypocalcaemic patient. PMID- 28337243 TI - Residue-Specific Interactions of an Intrinsically Disordered Protein with Silica Nanoparticles and their Quantitative Prediction. AB - Elucidation of the driving forces that govern interactions between nanoparticles and intrinsically disordered proteins (IDP) is important for the understanding of the effect of nanoparticles in living systems and for the design of new nanoparticle-based assays to monitor health and combat disease. The quantitative interaction profile of the intrinsically disordered transactivation domain of p53 and its mutants with anionic silica nanoparticles is reported at atomic resolution using nuclear magnetic spin relaxation experiments. These profiles are analyzed with a novel interaction model that is based on a quantitative nanoparticle affinity scale separately derived for the 20 natural amino acids. The results demonstrate how the interplay of attractive and repulsive Coulomb interactions with hydrophobic effects is responsible for the sequence-dependent binding of a disordered protein to nanoparticles. PMID- 28337246 TI - Lipid Peroxidation Products in Human Health and Disease 2016. PMID- 28337244 TI - Rat Liver Enzyme Release Depends on Blood Flow-Bearing Physical Forces Acting in Endothelium Glycocalyx rather than on Liver Damage. AB - We have found selective elevation of serum enzyme activities in rats subjected to partial hepatectomy (PH), apparently controlled by hemodynamic flow-bearing physical forces. Here, we assess the involvement of stretch-sensitive calcium channels and calcium mobilization in isolated livers, after chemical modifications of the endothelial glycocalyx and changing perfusion directionality. Inhibiting in vivo protein synthesis, we found that liver enzyme release is influenced by de novo synthesis of endothelial glycocalyx components, and released enzymes are confined into a liver "pool." Moreover, liver enzyme release depended on extracellular calcium entry possibly mediated by stretch sensitive calcium channels, and this endothelial-mediated mechanotransduction in liver enzyme release was also evidenced by modifying the glycocalyx carbohydrate components, directionality of perfusing flow rate, and the participation of nitric oxide (NO) and malondialdehyde (MDA), leading to modifications in the intracellular distribution of these enzymes mainly as nuclear enrichment of "mitochondrial" enzymes. In conclusion, the flow-induced shear stress may provide fine-tuned control of released hepatic enzymes through mediation by the endothelium glycocalyx, which provides evidence of a biological role of the enzyme release rather to be merely a biomarker for evaluating hepatotoxicity and liver damage, actually positively influencing progression of liver regeneration in mammals. PMID- 28337247 TI - Neuroprotection in Neurodegenerative Disease: From Basic Science to Clinical Applications. PMID- 28337245 TI - Multifarious Beneficial Effect of Nonessential Amino Acid, Glycine: A Review. AB - Glycine is most important and simple, nonessential amino acid in humans, animals, and many mammals. Generally, glycine is synthesized from choline, serine, hydroxyproline, and threonine through interorgan metabolism in which kidneys and liver are the primarily involved. Generally in common feeding conditions, glycine is not sufficiently synthesized in humans, animals, and birds. Glycine acts as precursor for several key metabolites of low molecular weight such as creatine, glutathione, haem, purines, and porphyrins. Glycine is very effective in improving the health and supports the growth and well-being of humans and animals. There are overwhelming reports supporting the role of supplementary glycine in prevention of many diseases and disorders including cancer. Dietary supplementation of proper dose of glycine is effectual in treating metabolic disorders in patients with cardiovascular diseases, several inflammatory diseases, obesity, cancers, and diabetes. Glycine also has the property to enhance the quality of sleep and neurological functions. In this review we will focus on the metabolism of glycine in humans and animals and the recent findings and advances about the beneficial effects and protection of glycine in different disease states. PMID- 28337248 TI - Oxidative Stress and Autophagy in Metabolism and Longevity. PMID- 28337249 TI - Cellular Homeostasis and Antioxidant Response in Epithelial HT29 Cells on Titania Nanotube Arrays Surface. AB - Cell growth and proliferative activities on titania nanotube arrays (TNA) have raised alerts on genotoxicity risk. Present toxicogenomic approach focused on epithelial HT29 cells with TNA surface. Fledgling cell-TNA interaction has triggered G0/G1 cell cycle arrests and initiates DNA damage surveillance checkpoint, which possibly indicated the cellular stress stimuli. A profound gene regulation was observed to be involved in cellular growth and survival signals such as p53 and AKT expressions. Interestingly, the activation of redox regulator pathways (antioxidant defense) was observed through the cascade interactions of GADD45, MYC, CHECK1, and ATR genes. These mechanisms furnish to protect DNA during cellular division from an oxidative challenge, set in motion with XRRC5 and RAD50 genes for DNA damage and repair activities. The cell fate decision on TNA-nanoenvironment has been reported to possibly regulate proliferative activities via expression of p27 and BCL2 tumor suppressor proteins, cogent with SKP2 and BCL2 oncogenic proteins suppression. Findings suggested that epithelial HT29 cells on the surface of TNA may have a positive regulation via cell homeostasis mechanisms: a careful circadian orchestration between cell proliferation, survival, and death. This nanomolecular knowledge could be beneficial for advanced medical applications such as in nanomedicine and nanotherapeutics. PMID- 28337250 TI - Podocyte Injury and Albuminuria in Experimental Hyperuricemic Model Rats. AB - Although hyperuricemia is shown to accelerate chronic kidney disease, the mechanisms remain unclear. Accumulating studies also indicate that uric acid has both pro- and antioxidant properties. We postulated that hyperuricemia impairs the function of glomerular podocytes, resulting in albuminuria. Hyperuricemic model was induced by oral administration of 2% oxonic acid, a uricase inhibitor. Oxonic acid caused a twofold increase in serum uric acid levels at 8 weeks when compared to control animals. Hyperuricemia in this model was associated with the increase in blood pressure and the wall-thickening of afferent arterioles as well as arcuate arteries. Notably, hyperuricemic rats showed significant albuminuria, and the podocyte injury marker, desmin, was upregulated in the glomeruli. Conversely, podocin, the key component of podocyte slit diaphragm, was downregulated. Structural analysis using transmission electron microscopy confirmed podocyte injury in this model. We found that urinary 8-hydroxy-2' deoxyguanosine levels were significantly increased and correlated with albuminuria and podocytopathy. Interestingly, although the superoxide dismutase mimetic, tempol, ameliorated the vascular changes and the hypertension, it failed to reduce albuminuria, suggesting that vascular remodeling and podocyte injury in this model are mediated through different mechanisms. In conclusion, vasculopathy and podocytopathy may distinctly contribute to the kidney injury in a hyperuricemic state. PMID- 28337251 TI - Pentaerythritol Tetranitrate In Vivo Treatment Improves Oxidative Stress and Vascular Dysfunction by Suppression of Endothelin-1 Signaling in Monocrotaline Induced Pulmonary Hypertension. AB - Objective. Oxidative stress and endothelial dysfunction contribute to pulmonary arterial hypertension (PAH). The role of the nitrovasodilator pentaerythritol tetranitrate (PETN) on endothelial function and oxidative stress in PAH has not yet been defined. Methods and Results. PAH was induced by monocrotaline (MCT, i.v.) in Wistar rats. Low (30 mg/kg; MCT30), middle (40 mg/kg; MCT40), or high (60 mg/kg; MCT60) dose of MCT for 14, 28, and 42 d was used. MCT induced endothelial dysfunction, pulmonary vascular wall thickening, and fibrosis, as well as protein tyrosine nitration. Pulmonary arterial pressure and heart/body and lung/body weight ratio were increased in MCT40 rats (28 d) and reduced by oral PETN (10 mg/kg, 24 d) therapy. Oxidative stress in the vascular wall, in the heart, and in whole blood as well as vascular endothelin-1 signaling was increased in MCT40-treated rats and normalized by PETN therapy, likely by upregulation of heme oxygenase-1 (HO-1). PETN therapy improved endothelium dependent relaxation in pulmonary arteries and inhibited endothelin-1-induced oxidative burst in whole blood and the expression of adhesion molecule (ICAM-1) in endothelial cells. Conclusion. MCT-induced PAH impairs endothelial function (aorta and pulmonary arteries) and increases oxidative stress whereas PETN markedly attenuates these adverse effects. Thus, PETN therapy improves pulmonary hypertension beyond its known cardiac preload reducing ability. PMID- 28337252 TI - Small Interfering RNA Targeting Mitochondrial Calcium Uniporter Improves Cardiomyocyte Cell Viability in Hypoxia/Reoxygenation Injury by Reducing Calcium Overload. AB - Intracellular Ca2+ mishandling is an underlying mechanism in hypoxia/reoxygenation (H/R) injury that results in mitochondrial dysfunction and cardiomyocytes death. These events are mediated by mitochondrial Ca2+ (mCa2+) overload that is facilitated by the mitochondrial calcium uniporter (MCU) channel. Along this line, we evaluated the effect of siRNA-targeting MCU in cardiomyocytes subjected to H/R injury. First, cardiomyocytes treated with siRNA demonstrated a reduction of MCU expression by 67%, which resulted in significant decrease in mitochondrial Ca2+ transport. siRNA treated cardiomyocytes showed decreased mitochondrial permeability pore opening and oxidative stress trigger by Ca2+ overload. Furthermore, after H/R injury MCU silencing decreased necrosis and apoptosis levels by 30% and 50%, respectively, and resulted in reduction in caspases 3/7, 9, and 8 activity. Our findings are consistent with previous conclusions that demonstrate that MCU activity is partly responsible for cellular injury induced by H/R and support the concept of utilizing siRNA-targeting MCU as a potential therapeutic strategy. PMID- 28337253 TI - Hepatoprotective Effects of Antrodia cinnamomea: The Modulation of Oxidative Stress Signaling in a Mouse Model of Alcohol-Induced Acute Liver Injury. AB - In the present study, the components of A. cinnamomea (AC) mycelia were systematically analyzed. Subsequently, its hepatoprotective effects and the underlying mechanisms were explored using a mouse model of acute alcohol-induced liver injury. AC contained 25 types of fatty acid, 16 types of amino acid, 3 types of nucleotide, and 8 types of mineral. The hepatoprotective effects were observed after 2 weeks of AC treatment at doses of 75 mg/kg, 225 mg/kg, and 675 mg/kg in the mouse model. These effects were indicated by the changes in the levels of aspartate aminotransferase, alanine aminotransferase, several oxidation related factors, and inflammatory cytokines in serum and/or liver samples. AC reduced the incidence rate of necrosis, inflammatory infiltration, fatty droplets formation, and cell apoptosis in liver detecting via histological and TUNEL assay. In addition, AC reduced the expression of cleaved caspase-3, -8, and -9 and the levels of phosphor-protein kinase B (Akt) and phosphor-nuclear factor kappaB (NF-kappaB) in the liver samples. Collectively, AC-mediated hepatoprotective effects in a mouse model of acute alcohol-induced liver injury are the result of reduction in oxidative stress. This may be associated with Akt/NF-kappaB signaling. These results provide valuable evidence to support the use of A. cinnamomea as a functional food and/or medicine. PMID- 28337255 TI - Combined therapy with melatonin and exendin-4 effectively attenuated the deterioration of renal function in rat cardiorenal syndrome. AB - This study tested the hypothesis that combined therapy with melatonin (Mel) and exendin-4 (Ex4) would be superior to either therapy alone for preventing the deterioration of renal function in cardiorenal syndrome (CRS). Male adult Sprague Dawley rats (n = 48) were randomly and equally divided into sham-control (SC), chronic kidney disease (CKD; induced by 5/6 nephrectomy), CRS (CKD + dilated cardiomyopathy, DCM; induced by doxorubicin 7 mg/kg i.p. every 5 days, 4 doses), CRS-Mel (20 mg/kg/day), CRS-Ex4 (10 ug/kg/day) and CRS-Mel-Ex4. They were euthanized by day 60 after CRS induction. By day 60, plasma creatinine level, urine protein/creatinine ratio and kidney injury histopathology score were highest in CRS, lowest in SC, and progressively decreased from CKD, CRS-Mel, CRS Ex4 to CRS-Mel-Ex4 (all P<0.0001). The kidney protein expressions of inflammation (TNF-alpha/NF-kappaB/MMP-9/iNOS/RANTES), oxidative stress (NOX-1/NOX-2/NOX 4/oxidized protein), apoptosis (cleaved caspase-3/cleaved PARP/Bax), DNA-damaged marker (gamma-H2AX) and fibrosis (p-mad3/TFG-beta) showed identical patterns of creatinine level, whereas kidney protein expressions of GLP-1R showed a progressive increase from SC to CRS-Mel-Ex4 (all P<0.0001). Cellular expressions of inflammatory (CD14/CD68), DNA/kidney-damaged (gamma-H2AX/KIM-1) and podocyte/renal tubule dysfunction signaling (beta-catenin/Wnt1/Wnt4) biomarkers in kidney tissue exhibited an identical pattern of creatinine level (all P<0.0001). Podocyte components (podocin/dystroglycan/p-cadherin/synatopodin) were highest in SC, lowest in CRS, and significantly progressively increased from CKD to CRS-Mel-Ex4 (all P<0.0001). In conclusion, combined Mel-Ex4 therapy was superior to either one alone in preserving renal-function and kidney architectural integrity in the setting of CRS. PMID- 28337254 TI - AMP-activated protein kinase and energy balance in breast cancer. AB - Cancer growth and metastasis depends on the availability of energy. Energy sensing systems are critical in maintaining a balance between the energy supply and utilization of energy for tumor growth. A central regulator in this process is AMP-activated protein kinase (AMPK). In times of energy deficit, AMPK is allosterically modified by the binding of increased levels of AMP and ADP, making it a target of specific AMPK kinases (AMPKKs). AMPK signaling prompts cells to produce energy at the expense of growth and motility, opposing the actions of insulin and growth factors. Increasing AMPK activity may thus prevent the proliferation and metastasis of tumor cells. Activated AMPK also suppresses aromatase, which lowers estrogen formation and prevents breast cancer growth. Biguanides can be used to activate AMPK, but AMPK activity is modified by many different interacting factors; understanding these factors is important in order to control the abnormal growth processes that lead to breast cancer neoplasia. Fatty acids, estrogens, androgens, adipokines, and another energy sensor, sirtuin 1, alter the phosphorylation and activation of AMPK. Isoforms of AMPK differ among tissues and may serve specific functions. Targeting AMPK regulatory processes at points other than the upstream AMPKKs may provide additional approaches for prevention of breast cancer neoplasia, growth, and metastasis. PMID- 28337256 TI - Human mesenchymal stem cell homing induced by SKOV3 cells. AB - Human mesenchymal stem cell (hMSC) homing is the migration of endogenous and exogenous hMSCS to the target organs and the subsequent colonization under the action chemotaxic factors. This is an important process involved in the repair of damaged tissues. However, we know little about the mechanism of hMSC homing. Stromal cell derived factor-1 (SDF-1) is a cytokine secreted by stromal cells. Its only receptor CXCR4 is widely expressed in blood cells, immune cells and cells in the central nervous system. SDF-1/CXCR4 signaling pathway plays an important role in hMSC homing and tissue repair. Human cbll1 gene encodes E3 ubiquitin-protein ligase Hakai (also known as CBLL1) consisting of RING-finger domain that is involved in ubiquitination, endocytosis and degradation of epithelial cadherin (E-cadherin) as well as in the regulation of cell proliferation. We successfully constructed LV3-CXCR4 siRNA lentiviral vector, LV3 CBLL1 RNAi lentiviral vector and the corresponding cell systems which were used to induce hMSC homing in the presence of SKOV3 cells. Thus the mechanism of hMSC homing was studied. PMID- 28337257 TI - Subcutaneous liraglutide ameliorates methylglyoxal-induced Alzheimer-like tau pathology and cognitive impairment by modulating tau hyperphosphorylation and glycogen synthase kinase-3beta. AB - Memory deterioration and synapse damage with accumulation of beta-amyloid and hyperphosphorylated tau are hallmark lesions of Alzheimer's disease (AD). Methylglyoxal (MG), a key intermediate of glucose metabolism, is elevated in AD brains and modifies Abeta42, increasing misfolding and leading to the accumulation of senile plaques. Liraglutide, an analog of glucagon-like peptide-1 (GLP-1), is neurotrophic and neuroprotective. However, whether liraglutide can protect against AD-like memory-related deficits and tau hyperphosphorylation caused by MG in vivo is not known. Here, we report that MG induces tau hyperphosphorylation and causes ultrastructural hippocampal damage and cognitive impairment in C57BL/6J mice. Liraglutide reduced these effects via activation of the protein kinase B and glycogen synthase kinase-3beta pathways. Our data reveal that liraglutide may alleviate AD-like cognitive impairment by decreasing the phosphorylation of tau. PMID- 28337259 TI - Intranasal basic fibroblast growth factor attenuates endoplasmic reticulum stress and brain injury in neonatal hypoxic-ischaemic injury. AB - Brain injury secondary to birth asphyxia is the major cause of death and long term disability in newborns. Intranasal drug administration enables agents to bypass the blood-brain barrier (BBB) and enter the brain directly. In this study, we determined whether intranasal basic fibroblast growth factor (bFGF) could exert neuroprotective effects in neonatal rats after hypoxic-ischaemic (HI) brain injury and assessed whether attenuation of endoplasmic reticulum (ER) stress was associated with these neuroprotective effects. Rats were subjected to HI brain injury via unilateral carotid artery ligation followed by 2.5 h of hypoxia and then treated with intranasal bFGF or vehicle immediately after HI injury. We found that the unfolded protein response (UPR) was strongly activated after HI injury and that bFGF significantly reduced the levels of the ER stress signalling proteins GRP78 and PDI. bFGF also decreased brain infarction volumes and conferred long-term neuroprotective effects against brain atrophy and neuron loss after HI brain injury. Taken together, our results suggest that intranasal bFGF provides neuroprotection function partly by inhibiting HI injury-induced ER stress. bFGF may have potential as a therapy for human neonates after birth asphyxia. PMID- 28337258 TI - Neuroprotective effect of WIN55,212-2 against 3-nitropropionic acid-induced toxicity in the rat brain: involvement of CB1 and NMDA receptors. AB - The endocannabinoid system (ECS), and agonists acting on cannabinoid receptors (CBr), are known to regulate several physiological events in the brain, including modulatory actions on excitatory events probably through N-methyl-D-aspartate receptor (NMDAr) activity. Actually, CBr agonists can be neuroprotective. The synthetic CBr agonist WIN55,212-2 acts mainly on CB1 receptor. In turn, the mitochondrial toxin 3-nitropropionic acid (3-NP) produces striatal alterations in rats similar to those observed in the brain of Huntington's disease patients. Herein, the effects of WIN55,212-2 were tested on different endpoints of the 3-NP induced toxicity in rat brain synaptosomes and striatal tissue. Motor activity was also evaluated. The 3-NP (1 mM)-induced mitochondrial dysfunction and lipid peroxidation was attenuated by WIN55,212-2 (1 uM) in synaptosomal fractions. The intrastriatal bilateral injection of 3-NP (500 nmol/uL) to rats increased lipid peroxidation and locomotor activity, augmented the rate of cell damage, and decreased the striatal density of neuronal cells. These alterations were accompanied by transcriptional changes in the NMDA (NR1 subunit) content. The administration of WIN55212-2 (1 mg/kg, i.p.) to rats for six consecutive days, before the 3-NP injection, exerted preventive effects on all alterations elicited by the toxin. The prevention of the 3-NP-induced NR1 transcriptional alterations by the CBr agonist together with the increase of CB1 content suggest an early reduction of the excitotoxic process via CBr activation. Our results demonstrate a protective role of WIN55,212-2 on the 3-NP-induced striatal neurotoxicity that could be partially related to the ECS stimulation and induction of NMDAr hypofunction, representing an effective therapeutic strategy at the experimental level for further studies. PMID- 28337260 TI - miR-590-3p mediates the protective effect of curcumin on injured endothelial cells induced by angiotensin II. AB - Curcumin (Cur) has multiple pharmacological effects including antitumor, anti inflammatory, antioxidant and cardiovascular protective effects. This research aims to further explore whether the cardiovascular protective effects of Cur are mediated by the miR-590-3p/CD40 pathway. Endothelial cells (ECs) were cultivated with 10-7 mol/L angiotensin II (Ang II) to establish a damage model. Real-time PCR was used to determine the expression of CD40 and eNOS mRNA on ECs. The protein expressions of CD40 and eNOS were detected by Western blot analysis. The intracellular activities of SOD, CAT and MDA level were determined by corresponding detection kits, and the level of reactive oxygen species (ROS) in ECs was measured by ROS assay kit. Ang II increased both the mRNA and protein level of CD40, while it down-regulated the expression of eNOS at mRNA and protein level. These observations were accompanied by decreased activities of SOD and CAT with increased levels of intracellular MDA and ROS. Cur and miR-590-3p mimics inhibited the expressions of CD40 mRNA and protein induced by Ang II and alleviated the intracellular oxidative stress seen with increased levels of eNOS. However, these beneficial effects caused by Cur were partially reversed in the presence of miR-590-3p inhibitors. Our results indicate miR-590-3p is involved in the anti-inflammatory effects of Cur in ECs damaged by Ang II. PMID- 28337261 TI - Glutathione-s-transferase A 4 (GSTA4) suppresses tumor growth and metastasis of human hepatocellular carcinoma by targeting AKT pathway. AB - Hepatocellular carcinoma (HCC) is one of the most lethal malignancies of cancers and its prognosis remains dismal due to the paucity of effective therapeutic targets. Up-regulation of glutathione-s-transferase A 4 (GSTA4) is associated with poor prognosis of HCC, but its functional mechanism in HCC remains unclear. In this study, we investigated the roles of GSTA4 in tumor growth and metastasis of HCC and found that GSTA4 was frequently up-regulated in HCC tissues. Through gain- and loss-of-function studies, GSTA4 was demonstrated to significantly regulate cell proliferation, migration, and invasion in vitro. Furthermore, GSTA4 overexpressing significantly promoted the tumorigenicity and metastasis of HCC cells in nude mice models bearing human HCC, whereas silencing endogenous GSTA4 caused an opposite outcome. Moreover, we demonstrated that GSTA4 enhanced HCC aggressiveness by activating protein kinase B (AKT) signaling. In multivariate analysis, our results GSTA4 overexpression promotes the progression of hepatocellular carcinoma and might represent a novel therapeutic target for its treatment. PMID- 28337262 TI - Osteopontin stimulates matrix metalloproteinase expression through the nuclear factor-kappaB signaling pathway in rat temporomandibular joint and condylar chondrocytes. AB - BACKGROUND: To examine the possible regulatory mechanisms of osteopontin (OPN) and the nuclear factor-kappaB (NF-kappaB) signaling pathway in the temporomandibular joint (TMJ) of rats subjected to chronic sleep deprivation (CSD). METHODS: Rats were subjected to CSD using the modified multiple platform method. The histomorphology of the TMJ was observed by hematoxylin-eosin staining. OPN and NF-kappaB/p65 expression were detected by immunohistochemical and immunofluorescence staining together with western blotting. The condylar chondrocytes were isolated from the rat TMJ and treated with recombinant OPN (r OPN) before detection for the expression of NF-kappaB/p65 and matrix metalloproteinases (MMPs). Western blotting and reverse transcription-polymerase chain reaction were performed to determine the expression of MMP-1, MMP-3, MMP-9, and MMP-13 in the TMJ and chondrocytes respectively. RESULTS: There was a statistically significant difference in OPN and NF-kappaB/p65 expression between the CSD group and control (CON) group. OPN and NF-kappaB/p65 expression was increased in the CSD group as compared with in the CON group. NF-kappaB/p65 expression was significantly increased by r-OPN treatment in the chondrocytes. Furthermore, MMP-1, MMP-3, MMP-9, and MMP-13 production was also remarkably elevated in the CSD group as well as in the chondrocytes. Treatment with 1 MUg/ml r-OPN for 48 h led to the highest production of inflammatory cytokines in chondrocytes. CONCLUSIONS: CSD causes pathological alterations in the TMJ. OPN treatment activates the NF-kappaB signaling pathway and stimulates MMPs in the TMJ and condylar chondrocytes through NF-kappaB signaling pathway. Chondrocytes treated with 1 MUg/ml r-OPN for 48 h produced the highest level of inflammatory cytokines. PMID- 28337263 TI - Receptor for advanced glycation end as drug targets in diabetes-induced skin lesion. AB - The involvement of the receptor for advanced glycation end (RAGE) in different diseases has been reviewed in great detail, previously, but the effects of diabetic drugs on RAGE-induced skin lesion during long course diabetes remains poorly understood. In the present study, we have shown that RAGE was overexpressed in both diabetic rats and human keratinocytes (HaCaT cells). Cell cycle arrest and apoptosis as well as alternations of relative protein levels were also found in diabetic rats and HaCaT cells with overexpression of RAGE that were rectified by metformin (Met) treatment. Moreover, overexpression of RAGE was also found to induce secretions of TNF-alpha, IL-1beta, IL-6, ICAM-1 and COX-2 in HaCaT cells, and Met treatment corrected these inflammatory factor secretions. In addition, treatment with Met markedly reduced RAGE overexpression-induced p38 and NF-kappaB activation. Taken together, the findings of the present study have demonstrated, for the first time that Met protects HaCaT cells against diabetes induced injuries and inflammatory responses through inhibiting activated RAGE. PMID- 28337264 TI - IP3R and RyR calcium channels are involved in neonatal rat cardiac myocyte hypertrophy induced by tumor necrosis factor-alpha. AB - To investigate which calcium channels are involved in cardiac myocyte hypertrophy induced by TNF-alpha, cultured cardiomyocytes were treated with 100 MUg/L TNF alpha. In addition, three different calcium channel blockers (2-APB, ryanodine and nifedipine) were used, and the effects of each calcium channel blocker on cardiac hypertrophy induced by TNF-alpha were carefully observed. Measurements included cytosolic calcium transients ([Ca2+]i), the level of intracellular calcium in individual cells, cell protein content, cell protein synthesis and cell volume. We found that the IP3R inhibitor (2-APB) and RyR inhibitor (ryanodine) both had significant suppressive effects on the level of [Ca2+]i, calcium concentration, cell protein content, cell protein synthesis and cell volume of cardiomyocytes treated with TNF-alpha (P<0.01). Moreover, their combined effects were significantly enhanced compared with their single effects (P<0.01). However, the inhibitor of the L type Ca2+ channel nifedipine exhibited no significant suppressive effects on the increase in [Ca2+]i, calcium concentration, cell protein content, cell protein synthesis and cell volume of cardiomyocytes induced by TNF-alpha (P>0.05). Our results suggest that TNF-alpha probably induces cardiac myocyte hypertrophy by activating IP3R and RyR calcium channels, which control the release of calcium ions from the sarcoplasmic reticulum (SR) in cardiomyocytes. On the other hand, extracellular calcium influx, which is mainly regulated by the L type Ca2+ channel, may not be involved in cardiac myocyte hypertrophy induced by TNF-alpha. PMID- 28337266 TI - Long non-coding RNA UCA1 promotes cell progression by acting as a competing endogenous RNA of ATF2 in prostate cancer. AB - Prostate cancer (PCa) is a leading cause of cancer-related deaths in elder men. This disease has limited therapeutic options and poor prognosis as the underlying molecular mechanisms are not clearly understood. LncRNA UCA1 functions as an oncogene in many types of cancers. However, the role of UCA1 in PCa remains unclear. In the present study, we showed that UCA1 was significantly up-regulated in PCa cell lines and tissue samples. High UCA1 expression was positively associated with high gleason score, advanced TNM stage and shorter overall survival of PCa patients. Inhibition of UCA1 suppressed PCa cells proliferation, migration and invasion in vitro. Moreover, UCA1 depletion inhibited the growth of PCa cells in vivo. In addition, we found that ATF2 was a direct target gene of UCA1. UCA1 regulated ATF2 expression through functioning as a competing endogenous RNA (ceRNA). UCA1 directly interacted with miR-204 and decreased the binding of miR-204 to ATF2 3'UTR, which suppressed the degradation of ATF2 mRNA by miR-204. In summary, we unveil a branch of the UCA1-miR-204-ATF2 pathway that regulates the progression of PCa. The inhibition of UCA1 expression may be a promising strategy for PCa therapy. PMID- 28337265 TI - Pulmonary surfactant synthesis in miRNA-26a-1/miRNA-26a-2 double knockout mice generated using the CRISPR/Cas9 system. AB - Pulmonary surfactant (PS), which is synthesized by type II alveolar epithelial cells (AECIIs), maintains alveolar integrity by reducing surface tension. Many premature neonates who lack adequate PS are predisposed to developing respiratory distress syndrome (RDS), one of the leading causes of neonatal morbidity and mortality. PS synthesis is influenced and regulated by various factors, including microRNAs. Previous in vitro studies have shown that PS synthesis is regulated by miR-26a in fetal rat AECIIs. This study aimed to investigate the role of miR-26a in PS synthesis in vivo. To obtain a miR-26a-1/miR-26a-2 double knockout mouse model, we used the clustered regularly interspaced short palindromic repeat/CRISPR-associated protein 9 (CRISPR/Cas9) system, an important genome editing technology. Real-time PCR was performed to determine the miR-26a levels in various organs, as well as the mRNA levels of surfactant-associated proteins. Moreover, AECIIs and surfactant-associated proteins in lung tissues were analyzed by hematoxylin-eosin staining and immunohistochemistry. Homozygous offspring of miR-26a-1/miR-26a-2 double knockout mice generated using the CRISPR/Cas9 system were successfully obtained, and PS synthesis and the number of AECIIs were significantly increased in the miR-26a knockout mice. These results indicate that miR-26a plays an important role in PS synthesis in AECIIs. PMID- 28337267 TI - Exploration of the effect of probiotics supplementation on intestinal microbiota of food allergic mice. AB - Environmental factor-induced alterations in intestinal microbiota have been demonstrated to be associated with increasing prevalence of food allergy. However, it is not clear to what extent oral administration of probiotics can affect gut microbiota composition, thus inhibiting food allergy development. Using ovalbumin (OVA)-sensitized murine model, it was demonstrated that probiotics ameliorated allergic symptoms, including reducing OVA specific-IgE, and -IgG1 levels in the serum, Th2 cytokines release in spleen, and occurrence of diarrhea. Moreover, 16S rRNA analysis showed that the probiotics-mediated protection was conferred by an enrichment of Coprococcus and Rikenella. The present study supports the theory that probiotics can treat food allergy by modulating specific genera of the gut microbiota. PMID- 28337268 TI - Geranylgeranylacetone attenuates myocardium ischemic/reperfusion injury through HSP70 and Akt/GSK-3beta/eNOS pathway. AB - Early reperfusion of myocardial infarction area is the most effective and important therapy to acute myocardial infarction, but could induce reperfusion injury. Geranylgeranylacetone (GGA), an acyclic polyisoprenoid used as an oral anti-ulcer medication, has been reported to have protective effects on reperfusion injury. In the present study, we explored the protective effect of GGA against MIRI and the underlying mechanism. We pretreated rats with four daily GGA, and then observed its effects on heart function parameters following in situ ischemia/reperfusion. GGA exhibited dramatic improvement in cardiac functions, as manifested by increased LVSP and +/- (dP/dt) max and decreased LVDP. Oxidative injury and inflammatory response were also relieved by GGA. Western blot showed that the HSP70 protein expression and the Akt/GSK-3beta/eNOS pathway were activated. The inhibition of HSP70 and the Akt/GSK-3beta/eNOS pathway significantly reversed the protective effects of GGA on MIRI, indicating the involvements of HSP70 and the Akt/GSK-3beta/eNOS pathway. PMID- 28337269 TI - The role of PRRX1 in the apoptosis of A549 cells induced by cisplatin. AB - Paired related homeobox1 (PRRX1) was a newly identified Epithelial mesenchymal transition (EMT) inducer. It was found that the decreased expression of PRRX1 in breast cancer and liver cancer could enable tumor cells to obtain tumor stem cell characteristics in vitro studies. However, the role of PRRX1 in lung cancer was still unknown. The down-regulated PRRX1 gene in A549 cells was established by slow virus infection in this study. The apoptosis of A549 cells was observed after the treatment of different concentrations of cisplatin and the role of PRRX1 in the apoptosis of A549 cells was explored. MTT results showed that down regulated PRRX1 gene could resist the inhibitory effect of cisplatin on cell proliferation. The results of flow cytometry assay showed that down-regulated PRRX1 gene could reduce the apoptosis and promote A549 cells to enter G2 phase. Mitochondrial membrane potential detection showed that PRRX1 gene could inhibit the decrease of mitochondrial membrane potential. Western blotting results showed that down-regulated PRRX1 gene could reduce the expression levels of Caspase3, caspase9, Apaf-1 and cytochrome C. In a word, down-regulation of PRRX1 could cause lung cancer cells to produce anti apoptotic ability and resistance to cisplatin, which maybe through caspase3 pathway. PMID- 28337270 TI - N-WASP promotes invasion and migration of cervical cancer cells through regulating p38 MAPKs signaling pathway. AB - Neural Wiskott-Aldrich syndrome protein (N-WASP) is an important member of the WASP family involved in the actin cytoskeleton reorganization. Recent evidence suggests that N-WASP may play important roles in tumor progression and metastasis. However, the contribution of N-WASP to cervical cancer is still unknown. The present study focused on elucidating the role of N-WASP in the malignant behavior of cervical cancer cells. We found that N-WASP overexpressed in cervical cancer tissues compared with paired paracancerous tissues and normal tissues, and similar results were observed in several cervical cancer cell lines. Furthermore, we demonstrated that overexpression of N-WASP facilitated migration and invasion of cervical cancer cells, while downregulation of N-WASP resulted in decreased cell migration and invasion. In addition, the data showed that N-WASP might promote invasion and migration of cervical cancer cells via regulating the activity of p38 MAPKs pathway. Altogether, the study suggested that N-WASP might serve as an oncogene in cervical cancer, and provided novel insights into the mechanism that how N-WASP promoted invasion and migration of cervical cancer cells. PMID- 28337271 TI - Effects of long term low- and high-dose sodium arsenite exposure in human transitional cells. AB - Epidemiological studies have revealed the association between increased risk of bladder cancer and chronic arsenic exposure. Here, we explored biological effects of arsenic in T24. Microarray analysis was applied to analyze mRNA in T24 following 0, 2 or 5 MUM sodium arsenite (As) exposure for 72 hours. Long term (up to 140 days) low-dose (200 nM) and high-dose (1,000 nM) As decreased E-cadherin protein level through different mechanisms because the mRNA levels of E-cadherin increased following low-dose As exposure but decreased following high-dose As exposure. Long term As increased the protein levels of N-cadherin, vimentin, beta catenin, and slug. Low-dose As exposure resulted in a change in the morphology of T24 cells from an epithelial to a mesenchymal-like appearance. Knockdown of E cadherin increased the protein levels of N-cadherin, vimentin, beta-catenin, and slug. Cell proliferation and growth of T24 with or without As exposure for 100 days were assayed using EdU and WST, respectively. Low-dose As exposure increased cell proliferation and growth while high-dose As exposure decreased both. Long term As activated p53 on account of increasing protein levels of p53, p-p53 (Ser15), and mRNA levels of p21. These demonstrate that arsenic exposure exerts multiple effects. Long term low- or high-dose arsenic induces epithelial mesenchymal transition, likely via downregulation of E-cadherin, activates p53, and differently affects cell proliferation/growth. PMID- 28337272 TI - Cold preservation with hyperbranched polyglycerol-based solution improves kidney functional recovery with less injury at reperfusion in rats. AB - Minimizing donor organ injury during cold preservation (including cold perfusion and storage) is the first step to prevent transplant failure. We recently reported the advantages of hyperbranched polyglycerol (HPG) as a novel substitute for hydroxyethyl starch in UW solution for both cold heart preservation and cold kidney perfusion. This study evaluated the functional recovery of the kidney at reperfusion after cold preservation with HPG solution. The impact of HPG solution compared to conventional UW and HTK solutions on tissue weight and cell survival at 4 degrees C was examined using rat kidney tissues and cultured human umbilical vein endothelial cells (HUVECs), respectively. The kidney protection by HPG solution was tested in a rat model of cold kidney ischemia-reperfusion injury, and was evaluated by histology and kidney function. Here, we showed that preservation with HPG solution prevented cell death in cultured HUVECs and edema formation in kidney tissues at 4 degrees C similar to UW solution, whereas HTK solution was less effective. In rat model of cold ischemia-reperfusion injury, the kidneys perfused and subsequently stored 1-hour with cold HPG solution showed less leukocyte infiltration, less tubular damage and better kidney function (lower levels of serum creatinine and blood urea nitrogen) at 48 h of reperfusion than those treated with UW or HTK solution. In conclusion, our data show the superiority of HPG solution to UW or HTK solution in the cold perfusion and storage of rat kidneys, suggesting that the HPG solution may be a promising candidate for improved donor kidney preservation prior to transplantation. PMID- 28337273 TI - T-box family of transcription factor-TBX5, insights in development and disease. AB - The T-box gene family refers to a group of transcription factors that share a highly conserved, sequence-specific DNA-binding domain (T-box) containing around 180-amino acids. According to HUGO gene nomenclature committee (HGNC), there are 18 T-box family members. These T-box genes have been implicated essential roles during embryogenesis and cardiac development, given their specific expression pattern in developing mammalian heart for several T-box genes, including TBX5. TBX5 is consisted of three transcriptional variants which cover 9 exons and encode two distinct isoforms that differ in N-terminus. TBX5 is probably the most frequently studied T-box gene over the past decade due to the typical cardiac defects observed in Holt-Oram syndrome (HOS), which is caused by TBX5 mutation. Most of the mutations are within exons 3-7 where locate sequence coding for the T box domain. Notably, a variety of cardiac defects, as well as abnormalities in limb and other organs have been seen in HOS syndrome with different kinds of TBX5 mutations, suggesting a heterogeneous disease mechanism. We have performed a meta analysis of TBX5 and found a significant correlation between its single nucleotide polymorphism (SNP) rs3825214 (A to G), and risk of atrial fibrillation and its subtypes, supporting TBX5 as a master transcription factor for cardiac development. In addition, bioinformatics analysis of this SNP identified several TFs that may be affected for their binding affinity with TBX5. Identification and characterization of more TBX5 mutations and SNPs hold promise for therapeutic strategy targeting TBX5 associated developmental abnormalities and diseases. PMID- 28337274 TI - Decitabine treatment sensitizes tumor cells to T-cell-mediated cytotoxicity in patients with myelodysplastic syndromes. AB - Decitabine treatment improves immunological recognition that increases expression of cancer-testis antigens (CTAs) against solid tumors. The mechanisms of decitabine enhancement of immunogenicity when used for patients with myelodysplastic syndromes (MDS) remain unclear. In the present study, we found relatively low baseline expression of MAGE-A1, MAGE-A3, and SP17 in MDS-derived cell lines. Decitabine treatment significantly improved MAGE-A1, MAGE-A3, and SP17 expression in these cell lines and in MDS patients. Decitabine-treated K562 and SKM-1 target cells with incrementally induced MAGE-A1, MAGE-A3, or SP17 levels up-regulated T lymphocyte function. Decitabine treatment improved CTA specific cytotoxic T lymphocyte (CTL) recognition of MDS cells via the up regulation of CTAs. This response was accompanied by enhanced T lymphocyte function and HLA class antigen expression, and increased ICAM-1. These findings suggested that decitabine may have a broad range of therapeutic applications when it is used in association with active adaptive immunity responses against up regulated CTAs. PMID- 28337275 TI - MicroRNA-215 targets NOB1 and inhibits growth and invasion of epithelial ovarian cancer. AB - MicroRNA-215 (miR-215) has been showed to play crucial roles in tumorigenesis and tumor progression in many types of cancer. However, its biological function and underlying mechanism in epithelial ovarian cancer (EOC) remains greatly unknown. The aims of this study were to investigate biological role and underlying mechanism of miR-215 in EOC. Here, we found that miR-215 expression was significantly decreased in EOC tissues or cell lines compared with adjacent normal tissues or normal ovarian cell line. Decreased miR-215 expression was significantly associated with International Federation of Gynaecology and Obstetrics (FIGO) stage and lymph node metastasis. Function analysis revealed that overexpression of miR-215 using miR-215 mimic significantly inhibit EOC cell proliferation, colony formation, migration and invasion in vitro. as well as suppress tumor growth in vivo. Moreover, we identified ribosome assembly factor NIN/RPN12 binding protein (NOB1) as a direct targets for miR-215 binding, resulting in suppression it expression, which in turn activated the MAPK signaling pathway. In clinical EOC specimens, NOB1 expression was upregulated, and inversely correlated with miR-215 expression (r = -0.675, P<0.001). Overexpression of NOB1 effectively rescued inhibition effect on EOC cells by induced miR-215 overexpression. Taken together, our findings suggested that miR 215 suppressed EOC growth and invasion by targeting NOB1. PMID- 28337276 TI - MicroRNA-9 regulates non-small cell lung cancer cell invasion and migration by targeting eukaryotic translation initiation factor 5A2. AB - MicroRNAs (miRNAs) play a critical role in cancer development and progression. Bioinformatics analyses has identified eukaryotic translation initiation factor 5A2 (eIF5A2) as a target of miR-9. In this study, we attempted to determine whether miR-9 regulates non-small cell lung cancer (NSCLC) cell invasion and migration by targeting eIF5A2 We examined eIF5A2 expression using reverse transcription-quantitative PCR (RT-qPCR) and subsequently transfected A549 and NCI-H1299 NSCLC cells with a miR-9 mimic or miR-9 inhibitor to determine the migration and invasive capability of the cells via wound healing assay and Transwell invasion assay, respectively. E-cadherin and vimentin expression was detected with western blotting. The miR-9 mimic significantly reduced NSCLC cell invasive and metastatic ability, and the miR-9 inhibitor enhanced NSCLC cell migration activity, increasing the number of migrated cells. There was no significant difference between the negative control siRNA and miR-9 mimic groups after knockdown of eIF5A2; western blotting showed that miR-9 regulated E cadherin and vimentin expression. These data show that miR-9 regulates NSCLC cell invasion and migration through regulating eIF5A2 expression. Taken together, our findings suggest that the mechanism of miR-9-regulated NSCLC cell invasion and migration may be related to epithelial-mesenchymal transition. PMID- 28337277 TI - Effect and mechanism of SHED on ulcer wound healing in Sprague-Dawley rat models with diabetic ulcer. AB - To evaluate the effect of stem cells from human exfoliated deciduous teeth (SHED) upon the ulcer wound healing and evaluate the mechanism underlying the role of SHED in Sprague-Dawley rat models with diabetic foot ulcer. The rats with diabetic ulcer were established and treated with SHED, mesenchymal stem cell (MSC) and PBS, respectively. The expression of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), matrix metalloproteinase-2 (MMP 2) and MMP9 at both protein and RNA levels was quantitatively measured. The serum levels of VEGF, IL-1beta, TNF-1alpha and IL-10 were detected by ELISA. The remaining tissues were fixed in 4% chloral hydrate for hematoxylin and eosin (H.E) staining and immunohistochemical staining. MSC and SHED administration could reduce ulceration area and accelerate wound healing at 7 and 14 d after treatment as compared with the control group (all P<0.05), which were validated by H.E and immunohistochemical staining. Western blot results revealed that the expression levels of VEGF, eNOS, MMP2 and MMP9 proteins in the MSC and SHED groups were considerably up-regulated compared with those in the control group at different time points (all P<0.05). The same trend was also observed in the mRNA expression of these cytokines detected by RT-PCR. At 3-d after treatment, no statistical significance was noted in the IL-10 level among three groups, but the IL-10 concentration in the SHED and MSC groups was significantly down-regulated at 7- and 14-d post-treatment (all P<0.05). SHED administration, similar to MSCs, could accelerate wound healing, promote angiogenesis and suppress inflammatory responses in rat models with diabetic ulceration. PMID- 28337278 TI - Synthesis of huaicarbon A/B and their activating effects on platelet glycoprotein VI receptor to mediate collagen-induced platelet aggregation. AB - Quercetin and rhamnose were efficiently converted into huaicarbon A/B by heating at 250 degrees C for 10-15 min or at 200 degrees C for 25-30 min. With the optimum molar ratio of quercetin/rhamnose (1:3), huaicarbon A and B yields reached 25% and 16% respectively after heating at 250 degrees C, with 55% quercetin conversion. Huaicarbon A/B both promoted washed platelet aggregation dose-dependently, which was antagonized by an inhibitor of glycoprotein VI (GPVI) receptor. Similarly, they both promoted collagen-induced platelet aggregation in platelet-rich plasma in dose-dependent manners. According to the S type dose response model, EC50 values of huaicarbon A and huaicarbon B were calculated as 33.48 MUM and 48.73 MUM respectively. They induced intracellular Ca2+ accumulation that was specifically blocked by GPVI antagonist. Huaicarbon A/B enhanced intracellular Ca2+ accumulation and facilitated collagen-induced platelet aggregation, which were blocked by GPVI antagonist. They were conducive to collagen-induced platelet aggregation by activating platelet GPVI receptor. PMID- 28337279 TI - AGR2 promotes the proliferation, migration and regulates epithelial-mesenchymal transition in salivary adenoid cystic carcinoma. AB - Salivary adenoid cystic carcinoma (AdCC) is a common head and neck cancer with the propensity for local spread and distant metastasis. In our previous study, elevated expression of Anterior gradient 2 (AGR2) was detected in head and neck squamous cell carcinoma (HNSCC), associated with epithelial-mesenchymal transition (EMT) and cancer stemness. However, to date, the expression and function of AGR2 in AdCC has yet to be elucidated. In the present study, human AdCC tissue microarrays including 18 cases of normal salivary gland (NSG), 12 cases of pleomorphic adenoma (PMA) and 72 cases of AdCC were employed for immunohistochemical staining analysis. Results indicated that AGR2, which was remarkably correlated with Ki-67, transforming growth factor beta-1 (TGF-beta1) and CD147, was significantly elevated in human salivary AdCC tissues. Knockdown of AGR2 significantly repressed the proliferation and migration of human SACC-83 and SACC-LM cell lines. Additionally, AGR2 silencing obviously reversed the EMT phenomena induced by TGF-beta1. Taken together, our present study revealed the potential pro-metastasis role of AGR2 in AdCC, indicating that AGR2 might be a novel therapeutic target of AdCC with distant metastasis. PMID- 28337280 TI - MiR-15a suppresses hepatocarcinoma cell migration and invasion by directly targeting cMyb. AB - PURPOSE: This study aimed to determine the function of miR-15a in HCC, and identify cMyb as a target of miR-15a. METHODS: RNA expression was evaluated by quantitative real-time PCR (qRT-PCR). The effects of miR-15a or cMyb on HCC cells were evaluated by transwell migration assay and western blot analysis. CMyb, the predicted target, has been frequently verified by luciferase assay. RESULTS: MiR 15a was markedly downregulated in sphere culture HCC cells by qRT-PCR. CMyb was predicted to be a potential target of miR-15a using bioinformatics analysis. This prediction has been frequently verified by luciferase assay and western blot. A positive correlation between cMyb and the migration ability of HCC cells was demonstrated by transwell assays. MiR-15a mimic suppressed cMyb expression to weaken HCC cell migration ability. On the other hand, miR-15a inhibitor upregulated cMyb and induced HCC cell migration. CONCLUSION: MiR-15a could suppress HCC progression through the repression of cMyb, making miR-15a a potential therapeutic target. PMID- 28337281 TI - C-MYC-induced upregulation of lncRNA SNHG12 regulates cell proliferation, apoptosis and migration in triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer, with a significantly higher recurrence and mortality rate. There is an urgent need to uncover the mechanism underlying TNBC and establish therapeutic targets. Long non-coding RNAs (lncRNAs) are involved in a series of biological functions and provide novel insights into the molecular mechanism of cancer. Based on their expression specificity and large number, lncRNAs are likely to serve as the basis for clinical applications in oncology. In our previous study, we utilized RNA sequencing (RNA-seq) to explore the lncRNAs expression profiles in TNBC and identified that small nucleolar RNA host gene 12 (SNHG12) was remarkably increased in TNBC. However, the role of SNHG12 in TNBC has not been clarified. Herein, we determine that SNHG12 is upregulated in TNBC, and its high expression is significantly correlated with tumor size and lymph node metastasis. Mechanistic investigations show that SNHG12 is a direct transcriptional target of c-MYC. Silencing SNHG12 expression inhibits TNBC cells proliferation and apoptosis promotion, whereas SNHG12 overexpression has the opposite effect. In addition, we reveal that SNHG12 may promote cells migration by regulating MMP13 expression. To the best of our knowledge, it is the first report indicating that SNHG12 is involved in breast cancer. Taken together, our findings suggest that SNHG12 contributes to the oncogenic potential of TNBC and may be a promising therapeutic target. PMID- 28337282 TI - Chronic intermittent hypoxia affects endogenous serotonergic inputs and expression of synaptic proteins in rat hypoglossal nucleus. AB - Evidence has shown that hypoxic episodes elicit hypoglossal neuroplasticity which depends on elevated serotonin (5-HT), in contrast to the rationale of obstructive sleep apnea (OSA) that deficient serotonergic input to HMs fails to keep airway patency. Therefore, understanding of the 5-HT dynamic changes at hypoglossal nucleus (HN) during chronic intermittent hypoxia (CIH) will be essential to central pathogenic mechanism and pharmacological therapy of OSA. Moreover, the effect of CIH on BDNF-TrkB signaling proteins was quantified in an attempt to elucidate cellular cascades/synaptic mechanisms following 5-HT alteration. Male rats were randomly exposed to normal air (control), intermittent hypoxia of 3 weeks (IH3) and 5 weeks (IH5) groups. Through electrical stimulation of dorsal raphe nuclei (DRN), we conducted amperometric technique with carbon fiber electrode in vivo to measure the real time release of 5-HT at XII nucleus. 5-HT2A receptors immunostaining measured by intensity and c-Fos quantified visually were both determined by immunohistochemistry. CIH significantly reduced endogenous serotonergic inputs from DRN to XII nucleus, shown as decreased peak value of 5 HT signals both in IH3 and IH5groups, whereas time to peak and half-life period of 5-HT were unaffected. Neither 5-HT2A receptors nor c-Fos expression in HN were significantly altered by CIH. Except for marked increase in phosphorylation of ERK in IH5 rats, BDNF-TrkB signaling and synaptophys consistently demonstrated downregulated levels. These results suggest that the deficiency of 5-HT and BDNF dependent synaptic proteins in our CIH protocol contribute to the decompensated mechanism of OSA. PMID- 28337283 TI - Intracoronary hypothermia for acute myocardial infarction in the isolated beating pig heart. AB - Hypothermia may attenuate reperfusion injury and thereby improve acute myocardial infarction therapy. Systemic cooling trials failed to reduce infarct size, perhaps because the target temperature was not reached fast enough. The use of selective intracoronary hypothermia combined with intracoronary temperature monitoring allows for titrating to target temperature and optimizing the cooling rate. We aimed to the test the feasibility of intracoronary cooling for controlled, selective myocardial hypothermia in an isolated beating pig heart. In five porcine hearts the left anterior descending artery (LAD) was occluded by an over-the-wire balloon (OTWB). After occlusion, saline at 22 degrees C was infused through the OTWB lumen for 5 minutes into the infarct area at a rate of 30 ml/min. Thereafter the balloon was deflated but infusion continued with saline at 4 degrees C for 5 minutes. Distal coronary temperature was continuously monitored by a pressure/temperature guidewire. Myocardial temperature at several locations in the infarct and control areas was recorded using needle thermistors. In the occlusion phase, coronary temperature decreased by 11.4 degrees C (range 9.4-12.5 degrees C). Myocardial temperature throughout the infarct area decreased by 5.1 degrees C (range 1.8-8.1 degrees C) within three minutes. During the reperfusion phase, coronary temperature decreased by 6.2 degrees C (range 4.1-10.3 degrees C) and myocardial temperature decreased by 4.5 degrees C (range 1.5-7.4 degrees C). Myocardial temperature outside the infarct area was not affected. In the isolated beating pig heart with acute occlusion of the LAD, we were able to rapidly "induce, maintain, and control" a stable intracoronary and myocardial target temperature of at least 4 degrees C below body temperature without side effects and using standard PCI equipment, justifying further studies of this technique in humans. PMID- 28337284 TI - Hepatoprotective effects of Gentianella turkestanerum extracts on acute liver injury induced by carbon tetrachloride in mice. AB - Objective: To investigate the contents of secoiridoid compounds (i.e. sweroside, swertiamarin and gentiopicrin) from Gentianella turkestanerum extracts, and the potential effects of G. turkestanerum extracts against carbon tetrachloride (CCl4) induced liver injury in mice. Methods: The contents of swertiamarin, gentiopicroside and sweroside from different G. turkestanerum extracts were determined with high performance liquid chromatography (HPLC). CCl4 was used to induce acute liver injury in mice. The serum aspartate amino transferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total protein (TP), total bilirubin (TB), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione transferase (GSH) and catalase (CAT) were measured. HE staining was performed to investigate the pathological changes of liver. Results: Iridoid glycoside showed the highest content in the product extracted by butanol (designated as GBA), but lower in the products extracted by ethyl acetate and water designated as GEA and GW, respectively. All G. turkestanerum extracts showed protective effects against CCl4 induced acute liver injury in mice, among which GBA showed the maximal protective effects. G. turkestanerum extracts induced significant decrease in the serum ALT, AST, ALP and TB compared with those in the mice with acute lung injury (P < 0.01). Obvious increase was noticed in serum TP (P < 0.01). Moreover, such effects presented in a dose-dependent manner. Compared with the control group, the MDA was significantly elevated in the model group (P < 0.01), while significant decrease was observed in the levels of SOD, GSH and CAT in model group compared with the control group (P < 0.01). Whereas, such phenomenon was completely reversed by G. turkestanerum extracts in a dose-dependent manner. Conclusion:G. turkestanerum showed protective effects against CCl4 induced acute liver injury in mice. PMID- 28337285 TI - Preclinical and clinical evaluation of the liver tumor irreversible electroporation by magnetic resonance imaging. AB - Irreversible electroporation (IRE) is a relatively new technique for tumor ablation. It has shown promising results in difficult cases where surgery is not recommended and delicate anatomic structures are present near or within the tumor. Currently, liver cancer is one of the most common targets for IRE treatment. Pre-operative and post-operative imaging has a key role in IRE procedures and research studies. Although ultrasound is usually the first choice, especially for intra-operative guidance, magnetic resonance imaging (MRI) plays an important role in the visualization and characterization of tumor before and after IRE in clinical and preclinical studies. However, the appearance of liver lesions after IRE with different MRI sequences has never been systematically investigated, and the most common practice is to limit the acquisition protocol to only contrast-enhanced T1-weighted images. In this work, the role of MRI in clinical and preclinical assessment of hepatic tumors treated with IRE is reviewed and discussed. PMID- 28337286 TI - LPS induces HUVEC angiogenesis in vitro through miR-146a-mediated TGF-beta1 inhibition. AB - Angiogenesis is an essential process for tissue growth and embryo development. However, inflammation, abnormal wound healing, vascular diseases, and tumor development and progression can result from inappropriate angiogenesis. Lipopolysaccharide (LPS) can activate various cells and alter endothelium function and angiogenesis. This study investigated the underlying molecular events involved in LPS-induced angiogenesis and revealed a novel strategy for controlling abnormal angiogenesis. LPS treatment promoted wound healing and tube formation in human umbilical vein endothelial cell (HUVEC) cultures and induced their expression of miR-146a. miR-146a was previously shown to regulate angiogenesis in HUVECs. Knockdown of miR-146a expression antagonized LPS-induced angiogenesis in vitro. Moreover, bioinformatic analyses predicted TGF-beta1 as a target gene for miR-146a, which was confirmed by aluciferase reporter assay. Expression of miR-146a in HUVECs resulted in downregulation of TGF-beta1 in HUVECs, whereas a miR-146a inhibitor upregulated the expression of TGF-beta1 and TGF-beta1 downstream proteins, such as phosphoraylation-Smad2 and plasminogen activator inhibitor type 1 (PAI-1). Furthermore, the TGF-beta1 signaling inhibitor SB431542 impaired the ability of miR-146a knockdown to suppress LPS induced angiogenesis. Thus, LPS-induced angiogenesis of HUVECs functions through miR-146a upregulation and TGF-beta1 inhibition. This study suggests that knockdown of miR-146a could activate TGF-beta1 signaling to inhibit angiogenesis as a potential therapy for angiogenesis-related diseases. PMID- 28337287 TI - MEMRI is a biomarker defining nicotine-specific neuronal responses in subregions of the rodent brain. AB - Nicotine dependence is defined by dopaminergic neuronal activation within the nucleus accumbens (ACB) and by affected neural projections from nicotine stimulated neurons. Control of any subsequent neural activities would underpin any smoking cessation strategy. While extensive efforts have been made to study the pathophysiology of nicotine addiction, more limited works were developed to find imaging biomarkers. If such biomarkers are made available, addictive behaviors could be monitored noninvasively. To such ends, we employed manganese (Mn2+)-enhanced magnetic resonance imaging (MEMRI) to determine whether it could be used to monitor neuronal activities after acute and chronic nicotine exposure in rats. The following were observed. Mn2+ infusion identified ACB and hippocampal (HIP) neuronal activities following acute nicotine administration. Chronic exposure was achieved by week long subcutaneously implanted nicotine mini pump. Here nicotine was shown to activate neurons in the ACB, HIP, and the prefrontal and insular cortex. These are all central nervous system reward regions linked to drug addiction. In conclusion, MEMRI is demonstrated to be a powerful imaging tool to study brain subregion specific neuronal activities affected by nicotine. Thus, we posit that MEMRI could be used to assess smoking associated tolerance, withdrawal and as such serve as a pre-clinical screening tool for addiction cessation strategies in humans. PMID- 28337289 TI - Overexpression of TRIM24 is correlated with the progression of human cervical cancer. AB - TRIM24, originally known as intermediary factor 1-alpha, is involved in the development of several cancers. This study aimed to evaluate the expression level and prognostic value of TRIM24 in cervical cancer. In the present study, we showed that the expression of TRIM24 was markedly upregulated in cervical cancer cell lines and cancerous specimens at both transcriptional and translational levels. TRIM24 expression was analyzed in 147 archived cervical cancer specimens using immunohistochemistry, and the correlation between TRIM24 expression and clinicopathological parameters was evaluated. Statistical analysis suggested that TRIM24 expression was significantly correlated with clinical stage and (P=0.007) and lymphatic metastasis (P=0.001). Patients with higher TRIM24 expression had shorter overall (P=0.005) and recurrence-free (P=0.011) survival time. Moreover, we found that silencing TRIM24 by short hairpin RNAi caused an inhibition of cell migration and invasion. Further study indicated that TRIM24 induced cervical cancer cell migration and invasion was through the NF-kappaB and AKT signaling pathways. In conclusion, TRIM24 is overexpressed in cervical cancer and regulates malignant cell metastasis, which makes TRIM24 a candidate therapeutic target for cervical cancer. PMID- 28337288 TI - Which has more stem-cell characteristics: Muller cells or Muller cells derived from in vivo culture in neurospheres? AB - OBJECTIVE: Muller cells can be acquired from in vitro culture or a neurosphere culture system. Both culture methods yield cells with progenitor-cell characteristics that can differentiate into mature nervous cells. We compared the progenitor-cell traits of Muller cells acquired from each method. METHODS: Primary murine Muller cells were isolated in serum culture media and used to generate Muller cells derived from neurospheres in serum-free culture conditions. Gene expression of neural progenitor cell markers was examined by Q-PCR in the two groups. Expression of rhodopsin and the cone-rod homeobox protein CRX were assessed after induction with 1 MUM all-trans retinoic acid (RA) for 7 days. RESULTS: After more than four passages, many cells were large, flattened, and difficult to passage. A spontaneously immortalized Muller cell line was not established. Three-passage neurospheres yielded few new spheres. Genes coding for Nestin, Sox2, Chx10, and Vimentin were downregulated in cells derived from neurospheres compared to the cells from standard culture, while Pax6 was upregulated. Muller cells from both culture methods were induced into rod photoreceptors, but expression of rhodopsin and CRX was greater in the Muller cells from the standard culture. CONCLUSION: Both culture methods yielded cells with stem-cell characteristics that can be induced into rod photoreceptor neurons by RA. Serum had no influence on the "stemness" of the cells. Cells from standard culture had greater "stemness" than cells derived from neurospheres. The standard Muller cells would seem to be the best choice for transplantation in cell replacement therapy for photoreceptor degeneration. PMID- 28337290 TI - Down-regulation of hsa-miR-148b inhibits vascular smooth muscle cells proliferation and migration by directly targeting HSP90 in atherosclerosis. AB - The abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are crucial pathological processes that are involved in atherosclerosis. Growing evidence suggests that microRNAs (miRNAs) play critical roles in VSMCs functions. Here, we analyzed the expression of four atherosclerosis-related miRNAs and found that hsa-miR-148b was significantly down-regulated in plaques from atherosclerotic patients compared to a healthy control group. The restoration of hsa-miR-148b function in cells transfected with a hsa-miR-148b mimicmarkedly inhibited VSMCs proliferation and migration compared to a hsa-miR-148b mimic control. Furthermore, we discovered that heat shock protein 90 (HSP90) was a direct target of hsa-miR-148b in VSMCs. Hsa-miR-148b suppressed HSP90 expression by directly binding its 3'-untranslated region (UTR). In addition, the expression of hsa-miR-148b was negatively correlated with the HSP90 mRNA levels in plaques of atherosclerotic patients. Interestingly, the overexpression of HSP90 partly abrogated the hsa-miR-148b-mediated inhibition of VSMCs proliferation and migration. Our study provides the first evidence that hsa-miR-148b has anti proliferative and migratory functions by targeting HSP90 in VSMCs and may aidin the development of new biomarkers and potential therapeutic targets for atherosclerosis. PMID- 28337291 TI - Cholecystokinin attenuates radiation-induced lung cancer cell apoptosis by modulating p53 gene transcription. AB - The deregulation of p53 in cancer cells is one of the important factors by which cancer cells escape from the immune surveillance. Cholecystokinin (CCK) has strong bioactivity in the regulation of a number of cell activities. This study tests a hypothesis that CCK interferes with p53 expression to affect the apoptotic process in lung cancer (tumor) cells. In this study, tumor-bearing mice and A549 cells (a tumor cell line) were irradiated. The expression of CCK and p53 in tumor cells was assessed with RT-qPCR and Western blotting. The binding of p300 to the promoter of p53 was evaluated by chromatin immunoprecipitation. We observed that, with a given amount and within a given period, small doses/more sessions of irradiation markedly increased the levels of CCK in the sera and tumor cells, which were positively correlated with the tumor growth in mice and negatively correlated with tumor cell apoptosis. CCK increased the levels of histone acetyltransferase p300 and repressed the levels of nuclear factor-kB at the p53 promoter locus in tumor cells, which suppressed the expression of p53. In conclusion, CCK plays an important role in attenuating the radiation-induced lung cancer cell apoptosis. CCK may be a novel therapeutic target in the treatment of lung cancers. PMID- 28337292 TI - MiR-217 promotes cutaneous squamous cell carcinoma progression by targeting PTRF. AB - Increasing evidences have suggested that microRNAs (miRNAs) act a critical role in tumor initiation, progression and metastasis. Deregulated expression of miR 217 has been identified in various tumors. However, the expression and role of miR-217 in the development of cutaneous squamous cell carcinoma (cSCC) remain unclear. In our study, we showed that miR-217 expression was upregulated in the cSCC tissues compared to adjacent non-tumor samples. We also demonstrated that miR-217 expression was upregualted in the cSCCcSCC cell lines. Overexpression of miR-217 promoted cSCCcSCC cell growth, cell cycle and invasion. We identified Polymerase I and Transcript Release Factor (PTRF) as a direct target gene of miR 217 in the SCC13 cell. In addition, PTRF expression was downregulated in the cSCCcSCC tissues. Moreover, we demonstrated that there was a significant inverse correlation between miR-217 and PTRF expression in the cSCCcSCC. Furthermore, overexpression of PTRF could rescue miR-217's oncogenic effect on cSCC. Therefore, these results suggested that upregulation of miR-217 could contribute to development of cSCCcSCC through targeting PTRF. PMID- 28337294 TI - Hypoxic preconditioning of human cardiosphere-derived cell sheets enhances cellular functions via activation of the PI3K/Akt/mTOR/HIF-1alpha pathway. AB - Cell sheet technology is a promising therapeutic strategy for the treatment of ischemic diseases such as myocardial infarction. We recently developed a novel protocol, termed "hypoxic preconditioning," capable of augmenting the therapeutic efficacy of cell sheets. Following this protocol, the pro-angiogenic and anti fibrotic activity of cell sheets were enhanced by brief incubation of cell sheets under hypoxic culture conditions. However, the precise molecular mechanism underlying the hypoxic preconditioning of cell sheets is unclear. In the present study, we examined signal transducers in cell sheets to identify those responsive to hypoxic preconditioning, using cardiosphere-derived cell (CDC) sheets. We initially tested whether sheet-like structures were suitable for hypoxic preconditioning by comparing them with individual cells. Hypoxic preconditioning was more effective in sheeted cells than in individual cells. Expression of hypoxia inducible factor-1alpha (HIF-1alpha) and mammalian target of rapamycin (mTOR) were induced upon hypoxic preconditioning of cell sheets, as was the phosphoinositide 3-kinase (PI3K)/Akt pathway. In addition, hypoxic preconditioning increased phosphorylation of epidermal growth factor receptor (EGFR) and heat shock protein 60 (HSP60) in CDC sheets. Our findings provide novel insights into the utility of hypoxic preconditioning in cell sheet-based technologies for the treatment of ischemic diseases. PMID- 28337293 TI - MiR-146b protects cardiomyocytes injury in myocardial ischemia/reperfusion by targeting Smad4. AB - MicroRNAs, a class of small and non-encoding RNAs that transcriptionally or post transcriptionally modulate the expression of their target genes, have been implicated as critical regulatory molecules in many cardiovascular diseases, including ischemia-/reperfusion-induced cardiac injury. In the present study, we report on the role of miR-146b in myocardial I/R injury and the underlying cardio protective mechanism. Antagomir-146b was used to explore the effects of miR-146b on cardiac ischemia/reperfusion injury (30 min ischemia followed by 180 min reperfusion). As predicted, miR-146b overexpression significantly reduced the infarct size and cardiomyocytes apoptosis and release of creatine kinase and lactate dehydrogenase. In addition, miR-146b attenuated H9c2 cell apoptosis. Furthermore, Smad4 was predicted and verified as a potential miR-146b target using bioinformatics and luciferase assay. In summary, this study demonstrated that miR-146b plays a critical protective role in cardiac ischemic injury and may provide a new therapeutic approach for the treatment of myocardial I/R injury. PMID- 28337296 TI - Tumor suppressor p53 induces miR-15a processing to inhibit neuronal apoptosis inhibitory protein (NAIP) in the apoptotic response DNA damage in breast cancer cell. AB - This study was aimed to investigate the functional role of miR-15a in breast cancer cells in response to DNA damage and to illustrate the possible potential underlying molecular mechanism(s). Human breast cancer cell lines MCF-7 cells and/or MDA-MB-231 cells were pre-treated with or without bleomycin. Cells were transfected with corresponding vectors. qRT-PCR was used to detect the expression of mRNA or miRNA, and immunoprecipitation and immunoblot analysis were performed to explore the status of protein association. Cell apoptosis was analyzed with flow cytometry. The results showed that neuronal apoptosis inhibitory protein (NAIP) was negatively regulated by p53 in MCF-7 cells, and NAIP expression was still high in bleomycin-treated MCF-7 cells. In addition, we observed that miR 15a expression was regulated by p53, and the effects of miR-15a on DNA damage was also mediated by p53. Furthermore, the results revealed that the cell apoptosis was mediated by miR-15a. Taken together, this study reveals that p53 negatively regulates NAIP expression by targeting miR-15a processing from primary into precursor miRNA in breast cancer. PMID- 28337295 TI - RNA helicase DHX9 may be a therapeutic target in lung cancer and inhibited by enoxacin. AB - RNA helicase DHX9 is a member of human RNA enzymes. Previous studies have reported that DHX9 is highly expressed in various types of malignant tumor. However, its role in the progression of lung cancer remains to be fully clarified. The present study aims to investigate the oncogenic role of DHX9 in serum, tissues and lung cancer cell lines in vitro. We used RNA interference to downregulate DHX9 expression in A549 cells using a small interfering RNA lentiviral vector. Subsequently, enoxacin was used to inhibit cell proliferation, and this effect was detected using MTT. The results showed that DHX9 was overexpressed in the serum and tissues of lung cancer, especially in small cell lung cancer. Though enoxacin suppressed the proliferation of NSCLC cells, the inhibition effect was diminished when DHX9 was knocked down. In conclusion, the present study provided evidence suggesting that DHX9 was overexpressed in lung cancer and may contribute to the growth of lung cancer, and enoxacin may inhibit the proliferation based on DHX9. Thus DHX9 may be used as a diagnostic marker and a potential therapeutic target for the treatment of NSCLC. PMID- 28337297 TI - Protective effect of a novel antibody against TLR2 on zymosan-induced acute peritonitis in NF-kappaB transgenic mice. AB - In addition to antibiotic therapy for treatment of peritonitis, biologics have also been found to exhibit both anti-inflammatory and inflammation-resolving properties. Here, we first developed NF-kappaB transgenic mice with zymosan induced acute peritonitis to investigate the effects of a novel anti-Toll-like receptor (TLR)2 antibody (anti-T20). In this mouse model, anti-T20 treatment significantly attenuated the increase of peritoneal NF-kappaB activity and serum levels of inflammatory cytokines, including monocyte chemoattractant protein (MCP)-1, interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha, in a dose dependent manner compared to mice treated with isotype control antibody. Additionally, anti-T20 treatment significantly reduced MCP-1 levels as well as the leukocyte and total protein concentrations in the peritoneal exudates of peritonitis mice. Moreover, anti-T20 treatment significantly reduced TLR2 signal transduction in the leukocytes in peritoneal exudates from the experimental peritonitis mice. In conclusion, we developed a zymosan-induced acute peritonitis mouse model that facilitated visualization of NF-kappaB activity and demonstrated that anti-T20 treatment plays a protective role in this model concomitant with the inhibition of the zymosan-induced inflammatory response. PMID- 28337298 TI - XBP1-LOX Axis is critical in ER stress-induced growth of lung adenocarcinoma in 3D culture. AB - Rapid growth of tumor cells needs to consume large amounts of oxygen and glucose, due to lack of blood supply within the tumor, cells live in an environment that lack of oxygen and nutrients. This environment results in endoplasmic reticulum (ER) stress and activates the UPR (unfolded protein response). More and more evidence suggests UPR provides a growth signal pathway required for tumor growth. In the present study, we investigated the relationship between XBP1, one transcription factor in UPR, and the expression of LOX. We found that ER stress induces high expression of XBP1, one transcription factor in UPR, in both 2D culture and 3D culture; but only promotes growth of lung adenocarcinoma cells in in vitro 3D culture other than 2D culture. In 3D culture, we further showed that knockdown XBP1 expression can block Tm/Tg-induced cell growth. LOX genes may be key downstream effector of XBP1. Knockdown LOX expression can partially block XBP1-induced cell growth. Then we showed XBP1 suppressed by RNA interference (RNAi) can reduce the expression of LOX. For the first time, it is being shown that XBP1 can regulate the expression of LOX to promote cell growth. PMID- 28337299 TI - Poly r(C) binding protein (PCBP) 1 expression is regulated at the post translation level in thyroid carcinoma. AB - Poly r(C) binding protein (PCBP) 1 or heterogeneous ribonucleoprotein (hnRNP) E1 is a RNA binding protein that plays a vital role in a wide variety of biological processes. PCBP1 has been shown to function as a tumor suppressor by negatively regulating translation of pro-metastatic proteins in different cancers. Loss of PCBP1 expression or its Akt2-mediated phosphorylation at serine 43 residue has both been indicated to de-repress its regulation of EMT inducer proteins. Our previous work has established that PCBP1 functions as a tumor suppressor in thyroid cancer, where its translation is inhibited by microRNA-490-3p. Here we show that thyroid cancer patients can be divided into 2 cohorts based on miR-490 3p expression and PCBP1 mRNA expression-one cohort with high PCBP1 mRNA expression and basal miR-490-3p expression and a second cohort with low PCBP1 mRNA expression and high miR-490-3p expression. However, PCBP1 protein expression is also downregulated in the cohort with high PCBP1 mRNA expression, with expression levels similar to what is observed in patients with the low PCBP1 mRNA expression. Our analysis shows that PCBP1 mRNA is actively translated in patients with high PCBP1 mRNA expression, but that the protein is post translationally degraded by the proteasome machinery. Our results thus elucidate a novel mechanism responsible for down regulation of PCBP1 expression in thyroid cancer. It will be important in future to identify the mechanism that causes degradation of PCBP1 protein and to identify if similar mechanisms are active in other tumors characterized by low PCBP1 protein expression. PMID- 28337300 TI - Mutation of miR-21 targets endogenous lipoprotein receptor-related protein 6 and nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is a chronic disorder characterized by hepatic fat accumulation and abnormal lipid metabolism. Although miR-21 has been implicated in nonalcoholic fatty liver disease, it is unknown whether miR-21 could function as a therapeutic target. Here, we perform transfection analysis of miR-21 mimic or control mimic to evaluate the effects of miR-21 expression levels on human HepG2 nonalcoholic fatty liver cells. We used siRNA techniques to knock down miR-21 in HepG2 and control 293T cell lines, and then monitored lipid production and the expression levels of genes involved in lipid metabolism. The effects of miR-21 expression levels on LDL receptor-related protein 6 (LRP6) expression were evaluated using qRT-PCR and western blot analyses. Luciferase reporter assays were conducted to confirm the effects of miR-21 expression levels on LRP6. The results indicated that transfection of miR-21 mimic induced changes in the expression levels of lipogenic enzymes, including acetyl-CoA carboxylase 1 (ACC1), stearoyl CoA desaturase (1SCD1), sterol regulatory element-binding protein 1 (SREBP1), and liver X receptor alpha (LXRalpha). Transfection of miR-21 mimic suppressed the transcription and translation of LRP6 at the mRNA and protein levels, whereas miR-21 knockdown increased the expression levels of LRP6. Transfection of miR-21 mimic in HepG2 cells also induced lipid production and triggered the expression of critical lipid metabolic enzymes. These data suggest that mutation of miR-21 may be a new therapeutic strategy to treat nonalcoholic fatty liver diseases by targeting endogenous LRP6. PMID- 28337302 TI - Different impairment of immune and inflammation functions in short and long-term after ischemic stroke. AB - Ischemic stroke therapy and prognosis outcomes largely depend on the time periods after symptom onset. This study aims to explore the difference of global gene expression profiles and impairment of biological functions between short-term and long-term after stroke onset. We compared three short-term (3 h, 5 h and 24 h) and a long-term (6-month) gene expression levels by a multi-platform microarray data integration method. RankProd was used to calculate the differentially expressed genes between stroke patients and controls. DAVID Bioinformatics Resources was utilized to determine affected biological functions. Consensus cluster and hierarchical cluster methods were employed to compare the gene expression patterns of the commonly biological functions among these four time course groups. The results showed that severe impairment of inflammation and immune related functions in 5 h and 24 h after symptom onset. However, these functions were less affected in the 3 h and the 6-month groups. In addition, several key genes (CCL20, THBS1, EREG, and IL6 et al.) were dramatically down regulated in 5 h and 24 h groups, whereas these genes showed no change or even a slight contrary expression in 3 h or 6-month groups. This study has identified the large differences of altered immune and inflammation functions based on gene levels between short and long-term after stroke onset. The findings provide valuable insight into the clinical practice and prognosis evaluation of ischemic stroke. PMID- 28337303 TI - The involvement and possible mechanism of NR4A1 in chondrocyte apoptosis during osteoarthritis. AB - Osteoarthritis (OA) is a joint disease caused by the breakdown of joint cartilage and underlying bone, and places great burdens to daily life of patients. Nuclear orphan receptor nuclear receptor subfamily 4, group A, member 1 (NR4A1) is vital for cell apoptosis, but little is known about its role in OA. This study aims to reveal the expression and function of NR4A1 during OA chondrocyte apoptosis. NR4A1 expression by qRT-PCR and western blot, and chondrocyte apoptosis by TUNEL assay were detected in normal and OA joint cartilage. NR4A1 was located in cartilage sections by immunohistofluorescence. Chondrocytes from normal joint cartilage were cultured in vitro for interleukin 6 (IL6) or tumor necrosis factor (TNF) treatment and si-NR4A1 transfection, after which the possible mechanism involving NR4A1 was analyzed. Results showed that NR4A1 expression and chondrocyte apoptosis were significantly elevated in OA cartilage (P < 0.05 and P < 0.01). NR4A1 was located in nuclei of normal cartilage chondrocytes, but was translocated to mitochondria and co-located with B-cell lymphoma 2 in OA chondrocytes. NR4A1 expression in cultured chondrocytes could be promoted by both IL6 and TNF treatment. si-NR4A1 partly reduced TNF-induced cell apoptosis. Inhibiting p38 by SB203580 could decrease TNF-induced NR4A1 to some extent, while inhibiting JNK could not. So NR4A1 is likely to facilitate OA chondrocyte apoptosis, which is associated with p38 MAPK and mitochondrial apoptosis pathway. This study provides a potential therapeutic target for OA treatment and offers information for regulatory mechanisms in OA. PMID- 28337301 TI - Endoplasmic reticulum stress, a new wrestler, in the pathogenesis of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) has attracted extensive attention for its unexplained progressive lung scarring, short median survival and its unresponsiveness to traditional therapies. Despite extensive studies, the mechanisms underlying IPF pathoetiologies, however, remain poorly understood. Recent advances delineated a potential function of endoplasmic reticulum (ER) stress in meeting the need of fibrotic response, which pinpointed a critical role for the unfolded protein response (UPR) pathways in IPF pathogenesis. In this review, we highlight the effect of ER stress and the activation of UPR on the survival, differentiation, function and proliferation of major profibrotic cells in lung tissues during the course of IPF, and discuss the feasibility whether targeting UPR components could be an orientation for developing effective therapeutic strategies against this devastating disorder in clinical settings. PMID- 28337304 TI - Down-regulation of mediator complex subunit 19 (Med19) induces apoptosis in human laryngocarcinoma HEp2 cells in an Apaf-1-dependent pathway. AB - Mediator 19 (Med19) is a component of the mediator complex which is a co activator for DNA-binding factors that activate transcription via RNA polymerase II. Accumulating evidence has shown that Med19 plays important roles in cancer cell proliferation and tumorigenesis. The physiological mechanism by which Med19 exerts its promoting effects in laryngocarcinoma is not yet fully understood. Here, we found that the expression of Med19 was increased in laryngocarcinoma samples from patients compared to normal bone tissues. Med19 knockdown significantly induced growth inhibition and suppressed migration in the HEp2 cell lines. Med19 knockdown also induced apoptosis in HEp2 cells via activation of caspase-3, 9 and Apaf-1. In addition, The tumorigenicity of Med19 short hairpin RNA (shRNA)-expressing cells were decreased after inoculating into nude mice. Taken together, our data suggest that Med19 acts as an oncogene in laryngocarcinoma via a possible caspase modulation pathway. PMID- 28337305 TI - Rho kinase regulates neurite outgrowth of hippocampal neurons via calcium dependent cytoskeleton regulation. AB - OBJECTIVE: To investigate whether calcium is involved in downstream signal transduction in neurite outgrowth regulated by Rho kinase. METHODS: In vitro primary hippocampal neurons were cultured and treated with Rho kinase agonist (LPA) or antagonist (Y-27632). Then, the cytoskeleton and neurite outgrowth were observed. After addition of calcium antagonist BAPTA/AM to reduce intracellular calcium, the cytoskeleton distribution and neurite outgrowth were observed. RESULTS: The activation or inhibition of Rho kinase could significantly alter the number and length of neurites of hippocampal neurons. Rho kinase regulated the cytoskeleton to regulate the neurite outgrowth, and LPA could significantly increase intracellular calcium. After BAPTA/AM treatment, the length and branch number of neurites of neurons reduced markedly. BAPTA/AM was able to reduce intracellular calcium and decrease neuronal cytoskeleton. Treatment with both BAPTA/AM and LPA could stop the retraction of neurites, but the length and branch number of neurites remained unchanged after treatment with Y-27632 and LPA. CONCLUSION: Calcium may affect the cytoskeleton arrangement to regulate neurite outgrowth, and calcium is involved in the downstream signal transduction of Rho kinase regulated neurite outgrowth of hippocampal neurons. PMID- 28337306 TI - Thymoquinone potentiates chemoprotective effect of Vitamin D3 against colon cancer: a pre-clinical finding. AB - Prevention of colon cancer among high-risk group has been long lasting research goal. Emerging data have evidenced the anticancer activities of Vitamin D3 (Vit.D) and Thymoquinone (TQ). The aim of the current study was to evaluate the synergistic potential of Thymoquinone and Vitamin D3 in the control of colon cancer progression using azoxymethane-induced rat model. Vit.D and TQ were given individually or in combination 4 week prior to induction and continued for a total of 20 week. At the end of the study, all animals were euthanized and their resected colons were examined macroscopically and microscopically for tumor growth. Colonic tissue preparations were used for measuring gene expression and/or protein levels of selected pro and anti-tumor biomarkers using quantitative RT-PCR, ELISA and immunohistochemistry. Compared with their individual supplementation, combined Vit.D/TQ showed prominent anti-tumor effect manifested by significant reduction (P < 0.05) of the numbers of grown tumors and large aberrant crypts foci. Mechanistically, gene expression and/or protein quantification studies revealed that combined Vit.D/TQ supplementation induced significant reduction (P < 0.01 and P < 0.05) of pro-cancerous molecules (Wnt, beta-catenin, NF-kappaB, COX-2, iNOS, VEGF and HSP-90) as well as significant increase (P < 0.01 and P < 0.05, respectively) of anti-tumorigenesis biomarkers (DKK-1, CDNK-1A, TGF-beta1, TGF-beta/RII and smad4) as compared to un supplemented or individually supplemented groups, respectively. In conclusion, TQ augmented the chemopreventive effect of Vit.D during the initiation phase of colon cancer in rat model, with the potential to suppress progression of pre neoplastic lesions in colon carcinogenesis. PMID- 28337307 TI - Effects of microRNA-29a on retinopathy of prematurity by targeting AGT in a mouse model. AB - BACKGROUND: This study aimed to explore the effects of microRNA-29a (miR-29a) on retinopathy of prematurity (ROP) by targeting angiotensinogen (AGT) expression in a mouse model. METHODS: Ninety-six C57BL/6J mice were selected and divided into the normal control group (n = 12) and the oxygen-induced retinopathy (OIR) group (n = 84). All the mice in the OIR group were assigned to the following seven groups (12 mice in each group): the blank, miR-29a mimics, miR-29a inhibitors, empty plasmid, miR-29a mimics + si-AGT, miR-29a inhibitors + si-AGT and si-AGT groups. ADPase histochemical staining was conducted to detect the morphology of retinal neovascularization. H&E staining was performed to quantify retinal neovascularization. The qRT-PCR assay was applied to detect the expression levels of miR-29a and the AGT mRNA. Western blotting was used to detect the protein expressions of AGT, vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), angiotensin (ANG) and angiotensin II (AngII). RESULTS: Compared with the normal control group, miR-29a expression decreased, while the AGT mRNA expression and the protein expression levels of AGT, VEGF, HGF, ANG and AngII increased, and retinal vascular density and neovascularization also increased in the OIR group. In the OIR group, compared with the blank, empty plasmid, miR-29a inhibitors and miR-29a inhibitors + si-AGT groups, miR-29a expression increased, while the AGT mRNA expression and protein expression levels of AGT, VEGF, HGF, ANG and AngII decreased, and retinal vascular density and neovascularization also decreased in the miR-29a mimics, miR-29a mimics + si-AGT and si-AGT groups. CONCLUSION: MiR-29a could inhibit retinal neovascularization to prevent the development and progression of ROP by down-regulating AGT. PMID- 28337308 TI - Erratum: Effect of granatin B on the glioma cancer by inducing apoptosis. AB - [This corrects the article on p. 3970 in vol. 8, PMID: 27725877.]. PMID- 28337309 TI - GKN2 increases apoptosis, reduces the proliferation and invasion ability of gastric cancer cells through down-regulating the JAK/STAT signaling pathway. AB - OBJECTIVES: To investigate the effect of gastric motility protein 2 (GKN2) on the proliferation, apoptosis and invasion of gastric cancer cell and on the JAK/signal transducer and activator of transcription 3 (STAT3) signaling pathway. METHODS: Expression of GKN2 was qualified using Western blot analysis in four gastric cancer cell lines and immortalized human gastric mucosal epithelial cell line GES-1. The cells were then transfected with pcDNA3.1-GKN2 and control vector using Lipofectaminetm2000 and assayed for viability, apoptosis, cell cycle changes, invasion ability as well as expression of cell cycle protein D1 (Cylin D1), Bcl-2, Bax, matrix metalloproteinase 2 (MMP2), MMP9, JAK2 and p-STAT3. RESULTS: Western blot analyses showed that the expression of GKN2 was significantly lower in 4 gastric cancer cell lines (BGC-823, SGC-7901, AGS and MKN-45) than in GES-1. Of them, SGC-7901 had the lowest expression. The line was chosen for subsequent transfection experiments. Compared with control (transfection with empty vector), pcDNA3.1-GKN2-transfected cells had significantly more GKN2 protein and mRNA, decreased cell viability, increased apoptosis, more cells arrested at G1 phase and reduced invasiveness. Expression analyses showed that expression of Cyclin D1, Bcl-2, MMP2, MMP9, JAK2 and STAT3 was significantly down-regulated, while Bax was significantly up-regulated. CONCLUSION: Over-expression of GKN2 can increase apoptosis, reduce proliferation and invasion ability of gastric cancer cells as a result of down-regulated JAK2/STAT3 signaling pathway. PMID- 28337310 TI - Upregulation of TSPAN12 is associated with the colorectal cancer growth and metastasis. AB - Tetraspanin 12 (TSPAN12), as an earliest member of tetraspanin family, has been recently shown to be highly expressed in several malignant tumors, such as lung cancer and breast cancer, which plays an important role in regulating cell proliferation, migration and invasion. However, the functional roles of TSPAN12 in colorectal cancer (CRC) remain largely unclear. In this study, the expression of TSPAN12 was up-regulated compared to that in paracarcinoma tissues. Higher TSPAN12 expression was significantly correlated with TNM stage, tumor size and lymph node metastasis. The vitro functional analysis, including MTT, colony formation, flow cytometry and transwell assays indicated that lentivirus-mediated TSPAN12 knockdown significantly suppressed cell proliferation, migration and invasion, induced cell apoptosis of CRC cells. In addition, knockdown of TSPAN12 remarkably decreased the growth of subcutaneously inoculated tumors in nude mice. Our findings for the first time supported that TSPAN12 might play a positive role in the regulation of CRC cell proliferation, migration and invasion. The inhibition of TSPAN12 may serve as a novel promising therapeutic strategy against human CRC. PMID- 28337314 TI - Curcumin May Defy Medicinal Chemists. PMID- 28337313 TI - Editorial: Medicinal Chemistry Research in India. PMID- 28337312 TI - pri-miR-34b/c rs4938723 polymorphism is associated with hepatocellular carcinoma risk: a case-control study in a Chinese population. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. miR 34 induces changes of its downstream genes, and plays a key role in altering the apoptotic cycle and pathways of downstream cells, and finally influences the development of cancer. We assessed the relationship of the pri-miR-34b/c rs4938723 polymorphism with hepatocellular carcinoma risk in a Chinese population. During the period of January 2014 and December 2015, a total of 164 HCC patients and 305 healthy controls were recruited from the Inner Mongolia People's Hospital. Genotyping of the pri-miR-34b/c rs4938723 was determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP). Using chi2 test, we observed that HCC patients were likely to have a habit of alcohol consumption (chi2 = 10.24, P = 0.001) and infect with HBV or HCV (chi2 = 128.17, P < 0.001). In co-dominant model, the CC genotype of pri-miR-34b/c rs4938723 had a significant higher risk of HCC as compared with the TT genotype, and the corresponding adjusted OR (95% CI) was 4.14 (1.91-9.75). In dominant model, we observed that the TC+CC genotype were associated with an increased risk of HCC in comparison to the TT genotype (OR = 1.67, 95% CI = 1.17-2.55). In recessive model, the CC genotype was correlated with an elevated risk of HCC when compared with the TT+TC genotype (OR = 3.46, 95% CI = 1.62-8.54). The pri-miR 34b/c rs4938723 polymorphism was associated with a higher risk of HCC in the Chinese population examined. Further large-scale and multi-center studies are required to confirm these results. PMID- 28337311 TI - Consciousness loss during epileptogenesis: implication for VLPO-PnO circuits. AB - There is a growing concern about consciousness loss during epileptic seizures. Understanding neural mechanisms could lead to a better comprehension of cerebral circuit function in the control of consciousness loss in intractable epilepsy. We propose that ventrolateral preoptic area (VLPO)- PnO (nucleus pontis oralis) circuits may serve a major role in the loss of consciousness in drug-refractory epilepsy. Future behavioural and neuroimaging studies are clearly needed to understand the functional connectivity between the VLPO and PnO during loss of consciousness in drug-refractory epilepsy, to greatly prevent unconsciousness in this disorder and improve the quality of life in patients with intractable epilepsy. PMID- 28337316 TI - Bicyclic Ketone Sulfonamide Compounds. PMID- 28337315 TI - Sodium Channel Blockers. PMID- 28337318 TI - Development of [18F]Maleimide-Based Glycogen Synthase Kinase-3beta Ligands for Positron Emission Tomography Imaging. AB - Dysregulation of glycogen synthase kinase-3beta (GSK-3beta) is implicated in the pathogenesis of neurodegenerative and psychiatric disorders. Thus, development of GSK-3beta radiotracers for positron emission tomography (PET) imaging is of paramount importance, because such a noninvasive imaging technique would allow better understanding of the link between the activity of GSK-3beta and central nervous system disorders in living organisms, and it would enable early detection of the enzyme's aberrant activity. Herein, we report the synthesis and biological evaluation of a series of fluorine-substituted maleimide derivatives that are high-affinity GSK-3beta inhibitors. Radiosynthesis of a potential GSK-3beta tracer [18F]10a is achieved. Preliminary in vivo PET imaging studies in rodents show moderate brain uptake, although no saturable binding was observed in the brain. Further refinement of the lead scaffold to develop potent [18F]-labeled GSK-3 radiotracers for PET imaging of the central nervous system is warranted. PMID- 28337319 TI - Bifunctional Inhibitors as a New Tool To Reduce Cancer Cell Invasion by Impairing MMP-9 Homodimerization. AB - Protein homodimers play important roles in physiological and pathological processes, including cancer invasion and metastasis. Recently, MMP-9 natural homodimerization via the PEX domain has been correlated with high migration rates of aggressive cancer cells. Here we propose that bifunctional MMP-9 inhibitors designed to impair natural MMP-9 homodimerization promoted by PEX-PEX interactions might be an effective tool to fight cancer cell invasion. Elaborating a previously described dimeric hydroxamate inhibitor 1, new ligands were synthesized with different linker lengths and branch points. Evaluation of the modified bifunctional ligands by X-ray crystallography and biological assays showed that 7 and 8 could reduce invasion in three glioma cell lines expressing MMP-9 at different levels. To rationalize these results, we present a theoretical model of full-length MMP-9 in complex with 7. This pioneering study suggests that a new approach using MMP-9 selective bifunctional inhibitors might lead to an effective therapy to reduce cancer cell invasion. PMID- 28337317 TI - Structural Requirements of HDAC Inhibitors: SAHA Analogues Modified at the C2 Position Display HDAC6/8 Selectivity. AB - Histone deacetylase (HDAC) proteins are epigenetic regulators that deacetylate protein substrates, leading to subsequent changes in cell function. HDAC proteins are implicated in cancers, and several HDAC inhibitors have been approved by the FDA as anticancer drugs, including SAHA (suberoylanilide hydroxamic acid; Vorinostat and Zolinza). Unfortunately, SAHA inhibits most HDAC isoforms, which limits its use as a pharmacological tool and may lead to side effects in the clinic. In this work SAHA analogues substituted at the C2 position were synthesized and screened for HDAC isoform selectivity in vitro and in cells. The most potent and selective compound, C2-n-hexyl SAHA, displayed submicromolar potency with 49- to 300-fold selectivity for HDAC6 and HDAC8 compared to HDAC1, 2, and -3. Docking studies provided a structural rationale for selectivity. Modification of the nonselective inhibitor SAHA generated HDAC6/HDAC8 dual selective inhibitors, which can be useful lead compounds toward developing pharmacological tools and more effective anticancer drugs. PMID- 28337320 TI - Discovery and Assessment of Atropisomers of (+/-)-Lesinurad. AB - (+)- and (-)-Lesinurad were isolated as atropisomers from racemic lesinurad for the first time. No interconversion was observed between the two atropisomers under various conditions tested. The two atropisomers showed significant differences in hURAT1 highly expressed HEK293 cell-based inhibition assays, monkey pharmacokinetic studies, and in vitro human recombinant CYP2C9 stability studies. It was speculated that (+)-lesinurad might offer a better hyperuricemia/gout therapy than (-)-lesinurad or the racemate. PMID- 28337321 TI - Prototypic 18F-Labeled Argininamide-Type Neuropeptide Y Y1R Antagonists as Tracers for PET Imaging of Mammary Carcinoma. AB - The neuropeptide Y (NPY) Y1 receptor (Y1R) selective radioligand (R)-Nalpha-(2,2 diphenylacetyl)-Nomega-[4-(2-[18F]fluoropropanoylamino)butyl]aminocarbonyl-N-(4 hydroxybenzyl)argininamide ([18F]23), derived from the high-affinity Y1R antagonist BIBP3226, was developed for imaging studies of Y1R-positive tumors. Starting from the argininamide core bearing amine-functionalized spacer moieties, a series of fluoropropanoylated and fluorobenzoylated derivatives was synthesized and studied for Y1R affinity. The fluoropropanoylated derivative 23 displayed high affinity (Ki = 1.3 nM) and selectivity toward Y1R. Radiosynthesis was accomplished via 18F-fluoropropanoylation, yielding [18F]23 with excellent stability in mice; however, the biodistribution study revealed pronounced hepatobiliary clearance with high accumulation in the gall bladder (>100 %ID/g). Despite the unfavorable biodistribution, [18F]23 was successfully used for imaging of Y1R positive MCF-7 tumors in nude mice. Therefore, we suggest [18F]23 as a lead for the design of PET ligands with optimized physicochemical properties resulting in more favorable biodistribution and higher Y1R-dependent enrichment in mammary carcinoma. PMID- 28337322 TI - Platinum(II) Ring-Fused Chlorins as Near-Infrared Emitting Oxygen Sensors and Photodynamic Agents. AB - Novel near-infrared luminescent compounds based on platinum(II) 4,5,6,7 tetrahydropyrazolo[1,5-a]pyridine-fused chlorins are described. These compounds have high photostability and display light emission, in particular simultaneous fluorescence and phosphorescence emission in solution at room temperature, in the biologically relevant 700-850 nm red and near-infrared (NIR) spectral region, making them excellent materials for biological imaging. The simultaneous presence of fluorescence and phosphorescence emission at room temperature, with the phosphorescence strongly quenched by oxygen whereas fluorescence remains unaffected, allows these compounds to be used as ratiometric oxygen sensors in chemical and biological media. Both steady-state (fluorescence vs phosphorescence intensities) and dynamic (dependence of phosphorescence lifetimes upon oxygen concentration) luminescence approaches can be used. Photocytotoxicity studies against human melanocytic melanoma cells (A375) indicate that these compounds display potential as photosensitizers in photodynamic therapy. PMID- 28337323 TI - Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure. AB - Apoptosis signal-regulating kinase 1 (ASK1/MAP3K) is a mitogen-activated protein kinase family member shown to contribute to acute ischemia/reperfusion injury. Using structure-based drug design, deconstruction, and reoptimization of a known ASK1 inhibitor, a lead compound was identified. This compound displayed robust MAP3K pathway inhibition and reduction of infarct size in an isolated perfused heart model of cardiac injury. PMID- 28337325 TI - Tetrahydroisoquinoline-7-carboxamide Derivatives as New Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors. AB - Acute lung injury (ALI) is a deadly symptom for serious lung inflammation. Discoidin Domain Receptor 1 (DDR1) is a new potential target for anti inflammatory drug discovery. A new selective tetrahydroisoquinoline-7-carboxamide based DDR1 inhibitor 7ae was discovered to tightly bind the DDR1 protein and potently inhibit its kinase function with a Kd value of 2.2 nM and an IC50 value of 6.6 nM, respectively. The compound dose-dependently inhibited lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) release in mouse primary peritoneal macrophages (MPMs). In addition, 7ae also exhibited promising in vivo anti-inflammatory effects in a LPS induced mouse ALI model. To the best of our knowledge, this is the first "proof of concept" investigation on the potential application of a small molecule DDR1 inhibitor to treat ALI. PMID- 28337326 TI - Crystal Structures of ERAP2 Complexed with Inhibitors Reveal Pharmacophore Requirements for Optimizing Inhibitor Potency. AB - Endoplasmic reticulum aminopeptidase 2 assists with the generation of antigenic peptides for presentation onto Major Histocompatibility Class I molecules in humans. Recent evidence has suggested that the activity of ERAP2 may contribute to the generation of autoimmunity, thus making ERAP2 a possible pharmacological target for the regulation of adaptive immune responses. To better understand the structural elements of inhibitors that govern their binding affinity to the ERAP2 active site, we cocrystallized ERAP2 with a medium activity 3,4-diaminobenzoic acid inhibitor and a poorly active hydroxamic acid derivative. Comparison of these two crystal structures with a previously solved structure of ERAP2 in complex with a potent phosphinic pseudopeptide inhibitor suggests that engaging the substrate N-terminus recognition properties of the active site is crucial for inhibitor binding even in the absence of a potent zinc-binding group. Proper utilization of all five major pharmacophores is necessary, however, to optimize inhibitor potency. PMID- 28337324 TI - Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin. AB - We report the discovery of a new potent allosteric effector of sickle cell hemoglobin, GBT440 (36), that increases the affinity of hemoglobin for oxygen and consequently inhibits its polymerization when subjected to hypoxic conditions. Unlike earlier allosteric activators that bind covalently to hemoglobin in a 2:1 stoichiometry, 36 binds with a 1:1 stoichiometry. Compound 36 is orally bioavailable and partitions highly and favorably into the red blood cell with a RBC/plasma ratio of ~150. This partitioning onto the target protein is anticipated to allow therapeutic concentrations to be achieved in the red blood cell at low plasma concentrations. GBT440 (36) is in Phase 3 clinical trials for the treatment of sickle cell disease (NCT03036813). PMID- 28337327 TI - Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach. AB - Misdirected catalytic activity of histone methyltransferase Dot1L is believed to be causative for a subset of highly aggressive acute leukemias. Targeting the catalytic domain of Dot1L represents a potential therapeutic approach for these leukemias. In the context of a comprehensive Dot1L hit finding strategy, a knowledge-based virtual screen of the Dot1L SAM binding pocket led to the discovery of 2, a non-nucleoside fragment mimicking key interactions of SAM bound to Dot1L. Fragment linking of 2 and 3, an induced back pocket binder identified in earlier studies, followed by careful ligand optimization led to the identification of 7, a highly potent, selective and structurally novel Dot1L inhibitor. PMID- 28337328 TI - Structure-Activity Relationship Study of QL47: A Broad-Spectrum Antiviral Agent. AB - Here we report the structure-activity relationship (SAR) investigations of QL-XII 47 (QL47), a compound that possesses broad-spectrum antiviral activity against dengue virus and other RNA viruses. A medicinal chemistry campaign initiated from QL47, a previously reported covalent BTK inhibitor, to derive YKL-04-085, which is devoid of any kinase activity when screened against a panel of 468 kinases and with improved pharmacokinetic properties. Both QL47 and YKL-04-085 are potent inhibitors of viral translation and exhibit cellular antiviral activity at 35 fold lower concentrations relative to inhibition of host-cell proliferation. PMID- 28337330 TI - Antimalarial Properties of Simplified Kalihinol Analogues. AB - Several kalihinol natural products, members of the broader isocyanoterpene family of antimalarial agents, are potent inhibitors of Plasmodium falciparum, the agent of the most severe form of human malaria. Our previous total synthesis of kalihinol B provided a blueprint to generate many analogues within this family, some as complex as the natural product and some much simplified and easier to access. Each analogue was tested for blood-stage antimalarial activity using both drug-sensitive and -resistant P. falciparum strains. Many considerably simpler analogues of the kalihinols retained potent activity, as did a compound with a different decalin scaffold made in only three steps from sclareolide. Finally, one representative compound showed reasonable stability toward microsomal metabolism, suggesting that the isonitrile functional group that is critical for activity is not an inherent liability in these compounds. PMID- 28337329 TI - Antiparasitic Lead Discovery: Toward Optimization of a Chemotype with Activity Against Multiple Protozoan Parasites. AB - Human African trypanosomiasis (HAT), Chagas disease, and leishmaniasis present a significant burden across the developing world. Existing therapeutics for these protozoal neglected tropical diseases suffer from severe side effects and toxicity. Previously, NEU-1045 (3) was identified as a promising lead with cross pathogen activity, though it possessed poor physicochemical properties. We have designed a library of analogues with improved calculated physicochemical properties built on the quinoline scaffold of 3 incorporating small, polar aminoheterocycles in place of the 4-(3-fluorobenzyloxy)aniline substituent. We report the biological activity of these inhibitors against Trypanosoma brucei (HAT), T. cruzi (Chagas disease), and Leishmania major (cutaneous leishmaniasis) and describe the identification of N-(5-chloropyrimidin-2-yl)-6-(4 (morpholinosulfonyl)phenyl)quinolin-4-amine (13t) as a promising inhibitor of L. major proliferation and 6-(4-(morpholinosulfonyl)phenyl)-N-(pyrimidin-4 yl)quinolin-4-amine (13j), a potent inhibitor of T. brucei proliferation with improved drug-like properties. PMID- 28337331 TI - Light-Regulated NO Release as a Novel Strategy To Overcome Doxorubicin Multidrug Resistance. AB - Nitric oxide (NO) release from a suitable NO photodonor (NOP) can be fine-tuned by visible light stimuli at doses that are not toxic to cells but that inhibit several efflux pumps; these are mainly responsible for the multidrug resistance of the anticancer agent doxorubicin (DOX). The strategy may thus increase DOX toxicity against resistant cancer cells. Moreover, a novel molecular hybrid covalently joining DOX and NOP showed similar increased toxicity toward resistant cancer cells and, in addition, lower cardiotoxicity than DOX. This opens new and underexplored approaches to overcoming the main therapeutic drawbacks of this chemotherapeutic based on light-controlled release of NO. PMID- 28337333 TI - Efficient Semisynthesis of (-)-Pseudoirroratin A from (-)-Flexicaulin A and Assessment of Their Antitumor Activities. AB - Accumulating evidence indicates that natural ent-kaurane diterpenoids show great potential for medical treatment of different pathological conditions including cytotoxicity, antibacterial, and anti-inflammatory activity. Among a variety of diterpenoids tested, (-)-pseudoirroratin A displayed a promising antitumor property in vitro and in vivo. However, this diterpenoid could merely be isolated in a limited amount from a rare source of Isodon pseudoirrorata. To overcome such scanty source, we developed a novel, facile, and efficient semisynthetic strategy to prepare (-)-pseudoirroratin A from natural (-)-flexicaulin A, which can be expediently obtained from I. flexicaulis in a great quantity. The three dimensional structure and the absolute configuration of our synthetic diterpenoid have been determined and confirmed with the X-ray crystallographic analysis. More importantly, we demonstrated for the first time that pseudoirroratin A exerted significant cytotoxicity against human colorectal carcinoma cells via an induction of apoptosis, as well as a remarkable suppression on tumor growth in a colon cancer xenograft mouse model. PMID- 28337334 TI - Correction to "Chiral Cyclohexane 1,3-Diones as Inhibitors of Mutant SOD1 Dependent Protein Aggregation for the Treatment of ALS". AB - [This corrects the article DOI: 10.1021/ml3000963.]. PMID- 28337332 TI - BMS-933043, a Selective alpha7 nAChR Partial Agonist for the Treatment of Cognitive Deficits Associated with Schizophrenia. AB - The therapeutic treatment of negative symptoms and cognitive dysfunction associated with schizophrenia is a significant unmet medical need. Preclinical literature indicates that alpha7 neuronal nicotinic acetylcholine (nACh) receptor agonists may provide an effective approach to treating cognitive dysfunction in schizophrenia. We report herein the discovery and evaluation of 1c (BMS-933043), a novel and potent alpha7 nACh receptor partial agonist with high selectivity against other nicotinic acetylcholine receptor subtypes (>100-fold) and the 5 HT3A receptor (>300-fold). In vivo activity was demonstrated in a preclinical model of cognitive impairment, mouse novel object recognition. BMS-933043 has completed Phase I clinical trials. PMID- 28337335 TI - Correction to "Sulfonamides as Selective NaV1.7 Inhibitors: Optimizing Potency and Pharmacokinetics to Enable in Vivo Target Engagement". AB - [This corrects the article DOI: 10.1021/acsmedchemlett.6b00243.]. PMID- 28337336 TI - SAR and identification of 2-(quinolin-4-yloxy)acetamides as Mycobacterium tuberculosis cytochrome bc1 inhibitors. AB - A previous phenotypic screen by GSK identified 2-(quinolin-4-yloxy)acetamides as potent growth inhibitors of Mycobacterium tuberculosis (Mtb). We report the results of a preliminary structure-activity relationship (SAR) study of the compound class which has yielded more potent inhibitors. An Mtb cytochrome bd oxidase deletion mutant (cydKO) was found to be hypersensitive to most members of the compound library, while strains carrying single-nucleotide polymorphisms of the qcrB gene, which encodes a subunit of the menaquinol cytochrome c oxidoreductase (bc1) complex, were resistant to the library. These results identify that the 2-(quinolin-4-yloxy)acetamide class of Mtb growth inhibitors can be added to the growing number of scaffolds that target the M. tuberculosis bc1 complex. PMID- 28337337 TI - Drug trapping in hERG K+ channels: (not) a matter of drug size? AB - Inhibition of hERG K+ channels by structurally diverse drugs prolongs the ventricular action potential and increases the risk of torsade de pointes arrhythmias and sudden cardiac death. The capture of drugs behind closed channel gates, so-called drug trapping, is suggested to harbor an increased pro arrhythmic risk. In this study, the trapping mechanisms of a trapped hERG blocker propafenone and a bulky derivative (MW: 647.24 g mol-1) were studied by making use of electrophysiological measurements in combination with molecular dynamics simulations. Our study suggests that the hERG cavity is able to accommodate very bulky compounds without disturbing gate closure. PMID- 28337338 TI - Synthesis of malhamensilipin A exploiting iterative epoxidation/chlorination: experimental and computational analysis of epoxide-derived chloronium ions. AB - We report a 12-step catalytic enantioselective formal synthesis of malhamensilipin A (3) and diastereoisomeric analogues from (E)-2-undecenal. The convergent synthesis relied upon iterative epoxidation and phosphorus(v)-mediated deoxydichlorination reactions as well a titanium-mediated epoxide-opening to construct the C11-C16 stereohexad. The latter transformation occurred with very high levels of stereoretention regardless of the C13 configuration of the parent epoxide, implicating anchimeric assistance of either the gamma- or delta-chlorine atoms, and the formation of chloretanium or chlorolanium ions, respectively. A computational analysis of the chloronium ion intermediates provided support for the involvement of chlorolanium ions, whereas the potential chloretanium ions were found to be less likely intermediates on the basis of their greater carbocationic character. PMID- 28337339 TI - Intermolecular oxidative decarbonylative [2 + 2 + 2] carbocyclization of N-(2 ethynylaryl)acrylamides with tertiary and secondary alkyl aldehydes involving C(sp3)-H functionalization. AB - A new metal-free oxidative decarbonylative [2 + 2 + 2] carbocyclization of N-(2 ethynylaryl)acrylamides with tertiary and secondary alkyl aldehydes is described. This reaction enables the formation of three new C-C bonds in a single reaction by a sequence of oxidative decarbonylation, radical addition across C-C unsaturated bonds, C-H functionalization and annulation, and represents the first oxidative decarbonylative [2 + 2 + 2] carbocyclization approach using tertiary and secondary alkyl aldehydes as a two carbon unit for assembling six-membered carbocycle-fused polycycles. PMID- 28163893 TI - Kv4.2 knockout mice display learning and memory deficits in the Lashley maze. AB - Background: Potassium channels have been shown to be involved in neural plasticity and learning. Kv4.2 is a subunit of the A-type potassium channel. Kv4.2 channels modulate excitability in the dendrites of pyramidal neurons in the cortex and hippocampus. Deletion of Kv4.2 results in spatial learning and conditioned fear deficits; however, previous studies have only examined deletion of Kv4.2 in aversive learning tests. Methods: For the current study, we used the Lashley maze as an appetitive learning test. We examined Kv4.2 wildtype (WT) and knockout (KO) mice in the Lashley maze over 4 days during adulthood. The first day consisted of habituating the mice to the maze. The mice then received five trials per day for the next 3 days. The number of errors and the time to the goal box was recorded for each trial. The goal box contained a weigh boat with an appetitive reward (gelatin with sugar). There was an intertrial interval of 15 minutes. Results: We found that Kv4.2 KO mice committed more errors across the trials compared to the WT mice p<0.001. There was no difference in the latency to find the goal box over the period. Discussion: Our finding that deletion of Kv4.2 resulted in more errors in the Lashley maze across 15 trials contribute to a growing body of evidence that Kv4.2 channels are significantly involved in learning and memory. PMID- 28337342 TI - First Indian report of IncX3 plasmid carrying blaNDM-7 in Escherichia coli from bloodstream infection: potential for rapid dissemination. AB - Enterobacteriaceae with blaNDM-7 is only infrequently observed. Self transmissible plasmids carrying the blaNDM gene increase the dissemination of carbapenem resistance in developing countries. This study investigates the whole genome sequence of a blaNDM-7-positive Escherichia coli. The isolate was an extended-spectrum beta-lactamase producer by combined disc diffusion test and carbapenemase producer by CarbaNP method. Sequencing results revealed the isolate as E. coli ST-167 with IncX3 plasmid carrying blaNDM-7 in addition to blaTEM-1 and blaCMY-42 genes. The identification of IncX3-blaNDM-7 combination is the first report in India where blaNDM-7 is known to cause higher resistance to carbapenems compared to its variants. PMID- 28337343 TI - Long-Term Outcomes of Primary Trabeculectomy in Diabetic Patients without Retinopathy with Primary Angle-Closure Glaucoma. AB - Purpose. To evaluate primary trabeculectomy with adjunctive mitomycin-C (MMC) in diabetic patients without retinopathy with primary angle-closure glaucoma (PACG). Design. This is a retrospective case series comparison. Participants. This retrospective trial compared outcomes of 88 eyes that underwent trabeculectomy in patients with diabetes mellitus (DM) without retinopathy and in 97 patients without DM. Methods. In this study, the intraocular pressure (IOP), visual acuity, visual field, and postoperative complications were compared between the two groups. Qualified surgical success is defined as an IOP between 6 and 18 mmHg with or without topical antiglaucoma medication. Results. After a follow-up of 5 years, the IOP decreased from a mean basal IOP of 27.8 +/- 7.3 mmHg to 15.0 +/- 5.6 mmHg in the DM group and from 27.3 +/- 6.0 mmHg to 12.4 +/- 5.3 mmHg in the control group. The mean number of antiglaucoma medications was 3.4 +/- 1.3 and 3.3 +/- 1.2 preoperatively (P = 0.587) whereas it was 1.7 +/- 1.5 and 1.1 +/- 1.4 at the 5-year follow-up (P = 0.049). The 5-year qualified surgical success rates were 42.9% and 65.4% for both groups (P = 0.046; log-rank test). Encysted blebs were seen in 21 (23.9%) patients in the DM group and in 12 (12.4%) patients in the control group (P = 0.041). Conclusion. PACG patients with DM without retinopathy undergoing primary trabeculectomy with MMC may have a lower long-term surgical survival rate compared with patients without DM. PMID- 28337341 TI - Aetiological influences on stability and change in emotional and behavioural problems across development: a systematic review. AB - Emotional and behavioural problems in childhood and adolescence can be chronic and are predictive of future psychiatric problems. Understanding what factors drive the development and maintenance of these problems is therefore crucial. Longitudinal behavioural genetic studies using twin, sibling or adoption data can be used to explore the developmental aetiology of stability and change in childhood and adolescent psychopathology. We present a systematic review of longitudinal, behavioural genetic analyses of emotional and behavioural problems between ages 0 to 18 years. We identified 58 studies, of which 19 examined emotional problems, 30 examined behavioural problems, and 9 examined both. In the majority of studies, stability in emotional and behavioural problems was primarily genetically influenced. Stable environmental factors were also widely found, although these typically played a smaller role. Both genetic and environmental factors were involved in change across development. We discuss the findings in the context of the wider developmental literature and make recommendations for future research. PMID- 28337345 TI - Effective role of CaO/P2O5 ratio on SiO2-CaO-P2O5 glass system. AB - In the present work, the effect of the CaO/P2O5 ratio on the composition of sol gel synthesized 58SiO2-(19 - x)P2O5-(23 + x)CaO (x = 0, 5, 10 and 15 mol%) glass samples was studied. Further, the effect of NBO/BO ratio on hydroxy carbonated apatite layer (HCA) forming ability based on dissolution behavior in simulated body fluid (SBF) solution was also investigated. CaO/P2O5 ratios of synthesized glass samples were 1.2, 2, 3.6, and 9.5, respectively. NBO/BO ratios were obtained using Raman spectroscopic analysis as 0.58, 1.20, 1.46, and 1.78, respectively. All samples were soaked in the SBF solution for 7 days. The calculated weight losses of these samples were 58%, 64%, 83%, and 89% for corresponding NBO/BO ratios. The increase in CaO/P2O5 ratio increases the NBO/BO ratios. However, the increase in NBO/BO ratio increases HCA forming ability of SBF treated samples. The HCA crystalline layer formation was confirmed through X ray Diffraction (XRD), Transmission Electron Microscopy (TEM), Scanning Electron Microscopy (SEM), Raman and Infrared spectroscopic analysis. Higher CaO/P2O5 ratio favors the increase in HCA formation for SBF treated calcium phospho silicate glasses. PMID- 28337344 TI - Is Fibroblast growth factor 23 the leading cause of increased mortality among chronic kidney disease patients? A narrative review. AB - The death rate among chronic kidney disease patients is the highest compared to other chronic diseases. 60% of these fatalities are cardiovascular. Cardiovascular calcifications and chronic inflammation affect almost all chronic kidney disease patients and are associated with cardiovascular mortality. Fibroblast growth factor 23 is associated with vascular calcification. Systemic inflammation in chronic kidney disease patients is multifactorial. The role of systemic inflammation in the pathogenesis of vascular calcification was recently reappraised. Fibroblast growth factor 23 was accused as a direct stimulus of left ventricular hypertrophy, uremic inflammation, and impaired neutrophil function. This review will discuss the underlying mechanisms that underlie the link between Fibroblast growth factor 23 and increased mortality encountered among chronic kidney disease patients. PMID- 28337346 TI - Therapeutic effect of green tea extract on alcohol induced hepatic mitochondrial DNA damage in albino wistar rats. AB - The present study principally sought to investigate the effect of green tea extract (GTE) supplementation on hepatic mitochondrial DNA (mtDNA) damage in alcohol receiving rats. MtDNA was isolated from hepatic tissues of albino wistar rats after alcohol treatment with and without GTE supplementation. Entire displacement loop (D-loop) of mtDNA was screened by PCR-Sanger's sequencing method. In addition, mtDNA deletions and antioxidant activity were measured in hepatic tissue of all rats. Results showed increased frequency of D-loop mutations in alcoholic rats (ALC). DNA mfold analysis predicted higher free energy for 15507C and 16116C alleles compared to their corresponding wild alleles which represents less stable secondary structures with negative impact on overall mtDNA function. Interestingly, D-loop mutations observed in ALC rats were successfully restored on GTE supplementation. MtDNA deletions were observed in ALC rats, but intact native mtDNA was found in ALC + GTE group suggesting alcohol induced oxidative damage of mtDNA and ameliorative effect of GTE. Furthermore, markedly decreased activities of glutathione peroxidise, superoxide dismutase, catalase and glutathione content were identified in ALC rats; however, GTE supplementation significantly (P < 0.05) restored these levels close to normal. In conclusion, green tea could be used as an effective nutraceutical against alcohol induced mitochondrial DNA damage. PMID- 28337347 TI - Myocardial Infarction after Endoscopic Removal of Foreign Body. AB - The development of cardiac complications during or after endoscopic procedures is rare. However, mortality from myocardial ischemia, particularly in the elderly population, is elevated. We illustrate the rare case of a 79-year-old man with multiple cardiovascular risk factors who developed a non-ST elevation myocardial infarction (NSTEMI) after endoscopic removal of a foreign body. This case report summarizes a rare complication of a low-risk procedure and highlights the importance of considering this potential adverse event, particularly in patients with significant cardiovascular risk factors, to promote early diagnosis and proper treatment. PMID- 28337348 TI - Effective and Safe Use of Glucocorticosteroids for Rescue of Late ARDS. AB - We describe a case of severe refractory hypoxemia requiring prolonged extra corporeal membrane oxygenation (ECMO) support in a case of postpartum acute respiratory distress syndrome (ARDS). The clinical course was marked by persistently poor lung compliance and several complications of ECMO, that is, significant hemolysis, hemothorax, and intracranial bleeding. We report marked improvement of lung mechanics and respiratory function, leading to accelerated separation from ECMO, following rescue administration of low dose methylprednisolone 24 days after the onset of ARDS. Corticosteroid treatment was safe and well tolerated. In contrast with the conclusions of the 2006 ARDS Network trial, our report establishes a case in support of the use of low dose methylprednisolone as a safe and effective rescue treatment option in selected subsets of patients with nonresolving ARDS. PMID- 28337349 TI - A Rational Approach to Sinus Augmentation: The Low Window Sinus Lift. AB - Sinus augmentation is a well-known approach to treating alveolar bone ridge atrophy in the posterior maxilla. The preparation of the lateral window is crucial. Its size, design, and position in the vestibular sinus wall may affect the intra- and postsurgical complication rates and affect the intrasurgical activity of both surgeons and assistants. The present paper describes a rational technique that also exploits the guided surgery approach for design and preparation of a lateral window for sinus augmentation, the Low Window Sinus Lift. To illustrate the use of this approach, a case is presented in which the 50 year-old patient had the left maxillary first molar extracted, followed two months later by sinus augmentation and placement of three implants. One year after delivery of the definitive prosthesis, all three implants were successful, and the prosthesis was fully functional. Controlled studies should be undertaken to assess whether this technique provides significant advantages compared to other sinus augmentation approaches. PMID- 28337350 TI - Seat Belt Compression Appendicitis following Motor Vehicle Collision. AB - Appendicitis and trauma both present in emergency department commonly but their presentation together in the same patient is unusual. We present a case of a middle-aged man brought by emergency medical services (EMS) to the emergency department with complaints of abdominal pain after he was involved in motor vehicle collision. He was perfectly fine before the accident. His primary survey was normal. Secondary survey revealed tenderness in right iliac fossa with seat belt mark overlying it. Computerized tomography (CT) of the abdomen and pelvis was performed which showed 8 mm thickening of appendix with minimal adjacent fat stranding. There is also subcutaneous fat stranding of anterior lower abdominal wall possibly due to bruising. Impression of posttraumatic seat belt compression appendicitis was made. Laparoscopic appendectomy was done and patient recovered uneventfully. Histopathology showed inflamed appendix, proving it to be a case of seat belt compression appendicitis. PMID- 28337351 TI - A Rare Form of Brucella Bursitis with Negative Serology: A Case Report and Literature Review. AB - Brucellosis is still endemic in certain parts of the world including the Mediterranean, the Middle East, Latin America, and African regions. Osteoarticular manifestations are common presenting features. Brucellosis presenting as prepatellar bursitis has already been reported. We present a case of seronegative olecranon bursitis with positive blood and aspirate cultures. The patient improved remarkably by treatment with streptomycin and doxycycline with no evidence or relapse. PMID- 28337352 TI - Revisiting Cementoblastoma with a Rare Case Presentation. AB - Cementoblastoma is a rare benign odontogenic neoplasm which is characterized by the proliferation of cellular cementum. Diagnosis of cementoblastoma is challenging because of its protracted clinical, radiographic features, and bland histological appearance; most often cementoblastoma is often confused with other cementum and bone originated lesions. The aim of this article is to overview/revisit, approach the diagnosis of cementoblastoma, and also present a unique radiographic appearance of a cementoblastoma lesion associated with an impacted tooth. PMID- 28337353 TI - Gastric Duplication: A Rare Cause of Recurrent Vomiting. AB - Vomiting is a physical finding that can occur at any age but presents the greatest challenge when it is recurrent in a child. The etiology is varied (Sieunarine and Manmohansingh, 1989; Suzuki, 1982), and recurrent vomiting can be a symptom of life threatening medical or surgical emergencies. Early recognition is mandatory for preventing delay in management and potential complications. Gastric duplication is rare and mostly diagnosed in infancy with only a few cases documented in the medical literature presenting in childhood. We present a three year-old Vietnamese female with recurrent vomiting. Obstruction and sepsis were ruled out as a cause of the recurrent vomiting by history and appropriate tests. Persistent vomiting and paucity of air on the plain abdominal films provided a clue to the diagnosis. A CT scan of the abdomen with contrast revealed a uniformly thin walled fluid attenuation mass in the epigastric region which did not opacify with contrast. An abdominal ultrasound confirmed gastric duplication cyst and the patient was taken to the operating room for excision of the cyst. PMID- 28337354 TI - Facial Asymmetry in a Crying Newborn: A Comparison of Two Cases and Review of Literature. AB - Facial asymmetry in a crying newborn can be due to a variety of different causes. Neonatal asymmetric crying facies (NACF) is a specific phenotype, which is often underrecognized. It is defined as asymmetry of the mouth and lips with grimacing or smiling, but a symmetric appearance at rest. NACF needs to be differentiated from complete facial palsy in a newborn, which can occur due to traumatic or developmental etiologies. Developmental causes can be present in isolation or may be a part of a recognized syndrome. While asymmetric lower lip depression may be seen in both conditions, complete facial palsy is also associated with upper and mid face deformities. We present a case of NACF and compare it to a case of facial palsy due to perinatal trauma. The purpose of this case series is to clarify some of the confusing nomenclatures and highlight the differences in the physical exam findings, diagnosis, and eventual prognosis of these cases. PMID- 28337355 TI - Osteonecrosis of the Femoral Head in an Adolescent on Long-Term Inhalational Corticosteroids. AB - A relationship between the development of osteonecrosis of the femoral head and systemic corticosteroids has been well established in the literature, particularly in adults. However, the link between osteonecrosis and inhaled corticosteroids is less researched and understood. We report an usual case report of a 10-year-old male who developed ipsilateral femoral head osteonecrosis after long-term inhalational corticosteroid and intermittent short courses of oral steroid usage with a unique presentation and delayed diagnosis. PMID- 28337356 TI - Cervical Stimulation in the Treatment of Children with Lymphedema of All Four Extremities: A Case Report and Literature Review. AB - Aim. The aim of this study is to report on the use of cervical stimulation as monotherapy to reduce swelling and normalize the size of limbs in two children with lymphedema of all four extremities. Case Presentation. One child also had hemifacial edema. In both cases, the mothers were trained to perform cervical stimulation under professional supervision. The cases of two girls, one of eight months and the other of six months, with primary congenital lymphedema are described. Outcome. After clinical diagnosis, the patients started treatment with cervical stimulation three times per week. The mothers were trained in cervical stimulation and, when the therapy team was confident about the mothers' ability to perform the technique, the children began to be treated at home. The Godoy & Godoy cervical stimulation technique consists of around 20 to 30 light stroking movements per minute in the cervical region which stimulate the lymphatics. Perimetric measurements were made of the feet, legs, and the hands. Only two points (3 and 6 cm) along the dorsum of the feet and hands and points at 5 cm intervals up the legs starting at the ankle were considered. Today, the children are 5 and 6 years of age, without edema and with a normal life, without limitations, except with respect to precautions against injuries to the limbs and against infections particularly erysipelas. Conclusion. Cervical Lymphatic Therapy as monotherapy is an option in the treatment of primary congenital lymphedema. PMID- 28337357 TI - Solitary Fibrous Tumor of the Prostate Which Was Initially Misdiagnosed as Prostate Cancer. AB - Solitary fibrous tumor (SFT) of the prostate is a very rare tumor. We report a case of 65-year-old man with SFT of the prostate which was initially misdiagnosed as prostate cancer. Finally, we performed total prostatectomy and the tumor was histologically diagnosed as SFT of the prostate. The patient's clinical course has progressed favorably with no obvious recurrence 18 months postoperatively. PMID- 28337358 TI - Gastric Cancer and Angiogenesis: Is VEGF a Useful Biomarker to Assess Progression and Remission? AB - Gastric cancer (GC) has high mortality owing to its aggressive nature. Tumor angiogenesis plays an essential role in the growth, invasion, and metastatic spread of GC. The aim of this work was to review the angiogenic biomarkers related to the behavior of GC, documented in the literature. A search of the PubMed database was conducted with the MeSH terms: "Stomach neoplasms/blood [MeSH] or stomach neoplasms/blood supply [MeSH] and angiogenic proteins/blood [Major]". A total of 30 articles were initially collected, and 4 were subsequently excluded. Among the 26 articles collected, 16 examined the role of vascular endothelial growth factor (VEGF), 4 studied endostatin, 3 investigated angiopoietin (Ang)-2, 2 studied the Ang-like protein 2 (ANGTPL2), and 1 each examined interleukin (IL)-12, IL-8, and hypoxia inducible factor. Regarding VEGF, 6 articles concluded that the protein was related to lymph node metastasis or distant metastases. Five articles concluded that VEGF levels were elevated in the presence of GC and decreased following tumor regression, suggesting that VEGF levels could be a predictor of recurrence. Four articles concluded that high VEGF levels were correlated with poor prognosis and lower survival rates. Ang-2 and ANGTPL2 were elevated in GC and associated with more aggressive disease. Endostatin was associated with intestinal GC. VEGF is the most extensively studied angiogenic factor. It is associated with the presence of neoplastic disease and lymph node metastasis. It appears to be a good biomarker for disease progression and remission, but not for diagnosis. The data regarding other biomarkers are inconclusive. PMID- 28337359 TI - Effect of Acupuncture on Postoperative Ileus after Distal Gastrectomy for Gastric Cancer. AB - PURPOSE: Acupuncture has recently been accepted as a treatment option for managing postoperative ileus (POI) and various functional gastrointestinal disorders. Therefore, we conducted a prospective randomized study to evaluate the effect of acupuncture on POI and other surgical outcomes in patients who underwent gastric surgery. MATERIALS AND METHODS: Thirty-six patients who underwent distal gastrectomy for gastric cancer from March to December 2015 were randomly assigned to acupuncture or non-acupuncture (NA) groups at 1:1 ratio. The acupuncture treatment was administered treatment once daily for 5 consecutive days starting at postoperative day 1. The primary outcome measure was the number of remnant sitz markers in the small intestine on abdominal radiograph. The secondary outcome measure was the surgical outcome, including the times to first flatus, first defecation, start of water intake, and start of soft diet, as well as length of hospital stay and laboratory findings. RESULTS: The acupuncture group had significantly fewer remnant sitz markers in the small intestine on postoperative days 3 and 5 compared to those in the NA group. A significant difference was observed in the numbers of remnant sitz markers in the small intestine with respect to group differences by time (P<0.0001). The acupuncture group showed relatively better surgical outcomes than those in the NA group, but the differences were not statistically significant. CONCLUSIONS: In this clinical trial, acupuncture promoted the passage of sitz markers, which may reflect the possibility of reducing POI after distal gastrectomy. PMID- 28337360 TI - Perioperative Epirubicin, Oxaliplatin, and Capecitabine Chemotherapy in Locally Advanced Gastric Cancer: Safety and Feasibility in an Interim Survival Analysis. AB - PURPOSE: Perioperative chemotherapy improves survival outcomes in locally advanced (LA) gastric cancer. MATERIALS AND METHODS: We retrospectively analyzed patients with LA gastric cancer who were offered perioperative chemotherapy consisting of epirubicin, oxaliplatin, and capecitabine (EOX) from May 2013 to December 2015 at Tata Memorial Hospital in Mumbai. RESULTS: Among the 268 consecutive patients in our study, 260 patients (97.0%) completed neoadjuvant chemotherapy, 200 patients (74.6%) underwent D2 lymphadenectomy, and 178 patients (66.4%) completed adjuvant chemotherapy. The median follow-up period was 17 months. For the entire cohort, the median overall survival (OS), 3-year OS rate, median progression-free survival (PFS), and 3-year PFS rate were 37 months, 64.4%, 31 months, and 40%, respectively. PFS and OS were significantly inferior in patients who presented with features of obstruction than in those who did not (P=0.0001). There was no difference in survival with respect to tumor histology (well to moderately differentiated vs. poorly differentiated, signet ring vs. non signet ring histology) or location (proximal vs. distal). Survival was prolonged in patients with an early pathological T stage and a pathological node-negative status. In a multivariate analysis, postoperative pathological nodal status and gastric outlet obstruction on presentation significantly correlated with survival. CONCLUSIONS: EOX chemotherapy with curative resection and D2 lymphadenectomy is a suggested alternative to the existing perioperative regimens. The acceptable postoperative complication rate and relatively high resection, chemotherapy completion, and survival rates obtained in this study require further evaluation and validation in a clinical trial. PMID- 28337362 TI - Analysis of G3BP1 and VEZT Expression in Gastric Cancer and Their Possible Correlation with Tumor Clinicopathological Factors. AB - PURPOSE: This study aimed to analyze G3BP1 and VEZT expression profiles in patients with gastric cancer, and examine the possible relationship between the expressions of each gene and clinicopathological factors. MATERIALS AND METHODS: Expression of these genes in formalin-fixed paraffin embedded (FFPE) tissues, collected from 40 patients with gastric cancer and 40 healthy controls, was analyzed. Differences in gene expression among patient and normal samples were identified using the GraphPad Prism 5 software. For the analysis of real-time polymerase chain reaction products, GelQuantNET software was used. RESULTS: Our findings demonstrated that both VEZT and G3BP1 mRNA expression levels were downregulated in gastric cancer samples compared with those in the normal controls. No significant relationship was found between the expression of these genes and gender (P-value, 0.4835 vs. 0.6350), but there were significant changes associated with age (P-value, 0.0004 vs. 0.0001) and stage of disease (P-value, 0.0019 vs. 0.0001). In addition, there was a direct relationship between VEZT gene expression and metastasis (P-value, 0.0462), in contrast to G3BP1 that did not demonstrate any significant correlation (P-value, 0.1833). CONCLUSIONS: The results suggest that expression profiling of VEZT and G3BP1 can be used for diagnosis of gastric cancer, and specifically, VEZT gene could be considered as a biomarker for the detection of gastric cancer progression. PMID- 28337361 TI - The Effect of Endoscopic Resection on Short-Term Surgical Outcomes in Patients with Additional Laparoscopic Gastrectomy after Non-Curative Resection for Gastric Cancer. AB - PURPOSE: Endoscopic submucosal dissection (ESD) in early gastric cancer causes an artificial gastric ulcer and local inflammation that has a negative intraprocedural impact on additional laparoscopic gastrectomy in patients with noncurative ESD. In this study, we analyzed the effect of ESD on short-term surgical outcomes and evaluated the risk factors. MATERIALS AND METHODS: From January 2003 to January 2013, 1,704 patients of the National Cancer Center underwent laparoscopic gastrectomy with lymph node dissection because of preoperative stage Ia or Ib gastric cancer. They were divided into 2 groups: (1) with preoperative ESD or (2) without preoperative ESD. Clinicopathologic factors and short-term surgical outcomes were retrospectively evaluated along with risk factors such as preoperative ESD. RESULTS: Several characteristics differed between patients who underwent ESD-surgery (n=199) or surgery alone (n=1,505). The mean interval from the ESD procedure to the operation was 43.03 days. Estimated blood loss, open conversion rate, mean operation time, and length of hospital stay were not different between the 2 groups. Postoperative complications occurred in 23 patients (11.56%) in the ESD-surgery group and in 189 patients (12.56%) in the surgery-only group, and 3 deaths occurred among patients with complications (1 patient [ESD-surgery group] vs. 2 patients [surgery-only group]; P=0.688). A history of ESD was not significantly associated with postoperative complications (P=0.688). Multivariate analysis showed that male sex (P=0.008) and laparoscopic total or proximal gastrectomy (P=0.000) were independently associated with postoperative complications. CONCLUSIONS: ESD did not affect short-term surgical outcomes during and after an additional laparoscopic gastrectomy. PMID- 28337363 TI - Epidemiologic Study of Human Epidermal Growth Factor Receptor 2 Expression in Advanced/Metastatic Gastric Cancer: an Assessment of Human Epidermal Growth Factor Receptor 2 Status in Tumor Tissue Samples of Gastric and Gastro-Esophageal Junction Cancer. AB - PURPOSE: The Trastuzumab for gastric cancer (GC) trial identified human epidermal growth factor receptor 2 (HER2) as a predictor of successful treatment with trastuzumab (HER2 receptor targeting agent) among patients with advanced/metastatic GC. To date, the prevalence of HER2 overexpression in the Korean population is unknown. The present study aimed to assess the incidence of HER2 positivity among GC and gastroesophageal (GE) junction cancer samples and the relationship between HER2 overexpression and clinicopathological characteristics in Korean patients. MATERIALS AND METHODS: Tumor samples collected from 1,695 patients with histologically proven GC or GE junction enrolled at 14 different hospitals in Korea were examined. After gathering clinicopathological data of all patients, HER2 status was assessed by immunohistochemistry (IHC) at each hospital, and IHC 2+ cases were subjected to silver-enhanced in situ hybridization at 3 central laboratories. RESULTS: A total of 182 specimens tested positive for HER2, whereas 1,505 tested negative. Therefore, the overall HER2-positive rate in this study was 10.8% (95% confidence interval=9.3%-12.3%). The HER2-positive rate was higher among intestinal-type cases (17.6%) than among other types, and was higher among patients older than 70 years and 50 years of age, compared to other age groups. CONCLUSIONS: Our evaluation of the HER2 positivity rate (10.8%) among Korean patients with GC and GE junction indicated the necessity of epidemiological data when conducting studies related to HER2 expression in GC and GE junction. PMID- 28337364 TI - Surgical Outcomes Associated with Operable Gastric Cancer in a Tertiary Care Indian Hospital. AB - PURPOSE: Data on operable gastric cancer from India is sparse. The purpose of this study was to investigate the clinical details, histopathological demographics, and 5-year overall survival (OS) and disease free survival (DFS) associated with operable, non-metastatic gastric cancer in a dedicated upper gastrointestinal (GI) surgical unit in India. MATERIALS AND METHODS: Data for patients diagnosed with operable gastric cancer between January 2006 and December 2014 were retrospectively analyzed. Data were collected from electronic hospital records in addition to mail and telephonic interviews when possible. RESULTS: A total of 427 patients were included. The tumor was located in the pyloro-antral region in 263 patients (61.7%). Subtotal gastrectomy was performed in 291 patients and total gastrectomy in 136 patients. Tumor stage classification revealed 43 patients (10.0%) with stage I, 40 patients (9.4%) with stage IIA, 59 patients (13.9%) with stage IIB, 76 patients (17.8%) with stage IIIA, 96 patients (22.5%) with stage IIIB, and 113 patients (26.4%) with stage IIIC disease. Follow up data were available for 71.6% of the patients with a mean duration of 32.4 months. Five-year DFS and OS were 39% and 59%, respectively. CONCLUSIONS: Despite presenting at an advanced stage, the 5-year DFS and OS of patients with operable gastric cancer treated at a dedicated upper GI unit of a tertiary care center in India was good. PMID- 28337366 TI - Natural History of Early Gastric Cancer: a Case Report and Literature Review. AB - Early detection and treatment decrease the mortality rate associated with gastric cancer (GC). However, the natural history of GC remains unclear. An 85-year-old woman was referred to our hospital for evaluation of a gastric tumor. Esophagogastroduodenoscopy identified a 6 mm, flat-elevated lesion at the lesser curvature of the antrum. A biopsy specimen showed a well-differentiated tubular adenocarcinoma. The depth of the lesion was estimated to be intramucosal. Although the lesion met the indications for endoscopic resection, periodic endoscopic follow-up was performed due to the patient's advanced age and comorbidities. The mucosal GC invaded into the submucosa 3 years later, and finally progressed to advanced cancer 5 years after the initial examination. The patient died of tumor hemorrhage 6.4 years after the initial examination. In this case, mucosal GC progressed to advanced GC, eventually leading to the patient's death from GC. Early and appropriate treatment is required to prevent GC-related death. PMID- 28337365 TI - Body Composition as a Prognostic Factor of Neoadjuvant Chemotherapy Toxicity and Outcome in Patients with Locally Advanced Gastric Cancer. AB - PURPOSE: Neoadjuvant chemotherapy has been shown to improve survival in locally advanced gastric cancer, but it is associated with significant toxicity. Sarcopenia and sarcopenic obesity have been studied in several types of cancers and have been reported to be associated with higher chemotherapy toxicity and morbi-mortality. The aim of this study was to assess the prevalence of sarcopenia/sarcopenic obesity in patients with gastric cancer, as well as its association with chemotherapy toxicity and long-term outcomes. MATERIALS AND METHODS: A retrospective analysis was performed using an academic cancer center patient cohort diagnosed with locally advanced gastric cancer between January 2012 and December 2014 and treated with neoadjuvant chemotherapy. We analyzed body composition (skeletal muscle and visceral fat index) in axial computed tomography images. RESULTS: A total of 48 patients met the inclusion criteria. The mean age was 68+/-10 years, and 33 patients (69%) were men. Dose-limiting toxicity was observed in 22 patients (46%), and treatment was terminated early owing to toxicity in 17 patients (35%). Median follow-up was 17 months. Sarcopenia and sarcopenic obesity were found at diagnosis in 23% and 10% of patients, respectively. We observed an association between termination of chemotherapy and both sarcopenia (P=0.069) and sarcopenic obesity (P=0.004). On multivariate analysis, the odds of treatment termination were higher in patients with sarcopenia (odds ratio=4.23; P=0.050). Patients with sarcopenic obesity showed lower overall survival (median survival of 6 months [95% confidence interval {CI}=3.9-8.5] vs. 25 months [95% CI=20.2-38.2]; log-rank test P=0.000). CONCLUSIONS: Sarcopenia and sarcopenic obesity were associated with early termination of neoadjuvant chemotherapy in patients with gastric cancer; additionally, sarcopenic obesity was associated with poor survival. PMID- 28337367 TI - A Case of Advanced Gastric Cancer with Para-Aortic Lymph Node Metastasis from Co Occurring Prostate Cancer. AB - An 84-year-old man was diagnosed with two synchronous adenocarcinomas, a Borrmann type IV advanced gastric adenocarcinoma in his antrum and a well-differentiated Borrmann type I carcinoma on the anterior wall of the higher body of his stomach. Pre-operatively, computed tomography of the abdomen revealed the presence of advanced gastric cancer with peri-gastric and para-aortic lymph node (LN) metastasis. He planned for palliative total gastrectomy owing to the risk of obstruction by the antral lesion. We performed a frozen biopsy of a para-aortic LN during surgery and found that the origin of the para-aortic LN metastasis was from undiagnosed prostate cancer. Thus, we performed radical total gastrectomy and D2 LN dissection. Post-operatively, his total prostate-specific antigen levels were high (227 ng/mL) and he was discharged 8 days after surgery without any complications. PMID- 28337368 TI - Do Personality and Organizational Politics Predict Workplace Victimization? A Study among Ghanaian Employees. AB - BACKGROUND: Workplace victimization is considered a major social stressor with significant implications for the wellbeing of employees and organizations. The aim of this study was to examine the influences of employees' personality traits and organizational politics on workplace victimization among Ghanaian employees. METHODS: Using a cross-sectional design, data were collected from 631 employees selected from diverse occupations through convenience sampling. Data collection tools were standardized questionnaires that measured experiences of negative acts at work (victimization), the Big Five personality traits, and organizational politics. RESULTS: The results from hierarchical multiple regression analysis showed that among the personality traits neuroticism and conscientiousness had significant, albeit weak relationships with victimization. Organizational politics had a significant positive relationship with workplace victimization beyond employees' personality. CONCLUSION: The study demonstrates that compared with personal characteristics such as personality traits, work environment factors such as organizational politics have a stronger influence on the occurrence of workplace victimization. PMID- 28337371 TI - Combinational therapy of crizotinib and afatinib for malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is a relative rare but highly aggressive neoplasm which is associated with asbestos exposure in most patients. The majority of patients are diagnosed in advanced stages so patients neither benefit from chemotherapy (e.g. pemetrexed-platinum combination) nor from surgery. It has been reported that cellular-mesenchymal to epithelial transition factor (MET) and epidermal growth factor receptor (EGFR) were critical for MPM cell proliferation. Moreover, targeting MET and EGFR drugs have gained promising results on anti tumor therapy. Here, a striking difference in overall survival was observed between the MET and EGFR co-expression group (median survival time = 13.5 months) and non-co-expression group (median survival time = 20.5 months). In addition, treatment with combination of crizotinib and afatinib showed stronger inhibition on cell proliferation of MPM than the treatment by either one in vitro and in vivo. In conclusion, our data illustrated that crizotinib combined with afatinib may be a potentially effective strategy for treating MPM patients with over expression of MET and EGFR. PMID- 28337370 TI - Role of epidermal growth factor receptor in lung cancer and targeted therapies. AB - Lung cancer is the foremost cause of cancer-related deaths world-wide. Both, the major forms of lung cancer, Non-small cell lung cancer (NSCLC) and Small cell lung cancers (SCLC), have responded effectively to chemo-, radiation and adjuvant therapies. Tumor removal through surgery also appeared as a good therapeutic strategy. However, these therapies demonstrated unfavourable side-effects, and hence novel drugs targeting lung cancer emerged essential. Activation of epidermal growth factor receptor (EGFR)-tyrosine kinases is a key reason for lung cancer progression. Two important strategies that have attenuated lung cancers were through treatments with EGFR-tyrosine kinase-inhibitors, erlotinib and gefitinib, or EGFR-neutralizing antibodies, cetuximab and bevacizumab. A major advantage with erlotinib and gefitinib was their role in second and third-line treatments following chemotherapies. Phase II/III clinical trials showed that combinatorial treatment of tyrosine kinase (TK)-inhibitors with chemotherapeutics, such as docetaxel and pemetrexed, caused significant improvements in progression-free survival and overall survival.Phase I and II clinical studies also revealed that combination of tyrosine kinase-inhibitors with the EGFR-targeted antibodies was an effective approach for treating lung cancer. However, patients having T790M-mutations within EGFR gene were resistant to erlotinib and gefitinib. Alternatively, another second-generation EGFR tyrosine kinase-inhibitor, afatinib, that could circumvent the problem of drug resistance has been developed as lung cancer therapy. The current review focuses on the role of EGFR in lung cancer progression and apprises about the EGFR targeted therapies. The review also informs on the adverse side-effects of these therapies and enlightens the need for safer therapeutic regimens to eradicate this dreaded disease. PMID- 28337369 TI - Role of Notch signaling pathway in pancreatic cancer. AB - Pancreatic cancer (PC) is one of the highly aggressive malignancies in the United States. It has been shown that multiple signaling pathways are involved in the pathogenesis of PC, such as JNK, PI3K/AKT, Rho GTPase, Hedgehog (Hh) and Skp2. In recent years, accumulated evidence has demonstrated that Notch signaling pathway plays critical roles in the development and progression of PC. Therefore, in this review we discuss the recent literature regarding the function and regulation of Notch in the pathogenesis of PC. Moreover, we describe that Notch signaling pathway could be down-regulated by its inhibitors or natural compounds, which could be a novel approach for the treatment of PC patients. PMID- 28337372 TI - miR-429 mediates tumor growth and metastasis in colorectal cancer. AB - Colorectal cancer (CRC), presenting the third most common malignancy worldwide. In recent years, the aberrantly upregulation or downregulation of miRNAs in CRC have been evidenced in a number of studies. In this study, our results showed that the expression of miR-429 was significantly higher in CRC tissue compared with adjacent non-tumor tissue. In addition, our findings showed that miR-429 level was significantly associated with clinicoplathological features and prognosis of patients with CRC. Moreover, our findings showed that miR-429 exerted oncogenic effect by directly targeting HOXA5, a transcription factor of HOX families that is involved in the development and progression of CRC. PMID- 28337373 TI - Heparanase promotes radiation resistance of cervical cancer by upregulating hypoxia inducible factor 1. AB - Heparanase (HPSE1) is elevated in various types of cancers including cervical cancer, and correlated with poor prognosis. Current study is to investigate the effects of HPSE1 on radiation response in cervical cancer. Colony formation assays after radiation were performed to compare the radiation response among control, HPSE1 knockdown and HPSE1 overexpression HeLa cells. The mRNA and protein levels of HIF1, bFGF and VEGF were measured as indicators for the activity of HIF1 pathway. Xenograft mouse model were used to study the HPSE1 radiation regulator effects in vivo. Microvessel densities (MVD) were measured in xenograft tumor samples. The survival fractions were significantly lower in HPSE1 knockdown cells and higher in HPSE1 overexpression cells compared with control cells. The mRNA and protein levels of HIF1, VEGF and bFGF are decreased in HPSE1 knockdown cells and increased in HPSE1 overexpression cells. HIF1 inhibition eliminated the radiation protection effects by HPSE1 overexpression. Our results demonstrate HPSE1 is an important regulator of radiation response both in vivo and in vitro. Further studies are warranted to determine the underlie mechanism of how HPSE1 regulate HIF1 activity and the clinical effects of HPSE1 inhibitors in cervical cancer. PMID- 28337376 TI - Curcumin derivative WZ35 efficiently suppresses colon cancer progression through inducing ROS production and ER stress-dependent apoptosis. AB - Colon cancer is characterized by its fast progression and poor prognosis, and novel agents of treating colon cancer are urgently needed. WZ35, a synthetic curcumin derivative, has been reported to exhibit promising antitumor activity. Here, we investigated the in vitro and in vivo activities of WZ35 and explored the underlying mechanisms in colon cancer cell lines. WZ35 treatment significantly decreased the cell viability associated with G2/M cell cycle arrest and apoptosis induction in colon cancer cell lines. We also show that WZ35 is highly effective in inhibiting tumor growth in a CT26 xenograft mouse model. Mechanistically, WZ35 treatment significantly induced reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress in CT26 cells. Abrogation of ROS production by N-acetylcysteine (NAC) co-treatment almost totally reversed the WZ35-induced cell apoptosis and ER stress activation. Inhibition of p-PERK by GSK2606414 can significantly reverse WZ35-induced cell apoptosis in CT26 cells. Taken together, the curcumin derivative WZ35 exhibited anti-tumor effects in colon cancer cells both in vitro and in vivo, via a ROS-ER stress-mediated mechanism. These findings indicate that activating ROS generation could be an important strategy for the treatment of colon cancers. PMID- 28337374 TI - Polypyrimidine Tract-Binding Protein 1 promotes proliferation, migration and invasion in clear-cell renal cell carcinoma by regulating alternative splicing of PKM. AB - Polypyrimidine Tract-Binding Protein 1 (PTBP1) is an essential RNA-binding protein that regulates diverse biological events through regulating alternative splice of mRNA. PTBP1 induces cancer-promoting splice variants and is related to tumorigenesis in several cancers. However, both the expression patterns and biological mechanisms of PTBP1 in clear-cell renal cell carcinoma (ccRCC) are unclear. We investigated PTBP1 expression in 533 ccRCC patients from TCGA and 30 ccRCC patients by immunohistochemistry, and found that PTBP1 expression levels were significantly increased in ccRCC tissues and that high PTBP1 expression was closely correlated with advanced tumor stage, AJCC stage and poor prognosis. Cell biological assays with siRNA-mediated knockdown and lentivirus vector-mediated over-expression demonstrated that PTBP1 promoted proliferation, migration and invasion in ccRCC cells in vitro. Furthermore, PTBP1 increased the transformation from pyruvate kinase muscle 1 (PKM1) to PKM2. Knockdown of PKM2 mainly abolished PTBP1-induced proliferation, migration and invasion in ccRCC cells in vitro. In conclusion, our study indicates that PTBP1 plays a tumorigenic role in ccRCC by mediating PKM2 alternative splicing and it may be a potential prognostic marker and a promising target for treatment of ccRCC. PMID- 28337375 TI - HMGA2 regulates CD44 expression to promote gastric cancer cell motility and sphere formation. AB - High mobility group AT-hook 2 (HMGA2) is a transcriptional modulator that mediates motility and self-renewal in cancer stem cells. Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. GC contains a population of stem-like cells that promote tumor invasion and resistance to therapy. In the current study, we investigated the expression of HMGA2 and the cancer stem cell marker CD44 in 200 GC samples and found that HMGA2 and CD44 were significantly associated with distant metastasis, histological differentiation and poor prognosis in GC patients. Positive clinical correlations of HMGA2 with CD44 were also observed in tissue sections. In vitro, overexpression of HMGA2 promoted GC sphere formation and migration in MKN74/MKN28 cells, whereas downregulation of HMGA2 decreased GC sphere formation and migration in MKN45/MGC803 cells. In addition, western blot and immunofluorescent analyses showed that HMGA2 increased the expression of the stem cell markers CD44, ALDH1, Sox2, and Oct4 and the EMT-related factors Snail and beta-catenin. In a xenograft mouse model, overexpression of HMGA2 promoted tumor growth. Further immunohistochemical (IHC) analysis showed that HMGA2 increased the expression of CD44 and beta-catenin, resulting in the promotion of tumor growth. Taken together, our findings indicate that HMGA2 promotes GC cancer stem cell induction and cell motility by regulating the expression of CD44. Therefore, targeting HMGA2 in GC may be therapeutically beneficial. PMID- 28337378 TI - In vivo growth and responses to treatment of renal cell carcinoma in different environments. AB - Renal cell carcinoma is the most common type of kidney cancer in adults and is associated with poor prognosis. The hydrodynamic cell delivery technique was employed in this study to establish tumor growth in mouse lung, liver and kidneys. We demonstrate that RencaLuc cells exhibit different growth rates and responses to the cancer treatment of 5-florouracil and cytokine gene therapy when growing in different organs. The tumor growth rate was faster in the kidneys compared to that in the lung and liver. The liver is the second-best organ in support of tumor growth. Tumors in the liver and lung respond to 5-florouracil treatment but are less responsive in the kidneys. IL-12 gene therapy resulted in whole-body tumor suppression and prolonged animal survival. IFN-beta gene therapy was effective in suppressing tumor growth in the liver but not effective for those in the lung and kidneys. These results suggest that kidney cancer cells, once metastasized in different organs, show different growth patterns and respond differently to treatment. Our data also imply that an animal model with multi organ tumor growth is critical for development of a new strategy for treatment of tumors when metastasis is suspected. At the same time, the results also provide direct evidence in support of the usefulness of the hydrodynamic tail vein injection as a tool for establishment of tumor growth in the lung, liver and kidneys. PMID- 28337377 TI - The E3 ubiquitin ligase CHIP/miR-92b/PTEN regulatory network contributes to tumorigenesis of glioblastoma. AB - Glioblastoma (GBM) is the most frequent, aggressive and fatal tumor in the central nervous system, while PTEN signaling is frequently deregulated in human GBM. We previously reported the up-regulation of the carboxyl terminal of Hsp70 interacting protein (CHIP) in GBM, however, the causal link between its dysregulation and tumorigenesis has not been established. Using miRNA microarrays and quantitative RT-PCR (qRT-PCR), we found activation of CHIP leads to increased transcription of miR-92b. Further studies in T98G and LN229 cells showed overexpression of miR-92b elicited reduction of PTEN and efficiently rescued glioma development in CHIP knock-down cells. The core pathway, PI3K/Akt pathway, was then upregulated, which promoted GBM cell proliferation. Meanwhile, genetic ablation of miR-92b could restore PTEN expression and inhibit glioma growth. These data demonstrate that the CHIP/miR-92b/PTEN axis serves as a new mechanism underlying GBM tumorigenesis, providing potential new therapeutic targets. PMID- 28337379 TI - Long intergenic non-coding RNA 00152 promotes renal cell carcinoma progression by epigenetically suppressing P16 and negatively regulates miR-205. AB - Long non-coding RNAs (lncRNAs) have been reported to play important roles in the tumorigenesis and development of several human cancers. Long intergenic non coding RNA 152 (LINC00152) is significantly up-regulated in some solid tumors. However, the role of LINC00152 in the pathogenesis and development of renal cell carcinoma (RCC) remains largely unclear. In the study, we showed that LINC00152 expression was up-regulated in RCC tissues compared with adjacent normal tissues and revealed that LINC00152 expression was positively correlated with lymph node metastasis, higher TNM stage, and poor over survival (OS) time in RCC patients. Furthermore, knockdown of LINC00152 inhibited RCC cell proliferation and S phase cell proportion in vitro. Mechanistically, RNA immunoprecipitation (RIP) and Chromatin immunoprecipitation (ChIP) verified that LINC00152 bound to Enhancer of zeste homolog 2 (EZH2), LSD1 and histone H3 at lysine 27 (H3K27me3) and epigenetically suppressing P16 expression. In addition, LINC00152 expression was negatively correlated with miR-205 in RCC and luciferase reporter assays demonstrated that miR-205 was a target of LINC00152. These findings suggested that LINC00152 may contribute to RCC progression by epigenetically repressing P16 expression and interacted with miR-205. Thus, LINC00152 acted as a novel prognostic marker and a potential therapeutic target for RCC. PMID- 28337380 TI - MicroRNA-122 inhibits proliferation and invasion in gastric cancer by targeting CREB1. AB - MicroRNA-122 (miR-122) has been implicated in tumor development and progression in various types of cancers. However, the biological function and regulatory mechanisms of miR-122 in gastric cancer (GC) remain largely unknown. We aimed to determine the biological role and underlying mechanism of miR-122 in GC. Real time quantitative RT-PCR (qRT-PCR) was performed to detect the expression of miR 122 in GC tissues and cell lines. CCK8, wound healing, and transwell assays were conducted to determine the effect of miR-122 on cell proliferation, migration, and invasion, respectively. Target molecules were identified by luciferase activity, quantitative RT-PCR, and western blotting. We found that miR-122 expression was significantly decreased in both GC tissues and cell lines and that reduced expression was significantly associated with aggressive clinicopathological features in patients. We also found that overexpression of miR-122 markedly inhibited proliferation, migration, and invasion in GC cell lines. In addition, cAMP responsive element binding protein 1 (CREB1) was identified as a direct target of miR-122, and its expression was negatively correlated with miR-122 expression in GC tissues (r = -0.711, P < 0.001). CREB1overexpression rescued the suppressive effect of miR-122 on GC cell proliferation, migration, and invasion. Moreover, we demonstrated that miR-122 inhibited GC tumorigenesis in vivo by repressing CREB1 expression. These findings suggest that miR-122 might function as a tumor suppressor in GC and could serve as a promising candidate for therapeutic applications regarding GC treatment. PMID- 28337381 TI - HLA-E inhibitor enhances the killing of neuroblastoma stem cells by co-cultured dendritic cells and cytokine-induced killer cells loaded with membrane-based microparticles. AB - Neuroblastoma stem cells (NSCs) can cause drug resistance and tumor recurrence. This study aimed to enhance the lytic effect of dendritic cells (DCs) co-cultured with cytokine-induced killer (CIK) cells. NSCs were obtained by suspension culture, and DC-CIK cells were loaded with extracted NSC membrane-based microparticles (MMPs) before evaluating the lytic effect of DC-CIK cells on NSCs. After inhibiting the function or expression of human leukocyte antigen-E (HLA-E) in NSCs by anti-HLA-E monoclonal antibody or siRNA, the DC-CIK cell lytic effect on NSCs was re-assessed. NSC nestin expression was high, but glial fibrillary acid protein expression and class IIIbeta-tubulin-1 expression were low. Moreover, NSCs exhibited strong tumorigenic ability in nude mice. Loading DCs with NSC-derived MMPs induced the differentiation of DCs and CIK cells and enhanced the killing of NSCs by DC-CIK cells. Inhibiting the function or expression of HLA-E in NSCs further enhanced the cytolytic capability of DC-CIK cells loaded with NSC-derived MMPs. HLA-E inhibitor can enhance the killing of NSC by DC-CIK cells loaded with NSC-derived MMPs. PMID- 28337382 TI - A new T staging system for nasopharyngeal carcinoma based on intensity-modulated radiation therapy: results from a prospective multicentric clinical study. AB - PURPOSE: This prospective multicentric study aimed to establish a new clinical T staging standard for nasopharyngeal carcinoma (NPC) based on intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: Between January 2006 and December 2009, four hundred and ninety-two NPC patients undergoing IMRT were staged according to the seventh edition of the UICC/AJCC staging system. The Kaplan Meier method was used to calculate survival rates, and the log-rank test was used to compare survival differences. RESULTS: The 5-year overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS), and distant metastasis-free survival (DMSF) rates were 80.5%, 78.6%, 94.1%, and 84.3%, respectively. Univariate and multivariate analyses showed that the invasion of the nasal cavity, parapharyngeal space, oropharynx, skull base, internal pterygoid muscle, external pterygoid muscle, paranasal sinus, infratemporal fossa, orbit, cranial nerves, cavernous sinus, and intracalvarium were independent prognostic factors (P<0.05). According to the results of risk variety and survival curves, we suggest that the new T staging system for NPC based on magnetic resonance imaging and intensity modulated radiation therapy can be classified as T1 (nasopharynx, nasal cavity, parapharyngeal space, oropharynx, skull base and internal pterygoid muscle) and T2 (external pterygoid muscle, paranasal sinus, infratemporal fossa, orbit, cranial nerves, cavernous sinus and intracalvarium). Compared to the seventh edition of UICC/AJCC staging system, our new recommended staging system performs better in risk difference and distribution balance. Furthermore, the differences between the substages of 5 year curves of LRFS, DMFS and OS were all statistically significant in our new recommended staging system. CONCLUSIONS: Our new recommended staging system is more adaptable to IMRT and can predict the prognosis of NPC patient in a more objective and accurate manner. PMID- 28337383 TI - Pancreatic cancer screening in different risk individuals with family history of pancreatic cancer-a prospective cohort study in Taiwan. AB - Pancreatic cancer (PC) is usually diagnosed at advanced stage. Our aim was to investigate the risk of malignant and premalignant pancreatic lesions in individuals with family history of PC. Individuals at risk of PC were enrolled prospectively in a screening program in Taiwan. All risk individuals received genetic testing of cationic trypsinogen (PRSS1) gene and the serine protease inhibitor Kazal type 1 (SPINK1) gene. They were stratified into three risk groups (high, moderate, and low) based on the family history and genetic testing. Magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatogram (MRCP) were performed in all screened individuals. A total of three hundred and three risk individuals in 165 families were enrolled with the mean age of 51.1 years, 38.3% of whom were male. A total of 24 of 303 (7.9%) screened individuals had the PRSS1 mutation, and 7/234 (0.3%) had the SPINK1 mutation. Nineteen (6.3%) risk individuals had pancreatic pathology including seven with pancreatic cancer, and four with pancreatic mucinous neoplasms. The earliest age of onset of PC in affected members was an independent factor associated with risk of developing PC in all risk groups. DM was associated with much-increased risk of developing PC in low and moderate risk groups (OR45.8. 95% CI. 13.82-151.64, P=0.001). Combined family history of non-PC malignancy in the family in the low-risk individual was associated with abnormal findings on MRI (OR8.4, 95% CI 3.29-21.88, P < 0.0001). There was no any complication of screening. In summary, pancreatic cancer screening may benefit in risk individuals with family history of pancreatic cancer in our population. The diagnostic yield is similar to prior studies. MRCP as initial screening modality is safe and effective. Future study will be needed to tailor PC screening strategy in different risk populations. PMID- 28337384 TI - Topoisomerase I (Top1): a major target of FL118 for its antitumor efficacy or mainly involved in its side effects of hematopoietic toxicity? AB - FL118 is a novel camptothecin (CPT) analogue that possesses exceptional antitumor efficacy in human tumor animal models. To date, two CPT analogues, irinotecan and topotecan, have been approved by the FDA for cancer treatment. FL118 exhibits superior antitumor activity over irinotecan and topotecan, and effectively overcomes the irinotecan- or topotecan-resistant human tumors in animal models. Accordingly, FL118 selectively inhibits the expression of multiple cancer associated proteins (survivin, Mcl-1, XIAP, cIAP2, MdmX). However, FL118 has hematopoietic toxicity similar to irinotecan and topotecan, suggesting that FL118's hematopoietic toxicity may share a mechanism similar to irinotecan and topotecan. It is known that CPTs including irinotecan, SN-38 (active metabolite of irinotecan) and topotecan are topoisomerase I (Top1) inhibitors. However, the evidence from our studies failed to reveal that FL118 is a better Top1 inhibitor than SN-38. It was documented that Top1 expression level is positively associated with CPTs' sensitivity. Low Top1 expression links to CPTs' resistance. In contrast to these findings, we found that human colorectal tumor sensitivity to FL118 is irrelevant to the expression level of Top1 protein. FL118 can show high antitumor efficacy in Top1-negative tumors, while Top1 highly positive tumors can exhibit FL118 resistance. This suggests that the presence of Top1 target is not critical for FL118 antitumor activity. In other words, targeting Top1 by FL118 may not play a major role for its antitumor efficacy. However, studies indicate that FL118 can bind to, and inhibit Top1 activity. This raises the possibility that inhibition of Top1 by FL118 may predominantly be involved in hematopoietic toxicity, but not in FL118 antitumor activity. In this article, we will summarize existing observations and provide our up-to-date research results to support our opinion on this important topic. PMID- 28337385 TI - Comparison of ticagrelor and high-dose clopidogrel on the platelet functions in patients with inadequate response to clopidogrel. AB - OBJECTIVE: To evaluate the effects of ticagrelor and high-dose clopidogrel on the platelet functions in patients with inadequate response to clopidogrel. METHODS: In this prospective, randomized and controlled study, patients who had been diagnosed as acute coronary syndrome (ACS) with inadequate response to clopidogrel in the Second Hospital of Hebei Medical University from July 2015 to June 2016 were enrolled. Inadequate response to clopidogrel was defined as absolute reduction of platelet aggregation rate (PAR) <30% or PAR >70%. Eligible patients were randomly assigned to two groups, the high-dose group and the ticagrelor group. Clinical information and intervention protocols were compared. The PAR of the two groups were measured at the time of baseline, the 24th hour, 72nd hour, and the 7th day after treatments, the other platelet-related parameters were measured including platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW) at the same time points. Besides, the markers of platelet activation human P-selectin (CD62P) and thromboxane A2 (TXA2) were also recorded to compare. The incidence of major adverse cardiac events (MACE) and the side effects between two groups were followed up for three months. RESULTS: A total of 74 patients were finally enrolled, 38 of whom were assigned to the ticagrelor group and the rest of them to the high-dose clopidogrel group. The baseline clinical and procedural characterists were similar. There were no significant differences in baseline levels of PAR between the two groups [(79.38+/-11.20)% vs. (73.97+/-12.74)%, P>0.05]. For both groups, the levels of PAR significantly decreased at each time point (P<0.001). Besides, the levels of PAR in ticagrelor group were lower than those in high-dose clopidogrel group at the 24th hour, 72nd hour and 7th day after treatments: [(25.92+/-10.31)% vs. (37.95+/-11.63)%, P<0.001], [(28.02+/-14.61)% vs. (30.64+/-10.73)%, P<0.001], [(37.17+/-11.11)% vs. (36.80+/-7.26)%, P<0.001]. The baseline levels of platelet related parameters were similar between the two groups (P>0.05), and there were no significant differences in the levels of PLT, PDW, and MPV at the 24th hour, 72nd hour and 7th day. It was lower in ticagrelor group than that in clopidogrel group at the 24th hour [(5.47+/-1.03) ng/ml vs. (8.02+/-1.45) ng/ml, P<0.001] while the CD62P concentrations in the two groups significantly decreased comparing to the baseline levels (P<0.001). During 3-month follow-up, the incidences of MACE and side effects were not significantly different between the two group. CONCLUSIONS: ticagrelor could further decrease levels of platelet aggression rate and CD62p compared with high-dose clopidogrel, without serious side effects. PMID- 28337386 TI - Long-term clinical outcomes of patients with rheumatoid arthritis and concomitant coronary artery disease. AB - BACKGROUND: Rheumatoid arthritis (RA) is associated with high morbidity and mortality predominately due to increased cardiovascular risk. Few reports are available regarding the management of coronary artery disease (CAD) in RA patients and the long-term clinical outcomes after coronary revascularization. METHODS AND RESULTS: All consecutive patients with RA were identified by retrospective review at a rheumatology tertiary center in Milan, Italy between 2001 and 2013. RA patients affected by significant CAD (RA-CAD+) were prospectively followed for major adverse cardiovascular and cerebrovascular events (MACCE) after percutaneous coronary revascularization (RA-PCI), coronary artery bypass grafting (RA-CABG) or medical therapy (RA-MT). Among 936 patients with RA, the presence of clinically significant CAD was found in 5.6% (53 patients, RA-CAD+). Of these, 32 patients (60%) underwent PCI (RA-PCI), 10 patients (19%) underwent CABG (RA-CABG) and 11 patients (21%) treated with MT (RA MT). After a mean follow-up of 9+/-7 years, the rate of MACCE was 56% in RA-PCI patients, 50% in RA-CABG and 27% in RA-MT patients (P=0.184). The high MACCE rate was mainly driven by repeat coronary revascularization (47%) in the RA-PCI group and high rate of strokes (30%) in RA-CABG patients. CONCLUSION: In patients with rheumatoid arthritis and concomitant coronary artery disease (RA-CAD+), we observed at long-term follow-up a high MACCE rate, predominantly in those who underwent coronary revascularization. PMID- 28337388 TI - The clinical significance of anti-mitotic spindle apparatus antibody (MSA) and anti-centromere antibody (ACA) detected in patients with small cell lung cancer (SCLC). AB - PURPOSE: The project is aimed to detect anti-mitotic spindle apparatus antibody (MSA) and anti-centromere antibody (ACA) and explore the clinical value for the diagnosis of small cell lung cancer (SCLC), providing clinical evidence for molecular studies of SCLC. METHODS: 93 SCLC patients, 208 patients with other cancers and 50 healthy controls were enrolled in this study. MSA antibodies were detected by enzyme linked immunosorbent assay (ELISA). MSA, ACA and anti nuclear antibodies (ANA) were examined by indirect immuno-fluorescence (IIF). And the results were retrospectively analyzed. RESULTS: 1 the positivity for MSA and ACA by IIF assay was respectively 36.56% and 30.11% in SCLC group, higher than in other tumor groups (P<0.01), 2 in correlative analysis, the RR (Relative Ratio) value between MSA and SCLC was as high as 12.93, 12.74, and the RR value of ACA and ANA with SCLC was respectively 4.31 and 3.48. 3 the area under ROC (Receiver operating characteristic) curve (AUC) of MSA detection for SCLC was 0.778, with medium diagnostic value. CONCLUSION: MSA and ACA might serve as a new marker for SCLC because of its high detection rate. These two markers may participate in the occurrence and development of SCLC, resulting from the highly strong risk. So, the study have some application value for early detection, clinical diagnosis and potential treatments of SCLC. PMID- 28337387 TI - Pro- and anti-inflammatory cytokines in children with malaria in Franceville, Gabon. AB - Severe Plasmodium falciparum malaria anemia (SMA) is a major cause of mortality in pediatric wards. Variations in inflammatory mediator production play an essential role in disease outcomes. Indeed, several studies have shown the involvement of pro- and anti-inflammatory cytokines such as IFN-gamma, IL-6, TNF alpha and IL-10 in malaria immunopathology. In other hand the exact role of Th17 cytokines such as IL-17, IL-22 and IL-21 in malaria remains poorly documented. Here, we investigated IFN-gamma, TNF-alpha, IL-6, IL-12, IL-10, IL-4, IL-13, IL 17, IL-22 and IL-21 circulating levels and their association with malaria anemia and parasitemia in Gabonese children. Levels of IFN-gamma (500 +/- 100.2 pg/ml), IL-6 (64 +/- 14.2 pg/ml), IL-10 (505 +/- 35 pg/ml), IL-13 (30.6 +/- 5.6 pg/ml) were significantly higher (P < 0.03) in infected children than in uninfected controls (210 +/- 20 pg/ml, 17.5 pg/ml, 50 +/- 25.9, pg/ml, 17.48 pg/ml, respectively). IFN-gamma levels were significantly lower (P = 0.04) in children with SMA (400 +/- 200 pg/ml) than in those with uncomplicated malaria (900 +/- 450 pg/ml) and higher in those with parasitemia (P = 0.019). Levels of IL-6 and IL-10 were significantly higher in children with malarial anemia (P < 0.001) and hyperparasitemia (P < 0.0001). A significant association between IL-10 levels and parasite density was observed (P < 0.00001). IL-22 levels were significantly higher (P = 0.01) in infected children (72.57 +/- 7.5 pg/ml) than in the controls (54.96 +/- 1.93 pg/ml). IL-21 levels (44.46 +/- 17.27 pg/ml) decreased with the severity of anemia (P < 0.05), whereas IL-17 levels increased in children with SMA (12.25 +/- 1.25 pg/ml) than in those with mild malaria anemia (MMA: 6.2 +/- 5.25 pg/ml, P = 0.002). Data suggest possible role of IFN-gamma in the protection against SMA and parasite clearance. However, IL-6 and IL-10 could play a role in inflammatory response and pathophysiology of severe malaria anemia. Also, the role of IL-22 and IL-17 in P. falciparum malaria infection should be investigated. PMID- 28337389 TI - Development of microsatellite markers using Illumina MiSeq sequencing to characterize Ephedra gerardiana (Ephedraceae). AB - PREMISE OF THE STUDY: Ephedragerardiana (Ephedraceae), occurring in the Himalayan ranges, is an important plant species used in Tibetan medicine. Due to the lack of molecular markers to characterize genetic diversity, knowledge for conservation and uses of E. gerardiana resources is limited; we therefore developed microsatellite markers for use in this species. METHODS AND RESULTS: Using Illumina MiSeq sequencing technology, we developed 29 polymorphic microsatellite loci suitable for E. gerardiana, of which 15 loci also showed polymorphisms in two related Ephedra species, E. saxatilis and E. monosperma. The average number of effective alleles per locus ranged from two to six. The observed and expected heterozygosity ranged from 0.23 to 0.83 and 0.44 to 0.86, respectively, in E. gerardiana populations. CONCLUSIONS: The developed 29 microsatellite markers are effective for the study of genetic structure and genetic diversity of E. gerardiana, and 15 of these markers are suitable for related Ephedra species. PMID- 28337390 TI - An rbcL reference library to aid in the identification of plant species mixtures by DNA metabarcoding. AB - PREMISE OF THE STUDY: DNA metabarcoding has broad-ranging applications in ecology, aerobiology, biosecurity, and forensics. A bioinformatics pipeline has recently been published for identification using a comprehensive database of ITS2, one of the common plant DNA barcoding markers. There is, however, no corresponding database for rbcL, the other primary marker used in plants. METHODS: Using publicly available data, we compiled a reference library of rbcL sequences and trained databases for use with UTAX and RDP classifier algorithms. We used this reference library, along with the existing bioinformatics pipeline and ITS2 reference library, to identify species in an artificial mixture of nine species of pollen. We have made this database publicly available in multiple formats, to allow use with multiple bioinformatics pipelines, now and in the future. RESULTS: Using the rbcL database, in addition to the ITS2 database, we succeeded in making species-level identifications for eight species and a family level identification of the ninth species. This is an improvement on ITS2 sequence alone. DISCUSSION: The reference library described here will assist with identification of plant species using rbcL. By making another gene region available for standard barcoding, this will increase the resolution and accuracy of identifications. PMID- 28337391 TI - An efficient field and laboratory workflow for plant phylotranscriptomic projects. AB - PREMISE OF THE STUDY: We describe a field and laboratory workflow developed for plant phylotranscriptomic projects that involves cryogenic tissue collection in the field, RNA extraction and quality control, and library preparation. We also make recommendations for sample curation. METHODS AND RESULTS: A total of 216 frozen tissue samples of Caryophyllales and other angiosperm taxa were collected from the field or botanical gardens. RNA was extracted, stranded mRNA libraries were prepared, and libraries were sequenced on Illumina HiSeq platforms. These included difficult mucilaginous tissues such as those of Cactaceae and Droseraceae. CONCLUSIONS: Our workflow is not only cost effective (ca. $270 per sample, as of August 2016, from tissue to reads) and time efficient (less than 50 h for 10-12 samples including all laboratory work and sample curation), but also has proven robust for extraction of difficult samples such as tissues containing high levels of secondary compounds. PMID- 28337392 TI - Microsatellite markers for population studies of the salt marsh species Juncus roemerianus (Juncaceae). AB - PREMISE OF THE STUDY: Juncus roemerianus (Juncaceae) is a foundational species and ecosystem engineer of salt marshes in the Gulf of Mexico. These ecosystems provide coastal flood attenuation, nurseries for important species, and other ecosystem services, but are experiencing significant decline. Nuclear microsatellite markers were developed for J. roemerianus to study genetic diversity and population structure for conservation and restoration efforts. METHODS AND RESULTS: Illumina NextSeq high-throughput sequencing was used to develop a panel of 19 polymorphic microsatellite markers that were tested across individuals from three populations on the Gulf Coast. All markers were polymorphic, with observed and expected heterozygosities ranging from 0.212 to 0.828 and from 0.362 to 0.873, respectively. Allelic richness ranged from two to 13 alleles per locus with an average of 5.737. CONCLUSIONS: The 19 microsatellite markers are useful for population studies throughout the range of J. roemerianus. Three loci cross-amplified in the related taxon J. effusus. PMID- 28337393 TI - Development and validation of EST-SSR markers for Fokienia hodginsii (Cupressaceae). AB - PREMISE OF THE STUDY: Fokienia hodginsii (Cupressaceae) is a Tertiary relict evergreen conifer of the monotypic genus Fokienia. Polymorphic microsatellite markers were developed to investigate its genetic diversity and population structure. METHODS AND RESULTS: RNA transcripts of F. hodginsii were sequenced and de novo assembled into 85,818 unigenes, and 1892 simple sequence repeat (SSR) markers were detected from the unigenes. A total of 273 expressed sequence tag SSR primer pairs were designed and tested, and 129 successfully amplified. Eleven displayed clear polymorphisms in F. hodginsii. Amplification of these polymorphic primers across three populations of F. hodginsii showed the number of alleles per locus ranged from two to seven, and the expected heterozygosity per locus varied from 0.067 to 0.847. All 11 polymorphic primers amplified in Thuja occidentalis, while 10 amplified in T. standishii, Platycladus orientalis, and Chamaecyparis obtusa. CONCLUSIONS: These microsatellite markers will be useful in exploring genetic diversity of F. hodginsii and other conifer trees. PMID- 28337395 TI - Isolation and characterization of microsatellite loci for Smilax sieboldii (Smilacaceae). AB - PREMISE OF THE STUDY: Polymorphic microsatellite markers were developed for Smilax sieboldii (Smilacaceae), a member of the S. hispida group with a biogeographic disjunction between eastern Asia and North America, to study the phylogeography and incipient speciation of this species and its close relatives. METHODS AND RESULTS: Transcriptome sequencing produced 47,628 unigenes. Seventeen loci were developed from 122 randomly selected primer pairs. Polymorphism and genetic variation were evaluated for 68 accessions representing five populations of S. sieboldii. The number of alleles per locus ranged from four to 18; the expected heterozygosity ranged from 0.59 to 0.92. Twelve loci were successfully amplified in five related species: S. scobinicaulis, S. californica, S. hispida, S. moranensis, and S. jalapensis. CONCLUSIONS: These novel expressed sequence tag derived microsatellite markers will facilitate further population genetic research of S. sieboldii and its close allies of the S. hispida group. PMID- 28337394 TI - Chloroplast microsatellite markers for Pseudotaxus chienii developed from the whole chloroplast genome of Taxus chinensis var. mairei (Taxaceae). AB - PREMISE OF THE STUDY: Pseudotaxus chienii (Taxaceae) is an old rare species endemic to China that has adapted well to ecological heterogeneity with high genetic diversity in its nuclear genome. However, the genetic variation in its chloroplast genome is unknown. METHODS AND RESULTS: Eighteen chloroplast microsatellite markers (cpSSRs) were developed from the whole chloroplast genome of Taxus chinensis var. mairei and successfully amplified in four P. chienii populations and one T. chinensis var. mairei population. Of these loci, 10 were polymorphic in P. chienii, whereas six were polymorphic in T. chinensis var. mairei. The unbiased haploid diversity per locus ranged from 0.000 to 0.641 and 0.000 to 0.545 for P. chienii and T. chinensis var. mairei, respectively. CONCLUSIONS: The 18 cpSSRs will be used to further investigate the chloroplast genetic structure and adaptive evolution in P. chienii populations. PMID- 28337396 TI - Development of a Miniature Mass Spectrometer and an Automated Detector for Sampling Explosive Materials. AB - The development of a robust ionization source using the counter-flow APCI, miniature mass spectrometer, and an automated sampling system for detecting explosives are described. These development efforts using mass spectrometry were made in order to improve the efficiencies of on-site detection in areas such as security, environmental, and industrial applications. A development team, including the author, has struggled for nearly 20 years to enhance the robustness and reduce the size of mass spectrometers to meet the requirements needed for on site applications. This article focuses on the recent results related to the detection of explosive materials where automated particle sampling using a cyclone concentrator permitted the inspection time to be successfully reduced to 3 s. PMID- 28337397 TI - Development and Application of a Brush-Spray Derived from a Calligraphy-Brush Style Synthetic Hair Pen for Use in ESI/MS. AB - The development of a novel type of a sampling/ionization kit for use in electrospray ionization/mass spectrometry is reported. Using a small calligraphy brush-style synthetic hair pen (nylon-brush), and analogous to paper-spray mass spectrometry, the analytes can be collected, elution/desorption and then ionized from the surface of the nylon-brush. The body of the kit was produced by means of a commercial 3D-printer, in which ABS (acrylonitrile butadiene styrene) was used as the starting material. Meanwhile, a small nylon-brush was embedded inside a 3D printed plastic cell, in which a solvent was supplied to rinse the brush by means of capillary action. The size and weight of the kit were 1 g and 4 cm, respectively. The kit is disposable and it has various functions, including non invasive sampling, sample-evaporation and ionization. As a result, when a type of pesticide was selected as the test sample (dimethoate; C5H12NO3PS2), the limit of detection was determined to be 0.1 MUg/mL. Collecting the pesticide from a leaf surface (lettuce) was also successful. The process for fabricating the nylon brush kit and the optimized experimental conditions are reported herein. PMID- 28337398 TI - Desorption in Mass Spectrometry. AB - In mass spectrometry, analytes must be released in the gas phase. There are two representative methods for the gasification of the condensed samples, i.e., ablation and desorption. While ablation is based on the explosion induced by the energy accumulated in the condensed matrix, desorption is a single molecular process taking place on the surface. In this paper, desorption methods for mass spectrometry developed in our laboratory: flash heating/rapid cooling, Leidenfrost phenomenon-assisted thermal desorption (LPTD), solid/solid friction, liquid/solid friction, electrospray droplet impact (EDI) ionization/desorption, and probe electrospray ionization (PESI), will be described. All the methods are concerned with the surface and interface phenomena. The concept of how to desorb less-volatility compounds from the surface will be discussed. PMID- 28337400 TI - Prototype of an Interface for Hyphenating Distillation with Gas Chromatography and Mass Spectrometry. AB - Chemical analysis of complex matrices-containing hundreds of compounds-is challenging. Two-dimensional separation techniques provide an efficient way to reduce complexity of mixtures analyzed by mass spectrometry (MS). For example, gasoline is a mixture of numerous compounds, which can be fractionated by distillation techniques. However, coupling conventional distillation with other separations as well as MS is not straightforward. We have established an automatic system for online coupling of simple microscale distillation with gas chromatography (GC) and electron ionization MS. The developed system incorporates an interface between the distillation condenser and the injector of a fused silica capillary GC column. Development of this multidimensional separation (distillation-GC-MS) was preceded by a series of preliminary off-line experiments. In the developed technique, the components with different boiling points are fractionated and instantly analyzed by GC-MS. The obtained data sets illustrate dynamics of the distillation process. An important advantage of the distillation-GC-MS technique is that raw samples can directly be analyzed without removal of the non-volatile matrix residues that could contaminate the GC injection port and the column. Distilling the samples immediately before the injection to the GC column may reduce possible matrix effects-especially in the early phase of separation, when molecules with different volatilities co-migrate. It can also reduce losses of highly volatile components (during fraction collection and transfer). The two separation steps are partly orthogonal, what can slightly increase selectivity of the entire analysis. PMID- 28337401 TI - A Rapid Approach for Fabricating Boronic Acid-Functionalized Plates for On-Probe Detection of Glycoprotein and Glycopeptide. AB - We developed a rapid and simple approach without using complex mechanical or chemical protocols to fabricate boronic acid-functionalized plates for glycoprotein or glycopeptide enrichment and mass spectrometry (MS) analysis. By coating the boronic acid-functionalized silica particles on a polydimethylsiloxane (PDMS)-coated matrix-assisted laser desorption/ionization (MALDI) plate, these particles can form a firmly monolayer of particles on PDMS membrane for sample handling without peeling off. The boronic acid particles coated PDMS plate (BP plate) was successfully applied to the enrichment of horseradish peroxidase (HRP) protein and their digested glycopeptides. PMID- 28337399 TI - Clinical Application of Ambient Ionization Mass Spectrometry. AB - Ambient ionization allows mass spectrometry analysis directly on the sample surface under atmospheric pressure with almost zero sample pretreatment. Since the development of desorption electrospray ionization (DESI) in 2004, many other ambient ionization techniques were developed. Due to their simplicity and low operation cost, rapid and on-site clinical mass spectrometry analysis becomes real. In this review, we will highlight some of the most widely used ambient ionization mass spectrometry approaches and their applications in clinical study. PMID- 28337402 TI - A Brief Review of Bioinformatics Tools for Glycosylation Analysis by Mass Spectrometry. AB - The purpose of this review is to provide updated information regarding bioinformatic software for the use in the characterization of glycosylated structures since 2013. A comprehensive review by Woodin et al.Analyst 138: 2793 2803, 2013 (ref. 1) described two main approaches that are introduced for starting researchers in this area; analysis of released glycans and the identification of glycopeptide in enzymatic digests, respectively. Complementary to that report, this review focuses on mass spectrometry related bioinformatics tools for the characterization of N-linked and O-linked glycopeptides. Specifically, it also provides information regarding automated tools that can be used for glycan profiling using mass spectrometry. PMID- 28337403 TI - An expanded conceptual framework for solution-focused management of chemical pollution in European waters. AB - BACKGROUND: This paper describes a conceptual framework for solutions-focused management of chemical contaminants built on novel and systematic approaches for identifying, quantifying and reducing risks of these substances. METHODS: The conceptual framework was developed in interaction with stakeholders representing relevant authorities and organisations responsible for managing environmental quality of water bodies. Stakeholder needs were compiled via a survey and dialogue. The content of the conceptual framework was thereafter developed with inputs from relevant scientific disciplines. RESULTS: The conceptual framework consists of four access points: Chemicals, Environment, Abatement and Society, representing different aspects and approaches to engaging in the issue of chemical contamination of surface waters. It widens the scope for assessment and management of chemicals in comparison to a traditional (mostly) perchemical risk assessment approaches by including abatement- and societal approaches as optional solutions. The solution-focused approach implies an identification of abatement- and policy options upfront in the risk assessment process. The conceptual framework was designed for use in current and future chemical pollution assessments for the aquatic environment, including the specific challenges encountered in prioritising individual chemicals and mixtures, and is applicable for the development of approaches for safe chemical management in a broader sense. The four access points of the conceptual framework are interlinked by four key topics representing the main scientific challenges that need to be addressed, i.e.: identifying and prioritising hazardous chemicals at different scales; selecting relevant and efficient abatement options; providing regulatory support for chemicals management; predicting and prioritising future chemical risks. The conceptual framework aligns current challenges in the safe production and use of chemicals. The current state of knowledge and implementation of these challenges is described. CONCLUSIONS: The use of the conceptual framework, and addressing the challenges, is intended to support: (1) forwarding sustainable use of chemicals, (2) identification of pollutants of priority concern for cost effective management, (3) the selection of optimal abatement options and (4) the development and use of optimised legal and policy instruments. PMID- 28337404 TI - Revising REACH guidance on information requirements and chemical safety assessment for engineered nanomaterials for aquatic ecotoxicity endpoints: recommendations from the EnvNano project. AB - The European Chemical Agency (ECHA) is in the process of revising its guidance documents on how to address the challenges of ecotoxicological testing of nanomaterials. In these revisions, outset is taken in the hypothesis that ecotoxicological test methods, developed for soluble chemicals, can be made applicable to nanomaterials. European Research Council project EnvNano Environmental Effects and Risk Evaluation of Engineered, which ran from 2011 to 2016, took another outset by assuming that: "The behaviour of nanoparticles in suspension is fundamentally different from that of chemicals in solution". The aim of this paper is to present the findings of the EnvNano project and through these provide the scientific background for specific recommendations on how ECHA guidance could be further improved. Key EnvNano findings such as the need to characterize dispersion and dissolution rates in stock and test media have partially been addressed in the updated guidance. However, it has to be made clear that multiple characterization methods have to be applied to describe state of dispersion and dissolution over time and for various test concentration. More detailed information is called for on the specific characterization methods and techniques available and their pros and cons. Based on findings in EnvNano, we recommend that existing algal tests are supplemented with tests where suspensions of nanomaterials are aged for 1-3 days for nanomaterials that dissolve in testing media. Likewise, for daphnia tests we suggest to supplement with tests where (a) exposure is shortened to a 3 h pulse exposure in daphnia toxicity tests with environmentally hazardous metal and metal oxide nanomaterials prone to dissolution; and (b) food abundance is three to five times higher than normal, respectively. We further suggest that the importance of considering the impact of shading in algal tests is made more detailed in the guidance and that it is specified that determination of uptake, depuration and trophic transfer of nanomaterials for each commercialized functionalization of the nanomaterials is required. Finally, as an outcome of the project a method for assessing the regulatory adequacy of ecotoxicological studies of nanomaterials is proposed. PMID- 28337406 TI - The influence of health concern on travel plans with focus on the Zika virus in 2016. AB - Tourists consider many factors, including health, when choosing travel destinations. The potential for exposure to novel or foreign diseases alone can deter travelers from selecting high-risk locations for disease transmission. The 2015-2016 Zika Virus (ZIKV) outbreak in the Americas and Caribbean prompted the World Health Organization (WHO) to declare a Public Health Emergency of International Concern. This study investigated factors that may contribute to travel avoidance to areas experiencing ZIKV transmission while also considering different levels of health concern and awareness among groups with varying demographics. An online survey was administered February 10-12, 2016 to a sample of U.S. residents (n = 964). Demographics, information about travel behaviors, and levels of health concern were collected. Ordered logit models were employed to assess the impacts of the ZIKV outbreak on travel planning. Respondents giving higher levels of attention to general health were more likely to avoid travel to areas experiencing ZIKV transmission. It is anticipated that the findings of this study may be of interest to public health officials, healthcare providers, and government officials attempting to mitigate impacts of ZIKV. Disease outbreaks in regions of the world typically frequented by vacation or leisure travelers are particularly problematic due to the increased amount of exposure to disease in an immunologically naive population that may then contribute to the outbreak through their travel plans. Avoiding travel to destinations experiencing outbreaks of disease due to health concerns may be interpreted positively by the public health community but can have negative economic consequences. PMID- 28337405 TI - Tailored algorithms for hepatocellular carcinoma surveillance: Is one-size-fits all strategy outdated? AB - PURPOSE OF REVIEW: Current clinical practice guidelines recommend regular hepatocellular carcinoma (HCC) surveillance with biannual ultrasound with or without serum alpha-fetoprotein uniformly applied to all patients with cirrhosis. However, clinical implementation of this one-size-fits-all strategy has been challenging as evidenced by very low application rate below 20% due to various reasons, including suboptimal performance of the surveillance modalities. RECENT FINDINGS: Newly emerging imaging techniques such as abbreviated MRI (AMRI) and molecular HCC risk biomarkers have increasingly become available for clinical evaluation and implementation. These technologies may have a potential to reshape HCC surveillance by enabling tailored strategies. This would involve performing optimized surveillance tests according to individual HCC risk, and allocating limited medical resources for HCC surveillance based on cost-effectiveness. SUMMARY: Tailored HCC surveillance could lead to achievement of precision HCC care and substantial improvement of the current dismal patient prognosis. PMID- 28337407 TI - Fentanyl-induced chest wall rigidity syndrome in a routine bronchoscopy. AB - Combination of sedatives such as fentanyl and midazolam during bronchoscopy is recommended by American College of Chest Physician due to its favourable drug profile. It improves patient comfort and tolerance, and is commonly given unless contraindicated. We describe a rare case of fentanyl-induced chest wall rigidity syndrome during a routine bronchoscopy with endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) in a 55 year old male presenting with a lung mass and mediastinal lymphadenopathy. This was effectively managed with neuromuscular blockade, intubation and reversal agents including naloxone. This rare complication should be effectively managed by all bronchoscopist as it carries significant mortality and morbidity if not recognised early. We review the literature on the occurrence of fentanyl-induced chest wall rigidity and its predisposing risks factors. PMID- 28337408 TI - Eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome) as a differential diagnosis of hypereosinophilic syndromes. AB - Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg Strauss syndrome, is a rare systemic disease situated between primary small vessel vasculitides associated with antineutrophil cytoplasmic antibodies (ANCAs) and hypereosinophilic syndromes (HES). Here, we present a case of EGPA in a 38 year-old male, with a previous diagnosis of asthma, who presented with fever, migratory lung infiltrates and systemic eosinophilia that was refractory to previous courses of antibiotics. This case highlights the importance of the primary care physician understanding the differential diagnosis of pulmonary eosinophilic syndromes. PMID- 28337410 TI - Damage to white matter bottlenecks contributes to language impairments after left hemispheric stroke. AB - Damage to the white matter underlying the left posterior temporal lobe leads to deficits in multiple language functions. The posterior temporal white matter may correspond to a bottleneck where both dorsal and ventral language pathways are vulnerable to simultaneous damage. Damage to a second putative white matter bottleneck in the left deep prefrontal white matter involving projections associated with ventral language pathways and thalamo-cortical projections has recently been proposed as a source of semantic deficits after stroke. Here, we first used white matter atlases to identify the previously described white matter bottlenecks in the posterior temporal and deep prefrontal white matter. We then assessed the effects of damage to each region on measures of verbal fluency, picture naming, and auditory semantic decision-making in 43 chronic left hemispheric stroke patients. Damage to the posterior temporal bottleneck predicted deficits on all tasks, while damage to the anterior bottleneck only significantly predicted deficits in verbal fluency. Importantly, the effects of damage to the bottleneck regions were not attributable to lesion volume, lesion loads on the tracts traversing the bottlenecks, or damage to nearby cortical language areas. Multivariate lesion-symptom mapping revealed additional lesion predictors of deficits. Post-hoc fiber tracking of the peak white matter lesion predictors using a publicly available tractography atlas revealed evidence consistent with the results of the bottleneck analyses. Together, our results provide support for the proposal that spatially specific white matter damage affecting bottleneck regions, particularly in the posterior temporal lobe, contributes to chronic language deficits after left hemispheric stroke. This may reflect the simultaneous disruption of signaling in dorsal and ventral language processing streams. PMID- 28337411 TI - Physiological and pathological high-frequency oscillations have distinct sleep homeostatic properties. AB - OBJECTIVE: The stage of sleep is a known modulator of high-frequency oscillations (HFOs). For instance, high amplitude slow waves during NREM sleep and the subtypes of REM sleep were shown to contribute to a better separation between physiological and pathological HFOs. This study investigated rates and spatial spread of the different HFO types (physiological and pathological ripples in the 80-250 Hz frequency band, and fast ripples above 250 Hz) depending on time spent in sleep across the different sleep cycles. METHODS: Fifteen patients with focal pharmaco-resistant epilepsy underwent one night of video-polysomnography during chronic intracranial EEG recording for presurgical epilepsy evaluation. The HFO rate and spread across the different sleep cycles were determined with an automatic HFO detector. We built models to explain the observed rate and spread based on time in sleep and other variables i.e. sleep stage, delta band and sigma band activity, and slow wave amplitude. Statistical significance of the different variables was determined by a model comparison using the Akaike information criterion. RESULTS: The rate of HFOs depends significantly on the accumulated time of sleep. As the night advanced, the rate of pathological ripples and fast ripples decreased during NREM sleep (up to 15% per hour spent in the respective sleep stages), while the rate of physiological ripples increased during REM sleep (8% per hour spent in REM sleep). Interestingly, the stage of sleep but not the sleep cycle determined the extent of spread of HFOs, showing a larger field during NREM sleep and a more restricted field during REM sleep. CONCLUSION: The different dependence with sleep time for physiological and pathological ripples is in keeping with their distinct underlying generating mechanisms. From a practical point of view, the first sleep cycle seems to be best suitable for studying HFOs in epilepsy, given that the contrast between physiological and pathological ripple rates is largest during this time. PMID- 28337409 TI - Network degeneration and dysfunction in presymptomatic C9ORF72 expansion carriers. AB - Hexanucleotide repeat expansions in C9ORF72 are the most common known genetic cause of familial and sporadic frontotemporal dementia and amyotrophic lateral sclerosis. Previous work has shown that patients with behavioral variant frontotemporal dementia due to C9ORF72 show salience and sensorimotor network disruptions comparable to those seen in sporadic behavioral variant frontotemporal dementia, but it remains unknown how early in the lifespan these and other changes in brain structure and function arise. To gain insights into this question, we compared 15 presymptomatic carriers (age 43.7 +/- 10.2 years, nine females) to matched healthy controls. We used voxel-based morphometry to assess gray matter, diffusion tensor imaging to interrogate white matter tracts, and task-free functional MRI to probe the salience, sensorimotor, default mode, and medial pulvinar thalamus-seeded networks. We further used a retrospective chart review to ascertain psychiatric histories in carriers and their non-carrier family members. Carriers showed normal cognition and behavior despite gray matter volume and brain connectivity deficits that were apparent as early as the fourth decade of life. Gray matter volume deficits were topographically similar though less severe than those in patients with behavioral variant frontotemporal dementia due to C9ORF72, with major foci in cingulate, insula, thalamus, and striatum. Reduced white matter integrity was found in the corpus callosum, cingulum bundles, corticospinal tracts, uncinate fasciculi and inferior longitudinal fasciculi. Intrinsic connectivity deficits were detected in all four networks but most prominent in salience and medial pulvinar thalamus-seeded networks. Carrier and control groups showed comparable relationships between imaging metrics and age, suggesting that deficits emerge during early adulthood. Carriers and non-carrier family members had comparable lifetime histories of psychiatric symptoms. Taken together, the findings suggest that presymptomatic C9ORF72 expansion carriers exhibit functionally compensated brain volume and connectivity deficits that are similar, though less severe, to those reported during the symptomatic phase. The early adulthood emergence of these deficits suggests that they represent aberrant network patterning during development, an early neurodegeneration prodrome, or both. PMID- 28337412 TI - Differential involvement of corticospinal tract (CST) fibers in UMN-predominant ALS patients with or without CST hyperintensity: A diffusion tensor tractography study. AB - Diagnosis of amyotrophic lateral sclerosis (ALS) depends on clinical evidence of combined upper motor neuron (UMN) and lower motor neuron (LMN) degeneration, although ALS patients can present with features predominantly of one or the other. Some UMN-predominant patients show hyperintense signal along the intracranial corticospinal tract (CST) on T2- and proton density (PD)-weighted images (ALS-CST +), and appear to have faster disease progression when compared to those without CST hyperintensity (ALS-CST -). The reason for this is unknown. We hypothesized that diffusion tensor tractography (DTT) would reveal differences in DTI abnormalities along the intracranial CST between these two patient subgroups. Clinical DTI scans were obtained at 1.5T in 14 neurologic controls and 45 ALS patients categorized into two UMN phenotypes based on clinical measures and MRI. DTT was used to quantitatively assess the CST in control and ALS groups. DTT revealed subcortical loss ('truncation') of virtual motor CST fibers (presumably) projecting from the precentral gyrus (PrG) in ALS patients but not in controls; in contrast, virtual fibers (presumably) projecting to the adjacent postcentral gyrus (PoG) were spared. No significant differences in virtual CST fiber length were observed between controls and ALS patients. However, the frequency of CST truncation was significantly higher in the ALS-CST + subgroup (9 of 21) than in the ALS-CST - subgroup (4 of 24; p = 0.049), suggesting this finding could differentiate these ALS subgroups. Also, because virtual CST truncation occurred only in the ALS patient group and not in the control group (p = 0.018), this DTT finding could prove to be a diagnostic biomarker of ALS. Significantly shorter disease duration and faster disease progression rate were observed in ALS patients with CST fiber truncation than in those without (p < 0.05). DTI metrics of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were also determined in four regions of interest (ROIs) along the CST, namely: cerebral peduncle (CP), posterior limb of internal capsule (PLIC), centrum semiovale at top of lateral ventricle (CSoLV) and subcortical to primary motor cortex (subPMC). Of note, FA values along the left hemisphere virtual CST tract were significantly different between controls and ALS-CST + patients (p < 0.05) only at the PLIC level, but not at the CSoLV or subPMC level. Also, no significant differences in FA values were observed between ALS subgroups or between control and ALS-CST - groups (p > 0.05) in any of the ROIs. In addition, comparing FA values between ALS patients with CST truncation and those without in the aforementioned four ROIs, revealed no significant differences in either hemisphere. However, visual evaluation of DTT was able to identify UMN degeneration in patients with ALS, particularly in those with a more aggressive clinical disease course and possibly different pathologic processes. PMID- 28337414 TI - Pheochromocytoma with Negative Metanephrines: A Rarity and the Significance of Dopamine Secreting Tumors. AB - We describe a case of a 25-year-old female with a dopamine secreting PPGL diagnosed retrospectively with biochemical analysis. This finding resulted in change in approach to investigation and management, given their important clinical implications. There are important differences in management of dopamine secreting PPGL compared to classical noradrenaline and adrenaline-secreting PPGL. This includes the risk of peri-operative cardiovascular collapse peri-operatively with alpha/beta blockade, risk of malignancy/recurrence, and associated genetic abnormalities. PMID- 28337413 TI - Draft genome sequence of Thermoanaerobacterium sp. strain PSU-2 isolated from thermophilic hydrogen producing reactor. AB - Thermoanaerobacterium sp. strain PSU-2 was isolated from thermophilic hydrogen producing reactor and subjected to draft genome sequencing on 454 pyrosequencing and annotated on RAST. The draft genome sequence of strain PSU-2 contains 2,552,497 bases with an estimated G + C content of 35.2%, 2555 CDS, 8 rRNAs and 57 tRNAs. The strain had a number of genes responsible for carbohydrates metabolic, amino acids and derivatives, and protein metabolism of 17.7%, 14.39% and 9.81%, respectively. Strain PSU-2 also had gene responsible for hydrogen biosynthesis as well as the genes related to Ni-Fe hydrogenase. Comparative genomic analysis indicates strain PSU-2 shares about 94% genome sequence similarity with Thermoanaerobacterium xylanolyticum LX-11. The nucleotide sequence of this draft genome was deposited into DDBJ/ENA/GenBank under the accession MSQD00000000. PMID- 28337415 TI - A modification of the constant-head permeameter to measure saturated hydraulic conductivity of highly permeable media. AB - The saturated hydraulic conductivity (Ks ) is a key characteristic of porous media, describing the rate of water flow through saturated porous media. It is an indispensable parameter in a broad range of simulation models that quantify saturated and/or unsaturated water flow. The constant-head permeameter test is a common laboratory method to determine Ks on undisturbed soil samples collected from the field. In this paper we show that the application of this conventional method may result in a biased Ks in the case of highly permeable media, such as the top layer of Sphagnum peat and gravel. Tubes in the conventional permeameter, that collect water under the sample, introduce a hydraulic head-dependent resistance for highly permeable media and result in an underestimation of Ks . We present a simple and low-budget alternative of the constant-head permeameter test that overcomes the disadvantages of conventional permeameters. The new method was successfully tested on intact highly permeable peatmoss collected from a northern peatland. *Conventional constant-head permeameters underestimate Ks of highly permeable media due to flow resistance in tubing systems*We developed the low resistance permeameter to overcome this disadvantage.*Testing of the low resistance permeameter demonstrated no systematic bias and successful application for highly permeable media. PMID- 28337416 TI - Reader's Forum. PMID- 28337417 TI - Skeletal and dentoalveolar changes after miniscrew-assisted rapid palatal expansion in young adults: A cone-beam computed tomography study. AB - OBJECTIVE: The aim of this study was to evaluate the skeletal and dentoalveolar changes after miniscrew-assisted rapid palatal expansion (MARPE) in young adults by cone-beam computed tomography (CBCT). METHODS: This retrospective study included 14 patients (mean age, 20.1 years; range, 16-26 years) with maxillary transverse deficiency treated with MARPE. Skeletal and dentoalveolar changes were evaluated using CBCT images acquired before and after expansion. Statistical analyses were performed using paired t-test or Wilcoxon signed-rank test according to normality of the data. RESULTS: The midpalatal suture was separated, and the maxilla exhibited statistically significant lateral movement (p < 0.05) after MARPE. Some of the landmarks had shifted forwards or upwards by a clinically irrelevant distance of less than 1 mm. The amount of expansion decreased in the superior direction, with values of 5.5, 3.2, 2.0, and 0.8 mm at the crown, cementoenamel junction, maxillary basal bone, and zygomatic arch levels, respectively (p < 0.05). The buccal bone thickness and height of the alveolar crest had decreased by 0.6-1.1 mm and 1.7-2.2 mm, respectively, with the premolars and molars exhibiting buccal tipping of 1.1 degrees -2.9 degrees . CONCLUSIONS: Our results indicate that MARPE is an effective method for the correction of maxillary transverse deficiency without surgery in young adults. PMID- 28337419 TI - Smile esthetics: Evaluation of long-term changes in the transverse dimension. AB - OBJECTIVE: To analyze the long-term changes in maxillary arch widths and buccal corridor ratios in orthodontic patients treated with and without premolar extractions. METHODS: The study included 53 patients who were divided into the extraction (n = 28) and nonextraction (n = 25) groups. These patients had complete orthodontic records from the pretreatment (T1), posttreatment (T2), and postretention (T3) periods. Their mean retention and postretention times were 4 years 2 months and 17 years 8 months, respectively. Dental models and smiling photographs from all three periods were digitized to compare the changes in three dental arch width measurements and three buccal corridor ratios over time between the extraction and nonextraction groups. Data were analyzed using analysis of variance tests. Post-hoc multiple comparisons were made using Bonferroni correction. RESULTS: Soft-tissue extension during smiling increased with age in both groups. The maximum dental width to smile width ratio (MDW/SW) also showed a favorable increase with treatment in both groups (p < 0.05), and remained virtually stable at T3 (p > 0.05). According to the MDW/SW ratio, the mean difference in the buccal corridor space of the two groups was 2.4 +/- 0.2% at T3. Additionally, no significant group * time interaction was found for any of the buccal corridor ratios studied. CONCLUSIONS: Premolar extractions did not negatively affect transverse maxillary arch widths and buccal corridor ratios. The long-term outcome of orthodontic treatment was comparable between the study groups. PMID- 28337418 TI - A three-dimensional photogrammetric analysis of the facial esthetics of the Miss Korea pageant contestants. AB - OBJECTIVE: The aims of this study were to measure and compare the facial dimensions of the Miss Korea pageant contestants and a selected group of women from the general population by using three-dimensional (3D) image analysis, as well as to compare various facial ratios to the golden ratio within each group. METHODS: Three-dimensional images of 52 Miss Korea pageant contestants (MK group) and 41 young female adults selected from the general population (GP group) were acquired. Fifty-four variables and ratios were measured and calculated. Intergroup comparisons were performed using multivariate analysis of variance. RESULTS: Compared to the GP group, the MK group showed greater total facial height and eye width, lesser lower-facial height, and lesser facial, lower facial, and nasal widths. Moreover, compared to the GP group, the MK group had more protruded noses with greater nasolabial angle, greater vertical curvature of the foreheads, lesser horizontal curvature of the cheek, and lesser lower-lip-and chin volume. CONCLUSIONS: The MK group had longer faces but smaller lower lips and chins than did the GP group. The golden ratio was not matching the current facial esthetic standards. These data might be beneficial for treatment planning of patients undergoing orthognathic and plastic surgeries. PMID- 28337420 TI - Effect of frontal facial type and sex on preferred chin projection. AB - OBJECTIVE: To investigate the effects of frontal facial type (FFT) and sex on preferred chin projection (CP) in three-dimensional (3D) facial images. METHODS: Six 3D facial images were acquired using a 3D facial scanner (euryprosopic [Eury FFT], mesoprosopic [Meso-FFT], and leptoprosopic [Lepto-FFT] for each sex). After normal CP in each 3D facial image was set to 10 degrees of the facial profile angle (glabella-subnasale-pogonion), CPs were morphed by gradations of 2 degrees from normal (moderately protrusive [6 degrees ], slightly protrusive [8 degrees ], slightly retrusive [12 degrees ], and moderately retrusive [14 degrees ]). Seventy-five dental students (48 men and 27 women) were asked to rate the CPs (6 degrees , 8 degrees , 10 degrees , 12 degrees , and 14 degrees ) from the most to least preferred in each 3D image. Statistical analyses included the Kolmogorov Smirnov test, Kruskal-Wallis test, and Bonferroni correction. RESULTS: No significant difference was observed in the distribution of preferred CP in the same FFT between male and female evaluators. In Meso-FFT, the normal CP was the most preferred without any sex difference. However, in Eury-FFT, the slightly protrusive CP was favored in male 3D images, but the normal CP was preferred in female 3D images. In Lepto-FFT, the normal CP was favored in male 3D images, whereas the slightly retrusive CP was favored in female 3D images. The mean preferred CP angle differed significantly according to FFT (Eury-FFT: male, 8.7 degrees , female, 9.9 degrees ; Meso-FFT: male, 9.8 degrees , female, 10.7 degrees ; Lepto-FFT: male, 10.8 degrees , female, 11.4 degrees ; p < 0.001). CONCLUSIONS: Our findings might serve as guidelines for setting the preferred CP according to FFT and sex. PMID- 28337421 TI - Zygomatic miniplates for skeletal anchorage in orthopedic correction of Class III malocclusion: A controlled clinical trial. AB - OBJECTIVE: To evaluate the effects of facemask therapy, which was anchored from the zygomatic buttresses of the maxilla by using two miniplates, in skeletal Class III patients with maxillary deficiency. METHODS: Eighteen skeletal Class III patients (10 girls and 8 boys; mean age, 11.4 +/- 1.28 years) with maxillary deficiency were treated using miniplate-anchored facemasks, and their outcomes were compared with those of a Class III control group (9 girls and 9 boys; mean age, 10.6 +/- 1.12 years). Two I-shaped miniplates were placed on the right and left zygomatic buttresses of the maxilla, and a facemask was applied with a 400 g force per side. Intragroup comparisons were made using the Wilcoxon test, and intergroup comparisons were made using the Mann-Whitney U-test (p < 0.05). RESULTS: In the treatment group, the maxilla moved 3.3 mm forward, the mandible showed posterior rotation by 1.5 degrees , and the lower incisors were retroclined after treatment. These results were significantly different from those in the control group (p < 0.05). No significant anterior rotation of the palatal plane was observed after treatment. Moreover, changes in the sagittal positions of the maxillary incisors and molars were similar between the treatment and control groups. CONCLUSIONS: Skeletally anchored facemask therapy is an effective method for correcting Class III malocclusions, which also minimizes the undesired dental side effects of conventional methods in the maxilla. PMID- 28337422 TI - The combined use of computer-guided, minimally invasive, flapless corticotomy and clear aligners as a novel approach to moderate crowding: A case report. AB - The aim of this case report was to describe an innovative orthodontic treatment method that combined surgical and orthodontic techniques. The novel method was used to achieve a positive result in a case of moderate crowding by employing a computer-guided piezocision procedure followed by the use of clear aligners. A 23 year-old woman had a malocclusion with moderate crowding. Her periodontal indices, oral health-related quality of life (OHRQoL), and treatment time were evaluated. The treatment included interproximal corticotomy cuts extending through the entire thickness of the cortical layer, without a full-thickness flap reflection. This was achieved with a three-dimensionally printed surgical guide using computer-aided design and computer-aided manufacturing. Orthodontic force was applied to the teeth immediately after surgery by using clear appliances for better control of tooth movement. The total treatment time was 8 months. The periodontal indices improved after crowding correction, but the oral health impact profile showed a slight deterioration of OHRQoL during the 3 days following surgery. At the 2-year retention follow-up, the stability of treatment was excellent. The reduction in surgical time and patient discomfort, increased periodontal safety and patient acceptability, and accurate control of orthodontic movement without the risk of losing anchorage may encourage the use of this combined technique in appropriate cases. PMID- 28337423 TI - Immediate changes in the mandibular dentition after maxillary molar distalization using headgear. AB - The purpose of this study was to investigate immediate changes in the mandibular dentition after maxillary molar distalization using headgear in non-growing patients. Sixteen patients (mean age, 18.9 +/- 2.0 years) with Class II molar relationship and crowding were included in the present study. To correct the molar relationship, headgear was used for maxillary molar distalization. Cone beam computed tomography-generated half-cephalograms (CG Cephs) and dental casts were used to evaluate dental changes for each subject before and immediately after molar distalization using headgear. The mean duration that subjects wore the headgear was 6.3 months. CG Cephs showed that the first maxillary molars were distalized 4.2 +/- 1.6 mm with 9.7 degrees +/- 6.1 degrees of distal angulation. The intercanine, interpremolar, and intermolar widths of the mandible increased after maxillary molar distalization. The present study's results suggest that maxillary molar distalization using headgear induces a spontaneous response in the untreated mandibular dentition of non-growing patients. PMID- 28337424 TI - Single Institutional Experience of Stereotactic Radiosurgery Alone for First Brain Metastatic Event and Salvage of Second Brain Metastatic Event in a Community Setting with Review of the Literature. AB - PURPOSE: To document survival for patients treated with stereotactic radiosurgery (SRS) alone for brain metastases either at initial presentation or for salvage in conjunction with other known prognostic factors in a single institutional community setting with comparison to current literature. METHODS: All patients treated for brain metastases with SRS between October 2006 and October 2013 were reviewed. We identified 91 patients treated with SRS alone for first brain metastatic event (FBME) and 87 patients treated with SRS for second brain metastatic event (SBME). We excluded the 14 patients treated with SRS for both FBME and SBME to satisfy the independence assumption for comparison of groups. Patient demographics, including age, gender, primary cancer type, presence of extracranial metastases, number of brain metastases, initial site of metastases (brain vs. other), recursive partitioning analysis (RPA), and Karnofsky Performance status (KPS) were documented. RESULTS: There were no significant differences in overall survival for patients treated with SRS for FBME compared with SBME (log-rank p = 0.9347). Univariate and multivariable Cox regression modeling revealed KPS (p = 0.0003) and RPA (p = 0.0143) were the only independent prognostic factors for survival. Specifically, patients with RPA 1 had a 61% decreased risk of death compared to those with RPA 3. Patients with RPA 2 had a 33% decreased risk of death compared to those with RPA 3. The 1-year survival rate was 36.5% for patients with RPA1, 33.3% for those with RPA 2, and 17.1% for those with RPA 3. Patients with KPS 90-100 had a 62% decreased risk of death compared to those with KPS < 70. The 1-year survival rate for patients KPS 90 100, 70-80, and <70 were 60.7, 24.6, and 16.7%, respectively. CONCLUSION: No difference in survival was noted for FBME and SBME with performance status, the single most important prognostic factor following SRS. Aggressive treatment should be considered for patients with good performance status regardless if presenting with FBME or SBME. Our results are consistent with single, multi institutional, and randomized trials after literature review. PMID- 28337425 TI - Post-Prostatectomy Image-Guided Radiotherapy: The Invisible Target Concept. AB - In the era of intensity-modulated radiation therapy, image-guided radiotherapy (IGRT) appears crucial to control dose delivery and to promote dose escalation while allowing healthy tissue sparing. The place of IGRT following radical prostatectomy is poorly described in the literature. This review aims to highlight some key points on the different IGRT techniques applicable to prostatic bed radiotherapy. Furthermore, methods used to evaluate target motion and to reduce planning target volume margins will also be explored. PMID- 28337426 TI - Pathogen Identification in Suspected Cases of Pyogenic Spondylodiscitis. AB - Pyogenic spinal infection continues to represent a worldwide problem. In approximately one-third of patients with pyogenic spondylodiscitis, the infectious agent is never identified. Of the cases that lead to organismal identification, bacteria are more commonly isolated from the spine rather than fungi and parasites. This study applied universal prokaryotic 16S rRNA PCR as a rapid diagnostic tool for the detection of bacterial agents in specimens from patients suspected of pyogenic spondylodiscitis. Gram and Ziehl-Neelsen staining were used as a preliminary screening measure for microbiologic evaluation of patient samples. PCR amplification targeting 16S rRNA gene was performed on DNA extracted from 57 cases including specimens from epidural abscesses, vertebral, and disc biopsies. Positive samples were directly sequenced. MRI findings demonstrated that disc destruction and inflammation were the major imaging features of suspected pyogenic spondylodiscitis cases, as 44 cases showed such features. The most common site of infection was the lumbar spine (66.7%), followed by thoracic spine (19%), the sacroiliac joint (9.5%), and lumbar thoracic spine (4.8%) regions. A total of 21 samples amplified the 16S rRNA-PCR product. Sanger sequencing of the PCR products identified the following bacteriological agents: Mycobacterium tuberculosis (n = 9; 42.9%), Staphylococcus aureus (n = 6; 28.5%), Mycobacterium abscessus (n = 5; 23.8%), and Mycobacterium chelonae (n = 1; 4.8%). 36 samples displayed no visible 16S rRNA PCR signal, which suggested that non-bacterial infectious agents (e.g., fungi) or non infectious processes (e.g., inflammatory, or neoplastic) may be responsible for some of these cases. The L3-L4 site (23.8%) was the most frequent site of infection. Single disc/vertebral infection were observed in 9 patients (42.85%), while 12 patients (57.15%) had 2 infected adjacent vertebrae. Elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) inflammatory markers were noted in majority of the patients. In conclusion, microbiological methods and MRI findings are vital components for the proper diagnosis of pyogenic spondylodiscitis. Our findings suggest that molecular methods such as clinical application of 16S rRNA PCR and sequencing may be useful as adjunctive diagnostic tools for pyogenic spondylodiscitis. The rapid turnaround time of 16S rRNA PCR and sequencing submission and results can potentially decrease the time to diagnosis and improve the therapeutic management and outcome of these infections. Although S. aureus and M. tuberculosis were the most common causes of pyogenic spinal infections in this study, other infectious agents and non infectious etiologies should be considered. Based on study results, we advise that antibiotic therapy should be initiated after a definitive etiological diagnosis. PMID- 28337429 TI - Investigating Cardiac Motion Patterns Using Synthetic High-Resolution 3D Cardiovascular Magnetic Resonance Images and Statistical Shape Analysis. AB - Diagnosis of ventricular dysfunction in congenital heart disease is more and more based on medical imaging, which allows investigation of abnormal cardiac morphology and correlated abnormal function. Although analysis of 2D images represents the clinical standard, novel tools performing automatic processing of 3D images are becoming available, providing more detailed and comprehensive information than simple 2D morphometry. Among these, statistical shape analysis (SSA) allows a consistent and quantitative description of a population of complex shapes, as a way to detect novel biomarkers, ultimately improving diagnosis and pathology understanding. The aim of this study is to describe the implementation of a SSA method for the investigation of 3D left ventricular shape and motion patterns and to test it on a small sample of 4 congenital repaired aortic stenosis patients and 4 age-matched healthy volunteers to demonstrate its potential. The advantage of this method is the capability of analyzing subject specific motion patterns separately from the individual morphology, visually and quantitatively, as a way to identify functional abnormalities related to both dynamics and shape. Specifically, we combined 3D, high-resolution whole heart data with 2D, temporal information provided by cine cardiovascular magnetic resonance images, and we used an SSA approach to analyze 3D motion per se. Preliminary results of this pilot study showed that using this method, some differences in end-diastolic and end-systolic ventricular shapes could be captured, but it was not possible to clearly separate the two cohorts based on shape information alone. However, further analyses on ventricular motion allowed to qualitatively identify differences between the two populations. Moreover, by describing shape and motion with a small number of principal components, this method offers a fully automated process to obtain visually intuitive and numerical information on cardiac shape and motion, which could be, once validated on a larger sample size, easily integrated into the clinical workflow. To conclude, in this preliminary work, we have implemented state-of-the-art automatic segmentation and SSA methods, and we have shown how they could improve our understanding of ventricular kinetics by visually and potentially quantitatively highlighting aspects that are usually not picked up by traditional approaches. PMID- 28337428 TI - Niacin-mediated Gene Expression and Role of NiaR as a Transcriptional Repressor of niaX, nadC, and pnuC in Streptococcus pneumoniae. AB - NAD (Nicotinamide Adenine Dinucleotide) biosynthesis is vital for bacterial physiology and plays an important role in cellular metabolism. A naturally occurring vitamin B complex, niacin (nicotinic acid), is a precursor of coenzymes NAD and NADP. Here, we study the impact of niacin on global gene expression of Streptococcus pneumoniae D39 and elucidate the role of NiaR as a transcriptional regulator of niaX, nadC, and pnuC. Transcriptome comparison of the D39 wild-type grown in chemically defined medium (CDM) with 0 to 10 mM niacin revealed elevated expression of various genes, including niaX, nadC, pnuC, fba, rex, gapN, pncB, gap, adhE, and adhB2 that are putatively involved in the transport and utilization of niacin. Niacin-dependent expression of these genes is confirmed by promoter lacZ-fusion studies. Moreover, the role of transcriptional regulator NiaR in the regulation of these genes is explored by DNA microarray analysis. Our transcriptomic comparison of D39 DeltaniaR to D39 wild-type revealed that the transcriptional regulator NiaR acts as a transcriptional repressor of niaX, pnuC, and nadC. NiaR-dependent regulation of niaX, nadC, and pnuC is further confirmed by promoter lacZ-fusion studies. The putative operator site of NiaR (5' TACWRGTGTMTWKACASYTRWAW-3') in the promoter regions of niaX, nadC, and pnuC is predicted and further confirmed by promoter mutational experiments. PMID- 28337427 TI - Comparative Proteomics Analysis of Human Macrophages Infected with Virulent Mycobacterium bovis. AB - Mycobacterium bovis (M. bovis), the most common pathogens of tuberculosis (TB), is virulent to human and cattle, and transmission between cattle and humans warrants reconsideration concerning food safety and public health. Recently, efforts have begun to analyze cellular proteomic responses induced by Mycobacterium tuberculosis (M. tb). However, the underlying mechanisms by which virulent M. bovis affects human hosts are not fully understood. For the present study, we utilized a global and comparative labeling strategy of isobaric tag for relative and absolute quantitation (iTRAQ) to assess proteomic changes in the human monocyte cell line (THP-1) using a vaccine strain and two virulent strains H37Rv and M. bovis. We measured 2,032 proteins, of which 61 were significantly differentially regulated. Ingenuity Pathway Analysis was employed to investigate the canonical pathways and functional networks involved in the infection. Several pathways, most notably the phagosome maturation pathway and TNF signaling pathway, were differentially affected by virulent strain treatment, including the key proteins CCL20 and ICAM1. Our qRT-PCR results were in accordance with those obtained from iTRAQ. The key enzyme MTHFD2, which is mainly involved in metabolism pathways, as well as LAMTOR2 might be effective upon M. bovis infection. String analysis also suggested that the vacuolar protein VPS26A interacted with TBC1D9B uniquely induced by M. bovis. In this study, we have first demonstrated the application of iTRAQ to compare human protein alterations induced by virulent M. bovis infections, thus providing a conceptual understanding of mycobacteria pathogenesis within the host as well as insight into preventing and controlling TB in human and animal hosts' transmission. PMID- 28337430 TI - Improving Access to, Use of, and Outcomes from Public Health Programs: The Importance of Building and Maintaining Trust with Patients/Clients. AB - The central argument in this paper is that "public trust" is critical for developing and maintaining the health and wellbeing of individuals, communities, and societies. I argue that public health practitioners and policy makers need to take "public trust" seriously if they intend to improve both the public's health and the engagement between members of the public and public health systems. Public health practitioners implement a range of services and interventions aimed at improving health but implicit a requirement for individuals to trust the practitioners and the services/interventions, before they engage with them. I then go on to provide an overview of the theory of trust within sociology and show why it is important to understand this theory in order to promote trust in public health services. I then draw on literature in three classic areas of public health-hospitals, cancer screening, and childhood immunization-to show why trust is vital in terms of understanding and potentially improving uptake of services. The case studies in this paper reveal that public health practitioners need to understand the centrality of building and maintaining trusting relationships with patients/clients because people who distrust public health services are less likely to use them, less likely to follow advice or recommendations, and more likely to have poorer health outcomes. PMID- 28337431 TI - Enhancing an International Perspective in Public Health Teaching through Formalized University Partnerships. AB - Teaching in the field of public health needs to employ a global perspective to account for the fact that public health problems and solutions have global determinants and implications as well. International university partnerships can promote such a perspective through the strengthening of cooperation, exchange, and communication between academic institutions across national boundaries. As an example for such an academic network in the field of public health, we introduce the International Public Health Partnership-a collaboration between a university in Germany and universities in India, Turkey, and Nigeria. Formed in 2005, it facilitated the exchange of information, fostered discussion about the transferability of public health concepts, contributed to the structural development of the universities involved, and promoted an intercultural dialog through a combination of local and distance learning activities. Although well accepted by students and staff, different obstacles were encountered; these included limited external funding, scarce own financial, time and personnel resources, and diverging regulations and structures of degree programs at the partnership sites. In the present article, we share several lessons that we learned during our joint collaboration and provide recommendations for other universities that are involved in partnerships with institutions of higher education or are interested to initiate such collaborations. PMID- 28337432 TI - The Current and Future Role of Heart Rate Variability for Assessing and Training Compassion. AB - The evolution of mammalian caregiving involving hormones, such as oxytocin, vasopressin, and the myelinated vagal nerve as part of the ventral parasympathetic system, enables humans to connect, co-regulate each other's emotions and create prosociality. Compassion-based interventions draw upon a number of specific exercises and strategies to stimulate these physiological processes and create conditions of "interpersonal safeness," thereby helping people engage with, alleviate, and prevent suffering. Hence, compassion-based approaches are connected with our evolved caring motivation and attachment and our general affiliative systems that help regulate distress. Physiologically, they are connected to activity of the vagus nerve and corresponding adaptive heart rate variability (HRV). HRV is an important physiological marker for overall health, and the body-mind connection. Therefore, there is significant value of training compassion to increase HRV and training HRV to facilitate compassion. Despite the significance of compassion in alleviating and preventing suffering, there remain difficulties in its precise assessment. HRV offers a useful form of measurement to assess and train compassion. Specific examples of what exercises can facilitate HRV and how to measure HRV will be described. This paper argues that the field of compassion science needs to move toward including HRV as a primary outcome measure in its future assessment and training, due to its connection to vagal regulatory activity, and its link to overall health and well-being. PMID- 28337433 TI - Occupational Stress and Burnout among Surgeons in Fiji. AB - AIM: This study examined the levels of occupational stress and burnout among surgeons in Fiji. METHODS: A document set comprising a cover letter; a consent form; a sociodemographic and supplementary information questionnaire; the Maslach Burnout Inventory (MBI); the 12-item General Health Questionnaire (GHQ-12); the Alcohol Use Disorders Identification Test (AUDIT); and the Professional Quality of Life (ProQOL) questionnaires were provided to surgeons from three public divisional hospitals in Fiji. Thirty-six of 43 (83.7%) invited surgeons participated in the study. RESULTS: According to their MBI scores, surgeons suffered from low (10, 27.8%), moderate (23, 63.9%), and high (3, 8.3%) levels of burnout. Comparatively, 23 (63.9%) demonstrated moderate burnout according to their ProQOL scores. Substantial psychiatric morbidity was observed in 16 (44.0%) surgeons per their GHQ-12 scores. Consumption of alcohol was noted in 29 (80.6%) surgeons, and 12 (33.4%) had AUDIT scores characterizing their alcohol use in excess of low-risk guidelines or as harmful or hazardous drinking. Surgeons of Fijian nationality showed higher MBI emotional exhaustion and depersonalization scores compared with surgeons of other nationalities. Surgeons with an awareness of the availability of counseling services at their hospitals showed low AUDIT and ProQOL burnout scores. Smokers, alcohol drinkers, and kava drinkers showed higher AUDIT scores. CONCLUSION: This study highlights a level of occupational stress and burnout among surgeons in Fiji and a lack of awareness of their mental and physical well-being. The authors recommend that occupational stress and burnout intervention strategies be put in place in hospitals in Fiji. PMID- 28337434 TI - Influence of Power Delivery Timing on the Energetics and Biomechanics of Humans Wearing a Hip Exoskeleton. AB - A broad goal in the field of powered lower limb exoskeletons is to reduce the metabolic cost of walking. Ankle exoskeletons have successfully achieved this goal by correctly timing a plantarflexor torque during late stance phase. Hip exoskeletons have the potential to assist with both flexion and extension during walking gait, but the optimal timing for maximally reducing metabolic cost is unknown. The focus of our study was to determine the best assistance timing for applying hip assistance through a pneumatic exoskeleton on human subjects. Ten non-impaired subjects walked with a powered hip exoskeleton, and both hip flexion and extension assistance were separately provided at different actuation timings using a simple burst controller. The largest average across-subject reduction in metabolic cost for hip extension was at 90% of the gait cycle (just prior to heel contact) and for hip flexion was at 50% of the gait cycle; this resulted in an 8.4 and 6.1% metabolic reduction, respectively, compared to walking with the unpowered exoskeleton. However, the ideal timing for both flexion and extension assistance varied across subjects. When selecting the assistance timing that maximally reduced metabolic cost for each subject, average metabolic cost for hip extension was 10.3% lower and hip flexion was 9.7% lower than the unpowered condition. When taking into account user preference, we found that subject preference did not correlate with metabolic cost. This indicated that user feedback was a poor method of determining the most metabolically efficient assistance power timing. The findings of this study are relevant to developers of exoskeletons that have a powered hip component to assist during human walking gait. PMID- 28337435 TI - Commentary: Bioceramics and Scaffolds: A Winning Combination for Tissue Engineering. PMID- 28337437 TI - Bioengineering Approaches to Mature Human Pluripotent Stem Cell-Derived Cardiomyocytes. AB - Human pluripotent stem cell-derived cardiomyocytes (hPSC-CM) represent a potential unlimited cell supply for cardiac tissue engineering and possibly regenerative medicine applications. However, hPSC-CMs produced by current protocols are not representative of native adult human cardiomyocytes as they display immature gene expression profile, structure and function. In order to improve hPSC-CM maturity and function, various approaches have been developed, including genetic manipulations to induce gene expression, delivery of biochemical factors, such as triiodothyronine and alpha-adrenergic agonist phenylephrine, induction of cell alignment in 3D tissues, mechanical stress as a mimic of cardiac load and electrical stimulation/pacing or a combination of these. In this mini review, we discuss biomimetic strategies for the maturation for hPSC-CMs with a particular focus on electromechanical conditioning methods. PMID- 28337436 TI - The Lid Domain in Lipases: Structural and Functional Determinant of Enzymatic Properties. AB - Lipases are important industrial enzymes. Most of the lipases operate at lipid water interfaces enabled by a mobile lid domain located over the active site. Lid protects the active site and hence responsible for catalytic activity. In pure aqueous media, the lid is predominantly closed, whereas in the presence of a hydrophobic layer, it is partially opened. Hence, the lid controls the enzyme activity. In the present review, we have classified lipases into different groups based on the structure of lid domains. It has been observed that thermostable lipases contain larger lid domains with two or more helices, whereas mesophilic lipases tend to have smaller lids in the form of a loop or a helix. Recent developments in lipase engineering addressing the lid regions are critically reviewed here. After on, the dramatic changes in substrate selectivity, activity, and thermostability have been reported. Furthermore, improved computational models can now rationalize these observations by relating it to the mobility of the lid domain. In this contribution, we summarized and critically evaluated the most recent developments in experimental and computational research on lipase lids. PMID- 28337438 TI - MAGE-A Antigens and Cancer Immunotherapy. AB - MAGE-A antigens are expressed in a variety of cancers of diverse histological origin and germinal cells. Due to their relatively high tumor specificity, they represent attractive targets for active specific and adoptive cancer immunotherapies. Here, we (i) review past and ongoing clinical studies targeting these antigens, (ii) analyze advantages and disadvantages of different therapeutic approaches, and (iii) discuss possible improvements in MAGE-A specific immunotherapies. PMID- 28337439 TI - A Brief Review of Non-invasive Monitoring of Respiratory Condition for Extubated Patients with or at Risk for Obstructive Sleep Apnea after Surgery. AB - Obstructive sleep apnea (OSA) is one of the important risk factors contributing to postoperative airway complications. OSA alters the respiratory physiology and increases the sensitivity of muscle tone of the upper airway after surgery to residual anesthetic medication. In addition, the prevalence of OSA was reported to be much higher among surgical patients than the general population. Therefore, appropriate monitoring to detect early respiratory impairment in postoperative extubated patients with possible OSA is challenging. Based on the comprehensive clinical observation, several equipment have been used for monitoring the respiratory conditions of OSA patients after surgery, including the continuous pulse oximetry, capnography, photoplethysmography (PPG), and respiratory volume monitor (RVM). To date, there has been no consensus on the most suitable device as a recommended standard of care. In this review, we describe the advantages and disadvantages of some possible monitoring strategies under certain clinical conditions. According to the literature, the continuous pulse oximetry, with its high sensitivity, is still the most widely used device. It is also cost-effective and convenient to use but has low specificity and does not reflect ventilation. Capnography is the most widely used device for detection of hypoventilation, but it may not provide reliable data for extubated patients. Even normal capnography cannot exclude the existence of hypoxia. PPG shows the state of both ventilation and oxygenation, but its sensitivity needs further improvement. RVM provides real time detection of hypoventilation, quantitative precise demonstration of respiratory rate, tidal volume, and MV for extubated patients, but no reflection of oxygenation. Altogether, the sole use of any of these devices is not ideal for monitoring of extubated patients with or at risk for OSA after surgery. However, we expect that the combined use of continuous pulse oximetry and RVM may be promising for these patients due to their complementary function, which need further study. PMID- 28337440 TI - Rabies Control: Could Innovative Financing Break the Deadlock? AB - The neglected zoonotic diseases (NZDs) have been all but eradicated in wealthier countries but remain major causes of ill-health and mortality in over 80 countries across Africa, Asia, and Latin America. The nature of neglect for the NZDs has been ascribed, in part, to underreporting resulting in an underestimation of their global burden that, together with a lack of advocacy, downgrades their relevance to policy-makers and funding agencies. While this may be the case for many NZDs, for rabies this is not the case. The global burden estimates for rabies (931,600 DALYs) more than justify prioritizing rabies control building on the strong advocacy platforms, functioning at local, regional, and global levels (including the Global Alliance for Rabies Control), and commitments from WHO, OIE, and FAO. Simple effective tools for rabies control exist together with blueprints for operationalizing control, yet, despite elimination targets being set, no global affirmative action has been taken. Rabies control demands activities both in the short term and over a long period of time to achieve the desired cumulative gains. Despite the availability of effective vaccines and messaging tools, rabies will not be sustainably controlled in the near future without long-term financial commitment, particularly as disease incidence decreases and other health priorities take hold. While rabies control is usually perceived as a public good, public private partnerships could prove equally effective in addressing endemic rabies through harnessing social investment and demonstrating the cost-effectiveness of control. It is acknowledged that greater attention to navigating local realities in planning and implementation is essential to ensuring that rabies, and other neglected diseases, are controlled sustainably. In the shadows of resource and institutional limitations in the veterinary sector in low- and middle-income countries, sufficient funding is required so that top-down interventions for rabies can more explicitly engage with local project organization capacity and affected communities in the long term. Development Impact Bonds have the potential to secure the financing required to deliver effective rabies control. PMID- 28337442 TI - Intelligent Informatics in Translational Medicine 2016. PMID- 28337441 TI - Pentoxifylline Regulates Plasminogen Activator Inhibitor-1 Expression and Protein Kinase A Phosphorylation in Radiation-Induced Lung Fibrosis. AB - Purpose. Radiation-induced lung fibrosis (RILF) is a serious late complication of radiotherapy. In vitro studies have demonstrated that pentoxifylline (PTX) has suppressing effects in extracellular matrix production in fibroblasts, while the antifibrotic action of PTX alone using clinical dose is yet unexplored. Materials and Methods. We used micro-computed tomography (micro-CT) and histopathological analysis to evaluate the antifibrotic effects of PTX in a rat model of RILF. Results. Micro-CT findings showed that lung density, volume loss, and mediastinal shift are significantly increased at 16 weeks after irradiation. Simultaneously, histological analysis demonstrated thickening of alveolar walls, destruction of alveolar structures, and excessive collagen deposition in the irradiated lung. PTX treatment effectively attenuated the fibrotic changes based on both micro-CT and histopathological analyses. Western analysis also revealed increased levels of plasminogen activator inhibitor- (PAI-) 1 and fibronectin (FN) and PTX treatment reduced expression of PAI-1 and FN by restoring protein kinase A (PKA) phosphorylation but not TGF-beta/Smad in both irradiated lung tissues and epithelial cells. Conclusions. Our results demonstrate the antifibrotic effect of PTX on radiation-induced lung fibrosis and its effect on modulation of PKA and PAI-1 expression as possible antifibrotic mechanisms. PMID- 28337444 TI - Female Functional Constipation Is Associated with Overactive Bladder Symptoms and Urinary Incontinence. AB - This noninterventional cross-sectional study aims to assess the association between functional constipation (FC) and urinary symptoms in female patients with no treatment for urination and defecation. The Rome III criteria for evaluation of defecation, Overactive Bladder Symptom Score (OABSS) for evaluation of urinary symptoms, and clinical features were investigated in 145 female patients. Latent FC and moderate to severe overactive bladder (OAB) were defined on the basis of positivity for two or more of the Rome III criteria and an OABSS >= 6 with OABSS Q3 >= 2, respectively. In 60 latent FC patients, the OABSS was higher (5.0 versus 3.2, p = 0.001), and concurrent moderate to severe OAB symptoms and OAB with urinary incontinence were more frequent than those in 85 nonlatent FC patients (33.3 versus 10.6%, p = 0.001, and 31.7 versus 7.1%, p < 0.001). Multivariate analysis demonstrated that moderate to severe OAB symptoms were a significant associated factor of latent FC (odds ratio (OR) = 4.125, p = 0.005), while latent FC was the only associated factor of moderate to severe OAB and OAB with urinary incontinence (OR = 4.227, p = 0.005 and OR = 4.753, p = 0.004). In conclusion, moderate to severe OAB symptoms are correlated with FC. Moreover, FC is related to moderate to severe OAB symptoms and to OAB with urinary incontinence. PMID- 28337443 TI - Urethral Reconstruction Using Mesothelial Cell-Seeded Autogenous Granulation Tissue Tube: An Experimental Study in Male Rabbits. AB - Objective. This study was to evaluate the utility of the compound graft for tubularized urethroplasty by seeding mesothelial cells onto autogenous granulation tissue. Methods. Silastic tubes were implanted subcutaneously in 18 male rabbits, of which nine underwent omentum biopsies simultaneously for in vitro expansion of mesothelial cells. The granulation tissue covering the tubes was harvested 2 weeks after operation. Mesothelial cells were seeded onto and cocultured with the tissue for 7 days. A pendulous urethral segment of 1.5 cm was totally excised. Urethroplasty was performed with mesothelial cell-seeded tissue tubes in an end-to-end fashion in nine rabbits and with unseeded grafts in others as controls. Serial urethrograms were performed at 1, 2, and 6 months postoperatively. Meanwhile, the neourethra was harvested and analyzed grossly and histologically. Results. Urethrograms showed cell-seeded grafts maintained wide at each time point, while strictures formation was found in unseeded grafts. Histologically, layers of urothelium surrounded by increasingly organized smooth muscles were observed in seeded grafts. In contrast, myofibroblasts accumulation and extensive scarring occurred in unseeded grafts. Conclusions. Mesothelial cell seeded granulation tissue tube can be successfully used for tubularized urethroplasty in male rabbits. PMID- 28337445 TI - Rapid Chondrocyte Isolation for Tissue Engineering Applications: The Effect of Enzyme Concentration and Temporal Exposure on the Matrix Forming Capacity of Nasal Derived Chondrocytes. AB - Laboratory based processing and expansion to yield adequate cell numbers had been the standard in Autologous Disc Chondrocyte Transplantation (ADCT), Allogeneic Juvenile Chondrocyte Implantation (NuQu(r)), and Matrix-Induced Autologous Chondrocyte Implantation (MACI). Optimizing cell isolation is a key challenge in terms of obtaining adequate cell numbers while maintaining a vibrant cell population capable of subsequent proliferation and matrix elaboration. However, typical cell yields from a cartilage digest are highly variable between donors and based on user competency. The overall objective of this study was to optimize chondrocyte isolation from cartilaginous nasal tissue through modulation of enzyme concentration exposure (750 and 3000 U/ml) and incubation time (1 and 12 h), combined with physical agitation cycles, and to assess subsequent cell viability and matrix forming capacity. Overall, increasing enzyme exposure time was found to be more detrimental than collagenase concentration for subsequent viability, proliferation, and matrix forming capacity (sGAG and collagen) of these cells resulting in nonuniform cartilaginous matrix deposition. Taken together, consolidating a 3000 U/ml collagenase digest of 1 h at a ratio of 10 ml/g of cartilage tissue with physical agitation cycles can improve efficiency of chondrocyte isolation, yielding robust, more uniform matrix formation. PMID- 28337446 TI - Lack of Clinical Relevance of ANA and ASMA Positivity in Patients with Liver Transplantation without a History of Autoimmune Diseases. AB - The relevance of isolated autoimmunity elevation in orthotopic liver transplantation (OLT) patients is unknown. Our aim was to analyse how serum autoantibodies change in time and to evaluate their clinical relevance in OLT patients. Patients were invited to provide samples to evaluate ANA, AMA, ASMA, and LKM at the time of enrolment (T0), after 6 months (T6), and after 12 months (T12). We included 114 patients in the study (76% males, median age 62.5 years), finding isolated elevation of at least one serum antibody in up to 80% of them. We described fluctuating positive autoantibodies in the one year of observation, with only 45.6% of patients positive for ANA and less than 2% positive for ASMA, at all three times. Isolated elevation of tissue antibodies was not related to gender, age, HCC at transplant, early rejection, cause of transplantation, immunotherapy taken, and age at the time of the study. We did not detect a higher prevalence of positive autoimmunity in patients with signs of liver injury. ANA and ASMA evaluation in patients with liver transplantation and no history of autoimmune disease has no clinical relevance, since it varies in time and is not related to any risk factors or liver injury. Routine autoimmunity evaluation should be avoided. PMID- 28337447 TI - Genotypic Diversity of Mycobacterium tuberculosis Clinical Isolates in the Multiethnic Area of the Xinjiang Uygur Autonomous Region in China. AB - Objectives. We studied the genetic diversity of clinical isolates from patients with tuberculosis in the multiethnic area of Xinjiang autonomous region in China. A total of 311 clinical M. tuberculosis isolates were collected in 2006 and 2011 and genotyped by two genotyping methods. All isolates were grouped into 68 distinct spoligotypes using the spoligotyping method. The Beijing family was dominant, followed by T1 and CAS. MIRU-VNTR results showed that a total of 195 different VNTR types were identified. Ten of the 15 loci were highly or moderately discriminant according to their HGDI scores, and 13 loci had good discriminatory power in non-Beijing family strains, whereas only two loci had good discriminatory power in Beijing family strains. Chi-square tests demonstrated that there were no correlations between four characteristics (sex, age, type of case, and treatment history) and the Beijing family. In summary, Beijing family strains were predominant in Xinjiang, and the VNTR-15China locus set was suitable for genotyping all Xinjiang strains, but not for the Beijing family strains. Thus, these data suggested that different genotype distributions may exist in different regions; MLVA locus-sets should be adjusted accordingly, with newly added loci to increase resolution if necessary. PMID- 28337448 TI - Percutaneous Transforaminal Endoscopic Lumbar Interbody Fusion: Clinical and Radiological Results of Mean 46-Month Follow-Up. AB - Background. Spinal fusion has been shown to be the preferred surgical option to reduce pain, recover function, and increase quality of life in the treatment of a variety of lumbar spinal disorders. The main goal of the present study is to report our clinical experience and results of percutaneous transforaminal endoscopic lumbar interbody fusion (PELIF) applications using the expandable spacer in a single institution. Methods. We performed a retrospective review of 18 patients with >12-month follow-up who had been operated on PELIF using expandable spacer from 2001 to 2007. Their clinical and radiological data were collected and analyzed. Results. The mean follow-up period was 46 months. The mean DH before the surgery was 8.3 mm which improved to 11.4 mm at the early postoperative period and regressed to 9.3 mm at the last follow-up visit. The VAS B, VAS-L, and ODI scores at the last follow-up showed a 54%, 72%, and 69% improvement from the preoperative period, respectively. Conclusions. The presented PELIF technique with the expandable spacer seems to be a promising surgical technique for the treatment of a variety of lumbar spinal disorders. Conversely, radiological results including disc space subsidence make the stand alone application of the expandable spacer debatable. PMID- 28337450 TI - Scalable Data Mining Algorithms in Computational Biology and Biomedicine. PMID- 28337449 TI - Prediction of Radix Astragali Immunomodulatory Effect of CD80 Expression from Chromatograms by Quantitative Pattern-Activity Relationship. AB - The current use of a single chemical component as the representative quality control marker of herbal food supplement is inadequate. In this CD80-Quantitative Pattern-Activity-Relationship (QPAR) study, we built a bioactivity predictive model that can be applicable for complex mixtures. Through integrating the chemical fingerprinting profiles of the immunomodulating herb Radix Astragali (RA) extracts, and their related biological data of immunological marker CD80 expression on dendritic cells, a chemometric model using the Elastic Net Partial Least Square (EN-PLS) algorithm was established. The EN-PLS algorithm increased the biological predictive capability with lower value of RMSEP (11.66) and higher values of Rp2 (0.55) when compared to the standard PLS model. This CD80-QPAR platform provides a useful predictive model for unknown RA extract's bioactivities using the chemical fingerprint inputs. Furthermore, this bioactivity prediction platform facilitates identification of key bioactivity related chemical components within complex mixtures for future drug discovery and understanding of the batch-to-batch consistency for quality clinical trials. PMID- 28337451 TI - In Vitro Studies on the Degradability, Bioactivity, and Cell Differentiation of PRP/AZ31B Mg Alloys Composite Scaffold. AB - In recent years, more and more methods have been developed to improve the bioactivity of the biodegradable materials in bone tissue regeneration. In present study, we used rat mesenchymal stem cells (rMSCs) to evaluate the outcomes of Mg alloys (AZ31B, Magnesium, and Aluminum) and Platelet-rich plasma (PRP)/Mg alloys on rMSCs biocompatibility and osteogenic differentiation. Water absorption experiments indicated that both bare AZ31B and PRP/AZ31B were capable of absorbing large amounts of water. But the water absorption ratio for PRP/AZ31B was significantly higher than that for bare AZ31B. The degradability experiments implied that both samples degraded at same speed. rMSCs on the surface of AZ31B distributed more and better than those on the AZ31B scaffold. In ALP activity experiment, the activity of rMSCs on the PRP/AZ31B was markedly higher than that on the AZ31B scaffolds on the 7th day and 14th day. qRT-PCR also showed that OPN and OCN were expressed in both samples. OPN and OCN expression in PRP/AZ31B sample were higher than those in bare AZ31B samples. In summary, the in vitro study implied that AZ31B combined with PRP could remarkably improve cell seeding, attachment, proliferation, and differentiation. PMID- 28337452 TI - Teratogenic Effect of Usnic Acid from Cladonia substellata Vainio during Organogenesis. AB - Studies about toxicological potential of usnic acid are limited. This way, the vast majority of data available in the literature are related only to biological activities. This is the first study that aimed to evaluate the oral toxicity of usnic acid during the period of organogenesis. Females rats were distributed in the control groups, treated I and II, at doses of 15 and 25 mg/kg, administered by gavage during the 6 degrees to 15 degrees days of pregnancy. After 20 days the fetuses were removed and analyzed. A reduction in weight gain during pregnancy, increased resorption, reduction in the number of viable fetuses, and their body weight were observed. Morphological changes in the litter were visualized as exposure of the eye and atrophy of the limbs at the dose of 25 mg/kg. Histological analysis of the liver of the fetus showed reduction in the number of megakaryocytes between experimental groups and increase in the number of hepatocytes in a dose of 25 mg/kg. The experimental model used in this study reveals teratogenic effect of usnic acid in the period of organogenesis. Since this achievement, the importance of evaluating the toxic effects of natural substances is imperative, in order to elucidate the care in their indication as drug. PMID- 28337453 TI - miR-373-3p Targets DKK1 to Promote EMT-Induced Metastasis via the Wnt/beta Catenin Pathway in Tongue Squamous Cell Carcinoma. AB - MicroRNAs (miRNAs) regulate gene expression and at the same time mediate tumorigenesis. miR-373-3p has diverse effects in tumors, but its role in tongue squamous cell carcinoma (TSCC) remains unknown. The purpose of this study is to determine the function of miR-373-3p in the progression of TSCC. Our results brought to light that miR-373-3p is markedly upregulated in clinical TSCC tissues compared with paired adjacent normal tissues and has significant correlation with a more aggressive TSCC phenotype in patients. Gain-of-function and loss-of function studies revealed that ectopic miR-373-3p overexpression promoted the metastasis of TSCC cells. Notably, Wnt/beta-catenin signaling was hyperactivated in TSCC cells overexpressing miR-373-3p, and this pathway was responsible for the epithelial-mesenchymal transition (EMT) induced by miR-373-3p. Furthermore, miR 373-3p directly targeted and suppressed Dickkopf-1 (DKK1), a negative regulator of the Wnt/beta-catenin signaling cascade. These results demonstrate that, by directly targeting DKK1, miR-373-3p constitutively activated Wnt/beta-catenin signaling, thus promoting the EMT-induced metastasis of TSCC. Taken together, our findings reveal a new regulatory mechanism for miR-373-3p and suggest that miR 373-3p might be a potential target in TSCC therapy. PMID- 28337454 TI - The State of the Art in Minimally Invasive Spine Surgery. PMID- 28337455 TI - Analysis of the Bacterial Communities in Two Liquors of Soy Sauce Aroma as Revealed by High-Throughput Sequencing of the 16S rRNA V4 Hypervariable Region. AB - Chinese liquor is one of the world's oldest distilled alcoholic beverages and an important commercial fermented product in China. The Chinese liquor fermentation process has three stages: making Daqu (the starter), stacking fermentation on the ground, and liquor fermentation in pits. We investigated the bacterial diversity of Maotai and Guotai Daqu and liquor fermentation using high-throughput sequencing of the V4 hypervariable region of the 16S rRNA gene. A total of 70,297 sequences were obtained from the Daqu samples and clustered into 17 phyla. The composition of the bacterial communities in the Daqu from these two soy sauce aroma-style Chinese liquors was the same, although some bacterial species changed in abundance. Between the Daqu and liquor fermentation samples, 12 bacterial phyla increased. The abundance of Lactobacillus and Pseudomonas increased in the liquor fermentation. This study has used high-throughput sequencing to provide new insights into the bacterial composition of the Chinese liquor Daqu and fermentation. Similarities in the distribution of bacteria in the soy sauce aroma style Chinese liquors Daqu suggest that the abundance of bacteria might be generally concerned to other liquor. PMID- 28337456 TI - Comparison of the Protective Effects of Individual Components of Particulated trans-Sialidase (PTCTS), PTC and TS, against High Cholesterol Diet-Induced Atherosclerosis in Rabbits. AB - Previous studies showed the presence of Mycoplasma pneumoniae (M. pneumoniae) and membrane-shed microparticles (MPs) in vulnerable atherosclerotic plaques. H&S Science and Biotechnology developed PTCTS, composed by natural particles from medicinal plants (PTC) combined with trans-Sialidase (TS), to combat MPs and Mycoplasma pneumoniae. Our aim was to determine the effects of the different components of PTCTS in a rabbit model of atherosclerosis. Rabbits were fed with high cholesterol diet for 12 weeks and treated during the last 6 weeks with either vehicle, PTC, TS, or PTCTS. Lipid profile and quantification of MPs positive for Mycoplasma pneumoniae and oxidized LDL antigens were carried out. Aortas and organs were then histologically analyzed. PTCTS reduced circulating MPs positive for Mycoplasma pneumoniae and oxidized LDL antigens, reduced the plaque area in the abdominal aorta, and caused positive remodeling of the ascendant aorta. PTC caused positive remodeling and reduced plaque area in the abdominal aorta; however, TS had a lipid lowering effect. PTCTS components combined were more effective against atherosclerosis than individual components. Our data reinforce the infectious theory of atherosclerosis and underscore the potential role of circulating MPs. Therefore, the removal of Mycoplasma-derived MPs could be a new therapeutic approach in the treatment of atherosclerosis. PMID- 28337457 TI - Screening for Tuberculosis in Health Care Workers: Experience in an Italian Teaching Hospital. AB - Health care workers (HCW) are particularly at risk of acquiring tuberculosis (TB), even in countries with low TB incidence. Therefore, TB screening in HCW is a useful prevention strategy in countries with both low and high TB incidence. Tuberculin skin test (TST) is widely used although it suffers of low specificity; on the contrary, the in vitro enzyme immunoassay tests (IGRA) show superior specificity and sensitivity but are more expensive. The present study reports the results of a three-year TB surveillance among HCW in a large teaching hospital in Rome, using TST (by standard Mantoux technique) and IGRA (by QuantiFERON-TB) as first- and second-level screening tests, respectively. Out of 2290 HCW enrolled, 141 (6.1%) had a positive TST; among them, 99 (70.2%) underwent the IGRA and 16 tested positive (16.1%). The frequency of HCW tested positive for TB seems not far from other experiences in low incidence countries. Our results confirm the higher specificity of IGRA, but, due to its higher cost, TST can be considered a good first level screening test, whose positive results should be further confirmed by IGRA before the patients undergo X-ray diagnosis and/or chemotherapy. PMID- 28337458 TI - Protein Array-Based Detection of Proteins in Kidney Tissues from Patients with Membranous Nephropathy. AB - Membranous nephropathy (MN) is an autoimmune inflammatory disease in which proteins related with plenty of biological processes play an important role. However, the role of these proteins in the pathogenesis of MN is still unclear. This study aimed to screen differential proteins in kidney tissue samples from MN patients by using protein arrays and determine the pathways involved in the pathogenesis of MN. This study first tested a quantitative protein array (QAH-INF 3) and two semiquantitative protein arrays (L-493 and L-507) with normal renal tissue and identified L-493 as the most appropriate assay to compare protein levels between MN tissues and normal control tissues. The L-493 array identified 66 differentially expressed proteins (DEPs) that may be associated with MN. The gene oncology (GO) and protein-protein interaction (PPI) analyses revealed several processes potentially involved in MN, including extracellular matrix disassembly and organization, cell adhesion, cell-cell signaling, cellular protein metabolic process, and immune response (P < 0.05). We suggest that these different pathways work together via protein signaling and result in the pathogenesis and progression of MN. PMID- 28337459 TI - Maxillofacial Prosthesis in Dentofacial Traumas: A Retrospective Clinical Study and Introduction of New Classification Method. AB - Background. Maxillofacial trauma represents a field of common interest as regards both the maxillofacial surgery and prosthodontics, especially for the functional and aesthetic stomatognathic rehabilitation. This condition necessitates relationship between maxillofacial surgeon and prosthodontist, to achieve the ultimate treatment goal. Purpose. The purpose of this study is to make predictable patients outcomes classifying their clinical data, using certain parameters and introducing a new classification method. Materials and Methods. We have chosen 7 parameters to classify the entity of the damage of these patients and to make their treatment and their prognosis predictable: number of teeth lost (T1-T4), upper/lower maxilla (U/L), alveolar/basal bone (Alv/B), gingival tissues (G), soft tissues (S), adult/child (a/c), and reconstructed patient (R). Results and Conclusions. The multidisciplinary approach and the collaboration between multiple clinical figures are therefore critical for the success of the treatment of these patients. The presence and quantification of above parameters influence the treatment protocol; patients undergo different levels of treatment depending on the measured data. The recognition of certain clinical parameters is fundamental to frame diagnosis and successful treatment planning. PMID- 28337460 TI - Caudal Epidural Block: An Updated Review of Anatomy and Techniques. AB - Caudal epidural block is a commonly used technique for surgical anesthesia in children and chronic pain management in adults. It is performed by inserting a needle through the sacral hiatus to gain entrance into the sacral epidural space. Using conventional blind technique, the failure rate of caudal epidural block in adults is high even in experienced hands. This high failure rate could be attributed to anatomic variations that make locating sacral hiatus difficult. With the advent of fluoroscopy and ultrasound in guiding needle placement, the success rate of caudal epidural block has been markedly improved. Although fluoroscopy is still considered the gold standard when performing caudal epidural injection, ultrasonography has been demonstrated to be highly effective in accurately guiding the needle entering the caudal epidural space and produce comparative treatment outcome as fluoroscopy. Except intravascular and intrathecal injection, ultrasonography could be as effective as fluoroscopy in preventing complications during caudal epidural injection. The relevant anatomy and techniques in performing the caudal epidural block will be briefly reviewed in this article. PMID- 28337461 TI - Molecular Mechanism for the Regulation of Microcystin Toxicity to Protein Phosphatase 1 by Glutathione Conjugation Pathway. AB - Glutathione (GSH) conjugation was an important pathway to regulate the toxicity of microcystins (MCs) targeted to protein phosphatases. To explore the specific molecular mechanism for GSH detoxification, two typical MC-GSHs (derived from MCLR and MCRR) were synthesized, prepared, and purified according to previous research. Then, the reduced inhibition effect for MC-GSHs on protein phosphatase 1 was verified by comparing with their original toxins. To further clarify the molecular mechanism for MC-GSHs detoxification, we evaluated the interactions between MCs/MC-GSHs and PP1 with the assistance of MOE molecule simulation. When GSH was introduced to MCs, the covalent binding (Mdha7 to Cys273), the hydrophobic interaction (Adda5 with PP1), the hydrogen bonds (especially for Lys2 Arg96 and Glu6-Tyr272), the covalent combination (between Mdha7 and Cys273), and the ion bonds (between Mn2+ and Asn124/His248/Asp64/His66) of MCLR/MCRR-PP1 complexes weakened to a certain extent, while the ion bonds between Mn2+ and His173/Asp92 residues increased. It was not difficult to find that the toxicity of MCs was closely related to the above sites/interactions and the above key information for MCs-PP1; MC-GSHs-PP1 complexes were important for clarifying the detoxification mechanism of MC-GSHs pathway. This study offers a comprehensive cognition on MCs toxicity regulation and provides valid theoretical support to control their potential risk. PMID- 28337462 TI - Time- and Dose-Dependent Effects of 17 Beta-Estradiol on Short-Term, Real-Time Proliferation and Gene Expression in Porcine Granulosa Cells. AB - The key mechanisms responsible for achievement of full reproductive and developmental capability in mammals are the differentiation and transformation of granulosa cells (GCs) during folliculogenesis, oogenesis, and oocyte maturation. Although the role of 17 beta-estradiol (E2) in ovarian activity is widely known, its effect on proliferative capacity, gap junction connection (GJC) formation, and GCs-luteal cells transformation requires further research. Therefore, the goal of this study was to assess the real-time proliferative activity of porcine GCs in vitro in relation to connexin (Cx), luteinizing hormone receptor (LHR), follicle stimulating hormone receptor (FSHR), and aromatase (CYP19A1) expression during short-term (168 h) primary culture. The cultured GCs were exposed to acute (at 96 h of culture) and/or prolonged (between 0 and 168 h of culture) administration of 1.8 and 3.6 MUM E2. The relative abundance of Cx36, Cx37, Cx40, Cx43, LHR, FSHR, and CYP19A1 mRNA was measured. We conclude that the proliferation capability of GCs in vitro is substantially associated with expression of Cxs, LHR, FSHR, and CYP19A1. Furthermore, the GC-luteal cell transformation in vitro may be significantly accompanied by the proliferative activity of GCs in pigs. PMID- 28337464 TI - Obesity, age, ethnicity, and clinical features of prostate cancer patients. AB - Approximately 36.5% of the U.S. adults (>= 20 years old) are obese. Obesity has been associated with type 2 diabetes mellitus, cardiovascular disease, stroke, and several types of cancer. The present study included 1788 prostate cancer patients who were treated with radical prostatectomy at the Ochsner Health System, New Orleans, Louisiana, from January, 2001 to March, 2016. The patient's medical records were retrospectively reviewed. Body mass index (BMI), age, ethnicity (Caucasians versus African Americans), clinical stage, Gleason score, and prostate-specific antigen (PSA) levels were retrieved. The relative risk of the patients was stratified into low risk and high risk groups. Associative analyses found that BMI was associated with age, clinical stage, Gleason score, but not ethnicity, PSA levels, or the relative risk in this cohort. Age was associated with ethnicity, clinical stage, Gleason score, and PSA levels, as well as the relative risk. Ethnicity was associated with Gleason score and PSA levels as well as the relative risk, but not clinical stage. These findings suggest that obesity is associated with advanced prostate cancer with stage T3 or Gleason score >= 7 diseases, and age and ethnicity are important factors that are associated with the clinical features of prostate cancer patients. PMID- 28337463 TI - Skin Tissue Engineering: Application of Adipose-Derived Stem Cells. AB - Perception of the adipose tissue has changed dramatically over the last few decades. Identification of adipose-derived stem cells (ASCs) ultimately transformed paradigm of this tissue from a passive energy depot into a promising stem cell source with properties of self-renewal and multipotential differentiation. As compared to bone marrow-derived stem cells (BMSCs), ASCs are more easily accessible and their isolation yields higher amount of stem cells. Therefore, the ASCs are of high interest for stem cell-based therapies and skin tissue engineering. Currently, freshly isolated stromal vascular fraction (SVF), which may be used directly without any expansion, was also assessed to be highly effective in treating skin radiation injuries, burns, or nonhealing wounds such as diabetic ulcers. In this paper, we review the characteristics of SVF and ASCs and the efficacy of their treatment for skin injuries and disorders. PMID- 28337465 TI - Inflammatory Response and Barrier Dysfunction by Different e-Cigarette Flavoring Chemicals Identified by Gas Chromatography-Mass Spectrometry in e-Liquids and e Vapors on Human Lung Epithelial Cells and Fibroblasts. AB - Recent studies suggest that electronic cigarette (e-cig) flavors can be harmful to lung tissue by imposing oxidative stress and inflammatory responses. The potential inflammatory response by lung epithelial cells and fibroblasts exposed to e-cig flavoring chemicals in addition to other risk-anticipated flavor enhancers inhaled by e-cig users is not known. The goal of this study was to evaluate the release of the proinflammatory cytokine (interleukin-8 [IL-8]) and epithelial barrier function in response to different e-cig flavoring chemicals identified in various e-cig e-liquid flavorings and vapors by chemical characterization using gas chromatography-mass spectrometry analysis. Flavorings, such as acetoin (butter), diacetyl, pentanedione, maltol (malt), ortho-vanillin (vanilla), coumarin, and cinnamaldehyde in comparison with tumor necrosis factor alpha (TNFalpha), were used in this study. Human bronchial epithelial cells (Beas2B), human mucoepidermoid carcinoma epithelial cells (H292), and human lung fibroblasts (HFL-1) were treated with each flavoring chemical for 24 hours. The cells and conditioned media were then collected and analyzed for toxicity (viability %), lung epithelial barrier function, and proinflammatory cytokine IL 8 release. Cell viability was not significantly affected by any of the flavoring chemicals tested at a concentration of 10 MUM to 1 mM. Acetoin and diacetyl treatment induced IL-8 release in Beas2B cells. Acetoin- and pentanedione-treated HFL-1 cells produced a differential, but significant response for IL-8 release compared to controls and TNFalpha. Flavorings, such as ortho-vanillin and maltol, induced IL-8 release in Beas2B cells, but not in H292 cells. Of all the flavoring chemicals tested, acetoin and maltol were more potent inducers of IL-8 release than TNFalpha in Beas2B and HFL-1 cells. Flavoring chemicals rapidly impaired epithelial barrier function in human bronchial epithelial cells (16-HBE) as measured by electric cell surface impedance sensing. Our findings suggest that some of the e-cig liquids/aerosols containing flavoring chemicals can cause significant loss of epithelial barrier function and proinflammatory response in lung cells. PMID- 28337467 TI - The data set describing cognitive performance after varenicline administration in a 3-choice serial reaction time task in rats. AB - The data shows attentional function, impulsivity, motivation, motor function, and motor activity in rats treated with varenicline, a stop-smoking aid. The data also shows these parameters in rats treated with varenicline after acute/chronic nicotine administration. Our interpretation and discussion of these data were described in the article "Varenicline Provokes Impulsive Action by Stimulating alpha4beta2 Nicotinic Acetylcholine Receptors in the Infralimbic Cortex in a Nicotine Exposure Status-Dependent Manner" (Ohmura et al., 2017) [1]. PMID- 28337468 TI - Comparative analysis data of SF1 and SF2 helicases from three domains of life. AB - SF1 and SF2 helicases are important molecular motors that use the energy of ATP to unwind nucleic acids or nucleic-acid protein complexes. They are ubiquitous enzymes and found in almost all organisms sequenced to date. This article provides a comparative analysis for SF1 and SF2 helicase families from three domains of life archaea, human, bacteria. Seven families are conserved in these three representatives and includes Upf1-like, UvrD-like, Rad3-like, DEAD-box, RecQ-like. Snf2 and Ski2-like. The data highlight conservation of the helicase core motifs for each of these families. Phylogenetic analysis presented on certain protein families are essential for further studies tracing the evolutionary history of helicase families. The data supplied in this article support publication "Genome-wide identification of SF1 and SF2 helicases from archaea" (Chamieh et al., 2016) [1]. PMID- 28337466 TI - In Vitro and Ex Vivo Approaches to Evaluate Next-Generation Tobacco and Non Tobacco Products on Human Blood Platelets. AB - Human blood platelets are major hemostatic regulators in the circulation and important in the mediation of chronic inflammation and immunomodulation. They are key elements that promote cardiovascular pathogenesis that leads to atherosclerosis, thrombosis, myocardial infarction, and stroke. New information on tobacco use and platelet dysregulation shows that these highly understudied vascular cells are dysregulated by tobacco smoke. Thus, platelet function studies should be an important consideration for the evaluation of existing and next generation tobacco and non-tobacco products. Novel in vitro approaches are being sought to investigate these products and their influence on platelet function. Platelets are ideally suited for product assessment, as robust and novel in vitro translational methods are available to assess platelet function. Furthermore, the use of human biological systems has the advantage that risk predictions will better reflect the human condition. PMID- 28337469 TI - A case of autoinflammatory skin and bone disease flared by a change in osteoporosis management. PMID- 28337470 TI - Bilateral malar milia en plaque as primary presentation of discoid lupus erythematosus. PMID- 28337471 TI - Intractable pyoderma gangrenosum in a Crohn's disease patient on vedolizumab. PMID- 28337472 TI - Bullous pemphigoid localized in a primarily hemiplegic distribution. PMID- 28337473 TI - Macular lymphocytic arteritis: Clinical-pathologic correlation of a rare vasculitis. PMID- 28337474 TI - Cervical cancer prevention in El Salvador (CAPE)-An HPV testing-based demonstration project: Changing the secondary prevention paradigm in a lower middle-income country. AB - *CareHPV tests were used to compare screen-and-treat and colposcopy management.*Screen-and-treat strategy with HPV testing was found to be very cost effective.*CAPE has screened > 25,000 women in the Paracentral region.*Over 70% of screen-positive women received recommended treatment within six months.*CAPE is an example of public-private partnership resulting in paradigm change. PMID- 28337475 TI - Age at injury is associated with the long-term cognitive outcome of traumatic brain injuries. AB - INTRODUCTION: The association between age at injury (AAI) and long-term cognitive outcome of traumatic brain injuries (TBI) is debatable. METHODS: Eligible participants with a history of TBI from Alzheimer's Disease Neuroimaging Initiative were divided into a childhood TBI (cTBI) group (the AAI <= 21 years old) and an adult TBI (aTBI) group (the AAI > 21 years old). RESULTS: The cTBI group has a higher Everyday Cognition total score than the aTBI group. All perceived cognitive functions are worse for the cTBI group than for the aTBI group except memory. By contrast, the cTBI group has higher assessment scores on either the Boston Naming Test or Rey Auditory Verbal Learning Test than the aTBI group. DISCUSSION: The AAI is associated with the long-term cognitive outcomes in older adults with a history of TBI. PMID- 28337478 TI - Efficacy of single-incision needle-knife biopsy for sampling subepithelial lesions. AB - Background and study aims Single-incision needle-knife (SINK) biopsy is a diagnostic method for acquiring tissue samples for subepithelial lesions (SELs). A single linear incision is made in the overlying mucosa and tissue samples are obtained by passing conventional biopsy forceps through the opening and deep into the lesion. The aim of this study was to describe the efficacy and safety of this technique. Patients and methods Consecutive patients who underwent SINK biopsy for an upper gastrointestinal SEL between October 2013 and September 2015 were retrospectively reviewed. Results Forty-nine patients underwent 50 SINK biopsies. Sufficient sampling for a definite pathologic diagnosis was obtained in 42 (86 %) cases, with 91 % (40/44) having sufficient sample to perform immunohistochemistry when deemed clinically relevant. Of the 26 patients with prior non-diagnostic biopsies or FNA, a specific diagnosis was obtained in 85 % (22/26). There were no significant adverse events. Conclusions SINK biopsy is a safe and feasible strategy for obtaining a definitive tissue diagnosis with immunohistochemistry for SELs. PMID- 28337477 TI - Heating Has No Effect on the Net Protein Utilisation from Egg Whites in Rats. AB - Egg whites (EW) are a good source of protein; however, they are typically heated prior to consumption. Therefore, we investigated the effects of different heating conditions on the protein utilisation rate of EW. Male Sprague-Dawley rats (n = 36, 198 +/- 1 g) were divided into six groups and fed American Institute of Nutrition-76 chow containing unheated EW, soft-boiled EW, boiled EW, milk whey protein, soybean protein, or no protein over a 10-day period using pair-feeding. Urine and faeces were sampled daily beginning on day 5 to measure nitrogen content and the net protein utilisation (NPU) rate. The soybean protein group had a significantly lower level of food intake and was thus excluded from subsequent analyses. The NPU value was similar among the unheated, soft-boiled, and boiled EW groups (97.5 +/- 0.4, 96.5 +/- 0.1, and 96.5 +/- 0.7, resp.). The EW group values were significantly higher than the whey group values (90.5 +/- 1.0). These results show that EW serve as a good source of protein, irrespective of heating. PMID- 28337476 TI - Cerebrospinal fluid biomarker examination as a tool to discriminate behavioral variant frontotemporal dementia from primary psychiatric disorders. AB - INTRODUCTION: To prospectively determine the diagnostic value of cerebrospinal fluid (CSF) levels total-tau (tau) to amyloid-beta1-42 ratio (Abeta1-42) ratio (tau/Abeta1-42 ratio), phosphorylated-tau (p-tau) to tau ratio (p-tau/tau ratio), neurofilament light chain (NfL) and YKL40 in the late-onset frontal lobe syndrome, in particular for the differential diagnosis of behavioral variant frontotemporal dementia (bvFTD) versus primary psychiatric disorders (PSY). METHOD: We included patients with a multidisciplinary 2-year-follow-up diagnosis of probable/definite bvFTD (n = 22) or PSY (n = 25), who underwent a detailed neuropsychiatric clinical examination, neuropsychological test battery, and magnetic resonance imaging at baseline. In all cases, CSF was collected through lumbar puncture at baseline. We compared CSF biomarker levels between the two groups and measured the diagnostic accuracy for probable/definite bvFTD, using the follow-up diagnosis as the reference standard. RESULTS: The best discriminators between probable/definite bvFTD and PSY were the levels of CSF NfL (area under the curve [AUC] 0.93, P < .001, 95% confidence interval [CI] 0.85 1.00), p-tau/tau ratio (AUC 0.87, P < .001, 95% CI 0.77-0.97), and YKL40 (AUC 0.82, P = .001, 95% CI 0.68-0.97). The combination of these three biomarkers had a sensitivity of 91% (95% CI 66%-100%) at a specificity of 83% (95% CI 65%-95%) with an AUC of 0.94 (P < .001, 95% CI 0.87-1.00) for bvFTD. CSF tau/Abeta1-42 ratio was less accurate in differentiating between bvFTD and PSY. DISCUSSION: We found a good diagnostic accuracy for higher levels of CSF NfL and YKL40 and reduced p-tau/tau ratio in distinguishing bvFTD from PSY. We advocate the use of these CSF biomarkers as potential additional tools to neuroimaging in the diagnosis of bvFTD versus PSY. PMID- 28337479 TI - Technical feasibility of line-assisted complete closure technique for large mucosal defects after colorectal endoscopic submucosal dissection. AB - Background and study aims Complete closure of large mucosal defects after colorectal endoscopic submucosal dissection (C-ESD) is considered impossible in most cases because of the limited width of the open clip. We therefore invented a simple closure technique using clip-and-line, named "line-assisted complete closure (LACC)", and assessed its technical feasibility. Patients and methods Between January and February 2016, we performed LACC in 11 patients after C-ESD and included them in this retrospective feasibility study. Outcome measures were procedural success rate, procedure time, and post-procedural complications. Results The median size of the resected specimen was 36 mm (range 30 - 72 mm). Procedural success was achieved in 10 of 11 cases (91 %). Those 10 cases required a median of 9 endoclips (range 6 - 12) for complete closure. Median procedure time for LACC was 14 minutes (range 6 - 22). No complications were observed in any of the cases after the procedure. Conclusion LACC is a simple and feasible technique for complete closure of large mucosal defects after C-ESD. PMID- 28337480 TI - Intra-channel stent release technique for fluoroless endoscopic ultrasound-guided lumen-apposing metal stent placement: changing the paradigm. AB - Background Recently, a novel lumen-apposing fully covered self-expanding metal stent (LA-FCSEMS) mounted on an electrocautery-enhanced delivery system has been developed to perform endoscopic ultrasound (EUS)-guided transluminal drainage. From early experience, however, release of the proximal flange of the stent has mostly been done using endoscopic view guidance to ensure proper positioning. Aim We describe a new technique that we have named the Intra-Channel Stent Release Technique (ICSRT) to perform stent placement under complete EUS control, without the use of either fluoroscopic or endoscopic views. Material and methods Data on all consecutive patients who underwent EUS-guided drainage using the new ICSRT between June 2014 and April 2016 were retrospectively retrieved from two institution databases. All EUS procedures were performed by experienced endoscopists with the patient under conscious or deep sedation. The total procedure and stent deployment time, and adverse events related to stent positioning with the ICSRT were evaluated. Results One hundred consecutive patients (51 women; mean age +/- SD, 66 +/- 15.2 years, range 34 - 95) underwent EUS-guided transluminal drainage with the Hot AXIOSTM device using the new ICSRT. The procedure was technically successful in all but one patient (1 %). The mean total procedural time was 21.9 minutes (range 7 - 50), while the mean time for stent placement was 3.2 minutes (range 1 - 15). No major adverse events occurred. Discussion The ICSRT has been used to deploy the newly developed lumen-apposing FCSEMS under complete EUS guidance without fluoroscopic and/or endoscopic assistance. The technique appears to be safe and highly effective and should be learned by all interventional endosonographers in order to be able to perform drainage in all clinical scenarios. PMID- 28337481 TI - Waterjet submucosal dissection of porcine esophagus with the HybridKnife and ERBEJET 2 system: a pilot study. AB - Background and study aims Esophageal endoscopic submucosal dissection (ESD) is technically difficult because of narrow working spaces and ease of perforation due to the lack of serosa. HybridKnife is a recently developed ESD device that is combined with the high pressure waterjet ERBEJET 2 system to lift mucosa. We hypothesized that this waterjet could make submucosal dissection safer and studied this in porcine esophagus. Materials and methods Water pressures of 30 - 70 bar were tested to determine the appropriate pressure for waterjet ESD with HybridKnife (WJ-ESD) in one pig. WJ-ESD safety and completion were compared with those of conventional ESD using DualKnife (C-ESD) as a reference. Each of three virtual esophageal lesions in two pigs were resected alternatively using both methods from the lower to upper esophagus. For WJ-ESD, the submucosa, apart from hard fibrous tissues, was dissected using water pressure alone. Results Using 50 bar of water pressure resulted in the best balance between proper dissection and view-disturbing water backflow. The dissection speeds for the lower, middle, and upper esophagus were 0.2, 0.9, and 0.2 cm2/min in 50 bar WJ-ESD and 1.1, 0.5, and 1.0 cm2/min in C-ESD, respectively. Minor bleeding was frequent in WJ-ESD, but was easily stopped by electrocoagulation with the same needle. No perforation was observed in either procedure. Thermal damage to dissected tissues appeared mild, and the extent of muscle injury was lower for WJ-ESD (4, 6, and 8 %) compared with C-ESD (14, 16, and 7 %). Conclusions WJ-ESD could be completed safely for porcine esophagus with less damage to the muscle layer compared with C-ESD. PMID- 28337482 TI - Efficacy and safety of novel digital single-operator peroral cholangioscopy guided laser lithotripsy for complicated biliary stones. AB - Background/study aims Laser lithotripsy can effectively fragment complicated biliary stones, but current cholangioscopes are limited by fragility, restricted mobility or moderate visual resolution. The efficacy and safety of a new digital single-operator peroral cholangioscope to guide laser lithotripsy were evaluated. Patients and methods In this prospective single-center series, consecutive patients with complicated biliary stones, defined as impacted stones > 1.5 cm in size and wider than the more distal common bile duct, or stones that failed extraction by basket mechanical lithotripsy, underwent ERCP and SpyGlass DS peroral cholangioscope (Boston Scientific, Marlborough, United States)-guided laser lithotripsy. Stone clearance rate and incidence of adverse events were determined. Results Seventeen patients (10 men, 7 women; median age 76 years) with a median biliary stone size of 2 cm underwent predominantly holmium:yttrium aluminum garnet laser lithotripsy, achieving a 94 % stone clearance rate over 1 median procedure. Lithotripsy was performed in 8 of 17 patients due to an impacted biliary stone. The remaining patients underwent lithotripsy due to prior failure of the basket mechanical lithotripter to capture or crush their stones. Post lithotripsy, 2 patients developed cholangitis and 1 patient with underlying COPD developed respiratory distress, all resolved with conservative management. There were no hemobilia, perforations, pancreatitis nor any deaths. Conclusion SpyGlass DS peroral cholangioscopy-guided laser lithotripsy is an efficient and safe modality for management of complicated biliary stones. PMID- 28337483 TI - Pocket-creation method facilitates endoscopic submucosal dissection of colorectal laterally spreading tumors, non-granular type. AB - Background and study aims The pocket-creation method (PCM) is a novel strategy for endoscopic submucosal dissection (ESD). The aim of this study is to determine the efficacy of the PCM for colorectal laterally spreading tumors, non-granular type (LST-NG). Patients and methods The records of 126 consecutive patients with colorectal LST-NG who underwent ESD between April 2012 and July 2015 were retrospectively reviewed. Patients were divided into PCM (n = 73) and conventional method (CM) (n = 53) groups. Results The en bloc resection rate in the PCM group was significantly higher than in the CM group (100 % [73/73] vs. 92 % [49/53], P = 0.03). The en bloc resection rate with severe fibrosis was higher in the PCM group than in the CM group (100 % [3/3] vs. 60 % [3/5]). The R0 resection rate for the two groups was not statistically significantly different (93 % [68/73] vs. 91 % [48/53], P = 0.74). The perforation rate in the PCM group was lower than in the CM group although not statistically significantly less (0 % 0/73 vs. 4 % 2/53, P = 0.18). For lesions resected en bloc, dissection speed for the PCM group was significantly faster than for the CM group (median [IQR], 19 [13 -24] vs. 14 [10 - 22] mm2/min, P = 0.03). Conclusion ESD using PCM achieves a reliable and safe resection of colorectal LST-NG. PMID- 28337484 TI - First reported case of per anal endoscopic myectomy (PAEM): A novel endoscopic technique for resection of lesions with severe fibrosis in the rectum. AB - Background and study aims A 54-year-old man was diagnosed with a rectal tumor extending through the submucosal layer. The patient refused surgery and therefore endoscopic submucosal dissection (ESD) was pursued. The lesion exhibited the muscle retraction sign. After dissecting circumferentially around the fibrotic area by double tunneling method, a myotomy was performed through the internal circular muscle layer, creating a plane of dissection between the internal circular muscle layer and the external longitudinal muscle layer, and a myectomy was completed. The pathologic specimen verified T1b grade 1 sprouting adenocarcinoma with 4350 um invasion into the submucosa with negative resection margins. PMID- 28337485 TI - Safety and efficacy of minimal biliary sphincterotomy with papillary balloon dilation (m-EBS+EPBD) in patients using clopidogrel or anticoagulation. AB - Background and study aims Endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic biliary sphincterotomy (EBS) or endoscopic papillary balloon dilation (EPBD) are common techniques of biliary decompression. Potential risks include gastrointestinal hemorrhage, which can be increased by antiplatelet agents, anticoagulants (AC) and/or novel oral anticoagulants (NOACs) (ie. apixaban, dabigatran and rivaroxaban). The study aim is to evaluate the safety/efficacy of an alternative technique, minimal-EBS plus EPBD (m-EBS + EPBD), in individuals for whom clopidogrel, AC, and/or NOACs cannot be interrupted due to high cardiovascular or thromboembolic risk. Patients and methods Patients undergoing m-EBS + EPBD while taking clopidogrel and/or AC were retrospectively evaluated at two United States tertiary care centers for efficacy, GIB and procedure-related, cardiovascular and thromboembolic adverse events (AE). Results Ninety-five patients were identified [55 = clopidogrel and 45 = AC (31.1 % NOACs)]. The main indication for ERCP was choledocholithiasis (34 %). 100 % clinical improvement and 97.9 % endoscopic success were found. The incidence of AE was 5.3 %. There was a 4.2 % incidence of gastrointestinal hemorrhage (2 cases requiring endoscopic intervention). Both severe gastrointestinal hemorrhages also experienced the cases of post-ERCP pancreatitis, and 2 /3 of cholangitis (all aspirin + AC). There was 1cardiovascular event (non-ST elevation myocardial infarction), and no thromboembolic events. Conclusions Minimal-EBS + EPBD is an effective and safe therapy with an incidence of gastrointestinal hemorrhage of 4.2 %, (2.1 % requiring endoscopic intervention), for patients on clopidogrel and/or AC, with a high risk for cardiovascular/thromboembolic events. PMID- 28337486 TI - Rapeseed-legume intercrops: plant growth and nitrogen balance in early stages of growth and development. AB - In this study we tested whether legumes can improve the growth and N and S nutrition of rapeseed in an intercropping system and compared the effect of mixtures on legume N-fixation and soil N-resources. Rapeseed was cultivated in low N conditions in monocrops using one (R) or two plants (RR) per pot and in mixtures with lupine, clover or vetch. The R monocrop was the most relevant control, intraspecific competition inducing a significant growth delay resulting in a significantly lower leaf number, in RR monocrop compared to R and the three mixtures considered. Plant biomass, and the N and S contents of rapeseed grown in mixtures were the same than those measured in R monocrop. Compared to the monocrop, the proportion of N derived from the atmosphere was increased by 34, 140 and 290% in lupine, clover and vetch, respectively when intercropped with rapeseed. In mixture with clover and lupine, the soil N pool at harvest was higher than in other treatments, while N export by crop was constant. Legumes suffered from competition for soil S resulting in a decrease of 40% in their S content compared to the monocrop. Compared to rapeseeds grown in R monocrop and in mixture with lupine and vetch, rapeseed mixed with clover showed significantly higher SPAD values in old leaves. In our conditions, mixing legumes with rapeseed is relevant to reduce N fertilization and improve nutrition and growth of rapeseed. PMID- 28337487 TI - Gender discrimination, gender disparities in obesity and human development. AB - Measuring gender inequality and women's empowerment is essential to understand the determinants of gender gaps, evaluate policies and monitor countries' progress. With this aim, over the past two decades, research has mainly been directed towards the development of composite indices. The purpose of this paper is to introduce a new and interdisciplinary perspective to the current debate on measuring gender inequality in human development. As a starting point, we develop a simple macroeconomic model of the interdependence between human development and gender inequality. We then introduce a biometric indicator, based on the ratio of female to male body mass index, to measure women's empowerment at the country level. Finally, by using the latest available data, we examine the ability of this biometric indicator to capture countries' performance in achieving gender equality. We obtain five main results: 1) we provide a theoretical framework to explain the joint determination of human development and gender inequality; 2) we show how to use this framework to simulate the impact of exogenous shocks or policy changes; 3) we demonstrate that exogenous changes have a direct and a multiplier effect on human development and gender inequality; 4) we find that the distribution of obesity between the female and male populations represents a useful proxy variable for measuring gender equality at the country level; 5) finally, we use these results to integrate and develop existing knowledge on the 'ecological' approach to the overweight and obesity pandemic. PMID- 28337488 TI - Supercritical carbon dioxide-based sterilization of decellularized heart valves. AB - OBJECTIVE: The goal of this research project encompasses finding the most efficient and effective method of decellularized tissue sterilization. BACKGROUND: Aortic tissue grafts have been utilized to repair damaged or diseased valves. Although, the tissues for grafting are collected aseptically, it does not eradicate the risk of contamination nor disease transfer. Thus, sterilization of grafts is mandatory. Several techniques have been applied to sterilize grafts; however, each technique shows drawbacks. In this study, we compared several sterilization techniques: supercritical carbon dioxide, electrolyzed water, gamma radiation, ethanol-peracetic acid, and hydrogen peroxide for impact on the sterility and mechanical integrity of porcine decellularized aortic valves. METHODS: Valve sterility was characterized by histology, microbe culture, and electron microscopy. Uniaxial tensile testing was conducted on the valve cusps along their circumferential orientation to study these sterilization techniques on their integrity. RESULTS: Ethanol-peracetic acid and supercritical carbon dioxide treated valves were found to be sterile. The tensile strength of supercritical carbon dioxide treated valves (4.28 +/- 0.22 MPa) was higher to those valves treated with electrolyzed water, gamma radiation, ethanol-peracetic acid and hydrogen peroxide (1.02 +/- 0.15, 1.25 +/- 0.25, 3.53 +/- 0.41 and 0.37 +/- 0.04 MPa, respectively). CONCLUSIONS: Superior sterility and integrity were found in the decellularized porcine aortic valves with supercritical carbon dioxide sterilization. This sterilization technique may hold promise for other decellularized soft tissues. SUMMARY: Sterilization of grafts is essential. Supercritical carbon dioxide, electrolyzed water, gamma radiation, ethanol peracetic acid, and hydrogen peroxide techniques were compared for impact on sterility and mechanical integrity of porcine decellularized aortic valves. Ethanol-peracetic acid and supercritical carbon dioxide treated valves were found to be sterile using histology, microbe culture and electron microscopy assays. The cusp tensile properties of supercritical carbon dioxide treated valves were higher compared to valves treated with other techniques. Superior sterility and integrity was found in the decellularized valves treated with supercritical carbon dioxide sterilization. This sterilization technique may hold promise for other decellularized soft tissues. PMID- 28337489 TI - ANTIBIOTIC RESISTANCE PROFILING AND MICROBIOTA OF THE UPPER RESPIRATORY TRACT OF APPARENTLY HEALTHY DOGS IN IBADAN, SOUTH WEST NIGERIA. AB - BACKGROUND: Rearing of dogs and other pets has become increasingly popular in modern society. Bacterial flora resides within the nasal and oral cavities of dogs and when chanced, can be pathogenic. Certain similarities between humans and dogs portends dangerous behavioral habits that could lead to zoonotic disease transmission. This study was aimed at isolation, identification and antibiotic profiling of bacteria from nasal swabs of apparently healthy dogs. The zoonotic risk was also considered. METHODOLOGY: A total of 173 nasal swabs were collected from 173 apparently healthy dogs. Structured questionnaires were administered to investigate human behavioral habits. RESULTS: Two hundred and twenty two (222) bacterial isolates were obtained from the culture with ten (10) potentially pathogenic bacteria in the order of Escherichia coli (18.5%), Proteus species (17.1%), Staphylococcus aureus (14.0%), Klebsiella species (9.0%), Acinetobacter species (9.0%), coagulase negative Staphylococcus species (7.7%), Pseudomonas species (6.8%), Actinobacter species (6.8%), Citrobacter species (5.9%) and Streptococcus species (5.4%). Overall, the Gram negative isolates showed resistance to ciprofloxacin (9.3%), sparfloxacin (16.0%), perfloxacin (17.3%), ofloxacin (21.6%), chloramphenicol (34..6%), gentamycin (36.4%), streptomycin (37.%), septrin (49.4%), amoxillin (59.3%), augmentin (62.3%) while the Gram positive bacteria showed resistance to ciprofloxacin (3.3%), perfloxacin (6.7%), erythromycin (13.3%), streptomycin (21.7%), rocephin (28.3%), septrin (28.3%), gentamycin (36.7%), zinnacef (68.3%), ampiclox (81.7%) and amoxillin (85.0%). Multi-drug resistance (MDR) to three or more antimicrobials was observed in some of the isolates. Seventy - seven resistance patterns were observed, 16 in Gram positive and 61 in Gram negative bacteria. CONCLUSION: This study revealed MDR to two or more antimicrobials in all the isolates. These can pose antibiotic resistance challenges in situation of primary or secondary canine respiratory infections. Also, this study revealed that 82% of the dog owners/lovers had less than 50cm face-to-face contact with these dogs while playing with them, thus increasing their chances of acquiring MDR bacteria from apparently healthy dogs. PMID- 28337490 TI - EFFECT OF TRIMETHOPRIM-SULFAMETHOXAZOLE PROPHYLAXIS ON FEACAL CARRIAGE RATES OF RESISTANT ISOLATES OF ESCHERICHIA COLI IN HIV-INFECTED ADULT PATIENTS IN LAGOS. AB - BACKGROUND: The daily use of Trimethoprim-Sulfamethoxazole (TMP-SMX) prophylaxis reduces morbidity and mortality among patients infected with human immunodeficiency virus (HIV) but its impact on increasing antimicrobial resistance rates has been of public health concern, globally. This study investigated the effect of daily TMP-SMX prophylaxis on feacal carriage rates of resistant isolates of Escherichia coli in HIV-infected adult patients in Lagos. METHODS: A total of 550 HIV-infected patients with CD4-cell counts of less than 350 cells/mm3 who were eligible for TMP-SMX prophylaxis and attending Lagos University Teaching Hospital, Lagos, Nigeria, were recruited for this study. Stool/rectal swab samples were aseptically collected from the patients and processed using standard methods for culture and sensitivity. RESULTS: There was a baseline Trimethoprim-Sulfamethoxazole resistance rate of 54% which increased to 77.9% in first 3 months, rising to 96.1% by 6 months and all isolates were resistant by the 9th month. There was also evidence of cross-resistance to other antibiotics with significance in association with TMP-SMX resistance (p<0.0001). The Escherichia coli isolates showed a progressive increase in resistance to the tested antibiotics over the 12-month period. The resistance was in the following order: Ampicillin (74% to 82.6% in the first 3 months; 98.3% by the 6th month and 99.4% by the 9th month; all isolates were resistant by the 12th month), Augmentin (32.5% to 47.7% in first 3 months; 76.1% by the 6th month; 86.3% by the 9th month; all isolates were resistant by 12 months), Ceftriaxone (2.0% to 10.8% in first 3 months; 20.6% by the 6th month; 24.2% by the 9th month; 54.3% by the 12 months). CONCLUSIONS: The carriage rate of feacal E. coli resistant to TMP-SMX is common before TMP-SMX prophylaxis. Initiation of TMP-SMX leads to further increase in resistance to TMP-SMX and cross-resistance to other antimicrobials. PMID- 28337491 TI - MEETING REPORT: UNESCO-MERCK AFRICA RESEARCH SUMMIT 2015- ACCELERATING ACCESS AND SUSTAINING INNOVATION 'FROM AFRICA FOR AFRICA'. AB - BACKGROUND: The Ebola virus disease outbreak of 2014 was the largest, longest and most devastating in the history of the disease. It demonstrated the social and economic impact an emerging infectious disease can have in a globalized world. Health systems in affected countries were stretched to the point of near collapse, while social relations and traditional practices were negatively impacted. Heads of African research institutions, African government representatives, leaders of global pharmaceutical companies, global infectious disease experts and close to 100 young African researchers from 25 countries; Assembled in Geneva on 19 and 20th October 2015, for the inaugural UNESCO-Merck Africa Summit sponsored by the United Nations Educational, Science and Culture Organization and Merck KGA. GOAL OF SUMMIT: The primary goal of the summit was to develop strategies to increase health research capacity in Africa, with special focus on Ebola and enhancing pandemic preparation for emerging infectious diseases. The summit was also provide a forum to showcase the research taking place in Africa, and provided platform for African researchers to network. Some of the key issues discussed included; strategies for enhancing policy frameworks to promote knowledge translation, strengthening of health systems, enhancing knowledge and data sharing, and increasing innovation in Africa. CONCLUSIONS: Summit attendees recognized that Africa still bore the heaviest burden of infectious disease, and increased commitment by African governments to fund health research, offered the best hope for developing health solutions and interventions to improve the health of Africans. Improved health in turn would enhance the productivity of Africans, further supporting the socio-economic transformation currently taking place on the continent. PMID- 28337493 TI - Editorial. AB - Adrian Lim On behalf of the UIO editorsIt is with great pleasure and honour that I introduce the March 2017 issue of Ultrasound International Open. The journal continues to grow from strength to strength with every issue and is now indexed in PubMed Central. This is a testament to the hardwork of the journal editors, editorial board, reviewers as well as the high quality publications and submissions. PMID- 28337492 TI - FLOCK-BASED SURVEILLANCE FOR LOW PATHOGENIC AVIAN INFLUENZA VIRUS IN COMMERCIAL BREEDERS AND LAYERS, SOUTHWEST NIGERIA. AB - BACKGROUND: Flock surveillance systems for avian influenza (AI) virus play a critical role in countries where vaccination is not practiced so as to establish the epidemiological characteristics of AI needed for the development of prevention and control strategies in such countries. MATERIALS AND METHODS: As part of routine AI monitoring in southwest Nigeria, a competitive ELISA was used for detecting influenza A virus antibodies in the sera of 461 commercial breeder and layer birds obtained from different flocks in Oyo State, Nigeria while haemagglutination inhibiting antibodies against low pathogenic AI viruses (LPAIVs) were detected using H5N2, H7N7 and H9N2 subtype-specific antigens. Suspensions prepared from cloacal swabs were tested for AI virus RNA using reverse transcriptase-polymerase chain reaction. RESULTS: Results showed that influenza A virus antibody prevalence was 12.8% and 9.3% for breeders and layers, respectively while HI assay revealed 22.0%, 2.0% and 78.0% prevalence of LPAIV H5N2, H7N7 and H9N2 antibodies respectively. All cloacal swab suspensions were negative for AIV RNA. CONCLUSION: Since LPAI infections result in decreased or complete cessation of egg production in breeder and layer birds, increased infection severity due to co-infection with other poultry viruses have occasionally been transmitted to humans, the detection of LPAIV H5N2, H7N7 and H9N2 antibodies in these birds is of both economic and public health significance. These findings underscore the need for continuous flock monitoring as part of early warning measure to facilitate rapid detection and sustainable control of AI in Nigerian poultry. PMID- 28337494 TI - H2O-Improved O2 activation on the Pd-Au bimetallic surface. AB - Improved activation of adsorbed O2 by co-adsorbed H2O on the Pd-Au(111) surface has been observed. When co-adsorbed with H2O, O2 admolecules on the Pd-Au surface are more strongly bound via their interactions with H2O. This interaction leads to large enhancements in the dissociation of O2 as determined via the generation of CO2 upon exposure to CO. PMID- 28337495 TI - Encapsulation induced aggregation: a self-assembly strategy for weakly pi stacking chromophores. AB - Molecular assembly of weakly pi-stacking core-substituted naphthalene diimides (cNDIs) requires the participation of strong side-group interactions. Spatial confinement within a micellar core leads to locally elevated concentrations and reduced entropy that drives a rapid aggregation, often followed by a slower aggregate reorganization. Fast aggregation kinetics leads to self-sorting of aggregates. PMID- 28337496 TI - Sugar-coated proteins: the importance of degree of polymerisation of oligo galacturonic acid on protein binding and aggregation. AB - We have simplified the structural heterogeneity of protein-polysaccharide binding by investigating protein binding to oligosaccharides. The interactions between bovine beta-lactoglobulin A (betaLgA) and oligo-galacturonic acids (OGAs) with various numbers of sugar residues have been investigated with a range of biophysical techniques. We show that the betaLgA-OGA interaction is critically dependent on the length of the oligosaccharide. Isothermal titration calorimetry results suggest that a minimum length of 7 or 8 sugar residues is required in order to exhibit appreciable exothermic interactions with betaLgA - shorter oligosaccharides show no enthalpic interactions at any concentration ratio. When titrating betaLgA into OGAs with more than 7-8 sugar residues the sample solution also became turbid with increasing amounts of betaLgA, indicating the formation of macroscopic assemblies. Circular dichroism, thioflavin T fluorescence and small angle X-ray/neutron scattering experiments revealed two structural regimes during the titration. When OGAs were in excess, betaLgA formed discrete assemblies upon OGA binding, and no subsequent aggregation was observed. However, when betaLgA was present in excess, multi-scale structures were formed and this eventually led to the separation of the solution into two liquid-phases. PMID- 28337498 TI - Palladium-catalyzed intermolecular amination of unactivated C(sp3)-H bonds via a cleavable directing group. AB - Palladium-catalyzed intermolecular amination of unactivated C(sp3)-H bonds was developed. Using NFSI as both the amino source and the oxidant, this protocol operates under mild conditions with excellent terminal selectivity and a broad substrate scope. Moreover, the directing group can be easily removed to produce 1,2-amino alcohols. PMID- 28337497 TI - Dimerization and conformation-related free energy landscapes of dye-tagged amyloid-beta12-28 linked to FRET experiments. AB - We have investigated the free energy landscape of Abeta-peptide dimer models in connection to gas-phase FRET experiments. We use a FRET-related distance coordinate and one conformation-related coordinate per monomer for accelerated structural exploration with well-tempered metadynamics in solvent and in vacuo. The free energy profiles indicate that FRET under equilibrium conditions should be significantly affected by the de-solvation upon the transfer of ions to the gas-phase. In contrast, a change in the protonation state is found to be less impacting once de-solvated. Comparing F19P and WT alloforms, for which we measure different FRET efficiencies in the gas-phase, we predict only the relevant structural differences in the solution populations, not under gas-phase equilibrium conditions. This finding supports the hypothesis that the gas-phase action-FRET measurement after ESI operates under non-equilibrium conditions, with a memory of the solution conditions - even for the dimer of this relatively short peptide. The structural differences in solution are rationalized in terms of conformational propensities around residue 19, which show a transition to a poly proline type of pattern upon mutation to F19P - a difference that gets lost in the gas-phase. PMID- 28337499 TI - Organic nanostructure-based probes for two-photon imaging of mitochondria and microbes with emission between 430 nm and 640 nm. AB - Multi-photon excitation and versatile fluorescent probes are in high need for biological imaging, since one probe can satisfy many needs as a biosensor. Herein we synthesize a series of two-photon excited probes based on tetraphenylethene (TPE) structures (TPE-Acr, TPE-Py, and TPE-Quino), which can image both mammalian cells and bacteria based on aggregation-induced emission (AIE) without washing them. Because of cationic moieties, the fluorescent molecules can aggregate into nanoscale fluorescent organic nanoscale dots to image mitochondria and bacteria with tunable emissions using both one-photon and two-photon excitation. Our research demonstrates that these AIE-dots expand the functions of luminescent organic dots to construct efficient fluorescent sensors applicable to both one photon and two-photon excitation for bio-imaging of bacteria and mammalian cells. PMID- 28337500 TI - Direct observation of orientation distributions of actin filaments in a solution undergoing shear banding. AB - Shear banding is frequently observed in complex fluids. However, the configuration of macromolecules in solutions undergoing shear banding has not yet been directly observed. In this study, by using the fact that F-actin solutions exhibit shear banding and actin filaments are visualized by fluorescent labels, we directly observed the intrinsic states of an actin solution undergoing shear banding. By combining the 3D imaging of labeled actin filaments and particle image velocimetry (PIV), we obtained orientation distributions of actin filaments in both high and low shear rate regions, whose quantitative differences are indicated. In addition, by using the orientation distributions and applying stress expression for rod-like polymers, we estimated stress tensors in both high and low shear rate regions. This evaluation indicates that different orientation distributions of filamentous macromolecules can exhibit a common shear stress. PMID- 28337501 TI - Behavior of Thiophanate Methyl and Propiconazole in Grape and Mango Fruits Under the Egyptian Field Conditions. AB - This research aims at determining residues of thiophanate methyl and propiconazole in grape and mango fruits as an indication for their persistence in this environmental compartment. Fruit extracts were analyzed for thiophanate methyl using High Performance Liquid Chromatography and using Gas Chromatography Electron Capture Detector (GC/ECD), respectively. The results indicated that propiconazole had a less environmental impact since propiconazole had shorter residue half-lives which were 1.24 and 1.19 days in grape and mango fruits, respectively, while thiophanate methyl had half-lives of 2.49 and 2.64 days in mango and grape, respectively. The degradation rates of propiconazole in grape and mango fruits did not change significantly and neither did those of thiophanate methyl. According to the maximum residue level, the pre-harvest intervals of propiconazole were set to be 3 and 7 days for grape and mango fruits, respectively, and the pre-harvest intervals for thiophanate methyl were 15 days for both grape and mango fruits. Propiconazole was generally considered to be less hazardous to humans and will leave the environment less altered because of its faster degradation than that of thiophanate methyl. PMID- 28337502 TI - [Metastasized urological malignancies : Is resection of the primary tumor or destruction using alternative procedures worthwhile?] PMID- 28337503 TI - Gut microbiome-related metabolic changes in plasma of antibiotic-treated rats. AB - The intestinal microbiota contributes to the metabolism of its host. Adequate identification of the microbiota's impact on the host plasma metabolites is lacking. As antibiotics have a profound effect on the microbial composition and hence on the mammalian-microbiota co-metabolism, we studied the effects of antibiotics on the "functionality of the microbiome"-defined as the production of metabolites absorbed by the host. This metabolomics study presents insights into the mammalian-microbiome co-metabolism of endogenous metabolites. To identify plasma metabolites related to microbiome changes due to antibiotic treatment, we have applied broad-spectrum antibiotics belonging to the class of aminoglycosides (neomycin, gentamicin), fluoroquinolones (moxifloxacin, levofloxacin) and tetracyclines (doxycycline, tetracycline). These were administered orally for 28 days to male rats including blood sampling for metabolic profiling after 7, 14 and 28 days. Fluoroquinolones and tetracyclines can be absorbed from the gut; whereas, aminoglycosides are poorly absorbed. Hippuric acid, indole-3-acetic acid and glycerol were identified as key metabolites affected by antibiotic treatment, beside changes mainly concerning amino acids and carbohydrates. Inter alia, effects on indole-3-propionic acid were found to be unique for aminoglycosides, and on 3-indoxylsulfate for tetracyclines. For each class of antibiotics, specific metabolome patterns could be established in the MetaMap(r)Tox data base, which contains metabolome data for more than 550 reference compounds. The results suggest that plasma-based metabolic profiling (metabolomics) could be a suitable tool to investigate the effect of antibiotics on the functionality of the microbiome and to obtain insight into the mammalian-microbiome co-metabolism. PMID- 28337504 TI - Biotransformation of 2,4-toluenediamine in human skin and reconstructed tissues. AB - Reconstructed human epidermis (RHE) is used for risk assessment of chemicals and cosmetics and RHE as well as reconstructed human full-thickness skin (RHS) become important for e.g., the pre-clinical development of drugs. Yet, the knowledge regarding their biotransformation capacity is still limited, although the metabolic activity is highly relevant for skin sensitization, genotoxicity, and the efficacy of topical dermatics. The biotransformation of the aromatic amine 2,4-toluenediamine (2,4-TDA) has been compared in two commercially available RHS to normal human skin ex vivo, and in primary epidermal keratinocytes and dermal fibroblasts as well as in vitro generated epidermal Langerhans cells and dermal dendritic cells. The mono N-acetylated derivative N-(3-amino-4-methyl phenyl)acetamide (M1) was the only metabolite detectable in substantial amounts indicating the predominance of N-acetylation. RHS exceeded human skin ex vivo in N-acetyltransferase activity and in cell cultures metabolite formation ranked as follows: keratinocytes > fibroblasts ~ Langerhans cells ~ dendritic cells. In conclusion, our results underline the principal suitability of RHS as an adequate test matrix for the investigation of N-acetylation of xenobiotics which is most relevant for risk assessment associated with cutaneous exposure to aromatic amines. PMID- 28337505 TI - Osteochondroma causing cervical spinal cord compression. AB - Osteochondromas are the most common benign tumors of the bone. They occur in young adolescent patients and are frequently located in the metaphyses of the long bones; they do not grow after skeletal maturity. The incidence of osteochondroma in the spine is reported to be rare. Moreover, patients with spinal osteochondroma who develop symptoms of myelopathy are extremely rare. We report the case of an 8-year-old girl who experienced myelopathy due to spinal compression of the cervical osteochondroma. This case suggests that if a cartilage cap is observed on the spinal canal with magnetic resonance imaging (MRI), the tumor may extend to the spinal canal, resulting in neurologic dysfunction. Therefore, careful follow-up until bone maturity should be performed. PMID- 28337506 TI - 24th Annual Scientific Meeting of the European Society of Musculoskeletal Radiology (ESSR), Bari/Italy, June 15-17, 2017. PMID- 28337507 TI - Reversal in order of ventricular filling is associated with a positive fluid balance in sepsis. PMID- 28337508 TI - Compliance and statistics : Discussion on "Severe hypercapnia and outcomes of mechanically ventilated patients with moderate or severe acute respiratory distress syndrome". PMID- 28337509 TI - Understanding renal recovery. PMID- 28337510 TI - [Seven years of the National Action League for People with Rare Diseases : NAMSE a success story?!] AB - It is estimated that four million people in Germany are living with a rare disease; in the EU, approximately 30 million people are affected. All rare diseases are chronic, linked to invalidity and/or restricted life expectancy, and their symptoms are often already manifest in childhood. Some 80% of rare diseases are genetically determined; they can rarely be cured. Furthermore, the pathogenesis of many rare diseases is unknown.In a move to ameliorate the situation of persons with rare diseases, the National Action League for People with Rare Diseases (NAMSE) published the National Plan of Action for People with Rare Diseases containing 52 measures that aim to achieve the desired improvements. More than half of these measures have already been implemented or are currently in the process of implementation. The Federal Ministry of Health is supporting this implementation process with numerous projects.NAMSE has achieved a great deal as a result of the National Plan of Action for People with Rare Diseases, even though not all of the measures included in the National Plan of Action have been implemented. The first results of individual measures are already becoming apparent. In order to achieve long-lasting improvements in the prevention, diagnosis and therapy of rare diseases, initiatives will have to be coordinated in the future as well.The Federal Ministry of Health will be funding the NAMSE Coordinating Office until mid-2018, thus ensuring that NAMSE will remain operational until that time. All of the partners collaborating in the Action League agree on the need for NAMSE, together with its coordinating office, to remain in place. To this end, a structure that keeps the health care situation of persons with rare diseases under observation, that suggests solutions and offers a possibility for the parties involved to network, is necessary. The question of conducting a legal restructuring of NAMSE in the future that will be sustainable in the long term is currently under discussion. PMID- 28337511 TI - [Dementia in the focus of health research : A comparative analysis of current ageing studies]. AB - Health research on an increasingly aging population calls for careful consideration of aging-associated phenomena, such as dementia. Accounting for such diseases is a necessary step for gaining a view of health in the elderly. It is moreover imperative to gather data on subjects' mental limitations in surveys to better evaluate the validity of answers disclosed by elderly participants. This article discusses the availability of data on individuals suffering from dementia in national studies on aging. It centers on the question of how surveys respond to the challenge of diagnosing dementia. The analysis is based on a literature review, which focuses on national studies on aging that were conducted no later than 2005, and that enforced an upper age limit of at least 79 years old for their subjects. By evaluating these published studies, and analyzing their data descriptively, it was determined how many subjects suffering from dementia were part of each sample, and which methods were applied to diagnose such illnesses. Overall, the availability of data on age and aging is satisfactory in Germany. The literature review discovered seven studies on aging, as well as five that lend themselves to a framework oriented toward research on aging. The number of subjects suffering from dementia in the samples is between 0 and 14% - over half of the studies reach less than 1.5% of those affected. These results thus point out problems in surveying individuals suffering from dementia. They highlight the limitations of studies on aging that do not account for dementia in their subjects. The following discussion aims to contribute to the debate on relevant research methodology, and to the development of methodological approaches that consider dementia as a crucial factor. PMID- 28337512 TI - Parks and green areas and the risk for depression and suicidal indicators. AB - OBJECTIVES: There is increasing evidence that parks and green areas have beneficial effects on mental health; however, most studies have been limited to a certain or small geographic area. This study investigated whether parks and green areas were associated with the risk for depression or suicidal indicators among adults. METHODS: We used the 2009 Korean Community Health Survey data (n = 169,029). Residential geographical codes were used to determine the amount of parks and green areas in each administrative district. RESULTS: The median amount of parks and green areas was 19.73 m2 per capita. Compared with adults living the highest amount of parks and green areas (1st quartile), those living in regions with the lowest amount of parks and green areas (4th quartile) had 16-27% greater odds for depression and suicidal indicators, after adjusting for all potential variables. People without moderate physical activity had higher odds for self reported depression and suicidal ideation than those with moderate physical activity. CONCLUSIONS: We observed protective associations between parks and green areas and depression and suicidal indicators. In addition, moderate physical activity may help to lower the risk for depression and suicidal indicators. PMID- 28337514 TI - Effect of Sequential Treatment with Bisphosphonates After Teriparatide in Ovariectomized Rats: A Direct Comparison Between Risedronate and Alendronate. AB - Teriparatide (TPTD), a recombinant human parathyroid hormone N-terminal fragment (1-34), is a widely used bone anabolic drug for osteoporosis. Sequential treatment with antiresorptives such as bisphosphonates after TPTD discontinuation is generally recommended. However, relative effects of bisphosphonates have not been determined. In the present study, we directly compared effects of risedronate (RIS) and alendronate (ALN) on bone mineral density (BMD), bone turnover, structural property and strength in ovariectomized (OVX) rats, when administered after TPTD. Female Sprague Dawley rats were divided into one sham operated and eight ovariectomized groups. TPTD, RIS, and ALN were given subcutaneously twice per week for 4 or 8 weeks after 4 week treatment with TPTD. TPTD significantly increased BMD (+9.6%) in OVX rats after 4 weeks of treatment. 8 weeks after TPTD withdrawal, vehicle-treated group showed a blunted BMD increase of +8.4% from the baseline. In contrast, 8 weeks of treatment with RIS and ALN significantly increased BMD to 17.4 and 21.8%, respectively. While ALN caused a consistently larger increase in BMD, sequential treatment with RIS resulted in lower Tb.Sp compared to ALN in the fourth lumbar vertebra as well as in greater stiffness in compression test. In conclusion, the present study demonstrated that sequential therapy with ALN and RIS after TPTD both improved bone mass and structure. Our results further suggest that RIS may have a greater effect on improving bone quality and stiffness than ALN despite less prominent effect on BMD. Further studies are necessary to determine clinical relevance of these findings to fracture rate. PMID- 28337515 TI - Assessment of Cardiac Function in Fetuses of Gestational Diabetic Mothers During the Second Trimester. AB - Fetuses of diabetic mothers may have structural or functional cardiac abnormalities which increase morbidity and mortality. Isolated functional abnormalities have been identified in the third trimester. The aim of the present study was to assess fetal cardiac function (systolic, diastolic, and global myocardial performance) in the second trimester in mothers with gestational diabetes, and also to relate cardiac function with glycemic control. Mothers with gestational diabetes mellitus referred for fetal cardiac evaluation in the second trimester (between 19 and 24 weeks) from March 2015 to February 2016 were enrolled as case subjects in this study. Non-diabetic mothers who had a fetal echocardiogram done between 19 and 24 weeks for other indications were enrolled as controls. Functional cardiac variables showed a statistically significant difference in isovolumetric relaxation and contraction times and the myocardial performance index and mitral E/A ratios in the gestational diabetic group (p = 0.003). Mitral annular plane systolic excursion was significantly less in the diabetic group (p = 0.01). The only functional cardiac variable found abnormal in mothers with poor glycemic control was the prolonged isovolumetric relaxation time. Functional cardiac abnormalities can be detected in the second trimester in fetuses of gestational diabetic mothers and timely intervention can improve postnatal outcomes. PMID- 28337516 TI - Exploring the potential of high resolution mass spectrometry for the investigation of lignin-derived phenol substitutes in phenolic resin syntheses. AB - Chemical degradation is an efficient method to obtain bio-oils and other compounds from lignin. Lignin bio-oils are potential substitutes for the phenol component of phenol formaldehyde (PF) resins. Here, we developed an analytical method based on high resolution mass spectrometry that provided structural information for the synthesized lignin-derived resins and supported the prediction of their properties. Different model resins based on typical lignin degradation products were analyzed by electrospray ionization in negative ionization mode. Utilizing enhanced mass defect filter techniques provided detailed structural information of the lignin-based model resins and readily complemented the analytical data from differential scanning calorimetry and thermogravimetric analysis. Relative reactivity and chemical diversity of the phenol substitutes were significant determinants of the outcome of the PF resin synthesis and thus controlled the areas of application of the resulting polymers. Graphical abstract ?. PMID- 28337517 TI - A column switching ultrahigh-performance liquid chromatography-tandem mass spectrometry method to determine anandamide and 2-arachidonoylglycerol in plasma samples. AB - This study reports a fast, sensitive, and selective column switching ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method to determine the endocannabinoids (eCBs), anandamide (AEA), and 2 arachidonoylglycerol (2-AG) in plasma samples. This bidimensional system used a restricted access media column (RP-8 ADS, 25 mm * 4 mm * 25 MUM) in the first dimension and a core-shell Kinetex C18 (100 mm * 2, 1.7 mm * 1 MUM) column in the second dimension, followed by detection in a mass spectrometer triple quadrupole (multiple reactions monitoring mode) operating in the positive mode. RP-8 ADS was used for trace enrichment of eCBs (reverse phase partitioning) and macromolecular matrix size exclusion; the core-shell column was used for the chromatographic separation. The column switching UHPLC-MS/MS method presented a linear range spanning from 0.1 ng mL-1 (LOQ) to 6 ng mL-1 for AEA and from 0.04 ng mL-1 (LOQ) to 10 ng mL-1 for 2-AG. Excluding the LLOQ values, the precision assays provided coefficients of variation lower than 8% and accuracy with relative standard error values lower than 14%. Neither carryover nor matrix effects were detected. This high-throughput column switching method compared to conventional methods is time saving as it involves fewer steps, consumes less solvent, and presents lower LLOQ. The column switching UHPLC-MS/MS method was successfully applied to determine AEA and 2-AG in plasma samples obtained from Alzheimer's disease patients. Graphical abstract A column switching ultra high-performance liquid chromatography-tandem mass spectrometry method using RP-8 ADS column and core shell column to determine endocannabinoids in plasma samples. PMID- 28337519 TI - The draped aorta sign of impending aortic aneurysm rupture. PMID- 28337518 TI - Both AtrbohD and AtrbohF are essential for mediating responses to oxygen deficiency in Arabidopsis. AB - KEY MESSAGE: Both AtrbohD and AtrbohF promote the increases in activities of ADH, PDC, LDH, and Ca2+ levels, and induce the expression of multiple hypoxia response genes, thus improving Arabidopsis adaptation to oxygen deficiency. NADPH oxidase AtrbohD and AtrbohF cooperatively play key roles in regulation of growth and stress signaling in Arabidopsis. However, reports on AtrbohD and AtrbohF functioning together in hypoxia signaling are scarce, and the underlying mechanisms remain elusive. Here, we show that the double null mutant atrbohD/F is more sensitive to oxygen deprivation compared with wild type (WT) and the single mutant atrbohD and atrbohF. Under oxygen deficiency, enhancements of the transcripts of alcohol dehydrogenase 1 (ADH1) and pyruvate decarboxylase 1 (PDC1) and the activities of ADH, PDC and lactate dehydrogenase in WT are clearly reduced in the single mutants, and more strongly reduced in the double mutant. Moreover, increases in the production of ATP, H2O2 and Ca2+ in WT are significantly arrested in atrbohD, atrbohF, and especially in atrbohD/F. Hypoxia promoted rise in the expression of some hypoxic responsive genes is also inhibited in atrbohD/F relative to WT, atrbohD and atrbohF. These genes include ethylene response factor 73, lactate dehydrogenase, MYB transcription factor 2, sucrose synthase 1 (SUS1), SUS4, heat stress transcription factor A2 and heat shock protein 18.2. These results suggest that both AtrbohD and AtrbohF are essential for mediating hypoxia signaling. H2O2 derived from AtrbohD and AtrbohF triggers the Ca2+ increase and induces the expression of multiple hypoxia response genes, thus improving Arabidopsis tolerance to low-oxygen stress. These findings provide new insights into the mechanisms of AtrbohF in regulating the responses to oxygen deprivation in Arabidopsis. PMID- 28337520 TI - The "polka-dot" sign. PMID- 28337521 TI - Evaluating histologic differentiation of hepatitis B virus-related hepatocellular carcinoma using intravoxel incoherent motion and AFP levels alone and in combination. AB - PURPOSE: To evaluate histologic differentiation of hepatitis B virus (HBV) related hepatocellular carcinomas (HCCs) using apparent diffusion coefficient (ADC) and intravoxel incoherent motion (IVIM)-derived metrics and to compare findings with alpha-fetoprotein (AFP) levels alone and in combination. MATERIALS AND METHOD: One hundred and six chronic HBV-related HCC patients who underwent IVIM diffusion-weighted magnetic resonance imaging with eleven b values were enrolled. Mean ADC, diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f) values were determined for all detected lesions. The metrics and AFP levels of different histologically differentiated groups were compared. Spearman's rank correlation was used to assess the statistical dependence among the histologically differentiated HCCs. Receiver operating characteristic (ROC) analysis was performed to evaluate diagnostic performance of these metrics and AFP levels alone and in combination. RESULTS: ADC, D, and f values and AFP levels were significantly different among well-, moderately, and poorly differentiated HCCs. The four metrics were significantly correlated with histologic differentiation. The area under the ROC curve (AUC-ROC) of ADC, D, f, and AFP for diagnosing well-differentiated HCCs was 0.903, 0.84, 0.782, and 0.806, respectively, and the AUC-ROC of above metrics for diagnosing poorly differentiated HCCs was 0.787, 0.726, 0.624, and 0.633, respectively. The combination of ADC and AFP provided an AUC-ROC of 0.945 for well-differentiated HCC. However, this did not provide better performance for diagnosing poorly differentiated HCC. CONCLUSION: ADC, IVIM metrics, and AFP levels may be useful for evaluating histologic differentiation of HBV-related HCCs, and the combination of ADC and AFP provides better diagnostic performance for well differentiated HCC. PMID- 28337523 TI - Hip fracture incidence and social deprivation: results from a French ecological study. AB - : The association between socioeconomic status (SES) and hip fracture (HF) incidence was analyzed in France in 2008. In men and women, a decrease in HF incidence was observed as the social deprivation index increased. This result may be partly due to the protective effect of increasing body weight against HF. INTRODUCTION: Regional variations in hip fracture (HF) incidence exist worldwide. Reasons for these variations remain unknown. As regional variations have also been observed for socioeconomic status, we analyzed the association between socioeconomic deprivation (SED) and HF incidence in France in 2008. METHODS: From the French Hospital National Database, we selected all HF encoded as primary diagnosis in persons aged 30 years and over. The recently published French version of the European Deprivation Index (EDI) was used for SED analysis, and an EDI score was measured for the year 2007 in each French local municipality. The EDI score was categorized in quintiles. Poisson regression was performed to examine the association between HF incidence and EDI adjusted for age and sex. The population attributable fraction (PAF) was measured to calculate the proportion of excess cases of HF associated with social affluence. RESULTS: In 2008, 83,538 HF were reported in France of which 59,143 were included in this study. Among them, 44,401 fractures occurred in women (75%) and 14,742 in men (25%). In both men and women, there was a decrease in the HF incidence with increasing SED index. In Poisson regression, the interaction of age class and sex was significant (p < 0.0001) and the EDI in quintiles was significantly associated with the incidence of HF (p < 0.0001). A higher number of people living in affluent residential areas corresponded to a higher risk of HF. The risk of HF is 2.42 times higher for those living in the most affluent group compared to those living in the most underprivileged group. The value of the PAF was calculated at 27.1%. CONCLUSION: Social disparities in HF incidence exist in France with the most deprived municipalities having the lowest incidence. Prior knowledge demonstrates the strong relationships between body weight and HF risk as well as between body weight and the SED. The link found in our study between EDI and HF incidence as well as regional and temporal variations in HF incidence may be partly due to the protective effect of increased body weight against HF. PMID- 28337522 TI - Pre-symptomatic autoimmunity in rheumatoid arthritis: when does the disease start? AB - It is well recognised that a state of autoimmunity, in which immunological tolerance is broken, precedes the development of symptoms in the majority of patients with rheumatoid arthritis (RA). For individuals who will later develop seropositive disease, this manifests as autoantibodies directed against proteins that have undergone specific post-translational modifications. There is evidence that the induction of this autoantibody response occurs at peripheral extra articular mucosal sites, such as the periodontium and lung. In addition to their utility as diagnostic markers, these autoantibodies may have a pathogenic role that helps localise disease to the synovium. Alongside the development of autoantibodies, other factors contributing to pre-symptomatic autoimmunity may include dysbiosis of the gastrointestinal tract, abnormal development of lymphoid tissue, and dysregulated autonomic and lipid-mediated anti-inflammatory signalling. These factors combine to skew the balance between pro-inflammatory and anti-inflammatory signalling in a manner that is permissive for the development of clinical arthritis. We present data to support the concept that the transitions from at-risk states to systemic autoimmunity and then to classifiable RA depend on multiple "switches". However, further prospective studies are necessary to define the molecular basis of these switches and the specific features of pre-symptomatic autoimmunity, so that preventative treatments can be targeted to individuals at high risk for RA. In this review, we analyse mechanisms that may contribute to the development of autoimmunity in at risk individuals and discuss the relationship between this pre-symptomatic state and subsequent development of RA. PMID- 28337524 TI - Quantitative analysis of efficacy and associated factors of calcium intake on bone mineral density in postmenopausal women. AB - : A model-based meta-analysis method was performed to quantitatively analyze the efficacy characteristics of calcium intake in BMD increase among postmenopausal women. We found that age and calcium intake dose were key factors affecting the efficiency and onset of BMD change, and daily 1200 mg calcium was suggested to be a beneficial dosage. INTRODUCTION: This paper aims to quantify the efficacy of calcium intake in preventing bone mineral density (BMD) decrease among postmenopausal women and to investigate the factors that may affect the efficacy. METHODS: Comprehensive literature search was conducted in PubMed and EMBASE from January 2016. Placebo-controlled or no-treatment controlled randomized trials focused on calcium intake for the management of osteoporosis in postmenopausal women were included. The clinical and demographic characteristics of participants and efficacy data, defined as the mean percentage change of spine BMD (L2-L4) at each observation time point compared with that of baseline, were extracted from the studies. Model-based meta-analysis (MBMA) was used to describe the time course of BMD change by calcium intake and identify the related factors. RESULTS: This study includes 17 trials involving 2537 subjects. The results showed that a classic pharmacodynamic maximal effect (E max) model could describe the time course of BMD change by calcium intake. Using this model, we found that age and calcium intake dose were key factors affecting the efficiency and onset of BMD change. A 60-year-old woman administered with 800 mg/day calcium can achieve a maximum BMD increasing rate of 2.38%, and the time to reach 50% of this maximum (known as onset time) was 9.44 months. An increase of 0.0817% per year was noted in the maximal effect value for women aged between 50 and 83 years. For calcium dose interval from 250 to 2000 mg/day, the onset time was expressed as 9.44 * (dose/800)-1.33 months. Two-year calcium intake of 700, 1200, and 2000 mg/day resulted in a maximum efficacy of BMD of 68.0, 81.3, and 89.6%, respectively. This indicates that the final efficacy had already reached the plateau (>80% E max) under the 1200-mg/day dose. CONCLUSION: Calcium intake can effectively postpone the tendency of BMD decrease in postmenopausal women. An increased calcium dose contributes to the shortening of the onset time. Considering the drug-acting rate and safety into account, menopausal women can be administered with a rational dose of 1200 mg/day to reduce bone loss. PMID- 28337525 TI - Phosphodiesterase-1b (Pde1b) knockout mice are resistant to forced swim and tail suspension induced immobility and show upregulation of Pde10a. AB - RATIONALE: Major depressive disorder is a leading cause of suicide and disability. Despite this, current antidepressants provide insufficient efficacy in more than 60% of patients. Most current antidepressants are presynaptic reuptake inhibitors; postsynaptic signal regulation has not received as much attention as potential treatment targets. OBJECTIVES: We examined the effects of disruption of the postsynaptic cyclic nucleotide hydrolyzing enzyme, phosphodiesterase (PDE) 1b, on depressive-like behavior and the effects on PDE1B protein in wild-type (WT) mice following stress. METHODS: Littermate knockout (KO) and WT mice were tested in locomotor activity, tail suspension (TST), and forced swim tests (FST). FST was also used to compare the effects of two antidepressants, fluoxetine and bupropion, in KO versus WT mice. Messenger RNA (mRNA) expression changes were also determined. WT mice underwent acute or chronic stress and markers of stress and PDE1B expression were examined. RESULTS: Pde1b KO mice exhibited decreased TST and FST immobility. When treated with antidepressants, both WT and KO mice showed decreased FST immobility and the effect was additive in KO mice. Mice lacking Pde1b had increased striatal Pde10a mRNA expression. In WT mice, acute and chronic stress upregulated PDE1B expression while PDE10A expression was downregulated after chronic but not acute stress. CONCLUSIONS: PDE1B is a potential therapeutic target for depression treatment because of the antidepressant-like phenotype seen in Pde1b KO mice. PMID- 28337526 TI - Arthritis and cognitive impairment in older adults. AB - Adults aged 65 or older with arthritis may be at increased risk for cognitive impairment [cognitive impairment but not dementia (CIND) or dementia]. Studies have found associations between arthritis and cognition impairments; however, none have examined whether persons with arthritis develop cognitive impairments at higher rates than those without arthritis. Using data from the Health and Retirement Study, we estimated the prevalence of cognitive impairments in older adults with and without arthritis, and examined associations between arthritis status and cognitive impairments. We calculated incidence density ratios (IDRs) using generalized estimating equations to estimate associations between arthritis and cognitive impairments adjusting for age, sex, race/ethnicity, marital status, education, income, depression, obesity, smoking, the number of chronic conditions, physical activity, and birth cohort. The prevalence of CIND and dementia did not significantly differ between those with and without arthritis (CIND: 20.8%, 95% CI 19.7-21.9 vs. 18.3%, 95% CI 16.8-19.8; dementia: 5.2% 95% CI 4.6-5.8 vs. 5.1% 95% CI 4.3-5.9). After covariate control, older adults with arthritis did not differ significantly from those without arthritis for either cognitive outcome (CIND IDR: 1.6, 95% CI = 0.9-2.9; dementia IDR: 1.1, 95% CI = 0.4-3.3) and developed cognitive impairments at a similar rate to those without arthritis. Older adults with arthritis were not significantly more at risk to develop cognitive impairments and developed cognitive impairments at a similar rate as older adults without arthritis over 6 years. PMID- 28337527 TI - Phase II study of the c-MET inhibitor tivantinib (ARQ 197) in patients with relapsed or relapsed/refractory multiple myeloma. AB - The hepatocyte growth factor/c-MET pathway has been implicated in the pathobiology of multiple myeloma, and c-MET inhibitors induce myeloma cell apoptosis, suggesting that they could be useful clinically. We conducted a phase II study with the c-MET inhibitor tivantinib in patients with relapsed, or relapsed and refractory myeloma whose disease had progressed after one to four prior therapies. Tivantinib, 360 mg orally per dose, was administered twice daily continuously over a 4-week treatment cycle without a cap on the number of allowed cycles, barring undue toxicities or disease progression. Primary objectives were to determine the overall response rate and the toxicities of tivantinib in this patient population. Sixteen patients were enrolled in a two-stage design. Notable grade 3 and 4 hematological adverse events were limited to neutropenia in five and four patients, respectively. Nonhematological adverse events of grade 3 or higher included hypertension (in four patients); syncope, infection, and pain (two each); and fatigue, cough, and pulmonary embolism (one each). Four of 11 evaluable patients (36%) had stable disease as their best response, while the remainder showed disease progression. Overall, tivantinib as a single agent did not show promise for unselected relapsed/refractory myeloma patients. However, the ability to achieve stable disease does suggest that combination regimens incorporating targeted inhibitors in patients with c-MET pathway activation could be of interest. PMID- 28337528 TI - A molecular study on the role of alpha-hemoglobin-stabilizing protein in hemoglobin H disease. AB - The clinical course of hemoglobin H (HbH) disease is remarkably variable. It is not completely clear how genetic and environmental factors interplay to modify clinical severity in affected individuals. Previous studies suggested that altered structure or function of alpha-hemoglobin-stabilizing protein (AHSP) could modify the clinical phenotypes of thalassemias. The present study attempted to explore the potential role of AHSP in the pathophysiology of HbH disease in 95 Chinese and Thai/Sino-Thai patients with deletional and non-deletional form of this disease. We identified six polymorphic sites in AHSP which were subgrouped into major haplotype clades. No association between AHSP genotypes or haplotypes and clinical phenotypes was observed. Instead, multiple linear regression analysis indicated that expression of AHSP correlated negatively with age (P < 0.001) and hemoglobin (P = 0.007), but positively with reticulocyte count (P = 0.003) and severity score (P = 0.003). Subgroup analysis showed that AHSP expression was higher in the non-deletional form than in the deletional form (P < 0.001). Moreover, specific types of non-deletional HbH disease with production of mutant alpha-globin chains that do not bind to AHSP (Hb Constant Spring and Hb Pakse) showed the highest AHSP expression. The present findings demonstrate that AHSP expression is a biomarker of HbH disease severity and infer an important role of AHSP in modulating the pathophysiology of this disease. Pharmacological or genetic means to alter AHSP expression may be a novel approach for amelioration of disease severity in HbH disease. PMID- 28337530 TI - Chronic sialadenitis due to the stone inside the accessory duct of submandibular gland. AB - PURPOSE: Sialolithiasis is the most common cause of chronic sialadenitis. In this case report, intraoperative finding of an accessory submandibular duct, obstructed with stone, originating from the same gland nearby the main Warthon's duct, is presented. CASE REPORT: A 22-year-old male patient, suffering from eating-related pain and swelling in his left submandibular region, was diagnosed with left sublandibular gland sialadenitis with radiologically manifested sialolithiasis, and gland excision was advised. Surgery was performed under general anesthesia. When the full anatomical scenery was delineated before excision of the gland, we surprisingly encountered two submandibular ducts originating from ipsilateral gland, one of them was obstructed with stone. After two ducts were ligated, the gland with sialolith was excised. According to histopathologic examination, the duct obstructed with stone was identified as the accessory duct and the other one was the main Wharton's duct. Postoperative days were uneventful; no neurologic complication was observed. CONCLUSIONS: Otolaryngologists should be aware of anatomic variations of the submandibular duct(s) to avoid possible complications, especially intraoperatively, because rutine preoperative radiologic preparation does not include investigation of possible accessory ducts. PMID- 28337529 TI - The impact of repeated cycles of radioligand therapy using [177Lu]Lu-PSMA-617 on renal function in patients with hormone refractory metastatic prostate cancer. AB - BACKGROUND: [177Lu]Lu-PSMA-617 is a well-tolerated therapy for the treatment of metastatic prostate cancer. However, because of the mainly renal excretion of the tracer, the kidneys are one of the most limiting organs. The purpose of this study was to examine the post-therapeutic changes in renal function over time and to identify risk factors for developing renal toxicity. We also tested the reliability of markers for renal function monitoring. METHODS: Fifty-five patients with castrate-resistant metastatic prostate cancer treated with at least three cycles of [177Lu]Lu-PSMA-617 were investigated. Renal function was assessed through laboratory tests (creatinine, GFR, cystatin C) and Tc-99 m-MAG3 measurements. Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. To identify risk factors for renal toxicity, we used Pearson's correlation coefficient and the corresponding p values. RESULTS: None of the 55 patients experienced severe nephrotoxicity (grade 3/4). In 14 patients (25%), we observed increased creatinine levels of CTC 1 degrees or 2 degrees . There were 16 cases of increased GFR (grade 1/2). At the baseline, only 14 patients had elevated cystatin C. However, post-therapeutic cystatin C was elevated in 32 patients (58%). A significant effect on renal function was found for age (p = 0.049), hypertension (p = 0.001) and pre-existing kidney disease (p = 0.001). The most reliable predictive markers of nephrotoxicity were TER-MAG3 and cystatin C. CONCLUSION: Renal toxicity in patients treated with [177Lu]Lu-PSMA-617 was low. There was no (sub)acute grade 3 or 4 nephrotoxicity. PMID- 28337531 TI - Advancement Flap for Treatment of Complex Cryptoglandular Anal Fistula: Prediction of Therapy Success or Failure Using Anamnestic and Clinical Parameters. AB - BACKGROUND: Multiple new procedures for treatment of complex anal fistula have been described in the past decades, but an ideal single technique has yet not been identified. Factors that predict the outcome are required to identify the best procedure for each individual patient. The aim of this study was to find those predictors for advancement flap at midterm follow-up. METHODS: From 2012 to 2015 in a tertiary university clinic, all patients who underwent advancement flap for treatment of complex cryptoglandular fistula were prospectively enrolled. Pre and postoperatively standardized anamnestic and clinical examinations were performed. Predictive factors for therapy failure were identified using univariate and multivariate analysis. RESULTS: Out of 65 patients, 61 (93%) completed all examinations and were included in the study. Therapy failure after a mean follow-up period of 25 months occurred in total n = 11 patients (18%). There was no significant disturbance of continence among the entire study cohort as shown by the incontinence score (preop 0.34 +/- 0.91 pts., postop 0.37 +/- 0.97 pts.; p = 0.59). Univariate analysis for risk factors for therapy failure revealed age (p = 0.004), history of surgical abscess drainage (p = 0.04), BMI (p = 0.002), suprasphincteric fistula (p = 0.019) and horseshoe abscess (p = 0.036) as independent parameters for therapy failure. During multivariate analysis, only history of surgical abscess drainage (OR = 8.09, p = 0.048, 95% CI 0.98-64.96), suprasphincteric fistula (OR = 6.83, p = 0.032, 95% CI 1.17-6.83) and BMI (OR = 1.23, p = 0.017, 95% CI 1.03-1.46) were independent parameters for therapy failure. CONCLUSION: Advancement flap for treatment of complex fistula is effective and has low risk of disturbed continence. BMI, suprasphincteric fistula and history of surgical abscess drainage are predictors for therapy failure. PMID- 28337532 TI - Transition from Laparoscopic Totally Extraperitoneal Inguinal Hernia Repair to Robotic Transabdominal Preperitoneal Inguinal Hernia Repair: A Retrospective Review of a Single Surgeon's Experience. AB - BACKGROUND: There is a paucity of literature comparing laparoscopic to robotic inguinal hernia repair. We present a single surgeon's transition from laparoscopic totally extraperitoneal (L-TEP) to robotic transabdominal preperitoneal (R-TAPP) inguinal hernia repair and compare outcomes from the two approaches. METHODS: This retrospective review and analysis of prospectively collected data compare outcomes during the transition from L-TEP to R-TAPP inguinal hernia repair by a single surgeon at one institution. Operating times and surgical outcomes and complications are analyzed. All consecutive L-TEP cases from November 2012 to August 2014 and all consecutive R-TAPP cases from March 2013 to October 2015 were included in the analysis. RESULTS: A total of 157 and 118 patients underwent L-TEP and R-TAPP inguinal hernia repair, respectively. The groups were similar regarding demographics and ASA class. A significantly higher number of complex cases were performed in the R-TAPP group compared to L-TEP group (n = 11 vs. n = 1, p = 0.0001). Mean surgical times were nearly identical (69.12 +/- 35.13 min, R-TAPP; 69.05 +/- 26.31, L-TEP) as were intraoperative and postoperative complication rates-despite the significantly higher number of complex cases in the R-TAPP group. CONCLUSIONS: This is the largest study in the literature comparing a single surgeon's experience transitioning from L-TEP to R TAPP inguinal hernia repair. Results from the R-TAPP cases were similar to those achieved from laparoscopic cases. The robotic platform may have facilitated the execution of complex hernia cases during the proficiency phase. PMID- 28337534 TI - Intermediate osteotomies in rhinoplasty: a new perspective. AB - The nasal dorsum framework plays a major role in nasal and facial harmony. This study presents a new approach to an already known technique, intermediate osteotomies, which can be used routinely in patients with cosmetically unpleasant changes in eyebrow-tip line features, allowing the acquisition of a natural, aesthetically agreeable and harmonious dorsum contour, while preserving nasal function. The approach was evaluated retrospectively in 50 consecutive patients at a tertiary referral hospital. Patients were asked to complete a survey to rate their satisfaction with the cosmetic outcome on a 5-point visual analog scale (VAS) and to compare the impact of nasal obstruction on their quality of life, pre- and postoperatively, by completing the validated Nasal Obstruction Symptom Evaluation (NOSE) scale. Satisfaction was scored as excellent (satisfaction level VAS average score, 4.4), with more than 50% of the patients completely satisfied with the aesthetic result, while NOSE scale scores demonstrated preservation of nasal function postoperatively. Typical complications of the upper third of the nose following osteotomies were not observed. PMID- 28337533 TI - Incidence of second surgery following pediatric adenotonsillar surgery: a population-based cohort study. AB - The aim of the study is to evaluate the incidence and risk factors of a second surgery of the adenoids or tonsils for hypertrophy in children who have already undergone surgery for the same condition. This is a retrospective study (2004 2013) based on data from the National patient registry in Sweden. A total of 41,401 children underwent a first surgery of the adenoids or tonsils during the studied period. The most commonly performed (first) surgical procedure was adenoidectomy followed by adenotonsillotomy, adenotonsillectomy, tonsillotomy, and tonsillectomy. A total of 4459 patients underwent a second surgery for the same condition. The incidence of a second surgery was the highest in the primary adenoidectomy group (72.2, 95% CI 69.7-74.7) and lowest in the primary adenotonsillectomy group (14.2, 95% CI 12.6-15.9). A lower age at first surgery significantly increased the risk for a second surgery. A second surgery of the adenoids and tonsils due to lymphoid hypertrophy was common in the pediatric population. Adenoidectomy stands out in a negative way in most aspects of this study compared to the other types of first surgery. However, due to the design of this study, the results of this study cannot be taken as proof of a full adenotonsillectomy as the most appropriate first surgery in children with lymphoid upper airway obstruction. Nevertheless, the results clearly show that the topic needs to be addressed in future studies. PMID- 28337535 TI - Anatomical and reverse shoulder replacement with a convertible, uncemented short stem shoulder prosthesis: first clinical and radiological results. PMID- 28337536 TI - Functional and patient-reported outcomes of the Swanson metacarpo-phalangeal arthroplasty in the rheumatoid hand. AB - INTRODUCTION: Replacement of the metacarpo-phalangeal joints (MCPJ) with silastic Swanson's implants can help decrease pain, stiffness and allow for improved function in rheumatoid arthritis (RA). There is a lack of patient reported outcome measure (PROM) studies assessing the efficacy of this procedure in RA. The aim of this study was to report any change in function, pain, stiffness and satisfaction following the Swanson MCPJ replacement using patient reported outcomes in a rheumatoid population. METHODS: The combined results of 64 RA patients (71 hands) with 284 Swanson MCPJ arthroplasties (mean follow-up: 75.85 months) were assessed using the validated M-SACRAH questionnaire and a separate satisfaction questionnaire. Radiographic evaluation was performed to insure correct alignment of the hinged prosthesis postoperatively. No attempt was made to identify other predictors, radiologically or clinically. Data analysed in the study was interpreted in the context of the number of hands and survivorship was defined as implant fracture, loosening or revision. RESULTS: The mean total functional outcome score improved by 46.2% and the total pain outcome improved by 60.2%. The total stiffness outcome improved by 56.9% postoperatively and the results obtained from the satisfaction questions revealed that 73.2% of patients would retrospectively elect to have the procedure again. We report two postoperative complications in this group of superficial wound infections. Radiographically, all MCPJs showed improved alignment, however five patients reported worsening pain, four patients reported increased stiffness and four reported reduced function postoperatively. There was one re-operation of a 5th MCPJ Swanson's, which did not require implant exchange and one implant was revised. Implant survivorship was 98.6%. CONCLUSIONS: Patient satisfaction and functional surrogate markers were overall favourable. Our results support the continued use of Swanson silastic arthoplasty in advanced RA. PMID- 28337538 TI - Prevalence and genetic characterization of Toxoplasma gondii in free-range chickens from grocery stores and farms in Maryland, Ohio and Massachusetts, USA. AB - Chickens are considered important in the epidemiology of Toxoplasma gondii. Chicken hearts (n = 1185) obtained from grocery stores were tested for T. gondii infection. Antibodies to T. gondii were assayed in fluid removed from the heart cavity using the modified agglutination test (MAT) at 1:5, 1:25, and 1:100 dilutions. MAT antibodies were detected in 222 hearts at 1:5 dilution and 8 hearts at 1:25 dilution, but none were positive at 1:100 dilution. Seropositive (n = 230, 19.4%) chicken hearts were bioassayed in mice and seronegative (n = 157) chickens were bioassayed in cats. Viable T. gondii was not isolated from any hearts by bioassays in mice. The 2 cats fed 60 and 97 hearts did not excrete T. gondii oocysts. The results indicate a low prevalence of viable T. gondii in chickens from grocery stores. Molecular typing of 23 archived T. gondii strains isolated from free-range chickens from Ohio and Massachusetts using the 10 PCR RFLP markers including SAG1, SAG2 (5'-3'SAG2 and altSAG2), SAG3, BTUB, GRA6, c22 8, c29-2, L358, PK1, and Apico revealed that seven were ToxoDB PCR-RFLP genotype #1, 11 were genotype #2, one was genotype #3, three were genotype #170, and one was mixed genotype. These results indicate that the clonal genotypes #1 (type II), #2 (type III), and #3 (type II variant) are common in free-range chickens. PMID- 28337537 TI - Is prepulse modification altered by continuous theta burst stimulation? DAT1 genotype and motor threshold interact on prepulse modification following brain stimulation. AB - Previous studies suggest an inhibitory top-down control of the amygdala by the prefrontal cortex (PFC). Both brain regions play a role in the modulation of prepulse modification (PPM) of the acoustic startle response by a pre-stimulus. Repetitive transcranial magnetic stimulation (rTMS) can modulate the activity of the PFC and might thus affect PPM. This study tested the effect of inhibitory rTMS on PPM accounting for a genetic variant of the dopamine transporter gene (DAT1). Healthy participants (N = 102) were stimulated with continuous theta burst stimulation (cTBS, an intense form of inhibitory rTMS) or sham treatment over the right PFC. Afterwards, during continuous presentation of a background white noise a louder noise burst was presented either alone (control startle) or preceded by a prepulse. Participants were genotyped for a DAT1 variable number tandem repeat (VNTR) polymorphism. Two succeeding sessions of cTBS over the right PFC (2 * 600 stimuli with a time lag of 15 min) attenuated averaged prepulse inhibition (PPI) in participants with a high resting motor threshold. An attenuation of PPI induced by prepulses with great distances to the pulse (480, 2000 ms) was observed following active cTBS in participants that were homozygous carriers of the 10-repeat-allele of the DAT1 genotype and had a high resting motor threshold. Our results confirm the importance of the prefrontal cortex for the modulation of PPM. The effects were observed in participants with a high resting motor threshold only, probably because they received a higher dose of cTBS. The effects in homozygous carriers of the DAT1 10-repeat allele confirm the relevance of dopamine for PPM. Conducting an exploratory study we decided against the use of a correction for multiple testing. PMID- 28337539 TI - Homer1 (VesL-1) in the rat esophagus: focus on myenteric plexus and neuromuscular junction. AB - Homer1, a scaffolding protein of the postsynaptic density (PSD), enriched at excitatory synapses is known to anchor and modulate group I metabotropic glutamate receptors (mGluRs) and different channel- and receptor-proteins. Homer proteins are expressed in neurons of different brain regions, but also in non neuronal tissues like skeletal muscle. Occurrence and location of Homer1 and mGluR5 in myenteric plexus and neuromuscular junctions (NMJ) of rat esophagus have yet not been characterized. We located Homer1 and mGluR5 immunoreactivity ( iry) in rat esophagus and focused on myenteric neurons, intraganglionic laminar endings (IGLEs) and NMJs, using double- and triple-label immunohistochemistry and confocal laser scanning microscopy. Homer1-iry was found in a subpopulation of vesicular glutamate transporter 2 (VGLUT2) positive IGLEs and cholinergic varicosities within myenteric ganglia, but neither in nitrergic nor cholinergic myenteric neuronal cell bodies. Homer1-iry was detected in 63% of esophageal and, for comparison, in 35% of sternomastoid NMJs. Besides the location in the PSD, Homer1-iry colocalized with cholinergic markers, indicating a presynaptic location in coarse VAChT/CGRP/NF200- immunoreactive (-ir) terminals of nucleus ambiguus neurons supplying striated esophageal muscle. mGluR5-iry was found in subpopulations of myenteric neuronal cell bodies, VGLUT2-ir IGLEs and cholinergic varicosities within the myenteric neuropil and NMJs of esophagus and sternomastoid muscles. Thus, Homer1 may anchor mGluR5 at presynaptic sites of cholinergic boutons at esophageal motor endplates, in a small subpopulation of VGLUT2-ir IGLEs and cholinergic varicosities within myenteric ganglia possibly modulating Ca2+-currents and neurotransmitter release. PMID- 28337540 TI - The discovery of plastid-to-nucleus retrograde signaling-a personal perspective. AB - DNA and machinery for gene expression have been discovered in chloroplasts during the 1960s. It was soon evident that the chloroplast genome is relatively small, that most genes for chloroplast-localized proteins reside in the nucleus and that chloroplast membranes, ribosomes, and protein complexes are composed of proteins encoded in both the chloroplast and the nuclear genome. This situation has made the existence of mechanisms highly probable that coordinate the gene expression in plastids and nucleus. In the 1970s, the first evidence for plastid signals controlling nuclear gene expression was provided by studies on plastid ribosome deficient mutants with reduced amounts and/or activities of nuclear-encoded chloroplast proteins including the small subunit of Rubisco, ferredoxin NADP+ reductase, and enzymes of the Calvin cycle. This review describes first models of plastid-to-nucleus signaling and their discovery. Today, many plastid signals are known. They do not only balance gene expression in chloroplasts and nucleus during developmental processes but are also generated in response to environmental changes sensed by the organelles. PMID- 28337541 TI - Tyrosine kinase inhibitor therapy-induced changes in humoral immunity in patients with chronic myeloid leukemia. AB - PURPOSE: Tyrosine kinase inhibitors (TKIs) have well-characterized immunomodulatory effects on T and NK cells, but the effects on the humoral immunity are less well known. In this project, we studied TKI-induced changes in B cell-mediated immunity. METHODS: We collected peripheral blood (PB) and bone marrow (BM) samples from chronic myeloid leukemia (CML) patients before and during first-line imatinib (n = 20), dasatinib (n = 16), nilotinib (n = 8), and bosutinib (n = 12) treatment. Plasma immunoglobulin levels were measured, and different B cell populations in PB and BM were analyzed with flow cytometry. RESULTS: Imatinib treatment decreased plasma IgA and IgG levels, while dasatinib reduced IgM levels. At diagnosis, the proportion of patients with IgA, IgG, and IgM levels below the lower limit of normal (LLN) was 0, 11, and 6% of all CML patients, respectively, whereas at 12 months timepoint the proportions were 6% (p = 0.13), 31% (p = 0.042) and 28% (p = 0.0078). Lower initial Ig levels predisposed to the development of hypogammaglobulinemia during TKI therapy. Decreased Ig levels in imatinib-treated patients were associated with higher percentages of immature BM B cells. The patients, who had low Ig levels during the TKI therapy, had significantly more frequent minor infections during the follow-up compared with the patients with normal Ig values (33% vs. 3%, p = 0.0016). No severe infections were reported, except recurrent upper respiratory tract infections in one imatinib-treated patient, who developed severe hypogammaglobulinemia. CONCLUSIONS: TKI treatment decreases plasma Ig levels, which should be measured in patients with recurrent infections. PMID- 28337544 TI - Complete genome sequences of cowpea polerovirus 1 and cowpea polerovirus 2 infecting cowpea plants in Burkina Faso. AB - The full-length genome sequences of two novel poleroviruses found infecting cowpea plants, cowpea polerovirus 1 (CPPV1) and cowpea polerovirus 2 (CPPV2), were determined using overlapping RT-PCR and RACE-PCR. Whereas the 5845-nt CPPV1 genome was most similar to chickpea chlorotic stunt virus (73% identity), the 5945-nt CPPV2 genome was most similar to phasey bean mild yellow virus (86% identity). The CPPV1 and CPPV2 genomes both have a typical polerovirus genome organization. Phylogenetic analysis of the inferred P1-P2 and P3 amino acid sequences confirmed that CPPV1 and CPPV2 are indeed poleroviruses. Four apparently unique recombination events were detected within a dataset of 12 full polerovirus genome sequences, including two events in the CPPV2 genome. Based on the current species demarcation criteria for the family Luteoviridae, we tentatively propose that CPPV1 and CPPV2 should be considered members of novel polerovirus species. PMID- 28337543 TI - Superiority of stapled side-to-side gastrojejunostomy over conventional hand-sewn end-to-side gastrojejunostomy for reducing the risk of primary delayed gastric emptying after subtotal stomach-preserving pancreaticoduodenectomy. AB - BACKGROUND AND PURPOSE: Delayed gastric emptying (DGE) is the most common complication following pancreaticoduodenectomy (PD). The clinical efficacy of stapled side-to-side anastomosis using a laparoscopic stapling device during alimentary reconstruction in PD is not well understood and its superiority over conventional hand-sewn end-to-side anastomosis remains controversial. The objective of this study was to evaluate the effectiveness of the stapled side-to side anastomosis in preventing the development of DGE after PD. METHODS: The subjects of this retrospective study were 137 patients who underwent pancreaticoduodenectomy, as subtotal stomach-preserving pancreaticoduodenectomy (SSPPD; n = 130), or conventional whipple procedure (n = 7) with Child reconstruction, between January 2010 and May 2014. The patients were divided into two groups according to whether they had had a stapled side-to-side anastomosis (SA group; n = 57) or a conventional hand-sewn end-to-side anastomosis (HA group; n = 80). RESULTS: SA reduced the operative time (SA vs. HA: 508 vs. 557 min, p = 0.028) and the incidence of delayed gastric emptying (SA vs. HA: 21.1 vs. 46.3%, p = 0.003) and was associated with shorter hospitalization (SA vs. HA: 33 vs. 39.5 days, p = 0.007). In this cohort, SA was the only significant factor contributing to a reduction in the incidence of DGE (p = 0.002). CONCLUSIONS: Stapled side-to-side gastrojejunostomy reduced the operative time and the incidence of DGE following PD with Child reconstruction, thereby also reducing the length of hospitalization. PMID- 28337545 TI - Retrospective investigation and evolutionary analysis of a novel porcine deltacoronavirus strain detected in Thailand from 2008 to 2015. AB - Porcine deltacoronavirus (PDCoV) in Thailand was first detected in 2015. We performed a retrospective investigation of the presence of PDCoV in intestinal samples collected from piglets with diarrhea in Thailand from 2008 to 2015 using RT-PCR. PDCoV was found to be present as early as February 2013. Phylogenetic analysis demonstrated that all PDCoV variants from Thailand differ from those from other countries and belong to a novel group of PDCoV that is separate from the US and Chinese PDCoV variants. Evolutionary analysis suggested that the Thai PDCoV isolates probably diverged from a different ancestor from that of the Chinese and US PDCoV isolates and that this separation occurred after 1994. PMID- 28337542 TI - alpha-Synuclein binds to the ER-mitochondria tethering protein VAPB to disrupt Ca2+ homeostasis and mitochondrial ATP production. AB - alpha-Synuclein is strongly linked to Parkinson's disease but the molecular targets for its toxicity are not fully clear. However, many neuronal functions damaged in Parkinson's disease are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. This signalling involves close physical associations between the two organelles that are mediated by binding of the integral ER protein vesicle-associated membrane protein-associated protein B (VAPB) to the outer mitochondrial membrane protein, protein tyrosine phosphatase interacting protein 51 (PTPIP51). VAPB and PTPIP51 thus act as a scaffold to tether the two organelles. Here we show that alpha-synuclein binds to VAPB and that overexpression of wild-type and familial Parkinson's disease mutant alpha synuclein disrupt the VAPB-PTPIP51 tethers to loosen ER-mitochondria associations. This disruption to the VAPB-PTPIP51 tethers is also seen in neurons derived from induced pluripotent stem cells from familial Parkinson's disease patients harbouring pathogenic triplication of the alpha-synuclein gene. We also show that the alpha-synuclein induced loosening of ER-mitochondria contacts is accompanied by disruption to Ca2+ exchange between the two organelles and mitochondrial ATP production. Such disruptions are likely to be particularly damaging to neurons that are heavily dependent on correct Ca2+ signaling and ATP. PMID- 28337547 TI - Retinal vascular changes after vitrectomy for idiopathic epiretinal membrane: a pilot study with dynamic vessel analysis. AB - PURPOSE: To investigate, using the Dynamic Vessel Analyzer (DVA), the retinal vascular changes that may occur after vitrectomy for idiopathic epiretinal membrane (ERM). METHODS: Twenty-six eyes of 13 patients affected by unilateral idiopathic ERM were prospectively analyzed. 13 fellow eyes were used as control. The static (central retinal artery and vein equivalents) and dynamic (after flicker light stimulus) DVA analysis was performed at baseline (1 day before surgery) and 6 months after vitrectomy. RESULTS: The static DVA analysis did not highlight any significant change between investigational eyes and controls at baseline and 6 months after surgery. The DVA dynamic analysis showed similar arterial flicker response between cases and controls at baseline (p = 0.3396), but disclosed a significant reduction of the arterial flicker response after surgery in the study eyes compared to fellow eyes (p = 0.0024). No significant changes were appreciated in the venous flicker response after surgery between cases and controls, both at baseline (p = 0.3450) and at the follow-up examination (p = 0.4214). CONCLUSIONS: The physiological flicker-induced vasoconstriction is reduced after vitrectomy in arteries. The oxygen saturation change occurring after vitrectomy might have a role in the vascular tone modification. PMID- 28337546 TI - Robotic thyroidectomy versus conventional open thyroidectomy for thyroid cancer: a systematic review and meta-analysis. AB - BACKGROUND: Despite the new technical alternative offered by the robotic surgery for minimally invasive thyroid surgery, the role of the robotic thyroidectomy (RT) in thyroid cancer has been highly disputed. This paper gives a systematic review and meta-analysis aiming to compare RT and open thyroidectomy (OT) based on the surgical outcomes and oncologic results. METHODS: Relevant literature was searched from various databases up to July 2016, including PubMed, MEDLINE, EMBASE, Cochrane Library, Web of science and Clinical Trials. gov. Outcomes of interest included patient characteristics, surgical outcomes, adverse events and complications, recurrence rate, and surgical completeness. RESULTS: The systematic review and meta-analysis were based on the 5200 cases selected from the twenty-three publications. RT was associated with an equivalent adverse event and complication rate including transient hypocalcemia, permanent hypocalcemia, transient hoarseness, permanent recurrent laryngeal nerve (RLN) palsy, transient hypoparathyroidism, permanent hypoparathyroidism, hematoma, postoperative bleeding, seroma, chyle leakage, the Voice Handicap Index-10 (VHI-10) score, as well as equivalent surgical completeness including postoperative radioactive iodine (RAI) ablation rate, number of RAI ablation sessions, mean total RAI ablation dose, mean stimulated Tg of postoperation RAI, and proportion of stimulated Tg < 1.0 ng/ml on first ablation. Moreover, RT had lesser blood loss (WMD - 1.47, p = 0.04), smaller number of retrieved lymph nodes (WMD - 1.21, p = 0.0002), a low level of swallowing impairment (WMD - 4.17, p < 0.00001), and better cosmetic satisfaction (OR 4.05, p < 0.00001). However, OT was associated with shorter operation time (WMD 69.80, p < 0.00001), less total drain amount (WMD 66.53, p < 0.0001), and lower postoperative serum Tg level (WMD 0.21, p < 0.00001). CONCLUSIONS: RT is as safe as OT for the treatment of thyroid cancer. Based on the long-time follow-up and surgical completeness, the adverse events and complications, and recurrence rate of RT were comparable with OT. RT was associated with a significantly lesser blood loss, smaller number of retrieved lymph nodes, a lower level of swallowing impairment, and better cosmetic satisfaction. In contrast, OT was associated with shorter operation time, smaller total drain amount, and lower postoperative serum Tg level. Overall, randomized clinical trials and larger patient cohort with long-term follow-up are still essential to further demonstrate the value of the robotic approach. PMID- 28337548 TI - The effects of anxiety and situation-specific context on perceptual-motor skill: a multi-level investigation. AB - We examined the effects of anxiety and situation-specific contextual information on attentional, interpretational, and behavioural processes underpinning perceptual-motor performance as proposed by Nieuwenhuys and Oudejans (Psychological Research 76:747-759; Nieuwenhuys, Oudejans, Psychological Research 76:747-759, 2012) using an in situ task. Twelve skilled cricket batsmen played against a skilled spin bowler under conditions manipulated to induce low and high levels of anxiety and the presence of low and high levels of situation-specific context. High anxiety decreased the number of good bat-ball contacts, while high levels of situation-specific context increased the number of times the ball was missed. When under high anxiety, participants employed significantly more fixations of shorter duration to more locations, but the effects of anxiety were restricted to the attentional level only. Situation-specific context affected performance and behavioural measures but not anxiety, cognitive load or perceptual-cognitive processes, suggesting that performance is influenced through different mechanisms from anxiety that are independent of working memory load. PMID- 28337549 TI - Perceptual impressions of causality are affected by common fate. AB - Many studies of perceptual impressions of causality have used a stimulus in which a moving object (the launcher) contacts a stationary object (the target) and the latter then moves off. Such stimuli give rise to an impression that the launcher makes the target move. In the present experiments, instead of a single target object, an array of four vertically aligned objects was used. The launcher contacted none of them, but stopped at a point between the two central objects. The four objects then moved with similar motion properties, exhibiting the Gestalt property of common fate. Strong impressions of causality were reported for this stimulus. It is argued that the array of four objects was perceived, by the likelihood principle, as a single object with some parts unseen, that the launcher was perceived as contacting one of the unseen parts of this object, and that the causal impression resulted from that. Supporting that argument, stimuli in which kinematic features were manipulated so as to weaken or eliminate common fate yielded weaker impressions of causality. PMID- 28337551 TI - Purkinje-related trigger and substrate of recurrent ventricular tachycardia in a patient with ischemic cardiomyopathy. PMID- 28337550 TI - Common genetic etiology between "multiple sclerosis-like" single-gene disorders and familial multiple sclerosis. AB - Several single-gene disorders with clinical and radiological characteristics similar to those observed in multiple sclerosis (MS) patients have been described. To evaluate whether this phenotypic overlap can be ascribed to a common genetic etiology, 28 genes known to present pathogenic mutations for 24 of these disorders were sequenced in 270 MS patients. All identified variants were genotyped in 2131 MS cases and 830 healthy controls, and those exclusively observed in patients were assessed for segregation within families. This analysis identified 9 rare variants in 6 genes segregating with disease in 13 families. Four different mutations were identified in CYP27A1, including a reported pathogenic mutation for cerebrotendinous xanthomatosis (p.R405W), which was observed in six patients from a multi-incident family, three diagnosed with MS, two with an undefined neurological disease and one seemingly healthy. A LYST p.V1678A and a PDHA1 p.K387Q mutation were both observed in five MS patients from three separate multi-incident families. In addition, CLCN2 p.V174G, GALC p.D162E and POLG p.R361G were each identified in two MS patients from one family. This study suggests a shared genetic etiology between MS and the characterized single gene disorders, and highlights cholesterol metabolism and the synthesis of oxysterols as important biological mechanisms for familial MS. PMID- 28337553 TI - Early palliative care: current status of integration within German comprehensive cancer centers. AB - PURPOSE: The aim of this study is to describe how models of early integration (EI) of specialized palliative care (SPC) are applied to German comprehensive cancer center (CCCs). METHODS: Heads of SPC departments of the 15 German CCCs were asked by email to describe the situation of early SPC in their CCC. The responses were analyzed using MAXQDA. RESULTS: Thirteen answers were allowed to be analyzed. Most of the department heads report that EI models of SPC are partially applied in the CCC (responses with "yes" or "partly," n = 10). Though they often describe that the models' implementation needs optimization and depends on temporary and financial restrictions or it has a pilot character. Models compromise structures like SPC unit, inpatient/outpatient SPC consultation team, and participation of members of SPC team in tumor boards. Moreover, other EI models of SPC quoted by the participants were standard operating procedures (SOP), screening tools, and information material for physicians, patients, and their related persons. CONCLUSIONS: Currently, German CCC models of EI of SPC are not applied in a standardized way. Approaches are still very diverse. PMID- 28337554 TI - Successive relaxation cycles during long-time cell aggregate rounding after uni axial compression. AB - The mean features of cell surface rearrangement during cell aggregate rounding after uni-axial compression between parallel plates are considered. This is based on long-time rheological modeling approaches in order to shed further light on collective cell migration. Many aspects of cell migration at the supra-cellular level, such as the coordination between surrounding migrating cell groups that leads to uncorrelated motility, have remained unclear. Aggregate shape changes during rounding are considered depending on the size and homogeneity of 2-D and 3 D cell aggregates. Cell aggregate shape changes that are taking place during successive relaxation cycles have various relaxation rates per cycle. Every relaxation rate is related to the corresponding cell migrating state. If most of the cells migrate per cycle, the relaxation rate is maximal. If most of the cells are in a resting state per cycle, the relaxation rate is nearing zero. If some cell groups migrate while the others, at the same time, stay in a resting state, the relaxation rate is lower than that obtained for the migrating cells. The relaxation rates per cycles are not random, but they have a tendency to gather around two or three values indicating an organized cell migrating pattern. Such behavior suggests that uncorrelated motility during collective cell migration in one cycle induces a decrease of the relaxation rate in the next cycle caused by an accumulation of cells in the resting state. However, cells have the ability to overcome these perturbations and re-establish an ordered migrating trend in the next cycle. These perturbations of the cell migrating state are more pronounced for: (1) more mobile cells, (2) a heterogeneous cell population, and (3) a larger cell population under the same experimental conditions. PMID- 28337552 TI - Clinical utility of resting-state functional connectivity magnetic resonance imaging for mood and cognitive disorders. AB - Although functional magnetic resonance imaging (fMRI) has long been used to assess task-related brain activity in neuropsychiatric disorders, it has not yet become a widely available clinical tool. Resting-state fMRI (rs-fMRI) has been the subject of recent attention in the fields of basic and clinical neuroimaging research. This method enables investigation of the functional organization of the brain and alterations of resting-state networks (RSNs) in patients with neuropsychiatric disorders. Rs-fMRI does not require participants to perform a demanding task, in contrast to task fMRI, which often requires participants to follow complex instructions. Rs-fMRI has a number of advantages over task fMRI for application with neuropsychiatric patients, for example, although applications of task fMR to participants for healthy are easy. However, it is difficult to apply these applications to patients with psychiatric and neurological disorders, because they may have difficulty in performing demanding cognitive task. Here, we review the basic methodology and analysis techniques relevant to clinical studies, and the clinical applications of the technique for examining neuropsychiatric disorders, focusing on mood disorders (major depressive disorder and bipolar disorder) and dementia (Alzheimer's disease and mild cognitive impairment). PMID- 28337555 TI - Erratum to: Construction of a thermo-sensitive pRI857 vector for efficient DNA capturing in Escherichia coli. PMID- 28337556 TI - Homologous gene targeting of a carotenoids biosynthetic gene in Rhodosporidium toruloides by Agrobacterium-mediated transformation. AB - OBJECTIVES: To target a carotenoid biosynthetic gene in the oleaginous yeast Rhodosporidium toruloides by using the Agrobacterium-mediated transformation (AMT) method. RESULTS: The RHTO_04602 locus of R. toruloides NP11, previously assigned to code the carotenoid biosynthetic gene CRTI, was amplified from genomic DNA and cloned into the binary plasmid pZPK-mcs, resulting in pZPK-CRT. A HYG-expression cassette was inserted into the CRTI sequence of pZPK-CRT by utilizing the restriction-free clone strategy. The resulted plasmid was used to transform R. toruloides cells according to the AMT method, leading to a few white transformants. Sequencing analysis of those transformants confirmed homologous recombination and insertional inactivation of CRTI. When the white variants were transformed with a CRTI-expression cassette, cells became red and produced carotenoids as did the wild-type strain NP11. CONCLUSIONS: Successful homologous targeting of the CrtI locus confirmed the function of RHTO_04602 in carotenoids biosynthesis in R. toruloides. It provided valuable information for metabolic engineering of this non-model yeast species. PMID- 28337557 TI - MiR-9 enhances the sensitivity of A549 cells to cisplatin by inhibiting autophagy. AB - OBJECTIVES: To demonstrate that miR-9 inhibits autophagy by down-regulating Beclin1 and thus enhances the sensitivity of A549 cells to cisplatin. RESULTS: MiR-9 inhibited Beclin1 expression by binding to its 3'UTR. The inhibition decreased the cisplatin-induced autophagy in A549 cells, evidenced by the decreased expression of LC3II and GFP-LC3 puncta and the increased expression of P62. Upregulation of miR-9 level enhanced the sensibility of A549 cells to cisplatin and increased the cisplatin-induced apoptosis. Overexpression of Beclin1 reversed above effects of miR-9 mimics, cisplatin-induced autophagy was increased and apoptosis was decreased. CONCLUSIONS: MiR-9 inhibits autophagy via targeting Beclin1 3'UTR and thus enhances cisplatin sensitivity in A549 cells. PMID- 28337558 TI - Improving on the diagnostic characteristics of echocardiography for pulmonary hypertension. AB - This retrospective study evaluated the diagnostic characteristics of a combination of echocardiographic parameters for pulmonary hypertension (PH). Right ventricular systolic pressure (RVSP) estimation by echocardiography (echo) is used to screen for PH. However, the sensitivity of this method is suboptimal. We hypothesized that RVSP estimation in conjunction with other echo parameters would improve the value of echo for PH. The Duke Echo database was queried for adult patients with known or suspected PH who had undergone both echo and right heart catheterization (RHC) within a 24 h period between 1/1/2008 and 12/31/2013. Patients with complex congenital heart disease, heart transplantation, ventricular assist device, or on mechanical ventilation at time of study were excluded. Diagnostic characteristics of several echo parameters (right atrial enlargement, pulmonary artery (PA) enlargement, RV enlargement, RV dysfunction, and RVSP) for PH (mean PA pressure 25 mmHg on RHC) were evaluated among 1007 patients. RVSP >=40 had a sensitivity of 77% (accuracy 77), while RVSP >=35 had the highest sensitivity at 88% (81% accuracy). PA enlargement had the lowest sensitivity at 17%. The area under the curve (AUC) for RVSP was 0.844. A model including RVSP, RA, PA, RV enlargement and RV dysfunction had a higher AUC (AUC = 0.87) than RVSP alone. The value of echo as a screening test for PH is improved by a model incorporating a lower RVSP in addition to other right heart parameters. These findings need to be validated in prospective cohorts. PMID- 28337559 TI - Dietary fiber intake and risk of breast cancer defined by estrogen and progesterone receptor status: the Japan Public Health Center-based Prospective Study. AB - PURPOSE: Epidemiological studies have suggested a protective effect of dietary fiber intake on breast cancer risk while the results have been inconsistent. Our study aimed to investigate the association between dietary fiber intake and breast cancer risk and to explore whether this association is modified by reproductive factors and hormone receptor status of the tumor. METHODS: A total of 44,444 women aged 45 to 74 years from the Japan Public Health Center-based Prospective Study were included in analyses. Dietary intake assessment was performed using a validated 138-item food frequency questionnaire (FFQ). Hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer incidence were calculated by multivariate Cox proportional hazards regression models. RESULTS: During 624,423 person-years of follow-up period, 681 breast cancer cases were identified. After adjusting for major confounders for breast cancer risk, inverse trends were observed but statistically non-significant. Extremely high intake of fiber was associated with decreased risk of breast cancer but this should be interpreted with caution due to limited statistical power. In stratified analyses by menopausal and hormone receptor status, null associations were observed except for ER-PR- status. CONCLUSIONS: Our findings suggest that extreme high fiber intake may be associated with decreased risk of breast cancer but the level of dietary fiber intake among Japanese population might not be sufficient to examine the association between dietary fiber intake and breast cancer risk. PMID- 28337560 TI - Medical mistrust as a key mediator in the association between perceived discrimination and adherence to antiretroviral therapy among HIV-positive Latino men. AB - Discrimination has been found to have deleterious effects on physical health. The goal of the present study was to examine the association between perceived discrimination and adherence to antiretroviral therapy (ART) among HIV-positive Latino men and the extent to which medical mistrust serves as a mediator of that association. A series of linear and logistic regression models was used to test for mediation for three types of perceived discrimination (related to being Latino, being perceived as gay and being HIV-positive). Medical mistrust was found to be significantly associated with perceived discrimination based on Latino ethnicity and HIV serostatus. Medical mistrust was found to mediate the associations between two types of perceived discrimination (related to being Latino and being HIV-positive) and ART adherence. Given these findings, interventions should be developed that increase the skills of HIV-positive Latino men to address both perceived discrimination and medical mistrust. PMID- 28337561 TI - Optimization of ultraviolet ozone treatment process for improvement of polycaprolactone (PCL) microcarrier performance. AB - Growing cells on microcarriers may have overcome the limitation of conventional cell culture system. However, the surface functionality of certain polymeric microcarriers for effective cell attachment and growth remains a challenge. Polycaprolactone (PCL), a biodegradable polymer has received considerable attention due to its good mechanical properties and degradation rate. The drawback is the non-polar hydrocarbon moiety which makes it not readily suitable for cell attachment. This report concerns the modification of PCL microcarrier surface (introduction of functional oxygen groups) using ultraviolet irradiation and ozone (UV/O3) system and investigation of the effects of ozone concentration, the amount of PCL and exposure time; where the optimum conditions were found to be at 60,110.52 ppm, 5.5 g PCL and 60 min, respectively. The optimum concentration of carboxyl group (COOH) absorbed on the surface was 1495.92 nmol/g and the amount of gelatin immobilized was 320 +/- 0.9 ug/g on UV/O3 treated microcarriers as compared to the untreated (26.83 +/- 3 ug/g) microcarriers. The absorption of functional oxygen groups on the surface and the immobilized gelatin was confirmed with the attenuated total reflectance Fourier transformed infrared spectroscopy (ATR-FTIR) and the enhancement of hydrophilicity of the surface was confirmed using water contact angle measurement which decreased (86.93 degrees 49.34 degrees ) after UV/O3 treatment and subsequently after immobilization of gelatin. The attachment and growth kinetics for HaCaT skin keratinocyte cells showed that adhesion occurred much more rapidly for oxidized surfaces and gelatin immobilized surface as compared to untreated PCL. PMID- 28337563 TI - Role of low-level laser therapy added to facial expression exercises in patients with idiopathic facial (Bell's) palsy. AB - The aim of the present study was to investigate the efficacy of low-level laser therapy in conjunction with conventional facial exercise treatment on functional outcomes during the early recovery period in patients with facial paralysis. Forty-six patients (mean age 41 +/- 9.7 years; 40 women and 6 men) were randomized into two groups. Patients in the first group received low-level laser treatment as well as facial exercise treatment, while patients in the second group participated in facial exercise intervention alone. Laser treatment was administered at a wavelength of 830 nm, output power of 100 Mw, and frequency of 1 KHz using a gallium-aluminum-arsenide (GaAIAs, infrared laser) diode laser. A mean energy density of 10 J/cm2 was administered to eight points of the affected side of the face three times per week, for a total of 6 weeks. The rate of facial improvement was evaluated using the facial disability index (FDI) before, 3 weeks after, and 6 weeks after treatment. Friedman analysis of variance was performed to compare the data from the parameters repeatedly measured in the inner-group analysis. Bonferroni correction was performed to compare between groups as a post hoc test if the variance analysis test result was significant. To detect the group differences, the Bonferroni Student t test was used. The Mann-Whitney U test was used to compare numeric data between the groups. In the exercise group, although no significant difference in FDI scores was noted between the start of treatment and week 3 (p < 0.05), significant improvement was observed at week 6 (p < 0.001). In the laser group, significant improvement in FDI scores relative to baseline was observed at 3 and 6 weeks (p < 0.001). Improvements in FDI scores were significantly greater at weeks 3 and 6 in the laser group than those in the exercise group (p < 0.05). Our findings indicate that combined treatment with low level laser therapy (LLLT) and exercise therapy is associated with significant improvements in FDI when compared with exercise therapy alone. PMID- 28337564 TI - Lower face cephalometry based on quadrilateral analysis with cone-beam computed tomography: a clinical pilot study. AB - OBJECTIVE: As most orthognathic surgeries focus on the lower face, the aim of this study was to transfer previously developed two-dimensional cephalometry which is useful for surgeons in the orthognathic surgery of the lower face-to three-dimensional (3D) cephalometry by using cone-beam computed tomography (CBCT). We selected the quadrilateral lower face analysis developed by the surgeon Di Paolo, who focused only for the lower face and mentioned that data in millimeters are more easy to use than angles for surgeons. Additionally, we wanted to create a 3D lower face analysis approach based on quadrilateral analysis and establish a reference table for surgical planning. STUDY DESIGN: Three investigators assigned 16 landmarks on CBCT images from 30 patients with normocclusion. Intra-class correlation coefficients (ICCs) and standard deviations (SDs) were calculated according to each landmark. The maxillary and mandibular lengths and widths and the anterior and posterior lower facial heights (ALFH and PLFH) are presented as means and SDs. The asymmetry of the face was calculated with paired t test, and the coherence of the lower face was assessed with correlation coefficients (r) and regression models. RESULTS: The ICCs were >=0.90, and the SDs of the landmarks were lower than 1.00 mm, except for the J point, which was located at the junction of the anterior border of the ramus and the corpus of the mandible. The SDs of linear measurements were 3.06-5.20 mm, and there was no significant facial asymmetry. The r among the structures was greater than 0.3 in 13 of 15 assessments. Based on these values, we could establish a floating norm of the lower face using the following five regressions: one linear regression for the mandibular length, two quadratic models for the ALFH and PLFH, and two multivariate regressions for the posterior widths of the maxillae and mandible. CONCLUSION: The adaptation of quadrilateral analysis can provide accurate 3D characterization of the morphology of the lower face and the floating norm based on millimeter values, which is practical for surgeons. As the 3D extension of quadrilateral analysis could provide references of the lower face, which might be an accurate 3D approach for presurgical planning, the further investigation in bigger sample would be relevant in the practice. PMID- 28337565 TI - Blood trace metals in a sporadic amyotrophic lateral sclerosis geographical cluster. AB - Amyotrophic lateral sclerosis (ALS) is a fatal disorder with unknown etiology, in which genetic and environmental factors interplay to determine the onset and the course of the disease. Exposure to toxic metals has been proposed to be involved in the etiology of the disease either through a direct damage or by promoting oxidative stress. In this study we evaluated the concentration of a panel of metals in serum and whole blood of a small group of sporadic patients, all living in a defined geographical area, for which acid mine drainage has been reported. ALS prevalence in this area is higher than in the rest of Italy. Results were analyzed with software based on artificial neural networks. High concentrations of metals (in particular Se, Mn and Al) were associated with the disease group. Arsenic serum concentration resulted lower in ALS patients, but it positively correlated with disease duration. Comet assay was performed to evaluate endogenous DNA damage that resulted not different between patients and controls. Up to now only few studies considered geographically well-defined clusters of ALS patients. Common geographical origin among patients and controls gave us the chance to perform metallomic investigations under comparable conditions of environmental exposure. Elaboration of these data with software based on machine learning processes has the potential to be extremely useful to gain a comprehensive view of the complex interactions eventually leading to disease, even in a small number of subjects. PMID- 28337562 TI - BACE2 suppression promotes beta-cell survival and function in a model of type 2 diabetes induced by human islet amyloid polypeptide overexpression. AB - BACE2 (beta-site APP-cleaving enzyme 2) is a protease expressed in the brain, but also in the pancreas, where it seems to play a physiological role. Amyloidogenic diseases, including Alzheimer's disease and type 2 diabetes (T2D), share the accumulation of abnormally folded and insoluble proteins that interfere with cell function. In T2D, islet amyloid polypeptide (IAPP) deposits have been shown to be a pathogenic key feature of the disease. The aim of the present study was to investigate the effect of BACE2 modulation on beta-cell alterations in a mouse model of T2D induced by IAPP overexpression. Heterozygous mice carrying the human transcript of IAPP (hIAPP-Tg) were used as a model to study the deleterious effects of IAPP upon beta-cell function. These animals showed glucose intolerance and impaired insulin secretion. When crossed with BACE2-deficient mice, the animals presented a significant improvement in glucose tolerance accompanied with an enhanced insulin secretion, as compared to hIAPP-Tg mice. BACE2 deficiency also partially reverted gene expression changes observed in islets from hIAPP-Tg mice, including a set of genes related to inflammation. Moreover, homozygous hIAPP mice presented a severe hyperglycemia and a high lethality rate from 8 weeks onwards due to a massive destruction of beta-cell mass. This process was significantly reduced when crossed with the BACE2-KO model, improving the survival rate of the animals. Altogether, the absence of BACE2 ameliorates glucose tolerance defects induced by IAPP overexpression in the beta-cell and promotes beta-cell survival. Thus, targeting BACE2 may represent a promising therapeutic strategy to improve beta-cell function in T2D. PMID- 28337566 TI - Liver mitochondrial membrane fluidity at early development of diabetes and its correlation with the respiration. AB - The biological membranes are important in cell function but, during development of diseases such as diabetes, they are impaired. Consequently, membrane associated biological processes are impaired as well. The mitochondria are important organelles where oxidative phosphorylation takes place, a process closely related with the membranes. In general, it is accepted that the development process of diabetes decreases membrane fluidity. However, in some cases, it has been found to increase membrane fluidity of mitochondria but to decrease the Respiratory Control (RC) index. In this study we found an increase of membrane fluidity and an increase of the RC at an early phase of the development of a type 2 diabetes model. We measured the lipoperoxidation, analyzed the fatty acids composition by gas chromatography, and assessed membrane fluidity using three fluorescent monitors located at different depths inside the bilayer, dipyrenilpropane (DPyP), diphenylhexatriene (DPH), and trimethylammonium diphenylhexatriene (TMA-DPH). Our findings indicate that in the initial stage of diabetes development, when lipoperoxidation still is not significant, the membrane fluidity of liver mitochondria increases because of the increment in the unsaturated to saturated fatty acids ratio (U/S), thus producing an increase of the RC. The membrane fluidity is not the same at all depths in the bilayer. Contrary to the results obtained in mitochondria, the diabetes induced a decrease in the U/S fatty acids ratio of liver total lipids, indicating that the mitochondria might have an independent mechanism for regulating its fatty acids composition. PMID- 28337567 TI - Novel 16S rDNA primers revealed the diversity and habitats-related community structure of sphingomonads in 10 different niches. AB - It is believed that sphingomonads are ubiquitously distributed in environments. However detailed information about their community structure and their co relationship with environmental parameters remain unclear. In this study, novel sphingomonads-specific primers based on the 16S rRNA gene were designed to investigate the distribution of sphingomonads in 10 different niches. Both in silico and in-practice tests on pure cultures and environmental samples showed that Sph384f/Sph701r was an efficient primer set. Illumina MiSeq sequencing revealed that community structures of sphingomonads were significantly different among the 10 samples, although 12 sphingomonad genera were present in all samples. Based on RDA analysis and Monte Carlo permutation test, sphingomonad community structure was significantly correlated with limnetic and marine habitat types. Among these niches, the genus Sphingomicrobium showed strong positive correlation with marine habitats, whereas genera Sphingobium, Novosphingobium, Sphingopyxis, and Sphingorhabdus showed strong positive correlation with limnetic habitats. Our study provided direct evidence that sphingomonads are ubiquitously distributed in environments, and revealed for the first time that their community structure can be correlated with habitats. PMID- 28337569 TI - Erratum to: A Profile on Emergency Department Utilization in Adolescents and Young Adults with Autism Spectrum Disorders. PMID- 28337568 TI - Hospital microbial surface colonization revealed during monitoring of Klebsiella spp., Pseudomonas aeruginosa, and non-tuberculous mycobacteria. AB - Hospital environmental conditions, human occupancy, and the characteristics of the equipment influence the survival of microbial communities and raise a concern with regard to nosocomial infections. The objective of the present work was to use the monitoring of Pseudomonas aeruginosa, Klebsiella spp. and non-tuberculous mycobacteria as a strategy to improve knowledge on microbial colonization of non critical equipment and surfaces, in a tertiary hospital from Central Portugal. A 3-month microbiological survey was performed in a district teaching hospital. A total of 173 samples were obtained from the wards Hematology, Urology, Medicine, and Renal Transplants, and 102 presumptive strains recovered. Per sampling, Pseudomonas Isolation agar showed 42.8 to 73.3% of presumptive P. aeruginosa colonies and MacConkey agar recovered mostly Staphylococcus. Most of the colonies recovered in Middlebrook 7H10-PANTA belonged to the genus Methylobacterium. Taps and WC shower curtains carry high bacterial species diversity. The Redundancy Analysis grouped the samples in those mostly handled by patients, and those mostly handled by healthcare staff or of mixed use. This study shows that the preferential users of the space and equipment seem to be important contributors to the microbial community. The most recovered genus was Methylobacterium, known as colonizer of the water distribution system therefore, it is possible that the water points and biofilms in taps also contribute as dispersion hotspots. PMID- 28337570 TI - Economics of Chronic Rhinosinusitis. AB - PURPOSE OF REVIEW: The objective of this article is to provide an updated review of the economic burden of chronic rhinosinusitis (CRS) and discuss how both medical and surgical interventions impact direct and indirect costs related to CRS. By understanding the economics of CRS, clinicians may improve the patient centeredness of their care and help distinguish between low and high value interventions. RECENT FINDINGS: Direct costs related to CRS are primarily driven by outpatient physician visits, prescription medical therapy, and endoscopic sinus surgery (ESS). CRS produces large indirect costs and these costs often vary based on the severity of the patients CRS-specific QoL impairment. The overall direct cost related to CRS is estimated to range between $10 and $13 billion per year in the USA. The overall indirect cost related to CRS-related losses in work productivity is estimated to be in excess of $20 billion per year. In the appropriate patients with refractory CRS, ESS provides significant reductions in both direct and indirect costs; however, continued medical therapy alone may be a high value intervention in select patients who have lower severity in their baseline QoL and work productivity. PMID- 28337572 TI - Genetic appraisal of serological response post vaccination against enterotoxaemia (ET) in Malpura and Avikalin sheep. AB - Enterotoxaemia (ET) is a fatal enteric disease of small ruminants attributable to a toxigenic type of Clostridium perfringens. The key strategy for prevention of ET is the management and vaccination. Present study aimed at identifying the sources of variation for ET vaccine response especially against epsilon toxin in 173 sheep that included 83 Avikalin and 90 Malpura lambs raised at the institute flock in the semi-arid region of India. The mean age at vaccination was 90 days. Sera were tested by blocking ELISA. Study showed significant variability for response to ET vaccine. 5.2% animals had + positivity, 20.8% animals had ++ positivity, 51.4% animals had +++ positivity and 22.5% animals had ++++ positivity. Amongst environmental determinants, breed, season, sex and age at vaccination proved to be non-significant sources of variation (P > 0.05). MHC genotypes with DRB1 gene and DQA2 genes also revealed non-significant association with ET vaccine response; however, a trend of decreasing PI values with increasing ranks was observed. Study revealed strong response of epsilon toxin along with complexity of the ET vaccine response as phenotype to be explained by genetic and non-genetic factors. The importance of better management practices and vaccination is suggested for preventive measures. PMID- 28337571 TI - Effects of feeding ground pods of Enterolobium cyclocarpum Jacq. Griseb on dry matter intake, rumen fermentation, and enteric methane production by Pelibuey sheep fed tropical grass. AB - An experiment was carried out to determine the effect of supplementing ground pods of Enterolobium cyclocarpum in a basal ration of Pennisetum purpureum grass on feed intake, rumen volatile fatty acids (VFAs), and protozoa and methane (CH4) production by hair sheep. Four male sheep (Pelibuey * Katahdin) with a mean live weight of 27.0 kg (SD +/- 0.5) were supplemented with 0.00, 0.15, 0.30, and 0.45 kg of dry matter (DM) of E. cyclocarpum pods daily; equivalent to 0.00, 4.35, 8.70, and 13.05 g of crude saponins, respectively. Dry matter intake (DMI), organic matter intake (OMI), and molar proportions of propionic acid increased linearly (P < 0.05) as pods of E. cyclocarpum in the ration were increased. Higher intakes of DM and OM were found when lambs were fed 0.45 kg DM per day of E. cyclocarpum, and the highest proportion of propionic acid (0.21 and 0.22, respectively) was obtained with 0.15 and 0.30 kg of DM per lamb of E. cyclocarpum, while apparent digestibility of neutral detergent fiber (NDF) and molar proportion of acetic acid were reduced (P < 0.05). Rumen CH4 production decreased (P < 0.05) when 0.30 and 0.45 kg of DM/lamb/day of E. cyclocarpum were fed (21.8 and 25.3 L CH4/lamb/day, respectively). These results suggest that to improve the feeding of sheep fed tropical grass, it is advisable to supplement the basal ration with up to 0.30 kg DM of E. cyclocarpum pods. PMID- 28337573 TI - Neuroimmune Pharmacology, 2nd Edition - A Perspective. AB - It has been almost nine years since the 1st edition of Neuroimmune Pharmacology was published on May 23rd, 2008. The 2nd edition of Neuroimmune Pharmacology by Ikezu and Gendelman (Editors) with Przedborski, Masliah and Cosentino (Associate Editors) manages to fulfill two separate missions: to provide comprehensive, but highly topical access to a rapidly evolving field and to serve as a standalone reference for scientists and clinicians in need of guidance regarding questions pertinent to neuroimmune pharmacology. Doing a PubMed search on the terms neuroimmune and pharmacology yields 1090 publications, with a first publication by Dougherty and Dafny, published in the Journal of Neuroscience Research in 1988, entitled "Neuroimmune intercommunication, central opioids, and the immune response to bacterial endotoxin." Since 2000, there have been 979 publications using these search terms, with 137 published since the beginning of 2016. The obvious conclusion to be drawn is that this is a burgeoning field that represents the cusp between our understanding of relationships between the immune and nervous systems and how we might treat disease with pharmacologic approaches when normal homeostatic mechanisms go awry. PMID- 28337574 TI - The RS504393 Influences the Level of Nociceptive Factors and Enhances Opioid Analgesic Potency in Neuropathic Rats. AB - Increasing evidence has indicated that activated glial cells releasing nociceptive factors, such as interleukins and chemokines, are of key importance for neuropathic pain. Significant changes in the production of nociceptive factors are associated with the low effectiveness of opioids in neuropathic pain. Recently, it has been suggested that CCL2/CCR2 signaling is important for nociception. Here, we studied the time course changes in the mRNA/protein level of CD40/Iba-1, CCL2 and CCR2 in the spinal cord/dorsal root ganglia (DRG) in rats following chronic constriction injury (CCI) of the sciatic nerve. Moreover, we examined the influence of intrathecal preemptive and repeated (daily for 7 days) administration of RS504393, CCR2 antagonist, on pain-related behavior and the associated biochemical changes of some nociceptive factors as well as its influence on opioid effectiveness. We observed simultaneous upregulation of Iba 1, CCL2, CCR2 in the spinal cord on 7th day after CCI. Additionally, we demonstrated that repeated administration of RS504393 not only attenuated tactile/thermal hypersensitivity but also enhanced the analgesic properties of morphine and buprenorphine under neuropathy. Our results proof that repeated administration of RS504393 reduced the mRNA and/or protein levels of pronociceptive factors, such as IL-1beta, IL-18, IL-6 and inducible nitric oxide synthase (iNOS), and some of their receptors in the spinal cord and/or DRG. Furthermore, RS504393 elevated the spinal protein level of antinociceptive IL 1alpha and IL-18 binding protein. Our data provide new evidence that CCR2 is a promising target for diminishing neuropathic pain and enhancing the opioid analgesic effects. PMID- 28337575 TI - A Novel Modeling Approach for Estimating Patterns of Migration into and out of San Francisco by HIV Status and Race among Men Who Have Sex with Men. AB - In the early 1980s, men who have sex with men (MSM) in San Francisco were one of the first populations to be affected by the human immunodeficiency virus (HIV) epidemic, and they continue to bear a heavy HIV burden. Once a rapidly fatal disease, survival with HIV improved drastically following the introduction of combination antiretroviral therapy in 1996. As a result, the ability of HIV positive persons to move into and out of San Francisco has increased due to lengthened survival. Although there is a high level of migration among the general US population and among HIV-positive persons in San Francisco, in- and out-migration patterns of MSM in San Francisco have, to our knowledge, never been described. Understanding migration patterns by HIV serostatus is crucial in determining how migration could influence both HIV transmission dynamics and estimates of the HIV prevalence and incidence. In this article, we describe methods, results, and implications of a novel approach for indirect estimation of in- and out-migration patterns, and consequently population size, of MSM by HIV serostatus and race in San Francisco. The results suggest that the overall MSM population and all the MSM subpopulations studied decreased in size from 2006 to 2014. Further, there were differences in migration patterns by race and by HIV serostatus. The modeling methods outlined can be applied by others to determine how migration patterns contribute to HIV-positive population size and output from these models can be used in a transmission model to better understand how migration can impact HIV transmission. PMID- 28337576 TI - Robotic video-assisted thoracoscopy: minimally invasive approach for management of mediastinal tumors. AB - In spite of difficult anatomic access for tumors of mediastinum, surgical resection remains the best diagnostic and therapeutic approach. Widespread acceptance of video-assisted thoracoscopy (VATS) is restricted by the limiting nature of instruments and suboptimal visualization. Robotic assisted minimally invasive surgery seems to hold most promise in remote, narrow anatomical regions. After obtaining approval from Institutional Review Board (IRB), a retrospective review of prospectively collected database on patients that underwent Robotic VATS between 2009 and 2013 was conducted. Forty-eight patients underwent RVATS resection of mediastinal tumor. One procedure (2.1%) was converted to open. The size of the mass ranged from 0.6 to 12.5 cm in greatest dimension (mean 5.16 cm). The mean duration of procedure was 127.96 min (60-240 min). Five patients (10.4%) had early postoperative complications including chylothorax (1 patient), new onset atrial fibrillation (1 patient), pleural effusion (1 patient), empyema (1 patient), and bleeding (1 patient). Mean follow-up time was 186 days (10-1300 days). Two patients (4%) with invasive thymoma developed local recurrence. The present study documents the feasibility of RVATS in the management of mediastinal tumors irrespective of the location in various mediastinal compartments. The role for careful and complete excision of the tumor, and surveillance afterward on invasive thymoma, was noted in our study, as in literature. PMID- 28337577 TI - Native American Vietnam-era Veterans' Access to VA Healthcare: Vulnerability and Resilience in Two Montana Reservation Communities. AB - As a growing segment of the military, Native Americans are expected to increase enrollment in Department of Veterans Affairs (VA) healthcare. Currently, 20% of Native American veterans are aged 65-74, which means they served during the Vietnam era. This study explores the experiences of rural American Indian veterans from two Montana reservations with accessing VA health services. Utilizing detailed data obtained in focus group and individual interviews, we examine the experiences, attitudes, barriers and needs of rural Vietnam-era veterans. Analyses indicate that while Native American Vietnam-era veterans experienced a poor reception returning to the US after military service, they had more positive receptions in their home reservation communities. However, reintegration was often impeded by poor local opportunity structures and limited resources. As they have aged and turned to the VA for healthcare, these veterans have encountered barriers such as lack of information regarding eligibility and services, qualifying for care, excessive distances to health services, the cost of travel, and poor quality of assistance from VA personnel. Despite variations in their resources, tribal community efforts to honor veterans have begun to facilitate better access to healthcare. Focusing on the roles and importance of place-based resources, this study clarifies challenges and obstacles that Native American Vietnam-era veterans experience with accessing VA health services in rural, reservation communities. Additionally, findings show how tribal efforts are facilitating access as they begin to implement the 2010 agreement between the VA and Indian Health Services to better serve Native veterans. PMID- 28337579 TI - Comorbidity and the risk of anastomotic leak in Chinese patients with colorectal cancer undergoing colorectal surgery. AB - PURPOSE: Comorbidities had considerable effects on the prognosis in patients with colorectal cancer (CRC). The primary aim of the present study was to examine the influence of comorbidity on the risk of anastomotic leak (AL) in patients with CRC who underwent surgical resection. METHODS: Using the electronic Hospitalization Summary Reports in the top-ranked public hospitals in China, we identified 11,397 patients with CRC undergoing resection surgery from 2013 through 2015. We estimated the risk of AL according to Charlson Comorbidity Index (CCI) score using logistic regression analysis, adjusting for age, sex, and geographic regions. RESULTS: The incidence rate of AL in the study population was 1.8% (204/11,397). Multivariable analyses identified male sex and CCI score as independent risk factors for AL. The CCI score had a positive graded association with the risk of AL (P for trend = 0.006). The risk increased by an estimated 10.2% (odds ratio [OR], 1.10; 95% confidence interval [CI], 1.03-1.18) for each additional 1 point in the CCI score. After adjusting for potential confounders, patients with a CCI score >=3 had 1.82 times (95% CI, 1.24-2.69) higher risk of AL compared with patients with a CCI score of 0. CONCLUSION: The findings suggested that CCI score was an independent risk factor for the development of AL in Chinese patients with CRC who underwent surgical resection. PMID- 28337578 TI - Evolution of the corpus luteum volume determined ultrasonographically and its relation to the plasma progesterone concentration after artificial insemination in pregnant and non-pregnant dairy cows. AB - The aim of this study was to assess the relationship of the evolution of the corpus luteum (CL) volume that was determined ultrasonographically with the pregnancy status in lactating dairy cows during early pregnancy. Ultrasound examinations were carried out on 76 cows following artificial insemination (AI). Plasma concentrations of progesterone were determined from blood samples collected at each ultrasound examination. Conception was confirmed by ultrasonography on day 30 after AI. Around day 14 post-insemination (p.i.), the CL volume tended to decrease in pregnant and non-pregnant cows, and, after day 19 p.i., both groups differed significantly, indicating the luteal regression in non pregnant cows. Reaching signification on day 20. The diminution in CL volume was also reflected in the plasma progesterone concentration. However, the patterns of CL volume, estimated by ultrasonography, differed more evidently and earlier between both groups (around 1 week p.i., at day 9 p.i. P < 0.05, whereas progesterone started to differ around 2 weeks p.i., at day 14 p.i, P < 0.05). These results indicate that the estimation of the CL volume by ultrasonography could be useful for assessing the presence of a functional CL. PMID- 28337581 TI - High lactic acid and fructose production via Mn2+-mediated conversion of inulin by Lactobacillus paracasei. AB - Lactobacillus paracasei DSM 23505 is able to produce high amounts of lactic acid (LA) by simultaneous saccharification and fermentation (SSF) of inulin. Aiming to obtain the highest possible amounts of LA and fructose, the present study is devoted to evaluate the impact of bivalent metal ions on the process of inulin conversion. It was shown that Mn2+ strongly increases the activity of the purified key enzyme beta-fructosidase. In vivo, batch fermentation kinetics revealed that the high Mn2+ concentrations accelerated inulin hydrolysis by raise of the inulinase activity, and increased sugars conversion to LA through enhancement of the whole glycolytic flux. The highest LA concentration and yield were reached by addition of 15 mM Mn2+-151 g/L (corresponding to 40% increase) and 0.83 g/g, respectively. However, the relative quantification by real-time reverse transcription assay showed that the presence of Mn2+ decreases the expression levels of fosE gene encoding beta-fructosidase. Contrariwise, the full exclusion of metal ions resulted in fosE gene expression enhancement, blocked fructose transport, and hindered fructose conversion thus leading to huge fructose accumulation. During fed-batch with optimized medium and fermentation parameters, the fructose content reached 35.9% (w/v), achieving yield of 467 g fructose from 675 g inulin containing chicory flour powder (0.69 g/g). LA received in course of the batch fermentation and fructose gained by the fed-batch are the highest amounts ever obtained from inulin, thus disclosing the key role of Mn2+ as a powerful tool to guide inulin conversion to targeted bio-chemicals. PMID- 28337582 TI - Radio-sensitising effect of T-DM1 should not be discarded for the efficacy of radiosurgery in the management of brain metastases in patients with HER2-positive metastatic breast cancer. PMID- 28337583 TI - Toward a Research Agenda: Building Character Strengths in School Settings. AB - Character strengths matter for long term success, and a growing body of evidence suggests that schools can be powerful places, and teachers powerful agents, by which these strengths are developed in adolescence. The articles in this volume move the field forward in important ways, and lead to a clear research agenda focused on creating testable interventions to build school and classroom environments that will assist young people in growing and leveraging these critical strengths. PMID- 28337580 TI - Bacteriophage-encoded virion-associated enzymes to overcome the carbohydrate barriers during the infection process. AB - Bacteriophages are bacterial viruses that infect the host after successful receptor recognition and adsorption to the cell surface. The irreversible adherence followed by genome material ejection into host cell cytoplasm must be preceded by the passage of diverse carbohydrate barriers such as capsule polysaccharides (CPSs), O-polysaccharide chains of lipopolysaccharide (LPS) molecules, extracellular polysaccharides (EPSs) forming biofilm matrix, and peptidoglycan (PG) layers. For that purpose, bacteriophages are equipped with various virion-associated carbohydrate active enzymes, termed polysaccharide depolymerases and lysins, that recognize, bind, and degrade the polysaccharide compounds. We discuss the existing diversity in structural locations, variable architectures, enzymatic specificities, and evolutionary aspects of polysaccharide depolymerases and virion-associated lysins (VALs) and illustrate how these aspects can correlate with the host spectrum. In addition, we present methods that can be used for activity determination and the application potential of these enzymes as antibacterials, antivirulence agents, and diagnostic tools. PMID- 28337585 TI - Background gamma radiation and childhood cancer in Germany: an ecological study. AB - The relationship of low-dose background gamma radiation and childhood leukaemia was investigated in a number of studies. Results from these studies are inconclusive. Therefore, in the present study 25 years of German childhood cancer data were analyzed using interpolated background annual gamma dose rate per community in an ecological study. The main question was leukaemia; as exploratory questions we investigate central nervous system (CNS) tumours, thyroid carcinomas and diagnoses less likely to be related to radiation. A Poisson regression model was applied and a fractional polynomial model building procedure. As the main sensitivity analysis a community deprivation index was included as a potential confounder. It was found that outdoor background gamma annual dose rates in Germany range roughly from 0.5-1.5 mSv/a with an average of 0.817 mSv/a. No association of annual ambient gamma dose rates with leukaemia incidence was found. Amongst the exploratory analyses, a strong association was found with CNS tumour incidence [rate ratio for 1.5 vs 0.5 mSv/a: 1.35; 95% confidence interval (1.17, 1.57)]. The community level deprivation index was not a confounder. It is concluded that the present study did not confirm an association of annual outdoor ambient gamma dose rate and childhood leukaemia, corresponding to some studies and contrasting others. An association with CNS incidence was found in the exploratory analyses. As this is an ecological study no causal interpretation is possible. PMID- 28337584 TI - "I can't Take Hold of Some Kind of a Life": The Role of Social Connectedness and Confidence in Engaging "Lost" Adolescents with Their Lives. AB - Erik Erikson's theoretical writings on identity have provided a rich foundation upon which decades of research on identity development have been built. However, literature is lacking regarding adolescents who are aware that they lack knowledge about the self (i.e., values, likes, and dislikes) to the extent that they are stuck and directionless, and therefore unable to engage in the process of identity formation, what we refer to as a state of "lostness." Furthermore, while it has been established that supportive relationships facilitate identity development, less is known about whether various domains of social connectedness may diminish "lostness" over time, and if so, what may be the specific processes or conditions within each connectedness domain that supports this aspect of identity development. To address this gap in the literature, this study drew upon self-report data collected from New Zealand adolescents who provided data for two out of three annual time points of measurement (N = 1996; 52% female; 52% European New Zealanders, 30% Maori, and 18% Pacific Islanders and Asian New Zealanders) to examine the longitudinal relationships among three domains of social connectedness (i.e., family, school, and peers), "lostness," and a potential mediator, confidence. The results showed that all three domains of social connectedness predicted diminished "lostness" over time, and confidence mediated these relationships. An examination of the opposite direction of influence showed that "lostness" predicted a decrease in confidence and the three domains of social connectedness, as well. Gender, age, and ethnic group were shown to be moderators of different parts of the model. This study addresses the paucity of research examining "lost" adolescents, while providing insight into the underlying processes through which three key social contexts-family, school, and peers-exert their influence, and are influenced by, identity processes through confidence. PMID- 28337587 TI - Erratum to: Internal exposure to neutron-activated 56Mn dioxide powder in Wistar rats-Part 2: pathological effects. PMID- 28337586 TI - The role of fluoride and chlorhexidine in preserving hardness and mineralization of enamel and cementum after gamma irradiation. AB - The purpose of this study was to evaluate the effect of 0.05% sodium fluoride and 0.12% chlorhexidine mouthwashes on the micro-hardness of tooth enamel and cementum that was exposed to therapeutic doses of gamma radiation. Sixty extracted human teeth were divided into two groups, one was irradiated, the other was not irradiated. The two groups were further subdivided into three subgroups, which were each treated either with 0.05% sodium fluoride or with 0.12% chlorhexidine; the third subgroup served as a control. After demineralization remineralization cycling, teeth from the irradiated groups showed a significantly lower micro-hardness when compared to those from the non-irradiated groups. Both in the irradiated and non-irradiated groups, teeth from the control subgroups showed a significantly lower micro-hardness, as compared to teeth treated with sodium fluoride and chlorhexidine. For non-irradiated enamel samples, those treated with chlorhexidine showed a significantly less micro-hardness compared to those treated with sodium fluoride. In contrast, irradiated enamel showed no significant difference in micro-hardness, whatever treatment (chlorhexidine or sodium fluoride) was applied. For cementum, treatment with chlorhexidine resulted in a significantly lower micro-hardness compared to sodium fluoride, both for the irradiated and non-irradiated groups. It is concluded that gamma irradiation with therapeutic doses typically used for head and neck carcinoma treatment has a direct effect in reducing micro-hardness of tooth enamel and cementum. Mouthwash protocols including, for example, application of 0.05% sodium fluoride or 0.12% chlorhexidine three times per day for 6 weeks, can protect enamel and cementum against the reduction in hardness and demineralization caused by gamma irradiation. Sodium fluoride offers more protection compared to chlorhexidine. PMID- 28337588 TI - Nephroendocrinology: When endocrinology meets nephrology. PMID- 28337589 TI - Colonization by non-pathogenic bacteria alters mRNA expression of cytochromes P450 in originally germ-free mice. AB - Gut microbiota provides a wide range of beneficial function for the host and has an immense effect on the host's health state. It has also been shown that gut microbiome is often involved in the biotransformation of xenobiotics; however, the molecular mechanisms of the interaction between the gut bacteria and the metabolism of drugs by the host are still unclear. To investigate the effect of microbial colonization on messenger RNA (mRNA) expression of liver cytochromes P450 (CYPs), the main drug-metabolizing enzymes, we used germ-free (GF) mice, lacking the intestinal flora and mice monocolonized by non-pathogenic bacteria Lactobacillus plantarum NIZO2877 or probiotic bacteria Escherichia coli Nissle 1917 compared to specific pathogen-free (SPF) mice. Our results show that the mRNA expression of Cyp1a2 and Cyp2e1 was significantly increased, while the expression of Cyp3a11 mRNA was decreased under GF conditions compared to the SPF mice. The both bacteria L. plantarum NIZO2877 and E. coli Nissle 1917 given to the GF mice decreased the level of Cyp1a2 mRNA and normalized it to the control level. On the other hand, the colonization by these bacteria had no effect on the expression of Cyp3a11 mRNA in the liver of the GF mice (which remained decreased). Surprisingly, monocolonization with chosen bacterial strains has shown a different effect on the expression of Cyp2e1 mRNA in GF mice. Increased level of Cyp2e1 expression observed in the GF mice was found also in mice colonized by L. plantarum NIZO2877; however, the colonization with probiotic E. coli Nissle 1917 caused a decrease in Cyp2e1 expression and partially restored the SPF mice conditions. PMID- 28337590 TI - ACL-reconstructed and ACL-deficient individuals show differentiated trunk, hip, and knee kinematics during vertical hops more than 20 years post-injury. AB - PURPOSE: Little is known regarding movement strategies in the long term following injury of the anterior cruciate ligament (ACL), and even less about comparisons of reconstructed and deficient knees in relation to healthy controls. The present purpose was to compare trunk, hip, and knee kinematics during a one-leg vertical hop (VH) ~20 years post-ACL injury between persons treated with surgery and physiotherapy (ACLR), solely physiotherapy (ACLPT), and controls (CTRL). Between leg kinematic differences within groups were also investigated. METHODS: Sixty six persons who suffered unilateral ACL injury on average 23 +/- 2 years ago (32 ACLR, 34 ACLPT) and 33 controls performed the VH. Peak trunk, hip, and knee angles during Take-off and Landing phases recorded with a 3D motion capture system were analysed with multivariate statistics. RESULTS: Significant group effects during both Take-off and Landing were found, with ACLPT differing from CTRL in Take-off with a combination of less knee flexion and knee internal rotation, and from both ACLR and CTRL in Landing with less hip and knee flexion, knee internal rotation, and greater hip adduction. ACLR also presented different kinematics to ACLPT and CTRL in Take-off with a combination of greater trunk flexion, hip flexion, hip internal rotation, and less knee abduction, and in Landing with greater trunk flexion and hip internal rotation. Further, different kinematics and hop height were found between legs within groups in both Take-off and Landing for both ACL groups, but not for CTRL. CONCLUSION: Different kinematics for the injured leg for both ACL groups compared to CTRL and between treatment groups, as well as between legs within treatment groups, indicate long term consequences of injury. Compensatory mechanisms for knee protection seem to prevail over time irrespective of initial treatment, possibly increasing the risk of re-injury and triggering the development of osteoarthritis. Detailed investigation of movement strategies during the VH provides important information and a more comprehensive evaluation of knee function than merely hop height. More attention should also be given to the trunk and hip in clinics when evaluating movement strategies after ACL injury. LEVEL OF EVIDENCE: Prospective cohort study, Level II. PMID- 28337591 TI - Arthroscopic R-LCL plication for symptomatic minor instability of the lateral elbow (SMILE). AB - PURPOSE: Minor instability has been proposed as a possible aetiology of lateral elbow pain. This study presents the results of the arthroscopic plication of the radial component of the lateral collateral ligament (R-LCL) to reduce minor instability of the lateral elbow. METHODS: Twenty-seven patients with recalcitrant lateral epicondylitis who had failed conservative therapy and who had no previous trauma or overt instability, were included. R-LCL plication was performed in the presence of at least one sign of lateral ligamentous patholaxity and one intra-articular abnormal finding. Single-assessment numeric evaluation (SANE), Oxford Elbow Score (OES), quickDASH (Disabilities of the Arm, Shoulder, Hand), patient satisfaction and post-operative range of motion were evaluated. RESULTS: SANE improved from a median of 30 [2-40] points pre-operatively to 90 [80-100] at final follow-up (p < 0.0001), and 96.3% patients obtained good or excellent subjective results. Post-operative median quickDASH was 9.1 [0-25] points and OES 42 [34-48]. Median post-operative flexion was 145 degrees , and extension was 0 degrees . Post-operative flexion was restrained in seven patients and extension in eight patients; 59% of patients reached full ROM at final follow up. CONCLUSIONS: R-LCL plication produces subjective satisfaction and positive clinical results in patients presenting with a symptomatic minor instability of the lateral elbow (SMILE) at 2-year median follow-up. A slight limitation in range of motion is a possible undesired consequence of this intervention. LEVEL OF EVIDENCE: Retrospective case series, Level IV. PMID- 28337593 TI - Family Income and Child Cognitive Development: A Response to Marks. PMID- 28337592 TI - Head and Neck Round Cell Sarcomas: A Comparative Clinicopathologic Analysis of 2 Molecular Subsets: Ewing and CIC-Rearranged Sarcomas. AB - CIC-rearranged sarcoma (CRS) is a relatively new entity defined by its pathognomonic genetic signature and undifferentiated round cell phenotype, initially grouped together with the 'Ewing sarcoma-like tumors'. However, increasing data suggest that these tumors should be regarded as a stand-alone pathologic entity. We conducted a clinicopathologic analysis on molecularly conformed Ewing sarcoma (ES) and CRS arising in the head and neck (HN) and compared to a well characterized cohort of ES and CRS from other locations. A total of 41 HN round cell sarcoma patients were selected from our institutional and consultation files, including 25 ES (median 20 years) and 16 CRS (median 29 years). Clinical follow-up information was available for all ES patients, ranging from 4 to 436 months (median 70 months), while for CRS, follow-up information was available in 11 patients (69%), ranging from 1 to 269 months (median 27 months). The most common location for ES was the facial and jaw bones (56%), while CRS occurred exclusively in the soft tissue, commonly in the neck. CRS showed variable CD99 staining in 75% of cases and diffuse WT1 (6/6) reactivity, while all ES expressed diffuse membranous staining for CD99 but none for WT1 (0/6). The 2-year overall survival (OS) rate for HN-CRS patients was 78%, while for HN-ES it was 100%. The OS of ES and CRS showed a trend toward a favorable outcome for HN round cell sarcomas compared to other sites. Our findings suggest that HN-CRS have different clinical presentation and pathologic features compared to ES and should be classified as a stand-alone pathologic entity. PMID- 28337596 TI - Prolactin regulation of the HPA axis is not mediated by a direct action upon CRH neurons: evidence from the rat and mouse. AB - Centrally acting prolactin has been shown to have anti-stress effects by modulating the activity of the hypothalamic-pituitary-adrenal axis. We tested the hypothesis that prolactin directly targets hypothalamic corticotropin-releasing hormone (CRH) neurons. In situ hybridisation confirmed expression of mRNA encoding the long, but not the short, isoform of the prolactin receptor (PRLR) within the paraventricular nucleus (PVN) of the virgin rat; however, only 6% of CRH neurons expressed long-form Prlr mRNA. Examination of the functional response of CRH neurons to intracerebroventricular prolactin (500 ng) showed that these neurons did not respond with activation of phosphorylated signal transducer and activator of transcription 5 (pSTAT5), a marker of long-form PRLR activation. However, as only a subset of neurons expressing Crh mRNA could be detected using immunohistochemistry, we utilised a transgenic mouse model to label CRH neurons with a fluorescent reporter (CRH-Cre-tdTomato). In lactating animals, chronically elevated prolactin levels resulted in significantly increased pSTAT5 expression in the PVN. Overall, few tdTomato-labelled CRH neurons were double-labelled, although a small subset of CRH neurons in the caudal PVN were pSTAT5 positive (approximately 10% of tdTomato neurons at this level, compared to 1% in the rostral PVN). These data suggest that most CRH neurons do not respond directly to prolactin. To confirm that prolactin was not activating another signalling pathway, we used a transgenic mouse line to label PRLR-expressing neurons with Cre-dependent green fluorescent protein (GFP) expression (CRH-Cre-Prlr lox/lox ). No GFP-expressing cells were evident in the PVN, indicating that in the mouse, as in the rat, the CRH neurons do not express either PRLR isoform. Together these data showed that the anti-stress effects of prolactin are not the result of prolactin directly regulating CRH neurons. PMID- 28337594 TI - Diagnostic accuracy of high-risk HPV DNA genotyping for primary cervical cancer screening and triage of HPV-positive women, compared to cytology: preliminary results of the PIPAVIR study. AB - PURPOSE: The purpose of the presented PIPAVIR (persistent infections with human papillomaviruses; http://www.pipavir.com ) subanalysis is to assess the performance of high-risk (hr) HPV-DNA genotyping as a method of primary cervical cancer screening and triage of HPV positive women to colposcopy compared to liquid-based cytology (LBC) in an urban female population. METHODS: Women, aged 30-60, provided cervicovaginal samples at the Family-Planning Centre, Hippokratio Hospital of Thessaloniki, Greece, and the Department of Gynecology and Obstetrics in Mare Klinikum, Kiel, Germany. Cytology and HPV genotyping was performed using LBC and HPV Multiplex Genotyping (MPG), respectively. Women positive for cytology [atypical squamous cells of undetermined significance (ASC-US) or worse] or hrHPV were referred for colposcopy. RESULTS: Among 1723/1762 women included in the final analysis, hrHPV and HPV16/18 prevalence was 17.7 and 9.6%, respectively. Cytology was ASCUS or worse in 7.6%. Cervical Intraepithelial Neoplasia grade 2 or worse (CIN2+) was detected in 28 women (1.6%). Sensitivity of cytology (ASCUS or worse) and HPV DNA testing for the detection of CIN2+ was 50.0 and 100%, and specificity was 94.49 and 85.49%, respectively. The screening approach according to which only women positive for HPV16/18 and for hrHPV(non16/18) with ASCUS or worse were referred to colposcopy presented 78.57% sensitivity and 13.17% positive predictive value (PPV). CONCLUSIONS: HPV testing represents a more sensitive methodology for primary cervical cancer screening compared to cytology. For triage of HPV positive women to colposcopy, partial HPV genotyping offers better sensitivity than cytology, at the cost of higher number of colposcopies. PMID- 28337595 TI - First trimester TTR-RBP4-ROH complex and angiogenic factors in the prediction of small for gestational age infant's outcome. AB - PURPOSE: To study the role of the TTR-RBP4-ROH complex components (transthyretin, serum retinol binding protein, retinol) and of angiogenic factors PlGF (placental growth factor) and sFlt-1 (soluble fms-like tyrosine kinase-1) in pregnancies complicated by small for gestational age infants (SGA). METHODS: Case control study conducted on maternal serum collected between 11 + 0 to 13 + 6 weeks of gestation. TTR, RBP4, ROH, PlGF and sFlt-1 were measured in SGA patients (birth weight <10%) who delivered at term (n = 37) and before 37 weeks of gestation (n = 17) and in a matched control group with uneventful pregnancies (n = 37). RESULTS: We found decreased RBP4 in SGA patients that delivered fetuses <3% and in fetuses delivered after the 37 weeks of gestation compared to controls [1.50 (95% CI 1.40 1.75) vs 1.62 (95% CI 1.47-1.98), p < 0.05]. Further, we found lower PlGF and sFlt-1 concentrations in SGA that delivered before 37 weeks of gestation compared to controls (respectively, PIGF and sFlt-1: 39.7 pg/ml (95% CI 32.3-66.3) vs 62.9 pg/ml (95% CI 45.2-78.4) and 906 pg/ml (95% CI 727-1626) vs 1610 pg/ml (95% CI 1088-212), p < 0.05). CONCLUSIONS: First trimester maternal serum RBP4 and angiogenic factors PlGF and sFlt-1 can differently predict the timing of delivery of pregnancies complicated by SGA fetuses. PMID- 28337597 TI - The functional role of post-movement beta oscillations in motor termination. AB - Shortly after movement termination, there is a strong increase or resynchronization of the beta rhythm (15-30 Hz) across the sensorimotor network of humans, known as the post-movement beta rebound (PMBR). This response has been associated with active inhibition of the motor network following the completion of a movement, sensory afferentation of the sensorimotor cortices, and other functions. However, studies that have directly probed the role of the PMBR in movement execution have reported mixed results, possibly due to differences in the amount of total motor output and/or movement complexity. Herein, we used magnetoencephalography during an isometric-force control task to examine whether alterations in the timing of motor termination demands modulate the PMBR, independent of differences in the motor output itself. Briefly, we manipulated the amount of time between the cue to initiate the force and the cue to terminate the force, such that participants were either forced to terminate quickly or slowly. We also performed a control experiment to test for temporal predictability effects. Our results indicated that the PMBR was stronger immediately following movement termination in the prefrontal cortices, supplementary motor area, left postcentral gyrus, paracentral lobule, and parietal cortex when participants were forced to terminate more quickly. These results were not attributable to the temporal predictability of each condition. These findings support the notion that the PMBR response at least partially serves motor inhibition, independent of the parameters within the motor output itself, and that particular nodes of the motor network may be differentially modulated by motor termination. PMID- 28337598 TI - Likelihood ratio formulae for disputed parentage when the product of conception is trisomic. AB - We present here the derivation of paternity index formulae that covers situations of a disputed paternity trio with a trisomic product of conception. We consider six possible mechanisms for trisomy to occur: dispermy, dieggy, paternal meiosis I or II, and maternal meiosis I or II in the calculation. We also provide a biological explanation for how each of the mechanisms could give rise to a trisomy. The paper is set out in a general manner so that the tables presented can be used on any instance of trisomic offspring. This work is motivated by a case of disputed paternity where the product of conception was trisomic, i.e. the electropherogram of the product of conception possessed three alleles at each locus. The outcome was extremely strong support for the alleged father's paternity of the product of conception. PMID- 28337599 TI - Genetic variation of 17 autosomal STR loci in the Dong ethnic minority from Guangxi Zhuang Autonomous Region, South China. AB - A total of 17 autosomal short tandem repeat (STR) loci were amplified with the PowerPlex 18D System from 3244 unrelated healthy individuals of Dong ethnic minority living in Guangxi Zhuang Autonomous Region, South China. Moreover, genetic distances between Dong and 12 published populations were compared, and a neighbor-joining (NJ) phylogenetic tree was developed using averaged F ST matrix and visualized. Results are generally in accordance with the geographical and linguistic distribution of studied populations and their historical relationships with Guangxi Dong. PMID- 28337600 TI - Technical note: EnVisionTM FLEX improves the detectability of depletions of myoglobin and troponin T in forensic cases of myocardial ischemia/infarction. AB - Immunohistochemistry is a well-established technique used in many research laboratories as well as in clinical diagnostics. The method allows to visualize the expression of proteins in biological tissues, as well as to evaluate this expression semi-quantitatively. For diagnosis, an optimal staining, based on a straightforward protocol, is crucial. In many sudden cardiac death cases, immunohistochemistry is the only tool enabling the diagnosis of myocardial ischemia/infarction, thus the diagnosis of the cause of death. Improvements in immunoreactions are actually possible thanks to optimized detection systems. The recently introduced detection system EnVision FlexTM by Dako allows to dramatically improve (in terms of intensity of the signal and practically absence of background) the visualization of antigens in formalin-fixed paraffin-embedded (FFPE) tissue sections. We tested this method for the detection of myoglobin and troponin T in human postmortem cases of myocardial infarction, as the results obtained by using the " classical " ABC (avidin-biotin complex) method have proven to be sub-optimal, thus rendering any interpretation very difficult, if not impossible. PMID- 28337601 TI - The Cortisol Awakening Response Mediates the Relationship Between Acculturative Stress and Self-Reported Health in Mexican Americans. AB - BACKGROUND: The assessment of acculturative stress as synonymous with acculturation level overlooks the dynamic, interactive, and developmental nature of the acculturation process. An individual's unique perception and response to a range of stressors at each stage of the dynamic process of acculturation may be associated with stress-induced alterations in important biological response systems that mediate health outcomes. Evidence suggests the cortisol awakening response (CAR) is a promising pre-clinical biomarker of stress exposure that may link acculturative stress to self-reported health in Mexican Americans. PURPOSE: The aim of the current study was to examine whether alterations in the CAR mediate the relationship between acculturative stress and self-reported health in Mexican Americans. METHODS: Salivary cortisol samples were collected at awakening, 30, 45, and 60 min thereafter, on two consecutive weekdays from a sample of adult Mexican Americans. Acculturative stress and self-reported health were assessed. Data were aggregated and analyzed (n = 89) using a mixed effects regression model and path analysis. RESULTS: Poorer self-reported health was associated with attenuated CAR profiles (primarily due to a diminished post awakening rise in cortisol) predicted by both moderate and high levels of exposure to acculturative stress. Stress-induced alterations in the CAR mediated the relationship between exposure to acculturative stressors and self-reported health. CONCLUSIONS: Findings demonstrate that different levels of acculturative stress are associated with distinct CAR profiles and suggest the CAR is one possible biological pathway through which exposure to culturally unique stressors may be linked to health disparities. PMID- 28337602 TI - Depressive Symptoms and Sleep Efficiency Sequentially Mediate Racial Differences in Temporal Summation of Mechanical Pain. AB - BACKGROUND: Racial differences in endogenous pain facilitatory processes have been previously reported. Evidence suggests that psychological and behavioral factors, including depressive symptoms and sleep, can alter endogenous pain facilitatory processes. Whether depressive symptoms and sleep might help explain racial differences in endogenous pain facilitatory processes has yet to be determined. PURPOSE: This observational, microlongitudinal study examined whether depressive symptoms and sleep were sequential mediators of racial differences in endogenous pain facilitatory processes. METHODS: A total of 50 (26 African American and 24 non-Hispanic white) community-dwelling adults without chronic pain (mean 49.04 years; range 21-77) completed the Center for Epidemiological Studies Depression Scale prior to seven consecutive nights of sleep monitoring with actigraphy in the home environment. Participants subsequently returned to the laboratory for assessment of endogenous pain facilitation using a mechanical temporal summation protocol. RESULTS: Findings revealed greater depressive symptoms, poorer sleep efficiency, and greater temporal summation of mechanical pain in African Americans compared to non-Hispanic whites. In a sequential mediation model, greater depressive symptoms predicted poorer sleep efficiency (t = -2.55, p = .014), and poorer sleep efficiency predicted enhanced temporal summation of mechanical pain (t = -4.11, p < .001), particularly for African Americans. CONCLUSIONS: This study underscores the importance of examining the contribution of psychological and behavioral factors when addressing racial differences in pain processing. Additionally, it lends support for the deleterious impact of depressive symptoms on sleep efficiency, suggesting that both sequentially mediate racial differences in endogenous pain facilitation. PMID- 28337603 TI - Multimodal Outcome Prognostication After Cardiac Arrest and Targeted Temperature Management: Analysis at 36 degrees C. AB - BACKGROUND: Targeted temperature management (TTM) represents the standard of care in comatose survivors after cardiac arrest (CA) and may be applied targeting 33 degrees or 36 degrees C. While multimodal prognostication has been extensively tested for 33 degrees C, scarce information exists for 36 degrees C. METHODS: In this cohort study, consecutive comatose adults after CA treated with TTM at 36 degrees C between July 2014 and October 2016 were included. A combination of neurological examination, electrophysiological features, and serum neuron specific enolase (NSE) was evaluated for outcome prediction at 3 months (mortality; good outcome defined as cerebral performance categories (CPC) score of 1-2, poor outcome defined as CPC 3-5). RESULTS: We analyzed 61 patients. The presence of two or more predictors out of, unreactive electroencephalogram (EEG) background, epileptiform EEG, absent pupillary and/or corneal reflex, early myoclonus, bilaterally absent cortical somatosensory evoked potentials, and serum NSE >75 MUg/l, had a high specificity for predicting mortality (positive predictive value [PPV] = 1.00, 95% CI 0.87-1.00) and poor outcome (PPV = 1.00, 95% CI 0.80-1.00). Reactive EEG background was highly sensitive for predicting good outcome (0.95, 95% CI 0.74-0.99). CONCLUSIONS: Prediction of outcome after CA and TTM targeting 36 degrees C seems valid in adults using the same features tested at 33 degrees C. A reactive EEG under TTM appears highly sensitive for good outcome. PMID- 28337605 TI - Application of diet theory reveals context-dependent foraging preferences in an herbivorous coral reef fish. AB - Dietary preferences of grazers can drive spatial variability in top-down control of autotroph communities, because diet composition may depend on the relative availability of autotroph species. On Caribbean coral reefs, parrotfish grazing is important in limiting macroalgae, but parrotfish dietary preferences are poorly understood. We applied diet-switching analysis to quantify the foraging preferences of the redband parrotfish (Sparisoma aurofrenatum). At 12 Caribbean reefs, we observed 293 redband parrotfish in 5-min feeding bouts and quantified relative benthic algal cover using quadrats. The primary diet items were macroalgal turfs, Halimeda spp., and foliose macroalgae (primarily Dictyota spp. and Lobophora spp.). When each resource was evaluated independently, there were only weak relationships between resource cover and foraging effort (number of bites taken). Electivity for each resource also showed no pattern, varying from positive (preference for the resource) to negative (avoidance) across sites. However, a diet-switching analysis consisting of pairwise comparisons of relative cover and relative foraging effort revealed clearer patterns: parrotfish (a) preferred Halimeda and macroalgal turfs equally, and those two resources were highly substitutable; (b) preferred Halimeda to foliose macroalgae, but those two resources were complementary; and (c) also preferred turf to foliose macroalgae, and those resources were also complementary. Thus parrotfish grazing rates depend on relative, not absolute, abundance of macroalgal types, due to differences in substitutability among resources. Application of similar analyses may help predict potential changes in foraging effort of benthic grazers over spatial gradients that could inform expectations for reef recovery following the protection of herbivore populations. PMID- 28337604 TI - Adjustment of control in the numerical Stroop task. AB - In the numerical Stroop task, participants are asked to compare the physical sizes (physical task) or numerical values (numerical task) of two digits and ignore the irrelevant dimension. Participants are unable to ignore the irrelevant dimension as indicated by facilitation and interference effects. The literature suggests that there is asymmetry in the ability to adjust control in the physical and numerical tasks. The present study examined this suggestion in two experiments in which we manipulated the proportion of neutral/congruent trials in an experimental block. In addition, we examined the effects of control adjustment on the resolution of the task and informational conflicts. Our results suggest that adjustment of control can be bidirectional and is dependent on task requirements. Moreover, it might be easier to inhibit irrelevant information than to inhibit irrelevant task activation. PMID- 28337607 TI - Phenotypic changes of methicillin-resistant Staphylococcus aureus during vancomycin therapy for persistent bacteraemia and related clinical outcome. AB - Persistent bacteraemia (PB) due to methicillin-resistant Staphylococcus aureus (MRSA) that fails to respond to glycopeptide therapy is a well-documented clinical problem. There are limited data on changes in agr functionality, vancomycin susceptibility and heteroresistance during MRSA PB. Thus, the frequency of these changes and their clinical significance remain unclear. Only patients with MRSA PB (>=7 days) from a prospective cohort of S. aureus bacteraemia were included. We collected isogenic paired strains and compared vancomycin MIC, vancomycin heteroresistance, and agr functionality between initial and final blood isolates. We also assessed the clinical outcome. A total of 49 patients had MRSA PB over 22 months. Bacteraemia persisted for a median of 13 days and most patients (98%) received glycopeptide as initial therapy. Among 49 isogenic pairs, only one pair showed a vancomycin MIC increase >=2-fold by broth microdilution method, and only seven (14%) by E-test. Significant portions of initial isolates had vancomycin heteroresistance (49%) and agr dysfunction (76%). Development of vancomycin heteroresistance during PB occurred in four (16%) among 25 initial vancomycin-susceptible isolates, and acquisition of agr dysfunction occurred in two (16%) among 12 initial agr-functional isolates. Changes in the opposite direction occasionally occurred. These phenotypic changes during PB were not associated with mortality, whereas agr dysfunction of the initial isolates was significantly associated with mortality. During MRSA PB, phenotypic changes of MRSA isolates occurred occasionally under prolonged vancomycin exposure but were not significantly associated with clinical outcome. In contrast, initial agr dysfunction could be a predictor for mortality in MRSA PB. PMID- 28337608 TI - Age-specific application of neutrophil-to-lymphocyte ratio in meningitis: a nationwide study. AB - Cerebrospinal fluid (CSF) neutrophil counts and neutrophil-to-lymphocyte ratio (NLR) are useful in distinguishing bacterial and viral meningitis. Given that meningitis is clinically heterogeneous with regard to age, here we investigated the validity of the CSF NLR and neutrophil assay according to age group. Data from the nationwide referral of >4,000 meningitis cases to the Hellenic Meningitis Reference Laboratory between 2006 and 2013 were examined. CSF NLR and neutrophil counts were stratified according to age, and assay performance was determined using previous cut-off values of 2 and 287 cells/MUl for CSF NLR and neutrophils respectively. The distribution of bacterial versus viral meningitis was heterogenous across age groups, with a low proportion of bacterial meningitis in patients aged 5-14. CSF neutrophil count and NLR were significantly more discriminatory for bacterial meningitis in patients aged over 14 years than those aged 0-14. The odds ratio (OR), sensitivity, specificity and positive predictive value (PPV) were significantly higher in older patients for both biomarkers. When combined, the false-positive and false-negative detection of bacterial meningitis was 3.9 and 8.5% respectively, and the OR of 262.2 was 2.5-fold greater than expected from a multiplicative effect alone in patients aged >14 years. Care is required when applying diagnostic tests for meningitis in different age groups because of patient heterogeneity. This is the first description of the age distribution of meningitis cases in Greece, and knowledge of the age-related distribution of neutrophils and NLR in meningitis cases could help towards developing age-specific meningitis diagnostic assays. PMID- 28337609 TI - Trans-eyebrow supraorbital approach in large suprasellar craniopharyngioma surgery in adults: analysis of optic nerve length and extent of tumor resection. Original article. AB - BACKGROUND: One of the main drawbacks in the surgery of large craniopharyngiomas is the presence of a prefixed optic chiasm. Our main objective in this study is to compare the predictive value of the optic nerve length and optic chiasm location on large craniopharyngiomas' extent of resection. METHOD: We retrospectively studied 21 consecutive patients with large craniopharyngiomas who underwent tumor resection through the trans-eyebrow supraorbital approach. Clinical and radiological findings on preoperative MRI were recorded, including the optic chiasm location classified as prefixed, postfixed or normal. We registered the optic nerve length measured intraoperatively prior to tumor removal and confirmed the measurements on preoperative MRI. Using a linear regression model, we calculated a prediction formula of the percentage of the extent of resection as a function of optic nerve length. RESULTS: On preoperative MRI, 15 patients were considered to have an optic chiasm in a normal location, 3 cases had a prefixed chiasm, and the remaining 3 had a postfixed chiasm. In the group with normal optic chiasm location, a wide range of percentage of extent of resection was observed (75-100%). The percentage of extent of resection of large craniopharyngiomas was observed to be dependent on the optic nerve length in a linear regression model (p < 0.0001). According to this model in the normal optic chiasm location group, we obtained an 87% resection in 9-mm optic nerve length patients, a 90.5% resection in 10-mm optic nerve length patients and 100% resection in 11-mm optic nerve length patients. CONCLUSIONS: Optic chiasm location provides useful information to predict the percentage of resection in both prefixed and postfixed chiasm patients but not in the normal optic chiasm location group. Optic nerve length was proven to provide a more accurate way to predict the percentage of resection than the optic chiasm location in the normal optic chiasm location group. PMID- 28337610 TI - A prospective multicenter study on laparoscopic treatment of gastroesophageal reflux disease in Italy : Type of surgery, conversions, complications, and early results. AB - BACKGROUND: A national survey was undertaken by the Italian Society for Laparoscopic Surgery to investigate the prevalence, indications, conversion rate, mortality, morbidity, and early results of laparoscopic antireflux surgery. METHODS: Beginning on January 1, 1996, all of the centers taking part in this study were asked to complete a questionnaire on each patient. The questionnaire was divided into four parts and covered such areas as indications for surgery and preoperative workup, type of operation performed and certain aspects of the surgical technique, conversions and their causes, intraoperative and postoperative complications (within 4 weeks), and details of the postoperative course. The last part of the questionnaire focused on the follow-up period and was designed to gather data on recurrence of preoperative symptoms, postoperative symptoms (dysphagia, gas bloat), and postoperative test findings. RESULTS: As of June 30 1998, 21 centers were taking part in the study and 621 patients were enrolled, with a median of 27 patients per center (less than one patient/month). The most popular technique was the Nissen-Rossetti (52%), followed by the Nissen (33%) and Toupet procedures (13%). Other techniques, such as the Dor and Lortat Jacob, were used in the remainder of cases. Patients who received a Toupet procedure had a higher incidence of defective peristalsis (p < 0.05). The conversion rate to open surgery was 2.9%. The most common causes of conversion were inability to reduce the hiatus hernia or distal esophagus in the abdomen and adhesions from previous surgery. Perforation of the stomach and esophagus occurred in <1% of patients. Mortality was nil. Postoperative complications were observed in 7.3% of cases. The most common complication was acute dysphagia (19 patients), which required reoperation in 10 patients. No differences in the incidence of acute dysphagia were found for the different surgical techniques employed. Follow-up data were obtained for 319 patients (53%): 91.5% of the patients remained GERD symptom-free; severe esophagitis (grade 2-3) healed in 95% of the patients; lower esophageal sphincter (LES) manometric characteristics (pressure, abdominal length, and overall length) improved significantly after surgery (p < 0.005); and acid exposure of the distal esophagus decreased. CONCLUSIONS: Laparoscopic antireflux surgery has no mortality and a low morbidity. Symptoms and esophagitis are resolved in >90% of patients. Despite these favorable results, however, this type of surgery is not yet as widely employed in Italy as in other countries. PMID- 28337611 TI - Comparison of insufflation vs retractional technique for laparoscopic-assisted intervertebral fusion of the lumbar spine. AB - Laparoscopic transperitoneal fusion of the L5-S1 spinal interspace has become a common procedure. Retroperitoneal retraction and laparoscopic instrumentation without insufflation also allows visualization of the upper lumbar spaces, but this procedure is much more difficult to accomplish. We review and compare our results using each of these techniques for the treatment of mechanical instability and chronic back pain. A total of 35 selected patients underwent intervertebral fusion between February 1996 and August 1998. Their mean age was 48 years. There were 22 female and 13 male patients. Standard CO2 insufflation was used in 10 patients with L5-S1 fusions. Retractional gasless technique was used in nine patients with fusions at L5-S1, 16 patients at L4-L5, one patient at L3-L4, three patients at L2-3, and one patient at L1-L2. Thus, we performed a total of 40 lumbar fusions in 35 patients. In the 19 patients with the gasless technique, a balloon dissector and retractor facilitated the retroperitoneal exposure. Seven of these 19 patients were converted to open procedures, most commonly due to lacerations of the peritoneal lining that prohibited visualization. None of the L5-S1 patients with insufflation were converted to open. Mean operative time in the insufflated patients was 152 min vs 181 min for the retractional technique. There were seven complications in the transperitoneal group: one fusion device migration, one postoperative UTI, one intracerebral hemorrhage, one severe postoperative pancreatitis, and three iliac vein lacerations. There were 16 complications in the retroperitoneal group: one deep vein thromboses, one serosal bowel injury, one small tear in the spleen, one cage migration, one postoperative pulmonary atelectasis, one postoperative hydrocele, four postoperative ileus, and six peritoneal tears. The mean postoperative stay was three days for both groups. There were no deaths. The L5-S1 interspace is best approached transperitoneally for anterior fusion. Although the retroperitoneal retractional technique is much more difficult and has a longer and steeper learning curve, it does allow laparoscopic anterior fusion of the upper lumbar spine. PMID- 28337612 TI - Liver retraction techniques for laparoscopic cholecystectomy. PMID- 28337613 TI - Trocar for laparoscopic placement of peritoneal dialysis catheter. PMID- 28337614 TI - Rituximab in refractory chronic inflammatory demyelinating polyradiculoneuropathy: report of four cases. PMID- 28337615 TI - Longer duration of obesity is associated with a reduction in urinary angiotensinogen in prepubertal children. AB - BACKGROUND: We aimed to study the impact of obesity on urinary excretion of angiotensinogen (U-AGT) in prepubertal children, focusing on the duration of obesity and gender. Also, we aimed to evaluate whether plasma angiotensinogen (P AGT) and hydrogen peroxide (H2O2) play a role in the putative association. METHODS: Cross-sectional evaluation of 305 children aged 8-9 years (160 normal weight, 86 overweight, and 59 obese). Anthropometric measurements and 24-h ambulatory blood pressure monitoring were performed. Angiotensinogen (AGT) was determined by a commercial enzyme-linked immunosorbent assay (ELISA) kit and H2O2 by a microplate fluorometric assay. RESULTS: U-AGT and P-AGT levels were similar across body mass index (BMI) groups and between sexes. However, boys who were overweight/obese since the age of 4 years presented lower levels of U-AGT compared with those of normal weight at the same age. In children who were overweight/obese since the age of 4, urinary H2O2 decreased with P-AGT. CONCLUSIONS: A higher duration of obesity was associated with decreased U-AGT in boys, thus reflecting decreased intrarenal activity of the renin-angiotensin system. Also, children with a longer duration of obesity showed an inverse association between urinary H2O2 and P-AGT. Future studies should address whether these results reflect an early compensatory mechanism to limit obesity-triggered renal dysfunction. PMID- 28337617 TI - Indications of Transconjunctival Orbital Septum Fat Release and Preservation for Orbitopalpebral Sulcus in Lower Eyelid Blepharoplasty. PMID- 28337616 TI - Follow-up results of patients with ADCK4 mutations and the efficacy of CoQ10 treatment. AB - BACKGROUND: ADCK4-related glomerulopathy is an important differential diagnosis in adolescents with steroid-resistant nephrotic syndrome (SRNS) and/or chronic kidney disease (CKD) of unknown origin. We screened adolescent patients to determine the frequency of ADCK4 mutation and the efficacy of early CoQ10 administration. METHODS: A total of 146 index patients aged 10-18 years, with newly diagnosed non-nephrotic proteinuria, nephrotic syndrome, or chronic renal failure and end-stage kidney disease (ESKD) of unknown etiology were screened for ADCK4 mutation. RESULTS: Twenty-eight individuals with bi-allelic mutation from 11 families were identified. Median age at diagnosis was 12.4 (interquartile range [IQR] 8.04-19.7) years. Upon first admission, all patients had albuminuria and 18 had CKD (6 ESKD). Eight were diagnosed either through the screening of family members following index case identification or during genetic investigation of proteinuria in an individual with a history of a transplanted sibling. Median age of these 8 patients was 21.5 (range 4.4-39) years. CoQ10 supplementation was administered following genetic diagnosis. Median estimated glomerular filtration rate (eGFR) just before CoQ10 administration was 140 (IQR 117-155) ml/min/1.73m2, proteinuria was 1,008 (IQR 281-1,567) mg/m2/day. After a median follow-up of 11.5 (range 4-21) months following CoQ10 administration, proteinuria was significantly decreased (median 363 [IQR 175-561] mg/m2/day, P=0.025), whereas eGFR was preserved (median 137 [IQR 113-158] ml/min/1.73m2, P=0.61). CONCLUSIONS: ADCK4 mutations are one of the most common causes of adolescent-onset albuminuria and/or CKD of unknown etiology in Turkey. CoQ10 supplementation appears efficacious at reducing proteinuria, and may thereby be renoprotective. PMID- 28337619 TI - Raised Serum IL-8 Levels Are Associated with Excessive Fatigue in Female Carriers of X-Linked Chronic Granulomatous Disease in the UK. PMID- 28337618 TI - Reply: Innovative Management of Implant Infection and Exposure in ADM/Implant Based Breast Reconstruction with Negative Pressure Wound Therapy. PMID- 28337620 TI - Date palm waste-derived biochar composites with silica and zeolite: synthesis, characterization and implication for carbon stability and recalcitrant potential. AB - Engineered organo-mineral composites were synthesized from date palm waste biochar and silica or zeolite via mechanochemical treatments. Date palm tree rachis (leaves) waste biomass was pre-treated with silica or zeolite minerals via ball milling and sonication prior to pyrolysis at 600 degrees C. The resultant organo-mineral composites and pristine materials were characterized using X-ray diffraction, thermogravimetric-differential thermal (TG-DTA), Fourier transform infrared, scanning electron microscope analyses and surface area and porosity analyzer to investigate the variations in physiochemical and structural characteristics. Compared to the resultant composites derived from non-milled date palm biomass, ball milling increased surface area, while decreased crystallinity index and effective particle size of the biochar composites. Silica composited biochars were located near origin in the van Krevelen diagram indicating lowest H/C and O/C molar ratios, thus suggesting higher aromaticity and lower polarity compared to other biochars. TGA thermograms indicated highest thermal stability of silica composited biochars. Ash and moisture corrected TGA thermograms were used to calculate recalcitrance index (R 50) of the materials, which speculated high degradability of biomass (R 50 < 0.4), minimal degradability of biochars and zeolite composited biochars (0.5 < R 50 < 0.7) and high recalcitrant nature of silica composited biochars (R 50 > 0.7). Silica composited biochars exhibited highest carbon sequestration potential (64.17 95.59%) compared to other biochars. Highest recalcitrance and carbon sequestration potential of silica composited biochars may be attributed to changes in structural arrangements in the silica-biochar complex. Encapsulations of biochar particles with amorphous silica via Si-C bonding may have prevented thermal degradation, subsequently increasing recalcitrance potential of silica composited biochars. PMID- 28337621 TI - Metal-contaminated potato crops and potential human health risk in Bolivian mining highlands. AB - This study assessed metals in irrigation water, soil and potato crops impacted by mining discharges, as well as potential human health risk in the high desert near the historic mining center of Potosi, Bolivia. Metal concentrations were compared with international concentration limit guidelines. In addition, an ingested average daily dose and minimum risk level were used to determine the hazard quotient from potato consumption for adults and children. Irrigation water maximum concentrations of Cd, Pb and Zn in mining-impacted sites were elevated 20 to 1100-fold above international concentration limit guidelines. Agricultural soils contained total metal concentrations of As, Cd, Pb and Zn that exceeded concentration limits in agricultural soil guidelines by 22-, 9-, 3- and 12-fold, respectively. Potato tubers in mining-impacted sites had maximum concentrations of As, Cd, Pb and Zn that exceeded concentration limits in commercially sold vegetables by 9-, 10-, 16- and fourfold, respectively. Using conservative assumptions, hazard quotients (HQ) for potatoes alone were elevated for As, Cd and Pb among children (range 1.1-71.8), in nearly all of the mining-impacted areas; and for As and Cd among adults (range 1.2-34.2) in nearly all of the mining-impacted areas. Only one mining-impacted area had a Pb adult HQ for potatoes above 1 for adults. Toxic trace elements in a major regional dietary staple may be a greater concern than previously appreciated. Considering the multitude of other metal exposure routes in this region, it is likely that total HQ values for these metals may be substantially higher than our estimates. PMID- 28337622 TI - Harnessing fertilizer potential of human urine in a mesocosm system: a novel test case for linking the loop between sanitation and aquaculture. AB - Human urine (HU) is a biogenic fertilizer which has raised immense interest owing to its capacity of combining sanitation and nutrient recovery. In search of an alternative organic fertilizer for fish culture, the nutrient potential of HU was evaluated. Fries of Indian carps and larvae of freshwater prawn were reared for 120 days under six conditions: (a) aerated and (b) non-aerated fresh HU (0.01%), (c) cattle manure (CM; 1.8 kg tank-1), mixed treatment with CM and HU under (d) iso-phosphorus and (e) iso-nitrogenous condition and (f) control. Monitoring of water quality and biological parameters revealed that total fish yield was the highest in CM (621.5 g tank-1) followed by mixed treatments under iso-nitrogenous (428 g tank-1) and iso-phosphorus (333 g tank-1) conditions, aerated HU (321 g tank-1) and HU (319 g tank-1). The gross primary productivity (GPP) in HU was satisfactory (601.8 mg C m-2 h-1) and superior to all but CM treatment. The abundance of heterotrophic bacteria (HB) was highest in CM and lowest in HU. Both GPP and HB population were correlated positively with fish yield per tank. Although pH in all treatments remained high (pH 8.4-8.9), no ammonia toxicity was observed. No E. coli infestation in any fish muscle was encountered. The concentrations of cadmium and lead in fish muscle were within respective safe level. The study established that high fertilizer potential of HU could be exploited as an alternative organic fertilizer or as a candidate to be blended with cattle manure. PMID- 28337623 TI - Erratum to: Isotherm, kinetic, and thermodynamic study of ciprofloxacin sorption on sediments. PMID- 28337624 TI - Geochemical behavior of ultramafic waste rocks with carbon sequestration potential: a case study of the Dumont Nickel Project, Amos, Quebec. AB - The geochemical behavior of ultramafic waste rocks and the effect of carbon sequestration by these waste rocks on the water drainage quality were investigated using laboratory-scale kinetic column tests on samples from the Dumont Nickel Project (RNC Minerals, QC, Canada). The test results demonstrated that atmospheric CO2 dissolution induced the weathering of serpentine and brucite within the ultramafic rocks, generating high concentrations of Mg and HCO3- with pH values ranging between 9 and 10 in the leachates that promote the precipitation of secondary Mg carbonates. These alkaline pH values appear to have prevented the mobilization of many metals; Fe, Ni, Cu, and Zn were found at negligible concentrations in the leachates. Posttesting characterization using chemical analyses, diffuse reflectance infrared Fourier transform (DRIFT), and scanning electron microscope (SEM) observations confirmed the precipitation of secondary hydrated Mg carbonates as predicted by thermodynamic calculations. The formation of secondary Mg carbonates induced cementation of the waste particles, resulting in the development of a hardpan. PMID- 28337625 TI - Using fluorescent dyes as proxies to study herbicide removal by sorption in buffer zones. AB - The performance of buffer zones for removing pesticides from runoff water varies greatly according to landscape settings, hydraulic regime, and system design. Evaluating the performance of buffers for a range of pesticides and environmental conditions can be very expensive. Recent studies suggested that the fluorescent dyes uranine and sulforhodamine B could be used as cost-effective surrogates of herbicides to evaluate buffer performance. However, while transformation mechanisms in buffers have been extensively documented, sorption processes of both dyes have rarely been investigated. In this study, we measured the adsorption, desorption, and kinetic sorption coefficients of uranine and sulforhodamine B for a diverse range of buffer zone materials (soils, litters, plants) and compared the adsorption coefficients (Kd) to those of selected herbicides. We also compared the global sorption capacity of 6 ditches, characterized by varying proportions of the aforementioned materials, between both dyes and a set of four herbicides using the sorption-induced pesticide retention indicator (SPRI). We found that both the individual Kd of uranine for the diverse buffer materials and the global sorption capacity of the ditches are equivalent to those of the herbicides diuron, isoproturon, and metolachlor. The Kd of sulforhodamine B on plants and soils are equivalent to those of glyphosate, and the global sorption capacities of the ditches are equivalent for both molecules. Hence, we demonstrate for the first time that uranine can be used as a proxy of moderately hydrophobic herbicides to evaluate the performance of buffer systems, whereas sulforhodamine B can serve as a proxy for more strongly sorbing herbicides. PMID- 28337626 TI - Application of a novel magnetic carbon nanotube adsorbent for removal of mercury from aqueous solutions. AB - In this research, multiwall carbon nanotube was magnetized and subsequently functionalized by thiosemicarbazide. After characterization by FTIR, BET, SEM, EDAX, and VSM techniques, the magnetized adsorbent (multi-walled carbon nanotubes (MWCNTs)/Fe3O4) was used for removal of Hg2+ from aqueous solutions and the experimental conditions were optimized. The adsorption capacity of 172.83 mg g-1 was obtained at 25 degrees C and pH = 3 which was superior to the value obtained for initial multiwall carbon nanotube, magnetized sample, and many previously reported values. In the presence of Pb+2 and Cd+2, the adsorbent was selective towards mercury when their concentration was respectively below 50 and 100 mg L 1. The adsorption process was kinetically fast and the equilibration was attained within 60 min with 69.5% of the capacity obtained within 10 min. The used adsorbent was regenerated by HNO3 solution, and the regenerated adsorbent retained 92% of its initial capacity. The magnetic sensitivity of the adsorbent allowed the simple separation of the used adsorbent from the solution by implying an appropriate external magnetic field. The adsorption data was well fitted to the Langmuir isotherm model, indicating homogeneous and monolayer adsorption of mercury by the adsorbent. PMID- 28337627 TI - Biological impacts of local vs. regional land use on a small tributary of the Seine River (France): insights from a food web approach based on stable isotopes. AB - As part of the landscape, streams are influenced by land use. Here, we contributed to the understanding of the biological impacts of land use on streams, investigating how landscape effects vary with spatial scales (local vs. regional). We adopted a food web approach integrating both biological structure and functioning, to focus on the overall effect of land use on stream biocoenosis. We selected 17 sites of a small tributary of the Seine River (France) for their contrasted land use, and conducted a natural experiment by sampling three organic matter sources, three macroinvertebrate taxa, and most of the fish community. Using stable isotope analysis, we calculated three food web metrics evaluating two major dimensions of the trophic diversity displayed by the fish community: (i) the diversity of exploited resources and (ii) the trophic level richness. The idea was to examine whether (1) land-use effects varied according to spatial scales, (2) land use affected food webs through an effect on community structure and (3) land use affected food webs through an effect on available resources. Beside an increase in trophic diversity from upstream to downstream, our empirical data showed that food webs were influenced by land use in the riparian corridors (local scale). The effect was complex, and depended on site's position along the upstream-downstream gradient. By contrast, land use in the catchment (regional scale) did not influence stream biocoenosis. At the local scale, community structure was weakly influenced by land use, and thus played a minor role in explaining food web modifications. Our results suggested that the amount of available resources at the base of the food web was partly responsible for food web modifications. In addition, changes in biological functioning (i.e. feeding interactions) can also explain another part of the land-use effect. These results highlight the role played by the riparian corridors as a buffer zone, and advocate that riparian corridor should be at the centre of water management attention. PMID- 28337628 TI - Study of plasma off-gas treatment from spent ion exchange resin pyrolysis. AB - Polystyrene divinylbenzene-based ion exchange resins are employed extensively within nuclear power plants (NPPs) and research reactors for purification and chemical control of the cooling water system. To maintain the highest possible water quality, the resins are regularly replaced as they become contaminated with a range of isotopes derived from compromised fuel elements as well as corrosion and activation products including 14C, 60Co, 90Sr, 129I, and 137Cs. Such spent resins constitute a major proportion (in volume terms) of the solid radioactive waste generated by the nuclear industry. Several treatment and conditioning techniques have been developed with a view toward reducing the spent resin volume and generating a stable waste product suitable for long-term storage and disposal. Between them, pyrolysis emerges as an attractive option. Previous work of our group suggests that the pyrolysis treatment of the resins at low temperatures between 300 and 350 degrees C resulted in a stable waste product with a significant volume reduction (>50%) and characteristics suitable for long term storage and/or disposal. However, another important issue to take into account is the complexity of the off-gas generated during the process and the different technical alternatives for its conditioning. Ongoing work addresses the characterization of the ion exchange resin treatment's off-gas. Additionally, the application of plasma technology for the treatment of the off-gas current was studied as an alternative to more conventional processes utilizing oil- or gas fired post-combustion chambers operating at temperatures in excess of 1000 degrees C. A laboratory-scale flow reactor, using inductively coupled plasma, operating under sub-atmospheric conditions was developed. Fundamental experiments using model compounds have been performed, demonstrating a high destruction and removal ratio (>99.99%) for different reaction media, at low reactor temperatures and moderate power consumption. The role of H2O as an important participant of the oxidation mechanisms in plasma conditions was established. The combination of both processes could represent a simple, safe, and effective alternative for treating spent ion exchange resins with a large reduction of generated gaseous byproducts in fuel cycle facilities where processes that utilize open flames are undesirable. PMID- 28337629 TI - An innovative application of extended exergy analysis into an industrial park. AB - Exergy is a thermodynamic term used to account all possible useful work theoretically throughout one process when it is brought into equilibrium with its environment. It however cannot directly incorporate non-physical flows, which can be accounted by extensions of the exergy consumption method. Extended exergy, which builds a bridge between thermal and anthropic dimensions, can both measure resource consumption and economic system. In this study, we applied extended exergy analysis to analyze an industrial park, including material consumption, social investment, and environmental influence. The total extended exergy consumption in the study park amounts to 2.52 EJ. The material-based exergy occupies the largest exergy consumption, followed by capital exergy, environmental remediation exergy, and labor exergy in decreasing order. The exergy capacity was proposed to depict the conversion ability from exergy consumption into economic benefits. In the study area, electronic information industry has the largest exergy capacity with a value of 70 RMB/GJ, indicating a high conversion power from exergy to money. New energy vehicles and parts manufacturing occupies bottom rung in terms of exergy capacity. From the view of material consumption, other industry consumed a lot more exergy compared to electronic information industry; for the environmental remediation, other industry has the lowest exergy capacity, indicating it discharged more pollutants than other clusters to output the same amount of money. Therefore, other industry needs to be urgently transformed and upgraded. The study could help to optimize industrial structure and environmental management in industrial parks. PMID- 28337630 TI - Erratum to: Differential Brain, Cognitive and Motor Profiles Associated with Partial Trisomy. Modeling Down Syndrome in Mice. PMID- 28337631 TI - Upregulation of Mineralocorticoid Receptor in the Hypothalamus Associated with a High Anxiety-like Level in Apolipoprotein E4 Transgenic Mice. AB - Anxiety symptoms occur in a large portion of Alzheimer's disease (AD) patients. ApolipoproteinE-4 (ApoE epsilon4 allele), a risk factor for AD, has been recognized as an important contributor to psychiatric disorders. In the present study, we aimed to investigate the corticosterone level in relation to anxiety like behavior changes in transgenic male mice with different glial fibrillary acidic protein (GFAP)-ApoE isoforms. GFAP-ApoE4 transgenic mice aged 3 months showed higher anxiety-like behavior in open field, light-dark box and elevated plus maze tasks compared with that of age-matched GFAP-ApoE3 mice. However, corticotropin releasing factor levels in the hypothalamus and plasma corticosterone secretion were similar in GFAP-ApoE3 and GFAP-ApoE4 transgenic male mice. Additionally, increased expression of the mineralocorticoid receptor (MR) and unchanged expression of the glucocorticoid receptor were observed in the hypothalamus of GFAP-ApoE4 mice. However, no significant differences were found in the expression levels of the MR in GFAP-ApoE3 and GFAP-ApoE4 mice at postnatal day 2. In conclusion, we found that MR upregulation rather than corticosterone level changes in the early stage of adulthood was associated with the higher anxiety-like level measured in GFAP-ApoE4 mice. PMID- 28337632 TI - Comparative toxicity of imidacloprid and thiacloprid to different species of soil invertebrates. AB - Neonicotinoid insecticides have come under increasing scrutiny for their impact on non-target organisms, especially pollinators. The current scientific literature is mainly focused on the impact of these insecticides on pollinators and some aquatic insects, leaving a knowledge gap concerning soil invertebrates. This study aimed at filling this gap, by determining the toxicity of imidacloprid and thiacloprid to five species of soil invertebrates: earthworms (Eisenia andrei), enchytraeids (Enchytraeus crypticus), Collembola (Folsomia candida), oribatid mites (Oppia nitens) and isopods (Porcellio scaber). Tests focused on survival and reproduction or growth, after 3-5 weeks exposure in natural LUFA 2.2 standard soil. Imidacloprid was more toxic than thiacloprid for all species tested. F. candida and E. andrei were the most sensitive species, with LC50s of 0.20-0.62 and 0.77 mg/kg dry soil for imidacloprid and 2.7-3.9 and 7.1 mg/kg dry soil for thiacloprid. EC50s for effects on the reproduction of F. candida and E. andrei were 0.097-0.30 and 0.39 mg/kg dry soil for imidacloprid and 1.7-2.4 and 0.44 mg/kg dry soil for thiacloprid. The least sensitive species were O. nitens and P. scaber. Enchytraeids were a factor of 5-40 less sensitive than the taxonomically related earthworm, depending on the endpoint considered. Although not all the species showed high sensitivity to the neonicotinoids tested, these results raise awareness about the effects these insecticides can have on non target soil invertebrates. PMID- 28337633 TI - The Development of an HIV Risk Environment Scale of Exotic Dance Clubs. AB - Exotic dancers have received little research attention despite evidence of high risk behaviours within exotic dance clubs (EDCs). We developed and assessed the reliability and validity of a risk environment score, examining differences between dancers (n = 107) and other staff (n = 172). In the summer of 2013, anonymous surveys were administered via A-CASI in EDCs (N = 26) in Baltimore among exotic dancers and staff. Surveys consisted of a brief demographic section followed by 65 statements. The overall domain had an alpha = 0.77 and subdomains had the following: social (alpha = 0.87), economic (alpha = 0.92), drug (alpha = 0.89), and policy (alpha = 0.66). In a factor analysis, each domain contributed significantly to the overall latent construct. The results indicate a high level of HIV/STI risk for dancers in EDCs and underscore the need for targeted interventions in these environments. As we continue to unpack the function of the broader environment in STI/HIV risk transmission, the scale could be instructive for other settings. PMID- 28337635 TI - Measurement of bovine body and scrotal temperature using implanted temperature sensitive radio transmitters, data loggers and infrared thermography. AB - Synchronous and continuous measurement of body (BT) and scrotal temperature (ST) without adverse welfare or behavioural interference is essential for understanding thermoregulation of the bull testis. This study compared three technologies for their efficacy for long-term measurement of the relationship between BT and ST by means of (1) temperature sensitive radio transmitters (RT), (2) data loggers (DL) and (3) infrared imaging (IRI). After an initial pilot study on two bulls to establish a surgical protocol, RTs and DLs were implanted into the flank and mid-scrotum of six Wagyu bulls for between 29 and 49 days. RT frequencies were scanned every 15 min, whilst DLs logged every 30 min. Infrared imaging of the body (flank) and scrotum of each bull was recorded hourly for one 24-h period and compared to RT and DL data. After a series of subsequent heat stress studies, bulls were castrated and testicular tissue samples processed for evidence of histopathology. Radio transmitters were less reliable than DLs; RTs lost >11 % of data, whilst 11 of the 12 DLs had 0 % data loss. IRI was only interpretable in 35.8 % of images recorded. Pearson correlations between DL and RT were strong for both BT (r > 0.94, P < 0.001) and ST (r > 0.80, P < 0.001). Surgery produced temporary minor inflammation and scrotal hematoma in two animals post-surgery. Whilst scar tissue was observed at all surgical sutured sites when bulls were castrated, there was no evidence of testicular adhesion and normal active spermatogenesis was observed in six of the eight implanted testicles. There was no significant correlation of IRI with either DL or RT. We conclude that DLs provided to be a reliable continuous source of data for synchronous measurement of BT and ST. PMID- 28337634 TI - Topical dura mater application of CFA induces enhanced expression of c-fos and glutamate in rat trigeminal nucleus caudalis: attenuated by KYNA derivate (SZR72). AB - BACKGROUND: Migraine is a debilitating neurological disorder where trigeminovascular activation plays a key role. We have previously reported that local application of Complete Freund's Adjuvant (CFA) onto the dura mater caused activation in rat trigeminal ganglion (TG) which was abolished by a systemic administration of kynurenic acid (KYNA) derivate (SZR72). Here, we hypothesize that this activation may extend to the trigeminal complex in the brainstem and is attenuated by treatment with SZR72. METHODS: Activation in the trigeminal nucleus caudalis (TNC) and the trigeminal tract (Sp5) was achieved by application of CFA onto the dural parietal surface. SZR72 was given intraperitoneally (i.p.), one dose prior CFA deposition and repeatedly daily for 7 days. Immunohistochemical studies were performed for mapping glutamate, c-fos, PACAP, substance P, IL-6, IL 1beta and TNFalpha in the TNC/Sp5 and other regions of the brainstem and at the C1-C2 regions of the spinal cord. RESULTS: We found that CFA increased c-fos and glutamate immunoreactivity in TNC and C1-C2 neurons. This effect was mitigated by SZR72. PACAP positive fibers were detected in the fasciculus cuneatus and gracilis. Substance P, TNFalpha, IL-6 and IL-1beta immunopositivity were detected in fibers of Sp5 and neither of these molecules showed any change in immunoreactivity following CFA administration. CONCLUSION: This is the first study demonstrating that dural application of CFA increases the expression of c fos and glutamate in TNC neurons. Treatment with the KYNA analogue prevented this expression. PMID- 28337636 TI - Evodiamine Inhibits Zymosan-Induced Inflammation In Vitro and In Vivo: Inactivation of NF-kappaB by Inhibiting IkappaBalpha Phosphorylation. AB - Evodiamine (EVO), an important alkaloidal component extracted from the fruit of Evodiae fructus, has been known to possess anti-tumor, anti-inflammatory, anti oxidative, and other therapeutic capabilities. In the present study, the effects of EVO on zymosan-induced inflammation and its underlying mechanism were investigated both in vitro and in vivo. Our results showed that EVO effectively suppressed both protein and mRNA expression of interleukin-1beta, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) in vitro. Zymosan-induced DNA binding activity of nuclear factor-kappa B (NF-kappaB) was attenuated by EVO, which was achieved through inhibitory effects on the phosphorylation of inhibitory kappaB alpha and p65 nuclear translocation, but there was very little association with mitogen-activated protein kinase activation. In vivo, treatment with EVO markedly decreased TNF-alpha and IL-6 levels in plasma. EVO also repressed inflammatory cytokine expression and ameliorated the abnormal state in both lung and intestine tissues by inactivation of NF-kappaB. Furthermore, EVO significantly reduced the mortality caused by zymosan. In summary, these results suggested that EVO could effectively suppress inflammatory responses in vitro and in vivo, and may be a potential therapeutic agent against inflammatory disorders. PMID- 28337637 TI - In Vivo Paracoccidioides sp. Biofilm on Vascular Prosthesis. AB - Paracoccidioidomycosis is an endemic mycosis caused by Paracoccidioides species limited to Latin America arising with the chronic form in 90% of cases. The capacity of microorganisms to form biofilms is considered of great importance medical since can contribute to the persistence and to the chronic state of the diseases. The ability of Paracoccidioides to form biofilm has been demonstrated in vitro. In our study, for the first time we have observed this capability in vivo on a vascular prosthesis using scanning electron microscope showing a dense network of Paracoccidioides yeasts covered by an extracellular matrix. PMID- 28337638 TI - Erratum to: Using a discrete choice experiment to value the QLU-C10D: feasibility and sensitivity to presentation format. PMID- 28337639 TI - The impact of mangiferin from Belamcanda chinensis on experimental colitis in rats. AB - BACKGROUND: Inflammatory bowel disease (IBD) [including Crohn's disease (CD) and ulcerative colitis (UC)] constitutes an important clinical problem. The pathogenesis of IBD remains unclear. It is believed that immune dysfunction, inflammatory mediators and oxidative damage play crucial roles in development of IBD. The condition is clinically associated with symptoms ranging from mild to severe during relapses, depending on the affected segment of the gastrointestinal tract. Bloody diarrhea with mucus, abdominal pain, weight loss and anemia are initial symptoms of both CD and UC. Differences between diseases become more evident in time, along with the development of intestinal and extraintestinal complications. Mangiferin (1,3,6,7-tetrahydroxyxanthone-C-2-beta-D-glucoside), a natural polyphenol in plants, exerts antioxidant and anti-inflammatory effects making it an interesting option for the treatment of inflammatory pathologies associated with oxidative stress in humans, such as IBD. PURPOSE: The aim of the current study was to elucidate the impact of mangiferin on colon tissues in 2,4,6 trinitrobenzensulfonic acid (TNBS)-induced colitis in rats. METHODS: Mangiferin was obtained from Belamcanda chinensis rhizomes by a multistage process. Groups of rats were pre-treated with 10, 30 or 100 mg/kg of mangiferin, or with distilled water administered intragastrically for 16 days. An ethanol solution of TNBS or saline was given rectally on the day 15 of the experiment. The experiment was terminated on the day 17. The colon was removed, cleaned, weighed and examined macro- and microscopically. Determination of tumor necrosis factor alpha (TNF-alpha), interleukin 17 (IL-17), malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity were performed spectrophotometrically in homogenates of colon tissues. RESULTS: Rats in the TNBS group developed symptoms of colitis, including: body weight loss, colon mass index increase and damage of intestinal tissues with concomitant increase in TNF-alpha, IL-17, MDA levels and decreased SOD activity. In non-TNBS-treated rats mangiferin did not cause any changes of studied parameters. Pre-treatment with mangiferin exerted a protective effect, reducing the intensity of damage caused by TNBS. Mangiferin at the doses of 30 and 100 mg/kg reduced the macro- and microscopic damage score and the MDA level in colon tissues. Only at the dose of 100 mg/kg, mangiferin decreased TNF-alpha and IL-17 concentrations, and SOD activity in colon tissues. CONCLUSION: Mangiferin attenuates inflammatory changes of colon tissues in experimental, TNBS induced colitis in rats. Protective effect exerted by mangiferin depends primarily on its anti-inflammatory activity and secondarily on its antioxidant properties. PMID- 28337640 TI - Erratum to: Intraoperative Patterns of Gastric Microperfusion During Laparoscopic Sleeve Gastrectomy. PMID- 28337641 TI - Inhibition of proliferation of prostate cancer cell line DU-145 in vitro and in vivo using Salvia miltiorrhiza Bunge. AB - OBJECTIVE: To investigate the antiproliferative activity of Salvia miltiorrhiza Bunge. (SM) on the castration-resistant prostate cancer (CRPC) cell line DU-145, in vitro and in vivo. METHODS: Prostate cancer cell line (DU-145) and normal prostate cell line (RWPE-1) were treated with SM at different concentrations (3.125, 12.5, 25 and 50 MUg/mL) to investigate the antiproliferative effects. DNA laddering analysis was performed to investigate the apoptosis of DU-145 cells. Molecular mechanism was investigated by Western blot analysis of p53, Bcl-2, prostate specific antigen (PSA), and androgen receptor (AR). Six-week-old male BALB/c nude mice were randomly divided into normal control group (n=101) and treated group (n=101) which administered 500 mg/kg SM for 2 weeks. Tumor volumes were measured. RESULTS: Treatment with SM resulted in a dose-dependent decrease in cell number of DU-145 cells in comparison with RWPE-1. DNA laddering analysis indicated the apoptosis of DU-145 cells. Treatment with SM increased the expression of p53 and reduced the expression of Bcl-2 proteins. The levels of PSA were considerably reduced in SM-treated group compared to the controls, and a decrease in AR expression was observed when cells were treated with SM in the same pattern as a reduction in PSA. In the tumour xenograft study, SM given once a day for 2 weeks significantly inhibited tumour growth. CONCLUSION: SM might contribute to the anticancer actions such as induction of apoptosis and inhibition of proliferation of prostate cancer cells. PMID- 28337642 TI - The small heat shock proteins alphaB-crystallin (HSPB5) and Hsp27 (HSPB1) inhibit the intracellular aggregation of alpha-synuclein. AB - Protein homeostasis, or proteostasis, is the process of maintaining the conformational and functional integrity of the proteome. Proteostasis is preserved in the face of stress by a complex network of cellular machinery, including the small heat shock molecular chaperone proteins (sHsps), which act to inhibit the aggregation and deposition of misfolded protein intermediates. Despite this, the pathogenesis of several neurodegenerative diseases has been inextricably linked with the amyloid fibrillar aggregation and deposition of alpha-synuclein (alpha-syn). The sHsps are potent inhibitors of alpha-syn aggregation in vitro. However, the limited availability of a robust, cell-based model of alpha-syn aggregation has, thus far, restricted evaluation of sHsp efficacy in the cellular context. As such, this work sought to establish a robust model of intracellular alpha-syn aggregation using Neuro-2a cells. Aggregation of alpha-syn was found to be sensitive to inhibition of autophagy and the proteasome, resulting in a significant increase in the proportion of cells containing alpha-syn inclusions. This model was then used to evaluate the capacity of the sHsps, alphaB-c and Hsp27, to prevent alpha-syn aggregation in cells. To do so, we used bicistronic expression plasmids to express the sHsps. Unlike traditional fluorescent fusion constructs, these bicistronic expression plasmids enable only individual transfected cells expressing the sHsps (via expression of the fluorescent reporter) to be analysed, but without the need to tag the sHsp, which can affect its oligomeric structure and chaperone activity. Overexpression of both alphaB-c and Hsp27 significantly reduced the intracellular aggregation of alpha-syn. Thus, these findings suggest that overexpressing or boosting the activity of sHsps may be a way of preventing amyloid fibrillar aggregation of alpha-syn in the context of neurodegenerative disease. PMID- 28337643 TI - Recombinant heat shock protein 27 (HSP27/HSPB1) protects against cadmium-induced oxidative stress and toxicity in human cervical cancer cells. AB - Cadmium (Cd) is a carcinogen with several well-described toxicological effects in humans, but its molecular mechanisms are still not fully understood. Overexpression of heat shock protein 27 (HSP27/HSPB1)-a multifunctional protein chaperone-has been shown to protect cells from oxidative damage and apoptosis triggered by Cd exposure. The aims of this work were to investigate the potential use of extracellular recombinant HSP27 to prevent/counteract Cd-induced cellular toxicity and to evaluate if peroxynitrite was involved in the development of Cd induced toxicity. Here, we report that the harmful effects of Cd correlated with changes in oxidative stress markers: upregulation of reactive oxygen species, reduction in nitric oxide (NO) bioavailability, increment in lipid peroxidation, peroxynitrite (PN), and protein nitration; intracellular HSP27 was reduced. Treatments with Cd (100 MUM) for 24 h or with the peroxynitrite donor, SIN-1, decreased HSP27 levels (~50%), suggesting that PN formation is responsible for the reduction of HSP27. Pre-treatments of the cells either with Nomega-nitro-L arginine methyl ester hydrochloride (L-NAME) (a pharmacological inhibitor of NO synthase) or with recombinant HSP27 (rHSP27) attenuated the disruption of the cellular metabolism induced by Cd, increasing in a 55 and 52%, respectively, the cell viability measured by CCK-8. Cd induced necrotic cell death pathways, although apoptosis was also activated; pre-treatment with L-NAME or rHSP27 mitigated cell death. Our findings show for the first time a direct relationship between Cd-induced toxicity and PN production and a role for rHSP27 as a potential therapeutic agent that may counteract Cd toxicity. PMID- 28337645 TI - Maintenance of memory for melodies: Articulation or attentional refreshing? AB - Past research on the effects of articulatory suppression on working memory for nonverbal sounds has been characterized by discrepant findings, which suggests that multiple mechanisms may be involved in the rehearsal of nonverbal sounds. In two experiments we examined the potential roles of two theoretical mechanisms of verbal working memory-articulatory rehearsal and attentional refreshing-in the maintenance of memory for short melodies. In both experiments, participants performed a same-different melody comparison task. During an 8-s retention interval, interference tasks were introduced to suppress articulatory rehearsal, attentional refreshing, or both. In Experiment 1, only the conditions that featured articulatory suppression resulted in worse memory performance than in a control condition, and the suppression of both attentional refreshing and articulatory rehearsal concurrently did not impair memory more than articulatory suppression alone. Experiment 2 reproduced these findings and also confirmed that the locus of interference was articulatory and not auditory (i.e., the interference was not attributable to the sound of participants' own voices during articulatory suppression). Both experiments suggested that articulatory rehearsal played a role in the maintenance of melodies in memory, whereas attentional refreshing did not. We discuss potential theoretical implications regarding the mechanisms used for the rehearsal of nonverbal sounds in working memory. PMID- 28337646 TI - The puzzle of study time allocation for the most challenging items. AB - Learners often allocate more study time to challenging items than to easier ones. Nevertheless, both predicted and actual memory performance are typically worse for difficult than for easier items. The resulting inverse relations between people's predictions of their memory performance (judgments of learning; JOLs) and self-paced study time (ST) are often explained by bottom-up, data-driven ST allocation that is based on fluency. However, we demonstrate robust inverted U shaped relations between JOLs and ST that cannot be explained by data-driven ST allocation alone. Consequently, we explored how two models of top-down, strategic ST allocation account for curvilinear JOL-ST relations. First, according to the Region of Proximal Learning model, people stop quickly on items for which they experience too little progress in learning. Second, according to the Diminishing Criterion Model, people set a time limit and stop studying when this time limit is reached. In three experiments, we manipulated motivation with different methods and examined which model best described JOL-ST relations. Consistent with the Diminishing Criterion Model but not with the Region of Proximal Learning model, results revealed that curvilinearity was due to people setting a time limit. PMID- 28337647 TI - Revisiting the role of language in spatial cognition: Categorical perception of spatial relations in English and Korean speakers. AB - The spatial relation of support has been regarded as universally privileged in nonlinguistic cognition and immune to the influence of language. English, but not Korean, obligatorily distinguishes support from nonsupport via basic spatial terms. Despite this linguistic difference, previous research suggests that English and Korean speakers show comparable nonlinguistic sensitivity to the support/nonsupport distinction. Here, using a paradigm previously found to elicit cross-language differences in color discrimination, we provide evidence for a difference in sensitivity to support/nonsupport between native English speakers and native Korean speakers who were late English learners and tested in a context that privileged Korean. Whereas the former group showed categorical perception (CP) when discriminating spatial scenes capturing the support/nonsupport distinction, the latter did not. An additional group of native Korean speakers relatively early English learners tested in an English-salient context-patterned with the native English speakers in showing CP for support/nonsupport. These findings suggest that obligatory marking of support/nonsupport in one's native language can affect nonlinguistic sensitivity to this distinction, contra earlier findings, but that such sensitivity may also depend on aspects of language background and the immediate linguistic context. PMID- 28337648 TI - Diagnosis and Treatment of Alternating Hemiplegia of Childhood. AB - OPINION STATEMENT: The diagnosis and treatment of patients with Alternating Hemiplegia of Childhood (AHC) and related disorders should be provided by a multidisciplinary team experienced with the spectrum of presentations of this disease, with its related disorders, with its complex and fluctuating manifestations, and with cutting edge advances occurring in the field. Involvement in research to advance the understanding of this disease and partnership with international collaborators and family organizations are also important. An example of such an approach is that of The Duke AHC and Related Disorders Multi-Disciplinary Clinic and Program, which, in partnership with the Cure AHC Foundation, has developed and applied this approach to patients seen since early 2013. The program provides comprehensive care and education directly to AHC patients and their families and collaborates with referring physicians on the care of patients with AHC whether evaluated at Duke clinics or not. It also is involved in clinical and basic research and in collaborations with other International AHC Research Consortium (IAHCRC) partners. The clinic is staffed with physicians and experts from Neurology, Cardiology, Child Behavioral Health, Medical Genetics, Neurodevelopment, Neuropsychology, Nursing, Physical and Occupational Therapies, Psychiatry, Sleep Medicine, and Speech/Language Pathology. Patients are seen either for full comprehensive evaluations that last several days or for targeted evaluations with one or few appointments. PMID- 28337644 TI - CNS Demyelination with TNF-alpha Blockers. AB - Tumor necrosis factor-alpha (TNF-alpha) blockers are a popular therapeutic choice in a number of inflammatory diseases. Thus far, five TNF- alpha blockers have been approved for clinical use (etanercept, infliximab, adalimumab, golimumab. and certolizumab). Despite being considered relatively safe, serious side effects associated with immune suppression have been reported, including central and peripheral nervous system (CNS) demyelinating disorders. It is still elusive whether these events are mere coincidence or a side effect of anti-TNF-alpha use. In this paper, we review the published case reports of CNS demyelination associated with anti-TNF-alpha therapy and present the follow-up of our 4 previously reported patients who developed neurologic symptoms suggestive of CNS demyelination after having received anti-TNF-alpha treatment. We also discuss the possible role of TNF-alpha blockers in demyelination. PMID- 28337649 TI - Conformational properties of block-polyampholytes adsorbed on charged cylindrical surfaces. AB - Polyampholytes are polymers that have positive and negative monomers along their chain. The adsorption of polyampholytes on charged surfaces has been the subject of a large number of theoretical, computational and experimental studies due to its importance in a variety of bio and nanothechnological systems. However, computational studies focusing on interaction between polyampholytes and cylindrical charged surfaces are rather scarce. This study, therefore, aims to investigate the conformational properties of block-polyampholytes in the presence of a negatively charged cylinder by means of Metropolis Monte Carlo simulations. Adopting a simplified model in which the electrolyte solution is treated at the Debye-Huckel level, the effects of the ionic strength, the linear charge density of the cylinder and the block length on monomers distributions have been investigated. It was found that increasing the salt concentration promotes a transition from a conformation characterized by large loops to a necklace-like conformation parallel to the surface. It was also shown that, at low cylinder charge density, the increase in salt concentration and the length of the blocks lead to a change in the orientation of the adsorbed chain. PMID- 28337650 TI - On the influence of a network on optically isotropic fluid phases with tetrahedral/octupolar order. AB - We investigate the influence of transient or permanent elasticity on liquid phases with octupolar (tetrahedral) order, a question that has never been addressed before. The focus will be on optically isotropic liquid phases with tetrahedral order including the T d phase and the chiral T phase introduced by Fel. It turns out that the presence of both, a network as well as tetrahedral order can lead to the formation of chiral domains of both hands in an optically isotropic fluid due to a completely novel mechanism, thus providing a possible macroscopic explanation for recent experimental observations. We study in detail how elasticity influences the macroscopic dynamics of both, the T d and the T phase. The simultaneous presence of a transient network as well as of octupolar order is shown to lead to completely new cross-coupling phenomena for optically isotropic systems including transient dissipative elastic strains due to temperature gradients. PMID- 28337651 TI - Editor's Spotlight/Take 5: Does Medicaid Insurance Confer Adequate Access to Adult Orthopaedic Care in the Era of the Patient Protection and Affordable Care Act? PMID- 28337652 TI - CORR Insights(r): What is the Ideal Route of Administration of Tranexamic Acid in TKA? A Randomized Controlled Trial. PMID- 28337653 TI - Letter to the Editor: Poor Survivorship and Frequent Complications at a Median of 10 Years After Metal-on-Metal Hip Resurfacing Revision. PMID- 28337654 TI - Letter to the Editor: What Does a Shoulder MRI Cost the Consumer? PMID- 28337655 TI - CORR Insights(r): Increased Risk of Revision, Reoperation, and Implant Constraint in TKA After Multiligament Knee Surgery. PMID- 28337656 TI - What Factors Are Associated With Femoral Component Internal Rotation in TKA Using the Gap Balancing Technique? AB - BACKGROUND: When using the gap-balancing technique for TKA, excessive medial release and varus proximal tibial resection can be associated with internal rotation of the femoral component. Previous studies have evaluated the causes of femoral component rotational alignment with a separate factor analysis using unadjusted statistical methods, which might result in treatment effects being attributed to confounding variables. QUESTIONS/PURPOSES: (1) What pre- and intraoperative factors are associated with internal rotation of the femoral component in TKA using the gap balancing technique? (2) To what degree does femoral component rotation as defined by the navigation system differ from rotation as measured by postoperative CT? METHODS: Three hundred seventy-seven knees that underwent computer-assisted primary TKA attributable to degenerative osteoarthritis with varus or mild valgus alignment in which medial soft tissue release was performed, and those with preoperative radiographs including preoperative CT between October 2007 and June 2014 were included in the study. To achieve a balanced mediolateral gap, the structures released during each medial release step were as follows: Step 1, deep medial collateral ligament (MCL); Step 2, superficial MCL (proximal, above the pes anserine tendon) and semimembranosus tendon; and Step 3, the superficial MCL (distal, below the pes anserine tendon). Knees with internal rotation of the femoral component, which was directed by navigation, to achieve a rectangular mediolateral flexion gap were considered cases, and knees without internally rotated femoral components were considered controls. Univariable analysis of the variables (age, sex, BMI, operated side, preoperative hip-knee-ankle angle, preoperative medial proximal tibial angle, preoperative rotation degree of the clinical transepicondylar axis [TEA] relative to the posterior condylar axis [PCA], coronal angle of resected tibia, resection of the posterior cruciate ligament, type of prosthesis, and extent of medial release) of cases and controls was performed, followed by a multivariable logistic regression analysis on those factors where p equals 0.15 or less. For an evaluation of navigation error, 88 knees that underwent postoperative CT were analyzed. Postoperative CT scans were obtained for patients with unexplained pain or stiffness after the operations. Using the paired t-test and Pearson's correlation analysis, the postoperative TEA-PCA measured with postoperative CT was compared with theoretical TEA-PCA, which was calculated with preoperative TEA PCA and actual femoral component rotation checked by the navigation system. RESULTS: After controlling for a relevant confounding variable such as postoperative hip-knee-ankle angle, we found that the extent of medial release (Step 1 as reference; Step 2: odds ratio [OR], 5.7, [95% CI, 2.2-15]; Step 3: OR, 22, [95% CI, 7.8-62], p < 0.001) was the only factor we identified that was associated with internal rotation of the femoral component. With the numbers available, we found no difference between the mean theoretical postoperative TEA PCA and the postoperative TEA-PCA measured using postoperative CT (4.8 degrees +/- 2.7o versus 5.0 degrees +/- 2.3o; mean difference, 0.2 degrees +/- 1.5o; p = 0.160). CONCLUSIONS: Extent of medial release was the only factor we identified that was associated with internal rotation of the femoral component in gap balancing TKA. To avoid internal rotation of the femoral component, we recommend a carefully subdivided medial-releasing technique, especially for the superficial MCL because once the superficial MCL has been completely released it cannot easily be restored. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 28337658 TI - Erratum to: Analysis of Monoclonal Antibodies in Human Serum as a Model for Clinical Monoclonal Gammopathy by Use of 21 Tesla FT-ICR Top-Down and Middle-Down MS/MS. PMID- 28337657 TI - Hypovitaminosis D in patients with heart failure: effects on functional capacity and patients' survival. AB - Chronic heart failure is a major cause of morbidity and mortality, but its prognosis remains poor. Vitamin D hormone has many extra-skeletal functions including a positive impact on the cardiovascular system, and has been proposed for mortality risk evaluation in heart failure patients. The aim of the present study was to evaluate vitamin D status in heart failure patients, measured by high performance liquid chromatography coupled with mass spectrometry and to correlate serum 25 hydroxy-vitamin D (25OHD) levels with functional (peak VO2%) and mortality (Metabolic Exercise Cardiac Kidney Index) heart failure parameters. We enrolled 261 consecutive patients diagnosed with heart failure; all patients underwent a comprehensive clinical and biochemical characterization, and serum 25OHD levels were measured by high performance liquid chromatography coupled with mass spectrometry. Cardiopulmonary test parameters and Metabolic Exercise Cardiac Kidney Index of mortality risk were measured in all patients. Serum 25OHD levels ranged between 2 and 45 ng/ml (mean 17 +/- 9 ng/ml); most patients (87%) showed hypovitaminosis D, and 25% showed severe vitamin D deficiency (serum 25OHD < 10 ng/ml). Patients with 25OHD < 10 ng/ml had significantly lower cardiopulmonary test VO2/kg, peak VO2% and significantly higher N-terminalproBrain natriuretic peptide and Metabolic Exercise Cardiac Kidney Index, than patients with 25OHD > 10 ng/ml. Patients with peak VO2% < 50% showed significantly lower 25OHD compared to those with peak VO2% > 50%. There was a significant, positive correlation (r = 0.16, p = 0.008) between 25OHD levels and peak VO2%, and an inverse correlation with Metabolic Exercise Cardiac Kidney Index (r = -0.21, p < 0.001), even when adjusted for age, Body Mass Index, MDRD, N-terminalproBrain natriuretic peptide. In conclusion, our findings show that vitamin D levels are associated with functional and mortality heart failure prognosis parameters. PMID- 28337659 TI - A20 in Multiple Sclerosis and Parkinson's Disease: Clue to a Common Dysregulation of Anti-Inflammatory Pathways? AB - Chronic inflammation significantly contributes to the pathogenesis of several neurodegenerative disorders. In physiological conditions, a chronic inflammatory state is prevented through the termination of the acute inflammatory response once the triggering insult is eliminated. Several mechanisms regulate the resolution of inflammation. Among these, a potent inhibitor of the pro inflammatory NF-kB signaling known as A20 has emerged as a key player. Recent studies have shown reduced blood levels of A20 in the patients of diverse chronic inflammatory diseases. Similar results have also been demonstrated in patients of multiple sclerosis (MS), a neurodegenerative disease characterized by persisting inflammation. In the present study, we investigate whether other similar neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) also demonstrate deregulated levels of A20 expression as compared to healthy controls (HC) and treatment-naive MS patients. Our results confirm previous data that the A20 expression is reduced in whole blood of MS patients as compared to HC. Additionally, we demonstrate that significantly diminished A20 expression is also evident in PD patients. The dysregulation of the A20 pathway could then contribute to the persistence of inflammation in these disorders. It would thus be interesting to investigate further whether such commonly deregulated pathways between different inflammatory diseases could represent novel targets for therapy. PMID- 28337660 TI - TOPGEAR: A Randomized, Phase III Trial of Perioperative ECF Chemotherapy with or Without Preoperative Chemoradiation for Resectable Gastric Cancer: Interim Results from an International, Intergroup Trial of the AGITG, TROG, EORTC and CCTG. AB - BACKGROUND: Postoperative chemoradiation and perioperative chemotherapy using epirubicin/cisplatin/5-fluorouracil (ECF) represent two standards of care for resectable gastric cancer. In the TOPGEAR (Trial Of Preoperative therapy for Gastric and Esophagogastric junction AdenocaRcinoma) trial, we hypothesized that adding preoperative chemoradiation to perioperative ECF will improve survival; however, the safety and feasibility of preoperative chemoradiation have yet to be determined. METHODS: TOPGEAR is an international phase III trial in which patients with adenocarcinoma of the stomach were randomized to perioperative ECF alone or with preoperative chemoradiation. The ECF-alone group received three preoperative cycles of ECF, while the chemoradiation group received two cycles of preoperative ECF followed by chemoradiation. Both groups received three postoperative cycles of ECF. A planned interim analysis of the first 120 patients was conducted, and was reviewed by the Independent Data Safety Monitoring Committee to assess treatment compliance, toxicity/safety, and response rates. RESULTS: The proportion of patients who received all cycles of preoperative chemotherapy was 93% (ECF group) and 98% (chemoradiation group), while 65 and 53%, respectively, received all cycles of postoperative chemotherapy. Overall, 92% of patients allocated to preoperative chemoradiation received this treatment. The proportion of patients proceeding to surgery was 90% (ECF group) and 85% (chemoradiation group). Grade 3 or higher surgical complications occurred in 22% of patients in both groups. Furthermore, grade 3 or higher gastrointestinal toxicity occurred in 32% (ECF group) and 30% (chemoradiation group) of patients, while hematologic toxicity occurred in 50 and 52% of patients. CONCLUSIONS: These results demonstrate that preoperative chemoradiation can be safely delivered to the vast majority of patients without a significant increase in treatment toxicity or surgical morbidity. PMID- 28337661 TI - The Value of Multidisciplinary Team Meetings for Patients with Gastrointestinal Malignancies: A Systematic Review. AB - INTRODUCTION: The incidence of gastrointestinal (GI) cancer is rising and most patients with GI malignancies are discussed by a multidisciplinary team (MDT). We performed a systematic review to assess whether MDTs for patients with GI malignancies can correctly change diagnosis, tumor stage and subsequent treatment plan, and whether the treatment plan was implemented. METHODS: We performed a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We conducted a search of the PubMed, MEDLINE and EMBASE electronic databases, and included studies relating to adults with a GI malignancy discussed by an MDT prior to the start of treatment which described a change of initial diagnosis, stage or treatment plan. Two researchers independently evaluated all retrieved titles and abstracts from the abovementioned databases. RESULTS: Overall, 16 studies were included; the study quality was rated as fair. Four studies reported that MDTs changed the diagnoses formulated by individual physicians in 18.4-26.9% of evaluated cases; two studies reported that MDTs formulated an accurate diagnosis in 89 and 93.5% of evaluated cases, respectively; nine studies described that the treatment plan was altered in 23.0-41.7% of evaluated cases; and four studies found that MDT decisions were implemented in 90-100% of evaluated cases. The reasons for altering a treatment plan included the patient's wishes, and comorbidities. CONCLUSIONS: MDT meetings for patients with a GI malignancy are responsible for changes in diagnoses and management in a significant number of patients. Treatment plans formulated by MDTs are implemented in 90-100% of discussed patients. All patients with a GI malignancy should be discussed by an MDT. PMID- 28337664 TI - Aromatase expression in atypical ductal hyperplasia in women. AB - PURPOSE: To determine the levels of aromatase in atypical ductal hyperplasia (ADH) lesions, tissue surrounding the ADH, and in dense and non-dense normal breast tissue. We postulated that excess aromatase in breast tissue might, through production of increased estrogen, drive the carcinogenic process. Estrogens and their metabolites are thought to contribute to the development of breast cancer through estrogen receptor-mediated mechanisms and genotoxic effects of estrogen metabolites. ADH is a benign lesion of the breast which is associated with substantially increased risk for subsequent development of breast cancer. After 25 years, approximately 30% of women with ADH develop breast cancer. In women with three or more separate ADH lesions at the same time, 47% will develop breast cancer over that time period. Another important risk factor for breast cancer is the presence of mammographically dense breast tissue. METHODS: We utilized quantitative immunochemical analysis of aromatase in biopsy tissue to test this possibility. Previously published results comparing dense with non dense breast tissue in normal women (Vachon et al. Breast Cancer Res Treat 125:243-252, 2011) were used for comparisons with ADH. A well-characterized histochemical H-score was employed for quantitative assessment of aromatase in the various tissue studied. RESULTS: The H-score of aromatase staining was statistically significantly higher (p = 0.003) in the ADH epithelium than surrounding epithelial tissue. In order of H-score from highest to lowest were ADH, issue surrounding ADH, dense normal and non-dense normal breast tissues. The levels of aromatase in a subset of women with ADH who went on to develop breast cancer were not higher than in women who did not. CONCLUSIONS: We suggest from these studies that overexpression of aromatase in breast tissue and its resultant increase in estradiol levels may contribute to the later development of breast cancer in women with ADH. PMID- 28337662 TI - A83-01 inhibits TGF-beta-induced upregulation of Wnt3 and epithelial to mesenchymal transition in HER2-overexpressing breast cancer cells. AB - PURPOSE: The aim of this study is to investigate the mechanisms of interactions between TGF-beta and Wnt/beta-catenin pathways that induce and regulate EMT and promote breast cancer cells to become resistant to treatment. METHODS: The effect of TGF-beta on Wnt/beta-catenin signaling pathway was examined by using a human Wnt/beta-catenin-regulated cDNA plate array and western blot analysis. The interaction of Twist at promoter of Wnt3 was examined by chromatin immunoprecipitation (ChIP) assay. Secreted Wnt3 level was determined by ELISA assay. RESULTS: HER2-overexpressing breast cancer cells treated with TGF-beta have a reduced response to trastuzumab and exhibited EMT-like phenotype. The TGF beta-induced EMT in HER2-cells was concordant with upregulation of Wnt3 and beta catenin pathways. The TGF-beta-induced induction of Wnt3 during EMT was found to be Smad3-dependent. ChIP analysis identified occupancy of Twist at promoter region of Wnt3. Knock-down of Twist by shRNA confirmed the significance of Twist in response to TGF-beta regulating Wnt3 during EMT. Subsequently, TGF-beta induced matrix metalloproteinases, MMP1, MMP7, MMP9, MMP26, Vascular endothelial growth factors (VEGF), and activation of Wnt/beta-catenin signaling were repressed by the shRNA treatment. TGF-betaR1 ALK5 kinase inhibitor, A83-01 can effectively prevent the TGF-beta-induced Twist and Wnt3. Co-treating A83-01 and trastuzumab inhibited TGF-beta-induced cell invasion significantly in both trastuzumab responsive and resistant cells. CONCLUSIONS: Our data demonstrated an important interdependence between TGF-beta and Wnt/beta-catenin pathways inducing EMT in HER2-overexpressing breast cancer cells. Twist served as a linkage between the two pathways during TGF-beta-induced EMT. A83-01 could inhibit the TGF-beta initiated pathway interactions and enhance HER2-cells response to trastuzumab treatment. PMID- 28337666 TI - Joint infection due to Raoultella planticola: first report. AB - The genus Raoultella has been separated from the genus Klebsiella in 2001. Two main species are responsible for human infections: R. ornithinolytica and R. planticola. The most frequent infections due to R. planticola include cystitis, pneumonia and bacteremia (mostly in immunocompromised hosts). To date, no joint or bone infection has been reported. We describe the first case of septic arthritis due to R. planticola following an arthroscopy with intra-articular injection of corticosteroids. Evolution was favorable after arthroscopic lavage and antibiotic therapy with quinolones. Raoultella planticola has been described rarely in human infection. It is mainly deemed responsible for cystitis, pneumonia and bacteremia (mostly in immunocompromised hosts) [1-3]. To our knowledge no case of bone or joint infection has been reported. We described here the first case of infective arthritis due to R. planticola involving a native knee joint following synovectomy and intra-articular injection of corticosteroids during arthroscopy. PMID- 28337663 TI - Outcomes of fulvestrant therapy among japanese women with advanced breast cancer: a retrospective multicenter cohort study (JBCRG-C06; Safari). AB - PURPOSE: This retrospective study evaluated the effect of clinical background and treatment line on time to treatment failure (TTF) in advanced/metastatic breast cancer (AMBC) patients receiving F500 in Japan (UMIN 000015168). METHODS: Patients who commenced F500 treatment were registered at 16 sites in Japan. Correlations between baseline clinicopathological factors, treatment line, and TTF were investigated by Kaplan-Meier analysis. TTF data were analyzed using univariate analysis and multivariate analysis with a Cox proportional hazards model. RESULTS: Data for 1072 patients were available; 1031 patients (96.2%) were evaluable for efficacy. F500 was administered as first-line treatment in 2.0%, second-line in 22.7%, third-line in 26.7%, and >=fourth-line in 48.6% patients. Median TTF was 5.4 months. Multivariate analysis found that earlier F500 use (first and second vs. third vs. >=fourth line; hazard ratio (HR) = 0.80, 95% confidence interval (CI) 0.74-0.86; P < 0.001), longer period from AMBC diagnosis to F500 use (>=3 vs. <3 years; HR 0.60, 95% CI 0.51-0.70; P < 0.001), and no prior palliative chemotherapy administered for unresectable or metastatic breast cancer (no vs. yes; HR 0.69, 95% CI 0.60-0.80; P < 0.001) were associated with significantly longer TTF. Among 691 patients, where information on histologic/nuclear grade was available, a low grade was also associated with a longer TTF, but this finding was not maintained among patients with recurrent breast cancer (N = 558). Among women with recurrent breast cancer, a longer DFI between a patient's initial breast cancer diagnosis and their recurrence was associated with a longer TTF on F500 therapy. CONCLUSIONS: Our study showed that treatment period of F500 was longer when used in earlier-line treatment. For patients on F500, TTF was also longer for patients who had not received prior palliative chemotherapy and for those who had a longer period from their AMBC diagnosis to F500 use. PMID- 28337665 TI - Effect of Efflux Transporter Inhibition on the Distribution of Fluconazole in the Rat Brain. AB - Multidrug resistance-associated proteins (MRPs) and organic anion transporters (OATs) are expressed on the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB), preventing the entry of or the pumping out of numerous molecules. Fluconazole is widely used to treat fungal meningoencephalitis. The effect of these transporters on the distribution of fluconazole in the brain is unclear. We used microdialysis to compare the distribution of fluconazole in the rat brain with and without co-administration of probenecid, a MRP and OAT inhibitor. Additionally, we also observed the difference in fluconazole distribution between the two barriers. The results showed that probenecid increased the penetration of fluconazole into the BBB but did not alter the penetration of fluconazole into the BCSFB of rats. The penetration of the BBB and BCSFB by fluconazole did not statistically differ according to physiological condition. These results demonstrate that transporters that can be inhibited by probenecid may be involved in fluconazole resistance at the BBB and provide a laboratory basis for predicting brain extracellular fluid (ECF) concentration using the cerebrospinal fluid (CSF) concentration of fluconazole. PMID- 28337670 TI - Supramolecular Systems and Chemical Reactions in Single-Molecule Break Junctions. AB - The major challenges of molecular electronics are the understanding and manipulation of the electron transport through the single-molecule junction. With the single-molecule break junction techniques, including scanning tunneling microscope break junction technique and mechanically controllable break junction technique, the charge transport through various single-molecule and supramolecular junctions has been studied during the dynamic fabrication and continuous characterization of molecular junctions. This review starts from the charge transport characterization of supramolecular junctions through a variety of noncovalent interactions, such as hydrogen bond, pi-pi interaction, and electrostatic force. We further review the recent progress in constructing highly conductive molecular junctions via chemical reactions, the response of molecular junctions to external stimuli, as well as the application of break junction techniques in controlling and monitoring chemical reactions in situ. We suggest that beyond the measurement of single molecular conductance, the single-molecule break junction techniques provide a promising access to study molecular assembly and chemical reactions at the single-molecule scale. PMID- 28337668 TI - Use of Information and Communication Technologies in Clinical Practice Related to the Treatment of Pain. Influence on the Professional Activity and the Doctor Patient Relationship. AB - The increasing relevance of Information and Communication Technologies (ICTs) in medical care is indisputable. This evidence makes it necessary to start studies that analyse the scope these new forms of access to information and understanding of medicine have on the professional activity of the physician, on the attitude and on the knowledge of patients or, on the doctor-patient relationship. The purpose of this study is to explore some of these aspects in a group of physicians whose clinical activity is related to one of the greatest social impact health problems which is the treatment of chronic pain. Starting with the completion of a questionnaire, in the study group it is observed that the interaction between social structure, increase of information flows and ICTs generate transformations in social practices and behaviour of the actors of the health system. Internet is confirmed as an information space on the subject, but is shown as an underutilized space of interaction between the doctor and his patient. PMID- 28337667 TI - Self-assembled polyelectrolyte complexes films as efficient compression coating layers for controlled-releasing tablets. AB - Currently, polysaccharide-based hydrogels are widely studied macromolecular networks to modify drug dissolution from controlled-releasing matrix tablets. Among them, polyelectrolyte complexes (PEC) films consisted of chitosan (CS) and sodium alginate (SA) could be obtained via spontaneously assembling under physiological gastrointestinal environment. Here, we utilized these self assembled PEC films as an efficient coating materials to develop controlled released matrix tablets through compression coating process, with paracetamol (APAP) as model drug. The constitutive and morphology characteristic studies on these PEC films illustrated that the mixture of CS and SA with the weight ratio of 1:1 would be an promising outer layer for compression-coating tablets. In addition, the in vitro drug releasing behavior experiments demonstrated that the optimized compression coating tablets displayed satisfied zero-order drug releasing profits. Furthermore, the in vivo pharmacokinetic studies of these APAP loaded compression-coated tablets in New Zealand rabbits gave that the Tmax (12.32 +/- 1.05 h) was significantly prolonged (p < 0.01), compared to that (0.89 +/- 0.26 h) of common APAP tablets (Jinfuning(r)) after oral administration. These studies suggest that the compression-coated tablets with self-assembled PEC film as coating outer layer may be a promising strategy for peroral controlled release delivery system of water soluble drugs. PMID- 28337669 TI - Sonocatalysis: A Potential Sustainable Pathway for the Valorization of Lignocellulosic Biomass and Derivatives. AB - Lignocellulosic biomass represents a natural renewable chemical feedstock that can be used to produce high value-added chemicals and platform molecules. Nowadays, there are extensive studies on a variety of aspects concerning the valorization of lignocellulosic biomass into desirable products. Among the current technologies for biomass conversion some require extreme conditions along with high temperatures and pressures. Therefore, major technological innovations based on more economical and environmental methodologies are currently developed both in academic laboratories and in industry. In this context, ultrasound assisted catalysis constitutes an alternative method offering new strategies to upgrade biomass. The possibility of combining catalysis with sonication indeed provides avenues that are worth exploring for the valorization of lignocellulosic compounds into value-added chemical feedstocks. In this mini-review, the available sonochemical systems are first presented, with a focus on the most important ultrasonic parameters, which is intended to provide a mechanistic background. Next, this contribution aims to provide insight into the most recent developments along with prominent examples in the field of sonocatalysis applied to the chemical transformation of lignocellulosic biomass and its derivatives. PMID- 28337671 TI - A Psychological Perspective on Factors Predicting Prophylactic Salpingo Oophorectomy in a Sample of Italian Women from the General Population. Results from a Hypothetical Study in the Context of BRCA Mutations. AB - The aim of this study was to assess attitudes toward ovarian cancer risk management options for BRCA mutation carriers in healthy Italian women, and to identify predictors of the preference for risk reducing salpingo-oophorectomy (RRSO) over surveillance. One hundred eighty-one women aged 30-45 completed a questionnaire about preferences, knowledge, risk perception, and socio demographic information. Participants were randomly presented with a pamphlet about BRCA1 or BRCA2 mutation-specific testing, consequences of testing and preventive options for carriers, and they were stratified by having children or not and by age group. Surveillance was the preferred option (64.6%), followed by RRSO (24.3%). Although RRSO is the only effective strategy available to BRCA carriers, most healthy women faced for the first time with this option may not consider it as their preferred choice. Predictors associated with a higher likelihood to prefer surgery over surveillance were: knowing that life expectancy is longer with surgery, perceived comprehension of the consequences of testing, previous knowledge about BRCA testing, anticipated worry about developing cancer, and feelings of risk. Childbearing intentions and the effect of childbearing intentions on choice were associated with a lower preference for surgery. Further research is needed to confirm the role of the factors identified in this study in order to promote informed decision-making about RRSO. PMID- 28337673 TI - Progression-Free Survival as a Surrogate for Overall Survival in Clinical Trials of Targeted Therapy in Advanced Solid Tumors. AB - Over the past 15 years, targeted therapy has revolutionized the systemic treatment of cancer. In parallel, there has been a growing debate on the choice of end points in clinical trials in oncology. This debate basically hinges on the choice between overall survival (OS) and progression-free survival (PFS). PFS is advantageous because it is measured earlier than OS, requires a smaller sample size than OS to achieve the desired power, and is not influenced by cross-over. On the other hand, PFS is prone to measurement error and bias, and may not capture the entire treatment effect on the outcomes of most interest to patients with an incurable disease: a prolonged survival and improved quality of life. Therefore, how can we choose between two imperfect end points? The answer to this question would certainly be made easier if PFS could be demonstrated to be a valid surrogate for OS. The validation of a surrogate end point is best made using individual-patient data (IPD) from randomized trials, which allows for standardized assessments of the patient-level and the trial-level correlations between surrogate and final end points. Proper IPD meta-analytical evaluations for targeted agents have still been rare, and to our knowledge only three studies on this topic are currently available in the metastatic setting: one in breast cancer, one in colorectal cancer and one in lung cancer. Although these three studies suffer from limitations inherent to the availability of IPD and the design of the original clinical trials, they have not been able to validate PFS as surrogate for OS, because only modest correlations were found between these two end points, both at the patient and at the trial level. Even if properly conducted surrogate-endpoint evaluations have thus far been unsuccessful, these evaluations are a step in the right direction and can be expected to be applied on a much larger scale in the era of data sharing of clinical trials. PMID- 28337675 TI - An ontology-based search engine for digital reconstructions of neuronal morphology. AB - Neuronal morphology is extremely diverse across and within animal species, developmental stages, brain regions, and cell types. This diversity is functionally important because neuronal structure strongly affects synaptic integration, spiking dynamics, and network connectivity. Digital reconstructions of axonal and dendritic arbors are thus essential to quantify and model information processing in the nervous system. NeuroMorpho.Org is an established repository containing tens of thousands of digitally reconstructed neurons shared by several hundred laboratories worldwide. Each neuron is annotated with specific metadata based on the published references and additional details provided by data owners. The number of represented metadata concepts has grown over the years in parallel with the increase of available data. Until now, however, the lack of standardized terminologies and of an adequately structured metadata schema limited the effectiveness of user searches. Here we present a new organization of NeuroMorpho.Org metadata grounded on a set of interconnected hierarchies focusing on the main dimensions of animal species, anatomical regions, and cell types. We have comprehensively mapped each metadata term in NeuroMorpho.Org to this formal ontology, explicitly resolving all ambiguities caused by synonymy and homonymy. Leveraging this consistent framework, we introduce OntoSearch, a powerful functionality that seamlessly enables retrieval of morphological data based on expert knowledge and logical inferences through an intuitive string-based user interface with auto-complete capability. In addition to returning the data directly matching the search criteria, OntoSearch also identifies a pool of possible hits by taking into consideration incomplete metadata annotation. PMID- 28337674 TI - Painful Hashimoto's thyroiditis: myth or reality? AB - Neck pain is a common complain, being in most cases due to non-thyroidal causes. However, a minority of patients suffer from painful thyroid diseases. Among them, sub-acute thyroiditis (SAT) is the most frequent one. Rare thyroid-related causes of neck pain include hemorrhage within a thyroid nodule as well as Riedel's thyroiditis and suppurative thyroiditis. In the last 30 years, a few cases of a painful variant of Hashimoto's thyroiditis (HT) have been described. Biochemical, ultrasound, and histologic features were clearly suggestive for HT in all of the published cases and definitely ruled out the diagnosis of SAT. While sound descriptions of painful HT are present in the literature, it is important to emphasize that only 20 cases were reported from the year 2000 until now. The condition, however, is clinically relevant because neck pain was reported to be refractory both to steroids and to other analgesic drugs, being thyroidectomy the only effective treatment for pain relief in these patients. This short review analyzes currently available data supporting a role for HT as a rare cause of neck pain. PMID- 28337672 TI - Fentanyl Formulations in the Management of Pain: An Update. AB - Fentanyl is a synthetic, highly selective opioid with many desirable physicochemical properties, including a high lipophilicity and predictable pharmacokinetics. These properties have an established record in the management of pain in a variety of settings, particularly acute pain and breakthrough cancer pain. Fentanyl was initially developed for parenteral use; however, this is invasive and impractical in the outpatient setting. Unfortunately, the high first pass metabolism of fentanyl makes oral formulations unfeasible. However, its high lipophilicity allows fentanyl to be absorbed via a number of other routes. Thus new formulations were designed to allow non-invasive methods of administration. Transmucosal and transdermal fentanyl formulations are well established, and have proven useful in the settings of breakthrough cancer pain, emergencies and in the paediatric population. The iontophoretic transdermal system was developed to provide a needle-free system of delivering bolus doses of fentanyl on demand, a novel way of delivering patient-controlled opioid analgesia. Transpulmonary administration of fentanyl remains experimental. The aim of this review is to provide an update on current non-parenteral fentanyl formulations, with attention to their particular pharmacokinetics and features relevant to clinical use in pain management. PMID- 28337676 TI - Logistic Proliferation of Cells in Scratch Assays is Delayed. AB - Scratch assays are used to study how a population of cells re-colonises a vacant region on a two-dimensional substrate after a cell monolayer is scratched. These experiments are used in many applications including drug design for the treatment of cancer and chronic wounds. To provide insights into the mechanisms that drive scratch assays, solutions of continuum reaction-diffusion models have been calibrated to data from scratch assays. These models typically include a logistic source term to describe carrying capacity-limited proliferation; however, the choice of using a logistic source term is often made without examining whether it is valid. Here we study the proliferation of PC-3 prostate cancer cells in a scratch assay. All experimental results for the scratch assay are compared with equivalent results from a proliferation assay where the cell monolayer is not scratched. Visual inspection of the time evolution of the cell density away from the location of the scratch reveals a series of sigmoid curves that could be naively calibrated to the solution of the logistic growth model. However, careful analysis of the per capita growth rate as a function of density reveals several key differences between the proliferation of cells in scratch and proliferation assays. Our findings suggest that the logistic growth model is valid for the entire duration of the proliferation assay. On the other hand, guided by data, we suggest that there are two phases of proliferation in a scratch assay; at short time, we have a disturbance phase where proliferation is not logistic, and this is followed by a growth phase where proliferation appears to be logistic. These two phases are observed across a large number of experiments performed at different initial cell densities. Overall our study shows that simply calibrating the solution of a continuum model to a scratch assay might produce misleading parameter estimates, and this issue can be resolved by making a distinction between the disturbance and growth phases. Repeating our procedure for other scratch assays will provide insight into the roles of the disturbance and growth phases for different cell lines and scratch assays performed on different substrates. PMID- 28337677 TI - Strain-induced electronic band convergence: effect on the Seebeck coefficient of Mg2Si for thermoelectric applications. AB - The present theoretical study, performed using density-functional theory and Boltzmann transport theory formalisms, shows that under 2.246 % isotropic tensile strain, the two energy-lowest conduction bands of Mg2Si overlap. The two, threefold-degenerated orbitals become a unique, sixfold-degenerated orbital. It is demonstrated that such degeneracy implies an increase of the Seebeck coefficient, of the electrical conductivity, of the power factor, and in fine of the figure of merit. PMID- 28337678 TI - Cation-pi interactions in competition with cation microhydration: a theoretical study of alkali metal cation-pyrene complexes. AB - Cation-pi interactions were systematically investigated for the adsorption of H+ and alkali metal cations M+ to pyrene by means of Moller-Plesset perturbation theory (MP2) and density functional theory (DFT). The main aims were to determine the preferred adsorption sites and how the microhydration shell influences the adsorption process. The preferred adsorption sites were characterized in terms of structural parameters and energetic stability. Stability analysis of the M+ pyrene complexes revealed that the binding strength and the barrier to transitions between neighboring sites generally decreased with increasing cation size from Li+ to Cs+. Such transitions were practically barrierless (<<1 kcal/mol) for the large Rb+ and Cs+ ions. Further, the influence of the first hydration shell on the adsorption behavior was investigated for Li+ and K+ as representatives of small and large (alkali metal) cations, respectively. While the isolated complexes possessed only one minimum, two minima-corresponding to an inner and an outer complex-were observed for microhydrated complexes. The small Li+ ion formed a stable hydration shell and preferentially interacted with water rather than pyrene. In contrast, K+ favored cation-pi over cation-water interactions. It was found that the mechanism for complex formation depends on the balance between cation-pi interactions, cation-water complexation, and the hydrogen bonding of water to the pi-system. PMID- 28337679 TI - Adsorption of Mn atom on pristine and defected graphene: a density functional theory study. AB - The functionalization of graphene with transition metals is of great interest due to its wide range of applications, such as hydrogen storage, spintronics, information storage, etc. Due to its magnetic property adsorption of Mn atom on graphene has a high consequence on the electronic properties of graphene. The increase in size of the graphene sheet with hydrogen termination has a high impact on the transformation of electronic properties of the graphene sheet. Hence in this work, we investigate the size as well as change in structural and electronic properties of pristine/defective graphene sheets on adsorption of Mn atom using density functional theory methods. From the results obtained a higher adsorption energy value of 3.04 eV is found for Mn adatom on the defected graphene sheet than the pristine, 1.85 eV. It is subject to the coverage effect which decreases on increasing number of carbon atoms. Moreover, a decrease in energy gap is observed in pristine and defected graphene sheets with a high number of carbon atoms. The density of states illustrates the significant effect for hydrogen termination in the conduction band of the Mn adsorbed graphene sheet with low carbon atoms. Graphical Abstract Mn adatom on graphene at different sites. PMID- 28337680 TI - Morphological and molecular identification of Habronema spp. (Nematoda: Habronematidae) from donkeys in Xinjiang, China, and notes on the taxonomical status of Habronema majus (Creplin, 1849) and H. microstoma (Schneider, 1866). AB - Habronematid nematodes were collected from the stomachs of donkeys, Equus asinus L., in the Tarim Basin, Xinjiang, China. After examination by light and scanning electron microscopy, Habronema muscae (Carter, 1861) and H. majus (Creplin, 1849) were identified. The morphology of our specimens representing H. muscae (Carter, 1861) agreed well with previous redescriptions in the shape of the lateral lips, origin of the lateral alae, ratio of left and right spicules, and number and arrangement of caudal papillae. However, H. majus (Creplin, 1849) differs from H. microstoma (Schneider, 1866) in the arrangement of the caudal papillae in the male. Moreover, molecular analysis also showed interspecific differences of 26.2 28.2% in ITS2 and 8.6-8.9% in cox1 between H. majus and H. microstoma, a divergence much higher than the known intraspecific variation of Habronema spp. (6.6-8.7% in ITS2; 0.2-2.2% in cox1). The results indicate that both H. microstoma (Schneider, 1866) and H. majus (Creplin, 1849) are valid species. PMID- 28337683 TI - Using Electronic Record Data to Encourage Better Care: Where We Are and Where We Could Be. PMID- 28337681 TI - Morphological and molecular evidence on the existence of a single estuarine and rocky intertidal acanthocephalan species of Profilicollis Meyer, 1931 (Acanthocephala: Polymorphidae) along the Atlantic and Pacific coasts of southern South America. AB - Profilicollis chasmagnathi Holcman-Spector, Mane-Garzon & Dei-Cas, 1977 (Acanthocephala: Polymorphidae) has been reported to parasitise different grapsid species as intermediate hosts along the South Atlantic shores, i.e. Cyrtograpsus angulatus (Dana) and Neohelice granulata (Dana) in Uruguay and Cyrtograpsus altimanus (Rathbun) in Argentina. Larvae of a similar acanthocephalan described as Profilicollis antarcticus Zdzitowiecki, 1985 were recorded in the crab Hemigrapsus crenulatus (Milne-Edwards) from an estuarine habitat on the Southeast Pacific shore in Chile. Earlier studies have questioned the specific assignation of the Chilean estuarine populations of Profilicollis Meyer, 1931. The aim of this study was to re-examine the identification of these acanthocephalans by means of morphological and molecular analyses of cystacanths of Profilicollis spp. gathered from C. angulatus, N. granulata, C. altimanus and H. crenulatus. Our analyses showed that a single species of Profilicollis, P. chasmagnathi, parasitises these four crab species. The assessment of specimens from the South Shetlands Islands, the type-locality of P. antarcticus, is needed before formally proposing that P. antarcticus is a junior subjective synonym of P. chasmagnathi. PMID- 28337684 TI - Capsule Commentary on Pham-Kanter et al., Public Awareness of and Contact with Physicians Who Receive Industry Payments: A National Survey. PMID- 28337682 TI - Three members of Opisthomonorcheides Parukhin, 1966 (Digenea: Monorchiidae) from carangid fishes (Perciformes) from Indonesia, with a review of the genus. AB - Three species of Opisthomonorcheides Parukhin, 1966 are reported for the first time from Indonesian waters: O. pampi (Wang, 1982) Liu, Peng, Gao, Fu, Wu, Lu, Gao & Xiao, 2010 and O. ovacutus (Mamaev, 1970) Machida, 2011 from Parastromateus niger (Bloch), and O. decapteri Parukhin, 1966 from Atule mate (Cuvier). Both O. pampi and O. ovacutus can now be considered widespread in the Indo-Pacific region, with earlier records of these species being from Fujian Province, China and Penang, Malaysia, respectively. We redescribe O. decapteri from one of its original hosts, Atule mate, off New Caledonia, and report this species from Jakarta Bay, Indonesia, extending its range throughout the Indian Ocean into the south-western Pacific. All three species possess a genital atrium that is long, sometimes very long, and a genital pore that is located in the forebody. This validates the interpretation that the original description was erroneous in reporting the genital pore in the hindbody, well posterior to the ventral sucker. These observations verify the synonymy of Retractomonorchis Madhavi, 1977 with Opisthomonorcheides. A major discrepancy between the species of Opisthomonorcheides is that some are described with the uterus entering the terminal organ laterally and some with it entering terminally; this feature needs further analysis. Based on the length of the genital atrium and the posterior extent of the vitellarium, the 27 species of Opisthomonorcheides considered valid can be divided into four groups. Among the 53 host records analysed, the families Carangidae (53% of records), Stromateidae (17%) and Serranidae (5.7%) are the most common; the reports are overwhelmingly from members of the Perciformes (91%), with further records in the Clupeiformes (5.7%), Gadiformes (1.9%) and Pleuronectiformes (1.9%). Two fish genera (Parastromateus Bleeker and Pampus Bonaparte) dominate the recorded hosts, with the black pomfret Parastromateus niger harbouring six species, the silver pomfret Pampus argenteus (Euphrasen) harbouring six, and the Chinese silver pomfret P. chinensis (Euphrasen) two. A host-parasite checklist is presented. We discuss the host-specificity of members of the genus, questioning some records such as that of O. decapteri in a deep-sea macrourid. We also comment on the morphological similarity, but phylogenetic distance, between the various Pomfret species, advancing the possibility that a series of host misidentifications has occurred. Sequences of the ITS2 rDNA gene generated for O. pampi and O. ovacutus are briefly discussed and molecular data are lodged in the GenBank database. PMID- 28337685 TI - Type III Hypersensitivity Reaction to Subcutaneous Insulin Preparations in a Type 1 Diabetic. AB - Management of type 1 diabetes in patients who have insulin hypersensitivity is a clinical challenge and places patients at risk for recurrent diabetic ketoacidosis (DKA). Hypersensitivity reactions can be due to the patient's response to the insulin molecule itself or one of the injection's non-insulin components. It is therefore crucial for clinicians to quickly recognize the type of hypersensitivity reaction that is occurring and identify potentially immunogenic additives for the purpose of directing therapy as various insulin preparations have differing ingredients. We present the case of a 23-year-old diabetic female with common variable immunodeficiency (CVID) and autoimmune enteropathy who developed a type III hypersensitivity reaction to multiple formulations of subcutaneous insulin after years of use and the challenges of devising a long-term management strategy. PMID- 28337686 TI - Telephone-Delivered Behavioral Skills Intervention for African American Adults with Type 2 Diabetes: A Randomized Controlled Trial. AB - BACKGROUND: Diabetes disproportionately affects African Americans and is associated with poorer outcomes. Self-management is important for glycemic control; however, evidence in African Americans is limited. OBJECTIVE: To assess the efficacy of a combined telephone-delivered education and behavioral skills intervention (TBSI) in reducing hemoglobin A1c (HbA1c) levels in African Americans with type 2 diabetes, using a factorial design. DESIGN: This is a four year randomized clinical trial, using a 2 x 2 factorial design.: Participants: African American adults >=18 years) with poorly controlled type 2 diabetes (HbA1c >=9%) were randomly assigned to one of four groups: 1) knowledge only, 2) skills only, 3) combined knowledge and skills (TBSI), or 4) control group. INTERVENTION: All participants received 12 telephone-delivered 30-min intervention sessions specific to their assigned group. Participants were assessed at baseline and 3, 6, and 12 months. MAIN MEASURE: The primary outcome was HbA1c at 12 months post randomization in the intent-to-treat (ITT) population. KEY RESULTS: Two hundred fifty-five participants were randomly assigned to the four groups. Based on the ITT population after multiple imputation, the analysis of covariance with baseline HbA1c as the covariate showed that HbA1c at 12 months for the intervention groups did not differ significantly from that of the control group (knowledge: 0.49, p = 0.123; skills: 0.23, p = 0.456; combined: 0.48, p = 0.105). Absolute change from baseline at 12 months for all treatment arms was 0.6. Longitudinal mixed effects analysis showed that, on average, there was a significant decline in HbA1c over time for all treatment groups (-0.07, p < 0.001). However, the rates of decline for the intervention groups were not significantly different from that of the control group (knowledge: 0.06, p = 0.052; skills: 0.02, p = 0.448; combined: 0.05, p = 0.062). Results from per protocol populations were similar. CONCLUSIONS: For African Americans with poorly controlled type 2 diabetes, combined education and skills training did not achieve greater reductions in glycemic control (i.e., HbA1c levels) at 12 months compared to the control group, education alone, or skills training alone. This trial is registered with ClinicalTrials.gov, identifier no. NCT00929838. PMID- 28337688 TI - When the Script Doesn't Fit: An Exercise in Clinical Reasoning. PMID- 28337687 TI - Assessing the Culture of Residency Using the C - Change Resident Survey: Validity Evidence in 34 U.S. Residency Programs. AB - BACKGROUND: A practical instrument is needed to reliably measure the clinical learning environment and professionalism for residents. OBJECTIVE: To develop and present evidence of validity of an instrument to assess the culture of residency programs and the clinical learning environment. DESIGN: During 2014-2015, we surveyed residents using the C - Change Resident Survey to assess residents' perceptions of the culture in their programs. PARTICIPANTS: Residents in all years of training in 34 programs in internal medicine, pediatrics, and general surgery in 14 geographically diverse public and private academic health systems. MAIN MEASURES: The C - Change Resident Survey assessed residents' perceptions of 13 dimensions of the culture: Vitality, Self-Efficacy, Institutional Support, Relationships/Inclusion, Values Alignment, Ethical/Moral Distress, Respect, Mentoring, Work-Life Integration, Gender Equity, Racial/Ethnic Minority Equity, and self-assessed Competencies. We measured the internal reliability of each of the 13 dimensions and evaluated response process, content validity, and construct related evidence validity by assessing relationships predicted by our conceptual model and prior research. We also assessed whether the measurements were sensitive to differences in specialty and across institutions. KEY RESULTS: A total of 1708 residents completed the survey [internal medicine: n = 956, pediatrics: n = 411, general surgery: n = 311 (51% women; 16% underrepresented in medicine minority)], with a response rate of 70% (range across programs, 51-87%). Internal consistency of each dimension was high (Cronbach alpha: 0.73-0.90). The instrument was able to detect significant differences in the learning environment across programs and sites. Evidence of validity was supported by a good response process and the demonstration of several relationships predicted by our conceptual model. CONCLUSIONS: The C - Change Resident Survey assesses the clinical learning environment for residents, and we encourage further study of validity in different contexts. Results could be used to facilitate and monitor improvements in the clinical learning environment and resident well-being. PMID- 28337689 TI - Managing Chronic Pain in Primary Care: It Really Does Take a Village. AB - Some healthcare systems are relieving primary care providers (PCPs) of "the burden" of managing chronic pain and opioid prescribing, instead offloading chronic pain management to pain specialists. Last year the Centers for Disease Control and Prevention recommended a biopsychosocial approach to pain management that discourages opioid use and promotes exercise therapy, cognitive behavioral therapy and non-opioid medications as first-line patient-centered, multi-modal treatments best delivered by an interdisciplinary team. In the private sector, interdisciplinary pain management services are challenging to assemble, separate from primary care and not typically reimbursed. In contrast, in a fully integrated health care system like the Veterans Health Administration (VHA), interdisciplinary clinics already exist, and one such clinic, the Integrated Pain Team (IPT) clinic, integrates and co-locates pain-trained PCPs, a psychologist and a pharmacist in primary care. The IPT clinic has demonstrated significant success in opioid risk reduction. Unfortunately, proposed legislation threatens to dismantle aspects of the VA such that these interdisciplinary services may be eliminated. This Perspective explains why it is critical not only to maintain interdisciplinary pain services in VHA, but also to consider disseminating this model to other health care systems in order to implement patient-centered, guideline-concordant care more broadly. PMID- 28337691 TI - Purification and Characterization of Elizabethkingia L-Amino Acid Esterase: an Enzyme Useful for Enzymatic Synthesis of the Dipeptide, Valyl-Glycine. AB - Valyl-glycine (Val-Gly) is useful as a synthetic substrate of gamma-glutamyl valyl-glycine (gamma-Glu-Val-Gly), which exhibits a strong taste of "kokumi." For efficient enzymatic synthesis of Val-Gly from valine methylester and glycine using L-amino acid esterase (LAE), we screened microorganisms producing LAE with synthetic activity toward Val-Gly. Among 17 isolates showing LAE activity, Elizabethkingia sp. TT1, which was identified by 16S rDNA sequence analysis, showed the highest synthetic activity toward Val-Gly. LAE from Elizabethkingia sp. TT1 (TT1LAE) was purified approximately 1300 times, resulting in a yield of 2.8% and specific activity of 118.8 MUmol/min/mg protein. SDS-PAGE analysis revealed a subunit molecular mass of 78 kDa. The molecular mass of the native enzyme determined by gel filtration was 103 kDa. The purified enzyme showed maximum activity at pH 9.0 and at a temperature of 25 degrees C, and it was stable over the pH range of 5.0-8.5 and 25 degrees C-40 degrees C. No metal ions that were tested had a significant effect on enzyme activity, but the enzyme was slightly inhibited by EDTA. PMID- 28337692 TI - A Successful Strategy for Linking Anonymous Data from Students' and Parents' Questionnaires Using Self-Generated Identification Codes. AB - We conducted a feasibility study for matching children (N = 2571, average age 12 years, 50.4% female) and their parents (N = 1931, average age 41 years, 83.3% female) represented by an anonymous self-generated identification code (SGIC) and assessed its methodological properties. We used a nine-character SGIC with the children and a mirrored version of the same code with the parents. The average overall error rate in generating the SGIC was 9.7% (4.0% in the parents and 13.9% in the children). We were able to link a total of 1765 parents' and children's codes uniquely (94.9% of all possible dyads) with any four-character combination and the employment of the "school" variable. The overall matching quality of linking using the SGIC only is characterized by precision (positive predictive value) of 0.979, recall (sensitivity, true positive rate) of 0.934, and an F measure (harmonic mean of precision and recall) of 0.956. The analysis of the discrepant characters in the dyads identified the paternal grandmother's name and eye color as those varying most often. This study is the first to look at SGIC match rates and error and omission rates in linking different subjects into dyads in prevention research. We identified a high number of unique child-parent matches while guaranteeing anonymity to the participants. We provided evidence that our SGIC is a suitable tool for between-group linking procedures and has a highly successful matching rate, while maintaining anonymity in the school-based prevention study samples. PMID- 28337690 TI - Using Active Choice Within the Electronic Health Record to Increase Influenza Vaccination Rates. AB - BACKGROUND: Despite the benefits of influenza vaccination, each year more than half of adults in the United States do not receive it. OBJECTIVE: To evaluate the association between an active choice intervention in the electronic health record (EHR) and changes in influenza vaccination rates. DESIGN: Observational study. PATIENTS: Adults eligible for influenza vaccination with a clinic visit at one of three internal medicine practices at the University of Pennsylvania Health System between September 2010 and March 2013. INTERVENTION: The EHR confirmed patient eligibility during the clinic visit and, upon accessing the patient chart, prompted the physician and their medical assistant to actively choose to "accept" or "cancel" an order for the influenza vaccine. MAIN MEASURES: Change in influenza vaccination order rates at the intervention practice compared to two control practices for the 2012-2013 flu season, comparing trends during the prior two flu seasons adjusting for time trends and patient and clinic visit characteristics. KEY RESULTS: The sample (n = 45,926 patients) was 62.9% female, 35.9% white, and 54.4% black, with a mean age of 50.2 years. Trends were similar between practices during the 2 years in the pre-intervention period. Vaccination rates increased in both groups in the post-intervention year, but the intervention practice using active choice had a significantly greater increase than the control (adjusted difference-in-difference: 6.6 percentage points; 95% CI, 5.1-8.1; P < 0.001), representing a 37.3% relative increase compared to the pre-intervention period. More than 99.9% (9938/9941) of orders placed during the study period resulted in vaccination. CONCLUSIONS: Active choice through the EHR was associated with a significant increase in influenza vaccination rates. PMID- 28337695 TI - Calcium-Impermeable NMDA Receptor: A Novel Target for Addiction. PMID- 28337693 TI - The Role of Norms in Marijuana Use Among American Indian Adolescents. AB - American Indian adolescents residing on reservations report high levels of marijuana use. Understanding the relationships between normative mechanisms and marijuana use in this group can be especially important in designing effective strategies to prevent use. Participants were 3446 students identifying as American Indian in grades 7-12 across four academic years (2009-2012) from 45 schools. Multilevel logistic analysis was used to examine the relationships between lifetime, last month, and frequent marijuana use and measures of the normative environment. Descriptive and injunctive norms were distinctly and directly associated with all measures of marijuana use, with family injunctive norms showing a strong relationship to use (0.49 < OR < 0.58 for a 9th grade student). Family injunctive norms moderated the relationship between descriptive norms and lifetime and last month use (OR = 0.79 and 0.82, respectively), with higher family disapproval associated with a weaker relationship between descriptive norms and use. Anticipatory socialization was positively related to all measures of marijuana use, with the relationship stronger for lifetime and last month use than for frequent use (OR = 1.88, 1.74, and 1.30, respectively). A contextual variable of descriptive norms was related to lifetime and last month use (OR = 1.66 and 1.51, respectively) but not frequent use. These findings reinforce the importance of parental norms in reducing the likelihood of using marijuana. In addition, prevention strategies that increase the perception that healthy behaviors not involving marijuana use are an enjoyable way to socialize may be more effective in preventing occasional marijuana use. PMID- 28337694 TI - The Posterior Fossa and Foreign Accent Syndrome: Report of Two New Cases and Review of the Literature. AB - Foreign accent syndrome is a rare motor speech disorder that causes patients to speak their language with a non-native accent. In the neurogenic condition, the disorder develops after lesions in the language dominant hemisphere, often affecting Broca's area, the insula, the supplementary motor area and the primary motor cortex. Here, we present two new cases of FAS after posterior fossa lesions. The first case is a 44-year-old, right-handed, Dutch-speaking man who suffered motor speech disturbances and a left hemiplegia after a pontine infarction. Quantified SPECT showed a bilateral hypoperfusion in the inferior lateral prefrontal and medial inferior frontal regions as well as a significant left cerebellar hypoperfusion. Further clinical investigations led to an additional diagnosis of brainstem cognitive affective syndrome which closely relates to Schmahmann's syndrome. The second patient was a 72-year-old right handed polyglot English man who suffered a stroke in the vascular territory of the left posterior inferior cerebellar artery (PICA) and developed a foreign accent in his mother tongue (English) and in a later learnt language (Dutch). In this paper, we discuss how the occurrence of this peculiar motor speech disorder can be related to a lesion affecting the posterior fossa structures. PMID- 28337697 TI - Cardiovascular disease in the literature: A selection of recent original research papers. PMID- 28337696 TI - Cerebral Dopamine Neurotrophic Factor: A Potential Therapeutic Agent for Parkinson's Disease. AB - The application of neurotrophic factors (NTFs) is a promising therapeutic strategy for neurodegenerative disorders such as Parkinson's disease (PD). Many NTFs have been reported to enhance the survival, regeneration, and differentiation of neurons and to induce synaptic plasticity. However, because of their potential side-effects and low efficacy after clinical administration, more potent treatments for neurodegenerative disorders are being sought. Cerebral dopamine neurotrophic factor (CDNF), a newly-identified NTF homologous to mesencephalic astrocyte-derived NTF, is structurally and functionally different from other NTFs, providing new hope especially for PD patients. In various animal models of PD, CDNF is efficient in protecting and repairing dopaminergic neurons, and it inhibits endoplasmic reticulum stress, neuroinflammation, and apoptosis. Recent progress in all facets of CDNF research has enabled researchers to better understand its beneficial effects in the treatment of PD. PMID- 28337698 TI - The importance of SPECT myocardial perfusion imaging in clinical practice; diagnosis, patient education, and evaluation of optimal medical therapy. PMID- 28337699 TI - Lung Ultrasound is Comparable with Chest Roentgenogram for Diagnosis of Community Acquired Pneumonia in Hospitalised Children. AB - OBJECTIVE: To evaluate the accuracy of lung ultrasound (LUS) in comparison to chest roentgenogram (CXR) in hospitalised children with community-acquired pneumonia (CAP). METHODS: This study was a hospital based prospective observational study, conducted between January 2014 and December 2014. Hospitalised children aged 2 to 59 mo with community-acquired pneumonia were included in the study. The informed written consent was taken from parents (or legal guardian) before recruitment. Children with suspected or proven asthma, cystic fibrosis, congenital heart disease, immunodeficiency, malignancy and hemodynamic unstability were excluded. CXR, posterio-anterior view, and LUS were done within 24 h of the hospitalisation. RESULTS: Of 176 consecutively hospitalised cases of CAP, 118 were recruited after screening (65, 55.1% boys; mean age in months +/- SD, 26.22 +/- 19.60). Abnormal CXR were found in 101 (85.6%) and abnormal LUS in 105 (89%) children. In radiologically proven CAP, LUS was positive in 99/101(98.01%) while among radiologically normal, LUS was abnormal in 6/17 (35.3%). LUS has high sensitivity (98.02%) and reasonable specificity (64.71%) for diagnosing radiologically proven CAP. In diagnosing the specific radiological type of CAP, there was very good concordance (Quadratic Weighted Cohen's Kappa =0.7) between CXR and LUS. Similarly, the authors also found excellent concordance between CXR and LUS (Linear Weighted Cohen's Kappa =0.9) for diagnosis of pleural effusion. CONCLUSIONS: LUS can be considered to be used first before radiography in children with suspected CAP. This will reduce the exposure of radiation. PMID- 28337700 TI - Experimental Research Showing the Reduction of Naloxone-Place Aversion by Oral Zinc Administration in Rats. AB - Previous studies showed the attenuation of both morphine-dependence and morphine place preference by zinc. Conditioned place preference and aversion are experimental models frequently used to test the reward-stimulating, respectively the aversive effects induced by different stimuli or substances. Addictive substances usually induce place preference (exhibit reward-stimulating properties), while their antagonists determine place-avoidance (aversion). The present study aimed to assess the effect determined by zinc sulphate oral administration (2 and 4 mg/kg/day, 14 days, prior to habituation) on the place aversion induced by two naloxone doses (1.5 and 2.5 mg/kg/administration). The results show a robust, dose-dependent reduction of the aversion determined by both naloxone doses (the aversion induced by 1.5 mg/kg naloxone was reduced with 15%-the lower zinc dose and with 24%-the higher zinc dose; the aversion induced by 2.5 mg/kg naloxone was reduced with 16%-the lower zinc dose and with 29%-the higher zinc dose). This represents a new proof of the interactions between zinc and opioidergic system and a further argument for dietary zinc supplementation in patients on opioids for cancer-related chronic pain. PMID- 28337701 TI - CT-Guided Drainage of Pericardial Effusion after Open Cardiac Surgery. AB - PURPOSE: This study was designed to evaluate the safety and efficacy of CT-guided drainage of the pericardial effusion in patients after cardiac surgery. MATERIALS AND METHODS: The study included 128 consecutive patients (82 males, 46 females; mean age 66.6 years, SD: 4.2) complicated by pericardial effusion or hemopericardium after cardiac surgeries between June 2008 and June 2016. The medical indication for therapeutic pericardiocentesis in all patients was hemodynamic instability caused by pericardial effusion. The treatment criteria for intervention were evidence of pericardial tamponade with ejection fraction (EF) <50%. The preintervention ejection fraction was determined echocardiographically with value between 30 and 40%. Exclusion criteria for drainage were hemodynamically unstable patients or impaired coagulation profile (INR <1.8 or platelet count <75,000). Drains (8F-10F) were applied using Seldinger's technique under CT guidance. RESULTS: Pericardiocentesis and placement of a percutaneous pericardial drain was technically successful in all patients. The mean volume of evacuated pericardial effusion was 260 ml (range 80 900 ml; standard deviation [SD]: +/-70). Directly after pericardiocentesis, there was a significant improvement of the ejection fraction to 40-55% (mean: 45%; SD: +/-5; p < 0.05). The mean percentage increase of the EF following pericardial effusion drainage was 10%. The drainage was applied anteriorly (preventricular) in 39 of 128 (30.5%), retroventricularly in 33 of 128 (25.8%), and infracardiac in 56 of 128 (43.8%). Recurrence rate of pericardial effusion after removal of drains was 4.7% (67/128). Complete drainage was achieved in retroventricular and infracardiac positioning of the catheter (p < 0.05) in comparison to the preventricular position of the catheter. Recorded complications included minimal asymptomatic pneumothorax and pneumomediastinum 2.3% (3/128) and sinus tachycardia 3.9% (5/128). CONCLUSION: CT-guided drainage of postoperative pericardial effusion is a minimally invasive technique for the release of the tamponade effect of the effusion and improvement of cardiac output. PMID- 28337702 TI - Synthesis and Characterization of Surface Modified, Fluorescent and Biocompatible ZnS Nanoparticles with a Hydrophobic Chitosan Derivative. AB - The introduction of a hydrophobic moiety on chitosan enhances the self-assembling properties, mucoadhesion, the permeability of the macromolecule and aids in target specific delivery. Our group synthesized a hydrophobic trans N-(6,6 Dimethyl-2-hepten-4-ynyl)chitosan derivative (CSD) and studied the surface modification of ZnS nanoparticles in a single pot reaction. X-ray diffraction studies and FESEM imaging confirms the nano size and morphology of the surface modified Zinc sulfide nanoparticles (ZnS-CSD NPs). The proposed ZnS-CSD NPs showed excellent emission at 457 nm. Photostability studies indicate that the surface modified ZnS-CSD NPs possess better photostability than Rhodamine B and FITC. Cell viability tests confirmed the biocompatibility of the modified nanoparticles. All these features of ZnS- CSD NPs makes these candidates an excellent choice in a wide range of in vitro or in vivo studies as fluorescent biological labels. PMID- 28337703 TI - UMI-77 primes glioma cells for TRAIL-induced apoptosis by unsequestering Bim and Bak from Mcl-1. AB - Malignant glioma is the most common and aggressive form of brain tumor with poor prognosis of survival. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent but is insufficient of inducing apoptosis in some types of gliomas. In this study, we showed that the small-molecule Mcl-1 inhibitor UMI-77 sensitized glioma cells to TRAIL treatment, as evidenced by cell viability assay, Annexin V staining and JC-1 staining. Combination of UMI-77 and TRAIL in glioma cells led to the activation of caspase-8 and Bid, cleavage of caspase-3 and poly-ADP ribose polymerase (PARP), accumulation of tBid in the mitochondria and release of cytochrome c into the cytosol. UMI-77 alone or in combination with TRAIL untethered pro-apoptotic Bcl-2 proteins Bim and Bak from the sequestration of Mcl-1 and promoted the conformational activation of Bak. Small hairpin RNA (shRNA) of Bid attenuated the cleavage of caspase-8, Bid, caspase-3 and PARP, and reduced the cytotoxicity of UMI-77 plus TRAIL as compared with control shRNA cells, indicating this synergy entails the crosstalk between extrinsic and intrinsic apoptotic signaling. Taken together, UMI-77 enhances TRAIL-induced apoptosis by unsequestering Bim and Bak, which provides a novel therapeutic strategy for the treatment of gliomas. PMID- 28337704 TI - Analysis of traditional and emerging risk factors in premenopausal women with coronary artery disease: A pilot-scale study from North India. AB - Premenopausal women are known to have less heart disease than their menopausal counterparts and men. However, there is a rising prevalence of coronary artery disease (CAD) in premenopausal females, which necessitates determination of risk factors that negate the effects of hormonal protection. There are few studies describing the prevalence of traditional and emerging risk factors in premenopausal women with CAD. Thus, our objective was to explore the prevalence of traditional and emerging risk factors and features of coronary lesions in premenopausal women with CAD in an Indian population. Forty premenopausal female patients with angiographically proven CAD and undergoing treatment with conventional therapies and 40 age-matched premenopausal females without any evidence of CAD were enrolled. Premenopausal females with CAD most commonly had the single-vessel CAD and the left anterior descending artery was most commonly involved. The prevalence of hypertension, diabetes, obesity, metabolic syndrome, family history of CAD and 10-year risk score was higher in premenopausal females with CAD than controls. Even after treatment with conventional therapies, premenopausal women with CAD had dyslipidemia and significantly elevated levels of emerging risk factors such as ApoB, ApoB/ApoA1 ratio, hsCRP, lipoprotein (a), uric acid, T4, fibrinogen, and total leukocyte count as compared to controls (p < 0.05). Further, they had significantly lower levels of HDL-C, and Apolipoprotein A1 and T3 which are protective markers for vascular risk. Multivariate regression analysis demonstrated that low levels of Apo A1 and high levels of fibrinogen, hsCRP and TG drive the vascular risk, and therefore these factors should be considered as candidates for better diagnosis, early detection, and intervention of CAD in premenopausal women. PMID- 28337705 TI - The effects of polyunsaturated fatty acids and antioxidant vitamins on atrial oxidative stress, nitrotyrosine residues, and connexins following extracorporeal circulation in patients undergoing cardiac surgery. AB - Cardiac surgery with extracorporeal circulation is characterized by different degrees of myocardial ischemia/reperfusion, which is often associated with postoperative atrial fibrillation (POAF). We have previously shown that a novel preventive therapy based on the reinforcement of the antioxidant system using omega-3 fatty acids plus antioxidant vitamin supplementation applied to patients undergoing cardiac surgery reduces POAF occurrence. We hypothesized that oxidative stress and nitrosative stress are involved in the development of an arrhythmogenic substrate by their effect on connexins (Cx40, Cx43 and Cx45) abundance and distribution pattern. Therefore, we have assessed the effect of redox status on atrial tissue in patients undergoing cardiac surgery. Placebo/POAF and supplemented/POAF patients showed 276 and 170% higher reactive oxygen species (ROS) levels and 223 and 96% higher nitrotyrosine residues levels, respectively, compared to sinus rhythm (SR). In POAF tissue, antioxidant supplementation prevented Cx40 and Cx43 lateralization on cardiomyocyte sarcolemma, keeping them at the intercalated disks. POAF samples showed Cx40 heterogeneous distribution pattern, presenting tissue areas lacking this protein (49 and 55% lower levels in placebo/POAF and supplemented/POAF groups, respectively, compared to SR). Of note, Cx45 overexpression occurred in POAF, being 211 and 167% higher in placebo/POAF and supplemented/POAF groups, respectively, compared to SR. It is concluded that treatment with omega-3 fatty acids and antioxidant vitamins reduces oxidative and nitrosative stress and prevents Cx40/Cx43 lateralization in atrial tissue likely contributing to POAF prevention. However, it failed to fully prevent POAF occurrence because these compounds have no effects on the normalization of Cx40 down-regulation and Cx45 up-regulation, which may promote POAF. PMID- 28337707 TI - Investigation of Yeast Mitophagy with Fluorescence Microscopy and Western Blotting. AB - Selective clearance of superfluous or dysfunctional mitochondria is a fundamental process that depends on the autophagic membrane trafficking pathways found in many cell types. This catabolic event, called mitophagy, is conserved from yeast to humans and serves to control mitochondrial quality and quantity. In budding yeast, degradation of mitochondria occurs under various physiological conditions, such as respiration at stationary phase, or starvation in a prolonged period. During these events, the transmembrane protein Atg32 localizes to the mitochondrial surface and plays a specific and essential role in yeast mitophagy. In this chapter, we describe methods to observe transport of mitochondria to the vacuole, a lytic compartment in yeast, using fluorescence microscopy, and semi quantify the progression of Atg32-mediated mitophagy by Western blotting. PMID- 28337708 TI - Intestinal Crypt Organoid: Isolation of Intestinal Stem Cells, In Vitro Culture, and Optical Observation. AB - The isolation and culture of intestinal stem cells (ISCs) was first demonstrated in the very recent decade with the identification of ISC marker Lgr5. The growth of ISCs into crypt organoids provides an in vitro model for studying the mucosal physiology, intestinal cancer tumorigenesis, and intestinal regeneration. Here, we describe two different isolation protocols and demonstrate a fixation method that aids in the confocal observation of the organoids. PMID- 28337709 TI - Exploring MicroRNAs on NIX-Dependent Mitophagy. AB - The dysregulation of autophagy is implicated in many pathological disorders including infections, aging, neurodegenerative diseases, and cancer. Autophagy can be precisely controlled both transcriptionally and translationally. Accumulating evidences show that the autophagy response is regulated by microRNAs, which therefore becomes subject area of interest in recent years. Herein, we give a brief introduction of the recent advancement in the regulation of microRNA on autophagy, and then we focus on the microRNA regulation of the mitophagy receptor, NIX. Finally, we present the methodology on how to study it in detail. PMID- 28337706 TI - Clinical and radiological outcomes of two-level endoscopic posterior cervical foraminotomy. AB - PURPOSE: The efficacy and safety of endoscopic posterior cervical foraminotomy (EPCF) have been demonstrated for single-level cervical radiculopathy, but no report in the medical literature has described the clinical results of two-level EPCF. The aim of this study was to assess the clinical and radiological outcomes of two-level EPCF performed in patients with cervical radiculopathy. METHODS: Twenty-two consecutive patients (9 females and 13 males) that underwent two-level EPCF with cervical radiculopathy from January 2012 to January 2014 were included in this study. Clinical outcomes were assessed before surgery and at 1, 3, 6, 12, and 24 months postoperatively using visual analogue scale for neck and arm, neck pain and disability scale (NPDS), and neck disability index (NDI) scores. Radiological outcomes were assessed by measuring segmental lordosis (SL), C2-7 lordosis, and disc height index (DHI) before surgery and at 12 and 24 months postoperatively. RESULTS: Mean VAS, NPDS, and NDI scores were significant improved at 1 month postoperatively versus preoperative values and these improvements were maintained at 2 years after surgery. SL and C2-7 lordosis were significantly increased after surgery, and no instability in dynamic view was observed during the 2-year follow-up period. Percentage DHIs of operated discs were also maintained without significant change at 2 years after surgery. One patient suffered from transient motor palsy due to root retraction. CONCLUSIONS: Two-level EPCF can be safely preformed and should be considered an alternative to two-level anterior cervical discectomy and fusion or open posterior cervical foraminotomy in selected patients. PMID- 28337712 TI - Mandatory Publications: An Approach to Kill 'Lack of Will' or 'Lack of Skill'? AB - The issue of 'mandatory publications' has generated serious flak about its usefulness among the various stakeholders. A lot of debate centers around the question of 'lack of will' or 'lack of skill' as a reason for the diminishing research interests among the medical faculty in India. In our view, it is the lack of will to publish good quality research which is to be blamed rather than the lack of skill to do good quality research. PMID- 28337710 TI - High-efficient n-butanol production by co-culturing Clostridium acetobutylicum and Saccharomyces cerevisiae integrated with butyrate fermentative supernatant addition. AB - Butanol is not only an important chemical intermediate and solvent in pharmaceutical and cosmetics industries, but also considered as an advanced biofuel. Although species of the natural host Clostridium have been engineered, butanol titers in the anaerobe seem to be limited by its intolerance to butanol less than 13 g/L. Here we aimed to develop a technology for enhancing butanol production by a co-culture system with butyrate fermentative supernatant addition. First, when adding 4.0 g/L butyrate into the acetone-butanol-ethanol (ABE) fermentation broth with single-shot at 24 h, the "acid crash" phenomenon occurred and the ABE fermentation performance deteriorated. Subsequently, we found that adding certain amino acids could effectively enhance butyrate re assimilation, butanol tolerance and titer (from 11.1 to 14.8 g/L). Additionally, in order to decrease the raw material cost, butyrate fermentative supernatant produced by Clostridium tyrobutyricum was applied to butanol production in the Clostridium acetobutylicum/Saccharomyces cerevisiae co-culture system, instead of adding synthetic butyrate. Final butanol and total ABE concentrations reached higher levels of 16.3 and 24.8 g/L with increments of 46.8 and 37.8%, respectively. These results show that the proposed fermentation strategy has great potential for efficiently butanol production with an economic approach. PMID- 28337711 TI - Circulating Tumor DNA for Mutation Detection and Identification of Mechanisms of Resistance in Non-Small Cell Lung Cancer. AB - Targeted therapies have changed the treatment landscape of non-small cell lung cancer over the past decade. Analyses of cell free circulating tumor DNA (ctDNA) provide a non-invasive and robust approach for cancer diagnosis and prognosis, real-time monitoring of treatment response, and the identification of appropriate therapeutic targets based on the detection of tumor genetic aberrations. Recent improvements in the sensitivity, specificity, and feasibility of ctDNA detection assays allow the possibility for implementation into clinical practice. This review will focus on key studies using ctDNA analysis in early lung cancer detection, prediction of treatment response, monitoring minimal residual disease and disease relapse, and the identification of resistance mechanisms. We explore how ctDNA can be used as a surrogate for tissue biopsy and an integral biomarker in the clinical management of patients with non-small cell lung cancer. PMID- 28337713 TI - The Potential Role of Fibroblast Growth Factor 21 in Lipid Metabolism and Hypertension. AB - Fibroblast growth factor (FGF) 21 belongs to the FGF superfamily that is involved in cell proliferation and differentiation, neural development, angiogenesis, and metabolism. FGF21 requires beta-Klotho as a co-receptor. Tissues involved in metabolism such as the liver, adipose tissues, skeletal muscle, and pancreas express FGF21. Starvation increases hepatic expression of FGF21, which then acts centrally to increase hepatic gluconeogenesis. FGF21 also increases fatty acid oxidation. This may be relevant in cold exposure, when expression of FGF21 is induced. Chronic treatment with recombinant FGF21 reduces serum and hepatic triglyceride levels and ameliorates fatty liver in obese mice, through the suppression of the lipogenic gene, Srebp-1. FGF21 reduces hepatic cholesterol production by inhibiting Srebp-2, a transactivator of proprotein convertase subtilisin/kexin type 9 (PCSK9). LY2045319, an FGF21 analog, reduces LDL-C and triglycerides and increases HDL-C in obese human subjects with type 2 diabetes. FGF21 does not seem to lower blood pressure acutely. In rats fed with high fructose water to induce mild hypertension, 4-week treatment with recombinant FGF21 led to normalization of systolic blood pressure and improved serum lipid profile. FGF receptors and beta-Klotho are expressed on the nucleus tractus solitarii and nodose ganglion in the baroreflex afferent pathway. Moreover, FGF21 acts on the hypothalamus to release corticosterone and induces in adipocytes the production of adiponectin, an adipokine with antihypertensive activities. Therefore, FGF21 may decrease blood pressure indirectly, through its actions in the liver, brain, and adipose tissues. PMID- 28337714 TI - Decreased live births among women of Middle Eastern/North African ethnicity compared to Caucasian women. AB - PURPOSE: The objective of this study is to determine if IVF outcome disparities exist among MENA women in the USA in comparison to a control group of Caucasian women. METHODS: A retrospective cohort study comparing MENA (N = 190) and Caucasian (N = 200) women undergoing their first IVF cycle between 5/2006 and 5/2014 was carried out at an academically affiliated fertility practice. All MENA cycles during that time period undergoing IVF/ICSI using autologous embryos and blastocyst transfers were compared to a control group of Caucasian women. RESULTS: MENA women were significantly younger (32.9 vs 34.5, P < 0.005) and had a lower BMI (25.2 vs 27.1, P < 0.001). Male factor infertility was higher among partners of MENA women (62 vs 50%, P < 0.05). MENA women experienced decreased live birth rates per blastocyst transfer compared to Caucasian women after controlling for age and BMI (OR 0.55, 95% CI 0.35-0.85 P = 0.007). The odds of a miscarriage were also significantly higher among MENA women (OR 2.55, 95% CI 1.04 6.27 P = 0.036). CONCLUSION: Middle Eastern/North African women have worse IVF outcomes with decreased live birth rates per blastocyst transfer and increased miscarriage rates compared to Caucasian women. PMID- 28337715 TI - Is incremental hemodialysis ready to return on the scene? From empiricism to kinetic modelling. AB - Most people who make the transition to maintenance dialysis therapy are treated with a fixed dose thrice-weekly hemodialysis regimen without considering their residual kidney function (RKF). The RKF provides effective and naturally continuous clearance of both small and middle molecules, plays a major role in metabolic homeostasis, nutritional status, and cardiovascular health, and aids in fluid management. The RKF is associated with better patient survival and greater health-related quality of life, although these effects may be confounded by patient comorbidities. Preservation of the RKF requires a careful approach, including regular monitoring, avoidance of nephrotoxins, gentle control of blood pressure to avoid intradialytic hypotension, and an individualized dialysis prescription including the consideration of incremental hemodialysis. There is currently no standardized method for applying incremental hemodialysis in practice. Infrequent (once- to twice-weekly) hemodialysis regimens are often used arbitrarily, without knowing which patients would benefit the most from them or how to escalate the dialysis dose as RKF declines over time. The recently heightened interest in incremental hemodialysis has been hindered by the current limitations of the urea kinetic models (UKM) which tend to overestimate the dialysis dose required in the presence of substantial RKF. This is due to an erroneous extrapolation of the equivalence between renal urea clearance (Kru) and dialyser urea clearance (Kd), correctly assumed by the UKM, to the clinical domain. In this context, each ml/min of Kd clears the urea from the blood just as 1 ml/min of Kru does. By no means should such kinetic equivalence imply that 1 ml/min of Kd is clinically equivalent to 1 ml/min of urea clearance provided by the native kidneys. A recent paper by Casino and Basile suggested a variable target model (VTM) as opposed to the fixed model, because the VTM gives more clinical weight to the RKF and allows less frequent hemodialysis treatments at lower RKF. The potentially important clinical and financial implications of incremental hemodialysis render it highly promising and warrant randomized controlled trials. PMID- 28337717 TI - Injectable Bioengineered Hydrogel Therapy in the Treatment of Ischemic Cardiomyopathy. AB - OPINION STATEMENT: Over the past two decades, the field of cardiovascular medicine has seen the rapid development of multiple different modalities for the treatment of ischemic myocardial disease. Most research efforts have focused on strategies aimed at coronary revascularization, with significant technological advances made in percutaneous coronary interventions as well as coronary artery bypass graft surgery. However, recent research efforts have shifted towards ways to address the downstream effects of myocardial infarction on both cellular and molecular levels. To this end, the broad application of injectable hydrogel therapy after myocardial infarction has stimulated tremendous interest. In this article, we will review what hydrogels are, how they can be bioengineered in unique ways to optimize therapeutic potential, and how they can be used as part of a treatment strategy after myocardial infarction. PMID- 28337718 TI - Sex-dependent effects of neonatal maternal deprivation on endocannabinoid levels in the adipose tissue: influence of diet. AB - Maternal deprivation (MD) during neonatal life has diverse long-term effects, including modification of metabolism. We have previously reported that MD modifies the metabolic response to high-fat diet (HFD) intake, with this response being different between males and females, while previous studies indicate that in mice with HFD-induced obesity, endocannabinoid (EC) levels are markedly altered in various brown and white adipose tissue depots. Here, we analyzed the effects of MD (24 h at postnatal day 9), alone or in combination with a HFD from weaning until the end of the experiment in Wistar rats of both sexes. Brown and white perirenal and subcutaneous adipose tissues were collected and the levels of anandamide (AEA), 2-arachidonoylglycerol (2-AG), palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) were determined. In males, MD increased the content of OEA in brown and 2-AG in subcutaneous adipose tissues, while in females the content of 2-AG was increased in perirenal fat. Moreover, in females, MD decreased AEA and OEA levels in perirenal and subcutaneous adipose tissues, respectively. HFD decreased the content of 2-AG in brown fat of both sexes and OEA in brown and subcutaneous adipose tissue of control females. In contrast, in subcutaneous fat, HFD increased AEA levels in MD males and OEA levels in control and MD males. The present results show for the first time that MD and HFD induce sex-dependent effects on the main ECs, AEA, and 2-AG, and of AEA-related mediators, OEA and PEA, in the rat brown and white (visceral and subcutaneous) adipose tissues. PMID- 28337721 TI - Erratum to: Feasibility, effectiveness and cost-effectiveness of a telephone based weight loss program delivered via a hospital outpatient setting. PMID- 28337716 TI - Long term variation of serum levels of uremic toxins in patients treated by post dilution high volume on-line hemodiafiltration in comparison to standard low-flux bicarbonate dialysis: results from the REDERT study. AB - PURPOSE OF THE STUDY: Little information have been provided till now regarding the effect of high volume HDF (hv-OL-HDF) in respect to standard bicarbonate dialysis (BHD) in medium-long term protein-bound toxins removal. PROCEDURES: A randomised cross-over multicentre study (REDERT study) was designed to compare the effects of hv-OL-HDF and low-flux BHD on uremic toxins serum levels in 36 chronic dialysis patients followed for 13 months. Group 1 patients were treated with BHD (Treatment A) for 6 months, and afterwards, they were transferred to hv OL-HDF for a further 6 months (Treatment B). Group 2 patients were treated with Treatment B for 6 months, and afterwards, they were transferred to Treatment A for a further 6 months. Total and free pre-dialysis indoxyl-sulfate (IS) and p cresyl-sulfate (pCS) were determined starting a midweek dialysis session at baseline and after six months of hv-OL-HDF or BHD. IS and pCS, were simultaneously measured, by liquid chromatography/electrospray ionization-tandem mass spectrometry, Kt/v and pre and post-dialysis b-2microglobulin (b2MG) levels were measured every three months. RESULTS: Kt/V was significantly increased in hv OL-HDF (from 1.47 +/- 0.24 to 1.49 +/- 0.16; p < 0.01) and was reduced in BHD (from 1.51 +/- 0.2 to 1.36 +/- 0.21; p < 0.001). The mean infusion volume in HDF was 20.9 +/- 2.1 L with a mean total convective volume of 23.8 +/- 2.3 L and a significant removal of b2MG was obtained in hv-OL-HDF at month 3 and month 6. Both free and total levels of IS and pCS were significantly reduced in hv-OL-HDF at month 6 in respect to BHD. CONCLUSIONS: In the present study we confirm the assumption that post-HDF is an effective technique in small and protein-bound uremic toxins removal. INTRODUCTION: PMID- 28337719 TI - An Early Health Economic Analysis of the Potential Cost Effectiveness of an Adherence Intervention to Improve Outcomes for Patients with Cystic Fibrosis. AB - BACKGROUND: Cystic fibrosis (CF) negatively impacts upon health-related quality of life and survival. Adherence to nebulised treatments is low; improving adherence is hypothesised to reduce rates of exacerbation requiring intravenous antibiotics and lung function decline. OBJECTIVE: A state transition model was developed to assess the cost effectiveness of an intervention aimed at increasing patient adherence to nebulised and inhaled antibiotics compared with current CF care, in advance of the forthcoming CFHealthHub randomised controlled trial (RCT). METHODS: The model estimated the costs and health outcomes for each option from the perspective of the UK National Health Service and Personal Social Services over a lifetime horizon. Health gains were valued in terms of quality adjusted life-years (QALYs) gained. Forced expiratory volume in 1 second (FEV1) trajectories were predicted over three lung function strata: (1) FEV1 >=70%, (2) FEV1 40-69% and (3) FEV1 <40%. Additional states were included to represent 'post lung transplantation' and 'dead'. The model was populated using CF Registry data, literature and expert opinion. Costs were presented at 2016 values. Uncertainty was assessed using deterministic and probabilistic sensitivity analyses. RESULTS: If effective, the adherence intervention is expected to produce an additional 0.19 QALYs and cost savings of L64,078 per patient. Across all analyses, the intervention dominated current care. Over a 5-year period, the intervention is expected to generate cost savings of L49.5 million for the estimated 2979 patients with CF with Pseudomonas aeruginosa currently aged >=16 years in the UK. If applied to a broader population of adult patients with CF receiving any nebulised therapy, the expected savings could be considerably greater. CONCLUSIONS: If effective, the adherence intervention is expected to produce additional health gains at a lower cost than current CF care. However, the economic analysis should be revisited upon completion of the full RCT. More generally, the analysis suggests that considerable gains could be accrued through the implementation of adherence interventions that shift care from expensive hospital-based rescue to community-based prevention. PMID- 28337720 TI - Defining Value: The Need for a Longer, Broader View. PMID- 28337723 TI - Assessment of safety, efficacy, and dosimetry of a novel 18-kDa translocator protein ligand, [11C]CB184, in healthy human volunteers. AB - BACKGROUND: N,N-di-n-propyl-2-[2-(4-[11C]methoxyphenyl)-6,8-dichloroimidazol[1,2 a]pyridine-3-yl]acetamide ([11C]CB184) is a novel selective radioligand for the 18-kD translocator protein (TSPO), which is upregulated in activated microglia in the brain, and may be useful in positron emission tomography (PET). We examined the safety, radiation dosimetry, and initial brain imaging with [11C]CB184 in healthy human volunteers. RESULTS: Dynamic [11C]CB184 PET scans (90 min) were performed in five healthy male subjects. During the scan, arterial blood was sampled at various time intervals, and the fraction of the parent compound in plasma was determined with high-performance liquid chromatography. No serious adverse events occurred in any of the subjects throughout the study period. [11C]CB184 was metabolized in the periphery: 36.7% +/- 5.7% of the radioactivity in plasma was detected as the unchanged form after 60 min. The total distribution volume (V T) was estimated with a two-tissue compartment model. The V T of [11C]CB184 was highest in the thalamus (5.1 +/- 0.4), followed by the cerebellar cortex (4.4 +/- 0.2), and others. Although regional differences were small, the observed [11C]CB184 binding pattern was consistent with the TSPO distribution in the normal human brain. Radiation dosimetry was determined in three healthy male subjects using a serial whole-body PET scan acquired over 2 h after [11C]CB184 injection. [11C]CB184 PET demonstrated high uptake in the gallbladder at a later time (>60 min). In urine obtained approximately 100 min post-injection, 0.3% of the total injected radioactivity was recovered, indicating hepatobiliary excretion of radioactivity. The absorbed dose (MUGy/MBq) was highest in the kidneys (21.0 +/- 0.5) followed by the lungs (16.8 +/- 2.7), spleen (16.6 +/- 6.6), and pancreas (16.5 +/- 2.2). The estimated effective dose for [11C]CB184 was 5.9 +/- 0.6 MUSv/MBq. CONCLUSIONS: This initial evaluation indicated that [11C]CB184 is feasible for imaging of TSPO in the brain. PMID- 28337722 TI - Advancing understanding of the sustainability of lay health advisor (LHA) programs for African-American women in community settings. AB - Lay health advisor (LHA) programs have made strong contributions towards the elimination of health disparities and are increasingly being implemented to promote health and prevent disease. Developed in collaboration with African American survivors, the National Witness Project (NWP) is an evidence-based, community-led LHA program that improves cancer screening among African-American women. NWP has been successfully disseminated, replicated, and implemented nationally in over 40 sites in 22 states in diverse community settings, reaching over 15,000 women annually. We sought to advance understanding of barriers and facilitators to the long-term implementation and sustainability of LHA programs in community settings from the viewpoint of the LHAs, as well as the broader impact of the program on African-American communities and LHAs. In the context of a mixed-methods study, in-depth telephone interviews were conducted among 76 African-American LHAs at eight NWP sites at baseline and 12-18 months later, between 2010 and 2013. Qualitative data provides insight into inner and outer contextual factors (e.g., community partnerships, site leadership, funding), implementation processes (e.g., training), as well as characteristics of the intervention (e.g., perceived need and fit in African-American community) and LHAs (e.g., motivations, burnout) that are perceived to impact the continued implementation and sustainability of NWP. Factors at the contextual levels and related to motivations of LHAs are critical to the sustainability of LHA programs. We discuss how findings are used to inform (1) the development of the LHA Sustainability Framework and (2) strategies to support the continued implementation and sustainability of evidence-based LHA interventions in community settings. PMID- 28337725 TI - Comparison of diagnostic performance of four software packages for phase dyssynchrony analysis in gated myocardial perfusion SPECT. AB - BACKGROUND: Phase analysis of gated myocardial perfusion single-photon emission computed tomography (SPECT) for assessment of left ventricular (LV) dyssynchrony was investigated using the following dedicated software packages: Corridor4DM (4DM), cardioREPO (cREPO), Emory Cardiac Toolbox (ECTb), and quantitative gated SPECT (QGS). The purpose of this study was to evaluate the normal values of 95% histogram bandwidth, phase standard deviation (SD), and entropy and to compare the diagnostic performance of the four software packages. A total of 122 patients with normal myocardial perfusion and cardiac function (58.9 +/- 12.3 years, 60 women, ejection fraction (EF) 74.3 +/- 5.7%, and end-diastolic volume (EDV) 83.5 +/- 3.6 mL) and 34 patients with suspected LV dyssynchrony (64.1 +/- 12.2 years, 9 women, EF 52.0 +/- 18.0%, and EDV 145.0 +/- 6.8 mL) who underwent Tc-99m methoxy-isobutyl-isonitrile/tetrofosmin gated SPECT were retrospectively evaluated. Dyssynchrony indices of the 95% histogram bandwidth, phase SD, and entropy were computed with the four software programs. Diagnostic performance of LV phase dyssynchrony assessments was determined by receiver operator characteristic (ROC) analysis. The area under the ROC curve (AUC) was used to compare the software programs. The optimal cutoff point was determined by ROC curve based on the Youden index. RESULTS: The average of normal bandwidth significantly differed among the four software programs except in the comparison of 4DM and ECTb. Moreover, the normal phase SD significantly differed among the four software programs except in the comparison of cREPO and ECTb. The software programs showed high correlation levels for bandwidth, phase SD, and entropy (r >= 0.73, p < 0.001). ROC AUCs of bandwidth, phase SD, and entropy were >=0.850, >=0.858, and >=0.900, respectively. Moreover, the ROC AUCs of bandwidth, phase SD, and entropy did not significantly differ among the four software programs. Optimal cutoff points for phase parameters were 24 degrees -42 degrees for bandwidth, 8.6 degrees -15.3 degrees for phase SD, and 31-48% for entropy. CONCLUSIONS: Although the optimal cutoff value for determining LV phase dyssynchrony by ROC analysis varied depending on the use of the different software programs, all software programs can be used reliably for phase dyssynchrony analysis. PMID- 28337724 TI - I-123 iomazenil single photon emission computed tomography for detecting loss of neuronal integrity in patients with traumatic brain injury. AB - BACKGROUND: Traumatic brain injury (TBI) causes brain dysfunction in many patients. Using C-11 flumazenil (FMZ) positron emission tomography (PET), we have detected and reported the loss of neuronal integrity, leading to brain dysfunction in TBI patients. Similarly to FMZ PET, I-123 iomazenil (IMZ) single photon emission computed tomography (SPECT) is widely used to determine the distribution of the benzodiazepine receptor (BZR) in the brain cortex. The purpose of this study is to examine whether IMZ SPECT is as useful as FMZ PET for evaluating the loss of neuronal integrity in TBI patients. The subjects of this study were seven patients who suffered from neurobehavioral disability. They underwent IMZ SPECT and FMZ PET. Nondisplaceable binding potential (BPND) was calculated from FMZ PET images. The uptake of IMZ was evaluated on the basis of lesion-to-pons ratio (LPR). The locations of low uptake levels were visually evaluated both in IMZ SPECT and FMZ PET images. We compared FMZ BPND and (LPR-1) of IMZ SPECT. RESULTS: In the visual assessment, FMZ BPND decreased in 11 regions. In IMZ SPECT, low uptake levels were observed in eight of the 11 regions. The rate of concordance between FMZ PET and IMZ SPECT was 72.7%. The mean values IMZ (LPR-1) (1.95 +/- 1.01) was significantly lower than that of FMZ BPND (2.95 +/- 0.80 mL/mL). There was good correlation between FMZ BPND and IMZ (LPR-1) (r = 0.80). CONCLUSIONS: IMZ SPECT findings were almost the same as FMZ PET findings in TBI patients. The results indicated that IMZ SPECT is useful for evaluating the loss of neuronal integrity. Because IMZ SPECT can be performed in various facilities, IMZ SPECT may become widely adopted for evaluating the loss of neuronal integrity. PMID- 28337726 TI - Opioid-Related Constipation in Patients With Non-cancer Pain Syndromes: a Review of Evidence-Based Therapies and Justification for a Change in Nomenclature. AB - PURPOSE OF REVIEW: Opioids are a mainstay in the treatment of chronic non-cancer pain syndromes, but their analgesic benefits come at a cost as opioid-related constipation occurs in 40-80% of individuals taking chronic opioids. Furthermore, as 10-20% of the population suffers from constipation at baseline, it should be expected that while a proportion of individuals will develop constipation as a direct consequence of opioids (OIC), others will experience it as an exacerbation of their baseline constipation (OEC). Herein, we review the evidence-based data for treatments directed at opioid-related constipation focusing on individuals with non-cancer pain syndromes and provide a template for the development of differentiated treatment algorithms for OIC and OEC. RECENT FINDINGS: Historical and current treatment protocols recommend traditional laxatives, but these are ineffective in up to 50%, due in part to the heterogeneous pathogenesis of constipation. Therapeutic decisions must be tailored to account for this overlapping pathogenesis. OIC and OEC are distinct entities. As such, additional research and guidelines should address these as different patient populations. PMID- 28337728 TI - Collinear masking effect in visual search is independent of perceptual salience. AB - Searching for a target in a salient region should be easier than looking for one in a nonsalient region. However, we previously discovered a contradictory phenomenon in which a local target in a salient structure was more difficult to find than one in the background. The salient structure was constructed of orientation singletons aligned to each other to form a collinear structure. In the present study, we undertake to determine whether such a masking effect was a result of salience competition between a global structure and the local target. In the first 3 experiments, we increased the salience value of the local target with the hope of adding to its competitive advantage and eventually eliminating the masking effect; nevertheless, the masking effect persisted. In an additional 2 experiments, we reduced salience of the global collinear structure by altering the orientation of the background bars and the masking effect still emerged. Our salience manipulations were validated by a controlled condition in which the global structure was grouped noncollinearly. In this case, local target salience increase (e.g., onset) or global distractor salience reduction (e.g., randomized flanking orientations) effectively removed the facilitation effect of the noncollinear structure. Our data suggest that salience competition is unlikely to explain the collinear masking effect, and other mechanisms such as contour integration, border formation, or the crowding effect may be prospective candidates for further investigation. PMID- 28337727 TI - Newer Antiepileptic Drugs in Status Epilepticus: Prescription Trends and Outcomes in Comparison with Traditional Agents. AB - INTRODUCTION: Newer antiepileptic drugs (AEDs) are increasingly prescribed; however, relatively limited data are available regarding their use in status epilepticus (SE) and the impact on outcome. OBJECTIVES: The aim of this study was to explore the evolution in prescription patterns of newer and traditional AEDs in this clinical setting, and their association with prognosis. METHODS: We analyzed our prospective adult SE registry over a 10-year period (2007-2016) and assessed the yearly use of newer and traditional AEDs and their association with mortality, return to baseline conditions at discharge, and SE refractoriness, defined as treatment resistance to two AEDs, including benzodiazepines. RESULTS: In 884 SE episodes, corresponding to 719 patients, the prescription of at least one newer AED increased from 0.38 per SE episode in 2007 to 1.24 per SE episode in 2016 (mostly due to the introduction of levetiracetam and lacosamide). Traditional AEDs (excluding benzodiazepines) decreased over time from 0.74 in 2007 to 0.41 in 2016, correlating with the decreasing use of phenytoin. The prescription of newer AEDs was independently associated with a lower chance of return to baseline conditions at discharge (odds ratio [OR] 0.58, 95% confidence interval [CI] 0.40-0.84) and a higher rate of SE refractoriness (OR 19.84, 95% CI 12.76-30.84), but not with changes in mortality (OR 1.08, 95% CI 0.58-2.00). CONCLUSION: We observed a growing trend in the prescription of newer AEDs in SE over the last decade; however, our findings might suggest an associated increased risk of SE refractoriness and new disability at hospital discharge. Pending prospective, comparative studies, this may justify some caution in the routine use of newer AEDs in SE. PMID- 28337729 TI - Adjacent level disease-background and update based on disc replacement data. AB - PURPOSE OF REVIEW: The precise etiology of adjacent segment disease following cervical spine surgery is controversial. Theories for development include inevitable changes secondary to the natural progression of the degenerative cascade and changes secondary to altered biomechanics of the fused cervical spine. Motion preserving techniques, such as cervical disc arthroplasties (CDA), have been introduced with the hopes of reducing the rates of adjacent segment pathology. Recently, 7-year data from the investigational device exemption (IDE) studies have been published. The purpose of this review is to provide an update on cervical adjacent segment disease incorporating this emerging data into the analysis. RECENT FINDINGS: Although the 7-year data for CDA has confirmed continued success, specifically regarding improved neck pain and reduced re operation rates, the influence of CDA on reducing rates of adjacent segment pathology remains questionable. Although some studies have found more radiographic adjacent segment disease after anterior cervical discectomy and fusion (ACDF) compared to CDA, an association between these findings and clinical symptoms has not been established. Cervical disc arthroplasty continues to outperform cervical disc fusion regarding some patient specific parameters, however, whether CDA reduces rates of radiographic and clinical adjacent segment pathology remains unknown. Without studies developed specifically to address this question, the answer remains elusive. PMID- 28337731 TI - Arthroplasty registries around the world: valuable sources of hip implant revision risk data. AB - PURPOSE OF REVIEW: National and regional arthroplasty registries have proliferated since the Swedish Knee Arthroplasty Register was started in 1975. Registry reports typically present implant-specific estimates of revision risk and patient- and technique-related factors that can inform clinical decision making about implants and techniques. However, annual registry reports are long and it is difficult for clinicians to extract comparable revision risk data. Since implants may appear in multiple registry reports, it is even more difficult to gather relevant data for clinical decision-making about implant selection. The purpose of this paper is to briefly describe arthroplasty registry concepts, international registries around the world, US registries, and provide a parsimonious summary of total hip arthroplasty (THA) implant revision risk reports across registries. RECENT FINDINGS: Revision risk data for conventional stem/cup combinations reported by the Australian, R.I.P.O. (Italian), Finnish, and Danish registries are summarized here. These registries were selected because they presented 10-year data on revision risk by stem/cup combination. Four tables of revision risk are presented based on fixation: cemented, uncemented, hybrid, and reverse hybrid. Review of these tables show there is wide variation in revision risk across conventional THA implants. It also demonstrates that some cemented implants have better 10-year risk than the best uncemented implants. Many arthroplasty registries prepare annual reports that include revision risk data for implants and they are posted on the registry websites. Arthroplasty surgeons should stay current with these registry reports on implant performance and potential outliers and keep them in mind when making implant decisions. PMID- 28337730 TI - Current concepts of shared decision making in orthopedic surgery. AB - PURPOSE OF REVIEW: The Shared Decision Making (SDM) model, a collaborative decision making process between the physician and patient to make an informed clinical decision that enhances the chance of treatment success as defined by each patient's preferences and values, has become a new and promising tool in the healthcare process; however, minimal data exists on its application in the orthopedic surgical specialty. Increasing evidence has demonstrated that this once novel idea can be implemented successfully in the orthopedic setting to improve patient outcomes. RECENT FINDINGS: SDM can be applied without significant increases in the office length. Patients report that a physician that takes the time to listen to them is among the most important factors in their care. When time was focused on the SDM process, there was a direct correlation between the time spent with a patient and patient satisfaction. Patients exposed to a decision aid prior to surgery gained a greater knowledge from baseline to make a higher quality decision that was consistent with their values. Involving family members preoperatively can help all patients adhere to postoperative regimens. Exposing patients to a decision aid can reduce expensive elective surgeries, in favor of non-operative management. Incorporating patient goals into the decision making process has increased satisfaction, compliance, and outcomes. SDM is a two way exchange of information that attempts to correct the inequality of power between the patient and physician. Decision-aids are helpful tools that facilitate the decision-making process. Treatment decisions are consistent with patient preferences and values when there may be no "best" therapy. A good patient-physician relationship is essential during the process to reduce decisional conflict and increase overall patient outcomes. PMID- 28337732 TI - Medicare reimbursement and orthopedic surgery: past, present, and future. AB - PURPOSE OF REVIEW: This paper reviews the history and structure of Medicare reimbursement with a focus on aspects relevant to the field of orthopedic surgery. Namely, this includes Parts A and B, with particular attention paid to the origins of Diagnosis Related Groups (DRG) and the physician fee schedule, respectively. We then review newer policies affecting orthopedic surgeons. RECENT FINDINGS: Recent Medicare reforms relevant to our field include readmission penalties, the evolution of bundled payments including the mandatory Comprehensive Care for Joint Replacement (CJR) and Surgical Hip and Femur Fracture Treatment (SHFFT) programs, and the new mandatory Merit-based Incentive Payment System (MIPS) pay-for-performance program. Providers are facing an increasingly complex payment system and are required to assume growing levels of financial risk. Physicians and practices who prepare for these changes will likely fare best and may even benefit. PMID- 28337734 TI - Diffusion tensor imaging (DTI) findings in adult civilian, military, and sport related mild traumatic brain injury (mTBI): a systematic critical review. AB - This review seeks to summarize diffusion tensor imaging (DTI) studies that have evaluated structural changes attributed to the mechanisms of mild traumatic brain injury (mTBI) in adult civilian, military, and athlete populations. Articles from 2002 to 2016 were retrieved from PubMed/MEDLINE, EBSCOhost, and Google Scholar, using a Boolean search string containing the following terms: "diffusion tensor imaging", "diffusion imaging", "DTI", "white matter", "concussion", "mild traumatic brain injury", "mTBI", "traumatic brain injury", and "TBI". We added studies not identified by this method that were found via manually-searched reference lists. We identified 86 eligible studies from English-language journals using, adult, human samples. Studies were evaluated based on duration between injury and DTI assessment, categorized as acute, subacute/chronic, remote mTBI, and repetitive brain trauma considerations. Since changes in brain structure after mTBI can also be affected by other co-occurring medical and demographic factors, we also briefly review DTI studies that have addressed socioeconomic status factors (SES), major depressive disorder (MDD), and attention-deficit hyperactivity disorder (ADHD). The review describes population-specific risks and the complications of clinical versus pathophysiological outcomes of mTBI. We had anticipated that the distinct population groups (civilian, military, and athlete) would require separate consideration, and various aspects of the study characteristics supported this. In general, study results suggested widespread but inconsistent differences in white matter diffusion metrics (primarily fractional anisotropy [FA], mean diffusivity [MD], radial diffusivity [RD], and axial diffusivity [AD]) following mTBI/concussion. Inspection of study designs and results revealed potential explanations for discrepant DTI findings, such as control group variability, analytic techniques, the manner in which regional differences were reported, and the presence or absence of persistent functional disturbances. DTI research in adult mTBI would benefit from more standardized imaging and analytic approaches. We also found significant overlap in white matter abnormalities reported in mTBI with those commonly affected by SES or the presence of MDD and ADHD. We conclude that DTI is sensitive to a wide range of group differences in diffusion metrics, but that it currently lacks the specificity necessary for meaningful clinical application. Properly controlled longitudinal studies with consistent and standardized functional outcomes are needed before establishing the utility of DTI in the clinical management of mTBI and concussion. PMID- 28337736 TI - Trans-cystic tube drainage a more viable option than T-tube for hepatic resection with cholecystectomy if external biliary drainage is desired. PMID- 28337735 TI - Isolation of nontuberculous mycobacteria from soil using Middlebrook 7H10 agar with increased malachite green concentration. AB - Environmental exposure is considered to be responsible for nontuberculous mycobacterial infections in humans. To facilitate the isolation of mycobacteria from soil, Middlebrook 7H10 agar was optimized as an enhanced selective medium by increasing the concentration of malachite green. A series of modified Middlebrook 7H10 agar media with malachite green concentrations ranging from 2.5 to 2500 mg/L was evaluated using 20 soil samples decontaminated with 3% sodium dodecyl sulfate plus 2% NaOH for 30 min. Among these modified Middlebrook 7H10 media, the medium with malachite green at a concentration of 250 mg/L, i.e., at the same concentration as in Lowenstein-Jensen medium, was the most effective in terms of the number of plates with mycobacterial growth. This medium was further evaluated with 116 soil samples. The results showed that 87.1% (101/116) of the samples produced mycobacterial growth, and 15 samples (12.9%) produced no mycobacterial growth. Of the plates inoculated with the soil samples, each in duplicate, 5.2% (12/232) showed late contamination. In total, 19 mycobacterial species were isolated, including seven (36.8%) rapidly growing mycobacteria and 12 (63.2%) slowly growing mycobacteria. Our results demonstrate that the modified Middlebrook 7H10 agar with 250 mg/L malachite green is useful for the primary isolation of nontuberculous mycobacteria from soil. PMID- 28337733 TI - Bias in cervical total disc replacement trials. AB - PURPOSE OF REVIEW: Cervical disc replacement (CDR) has emerged as a motion preserving alternative to anterior cervical discectomy and fusion in selected cases. Despite favorable literature, CDR is not universally accepted because of concerns regarding bias in the existing literature. The purpose of this review is to identify the possible biases in the disc replacement literature. RECENT FINDINGS: Recent studies that compare CDR and ACDF have demonstrated equivalent or superior outcomes, lower rates of secondary surgery, and equivalent safety at medium- and long-term follow-up. In our review, we identified four types of bias that may affect the CDR literature: publication bias, external validity, confounding bias, and financial conflicts of interest. Bias, whether intentional or unintentional, can impact the interpretation and outcome of CDR studies. Recognition of this issue is critical when utilizing the existing literature to determine the efficacy of CDR and designing future studies. PMID- 28337737 TI - Intraoperative ultrasound detection of spontaneous intrahepatic portocaval shunt. PMID- 28337738 TI - Does birth under-registration reduce childhood immunization? Evidence from the Dominican Republic. AB - The consequences of lacking birth certificates remain largely unexplored in the economic literature. We intend to fill this knowledge gap studying the effect of lacking birth certificates on immunization of children in the Dominican Republic. This is an interesting country because a significant number of children of Haitian descent face the consequences of lacking proper documentation. We use the distance to the civil registry office and the mother's document of identification as instrumental variables of the child's birth certificate. After controlling for distance to immunization services and other determinants, this paper finds that children between 0 and 59 months of age that do not have birth certificates are behind by nearly one vaccine (out of a total of nine) compared to those that have birth certificates. PMID- 28337739 TI - Intraductal neoplasms of the bile duct. A new challenge to biliary tract tumor pathology. AB - Invasive biliary tract carcinomas are usually tubular adenocaricnomas with abundant desmoplastic reactions and frequent ductal and periductal invasion at the time of the diagnosis. Recently, several intraductal neoplasms of the bile duct, particularly at a pre-invasive stage, have been recognized. They include intraductal papillary neoplasm of the bile duct (IPNB), biliary intraepithelial neoplasm (BilIN), and others, such as intraductal tubulopapillary neoplasm (ITPN) of the bile duct. IPNBs are grossly visible predominantly intraductal-growing papillary neoplasms covered by well-differentiated neoplastic epithelium with fine fibrovascular cores in the dilated bile ducts. Regarding their similarities to intraductal papillary mucinous neoplasm of the pancreas (IPMN) of main pancreatic duct type, some IPNBs resemble IPMN ("pancreatic type"), while others are only somewhat similar or variably different from IPMN ("non-pancreatic type"). Some IPNBs develop via a common oncogenic signaling pathway, and others, particularly those of intestinal type, frequently show GNAS mutations, as in IPMN. BilINs are a microscopically recognizable flat or micropapillary pre invasive neoplasm and are presumed to precede conventional nodular-sclerosing cholangiocarcinomas. ITPN of the bile duct is a rare neoplasm composed of densely packed tubular glands. These three types of neoplasms are not infrequently associated with invasive adenocarcinoma. Pre-invasive intraglandular neoplasms of the peribiliary glands, another epithelial system in the biliary tree, have been also reported. Further characterization of these intraductal and intraglandular neoplasms of the bile duct is needed to overcome devastating invasive biliary tract carcinoma. PMID- 28337740 TI - Proteome comparison for discrimination between honeydew and floral honeys from botanical species Mimosa scabrella Bentham by principal component analysis. AB - BACKGROUND: Due to the increasing valuation and appreciation of honeydew honey in many European countries and also to existing contamination among different types of honeys, authentication is an important aspect of quality control with regard to guaranteeing the origin in terms of source (honeydew or floral) and needs to be determined. Furthermore, proteins are minor components of the honey, despite the importance of their physiological effects, and can differ according to the source of the honey. In this context, the aims of this study were to carry out protein extraction from honeydew and floral honeys and to discriminate these honeys from the same botanical species, Mimosa scabrella Bentham, through proteome comparison using two-dimensional gel electrophoresis and principal component analysis. RESULTS: The results showed that the proteome profile and principal component analysis can be a useful tool for discrimination between these types of honey using matched proteins (45 matched spots). Also, the proteome profile showed 160 protein spots in honeydew honey and 84 spots in the floral honey. CONCLUSION: The protein profile can be a differential characteristic of this type of honey, in view of the importance of proteins as bioactive compounds in honey. (c) 2017 Society of Chemical Industry. PMID- 28337741 TI - A plant-derived dehydrorotenoid: a new inhibitor of hepatitis C virus entry. AB - Emergence of drug-resistant viruses, high cost and adverse side-effects associated with the standard therapy against hepatitis C virus (HCV) infection demonstrate the need for development of well tolerated and effective antivirals. We identified and chemically characterised the dehydrorotenoid boeravinone H, isolated from the herb Boerhavia diffusa, as a new inhibitor of HCV entry. The compound significantly inhibits the binding and entry of hepatitis C-like particles (HCV-LPs) in hepatoma cells in vitro with no apparent cytotoxicity. Boeravinone H inhibits the initial phase of HCV entry probably by acting directly on the viral particle. Importantly, the compound prevents HCV entry and infection in cell culture (ex vivo). Thus, boeravinone H is a potential antiviral agent for the prevention and control of HCV infection. PMID- 28337743 TI - New indices of left ventricular function: let's move from ejection fraction to more physiological parameters. PMID- 28337742 TI - Post-cardiac arrest level of free-plasma DNA and DNA-histone complexes. AB - BACKGROUND: Plasma DNA-histone complexes and total free-plasma DNA have the potential to quantify the ischaemia-reperfusion damages occurring after cardiac arrest. Furthermore, DNA-histone complexes may have the potential of being a target for future treatment. The aim was to examine if plasma DNA-histone complexes and the levels of total free-plasma DNA were elevated in post-cardiac arrest patients compared with healthy individuals, and to examine if these biomarkers were capable of predicting mortality. METHODS: We included 42 comatose out-of-hospital cardiac arrest patients and collected blood samples after 22, 46 and 70 h. Samples for DNA-histone complexes were quantified by Cell Death Detection ELISAplus . The total free-plasma DNA analyses were quantified with qPCR by analysing the Beta-2 microglobulin gene. The control group comprised 40 healthy individuals. RESULTS: We found no difference in the level of DNA-histone complexes between the 22-h sample and healthy individuals (P = 0.10). In the 46-h sample, there was an increased level of DNA-histone complexes in non-survivors compared with survivors 30 days after the cardiac arrest (P < 0.01) and the area under the ROC curve was 0.78 (95% confidence interval: 0.59;0.96). The level of total free-plasma DNA was increased in the 22-h sample compared with healthy individuals (P < 0.001) but no significant difference was found between non survivors and survivors 30 days after the cardiac arrest (all P >= 0.06). CONCLUSION: An increased level of DNA-histone complexes was associated with increased mortality and that the level of total free-plasma DNA was elevated post cardiac arrest. PMID- 28337744 TI - Knockdown of an inflorescence meristem-specific cytokinin oxidase - OsCKX2 in rice reduces yield penalty under salinity stress condition. AB - Cytokinins play a significant role in determining grain yield in plants. Cytokinin oxidases catalyse irreversible degradation of cytokinins and hence modulate cellular cytokinin levels. Here, we studied the role of an inflorescence meristem-specific rice cytokinin oxidase - OsCKX2 - in reducing yield penalty under salinity stress conditions. We utilized an RNAi-based approach to study the function of OsCKX2 in maintaining grain yield under salinity stress condition. Ultra-performance liquid chromatography-based estimation revealed a significant increase in cytokinins in the inflorescence meristem of OsCKX2-knockdown plants. To determine if there exists a correlation between OsCKX2 levels and yield under salinity stress condition, we assessed the growth, physiology and grain yield of OsCKX2-knockdown plants vis-a-vis the wild type. OsCKX2-knockdown plants showed better vegetative growth, higher relative water content and photosynthetic efficiency and reduced electrolyte leakage as compared with the wild type under salinity stress. Importantly, we found a negative correlation between OsCKX2 expression and plant productivity as evident by assessment of agronomical parameters such as panicle branching, filled grains per plant and harvest index both under control and salinity stress conditions. These results suggest that OsCKX2, via controlling cytokinin levels, regulates floral primordial activity modulating rice grain yield under normal as well as abiotic stress conditions. PMID- 28337746 TI - Thymidylate synthase is functionally associated with ZEB1 and contributes to the epithelial-to-mesenchymal transition of cancer cells. AB - Thymidylate synthase (TS) is a fundamental enzyme of nucleotide metabolism and one of the oldest anti-cancer targets. Beginning from the analysis of gene array data from the NCI-60 panel of cancer cell lines, we identified a significant correlation at both gene and protein level between TS and the markers of epithelial-to-mesenchymal transition (EMT), a developmental process that allows cancer cells to acquire features of aggressiveness, like motility and chemoresistance. TS levels were found to be significantly augmented in mesenchymal-like compared to epithelial-like cancer cells, to be regulated by EMT induction, and to negatively correlate with micro-RNAs (miRNAs) usually expressed in epithelial-like cells and known to actively suppress EMT. Transfection of EMT suppressing miRNAs reduced TS levels, and a specific role for miR-375 in targeting the TS 3'-untranslated region was identified. A particularly relevant association was found between TS and the powerful EMT driver ZEB1, the shRNA mediated knockdown of which up-regulated miR-375 and reduced TS cellular levels. The TS-ZEB1 association was confirmed in clinical specimens from lung tumours and in a genetic mouse model of pancreatic cancer with ZEB1 deletion. Interestingly, TS itself appeared to have a regulatory role in EMT in cancer cells, as TS knockdown could directly reduce the EMT phenotype, the migratory ability of cells, the expression of stem-like markers, and chemoresistance. Taken together, these data indicate that the TS enzyme is functionally linked with EMT and cancer differentiation, with several potential translational implications. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28337748 TI - Interaction of copper nanoparticles and an endophytic growth promoter Piriformospora indica with Cajanus cajan. AB - BACKGROUND: In recent years, agro-bionanotechnology has paved the way towards revolutionizing current practices in the food and agricultural fields. In the present study, the effect of copper nanoparticles (CuNPs) alone and in combination with the growth-promoting fungus Piriformospora indica on 2-week-old seedlings of Cajanus cajan was evaluated. Gelatin-coated stable CuNPs were synthesized by the chemical reduction method using hydrazine hydrate as a reducing agent. RESULTS: CuNPs were characterized by using UV-visible spectroscopy, zeta potential measurement and transmission electron microscopy. The nanoparticles were found to be quite spherical with a diameter within the range 40 +/- 10 nm. After the application of CuNPs and P. indica to the host plant C. cajan, the vitality of plants was determined using a Handy-PEA (plant efficiency analyzer) instrument. Handy-PEA analysis (which measures chlorophyll a fluorescence) indicated that seedlings inoculated with a combination of CuNPs and P. indica were the healthiest and also showed maximum vitality as compared to seedlings inoculated with CuNPs or P. indica alone. CONCLUSION: These results suggest that CuNPs in combination with P. indica can serve as a nanobiofertilizer for enhancement of the growth and productivity of C. cajan. (c) 2017 Society of Chemical Industry. PMID- 28337749 TI - Branched I antigens on leukemia cells enhanced sensitivity against natural killer cell cytotoxicity through affecting the target-effector interaction. AB - BACKGROUND: The aberrant glycosylation on proteins and lipids has been implicated in malignant transformations for promoting the tumorigenesis, metastasis, and evasion from the host immunity. The I-branching beta-1,6-N acetylglucosaminyltransferase, converting the straight i to branched I histo blood group antigens, reportedly could influence the migration, invasion, and metastasis of solid tumors. STUDY DESIGN AND METHODS: We first chose the highly cytotoxic natural killer (NK)-92MI cells as effector against leukemia for this cell line has been used in several clinical trials. Fluorescence-activated cell sorting and nonradioactive cytotoxicity assay were performed to reexamine the role of NK-activating receptors, their corresponding ligands, and the tumor associated carbohydrate antigens in this NK-92MI-leukemia in vitro system. The I role on cytotoxic mechanism was further studied especially on the effector-target interactions by cytotoxic analysis and conjugate formation assay. RESULTS: We showed that expression levels of leukemia surface ligands for NK-activating receptors did not positively reflect susceptibility to NK-92MI. Instead, the expression of I antigen on the leukemia cells was found important in mediating the susceptibility to NK targeting by affecting the interaction with effector cells. Furthermore, susceptibility was shown to dramatically increase while overexpressing branched I antigens on the I- cells. By both conjugate and cytotoxicity assay, we revealed that the presence of I antigen on leukemia cells enhanced the interaction with NK-92MI cells, increasing susceptibility to cell mediated lysis. CONCLUSION: In our system, branched I antigens on the leukemia were involved in the immunosurveillance mediated by NK cells specifically through affecting the effector-target interaction. PMID- 28337747 TI - Structure-dependent effects of amyloid-beta on long-term memory in Lymnaea stagnalis. AB - Amyloid-beta (Abeta) peptides are implicated in the causation of memory loss, neuronal impairment, and neurodegeneration in Alzheimer's disease. Our recent work revealed that Abeta 1-42 and Abeta 25-35 inhibit long-term memory (LTM) recall in Lymnaea stagnalis (pond snail) in the absence of cell death. Here, we report the characterization of the active species prepared under different conditions, describe which Abeta species is present in brain tissue during the behavioral recall time point and relate the sequence and structure of the oligomeric species to the resulting neuronal properties and effect on LTM. Our results suggest that oligomers are the key toxic Abeta1-42 structures, which likely affect LTM through synaptic plasticity pathways, and that Abeta 1-42 and Abeta 25-35 cannot be used as interchangeable peptides. PMID- 28337750 TI - Efficacy and safety of the drugs used to reverse direct oral anticoagulants: a systematic review and meta-analysis. AB - BACKGROUND: Direct oral anticoagulants (DOACs) are effective and safe for prophylaxis and treatment of thromboembolic phenomena. However, managing DOACs during bleeding emergencies is challenging. A systematic review and meta-analysis was conducted on studies addressing efficacy and safety of the drugs used for reversal of DOACs. STUDY DESIGN AND METHODS: Medline, Embase, Cochrane Library, and ClinicalTrials.gov were searched up to September 2016. Studies that examined clinical and laboratory effects of drugs used to reverse DOACs were included. Risk of bias was assessed using Newcastle-Ottawa scale and Cochrane Collaboration tool. Primary and secondary outcomes assessed were reversal of clinical bleeding, clotting assays, and safety, respectively. Overall effect estimates were pooled, and clinical and statistical heterogeneity were assessed. Meta-analysis was conducted using random-effects model. RESULTS: Four cohort studies in bleeding patients (n = 230) and eight randomized controlled trials in healthy volunteers (n = 381) were included, both with moderate risk of bias. Reversal of clotting assays in healthy volunteers was frequently reported, demonstrating that prothrombin complex concentrate (PCC) reversed prothrombin time (PT) and endogenous thrombin potential (ETP) substantially. For PT, pooled mean difference was 1.68 seconds (95% confidence interval [CI], -0.33 to 3.70 sec; p < 0.01; I2 = 97%). For ETP, pooled mean difference was 2.16 seconds (95% CI, 0.57 to 3.75 sec; p < 0.01; I2 = 98%). Andexanet alfa and idarucizumab both reverse clotting assays. No important safety concerns were identified. CONCLUSIONS: Clotting assays are partially reversed by PCC in healthy volunteers. Idarucizumab and andexanet alfa have solid laboratory reversal effect and potential to be clinically efficacious and safe. However, clinical evidence is still lacking for all agents. PMID- 28337752 TI - Report of the editors-2016. PMID- 28337756 TI - Issue Information - Info for Authors. PMID- 28337751 TI - A novel network analysis tool to identify relationships between disease states and risks for red blood cell alloimmunization. AB - We hypothesized that diagnoses may be associated with alloantibody 'responder' status and examined associations between disease states and alloimmunization. Patients with >=1 alloantibody and non-alloimmunized controls were analysed. Pearson's coefficients were calculated to determine associations between alloimmunization and diseases; significant correlations were selected to construct a network. Inflammatory disorders and diseases requiring chronic transfusion support were associated with responder status. Mitigation steps may be considered in patients with these disorders. PMID- 28337745 TI - Placental phenotype and the insulin-like growth factors: resource allocation to fetal growth. AB - The placenta is the main determinant of fetal growth and development in utero. It supplies all the nutrients and oxygen required for fetal growth and secretes hormones that facilitate maternal allocation of nutrients to the fetus. Furthermore, the placenta responds to nutritional and metabolic signals in the mother by altering its structural and functional phenotype, which can lead to changes in maternal resource allocation to the fetus. The molecular mechanisms by which the placenta senses and responds to environmental cues are poorly understood. This review discusses the role of the insulin-like growth factors (IGFs) in controlling placental resource allocation to fetal growth, particularly in response to adverse gestational environments. In particular, it assesses the impact of the IGFs and their signalling machinery on placental morphogenesis, substrate transport and hormone secretion, primarily in the laboratory species, although it draws on data from human and other species where relevant. It also considers the role of the IGFs as environmental signals in linking resource availability to fetal growth through changes in the morphological and functional phenotype of the placenta. As altered fetal growth is associated with increased perinatal morbidity and mortality and a greater risk of developing adult-onset diseases in later life, understanding the role of IGFs during pregnancy in regulating placental resource allocation to fetal growth is important for identifying the mechanisms underlying the developmental programming of offspring phenotype by suboptimal intrauterine growth. PMID- 28337757 TI - Death receptor 3 signaling enhances proliferation of human regulatory T cells. AB - Exploiting regulatory T cells (Tregs) to control aberrant immune reactions is a promising therapeutic approach, but is hampered by their relative paucity. In mice, activation of death receptor 3 (DR3), a member of the TNF-receptor superfamily (TNFRSF), increases Treg frequency and efficiently controls exuberant immune activation. For human Tregs, neither DR3 expression nor potential functions have been described. Here, we show that human Tregs express DR3 and demonstrate DR3-mediated activation of p38, ERK, and NFkappaB. DR3 stimulation enhances Treg expansion ex vivo while retaining their suppressive capacity. In summary, our results establish a functional role for DR3 signaling in human Tregs and could potentially help to tailor Treg-based therapies. PMID- 28337758 TI - Novel immunoassays to detect methionine adenosyltransferase activity and quantify S-adenosylmethionine. AB - We present a novel real-time immunoassay to measure methionine adenosyltransferase (MAT) activity that integrates the MAT-catalyzed reaction of Met and adenosine triphosphate to produce S-adenosylmethionine (SAM) and a highly sensitive immunoassay to specifically quantify SAM simultaneously. The cellular localization of SAM and S-adenosylhomocysteine varies with cell proliferation status: in normal cells, they are found mostly in the cytoplasm, but localize to the nucleus in proliferating cells. MAT-I/III activity is stimulated by Met, but inhibited by S-nitrosoglutathione, and the methylation index (MI) increases after Met stimulation of L02 cells. Met and S-nitrosoglutathione inhibit MAT-II activity, and the MI decreases after Met stimulation of HepG2 cells. The method described provides a significant advancement in the field for the measurement of MAT activity under various conditions. PMID- 28337760 TI - Proteomics of contrasting rice genotypes: Identification of potential targets for raising crops for saline environment. AB - High salinity is one of the major problems in crop productivity, affecting seed germination as well as yield. In order to enhance tolerance of crops towards salinity, it is essential to understand the underlying physiological and molecular mechanisms. In this endeavor, study of contrasting genotypes of the same species differing in their response towards salinity stress can be very useful. In the present study, we have investigated temporal differences in morphological, physiological and proteome profiles of two contrasting genotypes of rice to understand the basis of salt tolerance. When compared to IR64 rice, Pokkali, the salt-tolerant wild genotype, has enhanced capacity to cope with stress, better growth rate and possesses efficient antioxidant system, as well as better photosynthetic machinery. Our proteome studies revealed a higher and an early abundance of proteins involved in stress tolerance and photosynthesis in Pokkali in comparison with IR64, which, in contrast, showed greater changes in metabolic machinery even during early duration of stress. Our findings suggest important differences in physicochemical and proteome profiles of the two genotypes, which may be the basis of observed stress tolerance in the salt tolerant Pokkali. PMID- 28337759 TI - Modulation of Escherichia coli serine acetyltransferase catalytic activity in the cysteine synthase complex. AB - In bacteria and plants, serine acetyltransferase (CysE) and O-acetylserine sulfhydrylase-A sulfhydrylase (CysK) collaborate to synthesize l-Cys from l-Ser. CysE and CysK bind one another with high affinity to form the cysteine synthase complex (CSC). We demonstrate that bacterial CysE is activated when bound to CysK. CysE activation results from the release of substrate inhibition, with the Ki for l-Ser increasing from 4 mm for free CysE to 16 mm for the CSC. Feedback inhibition of CysE by l-Cys is also relieved in the bacterial CSC. These findings suggest that the CysE active site is allosterically altered by CysK to alleviate substrate and feedback inhibition in the context of the CSC. PMID- 28337761 TI - Depression and cognitive deficits as long-term consequences of thrombotic thrombocytopenic purpura. AB - BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is an acute life threatening microangiopathy with a tendency of relapse characterized by consumptive thrombocytopenia, microangiopathic hemolytic anemia, and spontaneous von Willebrand factor-induced platelet clumping leading to microthrombi. The brain is frequently affected by microthrombi leading to neurologic abnormalities of varying severity. STUDY DESIGN AND METHODS: The aim of this observational cohort study was to investigate the prevalence of depression and cognitive deficits in 104 patients having survived acute TTP. TTP survivors were repeatedly assessed by means of different standardized questionnaires to evaluate depression (IDS-SR) and mental performance (FLei). We received answers of 104 individual TTP patients and 55 of them participated in both surveys. RESULTS: Seventy-one of the 104 responding TTP patients (68%) suffered from depression and the severity of depression was similar in both surveys performed 1 year apart. Furthermore, TTP patients had considerably lower cognitive performance than controls. There was no correlation between prevalence of depression and cognitive deficits and the number and the severity of acute episodes. Impairment of mental performance correlated with the severity of depression (rs = 0.779). CONCLUSION: The prevalence of depression and cognitive deficits was significantly higher in TTP patients. Cognitive impairment seemed to be a consequence of depression, almost independently of number and severity of TTP episodes. PMID- 28337762 TI - Molecular interaction between PHO2 and GIGANTEA reveals a new crosstalk between flowering time and phosphate homeostasis in Oryza sativa. AB - Plants are often confronted to nutrient limiting conditions, such as inorganic phosphate (Pi) deficiency, resulting in a reduction in growth and yield. PHO2, encoding a ubiquitin-conjugating E2 enzyme, is a central component of the Pi starvation response signalling pathway. A yeast-two-hybrid screen using Oryza sativa (rice) PHO2 as bait, revealed an interaction between OsPHO2 and OsGIGANTEA, a key regulator of flowering time, which was confirmed using bimolecular fluorescence complementation (BiFC). Characterization of rice Osgi and Ospho2 mutants revealed that they displayed several similar phenotypic features supporting a physiological role for this interaction. Reduced growth, leaf tip necrosis, delayed flowering and over-accumulation of Pi in leaves compared to wild type were shared features of Osgi and Ospho2 plants. Pi analysis of individual leaves demonstrated that Osgi, similar to Ospho2 mutants, were impaired in Pi remobilization from old to young leaves, albeit to a lesser extent. Transcriptome analyses revealed more than 55% of the genes differentially expressed in Osgi plants overlapped with the set of differentially expressed genes in Ospho2 plants. The interaction between OsPHO2 and OsGI links high-level regulators of Pi homeostasis and development in rice. PMID- 28337764 TI - A national French noninterventional study to assess the long-term safety and efficacy of reformulated nonacog alfa. AB - BACKGROUND: Nonacog alfa, the recombinant Factor IX (F IX) used for the treatment of hemophilia B, was approved in Europe in 1998. A reformulated version was approved for European use in 2007. STUDY DESIGN AND METHODS: This postmarketing study, as recommended by the risk management plan, was conducted to confirm the safety of reformulated nonacog alfa in a usual care setting in France. This open label, noninterventional, prospective, longitudinal postmarketing study comprised 19 French hemophilia centers. Patients with hemophilia B receiving reformulated nonacog alfa for prophylaxis or on-demand treatment were followed up on usual care schedule. RESULTS: A total of 58 subjects were enrolled, of whom 29 (50%) were less than 18 years of age. Hemophilia was severe (baseline F IX activity < 1%) in 47 (81%) patients. All subjects except one were already treated with reformulated nonacog alfa before enrollment. One subject was receiving reformulated nonacog alfa as immune tolerance induction at time of enrollment. At enrollment, treatment regimen was mainly prophylactic in subjects less than 18 years and on-demand in subjects 18 years or older. Median duration of follow-up in the survey was 3.3 (2.3-3.8) years. The median annualized bleeding rate was 3.9 (1.5-5.2) for prophylaxis regimen and 12.2 (3.9-22.1) for on-demand regimen. One subject, a previously untreated patient, developed F IX inhibitors during follow-up. No allergic reaction, no blood cell agglutination, no lack of efficacy or recovery, and no thrombotic events were reported. CONCLUSION: Reformulated nonacog alfa was shown to be safe in a usual care setting. PMID- 28337763 TI - Automatic washing of thawed haematopoietic progenitor cell grafts: a preclinical evaluation. AB - BACKGROUND AND OBJECTIVES: Autologous haematopoietic progenitor cell (HPC) is a prerequisite for high-dose chemotherapy in treatment of several haematologic and non-haematologic malignancies. HPCs are collected by apheresis and cryopreserved until infusion. Postinfusion adverse events have been in part related to the dimethyl sulphoxide (DMSO) used as cryoprotectant. The aim was to evaluate (i) an automated sequential washing procedure for DMSO removal in thawed HPC grafts and (ii) washing solutions in replacement of hydroxyethyl starch (HES)-based solutions. MATERIALS AND METHODS: A total of 26 HPC bags cryopreserved with 10% DMSO and intended for disposal were used. The Sepax-2 (Biosafe, Eysins, Switzerland) was evaluated using a sequential washing procedure. Outcomes were CD34+ cell recovery and viability after washing. RESULTS: The Ringer lactate supplemented or not with albumin 2.5-5% presented satisfactory results compared with HES solution in terms of CD34+ cell recovery and viability after washing. However, the apparition of aggregates led us to renounce to these alternative solutions. Using HES solution and a sequential washing of three bags, we showed the elimination of 95% of the DMSO, a postwash viable CD34+ cell recovery of 79.9 +/- 9.4% and a total nucleated cell viability of 66.5 +/- 9.3%. CONCLUSION: The preclinical evaluation of an automated sequential washing procedure for DMSO removal in thawed HPC grafts has proven to be effective and comparable to previously published data. Despite our attempt to find an alternative solution to the HES solution, more efforts should be done on this side to reach a consensus on cryopreservation protocols. PMID- 28337765 TI - Quality control of apheresis platelets: a multicentre study to evaluate factors that can influence pH measurement. AB - BACKGROUND AND OBJECTIVES: Blood operators routinely monitor the pH of apheresis platelets as a marker of the so-called storage lesion, which can result from manufacturing problems. It is also suspected that some donor characteristics can increase the risk of poor platelet storage. To explore this hypothesis, we analysed a large, multinational data set of quality control (QC) pH test results on apheresis platelets. MATERIALS AND METHODS: For the period between September 2011 and August 2014, seven blood operators in Canada, the USA, the Netherlands, the United Kingdom, France and Australia provided pH QC test results and donor characteristics on a total of 21,671 apheresis platelets. RESULTS: Some variations in pH distribution between blood operators were in part explained by differences in collection, processing and testing methods. Younger age and female gender were significantly associated with a pH value below the 10th percentile. Among donors who had two or more pH measurements (n = 3672), there was a strong correlation between pH results (r = 0.726; P < 0.0001). CONCLUSION: The strong intradonor correlation of pH measurements and the association between donor characteristics and pH results suggest that donor factors play a role in the quality of platelets. PMID- 28337766 TI - Integration of Family Planning Services into HIV Care and Treatment Services: A Systematic Review. AB - Evidence on the feasibility, effectiveness, and cost-effectiveness of integrating family planning (FP) and HIV services has grown significantly since the 2004 Glion Call to Action. This systematic review adds to the knowledge base by characterizing the range of models used to integrate FP into HIV care and treatment, and synthesizing the evidence on integration outcomes among women living with HIV. Fourteen studies met our inclusion criteria, eight of which were published after the last systematic review on the topic in 2013. Overall, integration was associated with higher modern method contraceptive prevalence and knowledge, although there was insufficient evidence to evaluate its effects on unintended pregnancy or achieving safe and healthy pregnancy. Evidence for change in unmet need for FP was limited, although two of the three evaluations that measured unmet need suggested possible improvements associated with integrated services. However, improving access to FP services through integration was not always sufficient to increase the use of more effective (noncondom) modern methods among women who wanted to prevent pregnancy. Integration efforts, particularly in contexts where contraceptive use is low, must address community wide and HIV-specific barriers to using effective FP methods alongside improving access to information, commodities, and services within routine HIV care. PMID- 28337767 TI - Impact of drying and micronization on the physicochemical properties and antioxidant activities of celery stalk. AB - BACKGROUND: The influence of convective drying and ball-mill treatment of celery stalk on particle size distribution, physicochemical properties, bioactive compounds and antioxidant activities were analyzed in this study. RESULTS: Ball milling of celery stalk dried at temperatures of 50, 75 and 100 degrees C resulted in decreased average particle sizes of 48.8, 10.5 and 7.2 um, respectively. Bulk density was increased with reduced particle size. Darker (L*) and reddish (a*) powders were formed at higher temperatures, while ball-milling increased greenness (-a*) of powders dried at 50 and 75 degrees C. Total content of phenol compounds increased with increasing temperature. 2,2-Diphenyl-1 picrylhydrazyl radical scavenging activity and reducing power were affected by ball-milling for 24 h and drying at elevated temperatures. Iron chelating ability was unaffected by increasing temperature or reduced particle size. CONCLUSION: Increasing drying temperatures not only decreased the average particle size of powders, but also increasingly reduced particle size after ball-milling. Micronization of celery stalk dried at the highest temperature had the best antioxidant activities. Drying and ball-milling were not highly deleterious to the major phenolic structures. (c) 2017 Society of Chemical Industry. PMID- 28337769 TI - Accuracy, intra- and inter-rater reliability of three scoring systems for the glottic view at videolaryngoscopy. AB - An accurate and reproducible recording of laryngoscopic view at tracheal intubation is an important aspect of anaesthetic practice. Unlike direct laryngoscopy, in which the view achieved by the line of sight directly relates to the ease of intubating the trachea, videolaryngoscopy can create a situation in which the view is good, but intubation difficult or impossible. Communicating this to a subsequent anaesthetist is important. We compared three scoring systems: Cormack and Lehane; POGO (percentage of glottic opening); and the Fremantle score, as used by 74 critical care doctors rating 30 anonymised videos of videolaryngoscopic intubations. Accuracy (degree of agreement of score with an expert panel assessment) was higher for POGO (75.5%) and the Fremantle score (73.9%) than for Cormack and Lehane (65.4%; p < 0.001). Intra-rater reliability (mean free marginal Kappa for ordinal scores and mean Cronbach's Alpha for continuous score) was higher for Fremantle score (0.796) and Cormack and Lehane (0.773) than POGO (0.693). Inter-rater reliability for Fremantle score (0.618) and POGO (0.614) were similar and higher than the inter-rater reliability of Cormack and Lehane 0.464 (p < 0.001). The higher accuracy and inter-rater reliability of POGO and the Fremantle score suggest they are preferable to Cormack and Lehane for use when documenting videolaryngoscopy. The additional information about ease of intubation conveyed by the Fremantle score may support its routine use in recording videolaryngoscopic intubation. PMID- 28337768 TI - TET2 mutations in B cells of patients affected by angioimmunoblastic T-cell lymphoma. AB - Angioimmunoblastic T-cell lymphomas (AITLs) frequently carry mutations in the TET2 and IDH2 genes. TET2 mutations represent early genetic lesions as they had already been detected in haematopoietic precursor cells of AITL patients. We show by analysis of whole-tissue sections and microdissected PD1+ cells that the frequency of TET2-mutated AITL is presumably even higher than reported (12/13 cases in our collection; 92%). In two-thirds of informative AITLs (6/9), a fraction of B cells was also TET2-mutated. Investigation of four AITLs by TET2 and IGHV gene sequencing of single microdissected B cells showed that between 10% and 60% of polyclonal B cells in AITL lymph nodes harboured the identical TET2 mutations of the respective T-cell lymphoma clone. Thus, TET2-mutated haematopoietic precursor cells in AITL patients not only give rise to the T-cell lymphoma but also generate a large population of mutated mature B cells. Future studies will show whether this is a reason why AITL patients frequently also develop B-cell lymphomas. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28337771 TI - 5-HT7 receptor shapes spinogenesis in cortical and striatal neurons: An Editorial Highlight for 'Serotonin 5-HT7 receptor increases the density of dendritic spines and facilitates synaptogenesis in forebrain neurons'. AB - Read the highlighted article 'Serotonin 5-HT7 receptor increases the density of dendritic spines and facilitates synaptogenesis in forebrain neurons' on page 647. PMID- 28337770 TI - Hypoglycemic effect of hawthorn in type II diabetes mellitus rat model. AB - BACKGROUND: Hawthorn is a popular herb in many different traditional medicine systems, including traditional Chinese medicine, where it has long been used for the treatment of hyperglycemia. However, most of its varied biological activities remain unexplored. This study investigated the hypoglycemic effect of hawthorn extracts in type II diabetic (T2DM) rat model. A total of 54 rats were randomly divided into six groups: normal control group; type II diabetic model group (T2DM; these rats were induced by high-fat diet and streptozotocin); high, middle and low concentrations of hawthorn treatment (HTH , HTM and HTL T2DM rats were given hawthorn extract at a dose of 50, 100 and 200 mg kg-1 body weight, respectively); and positive control group (orlistat 40 mg kg-1 body weight). RESULTS: Triglyceride and total cholesterol serum levels were lower in the hawthorn extract-treated groups than in the T2DM control group (P < 0.01). Furthermore, hawthorn extracts decreased blood glucose level and increased plasma insulin release from pancreas. CONCLUSION: Positive effects of hawthorn against streptozotocin-induced T2DM were demonstrated. This study suggests that hawthorn extract represents a useful agent for the prevention or treatment of T2DM. (c) 2017 Society of Chemical Industry. PMID- 28337772 TI - Anti-fatigue activity of sea cucumber peptides prepared from Stichopus japonicus in an endurance swimming rat model. AB - BACKGROUND: Sea cucumber (Stichopus japonicus) is a well-known nutritious and luxurious seafood in Asia which has attracted increasing attention because of its nutrition and bioactivities in recent years. In this study, the anti-fatigue activity of sea cucumber peptides (SCP) prepared from S. japonicus was evaluated in a load-induced endurance swimming model. RESULTS: The SCP prepared in this study was mainly made up of low-molecular-weight peptides (<2 kDa). The analysis result of amino acid composition revealed that SCP was rich in glycine, glutamic acid and proline. The endurance capability of rats to fatigue was significantly improved by SCP treatment. Meanwhile, the remarkable alterations of energy metabolic markers, antioxidant enzymes, antioxidant capacity and oxidative stress biomarkers were normalized. Moreover, administration of SCP could modulate alterations of inflammatory cytokines and downregulate the overexpression of TRL4 and NF-kappaB. CONCLUSION: SCP has anti-fatigue activity and it exerted its anti fatigue effect probably through normalizing energy metabolism as well as alleviating oxidative damage and inflammatory responses. (c) 2017 Society of Chemical Industry. PMID- 28337773 TI - Histone H2B monoubiquitination regulates salt stress-induced microtubule depolymerization in Arabidopsis. AB - Histone H2B monoubiquitination (H2Bub1) is recognized as a regulatory mechanism that controls a range of cellular processes. We previously showed that H2Bub1 was involved in responses to biotic stress in Arabidopsis. However, the molecular regulatory mechanisms of H2Bub1 in controlling responses to abiotic stress remain limited. Here, we report that HISTONE MONOUBIQUITINATION1 (HUB1) and HUB2 played important regulatory roles in response to salt stress. Phenotypic analysis revealed that H2Bub1 mutants confer decreased tolerance to salt stress. Further analysis showed that H2Bub1 regulated the depolymerization of microtubules (MTs), the expression of PROTEIN TYROSINE PHOSPHATASE1 (PTP1) and MAP KINASE PHOSPHATASE (MKP) genes - DsPTP1, MKP1, IBR5, PHS1, and was required for the activation of mitogen-activated protein kinase3 (MAP kinase3, MPK3) and MPK6 in response to salt stress. Moreover, both tyrosine phosphorylation and the activation of MPK3 and MPK6 affected MT stability in salt stress response. Thus, the results indicate that H2Bub1 regulates salt stress-induced MT depolymerization, and the PTP-MPK3/6 signalling module is responsible for integrating signalling pathways that regulate MT stability, which is critical for plant salt stress tolerance. PMID- 28337776 TI - Approaches to expanding the two-arm biased coin randomization to unequal allocation while preserving the unconditional allocation ratio. AB - The paper discusses three methods for expanding the biased coin randomization (BCR) to unequal allocation while preserving the unconditional allocation ratio at every step. The first method originally proposed in the contexts of BCR and minimization is based on mapping from an equal allocation multi-arm BCR. Despite the improvement proposed in this paper to ensure tighter adherence to the targeted unequal allocation, this method still distributes the probability mass at least as wide as the permuted block randomization (PBR). This works for smaller block sizes, but for larger block sizes, a tighter control of the imbalance in the treatment assignments is desired. The second method, which has two versions, allows to tighten the distribution of the imbalance compared with that achieved with the PBR. However, the distribution of the imbalance remains considerably wider than that of the brick tunnel randomization - the unequal allocation procedure with the tightest possible imbalance distribution among all allocation ratio preserving procedures with the same allocation ratio. Finally, the third method, the BCR with a preset proportion of maximal forcing, mimics the properties of the equal allocation BCR. With maximum forcing, it approaches the brick tunnel randomization, similar to how 1:1 BCR approaches 1:1 PBR with the permuted block size of 2 (the equal allocation procedure with the lowest possible imbalance) when the bias approaches 1. With minimum forcing, the BCR with a preset proportion of maximal forcing approaches complete randomization (similar to 1:1 BCR). Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28337774 TI - Alumina at 50 and 13 nm nanoparticle sizes have potential genotoxicity. AB - Although nanomaterials have the potential to improve human life, their sideline effects on human health seem to be inevitable and still are unknown. Some studies have investigated the genotoxicity of alumina nanoparticles (AlNPs); however, this effect is still unclear due to insufficient evaluation and conflicting results. Using a battery of standard genotoxic assays, the present study offers evidence of the genotoxicity associated with aluminum oxide (alumina) at NP sizes of 50 and 13 nm, when compared with bulk alumina (10 MUm). The genotoxicity induced by alumina at bulk and NP sizes was evaluated with Ames test, comet test, micronucleus assay and sperm deformity test. The mechanism related to the induction of reactive oxygen species was explored as well. Our results showed that AlNPs (13 and 50 nm) were able to enter cells and induced DNA damage, micronucleus in bone marrow, sperm deformation and reactive oxygen species induction in a time-, dose- and size-dependent manner. Therefore, we conclude that AlNPs (13 and 50 nm), rather than bulk alumina, induce markers of genotoxicity in mice, with oxidative stress as a potential mechanism driving these genotoxic effects. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28337775 TI - Effectiveness and Safety Assessment of Citrate Anticoagulation During Albumin Dialysis in Comparison to Other Methods of Anticoagulation. AB - Liver failure is a serious and often deadly disease often requiring MARS (Molecular Adsorbent Recirculating System) therapy. Choosing the safe and effective method of anticoagulation during artificial liver support systems seems to be very difficult and extremely important. The aim of this study was to assess effectiveness and safety of regional anticoagulation with citrate in liver failure patients during MARS. We used a single center observational study. We analyzed 158 MARS sessions performed in 65 patients: 105 (66.5%) sessions in 41 patients with heparin anticoagulation, 40 (25.3%) sessions in 19 patients with citrate, and 13 (8%) sessions in only five patients without anticoagulation, that were excluded from part of the analysis. To determine the effectiveness of regional anticoagulation with citrate, probability of filter survival and changes in laboratory parameters were analyzed according to the applied method of anticoagulation. The safety of citrate was determined by Ca/Ca2+ ratio, acid-base balance, bleeding complications, and the need for blood product transfusions. The probability of filter survival in the citrate group was 94% and in the heparin group 82% (P = 0.204). There was no relationship between the method of anticoagulation and effectiveness of MARS therapy in lowering the levels of the analyzed parameters. Only one patient had a Ca/Ca2+ ratio higher than he safety margin. There were no statistically significant changes in pH and lactate level irrespective of anticoagulation; bicarbonate dropped significantly only in the heparin group (P = 0.03). The frequency of bleeding complications and the need for transfusions did not differ significantly between groups. Regional anticoagulation with citrate can be an effective and safe method of anticoagulation during MARS therapy, but requires attentive monitoring and further studies in liver failure patients. PMID- 28337777 TI - Syringocystadenocarcinoma papilliferum: Clinicopathologic analysis of 10 cases. AB - BACKGROUND: Syringocystadenocarcinoma papilliferum (SCACP) is an exceedingly rare cutaneous adnexal neoplasm. We aimed to investigate the clinicopathologic and immunophenotypic features of SCACP, and to discuss the prognosis of this rare entity. METHOD: We retrospectively collected clinical, pathological and follow-up data of 10 cases with SCACP. RESULTS: There were 8 males and 2 females, with ages ranging from 26 to 74 years. The chest was most frequently involved. Histologically, 1 case only showed SCACP in situ, 9 cases presented with variable invasive components of adenocarcinoma and/or squamous cell carcinoma in addition to areas of in situ. Apocrine differentiation with decapitation was evident in 4 cases and mucinous metaplasia was noted in 1 case. P63 was positive in invasive squamous cell carcinoma, while CK7 was variably positive in invasive adenocarcinoma. Regional lymph node metastasis was confirmed by pathological examination in 4 patients. Follow up was available for 9 patients, ranging from 3 to 112 months. Three patients died of the disease within 1 year after recurrences. CONCLUSIONS: Because of high rates of regional lymph node metastasis and mortality in our patients, clinical behavior of SCACP seems to be more aggressive than that previously reported. PMID- 28337779 TI - The chemistry, function and (patho)physiology of stratum corneum barrier ceramides. AB - Research on understanding of the chemistry, function and (patho)physiology of stratum corneum (SC) lipids and especially ceramides has evolved over the last two decades. This has been made successful through the application of separation techniques that have become increasingly more sophisticated, and it has become increasingly evident that our understanding of these molecules remains in its infancy. Thirteen classes of ceramides with over 300 and possibly up to 1000 distinct ceramide species have been identified suggesting an exquisitely subtle relationship between the types of ceramides and physical and chemical behaviour. Nevertheless, research has demonstrated the importance of the correct SC lipid lamellar architecture with conformationally-ordered lipid bilayers, the presence of long-chain ceramides, as either free or covalently bound lipids, greater quantities of phytosphingosine-containing ceramides and a high SC lipid/protein ratio is essential for optimal barrier function. These features are known to change in a variety of physiological and pathophysiological conditions. Clearly, there is more to be learned but as we further decipher the complexity of SC lipids and understand their individual roles in the SC, we will learn how to better treat the disorders of cornification. PMID- 28337778 TI - Biochemical alterations in duckweed and algae induced by carrier solvents: Selection of an appropriate solvent in toxicity testing. AB - Carrier solvents are often used in aquatic toxicity testing for test chemicals with hydrophobic properties. However, the knowledge of solvent effects on test organisms remains limited. The present study aimed to determine the biochemical effects of the 4 common solvents methanol, ethanol, acetone, and dimethyl sulfoxide (DMSO) on 2 test species, Lemna minor and Raphidocelis subcapitata, by applying Fourier transform infrared spectroscopy (FTIR) coupled with multivariate analysis to select appropriate solvents for toxicity testing. The results showed biochemical variations associated with solvent treatments at different doses on test species. From the infrared spectra obtained, the structures of lipid membrane and protein phosphorylation in the test species were found to be sensitive to the solvents. Methanol and ethanol mainly affected the protein secondary structure, whereas acetone and DMSO primarily induced alterations in carbohydrates and proteins in the test species. The FTIR results demonstrated that methanol and ethanol showed higher biochemical alterations in the test species than acetone and DMSO, especially at the high doses (0.1 and 1% v/v). Based on the growth inhibition displayed and FTIR spectroscopy, acetone, and DMSO can be used as carrier solvents in toxicity testing when their doses are lower than 0.1% v/v. Environ Toxicol Chem 2017;36:2631-2639. (c) 2017 SETAC. PMID- 28337780 TI - Mechanisms of resistance to quinolones in Salmonella Typhimurium from patients with infectious diarrhea. AB - This study investigated the mechanisms of resistance of 36 quinolone-resistant Salmonella Typhimurium strains isolated from outpatients with infectious diarrhea in Beijing Tian Tan Hospital between 2013 and 2015. The resistance spectrum of the 36 strains was measured using a broth dilution method. Class 1 integrons harboring the beta-lactamase gene and mutations in quinolone resistance determining regions were also investigated. All 36 quinolone-resistant Salmonella Typhimurium strains were found to be multidrug-resistant and the majority of these strains harbored Class 1 integrons. These findings study suggests that strategies for determining resistance spectrums should be implemented with greater urgency. PMID- 28337782 TI - Three-dimensional oxygen-enhanced MRI of the human lung at 1.5T with ultra-fast balanced steady-state free precession. AB - PURPOSE: To assess the feasibility of 3D oxygen-enhanced (OE) MRI of the lung at 1.5T using multi-volumetric ultra-fast balanced steady-state free precession (ufSSFP) acquisitions. METHODS: Isotropic imaging of the lung for OE-MRI was performed with an adapted 3D ufSSFP sequence using five breath-hold acquisitions ranging from functional residual capacity to tidal inspiration under both normoxic (room air) and hyperoxic (100% O2 ) gas conditions. For each O2 concentration, a sponge model (which captures the parenchymal signal intensity variation as a function of the lung volume) was fitted to the acquired multi volumetric datasets after semiautomatic lung segmentation and deformable image registration. From the retrieved model parameters, 3D oxygen-enhancement maps were calculated. RESULTS: For OE ufSSFP imaging, the maximum parenchymal signal is observed for flip angles around 23 degrees under both normoxic and hyperoxic conditions. It is found that the sponge model accurately describes parenchymal signal at different breathing positions, thereby mitigating the confounding bias in the estimated oxygen enhancement from residual density modulations. From the model, an average lung oxygen enhancement of 7.0% +/- 0.3% was found in the healthy volunteers, and the oxygen-enhancement maps indicate a ventral to dorsal gravitation-related gradient. CONCLUSION: The study demonstrates the feasibility of whole-lung OE-MRI from multi-volumetric ufSSFP in healthy volunteers. Magn Reson Med 79:246-255, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28337783 TI - Primary cutaneous anaplastic large cell lymphoma with intralymphatic involvement associated with chronic lymphedema. AB - Chronic lymphedema predisposes to develop malignant cutaneous tumors, including angiosarcoma, Kaposi's sarcoma and B-cell lymphoma. T-cell malignancy has rarely been associated with chronic lymph stasis. Here, we report a case of primary cutaneous anaplastic large cell lymphoma (pcALCL) with lymphatic spread associated with chronic lymphedema. The patient is a 56-year-old man who received orchiectomy and right inguinal lymphadenectomy for malignant seminoma 10 years ago, which led to prominent lymphedema of the right leg. He developed extensive skin nodules on the lymphedematous area for 3 months. Histopathology findings confirmed a diagnosis of pcALCL, which is a subtype of cutaneous T-cell lymphoma characterized by the presence of CD30+ T cells. Intralymphatic infiltration of malignant cells is prominent. The pathogenesis of intralymphatic cutaneous anaplastic large cell lymphoma is largely unknown. Our case suggests that chronic lymphedema resulted in persistent CD4+ T-cell inflammation, which then may contribute to the development of pcALCL. PMID- 28337781 TI - Rationale and design of a multicenter, international and collaborative Coronary Artery Aneurysm Registry (CAAR). AB - : Coronary artery aneurysm is defined as a coronary dilation that exceeds the diameter of adjacent segments or the diameter of the patient's largest normal coronary vessel by 1.5*. It is an uncommon disease that has been diagnosed with increasing frequency since the widespread appearance of coronary angiography. The published incidence varies from 1.5% to 5%, suggesting male dominance and a predilection for the right coronary artery. Although several causes have been described, atherosclerosis accounts for >=50% of coronary aneurysms in adults. Reported complications include thrombosis and distal embolization, rupture, and vasospasm, causing ischemia, heart failure, or arrhythmias. The natural history and prognosis remain unknown, as definitive data are scarce. Controversies persist regarding the use of medical management (antithrombotic therapy) or interventional/surgical procedures. Only some case reports or small case series are available about this condition. The Coronary Artery Aneurysm Registry (CAAR; http://www.ClinicalTrials.gov NCT02563626) is a multicenter international ambispective registry that aims to provide insights on anatomic, epidemiologic, and clinical aspects of this substantially unknown entity. In addition, the registry will assess management strategies (conservative, interventional, or surgical) and their short- and long-term results in a large cohort of patients. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov. Unique identifier: NCT02563626. PMID- 28337784 TI - Response to Letter to the Editor regarding the manuscript "Expression of programmed cell death-1 and its ligand B7 homolog 1 in peripheral blood lymphocytes from patients with peripartum cardiomyopathy". PMID- 28337786 TI - Vulnerable Emotional Expression In Emotion Focused Couples Therapy: Relating Interactional Processes To Outcome. AB - This study examined whether interactions characterized by high expression of emotional vulnerability in one partner followed by a highly supportive response style by the other partner predicted greater improvement on domains of forgiveness, unfinished business, trust, and relationship satisfaction in a sample of 32 couples presenting for Emotion Focused Couples Therapy with unresolved emotional injuries. For each outcome measure, two separate hierarchical regression models were tested (injured partner vulnerability and offending partner supportiveness; offending partner vulnerability and injured partner supportiveness). Both models significantly predicted improvement on the majority of outcome measures. Practice suggestions for working with emotionally injured couples are provided in light of the findings. PMID- 28337785 TI - Transcriptomic and metabolic analyses provide new insights into chilling injury in peach fruit. AB - Low temperature conditioning (LTC) alleviates peach fruit chilling injury but the underlying molecular basis is poorly understood. Here, changes in transcriptome, ethylene production, flesh softening, internal browning and membrane lipids were compared in fruit maintained in constant 0 degrees C and LTC (pre-storage at 8 degrees C for 5 d before storage at 0 degrees C). Low temperature conditioning resulted in a higher rate of ethylene production and a more rapid flesh softening as a result of higher expression of ethylene biosynthetic genes and a series of cell wall hydrolases. Reduced internal browning of fruit was observed in LTC, with lower transcript levels of polyphenol oxidase and peroxidase, but higher lipoxygenase. Low temperature conditioning fruit also showed enhanced fatty acid content, increased desaturation, higher levels of phospholipids and a preferential biosynthesis of glucosylceramide. Genes encoding cell wall hydrolases and lipid metabolism enzymes were coexpressed with differentially expressed ethylene response factors (ERFs) and contained ERF binding elements in their promoters. In conclusion, LTC is a special case of cold acclimation which increases ethylene production and, operating through ERFs, promotes both softening and changes in lipid composition and desaturation, which may modulate membrane stability, reducing browning and contributing to alleviation of peach fruit chilling injury. PMID- 28337787 TI - Hepatobiliary and Pancreatic: Gastric outlet obstruction from pancreatitis induced intramural duodenal haematoma. PMID- 28337788 TI - Gastrointestinal: Intermittent chronic small bowel obstruction from a bezoar within an ileal J-pouch. PMID- 28337789 TI - Hepatobiliary and Pancreatic: Malignant rhabdoid tumor of the liver. PMID- 28337790 TI - Gastrointestinal: Intractable delayed gastrointestinal bleeding after pancreatoduodenectomy. PMID- 28337791 TI - Gastrointestinal: Isolated renal pseudocyst treated with endoscopic transmural drainage. PMID- 28337793 TI - Solvent-Regulated Self-Assembly of an Achiral Donor-Acceptor Complex in Confined Chiral Nanotubes: Chirality Transfer, Inversion and Amplification. AB - A chiral gelator was designed and found to form chiral nanotwists and nanotubes in toluene and DMSO, respectively, which could serve as host chiral matrices for fabricating functional soft materials. Achiral, pi-conjugated donor and acceptor guests were doped into the gel, and solvent-regulated self-assembly was observed. Although both the DMSO and toluene gels containing three components look similar as transparent gels, it was clarified microscopically that, whereas achiral dopants self-assemble in the confined nanotubes in the DMSO gel, they only dissolve in the liquid phase in the toluene gel. The existence of the achiral donor and acceptor in different phases made their properties completely different. Chirality transfer occurred from the host chiral gel matrixes to guest achiral porphyrin in DMSO. Remarkably, the addition of C60 to the porphyrin/gelator gel could invert and further amplify the induced chirality of the porphyrin due to the formation of donor-acceptor pairs. On the other hand, no chirality transfer was observed in the toluene gel. These observations clearly unveiled the selective self-assembly of different components in distinct gel phases, which could provide new insight into the design of chiroptical soft materials. PMID- 28337795 TI - Current update on the diagnosis and management of head and neck hard tissue sarcomas. AB - Head and neck hard tissue sarcomas form a rare group of mesenchymal-derived tumours that comprise less than 1% of all head and neck neoplasms. Hard tissue sarcomas account for 20% of head and neck sarcomas and they form a heterogeneous group with a diverse origin. Unlike head and neck soft-tissue sarcomas, they have lower recurrence and mortality rates. In this study, we review the current management of head and neck hard tissue sarcomas. PMID- 28337794 TI - Muramyl Dipeptide, a Shared Structural Motif of Peptidoglycans, Is a Novel Inducer of Bone Formation through Induction of Runx2. AB - Peptidoglycan fragments released from gut microbiota can be delivered to the bone marrow and affect bone metabolism. We investigated the regulation of bone metabolism by muramyl dipeptide (MDP), which is a shared structural unit of peptidoglycans. Increased bone and mineral density by enhanced bone formation were observed in mice administered with MDP. Remarkably, pretreatment or posttreatment with MDP alleviated bone loss in RANKL-induced osteoporosis mouse models. MDP directly augmented osteoblast differentiation and bone-forming gene expression by Runx2 activation. Despite no direct effect, MDP indirectly attenuated osteoclast differentiation through downregulation of the RANKL/osteoprotegerin (OPG) ratio. MDP increased the expression of the MDP receptor, Nod2, and MDP-induced bone formation and osteoblast activation did not occur during Nod2 deficiency. Other Nod2 ligands also increased bone formation through the induction of Runx2, as MDP did. In conclusion, we suggest that MDP is a novel inducer of bone formation that could potentially be a new therapeutic molecule to protect against osteoporosis. (c) 2017 American Society for Bone and Mineral Research. PMID- 28337792 TI - Overestimation of stereo thresholds by the TNO stereotest is not due to global stereopsis. AB - PURPOSE: It has been repeatedly shown that the TNO stereotest overestimates stereo threshold compared to other clinical stereotests. In the current study, we test whether this overestimation can be attributed to a distinction between 'global' (or 'cyclopean') and 'local' (feature or contour-based) stereopsis. METHODS: We compared stereo thresholds of a global (TNO) and a local clinical stereotest (Randot Circles). In addition, a global and a local psychophysical stereotest were added to the design. One hundred and forty-nine children between 4 and 16 years old were included in the study. RESULTS: Stereo threshold estimates with TNO were a factor of two higher than with any of the other stereotests. No significant differences were found between the other tests. Bland Altman analyses also indicated low agreement between TNO and the other stereotests, especially for higher stereo threshold estimates. Simulations indicated that the TNO test protocol and test disparities can account for part of this effect. DISCUSSION: The results indicate that the global - local distinction is an unlikely explanation for the overestimated thresholds of TNO. Test protocol and disparities are one contributing factor. Potential additional factors include the nature of the task (TNO requires depth discrimination rather than detection) and the use of anaglyph red/green 3D glasses rather than polarizing filters, which may reduce binocular fusion. PMID- 28337796 TI - Direct Asymmetric Aza-Vinylogous-Type Michael Additions of Nitrones from Isatins to Nitroalkenes. AB - Nitrones commonly act as 1,3-dipoles and electrophiles to furnish valuable isoxazolidine and N-hydroxyl products, respectively. They also can be converted to nitrone ylide species and undergo [3+2] formal cycloadditions to access N hydroxyl pyrrolidines. Here, asymmetric direct aza-vinylogous-type additions of nitrones from isatins to nitroalkenes are presented, catalyzed by a bifunctional thiourea-tertiary amine, affording highly functionalized nitrones with extended carbon skeletons in excellent stereoselectivity. Notably, the nitrone moiety can be easily removed, thus furnishing the formal asymmetric alpha-functionalization of alkylamine-type substances. Moreover, the remaining electrophilic nitrone motif enables the subsequent annulations to construct spirocyclic products in high molecular complexity and diversity, which might have potential applications for drug discovery. PMID- 28337797 TI - Standardized Sophora pachycarpa Root Extract Enhances Osteogenic Differentiation in Adipose-derived Human Mesenchymal Stem Cells. AB - Bone defect is an important topic in public health. Novel therapies are based on osteogenic induction by natural antiosteoporotic compounds including plant derived estrogens. In the current study, the osteogenic potential of Sophora pachycarpa root extract (SPRE) was explored on human adipose-derived mesenchymal stem cells. Herein, adipose-derived mesenchymal stem cells were osteoinducted in the presence of increased concentrations of the extract for 21 days. Then, cell viability was evaluated by MTT assay, and the differentiated cells were stained by Alizarin Red S for calcium deposition and subjected to alkaline phosphatase (ALP) assay for enzymatic activity. To assess the expression of bone-related genes, treated cells were evaluated by real-time polymerase chain reaction. The MTT test demonstrated that SPRE had no toxic effects on the cell viability. Treating the cells with SPRE noticeably promoted ALP activity, mineralization, and mRNA expression of runt-related transcription factor 2 (RUNX2), bone gamma carboxyglutamate protein (BGLAP), secreted phosphoprotein 1 (SPP1), and collagen type I alpha 1 (COL1A1). Additionally, cells subjected to 0.1 MUg/mL SPRE showed the highest osteogenic effects. According to high-performance liquid chromatography fingerprinting of SPRE, the osteoprotective effects of SPRE is probably due to presence of phytochemicals with estrogen-like activity in the extract. Thus, SPRE might be a suitable therapeutic agent for bone defects therapy in the future research. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28337798 TI - Latent classes of polydrug and polyroute use and associations with human immunodeficiency virus risk behaviours and overdose among people who inject drugs in Tijuana, Baja California, Mexico. AB - INTRODUCTION AND AIMS: Patterns of polydrug use among people who inject drugs (PWID) may be differentially associated with overdose and unique human immunodeficiency virus (HIV) risk factors. Subgroups of PWID in Tijuana, Mexico, were identified based on substances used, route of administration, frequency of use and co-injection indicators. DESIGN AND METHODS: Participants were PWID residing in Tijuana age >=18 years sampled from 2011 to 2012 who reported injecting an illicit substance in the past month (n = 735). Latent class analysis identified discrete classes of polydrug use characterised by 11 indicators of past 6 months substance use. Multinomial logistic regression examined class membership association with HIV risk behaviours, overdose and other covariates using an automated three-step procedure in mplus to account for classification error. RESULTS: Participants were classified into five subgroups. Two polydrug and polyroute classes were defined by use of multiple substances through several routes of administration and were primarily distinguished from each other by cocaine use (class 1: 5%) or no cocaine use (class 2: 29%). The other classes consisted primarily of injectors: cocaine, methamphetamine and heroin injection (class 3: 4%); methamphetamine and heroin injection (class 4: 10%); and heroin injection (class 5: 52%). Compared with the heroin-only injection class, memberships in the two polydrug and polyroute use classes were independently associated with both HIV injection and sexual risk behaviours. DISCUSSION AND CONCLUSIONS: Substance use patterns among PWID in Tijuana are highly heterogeneous, and polydrug and polyroute users are a high-risk subgroup who may require more tailored prevention and treatment interventions. [Meacham MC, Roesch SC, Strathdee SA, Lindsay S, Gonzalez-Zuniga P, Gaines TL. Latent classes of polydrug and polyroute use and associations with human immunodeficiency virus risk behaviours and overdose among people who inject drugs in Tijuana, Baja California, Mexico. Drug Alcohol Rev 2018;37:128-136]. PMID- 28337799 TI - Bergamot (Citrus bergamia) Essential Oil Inhalation Improves Positive Feelings in the Waiting Room of a Mental Health Treatment Center: A Pilot Study. AB - Mental health issues have been increasingly recognized as public health problems globally. Their burden is projected to increase over the next several decades. Additional therapies for mental problems are in urgent need worldwide due to the limitations and costs of existing healthcare approaches. Essential oil aromatherapy can provide a cost-effective and safe treatment for many mental problems. This pilot study observed the effects of bergamot essential oil inhalation on mental health and well-being, as measured by the Positive and Negative Affect Scale, in a mental-health treatment center located in Utah, USA. Fifty-seven eligible participants (50 women, age range: 23-70 years) were included for analysis. Fifteen minutes of bergamot essential oil exposure improved participants' positive feelings compared with the control group (17% higher). Unexpectedly, more participants participated in experimental periods rather than control periods, suggesting even brief exposure to essential oil aroma may make people more willing to enroll in clinical trials. This study provides preliminary evidence of the efficacy and safety of bergamot essential oil inhalation on mental well-being in a mental health treatment center, suggesting that bergamot essential oil aromatherapy can be an effective adjunct treatment to improve individuals' mental health and well-being. (c) 2017 The Authors. Phytotherapy Research published by John Wiley & Sons Ltd. PMID- 28337800 TI - Mycoplasma infection of the middle ear in three cats. AB - BACKGROUND: Mycoplasma spp. are commensal organisms found in association with the mucus membranes of all mammalian species and are implicated in bacterial infections of many different locations. Mycoplasma spp. as a primary pathogen associated with otitis media in cats has not been reported. OBJECTIVES: To describe three cats with Mycoplasma infection of the middle ear associated with various underlying disease processes. ANIMALS: Three client-owned cats. METHODS: Clinical examination, aerobic culture of the middle ear and computed tomography or magnetic resonance imaging of the skull. RESULTS: Mycoplasma spp. were grown on aerobic culture from the middle ear of three cats. In Case 1, concurrent neoplasia of the bulla was identified. Mycoplasma alone was cultured in Case 2 and Mycoplasma was grown in addition to Bordetella in Case 3. Case 1 was euthanized, Case 2 responded to Mycoplasma targeted therapy and Case 3 responded to Bordetella targeted therapy. CONCLUSIONS AND CLINICAL IMPORTANCE: Mycoplasma infections of the middle ear may be clinically important and require targeted treatment in some cases. PMID- 28337801 TI - Cross-cultural comparisons of drinking motives in 10 countries: Data from the DRINC project. AB - INTRODUCTION AND AIMS: This study tested the measurement invariance of the Drinking Motives Questionnaire-Revised Short Form (DMQ-R-SF) in undergraduates across 10 countries. We expected the four-factor structure to hold across countries, and for social motives to emerge as the most commonly endorsed motive, followed by enhancement, coping and conformity motives. We also compared individualistic and collectivistic countries to examine potential differences in the endorsement of drinking motives when countries were divided according to this broad cultural value. DESIGN AND METHODS: A sample of 8478 undergraduate drinkers from collectivistic (Portugal, Mexico, Brazil, Spain; n = 1567) and individualistic (Switzerland, Hungary, Canada, the Netherlands, the UK and Ireland, and the USA; n = 6911) countries completed the DMQ-R-SF. Countries were classified as individualistic or collectivistic based on world-wide norms. RESULTS: Using multigroup confirmatory factor analysis, the 4-factor model of the DMQ-R-SF showed configural and metric invariance across all 10 countries. As predicted, the rank order of undergraduates' drinking motive endorsement was identical across countries (social > enhancement > coping > conformity), although a mixed model analysis of variance revealed a significant interaction where undergraduates from individualistic countries more strongly endorsed social and enhancement motives relative to undergraduates from collectivistic countries. DISCUSSION AND CONCLUSIONS: There was broad cross-cultural consistency in the factor structure and mean patterns of drinking motives. Undergraduate students appear to drink mainly for positive reinforcement (i.e. for social and enhancement reasons), although this tendency is particularly pronounced among those from more individualistic countries. [Mackinnon SP, Couture M-E, Cooper ML, Kuntsche E, O'Connor RM, Stewart SH, and the DRINC Team. Cross-cultural comparisons of drinking motives in 10 countries: Data from the DRINC project. PMID- 28337802 TI - The Snf1-activating kinase Sak1 is a key regulator of metabolic adaptation and in vivo fitness of Candida albicans. AB - The metabolic flexibility of the opportunistic fungal pathogen Candida albicans is important for colonisation and infection of different host niches. Complex regulatory networks, in which protein kinases play central roles, link metabolism and other virulence-associated traits, such as filamentous growth and stress resistance, and thereby control commensalism and pathogenicity. By screening a protein kinase deletion mutant library that was generated in the present work using an improved SAT1 flipper cassette, we found that the previously uncharacterised kinase Sak1 is a key upstream activator of the protein kinase Snf1, a highly conserved regulator of nutrient stress responses that is essential for viability in C. albicans. The sak1Delta mutants failed to grow on many alternative carbon sources and were hypersensitive to cell wall/membrane stress. These phenotypes were mirrored in mutants lacking other subunits of the SNF1 complex and partially compensated by a hyperactive form of Snf1. Transcriptional profiling of sak1Delta mutants showed that Sak1 ensures basal expression of glyoxylate cycle and gluconeogenesis genes even in glucose-rich media and thereby contributes to the metabolic plasticity of C. albicans. In a mouse model of gastrointestinal colonisation, sak1Delta mutants were rapidly outcompeted by wild type cells, demonstrating that Sak1 is essential for the in vivo fitness of C. albicans. PMID- 28337804 TI - Endo 2017: WEO's successful first World Congress of GI Endoscopy. PMID- 28337803 TI - Synthesis, Electronic Structure, and Reactivities of Two-Sulfur-Stabilized Carbones Exhibiting Four-Electron Donor Ability. AB - Bis(sulfane)carbon(0) (BSC; Ph2 S->C<-SPh2 (1)) is successfully synthesized by deprotonation of the corresponding protonated salt 1?HTfO. The diprotonated salt 1?(HTfO)2 as the starting material can be also easily accessed by the deimination of iminosulfane(sulfane)carbon(0) (iSSC)?HBF4 . Density functional theory calculations revealed the peculiar electronic structure of 1, which has two lone pairs of electrons at the central carbon atom. The largest proton affinities (PA(1): 297.5 kcal mol-1 ; PA(2): 183.7 kcal mol-1 ) and the highest energy levels of the HOMOs (HOMO: -4.89 eV; HOMO-1: -5.02 eV) for 1 among the two-sulfur stabilized carbones clearly indicate the strong donor ability of carbon center stabilized by two SII ligands. The donating ability of these lone pairs of electrons is demonstrated by the C-diaurated and C-proton-aurated complexes, which provide the first experimental evidence for two-sulfurstabilized carbones behaving as four-electron donors. Furthermore, the syntheses and application of AgI carbone complexes as carbone transfer agents are also reported. PMID- 28337805 TI - Defining the Anti-Cancer Activity of Tricarbonyl Rhenium Complexes: Induction of G2/M Cell Cycle Arrest and Blockade of Aurora-A Kinase Phosphorylation. AB - Rhenium and ruthenium complexes containing N-heterocylic carbene (NHC) ligands and conjugated to indomethacin were prepared. The anticancer properties were probed against pancreatic cell lines, revealing a remarkable activity of the rhenium fragment as anticancer agent. The ruthenium complexes were found to be inactive against the same pancreatic cancer cell lines, either alone or in conjugation with indomethacin. An in-depth biological study revealed the origin of the anticancer properties of the rhenium tricarbonyl fragment, of which a complete elucidation had yet to be achieved. It was found that the rhenium complexes induce cell cycle arrest at the G2/M phase by inhibiting the phosphorylation of Aurora-A kinase. A preliminary study on the structure-activity relationship on a large family of these complexes revealed that the anticancer properties are mainly associated with the lability of the ancillary ligand, with inert complexes showing limited to no anticancer properties. PMID- 28337806 TI - The Pharmacological Profile of a Novel Highly Potent Bisphosphonate, OX14 (1 Fluoro-2-(Imidazo-[1,2-alpha]Pyridin-3-yl)-Ethyl-Bisphosphonate). AB - Bisphosphonates are widely used in the treatment of clinical disorders characterized by increased bone resorption, including osteoporosis, Paget's disease, and the skeletal complications of malignancy. The antiresorptive potency of the nitrogen-containing bisphosphonates on bone in vivo is now recognized to depend upon two key properties, namely mineral binding affinity and inhibitory activity on farnesyl pyrophosphate synthase (FPPS), and these properties vary independently of each other in individual bisphosphonates. The better understanding of structure activity relationships among the bisphosphonates has enabled us to design a series of novel bisphosphonates with a range of mineral binding properties and antiresorptive potencies. Among these is a highly potent bisphosphonate, 1-fluoro-2-(imidazo-[1,2 alpha]pyridin-3-yl)-ethyl bisphosphonate, also known as OX14, which is a strong inhibitor of FPPS, but has lower binding affinity for bone mineral than most of the commonly studied bisphosphonates. The aim of this work was to characterize OX14 pharmacologically in relation to several of the bisphosphonates currently used clinically. When OX14 was compared to zoledronate (ZOL), risedronate (RIS), and minodronate (MIN), it was as potent at inhibiting FPPS in vitro but had significantly lower binding affinity to hydroxyapatite (HAP) columns than ALN, ZOL, RIS, and MIN. When injected i.v. into growing Sprague Dawley rats, OX14 was excreted into the urine to a greater extent than the other bisphosphonates, indicating reduced short-term skeletal uptake and retention. In studies in both Sprague Dawley rats and C57BL/6J mice, OX14 inhibited bone resorption, with an antiresorptive potency equivalent to or greater than the comparator bisphosphonates. In the JJN3-NSG murine model of myeloma-induced bone disease, OX14 significantly prevented the formation of osteolytic lesions (p < 0.05). In summary, OX14 is a new, highly potent bisphosphonate with lower bone binding affinity than other clinically relevant bisphosphonates. This renders OX14 an interesting potential candidate for further development for its potential skeletal and nonskeletal benefits. (c) 2017 American Society for Bone and Mineral Research. PMID- 28337807 TI - A Strategy for Breaking Polyoxometalate-based MOFs To Obtain High Loading Amounts of Nanosized Polyoxometalate Clusters to Improve the Performance of Dye sensitized Solar Cells. AB - Polyoxometalates (POM) have already been confirmed to act as effective electron transfer mediators for improving the power conversion efficiency (PCE) of dye sensitized solar cells (DSSCs) based on previous studies. However, the improvement may be limited by the agglomeration of the polyoxoanions. In this paper, the previous synthesis strategy is improved upon by breaking the metal organic frameworks (MOFs) with POMs as the secondary building units ([Ni(bpp)(H2 O)2 ]3 [P2 W18 O62 ]?24 H2 O (1) (bpp=1,3-bis(4-pyridyl)propane) and H6 [Cu3 (H2 O)6 (P2 W18 O62 )2 (3-dpye)6 ]?28 H2 O (2) (3-dpye=N,N'-bis(3 pyridinecarboxamide)-1,2-ethane)) to design and synthesize small sized and highly disperse POM nanoparticles by means of compositing with TiO2 , through calcination to remove the organic ligand. TEM and element mapping confirm that P2 W18 O626- (denoted as P2 W18 ) nanoparticles with the diameter of ~1 nm are uniformly distributed in TiO2 composites. The loading amount (wt. %) of POM in MOFs reaches 75.67 %. The small sized and highly disperse P2 W18 nanoparticles may provide more active sites and specific surface areas for improving the PCE of DSSCs. Finally, the investigations indicate that the PCE of composite P2 W18 ?NiO@TiO2 photoanodes is up to 7.56 %, which was 26 % higher than the pristine TiO2 based photoanodes. PMID- 28337808 TI - Low-molecular-weight heparin associated with reduced fetal fraction and subsequent false-negative cell-free DNA test result for trisomy 21. PMID- 28337812 TI - Psoriasis - What's Up ? PMID- 28337809 TI - Expanded Newborn Screening Program in Saudi Arabia: Incidence of screened disorders. AB - AIM: To address the implementation of the National Newborn Screening Program (NBS) in Saudi Arabia and stratify the incidence of the screened disorders. METHODS: A retrospective study conducted between 1 August 2005 and 31 December 2012, total of 775 000 newborns were screened from 139 hospitals distributed among all regions of Saudi Arabia. The NBS Program screens for 16 disorders from a selective list of inborn errors of metabolism (IEM) and endocrine disorders. Heel prick dry blood spot samples were obtained from all newborns for biochemical and immunoassay testing. Recall screening testing was performed for Initial positive results and confirmed by specific biochemical assays. RESULTS: A total of 743 cases were identified giving an overall incidence of 1:1043. Frequently detected disorders nationwide were congenital hypothyroidism and congenital adrenal hyperplasia with an incidence of 1:7175 and 1:7908 correspondingly. The highest incidence among the IEM was propionic acidaemia with an incidence rate of 1:14 000. CONCLUSION: The article highlights the experience of the NBS Program in Saudi Arabia and providing data on specific regional incidences of all the screened disorders included in the programme; and showed that the incidence of these disorders is one of the highest reported so far world-wide. PMID- 28337814 TI - Abstracts of Papers Presented at the Health Services Research and Pharmacy Practice Conference, University of Nottingham, UK, 10-11 April 2017. PMID- 28337810 TI - Electronic spatiotemporal image correlation improves four-dimensional fetal echocardiography. AB - OBJECTIVES: To compare the efficiency of electronic spatiotemporal image correlation (eSTIC) with that of conventional STIC to acquire four-dimensional (4D) fetal cardiac volumes of diagnostic quality. METHODS: This was a randomized controlled trial of 100 patients in mid-gestation with normal sonograms. In half of the cases, STIC volumes of the fetal heart were obtained with a conventional mechanical 4D probe and in the remaining cases eSTIC volumes were obtained with an electronic 4D probe. Examinations were kept within the timeframe allotted for a standard examination of fetal anatomy, and a maximum of two attempts were made at obtaining a 4D cardiac volume. Datasets were stored on a computer and subsequently analyzed and categorized as being of optimal, satisfactory or inadequate quality, depending on whether or not it was possible to perform an extended basic cardiac examination, including obtaining a three vessels and trachea view, as well as a clear reconstruction of both the aortic and ductal arches in the sagittal plane. RESULTS: The eSTIC volume datasets were more frequently of optimal or satisfactory diagnostic quality compared with conventional STIC (94% vs 76%, P < 0.0001). Failure to obtain an eSTIC volume of adequate quality was in all cases the consequence of an unfavorable position of the fetus. CONCLUSIONS: Compared with a standard mechanical probe, the electronic 4D probe facilitates acquisition of sonographic cardiac volumes in mid-trimester fetuses. In our hands, eSTIC volumes of optimal or satisfactory diagnostic quality, allowing a detailed offline evaluation of the fetal heart, were obtained in more than 90% of cases within the time frame of a standard examination of fetal anatomy. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28337813 TI - Health care experiences among women diagnosed with gestational breast cancer. AB - Gestational breast cancer (GBC) presents many challenges for women and the clinicians who care for them. The aim of this study was to explore the health care experiences of women diagnosed with GBC to inform and improve clinical care of women in this predicament. Semi-structured interviews were conducted with 17 women who had been diagnosed with GBC in the previous 5 years. The overarching themes for perceived quality of care were "communication" and "comprehensive care." "Communication" had two sub themes: "interdisciplinary communication" (the way health professionals from different disciplines communicated with each other about the management of the woman's care) and "patient communication" (how they communicated this to the woman). The "comprehensive care" theme incorporated three sub themes: "the spirit" (psychological care); "the mind" (information provision); and "the body" (management of treatment side effects). Women's own accounts of positive and negative experiences of GBC care provide unique and specific insights which improve understanding of their concerns and needs. The findings can inform advances in quality and efficacy of clinical care; offer guidance for obstetricians, oncologists and allied health professionals about the needs of women diagnosed with GBC and how care can be optimised; and inform the development of resources to assist women and their families. PMID- 28337816 TI - Vertebral venous system abnormalities identified with magnetic resonance imaging in sighthounds. AB - In humans, abnormalities of the vertebral venous system are considered rare but significant causes of radiculopathy and myelopathy. Published information on abnormalities of the canine vertebral venous system is currently lacking. Aims of this retrospective descriptive study were to characterize magnetic resonance imaging (MRI) abnormalities of the vertebral venous system in a population of sighthounds, report prevalence of vertebral venous system abnormalities within that population and explore possible clinical significance. Our hospital database was searched over the period of 2002-2013 for sighthounds with MRI studies of the vertebral column. Medical records and MRI studies for included dogs were retrieved and findings were recorded by a single observer. A total of 92 sighthounds were sampled. Eleven cases (prevalence 12%) showed abnormal enlargement of the internal vertebral venous plexus (10/11 unilaterally, 1/11 bilaterally), external vertebral venous plexus (7/11 cases unilaterally), and/or intervertebral veins (8/11 unilaterally, 2/11 bilaterally, and 1/11 unilaterally and bilaterally at different sites). The majority of the abnormalities were right sided and the most common location for abnormalities was C6/7. Of the 11 cases, nine did not have a definitive diagnosis. Seven of those nine cases had an abnormality in a neuroanatomical localization that could wholly or partly explain the clinical signs. Findings indicated that, while the prevalence of vertebral venous system abnormalities was low in this sample of sighthounds, the majority of dogs with these abnormalities had clinical signs that matched the location of the abnormalities. Further prospective research is needed to investigate potential underlying aetiologies for vertebral venous system abnormalities in dogs and clarify their clinical significance. PMID- 28337818 TI - Exploration of information and support needs in relation to health concerns, diet and physical activity in colorectal cancer survivors. AB - : The purpose of the current study was to explore colorectal cancer survivors' information and support needs in relation to health concerns and health behaviour change. Face-to-face interviews were conducted with participants who had completed active treatment for cancer within the previous 2 years. Participants were colorectal cancer survivors (N = 24, men = 11, women = 13 M, age = 69.38 years, SD = 4.19) recruited from a hospital in Perth, Australia on the basis that they had existing morbidities that put them at increased risk of cardiovascular disease. Interview transcripts were analysed using thematic analysis. RESULTS: Five main themes emerged: bowel changes; Lack of knowledge concerning healthy eating and physical activity; conflicting information; desire for support; and, need for simple messages and strategies to stay healthy. Where dietary recommendations were provided, these were to resolve bowel problems rather than to promote healthy eating. The provision of lifestyle advice from the oncologists is limited and patients' lack knowledge of guidelines for diet and physical activity. Oncologists could provide patients with clear messages from the World Cancer Research Fund (); that is to increase physical activity and dietary fibre and reduce consumption of red meat, processed meat, alcohol and body fatness. PMID- 28337817 TI - The Cytotoxic Effects of Camptothecin and Mastoparan on the Unicellular Green Alga Chlamydomonas reinhardtii. AB - We have recently reported that protease inhibitors affecting the activity of the proteasome cause necrotic cell death in Chlamydomonas reinhardtii instead of inducing apoptosis as shown for some mammalian cell lines. Therefore, we have studied other well-known inducers of apoptosis in mammalian cells for their effects on C. reinhardtii cells. Mastoparan caused rapid cell death without a prominent lag-phase under all growth conditions, whereas the cytotoxic effect of the topoisomerase I inhibitor camptothecin exclusively occurred during the cell division phase. Essentially no differences between wall-deficient and wild-type cells were observed with respect to dose-response and time-course of camptothecin and mastoparan. In cultures of the wall-deficient strain, cell death was accompanied by swelling and subsequent disruption of the cells, established markers of necrosis. In case of the wild-type strain, camptothecin and mastoparan caused accumulation of apparently intact, but dead cells instead of cell debris due to the presence of the wall. Both in cultures of the wall-deficient and the wild-type strains, cell death was accompanied by an increase of the protein concentration in the culture medium indicating a lytic process like necrosis. Taking together, we have severe doubts on the existence of an apoptotic program in case of C. reinhardtii. PMID- 28337820 TI - Selective Radiofrequency Stimulation of the Dorsal Root Ganglion (DRG) as a Method for Predicting Targets for Neuromodulation in Patients With Post Amputation Pain: A Case Series. AB - OBJECTIVE: While spinal cord stimulation (SCS) has established itself as an accepted and validated treatment for neuropathic pain, there are a number of conditions where it has experienced less, long-term success: post amputee pain (PAP) being one of them. Dorsal root ganglion (DRG) stimulation has shown great promise, particularly in conditions where traditional SCS has fallen short. One major difference between DRG stimulation and traditional SCS is the ability to provide focal stimulation over targeted areas. While this may be a contributing factor to its superiority, it can also be a limitation insofar stimulating the wrong DRG(s) can lead to failure. This is particularly relevant in conditions like PAP where neuroplastic maladaptation occurs causing the pain to deviate from expected patterns, thus creating uncertainty and variability in predicting targets for stimulation. We propose selective radiofrequency (RF) stimulation of the DRG as a method for preoperatively predicting targets for neuromodulation in patients with PAP. METHODS: We present four patients with PAP of the lower extremities. RF stimulation was used to selectively stimulate individual DRG's, creating areas of paresthesias to see which most closely correlated/overlapped with the painful area(s). RF stimulation to the DRG's that resulted in the desirable paresthesia coverage in the residual or the missing limb(s) was recorded as "positive." Trial DRG leads were placed based on the positive RF stimulation findings. RESULTS: In each patient, stimulating one or more DRG(s) produced paresthesias patterns that were contradictory to know dermatomal patterns. Upon completion of a one-week trial all four patients reported 60-90% pain relief, with coverage over the painful areas, and opted for permanent implant. CONCLUSIONS: Mapping the DRG via RF stimulation appears to provide improved accuracy for determining lead placement in the setting of PAP where pain patterns are known to deviate from conventional dermatomal mapping. PMID- 28337819 TI - PAI-1 in granulosa cells is suppressed directly by statin and indirectly by suppressing TGF-beta and TNF-alpha in mononuclear cells by insulin-sensitizing drugs. AB - PROBLEM: Plasminogen activator inhibitor-1 (PAI-1) is elevated in women with polycystic ovary syndrome (PCOS), but the regulation in granulosa cells (GCs) is unclear. METHOD OF STUDY: PAI-1 expression in PCOS ovaries was investigated immunohistologically. PAI-1 expressions in HGrC1, a human GC cell line, were investigated at mRNA and activity levels. The expressions of TGF-beta and TNF alpha in peritoneal fluid mononuclear cells (PFMCs) were measured with quantitative PCR. RESULTS: Little PAI-1 expression is observed in healthy GCs, whereas GCs of PCOS and atretic follicle exhibit distinct expression in vivo. In vitro study using HGrC1 shows that TGF-beta and TNF-alpha increase PAI-1 mRNA and its activity, and both together exhibit a synergistic effect. The expression of PAI-1 mRNA is suppressed by simvastatin. Moreover, insulin-sensitizing drugs (metformin, pioglitazone, and rosiglitazone) suppress LPS-induced TGF-beta and TNF-alpha mRNA expression in PFMC. CONCLUSION: Statin and insulin-sensitizing drugs may provide a potential therapy for PCOS via down-regulation of PAI-1 expression in GCs and down-regulation of TGF-beta and TNF-alpha expression in PFMC, respectively. PMID- 28337821 TI - Mindfulness-based stress reduction added to care as usual for lung cancer patients and/or their partners: A multicentre randomized controlled trial. AB - OBJECTIVE: Lung cancer patients report among the highest distress rates of all cancer patients. Partners report similar distress rates. The present study examined the effectiveness of additional mindfulness-based stress reduction (care as usual [CAU] + MBSR) versus solely CAU to reduce psychological distress in lung cancer patients and/or their partners. METHODS: We performed a multicentre, parallel-group, randomized controlled trial. Mindfulness-based stress reduction is an 8-week group-based intervention, including mindfulness practice and teachings on stress. Care as usual included anticancer treatment, medical consultations, and supportive care. The primary outcome was psychological distress. Secondary outcomes included quality of life, caregiver burden, relationship satisfaction, mindfulness skills, self-compassion, rumination, and posttraumatic stress symptoms. Outcomes were assessed at baseline, post intervention, and 3-month follow-up. Linear mixed modeling was conducted on an intention-to-treat sample. Moderation (gender, disease stage, baseline distress, participation with/without partner) and mediation analyses were performed. RESULTS: A total of 31 patients and 21 partners were randomized to CAU + MBSR and 32 patients and 23 partners to CAU. After CAU + MBSR patients reported significantly less psychological distress (p = .008, d = .69) than after CAU. Baseline distress moderated outcome: those with more distress benefitted most from MBSR. Additionally, after CAU + MBSR patients showed more improvements in quality of life, mindfulness skills, self-compassion, and rumination than after CAU. In partners, no differences were found between groups. CONCLUSION: Our findings suggest that psychological distress in lung cancer patients can be effectively treated with MBSR. No effect was found in partners, possibly because they were more focused on patients' well-being rather than their own. PMID- 28337823 TI - Interest of the trajectory method for the evaluation of outcomes after in utero drug exposure: example of anxiolytics and hypnotics. AB - PURPOSE: The aim of this study was to examine the potential benefit to take into account duration and intensity of drug exposure using the recently published method based on individual drug trajectories. This approach was used to define profiles of exposure to anxiolytics/hypnotics during pregnancy and to evaluate the potential effect on newborn health. METHODS: The study was performed in EFEMERIS database (54 918 mother-children pairs). An estimation of adaptation to extrauterine life was assessed using several criteria especially cardio respiratory symptoms. A proxy variable called "neonatal pathology" was created. The occurrence of this event was studied using two approaches: The Standard Method comparing exposed and unexposed newborns, The Trajectory Method comparing the different profiles of exposure. RESULTS: Around 5% of newborns (n = 2768) were identified to be exposed to anxiolytics or hypnotics during pregnancy. Using the Standard Method, 6.2% of exposed newborns developed a "neonatal pathology" against 4.8% of unexposed newborns (odds ratios [OR] = 0.9[0.8-1.2], p = 0.7). With the Trajectory Method taking into account evolution of exposure during pregnancy and treatment intensity, four profiles of pregnant women were identified. A significant difference in the rates of "neonatal pathologies" was observed between profiles (p = 0.0002). Newborns of the two profiles exposed in utero to high constant level of anxiolytics or hypnotics were more at risk of developing "neonatal pathology" than unexposed newborns (OR1 = 2.0 [1.0-3.9] and OR2 = 7.6 [2.8-20.5]). CONCLUSIONS: The present study demonstrates the interest of this method based on individual drug trajectories for the evaluation of outcomes in pharmaco-epidemiological studies and more specifically during pregnancy. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28337826 TI - Diagnostic outcome of contrast videofluoroscopic swallowing studies in 216 dysphagic dogs. AB - Determining the anatomic and functional origin for dysphagia is critical for development of an appropriate therapeutic plan and determination of the prognosis. The purpose of this retrospective study was to report the quantitative and qualitative outcome of contrast videofluoroscopic swallowing studies in a large cohort of dysphagic dogs presenting to a tertiary veterinary care hospital. The videofluoroscopic swallowing studies were reviewed to generate values for pharyngeal constriction ratio, timing of swallowing events (maximum pharyngeal contraction, opening of upper esophageal sphincter, closing of upper esophageal sphincter, and reopening of epiglottis), type of esophageal peristalsis generated, and esophageal transit time. One or more anatomic locations for origin of dysphagia were assigned (pharyngeal, cricopharyngeal, esophageal (primary motility disorder), other esophageal (stricture, vascular ring anomaly, mass), lower esophageal sphincter/hiatus. Sixty-one of 216 studies (28%) were deemed unremarkable. Twenty-seven of 216 dogs (13%) had pharyngeal dysphagia, 17/216 dogs (8%) had cricopharyngeal dysphagia, 98/216 dogs (45%) had dysphagia secondary to esophageal dysmotility, 19/216 dogs (9%) had dysphagia secondary to focal esophageal disorders, and 97/216 dogs (45%) had dysphagia of lower esophageal sphincter/hiatus origin. Multiple abnormalities were present in 82/216 (38%) dogs. Elevated pharyngeal constriction ratio was associated with pharyngeal, cricopharyngeal, and esophageal motility disorders, delayed upper esophageal sphincter opening was associated with cricopharyngeal disorders, a lower percentage of primary esophageal peristaltic waves was associated with cricopharyngeal, pharyngeal, or primary esophageal motility disorders. In conclusion, videofluoroscopic swallowing studies was pivotal in the diagnosis of dysphagia with 155/216 (72%) dogs receiving a final diagnosis. PMID- 28337822 TI - UniEuk: Time to Speak a Common Language in Protistology! AB - Universal taxonomic frameworks have been critical tools to structure the fields of botany, zoology, mycology, and bacteriology as well as their large research communities. Animals, plants, and fungi have relatively solid, stable morpho taxonomies built over the last three centuries, while bacteria have been classified for the last three decades under a coherent molecular taxonomic framework. By contrast, no such common language exists for microbial eukaryotes, even though environmental '-omics' surveys suggest that protists make up most of the organismal and genetic complexity of our planet's ecosystems! With the current deluge of eukaryotic meta-omics data, we urgently need to build up a universal eukaryotic taxonomy bridging the protist -omics age to the fragile, centuries-old body of classical knowledge that has effectively linked protist taxa to morphological, physiological, and ecological information. UniEuk is an open, inclusive, community-based and expert-driven international initiative to build a flexible, adaptive universal taxonomic framework for eukaryotes. It unites three complementary modules, EukRef, EukBank, and EukMap, which use phylogenetic markers, environmental metabarcoding surveys, and expert knowledge to inform the taxonomic framework. The UniEuk taxonomy is directly implemented in the European Nucleotide Archive at EMBL-EBI, ensuring its broad use and long-term preservation as a reference taxonomy for eukaryotes. PMID- 28337824 TI - Phenotype-genotype correlations of PIGO deficiency with variable phenotypes from infantile lethality to mild learning difficulties. AB - Inherited GPI (glycosylphosphatidylinositol) deficiencies (IGDs), a recently defined group of diseases, show a broad spectrum of symptoms. Hyperphosphatasia mental retardation syndrome, also known as Mabry syndrome, is a type of IGDs. There are at least 26 genes involved in the biosynthesis and transport of GPI anchored proteins; however, IGDs constitute a rare group of diseases, and correlations between the spectrum of symptoms and affected genes or the type of mutations have not been shown. Here, we report four newly identified and five previously described Japanese families with PIGO (phosphatidylinositol glycan anchor biosynthesis class O) deficiency. We show how the clinical severity of IGDs correlates with flow cytometric analysis of blood, functional analysis using a PIGO-deficient cell line, and the degree of hyperphosphatasia. The flow cytometric analysis and hyperphosphatasia are useful for IGD diagnosis, but the expression level of GPI-anchored proteins and the degree of hyperphosphatasia do not correlate, although functional studies do, with clinical severity. Compared with PIGA (phosphatidylinositol glycan anchor biosynthesis class A) deficiency, PIGO deficiency shows characteristic features, such as Hirschsprung disease, brachytelephalangy, and hyperphosphatasia. This report shows the precise spectrum of symptoms according to the severity of mutations and compares symptoms between different types of IGD. PMID- 28337827 TI - Prostaglandin F2alpha-induced luteolysis involves activation of Signal transducer and activator of transcription 3 and inhibition of AKT signaling in cattle. AB - Prostaglandin F2alpha (PGF) induces the precipitous loss of steroidogenic capabilities and cellular death in the corpus luteum of many species, yet the molecular mechanisms underlying this event are not completely understood. Signal transducer and activator of transcription 3 (STAT3) was activated in granulosa cells during follicle atresia, whereas AKT is immediately down-regulated in the corpus luteum after PGF treatment in cattle; however, their involvement in both functional and morphological luteolysis in monovular species still need to be determined. Blood samples and corpus lutea were collected from cows before (0) and 2, 12, 24, and 48 hr after PGF treatment on Day 10 of the estrous cycle (4-5 cows per time point). Serum progesterone concentrations decreased by threefold (p < 0.05) within 2 hr, confirming functional luteolysis. The mRNA abundance of the pro-apoptotic gene BAX increased 12-48 hr post-PGF treatment (p < 0.05), while morphological luteolysis was observed 24 and 48 hr after PGF treatment, based on the loss of plasma membrane integrity, reduction of cytoplasmic volume, and pyknotic nuclei. Phosphorylated STAT3 increased, peaking at 12 hr, and remained elevated until 48 hr after PGF treatment. SOCS3 transcript abundance also increased (p < 0.05) starting at 2 hr post-PGF treatment. In contrast, AKT phosphorylation decreased by 12 hr after treatment. Thus, activation of STAT3 and inactivation of AKT signaling are involved in structural regression of the corpus luteum. PMID- 28337825 TI - Expression of TWIST in the first-trimester trophoblast and decidual tissue of women with recurrent pregnancy losses. AB - PROBLEM: In this study, we aim to investigate if the expression of TWIST in the first-trimester placenta and decidua has any association with spontaneous abortion (SAB) and recurrent pregnancy losses (RPL). METHODS: Expression of TWIST was measured in the first-trimester trophoblast and decidual tissues using RT-PCR and immunohistochemistry. Women with a pregnancy loss comprised the study group (AB group) including women with two or more recurrent pregnancy loses (RPL group), and women with a spontaneous abortion who had no history of previous pregnancy losses (SAB group). Controls were women with elective abortion of normal pregnancy (NP group). RESULTS: In in-vitro culture study of endometrial cells, expression of TWIST was detected with the induction of decidualization. In syncytiotrophoblast, expression of TWIST in NP group was significantly higher than that of AB group. RPL group had no expression of TWIST, both in the nucleus and cytoplasm of syncytiotrophoblast. In decidual tissue, majority of TWIST was expressed on the decidual stromal cells. NP group showed significantly higher expression of TWIST in cytoplasm and nucleus as compared with those of SAB group. CONCLUSION: This suggests that TWIST may have a functional role in decidualization of endometrial cells and syncytialization of cytotrophoblast cells. PMID- 28337828 TI - TRADD, TRAF2, RIP1 and TAK1 are required for TNF-alpha-induced pro-labour mediators in human primary myometrial cells. AB - PROBLEM: TNF-alpha plays a central role in the processes of human labour and delivery. This study sought to determine the role of the adaptor proteins TNFR1 associated death domain protein (TRADD), TNF receptor-associated factor 2 (TRAF2), receptor interacting protein 1 (RIP1) and transforming growth factor beta-activated kinase 1 (TAK1) in TNF-alpha-induced formation of pro-labour mediators. METHOD OF STUDY: Human primary myometrial cells were transfected with siRNA against TRADD (siTRADD), TRAF2 (siTRAF2), RIP1 (siRIP1) or TAK1 (siTAK1), treated with TNF-alpha, and assayed for pro-inflammatory mediators expression. RESULTS: siTRADD, siTRAF2, siRIP1 and siTAK1 significantly decreased TNF-alpha induced IL-1alpha, IL-1beta, IL-6, IL-8, MCP-1 mRNA expression and release of IL 6, IL-8 and MCP-1; and cyclooxygenase (COX)-2 expression and release of prostaglandin PGF2alpha . There was a significant attenuation of TNF-alpha induced expression of adhesion molecules ICAM-1 and VCAM-1 mRNA with siTRADD, siTRAF2 or siRIP1. siTRADD and siRIP1 significantly attenuated TNF-alpha-induced MMP-9 mRNA expression and release and nuclear factor kappaB (NF-kappaB) transcriptional activity. There was a significant increase in TNF-alpha-induced sVCAM-1 release, MMP-9 mRNA expression and NF-kappaB activity with siTAK1. CONCLUSION: TRADD, TRAF2, RIP1 and TAK1 are involved in TNF-alpha signalling in human myometrium. Further studies are required to determine whether inhibition of these proteins can prevent preterm birth. PMID- 28337829 TI - Peer bullying in seniors' subsidised apartment communities in Saskatoon, Canada: participatory research. AB - Given that 'home' is the major physical-spatial environment of many older adults and that home, social and neighbourhood environments are well-recognised to impact both the ability to age in place and quality of life in this population, a better understanding of the nature of social interactions within seniors' communal living environments is critical for health promotion. This paper describes a two-phase participatory research study examining peer bullying by older adults conducted in April and May, 2016. Responding to needs expressed by tenants, the objectives of this study were to identify the nature, prevalence and consequences of peer bullying for tenants of two low-income senior apartment communities. In collaboration with the local Older Adult Abuse Task Force, a screening survey on bullying was distributed to all tenants. Findings (n = 49) indicated that 39% of tenants had witnessed peer bullying and 29% had experienced bullying by peers. An adapted version of a youth bullying survey was administered in follow-up face-to-face interviews with 13 tenants. The most common forms of peer bullying were deliberate social exclusion and hurtful comments. The majority of respondents indicated that bullying was a problem for seniors and that bullies hurt other people. Outcomes of bullying included feelings of dejection and difficulties conducting everyday activities. PMID- 28337830 TI - Anatomical subgroup analysis of the MERIDIAN cohort: ventriculomegaly. AB - OBJECTIVE: To assess the contribution of fetal magnetic resonance imaging (MRI) in fetuses of the MERIDIAN cohort diagnosed with ventriculomegaly (VM) as the only abnormal intracranial finding on antenatal ultrasound. METHODS: This was a subgroup analysis of the MERIDIAN study of fetuses with only VM diagnosed on ultrasound in women who had a subsequent MRI examination within 2 weeks and for whom outcome reference data were available. The diagnostic accuracy of ultrasound and MRI was reported in relation to the severity of VM. The difference in measurements of trigone size on the two imaging methods and the clinical impact of adding MRI to the diagnostic pathway were also studied. RESULTS: In 306 fetuses with VM, ultrasound failed to detect 31 additional brain abnormalities, having an overall diagnostic accuracy of 89.9% for ultrasound, whilst MRI correctly detected 27 of the additional brain abnormalities, having a diagnostic accuracy of 98.7% (P < 0.0001). There were other brain abnormalities in 14/244 fetuses with mild VM on ultrasound (diagnostic accuracy, 94.3%) and MRI correctly diagnosed 12 of these (diagnostic accuracy, 99.2%; P = 0.0005). There was a close agreement between the size of trigones measured on ultrasound and on MRI, with categorical differences in only 16% of cases, showing that MRI did not systematically overestimate or underestimate trigone size. Complete prognostic data were available in 295/306 fetuses and the prognosis category changed after MRI in 69/295 (23.4%) cases. The overall effect of MRI on clinical management was considered to be 'significant', 'major' or 'decisive' in 76/295 (25.8%) cases. CONCLUSION: Our data suggest that a woman carrying a fetus with VM as the only intracranial finding on ultrasound should be offered an adjuvant investigation by MRI for further evaluation. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28337831 TI - Interleukin 1-alpha deficiency increases the expression of Follicle-stimulating hormone receptors in granulosa cells. AB - Follicle-stimulating hormone receptor (FSHR) is a pivotal regulator of ovarian response to hormonal stimulation. Inflammatory conditions have been linked to lower FSHR expression in granulosa cells (GCs) as well as an attenuated response to hormonal stimulation. The current study aimed to reveal if deficiency and/or blockage of the pro-inflammatory cytokine interleukin 1-alpha (IL1A) increased Fshr expression in rodent GCs. We found elevated Fshr transcript abundance, as assessed by quantitative PCR, in primary GCs isolated from Il1a-knockout compared to wild-type mice, and that the expression of FSHR is significantly higher in Il1a-knockout compared to wild-type ovaries. Supplementing GC cultures with recombinant IL1A significantly lowered Fshr expression in these cells. In accordance with the Fshr expression pattern, proliferation of GCs was higher in follicles from Il1a-knockout mice compared to wild-type mice, as indicated by the MKI67 immunohistochemical staining. Furthermore, treating wild-type mice with anakinra, an IL1 receptor 1 antagonist, significantly increased the expression of Fshr in primary GCs from treated compared to control mice. These data highlight an important interdependency between the potent pro-inflammatory cytokine IL1A and Fshr expression. PMID- 28337832 TI - Retroperitoneal dedifferentiated liposarcoma with huge cystic degeneration: A case report. AB - Prominent cyst formation is an unusual feature of liposarcoma. We report here a case of dedifferentiated liposarcoma with huge cystic change without preoperative chemo- or radiation therapy. The lesion arose in the retroperitoneum juxtaposed to the right kidney of a 67-year-old woman. She underwent a surgical removal of the retroperitoneal cyst. The cystic tumor contained 1600 mL of old bloody fluid, and its wall was composed of edematous, inflamed or sclerosing fibrous tissue with fatty tissue containing abundant atypical stromal cells, which were immunohistochemically positive for MDM2 and CDK4, and demonstrated MDM2 gene amplification by fluorescence in situ hybridization. The wall was contiguous to an atypical lipomatous nodule located in the mesentery. The following surgical specimens of the right hemicolectomy and right nephrectomy revealed atypical cells infiltrating into the subserosa of the colon and the perirenal fat tissue or that in the renal sinus. This case indicates that well differentiated or dedifferentiated liposarcoma should be also considered as a differential diagnosis of perirenal cystic mass. PMID- 28337833 TI - Acute cholangitis: current concepts. AB - BACKGROUND: Acute cholangitis, also known as ascending cholangitis, is a life threatening systemic condition that results from a biliary tree infection and obstruction. Severe acute cholangitis was reported to have a mortality rate between 11 and 27% in the 1990s. This article is a literature review about acute cholangitis. Its aim is to review the latest literature about acute cholangitis and to discuss its pathogenesis, clinical presentation, diagnosis, prognosis, risk factors and treatment. METHODS: Ovid Medline and PubMed database searches were performed for articles about acute cholangitis published in English from 1877 to 2016. The keyword search headings included 'acute', 'ascending' and 'cholangitis', and a combination of these were used. Only articles with full-text descriptions were chosen for this literature review. RESULTS: Common causes of biliary tree obstruction include choledocholithiasis, benign and malignant biliary strictures. According to the Tokyo Guidelines, clinical presentation, laboratory blood results and diagnostic imaging are important in the diagnosis of acute cholangitis. Treatments consist of intravenous fluids and antibiotics followed by biliary decompression and drainage. Available drainage options include endoscopic retrograde cholangiopancreatography, percutaneous transhepatic cholangiography, endoscopic ultrasound and open surgical drainage. CONCLUSION: It is important to diagnose acute cholangitis as early as possible to initiate appropriate treatments to reduce mortality and morbidity. PMID- 28337834 TI - Retinal dystrophy in two boys with Costello syndrome due to the HRAS p.Gly13Cys mutation. AB - Features of Costello Syndrome, a systemic disorder caused by germline mutations in the proto-oncogene HRAS from the RAS/MAPK pathway, include failure-to-thrive, short stature, coarse facial features, cardiac defects including hypertrophic cardiomyopathy, intellectual disability, and predisposition to neoplasia. Two unrelated boys with Costello syndrome and an HRAS mutation (p.Gly13Cys) are presented with their ophthalmologic findings. Both had early symptoms of nystagmus, photophobia, and vision abnormalities. Fundus examination findings of retinal dystrophy were present at age 3 years. Both boys have abnormal electroretinograms with reduced or undetectable rod responses along with reduced cone responses consistent with rod-cone dystrophy. Our observations suggest that early ophthalmic examination and re-evaluations are indicated in children with Costello syndrome. PMID- 28337835 TI - Rare finding of a fourth branchial cleft anomaly. PMID- 28337836 TI - Plant transcription factors from the homeodomain-leucine zipper family I. Role in development and stress responses. AB - In front of stressful conditions plants display adaptation mechanisms leading to changes in their morphology, physiology, development and molecular composition. Transcription factors (TFs) play crucial roles in these complex adaptation processes. This work is focused in the homeodomain-leucine zipper I (HD-Zip I) family of TFs, unique to plants. First discovered in 1991, they were identified and isolated from monocotyledonous and dicotyledonous plants showing high structural similarity and diversified functions. These TFs have, besides the homeodomain and leucine zipper, conserved motifs in their carboxy-termini allowing the interaction with the basal machinery and with other regulatory proteins. The model dicotyledonous plant Arabidopsis thaliana has 17 HD-Zip I members; most of them regulated by external stimuli and hormones. These TFs are involved in key developmental processes like root and stem elongation, rosette leaves morphology determination, inflorescence stem branching, flowering and pollen hydration. Moreover, they are key players in responses to environmental stresses and illumination conditions. Several HD-Zip I encoding genes from different species were protected in patents because their overexpression or mutation generates improved agronomical phenotypes. Here we discuss many aspects about these TFs including structural features, biological functions and their utilization as biotechnological tools to improve crops. (c) 2017 IUBMB Life, 69(5):280-289, 2017. PMID- 28337837 TI - Sulfated hyaluronan attenuates inflammatory signaling pathways in macrophages involving induction of antioxidants. AB - It is well recognized that high molecular weight hyaluronan (H-HA) exerts potent anti-inflammatory effects while its fragmentation into low molecular weight HA (L HA) is discussed to promote inflammation. Chemical modification of HA with sulfate groups has been shown to foster its anti-inflammatory activity which seems to be maintained in sulfated low molecular weight HA derivatives (sL-HA). However, the molecular mechanisms by which sL-HA produces its anti-inflammatory activity are not understood. In this study, we used global quantitative proteomics combined with targeted analysis of key proteins to characterize the effect of sL-HA on fully differentiated human inflammatory macrophages (iMF). Culture of iMF with sL-HA did not affect cell viability but resulted in a reduced pro-inflammatory cytokine response of iMF after activation indicating a profound counter-regulation of their initial inflammatory phenotype. Rapid internalization of sL-HA involving CD44 and scavenger receptors was observed. Furthermore, an upregulation of the antioxidants SOD2 and SOD3 was found while no oxidative stress was induced. Consequently, activity of transcription factors for inflammatory gene expression was downregulated in iMF with sL-HA after activation whereas anti-inflammatory proteins were induced. This study proves anti inflammatory properties of sL-HA and provides information on its regulatory mode of action on iMF. This article is protected by copyright. All rights reserved. PMID- 28337840 TI - Electrogenic Single-Species Biocomposites as Anodes for Microbial Fuel Cells. AB - Integration of electrogenic microorganisms remains a challenge in biofuel cell technology. Here, synthetic biocomposites ("artificial biofilms") are proposed. Bacteria (Shewanella oneidensis) are embedded in a hydrogel matrix (poly(vinyl alcohol)) via wet- and electrospinning, creating fibers and nonwoven gauzes. The bacteria remain viable and metabolically active. The performance is compared to S. oneidensis suspension cultures and "natural" biofilms. While lower than with the suspension cultures, the power output from the fuel cells with the artificial biofilms is higher than with the natural one. Handling, reproducibility, and stability are also better. Artificial biofilms can therefore contribute to resolving fundamental issues of design, scale up, and monosepsis in biofuel cell technology. PMID- 28337839 TI - Poly(Ethylene Glycol) Dimethacrylates with Cleavable Ketal Sites: Precursors for Cleavable PEG-Hydrogels. AB - The authors introduce poly(ethylene glycol) (PEG) based macromonomers containing acid-labile ketal moieties as well as terminal methacrylate units that are amenable to radical polymerization. The synthesis of PEGs of different molecular weights (ranging from 2000 to 13 000 g mol-1 with polydispersities <1.15) with a central ketal unit (PEG-ketal-diol) and their conversion to PEG-ketal dimethacrylates (PEG-ketal-DMA) is introduced. Degradation rates of both PEG ketal-diols and PEG-ketal-DMA are investigated by in situ 1 H NMR kinetic studies in deuterated phosphate buffer. Hydrogels containing 0, 5, or 10 wt% of PEG-ketal DMA and 100, 95, or 90 wt% of PEG-DMA, respectively, are synthesized and disintegration of the gels is investigated in buffer at different pH values. Visible disintegration of the gels appears at pH 5 for hydrogels containing PEG ketal-DMA, whereas no visible degradation is observed at all at neutral pH or for PEG hydrogels without PEG-ketal-DMA. PMID- 28337838 TI - The selective metabotropic glutamate receptor 5 antagonist mavoglurant (AFQ056) reduces the incidence of reflux episodes in dogs and patients with moderate to severe gastroesophageal reflux disease. AB - BACKGROUND: Transient lower esophageal sphincter relaxations (TLESRs) induced by gastric distension are modulated by the metabotropic glutamate receptor 5 (mGluR5) that influences the vagal reflex loop. We therefore aimed to examine the effects of the selective mGluR5 antagonist mavoglurant (AFQ056) on the number of TLESRs in dogs and reflux episodes in patients with gastroesophageal reflux disease (GERD). METHODS: In a dog model, the number of meal-induced TLESRs was determined after intravenous (0.03, 0.1, 0.3, and 1 mg kg-1 ) and oral (1, 3, and 10 mg kg-1 ) doses of mavoglurant with reference to vehicle. In a multicenter, randomized, double-blind, placebo-controlled, three-period crossover study, the incidence of meal-induced reflux episodes was assessed by esophageal impedance monitoring after single, oral doses of mavoglurant (50 and 400 mg) or baclofen (40 mg) in 30 patients with moderate to severe GERD. KEY RESULTS: In dogs, mavoglurant reduced the number of TLESRs after intravenous and oral administration. In patients with GERD, the incidence of postprandial reflux episodes was significantly lower at a dose of 400 mg mavoglurant (-37.5% ; 90% confidence interval [CI]: -57.8, -17.2), whereas there was no significant difference at 50 mg of mavoglurant compared to placebo. A significantly lower incidence of reflux episodes was also noted with the active comparator baclofen ( 50.3%; 90% CI: -66.2, -34.3), thereby validating this study. CONCLUSIONS AND INFERENCES: These data suggest a potential clinical benefit of mGluR5 antagonists such as mavoglurant in patients with GERD, particularly in those with persisting symptoms despite treatment with proton pump inhibitors. PMID- 28337841 TI - Yeast aquaporin regulation by 4-hydroxynonenal is implicated in oxidative stress response. AB - Reactive oxygen species, especially hydrogen peroxide (H2 O2 ), contribute to functional molecular impairment and cellular damage, but also are necessary in normal cellular metabolism, and in low doses play stimulatory role in cell proliferation and stress resistance. In parallel, reactive aldehydes such as 4 hydroxynonenal (HNE), are lipid peroxidation breakdown products which also contribute to regulation of numerous cellular processes. Recently, channeling of H2 O2 by some mammalian aquaporin isoforms has been reported and suggested to contribute to aquaporin involvement in cancer malignancies, although the mechanism by which these membrane water channels are implicated in oxidative stress is not clear. In this study, two yeast models with increased levels of membrane polyunsaturated fatty acids (PUFAs) and aquaporin AQY1 overexpression, respectively, were used to evaluate their interplay in cell's oxidative status. In particular, the aim of the study was to investigate if HNE accumulation could affect aquaporin function with an outcome in oxidative stress response. The data showed that induction of aquaporin expression by PUFAs results in increased water permeability in yeast membranes and that AQY1 activity is impaired by HNE. Moreover, AQY1 expression increases cellular sensitivity to oxidative stress by facilitating H2 O2 influx. On the other hand, AQY1 expression has no influence on the cellular antioxidant GSH levels and catalase activity. These results strongly suggest that aquaporins are important players in oxidative stress response and could contribute to regulation of cellular processes by regulation of H2 O2 influx. (c) 2017 IUBMB Life, 69(5):355-362, 2017. PMID- 28337842 TI - Halogenated Briarane Diterpenes with Acetyl Migration from the Gorgonian Coral Junceella fragilis. AB - Chemical examination of the gorgonian coral Junceella fragilis resulted in the isolation of four pairs of acetyl isomers belonging to briarane diterpenoids, including five new compounds. Their structures were determined on the basis of extensive spectroscopic (IR, MS, NMR, and single-crystal X-ray diffraction) analysis in association with the chemical conversion. Each pair of isomers featured by dynamical interconversion through as acetyl migration in 1,2-diol, which was postulated to be generated under the formation of a cyclic orthoacetate intermediate. All compounds exerted the inhibitory activities against the nitric oxide production in RAW264.7 macrophage cells. PMID- 28337844 TI - Synthesis of Complex Phenols Enabled by a Rationally Designed Hydroxide Surrogate. AB - The conversion of aryl halides to phenols under mild reaction conditions is a longstanding and formidable challenge in organic chemistry. Herein, we report the rational design of a broadly applicable Pd-catalyzed method to prepare phenols with benzaldehyde oxime as a hydroxide surrogate. These reactions occur under mildly basic conditions and enable the late-stage hydroxylation of several functionally-dense drug-like aryl halides. PMID- 28337843 TI - Exploring the role of the dental hygienist in reducing oral health disparities in Canada: A qualitative study. AB - OBJECTIVES: Reducing oral health disparities has been an ongoing challenge in Canada with the largest burden of oral disease exhibited in vulnerable populations, including Aboriginal people, the elderly, rural and remote residents, and newcomers. Dental hygienists are a unique set of professionals who work with and within communities, who have the potential to act as key change agents for improving the oral health of these populations. The purpose of this qualitative study was to explore, from the dental hygiene perspective, the role of dental hygienists in reducing oral health disparities in Canada. METHODS: Dental hygienists and key informants in dental hygiene were recruited, using purposeful and theoretical sampling, to participate in a non-directed, semi structured one-on-one in-depth telephone interview using Skype and Call Recorder software. Corbin and Strauss's grounded theory methodology was employed with open, axial, and selective coding analysed on N-Vivo Qualitative software. RESULTS: The resulting theoretical framework outlines strategies proposed by participants to address oral health disparities; these included alternate delivery models, interprofessional collaboration, and increased scope of practice. Participants identified variation in dental care across Canada, public perceptions of oral health and dental hygiene practice, and lack of applied research on effective oral health interventions as challenges to implementing these strategies. CONCLUSION: The research confirmed the important role played by dental hygienists in reducing oral health disparities in Canada. However, due to the fragmentation of dental hygiene practice across Canada, a unified voice and cohesive action plan is needed in order for the profession to fully embrace their role. PMID- 28337845 TI - Nurses' attitudes towards the use of PRN psychotropic medications in acute and forensic mental health settings. AB - Many countries now have national mental health policies and guidelines to decrease or eliminate the use of seclusion and restraint yet the use of Pro Re Nata (PRN) medications has received less practice evaluation. This research aimed to identify mental health nurses' attitudes towards the use of PRN medications with mental health consumers. Participants were working in forensic mental health and non-forensic acute mental health settings. The "Attitudes towards PRN medication use survey" was used and data were collected online. Data were analysed using the Statistical Package Social Sciences, Version 22.0. Practice differences between forensic and other acute mental health settings were identified related to the use of PRN medications to manage symptoms from nicotine, alcohol and other drug withdrawal. Differences related to the useage of comfort rooms and conducting comprehensive assessments of consumers' psychiatric symptoms were also detected. Qualitative findings highlighted the need for increased accountability for the prescribing and administration of PRN medications along with more nursing education/training to use alternative first line interventions. Nurses administering PRN medications should be vigilant regarding the indications for this practice to ensure they are facilitating the consumer's recovery by reducing the use of all forms of potentially restrictive practices in the hospital setting. The reasons for using PRN medications and PRN administration rates must be continually monitored to avoid practices such as high dose antipsychotics use and antipsychotic polypharmacy to ensure the efficacy of the consumers' management plans on their health care outcomes. PMID- 28337846 TI - Obesity in heart failure: is it time to rethink the paradox? PMID- 28337847 TI - Efficacy of environmental and acceptance-based enhancements to behavioral weight loss treatment: The ENACT trial. AB - OBJECTIVE: This study was designed to compare weight loss through a traditional behavioral treatment (BT) approach that integrated skills for managing the obesogenic food environment (BT + E) with an approach that integrated environmental and acceptance-based skills (BT + EA). Moderators were examined as an exploratory aim. METHODS: Adults (N = 283) were randomly assigned to treatment condition and provided with 26 group-based sessions over the course of 12 months. Weight was measured in the clinic at months 0, 6, and 12. RESULTS: Change in weight over time did not significantly differ by condition. However, race significantly moderated the effect of condition on weight loss (P = 0.04), such that African-American participants lost less weight than non-Hispanic white participants in the BT (6.2% vs. 11.5%) and BT + E conditions (6.6% vs. 12.2%), but weight loss in these two groups was similar in the BT + EA condition (9.4% vs. 11.5%). Among African Americans, rates of achieving a clinically significant weight loss (i.e., > 5%) at 12 months were higher in BT + EA (80%) than BT (57%) or BT + E (48%) (P = 0.04). CONCLUSIONS: This innovative behavioral approach shows promise for treatment of African Americans, which is notable given the lack of progress to date addressing racial disparities in obesity intervention efficacy. PMID- 28337849 TI - Early infancy interventions to prevent childhood obesity. PMID- 28337850 TI - High-Throughput Screening of Vascular Endothelium-Destructive or Protective Microenvironments: Cooperative Actions of Extracellular Matrix Composition, Stiffness, and Structure. AB - Pathological modification of the subendothelial extracellular matrix (ECM) has closely been associated with endothelial activation and subsequent cardiovascular disease progression. To understand regulatory mechanisms of these matrix modifications, the majority of previous efforts have focused on the modulation of either chemical composition or matrix stiffness on 2D smooth surfaces without simultaneously probing their cooperative effects on endothelium function on in vivo like 3D fibrous matrices. To this end, a high-throughput, combinatorial microarray platform on 2D and 3D hydrogel settings to resemble the compositions, stiffness, and structure of healthy and diseased subendothelial ECM has been established, and further their respective and combined effects on endothelial attachment, proliferation, inflammation, and junctional integrity have been investigated. For the first time, the results demonstrate that 3D fibrous structure resembling native ECM is a critical endothelium-protective microenvironmental factor by maintaining the stable, quiescent endothelium with strong resistance to proinflammatory stimuli. It is also revealed that matrix stiffening, in concert with chemical compositions resembling diseased ECM, particularly collagen III, could aggravate activation of nuclear factor kappa B, disruption of endothelium integrity, and susceptibility to proinflammatory stimuli. This study elucidates cooperative effects of various microenvironmental factors on endothelial activation and sheds light on new in vitro model for cardiovascular diseases. PMID- 28337851 TI - Low prevalence of knee chondrocalcinosis and its catabolic association by use of serum matrix metalloproteinase 3: A rural Japanese population study. AB - AIM: This study aimed to elucidate the prevalence of radiographic knee chondrocalcinosis (CC) and to clarify whether CC is correlated with self-reported knee symptoms and a serum catabolic biomarker. METHODS: A total of 1278 volunteers participated. Plain radiographs of both knees were obtained. Identification of a linear calcification in the knee joint space was defined as CC. Patients with a Kellgren-Lawrence grade of 2 or more were considered to have knee osteoarthritis (OA). Symptoms were evaluated using the Knee injury and Osteoarthritis Outcome Score (KOOS) Pain scale, and serum matrix metalloproteinase-3 (MMP-3) concentration was determined. Multiple regression analysis was conducted to determine whether CC was correlated with OA, the KOOS Pain scale and MMP-3 concentration. RESULTS: Twenty-eight subjects were found to have CC (2.2%), and 389 had OA (30.4%). CC was correlated with OA (odds ratio: 5.797; P = 0.006). Additionally, CC was correlated with MMP-3 concentration (B = 11.415, beta = 0.059, P = 0.014), but not with KOOS Pain scale. CONCLUSIONS: The prevalence of CC was low in the Japanese population evaluated in this study. While CC was not correlated with self-reported knee symptoms, it was positively correlated with serum MMP-3 concentration. PMID- 28337848 TI - Designing Smart Materials with Recombinant Proteins. AB - Recombinant protein design allows modular protein domains with different functionalities and responsive behaviors to be easily combined. Inclusion of these protein domains can enable recombinant proteins to have complex responses to their environment (e.g., temperature-triggered aggregation followed by enzyme mediated cleavage for drug delivery or pH-triggered conformational change and self-assembly leading to structural stabilization by adjacent complementary residues). These "smart" behaviors can be tuned by amino acid identity and sequence, chemical modifications, and addition of other components. A wide variety of domains and peptides have smart behavior. This review focuses on protein designs for self-assembly or conformational changes due to stimuli such as shifts in temperature or pH. PMID- 28337852 TI - Turning Potential Into Action: Using Pluripotent Stem Cells to Understand Heart Development and Function in Health and Disease. AB - Pluripotent stem cells hold enormous potential for regenerative therapies, however their ability to provide insight into early human development and the origins of disease could arguably provide an even greater outcome. This is primarily due to their contribution to the establishment of a powerful knowledge base of human development, something which all researchers and clinicians can potentially benefit from. Modeling human heart development and disease using pluripotent stem cells has already provided many important insights into cardiogenesis and cardiovascular disease mechanisms however, it is important to be aware of the complexities of this model system. Thorough contemplation of experimental models and specialized techniques is required to provide high quality evidence of the intricacies of both normal early development, and when this process goes awry in disease states. Stem Cells Translational Medicine 2017;6:1452-1457. PMID- 28337853 TI - Long-term efficacy and tolerability of mycophenolate mofetil therapy in diffuse scleroderma skin disease. AB - OBJECTIVES: To assess the long-term efficacy and tolerability of mycophenolate mofetil (MMF) in patients with diffuse cutaneous systemic sclerosis (dcSSc). METHODS: Patients enrolled in the Australian Scleroderma Cohort study with dcSSc and baseline modified Rodnan skin score (mRSS) >= 12 who were treated for a minimum of 12 months with MMF for the primary indication of skin disease were included and their prospectively collected data retrieved. Change in mRSS, the proportion with a clinically significant improvement (reduction in mRSS >= 5 from baseline) and adverse effects due to therapy were determined. RESULTS: Seventy four participants treated with MMF were identified and of these, 42 met inclusion criteria. The mean age was 53 +/- 12 years, with mean disease duration at MMF commencement of 4.8 +/- 4.3 years. Twenty-one participants (50%) commenced MMF within 2 years of disease onset and the mean duration of therapy was 2.7 +/- 1.7 years. The mean mRSS at baseline was 25.9 +/- 9.2 with a reduction of 3.7 +/- 7.1 (P = 0.07) after 1 year of therapy, 7.6 +/- 8.3 after 2 years (P = 0.01) and 10.5 +/- 10.3 after 5 years (P < 0.01). Response to treatment was not affected by disease duration at MMF commencement or baseline skin score. Eighteen participants (43%) demonstrated clinically significant improvement after 1 year, increasing to 92% after 4 years. Two participants (5%) ceased MMF due to adverse effects. CONCLUSION: MMF was associated with a modest improvement in mRSS and was well tolerated in the treatment of dcSSc. Given the natural history of dcSSc where skin involvement can spontaneously improve, randomized, placebo-controlled studies are required to confirm whether improvement can be attributed to MMF therapy. PMID- 28337854 TI - Silk Fibroin Biomaterial Shows Safe and Effective Wound Healing in Animal Models and a Randomized Controlled Clinical Trial. AB - Due to its excellent biological and mechanical properties, silk fibroin has been intensively explored for tissue engineering and regenerative medicine applications. However, lack of translational evidence has hampered its clinical application for tissue repair. Here a silk fibroin film is developed and its translational potential is investigated for skin repair by performing comprehensive preclinical and clinical studies to fully evaluate its safety and effectiveness. The silk fibroin film fabricated using all green chemistry approaches demonstrates remarkable characteristics, including transmittance, fluid handling capacity, moisture vapor permeability, waterproofness, bacterial barrier properties, and biocompatibility. In vivo rabbit full-thickness skin defect study shows that the silk fibroin film effectively reduces the average wound healing time with better skin regeneration compared with the commercial wound dressings. Subsequent assessment in porcine model confirms its long-term safety and effectiveness for full-thickness skin defects. Finally, a randomized single-blind parallel controlled clinical trial with 71 patients shows that the silk fibroin film significantly reduces the time to wound healing and incidence of adverse events compared to commercial dressing. Therefore, the study provides systematic preclinical and clinical evidence that the silk fibroin film promotes wound healing thereby establishing a foundation towards its application for skin repair and regeneration in the clinic. PMID- 28337855 TI - Simple Protein Modification Using Zwitterionic Polymer to Mitigate the Bioactivity Loss of Conjugated Insulin. AB - Polymer-protein conjugation has been extensively explored toward a better protein drug with improved pharmacokinetics. However, a major problem with polymer protein conjugation is that the polymers drastically reduce the bioactivity of the modified protein. There is no perfect solution to prevent the bioactivity loss, no matter the polymer is conjugated in a non-site specific way, or a more complex site-specific procedure. Here the authors report for the first time that when zwitterionic carboxybetaine polymer (PCB) is conjugated to insulin through simple conventional coupling chemistry. The resulting PCB-insulin does not show a significant reduction of in vitro bioactivity. The obtained PCB-insulin shows two significant advantages as a novel pharmaceutical agent. First, its therapeutic performance is remarkable. For PCB-insulin, there is a 24% increase of in vivo pharmacological activity of lowering blood glucose compared with native insulin. Such uncommonly seen increase has rarely been reported and is expected to be due to both the improved pharmacokinetics and retained bioactivity of PCB-insulin. Second, the production is simple from manufacturing standpoints. Conjugation procedure involves only one-step coupling reaction without complex site-specific linkage technique. The synthesized PCB-insulin conjugates do not require chromatographic separation to purify and obtain particular isoforms. PMID- 28337856 TI - Contribution of snacks to dietary intakes of young children in the United States. AB - Nutritional quality of children's diets is a public health priority in the fight against childhood obesity and chronic diseases. The main purpose of this study was to determine contribution of snacks to energy and nutrient intakes and to identify leading snack food sources of energy, total fat, and added sugars amongst young children in the United States. Using the 2005-2012 NHANES data, dietary intakes of 2- to 5-year-old children were analysed from a parent-reported 24-hour dietary recall (n = 3,429). Snacking occasions were aggregated to determine the proportion of total food/beverage intake obtained from snacks, estimate energy, and nutrient intakes, and identify the leading snack food sources of energy, added sugars, and total fat. Nearly all children consumed a snack on the reported day (62% morning, 84% afternoon, and 72% evening). Snacks accounted for 28% of total energy intake, 32% of carbohydrates, 39% of added sugars, and 26% of total fat and dietary fiber intakes for the day. Snacking occasions accounted for 46.6% of all beverages consumed on the reported day. Snacks and sweets food category (i.e., cookies and pastries) were the leading sources of energy (44%), total fat (52%), and added sugars (53%) consumed during snacking occasions. Sweetened beverages (e.g., fruit and sport drinks) contributed 1-quarter of all added sugars obtained from snacks. Snacks contribute considerable amount of energy and nutrients to young children's diets, with a heavy reliance on energy-dense foods and beverages. Targeted interventions are needed to improve the nutritional quality of snacks consumed by young children. PMID- 28337858 TI - Transdermal Protein Delivery Using Choline and Geranate (CAGE) Deep Eutectic Solvent. AB - Transdermal delivery of peptides and other biological macromolecules is limited due to skin's inherent low permeability. Here, the authors report the use of a deep eutectic solvent, choline and geranate (CAGE), to enhance topical delivery of proteins such as bovine serum albumin (BSA, molecular weight: ~66 kDa), ovalbumin (OVA, molecular weight: ~45 kDa) and insulin (INS, molecular weight: 5.8 kDa). CAGE enhances permeation of BSA, OVA, and insulin into porcine skin ex vivo, penetrating deep into the epidermis and dermis. Studies using tritium labeled BSA and fluorescein isothiocyanate labeled insulin show significantly enhanced delivery of proteins into and across porcine skin, penetrating the skin in a time-dependent manner. Fourier transform IR spectra of porcine stratum corneum (SC) samples before and after incubation in CAGE show a reduction in peak area attributed to SC lipid content, suggesting lipid extraction from the SC. Circular dichroism confirms that CAGE does not affect insulin's secondary conformation. In vivo studies in rats show that topical application of 10 U insulin dispersed in CAGE (25 U kg-1 insulin dose) leads to a highly significant 40% drop in blood glucose levels in 4 h that is relatively sustained for 12 h. Taken together, these studies demonstrate that CAGE is a promising vehicle for transdermal delivery of therapeutic proteins; specifically, as a noninvasive delivery alternative to injectable insulin for the treatment of diabetes. PMID- 28337857 TI - Efficient Electrocatalyst for the Hydrogen Evolution Reaction Derived from Polyoxotungstate/Polypyrrole/Graphene. AB - Efficient hydrogen evolution reaction (HER) from water by electrocatalysis using cost-effective materials is critical to realize the clean hydrogen production. Herein, with controlling the structure and composition of polyoxotungstate/conductive polypyrrole/graphene (PCG) precursor precisely and followed by a temperature-programmed reaction, we developed a highly active and stable catalyst: NC@Wx C/NRGO (NC: nitrogen-doped porous carbon, NRGO: nitrogen doped reduced graphene oxide). The composite presents splendid performance towards HER in acidic media, with a small onset overpotential of 24 mV versus RHE (reversible hydrogen electrode), a low Tafel slope of 58.4 mV dec-1 , a low overpotential of 100 mV at 10 mA cm-2 , and remarkable long-term cycle stability. This is one of the highest HER catalysts among the tungsten carbide-based materials ever reported. PMID- 28337859 TI - Self-Healable Supramolecular Hydrogel Formed by Nor-Seco-Cucurbit[10]uril as a Supramolecular Crosslinker. AB - A supramolecular hydrogel was formed by a simple mixing of solutions of nor-seco cucurbit[10]uril (NS-CB[10]) and adamantylamine-terminated 4-armed polyethylene glycol (AdA-4-arm-PEG). In the formation of the hydrogel, NS-CB[10] acted as a noncovalent crosslinker to form a ternary complex with two AdA moieties. The dynamic and selective nature of the host-guest interaction between NS-CB[10] and AdA enabled the supramolecular hydrogel to rapidly recover its physical properties after it was damaged. In addition, the recovered hydrogel retained its physical properties with negligible differences from those of the pristine material, even after multiple self-healing cycles. The NS-CB[10]-based hydrogel with the self-healing property may be useful for various biological applications such as drug delivery, cell therapy and tissue engineering. PMID- 28337860 TI - Clinical features and long-term outcomes of 105 granulomatosis with polyangiitis patients: A single center experience from north India. AB - AIM: To describe the clinical features, treatment and long-term outcomes in north Indian patients with granulomatosis with polyangiitis (GPA). METHODS: Clinical details, Birmingham Vasculitis Activity Score (BVAS-v3), laboratory data, histopathology findings, treatment details and outcomes of all consecutive patients diagnosed as having GPA between April 2005 and April 2016 were retrieved. European Vasculitis Study Group definitions were used to classify patients into localized, early systemic, generalized, severe and refractory categories. The findings were compared with large single center cohorts from USA, Germany and France. RESULTS: One hundred and five patients (median age 40 years; 60 females and 45 males) were diagnosed as having GPA. Median duration of follow up was 28 months. Upper respiratory tract, renal and lung involvement were seen in 76.19%, 51.43% and 67.62% of patients, respectively. Ocular, ear, central nervous system, peripheral nervous system, heart, gastrointestinal and skin involvement were seen in 40.95%, 18.1%, 26.67%, 11.43%, 5.71%, 12.38% and 29.52%, respectively. The median BVAS v3 score was 17. Localized, early systemic, generalized, severe and refractory disease were seen in three, 44, 38, 17 and one patient, respectively. Eighteen patients expired and the cause of death was disease activity in 11, disease activity plus sepsis in four and sepsis alone in three patients. Twenty-six patients experienced relapses. No hemorrhagic cystitis or bladder cancers were observed; however, one patient developed myelodysplastic syndrome during follow up. CONCLUSION: Indian patients are younger and have less arthritis, renal and peripheral nerve involvement as compared to the patients in Western cohorts. PMID- 28337861 TI - Identification of 2 novel HLA-B alleles, HLA-B*55:02:09 and HLA-B*55:80 in Chinese individuals. AB - HLA-B*55:02:09 and HLA-B*55:80 differ from HLA-B*55:02:01 by 1 single nucleotide substitution, respectively. PMID- 28337862 TI - Bayesian sensitivity analysis of a 1D vascular model with Gaussian process emulators. AB - One-dimensional models of the cardiovascular system can capture the physics of pulse waves but involve many parameters. Since these may vary among individuals, patient-specific models are difficult to construct. Sensitivity analysis can be used to rank model parameters by their effect on outputs and to quantify how uncertainty in parameters influences output uncertainty. This type of analysis is often conducted with a Monte Carlo method, where large numbers of model runs are used to assess input-output relations. The aim of this study was to demonstrate the computational efficiency of variance-based sensitivity analysis of 1D vascular models using Gaussian process emulators, compared to a standard Monte Carlo approach. The methodology was tested on four vascular networks of increasing complexity to analyse its scalability. The computational time needed to perform the sensitivity analysis with an emulator was reduced by the 99.96% compared to a Monte Carlo approach. Despite the reduced computational time, sensitivity indices obtained using the two approaches were comparable. The scalability study showed that the number of mechanistic simulations needed to train a Gaussian process for sensitivity analysis was of the order O(d), rather than O(d*103) needed for Monte Carlo analysis (where d is the number of parameters in the model). The efficiency of this approach, combined with capacity to estimate the impact of uncertain parameters on model outputs, will enable development of patient-specific models of the vascular system, and has the potential to produce results with clinical relevance. PMID- 28337863 TI - Zoonotic influenza viruses: antigenic and genetic characteristics and development of candidate vaccine viruses for pandemic preparedness. PMID- 28337865 TI - Helicobacter pylori and Barrett?s esophagus: a protective factor or a real cause? AB - Notwithstanding the definite aetiopathogenetic path of certain diseases, the relationship between Helicobacter pylori (H. pylori) and Barrett?s esophagus (BE), a condition that increases the risk for dysplasia and consequently adenocarcinoma of the distal esophagus and esophagogastric junction, remains uncertain. This paper reviews the current scientific literature with emphasis on the protective correlation between H. pylori infection and BE and demonstrates that a causal relationship has not been disproved with certainty. Furthermore, H. pylori infection could pose a risk for the onset of gastroesophageal reflux disease (GERD), which could in turn trigger BE, a precancerous lesion, and subsequently cause cancer. By analyzing the current available data, this article tries to verify that H. pylori infection is the underlying cause of esophageal cancer. PMID- 28337864 TI - Molecular basis of growth, proliferation, and differentiation of mammalian follicular granulosa cells. AB - For normal folliculogenesis and oogenesis to occur many intrinsic and extrinsic factors are needed, i.e. positive feedback of hormone secretion and local ovarian follicular growth factors distribution. During follicle formation, granulosa cells (GCs) change their morphology and physiological properties. The factors needed for GCs to differentiate within each layer are transforming growth factor beta (TGFB) and insulin-like growth factor (IGF), as well as the activation and modification of biochemical pathways involved in folliculogenesis. Physiological alterations occur when GC genes are characterized by several differences in their gene expression profile. Studies in recent years indicate a variety of processes involved in follicle morphology and biochemical remodeling during growth and development. It was demonstrated that IGFs play a central role in the differentiation of GCs both in vivo and in vitro. Moreover, the primary role of FSH and LH in the formation of the ovarian follicle, was also described. Our review article characterizes the most important pathways involved in the differentiation of GCs and the effect of various factors on gene expression in GCs during folliculogenesis. PMID- 28337866 TI - Fibromyalgia and bipolar disorder: extent of comorbidity and therapeutic implications. AB - Fibromyalgia (FM) is a syndrome that affects muscles and soft tissues. Presenting symptoms include chronic muscle pain, fatigue, sleep problems and psychological symptoms, including depression and anxiety. There exists strong evidence of a comorbidity between FM and Bipolar Disorder (BD). In this study, papers from 2006 to February 2016 that examined the comorbidity and etiological similarities of FM and BD were reviewed, as well as the therapeutic implications of these findings. The reviewed articles showed that an adequate psychiatric screening for BD is recommended in FM patients with depressive symptoms, in order to decrease administration of antidepressants for BD, due to the lack of proven efficacy, and to limit antidepressant-induced mania. Alternative therapies, such as agomelatine, memantine and psychotherapic treatment should be considered. PMID- 28337867 TI - Alexithymia and its relationships with inflammatory response mediated by IL-1 family members. AB - The major aim of this study is to provide a review of the research studies regarding the clinical link between alexithymia and interleukins (IL). We performed a search for the relevant literature by using search terms as "alexithymia" combined with "interleukin or IL". A total of 9 original research studies were identified and included. Alexithymia was found to be prevalent in inflammatory response and associated with inflammatory cytokines. Our review emphasized for the first time the relationships of alexithymia with inflammatory response mediated by IL-1 family members. Therefore, the screening of alexithymic traits and the administration of appropriate psychological and psychotherapeutical interventions should be integral parts of disease management programs. Supplying such interventions will probably help with prevention of the development of the disease and/or its exacerbation by improving the quality of life of alexithymic individuals. PMID- 28337868 TI - Inflammation in lung after acute myocardial infarction is induced by dendritic cell-mediated immune response. AB - The present study was performed to describe the changes of lung tissues in mice with acute myocardial infarction (AMI) and also explain the cell mechanism involved in inflammation in lung. AMI was established by left coronary ligation in mice. Then mice were divided into three groups: control group, MW1 group (sampling after surgery for one week) and MW2 group (sampling after surgery for two weeks). Afterwards, measurement of lung weight and lung histology, cell sorting in bronchoalveolar lavage (BAL) fluid and detection of several adhesive molecules, inflammatory molecules as well as enzyme associated with inflammation were performed. Moreover, dendritic cells (DCs) were isolated from bone marrow of C57B/L6 mice. After incubating with necrotic myocardium, the expression of antigen presenting molecules, co-stimulatory molecules and inflammatory molecules were detected by flow cytometry or immunohistochemistry in DCs. We also detected T-cell proliferation after incubating with necrotic myocardium-treated DCs. AMI induced pathological changes of lung tissue and increased inflammatory cell amount in BAL fluid. AMI also increased the expression of several inflammatory factors, adhesive molecules and enzymes associated with inflammation. CD11c and TLR9, which are DC surface markers, showed a significantly increased expression in mice with AMI. Additionally, necrotic myocardium significantly increased the expression of co-stimulatory factors including CD83 and CD80, inflammatory cytokines including TNF-alpha, IFN-gamma and NF-kappaB in DCs. Furthermore, DCs treated with necrotic myocardium also significantly promoted T-cell proliferation. AMI induced inflammation in lung and these pathological changes were mediated by DC-associated immune response. PMID- 28337870 TI - JAK2 tyrosine kinase inhibitor AG490 suppresses cell growth and invasion of gallbladder cancer cells via inhibition of JAK2/STAT3 signaling. AB - The Janus kinase-signal transducers and activators of transcription signaling pathway (JAK/STAT pathway) have displayed a critical role in tumor development and progression in multiple malignancies. Previous studies showed that inhibition of JAK/STAT signaling blocked cell growth and metastasis in cancer cells, however, the antitumor effects of JAK inhibitor AG490 on gallbladder cancer (GBC) have not been reported. Our present study aimed to investigate the effects and associated mechanisms of JAK inhibitor AG490 on cell growth, invasive potential and apoptosis in GBC cells (GBC-SD and SGC-996) indicated by MTT, cell colony formation, Transwell and flow cytometry. As a consequence, we found that JAK2 inhibitor AG490 inhibited cell growth and invasion, and induced cell apoptosis and cycle arrest in GBC-SD and SGC-996 cells. Furthermore, the expression levels of p-JAK2, p-STAT3, VEGFC-/-D and cyclinD1 were downregulated, while p53 expression was upregulated in AG490-treated GBC cells indicated by Western blot assay. Therefore, our findings demonstrate that JAK inhibitor AG490 inhibits growth and invasion of GBC cells via blockade of JAK2/STAT3 signaling and provides the potential therapeutic strategy for the treatment of GBC patients. PMID- 28337869 TI - Knockdown of HMGB1 inhibits cell proliferation and induces apoptosis in hemangioma via downregulation of AKT pathway. AB - The high mobility group box 1 (HMGB1) as a conserved non-histone nuclear protein has been involved in a variety of biological processes of cancer, such as cell proliferation, apoptosis, angiogenesis and metastasis. Despite the increased expression of HMGB1 in many malignant tumors, the functions and molecular mechanisms by which HMGB1 contributes to the formation of hemangioma (HA) remain unclear. In the present study, immunohistochemistry was used to detect the expression levels of HMGB1 in different phases of human HAs. Cell function experiments, including MTT, cell colony formation and flow cytometry analysis were performed to evaluate the effects of HMGB1 knockdown on cell proliferation and apoptosis in HA CRL-2586 EOMA cells. As a consequence, we found that HMGB1 expression was significantly increased in proliferating phase HAs compared with the involuting phase HAs and normal skin tissues (P less than 0.01). Moreover, knockdown of HMGB1 gene in vitro suppressed EOMA cell proliferation and colony formation and induced cell apoptosis and cycle arrest at G0/G1 phase by downregulation of PCNA, CyclinD1, p-AKT and upregulation of p53 and cleaved PARP. Taken together, our findings demonstrate that HMGB1 may be implicated in the formation of HA through upregulation of AKT pathway, and represent a potential therapeutic target for treating HA. PMID- 28337871 TI - Cytokine modulation in patients with idiopathic pulmonary fibrosis undergoing treatment with steroids, immunosuppressants, and IFN-gamma 1b. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown etiology and pathogenic mechanisms. From an etiopathogenic point of view, alveolar macrophages play a key role in accumulation of fibroblasts and deposition of collagen and extracellular matrix by releasing specific cytokines and inflammatory mediators. IPF seems to be also associated with circulating fibrocytes, which might be involved with an abnormal pulmonary vascular repair and remodeling. Based on its hypothesized pathologic mechanisms, anti inflammatory, anti-fibrotic and immunosuppressive therapies are often used. For these reasons, Interferon-g (IFN-g) has been used to exploit its activity on macrophages and fibroblasts. The aim of this study was to investigate the response to corticosteroids and/or IFN-g 1b treatments based on pulmonary function tests and on inflammatory cytokine patterns of expression on bronchoalveolar lavage (BAL), at baseline and during and after the therapies. Unlike previous studies, we analyzed a period of therapy longer than 1 year. Our results demonstrated the effectiveness of IFN-gamma in a group of IPF patients in whom the treatment was prolonged for over a year. These data suggest a positive role of IFN-gamma; treatment in patients in the initial stage of the disease. PMID- 28337872 TI - Safety and pharmacodynamic mechanism of ropivacaine lumbar anesthesia in Cesarean section. AB - Lumbar anesthesia is the preferred anesthetic approach for puerperae undergoing cesarean section in China. To observe the safety of administering different doses of ropivacaine for cesarean section and its pharmacodynamic mechanism, we randomly divided 180 pregnant women undergoing cesarean section into three groups: group A, 10 mg ropivacaine (0.50%); group B, 12 mg ropivacaine (0.50%); and group C, 14 mg ropivacaine (0.50%). Pharmacodynamic index, anesthesia quality and incidence of untoward reactions of each group were observed. Group A performed the poorest and group C the best in evaluation of sensory and motory block (P less than 0.05). With regard to evaluation of hemodynamic index, hemodynamic parameters of the three groups had significant differences after medication; mean arterial pressure (MAP) of patients in group B decreased at time points T1, T2 and T3 and heart rate (HR) became much higher at T1 (P less than 0.05); MAP of the patients in group C decreased at T1, T2, T3 and T4, but HR became higher at T1 and T2 (P less than 0.05); HR of group B was higher than that of group A at T1 (P less than 0.05); MAP of the patients in group C had a significant decrease at T1, T2, T3 and T4, but HR became higher at T2 (P less than 0.05); MAP of patients in group C significantly decreased compared to group B at T1 and T2, but HR became higher at T2 (P less than 0.05). Fluctuation of oxyhemoglobin saturation (SpO2) of all patients was between 95% and 99%. There was no occurrence of myocardial ischemia or arrhythmia. 1-min Apgar score of neonates of the three groups had no significant difference (P0.05). The incidence of adverse reactions of the patients in group C was much higher than that of the patients in the other groups (P less than 0.05). Twelve mg ropivacaine (5%) is the most suitable dose for pregnant women undergoing cesarean section as it can achieve a sound anesthetic effect and high safety and, moreover, has little influence on respiratory and circulatory functions. PMID- 28337873 TI - Cyclosporine?A augments endoplasmic reticulum stress markers and expression of matrix protein mRNA. AB - Cyclosporine-A induces gingival overgrowth with disturbance in the homeostasis of cells and connective tissue proteins. Human gingival fibroblasts were cultured with cyclosporine A, and the expression of two vital endoplasmic stress markers and two prime matrix proteins (connective tissue growth factor (CTGF and periostin) were assessed by RT-PCR. We found that expression of Glucose-Regulated Protein 78 (GRP78/BIP) and CCAAT/enhancer binding protein, C/EBP homologous protein (CHOP) were significantly increased, along with CTGF and periostin, suggesting a role for these factors in gingival overgrowth. PMID- 28337875 TI - The pig as a model for premature infants - the importance of immunoglobulin supplementation for growth and development. AB - Preterm human neonates, contrary to preterm piglets, obtain immunoglobulins from their mothers via the placenta during intrauterine development. However, one should note that the majority of trans-placental transfer of immunoglobulins in humans takes place during the last trimester of pregnancy. It is also known that the feeding of limited amounts of colostrum or systemic infusion of small amounts of serum improves the survival of preterm and full-term piglets. Full-term piglets deprived of their mother's immunoglobulins exhibit strong apathy and develop watery diarrhoea, often resulting in death. The aim of the current study was to determine if provision of immunoglobulins using different approaches would be beneficial for survival outcomes. To reach the immunological sufficient level we infused immunoglobulins intravenously in amount mimicking the blood level in piglets fed with sow colostrum. Intravenous infusion of immunoglobulins in both preterm and full-term newborn piglets fully ensured their survival, growth and blood immunoglobulin G and protein levels similar to those observed in piglets fed colostrum. Piglets completely deprived of immunoglobulins exhibited significantly lower blood levels of immunoglobulins and protein compared to colostrum-fed animals. Piglets infused with only serum exhibited significantly lower blood immunoglobulin G level compared to those infused with immunoglobulins. In conclusion, based on the data obtained, we suggest that passive immune support provided by colostrum intake or early systemic infusion of Ig's in sufficient amounts is key to ensuring the general well-being of preterm and full-term new born piglets, used as an animal model for the human infant. PMID- 28337874 TI - The biomedical aspects of oral mucosal epithelial cell culture in mammals. AB - In recent years, there has been a growing interest in epithelial cell tissue culture, particularly oral mucosa and its application utilizing in vitro cell culture in medicine. This involves tests using animal models to better understand oral mucosa function, and the differences in its construction in various animal models. The use of buccal pouch mucosal cell culture provides insight into the processes of trans mucosal transport and regeneration of the oral epithelium. The processes associated with epithelium regeneration is the base for stem cell research and/or oral cancer investigation. These artificially cultured tissue equivalents are used in transplant surgery for the treatment of a variety of tissue dysfunctions, i.e. eye, esophagus, or urethra. In this review, the most recent results from studies carried out on in animal models, which may be applied in areas such as regenerative medicine and reconstructive surgery, were explored. PMID- 28337877 TI - Correlation between Cystatin C and retinopathy of type-two diabetes mellitus patients. AB - Diabetic retinopathy is one of most common diabetic microvascular complications. In recent years the incidence of the disease has increased, hence early diagnosis and treatment are of great importance. In order to find reliable biological indexes to diagnose and treat type-two diabetes mellitus promptly, this study focused on the correlation between Cystatin C (Cys C) and retinopathy of type-two diabetes mellitus patients. One hundred and eighty type-two diabetes mellitus patients and one hundred healthy controls (the control group) were chosen in this study. Of the patients ninety-eight patients had typetwo diabetes mellitus without retinopathy (non-diabetic retinopathy group) and eighty-two had typetwo diabetes mellitus with retinopathy (diabetic retinopathy group). Correlation of Cys C and typetwo diabetic retinopathy was analyzed by examining the waist-hip ratio, fasting blood glucose (FBG), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), glycosylated hemoglobin (HbA1c), and Cys C of both groups. The results showed that FBG, TC, TG, LDL-C, HbA1c, Cys C in the type-two diabetes mellitus patients group were higher than those of the control group (P less than 0.05). Age, course of diabetes, FBG, HbA1c, and Cys C levels were statistically significant in both the DR group and NDR group (P less than 0.05). The result of logistic regression analysis indicates that there was a positive correlation between type-two diabetic retinopathy development and age, course of diabetes, and Cys C level (P less than 0.05). Thus, it can be seen that changes of Cys C levels can assist early diagnosis and treatment of diabetic retinopathy to some extent. The patients with high Cys C level, long course of diabetes, and old age are more likely to have diabetic retinopathy. PMID- 28337878 TI - Salivary cortisol, alpha-amylase and immunoglobulin a responses to a morning session of basketball or volleyball training in boys aged 14-18 years. AB - This study investigates whether a single session of routine morning basketball or volleyball training affects saliva levels of cortisol, alpha-amylase (sAA) and secretory immunoglobulin A (sIgA) in boys aged 14?18 years. Twenty-nine boys who participate in basketball or volleyball training, recruited from the Marcin Gortat?s Athletic Championship School in Lodz, were enrolled in the study. The 90 minute routine exercise program included 15 minutes of warm-up followed by basketball or volleyball practice. Unstimulated saliva samples were collected prior to and immediately after the exercise, and were analysed using ELISA. One training session resulted in a significant increase of sAA concentration in all participants, as well as in the volleyball and basketball subgroups (p=0.00022; p=0.0029; p=0.0011; respectively). Post-exercise cortisol levels were significantly lower than pre-exercise levels (p=0.00002) throughout the group, as well as in the volleyball and basketball subgroups (p=0.0048; p=0.0019; p=0.0048; respectively). The exercise protocol did not significantly affect sIgA level, either in the whole examined group or the volleyball subgroup, however a weak significant increase of sIgA was observed in the basketball subgroup (p=0.046). The routine morning training session comprising a warm-up followed by basketball or volleyball practice seems to activate the sympatho-adrenal-medullary system, with a subsequent increase of alpha-amylase, but does not affect oral immunity in 14-18-year-old boys. PMID- 28337876 TI - The efficacy of proanthocyanidins and secnidazole in the treatment of chronic periodontitis after scaling and root planing therapy. AB - The aim of this study is to evaluate the clinical and microbiological effect of the systemic antibiotic therapy of proanthocyanidins and secnidazole on periodontitis. Seventy-five subjects with chronic periodontitis were randomly divided into two treatment groups (secnidazole or proanthocyanidins) and one placebo control group (25 cases each). Plaque index (PI), gingival index (GI), gingival bleeding index (BI), probing pocket depth (PPD), and clinical attachment level (CAL) were carried out at baseline, post-treatment and 3 months after treatment. Microbial analysis was performed at baseline and post-treatment. The results show that the two treatment groups had greater mean reduction in BI, GI, and PPD evaluated at both post-treatment and 3 months after treatment compared to the control group (p less than 0.05), but there were no significant differences in those of PI and CAL (except CAL evaluated at post-treatment, p 0.05). After treatment, culturable bacteria counts significantly decreased. In conclusion, the adjunctive use of proanthocyanidins or secnidazole in combination with scaling and root planing in adults with periodontitis is effective in reducing the pathogenic flora and achieves significantly better clinical results to a certain degree. PMID- 28337880 TI - Effects of anesthesia using propofol and etomidate on T lymphocyte subpopulation of infectious shock patients in perioperative period. AB - Infectious or septic shock is induced when a toxic microorganism invades blood circulation in the human body. Emergency operation is an effective method for treating infectious shock in the early stages although the use of anesthesia is more complex due to the internal disorders caused by the disease. This study explored the effects of propofol and etomidate anesthesia on the cellular immune function (T lymphocyte subpopulation) of infectious shock patients, aiming to provide a basis for the selection of the proper anesthetic method. One hundred and twenty patients with infectious shock were selected and randomly divided into an observation and a control group. The control group were narcotized using propofol, while the observation group were narcotized using etomidate. The effects on the immune functions of patients and drug-related adverse reactions were compared between the two groups. Results demonstrated that the levels of CD3+ and CD4+ of the two groups were similar before anesthesia and the differences had no statistical significance (P 0.05). After anesthesia, the levels of both groups showed a tendency to decrease and the levels of CD3+ and CD4+ of the observation group were much higher than those of the control group in the different periods. The differences were statistically significant (P less than 0.05); the differences of CD8+ level and CD4+/CD8+ between the two groups had no statistical significance before anesthesia (P0.05); after anesthesia, CD8+ level and CD4+/CD8+ of the observation group were all much higher than those of the control group in the different periods and the differences had statistical significance (P less than 0.05). Therefore, the conclusion is that etomidate anesthesia has little influence on the immune functions of infectious shock patients in perioperative period and the incidence of adverse reaction is low, hence, worth clinical promotion. PMID- 28337879 TI - Effects of human parathyroid hormone on bone morphogenetic protein signal pathway following spinal fusion in diabetic rats. AB - Osteoporosis is a major complication in patients with diabetes mellitus. Thus, it is crucial to study the signal mechanisms responsible for enhancement of bone mass in diabetes. Administration of human parathyroid hormone (hPTH) has been reported to prevent osteoblast apoptosis and have anabolic effects on bone in animals and humans. In the present study, we examined the effects of hPTH on expression of bone morphogenetic protein type 2 (BMP-2) and its receptor BMPR2 in diabetic rats following spinal fusion. Our data show that hPTH amplified BMP-2 and BMPR2 in bone tissues of non-diabetic rats, but not in diabetic rats. Our data further demonstrate that hPTH plays a role in regulating BMP-2 and BMPR2 via mTOR-PI3K signal pathway. We suggest specific signaling pathways by which hPTH regulates BMP-2 via mTOR-PI3K mechanism in bone formation following spinal fusion. Notably, our data indicate under diabetic conditions this signal pathway is impaired, thereby likely affecting bone formation after spinal fusion. The subsequent induction of BMP-2 and BMPR2 are likely a part of the protective effects aimed at attenuating pathological bone damage as a result of diabetes. PMID- 28337881 TI - Indoleamine 2,3-dioxygenase and regulatory t cells in intestinal mucosa in children with inflammatory bowel disease. AB - Impaired immune regulation has been suggested as an underlying mechanism of inflammatory bowel disease. Indoleamine 2,3-dioxygenase (IDO) and regulatory T cells expressing FOXP3 are crucial elements of immune regulation. Conversion of FOXP3- lymphocytes to Tregs is one of the functions of IDO. The aim of this study was to evaluate the number of cells expressing FOXP3 and IDO in the lamina propria of intestinal mucosa and to evaluate correlations between these parameters and disease activity. Sixty-six children newly diagnosed with inflammatory bowel disease (41 patients with ulcerative colitis and 25 patients with Crohn?s disease) were included in the study. Clinical activity of the disease was assessed by the Pediatric Ulcerative Colitis Activity Index and the Pediatric Crohn?s Disease Activity Index. Histopathological activity was scored according to the system described by Geboes. The infiltration of FOXP3+ and IDO+ cells was evaluated by immunohistochemistry. Sixteen patients with a diagnosis of irritable bowel syndrome (IBS) served as a control group. Lamina propria demonstrated a significantly higher infiltration of FOXP3+ and IDO+ cells in inflammatory bowel disease compared to the control group (p=0.001, p=0.004, respectively). The number of IDO+ and FOXP3+ cells correlated with clinical and histopathologic activity of Crohn?s disease. A positive correlation between the number of IDO+ and FOXP3+ cells was found in both types of inflammatory disease but not in patients with IBS. We conclude that indoleamine dioxygenase and FOXP3+ cells are upregulated in the intestinal mucosa of children with inflammatory bowel disease. IDO mediated conversion of FOXP3 -T cells to Tregs predominantly occurs in inflammation. PMID- 28337883 TI - Evaluation of tolerance and safety of conversion from mycophenolate mofetil to enteric-coated mycophenolic acid in renal transplant recipients. AB - This study was designed to evaluate the curative effect of conversion from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium tablets (EC MPS) and its safety. One hundred and twenty renal transplant recipients who developed MMF-associated chronic diarrhea were selected as research subjects and treated with EC-MPS. The patients were followed up for 12 months to compare the improvement of gastrointestinal symptoms and the indexes such as carbon dioxide combining power (CO2CP), serum sodium, serum potassium, serum creatinine (Scr) and 24-h urine protein before and after conversion treatment. One hundred and ten of the 120 patients tolerated the conversion treatment and the dose increment of EC-MPS at week 28. After initiating the conversion treatment, the improvement rate of diarrhea within 2 weeks was 95% (114/120). Indexes, such as CO2CP, serum sodium, serum potassium, after conversion treatment were higher than those before treatment (P less than 0.05). No acute rejection reactions were observed in the 12-month follow-up. Indexes of Scr and 24-h urine protein had significant improvement after conversion treatment compared to before conversion treatment (P less than 0.05). Compared to before treatment, the average values of indexes in gastrointestinal symptom rating scale in the 12th month remained stable, except for the increase of dose. For renal transplant recipients who received suboptimal EC-MPS treatment due to gastrointestinal symptoms, conversion from MMF to EC-MPS can significantly lower gastrointestinal symptom load, improve quality of life, relieve electrolyte disturbance and improve the injured functions of transplanted kidney, without increasing the risks of acute rejection reactions. PMID- 28337882 TI - Correlation between blood asymmetric dimethylarginine level and the complications of patients with cardiovascular diseases. AB - This study aimed to investigate the correlation between blood asymmetric dimethylarginine (ADMA) and the complications of patients with cardiovascular diseases through studying the level changes of ADMA, endothelial nitric oxide synthase (eNOS) and NO. Two hundred research subjects with small differences in gender ratio and age, including 50 patients with hypertension combined with myocardial infarction, 50 patients with hypertension, 50 patients with myocardial infarction and 50 healthy normal controls, were enrolled. Relevant basic indexes were measured and recorded; the blood ADMA levels of all the research subjects were detected using high pressure liquid chromatography (HPLC) within the required time. Furthermore, the levels of eNOS and NO were detected using enzyme linked immunosorbent assay and the relevant information, such as blood pressure, was recorded. The comparison and analysis results of data obtained through detection demonstrated that the subjects in the four groups were well comparable. It was found that the myocardial infarction combined with hypertension group had a much higher serum ADMA level and relatively low levels of eNOS and NO compared to those of the other three groups; the myocardial infarction group and the hypertension group had a much higher serum ADMA level compared to that of the healthy control group and the two groups had much lower levels of eNOS and NO. Moreover, the serum ADMA level was in a positive correlation with the severity of cardiovascular diseases and it showed a significant difference in patients with different severity of hypertension. The change of blood ADMA level can induce acute myocardial infarction as well as the occurrence of cardiovascular disease associated complications. PMID- 28337884 TI - Neurochemical effects of photobiostimulation in the trigeminal ganglion after inferior alveolar nerve injury. AB - Orofacial pain is associated with peripheral and central sensitization of trigeminal nociceptive neurons. Nerve injury results in release of chemical mediators that contribute to persistent pain conditions. The activation of the transient receptor potential vanilloid 1 (TRPV1), promotes release of calcitonin gene-related peptide (CGRP) and substance P (SP) from trigeminal nerve terminals. CGRP and SP contribute to the development of peripheral hyperalgesia. The expression of SP and CGRP by primary afferent neurons is rapidly increased in response to peripheral inflammation. CGRP receptor activation promotes activation of AMPA receptors, leading to increased firing of neurons which is reflected as central sensitization. In this study we investigated whether inferior alveolar nerve (IAN) injury influences AMPA receptors, CGRP, SP and TRPV1 expression in the trigeminal ganglion (TG). The relative expression of the protein of interest from naive rats was compared to those from injured rats and animals that received low level laser therapy (LLLT). IAN-injury did not change expression of GluA1, GluA2 and CGRP, but increased the expression of TRPV1 and SP. LLLT increases GluA1 and GluA2 expression and decreases TVPV1, SP and CGRP. These results, together with previous behavioral data, suggest that IAN-injury induced changes in the proteins analyzed, which could impact on nociceptive threshold. These data may help to understand the molecular mechanisms of pain sensitization in the TG. PMID- 28337885 TI - Role of diode lasers in oro-facial pain management. AB - With the increasing use of low level laser therapy (LLLT) in clinical dentistry, the aim of the present study was to assess the effectiveness of diode lasers in the management of orofacial pain. Indexed databases were searched without language and time restrictions up to and including July 2016 using different combinations of the following key words: oral, low level laser therapy, dental, pain, diode lasers, discomfort and analgesia. From the literature reviewed it is evident that LLLT is effective compared to traditional procedures in the management of oro-facial pain associated to soft tissue and hard tissue conditions such as premalignant lesions, gingival conditions and dental extractions. However, it remains to be determined which particular wavelength will produce the more favorable and predictable outcome in terms of pain reduction. It is highly recommended that further randomized control trials with well-defined control groups should be performed to determine the precise wavelengths of the diode lasers for the management of oro-facial pain. Within the limits of the present review, it is concluded that diode lasers therapy is more effective in the management of oro-facial pain compared to traditional procedures. PMID- 28337886 TI - Osteogenesis-promoting activity of composites SBA-15 mesoporous particles carrying oxytocin in vitro and in vivo. AB - This study analyzes the performance of SBA-15 mesoporous particles carrying oxytocin (OT) in promoting osteogenesis in vitro and in vivo. The SBA-15 particles synthesized in the previous studies (about 30 MUm in diameter and containing 10 nm deep pores) were loaded with the drug oxytocin and cultured with human osteosarcoma MG-63 cell line in vitro. The influence of particles on cell proliferation was studied. The level of the osteogenic marker (alkaline phosphatase and type I collagen) was measured. For in vivo studies, the connectivity defects of rabbit skull were prepared, and SBA-15 suspensions were regularly injected at the defect sites. The changes in the defect site calcium salt deposition were measured, and morphological changes were observed by microscopy. The material had to promote effect on osteogenesis-related indicators such as alkaline phosphatase and collagen I in bone sarcoma cell line MG-63. In vivo, the calcium salt deposition in OT/SBA-15 group was significantly higher than in the blank group. SBA-15 carriers appeared to persist in the region of the defect after the injection and release the drugs slowly, thus playing a more distinct role in promoting bone repair of local bone defects. The results showed that SBA-15 particles with OT could slow the release drugs and could help in promoting osteogenesis. PMID- 28337888 TI - Decitabine treatment for acute myeloid leukemia relapse after allogeneic hematopoietic stem cell transplantation. AB - Therapeutic options for patients with relapse of acute myeloid leukemia (AML) after allo-SCT are limited. Here, we present a case of a 49-year female with AML who underwent myeloablative allo-SCT from a matched sibling donor. Seven months after transplantation she developed cGVHD and suffered from extramedullary plus concurrent medullary relapse. The presence of CNS extramedullary disease is unique. Our patient was treated with decetabine. After one cycle the patient achieved complete remission and full donor chimerism without severe side effects or the occurrence of GVHD. Our case report, together with previous studies, provides strong evidence that decitabine may be a suitable treatment option for AML relapse after allogeneic transplantation, especially in patients who developed GVHD. PMID- 28337887 TI - Up-regulation of miR-888-5p in hepatocellular carcinoma cell lines and its effect on malignant characteristics of cells. AB - MicroRNA (miRNA) expression has been linked to the molecular pathogenesis of hepatocellular carcinoma (HCC). The aberrant expression of miRNA is involved in the processes of tumorigenesis and cancer progression. According to the latest research, miR-888-5p is associated with strong cancer-promoting effect. For instance, miR-888-5p is up-regulated in prostate cancer and breast cancer. Nevertheless, the role of miR-888-5p in HCC has not been investigated to date. In this study, we found that miR-888-5p levels in four HCC cell lines (SMMC7721, HepG2, Huh-7 and Bel7402) were significantly up-regulated compared with human hepatocyte cell line (HHL-5). After transiently transfected with miR-888-5p mimic, our results demonstrated that miR-888-5p plays a major role in promoting the proliferation and metastatic potential of HCC cells. Moreover, miR-888-5p also increased the expression of MMP-2 and MMP-9 proteins which account for cell migration and invasion, and decreased the expression of p53 protein which further promoted malignance of HCC. Therefore, miR-888-5p may be considered a potential biomarker for diagnostics and prognosis of HCC. PMID- 28337889 TI - Detection of combined procalcitonin and c-reactive protein applied in the diagnosis of bacterial infections. AB - In recent years, procalcitonin and C-reactive protein have been used as important indexes in the detection of inflammation. In order to analyze the combined detection of procalcitonin and C-reactive protein in infected patients, 57 subjects in the Clinical Laboratory of Zhengzhou Maternal and Child Health Hospital with a bacterial infection were selected as the observation group. Correspondingly, 57 non-infected subjects were selected for the control group. The procalcitonin and C-reactive protein levels in the included cases were analyzed and compared by extracting peripheral blood. The results showed that the two indexes of C-reactive protein (46.13+/-8.24 mg/L) and procalcitonin (6.61+/ 3.45 ug/L) of the observation group were significantly higher than those of the control group (P less than 0.05). The positive rates of C-reactive protein (71.93%) and procalcitonin (91.23%) of the observation group were significantly higher than those of the control group (P less than0.05). Within the observation group, the C-reactive protein and procalcitonin levels in the infected patients after 2 and 3 days of treatment, decreased significantly (P less than 0.05). This study indicates that the combined detection of procalcitonin and C-reactive protein in patients with bacterial infections is effective and can be used in clinical settings. PMID- 28337891 TI - Screening and comparison of polychromatic and monochromatic image reconstruction of abdominal arterial energy spectrum CT. AB - We screened the suitable image reconstruction to observe the abdominal artery and compare the quality between the polychromatic and the monochromatic reconstruction images of the abdominal artery spectrum CT. Eighty patients underwent Gemstone CT energy spectrum imaging to obtain an abdominal artery polychromatic image (140 kVp) and a monochromatic image from 40 ~ 140 keV. The CT value of region of interest (ROI) was measured on the polychromatic image and the single energy image. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of the abdominal aorta and hepatic artery were determined. The images in each group underwent image quality subjective scoring by three experienced radiologists using a blinded method. Finally, comprehensive comparisons and image quality subjective scorings were performed on the CT, SNR, and CNR values of the abdominal aorta. The obtained data were statistically analyzed by SPSS 19.0 software. When the keV value was reduced, the CT value of the abdominal artery gradually increased, and the image noise also changed. The comprehensive comparisons and subjective scorings were finalized for each single energy image based on the abdominal artery image quality objective indicators (CT value, SNR, and CNR). Results revealed that the abdominal artery image quality in the 50 ~ 60 keV monochromatic group was better compared to the polychromatic group. Furthermore, onochromatic imaging had different impacts on the abdominal aorta and hepatic artery image qualities. In different types of abdominal arterial reconstruction images obtained using abdominal energy spectrum CT conventional enhanced scanning, the image quality of the 50 ~ 60keV monochromatic reconstruction was higher when compared with the polychromatic reconstruction. Thus, it is recommended to apply the conventional reconstruction for abdominal artery energy spectrum CT scanning. PMID- 28337890 TI - Beneficial effects of protein hydrolysates in exercise and sports nutrition. AB - Protein hydrolysates (PH) are rich sources of proteins that supply the need of exercising muscles. PHs are enriched in di- and tripeptides and are better than free amino acids or intact proteins when muscle anabolic effect is considered. Digestion, absorption and muscle uptake of amino acids are faster and more efficient when PH is ingested in comparison to the respective intact protein. PHs not only enhance endurance in high intensity exercise regimen, but also help in faster post-exercise recovery of muscle by promoting glycogen synthesis, although the latter effect requires more convincing evidence. PHs have been shown to exhibit insulinotrophic effect as it enhances the secretion of insulin and the hormone, in turn, exerts muscle anabolic effect. PMID- 28337892 TI - Idiopathic intracranial hypertension in a paediatric population: a retrospective observational study on epidemiology, symptoms and treatment. AB - Idiopathic intracranial hypertension (IIH) is a disorder of unknown origin, which is characterized by elevated intracranial pressure (ICP) without underlying etiological evidence of neurological disease. The purpose of the current study was to evaluate epidemiological features, clinical presentation, diagnostic findings and treatment of sixteen children (7 males and 9 females) with IIH. Medical records of the patients were obtained from the University Paediatric Hospital of Catania, Italy. Clinical features, investigations and treatment approaches were retrieved. The mean age of the sixteen children at onset of symptoms was 9 years (range: 4 to 16 years). Most of the patients were classified as pre-pubertal. Mean BMI was 28.9 kg/m2. In 93.75% of patients headache was the presenting clinical symptom; and in the same percentage papilledema was detected as the accompanied sign during diagnostic flow-chart. The mean lumbar puncture opening pressure (LPOP) was 350 mm H2O. Fifty percent of the cases had normal brain imaging, while 12.5% showed enlarged optic nerve diameter and one patient had an intraocular protrusion of the optic nerve on MRI. Two patients (12.5%) had venous sinus stenosis, and one case showed an abnormal spinal MRI. With regard to therapeutic approaches, 93.75% of the cases were successfully treated with Acetazolamide. None of the patients required surgical procedures, and all neuroimaging findings disappeared after receiving treatment. In the present study we investigated the association of IIH with venous sinus stenosis. We also found ocular ultrasound to be a useful non-invasive alternative method for determining papilledema in paediatric IIH, specifically in an emergency. PMID- 28337894 TI - ACTN3/ACE genotypes and mitochondrial genome in professional soccer players? performance. AB - Two nuclear genes, ACTN3, encoding for the alpha-actinin skeletal muscle isoform 3, and ACE encoding the angiotensin-converting enzyme, have both been associated with quantitative physical performance traits in the general population. The purpose of our study was to assess the association between the two nuclear gene variants, R577X (rs1815739) in ACTN3 and I/D (rs4340) in ACE, with elite athletes? performance and the effect of training on the mitochondrial DNA (mtDNA) content in peripheral blood. We evaluated the genotypes and frequencies of ACTN3 R577X and ACE I/D polymorphisms between soccer players (n = 43) and healthy non athletic controls (n = 128). Total DNA was extracted from peripheral blood samples using the standard procedure. The genotypes were assessed by PCR-RFLP analysis and mtDNA cellular content by RT-PCR. The soccer players showed a tendency to a prevalence of ACTN3RR and ACEDD genotypes both independently and in co-occurrence. The effect of physical training on the mitochondrial DNA content in the athletic population was reflected strikingly in its increase in peripheral blood. Based on our results, we suggest that the analysis of ACTN3 and ACE genotypes could predict talent in the soccer field and that knowledge of the genetic variants could determine types and training times for soccer players. In addition, the novelty of this work, never before described in the sports literature, is that the increase of mitochondrial content can be correlated with the training load, suggesting that the mtDNA copy number may be considered a viable bioenergetics biomarker. PMID- 28337893 TI - Adjuvant treatment with a symbiotic in patients with inflammatory non-allergic rhinitis. AB - Inflammatory non-allergic rhinitis (INAR) is characterized by the presence of an inflammatory infiltrate and a non-IgE-mediated pathogenesis. This retrospective, controlled, multicentre study investigated whether a symbiotic, containing Lactobacillus acidophilus NCFM, Bifidobacterium lactis, and fructo oligosaccharides (Pollagen(r), Allergy Therapeutics, Italy), prescribed as adjunctive therapy to a standard pharmacological treatment, was able to reduce symptom severity, endoscopic features, and nasal cytology in 93 patients (49 males and 44 females, mean age 36.3+/-7.1 years) with INAR. The patients were treated with nasal corticosteroid, oral antihistamine, and isotonic saline. At randomization, 52 patients were treated also with symbiotic as adjunctive therapy, whereas the remaining 41 patients served as controls. Treatment lasted for 4 weeks. Patients were visited at baseline, after treatment, and after 4-week follow-up. Adjunctive symbiotic treatment significantly reduced the percentages of patients with symptoms and endoscopic signs, and diminished inflammatory cells. In conclusion, the present study demonstrates that a symbiotic was able, as adjuvant treatment, to significantly improve symptoms, endoscopic feature, and cytology in patients with INAR, and its effect may be long lasting. PMID- 28337895 TI - Use of supercharged cover screw as static magnetic field generator for bone healing, 1st part: in vitro enhancement of osteoblast-like cell differentiation. AB - Since 1979, Pulsed electromagnetic fields (PEMFs) have been approved by the Food and Drug Administration as an effective method in the treatment of non-unions. As well as PEMFs, also static magnetic fields (SMFs) have been widely investigated in orthopaedic studies. Even if the exact mechanism of action is not well understood, a large number of studies showed specific effects both at cellular and tissue levels. As bone fracture healing and osseointegration share the same biological events, the application of magnetic field stimulation in order to facilitate the osseointegration process has been suggested. In this study we investigated the proliferation rate and gene expression profile of MG63 osteoblastic-like cells after a 24, 48 and 72-hour SMF stimulation, generated by a small, customized cover screw-shaped neodymium-iron-bore magnet placed in the inner cavity of a dental implant. As a result, we found that the application of a SMF to osteoblastic-like cells does slightly decrease cell proliferation rate while enhancing the expression of those genes correlated to differentiation and mineralization. Our findings represent, to our knowledge, the first clinical ready technique for dental implants showing the ability of SMF to promote the osteogenesis process in vitro. PMID- 28337896 TI - Maternal obesity and perinatal oxidative stress: the strength of the association. AB - Maternal obesity is a chronic inflammatory state, which has been shown to induce increased levels of free fatty acids, reactive oxygen species and inflammatory cells. Recent evidence reveals increased levels of lipid peroxidation products in the plasma of obese women during pregnancy. The aim of this study was to test the hypothesis that maternal overweight or obesity is associated with increased oxidative stress (OS) in offspring. Two hundred and forty-five pregnant women and their newborns were prospectively enrolled. Mothers were divided in two groups: lean control - LC (n=175, Group I); overweight or obese (n=70, Group II) according to BMI >= 25 before pregnancy. Cord blood F2-isoprostanes (F2-IsoPs), as reliable markers of OS, were measured in all newborns. Lower 1 minute APGAR score and higher weight at discharge were found in Group II neonates, compared to those of Group I (p less than 0.05). Small for gestational age (SGA) newborns of both groups showed increased levels of F2-IsoPs than appropriate (AGA) or large (LGA) for gestational age (GA) (p less than 0.01). SGA newborns of Group II had higher F2-IsoPs levels compared to SGA of Group I (p less than 0.01), which were significantly correlated to maternal BMI at the end of pregnancy (r=0.451, p less than 0.01). Multivariate regression analysis corrected for confounding factors, showed that maternal overweight or obesity was significantly associated with high F2-IsoPs levels in SGA offspring (p less than 0.01). Maternal overweight or obesity is associated with increased OS in their SGA newborns. Data suggest the need of antioxidant protection for both mothers during pregnancy and infants soon after birth. PMID- 28337897 TI - Exhaled breath temperature measurement: influence of circadian rhythm. AB - Exhaled breath temperature (EBT) is an expression of airway inflammation, an event that drives several lung diseases. The measurement of the exhaled breath temperature has recently been proposed as a popular tool in the diagnosis and monitoring of inflammatory lung diseases due to the fact that it is a non invasive method. The influence of external factors on EBT, its reproducibility, and its sensitivity to treatment have already been explored. However, to reach clinical practice, EBT requires a complete validation that is still lacking. The aim of this study was to analyse the possible influence of an important internal variable, i.e the circadian rhythm on EBT values in a group of 24 healthy adult volunteers. We repeated measurement of EBT at different hours of the day: 8.00 AM, 12.00 AM, 4.00 PM, 8.00 PM and analysed the correlation with axillary temperature measurement at these times. The EBT resulted significantly different during daily measurements (8.00 AM vs 12.00 AM vs 4.00 PM vs 8.00 PM: 28.01+/ 1.64 degrees C vs 28.8+/-1.82 degrees C vs 29.34+/-1.79 degrees C vs 28.06+/-1.34 degrees C). The highest EBT was reported at 4.00 PM and the lowest at 8.00 AM. For the first time we found an influence of the circadian rhythm on EBT. These data support the validation of the EBT necessary for its promotion in clinical practice. PMID- 28337898 TI - Melanin of the nipple areola complex. AB - Biological pigments or biochromes are ubiquitous in animals, plants, and simpler organisms such as fungi and bacteria. They serve a wide spectrum of functions from photosynthesis, camouflage, mimicry, photo protection from the environment to attracting mates. The human female nipple areola complex (NAC) is a highly pigmented area. Currently, the prevailing theory as to the evolution of the pigmented human NAC is based on infant recognition of breast feeding latching zone; however, due to the protruding shape of the nipple and surrounding breast, the authors of this letter believe that the evolutionary advantage of the pigmented NAC has a direct physiological function, namely the initiation of involution at the end of the infant lactation period. PMID- 28337899 TI - Substance P expression in the gingival tissue after upper third molar extraction: effect of ketoprofen, a preliminary study. AB - The aim of this study was to evaluate substance P (SP) levels and the effect of a non-steroidal anti-inflammatory drug (NSAID), ketoprofen, on SP in the pericoronal gingival tissue after extraction of upper third molars. A sample of 20 young non-smoking systemically healthy adults of both sexes, with a healthy upper third molar to extract for orthodontic purposes, was selected. After extraction, a sample of the gingival tissue of the pericoronal region was collected with a sterile scalpel, placed into test tubes and kept frozen at -20 degrees C until the SP determination. SP levels were determined by using a commercially available enzyme immunoassay (ELISA) kit. The subjects were randomly divided into two groups: group 1 received a single dose of ketoprofen 30 minutes prior to the experimental procedure. The subjects of group 2 did not receive any kind of drug administration before extraction. The patients were asked to complete a diary on the postoperative pain. A relevant amount of SP was measured in all the gingival samples. No statistically significant difference could be detected in SP expression between the two groups. In group 1 pain appearance was significantly delayed (6.2+/-0.13 hours) in comparison with group 2 (3.95+/-0.2 hours). In this small selected group of subjects and limited study design, preventive administration of ketoprofen did not significantly affect the gingival levels of SP, the clinical recommendation emerging is that of NSAID administration postoperatively but before pain appearance in order to optimize the management of pain of the patient. PMID- 28337900 TI - The fingerprint of the human gastrointestinal tract microbiota: a hypothesis of molecular mapping. AB - The precise etiology of Inflammatory Bowel Disease (IDB) remains unclear and several factors are believed to play a role in its development and progression, including the composition of microbial communities resident in the gastrointestinal tract. Human intestinal microbiota are extensive with at least 15,000-36,000 bacterial species. However, thanks to the new development in sequencing and molecular taxonomic methodologies, our understanding of the microbiota population composition, dynamics, and ecology has greatly increased. Intestinal microbiota play a critical role in the maintenance of the host intestinal barrier homeostasis, while dysbiosis, which involves reduction in the microbiome diversity, can lead to progression of inflammatory disorders, such as IBD and colorectal cancer. It is hypothesized that fingerprinting characterization of the microbiota community composition is the first step in the study of this complex bacterial ecosystem and a crucial step in the targeted therapy. Molecular fingerprinting of human gastrointestinal tract microbiota could be performed by different techniques including the semi quantitation, 16SrRNA, the DNA- microarray as well as other relatively new methods which were developed to study many complex bacterial ecosystems. These techniques provide individual data and profiles, using fast and sensitive tools for the high taxonomic level fingerprint of the human intestinal microbiota and provide estimation of the relative presence of the microbial target groups within each individual. Such personalized information serves as a remarkable and unprecedented opportunity to improve targeted medical treatment and probably develop strategies to prevent disease. PMID- 28337901 TI - Cardiopathy and osteoporosis: the epidemiology in a region of Italy. AB - Cardiopathies and osteoporosis are inter-related due to pathogenetic, hormonal, genetic features as well as an increased risk of fragility. An important feature is attributed to the process of atherosclerosis, which is responsible for an osteopenia effect and degeneration of vascular walls. To date the study populations have been limited. To verify the incidence of cardio-vascular disease in a larger osteoporotic population, we designed a retrospective clinical study analyzing the ?Hospital Discharge Data? (HDD) in Apulia between 2006 and 2010. All patients over 55 years with a hospitalization for a fragility fracture and/or drugs prescription for osteoporosis were crossed with the diagnosis and/or drugs prescription for cardiovascular disease. We observed that between 2006 and 2010, in Apulia, 177,639 patients were hospitalized and diagnosed as having fragility fractures, 66.3% had a diagnosis of cardiopathy, with a higher prevalence in males and in patients over 80 years. The incidence of fractures were as follows: femur (51.9%), spine (20.2%), humerus (10.6%), forearm (9%), tibial pilon (7.2%) and tarsus and metatarsus (1.1%). Cerebrovascular diseases were the most frequent, followed by arrhythmias, heart failure and cardiomyopathies. In these patients, the most prescribed drugs were anti-coagulants, ACE inhibitors and diuretics. In patients affected by cerebral circulation disorder there is a greater propensity to fall and thus have a fragility fracture, particularly of the femur. The vertebral fracture, misdiagnosed in 60-70% of patients, may compromise the cardio-respiratory function of these patients. We verified a higher incidence of fragility fractures in patients who were prescribed certain categories of drugs for the treatment of cardio-vascular disease. This hypothesis is not supported by the literature, where contradictory results on the potential effects of these drugs on bone have been published. The high incidence of heart disease found in patients with fragility fractures supports the need for specific screening for osteoporosis in the population with cardio-circulatory pathology. PMID- 28337903 TI - Air-Liquid Interfacial Self-Assembly of Non-Amphiphilic Poly(3-hexylthiophene) Homopolymers. AB - Here, we demonstrate that the self-assembly of poly(3-hexylthiophene) (P3HT) at the air-water interface can lead to free-standing films of densely packed P3HT nanowires. Interfacial self-assembly on various liquid subphases, such as water, diethylene glycol, and glycerol, indicates that the viscosity of the subphase is an important factor for the formation of well-ordered nanostructures. The thin film morphology is also sensitive to the concentration of P3HT, its molecular weight (MW), and the presence of oxidative defects. The densely packed nanowire films can be easily transferred to solid substrates for device applications. The ultrathin films of P3HT prepared by the interfacial assembly showed significantly higher hole mobility (~3.6 * 10-2 cm2/V s) in a field-effect transistor than comparably thin spin-cast films. This work demonstrates that the air-liquid interfacial assembly is not limited to amphiphilic polymers and can, under optimized conditions, be applied to fabricate ultrathin films of widely used conjugated polymers with controlled morphologies. PMID- 28337902 TI - Helicobacter pylori in periodontal pockets and saliva: a possible role in gastric infection relapses. AB - It has been a long time since the scientific community started to speculate upon the presence of Helicobacter pylori (HP) in periodontal pockets as an extra gastric reservoir responsible for gastric relapses after eradication therapy. The aim of this study is to evaluate the presence of oral HP in a group of patients who underwent examination for gastric infection. Sixty patients were enrolled in the current study, subdivided into two groups: 30 patients with a positive result for HP gastric infection with C-Breath Test Urea examination, and 30 patients with a negative result for HP gastric infection. Crevicular fluid and salivary samples were collected in a sterile tube and then sent to the laboratory for evaluation. Specimens were processed to quantify the levels of HP and bacterial load by real time PCR technique. Even though there was no statistically significant difference among the two groups (A vs B) with regard to the total amount of HP in saliva or in periodontal tissues, this study demonstrates that the oral cavity is an extra-gastric reservoir of HP when it is affected by periodontal disease, and that periodontal disease is correlated to gastric HP infection. PMID- 28337904 TI - Shallow Acceptor State in Mg-Doped CuAlO2 and Its Effect on Electrical and Optical Properties: An Experimental and First-Principles Study. AB - Shallow acceptor states in Mg-doped CuAlO2 and their effect on structural, electrical, and optical properties are investigated by combining first-principles calculations and experiments. First-principles calculations demonstrate that Mg substituting at the Al site in CuAlO2 plays the role of shallow acceptor and has a low formation energy, suggesting that Mg doping can increase hole concentration and improve the conductivity of CuAlO2. Hall effect measurements indicate that the hole concentration of the Mg-doped CuAlO2 thin film is 2 orders of magnitude higher than that of undoped CuAlO2. The best room temperature conductivity of 8.0 * 10-2 S/cm is obtained. A band gap widening is observed in the optical absorption spectra of Mg-doped CuAlO2, which is well supported by the results from first-principles electronic structure calculations. PMID- 28337905 TI - Simultaneous Detection of Dihydroxybenzene Isomers with ZnO Nanorod/Carbon Cloth Electrodes. AB - Herein, ZnO nanorods with an average diameter of 50 nm were uniformly anchored on the surface of carbon cloth directly by a simple hydrothermal method. The nanorods growing in situ along the specific direction of (002) have single crystalline features and a columnar structure. On the basis of the ZnO nanorod/carbon cloth composite, free-standing electrodes were fabricated for the simultaneous determination of dihydroxybenzene isomers. The ZnO nanorod/carbon cloth electrodes exhibited excellent electrochemical stability, high sensitivity, and high selectivity. The linear ranges of concentration for hydroquinone, catechol, and resorcinol were 2-30, 2-45, and 2-385 MUM, respectively, and the corresponding limits of detection (S/N = 3) were 0.57, 0.81, and 7.2 MUM. The outstanding sensing properties of ZnO/carbon cloth electrodes have a great promise for the development of free-standing biosensors and other electrochemical devices. PMID- 28337906 TI - Fates of Chemical Elements in Biomass during Its Pyrolysis. AB - Biomass is increasingly perceived as a renewable resource rather than as an organic solid waste today, as it can be converted to various chemicals, biofuels, and solid biochar using modern processes. In the past few years, pyrolysis has attracted growing interest as a promising versatile platform to convert biomass into valuable resources. However, an efficient and selective conversion process is still difficult to be realized due to the complex nature of biomass, which usually makes the products complicated. Furthermore, various contaminants and inorganic elements (e.g., heavy metals, nitrogen, phosphorus, sulfur, and chlorine) embodied in biomass may be transferred into pyrolysis products or released into the environment, arousing environmental pollution concerns. Understanding their behaviors in biomass pyrolysis is essential to optimizing the pyrolysis process for efficient resource recovery and less environmental pollution. However, there is no comprehensive review so far about the fates of chemical elements in biomass during its pyrolysis. Here, we provide a critical review about the fates of main chemical elements (C, H, O, N, P, Cl, S, and metals) in biomass during its pyrolysis. We overview the research advances about the emission, transformation, and distribution of elements in biomass pyrolysis, discuss the present challenges for resource-oriented conversion and pollution abatement, highlight the importance and significance of understanding the fate of elements during pyrolysis, and outlook the future development directions for process control. The review provides useful information for developing sustainable biomass pyrolysis processes with an improved efficiency and selectivity as well as minimized environmental impacts, and encourages more research efforts from the scientific communities of chemistry, the environment, and energy. PMID- 28337907 TI - Single-Cell-Based Platform for Copy Number Variation Profiling through Digital Counting of Amplified Genomic DNA Fragments. AB - We develop a novel single-cell-based platform through digital counting of amplified genomic DNA fragments, named multifraction amplification (mfA), to detect the copy number variations (CNVs) in a single cell. Amplification is required to acquire genomic information from a single cell, while introducing unavoidable bias. Unlike prevalent methods that directly infer CNV profiles from the pattern of sequencing depth, our mfA platform denatures and separates the DNA molecules from a single cell into multiple fractions of a reaction mix before amplification. By examining the sequencing result of each fraction for a specific fragment and applying a segment-merge maximum likelihood algorithm to the calculation of copy number, we digitize the sequencing-depth-based CNV identification and thus provide a method that is less sensitive to the amplification bias. In this paper, we demonstrate a mfA platform through multiple displacement amplification (MDA) chemistry. When performing the mfA platform, the noise of MDA is reduced; therefore, the resolution of single-cell CNV identification can be improved to 100 kb. We can also determine the genomic region free of allelic drop-out with mfA platform, which is impossible for conventional single-cell amplification methods. PMID- 28337908 TI - Detection of 2,4,6-Trinitrotoluene Using a Miniaturized, Disposable Electrochemical Sensor with an Ionic Liquid Gel-Polymer Electrolyte Film. AB - A new electrochemical method to detect and quantify the explosive compound 2,4,6 trinitrotoluene (TNT) in aqueous solutions is demonstrated. A disposable thin film electrode modified with a droplet of a gel-polymer electrolyte (GPE) was immersed directly into samples of TNT at concentrations of 1-10 MUg/mL. The GPE contained the hydrophobic room-temperature ionic liquid (RTIL) trihexyltetradecylphosphonium bis(trifluoromethylsulfonyl)imide ([P14,6,6,6][NTf2]) and the polymer poly(hexyl methacrylate). The RTIL acted to preconcentrate TNT into the GPE and provided ionic conductivity. The polymer provided both (i) sufficient viscosity to ensure mechanical stability of the GPE and (ii) strong hydrophobicity to minimize leaching of the RTIL. Square wave voltammetry was performed on the first reduction peak of TNT-preconcentrated samples (15 min soaking with mechanical stirring), with linear plots of peak current vs cumulative concentration of TNT, giving an averaged limit of detection of 0.37 MUg/mL (aqueous phase concentration). Additionally, the voltammetry of the first reduction peak of TNT in [P14,6,6,6][NTf2] was unaffected by the presence of oxygen-in contrast to that observed in an imidazolium-based RTIL providing excellent selectivity over oxygen in real environments. The sensor device was able to quickly and easily quantify TNT concentrations at typical ground water contamination levels. The low-cost and portability of the sensor device, along with the minimal amounts of GPE materials required, make this a viable platform for the onsite monitoring of explosives, which is currently a significant operational challenge. PMID- 28337910 TI - Large-Area and Transferred High-Quality Three-Dimensional Topological Insulator Bi2-xSbxTe3-ySey Ultrathin Film by Catalyst-Free Physical Vapor Deposition. AB - Uniform and large-area synthesis of bulk insulating ultrathin films is an important subject toward applications of a surface of three-dimensional topological insulators (3D-TIs) in various electronic devices. Here we report epitaxial growth of bulk insulating three-dimensional topological insulator (3D TI) Bi2-xSbxTe3-ySey (BSTS) ultrathin films, ranging from a few quintuple to several hundreds of layers, on mica in a large-area (1 cm2) via catalyst-free physical vapor deposition. These films can nondestructively be exfoliated using deionized water and transferred to various kinds of substrates as desired. The transferred BSTS thin films show good ambipolar characteristics as well as well defined quantum oscillations arising from the topological surface states. The carrier mobility of 2500-5100 cm2/(V s) is comparable to the high-quality bulk BSTS single crystal. Moreover, tunable electronic states from the massless to the massive Dirac fermion were observed with a decrease in the film thickness. Both the feasible large-area synthesis and the reliable film transfer process can promise that BSTS ultrathin films will pave a route to many applications of 3D TIs. PMID- 28337911 TI - Mathematical Model of Serodiagnostic Immunochromatographic Assay. AB - This article describes the mathematical model for an immunochromatographic assay for the detection of specific immunoglobulins against a target antigen (antibodies) in blood/serum (serodiagnosis). The model utilizes an analytical (non-numerical) approach and allows the calculation of the kinetics of immune complexes' formation in a continuous-flow system using commonly available software, such as Microsoft Excel. The developed model could identify the nature of the influence of immunochemical interaction constants and reagent concentrations on the kinetics of the formation of the detected target complex. On the basis of the model, recommendations are developed to decrease the detection limit for an immunochromatographic assay of specific immunoglobulins. PMID- 28337909 TI - Engineering of Ferroelectric HfO2-ZrO2 Nanolaminates. AB - In this work, the ferroelectric properties of nanolaminates made of HfO2 and ZrO2 were studied as a function of the deposition temperature and the individual HfO2/ZrO2 layer thickness before and after electrical field cycling. The ferroelectric response was found to depend on the structure of the nanolaminates before any postdeposition annealing treatment. After annealing with a TiN cap, an "antiferroelectric-like" response was obtained from nanolaminates deposited in an amorphous state at a lower temperature, whereas a ferroelectric response was obtained from nanolaminates deposited at a higher temperature, where crystallites were detected in thick films before annealing. As the individual layer thicknesses were decreased, an increased lattice distortion and a concurrent increase in remanent polarization were observed from the nanolaminates deposited at high temperatures. After field cycling, nanolaminates deposited at lower temperatures exhibited an antiferroelectric-like to ferroelectric transition, whereas those deposited at higher temperatures exhibited a larger remanent polarization. Finally, we demonstrate that by leveraging the proper choice of process conditions and layer thickness, remanent polarizations exceeding those of the HfZrO4 solid solution can be obtained. PMID- 28337912 TI - Nanostructured Nickel-Cobalt-Titanium Alloy Grown on Titanium Substrate as Efficient Electrocatalyst for Alkaline Water Electrolysis. AB - One of the important challenges in alkaline water electrolysis is to utilize a bifunctional catalyst for both hydrogen evolution (HER) and oxygen evolution (OER) reactions to increase the efficiency of water splitting devices for the long durable operations. Herein, nickel-cobalt-titanium (NCT) alloy is directly grown on a high corrosion resistance titanium foil by a simple, single, and rapid electrochemical deposition at room temperature. The electrocatalytic activity of NCT alloy electrodes is evaluated for both HER and OER in aqueous electrolyte. Our NCT electrocatalyst exhibits low overpotentials around 125 and 331 mV for HER and OER, respectively, in 1 M KOH. In addition to this outstanding activity, the bifunctional catalyst also exhibits excellent OER and HER electrode stability up to 150 h of continuous operation with a minimal loss in activity. Further, the NCT alloy directly grown on titanium foil is used to directly construct membrane electrode assembly (MEA) for alkaline electrolyte membrane (AEM) water electrolyzer, which make the practical applicability. This single-step electrodeposition reveals NCT on titanium foil with high activity and excellent electrode stability suitable for replacing alternative commercial viable catalyst for the alkaline water splitting. PMID- 28337913 TI - Selective Conversion from p-Type to n-Type of Printed Bottom-Gate Carbon Nanotube Thin-Film Transistors and Application in Complementary Metal-Oxide-Semiconductor Inverters. AB - The fabrication of printed high-performance and environmentally stable n-type single-walled carbon nanotube (SWCNT) transistors and their integration into complementary (i.e., complementary metal-oxide-semiconductor, CMOS) circuits are widely recognized as key to achieving the full potential of carbon nanotube electronics. Here, we report a simple, efficient, and robust method to convert the polarity of SWCNT thin-film transistors (TFTs) using cheap and readily available ethanolamine as an electron doping agent. Printed p-type bottom-gate SWCNT TFTs can be selectively converted into n-type by deposition of ethanolamine inks on the transistor active region via aerosol jet printing. Resulted n-type TFTs show excellent electrical properties with an on/off ratio of 106, effective mobility up to 30 cm2 V-1 s-1, small hysteresis, and small subthreshold swing (90 140 mV dec-1), which are superior compared to the original p-type SWCNT devices. The n-type SWCNT TFTs also show good stability in air, and any deterioration of performance due to shelf storage can be fully recovered by a short low temperature annealing. The easy polarity conversion process allows construction of CMOS circuitry. As an example, CMOS inverters were fabricated using printed p type and n-type TFTs and exhibited a large noise margin (50 and 103% of 1/2 Vdd = 1 V) and a voltage gain as high as 30 (at Vdd = 1 V). Additionally, the CMOS inverters show full rail-to-rail output voltage swing and low power dissipation (0.1 MUW at Vdd = 1 V). The new method paves the way to construct fully functional complex CMOS circuitry by printed TFTs. PMID- 28337914 TI - Electrically-Actuated Valves for Woven Fabric Lateral Flow Devices. AB - The integration of flow control elements into low-cost biosensors presents a significant engineering challenge. This Article describes the development and integration of active, chemical valves into lateral flow devices, using a scalable, single-step, weaving-based manufacturing approach. The valve was constructed from an electrically conductive polymer, polypyrrole. The polymer switches between wetting and nonwetting states when it is reduced and oxidized via the application of an electrochemical potential. In this work, yarns were first coated with polypyrrole and integrated into fabric lateral flow sensors. The coated yarns were stimulated in situ via integrated electrodes. Coated textiles were characterized for their response to variations in the applied electrical potential, the duration for which the potential is applied, and the chemical composition of the polymer. Among these tuning parameters, the concentration of iron (iii) chloride utilized to catalyze the synthesis of the polymer, was found to be a significant determinant in the wetting range of the polymer. Complete ON/OFF flow control was achieved at applied potentials of 20 V.cm-1, within 120 s of stimulation, using 0.1 M iron (iii) chloride, making the valve fairly easy to incorporate into point-of-care format. The practical utility of the valve was demonstrated by performing a Lowry protein assay in the device, wherein fluid flow was deactivated to allow individual reaction steps to go to completion prior to reactivation. Significant improvements in the sensitivity and linear range of the devices are reported in a simple straight-channel, lateral flow device, with the potential to develop more complex channel geometries via the weaving-based approach. PMID- 28337915 TI - Nano-Raman Scattering Microscopy: Resolution and Enhancement. AB - Raman scattering microscopy is becoming one of the hot topics in analytical microscopy as a tool for analyzing advanced nanomaterials, such as biomolecules in a live cell for the study of cellular dynamics, semiconductor devices for characterizing strain distribution and contamination, and nanocarbons and nano-2D materials. In this paper, we review the recent progress in the development of Raman scattering microscopy from the viewpoint of spatial resolution and scattering efficiency. To overcome the extremely small cross section of Raman scattering, we discuss three approaches for the enhancement of scattering efficiency and show that the scattering enhancement synergistically increases the spatial resolution. We discuss the mechanisms of tip-enhanced Raman scattering, deep-UV resonant Raman scattering, and coherent nonlinear Raman scattering for micro- and nanoscope applications. The combinations of these three approaches are also shown as nanometer-resolution Raman scattering microscopy. The critical issues of the structures, materials, and reproducibility of tips and three dimensionality for TERS; photodegradation for resonant Raman scattering; and laser availability for coherent nonlinear Raman scattering are also discussed. PMID- 28337916 TI - Ag-Incorporated Organic-Inorganic Perovskite Films and Planar Heterojunction Solar Cells. AB - Controlled doping for adjustable material polarity and charge carrier concentration is the basis of semiconductor materials and devices, and it is much more difficult to achieve in ionic semiconductors (e.g., ZnO and GaN) than in covalent semiconductors (e.g., Si and Ge), due to the high intrinsic defect density in ionic semiconductors. The organic-inorganic perovskite material, which is frenetically being researched for applications in solar cells and beyond, is also an ionic semiconductor. Here we present the Ag-incorporated organic inorganic perovskite films and planar heterojunction solar cells. Partial substitution of Pb2+ by Ag+ leads to improved film morphology, crystallinity, and carrier dynamics as well as shifted Fermi level and reduced electron concentration. Consequently, in planar heterojunction photovoltaic devices with inverted stacking structure, Ag incorporation results in an enhancement of the power conversion efficiency from 16.0% to 18.4% in MAPbI3 based devices and from 11.2% to 15.4% in MAPbI3-xClx based devices. Our work implies that Ag incorporation is a feasible route to adjust carrier concentrations in solution processed perovskite materials in spite of the high concentration of intrinsic defects. PMID- 28337917 TI - Micrometer-Precise Determination of the Thin Electrolyte Layer of a Spectroelectrochemical Cell by Microelectrode Approach Curves. AB - A spectroelectrochemical cell is presented that allows investigations of electrochemical reactions by means of attenuated total reflection infrared (ATR IR) spectroscopy. The electrode holder for the working (WE), counter and reference electrode as mounted in the IR spectrometer cause the formation of a thin electrolyte layer between the internal reflection element (IRE) and the surface of the WE. The thickness of this thin electrolyte layer (dTL) was estimated by performing a scanning electrochemical microscopy-(SECM) like approach of a Pt microelectrode (ME), which was leveled with the WE toward the IRE surface. The precise lowering of the ME/WE plane toward the IRE was enabled by a micrometer screw. The approach curve was recorded in negative feedback mode of SECM and revealed the contact point of the ME and WE on the IRE, which was used as reference point to perform the electro-oxidation of ethanol over a drop casted Pd/NCNT catalyst on the WE at different thin-layer thicknesses by cyclic voltammetry. The reaction products were detected in the liquid electrolyte by IR spectroscopy, and the effect of variations in dTL on the current densities and IR spectra were analyzed and discussed. The obtained data identify dTL as an important variable in thin-layer experiments with electrochemical reactions and FTIR readout. PMID- 28337918 TI - Rh-Catalyzed Annulations of N-Methoxybenzamides and Ketenimines: Sterically and Electronically Controlled Synthesis of Isoquinolinones and Isoindolinones. AB - Rhodium-catalyzed C-H activation/annulation reactions of ketenimines with N methoxybenzamides are reported. The outcome of reactions is dependent on the structure of ketenimines. The beta-alkyl-substituted ketenimines furnish 3 iminoisoquinolin-1(2H)-ones in a formal [4 + 2] annulation manner, while the beta ester substituted ketenimines afford 3-aminoisoindolin-1-ones in a formal [4 + 1] annulation manner. The synthesized [4 + 2] products undergo an intramolecular Cu catalyzed C-N coupling to be converted to benzo[4,5]imidazo[1,2-b]isoquinolin-11 ones, which can be directly prepared from ketenimines and N-methoxybenzamides by a one-pot Rh-catalyzed annulation/Cu-catalyzed C-N coupling sequence. PMID- 28337919 TI - New Insights toward Efficient Charge-Separation Mechanism for High-Performance Photoelectrochemical Aptasensing: Enhanced Charge-Carrier Lifetime via Coupling Ultrathin MoS2 Nanoplates with Nitrogen-Doped Graphene Quantum Dots. AB - Deeply understanding the internal mechanism of the photoelectrohemical (PEC) process is conducive to fabricate high-performance PEC biosensors. In this work, we proposed a new insight toward an efficient charge-separation mechanism in high performance PEC biosensors. Specifically, we disclosed that the lifetimes of photogenerated charge carriers of ultrathin MoS2 nanosheets could be prolonged by approximately millisecond time scales after a proper mole ratio of NGQDs were coupled, leading to the promoted charge separation and a giant photocurrent signal magnification. Benefiting from the dramatic signal amplification and the introduction of acetamiprid aptamer, subfemtomolar level detection of acetamiprid is achieved, which makes our strategy among the most sensitive electronic approaches for PEC-based monitoring of targets. This study was beneficial to further understand the charge-separation mechanism in PEC biosensing, which paved the way for the development of more efficient PEC biosensors. PMID- 28337920 TI - Nonradiative Step Facets in Semiconductor Nanowires. AB - One of the main advantages of nanowires for functional applications is their high perfection, which results from surface image forces that act on line defects such as dislocations, rendering them unstable and driving them out of the crystal. Here we show that there is a class of step facets that are stable in nanowires, with no long-range strain field or dislocation character. In zinc-blende semiconductors, they take the form of Sigma3 (112) facets with heights constrained to be a multiple of three {111} monolayers. Density functional theory calculations show that they act as nonradiative recombination centers and have deleterious effects on nanowire properties. We present experimental observations of these defects on twin boundaries and twins that terminate inside GaAsP nanowires and find that they are indeed always multiples of three monolayers in height. Strategies to use the three-monolayer rule during growth to prevent their formation are discussed. PMID- 28337921 TI - Resonant Coupling between Molecular Vibrations and Localized Surface Plasmon Resonance of Faceted Metal Oxide Nanocrystals. AB - Doped metal oxides are plasmonic materials that boast both synthetic and postsynthetic spectral tunability. They have already enabled promising smart window and optoelectronic technologies and have been proposed for use in surface enhanced infrared absorption spectroscopy (SEIRA) and sensing applications. Herein, we report the first step toward realization of the former utilizing cubic F and Sn codoped In2O3 nanocrystals (NCs) to couple to the C-H vibration of surface-bound oleate ligands. Electron energy loss spectroscopy is used to map the strong near-field enhancement around these NCs that enables localized surface plasmon resonance (LSPR) coupling between adjacent nanocrystals and LSPR molecular vibration coupling. Fourier transform infrared spectroscopy measurements and finite element simulations are applied to observe and explain the nature of the coupling phenomena, specifically addressing coupling in mesoscale assembled films. The Fano line shape signatures of LSPR-coupled molecular vibrations are rationalized with two-port temporal coupled mode theory. With this combined theoretical and experimental approach, we describe the influence of coupling strength and relative detuning between the molecular vibration and LSPR on the enhancement factor and further explain the basis of the observed Fano line shape by deconvoluting the combined response of the LSPR and molecular vibration in transmission, absorption and reflection. This study therefore illustrates various factors involved in determining the LSPR-LSPR and LSPR-molecular vibration coupling for metal oxide materials and provides a fundamental basis for the design of sensing or SEIRA substrates. PMID- 28337922 TI - Acquired pulmonary artery pseudoaneurysms: a pictorial review. AB - Pulmonary artery pseudoaneurysms (PAPs) are uncommon but potentially lethal. They may be incidentally discovered on imaging, or following massive haemoptysis if they rupture, with high risk of mortality. The most frequent causes of PAP are trauma and infectious disease. Vasculitis, in particular Behcet's disease, neoplasm, congenital disease and pulmonary hypertension are rarer causes of PAP. A PAP can be suspected from chest X-ray and contrast CT, but requires confirmation by CT angiography. Arteriography is no longer performed for diagnostic purposes, but can be useful in preparing endovascular occlusion of the PAP. In rare cases, surgery is necessary. The aim of this pictorial review was to illustrate the most common causes of acquired PAPs. PMID- 28337923 TI - The Communicative Function of Sad Facial Expressions. AB - What are the communicative functions of sad facial expressions? Research shows that people feel sadness in response to losses but it's unclear whether sad expressions function to communicate losses to others and if so, what makes these signals credible. Here we use economic games to test the hypothesis that sad expressions lend credibility to claims of loss. Participants play the role of either a proposer or recipient in a game with a fictional backstory and real monetary payoffs. The proposers view a (fictional) video of the recipient's character displaying either a neutral or sad expression paired with a claim of loss. The proposer then decided how much money to give to the recipient. In three experiments, we test alternative theories by using situations in which the recipient's losses were uncertain (Experiment 1), the recipient's losses were certain (Experiment 2), or the recipient claims failed gains rather than losses (Experiment 3). Overall, we find that participants gave more money to recipients who displayed sad expressions compared to neutral expressions, but only under conditions of uncertain loss. This finding supports the hypothesis that sad expressions function to increase the credibility of claims of loss. PMID- 28337924 TI - Making Sense of the Public Stigma of Suicide. AB - BACKGROUND: Research suggests that stigma is a barrier to care for individuals who have attempted suicide. While extensive work has examined the stigma of mental illness, less research has focused on the public stigma of suicide. Existing measures of suicide stigma have lacked a conceptual foundation or have failed to include the perspectives of suicide stakeholders. AIMS: This research draws on previous qualitative research with suicide stakeholders to create a measure of public suicide stigma. METHOD: This study used a community-based participatory research (CBPR) approach to define a factor structure for suicide stigma. The CBPR team used focus groups to generate items for each component of stigma (stereotypes, prejudice, and discrimination). Two online surveys (N = 372; N = 243) asked members of the public to rate candidate items for stereotypes, prejudice, and discrimination. RESULTS: Analyses revealed three factors for stereotypes (weak, crazy, distressed), two factors for prejudice (fear/distrust, anger), and three for discrimination (avoidance, disdain, coercion). LIMITATIONS: Results should be confirmed in other samples and further evidence gathered on convergent, divergent, and discriminant validity. CONCLUSION: The resulting 44 item Suicide Stigma Assessment Scale (SSAS) can be further validated and used to measure efficacy of stigma change interventions. PMID- 28337925 TI - The Impact of a Highly Publicized Celebrity Suicide on Suicide-Related Online Information Seeking. AB - BACKGROUND: Research has already acknowledged the importance of the Internet in suicide prevention as search engines such as Google are increasingly used in seeking both helpful and harmful suicide-related information. AIMS: We aimed to assess the impact of a highly publicized suicide by a Hollywood actor on suicide related online information seeking. METHOD: We tested the impact of the highly publicized suicide of Robin Williams on volumes of suicide-related search queries. RESULTS: Both harmful and helpful search terms increased immediately after the actor's suicide, with a substantial jump of harmful queries. LIMITATIONS: The study has limitations (e.g., possible validity threats of the query share measure, use of ambiguous search terms). CONCLUSION: Online suicide prevention efforts should try to increase online users' awareness of and motivation to seek help, for which Google's own helpline box could play an even more crucial role in the future. PMID- 28337927 TI - Suicide in the Mountain West Region of the United States. AB - BACKGROUND: The Mountain West region of the United States consistently reports the highest rates of suicide in the country. This pattern could reflect a regional culture-of-suicide script in support of suicide that implicitly influences individual's behavior. AIMS: The primary aim of this study was to investigate whether suicide rates are elevated in the Mountain West across a wide range of demographic groups, thereby supporting a regional cultural script. METHOD: Suicide rates in the Mountain West between 1999 and 2014 were compared to the rest of the country across a wide range of demographic categories and levels of population density using the Center for Disease Control Multiple Causes of Death dataset published on the WONDER online database. RESULTS: Suicide rates are elevated in the Mountain West for men and women, all racial groups, all age groups, and at every level of population density compared to the rest of the country. LIMITATIONS: Missing and suppressed data, the use of coroner reports, and the arbitrary nature of state and regional boundaries are all discussed as possible limitations to this study. CONCLUSION: These findings support a broad culture-of-suicide script that is pervasive in this region across demographic groups and all levels of population density. PMID- 28337926 TI - Telephone Crisis Support Workers' Psychological Distress and Impairment. AB - BACKGROUND: In order to respond to crises with appropriate intervention, crisis workers are required to manage their own needs as well as the needs of those they respond to. AIMS: A systematic review of the literature was conducted to examine whether telephone crisis support workers experience elevated symptoms of psychological distress and are impaired by elevated symptoms. METHOD: Studies were identified in April 2015 by searching three databases, conducting a gray literature search, and forward and backward citation chaining. RESULTS: Of 113 identified studies, seven were included in the review. Results suggest that that telephone crisis support workers experience symptoms of vicarious traumatization, stress, burnout, and psychiatric disorders, and that they may not respond optimally to callers when experiencing elevated symptoms of distress. However, definitive conclusions cannot be drawn due to the paucity and methodological limitations of available data. LIMITATIONS: While the most comprehensive search strategy possible was adopted, resource constraints meant that conference abstracts were not searched and authors were not contacted for additional unpublished information. CONCLUSION: There is an urgent need to identify the impact of telephone crisis support workers' role on their well-being, the determinants of worker well-being in the telephone crisis support context, and the extent to which well-being impacts their performance and caller outcomes. This will help inform strategies to optimize telephone crisis support workers' well-being and their delivery of support to callers. PMID- 28337928 TI - Suicide Risk Assessment in Adolescents - C-SSRS, K10, and READ. AB - BACKGROUND: Assessment and screening are often the first step in planning interventions to help adolescents at risk of suicide. Causes of suicidal thoughts and behavior are multifaceted and it is important for clinical work that assessment reflects this complexity. AIMS: To investigate whether a general psychological Resilience Scale for Adolescents (READ) is associated with a validated suicide rating scale (C-SSRS). METHOD: An observational study of self reported suicidality (C-SSRS), psychological distress (K10), and resiliency (READ) in three adolescent samples: suicide clinic (N = 147); general psychiatric clinic (N = 85); and a nonclinical sample (N = 92). RESULTS: Resiliency scores were significantly higher (p < .05) in the nonclinical compared with the clinic samples on all READ scales. READ scores were similar in the two clinic samples apart from the family cohesion subscale, which was significantly lower in the suicide clinic sample. READ was predictive of levels of suicidality within all samples independently of general psychological distress (K10). LIMITATIONS: The study did not examine other early childhood factors that may contribute to individual resiliency or suicidality. CONCLUSION: READ provides a reliable and valid assessment of individual resilience for both clinical and nonclinical settings. Evaluation of protective resources is a useful adjunct to the assessment and treatment of suicidal behavior. PMID- 28337930 TI - An evaluation of two different screening criteria in gestational diabetes mellitus. AB - BACKGROUND: The objective of this study was to identify the gestational diabetes mellitus (GDM) prevalence difference according to American Diabetes Association (ADA) criteria and International Association of Diabetes and Pregnancy Study Group (IADPSG) criteria for 75 g oral glucose tolerance test (OGTT). METHODS: This study was conducted at Erciyes University Department of Obstetrics and Gynecology. A total of 320 pregnant who met the criteria were included in the study and 75 g OGTT was applied. Irrespective of the first results, the test was applied to most participants 2 weeks later. RESULTS: The GDM prevalence was found to be 9.1% according to the ADA criteria and 19.4% according to the IADPSG criteria. According to the ADA criteria, GDM prevalence was found to be statistically significantly high (p < .05) in patients with risk factors. According to the IADPSG criteria no relationship was found between GDM prevalence and any of the risk factors (p > .05). The patients diagnosed with GDM were observed not to reach the threshold levels for HbA1c. CONCLUSION: According to the IADPSG criteria, GDM prevalence doubles and leads to an increase in healthcare costs and workloads. HbA1c has no role in the diagnosis of GDM. PMID- 28337929 TI - A Public Health Approach in Responding to the Spread of Helium Suicide in Hong Kong. AB - BACKGROUND: The use of the helium suicide method has been increasing in popularity in Hong Kong since 2012. We have learned a valuable lesson in curbing the spread of charcoal burning (CB) suicide in the past 15 years and hope to prevent the helium suicide method from taking off in the community. AIMS: To document what actions have been taken to contain the spread of the helium suicide method and review the preliminary impact of these actions. METHOD: We adopted a public health approach by engaging stakeholders from multiple sectors, including the police force, the fire services department, coroners, pathologists, mass media, and online media outlets. RESULTS: A monitoring system was established by compiling data extracted from news reports, coroners' reports, and police investigations. Risk and protective factors were identified. Intervention strategies were developed to strengthen protective factors and minimize risk factors. This novel suicide method has not spread as rapidly as the CB suicide method. The preliminary outcomes suggest our actions to be effective. LIMITATIONS: The count of helium suicides in 2015 might be low. The impacts of the interventions are only estimated and require additional empirical verifications. CONCLUSION: The public health approach of engaging multiple partners in the early phase of a potential epidemic can be a good guide to meeting the challenges posed by any new suicide methods that emerge in the future. PMID- 28337931 TI - Utilizing nutritional genomics to tailor diets for the prevention of cardiovascular disease: a guide for upcoming studies and implementations. AB - INTRODUCTION: Personalized diets based on an individual's genome to optimize the success of dietary intervention and reduce genetic cardiovascular disease (CVD) risk, is one of the challenges most frequently discussed in the scientific community. Areas covered: The authors gathered literature-based evidence on nutritional genomics and CVD phenotypes, our own results and research experience to provide a critical overview of the current situation of using nutritional genomics to tailor diets for CVD prevention and to propose guidelines for future studies and implementations. Expert commentary: Hundreds of studies on gene-diet interactions determining CVD intermediate (plasma lipids, hypertension, etc.) and final phenotypes (stroke, etc.) have furnished top-level scientific evidence for claiming that the genetic effect in cardiovascular risk is not deterministic, but can be modified by diet. However, despite the many results obtained, there are still gaps in practically applying a personalized diet design to specific genotypes. Hence, a better systemization and methodological improvement of new studies is required to obtain top-level evidence that will allow their application in the future precision nutrition/medicine. The authors propose several recommendations for tackling new approaches and applications. PMID- 28337933 TI - Biotinidase deficiency masquerading as multiple sclerosis? PMID- 28337934 TI - Reply to the letter: Biotinidase deficiency masquerading as multiple sclerosis? PMID- 28337932 TI - Stroke Lesions in a Large Upper Limb Rehabilitation Trial Cohort Rarely Match Lesions in Common Preclinical Models. AB - BACKGROUND: Stroke patients with mild-moderate upper extremity motor impairments and minimal sensory and cognitive deficits provide a useful model to study recovery and improve rehabilitation. Laboratory-based investigators use lesioning techniques for similar goals. OBJECTIVE: To determine whether stroke lesions in an upper extremity rehabilitation trial cohort match lesions from the preclinical stroke recovery models used to drive translational research. METHODS: Clinical neuroimages from 297 participants enrolled in the Interdisciplinary Comprehensive Arm Rehabilitation Evaluation (ICARE) study were reviewed. Images were characterized based on lesion type (ischemic or hemorrhagic), volume, vascular territory, depth (cortical gray matter, cortical white matter, subcortical), old strokes, and leukoaraiosis. Lesions were compared with those of preclinical stroke models commonly used to study upper limb recovery. RESULTS: Among the ischemic stroke participants, median infarct volume was 1.8 mL, with most lesions confined to subcortical structures (61%) including the anterior choroidal artery territory (30%) and the pons (23%). Of ICARE participants, <1% had lesions resembling proximal middle cerebral artery or surface vessel occlusion models. Preclinical models of subcortical white matter injury best resembled the ICARE population (33%). Intracranial hemorrhage participants had small (median 12.5 mL) lesions that best matched the capsular hematoma preclinical model. CONCLUSIONS: ICARE subjects are not representative of all stroke patients, but they represent a clinically and scientifically important subgroup. Compared with lesions in general stroke populations and widely studied animal models of recovery, ICARE participants had smaller, more subcortically based strokes. Improved preclinical clinical translational efforts may require better alignment of lesions between preclinical and human stroke recovery models. PMID- 28337936 TI - Females exposed to 24 h of sleep deprivation do not experience greater physiological strain, but do perceive heat illness symptoms more severely, during exercise-heat stress. AB - There is limited and inconclusive evidence surrounding the physiological and perceptual responses to heat stress while sleep deprived, especially for females. This study aimed to quantify the effect of 24 h sleep deprivation on physiological strain and perceptual markers of heat-related illness in females. Nine females completed two 30-min heat stress tests (HST) separated by 48 h in 39 degrees C, 41% relative humidity at a metabolic heat production of 10 W . kg-1. The non-sleep deprived HST was followed by the sleep deprivation (SDHST) trial for all participants during the follicular phase of the menstrual cycle. Physiological and perceptual measures were recorded at 5 min intervals during the HSTs. On the cessation of the HSTs, heat illness symptom index (HISI) was completed. HISI scores increased after sleep deprivation by 28 +/- 16 versus 20 +/- 16 (P = 0.01). Peak (39.40 +/- 0.35 degrees C vs. 39.35 +/- 0.33 degrees C) and change in rectal temperature (1.91 +/- 0.21 vs. 1.93 +/- 0.34 degrees C), and whole body sweat rate (1.08 +/- 0.31 vs. 1.15 +/- 0.36 L . h-1) did not differ (P > 0.05) between tests. No difference was observed in peak, nor rise in: heart rate, mean skin temperature, perceived exertion or thermal sensation during the HSTs. Twenty-four hours sleep deprivation increased perceptual symptoms associated with heat-related illness; however, no thermoregulatory alterations were observed. PMID- 28337935 TI - A novel approach in the treatment of neonatal gastroschisis: a review of the literature and a single-center experience. AB - Gastroschisis is a congenital abdominal wall defect and its management remains an issue. We performed a review of the literature to summarize its evaluation, management and outcome and we describe a new type of surgical reduction performed in our center without anesthesia (GA), immediately after birth, in the delivery room. Between January 2002 and March 2013, we enrolled all live born infants with gastroschisis referred to the third-level Division of Obstetrics and Gynecology "San Camillo" of Rome. Two groups of infants were identified: group 1 in which gastroschis reduction was performed by the traditional technique and group 2 in which reduction was immediately performed after birth in the delivery room without GA. Twelve infants were enrolled in group 1, and seven infants in group 2. Statistical significance was observed between the groups regarding the hospital stay, for the duration of parenteral nutrition and full oral feeds (p = .004). Survival was similar between two groups. The reduction without GA performed immediately after birth in a delivery room encourages the relationship between the mother and her child and appears to be a safe and feasible technique in a selected group of patients with simple gastroschisis defect; for this reason, it could represent a valid alternative to traditional approach. PMID- 28337937 TI - Evaluation of methanogenic microbial electrolysis cells under closed/open circuit operations. AB - The present study investigated the independent roles of biofilm and external power supply for volatile fatty acids degradation and methane production in the microbial electrolysis cell. Reactors were operated in fed-batch mode in the presence of graphite felt (GF) or titanium rod (Ti) as electrodes, in open circuit (OC, without applied voltage) or closed circuit (CC) conditions, i.e. R1 (Ti + CC), R2 (GF + CC) and R3 (GF + OC). The first-order kinetic analysis of acetate degradation indicated that the presence of GF biofilm and applied voltage in R2 improved the degradation rate of acetate by 23% as compared to R1, while it was only a 7% increment in R3 with GF biofilm. The degradation of butyrate was accelerated by 12% in the first 24 h, whereas there was no enhancement of the propionic acid digestion. Generally, methane yields from the three reactors followed the sequence: R2 > R1 > R3, indicating the positive effect of external power supply on methane generation. High-throughput sequencing revealed that Geobacter sp. could be enriched on conductive GF even without electric stimulation. The clustered Geobacter and Methanosarcina in R2 presented the potential to promote interspecies electron transfer and accelerate substrate utilization and methane production. PMID- 28337938 TI - Optimization and development of antidiabetic phytosomes by the Box-Behnken design. AB - Researchers have extensively reviewed on herbs and natural products for their marked clinical efficacy in some recent years, however, maximum of the newly discovered bioactive constituents offer poor bioavailability due to their large size molecules or to their poor miscibility with oils and lipids, thereby limiting their ability to pass across the lipid-rich outer membranes of the enterocytes of the small intestine. Phytosomes are more bioavailable as compared to herbal extracts owing to their enhanced capacity to cross the bio-membranes and thus reaching the systemic circulation. This study was aimed to investigate the development and optimization of antidiabetic phytosomes using a three-factor, three-level the Box-Behnken design (17 batches). The fruits of Citrullus colocynthis (L.) Momordica balsamina and Momordica dioica were extracted using Soxhlet's apparatus. The phytochemical fingerprint profile of the combined methanolic extracts was done by using high-performance thin layer chromatography (HPTLC). The polynomial quadratic equation analysis was designed to study the response (entrapment efficiency (EE), % yield) of independent significant factors at different levels. Phytosomes were characterized in terms of drug content, particle size, EE, zeta potential and in vitro dissolution. TEM analysis revealed good stability and a spherical, self-closed structure of phytosomes in complex formulations. Average particle size was found to 450 nm. Total flavonoid content was found to be 10.0 +/- 0.002 MUg/g. Optimized formulation was selected and was prepared using A (1:3), B (60 degrees C) and C (2.5 h) to give maximum yield and entrapment efficiencies (72% and 92.1 +/- 5.1%). Phytosomes were found to have antidiabetic activity comparable to metformin in low dose. HPTLC showed the presence of the phyto-constituent quercetin. PMID- 28337940 TI - Genome-wide analysis of LPS-induced inflammatory response in the rat ventral hippocampus: Modulatory activity of the antidepressant agomelatine. AB - OBJECTIVES: Several studies reported that antidepressant drugs have immune regulatory effects by acting on specific inflammatory mediators. However, considering the highly complex nature of the inflammatory response, we have adopted an unbiased genome-wide strategy to investigate the immune-regulatory activity of the antidepressant agomelatine in modulating the response to an acute inflammatory challenge. METHODS: Microarray analysis was used to identify genes modulated in the ventral hippocampus of adult rats chronically treated with agomelatine (40 mg/kg, os) before being challenged with a single injection of lipopolysaccharide (LPS; 250 MUg/kg, i.p.). RESULTS: The administration of LPS induced the transcription of 284 genes mainly associated with pathways related to the immune/inflammatory system. Agomelatine modulated pathways not only connected to its antidepressant activity, but was also able to prevent the activation of genes induced by LPS. Further comparisons between gene lists of the diverse experimental groups led to the identification of a few transcripts modulated by LPS on which agomelatine has the larger effect of normalisation. Among them, we found the pro-inflammatory cytokine Il-1beta and, interestingly, the metabotropic glutamatergic transporter Grm2. CONCLUSIONS: These results are useful to better characterise the association between depression and inflammation, revealing new potential targets for pharmacological intervention for depression associated to inflammation. PMID- 28337939 TI - Bidirectional apical-basal traffic of the cation-independent mannose-6-phosphate receptor in brain endothelial cells. AB - Brain capillary endothelium mediates the exchange of nutrients between blood and brain parenchyma. This barrier function of the brain capillaries also limits passage of pharmaceuticals from blood to brain, which hinders treatment of several neurological disorders. Receptor-mediated transport has been suggested as a potential pharmaceutical delivery route across the brain endothelium, e.g. reports have shown that the transferrin receptor (TfR) facilitates transcytosis of TfR antibodies, but it is not known whether this recycling receptor itself traffics from apical to basal membrane in the process. Here, we elucidate the endosomal trafficking of the retrograde transported cation-independent mannose-6 phosphate receptor (MPR300) in primary cultures of brain endothelial cells (BECs) of porcine and bovine origin. Receptor expression and localisation of MPR300 in the endo-lysosomal system and trafficking of internalised receptor are analysed. We also demonstrate that MPR300 can undergo bidirectional apical-basal trafficking in primary BECs in co-culture with astrocytes. This is, to our knowledge, the first detailed study of retrograde transported receptor trafficking in BECs, and the study demonstrates that MPR300 can be transported from the luminal to abluminal membrane and reverse. Such trafficking of MPR300 suggests that retrograde transported receptors in general may provide a mechanism for transport of pharmaceuticals into the brain. PMID- 28337941 TI - Lesion symptom map of cognitive-postural interference in multiple sclerosis. AB - OBJECTIVE: To investigate the disease-altered structure-function relationship underlying the cognitive-postural interference (CPI) phenomenon in multiple sclerosis (MS). METHODS: We measured postural sway of 96 patients and 48 sex-/age matched healthy controls by force platform in quiet standing (single-task (ST)) while performing the Stroop test (dual-task (DT)) to estimate the dual-task cost (DTC) of balance. In patient group, binary T2 and T1 lesion masks and their corresponding lesion volumes were obtained from magnetic resonance imaging (MRI) of brain. Normalized brain volume (NBV) was also estimated by SIENAX. Correlations between DTC and lesion location were determined by voxel-based lesion symptom mapping (VLSM) analyses. RESULTS: Patients had greater DTC than controls ( p < 0.001). Among whole brain MRI metrics, only T1 lesion volume correlated with DTC ( r = -0.27; p < 0.01). However, VLSM analysis did not reveal any association with DTC using T1 lesion masks. By contrast, we found clusters of T2 lesions in distinct anatomical regions (anterior and superior corona radiata, bilaterally) to be correlated with DTC ( p < 0.01 false discovery rate (FDR) corrected). A multivariable stepwise regression model confirmed findings from VLSM analysis. NBV did not contribute to fit the model. CONCLUSION: Our findings suggest that the CPI phenomenon in MS can be explained by disconnection along specific areas implicated in task-switching abilities and divided attention. PMID- 28337942 TI - Is fetal analgesia necessary during prenatal surgery? AB - : Fetal pain and fetal anesthesia are still matter of debate: some authors hypothesize that several intrauterine endocrine neuroinhibitors (ENIn) anesthetize the fetus, keeping it in a constant state of sleep, and making pharmacological fetal anesthesia useless for fetal surgery, while others argue fetal pain is possible and shoud be prevented with fetal anesthesy. AIM: To retrieve evidences about fetal pain, fetal arousability and about the level of sedation induced by the ENIn, in order to assess the necessity of direct fetal anesthesia during prenatal fetal surgery. METHODS: We performed a careful literature review (1990-2016) on fetal arousability, and on the possibility that ENIn at the average fetal blood levels induce actual anesthesia. We retrieved the papers that fulfilled the research criteria, with particular attention to the second half of pregnancy, the period when most fetal surgery is performed. RESULTS: Fetuses are awake about 10% of the total time in the last gestational weeks, and they can be aroused by external stimuli. ENIn have not an anesthetic effect at normal fetal values, but only when they areartificialy injected at high doses; their blood levels in the last trimester of average pregnancies are not dissimilar either in the fetus or in the mother. CONCLUSIONS: During the second half of the pregnancy, external stimuli can awake the fetuses, although they spend most of the time in sleeping state; the presence of ENIn is absolutely not enough to guarantee an effective anesthesia during surgery. Thus, direct fetal analgesia/anesthesia is mandatory, though further studies on its possible drawbacks are necessary. PMID- 28337943 TI - Together We Are Stronger: Multicenter Studies. PMID- 28337944 TI - The influence of gate start position on physical performance and anxiety perception in expert BMX athletes. AB - The critical importance of the start phase in bicycle motocross (BMX) racing is increasingly acknowledged. Past experiments underlined that the internal lane of the starting gate provides a strong positional advantage. However, how lane position affects start performance and cognitive and somatic state anxiety remains unexplored. We examined the start performance and anxiety responses of youth national-level BMX riders in both experimental and ecological contexts. We used contextualization motor imagery routines to evaluate start performance and state anxiety from the internal and external lanes. Cycle ergometer measures revealed a better start performance from the external lane, but we did not record any lane effect on actual gate start times. Both somatic and cognitive anxiety scores were higher before racing from the internal compared to the external lane. Finally, state anxiety (i.e., somatic anxiety, worry and concentration disruptions) negatively predicted the start performance. Present findings provide original insights on psychological factors involved in BMX start performance, and might contribute to fruitful coping interventions and training programmes in sports overlapping the framework of "handicap races" taking the specific form of positional advantages/disadvantages at the start (e.g., ski/snowboard cross, athletics, swimming, motorsports, etc.). PMID- 28337945 TI - Client interpersonal impacts as mediators of long-term outcome in cognitive behavioral therapy integrated with motivational interviewing for generalized anxiety disorder. AB - OBJECTIVE: A recent trial of generalized anxiety disorder treatment (Westra, H. A., Constantino, M. J., & Antony, M. M. (2016). Integrating Motivational Interviewing With Cognitive-Behavioral Therapy for Severe Generalized Anxiety Disorder: An Allegiance-Controlled Randomized Clinical Trial. Journal of Consulting and Clinical Psychology, 84, 768-782. doi: 10.1037/ccp0000098 ) revealed that cognitive-behavioral therapy (CBT) integrated with motivational interviewing (MI) outperformed CBT alone across a 12-month follow up. The present study examined whether this treatment effect was mediated by MI-CBT clients engaging over time in during-session interpersonal behaviors reflecting more friendly dominance, or agentic actions, and less friendly submissiveness (FS), or trustingly compliant actions both theory-specific MI mechanisms. METHOD: Clients received 15 sessions of MI-CBT (n = 42) or CBT alone (n = 43). Therapists rated client interpersonal behavior following five sessions, and clients rated their worry at baseline, each session, and 6- and 12-month follow up. Mediator and outcome variables were derived from multilevel models. Mediation was tested using a bootstrapping procedure. RESULTS: There was a significant indirect effect for FS. As expected, CBT clients evidenced greater increases in FS than MI-CBT clients, which in turn, though unexpectedly, related to lower 12-month worry. However, long-term CBT outcomes remained inferior to MI-CBT outcomes even with CBT clients'greater increase in FS. CONCLUSIONS: Results suggest that CBT outcomes are more positive when clients trustingly comply; however, MI-CBT remained superior, but for as yet unexplained reasons. PMID- 28337947 TI - Memory demands in linguistic compensation. AB - Individuals often modify speech characteristics to accommodate their listeners. In the present study, we investigate how speakers modify their speech in a dictation task and what this says about their beliefs with respect to the listener's information processing limitations. To do so, we asked participants to either read a set of numbers aloud, or dictate numbers so that another person could write them down. Our results suggest that speech modification in this task was not related to individual differences in working memory capacity, and could represent speakers' attempt to minimize working memory demands of the listener. This account is similar to minimal memory strategies, whereby individuals often try to minimize memory demands in cognitive tasks. PMID- 28337948 TI - Software version of Roland Morris Disability questionnaire for outcome assessment in low back pain. AB - BACKGROUND: Developing and using the software version of existing validated paper version of patient-related outcome can go a long way in saving cost, time and effort. However, the equivalence of paper version and software versions cannot be assumed. The aim of the study is to test the equivalence between paper version and software version of Roland Morris Disability Questionnaire and its acceptability among patients. METHODS: This is a within-subject cross over equivalence study. Fifty-five patients with back pain were asked to complete the paper and software version of RMDQ in random order. Patients were included from the Neuro Spinal surgery outpatient department of Lilavati Hospital and Research Center. RESULTS: Statistical analysis of 52 patients who completed the study showed high agreement between the paper and software version of the questionnaire (intraclass correlation coefficient 0.994, 95% confidence interval (0.989 0.996)). High sensitivity and specificity of 84 and 88% of the software version was noted. About 69.2% patients preferred software version over paper version. CONCLUSION: Our study shows that software version is comparable to the paper version. It may prove to be a useful tool for epidemiological studies and patient follow-up over longer period. PMID- 28337949 TI - Efficacy of metacognitive therapy for hypoactive sexual desire disorder among Iranian couples. AB - OBJECTIVE: The aim of present study was to compare the efficacy of metacognitive therapy (MCT) against Masters-Johnson sex therapy (MJST) for hypoactive sexual desire disorder (HSDD) in Iranian couples. METHODS: A randomized treatment trial was conducted. Participants were recruited from the family counseling clinics in Tehran and Isfahan. All were suffering from HSDD as defined by DSM-IV-R criteria. They were assigned randomly to two groups that received 10 sessions of either MCT or MJST. A sexual desire questionnaire was completed by participants before and after therapy and at 6-month follow-up. RESULTS: Sexual desire increased significantly in the MCT group with respect to the MJST group which failed to show any significant improvement from baseline. Both groups showed a reduction in scores at 6-month follow-up. The difference recorded between the two groups after therapy was no longer significant at 6-month follow-up. CONCLUSION: MCT affected sexual desire more than MJST as evaluated after therapy but the gain was not maintained at follow-up. Future research needs to investigate whether a greater focus on metacognitive beliefs about sexual behavior can improve the stability of treatment effects. PMID- 28337946 TI - Up-regulation of CXCR4 expression contributes to persistent abdominal pain in rats with chronic pancreatitis. AB - Background Pain in patients with chronic pancreatitis is critical hallmark that accompanied inflammation, fibrosis, and destruction of glandular pancreas. Many researchers have demonstrated that stromal cell-derived factor 1 (also named as CXCL12) and its cognate receptor C-X-C chemokine receptor type 4 (CXCR4) involved in mediating neuropathic and bone cancer pain. However, their roles in chronic pancreatic pain remain largely unclear. Methods Chronic pancreatitis was induced by intraductal injection of trinitrobenzene sulfonic acid to the pancreas. Von Frey filament tests were conducted to evaluate pancreas hypersensitivity of rat. Expression of CXCL12, CXCR4, NaV1.8, and pERK in rat dorsal root ganglion was detected by Western blot analyses. Dorsal root ganglion neuronal excitability was assessed by electrophysiological recordings. Results We showed that both CXCL12 and CXCR4 were dramatically up-regulated in the dorsal root ganglion in trinitrobenzene sulfonic acid-induced chronic pancreatitis pain model. Intrathecal application with AMD3100, a potent and selective CXCR4 inhibitor, reversed the hyperexcitability of dorsal root ganglion neurons innervating the pancreas of rats following trinitrobenzene sulfonic acid injection. Furthermore, trinitrobenzene sulfonic acid-induced extracellular signal-regulated kinase activation and Nav1.8 up-regulation in dorsal root ganglias were reversed by intrathecal application with AMD3100 as well as by blockade of extracellular signal-regulated kinase activation by intrathecal U0126. More importantly, the trinitrobenzene sulfonic acid-induced persistent pain was significantly suppressed by CXCR4 and extracellular signal-regulated kinase inhibitors. Conclusions The present results suggest that the activation of CXCL12-CXCR4 signaling might contribute to pancreatic pain and that extracellular signal regulated kinase-dependent Nav1.8 up-regulation might lead to hyperexcitability of the primary nociceptor neurons in rats with chronic pancreatitis. PMID- 28337950 TI - End-of-Life Directives: Follow-Up Comments. PMID- 28337951 TI - True Atomic-Scale Imaging in Three Dimensions: A Review of the Rebirth of Field Ion Microscopy. AB - This article reviews recent advances utilizing field-ion microscopy (FIM) to extract atomic-scale three-dimensional images of materials. This capability is not new, as the first atomic-scale reconstructions of features utilizing FIM were demonstrated decades ago. The rise of atom probe tomography, and the application of this latter technique in place of FIM has unfortunately severely limited further FIM development. Currently, the ubiquitous availability of extensive computing power makes it possible to treat and reconstruct FIM data digitally and this development allows the image sequences obtained utilizing FIM to be extremely valuable for many material science and engineering applications. This article demonstrates different applications of these capabilities, focusing on its use in physical metallurgy and semiconductor science and technology. PMID- 28337952 TI - Prenatal maternal stress shapes children's theory of mind: the QF2011 Queensland Flood Study. AB - Research shows that stress in pregnancy has powerful and enduring effects on many facets of child development, including increases in behavior problems and neurodevelopmental disorders. Theory of mind is an important aspect of child development that is predictive of successful social functioning and is impaired in children with autism. A number of factors related to individual differences in theory of mind have been identified, but whether theory of mind development is shaped by prenatal events has not yet been examined. In this study we utilized a sudden onset flood that occurred in Queensland, Australia in 2011 to examine whether disaster-related prenatal maternal stress predicts child theory of mind and whether sex of the child or timing of the stressor in pregnancy moderates these effects. Higher levels of flood-related maternal subjective stress, but not objective hardship, predicted worse theory of mind at 30 months (n=130). Further, maternal cognitive appraisal of the flood moderated the effects of stress in pregnancy on girls' theory of mind performance but not boys'. These results illuminate how stress in pregnancy can shape child development and the findings are discussed in relation to biological mechanisms in pregnancy and stress theory. PMID- 28337954 TI - Clinical Value of Capecitabine-Based Combination Adjuvant Chemotherapy in Early Breast Cancer: A Meta-Analysis of Randomized Controlled Trials. AB - Capecitabine has consistently demonstrated high efficacy and acceptable tolerability in salvage chemotherapy for advanced breast cancer. However, there remains no consensus on its role in adjuvant chemotherapy for early breast cancer (EBC). To estimate the value of capecitabine-based combination adjuvant treatment in EBC, eight randomized controlled trials with 14,072 participants were analyzed. The efficacy and safety outcomes included disease-free survival (DFS), overall survival (OS), relapse, breast cancer-specific survival (BCSS), and grades 3-5 adverse events. Capecitabine-based combination adjuvant chemotherapy demonstrated a 16% increase in BCSS (HR = 0.84, 95% CI = 0.71-0.98, p = 0.03) in the overall analysis and a 22% improvement in DFS (HR = 0.78, 95% CI = 0.64-0.96, p = 0.02) in the hormone receptor-negative (HR-) subgroup. However, there were no significant differences in DFS (HR = 0.96, 95% CI = 0.89-1.05, p = 0.38), OS (HR = 0.91, 95% CI = 0.82-1.00, p = 0.06), or relapse between capecitabine-based and capecitabine-free combination adjuvant chemotherapy. Analogous results were observed in the subgroup analyses of HR+, HER2-, HER2+, and triple-negative EBC. Regarding safety, reduced myelosuppression and hand-foot syndrome development were observed in capecitabine-treated patients. Capecitabine-based combination adjuvant chemotherapy might provide some BCSS benefit compared with capecitabine free regimens in EBC, but the absolute survival gain is small, and the survival benefit appears to be restricted to patients with HR- EBC, which may indicate a target population for capecitabine-based combination adjuvant chemotherapy. PMID- 28337955 TI - Examining the In Vitro Efficacy of the IAP Antagonist Birinapant as a Single Agent or in Combination With Dacarbazine to Induce Melanoma Cell Death. AB - Antagonists of inhibitors of apoptosis proteins (IAPs), alone or in combination with genotoxic therapeutics, have been shown to efficiently induce cell death in various solid tumors. The IAP antagonist birinapant is currently being tested in phase II clinical trials. We herein aimed to investigate the antitumor efficacy of dacarbazine in vitro, both as a single agent and in combination with birinapant, in melanoma cell lines. Covering clinically relevant drug concentration ranges, we conducted a total of 5,400 measurements in a panel of 12 human melanoma cell lines representing different stages of disease progression. Surprisingly, functionally relevant synergies or response potentiation in combination treatments was not observed, and only one cell line modestly responded to birinapant single treatment (approximately 16% cell death). Although we did not study the underlying resistance mechanisms or more complex in vivo scenarios in which dacarbazine/birinapant response synergies may still possibly manifest, our findings are nevertheless noteworthy because IAP antagonists were demonstrated to strongly enhance responses to DNA-damaging agents in cell lines of other cancer types under comparable experimental conditions in vitro. PMID- 28337958 TI - Knockdown of Homeobox B5 (HOXB5) Inhibits Cell Proliferation, Migration, and Invasion in Non-Small Cell Lung Cancer Cells Through Inactivation of the Wnt/beta Catenin Pathway. AB - Homeobox B5 (HOXB5), a member of the HOX gene family, has been shown to play an important role in tumor progression. However, the expression and functional role of HOXB5 in human non-small cell lung cancer (NSCLC) have not been defined. Thus, the purpose of this study was to elucidate the expression and functional role of HOXB5 in human NSCLC. Our results showed that HOXB5 expression was elevated in human NSCLC tissues and cell lines. The in vitro experiments demonstrated that knockdown of HOXB5 inhibited proliferation, migration, and invasion and prevented the EMT phenotype in NSCLC cells. In vivo experiments indicated that knockdown of HOXB5 attenuated the growth of NSCLC xenografts in vivo. Furthermore, knockdown of HOXB5 suppressed the protein expression levels of beta-catenin and its downstream targets c-Myc and cyclin D1 in A549 cells. Taken together, for the first time we have shown that knockdown of HOXB5 significantly inhibited NSCLC cell proliferation, invasion, metastasis, and EMT, partly through the Wnt/beta catenin signaling pathway. These findings suggest that HOXB5 may be a novel therapeutic target for the treatment of NSCLC. PMID- 28337960 TI - G-Protein Signaling Protein-17 (RGS17) Is Upregulated and Promotes Tumor Growth and Migration in Human Colorectal Carcinoma. AB - Colorectal carcinoma is one of the leading causes of cancer-related deaths and has a high tendency for metastasis, which makes it a priority to find novel methods to diagnose and treat colorectal carcinoma at a very early stage. We studied the role of the regulator of G-protein signaling (RGS) family of proteins RGS17 in colorectal carcinoma growth and metastasis. We found that RGS17 was upregulated in both clinical colorectal carcinoma tissues and cultured colorectal carcinoma cells. Knockdown of RGS17 by specific siRNA decreased the cell proliferation rate, whereas overexpression of RGS17 with expression plasmid increased the rate in cultured cells. Consistently, a mouse model for colorectal carcinoma also showed that depletion of RGS17 significantly inhibited tumor growth in vivo. Moreover, a Transwell assay showed that RGS17 promoted the ability of colorectal carcinoma cells to migrate and invade. These data suggest that RGS17 is overexpressed in colorectal carcinoma and promotes cell proliferation, migration, and invasion. PMID- 28337957 TI - Transplantation of Cultured Olfactory Bulb Cells Prevents Abnormal Sensory Responses During Recovery From Dorsal Root Avulsion in the Rat. AB - The central branches of the C7 and C8 dorsal roots were avulsed close to their entry point into the spinal cord in adult rats. The forepaw responses to heat and cold stimuli were tested at 1, 2, and 3 weeks after injury. Over this period, the paws were sensitive to both stimuli at 1-2 weeks and returned toward normal at 3 weeks. Immunohistology showed no evidence of axonal regeneration into the spinal cord in a control group of rats with avulsion only, implying that adjacent dorsal roots and their corresponding dermatomes were involved in the recovery. In a further group of rats, a mixture of bulbar olfactory ensheathing cells and olfactory nerve fibroblasts were transplanted into the gap between the avulsed roots and the spinal cord at the time of avulsion. These rats showed no evidence of either loss of sensation or exaggerated responses to stimuli at any of the time points from 1 to 3 weeks. Immunohistology showed that the transplanted cells formed a complete bridge, and the central branches of the dorsal root fibers had regenerated into the dorsal horn of the spinal cord. These regenerating axons, including Tuj1 and CGRP immunoreactive fibers, were ensheathed by the olfactory ensheathing cells. This confirms our previous demonstration of central regeneration by these transplants and suggests that such transplants may provide a useful means to prevent the development of abnormal sensations such as allodynia after spinal root lesions. PMID- 28337961 TI - Biosorption of heavy metals from aqueous solution by bacteria isolated from contaminated soil. AB - The study was carried out to analyze the heavy metals biosorption potential of bacteria isolated from electroplating industrial effluents contaminated soil. Bacterial isolates were screened for their multi-metal biosorption potential against copper, nickel, lead and chromium. Bacterial isolate CU4A showed maximum uptake of copper, nickel, lead and chromium in aqueous solution with biosorption efficiency as 87.16 %, 79.62%, 84.92% and 68.12%, respectively. The bacterial strain CU4A was identified as Bacillus cereus following 16S rRNA gene sequence analysis. The surface chemical functional groups of bacterial biomass were identified by Fourier transform infrared (FTIR) spectroscopy as hydroxyl, carboxyl, amine and halide, which may be involved in the biosorption of heavy metals. The SEM (Scanning Electron Microscopy) and EDS (Energy Dispersive Spectroscopy) analysis confirmed the adsorption of metals on the bacterial cell mass. The results of our study are significant and could be further investigated for removal of heavy metals from contaminated environment. PMID- 28337959 TI - MicroRNA-940 Targets INPP4A or GSK3beta and Activates the Wnt/beta-Catenin Pathway to Regulate the Malignant Behavior of Bladder Cancer Cells. AB - In this report, we aimed to explore the role and regulatory mechanism of microRNA 940 (miR-940) in bladder cancer development. The expressions of miR-940 in bladder cancer tissues and cells were measured. miR-940 mimics, miR-940 inhibitor small interference RNA against INPP4A (si-INPP4A), and GSK3beta (si-GSK3beta) and their corresponding controls were then transfected into cells. We investigated the effects of miR-940, INPP4A, or GSK3beta on cell proliferation, migration, invasion, and apoptosis. Additionally, target prediction and luciferase reporter assays were performed to investigate the targets of miR-940. The regulatory relationship between miR-940 and the Wnt/beta-catenin pathway was also investigated. miR-940 was upregulated in bladder cancer tissues and cells. Overexpression of miR-940 significantly increased bladder cancer cell proliferation, promoted migration and invasion, and inhibited cell apoptosis. INPP4A and GSK3beta were the direct targets of miR-940, and knockdown of INPP4A or GSK3beta significantly increased cancer cell proliferation, migration, and invasion and inhibited cell apoptosis. After miR-940 overexpression, the protein expression levels of c-Myc, cyclin D1, and beta-catenin were significantly increased, and the expression levels of p27 and p-beta-catenin were markedly decreased. The opposite effects were obtained after suppression of miR-940. XAV939, a tankyrase 1 inhibitor that could inhibit Wnt/beta-catenin signaling, significantly reversed the effects of miR-940 overexpression on cell migration and invasion. Our results indicate that overexpression of miR-940 may promote bladder cancer cell proliferation, migration, and invasion and inhibit cell apoptosis via targeting INPP4A or GSK3beta and activating the Wnt/beta-catenin pathway. Our findings imply the key roles of suppressing miRNA-940 in the therapy of bladder cancer. PMID- 28337963 TI - Enhanced Treatment Properties of Iron Oxide Amended Sands Coupled with Polyelectrolyte to Humic Acid. AB - To improve the removal efficiency of micropollutant humic acid at low temperature, microflocculation filtration experiments were conducted with homemade iron oxide amended sands (IOAS), cationic polyelectrolyte (CPE) and polyaluminium chloride (PACl). Fractal properties of flocs structures and IOAS surface and their effects on the removal efficiency of humic acid were investigated. Results showed that IOAS had a porous surface with fractal dimensions (D) (D = 1.744) and a strong adsorption capacity for humic acid. The flocs produced by PACl were small in size, loosely packed with a higher D, and therefore settled slowly. By contrast, the formed flocs by adding CPE with only 1~5% of PACl had strong and open structures with a high effective density, rapid settling velocity and a lower D. Compared with PACl flocs, the larger size CPE flocs and PACl+CPE flocs deposited and packed up on IOAS, creating smaller pores and resulting in a lower D and higher filtration capacity. PMID- 28337962 TI - LINC00052 Promotes Gastric Cancer Cell Proliferation and Metastasis via Activating the Wnt/beta-Catenin Signaling Pathway. AB - Gastric cancer (GC) is one of the most common malignant tumors of the digestive system. The etiology of GC is complex, and much more attention should be paid to genetic factors. In this study, we explored the role and function of LINC00052 in GC. We applied qRT-PCR and Northern blot to detect the expression of LINC00052 and found it was highly expressed during GC. We also investigated the effects of LINC00052 on tumor prognosis and progression and found that LINC00052 indicated poor prognosis and tumor progression. By performing MTT, colony formation, and Transwell assays, we found that LINC00052 promoted MGC-803 cell proliferation and metastasis. Pull-down and RIP assays showed that LINC00052 could interact with beta-catenin and methyltransferase SMYD2, and immunoprecipitation detection showed that LINC00052 promoted beta-catenin methylation to maintain its stability, so as to activate the Wnt/beta-catenin pathway. Furthermore, XAV939 (inhibitor of beta-catenin) was used to treat MGC-803 cells, and we found that LINC00052 promoted proliferation and metastasis, possibly by activation of the Wnt/beta-catenin pathway. In conclusion, our research demonstrated a carcinogenic role for LINC000052 in GC, which may represent a new approach for the prevention and therapy of this cancer. PMID- 28337964 TI - Targeting CD47 Enhances the Efficacy of Anti-PD-1 and CTLA-4 in an Esophageal Squamous Cell Cancer Preclinical Model. AB - Esophageal squamous cell cancer is a highly aggressive cancer with a dismal 5 year survival rate. CD47 is a cell transmembrane protein that is involved in cell apoptosis, proliferation, adhesion, migration, and antigen presentation in the immune system. By interacting with signal regulatory protein-alpha expressed in antigen-presenting cells (APCs), CD47 acts as an antiphagocytic mechanism to inhibit APC-dependent antigen presentation. Overexpression of CD47 was found in various types of cancer. However, its role in esophageal squamous cell cancer is not yet clear. Anti-CD47 is an antagonist of CD47 signaling pathways by competing with its ligand. In the current study, we investigated the effects of anti-CD47 treatment on the antitumor immune response in an esophageal squamous cell cancer preclinical model. We found that anti-CD47 treatment enhanced proinflammatory responses and increased CD8+ T-cell infiltration in tumor tissue in the animal model. T cells in anti-CD47-treated tumors showed higher PD-1 and CTLA-4 expression, indicating T-cell activation and the rationale of combining anti-CD47 with anti-PD-1 and CLTA-4. The combinatory treatment showed the best antitumor response, implying a novel treatment strategy. The effects of anti-CD47 depended on dendritic cell function. In patient samples, expression of CD47 was negatively correlated with CD8+ T-cell infiltration in esophageal squamous cell cancer patients. Taken together, CD47 might be a novel target to enhance anti-PD-1 and CLTA-4 efficacy in esophageal squamous cell cancer. PMID- 28337965 TI - Knockdown of E2F3 Inhibits Proliferation, Migration, and Invasion and Increases Apoptosis in Glioma Cells. AB - E2F3a, as a member of the E2F family, is essential for cell division associated with the progression of many cancers. However, the biological effect of E2F3a on glioma is not understood as well. To investigate the functional mechanism of E2F3a in glioma, we examined the expression of E2F3a in glioma tissue and cell lines. We found that E2F3a was upregulated in glioma tissue compared with adjacent tissue, and this was associated with a poor survival rate. E2F3a was highly expressed in glioma cell lines compared with normal HEB cell lines. Knockdown of E2F3a significantly inhibited cell proliferation, promoted G0/G1 phase arrest, elevated apoptosis rates, and suppressed cell migration and invasion. However, overexpression of E2F3a markedly promoted cell proliferation, migration, and invasion and inhibited apoptosis. Moreover, in vivo studies showed that knockdown of E2F3a expression dramatically inhibited U373 tumor growth in a nude mouse model. Results of real-time PCR and Western blot showed that the depletion of E2F3a upregulated the expression levels of cell apoptosis-related proteins and downregulated migration-related proteins. Conversely, E2F3a overexpression downregulated the expression levels of cell apoptosis-related proteins and upregulated migration-related proteins. In conclusion, our results highlight the importance of E2F3a in glioma and provide new insights into the diagnostics and therapeutics of gliomas. PMID- 28337966 TI - Acid-Fast Positive and Acid-Fast Negative Mycobacterium tuberculosis: The Koch Paradox. AB - Acid-fast (AF) staining, also known as Ziehl-Neelsen stain microscopic detection, developed over a century ago, is even today the most widely used diagnostic method for tuberculosis. Herein we present a short historical review of the evolution of AF staining methods and discuss Koch's paradox, in which non-AF tubercle bacilli can be detected in tuberculosis patients or in experimentally infected animals. The conversion of Mycobacterium tuberculosis from an actively growing, AF-positive form to a nonreplicating, AF-negative form during the course of infection is now well documented. The mechanisms of loss of acid-fastness are not fully understood but involve important metabolic processes, such as the accumulation of triacylglycerol-containing intracellular inclusions and changes in the composition and spatial architecture of the cell wall. Although the precise component(s) responsible for the AF staining method remains largely unknown, analysis of a series of genetically defined M. tuberculosis mutants, which are attenuated in mice, pointed to the primary role of mycolic acids and other cell wall-associated (glyco)lipids as molecular markers responsible for the AF property of mycobacteria. Further studies are now required to better describe the cell wall reorganization that occurs during dormancy and to develop new staining procedures that are not affected by such cell wall alterations and that are capable of detecting AF-negative cells. PMID- 28337967 TI - One year in review 2017: primary Sjogren's syndrome. AB - Primary Sjogren's syndrome (pSS) is a complex and heterogeneous disease. Last year, a great deal of basic and clinical research was carried out in pSS. Following the previous reviews of this publishing series, we will herewith provide a critical digest of the most recent literature on pSS pathogenesis, clinical manifestations and treatment. More specifically, we will focus on the heterogeneity of the disease, on the underlying pathogenetic pathways and on the possible new targeted treatments on the horizon. PMID- 28337969 TI - Signatures of relativistic spin-light coupling in magneto-optical pump-probe experiments. AB - Femtosecond magneto-optical pump-probe measurements of ultrafast demagnetization show an intriguing difference in the first 100 fs of the magneto-optical Kerr response depending on whether the polarization of the pump and probe beams are in parallel or perpendicular configuration (Bigot et al 2009 Nat. Phys. 5 515). Starting from a most general relativistic Hamiltonian we focus on the ultra relativistic light-spin interaction and show that this coupling term leads to different light-induced opto-magnetic fields when pump and probe polarization are parallel and perpendicular to each other, providing thus an explanation for the measurements. We also analyze other pump-probe configurations where the pump laser is circularly polarized and the employed probe contains only linearly polarized light and show that similar opto-magnetic effects can be anticipated. PMID- 28337968 TI - CRISPR/Cas9 mutagenesis invalidates a putative cancer dependency targeted in on going clinical trials. AB - The Maternal Embryonic Leucine Zipper Kinase (MELK) has been reported to be a genetic dependency in several cancer types. MELK RNAi and small-molecule inhibitors of MELK block the proliferation of various cancer cell lines, and MELK knockdown has been described as particularly effective against the highly aggressive basal/triple-negative subtype of breast cancer. Based on these preclinical results, the MELK inhibitor OTS167 is currently being tested as a novel chemotherapy agent in several clinical trials. Here, we report that mutagenizing MELK with CRISPR/Cas9 has no effect on the fitness of basal breast cancer cell lines or cell lines from six other cancer types. Cells that harbor null mutations in MELK exhibit wild-type doubling times, cytokinesis, and anchorage-independent growth. Furthermore, MELK-knockout lines remain sensitive to OTS167, suggesting that this drug blocks cell division through an off-target mechanism. In total, our results undermine the rationale for a series of current clinical trials and provide an experimental approach for the use of CRISPR/Cas9 in preclinical target validation that can be broadly applied. PMID- 28337971 TI - Semiconductor meta-surface based perfect light absorber. AB - We numerically proposed and demonstrated a semiconductor meta-surface light absorber, which consists of a silicon patches array on a silicon thin-film and an opaque silver substrate. The Mie resonances of the silicon patches and the fundamental cavity mode of the ultra-thin silicon film couple strongly to the incident optical field, leading to a multi-band perfect absorption. The maximal absorption is above 99.5% and the absorption is polarization-independent. Moreover, the absorption behavior is scalable in the frequency region via tuning the structural parameters. These features hold the absorber platform with wide applications in optoelectronics such as hot-electron excitation and photo detection. PMID- 28337970 TI - Quantum coherence phenomenon in disordered Bi2SeTe2 topological single crystal: effect of annealing. AB - We report a comparative magnetotransport study on pristine and annealed Bi2SeTe2 single crystals. The pristine sample shows a metallic trend from 300 to 180 K, and an insulating behavior for T < 180 K, whereas the annealed sample exhibits an insulating nature in the entire 4.2-300 K temperature range. Magnetoresistance (MR) of pristine and annealed samples reveals contrasting behaviour as a function of temperature (T) and magnetic field (B). At 4.2 K, the pristine sample shows weak antilocalization (WAL) behavior at low fields and transforms to weak localization (WL) behavior (negative MR) for B > 2.5 T. Further, the quantum MR behaviours seen at low temperature gradually transform to classical B 2 dependent upon increasing the temperatures. In contrast, the annealed sample shows a WAL at small field superimposed on a parabolic feature for B > +/-4 T at low temperatures (T < 20 K). It shows a linear MR at intermediate temperatures (40 K < T < 100 K) and a parabolic MR at temperatures T > 100 K. Hall measurements on both samples exhibit a nonlinear behavior at 4.2 K pointing to the existence of two types of carriers with different mobility. The annealed sample also shows a drastic decrease in mobility by one order of magnitude and a reduction in Ioffe-Regel parameter (k F l) by a factor of ~3. Disorder-induced localization of bulk carriers and its coexistence with localization-immune surface carriers at low T leads to WAL and WL. MR observed in the annealed sample can be attributed to the presence of both quantum-classical contribution and has been analysed using the Hikami-Larkin-Nagaoka (HLN) equation. PMID- 28337972 TI - Silicon hollow sphere anode with enhanced cycling stability by a template-free method. AB - Silicon is a promising alternative anode material since it has a ten times higher theoretical specific capacity than that of a traditional graphite anode. However, the poor cycling stability due to the huge volume change of Si during charge/discharge processes has seriously hampered its widespread application. To address this challenge, we design a silicon hollow sphere nanostructure by selective etching and a subsequent magnesiothermic reduction. The Si hollow spheres exhibit enhanced electrochemical properties compared to the commercial Si nanoparticles. The initial discharge and charge capacities of the Si hollow sphere anode are 2215.8 mAh g-1 and 1615.1 mAh g-1 with a high initial coulombic efficiency (72%) at a current density of 200 mA g-1, respectively. In particular, the reversible capacity is 1534.5 mAh g-1 with a remarkable 88% capacity retention against the second cycle after 100 cycles, over four times the theoretical capacity of the traditional graphite electrode. Therefore, our work demonstrates the considerable potential of silicon structures for displacing commercial graphite, and might open up new opportunities to rationally design various nanostructured materials for lithium ion batteries. PMID- 28337973 TI - Crystal growth, structure and magnetic properties of Ca10Cr7O28. AB - A detailed diffraction study of Ca10Cr7O28 is presented which adds significant new insights into the structural and magnetic properties of this compound. A new crystal structure type was used where the a and b axes are doubled compared to previous models providing a more plausible structure where all crystallographic sites are fully occupied. The presence of two different valences of chromium was verified and the locations of the magnetic Cr5+ and non-magnetic Cr6+ ions were identified. The Cr5+ ions have spin-[Formula: see text] and form distorted kagome bilayers which are stacked in an ABC arrangement along the c axis. These results lay the foundation for understanding of the quantum spin liquid behavior in Ca10Cr7O28 which has recently been reported in Balz et al (2016 Nat. Phys. 12 942). PMID- 28337974 TI - Theory of electrical conductivity and dielectric permittivity of highly aligned graphene-based nanocomposites. AB - Highly aligned graphene-based nanocomposites are of great interest due to their excellent electrical properties along the aligned direction. Graphene fillers in these composites are not necessarily perfectly aligned, but their orientations are highly confined to a certain angle, [Formula: see text] with 90 degrees giving rise to the randomly oriented state and 0 degrees to the perfectly aligned one. Recent experiments have shown that electrical conductivity and dielectric permittivity of highly aligned graphene-polymer nanocomposites are strongly dependent on this distribution angle, but at present no theory seems to exist to address this issue. In this work we present a new effective-medium theory that is derived from the underlying physical process including the effects of graphene orientation, filler loading, aspect ratio, percolation threshold, interfacial tunneling, and Maxwell-Wagner-Sillars polarization, to determine these two properties. The theory is formulated in the context of preferred orientational average. We highlight this new theory with an application to rGO/epoxy nanocomposites, and demonstrate that the calculated in-plane and out-of plane conductivity and permittivity are in agreement with the experimental data as the range of graphene orientations changes from the randomly oriented to the highly aligned state. We also show that the percolation thresholds of highly aligned graphene nanocomposites are in general different along the planar and the normal directions, but they converge into a single one when the statistical distribution of graphene fillers is spherically symmetric. PMID- 28337977 TI - Remarkably enhanced photovoltaic effects and first-principles calculations in neodymium doped BiFeO3. AB - Remarkably enhanced photovoltaic effects have been observed in the heterostructures of p-type A-site Nd3+-doped BiFeO3 (Bi0.9375Nd0.0625)FeO3 (or BFONd) polycrystalline ceramics and the n-type ITO thin film. The maximum power conversion is ~0.82%, which is larger than 0.015% in BiFeO3 (BFO) under blue ultraviolet irradiation of wavelength lambda = 405 nm. The current-voltage (I-V) characteristic curve suggests a p-n junction interface between the ITO thin film and BFO (or BFONd) ceramics. The band gaps calculated from first-principles for BFO and BFONd are respectively 2.25 eV and 2.23 eV, which are consistent with the experimental direct band gaps of 2.24 eV and 2.20 eV measured by optical transmission spectra. The reduction of the band gap in BFONd can be explained by the lower electronic Fermi level due to acceptor states revealed by first principles calculations. The optical calculations show a larger absorption coefficient in BFONd than in BFO. PMID- 28337976 TI - Antiproliferative Activity of Crocin Involves Targeting of Microtubules in Breast Cancer Cells. AB - Crocin, a component of saffron spice, is known to have an anticancer activity. However, the targets of crocin are not known. In this study, crocin was found to inhibit the proliferation of HCC70, HCC1806, HeLa and CCD1059sk cells by targeting microtubules. Crocin depolymerized both the interphase and mitotic microtubules of different cancer cells, inhibited mitosis and induced multipolar spindle formation in these cells. In vitro, crocin inhibited the assembly of pure tubulin as well as the assembly of microtubule-associated protein rich tubulin. Electron microscopic analysis showed that crocin inhibited microtubule assembly while it induced aggregation of tubulin at higher concentrations. Crocin co eluted with tubulin suggesting that it binds to tubulin. Vinblastine inhibited the binding of crocin to tubulin while podophyllotoxin did not inhibit the crocin binding indicating that crocin binds at the vinblastine site on tubulin. The results suggested that crocin inhibited cell proliferation mainly by disrupting the microtubule network. PMID- 28337975 TI - A chemical chaperone improves muscle function in mice with a RyR1 mutation. AB - Mutations in the RYR1 gene cause severe myopathies. Mice with an I4895T mutation in the type 1 ryanodine receptor/Ca2+ release channel (RyR1) display muscle weakness and atrophy, but the underlying mechanisms are unclear. Here we show that the I4895T mutation in RyR1 decreases the amplitude of the sarcoplasmic reticulum (SR) Ca2+ transient, resting cytosolic Ca2+ levels, muscle triadin content and calsequestrin (CSQ) localization to the junctional SR, and increases endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and mitochondrial ROS production. Treatment of mice carrying the I4895T mutation with a chemical chaperone, sodium 4-phenylbutyrate (4PBA), reduces ER stress/UPR and improves muscle function, but does not restore SR Ca2+ transients in I4895T fibres to wild type levels, suggesting that decreased SR Ca2+ release is not the major driver of the myopathy. These findings suggest that 4PBA, an FDA-approved drug, has potential as a therapeutic intervention for RyR1 myopathies that are associated with ER stress. PMID- 28337978 TI - MicroRNA filters Hox temporal transcription noise to confer boundary formation in the spinal cord. AB - The initial rostrocaudal patterning of the neural tube leads to differential expression of Hox genes that contribute to the specification of motor neuron (MN) subtype identity. Although several 3' Hox mRNAs are expressed in progenitors in a noisy manner, these Hox proteins are not expressed in the progenitors and only become detectable in postmitotic MNs. MicroRNA biogenesis impairment leads to precocious expression and propagates the noise of Hoxa5 at the protein level, resulting in an imprecise Hoxa5-Hoxc8 boundary. Here we uncover, using in silico simulation, two feed-forward Hox-miRNA loops accounting for the precocious and noisy Hoxa5 expression, as well as an ill-defined boundary phenotype in Dicer mutants. Finally, we identify mir-27 as a major regulator coordinating the temporal delay and spatial boundary of Hox protein expression. Our results provide a novel trans Hox-miRNA circuit filtering transcription noise and controlling the timing of protein expression to confer robust individual MN identity. PMID- 28337979 TI - Monolayer optical memory cells based on artificial trap-mediated charge storage and release. AB - Monolayer transition metal dichalcogenides are considered to be promising candidates for flexible and transparent optoelectronics applications due to their direct bandgap and strong light-matter interactions. Although several monolayer based photodetectors have been demonstrated, single-layered optical memory devices suitable for high-quality image sensing have received little attention. Here we report a concept for monolayer MoS2 optoelectronic memory devices using artificially-structured charge trap layers through the functionalization of the monolayer/dielectric interfaces, leading to localized electronic states that serve as a basis for electrically-induced charge trapping and optically-mediated charge release. Our devices exhibit excellent photo-responsive memory characteristics with a large linear dynamic range of ~4,700 (73.4 dB) coupled with a low OFF-state current (<4 pA), and a long storage lifetime of over 104 s. In addition, the multi-level detection of up to 8 optical states is successfully demonstrated. These results represent a significant step toward the development of future monolayer optoelectronic memory devices. PMID- 28337981 TI - Field-emission from quantum-dot-in-perovskite solids. AB - Quantum dot and well architectures are attractive for infrared optoelectronics, and have led to the realization of compelling light sensors. However, they require well-defined passivated interfaces and rapid charge transport, and this has restricted their efficient implementation to costly vacuum-epitaxially grown semiconductors. Here we report solution-processed, sensitive infrared field emission photodetectors. Using quantum-dots-in-perovskite, we demonstrate the extraction of photocarriers via field emission, followed by the recirculation of photogenerated carriers. We use in operando ultrafast transient spectroscopy to sense bias-dependent photoemission and recapture in field-emission devices. The resultant photodiodes exploit the superior electronic transport properties of organometal halide perovskites, the quantum-size-tuned absorption of the colloidal quantum dots and their matched interface. These field-emission quantum dot-in-perovskite photodiodes extend the perovskite response into the short wavelength infrared and achieve measured specific detectivities that exceed 1012 Jones. The results pave the way towards novel functional photonic devices with applications in photovoltaics and light emission. PMID- 28337982 TI - The fourth crystallographic closest packing unveiled in the gold nanocluster crystal. AB - Metal nanoclusters have recently attracted extensive interest not only for fundamental scientific research, but also for practical applications. For fundamental scientific research, it is of major importance to explore the internal structure and crystallographic arrangement. Herein, we synthesize a gold nanocluster whose composition is determined to be Au60S6(SCH2Ph)36 by using electrospray ionization mass spectrometry and single crystal X-ray crystallography (SCXC). SCXC also reveals that Au60S6(SCH2Ph)36 consists of a fcc like Au20 kernel protected by a pair of giant Au20S3(SCH2Ph)18 staple motifs, which contain 6 tetrahedral-coordinate MU4-S atoms not previously reported in the Au-S interface. Importantly, the fourth crystallographic closest-packed pattern, termed 6H left-handed helical (6HLH) arrangement, which results in the distinct loss of solid photoluminescence of amorphous Au60S6(SCH2Ph)36, is found in the crystals of Au60S6(SCH2Ph)36. The solvent-polarity-dependent solution photoluminescence is also demonstrated. Overall, this work provides important insights about the structure, Au-S bonding and solid photoluminescence of gold nanoclusters. PMID- 28337980 TI - Light-sensing via hydrogen peroxide and a peroxiredoxin. AB - Yeast lacks dedicated photoreceptors; however, blue light still causes pronounced oscillations of the transcription factor Msn2 into and out of the nucleus. Here we show that this poorly understood phenomenon is initiated by a peroxisomal oxidase, which converts light into a hydrogen peroxide (H2O2) signal that is sensed by the peroxiredoxin Tsa1 and transduced to thioredoxin, to counteract PKA dependent Msn2 phosphorylation. Upon H2O2, the nuclear retention of PKA catalytic subunits, which contributes to delayed Msn2 nuclear concentration, is antagonized in a Tsa1-dependent manner. Conversely, peroxiredoxin hyperoxidation interrupts the H2O2 signal and drives Msn2 oscillations by superimposing on PKA feedback regulation. Our data identify a mechanism by which light could be sensed in all cells lacking dedicated photoreceptors. In particular, the use of H2O2 as a second messenger in signalling is common to Msn2 oscillations and to light induced entrainment of circadian rhythms and suggests conserved roles for peroxiredoxins in endogenous rhythms. PMID- 28337983 TI - Self-inflicted DNA double-strand breaks sustain tumorigenicity and stemness of cancer cells. AB - DNA double-strand breaks (DSBs) are traditionally associated with cancer through their abilities to cause chromosomal instabilities or gene mutations. Here we report a new class of self-inflicted DNA DSBs that can drive tumor growth irrespective of their effects on genomic stability. We discover a mechanism through which cancer cells cause DSBs in their own genome spontaneously independent of reactive oxygen species or replication stress. In this mechanism, low-level cytochrome c leakage from the mitochondria leads to sublethal activation of apoptotic caspases and nucleases, which causes DNA DSBs. In response to these spontaneous DNA DSBs, ATM, a key factor involved in DNA damage response, is constitutively activated. Activated ATM leads to activation of transcription factors NF-kappaB and STAT3, known drivers of tumor growth. Moreover, self-inflicted DNA DSB formation and ATM activation are important in sustaining the stemness of patient-derived glioma cells. In human tumor tissues, elevated levels of activated ATM correlate with poor patient survival. Self inflicted DNA DSBs therefore are functionally important for maintaining the malignancy of cancer cells. PMID- 28337986 TI - Simultaneous treatment of temporomandibular joint ankylosis with severe mandibular deficiency by standard TMJ prosthesis. AB - Temporomandibular joint (TMJ) ankylosis is a refractory disease that is difficult to predictably treat. This study evaluated the prognosis of using standard alloplastic TMJ prostheses for the treatment of TMJ ankylosis in Chinese patients with severe mandibular deficiency. Patients treated from 2013 to 2015 were reviewed. The computer-aided design and manufacture (CAD/CAM) technique was used to guide bony mass removal and locate the TMJ prosthesis (Biomet, USA). Eleven patients were included in this study. All prostheses were successfully installed and stabilized intraoperatively. In 4 patients with severe mandibular deficiency, their mandibular ramus was elongated by the TMJ prosthesis and 2 patients were combined with Le Fort I osteotomy guided by digital templates. Their mean chin advancement was 10.19 mm. Their SNB and ramus heights were also significantly improved after operation (P < 0.05). There was no prosthesis loosening, breakage, or infection leading to removal after a mean follow-up period of 22 months (range, 12-31mos.). Mouth opening was significantly improved from 5.5 mm preoperatively to 31.5 mm postoperatively. TMJ reconstruction with standard alloplastic prosthesis is a reliable treatment for ankylosis, especially in recurrent cases. By CAD/CAM technique, it can correct jaw deformities simultaneously and produce stable results. PMID- 28337985 TI - Synthesis and reactivity of a mononuclear non-haem cobalt(IV)-oxo complex. AB - Terminal cobalt(IV)-oxo (CoIV-O) species have been implicated as key intermediates in various cobalt-mediated oxidation reactions. Herein we report the photocatalytic generation of a mononuclear non-haem [(13-TMC)CoIV(O)]2+ (2) by irradiating [CoII(13-TMC)(CF3SO3)]+ (1) in the presence of [RuII(bpy)3]2+, Na2S2O8, and water as an oxygen source. The intermediate 2 was also obtained by reacting 1 with an artificial oxidant (that is, iodosylbenzene) and characterized by various spectroscopic techniques. In particular, the resonance Raman spectrum of 2 reveals a diatomic Co-O vibration band at 770 cm-1, which provides the conclusive evidence for the presence of a terminal Co-O bond. In reactivity studies, 2 was shown to be a competent oxidant in an intermetal oxygen atom transfer, C-H bond activation and olefin epoxidation reactions. The present results lend strong credence to the intermediacy of CoIV-O species in cobalt catalysed oxidation of organic substrates as well as in the catalytic oxidation of water that evolves molecular oxygen. PMID- 28337984 TI - Lipid-dependent conformational dynamics underlie the functional versatility of T cell receptor. AB - T-cell receptor-CD3 complex (TCR) is a versatile signaling machine that can initiate antigen-specific immune responses based on various biochemical changes of CD3 cytoplasmic domains, but the underlying structural basis remains elusive. Here we developed biophysical approaches to study the conformational dynamics of CD3epsilon cytoplasmic domain (CD3epsilonCD). At the single-molecule level, we found that CD3epsilonCD could have multiple conformational states with different openness of three functional motifs, i.e., ITAM, BRS and PRS. These conformations were generated because different regions of CD3epsilonCD had heterogeneous lipid binding properties and therefore had heterogeneous dynamics. Live-cell imaging experiments demonstrated that different antigen stimulations could stabilize CD3epsilonCD at different conformations. Lipid-dependent conformational dynamics thus provide structural basis for the versatile signaling property of TCR. PMID- 28337987 TI - High-performance and compact-designed flexible thermoelectric modules enabled by a reticulate carbon nanotube architecture. AB - It is a great challenge to substantially improve the practical performance of flexible thermoelectric modules due to the absence of air-stable n-type thermoelectric materials with high-power factor. Here an excellent flexible n type thermoelectric film is developed, which can be conveniently and rapidly prepared based on the as-grown carbon nanotube continuous networks with high conductivity. The optimum n-type film exhibits ultrahigh power factor of ~1,500 MUW m-1 K-2 and outstanding stability in air without encapsulation. Inspired by the findings, we design and successfully fabricate the compact-configuration flexible TE modules, which own great advantages compared with the conventional pi type configuration modules and well integrate the superior thermoelectric properties of p-type and n-type carbon nanotube films resulting in a markedly high performance. Moreover, the research results are highly scalable and also open opportunities for the large-scale production of flexible thermoelectric modules. PMID- 28337988 TI - Molecular heterogeneity in major urinary proteins of Mus musculus subspecies: potential candidates involved in speciation. AB - When hybridisation carries a cost, natural selection is predicted to favour evolution of traits that allow assortative mating (reinforcement). Incipient speciation between the two European house mouse subspecies, Mus musculus domesticus and M.m.musculus, sharing a hybrid zone, provides an opportunity to understand evolution of assortative mating at a molecular level. Mouse urine odours allow subspecific mate discrimination, with assortative preferences evident in the hybrid zone but not in allopatry. Here we assess the potential of MUPs (major urinary proteins) as candidates for signal divergence by comparing MUP expression in urine samples from the Danish hybrid zone border (contact) and from allopatric populations. Mass spectrometric characterisation identified novel MUPs in both subspecies involving mostly new combinations of amino acid changes previously observed in M.m.domesticus. The subspecies expressed distinct MUP signatures, with most MUPs expressed by only one subspecies. Expression of at least eight MUPs showed significant subspecies divergence both in allopatry and contact zone. Another seven MUPs showed divergence in expression between the subspecies only in the contact zone, consistent with divergence by reinforcement. These proteins are candidates for the semiochemical barrier to hybridisation, providing an opportunity to characterise the nature and evolution of a putative species recognition signal. PMID- 28337990 TI - Lateral orbitofrontal cortex anticipates choices and integrates prior with current information. AB - Adaptive behavior requires integrating prior with current information to anticipate upcoming events. Brain structures related to this computation should bring relevant signals from the recent past into the present. Here we report that rats can integrate the most recent prior information with sensory information, thereby improving behavior on a perceptual decision-making task with outcome dependent past trial history. We find that anticipatory signals in the orbitofrontal cortex about upcoming choice increase over time and are even present before stimulus onset. These neuronal signals also represent the stimulus and relevant second-order combinations of past state variables. The encoding of choice, stimulus and second-order past state variables resides, up to movement onset, in overlapping populations. The neuronal representation of choice before stimulus onset and its build-up once the stimulus is presented suggest that orbitofrontal cortex plays a role in transforming immediate prior and stimulus information into choices using a compact state-space representation. PMID- 28337991 TI - Contrasting influences of aerosols on cloud properties during deficient and abundant monsoon years. AB - Direct aerosol radiative forcing facilitates the onset of Indian monsoon rainfall, based on synoptic scale fast responses acting over timescales of days to a month. Here, we examine relationships between aerosols and coincident clouds over the Indian subcontinent, using observational data from 2000 to 2009, from the core monsoon region. Season mean and daily timescales were considered. The correlation analyses of cloud properties with aerosol optical depth revealed that deficient monsoon years were characterized by more frequent and larger decreases in cloud drop size and ice water path, but increases in cloud top pressure, with increases in aerosol abundance. The opposite was observed during abundant monsoon years. The correlations of greater aerosol abundance, with smaller cloud drop size, lower evidence of ice processes and shallower cloud height, during deficient rainfall years, imply cloud inhibition; while those with larger cloud drop size, greater ice processes and a greater cloud vertical extent, during abundant rainfall years, suggest cloud invigoration. The study establishes that continental aerosols over India alter cloud properties in diametrically opposite ways during contrasting monsoon years. The mechanisms underlying these effects need further analysis. PMID- 28337992 TI - Quantum Capacitance of a Topological Insulator-Ferromagnet Interface. AB - We study the quantum capacitance in a topological insulator thin film system magnetized in the in-plane direction in the presence of an out-of-plane magnetic field and hexagonal warping. To first order, the modification in quantum capacitance due to hexagonal warping compared to the clean case, where both the in-plane magnetization and hexagonal warping are absent, is always negative, and increases in magnitude monotonically with the energy difference from the charge neutrality point. In contrast, the change in the quantum capacitance due to in plane magnetization oscillates with the energy in general, except when a certain relation between the inter-surface coupling, out of plane Zeeman energy splitting and magnetic field strength is satisfied. In this special case, the quantum capacitance remains unchanged by the in-plane magnetization for all energies. PMID- 28337993 TI - Evaluation of 5 Novel protein biomarkers for the rapid diagnosis of pulmonary and extra-pulmonary tuberculosis: preliminary results. AB - Improved methods are required for the early and accurate diagnosis of tuberculosis, especially in the patients with smear-negative disease. Several biomarkers have been tried but most have shown poor sensitivity or specificity. In present study we aimed to evaluate the diagnostic utility of five novel antigens identified earlier by us. This is an initial study conducted on 250 subjects. The five recombinant antigens, named as rSS1 (Rv2145c), rSS2 (Rv0164), rSS3 (Rv1437), rSS4 (Rv1827) and rSS5 (Rv2970c), were expressed in pQE-30 expression vector, purified and their sero-diagnostic efficacy was evaluated in an unblinded manner using dot-blot and ELISA methods. The sensitivity and specificity of these novel antigens were compared with commercially available standard esat6 and 38 kDa antigens. Bacteriologically confirmed TB patients, non TB disease controls and healthy individuals were included. which are based on novel antigen or novel technology, Area under curve (AUC) of the selected antigens were 0.98 (0.98-0.99) for rSS1, 0.88 (0.84-0.92) for rSS2, 0.88 (0.84 0.92) for rSS3, 0.95 (0.93-0.98) for rSS4 and 0.99 (0.98-1.0) for rSS5. Receiver operative characteristic (ROC) curve showed highly significant difference between TB and healthy subjects (p = <0.001). These initial findings, show that the recombinant antigens rSS1, rSS4 and rSS5 could be used as highly potential biomarkers for the serological diagnosis of active TB. PMID- 28337989 TI - Post-Hoc Study: Intravenous Hydration Treatment in Chinese Patients with High Risk of Contrast-Induced Nephropathy Following Percutaneous Coronary Intervention. AB - Contrast-induced nephropathy (CIN) develops after the injection of iodinated contrast media. This is a post hoc analysis of the data obtained from the TRUST study, which was a prospective, multicentre, observational study conducted to evaluate the safety and tolerability of the contrast medium iopromide in patients undergoing cardiac catheterization from August 2010 to September 2011 in China, conducted to explore the current status, trends and risk predictors of hydration treatment. The status of hydration to prevent CIN in each patient was recorded. Of the total 17,139 patients from the TRUST study (mean age, 60.33 +/- 10.38 years), the overall hydration usage was 46.1% in patients undergoing percutaneous coronary intervention (PCI) and 77.4%, 51.7%, and 48.5% in patients with pre existing renal disease, diabetes mellitus, and hypertension, respectively. The proportion of hydration use increased from 36.5% to 55.5% from August 2010 to September 2011, which was independently associated with risk predictors like older age, pre-existing renal disease, hypertension, diabetes mellitus, prior myocardial infarction, ST segment elevation MI, high contrast dose, multi-vessel disease and reduced LVEF (<45%). Overall, the usage of intravenous hydration treatment for patients with a high risk of CIN following PCI was high in China. PMID- 28337994 TI - The New Phases due to Symmetry Protected Piecewise Berry Phases; Enhanced Pumping and Non-reciprocity in Trimer Lattices. AB - Finding new phase of matter is a fundamental task in physics. Generally, various phases or states of matter (for instance solid/liquid/gas phases) have different symmetries, the phase transitions among them can be explained by Landau's symmetry breaking theory. The topological phases discovered in recent years show that different phases may have the same symmetry. The different topological phases are characterized by different integer values of the Berry phases. By studying one dimensional (1D) trimer lattices we report new phases beyond topological phases. The new phases that we find are characterized by piecewise continuous Berry phases with the discontinuity occurring at the transition point. With time-dependent changes in trimer lattices, we can generate two dimensional (2D) phases, which are characterized by the Berry phase of half period. This half period Berry phase changes smoothly within one state of the system while changes discontinuously at the transition point. We further demonstrate the existence of adiabatic pumping for each phase and gain assisted enhanced pumping. The non reciprocity of the pumping process makes the system a good optical diode. PMID- 28337996 TI - Protein interaction evolution from promiscuity to specificity with reduced flexibility in an increasingly complex network. AB - A key question regarding protein evolution is how proteins adapt to the dynamic environment in which they function and how in turn their evolution shapes the protein interaction network. We used extant and resurrected ancestral plant MADS domain transcription factors to understand how SEPALLATA3, a protein with hub and glue properties, evolved and takes part in network organization. Although the density of dimeric interactions was saturated in the network, many new interactions became mediated by SEPALLATA3 after a whole genome triplication event. By swapping SEPALLATA3 and its ancestors between dimeric networks of different ages, we found that the protein lost the capacity of promiscuous interaction and acquired specificity in evolution. This was accompanied with constraints on conformations through proline residue accumulation, which made the protein less flexible. SHORT VEGETATIVE PHASE on the other hand (non-hub) was able to gain protein-protein interactions due to a C-terminal domain insertion, allowing for a larger interaction interface. These findings illustrate that protein interaction evolution occurs at the level of conformational dynamics, when the binding mechanism concerns an induced fit or conformational selection. Proteins can evolve towards increased specificity with reduced flexibility when the complexity of the protein interaction network requires specificity. PMID- 28337995 TI - Cigarette Smoke Impairs A2A Adenosine Receptor Mediated Wound Repair through Up regulation of Duox-1 Expression. AB - Cigarette smoke (CS) exposure and intrinsic factors such as the NADPH oxidases produce high levels of reactive oxygen species (ROS), ensuing inflammatory tissue injury. We previously demonstrated that CS-generated ROS, particularly hydrogen peroxide (H2O2), impaired adenosine stimulated wound repair. We hypothesized that CS exposure modulates expression of Dual oxidase 1 (Duox-1), a NADPH oxidases known to generate H2O2. To test this hypothesis, we used human bronchial epithelial cell line Nuli-1 and C57BL/6 mice. Cells were treated with 5% CS extract (CSE) for various periods of time, and mice were exposed to whole body CS for six weeks. Both CSE and CS treatment induced increased expression of Duox-1, and silencing of Doux-1 improved the rate of cell wound repair induced by CSE treatment. Nuli-1 cells pretreated with thapsigargin but not calcium ionophore exhibited increased Duox-1 mRNA expression. CSE treatment stimulated PKCalpha activation, which was effectively blocked by pretreatment with diphenylene iodonium, a NADPH oxidase inhibitor. Compared to control, lungs from CS-exposed mice showed a significant increase in PKCalpha activity and Duox-1 expression. Collectively, the data demonstrated that CS exposure upregulates expression of Duox-1 protein. This further leads to H2O2 production and PKCalpha activation, inhibiting A2AAR-stimulated wound repair. PMID- 28337997 TI - The miR-24-3p/p130Cas: a novel axis regulating the migration and invasion of cancer cells. AB - MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression by suppressing translation or facilitating mRNA decay. Differential expression of miRNAs is involved in the pathogenesis of several diseases including cancer. Here, we investigated the role of-miR-24-3p as a downregulated miRNA in metastatic cancer. miR-24-3p was decreased in metastatic cancer and lower expression of miR-24-3p was related to poor survival of cancer patients. Consistently, ectopic expression of miR-24-3p suppressed the cell migration, invasion, and proliferation of MCF7, Hep3B, B16F10, SK-Hep1, and PC-3 cells by directly targeting p130Cas. Stable expression of p130Cas restored miR-24-3p mediated inhibition of cell migration and invasion. These results suggest that miR-24-3p functions as a tumor suppressor and the miR-24-3p/p130Cas axis is a novel factor of cancer progression by regulating cell migration and invasion. PMID- 28337998 TI - Circulating tumor cell status monitors the treatment responses in breast cancer patients: a meta-analysis. AB - Whether circulating tumor cells (CTCs) can be used as an indicator of treatment response in breast cancer (BC) needs to be clarified. We addressed this issue by a meta-analysis. PubMed, EMBase and Cochrane library databases were searched in June 2016. Effect measures were estimated as pooled risk ratio (RR), odds ratio (OR) or mean difference by fixed- or random-effect models, according to heterogeneity of included studies. In total, 50 studies with 6712 patients were recruited. Overall analysis showed that there was a significant reduction of CTC positive rate (RR = 0.68, 95% CI: 0.61-0.76, P < 0.00001) after treatment. Subgroup analyses revealed that neoadjuvant treatment, adjuvant treatment, metastatic treatment or combination therapy could reduce the CTC-positive rate, but surgery could not; moreover, the reduction was only found in HER2+ or HER2- patients but not in the triple-negative ones. Reduction of CTC-positive rate was associated with lower probability of disease progression (OR = 0.54, 95% CI: 0.33 0.89, P = 0.01) and longer overall survival period (mean difference = 11.61 months, 95% CI: 8.63-14.59, P < 0.00001) as well as longer progression-free survival period (mean difference = 5.07 months, 95% CI: 2.70-7.44, P < 0.0001). These results demonstrate that CTC status can serve as an indicator to monitor the effectiveness of treatments and guide subsequent therapies in BC. PMID- 28337999 TI - Comparison of validation and application on various cardiovascular disease mortality risk prediction models in Chinese rural population. AB - This research aims to assess application of different cardiovascular disease (CVD) mortality risk prediction models in Chinese rural population. Data was collected from a 6-year follow-up survey in rural area of Henan Province, China. 10338 participants aged 40 to 65 years were included. Baseline study was conducted between 2007 and 2008, and followed up from 2013 to 2014. Seven models: general Framingham risk score (general-FRS), simplified-FRS, Systematic Coronary Risk Evaluation for high (SCORE-high), SCORE-low, Chinese ischemic CVD (CN-ICVD), Pooled Cohort Risk Equation for white (PCE-white) and for African-American (PCE AA) were assessed and recalibrated. The model performance was evaluated by C statistics and modified Nam-D'Agostino test. 168 CVD deaths occurred during follow-up. All seven models showed moderate C-statics ranging from 0.727 to 0.744. Following recalibration, general-FRS, simplified-FRS, CN-ICVD, PCE-white and PCE-AA had improved C-statistics of 0.776, 0.795, 0.793, 0.779, and 0.776 for men and 0.756, 0.753, 0.755, 0.758 and 0.760 for women, respectively. Calibrations chi2 of general-FRS, simplified-FRS, SCORE-high, CN-ICVD and PCE-AA model for men, and general-FRS, CN-ICVD and PCE-white model for women were statistically acceptable, indicating these models predicts CVD mortality risk more accurately than others and could be recommended in Chinese rural population. PMID- 28338001 TI - Renin-angiotensin system acting on reactive oxygen species in paraventricular nucleus induces sympathetic activation via AT1R/PKCgamma/Rac1 pathway in salt induced hypertension. AB - Brain renin-angiotensin system (RAS) could regulate oxidative stress in the paraventricular nucleus (PVN) in the development of hypertension. This study was designed to explore the precise mechanisms of RAS acting on reactive oxygen species (ROS) in salt-induced hypertension. Male Wistar rats were administered with a high-salt diet (HS, 8.0% NaCl) for 8 weeks to induced hypertension. Those rats were received PVN infusion of AT1R antagonist losartan (LOS, 10 MUg/h) or microinjection of small interfering RNAs for protein kinase C gamma (PKCgamma siRNA) once a day for 2 weeks. High salt intake resulted in higher levels of AT1R, PKCgamma, Rac1 activity, superoxide and malondialdehyde (MDA) activity, but lower levels of copper/zinc superoxide dismutase (Cu/Zn-SOD), superoxide dismutase (SOD) and glutathione (GSH) in PVN than control animals. PVN infusion of LOS not only attenuated the PVN levels of AT1R, PKCgamma, Rac1 activity, superoxide and decreased the arterial pressure, but also increased the PVN antioxidant capacity in hypertension. PVN microinjection of PKCgamma siRNA had the same effect on LOS above responses to hypertension but no effect on PVN level of AT1R. These results, for the first time, identified that the precise signaling pathway of RAS regulating ROS in PVN is via AT1R/PKCgamma/Rac1 in salt-induced hypertension. PMID- 28338002 TI - Integration of thermocouple microelectrode in the scanning electrochemical microscope at variable temperatures: simultaneous temperature and electrochemical imaging and its kinetic studies. AB - We describe herein a method for the simultaneous measurement of temperature and electrochemical signal with a new type of thermocouple microelectrode. The thermocouple microelectrode can be used not only as a thermometer but also as a scanning electrochemical microscope (SECM) tip in the reaction between tip generated bromine and a heated Cu sample. The influence of temperature on the SECM imaging process and the related kinetic parameters have been studied, such as kinetic constant and activation energy. PMID- 28338000 TI - Cavity filling mutations at the thyroxine-binding site dramatically increase transthyretin stability and prevent its aggregation. AB - More than a hundred different Transthyretin (TTR) mutations are associated with fatal systemic amyloidoses. They destabilize the protein tetrameric structure and promote the extracellular deposition of TTR as pathological amyloid fibrils. So far, only mutations R104H and T119M have been shown to stabilize significantly TTR, acting as disease suppressors. We describe a novel A108V non-pathogenic mutation found in a Portuguese subject. This variant is more stable than wild type TTR both in vitro and in human plasma, a feature that prevents its aggregation. The crystal structure of A108V reveals that this stabilization comes from novel intra and inter subunit contacts involving the thyroxine (T4) binding site. Exploiting this observation, we engineered a A108I mutation that fills the T4 binding cavity, as evidenced in the crystal structure. This synthetic protein becomes one of the most stable TTR variants described so far, with potential application in gene and protein replacement therapies. PMID- 28338003 TI - Directional Phonon Suppression Function as a Tool for the Identification of Ultralow Thermal Conductivity Materials. AB - Boundary-engineering in nanostructures has the potential to dramatically impact the development of materials for high- efficiency conversion of thermal energy directly into electricity. In particular, nanostructuring of semiconductors can lead to strong suppression of heat transport with little degradation of electrical conductivity. Although this combination of material properties is promising for thermoelectric materials, it remains largely unexplored. In this work, we introduce a novel concept, the directional phonon suppression function, to unravel boundary-dominated heat transport in unprecedented detail. Using a combination of density functional theory and the Boltzmann transport equation, we compute this quantity for nanoporous silicon materials. We first compute the thermal conductivity for the case with aligned circular pores, confirming a significant thermal transport degradation with respect to the bulk. Then, by analyzing the information on the directionality of phonon suppression in this system, we identify a new structure of rectangular pores with the same porosity that enables a four-fold decrease in thermal transport with respect to the circular pores. Our results illustrate the utility of the directional phonon suppression function, enabling new avenues for systematic thermal conductivity minimization and potentially accelerating the engineering of next-generation thermoelectric devices. PMID- 28338004 TI - TIGAR knockdown radiosensitizes TrxR1-overexpressing glioma in vitro and in vivo via inhibiting Trx1 nuclear transport. AB - The up-regulation of thioredoxin reductase-1 (TrxR1) is detected in more than half of gliomas, which is significantly associated with increased malignancy grade and recurrence rate. The biological functions of NADPH-dependent TrxR1 are mainly associated with reduced thioredoxin-1 (Trx1) which plays critical roles in cellular redox signaling and tumour radio-resistance. Our previous work has proved that TP53 induced glycolysis and apoptosis regulator (TIGAR) knockdown could notably radiosensitize glioma cells. However, whether TrxR1-overexpressing glioma cells could be re-radiosensitized by TIGAR silence is still far from clear. In the present study, TrxR1 was stably over-expressed in U-87MG and T98G glioma cells. Both in vitro and in vivo data demonstrated that the radiosensitivity of glioma cells was considerably diminished by TrxR1 overexpression. TIGAR abrogation was able to radiosensitize TrxR1-overexpressing gliomas by inhibiting IR-induced Trx1 nuclear transport. Post-radiotherapy, TIGAR low-expression predicted significant longer survival time for animals suffering from TrxR1-overexpessing xenografts, which suggested that TIGAR abrogation might be a promising strategy for radiosensitizing TrxR1-overexpressing glial tumours. PMID- 28338006 TI - High Curie temperature and enhanced magnetoelectric properties of the laminated Li0.058(Na0.535K0.48)0.942NbO3/Co0.6 Zn0.4Fe1.7Mn0.3O4 composites. AB - Laminated magnetoelectric composites of Li0.058(Na0.535K0.48)0.942NbO3 (LKNN)/Co0.6Zn0.4Fe1.7Mn0.3O4 (CZFM) prepared by the conventional solid-state sintering method were investigated for their dielectric, magnetic, and magnetoelectric properties. The microstructure of the laminated composites indicates that the LKNN phase and CZFM phase can coexist in the composites. Compared with the particulate magnetoelectric composites, the laminated composites have better piezoelectric and magnetoelectric properties due to their higher resistances and lower leakage currents. The magnetoelectric behaviors lie on the relative mass ratio of LKNN phase and CZFM phase. The laminated composites possess a high Curie temperature (TC) of 463 degrees C, and the largest ME coefficient of 285 mV/cm Oe, which is the highest value for the lead-free bulk ceramic magnetoelectric composites so far. PMID- 28338005 TI - The Association between Diffuse Myocardial Fibrosis on Cardiac Magnetic Resonance T1 Mapping and Myocardial Dysfunction in Diabetic Rabbits. AB - The objective of this study was to assess the relationship between imaging surrogates for diffuse fibrosis and myocardial dysfunction. Thirty-six New Zealand white rabbits were classified into two groups: a control group (n = 18) and an alloxan-induced diabetes mellitus (DM) group (n = 18). For all rabbits, conventional ultrasonography, two-dimensional speckle tracking, and cardiac magnetic resonance (CMR) T1 mapping were performed; all of the rabbits were then sacrificed for Masson's staining. The extracellular volume (ECV) was calculated from pre- and post-contrast T1 values and compared with myocardial function measured by echocardiography using Pearson's correlation. In the DM group, ECV increased as the duration of diabetes increased, consistent with the changes in myocardial fibrosis verified by pathology. Moreover, ECV was strongly correlated with the early diastolic strain rate (r = -0.782, p < 0.001) and moderately correlated with the radial systolic peak strain (r = 0.478, p = 0.045). Thus, ECV is an effective surrogate for myocardial diffuse fibrosis on CMR imaging, and higher ECV values are associated with an increased impairment of myocardial diastolic function. PMID- 28338007 TI - Human Immunodeficiency Virus Type-1 Myeloid Derived Suppressor Cells Inhibit Cytomegalovirus Inflammation through Interleukin-27 and B7-H4. AB - HIV/CMV co-infected persons despite prolonged viral suppression often experience persistent immune activation, have an increased frequency of myeloid derived suppressor cells (MDSC) and are at increased risk for cardiovascular disease. We examined how HIV MDSC control CD4+ T cell IFNgamma response to a CMVpp65 peptide pool (CMVpp65). We show that HIV/CMV co-infected persons with virologic suppression and recovered CD4+ T cells compared to HIV(-)/CMV(+) controls exhibit an increase in CD4+CX3CR1+IFNgamma+ cells in response to CMVpp65; MDSC depletion further augmented CD4+CX3CR1+IFNgamma+ cells and IFNgamma production. IL-2 and IFNgamma in response to CMVpp65 were enhanced with depletion of MDSC expanded in presence of HIV (HIV MDSC), but decreased with culture of HIV MDSC with autologous PBMCs. CMVpp65 specific CD4+CX3CR1+IFNgamma+ cells were also decreased in presence of HIV MDSC. HIV MDSC overexpressed B7-H4 and silencing B7-H4 increased the production of IL-2 and IFNgamma from autologous cells; a process mediated through increased phosphorylated (p)-Akt upon stimulation with CMVpp65. Additionally, IL-27 regulated the expression of B7-H4 on HIV MDSC, and controlled CMV-specific T cell activity by limiting CMVpp65-IFNgamma production and expanding CD4+IL-10+ regulatory T cells. These findings provide new therapeutic targets to control the chronic immune activation and endothelial cell inflammation observed in HIV-infected persons. PMID- 28338008 TI - Noninvasive measurement of transdermal drug delivery by impedance spectroscopy. AB - The effectiveness in transdermal delivery of skin permeation strategies (e.g., chemical enhancers, vesicular carrier systems, sonophoresis, iontophoresis, and electroporation) is poorly investigated outside of laboratory. In therapeutic application, the lack of recognized techniques for measuring the actually released drug affects the scientific concept itself of dosage for topically- and transdermally-delivered drugs. Here we prove the suitability of impedance measurement for assessing the amount of drug penetrated into the skin after transdermal delivery. In particular, the measured amount of drug depends linearly on the impedance magnitude variation normalized to the pre-treated value. Three experimental campaigns, based on the electrical analysis of the biological tissue behavior due to the drug delivery, are reported: (i) laboratory emulation on eggplants, (ii) ex-vivo tests on pig ears, and finally (iii) in-vivo tests on human volunteers. Results point out that the amount of delivered drug can be assessed by reasonable metrological performance through a unique measurement of the impedance magnitude at one single frequency. In particular, in-vivo results point out sensitivity of 23 ml-1, repeatability of 0.3%, non-linearity of 3.3%, and accuracy of 5.7%. Finally, the measurement resolution of 0.20 ml is compatible with clinical administration standards. PMID- 28338010 TI - Brilliant petawatt gamma-ray pulse generation in quantum electrodynamic laser plasma interaction. AB - We show a new resonance acceleration scheme for generating ultradense relativistic electron bunches in helical motions and hence emitting brilliant vortical gamma-ray pulses in the quantum electrodynamic (QED) regime of circularly-polarized (CP) laser-plasma interactions. Here the combined effects of the radiation reaction recoil force and the self-generated magnetic fields result in not only trapping of a great amount of electrons in laser-produced plasma channel, but also significant broadening of the resonance bandwidth between laser frequency and that of electron betatron oscillation in the channel, which eventually leads to formation of the ultradense electron bunch under resonant helical motion in CP laser fields. Three-dimensional PIC simulations show that a brilliant gamma-ray pulse with unprecedented power of 6.7 PW and peak brightness of 1025 photons/s/mm2/mrad2/0.1% BW (at 15 MeV) is emitted at laser intensity of 1.9 * 1023 W/cm2. PMID- 28338011 TI - Towards sub-nanometer real-space observation of spin and orbital magnetism at the Fe/MgO interface. AB - While the performance of magnetic tunnel junctions based on metal/oxide interfaces is determined by hybridization, charge transfer, and magnetic properties at the interface, there are currently only limited experimental techniques with sufficient spatial resolution to directly observe these effects simultaneously in real-space. In this letter, we demonstrate an experimental method based on Electron Magnetic Circular Dichroism (EMCD) that will allow researchers to simultaneously map magnetic transitions and valency in real-space over interfacial cross-sections with sub-nanometer spatial resolution. We apply this method to an Fe/MgO bilayer system, observing a significant enhancement in the orbital to spin moment ratio that is strongly localized to the interfacial region. Through the use of first-principles calculations, multivariate statistical analysis, and Electron Energy-Loss Spectroscopy (EELS), we explore the extent to which this enhancement can be attributed to emergent magnetism due to structural confinement at the interface. We conclude that this method has the potential to directly visualize spin and orbital moments at buried interfaces in magnetic systems with unprecedented spatial resolution. PMID- 28338009 TI - Resveratrol attenuates ICAM-1 expression and monocyte adhesiveness to TNF-alpha treated endothelial cells: evidence for an anti-inflammatory cascade mediated by the miR-221/222/AMPK/p38/NF-kappaB pathway. AB - Resveratrol, an edible polyphenolic phytoalexin, improves endothelial dysfunction and attenuates inflammation. However, the mechanisms have not been thoroughly elucidated. Therefore, we investigated the molecular basis of the effects of resveratrol on TNF-alpha-induced ICAM-1 expression in HUVECs. The resveratrol treatment significantly attenuated the TNF-alpha-induced ICAM-1 expression. The inhibition of p38 phosphorylation mediated the reduction in ICAM-1 expression caused by resveratrol. Resveratrol also decreased TNF-alpha-induced IkappaB phosphorylation and the phosphorylation, acetylation, and translocation of NF kappaB p65. Moreover, resveratrol induced the AMPK phosphorylation and the SIRT1 expression in TNF-alpha-treated HUVECs. Furthermore, TNF-alpha significantly suppressed miR-221/-222 expression, which was reversed by resveratrol. miR-221/ 222 overexpression decreased p38/NF-kappaB and ICAM-1 expression, which resulted in reduced monocyte adhesion to TNF-alpha-treated ECs. In a mouse model of acute TNF-alpha-induced inflammation, resveratrol effectively attenuated ICAM-1 expression in the aortic ECs of TNF-alpha-treated wild-type mice. These beneficial effects of resveratrol were lost in miR-221/222 knockout mice. Our data showed that resveratrol counteracted the TNF-alpha-mediated reduction in miR 221/222 expression and decreased the TNF-alpha-induced activation of p38 MAPK and NF-kappaB, thereby suppressing ICAM-1 expression and monocyte adhesion. Collectively, our results show that resveratrol attenuates endothelial inflammation by reducing ICAM-1 expression and that the protective effect was mediated partly through the miR-221/222/AMPK/p38/NF-kappaB pathway. PMID- 28338012 TI - Prevalence of ST1193 clone and IncI1/ST16 plasmid in E-coli isolates carrying blaCTX-M-55 gene from urinary tract infections patients in China. AB - To study molecular epidemiology of CTX-M-55-carrying Escherichia coli isolates from urinary tract infections (UTIs) in China. 111 blaCTX-M-55-positive E.coli isolates from UTIs patients in China were studied. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) were used to analyze the homologies among the strains. Conjugation experiments, S1nuclease PFGE and PCR analysis were performed to characterize plasmids harboring blaCTX-M-55 and their genetic environment. 111 isolates were clustered into 86 individual pulsotypes and three clusters by PFGE. Fifty-five (49.5%) of the isolates belonged to 8 STs. Most of the ST1193 isolates belonged to one PFGE cluster. Transconjugants (n = 45) derived from randomly selected blaCTX-M-55 donors (n = 58), were found to contain a single 90-kb conjugative plasmid, which mainly belonged to the IncI1 groups (34, 76%). Among the IncI1 plasmids, the blaCTX-M 55/IncI1/ST16 predominated (23/34, 68%). The blaTEM-1 and aac (3')-II genes were frequently detected on the IncI1 plasmids, and the insertion of ISEcp1 or IS26 was observed at the 48 bp or 45 bp upstream of the start codon of blaCTX-M-55 gene. The dissemination of blaCTX-M-55 gene among E. coli UTI isolates, appeared to be due to both the major clonal lineage of ST1193 and the horizontal transfer of epidemic plasmid IncI1/ST16. PMID- 28338013 TI - Effect of prolonged freezing of semen on exosome recovery and biologic activity. AB - Exosomes are important vehicles of intercellular communication that shape host responses to physiologic, tumorigenic, and pathogenic conditions. The composition and function of exosomes are dynamic and depends on the state and condition of the cellular source. In prior work, we found that semen exosomes (SE) from healthy donors who do not use illicit drugs potently inhibit HIV-1. Following semen donation, specimens are either used immediately or frozen for use at a later time. It has been shown that short-term freezing of semen has no effect on SE-mediated HIV-1 inhibition. However, the effect of illicit drugs and prolonged freezing on SE bioactivity is unknown. Here, we show preservation of SE physical properties, (morphology, concentration, intensity/size) irrespective of illicit drug use or duration of semen freezing. Interestingly, illicit drugs and prolonged freezing decreased the levels of SE-bound CD63/CD9 and acetylcholinesterase activity respectively. Furthermore, we show differential effects of illicit drug use and prolonged freezing on SE-mediated HIV-1 inhibition. Our results highlight the importance of the source of SE and condition of semen storage on SE content and function. In-depth evaluation of donor drug-use and duration of semen storage on SE cargo and bioactivity will advance our understanding of SE composition and function. PMID- 28338015 TI - Simultaneously measuring multiple protein interactions and their correlations in a cell by Protein-interactome Footprinting. AB - Quantitatively detecting correlations of multiple protein-protein interactions (PPIs) in vivo is a big challenge. Here we introduce a novel method, termed Protein-interactome Footprinting (PiF), to simultaneously measure multiple PPIs in one cell. The principle of PiF is that each target physical PPI in the interactome is simultaneously transcoded into a specific DNA sequence based on dimerization of the target proteins fused with DNA-binding domains. The interaction intensity of each target protein is quantified as the copy number of the specific DNA sequences bound by each fusion protein dimers. Using PiF, we quantitatively reveal dynamic patterns of PPIs and their correlation network in E. coli two-component systems. PMID- 28338014 TI - Entropic stabilization of a deubiquitinase provides conformational plasticity and slow unfolding kinetics beneficial for functioning on the proteasome. AB - Human ubiquitin C-terminal hydrolyase UCH-L5 is a topologically knotted deubiquitinase that is activated upon binding to the proteasome subunit Rpn13. The length of its intrinsically disordered cross-over loop is essential for substrate recognition. Here, we showed that the catalytic domain of UCH-L5 exhibits higher equilibrium folding stability with an unfolding rate on the scale of 10-8 s-1, over four orders of magnitudes slower than its paralogs, namely UCH L1 and -L3, which have shorter cross-over loops. NMR relaxation dynamics analysis confirmed the intrinsic disorder of the cross-over loop. Hydrogen deuterium exchange analysis further revealed a positive correlation between the length of the cross-over loop and the degree of local fluctuations, despite UCH-L5 being thermodynamically and kinetically more stable than the shorter UCHs. Considering the role of UCH-L5 in removing K48-linked ubiquitin to prevent proteasomal degradation of ubiquitinated substrates, our findings offered mechanistic insights into the evolution of UCH-L5. Compared to its paralogs, it is entropically stabilized to withstand mechanical unfolding by the proteasome while maintaining structural plasticity. It can therefore accommodate a broad range of substrate geometries at the cost of unfavourable entropic loss. PMID- 28338016 TI - Superposition-free comparison and clustering of antibody binding sites: implications for the prediction of the nature of their antigen. AB - We describe here a superposition free method for comparing the surfaces of antibody binding sites based on the Zernike moments and show that they can be used to quickly compare and cluster sets of antibodies. The clusters provide information about the nature of the bound antigen that, when combined with a method for predicting the number of direct antibody antigen contacts, allows the discrimination between protein and non-protein binding antibodies with an accuracy of 76%. This is of relevance in several aspects of antibody science, for example to select the framework to be used for a combinatorial antibody library. PMID- 28338017 TI - A role of the SAM domain in EphA2 receptor activation. AB - Among the 20 subfamilies of protein receptor tyrosine kinases (RTKs), Eph receptors are unique in possessing a sterile alpha motif (SAM domain) at their C terminal ends. However, the functions of SAM domains in Eph receptors remain elusive. Here we report on a combined cell biology and quantitative fluorescence study to investigate the role of the SAM domain in EphA2 function. We observed elevated tyrosine autophosphorylation levels upon deletion of the EphA2 SAM domain (EphA2DeltaS) in DU145 and PC3 prostate cancer cells and a skin tumor cell line derived from EphA1/A2 knockout mice. These results suggest that SAM domain deletion induced constitutive activation of EphA2 kinase activity. In order to explain these effects, we applied fluorescence correlation spectroscopy to investigate the lateral molecular organization of EphA2. Our results indicate that SAM domain deletion (EphA2DeltaS-GFP) increases oligomerization compared to the full length receptor (EphA2FL-GFP). Stimulation with ephrinA1, a ligand for EphA2, induced further oligomerization and activation of EphA2FL-GFP. The SAM domain deletion mutant, EphA2DeltaS-GFP, also underwent further oligomerization upon ephrinA1 stimulation, but the oligomers were larger than those observed for EphA2FL-GFP. Based on these results, we conclude that the EphA2 SAM domain inhibits kinase activity by reducing receptor oligomerization. PMID- 28338018 TI - Isolation and characterization of the E. coli membrane protein production strain Mutant56(DE3). AB - Membrane protein production is usually toxic to E. coli. However, using genetic screens strains can be isolated in which the toxicity of membrane protein production is reduced, thereby improving production yields. Best known examples are the C41(DE3) and C43(DE3) strains, which are both derived from the T7 RNA polymerase (P)-based BL21(DE3) protein production strain. In C41(DE3) and C43(DE3) mutations lowering t7rnap expression levels result in strongly reduced T7 RNAP accumulation levels. As a consequence membrane protein production stress is alleviated in the C41(DE3) and C43(DE3) strains, thereby increasing membrane protein yields. Here, we isolated Mutant56(DE3) from BL21(DE3) using a genetic screen designed to isolate BL21(DE3)-derived strains with mutations alleviating membrane protein production stress other than the ones in C41(DE3) and C43(DE3). The defining mutation of Mutant56(DE3) changes one amino acid in its T7 RNAP, which weakens the binding of the T7 RNAP to the T7 promoter governing target gene expression rather than lowering T7 RNAP levels. For most membrane proteins tested yields in Mutant56(DE3) were considerably higher than in C41(DE3) and C43(DE3). Thus, the isolation of Mutant56(DE3) shows that the evolution of BL21(DE3) can be promoted towards further enhanced membrane protein production. PMID- 28338020 TI - Epigenetic Regulation of Intronic Transgenes in Arabidopsis. AB - Defense mechanisms of plant genomes can epigenetically inactivate repetitive sequences and exogenous transgenes. Loss of mutant phenotypes in intronic T-DNA insertion lines by interaction with another T-DNA locus, termed T-DNA suppression, has been observed in Arabidopsis thaliana, although the molecular basis of establishment and maintenance of T-DNA suppression is poorly understood. Here we show that maintenance of T-DNA suppression requires heterochromatinisation of T-DNA sequences and the nuclear proteins, INCREASED IN BONSAI METHYLATION 2 (IBM2) and ENHANCED DOWNY MILDEW 2 (EDM2), which prevent ectopic 3' end processing of mRNA in atypically long introns containing T-DNA sequences. Initiation of T-DNA suppression is mediated by the canonical RdDM pathway after hybridisation of two T-DNA strains, accompanied by DNA hypermethylation of T-DNA sequences in the F1 generation. Our results reveal the presence of a genome surveillance mechanism through genome hybridisation that masks repetitive DNAs intruding into transcription units. PMID- 28338019 TI - Ghrelin Facilitates GLUT2-, SGLT1- and SGLT2-mediated Intestinal Glucose Transport in Goldfish (Carassius auratus). AB - Glucose homeostasis is an important biological process that involves a variety of regulatory mechanisms. This study aimed to determine whether ghrelin, a multifunctional gut-brain hormone, modulates intestinal glucose transport in goldfish (Carassius auratus). Three intestinal glucose transporters, the facilitative glucose transporter 2 (GLUT2), and the sodium/glucose co transporters 1 (SGLT1) and 2 (SGLT2), were studied. Immunostaining of intestinal sections found colocalization of ghrelin and GLUT2 and SGLT2 in mucosal cells. Some cells containing GLUT2, SGLT1 and SGLT2 coexpressed the ghrelin/growth hormone secretagogue receptor 1a (GHS-R1a). Intraperitoneal glucose administration led to a significant increase in serum ghrelin levels, as well as an upregulation of intestinal preproghrelin, ghrelin O-acyltransferase and ghs-r1 expression. In vivo and in vitro ghrelin treatment caused a concentration- and time-dependent modulation (mainly stimulatory) of GLUT2, SGLT1 and SGLT2. These effects were abolished by the GHS-R1a antagonist [D-Lys3]-GHRP-6 and the phospholipase C inhibitor U73122, suggesting that ghrelin actions on glucose transporters are mediated by GHS-R1a via the PLC/PKC signaling pathway. Finally, ghrelin stimulated the translocation of GLUT2 into the plasma membrane of goldfish primary intestinal cells. Overall, data reported here indicate an important role for ghrelin in the modulation of glucoregulatory machinery and glucose homeostasis in fish. PMID- 28338022 TI - Alizarin Red S for Online Pyrophosphate Detection Identified by a Rapid Screening Method. AB - We identified Alizarin Red S and other well known fluorescent dyes useful for the online detection of pyrophosphate in enzymatic assays, including the loop mediated isothermal amplification (LAMP) and polymerase chain reaction (PCR) assays. An iterative screening was used for a selected set of compounds to first secure enzyme compatibility, evaluate inorganic pyrophosphate sensitivity in the presence of manganese as quencher and optimize conditions for an online detection. Of the selected dyes, the inexpensive alizarin red S was found to selectively detect pyrophosphate under LAMP and PCR conditions and is superior with respect to its defined red-shifted spectrum, long shelf life and low toxicity. In addition, the newly identified properties may also be useful in other enzymatic assays which do not generate nucleic acids but are based on inorganic pyrophosphate. Finally, we propose that our screening method may provide a blueprint for rapid screening of compounds for detecting inorganic pyrophosphate. PMID- 28338023 TI - Implant maintenance treatment and peri-implant health. AB - Data sourcesMedline (PubMed), Embase, Cochrane Central Register of Controlled Trials and Cochrane Oral Health Group Trials Register databases and a manual search of the Journal of Dental Research, Journal of Clinical Periodontology, Journal of Periodontology and the International Journal of Periodontics and Restorative Dentistry from January 2014 to February 2015.Study selectionProspective, retrospective, randomised or not, case-controlled or case series trials showing the incidence or recurrence of peri-implant disease plus or minus PIMT over more than six months.Data extraction and synthesisThree reviewers independently selected studies and abstracted data with two reviewers assessing study quality using the Newcastle-Ottawa Scale (NOS). A multivariate binomial regression was used to examine the data.ResultsThirteen studies were included with ten contributing to the meta-analysis. The average quality assessment score (NOS) was 5.3 out of a possible nine, only one paper achieved eight. At patient level mucositis ranged from 18.5-74.2% and peri-implantitis from 8-28%, with significant effects being seen for treatment (z= -14.36, p<0.001). Mucositis was affected by history of periodontitis and mean PIMT at implant and patient levels, respectively. For peri-implantitis there were also significant effects of treatment (z = -16.63, p<0.001). Increased peri-implantitis was observed for patients with a history of periodontal disease. (z=3.76, p<0.001). Implants under PIMT have 0.958 the incident event compared to those with no PIMT.ConclusionsWithin the limitations of the present systematic review it can be concluded that implant therapy must not be limited to placement and restoration of dental implants, but to the implementation of PIMT to potentially prevent biological complications and heighten the long-term success rate. Although it must be tailored to a patients risk profiling, our findings suggest reason to claim a minimum recall PIMT interval of five to six months. Additionally, it must be stressed that even in the establishment of PIMT, biological complications might occur. Hence, patient-, clinical-, and implant-related factors must be thoroughly explored. PMID- 28338021 TI - Absence of a gestational diabetes phenotype in the LepRdb/+ mouse is independent of control strain, diet, misty allele, or parity. AB - Treatment options for gestational diabetes (GDM) are limited. In order to better understand mechanisms and improve treatments, appropriate animal models of GDM are crucial. Heterozygous db mice (db/+) present with glucose intolerance, insulin resistance, and increased weight gain during, but not prior to, pregnancy. This makes them an ideal model for GDM. However, several recent studies have reported an absence of GDM phenotype in their colony. We investigated several hypotheses for why the phenotype may be absent, with the aim of re-establishing it and preventing further resources being wasted on an ineffective model. Experiments were carried out across two laboratories in two countries (New Zealand and China), and were designed to assess type of control strain, diet, presence of the misty allele, and parity as potential contributors to the lost phenotype. While hyperleptinemia and pre-pregnancy weight gain were present in all db/+mice across the four studies, we found no consistent evidence of glucose intolerance or insulin resistance during pregnancy. In conclusion, we were unable to acquire the GDM phenotype in any of our experiments, and we recommend researchers do not use the db/+ mouse as a model of GDM unless they are certain the phenotype remains in their colony. PMID- 28338024 TI - Evidence for use of intraoral scanners under clinical conditions for obtaining full-arch digital impressions is insufficient. AB - Data sourcesPubMed, Scopus, Cochrane Library, Web of Science, Embase. Relevant papers were also searched from the reference lists of selected studies. A web search of current manufacturers of intraoral scanners.Study selectionStudies with full-arch digital impressions recorded intraorally that tested any of the following outcomes; validity, repeatability, reproducibility, time efficiency. Patient acceptance of digital impressions were considered for the review.Data extraction and synthesisInitially, only titles of the papers identified from the databases were screened, then further screening of the abstracts of the selected titles was carried out. Then finally, full text articles of the selected abstracts were read and only relevant articles were included in the review. Two examiners assessed the quality of the chosen articles using the QUADAS checklist. Any disagreement was resolved by discussion between the two examiners.ResultsOnly eight studies were found that carried out full-arch intraoral scanning. Four studies reported on validity, repeatability and reproducibility of digital measurements. These studies were included in the qualitative assessment. Two intraoral scanners were tested, Lava COS and iTero. In assessing scanning times and patient perception, six and four studies were included, respectively. A decrease in the scanning time was noted as the operator gained experience.ConclusionsThe literature lacks sufficient evidence to comment on the use of intraoral scanners under clinical conditions. Further studies are needed to properly assess the reliability, accuracy, reproducibility and scanning times of intraoral scans. PMID- 28338025 TI - Preventing perioperative bleeding in patients with inherited bleeding disorders. AB - Data sourcesCochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, a regularly updated database informed by trials identified within electronic databases including MEDLINE. Further defined searches were undertaken in PubMed, Embase, The Cochrane Library, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform. Additional hand searching of relevant journals and books of conference proceedings was undertaken.Study selectionRandomised and quasi-randomised controlled trials in people of all ages with haemophilia or VWD undergoing oral or dental procedures using antifibrinolytic agents (tranexamic acid (TXA) or epsilon aminocaproic acid (EACA)) to prevent perioperative bleeding compared to no intervention with or without placebo.Data extraction and synthesisTwo authors independently assessed identified publications for inclusion based on defined selection criteria. The two authors performed data extraction and risk of bias assessments using standardised forms and the Cochrane risk of bias tools. A third author, deemed to have particular subject expertise, verified eligibility of inclusion.ResultsOne randomised, double-blinded placebo controlled trial and one quasi-randomised trial were included. A total of 59 participants with haemophilia undergoing dental extraction were involved. Both trials evidenced a notable reduction in post-operative bleeding following dental extraction when either TXA or EACA were used, in addition to routine preoperative factor replacement, when compared to placebo. The number of post-operative bleeds, amount of blood loss and the need for additional clotting factors were reduced in the groups receiving antifibrinolytic therapy. No eligible trials in people with VWD were identified.ConclusionsLow quality evidence exists to support the use of adjuvant antifibrinolytic therapy to reduce perioperative bleeding in patients with haemophilia undergoing dental extraction. The limited number of trials identified (N=2), minimal sample size (N=28, N=31) and historic nature of the studies, originating from the 1970s, in addition to study heterogeneity and subsequent selection bias results in a low quality evidence grade for recommending adjuvant antifibrinolytic therapy. There is no clear indication to alter current practice utilising antifibrinolytic therapy to manage patients with haemophilia undergoing dental surgery in accordance with internationally accepted guidelines. However, further research with standardised study deigns would be welcomed in order to enhance the evidence base in the management of people with haemophilia and VWD. PMID- 28338026 TI - Rubber dam may increase the survival time of dental restorations. AB - Data sourcesCochrane Oral Health's Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, LILACS, SciELO, Chinese BioMedical Literature Database, VIP, China National Knowledge Infrastructure, ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, OpenGrey and Sciencepaper Online databases. Handsearches in a number of journals.Study selectionRandomised controlled trials, including split mouth studies assessing the effects of rubber dam isolation for restorative treatments in dental patients.Data extraction and synthesisTwo review authors independently screened the results of the electronic searches, extracted data and assessed the risk of bias of the included studies.ResultsFour studies involving a total of 1,270 patients were included. The studies were at high risk of bias. One trial was excluded from the analysis due to inconsistencies in the presented data. Restorations had a significantly higher survival rate in the rubber dam isolation group compared to the cotton roll isolation group at six months in participants receiving composite restorative treatment of non-carious cervical lesions (risk ratio (RR) 1.19, 95% confidence interval (CI) 1.04 to 1.37, very low-quality evidence). The rubber dam group had a lower risk of failure at two years in children undergoing proximal atraumatic restorative treatment in primary molars (hazard ratio (HR) 0.80, 95% CI 0.66 to 0.97, very low-quality evidence). One trial reported limited data showing that rubber dam usage during fissure sealing might shorten the treatment time. None of the included studies mentioned adverse effects or reported the direct cost of the treatment, or the level of patient acceptance/satisfaction. There was also no evidence evaluating the effects of rubber dam usage on the quality of the restorations.ConclusionsWe found some very low-quality evidence, from single studies, suggesting that rubber dam usage in dental direct restorative treatments may lead to a lower failure rate of the restorations, compared with the failure rate for cotton roll usage. Further high quality research evaluating the effects of rubber dam usage on different types of restorative treatments is required. PMID- 28338029 TI - Unclear if non-surgical adjuncts accelerate orthodontic treatment. AB - Data sourcesCochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, LILACS, the metaRegister of Controlled Trials, the US National Institutes of Health Trials Register and the WHO International Clinical Trials Registry Platform.Study selectionRandomised controlled trials of orthodontic treatment using fixed appliances along with non-surgical adjunctive interventions to accelerate tooth movement.Data extraction and synthesisTwo reviewers independently selected studies, abstracted data and assessed risk of bias. Meta-analysis was not possible.ResultsTwo studies involving a total of 111 patients were included, both were at high risk of bias. The studies compared the use of Tooth Masseuse and OrthoAccel with conventional treatment mechanics. Using OrthoAccel with 30 Hz at 0.25 N for 20 minutes daily produced a higher rate of maxillary canine distalisation in comparison to the control group (MD 0.37 mm/month; 95% CI -0.07 to 0.81; P = 0.05). Whilst this difference suggested 50% faster tooth movement using the vibrational appliance, the absolute differences were marginal and deemed clinically unimportant. Similar levels of non-serious adverse effects were reported in the intervention and control groups with a risk ratio of 0.96 (95% CI 0.32 to 2.85). Overall, the quality of the evidence was very low and therefore we cannot rely on the findings.ConclusionsThere is very little clinical research concerning the effectiveness of non-surgical interventions to accelerate orthodontic treatment. The available evidence is of very low quality and so it is not possible to determine if there is a positive effect of non-surgical adjunctive interventions to accelerate tooth movement. Although there have been claims that there may be a positive effect of light vibrational forces, results of the current studies do not reach either statistical or clinical significance. Further well-designed and rigorous RCTs with longer follow-up periods are required to determine whether non-surgical interventions may result in a clinically important reduction in the duration of orthodontic treatment, without any adverse effects. PMID- 28338027 TI - Molar incisor hypomineralisation. AB - Data sourcesThe Medline and Embase databases and hand searches in the journals International Journal of Paediatric Dentistry and European Archives of Paediatric Dentistry.Study selectionEnglish language cohort and case-control studies.Data extraction and synthesisStudy selection was carried out independently by two reviewers with data abstraction being conducted by a single reviewer and checked by a second reviewer. Risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale (NOS). Adjusted (aOR) and unadjusted odds ratios (uOR), P values and 95% confidence intervals (CI) were obtained from the studies. Meta analysis was not conducted.ResultsTwenty-eight studies were included; 25 reported on MIH, three on hypomineralised second primary molars (HSPM). Nineteen of the studies were of cohort design (six prospective,13 retrospective) and nine were case controls. There was little evidence of an association between the most frequently investigated prenatal factors (smoking, maternal illness, maternal medication, maternal stress) and MIH. Similarly there was little evidence of an association between MIH and perinatal factors such as prematurity, low birth weight, caesarean delivery and birth complications. Early childhood illness, up to three or four years of age, was widely investigated, with six studies reporting a crude association. Associations between antibiotics, anti-asthma medication and breastfeeding were also evaluated. Only three studies looked at HSPM; one study suggested that maternal antibiotic use during pregnancy is unlikely to be associated with HSPM but maternal alcohol intake may be. Another study reported possible associations with a large number of factors, with perinatal factors and neonatal illness being most common, followed by prenatal factors.ConclusionsPrenatal and perinatal factors are infrequently associated with MIH. However, despite a lack of prospective studies, early childhood illness (in particular fever) appears to be associated with MIH. Further prospective studies that adjust for confounding based on biological principles, as well as genetic and epigenetic studies, are needed because the aetiology is likely to be multifactorial. PMID- 28338030 TI - Implant outcomes poorer in patients with history of periodontal disease. AB - Data sourcesMedline and Embase databases and bibliographies of all included articles and relevant review articles were screened for possible inclusion.Study selectionLongitudinal studies were included reporting on implant survival, success, incidence of peri-implantitis, bone loss and periodontal status and on partially dentate patients with a history of treatment for periodontitis. There were no language restrictions for the included studies.Data extraction and synthesisAuthors independently and in duplicate assessed the studies for eligibility and data extraction. Disagreements were resolved by discussion and consensus. The methodological quality assessment of the included studies was done using an adapted Newcastle-Ottawa Scale (NOS). Confounding factors such as smoking, systemic disease influencing osseointegration, chemotherapy and radiation were assessed and adjusted in the analysis. Data were organised into tables and grouped in accordance with the study design.ResultsTwenty-four studies reported in 27 publications were included. Implant survival and success rate were higher in periodontally healthy patients.Twelve prospective cohort studies, five case series with a control group, four retrospective cohort studies and three studies with a sub group comparison were included.Bone loss and peri-implantitis were increased in patients with a history of treated periodontitis. More complications were reported in patients presenting with more severe forms of periodontitis. High heterogeneity among the studies in terms of study design, population, therapy, unit of analysis, inconsistent definitions of baseline and outcomes, inadequate reporting and confounding factors meant a meta-analysis could not be performed.Most of the studies showed better implant survival rates for the non-periodontitis group ranging from 91.67% to 100% compared to the treated periodontitis group 79.22% to 100% over a 1.2 to 16 year follow up.ConclusionsImplants placed in patients treated for periodontal disease are associated with higher incidence of biological complications and lower success and survival rates than those placed in periodontally healthy patients. Severe forms of periodontal disease are associated with higher rates of implant loss. The conclusion of the review is limited by the strength of the evidence. PMID- 28338031 TI - Preoperative analgesia for children and adolescents to reduce pain associated with dental treatment. AB - Data sourcesCochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, LILACS, ISI Web of Science, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform.Study selectionRandomised controlled clinical trials of analgesics given before dental treatment versus placebo or no analgesics in children and adolescents up to 17 years of age. Children and adolescents having dental treatment under sedation (including nitrous oxide/oxygen) or general anaesthesia were excluded.Data extraction and synthesisTwo reviewers independently selected studies, abstracted data and assessed risk of bias. Standard Cochrane methodological approaches were used.ResultsFive trials involving 190 patients were included. None of the studies were at low risk of bias. Three trials involved dental treatment and two involved orthodontic treatment. Three of the included trials compared paracetamol with placebo. Meta-analysis of the two trials showed no evidence of a benefit in taking paracetamol preoperatively; (RR) for postoperative pain of 0.81 (95%CI; 0.53 to 1.22). Four trials compared ibuprofen with placebo. Pooled data from two studies showed a statistically significant mean difference in severity of postoperative pain of -13.44 (95%CI; 23.01 to -3.88) on a visual analogue scale (0 to 100), which indicated a probable benefit. Both trials were at high risk of bias and the quality of the evidence is low.ConclusionsFrom the available evidence, we cannot determine whether or not preoperative analgesics are of benefit in paediatric dentistry for procedures under local anaesthetic. There is probably a benefit in using preoperative analgesics prior to orthodontic separator placement. The quality of the evidence is low. Further randomised clinical trials should be completed with appropriate sample sizes and well defined outcome measures. PMID- 28338032 TI - Reliability of CBCT diagnosing root fractures remains uncertain. AB - Data sourcesPubMed, Web of Science, Science Direct, Cochrane library, Embase, SCOPUS, CNKI and Wanfang databases were searched until April 2014 followed by hand searching of relevant references.Study selectionUsing no language restrictions two authors independently assessed for inclusion of in vivo and in vitro studies involving at least ten teeth on the use of CBCT for diagnosing complete root fractures on non-endodontically treated teeth.Data extraction and synthesisTwo authors independently assessed for inclusion and performed quality assessment using QUADAS-2 (quality assessment of studies of diagnostic accuracy 2). A random effects model was used to calculate pooled sensitivity, specificity and likelihood ratio (positive and negative). In addition, the correlation between voxel size and diagnostic accuracy was calculated.ResultsTwelve studies were included in the review. Seven used i-CAT with 372 teeth and four used 3D Accuitomo with 237 teeth (one study used both). For i-CAT pooled sensitivity was 0.83 (0.78 to 0.86), while specificity was 0.91(0.87 to 0.93). For 3D Accuitomo sensitivity was 0.95 (0.90 to 0.96) and the specificity 0.96 (0.92 to 0.99) Correlation between voxel size and diagnostic accuracy was analysed among five subgroups for i-CAT and two subgroups on the 3D Accuitomo group. No statistically significant difference was observed based on voxel size.ConclusionsAccording to the authors CBCT provides clinically relevant accuracy and reliability to detect root fractures in untreated teeth independently of the voxel size. PMID- 28338034 TI - Letters to the editor. PMID- 28338036 TI - To cord or not to cord? That is still a question. AB - Data sourcesA broad computerised search with similar key terms was performed in different databases that included: Ovid Medline, Thomson's ISI Web of Science, PubMed, Science Direct, EMBASE and the Cochrane Library. Grey literature, dissertations, abstracts and theses were searched too. Reference lists of the selected articles were hand-searched.Study selectionThe inclusion criteria included in vivo randomised clinical trials and quasi-randomised clinical trials using gingival retraction techniques with and without cord. Studies were included if they examined the primary outcome from the review: efficiency of haemostasis control, the amount of gingival displacement and the influence of the techniques on gingival/periodontal health. Secondary outcomes accepted for the review included subjective factors reported by the patient such as pain, sensitivity, unpleasant taste and discomfort and operator's experience with both techniques. Non-English papers, clinical reports, animals studies or in vitro studies were excluded.Data extraction and synthesisTwo authors independently searched and screened the articles. Disagreements were resolved by discussion. A third reviewer participated in the eligibility of the studies. The risk of bias was assessed using the Cochrane Collaboration tool. Due to the heterogeneity of measurement variables across the studies and the differences among the studies, a meta-analysis was not performed. A narrative assessment was performed for the outcomes: moisture/bleeding control, gingival displacement, gingival/periodontal health and the subjective outcomes.ResultsFrom the initial search that retrieved 1,342 articles, 19 potential relevant full-text articles were considered for the review. Seven studies were selected for the systematic review. Four randomised clinical trials were included. Sample size ranged from eight to 252 participants per study. Five studies were conducted on patients requiring any indirect fixed restorations on prepared teeth. Two studies were done on unprepared teeth. In all studies, participants were in good health, had a healthy gingival condition and a sound periodontal status.ConclusionsBoth techniques are reliable in achieving gingival retraction. The review supports the observation that gingival retraction paste can more effectively help to achieve a dry field and at the same time be less injurious to soft tissues, however its ability to displace gingival tissues, compared to retraction cord, was compromising. Rather than considering the cost of material or the individual preference of the operator, choosing the right technique to maximise clinical efficiency should be based on scientific evidence. It seems that impregnated gingival cords are more effective on thick gingival tissue whereas paste is more effective when minimal retraction is required for haemostasis control, preservation of the gingiva and less tissue displacement. PMID- 28338037 TI - Psychological approaches to behaviour for improving plaque control. AB - Data sourcesThe Cochrane Oral Health Groups Trial Register, Medline, Embase and PsycINFO.Study selectionRandomised controlled trials (RCTs), controlled clinical trials (CCTs), cohort studies or case-control studies were considered. Only studies in patients aged 18 or older with pre-existing periodontal disease and clearly stating a psychological model or theory had been used were included. Studies exploring smoking cessation were not included.Data extraction and synthesisAll data were collected by a single author using pre-decided parameters. The reviewers used the Cochrane criteria to assess risk of bias in clinical trials and the Newcastle Ottawa Scale for observational studies. Marked heterogeneity from the wide variety of psychological approaches used in the studies prevented meta-analysis.ResultsFifteen papers relating to 14 different studies were included from an initial 722 articles identified. This included three cohort studies, ten RCTs and a before/after study. A total of 1,106 patients were included across the studies. Of the 19 psychological models included in the initial search, seven were shown to have some form of impact on oral hygiene motivation, demonstrated by observed behavioural and clinical outcomes.ConclusionsThe authors concluded that, in adult patients with pre existing periodontal disease, understanding of the seriousness of periodontal disease and the benefits of behavioural change resulted in improved adherence to oral hygiene instructions. They concluded that goal-setting, self-monitoring and indeed planning can be useful in improving oral health-related behaviours. PMID- 28338038 TI - School-based dental sealant programmes may be effective in caries prevention. AB - DesignSplit-mouth randomised controlled clinical trial.InterventionSchool-based dental sealant (SBDS) programme. The study population that was selected from 67 year-old pupils of 16 elementary schools in areas of low socioeconomic status within Nice, France. Children with first permanent molar pairs sufficiently erupted for sealing with no caries (ICDAS [International Caries Detection and Assessment System] 0) or initial enamel lesions (ICDAS 1-2) were included. Children were randomised to either the intervention group (light polymerised resin-based sealant with fluoride) or the control group (no treatment).Outcome measureThe primary outcome measure was caries with sealant retention as a secondary outcome.ResultsFour hundred and fifty-seven pairs of permanent first molars belonging to 276 school children were randomised. At three years 378 pairs in 228 children were available for analysis. The overall retention rate was 32.3%. Sealed molars had 67% less risk of new carious lesions, adjusted hazard ratio = 0.33(95%CI; 0.24-0.46).ConclusionsSBDS programmes can be effective in preventing the development of carious lesions in school children, particularly those who come from low socioeconomic backgrounds and may, as a result, be unable to receive adequate oral healthcare in other settings outside the school. ICR should determine the selection of at-risk sub-groups for which the intervention could be considered. PMID- 28338040 TI - Regular supervised fluoride mouthrinse use by children and adolescents associated with caries reduction. AB - Data sourcesCochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, CINAHL, LILACS, BBO, Proquest Dissertations and Theses, Web of Science Conference Proceedings, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform.Study selectionRandomised or quasi-randomised controlled trials where blind outcome assessment was stated or indicated, comparing fluoride mouthrinse with placebo or no treatment in children up to 16 years of age with a duration of at least 12 months.Data extraction and synthesisA least two reviewers independently selected studies, abstracted data and assessed risk of bias.ResultsThirty-seven trials involving 15,813 children and adolescents were included. Supervised rinsing in schools was tested in all trials. Twenty-eight studies were at high risk of bias, nine at unclear risk. Thirty-five trials (15,305 participants) contributed data on permanent tooth surface for meta analysis and found a prevented fraction for D(M)FS = 27%(95%CI 23% to 30%; I2 = 42%) (moderate quality evidence). Meta-regression showed no significant association between estimates of D(M)FS with baseline caries severity, background exposure to fluorides, rinsing frequency or fluoride concentration. The pooled estimate of prevented fraction from 13 studies for D(M)FT = 23% (95%CI, 18% to 29%; I2 = 54%).There was limited information on possible adverse effects or acceptability of the treatment regimen in the included trials.ConclusionsThis review found that supervised regular use of fluoride mouthrinse by children and adolescents is associated with a large reduction in caries increment in permanent teeth. We are moderately certain of the size of the effect. Most of the evidence evaluated use of fluoride mouthrinse supervised in a school setting, but the findings may be applicable to children in other settings with supervised or unsupervised rinsing, although the size of the caries-preventive effect is less clear. Any future research on fluoride mouthrinses should focus on head-to-head comparisons between different fluoride rinse features or fluoride rinses against other preventive strategies, and should evaluate adverse effects and acceptability. PMID- 28338039 TI - Coronally advanced flap combined with connective tissue graft; treatment of choice for root coverage following recession? AB - Data sourcesMedline, The Cochrane Database Trials Register, Embase, supplemented by handsearching of five prominent periodontal journals, references from reviewed papers and contact with experts in the field of mucogingival surgery.Study selectionRandomised controlled trials (RCTs) with or without a split-mouth design, on human patients. RCTs had to compare at least two different surgical interventions on clearly specified recession defects, be over six months in duration and have clearly specified clinical measurements regarding root coverage.Data extraction and synthesisThe initial search for studies was carried out by one operator. The studies were quality assessed by two independent review authors using the Cochrane risk of bias tool. Odds Ratios were combined for dichotomous data and mean differences in continuous data using a random-effect model. The strength of the evidence of included studies was assessed according to the GRADE recommendations for bias and heterogeneity.ResultsFifty-one RCTs were reviewed encompassing 1574 patients and 1744 recession defects. Eighty meta analyses were conducted. Results showed that surgical intervention using a coronally advanced flap (CAF) in conjunction with a connective tissue graft (CTG) was more effective at obtaining complete root coverage (CRC), reduced recession (RecRed) and keratinised tissue (KT) gain compared to CAF alone. The use of barrier membranes with CAF showed no significant improvement to CAF alone with regard to CRC and RecRed. The use of enamel matrix derivatives (EMD) in conjunction with CAF had significant improvement in CRC, RecRed and KT gain compared to CAF alone. Using multiple techniques or biomaterials yielded similar or fewer benefits than simpler proceduresConclusionsTreatment of recession defects is best achieved with a coronally advanced flap combined with a connective tissue graft. PMID- 28338041 TI - Meibomian Gland Dysfunction Correlates to the Tear Film Instability and Ocular Discomfort in Patients with Pterygium. AB - Pterygium is a very common disease in an eye clinic characterized by a benign proliferation of local conjunctiva that often crosses the limber of cornea and extends into corneal surface. Variety of studies has showed that pterygium is able to result in ocular discomfort and the change of ocular surface environment, such as dry eye. However, the link between abnormal tear film function and pterygium is controversial. Meibomian gland dysfunction (MGD) is a common cause of dry eye and ocular discomfort but is often neglected, which may be the missing link between dry eye and pterygium. In this study, our data firstly revealed increased abnormality of meibomian gland structure and function in pterygium patients, representing with increased abnormality of MGD parameters such as meibum expression (P < 0.001) and meibomian gland loss (P < 0.001). Besides, the scores of MGD severity in patients with progressive pterygium were higher than those in patients with resting pterygium. The correlation between MGD parameters and ocular discomfort as well as dry eye indexes is also established. These findings suggest that MGD correlates to the tear film instability and ocular discomfort in patients with pterygium. PMID- 28338042 TI - Simulating electric field interactions with polar molecules using spectroscopic databases. AB - Ro-vibrational Stark-associated phenomena of small polyatomic molecules are modelled using extensive spectroscopic data generated as part of the ExoMol project. The external field Hamiltonian is built from the computed ro-vibrational line list of the molecule in question. The Hamiltonian we propose is general and suitable for any polar molecule in the presence of an electric field. By exploiting precomputed data, the often prohibitively expensive computations associated with high accuracy simulations of molecule-field interactions are avoided. Applications to strong terahertz field-induced ro-vibrational dynamics of PH3 and NH3, and spontaneous emission data for optoelectrical Sisyphus cooling of H2CO and CH3Cl are discussed. PMID- 28338043 TI - Redshifted Cherenkov Radiation for in vivo Imaging: Coupling Cherenkov Radiation Energy Transfer to multiple Forster Resonance Energy Transfers. AB - Cherenkov Radiation (CR), this blue glow seen in nuclear reactors, is an optical light originating from energetic beta-emitter radionuclides. CR emitter 90Y triggers a cascade of energy transfers in the presence of a mixed population of fluorophores (which each other match their respective absorption and emission maxima): Cherenkov Radiation Energy Transfer (CRET) first, followed by multiple Forster Resonance Energy transfers (FRET): CRET ratios were calculated to give a rough estimate of the transfer efficiency. While CR is blue-weighted (300-500 nm), such cascades of Energy Transfers allowed to get a) fluorescence emission up to 710 nm, which is beyond the main CR window and within the near-infrared (NIR) window where biological tissues are most transparent, b) to amplify this emission and boost the radiance on that window: EMT6-tumor bearing mice injected with both a radionuclide and a mixture of fluorophores having a good spectral overlap, were shown to have nearly a two-fold radiance boost (measured on a NIR window centered on the emission wavelength of the last fluorophore in the Energy Transfer cascade) compared to a tumor injected with the radionuclide only. Some CR embarked light source could be converted into a near-infrared radiation, where biological tissues are most transparent. PMID- 28338044 TI - Effect of decomposition and organic residues on resistivity of copper films fabricated via low-temperature sintering of complex particle mixed dispersions. AB - Mixtures of a copper complex and copper fine particles as copper-based metal organic decomposition (MOD) dispersions have been demonstrated to be effective for low-temperature sintering of conductive copper film. However, the copper particle size effect on decomposition process of the dispersion during heating and the effect of organic residues on the resistivity have not been studied. In this study, the decomposition process of dispersions containing mixtures of a copper complex and copper particles with various sizes was studied. The effect of organic residues on the resistivity was also studied using thermogravimetric analysis. In addition, the choice of copper salts in the copper complex was also discussed. In this work, a low-resistivity sintered copper film (7 * 10-6 Omega.m) at a temperature as low as 100 degrees C was achieved without using any reductive gas. PMID- 28338046 TI - Solitary perturbations in the steep boundary of magnetized toroidal plasma. AB - Solitary perturbations (SPs) localized both poloidally and radially are detected within ~100 MUs before the partial collapse of the high pressure gradient boundary region (called pedestal) of magnetized toroidal plasma in the KSTAR tokamak device. The SP develops with a low toroidal mode number (typically unity) in the pedestal ingrained with quasi-stable edge-localized mode (QSM) which commonly appears during the inter-collapse period. The SPs have smaller mode pitch and different (often opposite) rotation velocity compared to the QSMs. Similar solitary perturbations are also frequently observed before the onset of complete pedestal collapse, suggesting a strong connection between the SP generation and the pedestal collapse. PMID- 28338045 TI - Abnormal levels of histone methylation in the retinas of diabetic rats are reversed by minocycline treatment. AB - In this study we quantified the alterations of retinal histone post-translational modifications (PTMs) in diabetic rats using a liquid chromatography - tandem mass spectrometry (LC-MS/MS) approach. Some diabetic rats were subsequently treated with minocycline, a tetracycline antibiotic, which has been shown to inhibit the diabetes-induced chronic inflammation in the retinas of rodents. We quantified 266 differentially modified histone peptides, including 48 out of 83 methylation marks with significantly different abundancein retinas of diabetic rats as compared to non-diabetic controls. About 67% of these marks had their relative abundance restored to non-diabetic levels after minocycline treatment. Mono- and di-methylation states of histone H4 lysine 20 (H4K20me1/me2), markers related to DNA damage response, were found to be up-regulated in the retinas of diabetic rats and restored to control levels upon minocycline treatment. DNA damage response biomarkers showed the same pattern once quantified by western blotting. Collectively, this study indicates that alteration of some histone methylation levels is associated with the development of diabetic retinopathy in rodents, and the beneficial effect of minocycline on the retinas of diabetic rodents is partially through its ability to normalize the altered histone methylation levels. PMID- 28338047 TI - Automated detection and enumeration of marine wildlife using unmanned aircraft systems (UAS) and thermal imagery. AB - Estimating animal populations is critical for wildlife management. Aerial surveys are used for generating population estimates, but can be hampered by cost, logistical complexity, and human risk. Additionally, human counts of organisms in aerial imagery can be tedious and subjective. Automated approaches show promise, but can be constrained by long setup times and difficulty discriminating animals in aggregations. We combine unmanned aircraft systems (UAS), thermal imagery and computer vision to improve traditional wildlife survey methods. During spring 2015, we flew fixed-wing UAS equipped with thermal sensors, imaging two grey seal (Halichoerus grypus) breeding colonies in eastern Canada. Human analysts counted and classified individual seals in imagery manually. Concurrently, an automated classification and detection algorithm discriminated seals based upon temperature, size, and shape of thermal signatures. Automated counts were within 95-98% of human estimates; at Saddle Island, the model estimated 894 seals compared to analyst counts of 913, and at Hay Island estimated 2188 seals compared to analysts' 2311. The algorithm improves upon shortcomings of computer vision by effectively recognizing seals in aggregations while keeping model setup time minimal. Our study illustrates how UAS, thermal imagery, and automated detection can be combined to efficiently collect population data critical to wildlife management. PMID- 28338048 TI - Reconfigurable superconducting vortex pinning potential for magnetic disks in hybrid structures. AB - High resolution scanning Hall probe microscopy has been used to directly visualise the superconducting vortex behavior in hybrid structures consisting of a square array of micrometer-sized Py ferromagnetic disks covered by a superconducting Nb thin film. At remanence the disks exist in almost fully flux closed magnetic vortex states, but the observed cloverleaf-like stray fields indicate the presence of weak in-plane anisotropy. Micromagnetic simulations suggest that the most likely origin is an unintentional shape anisotropy. We have studied the pinning of added free superconducting vortices as a function of the magnetisation state of the disks, and identified a range of different phenomena arising from competing energy contributions. We have also observed clear differences in the pinning landscape when the superconductor and the ferromagnet are electron ically coupled or insulated by a thin dielectric layer, with an indication of non-trivial vortex-vortex interactions. We demonstrate a complete reconfiguration of the vortex pinning potential when the magnetisation of the disks evolves from the vortex-like state to an onion-like one under an in-plane magnetic field. Our results are in good qualitative agreement with theoretical predictions and could form the basis of novel superconducting devices based on reconfigurable vortex pinning sites. PMID- 28338049 TI - Breeding system and spatial isolation from congeners strongly constrain seed set in an insect-pollinated apomictic tree: Sorbus subcuneata (Rosaceae). AB - In plants, apomixis results in the production of clonal offspring via seed and can provide reproductive assurance for isolated individuals. However, many apomicts require pollination to develop functional endosperm for successful seed set (pseudogamy) and therefore risk pollination-limitation, particularly in self incompatible species that require heterospecific pollen. We used microsatellite paternity analysis and hand pollinations to investigate pollen-limitation in Sorbus subcuneata, a threatened endemic tree that co-occurs with its congener, S. admonitor. We confirmed that S. subcuneata is an obligate pseudogamous apomict, but open-pollinated flowers rarely produced seed (flower-to-seed conversion < 1%) even though they rapidly accumulated pollen on their stigmas. Manual heterospecific pollination by S. admonitor resulted in a high flower-to-seed conversion rate (65%), however, we estimate that the ratio of self: heterospecific pollination in open-pollinated flowers was at least 22:1. Despite the efficacy of heterospecific pollination, the contribution of S. admonitor trees to paternity in seed from open-pollinated flowers of S. subcuneata decreased rapidly with the spatial separation between paternal and maternal trees. Conservation efforts aimed at maintaining species with this breeding system must therefore manage the congeners in tandem which will also maintain the potential for rare heterospecific fertilisation that typically cause rapid diversification in these lineages. PMID- 28338051 TI - Configurational Molecular Glue: One Optically Active Polymer Attracts Two Oppositely Configured Optically Active Polymers. AB - D-configured poly(D-lactic acid) (D-PLA) and poly(D-2-hydroxy-3-methylbutanoic acid) (D-P2H3MB) crystallized separately into their homo-crystallites when crystallized by precipitation or solvent evaporation, whereas incorporation of L configured poly(L-2-hydroxybutanoic acid) (L-P2HB) in D-configured D-PLA and D P2H3MB induced co-crystallization or ternary stereocomplex formation between D configured D-PLA and D-P2H3MB and L-configured L-P2HB. However, incorporation of D-configured poly(D-2-hydroxybutanoic acid) (D-P2HB) in D-configured D-PLA and D P2H3MB did not cause co-crystallization between D-configured D-PLA and D-P2H3MB and D-configured D-P2HB but separate crystallization of each polymer occurred. These findings strongly suggest that an optically active polymer (L-configured or D-configured polymer) like unsubstituted or substituted optically active poly(lactic acid)s can act as "a configurational or helical molecular glue" for two oppositely configured optically active polymers (two D-configured polymers or two L-configured polymers) to allow their co-crystallization. The increased degree of freedom in polymer combination is expected to assist to pave the way for designing polymeric composites having a wide variety of physical properties, biodegradation rate and behavior in the case of biodegradable polymers. PMID- 28338050 TI - Schisandrin A inhibits dengue viral replication via upregulating antiviral interferon responses through STAT signaling pathway. AB - Dengue virus (DENV) infects 400 million people worldwide annually. Infection of more than one serotype of DENV highly corresponds to dengue hemorrhagic fever and dengue shock syndrome, which are the leading causes of high mortality. Due to lack of effective vaccines and unavailable therapies against DENV, discovery of anti-DENV agents is urgently needed. We first characterize that Schisandrin A can inhibit the replication of four serotypes of DENV in a concentration- and time dependent manner, with an effective half-maximal effective concentration 50% (EC50) value of 28.1 +/- 0.42 MUM against DENV serotype type 2 without significant cytotoxicity. Furthermore, schisandrin A can effectively protect mice from DENV infection by reducing disease symptoms and mortality of DENV-infected mice. We demonstrate that STAT1/2-mediated antiviral interferon responses contribute to the action of schisandrin A against DENV replication. Schisandrin A represents a potential antiviral agent to block DENV replication in vitro and in vivo. In conclusion, stimulation of STAT1/2-mediated antiviral interferon responses is a promising strategy to develop antiviral drug. PMID- 28338053 TI - Optimal array of sand fences. AB - Sand fences are widely applied to prevent soil erosion by wind in areas affected by desertification. Sand fences also provide a way to reduce the emission rate of dust particles, which is triggered mainly by the impacts of wind-blown sand grains onto the soil and affects the Earth's climate. Many different types of fence have been designed and their effects on the sediment transport dynamics studied since many years. However, the search for the optimal array of fences has remained largely an empirical task. In order to achieve maximal soil protection using the minimal amount of fence material, a quantitative understanding of the flow profile over the relief encompassing the area to be protected including all employed fences is required. Here we use Computational Fluid Dynamics to calculate the average turbulent airflow through an array of fences as a function of the porosity, spacing and height of the fences. Specifically, we investigate the factors controlling the fraction of soil area over which the basal average wind shear velocity drops below the threshold for sand transport when the fences are applied. We introduce a cost function, given by the amount of material necessary to construct the fences. We find that, for typical sand-moving wind velocities, the optimal fence height (which minimizes this cost function) is around 50 cm, while using fences of height around 1.25 m leads to maximal cost. PMID- 28338052 TI - Dissociable diffusion MRI patterns of white matter microstructure and connectivity in Alzheimer's disease spectrum. AB - Recent efforts using diffusion tensor imaging (DTI) have documented white matter (WM) alterations in Alzheimer's disease (AD). The full potential of whole-brain DTI, however, has not been fully exploited as studies have focused on individual microstructural indices independently. In patients with AD (n = 79), mild (MCI, n = 55) and subjective (SCI, n = 30) cognitive impairment, we applied linked independent component analysis (LICA) to model inter-subject variability across five complementary DTI measures (fractional anisotropy (FA), axial/radial/mean diffusivity, diffusion tensor mode), two crossing fiber measures estimated using a multi-compartment crossing-fiber model reflecting the volume fraction of the dominant (f1) and non-dominant (f2) diffusion orientation, and finally, connectivity density obtained from full-brain probabilistic tractography. The LICA component explaining the largest data variance was highly sensitive to disease severity (AD < MCI < SCI) and revealed widespread coordinated decreases in FA and f1 with increases in all diffusivity measures in AD. Additionally, it reflected regional coordinated decreases and increases in f2, mode and connectivity density, implicating bidirectional alterations of crossing fibers in the fornix, uncinate fasciculi, corpus callosum and major sensorimotor pathways. LICA yielded improved diagnostic classification performance compared to univariate region-of-interest features. Our results document coordinated WM microstructural and connectivity alterations in line with disease severity across the AD continuum. PMID- 28338054 TI - Identification of hexose kinase genes in Kluyveromyces marxianus and thermo tolerant one step producing glucose-free fructose strain construction. AB - In yeast, the hexose assimilation is started at hexose phosphorylation. However, in Kluyveromyces marxianus, the hexokinase (HXK) and glucokinase (GLK) genes were not identified by experiments. Meanwhile, the glucose-free fructose product requires more cost-efficient method. In this study, the KmHXK1 and KmGLK1 genes were functionally identified through gene disruption, over-expression and recombinant enzymes characterization. Both glucose and fructose assimilation ability decreased significantly in KmHXK1 disrupted strain YLM001, however, this ability was not changed obviously in KmGLK1 disrupted strain YLM002. When over expressing KmGLK1 in YLM001, only the glucose assimilation ability was recovered in obtained strain (YLM005). The kinetic constant analysis of recombinant enzymes also proved that KmHXK1 could phosphorylate glucose (Vmax 553.01 U/mg, Km 0.83 mM) and fructose (Vmax 609.82 U/mg, Km 0.52 mM), and KmGLK1 only phosphorylate glucose with a Vmax of 0.73 U/mg and a Km 4.09 mM. A thermo-tolerant strain YGR003 which produced glucose-free fructose from Jerusalem artichoke tuber in one step was constructed based on the obtained information. The highest production and fastest productivity were 234.44 g/L and 10.26 g/L/h, respectively, which were several folds of the results in previous reports. PMID- 28338055 TI - Fully printable, strain-engineered electronic wrap for customizable soft electronics. AB - Rapid growth of stretchable electronics stimulates broad uses in multidisciplinary fields as well as industrial applications. However, existing technologies are unsuitable for implementing versatile applications involving adaptable system design and functions in a cost/time-effective way because of vacuum-conditioned, lithographically-predefined processes. Here, we present a methodology for a fully printable, strain-engineered electronic wrap as a universal strategy which makes it more feasible to implement various stretchable electronic systems with customizable layouts and functions. The key aspects involve inkjet-printed rigid island (PRI)-based stretchable platform technology and corresponding printing-based automated electronic functionalization methodology, the combination of which provides fully printed, customized layouts of stretchable electronic systems with simplified process. Specifically, well controlled contact line pinning effect of printed polymer solution enables the formation of PRIs with tunable thickness; and surface strain analysis on those PRIs leads to the optimized stability and device-to-island fill factor of strain engineered electronic wraps. Moreover, core techniques of image-based automated pinpointing, surface-mountable device based electronic functionalizing, and one step interconnection networking of PRIs enable customized circuit design and adaptable functionalities. To exhibit the universality of our approach, multiple types of practical applications ranging from self-computable digital logics to display and sensor system are demonstrated on skin in a customized form. PMID- 28338056 TI - First order reversal curves and intrinsic parameter determination for magnetic materials; limitations of hysteron-based approaches in correlated systems. AB - The generic problem of extracting information on intrinsic particle properties from the whole class of interacting magnetic fine particle systems is a long standing and difficult inverse problem. As an example, the Switching Field Distribution (SFD) is an important quantity in the characterization of magnetic systems, and its determination in many technological applications, such as recording media, is especially challenging. Techniques such as the first order reversal curve (FORC) methods, were developed to extract the SFD from macroscopic measurements. However, all methods rely on separating the contributions to the measurements of the intrinsic SFD and the extrinsic effects of magnetostatic and exchange interactions. We investigate the underlying physics of the FORC method by applying it to the output predictions of a kinetic Monte-Carlo model with known input parameters. We show that the FORC method is valid only in cases of weak spatial correlation of the magnetisation and suggest a more general approach. PMID- 28338057 TI - The identification of ?-tryptophan as a bioactive substance for postembryonic ovarian development in the planarian Dugesia ryukyuensis. AB - Many metazoans start germ cell development during embryogenesis, while some metazoans possessing pluripotent stem cells undergo postembryonic germ cell development. The latter reproduce asexually but develop germ cells from pluripotent stem cells or dormant primordial germ cells when they reproduce sexually. Sexual induction of the planarian Dugesia ryukyuensis is an important model for postembryonic germ cell development. In this experimental system, hermaphroditic reproductive organs are differentiated in presumptive gonadal regions by the administration of a crude extract from sexual planarians to asexual ones. However, the substances involved in the first event during postembryonic germ cell development, i.e., ovarian development, remain unknown. Here, we aimed to identify a bioactive compound associated with postembryonic ovarian development. Bioassay-guided fractionation identified L-tryptophan (Trp) on the basis of electrospray ionization-mass spectrometry, circular dichroism, and nuclear magnetic resonance spectroscopy. Originally masked by a large amount of L-Trp, ?-Trp was detected by reverse-phase high-performance liquid chromatography. The ovary-inducing activity of ?-Trp was 500 times more potent than that of L-Trp. This is the first report describing a role for an intrinsic ? amino acid in postembryonic germ cell development. Our findings provide a novel insight into the mechanisms of germ cell development regulated by low-molecular weight bioactive compounds. PMID- 28338058 TI - The role of CREB3L4 in the proliferation of prostate cancer cells. AB - The incidence of prostate cancer (PC) is growing rapidly throughout the world, in probable association with the adoption of western style diets. Thus, understanding the molecular pathways triggering the development of PC is crucial for both its prevention and treatment. Here, we investigated the role of the metabolism-associated protein, CREB3L4, in the proliferation of PC cells. CREB3L4 was upregulated by the synthetic androgen, R1881, in LNCaP PC cells (an androgen dependent cell line). Knockdown of CREB3L4 resulted in decreased androgen dependent PC cell growth. LNCaP cells transfected with siCREB3L4 underwent G2/M arrest, with upregulation of the proteins cyclin B1, phospho-CDK1, p21Waf1/Cip1, and INCA1, and downregulation of cyclin D1. Moreover, depletion of CREB3L4 resulted in significantly decreased expression of a subset of androgen-receptor (AR) target genes, including PSA, FKBP5, HPGD, KLK2, and KLK4. We also demonstrated that CREB3L4 directly interacts with the AR, and increases the binding of AR to androgen response elements (AREs). We also identified a role for the unfolded protein response (and its surrogate, IRE1alpha), in activating CREB3L4. Cumulatively, we postulate that CREB3L4 expression is mediated by an AR IRE1alpha axis, but is also directly regulated by AR-to-ARE binding. Thus, our study demonstrates that CREB3L4 plays a key role in PC cell proliferation, which is promoted by both AR and IRE1alpha. PMID- 28338059 TI - Non-thermal air plasma promotes the healing of acute skin wounds in rats. AB - Non-thermal plasma (NTP) has nonspecific antibacterial effects, and can be applied as an effective tool for the treatment of chronic wounds and other skin pathologies. In this study we analysed the effect of NTP on the healing of the full-thickness acute skin wound model in rats. We utilised a single jet NTP system generating atmospheric pressure air plasma, with ion volume density 5 . 1017 m-3 and gas temperature 30-35 degrees C. The skin wounds were exposed to three daily plasma treatments for 1 or 2 minutes and were evaluated 3, 7 and 14 days after the wounding by histological and gene expression analysis. NTP treatment significantly enhanced epithelization and wound contraction on day 7 when compared to the untreated wounds. Macrophage infiltration into the wound area was not affected by the NTP treatment. Gene expression analysis did not indicate an increased inflammatory reaction or a disruption of the wound healing process; transient enhancement of inflammatory marker upregulation was found after NTP treatment on day 7. In summary, NTP treatment had improved the healing efficacy of acute skin wounds without noticeable side effects and concomitant activation of pro-inflammatory signalling. The obtained results highlight the favourability of plasma applications for wound therapy in clinics. PMID- 28338060 TI - Strong coupling of diffraction coupled plasmons and optical waveguide modes in gold stripe-dielectric nanostructures at telecom wavelengths. AB - We propose a hybrid plasmonic device consisting of a planar dielectric waveguide covering a gold nanostripe array fabricated on a gold film and investigate its guiding properties at telecom wavelengths. The fundamental modes of a hybrid device and their dependence on the key geometric parameters are studied. A communication length of 250 MUm was achieved for both the TM and TE guided modes at telecom wavelengths. Due to the difference between the TM and TE light propagation associated with the diffractive plasmon excitation, our waveguides provide polarization separation. Our results suggest a practical way of fabricating metal-nanostripes-dielectric waveguides that can be used as essential elements in optoelectronic circuits. PMID- 28338062 TI - Coexistence of superconductivity and charge-density wave in the quasi-one dimensional material HfTe3. AB - We present the first experimental evidence for metallicity, superconductivity (SC) and the co-existence of charge density waves (CDW) in the quasi-one dimensional material HfTe3. The existence of such phenomena is a typical characteristic of the transition metal chalcogenides however, without the application of hydrostatic pressure/chemical doping, it is rare for a material to exhibit the co-existence of both states. Materials such as HfTe3 can therefore provide us with a unique insight into the relationship between these multiple ordered states. By improving on the original synthesis conditions, we have successfully synthesised single phase HfTe3 and confirmed the resultant structure by performing Rietveld refinement. Using low temperature resistivity measurements, we provide the first experimental evidence of SC at ~1.4 K as well as a resistive anomaly indicative of a CDW formation at ~82 K. By the application of hydrostatic-pressure, the resistivity anomaly shifts to higher temperature. The results show that HfTe3 is a promising new material to help study the relationship between SC and CDW. PMID- 28338061 TI - Heteroleptic Copper(I) Complexes of "Scorpionate" Bis-pyrazolyl Carboxylate Ligand with Auxiliary Phosphine as Potential Anticancer Agents: An Insight into Cytotoxic Mode. AB - New copper(I) complexes [CuCl(PPh3)(L)] (1: L = LA = 4-carboxyphenyl)bis(3,5 dimethylpyrazolyl)methane; (2: L = LB = 3-carboxyphenyl)bis(3,5 dimethylpyrazolyl)methane) were prepared and characterised by elemental analysis and various spectroscopic techniques such as FT-IR, NMR, UV-Vis, and ESI-MS. The molecular structures of complexes 1 and 2 were analyzed by theoretical B3LYP/DFT method. Furthermore, in vitro DNA binding studies were carried out to check the ability of complexes 1 and 2 to interact with native calf thymus DNA (CT-DNA) using absorption titration, fluorescence quenching and circular dichroism, which is indicative of more avid binding of the complex 1. Moreover, DNA mobility assay was also conducted to study the concentration-dependent cleavage pattern of pBR322 DNA by complex 1, and the role of ROS species to have a mechanistic insight on the cleavage pattern, which ascertained substantial roles by both hydrolytic and oxidative pathways. Additionally, we analyzed the potential of the interaction of complex 1 with DNA and enzyme (Topo I and II) with the aid of molecular modeling. Furthermore, cytotoxic activity of complex 1 was tested against HepG2 cancer cell lines. Thus, the potential of the complex 1 is promising though further in vivo investigations may be required before subjecting it to clinical trials. PMID- 28338063 TI - Greater postprandial glucose excursions and inadequate nutrient intake in youth with type 1 diabetes and celiac disease. AB - The gluten free diet (GFD) has a high glycemic index and low-fiber content, which potentially influences glycemic excursions in type 1 diabetes (T1D) and celiac disease (CD). Participants in this case-control study of youth with T1D+CD (n = 10) and T1D only (n = 7) wore blinded continuous glucose monitoring systems for six days. Blood glucose levels (BGLs) were compared between groups for each meal, including pre-meal, peak, 2-hour postprandial and time-to-peak. Participants consumed a test-breakfast of GF cereal and milk for three days and kept weighed food diaries; nutrient intake was analyzed and compared to national recommendations. Youth with T1D+CD had shorter time-to-peak BGL (77 vs 89 mins, P = 0.03), higher peak (9.3 vs 7.3 mmol/L, P = 0.001) and higher postprandial BGLs than T1D (8.4 vs 7.0 mmol/L, P = 0.01), despite similar pre-meal BGLs (9.2 vs 8.6 mmol/L, P = 0.28). Regarding test breakfast, greater pre and post-meal BGL difference correlated with longer CD duration (R = 0.53, P = 0.01). Total energy and macronutrient intake didn't differ between groups; however the majority of participants collectively had inadequate intake of calcium (76%), folate (71%) and fiber (53%), with excessive saturated fat (12%) and sodium (>2,000 mg/day). The GFD is associated with greater glycemic excursions and inadequate nutritional intake in youth with T1D+CD. Clinical management should address both glycemic variability and dietary quality. PMID- 28338065 TI - Prospects for combining targeted and conventional cancer therapy with immunotherapy. AB - Over the past 25 years, research in cancer therapeutics has largely focused on two distinct lines of enquiry. In one approach, efforts to understand the underlying cell-autonomous, genetic drivers of tumorigenesis have led to the development of clinically important targeted agents that result in profound, but often not durable, tumour responses in genetically defined patient populations. In the second parallel approach, exploration of the mechanisms of protective tumour immunity has provided several therapeutic strategies - most notably the 'immune checkpoint' antibodies that reverse the negative regulators of T cell function - that accomplish durable clinical responses in subsets of patients with various tumour types. The integration of these potentially complementary research fields provides new opportunities to improve cancer treatments. Targeted and immune-based therapies have already transformed the standard-of-care for several malignancies. However, additional insights into the effects of targeted therapies, along with conventional chemotherapy and radiation therapy, on the induction of antitumour immunity will help to advance the design of combination strategies that increase the rate of complete and durable clinical response in patients. PMID- 28338064 TI - Acceleration of bone regeneration by activating Wnt/beta-catenin signalling pathway via lithium released from lithium chloride/calcium phosphate cement in osteoporosis. AB - By virtue of its excellent bioactivity and osteoconductivity, calcium phosphate cement (CPC) has been applied extensively in bone engineering. Doping a trace element into CPC can change physical characteristics and enhance osteogenesis. The trace element lithium has been demonstrated to stimulate the proliferation and differentiation of osteoblasts. We investigated the fracture-healing effect of osteoporotic defects with lithium-doped calcium phosphate cement (Li/CPC) and the underlying mechanism. Li/CPC bodies immersed in simulated body fluid converted gradually to hydroxyapatite. Li/CPC extracts stimulated the proliferation and differentiation of osteoblasts upon release of lithium ions (Li+) at 25.35 +/- 0.12 to 50.74 +/- 0.13 mg/l through activation of the Wnt/beta catenin pathway in vitro. We also examined the effect of locally administered Li+ on defects in rat tibia between CPC and Li/CPC in vivo. Micro-computed tomography and histological staining showed that Li/CPC had better osteogenesis by increasing bone mass and promoting repair in defects compared with CPC (P < 0.05). Li/CPC also showed better osteoconductivity and osseointegration. These findings suggest that local release of Li+ from Li/CPC may accelerate bone regeneration from injury through activation of the Wnt/beta-catenin pathway in osteoporosis. PMID- 28338066 TI - Chemical Composition, Antioxidant, DNA Damage Protective, Cytotoxic and Antibacterial Activities of Cyperus rotundus Rhizomes Essential Oil against Foodborne Pathogens. AB - Cyperus rotundus L. (Cyperaceae) is a medicinal herb traditionally used to treat various clinical conditions at home. In this study, chemical composition of Cyperus rotundus rhizomes essential oil, and in vitro antioxidant, DNA damage protective and cytotoxic activities as well as antibacterial activity against foodborne pathogens were investigated. Results showed that alpha-cyperone (38.46%), cyperene (12.84%) and alpha-selinene (11.66%) were the major components of the essential oil. The essential oil had an excellent antioxidant activity, the protective effect against DNA damage, and cytotoxic effects on the human neuroblastoma SH-SY5Y cell, as well as antibacterial activity against several foodborne pathogens. These biological activities were dose-dependent, increasing with higher dosage in a certain concentration range. The antibacterial effects of essential oil were greater against Gram-positive bacteria as compared to Gram negative bacteria, and the antibacterial effects were significantly influenced by incubation time and concentration. These results may provide biological evidence for the practical application of the C. rotundus rhizomes essential oil in food and pharmaceutical industries. PMID- 28338067 TI - Ultrathin nickel hydroxide nanosheet arrays grafted biomass-derived honeycomb like porous carbon with improved electrochemical performance as a supercapacitive material. AB - Three-dimensional hierarchical honeycomb-like activated porous carbon pillared ultrathin Ni(OH)2 nanosheets (Ni(OH)2 NSs@HAPC) for use as supercapacitor materials were facilely synthesized. With an aid of pine cone flowers as a biomass source, HAPC conducting scaffolds were prepared by the alkali treatment and pyrolysis methods under an inert gas atmosphere. Subsequently, the Ni(OH)2 NSs were synthesized evenly on the surface of HAPC via a solvothermal method. The resulting HAPC and Ni(OH)2 NSs@HAPC composite materials offered free pathways for effective diffusion of electrolyte ions and fast transportation of electrons when employed as an electrode material. The Ni(OH)2 NSs@HAPC composite electrode exhibited excellent electrochemical properties including a relatively high specific capacitance (Csp) value of ~ 916.4 F/g at 1 A/g with good cycling stability compared to the pristine HAPC and Ni(OH)2 NSs electrodes. Such bio friendly derived carbon-based materials with transition metal hydroxide/oxide composite materials could be a promising approach for high-performance energy storage devices because of their advantageous properties of cost effectiveness and easy availability. PMID- 28338069 TI - RRAM-based parallel computing architecture using k-nearest neighbor classification for pattern recognition. AB - Resistive switching memory (RRAM) is considered as one of the most promising devices for parallel computing solutions that may overcome the von Neumann bottleneck of today's electronic systems. However, the existing RRAM-based parallel computing architectures suffer from practical problems such as device variations and extra computing circuits. In this work, we propose a novel parallel computing architecture for pattern recognition by implementing k-nearest neighbor classification on metal-oxide RRAM crossbar arrays. Metal-oxide RRAM with gradual RESET behaviors is chosen as both the storage and computing components. The proposed architecture is tested by the MNIST database. High speed (~100 ns per example) and high recognition accuracy (97.05%) are obtained. The influence of several non-ideal device properties is also discussed, and it turns out that the proposed architecture shows great tolerance to device variations. This work paves a new way to achieve RRAM-based parallel computing hardware systems with high performance. PMID- 28338068 TI - A Portable Immunosensor with Differential Pressure Gauges Readout for Alpha Fetoprotein Detection. AB - A portable, affordable and simple detector is requested in a "Point-of-Care Testing" (POCT) system. In this study, we exploited the potentialities of Differential Pressure Gauge (DPG) to the orientation of POCT technology. Alpha fetoprotein (AFP) was chosen as a model analyte that could specifically recognized by its antigen, and a tiny outfits equipped with a DPG was employed as the signal readout. Pt/SiO2 nanospheres were synthesized and modified with the detection antibody. In the presence of target, a sandwich of immunocomplex specifically formed and the Pt/SiO2 had been modified on the capture antibody. Which then can be dissolved to release plenty of Pt and the suspensions were transferred into a closed vial filled with appropriated amount of hydrogen peroxide. Subsequently, hydrogen peroxide was decomposed to produce oxygen, resulting in the enhancement of pressure in the closed vial and which can be detected by DPG easily. Under the optimized conditions, the read out signal from DPG had a direct relationship with AFP concentrations in the range of 10~200 ng/mL, and the detection limit was as low as 3.4 ng/mL. The proposed portable sensor had been successfully applied to detect AFP in serum samples with satisfactory results. This strategy holds a great promising in biological analysis as its convenient operations, reliable results and flexible apparatus. PMID- 28338070 TI - The co-evolution of networks and prisoner's dilemma game by considering sensitivity and visibility. AB - Strategies adopted by individuals in a social network significantly impact the network, and they strongly affect relationships between individuals in the network. Links between individuals also heavily influence their levels of cooperation. Taking into account the evolution of each individual's connection, we explore how sensitivity and visibility affect the prisoner's dilemma game. The so-called 'sensitivity' and 'visibility' respectively present one's self protection consciousness and the ability of gaining information. We find that at moderate levels of player sensitivity cooperative behavior increases, but that at high levels it is inhibited. We also find that the heterogeneity of the weight of individuals at the end of the game is higher when sensitivity and visibility are increased, but that the successful-defection-payoff has less impact on the weight of individuals and on the relationship between the heterogeneity of the weight of individuals and the density of cooperators. This framework can be used to clarify the interaction mechanism between the micro-level of individual behavior and the macro-level of individual co-evolutionary processes. PMID- 28338071 TI - Phase-Transition Nanodroplets for Real-Time Photoacoustic/Ultrasound Dual Modality Imaging and Photothermal Therapy of Sentinel Lymph Node in Breast Cancer. AB - Pathological status of lymph nodes (LNs) plays a critical role in staging and treatment for the patients with breast cancer. Sentinel lymph node biopsy has become the standard method in determining pathological status of axillary LNs. Therefore, the determination of sentinel lymph nodes (SLNs) and therapy of metastatic LNs are highly desirable in clinic. Herein, an unprecedented carbon nanoparticles (CNs)-incorporated liquid-gas phase-transition nanodroplets (CNPs) with strong near-infrared (NIR) absorption, good biocompatibility, excellent photoacoustic (PA) and ultrasound (US) contrast, and high photothermal-conversion efficiency are reported in this study. Upon laser irradiation, liquid-gas phase transition of the CNPs has been demonstrated to provide excellent contrasts for PA/US dual-modality imaging both in vitro and in vivo. Additionally, the CNPs are capable of staining lymph nodes, which can contribute significantly to the identification of LNs with naked eyes. With increased laser energy, the CNPs exhibit the high performance in killing the breast cancer cells both in vitro and in vivo, due to the photothermal effect induced from the CNs within CNPs. These results suggest that the developed multifunctional phase-transition nanodroplets have high potential to act as the theranostic agents in both SLNs detection and therapy of metastatic LNs. PMID- 28338072 TI - A post-weaning obesogenic diet exacerbates the detrimental effects of maternal obesity on offspring insulin signaling in adipose tissue. AB - Previous studies have shown that maternal diet-induced obesity leads to increased risk of type 2 diabetes in offspring. The current study investigated if weaning onto an obesogenic diet exaggerated the detrimental effects of maternal diet induced obesity in adipose tissue. Maternal obesity and offspring obesity led to reduced expression of key insulin signalling proteins, including insulin receptor substrate-1 (IRS-1). The effects of maternal obesity and offspring obesity were, generally, independent and additive. Irs1 mRNA levels were similar between all four groups of offspring, suggesting that in both cases post-transcriptional regulation was involved. Maternal diet-induced obesity increased miR-126 expression however levels of this miR were not influenced by a post-weaning obesogenic diet. In contrast, a post-weaning obesogenic diet was associated with increased levels of suppressor of cytokine signaling-1, implicating increased degradation of IRS-1 as an underlying mechanism. Our results suggest that whilst programmed reductions in IRS-1 are associated with increased levels of miR-126 and consequently reduced translation of Irs1 mRNA, the effects of a post-weaning obesogenic diet on IRS-1 are mediated by miR-126 independent mechanisms, including increased IRS-1 protein degradation. These divergent mechanisms explain why the combination of maternal obesity and offspring obesity leads to the most pronounced effects on offspring metabolism. PMID- 28338075 TI - Alzheimer disease: Localized proteomics distinguishes AD subtypes. PMID- 28338074 TI - Self-Phase-Matched Second-Harmonic and White-Light Generation in a Biaxial Zinc Tungstate Single Crystal. AB - Second-order nonlinear optical materials are used to generate new frequencies by exploiting second-harmonic generation (SHG), a phenomenon where a nonlinear material generates light at double the optical frequency of the input beam. Maximum SHG is achieved when the pump and the generated waves are in phase, for example through birefringence in uniaxial crystals. However, applying these materials usually requires a complicated cutting procedure to yield a crystal with a particular orientation. Here we demonstrate the first example of phase matching under the normal incidence of SHG in a biaxial monoclinic single crystal of zinc tungstate. The crystal was grown by the micro-pulling-down method with the (102) plane perpendicular to the growth direction. Additionally, at the same time white light was generated as a result of stimulated Raman scattering and multiphoton luminescence induced by higher-order effects such as three-photon luminescence enhanced by cascaded third-harmonic generation. The annealed crystal offers SHG intensities approximately four times larger than the as grown one; optimized growth and annealing conditions may lead to much higher SHG intensities. PMID- 28338073 TI - Veratridine produces distinct calcium response profiles in mouse Dorsal Root Ganglia neurons. AB - Nociceptors are a subpopulation of dorsal root ganglia (DRG) neurons that detect noxious stimuli and signal pain. Veratridine (VTD) is a voltage-gated sodium channel (VGSC) modifier that is used as an "agonist" in functional screens for VGSC blockers. However, there is very little information on VTD response profiles in DRG neurons and how they relate to neuronal subtypes. Here we characterised VTD-induced calcium responses in cultured mouse DRG neurons. Our data shows that the heterogeneity of VTD responses reflects distinct subpopulations of sensory neurons. About 70% of DRG neurons respond to 30-100 MUM VTD. We classified VTD responses into four profiles based upon their response shape. VTD response profiles differed in their frequency of occurrence and correlated with neuronal size. Furthermore, VTD response profiles correlated with responses to the algesic markers capsaicin, AITC and alpha, beta-methylene ATP. Since VTD response profiles integrate the action of several classes of ion channels and exchangers, they could act as functional "reporters" for the constellation of ion channels/exchangers expressed in each sensory neuron. Therefore our findings are relevant to studies and screens using VTD to activate DRG neurons. PMID- 28338076 TI - Movement disorders: Comparison of cognitive impairment in Parkinson disease and essential tremor. PMID- 28338077 TI - Characterization of the Soluble NSF Attachment Protein gene family identifies two members involved in additive resistance to a plant pathogen. AB - Proteins with Tetratricopeptide-repeat (TPR) domains are encoded by large gene families and distributed in all plant lineages. In this study, the Soluble NSF Attachment Protein (SNAP) subfamily of TPR containing proteins is characterized. In soybean, five members constitute the SNAP gene family: GmSNAP18, GmSNAP11, GmSNAP14, GmSNAP02, and GmSNAP09. Recently, GmSNAP18 has been reported to mediate resistance to soybean cyst nematode (SCN). Using a population of recombinant inbred lines from resistant and susceptible parents, the divergence of the SNAP gene family is analysed over time. Phylogenetic analysis of SNAP genes from 22 diverse plant species showed that SNAPs were distributed in six monophyletic clades corresponding to the major plant lineages. Conservation of the four TPR motifs in all species, including ancestral lineages, supports the hypothesis that SNAPs were duplicated and derived from a common ancestor and unique gene still present in chlorophytic algae. Syntenic analysis of regions harbouring GmSNAP genes in soybean reveals that this family expanded from segmental and tandem duplications following a tetraploidization event. qRT-PCR analysis of GmSNAPs indicates a co-regulation following SCN infection. Finally, genetic analysis demonstrates that GmSNAP11 contributes to an additive resistance to SCN. Thus, GmSNAP11 is identified as a novel minor gene conferring resistance to SCN. PMID- 28338078 TI - The Transmembrane Serine Protease HAT-like 4 Is Important for Epidermal Barrier Function to Prevent Body Fluid Loss. AB - Membrane-bound proteases are essential for epidermal integrity. Human airway trypsin-like protease 4 (HAT-L4) is a type II transmembrane serine protease. Currently, its biochemical property, cellular distribution and physiological function remain unknown. Here we examined HAT-L4 expression and function in vitro and in vivo. In Western analysis, HAT-L4 expressed in transfected CHO cells appeared as a 48-kDa protein. Flow cytometry confirmed HAT-L4 expression on the cell surface with the expected membrane topology. RT-PCR and immunostaining experiments indicated that HAT-L4 was expressed in epithelial cells and exocrine glands in tissues including skin, esophagus, trachea, tongue, eye, bladder, testis and uterus. In the skin, HAT-L4 expression was abundant in keratinocytes and sebaceous glands. We generated HAT-L4 knockout mice by disrupting the Tmprss11f gene encoding HAT-L4. HAT-L4 knockout mice were viable and fertile. No defects were found in HAT-L4 knockout mice in hair growth, wound healing, water repulsion and body temperature regulation. Compared with wild-type controls, HAT L4-deficient newborn mice had greater body fluid loss and higher mortality in a trans-epidermal body fluid loss test. In metabolic studies, HAT-L4-deficient adult mice drank water more frequently than wild-type controls did. These results indicate that HAT-L4 is important in epidermal barrier function to prevent body fluid loss. PMID- 28338080 TI - Bivariate genomic analysis identifies a hidden locus associated with bacteria hypersensitive response in Arabidopsis thaliana. AB - Multi-phenotype analysis has drawn increasing attention to high-throughput genomic studies, whereas only a few applications have justified the use of multivariate techniques. We applied a recently developed multi-trait analysis method on a small set of bacteria hypersensitive response phenotypes and identified a single novel locus missed by conventional single-trait genome-wide association studies. The detected locus harbors a minor allele that elevates the risk of leaf collapse response to the injection of avrRpm1-modified Pseudomonas syringae (P = 1.66e-08). Candidate gene AT3G32930 with in the detected region and its co-expressed genes showed significantly reduced expression after P. syringae interference. Our results again emphasize that multi-trait analysis should not be neglected in association studies, as the power of specific multi-trait genotype phenotype maps might only be tractable when jointly considering multiple phenotypes. PMID- 28338079 TI - Dissecting miRNA gene repression on single cell level with an advanced fluorescent reporter system. AB - Despite major advances on miRNA profiling and target predictions, functional readouts for endogenous miRNAs are limited and frequently lead to contradicting conclusions. Numerous approaches including functional high-throughput and miRISC complex evaluations suggest that the functional miRNAome differs from the predictions based on quantitative sRNA profiling. To resolve the apparent contradiction of expression versus function, we generated and applied a fluorescence reporter gene assay enabling single cell analysis. This approach integrates and adapts a mathematical model for miRNA-driven gene repression. This model predicts three distinct miRNA-groups with unique repression activities (low, mid and high) governed not just by expression levels but also by miRNA/target-binding capability. Here, we demonstrate the feasibility of the system by applying controlled concentrations of synthetic siRNAs and in parallel, altering target-binding capability on corresponding reporter-constructs. Furthermore, we compared miRNA-profiles with the modeled predictions of 29 individual candidates. We demonstrate that expression levels only partially reflect the miRNA function, fitting to the model-projected groups of different activities. Furthermore, we demonstrate that subcellular localization of miRNAs impacts functionality. Our results imply that miRNA profiling alone cannot define their repression activity. The gene regulatory function is a dynamic and complex process beyond a minimalistic conception of "highly expressed equals high repression". PMID- 28338082 TI - A clinical trial for patients with acute myeloid leukemia or myelodysplastic syndromes not eligible for standard clinical trials. AB - This corrects the article DOI: 10.1038/leu.2016.303. PMID- 28338081 TI - A distinct bacterial dysbiosis associated skin inflammation in ovine footrot. AB - Ovine footrot is a highly prevalent bacterial disease caused by Dichelobacter nodosus and characterised by the separation of the hoof horn from the underlying skin. The role of innate immune molecules and other bacterial communities in the development of footrot lesions remains unclear. This study shows a significant association between the high expression of IL1beta and high D. nodosus load in footrot samples. Investigation of the microbial population identified distinct bacterial populations in the different disease stages and also depending on the level of inflammation. Treponema (34%), Mycoplasma (29%) and Porphyromonas (15%) were the most abundant genera associated with high levels of inflammation in footrot. In contrast, Acinetobacter (25%), Corynebacteria (17%) and Flavobacterium (17%) were the most abundant genera associated with high levels of inflammation in healthy feet. This demonstrates for the first time there is a distinct microbial community associated with footrot and high cytokine expression. PMID- 28338084 TI - Late Neurosyphilis and Tertiary Syphilis in Guangdong Province, China: Results from a Cross-sectional Study. AB - Due to challenges in diagnosis and the need for complex laboratory tests, misdiagnosis of neurosyphilis and tertiary syphilis is common in China. We validated the diagnosis and examined the treatment of late neurosyphilis and tertiary syphilis in Guangdong Province, China. A cross-sectional study was conducted to collect data from late neurosyphilis and tertiary syphilis cases reported between 2009 and 2014 in Guangdong, China. Descriptive analysis, bivariate analyses and multiple logistic regressions were performed to determine the structural factors associated with correct diagnosis and standard treatment of late neurosyphilis and tertiary syphilis. Among the 3805 respondents (3805/3936, 96.7%), 1,837 (48.3%) met the misdiagnosed criteria. The misdiagnosis rate decreased over the study period (54.2% in 2009 and 41.8% in 2014). Only 27.1% and 24.9% of the correctly diagnosed late neurosyphilis and tertiary syphilis cases received standard treatment, respectively. Multiple logistic regression revealed that departments of dermatology or STDs [aOR = 3.24, 95% CI: 2.66-3.95], county or township level hospitals [aOR = 2.89, 95% CI: 2.14-3.89], and hospitals situated outside of Pearl River Delta area [aOR = 1.70, 95% CI: 1.46-1.97] had higher likelihood in misdiagnosis of neurosyphilis, compared to the reference groups. Targeted trainings for physicians and expanded syphilis screening services are urgently needed. PMID- 28338085 TI - Morphometric analysis of sinus depth in the posterior maxilla and proposal of a novel classification. AB - The aim of this study was to analyse the posterior maxillary sinus based on its extension into the alveolar process and to provide a simple clinical classification. A retrospective cohort study was conducted in CT scans of 200 dentate and 200 edentulous patients (100 women and 100 men, respectively). After manual placement of 12 reference points morphometric analysis was performed and sinus depth, residual alveolar ridge height (RH) and the sinus opening angle were calculated. Sinuses were classified according to the quartiles of sinus depth: class I (above the hard palate), class II (0-6 mm below the hard palate) and class III (>6 mm below the hard palate). Sinus depth was found to be a reliable anatomical landmark and did not vary significantly between gender (p = 0.8940) or dentition groups (p = 0.9723). Alveolar height varied significantly between sinus classes (p < 2 * 10-16) and dentition groups (p < 2 * 10-16) but not between genders (p = 0.5178). The sinus opening angle was significantly different between sinus classes (p < 2.2 * 10-16) but not between gender or dentition groups. We propose a novel classification built upon the quartiles of sinus depth, dividing the sinuses into three classes. Our classification is the first one that represents the anatomy of the patient independent of gender and dentition. PMID- 28338083 TI - Microvasculature on a chip: study of the Endothelial Surface Layer and the flow structure of Red Blood Cells. AB - Microvasculatures-on-a-chip, i.e. in vitro models that mimic important features of microvessel networks, have gained increasing interest in recent years. Such devices have allowed investigating pathophysiological situations involving abnormal biophysical interactions between blood cells and vessel walls. Still, a central question remains regarding the presence, in such biomimetic systems, of the endothelial glycocalyx. The latter is a glycosaminoglycans-rich surface layer exposed to blood flow, which plays a crucial role in regulating the interactions between circulating cells and the endothelium. Here, we use confocal microscopy to characterize the layer expressed by endothelial cells cultured in microfluidic channels. We show that, under our culture conditions, endothelial cells form a confluent layer on all the walls of the circuit and display a glycocalyx that fully lines the lumen of the microchannels. Moreover, the thickness of this surface layer is found to be on the order of 600 nm, which compares well with measurements performed ex or in vivo on microcapillaries. Furthermore, we investigate how the presence of endothelial cells in the microchannels affects their hydrodynamic resistance and the near-wall motion of red blood cells. Our study thus provides an important insight into the physiological relevance of in vitro microvasculatures. PMID- 28338086 TI - Halo-free Phase Contrast Microscopy. AB - We present a new approach for retrieving halo-free phase contrast microscopy (hfPC) images by upgrading the conventional PC microscope with an external interferometric module, which generates sufficient data for reversing the halo artifact. Acquiring four independent intensity images, our approach first measures haloed phase maps of the sample. We solve for the halo-free sample transmission function by using a physical model of the image formation under partial spatial coherence. Using this halo-free sample transmission, we can numerically generate artifact-free PC images. Furthermore, this transmission can be further used to obtain quantitative information about the sample, e.g., the thickness with known refractive indices, dry mass of live cells during their cycles. We tested our hfPC method on various control samples, e.g., beads, pillars and validated its potential for biological investigation by imaging live HeLa cells, red blood cells, and neurons. PMID- 28338088 TI - Functional solid additive modified PEDOT:PSS as an anode buffer layer for enhanced photovoltaic performance and stability in polymer solar cells. AB - Poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) is most commonly used as an anode buffer layer in bulk-heterojunction (BHJ) polymer solar cells (PSCs). However, its hygroscopic and acidic nature contributes to the insufficient electrical conductivity, air stability and restricted photovoltaic (PV) performance for the fabricated PSCs. In this study, a new multifunctional additive, 2,3-dihydroxypyridine (DOH), has been used in the PEDOT: PSS buffer layer to obtain modified properties for PEDOT: PSS@DOH and achieve high PV performances. The electrical conductivity of PEDOT:PSS@DOH films was markedly improved compared with that of PEDOT:PSS. The PEDOT:PSS@DOH film exhibited excellent optical characteristics, appropriate work function alignment, and good surface properties in BHJ-PSCs. When a poly(3-hexylthiohpene):[6,6]-phenyl C61 butyric acid methyl ester blend system was applied as the photoactive layer, the power conversion efficiency of the resulting PSCs with PEDOT:PSS@DOH(1.0%) reached 3.49%, outperforming pristine PEDOT:PSS, exhibiting a power conversion enhancement of 20%. The device fabricated using PEDOT:PSS@DOH (1.0 wt%) also exhibited improved thermal and air stability. Our results also confirm that DOH, a basic pyridine derivative, facilitates adequate hydrogen bonding interactions with the sulfonic acid groups of PSS, induces the conformational transformation of PEDOT chains and contributes to the phase separation between PEDOT and PSS chains. PMID- 28338087 TI - Gsalpha Controls Cortical Bone Quality by Regulating Osteoclast Differentiation via cAMP/PKA and beta-Catenin Pathways. AB - Skeletal bone formation and maintenance requires coordinate functions of several cell types, including bone forming osteoblasts and bone resorbing osteoclasts. Gsalpha, the stimulatory subunit of heterotrimeric G proteins, activates downstream signaling through cAMP and plays important roles in skeletal development by regulating osteoblast differentiation. Here, we demonstrate that Gsalpha signaling also regulates osteoclast differentiation during bone modeling and remodeling. Gnas, the gene encoding Gsalpha, is imprinted. Mice with paternal allele deletion of Gnas (Gnas+/p-) have defects in cortical bone quality and strength during early development (bone modeling) that persist during adult bone remodeling. Reduced bone quality in Gnas+/p- mice was associated with increased endosteal osteoclast numbers, with no significant effects on osteoblast number and function. Osteoclast differentiation and resorption activity was enhanced in Gnas+/p- cells. During differentiation, Gnas+/p- cells showed diminished pCREB, beta-catenin and cyclin D1, and enhanced Nfatc1 levels, conditions favoring osteoclastogenesis. Forskolin treatment increased pCREB and rescued osteoclast differentiation in Gnas+/p- by reducing Nfatc1 levels. Cortical bone of Gnas+/p- mice showed elevated expression of Wnt inhibitors sclerostin and Sfrp4 consistent with reduced Wnt/beta-catenin signaling. Our data identify a new role for Gsalpha signaling in maintaining bone quality by regulating osteoclast differentiation and function through cAMP/PKA and Wnt/beta-catenin pathways. PMID- 28338089 TI - Neurotoxicity Comparison of Two Types of Local Anaesthetics: Amide-Bupivacaine versus Ester-Procaine. AB - Local anaesthetics (LAs) may lead to neurological complications, but the underlying mechanism is still unclear. Many neurotoxicity research studies have examined different LAs, but none have comprehensively explored the distinct mechanisms of neurotoxicity caused by amide- (bupivacaine) and ester- (procaine) type LAs. Here, based on a CCK8 assay, LDH assay, Rhod-2-AM and JC-1 staining, 2',7'-dichlorohy-drofluorescein diacetate and dihydroethidium probes, an alkaline comet assay, and apoptosis assay, we show that both bupivacaine and procaine significantly induce mitochondrial calcium overload and a decline in the mitochondrial membrane potential as well as overproduction of ROS, DNA damage and apoptosis (P < 0.05). There were no significant differences in mitochondrial injury and apoptosis between the bupivacaine and procaine subgroups (P > 0.05). However, to our surprise, the superoxide anionic level after treatment with bupivacaine, which leads to more severe DNA damage, was higher than the level after treatment with procaine, while procaine produced more peroxidation than bupivacaine. Some of these results were also affirmed in dorsal root ganglia neurons of C57 mice. The differences in the superoxidation and peroxidation induced by these agents suggest that different types of LAs may cause neurotoxicity via different pathways. We can target more accurate treatment based on their different mechanisms of neurotoxicity. PMID- 28338090 TI - Septin 9_i2 is downregulated in tumors, impairs cancer cell migration and alters subnuclear actin filaments. AB - Functions of septin cytoskeletal polymers in tumorigenesis are still poorly defined. Their role in the regulation of cytokinesis and cell migration were proposed to contribute to cancer associated aneuploidy and metastasis. Overexpression of Septin 9 (Sept9) promotes migration of cancer cell lines. SEPT9 mRNA and protein expression is increased in breast tumors compared to normal and peritumoral tissues and amplification of SEPT9 gene was positively correlated with breast tumor progression. However, the existence of multiple isoforms of Sept9 is a confounding factor in the analysis of Sept9 functions. In the present study, we analyze the protein expression of Sept9_i2, an uncharacterized isoform, in breast cancer cell lines and tumors and describe its specific impact on cancer cell migration and Sept9 cytoskeletal distribution. Collectively, our results showed that, contrary to Sept9_i1, Sept9_i2 did not support cancer cell migration, and induced a loss of subnuclear actin filaments. These effects were dependent on Sept9_i2 specific N-terminal sequence. Sept9_i2 was strongly down regulated in breast tumors compared to normal mammary tissues. Thus our data indicate that Sept9_i2 is a negative regulator of breast tumorigenesis. We propose that Sept9 tumorigenic properties depend on the balance between Sept9_i1 and Sept9_i2 expression levels. PMID- 28338092 TI - High-rate squeezing process of bulk metallic glasses. AB - High-rate squeezing process of bulk metallic glasses from a cylinder into an intact sheet achieved by impact loading is investigated. Such a large deformation is caused by plastic flow, accompanied with geometrical confinement, shear banding/slipping, thermo softening, melting and joining. Temperature rise during the high-rate squeezing process makes a main effect. The inherent mechanisms are illustrated. Like high-pressure torsion (HPT), equal channel angular pressing (ECAP) and surface mechanical attrition treatments (SMAT) for refining grain of metals, High-Rate Squeezing (HRS), as a multiple-functions technique, not only creates a new road of processing metallic glasses and other metallic alloys for developing advanced materials, but also directs a novel technology of processing, grain refining, coating, welding and so on for treating materials. PMID- 28338093 TI - 210Pb-226Ra disequilibria in young gas-laden magmas. AB - We present new 238U-230Th-226Ra-210Pb and supporting data for young lavas from southwest Pacific island arcs, Eyjafjallajokull, Iceland, and Terceira, Azores. The arc lavas have significant 238U and 226Ra excesses, whereas those from the ocean islands have moderate 230Th and 226Ra excesses, reflecting mantle melting in the presence of a water-rich fluid in the former and mantle melting by decompression in the latter. Differentiation to erupted compositions in both settings appears to have taken no longer than a few millennia. Variations in the (210Pb/226Ra)0 values in all settings largely result from degassing processes rather than mineral-melt partitioning. Like most other ocean island basalts, the Terceira basalt has a 210Pb deficit, which we attribute to ~8.5 years of steady 222Rn loss to a CO2-rich volatile phase while it traversed the crust. Lavas erupted from water-laden magma systems, including those investigated here, commonly have near equilibrium (210Pb/226Ra)0 values. Maintaining these equilibrium values requires minimal persistent loss or accumulation of 222Rn in a gas phase. We infer that degassing during decompression of water-saturated magmas either causes these magmas to crystallize and stall in reservoirs where they reside under conditions of near stasis, or to quickly rise towards the surface and erupt. PMID- 28338091 TI - Intermediate filament reorganization dynamically influences cancer cell alignment and migration. AB - The interactions between a cancer cell and its extracellular matrix (ECM) have been the focus of an increasing amount of investigation. The role of the intermediate filament keratin in cancer has also been coming into focus of late, but more research is needed to understand how this piece fits in the puzzle of cytoskeleton-mediated invasion and metastasis. In Panc-1 invasive pancreatic cancer cells, keratin phosphorylation in conjunction with actin inhibition was found to be sufficient to reduce cell area below either treatment alone. We then analyzed intersecting keratin and actin fibers in the cytoskeleton of cyclically stretched cells and found no directional correlation. The role of keratin organization in Panc-1 cellular morphological adaptation and directed migration was then analyzed by culturing cells on cyclically stretched polydimethylsiloxane (PDMS) substrates, nanoscale grates, and rigid pillars. In general, the reorganization of the keratin cytoskeleton allows the cell to become more 'mobile'- exhibiting faster and more directed migration and orientation in response to external stimuli. By combining keratin network perturbation with a variety of physical ECM signals, we demonstrate the interconnected nature of the architecture inside the cell and the scaffolding outside of it, and highlight the key elements facilitating cancer cell-ECM interactions. PMID- 28338094 TI - In-situ Raman spectroscopy to elucidate the influence of adsorption in graphene electrochemistry. AB - Electrochemistry on graphene is of particular interest due to graphene's high surface area, high electrical conductivity and low interfacial capacitance. Because the graphene Fermi level can be probed by its strong Raman signal, information on the graphene doping can be obtained which in turn can provide information on adsorbed atoms or molecules. For this paper, the adsorption analysis was successfully performed using three electroactive substances with different electrode interaction mechanisms: hexaammineruthenium(III) chloride (RuHex), ferrocenemethanol (FcMeOH) and potassium ferricyanide/potassium ferrocyanide (Fe(CN)6). The adsorption state was probed by analysing the G-peak position in the measured in-situ Raman spectrum during electrochemical experiments. We conclude that electrochemical Raman spectroscopy on graphene is a valuable tool to obtain in-situ information on adsorbed species on graphene, isolated from the rest of the electrochemical behaviour. PMID- 28338095 TI - The Effect Of microbial Mats In The Decay Of Anurans With Implications For Understanding Taphonomic Processes In The Fossil Record. AB - The pattern and sequence of the decomposition of the Pipidae African dwarf frog (Hymenochirus boettgeri) is tracked in an experiment with microbial mats in order to explore soft tissue preservation over three years. Frog decay in microbial mats is preceded by rapid entombment (25-30 days) and mediated by the formation of a sarcophagus, which is built by a complex microbial community. The frog carcasses maintained a variety of soft tissues for years. Labile organic structures show greater durability within the mat, cells maintain their general shape (bone marrow cells and adipocytes), and muscles and connective tissues (adipose and fibrous tendons) exhibit their original organic structures. In addition, other soft tissues are promptly mineralized (day 540) in a Ca-rich carbonate phase (encephalic tectum) or enriched in sulphur residues (integumentary system). The result is coherent with a bias in soft-tissue preservation, as some tissues are more likely to be conserved than others. The outcomes support observations of exceptionally preserved fossil anurans (adults and tadpoles). Decomposition in mats shows singular conditions of pH and dissolved oxygen. Mineralization processes could be more diverse than in simple heterotrophic biofilms, opening new taphonomic processes that have yet to be explored. PMID- 28338096 TI - Identification of cardiac hemo-vascular precursors and their requirement of sphingosine-1-phosphate receptor 1 for heart development. AB - The cardiac endothelium plays a crucial role in the development of a functional heart. However, the precise identification of the endocardial precursors and the mechanisms they require for their role in heart morphogenesis are not well understood. Using in vivo and in vitro cell fate tracing concomitant with specific cell ablation and embryonic heart transplantation studies, we identified a unique set of precursors which possess hemogenic functions and express the stem cell leukemia (SCL) gene driven by its 5' enhancer. These hemo-vascular precursors give rise to the endocardium, atrioventricular cushions and coronary vascular endothelium. Furthermore, deletion of the sphingosine-1-phosphate receptor 1 (S1P1) in these precursors leads to ventricular non-compaction cardiomyopathy, a poorly understood condition leading to heart failure and early mortality. Thus, we identified a distinctive population of hemo-vascular precursors which require S1P1 to exert their functions and are essential for cardiac morphogenesis. PMID- 28338098 TI - Genome-wide random regression analysis for parent-of-origin effects of body composition allometries in mouse. AB - Genomic imprinting underlying growth and development traits has been recognized, with a focus on the form of absolute or pure growth. However, little is known about the effect of genomic imprinting on relative growth. In this study, we proposed a random regression model to estimate genome-wide imprinting effects on the relative growth of multiple tissues and organs to body weight in mice. Joint static allometry scaling equation as sub-model is nested within the genetic effects of markers and polygenic effects caused by a pedigree. Both chromosome wide and genome-wide statistical tests were conducted to identify imprinted quantitative trait nucleotides (QTNs) associated with relative growth of individual tissues and organs to body weight. Real data analysis showed that three of six analysed tissues and organs are significantly associated with body weight in terms of phenotypic relative growth. At the chromosome-wide level, a total 122 QTNs were associated with allometries of kidney, spleen and liver weights to body weight, 36 of which were imprinted with different imprinting fashions. Further, only two imprinted QTNs responsible for relative growth of spleen and liver were verified by genome-wide test. Our approach provides a general framework for statistical inference of genomic imprinting underlying allometry scaling in animals. PMID- 28338099 TI - Difference in diel mating time contributes to assortative mating between host plant-associated populations of Chilo suppressalis. AB - Behavioral isolation in animals can be mediated by inherent mating preferences and assortative traits, such as divergence in the diel timing of mating activity. Although divergence in the diel mating time could, in principle, promote the reproductive isolation of sympatric, conspecific populations, there is currently no unequivocal evidence of this. We conducted different mate-choice experiments to investigate the contribution of differences in diel mating activity to the reproductive isolation of the rice and water-oat populations of Chilo suppressalis. The results show that inter-population difference in diel mating activity contributes to assortative mating in these populations. In the rice population, most mating activity occurred during the first half of the scotophase, whereas in the water-oat population virtually all mating activity was confined to the second half of the scotophase. However, when the photoperiod of individuals from the water-oat population was altered to more closely align their mating activity with that of the rice population, mate choice was random. We conclude that inter-population differences in diel mating time contribute to assortative mating, and thereby the partial reproductive isolation, of these host associated populations of C. suppressalis. PMID- 28338097 TI - The cellular protein hnRNP A2/B1 enhances HIV-1 transcription by unfolding LTR promoter G-quadruplexes. AB - G-quadruplexes are four-stranded conformations of nucleic acids that act as cellular epigenetic regulators. A dynamic G-quadruplex forming region in the HIV 1 LTR promoter represses HIV-1 transcription when in the folded conformation. This activity is enhanced by nucleolin, which induces and stabilizes the HIV-1 LTR G-quadruplexes. In this work by a combined pull-down/mass spectrometry approach, we consistently found hnRNP A2/B1 as an additional LTR-G-quadruplex interacting protein. Surface plasmon resonance confirmed G-quadruplex specificity over linear sequences and fluorescence resonance energy transfer analysis indicated that hnRNP A2/B1 is able to efficiently unfold the LTR G-quadruplexes. Evaluation of the thermal stability of the LTR G-quadruplexes in different-length oligonucleotides showed that the protein is fit to be most active in the LTR full length environment. When hnRNP A2/B1 was silenced in cells, LTR activity decreased, indicating that the protein acts as a HIV-1 transcription activator. Our data highlight a tightly regulated control of transcription based on G quadruplex folding/unfolding, which depends on interacting cellular proteins. These findings provide a deeper understanding of the viral transcription mechanism and may pave the way to the development of drugs effective against the integrated HIV-1, present both in actively and latently infected cells. PMID- 28338100 TI - Hyperspectral imaging using the single-pixel Fourier transform technique. AB - Hyperspectral imaging technology is playing an increasingly important role in the fields of food analysis, medicine and biotechnology. To improve the speed of operation and increase the light throughput in a compact equipment structure, a Fourier transform hyperspectral imaging system based on a single-pixel technique is proposed in this study. Compared with current imaging spectrometry approaches, the proposed system has a wider spectral range (400-1100 nm), a better spectral resolution (1 nm) and requires fewer measurement data (a sample rate of 6.25%). The performance of this system was verified by its application to the non destructive testing of potatoes. PMID- 28338102 TI - The role of dentistry in the ?opioids crisis. PMID- 28338101 TI - The histone deacetylase inhibitor valproic acid inhibits NKG2D expression in natural killer cells through suppression of STAT3 and HDAC3. AB - NKG2D is a major activating receptor of NK cells and plays a critical role in tumor immunosurveillance. NKG2D expression in NK cells is inhibited by the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and enhanced by the narrow-spectrum HDAC inhibitor entinostat. We previously demonstrated that entinostat enhanced NKG2D transcription by increasing acetylation of Histones H3 and H4. However, the mechanism by which VPA reduces NKG2D expression in NK cells is not known. We have also shown that NKG2D transcription is regulated by STAT3 phosphorylation. In this study, we investigated regulation of NKG2D expression in NK cells by VPA and entinostat by assessing protein expression, phosphorylation, and interaction of HDACs and STAT3. We find that VPA selectively inhibits STAT3 tyrosine705 phosphorylation, but entinostat does not. STAT3 complexes with HDAC3, and HDAC3 inhibition represses STAT3 phosphorylation and therefore NKG2D expression. NK cells from STAT3 wild-type mice downregulate NKG2D in response to VPA, but not NK cells from STAT3 knockout mice. These results show that VPA is a potent inhibitor of STAT3 phosphorylation and demonstrate that histone acetylation and STAT3 tyrosine705 phosphorylation cooperate in regulating NKG2D expression in NK cells. PMID- 28338103 TI - Transreplantation: ?An alternative for periodontally hopeless teeth. AB - The periodontal therapy of severely damaged teeth that have advanced bone loss, a significant degree of mobility, and often tooth migration and elongation, frequently exposes the dental clinician to difficult decisions regarding the appropriate therapy for the patient. Extensive rehabilitation, with the replacement of periodontally hopeless teeth, has biologic, prognostic, and financial limitations. A possible alternative in such cases is the transreplantation of periodontally hopeless teeth. Ankylosis of the tooth is induced by appropriate extraoral pretreatment and thus the mobility disappears and the alveolar bone is reformed. This little-known technique is described step by step, with reference to a clinical case. PMID- 28338105 TI - A giant abdominal mass in a 23-year-old woman. PMID- 28338104 TI - Steroid-induced ischemic pancolitis. PMID- 28338106 TI - Pancreatic solid pseudopapillary neoplasm as an incidental discovery in a patient with rectal neoplasm. PMID- 28338107 TI - Gastric cancer in patients with inflammatory bowel disease: more than just a random association? PMID- 28338108 TI - VKORC1-1639 G>A Polymorphism and the Risk of Non-Variceal Upper Gastrointestinal Bleeding. AB - BACKGROUND AND AIMS: The mutations in the gene that encodes vitamin K epoxide reductase (VKOR) enzyme are responsible for low levels of vitamin K. The purpose of this study was to evaluate whether the presence of the VKORC1 -1639 G> A polymorphism is a risk factor for non-variceal upper gastrointestinal bleeding (UGIB) in patients without concomitant therapy with vitamin K antagonists. METHODS: This case-control study comprised 163 consecutive patients diagnosed with UGIB and 178 controls, in whom the diagnosis of UGIB was excluded. The following data were recorded: age, gender, alcohol consumption, smoking, history of UGIB, nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin consumption. Genetic analysis included genotyping for the VKORC1 -1639 G>A polymorphism. RESULTS: History of UGIB (OR 3.463, CI95% 1.463-8.198, p=0.005), smoking (OR 2.498, CI95% 1.358-4.597, p=0.003), alcohol consumption (OR 3.283, CI95% 1.796-6.000, p<0.001), use of NSAIDs (OR 4.542, CI95% 2.502-8.247, p<0.001) or of low-dose aspirin (OR 2.390, CI95% 1.326-4.310), and the VKORC1 -1639 G> A AA genotype (OR 1.364, CI95% 0.998-1.863, p=0.05) were associated with an increased risk of UGIB. The risk of UGIB was analyzed in patients with genotype AA who used aspirin or NSAIDs. The genotype AA has not kept its status of independent risk factor (p=0.3). In subjects with NSAIDs/aspirin therapy and genotype AA there was a two times higher chance of UGIB compared to those under NSAIDs/aspirin therapy alone (OR 7.6 vs. 3.6, p<0.001). CONCLUSION: Patients with non-variceal UGIB caused by the use of NSAIDs or low-dose aspirin are more frequent carriers of the VKORC1 -1639 G>A AA genotype, as compared to those without UGIB. PMID- 28338110 TI - Frequency of the UGT1A1*28 Polymorphism in a Romanian Cohort of Gilbert Syndrome Individuals. AB - BACKGROUND AND AIMS: Gilbert syndrome (GS) is characterized by unconjugated hyperbilirubinemia without liver disease or overt hemolysis and it is found in 3 10% of the general population. Inherited hyperbilirubinaemia is attributable to a reduced UGT1A1 activity. The UGT1A1 promoter (TA) repeats variants are documented of being involved in abnormally elevated bilirubin levels. The aim of the present study is to analyze the impact of UGT1A1 promoter variants on bilirubin levels in Romanian patients clinically supected with GS. METHODS: The study group included 897 subjects: 292 GS patients and 605 healthy controls. Genomic DNA was extracted from the peripheral blood leukocytes. All individuals were screened for the presence of the (TA) insertion in the TATA box region of UGT1A1 gene by PCR amplification. This case-control study was conducted at the Department of Medical Genetics, Synevo, Romania. RESULTS: UGT1A1*28 (7TA) revealed the highest frequency (61.87%) of all individuals, while the UGT1A1*1 (6TA) allele was found in 36.79%. We identified two other variants of the UGT1A1 gene, depending on the number of TA repeats in the promoter: 5TA (0.61%) and 8TA (0.72%). The (TA)7/7 homozygous genotype was identified in 32.33% of all individuals, while the (TA)6/7 heterozygous genotype was the most prevalent (57.64%). The wild type (TA)6/6 was identified in 7.36% of the whole cohort. CONCLUSIONS: Because other polymorphisms have been associated with GS, the absence of the UGT1A1*28 allele does not rule out this condition. The results suggest that in the Romanian population there is a strong correlation between the UGT1A1*28 polymorphism and hyperbilirubinemia in patients with GS. PMID- 28338109 TI - Dual-focus Magnification, High-Definition Endoscopy Improves Pathology Detection in Direct-to-Test Diagnostic Upper Gastrointestinal Endoscopy. AB - BACKGROUND: In the UK, the majority of diagnostic upper gastrointestinal (UGI) endoscopies are a result of direct-to-test referral from the primary care physician. The diagnostic yield of these tests is relatively low, and the burden high on endoscopy services. Dual-focus magnification, high-definition endoscopy is expected to improve detection and classification of UGI mucosal lesions and also help minimize biopsies by allowing better targeting. METHODS: This is a retrospective study of patients attending for direct-to-test UGI endoscopy from January 2015 to June 2015. The primary outcome of interest was the identification of significant pathology. Detection of significant pathology was modelled using logistic regression. RESULTS: 500 procedures were included. The mean age of patients was 61.5 (+/-15.6) years; 60.8% of patients were female. Ninety-four gastroscopies were performed using dual-focus magnification high-definition endoscopy. Increasing age, male gender, type of endoscope, and type of operator were all identified as significant factors influencing the odds of detecting significant mucosal pathology. Use of dual-focus magnification, high-definition endoscopy was associated with an odds ratio of 1.87 (95%CI 1.11-3.12) favouring the detection of significant pathology. Subsequent analysis suggested that the increased detection of pathology during dual-focus magnification, high-definition endoscopy also influenced patient follow-up and led to a 3.0 fold (p=0.04) increase in the proportion of patients entered into an UGI endoscopic surveillance program. CONCLUSION: Dual-focus magnification, high-definition endoscopy improved the diagnostic yield for significant mucosal pathology in patients referred for direct-to-test endoscopy. If this finding is recapitulated elsewhere it will have substantial impact on the provision of UGI endoscopic services. PMID- 28338111 TI - G Protein-Coupled Receptor 30 (GPR30) Expression Pattern in Inflammatory Bowel Disease Patients Suggests its Key Role in the Inflammatory Process. A Preliminary Study. AB - BACKGROUND AND AIMS: G protein-coupled receptor 30 (GPR30) is a recently de orphanized estrogen receptor that mediates the effects of estrogens on different cells. It has been postulated that in inflammatory bowel diseases (IBD) activation of GPR30 blocks the pathways dependent on pro-inflammatory cytokines. The aim of our study was to investigate GPR30 expression in patients with IBD and its potential implication in future therapies. METHODS: Fifty-seven patients were enrolled in our study: 20 subjects with Crohn's disease (CD), 22 with ulcerative colitis (UC) and 15 controls. In each subject, biopsies were taken from various left-colonic locations. Gene and protein expression of GPR30 was quantified using real time RT-PCR or Western blot. RESULTS: GPR30 mRNA and protein expression were detected in all tested colonic tissues. No significant differences in GPR30 gene expression were observed. In non-inflamed areas, GPR30 protein was strongly increased in CD patients, but moderately in UC patients (p= 0.014 and p=0.143, respectively, vs. controls). In CD patients, a significantly lower GPR30 protein content in inflamed than in non-inflamed tissue was observed (p=0.039). The change was independent of patient gender. CONCLUSION: Our observations indicate that GPR30 may play a role in the development and progression of inflammatory lesions in IBD, thus affecting disease severity, and consequently IBD treatment. Therefore, GPR30 may become an attractive target for novel anti-IBD drugs, particularly in CD. PMID- 28338112 TI - PNPLA3 and RNF7 Gene Variants are Associated with the Risk of Developing Liver Fibrosis and Cirrhosis in an Eastern European Population. AB - BACKGROUND AND AIMS: Genome-wide association studies have revealed an association between the risk of developing liver fibrosis or cirrhosis and the single nucleotide polymorphisms (SNPs) of the PNPLA3, RNF7, MERTK and PCSK7 genes. We aimed to validate these results in an Eastern European population. METHODS: We evaluated the associations between the PNPLA3 (rs738409), RNF7 (rs16851720), MERTK (rs4374383) and PCSK7 (rs236918) variants and liver fibrosis and cirrhosis in a series of consecutive patients recruited at the Department of Gastroenterology, Lithuanian University of Health Sciences Hospital, during the period 2012-2015. The study included 317 individuals with liver cirrhosis, 154 individuals with liver fibrosis, and 498 controls. The studied SNPs were determined using RT-PCR TaqMan assays. RESULTS: MERTK and PCSK7 SNPs were not associated with liver fibrosis or cirrhosis. The PNPLA3 SNP rs738409 was associated with a higher risk of developing liver fibrosis (aOR: 1.65, P=0.001) and cirrhosis (aOR: 1.92, P=5.57*10-7). PNPLA3 genotypes were also associated with higher risk of developing liver fibrosis and cirrhosis in dominant (aOR: 1.98, P=2.20*10-5; aOR: 1.67, P=0.008, respectively) and recessive (aOR: 3.94, P=5.16*10-5; aOR: 3.02, P=0.003, respectively) models. RNF7 rs16851720 was associated with liver cirrhosis comparing CC vs. AA + CA genotypes (aOR: 0.26, P=0.020). CONCLUSION: Our study showed that PNPLA3 rs738409 and RNF7 rs16851720 confer an increased risk of developing liver fibrosis and cirrhosis in this Eastern European population, while the MERTK and PCSK7 SNPs are not associated with these conditions. PMID- 28338113 TI - Antiproliferative and Apoptotic Effects of Lidocaine on Human Hepatocarcinoma Cells. A preliminary study. AB - BACKGROUND AND AIMS: It is now well documented that certain anesthetic techniques may influence long term outcome in cancer patients undergoing surgery. More recently, local anesthetics proved certain antiproliferative effects in cancer cells. In our study, we aimed to investigate if lidocaine has antiproliferative effects in human hepatocarcinoma cells and to identify possible mechanisms of these effects. METHODS: We investigated the inhibitory effect of different concentrations of lidocaine on the proliferation of cultured HepG2 human hepatocarcinoma cells and LX2 normal liver fibroblasts. Cells were exposed to nine different concentrations of lidocaine for 72h. MTT assay was used to investigate HepG2 and LX2 proliferation while Western blotting was used for detection of p53 expression level. RESULTS: Our data showed that lidocaine inhibited cell proliferation in a concentration-dependent manner in both HepG2 and LX2. The antiproliferative effects of lidocaine in LX2 were significantly diminished as compared with those in HepG2 (p< 0.001). Similarly, the expression level of p53 was significant decreased in HepG2 lines treated with lidocaine as compared with control and LX2 (p = 0.0241). CONCLUSIONS: In clinically relevant concentrations, lidocaine had significant antiproliferative effects on human hepatocarcinoma cells. These effects were time and dose-dependent. One of the possible mechanisms of these effects is by modifying the P53 expression level. The relevance of these findings in clinical practice is limited; clinical impact of these effects on the outcome of patients with hepatocarcinoma undergoing surgery or minimal invasive procedures needs to be demonstrated in future animal models and clinical studies. PMID- 28338114 TI - Molecular Analysis of Vascular Endothelial Growth Factor (VEGF) Receptors in EUS guided Samples Obtained from Patients with Pancreatic Adenocarcinoma. AB - BACKGROUND AND AIMS: Vascular endothelial growth factor (VEGF) and its receptors (VEGF-R1 and VEGF-R2) are the most important angiogenesis stimulating factors in pancreatic cancer. This study aims to assess VEGF-R1 and VEGF-R2 gene expression in EUS-FNA samples and identify prognostic markers in pancreatic adenocarcinoma. METHODS: This was a retrospective study of prospectively collected data of 88 consecutive patients, with clinical and imaging suspicion of pancreatic neoplasms, based on samples obtained through endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). RESULTS: EUS had an accuracy of 93.2% for the diagnosis of pancreatic cancer. Based on real-time qPCR analysis, VEGF-R1 and VEGF-R2 expressions were present in 90% and 65% of the analysed malignant samples, respectively; 89% of the patients died during the study, with a median survival rate of only 9 months. The survival was correlated with the initial stage and with the presence of VEGF-R1 and VEGF-R2 gene expression. We found that there are significant correlations between death/survival and T stage, N stage, resectability status, VEGF-R1, VEGF-R2 and VEGF-R1/VEGF-R2 coexpression. Using a Cox model regression our study demonstrates that VEGF-R1/VEGF-R2 coexpression might be considered as a poor prognostic factor in pancreatic cancer. CONCLUSIONS: EUS is a very effective technique for the diagnosis and staging of pancreatic adenocarcinoma in patients with clinical and imaging suspicion of pancreatic neoplasm, with an accuracy of 93.2%. Furthermore, the role of molecular analysis of EUS-guided FNA samples was established by the assessment of VEGF-R1, VEGF-R2 gene expression, which might be considered prognostic markers in pancreatic cancer. PMID- 28338115 TI - Resveratrol Supplementation in Patients with Non-Alcoholic Fatty Liver Disease: Systematic Review and Meta-analysis. AB - BACKGROUND: Resveratrol is a potential treatment option for management of non alcoholic fatty liver disease (NAFLD) due to its anti-inflammatory, antioxidant properties, and calorie restriction-like effects. We aimed to synthesise evidence from published randomized clinical trials (RCTs) about the efficacy of resveratrol in the management of NAFLD. METHODS: A computer literature search of PubMed, Scopus, Web of Science, and Cochrane Central was conducted using relevant keywords. Records were screened for eligible studies and data were extracted and synthesized using Review Manager Version 5.3 for windows. Subgroup analysis and sensitivity analysis were conducted. RESULTS: Four RCTs (n=158 patients) were included in the final analysis. The overall effect estimates did not favor resveratrol group in terms of: serum ALT (MD -2.89, 95%CI [-15.66, 9.88], p=0.66), serum AST (MD -3.59, 95%CI [-13.82, 6.63], p=0.49), weight (MD -0.18, 95%CI [-0.92, 0.55], p=0.63), BMI (MD -0.10, 95 %CI [-0.43, 0.24], p=0.57), blood glucose level (MD -0.27, 95%CI [-0.55, 0.01], p=0.05), insulin level (MD -0.12, 95%CI [-0.69, 0.46], p=0.69), triglyceride level (MD 0.04, 95%CI [-0.45, 0.53], p=0.87), and LDL level (MD 0.21, 95%CI [-0.41, 0.83], p=0.51). Pooled studies were heterogeneous. CONCLUSION: Current evidence is insufficient to support the efficacy of resveratrol in the management of NAFLD. Resveratrol does not attenuate the degree of liver fibrosis or show a significant decrease in any of its parameters. PMID- 28338116 TI - How to Diagnose and Treat a Cancer of Unknown Primary Site. AB - Almost one in every three patients with advanced tumors have distant metastasis at the time of clinical diagnosis. In most cases, the primary tumor site is identified immediately, within a few days. But for some patients, the primary lesion cannot be found after the initial clinical assessment. These cases are called cancers of unknown primary origin (CUPs), a clinical diagnosis very difficult to manage by physicians due to the absence of a standard-of-care for the initial therapeutic regimen, as well as due to the impossibility to include these cases in randomized clinical trials. A cancer of unknown primary site is often associated with a poor prognosis as patients are usually treated with a non selective empirical therapy. In the current paper, we summarize both the diagnostic challenges for patients with a cancer of unknown primary site as well as the current available therapeutic options, with emphasis on the management of this unique disease entity. PMID- 28338117 TI - Endovascular Treatment for Acute Mesenteric Ischaemia in a Young Woman with Polyarterial Disease. AB - BACKGROUND: Acute mesenteric ischaemia is a condition with a grim prognosis on conservative treatment. Endovascular revascularisation is a promising approach for some of these patients. CASE REPORT: We present the case of a 44-year-old woman with a history of severe arterial hypertension, left leg claudication, and overlooked symptoms of chronic mesenteric ischaemia for one year, who was admitted for severe abdominal pain for one week. Computed tomographic angiography (CTA) showed acute mesenteric ischaemia by occlusion of the coeliac trunk and the superior mesenteric artery (SMA), without bowel perforation. In addition, CTA showed tight left renal stenosis and left external iliac stenosis. We performed angioplasty with a stent of the SMA, followed by revascularisation of the left renal artery. On control injection, the SMA appeared re-occluded, requiring a second stent implantation and a loading dose of dual antiplatelet therapy, with a good final result. Subsequently, the clinical course was uneventful, with no need of surgical exploration; a second procedure was planned, aiming at iliac revascularisation. At one month, the patient was asymptomatic, with normal Doppler flow in the SMA. Angiographic control during iliac revascularisation procedure showed a permeable SMA with a good filling of the coeliac trunk territory. Because of the suspicion of fibro-muscular dysplasia as aetiology, coronary angiography and cerebral CTA were performed, in order to exclude other potential lesions. CONCLUSIONS: Endovascular revascularisation in AMI is a promising alternative to the surgical approach in patients presenting without bowel perforation. Nevertheless, its safety and many tactical details remain to be clarified. Existing networks for revascularisation in acute myocardial infarction may be useful for the implementation of this approach. PMID- 28338118 TI - Unusual Discovery after an Examination for Abdominal Pain: Abernethy 1b Malformation and Liver Adenomatosis. A Case Report. AB - Congenital extrahepatic portosystemic shunt (Abernethy malformation) is a rare condition characterized by developmental abnormalities of the portal venous system resulting in the diversion of the portal blood from the liver to the systemic venous system through a complete or partial shunt of the portomesenteric blood. We report the case of an 18 year-old female examined for abdominal pain, presenting cholestasis syndrome and an elevated serum aspartate aminotransferase level. Liver ultrasound examination revealed the absence of the portal vein with a complete extrahepatic shunt of the portal blood, multiple focal liver lesions, and multiple associated vascular anomalies. A surgical portosystemic shunt and a secondary portosystemic shunt due to portal vein thrombosis were excluded, enabling the diagnosis of a congenital portosystemic shunt. A complex investigation also discovered bone anomalies, and the liver biopsy of the dominant focal lesion revealed adenoma. On a short-term follow-up under hepatoprotective medication, the biochemical parameters improved mildly; however, the size of the main focal lesion increased. Congenital absence of the portal vein often remains an incidental diagnosis. In experienced hands, ultrasonography can diagnose it, but a comprehensive thoraco-abdominal evaluation is compulsory, considering the many potential associated anomalies. In these patients, development of adenomatous liver lesions secondary to Abernethy type Ib malformation represents an indication for liver transplantation. PMID- 28338119 TI - Anti-Xa activity in patients with hepatocellular carcinoma. PMID- 28338120 TI - Celiac disease: past, present and future - boundless explorations of a disease of modern times. PMID- 28338121 TI - Reply. PMID- 28338122 TI - Fatal acute liver failure during Ritonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir plus Ribavirin therapy. PMID- 28338123 TI - Potential pitfalls of Viekira PakTM therapy in patients with HCV genotype 1b cirrhosis. PMID- 28338124 TI - Assessing mucosal healing in IBD in daily practice. PMID- 28338125 TI - Reply. PMID- 28338127 TI - Phonon bottleneck and long-lived excited states in pi-conjugated pyrene hoop. AB - In the last decade, recent synthetic advances have launched carbon-based pi conjugated hoops to the forefront of theoretical and experimental investigation not only for their potential use as bottom-up templates for carbon nanotube (CNT) growth, but also for the interesting excitonic effects arising from the cyclic geometry, unique pi-system orientation, and unusual electronic interactions and couplings. In particular, cyclic materials based on pyrene, a common component in organic electronics, are popular candidates for the future design of pi conjugated nanorings for optoelectronic applications. Understanding the photophysical response in cyclic oligopyrenes can be achieved using non-adiabatic excited state molecular dynamics (NA-ESMD). Through NA-ESMD modeling, we reveal details of the nonradiative relaxation processes in the circular pyrene tetramer [4]cyclo-2,7-pyrenylene ([4]CPY) where we find that the strong non-adiabatic coupling combined with the dense manifold of excited states creates an internal conversion mechanism dominated by ultrafast sequential quantum transitions. However, we observe two long-lived electronic excited states that introduce a phonon bottleneck in the electronic relaxation process. In fact, the timescale for the electronic relaxation is almost exclusively dominated by the lifetimes of the long-lived states. We find that the states associated with the phonon bottleneck are separated from lower energy states by large energy gaps and are characterized by localization on a single pyrene unit resulting in a spatial mismatch with strongly delocalized neighboring states. PMID- 28338129 TI - Prediction of metabolic fluxes from gene expression data with Huber penalty convex optimization function. AB - As one of the critical parameters of a metabolic pathway, the metabolic flux in a metabolic network serves as an essential role in physiology and pathology. Constraint-based metabolic models are the widely used frameworks for predicting metabolic fluxes in genome-scale metabolic networks. Integrating the transcriptomic data into the constraint-based metabolic models can effectively predict context-specific fluxes across different conditions. However, these methods always need user-defined thresholds to identify the expression levels of metabolic genes or restrain the rate of biomass production, and the predictive results are sensitive to the thresholds. In this work, we present the Huber penalty convex optimization function (HPCOF) combined with the flux minimization principle to predict metabolic fluxes. Our HPCOF method integrates gene expression profiles into the genome-scale metabolic models (GEMs) to reduce the sensitivity to outliers, and uses continuous expression data to avoid selection of arbitrary threshold parameters. In the case studies of Saccharomyces cerevisiae (S. cerevisiae) and Escherichia coli (E. coli) strains under different conditions, the results show that our HPCOF method has a better fit to the experimentally measured values, and has a higher Pearson correlation coefficient, a smaller P-value and a lower sum of squared error than other methods. The HPCOF code can be freely downloaded from for academic users. PMID- 28338131 TI - Structural formation and charge storage mechanisms for intercalated two dimensional carbides MXenes. AB - Although many studies have been focused on the characterization of MXenes, surface structures and formation mechanisms in terms of their experimental processes still remain controversial. Herein, we systematically investigated the structures formed from MX intercalated with different atoms from group IA to VIIA (A = H, Li, Na, K, Mg, Al, Si, P, O, S, F, and Cl) at different sites. An effective procedure based on first-principles calculations was developed to reveal the formation mechanisms of MAX, MXA2, MXTx, and MXTxAx' structures. The competition and matching mechanisms were introduced to determine the formation probabilities of the MAX phase. The transformation processes from MAX to MXA2 have been correlated with the energies and configurations of the transformed MX and the chemical potential of the A atom in terms of the experimental processes. The structure of MXTx obtained using different methods has been formulated as a function of the experimental conditions and the c lattice parameter. The experimental results can be well explained based on these results. As a representative, it was proved that the capacity of Ti3C2TxAx' (A = Li) depends on the c lattice parameter and the calculated allowable value can range from 130.3 mA h g-1 (Ti3C2F2Li) to 536.8 mA h g-1 (Ti3C2O2Li4). A higher value can be expected if the sample with a suitable c-axis value can be obtained. Energy storage mechanism should be classified into a double-layer capacitance process in the Ti3C2F2 units and a redox storage mechanism in the Ti3C2O2 units. The procedure can be employed to optimize the structures and compositions of the MXenes. PMID- 28338130 TI - The aqueous supramolecular chemistry of cucurbit[n]urils, pillar[n]arenes and deep-cavity cavitands. AB - This tutorial review summarizes the continuing exploration of three prominent water-soluble hosts: cucurbiturils, pillar[n]arenes and deep-cavity cavitands. As we describe, these hosts are revealing how orchestrating the hydrophobic effect can lead to a broad range of properties and applications, from: nano-reactors, supramolecular polymers, stimuli-responsive biointerfaces, switches, and novel purification devices. We also describe how their study is also revealing more details about the properties of water and aqueous solutions. PMID- 28338132 TI - in/out Isomerism of cyclophanes: a theoretical account of 2,6,15-trithia [34,10][7]metacyclophane and [34,10][7]metacyclophane as well as their halogen substituted analogues. AB - A detailed theoretical investigation of cyclophanes with a divergent set of methods ranging from molecular mechanics through semiempirical to ab initio is presented. Cyclophanes have attracted interest over the years due to their unusual chemistry and increasing applications. There has been previous debate over the effects contributing to the greater stability of more-crowded in isomers of certain cyclophanes, and a higher strain in the out isomer was the prevailing explanation. Application of EDA-NOCV and SAPT analysis has enabled us to distinguish between different effects controlling isomer stability and determine the significance of all effects involved. Our results show that, although strain has a large significance, orbital stabilization within the molecule from the aromatic electron density is crucial. Furthermore, we analysed halogen substituted cyclophanes in order to further understand these subtle effects. PMID- 28338133 TI - Stereoselective binding of agonists to the beta2-adrenergic receptor: insights into molecular details and thermodynamics from molecular dynamics simulations. AB - The beta2-adrenergic receptor (beta2-AR) is one of the most studied G-protein coupled receptors. When interacting with ligand molecules, it exhibits a binding characteristic that is strongly dependent on ligand stereoconfiguration. In particular, many experimental and theoretical studies confirmed that stereoisomers of an important beta2-AR agonist, fenoterol, are associated with diverse mechanisms of binding and activation of beta2-AR. The objective of the present study was to explore the stereoselective binding of fenoterol to beta2-AR through the application of an advanced computational methodology based on enhanced-sampling molecular dynamics simulations and potentials of interactions tailored to investigate the stereorecognition effects. The results remain in very good, quantitative agreement with the experimental data (measured in the context of ligand-receptor affinities and their dependence on the temperature), which provides an additional validation for the applied computational protocols. Additionally, our results contribute to the understanding of stereoselective agonist binding by beta2-AR. Although the significant role of the N2936.55 residue is confirmed, we additionally show that stereorecognition does not depend solely on the N293-ligand interactions; the stereoselective effects rely on the co-operation of several residues located on both the 6th and 7th transmembrane domains and on extracellular loops. The magnitude and character of the contributions of these residues may be very diverse and result in either enhancing or reducing the stereoselective effects. The same is true when considering the enthalpic and entropic contributions to the binding free energies, which also are dependent on the ligand stereoconfiguration. PMID- 28338134 TI - Uniform TiO2 nanoparticles induce apoptosis in epithelial cell lines in a size dependent manner. AB - The size of titanium dioxide (TiO2) nanoparticles is a vital parameter that determines their cytotoxicity. However, most reported studies have employed irregular shapes and sizes of TiO2 nanoparticles, as it is difficult to produce nanoparticles of suitable sizes for research. We produced good model TiO2 nanoparticles of uniform shape and size for use in studying their cytotoxicity. In this work, spherical, uniform polyethylene glycol-modified TiO2 (TiO2-PEG) nanoparticles of differing sizes (100, 200, and 300 nm) were prepared using the sol-gel method. A size-dependent decrease in cell viability was observed with increasing nanoparticle size. Furthermore, apoptosis was found to be positively associated with nanoparticle size, as evidenced by an increase in caspase-3 activity with increasing nanoparticle size. Larger nanoparticles exhibited higher cellular uptake, suggesting that larger nanoparticles more strongly induce apoptosis. In addition, the cellular uptake of different sizes of nanoparticles was energy dependent, suggesting that there are size-dependent uptake pathways. We found that 100 and 200 nm (but not 300 nm) nanoparticles were taken up via clathrin-mediated endocytosis. These results utilizing uniform nanoparticles suggest that the size-dependent cytotoxicity of nanoparticles involves active cellular uptake, caspase-3 activation, and apoptosis in the epithelial cell line (NCI-H292). These findings will hopefully aid in the future design and safe use of nanoparticles. PMID- 28338135 TI - Detection of chemical warfare agent simulants and hydrolysis products in biological samples by paper spray mass spectrometry. AB - Paper spray ionization coupled to a high resolution tandem mass spectrometer (a quadrupole orbitrap) was used to identify and quantitate chemical warfare agent (CWA) simulants and their hydrolysis products in blood and urine. Three CWA simulants, dimethyl methylphosphonate (DMMP), trimethyl phosphate (TMP), and diisopropyl methylphosphonate (DIMP), and their isotopically labeled standards were analyzed in human whole blood and urine. Calibration curves were generated and tested with continuing calibration verification standards. Limits of detection for these three compounds were in the low ng mL-1 range for the direct analysis of both blood and urine samples. Five CWA hydrolysis products, ethyl methylphosphonic acid (EMPA), isopropyl methylphosphonic acid (IMPA), isobutyl methylphosphonic acid (iBuMPA), cyclohexyl methylphosphonic acid (CHMPA), and pinacolyl methylphosphonic acid (PinMPA), were also analyzed. Calibration curves were generated in both positive and negative ion modes. Limits of detection in the negative ion mode ranged from 0.36 ng mL-1 to 1.25 ng mL-1 in both blood and urine for the hydrolysis products. These levels were well below those found in victims of the Tokyo subway attack of 2 to 135 ng mL-1. Improved stability and robustness of the paper spray technique in the negative ion mode was achieved by the addition of chlorinated solvents. These applications demonstrate that paper spray mass spectrometry (PS-MS) can be used for rapid, sample preparation-free detection of chemical warfare agents and their hydrolysis products at physiologically relevant concentrations in biological samples. PMID- 28338136 TI - Investigation of the complexation of natZr(iv) and 89Zr(iv) by hydroxypyridinones for the development of chelators for PET imaging applications. AB - Three hydroxypyridinone (HOPO) positional isomers - 1,2-HOPO (L1H) and its water soluble analogue (L1'H), 3,2-HOPO (L2H) and 3,4-HOPO (L3H) have been investigated for the complexation of Zr(iv). Potentiometric and UV-Vis spectrometric studies show a higher thermodynamic stability for the formation of Zr(L1')4 in comparison with Zr(L2)4 and Zr(L3)4 as well as a higher kinetic inertness in competition studies with EDTA or Fe3+ at a radiotracer concentration with 89Zr. Besides the low pKa of L1H or L1'H (pKa = 5.01) in comparison with L2H and L3H (pKa = 8.83 and 9.55, respectively), the higher stability of Zr(L1')4 can be attributed in part to the presence of the amide group next to the chelating oxygen that induces intramolecular H-bond and amide/pi interactions that were observed by X-ray crystallography and confirmed by quantum chemical calculations. The data presented here indicate that the 1,2-HOPO L1' exhibits the best characteristics for Zr(iv) complexation. However, 3,2-HOPO and 3,4-HOPO patterns, if appropriately tuned, for instance with the addition of an amide group as in the 1,2-HOPO ligand, may also become interesting alternatives for the design of Zr(iv) chelators with improved characteristics for applications in nuclear imaging with 89Zr. PMID- 28338128 TI - Metal-organic and covalent organic frameworks as single-site catalysts. AB - Heterogeneous single-site catalysts consist of isolated, well-defined, active sites that are spatially separated in a given solid and, ideally, structurally identical. In this review, the potential of metal-organic frameworks (MOFs) and covalent organic frameworks (COFs) as platforms for the development of heterogeneous single-site catalysts is reviewed thoroughly. In the first part of this article, synthetic strategies and progress in the implementation of such sites in these two classes of materials are discussed. Because these solids are excellent playgrounds to allow a better understanding of catalytic functions, we highlight the most important recent advances in the modelling and spectroscopic characterization of single-site catalysts based on these materials. Finally, we discuss the potential of MOFs as materials in which several single-site catalytic functions can be combined within one framework along with their potential as powerful enzyme-mimicking materials. The review is wrapped up with our personal vision on future research directions. PMID- 28338137 TI - An investigation of the PM2.5 and NO2 concentrations and their human health impacts in the metro subway system of Suzhou, China. AB - This study measured the particle concentrations with an aerodynamic diameter smaller than 2.5 MUm (PM2.5), nitrogen dioxide (NO2), and relative humidity (RH) at five metro subway stations in Suzhou's subway system (Lines 1 and 2). The real time monitoring campaign was conducted from March 30th to April 10th and August 4th to August 21st, 2015. The monitoring practice was carried out during rush (7:00-9:00 AM and 17:00-19:00 PM) and regular hours (other times) at the ground and underground levels under different weather conditions with a purpose of obtaining representative data. The monitored results show that the concentrations of PM2.5 in the train carriages were lower than the concentrations at the underground platforms during both spring and summer. The mean PM2.5 concentrations at all the underground platforms in all the sub-stations monitored were significantly higher than those at the ground level. The human health impact was calculated to be 6300 annual DALYs (or 375 deaths) due to exposure to the subway system in Suzhou according to the UNEP-SETAC toxicity (USEtox) model. Linear regression models were applied to evaluate the relationships between the PM2.5, NO2 concentrations, and RH. We found that a 10% increment in RH from the current average level of 50-60% can lead to a 9.8 MUg m-3 concentration decrease in PM2.5. This further results in the total human health impact being reduced to 2451 DALYs (150-4753 DALYs), representing a 20% decrease (1.2-38%). PMID- 28338138 TI - A novel colorimetric assay for alpha-methylacyl-CoA racemase 1A (AMACR; P504S) utilizing the elimination of 2,4-dinitrophenolate. AB - alpha-Methylacyl-CoA racemase (AMACR; P504S) regulates branched-chain fatty acid degradation, activates Ibuprofen and is a recognised cancer drug target. A novel, facile colorimetric assay was developed based on elimination of 2,4 dinitrophenolate. The assay was used to test 5 known inhibitors, determining IC50 and Ki values, reversibility and characterizing irreversible inhibition. PMID- 28338139 TI - Adsorption of small inorganic molecules on a defective MoS2 monolayer. AB - We present a theoretical study of molecular adsorption on defects on a MoS2 monolayer. Based on Density Functional Theory, our calculations confirm that small inorganic molecules, such as CO2, CO, H2O, NO, NO2, H2 and N2, remain bonded to the pristine monolayer through weak van der Waals interactions, suggesting that the molecules may easily diffuse over the clean monolayer. On the other hand, the introduction of defects can lead to three different situations, depending on the defect and the molecule considered: physisorption, chemical (strong) bonding to the metallic defects, namely the Mo substitutional atoms on the S vacancies, and dissociation, that can take place spontaneously at 0 K in some specific cases or by the effect of thermal agitation in molecules such as CO2 or NO2 on the S vacancy. Our energetic and electronic analyses provide an explanation to such bonding possibilities, showing that in the low interacting situations, the molecules tend to adopt a planar configuration parallel to the monolayer, while a molecular rotation is favored in order to facilitate the bond formation on the reactive sites. Finally, the ab initio based Scanning Tunneling Microscopy (STM) simulations show the fingerprint of each molecule adsorbed on the most reactive site. This work opens the way to the possibility of tuning the catalytic properties of MoS2 by controlling the creation of specific defects in the MoS2 monolayer. PMID- 28338140 TI - Enhanced single-ion magnetic and ferroelectric properties of mononuclear Dy(iii) enantiomeric pairs through the coordination role of chiral ligands. AB - The structures and properties of two mononuclear Dy(iii) enantiomeric pairs were dramatically controlled by crystallization temperature; the enantiomeric pair with coordinated chiral N,N'-donor ligands exhibits enhanced single-ion magnetic, ferroelectric and chiroptical properties with respect to the other one with protonated chiral N,N'-donor ligands. PMID- 28338142 TI - C(sp3)-H dehydrogenation and C(sp2)-H alkoxy carbonylation of inactivated cyclic amines towards functionalized N-heterocycles. AB - A novel and efficient synthesis of tetrahydropyridine (THP)-, dihydropyrrole (DHP)-, or tetrahydroazepine (THA)-3-carboxylates via cascade reactions of inactivated cyclic amines with CO and alcohols is presented. To our knowledge, this should be the first example in which functionalized N-heterocycles were prepared directly from Pd-catalyzed C(sp3)-H dehydrogenation and C(sp2)-H carbonylation of saturated cyclic amines. Moreover, the DHP-3-carboxylates thus obtained could readily undergo an oxidative aromatization to give pyrrole-3 carboxylates by using O2 as a green oxidant. Notable features of the methods developed herein include simple substrates, high efficiency and excellent atom economy, mild reaction conditions, and broad substrate scope. PMID- 28338141 TI - Structurally related hydrazone-based metal complexes with different antitumor activities variably induce apoptotic cell death. AB - Three new complexes bearing the tridentate hydrazone-based ligand 2-(2-(1 (pyridin-2-yl)ethylidene)hydrazinyl)pyridine (L) were synthesized and structurally characterized. Biological tests indicate that the Zn(ii) complex [ZnCl2(L)] is of low cytotoxicity against the hepatocellular carcinoma cell line HepG2. In contrast, the Cu(ii) and Mn(ii) complexes [CuCl2(L)] and [MnCl2(L)] are highly cytotoxic with EC50 values of 1.25 +/- 0.01 MUM and 20 +/- 1 MUM, respectively. A quantitative proteome analysis reveals that treatment of the cells with the Cu(ii) complex leads to a significantly altered abundance of 102 apoptosis-related proteins, whereas 38 proteins were up- or down-regulated by the Mn(ii) complex. A closer inspection of those proteins regulated only by the Cu(ii) complex suggests that the superior cytotoxic activity of this complex is likely to be related to an initiation of the caspase-independent cell death (CICD). In addition, an increased generation of reactive oxygen species (ROS) and a strong up-regulation of proteins responsive to oxidative stress suggest that alterations of the cellular redox metabolism likely contribute to the cytotoxicity of the Cu(ii) complex. PMID- 28338143 TI - Mastering the non-equilibrium assembly and operation of molecular machines. AB - In mechanically interlocked compounds, such as rotaxanes and catenanes, the molecules are held together by mechanical rather than chemical bonds. These compounds can be engineered to have several well-defined mechanical states by incorporating recognition sites between the different components. The rates of the transitions between the recognition sites can be controlled by introducing steric "speed bumps" or electrostatically switchable gates. A mechanism for the absorption of energy can also be included by adding photoactive, catalytically active, or redox-active recognition sites, or even charges and dipoles. At equilibrium, these Mechanically Interlocked Molecules (MIMs) undergo thermally activated transitions continuously between their different mechanical states where every transition is as likely as its microscopic reverse. External energy, for example, light, external modulation of the chemical and/or physical environment or catalysis of an exergonic reaction, drives the system away from equilibrium. The absorption of energy from these processes can be used to favour some, and suppress other, transitions so that completion of a mechanical cycle in a direction in which work is done on the environment - the requisite of a molecular machine - is more likely than completion in a direction in which work is absorbed from the environment. In this Tutorial Review, we discuss the different design principles by which molecular machines can be engineered to use different sources of energy to carry out self-organization and the performance of work in their environments. PMID- 28338144 TI - Selective surface tension induced patterning on flexible textiles via click chemistry. AB - A solid surface commonly forms two wetting modes by alternating the type of the liquids, i.e. wetting and nonwetting. Here we report that a textile can be programmed to exhibit three wetting modes by simply alternating the surface tension of the liquids, they are in turn, wetting, selective wetting and nonwetting. The hidden patterns are prepared via a combination of wet chemical etching and two-step UV-induced thiol-ene click chemistry to graft low-surface tension thiols and high-surface-tension thiols, respectively, on the textile surface. The as-prepared flexible textiles possess the nonwetting and wetting properties of the high-surface-tension liquids, such as water and glycerol, and the low-surface-tension liquids, such as decane and ethanol, respectively. Furthermore, the selective wetting behavior can be revealed only if the surface tension of the liquids is within a narrow range of approximately 44.8 mN m-1 to 28.1 mN m-1, such as N,N-dimethylformamide and acetonitrile. In addition, the as patterned textiles demonstrated high mechanical and chemical stability with long term and repeated usage, which implies their high potential to act as novel encoded information carrier materials for flexible and textile-based devices. PMID- 28338146 TI - A gold nanoparticle-mediated rapid in vitro assay of anti-aggregation reagents for amyloid beta and its validation. AB - Herein, we report a rapid in vitro assay of amyloid beta anti-aggregation reagents using gold nanoparticles as nucleation cores and optical reporters. Based on the colorimetric responses observed with the naked eye, effective anti aggregation reagents were rapidly (<15 min) distinguished. For these reagents, conventional methods showed fewer amyloid beta aggregates and an increased viability of neuroblastoma cells after treatment. We envision that our proposed method will facilitate the discovery of efficient drug components for the treatment of Alzheimer's disease. PMID- 28338147 TI - Symmetry breaking during nanocrystal growth. AB - Symmetry breaking is a ubiquitous phenomenon that occurs spontaneously when a system is subjected to changes in size and/or variations in terms of thermodynamic parameters. As a stochastic process, even small fluctuations acting on a system can arbitrarily push it down one of the branches of a bifurcation. In this feature article, we use nanocrystal growth to illustrate the concept of symmetry breaking. Our aim is to convey its importance from a mechanistic perspective, by which one can rationally alter the experimental conditions to manipulate the growth pattern (symmetric vs. asymmetric) and thus generate colloidal nanocrystals with controlled shapes, structures, and properties for various applications. PMID- 28338148 TI - Extraction of minor actinides, lanthanides and other fission products by silica immobilized BTBP/BTPhen ligands. AB - Novel BTBP [bis-(1,2,4-triazin-3-yl)-2,2'-bipyridine]/BTPhen [bis-(1,2,4-triazin 3-yl)-1,10-phenanthroline] functionalized silica gels have been developed to extract minor actinides, lanthanides and other fission products. BTPhen functionalized silica gel is capable of near-quantitative removal of Am(iii) in the presence of Eu(iii) from aqueous HNO3, while BTBP functionalized silica gel is able to remove problematic corrosion and fission products that are found in PUREX raffinates. PMID- 28338149 TI - Ligand controlled switchable selectivity in ruthenium catalyzed aerobic oxidation of primary amines. AB - A ligand controlled catalytic system for the aerobic oxidation of 1 degrees amines to nitriles and imines has been developed where the varying pi-acidic feature of BIAN versus phen in the frameworks of ruthenium catalysts facilitates switchable selectivity. PMID- 28338150 TI - Stereoselective synthesis of novel adamantane derivatives with high potency against rimantadine-resistant influenza A virus strains. AB - A series of (R)- and (S)-isomers of new adamantane-substituted heterocycles (1,3 oxazinan-2-one, piperidine-2,4-dione, piperidine-2-one and piperidine) with potent activity against rimantadine-resistant strains of influenza A virus were synthesized through the transformation of adamantyl-substituted N-Boc homoallylamines 8 into piperidine-2,4-diones 11 through the cyclic bromourethanes 9 and key intermediate enol esters 10. Biological assays of the prepared compounds were performed on the rimantadine-resistant S31N mutated strains of influenza A - A/California/7/2009(H1N1)pdm09 and modern pandemic strain A/IIV Orenburg/29-L/2016(H1N1)pdm09. The most potent compounds were both enantiomers of the enol ester 10 displaying IC50 = 7.7 MUM with the 2016 Orenburg strain. PMID- 28338151 TI - Field-theoretic simulations of random copolymers with structural rigidity. AB - Copolymers play an important role in a range of soft-materials applications and biological phenomena. Prevalent works on block copolymer phase behavior use flexible chain models and incorporate interactions using a mean-field approximation. However, when phase separation takes place on length scales comparable to a few monomers, the structural rigidity of the monomers becomes important. In addition, concentration fluctuations become significant at short length scales, rendering the mean-field approximation invalid. In this work, we use simulation to address the role of finite monomer rigidity and concentration fluctuations in microphase segregation of random copolymers. Using a field theoretic Monte-Carlo simulation of semiflexible polymers with random chemical sequences, we generate phase diagrams for random copolymers. We find that the melt morphology of random copolymers strongly depends on chain flexibility and chemical sequence correlation. Chemically anti-correlated copolymers undergo first-order phase transitions to local lamellar structures. With increasing degree of chemical correlation, this first-order phase transition is softened, and melts form microphases with irregular shaped domains. Our simulations in the homogeneous phase exhibit agreement with the density-density correlation from mean-field theory. However, conditions near a phase transition result in deviations between simulation and mean-field theory for the density-density correlation and the critical wavemode. Chain rigidity and sequence randomness lead to frustration in the segregated phase, introducing heterogeneity in the resulting morphologies. PMID- 28338152 TI - [Development and future of minimally invasive surgery in western China]. AB - There are vast land and lots of people in western China, but the economy developing is relatively slow. However, the minimally invasive surgery was carried out firstly in China. Moreover, the type, number and difficulty of the minimally invasive surgery increased year by year. Especially, in the western area of China, Dr Zhou Zongguang, Yu Peiwu and Zheng Shuguo et al. have performed much pioneering work in laparoscopic surgery for rectal cancer, gastric cancer and laparoscopic liver resection. They led the standard development of minimally invasive in China. In the future, western China should continue to strengthen the standardized training of minimally invasive surgery, make great effort to carry out evidence-based research of minimally invasive surgery, provide evidences of high level of clinical application in minimally invasive surgery. At the same time, we should carry out the robotic and 3D laparoscopic surgery actively, leading the development of minimally invasive surgery more standardized and more widespread in western China. PMID- 28338153 TI - [Experience and present situation of Western China Gastric Cancer Collaboration]. AB - The Western China Gastric Cancer Collaboration (WCGCC) was founded in Chongqing, China in 2011. At the early stage of the collaboration, there were only about 20 centers. While now, there are 36 centers from western area of China, including Sichuan, Chongqing, Yunnan, Shanxi, Guizhou, Gansu, Qinghai, Xinjiang, Ningxia and Tibet. During the past few years, the WCGCC organized routinely gastric cancer standardized treatment tours, training courses of mini-invasive surgical treatment of gastric cancer and the clinical research methodology for members of the collaboration. Meanwhile, the WCGCC built a multicenter database of gastric cancer since 2011 and the entering and management refer to national gastric cancer registration entering system of Japan Gastric Cancer Association. During the entering and collection of data, 190 items of data have unified definition and entering standard from Japan Gastric Cancer Guidelines. Nowadays, this database included about 11 872 gastric cancer cases, and in this paper we will introduce the initial results of these cases. Next, the collaboration will conduct some retrospective studies based on this database to analyze the clinicopathological characteristics of patients in the western area of China. Besides, the WCGCC performed a prospective study, also. The first randomized clinical trial of the collaboration aims to compare the postoperative quality of life between different reconstruction methods for total gastrectomy(WCGCC-1202, ClinicalTrials.gov Identifier: NCT02110628), which began in 2015, and now this study is in the recruitment period. In the next steps, we will improve the quality of the database, optimize the management processes. Meanwhile, we will engage in more exchanges and cooperation with the Chinese Cochrane Center, reinforce the foundation of the clinical trials research methodology. In aspect of standardized surgical treatment of gastric cancer, we will further strengthen communication with other international centers in order to improve both the treatment and research levels of gastric cancer in Western China. PMID- 28338154 TI - [Experience of the three-stage strategy for intestinal fistula complicated with complex abdominal infection]. AB - Intestinal fistula, as a serious complication after abdominal surgery, not only leads to a series of pathophysiological changes such as fluid loss, malnutrition and organ dysfunction, but also causes the severe abdominal infection, which often threatens the life of patients. How to make the diagnosis and give the treatment of intestinal fistula is the key to save the lives of high-risk patients. In our hospital, during the past course of diagnosis and treatment for intestinal fistula complicated with severe abdominal infection, based on the combination of literatures at home and abroad with our clinical experiences for many years, an effective three-stage prevention and treatment strategy was formed gradually, which included early diagnosis, effective treatment of infection source, open drainage of abdominal infection and early enteral nutrition support. This strategy subverts the traditional concept of surgery alone, and becomes an effective means to save patients with severe abdominal infection. PMID- 28338155 TI - [Correlation between chronic constipation and colorectal neoplasms]. AB - The correlation between chronic constipation and colorectal neoplasms has been arousing wide interest. There have been a number of domestic and international epidemiological and clinical researches focusing on this issue. Based on these researches, the correlation between constipation and colorectal neoplasms was studied from three aspects: constipation and colorectal polyps; constipation and colorectal cancer; melanosis coli (MC), laxatives and colorectal neoplasms. We find that constipation can significantly increase the incidence of colorectal polyps and constipation does not significantly increase the incidence of colorectal cancer but is one of the risk factors for colorectal cancer. In addition, MC, laxatives and the incidence of colorectal polyps are also closely correlated. Given the fact that colorectal polyps are precancerous lesions, patients with long-term constipation should take less anthraquinone laxatives, and those with colorectal polyps should be followed up periodically. PMID- 28338156 TI - [Pay attention to the selective lateral pelvic lymph node dissection in mid-low rectal cancer]. AB - Lateral pelvic lymph node metastasis is an important metastatic mode and a major cause of locoregional recurrence of mid-low rectal cancer. Recently, there is an East-West discrepancy in regard to the diagnosis, clinical significance, treatment and prognosis of lateral pelvic lymph node metastasis. In the West, lateral nodal involvement may represent systemic disease and preoperative chemoradiotherapy can sterilize clinically suspected lateral nodes. Thus, in many Western countries, the standard therapy for lower rectal cancer is total mesorectal excision with chemoradiotherapy, and pelvic sidewall dissection is rarely performed. In the East, and Japan in particular, however, there is a positive attitude in regard to lateral pelvic lymph node dissection (LPND). They consider that lateral pelvic lymph node metastasis is as regional metastasis, and the clinically suspected lateral nodes can not be removed by neoadjuvant chemoradiotherapy. The selective LPND after neoadjuvant chemoradiotherapy may be found to be promising treatment for the improvement of therapeutic benefits in these patients. Therefore, the large-scale prospective studies are urgently required to improve selection criteria for LPND and neoadjuvant treatment to prevent overtreatment in the near future. Selective LPND after neoadjuvant treatment based on modern imaging techniques is expected to reduce locoregional recurrence and improve long-term survival in patients with mid-low rectal cancer. PMID- 28338157 TI - [Enhanced recovery after surgery in the west China: problems, strategy and future]. AB - Enhanced recovery after surgery (ERAS) has been widely used in the world for near 20 years, which should be considered as the milestone of modern medicine advancement, changing the routine perioperative principle, accelerating the recovery speed following operation, minimizing the postoperative pain, and saving the medical resources. Despite the remarkable advance, the quality and application of ERAS in the west China needs further improvement if compared with international level or even some domestic hospitals. The postoperative hospital stay in west China is much longer than the reported 3 to 5 days according to published references. Several suggestions can be help: (1) Based on the published consensus and the successful experiences of ERAS in colorectal surgery, the medical institution should make great effort to extend this technique to change the profound traditional idea in medical staffs and patients. (2) The medical administrations should take the application of ERAS as a key performance index and annual work plan in hospital. (3) Multiple disciplinary team including anesthetist, surgeon, dietitian, and nurses is essential for hospital to promote the quality of ERAS. Undoubtedly, ERAS is going to be the conventional medical care in the western area of China. We may look forward to seeing more researches from western China to update the ERAS consensus. PMID- 28338158 TI - [Diagnosis and treatment of duodenal injury and fistula]. AB - Duodenal injury is a serious abdominal organ injury. Duodenal fistula is one of the most serious complications in gastrointestinal surgery, which is concerned for its critical status, difficulty in treatment and high mortality. Thoracic and abdominal compound closed injury and a small part of open injury are common causes of duodenal injury. Iatrogenic or traumatic injury, malnutrition, cancer, tuberculosis, Crohn's disease etc. are common causes of duodenal fistula, however, there has been still lacking of ideal diagnosis and treatment by now. The primary treatment strategy of duodenal fistula is to determine the cause of disease and its key point is prevention, including perioperative parenteral and enteral nutrition support, improvement of hypoproteinemia actively, avoidance of stump ischemia by excessive separate duodenum intraoperatively, performance of appropriate duodenum stump suture to ensure the stump blood supply, and avoidance of postoperative input loop obstruction, postoperative stump bleeding or hematoma etc. Once duodenal fistula occurs, a simple and reasonable operation can be selected and performed after fluid prohibition, parenteral and enteral nutrition, acid suppression, enzyme inhibition, anti-infective treatment and maintaining water salt electrolyte and acid-base balance. Double tube method, duodenal decompression and peritoneal drainage can reduce duodenal fistula-related complications, and then reduce the mortality, which can save the lives of patients. PMID- 28338159 TI - [Application of multimodal analgesia in radical gastrectomy for gastric cancer patients: a prospective nonrandomized controlled study]. AB - OBJECTIVE: To compare the postoperative analgesia efficacy, rehabilitation parameters and complication between multimodal analgesia and traditional analgesia after radical gastrectomy for gastric cancer patients. METHODS: Patients with gastric cancer who underwent surgery in our hospital from October 2016 to December 2016 were enrolled in this prospective study. According to the non-randomized method, patients were assigned to multimodal analgesia group(n=32) and traditional analgesia group(n=33) in gastric cancer treatment team A and B in Department of Gastrointestinal Surgery, West China Hospital, Sichuan University. The treatment measures of group A were as follows: (1) The ratio of 1/1 diluted ropivacaine (100 mg, 10 ml) was infiltrated around the incision before abdomen closure, with incision sutured layer by layer. (2) Parecoxib sodium (40 mg) was injected intravenously every 12 hours after operation for 5 days. (3) Oxycodone acetaminophen tablet was given orally on the first day or the second day after operation, 50 mg twice a day. (4) Patient-controlled analgesia was not used after operation. Patients in group B received direct suture of incision and patient controlled analgesia. The pain score, postoperative rehabilitation and 30-day postoperative complications were collected and analyzed. RESULTS: Multimodal analgesia group had lower pain scores at 1 d (4.8+/-0.9), 2 d (4.3+/-1.0), 3 d (2.9+/-0.8), 4 d (2.4+/-0.7) and 5 d (1.7+/-0.7) after surgery, as compared to traditional analgesia group (5.9+/-0.9, P=0.000), (5.1+/-0.7, P=0.001), (3.9+/ 0.8, P=0.000), (3.0+/-0.6, P=0.000), (2.6+/-0.7, P=0.000), with significant difference. Postoperative hospital stay [(8.2+/-1.6) days vs. (10.6+/-2.2) days, P=0.000], time to ambulation [(47.5+/-13.8) days vs. (66.2+/-16.8) days, P=0.000], time to first flatus [(76.4+/-25.2) days vs. (120.0+/-29.9) days, P=0.000], time to first defecate [(117.3+/-42.2) days vs. (159.7+/-30.7) days, P=0.000] and time to first fluid diet [(83.8+/-21.6) days vs. (141.9+/-33.9) days, P=0.000] in the multimodal analgesia group were significantly shorter than those in the traditional analgesia group. There was no significant difference between the two groups with respect to 30-day postoperative complication rate(9.4% vs. 9.1%, P=1.000). CONCLUSIONS: Multimodal analgesia can significantly reduce the postoperative pain and is beneficial to rehabilitation, meanwhile it does not increase the risk of postoperative complications. Multimodal analgesia is safe and effective for gastric cancer patients undergoing radical gastrectomy. PMID- 28338160 TI - [Value of tumor deposits in staging and prognostic evaluation in gastric cancer patients]. AB - OBJECTIVE: To analyze relationships between the tumor deposits (TD) and clinicopathologic features of gastric cancer and investigate the value of TD in staging and prognosis in gastric cancer patients. METHODS: Retrospective cohort study was conducted to evaluate the clinicopathologic data of 388 gastric cancer patients who underwent surgical procedures in Chinese PLA General Hospital between November 2011 and December 2012. Relationships between TD and clinicopathologic features were analyzed by chi2 or Fisher exact tests. Survival curves were also generated by Kaplan-Meier method. The univariate and multivariate analysis were performed with Log-rank and COX proportional hazard model to examine the association between prognosis and TD. RESULTS: TD were observed in 67 (17.3%) of 388 gastric cancer patients, including 48 male patients (48/289, 16.6%) and 19 female patients (19/99, 19.2%). There were 40 patients (40/198, 20.2%) whose age was above 64 years old. TNM staging of positive TD patients was as follows: for pathology, there were 5 patients (5/64, 7.8%) in stage II(b, 6 patients (6/58, 10.3%) in stage III(a, 14 patients (14/75, 18.7%) in stage III(b, 30 patients (30/135, 22.2%) in stage III(c, 12 patients (12/39, 30.8%) in stage IIII( and no one in stage I(b or II(a; for T-staging, there were 2 patients (2/18, 11.1%) in stage T2, 2 patients (2/27, 7.4%) in stage T3, 36 patients (36/259, 13.9%) in stage T4a and 27 patients (27/84, 32.1%) in stage T4b; for N-stage, there were 5 patients (5/72, 6.9%) in stage N0, 6 patients (6/72, 8.3%) in stage N1, 19 patients (19/82, 23.2%) in stage N2, 27 patients (27/100, 27.0%) in stage N3a and 10 patients(10/62, 16.1%) in stage N3b; for M stage, there were 12 patients (12/40, 30.0%) in distal metastases; for vascular invasion, there were 29 patients (29/129, 22.5%). Among positive TD patients, the number of TD >3 was found in 38 of 67 cases(56.7%). TD was associated with pTNM stage (chi2=16.898, P=0.010), T-stage (chi2=17.382, P=0.001), N-stage (chi2=18.080, P=0.001), M-stage (chi2=5.060, P=0.036) and vascular invasion(chi2=3.675, P=0.039). The median survival time of positive TD patients was significantly shorter as compared to negative TD patients (22 months vs. 32 months, chi2=23.391, P=0.012). Among positive TD patients, the median survival time of patients with TD number >3 was significantly shorter as compared to those with TD number <3 (17 months vs. 25 months, chi2=5.157, P=0.023). Multivariate survival analysis showed that TD number >3 was the independent risk factor of prognosis (RR=2.350, 95%CI:1.345 to 4.106, P=0.003). CONCLUSIONS: TD state is closely associated with the staging of gastric cancer and TD number >3 indicates a poor prognosis. PMID- 28338161 TI - [Clinical significance of No.12 lymph node dissection for advanced gastric cancer]. AB - OBJECTIVE: To evaluate the clinical significance of No.12 lymph node dissection for advanced gastric cancer with D2 lymphadenectomy. METHODS: Clinicopathologic data and No.12 lymph node dissection of 256 advanced gastric cancer patients undergoing radical operation in our department between January 2005 and December 2010 were retrospectively summarized and the influence factors of metastasis in No.12 lymph nodes were analyzed. RESULTS: Of 256 patients, 179 were male and 77 were female with the average age of 59.2 years. Tumor located in the upper of stomach in 24 cases, middle of stomach in 41 cases, lower of stomach in 174 cases, multi-focus or diffuse distribution of stomach in 17 cases. Tumor diameter was <3 cm in 39 cases, 3 to 5 cm in 100 cases, >5 cm in 117 cases. Serum carcinoembryonic antigen (CEA) level increased in 61 cases, serum carbohydrate antigens (CA)72-4 increased in 56 cases and CA19-9 increased in 61 cases. The number of No.12 lymph nodes resected from all the patients was 1 152, and the average number was 4.5+/-1.9. The metastasis rate of No.12 lymph nodes was 9.4%(24/256) after hematoxylin eosin staining (positive group). All the patients received effective follow-up to December 2015, and the average follow-up time was 101.2 months. The median survival time of positive No.12 group (24 cases) was 29.8 months and of negative No.12 group (232 cases) was 78.2 months, whose difference was statistically significant (chi2=21.715, P=0.000). Univariate analysis found that No.12 lymph node metastasis was not associated with age, gender, tumor differentiation (all P>0.05), but was associated with tumor location, tumor diameter, invasive depth (all P<0.05), and was closely associated with Borrmann type, outside metastatic lymph nodes of No.12 and high levels of serum CEA, CA72-4 and CA19-9 (all P=0.000). Multivariate regression analysis found that tumor location (RR=2.452, 95%CI:1.537 to 3.267, P=0.000), Borrmann type (RR=1.864, 95%CI:1.121 to 3.099, P=0.016) and number of outside metastatic lymph nodes of No.12 (RR=2.979, 95%CI: 2.463 to 3.603, P=0.000) were the independent risk factors of the No.12 metastasis (P<0.05). CONCLUSIONS: Metastasis in No.12 lymph nodes indicates poorer prognosis. The No.12 lymph nodes of advanced gastric cancer patients with curative resection, especially those with the tumor located in the lower part, Borrmann type IIII(, outside metastatic lymph nodes of No.12, should be regularly cleaned. PMID- 28338162 TI - [Risk factor analysis of low anterior resection syndrome after anal sphincter preserving surgery for rectal carcinoma]. AB - OBJECTIVE: To investigate the risk factors of low anterior resection syndrome (LARS) after anal sphincter preserving surgery (SPS) for rectal cancer patients. METHODS: Clinicopathological and follow-up data of rectal cancer patients who underwent SPS from January 2010 to June 2014 in Department of Gastroenterological Surgery, Peking University People's Hospital, were retrospectively analyzed. Patients receiving permanent colostomy and local resection were excluded. Meanwhile, during October 2014 and March 2015, the enrolled patients were asked to fill out a specially designed questionnaire for LARS through face-to-face interview or telephone inquiry, according to the chronological order of operation. Based on the score of questionnaire, patients were divided into three groups: 0-20 points: non LARS; 21-29: minor LARS; 30-42: major LARS. The demographic and clinicopathologic features were compared among groups and the risk factors of major LARS were tested by logistic regression analysis. RESULTS: A total of 100 patients (61 males, 39 females) completed the bowel function survey, with an average age of 66.2(41-86) years, 33 patients <60 years versus 67 patients >=60 years. No significant difference was observed in age distribution (P=0.204). Interval from operation to first follow-up was more than 1 year in 70 patients, and the median follow-up was 23 months. Thirty-seven patients were non LARS, 18 were minor LARS and 45 were major LARS. No significant differences in clinicopathological data (all P>0.05) were observed among three groups except radiotherapy history (P=0.025), tumor location(P=0.000) and distance from anastomotic site to anal verge(P=0.008). After comparison of non LARS group combined with minor LARS group versus major LARS, re-analysis of risk factors showed that radiotherapy history (RR=5.608, 95%CI:1.457 to 21.584, P=0.006), distance from tumor lower margin to anal verge (RR=0.125, 95%CI:0.042 to 0.372, P=0.000), distance from anastomotic site to anal verge (RR=0.255, 95%CI:0.098 to 0.665, P=0.004) and preventive ileostomy history(RR=3.643, 95%CI:1.058 to 12.548, P=0.032) were associated with major LARS. One potential risk factor detected in combined analysis was female (RR=2.138, 95%CI: 0.944 to 4.844, P=0.078). Multivariate analysis revealed that female (RR=2.654, 95%CI: 1.005 to 7.014, P=0.049), radiotherapy history (RR=10.422, 95%CI:2.394 to 45.368, P=0.002) and distance from tumor lower margin to anal verge <=7 cm (RR=8.935, 95%CI:2.827 to 28.243, P=0.000) were independent risk factors of major LARS. CONCLUSIONS: LARS is a significant problem in most rectal cancer patients after SPS. The risk of major LARS increases on condition of radiotherapy, low tumor position and female. When dealing with these patients, preventive measures should be taken into consideration during SPS. PMID- 28338163 TI - [Risk factors of postoperative urinary retention after rectal cancer surgery]. AB - OBJECTIVE: To investigate the risk factors of postoperative urinary retention after rectal cancer surgery. METHODS: Clinical data of 133 patients with rectal cancer undergoing radical surgery from January 2013 to September 2014 in the General Hospital of the PLA Rocket Force were retrospectively analyzed. Time to the first removal of urinary catheter, incidence of postoperative urinary retention, and time to re-insert indwelling catheter were recorded. Risk factors of urinary retention were analyzed. RESULTS: Of 133 patients, 70 were males and 63 were females, with a median age of 62 (20-79) years old. Distance from tumor lower margin to anal verge were <=5 cm in 58 patients, >5 cm to 10 cm in 41 patients, and >10 cm to 15 cm in 34 patients. The postoperative TNM stage was recorded in 35 patients with stage I(, 34 with stage II(, 59 with stage III( and 5 with stage IIII(. Surgical procedures included anterior resection (AR) for 92 patients, abdominoperineal resection (APR) for 25 patients and intersphincteric resection (ISR) for 16 patients. Laparoscopic approach was performed in 89 patients compared with open operation in 44 patients. Time to the first removal of urinary catheter was 2-7 days after operation (median, 5 days) and 36 (27.1%) patients developed urinary retention. All the 36 patients achieved spontaneous voiding by re-inserting urinary catheter for 2-28 days (median, 6 days). Univariate analysis showed that elderly (>65 years) and laparoscopic approach had significantly higher incidence of urinary retention [37.5%(21/56) vs. 19.5%(15/77), chi2=5.333, P=0.021; 34.8%(31/89) vs. 11.4%(5/44), chi2=8.214, P=0.004; respectively]. Multivariate logistic analysis demonstrated that old age(OR=3.949, 95%CI:1.622 to 9.612, P=0.002), laparoscopic approach (OR=5.665, 95%CI:1.908 to 16.822, P=0.002), and abdominoperineal resection (OR=3.443, 95%CI:1.199 to 9.887, P=0.022) were independent risk factors of urinary retention after rectal cancer surgery. CONCLUSIONS: Patients undergoing rectal cancer surgery have a high risk of postoperative urinary retention. More attention should be paid to the old patients, especially those undergoing laparoscopic procedure or abdominoperineal resection, to prevent postoperative urinary retention and urinary dysfunction. PMID- 28338165 TI - [Clinical efficacy of partial resection of puborectalis combined with mutilation of internal anal sphincter in the treatment of puborectalis syndrome with high anal pressure]. AB - OBJECTIVE: To explore the efficacy of partial resection of puborectalis combined with mutilation of internal anal sphincter(IAS) in the treatment of puborectalis syndrome with high anal pressure. METHODS: Twenty-five cases of puborectalis syndrome with high anal resting pressure in the preoperative examination received the operation of partial resection of puborectalis combined with mutilation of IAS in Zhongnan Hospital of Wuhan University between January 2013 and May 2015. The position of puborectalis was confirmed by touching with the exposure under the transfixion device, and a transverse incision was made by electrotome between 3 and 5 o'clock direction of puborectalis, then partial puborectalis was lifted by vessel clamp at 5 o'clock direction, and about 0.5 cm of muscular tissue was resected. Between 8 to 10 o'clock direction of anal tube, about 1 cm length of transverse incision was made by electrotome, then partial IAS was lifted by vessel clamp and cut off. Preoperative and postoperative 3-month anorectal manometry and defecography were carried out. Wexner constipation score and Cleveland Clinic incontinence score were implemented before surgery and 3, 6, 12 months after operation. This study was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR-ORB-16007695). RESULTS: Of the 25 cases, 18 were male and 7 were female, the average age was 55 years old and the average course of disease was 9 years. Compared with pre-operation, the postoperative 3 month anal resting pressure and maximal squeeze pressure were significantly decreased [(53.56+/-9.05) mmHg vs. (92.44+/-7.06) mmHg, (142.80+/-20.35) mmHg vs. (210.88+/-20.56) mmHg, respectively, both P=0.000]; anorectal angulation at resting state and forced defecation state increased significantly [(102.32+/ 4.96)degree vs. (95.88+/-4.01)degree, (117.88+/-5.95)degree vs. (89.52+/ 3.25)degree, respectively, both P=0.000]. Wexner constipation score of postoperative 3-month, 6-month, 12-month (8.28+/-3.91, 7.40+/-3.64 and 8.04+/ 4.74) was significantly lower than the preoperative score (16.00+/-3.69, all P<0.05), while the score was not significantly different among 3 time points after operation (P>0.05). Cleveland Clinic incontinence score was 0 at postoperative 6 and 12 months, and revealed 20 cases were effective among all the surgical patients(80%). CONCLUSION: Partial resection of puborectalis combined with mutilation of internal anal sphincter can effectively reduce anal pressure and improve symptoms of outlet obstruction, which is an effective method in the treatment of puborectalis syndrome with high anal pressure. PMID- 28338164 TI - [A prospective randomized controlled trial of laparoscopic repair versus open repair for perforated peptic ulcers]. AB - OBJECTIVE: To compared the clinical efficacy of laparoscopic repair (LR) versus open repair (OR) for perforated peptic ulcers. METHODS: From January 2010 to June 2014, in Shanghai Tongji Hospital, 119 patients who were diagnosed as perforated peptic ulcers and planned to receive operation were prospectively enrolled. Patients were randomly divided into LR (58 patients) and OR(61 patients) group by computer. Intra-operative and postoperative parameters were compared between two groups. This study was registered as a randomized controlled trial by the China Clinical Trials Registry (registration No.ChiCTR-TRC-11001607). RESULTS: There was no significant difference in baseline data between two groups (all P>0.05). No significant differences of operation time, morbidity of postoperative complication, mortality, reoperation probability, decompression time, fluid diet recovery time and hospitalization cost were found between two groups (all P>0.05). As compared to OR group, LR group required less postoperative fentanyl [(0.74+/-0.33) mg vs. (1.04+/-0.39) mg, t=-4.519, P=0.000] and had shorter hospital stay [median 7(5 to 9) days vs. 8(7 to 10) days, U=-2.090, P=0.001]. In LR group, 3 patients(5.2%) had leakage in perforation site after surgery. One case received laparotomy on the second day after surgery for diffuse peritonitis. The other two received conservative treatment (total parenteral nutrition and enteral nutrition). There was no recurrence of perforation in OR group. One patient of each group died of multiple organ dysfunction syndrome (MODS) 22 days after surgery. CONCLUSION: LR may be preferable for treating perforated peptic ulcers than OR, however preventive measures during LR should be taken to avoid postopertive leak in perforation site. PMID- 28338166 TI - [Preoperative assessment value of spectral CT quantitative parameters in lymph node metastasis of gastric cancer]. AB - OBJECTIVE: To investigate the preoperative assessment value of spectral CT quantitative parameters in lymph node metastasis of gastric cancer. METHODS: From December 2013 to June 2015, clinical and image data of 86 patients with gastric cancer confirmed by gastroscope pathology undergoing preoperative enhanced CT were prospectively collected. Enhanced CT included nonenhanced CT of conventional 120 kVp mode, arterial phase (AP) and venous phase (VP) with GSI mode on Discover GSI CT scanner. The raw data were transferred to ADW4.6 workstation to reconstruct the monochromatic images at 70 keV and iodine-based images in AP and VP with 1.25 mm thickness. The short diameter, long diameter, ratio of short to long diameter, CT attenuation and iodine value of lymph nodes in each phase were measured and recorded. Pathology results were used as golden standard. The spectral CT quantitative parameters of positive and negative lymph nodes were compared by t test and the sensitivity and specificity analyses were performed by ROC curves. This clinical study registration number 81271573. RESULTS: Among these 86 gastric cancer patients (53 male and 33 female), tumors of 28 cases were in upper part, of 12 cases in middle part, of 27 cases in distal part and of 19 cases involved two parts. Thirty-five cases were differentiated type and 51 cases were undifferentiated type. A total of 1 072 lymph nodes were found in operation, of which 412 nodes were positive and 660 were negative. Among 552 lymph nodes found in CT images, 338 nodes were positive and 214 were negative. Compared to negative lymph nodes, short diameter [(9.52+/-3.58) mm vs. (6.48+/-2.94) mm, t=4.639, P=0.000], ratio of short to long diameter (0.82+/-0.14 vs. 0.61+/-0.08, t=13.514, P=0.000), CT attenuation in precontrast [(20.44+/-6.77) Hu vs. (16.06+/ 7.14) Hu, t=3.154, P=0.002], CT attenuation in AP[(61.71+/-11.78) Hu vs. (40.11+/ 10.18) Hu, t=9.588, P=0.000], CT attenuation in VP[(71.34+/-13.03) Hu vs. (53.81+/-11.39) Hu, t=7.888, P=0.000], iodine value in AP [(16.17+/-4.22) 100 MUg/cm3 vs. (8.03+/-3.10) 100 MUg/cm3, t=9.781, P=0.000], the iodine value in VP [(20.13+/-6.04) 100 MUg/cm3 vs. (11.58+/-4.13) 100 MUg/cm3, t=10.147, P=0.000] of positive lymph nodes were greater. The long diameter was not significantly different between positive and negative lymph nodes [(11.71+/-5.63) mm vs. (10.64+/-3.20) mm, t=1.380, P=0.169]. The area under ROC curve of short diameter, ratio of short to long diameter, CT attenuation in precontrast, AP and VP, iodine value in AP and VP of lymph nodes was 0.600, 0.880, 0.648, 0.832, 0.755, 0.864, 0.835, respectively. Taking the ratio of short to long diameter over 0.72 as diagnosis standard, the sensitivity was 75.6% and the specificity was 93.5%. Taking the CT number in AP over 49.75 Hu, the sensitivity was 66.9% and the specificity was 88.8%. Taking the CT number in VP over 59.80 Hu, the sensitivity was 69.9% and the specificity was 77.6%. Taking the iodine value in AP over 9.65 (100 MUg/cm3), the sensitivity was 80.4% and the specificity was 82.2%. Taking the iodine value in VP over 15.65 (100 MUg/cm3), the sensitivity was 69.9% and the specificity was 86.9%. Combinong the ratio of short to long diameter with the iodine value in AP, the sensitivity was 95.2% and the specificity was 76.9%. CONCLUSIONS: The ratio of short to long diameter, the iodine value and CT attenuation in AP and VP of lymph nodes in spectral CT are important criteria to evaluate the metastasis of gastric cancer. Combining the ratio of short to long diameter with the iodine value in AP can obviously improve the sensitivity. PMID- 28338167 TI - [Comparison of CT manifestations of primary colorectal mucinous adenocarcinoma and signet ring cell carcinoma]. AB - OBJECTIVE: To compare the difference in CT manifestations between primary colorectal mucinous adenocarcinoma and signet ring cell carcinoma in order to improve radiologic diagnosis. METHODS: Clinicopathological data and CT findings of 109 patients with colorectal mucinous adenocarcinoma and 46 patients with primary colorectal signet-ring cell carcinoma confirmed by surgery and pathology from March 2008 to February 2015 in the Tumor Hospital of Yunnan Province were retrospectively collected. Differences in age, gender, tumor location, length and thickness of the involved intestinal wall, thickening pattern of the intestinal wall, lesion density, calcification, contrast-enhanced form, peri-intestinal invasion, occurrence of intestinal obstruction and metastasis of other organs were compared between the two groups. RESULTS: Among 109 patients with colorectal mucinous adenocarcinoma, 68 were men and 41 were women with a mean age of (56.8+/ 15.4) years. Among 46 patients with primary colorectal signet-ring cell carcinoma, 26 were men and 20 were women with a mean age of (42.9+/-15.6) years. Compared with mucinous adenocarcinoma group, signet-ring cell carcinoma group showed more concentric bowel-wall thickening[93.5%(43/46) vs. 81.6%(89/109), chi2=9.19, P=0.030], higher lesion density [(42.0+/-3.0) Hu vs. (28.5+/-1.5) Hu, t=37.30, P=0.000], more marked enhancement [54.3%(25/46) vs. 12.8%(14/109), chi2=35.21, P=0.000], less vast-low-density region in enhanced CT imaging[2.2%(1/46) vs. 45.0%(49/109), chi2=73.31, P=0.000] and more severe peri intestinal invasion [41.3% (19/46) vs. 17.4%(19/109), chi2=10.25, P=0.006]. Calcification was found in 18.3%(20/109) of mucinous adenocarcinoma cases, but was not found in signet-ring cell carcinoma cases (chi2=9.69, P=0.002). Target ring sign in contrast-enhanced scan was observed in 15.2%(7/46) of signet-ring cell carcinoma cases, while in none of mucinous adenocarcinoma cases (chi2=17.37, P=0.000). There were no statistically significant differences in lesion location, length and thickness of the involved intestinal wall, occurrence of intestinal obstruction, lymph node metastasis, liver or peritoneum metastasis between two groups(all P>0.05). CONCLUSIONS: Signet-ring cell carcinoma is often found in younger patients, whose CT manifestation is characterized by the target ring sign in contrast-enhanced scan, while primary colorectal mucinous adenocarcinoma is often in older patients, whose CT manifestation is characterized by calcification in unenhanced scan and low density region in enhanced CT show. PMID- 28338168 TI - [Safety and efficacy of hand-assisted laparoscopic versus open distal gastrectomy for gastric cancer: A systematic review and meta-analysis]. AB - OBJECTIVE: To systematically assess the safety and efficacy of hand-assisted laparoscopic distal gastrectomy (HALG) versus open distal gastrectomy (ODG) for gastric cancer. METHODS: Chinese or English literature regarding comparison of HALG and ODG were collected by searching in databases (such as PubMed, Cochrane Library, CNKI, Wanfang database) between January 1996 and September 2016. The data of operative time, incision length, blood loss, number of harvested lymph nodes, time to flatus, hospital stay, postoperative complication morbidity and long-term outcomes were compared between the two procedures. Then funnel plot was used to evaluate publication bias and sensitivity analysis was used to evaluate the stability of the results. All these data analyses were performed using the Meta for or Meta package of R version 3.3.1. RESULTS: A total of 7 studies with 835 patients (323 cases in HALG group and 512 cases in ODG group) were included. Compared with ODG, HALG had a longer operative time (WMD=28.93 minutes, 95%CI=9.59 to 48.28, Z=2.93, P=0.000), a shorter incision length (WMD=-10.31 cm, 95%CI=-14.01 to -6.62, Z=-5.47, P=0.000), less blood loss (WMD=-140.08 ml, 95%CI= 215.07 to -65.09, Z=-3.66, P=0.000), faster gastrointestinal recovery (WMD=-1.23 days, 95%CI=-1.89 to -0.56, Z=-3.62, P=0.000), shorter postoperative hospital stay (WMD=-3.24 days, 95%CI=-5.47 to -1.02, Z=-2.85, P=0.000). In subgroup analysis, 3 studies published before 2013 vs. 4 studies published afterwards, the number of harvested lymph nodes (WMD=-0.78, 95%CI=-2.05 to 0.50, Z=-1.19, P=0.235) and postoperative complication morbidity (RR=1.02, 95%CI=0.43 to 2.44, Z=0.05, P=0.961) did not differ significantly between two groups. Compared with ODG, the RR(95%CI) of ileus of HALG was 0.43 (0.07 to 2.82), but the difference was not statistically significant (P=0.383). One study reported the 5-year overall survival rates of HALG and ODG were 81.0% vs 67.5%, and the tumor recurrence rates were 7.1% vs 22%, respectively, but the differences were not statistically significant(all P>0.05). Sensitivity analysis showed that the above results were stable. The funnel plots of the lymph nodes and postoperative complication morbidity did not present significant publication bias. CONCLUSIONS: HALG has the advantages of minimal invasiveness such as shorter incision length and quicker recovery. Furthermore, the short-term efficacy of HALG is similar to conventional open surgery. However, the long-term efficacy is lack of support from multicenter long-term follow-up results. PMID- 28338169 TI - [Meta-analysis of extralevator abdominoperineal excision for rectal cancer]. AB - OBJECTIVE: To evaluate the efficacy of extralevator abdominoperineal excision (ELAPE) of rectal cancer. METHODS: PubMed, Cochrane Library and Embase database were searched for clinical studies comparing the ELAPE and abdominoperineal excision (APE) for rectal cancer between 2007 and 2016. Two reviewers independently screened the articles and extracted the data. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the observational studies and the score more than 5 points was the inclusion criteria. Cochrane Handbook for Systematic Reviews of Interventions v5.1.0 was used to evaluate the quality of the randomized controlled trials (RCT). Intra-operative perforation rate, circumferential resection margin (CRM) involvement, local recurrence rate, perineal wound complications were brought into meta-analysis by Review Manager 5.3 software. RESULTS: A total of 556 articles were retrieved and 12 articles were enrolled finally, including 11 observational studies and 1 RCT study. All the 12 articles were high quality (scores of all observational studies were more than 11 points, RCT study accorded with 6 criteria of the quality evaluation). A total of 3 788 patients were enrolled, including 2 141 cases of ELAPE and 1 647 cases of APE. Meta-analysis revealed that intra-operative perforation rate of ELAPE was lower than APE (RR=0.52, 95%CI:0.34-0.79, P=0.002). There were no significant differences between two groups in CRM involvement (RR=0.72, 95%CI:0.49-1.07, P=0.10), local recurrence rate (OR=0.55, 95%CI:0.24-1.29, P=0.17) and perineal wound complications (RR=0.94, 95%CI:0.58-1.53, P=0.800). CONCLUSIONS: Compared with APE, ELAPE reduces the intra-operative perforation rate, and does not increase the perineal wound complications, but it has no advantages in decreasing the CRM involvement and local recurrence rate. PMID- 28338170 TI - [Clinical research progress of mesenteric internal hernia after Roux-en-Y reconstruction]. AB - Postoperative internal hernia is a rare clinical complication which often occurs after digestive tract reconstruction. Roux-en-Y anastomosis is a common type of digestive tract reconstruction. Internal hernia after Roux-en-Y reconstruction, which occurs mainly in the mesenteric defect caused by incomplete closure of mesenteric gaps in the process of digestive tract reconstruction, is systematically called, in our research, as mesenteric internal hernia after Roux en-Y reconstruction. Such internal hernia can be divided, according to the different structures of mesentric defect, into 3 types: the type of mesenteric defect at the jejunojejunostomy (J type), the type of Petersen's defect (P type), and the type of mesenteric defect in the transverse mesocolon (M type). Because of huge differences in the number of cases and follow-up time among existing research reports, the morbidity of internal hernia after LRYGB fluctuates wildly between 0.2% and 9.0%. Delayed diagnosis and treatment of mesenteric internal hernia after Roux- en-Y reconstruction may result in disastrous consequences such as intestinal necrosis. Clinical manifestations of internal hernia vary from person to person: some, in mild cases, may have no symptoms at all while others in severe cases may experience acute intestinal obstruction. Despite the difference, one common manifestation of internal hernia is abdominal pain. Surgical treatment should be recommended for those diagnosed as internal hernia. A safer and more feasible way to conduct the manual reduction of the incarcerated hernia is to start from the distal normal empty bowel and trace back to the hernia ring mouth, enabling a faster identification of hernia ring and its track. The prevention of mesenteric internal hernia after Roux-en-Y reconstruction is related to the initial surgical approach and the technique of mesenteric closure. Significant controversy remains on whether or not the mesenteric defect should be closed in laparoscopic Roux-en-Y anastomosis. This article is to review the reports and researches on internal hernia resulting from the mesenteric defect after Roux-en-Y digestive tract reconstruction in recent years, so as to promote understanding and attention on this disease. And more active preventive measures are strongly suggested to be taken in operations where digestive tract reconstruction is involved. PMID- 28338171 TI - [Advances of circulating biomarkers in gastroenteropancreatic neuroendocrine neoplasms]. AB - Gastroenteropancreatic neuroendocrine neoplam (GEP-NEN) is a rare group of tumors with its incidence rising significantly in recent decades. Because of the late presentation of the disease and limitations in conventional biomarkers, about 50% of GEP-NEN patients manifests advanced disease when diagnosed. Therefore, it is vital to identify circulating biomarkers which can not only be used for early diagnosis but also accurately evaluating the biological behavior of GEP-NEN. This review summarizes the advances of circulating biomarkers in diagnosing and evaluating efficacy of treatment in GEP-NEN. Well-known circulating biomarkers include chromogranin A (CgA), pancreastatin (PST), chromogranin B (CgB), neuron specific enolase (NSE) and pancreatic peptide(PP). Novel biomarkers including circulating tumor cell(CTC), microRNA and NETest are promising biomarkers with potential clinical benefit, but further researches are needed before their clinical applications. PMID- 28338172 TI - Antidiabetic drug metformin mitigates ovarian cancer SKOV3 cell growth by triggering G2/M cell cycle arrest and inhibition of m-TOR/PI3K/Akt signaling pathway. AB - OBJECTIVE: Metformin is one of most extensively prescribed oral hypoglycemic drug and has received increased attention in recent times for its antitumorigenic potential. Many possible mechanisms have been proposed for the ability of metformin to overturn cancer growth in vitro and in vivo. The objective of the present study was to evaluate the anticancer activity of metformin against ovarian SKOV3 cancer cells. MATERIALS AND METHODS: Anticancer activity and IC50 value of metformin were determined by MTT assay. Reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and effect on cycle were determined by flow cytometry. Protein expression was estimated by Western blotting. RESULTS: Results indicated that metformin exhibited an IC50 of 20 mM against ovarian SKOV3 cancer cell line. Metformin also caused DNA damage in SKOV3 cells and also prompted ROS-mediated alterations in mitochondrial membrane potential. Nonetheless, it triggered cell cycle arrest of SKOV3 at G2/M checkpoint. The activation of the PI3K/AKT/mTOR pathway plays a vital role in ovarian cancer tumorigenesis, progression and chemotherapy resistance. The results showed that metformin significantly inhibited the expression levels of key proteins of PI3K/Akt/mTOR signaling pathway. CONCLUSIONS: We propose that metformin exhibits anticancer activity in SKOV3 cells and may prove beneficial in the management of ovarian cancers. PMID- 28338173 TI - Valsartan reduces AT1-AA-induced apoptosis through suppression oxidative stress mediated ER stress in endothelial progenitor cells. AB - OBJECTIVE: Valsartan has been reported to have the function of treating hypertension and improving the prognosis of patients. Many studies indicated that valsartan can also increase angiotensin II, andosterone and plasma renin activity (PRA). Autoantibodies against the angiotensin II type 1 receptor (AT1-AA) have been showed to increase reactive oxygen species (ROS) and calcium (Ca2+) and result in apoptosis in vascular smooth muscle cells. In this study, we attempted to explore the effect of valsartan on AT1-AA-induced apoptosis in endothelial progenitor cells. MATERIALS AND METHODS: Endothelial progenitor cells (EPCs) were cultured. The cytotoxicity was determined by MTT assay. EPCs apoptosis was determined by DAPI staining and flow cytometry. Reactive oxygen species, intracellular calcium concentration and calpain activity were measured using Fluostar Omega Spectrofluorimeter. The expression of p-ERK, p-eIF-2a, CHOP, Bcl-2 and caspase-3 were detected by Western blot. RESULTS: MTT assays showed valsartan significantly inhibited AT1-AA- induced decline of the viability of EPCs. DAPI staining and flow cytometry results indicated valsartan inhibited AT1-AA-induced decline of the viability of EPCs via inhibiting AT1-AA-induced apoptosis. Furthermore, the increasing of reactive oxygen species, intracellular calcium and calpain activity induced by AT1-AA in EPCs were also recovered after pre-treated with valsartan. Meanwhile, the upregulation of p-ERK, p-eIF-2a and CHOP, downregulation of Bcl-2, and activation of Caspase-3 caused by AT1-AA were reversed after pre-incubated with valsartan. CONCLUSIONS: Valsartan could inhibit AT1-AA-induced apoptosis through inhibiting oxidative stress mediated ER stress in EPCs. PMID- 28338174 TI - The impact of rifaximin in the prevention of bacterial infections in cirrhosis. AB - OBJECTIVE: Bacterial infections are a leading factor in the progression from compensated to decompensated cirrhosis, with consequent worsening of the prognosis, and concerted efforts have been made to reduce infections and improve the survival rate of these patients. We retrospectively investigated the rate of infections in hospitalized cirrhotic patients under treatment with rifaximin. PATIENTS AND METHODS: We enrolled 649 patients whose clinical and personal data, prescribed therapy, microbiological findings and laboratory tests were collected from previous discharge letters and our institution database. The efficacy of rifaximin in preventing several types infection was evaluated by comparing outcomes for rifaximin-treated patients vs patients receiving no antibiotic treatment. RESULTS: The risk of developing selected bacterial infections was significantly lower in patients treated with rifaximin (OR 0.29; 95% CI 0.20 0.40, p < 0.001). CONCLUSIONS: Continuous treatment with rifaximin may prevent bacterial infections in cirrhotic patients. PMID- 28338175 TI - Study on the mechanism of AMPK signaling pathway and its effect on apoptosis of human hepatocellular carcinoma SMMC-7721 cells by curcumin. AB - OBJECTIVE: Liver cancer is a common malignant tumor in the digestive system. Curcumin is a kind of phenolic pigment, which is extracted from herbage and has a plenty of physiological roles in anti-inflammation, anti-oxidation and anti tumor. In our study, human hepatoma SMMC-7721 cell lines were selected and treated with curcumin to detect its effects on the apoptosis and AMPK signaling pathway. MATERIALS AND METHODS: Human liver cancer cell strain SMMC-7721 was cultured and treated with different curcumin concentrations for different times followed by measuring the changes of cell proliferation activity and cycle by MTT and flow cytometry, respectively. Protein expression of Bcl-2, Bax and Caspase-3 were tested by Western blot, and the activation level of AMPK was also detected. RESULTS: Different concentrations of curcumin could inhibit the proliferation of tumor cells in a dose-dependent manner. After 48 h inhibition by curcumin with a concentration of 40 mmol/L, the inhibitory effect was more obvious with statistically significant (p<0.05). The number of human liver cancer SMMC-7721 cells increased in G1 stage and decreased in S stage after treated with different concentrations of curcumin. During the G1 stage to the S stage, inhibition occurred and the effect of curcumin intervention group with 40 mmol/L was more evident than that of 10 mmol/L group, 20 mmol/L group and the control group with statistically significant (p<0.05). SMMC-7721 cell stains had been intervening by curcumin with concentrations of 10 mmol/L, 20 mmol/L and 40 mmol/L for 12 h, 24 h and 48 h, as the drug concentration increased, the reaction time prolonged, the protein expressions of Bcl-2 and Survivin were significantly decreased and Bax protein expression was significantly increased (p<0.05). CONCLUSIONS: Curcumin decreased the proliferation activity of tumor cells, increased the cell quantities in G1 stage and decreased the cell numbers in S stage in human liver cancer SMMC-7721 cells. The Bcl-2 and Survivin proteins were downregulated and Bax protein was upregulated; furthermore, the AMPK signaling pathway was activated. PMID- 28338176 TI - The inhibitory effect of resveratrol on COX-2 expression in human colorectal cancer: a promising therapeutic strategy. AB - OBJECTIVE: The objective of this study is to investigate the mechanism of resveratrol (RSVL) on the inhibitory effect on the expression of COX-2 in human colorectal cancer. MATERIALS AND METHODS: In this study, we used the HCT-116 cells as the observation group, and the normal cells as the control group. The inhibitory effect induced by RSVL on the COX-2 expression in human colorectal cancer was investigated. For the observation group, cells were cultured in the nutrition solution with RSVL, while the cells in both control group (normal colon epithelial cells) and blank control group (none-treated HCT-116 cells) were cultured in the regular nutrition solution. We assayed the mRNA expression and the protein expression of COX-2 in different groups using Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot methods, respectively. Also, we measured the cell growth and apoptosis in different treatment groups by using methyl thiazolyl tetrazolium assay (MTT) method, and detected the differences in COX-2 expression among different groups through immunohistochemistry staining RESULTS: Compared with blank control group, the rate of cell proliferation in the observation group treated with RSVL was significantly reduced. The results of RT qPCR revealed that the mRNA expression of COX-2 of the observation group was affected compared with the blank control group. According to the results from enzyme-linked immunosorbent assay (ELISA) and Western blot, the expression of the COX-2 protein in the observation group treated with RSVL was significantly lower than that in the blank control group; however, results from the observation group and the control group were similar. Also, the immunohistochemistry results showed the positive rate of COX-2 expression in the observation group was significantly lower than that in the control group. CONCLUSIONS: RSVL (in a certain concentration) can suppress the human colorectal cancer through inhibition of COX 2 expression. PMID- 28338177 TI - 5-Aminolevulinic acid photodynamic therapy stimulates local immunity in patients with condylomata acuminata via activation of T lymphocytes. AB - OBJECTIVE: 5-Aminolevulinic acid photodynamic therapy (5-ALA-PDT) for condylomata acuminate (CA) is effective and safe, but how this treatment affects immune reaction is poorly understood. We aimed to explore the effects of PDT on local immunity in CA. PATIENTS AND METHODS: Immunohistochemical analysis before and after PDT was performed to analyze local changes in the distribution of T lymphocytes, CD123+ plasmacytoid dendritic cells (pDCs) and CD1a+ myeloid DCs. Quantitative Real-time PCR (qRT-PCR) was used to detect changes in mRNA levels of interferon (IFN), ISG-15, Mx-2, TLR9, and IRF7. RESULTS: Compared to the healthy foreskin, tissue from patient showed increased CD3+ and CD8+ cells but no significant changes in CD4+ cells or CD123+ pDCs, and a significantly decreased CD1a+ Langerhans cells (LCs). Twenty-four hours after a PDT session, local CD3+, CD4+, and CD123+ pDCs in lesions significantly increased and migrated to the superficial dermis. CD1a+ LCs in the epidermis gradually decreased, while DCs gradually increased. The number, distribution, and morphology of CD8+ cells did not change after a PDT session. The mRNA expressions of IFN-gamma, IFN-alpha, IFN beta, ISG-15, Mx-2, TLR9, and IRF7 were all elevated. As compared to the patients without significantly increased IFN-a and IFN-b after a PDT session, patients with significant increases needed fewer sessions of PDT for a cure. CONCLUSIONS: These results suggest that PDT for CA can activate T-lymphocyte-meditated immunity, and pDC-related immunity is also activated. The clinical efficacy of 5 ALA-PDT against CA may be related to the increased IFN-alpha and IFN-beta after treatment. PMID- 28338178 TI - The involvement of senescence induced by the telomere shortness in the decline of osteogenic differentiation in BMSCs. AB - OBJECTIVE: BMSC (Bone marrow mesenchymal stem cells) is an important seed cell for the repair of bone and cartilage defect in the tissue engineering. The proliferation rate and differentiation capacity of BMSCs from the old donors were less than that from young donors; however, the related mechanism remained unclear. MATERIALS AND METHODS: Sprague Dawley (SD) rats BMSCs were cultured and treated. Hydrogen peroxide (H2O2) and continual passage of BMSCs were performed to induce senescence. Senescence was detected by the SA-b-Gal staining and the telomere length analysis. Cell proliferation and osteogenic differentiation were also observed. Finally, Olaparib was used to maintain the telomere length and investigate the role of telomere length and senescence on the cell proliferation and differentiation. RESULTS: H2O2 could increase the positive rate of SA-b-Gal staining in BMSCs and shorten the length of the telomere. The proliferation rate and ALP activity were also decreased by the H2O2. The senescence and decline of osteogenic differentiation could also be observed after prolonged passage of BMSCs. Inhibition of telomere length decline could attenuate the increased positive rate of SA-b-Gal staining induced by the H2O2, promote the cell proliferation, and enhance the capacity of osteogenic differentiation. CONCLUSIONS: Senescence induced by the decline of telomere length could reduce the capacity of osteogenic differentiation and inhibit cell proliferation in BMSCs. PMID- 28338179 TI - Effect of dexmedetomidine on immune function of patients undergoing radical mastectomy: a double blind and placebo control study. AB - OBJECTIVE: To observe and evaluate the effect of dexmedetomidine on the perioperative immune function of patients undergoing a radical mastectomy. PATIENTS AND METHODS: 124 patients undergoing radical mastectomy were divided into the observation group (treated with dexmedetomidine) and the control group (treated with saline) by randomized digital table and double blinded and randomized design. 10 min before anesthesia induction, the patients in the observation group were injected with dexmedetomidine 0.1 ug.kg-1.min-1. The injection of 0.9% sodium chloride solution was given to the control group at the same rate. In the experiment, the medications of anesthesia induction and anesthesia maintain were identical. Venous blood at five times: T0 (before anesthesia), T1 (6 h after surgery), T2 (24 h after surgery), T3 (48 h after surgery), T4 (72 h after surgery) were collected. ELISA (Enzyme Linked Immunosorbent Assay) was used to detect concentrations of IL-2, IFN-gamma, IL-4, IL-6 and IL-10; FACS flow cytometry was used to determine the level of T lymphocyte subsets (CD3+, CD4+, CD8+) and NK cells. RESULTS: Compared with the control group, the cell levels of CD3+ and CD4+ in the observation group rose remarkably at T3 and T2 (p<0.05). The cell level of CD8+ fell at T2 with significant difference; NK cell level increased noticeably at T1 and T2, and CD4+/CD8+ rose dramatically at all postoperative time points. Obviously, the patients' immune function, to some extent, has been affected; in addition, the concentration of INF-gamma in observation group increased prominently at T1, T2 and T3 (p<0.05), and the concentration of IL-2 at T2, IL-10 at T1 and T2, and IL 6 at T2 and T3 in the observation group all rose significantly (p<0.05), and less cytokine Th1 drifted to Th2. CONCLUSIONS: The dexmedetomidine can effectively maintain the homeostasis of cell immune function of patients undergoing a radical mastectomy. PMID- 28338180 TI - Influence of dexmedetomidine to cognitive function during recovery period for children with general anesthesia. AB - OBJECTIVE: We studied the influence of Dexmedetomidine on cognitive function in children during the recovery period of general anesthesia. PATIENTS AND METHODS: Ninety-three children who underwent general anesthesia were selected and randomly divided into (1) the control group, (2) the dexmedetomidine group, and (3) the dezocine group. Fentanyl, propofol, and rocuronium were used in all patients to induce anesthesia, while sevoflurane inhalation and propofol were used to maintain anesthesia. In the control group, 20 ml NS were infused intravenously 10 min before anesthetic induction. In the dexmedetomidine group, 1.0 MUg/kg dexmedetomidine in 20 ml was infused for 10 min. In the dezocine group, 0.1 mg/kg dezocine in 20 ml was infused for 10 min. Mean arterial blood pressure, average heart rate, and average oxygen saturation (SaO2) were compared at the following time points: end of surgery (T0), before extubation (T1), during extubation (T2), and 30 min after extubation (T3). The VAS scale, Ramsay sedation score, delirium grading scale and occurrence of adverse reactions at 30 min after extubation were recorded. The occurrence of postoperative cognitive dysfunction (POCD) and the expression of serum neuron-specific enolase (NSE) and IL-6 at postoperative days 1 and 7 were recorded. RESULTS: Comparing mean arterial blood pressure, average heart rate, and average oxygen saturation (SaO2) at the different time points in the dexmedetomidine group, there were no statistically significant differences (p>0.05). The difference in the occurrence of adverse reactions in the different groups was statistically significant (p<0.05). The occurrence of postoperative cognitive dysfunction (POCD) at postoperative day 1 was significantly higher in the control group than the other two groups (p<0.05), and on the postoperative day 7th, the differences were not statistically significant (p>0.05). Regarding the expression of neuron-specific enolase (NSE) and IL-6, the levels were the highest in the control group, followed by the dezocine group (p<0.05). CONCLUSIONS: The dexmedetomidine is safer than dezocine in aspects of hemodynamics, sedation, analgesia, degree of delirium, occurrence of adverse reactions, and postoperative cognitive dysfunction (POCD). The improvement in the occurrence of postoperative cognitive dysfunction (POCD) is related to the levels of serum neuron-specific enolase (NSE) and IL-6. PMID- 28338181 TI - Gene expression of inflammatory markers in adipose tissue between obese women with polycystic ovary and normal obese women. AB - OBJECTIVE: The pathogenesis of polycystic ovary syndrome (PCOS), a common endocrine disease and metabolic disturbance, is still unknown. The aim of the study was to investigate whether patients with PCOS display increased expression of inflammatory markers in adipose tissue. PATIENTS AND METHODS: Two groups of women were investigated, those diagnosed with PCOS (n = 8) and age and BMI matched normal women (n = 12). Their age was between 20-45 years and all subjects were apparently healthy and did not take any medications. Adipose tissue levels of mRNA of inflammatory markers were determined by use of real-time PCR. RESULTS: There were no differences between obese patients and obese PCOS in levels of adipocytokines. CONCLUSIONS: There were no effects of PCOS on the expression of any of the adipocytokines genes measured in subcutaneous adipose tissue. PMID- 28338182 TI - microRNA-199a-5p mediates high glucose-induced reactive oxygen species production and apoptosis in INS-1 pancreatic beta-cells by targeting SIRT1. AB - OBJECTIVE: Hyperglycemia-induced pancreatic beta-cell loss is a pathologic hallmark of type 2 diabetes mellitus (T2DM). This study was conducted to clarify the function of microRNA (miR)-199a-5p in high glucose-elicited beta-cell toxicity and associated molecular mechanisms. MATERIALS AND METHODS: INS-1 rat pancreatic beta-cells were cultured under normal (11 mM) or high (30 mM) glucose for 16-72 h and examined for miR-199a-5p expression. Gain and loss-of-function studies were performed to determine the role of miR-199a-5p in high glucose induced apoptosis and reactive oxygen species (ROS) production. Additionally, the involvement of SIRT1 in the action of miR-199a-5p was checked. RESULTS: High glucose caused a significant upregulation of miR-199a-5p in INS-1 cells compared to cells under normal glucose conditions. Pre-transfection with anti-miR-199a-5p inhibitors prevented the reduction in cell viability and inhibited ROS generation in INS-1 cells after high glucose treatment. In contrast, overexpression of miR 199a-5p significantly reduced cell viability and promoted apoptosis and ROS formation in INS-1 cells, which was coupled with a downregulation of SIRT1. Knockdown of SIRT1 led to apoptotic death in INS-1 cells. Moreover, enforced expression of SIRT1 blocked miR-199a-5p-induced ROS generation and attenuated high glucose-mediated apoptosis in INS-1 cells. CONCLUSIONS: miR-199a-5p is upregulated in pancreatic beta-cells in response to high glucose and promotes apoptosis and ROS generation by targeting SIRT1. The miR-199a-5p/SIRT1 axis may represent a promising target for the treatment of T2DM. PMID- 28338183 TI - Psychogenic convergence spasm mimicking ocular myasthenia. AB - A 14-year-old girl presented with a two-years history of fluctuating convergent strabismus, diplopia, and reading difficulty. She has been previously diagnosed by experienced neurologists as having ocular myasthenia and she had been treated for two years with anticholinesterase inhibitors and immunomodulatory drugs. After a thorough medical interview and neurological examination, a diagnosis of psychogenic convergence spasm was made. The patient was then reassured and the symptoms immediately disappeared. She also had psychotherapy and maintained a condition of sustained freedom from symptoms. PMID- 28338184 TI - MicroRNA-370-3p inhibits human vascular smooth muscle cell proliferation via targeting KDR/AKT signaling pathway in cerebral aneurysm. AB - OBJECTIVE: Cerebral aneurysm is a common vascular disease with high morbidity and mortality. Vascular smooth muscle deletion or dysplasia is an important reason for the development of cerebral aneurysm. MiRNAs participate in a variety of biological functions through inhibiting target gene translation. The aim of the present study was to evaluate the role of miRNAs in the regulation of vascular smooth muscle cell proliferation. MATERIALS AND METHODS: MiRNA and mRNA expressions were tested by Real-time PCR. Cell cycle was detected by flow cytometry. Cell viability was evaluated by MTT assay. HUASMC cell proliferation was determined by BrdU assay. Protein expressions were determined using Western blot. MiRNA target gene was confirmed by luciferase assay. RESULTS: MiR-370-3p expression was increased in cerebral aneurysm tissues. Ectopic expression of miR 370-3p suppressed proliferation of vascular smooth muscle cells and blocked cell cycle. Numerous cell proliferation and apoptosis-related factors were down regulated by miR-370-3p. Results of target prediction database and dual luciferase assay revealed that KDR is a direct target of miR-370-3p. Importantly, FOXO1 activity and AKT and FOXO1 phosphorylation were inhibited by miR-370-3p. We suggest that miR-370-3p directly targets KDR, resulting in the activation of AKT signaling pathway. CONCLUSIONS: MiR-370-3p was involved in the development of cerebral aneurysm by targeting KDR and blocking AKT/FOXO1 signaling pathway. The results provide theoretical basis for further investigation of potential clinical prevention and treatment of cerebral aneurysm. PMID- 28338185 TI - A structured blood conservation program in pediatric cardiac surgery. AB - OBJECTIVE: The limitation of alternative transfusion practices in infants increases the benefits of blood conservation. We analyzed the efficacy of a structured program to reduce transfusions and transfusion-associated complications in cardiac surgery PATIENTS AND METHODS: Our pediatric surgery database was reviewed retrospectively, comparing outcomes from two different time periods, after the implementation of an effective blood conservation program beginning in March 2014. A total of 214 infants (8.1+/-3.4 months) who underwent biventricular repair utilizing CPB (Group 1 - Blood conservation) were studied in a 12-month period (March 2014-February 2015) after the implementation of the new program, and compared with 250 infants (7.91+/-3.2 months) (Group 2 - Control-No blood conservation) of the previous 12-month period (March 2013-February 2014). RESULTS: The proportion of patients transfused with red blood cells was 75.2% (N=188) in control group and reduced by 16.4% in the study group (58.8% - 126 patients, p <0.01). The mean number of transfusions was 1.25 +/- 0.5 units per patient in control group and decreased to 0.7 +/- 0.5 units per patient after the start of the program (p = 0.035). Cerebral oximetry demonstrated better follow-up during the operative period confirming less hemodilution in Group 1. Respiratory support, inotropic need and ICU stay were significantly better in the study group. CONCLUSIONS: These findings, in addition to attendant risks and side effects of blood transfusion and the rising cost of safer blood products, justify blood conservation in pediatric cardiac operations. Circuit miniaturization, ultrafiltration, and reduced postoperative bleeding, presumably secondary to higher fibrinogen and other coagulation factor levels, contributed to this outcome. PMID- 28338186 TI - Increase in G protein-coupled receptor autoantibodies with decline of cardiac function in hypercholesterolemic rats. AB - OBJECTIVE: This study aimed to explore the effects of diet-induced hypercholesterolemia (HC) on the production of G protein-coupled receptor autoantibodies and to elucidate the potential mechanisms involved. MATERIALS AND METHODS: Male Wistar rats were fed a normal or high-cholesterol diet for 8 weeks. Cardiac function, autoantibodies against G protein-coupled receptors, the beat frequency of neonatal cardiomyocytes, the CD4+/CD8+ T-lymphocyte ratio and lymph leukocyte counts in the spleen were determined. RESULTS: Diet-induced hypercholesterolemia significantly increased the levels of autoantibodies against alpha1- and beta1-adrenergic receptors and the angiotensin II type 1 receptor in sera, as well as the CD4+/CD8+ T-lymphocyte ratio and lymph leukocyte count in the spleen, and decreased cardiac function. There were strong negative correlations between the levels of autoantibodies and cardiac injury. CONCLUSIONS: The present study demonstrates, for the first time, that G protein coupled receptor autoantibodies exist in the sera of hypercholesterolemic rats and that the levels of these autoantibodies are related to cardiac function, which implies that these cardiac receptor autoantibodies may play a role in cardiac dysfunction in hypercholesterolemic rats. PMID- 28338187 TI - The predictive value of baseline LDL-TG level on major adverse cardiovascular events in a followed up cohort population. AB - OBJECTIVE: We aimed at identifying the predictive roles of Low-Density Lipoprotein Triglycerides (LDL-TG) for major adverse cardiovascular events (MACEs). PATIENTS AND METHODS: A longitudinal study in a routine health check-up population was performed with an average follow-up of 4.8 years. The participants involved in this study were 1680, from 2007 to 2009, and all had followed-up for all-cause mortality, cardiovascular disease mortality, and the development of MACEs. The demographic information and anthropometric parameters at baseline were recorded. The baseline and follow-up conventional lipid parameters were measured. We also examined the level LDL-TG, as well as the relationship between its level and MACEs. RESULTS: MACEs individuals were characterized by statistically higher baseline LDL-TG (17.22 +/- 8.05 vs. 16.39 +/-7.35 nmol/l, p = 0.017). The univariate regression for MACEs group indicated that the LDL-TG (b = 0.813, HR = 2.254, 95% CI: 1.454-3.494, p < 0.001), older age, sex and other factors were a significant risk for MACEs. Furthermore, in the adjusted Cox model showed that only higher baseline LDL-TG (b =0.512, HR = 1.669, 95% CI: 1.013-2.748, p = 0.044) and older age (b = 0.062, HR = 1.064, 95% CI: 1.034-1.094, p < 0.001, Table IV) were still predictors for MACEs. CONCLUSIONS: Higher baseline LDL-TG closely associated with MACEs and it is a moderate and independent predictive factor for MACEs. PMID- 28338188 TI - Implication of peripheral blood miRNA-124 in predicting acute myocardial infarction. AB - OBJECTIVE: This study aimed to determine the expression of miR-124 in the patients with acute myocardial infarction (AMI) and elucidated the role of miR 124 on early diagnosis of AMI. PATIENTS AND METHODS: A total of 90 AMI patients were recruited, along with 45 healthy individuals as the control group. Blood samples were collected at different time points (0 h at admission, 6 h, 12 h and 24 h of disease onset). Real-time PCR was used to test miRNA-124 level. ELISA was used to test serum troponin (cTnI) and creatine kinase-MB isoenzyme (CK-MB) levels. The correlation between miRNA-124, cTnI and CK-MB was analyzed. Receiver operating characteristic curve (ROC) was used to analyze sensitivity and specificity of AMI. RESULTS: MiRNA-124 expression in experimental group was significantly elevated in peripheral blood of AMI patients. It can reach the peak at 6h after onset. AMI patients had significantly elevated cTnI and CK-MB expression level (p<0.05 compared to control group). The expression of miRNA-124 reached the peak earlier than cTnI and CK-MB. miRNA-124 was positively correlated with cTnI and CK-MB (p<0.05). The area under the curve of ROC of miRNA-124 was 0.86 (95% CI: 0.815-0.937), with 52% sensitivity and 91% specificity. CONCLUSIONS: AMI patients presented a significantly elevated level of miRNA-124 in peripheral blood. Our data suggested that miR-124 contributed to an earlier detection than other diagnostic markers for AMI. Therefore, peripheral miRNA-124 can serve as a novel biological marker for early diagnosis of AMI. PMID- 28338189 TI - Research progress about effects of myocardial enzyme and troponin on uremia with acute left ventricular failure. AB - OBJECTIVE: We studied the diagnostic value of CK-MB and troponin (cTnI) in uremia with acute left ventricular failure patients. PATIENTS AND METHODS: We enrolled 130 uremia patients with maintenance hemodialysis (MHD) and divided them into two groups: (i) the observation group with patients suffering from acute left ventricular failure (n=30) and (ii) the control group which contained cases without acute left ventricular failure (n=100). We verified CK-MB, cTnI, serum creatinine, blood urea nitrogen, pro-BNP and LVEF levels at 6 h, 12 h, 24 h, 48 h, 72 h, 7 d and 14 d after the attack and carried out 1-year follow-up to compare total mortality and cardiogenic mortality. RESULTS: Our results showed that CK-MB and cTnI levels in the observation group were significantly higher than those in the control group (p<0.05). CK-MB and cTnI in the observation group increased into platform stage slowly with no peak or downtrend. They were in a linear pattern in the control group. Comparison of SCr and BUN in two groups at different time points produced no statistically significant differences (p>0.05). Pro-BNP levels in the hospital as well as 1 month, 6 months and 12 months follow ups were higher than those in the control group, and differences were of statistical significant (p<0.05). While in hospital LVEF level in the observation group was higher than that in the other group, differences regarding 1 month, 6 months and 12 months follow-up between two groups had no statistical significance (p>0.05). Total mortality and cardiogenic mortality in the observation group were higher than those in the control group, and differences were statistically significant (p<0.05). CONCLUSIONS: CK-MB, cTnI, SCr, BUN, pro-BNP and LVEF were independent risk factors for total mortality while CK-MB, cTnI and pro-BNP were independent risk factors for cardiogenic mortality. PMID- 28338190 TI - The role of miR-146a in modulating TRAF6-induced inflammation during lupus nephritis. AB - OBJECTIVE: Lupus nephritis (LN) is a major complication of systemic lupus erythematosus (SLE). A previous study showed decreased expression level of microRNA (miR)-146a in LN patients, indicating its possible role in LN pathogenesis. PATIENTS AND METHODS: A total of 98 LN patients were recruited, for the collection of renal tissue samples during biopsy or surgery. Another cohort of 15 patients who had renal tumor resection was recruited as the control group, for the further comparison of expression levels of miR-146a, TRAF6 and p-p65 in tissues. Human glomerular mesangial cells were treated with miR-146a mimics, si TRAF6 or both, followed by the evaluation of p65, p-p65, IL-1beta, IL-6, IL-8 and TNF-alpha. Transwell assay was performed to detect the effect of mesangial cells on chemotaxis of macrophage. RESULTS: MiR-146a expression was significantly depressed in renal tissues of LN patients, while TRAF6 expression, macrophage infiltration and p-p65 expression were all elevated as the activity of LN was induced. The up-regulation of miR-146a and/or down-regulation of TRAF6 can significantly inhibit NF-kappaB transcriptional activity of glomerular mesangial cells, while the gene expressions of IL-1beta, IL-6, IL-8 and TNF-alpha were suppressed. CONCLUSIONS: The expression of miR-146a in renal tissues of LN patients was significantly depressed, while the transcriptional activity of TRAF6 and NF-kappaB was enhanced. MiR-146 thus inhibited NF-kappaB transcriptional activity and inflammatory factor synthesis, and alleviated chemotactic effect towards macrophage via the inhibition of TRAF6 activity. PMID- 28338191 TI - A randomized single-center study to compare the efficacy and tolerability of tadalafil once daily plus lidocaine anesthetic spray on premature ejaculation. AB - OBJECTIVE: The use of topical local anesthetics in the form of creams, gel or spray is the oldest method of retarding ejaculation. However, several studies have suggested that phosphodiesterase type 5 inhibitors (5-PDEiS) show a potential therapeutic use in the treatment of premature ejaculation (PE). The aim of this study was to compare the efficacy and tolerability of tadalafil-only, tadalafil plus local anesthetic spray (lidocaine), and topical lidocaine spray only before intercourse on the intravaginal ejaculatory latency time (IELT) of patients with lifelong PE. PATIENTS AND METHODS: The study included 78 men in stable heterosexual, monogamous relationships (of >=3 months) who were diagnosed with lifelong PE. The patients were divided into three groups: G1: 25 patients who received lidocaine spray 10 g/100 ml at 5 min before intercourse; G2: 27 patients who received tadalafil 5 mg once daily; G3: 26 patients who treated with tadalafil once daily plus lidocaine spray before planned sexual activity. The treatments were continued for up to three months in all groups. Moreover, the quality of their sexual attempts was rated on a 5-point scale. Follow-up was made at 1-month and 3-month. RESULTS: Not statistically significant differences emerged between the three groups at baseline. Mean ejaculatory latency time at the 3-month follow-up in G1, G2 and G3 was 3.7+/-1.3, 3.4+/-1.5, 5.6+/-1.7 (p<0.001). Mean satisfaction score was at the 3-month follow-up in G1: 2.8+/-1.4, in G2: 2.9+/-1.8, and G3: 3.7+/-1.5 (p<0.002). None of the patients withdrew from the study because of these adverse events. CONCLUSIONS: This study demonstrates that tadalafil used daily has a role on treatment in lifelong PE. This action is valid when combined strategically to the synergistic action of lidocaine spray applied before intercourse increasing significantly the mean IELT. PMID- 28338192 TI - Application of percutaneous epididymal sperm aspiration in azoospermia. AB - OBJECTIVE: The present study introduces the application of percutaneous epididymal sperm aspiration (PESA) for diagnosis of obstructive azoospermia and non-obstructive azoospermia. PATIENTS AND METHODS: 96 cases diagnosed with azoospermia were selected, standard methods were used to measure testicular volume, chemiluminescence was used to test serum sexual hormone levels, and No. 7 butterfly needles were applied to puncture the head of the epididymis and aspirate epididymal luminal fluid. RESULTS: Among 96 cases of azoospermia, sperm was found in the epididymal luminal fluid of 49 cases, among which there were 41 cases with normal testicular volume and 8 cases with low volume. 39 cases had normal serum FSH levels, and 10 cases had increased serum FSH levels. There were 47 cases with no sperm, among which there were 26 cases with normal testicular volume and 21 cases with low volume. 29 cases had normal serum FSH levels, and 18 cases had increased levels. The success rate of puncture for patients with normal testicular volume was higher than that of patients with low volume, and the difference was statistically significant (p < 0.05). The success rate of puncture for patients with normal serum FSH levels was higher than that of patients with increased levels, and the difference was statistically significant (p < 0.05). CONCLUSIONS: PESA is simple and efficient, and is a feasible method for diagnosis of azoospermia. PMID- 28338193 TI - Oncogenic miR-155 down-regulated upon activation of antitumor cytotoxic T lymphocytes by the fusion of dendritic cells with breast carcinoma cells. AB - OBJECTIVE: MicroRNAs has been proved to play vital roles in many biological processes. In the present study, the expression profile of oncogenic miR-155 in the activated antitumor cytotoxic T lymphocytes generated by the fusion of dendritic cells with breast carcinoma cells has been demonstrated. MATERIALS AND METHODS: Expression profile of oncogenic miR-155 was noted in antitumor cytotoxic T lymphocytes, which was generated by the fusion of dendritic cells (DC) with breast carcinoma cells (MCF-7). The fused cells were used to induce and generate antitumor CTL with the standard procedure. Flow cytometry, as well as qPCR analysis, were performed to identify the expression profile of oncogenic miR-155 in the generated antitumor CTL against breast cancer. RESULTS: Compared with controls, the presence of MUC-1 and MHC-II in the DC/MCF-7 fused cells was confirmed by flow cytometry analysis. qPCR experimental results conclude that oncogenic miR-155 level was decreased in the antitumor CTL generated against breast cancer cells. CONCLUSIONS: We observed that the oncogenic miR-155 level was down-regulated in the antitumor CTL against breast cancer, and it may be used as the effective treatment to eliminate the malignant cells in the breast cancer patients. PMID- 28338194 TI - lncRNA NEAT1 is closely related with progression of breast cancer via promoting proliferation and EMT. AB - OBJECTIVE: Breast cancer (BC) is one of the most common cancers in females. Abnormal proliferation and metastasis are key reasons that cause mortality in BC patients. More and more evidence showed that lncRNA played an important role in the BC development, but the mechanism was not well established. PATIENTS AND METHODS: The expression of lncRNA NEAT1 was detected in 40 BC patients by qRT-PCR technology. MTT and Wound Healing assays were applied to detect the effect of lncRNA NEAT1 in proliferation and metastasis in BC. Western blot was used to detect possible protein, which was regulated by lncRNA NEAT1. RESULTS: lncRNA NEAT1 was highly expressed in BC tissue, and the expression was also closely related to the tumor size and lymph node metastasis. Survival study also showed that the expression of lncRNA NEAT1 was closely related with prognosis of BC patients. MTT and Wound Healing assays showed that suppression of lncRNA NEAT1 could lead to decreased proliferation and metastasis in BC cell lines. Western blot also showed that beta-catenin and N-cad were decreased while E-cad was increased after lncRNA NEAT1 being suppressed. CONCLUSIONS: lncRNA NEAT1 may act as an oncogene in BC, which can promote proliferation and metastasis of BC. PMID- 28338195 TI - TGF-beta1 promotes human gastric carcinoma SGC7901 cells invasion by inducing autophagy. AB - OBJECTIVE: To investigate the role of TGF-b1 in autophagy and invasion ability in human gastric carcinoma cell line SGC7901. MATERIALS AND METHODS: Cultured SGC7901 cells were treated with different concentrations of TGF-b1 for 24 h. The protein expression levels of autophagy relative marker LC3 and Beclin1 were detected by Western blot. The effect of TGF-b1 on invasion ability of SGC7901 cells was detected with transwell method. RESULTS: The results demonstrated that TGF-b1 was able to induced autophagy of SGC7901 cells in a dose-dependent manner. Autophagy inhibitor 3-MA could inhibit TGF-b1 upregulated autophagy. Furthermore, TGF-b1 significantly enhances the invasion ability of SGC7901 cells. However, autophagy inhibitor 3-MA could effectively reverse this process. CONCLUSIONS: TGF b1 enhances SGC7901 cells migration by inducing autophagy. PMID- 28338196 TI - Study on the proliferation of human gastric cancer cell AGS by activation of EGFR in H2O2. AB - OBJECTIVE: This study is to investigate the effect of low concentration hydrogen peroxide (H2O2) on the proliferation of gastric cancer AGS cell line in vitro and the mechanism. MATERIALS AND METHODS: AGS cells were treated with different low concentrations of H2O2 (1, 0.1, 0.01, and 0.001 MUm) for 48 hours. The effect of H2O2 concentration gradient on the activity of AGS cell activities was detected by methyl thiazolyl tetrazolium (MTT) method. The expression of the epidermal growth factor receptor (EGFR) and its downstream signaling pathway extracellular signal-regulated kinase (ERK) protein in H2O2 was detected by Western blot method; moreover, the effect of H2O2 on intracellular reactive oxygen species (ROS) in AGS cells was observed under the fluorescence microscope and quantitative analysis by flow cytometry. The effect of H2O2 on the level of c-myc mRNA in AGS cells was also detected by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: MTT detection results showed that 1 MUm and 0.1 MUm H2O2 at 48h can effectively promote the proliferation of AGS cells (p<0.05). The Western blot results showed that after 48 hours of low concentration of H2O2 treatment of AGS cells, the EGFR protein levels and ERK protein phosphorylation levels increased significantly (p<0.05). Fluorescence microscopy and flow cytometry showed that the low concentration of H2O2 increased the intracellular reactive oxygen species (ROS). RT-PCR results showed the levels of c-myc mRNA in AGS cells treated with a low concentration of H2O2 were significantly increased (p<0.05) and EGFR blocking agent AG1478 can resist the above effects. CONCLUSIONS: Low concentration of H2O2 can significantly promote the proliferation of AGS cells by activating EGFR/ERK signaling pathway. PMID- 28338197 TI - Predictive value and modeling analysis of MSCT signs in gastrointestinal stromal tumors (GISTs) to pathological risk degree. AB - OBJECTIVE: By analyzing MSCT (multi-slice computed tomography) signs with different risks in gastrointestinal stromal tumors, this paper aimed to discuss the predictive value and modeling analysis of MSCT signs in GISTs (gastrointestinal stromal tumor) to pathological risk degree. PATIENTS AND METHODS: 100 cases of primary GISTs with abdominal and pelvic MSCT scan were involved in this study. All MSCT scan findings and enhanced findings were analyzed and compared among cases with different risk degree of pathology. Then GISTs diagnostic model was established by using support vector machine (SVM) algorithm, and its diagnostic value was evaluated as well. RESULTS: All lesions were solitary, among which there were 46 low-risk cases, 24 medium-risk cases and 30 high-risk cases. For all high-risk, medium-risk and low-risk GISTs, there were statistical differences in tumor growth pattern, size, shape, fat space, with or without calcification, ulcer, enhancement method and peritumoral and intratumoral vessels (p<0.05). However, there were no statistical differences in the location of tumor and CT value at each period (plain scan, arterial phase, venous phase) (p>0.05). The apparent difference lied in plain scan, arterial phase and venous phase for each risk degree. The diagnostic accuracy of SVM diagnostic model established with 10 imaging features as indexes was 70.0%, and it was especially reliable when diagnosing GISTs of high or low risk. CONCLUSIONS: Preoperative analysis of MSCT features is clinically significant for its diagnosis of risk degree and prognosis; GISTs diagnostic model established on the basis of SVM possesses high diagnostic value. PMID- 28338198 TI - The expression of SIRT3 in primary hepatocellular carcinoma and the mechanism of its tumor suppressing effects. AB - OBJECTIVE: To observe the SIRT 3 expression in primary hepatocellular carcinoma (HCC), and then establish the eukaryotic expression vector of SIRT3 to observe the proliferation and apoptosis of pZsGreen-c1-SIRT3 HepG2 cells. Furthermore, we explored the mechanism of SIRT3 in inhibiting HCC. PATIENTS AND METHODS: Immunohistochemistry was used to detect the expression of SIRT3 in the tumor tissue and para-tumor tissue in 32 patients with HCC and the normal liver tissue in 10 patients. The mRNA of SIRT3 from the normal liver tissue was used as a template, reverse transcription-polymerase chain reaction (RT-PCR) was used to obtain the total sequence of SIRT3 gene, and then the gene was cloned and combined with vector pZsGreen-c1, liposome transfection technology was used to transfect the recombined plasmid into HepG2. The cells were divided into three groups: group A (HepG2 cells as a blank control group), group B (pZsGreen-c1 HepG2 cells as an experimental control group) and group C (pZsGreen-c1-SIRT3 HepG 2 cells as an experimental group). MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl 2-H-tetrazolium bromide) assay was used to detect the growth and proliferation of cells in 3 groups; annexinV/PI double staining was used to detect the apoptotic rates of cells in 3 groups. Western blot was used to detect the protein expression of SIRT3, Fas, Bax and P53, and water-soluble tetrazolium salt (WST-1) was used to detect MnSOD content in 3 groups. RESULTS: Immunohistochemistry results showed that SIRT3 in the tumor tissue sample was positive in 19 patients out of 32 HCC patients; however, there was no strong positive case, the positive rate of SIRT3 expression was 59.38% (19/32). SIRT3 in the para-tumor tissue was positive in 31 HCC patients, the positive rate was 96.88% (31/32), and 18 cases were strongly positive; SIRT3 in normal liver tissue was positive in all 10 cases, the positive rate was 100.0% (10/10), and 7 cases were strongly positive. The differences of SIRT3 positive rate and positive score in tumor tissue from para-tumor tissue and normal liver tissue were statistically significant (p<0.05). However, the differences between para-tumor tissue and normal liver tissue were not statistically significant (p>0.05). After pZsGreen-c1-SIRT3 transfection, MTT results showed that the OD values in 3 groups were increased with the time, showing time-dependent manner. At 48 h after culture, the OD values in-group C were significantly different from group A and B, and the inhibitory rates were statistically different (p<0.05). After 48 h, the OD values and inhibitory rates in-group C showed that the cells were obviously inhibited, and the inhibitory rates were increased with the time, showing time-dependent manner. Flow cytometry results showed that the cell numbers of early stage apoptosis and late stage apoptosis were significantly increased in group C, which was significantly higher than group A and B, the differences were statistically significant (p<0.01). Western blot results showed that expression levels of SIRT3, p53, Bax and Fas were not different between group A and B (p>0.05); SIRT3, p53, Bax and Fas in group C were significantly increased, which were statistically higher than group A and B (p<0.01). WST-1 results showed that MnSOD contents were not statistically different between group A and B (p>0.01). MnSOD content in-group C was significantly higher than the other groups, which were statistically significant (p<0.01). CONCLUSIONS: SIRT3 shows low expression or deficiency in HCC tissue, indicating that SIRT3 expression can affect the occurrence and development of HCC. SIRT3 can inhibit the growth and proliferation of HepG2 cells and induce HepG2 cell apoptosis. The mechanism may be related to the up-regulation of MnSOD and p53, the up-regulation of Bax and Fas by MnSOD. PMID- 28338199 TI - MiR-576-3p is a novel marker correlated with poor clinical outcome in bladder cancer. AB - OBJECTIVE: MicroRNAs play important roles in the regulation of the initiation and progression of bladder cancer. To our best knowledge, the prognostic value of miR 576-3p in bladder cancer has not been reported. Thus, the purpose of the current study was to determine the expression of miR-576-3p and assess the clinical significance of miR-576-3p in bladder cancer. PATIENTS AND METHODS: Quantitative real-time polymerase chain reaction (RT-PCR) was performed to evaluate miR-576-3p levels in 232 pairs of bladder cancer specimens and adjacent noncancerous tissues. The association of miR-576-3p expression with clinicopathological factors was statistically analyzed. Overall survival was calculated and survival curves were plotted using the Kaplan-Meier method. The influence of each variable on survival was examined by the Cox multivariate regression analysis. RESULTS: Our data showed that the expression of miR-576-3p was significantly decreased in bladder cancer tissue compared with matched bladder tissues (p < 0.01). Low miR 576-3p expression level was significantly associated with advanced tumor stage (p = 0.004), lymph node metastasis (p = 0.027), and recurrence (p = 0.018). The results of Kaplan-Meier survival analysis showed that patients with low miR-576 3p expression presented shorter mean months of overall survival than patients with high miR-576-3p expression (p < 0.0001). Finally, the univariate and multivariate analysis showed that miR-576-3p expression was an independent prognostic marker of overall survival of bladder cancer patients. CONCLUSIONS: Our results demonstrated that down expression of miR-576-3p in bladder cancer was associated with an unfavorable prognosis, and miR-576-3p might be clinically applicable as an indicator of favorable prognosis. PMID- 28338200 TI - Glioma cells promote angiogenesis through the release of exosomes containing long non-coding RNA POU3F3. AB - OBJECTIVE: Angiogenesis is a key event in the progression of gliomas, and emerging evidence suggests that exosomes are signaling extracellular organelles that modulate the tumor microenvironment and promote angiogenesis and tumor progression. This study aimed to explore the mechanism by which glioma-derived exosomes affect angiogenesis. MATERIALS AND METHODS: qRT-PCR was used to determine the expression level of linc-POU3F3 in glioma tissue as well as glioma cell lines. Ultrafiltration combined with a purification method was used to isolate exosomes derived from A172 cells (A172-Exo) and linc-POU3F3 shRNA-treated A172 cells (shA172-Exo). Transmission electron microscopy, Western blot and tunable resistive pulse sensing (TRPS) were used to identify exosomes. In vitro migration, proliferation, and tube formation experiments, as well as in vivo CAM assays, were used to analyze the pro-angiogenesis ability of exosomes. qRT-PCR and Western blot were used to identify expression levels of angiogenesis-related genes and proteins in human brain microvascular endothelial cells (HBMECs) after being cultured with exosomes. RESULTS: The levels of linc-POU3F3 were upregulated in glioma tissue and significantly correlated with the advanced tumor stage. A172 cells exhibited the highest expression level. A172-Exo was similar to shA172-Exo (50-100 nm in diameter) and expressed Alix, Tsg101 and CD9, while the expression level of linc-POU3F3 in A172-Exo was significantly higher than that in shA172 Exo. HBMECs rapidly internalized A172-Exo and shA172-Exo, and the linc-POU3F3 expression level in HBMECs treated with A172-Exo was significantly higher than the level in HBMECs treated with shA172-Exo. A172-Exo exhibited better function in promoting HBMECs migration, proliferation, tubular-like structure formation in vitro and arteriole formation in vivo. The gene and protein expression level of bFGF, bFGFR, VEGFA, and Angio in HBMECs treated with A172-Exo was much higher than that of HBMECs treated with shA172-Exo. CONCLUSIONS: These results indicated that gliomas can induce angiogenesis by secreting exosomes enriched in linc POU3F3. Exosomes and lncRNA-POU3F3 may, therefore, function as a putative therapeutic target in glioma. PMID- 28338201 TI - The clinical relationship between the slug-mediated Puma/p53 signaling pathway and radiotherapy resistance in nasopharyngeal carcinoma. AB - OBJECTIVE: To explore the clinical relationship between the Slug-mediated Puma/p53 signaling pathway and radiotherapy resistance in nasopharyngeal carcinoma. PATIENTS AND METHODS: Forty surgical specimens were collected from nasopharyngeal carcinoma patients treated at our hospital between February 2010 and February 2015. Twenty patients with poorly differentiated nasopharyngeal carcinoma with and without radiotherapy resistance were included in the experimental and control groups, respectively. Slug, Puma, and p53 expression were quantified in all tissues using fluorescence quantitative polymerase chain reaction, enzyme-linked immunosorbent assay (ELISA), Western blotting, and immunohistochemistry. RESULTS: Slug and p53 mRNA levels were significantly higher in the experimental group than in the control group (p < 0.01). Puma mRNA levels were significantly lower in the experimental group than in the control group (p < 0.01). Slug protein expression was significantly higher in the experimental group (6.07 +/- 0.203 MUg/L) than in the control group (1.24 +/- 0.171 MUg/L) (p < 0.01). p53 protein expression was significantly higher in the experimental group (4.28 +/- 0.108 MUg/L) than in the control group (0.63 +/- 0.101 MUg/L) (p < 0.01). Puma protein expression was significantly lower in the experimental group (0.43 +/- 0.11 MUg/L) than in the control group (3.37 +/- 0.112 MUg/L) (v < 0.01). The number of Slug, Puma, and p53-positive cells in the experimental group and the control group were quantified; these values confirmed the ELISA and Western blot findings. CONCLUSIONS: Slug downregulated the Puma protein expression signaling pathway and promoted radiotherapy resistance in poorly differentiated squamous cell carcinoma tissue, in a p53-independent manner. PMID- 28338202 TI - HOXA10 promotes nasopharyngeal carcinoma cell proliferation and invasion via inducing the expression of ZIC2. AB - OBJECTIVE: In this study, we aimed to explore the dysregulated genes in nasopharyngeal carcinoma (NPC) and to investigate the regulative effect of HOXA10 on ZIC2 expression and their involvement in NPC cell proliferation and invasion. MATERIALS AND METHODS: Microarray data that compared the transcription profile of NPC tissues and normal tissues was searched in GEO datasets and was re-analyzed. The expression of HOXA10 and ZIC2 mRNA were retrieved in TCGA database. CNE1 and CNE2 cells were used as an in-vitro cell model. Luciferase reporters carrying truncated ZIC2 promoter sequences were generated to verify the predicted HOXA10 binding site. CCK-8 assay and transwell assay were applied to assess cell proliferation and invasion respectively. RESULTS: HOXC6, HOXA3, and HOXA10 were upregulated in NPC tissues. Data mining in TCGA database showed that HOXA10, but not HOXC6 or HOXA3 is positively correlated to ZIC2 expression. Enforced HOXA10 expression significantly elevated ZIC2 expression at both mRNA and protein levels in both CNE1 and CNE2 cells. HOXA10 can directly bind to the promoter of ZIC2 and upregulate ZIC2 transcription. ZIC2 knockdown significantly reduced cell proliferation and invasion capability of CNE1 cells and also partly abrogated the effect of HOXA10 overexpression on enhancing cell proliferation and invasion. CONCLUSIONS: Both HOXA10 and ZIC2 are upregulated in NPC tissues compared to the normal tissues. HOXA10 can increase ZIC2 expression via binding to the ZIC2 promoter. Functionally, the HOXA10-ZIC2 axis can enhance NPC cell proliferation and invasion. PMID- 28338203 TI - MiR-155 regulates oral squamous cell carcinoma Tca8113 cell proliferation, cycle, and apoptosis via regulating p27Kip1. AB - OBJECTIVE: P27Kip1 is the one of the negative regulators of the cell cycle that plays an important role in regulating cell cycle and inhibiting cell proliferation by restraining cell in G1 phase. P27Kip1 downregulation maybe related to the occurrence of oral squamous cell carcinoma (OSCC). It was found that miR-155 significantly upregulated in OSCC tissue. Bioinformatics analysis revealed that miR-155 may bind with the 3'-UTR of p27Kip1. This study investigated the role of miR-155 in regulating p27Kip1 and affecting Tca8113 cell proliferation, cycle, and apoptosis. PATIENTS AND METHODS: A total of 46 cases of OSCC patients received treatment in our hospital were enrolled to obtain tumor tissue. Another 25 normal oral mucosa samples were selected as control to detect the relationship between miR-155 and p27Kip1 expressions. Dual luciferase assay was adopted to confirm the targeted relationship between miR-155 and p27Kip1. Flow cytometry was applied to test cell apoptosis and cell cycle. CCK-8 assay was used to evaluate cell proliferation. Caspase-3 activity was detected by spectrophotometry. RESULTS: MiR-155 upregulated, while p27Kip1 declined in OSCC tissue compared with normal oral mucosa. Their expressions were related to TNM stage. MiR-155 targeted suppressed p27Kip1 expression. MiR-155 mimic and/or pEGFP p27Kip1 transfection obviously declined p27Kip1 expression, blocked cell cycle in G1 phase, reduced cell proliferation, enhanced Caspase-3 activity, and increased cell apoptosis in Tca8113 cells. CONCLUSIONS: MiR-155 increased, while p27Kip1 reduced in OSCC tissue. Inhibition of miR-155 upregulated p27Kip1 expression, blocked cell cycle in G1 phase, weakened cell proliferation, and induced cell apoptosis. PMID- 28338204 TI - NSD2 promotes osteosarcoma cell proliferation and metastasis by inhibiting E cadherin expression. AB - OBJECTIVE: Osteosarcoma is one of the most common malignant bone tumors. The mechanisms of osteosarcoma development and invasion have been studied for periods of time, yet targeted therapy for improving survival has not been well established. Histone lysine methyltransferase NSD2 was frequently overexpressed in multiple types of cancer such as multiple myeloma, stomach and colon cancer, and the overexpression of it usually associated with aggressiveness tumor type. However, the expression status and function of NSD2 are still ambiguous in osteosarcoma. MATERIALS AND METHODS: Here, we evaluate the abnormal expression levels of NSD2 in osteosarcoma samples and cell lines. The higher expression of NSD2 in tumors resulted in a poorer outcome and a worse 5-year overall survival. To investigate the role of NSD2 in osteosarcoma cell proliferation and invasion in vitro, MTT assay, cell cycle distribution, wound healing, transwell assay was performed in relative cell lines, using a recombinant lentivirus expressing NSD2 short hairpin RNA or NSD2 construction. RESULTS: Our results imply that NSD2 promotes osteosarcoma cell proliferation and invasion, and the mechanism was possibly through the suppression of E-cadherin and induction of the epithelial mesenchymal transition, further to proceed invasion of osteosarcoma cells. CONCLUSIONS: NSD2 may work as a novel repression of E-cadherin; therefore, NSD2 has potential as a target of OS therapy. In the future, the monitoring of NSD2 in the serum/plasma from the RNA level may be used as a non-invasive method for selecting patients for target therapy. PMID- 28338205 TI - Association between hepatitis B and hearing status. AB - OBJECTIVE: This study was performed to investigate the correlation between the chronic hepatitis B virus infection and hearing status. This study was performed to investigate the correlation between the chronic hepatitis B virus infection and hearing status. PATIENTS AND METHODS: This research was based on 76 hepatitis B infections as the case group (including 35 HBV carriers and 41 chronic hepatitis B (CHB) patients) and 54 normal cases as the control group. They were selected sequentially and audiologic tests were performed on the participants. RESULTS: The average hearing thresholds (HTs) of control group and hepatitis-B infection were 10.70 and 12.42 dBHL respectively with statistically significant difference (p < 0.01). Frequency-specific HT of 114 ears in control group and hepatitis-B infection were found statistical differences for hearing frequency ranged 250 to 8000 (p < 0.05), and statistically significant differences for 250, 2000 and 4000 Hz (p < 0.01). Significant differences were only measured for HT at 250 Hz frequencies between control and HBV carriers (p < 0.01), while for control and CHB group, the differences were detected for all tested frequency (p < 0.01). The SNR for f2 frequencies (553, 1105, 2211, 3125, 4416, 4416, 6250 Hz) of the CHB patients and HBV carriers were compared with statistical differences (p < 0.01). CONCLUSIONS: The results showed that the hepatitis-B patients were more prone to hearing loss and that the hepatitis B disease can cause hearing loss. The infection of the inner ear and the pathological changes of the patients with HBV infection still need to be further explored. PMID- 28338206 TI - Impact and clinical significance of Embosphere microsphere artery embolization therapy in serum VEGF expression level of women patients with uterine fibroids. AB - OBJECTIVE: We aimed to investigate the effect of Embosphere microsphere artery embolization on the serum level of vascular endothelial growth factor (VEGF) in patients with uterine fibroid. PATIENTS AND METHODS: From March 2014 to December 2015, 128 women in child-bearing age with uterine intramural fibroids were enrolled in the patient group. At the same time, 128 healthy cases in child bearing age were randomly selected and enrolled in the control group. Enzyme linked immunosorbent assay was used to measure the serum level of VEGF, and immunohistochemical staining method was used to study the expression of VEGF in the uterine fibroids. Embosphere microsphere artery embolization surgery was performed on cases in the patient group. RESULTS: The serum level of VEGF in the patient group was significantly higher than that of the control group. Immunohistochemical staining results showed that in the control group, VEGF expression level in uterine fibroid tissue was significantly higher. Compared with before the treatment, tumor diameter in the patient group reduced significantly 3 months after the treatment. Erythrocyte count, hemoglobin, and menstrual blood volume increased significantly 6 months after treatment. CONCLUSIONS: Serum VEGF level can be considered as a marker for uterine fibroid, and by using VEGF as a marker we can increase the probability of early diagnosis. We showed that, compared with hysterectomy, Embosphere microsphere embolization had an evident advantage and might be an excellent candidate to replace hysterectomy. PMID- 28338207 TI - Evaluation of failed immunotherapy among patients with negative APLA recurrent spontaneous abortion by serum anticardiolipin antibodies and mononuclear cell of Tim-1. AB - OBJECTIVE: The present study is aimed to analyze the expression of serum anticardiolipin antibody (ACA) and mononuclear cells of Tim-1 among the patients with negative anti paternal lymphocyte antibody (APLA) recurrent spontaneous abortion conducted by lymphocyte immunotherapy resulting in failure. PATIENTS AND METHODS: 58 patients with negative APLA recurrent spontaneous abortion (RSA) who was diagnosed for the first time and received lymphocyte immunotherapy in our hospital were selected continuously. According to the therapeutic outcome, the patients were divided into success group with 31 cases and failure group with 27 cases. The positive rate of APLA and ACA in serum were compared, as well as the expressions of serum IL-6, IL-10, TNF-alpha, and IFN-gamma were studied by the method of ELISA. Furthermore, the ratios of CD4+CD25+ regulatory T cells (Treg) were detected by flow cytometry, and mRNA expression levels of Tim-1 were tested by the fluorogenic quantitative RT-PCR method. RESULTS: The positive rate of APLA after treatments of both the groups were compared, without any difference. The positive rate of ACA in failure group before treatment was higher than the data of after treatment, and the difference was statistically significant (p < 0.05). After treatment, serum IL-6 and IL-10 levels of two groups increased, TNF-alpha and IFN-gamma levels were observed to be decreased in comparison with the data before treatment. Furthermore, the improvement in success group was greater than failure group, and the difference was statistical significant (p < 0.05). After treatment, Treg proportion of two groups increased compared with before, and the proportion of success group was greater than that of failure group; mRNA expression levels of Tim-1 in failure group before and after treatment were higher than that of success group, and the differences had statistical significance (p < 0.05). CONCLUSIONS: High level of serum anticardiolipin antibody and mononuclear cell Tim-1 might lead to failed immunotherapy for the patients with negative APLA recurrent spontaneous abortion by influencing T lymphocyte immunity. PMID- 28338208 TI - Effects of combining CBCT technology with visual root canal recurrence in treatment of elderly patients with dental pulp disease. AB - OBJECTIVE: The aim of this study is to analyze the effects of combining cone beam computed tomography (CBCT) technology with visual root canal recurrence in the treatment of elderly patients with dental pulp disease. PATIENTS AND METHODS: 56 cases of elderly patients with dental pulp disease were contiguously selected, and randomly divided into the control group (70 teeth from 27 patients) and the observation group (77 teeth from the rest 29 patients). We adopted CBCT technology combined with conventional root canal therapy in control group and CBCT technology combined with visual root canal recurrence in observation group to compare the clinical effects. RESULTS: It was found that there was no statistical difference in duration of operation between the two groups (p>0.05). The operation times and the VAS during and after operation of the observation group were significantly less than that of the control group (p<0.05). The duration of follow-up of the two groups was both about 18 months. Successful rates of treatment for 6 months and by the end of follow-up visit in the observation group were both significantly higher than those in the control group (p<0.05). The correct filling rate, good filling rate and fair filling rate in the observation group were significantly higher than those of the control group (p<0.05). CONCLUSIONS: CBCT technology combined with visual root canal recurrence can significantly improve the near and long-term treatment effects of elderly patients with dental pulp disease. PMID- 28338209 TI - Bridging the Dialectic: Diversity, Psychological Sense of Community, and Inclusion. AB - Although, there are many times when P/SOC and diversity appear in opposition, I argue that this conflict is not inherent to the concepts or their joint value, but to social contexts in which they are enacted in real life. The primary values of community psychology-building and supporting positive communities, social change, and social justice within a framework that recognizes the centrality of diversity, culture, inclusion, power, and privilege-actually bind diversity and community together. Thus, we can bridge this seeming dialectic through deeper reflection about the real and intended meaning, operationalization, and application of these two terms, and a reliance on the central values of our field. PMID- 28338210 TI - Testing food-related inhibitory control to high- and low-calorie food stimuli: Electrophysiological responses to high-calorie food stimuli predict calorie and carbohydrate intake. AB - Maintaining a healthy diet has important implications for physical and mental health. One factor that may influence diet and food consumption is inhibitory control-the ability to withhold a dominant response in order to correctly respond to environmental demands. We examined how N2 amplitude, an ERP that reflects inhibitory control processes, differed toward high- and low-calorie food stimuli and related to food intake. A total of 159 participants (81 female; M age = 23.5 years; SD = 7.6) completed two food-based go/no-go tasks (one with high-calorie and one with low-calorie food pictures as no-go stimuli) while N2 amplitude was recorded. Participants recorded food intake using the Automated Self-Administered 24-hour Dietary Recall system. Inhibiting responses toward high-calorie stimuli elicited a larger (i.e., more negative) no-go N2 amplitude; inhibiting responses toward low-calorie stimuli elicited a smaller no-go N2 amplitude. Participants were more accurate during the high-calorie than low-calorie task, but took longer to respond on go trials toward high-calorie rather than low-calorie stimuli. When controlling for age, gender, and BMI, larger high-calorie N2 difference amplitude predicted lower caloric intake (beta = 0.17); low-calorie N2 difference amplitude was not related to caloric intake (beta = -0.03). Exploratory analyses revealed larger high-calorie N2 difference amplitude predicted carbohydrate intake (beta = 0.22), but not protein (beta = 0.08) or fat (beta = 0.11) intake. Results suggest that withholding responses from high-calorie foods requires increased recruitment of inhibitory control processes, which may be necessary to regulate food consumption, particularly for foods high in calories and carbohydrates. PMID- 28338211 TI - Multidisciplinary care of children and young people with ataxia-telangiectasia. PMID- 28338212 TI - Management of temporomandibular disorders by Ministry of Public Health dentists in Central Thailand. AB - : Very little is known about the ability of dentists to diagnose and treat temporomandibular disorders (TMDs). The aims of this study were to investigate whether dentists in Central Thailand diagnosed TMD subcategories before initiating treatment for TMDs and to explore the frequency of corresponding treatments. METHODS: A questionnaire covering TMD management was developed and posted to all Ministry of Public Health dentists (n = 969) in Central Thailand. The data were analysed using descriptive statistics. RESULTS: The respondents (n = 502) comprised 109 (21.7%) male and 393 (78.3%) female dentists between 23 and 59 years of age (mean age = 34.7 years). In the preceding year, 427 (85.1%) reported encountering patients with TMDs, 356 (70.9%) had treated patients who had TMDs and 176 (49.4%) had diagnosed TMD subcategories. Most respondents regularly treated patients by providing patient education and encouraging self care. The respondents who did not diagnose subcategories primarily treated TMDs with pharmacotherapy and physical therapy; orthopaedic appliances and occlusal therapy were used less often. Respondents who diagnosed TMD subcategories did not often use orthopaedic appliances or occlusal therapy to treat muscle disorders. For the treatment of derangement disorders, respondents used fewer pharmacotherapy, physical therapy and occlusal therapy techniques. For the treatment of osteoarthritis, respondents used less physical therapy and fewer orthopaedic appliances. CONCLUSION: Most Ministry of Public Health dentists in the Central Thailand region encounter and treat patients with TMDs. Approximately 50% of the respondents diagnosed TMD subcategories before providing treatment for TMDs. PMID- 28338213 TI - Biochemical model of C3 photosynthesis applied to wheat at different temperatures. AB - We examined the effects of leaf temperature on the estimation of maximal Rubisco capacity (Vcmax ) from gas exchange measurements of wheat leaves using a C3 photosynthesis model. Cultivars of spring wheat (Triticum aestivum (L)) and triticale (X Triticosecale Wittmack) were grown in a greenhouse or in the field and measured at a range of temperatures under controlled conditions in a growth cabinet (2 and 21% O2 ) or in the field using natural diurnal variation in temperature, respectively. Published Rubisco kinetic constants for tobacco did not describe the observed CO2 response curves well as temperature varied. By assuming values for the Rubisco Michaelis-Menten constants for CO2 (Kc ) and O2 (Ko ) at 25 degrees C derived from tobacco and the activation energies of Vcmax from wheat and respiration in the light, Rd , from tobacco, we derived activation energies for Kc and Ko (93.7 and 33.6 kJ mol-1 , respectively) that considerably improved the fit of the model to observed data. We confirmed that temperature dependence of dark respiration for wheat was well described by the activation energy for Rd from tobacco. The new parameters improved the estimation of Vcmax under field conditions, where temperatures increased through the day. PMID- 28338214 TI - Light therapies for acne: abridged Cochrane systematic review including GRADE assessments. AB - We undertook a Cochrane review of randomized controlled trials (RCTs) evaluating the effects of light-based interventions for acne vulgaris. We searched the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, LILACS, ISI Web of Science and grey literature sources (September 2015). We used the Grading of Recommendations Assessment, Development and Evaluation Working Group approach to assess the quality of evidence (QoE). We included 71 RCTs (4211 participants, median sample size 31). Results from a single study (n = 266, low QoE) showed little or no difference in effectiveness on participants' assessment of improvement between 20% aminolaevulinic acid (ALA) photodynamic therapy (PDT), activated by blue light, vs. vehicle plus blue light, whereas another study (n = 180) comparing ALA-PDT (red light) concentrations showed that 20% ALA-PDT was no more effective than 15% ALA-PDT but better than 10% and 5% ALA-PDT. Pooled data from three studies (n = 360, moderate QoE) showed that methyl aminolaevulinate PDT, activated by red light, had a similar effect on changes in lesion counts vs. placebo cream with red light. Several studies compared yellow light with placebo or no treatment, infrared light with no treatment, gold microparticle suspension with vehicle and clindamycin/benzoyl peroxide (C/BPO) combined with pulsed dye laser with C/BPO alone. None of these showed any clinically significant effects. Most studies reported adverse effects, but inadequately, with scarring reported as absent, and blistering only in studies on intense pulsed light, infrared light and PDT (very low QoE). Carefully planned studies, using standardized outcome measures and common acne treatments as comparators, are needed. PMID- 28338215 TI - Delirium During Postacute Nursing Home Admission and Risk for Adverse Outcomes. AB - OBJECTIVES: To identify the rate of delirium present during admission to postacute care (PAC) in the nursing home setting and to determine whether patients with delirium had higher risk for adverse outcomes. DESIGN: Retrospective cohort study. SETTING: US Medicare- and Medicaid-certified nursing homes, 2011 to 2014. PARTICIPANTS: Individuals admitted to all US nursing homes for PAC, aged >=65 years, and without prior history of nursing home residence (n = 5,588,702). MEASUREMENTS: Minimum Data Set (MDS) 3.0 admission assessments identified delirium based upon Confusion Assessment Method (CAM) items. Robust Poisson regression was used to calculate adjusted relative risks (aRRs) with 95% confidence intervals (CIs) for death following PAC admission, and for 30-day discharge outcomes including re-hospitalization from PAC, discharge home, and functional improvement. RESULTS: Delirium was identified in 4.3% of new postacute nursing home admissions. Mortality within 30 days of PAC admission was observed in 16.3% of patients with delirium and 5.8% of patients without delirium (aRR = 2.27, CI = 2.24-2.30). The rate of 30-day readmission from PAC was 21.3% for patients with delirium compared with 15.1% among patients without delirium (aRR = 1.42, 95% CI = 1.40, 1.43). 26.9% of patients with delirium were discharged home within 30 days of admission compared to 52.5% of patients without delirium (aRR = 0.57, 95% CI = 0.57, 0.58). 48.9% of patients with delirium showed functional improvement at discharge compared to 59.9% of patients without delirium (aRR = 0.83, 95% CI = 0.82, 0.83). CONCLUSIONS: Patients with delirium present upon PAC admission were at high risk for mortality and 30-day re-hospitalization and were less likely to have timely discharge to home or to improve in physical function at discharge. Early identification and care planning for individuals with delirium at PAC admission may be essential to improve outcomes. PMID- 28338216 TI - The diversified function and potential therapy of ectopic olfactory receptors in non-olfactory tissues. AB - Olfactory receptors (ORs) are mainly distributed in olfactory neurons and play a key role in detecting volatile odorants, eventually resulting in the production of smell perception. Recently, it is also reported that ORs are expressed in non olfactory tissues including heart, lung, sperm, skin, and cancerous tissues. Interestingly, ectopic ORs are associated with the development of diseases in non olfactory tissues. For instance, ectopic ORs initiate the hypoxic ventilatory responses and maintain the oxygen homeostasis of breathing in the carotid body when oxygen levels decline. Ectopic ORs induce glucose homeostasis in diabetes. Ectopic ORs regulate systemic blood pressure by increasing renin secretion and vasodilation. Ectopic ORs participate in the process of tumor cell proliferation, apoptosis, metastasis, and invasiveness. Ectopic ORs accelerate the occurrence of obesity, angiogenesis and wound-healing processes. Ectopic ORs affect fetal hemoglobin levels in sickle cell anemia and thalassemia. Finally, we also elaborate some ligands targeting for ORs. Obviously, the diversified function and related signal pathway of ectopic ORs may play a potential therapeutic target in non-olfactory tissues. Thus, this review focuses on the latest research results about the diversified function and therapeutic potential of ectopic ORs in non olfactory tissues. PMID- 28338217 TI - Fasting up-regulates ferroportin 1 expression via a Ghrelin/GHSR/MAPK signaling pathway. AB - The significant positive correlation between ghrelin and iron and hepcidin levels in the plasma of children with iron deficiency anemia prompted us to hypothesize that ghrelin may affect iron metabolism. Here, we investigated the effects of fasting or ghrelin on the expression of hepcidin, ferroportin 1 (Fpn1), transferrin receptor 1 (TfR1), ferritin light chain (Ft-L) proteins, and ghrelin, and also hormone secretagogue receptor 1 alpha (GHSR1alpha) and ghrelin O acyltransferase (GOAT) mRNAs in the spleen and/or macrophage. We demonstrated that fasting induces a significant increase in the expression of ghrelin, GHSR1alpha, GOAT, and hepcidin mRNAs, as well as Ft-L and Fpn1 but not TfR1 proteins in the spleens of mice in vivo. Similar to the effects of fasting on the spleen, ghrelin induced a significant increase in the expression of Ft-L and Fpn1 but not TfR1 proteins in macrophages in vitro. In addition, ghrelin was found to induce a significant enhancement in phosphorylation of ERK as well as translocation of pERK from the cytosol to nuclei. Furthermore, the increased pERK and Fpn1 induced by ghrelin was demonstrated to be preventable by pre-treatment with either GHSR1alpha antagonist or pERK inhibitor. Our findings support the hypothesis that fasting upregulates Fpn1 expression, probably via a ghrelin/GHSR/MAPK signaling pathway. PMID- 28338218 TI - Evaluation of targeted exome sequencing for 28 protein-based blood group systems, including the homologous gene systems, for blood group genotyping. AB - BACKGROUND: Blood group single nucleotide polymorphism genotyping probes for a limited range of polymorphisms. This study investigated whether massively parallel sequencing (also known as next-generation sequencing), with a targeted exome strategy, provides an extended blood group genotype and the extent to which massively parallel sequencing correctly genotypes in homologous gene systems, such as RH and MNS. STUDY DESIGN AND METHODS: Donor samples (n = 28) that were extensively phenotyped and genotyped using single nucleotide polymorphism typing, were analyzed using the TruSight One Sequencing Panel and MiSeq platform. Genes for 28 protein-based blood group systems, GATA1, and KLF1 were analyzed. Copy number variation analysis was used to characterize complex structural variants in the GYPC and RH systems. RESULTS: The average sequencing depth per target region was 66.2 +/- 39.8. Each sample harbored on average 43 +/- 9 variants, of which 10 +/- 3 were used for genotyping. For the 28 samples, massively parallel sequencing variant sequences correctly matched expected sequences based on single nucleotide polymorphism genotyping data. Copy number variation analysis defined the Rh C/c alleles and complex RHD hybrids. Hybrid RHD*D-CE-D variants were correctly identified, but copy number variation analysis did not confidently distinguish between D and CE exon deletion versus rearrangement. CONCLUSION: The targeted exome sequencing strategy employed extended the range of blood group genotypes detected compared with single nucleotide polymorphism typing. This single-test format included detection of complex MNS hybrid cases and, with copy number variation analysis, defined RH hybrid genes along with the RHCE*C allele hitherto difficult to resolve by variant detection. The approach is economical compared with whole-genome sequencing and is suitable for a red blood cell reference laboratory setting. PMID- 28338219 TI - Human orf complicated by epidermolysis bullosa acquisita. AB - Orf is a DNA parapoxvirus transmitted to humans by contact with infected goats and sheep. Many complications have been reported after orf infection, including erythema multiforme. A few cases of autoimmune bullous dermatosis complicating orf disease have been reported to date. They are usually characterized by tense blister eruptions with or without mucosal involvement; linear deposition of C3, IgG and/or IgA along the basement membrane; and negativity of indirect immunofluorescence analysis and enzyme-linked immunosorbent assay (ELISA) (performed in four of 11 reported cases). These analyses have targeted antigens of bullous pemphigoid, mucous membrane pemphigoid or epidermolysis bullosa acquisita, except one case of mucosal pemphigoid with antilaminin-332 antibodies. We describe the case of a patient who presented with an ulceration on his finger 10 days after direct contact with a lamb during Eid al-Adha. Four weeks later he developed a severe tense blistering eruption associated with mucous membrane erosions. Indirect immunofluorescence analysis using the patient's serum revealed circulating antibasement membrane IgG that bound the dermal side of salt-split skin. ELISA was positive for recombinant immunodominant NC1 domain of type VII collagen. We finally diagnosed epidermolysis bullosa acquisita complicating probable human orf infection. PMID- 28338220 TI - Referred by Google: mining Google Trends data to identify patterns in and correlates to searches for dermatological concerns and providers. PMID- 28338221 TI - Predictors of low quality of life in patients with discoid lupus. PMID- 28338222 TI - Long-Term Self-Reported Cognitive Problems After Delirium in the Intensive Care Unit and the Effect of Systemic Inflammation. AB - OBJECTIVES: To describe the association between intensive care unit (ICU) delirium and self-reported cognitive problems in 1-year ICU survivors, and investigate whether this association was altered by exposure to systemic inflammation during ICU stay. DESIGN: Prospective cohort study. SETTING: Dutch medical-surgical ICU. PARTICIPANTS: One-year ICU survivors, admitted to the ICU >=48 hours. MEASUREMENTS: Self-reported cognitive problems were measured with the Cognitive Failures Questionnaire (CFQ). Cumulative exposure to systemic inflammation was based on all daily C-reactive protein (CRP) measurements during ICU stay, expressed as the area under the curve (AUC). Multivariable linear regression was conducted to evaluate the association between delirium and the CFQ. The effect of inflammation on the association between delirium and CFQ was assessed, comparing the effect estimate (B) of delirium and CFQ between models with and without inclusion of the AUC of CRP. RESULTS: Among 567 1-year ICU survivors, the CFQ was completed by 363 subjects. Subjects with multiple days of delirium during ICU stay reported more self-reported cognitive problems (Badj = 5.10, 95% CI 1.01-9.20), whereas a single day delirium was not associated with higher CFQ scores (Badj = -0.72, 95% CI -5.75 to 4.31). Including the AUC of CRP did not change the association between delirium and the CFQ (ratio for a single and multiple days were respectively: 1.00, 95%CI 0.59-1.44 and 0.86, 95% CI 0.47 1.16). CONCLUSION: Multiple days of delirium was associated with long-term self reported cognitive problems. The cumulative exposure to systemic inflammation did not alter this association, suggesting that delirium in the context of little inflammation is also detrimental. PMID- 28338223 TI - Efficacy and safety of ustekinumab in Japanese patients with severe atopic dermatitis: a randomized, double-blind, placebo-controlled, phase II study. AB - BACKGROUND: Ustekinumab, a fully human monoclonal antibody against interleukin 12/23, may potentially be effective for severe atopic dermatitis (AD) treatment. OBJECTIVES: To evaluate efficacy and safety of ustekinumab 45 mg and 90 mg in patients with severe AD. METHODS: In this randomized, placebo-controlled, phase II study, Japanese patients (aged 20-65 years) with severe or very severe AD entered a 12-week double-blind treatment period during which they received (1 : 1 : 1) ustekinumab 45 mg, 90 mg or placebo subcutaneous injections at weeks 0 and 4, with follow-up until week 24. The primary efficacy end point was percentage change from baseline in Eczema Area and Severity Index (EASI) score at week 12. Major secondary efficacy end points included the proportion of patients achieving EASI 50, EASI 75, Investigator's Global Assessment score 0-1, change from baseline Atopic Dermatitis Itch Scale and Dermatology Life Quality Index. RESULTS: A total of 79 patients were randomized [ustekinumab 45 mg (n = 24), 90 mg (n = 28), placebo (n = 27)]. Ustekinumab treatment showed nonsignificant improvement in least square mean change from baseline EASI score at week 12 [45 mg: -38.2%, 95% confidence interval (CI) -21.02-19.51; P < 0.94 and 90 mg: 39.8%, 95% CI -21.84-17.14; P < 0.81] vs. placebo (-37.5%). A nonsignificant improvement in major secondary efficacy end points was observed in both ustekinumab groups vs. placebo. The most common treatment-emergent adverse events were nasopharyngitis and worsened AD (higher in placebo vs. ustekinumab groups). CONCLUSIONS: Ustekinumab 45 mg and 90 mg did not demonstrate meaningful efficacy in Japanese patients with severe AD. The treatment was generally well tolerated. PMID- 28338224 TI - Adolescent externalizing behaviour, psychological control, and peer rejection: Transactional links and dopaminergic moderation. AB - This study investigated (1) reciprocal links among parental psychological control, peer rejection, and adolescent externalizing (aggressive and rule breaking behaviour), and (2) the moderating effect of an adolescent genetic factor (biologically informed polygenic score for dopamine signalling). Three year longitudinal data from 1,116 adolescents (51% boys; M age = 13.79) and their parents included psychological measures (adolescent-reported psychological control, peer-reported rejection, and parent-reported aggressive and rule breaking behaviour). Cross-lagged analyses showed bidirectional effects between psychological control and both aggressive and rule-breaking behaviour and a unidirectional effect of peer rejection on both forms of problem behaviour over time. Multigroup structural equation modelling revealed genetic moderation only for rule-breaking behaviour: for adolescents with intermediate levels of dopamine signalling significant environmental effects were present, whereas adolescent effects of rule-breaking behaviour on psychological control were significant for adolescents with both intermediate and high profiles and effects on peer rejection only for adolescents with high dopamine profiles. Statement of contribution What is already known on this subject? Parental psychological control is related to adolescent externalizing problems. Experiencing peer rejection reinforces aggressive and rule-breaking behaviour. Single-gene studies show that dopaminergic genes influence externalizing problems directly or in interaction with the environment. What does this study add? Parental psychological control and adolescent aggressive and rule-breaking behaviour exacerbate one another longitudinally. Longitudinal associations between peer rejection and both subtypes of externalizing behaviour are unidirectional. With a polygenic approach, dopaminergic moderation is present for rule-breaking behaviour only. PMID- 28338225 TI - The Impact of Family Unification Housing Vouchers on Child Welfare Outcomes. AB - This study addresses whether providing housing vouchers through the Family Unification Program (FUP) to families involved in the child welfare system reduces child maltreatment and the need for child welfare services. The study uses child welfare administrative data on 326 children in Portland, Oregon, and 502 children in San Diego, California from the point at which their families were referred to the program through 18 months post-referral. Using a quasi experimental waitlist comparison design, probit regressions show little impact of FUP on preventing child removal from home, but some positive impact on reunification among children already placed out of home. Hazard estimations show receipt of FUP speeds up child welfare case closure. Impacts on new reports of abuse and neglect are mixed, but point toward reduced reports. Low rates of removal among intact comparison families and high rates of reunification for children in out-of-home care suggest poor targeting of housing resources. Housing vouchers are being given to families not bearing the risks the program is intended to address. The presence of some positive findings suggests that housing vouchers might help reduce child welfare involvement if better targeting were practiced by child welfare agencies. PMID- 28338227 TI - Smartphones in the dermatology department: acceptable to patients? PMID- 28338226 TI - Exploring and modelling impacts of third molar experience on quality of life: a real-time qualitative study using Twitter. AB - OBJECTIVES: This study had two objectives: (i) to explore and model domains describing the real-time impact of third molars (TMs) on quality of life (QoL); and (ii) to assess the percentage coverage, in some generic health-related quality of life (HRQoL) and oral health-related quality of life (OHRQoL) instruments, of the TM QoL domains identified in this study. METHODOLOGY: A global cross-sectional sample of tweets containing 'wisdom tooth' over a 1-week period retrieved 3,537 tweets. After random quota sampling, classification and filtering, only 843 tweets were included in the thematic analysis. A TM QoL model was constructed based on the associations of the identified domains. Domains for the selected generic HRQoL and OHRQoL instruments were plotted against the domains identified in the study to calculate the percentage coverage for each. RESULTS: The QoL domains identified were pain (n = 348, 41%), mood (n = 173, 20%), anxiety and fear (n = 54, 7%), enjoying food (n = 41, 4%), coping (n = 37, 4%), daily activities (n = 34, 4%), sleep (n = 24, 2%), social life (n = 19, 2%), physical health (n = 17, 2%), ability to think (n = 9, 1%), self-care (n = 8, 1%) and sporting & recreation (n = 2, <1%). The Assessment Quality of Life instrument (AQoL-8D) covers 87% of the TM QoL domains, while the rest of the HRQoL and OHRQoL instruments cover 33-60%. CONCLUSION: This study shows how Twitter can be used to obtain real-time QoL data, which might be used to model how TMs impact on QoL. The TM QoL domains identified in the study were generally under-represented among the generic OHRQoL instruments assessed while, the HRQoL AQoL-8D covered most of the TM QoL domains. The QoL domains identified in the study might be used to develop a new OHRQoL measure for TMs. PMID- 28338228 TI - Taking Stock of the Diversity and Sense of Community Debate. AB - Over the past couple of years, a debate has played out in the pages of the American Journal of Community Psychology concerning the relationship between two of Community Psychology's core values: promoting diversity and promoting a sense of community. This special section is to continue a discussion about diversity and community, both among the debate's initial contributors (Alex Stivala, Greg Townley, and Zachary Neal), as well as among others whose own work has touched on these issues (Anne Brodsky, Richard Florida, Jean Hill, and Roderick Watts). In this essay, I address some broad questions that have emerged through this discussion. First, because much has been written on the relationship between diversity and community, both in community psychology and in other disciplines, what do we know, or at least think we know? Second, since the constructs of diversity and sense of community are complex and multi-faceted, how can definitions get in the way and how can we avoid talking past one another in this discussion? Finally, looking across the original papers that initiated this discussion, as well as the contributions in this special section, what path(s) forward do we have? PMID- 28338230 TI - Thyroid hormone and pancreas development: diabetes culprit or innocent bystander? PMID- 28338229 TI - Response to Endurance Exercise Training in Older Adults with Heart Failure with Preserved or Reduced Ejection Fraction. AB - OBJECTIVES: To systematically examine the relative magnitude and predictors of responses to exercise training in older adult with heart failure (HF) with reduced ejection fraction (HFrEF), and preserved EF (HFpEF). DESIGN: Secondary analysis of a randomized controlled trial. SETTING: Outpatient cardiac rehabilitation program. PARTICIPANTS: Individuals with HF (24 HFrEF, 24 HFpEF) who underwent supervised exercise training. MEASUREMENTS: The study included individual-level data from the exercise training arms of a randomized controlled trial that evaluated the effect of 16 weeks of supervised moderate-intensity endurance exercise training in older adults with chronic, stable HFpEF and HFrEF. Changes in peak oxygen uptake (VO2peak ) in response to supervised training in individuals with HFpEF were compared with that of individuals with HFrEF. The significant clinical predictors of changes in VO2peak with exercise training were assessed using univariate and multivariate regression models. RESULTS: Training related improvement in VO2peak was higher in participants with HFpEF than in those with HFrEF (change: 18.7 +/- 17.6% vs -0.3 +/- 15.4%, P < .001). In univariate analysis, echocardiographic abnormalities in left ventricular structure and function and lower body mass index were associated with blunted response of VO2peak with exercise training. In multivariate regression analysis using stepwise selection, submaximal exercise systolic blood pressure, and resting early deceleration time were independent predictors of change in VO2peak . CONCLUSION: The change in VO2peak in response to endurance exercise training in older adults with HF differs significantly according to HF subtype, with greater VO2peak improvement in HFpEF than HFrEF. These results suggest that the current Centers for Medicare and Medicaid Services policy excluding individuals with HFpEF from reimbursement from cardiac rehabilitation may need to be revisited. PMID- 28338232 TI - William W. Grings (1918-2016). PMID- 28338231 TI - Caesarean risk in obese women at term: A retrospective cohort analysis. AB - BACKGROUND: Obesity in pregnancy is a growing health problem conferring higher risk to both the woman and her infant. Internationally, peak bodies offer little guidance regarding the method and timing of delivery in these patients. Our hypothesis is that induction of labour (IOL) at term will not increase the caesarean section (CS) rate when compared to expectant management. AIMS: To compare perinatal outcomes between IOL and expectant management in obese women at term. METHODS: A retrospective cohort study of all term, singleton, vertex deliveries at the Townsville Hospital and Health Service from January 2011 to June 2015 in women with a body mass index (BMI) >= 35. Women undergoing IOL at 37 weeks were compared with women expectantly managed at that gestational age. Similar comparisons were made at 38, 39 and 40 weeks. chi2 tests and binary logistic regression were used for statistical comparison. The primary outcome measure was mode of delivery, with secondary measures of perinatal morbidity also considered. RESULTS: There was no difference in outcome of CS, or other maternal secondary outcomes. There was no difference in rates of neonatal nursery admission. Expectant management at 38 weeks was associated with lower odds of post-partum haemorrhage (odds ratio 0.371; 95% confidence interval 0.163-0.845). CONCLUSIONS: In women with a BMI >= 35, IOL does not affect the CS rate, or the risk of neonatal adverse events, but may increase the rate of postpartum haemorrhage when compared with expectant management. PMID- 28338233 TI - Unraveling the roles of orienting and inhibition in the Concealed Information Test. AB - The Concealed Information Test (CIT) is a well-validated tool for physiological and behavioral detection of concealed knowledge. Two distinct theoretical frameworks have been proposed to explain the differential responses to the concealed critical items: orienting response theory versus arousal inhibition theory. klein Selle, Verschuere, Kindt, Meijer, and Ben-Shakhar (2016), however, argued for a response fractionation model and showed that, while the skin conductance reflects pure orienting, both the respiratory and heart rate measures reflect arousal inhibition. The present study intends to (1) provide a constructive replication of klein Selle et al. (2016) using the autobiographical CIT, and (2) extend their work by testing an additional prediction derived from orienting theory, using an item-salience manipulation. One hundred and nine participants were tested on four high salient and four low salient identity items. Half of the participants were motivated to hide their identity (orienting + arousal inhibition), while the other half were motivated to reveal their identity (orienting only). Confirming earlier findings, the results revealed a fractionation between the different measures: while the skin conductance response (SCR) increased to a similar extent in the two motivational conditions, the respiration line length (RLL) shortened and the heart rate (HR) decelerated solely in the conceal condition. Moreover, while the SCR was larger for high than for low salient critical items, the RLL and HR responses were similar for these two item types. These data led us to conclude that, in the CIT, the skin conductance measure reflects orienting and the respiratory and heart rate measures reflect arousal inhibition. PMID- 28338235 TI - Overexpression of Hsa-miR-320 Is Associated With Invasion and Metastasis of Ovarian Cancer. AB - Ovarian cancer is one of the most common malignant tumor of female genital organs which ranks the third morbidity. We aimed to provide a better understanding of the mechanism of invasion and metastasis of ovarian cancer. The ovarian cancer samples were downloaded from GEO. Then clustering was performed to classify the stage of miRNAs based on the difference of prognosis and metastasis. Furthermore, the miRNAs model was build and the survival analysis processes was performed to observe the influence on prognosis, invasion and metastasis. At last, miRNAs co expression network was built to explore the core miRNAs and the risk classification model was built to perform the risk assessment based on these core miRNAs. A total of 17 significantly differential expressed miRNAs were obtained. Functional enrichment of 1,488 target genes, pathways like cell cycle, focal adhesion, and pathways in cancer, which are closely related to the proliferation and metastasis of cancer cells were highly enriched, this indicate that these miRNAs are related to the proliferation and metastasis of cancer cells. The co expressed network shows that the high expression of hsa-miR-320 indicated negative prognosis and high risk of metastasis. In conclusion, the expression level of hsa-miR-320 is highly related to the migration and invasion of cancer. The high expression of hsa-miR-320 directly indicated negative prognosis and high risk of metastasis. These findings reveal that hsa-miR-320 may serve as an important therapeutic target in ovarian cancer therapy. J. Cell. Biochem. 118: 3654-3661, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28338234 TI - Extent of surgery did not affect recurrence during 7-years follow-up in papillary thyroid cancer sized 1-4 cm: Preliminary results. AB - OBJECTIVE: There is debate whether hemithyroidectomy is sufficient for patients with papillary thyroid cancer (PTC) sized 1-4 cm. Therefore, we investigated whether hemithyroidectomy affects recurrence rate compared with thyroidectomy in patients with PTC sized 1-4 cm. DESIGN: Retrospective observational study. PATIENTS: We included 147 patients with 1-4 cm PTC who underwent hemithyroidectomy between 2004 and 2008. They were matched with 298 patients who underwent thyroidectomy, comparing age, sex, tumour size, multiplicity, extrathyroidal extension status and lymph node (LN) metastasis status. MEASUREMENTS: Recurrence-free survival (RFS) was compared between hemithyroidectomy and thyroidectomy groups. RESULTS: Median follow-up length was 7 years, during which there were nine (6.1%) and 17 (5.7%) recurrences in hemithyroidectomy and thyroidectomy groups, respectively. Recurrence-free survival in the hemithyroidectomy group was not different from that in the thyroidectomy group regardless of variant, multifocality, LN metastasis and radioactive iodine treatment. However, in subgroup analysis, hemithyroidectomy significantly increased the risk of recurrence in patients with contralateral nodules on the preoperative imaging. CONCLUSIONS: Recurrence after hemithyroidectomy was not different from that after thyroidectomy during a median follow-up of 7 years. However, because thyroidectomy might be favoured in patients with contralateral nodules at preoperative evaluation, a thorough evaluation of the contralateral thyroid lobe is necessary. PMID- 28338237 TI - Highlights: Volume 230, Number 2. PMID- 28338240 TI - Journal of Cellular Physiology: Volume 230, Number 2, February 2015. AB - Cover: Diagram illustrating the chromatic median analysis. See article by Pliss et al. on pages 427-439. PMID- 28338236 TI - hsa-mir-3199-2 and hsa-mir-1293 as Novel Prognostic Biomarkers of Papillary Renal Cell Carcinoma by COX Ratio Risk Regression Model Screening. AB - Papillary renal cell carcinoma(PRCC) is the second most common and aggressive renal cell carcinoma. Identification of novel microRNA biomarkers could be beneficial for the diagnosis and prognosis of PRCC patients. We aimed to screen differentially expressed miRNAs that can act as prognostic factors and to predict the survival of PRCC patients. High-throughput data of miRNAs of 274 PRCC samples were downloaded from TCGA (The Cancer Genome Atlas) dataset and interested miRNAs were identified. Hierarchical clustering and principal component analysis (PCA) were performed on these miRNAs. Critical genes that can act as prognostic factors were screened by LASSO. What's more, Kaplan-Meier survival analysis and ROC (Receiver Operating Characteristic) growth curve were used to testify the accuracy of the model. Biological processes of putative targets of miRNAs were analyzed by bioinformatics methods such as GO (Go Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis. A total of 105 differentially expressed miRNAs were screened out in PRCC samples compared with healthy controls. Two critical miRNAs, hsa-mir-3199-2, and hsa-mir-1293, were screened out by LASSO (Least Absolute Shrinkage and Selection Operator), including 197 and 189 target genes, respectively. Furthermore, its' accuracy was testified by ROC analysis with the AUC (Area under the curve) value of 0.7774968 and 0.6743466. These miRNAs were significantly enriched in pathways as platelet activating factor biosynthetic process, epithelial cell maturation, and IkappaB kinase complex. In conclusion, hsa-mir-3199-2 and hsa-mir-1293 that can act as prognostic biomarkers of PRCC were screened out, which can provide new insights for the clinical treatment of the disease. J. Cell. Biochem. 118: 3488-3494, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28338241 TI - Neuroprotective Effects of Loganin on MPTP-Induced Parkinson's Disease Mice: Neurochemistry, Glial Reaction and Autophagy Studies. AB - Parkinson's disease (PD) is a progressive neurodegenerative disease, involving resting tremor and bradykinesia, for which no recognized therapies or drugs are available to halt or slow progression. In recent years, natural botanic products have been considered relatively safe, with limited side effects, and are expected to become an important source for clinical mediation of PD in the future. Our study focuses on the ability of loganin, a compound derived from fruits of cornus, to mediate neuroprotection in a mouse model of PD. Mice were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) with a dosage of 30 mg/kg daily for 5 days to establish a subacute PD model and treated with loganin. Locomotor activity was assessed by a pole test, then mice were euthanized at 1 and 3 days after the last treatment, and brain tissue was prepared for subsequent assays. Loganin rescued decrease of dopamine levels and tyrosine hydroxylase (TH) expression in the striatum, and shortened total locomotor activity (TLA) time of mice. Furthermore, loganin alleviated microglia and astrocyte activation, and suppressed TNF-alpha and caspase-3 expression through a c-Abl-p38-NFkappaB pathway. Loganin also downregulated LC3-II and Drp1 expression, and decreased the level of acidic vesicular organelles (AVOs). Loganin exerts neuroprotective effects on MPTP-induced PD mice by decreasing inflammation, autophagy, and apoptosis, suggesting that loganin could serve as a therapeutic drug to ameliorate PD. J. Cell. Biochem. 118: 3495-3510, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28338242 TI - What can community pharmacy learn from the experiences of transition to practice for novice doctors and nurses? A narrative review. AB - OBJECTIVES: In the absence of literature reporting the transition experiences of novice community pharmacists, peer-reviewed evidence on the transition experiences of novice doctors and nurses was identified and reviewed. Specific objectives included identifying the challenges to transition and their perceived impact, before considering the implications for novice community pharmacists. METHODS: The electronic databases MEDLINE, EMBASE, CINAHL, PsycINFO and ScienceDirect were searched for full peer-reviewed original research papers published 1990-March 2015, reporting the transition experiences of novice doctors and nurses. A narrative review following coding of themes was undertaken to synthesise findings with transferability. KEY FINDINGS: Twenty-five papers using qualitative and quantitative methods were retrieved from nursing (18) and medicine (6). Challenges were categorised into three themes: personal experiences (where acquiring professional accountability, failing to meet expectations, and emotional, cognitive and physical demands of the job heightened stress), social experiences (where support and acceptance at work were hindered by organisational culture, hierarchy or interpersonal conflict) and challenges from job-related experiences (high workloads, task complexity, staffing, rotations and shift patterns). Challenging transitions were perceived by novice practitioners and their peers as impeding learning, impairing performance and having negative implications for patient care. CONCLUSIONS: While some of these findings may be transferable to community pharmacy settings, contextual differences exist: relative isolation from professional peers, commercially driven private-sector settings, full and immediate acquisition of professional accountability and the lack of clinical career pathways or formalised support. Given these differences, is it appropriate that 'day-one' community pharmacists are fully and immediately accountable? Empirical research exploring transition to practice in the community pharmacy setting is needed. PMID- 28338243 TI - Influence of the Transition-Metal Fragment on the Reactivity of Metallaanthracenes. AB - The influence of the nature of the transition-metal fragment on the Diels-Alder reactivity of metallaanthracenes has been explored computationally within the Density Functional Theory framework. It is found that the cycloaddition reactions with maleic anhydride become kinetically less favored for those processes involving metallaanthracenes compared with the analogous reaction involving the parent anthracene. The origins of this reduction in the Diels-Alder reactivity have been quantitatively analyzed in detail by using the activation strain model of reactivity in combination with the energy decomposition analysis method. In general, the transition-metal fragment makes the interaction energy between the reactants significantly lower, particularly at the transition state region, which is translated into a higher activation barrier. In addition, the influence of the aromaticity strength of the metallabenzene present in the considered metallaanthracenes on the barriers of the cycloaddition reactions has also been assessed. PMID- 28338244 TI - Photoalignment of Vertically Oriented Microphase Separated Lamellae in LC-LC Diblock Copolymer Thin Film. AB - The microphase separation and photoalignment behavior of a diblock copolymer consisting of two kinds of side chain liquid crystalline (LC) polymers are investigated. Here, the mesogens of photoresponsive azobenzene and non photoresponsive cyanobiphenyl are introduced in the side chains. The azobenzene and cyanobiphenyl mesogens orient homeotropically and planarly, respectively, in a thin film state. The combination of these contrasting orienting properties leads to a formation of vertically oriented lamella in the microphase separation structure. Irradiation with linearly polarized light onto this polymer film induces a highly oriented microphase separation structure having regularly elongated stripe morphology with 30 nm periodicity. The nearly defect-free morphology of this LC-LC diblock copolymer after the photoalignment is a distinct feature when compared with those of coil (amorphous)-LC diblock copolymer films possessing the same azobenzene side chain. PMID- 28338245 TI - Infective capacity of Cryptococcus neoformans and Cryptococcus gattii in a human astrocytoma cell line. AB - Pathogenesis of cryptococcosis in the central nervous system (CNS) is a topic of ongoing research, including the mechanisms by which this fungus invades and infects the brain. Astrocytes, the most common CNS cells, play a fundamental role in the local immune response. Astrocytes might participate in cryptococcosis either as a host or by responding to fungal antigens. To determine the infectivity of Cryptococcus neoformans var. grubii and Cryptococcus gattii in a human astrocytoma cell line and the induction of major histocompatibility complex (MHC) molecules. A glioblastoma cell line was infected with C. neoformans var. grubii and C. gattii blastoconidia labelled with FUN-1 fluorescent stain. The percentage of infection and expression of HLA class I and II molecules were determined by flow cytometry. The interactions between the fungi and cells were observed by fluorescence microscopy. There was no difference between C. neoformans var. grubii and C. gattii in the percentage infection, but C. neoformans var. grubii induced higher expression of HLA class II than C. gattii. More blastoconidia were recovered from C. neoformans-infected cells than from C. gattii infected cells. Cryptococcus neoformans var. grubii may have different virulence mechanisms that allow its survival in human glia-derived cells. PMID- 28338246 TI - Insights into trans-Ligand and Spin-Orbit Effects on Electronic Structure and Ligand NMR Shifts in Transition-Metal Complexes. AB - Surprisingly general effects of trans ligands L on the ligand NMR shifts in third row transition-metal complexes have been found by quasi-relativistic computations, encompassing 5d10 , 5d8 , and to some extent even 5d6 situations. Closer analysis, with emphasis on 1 H shieldings in a series of linear HAuI Lq complexes, reveals a dominance of spin-orbit (SO) effects, which can change sign from appreciably shielding for weak trans ligands to appreciably deshielding for ligands with strong trans influence. This may be traced back to increasing destabilization of a sigma-type MO at scalar relativistic level, which translates into very different sigma-/pi-mixing if SO coupling is included. For the strongest trans ligands, the sigma-MO may move above the highest occupied pi-type MOs, thereby dramatically reducing strongly shielding contributions from predominantly pi-type spinors. The effects of SO-mixing are in turn related to angular momentum admixture from atomic spinors at the metal center. These SO induced trends hold for other nuclei and may also be used to qualitatively predict shifts in unknown complexes. PMID- 28338247 TI - Impact of diabetic ketoacidosis management in the medical intensive care unit after order set implementation. AB - OBJECTIVE: To determine the rate of compliance to the 2006 and 2009 ADA DKA guidelines in the medical intensive care unit (MICU) at a large academic medical centre after the implementation of a computerised DKA order set and protocol. METHODS: Retrospective chart review of adult patients with DKA admitted to the MICU. Results of pre-order set (PRE) were compared to those of data post-order set (POST). The primary outcome was a composite administration of intravenous fluid resuscitation in the first 24 h, insulin bolus and initial insulin infusion rate. KEY FINDINGS: Twelve of 60 patients (20%) in the PRE group received treatment compliant with the 2006 guidelines versus 14 of 55 patients (25.5%) in the POST group (OR 1.22 95% CI 0.44 to 3.4, P = 0.51). Compliance to the 2009 guidelines was significantly higher in the POST group (31.7% versus 65.5%, OR 4.44 95% CI 1.8 to 10.92, P = 0.0004). Compliance for individual components was 26.7% versus 70.9% for fluid resuscitation (P = 0.0001), 55% versus 49.1% for insulin bolus (P = 0.58) and 60% versus 81.3% for initial insulin infusion rate (P = 0.014), respectively. Time to DKA resolution was decreased (P = 0.04), and hypoglycaemia was increased (P = 0.0022). CONCLUSION: Implementation of a computerised DKA order set and protocol was associated with improved compliance to the 2009 ADA DKA guidelines, 24-h fluid resuscitation, initial insulin infusion rate, time to DKA resolution and appropriate transition to subcutaneous insulin. However, patients in the POST implementation group were more likely to exhibit hypoglycaemia. Future assessment is warranted. PMID- 28338248 TI - Surgical strategy for Apert syndrome: Retrospective study of developmental quotient and three-dimensional computerized tomography. AB - There are many surgical techniques for craniosynostosis. However, the indications for and timing of surgery still remain unclarified. Most of the skull growth in craniosynostosis is completed in the first year, and the bone is strong enough to undergo distraction osteogenesis. However, previous reports showed that patients operated on before 1 year of age had better IQ than those operated later in life. This report aims to consider the best timing for cranial expansion and surgical strategy for Apert syndrome. From January 2002 to December 2011, 13 patients with Apert syndrome were operated on and were followed up for more than 5 years. Nine patients underwent operations before 1 year of age (early surgery group) and three patients underwent operations later in life (late surgery group). They underwent fronto-orbital advancement for primary surgery. We evaluated postoperative developmental quotient every year and cephalic index (CI) measured by three-dimensional computerized tomography (3D-CT) at the age over 5 years retrospectively. Eleven of 13 patients improved their developmental quotient scores, with no significant intergroup differences. The CI evaluation showed cases with remnant brachycephalic deformity in both groups. Two patients with remnant plagiocephalic deformities tend to have primary surgery early in life compared to the others. Thus the delay in primary surgery had little influence on psychological development. We conclude that the primary surgery can be delayed unless the intracranial pressure needs to be controlled. In addition, fronto orbital advancement could not sufficiently improve the brachycephalic appearance, other procedures like posterior vault distraction might be better alternatives. PMID- 28338249 TI - Epidemiology, species distribution, clinical characteristics and mortality of candidaemia in a tertiary care university hospital in Turkey, 2007-2014. AB - Candidaemia still continues to be a serious medical concern and the epidemiology of candidaemia varies according to geographical areas. We aim to determine the incidence, local epidemiology, Candida species distribution and crude mortality rates of candidaemia. We retrospectively evaluated candidaemia episodes in between January 2007 and August 2014. We compared demographic, clinical, microbiological findings and mortality rates of episodes caused by Candida albicans and non-albicans Candida species. Overall the candidaemia incidences were 1.23 episodes/1000 admissions. A significant negative slope among candidaemia episodes and years was determined. Overall C. albicans (54.6%) was the most common species followed by Candida glabrata, Candida tropicalis and Candida parapsilosis respectively. Preinfection hospital stay and length of hospital stay were statistically longer in patients with non-albicans Candida candidaemia than in patients with C. albicans candidaemia. The source of candidaemia was unknown in 52.5% of all episodes. Central venous catheters among non-albicans Candida candidaemia episodes and urinary system among C. albicans candidaemia episodes were common source of candidaemia compared to each other. Previous antifungal therapy preceding candidaemia and concomitant bacteraemia were significantly associated with non-albicans Candida candidaemia. Continuous local surveillance will preserve its pivotal importance in formulating empirical antifungal therapy and improving management of candidaemia. PMID- 28338251 TI - A technique for relative quantitation of cancer biomarkers in formalin-fixed, paraffin-embedded (FFPE) tissue using stable-isotope-label based mass spectrometry imaging (SILMSI). AB - We developed a novel technique for the relative quantitation of pairs of cancer biomarkers in formalin-fixed paraffin-embedded (FFPE) tissue. The method utilizes stable isotope labeled (SIL) chromogens deposited during the standard immunohistochemistry (IHC) tissue staining process. The labeled chromogens are precipitated on tissue enzymatically using the standard IHC protocols. The tissue is then imaged with matrix-free laser desorption ionization time-of-flight mass spectrometry, and peak intensities of reporter ions are used to estimate the relative quantitation of protein biomarkers across the tissue. The relative abundance of two breast cancer biomarkers, estrogen receptor (ER) and progesterone receptor (PgR), were quantitated using their ratio of expression in xenograft models, and the ratios were found to be reproducible both within and across serial sections. The relative quantification of multiple biomarkers in situ across a single tissue section adds an additional dimension in cancer histological evaluation by allowing a visual and statistical assessment of tumor heterogeneity. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28338250 TI - Diversity in warning coloration is easily recognized by avian predators. AB - Warning coloration is a widespread strategy to alert predators about prey unprofitability. The success of this strategy partly depends on predators being able to learn and recognize certain signals as indicators of toxicity, and theory predicts that this is easier if signals converge on similar colours. However, the diversity in warning signal form is astonishing, contradicting predictions. Here, we quantified ladybird signal diversity with respect to avian vision, measuring how unique and discernible each signal is from one another. In addition, we measured signal conspicuousness against a series of backgrounds, namely an average green, average brown, and where we collected each species, to determine whether signals are more contrasting against the ladybirds' local substrates than compared to average ones. This allowed us to establish whether there are local adaptations in conspicuousness that promote signal diversity. We found that while ladybird signals are unique and recognizable, specialist species are more contrasting against the background they are most commonly found on. However, overall our study suggests that warning signals have evolved to be effective against a wide range of natural backgrounds, partly explaining the success of this strategy in nature. PMID- 28338252 TI - Identification and structural characterization of novel O- and N-glycoforms in the urine of a Schindler disease patient by Orbitrap mass spectrometry. AB - Schindler disease is an inherited metabolic disorder caused by the deficient activity of alpha-N-acetylgalactosaminidase enzyme. An accurate diagnosis requires, besides clinical examination, complex and costly biochemical and molecular genetic tests. In the last years, mass spectrometry (MS) based on nanofluidics and high-resolution instruments has become a successful alternative for disease diagnosis based on the investigation of O-glycopeptides in patient urine. A complex mixture of glycoforms extracted from the urine of a 3-year-old patient was investigated by Orbitrap MS equipped with Nanospray Flex Ion Source in the negative ion mode. For structural characterization of several molecular species, collision-induced dissociation MS2 -MS3 was carried out using collision energy values within 20-60 eV range. By our approach, 39 novel species associated to this condition were identified, among which O-glycopeptides, free O-glycans and one structure corresponding to an N-glycan never characterized in the context of Schindler disease. The experiments conducted at a resolution of 60 000 allowed the discrimination and identification of a total number of 69 different species with an average mass accuracy of 9.87 ppm, an in-run reproducibility of almost 100%, an experiment-to-experiment and day-to-day reproducibility of about 95%. This study brings contributions in the diagnosis of Schindler disease through the elucidation of potential biomarker species in urine. Our multistage MS results completed with 39 new glycoforms the inventory of potential biomarker structures associated to Schindler disease. For the first time, an N-glycan was identified and structurally characterized in Schindler patient urine, which opens new research directions in the field. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28338253 TI - Supermetallization of peptides and proteins during electrospray ionization. AB - The formation of metal-peptide complexes during electrospray ionization (ESI) is a widely known phenomenon and is often considered to be undesirable. Such effect considerably limits the use of ESI mass spectrometry for the investigation of biologically relevant metal-peptide compounds that are present in the solution and play critical roles in many bioprocesses such as progression of neurodegenerative diseases. In the article, it is demonstrated that under specific conditions such as high temperature of the desolvating capillary, an interesting effect, which can be called as 'supermetallization', occurs. Using a model peptide Alphabeta amyloid domain 1-16, it was observed that an increase in the temperature of the desolvating capillary results in multiple substitutions of hydrogen atoms by Zn atoms in this peptide. At high temperatures (T ~ 400 degrees C), up to 11 zinc atoms can be covalently bound to (1-16) Alphabeta. It was observed that supermetallization of (1-16) Alphabeta depends on the solvent composition and pH. Supermetallization was also demonstrated for proteins, such as ubiquitin and cytochrome C. That proves that the supermetallization is a general phenomenon for peptides and proteins. For the structural investigation of supermetallized complexes, electron-capture dissociation (ECD) fragmentation was applied. The effect of hydrogen rearranging during ECD was observed. In addition, quantum chemical calculations were used to estimate the possible structures of different supermetallized complexes. These results allow a more deep understanding of the limitations of the use of ESI mass spectrometry for the investigation of biologically relevant metal-peptide complexes. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28338254 TI - Static and dynamic headspace analysis of instant coffee blends by proton-transfer reaction mass spectrometry. AB - Instant coffee is a widespread product, generally related to a high consumer acceptability, also because of its ease of preparation. The present work addresses the characterization of the headspace of freshly brewed instant coffees resulting from different blends, during and immediately after preparation. The sample set consisted of 10 coffees, obtained by mixing three different blends in different proportions. The employment of Proton Transfer Reaction-Mass Spectrometry (PTR-MS) allowed for direct and real-time sampling from the headspace, under conditions that mimic those that are encountered above the cup during and right after brewing. Different coffee brews were separated on the basis of the respective volatile profiles, and data showed good consistency with the respective blend compositions. When the headspace evolution was monitored during preparation, similar results were obtained in terms of blend separation; moreover, different blends displayed different and reproducible 'signatures' in terms of time evolution. A straightforward method for the prediction of headspace composition is proposed, allowing to predict the volatile profiles of two component and three-component blends on the basis of the respective parent components. Overall, the results constitute a successful example of the applicability of PTR-MS as a tool for product development in food science. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28338255 TI - A fast and reliable detection of indigo in historic and prehistoric textile samples. AB - Across all cultures and over all time periods, as early as the third millennium BC, indigo, a very intense blue vat dye, has been used to dye textiles. Even today, indigo is regarded as one of the most popular blue colorants in items such as blue jeans. While synthetic indigo is used to color textiles today, throughout history, a variety of plants have provided indigo. In this special feature article, Rene Csuk and co-authors propose to use atmospheric solids analysis probe mass spectrometry (ASAP-MS) to very rapidly and reliably identify indigo colorants tiny amounts in ancient historic fabrics without any sample preparation. The ionization in ASAP experiments is effected by Penning ionization or by the transfer of protons originating from protonated clusters of water. Dr. Rene Csuk is Professor of organic bioorganic chemistry at the Martin-Luther Universitat Halle-Wittenberg (Halle, Germany). His main research interests are in organic and medicinal chemistry, chemical biology and phytochemistry. Graphical Abstract: Historical samples can be investigated conveniently using ASAP(r)-MS experiments. ASAP(r)-MS allowed for rapid direct sampling without any preparation of the sample prior to its measurements, and reliable results were generated in less than 1 minute. As demonstrated for indigoid-type dyes, the efficacy of ASAP(r)-MS analysis is independent of the type of fiber, the age of the sample, the workmanship, and the state of preservation. PMID- 28338256 TI - Direct analysis in real time mass spectrometry (DART-MS) of highly non-polar low molecular weight polyisobutylenes. AB - Low molecular weight polyisobutylenes (PIB) with chlorine, olefin and succinic acid end-groups were studied using direct analysis in real time mass spectrometry (DART-MS). To facilitate the adduct ion formation under DART conditions, NH4 Cl as an auxiliary reagent was deposited onto the PIB surface. It was found that chlorinated adduct ions of olefin and chlorine telechelic PIBs, i.e. [M + Cl]- up to m/z 1100, and the deprotonated polyisobutylene succinic acid [M?H]- were formed as observed in the negative ion mode. In the positive ion mode formation of [M + NH4 ]+ , adduct ions were detected. In the tandem mass (MS/MS) spectra of [M + Cl]- , product ions were absent, suggesting a simple dissociation of the precursor [M + Cl]- into a Cl- ion and a neutral M without fragmentation of the PIB backbones. However, structurally important product ions were produced from the corresponding [M + NH4 ]+ ions, allowing us to obtain valuable information on the arm-length distributions of the PIBs containing aromatic initiator moiety. In addition, a model was developed to interpret the oligomer distributions and the number average molecular weights observed in DART-MS for PIBs and other polymers of low molecular weight. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28338257 TI - A fast and reliable detection of indigo in historic and prehistoric textile samples. AB - We present a method requiring no sample preparation for the direct identification of indigoid colorants in tiny amounts in ancient historic fabrics using ASAP(r) MS. Exact determinations were completed in less than 1 min. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28338258 TI - Electroosmotically driven solution mixing in borosilicate theta glass nESI emitters. AB - The use of borosilicate theta glass capillaries as nanoelectrospray ionization emitters has recently been demonstrated as a method for mixing two solutions as they are sprayed into the mass spectrometer for analysis. All previous experiments resulted in a solution mixing timescale limited to the time the analytes spend in the Taylor cone and subsequent droplets (i.e. sub-millisecond timescale). In an effort to extend the solution mixing timescale to the milliseconds regime, we demonstrate that solution can be moved from one channel of the theta tip to the opposite channel via electroosmosis by applying a potential difference between the two wire electrodes inserted into each channel of the theta tip. First, we establish that electroosmosis is responsible for solution movement using fluorescence microscopy to track fluorescent tracer dyes. We then demonstrate the utility of this technique in varying the extent of denaturation of holomyoglobin to apomyoglobin on the millisecond timescale just prior to analysis by mass spectrometry. Finally, we induce additional turbulence for better mixing by applying a square wave potential to one of the wire electrodes while holding the opposite wire at a constant voltage between the low and high potentials of the square wave. This experiment was found to provide nearly complete mixing after a single cycle of the square wave. The use of electroosmosis significantly expands the flexibility of theta tips for altering solutions prior to nESI without the need for off-line sample manipulation. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28338259 TI - Theoretical investigation on confinement of ions in a cube-shaped ion trap. AB - The confinement of ions in a cube-shaped ion trap and the mathematical formalism governing the behavior of ions in the trap is investigated theoretically. Afterwards, the stability regions are computed using the fourth-order Rung-Kutta method. Consequently, the influence of the direction of ions, injected into the trap from its center on the stability region, is numerically discussed. Moreover, the maximum angle of injection with respect to the vertical axis of the cube for which the ions could be confined in the trap without invoking any direct current component of voltage (henceforth referred to as limiting angle) was calculated. Strong linear correlation between the angle of injection and the ratio of the stability region areas is confirmed. A nonlinear feature of a cube-shaped ion trap is demonstrated with a focus on the equations of motion for an ion confined into the trap. It is worthwhile to note that the stability region of our cubic ion trap, which has its own boundary conditions and electrodynamics, has been theoretically investigated for the first time. Besides, the limiting angle as well as the aforementioned strong linear correlation has not been reported in the literature previously. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28338260 TI - Iron(II)-Catalyzed Hydrophosphination of Isocyanates. AB - The first transition metal catalyzed hydrophosphination of isocyanates is presented. The use of low-coordinate iron(II) precatalysts leads to an unprecedented catalytic double insertion of isocyanates into the P-H bond of diphenylphosphine to yield phosphinodicarboxamides [Ph2 PC(=O)N(R)C(=O)N(H)R], a new family of derivatized organophosphorus compounds. This remarkable result can be attributed to the low-coordinate nature of the iron(II) centers whose inherent electron deficiency enables a Lewis-acid mechanism in which a combination of the steric pocket of the metal center and substrate size determines the reaction products and regioselectivity. PMID- 28338261 TI - Extracorporeal photopheresis for the treatment of early-stage mycosis fungoides. AB - Extracorporeal photopheresis (ECP) has been used for nearly 30 years in the treatment of cutaneous T-cell lymphoma. However, current clinical practice largely reserves ECP for patients with late-stage mycosis fungoides (MF) or Sezary syndrome or for those who are refractory to other therapies. We briefly describe a 48-year-old male who experienced long-term complete remission of his patch MF disease with ECP, and we suggest a role for ECP in the treatment of early-stage MF given evidence of its efficacy, safety, and tolerability. PMID- 28338262 TI - Steering On-Surface Reactions by a Self-Assembly Approach. AB - 4,4'-Bis(2,6-difluoropyridin-4-yl)-1,1':4',1''-terphenyl (BDFPTP) molecules underwent dehydrocyclization and covalent coupling reactions on Au(111) according to scanning tunneling microscopy (STM) measurements and density functional theory (DFT) calculations. Self-assembly of the reactants in well-defined molecular domains prior to reaction could greatly enhance the regioselectivity of the dehydrocyclization reaction and suppress defluorinated coupling, demonstrating that self-assembly can efficiently steer on-surface reactions. Such a strategy could be of great importance in surface chemistry and widely applied to control on-surface reactions. PMID- 28338263 TI - Synthesis of Poly(arylene vinylene)s with Different End Groups by Combining Acyclic Diene Metathesis Polymerization with Wittig-type Couplings. AB - A series of end-functionalized poly(9,9'-di-n-octylfluorene vinylene)s (EF-PFVs) with different end groups were obtained by 1) synthesizing EF-PFV with vinyl end groups by acyclic diene metathesis (ADMET) polymerization with a molybdenum catalyst and termination with an aldehyde and 2) subsequent olefin metathesis of the vinyl group with the molybdenum catalyst followed by Wittig-type coupling with another aldehyde. The exclusive formation of EF-PFVs containing a vinyl end group by the ADMET polymerization was confirmed by grafting PEG, and by the synthesis of amphiphilic triblock copolymers by combining atom transfer radical polymerization from the PFV chain end with PEG grafting through a click reaction. Various EF-PFVs with different end groups, such as C6 F5 , pyridyl, ferrocenyl, and terthiophene, have thus been prepared. Their fluorescence spectra (e.g., intensities, emission wavelengths) were influenced by the end groups and the length of the conjugation. PMID- 28338264 TI - Engineering High-Energy Interfacial Structures for High-Performance Oxygen Involving Electrocatalysis. AB - Engineering high-energy interfacial structures for high-performance electrocatalysis is achieved by chemical coupling of active CoO nanoclusters and high-index facet Mn3 O4 nano-octahedrons (hi-Mn3 O4 ). A thorough characterization, including synchrotron-based near edge X-ray absorption fine structure, reveals that strong interactions between both components promote the formation of high-energy interfacial Mn-O-Co species and high oxidation state CoO, from which electrons are drawn by MnIII -O present in hi-Mn3 O4 . The CoO/hi Mn3 O4 demonstrates an excellent catalytic performance over the conventional metal oxide-based electrocatalysts, which is reflected by 1.2 times higher oxygen evolution reaction (OER) activity than that of Ru/C and a comparable oxygen reduction reaction (ORR) activity to that of Pt/C as well as a better stability than that of Ru/C (95 % vs. 81 % retained OER activity) and Pt/C (92 % vs. 78 % retained ORR activity after 10 h running) in alkaline electrolyte. PMID- 28338265 TI - Acupuncture plus moxibustion for herpes zoster: A systematic review and meta analysis of randomized controlled trials. AB - Herpes zoster is an acute inflammatory condition which can have a significant impact on quality of life. Antiviral therapies are effective, but do not meet patients' expectations of symptomatic relief. Acupuncture and moxibustion have been used for herpes zoster; this systematic review evaluated their efficacy and safety. Nine English and Chinese databases were searched from their inceptions to March 2016. Randomized controlled trials evaluating the combination of acupuncture plus moxibustion in adult herpes zoster were included. Outcomes included pain intensity and duration, quality of life and adverse events. Meta analysis was performed using RevMan software (version 5.3). Nine studies (945 participants) were included. Studies were of low to moderate methodological quality based on risk of bias assessment. Pain intensity (visual analogue scale) was lower among those who received acupuncture plus moxibustion compared with pharmacotherapy (one study; MD -8.25 mm, 95% CI -12.36 to -4.14). The clinical significance of this result is yet to be established. Some benefits were seen for other pain and cutaneous outcomes, and global improvement in symptoms. Mild adverse events were reported in the intervention groups. Acupuncture plus moxibustion may improve pain and cutaneous outcomes, although current evidence is limited by the number of studies and methodological shortcomings. PMID- 28338266 TI - Accelerated Oxygen Atom Transfer and C-H Bond Oxygenation by Remote Redox Changes in Fe3 Mn-Iodosobenzene Adducts. AB - We report the synthesis, characterization, and reactivity of [LFe3 (PhPz)3 OMn(s PhIO)][OTf]x (3: x=2; 4: x=3), where 4 is one of very few examples of iodosobenzene-metal adducts characterized by X-ray crystallography. Access to these rare heterometallic clusters enabled differentiation of the metal centers involved in oxygen atom transfer (Mn) or redox modulation (Fe). Specifically, 57 Fe Mossbauer and X-ray absorption spectroscopy provided unique insights into how changes in oxidation state (FeIII2 FeII MnII vs. FeIII3 MnII ) influence oxygen atom transfer in tetranuclear Fe3 Mn clusters. In particular, a one-electron redox change at a distal metal site leads to a change in oxygen atom transfer reactivity by ca. two orders of magnitude. PMID- 28338268 TI - Chiral Amino Alcohol Accelerated and Stereocontrolled Allylboration of Iminoisatins: Highly Efficient Construction of Adjacent Quaternary Stereogenic Centers. AB - We have developed a highly efficient asymmetric allylboration of ketimines with nonchiral gamma,gamma-disubstituted allylboronic acids by using a chiral amino alcohol as the directing group, which is otherwise challenging. The amino alcohol not only serves as a cheap source of nitrogen and chirality, but also dramatically enhances the reactivity. The versatility of this method was demonstrated by its ability to access all four stereoisomers with adjacent quaternary carbon centers. A reaction model was proposed to explain the diastereoselectivity and the rate-accelerating effect. PMID- 28338267 TI - Disrupted intrinsic connectivity of the periaqueductal gray in patients with functional dyspepsia: A resting-state fMRI study. AB - BACKGROUND: Functional dyspepsia (FD) is a common functional gastrointestinal disorder. Accumulating evidence suggests the crucial role of central nervous system in the development and maintenance of FD. In particular, periaqueductal gray (PAG) has demonstrated an important role in modulation of pain and emotion, which may be related to FD. However, the study of the PAG in FD is still limited. This study aimed to assess intrinsic connectivity of the PAG in FD patients. METHODS: Resting-state functional magnetic imaging (fMRI) data were collected from 66 FD patients and 42 healthy controls (HCs). Functional connectivity analysis was performed to investigate the PAG connectivity pattern differences between the patients and HCs. We then examined the relationships between functional connectivity within the PAG networks and FD symptoms. KEY RESULTS: Compared to HCs, patients had increased PAG connectivity with the insula, and decreased PAG connectivity with the orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (dlPFC) and hippocampus/parahippocampus (HIPP/paraHIPP). There were positive correlations between disease duration and PAG connectivity with the putamen and supplementary motor area (SMA), and positive correlations between symptom severity and PAG connectivity with the insula. FD patients with high level of anxiety and depression had altered PAG connectivity with the anterior cingulate cortex (ACC), precuneus, dlPFC and caudate, compared to other patients. CONCLUSIONS & INFERENCES: These findings indicate that abnormal intrinsic network of the PAG might be associated with abnormality of pain processing and disruption of emotion processing in FD patients. Our study further complements neuroimaging findings about FD. PMID- 28338269 TI - Silymarin for the treatment of obsessive-compulsive disorders in dermatology. PMID- 28338270 TI - High-resolution MALDI-TOF MS study on analysis of low-molecular-weight products from photo-oxidation of poly(3-hexylthiophene). AB - High-resolution matrix-assisted laser desorption/ionization (MALDI) time-of flight mass spectrometry (TOF MS) was used for the analysis of the low-molecular weight products from the photo-oxidation of poly(3-hexylthiophene) (P3HT) in solution and thin film. Eight new peak series were observed in the low-mass range of the mass spectra of the products degraded in solution, and the formulas of the eight components were determined from the accurate mass. From SEC/MALDI-TOF MS, two components were identified as the degraded products, and the other six components were derived from the fragmentation of the degraded products during the MALDI process. A mechanism for the formation of these components was proposed on the basis of the results of MALDI-TOF MS. For the thin film degradation, a part of products in the solution degradation were observed, which supports that the oxidation of P3HT in solution and thin film proceeded in the same mechanism. This study shows that high-resolution MALDI-TOF MS is effective for the analysis of the low-molecular-weight products from P3HT photo-oxidation and expected to be feasible for the degradation analyses of other polymers. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28338271 TI - Identification strategies for flame retardants employing time-of-flight mass spectrometric detectors along with spectral and spectra-less databases. AB - In the past, the preferred strategy for the identification of unknown compounds was to search in an appropriate mass spectral database for spectra obtained using either electron ionisation (GC-MS analyses) or collision-induced dissociation (LC MS/MS analyses). Recently, an increase has been seen in the use of accurate mass instruments and spectra-less databases, based on monoisotopic accurate mass alone. In this article, we describe a systematic workflow for the screening and identification of new flame retardants. This approach utilises LC-quadrupole-time of-flight MS and spectra-less databases based only on monoisotopic accurate mass for the identification of 'unknowns'. An in-house database was built, and the input parameters used in the data analysis process were optimised for flame retardant chemicals, so that it can be easily transferred to other laboratories. The procedure was successfully applied to dust, foam and textiles from car interiors and indoor consumer products. The developed method was demonstrated for the main new flame retardant present in Antiblaze V6 and for the three unreported reaction by-products/impurities present in the same technical mixture. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28338273 TI - Effects of GC temperature and carrier gas flow rate on on-line oxygen isotope measurement as studied by on-column CO injection. AB - Although deemed important to delta18 O measurement by on-line high-temperature conversion techniques, how the GC conditions affect delta18 O measurement is rarely examined adequately. We therefore directly injected different volumes of CO or CO-N2 mix onto the GC column by a six-port valve and examined the CO yield, CO peak shape, CO-N2 separation, and delta18 O value under different GC temperatures and carrier gas flow rates. The results show the CO peak area decreases when the carrier gas flow rate increases. The GC temperature has no effect on peak area. The peak width increases with the increase of CO injection volume but decreases with the increase of GC temperature and carrier gas flow rate. The peak intensity increases with the increase of GC temperature and CO injection volume but decreases with the increase of carrier gas flow rate. The peak separation time between N2 and CO decreases with an increase of GC temperature and carrier gas flow rate. delta18 O value decreases with the increase of CO injection volume (when half m/z 28 intensity is <3 V) and GC temperature but is insensitive to carrier gas flow rate. On average, the delta18 O value of the injected CO is about 10/00 higher than that of identical reference CO. The delta18 O distribution pattern of the injected CO is probably a combined result of ion source nonlinearity and preferential loss of C16 O or oxygen isotopic exchange between zeolite and CO. For practical application, a lower carrier gas flow rate is therefore recommended as it has the combined advantages of higher CO yield, better N2 -CO separation, lower He consumption, and insignificant effect on delta18 O value, while a higher-than-60 degrees C GC temperature and a larger-than-100 ul CO volume is also recommended. When no N2 peak is expected, a higher GC temperature is recommended, and vice versa. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28338272 TI - In vitro metabolism studies of desoxy-methyltestosterone (DMT) and its five analogues, and in vivo metabolism of desoxy-vinyltestosterone (DVT) in horses. AB - The positive findings of norbolethone in 2002 and tetrahydrogestrinone in 2003 in human athlete samples confirmed that designer steroids were indeed being abused in human sports. In 2005, an addition to the family of designer steroids called 'Madol' [also known as desoxy-methyltestosterone (DMT)] was seized by government officials at the US-Canadian border. Two years later, a positive finding of DMT was reported in a mixed martial arts athlete's sample. It is not uncommon that doping agents used in human sports would likewise be abused in equine sports. Designer steroids would, therefore, pose a similar threat to the horseracing and equestrian communities. This paper describes the in vitro metabolism studies of DMT and five of its structural analogues with different substituents at the 17alpha position (R?H, ethyl, vinyl, ethynyl and 2 H3 -methyl). In addition, the in vivo metabolism of desoxy-vinyltestosterone (DVT) in horses will be presented. The in vitro studies revealed that the metabolic pathways of DMT and its analogues occurred predominantly in the A-ring by way of a combination of enone formation, hydroxylation and reduction. Additional biotransformation involving hydroxylation of the 17alpha-alkyl group was also observed for DMT and some of its analogues. The oral administration experiment revealed that DVT was extensively metabolised and the parent drug was not detected in urine. Two in vivo metabolites, derived respectively from (1) hydroxylation of the A-ring and (2) di-hydroxylation together with A-ring double-bond reduction, could be detected in urine up to a maximum of 46 h after administration. Another in vivo metabolite, derived from hydroxylation of the A-ring with additional double-bond reduction and di-hydroxylation of the 17alpha-vinyl group, could be detected in urine up to a maximum of 70 h post-administration. All in vivo metabolites were excreted mainly as glucuronides and were also detected in the in vitro studies. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28338274 TI - Identification of hydroxymethylpyrazines using mass spectrometry. AB - Pyrazines are well-known natural products that are present in bacterial odours and food flavouring agents and are used as insect pheromones. Recently, a number of hydroxymethylpyrazines have been identified as thynnine wasp pheromones and orchid semiochemicals that are essential for pollination in sexually deceptive plants. These compounds are present in low amounts in complex blends, making GC MS (including high-resolution techniques) the method of choice for their structure elucidation. We report the EI mass spectra for 14 representative compounds and have found that based on characteristic fragmentations, it is possible to distinguish between different positional isomers of hydroxymethylpyrazines. The presence or absence of either [M - 17]+ , [M - 18]+. or [M - 19]+ fragment species provides characteristic information to allow the distinction between the different isomers. Considering the importance of pyrazines as a group of bioactive natural products, and the recent findings of biological activity for hydroxymethylpyrazines, our results presented here will aid the identification of these compounds in other biological systems. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28338275 TI - Fast quantitative determination of methylphenidate levels in rat plasma and brain ex vivo by MALDI-MS/MS. AB - This study presents a simple and sensitive high-throughput matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry (MALDI-MS/MS) method for ex vivo quantification of methylphenidate (MPH) in rat plasma and brain. The common MALDI matrix alpha-cyano-4-hydroxycinnamic acid was used to obtain an optimal dried droplet preparation. For method validation, standards diluted in plasma and brain homogenate prepared from untreated (control) rats were used. MPH was quantified within a concentration range of 0.1-40 ng/ml in plasma and 0.4-40 ng/ml in brain homogenate with an excellent linearity (R2 >= 0.9997) and good precision. The intra-day and inter-day accuracies fulfilled the FDA's +/-15/20 critera. The recovery of MPH ranged from 93.8 to 98.5% and 87.2 to 99.8% in plasma and homogenate, respectively. We show that MPH is successfully quantified in plasma and brain homogenate of rats pre-treated with this drug using the internal standard calibration method. By means of this method, a linear correlation between plasma and brain concentration of MPH in rodents pre-treated with MPH was detected. The simple sample preparation based on liquid-liquid extraction and MALDI-MS/MS measurement requires approximately 10 s per sample, and this significantly reduces analysis time compared with other analytical methods. To the best of our knowledge, this is the first MALDI-MS/MS method for quantification of MPH in rat plasma and brain. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28338276 TI - Loss of atomic nitrogen from even-electron ions? A study on benzodiazepines. AB - The fragment spectra of protonated nitro-substituted benzodiazepines show an unusual fragment [M + H - 14]+ , which is shown by accurate mass measurement to be due to the loss of a nitrogen atom. Our investigations show that this apparent loss of atomic nitrogen is rather an attachment of molecular oxygen to the [M + H - NO2 ]+* ion, which is the main fragment ion in these spectra. The oxygen attachment is exothermic, and rate constants have been derived. MSn spectra show that it is not easily reversible upon fragmentation of the adduct ion and that it is also observed with some secondary and tertiary fragments, which allows to limit the attachment site to the aromatic ring annulated to the diazepine moiety. Fragments of the oxygen adduct ion indicate that the O2 molecule dissociates in the adduct formation process, and the two oxygen atoms are bound to different sites of the ion. Comparison with radical cations generated by fragmentation of non-nitro-substituted benzodiazepines, none of which showed an oxygen attachment, and the fragmentation mechanisms involved in their formation indicates that the [M + H - NO2 ]+* ion is a distonic ion with the charge and radical site neighbored on the aromatic ring. From these results, we derive a proposal for the formation and structure of the [M + H - NO2 + O2 ]+* ion, which explains the experimental observations. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28338277 TI - Emission of volatile sesquiterpenes and monoterpenes in grapevine genotypes following Plasmopara viticola inoculation in vitro. AB - The grapevine (Vitis vinifera) is one of the most widely cultivated fruit crops globally, and one of its most important diseases in terms of economic losses is downy mildew, caused by Plasmopara viticola. Several wild Vitis species have been found to be resistant to this pathogen and have been used in breeding programs to introduce resistance traits to susceptible cultivars. Plant defense is based on different mechanisms, and volatile organic compounds (VOCs) play a major role in the response to insects and pathogens. Although grapevine resistance mechanisms and the production of secondary metabolites have been widely characterized in resistant genotypes, the emission of VOCs has not yet been investigated following P. viticola inoculation. A Proton Transfer Reaction-Time of Flight-Mass Spectrometer (PTR-ToF-MS) was used to analyze the VOCs emitted by in vitro-grown plants of grapevine genotypes with different levels of resistance. Downy mildew inoculation significantly increased the emission of monoterpenes and sesquiterpenes by the resistant SO4 and Kober 5BB genotypes, but not by the susceptible V. vinifera Pinot noir. Volatile terpenes were implicated in plant defense responses against pathogens, suggesting that they could play a major role in the resistance against downy mildew by direct toxicity or by inducing grapevine resistance. The grapevine genotypes differed in terms of the VOC emission pattern of both inoculated and uninoculated plants, indicating that PTR ToF-MS could be used to screen hybrids with different levels of downy mildew resistance. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28338278 TI - Processed eggshell as sample carrier for rapid analysis of organometallic compounds by desorption electrospray ionization mass spectrometry. PMID- 28338279 TI - Elemental Boron for Efficient Carbon Dioxide Reduction under Light Irradiation. AB - The photoreduction of CO2 is attractive for the production of renewable fuels and the mitigation of global warming. Herein, we report an efficient method for CO2 reduction over elemental boron catalysts in the presence of only water and light irradiation through a photothermocatalytic process. Owing to its high solar-light absorption and effective photothermal conversion, the illuminated boron catalyst experiences remarkable self-heating. This process favors CO2 activation and also induces localized boron hydrolysis to in situ produce H2 as an active proton source and electron donor for CO2 reduction as well as boron oxides as promoters of CO2 adsorption. These synergistic effects, in combination with the unique catalytic properties of boron, are proposed to account for the efficiency of the CO2 reduction. This study highlights the promise of photothermocatalytic strategies for CO2 conversion and also opens new avenues towards the development of related solar-energy utilization schemes. PMID- 28338280 TI - Patients' views on their decision making during inpatient rehabilitation after newly acquired spinal cord injury-A qualitative interview-based study. AB - INTRODUCTION: Involving patients in decision making is a legal requirement in many countries, associated with better rehabilitation outcomes, but not easily accomplished during initial inpatient rehabilitation after severe trauma. Providing medical treatment according to the principles of shared decision making is challenging as a point in case for persons with spinal cord injury (SCI). OBJECTIVES: The aim of this study was to retrospectively explore the patients' views on their participation in decision making during their first inpatient rehabilitation after onset of SCI, in order to optimize treatment concepts. METHODS: A total of 22 participants with SCI were interviewed in-depth using a semi-structured interview scheme between 6 months and 35 years post-onset. Interviews were transcribed verbatim and analysed with the Mayring method for qualitative content analysis. RESULTS: Participants experienced a substantially reduced ability to participate in decision making during the early phase after SCI. They perceived physical, psychological and environmental factors to have impacted upon this ability. Patients mentioned regaining their ability to make decisions was an important goal during their first rehabilitation. Receiving adequate information in an understandable and personalized way was a prerequisite to achieve this goal. Other important factors included medical and psychological condition, personal engagement, time and dialogue with peers. CONCLUSION: During the initial rehabilitation of patients with SCI, professionals need to deal with the discrepancy between the obligation to respect a patient's autonomy and their diminished ability for decision making. PMID- 28338281 TI - Cardiovascular safety of vildagliptin in patients with type 2 diabetes: A European multi-database, non-interventional post-authorization safety study. AB - The aim of this non-interventional, multi-database, analytical cohort study was to assess the cardiovascular (CV) safety of vildagliptin vs other non-insulin antidiabetic drugs (NIADs) using real-world data from 5 European electronic healthcare databases. Patients with type 2 diabetes aged >=18 years on NIAD treatment were enrolled. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the outcomes of interest (myocardial infarction [MI], acute coronary syndrome [ACS], stroke, congestive heart failure [CHF], individually and as a composite) were estimated using negative binomial regression. Approximately 2.8% of the enrolled patients (n = 738 054) used vildagliptin at any time during the study, with an average follow-up time of 1.4 years, resulting in a cumulative current vildagliptin exposure of 28 330 person-years. The adjusted IRRs (vildagliptin [+/-other NIADs] vs other NIADs) were in the range of 0.61 to 0.97 (MI), 0.55 to 1.60 (ACS), 0.02 to 0.77 (stroke), 0.49 to 1.03 (CHF), and 0.22 to 1.02 (composite CV outcomes). The IRRs and their 95% CIs were close to 1, demonstrating no increased risk of adverse CV events, including the risk of CHF, with vildagliptin vs other NIADs in real-world conditions. PMID- 28338284 TI - Palladium-Catalyzed Enantioselective Synthesis of 2-Aryl Cyclohex-2-enone Atropisomers: Platform Molecules for the Divergent Synthesis of Axially Chiral Biaryl Compounds. AB - The palladium-catalyzed asymmetric synthesis of enone-based atropisomers from 2 iodo-3-methylcyclohex-2-enones and aryl boronic acid is reported. BoPhoz-type phosphine-aminophosphine ligands showed superior enantioselectivity over other ligands. These cyclohexenone-based atropisomers are useful compounds for further elaboration. The divergent synthesis of biaryl atropisomers with different ortho substituents was demonstrated. PMID- 28338282 TI - Don't forget to look down - collaborative approaches to predator conservation. AB - Finding effective ways of conserving large carnivores is widely recognised as a priority in conservation. However, there is disagreement about the most effective way to do this, with some favouring top-down 'command and control' approaches and others favouring collaboration. Arguments for coercive top-down approaches have been presented elsewhere; here we present arguments for collaboration. In many parts of the developed world, flexibility of approach is built into the legislation, so that conservation objectives are balanced with other legitimate goals. In the developing world, limited resources, poverty and weak governance mean that collaborative approaches are likely to play a particularly important part in carnivore conservation. In general, coercive policies may lead to the deterioration of political legitimacy and potentially to non-compliance issues such as illegal killing, whereas collaborative approaches may lead to psychological ownership, enhanced trust, learning, and better social outcomes. Sustainable hunting/trapping plays a crucial part in the conservation and management of many large carnivores. There are many different models for how to conserve carnivores effectively across the world, research is now required to reduce uncertainty and examine the effectiveness of these approaches in different contexts. PMID- 28338285 TI - Remote Control of Cellular Functions: The Role of Smart Nanomaterials in the Medicine of the Future. AB - The remote control of cellular functions through smart nanomaterials represents a biomanipulation approach with unprecedented potential applications in many fields of medicine, ranging from cancer therapy to tissue engineering. By actively responding to external stimuli, smart nanomaterials act as real nanotransducers able to mediate and/or convert different forms of energy into both physical and chemical cues, fostering specific cell behaviors. This report describes those classes of nanomaterials that have mostly paved the way to a "wireless" control of biological phenomena, focusing the discussion on some examples close to the clinical practice. In particular, magnetic fields, light irradiation, ultrasound, and pH will be presented as means to manipulate the cellular fate, due to the peculiar physical/chemical properties of some smart nanoparticles, thus providing realistic examples of "nanorobots" approaching the visionary ideas of Richard Feynman. PMID- 28338286 TI - Structural Reversibility and Nickel Particle stability in Lanthanum Iron Nickel Perovskite-Type Catalysts. AB - Perovskite-type oxides have shown the ability to reversibly segregate precious metals from their structure. This reversible segregation behavior was explored for a commonly used catalyst metal, Ni, to prevent Ni sintering, which is observed on most catalyst support materials. Temperature-programmed reduction, X ray diffraction, X-ray absorption spectroscopy, electron microscopy, and catalytic activity tests were used to follow the extent of reversible Ni segregation. LaFe1-x Nix O3+/-delta (0<=x<=0.2) was synthesized using a citrate based solution process. After reduction at 600 degrees C, metallic Ni particles were displayed on the perovskite surfaces, which were active towards the hydrogenation of CO2 . The overall Ni reducibility was proportional to the Ni content and increased from 35 % for x=0.05 to 50 % for x=0.2. Furthermore, Ni could be reincorporated reversibly into the perovskite lattice during reoxidation at 650 degrees C. This could be exploited for catalyst regeneration under conditions under which impregnated materials such as Ni/LaFeO3+/-delta and Ni/Al2 O3 suffer from sintering. PMID- 28338287 TI - Synthesis of Rationally Halogenated Buckybowls by Chemoselective Aromatic C-F Bond Activation. AB - Halogenated buckybowls or bowl-shaped polycyclic aromatic hydrocarbons (BS-PAHs) are key building blocks for the "bottom-up" synthesis of various carbon-based nanomaterials with outstanding potential in different fields of technology. The current state of the art provides quite a limited number of synthetic pathways to BS-PAHs; moreover, none of these approaches show high selectivity and tolerance of functional groups. Herein we demonstrate an effective route to BS-PAHs that includes directed intramolecular aryl-aryl coupling through C-F bond activation. The coupling conditions were found to be completely tolerant toward aromatic C-Br and C-Cl bonds, thus allowing the facile synthesis of rationally halogenated buckybowls with an unprecedented level of selectivity. This finding opens the way to functionalized BS-PAH systems that cannot be obtained by alternative methods. PMID- 28338288 TI - A comparison inhibitory effects of cisplatin and MNPs-PEG-cisplatin on the adhesion capacity of bone metastatic breast cancer. AB - To date, high mortality in women due to malignancy breast cancer related to the metastasis to the bone is a significant challenge. As, magnetic nanoparticles (MNPs) conjugated with the biocompatible polymers was employed for the delivery of some hydrophobic anticancer agents, the main aim of the current research was to assess whether cisplatin-loaded MNPs enhanced the anticancer effect of free cisplatin in breast cancer cells. MNPs decorated with PEG were synthesized by an improved coprecipitation technique, and then cisplatin was loaded onto the MNPs via a simple mixing method. Afterward, its morphology, size, chemical structure, magnetic property, hydrodynamic diameter, zeta potential, and crystal structure were characterized by scanning and transmittance electron microscopy, Fourier transforms infrared spectroscopy, vibrating sample magnetometer, dynamic light scattering, and X-ray powder diffraction and flame atomic absorption spectroscopy respectively. Additionally, the effects of cisplatin and MNPs-PEG-cisplatin on viability, migration and adhesion capacity of T47D cells were investigated by evaluating alpha2-integrin and beta1-integrin; mRNAs were assessed by real-time RT-PCR. Consequently, the in vitro assay results showed a considerable dose dependent inhibitory effect of cisplatin and MNPs-PEG-cisplatin on proliferation, migration, and adhesion of T47D cells. Finally, current research was shown that MNPs-PEG-cisplatin strongly increased anticancer effects compared with free cisplatin in the T47D cell line. PMID- 28338289 TI - A Sodium-Ion-Conducting Direct Formate Fuel Cell: Generating Electricity and Producing Base. AB - A barrier that limits the development of the conventional cation-exchange membrane direct liquid fuel cells (CEM-DLFCs) is that the CEM-DLFCs need additional base to offer both alkaline environment and charge carriers. Herein, we propose a Na+ -conducting direct formate fuel cell (Na-DFFC) that is operated in the absence of added base. A proof-of-concept Na-DFFC yields a peak power density of 33 mW cm-2 at 60 degrees C, mainly because the hydrolysis of sodium formate provides enough OH- and Na+ ions, proving the conceptual feasibility. Moreover, contrary to the conventional chlor-alkali process, this Na-DFFC enables to generate electricity and produce NaOH simultaneously without polluting the environment. The Na-DFFC runs stably during 13 hours of continuous operation at a constant current of 10 mA, along with a theoretical production of 195 mg NaOH. This work presents a new type of electrochemical conversion device that possesses a wide range of potential applications. PMID- 28338290 TI - Identification of natural inhibitors of Bcr-Abl for the treatment of chronic myeloid leukemia. AB - Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of the hematopoietic stem cells, characterized at the molecular level by the bcr/abl gene rearrangement. Even though targeting the fusion gene product Bcr-Abl protein is a successful strategy, development of drug resistance and that of drug intolerance are currently the limitations for Bcr-Abl-targeted CML therapy. With an aim to develop natural Bcr-Abl inhibitors, we performed virtual screening (VS) of ZINC natural compound database by docking with Abl kinase using Glide software. Two natural inhibitors ZINC08764498 (hit1) and ZINC12891610 (hit2) were selected by considering their high Glide docking score and critical interaction with the hinge region residue Met-318 of Abl kinase. The reactivity of the two molecules was assessed computationally by density functional theory calculations. Further, the conformational transition, hydrogen bond interactions, and the binding energies were investigated during 10-ns molecular dynamics simulation of the Abl-hit complex. When tested in vitro, hit1 compared to hit2 showed selective inhibition of cell proliferation and induction of apoptosis in Bcr-Abl-positive K 562 leukemia cells. In summary, our results demonstrate that ZINC08764498, a coumarin derivative identified through VS, is a potential natural inhibitor for the treatment of CML. PMID- 28338291 TI - Versatile Polymer Nanoparticles as Two-Photon-Triggered Photosensitizers for Simultaneous Cellular, Deep-Tissue Imaging, and Photodynamic Therapy. AB - Clinical applications of current photodynamic therapy (PDT) photosensitizers (PSs) are often limited by their absorption in the UV-vis range that possesses limited tissue penetration ability, leading to ineffective therapeutic response for deep-seated tumors. Alternatively, two-photon excited PS (TPE-PS) using NIR light triggered is one the most promising candidates for PDT improvement. Herein, multimodal polymer nanoparticles (PNPs) from polythiophene derivative as two photon fluorescence imaging as well as two-photon-excited PDT agent are developed. The prepared PNPs exhibit excellent water dispersibility, high photostability and pH stability, strong fluorescence brightness, and low dark toxicity. More importantly, the PNPs also possess other outstanding features including: (1) the high 1 O2 quantum yield; (2) the strong two-photon-induced fluorescence and efficient 1 O2 generation; (3) the specific accumulation in lysosomes of HeLa cells; and (4) the imaging detection depth up to 2100 um in the mock tissue under two-photon. The multifunctional PNPs are promising candidates as TPE-PDT agent for simultaneous cellular, deep-tissue imaging, and highly efficient in vivo PDT of cancer. PMID- 28338292 TI - Rational drug design of indazole-based diarylurea derivatives as anticancer agents. AB - A series of novel indazole-based diarylurea derivatives targeting c-kit were designed by structure-based drug design. The derivatives were prepared, and their antiproliferative activities were evaluated against human colon cancer HCT-116 cell line and hepatocellular carcinoma PLC/PRF/5 cell line. The antiproliferative activities demonstrated that six of nine compounds exhibited comparable activities with sorafenib against HCT-116. The structure-activity relationship (SAR) analysis indicated that the indazole ring part tolerated different kinds of substituents, and the N position of the central pyridine ring played key roles in antiproliferative activity. The SAR and interaction mechanisms were further explored using molecular docking method. Compound 1i with N-(2-(pyrrolidin-1 yl)ethyl)-carboxamide possessed improved solubility, 596.1 ng/ml and best activities, IC50 at 1.0 MUm against HCT-116, and 3.48 MUm against PLC/PRF/5. It is a promising anticancer agent for further development. PMID- 28338294 TI - Paradoxical gain-of-function mutant of the G-protein-coupled receptor PROKR2 promotes early puberty. AB - The human genome encodes ~750 G-protein-coupled receptors (GPCRs), including prokineticin receptor 2 (PROKR2) involved in the regulation of sexual maturation. Previously reported pathogenic gain-of-function mutations of GPCR genes invariably encoded aberrant receptors with excessive signal transduction activity. Although in vitro assays demonstrated that an artificially created inactive mutant of PROKR2 exerted paradoxical gain-of-function effects when co transfected with wild-type proteins, such a phenomenon has not been observed in vivo. Here, we report a heterozygous frameshift mutation of PROKR2 identified in a 3.5-year-old girl with central precocious puberty. The mutant mRNA escaped nonsense-mediated decay and generated a GPCR lacking two transmembrane domains and the carboxyl-terminal tail. The mutant protein had no in vitro signal transduction activity; however, cells co-expressing the mutant and wild-type PROKR2 exhibited markedly exaggerated ligand-induced Ca2+ responses. The results indicate that certain inactive PROKR2 mutants can cause early puberty by enhancing the functional property of coexisting wild-type proteins. Considering the structural similarity among GPCRs, this paradoxical gain-of-function mechanism may underlie various human disorders. PMID- 28338293 TI - Long non-coding RNA 00312 regulated by HOXA5 inhibits tumour proliferation and promotes apoptosis in Non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer. The abnormal expression of many long non-coding RNAs (lncRNAs) has been reported involved in the progression of various tumours, which can be used as diagnostic indicators or antitumour targets. Here, we found that the long non-coding RNA 00312 was down-regulated in paired NSCLC tissues and correlated with poor clinical outcome; decreased linc00312 expression in NSCLC was associated with larger and later stage tumours. Functional experiments showed that linc00312 could inhibit cell proliferation and promote apoptosis in vitro and in vivo. Furthermore, we found that HOXA5 could bind in the promoter of linc00312 and up regulated the expression of it. Moreover, linc00312 was down-regulated in the plasma of NSCLC patients compared with that of healthy volunteers or other pulmonary diseases patients. Taken together, our findings indicated that linc00312 could be a novel diagnosis biomarker and a promising therapeutic target for NSCLC. PMID- 28338296 TI - Photochromism and Dual-Color Fluorescence in a Polyoxometalate-Benzospiropyran Molecular Switch. AB - The photophysical properties of a Keggin-type polyoxometalate (POM) covalently bounded to a benzospiropyran (BSPR) unit have been investigated. These studies reveal that both closed and open forms are emissive with distinct spectral features (lambdaem (closed form)=530 nm, lambdaem (open form)=670 nm) and that the fluorescence of the BSPR unit of the hybrid is considerably enhanced compared to BSPR parent compounds. While the fluorescence excitation energy of the BSPR reference compounds (370 nm) is close to the intense absorption responsible of the photochromic character (350 nm), the fluorescence excitation of the hybrid is shifted to lower energy (400 nm), improving the population of the emissive state. Combined NOESY NMR and theoretical calculations of the closed form of the hybrid give an intimate understanding of the conformation adopted by the hybrid and show that the nitroaryl moieties of the BSPR is folded toward the POM, which should affect the electronic properties of the BSPR. PMID- 28338297 TI - Atrial flutter regression in HIV-associated pulmonary arterial hypertension after treatment with bosentan. AB - Pulmonary arterial hypertension (PAH) is a rare condition characterized by an increase in pulmonary arterial resistance leading to right heart failure and death. Arrhythmias are a growing problem in PAH; therefore, maintenance of sinus rhythm is considered to be an important treatment aim in these patients. We described the case of a 46-year-old woman with HIV-associated pulmonary arterial hypertension who developed atrial flutter. After treatment with bosentan, it was observed a significant improvement in clinical and haemodynamic parameters. In addition, the AFL, which had previously persisted to both antiarrhythmic drug therapy and electrical stimulation, and had recurred after transthoracic electrical cardioversion, disappeared in absence of any antiarrhythmic drug. Though the precise factors responsible for supraventricular arrhythmogenesis are still largely obscure, it is likely that initiation and maintenance of AFL may depend on all the conditions that can lead to increase in right atrial pressure, size, and wall stress, such as PAH. In our case, bosentan reduced both mean pulmonary artery pressure (mPAP) value and right heart chambers pressures. Therefore, it is conceivable that with the anatomical substrate needed for the maintenance of AFL being disappeared, sinus rhythm was restored. PMID- 28338295 TI - Insights into the Mechanism of a Covalently Linked Organic Dye-Cobaloxime Catalyst System for Dye-Sensitized Solar Fuel Devices. AB - A covalently linked organic dye-cobaloxime catalyst system based on mesoporous NiO is synthesized by a facile click reaction for mechanistic studies and application in a dye-sensitized solar fuel device. The system is systematically investigated by photoelectrochemical measurements, density functional theory, time-resolved fluorescence, transient absorption spectroscopy, and photoelectron spectroscopy. The results show that irradiation of the dye-catalyst on NiO leads to ultrafast hole injection into NiO from the excited dye, followed by a fast electron transfer process to reduce the catalyst. Moreover, the dye adopts different structures with different excited state energies, and excitation energy transfer occurs between neighboring molecules on the semiconductor surface. The photoelectrochemical experiments also show hydrogen production by this system. The axial chloride ligands of the catalyst are released during photocatalysis to create the active sites for proton reduction. A working mechanism of the dye catalyst system on the photocathode is proposed on the basis of this study. PMID- 28338298 TI - Tidal airway closure in asthma and COPD. AB - Functional closure of small airways can occur during tidal breathing above functional residual capacity (FRC) both in asthma and COPD patients, especially during exacerbations. Such event has several noxious consequences on gas exchange, airway hyperresponsiveness and mechanical stress and strain within lung tissue and airway wall, mostly due to increase in ventilation heterogeneity. The availability of simple functional tests based on sequential measurements of lung volumes (i.e.: FRC), by plethysmography and dilutional techniques may reveal and monitor easily tidal airway closure that can be and should be treated with the aim of abolishing or at least reducing this dangerous condition. PMID- 28338299 TI - Erratum - Osteophytes may be a rare cause of recurrent pleural effusions. AB - This corrects the article published on Monaldi Archives for Chest Disease 2013;79(2):87-89. PMID- 28338300 TI - "Separated Root Canal Instruments - An overview of incidence, localisation, treatment strategies and outcome" AB - The dreaded fracture of a root canal instrument is in fact a rare adverse event. Most instrument fractures occur in molar teeth with the highest degree of root curvature. Various treatment options (leaving the fractured instrument with or without apicoectomy, bypassing or removing the fragment) and removing techniques (using ultrasonics, hollow tubes or bypassing and removing with debriders) are discussed. The clinical prognosis for teeth with fractured instruments is not necessarily compromised if appropriate further treatment is undertaken. Indeed, it is the timing of instrument fracture and the associated level of infection that will dictate treatment outcomes. PMID- 28338302 TI - Use of the Uro Dyna-CT in endourology - the new frontier. AB - We describe the use of the Uro Dyna-CT, an imaging system used in the operating room that produces real-time three-dimensional (3D) imaging and cross-sectional image reconstructions similar to an intraoperative computerized tomography, during a percutaneous nephrolithotomy and a contralateral flexible ureteroscopy in a complete supine position. A 65 year-old female patient had an incomplete calyceal staghorn stone in the right kidney and a 10mm in the left one. The procedure was uneventful and the intraoperative use of the Uro Dyna-CT identified 2 residual stones that were not found by digital fluoroscopy and flexible nephroscopy at the end of surgery, helping us to render the patient stone-free in one procedure, which was confirmed by a postoperative CT scan. Prospective studies will define the real role of the Uro Dyna-CT for endourological procedures, but its use seems to be a very promising tool for improving stone free rates and decreasing auxiliary procedures, especially for complex cases. PMID- 28338301 TI - Analgesia for patients undergoing shockwave lithotripsy for urinary stones - a systematic review and meta-analysis. AB - BACKGROUND: Shock wave lithotripsy (SWL) is the first line treatment modality for a significant proportion of patients with upper urinary tracts stones. Simple analgesics, opioids and non-steroidal anti-inflammatory drugs (NSAIDs) are all suitable agents but the relative efficacy and tolerability of these agents is uncertain. OBJECTIVES: To determine the efficacy of the different types of analgesics used for the control of pain during SWL for urinary stones. MATERIALS AND METHODS: We searched the Cochrane Renal Group's Specialised Register, MEDLINE, EMBASE and also hand-searched reference lists of relevant articles (Figure-1). Randomised controlled trials (RCT's) comparing the use of any opioid, simple analgesic or NSAID during SWL were included. These were compared with themselves, each-other or placebo. We included any route or form of administration (bolus, PCA). We excluded agents that were used for their sedative qualities. Data were extracted and assessed for quality independently by three reviewers. Meta-analyses have been performed where possible. When not possible, descriptive analyses of variables were performed. Dichotomous outcomes are reported as relative risk (RR) and measurements on continuous scales are reported as weighted mean differences (WMD) with 95% confidence intervals. RESULTS: Overall, we included 9 RCTs (539 participants from 6 countries). Trial agents included 7 types of NSAIDs, 1 simple analgesic and 4 types of opioids. There were no significant differences in clinical efficacy or tolerability between a simple analgesic (paracetamol) and an NSAID (lornoxicam). When comparing the same simple analgesic with an opioid (tramadol), both agents provided safe and effective analgesia for the purpose of SWL with no significant differences. There were no significant differences in pain scores between NSAIDs or opioids in three studies. Adequate analgesia could be achieved more often for opioids than for NSAIDs (RR 0.358; 95% CI 043 to 0.77, P=0.0002) but consumed doses of rescue analgesia were similar between NSAIDs and opioids in two studies (P=0.58, >0.05). In terms of tolerability, there is no difference in post-operative nausea and vomiting (PONV) between the groups (RR 0.72, 95% CI 0.24 to 2.17, P=0.55). One study compared outcomes between two types of NSAIDs (diclofenac versus dexketoprofen). There were no significant differences in any of our pre-defined outcomes measures. CONCLUSION: Simple analgesics, NSAIDs and opioids can all reduce the pain associated with shock wave lithotripsy to a level where the procedure is tolerated. Whilst there are no compelling differences in safety or efficacy of simple analgesics and NSAIDs, analgesia is described as adequate more often for opioids than NSAIDs. PMID- 28338303 TI - What is the quickest scoring system to predict percutaneous nephrolithotomy outcomes? A comparative study among S.T.O.N.E score, guy's stone score and croes nomogram. AB - OBJECTIVE: To compare the application time and the capacity of the nomograms to predict the success of Guy's Stone Score (GSS), S.T.O.N.E. Nephrolithometry (STONE) and Clinical Research Office of the Endourological Society nephrolithometric nomogram (CROES) of percutaneous nephrolithotomy (PCNL), evaluating the most efficient one for clinical use. MATERIALS AND METHODS: We studied 48 patients who underwent PCNL by the same surgeon between 2010 and 2011. We calculated GSS, STONE and CROES based on preoperative non-contrast computed tomography (CT) images and clinical data. A single observer, blinded to the outcomes, reviewed all images and assigned scores. We compared the application time of each nomogram. We used an analysis of variance for repeated measures and multiple comparisons by the Tukey test. We compared the area under the ROC curve (AUC) of the three nomograms two by two to determine the most predictive scoring system. RESULTS: The immediate success rate was 66.7% and complications occurred in 16.7% of cases. The average operative time was 122 minutes. Mean application time was significantly lower for the GSS (27.5 seconds) when compared to 300.6 seconds for STONE and 213.4 seconds for CROES (p<0.001). There was no significant difference among the GSS (AUC=0.653), STONE (AUC=0.563) and CROES (AUC=0.641) in the ability to predict immediate success of PCNL. CONCLUSIONS: All three nomograms showed similar ability to predict success of PCNL, however the GSS was the quickest to be applied, what is an important issue for routine clinical use when counseling patients who are candidates to PCNL. PMID- 28338304 TI - Hyberbaric oxygen as sole treatment for severe radiation - induced haemorrhagic cystitis. AB - PURPOSE: To examine the safety and efficacy of hyperbaric oxygen as the primary and sole treatment for severe radiation-induced haemorrhagic cystitis. MATERIALS AND METHODS: Hyperbaric oxygen was prospectively applied as primary treatment in 38 patients with severe radiation cystitis. Our primary endpoint was the incidence of complete and partial response to treatment, while the secondary endpoints included the duration of response, the correlation of treatment success rate to the interval between the onset of haematuria and initiation of therapy, blood transfusion need and total radiation dose, the number of sessions to success, the avoidance of surgery and the overall survival. RESULTS: All patients completed therapy without complications with a mean follow-up of 29.33 months. Median number of sessions needed was 33. Complete and partial response rate was 86.8% and 13.2%, respectively. All 33 patients with complete response received therapy within 6 months of the haematuria onset. One patient needed cystectomy, while 33 patients were alive at the end of follow-up. CONCLUSIONS: Our study suggests the early primary use of hyperbaric oxygen for radiation-induced severe cystitis as an effective and safe treatment option. PMID- 28338305 TI - Prostate cancer in renal transplant recipients. AB - As patients with end-stage renal disease are receiving renal allografts at older ages, the number of male renal transplant recipients (RTRs) being diagnosed with prostate cancer (CaP) is increasing. Historically, the literature regarding the management of CaP in RTR's is limited to case reports and small case series. To date, there are no standardized guidelines for screening or management of CaP in these complex patients. To better understand the unique characteristics of CaP in the renal transplant population, we performed a literature review of PubMed, without date limitations, using a combination of search terms including prostate cancer, end stage renal disease, renal transplantation, prostate cancer screening, prostate specific antigen kinetics, immunosuppression, prostatectomy, and radiation therapy. Of special note, teams facilitating the care of these complex patients must carefully and meticulously consider the altered anatomy for surgical and radiotherapeutic planning. Active surveillance, though gaining popularity in the general low risk prostate cancer population, needs further study in this group, as does the management of advance disease. This review provides a comprehensive and contemporary understanding of the incidence, screening measures, risk stratification, and treatment options for CaP in RTRs. PMID- 28338306 TI - Implantation of a biodegradable rectum balloon implant: tips, Tricks and Pitfalls. AB - INTRODUCTION: A rectum balloon implant (RBI) is a new device to spare rectal structures during prostate cancer radiotherapy. The theoretical advantages of a RBI are to reduce the high radiation dose to the anterior rectum wall, the possibility of a post-implant correction, and their predetermined shape with consequent predictable position. OBJECTIVE: To describe, step-by-step, our mini invasive technique for hands-free transperineal implantation of a RBI before start of radiotherapy treatment. MATERIALS AND METHODS: We provide step-by-step instructions for optimization of the transperineal implantation procedure performed by urologists and/or radiation oncologists experienced with prostate brachytherapy and the use of the real-time bi-plane transrectal ultrasonography (TRUS) probe. A RBI was performed in 15 patients with localised prostate cancer. Perioperative side-effects were reported. RESULTS: We provide 'tips and tricks' for optimizing the procedure and proper positioning of the RBI. Please watch the animation, see video in https://vimeo.com/205852376/789df4fae4. The side-effects included mild discomfort to slight pain at the perineal region in 8 out of 15 patients. Seven patients (47%) had no complaints at all. Two patients developed redness of the skin, where prompt antibiotic regimen was started with no further sequelae. One patient revealed a temporary urine retention, which resolved in a few hours following conservative treatment. Further no perioperative complications occurred. CONCLUSION: This paper describes in detail the implantation procedure for an RBI. It is a feasible, safe and very well-tolerated procedure. PMID- 28338307 TI - Evaluation of the Spies TM modalities image quality. AB - INTRODUCTION: The SpiesTM system (Karl-Storz(r)) was introduced into digital ureteroscopy to improve endoscopic vision. To date, there is no data to either indicate which of the Spies modalities is better for improving diagnosis and treatment procedures, nor to compare the modalities in terms of image quality. The aim of this study was to evaluate and compare the image quality of five SpiesTM modalities (SM) to the standard white light in an in-vitro model. MATERIALS AND METHODS: Two standardized grids and 3 stones of different composition were recorded in white light and the 5SM (Clara, Chroma, Clara+Chroma), Spectra A and B) using 4 standardized aqueous scenarios. Twelve templates were done in order to simultaneously compare the same objective in the different modalities. Six urologists, five medical students, five urology residents, and five persons not involved with urology evaluated each video on a scale of 1 (very bad) to 5 (very good). RESULTS: Comparing white light to SM, subjects scored better the quality of Clara and Clara+Chroma than white light (p=0.0139 and p<0.05) and scored worse Spectra A and B (p=0.0005 and p=0.0023). When comparing Clara to the other SM, it was ranked equivalent to Clara+Chroma (p=0.67) and obtained a higher rank than Chroma, Spectra A and B (p<0.05, p=0.0001 and p=0.0001). In the multivariate analysis mean scores were higher among urologists. CONCLUSION: In all analyzed scenarios, the subjects ranked Clara and Clara+Chroma as the modalities with better image quality compared to white light. PMID- 28338308 TI - Penile alterations at early stage of type 1 diabetes in rats. AB - OBJECTIVE: Diabetes affects the erectile function significantly. However, the penile alterations in the early stage of diabetes in experimental animal models have not been well studied. We examined the changes of the penis and its main erectile components in diabetic rats. MATERIALS AND METHODS: Male Sprague-Dawley rats were divided into 2 groups: streptozotocin (STZ)-induced diabetics and age matched controls. Three or nine weeks after diabetes induction, the penis was removed for immunohistochemical staining of smooth muscle and neuronal nitric oxide synthase (nNOS) in midshaft penile tissues. The cross-sectional areas of the whole midshaft penis and the corpora cavernosa were quantified. The smooth muscle in the corpora cavernosa and nNOS in the dorsal nerves were quantified. RESULTS: The weight, but not the length, of the penis was lower in diabetics. The crosssectional areas of the total midshaft penis and the corpora cavernosa were lower in diabetic rats compared with controls 9 weeks, but not 3 weeks after diabetes induction. The cross-sectional area of smooth muscle in the corpora cavernosa as percentage of the overall area of the corpora cavernosa was lower in diabetic rats than in controls 9 weeks, but not 3 weeks after diabetes induction. Percentage change of nNOS in dorsal nerves was similar at 3 weeks, and has a decreased trend at 9 weeks in diabetic rats compared with controls. CONCLUSIONS: Diabetes causes temporal alterations in the penis, and the significant changes in STZ rat model begin 3-9 weeks after induction. Further studies on the reversibility of the observed changes are warranted. PMID- 28338309 TI - Impact of personalized three-dimensional -3D- printed pelvicalyceal system models on patient information in percutaneous nephrolithotripsy surgery: a pilot study. AB - OBJECTIVE: To investigate the impact of personalized three dimensional (3D) printed pelvicalyceal system models on patient information before percutaneous nephrolithotripsy surgery. MATERIAL AND METHODS: Patients with unilateral complex renal stones with indicatation of percutaneous nephrolithotripsy surgery were selected. Usable data of patients were obtained from CT scans as Digital Imaging and Communications in Medicine (DICOM) format. Mimics software version 16.0 (Materialise, Belgium) was used for segmentation and extraction of pelvicalyceal systems. DICOM format were converted to Stereolithography file format. Finally, fused deposition modeling was used to create plasticine 3D models of pelvicalyceal systems. A questionnaire was designed for patients to assess personalized 3D models effect on patient's understanding their conditions before percutaneous nephrolithotripsy surgery (PCNL). The day before surgery, each patient was seen by a urologist to deliver information about surgery. Questionnaire forms were asked to patients complete before and after presentation of 3D models and the results of the questions were compared. RESULTS: Five patient's anatomically accurate models of the human renal collecting system were successfully generated. After the 3D printed model presentation, patients demonstrated an improvement in their understanding of basic kidney anatomy by 60% (p=0.017), kidney stone position by 50% (p=0.02), the planned surgical procedure by 60% (p=0.017), and understanding the complications related to the surgery by 64% (p=0.015). In addition, overall satisfaction of conservation improvement was 50% (p=0.02). CONCLUSION: Generating kidney models of PCSs using 3D printing technology is feasible, and understandings of the disease and the surgical procedure from patients were well appreciated with this novel technology. PMID- 28338310 TI - Metastatic prostate cancer in the modern era of PSA screening. AB - INTRODUCTION: To characterize initial presentation and PSA screening status in a contemporary cohort of men treated for metastatic prostate cancer at our institution. MATERIALS AND METHODS: We reviewed records of 160 men treated for metastatic prostate cancer between 2008-2014 and assessed initial presentation, categorizing patients into four groups. Groups 1 and 2 presented with localized disease and received treatment. These men suffered biochemical recurrence late (>1 year) or earlier (<1 year), respectively, and developed metastases. Groups 3 and 4 had asymptomatic and symptomatic metastases at the outset of their diagnosis. Patients with a first PSA at age 55 or younger were considered to have guideline-directed screening. RESULTS: Complete records were available on 157 men for initial presentation and 155 men for PSA screening. Groups 1, 2, 3 and 4 included 27 (17%), 7 (5%), 69 (44%) and 54 (34%) patients, respectively. Twenty (13%) patients received guideline-directed PSA screening, 5/155 (3%) patients presented with metastases prior to age 55 with their first PSA, and 130/155 (84%) had their first PSA after age 55, of which 122/130 (94%) had metastasis at the time of diagnosis. CONCLUSION: Despite widespread screening, most men treated for metastatic prostate cancer at our institution presented with metastases rather than progressed after definitive treatment. Furthermore, 25 (16%) patients received guideline-directed PSA screening at or before age 55. These data highlight that, despite mass screening efforts, patients treated for incurable disease at our institution may not have been a result of a failed screening test, but a failure to be screened. PMID- 28338312 TI - Engineering Nanoscale Iron Oxides for Uranyl Sorption and Separation: Optimization of Particle Core Size and Bilayer Surface Coatings. AB - Herein, we describe engineered superparamagnetic iron oxide nanoparticles (IONPs) as platform materials for enhanced uranyl (UO22+) sorption and separation processes under environmentally relevant conditions. Specifically, monodispersed 8-25 nm iron oxide (magnetite, Fe3O4) nanoparticles with tailored organic acid bilayered coatings have been systematically evaluated and optimized to bind, and thus remove, uranium from water. The combined nonhydrolytic synthesis and bilayer phase transfer material preparation methods yield highly uniform and surface tailorable IONPs, which allow for direct evaluation of the size-dependent and coating-dependent sorption capacities of IONPs. Optimized materials demonstrate ultrahigh sorption capacities (>50% by wt/wt) at pH 5.6 for 8 nm oleic acid (OA) bilayer and sodium monododecyl phosphate (SDP) surface-stabilized IONPs. Synchrotron-based X-ray absorption spectroscopy shows that iron oxide core particle size and stabilizing surface functional group(s) substantially affect U(VI)-removal mechanisms, specifically the ratio of uptake via adsorption versus reduction to U(IV). Taken together, tunable size and surface functionality, high colloidal stability, and favorable affinity toward uranium provide distinct synergistic advantage(s) for the application of bilayered IONPs as part of the next-generation material-based uranium recovery, remediation, and sensing technologies. PMID- 28338311 TI - Validation of self - confidence scale for clean urinary intermittent self - catheterization for patients and health - caregivers. AB - OBJECTIVE: To validate a measurement instrument for clean intermittent self catheterization for patients and health-caregivers. MATERIAL AND METHODS: Methodological study of instrument validation performed at a Rehabilitation Center in a University hospital for patients submitted to clean intermittent self catheterization and their health-caregivers. Following ethical criteria, data were collected during interview with nurse staff using a Likert question form containing 16 items with 5 points each: "no confidence"=1, "little confidence"=2, "confident"=3, "very confident"=4 and "completely confident"=5. Questionnaire called "Self- Confident Scale for Clean Intermittent Self-catheterization" (SCSCISC) was constructed based on literature and previously validated (appearance and content). RESULTS: The instrument was validated by 122 patients and 119 health-caregivers, in a proportion of 15:1. It was observed a good linear association and sample adequacy KMO 0.931 and X2=2881.63, p<0.001. Anti-image matrix showed high values at diagonal suggesting inclusion of all factors. Screen plot analysis showed a suggestion of items maintenance in a single set. It was observed high correlation of all items with the total, alpha-Cronbach 0.944. The same results were obtained in subsamples of patients and health-caregivers. CONCLUSION: The instrument showed good psychometric adequacy corroborating its use for evaluation of self-confidence during clean intermittent self catheterization. PMID- 28338313 TI - Ultimate Control of Rate-Dependent Adhesion for Reversible Transfer Process via a Thin Elastomeric Layer. AB - Adhesion between a stamp with an elastomeric layer and various devices or substrates is crucial to successfully fabricate flexible electronics using a transfer process. Although various transfer processes using stamps with different adhesion strengths have been suggested, the controllable range of adhesion is still limited to a narrow range. To precisely transfer devices onto selected substrates, however, the difference in adhesion between the picking and placing processes should be large enough to achieve a high yield. Herein, we report a simple way to extend the controllable adhesion range of stamps, which can be achieved by adjusting the thickness of the elastomeric layer and the separation velocity. The adhesion strength increased with decreasing layer thickness on the stamp due to a magnification of the confinement and rate-dependent effects on the adhesion. This enabled the controllable range of the adhesion strength for a 15 MUm-thick elastomeric layer to be extended up to 12 times that of the bulk under the same separation conditions. The strategy of designing stamps using simple adhesion tests is also introduced, and the reversible transfer of thin Si chips was successfully demonstrated. Tuning and optimizing the adhesion strength of a stamp according to the design process suggested here can be applied to various materials for the selective transfer and replacement of individual devices. PMID- 28338314 TI - Surface Layer Evolution on Graphite During Electrochemical Sodium-tetraglyme Co intercalation. AB - One obstacle in sodium ion batteries is the lack of suitable anode materials. As recently shown, the most common anode material of the state of the art lithium ion batteries, graphite, can be used for sodium ion storage as well, if ether based electrolyte solvents are used. These solvents cointercalate with the sodium ions leading to the highly reversible formation of ternary graphite intercalation compounds (t-GIC). In order for the solvent cointercalation to work efficiently, it is expected that only a very thin surface layer forms during electrochemical cycling. In this article, we therefore present the first dedicated study of the surface layer evolution on t-GICs using soft X-ray photoelectron spectroscopy. This technique with its inherent high surface sensitivity and low probing depth is an ideal tool to study the underlying interfacial reactions during the sodiation and desodiation of graphite. In this report, we apply this approach to graphite composite electrodes cycled in Na half cells with a 1 M sodium bis(fluorosulfonyl)imide/tetraethylene glycol dimethyl ether (NaFSI/TEG-DME) electrolyte. We have found a surface layer on the cycled electrodes, mainly composed of salt decomposition products and hydrocarbons, in line with irreversible capacity losses observed in the electrochemical cycling. Although this surface layer does not seem to block cointercalation completely, it seems to affect its efficiency resulting in a low Coulombic efficiency of the studied battery system. PMID- 28338315 TI - Solid-Solution Alloying of Immiscible Ru and Cu with Enhanced CO Oxidation Activity. AB - We report on novel solid-solution alloy nanoparticles (NPs) of Ru and Cu that are completely immiscible even above melting point in bulk phase. Powder X-ray diffraction, scanning transmission electron microscopy, and energy-dispersive X ray measurements demonstrated that Ru and Cu atoms were homogeneously distributed in the alloy NPs. Ru0.5Cu0.5 NPs demonstrated higher CO oxidation activity than fcc-Ru NPs, which are known as one of the best monometallic CO oxidation catalysts. PMID- 28338316 TI - Quantitative Characterization of the Surface Evolution for LiNi0.5Co0.2Mn0.3O2/Graphite Cell during Long-Term Cycling. AB - Many factors have been brought forward to explain the capacity degradation mechanisms of LiNixCoyMnzO2 (NCM)/graphite cells at extreme conditions such as under high temperature or with high cutoff voltage. However, the main factors dominating the long-term cycling performance under normal operations remain elusive. Quantitative analyses of the electrode surface evolution for a commercial 18650 LiNi0.5Co0.2Mn0.3O2 (NCM523)/graphite cell during ca. 3000 cycles under normal operation are presented. Electrochemical analyses and inductively coupled plasma-optical emission spectroscopy (ICP-OES) confirm lithium inventory loss makes up for ca. 60% of the cell's capacity loss. Electrochemical deterioration of the NCM523 cathode is identified to be another important factor, which accounts for more than 30% of the capacity decay. Irregular primary particle cracking due to the mechanical stress and the phase change aroused from Li-Ni mixing during repetitive cycles are identified to be the main contributors for the NCM cathode deterioration. The amount of transition metal dissolved into electrolyte is determined to be quite low, and the resulting impedance rise after about 3000 cycles is obtained to be twice that of the reference cell, which are not very significant affecting the long-term cycling performance under normal operations. PMID- 28338317 TI - Kinetics and Mechanism of the Oxidation of Thiourea Dioxide by Iodine in a Slightly Acidic Medium. AB - The thiourea dioxide (TDO)-iodine reaction was investigated spectrophotometrically monitoring the consumption of total amount of iodine at 468 nm, at T = 25.0 +/- 0.1 degrees C, and at 0.5 M ionic strength in buffered slightly acidic medium. The nitrogen- and carbon-containing products were found to be ammonium ion and dissolved carbon dioxide, respectively, while from sulfur part sulfate ion was exclusively detected, when fresh TDO solution was used. The stoichiometry of the reaction was established as 2I2 + TDO + 4H2O -> SO42- + 2NH4+ + 4I- + CO2 + 4H+ indicating a strict 2:1 stoichiometric ratio. However, using aged TDO solution this stoichiometric ratio is shifted to lower values suggesting the formation of elementary sulfur augmented by the 2TDO + I2 + 4H2O > S + SO42- + 4NH4+ + 2I- + 2CO2 hypothetical limiting stoichiometry. We also confirmed experimentally that in aqueous solution TDO slowly rearranges into an unindentified species. This species then produces elementary sulfur at a later stage of the aging process via subsequent reactions accounting for a loss of reducing power. The direct reaction between TDO and iodine was found to be relatively rapid and completed within seconds in absence of initially added iodide ion. Formation of the latter ion, however, strongly inhibits the oxidation process; hence, the system is autoinhibitory with respect to iodide ion. Furthermore, increase of pH markedly accelerates the reaction as well. These observations suggest that a short-lived steady-state intermediate (iodinated TDO) is produced in a rapid pre-equilibrium, where iodide and hydrogen ions are also involved. A nine-step kinetic model, to be able to describe the most important characteristics of the experimental curves with four fitted parameters, is proposed and discussed. PMID- 28338318 TI - Iron(II) Complexes with Scorpiand-Like Macrocyclic Polyamines: Kinetico Mechanistic Aspects of Complex Formation and Oxidative Dehydrogenation of Coordinated Amines. AB - The Fe(II) coordination chemistry of a pyridinophane tren-derived scorpiand type ligand containing a pyridine ring in the pendant arm is explored by potentiometry, X-ray, NMR, and kinetics methods. Equilibrium studies in water show the formation of a stable [FeL]2+ complex that converts to monoprotonated and monohydroxylated species when the pH is changed. A [Fe(H-2L)]2+ complex containing an hexacoordinated dehydrogenated ligand has been isolated, and its crystal structure shows the formation of an imine bond involving the aliphatic nitrogen of the pendant arm. This complex is low spin Fe(II) both in the solid state and in solution, as revealed by the Fe-N bond lengths and by the NMR spectra, respectively. The formation rate of [Fe(H-2L)]2+ in aqueous solutions containing Fe2+ and L (1:1 molar ratio) is strongly dependent on the pH, the process being completed in times that range from months in acid solutions to hours in basic conditions. However, detailed kinetic studies show that those differences are caused, at least in part, by the effect of pH on the rate of formation of the unoxidized [FeL]2+ complex. In this sense, the protonation of the donor atoms in the pendant arm of the scorpiand ligand leads to the formation of protonated species resistant to oxidative dehydrogenation. Complementary studies in acetonitrile solution indicate that the initial stage in the oxidative dehydrogenation process is the oxidation of the starting complex to form a [FeL]3+ complex, which then undergoes disproportionation into [Fe(H-2L)]2+ and [FeL]2+. Experiments starting with Fe(III) have allowed us to determine that disproportionation occurs with first order kinetics both in water and acetonitrile solutions. However, whereas a significant acceleration is observed in water when the pH is increased, no effect of the addition of acid or base on the rate of disproportionation is observed in acetonitrile. Oxidative dehydrogenation of the Fe(II) complex formed in experiments starting with an Fe(III) salt is slower than that occurring when an Fe(II) salt is used, an observation that can be explained in terms of the formation of two different Fe(III) complexes, one of them with a structure unable to evolve directly toward the product of oxidative dehydrogenation. PMID- 28338319 TI - Postmetalated Zirconium Metal Organic Frameworks as a Highly Potent Bactericide. AB - Metal-organic frameworks (MOFs) have emerged as an important class of hybrid organic-inorganic materials. One of the reasons they have gained remarkable attention is attributed to the possibility of altering them by postsynthetic modification, thereby providing access to new and novel advanced materials. MOFs have been applied in catalysis, gas storage, gas separation, chemical sensing, and drug delivery. However, their bactericidal use has rarely been explored. Herein, we developed a two-step process for the synthesis of zirconium-based MOFs metalated with silver cations as a potent antibacterial agent. The obtained products were thoroughly characterized by powder X-ray diffraction, scanning electron microscopy, UV-visible, IR, thermogravimetric, and Brunauer-Emmett Teller analyses. Their potency was evaluated against E. coli with a reported minimal inhibitory concentration and minimal bactericidal concentration of as low as 6.5 MUg/mL of silver content. Besides the novelty of the system, the advantage of this strategy is that the MOFs could be potentially regenerated and remetalated after each antibacterial test, unlike previously reported frameworks, which involved the destruction of the framework. PMID- 28338321 TI - Thiol-Reactive Star Polymers Display Enhanced Association with Distinct Human Blood Components. AB - Directing nanoparticles to specific cell types using nonantibody-based methods is of increasing interest. Thiol-reactive nanoparticles can enhance the efficiency of cargo delivery into specific cells through interactions with cell-surface proteins. However, studies to date using this technique have been largely limited to immortalized cell lines or rodents, and the utility of this technology on primary human cells is unknown. Herein, we used RAFT polymerization to prepare pyridyl disulfide (PDS)-functionalized star polymers with a methoxy-poly(ethylene glycol) brush corona and a fluorescently labeled cross-linked core using an arm first method. PDS star polymers were examined for their interaction with primary human blood components: six separate white blood cell subsets, as well as red blood cells and platelets. Compared with control star polymers, thiol-reactive nanoparticles displayed enhanced association with white blood cells at 37 degrees C, particularly the phagocytic monocyte, granulocyte, and dendritic cell subsets. Platelets associated with more PDS than control nanoparticles at both 37 degrees C and on ice, but they were not activated in the duration examined. Association with red blood cells was minor but still enhanced with PDS nanoparticles. Thiol-reactive nanoparticles represent a useful strategy to target primary human immune cell subsets for improved nanoparticle delivery. PMID- 28338322 TI - Hydrothermal Synthesis of the Oxofluoride FeSbO2F2-An Anti-ferromagnetic Spin S = 5/2 Compound. AB - The new oxofluoride compound FeSbO2F2 was synthesized by hydrothermal techniques at 230 degrees C. Its crystal structure was determined from single-crystal X-ray diffraction data. The compound crystallizes in the monoclinic space group C2/c with one crystallographic site for Fe3+ and Sb3+, respectively. The crystal structure is made of [FeO2F4] octahedra and seesaw [SbO4] building blocks. These are connected to form [FeO2F2]n layers and [SbO2]n chains that bond together via the oxygen atoms to form the three-dimensional framework structure. Magnetic susceptibility and heat capacity measurements indicate long-range anti ferromagnetic ordering below a Neel temperature of ~175 K. Two-dimensional anti ferromagnetic short-range order in the square planar net of the Fe3+ cations extends to temperatures far above the Neel temperature. PMID- 28338323 TI - Shape-Dependent Radiosensitization Effect of Gold Nanostructures in Cancer Radiotherapy: Comparison of Gold Nanoparticles, Nanospikes, and Nanorods. AB - The shape effect of gold (Au) nanomaterials on the efficiency of cancer radiotherapy has not been fully elucidated. To address this issue, Au nanomaterials with different shapes but similar average size (~50 nm) including spherical gold nanoparticles (GNPs), gold nanospikes (GNSs), and gold nanorods (GNRs) were synthesized and functionalized with poly(ethylene glycol) (PEG) molecules. Although all of these Au nanostructures were coated with the same PEG molecules, their cellular uptake behavior differed significantly. The GNPs showed the highest cellular responses as compared to the GNSs and the GNRs (based on the same gold mass) after incubation with KB cancer cells for 24 h. The cellular uptake in cells increased in the order of GNPs > GNSs > GNRs. Our comparative studies indicated that all of these PEGylated Au nanostructures could induce enhanced cancer cell-killing rates more or less upon X-ray irradiation. The sensitization enhancement ratios (SERs) calculated by a multitarget single-hit model were 1.62, 1.37, and 1.21 corresponding to the treatments of GNPs, GNSs, and GNRs, respectively, demonstrating that the GNPs showed a higher anticancer efficiency than both GNSs and GNRs upon X-ray irradiation. Almost the same values were obtained by dividing the SERs of the three types of Au nanomaterials by their corresponding cellular uptake amounts, indicating that the higher SER of GNPs was due to their much higher cellular uptake efficiency. The above results indicated that the radiation enhancement effects were determined by the amount of the internalized gold atoms. Therefore, to achieve a strong radiosensitization effect in cancer radiotherapy, it is necessary to use Au-based nanomaterials with a high cellular internalization. Further studies on the radiosensitization mechanisms demonstrated that ROS generation and cell cycle redistribution induced by Au nanostructures played essential roles in enhancing radiosensitization. Taken together, our results indicated that the shape of Au-based nanomaterials had a significant influence on cancer radiotherapy. The present work may provide important guidance for the design and use of Au nanostructures in cancer radiotherapy. PMID- 28338326 TI - Pd-Catalyzed Direct ortho-C-H Arylation of Aromatic Ketones Enabled by a Transient Directing Group. AB - The Pd-catalyzed direct C(sp2)-H arylation of aromatic ketones using a transient directing group is described. The ketimine/carboxylate bidentate directing group in situ generated from aromatic ketone and glycine enabled a palladium-catalyzed ortho-C-H arylation, which shows extensive substrate compatibility. PMID- 28338325 TI - Enhanced Electrochemical Performances of Bi2O3/rGO Nanocomposite via Chemical Bonding as Anode Materials for Lithium Ion Batteries. AB - Bismuth oxide/reduced graphene oxide (termed Bi2O3@rGO) nanocomposite has been facilely prepared by a solvothermal method via introducing chemical bonding that has been demonstrated by Raman and X-ray photoelectron spectroscopy spectra. Tremendous single-crystal Bi2O3 nanoparticles with an average size of ~5 nm are anchored and uniformly dispersed on rGO sheets. Such a nanostructure results in enhanced electrochemical reversibility and cycling stability of Bi2O3@rGO composite materials as anodes for lithium ion batteries in comparison with agglomerated bare Bi2O3 nanoparticles. The Bi2O3@rGO anode material can deliver a high initial capacity of ~900 mAh/g at 0.1C and shows excellent rate capability of ~270 mAh/g at 10C rates (1C = 600 mA/g). After 100 electrochemical cycles at 1C, the Bi2O3@rGO anode material retains a capacity of 347.3 mAh/g with corresponding capacity retention of 79%, which is significantly better than that of bare Bi2O3 material. The lithium ion diffusion coefficient during lithiation delithiation of Bi2O3@rGO nanocomposite has been evaluated to be around ~10-15-10 16 cm2/S. This work demonstrates the effects of chemical bonding between Bi2O3 nanoparticles and rGO substrate on enhanced electrochemical performances of Bi2O3@rGO nanocomposite, which can be used as a promising anode alterative for superior lithium ion batteries. PMID- 28338327 TI - Analysis of the Acting Forces in a Theory of Catalysis and Mechanochemistry. AB - The theoretical description of a chemical process resulting from the application of mechanical or catalytical stress to a molecule is performed by the generation of an effective potential energy surface (PES). Changes for minima and saddle points by the stress are described by Newton trajectories (NTs) on the original PES. From the analysis of the acting forces we postulate the existence of pulling corridors built by families of NTs that connect the same stationary points. For different exit saddles of different height we discuss the corresponding pulling corridors; mainly by simple two-dimensional surface models. If there are different exit saddles then there can exist saddles of index two, at least, between. Then the case that a full pulling corridor crosses a saddle of index two is the normal case. It leads to an intrinsic hysteresis of such pullings for the forward or the backward reaction. Assuming such relations we can explain some results in the literature. A new finding is the existence of roundabout corridors that can switch between different saddle points by a reversion of the direction. The findings concern the mechanochemistry of molecular systems under a mechanical load as well as the electrostatic force and can be extended to catalytic and enzymatic accelerated reactions. The basic and ground ansatz includes both kinds of forces in a natural way without an extra modification. PMID- 28338324 TI - Studies To Examine Potential Tolerability Differences between the 5-HT2C Receptor Selective Agonists Lorcaserin and CP-809101. AB - Lorcaserin (LOR) is a selective 5-HT2C receptor agonist that has been FDA approved as a treatment for obesity. The most frequently reported side-effects of LOR include nausea and headache, which can be dose limiting. We have previously reported that in the rat, while LOR produced unconditioned signs characteristic of nausea/malaise, the highly selective 5-HT2C agonist CP-809101 (CP) produced fewer equivalent signs. Because this may indicate a subclass of 5-HT2C agonists having better tolerability, the present studies were designed to further investigate this apparent difference. In a conditioned gaping model, a rodent test of nausea, LOR produced significantly higher gapes compared to CP consistent with it having higher emetogenic properties. Subsequent studies were designed to identify features of each drug that may account for such differences. In rats trained to discriminate CP-809101 from saline, both CP and LOR produced full generalization suggesting a similar interoceptive cue. In vitro tests of functional selectivity designed to examine signaling pathways activated by both drugs in CHO (Chinese hamster ovary) cells expressing h5-HT2C receptors failed to identify evidence for biased signaling differences between LOR and CP. Thus, both drugs showed similar profiles across PLC, PLA2, and ERK signaling pathways. In studies designed to examine pharmacokinetic differences between LOR and CP, while drug plasma levels correlated with increasing dose, CSF levels did not. CSF levels of LOR increased proportionally with dose; however CSF levels of CP plateaued from 6 to 12 mg/kg. Thus, the apparently improved tolerability of CP likely reflects a limit to CNS levels attained at relatively high doses. PMID- 28338328 TI - Polysulfide-Breathing/Dual-Conductive, Heterolayered Battery Separator Membranes Based on 0D/1D Mingled Nanomaterial Composite Mats. AB - Facile/sustainable utilization of sulfur active materials is an ultimate challenge in high-performance lithium-sulfur (Li-S) batteries. Here, as a membrane-driven approach to address this issue, we demonstrate a new class of polysulfide-breathing (capable of reversibly adsorbing and desorbing polysulfides)/dual (electron and ion) conductive, heterolayered battery separator membranes (denoted as "MEC-AA separators") based on 0D (nanoparticles)/1D (nanofibers) composite mats. The MEC-AA separator is fabricated through an in series, concurrent electrospraying/electrospinning process. The top layer of the MEC-AA separator comprises close-packed mesoporous MCM-41 nanoparticles spatially besieged by multiwalled carbon nanotubes (MWNT) wrapped poly(ether imide) (PEI) nanofibers. The MCM-41 in the top layer shows reversible adsorption/desorption of polysulfides, and the MWNT-wrapped PEI nanofibers act as a dual-conductive upper current collector. Preferential deposition of the MWNTs along the PEI nanofibers and dispersion state of the separator components are elucidated theoretically using computational methods. The support layer, which consists of densely packed Al2O3 nanoparticles and polyacrylonitrile nanofibers, serves as a mechanically/thermally stable and polysulfide-capturing porous membrane. The unique structure and multifunctionality of the MEC-AA separator allow for substantial improvements in redox reaction kinetics and cycling performance of Li S cells far beyond those achievable with conventional polyolefin separators. The heterolayered nanomat-based membrane strategy opens a new route toward electrochemically active/permselective advanced battery separators. PMID- 28338329 TI - Evidence for Electron-Hole Pair Excitation in the Associative Desorption of H2 and D2 from Au(111). AB - The dissociative adsorption reaction of hydrogen on noble metals is believed to be well-described within the Born-Oppenheimer approximation. In this work, we have experimentally derived translational energy distributions for selected quantum states of H2 and D2 formed in associative desorption reactions at a Au(111) surface. Using the principle of detailed balance, we compare our results to theory carried out at the same level of sophistication as was done for the reaction on copper. The theory predicts translational excitation that is much higher than is seen in experiment and fails to reproduce the experimentally observed isotope effect. The large deviations between experiment and theory are surprising because, for the same reactions occurring on Cu(111), a similar theoretical strategy agreed with experiment, yielding "chemical accuracy". We argue that electron-hole pair excitation is more important for the reaction on gold, an effect that may be related to the reaction's later transition state. PMID- 28338330 TI - Stereoselective Synthesis of (+)-Annuionone A and (-)-Annuionone B. AB - A stereoselective synthetic approach was utilized to synthesize enantiopure annuionones A (1b) and B (2b), two ionone-type norsesquiterpenoids that both bear a 6-oxabicyclo[3.2.1]octane framework and possess allelopathic activity. A stereoselective Diels-Alder reaction based on chiral trisubstituted dienophile 20 was employed to obtain the optically active polysubstituted cyclohexane core of both natural products. Using this approach, (+)-annuionone A (1b) and (-) annuionone B (2b) were synthesized from lactol (+)-15 in 10% overall yield. PMID- 28338331 TI - An In Silico Study on the Isomers of Pentacene: The Case for Air-Stable and Alternative C22H14 Acenes for Organic Electronics. AB - Pentacene is one of the most investigated candidates for organic thin film transistor (OTFT) applications over the last few decades even though it unstable in air (Eg = 1.80 eV), owing in part to its planar nature and high charge transfer mobilities as both a single crystal (35 cm2 V-1 s-1) and as a thin-film (3.0 cm2 V-1 s-1). Until now, picene is the only isomer of pentacene to be investigated for organic electronic applications, due to its greater stability (Eg = 4.21 eV) and high-charge transfer mobility (3.0 cm2 V-1 s-1); even benefiting from oxygen doping. In the present study, a total of 12 fused-ring isomers (including pentacene, picene and ten other structures) of the formula C22H14 were analyzed and investigated for their electronic and optical properties for worth in OTFT applications. We screened several pure and hybrid DFT functionals against the experimental frontier molecular orbitals (FMOs) of pentacene, then deployed Marcus Theory, Koopmans' Theorem and Green's function with the P3 electron propagator variant, for the internal hole reorganization energy, the hole transfer integral (via the "splitting-in-dimer method" at d = 3.0, 3.5, and 4.0 A), the charge transfer rate constant, and vertical ionization energies. Using these as a basis, we studied pentacene's isomers and found that the four nonplanar structures, namely, benzo[g]chrysene (3), naphtho[c]phenanthrene (7), benzo[c]chrysene (11) and dibenzo[c,c']phenthrene (12), are (I) more stable than pentacene, by up to 2 eV, and (II) have relatively similar ionization energies (7.5-7.6 eV) to those of picene's experimental value (7.51 eV). The largest charge transfer rates at 3.5 A dimer separations were given by the isomers benzo[b]chrysene 4, naphtha[c]phenanthrene 7, dibenzo[a,c]anthracene 8 and benzo[a]tetracene 10 and found to be 2.92, 1.72, 1.30, and 3.09 * 1014 s-1 respectively. In comparison to that of pentacene (KCT = 3.97 * 1014 s-1), these unusual isomers are thus promising air-stable and alternative candidates for organic electronic applications. PMID- 28338332 TI - Benchmark ab Initio Characterization of the Complex Potential Energy Surface of the F- + CH3CH2Cl Reaction. AB - We compute benchmark structures, frequencies, and relative energies for the stationary points of the potential energy surface of the F- + CH3CH2Cl reaction using explicitly correlated ab initio levels of theory. CCSD(T)-F12b geometries and harmonic vibrational frequencies are obtained with the aug-cc-pVTZ and aug-cc pVDZ basis sets, respectively. The benchmark relative energies are determined using a high-level composite method based on CCSD(T)-F12b/aug-cc-pVQZ frozen-core energies, CCSD(T)-F12b/cc-pCVTZ-F12 core electron correlation effects, and CCSD(T)-F12b/aug-cc-pVDZ zero-point energy corrections. The SN2 channel leading to Cl- + CH3CH2F (-33.2) can proceed via back-side (-11.5), front-side (29.1), and double-inversion (18.0) transition states, whereas the bimolecular elimination (E2) products, Cl- + HF + C2H4 (-19.3), can be formed via anti ( 15.0) and syn (-7.3) saddle points, whose best adiabatic energies relative to F- + CH3CH2Cl are shown in parentheses in kcal/mol. Besides the SN2 and E2 channels, the 0 K reaction enthalpies of the HF + H3C-CHCl- (29.4), H- + H3C-CHClF (46.2), H- + FH2C-CH2Cl (51.1), and FCl- + CH3CH2 (49.7) product channels are determined. Utilizing the new benchmark data, the performance of the DF-MP2, MP2, MP2-F12, CCSD(T), and CCSD(T)-F12b methods with aug-cc-pVDZ and aug-cc-pVTZ basis sets is tested. PMID- 28338333 TI - 1,2-Benzothiazines from Sulfoximines and Allyl Methyl Carbonate by Rhodium Catalyzed Cross-Coupling and Oxidative Cyclization. AB - 4-Unsubstituted 1,2-benzothiazines are prepared from sulfoximines and allyl methyl carbonate by Rh(III)-catalyzed domino allylation/oxidative cyclization. A wide range of functional groups on the sulfoximine are tolerated. A plausible mechanism is proposed, and chemical modifications of the products have been explored. PMID- 28338334 TI - A Theoretical Study on Methane C-H Bond Activation by Bare [FeO]+/0/. AB - The first C-H bond activation of methane by bare diatomic FeO in different charge states (cationic + , neutral 0, and anionic - ) has been studied by means of density functional theory (DFT) and CCSD(T) methods. The structures were optimized by using 10 popular different density functionals (DFs) with different Hartree-Fock exchange fractions, as well as the CCSD method and then were subjected to single point energy calculations at both the DFT level and the CCSD(T) level. The performance of these methods on the energies and structures in different charged states of the systems was discussed. The results show that the cationic system has lower barrier than the neutral and anionic systems. In most cases, the impact of density functionals is larger than that of structures on energies. Among the three charged states, the anionic system is the least sensitive to the density functionals. The electronic structure analysis demonstrates that the cationic and neutral systems proceed by either hydrogen atom transfer (HAT) or proton-coupled electron transfer (PCET), while the anionic system only employs the proton transfer (PT) mechanism. Knowledge from this study is of value for further studies on methane activation. PMID- 28338336 TI - The Journey Commemorating BIO's 15th Anniversary. PMID- 28338337 TI - An Interactive Picture Worth a Thousand References: Consciousness and Healing Initiative's Exemplary Infographic on Nontouch Therapies. PMID- 28338335 TI - Stress-Induced Protein S-Glutathionylation and S-Trypanothionylation in African Trypanosomes-A Quantitative Redox Proteome and Thiol Analysis. AB - AIMS: Trypanosomatids have a unique trypanothione-based thiol redox metabolism. The parasite-specific dithiol is synthesized from glutathione and spermidine, with glutathionylspermidine as intermediate catalyzed by trypanothione synthetase. In this study, we address the oxidative stress response of African trypanosomes with special focus on putative protein S-thiolation. RESULTS: Challenging bloodstream Trypanosoma brucei with diamide, H2O2 or hypochlorite results in distinct levels of reversible overall protein S-thiolation. Quantitative proteome analyses reveal 84 proteins oxidized in diamide-stressed parasites. Fourteen of them, including several essential thiol redox proteins and chaperones, are also enriched when glutathione/glutaredoxin serves as a reducing system indicating S-thiolation. In parasites exposed to H2O2, other sets of proteins are modified. Only three proteins are S-thiolated under all stress conditions studied in accordance with a highly specific response. H2O2 causes primarily the formation of free disulfides. In contrast, in diamide-treated cells, glutathione, glutathionylspermidine, and trypanothione are almost completely protein bound. Remarkably, the total level of trypanothione is decreased, whereas those of glutathione and glutathionylspermidine are increased, indicating partial hydrolysis of protein-bound trypanothione. Depletion of trypanothione synthetase exclusively induces protein S-glutathionylation. Total mass analyses of a recombinant peroxidase treated with T(SH)2 and either diamide or hydrogen peroxide verify protein S-trypanothionylation as stable modification. INNOVATION: Our data reveal for the first time that trypanosomes employ protein S thiolation when exposed to exogenous and endogenous oxidative stresses and trypanothione, despite its dithiol character, forms protein-mixed disulfides. CONCLUSION: The stress-specific responses shown here emphasize protein S trypanothionylation and S-glutathionylation as reversible protection mechanism in these parasites. Antioxid. Redox Signal. 27, 517-533. PMID- 28338339 TI - Drugs that Suppress Lactation, Part 2. PMID- 28338320 TI - Inhibitors of Protein Methyltransferases and Demethylases. AB - Post-translational modifications of histones by protein methyltransferases (PMTs) and histone demethylases (KDMs) play an important role in the regulation of gene expression and transcription and are implicated in cancer and many other diseases. Many of these enzymes also target various nonhistone proteins impacting numerous crucial biological pathways. Given their key biological functions and implications in human diseases, there has been a growing interest in assessing these enzymes as potential therapeutic targets. Consequently, discovering and developing inhibitors of these enzymes has become a very active and fast-growing research area over the past decade. In this review, we cover the discovery, characterization, and biological application of inhibitors of PMTs and KDMs with emphasis on key advancements in the field. We also discuss challenges, opportunities, and future directions in this emerging, exciting research field. PMID- 28338338 TI - The Strategies of Heterosexuals from Large Metropolitan Areas for Assessing the Risks of Exposure to HIV or Other Sexually Transmitted Infections from Partners Met Online. AB - Heterosexuals' use of the Internet for meeting romantic or sexual partners is rapidly increasing, raising concerns about the Internet's potential to facilitate encounters that place individuals at risk for acquiring HIV or other sexually transmitted infections (STIs). For example, online sharing of personal information and self-revelations can foster virtual intimacy, promoting a false sense of familiarity that might accelerate progression to unprotected sex. Therefore, it is critical to understand how those who meet sexual partners online attempt to assess the possible risk of acquiring HIV or STIs posed by having unprotected sex with a new partner and decide whether to use a condom. To investigate this issue, in-depth interviews were conducted with a diverse sample of heterosexual male and female participants from large metropolitan cities who had had unprotected vaginal or anal sex with at least two partners met online in the past 3 months. With few exceptions, participants relied on faulty strategies and heuristics to estimate these risks; yet, most engaged in unprotected sex at their first meeting or very soon afterward. While some seemed to try to make a genuine effort to arrive at a reliable assessment of the HIV risk posed, most appeared to be looking for a way to justify their desire and intention to have unprotected sex. The findings suggest the need for more HIV and sexual health education targeted at heterosexuals, especially for those who go online to meet partners. PMID- 28338340 TI - Serum interleukin-6 is related to lower cognitive functioning in elderly patients with major depression. AB - BACKGROUND: There is an increased evidence of an association between inflammatory mediators, particularly serum IL-6, depression and cognitive impairment in the elderly. This study aims at exploring the relation of peripheral IL-6 to cognitive functions in elderly patients with major depressive disorder (MDD). OBJECTIVES: (1) Assessment of serum IL-6 levels and cognitive functions in elderly patients suffering from major depression and comparing them to healthy age-matched control subjects; (2) correlation between serum IL-6 levels and clinical characteristics of depression and cognitive functions in these patients. SUBJECTS AND METHODS: The study is an observational, case-control study. It consisted of 80 subjects, 40 with the diagnosis of MDD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM IV-TR) with early onset (first episode before the age of 60) and 40 community-dwelling subjects. They were subjected to the Structured Clinical Interview according to DSM-IV, Montreal Cognitive Assessment, Montgomery Asberg Depression Rating Scale, and serum IL-6 assay using ELISA. RESULTS: In the depression group, subjects had lower scores in cognitive testing, than the control group (p = 0.001). Serum IL-6 was found to have a negative correlation with cognitive testing in these patients even after controlling for the severity of depressive status and Body Mass Index (BMI) (p = 0.025). CONCLUSIONS: MDD in elderly subjects is associated with decline in cognitive functions that may be related to peripheral IL-6 levels. PMID- 28338342 TI - Development of matrix solid-phase dispersion coupled with high-performance liquid chromatography for determination of jolkinolide A and jolkinolide B in Euphorbia fischeriana Steud. AB - A novel and simple method was established for the extraction and determination of jolkinolide A and B in Euphorbia fischeriana Steud. using matrix solid-phase dispersion (MSPD) extraction and high-performance liquid chromatography (HPLC). The optimised conditions for the MSPD extraction were determined to be that silica gel was served as dispersant, the mass ratio of sample to silica gel was selected to be 1:4, and 5 mL of acetonitrile was used as elution solvent. The method exhibited a good performance in terms of linearity (r2 >= 0.9997) and the limits of detection in the range of 0.052-0.065 MUg mL-1. The recoveries were in the range of 90.2-98.9% with relative standard deviations (RSDs) ranging from 1.3 to 3.5%. The extraction efficiencies obtained by the MSPD were higher than other extraction method with less cost of sample and solvent. At last, the optimised method was applied for analysing real samples. PMID- 28338341 TI - Natural product inhibitors of carbonic anhydrase I and II isoenzymes: osajin and pomiferin. AB - The aim of this study is to purify carbonic anhydrase I and II isoenzymes from human erythrocyte, isolate two natural products osajin (OSJ) and pomiferin (PMF) from Maclura pomifera fruits, and evaluate the in vitro effect of these natural metabolites on these isoenzymes. These natural products may be used as starting points for drug discovery (like drugs used in several therapeutic applications, including antiglaucoma activity). For the purification procedure, the Sepharose 4B-l-tyrosine-sulphonamide affinity chromatography was used. Column chromatography and thin layer chromatography methods were used for isolation of OSJ and PMF from M. pomifera fruits and their chemical structures were elucidated by IR, 1D, and 2D NMR methods. We compared inhibitory effects of these natural products with inhibitory effects of phenolic compounds and found that these products demonstrated average inhibition effects. We thought that this study will give inspiration to scientists interested in this issue. PMID- 28338343 TI - Nuggets of Wisdom: Salmonella Enteritidis Outbreaks and the Case for New Rules on Uncooked Frozen Processed Chicken. AB - In 2014 and 2015, three Canadian Salmonella serotype Enteritidis outbreak investigations implicated uncooked, frozen, processed chicken products produced at the same establishment, namely establishment A. In November 2014, a sustained increase in the number of reported domestically acquired Salmonella Enteritidis cases in Ontario led to the first outbreak investigation, which implicated uncooked, frozen, processed chicken products produced at establishment A. In June 2015, the identification of pulsed-field gel electrophoresis patterns that had not been previously reported in Canada led to a national Salmonella Enteritidis investigation. Of 51 cases reported nationally, 35 were from Ontario. Uncooked, frozen, processed chicken products produced at establishment A were identified as the source of the outbreak, and public health action was taken as a result of this second investigation. In September 2015, a sustained increase in the number of domestically acquired Salmonella Enteritidis PT13a cases in Ontario led to a third outbreak investigation, which identified a total of 36 PT13a cases. Uncooked, frozen, processed chicken products produced at establishment A were again identified as the source of the outbreak. Outbreaks have been linked to uncooked, frozen, processed chicken products since the late 1990s. Information collected during the three outbreak investigations, and from other jurisdictions, suggests that the breaded and prebrowned appearance of the product, as well as factors related to product packaging and marketing, result in consumer misperception that this raw product is cooked. This misperception may result in mishandling and improper cooking. The three outbreaks described in this article highlight the potential ongoing risks to consumers from these products and support interventions to prevent contamination at the source level and infection at the consumer level. PMID- 28338344 TI - New flavonol glycoside from Scabiosa prolifera L. aerial parts with in vitro antioxidant and cytotoxic activities. AB - Phytochemical investigation of the chemical constituents of the aerial parts of Scabiosa prolifera L. led to the isolation of one new flavonol glycoside, kaempferol-3-O-(4",6"-di-E-p-coumaroyl)-beta-D-galactopyranoside (1), along with ten other known compounds including luteolin-7-O-(2"-O-ethyl-beta glucopyranoside), beta-sitosterol, beta-sitosterylglucoside, ursolic acid, corosolic acid, ursolic acid 3-O-beta-D-arabinopyranoside, apigenin, methyl-alpha D-glucopyranoside, luteolin-7-O-beta-glucopyranoside and isoorientin. The structures of all isolated compounds were established using chemical methods and spectroscopic methods including IR, UV, NMR (1D and 2D) and HRESIMS. All compounds were isolated for the first time from the plant. The antioxidant and cytotoxic activities of compounds 1 and 2 were also investigated. PMID- 28338345 TI - Challenges and Driving Forces for Business Plans in Biobanking. AB - BACKGROUND: Due to increased utilization of biospecimens for research and emergence of new technologies, the availability and quality of biospecimens and their collection are coming more and more into focus. However, the long-term economic situation of biobanks is still mostly unclear. Also, the common sustainable utilization of various international biobanks is challenging due to local differences in sample processing, law and ethics. AIM: This article discusses possible strategies to achieve a sustainable utilization of biospecimens as part of the business plan of biobanks. METHODS: The following questions were addressed as part of a business plan: (1) How can a biobank build up and maintain an up-to-date infrastructure? (2) What kind of funding can support the sustainability of a biobank? (3) Is there an international solution for informed consents to enable sample and data sharing? (4) How can a biobank react during economically unstable periods? (5) Which kind of biobanking research is innovative? (6) What kind of education could be most needful for knowledge transfer in biobanking? (7) Does an expiration date for a biobank make sense according to the period of funding? CONCLUSION: A strategy for optimal utilization begins with sharing of resources, infrastructure, and investments at the planning stage of a biobank, and continues to the transfer of knowledge and know-how by education. For clinical biobanks in particular, a long-term funding and cost recovery strategy is necessary for sustainable utilization. PMID- 28338346 TI - Chemical variability in essential oils from Ruta species among seasons, and its taxonomic and ecological significance. AB - Leaf essential oils of 11 samples from Ruta montana, Ruta chalepensis subsp. latifolia and Ruta chalepensis subsp. angustifolia collected from two sites have been studied by GC/MS that allowed to identify 22, 25 and 12 components, respectively. The variability in the composition of essential oils among species and seasons was very high, and hence the existence of different chemotypes has been inferred. The major components were 2-undecanone, (E) caryophyllene, 2 nonanone and 2-methyloctyl acetate. Multivariate analysis of the 11 samples suggest that the main factors capable to influence the chemical composition of leaf essential oils was both the collection period and the geographical origin. 2 Undecanone seems to be the chemotaxonomic marker of Ruta genus. Furthermore, the formation of distinct clusters and sub-clusters at high distance also supports that the patterns of distribution of chemical constituents among seasons can be used in delimiting species and infraspecific taxa within the species complexes. PMID- 28338347 TI - Ceftazidime-avibactam: novel antimicrobial combination for the treatment of complicated urinary tract infections. AB - Ceftazidime-avibactam is a combination of a third-generation cephalosporin and a novel non-beta-lactam beta-lactamase inhibitor. This combination was recently recommended for the treatment of complicated urinary tract infections, including acute pyelonephritis, in adults with limited or no alternative treatment options. The current review is aimed to determine activity, efficacy and safety of ceftazidime-avibactam in the treatment of patients with complicated urinary tract infections. PMID- 28338348 TI - Liver injury following small intestinal ischemia reperfusion in rats is attenuated by Pistacia lentiscus oil: antioxidant and anti-inflammatory effects. AB - CONTEXT: Intestinal ischemia-reperfusion (IIR) not only leads to severe intestine damage but also induced subsequent destruction of remote organs. OBJECTIVE: We investigated the protective effect of Pistascia lentiscus L. (Anacardiaceae) oil on IIR. MATERIALS AND METHODS: Wistar rats were divided into three groups: sham, intestinal IR and P. lentiscus pretreatment (n = 18 each). In the pretreatment group, oil was administered 1 h before induction of warm ischemia. RESULTS: IIR led to severe liver damage manifested as a significant (p < .05) increase of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Pistacia lentiscus oil decreased the visible intestinal damage, as well as a significant decrease in serum AST and ALT levels. In addition, Pistacia lentiscus reduce liver injury, as evidenced by the decrease in liver tissue myeloperoxidase activity and lipoperoxidation (MDA) level. CONCLUSION: Pistascia lentiscus attenuates liver injury induced by IIR, attributable to the antioxidant and anti inflammatory effect. PMID- 28338349 TI - Clinical features of children and adults with a muscular dystrophy using powered indoor/outdoor wheelchairs: disease features, comorbidities and complications of disability. AB - PURPOSE: To describe the clinical features of electric powered indoor/outdoor wheelchair users with a muscular dystrophy, likely to influence optimal prescription; reflecting features of muscular dystrophies, conditions secondary to disability, and comorbidities impacting on equipment provision. METHODS: Cross sectional retrospective case note review of recipients of electric powered indoor/outdoor wheelchairs provided by a specialist regional wheelchair service. Data on demography, diagnostic/clinical, and wheelchair prescription were systematically extracted. RESULTS: Fifty-one men and 14 women, mean age 23.7 (range 10-67, s.d. 12.95) years, were studied. Forty had Duchenne muscular dystrophy, 22 had other forms of muscular dystrophy, and three were unclassified. Twenty-seven were aged under 19. Notable clinical features included problematic pain (10), cardiomyopathy (5), and ventilatory failure (4). Features related to disability were (kypho)scoliosis (20) and edema/cellulitis (3) whilst comorbidities included back pain (5). Comparison of younger with older users revealed younger users had more features of muscular dystrophy affecting electric powered chair provision (56%) whilst older users had more comorbidity (37%). Tilt in-space was prescribed for 81% of users, specialized seating for 55% and complex controls for 16%. CONCLUSIONS: Muscular dystrophy users were prescribed electric powered indoor/outdoor chairs with many additional features reflecting the consequences of profound muscle weakness. In addition to facilitating independence and participation, electric powered indoor/outdoor chairs have major therapeutic benefits. Implications for rehabilitation Powered wheelchairs have therapeutic benefits in managing muscular dystrophy pain and weakness. The use of specialized seating needs careful consideration in supporting progressive muscle weakness and the management of scoliosis. Pain, discomfort, pressure risk, and muscle fatigue may be reduced by use of tilt-in-space. PMID- 28338350 TI - Consensus-Driven Development of a Terminology for Biobanking, the Duke Experience. AB - Biobanking at Duke University has existed for decades and has grown over time in silos and based on specialized needs, as is true with most biomedical research centers. These silos developed informatics systems to support their own individual requirements, with no regard for semantic or syntactic interoperability. Duke undertook an initiative to implement an enterprise-wide biobanking information system to serve its many diverse biobanking entities. A significant part of this initiative was the development of a common terminology for use in the commercial software platform. Common terminology provides the foundation for interoperability across biobanks for data and information sharing. We engaged experts in research, informatics, and biobanking through a consensus driven process to agree on 361 terms and their definitions that encompass the lifecycle of a biospecimen. Existing standards, common terms, and data elements from published articles provided a foundation on which to build the biobanking terminology; a broader set of stakeholders then provided additional input and feedback in a secondary vetting process. The resulting standardized biobanking terminology is now available for sharing with the biobanking community to serve as a foundation for other institutions who are considering a similar initiative. PMID- 28338351 TI - Worldwide Impact of Warmer Seasons on the Incidence of Renal Colic and Kidney Stone Disease: Evidence from a Systematic Review of Literature. AB - INTRODUCTION: Several studies have examined the link between temperature or monthly seasonal variations and urolithiasis. The majority of these studies have demonstrated a link between higher ambient monthly temperatures and the incidence of renal colic and kidney stone disease (KSD). However, a worldwide trend on this association has not been explored and we perform a systematic review to examine the effect of seasonal variations on renal colic and KSD. MATERIALS AND METHODS: A systematic review of the literature for a 26-year period (1990-2017) was conducted on all studies reporting on the effect of seasonal variations and its link to KSD. Two reviewers independently extracted the data from each study, which were analyzed using SPSS version 24. RESULTS: A total of 59 studies were identified, and after screening, 13 were included in this review. The studies ranged in duration from 1 to 9 years (mean: 5.5 years) and included seasonal/monthly variations for proven stones or lithotripsy treatments or emergency department presentations with renal colic. Except for one study, there was a statistically significant association between higher monthly mean temperatures and the incidence of KSD-related events reported from the United Kingdom, South Korea, the United States, Saudi Arabia, Italy, Spain, Taiwan, Japan, and New Zealand. CONCLUSIONS: Worldwide trends on the incidence of renal colic and KSD seem be affected by seasonal variation favoring warmer months, with data suggesting that higher ambient temperature has an association with KSD. PMID- 28338352 TI - Formulation challenges for 21st century topical and transdermal delivery systems. PMID- 28338353 TI - The burden of familial chylomicronemia syndrome: interim results from the IN FOCUS study. AB - BACKGROUND: Familial Chylomicronemia Syndrome (FCS) is a rare genetic disorder that is caused by a decrease or an absence of lipoprotein lipase activity. FCS is characterized by marked accumulation of chylomicrons and extreme hypertriglyceridemia, which have major effects on both physical and mental health. To date, there have been no systematic efforts to characterize the impact of chylomicronemia on FCS patients' lives. In particular, the impact of FCS on the burden of illness (BoI) and quality of life (QoL) has not been fully described in the literature. METHODS: IN-FOCUS was a comprehensive web-based research survey of patients with FCS focused on capturing the BoI and impact on QoL associated with FCS. Sixty patients from the US diagnosed with FCS participated. Patients described multiple symptoms spanning across physical, emotional and cognitive domains. RESULTS: Patients on average cycled through 5 physicians of varying specialty before being diagnosed with FCS, reflecting a lengthy journey to diagnosis Nearly all respondents indicated that FCS had a major impact on BoI and QoL and significantly influenced their career choice and employment status, and caused significant work loss due to their disease. CONCLUSION: FCS imparts a considerable burden across multiple domains with reported impairment on activities of daily living and QoL. PMID- 28338355 TI - The Potential for a Targeted Strength-Training Program to Decrease Asymmetry and Increase Performance: A Proof of Concept in Sprinting. AB - The global application of horizontal force (FH) via hip extension is related to improvements in sprint performance (eg, maximal velocity [vmax] and power [Pmax]). Little is known regarding the contribution of individual leg FH and how a difference between the legs (asymmetry) might subsequently affect sprint performance. The authors assessed a single male athlete for pre-post outcomes of a targeted hip-extension training program on FH asymmetry and sprint-performance metrics. An instrumented nonmotorized treadmill was used to obtain individual leg and global sprint kinetics and determine the athlete's strong and weak leg, with regard to the ability to produce FH while sprinting. Following a 6-wk control block of testing, a 6-wk targeted training program was added to the athlete's strength-training regimen, which aimed to strengthen the weak leg and improve hip extension function during sprinting. Preintervention to postintervention, the athlete increased FH (standardized effect [ES] = 2.2; +26%) in his weak leg, decreased the FH asymmetry (ES = -0.64; -19%), and increased vmax (ES = 0.67; +2%) and Pmax (ES = 3.2; +15%). This case study highlighted a promising link between a targeted training intervention to decrease asymmetry in FH and subsequent improvement of sprint-performance metrics. These findings also strengthen the theoretical relationship between the contribution of individual leg FH and global FH while sprinting, indicating that reducing asymmetry may decrease injury risk and increase practical performance measures. This case study may stimulate further research investigating targeted training interventions in the field of strength and conditioning and injury prevention. PMID- 28338354 TI - Functional oligopeptide as a novel strategy for drug delivery. AB - Oligopeptides, a type of short peptide, which consist of 2-20 amino acids, exhibit a variety of biological functions in drug delivery systems, such as specific targeting, cell penetration, self-assembled capacity and responsiveness to the environment. In this review, we aim to highlight the importance of functional oligopeptides for nanomedical applications and put forward the views on the future development direction of oligopeptide medicines. Oligopeptides have gained wide attentions due to their inherent properties, but the lack of understanding the mechanisms of in vivo transport behavior is the biggest problem and challenge at the present stage. Therefore, it is an important direction for the future clinical research to systematically evaluate its metabolic behavior and safety in vivo. PMID- 28338356 TI - The accessory gene regulator-1 as a therapeutic target for C. difficile infections. PMID- 28338357 TI - Neuromuscular Fatigue After Repeated Jumping With Concomitant Electrical Stimulation. AB - PURPOSE: To evaluate the etiology and extent of neuromuscular fatigue induced by 50 squat jumps performed with and without neuromuscular electrical stimulation (NMES) of the knee extensors. METHODS: Nine healthy, recreationally active men (24 +/- 2 y) took part in 2 experiments. These consisted of 50 squat jumps performed with stimulation (NMES) or without (CON). Maximal voluntary contraction (MVC) force, maximal voluntary activation level (VAL), and forces evoked by single and double (10 and 100 Hz) stimulations were recorded before and after the 50 jumps. NMES was delivered at the maximal tolerated intensity. RESULTS: Despite average jump height being ~16% lower in the NMES than in the CON session, a reduction over time in jump height was only found in the NMES condition (-6%). After the 50 jumps, MVC force was reduced to a greater extent in NMES than in CON (-25% +/- 11% vs -11% +/- 12%). Similarly, forces evoked by single stimulations, as well as by 10-Hz and 100-Hz paired stimulations, were reduced to a greater extent in NMES (-33% +/- 12%, -42% +/- 15%, and -25% +/- 13%) than in CON (-21% +/- 6%, -30% +/- 9%, and -14% +/- 11%). VAL was not significantly altered by either condition. CONCLUSION: Performing repeated squat jumps with concomitant NMES induced a greater fatigue than squat jumps performed alone and might potentially represent a stronger training stimulus. PMID- 28338358 TI - A Mismatch Between Athlete Practice and Current Sports Nutrition Guidelines Among Elite Female and Male Middle- and Long-Distance Athletes. AB - Contemporary nutrition guidelines promote a variety of periodized and time sensitive recommendations, but current information regarding the knowledge and practice of these strategies among world-class athletes is limited. The aim of this study was to investigate this theme by implementing a questionnaire on dietary periodization practices in national/international level female (n = 27) and male (n = 21) middle- and long-distance runners/race-walkers. The questionnaire aimed to gain information on between and within-day dietary choices, as well as timing of pre- and posttraining meals and practices of training with low or high carbohydrate (CHO) availability. Data are shown as percentage (%) of all athletes, with differences in responses between subgroups (sex or event) shown as Chi-square x2 when p < .05. Nearly two-thirds of all athletes reported that they aim to eat more food on, or after, hard training days. Most athletes said they focus on adequate fueling (96%) and adequate CHO and protein (PRO) recovery (87%) around key sessions. Twenty-six percent of athletes (11% of middle vs 42% of long-distance athletes [x2 (1, n = 46) = 4.308, p = .038, phi = 0.3])) reported to undertake training in the fasted state, while 11% said they periodically restrict CHO intake, with 30% ingesting CHO during training sessions. Our findings show that elite endurance athletes appear to execute pre- and post-key session nutrition recovery recommendations. However, very few athletes deliberately undertake some contemporary dietary periodization approaches, such as training in the fasted state or periodically restricting CHO intake. This study suggests mismatches between athlete practice and current and developing sports nutrition guidelines. PMID- 28338359 TI - Optimizing the Team for Required Power During Track-Cycling Team Pursuit. AB - PURPOSE: Since the aim of the men's team pursuit in time-trial track cycling is to accomplish a distance of 4000 m as fast as possible, optimizing aerodynamic drag can contribute to achieving this goal. The aim of this study was to determine the drafting effect in second, third, and fourth position during the team pursuit in track cycling as a function of the team members' individual frontal areas in order to minimize the required power. METHOD: Eight experienced track cyclists of the Dutch national selection performed 39 trials of 3 km in different teams of 4 cyclists at a constant velocity of 15.75 m/s. Frontal projected areas were determined, and together with field-derived drag coefficients for all 4 positions, the relationships between frontal areas of team members and drag fractions were estimated using generalized estimating equations. RESULTS: The frontal area of both the cyclist directly in front of the drafter and the drafter himself turned out to be significant determinants of the drag fraction at the drafter's position (P < .05) for all 3 drafting positions. Predicted required power for individuals in drafting positions differed up to 35 W depending on team composition. For a team, a maximal difference in team efficiency (1.2%) exists by selecting cyclists in a specific sequence. CONCLUSION: Estimating required power for a specific team composition gives insight into differences in team efficiency for the team pursuit. Furthermore, required power for individual team members ranges substantially depending on team composition. PMID- 28338360 TI - Resuscitation-promoting factors are important determinants of the pathophysiology in Mycobacterium tuberculosis infection. AB - Resuscitation promoting factors (Rpf) are peptidoglycan-hydrolyzing enzymes that are pivotal in the resuscitation of quiescent actinobacteria including Mycobacterium tuberculosis. From the published data, it is clear that Rpf are required for the resuscitation of non-replicating bacilli and pathogenesis in murine infection model of tuberculosis, although their direct influence on human Mycobacterium tuberculosis infection is ill-defined. In this review, we describe the progress in the understanding of the roles that Rpf play in human tuberculosis pathogenesis and importance of bacilli dependent upon Rpf for growth for the outcome of human tuberculosis. We outline how this research is opening up important opportunities for the diagnosis, treatment and prevention of human disease, progress in which is essential to attain the ultimate goal of tuberculosis eradication. PMID- 28338361 TI - Method-Induced Differences of Energy Contributions in Women's Kayaking. AB - CONTEXT: Different relative aerobic energy contribution (WAER%) has been reported for the 2 women's Olympic kayaking disciplines (ie, 200 and 500 m). PURPOSE: To investigate whether the adopted method of energy calculation influences the value of WAER% during kayaking time trials. METHODS: Eleven adolescent female kayakers (age 14 +/- 1 y, height 172 +/- 4 cm, body mass 65.4 +/- 4.2 kg, VO2peak 42.6 +/- 4.9 mL.min-1.kg-1, training experience 1.5 +/- 0.3 y) volunteered to participate in 1 incremental exercise test and 2 time trials (40 and 120 s) on the kayak ergometer. A portable spirometric system was used to measure gas metabolism. Capillary blood was taken from the ear lobe during and after the tests and analyzed for lactate afterward. The method of modified maximal accumulated oxygen deficit (m-MAOD) and the method based on the fast component of oxygen-uptake off kinetics (PCr-La-O2) were used to calculate the energy contributions. RESULTS: The anaerobic energy portions from m-MAOD were lower than those from PCr-La-O2 in the 40-s (41.9 +/- 8.8 vs 52.8 +/- 4.0 kJ, P > .05) and 120-s (64.1 +/- 27.9 vs 68.2 +/- 10.0 kJ, P > .05) time trials, which induced differences of WAER% between m-MAOD and PCr-La-O2 (36.0% vs 30.0% in 40 s, P > .05; 60.9% vs 57.5% in 120 s, P > .05). CONCLUSIONS: The reported different WAER% in women's Olympic kayaking could be partly attributed to the adopted method of energy calculation (ie, m-MAOD vs PCr-La-O2). A fixed method of energy calculation is recommended during the longitudinal assessment on the relative energy contribution in women's Olympic kayaking. PMID- 28338362 TI - The Effects of Caffeine, Taurine, or Caffeine-Taurine Coingestion on Repeat Sprint Cycling Performance and Physiological Responses. AB - PURPOSE: To investigate the effects of caffeine (C), taurine (T), caffeine and taurine coingestion (C +T), or placebo (P) on repeated Wingate cycling performance and associated physiological responses. METHODS: Seven male team sport players participated in a randomized, single-blind, crossover study, where they completed 3 Wingate tests, each separated by 2 min, an hour after ingesting: C (5 mg/kg body mass [BM]), T (50 mg/kg BM), C +T (5 mg/kg BM + 50 mg/kg BM), or P (5 mg/kg BM) in a gelatin capsule. Performance was measured on an ergometer, and blood lactate, perceived exertion, heart rate (HR), mean arterial pressure (MAP), and rate pressure product (RPP) were measured at rest (presupplement), baseline (1 h postsupplement), and during and after exercise. RESULTS: Magnitude based inferences revealed that all of the supplements increased (small to moderate, likely to very likely) mean peak power (MPP), peak power (PP), and mean power (MP) compared to P, with greater MPP, PP, and MP in T compared to C (small, possible). Intrasprint fatigue index (%FIIntra) was greater in T compared to P and C (moderate, likely), and %FIInter was lower in T compared to C (small, possible). C and C +T increased HR, MAP, and RPP compared to P and T at baseline (moderate to very large, likely to most likely); however, these only remained higher in C compared to all conditions in the final sprint. CONCLUSIONS: T elicited greater improvements in performance compared to P, C, or C +T while reducing the typical chronotropic and pressor effects of C. PMID- 28338363 TI - Decrement in Professional Cyclists' Performance After a Grand Tour. AB - PURPOSE: To analyze professional cyclists' performance declines after, and the exercise demands during, a Grand Tour. METHODS: Seven professional cyclists performed 2 incremental exercise tests, 1 wk before and the day after the Vuelta Espana. During the race the exercise demands were analyzed on the basis of heart rate (HR). Three intensity zones were established according to reference HR values corresponding to the ventilatory- (VT) and respiratory-compensation (RCT) thresholds determined during the prerace test. In addition, exercise demands for the last weeks of the Vuelta were recalculated using the reference HR determined during the postrace test for the 3rd week and averaging the change observed in the VT and RCT per stage for the 2nd week. The reference HR for the beginning of the 2nd week was estimated. RESULTS: A significant (P-value range, .044-.000) decrement in oxygen uptake, power output, and HR at maximal exercise, VT, and RCT was found after the race. Based on the prerace test, the mean time spent daily above the RCT was 13.8 +/- 10.2 min. This time decreased -1.2 min.day-1 across the race. When the exercise intensity was corrected according to the postrace test, the time above RCT (34.1 +/- 9.9 min) increased 1.0 min.day-1. CONCLUSION: These data indicate that completing a Grand Tour may result in a significant decrement in maximal and submaximal endurance performance capacity. This may modify reference values used to analyze exercise demands. As a consequence, the high-intensity exercise performed by cyclists may be underestimated. PMID- 28338364 TI - Indications, risk of lower airway infection, and complications to pediatric tracheotomy: report from a tertiary referral center. AB - BACKGROUND: Although pediatric tracheotomy is potentially life-saving, the procedure is associated with high risk of complications, and indications have changed the last decade. We report indications, complications, and lower airway infections (LAIs) to pediatric tracheotomy performed at a tertiary referral center. METHODS: We identified all children (<18 years) who underwent tracheotomy at our institution during 2008-2015. A review of hospital records was performed to extract data on indication of the procedure, complications, and information on pre- and postoperative LAI. RESULTS: At a median age of 8 years (range: 4 months to 17 years), a total of 69 tracheotomies were performed. Neuromuscular disease (n = 21) was the most common cause for tracheotomy. The postoperative complication rate was 22%; early complications (<30 days) occurred in four patients, and nine patients encountered late complications such as wound granulation and tracheocutaneous fistula. Children without LAI prior to tracheotomy were at increased risk of LAI from the initial 30-days following surgery (OR: 2.91, 95% CI: 1.17-7.21; p = .02). Fifty-three percent (10/19) of all LAIs following tracheotomy were caused by Staphylococcus aureus (p < .01). CONCLUSIONS: Pediatric tracheotomy was associated with considerable rates of minor early and late complications and high risk of short-term LAI. The main cause leading to tracheotomy was neuromuscular disease. PMID- 28338365 TI - Movement Velocity as Indicator of Relative Intensity and Level of Effort Attained During the Set in Pull-Up Exercise. AB - PURPOSE: To analyze the relationship between movement velocity and relative load (%1RM) in the pull-up exercise (PU) and to determine the pattern of repetition velocity loss during a single set to failure in pulling one's own body mass. METHODS: Fifty-two men (age = 26.5 +/- 3.9 y, body mass = 74.3 +/- 7.2 kg) performed a first evaluation (T1) consisting of an 1-repetition-maximum test (1RM) and a test of maximum number of repetitions to failure pulling one's own body mass (MNR) in the PU exercise. Thirty-nine subjects performed both tests on a second occasion (T2) following 12 wk of training. RESULTS: The authors observed a strong relationship between mean propulsive velocity (MPV) and %1RM (r = -.96). Mean velocity attained with 1RM load (V1RM) was 0.20 +/- 0.05 m.s-1, and it influenced the MPV attained with each %1RM. Although 1RM increased by 3.4% from T1 to T2, the relationship between MPV and %1RM, and V1RM, remained stable. The authors also confirmed stability in the V1RM regardless of individual relative strength. The authors found a strong relationship between percentage of velocity loss and percentage of performed repetitions (R2 = .88), which remained stable despite a 15% increase in MNR. CONCLUSIONS: Monitoring repetition velocity allows estimation of the %1RM used as soon as the first repetition with a given load is performed, and the number of repetitions remaining in reserve when a given percentage of velocity loss is achieved during a PU exercise set. PMID- 28338366 TI - Effects of Bout Duration on Players' Internal and External Loads During Small Sided Games in Young Soccer Players. AB - PURPOSE: To investigate the effects of different bout durations on internal and external loads of young soccer players during different small-sided games (SSGs). METHODS: Fifteen young male soccer players (average age 17 +/- 1 y) participated in 2 vs 2, 3 vs 3, and 4 vs 4 SSGs. All games lasted 12 min playing time in total, but each SSG format further consisted of 4 bout durations: continuous (CON: 1 bout * 12 min) or interval with short (SBD: 6 bouts * 2 min), medium (MBD: 3 bouts * 4 min), or long (LBD: 2 bouts * 6 min) bout durations. During the SSGs, heart-rate (HR) responses and distance covered in different speed zones (walking and low-intensity, moderate-intensity, and high-intensity running) were measured. Rating of perceived exertion (RPE) and blood lactate (La-) were determined at the end of each SSG. RESULTS: The SBD format elicited significantly lower %HRmax responses compared to LBD and CON in all formats (P < .05). The SBD format also showed significantly shorter distances covered in walking and greater distances covered in moderate-intensity running, as well as significantly greater total distance covered compared to LBD and CON in all formats (P < .05). In addition, LBD produced significantly lower La- and RPE responses than SBD and CON in all formats (P < .05). CONCLUSIONS: These results suggest that coaches and sport scientists who want to achieve higher internal loads could use SBD and CON timing protocols, while those who want to achieve higher external loads might prefer to use SBD and MBD when planning all SSG formats. PMID- 28338367 TI - Full-participation of students with physical disabilities in science and engineering laboratories. AB - PURPOSE: To conduct a literature review identifying barriers and facilitators students with physical disabilities (SwD-P) may encounter in science and engineering (S&E) laboratories. METHOD: Publications were identified from 1991 to 2015 in ERIC, web of science via web of knowledge, CINAHL, SCOPUS, IEEEXplore, engineering village, business source complete and PubMed databases using search terms and synonyms for accommodations, advanced manufacturing, additive manufacturing, assistive technology (AT), barriers, engineering, facilitators, instructor, laboratory, STEM education, science, students with disabilities and technology. RESULTS: Twenty-two of the 233 publications that met the review's inclusion criteria were examined. Barriers and facilitators were grouped based on the international classification of functioning, disability and health framework (ICF). None of the studies directly found barriers or facilitators to SwD-P in science or engineering laboratories within postsecondary environments. The literature is not clear on the issues specifically related to SwD-P. CONCLUSION: Given these findings, further research (e.g., surveys or interviews) should be conducted to identify more details to obtain more substantial information on the barriers that may prevent SwD-P from fully participating in S&E instructional laboratories. Implications for Rehabilitation Students with disabilities remain underrepresented going into STEM careers. A need exist to help uncover barriers students with disabilities encounter in STEM laboratory. Environments. Accommodations and strategies that facilitate participation in STEM laboratory environments are promising for students with disabilities. PMID- 28338368 TI - Alginate and whey protein based-multilayered particles: production, characterisation and resistance to pH, ionic strength and artificial gastric/intestinal fluid. AB - Multiple layers of whey protein and sodium alginate were assembled onto gelled alginate microparticles using electrostatic interaction. An experimental design was employed to evaluate the effect of the concentration of both hydrocolloids on the amount of protein that was adsorbed. In the first layer, a higher protein adsorption 32.5% w/w was obtained at pH 3.75. In the multilayered particle, the protein adsorbed reached 64.9% w/w. An analysis of protein solubilisation verified that 22% w/w was solubilised at an acidic pH (pH 2.0). The protein solubilisation increased with ionic strength, reaching 19.5% w/w in the highest NaCl concentration evaluated (200 mM). The particles were partially resistant to gastric conditions, with 30.5% w/w of total nitrogen protein solubilisation occurring after 2 h at pH 2.0; however, they did not resist the artificial intestine conditions, reaching 86.0% w/w of total nitrogen protein solubilisation after 5 h. PMID- 28338369 TI - DHA-rich Fish Oil Increases the Omega-3 Index and Lowers the Oxygen Cost of Physiologically Stressful Cycling in Trained Individuals. AB - Dietary fish oil, providing docosahexaenoic acid (DHA) modulates oxygen consumption and fatigue in animal models. However, in humans predominately supplemented with high eicosapentaenoic acid (EPA), there is no evidence of endurance performance enhancement. Therefore, this study examined if DHA-rich fish oil could improve repeated bouts of physiologically stressful cycling and a subsequent time trial in a state of fatigue. Twenty-six trained males took part in a double-blind study and were supplemented with either 2 * 1g/day soy oil, Control) or DHA-rich tuna fish oil (Nu-Mega) (FO) (560mg DHA / 140mg eicosapentaenoic acid (EPA), for 8 weeks. Maximal cycling power (3 * 6s), isometric quadriceps strength (MVC), Wingate cycling protocol (6 * 30s) and a 5min cycling time-trial were assessed at baseline and eight weeks. The Omega-3 Index was not different at baseline (Control: 4.2 +/- 0.2; FO: 4.7 +/- 0.2%) and increased in the FO group after eight weeks (Control: 3.9 +/- 0.2; FO: 6.3 +/- 0.3%, p < .01). There was no effect of DHA-rich fish oil on power output of maximal 6s cycle sprinting (Control: Pre 1100 +/- 49 Post 1067 +/- 51; FO: Pre 1070 +/- 46 Post 1042 +/- 46W), during 5min time trail (Control: Pre 267 +/- 19 Post 278 +/- 20; FO: Pre 253 +/- 16 Post 265 +/- 16 W) or maximal voluntary contraction force (Control: Pre 273 +/- 19 Post 251 +/- 19; FO: Pre 287 +/- 17 Post 283 +/- 16 Nm). Nevertheless, relative oxygen consumption was reduced the FO group during the cycling time trial (Control: -23 +/- 26; FO: -154 +/- 59ml O2/min/100W p < .05) suggesting improved economy of cycling. We conclude that DHA rich fish oil, successful at elevating the Omega-3 Index, and reflective of skeletal muscle membrane incorporation, can modulate oxygen consumption during intense exercise. PMID- 28338370 TI - The potential of stimulating nitric oxide formation in the treatment of hypertension. AB - INTRODUCTION: Hypertension is a leading cause of morbidity and mortality worldwide. A major pathophysiological factor contributing to hypertension is reduced nitric oxide (NO) bioavailability. Strategies to address this pathophysiological mechanism could offer significant advantages. Areas covered: In this review we aimed at examining a variety of drugs (statins, beta-adrenergic receptor blockers, calcium channel blockers, angiotensin converting enzyme inhibitors, angiotensin II type-1 receptor blockers) used to treat hypertension and other cardiovascular diseases, particularly with respect to their potential of increasing NO bioavailability and activity in the cardiovascular system. There is now evidence supporting the notion that many cardiovascular drugs activate NO signaling or enhance NO bioavailability as a contributing mechanism to their beneficial cardiovascular effects. Moreover, other drugs may attenuate NO inactivation by superoxide and other reactive oxygen species by exerting antioxidant effects. More recently, the NO oxidation products nitrite and nitrate have been acknowledged as sources of NO after recycling back to NO. Activation of the nitrate-nitrite-NO pathway is an alternate pathway that may generate NO from both anions and exert antihypertensive effects. Expert opinion: In this review, we provide an overview of the possible mechanisms by which these drugs enhance NO bioavailability and help in the therapy of hypertension. PMID- 28338371 TI - Reliability and Seasonal Changes of Submaximal Variables to Evaluate Professional Cyclists. AB - PURPOSE: The aim of this study was to determine the reliability and validity of several submaximal variables that can be easily obtained by monitoring cyclists' performances. METHODS: Eighteen professional cyclists participated in this study. In a first part (n = 15) the test-retest reliability of heart rate (HR) and rating of perceived exertion (RPE) during a progressive maximal test was measured. Derived submaximal variables based on HR, RPE, and power output (PO) responses were analyzed. In a second part (n = 7) the pattern of the submaximal variables according to cyclists' training status was analyzed. Cyclists were assessed 3 times during the season: at the beginning of the season, before the Vuelta a Espana, and the day after this Grand Tour. RESULTS: Part 1: No significant differences in maximal and submaximal variables between test-retest were found. Excellent ICCs (0.81-0.98) were obtained in all variables. Part 2: The HR and RPE showed a rightward shift from early to peak season. In addition, RPE showed a left shift after the Vuelta a Espana. Submaximal variables based on RPE had the best relationship with both performance and changes in performance. CONCLUSION: The present study showed the reliability of different maximal and submaximal variables used to assess cyclists' performances. Submaximal variables based on RPE seem to be the best to monitor changes in training status over a season. PMID- 28338372 TI - The modified temporalis muscle flap in reconstruction of palate and temporal deformity. AB - PURPOSE: The purpose of this article was to introduce a modified temporalis muscle flap (TMF) which was used to reconstruct palate and temporal deformity. PATIENT AND METHODS: This was a retrospective review of the use of the modified TMF in reconstruction of palate and temporal deformity. We evaluated the result which included operative time, bleeding, necrosis, infection, facial nerve deficit, and cosmetic deformity. RESULTS: All the 16 patients accepted the modified TMF surgery successfully. There were no complications. All of them were satisfied with the postoperative appearance. CONCLUSIONS: The modified TMF was a reliable and safe flap that can be used to reconstruct the surgical defect of plate and fill the temporal fossa. PMID- 28338373 TI - Risk of major cardiac events following adjuvant proton versus photon radiation therapy for patients with thymic malignancies. AB - BACKGROUND: While often managed with surgery alone, patients with thymic malignancies with high-risk features may benefit from adjuvant radiation therapy but are at risk for late toxicities. Previously, the risk of major cardiac events (MCEs) was reported to increase by 7% per one Gray (Gy) to the heart. In this study, we compare dose to organs at risk (OARs) with intensity-modulated (IMRT) versus proton beam therapy (PBT). We hypothesize a decrease risk of predicted MCEs with PBT. MATERIAL AND METHODS: Patients requiring adjuvant therapy for thymic malignancies were treated with double scattered proton beam therapy (DS PBT). Clinical backup IMRT plans were generated. Predicted MCEs were calculated based on median dose to the heart. A Wilcoxon rank sum test was used for statistical comparisons. RESULTS: Twenty-two consecutive patients were evaluated. DS-PBT resulted in statistically significant decreases in dose to the heart, lungs, left ventricle, esophagus, and spinal cord (all p <= .01). The increase in risk of MCEs from 0 to >=20 years was lower with PBT (74% versus 135%, p = .04). DISCUSSION: DS-PBT results in decreased dose to OARs and may reduce the risk of MCEs compared with IMRT. Long-term follow-up is required to assess for clinical benefit from DS-PBT. PMID- 28338375 TI - Updated Review of the Applied Physiology of American College Football: Physical Demands, Strength and Conditioning, Nutrition, and Injury Characteristics of America's Favorite Game. AB - While there are various avenues for performance improvement in college American football (AF), there is no comprehensive evaluation of the collective array of resources around performance, physical conditioning, and injury and training/game characteristics to guide future research and inform practitioners. Accordingly, the aim of the present review was to provide a current examination of these areas in college AF. Recent studies show that there is a wide range of body compositions and strength characteristics between players, which appear to be influenced by playing position, level of play, training history/programming, and time of season. Collectively, game demands may require a combination of upper- and lower-body strength and power production, rapid acceleration (positive and negative), change of direction, high running speed, high-intensity and repetitive collisions, and muscle-strength endurance. These may be affected by the timing of and between-plays and/or coaching style. AF players appear to possess limited nutrition and hydration practices, which may be disadvantageous to performance. AF injuries appear due to a multitude of factors-strength, movement quality, and previous injury-while there is also potential for extrinsic factors such as playing surface type, travel, time of season, playing position, and training load. Future proof-of-concept studies are required to determine the quantification of game demands with regard to game style, type of opposition, and key performance indicators. Moreover, more research is required to understand the efficacy of recovery and nutrition interventions. Finally, the assessment of the relationship between external/internal-load constructs and injury risk is warranted. PMID- 28338374 TI - The clinical features and prognosis of mumps-associated hearing loss: a retrospective, multi-institutional investigation in Japan. AB - CONCLUSIONS: The majority of hearing loss due to mumps presents as unilateral profound sensorineural hearing loss, which is refractory to treatment. In rare cases of bilateral total deafness, cochlear implants were beneficial for speech perception. Vaccination against mumps is recommended to prevent mumps-associated hearing loss. OBJECTIVE: The objective of this study is to investigate the clinical characteristics of hearing loss due to mumps and to evaluate hearing outcomes. SUBJECTS AND METHODS: The clinical parameters were analyzed under a retrospective multi-institutional study design in patients diagnosed with hearing loss due to mumps at the Otolaryngology departments of 19 hospitals between 1987 and 2016. RESULTS: Sixty-seven patients with hearing loss due to mumps were enrolled. The study population consisted of 35 males and 32 females, ranging in age from 1 to 54, with a median age of 9.5 years. Sixty-three patients presented with unilateral, and 4 with bilateral hearing loss. Profound hearing loss was observed in 65 ears. Only one ear with severe hearing loss showed complete recovery. Four patients with bilateral hearing loss received cochlear implant surgery. Most of the patients with hearing loss due to mumps had no history of vaccination. PMID- 28338376 TI - Pembrolizumab for the treatment of non-small cell lung cancer. AB - INTRODUCTION: In the last years, a spectacular development of immunotherapeutic agents aimed at the PD-1/PD-L1 axis has taken place. This development of these checkpoint inhibitors has greatly influenced our approach to the treatment of lung cancer in first and second line. The limited toxicity profile and the ability to treat for prolonged periods, even in smokers, is a welcome expansion of the therapeutic arsenal of the oncologist. Areas covered: This review highlights the results of recent clinical trials on pembrolizumab for the treatment of non-small cell lung cancer. The authors discuss both first and second line treatment with pembrolizumab as monotherapy and in combination therapies. Additionally, implications of the PD-L1 immunohistochemistry assay with the 22C3 antibody and its use in clinical practice and trials is discussed. Expert commentary: A higher overall response, overall survival and a moderate toxicity profile is observed with the use of pembrolizumab, compared to chemotherapy, in both first and second line. These promising results have already translated into the registration of pembrolizumab in first and second line in patients with a high expression of PD-L1. However, as PD-L1 staining does not sufficiently discriminate responders from non-responders for all checkpoint inhibitors, there still is a need for a better predictive biomarker. PMID- 28338378 TI - Validation of a Maximal Incremental Skating Test Performed on a Slide Board: Comparison With Treadmill Skating. AB - PURPOSE: To investigate the criterion validity of a maximal incremental skating test performed on a slide board (SB). METHODS: Twelve subelite speed skaters performed a maximal skating test on a treadmill and on a SB. Gas exchange threshold (GET), respiratory compensation point (RCP), and maximal variables were determined. RESULTS: Oxygen uptake ([Formula: see text]) (31.0 +/- 3.2 and 31.4 +/- 4.1 mL.min-1.kg-1), percentage of maximal [Formula: see text] ([Formula: see text]) (66.3 +/- 4 and 67.7 +/- 7.1%), HR (153 +/- 14 and 150 +/-12 bpm), and ventilation (59.8 +/- 11.8 and 57.0 +/- 10.7 L.min-1) at GET, and [Formula: see text] (42.5 +/- 4.4 and 42.9 +/- 4.8 mL.min-1.kg-1), percentage of [Formula: see text] (91.1 +/- 3.3 and 92.4 +/- 2.1%), heart rate (HR) (178 +/- 9 and 178 +/- 6 bpm), and ventilation (96.5 +/- 19.2 and 92.1 +/- 12.7 L.min-1) at RCP were not different between skating on a treadmill and on a SB. [Formula: see text] (46.7 +/- 4.4 vs 46.4 +/-6.1 mL.min-1.kg-1) and maximal HR (195 +/- 6 vs 196 +/- 10 bpm) were not significantly different and correlated (r = .80 and r = .87, respectively; P < .05) between the treadmill and SB. [Formula: see text] at GET, RCP, and [Formula: see text] obtained on a SB were correlated (r > .8) with athletes' best times on 1500 m. CONCLUSIONS: The incremental skating test on a SB was capable to distinguish maximal ([Formula: see text] and HR) and submaximal ([Formula: see text], % [Formula: see text], HR, and ventilation) parameters known to determine endurance performance. Therefore, the SB test can be considered as a specific and practical alternative to evaluate speed skaters. PMID- 28338379 TI - Head, Neck, Trunk, and Pelvis Tissue Mass Predictions for Young Adults Using Anthropometric Measures and Dual-Energy X-Ray Absorptiometry. AB - Accurate prediction of wobbling mass (WM), fat mass (FM), lean mass (LM), and bone mineral content (BMC) of living people using regression equations developed from anthropometric measures (lengths, circumferences, breadths, skinfolds) has previously been reported, but only for the extremities. Multiple linear stepwise regression was used to generate comparable equations for the head, neck, trunk, and pelvis of young adults (38 males, 38 females). Equations were validated using actual tissue masses from an independent sample of 13 males and 13 females by manually segmenting full-body dual-energy x-ray absorptiometry scans. Prediction equations exhibited adjusted R2 values ranging from .249 to .940, with more explained variance for LM and WM than BMC and FM, especially for the head and neck. Mean relative errors between predicted and actual tissue masses ranged from -11.07% (trunk FM) to 7.61% (neck FM). Actual and predicted tissue masses from all equations were significantly correlated (R2 = .329 to .937), except head BMC (R2 = .046). These results show promise for obtaining in-vivo head, neck, trunk, and pelvis tissue mass estimates in young adults. Further research is needed to improve head and neck FM and BMC predictions and develop tissue mass prediction equations for older populations. PMID- 28338381 TI - A Novel Method to Compute Breathing Volumes via Motion Capture Systems: Design and Experimental Trials. AB - Respiratory assessment can be carried out by using motion capture systems. A geometrical model is mandatory in order to compute the breathing volume as a function of time from the markers' trajectories. This study describes a novel model to compute volume changes and calculate respiratory parameters by using a motion capture system. The novel method, ie, prism-based method, computes the volume enclosed within the chest by defining 82 prisms from the 89 markers attached to the subject chest. Volumes computed with this method are compared to spirometry volumes and to volumes computed by a conventional method based on the tetrahedron's decomposition of the chest wall and integrated in a commercial motion capture system. Eight healthy volunteers were enrolled and 30 seconds of quiet breathing data collected from each of them. Results show a better agreement between volumes computed by the prism-based method and the spirometry (discrepancy of 2.23%, R 2 = .94) compared to the agreement between volumes computed by the conventional method and the spirometry (discrepancy of 3.56%, R 2 = .92). The proposed method also showed better performances in the calculation of respiratory parameters. Our findings open up prospects for the further use of the new method in the breathing assessment via motion capture systems. PMID- 28338380 TI - The Association Between Physical Activity With Cognitive Function and Brain Derived Neurotrophic Factor in People With Parkinson's Disease: A Pilot Study. AB - The objective of this study was to examine the effect of physical capacity on the relationship of brain-derived neurotrophic factor (BDNF) with cognitive function in people with PD. For this study, serum BDNF levels were measured in 29 PD participants and 30 healthy controls. Cognitive function was assessed using the Montreal Cognitive Assessment (MOCA) scale. Physical capacity was evaluated using the 6-min walk distance (6-MWD). Participants were categorized into low or high physical capacity group according to their 50th percentile 6-MWD. It was found that MOCA total score correlated with serum BDNF level (r = .44, P = .012) in the entire PD sample. This correlation remained significant only in the low physical capacity group (r = .62; P = .03) but not in the high physical capacity group (r = .31; P = .22). It was concluded that the relationship of BDNF with cognitive function might be dependent on physical capacity. The results are preliminary, thus future studies are needed to confirm these findings. PMID- 28338382 TI - Does Foot Anthropometry Predict Metabolic Cost During Running? AB - Several recent investigations have linked running economy to heel length, with shorter heels being associated with less metabolic energy consumption. It has been hypothesized that shorter heels require larger plantar flexor muscle forces, thus increasing tendon energy storage and reducing metabolic cost. The goal of this study was to investigate this possible mechanism for metabolic cost reduction. Fifteen male subjects ran at 16 km?h-1 on a treadmill and subsequently on a force-plate instrumented runway. Measurements of oxygen consumption, kinematics, and ground reaction forces were collected. Correlational analyses were performed between oxygen consumption and anthropometric and kinetic variables associated with the ankle and foot. Correlations were also computed between kinetic variables (peak joint moment and peak tendon force) and heel length. Estimated peak Achilles tendon force normalized to body weight was found to be strongly correlated with heel length normalized to body height (r = -.751, p = .003). Neither heel length nor any other measured or calculated variable were correlated with oxygen consumption, however. Subjects with shorter heels experienced larger Achilles tendon forces, but these forces were not associated with reduced metabolic cost. No other anthropometric and kinetic variables considered explained the variance in metabolic cost across individuals. PMID- 28338377 TI - Sodium potassium adenosine triphosphatase (Na/K-ATPase) as a therapeutic target for uremic cardiomyopathy. AB - INTRODUCTION: Clinically, patients with significant reductions in renal function present with cardiovascular dysfunction typically termed, uremic cardiomyopathy. It is a progressive series of cardiac pathophysiological changes, including left ventricular diastolic dysfunction and hypertrophy (LVH) which sometimes progress to left ventricular dilation (LVD) and systolic dysfunction in the setting of chronic kidney disease (CKD). Uremic cardiomyopathy is almost ubiquitous in patients afflicted with end stage renal disease (ESRD). Areas covered: This article reviews recent epidemiology, pathophysiology of uremic cardiomyopathy and provide a board overview of Na/K-ATPase research with detailed discussion on the mechanisms of Na/K-ATPase/Src/ROS amplification loop. We also present clinical and preclinical evidences as well as molecular mechanism of this amplification loop in the development of uremic cardiomyopathy. A potential therapeutic peptide that targets on this loop is discussed. Expert opinion: Current clinical treatment for uremic cardiomyopathy remains disappointing. Targeting the ROS amplification loop mediated by the Na/K-ATPase signaling function may provide a novel therapeutic target for uremic cardiomyopathy and related diseases. Additional studies of Na/K-ATPase and other strategies that regulate this loop will lead to new therapeutics. PMID- 28338383 TI - Intersession Reliability of Isokinetic Strength Testing in Knee and Elbow Extension and Flexion Using the BTE PrimusRS. AB - CONTEXT: The use of isokinetic dynamometers playing an important role in different settings of sports and medicine. Therefore, a high reliability of these devices is required. OBJECTIVE: The aim of this study was to examine the intersession reliability of the dynamometer BTE PrimusRS regarding to the isolated single-joint exercises extension/flexion of the knee and elbow for isokinetic testing DESIGN: Intersession reliability. SETTING: Clinical settings and sports science. PARTICIPANTS: 16 young male students. INTERVENTION: The testing protocol includes 5 consecutive repetitions (concentric/concentric) at a velocity of 60 degrees /s for the exercises. MAIN OUTCOME MEASURES: Raw data of torque curves were used to determine the peak torque. Reliability was evaluated with the intraclass correlation coefficient (ICC), the limits of agreement (LoA), and the bias and the variability of measurements (V). RESULTS: High ICC values (.954-.991) were found for the used exercises. However, the LoAs yielded up to over 16 Nm and the V yielded up to nearly 9 % in several testing exercises, indicating poor absolute reliability. CONCLUSION: The BTE PrimusRS shows good to excellent reliability. However, regarding the absolute measures of reliability, the users must decide as experts in their fields whether this reliability is sufficient for their purposes. PMID- 28338385 TI - Self-Regulatory Imagery and Physical Activity in Middle-Aged and Older Adults: A Social-Cognitive Perspective. AB - Limited research has investigated exercise imagery use in middle-aged and older adults and its relationship with affective and behavioral correlates. The study examined the association between self-regulatory imagery and physical activity (PA) through key social cognitive variables. Middle-aged and older adults (N = 299; M age = 59.73 years, SD = 7.73, range = 50 to 80) completed self-report measures assessing self-regulatory imagery use, self-efficacy, outcome expectations, perceived barriers, self-regulatory behavior, enjoyment, and PA levels. Path analysis supported a model (chi2 [14] = 21.76, p = .08, CFI = .99, TLI = .97, SRMR = .03, RMSEA = .04) whereby self-regulatory imagery positively predicted self-efficacy, outcome expectations, and self-regulatory behaviors. Furthermore, self-regulatory imagery indirectly predicted barriers, outcome expectations, self-regulation, enjoyment, and PA. This research highlights self regulatory imagery as an effective strategy in modifying exercise-related cognitions and behaviors. Incorporating social cognitive constructs into the design of imagery interventions may increase PA engagement. PMID- 28338384 TI - Methotrexate-Induced Neurotoxicity in Hispanic Adolescents with High-Risk Acute Leukemia-A Case Series. AB - Intrathecal methotrexate (IT MTX) and high-dose intravenous methotrexate (HD MTX) are important components of treatment in high-risk acute leukemia. We describe five Hispanic adolescents with high-risk acute leukemia at our institution who experienced MTX-induced neurotoxicity. All patients were eventually rechallenged with MTX. Two of the five patients had a second episode of neurotoxicity, but all patients recovered. Further studies should be performed to determine whether Hispanic patients are more susceptible to MTX neurotoxicity. PMID- 28338386 TI - Targeted Functional Movement Retraining to Improve Pain, Function, and Biomechanics in Subjects With Anterior Knee Pain: A Case Series. AB - CONTEXT: Anterior knee pain (AKP) is a common condition, especially in a young active population. The clinical presentations of this condition vary considerably, and therefore, an individualized approach to treatment is needed. OBJECTIVE: The primary objective of this study was to assess the effect of a novel targeted biomechanical intervention on subjects with AKP. DESIGN: A case series was conducted on 8 participants with AKP. SETTING: The study was conducted at the Tygerberg Motion Analysis Laboratory and Tygerberg Physiotherapy Clinic in Cape Town, South Africa. PARTICIPANTS: Eight subjects (5 females and 3 males) diagnosed with AKP were included in this case series. INTERVENTION: Participants received a 6-week subject-specific functional movement retraining intervention. MAIN OUTCOME MEASURES: Three-dimensional hip, knee, and ankle kinematics were used for analysis for each participant preintervention and postintervention. Pain was measured weekly using the Numeric Pain Rating Scale. Two functional scales (Lower-Extremity Functional Scale and Anterior Knee Pain Scale) were used to assess pain and function the preintervention and postintervention. RESULTS: All 8 subjects demonstrated improved pain levels (Numeric Pain Rating Scale) and functional outcomes (Anterior Knee Pain Scale and Lower-Extremity Functional Scale). Seven of the 8 participants (87.7%) demonstrated improvements in their main biomechanical outcome. CONCLUSION: A subject-specific functional movement retraining intervention may be successful in the treatment of subjects with AKP presenting with biomechanical risk factors. Research on a larger sample is required to further investigate this approach. PMID- 28338387 TI - Comparison of the Effects of Curcumin and RG108 on NGF-Induced PC-12 Adh Cell Differentiation and Neurite Outgrowth. AB - DNA methyltransferases (DNMTs) are promising epigenetic targets for the development of novel drugs, especially for neurodegenerative disorders. In recent years, there has been increased interest in small molecules that can cross the blood-brain barrier for the treatment of neurodegenerative diseases. Therefore, comparing the neuronal differentiative effects of a natural compound curcumin and a synthetic small molecule RG108 was the aim of this study. The effects of curcumin and RG108 on neuronal differentiation and neurite outgrowth were investigated in the PC-12 Adh cell line. First, a nontoxic concentration was determined to be 100 nM with WST-1 assay. Subsequently, cells were treated with 100 nM curcumin and RG108 alone or in combination with 50 nM nerve growth factor (NGF). Cell differentiations were evaluated by a real-time cell analyzer system. Neurite outgrowth was determined and morphologically shown by immunofluorescence staining with anti-beta III tubulin antibody on PC-12 Adh cells. Also, growth associated protein-43 (GAP-43) and beta-tubulin III mRNA expression levels, associated with neurite outgrowth promotion, were determined with real-time polymerase chain reaction (RT-PCR). According to our results, 100 nM curcumin and RG108 significantly induced neurite outgrowth of PC-12 Adh cells with 50 nM NGF. Curcumin + NGF combination further increased cell differentiations and total neurite lengths more than curcumin alone and RG108 + NGF combination groups. Strikingly, curcumin and NGF combination upregulated GAP-43 and beta-tubulin mRNA expression levels excessively. In conclusion, curcumin was found to be more effective than RG108 on neuronal differentiation and neurite outgrowth of PC-12 Adh cells in a combination with NGF. Therefore, natural DNMT1 inhibitors, such as curcumin, can be a novel approach for the neurodegenerative disorders treatment. PMID- 28338388 TI - Preferred Hip Strategy During Landing Reduces Knee Abduction Moment in Collegiate Female Soccer Players. AB - CONTEXT: Hip-focused interventions are aimed to decrease frontal plane knee loading related to anterior cruciate ligament injuries. Whether a preferred hip landing strategy decreases frontal plane knee loading is unknown. OBJECTIVE: To determine if a preferred hip landing strategy during a drop vertical jump (DVJ) is utilized during a single-leg landing (SLL) task and whether differences in frontal plane knee loading are consistent between a DVJ and an SLL task. DESIGN: Descriptive laboratory study. SETTING: Research laboratory. PARTICIPANTS: Twenty three collegiate, female soccer players. MAIN OUTCOME MEASURES: Participants were dichotomized into a hip (HIP; n = 9) or knee/ankle (KA; n = 14) strategy group based on the percentage distribution of each lower extremity joint relative to the summated moment (% distribution) during the DVJ. Separate 1-way analysis of variances examined the differences in joint-specific % distribution and external knee abduction moment between the HIP and KA groups. RESULTS: The HIP group had significantly greater % distribution of hip moment and less % distribution of knee moment compared with the KA group during the DVJ and SLL. External knee abduction moment was also significantly less in the HIP group compared with the KA group during the DVJ. CONCLUSIONS: Female soccer athletes who land with a preferred hip strategy during a DVJ also land with a preferred hip strategy during an SLL. The preferred hip strategy also resulted in less external knee abduction moments during the DVJ. CLINICAL RELEVANCE: Targeting the neuromuscular control of the hip extensor may be useful in reducing risk of noncontact anterior cruciate ligament injuries. PMID- 28338389 TI - Somatosensory Electrical Stimulation Does Not Augment Motor Skill Acquisition and Intermanual Transfer in Healthy Young Adults-A Pilot Study. AB - Sensory input can modify motor function and magnify interlimb transfer. We examined the effects of low-intensity somatosensory electrical stimulation (SES) on motor practice-induced skill acquisition and intermanual transfer. Participants practiced a visuomotor skill for 25 min and received SES to the practice or the transfer arm. Responses to single- and double-pulse transcranial magnetic stimulation were measured in both extensor carpi radialis. SES did not further increase skill acquisition (motor practice with right hand [RMP]: 30.8% and motor practice with right hand + somatosensory electrical stimulation to the right arm [RMP + RSES]: 27.8%) and intermanual transfer (RMP: 13.6% and RMP + RSES: 9.8%) when delivered to the left arm (motor practice with right hand + somatosensory electrical stimulation to the left arm [RMP + LSES]: 44.8% and 18.6%, respectively). Furthermore, transcranial magnetic stimulation measures revealed no changes in either hand. Future studies should systematically manipulate SES parameters to better understand the mechanisms of how SES affords motor learning benefits documented but not studied in patients. PMID- 28338390 TI - Biologic Remodeling of Periodontal Dimensions of Areas Treated With Gingival Augmentation Procedure: A 25-Year Follow-Up Observation. AB - BACKGROUND: The role of keratinized tissue (KT) for maintenance of periodontal health has been debated for many years. This study assesses the long-term "biologic remodeling" of periodontal dimensions of teeth treated with free gingival grafts (FGGs) compared with adjacent/untreated teeth. METHODS: Seventy four patients with at least one site showing absence or a reduced amount of attached gingiva associated with gingival recession (GR) at baseline were treated with FGGs in a private practice. Patient/tooth/site-associated variables were recorded for each patient (treated and mesial/distal adjacent teeth) at baseline (T0), 6 months after surgery (T1), during the follow up period (T2) (mean 15.3 years), and at the end of the follow-up period (T3) over 25 years. Parametric, non-parametric, and mixed effects logistic regression statistics were used throughout the study. RESULTS: A total of 182 teeth submitted to FGGs were compared with 247 untreated/adjacent teeth. The majority of treated teeth (n = 152; 83.5%) showed GR depth (GRD) reduction (P <0.001). Conversely, untreated/adjacent teeth displayed GRD increase at T3 (P <0.001). Statistically significant KT band contraction was also found at treated sites, whereas adjacent sites presented small clinical improvements (P <0.001). The total root-coverage esthetic score of the areas including treated and adjacent untreated teeth improved from T2 to T3 (P <0.001). Some independent variables, such as age, tooth type, and GRD at T1 seem to influence GRD and KT changes over time. CONCLUSIONS: Soft tissue augmentation procedures may modify the biologic remodeling of periodontal dimensions over time associated with aging. Use of FGGs may promote more favorable KT dimensions and improve marginal tissue recession. PMID- 28338391 TI - Modifications in Human Oral Fibroblast Ultrastructure, Collagen Production, and Lysosomal Compartment in Response to Electronic Cigarette Fluids. AB - BACKGROUND: Many smokers have recently turned to electronic cigarettes (e cigarettes) because they have been marketed as a cheaper, safer smokeless alternative to traditional cigarettes and a possible smoking cessation tool. Although the safety of these electronic devices is still not fully known, there is evidence of their cytotoxicity on cells belonging to the oral cavity. In a previous study by the authors, the increase of reactive oxygen production and Bax expression, followed by the occurrence of apoptosis, was demonstrated in human gingival fibroblasts (HGFs). The aim of this paper is to further investigate the effects of the e-cigarette liquids (with and without nicotine) on the same experimental model. METHODS: HGFs were treated with e-cigarette fluids containing nicotine (final concentration 1 mg/mL) and the equivalent volume of a fluid without nicotine, for periods <=48 hours. Lactate dehydrogenase assay (LDH), electronic microscopy analysis, collagen I production, flow cytometry lysosome compartment evaluation, and western blotting light chain 3 (microtubule associated protein 1A/1B-LC3) expression were performed. RESULTS: Fluids containing nicotine exerted cytotoxicity as demonstrated by increased levels of LDH, in parallel to the presence of numerous vacuoles in the cytoplasm, a decrease in collagen I production, and augmented LC3 II expression. Autophagic vesicles and more procollagen I molecules were present in the cytoplasm of fibroblasts exposed to nicotine-free fluids. In the same samples, time-dependent activation of the lysosomal compartment with no changes in LC3 expression was detected. CONCLUSION: E-cigarette fluids (with and without nicotine) trigger molecular and morphologic responses in oral fibroblasts, raising concerns about their role in the pathogenesis of oral diseases. PMID- 28338392 TI - The Effects of Low-Intensity Therapeutic Ultrasound on Measurable Outcomes: A Critically Appraised Topic. AB - : Clinical Scenario: Therapeutic ultrasound (US) is a popular modality among health care professionals and is used to treat a variety of musculoskeletal conditions. A new technology has been established to allow for the miniaturization of the US unit. Patients receive treatment with the device secured to them, eliminating the portability constraint of traditional US units. Early studies suggest that this portable unit can deliver low-intensity acoustic energy achieving the same temperature increase and pain relief that come from traditional US units, in a more versatile and patient-friendly manner. CLINICAL QUESTION: What effects does low-intensity therapeutic ultrasound (LITUS) have on measurable outcomes? Summary of Key Findings: The literature was searched for level 4 evidence or higher that investigated the effectiveness of LITUS. The literature search produced 3 possible studies related to the clinical question: 2 randomized controlled trials and 1 case series met the inclusion and exclusion criteria. Of the included studies, 1 study investigated the effects of LITUS on tissue temperature, 2 studies investigated the effects of LITUS on pain, and 1 study investigated LITUS effects on function. Clinical Bottom Line: The evidence supports the use of the LITUS unit to increase tissue temperature, decrease pain, and increase function. Therefore, practitioners may consider the use of the LITUS unit in patient populations over the use of the traditional high-intensity US treatment. Strength of Recommendation: In accordance with the 2009 Centre for Evidence-Based Medicine levels of evidence, there is grade I (insufficient) evidence to support the positive effects of the LITUS device for improving the following clinical outcomes: tissue temperature, decreasing pain, and increasing function. The inconsistency in the measured outcomes across the 3 studies only allows for minimal support of the LITUS device, warranting further research. Although clinical outcomes were different in each study, consistent evidence ranging from 4 to 1B levels were found in the 3 included studies. PMID- 28338393 TI - Contraception for women with multiple sclerosis: Guidance for healthcare providers. AB - Family planning is essential for any comprehensive treatment plan for women of reproductive age with multiple sclerosis (MS), including counseling on using effective contraception to optimally time desired and prevent unintended pregnancies. This topical review summarizes the first evidence-based recommendations on contraception safety for women with MS. In 2016, evidence based recommendations for contraceptive use by women with MS were included in US Medical Eligibility Criteria for Contraceptive Use. They were developed after review of published scientific evidence on contraception safety and consultation with experts. We summarize and expand on the main conclusions of the Centers for Disease Control and Prevention guidance. Most contraceptive methods appear based on current evidence to be safe for women with MS. The only restriction is use of combined hormonal contraceptives among women with MS with prolonged immobility because of concerns about possible venous thromboembolism. Disease-modifying therapies (DMTs) do not appear to decrease the effectiveness of hormonal contraception although formal drug-drug interaction studies are limited. Neurologists can help women with MS make contraceptive choices that factor their level of disability, immobility, and medication use. For women with MS taking potentially teratogenic medications, highly effective methods that are long acting (e.g. intrauterine devices, implants) might be the best option. PMID- 28338394 TI - Inter- and Intrasubject Similarity of Muscle Synergies During Bench Press With Slow and Fast Velocity. AB - We investigated the effect of low and high bar velocity on inter- and intrasubject similarity of muscle synergies during bench press. A total of 13 trained male subjects underwent two exercise conditions: a slow- and a fast velocity bench press. Surface electromyography was recorded from 13 muscles, and muscle synergies were extracted using a nonnegative matrix factorization algorithm. The intrasubject similarity across conditions and intersubject similarity within conditions were computed for muscle synergy vectors and activation coefficients. Two muscle synergies were sufficient to describe the dataset variability. For the second synergy activation coefficient, the intersubject similarity within the fast-velocity condition was greater than the intrasubject similarity of the activation coefficient across the conditions. An opposite pattern was observed for the first muscle synergy vector. We concluded that the activation coefficients are robust within conditions, indicating a robust temporal pattern of muscular activity across individuals, but the muscle synergy vector seemed to be individually assigned. PMID- 28338395 TI - Functional Outcomes and Quality of Life After Ankle Fracture Surgically Treated: A Systematic Review. AB - CONTEXT: Ankle fractures (AFs) are the most common fractures of the lower limbs found in emergency services. Approximately 53% of these fractures are unstable and treated surgically. OBJECTIVE: To conduct a systematic review evaluating functional outcomes and quality of life of patients with AFs surgically treated. EVIDENCE ACQUISITION: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. Five electronic databases were searched, without any limit on publication dates. Only patients with an unstable AF that was surgically treated were included; functional outcomes and the quality of life were controlled by the 36-Item Short Form Health Survey instrument. EVIDENCE SYNTHESIS: Five studies were included in the analysis, including 267 patients. The values of the Physiotherapy Evidence Database scale ranged between a minimum of 5 and a maximum of 7 points. Patients with surgically treated AF reported less functionality and physical capacity compared with the nonfractured population. Some patients experienced vitality, emotional, and mental health limitations for a long period. Most surgically treated patients reported no pain and a good health and social status. CONCLUSION: Limitations in functionality and physical capacity represent the main threats to health-related quality of life in patients with surgically treated AFs. PMID- 28338396 TI - Should Ballet Dancers Vary Postures and Underfoot Surfaces When Practicing Postural Balance? AB - BACKGROUND: Postural balance (PB) is an important component skill for professional dancers. However, the effects of different types of postures and different underfoot surfaces on PB have not adequately been addressed. PURPOSE: The main aim of this study was to investigate the effect of different conditions of footwear, surfaces, and standing positions on static and dynamic PB ability of young ballet dancers. METHODS: A total of 36 male and female young professional ballet dancers (aged 14-19 years) completed static and dynamic balance testing, measured by head and lumbar accelerometers, while standing on one leg in the turnout position, under six different conditions: (1) "relaxed" posture; (2) "ballet" posture; (3) barefoot; (4) ballet shoes with textured insoles; (5) barefoot on a textured mat; and (6) barefoot on a spiky mat. RESULTS: A condition effect was found for static and dynamic PB. Static PB was reduced when dancers stood in the ballet posture compared with standing in the relaxed posture and when standing on a textured mat and on a spiky mat (p < .05), and static PB in the relaxed posture was significantly better than PB in all the other five conditions tested. Dynamic PB was significantly better while standing in ballet shoes with textured insoles and when standing on a spiky mat compared with all other conditions (p < .05). CONCLUSIONS: The practical implications derived from this study are that both male and female dancers should try to be relaxed in their postural muscles when practicing a ballet aligned position, including dance practice on different types of floors and on different types of textured/spiky materials may result in skill transfer to practice on normal floor surfaces, and both static and dynamic PB exercises should be assessed and generalized into practical dance routines. PMID- 28338397 TI - Clove and Its Active Compound Attenuate Free Fatty Acid-Mediated Insulin Resistance in Skeletal Muscle Cells and in Mice. AB - Several reports indicate anti-hyperglycemic effects of Syzygium aromaticum. In the present study, we report for the first time that clove extract (SAM) and its compound nigricin (NGC) decreases free fatty acid-mediated insulin resistance in mouse myoblasts. In addition, NGC was able to diminish insulin resistance in a diabetic mouse model. We observed that SAM and its compound NGC exhibited significant antioxidant activity in murine skeletal muscle cells. They also modulated stress signaling by reducing p38 MAP kinase phosphorylation. NGC and SAM treatments enhanced proximal insulin signaling by decreasing serine phosphorylation of insulin receptor substrate-1 (IRS-1) and increasing its tyrosine phosphorylation. SAM and NGC treatments also modified distal insulin signaling by enhancing protein kinase B (PKB) and glycogen synthase kinase-3-beta (GSK-3 beta) phosphorylation in muscle cells. Glucose uptake was enhanced in muscle cells after treatment with SAM and NGC. We observed increased glucose tolerance, glucose-stimulated insulin secretion, decreased insulin resistance, and increased beta cell function in diabetic mice treated with NGC. The results of our study demonstrate that clove extract and its active agent NGC can be potential therapeutic agents for alleviating insulin resistance. PMID- 28338399 TI - Longitudinal Association Between Objectively Measured Walking and Depressive Symptoms Among Estonian Older Adults. AB - Although an inverse correlation between physical activity and depressive symptoms among older adults has been found in research, this relation has seldom been examined prospectively. Accordingly, the current study examined the reciprocal relations between physical activity and depressive symptoms in Estonian older adults over a 2-year period. A three-wave longitudinal model was tested using cross-lagged analysis for 195 individuals aged over 70 years (mean = 72.1, SD = 2.1; 145 females). Results indicated that a cross-lagged model in which depressive symptoms predicted walking at subsequent time points (higher depressive symptoms were related to fewer walking steps), and walking predicted depressive symptoms at subsequent time points (higher walking steps were related to lower depressive symptoms) was most parsimonious and provided acceptable model fit. These results suggest that reduced physical activity may be a long-term consequence of depressive symptoms in older adults. PMID- 28338400 TI - Systematic, Unintended Drifts in the Cyclic Force Produced with the Fingertips. AB - Cyclic isometric finger-force patterns established using visual feedback show systematic drifts when the feedback is removed. Force changes at multiple time scales and in opposite directions have been reported. For further characterization of these drifts, healthy subjects produced isometric, cyclic finger force with and without visual feedback at various initial amplitudes and frequencies. We hypothesized that on feedback removal, the amplitude will be attracted toward a preferred value that is frequency dependent. We found that the amplitude always increased after feedback removal. The magnitude of the amplitude increase changed with initial frequency, but it was invariant over the explored range of initial amplitudes. Thus, the existence of a preferred amplitude of force oscillations was not supported. We interpret these results within the referent configuration and the referent configuration back-coupling hypotheses. These data will inform a mathematical model of finger-force drifts. However, currently, they raise more questions than they answer, and a coherent account of finger-force drifts remains a challenge. PMID- 28338398 TI - Dexamethasone suppresses JMJD3 gene activation via a putative negative glucocorticoid response element and maintains integrity of tight junctions in brain microvascular endothelial cells. AB - The blood-brain barrier (BBB) exhibits a highly selective permeability to support the homeostasis of the central nervous system (CNS). The tight junctions in the BBB microvascular endothelial cells seal the paracellular space to prevent diffusion. Thus, disruption of tight junctions results in harmful effects in CNS diseases and injuries. It has recently been demonstrated that glucocorticoids have beneficial effects on maintaining tight junctions in both in vitro cell and in vivo animal models. In the present study, we found that dexamethasone suppresses the expression of JMJD3, a histone H3K27 demethylase, via the recruitment of glucocorticoid receptor alpha (GRalpha) and nuclear receptor co repressor (N-CoR) to the negative glucocorticoid response element (nGRE) in the upstream region of JMJD3 gene in brain microvascular endothelial cells subjected to TNFalpha treatment. The decreased JMJD3 gene expression resulted in the suppression of MMP-2, MMP-3, and MMP-9 gene activation. Dexamethasone also activated the expression of the claudin 5 and occludin genes. Collectively, dexamethasone attenuated the disruption of the tight junctions in the brain microvascular endothelial cells subjected to TNFalpha treatment. Therefore, glucocorticoids may help to preserve the integrity of the tight junctions in the BBB via transcriptional and post-translational regulation following CNS diseases and injuries. PMID- 28338401 TI - Challenges associated and approaches for successful translation of nanomedicines into commercial products. PMID- 28338402 TI - Testosterone Plus Finasteride Prevents Bone Loss without Prostate Growth in a Rodent Spinal Cord Injury Model. AB - We have reported that testosterone-enanthate (TE) prevents the musculoskeletal decline occurring acutely after spinal cord injury (SCI), but results in a near doubling of prostate mass. Our purpose was to test the hypothesis that administration of TE plus finasteride (FIN; type II 5alpha-reductase inhibitor) would prevent the chronic musculoskeletal deficits in our rodent severe contusion SCI model, without inducing prostate enlargement. Forty-three 16-week-old male Sprague-Dawley rats received: 1) SHAM surgery (T9 laminectomy); 2) severe (250 kdyne) contusion SCI; 3) SCI+TE (7.0 mg/week, intramuscular); or 4) SCI+TE+FIN (5 mg/kg/day, subcutaneous). At 8 weeks post-surgery, SCI animals exhibited reduced serum testosterone and levator ani/bulbocavernosus (LABC) muscle mass, effects that were prevented by TE. Cancellous and cortical (periosteal) bone turnover (assessed by histomorphometry) were elevated post-SCI, resulting in reduced distal femur cancellous and cortical bone mass (assessed by microcomputed tomography). TE treatment normalized cancellous and cortical bone turnover and maintained cancellous bone mass at the level of SHAM animals, but produced prostate enlargement. FIN coadministration did not inhibit the TE-induced musculoskeletal effects, but prevented prostate growth. Neither drug regimen prevented SCI-induced cortical bone loss, although no differences in whole bone strength were present among groups. Our findings indicate that TE+FIN prevented the chronic cancellous bone deficits and LABC muscle loss in SCI animals without inducing prostate enlargement, which provides a rationale for the inclusion of TE+FIN in multimodal therapeutic interventions intended to alleviate the musculoskeletal decline post-SCI. PMID- 28338404 TI - Effect of Histone Deacetylase Inhibitor, Butyroyloxymethyl-Diethyl Phosphate (AN 7), on Corneal Neovascularization in a Mouse Model. AB - PURPOSE: To examine whether butyroyloxymethyl-diethyl phosphate (AN-7), a histone deacetylase inhibitor, inhibits chemically induced corneal neovascularization (NV) in mice. METHODS: Corneal NV was induced in the right eye of male C57BL mice by application of a mixture of 75% silver nitrate and 25% potassium nitrate to the corneal center. Immediately thereafter, the mice were randomized into 2 groups, receiving an intraperitoneal injection of AN-7 or saline, which served as control. Corneal NV was evaluated at constant time intervals from the corneal injury by corneal photographs and the area of corneal NV was measured. Centricity and density of the corneal vascularization were graded. Corneal flat mounts blood vessels staining and histological studies were performed on day 10. Unpaired t test was used for group comparisons. RESULTS: The corneal neovascular area was statistically significantly reduced by AN-7 treatment on days 10 and 14 postinjury and compared with the untreated group. The centricity and density of the corneal NV between treated and untreated groups showed no significant difference at any time point. CONCLUSIONS: Systemic treatment with AN-7 had a significant inhibitory effect on chemical burn-induced corneal NV in mice. These results suggest that AN-7 should be further evaluated for its therapeutic potential for the treatment of corneal NV. PMID- 28338403 TI - Personalized Mobile Health Intervention for Health and Weight Loss in Postpartum Women Receiving Women, Infants, and Children Benefit: A Randomized Controlled Pilot Study. AB - BACKGROUND: Prepregnancy maternal obesity and excessive weight gain during pregnancy lead to significant morbidities in mothers and their children. Mothers who never return to their prepregnancy weight begin subsequent pregnancies at a greater weight and have a larger propensity for excess gestational weight gain and postpartum weight retention. METHODS: In this pilot study, 40 postpartum women credentialed to receive postpartum women, infants, and children (WIC) service were randomized to usual care ("WIC Moms") or a personalized health intervention delivered via a SmartPhone ("E-Moms"). Assessments, including body weight, vital signs, circumferences, and body composition, were completed at week 0 (6-8 weeks postpartum), week 8, and week 16. RESULTS: Results are presented as change from week 0 at 16. As per the completers analysis, body weight change was not different between the groups (WIC Moms vs. E-Moms; 1.8 +/- 0.9 vs. -0.1 +/- 0.9 kg; p = 0.10), neither was the change in percent body fat (1.7 +/- 0.6 vs. 0.1% +/- 0.6%; p = 0.90) or waist/hip ratio (-0.01 +/- 0.01 vs. -0.02 +/- 0.01 cm; p = 0.60). However, due to notable variability in intervention adherence as the study progressed, participants were classified post hoc as having low (<40% adherence), medium (40%-70% adherence), or high adherence (>70% adherence). Participants with high intervention adherence (n = 5) had a significant reduction in body weight (-3.6 +/- 1.6 vs. 1.8 +/- 0.9 kg; p = 0.005) and percent body fat (-2.5 +/- 1.0 vs. 1.7% +/- 0.6%; p = 0.001) when compared to WIC Moms. CONCLUSIONS: Overall, the E-Moms intervention was not able to decrease postpartum weight retention in women receiving WIC benefits compared to usual care received through the current WIC program. However, there is some evidence to suggest improved adherence to the intervention would improve weight management. PMID- 28338405 TI - Physiological Responses to Treadmill Running With Body Weight Support in Hypoxia Compared With Normoxia. AB - CONTEXT: Anecdotal reports suggest elite sports clubs combine lower-body positive pressure rehabilitation with a hypoxic stimulus to maintain or increase physiological and metabolic strain, which are reduced during lower-body positive pressure. However, the effects of hypoxia on cardiovascular and metabolic response during lower-body positive-pressure rehabilitation are unknown. OBJECTIVE: Evaluate the use of normobaric hypoxia as a means to increase physiological strain during body-weight-supported (BWS) running. DESIGN: Crossover study. SETTING: Controlled laboratory. PARTICIPANTS: Seven familiarized males (mean (SD): age, 20 (1) y; height, 1.77 (0.05) m; mass, 69.4 (5.1) kg; hemoglobin, 15.2 (0.8) g.dL-1) completed a normoxic and hypoxic (fraction of inspired oxygen [O2] = 0.14) trial, during which they ran at 8 km.h-1 on an AlterGTM treadmill with 0%, 30%, and 60% BWS in a randomized order for 10 minutes interspersed with 5 minutes of recovery. MAIN OUTCOME MEASURES: Arterial O2 saturation, heart rate, O2 delivery, and measurements of metabolic strain via indirect calorimetry. RESULTS: Hypoxic exercise reduced hemoglobin O2 saturation and elevated heart rate at each level of BWS compared with normoxia. However, the reduction in hemoglobin O2 saturation was attenuated at 60% BWS compared with 0% and 30%, and consequently, O2 delivery was better maintained at 60% BWS. CONCLUSION: Hypoxia is a practically useful means of increasing physiological strain during BWS rehabilitation. In light of the maintenance of hemoglobin O2 saturation and O2 delivery at increasing levels of BWS, fixed hemoglobin saturations rather than a fixed altitude are recommended to maintain an aerobic stimulus. PMID- 28338406 TI - A Feasibility Study for Improved Physical Activity After Total Knee Arthroplasty. AB - Physical activity outcomes are poor following total knee arthroplasty (TKA). The purpose was to evaluate feasibility of a physical activity feedback intervention for patients after TKA. Participants completing conventional TKA rehabilitation were randomized to a physical activity feedback (PAF; n = 22) or control (CTL; n = 23) group. The PAF intervention included real-time activity feedback, weekly action planning, and monthly group support meetings (12 weeks). The CTL group received attention control education. Feasibility was assessed using retention, adherence, dose goal attainment, and responsiveness with pre- and postintervention testing. The PAF group had 100% retention, 92% adherence (frequency of feedback use), and 65% dose goal attainment (frequency of meeting goals). The PAF group average daily step count increased from 5,754 (2,714) (pre) to 6,917 (3,445) steps/day (post). This study describes a feasible intervention to use as an adjunct to conventional rehabilitation for people with TKA. PMID- 28338407 TI - Optimizing a Retention Strategy with Young People for BRIGHTLIGHT, a Longitudinal Cohort Study Examining the Value of Specialist Cancer Care for Young People. AB - PURPOSE: To maximize retention of participants in a longitudinal cohort study, we sought to understand young peoples' views about barriers and facilitators to continuing study participation. METHODS: Ten young people with a previous cancer diagnosis aged 15-24 participated in a 1 day workshop. The workshop used participatory methodology consisting of three exercises as follows: role play/scene setting; force field analysis of research participation in small groups; and focus group discussion. A final prioritization exercise was administered individually after the workshop. RESULTS: Twenty-four barriers to maintaining participation were summarized in five themes as follows: life commitments; concerns specific to the study; emotional barriers; practical barriers; and other reasons. The top 3 specific barriers were as follows: not a priority/other things are more important; too time consuming; and forgetting/memory. The top 3 facilitators for participation were as follows: wishing to help other young people; giving back to the cancer community; and honoring an initial commitment to participation. The top 3 suggested solutions to encourage continued participation were as follows: reminder text message or email before each survey to check preferred method of delivery; breaking up the online survey into modules to make completion less overwhelming; and consolidation of study information in one location. CONCLUSION: Involving young people in designing a retention strategy for young people with cancer has informed the BRIGHTLIGHT retention strategy. Patient and public involvement is imperative for successful research but measuring impact is challenging. The success of implementing the changes to optimize retention was shown in the increase in retention in Wave 3 from 30% to final participation of 58%. PMID- 28338408 TI - Clofazimine encapsulation in nanoporous silica particles for the oral treatment of antibiotic-resistant Mycobacterium tuberculosis infections. AB - AIM: First extensive reformulation of clofazimine (CLZ) in nanoporous silica particles (NSPs) for tackling antibiotic-resistant tuberculosis (TB) infections. MATERIALS & METHODS: Solid-state characterization of several CLZ-encapsulated NSP formulations was followed by in vitro drug solubility, Caco-2 intestinal cells drug permeability and TB antibacterial activity. RESULTS: NSPs stabilize the amorphous state of CLZ (shelf stability >6 months) and dramatically increase the drug solubility in simulated gastric fluid (up to 20-fold) with different dissolution kinetics depending on the NSPs used. CLZ encapsulation in NSP substantially enhances the permeation through model intestinal cell layer, achieving effective antimicrobial concentrations in TB-infected macrophages. CONCLUSION: Promising results toward refurbishment of an approved marketed drug for a different indication suitable for oral anti-TB formulation. PMID- 28338409 TI - Self-emulsifying preconcentrates of daidzein-phospholipid complex: design, in vitro and in vivo appraisal. AB - AIM: Self-emulsifying phospholipid-complex preconcentrates (SEPPs) were fabricated to improve oral bioavailability of daidzein (DAI), an anticancer drug with challenging amphiphobic nature and extensive presystemic metabolism. METHODS: DAI-phosphatidylcholine complex was prepared to enhance DAI lipophilicity and loading in SEPPs. The physicochemical characteristics and the pharmacokinetic behavior in rats were studied. RESULTS: Surfactant-free SEPP (plain DAI:Phosal(r) 53MCT complex) was monodisperse upon aqueous dilution with nanorange globule size (485 +/- 15 nm). Compared with drug suspension, it showed enhanced drug release and 2.38-fold enhanced oral bioavailability with minimized drug-induced intestinal irritation. Addition of 30% surfactant/co-surfactant mixture did not show any significant difference in drug release rate or absorption profile. CONCLUSION: The highly safe surfactant-free SEPP could be an effective approach to improve DAI oral bioavailability. PMID- 28338411 TI - Magnetic nanoparticles for medical applications. PMID- 28338410 TI - Intracellular delivery of proteins by nanocarriers. AB - Intracellular delivery of proteins is potentially a game-changing approach for therapeutics. However, for most applications, the protein needs to access the cytosol to be effective. A wide variety of strategies have been developed for protein delivery, however access of delivered protein to the cytosol without acute cytotoxicity remains a critical issue. In this review we discuss recent trends in protein delivery using nanocarriers, focusing on the ability of these strategies to deliver protein into the cytosol. PMID- 28338412 TI - Adolescent Changes in Aerobic Fitness Are Related to Changes in Academic Achievement. AB - : There is a growing trend of decreasing physical fitness among adolescents, which may result not only in poorer physical health, but also in poorer academic achievement. PURPOSE: The purpose of this study was to investigate the changes in aerobic fitness and academic achievement in reading and mathematics during middle school. METHODS: This study employed a prospective, longitudinal cross-sectional design. Fifty-two adolescents were followed from sixth grade through eighth grade. In the spring, sixth-, seventh-, and eighth-grade students completed Progressive Aerobic Cardiovascular Endurance Run tests measuring aerobic fitness. In addition, students also completed Illinois Standards Achievement Test academic achievement tests in reading and mathematics. RESULTS: Changes in aerobic fitness between sixth and eighth grade were positively related to changes in academic achievement in both reading and mathematics between sixth and eighth grade. CONCLUSION: These data suggest that changes in aerobic fitness may modulate changes in academic achievement. These findings highlight the importance of physical activity and have broad relevance for educational systems and policies. PMID- 28338413 TI - Human, Tissue-Engineered, Skeletal Muscle Myobundles to Measure Oxygen Uptake and Assess Mitochondrial Toxicity. AB - Mitochondrial dysfunction is responsible for the toxicity of a number of drugs. Current isolated mitochondria or cellular monoculture mitochondrial respiration measurement systems lack physiological relevance. Using a tissue engineering rather than cell- or mitochondria-based approach enables a more physiologically relevant detection of drug-induced mitochondrial impairment. To probe oxygen consumption and mitochondrial health, we assayed the bioenergetic profile of engineered three-dimensional human skeletal muscle myobundles derived from primary myoblasts. Through experimental and computational techniques, we did not find external or internal oxygen transport limiting the engineered myobundles in the commercial O2k system to measure oxygen consumption. In response to the complex I inhibitor rotenone, myobundle basal respiration decreased dose dependently with an IC50 of 9.24 +/- 0.03 nM. At a 20 nM concentration of rotenone, myobundle maximal respiration decreased by 44.4% +/- 9.8%. Respiratory depression by rotenone suggests that cultured myobundles rely heavily on the complex I pathway for ATP synthesis during times of both basal and increased energy demand. To address whether these decrements in mitochondrial function corresponded to alterations in physiological muscle function, we determined fatigue susceptibility that revealed a 46.0% +/- 7.4% depression at 20 nM rotenone. The bioenergetic health index, which is a measure of normal oxidative mitochondrial function, was inversely correlated with the extent of fatigue. The human myobundles reproduce normal muscle metabolism under both basal and maximal energy demand conditions enabling the detection of drug-induced mitochondrial toxicity. PMID- 28338414 TI - Targeted therapy of octreotide-modified oleanolic acid liposomes to somatostatin receptor overexpressing tumor cells. AB - AIM: To prepare and validate the efficacy of a novel targeted drug delivery system - octreotide (Oct)-modified oleanolic acid (OA) liposomes. MATERIALS & METHODS: OA liposomes (OA-L) were prepared by an ethanol injection method. The Oct-modified OA liposomes (O-OA-L) were synthesized and their properties were evaluated. Cellular uptake and competition inhibition studies were performed. RESULTS: The OA vesicles presented satisfactory particles size (100-200 nm), stability and drug release characteristics; their zeta potential was -1.42 +/- 0.08 mV. The O-OA-L had a higher cell proliferation inhibitory activity and cellular uptake than that of OA-L for somatostatin receptor-positive A549 cells. CONCLUSION: The O-OA-L, as a promising agent, can target actively the lesion site with safe and high-efficiency pattern. PMID- 28338415 TI - Hyaluronic Acid Hydrogel Functionalized with Self-Assembled Micelles of Amphiphilic PEGylated Kartogenin for the Treatment of Osteoarthritis. AB - Synthetic hyaluronic acid (HA) containing a covalently integrated drug is capable of releasing therapeutic molecules and is an attractive candidate for the intra articular treatment of osteoarthritis (OA). Herein, self-assembled PEGylated kartogenin (PEG/KGN) micelles consisting of hydrophilic polyethylene glycol (PEG) and hydrophobic KGN, which has been shown to induce chondrogenesis in human mesenchymal stem cells, were prepared by covalent crosslinking. HA hydrogels containing PEG/KGN micelles (HA/PEG/KGN) were prepared by covalently bonding PEG chains to HA. The physicochemical properties of the HA/PEG/KGN conjugate gels were investigated using Fourier transform infrared spectroscopy, 1H NMR, dynamic light scattering (DLS), and scanning electron microscopy (SEM). HA/PEG/KGN gels exhibited larger micelles in aqueous solution than PEG/KGN. SEM images of PEG/KGN micelles showed a dark core and a bright shell, whereas PEG/KGN micelles covalently integrated into HA had an irregular oval shape. Covalent integration of PEG/KGN micelles in HA hydrogels significantly reduced drug release rates and provided sustained release over a prolonged period of time. HA/PEG/KGN hydrogels were degradable enzymatically by collagenase and hyaluronidase in vitro. Injection of HA/PEG/KGN hydrogels into articular cartilage significantly suppressed the progression of OA in rats compared with free-HA hydrogel injection. These results suggest that the HA/PEG/KGN hydrogels have greater potency than free-HA hydrogels against OA as biodegradable synthetic therapeutics. PMID- 28338416 TI - Impact of a Complex Care Management Model on Cost and Utilization Among Adolescents and Young Adults with Special Care and Health Needs. AB - Adolescents and young adults with special care and health needs in the United States-many of whom have Medicaid coverage-at the transition phase between pediatric and adult care often experience critical care gaps. To address this challenge, a new model-referred to as Comprehensive Care Clinic (CCC)-has been developed and implemented by Geisinger Health System since 2012. CCC comprises a care team, consisting of a generalist physician, advanced practitioner, pharmacist, and a nurse case manager, that develops and closely follows a coordinated care plan. This study examines the CCC impact on total cost of care and utilization by analyzing Geisinger Health Plan claims data obtained from 83 Medicaid patients enrolled in CCC. A set of multivariate regression models with patient fixed effects was estimated to obtain adjusted differences in cost and acute care utilization between the months in which the patients were enrolled and the months not enrolled in CCC. The results indicate that CCC enrollment was associated with a 28% reduction in per-member-per-month total cost ($3931 observed vs. $5451 expected; P = 0.028), driven by reductions in hospitalization and emergency department visits. This finding suggests a clinical redesign focused on adolescent and young adults with complex care needs can potentially reduce total cost and acute care utilization among such patients. PMID- 28338418 TI - Hybrid MF and membrane bioreactor process applied towards water and indigo reuse from denim textile wastewater. AB - This work investigates the application of a microfiltration (MF)-membrane bioreactor (MBR) hybrid process for textile dyeing process wastewater reclamation. The indigo blue dye was efficiently retained by the MF membrane (100%), which allows its recovery from the concentrate stream. MF promotes 100% of colour removal, and reduces the chemical oxygen demand (COD) and conductivity by about 65% and 25%, respectively, and improves the wastewater biodegradability. MF flux decline was mostly attributed to concentration polarization and the chemical cleaning was efficient enough to recover initial hydraulic resistance. The MBR provides to be a stable process maintaining its COD and ammonia removal efficiency (73% and 100%, respectively) mostly constant throughout and producing a permeate that meets the reuse criteria for some industry activities, such as washing-off and equipment washdown. The use of an MF or ultrafiltration (UF) membrane in the MBR does not impact the MBR performance in terms of COD removal. Although the membrane of MBR-UF shows permeability lower than MBR-MF membrane, the UF membrane contributes to a more stable operation in terms of permeability. PMID- 28338417 TI - * A 3D Tissue-Printing Approach for Validation of Diffusion Tensor Imaging in Skeletal Muscle. AB - The ability to noninvasively assess skeletal muscle microstructure, which predicts function and disease, would be of significant clinical value. One method that holds this promise is diffusion tensor magnetic resonance imaging (DT-MRI), which is sensitive to the microscopic diffusion of water within tissues and has become ubiquitous in neuroimaging as a way of assessing neuronal structure and damage. However, its application to the assessment of changes in muscle microstructure associated with injury, pathology, or age remains poorly defined, because it is difficult to precisely control muscle microstructural features in vivo. However, recent advances in additive manufacturing technologies allow precision-engineered diffusion phantoms with histology informed skeletal muscle geometry to be manufactured. Therefore, the goal of this study was to develop skeletal muscle phantoms at relevant size scales to relate microstructural features to MRI-based diffusion measurements. A digital light projection based rapid 3D printing method was used to fabricate polyethylene glycol diacrylate based diffusion phantoms with (1) idealized muscle geometry (no geometry; fiber sizes of 30, 50, or 70 MUm or fiber size of 50 MUm with 40% of walls randomly deleted) or (2) histology-based geometry (normal and after 30-days of denervation) containing 20% or 50% phosphate-buffered saline (PBS). Mean absolute percent error (8%) of the printed phantoms indicated high conformity to templates when "fibers" were >50 MUm. A multiple spin-echo echo planar imaging diffusion sequence, capable of acquiring diffusion weighted data at several echo times, was used in an attempt to combine relaxometry and diffusion techniques with the goal of separating intracellular and extracellular diffusion signals. When fiber size increased (30-70 MUm) in the 20% PBS phantom, fractional anisotropy (FA) decreased (0.32-0.26) and mean diffusivity (MD) increased (0.44 * 10-3 mm2/s-0.70 * 10-3 mm2/s). Similarly, when fiber size increased from 30 to 70 MUm in the 50% PBS diffusion phantoms, a small change in FA was observed (0.18-0.22), but MD increased from 0.86 * 10-3 mm2/s to 1.79 * 10-3 mm2/s. This study demonstrates a novel application of tissue engineering to understand complex diffusion signals in skeletal muscle. Through this work, we have also demonstrated the feasibility of 3D printing for skeletal muscle with relevant matrix geometries and physiologically relevant tissue characteristics. PMID- 28338420 TI - Exploring the Facilitators and Barriers to Physical Activity in Older People With Sight Loss. AB - This study aimed to explore facilitators and barriers to physical activity in older people with sight loss. Focus groups were conducted with 13 community dwelling older adults with sight loss ranging from poor to completely blind. Transcripts were analyzed using an inductive thematic analysis. Facilitators and barriers are experienced in three ways: psychologically; through opportunity and access; and at a societal and policy level. Campaigns are needed to challenge unhelpful age-related stereotypes at both psychological and societal levels. Additionally, interventions grounded in evidence and theory should be trialled and evaluated for increasing physical activity in this population. PMID- 28338419 TI - Competitive Protein Binding Influences Heparin-Based Modulation of Spatial Growth Factor Delivery for Bone Regeneration. AB - Tissue engineering strategies involving the in vivo delivery of recombinant growth factors are often limited by the inability of biomaterials to spatially control diffusion of the delivered protein within the site of interest. The poor spatiotemporal control provided by porous collagen sponges, which are used for the clinical delivery of bone morphogenetic protein-2 (BMP-2) for bone regeneration, has necessitated the use of supraphysiological protein doses, leading to inflammation and heterotopic ossification. This study describes a novel tissue engineering strategy to spatially control rapid BMP-2 diffusion from collagen sponges in vivo by creating a high-affinity BMP-2 sink around the collagen sponge. We designed an electrospun poly-E-caprolactone nanofiber mesh containing physically entrapped heparin microparticles, which have been previously demonstrated to bind and retain large amounts of BMP-2. Nanofiber meshes containing 0.05 and 0.10 mg of microparticles/cm2 demonstrated increased BMP-2 binding and decreased BMP-2 release in vitro compared with meshes without microparticles. However, when microparticle-containing meshes were used in vivo to limit the diffusion of BMP-2 delivered by using collagen sponges in a rat femoral defect, no differences in heterotopic ossification or biomechanical properties were observed. Further investigation revealed that, although BMP-2 binding to heparin microparticles was rapid, the presence of serum components attenuated microparticle-BMP-2 binding and increased BMP-2 release in vitro. These observations provide a plausible explanation for the results observed in vivo and suggest that competitive protein binding in vivo may hinder the ability of affinity-based biomaterials to modulate growth factor delivery. PMID- 28338421 TI - * Harnessing the Osteogenicity of In Vitro Stem Cell-Derived Mineralized Extracellular Matrix as 3D Biotemplate to Guide Bone Regeneration. AB - Advanced biomaterials that are capable of guiding robust bone regeneration are highly demanded for translational therapy of bone defects or bone augmentation in clinics. One of the strategic approaches is to produce tissue engineering (TE) constructs that mediate bone regeneration by recapitulating the natural bone formation or healing process. In this study, we aimed at producing devitalized mineralized carriers with augmented bone forming capacity via a modified culture protocol (i.e., culture conditions with high calcium and/or phosphate concentrations) that first promotes cell growth and, subsequently, mineralized extracellular matrix (ECM) deposition by human periosteum-derived osteoprogenitor cells (hPDCs) on additive manufactured three-dimensional (3D) porous titanium (Ti)-based scaffolds. Qualitative and quantitative analysis was performed to characterize the physicochemical properties of the produced devitalized mineralized carriers, as well as their effects as carriers on in vitro cell growth and osteochondrogenic differentiation of hPDCs under a perfusion bioreactor culture set-up. The results showed that the modified culture protocol was useful to produce devitalized mineralized carriers with different amount, distribution, composition, and morphology of mineralized matrix that resembled hydroxyapatite, and exhibited different Ca2+ release kinetics, distinct human bone morphogenetic protein (hBMP)-2, human vascular endothelial growth factor (hVEGF) proteins, and collagen contents. The produced devitalized mineralized carriers supported 3D growth of hPDCs, with minor osteochondrogenic differentiation effects under the perfusion bioreactor culture condition. Subcutaneous implantation of hPDC-seeded devitalized mineralized carriers in athymic nude rats showed nearly five-fold augmentation in the ectopic bone forming capacity, with no bone induction obtained for unseeded, devitalized mineralized carriers and plain Ti scaffolds. Implantation of devitalized mineralized carriers in critical-sized calvarial defects resulted in encouraging defect bridging as compared with limited defect bridging by plain Ti scaffolds or in empty defects. This defect bridging was not enhanced by implanting hPDC-seeded devitalized mineralized carriers. In conclusion, the investigated modified culture protocol was useful to produce devitalized mineralized carriers with augmented bone-forming capacity, which potentially could aid bone repair or augmentation in clinics. PMID- 28338422 TI - Therapeutic Hypothermia Reduces the Inflammatory Response Following Ischemia/Reperfusion Injury in Rat Hearts. AB - Therapeutic hypothermia (TH) is known to protect against ischemia/reperfusion (I/R) injury. One mechanism of I/R injury includes secondary injury due to the inflammatory cascade. We hypothesized that TH reduces the inflammatory response following I/R injury. Rats were randomized to sham, normothermic, or hypothermic groups and subjected to 1 hour of coronary artery occlusion and 48 hours of reperfusion. Hypothermia was initiated, using the ThermoSuit(r) device, 2 minutes after the onset of coronary artery occlusion to a core temperature of 32 degrees C, and then the rats were allowed to rewarm. After 48 hours, rats in the hypothermia group demonstrated a preserved left ventricular fractional shortening by echocardiography. TH decreased the inflammatory cytokines in the risk zone of the heart, which included monocyte chemoattractant protein-1, interleukin-6, tumor necrosis factor-alpha, and inducible nitric oxide synthase gene expression, and altered expression of the remodeling genes of matrix metalloproteinase and tissue inhibitor of metalloproteinase. Furthermore, rat inflammatory cytokines & receptors PCR array was performed and the data showed that 71 out of 84 genes were upregulated in the risk zone of normothermia hearts versus shams. The upregulation was largely reversed in the risk zone of hypothermia hearts compared to normothermia. TH preserves cardiac function, decreases excessive inflammatory gene expression, and regulates myocardial matrix remodeling related genes. PMID- 28338423 TI - Assessment of leg muscles mechanical capacities: Which jump, loading, and variable type provide the most reliable outcomes? AB - This study aimed to explore the strength of the force-velocity (F-V) relationship of lower limb muscles and the reliability of its parameters (maximum force [F0], slope [a], maximum velocity [V0], and maximum power [P0]). Twenty-three men were tested in two different jump types (squat and countermovement jump: SJ and CMJ), performed under two different loading conditions (free weight and Smith machine: Free and Smith) with 0, 17, 30, 45, 60, and 75 kg loads. The maximum and averaged values of F and V were obtained for the F-V relationship modelling. All F-V relationships were strong and linear independently whether observed from the averaged across the participants (r >= 0.98) or individual data (r = 0.94-0.98), while their parameters were generally highly reliable (F0 [CV: 4.85%, ICC: 0.87], V0 [CV: 6.10%, ICC: 0.82], a [CV: 10.5%, ICC: 0.81], and P0 [CV: 3.5%, ICC: 0.93]). Both the strength of the F-V relationships and the reliability of their parameters were significantly higher for (1) the CMJ over the SJ, (2) the Free over the Smith loading type, and (3) the maximum over the averaged F and V variables. In conclusion, although the F-V relationships obtained from all the jumps tested were linear and generally highly reliable, the less appropriate choice for testing the F-V relationship could be through the averaged F and V data obtained from the SJ performed either in a Free weight or in a Smith machine. Insubstantial differences exist among the other combinations tested. PMID- 28338424 TI - Monocytes Seeded on Engineered Hypertrophic Cartilage Do Not Enhance Endochondral Ossification Capacity. AB - Engineered hypertrophic cartilage (HC) represents an attractive bone substitute material, capable to induce bone formation by endochondral ossification. Since bone formation by HC depends on factors released from the extracellular matrix, in this study, we hypothesized that HC seeding with monocytes committed to osteoclastogenesis could enhance its remodeling, improve chemotaxis of skeletal and vascular cells, and consequently enhance bone formation. This would be particularly relevant for devitalized HC, which currently exhibits only limited osteoinductivity. Living or devitalized HC engineered from human bone marrow derived mesenchymal stromal cells (MSCs) was seeded or not with human monocytes in the presence of macrophage colony-stimulating factor and RANK-ligand, cultured for up to 15 days, or implanted ectopically in nude mice. Monocytes seeded on devitalized, but not living, HC induced its in vitro resorption, resulting in 30 fold higher release and 2.7-fold lower content of glycosaminoglycans compared with unseeded samples. In vitro, supernatants from monocyte-seeded devitalized HC attracted more monocytes compared with unseeded samples, but did not enhance chemotaxis of MSCs or human umbilical vein endothelial cells. In vivo, however, neither remodeling nor invasion by osteoclasts, endothelial cells, and mouse MSCs were significantly affected by the seeding with monocytes. Finally, in vitro priming of living or devitalized HC by monocytes did not enhance their bone forming capacity. Further investigations should test the proposed approach on HC engineered to prevent rapid degradation and support osteoclastogenesis, or identify alternative strategies to enhance engineered HC remodeling and bone forming capacity. PMID- 28338425 TI - Assessing the Reliability of Performing Citywide Chronic Disease Surveillance Using Emergency Department Data from Sentinel Hospitals. AB - Given the inequalities in the distribution of disease burden, geographically detailed methods of disease surveillance are needed to identify local hot spots of chronic disease. However, few data sources include the patient-level addresses needed to perform these studies. Given that individual hospitals would have access to this geographically granular data, this study assessed the reliability of estimating chronic disease prevalence using emergency department surveillance at specific hospitals. Neighborhood-level diabetes, hypertension, and asthma prevalence were estimated using emergency claims data from each individual hospital in New York City from 2009-2012. Estimates were compared to prevalence obtained from a traditional health survey. A multivariable analysis also was performed to identify which individual hospitals were more accurate at estimating citywide disease prevalence. Among 52 hospitals, variation was found in the accuracy of disease prevalence estimates using emergency department surveillance. Estimates at some hospitals, such as NYU Langone Medical Center, had strong correlations for all diseases studied (diabetes: 0.81, hypertension: 0.84, and asthma: 0.84). Hospitals with patient populations geographically distributed throughout New York City had better accuracy in estimating citywide disease prevalence. For diabetes and hypertension, hospitals with racial/ethnic patient distributions similar to Census estimates and higher fidelity of diagnosis coding also had more accurate prevalence estimates. This study demonstrated how citywide chronic disease surveillance can be performed using emergency data from specific sentinel hospitals. The findings may provide an alternative means of mapping chronic disease burden by using existing data, which may be critical in regions without resources for geographically detailed health surveillance. PMID- 28338426 TI - The Role of Exercise in Prevention and Treatment of Osteopenia of Prematurity: An Update. AB - Premature infants have an increased risk of osteopenia due to limited bone mass accretion in utero and a greater need for bone nutrients. Until recently, most efforts to prevent osteopenia of prematurity focused on nutritional changes. Recent studies indicate that passive range-of-motion exercise of the extremities may lead to beneficial effects on body weight, increased bone mineralization, increased bone formation markers and leptin levels, and attenuation of the natural postnatal decline in bone speed of sound. These results suggest that exercise may play an important role in the prevention and treatment of osteopenia of prematurity. This review summarizes our current knowledge on the role of exercise in the prevention and treatment of osteopenia of prematurity. PMID- 28338427 TI - Long-term endocrine outcome of suprasellar arachnoid cysts. AB - OBJECTIVE Due to their distinct location, suprasellar arachnoid cysts are known to cause a wide variety of problems, such as hydrocephalus, endocrine symptoms, and visual abnormalities. The long-term outcome of these cysts has not been elucidated. To find out the long-term outcome of suprasellar arachnoid cysts, a retrospective review of the patients was performed. The neurological and endocrine symptoms were thoroughly reviewed. METHODS Forty-five patients with suprasellar arachnoid cysts, with an average follow-up duration of 9.7 years, were enrolled in the study. A comprehensive review was performed of the results of follow-up regarding not only neurological symptoms but also endocrine status. The outcomes of 8 patients who did not undergo operations and were asymptomatic or had symptoms unrelated to the cyst were included in the series. RESULTS Surgery was most effective for the symptoms related to hydrocephalus (improvement in 32 of 32), but endocrine symptoms persisted after surgery (4 of 4) and required further medical management. More surprisingly, a fairly large number of patients (14 of 40; 1 was excluded because no pre- or postoperative endocrine evaluation was available) who had not shown endocrine symptoms at the time of the initial diagnosis and treatment later developed endocrine abnormalities such as precocious puberty and growth hormone deficiency. The patients with endocrine symptoms detected during the follow-up included those in both the operated (n = 12 of 32) and nonoperated (n = 2 of 8) groups who had been stable during follow up since the initial diagnosis. CONCLUSIONS This study implies that patients with suprasellar arachnoid cysts can develop late endocrine problems during follow-up, even if other symptoms related to the cyst have been successfully treated. Hence, patients with these cysts need long-term follow-up for not only neurological symptoms but also endocrine abnormalities. PMID- 28338428 TI - A Surgical Device to Study the Efficacy of Bioengineered Skin Substitutes in Mice Wound Healing Models. AB - Due to the poor regenerative capacity of adult mammalian skin, there is a need to develop effective skin substitutes for promoting skin regeneration after a severe wound. However, the complexity of skin biology has made it difficult to enable perfect regeneration of skin. Thus, animal models are being used to test potential skin substitutes. Murine models are valuable but their healing process involves dermal contraction. We have developed a device called a dome that is able to eliminate the contraction effect of rodent skin while simultaneously housing a bioengineered skin graft. The dome comes in two models, which enables researchers to evaluate the cells that contribute in wound healing from neighboring intact tissue during skin healing/regeneration. This protocol simplifies grafting of skin substitutes, eliminates the contraction effect of surrounding skin, and summarizes a simple method for animal surgery for wound healing and skin regeneration studies. PMID- 28338429 TI - Release of carbon nanoparticles of different size and shape from nanocomposite poly(lactic) acid film into food simulants. AB - Poly(lactic) acid (PLA) film with 2 wt% mixed carbon nanofillers of graphene nanoplates (GNPs) and multiwall carbon nanotubes (MWCNTs) in a weight ratio of 1:1 with impurities of fullerene and carbon black (CB) was produced by layer-to layer deposition and hot pressing. The release of carbon nanoparticles from the film was studied at varying time-temperature conditions and simulants. Migrants in simulant solvents were examined with laser diffraction analysis and transmission electron microscopy (TEM). Film integrity and the presence of migrants on the film surfaces were visualised by scanning electron microscopy (SEM). The partial dissolution of PLA polymer in the solvents was confirmed by swelling tests and differential scanning calorimetry (DSC). Nanoparticle migrants were not detected in the simulants (at the LOD 0.020 MUm of the laser diffraction analysis) after migration testing at 40 degrees C for 10 days. However, high temperature migration testing at 90 degrees C for 4 h provoked a release of GNPs from the film into ethanol, acetic acid and oil-based food simulants. Short carbon nanotubes were observed rarely to release in the most aggressive acetic acid solvent. Obviously, the enhanced molecular mobility at temperatures above the glass transition and partial dissolution of PLA polymer by the food simulant facilitate the diffusion processes. Moreover, shape, size and concentration of nanoparticles play a significant role. Flexible naked GNPs (lateral size 100-1000 nm) easily migrate when the polymer molecules exhibit enhanced mobility, while fibrous MWCNTs (> 1 MUm length) formed entangled networks on the film surfaces as the PLA polymer is partly dissolved, preventing their release into food simulants. The impurities of fullerenes and CB (5-30 nm) were of minor concentration in the polymer, therefore their migration is low or undetectable. The total amount of released migrants is below overall migration limits. PMID- 28338431 TI - Letter to the Editor. Is gender a factor in long-term outcomes after radiosurgery for vestibular schwannoma? PMID- 28338430 TI - Trends of Second Primary Malignancy in Patients with Thyroid Cancer: A Population Based Cohort Study in Israel. AB - BACKGROUND: Thyroid cancer (TC) is the most common endocrine malignancy. TC patients have a good prognosis and a low disease-related mortality rate. Since such patients are often young, they may be at a higher risk for a second primary malignancy (SPM). This study sought to determine the incidence, risk, and types of SPM between 1980 and 2011, and to assess SPM trends over time among Israeli TC patients. METHODS: Data were derived from the Israel National Cancer Registry. Primary TC patients diagnosed during 1980-2009 were followed up for SPM incidence until December 31, 2011. Standardized incidence ratios (SIRs) of observed to expected SPM (based on the general population rates) were calculated using Poisson regression. Analyses were stratified by time period of initial TC diagnosis (1980-1995 and 1996-2009). RESULTS: A total of 11,538 TC patients were identified. After exclusion of 107 duplicate cases, records of 1032 patients with SPM were analyzed (an SPM incidence of 8.9%). SIRs for all-site SPMs were 1.23 [confidence interval 1.08-1.35] for males and 1.19 [confidence interval 1.10 1.27] for females. SIRs for tumors of the urinary system and prostate were significantly elevated in males, as were SIRs for tumors of the brain, urinary system, breast, and lung in females. Variables associated with increased risk of developing SPMs included a younger age at TC diagnosis, a shorter latency period, being born in Asia/Africa for both sexes, and being born in Israel for females. Compared with the general population, a subanalysis by TC diagnosis during 1980 1995 and 1996-2009 disclosed a higher SPM incidence for the latter time period in males and for both time periods, with a slightly higher SIR for the latter time period in females. CONCLUSIONS: The overall risk of SPM in Israeli TC patients was significantly greater for both sexes compared with the general population, thus identifying TC patients as a high-risk group and calling for caretakers to apply specific follow-up guidelines. PMID- 28338432 TI - Dual-labeling with 5-aminolevulinic acid and fluorescein for fluorescence-guided resection of high-grade gliomas: technical note. AB - OBJECTIVE Fluorescence guidance with 5-aminolevulinic acid (5-ALA) helps improve resections of malignant gliomas. However, one limitation is the low intensity of blue light for background illumination. Fluorescein has recently been reintroduced into neurosurgery, and novel microscope systems are available for visualizing this fluorochrome, which highlights all perfused tissues but has limited selectivity for tumor detection. Here, the authors investigate a combination of both fluorochromes: 5-ALA for distinguishing tumor and fluorescein for providing tissue fluorescence of adjacent brain tissue. METHODS The authors evaluated 6 patients who harbored cerebral lesions suggestive of high-grade glioma. Patients received 5-ALA (20 mg/kg) orally 4 hours before induction of anesthesia. Low-dose fluorescein (3 mg/kg intravenous) was injected immediately after anesthesia induction. Pentero microscopes (equipped either with Yellow 560 or Blue 400 filters) were used to visualize fluorescence. To simultaneously visualize both fluorochromes, the Yellow 560 module was combined with external blue light illumination (D-light C System). RESULTS Fluorescein-induced fluorescence created a useful background for protoporphyrin IX (PPIX) fluorescence, which appeared orange to red, surrounded by greenly fluorescent normal brain and edematous tissue. Green brain-tissue fluorescence was helpful in augmenting background. Levels of blue illumination that were too strong obscured PPIX fluorescence. Unspecific extravasation of fluorescein was noted at resection margins, which did not interfere with PPIX fluorescence detection. CONCLUSIONS Dual labeling with both PPIX and fluorescein fluorescence is feasible and gives superior background information during fluorescence-guided resections. The authors believe that this technique carries potential as a next step in fluorescence-guided resections if it is completely integrated into the surgical microscope. PMID- 28338433 TI - Letter to the Editor: Ultrasound in peripheral nerve injuries: the challenge. PMID- 28338434 TI - Coexistence of obstructive sleep apnea worsens the overall outcome of intracranial aneurysm: a pioneer study. AB - OBJECTIVE Obstructive sleep apnea (OSA) is associated with the progression of abdominal and thoracic aortic aneurysms. However, the role of OSA in the overall outcome of intracranial aneurysms (IAs) has not yet been established. Authors of this report investigated the role of OSA in the overall outcome of IAs. METHODS Radiological and clinical data on patients (from 2010 through 2015) with confirmed IA were retrospectively reviewed. Significant differences between the OSA and non-OSA groups were determined using a chi-square test. Logistic regression analysis was performed to identify the predictors of an unfavorable IA outcome. RESULTS Among the 283 patients with confirmed IAs, 45 patients (16%) were positively screened for OSA, a proportion that was significantly higher than the prevalence of OSA in nonaneurysmal neurosurgical patients (4%, p = 0.008). The percentage of patients with hypertension (p = 0.018), a body mass index >= 30 kg/m2 (p < 0.0001), hyperlipidemia (p = 0.034), diabetes mellitus (p = 0.005), chronic heart disease (CHD; p = 0.024), or prior stroke (p = 0.03) was significantly higher in the OSA group than in the non-OSA group. Similarly, the percentage of wide-necked aneurysms (p = 0.00001) and patients with a poor Hunt and Hess Grade IV-V (p = 0.01) was significantly higher in the OSA group than in the non-OSA group. In addition, the percentage of ruptured aneurysms (p = 0.03) and vasospasms (p = 0.03) was significantly higher in the OSA group. The percentage of patients with poor modified Rankin Scale (mRS) scores (3-6) was significantly higher in the OSA group (p = 0.03). A separate cohort of patients with ruptured IAs showed similar results. In both univariate (p = 0.01) and multivariate (p = 0.04) regression analyses, OSA was identified as an individual predictor of an unfavorable outcome. In addition, hypertension and prior stroke were revealed as predictors of a poor IA outcome. CONCLUSIONS Complications of IA such as rupture and vasospasm are often the consequence of uncontrolled OSA. Overall outcome (mRS) of IAs is also affected by the co-occurrence of OSA. Therefore, the coexistence of OSA with IA affects the outcome of IAs. Obstructive sleep apnea is a risk factor for a poor outcome in IA patients. PMID- 28338435 TI - Erratum. Hearing subclassification may predict long-term auditory outcomes after radiosurgery for vestibular schwannoma patients with good hearing. PMID- 28338436 TI - Letter to the Editor: Threshold criterion in transcranial motor evoked potentials. PMID- 28338437 TI - Contralateral peripheral neurotization for a hemiplegic hindlimb after central neurological injury. AB - OBJECTIVE Contralateral peripheral neurotization surgery has been successfully applied to rescue motor function of the hemiplegic upper extremity in patients with central neurological injury (CNI). It may contribute to strengthened neural pathways between the contralesional cortex and paretic limbs. However, the effect of this surgery in the lower extremities remains unknown. In the present study the authors explored the effectiveness and safety of contralateral peripheral neurotization in treating a hemiplegic lower extremity following CNI in adult rats. METHODS Controlled cortical impact (CCI) was performed on the hindlimb motor cortex of 36 adult Sprague-Dawley rats to create severe unilateral traumatic brain injury models. These CCI rats were randomly divided into 3 groups. At 1 month post-CCI, the experimental group (Group 1, 12 rats) underwent contralateral L-6 to L-6 transfer, 1 control group (Group 2, 12 rats) underwent bilateral L-6 nerve transection, and another control group (Group 3, 12 rats) underwent an L-6 laminectomy without injuring the L-6 nerves. Bilateral L-6 nerve transection rats without CCI (Group 4, 12 rats) and naive rats (Group 5, 12 rats) were used as 2 additional control groups. Beam and ladder rung walking tests and CatWalk gait analysis were performed in each rat at baseline and at 0.5, 1, 2, 4, 6, 8, and 10 months to detect the skilled walking functions and gait parameters of both hindlimbs. Histological and electromyography studies were used at the final followup to verify establishment of the traumatic brain injury model and regeneration of the L6-L6 neural pathway. RESULTS In behavioral tests, comparable motor injury in the paretic hindlimbs was observed after CCI in Groups 1-3. Group 1 started to show significantly lower slip and error rates in the beam and ladder rung walking tests than Groups 2 and 3 at 6 months post-CCI (p < 0.05). In the CatWalk analysis, Group 1 also showed a higher mean intensity and swing speed after 8 months post-CCI and a longer stride length after 6 months post-CCI than Groups 2 and 3 (p < 0.05). Transection of L-6 resulted in transient skilled walking impairment in the intact hindlimbs in Groups 1 and 2 (compared with Group 3) and in the bilateral hindlimbs in Group 4 (compared with Group 5). All recovered to baseline level within 2 months. Histological study of the rat brains verified comparable injured volumes among Groups 1-3 at final examinations, and electromyography and toluidine blue staining indicated successful regeneration of the L6-L6 neural pathways in Group 1. CONCLUSIONS Contralateral L-6 neurotization could be a promising and safe surgical approach for improving motor recovery of the hemiplegic hindlimb after unilateral CNI in adult rats. Further investigations are needed before extrapolating the present conclusions to humans. PMID- 28338438 TI - Learning brain aneurysm microsurgical skills in a human placenta model: predictive validity. AB - OBJECTIVE Surgery for brain aneurysms is technically demanding. In recent years, the process to learn the technical skills necessary for these challenging procedures has been affected by a decrease in the number of surgical cases available and progressive restrictions on resident training hours. To overcome these limitations, surgical simulators such as cadaver heads and human placenta models have been developed. However, the effectiveness of these models in improving technical skills is unknown. This study assessed concurrent and predictive validity of brain aneurysm surgery simulation in a human placenta model compared with a "live" human brain cadaveric model. METHODS Two human cadaver heads and 30 human placentas were used. Twelve neurosurgeons participated in the concurrent validity part of this study, each operating on 1 human cadaver head aneurysm model and 1 human placenta model. Simulators were evaluated regarding their ability to simulate different surgical steps encountered during real surgery. The time to complete the entire aneurysm task in each simulator was analyzed. The predictive validity component of the study involved 9 neurosurgical residents divided into 3 groups to perform simulation exercises, each lasting 6 weeks. The training for the 3 groups consisted of educational video only (3 residents), human cadaver only (3 residents), and human placenta only (3 residents). All residents had equivalent microsurgical experience with superficial brain tumor surgery. After completing their practice training, residents in each of the 3 simulation groups performed surgery for an unruptured middle cerebral artery (MCA) aneurysm, and their performance was assessed by an experienced vascular neurosurgeon who watched the operative videos. RESULTS All human cadaver heads and human placentas were suitable to simulate brain aneurysm surgery. In the concurrent validity portion of the experiment, the placenta model required a longer time (p < 0.001) than cadavers to complete the task. The placenta model was considered more effective than the cadaver model in simulating sylvian fissure splitting, bipolar coagulation of oozing microvessels, and aneurysm neck and dome dissection. Both models were equally effective in simulating neck aneurysm clipping, while the cadaver model was considered superior for simulation of intraoperative rupture and for reproduction of real anatomy during simulation. In the predictive validity portion of the experiment, residents were evaluated for 4 tasks: sylvian fissure dissection, microvessel bipolar coagulation, aneurysm dissection, and aneurysm clipping. Residents trained in the human placenta simulator consistently had the highest overall performance scores when compared with those who had trained in the cadaver model and those who had simply watched operative videos (p < 0.001). CONCLUSIONS The human placenta biological simulator provides excellent simulation for some critical tasks of aneurysm surgery such as splitting of the sylvian fissure, dissection of the aneurysm neck and dome, and bipolar coagulation of surrounding microvessels. When performing surgery for an unruptured MCA aneurysm, residents who had trained in the human placenta model performed better than residents trained with other simulation scenarios/models. In this age of reduced exposure to aneurysm surgery and restrictions on resident working hours, the placenta model is a valid simulation for microneurosurgery with striking similarities with real surgery. PMID- 28338439 TI - Stereotactic radiosurgery in the treatment of parasellar meningiomas: long-term volumetric evaluation. AB - OBJECTIVE Parasellar meningiomas tend to invade the suprasellar, cavernous sinus, and petroclival regions, encroaching on adjacent neurovascular structures. As such, they prove difficult to safely and completely resect. Stereotactic radiosurgery (SRS) has played a central role in the treatment of parasellar meningiomas. Evaluation of tumor control rates at this location using simplified single-dimension measurements may prove misleading. The authors report the influence of SRS treatment parameters and the timing and volumetric changes of benign WHO Grade I parasellar meningiomas after SRS on long-term outcome. METHODS Patients with WHO Grade I parasellar meningiomas treated with single-session SRS and a minimum of 6 months of follow-up were selected. A total of 189 patients (22.2% males, n = 42) form the cohort. The median patient age was 54 years (range 19-88 years). SRS was performed as a primary upfront treatment for 44.4% (n = 84) of patients. Most (41.8%, n = 79) patients had undergone 1 resection prior to SRS. The median tumor volume at the time of SRS was 5.6 cm3 (0.2-54.8 cm3). The median margin dose was 14 Gy (range 5-35 Gy). The volumes of the parasellar meningioma were determined on follow-up scans, computed by segmenting the meningioma on a slice-by-slice basis with numerical integration using the trapezoidal rule. RESULTS The median follow-up was 71 months (range 6-298 months). Tumor volume control was achieved in 91.5% (n = 173). Tumor progression was documented in 8.5% (n = 16), equally divided among infield recurrences (4.2%, n = 8) and out-of-field recurrences (4.2%, n = 8). Post-SRS, new or worsening CN deficits were observed in 54 instances, of which 19 involved trigeminal nerve dysfunction and were 18 related to optic nerve dysfunction. Of these, 90.7% (n = 49) were due to tumor progression and only 9.3% (n = 5) were attributable to SRS. Overall, this translates to a 2.64% (n = 5/189) incidence of direct SRS-related complications. These patients were treated with repeat SRS (6.3%, n = 12), repeat resection (2.1%, n = 4), or both (3.2%, n = 6). For patients treated with a margin dose >= 16 Gy, the 2-, 4-, 6-, 8-, 10-, 12-, and 15-year actuarial progression-free survival rates are 100%, 100%, 95.7%, 95.7%, 95.7%, 95.7%, and 95.7%, respectively. Patients treated with a margin dose < 16 Gy, had 2-, 4-, 6-, 8-, 10-, 12-, and 15-year actuarial progression-free survival rates of 99.4%, 97.7%, 95.1%, 88.1%, 82.1%, 79.4%, and 79.4%, respectively. This difference was deemed statistically significant (p = 0.043). Reviewing the volumetric patient specific measurements, the early follow-up volumetric measurements (at the 3-year follow-up) reliably predicted long-term volume changes and tumor volume control (at the 10-year follow-up) (p = 0.029). CONCLUSIONS SRS is a durable and minimally invasive treatment modality for benign parasellar meningiomas. SRS offers high rates of growth control with a low incidence of neurological deficits compared with other treatment modalities for meningiomas in this region. Volumetric regression or stability during short-term follow-up of 3 years after SRS was shown to be predictive of long-term tumor control. PMID- 28338440 TI - A study of cognitive function in treatment-refractory obsessive-compulsive disorder treated with capsulotomy. AB - OBJECTIVE Anterior capsulotomy (AC) is sometimes used as a last resort for treatment-refractory obsessive-compulsive disorder (OCD). Previous studies assessing neuropsychological outcomes in patients with OCD have identified several forms of cognitive dysfunction that are associated with the disease, but few have focused on changes in cognitive function in OCD patients who have undergone surgery. In the present study, the authors investigated the effects of AC on the cognitive function of patients with treatment-refractory OCD. METHODS The authors selected 14 patients with treatment-refractory OCD who had undergone bilateral AC between 2007 and 2013, 14 nonsurgically treated OCD patients, and 14 healthy control subjects for this study. The 3 groups were matched for sex, age, and education. Several neuropsychological tests, including Similarities and Block Design, which are subsets of the Wechsler Abbreviated Scale of Intelligence; Immediate and Delayed Logical Memory and Immediate and Delayed Visual Reproduction, which are subsets of the Wechsler Memory Scale-Revised; and Corrects, Categories, Perseverative Errors, Nonperseverative Errors, and Errors, subtests of the Wisconsin Card Sorting Test, were conducted in all 42 subjects at baseline and after AC, after nonsurgical treatment, or at 6-month intervals, as appropriate. The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) was used to measure OCD symptoms in all 28 OCD patients. RESULTS The Y-BOCS scores decreased significantly in both OCD groups during the 12-month follow-up period. Surgical patients showed higher levels of improvement in verbal memory, visual memory, visuospatial skills, and executive function than the nonsurgically treated OCD patients. CONCLUSIONS The findings of this study suggest that AC not only reduces OCD symptoms but also attenuates moderate cognitive deficits. PMID- 28338441 TI - Radiosurgery in the management of brain metastasis: a retrospective single-center study comparing Gamma Knife and LINAC treatment. AB - OBJECTIVE The authors present a retrospective analysis of a single-center experience with treatment of brain metastases using Gamma Knife (GK) and linear accelerator (LINAC)-based radiosurgery and compare the results. METHODS From July 2010 to July 2012, 63 patients with brain metastases were treated with radiosurgery. Among them, 28 (with 83 lesions) were treated with a GK unit and 35 (with 47 lesions) with a LINAC. The primary outcome was local progression-free survival (LPFS), evaluated on a per-lesion basis. The secondary outcome was overall survival (OS), evaluated per patient. Statistical analysis included standard tests and Cox regression with shared-frailty models to account for the within-patient correlation. RESULTS The mean follow-up period was 11.7 months (median 7.9 months, range 1.7-32 months) for GK and 18.1 months (median 17 months, range 7.5-28.7 months) for LINAC. The median number of lesions per patient was 2.5 (range 1-9) in the GK group and 1 (range 1-3) in the LINAC group (p < 0.01, 2-sample t-test). There were more radioresistant lesions (e.g., melanoma) and more lesions located in functional areas in the GK group. Additional technical reasons for choosing GK instead of LINAC were limitations of LINAC movements, especially if lesions were located in the lower posterior fossa or multiple lesions were close to highly functional areas (e.g., the brainstem), precluding optimal dosimetry with LINAC. The median marginal dose was 24 Gy with GK and 20 Gy with LINAC (p < 0.01, 2-sample t-test). For GK, the actuarial LPFS rate at 3, 6, 9, 12, and 17 months was 96.96%, 96.96%, 96.96%, 88.1%, and 81.5%, remaining stable until 32 months. For LINAC the rate at 3, 6, 12, 17, 24, and 33 months was 91.5%, 91.5%, 91.5%, 79.9%, 55.5%, and 17.1% (log-rank p = 0.03). In the Cox regression with shared-frailty model, the risk of local progression in the LINAC group was almost twice that of the GK group (HR 1.92, p > 0.05). The mean OS was 16.0 months (95% CI 11.2-20.9 months) in the GK group, compared with 20.9 months (95% CI 16.4-25.3 months) in the LINAC group. Univariate and multivariate analysis showed that a lower graded prognostic assessment (GPA) score, noncontrolled systemic status at last radiological assessment, and older age were associated with lower OS; after adjustment of these covariables by Cox regression, the OS was similar in the 2 groups. CONCLUSIONS In this retrospective study comparing GK and LINAC-based radiosurgery for brain metastases, patients with more severe disease were treated by GK, including those harboring lesions of greater number, of radioresistant type, or in highly functional areas. The risk of local progression for the LINAC group was almost twice that in the GK group, although the difference was not statistically significant. Importantly, the OS rates were similar for the 2 groups, although GK was used in patients with more complex brain metastatic disease and with no other therapeutic alternative. PMID- 28338442 TI - The Important Role of Health Care Alliances in Improving Strategies for Cancer Prevention Protocols. PMID- 28338443 TI - Fluorescent Labeling of Collagen Production by Cells for Noninvasive Imaging of Extracellular Matrix Deposition. AB - Extracellular matrix (ECM) is an essential component of tissues and provides both integrity and biological cues for cells. Collagen is one of the major proteins found within the ECM and therefore is an essential component of all engineered tissues. Therefore, in this article, we present a method for the online real-time monitoring of collagen deposition in three-dimensional engineered constructs. This method revolves around modification of collagen through the addition of azide-L-proline to cell culture media. The incorporation of azide-L-proline into the neocollagen produced by cells can then be detected by reaction with 10 mM of a Click-IT Alexa Fluor 488 DIBO Alkyne. The reaction was shown as being specific to the collagen as little background staining was observed in cultures, which did not contain the modified proline, and the staining was also depleted after treatment with collagenase and colocalization of collagen type I staining by immunochemistry assay. Real-time online staining of collagen deposition was observed under different culture conditions without affecting proliferation. Collagen deposition was observed to be increased under mechanical stimulation; however, the localization varied across stimulation regimes. This is a new technique for real-time monitoring of cell-produced collagen and will be a valuable addition to the tissue engineering field. PMID- 28338444 TI - The role of diet in multiple sclerosis: A review. AB - Multiple sclerosis (MS) is a multifactorial, inflammatory, and neurodegenerative disease of the central nervous system, where environmental factors interact with genetic susceptibility. The role of diet on MS has not been comprehensively elucidated; therefore, through an extensive search of relevant literature, this review reports the most significant evidence regarding nutrition as a possible co factor influencing the inflammatory cascade by acting on both its molecular pathways and gut microbiota. Since nutritional status and dietary habits in MS patients have not been extensively reported, the lack of a scientific-based consensus on dietary recommendation in MS could encourage many patients to experiment alternative dietetic regimens, increasing the risk of malnutrition. This work investigates the health implications of an unbalanced diet in MS, and collects recent findings on nutrients of great interest among MS patients and physicians. The aim of this review is to elucidate the role of an accurate nutritional counseling in MS to move toward a multidisciplinary management of the disease and to encourage future studies demonstrating the role of a healthy diet on the onset and course of MS. PMID- 28338445 TI - Socioeconomic status and outcomes after sport-related concussion: a preliminary investigation. AB - OBJECTIVE A significant proportion of patients experience long-term symptoms after sport-related concussion (SRC), and several factors have been associated with this protracted recovery. Limited data exist on the role of socioeconomic status (SES) on SRC outcomes. The objective in this study was to conduct a preliminary investigation to determine the effect of SES on outcomes after SRC in student-athletes treated at a regional sports concussion center. METHODS A retrospective cohort study of 282 middle school, high school, and collegiate student-athletes was conducted. An attempt was made to contact all patients seen at a comprehensive SRC center between January 2012 and May 2015 for in-depth interviews. Subsequent demographic data were collected. The SES was defined as follows: cost of living percentile, median income percentile, percentage of college graduates, percentage of homeowners, county type, and insurance status. Outcomes after SRC were defined as follows: days of symptom duration, days of missed school, and days of missed practice. Statistically controlled covariates included sex, race, age, body mass index, concussion history, neuropsychiatric history, and type of sport. RESULTS A total of 282 student-athletes consented and were studied. The median age was 15.8 years (range 11.6-22.2 years) and 61.4% of student-athletes were male. A previous concussion was incurred by 34.0% of student-athletes. Football was the most common sport (32.3%), followed by soccer (16.3%), and basketball (15.6%). The median symptom duration was 21 days (range 1 365 days); the median missed school days was 2 (range 0-90 days); and median for days of missed practice was 10 (range 0-150 days). After multivariate Cox regression analysis, no relationship between any of the 6 SES variables and symptom duration or missed practice was seen. However, individuals with private insurance had more missed days of school than those with public insurance (hazard ratio 0.46, 95% CI 0.26-0.83, p = 0.009). CONCLUSIONS In a preliminary study of middle school, high school, and collegiate student-athletes, SES had no impact on the outcomes of symptom duration and missed practice. However, for individuals with private insurance, the return to school was slower than for those with public insurance. This pilot study reveals the complex relationship between SES and SRC recovery, which demands further study with more accurate and validated assessments of SES. PMID- 28338446 TI - The use of hippocampal volumetric measurements to improve diagnostic accuracy in pediatric patients with mesial temporal sclerosis. AB - OBJECTIVE Many patients with medically intractable epilepsy have mesial temporal sclerosis (MTS), which significantly affects their quality of life. The surgical excision of MTS lesions can result in marked improvement or even complete resolution of the epileptic episodes. Reliable radiological diagnosis of MTS is a clinical challenge. The purpose of this study was to evaluate the utility of volumetric mapping of the hippocampi for the identification of MTS in a case controlled series of pediatric patients who underwent resection for medically refractory epilepsy, using pathology as a gold standard. METHODS A cohort of 57 pediatric patients who underwent resection for medically intractable epilepsy between 2005 and 2015 was evaluated. On pathological investigation, this group included 24 patients with MTS and 33 patients with non-MTS findings. Retrospective quantitative volumetric measurements of the hippocampi were acquired for 37 of these 57 patients. Two neuroradiologists with more than 10 years of experience who were blinded to the patients' MTS status performed the retrospective review of MR images. To produce the volumetric data, MR scans were parcellated and segmented using the FreeSurfer software suite. Hippocampal regions of interest were compared against an age-weighted local regression curve generated with data from the pediatric normal cohort. Standard deviations and percentiles of specific subjects were calculated. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were determined for the original clinical read and the expert readers. Receiver operating characteristic curves were generated for the methods of classification to compare results from the readers with the authors' results, and an optimal threshold was determined. From that threshold the sensitivity, specificity, PPV, and NPV were calculated for the volumetric analysis. RESULTS With the use of quantitative volumetry, a sensitivity of 72%, a specificity of 95%, a PPV of 93%, an NPV of 78%, and an area under the curve of 0.84 were obtained using a percentage difference of normalized hippocampal volume. The resulting specificity (95%) and PPV (93%) are superior to the original clinical read and to Reader A and Reader B's findings (range for specificity 74%-86% and for PPV 64%-71%). The sensitivity (72%) and NPV (78%) are comparable to Reader A's findings (73% and 81%, respectively) and are better than those of the original clinical read and of Reader B (sensitivity 45% and 63% and NPV 71% and 70%, respectively). CONCLUSIONS Volumetric measurement of the hippocampi outperforms expert readers in specificity and PPV, and it demonstrates comparable to superior sensitivity and NPV. Volumetric measurements can complement anatomical imaging for the identification of MTS, much like a computer-aided detection tool would. The implementation of this approach in the daily clinical workflow could significantly improve diagnostic accuracy. PMID- 28338447 TI - Vein of Galen malformation treated with the Micro Vascular Plug system: case report. AB - This case report describes the use of the Micro Vascular Plug (MVP) system in a mural-type vein of Galen aneurysmal malformation, resulting in successful occlusion of the cerebrovascular fistula. This result was confirmed with immediate cessation in blood flow and 6-month follow-up angiography. The unique characteristics of the MVP provide potential advantages over current embolic techniques for occlusion of high-flow, fistulous, intracranial vessels such as those seen in the vein of Galen aneurysmal malformation, and may represent a valuable addition to the currently available options. PMID- 28338448 TI - Frederic Bartlett: A question of priority. PMID- 28338449 TI - Development of a preoperative predictive model for major complications following adult spinal deformity surgery. AB - OBJECTIVE The operative management of patients with adult spinal deformity (ASD) has a high complication rate and it remains unknown whether baseline patient characteristics and surgical variables can predict early complications (intraoperative and perioperative [within 6 weeks]). The development of an accurate preoperative predictive model can aid in patient counseling, shared decision making, and improved surgical planning. The purpose of this study was to develop a model based on baseline demographic, radiographic, and surgical factors that can predict if patients will sustain an intraoperative or perioperative major complication. METHODS This study was a retrospective analysis of a prospective, multicenter ASD database. The inclusion criteria were age >= 18 years and the presence of ASD. In total, 45 variables were used in the initial training of the model including demographic data, comorbidities, modifiable surgical variables, baseline health-related quality of life, and coronal and sagittal radiographic parameters. Patients were grouped as either having at least 1 major intraoperative or perioperative complication (COMP group) or not (NOCOMP group). An ensemble of decision trees was constructed utilizing the C5.0 algorithm with 5 different bootstrapped models. Internal validation was accomplished via a 70/30 data split for training and testing each model, respectively. Overall accuracy, the area under the receiver operating characteristic (AUROC) curve, and predictor importance were calculated. RESULTS Five hundred fifty-seven patients were included: 409 (73.4%) in the NOCOMP group, and 148 (26.6%) in the COMP group. The overall model accuracy was 87.6% correct with an AUROC curve of 0.89 indicating a very good model fit. Twenty variables were determined to be the top predictors (importance >= 0.90 as determined by the model) and included (in decreasing importance): age, leg pain, Oswestry Disability Index, number of decompression levels, number of interbody fusion levels, Physical Component Summary of the SF-36, Scoliosis Research Society (SRS) Schwab coronal curve type, Charlson Comorbidity Index, SRS activity, T-1 pelvic angle, American Society of Anesthesiologists grade, presence of osteoporosis, pelvic tilt, sagittal vertical axis, primary versus revision surgery, SRS pain, SRS total, use of bone morphogenetic protein, use of iliac crest graft, and pelvic incidence-lumbar lordosis mismatch. CONCLUSIONS A successful model (87% accuracy, 0.89 AUROC curve) was built predicting major intraoperative or perioperative complications following ASD surgery. This model can provide the foundation toward improved education and point-of-care decision making for patients undergoing ASD surgery. PMID- 28338450 TI - Postoperative quality-of-life assessment in patients with spine metastases treated with long-segment pedicle-screw fixation. AB - OBJECTIVE In recent decades, progress in the medical management of cancer has been significant, resulting in considerable extension of survival for patients with metastatic disease. This has, in turn, led to increased attention to the optimal surgical management of bone lesions, including metastases to the spine. In addition, there has been a shift in focus toward improving quality of life and reducing hospital stay for these patients, and many minimally invasive techniques have been introduced with the aim of reducing the morbidity associated with more traditional open approaches. The goal of this study was to assess the efficacy of long-segment percutaneous pedicle screw stabilization for the treatment of instability associated with thoracolumbar spine metastases in neurologically intact patients. METHODS This study was a retrospective review of data from a prospective database. The authors analyzed cases in which long-segment percutaneous pedicle screw fixation was performed for the palliative treatment of thoracolumbar spinal instability due to spinal metastases in neurologically intact patients. All of the patients included in the study underwent surgery between January 2014 and May 2015 at the authors' institution. Postoperative radiation therapy was planned within 10 days following the stabilization in all cases. Clinical and radiological follow-up assessments were planned for 3 days, 3 weeks, 6 weeks, 3 months, 6 months, and 1 year after surgery. Outcome was assessed by means of standard postoperative evaluation and oncological and spinal quality of life measures (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0 [EORTC QLQ-C30] and Oswestry Disability Index [ODI], respectively). Moreover, 5 patients were given an activity monitoring device for recording the distance walked daily; preoperative and postoperative daily distances were compared. RESULTS Data from 17 cases were analyzed. There were no complications, and patients showed improvement in pain level and quality of life from the early postoperative period on. The mean ODI score was 62.7 (range 40-84) preoperatively, 35.4 (range 24-59) on postoperative Day 3, and 46.1 (range 30-76) at 3 weeks, 37.6 (range 25-59) at 6 weeks, 34.0 (range 24-59) at 3 months, 39.1 (range 22-64) at 6 months, and 30.0 (range 20-55) at 1 year after screw placement. The mean ODI was significantly improved in the first 45 days (p < 0.001). Improvement was also evident in scores for functional and symptomatic scales of the EORTC QLQ-C30. All patients underwent postoperative radiation therapy within 10 days (mean 7.5). All patients (n = 5) with an activity monitoring device showed improvement in daily walking distance. CONCLUSIONS Less-invasive palliative treatment for advanced spinal metastases is promising as part of a multidisciplinary approach to the care of patients with metastatic disease. The results of this study indicate that percutaneous surgery may allow for rapid improvement in quality of life and walking ability for patients with thoracolumbar instability due to spine metastases. Long-segment percutaneous screw fixation followed by early radiation therapy appears to be a safe and effective treatment option for providing solid and durable stability and improved quality of life for these patients. PMID- 28338451 TI - Superficial siderosis of the central nervous system associated with intraspinal hemorrhage from ventral thoracic epidural veins and a ventral spinal CSF leak: case report. AB - In most patients with superficial siderosis of the CNS, the exact source of bleeding remains unknown because of a lack of objective surgical data. The authors herein describe the case of a 58-year-old man with superficial siderosis of the CNS. The patient also had spinal CSF leakage due to a spinal dural defect. Repair surgery for the dural defect was performed using posterior laminoplasty with a transdural approach without spinal fixation. During repair surgery, the bleeding source was found to be the epidural vein around the defect. The intraoperative and histological results of the present case suggest that epidural veins exposed to CSF represent a chronic bleeding source in patients with superficial siderosis of the CNS complicated by CSF leakage. Dural repair surgery may result in discontinuation of the CSF leaks, resolution of the epidural CSF collection, and cessation of chronic epidural bleeding. PMID- 28338452 TI - Differentiation of idiopathic spinal cord herniation from dorsal arachnoid webs on MRI and CT myelography. AB - OBJECTIVE Dorsal arachnoid webs (DAWs) and spinal cord herniation (SCH) are uncommon abnormalities affecting the thoracic spinal cord that can result in syringomyelia and significant neurological morbidity if left untreated. Differentiating these 2 entities on the basis of clinical presentation and radiological findings remains challenging but is of vital importance in planning a surgical approach. The authors examined the differences between DAWs and idiopathic SCH on MRI and CT myelography to improve diagnostic confidence prior to surgery. METHODS Review of the picture archiving and communication system (PACS) database between 2005 and 2015 identified 6 patients with DAW and 5 with SCH. Clinical data including demographic information, presenting symptoms and neurological signs, and surgical reports were collected from the electronic medical records. Ten of the 11 patients underwent MRI. CT myelography was performed in 3 patients with DAW and in 1 patient with SCH. Imaging studies were analyzed by 2 board-certified neuroradiologists for the following features: 1) location of the deformity; 2) presence or absence of cord signal abnormality or syringomyelia; 3) visible arachnoid web; 4) presence of a dural defect; 5) nature of dorsal cord indentation (abrupt "scalpel sign" vs "C"-shaped); 6) focal ventral cord kink; 7) presence of the nuclear trail sign (endplate irregularity, sclerosis, and/or disc-space calcification that could suggest a migratory path of a herniated disc); and 8) visualization of a complete plane of CSF ventral to the deformity. RESULTS The scalpel sign was positive in all patients with DAW. The dorsal indentation was C-shaped in 5 of 6 patients with SCH. The ventral subarachnoid space was preserved in all patients with DAW and interrupted in cases of SCH. In no patient was a web or a dural defect identified. CONCLUSIONS DAW and SCH can be reliably distinguished on imaging by scrutinizing the nature of the dorsal indentation and the integrity of the ventral subarachnoid space at the level of the cord deformity. PMID- 28338453 TI - Letter to the Editor. The ancient "apples and oranges" conundrum: a call for methodological precision. PMID- 28338454 TI - Impact of preoperative diagnosis on patient satisfaction following lumbar spine surgery. AB - OBJECTIVE Patient satisfaction is a commonly used metric in the current health care environment. While factors that affect patient satisfaction following spine surgery are complex, the authors of this study hypothesized that specific diagnostic groups of patients are more likely to be satisfied after spine surgery and that this is reflected in patient-reported outcome measures. The purpose of this study was to determine if the preoperative diagnosis-disc herniation, stenosis, spondylolisthesis, adjacent segment degeneration, or mechanical disc collapse-would impact patient satisfaction following surgery. METHODS Patients enrolled in the Quality Outcomes Database, formerly known as the National Neurosurgery Quality and Outcomes Database (N2QOD), completed patient-reported outcome measures, including the Oswestry Disability Index (ODI) and Numeric Rating Scale (NRS) for back pain (NRS-BP) and leg pain (NRS-LP) preoperatively and 1-year postoperatively. Patients were stratified by diagnosis and by their response to the satisfaction question: 1) surgery met my expectations; 2) I did not improve as much as I hoped, but I would undergo the same operation for the same results; 3) surgery helped, but I would not undergo the same operation for the same results; or 4) I am the same or worse as compared with before surgery. RESULTS A greater proportion of patients with primary disc herniation or spondylolisthesis reported that surgery met expectations (66% and 67%, respectively), followed by recurrent disc herniation and stenosis (59% and 60%, respectively). A smaller proportion of patients who underwent surgery for adjacent segment degeneration or mechanical disc collapse had their expectations met (48% and 41%, respectively). The percentage of patients that would undergo the same surgery again, by diagnostic group, was as follows: disc herniation 88%, recurrent disc herniation 79%, spondylolisthesis 86%, stenosis 82%, adjacent segment disease 75%, and mechanical collapse 73%. Regardless of diagnosis, mean improvement and ultimate 1-year postoperative ODI, NRS-BP, and NRS-LP reflected patient satisfaction. CONCLUSIONS Preoperative diagnosis was predictive of patient satisfaction following spine surgery. The mean change in and 1-year ODI, NRS-BP, and NRS-LP reflected patient satisfaction regardless of preoperative diagnosis. PMID- 28338455 TI - Long-term administration of bisphosphonate to reduce local recurrence of sacral giant cell tumor after nerve-sparing surgery. AB - OBJECTIVE The objective of this study was to investigate the effect of long-term bisphosphonate treatment on reducing local recurrence of sacral giant cell tumors (GCTs) after nerve-sparing surgery. METHODS Thirty-five consecutive patients with sacral GCTs who received treatment in Shanghai Changzheng Hospital between January 2000 and December 2010 were included in this study. Between January 2007 and December 2010, 19 patients received bisphosphonates following nerve-sparing surgery. Before January 2007, 16 patients received nerve-sparing surgery alone, and these cases were included as the control group. The difference in clinical data between the groups was compared by Student's t-test and 2-tailed chi-square or Fisher's exact test. The postoperative recurrence-free survival (RFS) and overall survival (OS) rates were estimated by the Kaplan-Meier method and compared between the groups by log-rank test. A p value < 0.05 was considered statistically significant. RESULTS All of the patients had relatively good nerve function. The clinical data were homogeneous between the groups. The local recurrence rate was 10.53% (2 of 19) in the bisphosphonate treatment group and 43.75% (7 of 16) in the control group. The log-rank test showed that the 3-year RFS and 3-year OS in the bisphosphonate treatment group were significantly higher than those in the control group (RFS 89.5% vs 56.3%, p = 0.04; OS 100% vs 81.3%, p = 0.05). CONCLUSIONS The long-term use of bisphosphonates after nerve-sparing surgery is a viable option for the treatment of sacral GCTs. This approach could reduce local recurrences while preserving nerve function. PMID- 28338457 TI - Transplant Renal Vein Thrombosis. AB - Transplant renal vein thrombosis usually occurs early after surgery with a reported prevalence of 0.1% to 4.2%. It is a devastating event that ultimately leads to graft loss in almost all cases. There are many predisposing factors related to donor, recipient, surgery, and immunosuppression, with mechanical factors being considered the most common causes of transplant renal vein thrombosis. The clinical manifestations of acute renal vein thrombosis are nonspecific and are not dissimilar to the features of urine leak, urinary obstruction, or severe acute rejection. The diagnosis of transplant renal vein thrombosis depends on a high index of clinical suspicion and duplex ultrasonographic scans. Although venography remains the criterion standard, this procedure is invasive and nephrotoxic, due to use of ionizing contrast agents and also due to exposure to ionizing radiation. There are 2 therapies that have been described in the literature for salvaging a renal allograft with transplant renal vein thrombosis: thrombolytic therapy and surgical thrombectomy. The usual end result is renal allograft. PMID- 28338458 TI - Hepatitis B in Solid-Organ Transplant Procedures Other Than Liver. AB - Transplant is often the best treatment available for patients with end-stage organ failure. Hepatitis B virus infection in transplant procedures other than liver is a major concern because it can be a significant cause of morbidity and mortality after transplant. Due to the increased risk of hepatic complications, such as fibrosing cholestatic hepatitis or histologic deterioration after transplant, systematic use of nucleoside or nucleotide analogues shortly before or at the time of transplant is recommended (tenofovir or entecavir are preferable to lamivudine) in all patients, whatever the baseline histologic evaluation. Sustained viral suppression may result in regression of fibrosis, which in turn may lead to decreased disease-related morbidity and improved survival. Finally, due to the high mortality after nonliver transplant procedures, decompensated cirrhosis from chronic hepatitis B should be considered as a contraindication to nonliver transplant but an indication to combined organ transplant (ie, liver-kidney transplant). Because of the high prevalence of hepatitis B virus exposure in allograft donors and recipients, hepatitis B virus status must be considered during organ allocation. Prevention of hepatitis B virus-related complications in transplant recipients starts with vaccination and donor-recipient matching. PMID- 28338459 TI - Comparison of Pfannenstiel or Extended Iliac Port Site Kidney Extraction in Laparoscopic Donor Nephrectomy: Do We Have Consensus? AB - OBJECTIVES: Our objective was to compare the outcomes of the different extraction sites between extended iliac port site incision and Pfannenstiel incision during laparoscopic donor nephrectomy. MATERIALS AND METHODS: We prospectively evaluated patients who underwent laparoscopic donor nephrectomy from June 2014 to March 2015 at our institution. Perioperative parameters were included, with particular reference to warm ischemic time. The other parameters recorded included operative time, blood loss, hospital stay, analgesic requirement, and cosmetic results. RESULTS: We analyzed a total of 41 patients. Kidney retrieval site of each patient was made randomly. Extraction sites were done by using extended iliac port site incisions in 23 patients and by Pfannenstiel incision in 18 patients. Mean warm ischemic time was 4.09 minutes with extended iliac port site incision versus 4.94 minutes with Pfannenstiel incision (P = .04). Mean operative time, blood loss, hospital stay, and analgesic requirements were comparable between the 2 groups. Mean cosmetic score was 10.39 with extended iliac port site versus 12.06 with Pfannenstiel incision. CONCLUSIONS: Extraction with extended iliac port site incision had significantly less warm ischemic time than Pfannenstiel incision in laparoscopic donor nephrectomy. It was also not inferior to Pfannenstiel incision regarding the other. PMID- 28338460 TI - Role of Computed Tomography Volumetry in Estimating Liver Weights in Surgical Patients with Hepatic Steatosis. AB - OBJECTIVES: Our objective was to assess the accuracy of computed tomography volumetry in estimating liver volume in steatotic patients. MATERIALS AND METHODS: We divided 641 liver donors (mean age 27 years, 71% male) into 4 groups according to the extent of steatosis on predonation biopsy: with < 5% comprising group 1, 5% to 9% comprising group 2, 10% to 19% comprising group 3, and >= 20% comprising group 4. Graft mass estimation error (%) was calculated as follows: [(computed tomography-measured volume minus graft weight)/graft weight] * 100. We obtained estimation errors, intraclass correlation coefficients, and Pearson correlation coefficients across the groups. RESULTS: Baseline alanine aminotransferase and gammaglutamyltranspeptidase values were signi ficantly correlated with extent of steatosis. Mean graft weight and computed tomography measured volume were 725.9 g and 741.2 mL. Mean estimation errors were comparable (1.5% for group 1, 2.7% for group 2, 3.0% for group 3, and 3.9% for group 4; P = .77). In multivariate linear regression, estimation error was inversely correlated with high-density lipoprotein cholesterol (P = .008). Overall, there was an excellent agreement between measured volume and actual weight, with intraclass correlation coefficients over 0.85 and Pearson correlation coefficients over 0.70 in all groups (P < .001). CONCLUSIONS: Preoperative computed tomography volumetry is an accurate tool for estimating volume regardless of the extent of steatosis. PMID- 28338461 TI - Mesenchymal Stem Cells Suppress Chronic Rejection in Heterotopic Small Intestine Transplant Rat Models Via Inhibition of CD68, Transforming Growth Factor- beta1, and Platelet-Derived Growth Factor Expression. AB - OBJECTIVES: Mesenchymal stem cells are easy to obtain and expand, with characteristics of low immunogenicity and strong tissue repair capacity. In this study, our aim was to investigate the role of mesenchymal stem cells in chronic immune rejection of heterotopic small intestine transplant in rats. MATERIALS AND METHODS: After successfully constructing a rat chronic immune rejection model of heterotopic small intestine transplant, we infused mesenchymal stem cells into the animal recipients. We observed mesenchymal stem cell location in the recipients, recipient survival, pathology changes, and the expression of CD68, transforming growth factor beta1, and platelet-derived growth factor C in the donor intestine. RESULTS: Mesenchymal stem cells inhibited the lymphocyte proliferation caused by concanavalin A in vitro. After stem cells were infused into recipients, they were mainly located in the donor intestine, as well as in the spleen and thymus. Recovery after transplant and pathology changes of the donor intestine in rats with stem cell infusion were better than in the control group; however, we observed no differences in survival time, accompanied by downregulated expression of CD68, transforming growth factor beta1, and platelet derived growth factor C. CONCLUSIONS: Mesenchymal stem cells, to a certain extent, could inhibit the process of chronic rejection. The mechanisms may include the inhibited function of these cells on lymphocyte proliferation, reduced infiltration of macrophages, and reduced expression of transforming growth factor beta1 and platelet-derived growth factor C. PMID- 28338462 TI - Perioperative Calcium, Magnesium, and Phosphorus in Living Liver Donors. PMID- 28338463 TI - Doceo ergo sum: mentoring surgeons. PMID- 28338465 TI - [A la memoire du Dr Jean Couture, un grand chirurgien au Canada et en Chine (1924 2016)]. PMID- 28338466 TI - Surrogate end points save lives. AB - SUMMARY: Patient-centric markers are important, and when they can be conveniently measured they should dominate research questions. However, when the research question pertains to serious or potentially fatal illnesses and it will take years or even decades to answer with patient-centric outcomes, then a pragmatic approach based on common sense and surrogate markers should be adopted. This commentary discusses the important role that surrogate markers can play in medical research. PMID- 28338467 TI - Somewhere in France (9 April 17): a centenary review of medical arrangements at Vimy Ridge. AB - SUMMARY: In April 1917, medical units of the 4 divisions of the Canadian Corps combined for the first time in support of a single action, the assault upon Vimy Ridge. Detailed planning, infrastructure development, information dissemination and rehearsal were features of preparations by the combat arms and medical elements of the Canadian Forces. Extraordinary coordination resulted in the rapid rescue and evacuation by Canadian medical services of 8000 casualties over 4 days. Characteristics of today's military medical services are evident in the work of the Canadian Army Medical Corps 100 years ago. PMID- 28338468 TI - Endoscopic mucosal resection for high-grade dysplasia and intramucosal carcinoma: a Canadian experience. AB - BACKGROUND: Endoscopic mucosal resection (EMR) is increasingly being used as a first-line treatment for Barrett esophagus (BE) with high-grade dysplasia (HGD) and intramucosal adenocarcinoma (IMC). We reviewed our experience with endoscopic treatment of BE with HGD and IMC at our institution with respect to eradication rates, complications and long-term recurrence. METHODS: We performed a single centre retrospective review of all patients referred between October 2010 and August 2014 for EMR with dysplastic BE or IMC. We performed EMR using a cap fitted endoscope, and the procedure was repeated every 3 months until eradication or progression of disease. RESULTS: A total of 28 patients were identified: 16 with dysplastic BE (14 HGD, 1 low-grade dysplasia, 1 intermediate dysplasia) and 12 with IMC. Complete eradication of HGD was achieved in 11 of 14 (79%) patients. Three of 12 (25%) patients initially referred with suspected IMC were found to have invasive adenocarcinoma on EMR. Eradication was successful in 8 of 9 (89%) patients with true IMC, with 1 patient progressing to salvage esophagectomy. Complications occurred in 2 of 28 (7%) patients; both had esophageal strictures managed with dilatation. Median duration of follow-up was 371 days. CONCLUSION: Our experience supports the safety of EMR as a first-line treatment for patients with BE with dysplasia and IMC in early short-term follow-up. PMID- 28338469 TI - The utility of thyroid ultrasonography in the management of thyroid nodules. AB - BACKGROUND: Ultrasonography for thyroid nodules is one of the most common imaging tests performed in the general population. Details from ultrasound reports guide biopsies and surgery. This study quantifies the completeness of these reports based on Thyroid Imaging and Reporting System (TI-RADS) criteria and considers their utility in predicting malignant disease. METHODS: We retrospectively reviewed ultrasound reports for 329 thyroidectomy patients and extracted data elements using the TI-RADS criteria: nodule size, echogenicity, margins, vascularity, solid/cystic composition and the presence or absence of microcalcifications and the halo sign. We assessed the reports to determine whether individual or multiple criteria were associated with malignancy. RESULTS: More than 97% of reports document nodule size; however, more than 90% of the reports noted only 3 or fewer of the 6 remaining TI-RADS criteria. The presence of microcalcifications was the most sensitive marker of malignancy (> 90%), whereas the documentation of irregular margins was the most specific indicator of malignancy (88%). Overall it was clear that microcalcifications, hypoechogenicity, irregular margins and solid nodules were significantly more likely to be found in malignant neoplasms; their absence predicted benign disease. Because so few reports consistently documented all criteria, the overall ability of thyroid ultrasonography to discriminate between lowerand higher-risk nodules is limited. CONCLUSION: Although the accuracy of thyroid ultrasonography is good, few ultrasound reports contain the necessary information, as defined by TI-RADS, to predict malignancy and guide management. When reported, microcalcifications and/or irregular margins are the best predictors of malignancy. PMID- 28338470 TI - Reducing scan angle using adaptive prior knowledge for a limited-angle intrafraction verification (LIVE) system for conformal arc radiotherapy. AB - The purpose of this study is to develop an adaptive prior knowledge guided image estimation technique to reduce the scan angle needed in the limited-angle intrafraction verification (LIVE) system for 4D-CBCT reconstruction. The LIVE system has been previously developed to reconstruct 4D volumetric images on-the fly during arc treatment for intrafraction target verification and dose calculation. In this study, we developed an adaptive constrained free-form deformation reconstruction technique in LIVE to further reduce the scanning angle needed to reconstruct the 4D-CBCT images for faster intrafraction verification. This technique uses free form deformation with energy minimization to deform prior images to estimate 4D-CBCT based on kV-MV projections acquired in extremely limited angle (orthogonal 3 degrees ) during the treatment. Note that the prior images are adaptively updated using the latest CBCT images reconstructed by LIVE during treatment to utilize the continuity of the respiratory motion. The 4D digital extended-cardiac-torso (XCAT) phantom and a CIRS 008A dynamic thoracic phantom were used to evaluate the effectiveness of this technique. The reconstruction accuracy of the technique was evaluated by calculating both the center-of-mass-shift (COMS) and 3D volume-percentage-difference (VPD) of the tumor in reconstructed images and the true on-board images. The performance of the technique was also assessed with varied breathing signals against scanning angle, lesion size, lesion location, projection sampling interval, and scanning direction. In the XCAT study, using orthogonal-view of 3 degrees kV and portal MV projections, this technique achieved an average tumor COMS/VPD of 0.4 +/- 0.1 mm/5.5 +/- 2.2%, 0.6 +/- 0.3 mm/7.2 +/- 2.8%, 0.5 +/- 0.2 mm/7.1 +/- 2.6%, 0.6 +/- 0.2 mm/8.3 +/- 2.4%, for baseline drift, amplitude variation, phase shift, and patient breathing signal variation, respectively. In the CIRS phantom study, this technique achieved an average tumor COMS/VPD of 0.7 +/- 0.1 mm/7.5 +/- 1.3% for a 3 cm lesion and 0.6 +/- 0.2 mm/11.4 +/- 1.5% for a 2 cm lesion in the baseline drift case. The average tumor COMS/VPD were 0.5 +/- 0.2 mm/10.8 +/- 1.4%, 0.4 +/- 0.3 mm/7.3 +/- 2.9%, 0.4 +/- 0.2 mm/7.4 +/ 2.5%, 0.4 +/- 0.2 mm/7.3 +/- 2.8% for the four real patient breathing signals, respectively. Results demonstrated that the adaptive prior knowledge guided image estimation technique with LIVE system is robust against scanning angle, lesion size, location and scanning direction. It can estimate on-board images accurately with as little as 6 projections in orthogonal-view 3 degrees angle. In conclusion, adaptive prior knowledge guided image reconstruction technique accurately estimates 4D-CBCT images using extremely-limited angle and projections. This technique greatly improves the efficiency and accuracy of LIVE system for ultrafast 4D intrafraction verification of lung SBRT treatments. PMID- 28338471 TI - Generalized PSF modeling for optimized quantitation in PET imaging. AB - Point-spread function (PSF) modeling offers the ability to account for resolution degrading phenomena within the PET image generation framework. PSF modeling improves resolution and enhances contrast, but at the same time significantly alters image noise properties and induces edge overshoot effect. Thus, studying the effect of PSF modeling on quantitation task performance can be very important. Frameworks explored in the past involved a dichotomy of PSF versus no PSF modeling. By contrast, the present work focuses on quantitative performance evaluation of standard uptake value (SUV) PET images, while incorporating a wide spectrum of PSF models, including those that under- and over-estimate the true PSF, for the potential of enhanced quantitation of SUVs. The developed framework first analytically models the true PSF, considering a range of resolution degradation phenomena (including photon non-collinearity, inter-crystal penetration and scattering) as present in data acquisitions with modern commercial PET systems. In the context of oncologic liver FDG PET imaging, we generated 200 noisy datasets per image-set (with clinically realistic noise levels) using an XCAT anthropomorphic phantom with liver tumours of varying sizes. These were subsequently reconstructed using the OS-EM algorithm with varying PSF modelled kernels. We focused on quantitation of both SUVmean and SUVmax, including assessment of contrast recovery coefficients, as well as noise bias characteristics (including both image roughness and coefficient of variability), for different tumours/iterations/PSF kernels. It was observed that overestimated PSF yielded more accurate contrast recovery for a range of tumours, and typically improved quantitative performance. For a clinically reasonable number of iterations, edge enhancement due to PSF modeling (especially due to over-estimated PSF) was in fact seen to lower SUVmean bias in small tumours. Overall, the results indicate that exactly matched PSF modeling does not offer optimized PET quantitation, and that PSF overestimation may provide enhanced SUV quantitation. Furthermore, generalized PSF modeling may provide a valuable approach for quantitative tasks such as treatment-response assessment and prognostication. PMID- 28338472 TI - Robust cardiac motion estimation using ultrafast ultrasound data: a low-rank topology-preserving approach. AB - Cardiac motion estimation is an important diagnostic tool for detecting heart diseases and it has been explored with modalities such as MRI and conventional ultrasound (US) sequences. US cardiac motion estimation still presents challenges because of complex motion patterns and the presence of noise. In this work, we propose a novel approach to estimate cardiac motion using ultrafast ultrasound data. Our solution is based on a variational formulation characterized by the L 2 regularized class. Displacement is represented by a lattice of b-splines and we ensure robustness, in the sense of eliminating outliers, by applying a maximum likelihood type estimator. While this is an important part of our solution, the main object of this work is to combine low-rank data representation with topology preservation. Low-rank data representation (achieved by finding the k-dominant singular values of a Casorati matrix arranged from the data sequence) speeds up the global solution and achieves noise reduction. On the other hand, topology preservation (achieved by monitoring the Jacobian determinant) allows one to radically rule out distortions while carefully controlling the size of allowed expansions and contractions. Our variational approach is carried out on a realistic dataset as well as on a simulated one. We demonstrate how our proposed variational solution deals with complex deformations through careful numerical experiments. The low-rank constraint speeds up the convergence of the optimization problem while topology preservation ensures a more accurate displacement. Beyond cardiac motion estimation, our approach is promising for the analysis of other organs that exhibit motion. PMID- 28338473 TI - Impact absorption properties of carbon fiber reinforced bucky sponges. AB - We describe the super compressible and highly recoverable response of bucky sponges as they are struck by a heavy flat-punch striker. The bucky sponges studied here are structurally stable, self-assembled mixtures of multiwalled carbon nanotubes (MWCNTs) and carbon fibers (CFs). We engineered the microstructure of the sponges by controlling their porosity using different CF contents. Their mechanical properties and energy dissipation characteristics during impact loading are presented as a function of their composition. The inclusion of CFs improves the impact force damping by up to 50% and the specific damping capacity by up to 7% compared to bucky sponges without CFs. The sponges also exhibit significantly better stress mitigation characteristics compared to vertically aligned CNT foams of similar densities. We show that delamination occurs at the MWCNT-CF interfaces during unloading, and it arises from the heterogeneous fibrous microstructure of the bucky sponges. PMID- 28338474 TI - Kagome-like chains with anisotropic ferromagnetic and antiferromagnetic interactions. AB - We consider a spin-[Formula: see text] kagome-like chain with competing ferro- and antiferromagnetic anisotropic exchange interactions. The ground state phase diagram of this model consists of the ferromagnetic and ferrimagnetic phases. We study the ground state and the low-temperature properties on the phase boundary between these phases. The ground state on this phase boundary is macroscopically degenerate and consists of localized magnon states. We calculate the ground state degeneracy and corresponding residual entropy. The spontaneous magnetization has a jump on the phase boundary confirming the first-order type of the phase transition. In the limit of a strong anisotropy, the spectrum of the low-energy excitations has multi-scale structure governing the peculiar features of the specific heat behavior. PMID- 28338475 TI - Evidence of a permanent electric polarisation in highly strained Cr2O3 clusters measured by a second harmonic generation technique. AB - We investigate the second harmonic generation (SHG) signal in strained Cr2O3 clusters. We show that the SHG signal generated by nanometric Cr2O3 clusters embedded in MgO varies under an applied electric field, at room temperature. The variation of the intensity follows a Langevin law as a function of the electric field, which is consistent with a super-paraelectric clusters assembly. This reveals the presence of a weak spontaneous electric dipole in Cr2O3 when in the shape of highly strained epitaxial clusters, whereas this material does not posses any permanent electric dipole in the bulk phase. These results indicate that the multiferroic state recently observed at low temperature in those clusters, which was associated to a giant magneto-electric effect, might still exist at room temperature: this opens the way to new applications based on chromium oxide strained nanoparticles. PMID- 28338476 TI - Frank-Kasper sigma phase in polybutadiene-poly(epsilon-caprolactone) diblock copolymer/polybutadiene blends. AB - Microphase-separated structures in a polybutadiene-poly(epsilon-caprolactone) diblock copolymer (PB-PCL)/polybutadiene homopolymer (PB) blend were investigated by small-angle x-ray scattering (SAXS). Non-equilibrium spherical micelles were observed at temperatures ranging between 60 and 100 degrees C. An SAXS profile with >60 scattering peaks was recorded at 140 degrees C. All the peak positions were in good agreement with theoretical Frank-Kasper sigma phase peak positions. Thus, these results indicate the formation of a Frank-Kasper sigma phase in the PB-PCL/PB blend at 140 degrees C. PMID- 28338477 TI - Osmotic and Hemodynamic Effects of Hypertonic Glucose During Hemodialysis. AB - It was the purpose to quantify the hemodynamic effects of a bolus of hypertonic glucose injected into the extracorporeal system in a group of stable and nondiabetic patients during hemodialysis (HD). Glucose and electrolytes were measured in frequent intervals. Arterial blood pressures and heart rates were continuously recorded by noninvasive vascular unloading technique. Beat-to-beat stroke volume, cardiac output, and total peripheral resistance were determined by Modelflow method. Relative blood volumes were continuously measured by ultrasonic and optical means. Eight patients were studied in two treatments. Although arterial pressures and heart rates remained stable, stroke volume and cardiac output transiently increased above (19.2 +/- 12.3%) and total peripheral resistance dropped below baseline (18.2 +/- 8.6%) by a comparable magnitude. Relative blood volume transiently increased above baseline at 100% (104.9 +/- 1.0%). Glucose concentrations were significantly related to relative blood volumes (r = 0.86, p < 0.001). In spite of a substantial increase in blood volume, a bolus of hypertonic glucose does not increase arterial pressures in nondiabetic patients because of concomitant vasodilatation. The relative increase in blood volume quantified by noninvasive HD technology follows the course of glucose and could be used as a surrogate to characterize patients with regard to their glucose metabolism during HD. PMID- 28338478 TI - Like Two Peas in a Pod: Heart Failure and Atrial Fibrillation. PMID- 28338479 TI - The Origins of Continuous Renal Replacement Therapy. AB - Peter Kramer's presentation at the 1982 ASAIO meeting was the inspiration that led to continuous renal replacement therapy in intensive care. PMID- 28338480 TI - The Challenges in Predicting ECMO Survival, and a Path Forward. AB - Extracorporeal membrane oxygenation (ECMO) support is a life-saving but complex technique for patients suffering from severe cardiac or pulmonary dysfunction. Increasingly greater utilization in the last 15 years means that a suite of mortality risk analytics is both feasible for researchers and required by clinicians, patients, administrators, and insurers. We argue that to date, research into such risk analytics has been insufficient and does not adequately reflect the various indications and configurations of extracorporeal life support (ECLS). We propose a path to address these challenges and ensure that clinicians and researchers obtain robust, specific, risk analytics. PMID- 28338481 TI - Clinical Use and Optimal Cutoff Value of Ca15-3 in Evaluation of Adnexal Mass: Retrospective Cohort Study and Review of the Literature. AB - OBJECTIVE: To estimate the diagnostic performance and reference values of serum cancer antigen (Ca)15-3 levels in the triage of adnexal masses. MATERIALS AND METHODS: This retrospective cohort study was carried out in 481 patients referred to the Gynecology Department at Carmel Medical Center due to adnexal mass between years 2005 and 2012. All patients underwent surgery with histopathologically confirmed diagnosis and routine preoperative measurements of serum Ca125 and Ca15 3. RESULTS: Combination of Ca125 with Ca15-3 elevated the sensitivity of Ca125 alone (from 86.9% to 93.2%; P=0.029), along with reduction of its specificity (from 80.5% to 69.5%; P=0.005) in differentiation between malignant and benign cases. According to receiver operating characteristic curve, Ca15-3 level of 21 U/mL was shown to be the optimal reference value for malignancy detection. All cases with Ca15-3 levels above 44.5 U/mL were malignant, mostly of primary ovarian source. CONCLUSIONS: As Ca15-3 assessment allowed detection of significantly more malignancy cases, we believe that measurement of this marker in combination with Ca125 is worthwhile in patients presenting with adnexal masses. The cutoff of 21 U/mL seems to be the optimal value in this specific population. High Ca15-3 levels (above 44.5 U/mL) strongly direct to a diagnosis of malignancy, mostly of primary ovarian tumors rather than breast malignancy. PMID- 28338482 TI - Axillary Ultrasound Fine Needle Aspiration Biopsy: Is There a Role in the Post Z 0011 Era? AB - OBJECTIVES: Axillary ultrasound with fine needle aspiration (AXUSFNA) in early stage breast cancer has required reappraisal. ACOSOG Z-0011 and after mapping of the axilla: radiotherapy or surgery have shown that women with limited nodal disease at sentinel lymph node biopsy got no survival advantage with completion axillary node dissection. We hypothesize that AXUSFNA may be sufficiently accurate for staging for some patients and sentinel lymph node biopsy need not be performed. We define the false negative rate (FNR) of AXUSFNA in different subsets of patients. MATERIALS AND METHODS: This retrospective cohort study included node positive patients who also underwent AXUSFNA between 1/2006 and 12/2010 followed by axillary surgery. The FNR was calculated for the entire group and for subgroups determined by tumor, nodal, and ultrasound findings. RESULTS: Out of ~700 AXUSFNA patients, 128 node positive patients were included in the study. The overall AXUSFNA FNR was 35.9% (95% confidence interval, 28.1%-44.6%). There was a significantly higher FNR with smaller tumors and presence of ductal carcinoma in situ on multivariate analysis. On ultrasound, benign-appearing nodes had a higher FNR than indeterminate nodes (78.9% vs. 60.9%, P=0.2) and significantly higher than suspicious nodes (78.9% vs. 2.9%, P<0.0001). CONCLUSIONS: In our cohort, the FNR for AXUSFNA was comparable with the rate of residual disease in the control arms of Z-0011 (27.4%) and after mapping of the axilla: radiotherapy or surgery (33%). However, our analysis suggests that we may be able to identify more appropriate patients for AXUSFNA and halve the FNR. As primary tumor characteristics and genomics drive systemic therapeutic recommendations, there may be an ongoing role for AXUSFNA in axillary staging. PMID- 28338483 TI - Prevalence and Impact on Weaning of Pleural Effusion at the Time of Liberation from Mechanical Ventilation: A Multicenter Prospective Observational Study. AB - BACKGROUND: Pleural effusion is frequent in intensive care unit patients, but its impact on the outcome of weaning remains unknown. METHODS: In a prospective study performed in three intensive care units, pleural ultrasound was performed at the first spontaneous breathing trial to detect and quantify pleural effusion (small, moderate, and large). Weaning failure was defined by a failed spontaneous breathing trial and/or extubation requiring any form of ventilatory support within 48 h. The primary endpoint was the prevalence of pleural effusion according to weaning outcome. RESULTS: Pleural effusion was detected in 51 of 136 (37%) patients and was quantified as moderate to large in 18 (13%) patients. As compared to patients with no or small pleural effusion, their counterparts were more likely to have chronic renal failure (39 vs. 7%; P = 0.01), shock as the primary reason for admission (44 vs. 19%; P = 0.02), and a greater weight gain (+4 [0 to 7] kg vs. 0 [-1 to 5] kg; P = 0.02). The prevalence of pleural effusion was similar in weaning success and weaning failure patients (odds ratio, 1.23; 95% CI, 0.61 to 2.49; P = 0.56), as was the prevalence of moderate to large pleural effusion (odds ratio, 0.89; 95% CI, 0.33 to 2.41; P = 1.00). Duration of mechanical ventilation and intensive care unit length of stay were similar between patients with no or small pleural effusion and those with moderate to large pleural effusion. CONCLUSIONS: Significant pleural effusion was observed in 13% of patients at the time of liberation from mechanical ventilation and was not associated with an alteration of weaning outcome. (ANESTHESIOLOGY 2017; 126:1107 15). PMID- 28338484 TI - The importance of biopsy sampling practices in the pathologic evaluation of gastrointestinal disorders. AB - PURPOSE OF REVIEW: To summarize the literature regarding appropriate endoscopic sampling and surveillance protocols for common inflammatory diseases of the digestive tract. Gastroenterologists increasingly use endoscopy with mucosal biopsy to detect inflammatory diseases, assess response to therapy, and monitor for progression to dysplasia. RECENT FINDINGS: Many diseases show a patchy distribution in the digestive tract and there may be poor correlation between the endoscopic appearance and presence of histologic abnormalities. Indeed, a clinician's ability to render a diagnosis is limited by endoscopic mucosal sampling. The appropriate number of tissue samples and required biopsy sites are not established for many gastrointestinal disorders, and adherence to guidelines may not yield a reliable diagnosis in all cases. SUMMARY: We discuss the evidence supporting current recommendations and emerging endoscopic techniques for the evaluation of eosinophilic esophagitis, Barrett esophagus, chronic gastritis, celiac disease, and inflammatory bowel disease. PMID- 28338485 TI - Creation of a Regional Human Milk Assembly: A Model to Influence Practice and Policy Change in the NICU. AB - BACKGROUND: The 2011 Surgeon General's Call to Action to Support Breastfeeding highlights a need for optimizing lactation-based education for all health professionals; however, few schools of nursing and medicine offer lactation-based curriculum. In an effort to address these gaps in education and care, the director of the lactation program at a large urban children's hospital developed and instituted the annual regional Human Milk Assembly (HMA), a half-day collaborative meeting of the hospital's regional and referral hospitals' neonatal intensive care unit (NICU) nursing staff, to address lactation-based educational and training needs of all participating institutions. PURPOSE: The purpose of this study was to determine whether and how participating HMA hospitals implemented the best practices surrounding human milk and breastfeeding shared by the host institution during a 10-year span of the HMA. METHODS: A prospective descriptive study was designed using an electronic web-based survey (SurveyMonkey.com) to elicit participant data. Quantitative data were analyzed using descriptive statistics whereas qualitative data were analyzed for themes via content analysis. RESULTS: Thirty-one of the 50 hospitals surveyed responded to the electronic survey for a total of 34 individual participants. Seventeen of the 22 (77%) of best practices were implemented at rates of over 50%. IMPLICATIONS FOR PRACTICE: By enabling a culture of transparency and sharing, hospital staff can be encouraged to implement best practices across a network of regional care centers. IMPLICATIONS FOR RESEARCH: This annual regional HMA could be a model for other areas and research should be conducted to evaluate such programs nationwide. PMID- 28338486 TI - Congenital cytomegalovirus infection: management update. AB - PURPOSE OF REVIEW: Until recently, management options in congenital cytomegalovirus (cCMV) infection have been either conservative or termination of pregnancy. However, medical therapies aimed at reducing the risk of infection and/or its severity have recently been investigated. RECENT FINDINGS: In a phase 2 open label, nonrandomized trial, valaciclovir (ValACV) was given to women carrying a CMV-infected fetus. ValACV was associated with a greater proportion of asymptomatic neonates when compared with a historical cohort (82 vs. 43%). However, the study design and the small number of treated women limit its applicability. Even though initial observational data suggested that hyperimmune globulin (HIG) therapy in pregnancy was associated with a significantly lower risk of cCMV, its efficacy has not been borne out in a subsequent phase 2 randomized, placebo controlled, double-blind study [cCMV 30% in the HIG group, 44% in the placebo group (P = 0.13)]. Furthermore, 11% of fetuses in the HIG group had transient or permanent abnormalities, compared with 16% in the placebo group. SUMMARY: ValACV might have a promising role in the antenatal treatment of cCMV infection, but definitive recommendations require further research. The use of HIG should currently be limited to the research setting.Video abstract http://links.lww.com/COID/A18. PMID- 28338487 TI - The evolution of disease: chronic lung disease of infancy and pulmonary hypertension. AB - PURPOSE OF REVIEW: Bronchopulmonary dysplasia (BPD) or chronic lung disease of infancy BPD was originally described 50 years ago, in 1967 by Northway et al. This article possesses two fundamental objectives to provide: a brief historical perspective on BPD; and an update relative to current notions of epidemiology, pathophysiology, evaluation, and clinical management of BPD complicated by vascular disease. The review highlights areas of consensus and ongoing uncertainty. RECENT FINDINGS: The clinical cause and presentation of infants with BPD has evolved over the past several decades. Considerable improvements in neonatal care, including surfactant replacement therapies, antenatal steroids, nutritional support, ventilator management, and attention to the potential of oxygen toxicity, underlie the evolution of BPD. Most children with BPD improve over time. However, in the presence of vascular disease, the morbidity and mortality associated with BPD increases considerably. Though recent recommendations include procuring an echocardiogram to screen for pulmonary hypertension in infants with established BPD, there is less agreement surrounding the additional diagnostic and putative treatment modalities for infants with BPD and pulmonary hypertension. The indications, rationale, potential benefits, and risks of vasodilator therapy in BPD are discussed. SUMMARY: The pediatric community has 50 years of experience with BPD. Past experience should be used to inform present and future diagnostic and treatment strategies. This review seeks to arm the clinician with evidence that motivates a physiology-based approach to the management of infants with BPD and pulmonary hypertension. PMID- 28338488 TI - Respiratory complications, management and treatments for neuromuscular disease in children. AB - PURPOSE OF REVIEW: To summarize current literature describing the respiratory complications of neuromuscular disease (NMD) and the effect of respiratory interventions and to explore new gene therapies for patients with NMD. RECENT FINDINGS: Measurements of respiratory function focus on vital capacity and maximal inspiratory and expiratory pressure and show decline over time. Management of respiratory complications includes lung volume recruitment, mechanical insufflation-exsufflation, chest physiotherapy and assisted ventilation. Lung volume recruitment can slow the progression of lung restriction. New gene-specific therapies for Duchenne muscular dystrophy and spinal muscular atrophy have the potential to preserve respiratory function longitudinally. However, the long-term therapeutic benefit remains unknown. SUMMARY: Although NMDs are heterogeneous, many lead to progressive muscle weakness that compromises the function of the respiratory system including upper airway tone, cough and secretion clearance and chest wall support. Respiratory therapies augment or support the normal function of these components of the respiratory system. From a respiratory perspective, the new mutation and gene specific therapies for NMD are likely to confer long-term therapeutic benefit. More sensitive and standard tools to assess respiratory function longitudinally are needed to monitor respiratory complications in children with NMD, particularly the youngest patients. PMID- 28338489 TI - Pediatric pulmonary medicine, then and next. PMID- 28338490 TI - Small-Volume Injections: Evaluation of Volume Administration Deviation From Intended Injection Volumes. AB - BACKGROUND: In the perioperative period, anesthesiologists and postanesthesia care unit (PACU) nurses routinely prepare and administer small-volume IV injections, yet the accuracy of delivered medication volumes in this setting has not been described. In this ex vivo study, we sought to characterize the degree to which small-volume injections (<=0.5 mL) deviated from the intended injection volumes among a group of pediatric anesthesiologists and pediatric postanesthesia care unit (PACU) nurses. We hypothesized that as the intended injection volumes decreased, the deviation from those intended injection volumes would increase. METHODS: Ten attending pediatric anesthesiologists and 10 pediatric PACU nurses each performed a series of 10 injections into a simulated patient IV setup. Practitioners used separate 1-mL tuberculin syringes with removable 18-gauge needles (Becton-Dickinson & Company, Franklin Lakes, NJ) to aspirate 5 different volumes (0.025, 0.05, 0.1, 0.25, and 0.5 mL) of 0.25 mM Lucifer Yellow (LY) fluorescent dye constituted in saline (Sigma Aldrich, St. Louis, MO) from a rubber-stoppered vial. Each participant then injected the specified volume of LY fluorescent dye via a 3-way stopcock into IV tubing with free-flowing 0.9% sodium chloride (10 mL/min). The injected volume of LY fluorescent dye and 0.9% sodium chloride then drained into a collection vial for laboratory analysis. Microplate fluorescence wavelength detection (Infinite M1000; Tecan, Mannedorf, Switzerland) was used to measure the fluorescence of the collected fluid. Administered injection volumes were calculated based on the fluorescence of the collected fluid using a calibration curve of known LY volumes and associated fluorescence.To determine whether deviation of the administered volumes from the intended injection volumes increased at lower injection volumes, we compared the proportional injection volume error (loge [administered volume/intended volume]) for each of the 5 injection volumes using a linear regression model. Analysis of variance was used to determine whether the absolute log proportional error differed by the intended injection volume. Interindividual and intraindividual deviation from the intended injection volume was also characterized. RESULTS: As the intended injection volumes decreased, the absolute log proportional injection volume error increased (analysis of variance, P < .0018). The exploratory analysis revealed no significant difference in the standard deviations of the log proportional errors for injection volumes between physicians and pediatric PACU nurses; however, the difference in absolute bias was significantly higher for nurses with a 2-sided significance of P = .03. CONCLUSIONS: Clinically significant dose variation occurs when injecting volumes <=0.5 mL. Administering small volumes of medications may result in unintended medication administration errors. PMID- 28338491 TI - Perioperative Management of Blood Loss in Spine Surgery. AB - Spine procedures are associated with high rates of blood loss which can result in a greater need for transfusions. Repeated exposure to blood products is associated with risks and adverse reactions such as transfusion-related acute lung injury, fluid shifting, and infections. With the higher number of spine procedures and the increasing open surgery times associated with difficult procedures, excessive blood loss has become more prevalent. Perioperative methods have been established to combat the excessive blood loss and decrease the need for blood products. Preoperatively, anemia and coagulopathy screening is standard at least 4 weeks before elective procedures. Erythropoietin, iron loading or transfusions are used to decrease preoperative anemia, a predisposing factor for blood loss. Autologous predonation of blood has been shown to be ineffective and decreases preoperative hemoglobin levels. Intraoperatively, antifibrinolytics such as tranexamic acid and aminocaproic acid are used to decrease blood loss. In addition, fibrinogen concentrates, thromboelastometry, acute normovolemic hemodilution, controlled hypotension, and temperature regulation are some of the techniques used to decrease blood loss and the need for transfusions. Postoperatively, fibrin sealants, shed blood salvage, and erythropoietin or intravenous iron are used in management of blood loss, especially in instances when the patient refuses blood products. PMID- 28338492 TI - The Evolution of Current Research Impact Metrics: From Bibliometrics to Altmetrics? AB - The prestige of publication has been based on traditional citation metrics, most commonly journal impact factor. However, the Internet has radically changed the speed, flow, and sharing of medical information. Furthermore, the explosion of social media, along with development of popular professional and scientific websites and blogs, has led to the need for alternative metrics, known as altmetrics, to quantify the wider impact of research. We explore the evolution of current research impact metrics and examine the evolving role of altmetrics in measuring the wider impact of research. We suggest that altmetrics used in research evaluation should be part of an informed peer-review process such as traditional metrics. Moreover, results based on altmetrics must not lead to direct decision making about research, but instead, should be used to assist experts in making decisions. Finally, traditional and alternative metrics should complement, not replace, each other in the peer-review process. PMID- 28338493 TI - Surgery for Recurrent Uterine Cancer: Surgical Outcomes and Implications for Survival-A Case Series. AB - OBJECTIVE: The purpose of this study was to describe the patterns of relapse in uterine cancer (UC) and the role of surgery in the recurrent setting. METHODS: We describe surgical and clinical outcomes of all patients who underwent surgery for recurrent UC in a gynecological oncology tertiary referral center between May 1, 2013, and April 30, 2016. Progression-free survival and overall survival were estimated using Kaplan-Meier methods with the surgery at relapse being the starting point. RESULTS: We evaluated 15 patients with a median age of 66 years. The predominant histology was the endometrioid variant (n = 11; 73.3%). The median interval between the end of previous treatment and relapse surgery was 24 months (range, 8-164). Locoregional pelvic recurrences were the most common type of recurrence (n = 13; 86.7%) with the para-aortic lymph node space being the most commonly affected extrapelvic site (13%). Patients predominantly presented with a multifocal pattern of relapse (n = 10; 66.7%) requiring multivisceral resections such as bowel (n = 7; 46.6%) and/or bladder/ureteric resections (n = 8; 53.3%) to achieve complete tumor clearance. All patients were operated tumor free with a 30-day major morbidity and mortality rate of 6.7% and 0%, respectively. Five patients (33.3%) received postoperative chemotherapy or radiotherapy. Five patients (33.3%) relapsed, and 3 died within a mean follow-up of 12.4 months (95% confidence interval [CI], 6.5-18.2). Two of those patients had a sarcoma.Mean progression-free survival and overall survival for the entire cohort postrelapse surgery was 21.7 months (95%CI, 13.9-29.5) and 26.0 months (95%CI, 18.4-33.7), respectively. Survival was significantly worse in patients with nonendometrioid histology (P < 0.0001). CONCLUSIONS: Surgery for UC relapse seems feasible with acceptable morbidity and high complete resection rates despite the multifocal patterns of relapse in a selected group of patients in a reference center for gynecological cancers. Larger scale studies are warranted to establish the value of surgery at relapse for UC. PMID- 28338494 TI - Combined Knockdown of D-dopachrome Tautomerase and Migration Inhibitory Factor Inhibits the Proliferation, Migration, and Invasion in Human Cervical Cancer. AB - OBJECTIVE: D-dopachrome tautomerase (D-DT) is a homologue of macrophage migration inhibitory factor (MIF) with similar functions. However, the possible biological roles of D-DT in cervical cancer remain unknown so far. METHODS: D-dopachrome tautomerase was assessed by immunohistochemistry in 83 cervical cancer and 31 normal cervix tissues. The stable knockdown of D-DT and MIF by lentivirus delivered short hairpin RNA was established, and tumor growth was examined in vitro and in vivo. The effects of D-DT and MIF on the migration and invasion were further detected by wound healing assay and transwell assay. Western blot was used to explore the mechanism of D-DT and MIF in cervical cancer pathogenesis. RESULTS: We found that D-DT was significantly high in cervical cancer, which correlated with lymph node metastasis. The knockdown of D-DT and MIF, individually and additively, inhibited the proliferation, migration, and invasion in HeLa and SiHa cells and restrained the growth of xenograft tumor. The ablation of D-DT and MIF rescued the expression of E-cadherin and inhibited the expression of PCNA, cyclin D1, gankyrin, Sam68, and vimentin, as well as phospho-Akt and phospho-glycogen synthase kinase 3-beta. CONCLUSIONS: The inhibition of D-DT and MIF in combination may represent a potential therapeutic strategy for cervical cancer. PMID- 28338495 TI - Burden of Hearing Loss on Communication Partners and Its Influence on Pursuit of Hearing Evaluation. AB - OBJECTIVE: Describe how the burden on the communication partner (CP) from the patient's hearing loss, as perceived by both the patient and their CP, influences a patient's pursuit of hearing evaluation. DESIGN: Cross-sectional design. Demographics, perception of patient's hearing loss, and associated burden on the CP were collected from both patient and CP via online questionnaires. Patients and their CPs from Duke University Medical Center Otolaryngology Clinic, 55 to 75 years of age, being seen for any reason, who indicated a CP has expressed concern about their hearing. Final sample was 245 matched pairs. RESULTS: Based on completed questionnaires, on average, patients perceived their own hearing loss as more burdensome to the CP than the CP did. However, CPs of patients who believed themselves to have no hearing handicap scored the patient's hearing loss 54.3% higher than the patient. The patient's perspective about the amount of burden their hearing loss placed on the CP predicted patients seeking a hearing evaluation. CONCLUSIONS: Recognition of early stage hearing loss and associated burden on CPs may be delayed in patients; CPs may help elucidate unrecognized concerns. Educational approaches that raise awareness of burden of hearing loss on CPs along with hearing loss indications could be a feasible, multidimensional strategy to promote help seeking behaviors. PMID- 28338496 TI - Infants' and Adults' Use of Temporal Cues in Consonant Discrimination. AB - OBJECTIVES: Adults can use slow temporal envelope cues, or amplitude modulation (AM), to identify speech sounds in quiet. Faster AM cues and the temporal fine structure, or frequency modulation (FM), play a more important role in noise. This study assessed whether fast and slow temporal modulation cues play a similar role in infants' speech perception by comparing the ability of normal-hearing 3 month-olds and adults to use slow temporal envelope cues in discriminating consonants contrasts. DESIGN: English consonant-vowel syllables differing in voicing or place of articulation were processed by 2 tone-excited vocoders to replace the original FM cues with pure tones in 32 frequency bands. AM cues were extracted in each frequency band with 2 different cutoff frequencies, 256 or 8 Hz. Discrimination was assessed for infants and adults using an observer-based testing method, in quiet or in a speech-shaped noise. RESULTS: For infants, the effect of eliminating fast AM cues was the same in quiet and in noise: a high proportion of infants discriminated when both fast and slow AM cues were available, but less than half of the infants also discriminated when only slow AM cues were preserved. For adults, the effect of eliminating fast AM cues was greater in noise than in quiet: All adults discriminated in quiet whether or not fast AM cues were available, but in noise eliminating fast AM cues reduced the percentage of adults reaching criterion from 71 to 21%. CONCLUSIONS: In quiet, infants seem to depend on fast AM cues more than adults do. In noise, adults seem to depend on FM cues to a greater extent than infants do. However, infants and adults are similarly affected by a loss of fast AM cues in noise. Experience with the native language seems to change the relative importance of different acoustic cues for speech perception. PMID- 28338498 TI - Challenge of progressive multiple sclerosis therapy. AB - PURPOSE OF REVIEW: Understanding the mechanisms underlying progression in multiple sclerosis (MS) and identifying appropriate therapeutic targets is a key challenge facing the MS community. This challenge has been championed internationally by organizations such as the Progressive MS Alliance, which has raised the profile of progressive MS and identified the key obstacles to treatment. This review will outline the considerable progress against these challenges. RECENT FINDINGS: New insights into mechanisms underlying progression have opened up potential therapeutic opportunities. This has been complemented by ongoing validation of clinical and imaging outcomes for Phase II trials of progression, coupled with the development of innovative trial designs. The field has been greatly encouraged by recent positive Phase III trials in both primary and secondary progressive MS, albeit with modest benefit. Early trials of neuroprotection and repair have provided important new data with which to drive the field. Improving symptom management and advancing rehabilitation approaches, critical for this patient population which, taken together with identifying and managing comorbidities and risk factors, has an appreciable impact on health related quality of life. SUMMARY: Raising the profile of progressive MS has resulted in the first effective treatments with the promise of more to come. PMID- 28338497 TI - Using Selective Serotonin Reuptake Inhibitors and Serotonin-Norepinephrine Reuptake Inhibitors in Critical Care: A Systematic Review of the Evidence for Benefit or Harm. AB - OBJECTIVE: Selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitors are among the most commonly prescribed drugs in patients admitted to the ICU. Our objective was to systematically review available literature for evidence of benefit or harm in ICU patients resulting from chronic effects, continued use, or withdrawal. DATA SOURCES: Medline, Embase, and Cochrane Central Register of Controlled Trials (1990 to November 2014). STUDY SELECTION: We searched for studies of ICU patients with recorded selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor prescription before or during admission, and reporting morbidity, mortality, adverse events, and resource measures like ICU length of stay. We considered all study designs. We excluded studies of deliberate overdose and depression in non ICU settings. Two authors independently and in duplicate screened citations and reviewed text of studies to apply selection criteria. DATA EXTRACTION: Two authors abstracted data on patient characteristics in exposed and control groups; use of selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitors previously or during ICU; comparator intervention; and outcomes, and also assessed methodologic quality. DATA SYNTHESIS: The database search retrieved 4,172 unique citations, of which 289 were reviewed, and 13 studies representing a total of 20,048 patients met selection criteria. There were five cohort studies, one case series, and seven case reports. Only one case report suggested benefit from selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor use and 11 studies reported morbidity in patients using these medications at admission to ICU. However, due to inadequate drug administration reporting, it was generally unclear if outpatient selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitors were continued in ICU, complicating interpretation. CONCLUSIONS: There may be excess morbidity in critically ill selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor users, but uncertainty remains whether this is due to chronic effects, ongoing use, or drug withdrawal. Further research with improved standards of drug administration reporting is needed to help clinicians decide when to use selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitors in critically ill patients. PMID- 28338499 TI - Development of the Irritable Bowel Syndrome Cognitive Affective Scale: a brief self-report measure for clinical and research settings. AB - OBJECTIVES: Measures of cognitive-affective processes believed to underlie Irritable Bowel Syndrome (IBS) symptom expression are used widely in both clinical and research settings. When combined, these measures can be time consuming and it is not clear whether they evaluate distinct or overlapping constructs. With this study, we seek to identify the most critical cognitive affective components contributing toward the expression of IBS and to identify which items in these constructs might be streamlined into a single, brief self report measure. PATIENTS AND METHODS: This measure was developed according to Food and Drug Administration guidelines for patient-reported outcome development. First, authors consolidated existing cognitive-affective measures (visceral sensitivity, anxiety sensitivity, and pain catastrophization) into a single questionnaire. Second, a principal components factor analysis was carried out on the basis of responses from a sample of participants with IBS. Third, on the basis of the results of the factor analysis, items were reduced to the final brief self-report measure and preliminary validity/reliability analyses (Cronbach's alpha, correlation with other related constructs) were carried out. RESULTS: An initial, 44-item measure was created. In all, 179 patients with ROME III IBS completed an online survey. Principal component analysis and item reduction yielded a 15-item scale with three factors: pain catastrophization, visceral hypervigilance, and extraintestinal hypervigilance. The final three factors showed comparable internal consistencies (alpha>0.90), concurrent validity, and predictive validity compared with the original 44 items. CONCLUSION: Although more research is warranted, the 15 items identified appear to provide an accurate measure of two important cognitive-affective constructs in the IBS population. PMID- 28338500 TI - Differential Diagnosis in Neuroendocrine Neoplasms of the Larynx. AB - The differential diagnosis of neuroendocrine neoplasms of the larynx is broad and includes lesions of epithelial, mesenchymal, and neuroectodermal origin. These lesions have overlapping clinical and pathologic aspects and must be carefully considered in the differential diagnosis of laryngeal neoplasms. The prognosis and treatment are also different among these tumor types, which necessitates making these distinctions clinically. The current literature was reviewed to provide updated information regarding the epithelial-derived tumors, including carcinoid, atypical carcinoid, small cell neuroendocrine carcinomas, large cell neuroendocrine carcinoma, and squamous cell carcinoma with neuroendocrine component. These tumors are compared and contrasted with non-epithelial-derived tumors such as paraganglioma and nonmucosal tumors, such as medullary thyroid carcinoma. The morphologic and cytologic features are discussed, along with helpful immunohistochemical and ancillary investigations. PMID- 28338501 TI - ALK Expression Is a Novel Marker for the WNT-activated Type of Pediatric Medulloblastoma and an Indicator of Good Prognosis for Patients. AB - ALK gene rearrangements were identified in a variety of cancers, including neuroblastoma, where the presence of ALK expression is associated with adverse prognosis. ALK mutations have recently been found in the pediatric brain tumor medulloblastoma, and microarray data indicate that ALK is highly expressed in a subset of these tumors. Therefore, we investigated whether ALK expression correlates with transcriptional profiles and clinical features of medulloblastoma. Tumors from 116 medulloblastoma patients were studied at diagnosis for the detection of ALK expression at the RNA level by an application of NanoString technology and at the protein level by immunohistochemistry using antibody ALK clone D5F3. The results indicate that ALK expression, at both the RNA and the protein levels, is strongly associated with the WNT-activated type of tumors and therefore may serve as a useful marker for the detection of this type of medulloblastoma. Importantly, ALK protein expression alone is also an indicator of good prognosis for medulloblastoma patients. PMID- 28338502 TI - Sellar Atypical Teratoid/Rhabdoid Tumor (AT/RT): A Clinicopathologically and Genetically Distinct Variant of AT/RT. AB - Atypical teratoid/rhabdoid tumors (AT/RTs) are rare aggressive tumors of the central nervous system that predominantly affect infants. Although adult AT/RT are rare, accumulated cases have revealed adult-specific AT/RT in the sellar region. Twelve previously reported cases of sellar AT/RT exclusively occurred in adult females, suggesting biological differences from conventional infant AT/RT. We herein investigated a series of 6 sellar AT/RT for histopathologic features, the molecular status of the INI1/SMARCB1 gene, and clinical courses. All 6 cases were adult females, ranging in age from 21 to 69 years old. Tumors were histologically characterized by a hemangiopericytoma-like stag-horn vasculature within a dense, diffuse proliferation of jumbled cells and a small number of scattered rhabdoid cells. This vascular pattern is not a common finding in AT/RT and appears to be a characteristic histology of sellar AT/RT. Biallelic alterations in the INI1 gene were identified by fluorescence in situ hybridization, direct sequencing, and multiple ligation-dependent probe amplification analyses in 4 of the 5 cases analyzed. Three of the 4 cases harbored 2 different mutations, presumably on different alleles (compound heterozygous mutations), and 1 case of which had a splice-site mutation. Combined with previous findings, the prevalence of compound heterozygous mutations and splice-site mutations was significantly higher in sellar AT/RT than in pediatric AT/RT. Sellar AT/RT represent a clinicopathologically and possibly genetically distinct variant of AT/RT showing a characteristic demography, different patterns of INI1 alterations, and a histology featured by a unique vasculature. PMID- 28338503 TI - Efficacy and Safety of Crystalline Valsartan/Sacubitril (LCZ696) Compared With Placebo and Combinations of Free Valsartan and Sacubitril in Patients With Systolic Hypertension: The RATIO Study. AB - We compared the systolic blood pressure (SBP)-lowering efficacy and safety of crystalline valsartan/sacubitril (LCZ696, an angiotensin receptor blocker neprilysin inhibitor) 400 mg daily against valsartan (320 mg once daily) alone or coadministered with placebo or increasing doses of free sacubitril (50, 100, 200, or 400 mg once daily) to identify the optimal antihypertensive combination dose. This multicenter, double-blinded, 7-arm parallel-group study recruited patients with mild-to-moderate systolic hypertension (office SBP 150-179 mm Hg). Primary dependent variable was change in office SBP from baseline to week 8. At entry (n = 907), mean age was 61.5 years, sitting office BP 160/90.2 mm Hg, and mean 24 hour ambulatory BP 142/82.1 mm Hg; 852 participants completed the study. At week 8, there were greater reductions in sitting office SBP and 24-hour ambulatory SBP with LCZ696 400 mg than with valsartan 320 mg (-5.7 and -3.4 mm Hg, respectively, P < 0.05 each). The SBP reduction with LCZ696 400 daily was similar to coadministered free valsartan 320 mg and sacubitril 200 mg. Effects were similar in those older and younger than 65 years, and active therapies had adverse event rates similar to placebo. We conclude that crystalline valsartan/sacubitril 400 mg daily (1) is superior to valsartan 320 mg daily for lowering SBP, (2) has similar efficacy to the combination of free valsartan 320 mg plus free sacubitril 200 mg, (3) represents the optimal dosage for systolic hypertension in patients of any age, and (4) is safe and well tolerated. PMID- 28338504 TI - Ventilation With High or Low Tidal Volume With PEEP Does Not Influence Lung Function After Spinal Surgery in Prone Position: A Randomized Controlled Trial. AB - BACKGROUND: Spinal surgery in the prone position is accompanied by increased intrathoracic pressure and decreased respiratory compliance. This study investigated whether intraoperative lung protective mechanical ventilation improved lung function evaluated with pulmonary function tests in patients at risk of postoperative pulmonary complications (PPCs) after major spinal surgery in the prone position. METHODS: Seventy-eight patients at potential risk of PPCs were randomly assigned to the protective group (tidal volume; 6 mL/kg predicted body weight, 6 cm H2O positive end-expiratory pressure with recruitment maneuvers) or the conventional group (10 mL/kg predicted body weight, no positive end-expiratory pressure). The primary efficacy variables were assessed by pulmonary function tests, performed before surgery, and 3 and 5 days afterward. RESULTS: Postoperative forced vital capacity (2.17+/-0.1 L vs. 1.91+/-0.1 L, P=0.213) and forced expiratory volume in 1 second (1.73+/-0.08 L vs. 1.59+/-0.08 L, P=0.603) at postoperative day (POD) 3 in the protective and conventional groups, respectively, were similar. Trends of a postoperative decrease in forced vital capacity (P=0.586) and forced expiratory volume in 1 second (P=0.855) were similar between the groups. Perioperative blood-gas analysis variables were comparable between the groups. Patients in the protective and conventional groups showed similar rates of clinically significant PPCs (8% vs. 10%, P>0.999). CONCLUSIONS: In patients at potential risk of developing PPCs undergoing major spinal surgery, we did not find evidence indicating any difference between the lung protective and conventional ventilation in postoperative pulmonary function and oxygenation. PMID- 28338505 TI - Effects of Hypertonic Saline and Sodium Lactate on Cortical Cerebral Microcirculation and Brain Tissue Oxygenation. AB - BACKGROUND: Hyperosmolar solutions have been used in neurosurgery to modify brain bulk. The aim of this animal study was to compare the short-term effects of equivolemic, equiosmolar solutions of hypertonic saline (HTS) and sodium lactate (HTL) on cerebral cortical microcirculation and brain tissue oxygenation in a rabbit craniotomy model. METHODS: Rabbits (weight, 1.5 to 2.0 kg) were anesthetized, ventilated mechanically, and subjected to a craniotomy. The animals were allocated randomly to receive a 3.75 mL/kg intravenous infusion of either 3.2% HTS (group HTS, n=9), half-molar sodium lactate (group HTL, n=10), or normal saline (group C, n=9). Brain tissue partial pressure of oxygen (PbtO2) and microcirculation in the cerebral cortex using sidestream dark-field imaging were evaluated before, 20 and 40 minutes after 15 minutes of hyperosmolar solution infusion. Global hemodynamic data were recorded, and blood samples for laboratory analysis were obtained at the time of sidestream dark-field image recording. RESULTS: No differences in the microcirculatory parameters were observed between the groups before and after the use of osmotherapy. Brain tissue oxygen deteriorated over time in groups C and HTL, this deterioration was not significant in the group HTS. CONCLUSIONS: Our findings suggest that equivolemic, equiosmolar HTS and HTL solutions equally preserve perfusion of cortical brain microcirculation in a rabbit craniotomy model. The use of HTS was better in preventing the worsening of brain tissue oxygen tension. PMID- 28338506 TI - A Preliminary Report: Radical Surgery and Stem Cell Transplantation for the Treatment of Patients With Pancreatic Cancer. AB - We examined the immunologic effects of allogeneic hematopoietic stem cell transplantation (HSCT) in the treatment of pancreatic ductal adenocarcinoma, a deadly disease with a median survival of 24 months for resected tumors and a 5 year survival rate of 6%. After adjuvant chemotherapy, 2 patients with resected pancreatic ductal adenocarcinoma underwent HSCT with HLA-identical sibling donors. Comparable patients who underwent radical surgery, but did not have a donor, served as controls (n=6). Both patients developed humoral and cellular (ie, HLA-A*01:01-restricted) immune responses directed against 2 novel tumor associated antigens (TAAs), INO80E and UCLH3 after HSCT. Both TAAs were highly expressed in the original tumor tissue suggesting that HSCT promoted a clinically relevant, long-lasting cellular immune response. In contrast to untreated controls, who succumbed to progressive disease, both patients are tumor-free 9 years after diagnosis. Radical surgery combined with HSCT may cure pancreatic adenocarcinoma and change the cellular immune repertoire capable of responding to clinically and biologically relevant TAAs. PMID- 28338507 TI - NY-ESO-1 Protein Cancer Vaccine With Poly-ICLC and OK-432: Rapid and Strong Induction of NY-ESO-1-specific Immune Responses by Poly-ICLC. AB - We conducted a clinical trial of a cancer vaccine using NY-ESO-1 protein with polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose (poly-ICLC) and/or OK-432 against solid tumors. A total of 15 patients were sequentially enrolled in 4 cohorts. Patients in cohort 1 received NY-ESO-1 protein; cohort 2a received NY-ESO-1 protein+OK-432; cohort 2b received NY-ESO-1 protein+poly-ICLC; cohort 3 received NY-ESO-1 protein+OK-432+poly-ICLC with Montanide ISA-51. The endpoints of this trial were safety, NY-ESO-1 immune responses, and clinical response. Vaccine-related adverse events observed were fever and injection-site reaction (grade 1). Two patients showed stable disease after vaccination. NY-ESO 1 antibodies were observed in 4 patients at the baseline (sero-positive) and augmented in all patients after vaccination. Eleven patients showed a conversion of negative antibody responses at baseline to positive after vaccination (seroconversion). The seroconversions were observed in all 11 sero-negative patients by the fourth immunization; in particular, it was observed by the second immunization in patients with poly-ICLC, and these induced antibody responses were stronger than those in patients immunized without poly-ICLC. The number of NY-ESO-1-specific interferon (IFN)gamma-producing T cells was increased in patients immunized with poly-ICLC and/or OK-432, and furthermore, the increase of IFNgamma-producing CD8 T cells in patients immunized with poly-ICLC was significantly higher than that in patients without poly-ICLC. Nonspecific activations of T-cell or antigen presenting cells were not observed. Our present study showed that poly-ICLC is a promising adjuvant for cancer vaccines. PMID- 28338508 TI - Autoimmune Frontotemporal Dementia: A New Nosological Entity? PMID- 28338509 TI - Patterns, Timing, and Predictors of Recurrence Following Pancreatectomy for Pancreatic Ductal Adenocarcinoma. AB - OBJECTIVE: To describe accurately the pattern, timing, and predictors of disease recurrence after a potentially curative resection for pancreatic ductal adenocarcinoma (PDAC). SUMMARY BACKGROUND DATA: After surgery for PDAC, most patients will develop disease recurrence. Understanding the patterns and timing of disease failure can help guide improvements in therapy. METHODS: Patients who underwent pancreatectomy for PDAC at the Johns Hopkins Hospital between 2000 and 2010 were included. Exclusion criteria were incomplete follow-up records, follow up <24 months, and neoadjuvant therapy. The first recurrence site was recorded and recurrence-free survival (RFS) was estimated using Kaplan-Meier curves. Predictive factors for specific recurrence patterns were assessed by univariate and multivariate analyses using Cox-proportional hazard regression models. RESULTS: From the identified cohort of 1103 patients, 692 patients had comprehensive and detailed follow-up data available. At a median follow-up of 25.3 months, 531 (76.7%) of the 692 had recurred after a median RFS of 11.7 months. Most patients recurred at isolated distant sites (n = 307, 57.8%), while isolated local recurrence was seen in 126 patients (23.7%). Liver-only recurrence (n = 134, 25.2%) tended to occur early (median 6.9 mo), while lung-only recurrence (n = 78, 14.7%) occurred later (median 18.6 mo). A positive lymph node ratio >0.2 was a strong predictor for all distant disease recurrence. Patients receiving adjuvant chemotherapy or chemoradiotherapy had fewer recurrences and a longer RFS of 18.0 and 17.2 months, respectively. CONCLUSIONS: Specific recurrence locations have different predictive factors and possess distinct RFS curves, supporting the hypothesis that unique biological differences exist among tumors leading to distinct patterns of recurrence. PMID- 28338510 TI - Laparoscopic Lavage Versus Primary Resection for Acute Perforated Diverticulitis: Review and Meta-analysis. AB - OBJECTIVE: To compare clinical outcomes after laparoscopic lavage (LL) or colonic resection (CR) for purulent diverticulitis. BACKGROUND: Laparoscopic lavage has been suggested as an alternative treatment for traditional CR. Comparative studies to date have shown conflicting results. METHODS: Electronic searches of Embase, Medline, Web of Science, and Cochrane databases were performed. Weighted mean differences (WMD) were calculated for effect size of continuous variables and pooled odds ratios (POR) calculated for discrete variables. RESULTS: A total of 589 patients recruited from 3 randomized controlled trials (RCTs) and 4 comparative studies were included; 85% as Hinchey III. LL group had younger patients with higher body mass index and lower ASA grades, but comparable Hinchey classification and previous diverticulitis rates. No significant differences were noted for mortality, 30-day reoperations and unplanned readmissions. LL had higher rates of intraabdominal abscesses (POR = 2.85; 95% confidence interval, CI, 1.52-5.34; P = 0.001), peritonitis (POR = 7.80; 95% CI 2.12-28.69; P = 0.002), and increased long-term emergency reoperations (POR = 3.32; 95% CI 1.73 6.38; P < 0.001). Benefits of LL included shorter operative time, fewer cardiac complications, fewer wound infections, and shorter hospital stay. Overall, 90% had stomas after CR, of whom 74% underwent stoma reversal within 12-months. Approximately, 14% of LL patients required a stoma; 48% obtaining gut continuity within 12-months, whereas 36% underwent elective sigmoidectomy. CONCLUSIONS: The preservation of diseased bowel by LL is associated with approximately 3 times greater risk of persistent peritonitis, intraabdominal abscesses and the need for emergency surgery compared with CR. Future studies should focus on developing composite predictive scores encompassing the wide variation in presentations of diverticulitis and treatment tailored on case-by-case basis. PMID- 28338511 TI - Surgical Performance: A Pathway to Excellence. PMID- 28338512 TI - Ductal Carcinoma Arising in a Largely Unchanged Presumed Branch-duct IPMN After 10 Years of Surveillance. PMID- 28338513 TI - Restrictive Transfusion Practices After Esophagectomy Are Associated With Improved Outcome: A Review of the Society of Thoracic Surgeons General Thoracic Database. AB - OBJECTIVE: Blood transfusion has been associated with poor outcomes in many disciplines, yet transfusion practices and related outcomes in esophagectomy are unknown. We analyzed the Society of Thoracic Surgeons General Thoracic Database to determine patient factors associated with transfusion after esophagectomy, risk-adjusted variation in transfusion practice among institutions, and the association of transfusion practice with mortality. METHODS: We performed a retrospective review of patients undergoing esophagectomy for cancer from October 2008 to December 31, 2014. Patient comorbidities and procedure variables were used to construct a risk model for transfusion. Using this model, each institution was assigned an observed to expected (O:E) transfusion rate. We examined institutional factors associated with variation in O:E transfusion rate. Finally, O:E transfusion rate was compared to risk-adjusted mortality to determine if there was an association of transfusion practice and survival. RESULTS: Seven thousand one hundred thirty-seven patients underwent esophagectomy at 182 institutions during the study period. The median unadjusted transfusion rate was 23.1%. The risk model for transfusion demonstrated patients who received transfusions were more likely to be older, female, and have low preoperative hemoglobin and other comorbidities, such as CAD, COPD, and low creatinine clearance. Patients who received a minimally invasive procedure were less likely to have received a transfusion.After adjusting for the characteristics above, 13 centers (7.1%) were classified as having lower than average O:E transfusion rate and 16 centers (8.7%) were classified as higher than average O:E transfusion rate.Institutions with lower than expected transfusion rates also had lower risk adjusted perioperative mortality than institutions with higher than expected transfusion rates (median [IQR] = 0.90 [0.77-0.94] vs. 0.99 [0.94-1.06], P = 0.028). CONCLUSION: Age, female sex, CAD, COPD, renal insufficiency, and open technique are associated with transfusion after esophagectomy, while tumor stage and preoperative chemoradiation are not. There is wide variation in transfusion practice. Centers with lower than expected transfusion rate also had lower than expected perioperative mortality. At an institutional level, lower transfusion rates are associated with improved outcomes. PMID- 28338514 TI - Are We Ready for Our Close-up?: Why and How We Must Embrace Video in the OR. PMID- 28338515 TI - Surgeon Participation in Early Accountable Care Organizations. AB - OBJECTIVE: We aimed to characterize the landscape of surgeon participation in early accountable care organizations (ACOs) and to identify specialty-, organization-, and market-specific factors associated with ACO participation. BACKGROUND: Despite rapid deployment of alternative payment models (APMs), little is known about the prevalence of surgeon participation, and key drivers behind surgeon participation in APMs. METHODS: Using data from SK&A, a research firm, we evaluated the near universe of US practices to characterize ACO participation among 125,425 US surgeons in 2015. We fit multivariable logistic regression models to characterize key drivers of ACO participation, and more specifically, the interaction between ACO affiliation and organizational structure. RESULTS: Of 125,425 US surgeons, 27,956 (22.3%) participated in at least 1 ACO program in 2015. We observed heterogeneity in participation by subspecialty, with trauma and transplant reporting the highest rate of ACO enrollment (36% for both) and plastic surgeons reporting the lowest (12.9%) followed by ophthalmology (16.0%) and hand (18.6%). Surgeons in group practices and integrated systems were more likely to participate relative to those practicing independently (aOR 1.57, 95% CI 1.50, 1.64; aOR 4.87, 95% CI 4.68, 5.07, respectively). We observed a statistically significant interaction (P <0.001) between surgical specialty and practice organization. Model-derived predicted probabilities revealed that, within each specialty, surgeons in integrated health systems had the highest predicted probabilities of ACO and those practicing independently generally had the lowest. CONCLUSIONS: We observed considerable variation in ACO enrollment among US surgeons, mediated at least in part by differences in practice organization. These data underscore the need for development of frameworks to characterize the strategic advantages and disadvantages associated with APM participation. PMID- 28338516 TI - Importance of Measuring Outcomes After Burns: Why They Matter. PMID- 28338517 TI - Improving Nutritional Support of Burn Service Patients by Increasing the Number of Days When 100% of Prescribed Formula Is Given. AB - The authors sought to increase the number of days when burn service patients receive 100% of prescribed enteral nutrition. The authors first performed a retrospective review of 37 patients (group 1) receiving enteral nutrition. The authors then created and implemented a nurse-directed feeding algorithm, placing patients into three age groups addressing maximum hourly infusion rates, high residual limits, initiating feeding, refeeding residuals, and replacing formula. The authors then performed a prospective review of 37 patients (group 2) fed utilizing the new algorithm. The amount of prescribed, infused, discarded, and missed feeds were recorded, as well as admitting diagnosis, age, gender, length of stay, ventilator days, infections, and mortality. All patients in group 1 (n = 37) received 100% of feeds 59.9% of prescribed days vs 76.5% in group 2 (n = 37; P = .003). Burn patients in group 1 (n = 26) received 100% of feeds 61.6% of prescribed days vs 85.4% in group 2 (n = 21; P < .001). The mean amount of hours tube feeds were held for surgery, procedures, clogged or dislodged tubes, in both historical control and the group using the restorative algorithm were the same. While there was a significant difference in burn size between groups (6.24 vs 18.39%, P = .01), there were no statistically significant differences in length of stay, ventilator days, or mortality. Implementation of a nurse-directed feeding algorithm improved delivery of enteral nutrition for all burn service patients, increasing the number of days when 100% of prescribed enteral nutrition is given. PMID- 28338518 TI - Scar Management Following Burn Injury. AB - At the 2016 State of the Science meeting, clinicians and burn survivors met to discuss the advances in scar prevention, evaluation and treatment. While emerging evidence exists to support pressure garment treatment of scars and the use of silicone gel, further research is necessary to better delineate indications duration and efficacy of established therapies and to develop and test badly needed new treatments. More accurate and objective assessment of burn depth would assist in the prevention and identification of wounds requiring customized surgery. Laser treatment of scar while rapidly gaining popularity, still lacks high quality evidence as to its efficacy. The psychological impact of burn scars on the recovering patient is poorly appreciated and increased interaction with our patients is needed to more fully understand and address the impact on health related quality of life of their burn scars. PMID- 28338519 TI - Incidence of Sinusitis in Burn Victims and Association With Inhalational Injury. AB - The purpose of this study is to determine the incidence of sinusitis in mechanically ventilated burn victims and to examine if the presence of inhalational injury increases the likelihood of developing sinusitis. The authors hypothesize that the incidence of sinusitis will be increased in burn victims who have concomitant inhalational injury. A retrospective chart analysis was performed on all patients who were admitted to the Nathan Speare Regional Burn Treatment Center over a 24-month time frame. Patients who were mechanically ventilated for greater than 24 hours were then selected, resulting in a total of 137 patients for analysis. Multiple variables including number of days on mechanical ventilation, presence of confirmed inhalational injury by bronchoscopy, and method of diagnosis were examined. Of 137 patients, a diagnosis of sinusitis was made in 32 patients (23%). In patients with sinusitis, 87.5% had inhalational injury confirmed with bronchoscopy, compared with only 33.3% of patients without sinusitis (P < .01). Rates of nasotracheal/nasogastric intubation, nasoenteric feeding, and length of mechanical ventilation before sinusitis diagnosis were not significantly different. Patients with sinusitis were found to have suffered inhalational injury at a significantly higher rate than those who did not develop sinusitis. This suggests that inhalational injury is a significant risk factor for developing sinusitis. PMID- 28338521 TI - Ethnicity, lipids and cardiovascular disease. AB - PURPOSE OF REVIEW: The prevalence of cardiovascular disease differs among ethnic groups and along geographic boundaries. At present, most of the projected increase in mortality from cardiovascular disease occurs in sub-Saharan African, Chinese and Southeast Asian populations. Ethnic disparities in the prevalence of cardiovascular disease coincide with quantitative and qualitative differences in risk factors for cardiovascular disease. High plasma cholesterol is one of the most important preventable causes of ischemic heart disease. RECENT FINDINGS: The current review summarizes recent evidence on ethnic differences in ischemic heart disease and its correlates with genetic and acquired differences in plasma lipid and lipoprotein levels. The nature of ethnic differences in plasma lipid levels, apolipoprotein L1 en lipoprotein(a) [Lp(a)] is outlined, and the effects of lipid lowering therapy and future efforts and challenges regarding implementation are discussed. SUMMARY: Ethnic differences in HDL-cholesterol (HDL-C), triglyceride levels and Lp(a) may impact ethnic differences in cardiovascular disease and result in higher residual risk during lipid-lowering therapy. Further efforts should be made to stimulate the use of statins in both high-income and low-income countries and study their effects in individuals with different ethnic backgrounds. PMID- 28338522 TI - Developments in intestinal cholesterol transport and triglyceride absorption. AB - PURPOSE OF REVIEW: To discuss recent advances in research focused on intestinal lipid handling. RECENT FINDINGS: An important strategy in reducing atherosclerosis and risk of cardiovascular events is to increase the rate of reverse cholesterol transport, including its final step; cholesterol excretion from the body. The rate of removal is determined by a complex interplay between the factors involved in regulation of intestinal cholesterol absorption. One of these factors is a process known as transintestinal cholesterol excretion. This pathway comprises transport of cholesterol directly from the blood, through the enterocyte, into the intestinal lumen. In humans, this pathway accounts for 35% of cholesterol excretion in the feces. Mechanistic studies in mice revealed that, activation of the bile acid receptor farnesoid X receptor increases cholesterol removal via the transintestinal cholesterol excretion pathway as well as decreases plasma cholesterol and triglyceride providing an interesting target for treatment of dyslipidemia in humans. The physical chemical properties of bile acids are under control of farnesoid X receptor and determine intestinal cholesterol and triglyceride solubilization as well as absorption, providing a direct link between these two important factors in the pathogenesis of cardiovascular disease. Besides bile acids, intestinal phospholipids are important for luminal lipid solubilization. Interestingly, phospholipid remodeling through LPCAT3 was shown to be pivotal for uptake of fatty acids by enterocytes, which may provide a mechanistic handle for therapeutic intervention. SUMMARY: The importance of the intestine in control of cholesterol and triglyceride homeostasis is increasingly recognized. Recently, novel factors involved in regulation of cholesterol excretion and intestinal triglyceride and fatty acid uptake have been reported and are discussed in this short review. PMID- 28338520 TI - Integration of Single-Center Data-Driven Vital Sign Parameters into a Modified Pediatric Early Warning System. AB - OBJECTIVES: Pediatric early warning systems using expert-derived vital sign parameters demonstrate limited sensitivity and specificity in identifying deterioration. We hypothesized that modified tools using data-driven vital sign parameters would improve the performance of a validated tool. DESIGN: Retrospective case control. SETTING: Quaternary-care children's hospital. PATIENTS: Hospitalized, noncritically ill patients less than 18 years old. Cases were defined as patients who experienced an emergent transfer to an ICU or out-of ICU cardiac arrest. Controls were patients who never required intensive care. Cases and controls were split into training and testing groups. INTERVENTIONS: The Bedside Pediatric Early Warning System was modified by integrating data driven heart rate and respiratory rate parameters (modified Bedside Pediatric Early Warning System 1 and 2). Modified Bedside Pediatric Early Warning System 1 used the 10th and 90th percentiles as normal parameters, whereas modified Bedside Pediatric Early Warning System 2 used fifth and 95th percentiles. MEASUREMENTS AND MAIN RESULTS: The training set consisted of 358 case events and 1,830 controls; the testing set had 331 case events and 1,215 controls. In the sensitivity analysis, 207 of the 331 testing set cases (62.5%) were predicted by the original tool versus 206 (62.2%; p = 0.54) with modified Bedside Pediatric Early Warning System 1 and 191 (57.7%; p < 0.001) with modified Bedside Pediatric Early Warning System 2. For specificity, 1,005 of the 1,215 testing set control patients (82.7%) were identified by original Bedside Pediatric Early Warning System versus 1,013 (83.1%; p = 0.54) with modified Bedside Pediatric Early Warning System 1 and 1,055 (86.8%; p < 0.001) with modified Bedside Pediatric Early Warning System 2. There was no net gain in sensitivity and specificity using either of the modified Bedside Pediatric Early Warning System tools. CONCLUSIONS: Integration of data-driven vital sign parameters into a validated pediatric early warning system did not significantly impact sensitivity or specificity, and all the tools showed lower than desired sensitivity and specificity at a single cutoff point. Future work is needed to develop an objective tool that can more accurately predict pediatric decompensation. PMID- 28338523 TI - Laparoscopic Anatomic Segment 6 Liver Resection Using the Glissonian Approach. AB - INTRODUCTION: Laparoscopic liver resection has become important procedure for malignant liver disease. In this report, we describe the relevant technical maneuvers and perioperative outcomes in laparoscopic anatomic segment 6 liver resection using the Glissonian approach. PATIENTS AND METHODS: From March 2003 and October 2015, 7 patients who diagnosed hepatocellular carcinoma had undergone laparoscopic anatomic segment 6 liver resection at the single institution. We performed retrospective analysis of the clinical and perioperative outcomes of these patients. RESULTS: All patients were men with mean age of 62.3 years (range, 49 to 73 y). The mean operation time was 352.8 minutes (range, 180 to 435 min) and there was no case of open conversion. The mean estimated blood loss was 521.4 mL (range, 200 to 800 mL) and intraoperative transfusion needed in 1 patient. There was no postoperative morbidity and mortality. The mean postoperative hospital stay was 7.5 days (range, 5 to 12 d). All patients obtained negative resection margins. There was no patient had developed tumor recurrence during a median follow-up period of 43 months (range, 7 to 60.7 mo). CONCLUSIONS: Laparoscopic anatomic segment 6 liver resection is a feasible operative procedure, being possible even in patients with limited liver function. PMID- 28338524 TI - Chronic Boutonniere Deformities, Supple, or Stiff: A New Surgical Technique With Early Mobilization in 11 Cases. AB - Injuries to the central slip of the extensor mechanism can lead to a Boutonniere deformity with important functional consequences. We report a series of 11 patients treated by lengthening-dorsalizing the lateral bands and tightening the central slip with early mobilization. The average age of the patients was 42 years (14;52). The extension defect of the proximal interphalangeal (PIP) joint was 64 degrees (80;55) and the hyperextension of the distal interphalangeal joint was 10 degrees (15;5). The surgery was performed with peripheral nerve block (sensitive), allowing dynamic adjustment of the tendinous sutures. With a dorsal incision, a tenolysis of the extensor was performed. The central slip was tightened and the lateral bands dorsalized by cross-stitches over the PIP joint. The active flexion/extension was tested, and then lengthening of the lateral bands by "mesh graft" tenotomy was performed over the second phalange. There was no immobilization. The deformity was improved in 10 patients with a total flexion of the finger. The mean lack of extension in the PIP was 8 degrees (0;20) and the active flexion of the distal interphalangeal joint was 80 degrees (70;85). There was 1 failure. The majority of techniques necessitate an immobilization of 3 to 6 weeks. Our procedure uses the elastic properties of the elongation and allows immediate mobilization. The result can be compromised in case of insufficient tendinous surface or if postoperative instructions are not followed. PMID- 28338525 TI - Orexin action on oxytocin neurons in the paraventricular nucleus of the hypothalamus. AB - Oxytocin neurons in the paraventricular nucleus (PVN) of the hypothalamus play an important role in food intake regulation. It has been shown that the secretion of oxytocin from the hypothalamus shows a diurnal circadian rhythmic pattern and disturbance of this pattern leads to the development of obesity. However, whether oxytocin secretion from the PVN has a diurnal pattern remains unknown. Here, we show that oxytocin secretion from the PVN does have a diurnal pattern and that the terminals of orexin neurons, the neuropeptide responsible for regulating the sleep-wake rhythm, are synapsed with PVN oxytocin neurons. Using transgenic rats selectively expressing monomeric red fluorescent protein 1 in oxytocin neurons, we found that orexin-A inhibits the activities of PVN oxytocin neurons by inhibiting glutamatergic excitatory synaptic input. These data suggest that orexin is a possible candidate to regulate the circadian rhythm of PVN oxytocin neurons. The circadian rhythmic secretion of oxytocin is considered to play an important role in maintaining homeostasis, including body weight regulation. Our present data indicate a possible contribution of orexin toward the development of circadian rhythm in PVN oxytocin neurons. PMID- 28338528 TI - Perceptual, Mechanical And Electromyographic Responses To Different Relative Loads In The Parallel Squat. AB - The effectiveness of the OMNI-RES (0-10) and the electromyographic signal for monitoring changes in the movement velocity was examined during a set to muscular failure using different percentages of one repetition maximum (1RM) in the parallel squat exercise (PSQ). Twelve males (26.3 +/- 5.8 years) were evaluated on eight separate days with 48 hours of rest between sessions. After determining the 1RM value, participants underwent seven tests until achieving muscular failure with the following percentage ranges: 30 to <40%; 40 to <50%, 50 to <60%, 60% to <70%, 70 to <80%, 80 to <90% and >90%. An optical rotary encoder measured mean accelerative velocity (MAV) and the OMNI-RES (0-10) scale was used to express the Rating of Perceived Exertion (RPE) after every repetition of each set. Additionally, the normalized root mean square (RMS) signal of the surface electromyography (N-EMG) was calculated for the vastus medialis muscle. The RPE expressed after the first repetition and when the maximum value of MAV was achieved along the sets was lower (p <0.001, d >0.8) than the RPE that corresponded to a 10% drop in MAV and at failure. Additionally, the initial RPE was useful to distinguish different loading zones by anchoring the OMNI-RES value to the magnitude of the relative load (<60%, 60 to <70% or <= 70% 1RM). Similar patterns were observed using the N-EMG. In conclusion, apart from differentiating between relative loads during a set to failure in the PSQ, the RPE and the N-EMG can both reflect changes associated with the initial, maximal, 10% drop in movement velocity and the muscular failure. PMID- 28338526 TI - Cutaneous Larva Migrans Associated With Loffler's Syndrome in a 6-Year-Old Boy. AB - Cutaneous larva migrans is a frequent dermatologic problem among travelers in tropical areas, but its association with Loffler's syndrome is an extremely rare condition, particularly in children. Here, we describe a 6-year-old boy presenting cutaneous larva migrans associated with Loffler's syndrome. PMID- 28338527 TI - A Slight Smell of Lemon. AB - We present here an example of urine substituted with a yellow cleaning product that leads us to develop the main risks to consider in urine toxicology analysis, ie, adulteration and analytical interferences, and how to deal with them. This grand round highlights the importance of the dialog between the clinician and a TDM consultant for optimal care of the patient. PMID- 28338529 TI - Dosimetry software Hermes Internal Radiation Dosimetry: from quantitative image reconstruction to voxel-level absorbed dose distribution. AB - OBJECTIVE: The aim of this work is to validate a software package called Hermes Internal Radiation Dosimetry (HIRD) for internal dose assessment tailored for clinical practice. The software includes all the necessary steps to perform voxel level absorbed dose calculations including quantitative reconstruction, image coregistration and volume of interest tools. METHODS: The basics of voxel-level dosimetry methods and implementations to HIRD software are reviewed. Then, HIRD is validated using simulated SPECT/CT data and data from Lu-DOTATATE-treated patients by comparing absorbed kidney doses with OLINDA/EXM-based dosimetry. In addition, electron and photon dose components are studied separately in an example patient case. RESULTS: The simulation study showed that HIRD can reproduce time-activity curves accurately and produce absorbed doses with less than 10% error for the kidneys, liver and spleen. From the patient data, the absorbed kidney doses calculated using HIRD and using OLINDA/EXM were highly correlated (Pearson's correlation coefficient, r=0.98). From Bland-Altman plot analysis, an average absorbed dose difference of -2% was found between the methods. In addition, we found that in Lu-DOTATATE-treated patients, photons can contribute over 10% of the kidney's total dose and is partly because of cross irradiation from high-uptake lesions close to the kidneys. CONCLUSION: HIRD is a straightforward voxel-level internal dosimetry software. Its clinical utility was verified with simulated and clinical Lu-DOTATATE-treated patient data. Patient studies also showed that photon contribution towards the total dose can be relatively high and voxel-level dose calculations can be valuable in cases where the target organ is in close proximity to high-uptake organs. PMID- 28338531 TI - Hormonal manipulation with finasteride or oral contraception does not influence incidence of renal cell carcinoma. AB - Androgens have been suspected to be involved in the initiation of renal cell carcinoma because of a two-fold increased risk in men compared with women. To investigate the role of self-reported finasteride or oral contraceptive use in the Prostate, Lung, Colorectal, and Ovarian (PCLO) to determine whether the androgen receptor reduces renal cancer development. We query the PCLO trial for predictor variables from the baseline questionnaire and follow-up questionnaires enquiring medication use, specifically the use of 5-alpha reductase inhibitors (dutasteride or finasteride) and oral contraceptive therapy. The primary outcome of this study was the incidence of renal cancer. Statistical analysis included Student's t-test for continuous variables, chi, or Fisher's exact tests for dichotomous or categorical variables, and multivariable analysis using Cox proportional hazards models. Eight percent (n=6117/73 694) of men in the PCLO trial reported the use of finasteride. 52 (10.6%) of the 492 men diagnosed with renal cancer had self-reported exposure to finasteride and this was not significant in univariable analysis (52/6169; 0.84% vs. 440/66 454; 0.67%, P=0.12) or multivariable main effects analysis (hazard ratio: 1.12; 95% confidence interval: 0.83-1.5; P=0.47). Approximately 54% of women (n=40 997/75 989) in the PCLO trial reported the use of oral contraceptives by questionnaire. 136 (52.1%) of the 261 women diagnosed with renal cancer had self-reported exposure to oral contraceptive therapy and this was not significant in univariable analysis (136/40 997; 0.33% vs. 125/34 992; 0.36%, P=0.36) or in multivariable main effects analysis (hazard ratio: 1.03; 95% confidence interval: 0.97-1.1; P=0.30). Self-reported use of finasteride or oral contraceptives is not associated with a reduced incidence of renal cancer. PMID- 28338530 TI - Pharmacologic characterizations of a P2X7 receptor-specific radioligand, [11C]GSK1482160 for neuroinflammatory response. AB - OBJECTIVE: The P2X7 receptor (P2X7R) is a key regulatory element in the neuroinflammatory cascade that provides a promising target for imaging neuroinflammation. GSK1482160, a P2X7R modulator with nanomolar binding affinity and high selectivity, has been successfully radiolabeled and utilized for imaging P2X7 levels in a mouse model of lipopolysaccharide-induced systemic inflammation. In the current study, we further characterized its binding profile and determined whether [C]GSK1482160 can detect changes in P2X7R expression in a rodent model of multiple sclerosis. METHODS: [C]GSK1482160 was synthesized with high specific activity and high radiochemical purity. Radioligand saturation and competition binding assays were performed for [C]GSK1482160 using HEK293-hP2X7R living cells. Micro-PET studies were carried out in nonhuman primates. In vitro autoradiography and immunohistochemistry studies were then carried out to evaluate tracer uptake and P2X7 expression in experimental autoimmune encephalomyelitis (EAE) rat lumbar spinal cord at EAE-peak and EAE-remitting stages compared with sham rats. RESULTS: [C]GSK1482160 binds to HEK293-hP2X7R living cells with high binding affinity (Kd=5.09+/-0.98 nmol/l, Ki=2.63+/-0.6 nmol/l). Micro-PET studies showed high tracer retention and a homogeneous distribution in the brain of nonhuman primates. In the EAE rat model, tracer uptake of [C]GSK1482160 in rat lumbar spinal cord was the highest at the EAE-peak stage (277.74+/-79.74 PSL/mm), followed by the EAE-remitting stage(149.00+/-54.14 PSL/mm) and sham (66.37+/-1.48 PSL/mm). The tracer uptake correlated strongly with P2X7-positive cell counts, activated microglia numbers, and disease severity. CONCLUSION: We conclude that [C]GSK1482160 has the potential for application in monitoring neuroinflammation. PMID- 28338532 TI - Is severe hypercalcemia immediately life-threatening? AB - OBJECTIVE: Severe hypercalcemia is often considered an emergency because of a potential risk of cardiac arrest or coma. However, there is little evidence to support this. The aim of our study was to assess whether severe hypercalcemia (Ca>4 mmol/l or 16 mg/dl) was associated with immediately life-threatening cardiac arrhythmias or neurological complications in patients admitted to the Emergency Department (ED). METHODS: A retrospective observational study was carried out over a 5-year period (2008-2012). Eligible patients were admitted to the Adult Emergency Department of Nantes University Hospital and had a calcium concentration in excess of 4 mmol/l. There were no exclusion criteria. The primary outcome was the number of life-threatening cardiac arrhythmias and/or neurological complications during the stay in the ED. The secondary outcomes were correlation between calcium concentrations/ECG QTc intervals and mortality. RESULTS: A total of 126 204 adult patients had calcium concentrations measured. Thirty one (0.025%) patients had severe hypercalcemia as defined in our study. The median calcium concentration was 4.3 mmol/l (Q1, 4.2; Q3, 4.7) and the median albumin-adjusted calcium concentration was 4.3 mmol/l (Q1, 4.1; Q3, 4.7). No patient presented with a life-threatening cardiac event during stay in the ED. The median ED stay was 7 h 32 min. One patient presented with a coma of multifactorial origin. There was no correlation between calcemia and QTc intervals (P=0.60). Mortality at 1 year was 55% (17 patients). CONCLUSION: We found no cases of immediately life-threatening cardiac arrhythmias or neurological complications associated with hypercalcemia above 4 mmol/l over a 5 year period in a large tertiary ED. PMID- 28338533 TI - Sepsis patients in the emergency department: stratification using the Clinical Impression Score, Predisposition, Infection, Response and Organ dysfunction score or quick Sequential Organ Failure Assessment score? AB - OBJECTIVE: The aim of this study was to compare the stratification of sepsis patients in the emergency department (ED) for ICU admission and mortality using the Predisposition, Infection, Response and Organ dysfunction (PIRO) and quick Sequential Organ Failure Assessment (qSOFA) scores with clinical judgement assessed by the ED staff. PATIENTS AND METHODS: This was a prospective observational study in the ED of a tertiary care teaching hospital. Adult nontrauma patients with suspected infection and at least two Systemic Inflammatory Response Syndrome criteria were included. The primary outcome was direct ED to ICU admission. The secondary outcomes were in-hospital, 28-day and 6 month mortality, indirect ICU admission and length of stay. Clinical judgement was recorded using the Clinical Impression Scores (CIS), appraised by a nurse and the attending physician. The PIRO and qSOFA scores were calculated from medical records. RESULTS: We included 193 patients: 103 presented with sepsis, 81 with severe sepsis and nine with septic shock. Fifteen patients required direct ICU admission. The CIS scores of nurse [area under the curve (AUC)=0.896] and the attending physician (AUC=0.861), in conjunction with PIRO (AUC=0.876) and qSOFA scores (AUC=0.849), predicted direct ICU admission. The CIS scores did not predict any of the mortality endpoints. The PIRO score predicted in-hospital (AUC=0.764), 28-day (AUC=0.784) and 6-month mortality (AUC=0.695). The qSOFA score also predicted in-hospital (AUC=0.823), 28-day (AUC=0.848) and 6-month mortality (AUC=0.620). CONCLUSION: Clinical judgement is a fast and reliable method to stratify between ICU and general ward admission in ED patients with sepsis. The PIRO and qSOFA scores do not add value to this stratification, but perform better on the prediction of mortality. In sepsis patients, therefore, the principle of 'treat first what kills first' can be supplemented with 'judge first and calculate later'. PMID- 28338534 TI - Management of pediatric head injury: a survey of EuSEM pediatric emergency section. PMID- 28338535 TI - Lung Cancers Associated With Cystic Airspaces: Natural History, Pathologic Correlation, and Mutational Analysis. AB - PURPOSE: The aim of the study was to investigate the natural history of non-small cell lung cancers (NSCLCs) associated with cystic airspaces, including histopathology and molecular analysis. MATERIALS AND METHODS: A total of 34,801 computed tomographic (CT) scans of 2954 patients diagnosed with NSCLC between 2010 and 2015 were evaluated for association with a cystic airspace. Characteristics on serial CT, 18F-fludeoxyglucose positron emission tomography, and pathologic analysis were recorded. RESULTS: Cystic airspaces were associated with 1% of NSCLC cases (12 men and 18 women; median age, 66 y [range, 44 to 87 y]). Of the total number of patients, 97% had a smoking history. Twenty-four adenocarcinomas, 4 squamous cell carcinomas, and 2 poorly differentiated carcinomas were distributed throughout all lobes and were predominantly peripheral. Some cystic airspaces appeared in previously normal lungs, whereas others were preceded by subcentimeter nodules. Twenty of 30 cases demonstrated increased soft tissue due to wall thickening, increased loculations, enlargement and/or increased attenuation of a mural nodule, or replacement by a mass. 18F fludeoxyglucose uptake was present if solid components measured >8 mm. Twenty of 30 patients demonstrated >1 cystic lesion or ground-glass nodule, lymphadenopathy, or evidence of prior lung resection. Pathologic analysis revealed that cystic airspaces correspond to a check-valve mechanism, adenocarcinoma superimposed on emphysema, cystification, and adenocarcinoma parasitizing a preexisting bulla. Fourteen of 26 tumors and 64% of adenocarcinomas tested positive for an alteration of KRAS with or without other alterations. CONCLUSIONS: Cystic airspaces preceded by nodules can evolve into NSCLCs. Wall thickening and/or mural nodularity may develop. Location in the periphery of the upper lobes, emphysema, additional cystic lesions or ground glass nodules, lymphadenopathy, and prior lung cancer should further increase suspicion. Cystic airspaces on CT can be due to a check-valve mechanism obstructing the small airways, lepidic growth of adenocarcinoma in an area of emphysema, cystification of tumor due to degeneration, or adenocarcinoma growing along the wall of a preexisting bulla. KRAS mutations are the predominant genetic alterations. PMID- 28338536 TI - Dual-energy Computed Tomography for the Evaluation of Enhancement of Pulmonary Nodules<=3 cm in Size. AB - PURPOSE: The aim of the study was to compare the accuracies of 4 different methods of assessing pulmonary nodule enhancement to distinguish benign from malignant solid pulmonary nodules using nondynamic contrast-enhanced dual-energy computed tomography. MATERIALS AND METHODS: Seventy-two patients (mean age, 62 y) underwent dual-energy chest computed tomography 3 minutes after intravenous contrast administration. Each of 118 pulmonary nodules (9+/-5.9 mm) were evaluated for enhancement by 4 methods: visual assessment, 3-dimensional automated postprocessing measurement tool, manually drawn region of interest with calculated iodine-related attenuation, and measurement of iodine concentration. The optimal cutoff for enhancement was defined as having the largest specificity among all cutoffs while maintaining 100% sensitivity. Accuracy of the methods was assessed with receiver operating characteristic curves. RESULTS: Ninety-three of 118 pulmonary nodules were benign (79%). Visual assessment of enhancement had sensitivity and specificity of 100% and 44%, respectively. For the automated 3 dimensional measurement tool, 20 HU was found to be the optimal threshold for defining enhancement, resulting in a specificity of 71% and a sensitivity of 100%, as well as an area under the curve (AUC) of 0.87 (95% confidence interval [CI], 0.82-0.92). The AUC was 0.79 (95% CI, 0.73-0.85) for the measured enhancement using a manually drawn region of interest. When a threshold of 21 HU was used for defining enhancement, maximum specificity was obtained (56%) while maintaining 100% sensitivity. The AUC for measured iodine concentration was 0.79 (95% CI, 0.77-0.85). At a cutoff iodine concentration of 0.6 mg/mL, the sensitivity was 100% with a specificity of 57%. CONCLUSIONS: Although use of automated postprocessing had the highest specificity while maintaining 100% sensitivity, there were only minor clinically relevant differences between measurement techniques given that no single technique misclassified a malignant nodule as nonenhancing. PMID- 28338537 TI - Allergenic Ingredients in Personal Hygiene Wet Wipes. AB - BACKGROUND: Wet wipes are a significant allergen source for anogenital allergic contact dermatitis. OBJECTIVE: The aim of the study was to calculate the frequency of potentially allergenic ingredients in personal hygiene wet wipes. METHODS: Ingredient lists from brand name and generic personal hygiene wet wipes from 4 large retailers were compiled. RESULTS: In the 54 personal hygiene wet wipes evaluated, a total of 132 ingredients were identified (average of 11.9 ingredients per wipe). The most common ingredients were Aloe barbadensis (77.8%), citric acid (77.8%), fragrance (72.2%), sorbic acid derivatives (63.0%), tocopherol derivatives (63.0%), glycerin (59.3%), phenoxyethanol (55.6%), disodium cocoamphodiacetate (53.7%), disodium ethylenediaminetetraacetic acid (EDTA) (42.6%), propylene glycol (42.6%), iodopropynyl butylcarbamate (40.7%), chamomile extracts (38.9%), sodium benzoate (35.2%), bronopol (22.2%), sodium citrate (22.2%), lanolin derivatives (20.4%), parabens (20.4%), polyethylene glycol derivatives (18.5%), disodium phosphate (16.7%), dimethylol dimethyl hydantoin (DMDM) (14.8%), and cocamidopropyl propylene glycol (PG)-dimonium chloride phosphate (11.1%). Of note, methylisothiazolinone (5.6%) was uncommon; methylchloroisothiazolinone was not identified in the personal hygiene wet wipes examined. CONCLUSIONS: There are many potential allergens in personal hygiene wet wipes, especially fragrance and preservatives. PMID- 28338538 TI - Allergenic Ingredients in Facial Wet Wipes. AB - BACKGROUND: Allergic contact dermatitis commonly occurs on the face. Facial cleansing wipes may be an underrecognized source of allergens. OBJECTIVE: The aim of this study was to determine the frequency of potentially allergenic ingredients in facial wet wipes. METHODS: Ingredient lists from name brand and generic facial wipes from 4 large retailers were analyzed. RESULTS: In the 178 facial wipes examined, a total of 485 ingredients were identified (average, 16.7 ingredients per wipe). Excluding botanicals, the top 15 potentially allergenic ingredients were glycerin (64.0%), fragrance (63.5%), phenoxyethanol (53.9%), citric acid (51.1%), disodium EDTA (44.4%), sorbic acid derivatives (39.3%), tocopherol derivatives (38.8%), polyethylene glycol derivatives (32.6%), glyceryl stearate (31.5%), sodium citrate (29.8%), glucosides (27.5%), cetearyl alcohol (25.8%), propylene glycol (25.3%), sodium benzoate (24.2%), and ceteareth-20 (23.6%)/parabens (23.6%). Of note, methylisothiazolinone (2.2%) and methylchloroisothiazolinone (1.1%) were uncommon. The top potential allergens of botanical origin included Aloe barbadensis (41.0%), chamomile extracts (27.0%), tea extracts (21.3%), Cucumis sativus (20.2%), and Hamamelis virginiana (10.7%). CONCLUSIONS: Many potential allergens are present in facial wet wipes, including fragrances, preservatives, botanicals, glucosides, and propylene glycol. PMID- 28338540 TI - Occupational Contact Dermatitis in North American Print Machine Operators Referred for Patch Testing: Retrospective Analysis of Cross-Sectional Data From the North American Contact Dermatitis Group 1998 to 2014. AB - BACKGROUND: Little is known about the epidemiology of contact dermatitis (CD) in print machine operators (PMOs). OBJECTIVE: The aims of this study were to estimate the prevalence of CD and characterize clinically relevant and occupationally related allergens among PMOs undergoing patch testing. METHODS: This was a retrospective cross-sectional analysis of the North American Contact Dermatitis Group data from 1998 to 2014. RESULTS: Of 39,332 patch-tested patients, 132 (0.3%) were PMOs. Among PMOs, most were male (75.0%) and white (92.4%). The majority were printing press operators (85.6%). The most frequent sites of dermatitis were hands (63.6%), arms (29.5%), and face/scalp (24.2%). More than half had an occupationally related skin condition (56.1%). Final diagnoses were most commonly allergic CD (58.3%) and irritant CD (33.3%). Cobalt (20.8%), carba mix (12.5%), thiuram mix (8.3%), and formaldehyde (8.3%) were the most frequent occupationally related allergens. The top allergen sources included inks (22.9%), gloves (20.8%), and coatings/dye/copy/photographic chemicals (14.6%). CONCLUSIONS: Allergic CD, irritant CD, and involvement of exposed body areas were common among PMOs. Common allergens included rubber accelerators, metals, and preservatives. PMID- 28338541 TI - Intralesional Treatment With 5-Fluorouracil and Steroid Improves Allergic Contact Dermatitis Without Causing Skin Atrophy and Rebound Lesions. PMID- 28338542 TI - Multicenter Patch Testing With Methylisothiazolinone and Methylchloroisothiazolinone/Methylisothiazolinone Within the International Contact Dermatitis Research Group. AB - BACKGROUND: The preservatives methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) and MI are well-known contact sensitizers. Recently, an increase in the contact allergy frequency for MI 0.2% aqueous (aq) has been seen in many European countries paralleled with an increase in MCI/MI allergy. Many of the MI-allergic patients do not react to MCI/MI 0.01% or 0.02% because the concentration of MI in these preparations is too low (25 and 50 ppm, respectively) to elicit a positive patch test reaction. OBJECTIVES: The aims of this study were to investigate the prevalence of contact allergy to MI in the participating clinics representing various countries all over the world, to assess how many additional individuals with contact allergy are found by testing MI 0.2% aq in parallel with MCI/MI 0.02%, and to assess the clinical relevance of MI and MCI/MI allergies. PATIENTS AND METHODS: In 9 dermatology clinics representing 9 countries, 3865 consecutive patients with dermatitis were patch tested with MI 0.2% aq and in parallel with MCI/MI 0.02% aq, provisionally included into the baseline series. An assessment of clinical relevance in those allergic to MI was also made. RESULTS: Contact allergy to MI was found in 284 patients (7.3%). The frequency of contact allergy varied from 0.8% to 10.9% in different centers. Simultaneous reactivity to 200 ppm of MCI/MI was found in 67.3% of the MI-positive patients. Contact allergy to MI alone without any simultaneous contact allergy to 200 ppm of MCI/MI was diagnosed in 93 patients (32.7%; 2.4% of all tested patients). The contact allergy to MI and/or MCI/MI could explain or contribute to dermatitis in more than 60% of the MI-allergic patients. CONCLUSIONS: Methylisothiazolinone of 2000 ppm needs to be patch tested on its own to not miss contact allergy. PMID- 28338543 TI - Perianal Dermatitis. AB - BACKGROUND: Perianal complaints are often consulted in dermatology clinics, and in many cases, a conclusive diagnosis is not easily made. OBJECTIVE: The aim of this study was to study and identify the epidemiological, clinical, and contact allergy features of patients with perianal dermatitis who attended at a contact dermatitis unit in a tertiary hospital in Spain. METHODS: Adult patients with long-lasting (>4 weeks) perianal dermatitis were recruited during the past 10 years for investigation and follow-up. Every patient underwent a diagnostic workup consisting of dermatological exploration and patch tests with the standard and specific series, as well as the patients' own products. General surgical exploration was also performed in some patients. RESULTS: One hundred twenty-four patients were included. The MOAHLFA index was as follows: 43.5, 0, 4.8, 11.3, 1.6, 8.1, and 75. The main final diagnoses were allergic contact dermatitis (32.3%), psoriasis (24.2%), irritant contact dermatitis (17.7%), and lichen simplex (neurodermatitis) (10%). Eighty-one patients (66.1%) showed 1 or more positive reactions, and in 52 patients (43%), positive reactions relevant to the present disease were found. CONCLUSIONS: Contact allergy in patients with long lasting perianal complaints is frequent. It is mandatory for these patients to be referred to a dermatologist for an adequate evaluation and patch testing. Methylchloroisothiazolinone/methylisothiazolinone seems as the most common allergen implicated in perianal contact dermatitis. PMID- 28338544 TI - Associations Between Medication Class and Subsequent Augmentation of Depression Treatment in Privately Insured US Adults. AB - IMPORTANCE: Treatment augmentation is an important clinical decision in the pharmacotherapy for depression, yet few studies have examined the rates of treatment augmentation by medication class. OBJECTIVE: The aim of this study was to examine which initial pharmacotherapies for depression are more likely than others to result in subsequent treatment augmentation. METHODS: This study is a retrospective cohort analysis of administrative data of 214,705 privately insured US adults between the age of 18 and 64 years who were diagnosed with a new episode of depression in 2009. Propensity score-adjusted logistic regression and Cox regression were used to model the effect of the class of initial monotherapy on treatment augmentation. Risk adjustors included depression severity, comorbidities, provider type, insurance, and demographic characteristics. EXPOSURE: The class of initial monotherapy and the health care provider type were the main independent variables of interest. MAIN OUTCOME: The outcome was the augmentation of monotherapy. RESULTS: Thirty-four percent of individuals received treatment augmentation. Compared with selective serotonin reuptake inhibitor monotherapy, second-generation antipsychotics as the initial treatment were associated with significant increase in the likelihood of augmentation compared with the other classes (hazards ratio, 2.59; 95% confidence interval [CI], 2.51 2.68). This result was corroborated after propensity score adjustment (odds ratio, 2.85; 95% CI, 2.70-3.00) when comparing second-generation antipsychotics to the other classes of pharmacotherapy. The other significant predictor of treatment augmentation was the provider type. Mental health specialists were 27% more likely to augment a treatment compared with generalists (hazards ratio, 1.27; 95% CI, 1.25-1.30). CONCLUSIONS: The type of initial antidepressant therapy is associated with the chances of treatment augmentation. Second-generation antipsychotics progressed to augmentation more rapidly than the other classes. PMID- 28338545 TI - Risperidone and Cardiometabolic Risk in Children and Adolescents: Clinical and Instrumental Issues. AB - PURPOSE/BACKGROUND: Although second-generation antipsychotics are used to treat and manage symptoms for several psychiatric disorders, data about their adverse effects in developmental age are limited. The aim of this prospective observational study was to verify the cardiovascular and metabolic risk in a sample of antipsychotic-naive children/adolescent patients starting risperidone therapy. METHODS: Twenty-two patients, younger than 18 years, were recruited. The assessment included anthropometric data, cardiovascular parameters, blood tests, and ultrasonographic abdominal study. RESULTS: After an average follow-up period of 7.6 months, statistically significant increases in mean values of waist circumference, body mass index (BMI), BMI percentile, BMI z score, total cholesterol, and prolactin were found. Other cardiometabolic parameters showed an upward trend in time. Subjects in pubertal/postpubertal stage and female patients were more susceptible to developing cardiometabolic changes. Moreover, significant correlations between changes in anthropometric and several metabolic parameters were found. A tendency to change in constitution of the liver parenchyma and distribution of the abdominal fat mass with ultrasonographic abdominal study was also evident. CONCLUSIONS: In our sample, several metabolic parameters showed a sensitivity to risperidone treatment. Because most of these parameters are age dependent, metabolic syndrome criteria used for adults were inappropriate in children and adolescents. Periodic clinical and instrumental evaluations and guidelines for monitoring of any metabolic, laboratory, and instrumental complications are necessary in the perspective of even long-time second-generation antipsychotics treatment in children and adolescents. PMID- 28338547 TI - Satisfaction With Methadone and Opioid Receptor Genes Polymorphisms in Treatment Refractory Heroin-Dependent Patients. PMID- 28338546 TI - A Double-Blind, Placebo-Controlled, Pilot Study of Riluzole Monotherapy for Acute Bipolar Depression. AB - BACKGROUND: Glutamatergic system abnormalities are implicated in the pathophysiology and treatment of both major depressive disorder and bipolar depression (BDep). Subsequent to studies demonstrating the rapid and robust antidepressant effects of ketamine, an N-methyl-D-aspartate receptor antagonist, other glutamatergic modulators are now being studied in clinical trials of mood disorders. A previous open-label study found that riluzole, administered in combination with the mood stabilizer lithium, had antidepressant effects. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of riluzole monotherapy for the treatment of BDep. Nineteen subjects aged 18 to 70 years with bipolar disorder currently experiencing a depressive episode were tapered off of excluded medications and randomized to receive riluzole (50-200 mg/d) or placebo for 8 weeks. Rating scale scores (Montgomery-Asberg Depression Rating Scale, Hamilton Rating Scale for Depression, Hamilton Rating Scale for Anxiety, and Young Mania Rating Scale) were obtained weekly. RESULTS: No significant differences in depressive symptoms were observed between subjects treated with riluzole and those receiving placebo (P = 0.12). Anxiety scores were significantly lower in the placebo group (P = 0.046). An interim analysis was conducted that resulted in stopping the study because of futility; no subjects had achieved treatment response. CONCLUSIONS: Although we found no change in severity of depressive symptoms in BDep patients receiving riluzole compared with placebo, this trial was limited by the relatively high number of subject withdrawals and the small sample size. Thus, while riluzole monotherapy did not demonstrate efficacy for BDep, further studies examining riluzole as adjunctive therapy for this disorder may be warranted.Clinical Trials Identifier NCT00054704. PMID- 28338548 TI - Lipophilic beta-Blockers and Suicide in the Elderly. PMID- 28338549 TI - Reply to Comments by Drs Glue and Menkes. PMID- 28338550 TI - Respiratory System Function in Patients After Minimally Invasive Aortic Valve Replacement Surgery: A Case Control Study. AB - OBJECTIVE: The aim of the study was to comparatively analyze respiratory system function after minimally invasive, through right minithoracotomy aortic valve replacement (RT-AVR) to conventional AVR. METHODS: Analysis of 201 patients scheduled for RT-AVR and 316 for AVR between January 2010 and November 2013. Complications of the respiratory system and pulmonary functional status are presented. RESULTS: Complications of the respiratory system occurred in 16.8% of AVR and 11.0% of RT-AVR patients (P = 0.067). The rate of pleural effusions, thoracenteses, pneumonias, or phrenic nerve dysfunctions was not significantly different between groups. Perioperative mortality was 1.9% in AVR and 1.0% in RT AVR (P = 0.417). Mechanical ventilation time after surgery was 9.7 +/- 5.9 hours for AVR and 7.2 +/- 3.2 hours for RT-AVR patients (P < 0.001). Stroke (odds ratio [OR] = 13.4, P = 0.008), increased postoperative blood loss (OR = 9.6, P < 0.001), and chronic obstructive pulmonary disease (OR = 7.7, P < 0.001) were risk factors of prolonged mechanical lung ventilation. A week after surgery, the results of most pulmonary function tests were lower in the AVR than in the RT-AVR group (P < 0.001 was seen for forced expiratory volume in the first second, vital capacity, total lung capacity, maximum inspiratory pressure and maximum expiratory pressure, P = 0.377 was seen for residual volume). CONCLUSIONS: Right anterior aortic valve replacement minithoracotomy surgery with single-lung ventilation did not result in increased rate of respiratory system complications. Spirometry examinations revealed that pulmonary functional status was more impaired after AVR in comparison with RT-AVR surgery. PMID- 28338551 TI - Standardizing Robotic Lobectomy: Feasibility and Safety in 128 Consecutive Lobectomies Within a Single Healthcare System. AB - OBJECTIVE: Single-surgeon cohorts assessing robotically assisted video-assisted thoracic (RA-VATS) lobectomy have reported good outcomes, but there are little data regarding multiple surgeons applying a standard technique in separate hospitals. The purpose of this study was to show how a standardized robotic technique is both safe and reproducible between surgeons and institutions. METHODS: From July 1, 2012, to October 1, 2013, patients undergoing RA-VATS lobectomy for both benign and malignant disease were identified from a prospectively collected database of two thoracic surgeons from different hospitals within the same healthcare system and retrospectively analyzed. Each surgeon employed an identical "rule of 10" completely port-based approach through all 128 cases. The primary end points of the study were in-hospital and 30-day mortality. Secondary end points were differences in morbidity and perioperative outcomes between the two surgeons based on their "rule of 10" technique. RESULTS: A total of 128 cases were performed with 121 lobectomies, 3 bilobectomies, and 4 pneumonectomies for both malignant and benign disease. Each surgeon had 64 cases without a single in-hospital or 30-day mortality. Overall morbidity was 16.4%. Each surgeon had one readmission and take back to operating room (a washout and a mechanical pleurodesis). The most common complication was prolonged air leak (38.1%, 8/21 patients). There was no statistical difference in length of stay, complications, severity of illness, and clinical staging between the two surgeons. There was a significant difference in resected lymph nodes (11.79 vs 14.45, P = 0.0086). Compared with published national meta-analysis on RA-VAT lobectomies, there was a significantly reduced length of stay (4.2 vs 6 days, P = 0.0436) and bleeding (0.8 vs 1.8%, P = 0.0003). Nodal upstaging from cN0 to pN1 was 8% and cN0 to pN2 was 2% for an overall nodal upstaging of 10% for stage I nonsmall cell lung cancer. CONCLUSIONS: By standardizing how a robotic lobectomy is performed, we were able to show that RA-VATS lobectomy is safe and may allow for the expansion of minimally invasive lobectomy to surgeons who otherwise have failed to adopt traditional VATS. When compared with the most recent national meta-analysis, we had reduced morbidity, mortality, bleeding, and length of stay. Robotic nodal upstaging for stage I nonsmall lung cancer was consistent with larger multicenter study. We hope that these results will help lead to the standardization robotic lobectomy and a larger multisurgeon/institutional study that could pave the way for greater adoption of minimally invasive lobectomy. PMID- 28338553 TI - Consequences of Hybrid Procedure Addition to Robotic-Assisted Direct Coronary Artery Bypass. AB - OBJECTIVE: Patients postcoronary artery revascularization surgery often receives blood product transfusion, which could delay their intensive care unit and hospital discharge. We investigated our robotic-assisted direct coronary artery bypass (RADCAB) transfusion rate to determine whether performing the minimal invasive coronary surgery with percutaneous coronary intervention in one stage would increase the incidence of blood transfusion, morbidity, and length of stay. METHODS: Between November 2003 and November 2015, 483 consecutive patients underwent RADCAB surgery. They were divided into two groups. Group 1 (147 patients; mean +/- SD age, 61.2 +/- 11 years; 23% females) underwent robotic assisted hybrid coronary artery revascularization with left internal thoracic artery to the left anterior descending coronary artery with percutaneous coronary intervention to a nonleft anterior descending coronary artery vessel in the same stage. Group 2 (336 patients; mean +/- SD age, 61.2 +/- 10.5 years; 25% females) underwent nonhybrid RADCAB. Early and late postoperative follow-up at mean +/- SD of 83.6 +/- 11.1 months was obtained. RESULTS: Blood transfusion rate in group 1 was statistically different, as illustrated in Table 2. Based on the intraoperative cardiac catheterization, the incidence of graft revision was higher in the nonhybrid group. There was no difference between the two groups in terms of renal failure, neurological complication, prolonged mechanical ventilation, and gastrointestinal bleed. CONCLUSIONS: Despite similar preoperative demographics in the two groups, we have observed a significant difference in the blood transfusion rate in group 1. However, this did not lead into a statistically significant re-exploration rate for bleeding. Hence, we assume that dual antiplatelet therapy usage in the hybrid group might be the cause of the increase in blood transfusion rate. Nevertheless, it did not affect postoperative morbidity and length of hospital stay. A randomized multicenter clinical trial is needed. PMID- 28338552 TI - Is the Future of Coronary Arterial Revascularization a Hybrid Approach?: The Canadian Experience Across Three Centers. AB - OBJECTIVE: Hybrid coronary revascularization offers and combines the advantages of both surgical and percutaneous revascularization and eliminates at the same time the disadvantages of both procedures. The objective of this study was to assess graft and stent patency at 6 months, rate of bleeding, intensive care unit and hospital stay, rate of reintervention, and long-term clinical follow-up. METHODS: From March 2004 to November 2015, a total of 203 patients underwent robotic-assisted minimally invasive direct coronary artery bypass graft of the left internal thoracic artery to the left anterior descending artery and PCI of a non-left anterior descending vessel in a single or two stage, at three different centers. Patients underwent 6-month angiographic follow-up. The mean +/- SD clinical follow-up was 77.82 +/- 41.4 months. RESULTS: Successful hybrid coronary revascularization occurred in 196 of the 203 patients. One hundred forty-six patients underwent simultaneous surgical and percutaneous intervention. Nineteen patients underwent PCI before surgery, and 38 patient underwent PCI after surgery. No in-hospital mortality occurred. The mean +/- SD ICU stay was 1 +/- 1 days and the mean +/- SD hospital stay was 5 +/- 2 days. Only 13.3% of the patients required a blood transfusion. Six-month angiographic follow-up has been performed in the 95 patients, and it demonstrated a left internal thoracic artery anastomotic patency of 97.9% and stent patency of 92.6%. A total of 77.8 +/- 41.4 month clinical follow-up demonstrated 95.1% survival, 92.6% freedom from angina, and 90.7% freedom from any form of coronary revascularization. CONCLUSIONS: Hybrid coronary revascularization seems to be a promising and safe revascularization strategy. It provides selected patients with an alternative, functionally complete revascularization with minimal surgical trauma and good long-term clinical outcomes. PMID- 28338554 TI - Eligibility for Minimally Invasive Coronary Artery Bypass: Examination of Epicardial Adipose Tissue Using Computed Tomography. AB - OBJECTIVE: A variable that necessitates conversion to a conventional full sternotomy coronary artery bypass procedure from a robotic-assisted endoscopic single-vessel small thoracotomy is the inability to visualize the left anterior descending coronary artery within the surrounding epicardial adipose tissue using the endoscopic camera. The purpose of this study was to determine whether anatomical properties of the epicardial adipose tissue examined using preoperative computed tomography (CT) images are able to predict and thus reduce the need for intraoperative conversion based on effective preoperative exclusion criteria. METHODS: Retrospective analysis of patient preoperative CT angiography scans from both converted (n = 17) and successful robotic-assisted (n = 17) procedures was performed. Where possible, measurements of epicardial adipose tissue were acquired from axial slices, at the most accessible segment of the left anterior descending coronary artery. RESULTS: Results indicate that patients who successfully underwent the endoscopic single-vessel small thoracotomy procedure (mean +/- SD depth, 4.9 +/- 1.9 mm) had significantly less epicardial adipose tissue (38%, P = 0.002) overlying the vessel toward the lateral chest wall than those who were converted to the full-sternotomy approach intraoperatively (mean +/- SD depth, 7.9 +/- 3.2 mm). Using this as a retrospective exclusion criterion reduces the conversion rate for this group by 47%, while maintaining a high specificity (94%). No significant differences exist between the two groups with respect to the remaining epicardial adipose tissue measurements or body mass index. CONCLUSIONS: The addition of CT angiography measurements of the epicardial adipose tissue overlying the left anterior descending coronary artery may enhance preoperative surgical planning for this procedure, thereby reducing the instances of procedural changes. PMID- 28338555 TI - RETINAL DETACHMENT AND RETROBULBAR CYSTS IN A LARGE COHORT OF OPTIC NERVE COLOBOMA. AB - PURPOSE: To examine the relationship between retinal detachment and retrobulbar cysts in patients with optic nerve coloboma (ONC) and Morning Glory syndrome (MGS). METHODS: Patients diagnosed with either ONC or MGS were identified through a search of the Sick Kids database. Seventy-one patients either agreed to come in for a B-scan or had an incidental orbital B-scan or magnetic resonance imaging or both. Eyes with orbital B-scan ultrasound and/or magnetic resonance imaging images were assessed independently by two ophthalmologists and a radiologist for the presence of retrobulbar cysts. Retinal detachment was identified clinically with either indirect ophthalmoscopy or from fundus photographs. RESULTS: Forty five of 71 (63%) and 26/71 (37%) patients had ONC and MGS, respectively. Retinal detachment occurred significantly more often in eyes with MGS than with ONC (9/17 [53%] vs. 5/45 [11%], P = 0.03, respectively). Retrobulbar cysts were not detected more often in MGS than in ONC (11/45 [24%] vs. 7/26 [27%]; P = 1.0). Eyes with retrobulbar cysts were significantly more likely to be associated with retinal detachment than those without (7/18 [39%] vs. 7/53 [13%]; P = 0.04). CONCLUSION: Retinal detachment occurs more frequently in MGS than in ONC in a cohort of patients referred to a specialist children's retinal service. Eyes with retrobulbar cysts are more likely to be associated with retinal detachment. PMID- 28338556 TI - ADULT-ONSET FOVEOMACULAR VITELLIFORM DYSTROPHY EVALUATED BY MEANS OF OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY: A Comparison With Dry Age-Related Macular Degeneration and Healthy Eyes. AB - PURPOSE: To investigate alterations of superficial and deep retinal vascular densities, as well as of choroidal thickness, in patients affected by adult-onset foveomacular vitelliform dystrophy (AOFVD). METHODS: A total of 22 eyes (15 patients) affected by AOFVD were recruited in the study. Furthermore, 20 eyes of 20 healthy subjects and 20 eyes of 18 patients affected by intermediate dry age related macular degeneration (AMD) were enrolled. All patients underwent a complete ophthalmologic examination, including optical coherence tomography angiography. Outcome measures were superficial vessel density, deep vessel density, and choroidal thickness. RESULTS: Parafoveal superficial vessel density was increased in patients with AOFVD compared with the AMD group (50.6 +/- 4.3% and 46.3 +/- 4.3%, respectively, P = 0.016). Parafoveal deep vessel density was 57.9 +/- 6.4% in patients with AOFVD, 52.2 +/- 3.8% in patients with AMD, and 52.7 +/- 6.0% in healthy controls (P = 0.006 and P = 0.035, respectively, after comparison with the AOFVD group). CONCLUSION: We demonstrated that both superficial and deep vessel densities were significantly increased in patients with AOFVD, after the comparison with intermediate patients with AMD. These findings suggest that the pathogenic mechanisms in AOFVD are different from those in AMD and that optical coherence tomography angiography could be useful in differentiate early stages of these two diseases. PMID- 28338557 TI - RUTHENIUM-106 BRACHYTHERAPY IN THE TREATMENT OF CIRCUMSCRIBED CHOROIDAL HEMANGIOMA. AB - PURPOSE: To examine the efficacy and safety of Ruthenium-106 plaque radiotherapy in the treatment of circumscribed choroidal hemangioma. METHODS: Twenty-one eyes of 21 patients diagnosed with symptomatic circumscribed choroidal hemangioma who underwent Ruthenium-106 plaque radiotherapy were included in the study. Clinical response, ancillary tests finding improvement, and major side effects were evaluated. RESULTS: From the initial to the 1-year follow-up visits, vision improved in 12 eyes (57%), was stable in 7 eyes (33%), and became worse in 2 eyes (10%). Based on fluorescein angiography and optical coherence tomography, subretinal fluid and cystoid macular edema resolved in all patients. Changes in logarithm of minimum angle of resolution visual acuity (P = 0.038); tumor thickness (P = 0.0001) and largest diameter (P = 0.007) on ultrasonography; and subfoveal thickness on optical coherence tomography (P < 0.0001), were statistically significant between the initial and the 1-year follow-up visits. Side effects as observed during the follow-up period included: radiation-related retinopathy in 5 (24%) eyes, radiation-related papillopathy in 1 eye (5%), and subretinal fibrosis in 2 eyes (10%). Subretinal fibrosis was the only permanent radiation-related side effect. CONCLUSION: Ruthenium-106 plaque radiotherapy is an effective and safe method of treatment for symptomatic circumscribed choroidal hemangiomas. The incidence of permanent visual loss is low with prompt treatment of complications. PMID- 28338558 TI - CORRELATION BETWEEN CENTRAL FOVEAL THICKNESS AND VISUAL ACUITY IN PATIENTS WITH IDIOPATHIC VITREOMACULAR TRACTION. AB - PURPOSE: To evaluate the impact of preoperative central foveal thickness (CFT) on visual acuity after surgery in patients with idiopathic vitreomacular traction and to calculate a cut-off value in preoperative CFT. METHODS: Thirty-five patients with idiopathic vitreomacular traction were evaluated retrospectively. A complete ophthalmological examination including spectral domain optical coherence tomography was performed preoperatively and at 12 months after the surgery. Receiver operating characteristic analysis was used to determine the critical point for the CFT associated with improvement of 10 or more letters in visual acuity on the Early Treatment Diabetic Retinopathy Study. RESULTS: Among 35 patients, the mean CFT at postoperative 12 months was significantly decreased from baseline (P = 0.001). Preoperative CFT and visual improvement were not significantly correlated (r = -0.090, P = 0.605), whereas preoperative CFT and preoperative visual acuity were significantly correlated (r = 0.757, P < 0.001). Improvement in CFT and visual improvement were also correlated significantly (r = 0.449, P = 0.007). According to the receiver operating characteristic analysis, the threshold CFT was 471 MUm. When 15 patients with CFT thickness under 471 MUm were evaluated, preoperative CFT was significantly correlated with improvement in visual acuity after the surgery (r = 0.561, P = 0.030). CONCLUSION: Preoperative CFT is important for the visual prognosis of patients with vitreomacular traction. Preoperative CFT of these patients should be considered in surgical decisions. PMID- 28338561 TI - Making Eye Health a Population Imperative: A Question of Priorities. PMID- 28338560 TI - Reply. PMID- 28338562 TI - Making Eye Health a Population Imperative: A Vision for Tomorrow-A Report by the Committee on Public Health Approaches to Reduce Vision Impairment and Promote Eye Health. PMID- 28338559 TI - Emerging Worldwide Antimicrobial Resistance, Antibiotic Stewardship and Alternative Intravitreal Agents for the Treatment of Endophthalmitis. PMID- 28338563 TI - Making Eye Health a Population Imperative: Putting Plans into Action. PMID- 28338564 TI - Studying the Retinal Source of Photophobia by Facial Electroretinography. AB - PURPOSE: Photophobia is a debilitating clinical condition that disrupts the ability to use vision for everyday tasks in bright lighting conditions. The goal of the study is to develop a methodology to study the neural basis of photophobia and the contribution of the melanopic pathway to its etiology with differential chromatic responses by means of standard electroencephalographic recording equipment. METHODS: We introduce and validate the approach of recording wavelength-specific electroretinographic (ERG) responses from the face electrodes of the high-density whole-head electroencephalography recording system under light-adapted conditions. RESULTS: ERGs recorded in this way to whole-field chromatic stimuli exhibit striking differences between the photophobic and non photophobic groups. The control responses were consistent with photopic intensity in peak time, and in the ordering of peak times as a function of wavelength condition, indicating a predominantly cone source of the signals. The photophobic responses, on the other hand, were substantially slowed relative to controls, with the peak times conforming to a different order as a function of wavelength condition than controls, implying that the cone response has been suppressed and that the responses derived from a different photoreceptor system consistent with mediation by melanopic retinal ganglion cells. CONCLUSIONS: The results will be important for determining the neural pathways involved in photophobia and potential approaches to its treatment on the basis of this etiology. PMID- 28338565 TI - Corneal Nerve Morphology, Sensitivity, and Tear Neuropeptides in Contact Lens Wear. AB - PURPOSE: To determine tear neuropeptide levels in contact lens wearers and non wearers, and to examine relationships with indices of corneal innervation, tear function, and ocular discomfort. METHODS: A cross-sectional, single-visit, investigator-masked pilot study. Assessments included Ocular Comfort Index (OCI), central and mid-peripheral corneal nerve density and morphology (HRT-Rostock), corneal sensitivity (Cochet-Bonnet aesthesiometer), tear Substance P and calcitonin gene-related peptide (CGRP) concentration (ELISA), in situ tear osmolarity (TearLab), tear secretion (Phenol Red Thread), and noninvasive tear break-up time (NITBUT; Keeler Tearscope). Groups were compared using independent t-test or Mann-Whitney U test, and regional differences assessed using paired t tests. Associations were analyzed using Pearson or Spearman correlation. Significance was determined at P < .05. RESULTS: Twenty contact lens wearers (7M:13F, 32 +/- 5 years) and 20 non-wearers (7M:13F, 31 +/- 5 years) completed the study. OCI score was numerically higher in lens wearers (32.27 +/- 5.33) than non-wearers (27.66 +/- 9.94). Tear osmolarity was higher [298.0 (IQR 291.0-309.8) vs. 288.5 (282.3-298.3) mOsmol/L; P = .01] whereas NITBUT was lower (9.8 +/- 3.4 vs. 13.8 +/- 5.6 s; P = .01) in lens wearers compared with non-wearers. Tear neuropeptide concentrations were not different between groups [Substance P 4.29 ng/ml (IQR 1.57-6.05), CGRP 14.89 ng/ml (5.08-59.26)], and there were no differences in nerve morphology or ocular surface sensitivity. Higher nerve density, interconnections, and tortuosity were observed in the central cornea than mid-peripherally (P < .05). OCI score was moderately associated with nerve tortuosity (r = 0.42, P = .01). CGRP was associated with central nerve density (rho = 0.38, P = .02), as was tear secretion (r = -0.37, P = .02). Nerve interconnections were strongly associated with corneal sensitivity (rho = 0.64, P < .001). CONCLUSIONS: Relationships were demonstrated between nerve density, tear CGRP, and corneal sensitivity. Markers of corneal neurobiology and sensory function do not appear to be altered in contact lens wear despite worse tear function (osmolarity and stability) in lens wearers. This suggests that mechanisms other than overt changes in corneal innervation regulate tear function during lens wear. The relationship between nerve tortuosity and ocular discomfort requires elucidation. PMID- 28338566 TI - Midazolam as an active placebo in 3 fentanyl-validated nociceptive pain models. AB - The use of inactive placebos in early translational trials of potentially analgesic compounds is discouraged because of the side-effect profiles of centrally acting analgesics. Therefore, benzodiazepines are used, although their use has not been validated in this context. Whether benzodiazepines confound the results of acute pain tests is unknown. Midazolam (0.06 mg/kg) as an active placebo was investigated in 3 nociceptive models that included contact heat, electrical pain, and pressure pain thresholds in 24 healthy volunteers. Fentanyl (1 MUg/kg) served as an internal validator in this randomized, placebo (saline) controlled, 3-way cross-over trial. The primary outcome parameter (contact heat pain) was analyzed using a one-way, repeated measures analysis of variance and Tukey's post test. Midazolam did not reduce pain ([numeric rating scale], 0-100) in a statistically significant manner compared with placebo for the contact heat (mean difference -1.7, 95% confidence interval -10.6 to 7.3; P = 0.89) or electrical pain (4.3, -5.1 to 13.7; P = 0.51) test, nor did it raise the pressure pain thresholds (-28 kPa, -122; 64 kPa, P = 0.73). The width of the confidence intervals suggested that there were no clinically meaningful analgesic effects compared with the placebo. In contrast, the analgesic efficacy of fentanyl was effectively demonstrated in all 3 models (P < 0.01 vs midazolam and placebo). The findings of this study show that midazolam can be used as an active placebo in analgesic drug trials. Furthermore, the proposed models were simple to implement and very effective in detecting analgesia. The test battery can be used in translational trials for new compounds and comes with an active placebo and an optional active comparator. PMID- 28338567 TI - Bevacizumab Therapy for Pilomyxoid Astrocytoma. AB - Pilomyxoid astrocytoma is a rare tumor of the central nervous system generally found in young children near the hypothalamus. Herein, we report a 19-month-old female infant with a pilomyxoid astrocytoma, who underwent surgery as well as carboplatin and vincristine chemotherapy in an attempt to delay radiation therapy to the brain. Magnetic resonance imaging revealed that the tumor had increased in tumor volume on therapy. Chemotherapy with carboplatin and vincristine was stopped and bevacizumab therapy (10 mg/kg every other week) was initiated. After 15 months of bevacizumab therapy, the patient's tumor was significantly smaller. Bevacizumab therapy was discontinued for 6 months due to stability in tumor size but was resumed after tumor growth was observed. Patient was again placed on bevacizumab therapy with subsequent magnetic resonance imagings revealing a decrease in tumor size. PMID- 28338568 TI - Pediatric Patient With Renal Cell Carcinoma Treated by Successive Antiangiogenics Drugs: A Case Report and Review of the Literature. AB - Antiangiogenic drugs are currently standard of care in adults with renal cell carcinoma (RCC), including translocation RCC. Although antitumor activity and toxicity profile are well known in adults, few data have been reported in children. Here we present the case of a patient diagnosed at 2 years old with a metastatic translocation RCC, consecutively treated with 5 tyrosine kinase inhibitors during 6 years. The antitumor activity and toxic effects are described, and a brief review of the literature is presented. PMID- 28338569 TI - Case Report: Immune-mediated Complete Response in a Patient With Recurrent Advanced Ewing Sarcoma (EWS) After Vigil Immunotherapy. AB - Ewing sarcoma is a highly resistant disease with a <10% chance of survival at 5 years after failure of frontline chemotherapy. This is a case report of an Ewing sarcoma patient with metastatic disease recurrence <2 years after standard chemotherapy/radiation who achieved a durable and sustained complete response after 2 series of treatments with Vigil (GMCSF/bi-shRNA furin DNA autologous tumor immunotherapy) serially manufactured from first and second recurrences with ELISPOT assay correlation. Results support justification of further testing of Vigil with ELISPOT assay as a biomarker to assess level of immune response and correlation with disease control. PMID- 28338570 TI - A Case of ALL Developing Posterior Reversible Encephalopathy Secondary to Hyponatremia. AB - Posterior reversible encephalopathy syndrome (PRES), may be due to different causes. It may develop secondary to hypertension, renal decompensation, electrolyte imbalance, and chemotherapeutic drugs. We describe a case of acute lymphoblastic leukemia in which PRES developed secondary to hyponatremia despite being normotensive during receipt of chemotherapy. Magnetic resonance imaging findings were suggestive of PRES. Partial diffusion restriction was observed in lesions in the bilateral occipitoparietal regions and the cerebellum. The patient was treated with appropriate medications with the resolution of his stroke-like symptoms. No neurological deficit was observed and clinical condition improved. The patient continued with chemotherapy. Early diagnosis and treatment of this syndrome is important in terms of preventing neurological sequelae. Cases of secondary PRES developing for several etiological reasons have been reported in induction therapy, but no pediatric cases of PRES developing secondary to hyponatremia despite being normotensive while receiving chemotherapy in acute lymphoblastic leukemia have previously been reported. PMID- 28338571 TI - Point of View. PMID- 28338572 TI - Drivers of Medicare Reimbursement for Thoracolumbar Fusion: An Analysis of Data From The Centers For Medicare and Medicaid Services. AB - STUDY DESIGN: A retrospective observational study. OBJECTIVE: The purpose of this study is to examine the variation in thoracolumbar fusion (TLF) payment and determine the drivers of this variation. SUMMARY OF BACKGROUND DATA: As health care spending continues to increase, variation in surgical procedures reimbursements has come under more scrutiny. TLF is an example of a high-cost, proven-benefit procedure that is often the focus of Centers for Medicare and Medicaid Services (CMS) administrators. There is a wide variation in TLF charges, but the drivers for this variation are not clear. METHODS: Claims for TLF were identified in the CMS data by analyzing Diagnosis Related Group (DRG) number 460 ("Spinal Fusion Except Cervical without Major Complications or Comorbidities"). Data on factors that may impact cost of care were collected from four sources: the United States Census Bureau, CMS, the Dartmouth Atlas, and WWAMI Rural Health Research Center. These were then grouped into seven categories: quality, supply, demand, substitute treatment availability, patient characteristics, competitive factors, and provider characteristics. Predictive reimbursement models were created from the data using multivariate linear regression to understand the factors that influence TLF reimbursement. RESULTS: There was significant geographic variability in reimbursement. The largest contribution to reimbursement variation came from variables in the demand (DeltaR = 13.4%, P < 0.001), supply (DeltaR = 9.2%, P < 0.001), and competitive factor domains (DeltaR = 9.1%, P < 0.001). The top three drivers that increased reimbursement were provider charges (beta = 0.37, P < 0.001), total Medicare reimbursement in the region (beta = 0.19, P < 0.001), and the number of spinal surgeries per 1000 patients in that region (beta = 0.06, P = 0.02). Institutional volume, a surrogate for quality was negatively associated with TLF reimbursement. CONCLUSION: There was wide variation in reimbursement for TLF across the U.S. The variables that drive TLF reimbursement variation include supply, demand, and competition. Interestingly, quality of care was not associated with increased TLF reimbursement. LEVEL OF EVIDENCE: N/A. PMID- 28338573 TI - A Machine Learning-based Surface Electromyography Topography Evaluation for Prognostic Prediction of Functional Restoration Rehabilitation in Chronic Low Back Pain. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: The aim of this study was to investigate the feasibility and applicability of support vector machine (SVM) algorithm in classifying patients with LBP who would obtain satisfactory or unsatisfactory progress after the functional restoration rehabilitation program. SUMMARY OF BACKGROUND DATA: Dynamic surface electromyography (SEMG) topography has demonstrated the potential use in predicting the prognosis of functional restoration rehabilitation for patients with low back pain (LBP). However, processing from raw SEMG topography to make prediction is not easy to clinicians. METHODS: A total of 30 patients with nonspecific LBP were recruited and divided into "responding" and "non-responding" group according to the change of Visual analog pain rating scale and Oswestry Disability Index. Each patient received a 12-week functional restoration rehabilitation program. A normal database was calculated from a control group from 48 healthy participants. Root-mean-square difference (RMSD) was extracted from the recorded dynamic SEMG topography during symmetrical and asymmetrical trunk-movement. SVM and cross-validation were applied to the prediction based on the optimized features selected by the sequential floating forward selection (SFFS) algorithm. RESULTS: RMSD feature parameters following rehabilitation in the "responding" group showed a significant difference (P < 0.05) with the one in the "nonresponding" group. The SVM classifier with Quadratic kernel based on SFFS-selected features showed the best prediction performance (accuracy: 96.67%, sensitivity: 100%, specificity: 93.75%, average area under curve [AUC]: 0.8925) comparing with linear kernel (accuracy: 80.00%, sensitivity: 85.71%, specificity: 75.00%, average AUC: 0.7825), polynomial kernel (accuracy: 93.33%, sensitivity: 92.86%, specificity: 93.75%, average AUC: 0.9675), and radial basis function (RBF) kernel (accuracy: 86.67%, sensitivity: 85.71%, specificity: 87.50%, average AUC: 0.7900). CONCLUSION: The use of SVM-based classifier of SEMG topography can be applied to identify the patient responding to functional restoration rehabilitation, which will help the healthcare worker to improve the efficiency of LBP rehabilitation. LEVEL OF EVIDENCE: 3. PMID- 28338574 TI - Rigid Occipitocervical Instrumented Fusion for Atlantoaxial Instability in an 18 Month-Old Toddler With Brachytelephalangic Chondrodysplasia Punctata: A Case Report. AB - STUDY DESIGN: Case report. OBJECTIVE: We report here on an 18-month-old boy with brachytelephalangic chondrodysplasia punctata (BCDP), whose atlantoaxial instability was successfully managed with occipitocervical instrumented fusion (OCF) using screw and rod instrumentations. SUMMARY OF BACKGROUND DATA: Recently, there have been a number of reports on BCDP with early onset of cervical myelopathy. Surgical OCF is a vital intervention to salvage affected individuals from the life-threatening morbidity. Despite recent advancement of instrumentation techniques, however, rigid OCF is technically demanding in very young children with small and fragile osseous elements. To our best knowledge, this is the first report on application of the instrumentation technique to a toddler patient with BCDP. METHODS: A 16-month-old boy with BCDP presented with tetraplegia and swallow obstacle. Hypoplasia of the odontoid process and atlantoaxial instability were present in lateral radiographs. T2-weighted magnetic resonance (MR) images revealed a high signal region in the spinal cord at the C1-2 and C7-T1 levels. Cervical computed tomography (CT) showed that the pedicles and lateral masses in the cervical spine were small and immature, but the laminae were comparatively thick. RESULTS: One week before surgery, the patient was fitted with a Halo-body jacket. We performed plate-rod placement with occipital cortical screws and C2/C3 interlaminar screws, and added an autogenous bone graft using the right 8 and 9 ribs. Rigid fixation of the occipito-cervical spine was completed successfully without major complications. Postoperative halo body jacket immobilization was continued for 3 months, after which Aspen collar was fitted. CT confirmed occipitocervical bone fusion at 6 months after surgery. Mild clinical improvements in motor power of the affected muscles and swallowing were witnessed at 1 year postoperatively. CONCLUSION: Rigid fixation using screw, rod, and occipital plate instrumentation was successful in an 18-month-old toddler with BCDP and atlantoaxial instability. Bone fusion was achieved at postoperative 6 months. LEVEL OF EVIDENCE: 5. PMID- 28338575 TI - Role of Cx43-Mediated NFkB Signaling Pathway in Ossification of Posterior Longitudinal Ligament: An In Vivo and In Vitro Study. AB - STUDY DESIGN: In vivo and in vitro experiments. OBJECTIVE: To illustrate the further molecular mechanism of Cx43-mediated osteoblastic differentiation of ligament cells. SUMMARY OF BACKGROUND DATA: Ossification of the posterior longitudinal ligament (OPLL) is one of the main causes of myelopathy in Asians, but its etiology has not been clarified. We have previously found the mechanical stress can upregulate Cx43 expression in ligament cells, which transduces mechanical signal to promote osteoblastic differentiation. METHODS: The posterior longitudinal ligaments were collected intraoperatively. Ligament fibroblasts were isolated and cultured, and an in vitro mechanical loading model was established. In vivo and in vitro expression levels of Cx43 protein were compared between OPLL and non-OPLL patients. The activation of nuclear factor (NF)-kappaB (p65) signal and related inflammatory responses were detected in ligament cells under mechanical loading. The mechanical stress-induced inflammatory response and osteoblastic differentiation of OPLL cells were investigated after the treatment with Cx43 siRNA or NFkB (p65) inhibitor. RESULTS: We first confirmed higher Cx43 levels in both in vivo ligament tissue from OPLL patients and in vitro cultured OPLL cells. We also found NFkappaB (p65) signal and related inflammatory response were activated by mechanical stimulation. The activation of NFkappaB (p65) signal was dependent upon Cx43, as its knockdown reduced signal. Moreover, treatment with Cx43 siRNA or NFkB (p65) inhibitor significantly decreased the mechanical induced inflammation response, but partly attenuated mechanical-stimulated osteoblastic differentiation of OPLL cells. CONCLUSION: Cx43-mediated NFkB (p65) signal played an important role in mechanical stress-induced OPLL by transduction of mechanical signal, while giving rise to the activation of inflammatory response in ligament fibroblastsLevel of Evidence: N/A. PMID- 28338576 TI - Genetic Polymorphism of NUCKS1 Is Associated With the Susceptibility of Adolescent Idiopathic Scoliosis. AB - STUDY DESIGN: A genetic association study. OBJECTIVE: The aim of this study was to investigate whether NUCKS1 is a susceptible gene of adolescent idiopathic scoliosis (AIS) in Chinese population and to further narrate its association with the clinical phenotypes. SUMMARY OF BACKGROUND DATA: AIS is characterized by late onset of menarche and disturbed growth rhythm. Previous studies showed that NUCKS1 is associated with age at menarche and pubertal height growth. METHODS: Single-nucleotide polymorphism rs951366 of NUCKS1 was genotyped in 972 patients and 1454 healthy controls. The differences of genotype and allele distributions between AIS patients and healthy controls were evaluated using the chi test. One way analysis of variance test was used to compare the relationship between different genotypes and clinical features including tissue expression of NUCKS1, age at menarche, and curve magnitude. RESULTS: Patients were found to have a significantly lower frequency of CC than the controls (5.9% vs. 10.6%, P < 0.001). Besides, the frequency of allele C was found to be remarkably lower in the patients than the controls (26.4% vs. 30.9%, P < 0.001), with an odds ratio of 0.80 (95% confidential interval = 0.71-0.91). Patients with genotype CC had a remarkably lower age at menarche than patients with genotype TT (12.1 +/- 1.7 vs. 12.8 +/- 2.4 years, P = 0.02). Patients with genotype TT had a remarkably lower expression level of NUCKS1 than patients with genotype CC (2.8 +/- 1.9 vs. 4.3 +/ 2.2, P = 0.03). As for curve magnitude, no significant difference was found among patients with different genotypes. CONCLUSION: Patients with allele T of rs951366 can be more vulnerable to the incidence of AIS as well as a late onset of menarche. Further functional analysis is warranted for a comprehensive knowledge on the contribution of this variant to the development of AIS. LEVEL OF EVIDENCE: 4. PMID- 28338577 TI - Weight Gain After Vertical Expandable Prosthetic Titanium Rib Surgery May Be From Nutritional Optimization Rather Than Improvement in Pulmonary Function. AB - STUDY DESIGN: Prospective comparative study. OBJECTIVE: To evaluate whether weight percentile (WP) increases after vertical expandable prosthetic titanium rib (VEPTR) insertion, and whether WP correlates with nutrition laboratories and pulmonary function. SUMMARY OF BACKGROUND DATA: Children with thoracic insufficiency syndrome often have "failure to thrive" (WP <=5). Previous authors have reported an increase in WP after VEPTR surgery. Weight gain was hypothesized to be secondary to improved pulmonary function. The presence of a correlation between WP and nutrition laboratories and pulmonary function tests (PFT) after VEPTR insertion has not been studied. METHODS: Demographic, nutrition, radiographic, and PFT data were collected on 35 VEPTR patients with a minimum follow-up of 2 years. The relationship between WP and nutrition laboratories and pulmonary function was analyzed. RESULTS: Preoperative WP was <=5 (PREOP<=5) in 13 patients (37%) and >5 (PREOP>5) in 22 patients (63%). Although all children gained weight, the PREOP<=5 group was more likely to have an increase in WP (P = 0.014). Sixty-eight percent of the PREOP>5 group had a decrease in WP and 32% of the PREOP>5 patients met the criteria for failure to thrive at final follow-up. Overall, there was no change in the number of children with a WP <=5 (13 vs. 15). Forty-two percent of the children who maintained or increased their WP had a gastrostomy tube, compared to 19% of those who decreased their WP. Seventy-three percent of the patients with failure to thrive at final follow-up did not have a gastrostomy tube. No significant correlations were found between WP and nutrition laboratories, radiographic measures, or PFTs. CONCLUSION: We did not find an overall change in WP after VEPTR insertion. We did not find any correlation between WP and nutrition laboratories or pulmonary function. Weight gain after VEPTR surgery may be secondary to nutritional optimization in high-risk patients. Children who do not have failure to thrive at presentation also require attention. LEVEL OF EVIDENCE: 2. PMID- 28338578 TI - Spinal Cord is the Primary Site of Action for Skeletal Muscle Relaxation by Sevoflurane. AB - : MINI: A modified selective anesthetics delivery rabbit model was used validated to a better preferential anesthesia than previous models. Furthermore, we found evidence that primarily the spinal cord mediated the skeletal muscle relaxation action of sevoflurane. STUDY DESIGN: A randomized, in vivo study was performed to explore the skeletal muscle relaxation action site of sevoflurane. OBJECTIVE: The aim of this study was to investigate the skeletal muscle relaxation action of sevoflurane by a modified selective anesthetics delivery rabbit model. SUMMARY OF BACKGROUND DATA: The action site and mechanisms of skeletal muscle relaxation caused by sevoflurane were unclear, so a modified selective anesthetics delivery model was used. METHODS: Sixteen male New Zealand White rabbits were randomly assigned to the sevoflurane or sham group. In situ measurement of train of four, maximum single twitch, and tetanic muscle force of left tibialis anterior muscle was repeatedly measured at three time points: at the beginning of lower torso bypass (baseline value), during preferential sevoflurane delivery to the brain (brain value), during preferential sevoflurane delivery to the spinal cord (spinal cord value). RESULTS: When 1.5MAC sevoflurane was administrated via the lungs, the arterial concentration and partial pressure of sevoflurane in the upper torso were 205.27 +/- 16.23 MUg/mL and 29.16 +/- 1.05 mmHg, whereas in the lower torso bypass circulation were 10.39 +/- 4.50 MUg/mL and 1.79 +/- 0.97 mmHg. Conversely, the arterial concentration and partial pressure of sevoflurane in the upper torso were 14.04 +/- 5.33 MUg/mL and 2.25 +/- 0.84 mmHg, whereas those values were 199.38 +/- 11.61 MUg/mLl and 29.20 +/- 1.08 mmHg in the lower torso, when 1.5MAC sevoflurane was delivered via an oxygenator. In sevoflurane group, maximum single twitch and tetanic muscle force were significantly reduced compared with baseline (single: P = 0.046; tetanic: P = 0.001) or brain values (single: P = 0.005; tetanic: P = 0.001), when spinal cord was selectively anesthetized. In the sham group, there were no significant differences among the three conditions compared. CONCLUSION: A modified selective anesthetics delivery rabbit model has been validated, which provided evidence that the spinal cord, not the brain, was the primary site mediating the skeletal muscle relaxation action of sevoflurane. LEVEL OF EVIDENCE: 5. PMID- 28338580 TI - Textiloma: A Case of Foreign Body Mimicking a Spinal Tumor. AB - STUDY DESIGN: Case report OBJECTIVE.: To report a case of foreign body mimicking spinal tumor. SUMMARY OF BACKGROUND DATA: Gossypiboma or more broadly retained foreign object is a surgical complication resulting from foreign materials such as cotton or gauze pads and surgical sponge, accidentally left inside a patient's body. Such foreign materials cause foreign body reaction in the surrounding tissue. METHODS: A retrospective case report was performed. Informed consent was obtained from patient. RESULTS: We describe a case of textiloma in which the patient presented with low back pain and radiculopathy 12 years after L5?S1 discectomy. Imaging revealed a round mass lesion in the sacral space. CONCLUSION: At the end of surgery, the operative site should be flushed with saline and carefully examined for any foreign materials. LEVEL OF EVIDENCE: 4. PMID- 28338579 TI - Correlative Analysis of Vertebral Trabecular Bone Microarchitecture and Mechanical Properties: A Combined Ultra-high Field (7 Tesla) MRI and Biomechanical Investigation. AB - STUDY DESIGN: High-resolution imaging and biomechanical investigation of ex-vivo vertebrae. OBJECTIVE: The aim of this study was to assess bone microarchitecture of cadaveric vertebrae using ultra-high field (UHF) 7 Tesla magnetic resonance imaging (MRI) and to determine whether the corresponding microarchitecture parameters were related to bone mineral density (BMD) and bone strength assessed by dual-energy x-ray absorptiometry (DXA) and mechanical compression tests. SUMMARY OF BACKGROUND DATA: Limitations of DXA for the assessment of bone fragility and osteoporosis have been recognized and criteria of microarchitecture alteration have been included in the definition of osteoporosis. Although vertebral fracture is the most common osteoporotic fracture, no study has assessed directly vertebral trabecular bone microarchitecture. METHODS: BMD of 24 vertebrae (L2, L3, L4) from eight cadavers was investigated using DXA. The bone volume fraction (BVF), trabecular thickness (Tb.Th), and trabecular spacing (Tb.Sp) of each vertebra were quantified using UHF MRI. Measurements were performed by two operators to characterize the inter-rater reliability. The whole set of specimens underwent mechanical compression tests to failure and the corresponding failure stress was calculated. RESULTS: The inter-rater reliability for bone microarchitecture parameters was good with intraclass correlation coefficients ranging from 0.82 to 0.94. Failure load and stress were significantly correlated with BVF, Tb.Sp, and BMD (P < 0.05). Tb.Th was only correlated with the failure stress (P < 0.05). Multiple regression analysis demonstrated that the combination of BVF and BMD improved the prediction of the failure stress from an adjusted R = 0.384 for BMD alone to an adjusted R = 0.414. CONCLUSION: We demonstrated for the first time that the vertebral bone microarchitecture assessed with UHF MRI was significantly correlated with biomechanical parameters. Our data suggest that the multimodal assessment of BMD and trabecular bone microarchitecture with UHF MRI provides additional information on the risk of vertebral bone fracture and might be of interest for the future investigation of selected osteoporotic patients. LEVEL OF EVIDENCE: N /A. PMID- 28338581 TI - Summary Statement for the Spinal Cord Stimulation Focus Issue. PMID- 28338582 TI - Validation of the Clinician-Graded Electronic Facial Paralysis Assessment. AB - BACKGROUND: Facial paralysis remains a debilitating condition despite advances in medical, surgical, and adjunctive interventions. Established grading systems used to assess facial paralysis and interventional outcomes have well-described limitations. The Electronic Facial Paralysis Assessment, a clinician-graded zone based facial function scale, has recently emerged as a grading tool that may provide greater sensitivity when assessing incomplete paralysis and postsurgical improvement. The authors perform the first comprehensive validation of this tool. METHODS: Video recordings of 83 facial paralysis patients were assessed. Grading was performed in two sittings by three individuals with varying degrees of experience in assessing facial paralysis. Interobserver reliability; intraobserver reliability; administration time; and agreement with the Facial Disability Index, House-Brackmann, Sunnybrook, and Sydney facial grading systems were assessed. RESULTS: The Electronic Facial Paralysis Assessment demonstrated high intra observer and interobserver reliability (intraclass correlation coefficient, 0.84 to 0.91 and 0.81 to 0.83, respectively). It correlated well with the House-Brackmann, Sunnybrook, and Sydney facial grading systems (Spearman rho, 0.73, 0.77 and 0.77, respectively). In subdomain analysis, it correlated well with the Sunnybrook and Sydney systems in dynamic movement (Spearman rho, 0.90 and 0.89, respectively) and synkinesis (Spearman rho, range 0.74 and 0.72, respectively). It had poor agreement with the Facial Disability Index (Spearman rho, 0.25). The mean time to complete the tool was 116 +/- 61 seconds. CONCLUSIONS: The Electronic Facial Paralysis Assessment is a valid facial assessment tool with high reliability and correlation with the established facial paralysis grading systems. It also provides an efficient and detailed analysis of paralysis according to each facial zone. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, II. PMID- 28338583 TI - Discussion: Toward Microsurgical Correction of Cleft Lip Ex Utero through Restoration of Craniofacial Developmental Programs. PMID- 28338584 TI - Spring-Assisted Cranioplasty for the Correction of Nonsyndromic Scaphocephaly: A Quantitative Analysis of 100 Consecutive Cases. AB - BACKGROUND: Spring-assisted cranioplasty has been proposed as an alternative to total calvarial remodeling for sagittal craniosynostosis. Advantages include its minimally invasive nature, and reduced morbidity and hospital stay. Potential drawbacks include the need for a second procedure for removal and the lack of published long-term follow-up. The authors present a single-institution experience of 100 consecutive cases using a novel spring design. METHODS: All patients treated at the authors' institution between April of 2010 and September of 2014 were evaluated retrospectively. Patients with isolated nonsyndromic sagittal craniosynostosis were included. Data were collected for operative time, anesthetic time, hospital stay, transfusion requirement, and complications in addition to cephalic index preoperatively and at 1 day, 3 weeks, and 6 months postoperatively. RESULTS: One hundred patients were included. Mean cephalic index was 68 preoperatively, 71 at day 1, and 72 at 3 weeks and 6 months postoperatively. Nine patients required transfusion. Two patients developed a cerebrospinal fluid leak requiring intervention. One patient required early removal of springs because of infection. One patient had a wound dehiscence over the spring and one patient sustained a venous infarct with hemiplegia. Five patients required further calvarial remodeling surgery. CONCLUSIONS: The authors' modified spring design and protocol represents an effective strategy in the management of single-suture sagittal craniosynostosis with reduced total operative time and blood loss compared with alternative treatment strategies. In patients referred within the first 6 months of birth, this technique has become the authors' procedure of choice. In a minority of cases, especially in the older age groups, further remodeling surgery is required. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28338585 TI - A 16-Year Journey in the Study of Rheumatoid Hand Disease. AB - Evidence-based medicine is a relatively new concept in hand surgery. A lack of high-level evidence often leads to uncertainty in the effectiveness of various procedures and regional variation in their use. Rheumatoid hand surgery has been plagued by a lack of quality data that has caused controversy between rheumatologists and hand surgeons. Research over the past 16 years has strived to provide data that can be used to provide evidence-based care for rheumatoid arthritis patients. The Silicone Arthroplasty in Rheumatoid Arthritis study is a prospective, long-term cohort study of rheumatoid arthritis patients with severe metacarpophalangeal joint deformity who have elected to undergo or not to undergo metacarpophalangeal joint arthroplasty; the study was funded for 10 years by the National Institutes of Health and has provided invaluable results on the effectiveness of this procedure in terms of outcomes and cost, improving knowledge for both physicians and patients. PMID- 28338586 TI - Toward Microsurgical Correction of Cleft Lip Ex Utero through Restoration of Craniofacial Developmental Programs. AB - BACKGROUND: Cleft lip with or without cleft palate is present in approximately one in 500 to 700 live births, representing the most common congenital craniofacial anomaly. Previously, the authors developed a unique murine model with compound Pbx deficiency that exhibits fully penetrant cleft lip with or without cleft palate. To investigate the possibility of tissue repair at an early gestational stage, the authors designed a minimally invasive surgical approach suitable for intrauterine repair using Wnt9b-soaked collagen microspheres to restore craniofacial developmental programs for cleft correction. METHODS: Collagen microspheres with diameters ranging from 20 to 50 MUm were fabricated to serve as a delivery vehicle for Wnt9b. At gestational day 11.5, wild-type and Pbx deficient murine embryos were isolated. Microspheres soaked in murine purified Wnt9b protein were microsurgically implanted at the midface lambdoidal junction. Embryos were cultured in a 37 degrees C modified whole-embryo culture system. RESULTS: Targeted release of Wnt9b resulted in augmented Wnt expression at the lambdoidal junction. Microsurgical implantation of Wnt9b-soaked microspheres resulted in cleft correction in 27.1 percent of the Pbx-deficient embryos. The difference in the ratio of the areas of clefting between implanted and nonimplanted embryos was significant (p < 0.05). CONCLUSIONS: Ex utero correction of cleft lip with or without cleft palate in the authors' murine model by means of microsurgical intervention and targeted delivery of Wnt proteins is an innovative and promising strategy. Although further refinement and optimization of this technique will be required to improve efficacy, the authors believe that this approach will open new avenues toward unconventional prenatal interventions for patients with cleft lip with or without cleft palate, and provide future approaches for prenatal repair of other congenital head and neck disorders. PMID- 28338588 TI - Vertical Midface Lifting with Periorbital Anchoring in the Management of Lower Eyelid Retraction: A 10-Year Clinical Retrospective Study. AB - BACKGROUND: Lower eyelid retraction can be the unfortunate result of aesthetic surgery, trauma, disease, or the aging processes. The purpose of this article is to assess whether midface lifting based on purely vertical repositioning constitutes an effective procedure for its correction. METHODS: A retrospective study was carried out on 199 patients (311 eyelids) operated on between January of 2004 and January of 2014. The various causes of eyelid retraction in this population included cosmetic blepharoplasty (56.8 percent), involutional ectropion (23.1 percent), tumor resection (9.5 percent), facial nerve paralysis (8.5 percent), and trauma and related surgery (2 percent). The study was restricted exclusively to cases of moderate and severe lower eyelid retraction addressed by means of midface lifting. The mean follow-up time was 16.8 months. All of the patients were subjected to midface lifting with strengthening of the lateral canthus. A spacer graft was also used in 37.7 percent of the cases. RESULTS: One hundred ninety-five patients (97.9 percent) displayed objective improvement of the eyelid retraction and a marked degree of improvement both in aesthetic terms and as regards the functional disorders reported. Only four patients (2 percent) presented complications such as needing another operation. CONCLUSION: Midface lifting based on purely vertical repositioning makes it possible to recruit a considerable amount of "new" skin at the lower eyelid, thus ensuring a decrease in vertical distraction and correct recovery of the height of the external lamellar plane. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28338587 TI - Medial Row Perforators Are Associated with Higher Rates of Fat Necrosis in Bilateral DIEP Flap Breast Reconstruction. AB - BACKGROUND: The purpose of this study was to evaluate perfusion-related complications in bilateral deep inferior epigastric perforator (DIEP) flap breast reconstruction based on perforator selection. METHODS: A retrospective review of a prospectively maintained database was performed on all patients undergoing bilateral DIEP flap reconstruction at a single institution between 2004 and 2014. The hemiflaps were separated into three cohorts based on perforator location: lateral row only, medial row only, and medial plus lateral rows. Postoperative flap-related complications were compared and analyzed. RESULTS: There were 728 total hemiflaps: 263 (36.1 percent) based on the lateral row, 225 (30.9 percent) based on the medial row, and 240 (33.0 percent) based on both the medial and lateral rows. The groups were well matched by perforator number and flap weight. Fat necrosis occurrence was significantly higher in flaps based solely on the medial row versus lateral row perforators (24.5 percent versus 8.2 percent; p < 0.001). There was no statistically significant difference in fat necrosis between flaps based only on the lateral row versus flaps based on both the medial and lateral rows (8.2 percent versus 11.6 percent; p = 0.203). Generally, within the same row, increasing the number of perforators decreased the incidence of fat necrosis. CONCLUSIONS: Perforator selection is critical for minimizing perfusion related flap complications. In bilateral DIEP flaps, lateral row-based perforators result in significantly less fat necrosis than medial row-based perforators. The authors' data suggest that the addition of a lateral row perforator to a dominant medial row perforator may decrease the risk of fat necrosis. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28338589 TI - Managing hip fracture and lower limb surgery in the emergency setting: Potential role of non-vitamin K antagonist oral anticoagulants. AB - Trauma, immobilization, and subsequent surgery of the hip and lower limb are associated with a high risk of developing venous thrombo-embolism (VTE). Individuals undergoing hip fracture surgery (HFS) have the highest rates of VTE among orthopedic surgery and trauma patients. The risk of VTE depends on the type and location of the lower limb injury. Current international guidelines recommend routine pharmacological thromboprophylaxis based on treatment with heparins, fondaparinux, dose-adjusted vitamin K antagonists and acetylsalicylic acid for patients undergoing emergency HFS; however, not all guidelines recommend pharmacological prophylaxis for patients with lower limb injuries. Non-vitamin K antagonist oral anticoagulants (NOACs) are indicated for VTE prevention after elective hip or knee replacement surgery, but at present are not widely recommended for other orthopedic indications despite their advantages over conventional anticoagulants and promising real-world evidence. In patients undergoing HFS or lower limb surgery, decisions on whether to anticoagulate and the most appropriate anti-coagulation strategy can be guided by weighing the risk of thromboprophylaxis against the benefit in relation to each patient's medical history and age. In addition, the nature and location of the fracture, operating times and times before fracture fixation should be considered. The current review discusses the need for anticoagulation in patients undergoing emergency HFS or lower limb surgery together with the current guidelines and available evidence on the use of NOACs in this setting. Appropriate thromboprophylactic strategies and practical advice on the peri-operative management of patients who present to the Emergency Department on a NOAC before emergency surgery are further outlined. PMID- 28338592 TI - Open abdomen with vacuum-assisted wound closure and mesh-mediated fascial traction in patients with complicated diffuse secondary peritonitis: A single center 8-year experience. AB - BACKGROUND: Open abdomen (OA) treatment in patients with peritonitis is increasing worldwide. Various temporary abdominal closure devices are being used. This study included patients with complicated diffuse secondary peritonitis, OA, and vacuum-assisted wound closure and mesh-mediated fascial traction (VAWCM). The aim of this study was to describe mortality and major morbidity in terms of delayed primary fascial closure and enteroatmospheric fistula rates. METHODS: This was a single-academic-center retrospective study of consecutive patients with diffuse peritonitis, OA, and VAWCM between years 2008 and 2016. Descriptive and univariate analyses were performed. RESULTS: Forty-one patients were identified and analyzed. Median age was 59 years, preoperative septic shock was diagnosed in 54% (n = 22), and 59% (n = 24) had a postoperative peritonitis. Mortality was 29% (n = 12), and 76% (n = 31) of patients were admitted in the intensive care unit. The median duration of OA was 7 days with a median of two dressing changes. Delayed primary fascial closure rate among survivors was 92% (n = 33), and enteroatmospheric fistulas developed in 7% (n = 3). In a subgroup analysis, patients with OA in the primary laparotomy for peritonitis (n = 27) were compared with patients with OA in the subsequent laparotomies (n = 14). There were no significant differences between groups. CONCLUSIONS: The VAWCM technique in patients with complicated secondary diffuse peritonitis and OA yields excellent results in terms of delayed primary fascial closure rate and a low number of enteroatmospheric fistulas. It seems to be safe to close the abdomen at the index laparotomy, if possible, even if there is a risk of a need of OA later. LEVEL OF EVIDENCE: Therapeutic/care management study, level IV. PMID- 28338590 TI - Small changes, big effects: The hemodynamics of partial and complete aortic occlusion to inform next generation resuscitation techniques and technologies. AB - BACKGROUND: The transition from complete aortic occlusion during resuscitative endovascular balloon occlusion of the aorta can be associated with hemodynamic instability. Technique refinements and new technologies have been proposed to minimize this effect. In order to inform new techniques and technology, we examined the relationship between blood pressure and aortic flow during the restoration of systemic circulation following aortic occlusion at progressive levels of hemorrhage. METHODS: An automated supraceliac aortic clamp, capable of continuously variable degrees of occlusion, was applied in seven swine. The swine underwent stepwise removal of 40% of their total blood volume in four equal aliquots. After each aliquot, progressive luminal narrowing to the point of complete aortic occlusion was achieved over 5 minutes, sustained for 5 minutes, and then released over 5 minutes. Proximal and distal blood pressure and distal aortic flow were continuously recorded throughout the study. RESULTS: Upon release of the clamp, hyperemic aortic flow was observed following 10% and 20% hemorrhage (1,599 +/- 785 mL/min, p < 0.01; and 1,070 +/- 396 mL/min, p < 0.01, respectively). Proximal blood pressure exhibited a nonlinear relationship to aortic flow during clamp removal; however, distal blood pressure increased linearly with distal flow upon clamp opening across all hemorrhage volumes. CONCLUSIONS: Hyperemic blood flow following return of circulation may contribute to cardiovascular collapse. Reintroduction of systemic blood flow after aortic occlusion should be guided by distal blood pressure rather than proximal pressure. Awareness of hemodynamic physiology during aortic occlusion is of paramount importance to the clinical implementation of next-generation resuscitative endovascular balloon occlusion of the aorta techniques and technologies. PMID- 28338596 TI - Operation versus antibiotics--The "appendicitis conundrum" continues: A meta analysis. AB - BACKGROUND: Acute appendicitis continues to constitute a diagnostic and therapeutic challenge. The aim of this study was to synthesize evidence from randomized controlled trials (RCTs) comparing nonoperative versus surgical management of uncomplicated acute appendicitis in adult patients. METHODS: A systematic literature search of the PubMed, Cochrane, and Scopus databases was performed with respect to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement (end-of-search date: January 29, 2017). Data on the study design, interventions, participants, and outcomes were extracted by two independent reviewers. The random-effects model (DerSimonian-Laird) was used to calculate pooled effect estimates when substantial heterogeneity was encountered; otherwise, the fixed-effects (Mantel-Haenszel) model was implemented. Quality assessment of included RCTs was performed using the modified Jadad scale. RESULTS: Five RCTs were included in this review. Overall, 1,430 adult patients with uncomplicated acute appendicitis underwent either nonoperative (n = 727) or operative management (n = 703). Treatment efficacy at 1 year follow-up was significantly lower (63.8%) for antibiotics compared with the surgery group (93%) (risk ratio [RR], 0.68; 95% confidence interval [CI], 0.60 0.77; p < 0.001). Overall complications were significantly higher in the surgery group (166/703 [23.6%]) compared with the antibiotics group (56/727 [7.7%]) (RR, 0.32; 95% CI, 0.24-0.43; p < 0.001). No difference was found between the two treatment modalities in terms of perforated appendicitis rates (RR, 0.52; 95% CI, 0.14-1.92), length of hospital stay (weighted mean difference [WMD], 0.20; 95% CI, -0.16 to 0.56), duration of pain (WMD, 0.22; 95% CI, -5.30 to -5.73), and sick leave (WMD, -2; 95% CI, -5.2 to 1.1). CONCLUSIONS: Conservative management of uncomplicated appendicitis in adults warrants further study. Addressing patients' expectations via a shared decision-making process is a crucial step in optimizing nonoperative outcomes. LEVEL OF EVIDENCE: Systematic review, level II. PMID- 28338597 TI - Skill learning and retention. PMID- 28338598 TI - Characterization of distinct coagulopathic phenotypes in injury: Pathway-specific drivers and implications for individualized treatment. AB - BACKGROUND: International normalized ratio (INR) and partial thromboplastin time (PTT) are used interchangeably to diagnose acute traumatic coagulopathy but reflect disparate activation pathways. In this study, we identified injury/patient characteristics and coagulation factors that drive contact pathway, tissue factor pathway (TF), and common pathway dysfunction by examining injured patients with discordant coagulopathies. We hypothesized that patients with INR/PTT discordance reflect differing phenotypes representing contact versus tissue factor pathway perturbations and that characterization will provide targets to guide individualized resuscitation. METHODS: Plasma samples were prospectively collected from 1,262 critically injured patients at a single Level I trauma center. Standard coagulation measures and an extensive panel of procoagulant and anticoagulant factors were assayed and analyzed with demographic and outcome data. RESULTS: Fourteen percent of patients were coagulopathic on admission. Among these, 48% had abnormal INR and PTT (BOTH), 43% had isolated prolonged PTT (PTT-CONTACT), and 9% had isolated elevated INR (INR-TF). PTT CONTACT and BOTH had lower Glasgow Coma Scale score than INR-TF (p < 0.001). INR TF had decreased factor VII activity compared with PTT-CONTACT, whereas PTT CONTACT had decreased factor VIII activity compared with INR-TF. All coagulopathic patients had factor V deficits, but activity was lowest in BOTH, suggesting an additive downstream effect of disordered activation pathways. Patients with PTT-CONTACT received half as much packed red blood cell and fresh frozen plasma as did the other groups (p < 0.001). Despite resuscitation, mortality was higher for coagulopathic patients; mortality was highest in BOTH and higher in PTT-CONTACT than in INR-TF (71%, 60%, 41%; p = 0.04). CONCLUSIONS: Discordant phenotypes demonstrate differential factor deficiencies consistent with dysfunction of contact versus tissue factor pathways with additive effects from common pathway dysfunction. Recognition and treatment of pathway-specific factor deficiencies driving different coagulopathic phenotypes in injured patients may individualize resuscitation and improve outcomes. LEVEL OF EVIDENCE: Prognostic/epidemiological study, level II. PMID- 28338599 TI - Volumetric control of whole blood collection in austere environments. AB - INTRODUCTION: Fresh whole blood transfusions are a powerful tool in prehospital care; however, the lack of equipment such as a scale in field situations frequently leads to collections being under- or overfilled, leading to complications for both patient and physician. This study describes two methods for simple, rapid control of collection bag volume: (1) a length of material to constrict the bag, and (2) folding/clamping the bag. METHOD: Whole blood collection bags were allowed to fill with saline via gravity. Paracord, zip-tie, beaded cable tie, or tourniquet was placed around the bag at circumferences of 6 to 8.75 inches. A hemostat was used to clamp folds of 1 to 1.5 inches. Several units were drawn during training exercises of the 75th Ranger Regiment with volume controlled by three methods: vision/touch estimation, constriction by paracord, and clamping with hemostat. RESULTS: Method validation in the Terumo 450-mL bag indicated that paracord, zip-tie, and beaded cable tie lengths of 6.5 inches or clamping 1.25 inches with a hemostat provided accurate filling. The volume variance was significantly lower when using the beaded cable tie. Saline filling time was approximately 2 minutes. With the Fenwal 450-mL bag, the beaded cable tie gave best results; even if incorrectly placed by one/two beads, the volume was still within limits. In training exercises, the use of the cord/clamp greatly reduced the variability; more bags were within limits. CONCLUSIONS: Both constricting and clamping allow for speed and consistency in blood collection. The use of common cord is appealing, but knot tying induces inevitable variability; a zip/cable tie is easier. Clamping was quicker but susceptible to high variance and bag rupturing. With proper methodological training, appropriate volumes can be obtained in any environment with minimal tools. LEVEL OF EVIDENCE: Therapeutic/care management study, level IV. PMID- 28338603 TI - Antioxidant Properties of Selenophene, Thiophene and Their Aminocarbonitrile Derivatives. AB - The oxygen radical absorbance capacity (ORAC) method was used to detect the antiperoxyradical ability of organoselenium compounds: selenophene and its derivative, 2-amino-4,5,6,7-tetrahydro-1-selenophene-3-carbonitrile (ATSe); while as a comparison, the sulfur-containing analogue of selenophene-thiophene and its derivative-2-amino-4,5,6,7-tetrahydro-1-thiophene-3-carbonitrile (ATS)-was selected. Cyclic voltammetry (CV), differential pulse voltammetry (DPV) and squarewave voltammetry (SWV) methods were used to determine the redox characteristics of organoselenium and organosulfur compounds. The antiradical activity and capacity of the studied compounds were also measured by using stable radical 2,2'-diphenyl-1-picrylhydrazyl (DPPH). Detected anodic peaks of the oxidation of selenophene, thiophene and their derivatives in CV, DPV and SWV in the interval of -1200 / (+1600) mV potentials in regard to the Ag/Ag+ medium of acetonitrile prove the presence of antiperoxyradical activity in regard to oxidizers, i.e., peroxyradicals. The chemical mechanism of the antiperoxyradical ability of selenophene, thiophene and their organic derivatives is proposed. PMID- 28338602 TI - Design and Synthesis of Novel Pyrazole-Substituted Different Nitrogenous Heterocyclic Ring Systems as Potential Anti-Inflammatory Agents. AB - With the aim of developing novel anti-inflammatory scaffolds, a new series of pyrazole-substituted various nitrogenous heterocyclic ring systems at C-4 position were synthesized through different chemical reactions and validated by means of spectral and elemental data. The new obtained compounds were investigated for their anti-inflammatory activity using the carrageenan-induced paw edema standard technique and revealed that, compound 6b showed increased potency with % inhibition of edema 85.23 +/- 1.92 and 85.78 +/- 0.99, respectively, higher than the standard reference drugs indomethacin and celebrex (72.99% and 83.76%). Molecular modeling studies were initiated herein to validate the attained pharmacological data and provide understandable evidence for the observed anti-inflammatory behavior. PMID- 28338601 TI - Mycotoxin Biotransformation by Native and Commercial Enzymes: Present and Future Perspectives. AB - Worldwide mycotoxins contamination has a significant impact on animal and human health, and leads to economic losses accounted for billions of dollars annually. Since the application of pre- and post- harvest strategies, including chemical or physical removal, are not sufficiently effective, biological transformation is considered the most promising yet challenging approach to reduce mycotoxins accumulation. Although several microorganisms were reported to degrade mycotoxins, only a few enzymes have been identified, purified and characterized for this activity. This review focuses on the biotransformation of mycotoxins performed with purified enzymes isolated from bacteria, fungi and plants, whose activity was validated in in vitro and in vivo assays, including patented ones and commercial preparations. Furthermore, we will present some applications for detoxifying enzymes in food, feed, biogas and biofuel industries, describing their limitation and potentialities. PMID- 28338604 TI - Radar Interferometry for Monitoring the Vibration Characteristics of Buildings and Civil Structures: Recent Case Studies in Spain. AB - The potential of a coherent microwave sensor to monitor the vibration characteristics of civil structures has been investigated in the past decade, and successful case studies have been published by different research teams. This remote sensing technique is based on the interferometric processing of real aperture radar acquisitions. Its capability to estimate, simultaneously and remotely, the displacement of different parts of the investigated structures, with high accuracy and repeatability, is its main advantage with respect to conventional sensors. A considerable amount of literature on this technique is available, including various case studies aimed at testing the ambient vibration of bridges, buildings, and towers. In the last years, this technique has been used in Spain for civil structures monitoring. In this paper, three examples of such case studies are described: the monitoring of the suspended bridge crossing the Ebro River at Amposta, the communications tower of Collserola in Barcelona, and an urban building located in Vilafranca del Penedes, a small town close to Barcelona. This paper summarizes the main outcomes of these case studies, underlining the advantages and limitations of the sensors currently available, and concluding with the possible improvements expected from the next generation of sensors. PMID- 28338605 TI - Comparing Species Composition of Passive Trapping of Adult Flies with Larval Collections from the Body during Scene-Based Medicolegal Death Investigations. AB - Collection of insects at the scene is one of the most important aspects of forensic entomology and proper collection is one of the biggest challenges for any investigator. Adult flies are highly mobile and ubiquitous at scenes, yet their link to the body and the time of colonization (TOC) and post-mortem interval (PMI) estimates is not well established. Collection of adults is widely recommended for casework but has yet to be rigorously evaluated during medicolegal death investigations for its value to the investigation. In this study, sticky card traps and immature collections were compared for 22 cases investigated by the Harris County Institute of Forensic Sciences, Houston, TX, USA. Cases included all manner of death classifications and a range of decomposition stages from indoor and outdoor scenes. Overall, the two methods successfully collected at least one species in common only 65% of the time, with at least one species unique to one of the methods 95% of the time. These results suggest that rearing of immature specimens collected from the body should be emphasized during training to ensure specimens directly associated with the colonization of the body can be identified using adult stages if necessary. PMID- 28338607 TI - How to Make Reliable, Washable, and Wearable Textronic Devices. AB - In this paper, the washability of wearable textronic (textile-electronic) devices has been studied. Two different approaches aiming at designing, producing, and testing robust washable and reliable smart textile systems are presented. The common point of the two approaches is the use of flexible conductive PCB in order to interface the miniaturized rigid (traditional) electronic devices to conductive threads and tracks within the textile flexible fabric and to connect them to antenna, textile electrodes, sensors, actuators, etc. The first approach consists in the use of TPU films (thermoplastic polyurethane) that are deposited by the press under controlled temperature and pressure parameters in order to protect the conductive thread and electrical contacts. The washability of conductive threads and contact resistances between flexible PCB and conductive threads are tested. The second approach is focused on the protection of the whole system-composed of a rigid electronic device, flexible PCB, and textile substrate by a barrier made of latex. Three types of prototypes were realized and washed. Their reliabilities are studied. PMID- 28338606 TI - Dystrophic Cardiomyopathy-Potential Role of Calcium in Pathogenesis, Treatment and Novel Therapies. AB - Duchenne muscular dystrophy (DMD) is caused by defects in the DMD gene and results in progressive wasting of skeletal and cardiac muscle due to an absence of functional dystrophin. Cardiomyopathy is prominent in DMD patients, and contributes significantly to mortality. This is particularly true following respiratory interventions that reduce death rate and increase ambulation and consequently cardiac load. Cardiomyopathy shows an increasing prevalence with age and disease progression, and over 95% of patients exhibit dilated cardiomyopathy by the time they reach adulthood. Development of the myopathy is complex, and elevations in intracellular calcium, functional muscle ischemia, and mitochondrial dysfunction characterise the pathophysiology. Current therapies are limited to treating symptoms of the disease and there is therefore an urgent need to treat the underlying genetic defect. Several novel therapies are outlined here, and the unprecedented success of phosphorodiamidate morpholino oligomers (PMOs) in preclinical and clinical studies is overviewed. PMID- 28338608 TI - Impact of High-Carbohydrate Diet on Metabolic Parameters in Patients with Type 2 Diabetes. AB - In patients with type 2 diabetes mellitus (T2DM), whether dietary carbohydrates have beneficial or detrimental effects on cardiometabolic risk factors has drawn attention. Although a high-carbohydrate (HC) diet and a low-carbohydrate (LC) diet have gained popularity for several decades, there is scarce review focusing on the effects of HC diet on glucose, lipids and body weight in patients with T2DM. In this review, we examined recently-published literature on the effects of HC diets on metabolic parameters in T2DM. HC diets are at least as effective as LC diets, leading to significant weight loss and a reduction in plasma glucose, HbA1c and low density lipoprotein-cholesterol (LDL-C) levels. The major concern is that HC diets may raise serum triglyceride levels and reduce high density lipoprotein-cholesterol (HDL-C) levels, increasing the risk of cardiovascular disease. However, these untoward effects were not a persistent consequence and may be ameliorated with the consumption of a low glycemic index (GI)/low glycemic load (GL) and high fiber. Carbohydrate intake should be individualized, and low caloric intake remains a crucial factor to improve insulin sensitivity and reduce body weight; however, an HC diet, rich in fiber and with a low GI/GL, may be recommendable in patients with T2DM. PMID- 28338611 TI - Disability and Psychiatric Symptoms in Men Referred for Treatment with Work Related Problems to Primary Mental Health Care. AB - The relationship between male sex and employment as barriers to accessing mental health care is unclear. The aim of this research was to examine (1) whether the clinical features of men referred to a shared mental health care (SMHC) service through primary care differed when symptoms were affecting them in the work domain; and (2) empirically re-evaluate the effectiveness of a SMHC model for work-related disability using a pre-post chart review of N = 3960 referrals to SMHC. ANOVA and logistic regression were performed to examine symptoms (Patient Health Questionnaire, PHQ) and disability (World Health Organization Disability Assessment Schedule, WHODAS 2) at entry and discharge. Men were RR (relative risk) = 1.8 (95% C.I.: 1.60-2.05) times more likely to be referred to SMHC with work problems than women. Having greater disability and more severe somatic symptoms increased the likelihood of a work-related referral. There were no significant differences after treatment. Problems in the work domain may play an important role in men's treatment seeking and clinicians' recognition of a mental health care need. This study is relevant because men are underrepresented in mental health (MH) treatment and primary care is the main gateway to accessing MH care. Asking men about functioning in the work domain may increase access to helpful psychiatric services. PMID- 28338609 TI - Ectopic Expression of Aeluropus littoralis Plasma Membrane Protein Gene AlTMP1 Confers Abiotic Stress Tolerance in Transgenic Tobacco by Improving Water Status and Cation Homeostasis. AB - We report here the isolation and functional analysis of AlTMP1 gene encoding a member of the PMP3 protein family. In Aeluropus littoralis, AlTMP1 is highly induced by abscisic acid (ABA), cold, salt, and osmotic stresses. Transgenic tobacco expressing AlTMP1 exhibited enhanced tolerance to salt, osmotic, H2O2, heat and freezing stresses at the seedling stage. Under greenhouse conditions, the transgenic plants showed a higher level of tolerance to drought than to salinity. Noteworthy, AlTMP1 plants yielded two- and five-fold more seeds than non-transgenic plants (NT) under salt and drought stresses, respectively. The leaves of AlTMP1 plants accumulated lower Na+ but higher K+ and Ca2+ than those of NT plants. Tolerance to osmotic and salt stresses was associated with higher membrane stability, low electrolyte leakage, and improved water status. Finally, accumulation of AlTMP1 in tobacco altered the regulation of some stress-related genes in either a positive (NHX1, CAT1, APX1, and DREB1A) or negative (HKT1 and KT1) manner that could be related to the observed tolerance. These results suggest that AlTMP1 confers stress tolerance in tobacco through maintenance of ion homeostasis, increased membrane integrity, and water status. The observed tolerance may be due to a direct or indirect effect of AlTMP1 on the expression of stress-related genes which could stimulate an adaptive potential not present in NT plants. PMID- 28338610 TI - Fructose-Rich Diet Affects Mitochondrial DNA Damage and Repair in Rats. AB - Evidence indicates that many forms of fructose-induced metabolic disturbance are associated with oxidative stress and mitochondrial dysfunction. Mitochondria are prominent targets of oxidative damage; however, it is not clear whether mitochondrial DNA (mtDNA) damage and/or its lack of repair are events involved in metabolic disease resulting from a fructose-rich diet. In the present study, we evaluated the degree of oxidative damage to liver mtDNA and its repair, in addition to the state of oxidative stress and antioxidant defense in the liver of rats fed a high-fructose diet. We used male rats feeding on a high-fructose or control diet for eight weeks. Our results showed an increase in mtDNA damage in the liver of rats fed a high-fructose diet and this damage, as evaluated by the expression of DNA polymerase gamma, was not repaired; in addition, the mtDNA copy number was found to be significantly reduced. A reduction in the mtDNA copy number is indicative of impaired mitochondrial biogenesis, as is the finding of a reduction in the expression of genes involved in mitochondrial biogenesis. In conclusion, a fructose-rich diet leads to mitochondrial and mtDNA damage, which consequently may have a role in liver dysfunction and metabolic diseases. PMID- 28338612 TI - Pesticide Knowledge and Safety Practices among Farm Workers in Kuwait: Results of a Survey. AB - The unsafe and indiscriminate use of pesticides in agriculture represents a major hazard to the environment and human health. The aim of this study was to assess the levels of knowledge, attitude and practices of Kuwaiti farmers regarding the safe use of pesticides. A total of 250 farmers participated in this study through in-depth interviews and observations on-farm. The majority of the farmers acknowledged that pesticides were harmful to their health (71%) and the environment (65%). However, farmers' level of knowledge of pesticide safety is insufficient. Over 70% of the farmers did not read or follow pesticide label instructions, and 58% did not use any personal protective equipment (PPE) when handling pesticides. Educated farmers were significantly more likely to use PPE compared with famers with limited formal education (chi2 = 9.89, p < 0.05). Storage of pesticides within living areas was reported by 20% of farmers. When disposing of pesticide wastes, respondents adopted unsafe practices such as discarding, incinerating, or burying empty pesticide containers on-farm, or reusing the containers. Farmers also reported disposing leftover pesticide solution or old pesticide stocks on-farm or in the sewer. A significant number (82%) of the farmers reported at least one symptom of acute pesticide poisoning. Although farmers' knowledge of pesticide hazards was high, the reported safety measures were poor. Comprehensive intervention measures to reduce the health and environmental risks of pesticides are needed, including pesticide safety training programs for farmers, stringent enforcement of pesticide laws, and promoting integrated pest management and non-synthetic methods of pest control. PMID- 28338613 TI - Slum Upgrading and Health Equity. AB - Informal settlement upgrading is widely recognized for enhancing shelter and promoting economic development, yet its potential to improve health equity is usually overlooked. Almost one in seven people on the planet are expected to reside in urban informal settlements, or slums, by 2030. Slum upgrading is the process of delivering place-based environmental and social improvements to the urban poor, including land tenure, housing, infrastructure, employment, health services and political and social inclusion. The processes and products of slum upgrading can address multiple environmental determinants of health. This paper reviewed urban slum upgrading evaluations from cities across Asia, Africa and Latin America and found that few captured the multiple health benefits of upgrading. With the Sustainable Development Goals (SDGs) focused on improving well-being for billions of city-dwellers, slum upgrading should be viewed as a key strategy to promote health, equitable development and reduce climate change vulnerabilities. We conclude with suggestions for how slum upgrading might more explicitly capture its health benefits, such as through the use of health impact assessment (HIA) and adopting an urban health in all policies (HiAP) framework. Urban slum upgrading must be more explicitly designed, implemented and evaluated to capture its multiple global environmental health benefits. PMID- 28338614 TI - Unintentional Injuries and Violence among Adults in Northern Jordan: A Hospital Based Retrospective Study. AB - Injuries (unintentional and intentional) are the main cause of death and disability worldwide, including Jordan. The main purpose of this hospital-based retrospective study was to identify characteristics, causes, and risk factors of unintentional injuries and violence among all adult patients who approached the Accidents and Emergency department because of injury in Northern Jordan. Data were collected retrospectively from four major hospitals from January 2008 to January 2013. A total of 2425 Jordanian individuals who accessed and were treated by the four hospitals were included in this study. The findings show that the majority of patients who approached the Accidents and Emergency departments in the four hospitals were males (n = 2044, 87.16%) versus females (n = 301, 12.8%). Violence was the most common reason of injury (70.66%), followed by road traffic crashes (23.21%). The most common anatomical locations of reported injuries were the head (38.74%), followed by abdomen/pelvis and lower back, among males and females (9.93%). Violence had a high significant effect on the site of injuries. Patients who had been injured to the head because of a stab wound or fighting were substantially over-involved in head injuries, with injury rates 3.88 and 7.51 times higher than those who had been injured to the head due to gunshot, respectively. Even patients who had been injured to the head because of assault show much higher involvement in injury risk than non-assault patients (Odds Ratio = 8.46). These findings highlight the need for a large national study to confirm the findings. It also draws attention to the importance of public awareness and to special injury prevention programs that not only focus on saving lives and lessening the number of injuries, illnesses, and fatalities, but also to limit the social and economic burden of injury among adults in Northern Jordan. PMID- 28338615 TI - Node Self-Deployment Algorithm Based on Pigeon Swarm Optimization for Underwater Wireless Sensor Networks. AB - At present, free-to-move node self-deployment algorithms aim at event coverage and cannot improve network coverage under the premise of considering network connectivity, network reliability and network deployment energy consumption. Thus, this study proposes pigeon-based self-deployment algorithm (PSA) for underwater wireless sensor networks to overcome the limitations of these existing algorithms. In PSA, the sink node first finds its one-hop nodes and maximizes the network coverage in its one-hop region. The one-hop nodes subsequently divide the network into layers and cluster in each layer. Each cluster head node constructs a connected path to the sink node to guarantee network connectivity. Finally, the cluster head node regards the ratio of the movement distance of the node to the change in the coverage redundancy ratio as the target function and employs pigeon swarm optimization to determine the positions of the nodes. Simulation results show that PSA improves both network connectivity and network reliability, decreases network deployment energy consumption, and increases network coverage. PMID- 28338616 TI - A Comparative Study of Phenols in Apulian Italian Wines. AB - Nutraceutics is a growing research field in which researchers study and attempt to improve the biological properties of metabolites in food. Wine is one of the most consumed products in the world and contains a plethora of molecules biologically relevant to human health. In this article, several polyphenols with potential antioxidant activity were measured in wines from Apulia, in Southeast Italy. Hydroxytyrosol, gallic and syringic acids, luteolin, quercetin, and trans resveratrol were identified and quantified by HPLC. The amount of the analyzed metabolites in wines were largely dependent on their color, with red ones being the richest compared to white and rose wines. Gallic acid was the most abundant polyphenol, followed by syringic acid and luteolin. Nevertheless, significant amounts of hydroxytyrosol, quercetin, and trans-resveratrol were also found. The average concentration of polyphenols found in these wines could have potential health-promoting effects, especially if consumed in moderate quantities on a regular basis. PMID- 28338617 TI - EGFR Family Members' Regulation of Autophagy Is at a Crossroads of Cell Survival and Death in Cancer. AB - The epidermal growth factor receptor (EGFR) signaling pathways are altered in many cancers contributing to increased cell survival. These alterations are caused mainly through increased expression or mutation of EGFR family members EGFR, ErbB2, ErbB3, and ErbB4. These receptors have been successfully targeted for cancer therapy. Specifically, a monoclonal antibody against ErbB2, trastuzumab, and a tyrosine kinase inhibitor against EGFR, gefitinib, have improved the survival of breast and lung cancer patients. Unfortunately, cancer patients frequently become resistant to these inhibitors. This has led to investigating how EGFR can contribute to cell survival and how cancer cells can overcome inhibition of its signaling. Indeed, it is coming into focus that EGFR signaling goes beyond a single signal triggering cell proliferation and survival and is a sensor that regulates the cell's response to microenvironmental stresses such as hypoxia. It acts as a switch that modulates the ability of cancer cells to survive. Autophagy is a process of self-digestion that is inhibited by EGFR allowing cancer cells to survive under stresses that would normally cause death and become resistant to chemotherapy. Inhibiting EGFR signaling allows autophagy to contribute to cell death. This gives new opportunities to develop novel therapeutic strategies to treat cancers that rely on EGFR signaling networks and autophagy. In this review, we summarize the current understanding of EGFR family member regulation of autophagy in cancer cells and how new therapeutic strategies could be developed to overcome drug resistance. PMID- 28338618 TI - Real-Time Gait Event Detection Based on Kinematic Data Coupled to a Biomechanical Model. AB - Real-time detection of multiple stance events, more specifically initial contact (IC), foot flat (FF), heel off (HO), and toe off (TO), could greatly benefit neurorobotic (NR) and neuroprosthetic (NP) control. Three real-time threshold based algorithms have been developed, detecting the aforementioned events based on kinematic data in combination with a biomechanical model. Data from seven subjects walking at three speeds on an instrumented treadmill were used to validate the presented algorithms, accumulating to a total of 558 steps. The reference for the gait events was obtained using marker and force plate data. All algorithms had excellent precision and no false positives were observed. Timing delays of the presented algorithms were similar to current state-of-the-art algorithms for the detection of IC and TO, whereas smaller delays were achieved for the detection of FF. Our results indicate that, based on their high precision and low delays, these algorithms can be used for the control of an NR/NP, with the exception of the HO event. Kinematic data is used in most NR/NP control schemes and is thus available at no additional cost, resulting in a minimal computational burden. The presented methods can also be applied for screening pathological gait or gait analysis in general in/outside of the laboratory. PMID- 28338620 TI - A Secure and Privacy-Preserving Navigation Scheme Using Spatial Crowdsourcing in Fog-Based VANETs. AB - Fog-based VANETs (Vehicular ad hoc networks) is a new paradigm of vehicular ad hoc networks with the advantages of both vehicular cloud and fog computing. Real time navigation schemes based on fog-based VANETs can promote the scheme performance efficiently. In this paper, we propose a secure and privacy preserving navigation scheme by using vehicular spatial crowdsourcing based on fog-based VANETs. Fog nodes are used to generate and release the crowdsourcing tasks, and cooperatively find the optimal route according to the real-time traffic information collected by vehicles in their coverage areas. Meanwhile, the vehicle performing the crowdsourcing task can get a reasonable reward. The querying vehicle can retrieve the navigation results from each fog node successively when entering its coverage area, and follow the optimal route to the next fog node until it reaches the desired destination. Our scheme fulfills the security and privacy requirements of authentication, confidentiality and conditional privacy preservation. Some cryptographic primitives, including the Elgamal encryption algorithm, AES, randomized anonymous credentials and group signatures, are adopted to achieve this goal. Finally, we analyze the security and the efficiency of the proposed scheme. PMID- 28338619 TI - Role and Function of A2A and A3 Adenosine Receptors in Patients with Ankylosing Spondylitis, Psoriatic Arthritis and Rheumatoid Arthritis. AB - Rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are chronic inflammatory rheumatic diseases that affect joints, causing debilitating pain and disability. Adenosine receptors (ARs) play a key role in the mechanism of inflammation, and the activation of A2A and A3AR subtypes is often associated with a reduction of the inflammatory status. The aim of this study was to investigate the involvement of ARs in patients suffering from early RA (ERA), RA, AS and PsA. Messenger RNA (mRNA) analysis and saturation binding experiments indicated an upregulation of A2A and A3ARs in lymphocytes obtained from patients when compared with healthy subjects. A2A and A3AR agonists inhibited nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappaB) activation and reduced inflammatory cytokines release, such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta and IL-6. Moreover, A2A and A3AR activation mediated a reduction of metalloproteinases (MMP)-1 and MMP-3. The effect of the agonists was abrogated by selective antagonists demonstrating the direct involvement of these receptor subtypes. Taken together, these data confirmed the involvement of ARs in chronic autoimmune rheumatic diseases highlighting the possibility to exploit A2A and A3ARs as therapeutic targets, with the aim to limit the inflammatory responses usually associated with RA, AS and PsA. PMID- 28338621 TI - Optimized 4,5-Diarylimidazoles as Potent/Selective Inhibitors of Protein Kinase CK1delta and Their Structural Relation to p38alpha MAPK. AB - The involvement of protein kinase CK1delta in the pathogenesis of severe disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, familial advanced sleep phase syndrome, and cancer has dramatically increased interest in the development of effective small molecule inhibitors for both therapeutic application and basic research. Unfortunately, the design of CK1 isoform-specific compounds has proved to be highly complicated due to the existence of six evolutionarily conserved human CK1 members that possess similar, different, or even opposite physiological and pathophysiological implications. Consequently, only few potent and selective CK1delta inhibitors have been reported so far and structurally divergent approaches are urgently needed in order to establish SAR that might enable complete discrimination of CK1 isoforms and related p38alpha MAPK. In this study we report on design and characterization of optimized 4,5 diarylimidazoles as highly effective ATP-competitive inhibitors of CK1delta with compounds 11b (IC50 CK1delta = 4 nM, IC50 CK1epsilon = 25 nM), 12a (IC50 CK1delta = 19 nM, IC50 CK1epsilon = 227 nM), and 16b (IC50 CK1delta = 8 nM, IC50 CK1epsilon = 81 nM) being among the most potent CK1delta-targeting agents published to date. Inhibitor compound 11b, displaying potential as a pharmacological tool, has further been profiled over a panel of 321 protein kinases exhibiting high selectivity. Cellular efficacy has been evaluated in human pancreatic cancer cell lines Colo357 (EC50 = 3.5 uM) and Panc89 (EC50 = 1.5 uM). SAR is substantiated by X-ray crystallographic analysis of 16b in CK1delta and 11b in p38alpha. PMID- 28338623 TI - A Study of Intramolecular Hydrogen Bonding in Levoglucosan Derivatives. AB - Organofluorine is a weak hydrogen-bond (HB) acceptor. Bernet et al. have demonstrated its capability to perturb OH...O intramolecular hydrogen bonds (IMHBs), using conformationally rigid carbohydrate scaffolds including levoglucosan derivatives. These investigations are supplemented here by experimental and theoretical studies involving six new levoglucosan derivatives, and complement the findings of Bernet et al. However, it is shown that conformational analysis is instrumental in interpreting the experimental data, due to the occurrence of non-intramolecular hydrogen-bonded populations which, although minor, cannot be neglected and appears surprisingly significant. The DFT conformational analysis, together with the computation of NMR parameters (coupling constants and chemical shifts) and wavefunction analyses (AIM, NBO), provides a full picture. Thus, for all compounds, the most stabilized structures show the OH groups in a conformation allowing IMHB with O5 and O6, when possible. Furthermore, the combined approach points out the occurrence of various IMHBs and the effect of the chemical modulations on their features. Thus, two-center or three-center IMHB interactions are observed in these compounds, depending on the presence or absence of additional HB acceptors, such as methoxy or fluorine. PMID- 28338626 TI - In Silico and In Vitro Analysis of Interaction between Ximelagatran and Human Leukocyte Antigen (HLA)-DRB1*07:01. AB - Idiosyncratic ximelagatran-induced hepatotoxicity has been reported to be associated with human leukocyte antigen (HLA)-DRB1*07:01 and ximelagatran has been reported to inhibit the binding of the ligand peptide to HLA-DRB1*07:01 in vitro. In order to predict the possible interaction modes of ximelagatran with HLA-DR molecules, in silico docking simulations were performed. Molecular dynamics (MD) simulations were also performed to predict the effect of ximelagatran on the binding mode of the ligand peptide to HLA-DRB1*07:01. A series of in silico simulations supported the inhibitory effect of ximelagatran on the binding of the ligand peptide to HLA-DRB1*07:01 in vitro. Furthermore, direct interactions of ximelagatran with HLA-DR molecules were evaluated in vitro, which supported the simulated interaction mode of ximelagatran with HLA DRB1*07:01. These results indicated that ximelagatran directly interacts with the peptide binding groove of HLA-DRB1*07:01 and competes with the ligand peptide for the binding site, which could alter the immune response and lead to the idiosyncratic ximelagatran-induced hepatotoxicity. PMID- 28338625 TI - (R)-(-)-Aloesaponol III 8-Methyl Ether from Eremurus persicus: A Novel Compound against Leishmaniosis. AB - Leishmaniosis is a neglected tropical disease which affects several millions of people worldwide. The current drug therapies are expensive and often lack efficacy, mainly due to the development of parasite resistance. Hence, there is an urgent need for new drugs effective against Leishmania infections. As a part of our ongoing study on the phytochemical characterization and biological investigation of plants used in the traditional medicine of western and central Asia, in the present study, we focused on Eremurus persicus root extract in order to evaluate its potential in the treatment of leishmaniosis. As a result of our study, aloesaponol III 8-methyl ether (ASME) was isolated for the first time from Eremurus persicus root extract, its chemical structure elucidated by means of IR and NMR experiments and the (R) configuration assigned by optical activity measurements: chiroptical aspects were investigated with vibrational circular dichroism (VCD) and electronic circular dichroism (ECD) spectroscopies and DFT (density functional theory) quantum mechanical calculations. Concerning biological investigations, our results clearly proved that (R)-ASME inhibits Leishmania infantum promastigotes viability (IC50 73 ug/mL), inducing morphological alterations and mitochondrial potential deregulation. Moreover, it is not toxic on macrophages at the concentration tested, thus representing a promising molecule against Leishmania infections. PMID- 28338624 TI - Nerve Growth Factor Signaling from Membrane Microdomains to the Nucleus: Differential Regulation by Caveolins. AB - Membrane microdomains or "lipid rafts" have emerged as essential functional modules of the cell, critical for the regulation of growth factor receptor mediated responses. Herein we describe the dichotomy between caveolin-1 and caveolin-2, structural and regulatory components of microdomains, in modulating proliferation and differentiation. Caveolin-2 potentiates while caveolin-1 inhibits nerve growth factor (NGF) signaling and subsequent cell differentiation. Caveolin-2 does not appear to impair NGF receptor trafficking but elicits prolonged and stronger activation of MAPK (mitogen-activated protein kinase), Rsk2 (ribosomal protein S6 kinase 2), and CREB (cAMP response element binding protein). In contrast, caveolin-1 does not alter initiation of the NGF signaling pathway activation; rather, it acts, at least in part, by sequestering the cognate receptors, TrkA and p75NTR, at the plasma membrane, together with the phosphorylated form of the downstream effector Rsk2, which ultimately prevents CREB phosphorylation. The non-phosphorylatable caveolin-1 serine 80 mutant (S80V), no longer inhibits TrkA trafficking or subsequent CREB phosphorylation. MC192, a monoclonal antibody towards p75NTR that does not block NGF binding, prevents exit of both NGF receptors (TrkA and p75NTR) from lipid rafts. The results presented herein underline the role of caveolin and receptor signaling complex interplay in the context of neuronal development and tumorigenesis. PMID- 28338628 TI - Revision of the Structure of Acremine P from a Marine-Derived Strain of Acremonium persicinum. AB - The previously published structure of the fungal metabolite acremine P is revised by re-evaluation of chemical shift values and NOESY data, and by DFT calculations. PMID- 28338627 TI - Morphology Analysis and Optimization: Crucial Factor Determining the Performance of Perovskite Solar Cells. AB - This review presents an overall discussion on the morphology analysis and optimization for perovskite (PVSK) solar cells. Surface morphology and energy alignment have been proven to play a dominant role in determining the device performance. The effect of the key parameters such as solution condition and preparation atmosphere on the crystallization of PVSK, the characterization of surface morphology and interface distribution in the perovskite layer is discussed in detail. Furthermore, the analysis of interface energy level alignment by using X-ray photoelectron spectroscopy and ultraviolet photoelectron spectroscopy is presented to reveals the correlation between morphology and charge generation and collection within the perovskite layer, and its influence on the device performance. The techniques including architecture modification, solvent annealing, etc. were reviewed as an efficient approach to improve the morphology of PVSK. It is expected that further progress will be achieved with more efforts devoted to the insight of the mechanism of surface engineering in the field of PVSK solar cells. PMID- 28338629 TI - Study of the Accumulation of Toxic and Essential Ultra-Trace Elements in Fruits of Sorbus domestica L. AB - In the present work, the accumulation of selected toxic and essential ultra-trace elements in fruits of service tree (Sorbus domestica L.) were determined depending on harvest time. Samples were collected from the same sampling area in two different years and within one year in September and October (maturity state). Harvesting the fruits in the same area excludes the influence of metals taken up via roots, thus the impact of airborne contamination by heavy metal translocation can be studied. All samples were dried and digested using an acidic microwave assisted digestion system prior to quantification by inductively coupled plasma-sector field mass spectrometry (ICP-SFMS). The elements chosen were Arsenic and Cadmium as well as Lithium, Molybdenum, and Selenium. The Arsenic content rose with maturity in mesocarp. Cadmium found in the mesocarp was unaffected by ripeness. For Selenium and Molybdenum, no statistically significant effect of ripeness could be found on their content in mesocarp. Lithium could not be detected in the majority of fruit samples. Differences between the metal concentrations based on the year of harvest were found for Arsenic, Molybdenum, and Selenium, depending on precipitation. The drier the season, the more Arsenic was accumulated. For Molybdenum and Selenium, the opposite effect was observed. PMID- 28338630 TI - Life cycle, Ecological Characteristics, and Control of Trachys yanoi (Coleoptera: Buprestidae), an Important Pest of Zelkova serrata. AB - This study was conducted to elucidate the life cycle and the ecological characteristics of Trachys yanoi Y. Kurosawa, an important pest of Zelkova serrata (Thunb.) Makino. Life cycle, mortality rates in developmental stages, annual population dynamics, and early leaf abscission were investigated. Adults emerged from under the bark of Zelkova trees in April and fed on Zelkova leaves. Females laid 49 eggs on average, mainly in May and early June. Eggs hatched after 17 days, and the larvae fed inside the leaves. They developed through three instars. In July, leaves with the final stage of larvae were abscised. Four days after abscission, the larvae pupated. New adults eclosed from pupae seven days after pupation, and the adults emerged from abscised leaves after an additional two days. In total, 1650 adults emerged per 1 m2 of forest floor, resulting in a major population increase. The newly emerged adults fed on the remaining Zelkova leaves, compounding the damage. In October, adults overwintered under the tree bark. Mortality rates in the egg, larval, and pupal stages were 41%, 58%, and 31%, respectively. The mortality rate among overwintering individuals was 43%. Because only Zelkova leaves that were abscised in July contained the larvae, and because only a small number of beetles emerged from non-abscised, mined leaves, the removal of abscised leaves at nine-day intervals over period of early leaf abscission is a simple and effective way to control the beetle. PMID- 28338631 TI - Death of an Ex-Spouse: Lessons in Family Communication about Disenfranchised Grief. AB - The death of a loved one is an emotional-laden experience, and while grief and mourning rituals are less formal today in many communities, there remain some social norms for individuals to process loss. The death of an ex-family member, such as a former spouse, is more complicated and expectations for how to respond are fraught with uncertainty. While grief has been studied and is primarily understood as an individual cognitive process, scholars in sociology and communication are considering the ways in which grief and mourning are social and take place in dialogue with others. This manuscript explores Kenneth Doka's concept of disenfranchised grief, which is "grief that is experienced when loss cannot be openly acknowledged, socially sanctioned, or publicly mourned" through the author's experience of the death of her ex-husband. The narrative will recount how the author learned about her ex-husband's death (via text message), and will challenge definitions of family and family communication about death and grief, particularly the communication strategies used to cope with this unique type of loss. PMID- 28338632 TI - A Polynomial Subset-Based Efficient Multi-Party Key Management System for Lightweight Device Networks. AB - Wireless Sensor Networks (WSNs) consist of lightweight devices to measure sensitive data that are highly vulnerable to security attacks due to their constrained resources. In a similar manner, the internet-based lightweight devices used in the Internet of Things (IoT) are facing severe security and privacy issues because of the direct accessibility of devices due to their connection to the internet. Complex and resource-intensive security schemes are infeasible and reduce the network lifetime. In this regard, we have explored the polynomial distribution-based key establishment schemes and identified an issue that the resultant polynomial value is either storage intensive or infeasible when large values are multiplied. It becomes more costly when these polynomials are regenerated dynamically after each node join or leave operation and whenever key is refreshed. To reduce the computation, we have proposed an Efficient Key Management (EKM) scheme for multiparty communication-based scenarios. The proposed session key management protocol is established by applying a symmetric polynomial for group members, and the group head acts as a responsible node. The polynomial generation method uses security credentials and secure hash function. Symmetric cryptographic parameters are efficient in computation, communication, and the storage required. The security justification of the proposed scheme has been completed by using Rubin logic, which guarantees that the protocol attains mutual validation and session key agreement property strongly among the participating entities. Simulation scenarios are performed using NS 2.35 to validate the results for storage, communication, latency, energy, and polynomial calculation costs during authentication, session key generation, node migration, secure joining, and leaving phases. EKM is efficient regarding storage, computation, and communication overhead and can protect WSN-based IoT infrastructure. PMID- 28338633 TI - Degradation of Marine Algae-Derived Carbohydrates by Bacteroidetes Isolated from Human Gut Microbiota. AB - Carrageenan, agarose, and alginate are algae-derived undigested polysaccharides that have been used as food additives for hundreds of years. Fermentation of dietary carbohydrates of our food in the lower gut of humans is a critical process for the function and integrity of both the bacterial community and host cells. However, little is known about the fermentation of these three kinds of seaweed carbohydrates by human gut microbiota. Here, the degradation characteristics of carrageenan, agarose, alginate, and their oligosaccharides, by Bacteroides xylanisolvens, Bacteroides ovatus, and Bacteroides uniforms, isolated from human gut microbiota, are studied. PMID- 28338634 TI - Construction of an Acetylcholinesterase Sensor Based on Synthesized Paramagnetic Nanoparticles, a Simple Tool for Neurotoxic Compounds Assay. AB - Magnetic particles (MPs) have been widely used in biological applications in recent years as a carrier for various molecules. Their big advantage is in repeated use of immobilized molecules including enzymes. Acetylcholinesterase (AChE) is an enzyme playing crucial role in neurotransmission and the enzyme is targeted by various molecules like Alzheimer's drugs, pesticides and warfare agents. In this work, an electrochemical biosensor having AChE immobilized onto MPs and stabilized through glutaraldehyde (GA) molecule was proposed for assay of the neurotoxic compounds. The prepared nanoparticles were modified by pure AChE and they were used for the measurement anti-Alzheimer's drug galantamine and carbamate pesticide carbofuran with limit of detection 1.5 uM and 20 nM, respectively. All measurements were carried out using screen-printed sensor with carbon working, silver reference, and carbon auxiliary electrode. Standard Ellman's assay was used for validation measurement of both inhibitors. Part of this work was the elimination of reversible inhibitors represented by galantamine from the active site of AChE. For this purpose, we used a lower pH to get the original activity of AChE after inhibition by galantamine. We also observed decarbamylation of the AChE-carbofuran adduct. Influence of organic solvents to AChE as well as repeatability of measurement with MPs with AChE was also established. PMID- 28338622 TI - Phosphodiesterase Inhibitors as a Therapeutic Approach to Neuroprotection and Repair. AB - A wide diversity of perturbations of the central nervous system (CNS) result in structural damage to the neuroarchitecture and cellular defects, which in turn are accompanied by neurological dysfunction and abortive endogenous neurorepair. Altering intracellular signaling pathways involved in inflammation and immune regulation, neural cell death, axon plasticity and remyelination has shown therapeutic benefit in experimental models of neurological disease and trauma. The second messengers, cyclic adenosine monophosphate (cyclic AMP) and cyclic guanosine monophosphate (cyclic GMP), are two such intracellular signaling targets, the elevation of which has produced beneficial cellular effects within a range of CNS pathologies. The only known negative regulators of cyclic nucleotides are a family of enzymes called phosphodiesterases (PDEs) that hydrolyze cyclic nucleotides into adenosine monophosphate (AMP) or guanylate monophosphate (GMP). Herein, we discuss the structure and physiological function as well as the roles PDEs play in pathological processes of the diseased or injured CNS. Further we review the approaches that have been employed therapeutically in experimental paradigms to block PDE expression or activity and in turn elevate cyclic nucleotide levels to mediate neuroprotection or neurorepair as well as discuss both the translational pathway and current limitations in moving new PDE-targeted therapies to the clinic. PMID- 28338635 TI - A Formaldehyde Sensor Based on Molecularly-Imprinted Polymer on a TiO2 Nanotube Array. AB - Today, significant attention has been brought to the development of sensitive, specific, cheap, and reliable sensors for real-time monitoring. Molecular imprinting technology is a versatile and promising technology for practical applications in many areas, particularly chemical sensors. Here, we present a chemical sensor for detecting formaldehyde, a toxic common indoor pollutant gas. Polypyrrole-based molecularly-imprinted polymer (PPy-based MIP) is employed as the sensing recognition layer and synthesized on a titanium dioxide nanotube array (TiO2-NTA) for increasing its surface-to-volume ratio, thereby improving the sensor performance. Our sensor selectively detects formaldehyde in the parts per million (ppm) range at room temperature. It also shows a long-term stability and small fluctuation to humidity variations. These are attributed to the thin fishnet-like structure of the PPy-based MIP on the highly-ordered and vertically aligned TiO2-NTA. PMID- 28338637 TI - Using an Active-Optical Sensor to Develop an Optimal NDVI Dynamic Model for High Yield Rice Production (Yangtze, China). AB - The successful development of an optimal canopy vegetation index dynamic model for obtaining higher yield can offer a technical approach for real-time and nondestructive diagnosis of rice (Oryza sativa L) growth and nitrogen (N) nutrition status. In this study, multiple rice cultivars and N treatments of experimental plots were carried out to obtain: normalized difference vegetation index (NDVI), leaf area index (LAI), above-ground dry matter (DM), and grain yield (GY) data. The quantitative relationships between NDVI and these growth indices (e.g., LAI, DM and GY) were analyzed, showing positive correlations. Using the normalized modeling method, an appropriate NDVI simulation model of rice was established based on the normalized NDVI (RNDVI) and relative accumulative growing degree days (RAGDD). The NDVI dynamic model for high-yield production in rice can be expressed by a double logistic model: RNDVI = ( 1 + e - 15.2829 * ( R A G D D i - 0.1944 ) ) - 1 - ( 1 + e - 11.6517 * ( R A G D D i - 1.0267 ) ) - 1 (R2 = 0.8577**), which can be used to accurately predict canopy NDVI dynamic changes during the entire growth period. Considering variation among rice cultivars, we constructed two relative NDVI (RNDVI) dynamic models for Japonica and Indica rice types, with R2 reaching 0.8764** and 0.8874**, respectively. Furthermore, independent experimental data were used to validate the RNDVI dynamic models. The results showed that during the entire growth period, the accuracy (k), precision (R2), and standard deviation of RNDVI dynamic models for the Japonica and Indica cultivars were 0.9991, 1.0170; 0.9084**, 0.8030**; and 0.0232, 0.0170, respectively. These results indicated that RNDVI dynamic models could accurately reflect crop growth and predict dynamic changes in high-yield crop populations, providing a rapid approach for monitoring rice growth status. PMID- 28338636 TI - Survey on Urinary Levels of Aflatoxins in Professionally Exposed Workers. AB - Feed mill workers may handle or process maize contaminated with aflatoxins (AFs). This condition may lead to an unacceptable intake of toxins deriving from occupational exposure. This study assessed the serological and urinary levels of AFs in workers exposed to potentially contaminated dusts in two mills. From March to April 2014, blood and urine samples were collected, on Monday and Friday morning of the same working week from 29 exposed workers and 30 non-exposed controls. AFs (M1, G2, G1, B1, B2) and aflatoxicol (AFOH) A were analyzed. Each subject filled in a questionnaire to evaluate potential food-borne exposures to mycotoxins. AFs contamination in environmental dust was measured in both plants. No serum sample was found to be positive. Seventy four percent of urine samples (73.7%) revealed AFM1 presence. AFM1 mean concentration was 0.035 and 0.027 ng/mL in exposed and non-exposed workers, respectively (p = 0.432); the concentration was slightly higher in Friday's than in Monday's samples, in exposed workers, 0.040 versus (vs.) 0.031 and non-exposed controls (0.030 vs. 0.024, p = 0.437). Environmental AFs contamination ranged from 7.2 to 125.4 ug/kg. The findings of this study reveal the presence of higher AFs concentration in exposed workers than in non-exposed controls, although these differences are to be considered consistent with random fluctuations. PMID- 28338638 TI - The Value of Coenzyme Q10 Determination in Mitochondrial Patients. AB - Coenzyme Q10 (CoQ) is a lipid that is ubiquitously synthesized in tissues and has a key role in mitochondrial oxidative phosphorylation. Its biochemical determination provides insight into the CoQ status of tissues and may detect CoQ deficiency that can result from either an inherited primary deficiency of CoQ metabolism or may be secondary to different genetic and environmental conditions. Rapid identification of CoQ deficiency can also allow potentially beneficial treatment to be initiated as early as possible. CoQ may be measured in different specimens, including plasma, blood mononuclear cells, platelets, urine, muscle, and cultured skin fibroblasts. Blood and urinary CoQ also have good utility for CoQ treatment monitoring. PMID- 28338639 TI - Beyond the Cholesterol-Lowering Effect of Soy Protein: A Review of the Effects of Dietary Soy and Its Constituents on Risk Factors for Cardiovascular Disease. AB - The hypocholesterolemic effect of soy is well-documented and this has led to the regulatory approval of a health claim relating soy protein to a reduced risk of cardiovascular disease (CVD). However, soybeans contain additional components, such as isoflavones, lecithins, saponins and fiber that may improve cardiovascular health through independent mechanisms. This review summarizes the evidence on the cardiovascular benefits of non-protein soy components in relation to known CVD risk factors such as hypertension, hyperglycemia, inflammation, and obesity beyond cholesterol lowering. Overall, the available evidence suggests non protein soy constituents improve markers of cardiovascular health; however, additional carefully designed studies are required to independently elucidate these effects. Further, work is also needed to clarify the role of isoflavone metabolizing phenotype and gut microbiota composition on biological effect. PMID- 28338641 TI - Nerolidol and Farnesol Inhibit Some Cytochrome P450 Activities but Did Not Affect Other Xenobiotic-Metabolizing Enzymes in Rat and Human Hepatic Subcellular Fractions. AB - Sesquiterpenes, 15-carbon compounds formed from three isoprenoid units, are the main components of plant essential oils. Sesquiterpenes occur in human food, but they are principally taken as components of many folk medicines and dietary supplements. The aim of our study was to test and compare the potential inhibitory effect of acyclic sesquiterpenes, trans-nerolidol, cis-nerolidol and farnesol, on the activities of the main xenobiotic-metabolizing enzymes in rat and human liver in vitro. Rat and human subcellular fractions, relatively specific substrates, corresponding coenzymes and HPLC, spectrophotometric or spectrofluorometric analysis of product formation were used. The results showed significant inhibition of cytochromes P450 (namely CYP1A, CYP2B and CYP3A subfamilies) activities by all tested sesquiterpenes in rat as well as in human hepatic microsomes. On the other hand, all tested sesquiterpenes did not significantly affect the activities of carbonyl-reducing enzymes and conjugation enzymes. The results indicate that acyclic sesquiterpenes might affect CYP1A, CYP2B and CYP3A mediated metabolism of concurrently administered drugs and other xenobiotics. The possible drug-sesquiterpene interactions should be verified in in vivo experiments. PMID- 28338642 TI - Determination of Ultra-trace Rhodium in Water Samples by Graphite Furnace Atomic Absorption Spectrometry after Cloud Point Extraction Using 2-(5-Iodo-2 Pyridylazo)-5-Dimethylaminoaniline as a Chelating Agent. AB - A highly sensitive method based on cloud point extraction (CPE) separation/preconcentration and graphite furnace atomic absorption spectrometry (GFAAS) detection has been developed for the determination of ultra-trace amounts of rhodium in water samples. A new reagent, 2-(5-iodo-2-pyridylazo)-5 dimethylaminoaniline (5-I-PADMA), was used as the chelating agent and the nonionic surfactant TritonX-114 was chosen as extractant. In a HAc-NaAc buffer solution at pH 5.5, Rh(III) reacts with 5-I-PADMA to form a stable chelate by heating in a boiling water bath for 10 min. Subsequently, the chelate is extracted into the surfactant phase and separated from bulk water. The factors affecting CPE were investigated. Under the optimized conditions, the calibration graph was linear in the range of 0.1-6.0 ng/mL, the detection limit was 0.023 ng/mL for rhodium and relative standard deviation was 3.67% (c = 1.0 ng/mL, n = 11).The method has been applied to the determination of trace rhodium in water samples with satisfactory results. PMID- 28338640 TI - Metal-Based PSMA Radioligands. AB - Prostate cancer is one of the most common malignancies for which great progress has been made in identifying appropriate molecular targets that would enable efficient in vivo targeting for imaging and therapy. The type II integral membrane protein, prostate specific membrane antigen (PSMA) is overexpressed on prostate cancer cells in proportion to the stage and grade of the tumor progression, especially in androgen-independent, advanced and metastatic disease, rendering it a promising diagnostic and/or therapeutic target. From the perspective of nuclear medicine, PSMA-based radioligands may significantly impact the management of patients who suffer from prostate cancer. For that purpose, chelating-based PSMA-specific ligands have been labeled with various diagnostic and/or therapeutic radiometals for single-photon-emission tomography (SPECT), positron-emission-tomography (PET), radionuclide targeted therapy as well as intraoperative applications. This review focuses on the development and further applications of metal-based PSMA radioligands. PMID- 28338643 TI - Geographical Correlations between Indoor Radon Concentration and Risks of Lung Cancer, Non-Hodgkin's Lymphoma, and Leukemia during 1999-2008 in Korea. AB - Indoor radon is the second most important risk factor for lung cancer and may also be a risk factor for hematopoietic cancers, particularly in children and adolescents. The present study measured indoor radon concentration nationwide at 5553 points during 1989-2009 and spatially interpolated using lognormal kriging. The incidences of lung cancer, non-Hodgkin's lymphoma (NHL), and leukemia, stratified by sex and five-year age groups in each of the 234 administrative regions in the country during 1999-2008, were obtained from the National Cancer Registry and used to calculate the standardized incidence ratios. After considering regional deprivation index values and smoking rates by sex in each region as confounding variables, the cancer risks were estimated based on Bayesian hierarchical modeling. We found that a 10 Bq/m3 increase in indoor radon concentration was associated with a 1% increase in the incidence of lung cancer in male and a 7% increase in NHL in female children and adolescents in Korea aged less than 20 years. Leukemia was not associated with indoor radon concentration. The increase in NHL risk among young women requires confirmation in future studies, and the radon control program should consider children and adolescents. PMID- 28338644 TI - Clinical Hypnosis, an Effective Mind-Body Modality for Adolescents with Behavioral and Physical Complaints. AB - Mind-body medicine is a system of health practices that includes meditation/relaxation training, guided imagery, hypnosis, biofeedback, yoga, art/music therapy, prayer, t'ai chi, and psychological therapies such as cognitive behavioral therapy. Clinical hypnosis is an important mind-body tool that serves as an adjunct to conventional medical care for the adolescent patient. Clinical hypnosis specifically uses self-directed therapeutic suggestions to cultivate the imagination and facilitate the mind-body connection, leading to positive emotional and physical well-being. There are many similarities between clinical hypnosis and other mind-body/self-regulatory modalities such as visual imagery, mindfulness meditation, yoga, and biofeedback that incorporate experiential learning and mechanisms for change. They may be viewed as subtypes of the hypnotic experience and share the common experience of trance as the entree into self-empowered change in physiologic and psychological states. Clinical hypnosis can be used by health care providers to teach adolescents coping skills to deal with a wide variety of conditions such as chronic headaches, recurrent abdominal pain, anxiety, depression, grief and bereavement, phobias, anger, family stressors, sleep disorders, or enuresis. Clinical vignettes are given to help illustrate the effectiveness of hypnosis in adolescents. PMID- 28338645 TI - Development of 44 Novel Polymorphic SSR Markers for Determination of Shiitake Mushroom (Lentinula edodes) Cultivars. AB - The shiitake mushroom (Lentinulaedodes) is one of the most popular edible mushrooms in the world and has attracted attention for its value in medicinal and pharmacological uses. With recent advanced research and techniques, the agricultural cultivation of the shiitake mushroom has been greatly increased, especially in East Asia. Additionally, demand for the development of new cultivars with good agricultural traits has been greatly enhanced, but the development processes are complicated and more challenging than for other edible mushrooms. In this study, we developed 44 novel polymorphic simple sequence repeat (SSR) markers for the determination of shiitake mushroom cultivars based on a whole genome sequencing database of L. edodes. These markers were found to be polymorphic and reliable when screened in 23 shiitake mushroom cultivars. For the 44 SSR markers developed in this study, the major allele frequency ranged from 0.13 to 0.94; the number of genotypes and number of alleles were each 2-11; the observed and expected heterozygosity were 0.00-1.00 and 0.10-0.90, respectively; and the polymorphic information content value ranged from 0.10 to 0.89. These new markers can be used for molecular breeding, the determination of cultivars, and other applications. PMID- 28338647 TI - Is primary prevention with antiepileptic drugs effective in brain tumors or brain metastases? AB - Patients with brain tumors ?primary or metastatic- have an increased risk of presenting seizures during the course of their disease. So, prophylactic antiepileptic drugs have been proposed. However, the effects of this intervention are not yet clear. To answer this question, we searched in Epistemonikos database, which is maintained by screening multiple databases. We identified 12 systematic reviews including 80 studies overall. Twelve corresponded to randomized trials, but only two answered the question of interest. We extracted data, conducted a meta-analysis and generated a summary of findings table using the GRADE method. We concluded primary prevention with antiepileptic drugs might not reduce the risk of seizures, and it is associated to frequent adverse effects. PMID- 28338648 TI - Letters to the editor in medical research. PMID- 28338649 TI - [Student scientific events in Cuba: an opportunity for all]. PMID- 28338646 TI - Type IV Secretion and Signal Transduction of Helicobacter pylori CagA through Interactions with Host Cell Receptors. AB - Helicobacter pylori is a highly successful human bacterium, which is exceptionally equipped to persistently inhabit the human stomach. Colonization by this pathogen is associated with gastric disorders ranging from chronic gastritis and peptic ulcers to cancer. Highly virulent H. pylori strains express the well established adhesins BabA/B, SabA, AlpA/B, OipA, and HopQ, and a type IV secretion system (T4SS) encoded by the cag pathogenicity island (PAI). The adhesins ascertain intimate bacterial contact to gastric epithelial cells, while the T4SS represents an extracellular pilus-like structure for the translocation of the effector protein CagA. Numerous T4SS components including CagI, CagL, CagY, and CagA have been shown to target the integrin-beta1 receptor followed by translocation of CagA across the host cell membrane. The interaction of CagA with membrane-anchored phosphatidylserine and CagA-containing outer membrane vesicles may also play a role in the delivery process. Translocated CagA undergoes tyrosine phosphorylation in C-terminal EPIYA-repeat motifs by oncogenic Src and Abl kinases. CagA then interacts with an array of host signaling proteins followed by their activation or inactivation in phosphorylation-dependent and phosphorylation-independent fashions. We now count about 25 host cell binding partners of intracellular CagA, which represent the highest quantity of all currently known virulence-associated effector proteins in the microbial world. Here we review the research progress in characterizing interactions of CagA with multiple host cell receptors in the gastric epithelium, including integrin-beta1, EGFR, c-Met, CD44, E-cadherin, and gp130. The contribution of these interactions to H. pylori colonization, signal transduction, and gastric pathogenesis is discussed. PMID- 28338650 TI - Risk factors associated to hospital mortality in patients with acute kidney injury on hemodialysis. AB - INTRODUCTION: The worldwide incidence of acute kidney injury is 18% and the overall hospital mortality can rise above 50%. In Peru, there are few series about mortality of acute kidney injury in hemodialysis patients. OBJECTIVES: To identify risk factors associated to hospital mortality of acute kidney injury in hemodialysis patients. METHODS: This is a retrospective cohort of patients with acute kidney injury in hemodialysis of Hospital Nacional Edgardo Rebagliati Martins gathered between January 2013 and December 2015. The sample size was 154 patients which allowed a power of 80% and a CI of 95%. ICD-10 codes were used to identify medical records of patients with acute kidney injury (N.17) and hemodialysis (Z.49). The independent variable was oliguria, and the primary outcome was hospital mortality. Poisson regression was used for multivariate analysis. RESULTS: We identified a total of 285 patients; 212 medical records were analyzed and 44 were excluded. Out of the 168 medical records, 129 belonged to living patients and 39 to deceased ones. The overall mortality incidence was 17.2%. The principal etiologies of acute kidney injury while in hemodialysis were sepsis (39.2%), and severe dehydration (10.8%). In the adjusted model, the risk factors associated to hospital mortality of acute kidney injury while in hemodialysis were elevated serum lactate (RR 1.09), elevated serum potassium (RR 0.93), and mean arterial pressure (RR 0.97). CONCLUSIONS: Lactate is an objective parameter that can predict prognosis and contributes to a better management of acute kidney injury in hemodialysis patients. PMID- 28338651 TI - Dichotomy in intrahepatic cholangiocarcinomas based on histologic similarities to hilar cholangiocarcinomas. AB - Intrahepatic cholangiocarcinomas were classified into two types based on their microscopic appearance. Tumors with histologic similarities to hilar cholangiocarcinomas (predominantly ductal adenocarcinomas with minor tubular components, if present, restricted to the invasive front) were defined as the perihilar type, whereas the others were classified as peripheral cholangiocarcinomas. Among the 47 cases examined in the present study, 26 (55%) were classified as the perihilar type, whereas 21 (45%) were the peripheral type. The perihilar type had higher pT stages and more frequently showed a periductal infiltrating gross appearance and microscopic perineural infiltration than peripheral cholangiocarcinomas. The presence of low-grade biliary intraepithelial neoplasia in the adjacent bile ducts was only found in perihilar cholangiocarcinomas (6/21, 29%). The immunophenotype also differed between the two types with MUC5AC and MUC6 being more commonly expressed in the perihilar type. One-third of perihilar cholangiocarcinomas lacked the expression of SMAD4, suggesting SMAD4 mutations, whereas the loss of BAP1 expression and IDH1 mutations were almost restricted to the peripheral type (35 and 15%, respectively). Patients with perihilar cholangiocarcinoma had worse overall survival than those with peripheral cancer (P=0.027). A multivariate analysis identified the histologic classification as an independent prognostic factor (P=0.005, HR=3.638). Comparisons between intrahepatic and hilar cholangiocarcinomas also revealed that the molecular features and prognosis of perihilar cholangiocarcinomas were very similar to those of hilar cholangiocarcinomas. In conclusion, this histology-based classification scheme of intrahepatic cholangiocarcinomas will be useful and clinically relevant because it represents different underlying molecular features and has an independent prognostic value. PMID- 28338652 TI - 3q26.2/EVI1 rearrangement is associated with poor prognosis in classical Philadelphia chromosome-negative myeloproliferative neoplasms. AB - Classical Philadelphia chromosome-negative myeloproliferative neoplasms are a group of closely related myeloid disorders with different histologic features and clinical presentations at an early stage, but all later develop into a similar fibrotic stage with variable risk of acute transformation. The significance of 3q26.2/EVI1 rearrangement has been well recognized in acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia. However, the clinical importance of 3q26.2/EVI1 rearrangement in classical Philadelphia chromosome negative myeloproliferative neoplasms is unknown. Here we reported 15 patients with classical Philadelphia chromosome-negative myeloproliferative neoplasms showing 3q26.2 rearrangement, including inv(3)(q21q26.2) (n=6), t(3;21)(q26.2;q22)(n=4), t(3;3)(q21;q26.2)(n=3), inv(3)(q13.3q26.2)(n=1), and t(3;12)(q26.2;p13)(n=1). In addition to 3q26.2 rearrangement, 9 of 15 cases had other concurrent karyotypical abnormalities, including -7/7q- and -5/5q-. There were 8 men and 7 women with a median age of 59 years (range, 35-79 years) at initial diagnosis of myeloproliferative neoplasms: 8 patients had primary myelofibrosis, 4 had polycythemia vera, and 3 had essential thrombocythemia. JAK2 V617F mutation was detected in 8/14 patients, including 4/4 with polycythemia vera. The median interval from the initial diagnosis of myeloproliferative neoplasms to the detection of 3q26.2 rearrangement was 44 months (range, 1-219 months). At time of emergence of 3q26.2 rearrangement, 11 patients were in blast phase and 2 patients had increased blasts (6-19%). Dyspoiesis, predominantly in megakaryocytes, were detected in all patients with adequate specimens at time of 3q26.2 rearrangement. Following 3q26.2 rearrangement, 12 patients received chemotherapy, but none of them achieved complete remission. Of 14 patients with follow-up information, all died with a median overall survival time of only 3 months (range 0-14 months) after the emergence of 3q26.2 rearrangement. In summary, 3q26.2 rearrangement in classical Philadelphia chromosome-negative myeloproliferative neoplasms is associated with other concurrent cytogenetic abnormalities, a rapid disease progression and blast transformation, a poor response to chemotherapy and a dismal prognosis. PMID- 28338654 TI - TFEB-VEGFA (6p21.1) co-amplified renal cell carcinoma: a distinct entity with potential implications for clinical management. AB - A subset of renal cell carcinomas shows TFEB overexpression secondary to MALAT1 TFEB gene fusion. As alternate mechanisms of TFEB overexpression are likely to have the same effect, we sought to determine the frequency of amplification of TFEB and the adjacent VEGFA gene at 6p21.1. As patients with metastatic renal cell carcinomas are managed with anti-VEGF therapies, we retrospectively assessed therapeutic response in patients with amplified tumors. Amplification status was analyzed for 875 renal cell carcinomas from our institution, a consultative case and 794 cases from The Cancer Genome Atlas. Cases were classified as having low level (5-10 copies), and high-level amplification (>10 copies), and were further analyzed for adjacent oncogene copy number status (n=6; 3 single-nucleotide polymorphism genomic microarray, 3 The Cancer Genome Atlas) and structural rearrangements (n=1; mate-pair sequencing). These were then reviewed for histopathology, immunophenotype, and response to VEGF-targeted therapy on follow up. In all, 10/875 (1.1%) institutional cases, 1 consultative case, and 3/794 (0.4%) of The Cancer Genome Atlas cases showed TFEB high-level amplification, while 14/875 (1.6%) cases showed TFEB low-level amplification. All cases had associated VEGFA amplification. This was confirmed with evaluation for copy number changes (n=6). The 6p21.1 high and low-level amplified tumors occurred in adults (mean age: 66), with over half being >=pT3 (13/25, 52%), and most showed oncocytic, tubulopapillary features and high grade (>=grade 3: 20/22, 91%). These were aggressive tumors with metastasis and death from renal cell carcinoma in 11 (of 24, 46%) cases. Four patients received targeted therapy and had a mean survival of 31 months (range: 17-50) post nephrectomy. In summary, a group of aggressive renal cell carcinomas show genomic amplification of the 6p21.1 region including TFEB and VEGFA genes and share morphologic features. Additional studies are warranted to determine whether these patients respond to anti-VEGF therapy. PMID- 28338653 TI - Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer. AB - The spectrum of genomic alterations in ductal carcinoma in situ (DCIS) is relatively unexplored, but is likely to provide useful insights into its biology, its progression to invasive carcinoma and the risk of recurrence. DCIS (n=20) with a range of phenotypes was assessed by massively parallel sequencing for mutations and copy number alterations and variants validated by Sanger sequencing. PIK3CA mutations were identified in 11/20 (55%), TP53 mutations in 6/20 (30%), and GATA3 mutations in 9/20 (45%). Screening an additional 91 cases for GATA3 mutations identified a final frequency of 27% (30/111), with a high proportion of missense variants (8/30). TP53 mutations were exclusive to high grade DCIS and more frequent in PR-negative tumors compared with PR-positive tumors (P=0.037). TP53 mutant tumors also had a significantly higher fraction of the genome altered by copy number than wild-type tumors (P=0.005), including a significant positive association with amplification or gain of ERBB2 (P<0.05). The association between TP53 mutation and ERBB2 amplification was confirmed in a wider DCIS cohort using p53 immunohistochemistry as a surrogate marker for TP53 mutations (P=0.03). RUNX1 mutations and MAP2K4 copy number loss were novel findings in DCIS. Frequent copy number alterations included gains on 1q, 8q, 17q, and 20q and losses on 8p, 11q, 16q, and 17p. Patterns of genomic alterations observed in DCIS were similar to those previously reported for invasive breast cancers, with all DCIS having at least one bona fide breast cancer driver event. However, an increase in GATA3 mutations and fewer copy number changes were noted in DCIS compared with invasive carcinomas. The role of such alterations as prognostic and predictive biomarkers in DCIS is an avenue for further investigation. PMID- 28338657 TI - The Bcl2a1 gene cluster finally knocked out: first clues to understanding the enigmatic role of the Bcl-2 protein A1. PMID- 28338655 TI - Evolution of caspase-mediated cell death and differentiation: twins separated at birth. AB - The phenotypic and biochemical similarities between caspase-mediated apoptosis and cellular differentiation are striking. They include such diverse phenomenon as mitochondrial membrane perturbations, cytoskeletal rearrangements and DNA fragmentation. The parallels between the two disparate processes suggest some common ancestry and highlight the paradoxical nature of the death-centric view of caspases. That is, what is the driving selective pressure that sustains death inducing proteins throughout eukaryotic evolution? Plausibly, caspase function may be rooted in a primordial non-death function, such as cell differentiation, and was co-opted for its role in programmed cell death. This review will delve into the links between caspase-mediated apoptosis and cell differentiation and examine the distinguishing features of these events. More critically, we chronicle the evolutionary origins of caspases and propose that caspases may have held an ancient role in mediating the fidelity of cell division/differentiation through its effects on proteostasis and protein quality control. PMID- 28338656 TI - Focal adhesion kinase depletion reduces human hepatocellular carcinoma growth by repressing enhancer of zeste homolog 2. AB - Hepatocellular carcinoma (HCC) is the most common type of liver cancer in humans. The focal adhesion tyrosine kinase (FAK) is often over-expressed in human HCC and FAK inhibition may reduce HCC cell invasiveness. However, the anti-oncogenic effect of FAK knockdown in HCC cells remains to be clarified. We found that FAK depletion in HCC cells reduced in vitro and in vivo tumorigenicity, by inducing G2/M arrest and apoptosis, decreasing anchorage-independent growth, and modulating the expression of several cancer-related genes. Among these genes, we showed that FAK silencing decreased transcription and nuclear localization of enhancer of zeste homolog 2 (EZH2) and its tri-methylation activity on lysine 27 of histone H3 (H3K27me3). Accordingly, FAK, EZH2 and H3K27me3 were concomitantly upregulated in human HCCs compared to non-tumor livers. In vitro experiments demonstrated that FAK affected EZH2 expression and function by modulating, at least in part, p53 and E2F2/3 transcriptional activity. Moreover, FAK silencing downregulated both EZH2 binding and histone H3K27me3 levels at the promoter of its target gene NOTCH2. Finally, we found that pharmacological inhibition of FAK activity resembled these effects although milder. In summary, we demonstrate that FAK depletion reduces HCC cell growth by affecting cancer-promoting genes including the pro-oncogene EZH2. Furthermore, we unveil a novel unprecedented FAK/EZH2 crosstalk in HCC cells, thus identifying a targetable network paving the way for new anticancer therapies. PMID- 28338659 TI - Intercellular cannibalism fuels tumor growth. PMID- 28338658 TI - Granzyme B enters the mitochondria in a Sam50-, Tim22- and mtHsp70-dependent manner to induce apoptosis. AB - We have found that granzyme B (GB)-induced apoptosis also requires reactive oxygen species resulting from the alteration of mitochondrial complex I. How GB, which does not possess a mitochondrial targeting sequence, enter this organelle is unknown. We show that GB enters the mitochondria independently of the translocase of the outer mitochondrial membrane complex, but requires instead Sam50, the central subunit of the sorting and assembly machinery that integrates outer membrane beta-barrel proteins. Moreover, GB breaches the inner membrane through Tim22, the metabolite carrier translocase pore, in a mitochondrial heat shock protein 70 (mtHsp70)-dependent manner. Granzyme A (GA) and caspase-3 use a similar route to the mitochondria. Finally, preventing GB from entering the mitochondria either by mutating lysine 243 and arginine 244 or depleting Sam50 renders cells more resistant to GB-mediated reactive oxygen species and cell death. Similarly, Sam50 depletion protects cells from GA-, GM- and caspase-3 mediated cell death. Therefore, cytotoxic molecules enter the mitochondria to induce efficiently cell death through a noncanonical Sam50-, Tim22- and mtHsp70 dependent import pathway. PMID- 28338661 TI - Adipose tissue: New route to functional human beige adipocytes. PMID- 28338662 TI - Diabetes: Pancreatic GLP1 is involved in glucose regulation. PMID- 28338663 TI - Prevalence and associated factors of blepharoptosis in Korean adult population: The Korea National Health and Nutrition Examination Survey 2008-2011. AB - PurposeThis study aimed to evaluate the prevalence and associated factors of involutional blepharoptosis in a nationwide representative sample in Korea.MethodsCross-sectional study 20 941 Korean men and women 40 years of age and older who participated in last 2 years (2008 and 2009) of the 4th wave of the Korean National Health and Nutrition Examination Survey (KNHANES) IV and the first 2 years (2010 and 2011) of KNHANES V. Ocular examinations were performed by ophthalmologists trained in procedure and grading methods, and blepharoptosis was defined as a marginal reflex distance <2 mm on either eye.ResultsThe prevalence of involutional blepharoptosis in the Korean adult was 13.5% (95% CI: 12.1%, 14.9%). It was increasing along with aging (5.4% among 40's and 32.8% in people over 70 years old). A statistically significant negative association between levator function and blepharoptosis was found. With right eye, while only 5.4% (95% CI: 4.5%, 6.2%) had blepharoptosis among people whose levator function was excellent (>=12 mm), 71.4% (95% CI: 60.0%, 85.9%) of people whose levator function was poor (<=4 mm) had blepharoptosis. Hypertension, diabetes, higher body mass index (BMI), and lower education had statistically significant association with blepharoptosis adjusting all other confounders.ConclusionsThe distribution and proportional changes of levator function and marginal reflex distance 1 (MRD1) with aging implicate a contributory role of muscular degeneration. Strong association with hypertension, diabetes, BMI, and education level suggests that etiology of involutional blepharoptosis would be multifactorial and further investigation would be necessary to determine precise mechanism and contribution of factors. PMID- 28338660 TI - Germline and somatic genetics of osteosarcoma - connecting aetiology, biology and therapy. AB - Clinical outcomes and treatment modalities for osteosarcoma, the most common primary cancer of bone, have changed very little over the past 30 years. The peak incidence of osteosarcoma occurs during the adolescent growth spurt, which suggests that bone growth and pubertal hormones are important in the aetiology of the disease. Tall stature, high birth weight and certain inherited cancer predisposition syndromes are well-described risk factors for osteosarcoma. Common genetic variants are also associated with osteosarcoma. The somatic genome of osteosarcoma is highly aneuploid, exhibits extensive intratumoural heterogeneity and has a higher mutation rate than most other paediatric cancers. Complex pathways related to bone growth and development and tumorigenesis are also important in osteosarcoma biology. In this Review, we discuss the contributions of germline and somatic genetics, tumour biology and animal models in improving our understanding of osteosarcoma aetiology, and their potential to identify novel therapeutic targets and thus improve the lives of patients with osteosarcoma. PMID- 28338664 TI - Characteristics of non-vitreoretinal ocular injury in child maltreatment: a systematic review. AB - : PurposeTo identify the spectrum of non-vitreoretinal ocular injury due to child maltreatment.MethodsAll language search of MEDLINE, PsychINFO, EMBASE, AMED, Web of Science, and CINAHL databases, 1950-2015, was conducted. INCLUSION CRITERIA: explicit confirmation of injury aetiology, age <18 years, examination conducted by an ophthalmologist. Exclusion: post-mortem data, organic diseases, review articles. Standardised critical appraisal and narrative synthesis was conducted of included publications by two independent reviewers.ResultsOf 1492 studies identified, 153 full texts were assessed, 49 underwent full review, resulting in five included studies: three case series and two case reports. The 26 included cases describe a wide variety of ocular, facial and skeletal injuries occurring as a consequence of child maltreatment. Ocular signs included periorbital oedema, chemosis, injection, abrasion, hyphaema, and cataract. Of interest all children that had suffered physical abuse with ocular injury had subconjunctival haemorrhages. Children presenting with abusive ocular injuries had a mean age of 13.9 months (range 1-68), while those who suffered violent corporal punishment were considerably older (mean 96 months). All cases, apart from severe corporal punishment, underwent screening for occult fractures, but neuroimaging only apparent in 2/5 eligible cases.ConclusionAlthough, the face is the most common site of abusive injury, there is a paucity of high-quality data on non vitreoretinal ocular abusive injury. Thus, while subconjunctival haemorrhages are a potential sentinel injury of maltreatment, and may warrant further evaluation, the lack of large-scale published data limits our ability to highlight further specific characteristics of non-vitreoretinal ocular injury indicative of child abuse. PMID- 28338665 TI - Vessel diameter study: intravitreal vs posterior subtenon triamcinolone acetonide injection for diabetic macular edema. AB - PurposeTo detect and compare the vessel diameter effect of intravitreal vs subtenon injection of triamcinolone for diabetic macular edema (DME).MethodsSixty patients with DME who underwent triamcinolone injection either intravitreally (N=30) or under the tenon capsule (N=30) were included. Non-injected fellow eyes served as control. The main outcome measures were central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), and artery-vein ratio (AVR).ResultsIn the intravitreal group, pre-injection mean CRAE (147.07 MU) decreased to 141.03 MU at 1 week and to 139.43 MU at 1 month (P<0.001) while baseline CRVE (209.61 MU) decreased initially to 198.85 MU at 1 week then to 198.49 MU at 1 month (P<0.001). In the subtenon group, pre-injection CRAE (152.18 MU) decreased to 149.49 MU at 1 week and to 147.47 MU at 1 month (P=0.017), while baseline CRVE (215.60 MU) decreased initially to 208.69 MU at 1 week then to 207.25 MU at 1 month (P=0.003). Pre-injection AVR values did not change at 1 week and at 1 month in both injection groups (P=0.66 and P=0.196, respectively). In the control group, none of the 3 parameters changed throughout the study period compared to the baseline (P>0.28).ConclusionIn eyes with DME, both intravitreal and subtenon triamcinolone injection led to a significant constriction of retinal arteries and veins. PMID- 28338666 TI - The association of maternal factors with epibulbar dermoid of newborn: a retrospective, matched case-control study. AB - PurposeTo determine the association of maternal factors and exposure during pregnancy with the incidence in newborns of epibulbar dermoid (ED), a congenital ocular surface benign tumor.Patients and methodsThis is a retrospective, paired case-control study in which 121 children with ED (case group) and 121 children without ED (control group) were recruited. Questionnaire-based interviews with mothers of participants were performed and maternal medical records during pregnancy were reviewed. The questionnaire investigated basic information, personal history, environmental exposure, exposure to maternal diseases, symptoms and corresponding medical treatments during pregnancy, and parental socioeconomic status. The case and control participants were matched for sex, birth weight, gestational age, and parental socioeconomic status level. Univariate and multivariate logistic regression analyses were conducted with ED as the main outcome variable.ResultsFactors significantly associated with ED were: history of maternal inevitable miscarriage (odds ratio (OR), 2.59; 95% confidence intervals (CI), 1.13-5.90), common cold in the first trimester (OR, 3.94; CI, 1.74-8.93), and paternal smoke exposure >half a pack per day during pregnancy (OR, 4.81; CI, 1.74-13.28).ConclusionHistory of maternal miscarriage, common cold exposure in the first trimester, and paternal smoking (>half a pack per day) during pregnancy could result in significant risk factors for ED of newborns. These data also imply that paternal smoking delivers nicotine to maternal respiratory system and uterine microenvironment that may both affect microvascular development and predispose the fetus to future ED. PMID- 28338667 TI - Primary photodynamic therapy with verteporfin for small pigmented posterior pole choroidal melanoma. AB - PurposeThe purpose of the study was to investigate the outcomes of primary photodynamic therapy (PDT) for small pigmented posterior pole choroidal melanoma.Patients and methodsProspective interventional consecutive case series of 15 patients with small pigmented posterior pole choroidal melanoma, who were treated with three sessions of PDT and followed-up thereafter. Risk factors for failure were assessed and outcome measures at presentation were compared to those at last follow-up visit.ResultsTumor control was achieved in 12 (80%) patients in a median follow-up time of 15 months (mean 14, range 8-18). Three patients failed treatment, diagnosed in a median time of 5 months (mean 4, range 3-6), after first PDT. In all failed cases, lesions were 100% pigmented; de novo melanoma rather than transformed nevi and showed a radial growth pattern rather than increased thickness. All failed cases were subsequently successfully treated with radiotherapy. In this cohort, subretinal fluid (SRF) was significantly reduced (P<0.001), vision did not deteriorate (P=0.11) and even improved in patients with subfoveal SRF at presentation (P=0.018), tumor height significantly decreased (P=0.037) and no complications were recorded.ConclusionPrimary PDT was found to be a safe and efficient treatment modality for small pigmented posterior pole choroidal melanoma, achieving short-term tumor control in 80% of patients. PDT offers patients the opportunity to preserve vision by avoiding the retinopathy associated with conventional radiation treatments for choroidal melanoma. However, the long-term local control of these tumors remains uncertain. PMID- 28338669 TI - Corrigendum: Inference of immune cell composition on the expression profiles of mouse tissue. PMID- 28338668 TI - Corrigendum: Long term outcome of Aldosteronism after target treatments. PMID- 28338670 TI - Encouraging impact of doxycycline on early mortality in cardiac light chain (AL) amyloidosis. PMID- 28338671 TI - Regulatory B cell-myeloma cell interaction confers immunosuppression and promotes their survival in the bone marrow milieu. PMID- 28338672 TI - Posttransplant maintenance therapy in multiple myeloma: the changing landscape. AB - Transplant-eligible patients with multiple myeloma (MM) now have extended survival after diagnosis owing to effective modern treatment strategies that include new agents in induction therapy, autologous stem cell transplant (ASCT), consolidation therapy and posttransplant maintenance therapy. Standard of care for newly diagnosed, fit patients includes ASCT and, often nowadays, posttransplant maintenance. Several large studies have shown the efficacy of maintenance with thalidomide, lenalidomide and bortezomib in the treatment scheme of MM with regards to prolonging progression-free survival and, to a lesser degree, overall survival. Herein we discuss the data currently available to support the use of maintenance therapy in patients after ASCT as well as the newer available agents that may be a part of its changing landscape in the years to come. PMID- 28338673 TI - Environmental fluctuation governs selection for plasticity in biofilm production. AB - Bacteria can grow in a free-swimming state, as planktonic cells, or in surface attached communities, termed biofilms. The planktonic and biofilm growth modes differ dramatically with respect to spatial constraints, nutrient access, population density and cell-cell interactions. Fitness trade-offs underlie how successfully bacteria compete in each of these environments. Accordingly, some bacteria have evolved to be specialists in biofilm formation, while others specialize in planktonic growth. There are species, however, that possess flexible strategies: they can transition between the molecular programs required for biofilm formation and for planktonic growth. Such flexible strategies often sacrifice competitive ability against specialists in a given habitat. There is little exploration of the ecological conditions favoring the evolution of the flexible biofilm production strategy for bacteria in competition with specialist biofilm producers or specialist non-producers. Here, we study the human pathogen Vibrio cholerae, a flexible biofilm-former, as well as constitutive biofilm producing and non-producing mutants. We assess the fitness of these strains under biofilm conditions, planktonic conditions and conditions that demand the ability to transition between the two growth modes. We show that, relative to the specialists, the wild type is superior at dispersal from biofilms to the planktonic phase; however, this capability comes at the expense of reduced competitive fitness against constitutive biofilm producers on surfaces. Wild-type V. cholerae can outcompete the constitutive biofilm producers and non-producers if habitat turnover is sufficiently frequent. Thus, selection for phenotypic flexibility in biofilm production depends on the frequency of environmental fluctuations encountered by bacteria. PMID- 28338674 TI - Biofilm formation enables free-living nitrogen-fixing rhizobacteria to fix nitrogen under aerobic conditions. AB - The multicellular communities of microorganisms known as biofilms are of high significance in agricultural setting, yet it is largely unknown about the biofilm formed by nitrogen-fixing bacteria. Here we report the biofilm formation by Pseudomonas stutzeri A1501, a free-living rhizospheric bacterium, capable of fixing nitrogen under microaerobic and nitrogen-limiting conditions. P. stutzeri A1501 tended to form biofilm in minimal media, especially under nitrogen depletion condition. Under such growth condition, the biofilms formed at the air liquid interface (termed as pellicles) and the colony biofilms on agar plates exhibited nitrogenase activity in air. The two kinds of biofilms both contained large ovoid shape 'cells' that were multiple living bacteria embedded in a sac of extracellular polymeric substances (EPSs). We proposed to name such large 'cells' as A1501 cyst. Our results suggest that the EPS, especially exopolysaccharides enabled the encased bacteria to fix nitrogen while grown under aerobic condition. The formation of A1501 cysts was reversible in response to the changes of carbon or nitrogen source status. A1501 cyst formation depended on nitrogen-limiting signaling and the presence of sufficient carbon sources, yet was independent of an active nitrogenase. The pellicles formed by Azospirillum brasilense, another free-living nitrogen-fixing rhizobacterium, which also exhibited nitrogenase activity and contained the large EPS-encapsuled A1501 cyst-like 'cells'. Our data imply that free-living nitrogen-fixing bacteria could convert the easy-used carbon sources to exopolysaccharides in order to enable nitrogen fixation in a natural aerobic environment. PMID- 28338675 TI - Biogeography and diversity of Collodaria (Radiolaria) in the global ocean. AB - Collodaria are heterotrophic marine protists that exist either as large colonies composed of hundreds of cells or as large solitary cells. All described species so far harbour intracellular microalgae as photosymbionts. Although recent environmental diversity surveys based on molecular methods demonstrated their consistently high contribution to planktonic communities and their worldwide occurrence, our understanding of their diversity and biogeography is still very limited. Here we estimated the 18S ribosomal DNA (rDNA) gene copies per collodarian cell for solitary (5770+/-1960 small subunit (SSU) rDNA copies) and colonial specimens (37 474+/-17 799 SSU rDNA copies, for each individual cell within a colony) using single-specimen quantitative PCR. We then investigated the environmental diversity of Collodaria within the photic zone through the metabarcoding survey from the Tara Oceans expedition and found that the two collodarian families Collosphaeridae and Sphaerozoidae contributed the most to the collodarian diversity and encompassed mostly cosmopolitan taxa. Although the biogeographical patterns were homogeneous within each biogeochemical biome considered, we observed that coastal biomes were consistently less diverse than oceanic biomes and were dominated by the Sphaerozoidae while the Collosphaeridae were dominant in the open oceans. The significant relationships with six environmental variables suggest that collodarian diversity is influenced by the trophic status of oceanic provinces and increased towards more oligotrophic regions. PMID- 28338678 TI - Organomimetic clusters: Precision in 3D. PMID- 28338676 TI - Dirhamnolipids secreted from Pseudomonas aeruginosa modify anjpegungal susceptibility of Aspergillus fumigatus by inhibiting beta1,3 glucan synthase activity. AB - Pseudomonas aeruginosa and Aspergillus fumigatus are the two microorganisms responsible for most of the chronic infections in cystic fibrosis patients. P. aeruginosa is known to produce quorum-sensing controlled rhamnolipids during chronic infections. Here we show that the dirhamnolipids secreted from P. aeruginosa (i) induce A. fumigatus to produce an extracellular matrix, rich in galactosaminogalactan, 1,8-dihydroxynaphthalene (DHN)- and pyo-melanin, surrounding their hyphae, which facilitates P. aeruginosa binding and (ii) inhibit A. fumigatus growth by blocking beta1,3 glucan synthase (GS) activity, thus altering the cell wall architecture. A. fumigatus in the presence of diRhls resulted in a growth phenotype similar to that upon its treatment with anjpegungal echinocandins, showing multibranched hyphae and thicker cell wall rich in chitin. The diRhl structure containing two rhamnose moieties attached to fatty acyl chain is essential for the interaction with beta1,3 GS; however, the site of action of diRhls on GS is different from that of echinocandins, and showed synergistic anjpegungal effect with azoles. PMID- 28338679 TI - Entomopathogenic bacteria use multiple mechanisms for bioactive peptide library design. AB - The production of natural product compound libraries has been observed in nature for different organisms such as bacteria, fungi and plants; however, little is known about the mechanisms generating such chemically diverse libraries. Here we report mechanisms leading to the biosynthesis of the chemically diverse rhabdopeptide/xenortide peptides (RXPs). They are exclusively present in entomopathogenic bacteria of the genera Photorhabdus and Xenorhabdus that live in symbiosis with nematodes delivering them to insect prey, which is killed and utilized for nutrition by both nematodes and bacteria. Chemical diversity of the biologically active RXPs results from a combination of iterative and flexible use of monomodular nonribosomal peptide synthetases including substrate promiscuity, enzyme cross-talk and enzyme stoichiometry as shown by in vivo and in vitro experiments. Together, this highlights several of nature's methods for diversification, or evolution, of natural products and sheds light on the biosynthesis of the bioactive RXPs. PMID- 28338677 TI - Integrated metabolism in sponge-microbe symbiosis revealed by genome-centered metatranscriptomics. AB - Despite an increased understanding of functions in sponge microbiomes, the interactions among the symbionts and between symbionts and host are not well characterized. Here we reconstructed the metabolic interactions within the sponge Cymbastela concentrica microbiome in the context of functional features of symbiotic diatoms and the host. Three genome bins (CcPhy, CcNi and CcThau) were recovered from metagenomic data of C. concentrica, belonging to the proteobacterial family Phyllobacteriaceae, the Nitrospira genus and the thaumarchaeal order Nitrosopumilales. Gene expression was estimated by mapping C. concentrica metatranscriptomic reads. Our analyses indicated that CcPhy is heterotrophic, while CcNi and CcThau are chemolithoautotrophs. CcPhy expressed many transporters for the acquisition of dissolved organic compounds, likely available through the sponge's filtration activity and symbiotic carbon fixation. Coupled nitrification by CcThau and CcNi was reconstructed, supported by the observed close proximity of the cells in fluorescence in situ hybridization. CcPhy facultative anaerobic respiration and assimilation by diatoms may consume the resulting nitrate. Transcriptional analysis of diatom and sponge functions indicated that these organisms are likely sources of organic compounds, for example, creatine/creatinine and dissolved organic carbon, for other members of the symbiosis. Our results suggest that organic nitrogen compounds, for example, creatine, creatinine, urea and cyanate, fuel the nitrogen cycle within the sponge. This study provides an unprecedented view of the metabolic interactions within sponge-microbe symbiosis, bridging the gap between cell- and community level knowledge. PMID- 28338680 TI - Real-time molecular scale observation of crystal formation. AB - How molecules in solution form crystal nuclei, which then grow into large crystals, is a poorly understood phenomenon. The classical mechanism of homogeneous crystal nucleation proceeds via the spontaneous random aggregation of species from liquid or solution. However, a non-classical mechanism suggests the formation of an amorphous dense phase that reorders to form stable crystal nuclei. So far it has remained an experimental challenge to observe the formation of crystal nuclei from five to thirty molecules. Here, using polyoxometallates, we show that the formation of small crystal nuclei is observable by cryogenic transmission electron microscopy. We observe both classical and non-classical nucleation processes, depending on the identity of the cation present. The experiments verify theoretical studies that suggest non-classical nucleation is the lower of the two energy pathways. The arrangement in just a seven-molecule proto-crystal matches the order found by X-ray diffraction of a single bulk crystal, which demonstrates that the same structure was formed in each case. PMID- 28338681 TI - Dynamics of the triplet-pair state reveals the likely coexistence of coherent and incoherent singlet fission in crystalline hexacene. AB - The absorption of a photon usually creates a singlet exciton (S1) in molecular systems, but in some cases S1 may split into two triplets (2*T1) in a process called singlet fission. Singlet fission is believed to proceed through the correlated triplet-pair 1(TT) state. Here, we probe the 1(TT) state in crystalline hexacene using time-resolved photoemission and transient absorption spectroscopies. We find a distinctive 1(TT) state, which decays to 2*T1 with a time constant of 270 fs. However, the decay of S1 and the formation of 1(TT) occur on different timescales of 180 fs and <50 fs, respectively. Theoretical analysis suggests that, in addition to an incoherent S1->1(TT) rate process responsible for the 180 fs timescale, S1 may couple coherently to a vibronically excited 1(TT) on ultrafast timescales (<50 fs). The coexistence of coherent and incoherent singlet fission may also reconcile different experimental observations in other acenes. PMID- 28338683 TI - Aldehydes as alkyl carbanion equivalents for additions to carbonyl compounds. AB - Nucleophilic addition reactions of organometallic reagents to carbonyl compounds for carbon-carbon bond construction have played a pivotal role in modern chemistry. However, this reaction's reliance on petroleum-derived chemical feedstocks and a stoichiometric quantity of metal have prompted the development of many carbanion equivalents and catalytic metal alternatives. Here, we show that naturally occurring carbonyls can be used as latent alkyl carbanion equivalents for additions to carbonyl compounds, via reductive polarity reversal. Such 'umpolung' reactivity is facilitated by a ruthenium catalyst and diphosphine ligand under mild conditions, delivering synthetically valuable secondary and tertiary alcohols in up to 98% yield. The unique chemoselectivity exhibited by carbonyl-derived carbanion equivalents is demonstrated by their tolerance to protic reaction media and good functional group compatibility. Enantioenriched tertiary alcohols can also be accessed with the aid of chiral ligands, albeit with moderate stereocontrol. Such carbonyl-derived carbanion equivalents are anticipated to find broad utility in chemical bond formation. PMID- 28338684 TI - Seven enzymes create extraordinary molecular complexity in an uncultivated bacterium. AB - Uncultivated bacteria represent a massive resource of new enzymes and bioactive metabolites, but such bacteria remain functionally enigmatic. Polytheonamides are potent peptide cytotoxins produced by uncultivated bacteria that exist as symbionts in a marine sponge. Outside glycobiology, polytheonamides represent the most heavily post-translationally modified biomolecules that are derived from amino acids. The biosynthesis of polytheonamides involves up to 50 site-specific modifications to create a membrane-spanning beta-helical structure. Here, we provide functional evidence that only seven enzymes are necessary for this process. They iteratively catalyse epimerization, methylation and hydroxylation of diverse amino acids. To reconstitute C-methylation, we employed the rarely used heterologous host Rhizobium leguminosarum to invoke the activities of two cobalamin-dependent C-methyltransferases. We observed 44 of the modifications to systematically unravel the biosynthesis of one of the most densely modified and metabolically obscure ribosome-derived molecules found in nature. PMID- 28338682 TI - Simple peptides derived from the ribosomal core potentiate RNA polymerase ribozyme function. AB - The emergence of functional interactions between nucleic acids and polypeptides was a key transition in the origin of life and remains at the heart of all biology. However, how and why simple non-coded peptides could have become critical for RNA function is unclear. Here, we show that putative ancient peptide segments from the cores of both ribosomal subunits enhance RNA polymerase ribozyme (RPR) function, as do derived homopolymeric peptides comprising lysine or the non-proteinogenic lysine analogues ornithine or, to a lesser extent, diaminobutyric acid, irrespective of chirality or chiral purity. Lysine decapeptides enhance RPR function by promoting holoenzyme assembly through primer template docking, accelerate RPR evolution, and allow RPR-catalysed RNA synthesis at near physiological (>=1 mM) Mg2+ concentrations, enabling templated RNA synthesis within membranous protocells. Our results outline how compositionally simple, mixed-chirality peptides may have augmented the functional potential of early RNAs and promoted the emergence of the first protocells. PMID- 28338685 TI - Prebiotic synthesis of phosphoenol pyruvate by alpha-phosphorylation-controlled triose glycolysis. AB - Phosphoenol pyruvate is the highest-energy phosphate found in living organisms and is one of the most versatile molecules in metabolism. Consequently, it is an essential intermediate in a wide variety of biochemical pathways, including carbon fixation, the shikimate pathway, substrate-level phosphorylation, gluconeogenesis and glycolysis. Triose glycolysis (generation of ATP from glyceraldehyde 3-phosphate via phosphoenol pyruvate) is among the most central and highly conserved pathways in metabolism. Here, we demonstrate the efficient and robust synthesis of phosphoenol pyruvate from prebiotic nucleotide precursors, glycolaldehyde and glyceraldehyde. Furthermore, phosphoenol pyruvate is derived within an alpha-phosphorylation controlled reaction network that gives access to glyceric acid 2-phosphate, glyceric acid 3-phosphate, phosphoserine and pyruvate. Our results demonstrate that the key components of a core metabolic pathway central to energy transduction and amino acid, sugar, nucleotide and lipid biosyntheses can be reconstituted in high yield under mild, prebiotically plausible conditions. PMID- 28338686 TI - An iron-catalysed C-C bond-forming spirocyclization cascade providing sustainable access to new 3D heterocyclic frameworks. AB - Heterocyclic architectures offer powerful creative possibilities to a range of chemistry end-users. This is particularly true of heterocycles containing a high proportion of sp3-carbon atoms, which confer precise spatial definition upon chemical probes, drug substances, chiral monomers and the like. Nonetheless, simple catalytic routes to new heterocyclic cores are infrequently reported, and methods making use of biomass-accessible starting materials are also rare. Here, we demonstrate a new method allowing rapid entry to spirocyclic bis-heterocycles, in which inexpensive iron(III) catalysts mediate a highly stereoselective C-C bond-forming cyclization cascade reaction using (2-halo)aryl ethers and amines constructed using feedstock chemicals readily available from plant sources. Fe(acac)3 mediates the deiodinative cyclization of (2-halo)aryloxy furfuranyl ethers, followed by capture of the intermediate metal species by Grignard reagents, to deliver spirocycles containing two asymmetric centres. The reactions offer potential entry to key structural motifs present in bioactive natural products. PMID- 28338687 TI - Remote C-H alkylation and C-C bond cleavage enabled by an in situ generated palladacycle. AB - The direct and selective functionalization of C-H bonds of arenes is one of the most challenging yet valuable aims in organic synthesis. Despite notable recent achievements, a pre-installed directing group proved to be essential in most of the methodologies reported so far. In this context, the use of a transient directing group that can be generated in situ has attracted attention and demonstrated the great potential of this strategy. Here we report the use of an in situ generated palladacycle to accomplish remote-selective C-H alkylation reactions of arenes. Following the C-H functionalization event, the alkylated aryl ring undergoes a formal migration to provide diversely substituted benzofuran and indole scaffolds. Computational studies revealed that a palladium(IV) intermediate is not involved in the alkylation step. The aryl migration was found to proceed through a sequential C-C bond cleavage, insertion and beta-hydride-elimination process. The increasing steric bulk that builds up during the C-H functionalization step drives the unusual C-C bond cleavage in a non-strained system. PMID- 28338688 TI - Organometallic chemistry: A shortcut to molecular complexity. PMID- 28338690 TI - A viscous solvent enables information transfer from gene-length nucleic acids in a model prebiotic replication cycle. AB - Many hypotheses concerning the nature of early life assume that genetic information was once transferred through the template-directed synthesis of RNA, before the emergence of coded enzymes. However, attempts to demonstrate enzyme free, template-directed synthesis of nucleic acids have been limited by 'strand inhibition', whereby transferring information from a template strand in the presence of its complementary strand is inhibited by the stability of the template duplex. Here, we use solvent viscosity to circumvent strand inhibition, demonstrating information transfer from a gene-length template (>300 nt) within a longer (545 bp or 3 kb) duplex. These results suggest that viscous environments on the prebiotic Earth, generated periodically by water evaporation, could have facilitated nucleic acid replication-particularly of long, structured sequences such as ribozymes. Our approach works with DNA and RNA, suggesting that viscosity mediated replication is possible for a range of genetic polymers, perhaps even for informational polymers that may have preceded RNA. PMID- 28338689 TI - A prebiotically plausible synthesis of pyrimidine beta-ribonucleosides and their phosphate derivatives involving photoanomerization. AB - Previous research has identified ribose aminooxazoline as a potential intermediate in the prebiotic synthesis of the pyrimidine nucleotides with remarkable properties. It crystallizes spontaneously from reaction mixtures, with an enhanced enantiomeric excess if initially enantioenriched, which suggests that reservoirs of this compound might have accumulated on the early Earth in an optically pure form. Ribose aminooxazoline can be converted efficiently into alpha-ribocytidine by way of 2,2'-anhydroribocytidine, although anomerization to beta-ribocytidine by ultraviolet irradiation is extremely inefficient. Our previous work demonstrated the synthesis of pyrimidine beta-ribonucleotides, but at the cost of ignoring ribose aminooxazoline, using arabinose aminooxazoline instead. Here we describe a long-sought route through ribose aminooxazoline to the pyrimidine beta-ribonucleosides and their phosphate derivatives that involves an extraordinarily efficient photoanomerization of alpha-2-thioribocytidine. In addition to the canonical nucleosides, our synthesis accesses beta-2 thioribouridine, a modified nucleoside found in transfer RNA that enables both faster and more-accurate nucleic acid template-copying chemistry. PMID- 28338691 TI - Surfactant-free single-layer graphene in water. AB - Dispersing graphite in water to obtain true (single-layer) graphene in bulk quantity in a liquid has been an unreachable goal for materials scientists in the past decade. Similarly, a diagnostic tool to identify solubilized graphene in situ has been long awaited. Here we show that homogeneous stable dispersions of single-layer graphene (SLG) in water can be obtained by mixing graphenide (negatively charged graphene) solutions in tetrahydrofuran with degassed water and evaporating the organic solvent. In situ Raman spectroscopy of these aqueous dispersions shows all the expected characteristics of SLG. Transmission electron and atomic force microscopies on deposits confirm the single-layer character. The resulting additive-free stable water dispersions contain 400 m2 l-1 of developed graphene surface. Films prepared from these dispersions exhibit a conductivity of up to 32 kS m-1. PMID- 28338693 TI - Life, but not as we know it. PMID- 28338692 TI - Computational design of self-assembling cyclic protein homo-oligomers. AB - Self-assembling cyclic protein homo-oligomers play important roles in biology, and the ability to generate custom homo-oligomeric structures could enable new approaches to probe biological function. Here we report a general approach to design cyclic homo-oligomers that employs a new residue-pair-transform method to assess the designability of a protein-protein interface. This method is sufficiently rapid to enable the systematic enumeration of cyclically docked arrangements of a monomer followed by sequence design of the newly formed interfaces. We use this method to design interfaces onto idealized repeat proteins that direct their assembly into complexes that possess cyclic symmetry. Of 96 designs that were characterized experimentally, 21 were found to form stable monodisperse homo-oligomers in solution, and 15 (four homodimers, six homotrimers, six homotetramers and one homopentamer) had solution small-angle X ray scattering data consistent with the design models. X-ray crystal structures were obtained for five of the designs and each is very close to their corresponding computational model. PMID- 28338694 TI - Iterations of ytterbium. PMID- 28338695 TI - Unprecedented highly efficient capture of glycopeptides by Fe3O4@Mg-MOF-74 core shell nanoparticles. AB - Magnetic Fe3O4 nanospheres coated with Mg-MOF-74 have been facilely prepared via epitaxial growth. Owing to the intrinsic hydrophilic pore surface and size exclusive properties of Mg-MOF-74, the Fe3O4@Mg-MOF-74 core-shell nanoparticles show effective and selective enrichment of 441 N-glycosylation sites of 418 glycopeptides from 125 glycoproteins in 1 MUL of human serum. PMID- 28338696 TI - Polymer-confined growth of perforated MoSe2 single-crystals on N-doped graphene toward enhanced hydrogen evolution. AB - The edge and corner atoms of 2D transition metal dichalcogenides (TMDCs) are the main electrocatalytically active sites for electrochemical reaction. Here, we demonstrate an approach to generate abundant edge/corner atoms in molybdenum diselenide (MoSe2) nanocrystals supported by nitrogen-doped graphene (NG) which consequently leads to significantly enhanced hydrogen evolution reaction (HER) activity. These structures were fabricated by firstly absorbing the Mo-containing precursor within polymer-functionalized graphene oxide, then selenized to obtain MoSe2 nanocrystals on the surface, and finally H2 etching was performed to form perforated structures. The use of a functional polymer as an absorption matrix efficiently mitigates aggregation which allows us to obtain MoSe2 single-crystals of ~150 nm in lateral dimension, while maintaining high MoSe2 loading. We observed a remarkably enhanced electrocatalytic activity resulting from a significantly increased abundance of edge/corner atoms in hydrogen evolution measurements. Specifically, with this perforated MoSe2/NG-modified cathode, current densities of -1 and -10 mA cm-2 were realized with the overpotentials of only 30 and 106 mV, along with a small Tafel slope of 57 mV dec-1 and large exchange current density of 127.4 MUA cm-2 in 0.5 M H2SO4. Such an efficient strategy also opens doors for the unparalleled design and fabrication of TMDC based nanocomposites for electrochemical applications. PMID- 28338697 TI - A catalytic scalable Pauson-Khand reaction in a plug flow reactor. AB - A catalytic, scalable intra- and intermolecular Pauson-Khand reaction protocol using generally 5 mol% of Co2(CO)8 as the catalyst in a plug flow reactor (PFR) is shown. PMID- 28338698 TI - Thermally driven bubble evolution at a heater wire in water characterized by high speed transmission electron microscopy. AB - This work investigates the early stage evolution of thermally nucleated microbubbles in water using in situ high-speed, 400 fps, transmission electron microscopy. A Pt wire Joule heater induced bubble nucleation and growth from air saturated water at different levels of power. For all powers below Pt breakdown, the dissolved gas initiates bubble nucleation at the concave surface defects adjacent to the area of highest temperature. A combination of interfacial forces and stress relaxation drive rapid migration of the bubbles away from the nucleation site. Thermocapillary forces ultimately dominate and drive their return to the region of highest temperature. The dynamic response highlights the importance of this length and time domain, which has until now received limited direct study. PMID- 28338699 TI - cis or trans with class II diterpene cyclases. AB - Isoprenoid precursors readily undergo (poly)cyclization in electrophilic reaction cascades, presumably as internal addition of the carbon-carbon double-bonds from neighboring isoprenyl repeats readily forms relatively stable cyclohexyl tertiary carbocation intermediates. This hypothesis is agnostic regarding alkene configuration (i.e., Z or E). Consistent with this, here it is shown that certain class II diterpene cyclases, which normally convert (E,E,E)-geranylgeranyl diphosphate to 13E-trans-decalin bicycles, will also act upon (Z,Z,Z)-nerylneryl diphosphate, producing novel 13Z-cis-decalin bicycles instead. PMID- 28338700 TI - Enhanced piezoelectric effect at the edges of stepped molybdenum disulfide nanosheets. AB - The development of piezoelectric layered materials may be one of the key elements enabling expansion of nanotechnology, as they offer a solution for the construction of efficient transducers for a wide range of applications, including self-powered devices. Here, we investigate the piezoelectric effect in multilayer (ML) stepped MoS2 flakes obtained by liquid-phase exfoliation, which is especially interesting because it may allow the scalable fabrication of electronic devices using large area deposition techniques (e.g. solution casting, spray coating, inkjet printing). By using a conductive atomic force microscope we map the piezoelectricity of the MoS2 flakes at the nanoscale. Our experiments demonstrate the presence of electrical current densities above 100 A cm-2 when the flakes are strained in the absence of bias, and the current increases proportional to the bias. Simultaneously collected topographic and current maps demonstrate that the edges of stepped ML MoS2 flakes promote the piezoelectric effect, where the largest currents are observed. Density functional theory calculations are consistent with the ring-like piezoelectric potential generated when the flakes are strained, as well as the enhanced piezoelectric effect at edges. Our results pave the way to the design of piezoelectric devices using layered materials. PMID- 28338702 TI - Hydrogen bonds between methanol and the light liquid olefins 1-pentene and 1 hexene: from application to fundamental science. AB - We have recently developed a new extraction process for significantly reducing the olefin content in commercial FCC gasoline. To gain insights into the origins of this process, we have investigated the dissolution of the light liquid olefins 1-pentene and 1-hexene in methanol through computer modelling together with NMR spectroscopy. We find two important hydrogen bonding modes for methanol olefin interactions - namely, O-Hpi and C-HO. PMID- 28338701 TI - Electrochemically stimulated drug release from flexible electrodes coated electrophoretically with doxorubicin loaded reduced graphene oxide. AB - The electrochemically triggered release of doxorubicin (DOX) from flexible electrodes modified electrophoretically with reduced graphene oxide (rGO)-DOX is reported. The release is driven by a positive potential pulse that decreases the pH of the rGO-DOX surface locally, which is confirmed by scanning electrochemical microscopy (SECM) in situ. In vitro cell viability tests confirms that the delivery system meets therapeutic needs. PMID- 28338703 TI - Theoretical investigation of proton collisions on prebiotic candidates: hydrogen cyanide polymers. AB - One of the major concerns in prebiotic chemistry is the formation and destruction routes of prebiotic compounds in space. As detected for a long time, hydrogen cyanide (HCN) has been suggested to be a feedstock molecule at the origin of life driving easy oligomerization, in particular to form adenine. This may focus on its first oligomers because its dimer cyanomethanimine was recently observed in star-forming regions, or its trimer aminomalononitrile. With regard to the assumption of an extra-terrestrial origin of life, the stability of such species under ultraviolet radiation or in ion-collisions is an open question. Thus, we investigated theoretically the proton collisions with dimer and trimer isomers of HCN in a wide impact energy range to model various astrophysical environments and exhibit qualitative tendencies. PMID- 28338704 TI - ipso-Cyclization: an emerging tool for multifunctional spirocyclohexadienones. AB - ipso-Annulation represents an attractive approach to synthesize a variety of spirocyclic compounds having a quaternary carbon center. Furthermore, these compounds also serve as a handy synthon for the construction of various complex molecules. This review presents various useful approaches for the intramolecular ipso-cyclization to afford a wide range of spirocyclohexadienones. In addition, the utility of spirocyclic compounds towards the synthesis of complex molecules is also included. PMID- 28338705 TI - Cohort Profile: Scottish Diabetes Research Network Type 1 Bioresource Study (SDRNT1BIO). PMID- 28338706 TI - Estimating mean change in population salt intake using spot urine samples. AB - Background: Spot urine samples are easier to collect than 24-h urine samples and have been used with estimating equations to derive the mean daily salt intake of a population. Whether equations using data from spot urine samples can also be used to estimate change in mean daily population salt intake over time is unknown. We compared estimates of change in mean daily population salt intake based upon 24-h urine collections with estimates derived using equations based on spot urine samples. Methods: Paired and unpaired 24-h urine samples and spot urine samples were collected from individuals in two Australian populations, in 2011 and 2014. Estimates of change in daily mean population salt intake between 2011 and 2014 were obtained directly from the 24-h urine samples and by applying established estimating equations (Kawasaki, Tanaka, Mage, Toft, INTERSALT) to the data from spot urine samples. Differences between 2011 and 2014 were calculated using mixed models. Results: A total of 1000 participants provided a 24-h urine sample and a spot urine sample in 2011, and 1012 did so in 2014 (paired samples n = 870; unpaired samples n = 1142). The participants were community-dwelling individuals living in the State of Victoria or the town of Lithgow in the State of New South Wales, Australia, with a mean age of 55 years in 2011. The mean (95% confidence interval) difference in population salt intake between 2011 and 2014 determined from the 24-h urine samples was -0.48g/day (-0.74 to -0.21; P < 0.001). The corresponding result estimated from the spot urine samples was -0.24 g/day (-0.42 to -0.06; P = 0.01) using the Tanaka equation, -0.42 g/day (-0.70 to -0.13; p = 0.004) using the Kawasaki equation, -0.51 g/day (-1.00 to -0.01; P = 0.046) using the Mage equation, -0.26 g/day (-0.42 to -0.10; P = 0.001) using the Toft equation, -0.20 g/day (-0.32 to -0.09; P = 0.001) using the INTERSALT equation and -0.27 g/day (-0.39 to -0.15; P < 0.001) using the INTERSALT equation with potassium. There was no evidence that the changes detected by the 24-h collections and estimating equations were different (all P > 0.058). Separate analysis of the unpaired and paired data showed that detection of change by the estimating equations was observed only in the paired data. Conclusions: All the estimating equations based upon spot urine samples identified a similar change in daily salt intake to that detected by the 24-h urine samples. Methods based upon spot urine samples may provide an approach to measuring change in mean population salt intake, although further investigation in larger and more diverse population groups is required. PMID- 28338707 TI - Sustained 10-year gain in adult life expectancy following antiretroviral therapy roll-out in rural Malawi: July 2005 to June 2014. AB - Background: Improved life expectancy in high HIV prevalence populations has been observed since antiretroviral therapy (ART) scale-up. However, it is unclear if the benefits are sustained, and the mortality among HIV-positive individuals not (yet) on ART is not well described. We assessed temporal change in mortality over 9 years in rural Malawi. Methods: Within a demographic surveillance site in northern rural Malawi, we combined demographic, HIV and ART uptake data. We calculated life expectancy using Kaplan-Meier estimates, and compared mortality rates and rate ratios using Poisson regression, by period of ART availability (July 2005-June 2008, July 2008-June 2011 and July 2011-June 2014). Results: Among 32 664 individuals there were 1424 deaths; 1930 individuals were known HIV positive, of whom 1382 started ART. Overall, life expectancy at age 15 years increased by 10 years within 5 years of ART introduction, and plateaued. Age standardized adult mortality rates declined from 11.3/1000 to 7.5/1000 person years between the first and last time period. In July 2011-June 2014 compared with July 2005-June 2008, mortality declined in HIV-positive individuals on ART (rate ratio adjusted (aRR) for age, sex, location and education, 0.3; 95% confidence interval (CI) 0.2-0.5) and in those not (yet) on ART (aRR 0.3; 95%CI 0.1-0.5) but not in HIV-negative individuals (aRR 1.1; 95%CI 0.7-1.9). Conclusions: Total population adult life expectancy increased toward that of HIV negative individuals by 2011 and remained raised. The reduction in all-cause and HIV-related mortality in HIV-positive individuals not (yet) on ART suggests ART uptake is occurring at an earlier disease stage, particularly in women. PMID- 28338708 TI - Lower risk of incident dementia among Chinese older adults having three servings of vegetables and two servings of fruits a day. AB - Background: dietary modification can potentially reduce dementia risk, but the importance of fruits and the amount of vegetables and fruits required for cognitive maintenance are uncertain. We examined whether the minimal daily requirement of vegetables and fruits recommended by the World Health Organization (WHO) would independently lower dementia risk. Methods: in this population-based observational study, we examined the diet of 17,700 community-living dementia free Chinese older adults who attended the Elderly Health Centres in Hong Kong at baseline and followed their cognitive status for 6 years. In line with the WHO recommendation, we defined the cutoff for minimal intake of vegetables and fruits as at least three and two servings per day, respectively. The study outcome was incident dementia in 6 years. Dementia was defined by presence of clinical dementia in accordance with the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) or Clinical Dementia Rating of 1-3. Results: multivariable logistic regression analysis showed that the estimated odds ratios for incident dementia were 0.88 (95% confidence interval 0.73-1.06; P = 0.17) for those consuming at least three servings of vegetables per day, 0.86 (0.74-0.99; P < 0.05) for those consuming at least two servings of fruits per day and 0.75 (0.60-0.95; P = 0.02) for those consuming at least these amounts of both at baseline, after adjusting for age, gender, education, major chronic diseases, physical exercise and smoking. Conclusion: having at least three servings of vegetables and two servings of fruits daily might help prevent dementia in older adults. PMID- 28338709 TI - Relationship between leaf functional traits and productivity in Aquilaria crassna (Thymelaeaceae) plantations: a tool to aid in the early selection of high yielding trees. AB - Physiological traits are frequently used as indicators of tree productivity. Aquilaria species growing in a research planting were studied to investigate relationships between leaf-productivity traits and tree growth. Twenty-eight trees were selected to measure isotopic composition of carbon (delta13C) and nitrogen (delta15N) and monitor six leaf attributes. Trees were sampled randomly within each of four diametric classes (at 150 mm above ground level) ensuring the variability in growth of the whole population was represented. A model averaging technique based on the Akaike's information criterion was computed to identify whether leaf traits could assist in diameter prediction. Regression analysis was performed to test for relationships between carbon isotope values and diameter and leaf traits. Approximately one new leaf per week was produced by a shoot. The rate of leaf expansion was estimated as 1.45 mm day-1. The range of delta13C values in leaves of Aquilaria species was from -25.50/00 to -310/00, with an average of -28.4 0/00 (+/-1.50/00 SD). A moderate negative correlation (R2 = 0.357) between diameter and delta13C in leaf dry matter indicated that individuals with high intercellular CO2 concentrations (low delta13C) and associated low water-use efficiency sustained rapid growth. Analysis of the 95% confidence of best-ranked regression models indicated that the predictors that could best explain growth in Aquilaria species were delta13C, delta15N, petiole length, number of new leaves produced per week and specific leaf area. The model constructed with these variables explained 55% (R2 = 0.55) of the variability in stem diameter. This demonstrates that leaf traits can assist in the early selection of high-productivity trees in Aquilaria species. PMID- 28338710 TI - The WRKY transcription factors PtrWRKY18 and PtrWRKY35 promote Melampsora resistance in Populus. AB - WRKY transcription factors play important roles in response to diverse environmental stresses, but exact functions of these proteins in poplar defense are still largely unknown. In a previous study, we have shown that poplar WRKY89 is induced by salicylic acid (SA) treatment and plays an important role in resistance against fungi in transgenic poplars. Here, we determined an increase in transcript levels of Group IIa WRKY members in transgenic poplars overexpressing WRKY89 using quantitative real-time polymerase chain reaction analysis. Yeast one-hybrid assay showed that PtrWRKY18 and PtrWRKY35 were potential target genes of WRKY89. Furthermore, we demonstrated that PtrWRKY18 and PtrWRKY35 were localized in the nucleus, and exhibited no transcription activation activity. Constitutive overexpression of PtrWRKY18 and PtrWRKY35 in poplars activated pathogenesis-related genes, and increased resistance to the biotrophic pathogen Melampsora. The results also provided support for the involvement of SA-mediated signaling in Melampsora resistance. PMID- 28338711 TI - The effects of age on crash risk associated with driver distraction. AB - Background: Driver distraction is a major contributing factor to crashes, which are the leading cause of death for the US population under 35 years of age. The prevalence of secondary-task engagement and its impacts on distraction and crashes may vary substantially by driver age. Methods: Driving performance and behaviour data were collected continuously using multiple cameras and sensors in situ for 3542 participant drivers recruited for up to 3 years for the Second Strategic Highway Research Program Naturalistic Driving Study. Secondary-task engagement at the onset of crashes and during normal driving segments was identified from videos. A case-cohort approach was used to estimate the crash odds ratios associated with, and the prevalence of, secondary tasks for four age groups: 16-20, 21-29, 30-64 and 65-98 years of age. Only severe crashes (property damage and higher severity) were included in the analysis. Results: Secondary task-induced distraction posed a consistently higher threat for drivers younger than 30 and above 65 when compared with middle-aged drivers, although senior drivers engaged in secondary tasks much less frequently than their younger counterparts. Secondary tasks with high visual-manual demand (e.g. visual-manual tasks performed on cell phones) affected drivers of all ages. Certain secondary tasks, such as operation of in-vehicle devices and talking/singing, increased the risk for only certain age groups. Conclusions: Teenaged, young adult drivers and senior drivers are more adversely impacted by secondary-task engagement than middle-aged drivers. Visual-manual distractions impact drivers of all ages, whereas cognitive distraction may have a larger impact on young drivers. PMID- 28338713 TI - Where does the carbon go? Thermal acclimation of respiration and increased photosynthesis in trees at the temperate-boreal ecotone. PMID- 28338712 TI - Molecular mechanisms of flowering under long days and stem growth habit in soybean. AB - Precise timing of flowering is critical to crop adaptation and productivity in a given environment. A number of classical E genes controlling flowering time and maturity have been identified in soybean [Glycine max (L.) Merr.]. The public availability of the soybean genome sequence has accelerated the identification of orthologues of Arabidopsis flowering genes and their functional analysis, and has allowed notable progress towards understanding the molecular mechanisms of flowering in soybean. Great progress has been made particularly in identifying genes and modules that inhibit flowering in long-day conditions, because a reduced or absent inhibition of flowering by long daylengths is an essential trait for soybean, a short-day (SD) plant, to expand its adaptability toward higher latitude environments. In contrast, the molecular mechanism of floral induction by SDs remains elusive in soybean. Here we present an update on recent work on molecular mechanisms of flowering under long days and of stem growth habit, outlining the progress in the identification of genes responsible, the interplay between photoperiod and age-dependent miRNA-mediated modules, and the conservation and divergence in photoperiodic flowering and stem growth habit in soybean relative to other legumes, Arabidopsis, and rice (Oryza sativa L.). PMID- 28338714 TI - Aldosterone a Relevant Factor in the Beginning and Evolution of Arterial Hypertension. PMID- 28338715 TI - Salt acclimation process: a comparison between a sensitive and a tolerant Olea europaea cultivar. AB - Saline soils are highly heterogeneous in time and space, and this is a critical factor influencing plant physiology and productivity. Temporal changes in soil salinity can alter plant responses to salinity, and pre-treating plants with low NaCl concentrations has been found to substantially increase salt tolerance in different species in a process called acclimation. However, it still remains unclear whether this process is common to all plants or is only expressed in certain genotypes. We addressed this question by assessing the physiological changes to 100 mM NaCl in two contrasting olive cultivars (the salt-sensitive Leccino and the salt-tolerant Frantoio), following a 1-month acclimation period with 5 or 25 mM NaCl. The acclimation improved salt tolerance in both cultivars, but activated substantially different physiological adjustments in the tolerant and the sensitive cultivars. In the tolerant Frantoio the acclimation with 5 mM NaCl was more effective in increasing plant salt tolerance, with a 47% increase in total plant dry mass compared with non-acclimated saline plants. This enhanced biomass accumulation was associated with a 50% increase in K+ retention ability in roots. On the other hand, in the sensitive Leccino, although the acclimation process did not improve performance in terms of plant growth, pre-treatment with 5 and 25 mM NaCl substantially decreased salt-induced leaf cell ultrastructural changes, with leaf cell relatively similar to those of control plants. Taken together these results suggest that in the tolerant cultivar the acclimation took place primarily in the root tissues, while in the sensitive they occurred mainly at the shoot level. PMID- 28338717 TI - Divergences in hydraulic architecture form an important basis for niche differentiation between diploid and polyploid Betula species in NE China. AB - Habitat differentiation between polyploid and diploid plants are frequently observed, with polyploids usually occupying more stressed environments. In woody plants, polyploidization can greatly affect wood characteristics but knowledge of its influences on xylem hydraulics is scarce. The four Betula species in NE China, representing two diploids and two polyploids with obvious habitat differentiation, provide an exceptional study system for investigating the impact of polyploidization on environmental adaptation of trees from the point view of xylem hydraulics. To test the hypothesis that changes in hydraulic architecture play an important role in determining their niche differentiation, we measured wood structural traits at both the tissue and pit levels and quantified xylem water transport efficiency and safety in these species. The two polyploids had significantly larger hydraulic weighted mean vessel diameters than the two diploids (45.1 and 45.5 vs 25.9 and 24.5 MUm) although the polyploids are occupying more stressed environments. As indicated by more negative water potentials corresponding to 50% loss of stem hydraulic conductivities, the two polyploids exhibited significantly higher resistance to drought-induced embolism than the two diploids (-5.23 and -5.05 vs -3.86 and -3.13 MPa) despite their larger vessel diameters. This seeming discrepancy is reconciled by distinct characteristics favoring greater embolism resistance at the pit level in the two polyploid species. Our results showed clearly that the two polyploid species have remarkably different pit-level anatomical traits favoring greater hydraulic safety than their congeneric diploid species, which have likely contributed to the abundance of polyploid birches in more stressed habitats; however, less porous inter-conduit pits together with a reduced leaf to sapwood area may have compromised their competitiveness under more favorable conditions. Contrasts in hydraulic architecture between diploid and polyploid Betula species suggest an important functional basis for their clear habitat differentiation along environmental gradients in Changbai Mountain of NE China. PMID- 28338716 TI - Neurological evidence for the role of construal level in future-directed thought. AB - The ability to mentally represent future events is a significant human psychological achievement. A challenge that people encounter is that they often lack detailed specifics about distant relative to near future events. Construal level theory proposes that people represent distant future events by their abstract and essential features-a process referred to as high-level construal. As events become temporally proximal, people represent events by their increasingly available and reliable concrete and idiosyncratic features-a process referred to as low-level construal. The present fMRI experiment provides direct neural evidence for these assertions. Using the why-how localizer as a measure of construal level, results revealed brain regions associated with both temporal distance and high-level construal (medial prefrontal cortex), as well as temporal proximity and low-level construal (precuneus). We discuss the implications of these findings for the neuroscience of mental time travel and cognitive representation. PMID- 28338718 TI - Identification and characterization of GRA6/GRA7 of Neospora caninum in MDBK cells. AB - Neospora caninum, an apicomplexan parasite, is recognized as a major bovine abortifacient. Dense granule antigens (GRAs) play important roles in the formation and modification of parasitophorous vacuoles (PVs) in Toxoplasma gondii. However, a few studies investigating GRAs have been reported in N. caninum. The aim of the present study was to characterize the dense GRA6/GRA7 of N. caninum in PVs using MDBK cells as a host cell model. Neospora caninum was inoculated into MDBK cells, and changes were observed using a transmission electron microscope (TEM). Neospora caninum GRA6/GRA7 were identified and characterized using bioinformatics, cell fractionation, and immunofluorescence. The TEM results revealed that integrated PVs were present in MDBK cells after N. caninum infection. Bioinformatics analysis showed that NcGRA6/NcGRA7 shared 28.76% and 29.66% homology with T. gondii GRA6/GRA7 (TgGRA6/TgGRA7) but had similar signal peptides, transmembrane domains, and motifs. Cell fractionation and subcellular localization analyses both showed that NcGRA6 was distributed in the lumen and intravacuolar network in soluble and transmembrane forms. The transmembrane form of NcGRA7 was observed in the PV membrane. These data lay a foundation for further study on bovine neosporosis and NcGRA6/NcGRA7 function during PV formation. PMID- 28338719 TI - The legume miR1514a modulates a NAC transcription factor transcript to trigger phasiRNA formation in response to drought. AB - Recent studies have identified microRNAs as post-transcriptional regulators involved in stress responses. miR1514a is a legume microRNA that is induced in response to drought stress in Phaseolus vulgaris (common bean) and shows differential accumulation levels in roots during water deficit in two cultivars with different drought tolerance phenotypes. A recent degradome analysis revealed that miR1514a targets the transcripts of two NAC transcription factors (TFs), Phvul.010g121000 and Phvul.010g120700. Furthermore, expression studies and small RNA-seq data indicate that only Phvul.010g120700 generates phasiRNAs, which also accumulate under water deficit conditions. To confirm these results, we over expressed miR1514a in transgenic hairy roots, and observed a reduced accumulation of Phvul.010g120700 and an increase in NAC-derived phasiRNAs; inhibition of miR1514a activity resulted in the opposite effect. Moreover, we determined that a NAC-derived phasiRNA associates with ARGONAUTE 1 (AGO1), suggesting that it is functional. In addition, a transcriptome analysis of transgenic hairy roots with reduced miR1514a levels revealed several differentially expressed transcripts, mainly involved in metabolism and stress responses, suggesting they are regulated by the NAC TF and/or by phasiRNAs. This work therefore demonstrates the participation of miR1514 in the regulation of a NAC transcription factor transcript through phasiRNA production during the plant response to water deficit. PMID- 28338721 TI - Mammographic density defined by higher than conventional brightness thresholds better predicts breast cancer risk. AB - Background: Mammographic density defined by the conventional pixel brightness threshold, and adjusted for age and body mass index (BMI), is a well-established risk factor for breast cancer. We asked if higher thresholds better separate women with and without breast cancer. Methods: We studied Australian women, 354 with breast cancer over-sampled for early-onset and family history, and 944 unaffected controls frequency-matched for age at mammogram. We measured mammographic dense area and percent density using the CUMULUS software at the conventional threshold, which we call Cumulus , and at two increasingly higher thresholds, which we call Altocumulus and Cirrocumulus , respectively. All measures were Box-Cox transformed and adjusted for age and BMI. We estimated the odds per adjusted standard deviation (OPERA) using logistic regression and the area under the receiver operating characteristic curve (AUC). Results: Altocumulus and Cirrocumulus were correlated with Cumulus (r ~ 0.8 and 0.6 , respectively) . For dense area, the OPERA was 1.62, 1.74 and 1.73 for Cumulus, Altocumulus and Cirrocumulus , respectively (all P < 0.001). After adjusting for Altocumulus and Cirrocumulus , Cumulus was not significant ( P > 0.6). The OPERAs for percent density were less but gave similar findings. The mean of the standardized adjusted Altocumulus and Cirrocumulus dense area measures was the best predictor; OPERA = 1.87 [95% confidence interval (CI): 1.64-2.14] and AUC = 0.68 (0.65-0.71). Conclusions: The areas of higher mammographically dense regions are associated with almost 30% stronger breast cancer risk gradient, explain the risk association of the conventional measure and might be more aetiologically important. This has substantial implications for clinical translation and molecular, genetic and epidemiological research. PMID- 28338723 TI - Non-specific effects of BCG vaccination on morbidity among children in Greenland: a population-based cohort study. AB - Background: The potential non-specific effects of BCG (Bacillus Calmette-Guerin) vaccination, with reported reduction of infectious disease morbidity among vaccinated children, in addition to the protective effect against tuberculosis (TB), are highly debated. In Greenland, BCG vaccination was introduced in 1955, but temporarily discontinued from 1991 to 1996 due to nationwide policy changes. Using the transient vaccination stop, we aimed to investigate possible non specific effects of BCG vaccination by measuring nation-wide hospitalization rates due to infectious diseases other than TB among vaccinated and unvaccinated children. Methods: A retrospective cohort study including all children born in Greenland aged 3 months to 3 years from 1989 to 2004. A personal identification number assigned at birth allowed for follow-up through national registers. Information on hospitalization due to infectious diseases was obtained from the Greenlandic inpatient register using ICD-8 and ICD-10 codes. Participants with notified TB were censored. Incidence rate ratios (IRR) were estimated using Poisson regression. Results: Overall, 19 363 children, hereof 66% BCG-vaccinated, were followed for 44 065 person-years and had 2069 hospitalizations due to infectious diseases. IRRs of hospitalization in BCG-vaccinated as compared with BCG-unvaccinated children were 1.07 [95% confidence interval (CI) 0.96-1.20] for infectious diseases overall, and specifically 1.10 (95% CI 0.98-1.24) for respiratory tract infections. Among BCG-vaccinated children aged 3 to 11 months, the IRR of hospitalization due to infectious diseases was 1.00 (95% CI 0.84-1.19) as compared with BCG-unvaccinated children. Conclusion: Our results do not support the hypothesis that neonatal BCG vaccination reduces morbidity in children caused by infectious diseases other than TB. PMID- 28338725 TI - Cohort Profile: Alberta's Tomorrow Project. PMID- 28338724 TI - Sex differences in the development of emotion circuitry in adolescents at risk for substance abuse: a longitudinal fMRI study. AB - There is substantial evidence for behavioral sex differences in risk trajectories for alcohol and substance use, with internalizing factors such as negative affectivity contributing more to female risk. Because the neural development of emotion circuitry varies between males and females across adolescence, it represents a potential mechanism by which underlying neurobiology contributes to risk for substance use. Longitudinal functional magnetic resonance imaging was conducted in males and females (n = 18 each) with a family history of alcohol use disorders starting at ages 8-13 years. Participants performed an affective word task during functional magnetic resonance imaging at 1- to 2-year intervals, covering the age range of 8.5-17.6 years (3-4 scans per participant). Significant age-related sex differences were found in the right amygdala and right precentral gyrus for the negative vs neutral word condition. Males showed a significant decrease in both amygdala and precentral gyrus activation with age, whereas the response in females persisted. The subjective experience of internalizing symptomatology significantly increased with age for females but not for males. Taken together, these results reveal sex differences in negative affect processing in at-risk adolescents, and offer longitudinal neural evidence for female substance use risk through internalizing pathways. PMID- 28338726 TI - Cumulative Exposure to Systolic Blood Pressure During Young Adulthood Through Midlife and the Urine Albumin-to-Creatinine Ratio at Midlife. AB - BACKGROUND: Higher blood pressure during young adulthood may increase cardiovascular and kidney disease risk later in life. This study examined the association of cumulative systolic blood pressure (SBP) exposure during young adulthood through midlife with urine albumin-to-creatinine ratios (ACR) measured during midlife. METHODS: We used data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a biracial cohort recruited in 4 urban areas during years 1985-1986. Cumulative SBP was calculated as the average SBP between 2 exams multiplied by years between exams over 20 year years. ACR was measured 20 years after baseline when participants were age 43-50 years (midlife). A generalized additive model was used to examine the association of log ACR as a function of cumulative SBP with adjustment for covariates including SBP measured concurrently with ACR. RESULTS: Cumulative SBP ranged from a low of 1,671 to a high of 3,260 mm Hg. Participants in the highest cumulative SBP quartile were more likely to be male (61.4% vs. 20.7%; P < 0.001), Black (61.5% vs. 25.6%; P < 0.001) and have elevated ACR (18.7% vs. 4.8%; P < 0.001) vs. lowest quartile. Spline regression curves of ACR vs. cumulative SBP demonstrated an inflection point in ACR with cumulative SBP levels >2,350 mm Hg with linear increases in ACR above this threshold. Adjusted geometric mean ACR values were significantly higher with cumulative SBP >=2,500 vs. <2500 (9.18 [1.06] vs. 6.92 [1.02]; P < 0.0001). CONCLUSION: Higher SBP during young adulthood through midlife is associated with higher ACR during midlife. PMID- 28338727 TI - RIN4 recruits the exocyst subunit EXO70B1 to the plasma membrane. AB - The exocyst is a conserved vesicle-tethering complex with principal roles in cell polarity and morphogenesis. Several studies point to its involvement in polarized secretion during microbial pathogen defense. In this context, we have found an interaction between the Arabidopsis EXO70B1 exocyst subunit, a protein which was previously associated with both the defense response and autophagy, and RPM1 INTERACTING PROTEIN 4 (RIN4), the best studied member of the NOI protein family and a known regulator of plant defense pathways. Interestingly, fragments of RIN4 mimicking the cleavage caused by the Pseudomonas syringae effector protease, AvrRpt2, fail to interact strongly with EXO70B1. We observed that transiently expressed RIN4, but not the plasma membrane (PM) protein aquaporin PIP2, recruits EXO70B1 to the PM. Unlike EXO70B1, RIN4 does not recruit the core exocyst subunit SEC6 to the PM under these conditions. Furthermore, the AvrRpt2 effector protease delivered by P. syringae is able to release both RIN4 and EXO70B1 to the cytoplasm. We present a model for how RIN4 might regulate the localization and putative function of EXO70B1 and speculate on the role the AvrRpt2 protease might have in the regulation of this defense response. PMID- 28338728 TI - Characterising root trait variability in chickpea (Cicer arietinum L.) germplasm. AB - Chickpea (Cicer arietinum L.) is an important grain legume crop but its sustainable production is challenged by predicted climate changes, which are likely to increase production limitations and uncertainty in yields. Characterising the variability in root architectural traits in a core collection of chickpea germplasm will provide the basis for breeding new germplasm with suitable root traits for the efficient acquisition of soil resources and adaptation to drought and other abiotic stresses. This study used a semi hydroponic phenotyping system for assessing root trait variability across 270 chickpea genotypes. The genotypes exhibited large variation in rooting patterns and branching manner. Thirty root-related traits were characterised, 17 of which had coefficients of variation >=0.3 among genotypes and were selected for further examination. The Pearson correlation matrix showed a strong correlation among most of the selected traits (P<=0.05). Principal component analysis revealed three principal components with eigenvalues >1 capturing 81.5% of the total variation. An agglomerative hierarchical clustering analysis, based on root trait variation, identified three genotype homogeneous groups (rescaled distance of 15) and 16 sub-groups (rescaled distance of 5). The chickpea genotypes characterised in this study with vastly different root properties could be used for further studies in glasshouses and field trials, and for molecular marker studies, gene mapping, and modelling simulations, ultimately aimed at breeding germplasm with root traits for improved adaptation to drought and other specific environments. PMID- 28338732 TI - My favourite flowering image: a capitulum of Asteraceae. PMID- 28338729 TI - Revealing the roles of GORK channels and NADPH oxidase in acclimation to hypoxia in Arabidopsis. AB - Regulation of root cell K+ is essential for acclimation to low oxygen stress. The potential roles of GORK (depolarization-activated guard cell outward-rectifying potassium) channels and RBOHD (respiratory burst oxidase homologue D) in plant adaptive responses to hypoxia were investigated in the context of tissue specificity (epidermis versus stele; elongation versus mature zone) in roots of Arabidopsis. The expression of GORK and RBOHD was down-regulated by 2- to 3-fold within 1 h and 24 h of hypoxia treatment in Arabidopsis wild-type (WT) roots. Interestingly, a loss of the functional GORK channel resulted in a waterlogging tolerant phenotype, while rbohD knockout was sensitive to waterlogging. To understand their functions under hypoxia stress, we studied K+, Ca2+, and reactive oxygen species (ROS) distribution in various root cell types. gork1-1 plants had better K+ retention ability in both the elongation and mature zone compared with the WT and rbohD under hypoxia. Hypoxia induced a Ca2+ increase in each cell type after 72 h, and the increase was much less pronounced in rbohD than in the WT. In most tissues except the elongation zone in rbohD, the H2O2 concentration had decreased after 1 h of hypoxia, but then increased significantly after 24 h of hypoxia in each zone and tissue, further suggesting that RBOHD may shape hypoxia-specific Ca2+ signatures via the modulation of apoplastic H2O2 production. Taken together, our data suggest that plants lacking functional GORK channels are more capable of retaining K+ for their better performance under hypoxia, and that RBOHD is crucial in hypoxia-induced Ca2+ signalling for stress sensing and acclimation mechanism. PMID- 28338731 TI - Purification and enzymatic characterization of Gallus gallus BLM helicase. AB - Mutations in human BLM helicase give rise to the autosomal recessive Bloom syndrome, which shows high predisposition to types of malignant tumours. Though lots of biochemical and structural investigations have shed lights on the helicase core, structural investigations of the whole BLM protein are still limited due to its low stability and production. Here by comparing with the expression systems and functions of other BLM homologues, we developed the heterologous high-level expression and high-yield purification systems for Gallus gallus BLM (gBLM) in Escherichia coli. Subsequent DNA binding and unwinding determinations demonstrated that gBLM was a vigorous atypical DNA structure specific helicase, which not only showed high preference for the 3'-tailed DNA structures but also could efficiently unwind bubble DNA structures with blunt ends, indicating its biological roles in processing DNA metabolism intermediates. Further comparative analysis between gBLM and gBLM Core revealed that the long N terminal domain facilitated the binding affinity of forked and bubble DNA structures and it was also required for the DNA unwinding activities of gBLM. Thus, we present the first enzymatic characterization of gBLM and its N-terminal domain, providing a new model for probing the mechanism and structure of human BLM. PMID- 28338733 TI - Genetic adaptation and phenotypic plasticity contribute to greater leaf hydraulic tolerance in response to drought in warmer climates. AB - The ability of plants to maintain an intact water transport system in leaves under drought conditions is intimately linked to survival and can been be seen as adaptive in shaping species climatic limits. Large differences in leaf hydraulic vulnerability to drought are known among species from contrasting climates, yet whether this trait varies among populations within a single species and, furthermore, whether it is altered by changes in growth conditions, remain unclear. We examined intraspecific variation in both leaf water transport capacity (Kleaf) and leaf hydraulic vulnerability to drought (P50leaf) among eight populations of Corymbia calophylla (R. Br.) K.D. Hill & L.A.S. Johnson (Myrtaceae) from both cool and warm climatic regions grown reciprocally under two temperature treatments representing the cool and warm edge of the species distribution. Kleaf did not vary between cool and warm-climate populations, nor was it affected by variable growth temperature. In contrast, population origin and growth temperature independently altered P50leaf. Using data pooled across growth temperatures, cool-climate populations showed significantly higher leaf hydraulic vulnerability (P50leaf = -3.55 +/- 0.18 MPa) than warm-climate populations (P50leaf = -3.78 +/- 0.08 MPa). Across populations, P50leaf decreased as population home-climate temperature increased, but was unrelated to rainfall and aridity. For populations from both cool and warm climatic regions, P50leaf was lower under the warmer growth conditions. These results provide evidence of trait plasticity in leaf hydraulic vulnerability to drought in response to variable growth temperature. Furthermore, they suggest that climate, and in particular temperature, may be a strong selective force in shaping intraspecific variation in leaf hydraulic vulnerability to drought. PMID- 28338730 TI - Genetic variability of the activity of bidirectional promoters: a pilot study in bovine muscle. AB - Bidirectional promoters are regulatory regions co-regulating the expression of two neighbouring genes organized in a head-to-head orientation. In recent years, these regulatory regions have been studied in many organisms; however, no investigation to date has been done to analyse the genetic variation of the activity of this type of promoter regions. In our study, we conducted an investigation to first identify bidirectional promoters sharing genes expressed in bovine Longissimus thoracis and then to find genetic variants affecting the activity of some of these bidirectional promoters. Combining bovine gene information and expression data obtained using RNA-Seq, we identified 120 putative bidirectional promoters active in bovine muscle. We experimentally validated in vitro 16 of these bidirectional promoters. Finally, using gene expression and whole-genome genotyping data, we explored the variability of the activity in muscle of the identified bidirectional promoters and discovered genetic variants affecting their activity. We found that the expression level of 77 genes is correlated with the activity of 12 bidirectional promoters. We also identified 57 single nucleotide polymorphisms associated with the activity of 5 bidirectional promoters. To our knowledge, our study is the first analysis in any species of the genetic variability of the activity of bidirectional promoters. PMID- 28338734 TI - Using remote sensing technology to measure environmental determinants of non communicable diseases. PMID- 28338735 TI - Can adjustments in foliar nitrogen-use efficiency reduce drought stress impacts on boreal trees? PMID- 28338736 TI - Microcompartmentation of cytosolic aldolase by interaction with the actin cytoskeleton in Arabidopsis. AB - Evidence is accumulating for molecular microcompartments formed when proteins interact in localized domains with the cytoskeleton, organelle surfaces, and intracellular membranes. To understand the potential functional significance of protein microcompartmentation in plants, we studied the interaction of the glycolytic enzyme fructose bisphosphate aldolase with actin in Arabidopsis thaliana. Homology modelling of a major cytosolic isozyme of aldolase, FBA8, suggested that the tetrameric holoenzyme has two actin binding sites and could therefore act as an actin-bundling protein, as was reported for animal aldolases. This was confirmed by in vitro measurements of an increase in viscosity of F actin polymerized in the presence of recombinant FBA8. Simultaneously, interaction with F-actin caused non-competitive inhibition of aldolase activity. We did not detect co-localization of an FBA8-RFP fusion protein, expressed in an fba8-knockout background, with the actin cytoskeleton using confocal laser scanning microscopy. However, we did find evidence for a low level of interaction using FRET-FLIM analysis of FBA8-RFP co-expressed with the actin-binding protein GFP-Lifeact. Furthermore, knockout of FBA8 caused minor alterations of guard cell actin cytoskeleton morphology and resulted in a reduced rate of stomatal closure in response to decreased humidity. We conclude that cytosolic aldolase can be microcompartmented in vivo by interaction with the actin cytoskeleton and may subtly modulate guard cell behaviour as a result. PMID- 28338737 TI - Retinol-Binding Protein 4 and Lipids Prospectively Measured During Early to Mid Pregnancy in Relation to Preeclampsia and Preterm Birth Risk. AB - BACKGROUND: Maternal retinol-binding protein 4 (RBP4) and lipids may relate to preeclampsia and preterm birth risk but longitudinal data are lacking. This study examines these biomarkers longitudinally during pregnancy in relation to preeclampsia and preterm birth risk. METHODS: Maternal serum samples from the Calcium for Preeclampsia Prevention (CPEP) trial were analyzed at baseline: average 15 gestational weeks; mid-pregnancy: average 27 weeks; and at >34 weeks. We measured RBP4, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides and lipoprotein (a) (Lp(a)). Cross-sectional logistic regression analyses estimated the odds ratio (OR) and 95% confidence intervals (CI) for preterm preeclampsia (n = 63), term preeclampsia (n = 104), and preterm delivery (n = 160) associated with RBP4 and lipids at baseline and mid-pregnancy compared with controls (n = 136). Longitudinal trajectories across pregnancy were assessed using mixed linear models with fixed effects. Adjusted models included clinical and demographic factors. RESULTS: RBP4 concentrations at baseline and mid-pregnancy were associated with a 4- to 8-fold increase in preterm preeclampsia risk but were not associated with term preeclampsia. RBP4 measured mid-pregnancy was also associated with preterm birth (OR = 6.67, 95% CI: 1.65, 26.84). Higher triglyceride concentrations in mid-pregnancy were associated with a 2- to 4-fold increased risk for both preeclampsia and preterm birth. Longitudinal models demonstrate that both preterm preeclampsia and preterm birth cases had elevated RBP4 throughout gestation. CONCLUSIONS: Elevated RBP4 is detectable early in pregnancy and its strong relation with preterm preeclampsia merits further investigation and confirmation to evaluate its potential use as a predictor, particularly among high-risk women. PMID- 28338739 TI - Retention of stored water enables tropical tree saplings to survive extreme drought conditions. AB - Trees generally maintain a small safety margin between the stem water potential (Psistem) reached during seasonal droughts and the Psistem associated with their mortality. This pattern may indicate that species face similar mortality risk during extreme droughts. However, if tree species vary in their ability to regulate Psistem, then safety margins would poorly predict drought mortality. To explore variation among species in Psistem regulation, I subjected potted saplings of six tropical tree species to extreme drought and compared their responses with well-watered plants and pretreatment reference plants. In the drought treatment, soil water potential reached <-10 MPa, yet three species, Bursera simaruba (L.) Sarg., Cavanillesia platanifolia (Bonpl.) Kunth and Cedrela odorata L. had 100% survival and maintained Psistem near -1 MPa (i.e., desiccation-avoiding species). Three other species, Cojoba rufescens (Benth.) Britton and Rose, Genipa americana L. and Hymenaea courbaril L. had 50%, 0% and 25% survival, respectively, and survivors had Psistem <-6 MPa (i.e., desiccation susceptible species). The desiccation-avoiding species had lower relative water content (RWC) in all organs and tissues (root, stem, bark and xylem) in the drought treatment than in the reference plants (means 72.0-90.4% vs 86.9-97.9%), but the survivors of the desiccation-susceptible C. rufescens had much lower RWC in the drought treatment (44.5-72.1%). Among the reference plants, the desiccation-avoiding species had lower tissue density, leaf-mass fraction and lateral-root surface area (LRA) than the desiccation-susceptible species. Additionally, C. platanifolia and C. odorata had reduced LRA in the drought treatment, which may slow water loss into dry soil. Together, these results suggest that the ability to regulate Psistem during extreme drought is associated with functional traits that favor retention of stored water and that safety margins during seasonal drought poorly predict survival during extreme drought. PMID- 28338738 TI - Task-Related Functional Connectivity Analysis of Emotion Discrimination in a Family Study of Schizophrenia. AB - Poor emotion recognition is a core deficit in schizophrenia and is associated with poor functional outcome. Functional magnetic resonance imaging (fMRI) multivariate analysis methods were used to elucidate the neural underpinnings of face and emotion processing associated with both genetic liability and disease specific effects. Schizophrenia patients, relatives, and controls completed a task that included 4 facial emotion discrimination conditions and an age discrimination condition during fMRI. Three functional networks were derived from the data: the first involved in visual attention and response generation, the second a default mode network (DMN), and a third involved in face and emotion processing. No differences in activation were found between groups for the visual attention and response generation network, suggesting that basic processes were intact. Both schizophrenia patients and relatives showed evidence for hyperdeactivation in the DMN compared to controls, with relatives being intermediate, suggesting a genetic liability effect. Both disease-specific and genetic liability effects were found for the face processing network, which included the amygdala. Patients exhibited lower coordinated network activity compared to controls and relatives across all facial discrimination conditions. Additionally, in relation to the other emotion discrimination conditions, a heightened coordinated response during fear and anger discrimination was observed in schizophrenia compared to other conditions, whereas relatives demonstrated heightened coordinated activity for anger discrimination only relative to other emotion conditions. With regards to brain functioning, this study found that schizophrenia is associated with abnormal processing of threat-related information, and that in part may be associated with the genetic risk for the disorder, suggesting that the facial and emotion processing network could be targeted for intervention. PMID- 28338741 TI - Tolerating dissimilar other when primed with death: neural evidence of self control engaged by interdependent people in Japan. AB - Mortality salience (MS) has been shown to lead to derogation of others with dissimilar worldviews, yet recent research has shown that Asian-Americans who presumably adopt an interdependent self-construal (SC) tend to reveal greater tolerance after MS induction. In the present study, we demonstrated that Japanese individuals who are high on interdependent SC indeed show greater tolerance toward worldview-threatening other in the MS (vs control) condition, thus replicating the prior research. Extending this research, we also found that interdependent people's tolerance toward worldview-threatening other was mediated by increased activity in the right ventrolateral prefrontal cortex in the MS condition. These data suggested that when exposed to death-related stimuli, highly interdependent individuals may spontaneously activate their neural self control system which may serve to increase tolerance toward others. PMID- 28338742 TI - Brain mechanisms for loss of awareness of thought and movement. AB - Loss or reduction of awareness is common in neuropsychiatric disorders and culturally influenced dissociative phenomena but the underlying brain mechanisms are poorly understood. fMRI was combined with suggestions for automatic writing in 18 healthy highly hypnotically suggestible individuals in a within-subjects design to determine whether clinical alterations in awareness of thought and movement can be experimentally modelled and studied independently of illness. Subjective ratings of control, ownership, and awareness of thought and movement, and fMRI data were collected following suggestions for thought insertion and alien control of writing movement, with and without loss of awareness. Subjective ratings confirmed that suggestions were effective. At the neural level, our main findings indicated that loss of awareness for both thought and movement during automatic writing was associated with reduced activation in a predominantly left sided posterior cortical network including BA 7 (superior parietal lobule and precuneus), and posterior cingulate cortex, involved in self-related processing and awareness of the body in space. Reduced activity in posterior parietal cortices may underlie specific clinical and cultural alterations in awareness of thought and movement. Clinically, these findings may assist development of imaging assessments for loss of awareness of psychological origin, and interventions such as neurofeedback. PMID- 28338743 TI - Incidental memory for faces in children with different genetic subtypes of Prader Willi syndrome. AB - The present study examined the effects of genetic subtype on social memory in children (7-16 years) with Prader-Willi syndrome (PWS). Visual event-related potentials (ERPs) during a passive viewing task were used to compare incidental memory traces for repeated vs single presentations of previously unfamiliar social (faces) and nonsocial (houses) images in 15 children with the deletion subtype and 13 children with maternal uniparental disomy (mUPD). While all participants perceived faces as different from houses (N170 responses), repeated faces elicited more positive ERP amplitudes ('old/new' effect, 250-500ms) only in children with the deletion subtype. Conversely, the mUPD group demonstrated reduced amplitudes suggestive of habituation to the repeated faces. ERP responses to repeated vs single house images did not differ in either group. The results suggest that faces hold different motivational value for individuals with the deletion vs mUPD subtype of PWS and could contribute to the explanation of subtype differences in the psychiatric symptoms, including autism symptomatology. PMID- 28338744 TI - Understanding the molecular mechanism of substrate channeling and domain communication in protozoal bifunctional TS-DHFR. AB - Most species, such as humans, have monofunctional forms of thymidylate synthase (TS) and dihydrofolate reductase (DHFR) that are key folate metabolism enzymes making critical folate components required for DNA synthesis. In contrast, several parasitic protozoa, including Leishmania major (Lm), Plasmodium falciparum (Pf), Toxoplasma gondii (Tg) and Cryptosporidium hominis (Ch), contain a unique bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) having the two sequential catalytic activities contained on a single polypeptide chain. It has been suggested that the bifunctional nature of the two catalytic activities may enable substrate channeling. The 3D structures for each of these enzymes reveals distinct features for each species. While three of the four species (Pf, Tg and Ch) contain a junctional region linking the two domains, this is lacking in Lm. The Lm and Pf contain N-terminal amino acid extensions. A multidisciplinary approach using structural studies and transient kinetic analyses combined with mutational analysis has investigated the roles of these unique structural features for each enzyme. Additionally, the possibility of substrate channeling behavior was explored. These studies have identified unique, functional regions in both the TS and DHFR domains that govern efficient catalysis for each species. Surprisingly, even though there are structural similarities among the species, each is regulated in a distinct manner. This structural and mechanistic information was also used to exploit species-specific inhibitor design. PMID- 28338746 TI - Genotypic and Phenotypic Heterogeneity-Hurdles and Opportunities in the Quest for Hypertension-Related Genes. PMID- 28338745 TI - Circadian oscillations of microbial and functional composition in the human salivary microbiome. AB - The human microbiomes across the body evidently interact with various signals in response to biogeographical physiological conditions. To understand such interactions in detail, we investigated how the salivary microbiome in the oral cavity would be regulated by host-related signals. Here, we show that the microbial abundance and gene participating in keeping the human salivary microbiome exhibit global circadian rhythm. Analysis of the 16S rRNA sequences of salivary microbial samples of six healthy adults collected at 4-h intervals for three days revealed that the microbial genera accounting for 68.4-89.6% of the total abundance were observed to significantly oscillate with the periodicity of ~24 h. These oscillation patterns showed high variations amongst individuals, and the extent of circadian variations in individuals was generally lower than that of interindividual variations. Of the microbial categories oscillated, those classified by aerobic/anaerobic growth and Gram staining, Firmicutes including Streptococcus and Gemella, and Bacteroidetes including Prevotella showed high association with the circadian oscillation. The circadian oscillation was completely abolished by incubating the saliva in vitro, suggesting that host's physiological changes mostly contributed to the microbial oscillation. Further metagenomic analysis showed that circadian oscillation enriched the functions of environmental responses such as various transporters and two-component regulatory systems in the evening, and those of metabolisms such as the biosynthesis of vitamins and fatty acids in the morning. PMID- 28338748 TI - Role of scavenger receptors as damage-associated molecular pattern receptors in Toll-like receptor activation. AB - Damage-associated molecular patterns (DAMPs) have been implicated in sterile inflammation in various tissue injuries. High-mobility group box 1 (HMGB1) is a representative DAMP, and has been shown to transmit signals through receptors for advanced glycation end products (RAGEs) and TLRs, including TLR2 and TLR4. HMGB1 does not, however, bind to TLRs with high affinity; therefore, the mechanism of HMGB1-mediated TLR activation remains unclear. In this study, we found that fluorescently labeled HMGB1 was efficiently internalized into macrophages through class A scavenger receptors. Although both M1- and M2-type macrophages internalized HMGB1, only M1-type macrophages secreted cytokines in response to HMGB1. The pan-class A scavenger receptor competitive inhibitor, maleylated bovine serum albumin (M-BSA), inhibited HMGB1 internalization and reduced cytokine production from macrophages in response to HMGB1 but not to LPS. The C terminal acidic domain of HMGB1 is responsible for scavenger receptor-mediated internalization and cytokine production. HMGB1 and TLR4 co-localized in macrophages, and this interaction was disrupted by M-BSA, suggesting that class A scavenger receptors function as co-receptors of HMGB1 for TLR activation. M-BSA ameliorated LPS-induced sepsis and dextran sulfate sodium (DSS)-induced colitis models in which HMGB1 has been shown to play progressive roles. These data suggest that scavenger receptors function as co-receptors along with TLRs for HMGB1 in M1-type inflammatory macrophages. PMID- 28338749 TI - Evaluation of contact tracing activities during the Ebola virus disease outbreak in Guinea, 2015. AB - Objectives: The objective of the study was to present the findings of an audit tool aimed at assessing contact tracing activities during an Ebola outbreak. Methods: The tool was based on Ebola guidelines and observations in the field. It was composed of 38 indicators covering contact tracing preparatives, resources, procedures and results. Results: All contact tracing teams were assessed in Boke and Conakry prefectures (24 supervisors, 22 community workers, 442 contacts) between 1 July and 10 August 2015. Contact lists had less than a 40% accomplishment rate. 7% of the contacts were not seen by community workers or supervisors. 'No touch policy' was fully respected. Conclusion: Audit checklist helped to systematically identify critical issues related to contact tracing. PMID- 28338750 TI - Association of Maternal Plasma Folate and Cardiometabolic Risk Factors in Pregnancy with Elevated Blood Pressure of Offspring in Childhood. AB - BACKGROUND: The prevalence of childhood elevated blood pressure (BP) has increased in the United States, particularly among African Americans. The influence of maternal plasma folate levels, alone or in combination with maternal cardiometabolic risk factors (hypertensive disorders, diabetes, and prepregnancy obesity), on child systolic BP (SBP) has not been examined in a prospective birth cohort. We hypothesize that adequate maternal folate levels can reduce the risk of elevated SBP in children born to mothers with cardiometabolic risk factors. METHODS: This study included 1,290 mother-child dyads (875 African Americans (67.8%)) recruited at birth and followed prospectively up to age 9 years from 2003 to 2014 at the Boston Medical Center. Child SBP percentile was calculated according to US reference data and elevated SBP was defined as SBP >=75th percentile. RESULTS: Maternal folate levels, overall, were not associated with child SBP. However, we found a significant multiplicative interaction between maternal cardiometabolic risk factors and maternal folate levels (Pinteraction = 0.015) on childhood elevated SBP. Among children born to mothers with any cardiometabolic risk factors, those whose mothers had folate levels above (vs. below) the median had 40% lower odds of elevated childhood SBP (odds ratio = 0.60, 95% confidence interval: 0.40-0.90). The associations did not differ appreciably in analyses restricted to African Americans, and they were not explained by gestational age, size at birth, prenatal folate intake, or breastfeeding. CONCLUSIONS: Findings from our urban minority birth cohort suggest that higher levels of maternal folate may help counteract the adverse associations of maternal cardiometabolic risk factors on child SBP. PMID- 28338753 TI - Second Chance. AB - My second career as a schizophrenia researcher will focus on infectious agents as a cause. It will include the collection of serial sera, cerebrospinal fluid, functional magnetic resonance imaging, and diffusion tensor imaging on a cohort of affected individuals over 20 years. Since I believe that the initial transmission of these agents occurs in childhood, I will also follow a cohort of children from birth to age 20. Additional projects will focus on rheumatoid arthritis, geographic case clusters, immigrants, and epidemiology. PMID- 28338752 TI - Strategies for evaluating the assumptions of the regression discontinuity design: a case study using a human papillomavirus vaccination programme. AB - Background: The regression discontinuity design (RDD) is a quasi-experimental approach used to avoid confounding bias in the assessment of new policies and interventions. It is applied specifically in situations where individuals are assigned to a policy/intervention based on whether they are above or below a pre specified cut-off on a continuously measured variable, such as birth date, income or weight. The strength of the design is that, provided individuals do not manipulate the value of this variable, assignment to the policy/intervention is considered as good as random for individuals close to the cut-off. Despite its popularity in fields like economics, the RDD remains relatively unknown in epidemiology where its application could be tremendously useful. Methods: In this paper, we provide a practical introduction to the RDD for health researchers, describe four empirically testable assumptions of the design and offer strategies that can be used to assess whether these assumptions are met in a given study. For illustrative purposes, we implement these strategies to assess whether the RDD is appropriate for a study of the impact of human papillomavirus vaccination on cervical dysplasia. Results: We found that, whereas the assumptions of the RDD were generally satisfied in our study context, birth timing had the potential to confound our effect estimate in an unexpected way and therefore needed to be taken into account in the analysis. Conclusions: Our findings underscore the importance of assessing the validity of the assumptions of this design, testing them when possible and making adjustments as necessary to support valid causal inference. PMID- 28338751 TI - Reduced Thickness of the Anterior Cingulate Cortex in Individuals With an At-Risk Mental State Who Later Develop Psychosis. AB - BACKGROUND: Despite the fact that only a part of the individuals with at-risk mental state (ARMS) for psychosis do develop psychosis, biological markers of future transition to psychosis have not been well documented. Structural abnormality of the anterior cingulate gyrus (ACG), which probably exists prior to the onset of psychosis, could be such a risk marker. METHODS: We conducted a multicenter magnetic resonance imaging (MRI) study of 3 scanning sites in Japan. 1.5-T 3D MRI scans were obtained from 73 ARMS subjects and 74 age- and gender matched healthy controls. We measured thickness, volume, and surface area of the ACG using labeled cortical distance mapping and compared these measures among healthy controls, ARMS subjects who later converted to overt psychosis (ARMS-C), and those who did not (ARMS-NC). RESULTS: Seventeen of 73 (23%) ARMS subjects developed overt psychosis within the follow-up period. The thickness of the left ACG was significantly reduced in ARMS-C relative to healthy subjects (P = .026) while both ARMS-C (P = .001) and ARMS-NC (P = .01) had larger surface areas of the left ACG compared with healthy controls. CONCLUSION: Further studies will be needed to identify potential markers of future transition to psychosis though cortical thinning of the ACG might be one of the candidates. PMID- 28338754 TI - Spatial quantification of the world population potentially exposed to Zika virus. AB - Background: Zika virus is an emerging Flaviviridae virus, which has spread rapidly in the last few years. It has raised concern because it has been associated with fetus microcephaly when pregnant women are infected. The main vector is the mosquito Aedes aegypti , distributed in tropical areas. Methods: Niche modelling techniques were used to estimate the potential distribution area of A. aegypti. This was overlapped with human population density, determining areas of potential transmission risk worldwide. Afterwards, we quantified the population at risk according to risk level. Results: The vector transmission risk is distributed mainly in Asia and Oceania on the shores of the Indian Ocean. In America, the risk concentrates in the Atlantic coast of South America and in the Caribbean Sea shores in Central and North America. In Africa, the major risk is concentrated in the Pacific and Atlantic coasts of Central and South Africa. The world population under high and very high risk levels includes 2.261 billion people. Conclusions: These results illustrate Zika virus risk at the global level and provide maps to target the prevention and control measures especially in areas with higher risk, in countries with less sanitation and poorer resources. Many countries without previous vector reports could become active transmission zones in the future, so vector surveillance should be implemented or reinforced in these areas. PMID- 28338755 TI - Red blotch disease alters grape berry development and metabolism by interfering with the transcriptional and hormonal regulation of ripening. AB - Grapevine red blotch-associated virus (GRBaV) is a major threat to the wine industry in the USA. GRBaV infections (aka red blotch disease) compromise crop yield and berry chemical composition, affecting the flavor and aroma properties of must and wine. In this study, we combined genome-wide transcriptional profiling with targeted metabolite analyses and biochemical assays to characterize the impact of the disease on red-skinned berry ripening and metabolism. Using naturally infected berries collected from two vineyards, we were able to identify consistent berry responses to GRBaV across different environmental and cultural conditions. Specific alterations of both primary and secondary metabolism occurred in GRBaV-infected berries during ripening. Notably, GRBaV infections of post-veraison berries resulted in the induction of primary metabolic pathways normally associated with early berry development (e.g. thylakoid electron transfer and the Calvin cycle), while inhibiting ripening associated pathways, such as a reduced metabolic flux in the central and peripheral phenylpropanoid pathways. We show that this metabolic reprogramming correlates with perturbations at multiple regulatory levels of berry development. Red blotch caused the abnormal expression of transcription factors (e.g. NACs, MYBs, and AP2-ERFs) and elements of the post-transcriptional machinery that function during red-skinned berry ripening. Abscisic acid, ethylene, and auxin pathways, which control both the initiation of ripening and stress responses, were also compromised. We conclude that GRBaV infections disrupt normal berry development and stress responses by altering transcription factors and hormone networks, which result in the inhibition of ripening pathways involved in the generation of color, flavor, and aroma compounds. PMID- 28338756 TI - Commentary: On the Harmfulness of Tobacco; Chekhov's journey from vaudeville to empathy. PMID- 28338758 TI - Mistletoe infestation mediates alteration of the phytohormone profile and anti oxidative metabolism in bark and wood of its host Pinus sylvestris. AB - European mistletoe (Viscum album L.) has largely infested Central European forests and causes high mortality probability particularly in dry years. However, little information is available about the consequences of mistletoe infestation for metabolic processes in bark and wood of its host, despite their important roles in infestation defense. We analyzed the tissue hydration, carbohydrate composition, phytohormone profile, reactive oxygen species and anti-oxidant levels in bark and wood of Scots pines (Pinus sylvestris L.), as dependent on mistletoe infestation. As a consequence of mistletoe infestation, host bark and wood showed impaired hydration and reduced total carbon content. In the bark, soluble sugar and lignin contents increased, apparently at the expense of holo cellulose. Hydrogen peroxide accumulation was accompanied by increased glutathione and decreased reduced ascorbic acid levels. Mistletoe infestation mediated alteration of the phytohormone profile in bark and wood of its host. Cytokinins, jasmonic acid and abscisic acid levels increased in both tissues, whereas salicylic acid and indole-3-acetic acid, which were only detected in the bark, declined. The present results show that mistletoe infestation affects both the host's anti-oxidative defense system and the phytohormone profile after establishment of the xylem tapping haustorium. The significance of these processes for the development of the woody mistletoe stem and the haustorium is discussed. PMID- 28338757 TI - Acceleration of leaf senescence is slowed down in transgenic barley plants deficient in the DNA/RNA-binding protein WHIRLY1. AB - WHIRLY1 in barley was isolated as a potential regulator of the senescence associated gene HvS40. In order to investigate whether the plastid-nucleus located DNA/RNA-binding protein WHIRLY1 plays a role in regulation of leaf senescence, primary foliage leaves from transgenic barley plants with an RNAi mediated knockdown of the WHIRLY1 gene were characterized by typical senescence parameters, namely pigment contents, function and composition of the photosynthetic apparatus, as well as expression of selected genes known to be either down- or up-regulated during leaf senescence. When the plants were grown at low light intensity, senescence progression was similar between wild-type and RNAi-W1 plants. Likewise, dark-induced senescence of detached leaves was not affected by reduction of WHIRLY1. When plants were grown at high light intensity, however, senescence was induced prematurely in wild-type plants but was delayed in RNAi-W1 plants. This result suggests that WHIRLY1 plays a role in light sensing and/or stress communication between chloroplasts and the nucleus. PMID- 28338759 TI - Erratum: Alcohol dependency in the elderly - are we capturing it? PMID- 28338760 TI - Childhood Maltreatment and Young Adulthood Hallucinations, Delusional Experiences, and Psychosis: A Longitudinal Study. AB - Child maltreatment is a widespread public health problem associated with a range of mental health disorders later in life. In order to effectively address these disorders, there is a need to understand more about the mental health consequences of different types of child maltreatment. This study examines the associations between prospectively substantiated child maltreatment (ages 0-14 y) and reports of hallucinations and delusional experiences at 21 years after birth. As well, we examined 12-month and lifetime psychotic disorders using data from a longitudinal birth cohort. The study comprised 3752 participants from the Mater University of Queensland Study of Pregnancy, a prospective Australian prebirth cohort study. Psychotic experiences and 12-month and lifetime psychosis were measured using the Achenbach Young Adults Self-Report, the Peter's Delusions Inventory, and Composite International Diagnostic Interview at the 21-year follow up. In adjusted analyses, those children who had experienced any maltreatment and who were emotionally abused and neglected were more likely to report (1) hallucinations and lifetime delusional experiences and (2) more likely to experience lifetime psychosis than their nonabused counterparts. In expanded models, those exposed to multiple forms of maltreatment, in particular with emotional abuse and neglect, had an increased likelihood of hallucinations and delusional experiences. There is an association between child maltreatment, especially emotional abuse and neglect, and later hallucinations, delusional experiences, and psychosis. It is, however, relevant to note that the vast majority of children experiencing childhood maltreatment do not appear to develop psychotic experiences or psychotic disorder. Further research to determine the reasons for highly variable outcomes of child maltreatment is warranted. PMID- 28338761 TI - Influence of polynucleosome preparation methods on sedimentation velocity analysis of chromatin. AB - Chromatin dynamics and higher order structures play essential roles in genomic DNA functions. Histone variants and histone post-translational modifications are involved in the regulation of chromatin structure and dynamics, cooperatively with DNA methylation and chromatin binding proteins. Therefore, studies of higher order chromatin conformations have become important to reveal how genomic DNA is regulated during DNA transcription, replication, recombination and repair. The sedimentation velocity analysis by analytical ultracentrifugation has been commonly used to evaluate the higher-order conformation of in vitro reconstituted polynucleosomes, as model chromatin. Three major preparation methods for the unpurified, purified, and partially purified polynucleosomes have been reported so far. It is important to clarify the effects of the different polynucleosome preparation methods on the sedimentation profiles. To accomplish this, in the present study, we prepared unpurified, purified and partially purified polynucleosomes, and compared their sedimentation velocity profiles by analytical ultracentrifugation. In addition, we tested how the histone occupancy affects the sedimentation velocities of polynucleosomes. Our results revealed how free histones and polynucleosome aggregates affect the sedimentation velocity profiles of the polynucleosomes, in the absence and presence of Mg2+ ions. PMID- 28338762 TI - Redox and Reactive Oxygen Species Network in Acclimation for Salinity Tolerance in Sugar Beet. AB - Fine-tuned and coordinated regulation of transport, metabolism and redox homeostasis allows plants to acclimate to osmotic and ionic stress caused by high salinity. Sugar beet is a highly salt tolerant crop plant and is therefore an interesting model to study sodium chloride (NaCl) acclimation in crops. Sugar beet plants were subjected to a final level of 300 mM NaCl for up to 14 d in hydroponics. Plants acclimated to NaCl stress by maintaining its growth rate and adjusting its cellular redox and reactive oxygen species (ROS) network. In order to understand the unusual suppression of ROS accumulation under severe salinity, the regulation of elements of the redox and ROS network was investigated at the transcript level. First, the gene families of superoxide dismutase (SOD), peroxiredoxins (Prx), alternative oxidase (AOX), plastid terminal oxidase (PTOX) and NADPH oxidase (RBOH) were identified in the sugar beet genome. Salinity induced the accumulation of Cu-Zn-SOD, Mn-SOD, Fe-SOD3, all AOX isoforms, 2-Cys PrxB, PrxQ, and PrxIIF. In contrast, Fe-SOD1, 1-Cys-Prx, PrxIIB and PrxIIE levels decreased in response to salinity. Most importantly, RBOH transcripts of all isoforms decreased. This pattern offers a straightforward explanation for the low ROS levels under salinity. Promoters of stress responsive antioxidant genes were analyzed in silico for the enrichment of cis-elements, in order to gain insights into gene regulation. The results indicate that special cis-elements in the promoters of the antioxidant genes in sugar beet participate in adjusting the redox and ROS network and are fundamental to high salinity tolerance of sugar beet. PMID- 28338763 TI - Mesenchymal stromal cells and autoimmunity. AB - Mesenchymal stromal cells (MSCs) are committed progenitors of mesodermal origin that are found virtually in every organ and exhibit multilineage differentiation into osteocytes, adipocytes and chondrocytes. MSCs also mediate a wide spectrum of immunoregulatory activities that usually dampen innate and adaptive immune responses. These features have attracted interest in the perspective of developing novel cell therapies for autoimmune disease. However, depending on the microenvironmental conditions, MSCs may show a plastic behavior and switch to an immunostimulatory phenotype. After thorough characterization of the effects of MSCs on the immune system, MSC cell therapy has been tested in animal models of autoimmunity using different cell sources, protocols of in vitro expansion and routes and schedules of administration. The pre-clinical results have been encouraging in some models [e.g. Crohn's disease (CD), multiple sclerosis] and heterogeneous in others (e.g. graft-versus-host disease, systemic lupus erythematosus, rheumatoid arthritis). Clinical trials have been carried out and many are ongoing. As discussed, the results obtained are too preliminary to draw any conclusion, with the only exception of topical administration of MSCs in CD that has proven efficacious. The mechanism of action of infused MSCs is still under investigation, but the apparent paradox of a therapeutic effect achieved in spite of the very low number of cells reaching the target organ has been solved by the finding that MSC-derived extracellular vesicles (EVs) closely mimic the therapeutic activity of MSCs in pre-clinical models. These issues are critically discussed in view of the potential clinical use of MSC-derived EVs. PMID- 28338765 TI - Cerebral Magnesium Levels in Preeclampsia; A Phosphorus Magnetic Resonance Spectroscopy Study. AB - BACKGROUND: Magnesium sulfate (MgSO4) is used as a prophylaxis for eclamptic seizures. The exact mechanism of action is not fully established. We used phosphorus magnetic resonance spectroscopy (31P-MRS) to investigate if cerebral magnesium (Mg2+) levels differ between women with preeclampsia, normal pregnant, and nonpregnant women. METHODS: This cross-sectional study comprised 28 women with preeclampsia, 30 women with normal pregnancies in corresponding gestational week (range: 23-41 weeks) and 11 nonpregnant healthy controls. All women underwent 31P-MRS from the parieto-occipital region of the brain and were interviewed about cerebral symptoms. Differences between groups were assessed by analysis of variance and Tukey's post-hoc test. Correlations between Mg2+ levels and specific neurological symptoms were estimated with Spearman's rank test. RESULTS: Mean maternal cerebral Mg2+ levels were lower in women with preeclampsia (0.12 mM +/- 0.02) compared to normal pregnant controls (0.14 mM +/- 0.03) (P = 0.04). Nonpregnant and normal pregnant women did not differ in Mg2+ levels. Among women with preeclampsia, lower Mg2+ levels correlated with presence of visual disturbances (P = 0.04). Plasma levels of Mg2+ did not differ between preeclampsia and normal pregnancy. CONCLUSIONS: Women with preeclampsia have reduced cerebral Mg2+ levels, which could explain the potent antiseizure prophylactic properties of MgSO4. Within the preeclampsia group, women with visual disturbances have lower levels of Mg2+ than those without such symptoms. PMID- 28338766 TI - A multi-proxy assessment of dieback causes in a Mediterranean oak species. AB - Drought stress causes forest dieback that is often explained by two interrelated mechanisms, namely hydraulic failure and carbon starvation. However, it is still unclear which functional and structural alterations, related to these mechanisms, predispose to dieback. Here we apply a multi-proxy approach for the characterization of tree structure (radial growth, wood anatomy) and functioning (delta13C, delta18O and non-structural carbohydrates (NSCs)) in tree rings before and after drought-induced dieback. We aim to discriminate which is the main mechanism and to assess which variables can act as early-warning proxies of drought-triggered damage. The study was tailored in southern Italy in two forests (i.e., San Paolo (SP) and Oriolo (OR)) where declining and non-declining trees of a ring-porous tree species (Quercus frainetto Ten.) showing anisohydric behavior coexist. Both stands showed growth decline in response to warm and dry spring conditions, although the onset of dieback was shifted between them (2002 in SP and 2009 in OR). Declining trees displayed a sharp growth drop after this onset with reductions of 49% and 44% at SP and OR sites, respectively. Further, contrary to what we expected, declining trees showed a lower intrinsic water-use efficiency compared with non-declining trees after the dieback onset (with reductions of 9.7% and 5.6% at sites SP and OR, respectively), due to enhanced water loss through transpiration, as indicated by the lower delta18O values. This was more noticeable at the most drought-affected SP stand. Sapwood NSCs did not differ between declining and non-declining trees, indicating no carbon starvation in affected trees. Thus, the characterized structural and functional alterations partially support the hydraulic failure mechanism of dieback. Finally, we show that growth data are reliable early-warning proxies of drought-triggered dieback. PMID- 28338764 TI - Fruit and vegetable intake and the risk of cardiovascular disease, total cancer and all-cause mortality-a systematic review and dose-response meta-analysis of prospective studies. AB - Background: Questions remain about the strength and shape of the dose-response relationship between fruit and vegetable intake and risk of cardiovascular disease, cancer and mortality, and the effects of specific types of fruit and vegetables. We conducted a systematic review and meta-analysis to clarify these associations. Methods: PubMed and Embase were searched up to 29 September 2016. Prospective studies of fruit and vegetable intake and cardiovascular disease, total cancer and all-cause mortality were included. Summary relative risks (RRs) were calculated using a random effects model, and the mortality burden globally was estimated; 95 studies (142 publications) were included. Results: For fruits and vegetables combined, the summary RR per 200 g/day was 0.92 [95% confidence interval (CI): 0.90-0.94, I 2 = 0%, n = 15] for coronary heart disease, 0.84 (95% CI: 0.76-0.92, I 2 = 73%, n = 10) for stroke, 0.92 (95% CI: 0.90-0.95, I 2 = 31%, n = 13) for cardiovascular disease, 0.97 (95% CI: 0.95-0.99, I 2 = 49%, n = 12) for total cancer and 0.90 (95% CI: 0.87-0.93, I 2 = 83%, n = 15) for all-cause mortality. Similar associations were observed for fruits and vegetables separately. Reductions in risk were observed up to 800 g/day for all outcomes except cancer (600 g/day). Inverse associations were observed between the intake of apples and pears, citrus fruits, green leafy vegetables, cruciferous vegetables, and salads and cardiovascular disease and all-cause mortality, and between the intake of green-yellow vegetables and cruciferous vegetables and total cancer risk. An estimated 5.6 and 7.8 million premature deaths worldwide in 2013 may be attributable to a fruit and vegetable intake below 500 and 800 g/day, respectively, if the observed associations are causal. Conclusions: Fruit and vegetable intakes were associated with reduced risk of cardiovascular disease, cancer and all-cause mortality. These results support public health recommendations to increase fruit and vegetable intake for the prevention of cardiovascular disease, cancer, and premature mortality. PMID- 28338767 TI - Decreased CD1d level is associated with CD86 over-expression in B cells from systemic lupus erythematosus. AB - The disorder of B cells is one of the hallmarks of systemic lupus erythematosus (SLE). The activation state indicated by CD86 of B cells from SLE is well known, while the defect of regulatory B cells mediated by CD1d is also responsible for the process of SLE. In the present study, we focused on the relationship between B cell activation mediated by CD86 and B cell regulatory function mediated by CD1d. Our results showed that the level of CD1d in B cells was decreased during the early stages of B6.MRLlpr SLE mice and imiquimod-treated (IMQ-treated) mice, while the level of CD86 was significantly increased at the late stage. Moreover, the expression of CD1d showed a significantly negative correlation with CD86 level in B cells from IMQ-treated mice (r = -05741; P = 0.0022), B6.MRLlpr mice (r = -0.7091; P = 0.0268), and SLE patients (r = -0.4125; P = 0.0404). The in vivo and in vitro experiments with splenocytes demonstrated that CD1d signaling pathway could inhibit toll-like receptor 7 (TLR7)-induced CD86 expression of B cells. Further studies showed that this relationship also affected antibody production. Thus, our results confirmed the association of CD1d and CD86 levels in B cells from SLE, and demonstrated the importance to preserve the immunoregulatory function of B cells mediated by CD1d in the progression of SLE. PMID- 28338768 TI - Integrative Blood Pressure Response to Upright Tilt Post Renal Denervation. AB - BACKGROUND: Whether renal denervation (RDN) in patients with resistant hypertension normalizes blood pressure (BP) regulation in response to routine cardiovascular stimuli such as upright posture is unknown. We conducted an integrative study of BP regulation in patients with resistant hypertension who had received RDN to characterize autonomic circulatory control. METHODS: Twelve patients (60 +/- 9 [SD] years, n = 10 males) who participated in the Symplicity HTN-3 trial were studied and compared to 2 age-matched normotensive (Norm) and hypertensive (unmedicated, HTN) control groups. BP, heart rate (HR), cardiac output (Qc), muscle sympathetic nerve activity (MSNA), and neurohormonal variables were measured supine, and 30 degrees (5 minutes) and 60 degrees (20 minutes) head-up-tilt (HUT). Total peripheral resistance (TPR) was calculated from mean arterial pressure and Qc. RESULTS: Despite treatment with RDN and 4.8 (range, 3-7) antihypertensive medications, the RDN had significantly higher supine systolic BP compared to Norm and HTN (149 +/- 15 vs. 118 +/- 6, 108 +/- 8 mm Hg, P < 0.001). When supine, RDN had higher HR, TPR, MSNA, plasma norepinephrine, and effective arterial elastance compared to Norm. Plasma norepinephrine, Qc, and HR were also higher in the RDN vs. HTN. During HUT, BP remained higher in the RDN, due to increases in Qc, plasma norepinephrine, and aldosterone. CONCLUSION: We provide evidence of a possible mechanism by which BP remains elevated post RDN, with the observation of increased Qc and arterial stiffness, as well as plasma norepinephrine and aldosterone levels at approximately 2 years post treatment. These findings may be the consequence of incomplete ablation of sympathetic renal nerves or be related to other factors. PMID- 28338769 TI - IQ, the Urban Environment, and Their Impact on Future Schizophrenia Risk in Men. AB - Exposure to an urban environment during early life and low IQ are 2 well established risk factors for schizophrenia. It is not known, however, how these factors might relate to one another. Data were pooled from the North Jutland regional draft board IQ assessments and the Danish Conscription Registry for men born between 1955 and 1993. Excluding those who were followed up for less than 1 year after the assessment yielded a final cohort of 153170 men of whom 578 later developed a schizophrenia spectrum disorder. We found significant effects of having an urban birth, and also experiencing an increase in urbanicity before the age of 10 years, on adult schizophrenia risk. The effect of urban birth was independent of IQ. However, there was a significant interaction between childhood changes in urbanization in the first 10 years and IQ level on the future adult schizophrenia risk. In short, those subjects who moved to more or less urban areas before their 10th birthday lost the protective effect of IQ. When thinking about adult schizophrenia risk, the critical time window of childhood sensitivity to changes in urbanization seems to be linked to IQ. Given the prediction that by 2050, over 80% of the developed world's population will live in an urban environment, this represents a major future public health issue. PMID- 28338770 TI - Response of human non-small-cell lung cancer cells to the influence of Wogonin with SGK1 dynamics. AB - A number of significant studies in the field of cell biology have revealed another pattern of intracellular signal transduction in which cells transmit information through the dynamics of key signaling molecules. Dynamical properties of p53 have been demonstrated to be the key factor in dictating cell fate, including cell cycle arrest, permanent cell cycle arrest, and cell death. Previous studies showed a negative feedback regulation pathway between SGK1 and p53, but the dynamics of SGK1 have never been reported before. Therefore, we used different dosing strategies of Wogonin to affect SGK1 dynamics and investigate its impact on cell response. Key factors, such as APAF1, BAX, GADD45A, p21, PML, and YPEL3, which are related to cell cycle arrest, senescence, and apoptosis, were measured at different time points after incubation with Wogonin. Western blot and quantitative reverse transcriptase-polymerase chain reaction analysis were used to examine protein and mRNA expression of these genes. In addition, we also used beta-galactosidase staining and flow cytometric analysis to further verify the results. It was found that Wogonin inhibited cell viability and downregulated SGK1 protein levels; 20 MUM Wogonin could induce non-small-cell lung cancer A549 cells into cell cycle arrest/senescence/apoptosis after 0.5/2/4 h, respectively; and SGK1 dynamics showed significant differences under different cell responses. Together, our findings showed that SGK1 protein dynamics can be an important part of intracellular signaling, directly influencing cellular response decisions. PMID- 28338771 TI - Blood Pressure Control During Chronic Kidney Disease Progression. AB - BACKGROUND: Hypertension is a major cause of end-stage renal disease, and blood pressure (BP) control is crucial in patients with chronic kidney disease (CKD). However, it is generally inadequately controlled in CKD patients. We investigated the prevalence of CKD patients with inadequate BP control and its related factors, based on the CKD stage. METHODS: We analyzed the health examination sample cohort database, which consisted of the randomly selected participants among all the citizens who received the health examination provided by National Health Insurance Service of Korea in 2012 and 2013. RESULTS: There were 27,350 CKD patients (7.9%) out of a total of 345,044 participants. As CKD stage progressed, there were more patients with poorly controlled hypertension compared to those with well-controlled hypertension. In addition, systolic BP increased with CKD stage progression, while diastolic BP was not significantly different. Age, female, body mass index, increased pulse pressure, CKD stage, and levels of fasting glucose, total cholesterol, hemoglobin, and proteinuria were significant factors associated with poor control of BP in hypertensive CKD patients. CONCLUSION: The proportion of CKD patients with poorly controlled hypertension significantly increased as CKD progressed, mainly associated with the increase in pulse pressure. However, future investigation for causal relationship between poorly controlled hypertension and its related factors is needed. PMID- 28338772 TI - Chemical strategies for pancreatic beta cell differentiation, reprogramming, and regeneration. AB - Generation of unlimited functional pancreatic beta cells is critical for the study of pancreatic biology and treatment of diabetes mellitus. Recent advances have suggested several promising directions, including directed differentiation of pancreatic beta cells from pluripotent stem cells, reprogramming of pancreatic beta cells from other types of somatic cells, and stimulated proliferation and enhanced functions of existing pancreatic beta cells. Small molecules are useful in generating unlimited numbers of functional pancreatic cells in vitro and could be further developed as drugs to stimulate endogenous pancreatic regeneration. Here, we provide an updated summary of recent major achievements in pancreatic beta cell differentiation, reprogramming, proliferation, and function. These studies will eventually lead to significant advances in the field of pancreatic biology and regeneration. PMID- 28338773 TI - CMV promoter and the mouse albumin promoter and enhancer triggered the elevation of hepatitis B virus envelope polypeptides. PMID- 28338774 TI - Pleiotropy-robust Mendelian randomization. AB - Background: The potential of Mendelian randomization studies is rapidly expanding due to: (i) the growing power of genome-wide association study (GWAS) meta analyses to detect genetic variants associated with several exposures; and (ii) the increasing availability of these genetic variants in large-scale surveys. However, without a proper biological understanding of the pleiotropic working of genetic variants, a fundamental assumption of Mendelian randomization (the exclusion restriction) can always be contested. Methods: We build upon and synthesize recent advances in the literature on instrumental variables (IVs) estimation that test and relax the exclusion restriction. Our pleiotropy-robust Mendelian randomization (PRMR) method first estimates the degree of pleiotropy, and in turn corrects for it. If (i) a subsample exists for which the genetic variants do not affect the exposure; (ii) the selection into this subsample is not a joint consequence of the IV and the outcome; (iii) pleiotropic effects are homogeneous, PRMR obtains unbiased estimates of causal effects. Results: Simulations show that existing MR methods produce biased estimators for realistic forms of pleiotropy. Under the aforementioned assumptions, PRMR produces unbiased estimators. We illustrate the practical use of PRMR by estimating the causal effect of: (i) tobacco exposure on body mass index (BMI); (ii) prostate cancer on self-reported health; and (iii) educational attainment on BMI in the UK Biobank data. Conclusions: PRMR allows for instrumental variables that violate the exclusion restriction due to pleiotropy, and it corrects for pleiotropy in the estimation of the causal effect. If the degree of pleiotropy is unknown, PRMR can still be used as a sensitivity analysis. PMID- 28338775 TI - Economic growth and mortality: do social protection policies matter? AB - Background: In the 20th century, periods of macroeconomic growth have been associated with increases in population mortality. Factors that cause or mitigate this association are not well understood. Evidence suggests that social policy may buffer the deleterious impact of economic growth. We sought to explore associations between changing unemployment (as a proxy for economic change) and trends in mortality over 30 years in the context of varying social protection expenditures. Methods: We model change in all-cause mortality in 21 OECD (Organization for Economic Cooperation and Development) countries from 1980 to 2010. Data from the Comparative Welfare States Data Set and the WHO Mortality Database were used. A decrease in the unemployment rate was used as a proxy for economic growth and age-adjusted mortality rates as the outcome. Social protection expenditure was measured as percentage of gross domestic product expended. Results: A 1% decrease in unemployment (i.e. the proxy for economic growth) was associated with a 0.24% increase in the overall mortality rate (95% confidence interval: 0.07;0.42) in countries with no changes in social protection. Reductions in social protection expenditure strengthened this association between unemployment and mortality. The magnitude of the association was diminished over time. Conclusions: Our results are consistent with the hypothesis that social protection policies that accompany economic growth can mitigate its potential deleterious effects on health. Further research should identify specific policies that are most effective. PMID- 28338776 TI - Integration of water, sanitation and hygiene intervention delivery at health facilities with a reactive ring vaccination programme to reduce cholera. PMID- 28338777 TI - The Chlamydia suis Genome Exhibits High Levels of Diversity, Plasticity, and Mobile Antibiotic Resistance: Comparative Genomics of a Recent Livestock Cohort Shows Influence of Treatment Regimes. AB - Chlamydia suis is an endemic pig pathogen, belonging to a fascinating genus of obligate intracellular pathogens. Of particular interest, this is the only chlamydial species to have naturally acquired genes encoding for tetracycline resistance. To date, the distribution and mobility of the Tet-island are not well understood. Our study focused on whole genome sequencing of 29 C. suis isolates from a recent porcine cohort within Switzerland, combined with data from USA tetracycline-resistant isolates. Our findings show that the genome of C. suis is very plastic, with unprecedented diversity, highly affected by recombination and plasmid exchange. A large diversity of isolates circulates within Europe, even within individual Swiss farms, suggesting that C. suis originated around Europe. New World isolates have more restricted diversity and appear to derive from European isolates, indicating that historical strain transfers to the United States have occurred. The architecture of the Tet-island is variable, but the tetA(C) gene is always intact, and recombination has been a major factor in its transmission within C. suis. Selective pressure from tetracycline use within pigs leads to a higher number of Tet-island carrying isolates, which appear to be lost in the absence of such pressure, whereas the loss or gain of the Tet-island from individual strains is not observed. The Tet-island appears to be a recent import into the genome of C. suis, with a possible American origin. PMID- 28338778 TI - Caregiving, volunteering or both? Comparing effects on health and mortality using census-based records from almost 250,000 people aged 65 and over. AB - Background: the health impacts of caregiving and volunteering are rarely studied concurrently, despite the potential for both synergies and conflicts. This population-based study examines the association of these activities on health and subsequent mortality. Method: a census-based record-linkage study of 244,429 people aged 65 and over, with cohort characteristics, caregiving and volunteering status, and presence of chronic health conditions derived from the Census returns. Mortality risk was assessed over the following 45 months with adjustment for baseline characteristics. Results: caregivers and volunteers were individually more mobile than those undertaking neither activity; caregivers who also volunteered were more mobile than those who did not volunteer, but no less likely to suffer from poor mental health. Both caregiving and volunteering were separately associated with reduced mortality risk (HR = 0.74: 95% confidence intervals (CIs) = 0.71, 0.77 and HR = 0.76: 0.73, 0.81, respectively); the lowest mortality was found amongst light caregivers who also volunteered (HR = 0.53: 95% CIs = 0.45, 0.62), compared to those engaged in neither. There was no evidence of a multiplicative effect of caregiving and volunteering at more intense levels of caregiving. Conclusion: there is a large overlap in caregiving and volunteering activities with complex associations with health status. There is some evidence that combining caregiving and volunteering activities, for those involved in less intense levels of caregiving, maybe associated with lower mortality risk than associated with either activity alone. Further research is needed to understand which aspects of caregiving and volunteering are best and for whom and in which circumstances. PMID- 28338780 TI - Commentary: New York City: measuring progress as it's made. PMID- 28338779 TI - Telomere Length and CCL11 Levels are Associated With Gray Matter Volume and Episodic Memory Performance in Schizophrenia: Evidence of Pathological Accelerated Aging. AB - Schizophrenia (SZ) is associated with increased somatic morbidity and mortality, in addition to cognitive impairments similar to those seen in normal aging, which may suggest that pathological accelerated aging occurs in SZ. Therefore, we aim to evaluate the relationships of age, telomere length (TL), and CCL11 (aging and inflammatory biomarkers, respectively), gray matter (GM) volume and episodic memory performance in individuals with SZ compared to healthy controls (HC). One hundred twelve participants (48 SZ and 64 HC) underwent clinical and memory assessments, structural MRI, and had their peripheral blood drawn for biomarkers analysis. Comparisons of group means and correlations were performed. Participants with SZ had decreased TL and GM volume, increased CCL11, and worse memory performance compared to HC. In SZ, shorter TL was related to increased CCL11, and both biomarkers were related to reduced GM volume, all of which were related to worse memory performance. Older age was only associated with reduced GM, but longer duration of illness was related with all the aforementioned variables. Younger age of disease onset was associated with increased CCL11 levels and worse memory performance. In HC, there were no significant correlations except between memory and GM. Our results are consistent with the hypothesis of accelerated aging in SZ. These results may indicate that it is not age itself, but the impact of the disease associated with a pathological accelerated aging that leads to impaired outcomes in SZ. PMID- 28338781 TI - Profile: The Dar Es Salaam Health and Demographic Surveillance System (Dar es Salaam HDSS). PMID- 28338782 TI - Source-sink interaction: a century old concept under the light of modern molecular systems biology. AB - Many approaches to engineer source strength have been proposed to enhance crop yield potential. However, a well-co-ordinated source-sink relationship is required finally to realize the promised increase in crop yield potential in the farmer's field. Source-sink interaction has been intensively studied for decades, and a vast amount of knowledge about the interaction in different crops and under different environments has been accumulated. In this review, we first introduce the basic concepts of source, sink and their interactions, then summarize current understanding of how source and sink can be manipulated through both environmental control and genetic manipulations. We show that the source-sink interaction underlies the diverse responses of crops to the same perturbations and argue that development of a molecular systems model of source-sink interaction is required towards a rational manipulation of the source-sink relationship for increased yield. We finally discuss both bottom-up and top-down routes to develop such a model and emphasize that a community effort is needed for development of this model. PMID- 28338783 TI - Empathy and moral emotions in post-apartheid South Africa: an fMRI investigation. AB - Moral emotions elicited in response to others' suffering are mediated by empathy and affect how we respond to their pain. South Africa provides a unique opportunity to study group processes given its racially divided past. The present study seeks insights into aspects of the moral brain by investigating behavioral and functional MRI responses of White and Black South Africans who lived through apartheid to in- and out-group physical and social pain. Whereas the physical pain task featured faces expressing dynamic suffering, the social pain task featured victims of apartheid violence from the South African Truth and Reconciliation Commission to elicit heartfelt emotion. Black participants' behavioral responses were suggestive of in-group favoritism, whereas White participants' responses were apparently egalitarian. However, all participants showed significant in-group biases in activation in the amygdala (physical pain), as well as areas involved in mental state representation, including the precuneus, temporoparietal junction (TPJ) and frontal pole (physical and social pain). Additionally, Black participants reacted with heightened moral indignation to own-race suffering, whereas White participants reacted with heightened shame to Black suffering, which was associated with blunted neural empathic responding. These findings provide ecologically valid insights into some behavioral and brain processes involved in complex moral situations. PMID- 28338784 TI - In God we trust? Neural measures reveal lower social conformity among non religious individuals. AB - Even in predominantly religious societies, there are substantial individual differences in religious commitment. Why is this? One possibility is that differences in social conformity (i.e. the tendency to think and behave as others do) underlie inclination towards religiosity. However, the link between religiosity and conformity has not yet been directly examined. In this study, we tested the notion that non-religious individuals show dampened social conformity, using both self-reported and neural (EEG-based ERPs) measures of sensitivity to others' influence. Non-religious vs religious undergraduate subjects completed an experimental task that assessed levels of conformity in a domain unrelated to religion (i.e. in judgments of facial attractiveness). Findings showed that, although both groups yielded to conformity pressures at the self-report level, non-religious individuals did not yield to such pressures in their neural responses. These findings highlight a novel link between religiosity and social conformity, and hold implications for prominent theories about the psychological functions of religion. PMID- 28338785 TI - Elevated nucleus accumbens structural connectivity associated with proneness to hypomania: a reward hypersensitivity perspective. AB - The Reward Hypersensitivity Model of bipolar disorder argues that hypersensitivity to reward-relevant cues characterizes risk for hypo/mania. This hypersensitivity leads to increased goal-directed motivation during reward relevant life events that, in the extreme, is reflected in hypo/manic symptoms. In line with this perspective, individuals with bipolar disorder display elevated activation in a cortico-striatal reward circuit including the nucleus accumbens (NAcc) and medial orbitofrontal cortex (mOFC). To date, however, research on reward-related neural circuitry underlying bipolar symptoms focuses on syndromal bipolar disorder (bipolar I, bipolar II), and typically examines neural regions in isolation of each other. Accordingly, this study examines the relationship between subsyndromal hypo/mania proneness and structural connectivity between the NAcc and both the mOFC and amygdala in a medication-free sample. Fifty-four community participants completed diffusion-weighted imaging and a self-report measure of bipolar risk (hypo/mania proneness). As predicted, elevated structural connectivity between the NAcc and both the mOFC and amygdala were associated with elevated hypo/mania proneness. This relationship was specific to NAcc-centered reward connectivity, as there was no relationship between hypo/mania proneness and either whole-brain or cortico-amygdala connectivity. Results suggest that reward-relevant tractography from cortical (mOFC) and subcortical (amygdala) regions amplify NAcc-centered reward processing in bipolar risk. PMID- 28338786 TI - Recombination-Mediated Host Adaptation by Avian Staphylococcus aureus. AB - Staphylococcus aureus are globally disseminated among farmed chickens causing skeletal muscle infections, dermatitis, and septicaemia. The emergence of poultry associated lineages has involved zoonotic transmission from humans to chickens but questions remain about the specific adaptations that promote proliferation of chicken pathogens. We characterized genetic variation in a population of genome sequenced S. aureus isolates of poultry and human origin. Genealogical analysis identified a dominant poultry-associated sequence cluster within the CC5 clonal complex. Poultry and human CC5 isolates were significantly distinct from each other and more recombination events were detected in the poultry isolates. We identified 44 recombination events in 33 genes along the branch extending to the poultry-specific CC5 cluster, and 47 genes were found more often in CC5 poultry isolates compared with those from humans. Many of these gene sequences were common in chicken isolates from other clonal complexes suggesting horizontal gene transfer among poultry associated lineages. Consistent with functional predictions for putative poultry-associated genes, poultry isolates showed enhanced growth at 42 degrees C and greater erythrocyte lysis on chicken blood agar in comparison with human isolates. By combining phenotype information with evolutionary analyses of staphylococcal genomes, we provide evidence of adaptation, following a human-to-poultry host transition. This has important implications for the emergence and dissemination of new pathogenic clones associated with modern agriculture. PMID- 28338787 TI - Total and Fetal Circulating Cell-Free DNA, Angiogenic, and Antiangiogenic Factors in Preeclampsia and HELLP Syndrome. AB - BACKGROUND: Preeclampsia (PE) is a hypertensive disorder of pregnancy characterized by hypertension and proteinuria. The HELLP syndrome is the most severe form of PE. The aim of the present study was to determine different potential biomarkers that may help us perform an early diagnosis of the disease, assess on the severity of the disease, and/or predict maternal or fetal adverse outcomes. METHODS: We measured serum levels of total and fetal circulating cell free DNA (cfDNA), soluble endoglin, soluble form of vascular endothelial growth factor receptor, and placental growth factor in a healthy control group of pregnant women (n = 26), patients with mild (n = 37) and severe PE (n = 25), and patients with HELLP syndrome (n = 16). RESULTS: We observed a gradual and strong relationship between all the biomarkers mentioned and the range of severity of PE, with the highest levels in patients with HELLP syndrome. Nevertheless, only the values of total cfDNA were able to significantly differentiate severe PE and HELLP syndrome (20957 +/- 2784 vs. 43184 +/- 8647 GE/ml, P = 0.01). Receiver operating characteristic (ROC) curves were constructed (i) for the healthy group with respect to the groups with PE and (ii) for patients with PE with respect to the group with HELLP syndrome; sensitivity and specificity values at different cutoff levels were calculated in each case. The maximum ROC area under the curve value for PE and HELLP syndrome (with respect to controls) was 0.91 (P < 0.001). CONCLUSIONS: The measured biomarkers of cell damage, angiogenesis, and antiangiogenesis may reflect the severity of PE, with higher levels in patients who develop HELLP syndrome. In addition, these biomarkers may also help predict adverse fetal and maternal outcomes. PMID- 28338788 TI - Hypertension and Atrial Fibrillation: An Intimate Association of Epidemiology, Pathophysiology, and Outcomes. AB - Atrial fibrillation (AF) is the most prevalent sustained arrhythmia found in clinical practice. AF rarely exists as a single entity but rather as part of a diverse clinical spectrum of cardiovascular diseases, related to structural and electrical remodeling within the left atrium, leading to AF onset, perpetuation, and progression. Due to the high overall prevalence within the AF population arterial hypertension plays a significant role in the pathogenesis of AF and its complications. Fibroblast proliferation, apoptosis of cardiomyocytes, gap junction remodeling, accumulation of collagen both in atrial and ventricular myocardium all accompany ageing-related structural remodeling with impact on electrical activity. The presence of hypertension also stimulates oxidative stress, systemic inflammation, rennin-angiotensin-aldosterone and sympathetic activation, which further drives the remodeling process in AF. Importantly, both hypertension and AF independently increase the risk of cardiovascular and cerebrovascular events, e.g., stroke and myocardial infarction. Given that both AF and hypertension often present with limited on patient wellbeing, treatment may be delayed resulting in development of complications as the first clinical manifestation of the disease. Antithrombotic prevention in AF combined with strict blood pressure control is of primary importance, since stroke risk and bleeding risk are both greater with underlying hypertension. PMID- 28338789 TI - Phosphorylation of the phytosulfokine peptide receptor PSKR1 controls receptor activity. AB - The phytosulfokine peptide receptor PSKR1 is modified by phosphorylation of its cytoplasmic kinase domain. We analyzed defined phosphorylation sites by site directed mutagenesis with regard to kinase activity in vitro and receptor activity in planta. S696 and S698 in the juxtamembrane (JM) domain are phosphorylated in planta. The phosphomimetic S696D/S698D replacements resulted in reduced transphosphorylation activity of PSKR1 kinase in vitro but did not reduce autophosphorylation activity. Growth-promoting activity of the PSKR1(S696D/S698D) receptor isoform was impaired in the shoot but not in the root. The JM domain thus seems to be important for phosphorylation of a target protein required for shoot growth promotion. The phosphomimetic replacement T998D at the C-terminus (CT) abolished kinase activity in vitro but not receptor function in planta, indicating that additional levels of regulation exist in planta. A possible mode of receptor regulation is the interaction with regulatory proteins such as the calcium sensor calmodulin (CaM). We show that the previously reported binding of CaM2 to PSKR1 is calcium-dependent, occurs predominately to the hypophosphorylated soluble PSKR1 kinase, and does not significantly change PSKR1 kinase activity. In conclusion, our results show that peptide signaling of growth by PSKR1 is regulated by differential phosphorylation of the juxtamembrane and C terminal domains of the intracellular receptor part and suggest that interaction of PSKR1 with CaM serves a function other than the regulation of kinase activity. PMID- 28338790 TI - Empathy for pain motivates actions without altruistic effects: evidence of motor dynamics and brain activity. AB - Empathy has been supposed to be a proximate mechanism of altruistic behavior. We investigated whether empathy for pain drives actions without altruistic effects and how such actions modulate neural responses to others' pain. In two experiments, we asked healthy adults to press a button for no reason when viewing video clips showing faces with pain expressions receiving needle penetration or faces with neutral expressions receiving a cotton swab touch. Experiment 1 found that participants pressed a button with greater response force when watching painful than non-painful stimuli. Participants who reported greater unpleasant feelings pressed the button harder when viewing painful stimuli. Experiment 2 revealed that passively viewing painful vs non-painful stimuli increased blood oxygen-level-dependent signals in the middle cingulate cortex, supplementary motor cortex, and bilateral second somatosensory and inferior frontal cortex, which, however, were reduced by the action of button press without altruistic effects. In addition, individuals who reported higher personal distress illustrated greater decrease of the second somatosensory activity induced by button press. Our results indicate that empathy for pain motivates simple actions without altruistic effects that in turn reduce neural responses to others' pain, suggesting a functional role of action execution in self distress relief when viewing others' suffering. PMID- 28338791 TI - Brains in dialogue: decoding neural preparation of speaking to a conversational partner. AB - In dialogue, language processing is adapted to the conversational partner. We hypothesize that the brain facilitates partner-adapted language processing through preparatory neural configurations (task sets) that are tailored to the conversational partner. In this experiment, we measured neural activity with functional magnetic resonance imaging (fMRI) while healthy participants in the scanner (a) engaged in a verbal communication task with a conversational partner outside of the scanner, or (b) spoke outside of a conversational context (to test the microphone). Using multivariate searchlight analysis, we identify cortical regions that represent information on whether speakers plan to speak to a conversational partner or without having a partner. Most notably a region that has been associated with processing social-affective information and perspective taking, the ventromedial prefrontal cortex, as well as regions that have been associated with prospective task representation, the bilateral ventral prefrontal cortex, are involved in encoding the speaking condition. Our results suggest that speakers prepare, in advance of speaking, for the social context in which they will speak. PMID- 28338792 TI - A polygalacturonase localized in the Golgi apparatus in Pisum sativum. AB - Pectin is a plant cell wall constituent that is mainly composed of polygalacturonic acid (PGA), a linear alpha1,4-d-galacturonic acid (GalUA) backbone. Polygalacturonase (PG) hydrolyzes the alpha1,4-linkages in PGA. Nearly all plant PGs identified thus far are secreted as soluble proteins. Here we describe the microsomal PG activity in pea (Pisum sativum) epicotyls and present biochemical evidence that it was localized to the Golgi apparatus, where pectins are biosynthesized. The microsomal PG was purified, and it was enzymatically characterized. The purified enzyme showed maximum activity towards pyridylaminated oligogalacturonic acids with six degrees of polymerization (PA GalUA6), with a Km value of 11 MUM for PA-GalUA6. The substrate preference of the enzyme was complementary to that of PGA synthase. The main PG activity in microsomes was detected in the Golgi fraction by sucrose density gradient ultracentrifugation. The activity of the microsomal PG was lower in rapidly growing epicotyls, in contrast to the high expression of PGA synthase. The role of this PG in the regulation of pectin biosynthesis or plant growth is discussed. PMID- 28338794 TI - Genome-wide association study unravels the genetic control of the apple volatilome and its interplay with fruit texture. AB - Fruit quality represents a fundamental factor guiding consumers' preferences. Among apple quality traits, volatile organic compounds and texture features play a major role. Proton Transfer Reaction-Time of Flight-Mass Spectrometry (PTR-ToF MS), coupled with an artificial chewing device, was used to profile the entire apple volatilome of 162 apple accessions, while the fruit texture was dissected with a TAXT-AED texture analyzer. The array of volatile compounds was classed into seven major groups and used in a genome-wide association analysis carried out with 9142 single nucleotide polymorphisms (SNPs). Marker-trait associations were identified on seven chromosomes co-locating with important candidate genes for aroma, such as MdAAT1 and MdIGS. The integration of volatilome and fruit texture data conducted with a multiple factor analysis unraveled contrasting behavior, underlying opposite regulation of the two fruit quality aspects. The association analysis using the first two principal components identified two QTLs located on chromosomes 10 and 2, respectively. The distinction of the apple accessions on the basis of the allelic configuration of two functional markers, MdPG1 and MdACO1, shed light on the type of interplay existing between fruit texture and the production of volatile organic compounds. PMID- 28338793 TI - Sensitivity to perception level differentiates two subnetworks within the mirror neuron system. AB - Mirror neurons are a subset of brain cells that discharge during action execution and passive observation of similar actions. An open question concerns the functional role of their ability to match observed and executed actions. Since understanding of goals requires conscious perception of actions, we expect that mirror neurons potentially involved in action goal coding, will be modulated by changes in action perception level. Here, we manipulated perception level of action videos depicting short hand movements and measured the corresponding fMRI BOLD responses in mirror regions. Our results show that activity levels within a network of regions, including the sensorimotor cortex, primary motor cortex, dorsal premotor cortex and posterior superior temporal sulcus, are sensitive to changes in action perception level, whereas activity levels in the inferior frontal gyrus, ventral premotor cortex, supplementary motor area and superior parietal lobule are invariant to such changes. In addition, this parcellation to two sub-networks manifest as smaller functional distances within each group of regions during task and resting state. Our results point to functional differences between regions within the mirror neurons system which may have implications with respect to their possible role in action understanding. PMID- 28338795 TI - 'Mom-I don't want to hear it': Brain response to maternal praise and criticism in adolescents with major depressive disorder. AB - Recent research has implicated altered neural response to interpersonal feedback as an important factor in adolescent depression, with existing studies focusing on responses to feedback from virtual peers. We investigated whether depressed adolescents differed from healthy youth in neural response to social evaluative feedback from mothers. During neuroimaging, twenty adolescents in a current episode of major depressive disorder (MDD) and 28 healthy controls listened to previously recorded audio clips of their own mothers' praise, criticism and neutral comments. Whole-brain voxelwise analyses revealed that MDD youth, unlike controls, exhibited increased neural response to critical relative to neutral clips in the parahippocampal gyrus, an area involved in episodic memory encoding and retrieval. Depressed adolescents also showed a blunted response to maternal praise clips relative to neutral clips in the parahippocampal gyrus, as well as areas involved in reward and self-referential processing (i.e. ventromedial prefrontal cortex, precuneus, and thalamus/caudate). Findings suggest that maternal criticism may be more strongly encoded or more strongly activated during memory retrieval related to previous autobiographical instances of negative feedback from mothers in depressed youth compared to healthy youth. Furthermore, depressed adolescents may fail to process the reward value and self-relevance of maternal praise. PMID- 28338796 TI - Temporal signatures of processing voiceness and emotion in sound. AB - This study explored the temporal course of vocal and emotional sound processing. Participants detected rare repetitions in a stimulus stream comprising neutral and surprised non-verbal exclamations and spectrally rotated control sounds. Spectral rotation preserved some acoustic and emotional properties of the vocal originals. Event-related potentials elicited to unrepeated sounds revealed effects of voiceness and emotion. Relative to non-vocal sounds, vocal sounds elicited a larger centro-parietally distributed N1. This effect was followed by greater positivity to vocal relative to non-vocal sounds beginning with the P2 and extending throughout the recording epoch (N4, late positive potential) with larger amplitudes in female than in male listeners. Emotion effects overlapped with the voiceness effects but were smaller and differed topographically. Voiceness and emotion interacted only for the late positive potential, which was greater for vocal-emotional as compared with all other sounds. Taken together, these results point to a multi-stage process in which voiceness and emotionality are represented independently before being integrated in a manner that biases responses to stimuli with socio-emotional relevance. PMID- 28338797 TI - AN ESTIMATION OF THE EXPOSURE OF THE POPULATION OF ISRAEL TO NATURAL SOURCES OF IONIZING RADIATION. AB - The radiation dose to the population of Israel due to exposure to natural sources of ionizing radiation was assessed. The main contributor to the dose is radon that accounts for 60% of the exposure to natural sources. The dose due to radon inhalation was assessed by combining the results of a radon survey in single family houses with the results of a survey in apartments in multi-storey buildings. The average annual dose due to radon inhalation was found to be 1.2 mSv. The dose rate due to exposure to cosmic radiation was assessed using a code that calculates the dose rate at different heights above sea level, taking into account the solar cycle. The annual dose was calculated based on the fraction of time spent indoors and the attenuation provided by buildings and was found to be 0.2 mSv. The annual dose due to external exposure to the terrestrial radionuclides was similarly assessed. The indoor dose rate was calculated using a model that takes into account the concentrations of the natural radionuclides in building materials, the density and the thickness of the walls. The dose rate outdoors was calculated based on the concentrations of the natural radionuclides in different geological units in Israel as measured in an aerial survey and measurements above ground. The annual dose was found to be 0.2 mSv. Doses due to internal exposure other than exposure to radon were also calculated and were found to be 0.4 mSv. The overall annual exposure of the population of Israel to natural sources of ionizing radiation is therefore 2 mSv and ranges between 1.7 and 2.7 mSv. PMID- 28338798 TI - Genetic dissection of metabolite variation in Arabidopsis seeds: evidence for mQTL hotspots and a master regulatory locus of seed metabolism. AB - To gain insight into genetic factors controlling seed metabolic composition and its relationship to major seed properties, an Arabidopsis recombinant inbred line (RIL) population, derived from accessions Col-0 and C24, was studied using an MS based metabolic profiling approach. Relative intensities of 311 polar primary metabolites were used to identify associated genomic loci and to elucidate their interactions by quantitative trait locus (QTL) mapping. A total of 786 metabolic QTLs (mQTLs) were unequally distributed across the genome, forming several hotspots. For the branched-chain amino acid leucine, mQTLs and candidate genes were elucidated in detail. Correlation studies displayed links between metabolite levels, seed protein content, and seed weight. Principal component analysis revealed a clustering of samples, with PC1 mapping to a region on the short arm of chromosome IV. The overlap of this region with mQTL hotspots indicates the presence of a potential master regulatory locus of seed metabolism. As a result of database queries, a series of candidate regulatory genes, including bZIP10, were identified within this region. Depending on the search conditions, metabolic pathway-derived candidate genes for 40-61% of tested mQTLs could be determined, providing an extensive basis for further identification and characterization of hitherto unknown genes causal for natural variation of Arabidopsis seed metabolism. PMID- 28338799 TI - Novel form of the Michaelis-Menten equation that enables accurate estimation of (kcat/KM)*KI with just two rate measurements; utility in directed evolution. AB - One of applications of directed evolution is to desensitize an enzyme to an inhibitor. kcat,1/KM and KI are three dimensions that when multiplied measure an enzyme's intrinsic capacity for catalysis in the presence of an inhibitor. The ideal values for the individual dimensions depend on substrate and inhibitor concentrations under the conditions of the application. When attempting to optimize those values by directed evolution, (kcat/KM)*KI can be an informative parameter for evaluating libraries of variants, but throughput is limited. We describe a manipulation of the Michaelis-Menten equation for competitive inhibition that isolates (kcat/KM)*KI on one side of the equation. If velocity is measured at constant enzyme and substrate concentrations with two different inhibitor concentrations (one of which can be 0), the data are sufficient to calculate (kcat/KM)*KI with just two rate measurements. The procedure is validated by correlating values obtained by the rapid method with those obtained by substrate saturation kinetics. PMID- 28338800 TI - A steady-state stomatal model of balanced leaf gas exchange, hydraulics and maximal source-sink flux. AB - Trees must simultaneously balance their CO2 uptake rate via stomata, photosynthesis, the transport rate of sugars and rate of sugar utilization in sinks while maintaining a favourable water and carbon balance. We demonstrate using a numerical model that it is possible to understand stomatal functioning from the viewpoint of maximizing the simultaneous photosynthetic production, phloem transport and sink sugar utilization rate under the limitation that the transpiration-driven hydrostatic pressure gradient sets for those processes. A key feature in our model is that non-stomatal limitations to photosynthesis increase with decreasing leaf water potential and/or increasing leaf sugar concentration and are thus coupled to stomatal conductance. Maximizing the photosynthetic production rate using a numerical steady-state model leads to stomatal behaviour that is able to reproduce the well-known trends of stomatal behaviour in response to, e.g., light, vapour concentration difference, ambient CO2 concentration, soil water status, sink strength and xylem and phloem hydraulic conductance. We show that our results for stomatal behaviour are very similar to the solutions given by the earlier models of stomatal conductance derived solely from gas exchange considerations. Our modelling results also demonstrate how the 'marginal cost of water' in the unified stomatal conductance model and the optimal stomatal model could be related to plant structural and physiological traits, most importantly, the soil-to-leaf hydraulic conductance and soil moisture. PMID- 28338801 TI - Evolutionary origin of mitochondrial cytochrome P450. AB - Different molecular species of cytochrome P450 (P450) are distributed between endoplasmic reticulum (microsomes) and mitochondria in animal cells. Plants and fungi have many microsomal P450s, but no mitochondrial P450 has so far been reported. To elucidate the evolutionary origin of mitochondrial P450s in animal cells, available evidence is examined, and the virtual absence of mitochondrial P450 in plants and fungi is confirmed. It is also suggested that a microsomal P450 is the ancestor of animal mitochondrial P450s. It is likely that the endoplasmic reticulum-targeting sequence at the amino-terminus of a microsomal P450 was converted to a mitochondria-targeting sequence possibly by point mutations of a few amino acid residues or by an exon-shuffling/moving event shortly after animal lineage diverged from plants and fungi in the course of evolution of eukaryotes. It is suggested that the microsome-type P450 first imported into mitochondria utilized the existing ferredoxin in the matrix to receive electrons from NADPH, retained its oxygenase activity in the mitochondria, and gradually diversified to several P450s with different substrate specificities in the course of the evolution of animals. PMID- 28338802 TI - Cross-Species Genome-Wide Identification of Evolutionary Conserved MicroProteins. AB - MicroProteins are small single-domain proteins that act by engaging their targets into different, sometimes nonproductive protein complexes. In order to identify novel microProteins in any sequenced genome of interest, we have developed miPFinder, a program that identifies and classifies potential microProteins. In the past years, several microProteins have been discovered in plants where they are mainly involved in the regulation of development by fine-tuning transcription factor activities. The miPFinder algorithm identifies all up to date known plant microProteins and extends the microProtein concept beyond transcription factors to other protein families. Here, we reveal potential microProtein candidates in several plant and animal reference genomes. A large number of these microProteins are species-specific while others evolved early and are evolutionary highly conserved. Most known microProtein genes originated from large ancestral genes by gene duplication, mutation and subsequent degradation. Gene ontology analysis shows that putative microProtein ancestors are often located in the nucleus, and involved in DNA binding and formation of protein complexes. Additionally, microProtein candidates act in plant transcriptional regulation, signal transduction and anatomical structure development. MiPFinder is freely available to find microProteins in any genome and will aid in the identification of novel microProteins in plants and animals. PMID- 28338803 TI - Vertical and seasonal variations in temperature responses of leaf respiration in a Chamaecyparis obtusa canopy. AB - Leaf respiration (R) is a major component of carbon balance in forest ecosystems. Clarifying the variability of leaf R within a canopy is essential for predicting the impact of global warming on forest productivity and the potential future function of the forest ecosystem as a carbon sink. We examined vertical and seasonal variations in short-term temperature responses of leaf R as well as environmental factors (light and mean air temperature) and physiological factors [leaf nitrogen (N), leaf mass per area (LMA), and shoot growth] in the canopy of a 10-year-old stand of hinoki cypress [Chamaecyparis obtusa (Sieb. et Zucc.) Endl.] in Kyushu, Japan. Leaf respiration rate adjusted to 20 degrees C (R20) exhibited evident vertical gradients in each season and was correlated with light, LMA and leaf N. In contrast, the temperature sensitivity of leaf R (Q10) did not vary vertically throughout the seasons. Seasonally, Q10 was higher in winter than in summer and was strongly negatively correlated to mean air temperature. A negative correlation of R20 with mean air temperature was also observed for each of the three canopy layers. These results clearly indicate that leaf R was able to adjust to seasonal changes in ambient temperature under field conditions and down-regulate during warmer periods. We also found that the degree of thermal acclimation did not vary with canopy position. Overall, our results suggest that vertical and seasonal variations in temperature responses of leaf R within a hinoki cypress canopy could be predicted by relatively simple parameters (light and temperature). There was an exception of extremely high R20 values in April that may have been due to the onset of shoot growth in spring. Understanding thermal acclimation and variations in leaf R within forest canopies will improve global terrestrial carbon cycle models. PMID- 28338804 TI - Duplications and Positive Selection Drive the Evolution of Parasitism-Associated Gene Families in the Nematode Strongyloides papillosus. AB - Gene duplication is a major mechanism playing a role in the evolution of phenotypic complexity and in the generation of novel traits. By comparing parasitic and nonparasitic nematodes, a recent study found that the evolution of parasitism in Strongyloididae is associated with a large expansion in the Astacin and CAP gene families.To gain novel insights into the developmental processes in the sheep parasite Strongyloides papillosus, we sequenced transcriptomes of different developmental stages and sexes. Overall, we found that the majority of genes are developmentally regulated and have one-to-one orthologs in the diverged S. ratti genome. Together with the finding of similar expression profiles between S. papillosus and S. ratti, these results indicate a strong evolutionary constraint acting against change at sequence and expression levels. However, the comparison between parasitic and free-living females demonstrates a quite divergent pattern that is mostly due to the previously mentioned expansion in the Astacin and CAP gene families. More detailed phylogenetic analysis of both gene families shows that most members date back to single expansion events early in the Strongyloides lineage and have undergone subfunctionalization resulting in clusters that are highly expressed either in infective larvae or in parasitic females. Finally, we found increased evidence for positive selection in both gene families relative to the genome-wide expectation.In summary, our study reveals first insights into the developmental transcriptomes of S. papillosus and provides a detailed analysis of sequence and expression evolution in parasitism associated gene families. PMID- 28338805 TI - Deciphering the genetic control of fruit texture in apple by multiple family based analysis and genome-wide association. AB - Fruit texture is a complex feature composed of mechanical and acoustic properties relying on the modifications occurring in the cell wall throughout fruit development and ripening. Apple is characterized by a large variation in fruit texture behavior that directly impacts both the consumer's appreciation and post harvest performance. To decipher the genetic control of fruit texture comprehensively, two complementing quantitative trait locus (QTL) mapping approaches were employed. The first was represented by a pedigree-based analysis (PBA) carried out on six full-sib pedigreed families, while the second was a genome-wide association study (GWAS) performed on a collection of 233 apple accessions. Both plant materials were genotyped with a 20K single nucleotide polymorphism (SNP) array and phenotyped with a sophisticated high-resolution texture analyzer. The overall QTL results indicated the fundamental role of chromosome 10 in controlling the mechanical properties, while chromosomes 2 and 14 were more associated with the acoustic response. The latter QTL, moreover, showed a consistent relationship between the QTL-estimated genotypes and the acoustic performance assessed among seedlings. The in silico annotation of these intervals revealed interesting candidate genes potentially involved in fruit texture regulation, as suggested by the gene expression profile. The joint integration of these approaches sheds light on the specific control of fruit texture, enabling important genetic information to assist in the selection of valuable fruit quality apple varieties. PMID- 28338806 TI - Influenza-Associated Hospitalizations for Cardiovascular Diseases in the Tropics. AB - Influenza is a major cause of mortality and morbidity. We aimed to examine the influenza-associated hospitalization rates and proportions for cardiovascular disease (CVD) in tropical Singapore. Hospital admissions for ischemic heart disease (IHD), congestive heart failure (CHF), and overall CVD were obtained from the national inpatient database for the period of 2010-2014. We used, as the key indicator of influenza virus activity, the overall proportion of specimens from outpatients with influenza-like illness in the community that tested positive for influenza as part of the national influenza surveillance program. The annual influenza-associated hospitalization rates per 100,000 person-years ranged from 9.5 to 12.2 for IHD, 7.7 to 9.1 for CHF, and 15.8 to 19.2 for overall CVD. The influenza-associated hospitalization rates increased with increasing age. Influenza was significantly associated with excess hospitalizations in elderly persons aged >=80 years, with an excess hospitalization rate per 100,000 person years of 242.7 for IHD (P = 0.02), 271.8 for CHF (P = 0.01), and 497.2 for overall CVD (P < 0.001). In the tropics, influenza accounts for excess cardiovascular-related hospitalizations, especially in the elderly. PMID- 28338807 TI - Is orthostatic hypotension related to falling? A meta-analysis of individual patient data of prospective observational studies. AB - Background: orthostatic hypotension (OH) is one out of many risk factors believed to contribute to an increased fall risk in elderly subjects but it is unclear whether an independent association between OH and falling exists. Objectives: to perform an individual patient data (IPD) meta-analysis of prospective observational studies investigating the relationship between OH and falling. Design: MEDLINE, EMBASE, the Cochrane Library and the abstracts of annual meetings of selected hypertension societies were searched. Both one-stage (analysing all IPD from all studies simultaneously) and two-stage (analysing IPD per study, and then pooling the results) methods were used, and both logistic and cox regression analyses were performed. The study protocol was published on PROSPERO (2015:CRD42015019178). Results: from 34 selected abstracts, 6 studies were included. IPD were provided in 1,022 patients from 3 cohorts and were included in the IPD meta-analysis. The one-stage meta-analysis showed a significant relationship between OH and time to first fall incident (hazard ratio (HR) 1.52 (95% Confidence Interval (CI) 1.23-1.88)). No significant relationship between OH and falling was found in the one-stage logistic regression analysis and the two-stage logistic and cox regression analyses. Conclusions: this IPD meta-analysis of prospective observational studies showed a clear and significant relationship between OH and time to first fall incident. Although the ORs of falling was not significantly different for patients with and without OH, a the cox regression analyses reporting HRs and including time to incident provided more clinically relevant information in present meta-analysis. PMID- 28338808 TI - The relationship between cognitive impairment, mortality and discharge characteristics in a large cohort of older adults with unscheduled admissions to an acute hospital: a retrospective observational study. AB - Background: older people with dementia admitted to hospital for acute illness have higher mortality and longer hospital stays compared to those without dementia. Cognitive impairment (CI) is common in older people, and they may also be at increased risk of poor outcomes. Methods: retrospective observational study of unscheduled admissions aged >=75 years. Admission characteristics, mortality rates and discharge outcomes were compared between three groups: (i) known dementia diagnosis (DD), (ii) CI but no diagnosis of dementia and (iii) no CI. Results: of 19,269 admissions (13,652 patients), 19.8% had a DD, 11.6% had CI and 68.6% had neither. Admissions with CI or DD were older and had more females than those with no CI, and were more likely to be admitted through the Emergency Department (88.4% and 90.7%, versus 82.0%) and to medical wards (89.4% and 84.4%, versus 76.8%). Acuity levels at admission were similar between the groups. Patients with CI or DD had more admissions at 'high risk' from malnutrition than patients with no CI (28.0% and 33.7% versus 17.5%), and a higher risk of dying in hospital (11.8% [10.5-13.3] and 10.8% [9.8-11.9] versus (6.6% [6.2-7.0])). Conclusions: the admission characteristics, mortality and length of stay of patients with CI resemble those of patients with diagnosed dementia. Whilst attention has been focussed on the need for additional support for people with dementia, patients with CI, which may include those with undiagnosed dementia or delirium, appear to have equally bad outcomes from hospitalisation. PMID- 28338809 TI - Resveratrol derivative BTM-0512 mitigates obesity by promoting beige remodeling of subcutaneous preadipocytes. AB - Recent studies revealed that sirtuin 1 (SIRT1) is involved in the regulation of energy metabolism and its agonist resveratrol showed anti-obesity effect. This study aims to determine whether BTM-0512, a novel derivative of resveratrol, acts as an antagonist of obesity and to explore its possible mechanisms. High-fat diet (HFD)-induced obese mice were intragastrically administered with BTM-0512 (5, 10, and 20 mg/kg/day) or resveratrol (10 mg/kg/day). It was found that the body weight, Lee's index, ratio of visceral adipose tissue (VAT) to body weight, and blood glucose were significantly reduced in BTM-0512-treated mice when compared with those in mice treated with resveratrol. BTM-0512 up-regulated the expressions of SIRT1, full length PRDM16 (fPRDM16), total PRDM16 (tPRDM16, including fPPRDM16 and other PRDM16 isoforms), and uncoupling protein 1 (UCP1) in both brown and subcutaneous adipose tissues. Although BTM-0512 and resveratrol also up-regulated SIRT1 and tPRDM16 levels in VAT of HFD-induced obese mice, the expressions of fPRDM16, UCP1, and TMEM26 were down-regulated. In mouse primary subcutaneous preadipocytes cultured with or without adipogenic medium, BTM-0512 up-regulated fPRDM16, tPRDM16, and UCP1 expressions, which was reversed by SIRT1 antagonists. But in cultured brown and visceral adipocytes, the UCP1 protein level showed no significant change after treatment with 1 MUM of BTM-0512. Moreover, transfection with human SIRT1 plasmid reduced lipid deposit, as well as the mRNA levels of fPRDM16, UCP1, and TMEM26, in cultured human visceral adipose derived stem cells. In conclusion, BTM-0512 has stronger anti-obesity effect than resveratrol, which might be associated with activation of beige remodeling in subcutaneous adipose tissue. PMID- 28338810 TI - Associations of Proatrial Natriuretic Peptide with Components of the Metabolic Syndrome in Adolescents and Young Adults from the General Population. AB - BACKGROUND: In middle-aged and elderly populations, circulating natriuretic peptide concentrations are negatively associated with several components of the metabolic syndrome. Whether these negative associations are also present in healthy adolescents and young adults from the general population are unknown. METHODS: In a cross-sectional setting, we measured plasma concentrations of mid regional proatrial natriuretic peptide (MR-proANP) in 343 adolescents (age 14-16 years) and 616 young adults (age 20-28 years) from the Danish site of the European Youth Heart Study, which is a population-based study of cardiovascular disease risk factors in children, adolescents and young adults. We used linear regression analysis to examine the associations, expressed as standardized regression coefficients, of various variables of interest with MR-proANP stratified according to age group, adjusting for age and gender. RESULTS: Among the young adults, MR-proANP was negatively associated with body mass index (BMI) (beta = -0.10, P = 0.02), waist circumference (WC) (beta = -0.14, P < 0.001), systolic blood pressure (BP) (beta = -0.08, P = 0.03), diastolic BP (beta = 0.23, P < 0.001), insulin (beta = -0.15, P < 0.001), and triglycerides (beta = 0.14, P < 0.001). Among the adolescents a somehow different pattern was observed since MR-proANP was not significantly associated with BMI (beta = -0.00, P = 0.98), WC (beta = -0.01, P = 0.90) and insulin (beta = -0.02, P = 0.69). Nevertheless, among the adolescents, MR-proANP was negatively associated with triglycerides (beta = -0.13, P = 0.01), diastolic BP (beta = -0.12, P = 0.01) and systolic BP (beta = -0.10, P = 0.10), although the latter association was of borderline significance. CONCLUSIONS: The young adults displayed significant negative associations between MR-proANP and several components of the metabolic syndrome, whereas such associations were not found among the adolescents besides triglycerides and diastolic BP. PMID- 28338811 TI - Interventions for the prevention and treatment of disability due to acquired joint contractures in older people: a systematic review. AB - Background: acquired joint contractures have significant effects on quality of life and functioning. Objective: to determine the effects of interventions to prevent and treat disabilities in older people with acquired joint contractures. Methods: systematic search (last 8/2016) via Cochrane Library, PubMed, EMBASE, PEDro, CINAHL, trial registries, reference lists of retrieved articles and scientific congress pamphlets. Controlled and randomised controlled trials in English or German comparing an intervention with another intervention or standard care were included. Two independent researchers performed the selection of publications, data extraction and critical appraisal. Results: seventeen studies with 992 participants met the inclusion criteria: 16 randomised controlled trials and 1 controlled trial (nursing homes = 4, community settings = 13). The methodological quality of the studies varied. Splints were examined in four studies, stretching exercises in nine studies, and ultrasound, passive movement therapy, bed-positioning and group exercise were each examined in one study. Studies on splints revealed inconclusive results regarding joint mobility or spasticity. Five of seven studies that assessed active stretching programmes for healthy older people reported statistically significant effects on joint mobility in favour of the intervention. Pain, quality of life, activity limitations and participation restrictions were rarely assessed. Conclusion: the evidence for the effectiveness of interventions to prevent and treat disability due to joint contractures is weak, particularly for established nursing interventions such as positioning and passive movement. Better understanding is required regarding the delivery of interventions, such as their intensity and duration. In addition to functional issues, activities and social participation should also be studied as outcomes. PMID- 28338812 TI - Association Between Age at Menarche and Gestational Diabetes Mellitus: The Australian Longitudinal Study on Women's Health. AB - In this study, we aimed to examine the association between age at menarche and gestational diabetes mellitus (GDM). Data were from 4,749 women participating in the Australian Longitudinal Study on Women's Health between 2000 and 2012. Age at menarche was reported at baseline in 2000 when women were aged 22-27 years. During 12 years of follow-up, information on GDM diagnosis was obtained for each live birth. Log-binomial regression analysis was used to estimate relative risks and 95% confidence intervals. Analyses adjusted for mother's highest completed educational qualification, nulliparity, polycystic ovary syndrome, physical activity, and body mass index. Mean age at menarche was 12.9 years (standard deviation, 1.4). A first diagnosis of GDM was reported by 357 women (7.5%). Compared with women with menarche at age 13 years, women who had their first menstruation at age <=11 years had a 51% higher risk of developing GDM (95% confidence interval: 1.10, 2.07) after adjustment for GDM risk factors. Our findings indicate that a young age at menarche may identify women at higher risk of GDM. Further prospective studies are needed to confirm our findings and to elucidate the role of early-life exposures in age at menarche and subsequent GDM risk. PMID- 28338813 TI - Antibiotic prescribing for acute respiratory infections in children in Jordan. AB - Background: Most acute respiratory infections (ARIs) in children are due to viral etiology; however, over-prescribing of antibiotics for ARIs is common. The aim of this investigation was to identify antibiotic prescribing prevalence for children with ARIs and to identify predictors of broad-spectrum antibiotic prescribing. Methods: This was a prospective cross sectional study in a sample of ambulatory care settings in Jordan. Children (<18 years) presenting with ARIs were assessed in terms of patient's demographics, antibiotic prescription and clinical diagnosis. Multivariable logistic regression analysis was used to identify predictors of broad-spectrum antibiotic prescription. Results: Antibiotics were prescribed for 78.4% (4575/5829) of children with ARIs. Antibiotic prescription for ARIs for which antibiotics are not indicated was 69.2% (2688/3883). Broad spectrum antibiotic prescription occurred in 51.1% (2337/4575) of all antibiotic prescribed participants. Some of the predictors of broad-spectrum antibiotic prescription were: otitis media (OR 4.93 [95% CI 3.44-7.14]), tonsillitis (OR 6.03 [95% CI 4.39-8.33]), age 0-5 years (OR 1.17 [95% CI 1.02-1.38]) compared to age 6-12 years, fever (OR 2.14 [95% CI 1.78-2.59]), outpatient setting (OR 73 [95% CI 2.17-3.42]) and military sector (OR 2.29 [95% CI 1.82-2.90]). Conclusions: Antibiotic prescribing is high and often inappropriate. Predictors of broad-spectrum antibiotic prescribing were identified. Health policy initiatives should involve all stakeholders to minimize inappropriate antibiotic prescription and to prevent poor outcomes associated with such practice. PMID- 28338814 TI - KOREAN PEDIATRIC AND ADULT HEAD COMPUTATIONAL PHANTOMS AND APPLICATION TO PHOTON SPECIFIC ABSORBED FRACTIONS CALCULATIONS. AB - In recent decades, applications of single photon emission computed tomography and positron emission tomography in clinical neuroimaging have markedly increased. In this study, we developed a series of Korean computational head phantoms with detailed cranial substructures for 6-, 9-, 12- and 15-year-old children and adult by non-uniformly adjusting a template head phantom to match the Korean standard head dimensions. The Korean head phantoms were coupled with a Monte Carlo transport code to calculate age-dependent specific absorbed fraction (SAF) for the combination of 10 source and target regions and mono-energetic photons ranging from 0.01 to 4 MeV. Compared to the adult phantom, the 6-y phantom showed up to 1.4-fold greater self-absorption SAF (cerebellum) and up to 1.8-fold greater cross-irradiation SAF (cerebellum < eye balls). With addition of electron SAFs in the future, our photon SAF data will facilitate dose calculations for various cranial substructures in patients undergoing cranial neuroimaging procedures. PMID- 28338815 TI - Enhanced tenogenic differentiation and tendon-like tissue formation by CHIP overexpression in tendon-derived stem cells. AB - The carboxyl terminus of Hsc70-interacting protein (CHIP, also known as STUB1) plays critical roles in the proliferation and differentiation of many types of cells. The potential function of CHIP in tendon-derived stem cells (TDSCs) remains largely unknown at present. Here, we investigated the effects of CHIP on tenogenic differentiation of TDSCs via lentivirus-mediated overexpression. Forced expression of CHIP induced morphological changes and significantly enhanced cell proliferation, as well as tendon differentiation in vitro. Upon stimulation with differentiation induction medium, CHIP-overexpressing TDSCs displayed significant inhibition of differentiation into osteogenic and adipogenic lineages. Subsequent implantation of TDSCs overexpressing CHIP with collagen sponges into nude mice induced a marked increase in ectopic tendon formation in vivo, compared with the control group. Our findings collectively suggest that CHIP is an important contributory factor to tenogenic tissue formation. PMID- 28338817 TI - Risk Factor Models for Neurodevelopmental Outcomes in Children Born Very Preterm or With Very Low Birth Weight: A Systematic Review of Methodology and Reporting. AB - The prediction of long-term outcomes in surviving infants born very preterm (VPT) or with very low birth weight (VLBW) is necessary to guide clinical management, provide information to parents, and help target and evaluate interventions. There is a large body of literature describing risk factor models for neurodevelopmental outcomes in VPT/VLBW children, yet few, if any, have been developed for use in routine clinical practice or adopted for use in research studies or policy evaluation. We sought to systematically review the methods and reporting of studies that have developed a multivariable risk factor model for neurodevelopment in surviving VPT/VLBW children. We searched the MEDLINE, Embase, and PsycINFO databases from January 1, 1990, to June 1, 2014, and identified 78 studies reporting 222 risk factor models. Most studies presented risk factor analyses that were not intended to be used for prediction, confirming that there is a dearth of specifically designed prognostic modeling studies for long-term outcomes in surviving VPT/VLBW children. We highlight the strengths and weaknesses of the research methodology and reporting to date, and provide recommendations for the design and analysis of future studies seeking to analyze risk prediction or develop prognostic models for VPT/VLBW children. PMID- 28338818 TI - Epidemiology in an age of anger and complaint. PMID- 28338816 TI - Conserved Patterns of Sex Chromosome Dosage Compensation in the Lepidoptera (WZ/ZZ): Insights from a Moth Neo-Z Chromosome. AB - Where previously described, patterns of sex chromosome dosage compensation in the Lepidoptera (moths and butterflies) have several unusual characteristics. Other female-heterogametic (ZW/ZZ) species exhibit female Z-linked expression that is reduced compared with autosomal expression and male Z expression. In the Lepidoptera, however, Z expression typically appears balanced between sexes but overall reduced relative to autosomal expression, that is Z ~ ZZ < AA. This pattern is not easily reconciled with theoretical expectations for the evolution of sex chromosome dosage compensation. Moreover, conflicting results linger due to discrepancies in data analyses and tissues sampled among lepidopterans. To address these issues, we performed RNA-seq to analyze sex chromosome dosage compensation in the codling moth, Cydia pomonella, which is a species from the earliest diverging lepidopteran lineage yet examined for dosage compensation and has a neo-Z chromosome resulting from an ancient Z:autosome fusion. While supported by intraspecific analyses, the Z ~ ZZ < AA pattern was further evidenced by comparative study using autosomal orthologs of C. pomonella neo-Z genes in outgroup species. In contrast, dosage compensation appears to be absent in reproductive tissues. We thus argue that inclusion of reproductive tissues may explain the incongruence from a prior study on another moth species and that patterns of dosage compensation are likely conserved in the Lepidoptera. Notably, this pattern appears convergent with patterns in eutherian mammals (X ~ XX < AA). Overall, our results contribute to the notion that the Lepidoptera present challenges both to classical theories regarding the evolution of sex chromosome dosage compensation and the emerging view of the association of dosage compensation with sexual heterogamety. PMID- 28338819 TI - UNLAMINATED GAFCHROMIC EBT3 FILM FOR ULTRAVIOLET RADIATION MONITORING. AB - Measurement of ultraviolet (UV) radiation is important for human health, especially with the expanded usage of short wavelength UV for sterilization purposes. This work examines unlaminated Gafchromic EBT3 film for UV radiation monitoring. The authors exposed the film to select wavelengths in the UV spectrum, ranging from 207 to 328 nm, and measured the change in optical density. The response of the film is wavelength dependent, and of the wavelengths tested, the film was most sensitive to 254 nm light, with measurable values as low as 10 uJ/cm2. The film shows a dose-dependent response that extends over more than four orders of magnitude. The response of the film to short wavelength UV is comparable to the daily safe exposure limits for humans, thus making it valuable as a tool for passive UV radiation monitoring. PMID- 28338820 TI - Evolutionary Dynamics of Regulatory Changes Underlying Gene Expression Divergence among Saccharomyces Species. AB - Heritable changes in gene expression are important contributors to phenotypic differences within and between species and are caused by mutations in cis regulatory elements and trans-regulatory factors. Although previous work has suggested that cis-regulatory differences preferentially accumulate with time, technical restrictions to closely related species and limited comparisons have made this observation difficult to test. To address this problem, we used allele specific RNA-seq data from Saccharomyces species and hybrids to expand both the evolutionary timescale and number of species in which the evolution of regulatory divergence has been investigated. We find that as sequence divergence increases, cis-regulatory differences do indeed become the dominant type of regulatory difference between species, ultimately becoming a better predictor of expression divergence than trans-regulatory divergence. When both cis- and trans-regulatory differences accumulate for the same gene, they more often have effects in opposite directions than in the same direction, indicating widespread compensatory changes underlying the evolution of gene expression. The frequency of compensatory changes within and between species and the magnitude of effect for the underlying cis- and trans-regulatory differences suggests that compensatory changes accumulate primarily due to selection against divergence in gene expression as a result of weak stabilizing selection on gene expression levels. These results show that cis-regulatory differences and compensatory changes in regulation play increasingly important roles in the evolution of gene expression as time increases. PMID- 28338821 TI - Phylogenomic Insights into Mouse Evolution Using a Pseudoreference Approach. AB - Comparative genomic studies are now possible across a broad range of evolutionary timescales, but the generation and analysis of genomic data across many different species still present a number of challenges. The most sophisticated genotyping and down-stream analytical frameworks are still predominantly based on comparisons to high-quality reference genomes. However, established genomic resources are often limited within a given group of species, necessitating comparisons to divergent reference genomes that could restrict or bias comparisons across a phylogenetic sample. Here, we develop a scalable pseudoreference approach to iteratively incorporate sample-specific variation into a genome reference and reduce the effects of systematic mapping bias in downstream analyses. To characterize this framework, we used targeted capture to sequence whole exomes (~54 Mbp) in 12 lineages (ten species) of mice spanning the Mus radiation. We generated whole exome pseudoreferences for all species and show that this iterative reference-based approach improved basic genomic analyses that depend on mapping accuracy while preserving the associated annotations of the mouse reference genome. We then use these pseudoreferences to resolve evolutionary relationships among these lineages while accounting for phylogenetic discordance across the genome, contributing an important resource for comparative studies in the mouse system. We also describe patterns of genomic introgression among lineages and compare our results to previous studies. Our general approach can be applied to whole or partitioned genomic data and is easily portable to any system with sufficient genomic resources, providing a useful framework for phylogenomic studies in mice and other taxa. PMID- 28338822 TI - Gene expression atlas of pigeonpea and its application to gain insights into genes associated with pollen fertility implicated in seed formation. AB - Pigeonpea (Cajanus cajan) is an important grain legume of the semi-arid tropics, mainly used for its protein rich seeds. To link the genome sequence information with agronomic traits resulting from specific developmental processes, a Cajanus cajan gene expression atlas (CcGEA) was developed using the Asha genotype. Thirty tissues/organs representing developmental stages from germination to senescence were used to generate 590.84 million paired-end RNA-Seq data. The CcGEA revealed a compendium of 28 793 genes with differential, specific, spatio-temporal and constitutive expression during various stages of development in different tissues. As an example to demonstrate the application of the CcGEA, a network of 28 flower-related genes analysed for cis-regulatory elements and splicing variants has been identified. In addition, expression analysis of these candidate genes in male sterile and male fertile genotypes suggested their critical role in normal pollen development leading to seed formation. Gene network analysis also identified two regulatory genes, a pollen-specific SF3 and a sucrose-proton symporter, that could have implications for improvement of agronomic traits such as seed production and yield. In conclusion, the CcGEA provides a valuable resource for pigeonpea to identify candidate genes involved in specific developmental processes and to understand the well-orchestrated growth and developmental process in this resilient crop. PMID- 28338824 TI - Farewell to the Editors of the International Journal of Epidemiology: an appreciation. PMID- 28338823 TI - Transporters involved in pH and K+ homeostasis affect pollen wall formation, male fertility, and embryo development. AB - Flowering plant genomes encode multiple cation/H+ exchangers (CHXs) whose functions are largely unknown. AtCHX17, AtCHX18, and AtCHX19 are membrane transporters that modulate K+ and pH homeostasis and are localized in the dynamic endomembrane system. Loss of function reduced seed set, but the particular phase(s) of reproduction affected was not determined. Pollen tube growth and ovule targeting of chx17chx18chx19 mutant pollen appeared normal, but reciprocal cross experiments indicate a largely male defect. Although triple mutant pollen tubes reach ovules of a wild-type pistil and a synergid cell degenerated, half of those ovules were unfertilized or showed fertilization of the egg or central cell, but not both female gametes. Fertility could be partially compromised by impaired pollen tube and/or sperm function as CHX19 and CHX18 are expressed in the pollen tube and sperm cell, respectively. When fertilization was successful in self-pollinated mutants, early embryo formation was retarded compared with embryos from wild-type ovules receiving mutant pollen. Thus CHX17 and CHX18 proteins may promote embryo development possibly through the endosperm where these genes are expressed. The reticulate pattern of the pollen wall was disorganized in triple mutants, indicating perturbation of wall formation during male gametophyte development. As pH and cation homeostasis mediated by AtCHX17 affect membrane trafficking and cargo delivery, these results suggest that male fertility, sperm function, and embryo development are dependent on proper cargo sorting and secretion that remodel cell walls, plasma membranes, and extracellular factors. PMID- 28338825 TI - Modular Organization of Residue-Level Contacts Shapes the Selection Pressure on Individual Amino Acid Sites of Ribosomal Proteins. AB - Understanding the molecular evolution of macromolecular complexes in the light of their structure, assembly, and stability is of central importance. Here, we address how the modular organization of native molecular contacts shapes the selection pressure on individual residue sites of ribosomal complexes. The bacterial ribosomal complex is represented as a residue contact network where nodes represent amino acid/nucleotide residues and edges represent their van der Waals interactions. We find statistically overrepresented native amino acid nucleotide contacts (OaantC, one amino acid contacts one or multiple nucleotides, internucleotide contacts are disregarded). Contact number is defined as the number of nucleotides contacted. Involvement of individual amino acids in OaantCs with smaller contact numbers is more random, whereas only a few amino acids significantly contribute to OaantCs with higher contact numbers. An investigation of structure, stability, and assembly of bacterial ribosome depicts the involvement of these OaantCs in diverse biophysical interactions stabilizing the complex, including high-affinity protein-RNA contacts, interprotein cooperativity, intersubunit bridge, packing of multiple ribosomal RNA domains, etc. Amino acid-nucleotide constituents of OaantCs with higher contact numbers are generally associated with significantly slower substitution rates compared with that of OaantCs with smaller contact numbers. This evolutionary rate heterogeneity emerges from the strong purifying selection pressure that conserves the respective amino acid physicochemical properties relevant to the stabilizing interaction with OaantC nucleotides. An analysis of relative molecular orientations of OaantC residues and their interaction energetics provides the biophysical ground of purifying selection conserving OaantC amino acid physicochemical properties. PMID- 28338826 TI - The evolutionary fate of the chloroplast and nuclear rps16 genes as revealed through the sequencing and comparative analyses of four novel legume chloroplast genomes from Lupinus. AB - The Fabaceae family is considered as a model system for understanding chloroplast genome evolution due to the presence of extensive structural rearrangements, gene losses and localized hypermutable regions. Here, we provide sequences of four chloroplast genomes from the Lupinus genus, belonging to the underinvestigated Genistoid clade. Notably, we found in Lupinus species the functional loss of the essential rps16 gene, which was most likely replaced by the nuclear rps16 gene that encodes chloroplast and mitochondrion targeted RPS16 proteins. To study the evolutionary fate of the rps16 gene, we explored all available plant chloroplast, mitochondrial and nuclear genomes. Whereas no plant mitochondrial genomes carry an rps16 gene, many plants still have a functional nuclear and chloroplast rps16 gene. Ka/Ks ratios revealed that both chloroplast and nuclear rps16 copies were under purifying selection. However, due to the dual targeting of the nuclear rps16 gene product and the absence of a mitochondrial copy, the chloroplast gene may be lost. We also performed comparative analyses of lupine plastomes (SNPs, indels and repeat elements), identified the most variable regions and examined their phylogenetic utility. The markers identified here will help to reveal the evolutionary history of lupines, Genistoids and closely related clades. PMID- 28338827 TI - Strategies for halting the rise of multidrug resistant TB epidemics: assessing the effect of early case detection and isolation. AB - Background: The increasing rates of multidrug resistant TB (MDR-TB) have posed the question of whether control programs under enhanced directly observed treatment, short-course (DOTS-Plus) are sufficient or implemented optimally. Despite enhanced efforts on early case detection and improved treatment regimens, direct transmission of MDR-TB remains a major hurdle for global TB control. Methods: We developed an agent-based simulation model of TB dynamics to evaluate the effect of transmission reduction measures on the incidence of MDR-TB. We implemented a 15-day isolation period following the start of treatment in active TB cases. The model was parameterized with the latest estimates derived from the published literature. Results: We found that if high rates (over 90%) of TB case identification are achieved within 4 weeks of developing active TB, then a 15-day patient isolation strategy with 50% effectiveness in interrupting disease transmission leads to 10% reduction in the incidence of MDR-TB over 10 years. If transmission is fully prevented, the rise of MDR-TB can be halted within 10 years, but the temporal reduction of MDR-TB incidence remains below 20% in this period. Conclusions: The impact of transmission reduction measures on the TB incidence depends critically on the rates and timelines of case identification. The high costs and adverse effects associated with MDR-TB treatment warrant increased efforts and investments on measures that can interrupt direct transmission through early case detection. PMID- 28338828 TI - Validity of a Dietary Questionnaire Assessed by Comparison With Multiple Weighed Dietary Records or 24-Hour Recalls. AB - The authors evaluated the validity of a 152-item semiquantitative food frequency questionnaire (SFFQ) by comparing it with two 7-day dietary records (7DDRs) or up to 4 automated self-administered 24-hour recalls (ASA24s) over a 1-year period in the women's Lifestyle Validation Study (2010-2012), conducted among subgroups of the Nurses' Health Studies. Intakes of energy and 44 nutrients were assessed using the 3 methods among 632 US women. Compared with the 7DDRs, SFFQ responses tended to underestimate sodium intake but overestimate intakes of energy, macronutrients, and several nutrients in fruits and vegetables, such as carotenoids. Spearman correlation coefficients between energy-adjusted intakes from 7DDRs and the SFFQ completed at the end of the data-collection period ranged from 0.36 for lauric acid to 0.77 for alcohol (mean r = 0.53). Correlations of the end-period SFFQ were weaker when ASA24s were used as the comparison method (mean r = 0.43). After adjustment for within-person variation in the comparison method, the correlations of the final SFFQ were similar with 7DDRs (mean r = 0.63) and ASA24s (mean r = 0.62). These data indicate that this SFFQ provided reasonably valid estimates for intakes of a wide variety of dietary variables and that use of multiple 24-hour recalls or 7DDRs as a comparison method provided similar conclusions if day-to-day variation was taken into account. PMID- 28338829 TI - Seeing is not stereotyping: the functional independence of categorization and stereotype activation. AB - Social categorization has been viewed as necessarily resulting in stereotyping, yet extant research suggests the two processes are differentially sensitive to task manipulations. Here, we simultaneously test the degree to which race perception and stereotyping are conditionally automatic. Participants performed a sequential priming task while either explicitly attending to the race of face primes or directing attention away from their semantic nature. We find a dissociation between the perceptual encoding of race and subsequent activation of associated stereotypes, with race perception occurring in both task conditions, but implicit stereotyping occurring only when attention is directed to the race of the face primes. These results support a clear conceptual distinction between categorization and stereotyping and show that the encoding of racial category need not result in stereotype activation. PMID- 28338830 TI - Varying Influences of Aldosterone on the Plasma Potassium Concentration in Blacks and Whites. AB - BACKGROUND: Aldosterone acts to restrain the extracellular potassium (K+) concentration. Blacks have on average lower plasma aldosterone concentrations (PACs) than Whites. Whether this ethnic difference is associated with similar changes in the concentration of K+ is unclear. METHODS: Subjects were Blacks and Whites from an observational study of blood pressure regulation. PAC was known to be significantly lower in Blacks than Whites. We sought to test the hypothesis that the concentration of K+ remains constant despite variability in PAC. Initial enrollment took place in childhood in 1986. Some of the original enrollees were studied again in adulthood: 160 healthy Blacks and 271 healthy Whites (ages 5 to 39 years; all were studied as children and as adults). RESULTS: Plasma renin activity [a biomarker of angiotensin II and, more proximally, extracellular fluid volume (ECFV)] and PAC were lower in Blacks (P < 0.0354 and P < 0.001, respectively, for all ages). At the same time no ethnic difference in levels of K+ was observed regardless of age. Plasma K+ concentration and PAC associated differently based on ethnicity: PAC increased in Blacks by 1.5-2.0 and in Whites by 2.3-3.0 ng/dl per mmol/l increase in K+ (P < 0.001). CONCLUSIONS: Lower aldosterone levels in Blacks did not translate into higher K+ concentrations. We speculate that reaching the right concentration of K+ was an endpoint of aldosterone production in the presence of varying levels of ECFV and angiotensin II. PMID- 28338831 TI - Improved clearing of lipid droplet-rich tissues for three-dimensional structural elucidation. PMID- 28338832 TI - Evidence of translation efficiency adaptation of the coding regions of the bacteriophage lambda. AB - Deciphering the way gene expression regulatory aspects are encoded in viral genomes is a challenging mission with ramifications related to all biomedical disciplines. Here, we aimed to understand how the evolution shapes the bacteriophage lambda genes by performing a high resolution analysis of ribosomal profiling data and gene expression related synonymous/silent information encoded in bacteriophage coding regions.We demonstrated evidence of selection for distinct compositions of synonymous codons in early and late viral genes related to the adaptation of translation efficiency to different bacteriophage developmental stages. Specifically, we showed that evolution of viral coding regions is driven, among others, by selection for codons with higher decoding rates; during the initial/progressive stages of infection the decoding rates in early/late genes were found to be superior to those in late/early genes, respectively. Moreover, we argued that selection for translation efficiency could be partially explained by adaptation to Escherichia coli tRNA pool and the fact that it can change during the bacteriophage life cycle.An analysis of additional aspects related to the expression of viral genes, such as mRNA folding and more complex/longer regulatory signals in the coding regions, is also reported. The reported conclusions are likely to be relevant also to additional viruses. PMID- 28338833 TI - A humidity shock leads to rapid, temperature dependent changes in coffee leaf physiology and gene expression. AB - Climate change is expected to increase the frequency of above-normal atmospheric water deficits contemporaneous with periods of high temperatures. Here we explore alterations in physiology and gene expression in leaves of Coffea canephora Pierre ex A. Froehner caused by a sharp drop in relative humidity (RH) at three different temperatures. Both stomatal conductance (gs) and CO2 assimilation (A) measurements showed that gs and A values fell quickly at all temperatures after the transfer to low RH. However, leaf relative water content measurements indicated that leaves nonetheless experienced substantial water losses, implying that stomatal closure and/or resupply of water was not fast enough to stop excessive evaporative losses. At 27 and 35 degrees C, upper leaves showed significant decreases in Fv/Fm compared with lower leaves, suggesting a stronger impact on photosystem II for upper leaves, while at 42 degrees C, both upper and lower leaves were equally affected. Quantitative gene expression analysis of transcription factors associated with conventional dehydration stress, and genes involved with abscisic acid signalling, such as CcNCED3, indicated temperature dependent, transcriptional changes during the Humidity Shock ('HuS') treatments. No expression was seen at 27 degrees C for the heat-shock gene CcHSP90-7, but it was strongly induced during the 42 degrees C 'HuS' treatment. Consistent with a proposal that important cellular damage occurred during the 42 degrees C 'HuS' treatment, two genes implicated in senescence were induced by this treatment. Overall, the data show that C. canephora plants subjected to a sharp drop in RH exhibit major, temperature-dependent alterations in leaf physiology and important changes in the expression of genes associated with abiotic stress and senescence. The results presented suggest that more detailed studies on the combined effects of low RH and high temperature are warranted. PMID- 28338835 TI - Healthy diet and better muscle function and quality in older women. PMID- 28338834 TI - Comparative genomics of microsporidian genomes reveals a minimal non-coding RNA set and new insights for transcription in minimal eukaryotic genomes. AB - Microsporidia are ubiquitous intracellular pathogens whose opportunistic nature led to their increased recognition with the rise of the AIDS pandemic. As the RNA world was largely unexplored in this parasitic lineage, we developed a dedicated in silico methodology to carry out exhaustive identification of ncRNAs across the Encephalitozoon and Nosema genera. Thus, the previously missing U1 small nuclear RNA (snRNA) and small nucleolar RNAs (snoRNAs) targeting only the LSU rRNA were highlighted and were further validated using 5' and 3'RACE-PCR experiments. Overall, the 15 ncRNAs that were found shared between Encephalitozoon and Nosema spp. may represent the minimal core set required for parasitic life. Interestingly, the systematic presence of a CCC- or GGG-like motif in 5' of all ncRNA and mRNA gene transcripts regardless of the RNA polymerase involved suggests that the RNA polymerase machineries in microsporidia species could use common factors. Our data provide additional insights in accordance with the simplification processes observed in these reduce genomes and underline the usefulness of sequencing closely related species to help identify highly divergent ncRNAs in these parasites. PMID- 28338836 TI - A novel pathogenesis of inflammatory bowel disease from the perspective of glyco immunology. AB - Oligosaccharide modifications play an essential role in various inflammatory diseases and cancers, but their pathophysiologic roles, especially in inflammation, are not clear. Inflammatory bowel disease (IBD) is an intractable chronic inflammatory disorder with an unknown aetiology, and the number of patients with IBD is increasing throughout the world. Certain types of immunosuppressant drugs, such as corticosteroids, are effective for IBD, suggesting that immune function is closely associated with the pathophysiology of IBD. Recent progress in the analysis of oligosaccharides revealed a role for oligosaccharides in intestinal inflammation based on both experimental models and human samples from IBD patients. Moreover, changes in the oligosaccharide structures on glycoproteins in the sera and tissue samples may serve as biomarkers of IBD. Here, we present current studies of IBD with regard to the immunologic aspects of glycobiology, suggesting a novel concept for IBD pathogenesis and the function of oligosaccharides on immune cells, termed "glyco immunology". PMID- 28338837 TI - Associations of Leukocyte Telomere Length With Aerobic and Muscular Fitness in Young Adults. AB - Decline in both telomere length and physical fitness over the life course may contribute to increased risk of several chronic diseases. The relationship between telomere length and aerobic and muscular fitness is not well characterized. We examined whether there are cross-sectional associations of mean relative leukocyte telomere length (LTL) with objective measures of aerobic fitness, muscle strength, and muscle endurance, using data on 31-year-old participants of the Northern Finland Birth Cohort 1966 (n = 4,952-5,205, varying by exposure-outcome analysis). Aerobic fitness was assessed by means of heart rate measurement following a standardized submaximal step test; muscular fitness was assessed by means of a maximal isometric handgrip strength test and a test of lower-back trunk muscle endurance. Longer LTL was associated with higher aerobic fitness and better trunk muscle endurance in models including adjustment for age, sex, body mass index, socioeconomic position, diet, smoking, alcohol consumption, physical activity level, and C-reactive protein. In a sex-stratified analysis, LTL was not associated with handgrip strength in either men or women. LTL may relate to aspects of physical fitness in young adulthood, but replication of these findings is required, along with further studies to help assess directions and causality in these associations. PMID- 28338839 TI - Alternative Approaches to Assessing Nonresponse Bias in Longitudinal Survey Estimates: An Application to Substance-Use Outcomes Among Young Adults in the United States. AB - We evaluated alternative approaches to assessing and correcting for nonresponse bias in a longitudinal survey. We considered the changes in substance-use outcomes over a 3-year period among young adults aged 18-24 years (n = 5,199) in the United States, analyzing data from the National Epidemiologic Survey on Alcohol and Related Conditions. This survey collected a variety of substance-use information from a nationally representative sample of US adults in 2 waves: 2001 2002 and 2004-2005. We first considered nonresponse rates in the second wave as a function of key substance-use outcomes in wave 1. We then evaluated 5 alternative approaches designed to correct for nonresponse bias under different attrition mechanisms, including weighting adjustments, multiple imputation, selection models, and pattern-mixture models. Nonignorable attrition in a longitudinal survey can lead to bias in estimates of change in certain health behaviors over time, and only selected procedures enable analysts to assess the sensitivity of their inferences to different assumptions about the extent of nonignorability. We compared estimates based on these 5 approaches, and we suggest a road map for assessing the risk of nonresponse bias in longitudinal studies. We conclude with directions for future research in this area given the results of our evaluations. PMID- 28338838 TI - Cohort Profile: The Hepatitis C Virus (HCV) Research UK Clinical Database and Biobank. PMID- 28338840 TI - Differences in functional and xylem anatomical features allow Cistus species to co-occur and cope differently with drought in the Mediterranean region. AB - A significant increase in drought events frequency is predicted for the next decades induced by climate change, potentially affecting plant species mortality rates and distributions worldwide. The main trigger of plant mortality is xylem hydraulic failure due to embolism and induced by the low pressures at which water is transported through xylem. As the Mediterranean basin will be severely affected by climate change, the aim of this study was to provide novel information about drought resistance and tolerance of one of its most widely distributed and common genera as a case study: the genus Cistus. Different functional and anatomical traits were evaluated in four co-occurring Cistus species in the Mediterranean Montado ecosystem. Soil water availability for each species was also assessed to evaluate if they show different ecological niches within the area. Results showed physiological and xylem anatomical differences between the four co-occurring species, as well as in the soil water availability of the sites they occupy. Despite the significant differences in embolism resistance across species, no trade-off between hydraulic safety and efficiency was observed. Interestingly, species with narrower vessels showed lower resistance to embolism than those with higher proportions of large conduits. No correlation, however, was observed between resistance to embolism and wood density. The four species showed different water-use and drought-tolerance strategies, occupying different ecological niches that would make them cope differently with drought. These results will allow us to improve the predictions about the expected changes in vegetation dynamics in this area due to ongoing climate change. PMID- 28338841 TI - OUT-OF-FIELD DOSE MEASUREMENTS FOR 3D CONFORMAL AND INTENSITY MODULATED RADIOTHERAPY OF A PAEDIATRIC BRAIN TUMOUR. AB - The purpose of this study was to measure out-of-field organ doses in clinical conditions in anthropomorphic paediatric phantoms which received a simulated treatment of a brain tumour with intensity modulated radiotherapy (IMRT) and 3D conformal radiotherapy (3D CRT). Organ doses measured with radiophotoluminescent and thermoluminescent dosemeters were on average 1.6 and 3.0 times higher for the 5 y-old than for the 10 y-old phantom for IMRT and 3D CRT, respectively. A larger 5-y to 10-y organ dose ratio for 3D CRT can be explained because the use of a mechanical wedge for the 5-y-old 3D CRT phantom treatment increased out-of-field doses. Due to different configurations of the radiation fields, for both phantoms, the IMRT technique resulted in a higher non-target brain dose and higher eye doses but lower thyroid doses compared to 3D CRT. For 3D CRT (which used a non-coplanar field configuration), eye doses were 3-6% and for IMRT (which used a coplanar field configuration) 27-30% of the treatment dose, respectively. For thyroid and more distant organs, doses were less than 1% of the treatment dose. Comparison of measured doses and doses calculated by the treatment planning system (TPS) showed that the TPS underestimated out-of-field doses both for IMRT and 3D CRT. PMID- 28338842 TI - Personal Exposimeter for Radiation Assessment in Real Environments in the 60-GHz Band. AB - For the first time, a personal exposimeter (PEX) for 60 GHz radiation measurements is presented. The PEX is designed based on numerical simulations and both on-body and on-phantom calibration measurements to determine the antenna aperture and measurement uncertainty of the PEX. The measurement uncertainty of the PEX is quantified in terms of 50 and 95% prediction intervals of its response. A PEX consisting of three nodes (antennas) with VHH (vertical horizontal-horizontal) polarization results in a 95% prediction interval of 6.6 dB. A 50% prediction interval of 1.3 dB (factor of 1.3) is obtained for measured power densities which is 3.1 dB lower than a single antenna experiment. The uncertainty is 19.7 dB smaller than that of existing commercial exposimeters at lower frequencies (<=6GHz). PMID- 28338843 TI - VanderWeele et al. Respond to "Church Attendance and Mortality". PMID- 28338844 TI - RE: "INVITED COMMENTARY: BEWARE THE TEST-NEGATIVE DESIGN". PMID- 28338845 TI - Computational Psychiatry and the Challenge of Schizophrenia. AB - Schizophrenia research is plagued by enormous challenges in integrating and analyzing large datasets and difficulties developing formal theories related to the etiology, pathophysiology, and treatment of this disorder. Computational psychiatry provides a path to enhance analyses of these large and complex datasets and to promote the development and refinement of formal models for features of this disorder. This presentation introduces the reader to the notion of computational psychiatry and describes discovery-oriented and theory-driven applications to schizophrenia involving machine learning, reinforcement learning theory, and biophysically-informed neural circuit models. PMID- 28338846 TI - PATIENT EXPOSURE DURING PLAIN RADIOGRAPHY AND MAMMOGRAPHY IN JAPAN IN 1974-2014. AB - We investigated changes in the entrance skin dose (ESD) and the mean glandular dose (MGD) during plain radiography or mammography in Japan from 1974 to 2014. Surveys regarding the conditions used for plain radiography and mammography were performed throughout Japan in 1974, 1979, 1989, 1993, 1997, 2001, 2003, 2007, 2011 and 2014. The anatomical regions considered were categorised as follows: skull anteroposterior (AP), lumbar AP, lumbar lateral (LAT), pelvis (AP), ankle, chest posteroanterior (PA), Guthmann (lateral pelviography for pregnant women), infant hip joint and mammography. The doses for all anatomical regions decreased from 1974 to 1993. The MGD for mammography remained low from 1993 to 2014, and the ESDs for chest (PA) radiography trended upward. After the 2000s, the use of digital imaging increased in Japan. This is the first long-term study to examine changes in ESDs and MGDs in Japan. PMID- 28338847 TI - Paradigm shift from diagnosing patients based on common symptoms to categorizing patients into subtypes with different pathogenic mechanisms to guide treatment for Alzheimer's disease. AB - Alzheimer's disease (AD) is a major cause of dementia in the elderly, and the number of AD patients is rapidly growing as life expectancy increases. However, disease-modifying drugs are not yet available. According to the amyloid hypothesis, disease onset is triggered by aggregation and accumulation of amyloid beta peptide, followed by the formation of neurofibrillary tangles composed of hyperphosphorylated tau, and synaptic loss/neuronal cell death leading to dementia. Based on this hypothesis, various clinical trials for treatment of AD have been conducted, but most were discontinued due to failure to achieve cognitive improvement or appearance of adverse effects. Here we discuss the reasons for the failure of these trials. We suggest that biomarkers of specific, distinct molecular mechanisms of amyloidogenesis should be developed concomitantly with disease-modifying drugs (the so-called companion diagnosis) to aid the proper design of clinical trials, as well as to enable personalized treatment of individual AD patients. PMID- 28338848 TI - Silent lives: why do we fail community-dwelling people with dementia? PMID- 28338849 TI - A preventative lifestyle intervention for older adults (lifestyle matters): a randomised controlled trial. AB - Objectives: to test whether an occupation-based lifestyle intervention can sustain and improve the mental well-being of adults aged 65 years or over compared to usual care, using an individually randomised controlled trial. Participants: 288 independently living adults aged 65 years or over, with normal cognition, were recruited from two UK sites between December 2011 and November 2015. Interventions: lifestyle Matters is a National Institute for Health and Care Excellence recommended multi-component preventive intervention designed to improve the mental well-being of community living older people at risk of decline. It involves weekly group sessions over 4 months and one to one sessions. Main outcome measures: the primary outcome was mental well-being at 6 months (mental health (MH) dimension of the SF-36). Secondary outcomes included physical health dimensions of the SF-36, extent of depression (PHQ-9), quality of life (EQ 5D) and loneliness (de Jong Gierveld Loneliness Scale), assessed at 6 and 24 months. Results: data on 262 (intervention = 136; usual care = 126) participants were analysed using intention to treat analysis. Mean SF-36 MH scores at 6 months differed by 2.3 points (95 CI: -1.3 to 5.9; P = 0.209) after adjustments. Conclusions: analysis shows little evidence of clinical or cost-effectiveness in the recruited population with analysis of the primary outcome revealing that the study participants were mentally well at baseline. The results pose questions regarding how preventive interventions to promote well-being in older adults can be effectively targeted in the absence of proactive mechanisms to identify those who at risk of decline. Trial Registration: ISRCTN67209155. PMID- 28338850 TI - Photo-documentation in the community: reflections on genetics, health and health disparities. PMID- 28338851 TI - Do-not-resuscitate orders and early mortality in hip fracture patients. AB - Background: factors affecting mortality after hip fracture surgery have been studied extensively. It has been suggested that do-not-resuscitate (DNR) orders are associated with higher mortality in surgical patients due to less aggressive treatment. However, the effect of DNR orders on mortality in hip fracture patients is unknown. The objective of this study was to investigate the effect of DNR orders on early mortality after hip fracture surgery. Methods: all patients undergoing hip fracture surgery between 2004 and 2015 were included in this retrospective study. Patient characteristics such as age, comorbidities and fracture type were collected, as were resuscitation preferences. Multivariable logistic regression analysis was performed to identify independent risk factors for early mortality. Results: a total of 1,803 patients were analysed, of which 823 (45.6%) had DNR orders. DNR patients were older, more often female, had lower haemoglobin levels and more comorbidities when compared with non-DNR patients. The unadjusted effect of DNR orders on mortality was high (OR: 2.39; P < 0.001). Multivariable analysis demonstrated that increased age, male gender, higher American Society of Anesthesiologists score, low admission haemoglobin, living in an institution, high Charlson Comorbidity Index and delay to surgery were associated with increased early mortality after hip fracture surgery. There was no independent effect of DNR orders on mortality after adjustment for these variables (P = 0.735). Conclusions: DNR patients have higher mortality rates due to poor health status. Resuscitation preferences on their own are not associated with early mortality after hip fracture surgery. PMID- 28338852 TI - THE GROWTH OF BIOSTATISTICS AND ESTIMATION OF CANCER RISK ESTIMATES: PAST, CURRENT, AND FUTURE CHALLENGES. AB - There has been a long process of growth and development of statistical approaches to the analysis of cancer incidence and mortality data obtained from the follow up of radiation exposed populations. The challenges of radiation risk analysis provided impetus for innovative statistical methods, including, the inception and continued improvement of hazard rate regression methods. Key statistical contributions that improved cancer risk estimation include statistical advances pertaining to the measurement error problem. Current statistical problems involve extensions of the measurement error methods to account for shared non-independent uncertainties in dose estimation, 'transportability' of risk coefficients for radioprotection and risk estimation world-wide, and extrapolation from high dose rate to low-dose rate exposures or from low LET to high LET. Future problems include quantification of individual sensitivity to radiation-related diseases due to individual genetic differences (or other factors), and in understanding the synergy (additive, multiplicative, etc.) between underlying individual risk and radiation exposure. PMID- 28338853 TI - RADIOLOGICAL IMPACTS ASSESSMENT FOR WORKERS IN CERAMIC INDUSTRY IN SERBIA. AB - Studies have been carried out to determine the natural radioactivity in some materials used in ceramic industry (zircon, zirkosil, Zircobit MO/S, zircon silicate, zirklonil frit, hematite, bentonite, wollastonite, raw kaolin, kaolinized granite, sileks ball, feldspar, pigment, white base serigraphic, engobe) and their associated radiation hazard. The external hazard index, Hex, values, radium equivalent activity, Raeq, total absorbed dose rates, D and annual effective dose, De were derived for all measured materials and compared with the recommended values to assess the external radiation hazards to workers who worked in ceramic industries in Serbia. PMID- 28338854 TI - COMPARISON OF THE PERIPHERAL DOSES FROM DIFFERENT IMRT TECHNIQUES FOR PEDIATRIC HEAD AND NECK RADIATION THERAPY. AB - Intensity-modulated radiation therapy (IMRT) can deliver high and homogeneous doses to the target area while limiting doses to organs at risk. We used a pediatric phantom to simulate the treatment of a head and neck tumor in a child. The peripheral doses were examined for three different IMRT techniques [dynamic multileaf collimator (DMLC), segmental multileaf collimator (SMLC) and volumetric modulated arc therapy (VMAT)]. Peripheral doses were evaluated taking thyroid, breast, ovary and testis as the points of interest. Doses were determined using a radio-photoluminescence glass dosemeter, and the COMPASS system was used for three-dimensional dose evaluation. VMAT achieved the lowest peripheral doses because it had the highest monitor unit efficiency. However, doses in the vicinity of the irradiated field, i.e. the thyroid, could be relatively high, depending on the VMAT collimator angle. DMLC and SMLC had a large area of relatively high peripheral doses in the breast region. PMID- 28338855 TI - Improving crop performance under drought - cross-fertilization of disciplines. PMID- 28338856 TI - Care home leadership: action is needed. PMID- 28338857 TI - Invited Commentary: Explaining the Relationship Between Attending Worship Services and Mortality-A Brief Excursion Into the Contribution of Social Relationships in Religious Institutions. AB - In this issue of the Journal, VanderWeele et al. (Am J Epidemiol. 2017;000(00):000-000) report that more frequent attendance at worship services is associated with a lower mortality risk. However, the underlying processes that might explain this relationship were not discussed fully. A problem arises because the potentially beneficial association between attending worship services and mortality risk may be due to a number of different factors. At least part of the explanation may be found by turning to social relationships that arise in religious institutions. Within this context, there are potentially important benefits of providing social support to others. Support can be provided in several ways that involve potentially important health-related associations. In this commentary, I briefly examine the possible relationships between religious social support systems and other dimensions of congregational life and health. In depth conceptual analyses are needed to move research in religious involvement and mortality to the next level. PMID- 28338858 TI - Commentary: On H. J. Muller's insights into the gene in 1912. PMID- 28338859 TI - The healthy Nordic diet predicts muscle strength 10 years later in old women, but not old men. AB - Background: a number of nutrients have been found to be associated with better muscle strength and mass; however, the role of the whole diet on muscle strength and mass remains still unknown. Objective: to examine whether the healthy Nordic diet predicts muscle strength, and mass 10 years later among men and women. Methods: about 1,072 participants belong to the Helsinki Birth Cohort Study, born 1934-44. Diet was assessed with a validated food-frequency questionnaire during 2001-04. The Nordic diet score (NDS) was calculated. The score included Nordic fruits, vegetables, cereals, ratio of polyunsaturated to saturated fatty acids, low-fat milk, fish, red meat, total fat and alcohol. Higher scores indicated better adherence to the healthy Nordic diet. Hand grip strength, leg strength (knee extension) and muscle mass were measured during the follow-up, between 2011 and 2013. Results: in women, each 1-unit increase in the NDS was related to 1.83 N greater leg strength (95% confidence interval [CI] 0.14-3.51; P = 0.034), and 1.44 N greater hand grip strength (95% CI: 0.04-2.84; P = 0.044). Women in the highest quartile of the NDS had on average 20.0 N greater knee extension results, and 14.2 N greater hand grip results than those in the lowest quartile. No such associations were observed among men. The NDS was not significantly related to muscle mass either in men or women. Conclusions: adherence to the healthy Nordic diet seems to protect from weaker muscle strength in old women. Therefore, the healthy Nordic diet may help to prevent disability. PMID- 28338860 TI - CALCULATION OF SKIN DOSE DUE TO BETA CONTAMINATION USING THE NEW QUANTITY OF THE ICRP 116: THE 'LOCAL SKIN DOSE'. AB - Values of the new protection quantity 'Local Skin Dose' LSD, introduced by the International Commission on Radiological Protection (ICRP) Publication 116, were calculated for 134 beta- or beta+ emitting radionuclides, using the Monte Carlo code MCNP6. Two types of source geometry are considered: a point source and disc type surface contamination (the source is placed in contact with the skin). This new protection quantity is compared with the operational quantity H'(0.07,0 degrees ), leading us to conclude that, in accordance with the rules of the ICRP, the operational quantity over-estimates the protection quantity to a reasonable extent, except in very rare cases for very low average beta energies. Thus, with the new skin model described in ICRP 116, there are no longer any major differences between the operational quantities and protection quantities estimated with the skin model described in ICRP 74. PMID- 28338861 TI - Assessment of direct interaction between CD36 and an oxidized glycerophospholipid species. AB - Cluster of differentiation 36 (CD36) is a transmembrane protein that recognizes multiple diverse ligands. It is believed that (i) oxidized glycerophosphatidylcholine species having a terminal gamma-hydroxyl(or oxo) alpha,beta-unsaturated carbonyl on the sn-2 acyl group (oxGPCCD36), which can occur on the surface of lipoprotein particles, serve as high-affinity ligands for CD36, and (ii) the amino acid 150-168 of CD36 (CD36150-168) is responsible for recognizing oxGPCCD36. However, it remains uncertain whether CD36150-168 directly interacts with oxGPCCD36 alone. In this study, we addressed this issue by investigating and comparing the banding pattern by non-denaturing polyacrylamide gel electrophoresis of a glutathione S-transferase (GST) fusion protein containing CD36150-168 (GST-CD36150-168), in the presence and absence of an oxGPCCD36 species, 1-(palmitoyl)-2-(5-keto-6-octenedioyl)phosphatidylcholine (KOdiA-PC). It was shown that GST-CD36150-168 pre-incubated with KOdiA-PC produced bands at upper positions than did the fusion protein alone. Further analyses revealed that the bands produced by the loading of GST-CD36150-168/KOdiA PC mixture represent complexes consisting of the fusion protein and lipid. To our knowledge, this is the first evidence for direct interaction between CD36150-168 and oxGPCCD36 alone. It is also notable that the electrophoresis-based technique provides a convenient means to evaluate protein-lipid interactions. PMID- 28338862 TI - Family aggregation of cardiovascular disease mortality: a register-based prospective study of pooled Nordic twin cohorts. AB - Background: Familial factors play an important role in the variation of risk factors of cardiovascular diseases (CVD), but less is known about how they affect the risk of death from CVD. We estimated familial aggregation of CVD mortality for twins offering the maximum level of risk due to genetic and other familial factors. Methods: Altogether, 132 771 twin individuals, including 65 196 complete pairs from Denmark, Finland and Sweden born in 1958 or earlier, participated in this study. During the register-based follow-up, 11 641 deaths occurred from coronary heart disease (CHD), including 6280 deaths from myocardial infarct and 4855 deaths occurred from stroke, with 1092 deaths from ischaemic stroke and 1159 deaths from haemorrhagic stroke. Relative recurrence risk ratios (RRRs) with 95% confidence intervals (95% CIs) for monozygotic and dizygotic twins were calculated. Results: In the analyses pooling men and women, the RRR for monozygotic twins was 1.49 (95% CI 1.40-1.57) for CHD and 1.81 for any stroke (95% CI 1.54-2.09). The highest RRR was found for haemorrhagic stroke (3.53 95% CI 2.01-5.04). For dizygotic twins, the RRRs were generally lower. Conclusions: Family aggregation was found for CHD and haemorrhagic stroke. Clustering of risk factors in families increases the risk of CVD. PMID- 28338863 TI - Attendance at Religious Services, Prayer, Religious Coping, and Religious/Spiritual Identity as Predictors of All-Cause Mortality in the Black Women's Health Study. AB - Previous longitudinal studies have consistently shown an association between attendance at religious services and lower all-cause mortality, but the literature on associations between other measures of religion and spirituality (R/S) and mortality is limited. We followed 36,613 respondents from the Black Women's Health Study from 2005 through December 31, 2013 to assess the associations between R/S and incident all-cause mortality using proportional hazards models. After control for numerous demographic and health covariates, together with other R/S variables, attending religious services several times per week was associated with a substantially lower mortality rate ratio (mortality rate ratio = 0.64, 95% confidence interval: 0.51, 0.80) relative to never attending services. Engaging in prayer several times per day was not associated with mortality after control for demographic and health covariates, but the association trended towards a higher mortality rate ratio when control was made for other R/S variables (for >2 times/day vs. weekly or less, mortality rate ratio = 1.28, 95% confidence interval: 0.99, 1.67; P-trend < 0.01). Religious coping and self-identification as a very religious/spiritual person were associated with lower mortality when adjustment was made only for age, but the association was attenuated when control was made for demographic and health covariates and was almost entirely eliminated when control was made for other R/S variables. The results indicate that service attendance was the strongest R/S predictor of mortality in this cohort. PMID- 28338864 TI - Lysine acetylation regulates the activity of Escherichia coli pyridoxine 5' phosphate oxidase. PMID- 28338865 TI - ASSESSMENT OF PUBLIC EXPOSURE FORM WLANS IN THE WEST BANK-PALESTINE. AB - A total of 271 measurements were conducted at 69 different sites including homes, hospitals, educational institutions and other public places to assess the exposure to radiofrequency emission from wireless local area networks (WLANs). Measurements were conducted at different distances from 40 to 10 m from the access points (APs) in real life conditions using Narda SRM-3000 selective radiation meter. Three measurements modes were considered at 1 m distance from the AP which are transmit mode, idle mode, and from the client card (laptop computer). All measurements were conducted indoor in the West Bank environment. Power density levels from WLAN systems were found to vary from 0.001 to ~1.9 MUW cm-2 with an average of 0.12 MUW cm-2. Maximum value found was in university environment, while the minimum was found in schools. For one measurement case where the AP was 20 cm far while transmitting large files, the measured power density reached a value of ~4.5 MUW cm-2. This value is however 221 times below the general public exposure limit recommended by the International Commission on Non-Ionizing Radiation Protection, which was not exceeded in any case. Measurements of power density at 1 m around the laptop resulted in less exposure than the AP in both transmit and idle modes as well. Specific absorption rate for the head of the laptop user was estimated and found to vary from 0.1 to 2 mW/kg. The frequency distribution of measured power densities follows a log-normal distribution which is generally typical in the assessment of exposure resulting from sources of radiofrequency emissions. PMID- 28338866 TI - The growing challenge of major trauma in older people: a role for comprehensive geriatric assessment? AB - In this commentary article, we describe the impact that an ageing population is having on the nature of major trauma seen in emergency departments. The proportion of major trauma victims who are older people is rapidly increasing and a fall from standing is now the most common mechanism of injury in major trauma. Potential barriers to effective care of this patient group are highlighted, including: a lack of consensus regarding triage criteria; potentially misleading physiological parameters within triage criteria; non-linear patient presentations and diagnostic nihilism. We argue that the complex ongoing care and rehabilitation needs of older patients with major trauma may be best met through Comprehensive Geriatric Assessment (CGA). Furthermore, the use of frailty screening tools may facilitate more informed early decision-making in relation to treatment interventions in older trauma victims. We call for geriatric medicine and emergency medicine departments to collaborate-equipping urgent care staff with the basic competencies necessary to initiate CGA should be a priority, and geriatricians have a key role to play in delivery of such educational interventions. PMID- 28338867 TI - Elevated Blood Pressure in Children of Cardiovascular Risk Mothers: Could Maternal Folic Acid Be the Link? PMID- 28338868 TI - EFFECTS OF FIELD SIZE AND DEPTH ON PHOTONEUTRON DOSE EQUIVALENT DISTRIBUTIONS IN AN 18 MV X-RAY MEDICAL ACCELERATOR. AB - Photoneutron (PN) dosimetry studies in high-energy X-ray medical accelerators are of high clinical and scientific interest in particular to protect patients undergoing radiotherapy. In this context, fast, epithermal and thermal PN dose equivalent distributions in different field sizes and depths in air and in a multilayer polyethylene phantom were studied. Polycarbonate track dosemeters in contact with a 10B convertor (with or without cadmium cover) when electrochemically etched were applied. PN dose equivalents in air and on the surface of the phantom are linear functions of field size. PN depth dose equivalents versus depth in air at the central axis are almost constant. Fast, epithermal and thermal PN dose equivalent responses versus depth in phantom peak respectively at 0.0, ~3.0 and ~3.0 cm while that of the sum PN dose equivalent value (3.32 +/- 0.19 mSv.Gy-1) peaks at ~1 cm. These values confirm those of some studies but contract some others. PMID- 28338869 TI - MEASUREMENT OF ABSORPTION DOSE OUTSIDE IRRADIATION FIELD IN IMRT. AB - The absorption dose outside the irradiation field for prostate intensity modulated radiation therapy was measured and evaluated by comparison with calculated values of radiation treatment planning system (TPS). The values of TPS calculated were using Varian CLINAC21EX/Eclipse and TomoTherapy Planning System for constant irradiation time. The absorption dose was measured by placing a glass-element dosemeter in a human-bone enclosure phantom with a planning target volume inside the irradiation field. The organs at risk were the rectum, spinal cord, thyroid, eyeball and the left lung. The calculated values of TPS, Varian CLINAC21EX/Eclipse and TomoTherapy Planning System were calculated, up to 17 and 55 cm from the isocenter, respectively. The absorbed dose outside the irradiation field diverged with increased distance from the isocenter (Varian/Eclipse: p = 0.03, TomoTherapy Planning System: p = 0.25). The calculated values for the absorbed dose outside the irradiation field were underestimated. PMID- 28338871 TI - Renal Sympathetic Denervation: A Viable Option for Treating Resistant Hypertension. AB - Accumulating evidence from mainly uncontrolled clinical studies with various types of ablation catheters have shown that renal denervation (RDN) can be applied safely and is effective in lowering blood pressure (BP) in patients with treatment-resistant hypertension. Sustained BP lowering has been documented up to 3 years. Furthermore, RDN has been associated with regression of target organ damage, such as left ventricular hypertrophy, arterial stiffness, and others. Several studies indicate potential benefit in other common clinical conditions associated with increased sympathetic tone including chronic kidney disease and heart failure. However, the recently published Symplicity HTN-3 study, the largest and most rigorously designed sham-controlled clinical trial, while confirming the safety of the procedure, failed to demonstrate a BP lowering effect beyond that of a sham procedure in patients with resistant hypertension. Efforts to unravel the reasons for the discrepant results from Symplicity HTN-3 have focused on a range of potential confounders including anatomical and procedural aspects. Indeed, data from post-hoc analyses indicate that sufficient RDN may not have been achieved in the majority of patients in Symplicity HTN-3. Furthermore, recent evidence from human postmortem and functional animal studies revealed new insights into the anatomical distribution of renal nerves and their accessibility by intravascular approaches. Initial results from recent clinical trials integrating these important findings indeed seem to confirm that RDN remains a viable option for the treatment of hypertension. Thorough further investigations will be key to determine the true potential of RDN in clinical conditions characterized by increased sympathetic drive. PMID- 28338870 TI - StMYB44 negatively regulates phosphate transport by suppressing expression of PHOSPHATE1 in potato. AB - Phosphorus is an important macronutrient for plant growth, but often deficient in soil. To understand the molecular basis of the complex responses of potato (Solanum tuberosum L.) to phosphate (Pi) deficiency stress, the RNA-Seq approach was taken to identify genes responding to Pi starvation in potato roots. A total of 359 differentially expressed genes were identified, among which the Solanum tuberosum transcription factor gene MYB44 (StMYB44) was found to be down regulated by Pi starvation. StMYB44 was ubiquitously expressed in potato tissues and organs, and StMYB44 protein was exclusively localized in the nucleus. Overexpression of StMYB44 in potato resulted in lower accumulation of Pi in shoots. Transcriptomic analysis indicated that the abundance of S. tuberosum PHOSPHATE1 (StPHO1), a Pi transport-related gene, was reduced in StMYB44 overexpression lines. In contrast, knock-out of StMYB44 by a CRISPR/Cas9 system failed to increase transcription of StPHO1. Moreover, StMYB44 was found to interact in the nucleus with AtWRKY6, a known Arabidopsis transcription factor directly regulating PHO1 expression, and StWRKY6, indicating that StMYB44 could be a member of the regulatory complex controlling transcription of StPHO1. Taken together, our study demonstrates that StMYB44 negatively regulates Pi transport in potato by suppressing StPHO1 expression. PMID- 28338872 TI - Data-Gathering, Belief Flexibility, and Reasoning Across the Psychosis Continuum. AB - Background: There is evidence for a group of nonclinical individuals with full blown, persistent psychotic experiences (PEs) but no need-for-care: they are of particular importance in identifying risk and protective factors for clinical psychosis. The aim of this study was to investigate whether reasoning biases are related to PEs or need-for-care. Method: Two groups with persistent PEs (clinical; n = 74; nonclinical; n = 92) and a control group without PEs (n = 83) were compared on jumping-to-conclusions (JTC) and belief flexibility. A randomly selected subset of interviews (n = 104) was analyzed to examine differences in experiential and rational reasoning. Results: As predicted JTC was more common in the clinical than the other 2 groups. Unexpectedly no group differences were observed between clinical and nonclinical groups on measures of belief flexibility. However, the clinical group was less likely to employ rational reasoning, while the nonclinical group was more likely to use experiential reasoning plus a combination of both types of reasoning processes, compared to the other 2 groups. Conclusions: Reasoning biases differ in groups with PEs with and without need-for-care. JTC is associated with need-for-care rather than with PEs. The ability to invoke rational reasoning processes, together with an absence of JTC, may protect against pathological outcomes of persistent PEs. However, marked use of experiential reasoning is associated with the occurrence of PEs in both clinical and nonclinical groups. Implications for theory development, intervention and further research are discussed. PMID- 28338873 TI - Molecular dissection of the actin-binding ability of the fission yeast alpha actinin, Ain1, in vitro and in vivo. AB - A contractile ring (CR) is involved in cytokinesis in animal and yeast cells. Although several types of actin-bundling proteins associate with F-actin in the CR, their individual roles in the CR have not yet been elucidated in detail. Ain1 is the sole alpha-actinin homologue in the fission yeast Schizosaccharomyces pombe and specifically localizes to the CR with a high turnover rate. S. pombe cells lacking the ain1+ gene show defects in cytokinesis under stress conditions. We herein investigated the biochemical activity and cellular localization mechanisms of Ain1. Ain1 showed weaker affinity to F-actin in vitro than other actin-bundling proteins in S. pombe. We identified a mutation that presumably loosened the interaction between two calponin-homology domains constituting the single actin-binding domain (ABD) of Ain1, which strengthened the actin-binding activity of Ain1. This mutant protein induced a deformation in the ring shape of the CR. Neither a truncated protein consisting only of an N-terminal ABD nor a truncated protein lacking a C-terminal region containing an EF-hand motif localized to the CR, whereas the latter was involved in the bundling of F-actin in vitro. We herein propose detailed mechanisms for how each part of the molecule is involved in the proper cellular localization and function of Ain1. PMID- 28338874 TI - Does Fetal Growth Restriction Cause Later Obesity? Pitfalls in Analyzing Causal Mediators as Confounders. AB - Recent studies finding that small-for-gestational-age (SGA) birth is associated with increased adiposity in childhood and adulthood have been based on analyses "adjusting" for height, weight, or body mass index (BMI; weight (kg)/height (m)2) measured concurrently with the adiposity measurement. To assess the potential for bias due to overadjustment for a causal mediator, we compared 2 approaches to analyzing the association between SGA birth and adiposity outcomes (skinfold thicknesses and bioelectrical impedance measurement of body fat) at age 11.5 years using the same data set in a cohort of Belarusian children followed from birth in 1996-1997 to age 11.5 years in 2008-2010. We 1) studied the association of SGA birth with adiposity, adjusting for baseline covariates only, and 2) made additional regression adjustment for concurrent height, weight, or BMI. The first approach yielded negative associations between SGA birth and all adiposity outcomes. Additional adjustment for concurrent weight or BMI reversed (i.e., to positive) the SGA-adiposity association. To explore the latter anthropometric measures as causal mediators, we also used marginal structural models to estimate the controlled direct effect of SGA birth. That effect was similar to the effect seen with the first approach when modeled on height, was null when modeled on BMI, but was confounded by differences in lean mass versus fat mass when modeled on weight. PMID- 28338875 TI - Does baseline hypotension predict incident depression in a cohort of community dwelling older people? Data from The Irish Longitudinal Study on Ageing (TILDA). AB - Background: hypotension is now recognised as a risk factor for syncope, cardiovascular events and mortality, but it may also represent a risk factor for late life depression (LLD). The aim of this study was to clarify the longitudinal relationship between hypotension and incident LLD. Methods: this is a longitudinal study involving community-dwelling participants aged >=50 years, using data from The Irish Longitudinal Study on Ageing. The Centre for Epidemiological Studies Depression Scale (CES-D) was administered at baseline and at follow-up 2 years later. Blood pressure (BP) was measured at baseline. Participants with a CES-D score >=16 at baseline and those taking antidepressants were excluded and considered to have a current diagnosis of depression. A score of >=16 at follow-up was used to define incident depression. Results: about 4,525 participants were included and 200 participants had diagnosis of incident LLD. The incident depression group had lower systolic BP at baseline than the non depressed group (132.8 +/- 1.43 mm Hg vs. 136.0 +/- 0.30 mm HG, P = 0.025). Logistic regression showed those with systolic BP <130 mm HG had an unadjusted odds ratio of 1.31 (1.01-1.68) for incident depression. This persisted after adjustment for confounding factors. Conclusion: systolic BP <130 mm Hg increased the likelihood of incident depression in a cohort of community-dwelling older adults. These findings are important because systolic hypotension may represent a potentially modifiable risk factor for LLD. They are also relevant in the context of BP treatment targets for older people. PMID- 28338877 TI - Data Resource Profile: National electronic medical record data from the Canadian Primary Care Sentinel Surveillance Network (CPCSSN). PMID- 28338876 TI - Subcellular localization of Arabidopsis arogenate dehydratases suggests novel and non-enzymatic roles. AB - Arogenate dehydratases (ADTs) catalyze the final step in phenylalanine biosynthesis in plants. The Arabidopsis thaliana genome encodes a family of six ADTs capable of decarboxylating/dehydrating arogenate into phenylalanine. Using cyan fluorescent protein (CFP)-tagged proteins, the subcellular localization patterns of all six A. thaliana ADTs were investigated in intact Nicotiana benthamiana and A. thaliana leaf cells. We show that A. thaliana ADTs localize to stroma and stromules (stroma-filled tubules) of chloroplasts. This localization pattern is consistent with the enzymatic function of ADTs as many enzymes required for amino acid biosynthesis are primarily localized to chloroplasts, and stromules are thought to increase metabolite transport from chloroplasts to other cellular compartments. Furthermore, we provide evidence that ADTs have additional, non-enzymatic roles. ADT2 localizes in a ring around the equatorial plane of chloroplasts or to a chloroplast pole, which suggests that ADT2 is a component of the chloroplast division machinery. In addition to chloroplasts, ADT5 was also found in nuclei, again suggesting a non-enzymatic role for ADT5. We also show evidence that ADT5 is transported to the nucleus via stromules. We propose that ADT2 and ADT5 are moonlighting proteins that play an enzymatic role in phenylalanine biosynthesis and a second role in chloroplast division or transcriptional regulation, respectively. PMID- 28338878 TI - Risk of Diabetes After Hysterectomy With or Without Oophorectomy in Postmenopausal Women. AB - The aim of this study was to determine the associations between hysterectomy, bilateral salpingo-oophorectomy (BSO), and incidence of diabetes in postmenopausal women participating in the Women's Health Initiative (WHI), a series of trials conducted in the United States, during the period 1993-1998. A total of 67,130 postmenopausal women aged 50-79 years were followed for a mean of 13.4 years. Among them, 7,430 cases of diabetes were diagnosed. Multivariable Cox proportional hazards models were used to assess the association between hysterectomy/oophorectomy status and diabetes incidence. Compared with women without hysterectomy, women with hysterectomy had a significantly higher risk of diabetes (hazard ratio = 1.13, 95% confidence interval: 1.06, 1.21). The increased risk of diabetes was similar for women with hysterectomy only and for women with hysterectomy with concomitant BSO. Compared with hysterectomy alone, hysterectomy with BSO was not associated with additional risk of diabetes after stratification by age at hysterectomy and hormone therapy status. In our large, prospective study, we observed that hysterectomy, regardless of oophorectomy status, was associated with increased risk of diabetes among postmenopausal women. However, our data did not support the hypothesis that early loss of ovarian estrogens is a risk factor for type 2 diabetes. The modest increased risk of diabetes associated with hysterectomy may be due to residual confounding, such as the reasons for hysterectomy. PMID- 28338880 TI - The yield and feasibility of integrated screening for TB, diabetes and HIV in four public hospitals in Ethiopia. AB - Background: Our objective was to demonstrate the feasibility of integrated care for TB, HIV and diabetes mellitus (DM) in a pilot project in Ethiopia. Methods: Healthcare workers in four hospitals screened patients with TB for HIV and DM; patients with HIV for DM and TB; and patients with DM for TB. Fasting and random plasma glucose (RPG) tests were used to confirm the diagnosis of DM. We used screening checklists for TB and DM, and additional risk scoring criteria to identify patients at risk of DM. Results: Of 3439 study participants, 888 were patients with DM, 439 patients with TB and 2112 from HIV clinics. Six of the patients with DM had TB of whom five were already on treatment; and 141 (32.4%) patients with TB had DM, of whom only five were previously diagnosed with DM. Symptomatic patients and those with a risk score of 5 or more were about three times more likely to have abnormal blood glucose level. Of 2075 HIV patients with RPG determined, only 31 (1.5%) had abnormal RPG. Conclusions: Tri-directional screening was feasible for detecting and managing previously undiagnosed TB and DM. More work is needed to better understand the interaction between HIV and DM. PMID- 28338879 TI - Evidence for Detection Bias by Medication Use in a Cohort Study of Breast Cancer Survivors. AB - In previous studies, we found modestly decreased and increased risks of second breast cancer events with the use of statins and antibiotics, respectively, after adjustment for surveillance mammography. We evaluated detection bias by comparing receipt of surveillance mammography among users of these 2 disparate classes of medication. Adult women diagnosed with early-stage breast cancer during 1990-2008 (n = 3,965) while enrolled in an integrated health-care plan (Group Health Cooperative; Washington State) were followed for up to 10 years in the Commonly Used Medications and Breast Cancer Outcomes (COMBO) Study. Categories of antibiotic use included infrequent (1-3 dispensings/12 months) and frequent (>=4 dispensings/12 months) use, and categories of statin use included less adherent (1 dispensing/6 months) and adherent (>=2 dispensings/6 months). We examined associations between medication use and surveillance mammography using multivariable generalized estimating equations and evaluated the impact of adjusting for surveillance within Cox proportional hazard models. Frequent antibiotic users were less likely to receive surveillance mammography (odds ratio (OR) = 0.90, 95% confidence interval (CI): 0.82, 0.99) than were nonusers; no association was found among infrequent users (OR = 0.96, 95% CI: 0.90, 1.03). Adherent statin use was associated with more surveillance compared with nonuse (OR = 1.11, 95% CI: 1.01, 1.25), but less adherent statin use was not (OR = 1.03, 95% CI: 0.81, 1.31). No difference in associations between medications of interest and second breast cancer events was observed when surveillance was removed from otherwise adjusted models. The influence of detection bias by medication use warrants further exploration. PMID- 28338881 TI - MdHB1 down-regulation activates anthocyanin biosynthesis in the white-fleshed apple cultivar 'Granny Smith'. AB - Coloration in apple (Malus*domestica) flesh is mainly caused by the accumulation of anthocyanin. Anthocyanin is biosynthesized through the flavonoid pathway and regulated by MYB, bHLH, and WD40 transcription factors (TFs). Here, we report that the HD-Zip I TF MdHB1 was also involved in the regulation of anthocyanin accumulation. MdHB1 silencing caused the accumulation of anthocyanin in 'Granny Smith' flesh, whereas its overexpression reduced the flesh content of anthocyanin in 'Ballerina' (red-fleshed apple). Moreover, flowers of transgenic tobacco (Nicotiana tabacum 'NC89') overexpressing MdHB1 showed a remarkable reduction in pigmentation. Transient promoter activation assays and yeast one-hybrid results indicated that MdHB1 indirectly inhibited expression of the anthocyanin biosynthetic genes encoding dihydroflavonol-4-reductase (DFR) and UDP glucose:flavonoid 3-O-glycosyltransferase (UFGT). Yeast two-hybrid and bimolecular fluorescence complementation determined that MdHB1 acted as a homodimer and could interact with MYB, bHLH, and WD40 in the cytoplasm, consistent with its cytoplasmic localization by green fluorescent protein fluorescence observations. Together, these results suggest that MdHB1 constrains MdMYB10, MdbHLH3, and MdTTG1 to the cytoplasm, and then represses the transcription of MdDFR and MdUFGT indirectly. When MdHB1 is silenced, these TFs are released to activate the expression of MdDFR and MdUFGT and also anthocyanin biosynthesis, resulting in red flesh in 'Granny Smith'. PMID- 28338882 TI - Tribal love: the neural correlates of passionate engagement in football fans. AB - The tribal character of the affective link between football fans and their teams is a well-recognized phenomenon. Other forms of love such as romantic or maternal attachment have previously been studied from a neuroimaging point of view. Here we aimed to investigate the neural basis of this tribal form of love, which implies both the feeling of belongingness and rivalry against opposing teams. A pool of 56 participants was submitted to an fMRI experimental design involving the presentation of winning and losing football moments of their loved, rival or neutral teams. We found recruitment of amygdala and reward regions, including the ventral tegmental area (VTA) and substantia nigra (SN), as well as other limbic regions involved in emotional cognition, for 'positive vs neutral' and 'positive vs negative' conditions. The latter contrast was correlated with neuropsychological scores of fanaticism in the amygdala and regions within the reward system, as the VTA and SN. The observation of increased response patterns in critical components of the reward system, in particular for positive content related to the loved team, suggests that this kind of non-romantic love reflects a specific arousal and motivational state, which is biased for emotional learning of positive outcomes. PMID- 28338884 TI - Erratum. PMID- 28338883 TI - The effects of oleanolic acid on atherosclerosis in different animal models. AB - In the present study, three animal models, including C57BL/6J mice, low-density lipoprotein receptor knockout (LDLR-/-) mice, and rabbit that mimicked atherosclerosis, were established to investigate the inhibitory effect of oleanolic acid (OA) on atherosclerosis. In rabbit model, serum total cholesterol (TC), triglyceride, low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C) were measured. Carotid artery lesions were isolated for histological analysis. The red oil O and hematoxylin-eosin staining in liver were examined. The messenger ribonucleicacid (mRNA) levels of PPARgamma, AdipoR1, and AdipoR2 related to lipid metabolism were determined. Compared with model group, OA and atorvastatin significantly lowered the levels of TC and LDL C. The result of red oil O staining showed that OA and atorvastatin had similar effect on reducing the accumulation of lipid. Histological result demonstrated that OA reduced the thickness of intima. AdipoR1 was markedly increased, while AdipoR2 was remarkably decreased in OA group compared with that in the control group of the rabbit model. In LDLR-/- mouse model, lipid parameters in blood and mRNA levels of PPARgamma, AdipoR1, and AdipoR2 were measured. It was found that OA exhibited similar effects as atorvastatin including reduced TG, LDL-C, and enhanced HDL-C. Notably, OA elevated the levels of AdipoR1 and PPARgamma. At the same time, OA decreased TC and LDL-C in C57BL/6J mice model. Our results in three different animal models all revealed that OA retarded the development of atherosclerosis by influencing serum lipid levels, lipid accumulation in liver and intimal thickening of artery. And the underlying mechanism of OA on atherosclerosis may involve in lipid metabolism genes: PPARgamma, AdipoR1, and AdipoR2. PMID- 28338885 TI - THE AUTHORS REPLY. PMID- 28338886 TI - RE: "RESIDENTIAL PROXIMITY TO TRAFFIC-RELATED POLLUTION AND ATHEROSCLEROSIS IN 4 VASCULAR BEDS AMONG AFRICAN-AMERICAN ADULTS: RESULTS FROM THE JACKSON HEART STUDY". PMID- 28338887 TI - Washing away your sins in the brain: physical cleaning and priming of cleaning recruit different brain networks after moral threat. AB - The association between moral purity and physical cleanliness has been widely discussed recently. Studies found that moral threat initiates the need of physical cleanliness, but actual physical cleaning and priming of cleaning have inconsistent effects on subsequent attitudes and behaviors. Here, we used resting state functional magnetic resonance imaging to explore the underlying neural mechanism of actual physical cleaning and priming of cleaning. After recalling moral transgression with strong feelings of guilt and shame, participants either actually cleaned their faces with a wipe or were primed with cleanliness through viewing its pictures. Results showed that actual physical cleaning reduced the spontaneous brain activities in the right insula and MPFC, regions that involved in embodied moral emotion processing, while priming of cleaning decreased activities in the right superior frontal gyrus and middle frontal gyrus, regions that participated in executive control processing. Additionally, actual physical cleaning also changed functional connectivity between insula/MPFC and emotion related regions, whereas priming of cleaning modified connectivity within both moral and sensorimotor areas. These findings revealed that actual physical cleaning and priming of cleaning led to changes in different brain regions and networks, providing neural evidence for the inconsistent effects of cleanliness on subsequent attitudes and behaviors. PMID- 28338888 TI - Vibration transmission of the spine during walking is different between the lumbar and thoracic regions in older adults. AB - Background: fractures occur more commonly in the thoracic than in the lumbar spine. Physical activity complemented with pharmacological interventions has been advocated as a preventive measure for osteoporosis. However, walking has been shown to produce only a small improvement in spinal bone mineral density. The characteristics of vibration transmission during walking at the lumbar and thoracic spines may be different, and this may help explain the relative incidence of fractures in the two spine regions. Objective: to determine how mechanical vibration is transmitted in the lumbar and thoracic spines in older adults with and without osteoporosis. Methods: 16 young healthy adults, 19 older adults without osteoporosis and 41 adults with osteoporosis were recruited. Inertial sensors were attached to the skin over the lumbar and thoracic spines for recording the vibration transmitted during level walking. Vibration characteristics were compared across lumbar and thoracic spines and across groups. Results: the lumbar spine generally amplified the vibration transmitted during walking, whereas the thoracic spine exhibited a much smaller amplification effect, except at the lowest frequency. The magnitude of vibration was generally reduced in the older spines. Osteoporosis had minimal effects on vibration transmission. Conclusions: the larger amplification of vibration in the lumbar spine may explain the lower incidence of vertebral fractures in this region when compared to the thoracic spine. Ageing alters the transmission of vibration in the spine while osteoporosis has minimal effects. Future research should determine the characteristics of vibration transmitted through the thoracic spine during other physical activities. PMID- 28338889 TI - Measuring Occupational Exposure to Extremely Low-Frequency Electric Fields at 220 kV Substations. AB - Earlier studies conducted at 400 and 110 kV substations in Finland have shown that the occupational exposure to electric fields can exceed the action levels (ALs) set by Directive 2013/35/EU. This is a case study investigating the level of occupational exposure experienced by workers at 220 kV substations in order to determine if the actions levels are being exceeded. The measurements were conducted at two old 220 kV substations in Finland. The higher AL of 20 kV m-1 was exceeded at both substations. PMID- 28338890 TI - Metabolic syndrome and insulin resistance are associated with frailty in older adults: a prospective cohort study. AB - Background: diabetes increases the risk of frailty that is a leading cause of disability and premature mortality in older people. Metabolic syndrome (MS) and insulin resistance (IR) are strong risk factors for diabetes and could, thus, lead to frailty. However, the association between MS or IR and frailty has barely been investigated. Methods: data were obtained from a cohort of 1,499 community dwelling individuals aged >=60, who were free of diabetes at 2008-10 and were followed up for 3.5 years. At baseline, MS was ascertained according to the harmonised definition, and IR with the Homoeostatic Model Assessment for IR index (HOMA-IR). Frailty was defined as having three or more of the Fried's criteria: exhaustion, low physical activity, slow walking, unintentional weight loss and low grip strength. Statistical analyses were performed with logistic regression, and adjusted for the main confounders. Results: in 2012, 84 cases of incident frailty were identified. Compared with subjects without MS, those with MS showed increased risk of frailty (multivariate odds ratio [OR]: 1.85; 95% confidence interval [CI] 1.12-3.05). The association persisted after further adjustment for fibrinogen and C-reactive protein. When the frailty criteria were considered individually, low grip strength was the criterion that showed a stronger association with MS (OR: 1.67; 95% CI: 1.25-2.21). Higher HOMA-IR values were also associated with higher risk of frailty. Conclusion: MS and IR were associated with increased risk of frailty. This work extends the spectrum of harmful consequences of MS, and suggests that preventing or controlling MS may serve to delay frailty. PMID- 28338891 TI - Associations of Statin Use With Colorectal Cancer Recurrence and Mortality in a Danish Cohort. AB - In earlier studies of the influence of hydroxymethylglutaryl-coenzyme A reductase inhibitors (also known as statins) on colorectal cancer prognosis, investigators reported a reduced rate of cancer-specific mortality. Studies of recurrence are few and small. Using data from Danish registries, we followed 21,152 patients diagnosed with stage I-III colorectal cancer from 2001 to 2011. We estimated the association between statin use in the preceding year and cancer recurrence, cancer-specific mortality, and all-cause mortality rates. We identified 5,036 recurrences, 7,084 deaths from any cause, and 4,066 deaths from colorectal cancer. After adjustment for potential confounders, statin use was not associated with recurrence (adjusted hazard ratio (aHR) = 1.01, 95% confidence interval (CI): 0.93, 1.09), but it was associated with death from colorectal cancer (aHR = 0.72, 95% CI: 0.65, 0.79) and death from any cause (aHR = 0.72, 95% CI: 0.67, 0.76). Statin use in the year preceding recurrence was associated with a reduced risk of cancer-specific mortality (aHR = 0.83, 95% CI: 0.74, 0.92) but also a reduced risk of death from any other cause (aHR = 0.78, 95% CI: 0.61, 1.00). Statin use was not associated with a reduced rate of colorectal cancer recurrence, but it was associated with a reduced rate of cancer-specific mortality, which suggests that there is no cancer-directed benefit; therefore, there is no basis to prescribe statins to colorectal cancer patients who do not have cardiovascular indications. PMID- 28338893 TI - Site-directed mutant libraries for isolating minimal mutations yielding functional changes. AB - Powerful, facile new ways to create libraries of site-directed mutants are demonstrated. These include: (1) one-pot-PCR, (2) multi-pot-PCR, and (3) split mix-PCR. One-pot-PCR uses mutant oligonucleotides to generate megaprimers in situ, and it was used to randomly incorporate 28 mutations in a gabT gene in a single reaction. In more difficult cases, multi-pot-PCR can be employed: mutant megaprimers are synthesized individually, then combined in a single mutagenesis PCR. This method was used to incorporate 14 out of 15 mutations in a pabB gene. Split-mix-PCR is a conceptually novel method for creation of site-directed mutant libraries. Separate PCRs for each mutant primer are performed, followed by pooling the products of the individual reactions. The pooled mixture is re aliquoted into individual mutant oligonucleotide PCRs. These steps are repeated for each cycle. Split-mix-PCR results in a nearly random distribution of mutation sites, and a distribution of number-of-mutations per gene that is computable and narrow. Split-mix-PCR was applied to the directed evolution of aminodeoxychorismate synthase into anthranilate synthase, and easily allowed the determination of the fewest mutations required for introduction of novel activity. PMID- 28338892 TI - Embodiment and Schizophrenia: A Review of Implications and Applications. AB - In recent decades, embodiment has become an influential concept in psychology and cognitive neuroscience. Embodiment denotes the study of the reciprocal (causal) relationships between mind and body, with the mind not only affecting the body but also vice versa. Embodied cognition comes to the fore in sensorimotor coupling, predictive coding, and nonverbal behavior. Additionally, the embodiment of the mind constitutes the basis of social interaction and communication, as evident in research on nonverbal synchrony and mimicry. These theoretical and empirical developments portend a range of implications for schizophrenia research and treatment. Sensorimotor dysfunctions are closely associated with affective and psychotic psychopathology, leading to altered timing in the processing of stimuli and to disordered appraisals of the environment. Problems of social cognition may be newly viewed as disordered embodied communication. The embodiment perspective suggests novel treatment strategies through psychotherapy and body-oriented interventions, and may ultimately provide biomarkers for diagnosis. PMID- 28338894 TI - ESTABLISHMENT OF RADIATION DOSES FOR PEDIATRIC X-RAY EXAMINATIONS IN A LARGE PEDIATRIC HOSPITAL IN TURKEY. AB - Pediatric patients are more sensitive to ionizing radiation when compared with adults. The aim of this study was to evaluate the radiation doses for some common pediatric x-ray examinations performed with various digital radiography systems. Quality control tests of the digital radiography systems were carried out according to international published protocols before the pediatric dose measurements. Radiation dose measurement was performed by using the x-ray tube outputs and thermoluminescent dosimeter dose measurement methods. In the present study, radiation doses were assessed for 247 chest, 230 pelvis, 194 skull and 73 abdomen x-ray examinations and in total 744 pediatric patients doses were measured. Pediatric patients were classified into four age groups 0-1, 1-5, 5-10 and 10-15 years as given by European Commission guidance. Effective doses were determined for each examination using a PCXMC 2.0 Monte Carlo program. The mean measured entrance skin doses for the age interval 1-5 years and AP projection by using tube output measurement methods were 149 uGy for chest, 304 uGy for pelvis, 387 uGy for skull and 199 uGy for abdomen examinations. The radiation dose results obtained in this study were in the range of the published results in the literature. PMID- 28338895 TI - Photosynthesis, nutrient accumulation and growth of two Betula species exposed to waterlogging in late dormancy and in the early growing season. AB - Increased risk of soil waterlogging in winter and spring at northern latitudes will potentially affect forest production in the future. We studied gas exchange, chlorophyll content index, chlorophyll fluorescence, nutrient concentration and biomass accumulation in 1-year-old silver (Betula pendula Roth) and pubescent birch (Betula pubescens Ehrh.) seedlings. We hypothesized that B. pubescens has different physiological mechanisms that make it tolerate waterlogging better than B. pendula. The treatments were: (i) no waterlogging throughout the experiment; (ii) 4-week waterlogging during dormancy (dormancy waterlogging 'DW'); (iii) 4 week waterlogging during the early growing season (growth waterlogging 'GW'); and (iv) 4-week DW followed by 4-week GW during the early growing season ('DWGW'). Stomatal conductance and light-saturated net assimilation rate were reduced by GW in both species, and in B. pubescens also by DW. However, recovery was seen during the follow-up growing season. In B. pendula, DW, GW and DWGW temporarily resulted in reduced stem biomass, and GW and DWGW caused reduced leaf biomass. In B. pubescens, the stem biomass was decreased in GW and DWGW. Leaf nitrogen (N) and phosphorus (P) concentrations were generally low, and increased by GW, while potassium, calcium, magnesium and to some extent, boron and zinc concentrations decreased in both species and additionally manganese in B. pendula. The increases in N and P are mostly due to a concentration effect due to smaller leaf biomass, yet suggest that their uptake was not impaired. The decreases in cation concentrations are likely to be connected to impaired root functioning, which was not yet fully recovered from GW. We conclude that morphological acclimation to waterlogging of the leaves and roots rather than photosynthesis explains why B. pubescens is able to grow better in wetter areas than B. pendula. PMID- 28338896 TI - Rapid Evolution of microRNA Loci in the Brown Algae. AB - Stringent searches for microRNAs (miRNAs) have so far only identified these molecules in animals, land plants, chlorophyte green algae, slime molds and brown algae. The identification of miRNAs in brown algae was based on the analysis of a single species, the filamentous brown alga Ectocarpus sp. Here, we have used deep sequencing of small RNAs and a recently published genome sequence to identify miRNAs in a second brown alga, the kelp Saccharina japonica. S. japonica possesses a large number of miRNAs (117) and these miRNAs are highly diverse, falling into 98 different families. Surprisingly, none of the S. japonica miRNAs share significant sequence similarity with the Ectocarpus sp. miRNAs. However, the miRNA repertoires of the two species share a number of structural and genomic features indicating that they were generated by similar evolutionary processes and therefore probably evolved within the context of a common, ancestral miRNA system. This lack of sequence similarity suggests that miRNAs evolve rapidly in the brown algae (the two species are separated by ~95 Myr of evolution). The sets of predicted targets of miRNAs in the two species were also very different suggesting that the divergence of the miRNAs may have had significant consequences for miRNA function. PMID- 28338898 TI - The hematopoietic cell-specific transcription factor PU.1 is critical for expression of CD11c. AB - PU.1 is a hematopoietic cell-specific transcription factor belonging to the Ets family, which plays an important role in the development of dendritic cells (DCs). CD11c (encoded by Itgax) is well established as a characteristic marker of hematopoietic lineages including DCs. In the present study, we analyzed the role of PU.1 (encoded by Spi-1) in the expression of CD11c. When small interfering RNA (siRNA) for Spi-1 was introduced into bone marrow-derived DCs (BMDCs), the mRNA level and cell surface expression of CD11c were dramatically reduced. Using reporter assays, the TTCC sequence at -56/-53 was identified to be critical for PU.1-mediated activation of the promoter. An EMSA showed that PU.1 directly bound to this region. ChIP assays demonstrated that a significant amount of PU.1 bound to this region on chromosomal DNA in BMDCs, which was decreased in LPS-stimulated BMDCs in accordance with the reduced levels of mRNAs of Itgax and Spi-1, and the histone acetylation degree. Enforced expression of exogenous PU.1 induced the expression of the CD11c protein on the cell surface of mast cells, whereas control transfectants rarely expressed CD11c. Quantitative RT-PCR also showed that the expression of a transcription factor Irf4, which is a partner molecule of PU.1, was reduced in PU.1-knocked down BMDCs. IRF4 transactivated the Itgax gene in a synergistic manner with PU.1. Taken together, these results indicate that PU.1 functions as a positive regulator of CD11c gene expression by directly binding to the Itgax promoter and through transactivation of the Irf4 gene. PMID- 28338897 TI - Specialized Information Processing Deficits and Distinct Metabolomic Profiles Following TM-Domain Disruption of Nrg1. AB - Although there is considerable genetic and pathologic evidence for an association between neuregulin 1 (NRG1) dysregulation and schizophrenia, the underlying molecular and cellular mechanisms remain unclear. Mutant mice containing disruption of the transmembrane (TM) domain of the NRG1 gene constitute a heuristic model for dysregulation of NRG1-ErbB4 signaling in schizophrenia. The present study focused on hitherto uncharacterized information processing phenotypes in this mutant line. Using a mass spectrometry-based metabolomics approach, we also quantified levels of unique metabolites in brain. Across 2 different sites and protocols, Nrg1 mutants demonstrated deficits in prepulse inhibition, a measure of sensorimotor gating, that is, disrupted in schizophrenia; these deficits were partially reversed by acute treatment with second, but not first-, generation antipsychotic drugs. However, Nrg1 mutants did not show a specific deficit in latent inhibition, a measure of selective attention that is also disrupted in schizophrenia. In contrast, in a "what-where when" object recognition memory task, Nrg1 mutants displayed sex-specific (males only) disruption of "what-when" performance, indicative of impaired temporal aspects of episodic memory. Differential metabolomic profiling revealed that these behavioral phenotypes were accompanied, most prominently, by alterations in lipid metabolism pathways. This study is the first to associate these novel physiological mechanisms, previously independently identified as being abnormal in schizophrenia, with disruption of NRG1 function. These data suggest novel mechanisms by which compromised neuregulin function from birth might lead to schizophrenia-relevant behavioral changes in adulthood. PMID- 28338899 TI - WORK PRACTICES AND RADIATION EXPOSURE AMONG MALE RADIOLOGIC TECHNOLOGISTS ASSISTING FLUOROSCOPICALLY GUIDED INTERVENTIONAL PROCEDURES. AB - This study investigated occupational characteristics and radiation exposure among radiologic technologists assisting fluoroscopically guided interventional (FGI) procedures. A nationwide survey of radiologic technologists in South Korea was conducted. Among 8058 male respondents, 664 (8.2%) assisted FGI procedures. The survey data were linked with dosimetry data from the National Dose Registry. Most radiologic technologists assisting FGI procedures were 30-40 years old and employed by general hospitals. These technologists worked in closer proximity to patients during procedures, less frequently used shield screens, more commonly utilized protective devices, and less commonly wore badge dosemeters than the ones not assisting FGI procedures. The average annual effective dose did not differ according to the performance of FGI procedures. The average cumulative effective dose among radiologic technologists assisting FGI procedures was significantly greater for those who had recently entered the field and personnel in rural areas than for those who did not assist these procedures. PMID- 28338900 TI - Exposure to the Chinese famine of 1959-61 in early life and long-term health conditions: a systematic review and meta-analysis. AB - Background: Most Chinese people over 55 years old today have experienced the Great Leap Forward Famine of 1959-61. Many reports suggested that the famine could have profound long-term health effects for exposed birth cohorts. A systematic review and meta-analysis was carried out to summarize reported famine effects on long-term health. Methods: Relevant reports were identified by searching PubMed, Embase, Chinese Wanfang Data and Chinese National Knowledge Infrastructure databases. Long-term health conditions were compared in exposed birth cohorts and unexposed controls. Fixed-effects models and random-effects models were used to combine results on adult overweight, obesity, type 2 diabetes, hyperglycaemia, hypertension, the metabolic syndrome and schizophrenia. The heterogeneity across reports was assessed. Subgroup analyses were carried out using reported famine severity, provincial mortality during famine, sex and other report characteristics. Results: In all, 36 reports were eligible for systematic review and 21 could be used for meta-analysis. The number of events we analysed ranged from 1029 for hyperglycaemia to 8973 for hypertension. As reported by others, overweight, type 2 diabetes, hyperglycaemia, the metabolic syndrome, and schizophrenia were more common among adults born during the famine compared with controls born after the famine. By contrast, there were no increases in overweight [odds ratio (OR) 0.68; 95% confidence interval (CI): 0.27-1.72], type 2 diabetes (OR 0.96; 95% CI: 0.73-1.28), hyperglycaemia (OR 0.99; 95% CI: 0.72 1.36) or the metabolic syndrome (OR 1.11; 95% CI: 1.00-1.22) comparing adults born during the famine with controls born either after or before the famine. For schizophrenia, the effect estimates (OR 1.60; 95% CI: 1.50-1.70, combining control groups) were similar in the two scenarios. Conclusions: Our findings suggest that uncontrolled age differences between famine and post-famine births could explain most effects commonly attributed to the famine. For more reliable estimates of long-term famine effects in China, other analyses will be needed with age-appropriate controls and better information on the severity and timing of the famine in the populations included. PMID- 28338901 TI - Characterization of the genuine type 2 chromatic acclimation in the two Geminocystis cyanobacteria. AB - Certain cyanobacteria can adjust the wavelengths of light they absorb by remodeling their photosynthetic antenna complex phycobilisome via a process called chromatic acclimation (CA). Although several types of CA have been reported, the diversity of the molecular mechanisms of CA among the cyanobacteria phylum is not fully understood. Here, we characterized the molecular process of CA of Geminocystis sp. strains National Institute of Environmental Studies (NIES) 3708 and NIES-3709. Absorption and fluorescence spectroscopy revealed that both strains dramatically alter their phycoerythrin content in response to green and red light. Whole-genome comparison revealed that the two strains share the typical phycobilisome structure consisting of a central core and peripheral rods, but they differ in the number of rod linkers of phycoerythrin and thus have differing capacity for phycoerythrin accumulation. RNA sequencing analysis suggested that the length of phycoerythrin rods in each phycobilisome is strictly regulated by the green light and red light-sensing CcaS/R system, whereas the total number of phycobilisomes is governed by the excitation-balancing system between phycobilisomes and photosystems. We reclassify the conventional CA types based on the genome information and designate CA of the two strains as genuine type 2, where components of phycoerythrin, but not rod-membrane linker of phycocyanin, are regulated by the CcaS/R system. PMID- 28338902 TI - Assessment of the Status of Measles Elimination in the United States, 2001-2014. AB - We assessed the status of measles elimination in the United States using outbreak notification data. Measles transmissibility was assessed by estimation of the reproduction number, R, the average number of secondary cases per infection, using 4 methods; elimination requires maintaining R at <1. Method 1 estimates R as 1 minus the proportion of cases that are imported. Methods 2 and 3 estimate R by fitting a model of the spread of infection to data on the sizes and generations of chains of transmission, respectively. Method 4 assesses transmissibility before public health interventions, by estimating R for the case with the earliest symptom onset in each cluster (Rindex). During 2001-2014, R and Rindex estimates obtained using methods 1-4 were 0.72 (95% confidence interval (CI): 0.68, 0.76), 0.66 (95% CI: 0.62, 0.70), 0.45 (95% CI: 0.40, 0.49), and 0.63 (95% CI: 0.57, 0.69), respectively. Year-to-year variability in the values of R and Rindex and an increase in transmissibility in recent years were noted with all methods. Elimination of endemic measles transmission is maintained in the United States. A suggested increase in measles transmissibility since elimination warrants continued monitoring and emphasizes the importance of high measles vaccination coverage throughout the population. PMID- 28338903 TI - Disulfide bridges as essential elements for the thermostability of lytic polysaccharide monooxygenase LPMO10C from Streptomyces coelicolor. AB - Lytic polysaccharide monooxygenases (LPMOs) are crucial components of cellulase mixtures but their stability has not yet been studied in detail, let alone been engineered for industrial applications. In this work, we have evaluated the importance of disulfide bridges for the thermodynamic stability of Streptomyces coelicolor LPMO10C. Interestingly, this enzyme was found to retain 34% of its activity after 2-h incubation at 80 degrees C while its apparent melting temperature (Tm) is only 51 degrees C. When its three disulfide bridges were broken, however, irreversible unfolding occurred and no residual activity could be detected after a similar heat treatment. Based on these findings, additional disulfide bridges were introduced, as predicted by computational tools (MOdelling of DIsulfide bridges in Proteins (MODiP) and Disulfide by Design (DbD)) and using the most flexible positions in the structure as target sites. Four out of 16 variants displayed an improvement in Tm, ranging from 2 to 9 degrees C. Combining the positive mutations yielded additional improvements (up to 19 degrees C) but aberrant unfolding patterns became apparent in some cases, resulting in a diminished capacity for heat resistance. Nonetheless, the best variant, a combination of A143C-P183C and S73C-A115C, displayed a 12 degrees C increase in Tm and was able to retain and was able to retain no less than 60% of its activity after heat treatment. PMID- 28338904 TI - Preeclampsia, Portliness, and Perturbation of Adipose Tissue Function-Are we Beginning to Connect the Dots? PMID- 28338905 TI - The Reverse J-Shaped Association Between Serum Total 25-Hydroxyvitamin D Concentration and All-Cause Mortality: The Impact of Assay Standardization. AB - We evaluated the impact of standardizing the originally measured serum total 25 hydroxyvitamin D (25(OH)D) values from Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994) on the association between 25(OH)D and rate of all-cause mortality. Values were standardized to the gold-standard laboratory method. Follow-up from 1990-2006 consisted of 15,099 participants aged at least 20 years at baseline, among whom there were 3,784 deaths. Relative risk of death was adjusted for age, sex, race/ethnicity, and season using Poisson regression. Results were obtained for eight 25(OH)D (nmol/L) categories: <20 nmol/L, 20-29 nmol/L, 30-39 nmol/L, 40-49 nmol/L, 50-59 nmol/L, 60-74 nmol/L, 75 99 nmol/L (reference), and >=100 nmol/L. Assay standardization dramatically shifted original 25(OH)D values toward zero. Accordingly, risk >=120 nmol/L could not be evaluated (i.e., n = 7 and ndeaths = 2). Relative risk (95% confidence interval (CI)) <40 nmol/L remained significant (30-39 nmol/L: relative risk (RR) = 1.4 (95% CI: 1.1, 1.6); 20-29 nmol/L: RR = 1.6 (95% CI: 1.3, 1.9), and <20 nmol/L: RR = 2.1 (95% CI: 1.6, 2.7). However, adjusted relative risk estimates for 25(OH)D levels >=40 nmol/L were no longer significant (40-49 nmol/L: RR = 1.2 (95% CI: 0.99, 1.4); 50-59 nmol/L: RR = 1.2 (95% CI: 1.04, 1.4); 60-74 nmol/L: RR = 1.1 (95% CI: 0.94, 1.2); 75-99 nmol/L: RR = 1.0 (referent), and >=100 nmol/L: RR = 1.1 (95% CI: 0.6, 2.1). In summary, after standardization, risk of death from all causes increased with decreasing 25(OH)D <40 nmol/L, while there was no association with values in categories between 40 nmol/L and 120 nmol/L. PMID- 28338906 TI - Vertical leaf mass per area gradient of mature sugar maple reflects both height driven increases in vascular tissue and light-driven increases in palisade layer thickness. AB - A key trait used in canopy and ecosystem function modeling, leaf mass per area (LMA), is influenced by changes in both leaf thickness and leaf density (LMA = Thickness * Density). In tall trees, LMA is understood to increase with height through two primary mechanisms: (i) increasing palisade layer thickness (and thus leaf thickness) in response to light and/or (ii) reduced cell expansion and intercellular air space in response to hydrostatic constraints, leading to increased leaf density. Our objective was to investigate within-canopy gradients in leaf anatomical traits in order to understand environmental factors that influence leaf morphology in a sugar maple (Acer saccharum Marshall) forest canopy. We teased apart the effects of light and height on anatomical traits by sampling at exposed and closed canopies that had different light conditions at similar heights. As expected, palisade layer thickness responded strongly to cumulative light exposure. Mesophyll porosity, however, was weakly and negatively correlated with light and height (i.e., hydrostatic gradients). Reduced mesophyll porosity was not likely caused by limitations on cell expansion; in fact, epidermal cell width increased with height. Palisade layer thickness was better related to LMA, leaf density and leaf thickness than was mesophyll porosity. Vein diameter and fraction of vascular tissue also increased with height and LMA, density and thickness, revealing that greater investment in vascular and support tissue may be a third mechanism for increased LMA with height. Overall, decreasing mesophyll porosity with height was likely due to palisade cells expanding into the available air space and also greater investments in vascular and support tissue, rather than a reduction of cell expansion due to hydrostatic constraints. Our results provide evidence that light influences both palisade layer thickness and mesophyll porosity and indicate that hydrostatic gradients influence leaf vascular and support tissues in mature Acer saccharum trees. PMID- 28338907 TI - Fish and seafood consumption during pregnancy and the risk of asthma and allergic rhinitis in childhood: a pooled analysis of 18 European and US birth cohorts. AB - Background: It has been suggested that prenatal exposure to n-3 long-chain fatty acids protects against asthma and other allergy-related diseases later in childhood. The extent to which fish intake in pregnancy protects against child asthma and rhinitis symptoms remains unclear. We aimed to assess whether fish and seafood consumption in pregnancy is associated with childhood wheeze, asthma and allergic rhinitis. Methods: We pooled individual data from 60 774 mother-child pairs participating in 18 European and US birth cohort studies. Information on wheeze, asthma and allergic rhinitis prevalence was collected using validated questionnaires. The time periods of interest were: infancy (0-2 years), preschool age (3-4 years), and school age (5-8 years). We used multivariable generalized models to assess associations of fish and seafood (other than fish) consumption during pregnancy with child respiratory outcomes in cohort-specific analyses, with subsequent random-effects meta-analyses. Results: The median fish consumption during pregnancy ranged from 0.44 times/week in The Netherlands to 4.46 times/week in Spain. Maternal fish intake during pregnancy was not associated with offspring wheeze symptoms in any age group nor with the risk of child asthma [adjusted meta-analysis relative risk (RR) per 1-time/week = 1.01, 95% confidence interval 0.97-1.05)] and allergic rhinitis at school age (RR = 1.01, 0.99-1.03). These results were consistently found in further analyses by type of fish and seafood consumption and in sensitivity analyses. Conclusion: We found no evidence supporting a protective association of fish and seafood consumption during pregnancy with offspring symptoms of wheeze, asthma and allergic rhinitis from infancy to mid childhood. PMID- 28338908 TI - Metabolite profiling of barley flag leaves under drought and combined heat and drought stress reveals metabolic QTLs for metabolites associated with antioxidant defense. AB - Barley (Hordeum vulgare L.) is among the most stress-tolerant crops; however, not much is known about the genetic and environmental control of metabolic adaptation of barley to abiotic stresses. We have subjected a genetically diverse set of 81 barley accessions, consisting of Mediterranean landrace genotypes and German elite breeding lines, to drought and combined heat and drought stress at anthesis. Our aim was to (i) investigate potential differences in morphological, physiological, and metabolic adaptation to the two stress scenarios between the Mediterranean and German barley genotypes and (ii) identify metabolic quantitative trait loci (mQTLs). To this end, we have genotyped the investigated barley lines with an Illumina iSelect 9K array and analyzed a set of 57 metabolites from the primary C and N as well as antioxidant metabolism in flag leaves under control and stress conditions. We found that drought-adapted genotypes attenuate leaf carbon metabolism much more strongly than elite lines during drought stress adaptation. Furthermore, we identified mQTLs for flag leaf gamma-tocopherol, glutathione, and succinate content by association genetics that co-localize with genes encoding enzymes of the pathways producing these antioxidant metabolites. Our results provide the molecular basis for breeding barley cultivars with improved abiotic stress tolerance. PMID- 28338909 TI - Therapeutic potential of mesenchymal stem cells in acute kidney injury is affected by administration timing. AB - Mesenchymal stem cell (MSC) transplantation is a promising therapy for acute kidney injury; however, the efficacy is limited due to poor survival after transplantation. In this study, we investigated how MSC transplantation timing affected the survival and therapeutic potential of MSCs in the kidney ischemia reperfusion (I/R) injury model. After kidney I/R injury, the inflammatory process and tissue damage were characterized over 1 week post-I/R, we found that inflammation peaked at 12-24 h post-I/R (h.p.i.), and urine neutrophil gelatinase-associated lipocalin (NGAL) measurements correlated highly with measures of inflammation. We cultured MSCs with supernatants from I/R injured kidney tissue homogenates collected at different time points and found that kidney homogenates from 12 and 24 h.p.i. were most toxic to MSCs, whereas homogenates from 1 h.p.i. were not as cytotoxic as those from 12 and 24 h.p.i. Compared with MSCs administered at 12, or 24 h.p.i., cells administered immediately after ischemia or 1 h.p.i. yielded the highest renoprotective and anti-inflammatory effects. Our findings indicate that MSC treatment for acute kidney injury is most effective when applied prior to the development of a potent inflammatory microenvironment, and urine NGAL may be helpful for detecting inflammation and selecting MSC transplantation timing in I/R kidney injury. PMID- 28338910 TI - The "Dry-Run" Analysis: A Method for Evaluating Risk Scores for Confounding Control. AB - A propensity score (PS) model's ability to control confounding can be assessed by evaluating covariate balance across exposure groups after PS adjustment. The optimal strategy for evaluating a disease risk score (DRS) model's ability to control confounding is less clear. DRS models cannot be evaluated through balance checks within the full population, and they are usually assessed through prediction diagnostics and goodness-of-fit tests. A proposed alternative is the "dry-run" analysis, which divides the unexposed population into "pseudo-exposed" and "pseudo-unexposed" groups so that differences on observed covariates resemble differences between the actual exposed and unexposed populations. With no exposure effect separating the pseudo-exposed and pseudo-unexposed groups, a DRS model is evaluated by its ability to retrieve an unconfounded null estimate after adjustment in this pseudo-population. We used simulations and an empirical example to compare traditional DRS performance metrics with the dry-run validation. In simulations, the dry run often improved assessment of confounding control, compared with the C statistic and goodness-of-fit tests. In the empirical example, PS and DRS matching gave similar results and showed good performance in terms of covariate balance (PS matching) and controlling confounding in the dry-run analysis (DRS matching). The dry-run analysis may prove useful in evaluating confounding control through DRS models. PMID- 28338911 TI - New horizons in hospital acquired pneumonia in older people. AB - Approximately 1.5% of hospital patients develop hospital acquired pneumonia. Aspiration is the major risk factor for pneumonia and is associated with reduced ability to mechanically clear respiratory pathogens into the stomach. Currently non-invasive methods of diagnosing hospital acquired pneumonia are less robust than invasive methods, and lead to over-diagnosis. Accurate diagnosis is key to surveillance, prevention and treatment of HAP, and also to improving outcomes; newer imaging modalities such as phase contrast X-ray imaging and nanoparticle enhanced magnetic resonance imaging may help. Potential preventative strategies such as systematic swallowing assessment in non-stroke patients, and interventions such as improving oral hygiene need further, robust randomised controlled trials. Antibiotics are likely to continue to be the mainstay of treatment, and new antibiotics such as ceftobiprole are likely to have a role in treating hospital acquired pneumonia. Given the spread of antimicrobial resistance, alternative treatment strategies including bacteriophages, peptides and antibodies are under investigation. Reducing the incidence of hospital acquired pneumonia could decrease length of hospital stay, reduce inappropriate antibiotic use, and both improve functional outcomes and mortality in our increasingly aged population. PMID- 28338912 TI - Invited Commentary: The Tao of Clinical Cohort Analysis-When the Transitions That Can Be Spoken of Are Not the True Transitions. AB - Patterns in risk-related behaviors identified using clinically deployed surveys may hold value for public health surveillance. However, because such surveys assess subjects only when subjects choose to visit clinics, clinical data are subject to variability in observation patterns that is not present in conventional longitudinal data sets in which research teams contact subjects at regular intervals. In this issue of the Journal, Wilkinson et al. (Am J Epidemiol. 2017;185(8):627-635) describe how they applied a latent transition analysis technique to surveillance data collected during clinic visits. In this commentary I discusses the selection bias that may arise in longitudinal analysis of clinical data due to subject-specific observation patterns, with particular focus on issues that may arise due to classifying successive clinical visits as waves. I suggest that quantitative bias analysis and inverse probability weighting may be useful techniques with which to assess and control bias in future latent transition analyses of clinical data. PMID- 28338913 TI - Assessing the impact of unmeasured confounding for binary outcomes using confounding functions. AB - A critical assumption of causal inference is that of no unmeasured confounding: for estimated exposure effects to have valid causal interpretations, a sufficient set of predictors of exposure and outcome must be adequately measured and correctly included in the respective inference model(s). In an observational study setting, this assumption will often be unsatisfied, and the potential impact of unmeasured confounding on effect estimates should be investigated. The confounding function approach allows the impact of unmeasured confounding on estimates to be assessed, where unmeasured confounding may be due to unmeasured confounders and/or biases such as collider bias or information bias. Although this approach is easy to implement and pertains to the sum of all bias, its use has not been widespread, and discussion has typically been limited to continuous outcomes. In this paper, we consider confounding functions for use with binary outcomes and illustrate the approach with an example. We note that confounding function choice encodes assumptions about effect modification: some choices encode the belief that the true causal effect differs across exposure groups, whereas others imply that any difference between the true causal parameter and the estimate is entirely due to imbalanced risks between exposure groups. The confounding function approach is a useful method for assessing the impact of unmeasured confounding, in particular when alternative approaches, e.g. external adjustment or instrumental variable approaches, cannot be applied. We provide Stata and R code for the implementation of this approach when the causal estimand of interest is an odds or risk ratio. PMID- 28338914 TI - Impact of decentralisation of antiretroviral therapy services on HIV testing and care at a population level in Agago District in rural Northern Uganda: results from the Lablite population surveys. AB - Background: We conducted unlinked cross-sectional population-based surveys in Northern Uganda before and after antiretroviral therapy (ART) provision (including Option B+ [lifelong ART for pregnant/breast-feeding women]) at a local primary care facility (Lira Kato Health Centre [HC]). Prior to decentralisation, people travelled 56-76 km round-trip for ART; we aimed to evaluate changes in uptake of HIV-testing, ART coverage and access to ART following decentralisation. Methods: A total of 2124 adults in 1351 households in two parishes closest to Lira Kato HC were interviewed using questionnaires between March and April 2013 and 2123 adults in 1229 households between January and March 2015. Results: Adults reporting HIV-testing in the last year increased from 1077/2124 (50.7%) to 1298/2123 (61.1%) between surveys (p<0.001). ART coverage increased from 74/136 (54.4%) self-reported HIV-positive adults in 2013 to 108/133 (81.2%) in 2015 (p<0.001). Post-decentralisation, 47/108 (43.5%) of those on ART were in care at Lira Kato HC (including 37 new initiations). Most of the remainder (47/61, 77%) started ART prior to any ART provision at Lira Kato HC; the most common reason given for not accessing ART locally was concern about drug-stock-outs (30/59, 51%). Conclusions: HIV-testing and ART coverage increased after decentralisation combined with Option B+ roll-out. However, patients on ART before decentralisation were reluctant to transfer to their local facility. PMID- 28338915 TI - Ungulate herbivory alters leaf functional traits and recruitment of regenerating aspen. AB - Herbivory by ungulates can affect forest regeneration success, but its long-term impacts on tree function and recruitment are less studied. We evaluated strategies of resistance, tolerance and vertical escape against ungulate herbivory by evaluating leaf traits (photosynthesis, morphology and chemistry) and growth rates of aspen in the presence and absence of ungulate herbivores 1, 2, 3 and 26 years after fires initiated aspen suckering. Over the initial 3-year period, ~60% of aspen stems in unfenced plots showed evidence of being browsed by ungulates. After 3 years, aspen in unfenced plots had smaller leaves, were 50% shorter, and had 33% lower nonstructural carbohydrate concentrations and 33% greater concentrations of condensed tannins, when compared with fenced aspen. Aspen exposed to ungulate herbivory over a 26-year period maintained smaller leaves, had lower annual radial growth rates and were still below the critical height threshold of 2 m required to escape ungulate herbivory for successful recruitment. In contrast, the average height of aspen protected from ungulates was approaching 6 m. Over the 26-year period leaves in unfenced plots had 41% lower nonstructural carbohydrate concentrations and greater expression of defense compounds-condensed tannins (63%) and phenolic glycosides (102%)-than leaves in fenced plots. Photosynthetic rates were slightly higher in aspen that experienced ungulate browsing, suggesting that changes in leaf anatomy and chemistry due to ungulate herbivory did not interfere with photosynthesis. Our data suggest that ungulate browsing increases investment in chemical defense, lowers nonstructural carbohydrate concentrations and reduces leaf area, which decreases the recruitment potential of regenerating aspen. PMID- 28338916 TI - Violent offenders respond to provocations with high amygdala and striatal reactivity. AB - The ability to successfully suppress impulses and angry affect is fundamental to control aggressive reactions following provocations. The aim of this study was to examine neural responses to provocations and aggression using a laboratory model of reactive aggression. We used a novel functional magnetic resonance imaging point-subtraction aggression paradigm in 44 men, of whom 18 were incarcerated violent offenders and 26 were control non-offenders. We measured brain activation following provocations (monetary subtractions), while the subjects had the possibility to behave aggressively or pursue monetary rewards. The violent offenders behaved more aggressively than controls (aggression frequency 150 vs 84, P = 0.03) and showed significantly higher brain reactivity to provocations within the amygdala and striatum, as well as reduced amygdala-prefrontal and striato-prefrontal connectivity. Amygdala reactivity to provocations was positively correlated with task-related behavior in the violent offenders. Across groups, striatal and prefrontal reactivity to provocations was positively associated with trait anger and trait aggression. These results suggest that violent individuals display abnormally high neural sensitivity to social provocations, a sensitivity related to aggressive behavior. These findings provide novel insight into the neural pathways that are sensitive to provocations, which is critical to more effectively shaped interventions that aim to reduce pathological aggressive behavior. PMID- 28338917 TI - Association Between Serum Levels of Uric Acid and Blood Pressure Tracking in Childhood. AB - BACKGROUND: Recent studies suggest that high levels of serum uric acid of very early life are a result of the in-utero environment and may lead to elevated blood pressure (BP) in adulthood. However, serum uric acid levels can change throughout life. We investigated the effect of serum uric acid levels in childhood on the BP tracking and analysed BP according to changes in serum uric acid levels in early life. METHODS: A total of 449 children from the Ewha Birth and Growth Cohort study underwent at least 2 follow-up examinations. Data were collected across 3 check-up cycles. Serum uric acid levels, BP, and anthropometric characteristics were assessed at 3, 5, and 7 years of age. RESULTS: Children with a serum uric acid level higher than the median values had significantly increased systolic BP (SBP) and diastolic BP at 3 years of age. Baseline serum uric acid levels measured at 3 years of age, significantly affected subsequent BP in the sex and body mass index adjusted longitudinal data analysis (P < 0.05). Considering the changing pattern of serum uric acid over time, subjects with high uric acid levels at both 3 and 5 years of age had the highest SBP at 7 years of age. CONCLUSIONS: These findings suggest the importance of maintaining an adequate level of serum uric acids from the early life. Appropriate monitoring and intervention of uric acid levels in a high-risk group can reduce the risk of a future increased BP. PMID- 28338918 TI - Integrated miRNA and mRNA expression profiling reveals the response regulators of a susceptible tomato cultivar to early blight disease. AB - Early blight, caused by the fungus Alternaria solani, is a devastating foliar disease of tomatoes, causes massive yield loss each year worldwide. Molecular basis of the compatible host-pathogen interaction was elusive. We adopted next generation sequencing approach to decipher miRNAs and mRNAs that are differentially expressed during Alternaria-stress in tomato. Some of the interesting findings were also validated by alternative techniques. Our analysis revealed 181 known-miRNAs, belonging to 121 miRNA families, of which 67 miRNAs showed at least 2-fold change in expression level with the majority being downregulated. Concomitantly, 5,450 mRNAs were significantly regulated in the same diseased tissues. Differentially expressed genes were most significantly associated with response to stimulus process, photosynthesis, biosynthesis of secondary metabolites, plant-pathogen interaction and plant hormone signal transduction pathways. GO term enrichment-based categorization of gene-functions further supported this observation, as terms related to pathogen perception, disease signal transduction, cellular metabolic processes including oxidoreductase and kinase activity were over represented. In addition, we have discovered 102 miRNA-mRNA pairs which were regulated antagonistically, and careful study of the targeted mRNAs depicted that multiple transcription factors, nucleotide-binding site leucine-rich repeats, receptor-like proteins and enzymes related to cellular ROS management were profoundly affected. These studies have identified key regulators of Alternaria-stress response in tomato and the subset of genes that are likely to be post-transcriptionally silenced during the infection. PMID- 28338919 TI - Genetic Overlap Between Schizophrenia and Developmental Psychopathology: Longitudinal and Multivariate Polygenic Risk Prediction of Common Psychiatric Traits During Development. AB - Background: Several nonpsychotic psychiatric disorders in childhood and adolescence can precede the onset of schizophrenia, but the etiology of this relationship remains unclear. We investigated to what extent the association between schizophrenia and psychiatric disorders in childhood is explained by correlated genetic risk factors. Methods: Polygenic risk scores (PRS), reflecting an individual's genetic risk for schizophrenia, were constructed for 2588 children from the Netherlands Twin Register (NTR) and 6127 from the Avon Longitudinal Study of Parents And Children (ALSPAC). The associations between schizophrenia PRS and measures of anxiety, depression, attention deficit hyperactivity disorder (ADHD), and oppositional defiant disorder/conduct disorder (ODD/CD) were estimated at age 7, 10, 12/13, and 15 years in the 2 cohorts. Results were then meta-analyzed, and a meta-regression analysis was performed to test differences in effects sizes over, age and disorders. Results: Schizophrenia PRS were associated with childhood and adolescent psychopathology. Meta regression analysis showed differences in the associations over disorders, with the strongest association with childhood and adolescent depression and a weaker association for ODD/CD at age 7. The associations increased with age and this increase was steepest for ADHD and ODD/CD. Genetic correlations varied between 0.10 and 0.25. Conclusion: By optimally using longitudinal data across diagnoses in a multivariate meta-analysis this study sheds light on the development of childhood disorders into severe adult psychiatric disorders. The results are consistent with a common genetic etiology of schizophrenia and developmental psychopathology as well as with a stronger shared genetic etiology between schizophrenia and adolescent onset psychopathology. PMID- 28338920 TI - Dendritic cell expression of the signaling molecule TRAF6 is required for immune tolerance in the lung. AB - Immune tolerance in the lung is important for preventing hypersensitivity, such as allergic asthma. Maintenance of tolerance in the lung is established by coordinated activities of poorly understood cellular and molecular mechanisms, including participation of dendritic cells (DCs). We have previously identified DC expression of the signaling molecule TRAF6 as a non-redundant requirement for the maintenance of immune tolerance in the small intestine of mice. Because mucosal tissues share similarities in how they interact with exogenous antigens, we examined the role of DC-expressed TRAF6 in the lung. As with the intestine, we found that the absence TRAF6 expression by DCs led to spontaneous generation of Th2-associated immune responses and increased susceptibility to model antigen induced asthma. To examine the role of commensal microbiota, mice deficient in TRAF6 in DCs were treated with broad-spectrum antibiotics and/or re-derived on a germ-free (GF) background. Interestingly, we found that antibiotics-treated specific pathogen-free, but not GF, mice showed restored immune tolerance in the absence of DC-expressed TRAF6. We further found that antibiotics mediate microbiota-independent effects on lung T cells to promote immune tolerance in the lung. This work provides both a novel tool for studying immune tolerance in the lung and an advance in our conceptual understanding of potentially common molecular mechanisms of immune tolerance in both the intestine and the lung. PMID- 28338921 TI - The Relationship Between Objectively Measured Walking and Risk of Pedestrian Motor Vehicle Collision. AB - Safe urban walking environments may improve health by encouraging physical activity, but the relationship between an individual's location and walking pattern and the risk of pedestrian-motor vehicle collision is unknown. We examined associations between individuals' walking bouts and walking risk, measured as mean exposure to the risk of pedestrian-vehicle collision. Walking bouts were ascertained through integrated accelerometry and global positioning system data and from individual travel-diary data obtained from adults in the Travel Assessment and Community Study (King County, Washington) in 2008-2009. Walking patterns were superimposed onto maps of the historical probabilities of pedestrian-vehicle collisions for intersections and midblock segments within Seattle, Washington. Mean risk of pedestrian-vehicle collision in specific walking locations was assessed according to walking exposure (duration, distance, and intensity) and participant demographic characteristics in linear mixed models. Participants typically walked in areas with low pedestrian collision risk when walking for recreation, walking at a faster pace, or taking longer-duration walks. Mean daily walking duration and distance were not associated with collision risk. Males walked in areas with higher collision risk compared with females, while vehicle owners, residents of single-family homes, and parents of young children walked in areas with lower collision risk. These findings may suggest that pedestrians moderate collision risk by using lower-risk routes. PMID- 28338923 TI - Erratum. PMID- 28338922 TI - The Hidden Epidemic of Firearm Injury: Increasing Firearm Injury Rates During 2001-2013. AB - Investigating firearm injury trends over the past decade, we examined temporal trends overall and according to race/ethnicity and intent in fatal and nonfatal firearm injuries (FFIs and NFIs) in United States during 2001-2013. Counts of FFIs and estimated counts of NFIs were obtained from the Centers for Disease Control and Prevention's Web-based Injury Statistics Query and Reporting System. Poisson regression was used to analyze overall and subgroup temporal trends and to estimate annual change per 100,000 persons (change). Total firearm injuries (n = 1,328,109) increased annually by 0.36 (Ptrend < 0.0001). FFIs remained constant (change = 0.02; Ptrend = 0.22) while NFIs increased (change = 0.35; Ptrend < 0.0001). Homicide FFIs declined (change = -0.05; Ptrend < 0.0001) while homicide NFIs increased (change = 0.43; Ptrend < 0.0001). Suicide FFIs increased (change = 0.07; Ptrend < 0.0001) while unintentional FFIs and NFIs declined (changes = 0.01 and -0.09, respectively; Ptrend < 0.0001 and 0.005). Among whites, FFIs (change = 0.15; Ptrend < 0.0001) and NFIs (change = 0.13; Ptrend < 0.0001) increased; among blacks, FFIs declined (change = -0.20; Ptrend < 0.0001). Among Hispanics, FFIs declined (change = -0.28; Ptrend < 0.0001) while NFIs increased (change = 0.55; Ptrend = 0.014). The endemic firearm-related injury rates during the first decade of the 21st century mask a shift from firearm deaths towards a rapid rise in nonfatal injuries. PMID- 28338925 TI - Tobacco Use, Oral Health, and Risk of Parkinson's Disease. AB - Few studies have investigated the associations between use of Swedish moist snuff (snus), associated poor oral health, and risk of Parkinson's disease (PD). We followed 20,175 participants who were free of PD in 1973-1974 in Uppsala, Sweden, until the end of 2012. We used Cox proportional hazards regression models to estimate hazard ratios and corresponding 95% confidence intervals for the associations between tobacco use, oral health indicators, and PD risk. We found that tobacco use was associated with a lower risk of PD in males. Compared with males who never used any tobacco daily, pure ever tobacco smokers, pure ever snus users, and combined users had adjusted hazard ratios of 0.68 (95% confidence interval (CI): 0.49, 0.93; n = 83), 0.51 (95% CI: 0.27, 0.95; n = 11), and 0.21 (95% CI: 0.07, 0.67; n = 3), respectively. No association was observed for number of teeth, dental plaque, or detectable oral mucosal lesions and PD risk, although there was a suggestive association with Candida-related oral mucosal lesions in males (hazard ratio = 1.56, 95% CI: 0.92, 2.65; P = 0.098). Use of snus is associated with a lower risk of PD in males, while poor oral health seems not to be associated with PD occurrence. PMID- 28338924 TI - A Nonsynonymous SNP Catalog of Mycobacterium tuberculosis Virulence Genes and Its Use for Detecting New Potentially Virulent Sublineages. AB - Mycobacterium tuberculosis is divided into several distinct lineages, and various genetic markers such as IS-elements, VNTR, and SNPs are used for lineage identification. We propose an M. tuberculosis classification approach based on functional polymorphisms in virulence genes. An M. tuberculosis virulence genes catalog has been established, including 319 genes from various protein groups, such as proteases, cell wall proteins, fatty acid and lipid metabolism proteins, sigma factors, toxin-antitoxin systems. Another catalog of 1,573 M. tuberculosis isolates of different lineages has been developed. The developed SNP-calling program has identified 3,563 nonsynonymous SNPs. The constructed SNP-based phylogeny reflected the evolutionary relationship between lineages and detected new sublineages. SNP analysis of sublineage F15/LAM4/KZN revealed four lineage specific mutations in cyp125, mce3B, vapC25, and vapB34. The Ural lineage has been divided into two geographical clusters based on different SNPs in virulence genes. A new sublineage, B0/N-90, was detected inside the Beijing-B0/W-148 by SNPs in irtB, mce3F and vapC46. We have found 27 members of B0/N-90 among the 227 available genomes of the Beijing-B0/W-148 sublineage. Whole-genome sequencing of strain B9741, isolated from an HIV-positive patient, was demonstrated to belong to the new B0/N-90 group. A primer set for PCR detection of B0/N-90 lineage specific mutations has been developed. The prospective use of mce3 mutant genes as genetically engineered vaccine is discussed. PMID- 28338926 TI - Nitrogen-controlled intra- and interspecific competition between Populus purdomii and Salix rehderiana drive primary succession in the Gongga Mountain glacier retreat area. AB - In this study, intra- and interspecific competition were investigated in early successional Salix rehderiana Schneider and later-appearing Populus purdomii Rehder under non-fertilized (control) and nitrogen (N)-fertilized conditions in the Hailuogou glacier retreat area. Our aim was to discover whether N is a key factor in plant-plant competition and whether N drives the primary succession process in a glacier retreat area. We analyzed differences in responses to intra- and interspecific competition and N fertilization between P. purdomii and S. rehderiana, including parameters such as biomass accumulation, nutrient absorption, non-structural carbohydrates, photosynthetic capacity, hydrolysable amino acids and leaf ultrastructure. In the control treatments, S. rehderiana individuals subjected to interspecific competition benefited from the presence of P. purdomii plants, as indicated by higher levels of biomass accumulation, photosynthetic capacity, N absorption, amino acid contents and photosynthetic N use efficiency. However, in the N-fertilized treatments, P. purdomii individuals exposed to interspecific competition benefited from the presence of S. rehderiana plants, as shown by a higher growth rate, enhanced carbon gain capacity, greater amino acid contents, and elevated water-use efficiency, whereas the growth of S. rehderiana was significantly reduced. Our results demonstrate that N plays a pivotal role in determining the asymmetric competition pattern among Salicaceae species during primary succession. We argue that the interactive effects of plant plant competition and N availability are key mechanisms that drive primary succession in the Gongga Mountain glacier retreat area. PMID- 28338928 TI - Reply to: Seasonality of birth for skin melanoma deserves further investigation. PMID- 28338927 TI - The effect of aluminum ion on the aggregation of human islet amyloid polypeptide (11-28). AB - Metal ions play a critical role in human islet amyloid polypeptide (hIAPP) aggregation, which is believed to be closely associated with beta-cell death in type II diabetes. In this work, the effect of Al3+ on the aggregation of hIAPP (11-28) was studied by several different experimental approaches. Atomic force microscopy measurements showed that Al3+ could remarkably inhibit hIAPP(11-28) fibrillogenesis, while Zn2+ had a slight promotion effect on peptide aggregation, which was also confirmed by Thioflavin T fluorescence observation. Furthermore, X ray photoelectron spectroscopy measurement indicated that Al ions might form chemical bonds with neighboring atoms and destroy the secondary structures of the protein. Our studies could deepen the understanding of the role of metal ions in the aggregation of amyloid peptides. PMID- 28338929 TI - PERFORMANCE TESTS OF ACTIVE PERSONAL DOSEMETER DEVELOPED BY CNRTC/NEL. AB - The Active personal dosemeter (APD) developed by Cekmece Nuclear Research and Training Center/Nuclear Electronic Laboratory (CNRTC/NEL) was calibrated at the reference radiation quality (137Cs). The performance tests were carried out with 137Cs, 60Co and X-ray beam qualities in compliance with the standards of International Organization for Standardization ISO4037-1,3 and The International Electrotechnical Commission, IEC61526:2010. Response of the personal dose equivalent was observed to be within the range from -7.6% to +4.2%. The dose equivalent rates were observed with the maximum deviation -26.8% for 0.1 mSv h-1 and within the range from -2.3% to +10.1% for dose rates over 0.5 mSv h-1. It is found that the APDs have lower readings up to 50% for 33 keV photons and perform a distribution in the acceptable limits for over 33 keV. Angular dependence was tested at 0 degrees , +/-30 degrees and +/-60 degrees in orthogonal plane and the angular dependence of the APDs is within acceptable limits except N40. PMID- 28338930 TI - EXPath tool-a system for comprehensively analyzing regulatory pathways and coexpression networks from high-throughput transcriptome data. AB - Next generation sequencing (NGS) has become the mainstream approach for monitoring gene expression levels in parallel with various experimental treatments. Unfortunately, there is no systematical webserver to comprehensively perform further analysis based on the huge amount of preliminary data that is obtained after finishing the process of gene annotation. Therefore, a user friendly and effective system is required to mine important genes and regulatory pathways under specific conditions from high-throughput transcriptome data. EXPath Tool (available at: http://expathtool.itps.ncku.edu.tw/) was developed for the pathway annotation and comparative analysis of user-customized gene expression profiles derived from microarray or NGS platforms under various conditions to infer metabolic pathways for all organisms in the KEGG database. EXPath Tool contains several functions: access the gene expression patterns and the candidates of co-expression genes; dissect differentially expressed genes (DEGs) between two conditions (DEGs search), functional grouping with pathway and GO (Pathway/GO enrichment analysis), and correlation networks (co-expression analysis), and view the expression patterns of genes involved in specific pathways to infer the effects of the treatment. Additionally, the effectively of EXPath Tool has been performed by a case study on IAA-responsive genes. The results demonstrated that critical hub genes under IAA treatment could be efficiently identified. PMID- 28338931 TI - Evolutionary Dynamics of Pathoadaptation Revealed by Three Independent Acquisitions of the VirB/D4 Type IV Secretion System in Bartonella. AB - The alpha-proteobacterial genus Bartonella comprises a group of ubiquitous mammalian pathogens that are studied as a model for the evolution of bacterial pathogenesis. Vast abundance of two particular phylogenetic lineages of Bartonella had been linked to enhanced host adaptability enabled by lineage specific acquisition of a VirB/D4 type IV secretion system (T4SS) and parallel evolution of complex effector repertoires. However, the limited availability of genome sequences from one of those lineages as well as other, remote branches of Bartonella has so far hampered comprehensive understanding of how the VirB/D4 T4SS and its effectors called Beps have shaped Bartonella evolution. Here, we report the discovery of a third repertoire of Beps associated with the VirB/D4 T4SS of B. ancashensis, a novel human pathogen that lacks any signs of host adaptability and is only distantly related to the two species-rich lineages encoding a VirB/D4 T4SS. Furthermore, sequencing of ten new Bartonella isolates from under-sampled lineages enabled combined in silico analyses and wet lab experiments that suggest several parallel layers of functional diversification during evolution of the three Bep repertoires from a single ancestral effector. Our analyses show that the Beps of B. ancashensis share many features with the two other repertoires, but may represent a more ancestral state that has not yet unleashed the adaptive potential of such an effector set. We anticipate that the effectors of B. ancashensis will enable future studies to dissect the evolutionary history of Bartonella effectors and help unraveling the evolutionary forces underlying bacterial host adaptation. PMID- 28338932 TI - Ursolic acid derivative FZU-03,010 inhibits STAT3 and induces cell cycle arrest and apoptosis in renal and breast cancer cells. AB - Advanced renal cell carcinoma and triple negative breast cancer (TNBC) are malignancies without effective therapeutics currently. Ursolic acid (UA) has been previously reported to have anti-cancer effects in multiple solid tumors. In order to develop more potent anti-cancer reagents, FZU-03,010 based on the chemical structure of UA were synthesized. The results demonstrated that, compared with UA, FZU-03,010 could suppress renal cancer cell 786-0 and TNBC cell HCC1806 cell viability more potently. Furthermore, FZU-03,010 could induce G1 cell cycle arrest and cell apoptosis more efficiently than UA. FZU-03,010 could also inhibit signal transducer and activator of transcription 3 activation, induce the expression of cell cycle-dependent kinase inhibitors (p21 and p27) and promote cell apoptosis. In conclusion, our results suggest that the UA derivative FZU-03,010 is more potent in inhibiting cancer cell survival, and FZU-03,010 has the potential to be developed as a therapeutic for renal cell cancers and TNBCs. PMID- 28338933 TI - Seasonality of birth for skin melanoma deserves further investigation. PMID- 28338934 TI - ALTERNATIVE FIGURES-OF-MERIT IN DIGITAL MAMMOGRAPHY. AB - The aim of this study is to explore the use of a quality (Q) factor in digital mammography as a figure-of-merit. Q factors take a reference value into account and can be compared to a theoretical value. They are also intended to summarise the performance of any unit based on a number. The mean glandular dose (MGD) normalised Q factors were also introduced based on the relationship of the Q factors with MGD. Interestingly, the automatic exposure control exposures did not render the maximum normalised Q factor values as expected, which could indicate the need for further optimisation. It was also noted that the Q factors and the CDMAM-related quality parameters can be confidently predicted for a given MGD which in turn may be compared to the measured values. This might be another way to consider or perform optimisation in digital mammography. PMID- 28338935 TI - Impact of the ion transportome of chloroplasts on the optimization of photosynthesis. AB - Ions play fundamental roles in all living cells, and their gradients are often essential to fuel transport, regulate enzyme activities, and transduce energy within cells. Regulation of their homeostasis is essential for cell metabolism. Recent results indicate that modulation of ion fluxes might also represent a useful strategy to regulate one of the most important physiological processes taking place in chloroplasts, photosynthesis. Photosynthesis is highly regulated, due to its unique role as a cellular engine for growth in the light. Controlling the balance between ATP and NADPH synthesis is a critical task, and availability of these molecules can limit the overall photosynthetic yield. Photosynthetic organisms optimize photosynthesis in low light, where excitation energy limits CO2 fixation, and minimize photo-oxidative damage in high light by dissipating excess photons. Despite extensive studies of these phenomena, the mechanism governing light utilization in plants is still poorly understood. In this review, we provide an update of the recently identified chloroplast-located ion channels and transporters whose function impacts photosynthetic efficiency in plants. PMID- 28338936 TI - Establishment of a human hepatocellular cell line capable of maintaining long term replication of hepatitis B virus. AB - Hepatitis B virus (HBV) is a virus whose replication cycle cannot be completely reproduced using cultured cell lines. Here, we report an engineered cell line capable of supporting the complete HBV life cycle. We generated HepG2 cells over expressing the HBV entry receptor human NTCP (sodium taurocholate cotransporting polypeptide), and defective in RIG-I (retinoic acid-inducible gene-I)-like receptor signaling, by knocking down the IPS-1 (IFNbeta-promoter stimulator-1) adaptor molecule. The resultant NtG20.i7 cells were susceptible to HBV, and its replication was detectable at 14 days post-infection and persisted for at least 35 days with a gradual increase of HBV core expression. The cells produced infectious HBV in the culture supernatant, and the addition of preS1 peptide myr47-WT, which blocks HBV entry, impaired the persistence of the infection. These findings suggest that the persistence of the infection was maintained by continuous release of infectious HBV virions and their re-infection. This system is useful for expanding our basic understanding of the HBV replication cycle and for screening of anti-HBV chemicals. PMID- 28338938 TI - Corrigendum: A closer look at the trajectory of physical functioning in chronic hemodialysis. PMID- 28338937 TI - Association of Blood Pressure Trajectory With Mortality, Incident Cardiovascular Disease, and Heart Failure in the Cardiovascular Health Study. AB - BACKGROUND: Common blood pressure (BP) trajectories are not well established in elderly persons, and their association with clinical outcomes is uncertain. METHODS: We used hierarchical cluster analysis to identify discrete BP trajectories among 4,067 participants in the Cardiovascular Health Study using repeated BP measures from years 0 to 7. We then evaluated associations of each BP trajectory cluster with all-cause mortality, incident cardiovascular disease (CVD, defined as stroke or myocardial infarction) (N = 2,837), and incident congestive heart failure (HF) (N = 3,633) using Cox proportional hazard models. RESULTS: Median age was 77 years at year 7. Over a median 9.3 years of follow-up, there were 2,475 deaths, 659 CVD events, and 1,049 HF events. The cluster analysis identified 3 distinct trajectory groups. Participants in cluster 1 (N = 1,838) had increases in both systolic (SBP) and diastolic (DBP) BPs, whereas persons in cluster 2 (N = 1,109) had little change in SBP but declines in DBP. Persons in cluster 3 (N = 1,120) experienced declines in both SBP and DBP. After multivariable adjustment, clusters 2 and 3 were associated with increased mortality risk relative to cluster 1 (hazard ratio = 1.21, 95% confidence interval: 1.06-1.37 and hazard ratio = 1.20, 95% confidence interval: 1.05-1.36, respectively). Compared to cluster 1, cluster 3 had higher rates of incident CVD but associations were not statistically significant in demographic-adjusted models (hazard ratio = 1.16, 95% confidence interval: 0.96-1.39). Findings were similar when stratified by use of antihypertensive therapy. CONCLUSIONS: Among community-dwelling elders, distinct BP trajectories were identified by integrating both SBP and DBP. These clusters were found to have differential associations with outcomes. PMID- 28338939 TI - It Remains Unknown Whether Filaggrin Gene Mutations Evolved to Increase Cutaneous Synthesis of Vitamin D. AB - About 8-10% of normal Northern Europeans are heterozygous carriers of common FLG mutations, while only 1-4% of southern Europeans display these mutations, and only very rarely are mutations detected in African populations. Although mutations are found in Asians, they are different from those encountered in Northern Europeans. Importantly, FLG mutation carriers have 10% increased serum vitamin D concentrations compared to controls. Based on these observations, we have proposed that this latitude-dependent gradient of FLG mutations across Europe, Asia and Africa could have provided an evolutionary advantage for heterozygous FLG mutation carriers, residing at northern latitudes, depletion of the FLG downstream product, trans-urocanic acid, would facilitate the intracutaneous synthesis of vitamin D3 by allowing increased transcutaneous absorption of UVB photons. Such loss-of-function FLG mutations would have provided an evolutionary advantage for modern humans, living in the far North of Europe, where little UV-B penetrates the atomosphere. In a recent article, it was concluded not only that the UVB-Vitamin D3 hypothesis is invalid, but also that FLG genetic variations, including loss-of-function variants, provide little or no impact on the fitness of modern humans. While we welcome studies that reassess our hypothesis, their conclusions are not valid for reasons explained in this letter. PMID- 28338940 TI - FEASIBILITY STUDY FOR IDENTIFICATION OF STATIC AND DYNAMIC EXPOSURE USING CCD IMAGING TECHNIQUE FOR Caso4:Dy TL DOSEMETERS. AB - The occupational exposure incurred by the radiation workers due to the external radiation is estimated using personal dosemeter placed on the human body during the monitoring period. In certain situations, it is required to determine whether the dosemeter alone was exposed accidentally/intentionally in radiation field (static exposure) or was exposed while being worn by a worker moving in his workplace (dynamic exposure). The present thermoluminscent (TL) based personnel monitoring systems are not capable of distinguishing between the above stated (static and dynamic) exposure conditions. The feasibility of a new methodology developed using the charge coupled device based imaging technique for identification of the static/dynamic exposure of CaSO4:Dy based TL detectors for low energy photons has been investigated. The techniques for the qualitative and the quantitative assessments of the exposure conditions are presented in this paper. PMID- 28338941 TI - Data Resource Profile: Hospital Episode Statistics Admitted Patient Care (HES APC). PMID- 28338942 TI - Structure and mechanism of benzaldehyde dehydrogenase from Pseudomonas putida ATCC 12633, a member of the Class 3 aldehyde dehydrogenase superfamily. AB - Benzaldehyde dehydrogenase from Pseudomonas putida (PpBADH) belongs to the Class 3 aldehyde dehydrogenase (ALDH) family. The Class 3 ALDHs are unusual in that they are generally dimeric (rather than tetrameric), relatively non-specific and utilize both NAD+ and NADP+. To date, X-ray structures of three Class 3 ALDHs have been determined, of which only two have cofactor bound, both in the NAD+ form. Here we report the crystal structure of PpBADH in complex with NADP+ and a thioacyl intermediate adduct. The overall architecture of PpBADH resembles that of most other members of the ALDH superfamily, and the cofactor binding residues are well conserved. Conversely, the pattern of cofactor binding for the rat Class 3 ALDH differs from that of PpBADH and other ALDHs. This has been interpreted in terms of a different mechanism for the rat enzyme. Comparison with the PpBADH structure, as well as multiple sequence alignments, suggest that one of two conserved glutamates, at positions 215 (209 in rat) and 337 (333 in rat), would act as the general base necessary to hydrolyze the thioacyl intermediate. While the latter is the general base in the rat Class 3 ALDH, site-specific mutagenesis indicates that Glu215 is the likely candidate for PpBADH, a result more typical of the Class 1 and 2 ALDH families. Finally, this study shows that hydride transfer is not rate limiting, lending further credence to the suggestion that PpBADH is more similar to the Class 1 and 2 ALDHs than it is to other Class 3 ALDHs. PMID- 28338943 TI - Dysfunction of Large-Scale Brain Networks in Schizophrenia: A Meta-analysis of Resting-State Functional Connectivity. AB - Schizophrenia is a complex mental disorder with disorganized communication among large-scale brain networks, as demonstrated by impaired resting-state functional connectivity (rsFC). Individual rsFC studies, however, vary greatly in their methods and findings. We searched for consistent patterns of network dysfunction in schizophrenia by using a coordinate-based meta-analysis. Fifty-six seed-based voxel-wise rsFC datasets from 52 publications (2115 patients and 2297 healthy controls) were included in this meta-analysis. Then, coordinates of seed regions of interest (ROI) and between-group effects were extracted and coded. Seed ROIs were categorized into seed networks by their location within an a priori template. Multilevel kernel density analysis was used to identify brain networks in which schizophrenia was linked to hyper-connectivity or hypo-connectivity with each a priori network. Our results showed that schizophrenia was characterized by hypo-connectivity within the default network (DN, self-related thought), affective network (AN, emotion processing), ventral attention network (VAN, processing of salience), thalamus network (TN, gating information) and somatosensory network (SS, involved in sensory and auditory perception). Additionally, hypo-connectivity between the VAN and TN, VAN and DN, VAN and frontoparietal network (FN, external goal-directed regulation), FN and TN, and FN and DN were found in schizophrenia. Finally, the only instance of hyper connectivity in schizophrenia was observed between the AN and VAN. Our meta analysis motivates an empirical foundation for a disconnected large-scale brain networks model of schizophrenia in which the salience processing network (VAN) plays the core role, and its imbalanced communication with other functional networks may underlie the core difficulty of patients to differentiate self representation (inner world) and environmental salience processing (outside world). PMID- 28338945 TI - Genetic variation in traits for nitrogen use efficiency in wheat. AB - Crop nutrient and especially nitrogen use efficiency (NUE) is both an economically and an environmentally highly desirable trait. It has been estimated that only a third of nitrogen inputs to cereal crop worldwide are recovered in grain for consumption, resulting in a huge waste of resource with major negative impacts on the environment. Most measures of NUE in wheat and other cereals are based on field assessments of crop yields at given N inputs, performance responses to added N fertilizer, or by quantifying N fertilizer recovery rates. However, NUE is a complex trait comprising two key major components, N uptake and N utilization efficiency, both also complex traits in themselves, each involving many physiological processes and biochemical pathways. A deeper understanding of the processes involved in NUE has been a target of the UK Wheat Genetic Improvement Network project (http://www.wgin.org.uk/). This has enabled the breakdown of characteristics contributing to NUE and an assessment of the variation present in those characteristics, predominantly in modern cultivars; a total of 13 years of data have been obtained to date. Significant but limited variation suggests a requirement for broader germplasm screening such as older varieties, landraces, and wild relatives. PMID- 28338944 TI - Salience network engagement with the detection of morally laden information. AB - Moral cognition is associated with activation of the default network, regions implicated in mentalizing about one's own actions or the intentions of others. Yet little is known about the initial detection of moral information. We examined the neural correlates of moral processing during a narrative completion task, which included an implicit moral salience manipulation. During fMRI scanning, participants read a brief vignette and selected the most semantically congruent sentence from two options to complete the narrative. The options were immoral, moral or neutral statements. RT was fastest for the selection of neutral statements and slowest for immoral statements. Neuroimaging analyses revealed that responses involving morally laden content engaged default and executive control network brain regions including medial and rostral prefrontal cortex, and core regions of the salience network, including anterior insula and dorsal anterior cingulate. Immoral vs moral conditions additionally engaged the salience network. These results implicate the salience network in the detection of moral information, which may modulate downstream default and frontal control network interactions in the service of complex moral reasoning and decision-making processes. These findings suggest that moral cognition involves both bottom-up and top-down attentional processes, mediated by discrete large-scale brain networks and their interactions. PMID- 28338946 TI - Instrumental Variable Methods for Continuous Outcomes That Accommodate Nonignorable Missing Baseline Values. AB - Instrumental variable (IV) methods provide unbiased treatment effect estimation in the presence of unmeasured confounders under certain assumptions. To provide valid estimates of treatment effect, treatment effect confounders that are associated with the IV (IV-confounders) must be included in the analysis, and not including observations with missing values may lead to bias. Missing covariate data are particularly problematic when the probability that a value is missing is related to the value itself, which is known as nonignorable missingness. In such cases, imputation-based methods are biased. Using health-care provider preference as an IV method, we propose a 2-step procedure with which to estimate a valid treatment effect in the presence of baseline variables with nonignorable missing values. First, the provider preference IV value is estimated by performing a complete-case analysis using a random-effects model that includes IV-confounders. Second, the treatment effect is estimated using a 2-stage least squares IV approach that excludes IV-confounders with missing values. Simulation results are presented, and the method is applied to an analysis comparing the effects of sulfonylureas versus metformin on body mass index, where the variables baseline body mass index and glycosylated hemoglobin have missing values. Our result supports the association of sulfonylureas with weight gain. PMID- 28338947 TI - Microenvironment in the canopy rivals the host tree water status in controlling sap flow of a mistletoe species. AB - Mistletoes absorb water from the vascular system of their hosts and thus the water use of mistletoes can be influenced by the water status of their hosts besides abiotic environmental conditions; however, there is a lack of studies on the dynamics of mistletoe water utilization in relation to both types of controlling factors. By building a canopy platform at 20 m above the ground, we monitored the dynamic changes of sap flow of Viscum coloratum (Kom.) Nakai (Loranthaceae) in combination with continuous measurements of microclimatic variables and volumetric water content (VWC) of its host tree branch xylem. We found that the host tree VWC exhibited substantial fluctuations during sunny days but lower VWC of the host did not negatively affect the sap flow of V. coloratum. Hourly and daily mean transpiration rates (Esap) of V. coloratum calculated from sap flow measurements showed strong positive correlations with photosynthetic photon flux density (PPFD) and vapor pressure deficit (VPD) measured in close vicinity to the point of mistletoe attachment. The mean Esap of V. coloratum was substantially higher than that of their host during clear days (4.55 +/- 0.54 vs 2.01 +/- 0.15 kg m-2 day-1). Moreover, the mistletoe-to-host transpiration ratio was not constant but became increasingly larger with the increase of PPFD or VPD on both hourly and daily bases, suggesting a weaker control of water loss in the mistletoe in comparison to its host species. The strong dependence of mistletoe Esap on micrometeorological variables and its decoupling from the host tree xylem water status suggests that the development of dense tree canopy functions as a potential mechanism for the host trees in reducing the competitive water use of mistletoes. These findings have important implications for the interactions between mistletoe species and their host trees in temperate forests. PMID- 28338948 TI - COMPARING MEASURED AND CALCULATED DOSES IN INTERVENTIONAL CARDIOLOGY PROCEDURES. AB - Interventional cardiology requires complex procedures and can result in high doses and dose rates to the patient and medical staff. The many variables that influence the dose to the patient and staff include the beam position and angle, beam size, kVp, filtration, kerma-area product and focus-skin distance. A number of studies using the Monte Carlo method have been undertaken to obtain prospective dose assessments. In this paper, detailed irradiation scenarios were simulated mathematically and the resulting dose estimates were compared with real measurements made previously under very similar irradiation conditions and geometries. The real measurements and the calculated doses were carried out using or simulating an interventional cardiology system with a flat monoplane detector installed in a dedicated room with an Alderson phantom placed on the procedure table. The X-ray spectra, beam angles, focus-skin distance, measured kerma-area product and filtration were simulated, and the real dose measurements and calculated doses were compared. It was shown that the Monte Carlo method was capable of reproducing the real dose measurements within acceptable levels of uncertainty. PMID- 28338949 TI - Long-term exposure to transportation noise and air pollution in relation to incident diabetes in the SAPALDIA study. AB - Background: Epidemiological studies have inconsistently linked transportation noise and air pollution (AP) with diabetes risk. Most studies have considered single noise sources and/or AP, but none has investigated their mutually independent contributions to diabetes risk. Methods: We investigated 2631 participants of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA), without diabetes in 2002 and without change of residence between 2002 and 2011. Using questionnaire and biomarker data, incident diabetes cases were identified in 2011. Noise and AP exposures in 2001 were assigned to participants' residences (annual average road, railway or aircraft noise level during day-evening-night (Lden), total night number of noise events, intermittency ratio (temporal variation as proportion of event-based noise level over total noise level) and nitrogen dioxide (NO2) levels. We applied mixed Poisson regression to estimate the relative risk (RR) of diabetes and their 95% confidence intervals (CI) in mutually-adjusted models. Results: Diabetes incidence was 4.2%. Median [interquartile range (IQR)] road, railway, aircraft noise and NO2 were 54 (10) dB, 32 (11) dB, 30 (12) dB and 21 (15) MUg/m3, respectively. Lden road and aircraft were associated with incident diabetes (respective RR: 1.35; 95% CI: 1.02-1.78 and 1.86; 95% CI: 0.96-3.59 per IQR) independently of Lden railway and NO2 (which were not associated with diabetes risk) in mutually adjusted models. We observed stronger effects of Lden road among participants reporting poor sleep quality or sleeping with open windows. Conclusions: Transportation noise may be more relevant than AP in the development of diabetes, potentially acting through noise-induced sleep disturbances. PMID- 28338951 TI - Measuring Transitions in Sexual Risk Among Men Who Have Sex With Men: The Novel Use of Latent Class and Latent Transition Analysis in HIV Sentinel Surveillance. AB - New combination human acquired deficiency (HIV) prevention strategies that include biomedical and primary prevention approaches add complexity to the task of measuring sexual risk. Latent transition models are beneficial for understanding complex phenomena; therefore, we trialed the application of latent class and latent transition models to HIV surveillance data. Our aims were to identify sexual risk states and model individuals' transitions between states. A total of 4,685 HIV-negative men who have sex with men (MSM) completed behavioral questionnaires alongside tests for HIV and sexually transmissible infections at one of 2 Melbourne, Victoria, Australia, general practices (2007-2013). We found 4 distinct classes of sexual risk, which we labeled "monogamous" (n = 1,224), "risk minimizer" (n = 1,443), "risk potential" (n = 1,335), and "risk taker" (n = 683). A positive syphilis, gonorrhea, or chlamydia test was significantly associated with class membership. Among a subset of 516 MSM who had at least 3 clinic visits, there was general stability across risk classes; MSM had on average a 0.70 (i.e., 70%) probability of remaining in the same class between visits 1 and 2 and between visits 2 and 3. Monogamous MSM were one exception; the probability of remaining in the monogamous class was 0.51 between visits 1 and 2. Latent transition analyses identified unobserved risk patterns in surveillance data, characterized high-risk MSM, and quantified transitions over time. PMID- 28338950 TI - Nonreplicative RNA Recombination of an Animal Plus-Strand RNA Virus in the Absence of Efficient Translation of Viral Proteins. AB - RNA recombination is a major driving force for the evolution of RNA viruses and is significantly implicated in the adaptation of viruses to new hosts, changes of virulence, as well as in the emergence of new viruses including drug-resistant and escape mutants. However, the molecular details of recombination in animal RNA viruses are only poorly understood. In order to determine whether viral RNA recombination depends on translation of viral proteins, a nonreplicative recombination system was established which is based on cotransfection of cells with synthetic bovine viral diarrhea virus (family Flaviviridae) RNA genome fragments either lacking the internal ribosome entry site required for cap independent translation or lacking almost the complete polyprotein coding region. The emergence of a number of recombinant viruses demonstrated that IRES-mediated translation of viral proteins is dispensable for efficient recombination and suggests that RNA recombination can occur in the absence of viral proteins. Analyses of 58 independently emerged viruses led to the detection of recombinant genomes with duplications, deletions and insertions in the 5' terminal region of the open reading frame, leading to enlarged core fusion proteins detectable by Western blot analysis. This demonstrates a remarkable flexibility of the pestivirus core protein. Further experiments with capped and uncapped genome fragments containing a luciferase gene for monitoring the level of protein translation revealed that even a ~1,000-fold enhancement of translation of viral proteins did not increase the frequency of RNA recombination. Taken together, this study highlights that nonreplicative RNA recombination does not require translation of viral proteins. PMID- 28338952 TI - Physiological and morphological responses to permanent and intermittent waterlogging in seedlings of four evergreen trees of temperate swamp forests. AB - Waterlogging decreases a plant's metabolism, stomatal conductance (gs) and photosynthetic rate (A); however, some evergreen species show acclimation to waterlogging. By studying both the physiological and morphological responses to waterlogging, the objective of this study was to assess the acclimation capacity of four swamp forest species that reside in different microhabitats. We proposed that species (Luma apiculata [D.C.] Burret. and Drimys winteri J.R. et G. Forster.) abundant in seasonally and intermittently waterlogged areas (SIWA) would have a higher acclimation capacity than species abundant in the inner swamp (Blepharocalyx cruckshanksii [H et A.] Mied. and Myrceugenia exsucca [D.C.] Berg.) where permanent waterlogging occurs (PWA); it was expected that the species from SIWA would maintain leaf expansion and gas exchange rates during intermittent waterlogging treatments. Conversely, we expected that PWA species would have higher constitutive waterlogging tolerance, and this would be reflected in the formation of lenticels and adventitious roots. Over the course of 2 months, we subjected seedlings to different waterlogging treatments: (i) permanent (sudden, SW), (ii) intermittent (gradual) or (iii) control (field capacity, C). Survival after waterlogging was high (>=80%) for all species and treatments, and only the growth rate of D. winteri subjected to SW was affected. Drimys winteri plants had low, but constant A and g during both waterlogging treatments. Conversely, L. apiculata had the highest A and g values, and g increased significantly during the first several days of waterlogging. In general, seedlings of all species subjected to waterlogging produced more adventitious roots and fully expanded leaves and had higher specific leaf area (SLA) and stomatal density (StD) than seedlings in the C treatment. From the results gathered here, we partially accept our hypothesis as all species showed high tolerance to waterlogging, maintained growth, and had increased A or g during different time points of waterlogging. Differences in leaf (SLA) and stomata functioning (gs, StD) plasticity likely allows plants to maintain positive carbon gains when waterlogging occurs. The species-specific differences found here were not entirely related to microhabitat distribution. PMID- 28338953 TI - Elabela, a new endogenous ligand of APJ, functions in embryos and adults organisms. PMID- 28338956 TI - Hemodynamic Consequences of Changes in Microvascular Structure. AB - In hypertension, an increased media-to-lumen ratio of small resistance arteries might play an important role in the increase of vascular resistance, and may also be an adaptive response to the increased hemodynamic load. The presence of morphological alteration in the microvasculature may be associated to an impaired tissue perfusion and/or to the development of target organ damage. Structural alterations in the microcirculation might represent a predictor of the onset of cardio-cerebrovascular events and hypertension complications. A cross-talk between the small and large artery may exaggerate arterial damage, following a vicious circle. Therefore, in the present review, possible hemodynamic consequences of the presence of microvascular structural alterations will be considered, in terms of their time of onset, role in the development and/or maintenance of high blood pressure values, and interrelationships with structural/mechanical alterations of large conductance arteries. PMID- 28338954 TI - Meta-analysis of Cerebrospinal Fluid Cytokine and Tryptophan Catabolite Alterations in Psychiatric Patients: Comparisons Between Schizophrenia, Bipolar Disorder, and Depression. AB - INTRODUCTION: Schizophrenia, bipolar disorder, and major depressive disorder (MDD) have all been associated with immune system dysfunction, including aberrant cerebrospinal fluid (CSF) levels of cytokines and tryptophan catabolites; however, the pattern of alterations has not been compared across disorders. We performed a meta-analysis of CSF cytokine and tryptophan catabolites in patients with these major psychiatric disorders. METHODS: Articles were identified by searching Pub Med, PsycInfo, and Web of Science, and the reference lists of these studies. RESULTS: Twenty-eight studies met the inclusion criteria (16 schizophrenia, 4 bipolar disorder, and 9 MDD). CSF levels of IL-1beta and kynurenic acid were significantly increased in patients with schizophrenia and bipolar disorder compared to healthy controls (P < .001). CSF levels of IL-6 and IL-8 were significantly increased in patients with schizophrenia and MDD compared to healthy controls (P <= .013). DISCUSSION: There is preliminary evidence for similarities in the pattern of CSF cytokine and tryptophan catabolite alterations across major psychiatric disorders, although findings must be interpreted with caution in light of small numbers of studies/subjects. Many CSF alterations are also concordant with those in the peripheral blood, particularly for schizophrenia. Findings have important implications for our understanding of the pathophysiology and treatment of major psychiatric disorders. PMID- 28338955 TI - The role of cognitive reappraisal in placebo analgesia: an fMRI study. AB - Placebo analgesia (PA) depends crucially on the prefrontal cortex (PFC), which is assumed to be responsible for initiating the analgesic response. Surprisingly little research has focused on the psychological mechanisms mediated by the PFC and underlying PA. One increasingly accepted theory is that cognitive reappraisal the reinterpretation of the meaning of adverse events-plays an important role, but no study has yet addressed the possible functional relationship with PA. We studied the influence of individual differences in reappraisal ability on PA and its prefrontal mediation. Participants completed a cognitive reappraisal ability task, which compared negative affect evoked by pictures in a reappraise versus a control condition. In a subsequent fMRI session, PA was induced using thermal noxious stimuli and an inert skin cream. We found a region in the left dorsolateral PFC, which showed a positive correlation between placebo-induced activation and (i) the reduction in participants' pain intensity ratings; and (ii) cognitive reappraisal ability scores. Moreover, this region showed increased placebo-induced functional connectivity with the periaqueductal grey, indicating its involvement in descending nociceptive control. These initial findings thus suggest that cognitive reappraisal mechanisms mediated by the dorsolateral PFC may play a role in initiating pain inhibition in PA. PMID- 28338957 TI - Regulation of TGF-beta-mediated endothelial-mesenchymal transition by microRNA 27. AB - Multiple microRNAs (miRNAs) regulate epithelial-mesenchymal transition and endothelial-mesenchymal transition (EndMT). Here we report that microRNA-27b (miR 27b) positively regulates transforming growth factor-beta (TGF-beta)-induced EndMT of MS-1 mouse pancreatic microvascular endothelial cells. TGF-beta induced miR-23b/24-1/27b expression, and inhibition of miR-27 suppressed TGF-beta mediated induction of mesenchymal genes. Genome-wide miRNA target analysis revealed that miR-27 targets Elk1, which acts as a competitive inhibitor of myocardin-related transcription factor-serum response factor signalling and as a myogenic repressor. miR-27b was also found to regulate several semaphorin receptors including Neuropilin 2, Plexin A2 and Plexin D1. These results suggest important roles of miR-27 in TGF-beta-driven EndMT. PMID- 28338958 TI - Molecular cloning and characterization of antimicrobial peptides from skin of Hylarana guentheri. AB - The cDNAs encoding antimicrobial peptides (AMPs) in the skin of Hylarana guentheri were identified, namely temporin (five peptides, termed temporin-GHa GHd and temporin-GUa), brevinin-1 (one peptide, brevinin-1GUb), and brevinin-2 (eight peptides, brevinin-2GHd-2GHj, and brevinin-2GHb). Eleven of the 14 peptides have novel primary structures. Synthesized temporin GHa-GHd have broad spectrum antimicrobial activities against Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis), Gram-negative bacteria (Escherichia coli, Vibrio alginolyticus, and Pseudomonas aeruginosa), as well as fungus (Candida albicans). Among these tested strains, S. aureus was the most sensitive to temporin-GHa-GHd with minimum inhibitory concentration (MIC) values between 6.8 and 12.9 MUM. They also exhibited antimicrobial activities against Methicillin-resistant S. aureus with the MIC ranging from 12.7 to 51.7 MUM. Interestingly, secondary structure prediction shows that there is no alpha-helix in temporin-GHb, which illustrates that alpha-helix is not required for the antimicrobial activity of temporin-GHb. NaCl (at final concentrations of 0.15-2 M) decreased the antimicrobial activity of temporin-GHa-GHd slightly, while human serum and S. aureus V8 proteinase had no effect on the antimicrobial activity. Scanning electron microscopy images of E. coli and S. aureus showed that the surface of microbial cells was considerably rough and shrived after 1 h of treatment with temporin-GHa-GHd at 37 degrees C. The stabilities of temporin-GHa-GHd in human serum or in S. aureus V8 proteinase make them to be promising candidates of novel antimicrobial agents or models for the development of novel AMPs. PMID- 28338959 TI - Increase in leaf temperature opens stomata and decouples net photosynthesis from stomatal conductance in Pinus taeda and Populus deltoides x nigra. AB - The effect of temperature on stomatal conductance (gs) and corresponding gas exchange parameters was studied in two tree species with contrasting leaf anatomy and ecophysiology-a broadleaf angiosperm, Populus deltoides x nigra (poplar), and a needle-leaf gymnosperm, Pinus taeda (loblolly pine). Experiments were conducted in growth chambers across a leaf temperature range of 19-48 degrees C. Manipulations of temperature were done in well-watered and drought soil conditions and under ambient (400 ppm) and elevated (800 ppm) air CO2 concentrations. Increases in leaf temperature caused stomatal opening at both ambient and elevated [CO2]. The gs increased by 42% in poplar and by 40% in loblolly pine when leaf temperature increased from 30 degrees C to 40 degrees C at a vapour pressure difference of 1 kPa. Stomatal limitation to photosynthesis decreased in elevated temperature in loblolly pine but not in poplar. The ratio of net photosynthesis to gs depended on leaf temperature, especially at high temperatures. Evaporative cooling of transpiring leaves resulted in reductions in leaf temperature up to 9 degrees C in well-watered poplar but only 1 degrees C in drought-stressed poplar and in loblolly pine. As global mean temperatures rise and temperature extremes become more frequent and severe, understanding the effect of temperature on gs, and modelling that relationship, will become increasingly important. PMID- 28338960 TI - Organellar Genomes from a ~5,000-Year-Old Archaeological Maize Sample Are Closely Related to NB Genotype. AB - The story of how preColumbian civilizations developed goes hand-in-hand with the process of plant domestication by Mesoamerican inhabitants. Here, we present the almost complete sequence of a mitochondrial genome and a partial chloroplast genome from an archaeological maize sample collected at the Valley of Tehuacan, Mexico. Accelerator mass spectrometry dated the maize sample to be 5,040-5,300 years before present (95% probability). Phylogenetic analysis of the mitochondrial genome shows that the archaeological sample branches basal to the other Zea mays genomes, as expected. However, this analysis also indicates that fertile genotype NB is closely related to the archaeological maize sample and evolved before cytoplasmic male sterility genotypes (CMS-S, CMS-T, and CMS-C), thus contradicting previous phylogenetic analysis of mitochondrial genomes from maize. We show that maximum-likelihood infers a tree where CMS genotypes branch at the base of the tree when including sites that have a relative fast rate of evolution thus suggesting long-branch attraction. We also show that Bayesian analysis infer a topology where NB and the archaeological maize sample are at the base of the tree even when including faster sites. We therefore suggest that previous trees suffered from long-branch attraction. We also show that the phylogenetic analysis of the ancient chloroplast is congruent with genotype NB to be more closely related to the archaeological maize sample. As shown here, the inclusion of ancient genomes on phylogenetic trees greatly improves our understanding of the domestication process of maize, one of the most important crops worldwide. PMID- 28338961 TI - Expressed Structurally-stable Inverted Duplicates in Mammalian Genomes as Functional Noncoding Elements. AB - Inverted duplicates are a type of repetitive DNA motifs consist of two copies of reverse complementary sequences separated by a spacer sequence. They can lead to genome instability and many may have no function, but some functional small RNAs are processed from hairpins transcribed from these elements. It is not clear whether the pervasive numbers of such elements in genomes, especially those of mammals, is the result of high generation rates of neutral or slightly deleterious duplication events or positive selection for functionality. To test the functionality of intergenic inverted duplicates without known functions, we used mirror duplicates, a type of repetitive DNA motifs with few reported functions and little potential to form hairpins when transcribed, as a nonfunctional control. We identified large numbers of inverted duplicates within intergenic regions of human and mouse genomes, as well as 19 other vertebrate genomes. Structure characterization of these inverted duplicates revealed higher proportion to form stable hairpins compared to converted mirror duplicates, suggesting that inverted duplicates may produce hairpin RNAs. Expression profiling across tissues demonstrated that 7.8% of human and 5.7% of mouse inverted duplicates were expressed even under strict criteria. We found that expressed inverted duplicates were more likely to be structurally stable than both unexpressed inverted duplicates and expressed converted mirror duplicates. By dating inverted duplicates in the vertebrate phylogenetic tree, we observed higher conservation of inverted duplicates than mirror duplicates. These observations support the notion that expressed inverted duplicates may be functional through forming hairpin RNAs. PMID- 28338963 TI - Where and when does stem cellulose delta18O reflect a leaf water enrichment signal? PMID- 28338962 TI - Higher order intentionality tasks are cognitively more demanding. AB - A central assumption that underpins much of the discussion of the role played by social cognition in brain evolution is that social cognition is unusually cognitively demanding. This assumption has never been tested. Here, we use a task in which participants read stories and then answered questions about the stories in a behavioural experiment (39 participants) and an fMRI experiment (17 participants) to show that mentalising requires more time for responses than factual memory of a matched complexity and also that higher orders of mentalising are disproportionately more demanding and require the recruitment of more neurons in brain regions known to be associated with theory of mind, including insula, posterior STS, temporal pole and cerebellum. These results have significant implications both for models of brain function and for models of brain evolution. PMID- 28338964 TI - Relationship between fine-root exudation and respiration of two Quercus species in a Japanese temperate forest. AB - Plants allocate a considerable amount of carbon (C) to fine roots as respiration and exudation. Fine-root exudation could stimulate microbial activity, which further contributes to soil heterotrophic respiration. Although both root respiration and exudation are important components of belowground C cycling, how they relate to each other is less well known. In this study, we aimed to explore this relationship on mature trees growing in the field. The measurements were performed on two canopy species, Quercus serrata Thunb. and Quercus glauca, in a warm temperate forest. The respiration and exudation rates of the same fine-root segment were measured in parallel with a syringe-basis incubation and a closed static chamber, respectively. We also measured root traits and ectomycorrhizal colonization ratio because these indexes commonly relate to root respiration and reflect root physiology. The microbial activity enhanced by root exudation was investigated by comparing the dissolved organic carbon (DOC) and microbial biomass carbon (MBC) between rhizosphere soils and bulk soils. Mean DOC concentration and MBC were ca two times higher in the rhizosphere soils and positively related to exudation rates, indicating that exudation further relates to the C dynamics in the soils. Flux rates of exudation and respiration were positively correlated with each other. Both root exudation and respiration rates positively related to ectomycorrhizal colonization and root tissue nitrogen, and therefore the relationship between the two fluxes may be attributed to fine-root activity. The flux rates of root respiration were 8.7 and 10.5 times as much as those of exudation on a root-length basis and a root-weight basis, respectively. In spite of the fact that flux rates of respiration and exudation varied enormously among the fine-root segments of the two Quercus species, exudation was in proportion to respiration. This result gives new insight into the fine-root C allocation strategy and the belowground C dynamics. PMID- 28338965 TI - Burrowers from the past: mitochondrial signatures of Ordovician bivalve infaunalization. AB - Bivalves and gastropods are the two largest classes of extant molluscs. Despite sharing a huge number of features, they do not share a key ecological one: gastropods are essentially epibenthic, while most bivalves are infaunal. However, this is not the ancestral bivalve condition; Cambrian forms were surface crawlers and only during the Ordovician a fundamental infaunalization process took place, leading to bivalves as we currently know them. This major ecological shift is linked to the exposure to a different redox environoments (hypoxic or anoxic) and with the Lower Devonian oxygenation event. We investigated selective signatures on bivalve and gastropod mitochondrial genomes with respect to a time calibrated mitochondrial phylogeny by means of dN/dS ratios. We were able to detect (i) a major signal of directional selection between the Ordovician and the Lower Devonian for bivalve mitochondrial Complex I, and (ii) an overall higher directional selective pressure on bivalve Complex V with respect to gastropods. These and other minor dN/dS patterns and timings are discussed, showing that the Ordovician infaunalization event left heavy traces in bivalve mitochondrial genomes. PMID- 28338966 TI - A comparison of sensitivity-specificity imputation, direct imputation and fully Bayesian analysis to adjust for exposure misclassification when validation data are unavailable. AB - Purpose: Measurement error is an important source of bias in epidemiological studies. We illustrate three approaches to sensitivity analysis for the effect of measurement error: imputation of the 'true' exposure based on specifying the sensitivity and specificity of the measured exposure (SS); direct imputation (DI) using a regression model for the predictive values; and adjustment based on a fully Bayesian analysis. Methods: We deliberately misclassify smoking status in data from a case-control study of lung cancer. We then implement the SS and DI methods using fixed-parameter (FBA) and probabilistic (PBA) bias analyses, and Bayesian analysis using the Markov-Chain Monte-Carlo program WinBUGS to show how well each recovers the original association. Results: The 'true' smoking-lung cancer odds ratio (OR), adjusted for sex in the original dataset, was OR = 8.18 [95% confidence limits (CL): 5.86, 11.43]; after misclassification, it decreased to OR = 3.08 (nominal 95% CL: 2.40, 3.96). The adjusted point estimates from all three approaches were always closer to the 'true' OR than the OR estimated from the unadjusted misclassified smoking data, and the adjusted interval estimates were always wider than the unadjusted interval estimate. When imputed misclassification parameters departed much from the actual misclassification, the 'true' OR was often omitted in the FBA intervals whereas it was always included in the PBA and Bayesian intervals. Conclusions: These results illustrate how PBA and Bayesian analyses can be used to better account for uncertainty and bias due to measurement error. PMID- 28338968 TI - Two-sample Mendelian randomization: avoiding the downsides of a powerful, widely applicable but potentially fallible technique. PMID- 28338969 TI - The Cascade of Stress: A Network Approach to Explore Differential Dynamics in Populations Varying in Risk for Psychosis. AB - Stress plays a central role in the development and persistence of psychosis. Network analysis may help to reveal mechanisms at the level of the micro-dynamic effects between stress, other daily experiences and symptomatology. This is the first study to examine time-lagged networks of the relations between minor daily stress, momentary affect/thoughts, psychotic experiences, and other potentially relevant daily life contexts in individuals varying in risk for psychosis. Intensive longitudinal data were obtained through 6 studies. The combined sample consisted of 654 individuals varying in risk for psychosis: healthy control subjects (n = 244), first-degree relatives of psychotic patients (n = 165), and psychotic patients (n = 245). Using multilevel models combined with permutation testing, group-specific time-lagged network connections between daily experiences were compared between groups. Specifically, the role of stress was examined. Risk for psychosis was related to a higher number of significant network connections. In all populations, stress had a central position in the network and showed direct and significant connections with subsequent psychotic experiences. Furthermore, the higher the risk for psychosis, the more variables "loss of control" and "suspicious" were susceptible to influences by other network nodes. These findings support the idea that minor daily stress may play an important role in inducing a cascade of effects that may lead to psychotic experiences. PMID- 28338970 TI - Woody-plant ecosystems under climate change and air pollution-response consistencies across zonobiomes? AB - Forests store the largest terrestrial pools of carbon (C), helping to stabilize the global climate system, yet are threatened by climate change (CC) and associated air pollution (AP, highlighting ozone (O3) and nitrogen oxides (NOx)). We adopt the perspective that CC-AP drivers and physiological impacts are universal, resulting in consistent stress responses of forest ecosystems across zonobiomes. Evidence supporting this viewpoint is presented from the literature on ecosystem gross/net primary productivity and water cycling. Responses to CC-AP are compared across evergreen/deciduous foliage types, discussing implications of nutrition and resource turnover at tree and ecosystem scales. The availability of data is extremely uneven across zonobiomes, yet unifying patterns of ecosystem response are discernable. Ecosystem warming results in trade-offs between respiration and biomass production, affecting high elevation forests more than in the lowland tropics and low-elevation temperate zone. Resilience to drought is modulated by tree size and species richness. Elevated O3 tends to counteract stimulation by elevated carbon dioxide (CO2). Biotic stress and genomic structure ultimately determine ecosystem responsiveness. Aggrading early- rather than mature late-successional communities respond to CO2 enhancement, whereas O3 affects North American and Eurasian tree species consistently under free-air fumigation. Insect herbivory is exacerbated by CC-AP in biome-specific ways. Rhizosphere responses reflect similar stand-level nutritional dynamics across zonobiomes, but are modulated by differences in tree-soil nutrient cycling between deciduous and evergreen systems, and natural versus anthropogenic nitrogen (N) oversupply. The hypothesis of consistency of forest responses to interacting CC-AP is supported by currently available data, establishing the precedent for a global network of long-term coordinated research sites across zonobiomes to simultaneously advance both bottom-up (e.g., mechanistic) and top down (systems-level) understanding. This global, synthetic approach is needed because high biological plasticity and physiographic variation across individual ecosystems currently limit development of predictive models of forest responses to CC-AP. Integrated research on C and nutrient cycling, O3-vegetation interactions and water relations must target mechanisms' ecosystem responsiveness. Worldwide case studies must be subject to biostatistical exploration to elucidate overarching response patterns and synthesize the resulting empirical data through advanced modelling, in order to provide regionally coherent, yet globally integrated information in support of internationally coordinated decision-making and policy development. PMID- 28338967 TI - Thought Disorder in Schizophrenia and Bipolar Disorder Probands, Their Relatives, and Nonpsychiatric Controls. AB - Thought disorder (TD) has long been associated with schizophrenia (SZ) and is now widely recognized as a symptom of mania and other psychotic disorders as well. Previous studies have suggested that the TD found in the clinically unaffected relatives of SZ, schizoaffective and bipolar probands is qualitatively similar to that found in the probands themselves. Here, we examine which quantitative measures of TD optimize the distinction between patients with diagnoses of SZ and bipolar disorder with psychotic features (BP) from nonpsychiatric controls (NC) and from each other. In addition, we investigate whether these same TD measures also distinguish their respective clinically unaffected relatives (RelSZ, RelBP) from controls as well as from each other. We find that deviant verbalizations are significantly associated with SZ and are co-familial in clinically unaffected RelSZ, but are dissociated from, and are not co-familial for, BP disorder. In contrast, combinatory thinking was nonspecifically associated with psychosis, but did not aggregate in either group of relatives. These results provide further support for the usefulness of TD for identifying potential non-penetrant carriers of SZ-risk genes, in turn enhancing the power of genetic analyses. These findings also suggest that further refinement of the TD phenotype may be needed in order to be suitable for use in genetic studies of bipolar disorder. PMID- 28338971 TI - Progressive silencing of the zinc transporter Zip8 (Slc39a8) in chronic cadmium exposed lung epithelial cells. AB - Cadmium (Cd), a non-essential metal, stealthily enters the cells by utilizing the essential metal importing pathways. The zinc transporters Zip8, Zip14, and divalent metal transporter 1 (Dmt1) are now emerging as several important metal transporters involved in cellular Cd incorporation and their expressions have been shown to be down-regulated in several Cd-resistant (CdR) cell lines, however, the involvement of these transporters during the development of Cd resistance in lung cells is unclear. In this study, we therefore check the expression of these metal transporters in our previously established rat lung epithelial cells (LECs) and show that the level of Zip8 is progressively silenced when LECs are adapted to increasing concentrations of CdCl2 (from 1 to 20 MUM). Subsequent measurement of the cellular Cd content indicated that CdR LECs exhibit a marked decrease of Cd accumulation, possibly due to the loss of Zip8 expression. We investigate the possibility that epigenetic silencing of the Zip8 gene by DNA hypermethylation is involved in the down-regulation of Zip8 expression. CdR LECs show a higher mRNA level of DNA methyltransferase 3b (Dnmt3b) than parental cells. Treatment of CdR LECs with 5-aza-2'-deoxycytidine, an inhibitor of DNA methyltransferases, reverted the expression of Zip8 and sensitivity to Cd in these cells, indicating the critical role of Zip8 for Cd import. Taken together, our results demonstrate that the progressive silencing of Zip8 expression is involved in the acquisition of resistance against Cd in lung cells, representing an adaptive survival mechanism that resists Cd-induced cytotoxicity. PMID- 28338972 TI - Wilkinson et al. Respond to "Latent Transition Analyses in Clinical Cohorts". PMID- 28338974 TI - Recombinant CC16 protein inhibits the production of pro-inflammatory cytokines via NF-kappaB and p38 MAPK pathways in LPS-activated RAW264.7 macrophages. AB - Accumulating evidence indicates that Clara cell protein-16 (CC16) has anti inflammatory functions, although the involved molecular pathways have not been completely elucidated. Here, we evaluated the effect of recombinant rat CC16 (rCC16) on the expression of tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and IL-8 in lipopolysaccharide (LPS)-stimulated mouse macrophages (RAW264.7 cells) and explored the underlying molecular mechanisms. It was found that rCC16 inhibited LPS-induced TNF-alpha, IL-6, and IL-8 expression at both the messenger ribonucleicacid (mRNA) level and protein level in a concentration dependent manner, as demonstrated by real-time reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. Such suppressive effects were accompanied by the inhibition of transcriptional activity and the deoxyribonucleic acid binding activity of nuclear factor (NF)-kappaB but not activator protein (AP)-1. Western blot analysis further revealed that rCC16 inhibited the increase of nuclear NF-kappaB and the reduction of cytosolic NF kappaB, the phosphorylation and reduction of NF-kappaB inhibitory protein IkappaBalpha, and the p38 mitogen-activated protein kinase (MAPK)-dependent NF kappaB activation by phosphorylation at Ser276 of its p65 subunit. Furthermore, rCC16 was found to have no effect on the phosphorylation of c-Jun N-terminal kinase, c-Jun, or the nuclear translocation of c-Jun. In addition, reduction of TNF-alpha, IL-6, and IL-8 were reversed when the level of endogenous uteroglobin binding protein was reduced by RNA interference in rCC16- and LPS-treated RAW264.7 cells. Our data suggest that rCC16 suppresses LPS-mediated inflammatory mediator TNF-alpha, IL-6, and IL-8 production by inactivating NF-kappaB and p38 MAPK but not AP-1 in RAW264.7 cells. PMID- 28338975 TI - Drought and reproductive effort interact to control growth of a temperate broadleaved tree species (Fagus sylvatica). AB - Interannual variation in radial growth is influenced by a range of physiological processes, including variation in annual reproductive effort, although the importance of reproductive allocation has rarely been quantified. In this study, we use long stand-level records of annual seed production, radial growth (tree ring width) and meteorological conditions to analyse the relative importance of summer drought and reproductive effort in controlling the growth of Fagus sylvatica L., a typical masting species. We show that both summer drought and reproductive effort (masting) influenced growth. Importantly, the effects of summer drought and masting were interactive, with the greatest reductions in growth found in years when high reproductive effort (i.e., mast years) coincided with summer drought. Conversely, mast years that coincided with non-drought summers were associated with little reduction in radial growth, as were drought years that did not coincide with mast years. The results show that the strength of an inferred trade-off between growth and reproduction in this species (the cost of reproduction) is dependent on environmental stress, with a stronger trade off in years with more stressful growing conditions. These results have widespread implications for understanding interannual variability in growth, and observed relationships between growth and climate. PMID- 28338976 TI - Synchronisms between bud and cambium phenology in black spruce: early-flushing provenances exhibit early xylem formation. AB - Bud and cambial phenology represent the adaptation of species to the local environment that allows the growing season to be maximized while minimizing the risk of frost for the developing tissues. The temporal relationship between the apical and radial meristems can help in the understanding of tree growth as a whole process. The aim of this study was to compare cambial phenology in black spruce (Picea mariana (Mill.) B.S.P.) provenances classified as early and late bud flushing. The different phases of cambial phenology were assessed on wood microcores sampled weekly from April to October in 2014 and 2015 from 61 trees growing in a provenance trial in Quebec, Canada. Trees showing an early bud flush also exhibited early reactivation of xylem differentiation, although an average difference of 12 days for buds corresponded to small although significant differences of 4 days for xylem. Provenances with early bud flush had an early bud set and completed xylem formation earlier than late bud flush provenances. No significant difference in the period of xylem formation and total growth was observed between the flushing classes. Our results demonstrate that the ecotype differentiation of black spruce provenances represented by the phenological adaptation of buds to the local climate corresponds to specific growth dynamics of the xylem. PMID- 28338978 TI - Isotope signals and anatomical features in tree rings suggest a role for hydraulic strategies in diffuse drought-induced die-back of Pinus nigra. AB - The 2003 and 2012 summer seasons were among the warmest and driest of the last 200 years over southeastern Europe, and in particular in the Karst region (northeastern Italy). Starting from winter-spring 2013, several black pines (Pinus nigra J.F. Arnold) suffered crown die-back. Declining trees occurred nearby individuals with no signs of die-back, raising hypotheses about the occurrence of individual-specific hydraulic strategies underlying different responses to extreme drought. We investigated possible processes driving black pine decline by dendrochronological and wood anatomical measurements, coupled with analysis of tree-ring carbon (delta13C) and oxygen (delta18O) isotopic composition in healthy trees (H) and trees suffering die-back (D). Die-back trees showed higher growth rates than H trees at the beginning of the last century, but suffered important growth reduction following the dry summers in 2003 and 2012. After the 2012 drought, D trees produced tracheids with larger diameter and greater vulnerability to implosion than H ones. Healthy trees had significantly higher wood delta13C than D trees, reflecting higher water-use efficiency for the surviving trees, i.e., less water transpired per unit carbon gain, which could be related to lower stomatal conductance and a more conservative use of water. Relatively high delta18O for D trees indicates that they were strongly dependent on shallow water sources, or that they sustained higher transpiration rates than H trees. Our results suggest that H trees adopted a more conservative water-use strategy under drought stress compared with D trees. We speculate that this diversity might have a genotypic basis, but other possible explanations, like different rooting depth, cannot be ruled out. PMID- 28338979 TI - Commentary: Incorporating concepts and methods from causal inference into life course epidemiology. PMID- 28338973 TI - Inflammation, Autoimmunity, and Hypertension: The Essential Role of Tissue Transglutaminase. AB - Inflammatory cytokines cause hypertension when introduced into animals. Additional evidence indicates that cytokines induce the production of autoantibodies that activate the AT1 angiotensin receptor (AT1R). Extensive evidence shows that these autoantibodies, termed AT1-AA, contribute to hypertension. We review here recent studies showing that cytokine-induced hypertension and AT1-AA production require the ubiquitous enzyme, tissue transglutaminase (TG2). We consider 3 mechanisms by which TG2 may contribute to hypertension. (i) One involves the posttranslational modification (PTM) of AT1Rs at a glutamine residue that is present in the epitope sequence (AFHYESQ) recognized by AT1-AA. (ii) Another mechanism by which TG2 may contribute to hypertension is by PTM of AT1Rs at glutamine 315. Modification at this glutamine prevents ubiquitination-dependent proteasome degradation and allows AT1Rs to accumulate. Increased AT1R abundance is likely to account for increased sensitivity to Ang II activation and in this way contribute to hypertension. (iii) The increased TG2 produced as a result of elevated inflammatory cytokines is likely to contribute to vascular stiffness by modification of intracellular contractile proteins or by crosslinking vascular proteins in the extracellular matrix. This process, termed inward remodeling, results in reduced vascular lumen, vascular stiffness, and increased blood pressure. Based on the literature reviewed here, we hypothesize that TG2 is an essential participant in cytokine induced hypertension. From this perspective, selective TG2 inhibitors have the potential to be pharmacologic weapons in the fight against hypertension. PMID- 28338980 TI - A MULTI-ELEMENT THICK GAS ELECTRON MULTIPLIER-BASED MICRODOSEMETER FOR MEASUREMENT OF NEUTRONS DOSE-EQUIVALENT: A MONTE CARLO STUDY. AB - To determine the dose-equivalent of neutrons in an extended energy range, in the present work a multi-element thick gas electron multiplier-based microdosemeter made of PMMA (Perspex) walls of 10 mm in thickness is designed. Each cavity is filled with the propane-based tissue-equivalent (TE) gas simulating 1 um of tissue. Also, a few weight fractions of 3He are assumed to be added to the TE gas. The dose-equivalents are determined for 11 neutron energies between thermal and 14 MeV using the lineal energy distributions calculated by Geant4 simulation toolkit and also the lineal energy-based quality factors. The results show that by adding 0.04% of 3He to the TE gas in each cavity, an energy-independent dose equivalent response within 30% uncertainty around a median value of 0.91 in the above energy range is achieved. It is concluded that after its construction, the studied microdosemeter can be used to measure the dose-equivalent of neutrons, favorably. PMID- 28338977 TI - Effects of Augmenting N-Methyl-D-Aspartate Receptor Signaling on Working Memory and Experience-Dependent Plasticity in Schizophrenia: An Exploratory Study Using Acute d-cycloserine. AB - Cognitive deficits in schizophrenia have been hypothesized to reflect N-methyl-D aspartate receptor (NMDAR) dysfunction. However, the mechanisms through which the NMDAR contributes to individual cognitive functions differ. To explore how NMDAR signaling relates to specific cognitive deficits in schizophrenia, we tested the effects of enhancing NMDAR signaling on working memory and experience-dependent plasticity using d-cycloserine (DCS). Plasticity was assessed using an EEG paradigm that utilizes high-frequency visual stimulation (HFvS) to induce neural potentiation, and 2 learning tasks, the information integration (IIT) and weather prediction (WPT) tasks. Working memory was assessed using an N-back task. Forty five schizophrenia patients were randomized to receive a single 100 mg DCS dose (SZ-DCS; n = 24) or placebo (SZ-PLC; n = 21) in a double-blind, between-groups design. Testing occurred on a single day after placebo or DCS administration; baseline values were not obtained. DCS did not affect plasticity, as indicated by similar neural potentiation, and similar IIT and WPT learning between groups. However, among patients who successfully engaged in the working memory task (ie, performed above chance), SZ-DCS (n = 17) showed superior 2-back performance compared to SZ-PLC (n = 16). Interestingly, SZ-DCS also showed larger pre-HFvS neural responses during the LTP task. Notably, this pattern of DCS effects is the opposite of those found in our prior study of healthy adults. Results are consistent with target engagement of the NMDAR by DCS, but suggest that NMDAR signaling was not translated into synaptic plasticity changes in schizophrenia. Results highlight the importance of considering how distinct NMDAR-associated processes contribute to individual cognitive deficits in schizophrenia. PMID- 28338981 TI - Continuity and changes in three types of caregiving and the risk of depression in later life: a 2-year prospective study. AB - Objective: previous studies have well documented the psychological consequences of family caregiving but less is known about the heterogeneity of older carers being affected during different temporal phases of caregiving over time. This study aimed to prospectively examine the impact of continuity and changes in grandchild care, parent care and spouse care on older carers' depressive symptoms 2 years later. Methods: the analytic sample contained 2,398 urban seniors who completed interviews for both the 2011 and 2013 waves of the China Health and Retirement Longitudinal Study. The generalized estimating equations approach estimated the longitudinal associations of caring transitions with depressive symptoms. Results: in comparison with non-carers, elders who continuously provided grandchild care, and those who stopped providing parent care reported significantly fewer depressive symptoms; those who entered into or exited from providing spousal care reported significantly more depressive symptoms. Conclusions: by separating the impact of caring transitions on subsequent depressive symptoms, our findings added evidence of the great diversity of caring experiences among older adults who provided care to grandchildren, parents or spouses. Our findings have implications for carer support programmes in targeting those older carers at higher risk of depression. PMID- 28338982 TI - RNA Editing During Sexual Development Occurs in Distantly Related Filamentous Ascomycetes. AB - RNA editing is a post-transcriptional process that modifies RNA molecules leading to transcript sequences that differ from their template DNA. A-to-I editing was found to be widely distributed in nuclear transcripts of metazoa, but was detected in fungi only recently in a study of the filamentous ascomycete Fusarium graminearum that revealed extensive A-to-I editing of mRNAs in sexual structures (fruiting bodies). Here, we searched for putative RNA editing events in RNA-seq data from Sordaria macrospora and Pyronema confluens, two distantly related filamentous ascomycetes, and in data from the Taphrinomycete Schizosaccharomyces pombe. Like F. graminearum, S. macrospora is a member of the Sordariomycetes, whereas P. confluens belongs to the early-diverging group of Pezizomycetes. We found extensive A-to-I editing in RNA-seq data from sexual mycelium from both filamentous ascomycetes, but not in vegetative structures. A-to-I editing was not detected in different stages of meiosis of S. pombe. A comparison of A-to-I editing in S. macrospora with F. graminearum and P. confluens, respectively, revealed little conservation of individual editing sites. An analysis of RNA-seq data from two sterile developmental mutants of S. macrospora showed that A-to-I editing is strongly reduced in these strains. Sequencing of cDNA fragments containing more than one editing site from P. confluens showed that at the beginning of sexual development, transcripts were incompletely edited or unedited, whereas in later stages transcripts were more extensively edited. Taken together, these data suggest that A-to-I RNA editing is an evolutionary conserved feature during fruiting body development in filamentous ascomycetes. PMID- 28338983 TI - Multi-Site Clinical Assessment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (MCAM): Design and Implementation of a Prospective/Retrospective Rolling Cohort Study. AB - In the Multi-Site Clinical Assessment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (MCAM), we relied on expert clinician diagnoses to enroll patients from 7 specialty clinics in the United States in order to perform a systematic collection of data on measures of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). Healthy persons and those with other illnesses that share some features with ME/CFS were enrolled in comparison groups. The major objectives were to: 1) use standardized questionnaires to measure illness domains of ME/CFS and to evaluate patient heterogeneity overall and between clinics; 2) describe the course of illness, identify the measures that best correlate with meaningful clinical differences, and assess the performances of questionnaires as patient/person-reported outcome measures; 3) describe prescribed medications, orders for laboratory and other tests, and management tools used by expert clinicians to care for persons with ME/CFS; 4) collect biospecimens for future hypothesis testing and for evaluation of morning cortisol profiles; and 5) identify measures that best distinguish persons with ME/CFS from those in the comparison groups and detect subgroups of persons with ME/CFS who may have different underlying causes. Enrollment began in 2012 and is planned to continue in multiple stages through 2017. We present the MCAM methods in detail, along with an initial description of the 471 patients with ME/CFS who were enrolled in stage 1. PMID- 28338984 TI - E3 ubiquitin ligases SIAH1/2 regulate hypoxia-inducible factor-1 (HIF-1)-mediated Th17 cell differentiation. AB - IL-17 is known to be a cytokine mainly secreted from Th17 cells, which well associate with autoimmune inflammatory responses. In the generation of Th17 cells, RORc and RORa have pivotal roles in controlling the transcription of Il17. We speculated additional regulation in Il17a transcription and randomly screened a 6344 clone cDNA library to identify specific modulators for Il17a promoter activity. After the screen, the E3 ubiquitin ligases SIAH1 and SIAH2 were investigated further and confirmed to increase Il17a promoter activity in a T cell line and to promote Th17 development ex vivo. This enhancement was a consequence of enhanced expression of hypoxia-inducible factor-1alpha (HIF 1alpha) protein, which is reported to directly regulate expression of Il17a and Rorgt at the transcriptional level. In the absence of HIF-1alpha, both ubiquitin ligases had little effect on Th17 cell differentiation. These results suggest that the SIAH1 and SIAH2 play a pivotal role to promote Th17 cell differentiation through maintaining the stability of HIF-1alpha protein. PMID- 28338985 TI - Regulatory mechanisms and cellular functions of non-centrosomal microtubules. AB - Proper organization of microtubule (MT) arrays is essential for numerous cellular functions, including intracellular transport and cell migration. Although the centrosome generally serves as the primary MT-organizing centre in proliferating animal cells, MTs are also organized at the Golgi apparatus in a wide range of cell types to regulate Golgi ribbon formation that is required for polarized cell migration. Furthermore, differentiated epithelial cells and neurons possess organized non-centrosomal MTs predominantly at the apical cortical regions and the axonal and dendritic neurites, respectively, to establish and maintain their highly polarized morphology. Unlike radial arrays of centrosomal MTs, non centrosomal MTs are organized into non-radial asymmetric network, which facilitates polarized transport and cell polarization. In this review, we will focus on recent advances in our understanding of the regulatory mechanisms and cellular functions of non-centrosomal MTs. PMID- 28338987 TI - Gamma-glutamyltransferase levels, prediabetes and type 2 diabetes: a Mendelian randomization study. AB - Background: High levels of serum gamma-glutamyltransferase (GGT) are associated with increased risk of prediabetes and type 2 diabetes in observational studies. It is unclear whether this relationship is causal, arises from residual confounding or is a consequence of reverse causation. Methods: We used data from a prospective population-based cohort study, compromising 8611 individuals without diabetes at baseline. Cox proportional hazard models were used to study the association between serum GGT levels and incident prediabetes and diabetes. A Mendelian randomization (MR) study was performed using a genetic risk score consisting of 26 GGT-related variants, based on a genome-wide association study (GWAS) on liver enzymes. Association with diabetes and glycaemic traits were investigated within the Rotterdam Study and large-scale GWAS. Results: During follow-up, 1125 cases of prediabetes (mean follow-up 5.7 years) and 811 cases of type 2 diabetes (6.9 years) were ascertained. The predicted hazard ratios per standard deviation (SD) change in GGT levels in the multivariable model were 1.10 for prediabetes [95% confidence interval (CI): 1.02-1.19] and 1.19 for type 2 diabetes (95% CI: 1.10-1.30). The genetic risk score associated with increased GGT levels (beta per SD log GGT = 0.41, 95% CI: 0.35-0.47), explaining 3.5% of the observed variation in GGT. MR analysis did not provide evidence for a causal role of GGT, with a causal relative risk for prediabetes and type 2 diabetes per SD of log GGT of 0.97 (95% CI: 0.91-1.04) and 0.96 (95% CI: 0.89-1.04), respectively. Multiple instrumental analysis using genetic associations with type 2 diabetes and glycaemic traits from previous GWA studies detected no causal effect of GGT. Conclusions: MR analyses did not support a causal role of GGT on the risk of prediabetes or diabetes. The association of GGT with diabetes in observational studies is likely to be driven by reverse causation or confounding bias. As such, therapeutics targeted at lowering GGT levels are unlikely to be effective in preventing diabetes. PMID- 28338986 TI - Genome-Wide Estimates of Transposable Element Insertion and Deletion Rates in Drosophila Melanogaster. AB - Knowing the rate at which transposable elements (TEs) insert and delete is critical for understanding their role in genome evolution. We estimated spontaneous rates of insertion and deletion for all known, active TE superfamilies present in a set of Drosophila melanogaster mutation-accumulation (MA) lines using whole genome sequence data. Our results demonstrate that TE insertions far outpace TE deletions in D. melanogaster. We found a significant effect of background genotype on TE activity, with higher rates of insertions in one MA line. We also found significant rate heterogeneity between the chromosomes, with both insertion and deletion rates elevated on the X relative to the autosomes. Further, we identified significant associations between TE activity and chromatin state, and tested for associations between TE activity and other features of the local genomic environment such as TE content, exon content, GC content, and recombination rate. Our results provide the most detailed assessment of TE mobility in any organism to date, and provide a useful benchmark for both addressing theoretical predictions of TE dynamics and for exploring large-scale patterns of TE movement in D. melanogaster and other species. PMID- 28338988 TI - Phylogenetics of Lophotrochozoan bHLH Genes and the Evolution of Lineage-Specific Gene Duplicates. AB - The gain and loss of genes encoding transcription factors is of importance to understanding the evolution of gene regulatory complexity. The basic helix-loop helix (bHLH) genes encode a large superfamily of transcription factors. We systematically classify the bHLH genes from five mollusc, two annelid and one brachiopod genomes, tracing the pattern of bHLH gene evolution across these poorly studied Phyla. In total, 56-88 bHLH genes were identified in each genome, with most identifiable as members of previously described bilaterian families, or of new families we define. Of such families only one, Mesp, appears lost by all these species. Additional duplications have also played a role in the evolution of the bHLH gene repertoire, with many new lophotrochozoan-, mollusc-, bivalve-, or gastropod-specific genes defined. Using a combination of transcriptome mining, RT-PCR, and in situ hybridization we compared the expression of several of these novel genes in tissues and embryos of the molluscs Crassostrea gigas and Patella vulgata, finding both conserved expression and evidence for neofunctionalization. We also map the positions of the genes across these genomes, identifying numerous gene linkages. Some reflect recent paralog divergence by tandem duplication, others are remnants of ancient tandem duplications dating to the lophotrochozoan or bilaterian common ancestors. These data are built into a model of the evolution of bHLH genes in molluscs, showing formidable evolutionary stasis at the family level but considerable within-family diversification by tandem gene duplication. PMID- 28338989 TI - A simple stable carbon isotope method for investigating changes in the use of recent versus old carbon in oak. AB - Stable carbon isotope ratios from early-wood (EW) and late-wood (LW) are used to test competing models of carbon storage and allocation, providing a cost effective alternative to measuring and dating non-structural carbohydrates in mature temperate broad-leaf forest trees growing under natural conditions. Annual samples of EW and LW from seven mature oaks (Quercus robur L.) from Scotland, covering AD 1924-2012, were pooled, treated to isolate alpha-cellulose and pyrolysed to measure the carbon isotope ratios. Late-wood values are strongly correlated with summer temperature of the year of growth and EW contains the same signal offset by 1 year. After a warm summer, isotopic ratios of EW are similar to those of the preceding LW, but following cold summers they are relatively enriched. The results conflict with established models of isotopic variation within oak tree rings but support 'two-pool' models for storage of non-structural carbohydrates, with EW formation, which occurs prior to budburst, preferentially using young reserves accumulated in the previous summer. Under poor growing conditions trees access older reserves. Slight average isotopic enrichment of EW may be explained by preferential accumulation of reserves during warmer summers rather than by isotopic enrichment during starch formation in non-photosynthetic tissue. PMID- 28338990 TI - THE MAYAK WORKER DOSIMETRY SYSTEM (MWDS-2013): AN INTRODUCTION TO THE DOCUMENTATION. AB - The reconstruction of radiation doses to Mayak Production Association workers in central Russia supports radiation epidemiological studies for the U.S.-Russian Joint Coordinating Committee on Radiation Effects Research. The most recent version of the dosimetry was performed with the Mayak Worker Dosimetry System 2013. This introduction outlines the logic and general content of the series of articles presented in this issue of Radiation Protection Dosimetry. The articles summarize the models, describe the basis for most of the key decisions made in developing the models and present an overview of the results. PMID- 28338991 TI - miR-30e is negatively regulated by myostatin in skeletal muscle and is functionally related to fiber-type composition. AB - Myostatin (MSTN) negatively regulates skeletal myogenesis in which microRNAs (miRNAs) also play critical roles. Using miRNA microarrays of skeletal muscle from MSTN-knockout (MSTN-/-) mice, we recently showed that miR-431 is regulated by MSTN signaling. To identify additional miRNAs regulated by MSTN, we re analyzed these miRNA arrays and validated their expression by quantitative RT PCR. Herein, we demonstrated that miR-30e was significantly upregulated in skeletal muscle of MSTN-/- mice compared with that of the wild-type littermates. Importantly, the predicted targets of miR-30e are functionally involved in myocyte differentiation and fiber-type formation. Using luciferase reporter gene assays, we further showed that peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (Pgc1alpha), is a direct target of miR-30e. Overexpression of miR-30e in C2C12 cells significantly decreased Pgc1alpha and increased type II form of myosin heavy chain gene expression, suggesting that miR-30e functionally associates with glycolytic myofiber formation. Thus, our data indicate that the altered fiber-type composition in MSTN-/- mice are attributable in part to deregulated expression of miR-30e. PMID- 28338992 TI - Identification of the Eucalyptus grandis chitinase gene family and expression characterization under different biotic stress challenges. AB - Eucalyptus grandis (W. Hill ex Maiden) is an Australian Myrtaceae tree grown for timber in many parts of the world and for which the annotated genome sequence is available. Known to be susceptible to a number of pests and diseases, E. grandis is a useful study organism for investigating defense responses in woody plants. Chitinases are widespread in plants and cleave glycosidic bonds of chitin, the major structural component of fungal cell walls and arthropod exoskeletons. They are encoded by an important class of genes known to be up-regulated in plants in response to pathogens. The current study identified 67 chitinase gene models from two families known as glycosyl hydrolase 18 and 19 (36 GH18 and 31 GH19) within the E. grandis genome assembly (v1.1), indicating a recent gene expansion. Sequences were aligned and analyzed as conforming to currently recognized plant chitinase classes (I-V). Unlike other woody species investigated to date, E. grandis has a single gene encoding a putative vacuolar targeted Class I chitinase. In response to Leptocybe invasa (Fisher & La Salle) (the eucalypt gall wasp) and Chrysoporthe austroafricana (Gryzenhout & M.J. Wingf. 2004) (causal agent of fungal stem canker), this Class IA chitinase is strongly up-regulated in both resistant and susceptible plants. Resistant plants, however, indicate greater constitutive expression and increased up-regulation than susceptible plants following fungal challenge. Up-regulation within fungal resistant clones was further confirmed with protein data. Clusters of putative chitinase genes, particularly on chromosomes 3 and 8, are significantly up-regulated in response to fungal challenge, while a cluster on chromosome 1 is significantly down regulated in response to gall wasp. The results of this study show that the E. grandis genome has an expanded group of chitinase genes, compared with other plants. Despite this expansion, only a single Class I chitinase is present and this gene is highly up-regulated within diverse biotic stress conditions. Our research provides insight into a major class of defense genes within E. grandis and indicates the importance of the Class I chitinase. PMID- 28338993 TI - Dihydrocelastrol inhibits multiple myeloma cell proliferation and promotes apoptosis through ERK1/2 and IL-6/STAT3 pathways in vitro and in vivo. AB - Multiple myeloma (MM) is the second most frequent malignant hematological disease. Dihydrocelastrol (DHCE) is synthesized by hydrogenated celastrol, a treterpene isolated from Chinese medicinal plant Tripterygium regelii. In this study, we first reported the anti-tumor activity of DHCE on MM cells. We found that DHCE could inhibit cell proliferation and promote apoptosis through caspase dependent way in vitro. In addition, DHCE could inactivate the expression of interleukin (IL)-6 and downregulate the phosphorylation of extracellular regulated protein kinases (ERK1/2) and the signal transducer and activator of transcription 3 (STAT3) in MM. It also retained its activity against MM cell lines in the presence of IL-6. Furthermore, treatment of MM cells with DHCE resulted in an accumulation of cells in G0/G1 phase of the cell cycle. Notably, DHCE reduced the expression of cyclin D1 and cyclin-dependent kinases 4 and 6 in MM cell lines. Additionally, its efficacy toward the MM cell lines could be enhanced in combination with the histone deacetylase inhibitor panobinostat (LBH589), which implied the possibility of the combination treatment of DHCE and LBH589 as a potential therapeutic strategy in MM. In addition, treatment of NCI H929 tumor-bearing nude mice with DHCE (10 mg/kg/d, i.p., 1-14 days) resulted in 73% inhibition of the tumor growth in vivo. Taken together, the results of our present study indicated that DHCE could inhibit cellular proliferation and induce cell apoptosis in myeloma cells mediated through different mechanisms, possibly through inhibiting the IL-6/STAT3 and ERK1/2 pathways. And it may provide a new therapeutic option for MM patients. PMID- 28338994 TI - Marfan Syndrome: Staging Nonsurgical vs Surgical Treatments in Children With Subluxated Lenses and Refractive Problems. PMID- 28338995 TI - "My Baby's Eyes Are Large. . . They Said It Was Nothing". PMID- 28338996 TI - The Directions Are on the Box. PMID- 28338997 TI - Establishing a Baseline for Meibomian Gland Morphology in Children. PMID- 28338998 TI - The Retinal Lesion is Moving! PMID- 28338999 TI - Knee Bracing After Anterior Cruciate Ligament Reconstruction. PMID- 28339000 TI - Outpatient Lower Extremity Total Joint Arthroplasty: Where Are We Heading? PMID- 28339001 TI - Centers for Medicare & Medicaid Services' Comprehensive Care for Joint Replacement: The Present and Future for Orthopedic Surgeons. AB - The primary aim of this article is to describe the structure and challenges of Medicare and Medicaid reimbursement for a total hip or knee arthroplasty within the context of the Comprehensive Care for Joint Replacement model. The secondary aims are to identify potential challenges for reimbursement and solutions to overcome challenges for the orthopedic surgeon, and to describe and compare the current and projected reimbursement structures for total arthroplasty procedures. Final decisions on reimbursement for total arthroplasty as outlined by the Centers for Medicare & Medicaid Services are reviewed. The impact of these decisions and the effect of the Centers for Medicare & Medicaid Services' payment structure on reimbursement for surgeons and organizations and the effect on patient care are highlighted. [Orthopedics. 2017; 40(2):77-80.]. PMID- 28339002 TI - RGN's Commitment to Moving Intervention Science Forward: Specifying Targets, Mechanisms of Action, and Outcomes. PMID- 28339003 TI - Influence of Leisure Competence and Level of Leisure Activity on Life Satisfaction in Low-Income Older Adults in Rural South Korea. AB - The purpose of the current study was to investigate the relationships among leisure competence, level of leisure activity, and life satisfaction in low income older adults in rural South Korea. A sample of 137 older adults answered the study questionnaire, and significant differences in leisure competence were noted depending on age, religion, and perceived health status as well as level of leisure activity based on perceived health status and type of leisure activities. There were also notable differences in life satisfaction regarding religion and perceived health status, and a correlation among leisure competence, level of leisure activity, and life satisfaction; the influencing power of leisure competence and level of leisure activity on life satisfaction was 47%. The findings suggest that enhancement of older adults' leisure competence may increase participation in leisure activities. [Res Gerontol Nurs. 2017; 10(2):67 75.]. PMID- 28339004 TI - Cyclocurcumin, a curcumin derivative, exhibits immune-modulating ability and is a potential compound for the treatment of rheumatoid arthritis as predicted by the MM-PBSA method. AB - The control and treatment of rheumatoid arthritis is a challenge in today's world. Therefore, the pursuit of natural disease-modifying antirheumatic drugs (DMRDs) remains a top priority in rheumatology. The present study focused on curcumin and its derivatives in the search for new DMRDs. We focused on prominent p38 mitogen-activated protein (MAP) kinase p38alpha which is a prime regulator of tumor necrosis factor-alpha (TNF-alpha), a key mediator of rheumatoid arthritis. In the present study, we used the X-ray crystallographic structure of p38alpha for molecular docking simulations and molecular dynamic simulations to study the binding modes of curcumin and its derivatives with the active site of p38alpha. The ATP-binding domain was used for evaluating curcumin and its derivatives. Molecular docking simulation results were used to select 4 out of 8 compounds. These 4 compounds were simulated using GROMACS molecular simulation platform; the results generated were subjected to molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) calculations. The results showed cyclocurcumin as a potential natural compound for development of a potent DMRD. These data were further supported by inhibition of TNF-alpha release from lipopolysaccharide (LPS) stimulated human macrophages following cyclocurcumin treatment. PMID- 28339005 TI - Curcumin inhibits angiotensin II-induced inflammation and proliferation of rat vascular smooth muscle cells by elevating PPAR-gamma activity and reducing oxidative stress. AB - Angiotensin II (AngII)-induced production of inflammatory factors and proliferation in vascular smooth muscle cells (VSMCs) play an important role in the progression of atherosclerotic plaques. Growing evidence has demonstrated that activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) effectively attenuates AngII-induced inflammation and intercellular reactive oxygen species (iROS) production. Curcumin (Cur) inhibits inflammatory responses by enhancing PPAR-gamma activity and reducing oxidative stress in various tissues. The aim of the present study was to ascertain whether Cur inhibits AngII induced inflammation and proliferation, and its underlying molecular mechanism, in VSMCs. Enzyme-linked immunosorbent assay (ELISA) and real-time PCR were used to measure the protein and mRNA expression of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). Nitric oxide (NO) production was measured by Griess reaction. Western blot analysis and a DNA-binding assay were used to measure PPAR-gamma activity. iROS production was measured using the DCFH-DA method. In rat VSMCs, Cur attenuated AngII-induced expression of IL-6 and TNF alpha mRNA and protein in a concentration-dependent manner, inhibited NO production by suppressing inducible NO synthase (iNOS) activity, and suppressed proliferation of VSMCs. This was accompanied by increased PPAR-gamma expression and activation in Cur-pretreated VSMCs. GW9662, a PPAR-gamma antagonist, reversed the anti-inflammatory effect of Cur. Moreover, Cur attenuated AngII-induced oxidative stress by downregulating the expression of p47phox, which is a key subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In conclusion, Cur inhibited the expression of IL-6 and TNF-alpha, decreased the production of NO, and suppressed the proliferation of VSMCs, by elevating PPAR gamma activity and suppressing oxidative stress, leading to attenuated AngII induced inflammatory responses in VSMCs. PMID- 28339006 TI - Substance P accelerates wound healing in type 2 diabetic mice through endothelial progenitor cell mobilization and Yes-associated protein activation. AB - Wound healing is delayed in diabetes due to a number of factors, including impaired angiogenesis and poor dermal healing. The present study demonstrated that subcutaneous administration of substance P (SP) accelerates wound healing in db/db type 2 diabetic mice (db/db mice). SP injection (10 nM/kg, subcutaneously) enhanced angiogenesis, induced the mobilization of endothelial progenitor cells (EPCs) and increased the number of EPC-colony forming units (EPC-CFUs) in the bone marrow of db/db mice. Immunohistochemistry was performed to check the effects of SP on the cellular proliferation and the subcellular localization of Yes-associated protein (YAP) in the wound dermis. SP also upregulated cellular proliferation in the injured dermis of db/db mice. Compared with the control group, an increased number of cells in the wound dermis of SP-treated mice exhibited nuclear localization of YAP, which induces cellular proliferation. The results of the current study indicate that subcutaneous administration of SP may be a promising therapeutic strategy to treat diabetic wounds exhibiting impaired angiogenesis and dysfunctional dermal wound healing. PMID- 28339007 TI - miR-217 inhibits osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells by binding to Runx2. AB - The elucidation of the underlying molecular mechanisms regulating the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) is of great importance in improving the treatment of bone-associated diseases. MicroRNAs (miRNAs) have been proven to regulate the osteogenic differentiation of BMSCs. The present study investigated the role of miR-217 in the osteogenic differentiation of rat BMSCs. It was observed that miR-217 expression levels were downregulated during the process of osteogenic differentiation. Subsequently, a dual-luciferase reporter gene assay demonstrated that miR-217 targets a putative binding site in the 3'-untranslated region of the runt related transcription factor 2 (Runx2) gene, which is a key transcription factor for osteogenesis. It was then demonstrated that overexpression of miR-217 attenuated the osteogenesis of BMSCs and downregulated the expression of Runx2, whereas inhibition of miR-217 promoted osteoblastic differentiation and upregulated Runx2 expression. Furthermore, the extracellular signal-regulated kinase (ERK) and p38 mitogen activated protein kinase (p38 MAPK) signaling pathways were investigated during osteogenic induction, and the data indicated that miR-217 may exert a negative effect on the osteogenic differentiation of BMSCs through alteration of ERK and p38 MAPK phosphorylation. The present study therefore concluded that miR-217 functions as a negative regulator of BMSC osteogenic differentiation via the inhibition of Runx2 expression, and the underlying molecular mechanisms may partially be attributed to mediation by the ERK and p38 MAPK signaling pathways. PMID- 28339009 TI - Identification of EGFLAM, SPATC1L and RNASE13 as novel susceptibility loci for aortic aneurysm in Japanese individuals by exome-wide association studies. AB - We performed an exome-wide association study (EWAS) to identify genetic variants in particular, low-frequency or rare variants with a moderate to large effect size - that confer susceptibility to aortic aneurysm with 8,782 Japanese subjects (456 patients with aortic aneurysm, 8,326 control individuals) and with the use of Illumina HumanExome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The correlation of allele frequencies for 41,432 single nucleotide polymorphisms (SNPs) that passed quality control to aortic aneurysm was examined with Fisher's exact test. Based on Bonferroni's correction, a P-value of <1.21x10 6 was considered statistically significant. The EWAS revealed 59 SNPs that were significantly associated with aortic aneurysm. None of these SNPs was significantly (P<2.12x10-4) associated with aortic aneurysm by multivariable logistic regression analysis with adjustment for age, gender and hypertension, although 8 SNPs were related (P<0.05) to this condition. Examination of the correlation of these latter 8 SNPs to true or dissecting aortic aneurysm separately showed that rs1465567 [T/C (W229R)] of the EGF-like, fibronectin type III, and laminin G domains gene (EGFLAM) (dominant model; P=0.0014; odds ratio, 1.63) was significantly (P<0.0016) associated with true aortic aneurysm. We next performed EWASs for true or dissecting aortic aneurysm separately and found that 45 and 19 SNPs were significantly associated with these conditions, respectively. Multivariable logistic regression analysis with adjustment for covariates revealed that rs113710653 [C/T (E231K)] of the spermatogenesis- and centriole associated 1-like gene (SPATC1L) (dominant model; P=0.0002; odds ratio, 5.32) and rs143881017 [C/T (R140H)] of the ribonuclease A family member 13 gene (RNASE13) (dominant model; P=0.0006; odds ratio, 5.77) were significantly (P<2.78x10-4 or P<6.58x10-4, respectively) associated with true or dissecting aortic aneurysm, respectively. EGFLAM and SPATC1L may thus be susceptibility loci for true aortic aneurysm and RNASE13 may be such a locus for dissecting aneurysm in Japanese individuals. PMID- 28339008 TI - Detection of lower levels of SNAP25 using multiple microarray systems and its functional significance in medulloblastoma. AB - Medulloblastoma (MB) is the most common pediatric malignant brain tumor and patients with high-risk or recurrent MB respond poorly to current therapies, and have a higher related mortality. For this reason, potential molecules related to MB need be identified in order to develop targets for the development of novel therapeutics. In the present study, we compared MB microarray data obtained using different microarray systems and significant targets were selected by gene annotation and enrichment analysis. Genes for soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) annotated with the function 'vesicle' were identified and one of these proteins, synaptosomal-associated protein 25 (SNAP25), was found to have significantly lower expression levels in MB. In addition, SNAP25 was detected in a very low number of MB cells as shown by western blot analysis and immunohistochemical analyses of archived and formalin fixed/paraffin-embedded human MB specimens. We found that SNAP25 altered the morphology and the chemotherapeutic effects of arabinofuranosyl cytidine (Ara-C) on SNAP25-expressing MB cells. On the whole, our data indicate that the expression of SNAP25 is crucial for dendrite formation and is associated with the effects of targeted chemotherapy. The detection of SNAP25 expression in MB cells may thus be essential for the chemotherapeutic application of Ara-C. PMID- 28339010 TI - Effects of different cellulose membranes regenerated from Styela clava tunics on wound healing. AB - The aim of this study was to investigate the therapeutic effects of three different cellulose membranes (CMs) manufactured from Styela clava tunics (SCTs) on the healing of cutaneous wounds. We examined the physical properties and therapeutic effects of three CMs regenerated from SCTs (referred to as SCT- CMs), including normal CM (SCT-CM), freeze-dried SCT-CM (FSCT-CM) and sodium alginate supplemented SCT-CM (ASCT-CM) on skin regeneration and angiogenesis using Sprague Dawley (SD) rats. FSCT-CM exhibited an outstanding interlayered structure, a high tensile strength (1.64 MPa), low elongation (28.59%) and a low water vapor transmission rate (WVTR) compared with the other SCT-CMs, although the fluid uptake rate was maintained at a medium level. In the SD rats with surgically wounded skin, the wound area and score of wound edge were lower in the FSCT-CM treated group than in the gauze (GZ)-treated group on days 3-6 and 12-14. In addition, a significant attenuation in the histopathological changes was observed in the FSCT-CM-treated group. Furthermore, the expression level of collagen-1 and the signaling pathway of transforming growth factor (TGF)-beta1 were significantly stimulated by the topical application of FSCT-CM. However, no signs of toxicity were detected in the livers or kidneys of the three SCT-CM-treated groups. Overall, our data indicate that the FSCT-CM may accelerate the process of wound healing in the surgically wounded skin of SD rats through the regulation of angiogenesis and connective tissue formation without inducing any specific toxicity. PMID- 28339011 TI - Reduction of miR-132-3p contributes to gastric cancer proliferation by targeting MUC13. AB - Abnormal expression of epidermal growth factor receptor (EGFR) signaling and microRNAs (miRNAs) has been widely seen in gastric cancer. The present study focused on the miRNAs that regulate human epidermal growth factor receptor (HER) activation through mucin 13 (MUC13). The protein level of MUC13 was demonstrated to be significantly increased in gastric cancer tissues compared with normal tissues by western blot analysis and immunohistochemistry. TargetScan bioinformatic predictions indicated that miRNA (miR)-212-3p and miR-132-3p may bind to the 3'-untranslated region of MUC13. Further investigation revealed that miR-132-3p was significantly decreased in gastric cancer tissues compared with normal tissues, whereas miR-212-3p expression was unaffected. Luciferase assays and western blot confirmed MUC13 as a target gene of miR-132-3p. Inhibition of miR-132-3p enhanced gastric cancer cell migration through activation of HER2, extracellular signal-regulated kinase (ERK) and Akt serine/threonine kinase (Akt) signaling, which was a similar effect to that of MUC13 overexpression. In summary, reduction of miR-132-3p may contribute to gastric cancer proliferation by targeting MUC13. PMID- 28339012 TI - Heavy metal content and molecular species identification in canned tuna: Insights into human food safety. AB - Canned tuna in olive oil and in brine of the most popular brands sold in Italian markets were analyzed to verify the authentication of transformed products, with the aim to unveil commercial frauds due to the substitutions of high value species with species of low commercial value, and to assess the health risk of consumers related to cadmium (Cd), lead (Pb) and mercury (Hg) contents. Species authentication was evaluated with amplification of COI DNA barcode and confirmed the declared species. Among tested metals, Hg had the highest concentrations, followed by Cd and Pb. None of the tested samples surpassed the European regulatory limits no. 1881/2006 fixed for Hg and Pb, whereas one batch of canned tuna in olive oil exceeded standard for Cd. Risk for human health was evaluated by the metals daily intake and target hazard quotient (THQ). As a result, Cd and Pb did not exceed the toxicological reference values established by World Health Organization (WHO) and the Environmental Protection Agency (EPA). Conversely, Hg content suggests a consumption no more than once a week and a continuous surveillance of this fishery products for consumer protection. PMID- 28339013 TI - Immunological effects of occupational exposure to lead (Review). AB - It is well-known that occupational and environmental exposure to several factors, including benzene, heavy metals, chemicals and mineral fibers, is associated with the risk of developing a great number of diseases. Numerous studies have been carried out in order to investigate the mechanisms of toxicity of these substances, with particular regard to the possible toxic effects on the immune system. However, little is known about the influence of heavy metals, such as lead, on the immune system in human populations. Lead is a heavy metal still used in many industrial activities. Human exposure to lead can induce various biological effects depending upon the level and duration of exposure, such as toxic effects on haematological, cardiovascular, nervous and reproductive systems. Several studies demonstrated that exposure to lead is associated to toxic effects also on the immune system, thus increasing the incidence of allergy, infectious disease, autoimmunity or cancer. However, the effects of lead exposure on the human immune system are not conclusive, mostly in occupationally exposed subjects; nevertheless some immunotoxic abnormalities induced by lead have been suggested. In particular, in vivo, in vitro and ex vivo lead is able to improve T helper 2 (Th2) cell development affecting Th1 cell proliferation. Further studies are required to better understand the mechanisms of lead immunotoxicity and the ability of lead to affect preferentially one type of immune response. PMID- 28339014 TI - Effects of remote ischemic post-conditioning on fracture healing in rats. AB - Remote ischemic post-conditioning (RIPC) is an established method to activate the hypoxia-inducible factor-1alpha (HIF-1alpha) pathway, which is involved in the impairment of fracture healing. However, the role of RIPC in fracture healing remains to be fully elucidated. In the present study, rats received fractures and were divided into two groups: Control and RIPC, in which hind limb occlusion was performed. Rats were sacrificed at 7, 14, 28 and 42 days subsequent to tibial fracture. Micro-computed tomography was performed to measure healing of the bone tissue and biomechanical testing was used to test mechanical strength. In addition, the effects of hind limb occlusion on the expression of two primary angiogenic mediators, HIF-1alpha and vascular endothelial growth factor (VEGF), as well as the osteoblast markers runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP) and osteocalcin (OCN), were determined at the mRNA and protein levels by reverse transcription-quantitative polymerase chain reaction, western blot analysis and immunohistochemistry. Systemic administration of hind limb occlusion (3 cycles/day, with each occlusion or release phase lasting 10 min) significantly promoted fracture healing and mechanical strength. The present study demonstrated that in rats treated with hind limb occlusion, the expression of HIF-1alpha, VEGF, Runx2, ALP and OCN was significantly increased at the mRNA and protein levels, and that RIPC enhances fracture repair in vivo. PMID- 28339015 TI - Protection of FK506 against neuronal apoptosis and axonal injury following experimental diffuse axonal injury. AB - Diffuse axonal injury (DAI) is the most common and significant pathological features of traumatic brain injury (TBI). However, there are still no effective drugs to combat the formation and progression of DAI in affected individuals. FK506, also known as tacrolimus, is an immunosuppressive drug, which is widely used in transplantation medicine for the reduction of allograft rejection. Previous studies have identified that FK506 may play an important role in the nerve protective effect of the central nervous system. In the present study, apoptosis of neuronal cells was observed following the induction of experimental DAI. The results demonstrated that it was closely related with the upregulation of death-associated protein kinase 1 (DAPK1). It was hypothesized that FK506 may inhibit the activity of DAPK1 by inhibiting calcineurin activity, which may be primarily involved in anti-apoptosis following DAI induction. Through researching the expression of nerve regeneration associated proteins (NF-H and GAP-43) following DAI, the present study provides novel data to suggest that FK506 promotes axon formation and nerve regeneration following experimental DAI. Therefore, FK506 may be a potent therapeutic for inhibiting nerve injury, as well as promoting the nerve regeneration following DAI. PMID- 28339016 TI - Paeonol ameliorates imiquimod-induced psoriasis-like skin lesions in BALB/c mice by inhibiting the maturation and activation of dendritic cells. AB - Paeonol, an active component derived from the traditional Chinese medicine Cortex Moutan, possesses anti-inflammatory, analgesic, antioxidant and anti-allergic properties. Psoriasis is a chronic, recurrent, inflammatory dermatosis accompanied by excessive activation of Toll-like receptors (TLRs) in dendritic cells (DCs), which are primarily responsible for initiating an immune response. We investigated the effect of paeonol on inflammation in an imiquimod (IMQ) induced psoriasis-like mouse model and murine bone marrow-derived dendritic cells (BMDCs) stimulated by R848. Mice were intragastrically administered 100 mg/kg (high), 50 mg/kg (medium) and 25 mg/kg (low) paeonol, respectively. We evaluated inflammation of psori-asis-like lesions based on histological changes, protein levels of myeloid differentiation factor 88 (MyD88) and TLR8 in skin lesions by western blotting, and levels of CD11c+ DCs in skin by immunoassay and in spleens by flow cytometry. Inflammatory cytokines [interleukin (IL)-23, IL-12 and IL 1beta] in skin lesions and BMDCs were also assessed by RT-PCR and ELISA. Application of paeonol decreased IMQ-induced keratinocyte proliferation, and infiltration of CD3+ cells, while the treatment ameliorated CD11c+ cells in the spleen and skin, and reduced MyD88 and TLR8 proteins in skin lesions. Paeonol inhibited IMQ-induced mRNA expression of IL-23, but not IL-12 and IL-1beta in BMDCs, along with significantly lower levels of DCs expressing MHCII, CD80 and CD86 in vitro. These results indicate that paeonol suppresses the maturation and activation of DCs by decreasing MyD88 and TLR8 proteins in the TLR7/8 signaling pathway which finally alleviates psoriasis-like skin lesions. The TLR7/8 signaling pathway in DCs provides an important insight into the mechanism of psoriasis, and paeonol may be a potent therapeutic drug for psoriasis. PMID- 28339017 TI - SIRT1 is required for mitochondrial biogenesis reprogramming in hypoxic human pulmonary arteriolar smooth muscle cells. AB - Although recent studies have reported that mitochondria are putative oxygen sensors underlying hypoxic pulmonary vasoconstriction, little is known concerning the sirtuin 1 (SIRT1)-mediated mitochondrial biogenesis regulatory program in pulmonary arteriolar smooth muscle cells (PASMCs) during hypoxia/reoxygenation (H/R). We investigated the epigenetic regulatory mechanism of mitochondrial biogenesis and function in human PASMCs during H/R. Human PASMCs were exposed to hypoxia of 24-48 h and reoxygenation of 24-48 h. The expression of SIRT1 was reduced in a time-dependent manner. Mitochondrial transcription factor A (TFAM) expression was increased during hypoxia and decreased during reoxygenation, while the release of TFAM was increased in a time-dependent manner. Lentiviral overexpression of SIRT1 preserved SIRT3 deacetylase activity in human PASMCs exposed to H/R. Knockdown of PGC-1alpha suppressed the effect of SIRT1 on SIRT3 activity. Knockdown of SIRT3 abrogated SIRT1-mediated deacetylation of cyclophilin D (CyPD). Notably, knockdown of SIRT3 or PGC-1alpha suppressed the incremental effect of SIRT1 on mitochondrial TFAM, mitochondrial DNA (mtDNA) content and cellular ATP levels. Importantly, polydatin restored SIRT1 levels in human PASMCs exposed to H/R. Knockdown of SIRT1 suppressed the effect of polydatin on mitochondrial TFAM, mtDNA content and cellular ATP levels. In conclusion, SIRT1 expression is decreased in human PASMCs during H/R. TFAM expression in mitochondria is reduced and the release of TFAM is increased by H/R. PGC-1alpha/SIRT3/CyPD mediates the protective effect of SIRT1 on expression and release of TFAM and mitochondrial biogenesis and function. Polydatin improves mitochondrial biogenesis and function by enhancing SIRT1 expression in hypoxic human PASMCs. PMID- 28339019 TI - Occupational exposure to Mount Etna's basaltic dust: Assessment of mutagenic and cytotoxic effects. AB - Basalt and volcanic ash are natural constituents of the ground surrounding volcanic areas such as Mount Etna. The dust may be daily inhaled by the general population as well as by several types of workers, such as construction workers. In this experiment, we analyzed the potential mutagenic and cytotoxic effects of the materials used in construction industry, excavated from Mt. Etna. Ground basalt (A), volcanic ash (B), mixed basalt and cement (C) and cement (D) were studied with Ames test, for mutagenic assessment and with MMT assay for cytotoxic evaluation. The Ames test revealed that cement (sample D), showed a higher and significant mutagenicity than the samples A, B and C. MTT assay showed that samples C and D had a slightly more negative impact on cell viability than A and B. In conclusion, no particular risks seem to exist for construction industry workers, while the exploitation of cement and cement mixed with basalt seems to be a risk for workers, given the high percentage of silica and iron. PMID- 28339018 TI - Role of autophagy in the progression of osteoarthritis: The autophagy inhibitor, 3-methyladenine, aggravates the severity of experimental osteoarthritis. AB - Accumulating evidence suggests that autophagy is closely related to the pathogenesis of osteoarthritis (OA). The aim of this study was to determine the changes in autophagy during the progression of OA and to elucidate the specific role of autophagy in OA. For this purpose, a cellular model of OA was generated by stimulating SW1353 cells with interleukin (IL)-1beta and a rabbit model of OA was also established by an intra-articular injection of collagenase, followed by treatment with the autophagy specific inhibitor, 3-methyladenine (3-MA). Cell viability was analyzed by MTS assay, and the mRNA expression levels of matrix metalloproteinases (MMP)-13 and tissue inhibitor of metalloproteinase (TIMP)-1 were determined by RT-qPCR. Cartilage degeneration was examined under a light microscope, and autophagosome and chondrocyte degeneration was observed by transmission electron microscopy. The protein expression of Beclin-1 and light chain 3 (LC3)B was evaluated by western blot analysis and immunofluorescence staining. We found that the autophagy was enhanced during the early stages and was weakened during the late stages of experimental OA. The inhibition of autophagy by 3-MA significantly aggravated the degeneration of chondrocytes and cartilage in experimental OA. Our results thus determine the changes in autophagy during different stages of OA, as well as the role of impaired autophagy in the development of OA. Our data suggest that the regulation of autophagy may be a potential therapeutic strategy with which to attenuate OA. PMID- 28339020 TI - Metformin inhibits endothelial progenitor cell migration by decreasing matrix metalloproteinases, MMP-2 and MMP-9, via the AMPK/mTOR/autophagy pathway. AB - The aim of the present study was to investigate the effect of metformin on endothelial progenitor cell (EPC) migration and to explore the possible mechanisms. EPCs were treated with metformin, and the migration of EPCs was evaluated by wound healing and Matrigel invasion assays. We also examined the expression levels of of MMP-2 and MMP-9 in EPCs with or without metformin treatment via RT-PCR and western blot analysis, and activities of MMP-2 and MMP-9 in EPCs under different conditions was examined by zymography. Moreover, we also assessed the AMPK/mTOR/autophagy pathway to explore the possible mechanisms. Metformin treatment significantly downregulated matrix metalloproteinase-2 (MMP 2) and MMP-9 expression, and subsequently decreased the migration of EPCs. Increased levels of phosphorylated (p)-AMPK and LC3II expression, as well as decreased levels of p-mTOR and p62 contributed to this phenomenon. The AMPK inhibitor compound C reversed the effect exerted by metformin. In conclusion, our results showed that metformin inhibited the migration of EPCs by decreasing MMP-2 and MMP-9. The AMPK/mTOR/autophagy pathway was demonstrated to be involved in the regulatory mechanisms. PMID- 28339021 TI - Determinants of serum manganese levels in an Italian population. AB - Manganese (Mn) is both essential and toxic for humans, mainly depending on the total levels and its species. Main sources of exposure include food and air pollution, particularly motorized traffic. We sought to determine the potential influence of these sources on serum total levels of Mn and Mn species. We selected a random sample of municipality residents from an Italian urban municipality, from whom we collected detailed personal information, dietary habits and a blood sample for serum Mn determination. We also assessed outdoor air Mn exposure, by modeling levels of particulate matter <=10 um (PM10) from motorized traffic at the residence of geocoded subjects. Serum Mn species generally showed higher levels in males and positive correlation with age, while no such differences were found according to smoking habits or use of dietary supplements. Among nutrients, only iron intake showed a relation with Mn [an inverse correlation with Mn-ferritin (Mn-Fer) and a direct one with inorganic-Mn (Inorg-Mn)]. Meat consumption directly correlated and fish and seafood inversely correlated with total Mn, Mn-transferrin (Mn-Tf) and Mn-citrate (Mn-Cit). Fruits and vegetables, including legumes and nuts, generally showed a positive correlation with all Mn species, especially Mn-Cit, and an inverse one with Inorg Mn. Odds ratios (ORs) of having serum Mn levels above median value increased with increasing PM10 tertiles, with an OR for highest-to-lowest tertile of 7.40 (1.36 40.25) in multivariate analysis. Analyses for Mn species did not highlight a clear comparable pattern. In conclusion, our results seem to demonstrate that PM10 exposure positively influences total Mn serum levels, while single Mn species show conflicting results. PMID- 28339022 TI - Cytochrome P450 2E1 increases the sensitivity of hepatoma cells to vitamin K2. AB - Although vitamin K2 (VK2) exhibits inhibitory effects on the viability of hepatoma cells, hepatoma cells are insensitive to VK2. Therefore, this investigation is an attempt to enhance the sensitivity of hepatoma cells to VK2. Our results showed that VK2 acted synergistically with ethanol (EtOH) to inhibit the viability of Smmc-7721 cells, mainly because cytochrome P450 2E1 (CYP2E1) was activated by EtOH. The synergistic effect of VK2 and EtOH was also observed in QGY-7703 cells, which also express CYP2E1. However, in HepG2 cells, which do not express CYP2E1, the synergistic effect of VK2 and EtOH was not observed. In addition, we demonstrated that CYP2E1 could be induced by VK2 via both post transcriptional and transcriptional mechanisms. These results suggest that induction of CYP2E1 can enhance the inhibitory effect of VK2 on the viability of hepatoma cells. CYP2E1 may be an attractive target for enhanced antitumor effects of VK2 in hepatocellular carcinoma treatment. PMID- 28339023 TI - Lead exposure and plasma mRNA expression in ERBB2 gene. AB - Epidemiologic data for carcinogenicity in those exposed to lead (Pb) suggests relations with cancers although the totality of the evidence is inconsistent. Alterations in the expression of ERBB receptors have been studied during the development and malignant transformation of different kinds of human tumors where they induce proliferation, angiogenesis and metastasis generation. Relevant clinical data demonstrate the role of ERBB2 receptors in the development and malignancy of human cancers. Therefore, the objective of the present investigation is to give more information on the link between plasma mRNA expression in ERBB2 gene and lead blood levels in a healthy population. Blood samples, socio-demographic, exposure and health data were obtained from 48 healthy men. Real-time polymerase chain reaction assays were performed to detect ERBB2 gene transcripts, DeltaDeltaCt method was used to quantify gene expression. Pb blood level was assayed using high-resolution sector field inductively coupled mass spectrometry and is expressed in ug/dl. Plasma mRNA expression in ERBB2 gene was 6.44+/-3.07 DeltaDeltaCt; Pb blood levels was 16.07+/-6.74 ug/dl. Regression analysis revealed a significant association (r2=0.5345; p<0.0001) between Pb levels and mRNA expression in ERBB2. So far, it has still not been established if the expression of ERBB2 receptors is influenced by Pb exposure. On the base of the above reported data, we believe an in vitro study might be useful, to understand the molecular mechanisms implicated. PMID- 28339024 TI - Effects of berberine on a rat model of chronic stress and depression via gastrointestinal tract pathology and gastrointestinal flora profile assays. AB - Chronic stress and depression are challenging conditions to treat, owing to their complexity and lack of clinically available and effective therapeutic agents. The aim of the present study was to investigate the mechanism by which berberine acts, by examining alterations to gastrointestinal tract histopathology and flora profile in a rat model, following the induction of stress. Research associating gastrointestinal flora and depression has increased, thus, the present study hypothesized that stress induces depression and changes in the gastrointestinal system. The chronic mild stress rat model was previously established based on a set of 10 chronic unpredictable stress methods. In the present study, the measurements of body weight, behavior, gastrointestinal tract histopathology and gastrointestinal flora profile were collected in order to elucidate understanding of chronic stress and depression in this region. In the present study, induced stress and the resulting depression was demonstrated to significantly decrease the body weight and sucrose preference of rats, as well as significantly increasing traverse time, vertical movement time, grooming time and motionless time in an open-field test. Following modeling and subsequent treatment with low or high doses of berberine, the measurements were significantly different when compared with unstressed rats. Berberine appears to reverse the physical damage brought about by stress within the gastric mucosa and intestinal microvilli of the stomach, ileum, cecum and colon. Using enterobacterial repetitive intergenic consensus sequence-based polymerase chain reaction analysis, several distinctive bands disappeared following modeling; however, novel distinctive bands appeared in response to the graded berberine treatment. In conclusion, the present study identified that high concentrations of berberine markedly protects rats from various symptoms of chronic stress and depression, with the potential of facilitating treatment within clinical practice. PMID- 28339025 TI - Cerebral hemorrhage therapy by targeting VEGF and HGF in a preclinical trial in rats. AB - Cerebral hemorrhage is the most common type of human cerebrovascular disease and frequently causes paralysis, vegetative state and mortality. The modulatory actions of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) are vital in the human nervous system. The present study investigated the association between cerebral hemorrhage and the expression of VEGF and HGF in a rat model of cerebral hemorrhage. The therapeutic potential of cerebral hemorrhage was also evaluated using targeted drugs for VEGF and HGF in the cerebral hemorrhage rat model. Behavioral and preclinical changes and the survival rates of rats were assessed after treatment with VEGF receptor (VEGFR) and HGF receptor (HGFR). The results of Tarlov scores demonstrated that movement of limbs and coordination when walking were significantly improved in moderate and severe hemorrhage lesions in the VEGFR plus HGFR-treated group and mainly alleviated in primary hemorrhage lesions compared with rats in the single VEGFR or HGFR-treated groups and the control group (**P<0.01). Decreasing expression levels of VEGF and HGF were observed in the neural tissue of animals treated with VEGFR plus HGFR compared with the control group (**P<0.01). These preclinical observations indicated that VEGF and HGF serve a function in the pathological injury and repair of cerebral tissue in rats with cerebral hemorrhages. The therapeutic benefits of VEGFR plus HGFR suggested that VEGFR plus HGFR may be candidate drugs for cerebral hemorrhage, and thus offer a promising treatment for clinicians and doctors. PMID- 28339026 TI - Opposite effects of tumor protein D (TPD) 52 and TPD54 on oral squamous cell carcinoma cells. AB - The tumor protein D52 (TPD52) protein family includes TPD52, -53, -54 and -55. Several reports have shown important roles for TPD52 and TPD53, and have also suggested the potential involvement of TPD54, in D52-family physiological effects. Therefore, we performed detailed expression analysis of TPD52 family proteins in oral squamous cell carcinoma (OSCC). Towards this end, TPD54 overexpressing or knocked-down cells were constructed using OSCC-derived SAS, HSC2 and HSC3 cells. tpd52 or tpd53 was expressed or co-expressed in these cells by transfection. The cells were then analyzed using cell viability (MTT), colony formation, migration, and invasion assays. In OSCC-xenograft experiments, the cells were transplanted into nude mice together with injection of anti-tpd siRNAs. MTT assay of cell monolayers showed little differences in growth of the transfected cells. tpd54 overexpression in SAS cells significantly decreased colony formation in an anchorage-independent manner. Additionally, knock-down of tpd54 enhanced the number of colonies formed and overexpression of tpd52 in tpd54 knock-down cells increased the size of the colonies formed. The chemotaxis assay showed that tpd54 overexpression decreased cell migration. In the OSCC-xenograft in vivo study, tpd54 overexpression slightly attenuated tumor volume in vivo, despite the fact that tumor metastasis or cell survival was not involved. Our results showed that TPD54 not only downregulated anchorage-independent growth and cell migration in vitro, but also attenuated tumor growth in vivo. Based on these results, it is considered that TPD54 might act as a negative regulator of tumor progression in OSCC cells. PMID- 28339027 TI - SU6668 modulates prostate cancer progression by downregulating MTDH/AKT signaling pathway. AB - Prostate cancer is the second leading cause of cancer deaths among men in Western counties and has increased in incidence also in China in recent years. Although diagnosis modalities for primary prostate cancer have markedly improved, there are still no effective therapies for metastatic prostate cancer. SU6668 is an inhibitor of the tyrosine kinase activity of three angiogenic receptors VEGFR2, PDGFRbeta and FGFR1. There is strong experimental evidence that SU6668 can induce growth inhibition of various primary tumors. However, the function and molecular mechanism of SU6668 in prostate cancer has not been fully elucidated. In the present study, we found that SU6668 inhibited the proliferation and invasion of prostate cancer cells. Functional studies also demonstrated that SU6668 inhibited epithelial-mesenchymal transition in DU145 and LNCap cells. After treatment with SU6668, MTDH protein, which has been reported to be significantly overexpressed in many human tumor tissues, was downregulated in DU145 and LNCap cells. siRNA mediated silencing of MTDH in prostate cancer cells decreased their proliferation and invasive capabilities, suggesting that SU6668 may inhibit cell proliferation and invasion of prostate cancer cells partly through downstream targeting of MTDH. Mechanistic investigations showed that AKT signaling pathway was inhibited after SU6668 treatment in prostate cancer cells. Moreover, a combination of SU6668 and PI3K-AKT pathway inhibitor LY29004 resulted in increased inhibition of cell proliferation and invasion in DU145 cells. Taken together, our findings revealed that SU6668 suppressed prostate cancer progression by downregulating MTDH/AKT signaling pathway and identified a promising therapeutic strategy for prostate cancer. PMID- 28339029 TI - Hydroxychloroquine sensitizes chronic myeloid leukemia cells to Vgamma9Vdelta2 T cell-mediated lysis independent of autophagy. AB - Hydroxychloroquine (HCQ) is the only autophagy inhibitor in clinical use and it has shown great potential in treating chronic myeloid leukemia (CML). By inhibiting autophagy, HCQ enhances the anti-CML efficiency of chemotherapy. In the present study, we demonstrated that HCQ sensitized CML cells to Vgamma9Vdelta2 T cell-mediated lysis. HCQ inhibited autophagy in CML cells, but the sensitizing effects of HCQ were autophagy-independent. Since the sensitization was not mimicked by ATG7 knockdown and even occurred in the absence of ATG7. We revealed that in a time-dependent manner HCQ induced the expression of NKG2D ligand ULBP4 on the surface of CML cells. This marks the leukemia cell for recognition by Vgamma9Vdelta2 T cells. Blocking the interaction of NKG2D with its ligands deleted the sensitizing effects of HCQ. In addition, we showed that HCQ did not affect the synthesis or degradation of ULBP4, but induced the translocation of ULBP4 from the cytoplasm to the cell membrane. Our results uncovered a previously unknown mechanism for HCQ in CML treatment that underlines the ability of HCQ to modulate the immune visibility of CML cells, and pave the way to the development of new combination treatments with HCQ and Vgamma9Vdelta2 T cells. PMID- 28339028 TI - 2-Methoxyestradiol enhances radiosensitivity in radioresistant melanoma MDA-MB 435R cells by regulating glycolysis via HIF-1alpha/PDK1 axis. AB - HIF-1alpha overexpression is associated with radio-resistance of various cancers. A radioresistant human melanoma cell model MDA-MB-435R (435R) was established by us previously. Compared with the parental cells MDA-MB-435 (435S), an elevated level of HIF-1alpha expression in 435R cells was demonstrated in our recent experiments. Therefore, in the current study, we sought to determine whether selective HIF-1alpha inhibitors could radiosensitize the 435R cells to X-ray, and to identify the potential mechanisms. Our data demonstrated that inhibition of HIF-1alpha with 2-methoxyestradiol (2-MeOE2) significantly enhanced radiosensitivity of 435R cells. 2-MeOE2 increased DNA damage and ratio of apoptosis cells induced by irradiation. Whereas, cell proliferation and the expression of pyruvate dehydrogenase kinase 1 (PDK1) were decreased after 2-MeOE2 treatment. The change of expression of GLUT1, LDHA and the cellular ATP level and extracellular lactate production indicates that 2-MeOE2 suppressed glycolytic state of 435R cells. In addition, the radioresistance, glycolytic state and cell proliferation of 435R cells were also decreased after inhibiting pyruvate dehydrogenase kinase 1 (PDK1) with dichloroacetate (DCA). DCA could also increase DNA damage and ratio of apoptotic cells induced by irradiation. These results also suggest that inhibition of HIF-1alpha with 2-MeOE2 sensitizes radioresistant melanoma cells 435R to X-ray irradiation through targeting the glycolysis that is regulated by PDK1. Selective inhibitors of HIF-1alpha and glycolysis are potential drugs to enhance radio-sensitivity of melanoma cells. PMID- 28339030 TI - Increased phosphorylation of 4E-binding protein 1 predicts poor prognosis for patients with colorectal cancer. AB - As demonstrated in previous studies, the phosphorylated form of 4E-binding protein 1 (p-4E-BP1) may be a suitable tumor biomarker. The aim of the current study was to examine the expression status of p-4E-BP1 in colorectal cancer (CRC), in order to determine its clinical significance. The present study enrolled 89 patients with CRC that had undergone radical resection. Paired tumor and adjacent normal tissues were evaluated using immunohistochemistry to detect the protein expression of p-4E-BP1 and phosphatase and tensin homolog (PTEN). The study identified 53 cases (59.6%) that exhibited moderate or high expression of p 4E-BP1 in tumor tissues, compared with little or no expression in the adjacent normal tissues. Conversely, PTEN protein expression was markedly lower in CRC compared with adjacent normal tissues. p-4E-BP1 protein upregulation tissues samples was consistent with PTEN downregulation in CRC samples. p-4E-BP1 overexpression was predominant in patients with metastasis to the regional lymph nodes. Moderate/high expression of p-4E-BP1 protein was significantly associated with adverse overall survival (OS) in patients. Statistical analysis using the Cox proportional hazards model, indicated that p-4E-BP1 expression was an independent factor suitable for predicting OS in CRC patients, which was independent of lymph node metastasis. In conclusion, p-4E-BP1 protein expression appears to be upregulated in CRC, suggesting that it may be a suitable biomarker for predicting CRC prognosis. PMID- 28339031 TI - p53-inducible long non-coding RNA PICART1 mediates cancer cell proliferation and migration. AB - Long non-coding RNAs (lncRNAs) function in the development and progression of cancer, but only a small portion of lncRNAs have been characterized to date. A novel lncRNA transcript, 2.53 kb in length, was identified by transcriptome sequencing analysis, and was named p53-inducible cancer-associated RNA transcript 1 (PICART1). PICART1 was found to be upregulated by p53 through a p53-binding site at -1808 to -1783 bp. In breast and colorectal cancer cells and tissues, PICART1 expression was found to be decreased. Ectopic expression of PICART1 suppressed the growth, proliferation, migration, and invasion of MCF7, MDA-MB-231 and HCT116 cells whereas silencing of PICART1 stimulated cell growth and migration. In these cells, the expression of PICART1 suppressed levels of p-AKT (Thr308 and Ser473) and p-GSK3beta (Ser9), and accordingly, beta-catenin, cyclin D1 and c-Myc expression were decreased, while p21Waf/cip1 expression was increased. Together these data suggest that PICART1 is a novel p53-inducible tumor-suppressor lncRNA, functioning through the AKT/GSK3beta/beta-catenin signaling cascade. PMID- 28339033 TI - Role of tropomyosin in silkworm allergy. AB - Silkworm pupae are widely consumed in Asian countries and allergic reactions following consumption have been described. However, false-positive responses in skin prick allergy tests or non-specific immunoglobulin E (IgE) responses to total extract of silkworm pupa make diagnosis difficult. Although improved allergy diagnosis is required, molecular characterization of silkworm allergens has not been performed to date, except for Bomb m 1, an arginine kinase. This study aimed to evaluate the allergenicity of tropomyosin, a well-established invertebrate pan-allergen, from silkworm pupa. The silkworm tropomyosin gene was cloned by reverse transcription and polymerase chain reaction, and the protein was overexpressed in Escherichia coli and purified by affinity chromatography using Nickel-resin. IgE reactivity of the recombinant protein was examined by ELISA and competitive inhibition analyses. Silkworm pupa tropomyosin shared 73.5 92.3% amino acid sequence identity with previously identified allergenic tropomyosins. Sera from eight of 15 patients with silkworm allergy (53.3%) exhibited binding of IgE to the recombinant protein. However, recombinant protein was able to inhibit less than 10% of IgE reactivity to silkworm pupa extract. Of the eight sera tested, six that specifically reacted with silkworm tropomyosin also demonstrated IgE reactivity to shrimp and crab. In the present study, specific IgE to silkworm tropomyosin was detected in patients with silkworm allergy, suggesting that it may be useful in diagnosis of allergy to silkworm pupa. PMID- 28339032 TI - ClC-7/Ostm1 contribute to the ability of tea polyphenols to maintain bone homeostasis in C57BL/6 mice, protecting against fluorosis. AB - Epidemiological investigations indicate that certain ingredients in tea bricks can antagonize the adverse effects of fluoride. Tea polyphenols (TPs), the most bioactive ingredient in tea bricks, have been demonstrated to be potent bone supporting agents. ClC-7 is known to be crucial for osteoclast (OC) bone resorption. Thus, in this study, we investigated the potential protective effects of TPs against fluorosis using a mouse model and explored the underlying mechanisms with particular focus on ClC-7. A total of 40, healthy, 3-week-old male C57BL/6 mice were randomly divided into 4 groups (n=10/group) by weight as follows: distilled water (control group), 100 mg/l fluoridated water (F group), water containing 10 g/l TPs (TP group) and water containing 100 mg/l fluoride and 10 g/l TPs (F + TP group). After 15 weeks, and after the mice were sacrificed, the long bones were removed and bone marrow-derived macrophages were cultured ex vivo in order to perform several experiments. OCs were identified and counted by tartrate-resistant acid phosphatase (TRAP) staining. The consumption of fluoride resulted in severe fluorosis and in an impaired OC function [impaired bone resorption, and a low mRNA expression of nuclear factor of activated T-cells 1 (NFATc1), ATPase H+ transporting V0 subunit D2 (ATP6v0d2) and osteopetrosis associated transmembrane protein 1 (Ostm1)]. In the F + TP group, fluorosis was attenuated and OC function was restored, but not the high bone fluoride content. Compared with the F group, mature OCs in the F + TP group expressed higher mRNA levels of ClC-7 and Ostm1; the transportation and retaining of Cl- was improved, as shown by the fluorescence intensity experiment. On the whole, our findings indicate that TPs mitigate fluorosis in C57BL/6 mice by regulating OC bone resorption. Fluoride inhibits OC resorption by inhibiting ClC-7 and Ostm1, whereas TPs attenuate this inhibitory effect of fluoride. PMID- 28339034 TI - The Sirt1 activator, SRT1720, attenuates renal fibrosis by inhibiting CTGF and oxidative stress. AB - The transforming growth factor-beta1 (TGF-beta1)/connective tissue growth factor (CTGF) pathway plays an important role in the pathogenesis and progression of chronic kidney disease. Oxidative stress is also involved in TGF-beta1 signalling. Sirtuin 1 (Sirt1) exerts a number of pleiotropic effects, protecting against renal disease, including inhibiting fibrosis and oxidative metabolism. In this study, we investigated the role of the Sirt1 activator, SRT1720, in unilateral ureteral obstruction (UUO)-induced tubulointerstitial fibrosis and aimed to determine whether this role depends on the inhibition of oxidative stress and the TGF-beta1/CTGF pathway. Renal fibrosis was induced by UUO in CD1 mice. SRT1720 (100 mg/kg) was administered by intraperitoneal injection for 3 days prior to UUO and this was continued for 7 days following UUO. Histological changes were examined by Masson's trichrome staining. The expression of fibrosis related factors was evaluated by immunohistochemistry, western blot analysis and RT-qPCR. Apoptosis was also examined. We also examined the superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GPx) and reduced glutathione (GSH) levels. UUO induced renal fibrosis and apoptosis and decreased Sirt1 expression. The administration of SRT1720 increased the Sirt1 levels and partially attenuated UUO-induced renal fibrosis and apoptosis. Furthermore, SRT1720 attenuated the levels of oxidative stress (it decreased the MDA levels, and increased the SOD, GPx and GSH levels), which suggests that it protected the cells against ROS-induced damage. Moreover, SRT1720 effectively inhibited the levels of TGF-beta1/CTGF induced by UUO. On the whole, these findings indicate that the Sirt1 activator, SRT1720, exerts protective effects against UUO-induced tubulointerstitial fibrosis. The mechanisms of action of SRT1720 may include, at least in part, the suppression of renal oxidative stress and the TGF-beta1/CTGF signalling pathway. The Sirt1 activator may therefore be prove to be a potent therapeutic agent for the treatment of fibrotic kidney disease. PMID- 28339035 TI - Duration of simulated microgravity affects the differentiation of mesenchymal stem cells. AB - Previous evidence has suggested that physical microenvironments and mechanical stresses, independent of soluble factors, influence mesenchymal stem cell (MSC) fate. In the present study, simulated microgravity (SMG) was demonstrated to regulate the differentiation of mesenchymal stem cells. This may be a novel strategy for tissue engineering and regenerative medicine. Rat MSCs were cultured for 72 h or 10 days in either normal gravity or a clinostat to model microgravity, followed with culture in diverse differential media. A short period of stimulation (72 h) promoted MSCs to undergo endothelial, neuronal and adipogenic differentiation. In comparison, extended microgravity (10 days) promoted MSCs to differentiate into osteoblasts. A short period of exposure to SMG significantly decreased ras homolog family member A (RhoA) activity. However, RhoA activity significantly increased following prolonged exposure to SMG. When RhoA activity was inhibited, the effects of prolonged exposure to SMG were reversed. These results demonstrated that the duration of SMG regulates the differentiation fate of MSCs via the RhoA-associated pathway. PMID- 28339037 TI - The long non-coding RNA lncFOXO1 suppresses growth of human breast cancer cells through association with BAP1. AB - Breast cancer, one of the common cancers of women, is the leading cause of death among women below the age of 50 years in western countries. Long non-coding RNAs (lncRNAs) have been shown to be involved in diverse biological processes, both physical and pathological. However, to date, only a few lncRNAs have been functionally identified in breast cancer, and the overall pathophysiological contributions of lncRNAs to breast cancer remain largely unknown. In the present study, we identified a novel lncRNA termed lncFOXO1 through microarray screening. lncFOXO1 is significantly decreased in breast cancer tissues and cell lines and downregulation of lncFOXO1 expression associates with poorer overall survival. Functional assays demonstrated its suppressive role in breast cancer in vivo and in vitro. Mechanistically, lncFOXO1 suppressed the growth of breast cancer by increasing FOXO1 transcription. Moreover, we found that lncFOXO1 associated with BRCA-1-associated protein 1 (BAP1) and regulates its binding and the level of mono-ubiquitinated H2A at K119 (ubH2AK119) at FOXO1 promoter. PMID- 28339036 TI - FGF7/FGFR2 signal promotes invasion and migration in human gastric cancer through upregulation of thrombospondin-1. AB - Fibroblast growth factor 7 (FGF7) is a mesenchyme-specific heparin-binding growth factor that binds FGF receptor 2 (FGFR2) to regulate numerous cellular and physiological processes. FGF7/FGFR2 signal is associated with gastric cancer progression. In the present study, we investigated the molecular mechanism by which FGF7/FGFR2 promotes invasion and migration in human gastric cancer. We first demonstrated that increased FGFR2 expression in human gastric cancer tissues was significantly associated with tumor depth and clinical stage in human gastric cancer tissues. Thrombospondin 1 (THBS1) is an extracellular glycoprotein that plays multiple roles in cell-matrix and cell-cell interactions. Increased expression of THBS1 significantly correlated with tumor differentiation. FGFR2 and THBS1 expression were both increased in cancer tissues as compared with adjacent normal tissues and their expression was positively correlated. In vitro, FGF7 stimulation of cell invasion and migration was partially suppressed by the FGFR2 knockdown. In addition, FGF7/FGFR2 upregulated THBS1, and cell invasion and migration were decreased by knockdown of THBS1. Furthermore, the PI3K/Akt/mTOR signaling pathway was predominantly responsible for FGF7/FGFR2-induced THBS1 upregulation. Taken together, our data suggest that FGF7/FGFR2/THBS1 is associated with the regulation of invasion and migration in human gastric cancer. PMID- 28339039 TI - The effects of air pollutants on the mortality rate of lung cancer and leukemia. AB - World Health Organization classifies air pollution as the first cause of human cancer. The present study investigated impact of air pollutants on the mortality rates of lung cancer and leukemia in Shiraz, one of the largests cities of Iran. This cross-sectional (longitudinal) study was carried out in Shiraz. Data on six main pollutants, CO, SO2, O3, NO2, PM10 and PM2.5, were collected from Fars Environmental Protection Agency for 3,001 days starting from 1 January, 2005. Also, measures of climatic factors (temperature, humidity, and air pressure) were obtained from Shiraz Meteorological Organization. Finally, data related to number of deaths due to lung and blood cancers (leukemia) were gathered from Shiraz University Hospital. Relationship between variations of pollutant concentrations and cancers in lung and blood was investigated using statistical software R and MiniTab to perform time series analysis. Results of the present study revealed that the mortality rate of leukemia had a direct significant correlation with concentrations of nitrogen dioxide and carbon monoxide in the air (P<0.05). Therefore, special attention should be paid to sources of these pollutants and we need better management to decrease air pollutant concentrations through, e.g., using clean energy respect to fossil fuels, better management of urban traffic planning, and the improvement of public transport service and car sharing. PMID- 28339038 TI - LncRNA-mediated SIRT1/FoxO3a and SIRT1/p53 signaling pathways regulate type II alveolar epithelial cell senescence in patients with chronic obstructive pulmonary disease. AB - The loss of alveolar structure and airspace enlargement are major pathological changes in chronic obstructive pulmonary disease (COPD). Type II alveolar epithelial cells (AECII) are involved in maintaining lung tissue repair and alveolar homeostasis. Long non-coding RNAs (lncRNAs) are involved in multi regulating gene transcription, affecting processes including embryonic development, cell differentiation and cellular senescence. The primary aim of the present study was to explore the mechanisms of AECII senescence regulated by lncRNA-mediated sirtuin 1 (SIRT1) and forkhead box O 3a (FoxO3a) signaling pathways in patients with COPD. Lung tissues from patients with COPD exhibited pathological characteristics and significantly increased senescence-associated beta-galactosidase activity. Furthermore, the expression levels of senescence associated lncRNA1 (SAL-RNA1), SIRT1 and FoxO3a were reduced, but SAL-RNA2, SAL RNA3, p53 and p21 were upregulated in the lung tissues of patients with COPD compared with control. The results of the present study indicated that lncRNA mediated SIRT1/p53 and FoxO3a signaling pathways may regulate AECII senescence in the pathogenesis of COPD, which may provide a novel experimental basis for the treatment of COPD. PMID- 28339040 TI - Detection assay for HPV16 and HPV18 by loop-mediated isothermal amplification with lateral flow dipstick tests. AB - Cervical cancer is the third highest cause of death in developing countries and most commonly results from high-risk human papillomavirus (HR-HPV) infection. Among HR-HPV genotypes, HPV16 and HPV18 are the most prevalent in cervical cancers. Therefore, the present study aimed to develop a detection assay for HPV16 and HPV18 infection using loop-mediated isothermal amplification (LAMP) with lateral flow dipstick (LFD) tests. This assay is a simplified, user-friendly method for the visual detection of HPV genotypes. DNA was extracted from clinical tissue samples, and HPV genotyping was performed using nested polymerase chain reaction (PCR). The clinical samples were demonstrated to include 44 HPV16 positive, 18 HPV18-positive and 80 HPV-negative samples. All DNA samples were also used as templates for a LAMP reaction (30 min at 65C), and subsequently, a fluorescein isothiocyanate-labelled probe was hybridized with the reaction product. Finally, the LFD test was performed. The sensitivity of the LAMP-LFD test was higher than LAMP-turbidity, exhibiting up to 100-fold higher sensitivity for HPV16 and 10-fold higher sensitivity for HPV18. All HPV16 and HPV18-positive samples generated positive results in both assays; however, 22 samples detected as HPV-negative by LAMP-turbidity exhibited positive results by LAMP-LFD test (22 of 80 samples). Therefore, these samples were further examined using quantitative (q)PCR. The results demonstrated that 20 out of the 22 samples designated positive by LAMP-LFD, but negative by LAMP turbidity, gave a positive result with qPCR, while the remaining 2 samples were negative by qPCR. The present results suggested that LAMP-LFD provided higher sensitivity than LAMP-turbidity and nested PCR. Thus, the LAMP-LFD test developed in the present study might be useful for the detection of HPV16 and HPV18 in local hospitals. PMID- 28339041 TI - Tanshinone IIA increases protein expression levels of PERK, ATF6, IRE1alpha, CHOP, caspase-3 and caspase-12 in pancreatic cancer BxPC-3 cell-derived xenograft tumors. AB - Tanshinone (Tan)-IIA is a derivative of phenanthrenequinone and the main active ingredient isolated from Salviae miltiorrhizae radix (Danshen). Previous studies have demonstrated that Tan-IIA increased the protein expressions levels of protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor (ATF) 6, caspase-12 and CCAAT-enhancer-binding protein homologous protein (CHOP), to induce endoplasmic reticulum (ER) stress and apoptosis in human pancreatic cancer BxPC-3 cells. However, to the best of our knowledge, the effects of Tan-IIA on pancreatic cancer cells have not been investigated in vivo. Further studies are required to elucidate the therapeutic potential of Tan-IIA in inducing ER stress in cancer cells in vivo. The present study aimed to investigate the effects of Tan-IIA on the expression of ER stress related proteins in BxPC-3-derived xenograft tumors. A total of 30 male severe combined immunodeficiency mice (age, 4 weeks) were implanted with BxPC-3 cells (2x106/0.2 ml) and subsequently treated with various doses of Tan-IIA (0, 30 and 90 mg/kg) for 4 weeks. After mice were sacrificed on day 33, the xenograft tumors were dissected and total protein was extracted for western blot analysis. The results of the present study demonstrated that Tan-IIA inhibited the growth of BxPC-3-derived xenograft tumors. In addition, Tan-IIA increased the protein expression levels of PERK, ATF6, caspase-12, inositol-requiring enzyme (IRE) 1alpha, eukaryotic initiation factor (eIF) 2alpha, phosphorylated (p)-c-Jun N terminal kinase (JNK), CHOP and caspase-3 in a dose-dependent manner. These results indicated that Tan-IIA induced ER stress via increasing the protein expression levels of PERK, ATF6, caspase-12, IRE1alpha, eIF2alpha, p-JNK, CHOP and caspase-3 in BxPC-3 cells in vivo. Therefore, it may be hypothesized that Tan IIA has potential for the development of novel therapeutic strategies for the treatment of patients with pancreatic cancer. PMID- 28339043 TI - High ATP2A2 expression correlates with better prognosis of diffuse astrocytic tumor patients. AB - Novel molecular markers are required for defining subsets of diffuse astrocytic tumor patients with differing prognoses. Here, we examined ATP2A2 expression in 109 human diffuse astrocytic tumor samples (39 grade II diffuse astrocytoma (DA), 19 grade III anaplastic astrocytoma (AA), 51 grade IV glioblastoma) and its correlation with patient clinicopathologic characteristics. ATP2A2 expression significantly correlated with tumor grade and survival (P<0.05). High ATP2A2 expression was detected in 35.3% (18/51) of glioblastoma patients, compared to 61.5% (24/39) in grade II, and 52.6% (10/19) in grade III astrocytoma patients (P=0.043). The median survival was 45+/-5.3 (95% CI, 34.7-55.3) months in patients with high ATP2A2 expression and 16+/-5.0 (95% CI, 6.3-25.7) months in patients with low ATP2A2 expression (P<0.0001). Additionally, high grade astrocytoma patients with high ATP2A2 expression showed longer survival (median, 31.0+/-4.9 months, 95% CI, 21.4-40.7) than those with low ATP2A2 expression (median: 13.0+/-1.6 months, 95% CI, 9.9-16.1; P=0.027). Furthermore, both ATP2A2 overexpression and IDH1 mutation were detected in secondary glioblastoma, AA developed from DA and oligodendrogiomas with IDH1 mutation. The MTT assays showed that lentiviral ATP2A2 overexpression significantly suppressed the clonogenic growth of glioblastoma U251MG cells (P<0.05). Xenografts stably overexpressing ATP2A2 were markedly smaller in size 4 weeks post inoculation (P<0.05). Our findings identified high ATP2A2 expression in a subset of astrocytoma patients that was associated with better prognosis and ATP2A2 suppressed astrocytoma growth. PMID- 28339042 TI - Immunomodulatory effects in workers exposed to naturally occurring asbestos fibers. AB - Natural asbestiform fibers are defined 'naturally occurring asbestos' (NOA) and refer to the mineral as a natural component of soils or rocks. The release of NOA fibers into the air from rocks or soils by routine human activities or natural weathering processes represents a risk for human beings. Fluoro-edenite (FE) is a NOA fiber detected in the benmoreitic lava in the area of Biancavilla, South-west slope of Mt. Etna. The aim of the present study was to investigate FE immunotoxicity pathways in a group of 38 occupationally exposed construction workers, in order to find any biological markers of its effect. Subjects underwent respiratory function tests and HRCT total chest scanning. Serum IL 1beta, IL-6, IL-8 and TNF-alpha were measured. The presence of PPs was significantly greater in subjects exposed than in the control (25 vs. 2). In subjects exposed to FE, IL-1beta and TNF-alpha values were significantly higher than the controls. The previously observed increase of IL-1beta and IL-18 showed a probable involvement of the proteic complex defined inflammosome by FE fibers. PMID- 28339044 TI - Suppression of nuclear factor erythroid-2-related factor 2-mediated antioxidative defense in the lung injury induced by chronic exposure to methamphetamine in rats. AB - The imbalance between oxidative stress and antioxidant defense is important in the pathogenesis of lung diseases. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a key transcriptional factor that regulates the antioxidant response. The purpose of the present study was to investigate whether Nrf2-mediated antioxidative defense is involved in methamphetamine (MA)-induced lung injury in rats. Following establishment of chronic MA toxicity in rats, Doppler ultrasonic detection was used to measure the changes of physiological indexes, followed by hematoxylin and eosin staining, ELISA and western blot analysis. MA was demonstrated to increase the heart rate and peak blood flow velocity of pulmonary arterial valves and to decrease the survival rate of rats, and resulted in lung injury characterized by perivascular exudates, airspace edema, slight hemorrhage and inflammatory cell infiltration. MA significantly inhibited the expression of nuclear Nrf2 protein and its target genes (glutamate-cysteine ligase catalytic subunit C and heme oxygenase-1), and dose-dependently reduced glutathione (GSH) levels and the ratio of GSH/oxidized glutathione, accompanied by increases in reactive oxygen species (ROS) levels in rat lungs. Linear regression analysis revealed that there was a positive correlation between lung ROS level and lung injury indexes. These findings suggested that chronic exposure to MA led to lung injury by suppression of Nrf2-mediated antioxidative defense, suggesting that Nrf2 may be an important therapeutic target for MA-induced chronic lung toxicity. PMID- 28339045 TI - Identification of circulating long non-coding RNA GAS5 as a potential biomarker for non-small cell lung cancer diagnosisnon-small cell lung cancer, long non coding RNA, plasma, GAS5, biomarker. AB - Non-small cell lung cancer (NSCLC) is one of the most malignant cancers in the world. Early diagnosis of NSCLC has become especially important for patient treatment and prognosis. Increasing evidence suggest that long non-coding RNA GAS5 plays vital roles in cancer proliferation and differentiation in NSCLC. However, its clinical value in the diagnosis of NSCLC is unclear. The objective of this study was to evaluate the importance of circulating GAS5 as a biomarker for NSCLC diagnosis. In our study, quantitative real-time PCR (QRT-PCR) was applied to detect the GAS5 expression level in 80 pairs of cancer tissues and 57 pairs of plasma samples of NSCLC patients. Further analysis was performed to study the differential expression of circulating GAS5 in 111 NSCLC patients and 78 healthy controls in our study. The results showed that GAS5 decreased in NSCLC tissues compared to noncancerous tissues (P<0.001). Furthermore, the GAS5 expression level was statistically declined in early stage of NSCLC before surgery compared with healthy controls (P<0.05) and sharply increased in postoperative groups (P=0.026). ROC curve analysis for early stage of NSCLC with the combination of GAS5, CEA and CA199 showed that the area under the ROC curve (AUC) was 0.734 (95% CI, 0.628-0.839; P<0.0005). In conclusion, circulating GAS5 could be functioned as a potential combined biomarker for screening NSCLC and patient monitoring after surgical treatment. PMID- 28339046 TI - Oncogenic function and prognostic significance of Abelson interactor 1 in hepatocellular carcinoma. AB - Aberrant expression of Abelson interactor 1 (ABI1) has been reported in multiple cancers. However, its clinical significance and potential biological roles in hepatocellular carcinoma (HCC) have not been fully elucidated. In this study, we found that ABI1 was obviously upregulated in HCC tissues compared with non-tumor tissues. Moreover, high ABI1 expression was significantly correlated with tumor size (P=0.041), tumor number (P<0.001), tumor encapsulation (P<0.001) and BCLC stage (P=0.010). Importantly, Kaplan-Meier survival analysis showed that increased ABI1 expression predicted shorter overall survival time (P<0.001) and a higher tendency of tumor recurrence (P=0.001) in HCC patients. Multivariate Cox regression analysis further confirmed high ABI1 expression was an independent predictor for both overall survival (HR=1.795, P=0.025) and early recurrence (HR=1.893, P=0.012) after surgical resection. Furthermore, in vitro studies indicated that overexpression of ABI1 induced an increase in cell proliferation, migration and invasion of HCC cells, whereas knockdown of ABI1 did the opposite. Xenograft mouse models verified the promoting effects of ABI1 on HCC growth and lung metastasis in vivo. Collectively, our findings indicated that ABI1 contributes to the development and progression of HCC as an oncogene and may serve as a valuable prognostic marker for HCC patients. PMID- 28339047 TI - Hypothalamo-hypophysial system in rats with autotransplantation of the adrenal cortex. AB - Patients with bilateral pheochromocytoma often require an adrenalectomy. Autotransplantation of the adrenal cortex is an alternative therapy that could potentially be performed instead of receiving glucocorticoid replacement following adrenalectomy. Adrenal cortex autotransplantation aims to avoid the side effects of long-term steroid treatment and adrenal insufficiency. Although the function of the hypothalamo-hypophysial system is critical for patients who have undergone adrenal cortex autotransplantation, the details of that system, with the exception of adrenocorticotropic hormone in the subjects with adrenal autotransplantation, have been overlooked for a long time. To clarify the precise effect of adrenal autotransplantation on the pituitary gland and hypothalamus, the current study examined the gene expression of hormones produced from the hypothalamus and pituitary gland. Bilateral adrenalectomy and adrenal autotransplantation were performed in 8 to 9-week-old male rats. The hypothalamus and pituitary tissues were collected at 4 weeks after surgery. Transcriptional regulation of hypothalamic and pituitary hormones was subsequently examined by reverse transcription-quantitative polymerase chain reaction. Proopiomelanocortin, glycoprotein hormone alpha polypeptide, and thyroid stimulating hormone beta were significantly elevated in the pituitary gland of autotransplanted rats when compared with sham-operated rats. In addition, there were significant differences in the levels of corticotropin releasing hormone receptor 1 (Crhr1), Crhr2, nuclear receptor subfamily 3 group C member 1 and thyrotropin releasing hormone receptor between the sham-operated rats and autotransplanted rats in the pituitary gland. In the hypothalamus, corticotropin releasing hormone and urocortin 2 mRNA was significantly upregulated in autotransplanted rats compared with sham-operated rats. The authors identified significant alterations in the function of not only the hypothalamus-pituitary adrenal axis, but also the adenohypophysis thyrotropes in autotransplanted rats. In the future, it will be important to examine other tissues affected by glucocorticoids following adrenal cortex autotransplantation. PMID- 28339049 TI - Kidney and heavy metals - The role of environmental exposure (Review). AB - Heavy metals are extensively used in agriculture and industrial applications such as production of pesticides, batteries, alloys, and textile dyes. Prolonged, intensive or excessive exposure can induce related systemic disorders. Kidney is a target organ in heavy metal toxicity for its capacity to filter, reabsorb and concentrate divalent ions. The extent and the expression of renal damage depends on the species of metals, the dose, and the time of exposure. Almost always acute kidney impairment differs from chronic renal failure in its mechanism and in the magnitude of the outcomes. As a result, clinical features and treatment algorithm are also different. Heavy metals in plasma exist in an ionized form, that is toxic and leads to acute toxicity and a bound, inert form when metal is conjugated with metallothionein and are then delivered to the liver and possible causing the kidney chronic damage. Treatment regimens include chelation therapy, supportive care, decontamination procedures and renal replacement therapies. This review adds specific considerations to kidney impairment due to the most common heavy metal exposures and its treatment. PMID- 28339048 TI - AGR2 ameliorates tumor necrosis factor-alpha-induced epithelial barrier dysfunction via suppression of NF-kappaB p65-mediated MLCK/p-MLC pathway activation. AB - Intestinal epithelial barrier dysfunction plays a critical role in the pathogenesis of inflammatory bowel disease (IBD). Anterior gradient protein 2 homologue (AGR2) assists in maintaining intestinal homeostasis in dextran sulphate sodium-induced mouse ileocolitis; however, it is unclear whether it modulates intestinal barrier function. Our study aimed to investigate the protective role of AGR2 in tumor necrosis factor (TNF)-alpha-induced intestinal epithelial barrier injury. Caco-2 cell monolayers were pre-transfected with an AGR2 plasmid and then exposed to TNF-alpha. Epithelial permeability was assessed by detecting transepithelial electrical resistance and fluorescein isothiocyanate dextran (40 kDa) flux. The protein expression levels of zonula occludens-1 (ZO 1), occludin, claudin-1, myosin light chain kinase (MLCK)/p-MLC, and nuclear factor (NF)-kappaB p65 were determined by western blotting. In addition, the cellular distributions of ZO-1, occludin, F-actin, and NF-kappaB p65 were evaluated by immunofluorescence staining. The results showed that the AGR2 mRNA and protein expression levels were both decreased in the Caco-2 cell monolayers, while AGR2 overexpression significantly ameliorated TNF-alpha-induced epithelial barrier hyperpermeability, increased the expression of tight junction (TJ) proteins and stabilized the cytoskeletal structure. Furthermore, AGR2 inhibited the changes in MLCK, MLC and p-MLC expression in response to TNF-alpha stimulation. Collectively, our study suggests that AGR2 inhibits TNF-alpha induced Caco-2 cell hyperpermeability by regulating TJ and that this protective mechanism may be promoted by inhibition of NF-kappaB p65-mediated activation of the MLCK/p-MLC signaling pathway. PMID- 28339051 TI - Protective effects of tacrolimus on podocytes in early diabetic nephropathy in rats. AB - The aim of the present study was to investigate the protective effect of tacrolimus on early podocyte damage in rats with diabetic nephropathy (DN). A total of 38 normal male Sprague-Dawley rats were randomly divided into four groups: Normal control group (group N; n=8), DN group (n=10), tacrolimus (FK506) treatment group (group F; n=10), benazepril (Lotensin) treatment group (group L; n=10). The rats in groups DN, F and L were administered with streptozotocin (STZ; 60 mg/kg) by intraperitoneal injection to establish the diabetic rat model. After 4 weeks, the diabetic rat model was established, and rats in the different groups were administered intragrastically with the respective drugs. Blood glucose (BS), body weight (BW) and 24-h urine protein were detected every 4 weeks, serum creatinine (SCr), blood urea nitrogen (BUN) and kidney weight/body weight (KW/BW) were measured at the end of the 8 weeks of drug treatment. Renal pathological changes were observed under a light microscope and electron microscope. Expression of nephrin, which is a podocyte-specific marker, was detected using western blot analysis. The results showed that the levels of SCr, BUN, KW/BW and 24-h urine protein in groups D, F and L were significantly higher, compared with those in group N (P<0.05). No significant differences were found between groups F and L for the above indicators, with the exception of BS. However, all indices were significantly lower, compared with those in group DN (P<0.05). Renal pathological expression was normal in group N under light microscopy. There were significant increases in the glomerular volume, proliferative mesangial cells, width of the mesangial area and thickness of the basement membrane in group DN, however, all the above pathological characteristics were reduced in groups F and L, compared with group DN (P<0.05). No significant difference was found between groups F and L. A widened glomerular basement membrane, and disorder, widening and fusion of podocyte processes were observed under the electron microscope in group DN, however, these were reduced in groups F and L, compared with group DN (P<0.05). The results of the western blot analysis showed that the expression of nephrin decreased by 60.1% in group DN, compared with group N, and significant recovery in the expression of nephrin was observed in groups F and L (P<0.05). Tacrolimus reduced urinary protein and slowed the progression of DN, partially by recovering the protein expression of nephrin in the renal tissue of diabetic rats, and maintaining the integrity of the structure and function of podocytes. PMID- 28339050 TI - p53 mutation status is a primary determinant of placenta-specific protein 1 expression in serous ovarian cancers. AB - Placenta-specific protein 1 (PLAC1) expression is co-opted in numerous human cancers. As a consequence of PLAC1 expression, tumor cells exhibit enhanced proliferation and invasiveness. This characteristic is associated with increased aggressiveness and worse patient outcomes. Recently, the presence of the tumor suppressor p53 was shown in vitro to inhibit PLAC1 transcription by compromising the P1, or distal/cancer, promoter. We sought to determine if this phenomenon occurs in primary patient tumors as well. Furthermore, we wanted to know if p53 mutation influenced PLAC1 expression as compared with wild-type. We chose to study serous ovarian tumors as they are well known to have a high rate of p53 mutation. We report herein that the phenomenon of PLAC1 transcription repression does occur in serous ovarian carcinomas but only when TP53 is wild-type. We find that mutant or absent p53 protein de-represses PLAC1 transcription. We further propose that the inability of mutant p53 to repress PLAC1 transcription is due to the fact that the altered TP53 protein is unable to occupy a putative p53 binding site in the PLAC1 P1 promoter thus allowing transcription to occur. Finally, we show that PLAC1 transcript number is significantly negatively correlated with patient survival in our samples. Thus, we suggest that characterizing tumors for TP53 mutation status, p53 protein status and PLAC1 transcription could be used to predict likely prognosis and inform treatment options in patients diagnosed with serous ovarian cancer. PMID- 28339052 TI - AhR-E2F1-KGFR signaling is involved in KGF-induced intestinal epithelial cell proliferation. AB - Keratinocyte growth factor (KGF) stimulates intestinal epithelial cell proliferation upon binding to the KGF receptor (KGFR). The activated aryl hydrocarbon receptor (AhR) serves an important role in the development of tissues by promoting the expression of AhR receptors, which can regulate cell proliferation. In the present study, the signaling pathway between AhR and KGFR in investigated with regards to KGF-induced intestinal epithelial cell proliferation. Male C57BL/6J wild type and AhR-/- mice, were randomized into four groups: Control, KGF, AhR-/- + KGF and AhR-/- (n=6 per group). The small bowel was harvested on day 5 post-treatment. LoVo cells were used to study signaling pathways in vitro and were divided into the following four treatment groups: DMSO, KGF, KGF + small-interfering (si)AhR and siAhR. In vivo, knockdown of AhR mRNA transcripts may abolish KGF-induced intestinal epithelial cell proliferation. Furthermore, KGFR expression was downregulated following knockdown or silencing of AhR expression in vivo and in vitro. The present study identified that the transcription factor E2F1 could regulate KGFR expression, and that siAhR treatment led to reduced expression of E2F1 in the nucleus and inhibited KGF induced cell proliferation. In conclusion, the current results demonstrated that the AhR-E2F1-KGFR pathway is involved in KGF-induced intestinal epithelial cell proliferation. PMID- 28339053 TI - miR-486 suppresses the development of osteosarcoma by regulating PKC-delta pathway. AB - Osteosarcoma is one of the most highly malignant types of cancer in adolescents and young adults with a high mortality rate. Despite advances in surgery, radiation therapy and chemotherapy, the prognosis for patients with osteosarcoma has not significantly improved over the past several decades. It is necessary to find new indicators of prognosis and therapeutic targets of osteosarcoma. Through the analysis of 40 osteosarcoma tissues, we found that the expression of miR-486 was low and the expression of PKC-delta was high in osteosarcoma. Median survival of patients with low expression of miR-486 (30 months) was shorter than the patients with higher expression of miR-486 (40 months). We further found that miR 486 can inhibit the targeting of PKC-delta signaling pathways, and this inhibition can inhibit the growth and invasion of osteosarcoma cells. After transfection of miR-486 for 24 h, the proliferation of osteosarcoma cells was inhibited by ~20%, and the migration was inhibited by ~15%. In the present investigation, we demonstrated that miR-486 is negatively associated with the expression of PKC-delta and could regulate the development of osteosarcoma. miR 486 may be a potential target for the treatment of osteosarcoma. PMID- 28339054 TI - Overexpression of Tim-3 reduces Helicobacter pylori-associated inflammation through TLR4/NFkappaB signaling in vitro. AB - The present study aimed to investigate the interaction between T-cell immunoglobulin and mucin-domain-containing molecule-3 (Tim-3) and Toll-like receptor 4 (TLR4)/nuclear factor kappaB (NF-kappaB) signaling in Helicobacter pylori-infected RAW264.7 macrophage cells. RAW264.7 cells were co-cultured with H. pylori SS1 at different bacteria/cell ratios, and subsequently the mRNA expression of Tim-3, TLR4, and myeloid differentiation factor 88 (MyD88) was measured by reverse transcription-quantitative polymerase chain reaction (RT qPCR). Furthermore, the effect of Tim-3 overexpression was examined by transfection of RAW264.7 with pLVX-IRES-ZsGreen-Tim-3 and co-culturing with H. pylori. mRNA and protein expression levels were then analyzed for Tim-3, TLR4, MyD88, and phosphorylated (p-) NF-kappaB by RT-qPCR and western blot analysis respectively. The concentrations of pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), interferon-gamma (IFN-gamma) and interleukin 10 (IL-10)] released in the culture supernatants were measured by ELISA. H. pylori stimulation resulted in a significant increase of Tim-3, TLR4, and MyD88 mRNA expression in RAW264.7 cells. H. pylori stimulation upregulated Tim-3 expression even in the Tim-3-overexpressing RAW264.7 cells compared with unstimulated cells. TLR4, MyD88, and pNF-kappaB protein expression and pro inflammatory cytokines (TNF-alpha, IL-6, and IFN-gamma) release levels were increased in the control RAW264.7 cells following H. pylori infection, but not in the Tim-3-overexpressing RAW264.7 cells. By contrast, IL-10 levels were decreased following H. pylori infection in both control and Tim-3-overexpressing RAW264.7 cells. Overexpression of Tim-3 reduced H. pylori-associated inflammation in RAW264.7 macrophages, by downregulating expression of proteins in the TLR4 pathway and release of pro-inflammatory cytokines. These findings suggest that Tim-3 serves a crucial role in the negative regulation of H. pylori-associated inflammation and may be a novel therapeutic target for H. pylori infection. PMID- 28339055 TI - New insights on 'old' toxicants in occupational toxicology (Review). AB - In order to deliver the best possible working environment, it is essential to identify professional conditions that could be harmful for worker's health and prevent (or limit) the occurrence of such conditions. The appropriate use of personal protective equipment and the development of appropriate regulations allowed to reduce the prevalence of 'classic' occupational diseases, such as occupational hearing loss or asbestosis, just to name a few. Nowadays, environmental pollution seems to be one of the most relevant concerns for human and animal health, and toxicology is becoming one of the most prominent fields of interest in occupational settings. An increasing number of studies demonstrate that the presence of toxicants in the workplace could be responsible for the development of chronic diseases, even at doses that were considered 'safe'. The present review summarizes some of the most recent advancements in occupational toxicology, focusing on topics that have long been debated in the past and that have recently returned to the fore. PMID- 28339056 TI - Nobiletin inhibits invasion via inhibiting AKT/GSK3beta/beta-catenin signaling pathway in Slug-expressing glioma cells. AB - Epithelial-mesenchymal transition (EMT) is a pivotal event in tumor progression during which cancer cells undergo dramatic changes acquiring highly invasive properties. In this study, we found that nobiletin, a polymethoxylated flavone, suppressed migration and invasion in both U87 and U251 glioma cells. Expression of epithelial markers (E-cadherin and occludin) was upregulated; mesenchymal markers (N-cadherin, fibronectin) and the transcriptional factor Slug were downregulated after nobiletin treatment. Transforming growth factor beta (TGF beta) was applied to stimulate EMT and the results showed that nobiletin not only influenced basal level cell migration but also prevented TGF-beta-triggered migration and EMT, with the AKT/GSK3beta/beta-catenin signaling pathway greatly involved. Furthermore, nobiletin remarkably diminished TGF-beta-induced beta catenin nuclear translocation and the binding to the Slug promoter. It is worth noting that nobiletin almost blocked invasion in Slug-expressing U87 and U251 cells, and only exhibiting faint effect on non-Slug-expressing U343 glioma cells. Reinforced Slug expression in U343 cells by transfecting Slug plasmid was significantly attenuated by nobiletin, demonstrating the essential role of Slug in the anti-metastasis effect of nobiletin. Nobiletin repressed tumor growth in vivo and abrogated EMT in nude mice bearing U87-Luc xenografts, as demonstrated by Xenogen IVIS imaging and immunohistochemistry assay. Our findings suggested that nobiletin might have a great potential for treating glioblastoma. PMID- 28339057 TI - GPR143 mutations in Chinese patients with ocular albinism type 1. AB - The aim of the present study was to evaluate mutations of the G protein-coupled receptor 143 (GPR143) gene for ocular albinism type 1 (OA1) in Chinese patients. For the current study, 8 patients with OA1 were selected from the database of ocular genetic diseases. Genomic DNA of OA1 was prepared from venous leukocytes collected from the patients. Cycle sequencing was used to analyze the exons and adjacent introns of GPR143. The variation detected was analyzed by bidirectional DNA sequencing and further evaluated in 96 controls using heteroduplex-single strand conformational polymorphism analysis. Additionally, slit lamp photography of anterior segment, fundus photography and optical coherence tomography (OCT) were performed to identify the clinical features of OA1. In five patients with OA1, 5 GPR143 gene mutations were identified and four of them there were novel mutations. The screening rate is 62.5%, including c.333G>A (p.W111X), c.353G>A (p.G118E) (known mutation), C.658+2T>G (splice mutation), c.215_216insCGCTGC (p.71-72insAA) and c.17T>C (p. L6P). These mutations were absent in the 96 normal controls. Only one patient with OA1 in the present study was female. Patients with OA1 often have congenital nystagmus, refractive error, severe decline of visual acuity (from 0.1 to 0.4) and foveal hypoplasia. Different degrees of pigment loss were evident in the patients' iris and retina, whereas macular structure was not identified in the OCT examination. The findings of the present study expanded the gene mutation spectrum of GPR143 and investigated the clinical phenotype of patients with OA1 in the Chinese population. Additional evidence for clinical diagnosis was provided along with differential diagnosis and genetic counseling. PMID- 28339058 TI - Toenail selenium as an indicator of environmental exposure: A cross-sectional study. AB - The relation between toxicity and essentiality of selenium (Se) is of growing interest in human health, as the effects may widely differ depending of its different chemical species and the exposure levels. Toenail Se has been proposed as a reliable biomarker of long-term Se exposure, but few studies investigated the correlation between its toenail content and environmental determinants (i.e., dietary food intake). We aimed to determine the relation of toenail Se levels with serum Se species as well as food items. We recruited a random sample of Modena (Northern Italy) municipal residents, from whom we collected detailed personal information, dietary habits, toenail specimen for Se determination and a blood sample for serum Se speciation analysis. Toenail Se mean value was 0.96 ug/g (range, 0.47-1.60), with slightly higher levels in females, in non-obese subjects and in Se supplements users, while it was lower in current smokers. Toenail Se positively correlated with organic Se forms, mainly selenoprotein P and selenocysteine, and inversely with the inorganic forms (selenite and selenate). Toenail Se was not associated with meat, cereals and dairy products consumption, positively correlated with fruit and slightly with vegetable intake, and negatively with fish and seafood consumption. Finally, no clear association emerged with estimated air Se exposure. PMID- 28339059 TI - Proteomic-based identification of HSP70 as a tumor-associated antigen in ovarian cancer. AB - Ovarian cancer commonly presents without prominent symptoms and is consequently diagnosed at advanced stages with unfavorable prognosis. Novel serological biomarkers for the early detection and clinical management of ovarian cancer are imminently needed. Proteomic-based methods for biomarker discovery are promising strategies implemented in cancer research. The aim of the present study was to identify new tumor antigens from the ovarian cancer cell line SKOV3 and their associated autoantibodies in sera of patients with ovarian cancer employing proteomic-based approaches. Proteins from the ovarian cancer cell line SKOV3 were extracted by two-dimensional polyacrylamide gel electrophoresis (2-DE) followed by western blotting and antibody reaction with sera from patients with ovarian cancer and normal controls. Positive spots were excised from Coomassie blue stained gels and identified by liquid chromatography-tandem mass spectrometry (LC MS/MS). The 2-DE analysis results revealed a total of 14 protein spots on the gel, and 7 proteins were finally identified by LC-MS/MS. In the subsequent experiment, using immunoassay on ovarian cancer sera and tissue-array slides, the well-known protein HSP70 was selected in order to validate this proteomic-based approach. In conclusion, the proteomic method used in the present study is a powerful instrument for identifying novel serum markers that may exhibit clinical usefulness in cancer. PMID- 28339060 TI - Chronological changes in the expression of phosphorylated tau and 5-AMP-activated protein kinase in the brain of senescence-accelerated P8 mice. AB - Senescence-accelerated mouse prone 8 (SAMP8), a non-transgenic animal model used for researching sporadic Alzheimer's disease (AD), presents AD pathologies and overall dysregulation in brain energy metabolism, which is one of the early pathogenic characteristics of AD. In the present study, the authors examined chronological changes in the expression patterns of phosphorylated tau and of proteins related to energy metabolism to evaluate the association of tau phosphorylation and metabolism, using young- (2-months-old), middle- (5-months old) and old-aged (10-months-old) SAMP8. The levels of phosphorylated 5'-AMP activated protein kinase at Thr172 (p-AMPK) and phosphorylated glycogen synthase kinase 3beta (p-GSK3betaS9) in the cortex of SAMP8 at 2 months were significantly higher than those in senescence-accelerated mouse resistant 1 (SAMR1). The differences were not detected at 5 and 10 months of age, which were concurrent with the changes in levels of phosphorylated tau at Ser396 (p-tauS396), but not with p-tauS262. The level of p-tauS262 was considerably higher in the cortex of middle-aged SAMP8 when compared with that of SAMR1 and sustained in old-aged SAMP8, but not in the young cortex. The levels of cortical sirtuin1 (Sirt1) and insulin receptor substrate 1 (IRS-1) expression of young SAMP8 were significantly lower, when compared with those in SAMR1. However, in the hippocampus of SAMP8, the patterns of chronological changes and levels of p-tau, p-AMPK, Sirt1 and IRS 1 relative to SAMR1 were different from those in the cortex. Taken together, the results suggested that regulation of tau phosphorylation via the AMPK-GSK3beta pathway concurrent with dysregulation of energy metabolism may precede the pathological tau hyperphosphorylation in the cortex of SAMP8, and that the regulation of AMPK-GSK3beta-mediated tau phosphorylation may be dependent on phosphor-epitope in tau or the region of brain. PMID- 28339061 TI - Identification of two novel mutations in the SLCO2A1 prostaglandin transporter gene in a Chinese patient with primary hypertrophic osteoarthropathy. AB - Primary hypertrophic osteoarthropathy (PHO), which is a rare multi-organic disease characterized by digital clubbing, pachydermia and periosteal reaction, typically begins during childhood or adolescence and progresses gradually over years prior to disease stabilization. To date, only two genes have been reported to be associated with PHO, 15-hydroxyprostaglandin dehydrogenase and solute carrier organic anion transporter family, member 2A1 (SLCO2A1). However, the pathogenesis and the functions of the underlying genes remain to be fully elucidated. In the present study, a 20-year-old Chinese patient with PHO was investigated using sequence analysis of PHO genes and bioinformatics analysis. A novel, compound heterozygous mutation in the SLCO2A1 gene was identified, which contained two novel mutations: c.349delC (p.L117SfsX56) in exon 3 and c.1286A>G (p.Y429C) in exon 9. These two novel genotypes in PHO are the first, to the best of our knowledge, to be reported in PHO. This finding expands the mutation spectrum of PHO, which contributes to improving genetic diagnosis and future genetic counseling, and provides clues to the phenotype-genotype associations. PMID- 28339062 TI - p53/microRNA-374b/AKT1 regulates colorectal cancer cell apoptosis in response to DNA damage. AB - Colorectal cancer (CRC) has a rising morbidity worldwide and its resistance to chemotherapy has been observed in clinical treatment. Tumor suppressor p53 is well-studied in CRC, but little is known about its effects during DNA damage of CRC cells. This study was aimed at uncovering potential mechanisms of p53 regarding microRNA-374b and v-akt murine thymoma viral oncogene homolog 1 (AKT1) during DNA damage of CRC cells. CRC cells HCT116 and HT29 were transfected with p53-specific small interfering RNA (siRNA), p53 overexpression vector or miR-374b inhibitor, and then treated with 10 uM bleomycin (BLM) for 24 h to induce DNA damage. Primary (pri), precursor (pre) and mature miR-374b levels were quantified by qRT-PCR. AKT1 and p53 protein levels were detected by western blotting. Cell apoptosis changes were assessed by flow cytometry. AKT1 mRNA was detected to be induced by BLM treatment (P<0.05), but its protein level was strongly inhibited. Knockdown of p53 reversed the inhibition of AKT1 protein by BLM. Overexpression of p53 in p53-knockout HCT116 and HT29 cells upregulated the AKT1 regulator miR 374b (P<0.05), and knockdown of p53 reversed the induction of miR-374b by BLM. qRT-PCR suggested that besides mature miR-374b, p53 could also promote pre-miR 374b level (P<0.05), rather than pri-miR-374b. Moreover, inhibition on miR-374b relieved the suppressed AKT1 protein, and reduced cell apoptosis induced by BLM. These data depict the p53/miR-374b/AKT1 signaling that may regulate BLM-induced apoptosis in CRC cells, thus facilitating to improve the outcome of chemotherapy in CRC. PMID- 28339064 TI - Extracellular matrix metabolism disorder induced by mechanical strain on human parametrial ligament fibroblasts. AB - Pelvic organ prolapse (POP) is a global health problem that may seriously impact the quality of life of the sufferer. The present study aimed to investigate the potential mechanisms underlying alterations in extracellular matrix (ECM) metabolism in the pathogenesis of POP, by investigating the expression of ECM components in human parametrial ligament fibroblasts (hPLFs) subject to various mechanical strain loads. Fibroblasts derived from parametrial ligaments were cultured from patients with POP and without malignant tumors, who underwent vaginal hysterectomy surgery. Fibroblasts at generations 3-6 of exponential phase cells were selected, and a four-point bending device was used for 0, 1,333 or 5,333 u mechanical loading of cells at 0.5 Hz for 4 h. mRNA and protein expression levels of collagen type I alpha 1 chain (COL1A1), collagen type III alpha 1 chain (COL3A1), elastin, matrix metalloproteinase (MMP) -2 and -9, and transforming growth factor (TGF)-beta1 were detected by reverse transcription quantitative polymerase chain reaction and western blotting, respectively. Under increased mechanical strain (5,333 u), mRNA and protein expression levels of COL1A1, COL3A1 elastin and TGF-beta1 decreased, particularly COL1A1; however, mRNA and protein expression levels of MMP-2 and -9 were significantly increased, compared with the control group (0 u strain). Following 1,333 u mechanical strain, mRNA and protein expression levels of COL1A1, COL3A1 elastin and MMP-2 increased, and MMP-9 decreased, whereas no significant differences were observed in TGF-beta1 mRNA and protein expression levels. In conclusion, ECM alterations may be involved in pathogenesis of POP, with decreased synthesis and increased degradation of collagen and elastin. Furthermore, the TGF-beta1 signaling pathway may serve an important role in this process and thus may supply a new target and strategy for understanding the etiology and therapy of POP. PMID- 28339063 TI - Viral and host factors associated with outcomes of hepatitis C virus infection (Review). AB - Hepatitis C virus (HCV) infection is a major health issue globally. Owing to the progress made in host genetics and HCV molecular virology, emerging data have suggested that the natural course and treatment response in patients with HCV infection are largely determined by complex host-viral interactions. HCV genotype is the most important viral factor predicting the response to pegylated interferon-alpha plus ribavirin therapy. The subtype of HCV genotype 1 is the key viral factor that predicts the efficacy of direct-acting antiviral therapy. HCV genome heterogeneity and baseline viral load are additionally associated with the treatment response. Multiple host genetic variants localized in genes associated with the immune response have been identified as predictors of spontaneous disease course and therapy outcome in chronic HCV. However, most findings from candidate gene association studies have not been proven universal for all investigated populations and independent studies. Previous findings in independent large genome wide association studies confirmed that interferon lambda3 gene polymorphisms are associated with spontaneous clearance and treatment responsiveness. A polymorphism of the inosine triphosphatase gene has been identified as a protective factor against ribavirin-induced anemia and dose reductions. Another genetic variant in the patatin-like phospholipase domain containing 3 genes is associated with hepatic steatosis and fibrosis in patients with HCV. The present review focused on the identified viral and host factors associated with outcomes of patients with HCV, and assessed the involvement of viral and host genetics in the natural history and treatment outcomes of HCV infection. This will provide novel ideas concerning personalized prevention and individualized clinical management. PMID- 28339065 TI - The risk of HCV infection among health-care workers and its association with extrahepatic manifestations (Review). AB - Health care workers (HCWs) are frequently exposed to different biological agents during their activities and are frequently monitored. Among these infectious agents, human hepatitis C (HCV) can infect HCWs. In this review article, the risk of HCV infection among HCWs is discussed along with extrahepatic HCV-related malignancies, such as non-Hodgkin lymphoma. Accidental contamination, represented by percutaneous and mucocutaneous infections is the main risk factor for such infection. The compliance of the protection procedures, included in the current regulation for HCWs, is the most important issue to reduce the risk of pathogen infections that in turn may produce reduction of infection-associated malignancies. PMID- 28339066 TI - MicroRNA-499 rs3746444 A/G polymorphism functions as a biomarker to predict recurrence following endoscopic submucosal dissection in primary early gastric cancer. AB - The aim of the present study was to investigate the molecular mechanism, including the potential regulatory and signaling pathways, of platelet-derived growth factor receptor beta (PDGFRB), which underlies the recurrence of early gastric cancer (EGC) following endoscopic submucosal dissection (ESD). Online microRNA (miRNA) target prediction tools were used, which identified PDGFRB as the candidate target gene of miR-499a in gastric cancer cells, and PFGRBR was then confirmed as the direct gene using a luciferase reporter assay system. The Kaplan-Meier method was used to plot recurrence-free curves, which were compared between genotype groups. A negative regulatory association between miR-499a and PDGFRB was established by investigating the relative luciferase activity at different concentrations of miR-499a mimics. Furthermore, as the rs3746444 polymorphism has been previously reported to interfere with the expression of miR 499a, the present study investigated the expression levels of different genotypes, including TT (n=20), TC (n=9) and CC (n=3), the results of which supported the hypothesis that the presence of the minor allele (C) of the rs3746444 polymorphism compromised the expression of miR-499a. The present study also performed polymerase chain reaction and western blot analyses to examine the mRNA and protein expression levels of PFGRBR among different genotypes or cells treated with different concentrations of miR-499a mimics/inhibitors, which indicated the negative regulatory association between miR-499a and PDGFRB. The present study also investigated the relative viabilities of EGC cells transfected with miR-499a mimics (50 and 100 nM) and miR-499a inhibitors (100 nM), and confirmed that miR-499a negatively interfered with the viability of the EGC cells. The miR-499a rs3746444 polymorphism was also recognized as a biomarker to predict recurrence following ESD in patients with EGC via analyzing the recurrence-free rates among patients with EGC with different genotypes. The results showed that PDGFRB was validated as a target of miR-499a, and rs3746444 was identified as a potential biomarker to predict the recurrence of EGC following ESD. PMID- 28339067 TI - Characterization of DAPK1 as a novel transcriptional target of BRMS1. AB - Breast cancer metastasis suppressor 1 (BRMS1) can specifically regulate tumor metastasis in many cancers. Our previous studies have demonstrated that BRMS1 can promote cell apoptosis through regulating osteopontin (OPN) expression in hepatocellular carcinoma (HCC) cells. However, the transcriptional targets of BRMS1 have not been thoroughly studied. In this study, death-associated protein kinase 1 (DAPK1), a tumor suppressor gene with multiple roles in regulating cell death, was identified as a potential transcriptional target of BRMS1 in the whole genome expression microarray. Quantitative real-time PCR and western blot analysis of HCC cells overexpressing BRMS1 further confirmed the transcriptional regulation relationship between BRMS1 and DAPK1. Moreover, DAPK1 expression was frequently decreased or even lost in HCC tissue samples by comparison with neighboring pathologically normal liver tissue, which was consistent with the decreased BRMS1 expression pattern. To unravel the molecular mechanism of BRMS1 in regulating DAPK1, a series of deletion mutants of DAPK1 promoter was subjected to luciferase assay. The luciferase units of -200 to -80 bp region, with two tandem putative NF-kappaB binding sites, were specifically enhanced by BRMS1 expression. Site-directed mutants of NF-kappaB binding sites blocked the transcriptional activation effect. In addition, the binding capability of BRMS1 and the putative NF-kappaB binding sites were demonstrated in the chromatin immunoprecipitation (ChIP) assay. In conclusion, our study characterized DAPK1 as a novel transcriptional target of BRMS1. Transcriptional activation of DAPK1 might be another important mechanism accounting for the metastasis suppressive activity of BRMS1. PMID- 28339068 TI - Iron and Parkinson's disease: A systematic review and meta-analysis. AB - A possible association between iron serum levels and Parkinson's disease (PD) using a meta-analytic approach was evaluated. A systematic MEDLINE search was conducted to identify published observational, case-control studies dealing with the association between iron blood levels and PD. In both groups, iron blood levels were extracted as means and standard deviations to calculate the standardized mean differences (SMDs) with 95% confidence intervals (CIs). Heterogeneity of selected studies was investigated. Then, a meta-analysis was performed applying a random effects model. Possible causes of bias were also examined. A meta-regression analysis was finally conducted to investigate whether associations varied according to specified confounding factors. Of 155 studies detected by the research strategy, a total of 23 case-control studies with full available data were selected based on the adopted criteria. A small, around zero, overall SMD of -0.052 (95% CI, -0.303-0.2) was estimated, indicating no substantial differences between groups among selected studies. High heterogeneity among studies was detected (I2=91.42%; p<0.001). By performing a meta-regression analysis considering single available demographic, geographical and clinical covariates, no significant association was detected. Based on our systematic revision and meta-analysis of available case-control studies, there was not sufficient evidence supporting a possible significant association between iron serum levels and PD as compared to controls. Principal reasons should be sought in the elevated methodological heterogeneity we found among available studies. A particular attention should be paid on bias and confounding effects to limit heterogeneity among studies and to facilitate the summary of results. PMID- 28339070 TI - 125I seed irradiation induces apoptosis and inhibits angiogenesis by decreasing HIF-1alpha and VEGF expression in lung carcinoma xenografts. AB - The purpose of this study was to examine the effects of irradiation by 125I seeds in human lung cancer xenograft model and to determine the underlying mechanisms involved, with a focus on angiogenesis. A group of 40 mice bearing A549 lung adenocarcinoma xenografts was randomly separated into 4 groups: control group (n=10), sham seed (0 mCi) implant group (n=10), 125I seed (0.6 mCi) implant group (n=10) and 125I seed (0.8 mCi) implant group (n=10), respectively. The body weight and tumor volume, were recorded every four days until the end of the study. At 30 days after irradiation, the microvessel density, proliferative index and apoptotic index were evaluated by quantitative morphometric analysis of the expression of CD34, proliferating cell nuclear antigen (Ki-67) and in situ terminal transferase-mediated fluorescein deoxy- UTP nick-end labeling (TUNEL), respectively. The changes in the expression of hypoxia inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) were detected by real time PCR and western blot analysis. Consequently, 125I seed irradiation suppressed the growth of lung cancer xenografts in nude mice, while inhibiting cell proliferation and angiogenesis and inducing apoptosis as demonstrated by Ki67, CD34 and TUNEL staining. HIF-1alpha and VEGF mRNA and protein expression levels were substantially downregulated following 125I seed irradiation. Collectively, our data suggest that irradiation by 125I seeds is a promising new option for lung cancer treatment. PMID- 28339069 TI - Transglutaminase 2 is upregulated in primary hepatocellular carcinoma with early recurrence as determined by proteomic profiles. AB - The mechanism of early recurrence of hepato-cellular carcinoma (HCC) is not well understood. To examine whether early intrahepatic metastasis of HCC can be determined by the reliable molecular characteristics of the primary HCC, we focused on early-stage tumors of primary and solitary HCC cases. Proteomic differences were investigated between two groups, 11 early (recurrence within 12 months) and 10 late (no recurrence within 48 months) HCC cases, using two dimensional fluorescence difference gel electrophoresis. Overall, 10 upregulated and 9 downregulated proteins were identified from a total of 1623 protein spots detected in early recurrent HCC. Cluster analysis using the 19 proteins successfully divided the 21 HCC samples exactly into the two above groups. A multifunctional protein, transglutaminase 2 (TGM2), was upregulated in the early recurrence group. Immunohistochemistry revealed the frequent observation of TGM2 positive HCC cells in the early group, with a tendency of TGM2-positive staining in HCC cells adjacent to fibrous stroma. To examine whether two major TGM2 associated pathways, epithelial-mesenchymal transition (EMT) and integrin signaling, were activated in the early recurrence group of HCC, downstream molecules of TGM2 were measured. The mRNA level of EMT-related genes was highly positively correlated with TGM2 mRNA. However, E-cadherin (CDH1) mRNA and protein were not downregulated in correlation with TGM2 expression. The phosphorylation of FAK and Akt and the downregulation of PTEN were not associated with the quantity of TGM2. Therefore, TGM2 might contribute to early HCC recurrence through signaling pathways not related to EMT and integrin signaling. The proteomics of strictly classified HCCs would be useful for characterizing pro metastatic HCC and for developing a new therapeutic target for treatment of metastasis. PMID- 28339071 TI - Direct interaction between caffeic acid phenethyl ester and human neutrophil elastase inhibits the growth and migration of PANC-1 cells. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant tumors of the digestive system, but the mechanisms of its development and progression are unclear. Inflammation is thought to be fundamental to pancreatic cancer development and caffeic acid phenethyl ester (CAPE) is an active component of honey bee resin or propolis with anti-inflammatory and anticancer activities. We investigated the inhibitory effects of CAPE on cell growth and migration induced by human neutrophil elastase (HNE) and report that HNE induced cancer cell migration at low doses and growth at higher doses. In contrast, lower CAPE doses inhibited migration and higher doses of CAPE inhibited the growth induced by HNE. HNE activity was significantly inhibited by CAPE (7.5-120 uM). Using quantitative real-time PCR and western blotting, we observed that CAPE (18-60 uM) did not affect transcription and translation of alpha1-antitrypsin (alpha1-AT), an endogenous HNE inhibitor. However, in an in silico drug target docking model, we found that CAPE directly bound to the binding pocket of HNE (25.66 kcal/mol) according to CDOCKER, and the residue of the catalytic site stabilized the interaction between CAPE and HNE as evidenced by molecular dynamic simulation. Response unit (RU) values of surface plasmon resonance (SPR) significantly increased with incremental CAPE doses (7.5-120 uM), indicating that CAPE could directly bind to HNE in a concentration-dependent manner. Thus, CAPE is an effective inhibitor of HNE via direct interaction whereby it inhibits the migration and growth of PANC-1 cells in a dose-dependent manner. PMID- 28339072 TI - Hepatitis B virus X protein increases microRNA-21 expression and accelerates the development of hepatoma via the phosphatase and tensin homolog/phosphoinositide 3 kinase/protein kinase B signaling pathway. AB - Hepatitis B virus (HBV) X protein (HBx) is a key regulatory protein that is involved in HBV infection, replication and carcinogenesis of hepatocellular carcinoma (HCC). The aim of the present study was to investigate the role of HBx in the progression and metastasis of liver cancer cells and to determine the underlying molecular mechanism of HBx in metastatic liver cancer cells. HBx protein expression was detected by western blot analysis, and microRNA (miR)-21 levels were determined by reverse transcription-quantitative polymerase chain reaction in the highly metastatic MHCC-97H low metastatic MHCC-97L and SMMC-7721 liver cancer cell lines. The results demonstrated that the levels of HBx and miR 21 were significantly increased in MHCC-97H cells compared with MHCC-97L and SMMC 7721 cells. In addition, three pairs of small interfering (si)RNA specific to HBx were designed and synthesized to interfere with endogenous HBx in liver cancer cells, and the results demonstrated that knockdown HBx was associated with a corresponding decrease in miR-21 expression. The MTT assay results demonstrated that cell viability significantly decreased in HBx-siRNA cells compared with scramble siRNA-transfected cells. In addition, transfection with an miR-21 inhibitor inhibited MHCC-97H cell proliferation. Furthermore, Transwell assay results revealed that downregulation of HBx and treatment with miR-21 inhibitors contributed to the inhibition of MHCC-97H cell invasion and metastasis. Western blot analysis demonstrated that miR-21 inhibitors and HBx-siRNA treatment led to the upregulation of phosphatase and tensin homolog (PTEN), and decreased levels of phosphoinositide 3-kinase (PI3K), phosphorylated protein kinase B (Akt) and matrix metalloproteinase (MMP)-2. The results of the present study indicated that HBx was positively associated with miR-21 expression, and downregulation of miR 21 and HBx suppressed MMP-2 activity via the PTEN/PI3K/Akt signaling pathway. Therefore, HBx and miR-21 may represent novel therapeutic targets for the treatment of HCC. PMID- 28339073 TI - Identification of proteins in the aqueous humor associated with cataract development using iTRAQ methodology. AB - Proteins in the aqueous humor (AH) are important in the induction of cataract development. The identification of cataract-associated proteins assists in identifying patients and predisposed to the condition and improve treatment efficacy. Proteomics analysis has previously been used for identifying protein markers associated with eye diseases; however, few studies have examined the proteomic alterations in cataract development due to high myopia, glaucoma and diabetes. The present study, using the isobaric tagging for relative and absolute protein quantification methodology, aimed to examine cataract-associated proteins in the AH from patients with high myopia, glaucoma or diabetes, and controls. The results revealed that 445 proteins were identified in the AH groups, compared with the control groups, and 146, 264 and 130 proteins were differentially expressed in the three groups of patients, respectively. In addition, 44 of these proteins were determined to be cataract-associated, and the alterations of five randomly selected proteins were confirmed using enzyme-linked immunosorbent assays. The biological functions of these 44 cataract-associated proteins were analyzed using Gen Ontology/pathways annotation, in addition to protein-protein interaction network analysis. The results aimed to expand current knowledge of the pathophysiologic characteristics of cataract development and provided a panel of candidates for biomarkers of the disease, which may assist in further diagnosis and the monitoring of cataract development. PMID- 28339074 TI - Absence of t(14;18) chromosome translocation in agricultural workers after short term exposure to pesticides. AB - Exposure to pesticides represents a potential health risk for the general population and for agricultural workers in particular. Some researchers observed that occupational exposure to pesticides is associated with risk of non-Hodgkin's lymphoma (NHL). The chromosomal translocation t(14;18)(q32;q21) is one of the most common chromosomal abnormalities in NHL. The aim of this study was to detect the effects of pesticides on t(14;18) chromosome translocation in agricultural workers after short-term exposure. Fifty-two workers occupationally exposed to pesticides (fungicides and insecticides) and 52 non-exposed were recruited. The farm workers were on average exposed to pesticides for ~3.7 h a day for 5 years. The frequency of BCL2-IGH t(14;18) translocation in workers occupationally exposed to pesticides was 10% (5 of 52) vs. 8% (4 of 52) in the control group. Overall, these data suggest that no significant association between occupational exposure to pesticides and an increased frequency of the chromosomal translocation BCL2-IGH t(14;18) in farmers was observed. However, further studies with a higher number of subjects exposed to pesticides are necessary to confirm this observation. PMID- 28339075 TI - Epigenetic alterations and occupational exposure to benzene, fibers, and heavy metals associated with tumor development (Review). AB - The chronic occupational exposure to contaminants and carcinogens leads to the development of cancer. Over the past decades, many carcinogens have been found in the occupational environment and their presence is often associated with an increased incidence of cancer. According to the International Agency for Research on Cancer (IARC), the majority of carcinogens are classified as 'probable' and 'possible' human carcinogens, while, direct evidence of carcinogenicity is provided in epidemiological and experimental studies. Additionally, accumulating evidence suggests that epigenetic alterations may be early indicators of genotoxic and non-genotoxic carcinogen exposure. In the present review, the relationship between exposures to benzene, mineral fibers, metals and epigenetic alterations are discussed as the most important cancer risk factors during work activities. PMID- 28339076 TI - An 'activatable' aptamer-based fluorescence probe for the detection of HepG2 cells. AB - It is significant to develop a probe with sensitivity and specificity for the detection of cancer cells. The present study aimed to develop an 'activatable' aptamer-based fluorescence probe (AAFP) to detect cancer cells and frozen cancer tissue. This AAFP consisted of two fragments: aptamer TLS11a that targets HepG2 cells, and two short extending complementary DNA sequences with a 5'- and 3' terminus that make the aptamer in hairpin structure a capable quencher to fluorophore. The ability of the AAFP to bind specifically to cancer cells was assessed using flow cytometry, fluorescence spectroscopy and fluorescence microscopy. Its ability to bind to frozen cancer tissue was assessed using fluorescence microscopy. As a result, in the absence of cancer cells, AAFP showed minimal fluorescence, reflecting auto-quenching. In the presence of cancer cells, however, AAFP showed a strong fluorescent signal. Therefore, this AAFP may be a promising tool for sensitive and specific detection of cancer. PMID- 28339077 TI - Paeoniflorin attenuates the neuroinflammatory response in a rat model of chronic constriction injury. AB - Neuropathic pain remains the most frequent cause of suffering and disability worldwide. Paeoniflorin (PF), a water-soluble monoterpene glycoside extracted from the roots of Paeonia lactiflora Pall, has a wide range of pharmacological functions. Although the neuroprotective effect of PF has been reported in animal models of neuropathology, no systematic investigation has reported on the analgesic properties of PF in neuropathic pain. The aim of the present study was to investigate whether PF can alleviate neuropathic pain and to examine its possible mechanism. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve in rats. Following CCI surgery, the rats were administered with PF for 11 days. Mechanical withdrawal threshold and thermal withdrawal latency were assessed prior to surgery, and on days 3, 7 and 11 post surgery. The levels of interleukin (IL)-1beta and tumor necrosis factor (TNF) alpha in the spinal cord were analyzed using enzyme-linked immunosorbent assays. The activation of astrocytes and microglia were observed using immunostaining. In addition, the phosphorylation of p38 mitogen-activated protein kinase (p-p38MAPK) and nuclear factor-kappaB (NF-kappaB) were examined using western blot analysis. The results indicated that PF significantly attenuated CCI-induced neuropathic pain and decreased the levels of TNF-alpha and IL-1beta proinflammatory cytokines in the spinal cord. Furthermore, PF inhibited the over-activation of microglia and reduced the elevated expression levels of p-p38 MAPK and NF-kappaB in the spinal cord. These results indicated that PF offers potential as a therapeutic agent for neuropathic pain, which merits further investigation. PMID- 28339079 TI - A p110delta-specific inhibitor combined with bortezomib blocks drug resistance properties of EBV-related B cell origin cancer cells via regulation of NF-kappaB. AB - Epstein-Barr virus (EBV) infection is closely related to carcinogenesis of various cancers, and is also associated with the development of drug resistance in cancer stem cells. However, in EBV-positive cancer cells, the mechanistic details of the downstream signaling and the connection of PI3K with the NF-kappaB pathway for development of drug resistance remain controversial. Diffuse large B cell lymphoma (DLBCL) and multiple myeloma (MM) cells infected by EBV display drug resistance-related proteins (MDR1, MRP1 and MRP2) and stem cell markers (OCT4 and SOX2). EBV-infected HT (HT/EBV) and H929 (H929/EBV) cells activated p110delta expression, but downregulated the expression of p110alpha and p110beta. A combination of CAL-101, a p110delta-specific inhibitor, with bortezomib treatment of HT/EBV cells synergistically suppressed proliferation, reduced levels of drug resistance-related proteins, activated caspase cleavage and recovered expression of p110alpha/p110beta. Additionally, co-treatment with CAL 101 and bortezomib attenuated the expression of OCT4 and SOX2 via inhibition of activated NF-kappaB. Co-treatment with CAL-101 and bortezomib also attenuated drug resistance and NF-kappaB activity of EBV-infected H929 cells. Our results provide supportive evidence for the clinical application of CAL-101 and bortezomib to treat EBV-infected hematologic cancer. PMID- 28339080 TI - Inhibition of CCR7 promotes NF-kappaB-dependent apoptosis and suppresses epithelial-mesenchymal transition in non-small cell lung cancer. AB - Activation of C-C chemokine receptor type 7 (CCR7) has been demonstrated to mediate the occurrence and progression of non-small cell lung cancer (NSCLC). However, the potential therapeutic role of CCR7 inhibition in NSCLC is still obscure. Thus, the present study was conducted to investigate the molecular mechanism underlying the inhibition of CCR7 on cell apoptosis and epithelial mesenchymal transition (EMT) in NSCLC A549 cells. Chemokine ligand 21 (CCL21) was used to activate CCR7 and the results revealed that CCR7 upregulation inhibited cell apoptosis and affected apoptosis-related protein levels. However, CCR7-siRNA treatment markedly promoted apoptosis and suppressed inflammatory response and transforming growth factor beta1 (TGF-beta1)-induced EMT. In addition, CCR7-siRNA inactivated the NF-kappaB signaling pathway and inhibition of NF-kappaB via its specific antagonist, pyrrolidine dithiocarbamate, indicated that NF-kappaB was involved in the CCR7-mediated apoptosis. In conclusion, upregulation of CCR7 promoted cell proliferation and inflammation in A549 cells. In conclusion, inhibition of CCR7 via siRNA treatment promoted cell apoptosis and suppressed the inflammatory response and TGF-beta1-induced EMT, which may be associated with NF kappaB signaling. PMID- 28339078 TI - Comparative evaluation of the effects of platelet-rich plasma formulations on extracellular matrix formation and the NF-kappaB signaling pathway in human articular chondrocytes. AB - Concentrated leukocytes in leukocyte and platelet-rich plasma (L-PRP) may deliver increased levels of pro-inflammatory cytokines to activate the nuclear factor (NF)-kappaB signaling pathway, to counter or overwhelm the beneficial effects of growth factors on cartilage regeneration. However, to date, no relevant studies have substantiated this. In the present study, L-PRP and pure platelet-rich plasma (P-PRP) were prepared, and leukocytes, platelets, pro-inflammatory cytokines and growth factor concentrations were quantified; they were then used to treat human articular chondrocytes (HACs). Pyrrolidine dithiocarbamate (PDTC; 50 uM) was used to inhibit the activation of NF-kappaB. The nuclear translocation of NF-kappaB p65 and the protein expression of cartilaginous markers (collagen II, aggrecan and sex-determining region Y-box 9) were determined using western blot analysis. The mRNA expression of NF-kappaB-dependent inflammatory mediators, including inducible nitric oxide synthase and cyclooxygenase-2, and cartilaginous markers were determined using reverse transcription-quantitative polymerase chain reaction analysis. The production of prostaglandin E2, nitric oxide and glycosaminoglycan (GAG) were quantified using enzyme-linked immunosorbent assays, the Griess reaction and a 1,9-dimethylmethylene blue assay, respectively. The results demonstrated that L-PRP induced the nuclear translocation of NF-kappaB p65, upregulated the mRNA expression of NF-kappaB-dependent inflammatory mediators and upregulated the production of their products, whereas P-PRP, which had similar growth factor concentrations but significantly lower pro-inflammatory cytokine concentrations than L-PRP, did not. P-PRP promoted the mRNA and protein expression levels of cartilaginous markers and the production of GAG more effectively, compared with L-PRP. Furthermore, inhibition of the activation of NF kappaB by PDTC enhanced the effects of L-PRP on extracellular matrix formation in the HACs to a level similar to that of P-PRP. These findings suggested that leukocytes in L-PRP activated the NF-kappaB signaling pathway via the delivery of interleukin-1beta and tumor necrosis factor-alpha to counter the beneficial effects of growth factors on extracellular matrix formation in HACs. Therefore, P PRP may be more suitable for the treatment of osteoarthritis. PMID- 28339081 TI - HBx represses RIZ1 expression by DNA methyltransferase 1 involvement in decreased miR-152 in hepatocellular carcinoma. AB - Hepatitis B virus (HBV) is mainly suspected to promote hepatocellular carcinoma (HCC) development by epigenetic alteration. The HBV X protein (HBx) plays a key role in the molecular pathogenesis of HBV-related HCC. However, the mechanism of HBx-mediated hepatocarcinogenesis remains to be elucidated. RIZ1 gene, a candidate HCC suppressor gene, is frequently found to be hypermethylated and downregulated in HCC. In the present study, we show that the expression of RIZ1 was downregulated in 65% HCC tissues. Decreased expression of RIZ1 was restored by 5'-Aza in MHCC-97H HCC cell lines. HBx recombinant transfection increased DNMT1 expression level and suppressed RIZ1 expression. Moreover, knockdown of DNMT1 by siRNA restored RIZ1 expression in HCC cell SMMC-7721 and reduced methylated CpG sites of RIZ1. ChIP results showed that DNMT1 protein could bind to RIZ1 promoter, and this interaction was further enhanced with the transfected HBX recombinant. Moreover, miR-152 was decreased and involved in upregulation of DNMT1 in HBx transfected cells, at least partly, contributed to the epigenetic inactivation of RIZ1. Taken together, our data found that HBx repressed RIZ1 expression via DNMT1, which offered a new mechanism of RIZ1 inactivation in HCC, except for the widely known DNA methylation. These results enriched the epigenetic mechanism by which HBx contributes to pathogenesis of HBV-HCC. PMID- 28339082 TI - Effects of autophagy and endocytosis on the activity of matrix metalloproteinase 2 in human renal proximal tubular cells under hypoxia. AB - Tubulointerstitial fibrosis is characterized by tubular atrophy with basement membrane thickening and accumulation of interstitial extracellular matrix (ECM). A decrease in the activity of matrix metalloproteinase-2 (MMP-2) may promote this process. Although proximal tubular cells are sensitive to oxygen deprivation, whether cellular autophagy or endocytosis induced by hypoxia can alter the activity of MMP-2 remains to be elucidated. The aim of the present study was to investigate whether autophagy and endocytosis induced by hypoxia can have an effect on the activity of MMP-2 in HK-2 cells. The investigations involved exposing the HK-2 cell line to an autophagy inhibitor, 3-MA, or an endocytotic inhibitor, filipin. The mRNA expression of MMP-2 was elevated in the hypoxic milieu. Furthermore, it was found that filipin increased the activity of MMP-2 under hypoxia. These results suggested that autophagy and endocytosis were potential mediators for the altered expression of MMP-2, and endocytosis was a potential target for regulating the activity of MMP-2. These data suggested that hypoxia may be an important pro-fibrogenic stimulus, which acts in part via endocytosis. PMID- 28339084 TI - Transcriptional activation of PD-L1 by Sox2 contributes to the proliferation of hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is one of the most common and lethal malignancies in the world. Sox2 is a potential oncogene in the pathogenesis of HCC, however, the actual mechanisms of Sox2 functions in HCC has not emerged yet. In this study, we explored the expression, function and the relationship between Sox2 and PD-L1 in HCC. We found that both Sox2 and PD-L1 were expressed at a markedly higher level in HCC tissues in comparison to adjacent non-tumor tissues. Moreover, the expression levels of both genes were correlated with each other. Knockdown of Sox2 reduced the cell proliferation ability and induces apoptosis of HCC cells, suggesting the function of Sox2 in regulating both the cell proliferation and apoptosis. Noteworthy, the depletion of Sox2 also reduced the expression of PD-L1. Further analysis showed that there is a consensus Sox2 binding site in the promoter region of PD-L1. Through in vitro EMSA assay and in vivo chromatin immunoprecipitation assays, we demonstrated that Sox2 directly bound to the PD-L1 promoter through the consensus Sox2 motif. Further evidence by luciferase reporter assays revealed that Sox2 promoted the transcription activity of PD-L1 promoter region through the Sox2 motif. Collectively, our data provide a novel insight into the function and the interplay of Sox2 and PD-L1 in HCC. PMID- 28339085 TI - Integrated analysis of mRNA and miRNA expression profiles in pancreatic ductal adenocarcinoma. AB - In the present study, to investigate the potential molecular mechanism of pancreatic ductal adenocarcinoma (PDAC), mRNA and miRNA expression profiles were integrated for systematic analysis. Results showed that a total of 76 common differentially expressed genes (DEGs) were identified from 2 mRNA expression profiles that contained 39 tumor and 15 normal samples. Notably, the tumor and normal samples were able to be clearly classified into 4 groups based on the DEGs. mRNA-miRNA regulation network analysis indicated that 22 out of the 76 DEGs including MUC4, RRM2 and CCL2 are regulated by 5 reported miRNAs. Survival analysis using SurvExpress database demonstrated that the common DEGs were able to significantly differentiate low- and high-risk PDAC groups in 4 datasets. In summary, various biological processes are probably involved in the development and progression of PDAC. Firstly, activation of MUC4 induces nuclear translocation of beta-catenin and promotes the process of angiogenesis that provides necessary nutrition or oxygen for cancer cells. Then, RRM2 induces the invasiveness of PDAC via NF-kappaB. Finally, the formation of an immunosuppressive tumor microenvironment by recruiting regulatory T cells with high expression of CCL2 further promotes cancer cell proliferation and vascularization. Identification of valuable biological processes and genes can be helpful for the understanding of the molecular mechanism of PDAC. PMID- 28339083 TI - Health risk assessment of environmental selenium: Emerging evidence and challenges (Review). AB - New data have been accumulated in the scientific literature in recent years which allow a more adequate risk assessment of selenium with reference to human health. This new evidence comes from environmental studies, carried out in populations characterized by abnormally high or low selenium intakes, and from high-quality and large randomized controlled trials with selenium recently carried out in the US and in other countries. These trials have consistently shown no beneficial effect on cancer and cardiovascular risk, and have yielded indications of unexpected toxic effects of selenium exposure. Overall, these studies indicate that the minimal amount of environmental selenium which is source of risk to human health is much lower than anticipated on the basis of older studies, since toxic effects were shown at levels of intake as low as around 260 ug/day for organic selenium and around 16 ug/day for inorganic selenium. Conversely, populations with average selenium intake of less than 13-19 ug/day appear to be at risk of a severe cardiomyopathy, Keshan disease. Overall, there is the need to reconsider the selenium standards for dietary intake, drinking water, outdoor and indoor air levels, taking into account the recently discovered adverse health effects of low-dose selenium overexposure, and carefully assessing the significance of selenium-induced proteomic changes. PMID- 28339086 TI - Identification of novel mutations in endometrial cancer patients by whole-exome sequencing. AB - The aim of the present study was to identify genomic alterations in Taiwanese endometrial cancer patients. This information is vitally important in Taiwan, where endometrial cancer is the second most common gynecological cancer. We performed whole-exome sequencing on DNA from 14 tumor tissue samples from Taiwanese endometrial cancer patients. We used the Genome Analysis Tool kit software package for data analysis, and the dbSNP, Catalogue of Somatic Mutations in Cancer (COSMIC) and The Cancer Genome Atlas (TCGA) databases for comparisons. Variants were validated via Sanger sequencing. We identified 143 non-synonymous mutations in 756 canonical cancer-related genes and 1,271 non-synonymous mutations in non-canonical cancer-related genes in 14 endometrial samples. PTEN, KRAS and PIK3R1 were the most frequently mutated canonical cancer-related genes. Our results revealed nine potential driver genes (MAPT, IL24, MCM6, TSC1, BIRC2, CIITA, DST, CASP8 and NOTCH2) and 21 potential passenger genes (ARMCX4, IGSF10, VPS13C, DCT, DNAH14, TLN1, ZNF605, ZSCAN29, MOCOS, CMYA5, PCDH17, UGT1A8, CYFIP2, MACF1, NUDT5, JAKMIP1, PCDHGB4, FAM178A, SNX6, IMP4 and PCMTD1). The detected molecular aberrations led to putative activation of the mTOR, Wnt, MAPK, VEGF and ErbB pathways, as well as aberrant DNA repair, cell cycle control and apoptosis pathways. We characterized the mutational landscape and genetic alterations in multiple cellular pathways of endometrial cancer in the Taiwanese population. PMID- 28339087 TI - Regulation of intestinal myofibroblasts by KRas-mutated colorectal cancer cells through heparin-binding epidermal growth factor-like growth factor. AB - In colorectal cancer, gain-of-function mutations in KRas play a critical role in malignant transformation. Tumor growth in colorectal cancer is known to be promoted by the intestinal myofibroblasts (IMFs) that localize adjacent to the cancer cells, but the mechanisms of interaction between KRas-mutated cancer cells and the myofibroblasts remain unclear. Here, we investigated the effects of KRas mutated cells on the behavior of myofibroblasts by using mouse primary IMFs and cells of an IMF cell line (LmcMF) and a mouse colon epithelial cell line (aMoC1). Conditioned medium (CM) was collected from aMoC1 cells overexpressing a control vector or KRasV12 vector (KRasV12-CM), and the effects of KRasV12-CM on IMFs were analyzed by performing proliferation assays, wound-healing assays, Boyden chamber assays, and western blotting. Whereas KRasV12-CM exerted little effect on the differentiation and proliferation of primary IMFs, the CM promoted migration of both primary IMFs and LmcMF cells. In KRasV12-overexpressing aMoC1 cells, mRNA expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF) was higher than in mock-transfected aMoC1 cells, and HB-EGF promoted the migration of primary IMFs and LmcMF cells. Moreover, KRasV12-CM-induced IMF migration was suppressed by dacomitinib, an inhibitor of HB-EGF receptors. Notably, in LmcMF cells, both KRasV12-CM and HB-EGF activated extracellular signal-regulated kinase (ERK) and c-jun N-terminal kinase (JNK), whereas KRasV12 CM-induced migration of IMFs was suppressed following treatment with either an ERK inhibitor (FR180204) or a JNK inhibitor (SP600125). These results suggest that HB-EGF secreted from KRas-mutated colorectal cancer cells promotes IMF migration through ERK and JNK activation, which, in turn, could support cancer progression. PMID- 28339088 TI - Sclerostin is a possible candidate marker of arterial stiffness: Results from a cohort study in Catania. AB - Osteoporosis and cardiovascular disease are worldwide public health issues. Recent evidence indicates a possible role of the canonical Wnt/beta-catenin signalling pathway as a common mediator between these two diseases. The aim of the present study was to investigate the relationship between serum concentrations of sclerostin and Dkk1, two extracellular inhibitors of Wnt/beta catenin signalling, with carotid intima-media thickness (CIMT) and with arterial stiffness, evaluated by measuring the pulse wave velocity (PWV) in an ambulatory population of adults. To this aim, 67 subjects were recruited in the 'Atherosclerosis and osteoporosis: identification of common pathogenetic factors' investigation. Serum sclerostin levels correlated positively with CIMT (r=0.314, p=0.03) and inversely with the augmentation index, a marker of arterial stiffness (r=-0.286, p<0.05), whereas Dkk1 did not. Moreover, in a multivariate linear regression model, sclerostin [beta -0.1472; p=0.0023; standard error (SE)=0.04620] was an independent predictor of PWV in the study subjects. Our study shows that, following adjustment for confounders, sclerostin is an independent predictor of arterial stiffness in an ambulatory population, whereas Dkk1 is not. PMID- 28339089 TI - HMGB1 induces lung fibroblast to myofibroblast differentiation through NF-kappaB mediated TGF-beta1 release. AB - The proinflammatory factor high-mobility group box protein 1 (HMGB1) has been implicated in the pathogenesis of lung fibrosis; however, the role of HMGB1 in lung fibrosis remains unclear. It has previously been reported that nuclear factor (NF)-kappaB and transforming growth factor (TGF)-beta1 may be involved in lung fibrosis. Therefore, the present study aimed to examine the potential molecular mechanisms that underlie HMGB1-induced lung fibrosis via the regulation of NF-kappaB and TGF-beta1. The results demonstrated that HMGB1 stimulation increased the activation of NF-kappaB and the release of TGF-beta1, as well as the expression of alpha-smooth muscle actin (alpha-SMA) and collagen I in human lung fibroblasts in vitro. In addition, inhibition of NF-kappaB activation blocked HMGB1-induced TGF-beta1 release, as well as alpha-SMA and collagen I expression in lung fibroblasts. Preventing the release of TGF-beta1 inhibited HMGB1-induced alpha-SMA and collagen I expression; however, it had no effect on NF-kappaB activation. Collectively, these findings indicate that HMGB1 induces fibroblast to myofibroblast differentiation of lung fibroblasts via NF-kappaB mediated TGF-beta1 release. PMID- 28339090 TI - Inhibition of farnesyl pyrophosphate synthase attenuates high glucose-induced vascular smooth muscle cells proliferation. AB - The proliferation of vascular smooth muscle cells (VSMCs) is one of the main features of atherosclerosis accelerated by hyperglycemia. Our previous studies found that farnesyl pyrophosphate synthase (FPPS, EC 2.5.1.10), an essential enzyme in the mevalonate pathway, was upregulated in aorta media from diabetic mice along with the process of atherosclerosis. However, the exact role of FPPS in high glucose-induced proliferation of VSMCs is largely unclear. In our study, we found that alendronate (an FPPS inhibitor) attenuated diabetic accelerated atherosclerosis in vivo and suppressed high glucose-induced VSMCs proliferation in vitro. Moreover, in aorta from streptozotocin (STZ)-induced diabetic mice, 16 week treatment of alendronate decreased the activation of small GTPase (Ras, RhoA, and Rac1), but had no effect on the expression of cystathionine gamma-lyase (CSE), the pivotal H2S-producing enzyme. Meanwhile, in VSMCs cultured in high glucose-containing media, alendronate remarkably decreased total CoQ content, increased the H2S level, depressed small GTPases (Ras, RhoA, and Rac1) activation, but yet had no effect on expression of CSE. In conclusion, FPPS inhibition by alendronate attenuated the high glucose-induced proliferation of VSMCs both in vivo and in vitro, probably though depressing H2S metabolism and suppressing small GTPases (Ras, RhoA, and Rac1) activation. PMID- 28339091 TI - Fibulin-4 promotes osteosarcoma invasion and metastasis by inducing epithelial to mesenchymal transition via the PI3K/Akt/mTOR pathway. AB - This study explored the role of fibulin-4 in osteosarcoma progression and the possible signaling pathway involved. Fibulin-4 mRNA and protein expression in normal tissue, benign fibrous dysplasia, osteosarcoma, osteosarcoma cell lines, the normal osteoblastic cell line hFOB, and different invasive subclones were evaluated by immunohistochemistry (IHC) or immunocytochemistry (ICC) and real time reverse transcriptase-polymerase chain reaction (real-time qRT-PCR). Using in vitro functional assays, we analyzed the invasive and proliferative abilities of different osteosarcoma cell lines and subclones with differing invasive potential. To assess the role of fibulin-4 in the invasion and metastasis of osteosarcoma cells, lentiviral vectors with fibulin-4 small hairpin RNA (shRNA) and pLVX-fibulin-4 were constructed and used to infect the highly invasive and low invasive subclones and osteosarcoma cell lines. The effects of fibulin-4 knockdown and upregulation on the biological behavior of osteosarcoma cells were investigated by functional in vitro and in vivo assays. The results revealed that fibulin-4 expression was upregulated in osteosarcoma, and was positively correlated with low differentiation, lymph node metastasis, and poor prognosis. Fibulin-4 was also found to be over-expressed in highly invasive cell lines and in the highly invasive subclones. Fibulin-4 could promote osteosarcoma cell invasion and metastasis by inducing EMT via the PI3K/AKT/mTOR pathway. Collectively, our findings demonstrate that fibulin-4 is a promoter of osteosarcoma development and progression, and suggest a novel therapeutic target for future studies. PMID- 28339092 TI - MACC1 decreases the chemosensitivity of gastric cancer cells to oxaliplatin by regulating FASN expression. AB - The effect of chemotherapeutic agents is limited as a result of drug resistance, which demands prompt solutions provided by clinical studies. To date, the underlying mechanisms of chemotherapy resistance are relatively unknown. Metastasis-associated in colon cancer 1 (MACC1) is an oncogene associated with the progression and prognosis of gastric cancer (GC). Bioinformatic analysis revealed that MACC1 is positively associated with fatty acid synthase (FASN), a major enzyme of lipogenesis, and drives chemoresistance to oxaliplatin in GC. Similar findings were demonstrated in two GC cell lines (BGC-823 and MKN-28) with MACC1 ectopic expression. We next employed FASN inhibitor C75 or siFASN (small interfering RNA targeted to FASN) to block endogenous fatty acid metabolism and it was revealed that cell proliferation and chemoresistance to oxaliplatin induced by MACC1 upregulation were attenuated by FASN blockade to various extents. Conclusively, these outcomes highlight a novel role of MACC1 in GC cell lipogenesis, and suggest that MACC1 may be an attractive target to decrease oxaliplatin resistance in GC. PMID- 28339093 TI - ROCK inhibition as a potential therapeutic target involved in apoptosis in hemangioma. AB - Gene expression was examined in hemangiomas (HA), benign, birthmark-like tumors occurring in infancy, and confirmed in HA-derived endothelial cells (HDEC), for which cell proliferation and apoptosis were also assessed. Protein and mRNA accumulation of Rho-associated protein kinase (ROCK), vascular endothelial growth factor (VEGF), Ki-67 and proliferating cell nuclear antigen was significantly higher in proliferating phase HAs than in involuting phase HAs. In contrast, p53 and caspase-3 exhibited higher levels of accumulation in involuting than proliferating HAs. Cell apoptotic indexes were low in proliferating phase HAs and increased in involuting phase HAs. HDECs were treated with the ROCK inhibitor Y 27632. Y-27632 induced p53 expression and downregulated VEGF expression, significantly inhibited cell proliferation, and induced cell apoptosis in HA cells. The inhibitor effects were confirmed in HAs from HDEC-injected nude mice. These results indicated that ROCK is involved in p53-mediated apoptosis and VEGF expression in HA cells and suggested that such inhibition may be exploited for future HA therapies. PMID- 28339094 TI - F221Y mutation in hepatitis B virus reverse transcriptase is associated with hepatocellular carcinoma prognosis following liver resection. AB - Hepatitis B virus (HBV) reverse transcriptase (RT) is encoded by the polymerase gene in the reverse transcriptase region, which overlaps with the S gene. The association between mutations of HBV RT and the pathobiological features of hepatocellular carcinoma (HCC) remain to be elucidated. The present study aimed to examine mutations in this region of the HBV genome and its clinical significance. Briefly, HBV total DNA was extracted from 84 pairs of HCC tumor tissue and corresponding adjacent non-tumor tissue samples. The RT/S regions (nt130-1161) were amplified and sequenced using the Sanger method, and associations between RT mutations and the clinical characteristics of patients with HCC were analyzed. Finally, 27 and 29 mutations with frequencies >5% were identified in the RT and S regions, respectively. The rtF221Y variation and a tumor size >8 cm were found to be independent risk factors for the postoperative recurrence of HCC, with hazard ratios of 2.345 (95% CI, 1.391-3.953; P=0.001) and 1.838 (95% CI, 1.069-3.161; P=0.028), respectively. rtF221Y was also an independent risk factor for poor overall survival rates (HR=2.557; 95% CI, 1.344 4.866; P=0.004). The mutation of R122 K in the HBV S protein was closely associated with tumor recurrence (P<0.001). As a result, rtF221Y was identified as a risk factor for poor prognosis and may be a potential viral marker for predicting prognosis in HCC. PMID- 28339095 TI - Expression of Yes-associated protein 1 and its clinical significance in ovarian serous cystadenocarcinoma. AB - Yes-associated protein 1 (YAP1) is a key transcriptional regulator in the Hippo signaling pathway that plays a critical role in the development and progression of several types of malignancies, including ovarian cancer. Herein, we investigated the expression of YAP1 and its clinical significance in a large population of patients with ovarian serous cystadenocarcinoma (OSC), which is the most common form of epithelial ovarian neoplasm, using the TCGA database. Surprisingly, cross-cancer mRNA expression and alterations in YAP1 were higher in OSC than in those of other types of cancers in the TCGA database. YAP1 mRNA expression was significantly higher in OSC compared with normal ovarian samples, and was higher in stages III and IV, than stages I and II. The level of YAP1 protein, which is mainly localized to the nucleus, was also higher in stage IV as compared with stages I, II and III. However, the protein level of pYAP1, which is inactive and is localized to the cytoplasm, was not significantly different between stages. The ratio of pYAP/YAP, which shows higher activity at a low ratio, was lower in stage III than in stages I and II. High YAP and low pYAP levels were significantly correlated with a poor prognosis in patients with OSC. The mRNA and protein expression of YAP1 were significantly increased in the proliferative subtype as compared to the differentiated, immunoreactive and mesenchymal subtypes. According to bioinformatics analysis, YAP1 is most highly correlated with the cell cycle. TGF-beta signaling and WNT signaling were significantly increased in the high YAP1 group according to gene set enrichment analysis. Taken together, our results suggest that not only high YAP1 expression but also its subcellular distribution may be associated with poor overall survival in patients with OSC. PMID- 28339097 TI - Erratum. PMID- 28339096 TI - Pathogenesis and management of antiphospholipid syndrome. AB - Antiphospholipid antibodies are a heterogeneous group of autoantibodies that have clear associations with thrombosis and pregnancy morbidity, and which together constitute the 'antiphospholipid syndrome' (APS). However, the pathophysiology of these complications is not well understood and their heterogeneity suggests that more than one pathogenic process may be involved. Diagnosis remains a combination of laboratory analysis and clinical observation but there have been significant advances in identifying specific pathogenic features, such as domain I-specific anti-beta2-glycoprotein-I antibodies. This in turn has pointed to endothelial and complement activation as important factors in the pathogenesis of APS. Consequently, although anticoagulation remains the standard treatment for thrombotic APS and during pregnancy, the realisation that these additional pathways are involved in the pathogenesis of APS has significant implications for treatment: agents acting outside the coagulation system, such as hydroxychloroquine for pregnancy complications and sirolimus as an inhibitor of the mammalian target of rapamycin (mTOR) pathway, are now under evaluation and represent a radical change in thinking for haematologists. Conventional anticoagulation is also under challenge from new, direct acting anticoagulants. This review will provide a comprehensive overview of the evolving understanding of APS pathogenesis and how this and novel therapeutics will alter diagnosis and management. PMID- 28339099 TI - Modern banking, collection, compatibility testing and storage of blood and blood components. PMID- 28339098 TI - Quality of life with cediranib in relapsed ovarian cancer: The ICON6 phase 3 randomized clinical trial. AB - BACKGROUND: The ICON6 trial showed that cediranib, an oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, improved clinical outcomes for patients with platinum-sensitive relapsed ovarian cancer when it was used with chemotherapy and was continued as maintenance therapy. This study describes health-related quality of life (QOL) during the first year of treatment. METHODS: Four hundred fifty-six women were randomly allocated to receive standard chemotherapy only, chemotherapy with concurrent cediranib, or chemotherapy with cediranib administered concurrently and continued as maintenance. Patients completed QOL questionnaires until disease progression every 3 weeks during chemotherapy and then every 6 weeks to 1 year. Patients alive with disease progression completed a QOL form 1 year after randomization. The primary QOL endpoint was the global score from the Quality of Life Questionnaire Core 30 (of the European Organization for Research and Treatment of Cancer) at 1 year, with the standard chemotherapy group compared with the concurrent-maintenance cediranib group. RESULTS: The rate of questionnaire compliance was 90% at the baseline and 76% at 1 year and was similar across the 3 groups. The mean global QOL score at 1 year was 62.6 points for the standard chemotherapy group and 68.7 points for the concurrent-maintenance group (+4.5; 95% confidence interval, -2.0 to 11.0; P = .18). Sensitivity analyses suggested that this finding was robust to the effect of missing data, and the improvement became statistically significant after adjustments for self-reported diarrhea. CONCLUSIONS: The 6th study by the International Collaboration in Ovarian Neoplasm (ICON6) showed a significant improvement in progression-free survival with cediranib as concurrent and maintenance therapy. No QOL detriment with cediranib was found 1 year after treatment was commenced. The maintenance of QOL along with prolonged cancer control suggests that cediranib has a valuable role in the treatment of relapsed ovarian cancer. Cancer 2017;123:2752-61. (c) 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 28339100 TI - Search strategies for finding systematic reviews: reply from the authors. PMID- 28339102 TI - Erratum. PMID- 28339101 TI - Peers, Policies, and Place: The Relation Between Context and Ethnic/Racial Identity. AB - This manuscript introduces the special section, Context and Ethnic/Racial Identity. PMID- 28339103 TI - Iterative dataset optimization in automated planning: Implementation for breast and rectal cancer radiotherapy. AB - PURPOSE: To develop a new automated treatment planning solution for breast and rectal cancer radiotherapy. METHODS: The automated treatment planning solution developed in this study includes selection of the iterative optimized training dataset, dose volume histogram (DVH) prediction for the organs at risk (OARs), and automatic generation of clinically acceptable treatment plans. The iterative optimized training dataset is selected by an iterative optimization from 40 treatment plans for left-breast and rectal cancer patients who received radiation therapy. A two-dimensional kernel density estimation algorithm (noted as two parameters KDE) which incorporated two predictive features was implemented to produce the predicted DVHs. Finally, 10 additional new left-breast treatment plans are re-planned using the Pinnacle3 Auto-Planning (AP) module (version 9.10, Philips Medical Systems) with the objective functions derived from the predicted DVH curves. Automatically generated re-optimized treatment plans are compared with the original manually optimized plans. RESULTS: By combining the iterative optimized training dataset methodology and two parameters KDE prediction algorithm, our proposed automated planning strategy improves the accuracy of the DVH prediction. The automatically generated treatment plans using the dose derived from the predicted DVHs can achieve better dose sparing for some OARs without compromising other metrics of plan quality. CONCLUSIONS: The proposed new automated treatment planning solution can be used to efficiently evaluate and improve the quality and consistency of the treatment plans for intensity modulated breast and rectal cancer radiation therapy. PMID- 28339104 TI - Transferable Antibiotic Resistances in Marketed Edible Grasshoppers (Locusta migratoria migratorioides). AB - Grasshoppers are the most commonly eaten insects by humans worldwide, as they are rich in proteins and micronutrients. This study aimed to assess the occurrence of transferable antibiotic resistance genes in commercialized edible grasshoppers. To this end, the prevalence of 12 selected genes [aac(6')-Ie aph(2")-Ia, blaZ, erm(A), erm(B), erm(C), mecA, tet(M), tet(O), tet(S), tet(K), vanA, vanB] coding for resistance to antibiotics conventionally used in clinical practice was determined. The majority of samples were positive for tet(M) (70.0%), tet(K) (83.3%) and blaZ (83.3%). A low percentage of samples were positive for erm(B) (16.7%), erm(C) (26.7%), and aac(6')-Ie aph(2")-Ia (13.3%), whereas no samples were positive for erm(A), vanA, vanB, tet(O), and mecA. Cluster analysis identified 4 main clusters, allowing a separation of samples on the basis of their country of origin. PMID- 28339105 TI - Influence of Extrusion Cooking on In Vitro Digestibility, Physical and Sensory Properties of Brazilian Pine Seeds Flour (Araucaria Angustifolia). AB - Brazilian pine seeds (pinhao) are gluten-free products derived from Araucaria angustifolia. The commercialization of these seeds is essentially associated with a low level of industrialization. In this context, extrusion cooking is a potential alternative for preparing extrudates of pinhao as a food product, which can be easily digested and is ready for human consumption. Brazilian pine seeds flour was processed in a single-screw extruder following a central composite rotatable design. Three factors (independent parameters) were considered: moisture content (14 to 22 g/100 g), screw speed (100 to 250 rpm), and temperature in the 3rd heating zone (120 to 200 degrees C). The structural characteristics, in vitro digestibility and sensory acceptance were also evaluated. The resistant starch contents is almost reduced to zero after extrusion cooking while the slowly digestible starch content is increased. An increase in moisture positively affected the hardness and the luminosity (L* ), although it negatively affected the volumetric expansion index, crispness, and color parameters (a* , b* , and DeltaE). The experimental conditions of this study allowed the production of expanded extrudates from Brazilian pine seeds with good expansion, texture properties, and acceptance qualities. Thus, extrusion cooking was found to be a potential method for the industrialization of Brazilian pine seeds as a food product. PMID- 28339106 TI - Incomplete ossification of the atlas in a dog: surgical stabilisation using a SOP plate. PMID- 28339108 TI - Very high-energy electron (VHEE) beams in radiation therapy; Treatment plan comparison between VHEE, VMAT, and PPBS. AB - PURPOSE: The aim of this study was to evaluate the performance of very high energy electron beams (VHEE) in comparison to clinically derived treatment plans generated with volumetric modulated arc therapy (VMAT) and proton pencil beam scanning (PPBS) technology. We developed a custom optimization script that could be applied automatically across modalities to eliminate operator bias during IMRT optimization. METHODS: Four clinical cases were selected (prostate cancer, lung cancer, pediatric brain tumor, and head and neck cancer (HNC)). The VHEE beams were calculated in the EGSnrc/DOSXYZnrc Monte Carlo code for 100 and 200 MeV beams. Treatment plans with VHEE, VMAT, and PPBS were optimized in a research version of RayStation using an in-house developed script to minimize operator bias between the different techniques. RESULTS: The in-house developed script generated similar or superior plans to the clinically used plans. In the comparisons between the modalities, the integral dose was lowest for the PPBS generated plans in all cases. For the prostate case, the 200 MeV VHEE plan showed reduced integral dose and reduced organ at risk (OAR) dose compared to the VMAT plan. For all other cases, both the 100 and the 200 MeV VHEE plans were superior to the VMAT plans, and the VHEE plans showed better conformity and lower spinal cord dose in the pediatric brain case and lower brain stem dose in the HNC case when compared to the PPBS plan. CONCLUSIONS: The automated optimization developed in this study generated similar or superior plans as compared to the clinically used plan and represents an unbiased approach to compare treatment plans generated for different modalities. In the present study, we also show that VHEE plans are similar or superior to VMAT plans with reduced mean OAR dose and increased target conformity for a variety of clinical cases, and VHEE plans can even achieve reductions in OAR doses compared to PPBS plans for shallow targets. With increased VHEE energy, better conformity and even higher reductions in mean OAR doses are achieved. On the whole, VHEE was intermediate between photon VMAT and PPBS for OAR sparing. PMID- 28339107 TI - Studies of signal estimation bias in grating-based x-ray multicontrast imaging. AB - PURPOSE: In grating-based x-ray multi-contrast imaging, signals of three contrast mechanisms-absorption contrast, differential phase contrast (DPC), and dark-field contrast-can be estimated from the same set of acquired data. The estimated signals, N0 (related to absorption), N1 (related to dark-field), and phi (related to DPC) may be intrinsically biased. However, it is yet unclear how large these biases are and how the data acquisition parameters affect the biases in the extracted signals. The purpose of this paper was to address these questions. METHODS: The biases of the extracted signals (i.e., N0 , N1 and phi) were theoretically studied for a well-known signal estimation method. Experimental data acquired from a grating-based x-ray multi-contrast benchtop imaging system with a photon counting detector were used to validate the theoretical results for the signal biases of the three contrast mechanisms. RESULTS: Both theoretical and experimental studies showed the following results: (1) The bias of signal estimation for the absorption contrast signal is zero; (2) The bias of signal estimation for N1 is inversely proportional to the number of phase steps and to the average fringe visibility of the grating interferometer, but the ratio between the bias and the signal level (i.e., the relative bias) is independent of the number of phase steps; (3) The bias of signal estimation for phi depends on the mean DPC signal level, the total exposure level of the multi-contrast data acquisition, and the mean fringe visibility of the interferometer. CONCLUSIONS: In grating-based x-ray multi-contrast imaging, the estimated absorption contrast signal is unbiased; the estimated dark-field contrast signal is biased, but the relative bias is only dependent on the mean fringe visibility of the interferometer and the exposure level. The estimated DPC signal may be biased, and the bias level depends on the mean signal level, the exposure level, and the interferometer performance. PMID- 28339109 TI - Validation of dynamic treatment-couch tracking for prostate SBRT. AB - PURPOSE: In stereotactic body radiation therapy (SBRT) of prostatic cancer, a high dose per fraction is applied to the target with steep dose gradients. Intrafractional prostate motion can occur unpredictably during the treatment and lead to target miss. This work investigated the dosimetric benefit of motion compensation with dynamic treatment-couch tracking for prostate SBRT treatments in the presence of prostatic motion. METHODS: Ten SBRT treatment plans for prostate cancer patients with integrated boosts to their index lesion were prepared. The treatment plans were applied with a TrueBeam linear accelerator to a phantom in (a) static reference position, (b) moved with five prostate motion trajectories without any motion compensation, and (c) with real-time compensation using transponder-guided couch tracking. The geometrical position of the electromagnetic transponder was evaluated in the tracked and untracked situation. The dosimetric performance of couch tracking was evaluated, using Gamma agreement indices (GAI) and other dose parameters. These were evaluated within the phantoms biplanar diode array, as well as target- and organ-specific. RESULTS: The root mean-square error of the motion traces (range: 0.8-4.4 mm) was drastically reduced with couch tracking (0.2-0.4 mm). Residual motion was mainly observed at abrupt direction changes with steep motion gradients. The phantom measurements showed significantly better GAI1%/1mm with tracked (range: 83.4%-100.0%) than with untracked motion (28.9%-99.7%). Also GAI2%/2mm was significantly superior for the tracked (98.4%-100.0%) than the untracked motion (52.3%-100.0%). The organ-specific evaluation showed significantly better target coverage with tracking. The dose to the rectum and bladder showed a dependency on the anterior posterior motion direction. CONCLUSIONS: Couch tracking clearly improved the dosimetric accuracy of prostate SBRT treatments. The treatment couch was able to compensate the prostatic motion with only some minor residual motion. Therefore, couch tracking combined with electromagnetic position monitoring for prostate SBRT is feasible and improves the accuracy in treatment delivery when prostate motion is present. PMID- 28339111 TI - Reflections on clinical trials - the distance from results to action. PMID- 28339110 TI - A fast, noniterative approach for accelerated high-temporal resolution cine-CMR using dynamically interleaved streak removal in the power-spectral encoded domain with low-pass filtering (DISPEL) and modulo-prime spokes (MoPS). AB - PURPOSE: To introduce a pair of accelerated non-Cartesian acquisition principles that when combined, exploit the periodicity of k-space acquisition, and thereby enable acquisition of high-temporal cine Cardiac Magnetic Resonance (CMR). METHODS: The mathematical formulation of a noniterative, undersampled non Cartesian cine acquisition and reconstruction is presented. First, a low-pass filtering step that exploits streaking artifact redundancy is provided (i.e., Dynamically Interleaved Streak removal in the Power-spectrum Encoded domain with Low-pass filtering [DISPEL]). Next, an effective radial acquisition for the DISPEL approach that exploits the property of prime numbers is described (i.e., Modulo-Prime Spoke [MoPS]). Both DISPEL and MoPS are examined using numerical simulation of a digital heart phantom to show that high-temporal cine-CMR is feasible without removing physiologic motion vs aperiodic interleaving using Golden Angles. The combined high-temporal cine approach is next examined in 11 healthy subjects for a time-volume curve assessment of left ventricular systolic and diastolic performance vs conventional Cartesian cine-CMR reference. RESULTS: The DISPEL method was first shown using simulation under different streak cycles to allow separation of undersampled radial streaking artifacts from physiologic motion with a sufficiently frequent streak-cycle interval. Radial interleaving with MoPS is next shown to allow interleaves with pseudo-Golden-Angle variants, and be more compatible with DISPEL against irrational and nonperiodic rotation angles, including the Golden-Angle-derived rotations. In the in vivo data, the proposed method showed no statistical difference in the systolic performance, while diastolic parameters sensitive to the cine's temporal resolution were statistically significant (P < 0.05 vs Cartesian cine). CONCLUSIONS: We demonstrate a high-temporal resolution cine-CMR using DISPEL and MoPS, whose streaking artifact was separated from physiologic motion. PMID- 28339112 TI - Canine penile hirudiniasis: an unusual cause of bleeding from the prepuce. PMID- 28339113 TI - Preparation and Oxidation Stability Evaluation of Tea Polyphenols-Loaded Inverse Micro-Emulsion. AB - Compared to synthetic antioxidants, tea polyphenols (TPs) has its own advantages in edible oil industry, however, the hydrophilic properties have restricted its applications. In this study, the ternary phase diagram of TPs-loaded micro emulsion (ME) system was constructed, in which glyceryl monooleate (GMO), Tween80, linoleic acid as the surfactants, ethanol as the co-surfactant and soybean, corn, sunflower oil as the oil phase, have been used for the preparation of ME. The results indicated that a composition of ME (57.5% oil, 18% Tween80, 18% GMO, 4% Linolic acid, and 2.5% water+ethanol) could dissolve maximum water and could stable for 2 mo at room temperature with an average diameter of 6 to 7 nm, as detected by means of dynamic light scattering (DLS). The loaded of TPs into ME led to an increase of particle size to 15 to 16 nm, due to increased polarity of the water phase. The antioxidant capacity of TPs in ME was characterized by the peroxide value (POV) method. The addition of 1% water phase with 0.1 g/mL TPs could retain the POV at low value for 30 d at accelerating temperature 50 degrees C. Meanwhile, comparing the three edible oil, ME with corn oil has lower conductivity and higher value of POV during the storage. This work provides an efficient and environmentally friendly approach for the preparation of TPs-loaded ME, which is beneficial to the application of TPs in edible oil. PMID- 28339114 TI - Cervical Length in Patients at Risk for Placenta Accreta. AB - OBJECTIVES: To evaluate cervical length measurements in women with placenta accreta compared to women with a nonadherent low-lying placenta or placenta previa and evaluate this relationship in terms of vaginal bleeding, preterm labor, and preterm birth. METHODS: We conducted a retrospective cohort study between 1997 and 2011 of gravidas with more than 1 prior cesarean delivery who had a transvaginal ultrasound examination between 24 and 34 weeks for a low-lying placenta or placenta previa. Cervical length was measured from archived images in accordance with national guidelines by a single investigator, who was blinded to outcomes and ultrasound reports. The diagnosis of placental accreta was based on histologic confirmation. For study purposes, preterm birth was defined as less than 36 weeks, and cervical lengths of 3 cm or less were considered short. Standard statistical analyses were used. RESULTS: A total of 125 patients met inclusion criteria. The cohort was divided into patients with (n = 43 [34%]) and without (n = 82 [66%]) placenta accreta and stratified by gestational age at the ultrasound examinations. Women with placenta accreta had shorter cervical length measurements during their 32- to 34-week ultrasound examinations (mean +/- SD, 3.23 +/- 0.98 versus 3.95 +/- 1.0 cm; P < .01) and were more likely to have a short cervix of 3 cm or less (P = .001). However, these findings did not correlate with the degree of invasion (P = .3), or higher rates of vaginal bleeding and preterm labor (P = .19) resulting in preterm birth before 36 weeks (P = .64). CONCLUSIONS: Women with placenta accreta had shorter cervical lengths at 32 to 34 weeks than women with a nonadherent low-lying placenta or placenta previa, but this finding did not correlate with a higher risk of vaginal bleeding or preterm labor resulting in preterm birth before 36 weeks. PMID- 28339116 TI - Technical Pitfalls in Sonography of the Inferior Vena Cava: Beware the Diaphragm. PMID- 28339115 TI - Near-IR and CP-OCT imaging of suspected occlusal caries lesions. AB - INTRODUCTION: Radiographic methods have poor sensitivity for occlusal lesions and by the time the lesions are radiolucent they have typically progressed deep into the dentin. New more sensitive imaging methods are needed to detect occlusal lesions. In this study, cross-polarization optical coherence tomography (CP-OCT) and near-IR imaging were used to image questionable occlusal lesions (QOC's) that were not visible on radiographs but had been scheduled for restoration on 30 test subjects. METHODS: Near-IR reflectance and transillumination probes incorporating a high definition InGaAs camera and near-IR broadband light sources were used to acquire images of the lesions before restoration. The reflectance probe utilized cross-polarization and operated at wavelengths from 1,500 to 1,700 nm where there is an increase in water absorption for higher contrast. The transillumination probe was operated at 1,300 nm where the transparency of enamel is highest. Tomographic images (6 * 6 * 7 mm3 ) of the lesions were acquired using a high speed swept-source CP-OCT system operating at 1,300 nm before and after removal of the suspected lesion. RESULTS: Near-IR reflectance imaging at 1,500-1,700 nm yielded significantly higher contrast (P < 0.05) of the demineralization in the occlusal grooves compared with visible reflectance imaging. Stains in the occlusal grooves greatly reduced the lesion contrast in the visible range yielding negative values. Only half of the 26 lesions analyzed showed the characteristic surface demineralization and increased reflectivity below the dentinal-enamel junction (DEJ) in 3D OCT images indicative of penetration of the lesion into the dentin. CONCLUSION: This study demonstrates that near-IR imaging methods have great potential for improving the early diagnosis of occlusal lesions. Lasers Surg. Med. 49:215-224, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28339117 TI - Intraexaminer and Interexaminer Variability in 3D Fetal Volume Measurements During the Second and Third Trimesters of Pregnancy. AB - OBJECTIVES: To assess intraexaminer and interexaminer reliability of 3 dimensional fetal sonographic measurements. METHODS: Three-dimensional fetal organ volumes (head, kidney, total thigh volume, and fractional thigh volume) were acquired during the second and third trimesters, with the addition of placental volume in the second trimester, by 2 different experienced, blinded sonographers. Fifty-eight fetuses were examined from 21 to 39 weeks' gestation. Intraexaminer and Interexaminer reliability was assessed with Bland-Altman plots, and their 95% limits of agreement and intraclass correlation coefficients. RESULTS: The most significant interexaminer error was observed in the second trimester kidney volume (95% limits of agreement, +/- 110%), and the best agreement was for the third-trimester fractional thigh volume (95% limits of agreement, +/- 25%) and second-trimester head volume (95% limits of agreement, 7%-25%). Second- and third-trimester intraclass correlation coefficient results were all greater than 0.75, apart from second-trimester kidney volume intraexaminer (0.374) and interexaminer (0.061) measurements, second-trimester placenta interexaminer measurements (0.390), and third-trimester kidney interexaminer measurements (0.647). CONCLUSIONS: Three-dimensional fetal sonographic volumes of the head, kidney, total thigh, and placenta have limited reproducibility, and improvements in measurement techniques are needed before they can be used routinely to assess fetal growth. The 3-dimensional fractional thigh volume can be reliably obtained in the late third trimester. PMID- 28339118 TI - Directional local field potential recordings for symptom-specific optimization of deep brain stimulation. PMID- 28339119 TI - Evidence brings hope for high-yield dopaminergic human-induced pluripotent stem cell transplant. PMID- 28339120 TI - Accessing Structurally Diverse Near-Infrared Cyanine Dyes for Folate Receptor Targeted Cancer Cell Staining. AB - Folate receptor (FR) targeting is one of the most promising strategies for the development of small-molecule-based cancer imaging agents considering that the FR is highly overexpressed on the surface of many cancer cell types. FR-targeted conjugates of near-infrared (NIR) emissive cyanine dyes are in advanced clinical trials for fluorescence-guided surgery and are valuable research tools for optical molecular imaging in animal models. Only a small number of promising conjugates has been evaluated so far. Analysis of structure-performance relations to identify critical factors modulating the performance of targeted conjugates is essential for successful further optimization. This contribution addresses the need for convenient synthetic access to structurally diverse NIR-emissive cyanine dyes for conjugation with folic acid. Structural variations were introduced to readily available cyanine precursors in particular via C-C-coupling reactions including Suzuki and (for the first time with these types of dyes) Sonogashira cross-couplings. Photophysical properties such as absorbance maxima, brightness, and photostability are highly dependent on the molecular structure. Selected modified cyanines were conjugated to folic acid for cancer cell targeting. Several conjugates display a favorable combination of high fluorescence brightness and photostability with high affinity to FR-positive cancer cells, and enable the selective imaging of these cells with low background. PMID- 28339121 TI - Connecting today's climates to future climate analogs to facilitate movement of species under climate change. AB - Increasing connectivity is an important strategy for facilitating species range shifts and maintaining biodiversity in the face of climate change. To date, however, few researchers have included future climate projections in efforts to prioritize areas for increasing connectivity. We identified key areas likely to facilitate climate-induced species' movement across western North America. Using historical climate data sets and future climate projections, we mapped potential species' movement routes that link current climate conditions to analogous climate conditions in the future (i.e., future climate analogs) with a novel moving-window analysis based on electrical circuit theory. In addition to tracing shifting climates, the approach accounted for landscape permeability and empirically derived species' dispersal capabilities. We compared connectivity maps generated with our climate-change-informed approach with maps of connectivity based solely on the degree of human modification of the landscape. Including future climate projections in connectivity models substantially shifted and constrained priority areas for movement to a smaller proportion of the landscape than when climate projections were not considered. Potential movement, measured as current flow, decreased in all ecoregions when climate projections were included, particularly when dispersal was limited, which made climate analogs inaccessible. Many areas emerged as important for connectivity only when climate change was modeled in 2 time steps rather than in a single time step. Our results illustrate that movement routes needed to track changing climatic conditions may differ from those that connect present-day landscapes. Incorporating future climate projections into connectivity modeling is an important step toward facilitating successful species movement and population persistence in a changing climate. PMID- 28339122 TI - Mortality risk in a nationwide cohort of individuals with tic disorders and with tourette syndrome. AB - BACKGROUND: Few studies have investigated mortality risk in individuals with tic disorders. METHODS: We thus measured the risk of premature death in individuals with tic disorders and with Tourette syndrome in a prospective cohort study with 80 million person-years of follow-up. We estimated mortality rate ratios and adjusted for calendar year, age, sex, urbanicity, maternal and paternal age, and psychiatric disorders to compare individuals with and without tic disorders. RESULTS: The risk of premature death was higher among individuals with tic disorders (mortality rate ratio, 2.02; 95% CI, 1.49-2.66) and with Tourette syndrome (mortality rate ratio, 1.63; 95% CI, 1.11-2.28) compared with controls. After the exclusion of individuals with comorbid attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, and substance abuse, tic disorder remained associated with increased mortality risk (mortality rate ratio, 2.30; 95% CI, 1.57-3.23), as did also Tourette Syndrome (mortality rate ratio, 1.81; 95% CI, 1.11-2.75). CONCLUSIONS: These results are of clinical significance for clinicians and advocacy organizations. Several factors may contribute to this increased risk of premature death, and more research mapping out these factors is needed. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28339123 TI - DESolution of CD and CB Macrocycles. AB - Supramolecular chemistry utilizing the macrocyclic hosts cyclodextrins (CDs) and cucurbit[n]urils (CB[n]s) is traditionally performed in aqueous media; however, their solubility is typically poor, especially for the family of CB[n]s. Through derivatization of these macrocycles their solubility can be augmented to enable enhanced solubility in water and in some organic solvents. The increase in solubility of these derivatized macrocycles allows for their use in a wider range of chemical environments and giving rise to myriad potential applications. The dissolution of parent CDs (alpha-, beta- and gamma-) and CB[n]s (n=6-8) in deep eutectic solvents (DES) is reported, showing dramatic enhanced solubility of the larger species in both families, CB[7] and CB[8] as well as beta- and gamma-CD, respectively. Furthermore, the host-guest properties are maintained in this new solvation medium. PMID- 28339124 TI - Gliadin-reactive T cells in Italian children from preventCD cohort at high risk of celiac disease. AB - BACKGROUND: Newborns at high risk of celiac disease (CD) were recruited in Italy in the context of the PreventCD study and closely monitored for CD, from 4 months up to a mean age of 8 years at follow-up. The aim of our study was to investigate intestinal T-cell reactivity to gliadin at the first clinical and/or serological signs of CD. METHODS: Gliadin-reactive T-cell lines were generated from intestinal biopsies of 19 HLA-DQ2-or HLA-DQ8-positive children. At biopsy, 11 children had a diagnosis of acute CD, two of potential CD, and six were non celiac controls. Immune reactivity was evaluated against gliadin and known immunogenic peptides from alpha-, gamma-, or omega-gliadins. The role of deamidation by transglutaminase (tTG) in determining the immunogenicity of gliadin was also investigated. RESULTS: Most of the children with CD (either acute or potential) had an inflammatory response to gliadin. Notably, signs of T cell reactivity to gliadin were also found in some non-celiac subjects, in which IFN-gamma responses occurred mainly when regulatory IL-10 and TGF-beta cytokines were blocked. Interestingly, PreventCD children reacted to gliadin peptides found active in adult CD patients, and tTG deamidation markedly enhanced gliadin recognition. CONCLUSIONS: T cells reactive to gliadin can be detected in the intestine of children at high risk of developing CD, in some cases also in the presence of a normal mucosa and negative CD-associated antibodies. Furthermore, children at a very early stage of CD recognize the same gliadin epitopes that are active in adult CD patients. Tissue transglutaminase strongly enhances gluten T cell immunogenicity in early CD. PMID- 28339125 TI - Is CuII Coordinated to Patellamides inside Prochloron Cells? AB - Dinuclear CuII -patellamide complexes (patellamides are naturally occurring cyclic pseudo-octapeptides) are known to be efficient catalysts for hydrolysis reactions of biological importance, for example, those of phosphatase, carbonic anhydrase, and glycosidase. However, the biological role of patellamides is still unknown. Patellamides were originally extracted from the sea squirt Lissoclinum patella, but are now known to be ribosomally expressed by the blue-green algae Prochloron that live in symbiosis with L. patella. In a further step to unravel the metabolic significance of the patellamide complexes, the question as to whether these are also formed inside Prochloron cells is addressed. In this study, a biocompatible patellamide-fluorescent dye conjugate has been introduced into living Prochloron cells and, by means of flow cytometry and confocal microscopy, it is shown that CuII ions are coordinated to patellamides in vivo. PMID- 28339126 TI - Boron-Doped Polygonal Carbon Nano-Onions: Synthesis and Applications in Electrochemical Energy Storage. AB - Doping of carbon nanostructures with heteroatoms, such as boron or nitrogen, is one of the most effective ways to change their properties to make them suitable for various applications. Carbon nano-onions (CNOs) doped with boron (B-CNOs) were prepared by annealing (1650 degrees C) nanodiamond particles (NDs) under an inert He atmosphere in the presence of B. Their physicochemical properties were measured using transmission (TEM) and scanning (SEM) electron microscopy, X-ray photoelectron spectroscopy (XPS), 10 B and 11 B solid-state magic-angle spinning (MAS) NMR spectroscopy, X-ray powder diffraction (XRD), Raman spectroscopy, porosimetry, and differential-thermogravimetric analyses (TGA-DTG). These properties were systematically discussed for the undoped and B-doped CNO samples. The amount of substitutional B in the CNO samples varied from 0.76 to 3.21 at. %. The TEM, XRD, and Raman analyses revealed that the increased amount of B doping resulted in decreased interlayer spacing and polygonization of the structures, which in turn led to their unusual physicochemical properties. All synthesized materials were tested as electrodes for electrochemical capacitors. The B-CNOs with low concentration of doping agent exhibited higher reversible capacitances, mainly owing to the formation of hydrophilic polygonal nanostructures and higher porosity. PMID- 28339127 TI - Quantitative Ultrasound Texture Analysis for Differentiating Preterm From Term Fetal Lungs. AB - OBJECTIVES: To differentiate preterm (<37 weeks' gestation) from term (>=37 weeks' gestation) fetal lungs by using quantitative texture analysis of ultrasound images. METHODS: This study retrospectively evaluated singleton gestations with valid dating at 20 weeks' gestational age (GA) or later between January 2015 and December 2015. Images were obtained from Voluson E8 ultrasound systems (GE Healthcare, Milwaukee, WI). A region of interest was selected in each fetal lung image at the level of the 4 heart chambers from an area that appeared most representative of the overall lung tissue and had the least shadow. Ultrasonic tissue heterogeneity (heterogeneity index) based on dynamic range calculation was determined for all lung images. This quantification was performed with a custom-made software program that used a dithering technique based on the Floyd-Steinberg algorithm, in which the pixels are transformed into a binary map. Regression analysis was used to determine the correlation and functional association between the heterogeneity index and GA. A receiver operating characteristic curve was used to identify the optimal heterogeneity index cutoff point for differentiating preterm from term fetal lungs. RESULTS: A total of 425 fetal lung ultrasound images (313 preterm and 112 term) were analyzed. Quantitative texture analysis predicted GA with sensitivity and specificity of 87.9% and 92.0%, respectively, based on the optimal receiver operating characteristic cutoff point. CONCLUSIONS: Quantitative ultrasound texture analysis of fetal lung tissue can differentiate preterm fetal lungs from term fetal lungs. Our data suggest that decreased fetal lung heterogeneity on ultrasound imaging is associated with preterm fetuses. PMID- 28339129 TI - Putting pyrodiversity to work for animal conservation. PMID- 28339128 TI - Life-course of atopy and allergy-related disease events in tropical sub-Saharan Africa: A birth cohort study. AB - BACKGROUND: In high-income countries, allergy-related diseases (ARDs) follow a typical sequence, the 'Atopic March'. Little is known about the life-course of ARDs in the markedly different, low-income, tropical environment. We describe ARDs in a tropical, African birth cohort. METHODS: Ugandan children were followed from birth to 9 years. ISAAC questionnaires were completed at intervals; doctor diagnosed ARDs were recorded throughout follow-up. Skin prick tests (SPTs) were performed at 3 and 9 years. Atopy was defined as >=1 positive SPT. RESULTS: Of the 2345 live-born children, 1214 (52%) were seen at 9 years. Wheeze and eczema were common in infancy, but by 9 years, only 4% reported recent wheeze, 5% eczema and 5% rhinitis. Between 3 and 9 years, atopy prevalence increased from 19% to 25%. Atopy at 3 or 9 years was associated with reported ARD events at 9 years, for example OR = 5.2 (95% CI 2.9-10.7) for atopy and recent wheeze at 9 years. Reported or doctor-diagnosed ARD events in early childhood were associated with the same events in later childhood, for example OR = 4.4 (2.3-8.4) for the association between reported wheeze before 3 years with reported recent wheeze at 9 years, but progression from early eczema to later rhinitis or asthma was not observed. CONCLUSION: Allergen sensitization started early in childhood and increased with age. Eczema and wheeze were common in infancy and declined with age. Atopy was strongly associated with ARD among the few affected children. The typical Atopic March did not occur. Environmental exposures during childhood may dissociate atopy and ARD. PMID- 28339130 TI - Partially hydrolyzed whey formula intolerance in cow's milk allergic patients. PMID- 28339131 TI - Tissue Deformation Index as a Reliable Measure of Lateral Abdominal Muscle Activation on M-Mode Sonography. AB - The aim of this article is to present a novel method of evaluating the activity of lateral abdominal muscles using M-mode sonography. The method leads to calculation of the tissue deformation index, representing the percent change in lateral abdominal muscle thickness over time. The objectives of this study were as follows: (1) to establish the mean tissue deformation index values for individual lateral abdominal muscles; and (2) to establish the reliability of the tissue deformation index. In a group of 34 healthy young volunteers (mean age, 24.03 years; body mass, 68.89 kg; body height, 174.25 cm), the reflex response of the lateral abdominal muscles to postural perturbation in the form of rapid arm abduction was recorded in 2 series, with 6 repetitions each, and the tissue deformation index was calculated. The mean tissue deformation index values formed a gradient, increasing from deep to superficial lateral abdominal muscles: 0.06%/ms for transversus abdominis, 0.11%/ms for oblique internal, and 0.16 for oblique external muscles. The tissue deformation index values differed significantly among individual lateral abdominal muscles (all paired comparisons, P < .001). Three repeated measurements are sufficient to achieve good intra-rater reliability of the tissue deformation index (intraclass correlation coefficient, > 0.8). PMID- 28339132 TI - Formation of endohedral metallofullerene (EMF) ions of MnC2m+ (M = La, Y, n <= 6, 50 <= 2m <= 194) in the laser ablation process with graphene as precursor. AB - RATIONALE: Graphene has proved to be a versatile precursor for the generation of mono-endohedral metallofullerenes (EMFs) of alkali and alkali earth metal atoms. Thus, it is important to investigate whether graphene is also a good precursor for the generation of EMFs including multi-metal atoms or some transition metal atoms. METHODS: Experiments were performed on a 7.0 T Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer. Laser ablation mass spectra were obtained by laser irradiation on mixtures of graphene and LaCl3 , YCl3 or HAuCl4 on a stainless steel plate. A 355 nm Nd:YAG laser with a typical energy of 2.5 mJ/pulse was employed in these experiments. Tandem mass spectrometry was performed by on-resonance excitation collision-induced dissociation (CID) for selected single isotopic peaks. RESULTS: Metallofullerene La1-6C2m+/ Y1-6C2m+ ions were observed in the laser ablation mass spectra of mixtures of graphene and LaCl3 /YCl3 . CID and reactant gas experiments on selected ions showed that these ions had endohedral structures. Considering the experimental condition applied here, a mechanism based on a top-down process for the generation of the EMF ions is suggested. Further experiments on HAuCl4 showed some weak signals of AuC2m+ for the first time. CONCLUSIONS: Mono- and multi-EMF ions of MnC2m+ (M = La, Y, n = 1-6, 50 <= 2 m <= 194) were generated by laser ablation of graphene and the corresponding metal salts and detected by FT-ICR mass spectrometry. The results have shed light on the formation and generation of some new EMF species. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28339133 TI - Prospective Comparison of Diagnostic Accuracy Between Point-of-Care and Conventional Ultrasound in a General Diagnostic Department: Implications for Resource-Limited Settings. AB - OBJECTIVES: To compare the diagnostic accuracy of hand-held point-of-care (POC) versus conventional sonography in a general diagnostic setting with the intention to inform medical providers or clinicians on the rational use of POC ultrasound in resource limited settings. METHODS: Over 3 months in 2010, 47 patients were prospectively enrolled at a single academic center to obtain 54 clinical conventional ultrasound examinations and 54 study-only POC ultrasound examinations. Indications were 48% abdominal, 26% retroperitoneal, and 24% obstetrical. Nine blinded readers (sonographers, residents, and attending radiologists) sequentially assigned diagnoses to POC and then conventional studies, yielding 476 interpreted study pairs. Diagnostic accuracy was obtained by comparing POC and conventional diagnoses to a reference diagnosis established by the unblinded, senior author. Analysis was stratified by study type, body mass index (BMI), diagnostic confidence, and image quality. RESULTS: The mean diagnostic accuracy of conventional sonography was 84% compared with 74% for POC (P < .001). This difference was constant regardless of reader, exam type, or BMI. The sensitivity and specificity to detect abnormalities with conventional was 85 and 83%, compared with 75 and 68% for POC. The POC sonography demonstrated greater variability in image quality and diagnostic confidence, and this accounted for lower diagnostic accuracy. When image quality and diagnostic confidence were similar between POC and conventional examinations, there was no difference in accuracy. CONCLUSIONS: Point-of-care was nearly as accurate as conventional sonography for basic, focused examinations. Observed differences in accuracy were attributed to greater variation in POC image quality. PMID- 28339134 TI - Paranasal sinus lymphoma: Retrospective review with focus on clinical features, histopathology, prognosis, and relationship to systemic lymphoma. AB - BACKGROUND: Paranasal sinus lymphoma is a rare clinical entity. METHODS: We conducted a retrospective case series of 68 patients with biopsy-confirmed paranasal sinus lymphoma with attention on systemic disease association. RESULTS: Of 63 patients with paranasal sinus lymphoma, 35 (56%) had systemic involvement. Four patient groups were identified: (1) primary paranasal sinus lymphoma (44%); (2) systemic disease occurring concurrently with paranasal sinus lymphoma (25%); (3) paranasal sinus lymphoma with relapse of preexisting systemic lymphoma (22%); and (4) progression to systemic disease after primary paranasal sinus lymphoma (8%). Most of the patients with systemic disease were diagnosed at 50 + years and had positive smoking histories. There was a trend toward disease activity in the neighboring ocular location. For patients with preexisting systemic lymphoma, the mean time to paranasal sinus lymphoma was 65 months. When systemic lymphoma developed after localized paranasal sinus lymphoma, mean time to progression was 23 months. Diffuse large B cell lymphoma was the most common paranasal sinus lymphoma. CONCLUSION: There is a risk of systemic involvement during the disease course of paranasal sinus lymphoma. Biopsy is the preferred first management step and should precede debulking or mass resection in nonemergent cases. (c) 2017 Wiley Periodicals, Inc. Head Neck 39: 1065-1070, 2017. PMID- 28339135 TI - Integrated models to support multiobjective ecological restoration decisions. AB - Many objectives motivate ecological restoration, including improving vegetation condition, increasing the range and abundance of threatened species, and improving species richness and diversity. Although models have been used to examine the outcomes of ecological restoration, few researchers have attempted to develop models to account for multiple, potentially competing objectives. We developed a combined state-and-transition, species-distribution model to predict the effects of restoration actions on vegetation condition and extent, bird diversity, and the distribution of several bird species in southeastern Australian woodlands. The actions reflected several management objectives. We then validated the models against an independent data set and investigated how the best management decision might change when objectives were valued differently. We also used model results to identify effective restoration options for vegetation and bird species under a constrained budget. In the examples we evaluated, no one action (improving vegetation condition and extent, increasing bird diversity, or increasing the probability of occurrence for threatened species) provided the best outcome across all objectives. In agricultural lands, the optimal management actions for promoting the occurrence of the Brown Treecreeper (Climacteris picumnus), an iconic threatened species, resulted in little improvement in the extent of the vegetation and a high probability of decreased vegetation condition. This result highlights that the best management action in any situation depends on how much the different objectives are valued. In our example scenario, no management or weed control were most likely to be the best management options to satisfy multiple restoration objectives. Our approach to exploring trade-offs in management outcomes through integrated modeling and structured decision-support approaches has wide application for situations in which trade-offs exist between competing conservation objectives. PMID- 28339137 TI - Perioperative midazolam hypersensitivity in a seven-year-old boy. PMID- 28339138 TI - Cognitive Performance and the Alteration of Neuroendocrine Hormones in Chronic Tension-Type Headache. AB - Tension-type headache (TTH) is the most prevalent primary headache. Chronic TTH (CTTH), the most serious form of TTH, is refractory, with a high socio-economic burden. Research studies have shown patients with migraine often had cognitive impairment, but few studies have focused on the cognition in patients with CTTH. In this study, we assumed that patients with CTTH also have cognitive impairments, which are modulated by the neuroendocrine state. Participants were recruited, including patients with CTTH and healthy controls. Cognitive ability was evaluated using the Montreal Cognitive Assessment and the Nine Box Maze Test. The administration of neuroendocrine hormones has been established to be associated with cognitive performance, and we detected the hormonal changes in the hypothalamus-pituitary-adrenal axis, the hypothalamus-pituitary-thyroid axis, and gonadotropin-releasing hormone. These results showed that compared to the controls, significant cognitive impairment and neuroendocrine dysfunction were present in the patients with CTTH. We also assessed the correlations between the neuroendocrine hormones and Pittsburgh Sleep Quality Index score, 17-term Hamilton's Depression Scale score, pain intensity, and duration of pain to determine whether the neuroendocrine hormones had any associations with these symptoms of CTTH. These results showed that changes in neuroendocrine hormones were involved in these symptoms of CTTH. Intervention with the neuroendocrine state may be a strategy for CTTH treatment. PMID- 28339136 TI - Eosinophilic esophagitis phenotypes: Ready for prime time? AB - Eosinophilic esophagitis (EoE) is one of the most common causes of reflux-like symptoms and feeding problems in children and food impaction and dysphagia in adults with a prevalence of 1:2500. Therapeutic options include diet, use of swallowed corticosteroids, or dilation. In the last several years, recent clinical and translational researches have identified some common and distinctive features, for example, the varying response to diet and medications. As EoE shares some characteristics with both asthma and inflammatory bowel disease, the advances in these fields suggest that various phenotypes may also exist in patients with EoE. Here, we provide a rationale for EoE phenotypes and provide some suggestions for potential phenotypes based on histology, molecular signature, response to therapy or dietary therapy. PMID- 28339139 TI - Gender-based outcomes of bivalirudin versus heparin in patients undergoing percutaneous coronary interventions: Meta-analysis of randomized controlled trials. AB - OBJECTIVES: We aimed to perform a gender-based meta-analysis of the outcome of bivalirudin versus heparin in patients undergoing percutaneous coronary interventions (PCI). BACKGROUND: Bivalirudin has been shown to decrease major bleeding when compared to heparin +/- glycoprotein IIb/IIIa inhibitors (GPI) in patients undergoing PCI. It is unclear, however, if those differences in outcomes are the same for men and women. METHODS: We included randomized controlled trials (RCTs) that compared bivalirudin to heparin with or without GPI in patients undergoing PCI and reported outcome data that were stratified by gender. Random effect model was used to pool odds ratio (OR) and 95% confidence intervals (CI). RESULTS: We included 9 trials with 33,224 patients. Bivalirudin decreased major bleeding when compared to heparin plus routine GPI in both men (OR: 0.51, P < 0.001) and women (OR: 0.55, P < 0.001). However, when GPI were used selectively with heparin, the bleeding lowering effect of bivalirudin was statistically significant in men (OR: 0.69, P = 0.02) but not in women (OR: 0.71, P = 0.21). When compared to heparin +/- GPI, there was a nonstatistically significant trend toward lower all-cause mortality with bivalirudin in both men (OR: 0.76, P = 0.055) and women (OR: 0.79, P = 0.21). There were no significant differences in major adverse cardiovascular events between heparin and bivalirudin in both men and women. CONCLUSION: Bivalirudin decreases major bleeding in both men and women when compared to heparin plus routine GPI. However, when compared to heparin alone, the bleeding lowering benefit of bivalirudin is less evident in women. (c) 2017 Wiley Periodicals, Inc. PMID- 28339140 TI - Acquisition of voice onset time in toddlers at high and low risk for autism spectrum disorder. AB - Although language delay is common in autism spectrum disorder (ASD), research is equivocal on whether speech development is affected. We used acoustic methods to investigate the existence of sub-perceptual differences in the speech of toddlers who developed ASD. Development of the distinction between b and p was prospectively tracked in 22 toddlers at low risk for ASD (LRC), 22 at high risk for ASD without ASD (HRA-), and 11 at high risk for ASD who were diagnosed with ASD at 36 months (HRA+). Voice onset time (VOT), the main acoustic difference between b and p, was measured from spontaneously produced words at 18, 24, and 36 months. Number of words, number of tokens (instances) of syllable-initial b and p produced, error rates, language scores, and motor ability were also assessed. All groups' mean language scores were within the average range or slightly higher. No between-group differences were found in number of words, b's, p's, or errors produced; or in mean or standard deviation of VOT. Binary logistic regression showed that only diagnostic status, not language score, motor ability, number of words, number of b's and p's, or number of errors significantly predicted whether a toddler produced acoustically distinct b and p populations at 36 months. HRA+ toddlers were significantly less likely to produce acoustically distinct b's and p's at 36 months, which may indicate that the HRA+ group may be using different strategies to produce this distinction. Autism Res 2017. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2017, 10: 1269 1279. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 28339141 TI - Don't touch me! autistic traits modulate early and late ERP components during visual perception of social touch. AB - Although individuals with autism spectrum disorder (ASD) have impaired responses to interpersonal touch, the underlying neural correlates remain largely unknown. Here, we examined the neural correlates that underlie interpersonal touch perception in individuals with either high or low autistic traits. Fifty-three participants were classified as having either high or low autistic traits based on their performance on the autism quotient (AQ) questionnaire. We hypothesized that individuals with high AQ scores would have relatively high touch hypervigilance, reflected as earlier P1 and stronger late positive potential (LPP) responses, two components of event-related potentials that serve as electrophysiological markers of anxiety bias. We recorded each participant's electroencephalography activity during presentation of images depicting human touch, object touch, and non-touch control images. Consistent with our hypothesis, AQ scores were positively correlated with social touch aversion. Moreover, participants with high AQ scores had earlier P1 and stronger LPP responses when presented with human touch compared to the control images. Importantly, a regression model revealed that earlier P1 and larger LPP amplitude measured during social touch observation can accurately predict higher autistic trait levels. Taken together, these findings indicate that individuals with high levels of autistic traits may have a hypervigilant response to observed social touch. Autism Res 2017, 0: 000-000. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2017, 10: 1141-1154. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 28339143 TI - Erratum. PMID- 28339142 TI - Selective effects of oral antiangiogenic tyrosine kinase inhibitors on an animal model of hereditary hemorrhagic telangiectasia. AB - : Essentials Antiangiogenic drugs are indicated as therapies for hereditary hemorrhagic telangiectasia. We interrogated the response to four antiangiogenic drugs for anemia and intestinal bleeding. Sorafenib and a pazopanib analog significantly improved while erlotinib worsened anemia. Some oral antiangiogenic drugs were effective in reducing intestinal bleeding. SUMMARY: Background Epistaxis and gastrointestinal (GI) tract hemorrhages are common symptoms of aged hereditary hemorrhagic telangiectasia (HHT) patients that result in anemia. Clinical as well as animal studies have suggested that vascular endothelial growth factor (VEGF) neutralizing antibodies lessen hemorrhage associated with adult-onset arteriovenous malformations (AVMs). Objectives The goal of this study is to evaluate potential therapeutic effects of oral delivery of four antiangiogenic tyrosine-kinase inhibitors (TKIs) in the development of adult onset AVMs in a murine model of HHT. Methods An adult activin receptor-like kinase 1 (Alk1)-inducible knockout (iKO) model was utilized to evaluate the effect of oral administration of sorafenib, sunitinib, erlotinib and a pazopanib analog (GW771806) on hemoglobin level, GI hemorrhages and formation of wound induced skin AVMs. Results and Conclusions Sorafenib and GW771806 significantly improved, yet erlotinib worsened, anemia and GI-bleeding in the Alk1-iKO model. However, none of these TKIs appeared to be effective for inhibiting the development of wound-induced skin AVMs. Taken together, these results suggest that oral delivery of antiangiogenic TKIs is selectively more effective for GI bleeding than mucocutaneous AVMs, and it may provide an experimental basis for selective therapeutic options depending on the symptoms of HHT. PMID- 28339146 TI - Planned parenthood, and female control over reproduction. PMID- 28339145 TI - Respiratory syncytial virus-Host interaction in the pathogenesis of bronchiolitis and its impact on respiratory morbidity in later life. AB - Respiratory syncytial virus (RSV) is the most common agent of severe airway disease in infants and young children. Large epidemiologic studies have demonstrated a clear relationship between RSV infection and subsequent recurrent wheezing and asthma into childhood, thought to be predominantly related to long term changes in neuroimmune control of airway tone rather than to allergic sensitization. These changes appear to be governed by the severity of the first RSV infection in infancy which in term depends on viral characteristics and load, but perhaps as importantly, on the genetic susceptibility and on the constitutional characteristic of the host. A variety of viral and host factors and their interplay modify the efficiency of the response to infection, including viral replication and the magnitude of structural and functional damage to the respiratory structures, and ultimately the extent, severity, and duration of subsequent wheezing. PMID- 28339147 TI - Is gender just a category? The two-plus sex advantage. PMID- 28339144 TI - Australian and New Zealand Pulmonary Rehabilitation Guidelines. AB - BACKGROUND AND OBJECTIVE: The aim of the Pulmonary Rehabilitation Guidelines (Guidelines) is to provide evidence-based recommendations for the practice of pulmonary rehabilitation (PR) specific to Australian and New Zealand healthcare contexts. METHODS: The Guideline methodology adhered to the Appraisal of Guidelines for Research and Evaluation (AGREE) II criteria. Nine key questions were constructed in accordance with the PICO (Population, Intervention, Comparator, Outcome) format and reviewed by a COPD consumer group for appropriateness. Systematic reviews were undertaken for each question and recommendations made with the strength of each recommendation based on the GRADE (Gradings of Recommendations, Assessment, Development and Evaluation) criteria. The Guidelines were externally reviewed by a panel of experts. RESULTS: The Guideline panel recommended that patients with mild-to-severe COPD should undergo PR to improve quality of life and exercise capacity and to reduce hospital admissions; that PR could be offered in hospital gyms, community centres or at home and could be provided irrespective of the availability of a structured education programme; that PR should be offered to patients with bronchiectasis, interstitial lung disease and pulmonary hypertension, with the latter in specialized centres. The Guideline panel was unable to make recommendations relating to PR programme length beyond 8 weeks, the optimal model for maintenance after PR, or the use of supplemental oxygen during exercise training. The strength of each recommendation and the quality of the evidence are presented in the summary. CONCLUSION: The Australian and New Zealand Pulmonary Rehabilitation Guidelines present an evaluation of the evidence for nine PICO questions, with recommendations to provide guidance for clinicians and policymakers. PMID- 28339150 TI - Application of a multivariate normal distribution methodology to the dissociation of doubly ionized molecules: The DMDS (CH3 -SS-CH3 ) case. AB - RATIONALE: The ion-ion-coincidence mass spectroscopy technique brings useful information about the fragmentation dynamics of doubly and multiply charged ionic species. We advocate the use of a matrix-parameter methodology in order to represent and interpret the entire ion-ion spectra associated with the ionic dissociation of doubly charged molecules. This method makes it possible, among other things, to infer fragmentation processes and to extract information about overlapped ion-ion coincidences. This important piece of information is difficult to obtain from other previously described methodologies. METHODS: A Wiley-McLaren time-of-flight mass spectrometer was used to discriminate the positively charged fragment ions resulting from the sample ionization by a pulsed 800 eV electron beam. We exemplify the application of this methodology by analyzing the fragmentation and ionic dissociation of the dimethyl disulfide (DMDS) molecule as induced by fast electrons. The doubly charged dissociation was analyzed using the Multivariate Normal Distribution. RESULTS: The ion-ion spectrum of the DMDS molecule was obtained at an incident electron energy of 800 eV and was matrix represented using the Multivariate Distribution theory. The proposed methodology allows us to distinguish information among [CHn SHn ]+ /[CH3 ]+ (n = 1-3) fragment ions in the ion-ion coincidence spectra using ion-ion coincidence data. Using the momenta balance methodology for the inferred parameters, a secondary decay mechanism is proposed for the [CHS]+ ion formation. As an additional check on the methodology, previously published data on the SiF4 molecule was re analyzed with the present methodology and the results were shown to be statistically equivalent. CONCLUSIONS: The use of a Multivariate Normal Distribution allows for the representation of the whole ion-ion mass spectrum of doubly or multiply ionized molecules as a combination of parameters and the extraction of information among overlapped data. We have successfully applied this methodology to the analysis of the fragmentation of the DMDS molecule. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28339149 TI - Effect of Food Intake on the Pharmacodynamics of Tenapanor: A Phase 1 Study. AB - Tenapanor (RDX5791/AZD1722) is a minimally systemic small-molecule inhibitor of the sodium/hydrogen exchanger NHE3. Tenapanor acts in the gut to reduce absorption of sodium and phosphate. This phase 1 open-label, 3-way crossover study (NCT02226783) evaluated the effect of food on the pharmacodynamics of tenapanor. Eighteen volunteers completed a randomized sequence of three 4-day treatments with tenapanor hydrochloride 15 mg twice daily: before food, after food, and while fasting. Participants received a diet standardized for sodium content. Stool sodium was significantly higher with tenapanor administration before versus after food (difference, +8.8 mmol/day, P = .006) or while fasting (+11.8 mmol/day, P = .0004). Differences in urinary sodium were not significant. Stool phosphorus was not significantly different with tenapanor before versus after food and significantly higher before food versus while fasting (+4.9 mmol/day, P = .006). Urinary phosphorus was significantly lower when tenapanor was administered before (-3.9 mmol/day, P = .0005) or after food (-3.7 mmol/day, P = .0009) versus while fasting. No serious adverse events were reported. These data suggest the effect of tenapanor on sodium absorption is most pronounced when administered before meals, whereas the effect on phosphate is similar whether administered before or after meals. This may support different timings of tenapanor administration with respect to food for sodium- and phosphate-related indications. PMID- 28339151 TI - Rapid identification of atypical tetracyclines using tandem mass spectrometric fragmentation patterns. AB - RATIONALE: When applying biosynthetic engineering approaches at the early stages of drug discovery, e.g. aiming to develop novel tetracycline analogues, target compounds are generally produced by engineered microorganisms in low yields. Rapid and reliable identification of metabolites with desired structural modification directly from bacterial cultures is therefore of great importance. METHODS: Structural elucidation of atypical tetracyclines was carried out by fragmentation applying electrospray ionisation tandem mass spectrometry (ESI MS/MS) (triple quadrupole - linear ion trap; Applied Biosystems 4000 QTRAP) and a high-resolution mass spectrometer (Agilent Technologies 6224 TOF). Fragmentation patterns were obtained either with direct injection or by applying separation of target compounds with high-performance liquid chromatography (HPLC) prior to mass spectrometry. In-source and CID fragmentation were compared. Theoretical calculations of target structures using the Gaussian programme suite were carried out with the aim of strengthening experimental structural elucidation. RESULTS: Recombinant strains of Amycolatopsis sulphurea producing atypical tetracyclines chelocardin, modified chelocardin analogues (9-demethylchelocardin and 2 carboxyamido-2-deacetyl-chelocardin (CDCHD), and anhydrotetracycline (ATC) were analysed by collision-induced dissociation (CID) fragmentation with higher collision energies to yield structurally important fragments which were identified. We have demonstrated that ATC is more prone to fragmentation compared to its epimer, which was further supported by comparison of both structures calculated with ab initio calculations. CONCLUSIONS: We have demonstrated that fragmentation patterns of atypical tetracyclines in CID-MS spectra enable rapid structural elucidation of target metabolites produced by cultures of genetically engineered bacteria. This method is of significant importance for early stages of drug development considering that isolation of target metabolites produced at low concentration is challenging. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28339152 TI - Fragmentation pathways of synthetic and naturally occurring coumarin derivatives by ion trap and quadrupole time-of-flight mass spectrometry. AB - RATIONALE: Synthetic and natural coumarin derivatives possess a wide range of biological activities. Fragmentation pathway studies are important in identifying both naturally occurring coumarins and synthetic coumarins with novel structures and properties. METHODS: The fragmentation pathways of eleven coumarin derivatives are investigated by electrospray ionization (ESI) ion-trap mass spectrometry (ESI-ITMSn ) and ESI quadrupole time-of-flight mass spectrometry (QTOFMS) in positive mode. Compounds 1-9 in this study were newly synthesized in our laboratory. Compounds 10 and 11 were isolated from the root of Zanthoxylum armatum. RESULTS: The major fragmentation pathways for 11 coumarin derivatives are greatly affected by the heterocyclic ring structures and the side-chain substituents. Typical losses of small neutral molecules, such as CH3 CH2 OH, CH2 =CH2 , CO, and H2 O, are observed for compounds 1-5. Compounds 6-9 share similar fragmentation pathways through losses of CO, aromatic rings, and the coumarin skeleton. The main product ions at m/z 205, 219, and 220 observed for compounds 10 and 11 are produced by the loss of C5 H12 O2 , C4 H10 O2 , and the C4 H9 O2 radical, respectively. CONCLUSIONS: The fragmentation pathways of 11 coumarin derivatives are elucidated based on ITMSn and QTOFMS spectral data. Differences in the structures of the heterocyclic rings and side-chain substituents strongly affect the fragmentation pathways of the coumarins. The present results will facilitate further research into the fragmentation pathways and structural characterization of these classes of compounds with diverse structures. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28339153 TI - Protonated N-benzyl- and N-(1-phenylethyl)tyrosine amides dissociate via ion/neutral complexes. AB - RATIONALE: The collisional-induced dissociations (CID) of the [M+H]+ ions of molecules having benzyl groups attached to N-atoms have been proposed to involve migration of the benzyl group through the intermediacy of ion/neutral complexes (INCs). We report the investigation of the mechanism of dissociation of protonated N-benzyl- and N-(1-phenylethyl)tyrosine amides by electrospray ionization (ESI) tandem mass spectrometry (MS/MS) and density functional theory (DFT) calculations. METHODS: The amides were synthesized from the corresponding amino acids and amines. The ESI-MS/MS spectra were recorded using an Agilent QTOF 6540 mass spectrometer. The DFT calculations were performed by using Gaussian 09 software. The structures of the [M+H]+ ions, intermediates, products and transition states (TS) were optimized at the B3LYP/6-31G(d,p) level of theory. RESULTS: CID of the [M+H]+ ions of N-benzyltyrosine amide yields two product ions due to rearrangements: (i) the [M+H-74]+ ion (m/z 197) due to benzyl migration to the hydroxyphenyl ring and (ii) the [M+H-45]+ ion (m/z 226) due to benzyl migration to the NH2 group. DFT calculations suggest that the rearrangements occur through an INC in which the benzyl cation is the cation partner. The [M+H]+ ion of N-(1-phenylethyl)tyrosine amide rearranges to an INC of the 1-phenylethyl cation. Subsequent elimination of styrene occurs by transfer of a proton from the 1-phenylethyl cation to the neutral partner. CONCLUSIONS: The [M+H]+ ions of both N-benzyl (1) and N-(1-phenylethyl) (2) tyrosine amide rearrange into INCs. The dissociation of [M+H]+ ion of 1 yields the benzyl cation and [M+H-74]+ and [M+H 45]+ due to benzyl migration to the hydroxyphenyl ring and NH2 group, respectively. However, the formation of the [M+H-74]+ ion is not observed when the aromatic ring is deactivated. The [M+H]+ ion of 2 either dissociates to form the 1-phenylethyl cation or [M+H-styrene]+ . Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28339154 TI - The genomic sequences near the mir-23b-27b-24-1 cluster form G-quadruplexes and are selectively bound by the natural alkaloid tetrandrine. AB - RATIONALE: Although the microRNAs miR-23b, miR-27b and miR-24 are located in the same cluster, their expressions in various pathological states are not always comparable. By searching the genomic sequence around mir23b-27b-24-1 in rat, we identified three potential G-quadruplex sequences (PQS) which can fold into different types of G-quadruplexes, including parallel or antiparallel. Natural alkaloids, tetrandrine (TET), displayed different binding affinity with the three G-quadruplexes which may potentially regulate the expression of mir23b-27b-24-1 cluster members. METHODS: Both electrospray ionization mass spectrometry (ESI-MS) and circular dichroism (CD) spectroscopy were utilized to detect the formation of G-quadruplexes. Six small molecules were screened by ESI-MS for their binding affinity with three G-quadruplexes, which were evaluated by their IRa values. RESULTS: The results of ESI-MS and CD experiments confirmed the formation of three G-quadruplexes neighboring the mir23b-27b-24-1 cluster; two of them adopted antiparallel G-quadruplexes, another adopted a parallel G-quadruplex. Screening of small molecules by ESI-MS showed tetrandrine had selective binding affinity for the parallel G-quadruplex. G-quadruplex stabilization by tetrandrine was verified by CD variable temperature measurements. CONCLUSIONS: The gene of the mir23b-27b-24-1 cluster harbors three G-quadruplexes with typical sequences and structures. Tetrandrine had a selective binding affinity to the parallel G quadruplex and stabilized it significantly. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28339155 TI - Use of atmospheric pressure solids analysis probe time-of-flight mass spectrometry to screen for plasticisers in gaskets used in contact with foods. AB - RATIONALE: Plasticisers are used in the PVC gaskets of metal closures on glass jars and bottles used for foods and beverages. They may migrate and so contaminate the packed foodstuff. The plasticisers are present in a high proportion and are often a complex mixture of substances leading to time consuming analytical methodologies. This work describes a rapid screening method to identify the plasticisers used. METHODS: Analysis was carried out by direct sampling of the gaskets using atmospheric pressure solids analysis probe (ASAP) with time-of-flight (TOF) mass spectrometry (MS) using a SYNAPT G2 HDMS system. The accurate mass information collected was then compared to a user-prepared database of plasticisers to aid identification. RESULTS: The rapid identification approach was shown to be successful for 24 gasket samples previously analysed by alternative more lengthy gas chromatographic (GC) methods. Quantification by dissolution followed by standard addition was also demonstrated to be reliable. CONCLUSIONS: The ASAP-TOFMS method is a useful technique for rapidly screening gaskets for the presence of plasticisers. It can be used to identify specific gaskets deserving of further quantitative analysis by chromatographic methods, saving time and money by avoiding unnecessary analyses. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28339156 TI - A high-resolution accurate mass (HR/AM) approach to identification, profiling and characterization of in vitro nefazodone metabolites using a hybrid quadrupole Orbitrap (Q-Exactive). AB - RATIONALE: This paper describes a strategy for the profiling and identification of metabolites based on chemical group classification using high-resolution accurate mass (HR/AM) full scan mass spectrometry (MS) and All-Ion fragmentation (AIF) MS2 data. METHODS: The proposed strategy uses a hybrid quadrupole Orbitrap (Q-Exactive) employing stepped normalised collision energy (NCE) at 35% and 80% to produce key chemically diagnostic product ions from full coverage of the product ion spectrum. This approach allows filtering of high-resolution AIF MS2 data in order to identify parent-related compounds produced following incubation in rat liver microsomes (RLMs). RESULTS: An antidepressant drug, nefazodone (NEF), was selected as the model test compound to demonstrate the proposed workflow for metabolite profiling. This resulted in the identification of three indicative chemical groups within NEF: triazolone, phenoxy and chlorophenylpiperazine. High-resolution mass spectrometry provides increased specificity to distinguish between two characteristic product ion masses m/z 154.0975 (C7 H12 N3 O) and 154.0419 (C8 H9 NCl), which are not fully resolved by spectrometers operating at nominal mass resolution, indicative of compounds containing the triazolone and chlorophenylpiperazine moieties, respectively. CONCLUSIONS: This post-acquisition processing strategy provides comprehensive detection and identification of high- and low-level metabolites from an 'all-in one' analysis. This enables functional groups to be systematically traced across a wide range of metabolites, leading to the successful identification of 28 in vitro NEF-related metabolites. In our hands this approach has been applied to agrochemical environmental fate and dietary metabolism studies, as well as metabolomics and biomarker analysis. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28339157 TI - Determination of residence times of ions in a resistive glass selected ion flow drift tube using the Hadamard transformation. AB - RATIONALE: Selected ion flow tube mass spectrometry, SIFT-MS, used for trace gas analyses has certain fundamental limitations that could be alleviated by adding a facility that allows reaction times and ion interaction energies to be varied. Thus, a selected ion flow-drift tube, SIFDT, has been created to explore the influence of an embedded electric field on these parameters and on reaction processes. METHODS: The new SIFTD instrument was constructed using a miniature resistive glass drift tube. Arrival times of ions, t, analysed by a downstream quadrupole mass spectrometer over the m/z range 10-100 were studied by modulating the injected ion current using a gate lens. Single pulse modulation was compared with pseudorandom time multiplexing exploiting the Hadamard transformation. A simple model involving analysis of ethanol and water vapour mixture in air was used to explore the advantages of the SIFDT concept to SIFT-MS analysis. RESULTS: It is shown that the resistive glass drift tube is suitable for SIFDT experiments. The Hadamard transformation can be used to routinely determine reagent ion residence time in the flow-drift tube and also to observe differences in arrival times for different product ions. Two-dimensional data combining arrival time and mass spectra can be obtained rapidly. The calculated ion drift velocities vary with the reduced field strength, E/N, and the calculated ion mobilities agree with theoretical and previous literature values. CONCLUSIONS: This study has provided evidence that the SIFDT-MS technique can be implemented in a miniature and low-cost instrument and two- or three-dimensional data can be obtained (product ion count rates as functions of m/z, t and E/N) using the Hadamard transformation thus providing exciting possibilities for further analytical additions and extensions of the SIFT-MS technique. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28339158 TI - Use of flower-like gold nanoparticles in time-of-flight mass spectrometry. AB - RATIONALE: Many kinds of nanoparticles (NPs) have been used for mass spectrometry (MS) so far. Here we report the first use of flower-like gold nanoparticles (AuNPs) as a mediator to enhance ionization in MS of peptides and proteins. METHODS: Flower-like AuNPs were characterized using transmission and scanning electron microscopy, UV-VIS spectrophotometry, and laser desorption/ionization (LDI)-MS and compared with polyhedral AuNPs. Mass spectra were obtained in positive ion mode using a time-of-flight (TOF) analyzer coupled with either matrix-assisted laser desorption/ionization (MALDI) or surface-assisted laser desorption/ionization (SALDI) methods. RESULTS: The intensities of peptide peaks (m/z 500-3500) were up to 7.5* and up to 7* higher using flower-like AuNPs and flower-like AuNPs-enriched alpha-cyano-4-hydroxycinnamic acid (CHCA) matrix respectively, than the classical CHCA matrix. The signals of higher mass peptide/protein peaks (m/z 3600-17000) were up to 2* higher with using flower like AuNPs-enriched CHCA matrix than conventional CHCA matrix. The signal of profile peaks generated by intact cell MALDI-TOFMS of fibroblast suspension (m/z 4000-20000) was 2* higher with using flower-like AuNPs combined with sinapinic acid (SA) compared to SA matrix alone. The use of flower-like AuNPs as internal calibration standard for the calibration of MS spectra of peptides was performed. CONCLUSIONS: Flower-like AuNPs and flower-like AuNPs combined with CHCA or SA as combined matrices for MS measurement of peptides and proteins were used. Comparison of the conventional MALDI method and our method with flower-like AuNPs was carried out. In addition, gold clusters generated from flower-like AuNPs by SALDI provide a suitable internal calibration standard for MS analysis of peptides. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28339159 TI - Differences in survival outcome for severely injured paediatric trauma by type of trauma centre. AB - AIM: Whether treatment at paediatric trauma centres (PTCs) provides a survival advantage for injured children over treatment at adult trauma centres (ATCs) remains inconclusive. This study examines the association between trauma centre type and in-hospital mortality for severely injured paediatric trauma patients in New South Wales, Australia. METHODS: A retrospective examination of paediatric patient characteristics (aged <=15 years), treatment and injury outcome was conducted using data from the New South Wales Trauma Registry for 2009-2014. Logistic regression was used to examine the association of in-hospital mortality and type of trauma centre. RESULTS: There were 1230 children who were severely injured (i.e. Injury Severity Score; ISS > 12) and 81.0% received definitive care at a PTC. Two-thirds were male, 37.8% were aged 11-15 years and falls represented 32.0% of the injuries. Almost half (48.9%) the injured children had an ISS between 16 and 24, 31.9% between 25 and 39 and 3.8% an ISS between 40 and 75. The mean and median hospital length of stay was 17.5 and 5 days, respectively. Fifty percent of children that received definitive care at a PTC were admitted to an ICU compared to 23.9% at a Level 1 ATC. There were 119 (9.7%) in-hospital deaths. Children aged <=15 years who were treated at a Level 1 ATC had 6.1 times higher odds of not surviving their injuries than if treated at a PTC. CONCLUSION: Children who received definitive care at a PTC had a survival advantage compared to those treated at a Level 1 ATC. Prospectively examining the processes of care for severely injured children may assist in identification of quality and system changes required to ensure optimal trauma care within the health-care system. PMID- 28339161 TI - Corrigendum. PMID- 28339160 TI - Biofortification of riboflavin and folate in idli batter, based on fermented cereal and pulse, by Lactococcus lactis N8 and Saccharomyces boulardii SAA655. AB - AIMS: Lactococcus lactis N8 and Saccharomyces boulardii SAA655 were investigated for their ability to synthesize B-vitamins (riboflavin and folate) and their functional role as microbial starters in idli fermentation. METHODS AND RESULTS: In this study, ultra-high performance liquid chromatography and microbiological assay were used to determine the total riboflavin and folate content respectively. Increased levels of folate were evident in both L. lactis N8 and S. boulardii SAA655 cultivated medium. Enhanced riboflavin levels were found only in S. boulardii SAA655 grown medium, whereas decreased riboflavin level was found in L. lactis N8 cultivated medium. To evaluate the functional role of microbial starter strains, L. lactis N8 and S. boulardii SAA655 were incorporated individually and in combination into idli batter, composed of wet grounded rice and black gram. For the experiments, naturally fermented idli batter was considered as control. The results indicated that natural idli fermentation did not enhance the riboflavin level and depleted folate levels by half. In comparison with control, L. lactis N8 and S. boulardii SAA655 incorporated idli batter (individually and in combination) increased riboflavin and folate levels by 40-90%. Apart from compensating the folate loss caused by natural fermentation, S. boulardii SAA655 fermented idli batter individually and in combination with L. lactis N8 also showed the highest leavening character. Moreover, the microbial starter incorporation did not significantly influence the pH of idli batter. CONCLUSION: Incorporation of L. lactis N8 and S. boulardii SAA655 can evidently enhance the functional and technological characteristics of idli batter. SIGNIFICANCE AND IMPACT OF THE STUDY: UN General Assembly declared 2016 the International Year of pulses emphasizing the importance of legumes as staple food. Furthermore, this is the first experimental report of in situ biofortifcation of riboflavin and folate using microbes in pulse based fermented staple food. The current study suggests possible avenues for research towards an economical strategy to reduce B-vitamin deficiency among the consuming population. PMID- 28339162 TI - Sofosbuvir-based treatment is safe and effective in Indian hepatitis C patients on maintenance haemodialysis: A retrospective study. AB - AIM: This study evaluates the safety and efficacy of direct-acting antivirals (DAAs) including sofosbuvir, ledipasvir and daclatasvir in patients with hepatitis C viraemia who were on maintenance haemodialysis. METHODS: Data on patients who received sofosbuvir and ribavirin were analysed. Patients who experienced treatment failure with the above regimen received sofosbuvir and ledipasvir for infection with hepatitis C virus (HCV) genotype 1. Those having HCV genotype 3 infection received sofosbuvir and daclatasvir. All treatment regimens were of 12 weeks duration. Side-effects were investigated. The HCV viral load was determined by RT-PCR at 4,16 and 24 weeks after the initiation of therapy; haemoglobin levels and liver function tests were monitored at regular intervals during therapy. RESULTS: Of the 22 subjects initially treated with sofosbuvir and ribavirin, 72.72% attained sustained virologic response at 12 weeks (SVR12). Four patients experienced treatment failure and received genotype specific therapy. Patients with HCV genotype one received sofosbuvir with ledipasvir. One patient with HCV genotype 3 infection received sofosbuvir and daclatasvir. All of them attained SVR12. A statistically significant reduction in the median serum glutamic-oxaloacetic transaminase (SGOT) and Serum glutamic pyruvic transaminase (SGPT) were observed from the baseline until the end of treatment. Anaemia was observed in 45% of patients receiving ribavirin. CONCLUSIONS: Our study demonstrates that sofosbuvir-based therapy is efficacious for HCV viraemia in patients on maintenance haemodialysis. The therapy was found to be reasonably safe with no major adverse effects noted with the use of sofosbuvir, ledipasvir or daclatasvir. However, larger studies are needed to validate our results. PMID- 28339164 TI - Are schizophrenia, autistic, and obsessive spectrum disorders dissociable on the basis of neuroimaging morphological findings?: A voxel-based meta-analysis. AB - Schizophrenia spectrum disorder (SCZD), autism spectrum disorder (ASD), and obsessive-compulsive spectrum disorder (OCSD) are considered as three separate psychiatric conditions with, supposedly, different brain alterations patterns. From a neuroimaging perspective, this meta-analytic study aimed to address whether this nosographical differentiation is actually supported by different brain patterns of gray matter (GM) or white matter (WM) morphological alterations. We explored two possibilities: (a) to find out whether GM alterations are specific for SCZD, ASD, and OCSD; and (b) to associate the identified brain alteration patterns with cognitive dysfunctions by means of an analysis of lesion decoding. Our analysis reveals that these psychiatric spectra do not present clear distinctive patterns of alterations; rather, they all tend to be distributed in two alteration clusters. Cluster 1, which is more specific for SCZD, includes the anterior insular, anterior cingulate cortex, ventromedial prefrontal cortex, and frontopolar areas, which are parts of the cognitive control system. Cluster 2, which is more specific for OCSD, presents occipital, temporal, and parietal alteration patterns with the involvement of sensorimotor, premotor, visual, and lingual areas, thus forming a network that is more associated with the auditory-visual, auditory, premotor visual somatic functions. In turn, ASD appears to be uniformly distributed in the two clusters. The three spectra share a significant set of alterations. Our new approach promises to provide insight into the understanding of psychiatric conditions under the aspect of a common neurobiological substrate, possibly related to neuroinflammation during brain development. Autism Res 2017. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2017, 10: 1079-1095. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 28339165 TI - A randomised controlled trial of sodium citrate spray for non-conductive olfactory disorders. AB - OBJECTIVES: Previous research has suggested that sodium citrate improves hyposmia by decreasing mucus calcium levels in the nose. This study aimed to confirm or refute this effect in a single application and assess potential side-effects. DESIGN: Study design was a randomised double-blind controlled trial of sodium citrate nasal spray (intervention) vs sterile water (control). Fifty-five patients with non-conductive olfactory loss were randomised to receive the intervention or placebo. SETTING: Tertiary care clinic. MAIN OUTCOME MEASURES: The primary outcome measure was improvement in measured olfactory thresholds for phenyl ethyl alcohol (PEA) over 2 hours. Other outcome measures assessed were improvement in olfactory thresholds in 1-butanol, eucalyptol and acetic acid; number of responders with a clinically relevant response in each arm; and adverse effects. RESULTS: A significant effect was seen in the intervention arm for PEA and for 1-butanol and eucalyptol when compared to the control arm (P<.05); 32% of the intervention arm responded in terms of improved sensitivity towards some of the odours. Minor adverse effects noted included sore throat, nasal paraesthesia, slight rhinorrhoea and itching. The duration of effect of the citrate is transient, peaking at 30-60 minutes after application. CONCLUSIONS: Sodium citrate yields some potential as a treatment for non-conductive olfactory loss; however, these findings require corroboration in further clinical trials looking at longer term regular use of the spray as a viable therapeutic option for patients where it would be applied at frequent intervals such as before mealtimes. PMID- 28339166 TI - Pharmacokinetics, Pharmacodynamics, Pharmacogenomics, Safety, and Tolerability of Avatrombopag in Healthy Japanese and White Subjects. AB - Avatrombopag, an orally administered, small-molecule thrombopoietin receptor (c Mpl) agonist, is currently in clinical development for the potential treatment of severe thrombocytopenia in patients with chronic liver disease undergoing an elective procedure. The objectives of this study were to characterize and compare the pharmacokinetics (including the food effect) and pharmacodynamics (platelet count) of avatrombopag following single doses in Japanese and white subjects. Following single dosing under fasted and fed conditions, mean peak concentrations occurred at 5 to 8 hours and subsequently declined with a half-life of 16 to 18 hours in Japanese and white subjects. Administration with food did not alter the rate or extent of avatrombopag absorption but substantially reduced pharmacokinetic variability relative to the fasted state. CYP2C9 polymorphism (*2, *3) was associated with higher pharmacokinetic variability but not with any clinically important effect on variability in platelet response. Plasma exposures of avatrombopag increased in a dose-proportional manner over the dose range tested. After a single dose, platelet count increased in a dose-related manner, reaching a maximum by day 11 and returning to baseline levels by day 27. No clinically important differences were found when avatrombopag pharmacokinetics and pharmacodynamics were compared between Japanese and white subjects. Administration of avatrombopag was generally well tolerated. PMID- 28339163 TI - Next-generation sequencing of urine specimens: A novel platform for genomic analysis in patients with non-muscle-invasive urothelial carcinoma treated with bacille Calmette-Guerin. AB - BACKGROUND: Biopsies from patients with high-risk (HR) non-muscle-invasive urothelial carcinoma (NMIUC), especially flat urothelial carcinoma in situ, frequently contain scant diagnostic material or denuded mucosa only, and this precludes further extensive genomic analysis. This study evaluated the use of next-generation sequencing (NGS) analysis of urine cytology material from patients with HR NMIUC in an attempt to identify genetic alterations that might correlate with clinical features and responses to bacille Calmette-Guerin (BCG) treatment. METHODS: Forty-one cytology slides from patients with HR NMIUC treated with intravesical BCG were selected for this study. Histological confirmation was available for all cases. The specimens were subjected to NGS analysis with a customized targeted exome capture assay composed of 341 genes. RESULTS: In this cohort, genomic alterations were successfully identified in all cytology samples. Mutations were detected down to a 2% allele frequency and chromosomal rearrangements including copy number alterations and gene fusions were identified. The most frequently altered genes included telomerase reverse transcriptase (TERT), tumor protein 53 (TP53), Erb-B2 receptor tyrosine kinase 2 (ERBB2), and chromatin remodeling genes such as lysine demethylase 6A (KDM6A) and AT-rich interaction domain 1A (ARID1A). For patients with matched tumor tissue, cytology specimens revealed all mutations detected in tissue as well as additional mutations, and this suggested that urine might more effectively capture the full genetic heterogeneity of disease than an individual cystectomy. Alterations in multiple genes correlated with clinical and histopathological features, including responses to BCG treatment, flat architecture versus papillary architecture, and smoking history. CONCLUSIONS: Urine specimens can replace tissue as a substrate for NGS analysis of HR NMIUC. Several genomic alterations identified in urine specimens might be associated with histological features and clinical characteristics. Cancer Cytopathol 2017;125:416-26. (c) 2017 American Cancer Society. PMID- 28339167 TI - If you know you will also see: population pharmacokinetics is the way to personalize and optimize prophylaxis in hemophilia. PMID- 28339168 TI - Parental relationship satisfaction in families of children with autism spectrum disorder (ASD): A multilevel analysis. AB - Caring for a child with Autism Spectrum Disorder (ASD) has been linked to a range of negative outcomes for parents but less is known about the putative impact upon the parental couple relationship. The relationship satisfaction of parents of children with ASD was investigated using multilevel modeling. Mothers and fathers (146 couples) reported on their relationship satisfaction, their own well-being, and the behavior problems of the child with ASD and a sibling. Results indicated that mothers and fathers reported similar levels of relationship satisfaction and it was significantly and negatively associated with parental depression and the behavior problems of the child with ASD. Relationship satisfaction was unrelated to the behavior problems of a sibling, the number of children in the household, and family socioeconomic position (SEP). Further longitudinal research that captures a broader range of variables is required to build a theoretical understanding of relationship satisfaction in families of children with ASD. Current evidence suggests that early intervention routes targeting either child behavior problems, parental mental health, or the couple relationship have the potential to benefit inter-connected subsystems within the broader family system. Autism Res 2017. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2017, 10: 1259-1268. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 28339171 TI - Corrigendum. PMID- 28339169 TI - gesp: A computer program for modelling genetic effective population size, inbreeding and divergence in substructured populations. AB - The genetically effective population size (Ne ) is of key importance for quantifying rates of inbreeding and genetic drift and is often used in conservation management to set targets for genetic viability. The concept was developed for single, isolated populations and the mathematical means for analysing the expected Ne in complex, subdivided populations have previously not been available. We recently developed such analytical theory and central parts of that work have now been incorporated into a freely available software tool presented here. gesp (Genetic Effective population size, inbreeding and divergence in Substructured Populations) is R-based and designed to model short- and long-term patterns of genetic differentiation and effective population size of subdivided populations. The algorithms performed by gesp allow exact computation of global and local inbreeding and eigenvalue effective population size, predictions of genetic divergence among populations (GST ) as well as departures from random mating (FIS , FIT ) while varying (i) subpopulation census and effective size, separately or including trend of the global population size, (ii) rate and direction of migration between all pairs of subpopulations, (iii) degree of relatedness and divergence among subpopulations, (iv) ploidy (haploid or diploid) and (v) degree of selfing. Here, we describe gesp and exemplify its use in conservation genetics modelling. PMID- 28339174 TI - In this December issue. PMID- 28339172 TI - Maternal high-fat diet consumption enhances offspring susceptibility to DSS induced colitis in mice. AB - OBJECTIVE: Maternal high-fat diet (HFD) may alter the offspring intestinal immune system, thereby enhancing susceptibility toward inflammatory bowel disease. The objective of the current study was to investigate the impact of maternal HFD on offspring intestinal health using a mouse model of dextran sulfate sodium (DSS) induced colitis. METHODS: Dams were provided with either HFD (60%) or control diet. After weaning, female offspring from both groups were kept on 45% HFD. At 14 weeks of age, offspring were subjected to 2.5% DSS in drinking water for 5 days, followed by 5 days of recovery. RESULTS: Offspring from maternal HFD had higher body weight gain before DSS induction and had higher liver and fat weights with increased adipocyte size at necropsy. When subjected to DSS treatment, HFD offspring had accelerated body weight loss and exaggerated disease activity index. HFD offspring had an elevated histopathological score and interleukin (IL) 1beta, IL-6, and IL-17 expression with upregulated NF-kappaB signaling. Maternal HFD resulted in enhanced neutrophil infiltration associated with elevated expression of monocyte chemoattractant protein-1. Furthermore, maternal HFD suppressed AMP-activated protein kinase activity and decreased sirtuin 1 and p53 protein contents in offspring gut. CONCLUSIONS: Maternal HFD consumption predisposes offspring to a higher susceptibility to develop inflammatory bowel disease. PMID- 28339176 TI - Identification of likely associations between cerebral folate deficiency and complex genetic- and metabolic pathogenesis of autism spectrum disorders by utilization of a pilot interaction modeling approach. AB - Recently, cerebral folate deficiency (CFD) was suggested to be involved in the pathogenesis of autism spectrum disorders (ASD). However, the exact role of folate metabolism in the pathogenesis of ASD, identification of underlying pathogenic mechanisms and impaired metabolic pathways remain unexplained. The aim of our study was to develop and test a novel, unbiased, bioinformatics approach in order to identify links between ASD and disturbed cerebral metabolism by focusing on abnormal folate metabolism, which could foster patient stratification and novel therapeutic interventions. An unbiased, automatable, computational workflow interaction model was developed using available data from public databases. The interaction network model of ASD-associated genes with known cerebral expression and function (SFARI) and metabolic networks (MetScape), including connections to known metabolic substrates, metabolites and cofactors involving folates, was established. Intersection of bioinformatically created networks resulted in a limited amount of interaction modules pointing to common disturbed metabolic pathways, linking ASD to CFD. Two independent interaction modules (comprising three pathways) covering enzymes encoded by ASD-related genes and folate cofactors utilizing enzymes were generated. Module 1 suggested possible interference of CFD with serine and lysine metabolism, while module 2 identified correlations with purine metabolism and inosine monophosphate production. Since our approach was primarily conceived as a proof of principle, further amendments of the presented initial model are necessary to obtain additional actionable outcomes. Our modelling strategy identified not only previously known interactions supported by evidence-based analyses, but also novel plausible interactions, which could be validated in subsequent functional and/or clinical studies. Autism Res 2017, 10: 1424-1435. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 28339179 TI - Synthesis of {111} Facet-Exposed MgO with Surface Oxygen Vacancies for Reactive Oxygen Species Generation in the Dark. AB - Seeking a simple and moderate route to generate reactive oxygen species (ROS) for antibiosis is of great interest and challenge. This work demonstrates that molecule transition and electron rearrangement processes can directly occur only through chemisorption interaction between the adsorbed O2 and high-energy {111} facet-exposed MgO with abundant surface oxygen vacancies (SOVs), hence producing singlet oxygen and superoxide anion radicals without light irradiation. These ROS were confirmed by electron paramagnetic resonance, in situ Raman, and scavenger experiments. Furthermore, heat plays a crucial role for the electron transfer process to accelerate the formation of .O2-, which is verified by temperature kinetic experiments of nitro blue tetrazolium reduction in the dark. Therefore, the presence of oxygen vacancy can be considered as an intensification of the activation process. The designed MgO is acquired in one step via constructing a reduction atmosphere during the combustion reaction process, which has an ability similar to that of noble metal Pd to activate molecular oxygen and can be used as an effective bacteriocide in the dark. PMID- 28339177 TI - Multisensory speech perception in autism spectrum disorder: From phoneme to whole word perception. AB - Speech perception in noisy environments is boosted when a listener can see the speaker's mouth and integrate the auditory and visual speech information. Autistic children have a diminished capacity to integrate sensory information across modalities, which contributes to core symptoms of autism, such as impairments in social communication. We investigated the abilities of autistic and typically-developing (TD) children to integrate auditory and visual speech stimuli in various signal-to-noise ratios (SNR). Measurements of both whole-word and phoneme recognition were recorded. At the level of whole-word recognition, autistic children exhibited reduced performance in both the auditory and audiovisual modalities. Importantly, autistic children showed reduced behavioral benefit from multisensory integration with whole-word recognition, specifically at low SNRs. At the level of phoneme recognition, autistic children exhibited reduced performance relative to their TD peers in auditory, visual, and audiovisual modalities. However, and in contrast to their performance at the level of whole-word recognition, both autistic and TD children showed benefits from multisensory integration for phoneme recognition. In accordance with the principle of inverse effectiveness, both groups exhibited greater benefit at low SNRs relative to high SNRs. Thus, while autistic children showed typical multisensory benefits during phoneme recognition, these benefits did not translate to typical multisensory benefit of whole-word recognition in noisy environments. We hypothesize that sensory impairments in autistic children raise the SNR threshold needed to extract meaningful information from a given sensory input, resulting in subsequent failure to exhibit behavioral benefits from additional sensory information at the level of whole-word recognition. Autism Res 2017. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2017, 10: 1280-1290. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 28339180 TI - Study of the Oxygen Evolution Reaction Catalytic Behavior of CoxNi1-xFe2O4 in Alkaline Medium. AB - Catalysts for the oxygen evolution reaction (OER) play an important role in the conversion of solar energy to fuel of earth-abundant water into H2 and O2 through splitting/electrolysis. Heterogeneous electrocatalysts for hydrogen and oxygen evolution reactions (HER and OER) exhibit catalytic activity that depends on the electronic properties, oxidation states, and local surface structure. Spinel ferrites (MFe2O4; M = Ni and Co) based materials have been attractive for the catalytic water oxidation due to their well-known stability in alkaline medium, easy synthesis, existence of metal cations with various oxidation states, low cost, and tunable properties by the desired metal substitution. To understand the better catalytic activity of MFe2O4 in detail the role of Ni and Co was studied through MxNi1-xFe2O4 (M = Co; 0 < x < 1), which was prepared by the sol-gel method. The results showed that bare NiFe2O4 has better catalytic activity (eta = 381 mV at 10 mA cm-2 and Tafel slope of 46.4 mV dec-1) compared to Co-containing MxNi1-xFe2O4 (eta = 450-470 mV at 10 mA cm-2 and Tafel slope of 50-73 mV dec-1) in alkaline medium, and the substitution of Co is found to suppress the catalytic activity of NiFe2O4. The degradation of catalytic activity with an increase in Co content was accounted for in further detailed investigations. PMID- 28339181 TI - Oxidative Polyoxometalates Modified Graphitic Carbon Nitride for Visible-Light CO2 Reduction. AB - Developing a photocatalysis system for converting CO2 to valuable fuels or chemicals is a promising strategy to address global warming and fossil fuel consumption. Exploring photocatalysts with high-performance and low-cost has been two ultimate goals toward photoreduction of CO2. Herein, noble-metal-free polyoxometalates (Co4) with oxidative ability was first introduced into g-C3N4 resulted in inexpensive hybrid materials (Co4@g-C3N4) with staggered band alignment. The staggered composited materials show a higher activity of CO2 reduction than bare g-C3N4. An optimized Co4@g-C3N4 hybrid sample exhibited a high yield (107 MUmol g-1 h-1) under visible-light irradiation (lambda >= 420 nm), meanwhile maintaining high selectivity for CO production (94%). After 10 h of irradiation, the production of CO reached 896 MUmol g-1. Mechanistic studies revealed the introduction of Co4 not only facilitate the charge transfer of g C3N4 but greatly increased the surface catalytic oxidative ability. This work creatively combined g-C3N4 with oxidative polyoxometalates which provide novel insights into the design of low-cost photocatalytic materials for CO2 reduction. PMID- 28339182 TI - Widespread and Indiscriminate Nanosilver Use: Genuine Potential for Microbial Resistance. AB - In this era of increasing antibiotic resistance, the use of alternative antimicrobials such as silver has become more widespread. Superior antimicrobial activity has been provided through fabrication of silver nanoparticles or nanosilver (NAg), which imparts cytotoxic actions distinct from those of bulk silver. In the wake of the recent discoveries of bacterial resistance to NAg and its rising incorporation in medical and consumer goods such as wound dressings and dietary supplements, we argue that there is an urgent need to monitor the prevalence and spread of NAg microbial resistance. In this Perspective, we describe how the use of NAg in commercially available products facilitates prolonged microorganism exposure to bioavailable silver, which underpins the development of resistance. Furthermore, we advocate for a judicial approach toward NAg use in order to preserve its efficacy and to avoid environmental disruption. PMID- 28339183 TI - Tunable Porosity of Cross-Linked-Polyhedral Oligomeric Silsesquioxane Supports for Palladium-Catalyzed Aerobic Alcohol Oxidation in Water. AB - Polyhedral oligomeric silsesquioxane (POSS)-based materials, poly-POSS-Tn [n = 8 (1), 10 (2), 12 (3), and mix (4)], were prepared in high yields via free radical polymerization of corresponding pure forms of methacrylate-functionalized POSS monomers, MMA-POSS-Tn (n = 8, 10, 12), and the mixture form, MMA-POSS-Tmix. Powder X-ray diffraction (XRD) spectra and BET analysis indicate that 1-4 are amorphous materials with high surface areas (683-839 m2 g-1). The surface areas and total pore volumes follow the trend: poly-POSS-T12 > poly-POSS-T10 > poly POSS-Tmix > poly-POSS-T8. In addition, on the basis of Barrett-Joyner-Halenda (BJH) analysis, poly-POSS-T12 contains the highest amount of mesopores. The Pd nanoparticles immobilized on poly-POSS-Tn [n = 8 (5), 10 (6), 12 (7), and mix (8)] are well dispersed with 4-6 wt % Pd content and similar average particle sizes of 6.2-6.5 nm, according to transmission electron microscopy-energy dispersive X-ray analysis (TEM-EDX) and microwave plasma-atomic emission spectroscopy (MP-AES). At 90 degrees C, the stabilized Pd nanoparticles in 5-8 catalyzed aerobic oxidation of benzyl alcohol to benzaldehyde in 72-100% yields at 6 h using a mixture of a H2O/Pluronic (P123) solution. The PdNp@poly-POSS-T8 catalyst (5) exhibited the lowest catalytic activity, as a result of its lowest surface areas, total pore volumes, and amounts of mesopores. With the catalyst 8, various benzyl alcohol derivatives were converted to the corresponding aldehydes in good to excellent yields. However, with alcoholic substrates featuring electron-withdrawing substituents, high conversions were achieved with 1 equiv of K2CO3 additive and longer reaction times. PMID- 28339184 TI - MXene Ti3C2: An Effective 2D Light-to-Heat Conversion Material. AB - MXene, a new series of 2D material, has been steadily advancing its applications to a variety of fields, such as catalysis, supercapacitor, molecular separation, electromagnetic wave interference shielding. This work reports a carefully designed aqueous droplet light heating system along with a thorough mathematical procedure, which combined leads to a precise determination of internal light-to heat conversion efficiency of a variety of nanomaterials. The internal light-to heat conversion efficiency of MXene, more specifically Ti3C2, was measured to be 100%, indicating a perfect energy conversion. Furthermore, a self-floating MXene thin membrane was prepared by simple vacuum filtration and the membrane, in the presence of a rationally chosen heat barrier, produced a light-to-water evaporation efficiency of 84% under one sun irradiation, which is among the state of art energy efficiency for similar photothermal evaporation system. The outstanding internal light-to-heat conversion efficiency and great light-to-water evaporation efficiency reported in this work suggest that MXene is a very promising light-to-heat conversion material and thus deserves more research attention toward practical applications. PMID- 28339185 TI - Red Emission B, N, S-co-Doped Carbon Dots for Colorimetric and Fluorescent Dual Mode Detection of Fe3+ Ions in Complex Biological Fluids and Living Cells. AB - Colorimetric and fluorescent dual mode detection methods have gained much attention in recent years; however, it is still desirable to develop new colorimetric and fluorescent dual mode nanosensors with more simple preparation procedures, low cost, and excellent biocompatibility. Herein, a colorimetric and fluorescent nanosensor based on B, N, S-co-doped carbon dots (BNS-CDs) was synthesized by one-step hydrothermal treatment of 2,5-diaminobenzenesulfonic acid and 4-aminophenylboronic acid hydrochloride. Using this nanosensor, a highly sensitive assay of Fe3+ in the range of 0.3-546 MUM with a detection limit of 90 nM was provided by quenching the red emission fluorescence. It is more attractive that Fe3+ can also be visualized by this nanosensor via evident color changes of the solution (from red to blue) under sunlight without the aid of an ultraviolet (UV) lamp. Furthermore, the designed nanosensor can be applied for efficient detection of intracellular Fe3+ with excellent biocompatibility and cellular imaging capability, and it holds great promise in biomedical applications. PMID- 28339186 TI - Quantum Chemical Strain Analysis For Mechanochemical Processes. AB - The use of mechanical force to initiate a chemical reaction is an efficient alternative to the conventional sources of activation energy, i.e., heat, light, and electricity. Applications of mechanochemistry in academic and industrial laboratories are diverse, ranging from chemical syntheses in ball mills and ultrasound baths to direct activation of covalent bonds using an atomic force microscope. The vectorial nature of force is advantageous because specific covalent bonds can be preconditioned for rupture by selective stretching. However, the influence of mechanical force on single molecules is still not understood at a fundamental level, which limits the applicability of mechanochemistry. As a result, many chemists still resort to rules of thumb when it comes to conducting mechanochemical syntheses. In this Account, we show that comprehension of mechanochemistry at the molecular level can be tremendously advanced by quantum chemistry, in particular by using quantum chemical force analysis tools. One such tool is the JEDI (Judgement of Energy DIstribution) analysis, which provides a convenient approach to analyze the distribution of strain energy in a mechanically deformed molecule. Based on the harmonic approximation, the strain energy contribution is calculated for each bond length, bond angle and dihedral angle, thus providing a comprehensive picture of how force affects molecules. This Account examines the theoretical foundations of quantum chemical force analysis and provides a critical overview of the performance of the JEDI analysis in various mechanochemical applications. We explain in detail how this analysis tool is to be used to identify the "force bearing scaffold" of a distorted molecule, which allows both the rationalization and the optimization of diverse mechanochemical processes. More precisely, we show that the inclusion of every bond, bending and torsion of a molecule allows a particularly insightful discussion of the distribution of mechanical strain in deformed molecules. We illustrate the usefulness of the JEDI analysis by rationalizing the finding that a knot tremendously weakens a polymer strand via a "choking" motion of the torsions in the curved part of the knot, thus leading to facilitated bond rupture in the immediate vicinity of the knot. Moreover, we demonstrate that the JEDI analysis can be exploited to devise methods for the stabilization of inherently strained molecules. In addition to applications in the electronic ground state, the JEDI analysis can also be used in the electronically excited state to determine the mechanical energy that a molecular photoswitch can release into its environment during photoisomerization. This approach allows the quantification of the mechanical efficiency of a photoswitch, i.e., the part of the energy that becomes available for the motion into a specific direction, which enables us to judge whether a photoswitch is capable of performing a desired switching function. PMID- 28339187 TI - Accurate MicroRNA Analysis in Crude Cell Lysate by Capillary Electrophoresis Based Hybridization Assay in Comparison with Quantitative Reverse Transcription Polymerase Chain Reaction. AB - Accurate quantitation of microRNA (miRNA) in tissue samples is required for validation and clinical use of miRNA-based disease biomarkers. Since sample processing, such as RNA extraction, introduces undesirable biases, it is advantageous to measure miRNA in a crude cell lysate. Here, we report on accurate miRNA quantitation in crude cell lysate by a CE-based hybridization assay termed direct quantitative analysis of multiple miRNAs (DQAMmiR). Accuracy and precision of miRNA quantitation were determined for miRNA samples in a crude cell lysate, RNA extract from the lysate, and a pure buffer. The results showed that the measurements were matrix-independent with inaccuracies of below 13% from true values and relative standard deviations of below 11% from the mean values in a miRNA concentration range of 2 orders of magnitude. We compared DQAMmiR-derived results with those obtained by a benchmark miRNA-quantitation method-quantitative reverse transcription-polymerase chain reaction (qRT-PCR). qRT-PCR-based measurements revealed multifold inaccuracies and relative standard deviations of up to 70% in crude cell lysate. Robustness of DQAMmiR to changes in sample matrix makes it a perfect candidate for validation and clinical use of miRNA-based disease biomarkers. PMID- 28339188 TI - Preparation and Characterization of Parent Phenylphosphinidene and Its Oxidation to Phenyldioxophosphorane: The Elusive Phosphorus Analogue of Nitrobenzene. AB - Triplet phenylphosphinidene was prepared by light-induced elimination of ethylene from the corresponding phenylphosphirane and was characterized by IR and UV/vis spectroscopy together with matching of its spectral data with density functional theory computations. The photolysis of phenylphosphirane in 3P-O2 doped matrices enabled the spectroscopic identification of a hitherto unknown phenyldioxophosphorane, the long elusive phosphorus analogue of nitrobenzene. PMID- 28339189 TI - Polymerization-Induced Self-Assembly (PISA) - Control over the Morphology of 19F Containing Polymeric Nano-objects for Cell Uptake and Tracking. AB - Fluorine-containing polymeric materials are receiving increasing attention as imaging probes in fluorine-19 magnetic resonance imaging (19F MRI), for example to enable quantitative in vivo detection of cells. Here we describe the one-pot polymerization synthesis of 19F-containing functional poly(oligo(ethylene glycol) methyl ether methacrylate-co-2,2,2-trifluoroethyl acrylate-b-poly(styrene-co-3 vinylbenzaldehyde) (poly(OEGA-co-TFEA)-b-poly(St-co-VBA)) copolymers as a new class of fluorinated MRI agent. A range of nanoparticle morphologies, including spheres, worm-like particles, and vesicles were formed as a consequence of polymerization-induced self-assembly (PISA). It was found that the extent of cell uptake strongly depends on the morphology of the nano-objects, with preferable uptake for worm-like particles compared to spherical nanoparticles and vesicles. All the nano-objects have a single resonance in the 19F NMR spectrum with relatively short MRI relaxation times, which were independent of the morphology of the nano-objects. These results confirm that these polymeric nano-objects of varied morphologies are promising as 19F MRI imaging agents for use in tracking of cells and selective MRI. PMID- 28339190 TI - Luminescent Zn(II) Coordination Polymers for Highly Selective Sensing of Cr(III) and Cr(VI) in Water. AB - Three photoluminescent zinc coordination polymers (CPs), {[Zn2(tpeb)2(2,5 tdc)(2,5-Htdc)2].2H2O}n (1), {[Zn2(tpeb)2(1,4-ndc)(1,4-Hndc)2].2.6H2O}n (2), and {[Zn2(tpeb)2(2,3-ndc)2].H2O}n (3) (tpeb = 1,3,5-tri-4-pyridyl-1,2-ethenylbenzene, 2,5-tdc = 2,5-thiophenedicarboxylic acid, 1,4-ndc = 1,4-naphthalenedicarboxylic acid, and 2,3-ndc = 2,3-naphthalenedicarboxylic acid) were prepared from reactions of Zn(NO3)2.6H2O with tpeb and 2,5-H2tdc, 1,4-H2ndc, or 2,3-H2ndc under solvothermal conditions. Compound 1 has a two-dimensional (2D) grid-like network formed from bridging 1D [Zn(tpeb)]n chains via 2,5-tdc dianions. 2 and 3 possess similar one-dimensional (1D) double-chain structures derived from bridging the [Zn(tpeb)]n chains via pairs of 1,4-ndc or 2,3-ndc ligands. The solid-state, visible emission by 1-3 was quenched by Cr3+, CrO42-, and Cr2O72- ions in water with detection limits by the most responsive complex 3 of 0.88 ppb for Cr3+ and 2.623 ppb for Cr2O72- (pH = 3) or 1.734 ppb for CrO42- (pH = 12). These values are well below the permissible limits set by the USEPA and European Union and the lowest so far reported for any bi/trifunctional CPs sensors. The mechanism of Cr3+ luminescence quenching involves irreversible coordination to free pyridyl sites in the CP framework, while the Cr6+ quenching involves reversible overlap of the absorption bands of the analytes with those of the excitation and/or emission bands for 3. PMID- 28339191 TI - Allosteric Activation of Cytochrome P450 3A4 via Progesterone Bioconjugation. AB - Human cytochrome P450 3A4 (CYP3A4) is responsible for the metabolism of the majority of drugs. As such, it is implicated in many adverse drug-drug and food drug interactions, and is of significant interest to the pharmaceutical industry. This enzyme is known to simultaneously bind multiple ligands and display atypical enzyme kinetics, suggestive of allostery and cooperativity. As well, evidence of a postulated peripheral allosteric binding site has provoked debate around its significance and location. We report the use of bioconjugation to study the significance of substrate binding at the proposed allosteric site and its effect on CYP3A4 activity. CYP3A4 mutants were created and covalently modified with various small molecules including progesterone. The labeled mutants displayed enhanced kinetic stability and improved activity in testosterone and 7-benzyloxy (4-trifluoromethyl)coumarin oxidation assays. Our work applies a new strategy to study cytochrome P450 allostery and supports the hypothesis that substrate binding at the postulated allosteric site of CYP3A4 may induce functional cooperativity. PMID- 28339192 TI - A Novel Exposure System Termed NAVETTA for In Vitro Laminar Flow Electrodeposition of Nanoaerosol and Evaluation of Immune Effects in Human Lung Reporter Cells. AB - A new prototype air-liquid interface (ALI) exposure system, a flatbed aerosol exposure chamber termed NAVETTA, was developed to investigate deposition of engineered nanoparticles (NPs) on cultured human lung A549 cells directly from the gas phase. This device mimics human lung cell exposure to NPs due to a low horizontal gas flow combined with cells exposed at the ALI. Electrostatic field assistance is applied to improve NP deposition efficiency. As proof-of-principle, cell viability and immune responses after short-term exposure to nanocopper oxide (CuO)-aerosol were determined. We found that, due to the laminar aerosol flow and a specific orientation of inverted transwells, much higher deposition rates were obtained compared to the normal ALI setup. Cellular responses were monitored with postexposure incubation in submerged conditions, revealing CuO dissolution in a concentration-dependent manner. Cytotoxicity was the result of ionic and nonionic Cu fractions. Using the optimized inverted ALI/postincubation procedure, pro inflammatory immune responses, in terms of interleukin (IL)-8 promoter and nuclear factor kappa B (NFkappaB) activity, were observed within short time, i.e. One hour exposure to ALI-deposited CuO-NPs and 2.5 h postincubation. NAVETTA is a novel option for mimicking human lung cell exposure to NPs, complementing existing ALI systems. PMID- 28339193 TI - 3D Printing Techniques in Environmental Science and Engineering Will Bring New Innovation. PMID- 28339194 TI - Systematic Evaluation of Chronic Metal-Mixture Toxicity to Three Species and Implications for Risk Assessment. AB - Metal contamination generally occurs as mixtures. However, it is yet unresolved how to address metal mixtures in risk assessment. Therefore, using consistent methodologies, we have set up experiments to identify which mixture model applies best at low-level effects, i.e., the independent action (IA) or concentration addition (CA) reference model. The toxicity of metal mixtures (Ni, Zn, Cu, Cd, and Pb) to Daphnia magna, Ceriodaphnia dubia, and Hordeum vulgare was investigated in different waters or soils, totaling 30 different experiments. Some mixtures of different metals, each individually causing <10% inhibition, yielded much larger inhibition (up to 66%) when dosed in combination. In general, IA was most accurate in predicting mixture toxicity, while CA was the most conservative. At low-effect levels important in risk assessments, CA overestimated mixture toxicity to daphnids and H. vulgare, on average, with a factor 1.4 to 3.6. Observed mixture interactions could be related to bioavailability or by competition interactions, either for binding sites of dissolved organic carbon or for biotic ligand sites. Our study suggests that the current metal-by-metal approach in risk evaluations may not be conservative enough for metal mixtures. PMID- 28339195 TI - Electronic Configuration and Ligand Nature of Five-Coordinate Iron Porphyrin Carbene Complexes: An Experimental Study. AB - The five-coordinate iron porphyrin carbene complexes [Fe(TPP) (CCl2)] (TPP = tetraphenylporphyrin), [Fe(TTP) (CCl2)] (TTP = tetratolylporphyrin) and [Fe(TFPP) (CPh2)] (TFPP = tetra(pentafluorophenyl)porphyrin), utilizing two types of carbene ligands (CCl2 and CPh2), have been investigated by single crystal X-ray, XANES (X-ray absorption near edge spectroscopy), Mossbauer, NMR and UV-vis spectroscopies. The XANES suggested the iron(II) oxidation state of the complexes. The multitemperature and high magnetic field Mossbauer experiments, which show very large quadrupole splittings (QS, DeltaEQ), determined the S = 0 electronic configuration. More importantly, combined structural and Mossbauer studies, especially the comparison with the low spin iron(II) porphyrin complexes with strong diatomic ligands (CS, CO and CN-) revealed the covalent bond nature of the carbene ligands. A correlation between the iron isomer shifts (IS, delta) and the axial bond distances is established for the first time for these donor carbon ligands (:C-R). PMID- 28339197 TI - Correction to Opportunistic Sampling of Roadkill as an Entry Point to Accessing Natural Products Assembled by Bacteria Associated with Non-Anthropoidal Mammalian Microbiomes. PMID- 28339196 TI - Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression. AB - The bromodomain and extra-terminal (BET) family proteins, consisting of BRD2, BRD3, BRD4, and testis-specific BRDT members, are epigenetic "readers" and play a key role in the regulation of gene transcription. BET proteins are considered to be attractive therapeutic targets for cancer and other human diseases. Recently, heterobifunctional small-molecule BET degraders have been designed based upon the proteolysis targeting chimera (PROTAC) concept to induce BET protein degradation. Herein, we present our design, synthesis, and evaluation of a new class of PROTAC BET degraders. One of the most promising compounds, 23, effectively degrades BRD4 protein at concentrations as low as 30 pM in the RS4;11 leukemia cell line, achieves an IC50 value of 51 pM in inhibition of RS4;11 cell growth and induces rapid tumor regression in vivo against RS4;11 xenograft tumors. These data establish that compound 23 (BETd-260/ZBC260) is a highly potent and efficacious BET degrader. PMID- 28339200 TI - Accurate Electron Affinities and Orbital Energies of Anions from a Nonempirically Tuned Range-Separated Density Functional Theory Approach. AB - The treatment of atomic anions with Kohn-Sham density functional theory (DFT) has long been controversial because the highest occupied molecular orbital (HOMO) energy, EHOMO, is often calculated to be positive with most approximate density functionals. We assess the accuracy of orbital energies and electron affinities for all three rows of elements in the periodic table (H-Ar) using a variety of theoretical approaches and customized basis sets. Among all of the theoretical methods studied here, we find that a nonempirically tuned range-separated approach (constructed to satisfy DFT-Koopmans' theorem for the anionic electron system) provides the best accuracy for a variety of basis sets, even for small basis sets where most functionals typically fail. Previous approaches to solve this conundrum of positive EHOMO values have utilized non-self-consistent methods; however, electronic properties, such as electronic couplings/gradients (which require a self-consistent potential and energy), become ill-defined with these approaches. In contrast, the nonempirically tuned range-separated procedure used here yields well-defined electronic couplings/gradients and correct EHOMO values because both the potential and resulting electronic energy are computed self-consistently. Orbital energies and electron affinities are further analyzed in the context of the electronic energy as a function of electronic number (including fractional numbers of electrons) to provide a stringent assessment of self-interaction errors for these complex anion systems. PMID- 28339198 TI - Discovery of 4-((3'R,4'S,5'R)-6"-Chloro-4'-(3-chloro-2-fluorophenyl)-1'-ethyl-2" oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indoline]-5' carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development. AB - We previously reported the design of spirooxindoles with two identical substituents at the carbon-2 of the pyrrolidine core as potent MDM2 inhibitors. In this paper we describe an extensive structure-activity relationship study of this class of MDM2 inhibitors, which led to the discovery of 60 (AA-115/APG-115). Compound 60 has a very high affinity to MDM2 (Ki < 1 nM), potent cellular activity, and an excellent oral pharmacokinetic profile. Compound 60 is capable of achieving complete and long-lasting tumor regression in vivo and is currently in phase I clinical trials for cancer treatment. PMID- 28339199 TI - Structure-Based Discovery of New Antagonist and Biased Agonist Chemotypes for the Kappa Opioid Receptor. AB - The ongoing epidemics of opioid overdose raises an urgent need for effective antiaddiction therapies and addiction-free painkillers. The kappa-opioid receptor (KOR) has emerged as a promising target for both indications, raising demand for new chemotypes of KOR antagonists as well as G-protein-biased agonists. We employed the crystal structure of the KOR-JDTic complex and ligand-optimized structural templates to perform virtual screening of available compound libraries for new KOR ligands. The prospective virtual screening campaign yielded a high 32% hit rate, identifying novel fragment-like and lead-like chemotypes of KOR ligands. A round of optimization resulted in 11 new submicromolar KOR binders (best Ki = 90 nM). Functional assessment confirmed at least two compounds as potent KOR antagonists, while compound 81 was identified as a potent Gi biased agonist for KOR with minimal beta-arrestin recruitment. These results support virtual screening as an effective tool for discovery of new lead chemotypes with therapeutically relevant functional profiles. PMID- 28339201 TI - High-Throughput in Silico Structure Validation and Revision of Halogenated Natural Products Is Enabled by Parametric Corrections to DFT-Computed 13C NMR Chemical Shifts and Spin-Spin Coupling Constants. AB - Halogenated natural products constitute diverse and promising feedstock for molecular pharmaceuticals. However, their solution-structure elucidation by NMR presents several challenges, including the lack of fast methods to compute 13C chemical shifts for carbons bearing heavy atoms. We show that parametric corrections to DFT-computed chemical shifts in conjunction with rff-computed spin spin coupling constants allow for fast and reliable screening of a large number of reported halogenated natural products, resulting in expedient structure validation or revision. In this paper, we examine more than 100 structures of halogenated terpenoids and other natural products with the new parametric approach and demonstrate that the accuracy of the combined method is sufficient to identify misassignments and suggest revisions in most cases (16 structures are revised). As the 1D 1H and 13C NMR data are ubiquitous and most routinely used in solution structure elucidation, this fast and efficient two-criterion method (nuclear spin-spin coupling and 13C chemical shifts) which we term DU8+ is recommended as the first essential step in structure assignment and validation. PMID- 28339203 TI - Correction to Nucleoside, Nucleotide, and Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B RNA-Dependent RNA-Polymerase. PMID- 28339202 TI - Novel Acylated Flavonol Tetraglycoside with Inhibitory Effect on Lipid Accumulation in 3T3-L1 Cells from Lu'an GuaPian Tea and Quantification of Flavonoid Glycosides in Six Major Processing Types of Tea. AB - A novel acylated flavonol tetraglycoside, kaempferol 3-O-[(E)-p-coumaroyl-(1 >2)][alpha-l-arabinopyranosyl-(1->3)][beta-d-glucopyranosyl (1->3)-alpha-l rhamnopyranosyl(1->6)]-beta-d-glucopyranoside (camellikaempferoside C, 1), together with 2 flavonols and 18 flavone and flavonol glycosides (FGs) (2-21) was isolated from the green tea Lu'an GuaPian (Camellia sinensis L.O. Kuntze). Their structures were identified by spectroscopic and chemical methods. Four acylated FGs (1, 7, 8, 9) were found to inhibit the proliferation and differentiation of 3T3-L1 preadipocytes at concentrations of 25, 50, and 100 MUM (P < 0.05). Furthermore, we established a rapid UPLC method to quantify nine FGs in six major processing types of tea. The results showed that dark tea had the highest amount of 20 (0.70 +/- 0.017 mg/g) and black tea had the highest amount of 8 (0.09 +/- 0.012 mg/g), whereas the amounts of 10 and 16 basically decreased with the increasing degree of fermentation and could contribute to the discrimination of different processing types of tea. PMID- 28339205 TI - Ultrafast Non-Forster Intramolecular Donor-Acceptor Excitation Energy Transfer. AB - Ultrafast intramolecular electronic energy transfer in a conjugated donor acceptor system is simulated using nonadiabatic excited-state molecular dynamics. After initial site-selective photoexcitation of the donor, transition density localization is monitored throughout the S2 -> S1 internal conversion process, revealing an efficient unidirectional donor -> acceptor energy-transfer process. Detailed analysis of the excited-state trajectories uncovers several salient features of the energy-transfer dynamics. While a weak temperature dependence is observed during the entire electronic energy relaxation, an ultrafast initially temperature-independent process allows the molecular system to approach the S2-S1 potential energy crossing seam within the first ten femtoseconds. Efficient energy transfer occurs in the absence of spectral overlap between the donor and acceptor units and is assisted by a transient delocalization phenomenon of the excited-state wave function acquiring Frenkel-exciton character at the moment of quantum transition. PMID- 28339204 TI - Liquid Marble Coalescence and Triggered Microreaction Driven by Acoustic Levitation. AB - Liquid marbles show promising potential for application in the microreactor field. Control of the coalescence between two or among multiple liquid marbles is critical; however, the successful merging of two isolated marbles is difficult because of their mechanically robust particle shells. In this work, the coalescence of multiple liquid marbles was achieved via acoustic levitation. The dynamic behaviors of the liquid marbles were monitored by a high-speed camera. Driven by the sound field, the liquid marbles moved toward each other, collided, and eventually coalesced into a larger single marble. The underlying mechanisms of this process were probed via sound field simulation and acoustic radiation pressure calculation. The results indicated that the pressure gradient on the liquid marble surface favors the formation of a liquid bridge between the liquid marbles, resulting in their coalescence. A preliminary indicator reaction was induced by the coalescence of dual liquid marbles, which suggests that expected chemical reactions can be successfully triggered with multiple reagents contained in isolated liquid marbles via acoustic levitation. PMID- 28339207 TI - Innovation's Mean Free Path. PMID- 28339206 TI - Utilizing Electron Spin Echo Envelope Modulation To Distinguish between the Local Secondary Structures of an alpha-Helix and an Amphipathic 310-Helical Peptide. AB - Electron spin echo envelope modulation (ESEEM) spectroscopy was used to distinguish between the local secondary structures of an alpha-helix and a 310 helix. Previously, we have shown that ESEEM spectroscopy in combination with site directed spin labeling (SDSL) and 2H-labeled amino acids (i) can probe the local secondary structure of alpha-helices, resulting in an obvious deuterium modulation pattern, where i+4 positions generally show larger 2H ESEEM peak intensities than i+3 positions. Here, we have hypothesized that due to the unique turn periodicities of an alpha-helix (3.6 residues per turn with a pitch of 5.4 A) and a 310-helix (3.1 residues per turn with a pitch of 5.8-6.0 A), the opposite deuterium modulation pattern would be observed for a 310-helix. In this study, 2H-labeled d10-leucine (Leu) was substituted at a specific Leu residue (i) and a nitroxide spin label was positioned 2, 3, and 4 residues away (denoted i+2 to i+4) on an amphipathic model peptide, LRL8. When LRL8 is solubilized in trifluoroethanol (TFE), the peptide adopts an alpha-helical structure, and alternatively, forms a 310-helical secondary structure when incorporated into liposomes. Larger 2H ESEEM peaks in the FT frequency domain data were observed for the i+4 samples when compared to the i+3 samples for the alpha-helix whereas the opposite pattern was revealed for the 310-helix. These unique patterns provide pertinent local secondary structural information to distinguish between the alpha-helical and 310-helical structural motifs for the first time using this ESEEM spectroscopic approach with short data acquisition times (~30 min) and small sample concentrations (~100 MUM) as well as providing more site-specific secondary structural information compared to other common biophysical approaches, such as CD. PMID- 28339208 TI - Doubly Resonant Photonic Antenna for Single Infrared Quantum Dot Imaging at Telecommunication Wavelengths. AB - Colloidal quantum dots (CQDs) have drawn strong interest in the past for their high prospects in scientific, medical, and industrial applications. However, the full characterization of these quantum emitters is currently restricted to the visible wavelengths, and it remains a key challenge to optically probe single CQDs operating in the infrared spectral domain, which is targeted by a growing number of applications. Here, we report the first experimental detection and imaging at room temperature of single infrared CQDs operating at telecommunication wavelengths. Imaging was done with a doubly resonant bowtie nanoaperture antenna (BNA) written at the end of a fiber nanoprobe, whose resonances spectrally fit the CQD absorption and emission wavelengths. Direct near-field characterization of PbS CQDs reveal individual nanocrystals with a spatial resolution of 75 nm (lambda/20) together with their intrinsic 2D dipolar free-space emission properties and exciton dynamics (blinking phenomenon). Because the doubly resonant BNA is strongly transmissive at both the CQD absorption and the emission wavelengths, we are able to perform all-fiber nanoimaging with a standard 20% efficiency InGaAs avalanche photodiode (APD). The detection efficiency is predicted to be 3000 fold larger than with a conventional circular aperture tip of the same transmission area. Double resonance BNA fiber probes thus offer the possibility of exploring extreme light-matter interaction in low band gap CQDs with current plug-and-play detection techniques, opening up new avenues in the fields of infrared light-emitting devices, photodetectors, telecommunications, bioimaging, and quantum information technology. PMID- 28339209 TI - Nitrogen-Terminated Diamond (111) Surface for Room-Temperature Quantum Sensing and Simulation. AB - The nitrogen-vacancy (NV) center in diamond has shown great promise of nanoscale sensing applications, however, near-surface NV suffer from relatively short spin coherence time that limits its sensitivity. This is presumably caused by improper surface termination. Using first-principles calculations, we propose that nitrogen-terminated (111) diamond provides electrical inactivity and surface spin noise free properties. We anticipate that the nitrogen-terminated (111) surface can be fabricated by nitrogen plasma treatment. Our findings pave the way toward an improved NV-based quantum sensing and quantum simulation operating at room temperature. PMID- 28339210 TI - Transition Metal, Azide, and Oxidant-Free Homo- and Heterocoupling of Ambiphilic Tosylhydrazones to the Regioselective Triazoles and Pyrazoles. AB - With N-tosylhydrazone as an ambiphilic reagent, an unprecedented cyclization reaction of two identical or different tosylhydrazones has been developed to access various 4,5-disubstituted-2H-triazoles under transition metal, azide, and oxidant-free conditions. A mechanistic rationalization study led to the identification of several electronically diverse unsaturated systems for regioselective synthesis of 1- and 2-substituted 1,2,3-triazoles and pyrazoles. PMID- 28339211 TI - Platinum-Catalyzed Double Acylation of 2-(Aryloxy)pyridines via Direct C-H Activation. AB - A unique, platinum-catalyzed, direct C-H acylation of 2-(aryloxy)pyridines with acyl chlorides is discovered. The reaction requires neither an oxidant nor other additives. When both ortho positions of the aryl group are accessible, the double acylation occurs readily to produce the diacylated products. Aliphatic, aromatic, and alpha,beta-unsaturated acyl groups can all be introduced. The acylation reaction may proceed through an analogous aromatic electrophilic substitution triggered by the nucleophilic attack of the platinum at the acyl chloride. PMID- 28339213 TI - Quaternary Carbon Center Forming Formal [3 + 3] Cycloaddition Reaction via Bifunctional Catalysis: Asymmetric Synthesis of Spirocyclohexene Pyrazolones. AB - A variety of spirocyclohexene pyrazolones were synthesized in good yields with excellent stereoselectivities through an asymmetric, intermolecular, quaternary carbon center forming [3 + 3] cycloaddition reaction catalyzed by a bifunctional catalyst. The vinylogous pyrazolones used as binucleophilic synthons in this reaction exhibited superior ability for constructing pyrazolone related spirocyclic scaffolds. PMID- 28339212 TI - Nickel-Catalyzed Reduction of Secondary and Tertiary Amides. AB - The nickel-catalyzed reduction of secondary and tertiary amides to give amine products is reported. The transformation is tolerant of extensive variation with respect to the amide substrate, proceeds in the presence of esters and epimerizable stereocenters, and can be used to achieve the reduction of lactams. Moreover, this methodology provides a simple tactic for accessing medicinally relevant alpha-deuterated amines. PMID- 28339214 TI - Muscle Protein Signaling in C2C12 Cells Is Stimulated to Similar Degrees by Diverse Commercial Food Protein Sources and Experimental Soy Protein Hydrolysates. AB - Dietary protein stimulates muscle protein synthesis and is essential for muscle health. We developed a screening assay using C2C12 mouse muscle cells to assess the relative abilities of diverse commercial protein sources and experimental soy protein hydrolysates (ESH), after simulated gut digestion (SGD), to activate the mechanistic target of rapamycin complex I (mTORC1) muscle protein synthesis signaling pathway (p70S6K(Thr389) phosphorylation). Activation of mTORC1 was expressed as a percentage of a maximal insulin response. The bioactivities of proteins grouped by source including fish (81.3 +/- 10.6%), soy (66.2 +/- 4.7%), dairy (61.8 +/- 4.3%), beef (53.7 +/- 8.6%), egg (52.3 +/- 10.6%), soy whey (43.4 +/- 8.6%), and pea (31.4 +/- 10.6%) were not significantly different from each other. Bioactivity for ESH ranged from 28.0 +/- 7.5 to 98.2 +/- 6.6%. The results indicate that both the protein source and processing conditions are key determinants for mTORC1 activation. Regression analyses demonstrated that neither leucine nor total branched-chain amino acid content of proteins is the sole predictor of mTORC1 activity and that additional factors are necessary. PMID- 28339216 TI - Embarking on a Chemical Space Odyssey. AB - The chemical space explored in drug discovery programs is restricted by a narrow reaction toolkit and the frequent failure of even these reactions with polar and functionalized substrates. Recently, high-throughput reaction optimization has been integrated into discovery workflows, thereby increasing the value of specific reaction classes in the toolkit. It is likely that high-throughput experimentation will enable expansion of the synthetic chemistry that is widely exploited in discovery, thereby increasing innovation in medicinal chemistry. PMID- 28339217 TI - Tandem Spirocyclopropanation/Rearrangement Reaction of Vinyl p-Quinone Methides with Sulfonium Salts: Synthesis of Spirocyclopentenyl p-Dienones. AB - A novel base-mediated tandem spirocyclopropanation/rearrangement reaction of vinyl p-quinone methides (p-VQMs) with sulfonium salts is described. The unprecedented reactivity of p-VQMs was explored for the first time in the spiroannulation cascade, providing a stereoselective approach to the construction of synthetically interesting, densely functionalized spirocyclopentenyl p dienones. PMID- 28339215 TI - Discovery and Pre-Clinical Characterization of Third-Generation 4-H Heteroaryldihydropyrimidine (HAP) Analogues as Hepatitis B Virus (HBV) Capsid Inhibitors. AB - Described herein are the discovery and structure-activity relationship (SAR) studies of the third-generation 4-H heteroaryldihydropyrimidines (4-H HAPs) featuring the introduction of a C6 carboxyl group as novel HBV capsid inhibitors. This new series of 4-H HAPs showed improved anti-HBV activity and better drug like properties compared to the first- and second-generation 4-H HAPs. X-ray crystallographic study of analogue 12 (HAP_R01) with Cp149 Y132A mutant hexamer clearly elucidated the role of C6 carboxyl group played for the increased binding affinity, which formed strong hydrogen bonding interactions with capsid protein and coordinated waters. The representative analogue 10 (HAP_R10) was extensively characterized in vitro (ADMET) and in vivo (mouse PK and PD) and subsequently selected for further development as oral anti-HBV infection agent. PMID- 28339218 TI - Quantifying Fusion Born Ion Populations in Magnetically Confined Plasmas using Ion Cyclotron Emission. AB - Ion cyclotron emission (ICE) offers a unique promise as a diagnostic of the fusion born alpha-particle population in magnetically confined plasmas. Pioneering observations from JET and TFTR found that ICE intensity P_{ICE} scales approximately linearly with the measured neutron flux from fusion reactions, and with the inferred concentration, n_{alpha}/n_{i}, of fusion born alpha particles confined within the plasma. We present fully nonlinear self-consistent kinetic simulations that reproduce this scaling for the first time. This resolves a long standing question in the physics of fusion alpha-particle confinement and stability in magnetic confinement fusion plasmas. It confirms the magnetoacoustic cyclotron instability as the likely emission mechanism and greatly strengthens the basis for diagnostic exploitation of ICE in future burning plasmas. PMID- 28339219 TI - Crystalline Electric-Field Randomness in the Triangular Lattice Spin-Liquid YbMgGaO_{4}. AB - We apply moderate-high-energy inelastic neutron scattering (INS) measurements to investigate Yb^{3+} crystalline electric field (CEF) levels in the triangular spin-liquid candidate YbMgGaO_{4}. Three CEF excitations from the ground-state Kramers doublet are centered at the energies homega=39, 61, and 97 meV in agreement with the effective spin-1/2 g factors and experimental heat capacity, but reveal sizable broadening. We argue that this broadening originates from the site mixing between Mg^{2+} and Ga^{3+} giving rise to a distribution of Yb-O distances and orientations and, thus, of CEF parameters that account for the peculiar energy profile of the CEF excitations. The CEF randomness gives rise to a distribution of the effective spin-1/2 g factors and explains the unprecedented broadening of low-energy magnetic excitations in the fully polarized ferromagnetic phase of YbMgGaO_{4}, although a distribution of magnetic couplings due to the Mg/Ga disorder may be important as well. PMID- 28339220 TI - Experimental Bayesian Quantum Phase Estimation on a Silicon Photonic Chip. AB - Quantum phase estimation is a fundamental subroutine in many quantum algorithms, including Shor's factorization algorithm and quantum simulation. However, so far results have cast doubt on its practicability for near-term, nonfault tolerant, quantum devices. Here we report experimental results demonstrating that this intuition need not be true. We implement a recently proposed adaptive Bayesian approach to quantum phase estimation and use it to simulate molecular energies on a silicon quantum photonic device. The approach is verified to be well suited for prethreshold quantum processors by investigating its superior robustness to noise and decoherence compared to the iterative phase estimation algorithm. This shows a promising route to unlock the power of quantum phase estimation much sooner than previously believed. PMID- 28339221 TI - Open Systems with Error Bounds: Spin-Boson Model with Spectral Density Variations. AB - In the study of open quantum systems, one of the most common ways to describe environmental effects on the reduced dynamics is through the spectral density. However, in many models this object cannot be computed from first principles and needs to be inferred on phenomenological grounds or fitted to experimental data. Consequently, some uncertainty regarding its form and parameters is unavoidable; this in turn calls into question the accuracy of any theoretical predictions based on a given spectral density. Here, we focus on the spin-boson model as a prototypical open quantum system, find two error bounds on predicted expectation values in terms of the spectral density variation considered, and state a sufficient condition for the strongest one to apply. We further demonstrate an application of our result, by bounding the error brought about by the approximations involved in the hierarchical equations of motion resolution method for spin-boson dynamics. PMID- 28339222 TI - Holographic Duals for Five-Dimensional Superconformal Quantum Field Theories. AB - We construct global solutions to type IIB supergravity with 16 residual supersymmetries whose space-time is AdS_{6}*S^{2} warped over a Riemann surface. Families of solutions are labeled by an arbitrary number L>=3 of asymptotic regions, in each of which the supergravity fields match those of a (p,q) five brane, and may therefore be viewed as near-horizon limits of fully localized intersections of five-branes in type IIB string theory. These solutions provide compelling candidates for holographic duals to a large class of five-dimensional superconformal quantum field theories which arise as nontrivial UV fixed points of perturbatively nonrenormalizable Yang-Mills theories, thereby making them more directly accessible to quantitative analysis. PMID- 28339223 TI - Experimental Minimum-Error Quantum-State Discrimination in High Dimensions. AB - Quantum mechanics forbids perfect discrimination among nonorthogonal states through a single shot measurement. To optimize this task, many strategies were devised that later became fundamental tools for quantum information processing. Here, we address the pioneering minimum-error (ME) measurement and give the first experimental demonstration of its application for discriminating nonorthogonal states in high dimensions. Our scheme is designed to distinguish symmetric pure states encoded in the transverse spatial modes of an optical field; the optimal measurement is performed by a projection onto the Fourier transform basis of these modes. For dimensions ranging from D=2 to D=21 and nearly 14 000 states tested, the deviations of the experimental results from the theoretical values range from 0.3% to 3.6% (getting below 2% for the vast majority), thus showing the excellent performance of our scheme. This ME measurement is a building block for high-dimensional implementations of many quantum communication protocols, including probabilistic state discrimination, dense coding with nonmaximal entanglement, and cryptographic schemes. PMID- 28339224 TI - Optical Manipulation of a Magnon-Photon Hybrid System. AB - We demonstrate an all-optical method for manipulating the magnetization in a 1-mm yttrium-iron-garnet (YIG) sphere placed in a ~0.17 T uniform magnetic field. A harmonic of the frequency comb delivered by a multi-GHz infrared laser source is tuned to the Larmor frequency of the YIG sphere to drive magnetization oscillations, which in turn give rise to a radiation field used to thoroughly investigate the phenomenon. The radiation damping issue that occurs at high frequency and in the presence of highly magnetizated materials has been overcome by exploiting the magnon-photon strong coupling regime in microwave cavities. Our findings demonstrate an effective technique for ultrafast control of the magnetization vector in optomagnetic materials via polarization rotation and intensity modulation of an incident laser beam. We eventually get a second-order susceptibility value of ~10^{-7} cm^{2}/MW for single crystal YIG. PMID- 28339225 TI - Effects of Quantum Spin-1/2 Impurities on the Magnetic Properties of Zigzag Spin Chains. AB - We investigate the effect of Co^{2+} (spin-1/2) impurities on the magnetic ground state and low-lying spin excitations of the quasione-dimensional spin-1/2 antiferromagnet SrCuO_{2} by means of neutron scattering, muon spin spectroscopy, and bulk (ac and dc) magnetic susceptibilities. We found that dilute Co doping induces an Ising-like anisotropy and enhances the magnetic ordering temperature rather significantly, but preserves the gapless nature of the spin excitations. These results are in apparent contradiction with the recent studies of Ni (spin 1) doped SrCuO_{2}. Low-temperature magnetic behavior of the Co-doped zigzag chains in SrCuO_{2} reveals the presence of a weak geometrical spin frustration. PMID- 28339226 TI - Percolation via Combined Electrostatic and Chemical Doping in Complex Oxide Films. AB - Stimulated by experimental advances in electrolyte gating methods, we investigate theoretically percolation in thin films of inhomogeneous complex oxides, such as La_{1-x}Sr_{x}CoO_{3} (LSCO), induced by a combination of bulk chemical and surface electrostatic doping. Using numerical and analytical methods, we identify two mechanisms that describe how bulk dopants reduce the amount of electrostatic surface charge required to reach percolation: (i) bulk-assisted surface percolation and (ii) surface-assisted bulk percolation. We show that the critical surface charge strongly depends on the film thickness when the film is close to the chemical percolation threshold. In particular, thin films can be driven across the percolation transition by modest surface charge densities. If percolation is associated with the onset of ferromagnetism, as in LSCO, we further demonstrate that the presence of critical magnetic clusters extending from the film surface into the bulk results in considerable enhancement of the saturation magnetization, with pronounced experimental consequences. These results should significantly guide experimental work seeking to verify gate induced percolation transitions in such materials. PMID- 28339227 TI - Cosmic Tsunamis in Modified Gravity: Disruption of Screening Mechanisms from Scalar Waves. AB - Extending general relativity by adding extra degrees of freedom is a popular approach for explaining the accelerated expansion of the Universe and to build high energy completions of the theory of gravity. The presence of such new degrees of freedom is, however, tightly constrained from several observations and experiments that aim to test general relativity in a wide range of scales. The viability of a given modified theory of gravity, therefore, strongly depends on the existence of a screening mechanism that suppresses the extra degrees of freedom. We perform simulations, and find that waves propagating in the new degrees of freedom can significantly impact the efficiency of some screening mechanisms, thereby threatening the viability of these modified gravity theories. Specifically, we show that the waves produced in the symmetron model can increase the amplitude of the fifth force and the parametrized post Newtonian parameters by several orders of magnitude. PMID- 28339228 TI - Universal Work Fluctuations During Shortcuts to Adiabaticity by Counterdiabatic Driving. AB - Counterdiabatic driving (CD) exploits auxiliary control fields to tailor the nonequilibrium dynamics of a quantum system, making possible the suppression of dissipated work in finite-time thermodynamics and the engineering of optimal thermal machines with no friction. We show that while the mean work done by the auxiliary controls vanishes, CD leads to a broadening of the work distribution. We derive a fundamental inequality that relates nonequilibrium work fluctuations to the operation time and quantifies the thermodynamic cost of CD in both critical and noncritical systems. PMID- 28339229 TI - First-Principles-Based Method for Electron Localization: Application to Monolayer Hexagonal Boron Nitride. AB - We present a first-principles-based many-body typical medium dynamical cluster approximation and density function theory method for characterizing electron localization in disordered structures. This method applied to monolayer hexagonal boron nitride shows that the presence of boron vacancies could turn this wide-gap insulator into a correlated metal. Depending on the strength of the electron interactions, these calculations suggest that conduction could be obtained at a boron vacancy concentration as low as 1.0%. We also explore the distribution of the local density of states, a fingerprint of spatial variations, which allows localized and delocalized states to be distinguished. The presented method enables the study of disorder-driven insulator-metal transitions not only in h-BN but also in other physical materials. PMID- 28339230 TI - Properties of a Rare-Earth-Ion-Doped Waveguide at Sub-Kelvin Temperatures for Quantum Signal Processing. AB - We characterize the 795 nm ^{3}H_{6} to ^{3}H_{4} transition of Tm^{3+} in a Ti^{4+}:LiNbO_{3} waveguide at temperatures as low as 800 mK. Coherence and hyperfine population lifetimes-up to 117 MUs and 2.5 h, respectively-exceed those at 3 K at least tenfold, and are equivalent to those observed in a bulk Tm^{3+}:LiNbO_{3} crystal under similar conditions. We also find a transition dipole moment that is equivalent to that of the bulk. Finally, we prepare a 0.5 GHz-bandwidth atomic frequency comb of finesse >2 on a vanishing background. These results demonstrate the suitability of rare-earth-ion-doped waveguides created using industry-standard Ti indiffusion in LiNbO_{3} for on-chip quantum applications. PMID- 28339231 TI - Chiral Dark Sector. AB - We present a simple and natural dark sector model in which dark matter particles arise as composite states of hidden strong dynamics and their stability is ensured by accidental symmetries. The model has only a few free parameters. In particular, the gauge symmetry of the model forbids the masses of dark quarks, and the confinement scale of the dynamics provides the unique mass scale of the model. The gauge group contains an Abelian symmetry U(1)_{D}, which couples the dark and standard model sectors through kinetic mixing. This model, despite its simple structure, has rich and distinctive phenomenology. In the case where the dark pion becomes massive due to U(1)_{D} quantum corrections, direct and indirect detection experiments can probe thermal relic dark matter which is generically a mixture of the dark pion and the dark baryon, and the Large Hadron Collider can discover the U(1)_{D} gauge boson. Alternatively, if the dark pion stays light due to a specific U(1)_{D} charge assignment of the dark quarks, then the dark pion constitutes dark radiation. The signal of this radiation is highly correlated with that of dark baryons in dark matter direct detection. PMID- 28339232 TI - Noiseless Quantum Measurement and Squeezing of Microwave Fields Utilizing Mechanical Vibrations. AB - A process which strongly amplifies both quadrature amplitudes of an oscillatory signal necessarily adds noise. Alternatively, if the information in one quadrature is lost in phase-sensitive amplification, it is possible to completely reconstruct the other quadrature. Here we demonstrate such a nearly perfect phase sensitive measurement using a cavity optomechanical scheme, characterized by an extremely small noise less than 0.2 quanta. The device also strongly squeezes microwave radiation by 8 dB below vacuum. A source of bright squeezed microwaves opens up applications in manipulations of quantum systems, and noiseless amplification can be used even at modest cryogenic temperatures. PMID- 28339233 TI - Glue Spin and Helicity in the Proton from Lattice QCD. AB - We report the first lattice QCD calculation of the glue spin in the nucleon. The lattice calculation is carried out with valence overlap fermions on 2+1 flavor domain-wall fermion gauge configurations on four lattice spacings and four volumes including an ensemble with physical values for the quark masses. The glue spin S_{G} in the Coulomb gauge in the modified minimal subtraction (MS[over -]) scheme is obtained with one-loop perturbative matching. We find the results fairly insensitive to lattice spacing and quark masses. We also find that the proton momentum dependence of S_{G} in the range 0<=|p[over ->]|<1.5 GeV is very mild, and we determine it in the large-momentum limit to be S_{G}=0.251(47)(16) at the physical pion mass in the MS[over -] scheme at MU^{2}=10 GeV^{2}. If the matching procedure in large-momentum effective theory is neglected, S_{G} is equal to the glue helicity measured in high-energy scattering experiments. PMID- 28339234 TI - Influence of Domain Walls in the Incommensurate Charge Density Wave State of Cu Intercalated 1T-TiSe_{2}. AB - We report a low-temperature scanning tunneling microscopy study of the charge density wave (CDW) order in 1T-TiSe_{2} and Cu_{0.08}TiSe_{2}. In pristine 1T TiSe_{2} we observe a long-range coherent commensurate CDW (CCDW) order. In contrast, Cu_{0.08}TiSe_{2} displays an incommensurate CDW (ICDW) phase with localized CCDW domains separated by domain walls. Density of states measurements indicate that the domain walls host an extra population of fermions near the Fermi level which may play a role in the emergence of superconductivity in this system. Fourier transform scanning tunneling spectroscopy studies suggest that the dominant mechanism for CDW formation in the ICDW phase may be electron-phonon coupling. PMID- 28339235 TI - Cross Interaction Drives Stratification in Drying Film of Binary Colloidal Mixtures. AB - When a liquid film of a colloidal solution consisting of particles of different sizes is dried on a substrate, the colloids often stratify, where smaller colloids are laid upon larger colloids. This phenomenon is counterintuitive because larger colloids which have a smaller diffusion constant, are expected to remain near the surface during the drying process, leaving a layer of larger colloids on top of smaller colloids. Here we show that the phenomenon is caused by the interaction between the colloids, and can be explained by a diffusion model accounting for the interaction between the colloids. By studying the evolution equations both numerically and analytically, we derive the condition at which the stratified structures are obtained. PMID- 28339236 TI - Effect of Biaxial Strain on the Phase Transitions of Ca(Fe_{1 x}Co_{x})_{2}As_{2}. AB - We study the effect of applied strain as a physical control parameter for the phase transitions of Ca(Fe_{1-x}Co_{x})_{2}As_{2} using resistivity, magnetization, x-ray diffraction, and ^{57}Fe Mossbauer spectroscopy. Biaxial strain, namely, compression of the basal plane of the tetragonal unit cell, is created through firm bonding of samples to a rigid substrate via differential thermal expansion. This strain is shown to induce a magnetostructural phase transition in originally paramagnetic samples, and superconductivity in previously nonsuperconducting ones. The magnetostructural transition is gradual as a consequence of using strain instead of pressure or stress as a tuning parameter. PMID- 28339237 TI - Current Noise from a Magnetic Moment in a Helical Edge. AB - We calculate the two-terminal current noise generated by a magnetic moment coupled to a helical edge of a two-dimensional topological insulator. When the system is symmetric with respect to in-plane spin rotation, the noise is dominated by the Nyquist component even in the presence of a voltage bias V. The corresponding noise spectrum S(V,omega) is determined by a modified fluctuation dissipation theorem with the differential conductance G(V,omega) in place of the linear one. The differential noise ?S/?V, commonly measured in experiments, is strongly dependent on frequency on a small scale tau_{K}^{-1}?T set by the Korringa relaxation rate of the local moment. This is in stark contrast to the case of conventional mesoscopic conductors where ?S/?V is frequency independent and defined by the shot noise. In a helical edge, a violation of the spin rotation symmetry leads to the shot noise, which becomes important only at a high bias. Uncharacteristically for a fermion system, this noise in the backscattered current is super-Poissonian. PMID- 28339238 TI - Publisher's Note: Search for Structure in the B_{s}^{0}pi^{+/-} Invariant Mass Spectrum [Phys. Rev. Lett. 117, 152003 (2016)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.117.152003. PMID- 28339239 TI - Photon Statistics of Propagating Thermal Microwaves. AB - In experiments with superconducting quantum circuits, characterizing the photon statistics of propagating microwave fields is a fundamental task. We quantify the n^{2}+n photon number variance of thermal microwave photons emitted from a blackbody radiator for mean photon numbers, 0.05?n?1.5. We probe the fields using either correlation measurements or a transmon qubit coupled to a microwave resonator. Our experiments provide a precise quantitative characterization of weak microwave states and information on the noise emitted by a Josephson parametric amplifier. PMID- 28339240 TI - Single Photon Thermal Ionization of C_{60}. AB - We report on experiments which show that C_{60} can ionize in an indirect, quasithermal boiloff process after absorption of a single photon. The process involves a large number of incoherently excited valence electrons and yields electron spectra with a Boltzmann distribution with temperatures exceeding 10^{4} K. It is expected to be present for other molecules and clusters with a comparatively large number of valence electrons. The astrophysical consequences are briefly discussed. PMID- 28339241 TI - Disordered Route to the Coulomb Quantum Spin Liquid: Random Transverse Fields on Spin Ice in Pr_{2}Zr_{2}O_{7}. AB - Inelastic neutron scattering reveals a broad continuum of excitations in Pr_{2}Zr_{2}O_{7}, the temperature and magnetic field dependence of which indicate a continuous distribution of quenched transverse fields (Delta) acting on the non-Kramers Pr^{3+} crystal field ground state doublets. Spin-ice correlations are apparent within 0.2 meV of the Zeeman energy. A random phase approximation provides an excellent account of the data with a transverse field distribution rho(Delta)?(Delta^{2}+Gamma^{2})^{-1}, where Gamma=0.27(1) meV. Established during high temperature synthesis due to an underlying structural instability, it appears disorder in Pr_{2}Zr_{2}O_{7} actually induces a quantum spin liquid. PMID- 28339242 TI - Comment on "Matter-Wave Interferometry of a Levitated Thermal Nano-Oscillator Induced and Probed by a Spin". PMID- 28339243 TI - Bose et al. Reply. PMID- 28339244 TI - Terahertz-Field-Induced Large Macroscopic Polarization and Domain-Wall Dynamics in an Organic Molecular Dielectric. AB - A rapid polarization control in paraelectric materials is important for an ultrafast optical switching useful in the future optical communication. In this study, we applied terahertz-pump second-harmonic-generation-probe and optical reflectivity-probe spectroscopies to the paraelectric neutral phase of an organic molecular dielectric, tetrathiafulvalene-p-chloranil and revealed that a terahertz pulse with the electric-field amplitude of ~400 kV/cm produces in the subpicosecond time scale a large macroscopic polarization whose magnitude reaches ~20% of that in the ferroelectric ionic phase. Such a large polarization generation is attributed to the intermolecular charge transfers and breathing motions of domain walls between microscopic neutral and ionic domains induced by the terahertz electric field. PMID- 28339245 TI - Precision Control of the Electron Longitudinal Bunch Shape Using an Emittance Exchange Beam Line. AB - We report on the experimental generation of relativistic electron bunches with a tunable longitudinal bunch shape. A longitudinal bunch-shaping (LBS) beam line, consisting of a transverse mask followed by a transverse-to-longitudinal emittance exchange (EEX) beam line, is used to tailor the longitudinal bunch shape (or current profile) of the electron bunch. The mask shapes the bunch's horizontal profile, and the EEX beam line converts it to a corresponding longitudinal profile. The Argonne wakefield accelerator rf photoinjector delivers electron bunches into a LBS beam line to generate a variety of longitudinal bunch shapes. The quality of the longitudinal bunch shape is limited by various perturbations in the exchange process. We develop a simple method, based on the incident slope of the bunch, to significantly suppress the perturbations. PMID- 28339246 TI - Impact of Atomic-Scale Contact Geometry on Andreev Reflection. AB - Charge transport has been examined in junctions comprising the normal-metal tip of a low-temperature scanning tunneling microscope, the surface of a conventional superconductor, and adsorbed C_{60} molecules. The Bardeen-Cooper-Schrieffer energy gap gradually evolves into a zero-bias peak with decreasing electrode separation. The peak is assigned to the spectroscopic signature of Andreev reflection. The conductance due to Andreev reflection is determined by the atomic termination of the tip apex and the molecular adsorption orientation. Transport calculations unveil the finite temperature and the strong molecule-electrode hybridization as the origin to the surprisingly good agreement between spectroscopic data and the Blonder-Tinkham-Klapwijk model that was conceived for macroscopic point contacts. PMID- 28339247 TI - Thermodynamic and Kinetic Fragility of Freon 113: The Most Fragile Plastic Crystal. AB - We present a dynamic and thermodynamic study of the orientational glass former Freon 113 (1,1,2-trichloro-1,2,2-trifluoroethane, CCl_{2}F-CClF_{2}) in order to analyze its kinetic and thermodynamic fragilities. Freon 113 displays internal molecular degrees of freedom that promote a complex energy landscape. Experimental specific heat and its microscopic origin, the vibrational density of states from inelastic neutron scattering, together with the orientational dynamics obtained by means of dielectric spectroscopy have revealed the highest fragility value, both thermodynamic and kinetic, found for this orientational glass former. The excess in both Debye-reduced specific heat and density of states (boson peak) evidences the existence of glassy low-energy excitations. We demonstrate that early proposed correlations between the boson peak and the Debye specific heat value are elusive as revealed by the clear counterexample of the studied case. PMID- 28339248 TI - Anderson Transition of Cold Atoms with Synthetic Spin-Orbit Coupling in Two Dimensional Speckle Potentials. AB - We investigate the metal-insulator transition occurring in two-dimensional (2D) systems of noninteracting atoms in the presence of artificial spin-orbit interactions and a spatially correlated disorder generated by laser speckles. Based on a high order discretization scheme, we calculate the precise position of the mobility edge and verify that the transition belongs to the symplectic universality class. We show that the mobility edge depends strongly on the mixing angle between Rashba and Dresselhaus spin-orbit couplings. For equal couplings a non-power-law divergence is found, signaling the crossing to the orthogonal class, where such a 2D transition is forbidden. PMID- 28339249 TI - Electric Control of Dirac Quasiparticles by Spin-Orbit Torque in an Antiferromagnet. AB - Spin orbitronics and Dirac quasiparticles are two fields of condensed matter physics initiated independently about a decade ago. Here we predict that Dirac quasiparticles can be controlled by the spin-orbit torque reorientation of the Neel vector in an antiferromagnet. Using CuMnAs as an example, we formulate symmetry criteria allowing for the coexistence of topological Dirac quasiparticles and Neel spin-orbit torques. We identify the nonsymmorphic crystal symmetry protection of Dirac band crossings whose on and off switching is mediated by the Neel vector reorientation. We predict that this concept verified by minimal model and density functional calculations in the CuMnAs semimetal antiferromagnet can lead to a topological metal-insulator transition driven by the Neel vector and to the topological anisotropic magnetoresistance. PMID- 28339250 TI - de Sitter Space as a Resonance. AB - A quantum mechanical formulation of de Sitter cosmological spacetimes still eludes string theory. In this Letter we conjecture a potentially rigorous framework in which the status of de Sitter space is the same as that of a resonance in a scattering process. We conjecture that transition amplitudes between certain states with asymptotically supersymmetric flat vacua contain resonant pole characteristic metastable intermediate states. A calculation employing constrained instantons illustrates this idea. PMID- 28339251 TI - Distinct Turbulence Saturation Regimes in Stellarators. AB - In the complex 3D magnetic fields of stellarators, ion-temperature-gradient turbulence is shown to have two distinct saturation regimes, as revealed by petascale numerical simulations and explained by a simple turbulence theory. The first regime is marked by strong zonal flows and matches previous observations in tokamaks. The newly observed second regime, in contrast, exhibits small-scale quasi-two-dimensional turbulence, negligible zonal flows, and, surprisingly, a weaker heat flux scaling. Our findings suggest that key details of the magnetic geometry control turbulence in stellarators. PMID- 28339252 TI - Helical Floquet Channels in 1D Lattices. AB - We show how dispersionless channels exhibiting perfect spin-momentum locking can arise in a 1D lattice model. While such spectra are forbidden by fermion doubling in static 1D systems, here we demonstrate their appearance in the stroboscopic dynamics of a periodically driven system. Remarkably, this phenomenon does not rely on any adiabatic assumptions, in contrast to the well known Thouless pump and related models of adiabatic spin pumps. The proposed setup is shown to be experimentally feasible with state-of-the-art techniques used to control ultracold alkaline earth atoms in optical lattices. PMID- 28339253 TI - Distinct Evolutions of Weyl Fermion Quasiparticles and Fermi Arcs with Bulk Band Topology in Weyl Semimetals. AB - The Weyl semimetal phase is a recently discovered topological quantum state of matter characterized by the presence of topologically protected degeneracies near the Fermi level. These degeneracies are the source of exotic phenomena, including the realization of chiral Weyl fermions as quasiparticles in the bulk and the formation of Fermi arc states on the surfaces. Here, we demonstrate that these two key signatures show distinct evolutions with the bulk band topology by performing angle-resolved photoemission spectroscopy, supported by first principles calculations, on transition-metal monophosphides. While Weyl fermion quasiparticles exist only when the chemical potential is located between two saddle points of the Weyl cone features, the Fermi arc states extend in a larger energy scale and are robust across the bulk Lifshitz transitions associated with the recombination of two nontrivial Fermi surfaces enclosing one Weyl point into a single trivial Fermi surface enclosing two Weyl points of opposite chirality. Therefore, in some systems (e.g., NbP), topological Fermi arc states are preserved even if Weyl fermion quasiparticles are absent in the bulk. Our findings not only provide insight into the relationship between the exotic physical phenomena and the intrinsic bulk band topology in Weyl semimetals, but also resolve the apparent puzzle of the different magnetotransport properties observed in TaAs, TaP, and NbP, where the Fermi arc states are similar. PMID- 28339254 TI - Efficient Vortex Generation in Subwavelength Epsilon-Near-Zero Slabs. AB - We show that a homogeneous and isotropic slab, illuminated by a circularly polarized beam with no topological charge, produces vortices of order 2 in the opposite circularly polarized components of the reflected and transmitted fields, as a consequence of the transverse magnetic and transverse electric asymmetric response of the rotationally invariant system. In addition, in the epsilon-near zero regime, we find that vortex generation is remarkably efficient in subwavelength thick slabs up to the paraxial regime. This physically stems from the fact that a vacuum paraxial field can excite a nonparaxial field inside an epsilon-near-zero slab since it hosts slowly varying fields over physically large portions of the bulk. Our theoretical predictions indicate that epsilon-near-zero media hold great potential as nanophotonic elements for manipulating the angular momentum of the radiation, since they are available without resorting to complicated micro- or nanofabrication processes and can operate even at very small (ultraviolet) wavelengths. PMID- 28339255 TI - Quantum Quenching of Radiation Losses in Short Laser Pulses. AB - Accelerated charges radiate, and therefore must lose energy. The impact of this energy loss on particle motion, called radiation reaction, becomes significant in intense-laser matter interactions, where it can reduce collision energies, hinder particle acceleration schemes, and is seemingly unavoidable. Here we show that this common belief breaks down in short laser pulses, and that energy losses and radiation reaction can be controlled and effectively switched off by appropriate tuning of the pulse length. This "quenching" of emission is impossible in classical physics, but becomes possible in QED due to the discrete nature of quantum emissions. PMID- 28339256 TI - Analytic Interatomic Forces in the Random Phase Approximation. AB - We discuss that in the random phase approximation (RPA) the first derivative of the energy with respect to the Green's function is the self-energy in the GW approximation. This relationship allows us to derive compact equations for the RPA interatomic forces. We also show that position dependent overlap operators are elegantly incorporated in the present framework. The RPA force equations have been implemented in the projector augmented wave formalism, and we present illustrative applications, including ab initio molecular dynamics simulations, the calculation of phonon dispersion relations for diamond and graphite, as well as structural relaxations for water on boron nitride. The present derivation establishes a concise framework for forces within perturbative approaches and is also applicable to more involved approximations for the correlation energy. PMID- 28339257 TI - Erratum: Model for Plane Turbulent Couette Flow [Phys. Rev. Lett. 75, 2956 (1995)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.75.2956. PMID- 28339258 TI - Atomistic Origin of Deformation Twinning in Biomineral Aragonite. AB - Deformation twinning rarely occurs in mineral materials which typically show brittle fracture. Surprisingly, it has recently been observed in the biomineral aragonite phase in nacre under high rate impact loading. In this Letter, the twinning tendency and the competition between fracture and deformation twinning were revealed by first principles calculations. The ratio of the unstable stacking fault energy and the stacking fault energy in orthorhombic aragonite is hitherto the highest in a broad range of metallic and oxide materials. The underlining physics for this high ratio is the multineighbor shared ionic bonds and the unique relaxation process during sliding in the aragonite structure. Overall, the unique deformation twining along with other highly coordinated deformation mechanisms synergistically work in the hierarchical structure of nacre, leading to the remarkable strengthening and toughening of nacre upon dynamic loading, and thus protecting the mother-of-pearl from predatory attacks. PMID- 28339259 TI - Sinking a Granular Raft. AB - We report experiments that yield new insights on the behavior of granular rafts at an oil-water interface. We show that these particle aggregates can float or sink depending on dimensionless parameters taking into account the particle densities and size and the densities of the two fluids. We characterize the raft shape and stability and propose a model to predict its shape and maximum length to remain afloat. Finally we find that wrinkles and folds appear along the raft due to compression by its own weight, which can trigger destabilization. These features are characteristics of an elastic instability, which we discuss, including the limitations of our model. PMID- 28339260 TI - Dynamic Chiral Magnetic Effect and Faraday Rotation in Macroscopically Disordered Helical Metals. AB - We develop an effective medium theory for electromagnetic wave propagation through gapless nonuniform systems with a dynamic chiral magnetic effect. The theory allows us to calculate macroscopic-disorder-induced corrections to the values of optical, as well as chiral magnetic conductivities. In particular, we show that spatial fluctuations of the optical conductivity induce corrections to the effective value of the chiral magnetic conductivity. The absolute value of the effect varies strongly depending on the system parameters, but yields the leading frequency dependence of the polarization rotation and circular dichroism signals. Experimentally, these corrections can be observed as features in the Faraday rotation angle near frequencies that correspond to the bulk plasmon resonances of a material. Such features are not expected to be present in single crystal samples. PMID- 28339261 TI - Ultimate Precision of Adaptive Noise Estimation. AB - We consider the estimation of noise parameters in a quantum channel, assuming the most general strategy allowed by quantum mechanics. This is based on the exploitation of unlimited entanglement and arbitrary quantum operations, so that the channel inputs may be interactively updated. In this general scenario, we draw a novel connection between quantum metrology and teleportation. In fact, for any teleportation-covariant channel (e.g., Pauli, erasure, or Gaussian channel), we find that adaptive noise estimation cannot beat the standard quantum limit, with the quantum Fisher information being determined by the channel's Choi matrix. As an example, we establish the ultimate precision for estimating excess noise in a thermal-loss channel, which is crucial for quantum cryptography. Because our general methodology applies to any functional that is monotonic under trace-preserving maps, it can be applied to simplify other adaptive protocols, including those for quantum channel discrimination. Setting the ultimate limits for noise estimation and discrimination paves the way for exploring the boundaries of quantum sensing, imaging, and tomography. PMID- 28339262 TI - Revealing Extremely Low Energy Amplitude Modes in the Charge-Density-Wave Compound LaAgSb_{2}. AB - Using infrared spectroscopy and ultrafast pump probe measurement, we have studied the two charge-density-wave (CDW) instabilities in the layered compound LaAgSb_{2}. The development of CDW energy gaps was clearly observed by optical spectroscopy, which removed most of the free carrier spectral weight. More interestingly, our time-resolved measurements revealed two coherent oscillations that softened by approaching the two phase transition temperatures, respectively. We addressed that these two oscillations come from the amplitude modes of CDW collective excitations, the surprisingly low energies (0.12 THz and 0.34 THz for the higher and lower temperature ones, respectively) of which are associated with the extremely small nesting wave vectors. Additionally, the amplitude and relaxation time of photoinduced reflectivity of LaAgSb_{2} single crystals stayed unchanged across the CDW phase transitions, which is quite rare and deserves further investigation. PMID- 28339263 TI - Electronic Stopping of Slow Protons in Transition and Rare Earth Metals: Breakdown of the Free Electron Gas Concept. AB - The electronic stopping cross sections (SCS) of Ta and Gd for slow protons have been investigated experimentally. The data are compared to the results for Pt and Au to learn how electronic stopping in transition and rare earth metals correlates with features of the electronic band structures. The extraordinarily high SCS observed for protons in Ta and Gd cannot be understood in terms of a free electron gas model, but are related to the high densities of both occupied and unoccupied electronic states in these metals. PMID- 28339264 TI - Anomalous Transport in the Superfluid Fluctuation Regime. AB - Motivated by a recent experiment in ultracold atoms [S. Krinner et al., Proc. Natl. Acad. Sci. U.S.A. 113, 8144 (2016)PNASA60027-842410.1073/pnas.1601812113], we analyze transport of attractively interacting fermions through a one dimensional wire near the superfluid transition. We show that in a ballistic regime where the conductance is quantized in the absence of interaction, the conductance is renormalized by superfluid fluctuations in reservoirs. In particular, the particle conductance is strongly enhanced, and the conductance plateau is blurred by emergent bosonic pair transport. For spin transport, in addition to the contact resistance, the wire itself is resistive, leading to a suppression of the measured spin conductance. Our results are qualitatively consistent with the experimental observations. PMID- 28339265 TI - Topology-Scaling Identification of Layered Solids and Stable Exfoliated 2D Materials. AB - The Materials Project crystal structure database has been searched for materials possessing layered motifs in their crystal structures using a topology-scaling algorithm. The algorithm identifies and measures the sizes of bonded atomic clusters in a structure's unit cell, and determines their scaling with cell size. The search yielded 826 stable layered materials that are considered as candidates for the formation of two-dimensional monolayers via exfoliation. Density functional theory was used to calculate the exfoliation energy of each material and 680 monolayers emerge with exfoliation energies below those of already existent two-dimensional materials. The crystal structures of these two dimensional materials provide templates for future theoretical searches of stable two-dimensional materials. The optimized structures and other calculated data for all 826 monolayers are provided at our database (https://materialsweb.org). PMID- 28339266 TI - Spin-Wave Excitations Evidencing the Kitaev Interaction in Single Crystalline alpha-RuCl_{3}. AB - Kitaev interactions underlying a quantum spin liquid have long been sought, but experimental data from which their strengths can be determined directly, are still lacking. Here, by carrying out inelastic neutron scattering measurements on high-quality single crystals of alpha-RuCl_{3}, we observe spin-wave spectra with a gap of ~2 meV around the M point of the two-dimensional Brillouin zone. We derive an effective-spin model in the strong-coupling limit based on energy bands obtained from first-principles calculations, and find that the anisotropic Kitaev interaction K term and the isotropic antiferromagnetic off-diagonal exchange interaction Gamma term are significantly larger than the Heisenberg exchange coupling J term. Our experimental data can be well fit using an effective-spin model with K=-6.8 meV and Gamma=9.5 meV. These results demonstrate explicitly that Kitaev physics is realized in real materials. PMID- 28339267 TI - Orbital Edge States in a Photonic Honeycomb Lattice. AB - We experimentally reveal the emergence of edge states in a photonic lattice with orbital bands. We use a two-dimensional honeycomb lattice of coupled micropillars whose bulk spectrum shows four gapless bands arising from the coupling of p-like photonic orbitals. We observe zero-energy edge states whose topological origin is similar to that of conventional edge states in graphene. Additionally, we report novel dispersive edge states in zigzag and armchair edges. The observations are reproduced by tight-binding and analytical calculations, which we extend to bearded edges. Our work shows the potentiality of coupled micropillars in elucidating some of the electronic properties of emergent two-dimensional materials with orbital bands. PMID- 28339268 TI - Entropy Evolution in the Magnetic Phases of Partially Frustrated CePdAl. AB - In the heavy-fermion metal CePdAl, long-range antiferromagnetic order coexists with geometric frustration of one-third of the Ce moments. At low temperatures, the Kondo effect tends to screen the frustrated moments. We use magnetic fields B to suppress the Kondo screening and study the magnetic phase diagram and the evolution of the entropy with B employing thermodynamic probes. We estimate the frustration by introducing a definition of the frustration parameter based on the enhanced entropy, a fundamental feature of frustrated systems. In the field range where the Kondo screening is suppressed, the liberated moments tend to maximize the magnetic entropy and strongly enhance the frustration. Based on our experiments, this field range may be a promising candidate to search for a quantum spin liquid. PMID- 28339269 TI - Portal Connecting Dark Photons and Axions. AB - The dark photon and the axion (or axionlike particle) are popular light particles of the hidden sector. Each of them has been actively searched for through the couplings called the vector portal and the axion portal. We introduce a new portal connecting the dark photon and the axion (axion-photon-dark photon, axion dark photon-dark photon), which emerges in the presence of the two particles. This dark axion portal is genuinely new couplings, not just from a product of the vector portal and the axion portal, because of the internal structure of these couplings. We present a simple model that realizes the dark axion portal and discuss why it warrants a rich phenomenology. PMID- 28339270 TI - Publisher's Note: First Experimental Study of Photon Polarization in Radiative B_{s}^{0} Decays [Phys. Rev. Lett. 118, 021801 (2017)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.118.021801. PMID- 28339271 TI - Magnetoelectric Behavior from S=1/2 Asymmetric Square Cupolas. AB - Magnetoelectric properties are studied by a combined experimental and theoretical study of a quasi-two-dimensional material composed of square cupolas, Ba(TiO)Cu_{4}(PO_{4})_{4}. The magnetization is measured up to the field above the saturation, and several anomalies are observed depending on the field directions. We propose a S=1/2 spin model with Dzyaloshinskii-Moriya interactions, which reproduces the full magnetization curves well. Elaborating the phase diagram of the model, we show that the anomalies are explained by magnetoelectric phase transitions. Our theory also accounts for the scaling of the dielectric anomaly observed in the experiments. The results elucidate the crucial role of the in-plane component of Dzyaloshinskii-Moriya interactions, which is induced by the noncoplanar buckling of a square cupola. We also predict a "hidden" phase and another magnetoelectric response, both of which appear in a nonzero magnetic field. PMID- 28339272 TI - Connecting Few-Body Inelastic Decay to Quantum Correlations in a Many-Body System: A Weakly Coupled Impurity in a Resonant Fermi Gas. AB - We study three-body recombination in an ultracold Bose-Fermi mixture. We first show theoretically that, for weak interspecies coupling, the loss rate is proportional to Tan's contact. Second, using a ^{7}Li/^{6}Li mixture we probe the recombination rate in both the thermal and dual superfluid regimes. We find excellent agreement with our model in the BEC-BCS crossover. At unitarity where the fermion-fermion scattering length diverges, we show that the loss rate is proportional to n_{f}^{4/3}, where n_{f} is the fermionic density. This unusual exponent signals nontrivial two-body correlations in the system. Our results demonstrate that few-body losses can be used as a quantitative probe of quantum correlations in many-body ensembles. PMID- 28339274 TI - Exact Model of Vacancy-Mediated Solute Transport in Magnesium. AB - Most substitutional solutes in solids diffuse via vacancies. However, widely used analytic models for diffusivity make uncontrolled approximations in the relations between atomic jump rates that reduce accuracy. Symmetry analysis of the hexagonal close packed crystal identifies more distinct vacancy transitions than prior models, and a Green function approach computes diffusivity exactly for solutes in magnesium. We find large differences for the solute drag of Al, Zn, and rare earth solutes, and improved diffusion activation energies-highlighting the need for exact analytic transport models. PMID- 28339275 TI - Ultrafast Photoinduced Electric-Polarization Switching in a Hydrogen-Bonded Ferroelectric Crystal. AB - Croconic acid crystals show proton displacive-type ferroelectricity with a large spontaneous polarization reaching 20 MUC/cm^{2}, which originates from the strong coupling of proton and pi-electron degrees of freedom. Such a coupling makes us expect a large polarization change by photoirradiations. Optical-pump second-harmonic-generation-probe experiments reveal that a photoexcited croconic acid crystal loses the ferroelectricity substantially with a maximum quantum efficiency of more than 30 molecules per one absorbed photon. Based on density functional calculations, we theoretically discuss possible pathways toward the formation of a one-dimensional domain with polarization inversion and its recovery process to the ground state by referring to the dynamics of experimentally obtained polarization changes. PMID- 28339276 TI - Two-Dimensional Platform for Networks of Majorana Bound States. AB - We model theoretically a two-dimensional electron gas (2DEG) covered by a superconductor and demonstrate that topological superconducting channels are formed when stripes of the superconducting layer are removed. As a consequence, Majorana bound states (MBSs) are created at the ends of the stripes. We calculate the topological invariant and energy gap of a single stripe, using realistic values for an InAs 2DEG proximitized by an epitaxial Al layer. We show that the topological gap is enhanced when the structure is made asymmetric. This can be achieved either by imposing a phase difference (by driving a supercurrent or using a magnetic-flux loop) over the strip or by replacing one superconductor by a metallic gate. Both strategies also enable control over the MBS splitting, thereby facilitating braiding and readout schemes based on controlled fusion of MBSs. Finally, we outline how a network of Majorana stripes can be designed. PMID- 28339277 TI - Turbulence Nonlinearities Shed Light on Geometric Asymmetry in Tokamak Confinement Transitions. AB - A comprehensive study of fully frequency-resolved nonlinear kinetic energy transfer has been performed for the first time in a diverted tokamak, providing new insight into the parametric dependences of edge turbulence transitions. Measurements using gas puff imaging in the turbulent L-mode state illuminate the source of the long known but as yet unexplained "favorable-unfavorable" geometric asymmetry of the power threshold for transition to the turbulence-suppressed H mode. Results from the recently discovered I mode point to a competition between zonal flow (ZF) and geodesic-acoustic modes (GAM) for turbulent energy, while showing new evidence that the I-to-H transition is still dominated by ZFs. The availability of nonlinear drive for the GAM against net heat flux through the edge corresponds very well to empirical scalings found experimentally for accessing the I mode. PMID- 28339278 TI - Erratum: X-Ray Optics on a Chip: Guiding X Rays in Curved Channels [Phys. Rev. Lett. 115, 203902 (2015)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.115.203902. PMID- 28339279 TI - Trade-Off Between Speed and Cost in Shortcuts to Adiabaticity. AB - Achieving effectively adiabatic dynamics is a ubiquitous goal in almost all areas of quantum physics. Here, we study the speed with which a quantum system can be driven when employing transitionless quantum driving. As a main result, we establish a rigorous link between this speed, the quantum speed limit, and the (energetic) cost of implementing such a shortcut to adiabaticity. Interestingly, this link elucidates a trade-off between speed and cost, namely, that instantaneous manipulation is impossible as it requires an infinite cost. These findings are illustrated for two experimentally relevant systems-the parametric oscillator and the Landau-Zener model-which reveal that the spectral gap governs the quantum speed limit as well as the cost for realizing the shortcut. PMID- 28339273 TI - Search for Electronic Recoil Event Rate Modulation with 4 Years of XENON100 Data. AB - We report on a search for electronic recoil event rate modulation signatures in the XENON100 data accumulated over a period of 4 yr, from January 2010 to January 2014. A profile likelihood method, which incorporates the stability of the XENON100 detector and the known electronic recoil background model, is used to quantify the significance of periodicity in the time distribution of events. There is a weak modulation signature at a period of 431_{-14}^{+16} day in the low energy region of (2.0-5.8) keV in the single scatter event sample, with a global significance of 1.9sigma; however, no other more significant modulation is observed. The significance of an annual modulation signature drops from 2.8sigma, from a previous analysis of a subset of this data, to 1.8sigma with all data combined. Single scatter events in the low energy region are thus used to exclude the DAMA/LIBRA annual modulation as being due to dark matter electron interactions via axial vector coupling at 5.7sigma. PMID- 28339280 TI - Size-Resolved Photoelectron Anisotropy of Gas Phase Water Clusters and Predictions for Liquid Water. AB - We report the first measurements of size-resolved photoelectron angular distributions for the valence orbitals of neutral water clusters with up to 20 molecules. A systematic decrease of the photoelectron anisotropy is found for clusters with up to 5-6 molecules, and most remarkably, convergence of the anisotropy for larger clusters. We suggest the latter to be the result of a local short-range scattering potential that is fully described by a unit of 5-6 molecules. The cluster data and a detailed electron scattering model are used to predict the anisotropy of slow photoelectrons in liquid water. Reasonable agreement with experimental liquid jet data is found. PMID- 28339281 TI - Gate-Tunable Band Structure of the LaAlO_{3}-SrTiO_{3} Interface. AB - The two-dimensional electron system at the interface between LaAlO_{3} and SrTiO_{3} has several unique properties that can be tuned by an externally applied gate voltage. In this work, we show that this gate tunability extends to the effective band structure of the system. We combine a magnetotransport study on top-gated Hall bars with self-consistent Schrodinger-Poisson calculations and observe a Lifshitz transition at a density of 2.9*10^{13}cm^{-2}. Above the transition, the carrier density of one of the conducting bands decreases with increasing gate voltage. This surprising decrease is accurately reproduced in the calculations if electronic correlations are included. These results provide a clear, intuitive picture of the physics governing the electronic structure at complex-oxide interfaces. PMID- 28339282 TI - Melatonin for Reducing Weight Gain Following Administration of Atypical Antipsychotic Olanzapine for Adolescents with Bipolar Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - OBJECTIVES: We aimed to evaluate melatonin effectiveness in weight gain reduction following olanzapine use for 11-17-year-old bipolar disorder patients. EXPERIMENTAL DESIGN: Seventy-seven adolescent outpatients, subsequent to their initial diagnosis of bipolar I disorder by a psychiatrist, entered this study. After assessing inclusion and exclusion criteria, 48 patients consented to participate. Twenty-four patients were allocated to receive olanzapine, lithium carbonate, and melatonin, and 24 patients were allocated to receive olanzapine, lithium carbonate, and placebo by simple randomization. The Young Mania Rating Scale (YMRS) was performed at baseline. Before treatment and after 6 and 12 weeks of treatment, weight, height, and body mass index (BMI) were measured. Analysis of variance (ANOVA) with repeated measure and t-test were used to analyze data. PRINCIPAL OBSERVATIONS: Nineteen patients in each group finished the study and their data were entered for analysis. Mean rise in BMI in the melatonin group compared with placebo (2.45 vs. 3.25 respectively) was marginally significant (t = 1.936; df = 36; p = 0.061). ANOVA with repeated measure also showed a marginally significant difference (F = 3.74; df = 1; p = 0.061) between groups and across time in regard to BMI. Mean body weight rise in the melatonin group compared with the placebo group (5.8 kg vs. 8.2 kg respectively) was marginally significant (t = 1.923; df = 28; p = 0.065). ANOVA with repeated measure also showed a marginally significant difference (F = 3.73; df = 1.1; p = 0.056) between groups and across time for body weight. CONCLUSIONS: Coadministration of melatonin with olanzapine and lithium carbonate in adolescents with bipolar disorder could reduce the sharp weight gain side effect of these drugs to near significance. PMID- 28339283 TI - Development, optimization and implementation of a centralized metabolic soft spot assay. AB - AIM: High clearance is a commonly encountered issue in drug discovery. Here we present a centralized metabolic soft spot identification assay with adequate capacity and turnaround time to support the metabolic optimization needs of an entire discovery organization. METHODOLOGY: An integrated quan/qual approach utilizing both an orthogonal sample-pooling methodology and software-assisted structure elucidation was developed to enable the assay. Major metabolic soft spots in liver microsomes (rodent and human) were generated in a batch mode, along with kinetics of parent disappearance and metabolite formation, typically within 1 week of incubation. RESULTS & CONCLUSION: A centralized metabolic soft spot identification assay has been developed and has successfully impacted discovery project teams in mitigating instability and establishing potential structure-metabolism relationships. PMID- 28339284 TI - DPC4 gene expression in primary pancreatic ductal adenocarcinoma: relationship with CT characteristics. AB - OBJECTIVE: To investigate the relationship between CT imaging findings and DPC4 gene expression and to determine the prognostic value of DPC4 gene expression to predict overall survival in patients with pancreatic ductal adenocarcinoma. METHODS: Between January and December 2011, we retrospectively analyzed 163 pancreatic ductal adenocarcinomas in 163 patients who had undergone surgical resection (mean age = 61.8 years; range = 35-81 years). We divided the study patients into two groups according to DPC4 gene expression: DPC4-expression or DPC4-non-expression group. The CT findings were analyzed by two reviewers. The associations between the CT imaging findings and DPC4 gene expression were evaluated using univariate analysis and multivariate logistic regression analysis. Overall survival was compared according to the DPC4 gene expression (DPC4-expression vs DPC4-non-expression) using Kaplan-Meier analysis and log-rank testing. To avoid bias, subgroup analyses of CT findings in T3 tumour and overall survival in patients with T3 tumour and R0 resection were performed. RESULTS: Between DPC4-expression group (n = 75) and DPC4-non-expression group (n = 88), three CT findings (i.e., tumour margin, peripancreatic infiltration, and the presence of background intraductal pancreatic mucinous neoplasm) were significantly different in univariate analysis. Of these, a well-defined tumour margin was significantly associated with DPC4-expression tumour (adjusted odds ratio = 2.06; p = 0.032) in multivariate analysis. Of the total 163 patients, the mean overall survival of the DPC4-expression group was significantly longer than that of the DPC4-non-expression group (30.0 vs 22.0 months; p = 0.049). Of the 150 T3 tumours, the presence of well-defined tumour margins was also a significant CT finding (adjusted odd ratio = 2.00; p = 0.044) in multivariate analysis. However, of 131 patients with T3 tumour and R0 resection, the overall survival period of the DPC4-expression group was not significantly different from that of the DPC4-non-expression group (24.0 vs 22.0 months; p = 0.240). CONCLUSION: The presence of well-defined tumour margins on CT was significantly linked with DPC4-expression tumour. Advances in knowledge: A well-defined tumour margin is an independent CT finding associated with DPC4-expression pancreatic ductal adenocarcinoma. PMID- 28339285 TI - Is the necrosis/wall ADC ratio useful for the differentiation of benign and malignant breast lesions? AB - OBJECTIVE: To determine whether the necrosis/wall apparent diffusion coefficient (ADC) ratio is useful for the malignant-benign differentiation of necrotic breast lesions. METHODS: Breast MRI was performed using a 3-T system. In this retrospective study, calculation of the necrosis/wall ADC ratio was based on ADC values measured from the necrosis and from the wall of malignant and benign breast lesions by diffusion-weighted imaging (DWI). By synchronizing post contrast T1 weighted images, the separate parts of wall and necrosis were maintained. All the diagnoses were pathologically confirmed. Statistical analyses were conducted using an independent sample t-test and receiver operating characteristic analysis. The intraclass and interclass correlations were evaluated. RESULTS: A total of 66 female patients were enrolled, 38 of whom had necrotic breast carcinomas and 28 of whom had breast abscesses. The ADC values were obtained from both the wall and necrosis. The mean necrosis/wall ADC ratio (+/- standard deviation) was 1.61 +/- 0.51 in carcinomas, and it was 0.65 +/- 0.33 in abscesses. The area under the curve values for necrosis ADC, wall ADC and the necrosis/wall ADC ratio were 0.680, 0.068 and 0.942, respectively. A wall/necrosis ADC ratio cut-off value of 1.18 demonstrated a sensitivity of 97%, specificity of 93%, a positive-predictive value of 95%, a negative-predictive value of 96% and an accuracy of 95% in determining the malignant nature of necrotic breast lesions. There was a good intra- and interclass reliability for the ADC values of both necrosis and wall. CONCLUSION: The necrosis/wall ADC ratio appears to be a reliable and promising tool for discriminating breast carcinomas from abscesses using DWI. Advances in knowledge: ADC values of the necrosis obtained by DWI are valuable for malignant-benign differentiation in necrotic breast lesions. The necrosis/wall ADC ratio appears to be a reliable and promising tool in the breast imaging field. PMID- 28339286 TI - Advantages of Arthroscopic Rotator Cuff Repair With a Transosseous Suture Technique: A Prospective Randomized Controlled Trial. AB - BACKGROUND: Rotator cuff tear is a common finding in patients with painful, poorly functioning shoulders. The surgical management of this disorder has improved greatly and can now be fully arthroscopic. PURPOSE: To evaluate clinical and radiological results of arthroscopic rotator cuff repair using 2 different techniques: single-row anchor fixation versus transosseous hardware-free suture repair. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Sixty-nine patients with rotator cuff tears were enrolled: 35 patients were operated with metal anchors and 34 with standardized transosseous repair. The patients were clinically evaluated before surgery, during the 28 days after surgery, and at least 1 year after the operation by the use of validated rating scores (Constant score, QuickDASH, and numerical rating scale [NRS]). Final follow-up was obtained at more than 3 years by a QuickDASH evaluation to detect any difference from the previous follow-up. During the follow-up, rotator cuff integrity was determined through magnetic resonance imaging and was classified according to the 5 Sugaya categories. RESULTS: Patients operated with the transosseous technique had significantly less pain, especially from the 15th postoperative day: In the third week, the mean NRS value for the anchor group was 3.00 while that for transosseous group was 2.46 ( P = .02); in the fourth week, the values were 2.44 and 1.76, respectively ( P < .01). No differences in functional outcome were noted between the 2 groups at the final evaluation. In the evaluation of rotator cuff repair integrity, based on Sugaya magnetic resonance imaging classification, no significant difference was found between the 2 techniques in terms of retear rate ( P = .81). CONCLUSION: No significant differences were found between the 2 arthroscopic repair techniques in terms of functional and radiological results. However, postoperative pain decreased more quickly after the transosseous procedure, which therefore emerges as a possible improvement in the surgical repair of the rotator cuff. Registration: NCT01815177 ( ClinicalTrials.gov identifier). PMID- 28339287 TI - Rapid Radiologic Progression of Silicosis. PMID- 28339288 TI - The Proximal Tibiofibular Joint: A Biomechanical Analysis of the Anterior and Posterior Ligamentous Complexes. AB - BACKGROUND: Dislocation of the proximal tibiofibular joint is a complex injury that is often overlooked or misdiagnosed. Surgical management is recommended for severe acute or for chronic symptomatic instability of the proximal tibiofibular joint. Although the anterior ligamentous complex has been reported to be stronger than the posterior complex, biomechanical data are lacking. PURPOSE: To determine the ultimate load of the anterior and posterior ligamentous complexes of the proximal tibiofibular joint to determine optimal graft selection. STUDY DESIGN: Controlled laboratory study. METHODS: Ten nonpaired, fresh-frozen knee specimens were dissected to expose the anterior and posterior proximal tibiofibular ligamentous complexes. The tibia was split in the coronal plane to separate the anterior and posterior ligamentous complexes, and the fibula was left intact. Specimens were secured in a dynamic testing machine and preconditioned for 10 cycles between 2 and 10 N at 0.1 Hz followed by loading to failure at a rate of 25 mm/min. RESULTS: The mean (+/-SD) ultimate load of the anterior complex (517 +/- 144 N) was significantly greater than the mean ultimate load of the posterior complex (322 +/- 160 N) ( P = .012). The mean surface areas of the anterior and posterior complexes were 761 +/- 174 mm2 and 565 +/- 103 mm2, respectively ( P = .008). The mean values for stiffness of the anterior (133 N/mm) and posterior (109 N/mm) complexes were similar ( P = .250). CONCLUSION: The ligaments of the human proximal tibiofibular joint were able to withstand a mean ultimate failure load of 517 +/- 144 N for the anterior complex and 322 +/- 160 N for the posterior complex. In this regard, it is recommended that the strengths of grafts chosen for proximal tibiofibular reconstructions meet or exceed these values. CLINICAL RELEVANCE: The optimal surgical treatment for addressing residual proximal tibiofibular instability is not well defined. Before an anatomic reconstruction of the proximal tibiofibular ligament is developed, the individual biomechanical properties of the anterior and posterior ligamentous structures of the proximal tibiofibular joint need to be considered to facilitate an optimal reconstruction design. PMID- 28339289 TI - The role of delineation education programs for improving interobserver variability in target volume delineation in gastric cancer. AB - OBJECTIVE: To assess whether delineation courses for radiation oncologists improve interobserver variability in target volume delineation for post-operative gastric cancer radiotherapy planning. METHODS: 29 radiation oncologists delineated target volumes in a gastric cancer patient. An experienced radiation oncologist lectured about delineation based on contouring atlas and delineation recommendations. After the course, the radiation oncologists, blinded to the previous delineation, provided delineation for the same patient. RESULTS: The difference between delineated volumes and reference volumes for pre- and post course clinical target volume (CTV) were 19.8% (-42.4 to 70.6%) and 12.3% (-12.0 to 27.3%) (p = 0.26), respectively. The planning target volume (PTV) differences pre- and post-course according to the reference volume were 20.5% (-40.7 to 93.7%) and 13.1% (-10.6 to 29.5%) (p = 0.30), respectively. The concordance volumes between the pre- and post-course CTVs and PTVs were 467.1 +/- 89.2 vs 597.7 +/- 54.6 cm3 (p < 0.001) and 738.6 +/- 135.1 vs 893.2 +/- 144.6 cm3 (p < 0.001), respectively. Minimum and maximum observer variations were seen at the cranial part and splenic hilus and at the caudal part of the CTV. The kappa indices compared with the reference contouring at pre- and post-course delineations were 0.68 and 0.82, respectively. CONCLUSION: The delineation course improved interobserver variability for gastric cancer. However, impact of target volume changes on toxicity and local control should be evaluated for further studies. Advances in knowledge: This study demonstrated that a delineation course based on current recommendations helped physicians delineate smaller and more homogeneous target volumes. Better target volume delineation allows proper target volume irradiation and preventing unnecessary normal tissue irradiation. PMID- 28339290 TI - Preventing the spread of infectious diseases: antivirulents versus antibiotics. PMID- 28339291 TI - Bronchial microbiome, PA biofilm-forming capacity and exacerbation in severe COPD patients colonized by P. aeruginosa. AB - AIM: The bronchial microbiome of severe chronic obstructive pulmonary disease patients colonized by Pseudomonas aeruginosa was analyzed using 16S rRNA gene sequencing to identify differences related to biofilm-forming capacity. PATIENTS & METHODS: Patient sputum samples from 21 patients were studied. RESULTS: Statistically significant differences related to biofilm-forming capacity were only found for genera with relative abundances <1%, and Fusobacterium was over represented when biofilm-forming capacity was high. Genera with relative abundances >50% which increased from baseline were observed in 10/14 exacerbations, but corresponded to Pseudomonas only in three episodes, while other pathogenic genera were identified in seven. CONCLUSION: The bronchial microbiome shows differences according with P. aeruginosa biofilm-forming capacity. Pathogenic microorganisms other than P. aeruginosa cause a significant part of the exacerbations in colonized chronic obstructive pulmonary disease patients. PMID- 28339292 TI - Thymbra capitata essential oil as potential therapeutic agent against Gardnerella vaginalis biofilm-related infections. AB - AIM: To evaluate the antibacterial activity of Thymbra capitata essential oil and its main compound, carvacrol, against Gardnerella vaginalis grown planktonically and as biofilms, and its effect of vaginal lactobacilli. MATERIALS & METHODS: Minimal inhibitory concentration, minimal lethal concentration determination and flow cytometry analysis were used to assess the antibacterial effect against planktonic cells. Antibiofilm activity was measured through quantification of biomass and visualization of biofilm structure by confocal laser scanning microscopy. RESULTS: T. capitata essential oil and carvacrol exhibited a potent antibacterial activity against G. vaginalis cells. Antibiofilm activity was more evident with the essential oil than carvacrol. Furthermore, vaginal lactobacilli were significantly more tolerant to the essential oil. CONCLUSION: T. capitata essential oil stands up as a promising therapeutic agent against G. vaginalis biofilm-related infections. PMID- 28339293 TI - The Context of Sexual Decisions and Intrapersonal and Interpersonal Factors Related to Sexual Initiation Among Female Military-Dependent Youth. AB - Despite the sizable population of military-dependent youth (MDY) in the United States and the military stressors they experience (e.g., relocations, parental deployment), little is known about MDY's sexual behavior, especially about the perceived role that military stressors play in their sexual decisions, such as the decision to initiate sex. We conducted 25 semistructured, in-depth interviews with sexually experienced female MDY aged 15 to 19 years to (a) describe MDY's general perceptions of military life and (b) identify intrapersonal and interpersonal characteristics related to MDY's sexual initiation, including the perceived impact of military stressors. We analyzed life history grids and transcripts to identify common and unique themes across participants' experiences. Most participants reported having positive experiences related to military life, and most did not believe that military stressors influenced their decision to initiate sex. Common intrapersonal and interpersonal characteristics related to sexual initiation were having an older first sexual partner, being in a dating relationship, receiving sexual health education prior to their first sexual experience, and discussing sex with a parent prior to their first sexual experience. These intrapersonal and interpersonal characteristics should be considered when developing sexual health programs for MDY, which should focus on building supportive peer and parental relationships. PMID- 28339294 TI - Rapid assessment of antimicrobial resistance prevalence using a Lot Quality Assurance sampling approach. AB - AIM: Increasing antimicrobial resistance (AMR) requires rapid surveillance tools, such as Lot Quality Assurance Sampling (LQAS). MATERIALS & METHODS: LQAS classifies AMR as high or low based on set parameters. We compared classifications with the underlying true AMR prevalence using data on 1335 Escherichia coli isolates from surveys of community-acquired urinary tract infection in women, by assessing operating curves, sensitivity and specificity. RESULTS: Sensitivity and specificity of any set of LQAS parameters was above 99% and between 79 and 90%, respectively. Operating curves showed high concordance of the LQAS classification with true AMR prevalence estimates. CONCLUSION: LQAS based AMR surveillance is a feasible approach that provides timely and locally relevant estimates, and the necessary information to formulate and evaluate guidelines for empirical treatment. PMID- 28339295 TI - Antifungal plant defensins: increased insight in their mode of action as a basis for their use to combat fungal infections. AB - Plant defensins are small, cationic peptides with a highly conserved 3D structure. They have been studied extensively in the past decades. Various biological activities have been attributed to plant defensins, such as anti insect and antimicrobial activities, but they are also known to affect ion channels and display antitumor activity. This review focuses on the structure, biological activity and antifungal mode of action of some well-characterized plant defensins, with particular attention to their fungal membrane target(s), their induced cell death mechanisms as well as their antibiofilm activity. As plant defensins are, in general, not toxic to human cells, show in vivo efficacy and have low frequencies of resistance occurrence, they are of particular interest in the fight against fungal infections. PMID- 28339296 TI - Synthetic parasites: a successful mucosal nanoparticle vaccine against Toxoplasma congenital infection in mice. AB - AIM: Development of protein vaccine to prevent congenital infection is a major public health priority. Our goal is the design of mucosal synthetic pathogen inducing protective immune responses against congenital toxoplasmosis. MATERIALS & METHODS: Mice were immunized intranasally, establishing pregnancy and challenging orally. Placental immune response, congenital infection, pup growth, parasitic load rates were studied. RESULTS: Pups born to vaccinated infected dams had significantly fewer brain cysts, no intraocular inflammation and normal growth. Protection was associated with a placental cellular Th1 response downregulated by IL-6 and correlated with persistence of vaccine for few hours in the nose before being totally eliminated. CONCLUSION: Our vaccine conferred high protection against congenital toxoplasmosis. These results provide support for future studies of other congenital vaccine. PMID- 28339297 TI - Long-term Effect of Panretinal Photocoagulation on Spectral Domain Optical Coherence Tomography Measurements in Diabetic Retinopathy. AB - PURPOSE: To evaluate the effects of panretinal photocoagulation on spectral domain optical coherence tomography measurements in diabetic retinopathy by comparing the thicknesses of the central macula, retinal nerve fiber layer, and ganglion cell layer, we used a Cirrus HD OCT(r) (Carl Zeiss Meditec, Dublin, CA, USA) in normal and diabetic retinopathy cohorts. METHODS: We analyzed patients who visited our retinal clinic between May 2013 and July 2014. The patients were classified into four groups: normal (Group A), diabetes without diabetic retinopathy (Group B), severe nonproliferative or proliferative diabetic retinopathy (Group C), and at least 3 years after panretinal photocoagulation treatment (Group D). The mean thicknesses of the macula, retinal nerve fiber layer, and ganglion cell layer in each group were compared by measuring a macular cube 512 * 128 scan and an optic disc cube 200 * 200 scan twice. RESULTS: In total, 154 patients were enrolled. The mean thickness of the central macula in groups A to D was 257.2, 256.8, 257.4, and 255.6 um, respectively, and did not differ significantly. The mean thickness of the RNFL in group A to D was 96.8, 96.5, 97.2, and 92.8 um, respectively, and was significantly lower in group D (decreased in the inferior, superior, and nasal sectors, but increased in the temporal). The mean thickness of the ganglion cell layer was also significantly lower in group D (A, 84.5 um; B, 84.4 um; C, 82.5 um; D, 78.5 um). CONCLUSIONS: The mean thicknesses of the retinal nerve fiber and ganglion cell layers were decreased significantly in eyes with diabetic eye disease treated with panretinal photocoagulation compared to normal or eyes with diabetic eye disease that had not been laser-treated. Laser treatment might have altered the thickness of the inner layer of the retina, and such changes should be considered in diabetic retinopathy patients after panretinal photocoagulation treatment. PMID- 28339298 TI - Evaluations and Future Plans After Casual Sexual Experiences: Differences Across Partner Type. AB - Casual sexual relationships and experiences (CSREs) are common among emerging adults, and their diversity may contribute to variability in their associations with mental health and future romantic relationship development. The present research used multiple regression analyses to examine how CSRE type (casual dating, friends with benefits [FWB], or booty call/one-night stand) is associated with short-term outcomes of these experiences, including positive and negative evaluations, plans to start a romantic relationship with a CSRE partner, and general plans for future CSREs. College students and non-college-attending emerging adults (N = 192, 80% female, mean age = 22.09 years) reported on recent sexual encounters through daily diaries collected around an alcohol consumption holiday. Individuals with casual dating partners evaluated their experiences more positively and/or less negatively than individuals with booty calls/one-night stands; these associations were moderated by gender and sexual behavior type. Individuals with casual dating partners were more oriented toward pursuing a romantic relationship with their partners than individuals with FWB or booty calls/one-night stands. However, no association was found between CSRE type and plans for future CSREs in general. Results highlight the diversity of CSREs and suggest that casual dating may be more rewarding than FWB and booty calls/one night stands, particularly for women. PMID- 28339300 TI - Genetic Manipulation by Zinc-Finger Nucleases in Rat-Induced Pluripotent Stem Cells. AB - Induced pluripotent stem cells (iPSCs) have an extensive application in regenerative medicine, pharmaceutical discovery, and basic research. With the recent derivation of rat iPSCs, it is now feasible to apply genetic manipulation in this species. But such tools do not yet exist for many rat strains, especially for disease model rat. The Sprague Dawley (SD) rat is an inbred disease model for hypertension, nephropathy, pulmonary hypertension, depression, and alcohol consumption. In this study, the SD rat iPSCs were generated using lentiviral method. The p53 gene was targeted in rat iPSCs using homologous recombination mediated by P53 zinc-finger nucleases (ZFNs). Our results showed that these rat iPSCs were pluripotent status. P53 gene was targeted successfully with high efficiency by coelectroporating the donor targeting vectors and p53 ZFN vector to these rat iPSCs. Southern blotting analysis confirmed the correct homologous recombination in rat iPSCs. At the same time, our results demonstrated that the P53 dependent function was abolished in p53-targeted iPSCs. This report also demonstrated that iPS technology, combined with homologous recombination mediated by ZFN, was suitable to develop human disease model in rat and other species. PMID- 28339301 TI - Cultivation of Human Oral Mucosal Explants on Contact Lenses. AB - : Purpose/Aim: Autologous cultivated oral mucosal (OM) epithelial transplantation has been successfully used as corneal epithelial replacement in bilateral limbal stem cell deficiency. Recently, lotrafilcon A contact lens (CL) surface was described as a suitable carrier for cultured stem cells in corneal epithelial transplantation. Our aim was to establish explant cultures from human OM on CL carriers that are free of animal-derived materials and feeder cells. MATERIALS AND METHODS: Human cadaveric 2 mm OM explants were sutured onto CL surfaces and cultivated with fetal calf serum (FCS) or human serum (HS) supplemented culture medium without feeder cells. Confluent cultures were harvested and evaluated morphologically with hematoxylin and eosin stain and with immunofluorescence microscopy for the presence of p63, vimentin and cytokeratins (CK) 3, 4, 13 and 14. RESULTS: Confluent cell sheets covering the whole CL surface were produced from OM explants after 2 weeks of culture with HS and after 3 weeks with FCS. A basal layer consisted of small, vimentin, p63 and CK14 positive putative stem/progenitor cells, which were present in the whole cell sheet. Large, CK3, CK4 and CK13 positive, differentiated cells appeared to spread above this confluent layer. CONCLUSIONS: We have established an animal-free culture system from human OM explants on CL surface. The cultured OM sheets contain large numbers of putative stem cells including limbal-like CK3 and CK14 positive cells. This method can be adapted to good manufacturing practice (GMP) conditions and has, therefore, great potential for clinical use. PMID- 28339302 TI - Driver trust in five driver assistance technologies following real-world use in four production vehicles. AB - OBJECTIVES: Information about drivers' experiences with driver assistance technologies in real driving conditions is sparse. This study characterized driver interactions with forward collision warning, adaptive cruise control, active lane keeping, side-view assist, and lane departure warning systems following real-world use. METHODS: Fifty-four Insurance Institute for Highway Safety employees participated and drove a 2016 Toyota Prius, 2016 Honda Civic, 2017 Audi Q7, or 2016 Infiniti QX60 for up to several weeks. Participants reported mileage and warnings from the technologies in an online daily-use survey. Participants reported their level of agreement with five statements regarding trust in an online post-use survey. Responses were averaged to create a composite measure of trust ranging from -2 (strongly disagree) to +2 (strongly agree) for each technology. Mixed-effect regression models were constructed to compare trust among technologies and separately among the study vehicles. Participants' free-response answers about what they liked least about each system were coded and examined. RESULTS: Participants reported driving 33,584 miles during 4 months of data collection. At least one forward collision warning was reported in 26% of the 354 daily reports. The proportion of daily reports indicating a forward collision warning was much larger for the Honda (70%) than for the Audi (18%), Infiniti (15%), and Toyota (10%). Trust was highest for side view assist (0.98) and lowest for active lane keeping (0.20). Trust in side-view assist was significantly higher than trust in active lane keeping and lane departure warning (0.53). Trust in active lane keeping was significantly lower than trust in adaptive cruise control (0.67) and forward collision warning (0.71). Trust in adaptive cruise control was higher for the Audi (0.72) and Toyota (0.75) compared with the Honda (0.30), and significantly higher for the Infiniti (0.93). Trust in Infiniti's side-view assist (0.58) was significantly lower than trust in Audi (1.17) and Honda (1.23) systems. Coding of answers to free-response questions showed that more than 80% of complaints about Honda's adaptive cruise control were about the way it functioned and/or performed. Infiniti's side-view assist was the only one with complaints mentioning circumstances where it was used. Trust in forward collision warning, lane departure warning, and active lane keeping was not significantly different among vehicles. CONCLUSIONS: Driver trust varied among driver assistance technologies, and trust in adaptive cruise control and side-view assist differed among vehicles. Trust may affect real-world use of driver assistance technologies and limit the opportunity for the systems to provide their intended benefits. PMID- 28339299 TI - The 10th GCC Closed Forum: rejected data, GCP in bioanalysis, extract stability, BAV, processed batch acceptance, matrix stability, critical reagents, ELN and data integrity and counteracting fraud. AB - The 10th Global CRO Council (GCC) Closed Forum was held in Orlando, FL, USA on 18 April 2016. In attendance were decision makers from international CRO member companies offering bioanalytical services. The objective of this meeting was for GCC members to meet and discuss scientific and regulatory issues specific to bioanalysis. The issues discussed at this closed forum included reporting data from failed method validation runs, GCP for clinical sample bioanalysis, extracted sample stability, biomarker assay validation, processed batch acceptance criteria, electronic laboratory notebooks and data integrity, Health Canada's Notice regarding replicates in matrix stability evaluations, critical reagents and regulatory approaches to counteract fraud. In order to obtain the pharma perspectives on some of these topics, the first joint CRO-Pharma Scientific Interchange Meeting was held on 12 November 2016, in Denver, Colorado, USA. The five topics discussed at this Interchange meeting were reporting data from failed method validation runs, GCP for clinical sample bioanalysis, extracted sample stability, processed batch acceptance criteria and electronic laboratory notebooks and data integrity. The conclusions from the discussions of these topics at both meetings are included in this report. PMID- 28339304 TI - Mid-treatment magnetic resonance imaging in pediatric intracranial low-grade gliomas treated with proton beam therapy. PMID- 28339303 TI - Development of RAP Tag, a Novel Tagging System for Protein Detection and Purification. AB - Affinity tag systems, possessing high affinity and specificity, are useful for protein detection and purification. The most suitable tag for a particular purpose should be selected from many available affinity tag systems. In this study, we developed a novel affinity tag called the "RAP tag" system, which comprises a mouse antirat podoplanin monoclonal antibody (clone PMab-2) and the RAP tag (DMVNPGLEDRIE). This system is useful not only for protein detection in Western blotting, flow cytometry, and sandwich enzyme-linked immunosorbent assay, but also for protein purification. PMID- 28339305 TI - Development of anxiety, depression and health-related quality of life in oncology patients without initial symptoms according to the Hospital Anxiety and Depression Scale - a comparative study. AB - BACKGROUND: Depression and anxiety are associated with decreased health-related quality of life (HRQoL). The knowledge about the development of anxiety, depression and HRQoL in cancer patients without depression or anxiety, that is initially scoring as non-cases (cutoff <8) according to the Hospital Anxiety and Depression Scale (HADS), is sparse. The objectives were: (1) to evaluate changes in anxiety, depression and HRQoL over 6 months in two independent cohorts of oncology patients initially scoring as non-cases by the HADS, (2) to compare stable non-case patients with the general population regarding HRQoL and (3) to explore the outcomes using >4 rather than >7 as cutoff on any of HADS subscales. METHODS: The study group (SG) included 245 and the validation group (VG), a previous cohort, included 281 non-cases. Patients who were non-cases (HADS <8) at all completed assessments were categorized as stable non-cases (stable-NC); those who were doubtful/clinical cases (HADS >7) in at least one follow-up were categorized as unstable-NC. Questionnaires were completed at baseline, and after 1, 3 and 6 months. Age- and sex-matched EORTC QLQ-C30 data from the general population were used for HRQoL comparisons. RESULTS: One hundred ninety-six (80%) SG and 244 (87%) VG patients were stable-NC and 49 (20%) SG and 37 (13%) VG patients were unstable-NC. SG and VG were similar in all outcomes. Anxiety, depression and HRQoL deteriorated over 6 months for unstable-NC (p < .05). HRQoL for stable-NC was comparable to that in the general population. If >4 had been used as cutoff, most unstable-NC (36/49 and 25/37, respectively) would have been identified at baseline. CONCLUSIONS: Most non-cases are stable-NC with a high stable HRQoL, indicating no need for re-assessment. A minority develop anxiety or depression symptoms and impaired HRQoL; for these a cutoff >4 rather than >7 on HADS subscales may be useful for early detection. PMID- 28339306 TI - Descriptive characteristics of colon and rectal cancer recurrence in a Danish population-based study. AB - BACKGROUND: Recurrence is a common outcome among patients that have undergone an intended curative resection for colorectal cancer. However, data on factors that influence colorectal cancer recurrence are sparse. We report descriptive characteristics of both colon and rectal cancer recurrence in an unselected population. MATERIAL AND METHODS: We identified 21,152 patients with colorectal cancer diagnosed between May 2001 and December 2011 and registered with the Danish Colorectal Cancer Group. Recurrences were identified in 3198 colon and 1838 rectal cancer patients during follow-up. We calculated the frequency, proportion, and incidence rates of colon and rectal cancer recurrence within descriptive categories, and the cumulative five- and ten-year incidences of recurrence, treating death as a competing risk. We used a Cox proportional hazard model to calculate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Recurrence risk was highest in the first three years of follow-up. Patients <55 years old at initial diagnosis (incidence rate for colon: 7.2 per 100 person years; 95% CI: 6.5-7.9; rectum: 8.1 per 100 person-years; 95% CI: 7.2-9.0) and patients diagnosed with stage III cancer (colon HR: 5.70; 95% CI: 4.61-7.06; rectal HR: 7.02; 95% CI: 5.58-8.82) had increased risk of recurrence. Patients diagnosed with stage III cancer from 2009 to 2011 had a lower incidence of recurrence than those diagnosed with stage III cancer in the years before. Cumulative incidences of colon and rectal cancer recurrence were similar for both cancer types among each descriptive category. CONCLUSIONS: In this population, increases in colorectal cancer recurrence risk were associated with younger age and increasing stage at diagnosis. Cumulative incidence of recurrence did not differ by cancer type. Descriptive characteristics of colon and rectal cancer recurrence may help to inform patient-physician decision-making, and could be used to determine adjuvant therapies or tailor surveillance strategies so that recurrence may be identified early, particularly within the first 3 years of follow-up. PMID- 28339307 TI - Testing for Clostridium difficile in Patients With Cancer. PMID- 28339308 TI - Association between EMS Question Bank Completion and Passing Rates on the EMS Certification Examination. AB - INTRODUCTION: A board review question bank was created to assist candidates in their preparation for the 2015 EMS certification examination. We aimed to describe the development of this question bank and evaluate its successes in preparing candidates to obtain EMS subspecialty board certification. METHODS: An online question bank was developed by 13 subject matter experts who participated as item writers, representing eight different EMS fellowship programs. The online question bank consisted of four practice tests, with each of the tests comprised of 100 questions. The number of candidates who participated in and completed the question bank was calculated. The passing rate among candidates who completed the question bank was calculated and compared to the publicly reported statistics for all candidates. The relationship between candidates' performance on the question bank and subspecialty exam pass rates was determined. RESULTS: A total of 252 candidates took at least one practice test and, of those, 225 candidates completed all four 100-question practice tests. The pass rate on the 2015 EMS certification exam was 79% (95%CI 74-85%) among candidates who completed the question bank, which is 12% higher than the overall pass rate (p = 0.003). Candidates' performance on the question bank was positively associated with overall success on the exam (X2 = 75.8, p < 0.0001). Achieving a score of >= 70% on the question bank was associated with a higher likelihood of passing the exam (OR = 17.8; 95% CI: 8.0-39.6). CONCLUSION: Completing the question bank program was associated with improved pass rates on the EMS certification exam. Strong performance on the question bank correlated with success on the exam. PMID- 28339309 TI - The Use of Non-invasive Ventilation during Exercise Training in COPD Patients. AB - Non-invasive ventilation (NIV) is increasingly used in addition to exercise training in patients with chronic obstructive pulmonary disease with the purpose to allow them to train at higher intensities. Different modalities of assisted ventilation have been used with benefits for relief of dyspnoea and increase in exercise capacity. Nevertheless there are some potential problems with the use of NIV in pulmonary rehabilitation programmes. Despite promising results, a generalised use of NIV during exercise training programmes is unlikely to have a role in routine settings. The use of NIV during exercise training as a component of pulmonary rehabilitation should be reserved to individual cases. PMID- 28339310 TI - Investigations of octylglyceryl dextran-graft-poly(lactic acid) nanoparticles for peptide delivery to the brain. AB - AIM: Develop modified dextran nanoparticles showing potential to assist with drug permeation across the blood-brain barrier for the delivery of neuropeptides. METHODS: Nanoparticles loaded by emulsification with model macromolecular actives were characterized in terms of stability, cytotoxicity and drug-release behavior. Peptide-loaded nanoformulations were tested in an in vivo trout model and in food deprived mice. RESULTS: Nanoformulations loaded with model peptides showed good stability and appeared nontoxic in low concentration against human brain endothelial cells. They were found to preserve the bioactivity of loaded peptides (angiotensin II) as demonstrated in vivo using a trout model, and to induce a transient reduction of food consumption in mice when loaded with an anorexigenic octaneuropeptide. CONCLUSION: Octylglyceryl dextran-graft-poly(lactic acid) nanoparticles formulated by emulsification demonstrate potential for peptide delivery. PMID- 28339311 TI - Lung-RADS Category 4X: Does It Improve Prediction of Malignancy in Subsolid Nodules? AB - Purpose To evaluate the added value of Lung CT Screening Reporting and Data System (Lung-RADS) assessment category 4X over categories 3, 4A, and 4B for differentiating between benign and malignant subsolid nodules (SSNs). Materials and Methods SSNs on all baseline computed tomographic (CT) scans from the National Lung Cancer Trial that would have been classified as Lung-RADS category 3 or higher were identified, resulting in 374 SSNs for analysis. An experienced screening radiologist volumetrically segmented all solid cores and located all malignant SSNs visible on baseline scans. Six experienced chest radiologists independently determined which nodules to upgrade to category 4X, a recently introduced category for lesions that demonstrate additional features or imaging findings that increase the suspicion of malignancy. Malignancy rates of purely size-based categories and category 4X were compared. Furthermore, the false positive rates of category 4X lesions were calculated and observer variability was assessed by using Fleiss kappa statistics. Results The observers upgraded 15% 24% of the SSNs to category 4X. The malignancy rate for 4X nodules varied from 46% to 57% per observer and was substantially higher than the malignancy rates of categories 3, 4A, and 4B SSNs without observer intervention (9%, 19%, and 23%, respectively). On average, the false-positive rate for category 4X nodules was 7% for category 3 SSNs, 7% for category 4A SSNs, and 19% for category 4B SSNs. Of the falsely upgraded benign lesions, on average 27% were transient. The agreement among the observers was moderate, with an average kappa value of 0.535 (95% confidence interval: 0.509, 0.561). Conclusion The inclusion of a 4X assessment category for lesions suspicious for malignancy in a nodule management tool is of added value and results in high malignancy rates in the hands of experienced radiologists. Proof of the transient character of category 4X lesions at short term follow-up could avoid unnecessary invasive management. (c) RSNA, 2017. PMID- 28339312 TI - Biomacromolecule/lipid hybrid nanoparticles for controlled delivery of sorafenib in targeting hepatocellular carcinoma therapy. AB - AIM: Hybrids composed of various materials are highly versatile for drug delivery in tumor therapy including hepatocellular carcinoma. Herein, a sorafenib (SF) loaded biomacromolecule hyaluronic acid (HA)/lipid hybrid nanoparticles (HA/SF cLNS) were developed for targeting drug delivery. MATERIALS & METHODS: In vitro assays determined HA/SF-cLNS release behavior, enzymatic degradation, uptake and cytotoxicity. H22-bearing liver cancer xenograft murine models were used to evaluate the biodistribution and therapeutic efficacy in vivo. RESULTS: HA/SF cLNS could be disassembled and drug was released in response to hyaluronidase. In vivo imaging results demonstrated HA/cLNS could enhance drug accumulation at tumor site. Meanwhile, HA/SF-cLNS exhibited improved antitumor efficacy in vitro and in vivo. CONCLUSION: HA/SF-cLNS demonstrated the potential to enhance antitumor efficacy of SF. PMID- 28339313 TI - Palliative Care in Surgery: Defining the Research Priorities. AB - Given the acute and often life-limiting nature of surgical illness, as well as the potential for treatment to induce further suffering, surgical patients have considerable palliative care needs. Yet, these patients are less likely to receive palliative care than their medical counterparts and palliative care consultations often occur when death is imminent, reflecting poor quality end-of life care. Surgical patients would likely benefit from early palliative care delivered alongside surgical treatment to promote goal-concordant decision making and to improve patients' physical, emotional, social, and spiritual well-being and quality of life. To date, evidence to support the role of palliative care in surgical practice is sparse and palliative care research in surgery is encumbered by methodological challenges and entrenched cultural norms that impede appropriate provision of palliative care. The objective of this article was to describe the existing science of palliative care in surgery within three priority areas and expose specific gaps within the field. We propose a research agenda to address these gaps and provide a road map for future investigation. PMID- 28339314 TI - An Analysis of EMS and ED Detection of Stroke. AB - BACKGROUND AND PURPOSE: Studies have shown a reduction in time-to-CT and improved process measures when EMS personnel notify the ED of a "stroke alert" from the field. However, there are few data on the accuracy of these EMS stroke alerts. The goal of this study was to examine diagnostic test performance of EMS and ED stroke alerts and related process measures. METHODS: The EMS and ED records of all stroke alerts in a large tertiary ED from August 2013-January 2014 were examined and data abstracted by one trained investigator, with data accuracy confirmed by a second investigator for 15% of cases. Stroke alerts called by EMS prior to ED arrival were compared to stroke alerts called by ED physicians and nurses (for walk-in patients, and patients transported by EMS without EMS stroke alerts). Means +/- SD, medians, unpaired t-tests (for continuous data), and two tailed Fisher's exact tests (for categorical data) were used. RESULTS: Of 260 consecutive stroke alerts, 129 were EMS stroke alerts, and 131 were ED stroke alerts (70 called by physicians, 61 by nurses). The mean NIH Stroke Scale was higher in the EMS group (8.1 +/- 7.6 vs. 3.0 +/- 5.0, p < 0.0001). The positive predictive value of EMS stroke alerts was 0.60 (78/129), alerts by ED nurses was 0.25 (15/61), and alerts by ED physicians was 0.31 (22/70). The PPV for EMS was better than for nurses or physicians (both p < 0.001), and more patients in the EMS group had final diagnoses of stroke (62/129 vs. 24/131, p < 0.001). The positive likelihood ratio was 1.53 for EMS personnel, 0.45 for physicians, and 0.77 for nurses. The mean time to order the CT (8.5 +/- 7.1 min vs. 23.1 +/- 18.2 min, p < 0.0001) and the mean ED length of stay (248 +/- 116 min vs. 283 +/- 128 min, p = 0.022) were shorter for the EMS stroke alert group. More EMS stroke alert patients received tPA (16/129 vs. 6/131, p = 0.027). CONCLUSIONS: EMS stroke alerts have better diagnostic test performance than stroke alerts by ED staff, likely due to higher NIH Stroke Scale scores (more obvious presentations) and are associated with better process measures. The fairly low PPV suggests room for improvement in prehospital stroke protocols. PMID- 28339316 TI - Practical Insight to Monitor Home NIV in COPD Patients. AB - Home noninvasive ventilation (NIV) is used in COPD patients with concomitant chronic hypercapnic respiratory failure in order to correct nocturnal hypoventilation and improve sleep quality, quality of life, and survival. Monitoring of home NIV is needed to assess the effectiveness of ventilation and adherence to therapy, resolve potential adverse effects, reinforce patient knowledge, provide maintenance of the equipment, and readjust the ventilator settings according to the changing condition of the patient. Clinical monitoring is very informative. Anamnesis focuses on the improvement of nocturnal hypoventilation symptoms, sleep quality, and side effects of NIV. Side effects are major cause of intolerance. Screening side effects leads to modification of interface, gas humidification, or ventilator settings. Home care providers maintain ventilator and interface and educate patients for correct use. However, patient's education should be supervised by specialized clinicians. Blood gas measurement shows a significant decrease in PaCO2 when NIV is efficient. Analysis of ventilator data is very useful to assess daily use, unintentional leaks, upper airway obstruction, and patient ventilator synchrony. Nocturnal oximetry and capnography are additional monitoring tools to assess the impact of NIV on gas exchanges. In the near future, telemonitoring will reinforce and change the organization of home NIV for COPD patients. PMID- 28339315 TI - Identification of Asymptomatic Prosthetic Joint Infection: Microbiologic and Operative Treatment Outcomes. AB - BACKGROUND: This prospective study investigated the role of mechanical and biological factors in aseptic implant loosening or presumed silent prosthetic joint infection (PJI). METHODS: Thirty-seven patients were investigated. Microbiologic and molecular methods were used to detect bacteria on the surface of the failed implants removed during revision arthroplasty. Histopathologic analysis was performed. The influence of body mass index (BMI) and various co morbidities on implant failure also was determined. RESULTS: The results of sonicated fluid cultures were positive for bacteria in 29.7% and the results of intra-operative tissue and joint liquid cultures in 18.9% and 16.2%, respectively. Molecular detection with 16S rRNA sequencing revealed a large variety of bacteria. The most frequent organism was coagulase-negative Staphylococcus (CNS). The outcomes of histopathologic tests of peri-prosthetic tissue showed evidence of the infection type in all culture-positive joints and in 41.4% of the cases with negative culture results. Overweight status or obesity was present in 82.8% of the culture-negative patients. CONCLUSIONS: The results of this study proved the presence of micro-organisms on the surface of implants in both aseptic and presumed PJI cases. Inclusion of the sonication procedure in the diagnostic algorithm increased the ability to identify the pathogen. The results of our study suggest the co-existing roles of BMI and the time to implant loosening as well as biological agents in causing prosthesis loosening. PMID- 28339317 TI - The Balance Super Learner: A robust adaptation of the Super Learner to improve estimation of the average treatment effect in the treated based on propensity score matching. AB - Consistency of the propensity score estimators rely on correct specification of the propensity score model. The propensity score is frequently estimated using a main effect logistic regression. It has recently been shown that the use of ensemble machine learning algorithms, such as the Super Learner, could improve covariate balance and reduce bias in a meaningful manner in the case of serious model misspecification for treatment assignment. However, the loss functions normally used by the Super Learner may not be appropriate for propensity score estimation since the goal in this problem is not to optimize propensity score prediction but rather to achieve the best possible balance in the covariate distribution between treatment groups. In a simulation study, we evaluated the benefit of a modification of the Super Learner by propensity score estimation geared toward achieving covariate balance between the treated and untreated after matching on the propensity score. Our simulation study included six different scenarios characterized by various degrees of deviation from the usual main term logistic model for the true propensity score and outcome as well as the presence (or not) of instrumental variables. Our results suggest that the use of this adapted Super Learner to estimate the propensity score can further improve the robustness of propensity score matching estimators. PMID- 28339318 TI - Predictors for lymph nodes involvement in low risk endometrial cancer. AB - Neutrophil-lymphocyte ratio (NLR) and BMI were examined as pre-operative predictors for lymph node metastases in patients with low-risk endometrial cancer. The study was a retrospective analysis of 534 endometrial cancer patients that underwent hysterectomy and lymph node dissection. Included subjects had a preoperative diagnosis of a grade 1 or 2 endometrioid carcinoma and no macroscopic extrauterine disease. We compared node-negative to node-positive patients to identify correlates of node-positive disease. The node-positive group presented with lower BMI than the node-negative group, 31.5 and 34.4, respectively (p = .03). The mean NLR was higher in the node-positive group 3.4 vs 2.9 (p = .08), showing a trend towards significance on univariate analysis. On multivariate analysis, lower BMI was found to be an independent predictor for nodal metastasis. Our data suggest that lower BMI is a risk factor for lymph nodes involvement in low-risk endometrial cancer. Impact statement Most endometrial cancer patients have low-risk disease with low risk for lymph nodes metastasis. In order to reduce the number of patients that will undergo unnecessary lymph node dissection, different types of preoperative predictors for lymph node involvement were studied. CA 125 and different imaging modalities were found as useful predictors for more advanced disease. Less studied predictors are the systemic inflammatory response markers and patient's BMI. This study suggests that lower BMI is a risk factor for lymph node involvement in low-risk endometrial cancer. The neutrophil to lymphocyte ratio was close to significance as a predictor for lymph node involvement. In practice, physicians might favour comprehensive lymph node dissection when there is a doubt regarding the procedure but the patient is lean. The study's conclusion can be utilised for triaging patients to general gynaecologist vs gynaecologic oncologist. Further research should focus on combining predictors such as age, BMI, NLR, CA 125 and imaging to better predict lymph nodes involvement in low-risk endometrial cancer. PMID- 28339319 TI - Intrathecal magnetic drug targeting for localized delivery of therapeutics in the CNS. AB - AIM: The challenge in treating neurological diseases is not lack of drug potency, but ineffective targeting techniques. We propose a technique called intrathecal magnetic drug targeting (IT-MDT), in which intrathecally injected magnetic nanoparticles (MNPs) are targeted to specific sites using external magnets. MATERIALS & METHODS: MRI and histology confirmed localization of MNPs via IT-MDT at target sites along the spine of Sprague-Dawley rats. RESULTS: MRI results confirmed greater MNP localization when the duration of magnet application was extended. Histological analysis quantified MNP tissue uptake and provided insight into their route of transport into deeper tissue regions. CONCLUSION: IT-MDT has potential for future use in neurological disease treatments. It can produce localized therapeutic effect, with decreased systemic toxicity. PMID- 28339320 TI - Basic Life Support Access to Injectable Epinephrine across the United States. AB - BACKGROUND: Aggressive epinephrine administration has growing support in the treatment of anaphylaxis, a life-threatening allergic reaction. Emergency Medical Services (EMS) providers are frequently in a position to provide the first care to someone experiencing an anaphylactic reaction. Intramuscular injection of epinephrine is the definitive pharmacologic treatment for many associated symptoms. While easy to use, epinephrine autoinjectors (EAI) are prohibitively expensive, having increased in price ten-fold in ten years. Some states and EMS departments have begun expanding the scope of practice to allow Basic Life Support (BLS) providers, previously restricted to noninvasive therapies, to administer epinephrine by syringe. OBJECTIVES: To compile a current and comprehensive list of how epinephrine is carried and used by EMS across the USA. METHODS: An online survey focusing on anaphylaxis protocols and epinephrine administration was sent to state EMS medical directors and officials in all 50 states. Follow-up telephone calls were made to ensure compliance. Data were analyzed with descriptive statistics. RESULTS: Forty-nine of the 50 states in the USA provided a survey response. Texas responded but declined to participate in the survey because of practice variability across the state. In the other states, the form of epinephrine allowed or required on BLS ambulances was consistent with the scope of practice of their Basic Emergency Medical Technician (EMT). Thirteen states had training programs to allow BLS providers to inject epinephrine; 7 were considering it; 29 were not. Twenty-seven states specified EAI as the only form of epinephrine required or allowed on their BLS ambulances. No states reported allowing any level of EMS provider below EMT to use alternatives to EAI. CONCLUSION: This study confirms that many states have expanded the training of BLS providers to include the use of syringe injectable epinephrine. Even so, the majority of states relied on EAI in BLS ambulances. PMID- 28339321 TI - A systematic review on community-based interventions for elder abuse and neglect. AB - Elder abuse and neglect is a societal issue that requires prevention and intervention strategies at the practice and policy level. A systematic review on the efficacy of community-based elder abuse interventions was undertaken to advance the state of knowledge in the field. The peer-reviewed literature between 2009 and December 2015 were searched across four databases. Two raters independently reviewed all articles, assessed their methodological quality, and used a modified Sackett Scale to assign levels of evidence. Four thousand nine hundred and five articles were identified; nine were selected for inclusion. Although there was Level-1 evidence for psychological interventions (n = 2), only one study on strategies for relatives (START) led to a reported decrease in elder abuse. There was Level-4 evidence for conservatorship, an elder abuse intervention/prevention program (ECARE), and a multidisciplinary intervention (n = 4), in which one study yielded significant decreases in elder abuse and/or neglect. The remaining three were classified as Level-5 evidence (n = 3) for elder mediation and multidisciplinary interventions. There are limited studies with high levels of evidence for interventions that decrease elder abuse and neglect. The scarcity of community-based interventions for older adults and caregivers highlights the need for further work to elevate the quality of studies. PMID- 28339322 TI - A Comparison of Note Writers and No Note Writers in Homicide-Suicide Cases in Germany. AB - The aim of this study is to investigate potential differences between homicide suicide cases in which the perpetrator does or does not write a suicide note. As homicide-suicides are complex types of lethal violence for which the aggressor cannot be held accountable, suicide notes may be a valuable source of information about the background of these cases and the perpetrators' motives. We use a national sample of N = 288 homicide-suicide cases in Germany applying group comparisons and chi-square tests for relevant variables. Perpetrators killing their own children and perpetrators leaving children behind before killing themselves write significantly more suicide notes than other perpetrators. Even though note writers and no note writers are similar regarding most sociodemographic characteristics, other differences question the generalizability between these 2 groups. PMID- 28339323 TI - Media Coverage of FDA Drug Safety Communications about Zolpidem: A Quantitative and Qualitative Analysis. AB - FDA issues Drug Safety Communications (DSCs) to alert health care professionals and the public about emerging safety information affecting prescription and over the-counter drugs. News media may amplify DSCs, but it is unclear how DSC messaging is transmitted through the media. We conducted a content analysis of the lay media coverage reaching the broadest audience to characterize the amount and content of media coverage of two zolpidem DSCs from 2013. After the first DSC, zolpidem news stories increased from 19 stories/week in the preceding 3 months to 153 following its release. Most (81%) appeared in the lay media, and 64% focused on the DSC content. After the second DSC, news stories increased from 24 stories/week in the preceding 3 months to 39 following. Among the 100 unique lay media news stories, at least half correctly reported three key DSC messages: next-day impairment and drowsiness as common safety hazards, lower doses for some but not all zolpidem products, and women's higher risk for impairment. Other DSC messages were reported in fewer than one-third of stories, such as the warning that impairment can happen even when people feel fully awake. The first-but not the second-zolpidem DSC generated high-profile news coverage. The finding that some messages were widely reported but others were not emphasizes the importance of ensuring translation of key DSC content. PMID- 28339324 TI - Mobile But Connected: Harnessing the Power of Self-Efficacy and Group Support for Weight Loss Success through mHealth Intervention. AB - Despite the growing popularity of mHealth applications, their usage outcomes have received limited empirical attention. Drawing on server-level user activity data and an online survey (N = 384), this study examines the use of an mHealth application for weight loss to elucidate the ways in which it can help individuals harness the power of self-efficacy and group support to enact behavior change and accomplish their health goals. The results of structural equation modeling based on 6-month user activity data demonstrated that (a) self efficacy had a positive impact on persistent food logging in an mHealth application; (b) social support received from a mobile group was positively associated with food logging and group participation; and (c) both food logging and group participation predicted weight loss success. Extending these findings, this study suggests theoretical and practical implications for designing individually tailored and evidence-based health intervention strategies using advanced mHealth technologies. PMID- 28339325 TI - Community-Based Services and Depression from Person-Environment Fit Perspective: Focusing on Functional Impairments and Living Alone. AB - Guided by the Person-Environment Fit perspective, we investigated the extent to which personal and environmental factors influence depression among community dwelling adults. The data came from the special section about community-based service utilization in the 2012 Health and Retirement Study (N=1,710). Although community-based service was not significantly associated with depression after controlling for covariates, respondents with functional limitations and living alone were less likely to be depressed when using community-based services. This study demonstrates the different associations between community-based services and depression depending on personal needs. It discusses the importance of community-based services for aging-in-place policy, particularly among vulnerable populations. PMID- 28339326 TI - Using Online Methods to Develop and Examine the Hong Kong Chinese Translation of the Dissociative Experiences Scale. AB - Identifying dissociation is important for mental health services because it could fundamentally affect one's diagnosis and treatment plan. The Dissociative Experiences Scale (DES) is a widely-used self-report scale for measuring dissociative experiences. It has been translated into many languages and used in many countries. However, there is no validated Hong Kong Chinese version of the DES available in the field, and there is no other validated Hong Kong Chinese instrument for assessing dissociative disorders. This pilot study used online methods to translate the DES to Hong Kong Chinese (HKC-DES). The results indicated that the HKC-DES has excellent internal consistency (alpha = .953) and very good test-retest reliability (r = .797). Bilingual participants' responses to the DES and HKC-DES indicated high similarity, and were significantly correlated (r = .960). These results initially verified the reliability and cross language equivalence of the scale. Implications for healthcare practice and research are discussed. PMID- 28339327 TI - Raising Public Awareness of Clinical Trials: Development of Messages for a National Health Communication Campaign. AB - Clinical trials are essential for developing new and effective treatments and improving patient quality of life; however, many trials cannot answer their primary research questions because they fall short of their recruitment goals. This article reports the results of formative research conducted in two populations, the public and primary care physicians, to identify messages that may raise awareness and increase interest in clinical trials and be used in a national communication campaign. Results suggested that participants were primarily motivated to participate in clinical trials out of a self-interest to help themselves first. Messages illustrated that current treatments were tested via clinical trials, helped normalize trials as routine practices, and reduced concerns over trying something new first. Participants wanted messages that portray trials as state-of-the-art choices that offer some hope, show people like themselves, and are described in a clear, concise manner with actionable steps for them to take. The study revealed some differences in message salience, with healthy audiences exhibiting lower levels of interest. Our results suggest that targeted messages are needed, and that communication with primary health-care providers is an important and necessary component in raising patient awareness of the importance of clinical trials. PMID- 28339328 TI - Mercaptopurine Ingestion Habits, Red Cell Thioguanine Nucleotide Levels, and Relapse Risk in Children With Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group Study AALL03N1. AB - Purpose Children with acute lymphoblastic leukemia (ALL) are generally instructed to take mercaptopurine (6-MP) in the evening and without food or dairy products. This study examines the association between 6-MP ingestion habits and 6-MP adherence, red cell thioguanine nucleotide (TGN) levels, and risk of relapse in children with TMPT wild-type genotype. Methods Participants included 441 children with ALL receiving oral 6-MP for maintenance. Adherence was monitored over 48,086 patient-days using the Medication Event Monitoring System; nonadherence was defined as adherence rate < 95%. 6-MP ingestion habits examined included: takes 6 MP with versus never with food, takes 6-MP with versus never with dairy, and takes 6-MP in the evening versus morning versus varying times. Results Median age at study was 6 years (range, 2 to 20 years); 43.8% were nonadherent. Certain 6-MP ingestion habits were associated with nonadherence (taking 6-MP with dairy [odds ratio (OR), 1.9; 95% CI, 1.3 to 2.9; P = .003] and at varying times [OR, 3.4; 95% CI, 1.8 to 6.3; P = .0001]). After adjusting for adherence and other prognosticators, there was no association between 6-MP ingestion habits and relapse risk (6-MP with food: hazard ratio [HR], 0.7; 95% CI, 0.3 to 1.9; P = .5; with dairy: HR, 0.3; 95% CI, 0.07 to 1.5; P = .2; taken in evening/night: HR, 1.1; 95% CI, 0.2 to 7.8; P = .9; at varying times: HR, 0.3; 95% CI, 0.04 to 2.7; P = .3). Among adherent patients, there was no association between red cell TGN levels and taking 6-MP with food versus without (206.1 +/- 107.1 v 220.6 +/- 121.6; P = .5), with dairy versus without (220.1 +/- 87.8 v 216.3 +/- 121.3; P =.7), or in the evening/night versus morning/midday versus varying times (218.8 +/- 119.7 v 195.5 +/- 82.3 v 174.8 +/- 93.4; P = .6). Conclusion Commonly practiced restrictions surrounding 6-MP ingestion might not influence outcome but may hinder adherence. Future recommendations regarding 6-MP intake during maintenance therapy for childhood ALL should aim to simplify administration. PMID- 28339329 TI - Morbidity and Mortality Associated With Meningioma After Cranial Radiotherapy: A Report From the Childhood Cancer Survivor Study. AB - Purpose Little is known about neurologic morbidity attributable to cranial radiotherapy (CRT) -associated meningiomas. Materials and Methods From 4,221 survivors exposed to CRT in the Childhood Cancer Survivor Study, a diagnosis of meningioma and onset of neurologic sequelae were ascertained. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% CIs to evaluate the factors associated with neurologic sequelae after subsequent meningioma. Results One hundred ninety-nine meningiomas were identified among 169 participants. The median interval from primary cancer to meningioma diagnosis was 22 years (5 to 37 years). The cumulative incidence of a subsequent meningioma by age 40 years was 5.6% (95% CI, 4.7% to 6.7%). CRT doses of 20 to 29.9 Gy (HR, 1.6; 95% CI,1.0 to 2.6) and doses >= 30 Gy (HR, 2.6; 95% CI, 1.6 to 4.2) were associated with an increased risk of meningioma compared with CRT doses of 1.5 to 19.9 Gy ( P < .001). Within 6 months before or subsequent to a meningioma diagnosis, 20% (30 of 149) reported at least one new neurologic sequela, including seizures (8.3%), auditory-vestibular-visual deficits (6%), focal neurologic dysfunction (7.1%), and severe headaches (5.3%). Survivors reporting a meningioma had increased risks of neurologic sequelae > 5 years after primary cancer diagnosis, including seizures (HR, 10.0; 95% CI, 7.0 to 15.3); auditory vestibular-visual sensory deficits (HR, 2.3; 95% CI, 1.3 to 4.0); focal neurologic dysfunction (HR, 4.9; 95% CI, 3.2 to 7.5); and severe headaches (HR, 3.2; 95% CI, 1.9 to 5.4). With a median follow-up of 72 months after meningioma diagnosis (range, 3.8 to 395 months), 22 participants (13%) were deceased, including six deaths attributed to a meningioma. Conclusion Childhood cancer survivors exposed to CRT and subsequently diagnosed with a meningioma experience significant neurologic morbidity. PMID- 28339331 TI - Differential diagnosis of a patient referred to physical therapy for dizziness: a case report. AB - STUDY DESIGN: Case report. BACKGROUND: Dizziness is a common and debilitating condition across the lifespan. Patients with this complaint must be carefully examined to determine the cause of dizziness, rule out the presence of central nervous system dysfunction, and determine the appropriateness of physical therapy intervention. CASE DESCRIPTION: A 90-year-old male was referred to physical therapy six months after the onset of dizziness. A thorough history was taken and examination was performed. Signs consistent with central nervous system dysfunction and peripheral vestibular dysfunction were observed. The patient was treated for the peripheral vestibular disorder and referred back to his physician for further testing. Imaging revealed that the patient had idiopathic normal pressure hydrocephalus. DISCUSSION: This case illustrates the need for physical therapists to perform thorough examinations of patients with a primary complaint of dizziness and properly interpret positive central signs, indicating a potential need for referral to a physician or other healthcare provider when they appear. PMID- 28339330 TI - "Clinical biopsychosocial physiotherapy assessment of patients with chronic pain: The first step in pain neuroscience education" by Amarins J Wijma et al., 2016. PMID- 28339332 TI - Disc displacement without reduction with limited opening: A clinical diagnostic accuracy study. AB - PURPOSE: The purpose of this study is to explore the diagnostic accuracy and clinical utility of an examination by a physical therapist using a clinical patient population for diagnosing a specific sub-type of disc displacement (DDWoR wLO) compared to the imaged disc position. METHODS: Data from 46 patients with a clinical diagnosis of DDWoR wLO (92 clinical examinations and MRI records) were collected. Clinical diagnosis was made based on predefined diagnostic criteria, and the MRI diagnosis was made based on the MRI radiology report obtained from the dental provider. A McNemar test was used to determine whether the outcomes of the clinical and MRI diagnoses differed significantly, and sensitivity, specificity, likelihood ratios, predicative values, 95% confidence intervals, and the overall diagnostic accuracy were computed. RESULTS: There was high sensitivity (85%), moderate but unacceptable specificity (73%), and acceptable overall diagnostic accuracy (80%) for using predefined criteria in the diagnosis of DDWoR wLO. The likelihood ratios and predictive values supported the clinical utility of the criteria used for diagnosing DDWoR wLO. CONCLUSION: This is the first study to characterize diagnostic accuracy by a physical therapist of a specific sub-type of TMD in a clinical patient population rather than a research based population. The results suggest that while sensitivity and the overall diagnostic accuracy were acceptable, specificity was lower than acceptable and these findings are discussed in relation to clinical utility of using diagnostic criteria in a clinical setting against a gold standard of MRI. PMID- 28339333 TI - Non-pharmacological conservative therapy for phantom limb pain: A systematic review of randomized controlled trials. AB - The aim of this manuscript was to investigate the effectiveness of conservative therapy for phantom limb pain (PLP). In this systematic review, CINAHL, AMED, the Cochrane database of systematic reviews, PEDro, psychology and behavioral sciences collection, and MEDLINE were systematically searched for appropriate randomized controlled trials (RCTs). Selected papers were assessed for risk of bias, and evidence was graded using the GRADE approach. Twelve RCTs met initial inclusion/exclusion criteria, of which five were of sufficient quality for final inclusion. There is conflicting evidence from two RCTs for the effectiveness of electromagnetic shielding limb liners on pain in the short term. There is limited evidence supporting the effectiveness of both hypnosis in the short term and graded motor imagery (GMI) in the short-to-medium term. Additionally, there is limited evidence that a single session of mirror therapy has no immediate effect on PLP. Limb liner discomfort was the only adverse effect identified. This review identifies a range of conservative therapies, many of which demonstrate preliminary evidence of potential with respect to clinically worthwhile effects above control interventions and few, if any, adverse effects. However, there is a paucity of high-quality evidence upon which to make any firm clinical conclusions. PMID- 28339334 TI - A Movement system impairment approach to evaluation and treatment of a person with lumbar radiculopathy: A case report. AB - BACKGROUND AND PURPOSE: There are several systems of classification and treatment of patients with low back pain (LBP) based on assessment of the effect of lumbar postures and movements on symptoms. The efficacy of one of these systems, The Movement System Impairment (MSI) method, has not yet been demonstrated in the literature. The purpose of this case report is to describe the approach of the MSI method for an individual with lumbar radiculopathy. CASE DESCRIPTION: A 79 year-old woman with a history of chronic LBP was referred to PT with a physician's diagnosis of sciatica. The patient was classified utilizing a standardized MSI evaluation. She was instructed to modify her daily postures and movements, as well as perform specific exercises to address these impairments. OUTCOMES: Her Oswestry LBP disability score improved by over 30% and pain level per the NPRS improved by 3 out of 10 points. DISCUSSION: Despite the challenges of advanced joint degeneration and neurological involvement, this approach of identifying and addressing specific movement impairments appeared helpful for this older individual. PMID- 28339335 TI - Description of movement quality in patients with low back pain: A qualitative study as a first step to a practical definition. AB - PURPOSE: As a first step to formulate a practical definition for movement quality (MQ), this study aims to explore how Dutch allied health care professionals (AHCPs) describe MQ of daily life activities in patients with low back pain (LBP). METHODS: In this qualitative cross-sectional digital survey study, Dutch AHCPs (n = 91) described MQ in open text (n = 91) and with three keywords (n = 90). After exploratory qualitative content analysis, the ICF linking rules (International Classification of Functioning, Disability and Health) were applied to classify MQ descriptions and keywords. FINDINGS: The identified meaningful concepts (MCs) of the descriptions (274) and keywords (239) were linked to ICF codes (87.5% and 80.3%, respectively), Personal factors (5.8% and 5.9%, respectively), and supplementary codes (6.6% and 13.8%, respectively). The MCs were linked to a total of 31 ICF codes, especially to b760 'control of voluntary movement functions', b7602 'coordination of voluntary movements', d4 'Mobility', and d230 'carry out daily routine'. Negative and positive formulated descriptions elucidated different MQ interpretations. CONCLUSIONS: Descriptions of MQ given by Dutch AHCPs in patients with LBP cover all ICF components. Coordination and functional movements are seen as the most elementary concepts of MQ. Variation in MQ descriptions and interpretations hinders defining MQ and indicates the necessity of additional steps. PMID- 28339336 TI - Response to Letter. PMID- 28339337 TI - "I know what I want but I'm not sure how to get it"-Expectations of physiotherapy treatment of persons with persistent pain. AB - Expectations of physiotherapy treatment of patients with persistent pain have been shown to influence treatment outcome and patient satisfaction, yet this is mostly explored and described in retrospective. The aim of the study was to explore and describe the expectations people with persistent pain have prior to physiotherapy treatment. Ten participants with persistent musculoskeletal pain from the back, neck, or shoulders were included in the study. Data were collected by interviews using a semi-structured interview guide and were analyzed with qualitative content analysis. The analysis resulted in one main category: "The multifaceted picture of expectations" and four categories: 1) Standing in the doorway: curious and uncertain; 2) Looking for respect, confirmation and knowledge; 3) Expecting treatment, regular training, and follow up; and 4) Having dreams, being realistic, or feeling resigned. The main category and the categories describe a multifaceted picture of the participants' expectations, gradually developed and eventually encompassing several aspects: good dialog and communication, the need to be confirmed as individuals, and getting an explanation for the pain. The results also show that the participants expected tailored training with frequent follow-ups and their expectations of outcome ranged from hope of the best possible results to realistic or resigned regarding pain relief and activity levels. PMID- 28339338 TI - Fertility treatments among female cancer survivors giving birth - a Finnish register-based study. AB - BACKGROUND: Long-term survival rates for most types of childhood cancers have improved dramatically over the past decades. However, because of advances in multimodality treatments, cancer survivors nowadays more often face long-term complications, including diminished gonadal and reproductive function. The aim of this study was to identify whether the use of fertility treatments among early onset (0-34 years) cancer survivors giving birth differed from that among siblings giving birth and to identify the subgroups of cancer survivors that were most likely to require fertility treatments. MATERIAL AND METHODS: Nationwide cancer and birth registries were merged to identify 1974 post-diagnosis deliveries of cancer survivors and 6107 deliveries of female siblings in 2004 2013. Unconditional multivariate logistic regression models were used to estimate the risk for different fertility treatments namely assisted reproductive technology, intrauterine insemination and ovulation induction. We adjusted for maternal age, year of delivery, parity and smoking. RESULTS: We found overall significantly increased odds for use of any fertility treatments in survivors compared to siblings (OR 1.84, 95% CI 1.18-2.86). As time from cancer treatment increased, the odds for need of fertility treatments increased, being highest at 11 to 15 years post cancer treatment (OR 2.88, 95% CI 1.13-7.30). Survivors diagnosed at ages 25-34 years had the highest odds for use of fertility treatments compared to siblings (OR 2.31, 95% CI 1.01-5.32). CONCLUSIONS: Our study supports previous findings indicating that cancer survivors have an increased risk for subfertility. Survivors diagnosed in their childhood had the lowest risk for fertility treatment and seemed to get pregnant with less extensive fertility treatments than survivors diagnosed as adults. Time elapsed from cancer treatment played a central role, increasing the need for fertility treatments compared to siblings, suggesting that cancer therapies might lead to diminished ovarian reserve. PMID- 28339340 TI - Patient Perspectives on Language Discordance During Healthcare Visits: Findings From the Extremely High-Density Multicultural State of Qatar. AB - Reducing language and cultural barriers in healthcare are significant factors in resolving health disparities. Qatar's rapidly growing multicultural population presents new challenges to the healthcare system. The purpose of this research was to explore patients' perspectives about language discordance, and the strategies used to overcome language barriers during patients' visits. Participants were recruited and interviewed from four language groups (Arabic = 24, English = 20, Hindi = 20, and Urdu = 20), all of whom were living in Qatar and utilizing Hamad General Hospital-Outpatient Clinics as a source of their healthcare services. Using qualitative analysis procedures, relevant themes and codes were generated and data analyzed using Atlas-ti. As for results, most participants had experienced or witnessed language barriers during their outpatient clinics visits. Participants essentially were unfamiliar with professional medical interpreters and described their adaptive solutions, for example utilizing incidental interpreters, stringing together fragments of multiple languages, and using body language. Those not speaking mainstream languages of Hamad General Hospital (English and Arabic) were more vulnerable to health disparities due to language barriers. Despite the patient impetus to do something, patient-reported adaptive strategies could compromise patients' safety and access to quality healthcare. Polices tackling the language barrier need to be reviewed in Qatar's multicultural healthcare system and similar settings. PMID- 28339339 TI - Use of Dietary Supplements Improved Diet Quality But Not Cardiovascular and Nutritional Biomarkers in Socioeconomically Diverse African American and White Adults. AB - Knowledge of the contribution of supplements to overall nutritional health is limited. The research objectives were to describe motivations for use of dietary supplements by African Americans and Whites examined in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study and to determine if supplements provided beneficial effects to micronutrient diet quality and nutritional and cardiovascular biomarkers. The majority of the HANDLS study population were smokers, overweight or obese, and self-reported their health as poor to good. The top two reasons for their supplement use were to supplement the diet and to improve overall health. Micronutrient intake was calculated from two 24-hour recalls and a supplement questionnaire. Diet quality was assessed by the Mean Adequacy Ratio (MAR) [Maximum score = 100] derived from the Nutrient Adequacy Ratio (NAR) for 17 micronutrients. The MAR score for nonusers was 73.12, for supplement users based on diet alone was 74.89, and for food and supplements was 86.61. Dietary supplements significantly increased each NAR score and MAR score. However, there were no significant differences between the population proportions with inadequate or excessive blood levels for any biomarkers examined. Nutrition education programs and intervention strategies addressing dietary supplement intake might lead to healthier food choices and may improve the health of this population. PMID- 28339342 TI - Change in Body Weight from Age 20 Years Is a Powerful Determinant of the Metabolic Syndrome. AB - BACKGROUND: Higher body weight is a well-known determinant of the metabolic syndrome (MetS) and its components. It is however less well studied how the change in weight from age 20 years to middle age or old age affects MetS development. METHODS: In the community-based EpiHealth (n = 19,000, age range 45 to 75 years, 56% females) and PIVUS (n = 1000, all aged 70 years, 50% females) studies, the participants were asked about their body weight at age 20 years. Data were collected to determine MetS prevalence (NCEP ATP III criteria). RESULTS: In EpiHealth, the probability of having MetS increased fairly linearly with increasing weight from age 20 in the obese [odds ratios (OR) 1.04 per kg change in weight, 95% confidence interval (CI) 1.03-1.05, P < 0.0001], as well as in the overweight (OR 1.15, 95% CI 1.14-1.17, P < 0.0001) and normal-weight (OR 1.18, 95% CI 1.14-1.21, P < 0.0001), subjects after adjustment for age, sex, body mass index (BMI) at age 20, alcohol intake, smoking, education, and exercise habits. Also in the PIVUS study, the change in weight over 50 years was related to prevalent MetS (OR 1.08 per kg change in weight, 95% CI 1.06-1.10, P < 0.0001). In both studies, self-reported BMI at age 20 was related to prevalent MetS. CONCLUSION: Self-reported weight gain from age 20 was strongly and independently associated with prevalent MetS both in middle age or old age. Interestingly, this relationship was not restricted only to obese subjects. Our data provide additional support for the importance of maintaining a stable weight throughout life. PMID- 28339341 TI - The Diffusion of Evidence-Based Practice: Reviewing the Evidence-Based Practice Networks in the United States and German-Speaking Countries. AB - Evidence-based practice (EBP) has had a major influence on U.S. social work while it has rarely been adapted in German-speaking countries. This study investigates how knowledge about EBP is diffused within and across geographical contexts. Network analysis methods reveals different diffusion patterns and provide reasons for these differences. For example, the U.S. discourse is self-contained and based on a more homogeneous knowledge base, while the German discourse is more heterogeneous and focuses on a notion of reflexive professionalism. The different conceptual influences within the U.S. and German discourses are discussed in light of future directions of disciplinary social work. PMID- 28339343 TI - Alterations in Multiple Lifestyle Factors in Subjects with the Metabolic Syndrome Independently of Obesity. AB - BACKGROUND: Many lifestyle factors have been associated with the metabolic syndrome (MetS). However, most of these studies have not considered the potential impact of obesity and have often only investigated one lifestyle factor at the time. We aimed to investigate the interplay between body mass index (BMI) and MetS with respect to multiple lifestyle factors. METHODS: BMI and MetS [National Cholesterol Education Program (NCEP)/Adult Treatment Panel III criteria] were assessed in a sample of 18,880 subjects aged 45-75 years from the population based EpiHealth study. Participants were categorized into six groups according to BMI category (normal weight/BMI <25 kg/m2, overweight/BMI 25-30 kg/m2, and obesity/BMI >30 kg/m2) and MetS status (+/-, NCEP criteria). A wide range of lifestyle factors related to physical activity, smoking, alcohol, sleep quality, working conditions, quality of life and stress, and eating patterns were assessed using a questionnaire. RESULTS: Prevalent MetS (23% in the sample) was associated with less physical activity (P < 0.0001), more TV watching (P < 0.0001), more years of smoking (P < 0.0001), lower education level (P = 0.007), and experiencing a poor general quality of life (P < 0.0001). These lifestyle factors were all associated with MetS, independently of each other and independently of BMI. Similar results were generated when number of MetS components and presence/absence of individual MetS components were used as outcomes. CONCLUSIONS: This cross-sectional study identified alterations in a number of lifestyle factors associated with MetS independently of each other and independently of BMI. Future longitudinal studies are needed to assess causal and temporal relationships between lifestyle factors and MetS development. PMID- 28339344 TI - Correlation of Leptin, Adiponectin, and Resistin Levels in Different Types of Lipodystrophy in HIV/AIDS Patients. AB - BACKGROUND: Leptin, adiponectin, and resistin may play an important role in the development of lipodystrophy (LD) in HIV/AIDS patients. The aim of this study was to correlate levels of leptin, adiponectin, and resistin between HIV/AIDS patients with LD and without lipodystrophy (non-LD), as well as between subgroups of LD [lipoatrophy (LA), lipohypertrophy (LH), and mixed fat redistribution (MFR)] and non-LD patients. METHODS: Cross-sectional study of 66 HIV/AIDS patients. Serum levels of leptin, adiponectin, and resistin were measured. The associations between adipocytokine levels and metabolic variables were estimated by Spearman correlation. Analysis of covariance with bootstrapping method was used to examine the relationship between adiponectin and leptin and lipodystrophy categories. RESULTS: The LD was observed in 29 (44%) patients, while 15 (52%) of them had LA, 4 (14%) had LH, and 10 (34%) patients had MFR. No significant differences regarding leptin, adiponectin, and resistin levels, between LD and non-LD patients, were observed. LH patients had significantly higher levels of leptin and adiponectin in comparison with non-LD patients (P = 0.039, P = 0.011, respectively). Within the LD group, LA patients had significantly lower levels of leptin (LA vs. LH, P = 0.020; LA vs. MFR, P = 0.027), while LH patients had significantly higher levels of adiponectin (LH vs. LA, P = 0.027; LH vs. MFR, P = 0.028). Correlation of adiponectin with LD remains significant in the LH subgroup after adjustment for age, body mass index, cystatin-C, plasminogen activator inhibitor-1 (PAI-1), and interferon gamma (IFN-gamma) (P = 0.001). CONCLUSIONS: Adiponectin and leptin levels differ significantly between LH patients and non-LD patients, as well as between the LD subgroups. Adiponectin may be a more useful marker of LD in HIV/AIDS patients. PMID- 28339345 TI - Alanine Aminotransferase Is a Marker of Lipotoxicity Consequences and Hyperandrogenemia in Women with Polycystic Ovary Syndrome. AB - BACKGROUND: Several studies have reported higher levels of Alanine aminotransferase (ALT) in women with polycystic ovary syndrome (PCOS) compared with control subjects. Plasma ALT levels are considered a marker of hepatic lipotoxicity because of their significant associations with different hepatic metabolic dysfunctions, such as hepatic steatosis and hepatic insulin resistance. METHODS: Retrospective chart review aiming to assess, in PCOS women, the relationship between ALT levels and measures of lipotoxicity consequences that are available clinically, both during fasting and using the oral glucose tolerance test. RESULTS: Women (n = 132) with PCOS, were in average 27.9 years of age, with a mean body mass index of 34.1 kg/m2 and 49% had a metabolic syndrome (MetS). ALT levels were significantly correlated with homeostatic model assessment for insulin resistance (r = 0.42, P < 0.001), HDL-C (r = -0.31, P < 0.001), Matsuda index (-0.45, P < 0.001), insulin secretion-sensitivity index-2 ( 0.26, P = 0.043), and free testosterone (0.38, P < 0.001), but not with fasting glucose and triglyceride levels. ALT cutoff >=24 IU/L was associated with all these parameters, including fasting glucose (P = 0.021) and triglyceride levels (P = 0.041), and detected more women with the MetS (59.2% vs. 36.1%, P = 0.008) and whole-body insulin resistance (Matsuda index <12.3 L2.10/mmol2, 85.3% vs. 51.9%, P = 0.004). CONCLUSIONS: Plasma ALT levels seem to be a strong predictor not only of liver lipotoxicity but also of systemic lipotoxic consequences and hyperandrogenemia in women with PCOS. Although it requires validation in another study, an ALT cutoff of >=24 IU/L may help clinicians identify women with increased metabolic risks. PMID- 28339346 TI - The caregiver and her friends. AB - This article is a personal essay about the lesbian friendship networks called upon when a dyke has to take on caregiving responsibilities for her dying mother and, especially, her partner who develops dementia and dies. The primary areas of concern are how friendships form a community's ethical base, the navigation of overlapping friendship networks, the different ways women come through, and the role our institutions play in creating "friendliness." Underpinning these concerns is the way that lesbians create informal groups to investigate, inform, and affirm difficult decisions. PMID- 28339348 TI - Geological occurrence, mineralogical characterization, and risk assessment of potentially carcinogenic erionite in Italy. AB - Erionite is a zeolite representing a well-known health hazard. In fact, exposure of humans to its fibers has been unequivocally associated with occurrence of malignant mesothelioma. For this reason, a multi-methodological approach, based upon field investigation, morphological characterization, scanning electron microscopy (SEM)/energy-dispersive spectroscopy (EDS) chemical analysis, and structure refinement through X-ray powder diffraction (XRPD), was applied to different samples of potentially carcinogenic erionite from Northern Italy. The studied crystals have a chemical composition ranging from erionite-Ca to erionite Na and display variable morphologies, varying from prismatic, through acicular and fibrous, to extremely fibrous asbestiform habits. The fibrous samples were characterized by an unusual preferred partition of aluminum (Al) at tetrahedral site T1 instead of tetrahedral site T2. Further, a mismatch between the a parameter of erionite-Ca and levyne-Ca that are intergrown in the asbestiform sample was detected. This misfit was coupled to a relevant micro-strain to maintain structure coherency at the boundary. Erionite occurs in 65% of the investigated sites, with an estimated quantity of 10 to 40 vol% of the associated minerals. The presence of this mineral is of concern for risk to human health, especially if one considers the vast number of quarries and mining-related activities that are operating in the zeolite host rocks. The discovery of fibrous and asbestiform erionite in Northern Italy suggests the need for a detailed risk assessment in all Italian areas showing the same potential hazard, with specific studies such as a quantification of the potentially respirable airborne fibers and targeted epidemiological surveillance. PMID- 28339350 TI - The Effect of Initial Knee Angle on Concentric-Only Squat Jump Performance. AB - PURPOSE: There is uncertainty as to which knee angle during a squat jump (SJ) produces maximal jump performance. Importantly, understanding this information will aid in determining appropriate ratios for assessment and monitoring of the explosive characteristics of athletes. METHOD: This study compared SJ performance across different knee angles-90o, 100o, 110o, 120o, 130o, and a self-selected depth-for jump height and other kinetic characteristics. For comparison between SJ and an unconstrained dynamic movement, participants also performed a countermovement jump from a self-selected depth. Thirteen participants (Mage = 25.4 +/- 3.5 years, Mheight = 1.8 +/- 0.06 m, Mweight = 79.8 +/- 9.5 kg) were recruited and tested for their SJ performance. RESULTS: In the SJ, maximal jump height (35.4 +/- 4.6 cm) was produced using a self-selected knee angle (98.7 +/- 11.2 degrees ). Differences between 90 degrees , 100 degrees , and self-selected knee angles for jump height were trivial (ES +/- 90% CL = 90 degrees -100 degrees 0.23 +/- 0.12, 90 degrees -SS -0.04 +/- 0.12, 100 degrees -SS -0.27 +/- 0.20; 0.5-2.4 cm) and not statistically different. Differences between all other knee angles for jump height ranged from 3.8 +/- 2.0 cm (mean +/- 90% CL) to 16.6 +/- 2.2 cm. A similar outcome to jump height was observed for velocity, force relative to body weight, and impulse for the assessed knee angles. CONCLUSIONS: For young physically active adult men, the use of a self-selected depth in the SJ results in optimal performance and has only a trivial difference to a constrained knee angle of either 90 degrees or 100 degrees . PMID- 28339349 TI - Is Triclosan a neurotoxic agent? AB - Triclosan (TCS) is an antibacterial agent that has been used in many products since 1960s. Given its broad usage as an antiseptic TCS is present ubiquitously in the environment. Trace levels of TCS continue to be detected in many organisms, and it has been shown to be particularly toxic to aquatic species. The mechanisms underlying TCS-mediated toxicity include hormone dyshomeostasis, induction of oxidative stress, apoptosis and inflammation. Although TCS has been considered to be non-toxic to mammals, the adverse effects of continuous, long term and low concentration exposure remain unknown. Epidemiological studies revealed that levels of TCS in human tissues, urine, plasma and breast milk correlate with the usage of this antimicrobial. This led to concerns regarding TCS safety and potential toxicity in humans, with special emphasis on early development. The Food and Drug Administration (FDA) recently issued a directive banning the use of TCS in consumer soaps, justifying the move attributed to data gaps on its effectiveness and safety, indicating the need for more studies addressing this chemical-mediated effects on various tissues including the central nervous system (CNS). The aim of this review was to (1) summarize the current findings on the neurotoxic effects of TCS and given the paucity of data, to (2) broaden the discussion to other effects of TCS, which might plausibly be related to neuronal functions. PMID- 28339351 TI - Experiencing Civil Unrest: Elder Voices on Ferguson. AB - Ferguson, Missouri became the center of the nation's attention when an unarmed African American teenager was killed by a Caucasian police officer. Civic unrest continued for weeks. The aim of this study was to learn how older adults experienced the social unrest. Ten focus groups were conducted with 73 participants. Eight themes were identified. Issues related to safety were most commonly discussed. Participants reported a breakdown in intergenerational communications and expressed a desire for more exchange. Findings are being discussed with relevant organizations to increase the involvement of older adults in on-going community development efforts and to provide opportunities for intergenerational dialogue. PMID- 28339352 TI - Approaching Environmental Sustainability: Perceptions of Self-Efficacy and Changeability. AB - This paper describes a model focused on the role of self-efficacy and belief in changeability of behavior in motivating environmentally sustainable behavior. The model was tested in two studies. The first study found that participants who had greater self-efficacy for sustainability behavior and a greater belief in their changeability of sustainability behavior had a higher level of approach motivation toward sustainability behavior and reported more such actual behavior. The second study investigated the effect of brief interventions intended to increase perception of self-efficacy for sustainability-related purchasing and changeability of sustainability-related purchasing. The intervention that focused on enhancing self-efficacy for making sustainability-related purchases had the strongest impact on intention to purchase. These findings have implications for interventions intended to change behavior related to environmental sustainability. PMID- 28339353 TI - Relationships between Ambivalent Sexism and the Five Moral Foundations in Domestic Violence: Is it a Matter of Fairness and Authority? AB - Ambivalent sexism has served to justify and maintain patriarchy and traditional gender roles characterized by inequality and male domination in the intimate partner violence (IPV) literature; according to the Moral Foundation Theory (MFT) there are two specific moral foundations related to inequality and domination: fairness and authority. We connect these separate fields arguing that sexist attitudes can be related to specific patterns of endorsement of the five moral foundations. Our hypothesis is that ambivalent sexism in men convicted of violence against the partner may be rooted in at least these two moral foundations, and that at least these two moral foundations may also serve to predict intention to change the violent behavior against the partner. Controlling for political orientation, the results show that benevolent sexism correlates positively with the authority foundation; and hostile sexism correlates negatively with the fairness foundation. Both foundations contribute to explaining the two dimensions of ambivalent sexism (benevolent and hostile) and only the fairness foundation predict intention to change the violent behavior against the partner. New treatment approaches could be designed to increase moral concerns about fairness and to reduce moral concerns about authority in people who, at least, have once used violence against their partners. PMID- 28339347 TI - The aging kidney and the nephrotoxic effects of mercury. AB - Owing to advances in modern medicine, life expectancies are lengthening and leading to an increase in the population of older individuals. The aging process leads to significant alterations in many organ systems, with the kidney being particularly susceptible to age-related changes. Within the kidney, aging leads to ultrastructural changes such as glomerular and tubular hypertrophy, glomerulosclerosis, and tubulointerstitial fibrosis, which may compromise renal plasma flow (RPF) and glomerular filtration rate (GFR). These alterations may reduce the functional reserve of the kidneys, making them more susceptible to pathological events when challenged or stressed, such as following exposure to nephrotoxicants. An important and prevalent environmental toxicant that induces nephrotoxic effects is mercury (Hg). Since exposure of normal kidneys to mercuric ions might induce glomerular and tubular injury, aged kidneys, which may not be functioning at full capacity, may be more sensitive to the effects of Hg than normal kidneys. Age-related renal changes and the effects of Hg in the kidney have been characterized separately. However, little is known regarding the influence of nephrotoxicants, such as Hg, on aged kidneys. The purpose of this review was to summarize known findings related to exposure of aged and diseased kidneys to the environmentally relevant nephrotoxicant Hg. PMID- 28339354 TI - The effects of an educational meeting and subsequent computer reminders on the ordering of laboratory tests by rheumatologists: an interrupted time series analysis. AB - OBJECTIVES: To examine the effects of an educational meeting and subsequent computer reminders on the number of ordered laboratory tests. METHODS: Using interrupted time series analysis we assessed whether trends in the number of laboratory tests ordered by rheumatologists between September 2012 and September 2015 at the Sint Maartenskliniek (the Netherlands) changed following an educational meeting (September 2013) and the introduction of computer reminders into the Computerised Physician Order Entry System (July 2014). The analyses were done for the set of tests on which both interventions had focussed (intervention tests; complement, cryoglobulins, immunoglobins, myeloma protein) and a set of control tests unrelated to the interventions (alanine transferase, anti-cyclic citrullinated peptide, C-reactive protein, creatine, haemoglobin, leukocytes, mean corpuscular volume, rheumatoid factor and thrombocytes). RESULTS: At the start of the study, 101 intervention tests and 7660 control tests were ordered per month by the rheumatologists. After the educational meeting, both the level and trend of ordered intervention and control tests did not change significantly. After implementation of the reminders, the level of ordered intervention tests decreased by 85.0 tests (95%-CI -133.3 to -36.8, p<0.01), the level of control tests did not change following the introduction of reminders. CONCLUSIONS: In summary, an educational meeting alone was not effective in decreasing the number of ordered intervention tests, but the combination with computer reminders did result in a large decrease of those tests. Therefore, we recommend using computer reminders in addition to education if reduction of inappropriate test use is aimed for. PMID- 28339355 TI - Psychometric properties of sleep and coping numeric rating scales in rheumatoid arthritis: a subanalysis of an etanercept trial. AB - OBJECTIVES: In rheumatoid arthritis, quality of sleep and ability to cope are important for patients; however their usefulness as outcome measures is not well established. METHODS: Post-hoc analysis of an open-label 12-week trial of etanercept in biologic-naive rheumatoid arthritis patients with visits at screening, baseline and over 12 weeks. Outcomes measured included Disease Activity Score 28 erythrocyte sedimentation rate (DAS28), numeric rating scales for sleep, coping, patient and physician-global assessment, pain and fatigue, and modified-HAQ. Reliability between screening and baseline visits by intra-class correlation, and responsiveness between baseline and 12 weeks by standardised response means were assessed for each outcome. RESULTS: In 108 patients, mean age 54 (standard deviation (SD) 13) years, mean disease duration 8 (SD 7) years, 75% women; disease activity was high at baseline: mean DAS28 5.5 (SD 0.8). Reliability intra-class correlation was 0.83[95% confidence interval: 0.77;0.88] for sleep, 0.81[0.74;0.87] for modified-HAQ, 0.80[0.71;0.86] for fatigue, 0.72[0.62;0.80] for physician-global assessment, 0.66[0.54;076] for coping, 0.65[0.53;0.75] for pain and 0.63[0.50;0.73] for patient-global assessment. Responsiveness standardised response means was 1.65[1.32;2.10] for physician global assessment, 1.37[1.09;1.73] for pain, 1.36[1.08;1.73] for patient-global assessment, 1.15[0.95;1.41] for fatigue, 0.96[0.70;1.28] for coping, 0.92[0.73;1.15] for sleep and 0.86[0.69;1.07] for modified-HAQ. CONCLUSIONS: Numeric rating scales assessing sleep and coping were found to be generally as reliable as 'usual' outcomes in rheumatoid arthritis. Responsiveness was less high, indicating these domains of health may be less accessible to biologic treatment. When assessing the patient's perspective on treatment, it is feasible and valid to measure sleep and coping by numeric rating scales. PMID- 28339356 TI - Diagnostic accuracy of musculoskeletal ultrasound and conventional radiography in the assessment of the wrist triangular fibrocartilage complex in patients with definite diagnosis of calcium pyrophosphate dihydrate deposition disease. AB - OBJECTIVES: To compare the diagnostic accuracy of musculoskeletal ultrasound (MSUS) and x-ray in evaluating wrist triangular fibrocartilage complex (TFCC) in patients with calcium pyrophosphate dihydrate deposition disease (CPPD) and to investigate the agreement between the extent of the calcium pyrophosphate dihydrate (CPP) crystal deposits assessed by MSUS and the radiographic findings. METHODS: We enrolled 84 patients: 36 patients with "definite" CPPD and 48 controls. The Ryan and McCarty diagnostic criteria were used. A rheumatologist performed bilateral MSUS examinations of the TFCC in all patients, assessing both the presence and absence of CCP crystals deposits and their extent (0-3; 0: absent; 1: 1-2 spots; 2: more than two spots covering <50% of the volume of the structure; 3: deposits covering >50% of the volume of the structure). A radiologist evaluated the presence/absence of x-ray calcifications at TFCC level in both groups. RESULTS: MSUS and x-ray sensitivity was 77.8% and 76.4%, respectively, whereas MSUS and x-ray specificity was 90.6% and 96.9%, respectively. Total agreement between MSUS and radiographic findings indicative of calcifications at TFCC level was 88.7%. CONCLUSIONS: This study supports the diagnostic accuracy of MSUS and x-ray in evaluating TFCC crystal deposits in patients with CPPD. Sensitivity and specificity of MSUS and x-ray resulted comparable. The highest MSUS score of the extent of the deposits correlated better with x-ray findings. PMID- 28339357 TI - Development of a score for assessment of radiologic damage in large-vessel vasculitis (Combined Arteritis Damage Score, CARDS). AB - OBJECTIVES: Outcome assessment in large-vessel vasculitis (LVV) remains challenging and this impairs patient management and the conduct of clinical studies. Previous proposals for outcome tools have not included imaging. This study aimed to develop an imaging score to quantify damage in LVV and to assess the difference between Takayasu (TAK) and giant cell arteritis (GCA). METHODS: Ninety-six patients (41 TAK, 55 GCA) were identified from local registries at two University Hospitals in the UK. Radiologic lesions including stenosis, occlusion and aneurysm were evaluated in 25 arterial regions by enhanced computed tomography or magnetic resonance angiography. Lesion correlation with combined damage assessment scores was employed in a multiple regression analysis to define the weight of individual lesions and develop a damage index. RESULTS: A numerical damage index was developed: the "Combined Arteritis Damage Score (CARDS)". The index was derived from a formula: number of regions with mild stenosis * 0.6 + number of regions with moderate to severe stenosis * 1.2 + number with occlusions * 1.6 + number with aneurysms * 0.8 in 25 arterial regions. The median CARDS was higher in TAK than GCA (4.1 and 0.6, interquartile range 1.3-5.7 and 0-3, p<0.001). CONCLUSIONS: We have developed a damage assessment tool, CARDS, based on imaging in LVV of potential value to clinical studies and patient management. TAK and GCA differ in the radiologic severity of disease. PMID- 28339358 TI - Effectiveness and healthcare costs among stabilised rheumatoid arthritis patients with dose reduction of adalimumab or etanercept in real world. AB - OBJECTIVES: We assessed the level of maintained effectiveness and associated healthcare costs in stabilised rheumatoid arthritis (RA) patients who reduced doses of adalimumab or etanercept. METHODS: Eligible patients were identified from a U.S. commercial insurance database using the following criteria: adults with >=2 RA diagnoses; effectively treated on standard dose of adalimumab or etanercept for a 6-month baseline period; and >=3 months of dose reduction within a 6-month assessment period following the index date (date of the first reduced dose). Effectiveness was estimated using a validated claims-based algorithm. Multivariate regression models were used to assess maintained effectiveness and healthcare costs in the short-term (months 7-12) and long-term (months 13-24) following the index date, while adjusting for baseline characteristics. Cost per patient maintaining effective treatment (CPME) was calculated as the average total healthcare costs divided by the proportion of patients with maintained effectiveness. RESULTS: Both groups (etanercept=375; adalimumab=610) had 70% females and a mean age of 48 years. Adjusted rates of maintained effectiveness for etanercept vs. adalimumab were 57.5% vs. 64.7% (p=0.028) in the short-term and 44.3% vs. 51.9% (p=0.047) in the long-term. Adjusted healthcare costs were similar for etanercept- and adalimumab-treated patients (short-term: $15,043 vs. $15,041; long-term: $31,461 vs. $30,449). The CPME was $2,915 higher with etanercept-treated patients in short-term and $12,349 higher in long-term compared with adalimumab-treated patients. CONCLUSIONS: Among stabilised RA patients who reduced biologic dosing, a greater proportion of adalimumab-treated patients maintained effectiveness than etanercept-treated patients. Adalimumab was associated with a lower total CPME than etanercept. PMID- 28339359 TI - Cardiac involvement as a presenting feature of eosinophilic granulomatosis with polyangiitis in childhood. PMID- 28339360 TI - Critical role of STIR MRI in early detection of post-streptococcal periostitis with dysproteinaemia (Goldbloom's syndrome). AB - OBJECTIVES: In 1966, Goldbloom et al. described two children who developed a peculiar clinical picture characterized by intermittent daily bone pain in the lower limbs, fever spikes, increased acute phase reactants and dysproteinaemia. The syndrome occurred two weeks after a group A beta-haemolytic streptococcus infection. So far, only a few cases have been reported in the medical literature in English. METHODS: We report two further cases of Goldbloom's syndrome with a review of the literature in English. RESULTS: Our two patients lived in the same Italian region and presented their syndrome onset a week apart. Early use of STIR MRI revealed an atypical metaphyseal hyperintensity in the femurs and tibias. X ray showed periosteal hyperostosis. A short cycle of corticosteroids led to rapid recovery of symptoms and disappearance of bone changes. CONCLUSIONS: The reported cases highlight a likely under-recognised post-streptococcal inflammatory periosteal reaction and emphasise the diagnostic utility of the newer imaging modalities. PMID- 28339361 TI - Anti-N-methyl-D-aspartate receptor antibodies are associated with fibromyalgia in patients with systemic lupus erythematosus: a case-control study. AB - OBJECTIVES: The high concordance between systemic lupus erythematosus (SLE) and fibromyalgia (FM) suggests common underlying mechanisms related to pain and distress in both patient groups. Increasing evidence indicates that N-methyl-D aspartate receptors (NMDARs) play a major role in the induction and maintenance of central sensitisation with chronic pain. In this study, we evaluated the role of anti-NMDAR antibodies in the development of FM in patients with SLE. METHODS: Sera from 104 patients with SLE, 112 patients with FM, and 110 healthy controls were analysed to detect antibodies to the N-terminus of the 2B subunit of NMDARs (GluN2B). Subjects underwent clinical examination and neuropsychiatric evaluation, and completed a questionnaire regarding FM and neuropsychiatric symptoms. RESULTS: Of the 104 patients with SLE, 18 (17.3%) had FM. The anti GluN2B antibody titer was significantly higher in patients with SLE (p<0.001). Among patients with SLE, those with concomitant FM had higher anti-GluN2B antibody titers (p<0.05). The anti-GluN2B antibody titer was associated positively with the tender point count (p=0.016) and the widespread pain index (p=0.005), but not with other symptom measurements. Anti-GluN2B antibody-positive patients with SLE were more likely to have neuropsychiatric systemic lupus erythematosus (NPSLE) and concomitant FM (p<0.05). Multivariate analysis showed that the anti-GluN2B antibody was an independent predictor of concomitant FM and NPSLE. CONCLUSIONS: To our knowledge, this report is the first to suggest that anti-NMDAR antibodies are associated with the pathogenesis of FM with SLE. PMID- 28339362 TI - Diagnostic performance of colour duplex ultrasonography along with temporal artery biopsy in suspicion of giant cell arteritis. AB - OBJECTIVES: Giant cell arteritis (GCA) is a vasculitis that occurs in older adults, affecting vessels of medium and large caliber. GCA diagnosis is a challenge for general practitioners and specialists. The aim of this study was to retrospectively analyse performances of temporal artery biopsy (TAB) and colour duplex ultrasonography (CDU) for GCA diagnosis. METHODS: All patients with suspicion of GCA and who underwent both TAB and CDU between April 2009 and March 2014 were included in the study. A positive CDU examination was defined by halos on both superficial temporal arteries. Patients were classified based on the physician final diagnosis. RESULTS: Among the 42 eligible patients, 12 had an alternative diagnosis and 30 were diagnosed with GCA. Sensitivities were 77% and 80% for TAB and CDU examinations, respectively. Specificities were 100% for both tests. Twenty-nine (96.7%) patients with GCA had their diagnosis confirmed either by CDU and/or by TAB. Time lengths between the first medical examination and results of TAB and CDU were 15 and 4.2 days (p<0.001), respectively. CONCLUSIONS: Our study suggests that in suspected GCA, CDU may be used as first line examination followed by TAB in case of CDU negative results. Such algorithm needs to be further assessed in a multicentre prospective study. PMID- 28339363 TI - Proangiogenic gene polymorphisms are associated with susceptibility to Paget's disease of bone and with its clinical features. PMID- 28339364 TI - Clinical and prognostic features of Korean patients with MPO-ANCA, PR3-ANCA and ANCA-negative vasculitis. AB - OBJECTIVES: We reclassified Korean patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) into 3 categories of AAV including MPO-ANCA, PR3-ANCA and ANCA-negative vasculitis, and investigated clinical and prognostic features. METHODS: We reviewed the medical records of 133 patients with microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic GPA (EGPA), who had either myeloperoxidase (MPO)-ANCA, proteinase 3 (PR3)-ANCA or no ANCA, and who had ever achieved the first remission. We compared clinical manifestations, initial Birmingham vasculitis activity score (BVAS) and five factor score (FFS), and relapse rates. RESULTS: Patients with ANCA-negative vasculitis had the youngest mean age at diagnosis (50.0 years old) among AAV categories. General, cutaneous and renal manifestations were commonly observed in MPO-ANCA vasculitis, while mucous membrane, eye, ear nose throat (ENT) and renal manifestations were often documented in PR3-ANCA vasculitis. ENT manifestation was also frequently observed in ANCA-negative vasculitis. However, there were no significant differences in pulmonary and nervous system manifestations among 3 AAV categories. There were no significant differences in cumulative relapse free survival according to the presence of MPO-ANCA or PR3-ANCA or no ANCA. Meanwhile, initial BVAS or BVAS for GPA >=13.5 in MPO-ANCA vasculitis and initial FFS (1996) >=1 in MPO-ANCA and ANCA-negative vasculitis were significant predictors of relapse of each AAV category. CONCLUSIONS: Clinical manifestations varied AAV categories, and neither MPO-ANCA nor PR3-ANCA significantly affected relapse of AAV. Initial BVAS or BVAS for GPA and FFS (1996) helped to predict relapse of specified AAV categories. PMID- 28339365 TI - Thresholds for the 28-joint disease activity score (DAS28) using C-reactive protein are lower compared to DAS28 using erythrocyte sedimentation rate in early rheumatoid arthritis. AB - OBJECTIVES: The 28-Joint Disease Activity Score (DAS28) using C-reactive protein (CRP) and DAS28 using erythrocyte sedimentation rate (DAS28-ESR) may not be interchangeable. We sought to compare and estimate optimal thresholds for the DA28-CRP for use in early rheumatoid arthritis (ERA). METHODS: Patients from the Canadian Early Arthritis Cohort with baseline and 12 months' data for both DAS28 ESR and DAS28-CRP were examined for correlations and differences between DAS28 CRP and DAS28-ESR across their range of values. Receiver operating characteristic analysis identified thresholds for DAS28-CRP that best corresponded to established thresholds for the DAS28-ESR using the total sample, then stratified by age and sex. Agreement between DAS28-CRP and DAS28-ESR thresholds was assessed with the kappa statistic. RESULTS: The sample included 995 patients with mean (SD) age of 53.7 (14.5) years, 5.8 (2.9) months of symptom duration and 74% were female. DAS28-CRP and DAS28-ESR scores were highly correlated (r= 0.92, p<0.0001), however DAS28-CRP values were consistently lower than DAS28-ESR values. Calculated thresholds for DAS28-CRP were lower with 2.5 for remission, 2.9 for low disease activity, and 4.6 for high disease activity but showed moderate agreement with the DAS28-ESR thresholds (kappa=0.70). CONCLUSIONS: In this large sample of ERA patients, newly estimated thresholds for DAS28-CRP were consistently lower than DAS28-ESR thresholds across the spectrum of disease activity. This may have important clinical implications if inflammatory markers are used interchangeably. Additional external validation of our findings is needed. PMID- 28339368 TI - Extrinsic motives to encourage extracurricular research activities: a reminder call to medical schools in Saudi Arabia. PMID- 28339366 TI - Jaccoud's arthropathy in systemic lupus erythematosus: clinical, laboratory and ultrasonographic features. AB - OBJECTIVES: Jaccoud's arthropathy (JA) is a deforming, non-erosive arthritis, occurring in 2-35% of systemic lupus erythematosus (SLE) patients. We aimed to evaluate JA patients in a wide monocentric SLE cohort in terms of clinical, serological and ultrasonographic features. METHODS: Consecutive SLE patients (ACR criteria 1997) were evaluated. The JA index was applied for patients with reducible deformities. Patients with a JA index >=5 underwent physical examination, blood testing and ultrasound (US) assessment. Detection of anti citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) was performed. A single rheumatologist performed the US assessment of bilateral wrist and hands. RESULTS: Four hundred and eighty SLE patients were evaluated: 17 (3.5%) showed a JA index >=5 (M:F 1:16; mean age+/-SD 50.7+/-11.1 years; mean disease duration+/ SD 247.8+/-116.2 months). Four patients (23.5%) showed ACPA positivity. Fifteen patients (88.2%) showed at least one US abnormality. Bone erosions were found in 10 patients (58.8%). ACPA+ve patients showed erosive damage more frequently in at least one joint compared with ACPA-ve (75% vs. 53.8%, p=0.002). CONCLUSIONS: JA should no longer be considered a non-erosive condition since bone damage can occur in more than half of patients. Moreover, the erosive damage seems to be associated with the presence of ACPA. PMID- 28339369 TI - PreScription: Stability Studies and United States Pharmacopeia-National Formulary Grade Chemicals. PMID- 28339367 TI - The functional significance of morphological changes in the dentitions of early mammals. AB - The Mesozoic marked a time of experimentation in the tooth morphology of early mammals. One particular experiment involved the movement of three points, or cusps, on the surface of a molar tooth from a line into a triangle. This transition is exemplified by two extinct insectivorous mammals, Morganucodon (cusps in a line) and Kuehneotherium (cusps in a triangle). Here we test whether this difference in cusp arrangement, alongside cusp heights and angles between cusps, is associated with differences in the ability of the teeth to fracture proxy-insect prey. We gathered measurements from molar teeth of both species and used them to create physical models. We then measured the force, time and energy at fracture and peak force, and the amount of damage inflicted by the models on hard and soft gels encased in a tough film that mimicked the material properties of insects. The Morganucodon model required less force and energy to fracture hard gels and reach peak force compared with KuehneotheriumKuehneotherium required a similar time, force and energy to fracture soft gels but reduced the time, force and energy to reach peak force. More importantly, Kuehneotherium also inflicted more damage to both the hard and the soft gels. These results suggest that changes in dental morphology in some early mammals was driven primarily by selection for maximizing damage, and secondarily for maximizing biomechanical efficiency for a given food material property. PMID- 28339370 TI - Menopausal Symptom Relief and Side Effects Experienced by Women Using Bioidentical Hormone Replacement Therapy and Synthetic Conjugated Equine Estrogen and/or Progestin Hormone Replacement Therapy, Part 1. AB - The use of compounded bioidentical hormone replacement therapy by menopausal women has become a popular alternative to traditional synthetic conjugated equine estrogen and progestin hormone replacement therapy due to safety concerns raised by recent studies. However, due to the lack of randomized, large-scale trials to evaluate the efficacy and side-effect profile of compounded bioidentical hormone replacement therapy many healthcare providers are reluctant to prescribe such therapy. The purpose of this study was to compare women's menopausal symptom relief and side effects experienced when using compounded bioidentical hormone replacement therapy and traditional hormone replacement therapy. A descriptive comparative design was used. Inferential and descriptive statistical procedures including a paired difference t -test, two-sample t -test, and f tests (percentage, mean, standard deviation, frequency) were run on the Statistical Package for the Social Sciences. The framework used to guide this study was Lenz and Pugh's Theory of Unpleasant Symptoms. Surveys were distributed once to a convenient sample of women aged 35 and older when they dropped off or picked up their prescriptions at a pharmacy. Of the 216 surveys distributed, 70 were returned from those women taking compounded bioidentical hormone replacement therapy and 53 from traditional hormone replacement therapy. The survey contained 15 questions pertaining to age, duration of hormone replacement therapy, type and formulation of hormone replacement therapy, reasons for initiating hormone replacement therapy, symptoms before and one month after hormone replacement therapy, and side effects related to hormone replacement therapy. The results of this study will be summarized in forthcoming articles in this series. PMID- 28339371 TI - Pharmaceutical Compounding: The Oldest, Most Symbolic, and Still Vital Part of Pharmacy. AB - Historically, compounding has been always an integral part of pharmacy. Medications were prepared by pharmacists for individual patients and compounding was the only source of drugs before mass production by pharmaceutical companies. This trend started diminishing around the middle of the 20th century due to more drugs being produced by mass manufacturers. Shortly after, clinical pharmacy was introduced and many schools of pharmacy reorganized their curricula to address that change. As a result, many compounding courses have been removed and emphasis was shifted towards clinical classes. Currently, however, compounding is on the rise again, gaining more importance mainly due to the fact that it can provide an individualized approach to patient care. This review is aimed to discuss the challenges of compounding education and the main areas of growth for compounding, as well as advantages and disadvantages of compounded medications. PMID- 28339372 TI - More than 300 Attendees Convene in Washington, DC, for the 22nd Annual Compounders on Capitol Hill: The United Voice of Compounders is Heard! PMID- 28339373 TI - Quality Control Analytical Methods: Method Validation. AB - To properly determine the accuracy of a pharmaceutical product or compounded preparation, tests must be designed specifically for that evaluation. The procedures selected must be verified through a process referred to as method validation, an integral part of any good analytical practice. The results from a method validation procedure can be used to judge the quality, reliability, and consistency of analytical results. The purpose of this article is to deliver the message of the importance of validation of a pharmaceutical product or compounded preparation and to briefly discuss the results of a lack of such validation. PMID- 28339374 TI - Basics of Compounding: Clinical Pharmaceutics, Part 1. AB - Pharmaceutics is relevant far beyond the pharmaceutical industry, compounding, and the laboratory. Pharmaceutics can be used to solve many clinical problems in medication therapy. A pharmacists' knowledge of the physicochemical aspects of drugs and drug products should help the patient, physician, and healthcare professionals resolve issues in the increasingly complex world of modern medicine. Pharmacy is unique as it contains a knowledge base significantly different from that of physicians, nurses, and other health-related practitioners. The separation of the science and the practice of pharmacy have prevented the complete utilization of pharmaceutical sciences in the clinical environment far too long. PMID- 28339375 TI - Basics of Sterile Compounding: Ophthalmic Preparations, Part 1: Ophthalmic Solutions. AB - Ophthalmic preparations are used to treat allergies, bacterial and viral infections, glaucoma, and numerous other eye conditions. When the eye's natural defensive mechanisms are compromised or overcome, an ophthalmic preparation, in a solution, suspension, or ointment form, may be indicated, with solutions being the most common form used to deliver a drug to the eye. This article provides a general discussion on ophthalmic preparations and specifically discusses the preparation of solutions. PMID- 28339376 TI - Long-term Stability of Vancomycin Hydrochloride in Glucose 5% Polyolefin Bags: The Brand Name Versus a Generic Product. AB - The objectives of this study were to determine if the preparation of vancomycin hydrochloride in advance of infusion could improve the quality of the drug, time management of drug delivery, cost savings of drug delivery, and to investigate the long-term stability of vancomycin hydrochloride (brand name Vancocin(r)) infusion in glucose 5% polyolefin bags versus the generic (Vancomycine(r)) at 5 degrees C +/- 3 degrees C. Five bags of each infusion 1 g/100 mL vancomycin hydrochloride in 5% glucose (Vancocin (r) and Vancomycine(r)) were stored up to 57 days at 5 degrees C +/- 3 degrees C. A visual inspection and pH measurement were performed periodically during the storage, and the concentrations were measured by high-performance liquid chromatography-diode array detection. No color change or precipitation in the solution was observed throughout the study period. As recommended by the U.S. Food and Drug Administration, the lower confidence limit at 95% of the concentration for the solutions remained superior to 90% of the initial concentration up to 43 days for the brand vancomycin (Vancocin(r)) infusion (96% +/- 2%) and up to 57 days for the generic (Vancomycine(r)) (95% +/- 4%). The solutions prepared either from brand or generic vancomycin hydrochloride were chemically stable more than one month (43 days for the brand and 57 days for the generic solution) and could be prepared in advance in a centralized intravenous additive service facility. PMID- 28339377 TI - Stability of Clindamycin Hydrochloride in PCCA Base SuspendIt. AB - Clindamycin is an effective antibiotic in the treatment of infections caused by certain gram-positive and gram-negative anaerobic microorganisms. While manufactured forms of the drug for pediatric use are available, there are instances when a compounded liquid dosage form is essential to meet unique patient needs. The purpose of this study was to determine the chemical stability of clindamycin hydrochloride in the PCCA base SuspendIt, a sugar-free, paraben- free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. It thickens upon standing to minimize settling of any insoluble drug particles and becomes fluid upon shaking to allow convenient pouring during administration to the patient. A robust stability indicating high-performance liquid chromatographic assay for the determination of clindamycin hydrochloride in SuspendIt was developed and validated. This assay was used to determine the chemical stability of the drug in SuspendIt. Samples were prepared and stored under three different temperature conditions (5 degrees C, 25 degrees C, and 40 degrees C), and assayed using the high-performance liquid chromatographic assay at pre-determined intervals over an extended period of time as follows: 7, 14, 30, 45, 60, 91, 120, and 182 days at each designated temperature. Physical data such as pH, viscosity, and appearance were also monitored. The study showed that drug concentration did not go below 90% of the label claim (initial drug concentration) at all three temperatures studied, barring isolated experimental errors. Viscosity and pH values also did not change significantly. Some variations in viscosity were attributed to the thixotropic nature of the vehicle. This study demonstrates that clindamycin hydrochloride is physically and chemically stable in SuspendIt for 182 days in the refrigerator and at room temperature, thus providing a viable, compounded alternative for clindamycin hydrochloride in a liquid dosage form, with an extended beyond-use date to meet patient needs. PMID- 28339378 TI - Stability of Allopurinol, Amitriptyline Hydrochloride, Carbamazepine, Domperidone, Isoniazid, Ketoconazole, Lisinopril, Naproxen, Paracetamol (Acetaminophen), and Sertraline Hydrochloride in SyrSpend SF PH4 Oral Suspensions. AB - Oral liquids are safe alternatives to solid dosage forms, notably for elderly and pediatric patients that present dysphagia. The use of ready-to-use suspending vehicles such as SyrSpend SF PH4 is a suitable resource for pharmacists as they constitute a safe and timesaving option that has been studied often. The objective of this study was to evaluate the stability of 10 commonly used active pharmaceutical ingredients (allopurinol 20 mg/mL; amitriptyline hydrochloride 10 mg/mL; carbamazepine 25 mg/mL; domperidone 5 mg/mL; isoniazid 10 mg/mL; ketoconazole 20 mg/mL; lisinopril 1 mg/mL; naproxen 25 mg/mL; paracetamol [acetaminophen] 50 mg/mL; and sertraline hydrochloride 10 mg/mL) compounded in oral suspensions using SyrSpend SF PH4 as the vehicle throughout the study period and stored both at controlled refrigerated (2 degrees C to 8 degrees C) and room temperature (20 degrees C to 25 degrees C). Stability was assessed by means of measuring the percent recovery at varying time points throughout a 90-day period. The quantification of the active pharmaceutical ingredients was performed by high performance liquid chromatography through a stability-indicating method. Methods were adequately validated. Forced-degradation studies showed that at least one parameter influenced the stability of the active pharmaceutical ingredients. All suspensions were assayed and showed active pharmaceutical ingredient contents between 90% and 110% during the 90-day study period. Although the forced degradation experiments led to visible fluctuations in the chromatographic responses, the final preparations were stable in the storage conditions. The beyond-use dates of the preparations were found to be at least 90 days for all suspensions, both for controlled refrigerated temperature and room temperature. This confirms that SyrSpend SF PH4 is a stable suspending vehicle for compounding with a broad range of different active pharmaceutical ingredients for different medical usages. PMID- 28339379 TI - Stability of Sodium Nitroprusside in 5% Dextrose Stored at 4 degrees C in Polypropylene Syringes Protected from Light. AB - Sodium nitroprusside is a potent vasodilator employed intraoperatively and within critical care areas. The photolabile pharmaceutical agent has been used for decades and various stability studies have been executed. Due to potential shortages and the desire to batch compound sodium nitroprusside at a concentration of 1 mg/mL in polypropylene syringes, a new stability study was performed. Chromatographic analysis was conducted on a C18 column, with elution via an aqueous phase of 0.01 M sodium phosphate monobasic, adjusted to pH 6.5 with sodium hydroxide, and methanol (97.5:2.5) at a rate of 1 mL/min, and subsequent ultraviolet detection at 210 nm. Triplicate determinations of four samples, stored under refrigeration at 4 degrees C, were obtained initially and on days 2, 5, and 9. Turbidity and pH measurements were performed in conjunction with visual observation on days of chromatographic analysis. Results demonstrate that sodium nitroprusside compounded in 5% dextrose at a concentration of 1 mg/mL, stored at 4 degrees C protected from light in polypropylene syringes, is physically and chemically stable for at least 9 days. PMID- 28339380 TI - A Simplified Extemporaneously Prepared Potassium Chloride Oral Solution. AB - Although commercial preparations of oral potassium supplements are usually available, there are times when our Medical Center is faced with situations in which the oral solution of potassium chloride is not available. This solution is necessary for our pediatric outpatients who cannot swallow tablets and need an oral solution. Moreover, there are no studies available which describe an extemporaneously prepared potassium chloride oral solution on which we can rely for assigning a beyond-use date. The aim of this study was to formulate an extemporaneous pediatric oral solution of potassium chloride and to determine the physical and chemical stability of this preparation. We prepared 1 mMoL/mL by withdrawing 25 mL of potassium chloride 14.9%. Ora-Sweet SF was added to 50 mL in a metered flask. The solution was kept refrigerated (2 degrees C to 8 degrees C). Samples were withdrawn to measure potassium concentration, pH, and microbial overgrowth. The test was performed by our biochemical laboratory. The oral solution of potassium chloride 1 mMoL/mL stored at 2 degrees C to 8 degrees C maintained at least 91% of the initial concentration for 28 days. There were no notable changes in pH, and the solution remained physically stable with no visual microbial growth. The oral solution of potassium chloride 1 mMoL/mL prepared in Ora-Sweet and stored at 2 degrees C to 8 degrees C in amber glass bottles is expected to remain stable for 28 days. PMID- 28339381 TI - PreScription: Two Decades of IJPC. PMID- 28339382 TI - Menopausal Symptom Relief and Side Effects Experienced by Women Using Compounded Bioidentical Hormone Replacement Therapy and Synthetic Conjugated Equine Estrogen and/or Progestin Hormone Replacement Therapy, Part 2. AB - The use of compounded bioidentical hormone replacement therapy by menopausal women has become a popular alternative to traditional synthetic conjugated equine estrogen and progestin hormone replacement therapy due to safety concerns raised by recent studies. However, due to the lack of randomized, large-scale trials to evaluate the efficacy and side-effect profile of compounded bioidentical hormone replacement therapy many healthcare providers are reluctant to prescribe such therapy. The purpose of this study was to compare women's menopausal symptom relief and side effects experienced when using compounded bioidentical hormone replacement therapy and traditional hormone replacement therapy. A descriptive comparative design was used. Inferential and descriptive statistical procedures including a paired difference t-test, two-sample t-test, and f-tests (percentage, mean, standard deviation, frequency) were run on the Statistical Package for the Social Sciences. The framework used to guide this study was Lenz and Pugh's Theory of Unpleasant Symptoms. Surveys were distributed once to a convenient sample of women aged 35 and older when they dropped off or picked up their prescriptions at a pharmacy. Of the 216 surveys distributed, 70 were returned from those women taking compounded bioidentical hormone replacement therapy and 53 from traditional hormone replacement therapy. The survey contained 15 questions pertaining to age, duration of hormone replacement therapy, type and formulation of hormone replacement therapy, reasons for initiating hormone replacement therapy, symptoms before and one month after hormone replacement therapy, and side effects related to hormone replacement therapy. Included in part 1 of this series of articles was the introduction to the study conducted and the results of the literature review that was conducted for the purpose of examining the current data related to the topic of hormone replacement therapy. Part 2 provides a brief discussion on the significance of this study to nursing and provides the methods used in this study. The results of this study will be summarized in forthcoming articles in this series. PMID- 28339383 TI - U.S. Food and Drug Administration List of Drugs NOT to be Used in Compounded Medications for Humans (The Negative List). PMID- 28339385 TI - Why Become Pharmacy Compounding Accreditation Board Accredited? AB - The Pharmacy Compounding Accreditation Board's goal is to assist pharmacies to obtain formal recognition of their status as a high-quality and fully compliant provider of pharmaceuticals and patient services. This article provides a brief outline of the application process, the survey preparation, points of information about the actual survey, and suggestions on how to remain in compliance with Pharmacy Compounding Accreditation Board's standards. PMID- 28339384 TI - Evaluation of the Most Frequently Prescribed Extemporaneously Compounded Veterinary Medications at a Large Independent Community Pharmacy. AB - Extemporaneous drug formulation is essential to provide optimal pharmaceutical care to veterinary patients. The need for this is exacerbated by the fact that commercially produced veterinary-specific products, without a human indication, require specialty veterinary manufacturing facilities and a new animal drug application process to gain marketing approval. This study examined the prescription patterns of extemporaneously compounded veterinary preparations in the compounding department at a large independent community pharmacy. Data was obtained from a total of 1348 prescriptions requiring extemporaneous compounding over the course of a two-year period (2014-2015). A database was constructed and each compounded prescription was allocated to a therapeutic category based on the American Hospital Formulary Service Drug Information. Data analysis showed that the most commonly prescribed preparations belonged to the central nervous system (39%), anti-infective agents (21%), and hormones (12%) therapeutic categories. Overall, suspensions were the most dispensed (47%), extemporaneously compounded dosage forms followed by solutions (28%), and capsules (10%). The majority (88%) of compounded preparations were administered by the oral route. The top three drugs that are compounded for veterinary medicine were (1) potassium bromide oral solution for canine epilepsy, (2) methimazole solution used to treat hyperthyroidism in cats, and (3) metronidazole suspension, an antibiotic for the treatment of diarrhea and other infections in dogs and cats. Remarkably, our findings are in good agreement with previously published survey data on the top drugs that are compounded for veterinary medicine. In the era of personalized medicine, veterinary extemporaneous compounding for specialized needs will continue to play an important role providing optimum therapy for veterinary patients. PMID- 28339387 TI - Introduction to Quality Control in a Compounding Pharmacy. AB - A quality-based program is vital in every compounding pharmacy to ensure that each preparation is compounded properly and is stable for its expected duration of use. This article discusses quality control, quality assurance, continuous quality improvement, and also describes the components of an in-house (in pharmacy) quality program, as well as the role of outside laboratories. PMID- 28339386 TI - The "Lists": What Do They Mean? PMID- 28339388 TI - Basics of Compounding: Clinical Pharmaceutics, Part 2. AB - This article represents part 2 of a 2-part article on the topic of clinical pharmaceutics. Pharmaceutics is relevant far beyond the pharmaceutical industry, compounding, and the laboratory. Pharmaceutics can be used to solve many clinical problems in medication therapy. A pharmacists' knowledge of the physicochemical aspects of drugs and drug products should help the patient, physician, and healthcare professionals resolve issues in the increasingly complex world of modern medicine. Part 1 of this series of articles discussed incompatibilities which can directly affect a clinical outcome and utilized pharmaceutics case examples of the application and importance of clinical pharmaceutics covering different characteristics. Part 2 continues to illustrate the scientific principles and clinical effects involved in clinical pharmaceutics. Also covered in this article are many of the scientific principles in typical to patient care. PMID- 28339389 TI - Basics of Sterile Compounding: Ophthalmic Preparations, Part 2: Suspensions and Ointments. AB - Ophthalmic preparations are used to treat allergies, bacterial and viral infections, glaucoma, and numerous other eye conditions. When the eye's natural defensive mechanisms are compromised or overcome, an ophthalmic preparation, in a solution, suspension, or ointment form, may be indicated, with solutions being the most common form used to deliver a drug to the eye. This article discusses ophthalmic suspensions and ointments and represents part 2 of a 2-part article, the first of which discussed ophthalmic solutions. PMID- 28339390 TI - Stability of Fentanyl Citrate in Polyolefin Bags. AB - Fentanyl is used to manage pain because it is a potent lipophilic opiate agonist. The stability of fentanyl in polyolefin bags when diluted to either 10 ug/mL or 50 ug/mL with sodium chloride 0.9% has not been studied. The chemical stability of fentanyl 50 ug/mL packaged in polyvinyl chloride bags has been studied, however, the stability in polyolefin bags is lacking. Polyolefin bags were aseptically filled with either 10-ug/mL or 50-ug/mL fentanyl solution. Containers were then stored at either 5 degrees C and protected from light or 22 degrees C and exposed to light for 93 days. Fentanyl peaks were monitored using a stability indicatin high-performance liquid chromatographic method. Changes to color, clarity, and pH were also monitored. There were no signs of chemical degradation of fentanyl packaged in polyolefin bags at either 5 degrees C or 22 degrees C after storage for 93 days. Over the course of the study, all solutions remained colorless and clear. The pH showed a slight decrease during the 93 days of storage. The stability of both undiluted (50-ug/mL) and diluted (10-ug/mL) fentanyl solutions when packaged in polyolefin bags was 93 days when stored at either 5 degrees C or 22 degrees C. PMID- 28339391 TI - Topical Ketamine 10% for Neuropathic Pain in Spinal Cord Injury Patients: An Open Label Trial. AB - Topical ketamine, an N-methyl-D-aspartate antagonist, has been shown to be effective in certain neuropathic pain syndromes. The objective of this study was to determine the efficacy of topical ketamine in spinal cord injury patients with neuropathic pain. An open label trial enrolled five subjects at an outpatient rehabilitation hospital with traumatic spinal cord injuries who had neuropathic pain at or below the level of injury. Subjects applied topical ketamine 10% three times a day for a two-week duration. Subjects recorded their numerical pain score ranging from 0 to 10, with 0 representing "no pain, 5 representing "moderate pain," and 10 being described as "worst possible pain"-in a journal at the time of application of topical ketamine and one hour after application. Using a numerical pain scale allows for something as subjective as pain to be given an objective quantification. Subjects also recorded any occurrence of adverse events and level of satisfaction. All five subjects had a decrease in their numerical pain scale by the end of two weeks, ranging from 14% to 63%. The duration ranged from one hour in one subject to the next application in other subjects. There were no adverse effects. Overall, four out of the five subjects stated they were satisfied. Topical ketamine 10% is an effective neuropathic pain medicine in patients with spinal cord injuries; however, further studies need to be done with a placebo and larger sample size. PMID- 28339392 TI - Stability of Ribavirin for Inhalation Packaged in Syringes or Glass Vials when Stored Frozen, Refrigerated, and at Room Temperature. AB - The primary aim of this study was to investigate ribavirin solution for inhalation stability under three different conditions (frozen, refrigerated, room temperature) over a 45-day period. A ribavirin 6000-mg vial was reconstituted with 90 mL of Sterile Water for Injection per the package insert to yield a concentration of approximately 67 mg/mL. The solution was then placed in either syringes or empty glass vials and stored in the freezer (-20 degrees C), in the refrigerator (~0 degrees C to 4 degrees C), or at room temperature (~20 degrees C to 25 degrees C). Original concentrations were measured on day 0 and subsequent concentrations were measured on day 2, 14, and 45 utilizing a validated liquid chromatography with tandem mass spectrometry assay. All analyses were performed in triplicate for each storage condition. Additionally, at each time point the physical stability was evaluated and the pH of solution was measured. The solution was considered stable if =90% of the original concentration was retained over the study period. A validated liquid chromatography with tandem mass spectrometry analysis demonstrated that >95% of the original ribavirin concentration was preserved over the 45-day period for all study conditions. The ribavirin concentration remained within the United States Pharmacopeia (USP) required range of 95% to 105% of the original labeled product amount throughout the entire study period for all study conditions. Precipitation of ribavirin was noted during the thawing cycle for frozen samples, but the drug went back into solution once the thawing process was completed. No changes in color or turbidity were observed in any of the prepared solutions. Values for pH remained stable over the study period and ranged from 4.1 to 5.3. Ribavirin for inhalation solution is physically and chemically stable for at least 45 days when frozen, refrigerated, or kept at room temperature after reconstitution to a concentration of approximately 67 mg/mL and placed in syringes or glass vials. PMID- 28339393 TI - PostScription: What Lies Beneath: Potentially Harmful Excipients to Avoid when Compounding for Small Animals--A Note of Caution. PMID- 28339394 TI - Global and regional assessment of sustained inflation pressure-volume curves in patients with acute respiratory distress syndrome. AB - OBJECTIVE: Static or quasi-static pressure-volume (P-V ) curves can be used to determine the lung mechanical properties of patients suffering from acute respiratory distress syndrome (ARDS). According to the traditional interpretation, lung recruitment occurs mainly below the lower point of maximum curvature (LPMC) of the inflation P-V curve. Although some studies have questioned this assumption, setting of positive end-expiratory pressure 2 cmH2O above the LPMC was part of a 'lung-protective' ventilation strategy successfully applied in several clinical trials. The aim of our study was to quantify the amount of unrecruited lung at different clinically relevant points of the P-V curve. APPROACH: P-V curves and electrical impedance tomography (EIT) data from 30 ARDS patients were analysed. We determined the regional opening pressures for every EIT image pixel and fitted the global P-V curves to five sigmoid model equations to determine the LPMC, inflection point (IP) and upper point of maximal curvature (UPMC). Points of maximal curvature and IP were compared between the models by one-way analysis of variance (ANOVA). The percentages of lung pixels remaining closed ('unrecruited lung') at LPMC, IP and UPMC were calculated from the number of lung pixels exhibiting regional opening pressures higher than LPMC, IP and UPMC and were also compared by one-way ANOVA. MAIN RESULTS: As results, we found a high variability of LPMC values among the models, a smaller variability of IP and UPMC values. We found a high percentage of unrecruited lung at LPMC, a small percentage of unrecruited lung at IP and no unrecruited lung at UPMC. SIGNIFICANCE: Our results confirm the notion of ongoing lung recruitment at pressure levels above LPMC for all investigated model equations and highlight the importance of a regional assessment of lung recruitment in patients with ARDS. PMID- 28339396 TI - Modulation of AbetaPP and GSK3beta by Endoplasmic Reticulum Stress and Involvement in Alzheimer's Disease. AB - Alzheimer's disease (AD) is a dementia disease with neuronal loss and synaptic impairment. This impairment is caused, at least partly, by the generation of two main AD hallmarks, namely the hyperphosphorylated tau protein comprising neurofibrillary tangles and senile plaques containing amyloid-beta (Abeta) peptides. The amyloid-beta protein precursor (AbetaPP) and glycogen synthase kinase-3beta (GSK3beta) are two main proteins associated with AD and are closely correlated with these hallmarks. Recently, both of the proteins were reported to be modulated by endoplasmic reticulum stress (ERS) and are involved in the pathogenesis of AD. The mechanism of ERS plus the modulation of AbetaPP processing and GSK3beta activity by ERS in AD are summarized and explored in this review. PMID- 28339395 TI - Effect of ovariectomy and Sideritis euboea extract administration on large artery mechanics, morphology, and structure in middle-aged rats. AB - BACKGROUND: Arterial function is regulated by estrogen, but no consistent pattern of arterial mechanical remodeling in response to depleted estrogen levels is available. OBJECTIVE: To examine long-term effects of ovariectomy (OVX) on the mechanical properties, morphology, and histological structure of the carotid artery in middle-aged rats and a potentially protective effect of Sideritis euboea extract (SID), commonly consumed as "mountain tea". METHODS: 10-month-old female Wistar rats were allocated into control (sham-operated), OVX, OVX+SID, and OVX+MALT (maltodextrin; excipient used for dilution of SID) groups. They were sacrificed after 6 months and their carotid arteries were submitted to inflation/extension tests and to dimensional and histological evaluation. RESULTS: Remodeling in OVX rats was characterized by a decreased in situ axial extension ratio, along with increased opening angle, thickness, and area of the vessel wall and of its medial layer, but unchanged lumen diameter. Compositional changes involved increased elastin/collagen densities. Characterization by the "four-fiber" microstructure-motivated model revealed similar in situ biaxial response of carotid arteries in OVX and control rats. CONCLUSIONS: Carotid artery remodeling in OVX rats was largely consistent with hypertensive remodeling, despite the minor arterial pressure changes found, and was not altered by administration of SID, despite previous evidence of its osteo-protective effect. PMID- 28339398 TI - N-Terminal Fragments of Huntingtin Longer than Residue 170 form Visible Aggregates Independently to Polyglutamine Expansion. AB - BACKGROUND: A hallmark of Huntington's disease is the progressive aggregation of full length and N-terminal fragments of polyglutamine (polyQ)-expanded Huntingtin (Htt) into intracellular inclusions. The production of N-terminal fragments appears important for enabling pathology and aggregation; and hence the direct expression of a variety of N-terminal fragments are commonly used to model HD in animal and cellular models. OBJECTIVE: It remains unclear how the length of the N terminal fragments relates to polyQ - mediated aggregation. We investigated the fundamental intracellular aggregation process of eight different-length N terminal fragments of Htt in both short (25Q) and long polyQ (97Q). METHODS: N terminal fragments were fused to fluorescent proteins and transiently expressed in mammalian cell culture models. These included the classic exon 1 fragment (90 amino acids) and longer forms of 105, 117, 171, 513, 536, 552, and 586 amino acids based on wild-type Htt (of 23Q) sequence length nomenclature. RESULTS: N terminal fragments of less than 171 amino acids only formed inclusions in polyQ expanded form. By contrast the longer fragments formed inclusions irrespective of Q-length, with Q-length playing a negligible role in extent of aggregation. The inclusions could be classified into 3 distinct morphological categories. One type (Type A) was universally associated with polyQ expansions whereas the other two types (Types B and C) formed independently of polyQ length expansion. CONCLUSIONS: PolyQ-expansion was only required for fragments of less than 171 amino acids to aggregate. Longer fragments aggregated predominately through a non polyQ mechanism, involving at least one, and probably more distinct clustering mechanisms. PMID- 28339397 TI - Cognitive Status, Gray Matter Atrophy, and Lower Orthostatic Blood Pressure in Older Adults. AB - BACKGROUND: Associations between orthostatic blood pressure and cognitive status (CS) have been described with conflicting results. OBJECTIVE: We hypothesize that long-term exposure to lower orthostatic blood pressure is related to having worse CS later in life and that atrophy of regions involved in central regulation of autonomic function mediate these associations. METHODS: Three-to-four measures of orthostatic blood pressure were obtained from 1997-2003 in a longitudinal cohort of aging, and average systolic orthostatic blood pressure response (ASOBPR) was computed as % change in systolic blood pressure from sit-to-stand measured at one minute post stand. CS was determined in 2010-2012 by clinician-adjudication (n = 240; age = 87.1+/-2.6; 59% women; 37% black) with a subsample also undergoing concurrent structural neuroimaging (n = 129). Gray matter volume of regions related to autonomic function was measured. Multinomial regression was used to compare ASOBPR in those who were cognitively intact versus those with a diagnosis of mild cognitive impairment or dementia, controlling for demographics, trajectories of seated blood pressure, incident cardiovascular risk/events and medications measured from 1997 to 2012. Models were repeated in the subsample with neuroimaging, before and after adjustment for regional gray matter volume. RESULTS: There was an inverse association between ASOBPR and probability of dementia diagnosis (9% lower probability for each % point higher ASOBPR: OR 0.91, CI95% = 0.85-0.98; p = 0.01). Associations were similar in the subgroup with neuroimaging before and after adjustment for regional gray matter volume. CONCLUSION: ASOBPR may be an early marker of risk of dementia in older adults living in the community. PMID- 28339399 TI - Early Huntington's Disease: Impulse Control Deficits but Correct Judgment Regarding Risky Situations. AB - BACKGROUND: Huntington's disease (HD) patients show alterations in decision making tasks. However, it is still uncertain if these deficits are due to poor judgment regarding risky situations, or to impulse control deficits. OBJECTIVE: To elucidate whether decision-making in patients is related to genuine risk behavior or to impulse control deficits. METHODS: To test between these two alternative possibilities, we evaluated the performance of 19 prodromal HD patients and 19 matched healthy controls in the Cambridge Gambling Task (CGT). This task assesses decision-making while dissociating between genuine risk-taking behaviors (ascending condition) from impulsive behavior (descending condition). RESULTS: The results showed that patients and controls had the same performance during all trials in the ascending condition, reflecting a correct judgment regarding risky situations; however, during the descending condition, patients responded before the controls in all trials, making a significantly larger number of higher bets. Unlike the control group, they did not wait for more optimal subsequent options. CONCLUSION: These results suggest impulse control deficits in HD gene carriers, but unimpaired risk-taking judgment. PMID- 28339400 TI - A Systematic Review of the Huntington Disease-Like 2 Phenotype. AB - BACKGROUND: Huntington Disease-like 2 (HDL2) is a neurodegenerative disorder similar to Huntington Disease (HD) in its clinical phenotype, genetic characteristics, neuropathology and longitudinal progression. Proposed specific differences include an exclusive African ancestry, lack of eye movement abnormalities, increased Parkinsonism, and acanthocytes in HDL2. OBJECTIVE: The objective was to determine the similarities and differences between HD and HDL2 by establishing the clinical phenotype of HDL2 with the published cases. METHODS: A literature review of all clinically described cases of HDL2 until the end of 2016 was performed and a descriptive analysis was carried out. RESULTS: Sixty nine new cases were described between 2001 and 2016. All cases had likely African ancestry, and most were found in South Africa and the USA. Many features were found to be similar to HD, including a strong negative correlation between repeat length and age of onset. Chorea was noted in 48/57 cases (84%). Dementia was reported in 74% patients, and Parkinsonism in 37%. Psychiatric features were reported in 44 out of 47 cases. Patients with chorea had lower expanded repeat lengths compared to patients without chorea. Eye movements were described in 19 cases, 8 were abnormal. Acanthocytes were detected in 4 of the 13 patients tested. Nineteen out of 20 MRIs were reported as abnormal with findings similar to HD. CONCLUSION: This review clarifies some aspects of the HDL2 phenotype and highlights others which require further investigation. Features that are unique to HDL2 have been documented in a minority of subjects and require prospective validation. PMID- 28339402 TI - Outcomes of Hospitalised Muscular Dystrophy Patients. AB - BACKGROUND: In France, referral centres in teaching hospitals were created 10 years ago to provide MD patients with treatments and follow-up designed to prevent complications and improve outcomes. Respiratory failure is a major cause of death among subjects with MD, and its prevention and treatment can serve as a touchstone for assessing the effectiveness of MD care pathways. OBJECTIVE: We report data from a preliminary study of admissions of MD patients in France and of factors associated with mortality, with special emphasis on respiratory failure [RF]. METHODS: Retrospective analysis of the data from the French nationwide hospital database [Programme de M e dicalisation des syst e mes d'information, PMSI] for 2009 and 2010. RESULTS: 7187 admissions of patients with MD were included in the study. Most admissions were to teaching hospitals [5913/7187, 82.3%]. 302 [4.2%] patients were admitted for RF requiring invasive ventilation, 924 [12.9%] for RF requiring only NIV or high-flow oxygen therapy, and 5961 [82.9%] required no respiratory assistance. 494 [6.9%] admissions occurred on an emergency basis. 77/7187 [1.1%] patients died while hospitalised. Teaching-hospital admission was associated with lower frequencies of emergency admission [3.08% vs. 24.5%, p < 0.01] and in-hospital death [0.71% vs. 2.75%, p < 0.01]. CONCLUSIONS: Our data suggest that there is room for improvement in care pathways for MD patients requiring admission. Admission to referral centres may provide the best outcomes.Further studies are needed to assess associations between healthcare pathways and outcomes of MD subjects. PMID- 28339403 TI - Dopamine Transporter Imaging has no Impact on Functional Outcomes in de Novo Probable Parkinson's Disease. AB - BACKGROUND: Parkinson's disease (PD) is among the most prevalent neurodegenerative conditions. While motor and non-motor aspects of this disease have been well characterized, no objective biomarker exists to support an accurate clinical diagnosis. However, newer imaging techniques, including [123I] FP-CIT (DaTSCAN), have demonstrated utility in differentiating between PD and non neurodegenerative tremor disorders. OBJECTIVE: DaTSCAN has been primarily investigated in situations where diagnostic confusion exists, and in these instances has been shown to significantly impact clinical management. The goal of this pilot study was to evaluate the impact of DaTSCAN on the clinical management of patients with early probable PD, where no diagnostic uncertainty exists. METHODS: This was a prospective, 54-week, comparative pilot study, in which twenty subjects with de novo PD were randomly assigned to DaTSCAN either immediately upon diagnosis (and again at 6 and 12 months) or delayed to 6 months (and again at 12 months). The primary outcome measure was the frequency of deviation from the initial treatment plan from baseline to 54 weeks between the two groups. Secondary outcomes included motor and non-motor assessments. RESULTS: There was no significant difference in the number of treatment changes over the course of the study between the two groups: initial imaging group = 4.2 (SD:2.74) vs. delayed imaging group = 2.3 (SD:2.0, p = 0.11). In addition, there were no group differences in medication requirements, motor performance, or patient expectations of disease. CONCLUSIONS: In patients with early, probable PD, DaTSCAN contributes no additional impact on clinical management or functional outcomes when added to the diagnostic algorithm. PMID- 28339404 TI - The influence of Task-Related Training combined with Transcutaneous Electrical Nerve Stimulation on paretic upper limb muscle activation in patients with chronic stroke. AB - OBJECTIVES: This study investigated the efficacy of Task-Related Training (TRT) Combined with Transcutaneous Electrical Nerve Stimulation (TENS) on the improvement of upper limb muscle activation in chronic stroke survivors with mild or moderate paresis. METHODS: A single-blind, randomized clinical trial was conducted with 46stroke survivors with chronic paresis. They were randomly allocated two groups: the TRT+TENS group (n = 23) and the TRT+ placebo TENS (TRT+PLBO) group (n = 23). The TRT+TENS group received 30 minutes of high frequency TENS on wrist and elbow extensors, while the TRT+PLBO group received placebo TENS that was not real ES. Both groups did 30 minutes of TRT after TENS application. Intervention was given five days a week for four weeks. The primary outcomes of upper limb muscle activation were measured by integrated EMG (IEMG), a digital manual muscle tester for muscle strength, active range of motion (AROM) and Fugl-Meyer Assessment of the upper extremity (FMA-UE). The measurements were performed before and after the 4 weeks intervention period. RESULTS: Both groups demonstrated significant improvements of outcomes in IEMG, AROM, muscle strength and FMA-UE during intervention period. When compared with the TRT+PLBO group, the TRT+TENS group showed significantly greater improvement in muscle activation (wrist extensors, P = 0.045; elbow extensors, P = 0.004), muscle strength (wrist extensors, P = 0.044; elbow extensors, P = 0.012), AROM (wrist extension, P = 0.042; elbow extensors, P = 0.040) and FMA-UE (total, P < 0.001; shoulder/elbow/forearm, P = 0.001; wrist, P = 0.002; coordination, P = 0.008) at the end of intervention. CONCLUSIONS: Our findings indicate that TRT Combined with TENS can improve paretic muscle activity in upper limb paresis, highlighting the benefits of somatosensory stimulation from TENS. PMID- 28339401 TI - Is Huntingtin Dispensable in the Adult Brain? AB - Huntingtin (HTT) is an essential protein during early embryogenesis and the development of the central nervous system (CNS). Conditional knock-out of mouse Huntingtin (Htt) expression in the CNS beginning during neural development, as well as reducing Htt expression only during embryonic and early postnatal stages, results in neurodegeneration in the adult brain. These findings suggest that HTT is important for the development and/or maintenance of the CNS, but they do not address the question of whether HTT is required specifically in the adult CNS for its normal functions and/or homeostasis. Recently, it was reported that although removing Htt expression in young adult mice causes lethality due to acute pancreatitis, loss of Htt expression in the adult brain is well tolerated and does not result in either motor deficits or neurodegeneration for up to 7 months after Htt inactivation. However, recent studies have also demonstrated that HTT participates in several cellular functions that are important for neuronal homeostasis and survival including sensing reactive oxygen species (ROS), DNA damage repair, and stress responses, in addition to its role in selective macroautophagy. In this review, HTT's functions in development and in the adult CNS will be discussed in the context of these recent discoveries, together with a discussion of their potential impact on the design of therapeutic strategies for Huntington's disease (HD) aimed at lowering total HTT expression. PMID- 28339405 TI - Speech production gains following constraint-induced movement therapy in children with hemiparesis. AB - PURPOSE: The purpose of this study was to investigate changes in speech skills of children who have hemiparesis and speech impairment after participation in a constraint-induced movement therapy (CIMT) program. While case studies have reported collateral speech gains following CIMT, the effect of CIMT on speech production has not previously been directly investigated to the knowledge of these investigators. METHODS: Eighteen children with hemiparesis and co-occurring speech impairment participated in a 21-day clinical CIMT program. The Goldman Fristoe Test of Articulation-2 (GFTA-2) was used to assess children's articulation of speech sounds before and after the intervention. Changes in percent of consonants correct (PCC) on the GFTA-2 were used as a measure of change in speech production. RESULTS: Children made significant gains in PCC following CIMT. Gains were similar in children with left and right-sided hemiparesis, and across age groups. CONCLUSION: This study reports significant collateral gains in speech production following CIMT and suggests benefits of CIMT may also spread to speech motor domains. PMID- 28339406 TI - Does intensive upper limb treatment modality Hybrid Constrained Induced Movement Therapy (H-CIMT) improve grip and pinch strength or fatigability of the affected hand? AB - PURPOSE: To investigate the effects of Hybrid-Constrained Induced Movement Therapy (H-CIMT), defined as CIMT combined with Bimanual Intensive Movement Therapy (BIMT), on grip and pinch strength and fatigability we measured grip and pinch strength and fatigability during clinical H-CIMT. METHODS: The children participated in a H-CIMT model organized in a therapeutic summer-camp. Children received 90 hours of intensive treatment. Grip and pinch strength and fatigability was measured and fatigue was calculated according to a Static Fatigue Index (SFI). RESULTS: Pinch strength significantly increased, grip strength did not increase significantly. A non-significant decrease was seen in SFI in pinch and grip. CONCLUSIONS: H-CIMT showed to be effective in increasing muscle pinch strength in the AH. Effectiveness in decreasing muscle fatigue during grip and pinch tests is not yet shown although there was a tendency towards a decrease in muscle fatigue. However, the long-term effects on these aspects are also important in future research. PMID- 28339407 TI - Upper extremity muscle activation in children with unilateral cerebral palsy during an auditory cued repetitive task: Effects on bimanual coordination. AB - PURPOSE: The aim of this exploratory study was to investigate mirror muscle activation in the upper limbs of children with unilateral cerebral palsy during an auditory-cued repetitive squeezing task and to compare upper limb muscle activation patterns to typically developing peers engaged in the same task. METHODS: A convenience sample of six children with unilateral cerebral palsy and six typically developing peers (7-17 y) participated in the study. Muscle activity was measured using a 16 channel Zerowire EMG system (Noraxon, USA Inc. Scottsdale, AZ) in the anterior deltoid, biceps brachii, extensor carpi radialis, flexor carpi radialis, and lateral triceps muscles bilaterally as children squeezed a pediatric bulb dynamometer to 3 pounds per square inch (PSI) for a one second duration, 10 times in one minute. Squeezing activity was cued by a computer generated auditory beep. Between hand differences in muscle onset times and onset amplitude for each muscle were determined using paired t-tests. Two group by two hand ANOVA measured between group differences. RESULTS: Results supported increased later muscle onset and lack of significant differences in onset amplitude bilaterally when the dominant hand was working in the CP population. CONCLUSIONS: There are differences in motor control mechanisms of muscle activation between populations. PMID- 28339408 TI - Exploring the feasibility and use of acceleromters before, during, and after a camp-based CIMT program for children with cerebral palsy. AB - PURPOSE: The aim of this pilot study was to determine the feasibility and use accelerometers before, during, and after a camp-based constraint-induced movement therapy (CIMT) program for children with hemiplegic cerebral palsy. METHODS: A pre-test post-test design was used for 12 children with CP (mean = 4.9 yrs) who completed a 30-hour camp-based CIMT program. The accelerometer data were collected using ActiGraph GT9X Link. Children wore accelerometers on both wrists one day before and after the camp and on the affected limb during each camp day. Three developmental assessments were administered pre-post CIMT program. RESULTS: Accelerometers were successfully worn before, during, and directly after the CIMT program to collect upper limb data. Affected upper limb accelerometer activity significantly increased during the CIMT camp compared to baseline (p< 0.05). Significant improvements were seen in all twelve children on all assessments of affected upper limb function (p< 0.05) measuring capacity and quality of affected upper limb functioning. CONCLUSION: Accelerometers can be worn during high intensity pediatric CIMT programs to collect data about affected upper limb function. Further study is required to determine the relationship between accelerometer data, measure of motor capacity, and real-world performance post CIMT. PMID- 28339409 TI - Practice-based evidence from a clinical cohort that received pediatric constraint induced movement therapy. AB - PURPOSE: Constraint-Induced Movement Therapy (CIMT) is now designated a highly efficacious treatment for children with cerebral palsy, based on rigorous clinical trials. Yet virtually no evidence confirms that these moderate to large size effects can be replicated in clinical practice for a more heterogeneous clinical population. Thus there is a need to collect and report treatment outcome data based on actual clinical practice as a critical next step for implementation. METHODS: This study presents results from a prospective study conducted on a clinical cohort of 88 children, 18 months to 12 years old (M = 55 months, SD = 5 months), who received high-intensity CIMT known as ACQUIREc. The children varied in severity and etiology of their hemiparesis and a subset was diagnosed with asymmetric quadriparesis. RESULTS: Pre- to post-CIMT assessments confirmed highly significant and clinically meaningful changes based on both parental report (Pediatric Motor Activity Log, p< 0.0001) and standardized measures (The Assisting Hand Assessment, p= 0.04). CONCLUSIONS: Clinical practice of high-intensity CIMT (120 hours in 4 weeks) with full-time casting of the less impaired upper extremity produced benefits of comparable magnitude to those from rigorous randomized controlled trials (RCTs). Therapists were highly trained and actively monitored. Children across a wide range of etiologies and severity levels realized positive outcomes. PMID- 28339410 TI - Unimanual versus bimanual therapy in children with unilateral cerebral palsy: Same, same, but different. AB - BACKGROUND: There is high-level evidence supporting constraint-induced movement therapy (CIMT) and bimanual therapy for children with unilateral cerebral palsy. Evidence-based intervention includes time-limited, goal-directed, skills-based, intensive blocks of practice based on motor learning theory. AIM AND METHODS: Using supporting literature and clinical insight, we provide a theoretical rationale to highlight previously unreported differences between CIMT and bimanual therapy. DISCUSSION: The current emphasis on total dosage of practice for achieving positive outcomes fails to recognise the influence of other critical concepts within motor learning. Limitations exist in the application of motor learning principles using CIMT due to its unimanual nature. CIMT is effective for development of unimanual actions brought about by implicit learning, however it is difficult to target explicit learning that is required for learning how to use two hands together. Using bimanual therapy, object properties can be adapted to trigger goal-related perceptual and cognitive processes required for children to learn to recognise when two hands are required for task completion. CONCLUSION: CIMT and bimanual should be viewed as complementary. CIMT could be used to target unimanual actions. Once these actions are established, bimanual therapy could be used for children to learn how to use these actions for bimanual skill development. PMID- 28339411 TI - Infant constraint induced movement therapy: Lessons learned from clinical implementation. AB - Current evidence supports the efficacy of pediatric constraint induced movement therapy (CIMT) for toddlers and children but little has been published about its use in early intervention with children eighteen months and younger. This paper and case report describes the clinical experience of developing and executing a modified pediatric CIMT intervention with infants under 18 months old. This is an emerging area of practice that is showing positive trends with initial cases. PMID- 28339413 TI - Pediatric Constraint Induced Movement Therapy: Harnessing Adaptive Neuroplasticity. PMID- 28339415 TI - Lifestyle factors in Croatian seafarers as relating to health and stress on board. AB - BACKGROUND: Seafaring is characterized by specific stressors and health risks. OBJECTIVE: The purpose of this article was to compare the prevalence of various lifestyle factors between the shipping and home environments, and in addition to test the relations between lifestyle factors, perceived stress on board, and health in seafarers. METHODS: A total of 530 Croatian seafarers participated in an on-line survey. The questionnaire contained requests for demographic data and a set of questions relating to lifestyle, stress on board, physical health symptoms, and mental health. RESULTS: The data showed higher sleep deprivation, higher levels of smoking and unhealthier diet at sea than at home, with prevalence of alcohol consumption and physical exercise being more favourable for the shipping environment. Sleep deprivation, unhealthy diet, lack of physical exercise, and smoking are shown as negative correlates of various measures of health. Stress on board was associated with sleep deprivation and unhealthy diet, and with more unfavourable physical and mental health. CONCLUSIONS: The results give practical implications for promoting health in seafarers. Some of the lifestyle factors tested, such as alcohol use, smoking and physical exercise, fall rather under individual control, but others, such as a healthy, balanced diet on board and sleeping hygiene at sea, should be improved by shipping management. PMID- 28339414 TI - Update on the application of optic nerve sheath fenestration. AB - BACKGROUND: With the ongoing development of surgical procedures and instruments, the safety of optic nerve sheath fenestration (ONSF) has been improved. OBJECTIVE: Through the past three decades, progress has been made in preventing visual loss from chronic optic nerve swelling in idiopathic intracranial hypertension (IIH), secondary intracranial hypertension and local optic nerve diseases. We now review the updated application of ONSF in those diseases. METHODS: The application of ONSF in papilledema due to IIH, secondary intracranial hypertension to cerebral venous sinus occlusion, Cryptococcal meningitis, and intracranial mass or tumors is reviewed. Additionally, the potential benefits of ONSF in local optic neuropathy from optic nerve sheath meningioma, optic nerve drusen, traumatic optic neuropathy and optic nerve/sheath biopsy are also described. RESULTS: Although ONSF has little or no effect on intracranial pressure, it is a safe, relative easy and effective surgical procedure to prevent or reverse visual loss in IIH. When other treatment modalities fail to timely protect vision, ONSF can be useful in protecting visual function or delay visual loss in secondary intracranial hypertension. CONCLUSION: We recommend that ONSF should be considered as a meaningful alternative or an adjunct therapy to reduce or delay the visual morbidity of these diseases, although the use of ONSF for some of them remains controversial. PMID- 28339416 TI - Improving vocational outcomes in first-episode psychosis by addressing cognitive impairments using Cognitive Adaptation Training. AB - BACKGROUND: Cognitive Adaptation Training (CAT) uses compensatory strategies and environmental supports to support cognitive impairments and improve functioning. CAT may be useful for addressing vocational recovery in first-episode psychosis (FEP) because cognitive impairments are common and vocational recovery is a key goal of young people with FEP. OBJECTIVE: To describe clinical observations and practice experience when delivering CAT with FEP clients and explore potential benefits via objective outcome measures for improving vocational outcomes. METHODS: In this pilot study, five FEP participants received 9 months of CAT. Participant goals and functional needs and clinical observations were recorded. Formal measures of functioning, quality of life and motivation were independently administered pre- and post-intervention. RESULTS: Vocational recovery (education, employment) was found to be a primary functional goal of FEP participants. Accordingly, CAT had a strong focus on vocational functioning, including functional domains required for successful work or educational outcomes, such as organization and planning, transportation and activities of daily living. Factors of clinical importance when delivering CAT with the FEP participants included cognitive heterogeneity, family involvement, flexibility in compensatory and environmental supports used, and experience of stigma. Improvements from baseline to post-intervention were observed on most measures, with the largest improvements seen in global functioning (including vocation), planning and organization, and quality of life. CONCLUSIONS: CAT is an intervention that appears well suited to addressing vocational functioning in FEP, but larger controlled trials are needed. PMID- 28339417 TI - Cynicism as subscale of burnout. AB - BACKGROUND: Cynicism, as a personality trait, has adverse effects on health. The question was asked whether cynical attitudes that develop due to work-related stress correlate with stress levels and whether it has a negative influence on health. OBJECTIVES: To investigate associations of the cynicism subscale scores of the Maslach Burnout Inventory-General Survey (MBI-GS) with levels of stress, anxiety, questionnaire-based physical health and with a number of physiological health risk indicators. METHODS: Cynicism, anxiety, questionnaire-based physical health scores, as well as allostatic load, heart rate variability and C-reactive protein, were assessed in 27 males working between 40 and 80 irregular hours per week. RESULTS: Cynicism scores related to stress levels (r = 0.411, p = 0.030). Effects of work-related cynicism on physical health were suggested by negative associations with questionnaire-based scores on physical health (r = -0.383, p = 0.044) and heart rate variability indicators (r = -0.379, p = 0.047 to r = 0.496, p = 0.007), and by positive associations with anxiety levels (r = 0.408, p = 0.031), heart rate (r = 0.449, p = 0.017), BMI (r = 0.426, p = 0.024) allostatic load (r = 0.360, p = 0.065) and levels of the inflammatory marker C reactive protein (r = 0.407, p = 0.035). CONCLUSIONS: Cynicism, as reflected by the MBI-GS, increases with increased stress levels and could contribute to the decline in the health reported for burnout. PMID- 28339418 TI - Survey of kinesiologists' functional capacity evaluation practice in Canada. AB - BACKGROUND: In Canada, functional capacity evaluations (FCEs) are commonly administered by several health care professions including kinesiologists. Kinesiologists have been recently regulated as health care professionals in Ontario and we know little about their demographics, the frequency of FCE administration, or the types of FCEs used by this group. OBJECTIVE: The purposes of this study were to identify: 1) the demographic characteristics and FCE education of kinesiology FCE practitioners; 2) the FCE systems most used by these practitioners and 3) the constructs from assessments used to determine functional capacity. METHODS: A survey was distributed to members of the Canadian Kinesiology Alliance. Descriptive statistics and frequency distributions were calculated from the survey responses (n = 77). RESULTS: FCE practitioners were represented by kinesiologists (79%) practicing more than 15 years and 1-5 years, who received FCE training from a certification course. ARCON (23%) was the most common FCE system used. Low-level lifting (43%), mid-lift (38%), pulling (38%) and walking (38%) are the most common FCE task components used to assess functional capacity. Although kinesiologists consider multiple factors when making decisions about task component endpoints, biomechanical observations/body mechanics are the primary methods used. CONCLUSIONS: Kinesiologists are conducting FCEs for the primary purpose of preparing return-to-work or workplace accommodation recommendations. Although functional capacity is determined using multiple factors, there is an emphasis on biomechanics and body mechanics. Focusing FCE training and research on these constructs may provide opportunities to further strengthen the reliability and validity of FCE outcomes. PMID- 28339419 TI - The (im)possibilities of returning to work after a stroke. AB - BACKGROUND: What a stroke means for working-age persons has not been sufficiently studied from a sociological perspective. OBJECTIVE: This article uses the empirical material of a larger study to describe and analyze how institutional practices and discourses influence attempts to return to work after a stroke. METHODS: Semi-structured interviews were conducted with ten persons who have had a stroke and ten civil servants and professionals from the Swedish Public Employment Service, the Social Insurance Agency, and different health care institutions. The qualitative analysis was inspired by institutional ethnography. RESULTS: The analysis shows how persons who have had a stroke and civil servants and professionals in welfare organizations share the same goal: a return to working life for the former. The persons in this study related to, translated, and put into practice discourses of normality and employability in this process. However, there were, at times, conflicting institutional practices between the different organizations. CONCLUSIONS: Conflicting institutional practices connected to the discourses of normality and employability contribute to the difficulties that persons who have had a stroke face when trying to return to work after recovery. PMID- 28339422 TI - Diffusion kurtosis imaging for diagnosis of Parkinson's disease: A novel software tool proposal. AB - In order to diagnose Parkinson disease (PD) at an early stage, it is important to develop a sensitive method for detecting structural changes in the substantia nigra (SN). Diffusion weighted imaging (DWI) and diffusion tensor imaging (DTI) have become important tools in supporting diagnosis of PD, with findings based on increased apparent diffusion coefficients (ADCs) in basal ganglia and decreased fractional anisotropy (FA) in SN. Based on the hypothesis that a diffusion kurtosis imaging (DKI) theory is a valuable method for PD diagnosis based on the non-Gaussian diffusion of water in biologic systems, the purpose of this study is to develop an image processing scheme (software) based on Image-J for the facilitating the application of DKI to assist PD diagnosis. Using the new DKI software enables to estimate the diffusional kurtosis and diffusion coefficients, which reflect the structural differences between regions of interest. The experimental results of applying the new software showed that diffusional kurtosis was highly sensitive to microstructural tissue changes, which were not noticeable in the diffusion coefficient values. Thus, the study results may suggest that applying the new image processing software can be useful for assessing tissue structural abnormalities, monitoring and following disease progression. PMID- 28339423 TI - Spherically symmetric volume elements as basis functions for image reconstructions in computed laminography. AB - BACKGROUND: Laminography is a tomographic technique that allows three-dimensional imaging of flat and elongated objects that stretch beyond the extent of a reconstruction volume. Laminography images can be reconstructed using iterative algorithms based on the Kaczmarz method. OBJECTIVE: This study aims to develop and demonstrate a new reconstruction algorithm that may provide superior image reconstruction quality for this challenged imaging application. METHODS: The images are initially represented using the coefficients over basis functions, which are typically piecewise constant functions (voxels). By replacing voxels with spherically symmetric volume elements (blobs) based on the generalized Kaiser-Bessel window functions, the images are reconstructed using this new adapted version of the algebraic image reconstruction technique. RESULTS: Band limiting properties of blob functions are beneficial particular in the case of noisy projections and with only a limited number of available projections. Study showed that using blob basis functions improved full-width-at-half-maximum resolution from 10.2+/-1.0 to 9.9+/-0.9 (p < 0.001). Signal-to-noise ratio also improved from 16.1 to 31.0. The increased computational demand per iteration was compensated by using a faster convergence rate, such that the overall performance is approximately identical for blobs and voxels. CONCLUSIONS: Despite the higher complexity, tomographic reconstruction from computed laminography data should be implemented using blob basis functions, especially if noisy data is expected. PMID- 28339420 TI - A pilot-study of a worksite based participatory intervention program: Its acceptability and short-term effects on work climate and attitudes in human service employees. AB - BACKGROUND: Psychosocial factors, including job demands and poor resources, have been linked to stress, health problems, and negative job attitudes. However, worksite based interventions and programs targeting psychosocial factors may change employees' perceptions of their work climate and work attitudes. OBJECTIVE: This pilot study describes a newly developed worksite based participatory organizational intervention program that was tested in the social service sector. It is evaluated using participants' perceptions of the intervention to investigate its acceptability as a feature of feasibility and its short-term effects on work climate factors (job demands and resources) and work related attitudes. METHODS: Forty employees of a Swedish social service unit provided self-reports before, during, and after the intervention. RESULTS: As for effects, quantitative role overload and social support decreased while turnover intention increased. Responses to an open-ended question showed that participants considered the intervention program valuable for addressing issues relating to the psychosocial work climate. CONCLUSIONS: Although the findings are preliminary, it was possible to carry out this worksite based participatory organizational program in this particular setting. Also, the preliminary findings underscore the challenges associated with designing and implementing this type of intervention program, thus adding to the methodological discussion on implementation and evaluation. PMID- 28339424 TI - Comparison of Weight Loss, Ghrelin, and Leptin Hormones After Ligation of Left Gastric Artery and Sleeve Gastrectomy in a Rat Model. AB - BACKGROUND Ligation of the left gastric artery (LLGA), which supplies the fundus of the stomach, may reduce the appetite hormone ghrelin, resulting in weight control. The aim of this study was to compare LLGA and sleeve gastrectomy (SG) in terms of postoperative outcomes in a rat model. MATERIAL AND METHODS Fifteen male Wistar albino rats, weighing >350 grams (range 350-525 grams), were enrolled in LLGA (N=5), SG (N=5), and control (N=5) groups. Blood samples were drawn preoperatively and also during the first and fourth week postoperatively to assay ghrelin and leptin hormone levels. Body weight was measured in each group. RESULTS The maximum reduction in ghrelin level (41.5%) was found in the LLGA group. Considerable% total weight loss (TWL) (mean 24.1%) was observed in the SG group, and slight%TWL was noted in the control and LLGA groups (means of 0.1% and 2.1%, respectively). There was no significant difference in mean percent weight change between the LLGA and the SG groups (p=0.08). Blood sample analysis revealed no statistically significant changes in ghrelin or leptin levels between the groups (p=0.9 and p=0.3, respectively). CONCLUSIONS We present evidence that LLGA causes the same reduction in ghrelin hormone levels as SG at 4 weeks after surgery in a rat model. However, LLGA did not cause the same%TWL as SG. The mechanism of weight loss in SG is most likely due to restriction and to the effects of the procedure, rather than due to neurohormonal changes. PMID- 28339426 TI - Evolution of US Health Care Reform. AB - Major health policy creation or changes, including governmental and private policies affecting health care delivery are based on health care reform(s). Health care reform has been a global issue over the years and the United States has seen proposals for multiple reforms over the years. A successful, health care proposal in the United States with involvement of the federal government was the short-lived establishment of the first system of national medical care in the South. In the 20th century, the United States was influenced by progressivism leading to the initiation of efforts to achieve universal coverage, supported by a Republican presidential candidate, Theodore Roosevelt. In 1933, Franklin D. Roosevelt, a Democrat, included a publicly funded health care program while drafting provisions to Social Security legislation, which was eliminated from the final legislation. Subsequently, multiple proposals were introduced, starting in 1949 with President Harry S Truman who proposed universal health care; the proposal by Lyndon B. Johnson with Social Security Act in 1965 which created Medicare and Medicaid; proposals by Ted Kennedy and President Richard Nixon that promoted variations of universal health care. presidential candidate Jimmy Carter also proposed universal health care. This was followed by an effort by President Bill Clinton and headed by first lady Hillary Clinton in 1993, but was not enacted into law. Finally, the election of President Barack Obama and control of both houses of Congress by the Democrats led to the passage of the Affordable Care Act (ACA), often referred to as "ObamaCare" was signed into law in March 2010. Since then, the ACA, or Obamacare, has become a centerpiece of political campaigning. The Republicans now control the presidency and both houses of Congress and are attempting to repeal and replace the ACA. Key words: Health care reform, Affordable Care Act (ACA), Obamacare, Medicare, Medicaid, American Health Care Act. PMID- 28339425 TI - Potential role of the OVOL1-OVOL2 axis and c-Myc in the progression of cutaneous squamous cell carcinoma. AB - OVOL1 and OVOL2 are ubiquitously conserved genes encoding C2H2 zinc-finger transcription factors in mammals. They promote epithelial cell proliferation, differentiation, and mesenchymal-to-epithelial transition, coordinately mediated via the Wnt signaling pathway. We previously reported that human OVOL1 and OVOL2 were preferentially expressed in the normal epidermis and hair follicles as well as their tumors, and found that OVOL1 is upregulated in Bowen's disease and downregulated in cutaneous squamous cell carcinoma. The aims of this study were to elucidate the potential role of the OVOL1-OVOL2 axis in Bowen's disease and squamous cell carcinoma, and to reveal the relationship between OVOL and c-Myc, a proto-oncogene that plays a pivotal role in the malignancy of epithelial tumors. We investigated 20 Bowen's disease and 20 squamous cell carcinoma clinical samples and a human squamous cell carcinoma cell line (A431) using immunohistochemical staining and molecular biological approaches. Immunohistochemical analysis revealed that OVOL1 was upregulated in Bowen's disease and markedly downregulated in squamous cell carcinoma; conversely, c-Myc was downregulated in Bowen's disease and upregulated in squamous cell carcinoma. OVOL2 was markedly upregulated in the nucleus of Bowen's disease cells, but the distribution of OVOL2 expression in squamous cell carcinoma varied widely; OVOL2 was typically expressed in the cytoplasm, but only sporadically in the nucleus. Furthermore, knockdown of OVOL1 using a specific small interfering RNA increased the mRNA and protein levels of c-Myc and OVOL2. Knockdown of OVOL2 did not significantly affect the mRNA and protein levels of either c-Myc or OVOL1. These results suggest that OVOL1 is an upstream suppressor of c-Myc and OVOL2, and the OVOL1-OVOL2 axis is a modulator of c-Myc, coordinately regulating the invasiveness of cutaneous squamous cell carcinoma. Taken together, this study suggests that the OVOL1-OVOL2 axis is a key modulator of c-Myc expression in the shift from in situ epidermal malignancy (Bowen's disease) to invasive squamous cell carcinoma. PMID- 28339427 TI - A Critical Analysis of Obamacare: Affordable Care or Insurance for Many and Coverage for Few? AB - The Affordable Care Act (ACA), of 2010, or Obamacare, was the most monumental change in US health care policy since the passage of Medicaid and Medicare in 1965. Since its enactment, numerous claims have been made on both sides of the aisle regarding the ACA's success or failure; these views often colored by political persuasion. The ACA had 3 primary goals: increasing the number of the insured, improving the quality of care, and reducing the costs of health care. One point often lost in the discussion is the distinction between affordability and access. Health insurance is a financial mechanism for paying for health care, while access refers to the process of actually obtaining that health care. The ACA has widened the gap between providing patients the mechanism of paying for healthcare and actually receiving it. The ACA is applauded for increasing the number of insured, quite appropriately as that has occurred for over 20 million people. Less frequently mentioned are the 6 million who have lost their insurance. Further, in terms of how health insurance is been provided, the majority the expansion was based on Medicaid expansion, with an increase of 13 million. Consequently, the ACA hasn't worked well for the working and middle class who receive much less support, particularly those who earn more than 400% of the federal poverty level, who constitute 40% of the population and don't receive any help. As a result, exchange enrollment has been a disappointment and the percentage of workers obtaining their health benefits from their employer has decreased steadily. Access to health care has been uneven, with those on Medicaid hampered by narrow networks, while those on the exchanges or getting employer benefits have faced high out-of-pocket costs.The second category relates to cost containment. President Obama claimed that the ACA provided significant cost containment, in that costs would have been even much higher if the ACA was not enacted. Further, he attributed cost reductions generally to the ACA, not taking into account factors such as the recession, increased out-of-pocket costs, increasing drug prices, and reduced coverage by insurers.The final goal was improvement in quality. The effort to improve quality has led to the creation of dozens of new agencies, boards, commissions, and other government entities. In turn, practice management and regulatory compliance costs have increased. Structurally, solo and independent practices, which lack the capability to manage these new regulatory demands, have declined. Hospital employment, with its associated increased costs, has been soaring. Despite a focus on preventive services in the management of chronic disease, only 3% of health care expenditures have been spent on preventive services while the costs of managing chronic disease continue to escalate.The ACA is the most consequential and comprehensive health care reform enacted since Medicare. The ACA has gained a net increase in the number of individuals with insurance, primarily through Medicaid expansion. The reduction in costs is an arguable achievement, while quality of care has seemingly not improved. Finally, access seems to have diminished.This review attempts to bring clarity to the discussion by reviewing the ACA's impact on affordability, cost containment and quality of care. We will discuss these aspects of the ACA from the perspective of proponents, opponents, and a pragmatic point of view.Key words: Affordable Care Act (ACA), Obamacare, Medicare, Medicaid, Medicare Modernization Act (MMA), cost of health care, quality of health care, Merit-Based Incentive Payments System (MIPS). PMID- 28339428 TI - Does Conservative Treatment Change the Brain in Patients with Chronic Musculoskeletal Pain? A Systematic Review. AB - BACKGROUND: Chronic musculoskeletal pain is characterized by maladaptive central neuroplastic changes. Many observational studies have demonstrated that chronic pain states are associated with brain alterations regarding structure and/or function. Rehabilitation of patients with chronic musculoskeletal pain may include cognitive, exercise, or multimodal therapies. OBJECTIVE: The current review aims to provide a constructive overview of the existing literature reporting neural correlates, based on brain magnetic resonance imaging (MRI) techniques, following conservative treatment in chronic musculoskeletal pain patients. STUDY DESIGN: Systematic review of the literature. SETTING: University medical centers in Belgium. METHODS: The current review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Literature was searched from 3 databases and screened for eligibility. Methodological quality across studies was assessed with Cochrane Collaboration's tool for assessing risk of bias and quality of evidence was determined applying the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. RESULTS: A total of 9 eligible studies were identified with a predominant high risk of bias. Cognitive behavioral therapy induced several structural and functional changes predominantly in prefrontal cortical regions and a shift from affective to sensory-discriminative brain activity after behavioral extinction training. Multidisciplinary treatment in pediatric complex regional pain syndrome facilitated normalization of functional connectivity of resting-state networks and the amygdala, and increased gray matter in prefrontal and specific subcortical areas. Exercise therapy led to specific for resting-state functional connectivity and a trend towards pressure induced brain activity changes. LIMITATIONS: A very small number of studies was available, which furthermore exhibited small study samples. Moreover, only 2 of the included studies were randomized controlled trials. CONCLUSIONS: It is likely that conservative treatments may induce mainly functional and structural brain changes in prefrontal regions in patients with chronic musculoskeletal pain. Due to the relatively high risk of bias across the included studies, future studies with randomized designs are needed to confirm the current findings. In addition, more research evaluating the treatment-induced effects on white matter and whole brain network dynamics are warranted.Key words: Chronic pain, musculoskeletal pain, MRI, functional MRI, therapy, rehabilitation, cognitive behavioral therapy, exercise therapy. PMID- 28339429 TI - Comparing the Efficacy of Surgery and Medical Therapy for Pain Management in Endometriosis: A Systematic Review and Meta-analysis. AB - BACKGROUND: Pain is considered as one of the main symptoms of endometriosis. The treatment for endometriosis remains controversial. OBJECTIVES: The aim of this study is to compare the effect of medical or surgical treatments for pain-relief in patients with endometriosis. STUDY DESIGN: Systematic review and meta analysis. SETTING: Published papers about evaluating pain treatment in endometriosis in PubMed, Scopus, and Google Scholar. METHODS: After searching all studies evaluating pain treatment in endometriosis in PubMed, Scopus, and Google Scholar, there were 23 related studies, containing 1,847 patients enrolled in our study. We used a variety of tests: fixed and random effects models, Q Cochrane test and I2 index, Egger and Begg tests, forest and funnel plots, Trim and fill method, and meta-regression in our analysis. RESULTS: There was no statistically significant difference in pain improvement between surgical and medical treatment. Interestingly, pain relief was more prominent longer after treatment. Both clinical trials and cross sectional studies showed higher improvement in pain than cohort studies. High quality studies and lower body mass index (BMI) had a greater effect on pain relief. All studies were heterogeneous, but there was no publication bias. LIMITATIONS: There was a higher probability of risk of bias in blinding, random sequence generation, and selective outcome reporting in clinical trial studies entered in our meta-analysis. CONCLUSIONS: Our results could not demonstrate the preference of each medical or surgical treatment effect for dysmenorrhea in endometriosis. Additional data is required before a standardized medical protocol can be offered, but we believe this study may encourage clinicians to consider a less invasive alternative for treating their patients' chronic pelvic pain in the near future.Key words: Endometriosis, pain, meta-analysis, therapy, disease management. PMID- 28339430 TI - Comparative Effectiveness Review of Cooled Versus Pulsed Radiofrequency Ablation for the Treatment of Knee Osteoarthritis: A Systematic Review. AB - BACKGROUND: Patients suffering from osteoarthritis of the knee and patients post total knee arthroplasty often develop refractory, disabling chronic knee pain. Radiofrequency ablation, including conventional, pulsed, and cooled, has recently become more accepted as an interventional technique to manage chronic knee pain in patients who have failed conservative treatment or who are not suitable candidates for surgical treatment. OBJECTIVE: This systematic review aimed to analyze published studies on radiofrequency ablation to provide an overview of the current knowledge regarding variations in procedures, nerve targets, adverse events, and temporal extent of clinical benefit. STUDY DESIGN: A systematic review of published studies investigating conventional, pulsed, or cooled radiofrequency ablation in the setting of chronic knee pain. METHODS: Medline, Google Scholar, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases were reviewed for studies on radiofrequency ablation for patients with chronic knee pain through July 29, 2016. From the studies, the procedural details, outcomes after treatment, follow-up points, and complications were compiled and analyzed in this literature review. Included studies were analyzed for clinical relevance and strength of evidence was graded using either the NHLBI Quality assessment of controlled intervention studies or the NHLBI quality assessment for before-after (pre-post) studies with no control group. RESULTS: Seventeen total publications were identified in the search, including articles investigating conventional, pulsed, or cooled radiofrequency ablation. These studies primarily targeted either the genicular nerves or used an intraarticular approach. Of the studies, 5 were small-sized randomized controlled trials, although one involved diathermy radiofrequency ablation. There were 8 retrospective or prospective case series and 4 case reports. Utilizing the strength of evidence grading, there is a low level of certainty to suggest a superior benefit between targeting the genicular nerve, an intraarticular approach, or targeting the larger nerves such as femoral and tibial nerves. Utilizing the strength of evidence grading, there is a low level of certainty in supporting the superiority of any specific RFA procedure modality. The majority of the studies report positive patient outcomes, but the inconsistent procedural methodology, inconsistent patient assessment measures, and small study sizes limit the applicability of any specific study to clinical practice. LIMITATIONS: While the wide search strategy included a variety of articles, broad conclusions and pooled data could not be obtained based on the studies analyzed. CONCLUSIONS: Overall, the studies showed promising results for the treatment of severe chronic knee pain by radiofrequency ablation at up to one year with minimal complications. Numerous studies, however, yielded concerns about procedural protocols, study quality, and patient follow-up. Radiofrequency ablation can offer substantial clinical and functional benefit to patients with chronic knee pain due to osteoarthritis or post total knee arthroplasty.Key words: Radiofrequency ablation, knee osteoarthritis, knee pain, genicular nerve, total knee arthroplasty (TKA), cooled radiofrequency ablation, pulsed radiofrequency ablation. PMID- 28339431 TI - Perioperative Ketamine Administration for Thoracotomy Pain. AB - BACKGROUND: Of all the postsurgical pain conditions, thoracotomy pain poses a particular therapeutic challenge in terms of its prevalence, severity, and ensuing postoperative morbidity. Multiple pain generators contribute to the severity of post-thoracotomy pain, and therefore a multimodal analgesic therapy is considered to be a necessary strategy. Along with opioids, thoracic epidural analgesia, and paravertebral blocks, N-Methyl-D-Aspartate (NMDA) receptor antagonists such as ketamine have been used as adjuvants to improve analgesia. OBJECTIVE: We reviewed the evidence for the efficacy of intravenous and epidural administration of ketamine in acute post-thoracotomy pain management, and its effectiveness in reducing chronic post-thoracotomy pain. STUDY DESIGN: Systematic literature review and an analytic study of a data subset were performed. METHODS: We searched PubMed, Embase, and Cochrane reviews using the key terms "ketamine," "neuropathic pain," "postoperative," and "post-thoracotomy pain syndrome." The search was limited to human trials and included all studies published before January 2015. Data from animal studies, abstracts, and letters were excluded. All studies not available in the English language were excluded. The manuscript bibliographies were reviewed for additional related articles. We included randomized controlled trials and retrospective studies, while excluding individual case reports. RESULTS: This systematic literature search yielded 15 randomized control trials evaluating the efficacy of ketamine in the treatment of acute post-thoracotomy pain; fewer studies assessed its effect on attenuating chronic post-thoracotomy pain. The majority of reviewed studies demonstrated that ketamine has efficacy in reduction of acute pain, but the evidence is limited on the long-term benefits of ketamine to prevent post-thoracotomy pain syndrome, regardless of the route of administration. A nested analytical study found there is a statistically significant reduction in acute post-thoracotomy pain with IV or epidural ketamine. However currently, the evidence for a role of ketamine as a preventative agent for chronic post-thoracotomy pain is insufficient due to the heterogeneity of the studies reviewed with regard to the route of administration, dosage, and outcome measures. LIMITATIONS: The evidence for a role of ketamine as a preventative agent for chronic post-thoracotomy pain is insufficient due to the heterogeneity of the studies reviewed. CONCLUSION: The majority of randomized controlled trials reviewed show no role for ketamine in attenuating or preventing post-thoracotomy pain syndrome at variable follow-up lengths. Therefore, additional research is warranted with consideration of risk factors and long-term follow-up for chronic post-thoracotomy pain though the evidence for benefit appears clear for acute post-thoracotomy pain.Key words: Ketamine, postoperative, thoracotomy pain, post thoracotomy pain syndrome, neuropathic pain. PMID- 28339432 TI - Bipolar Versus Unipolar Intraarticular Pulsed Radiofrequency Thermocoagulation in Chronic Knee Pain Treatment: A Prospective Randomized Trial. AB - BACKGROUND: Chronic knee pain is a major widespread problem causing significant impairment of daily function. Pulsed radiofrequency has been shown to reduce severe chronic joint pain as a non-pharmacological and less invasive treatment method. OBJECTIVE: We aimed to compare the effectiveness of unipolar and bipolar intraarticular pulsed radiofrequency methods in chronic knee pain control. STUDY DESIGN: Prospective, randomized, double-blind study. SETTING: Pain clinic in Cukurova University Faculty of Medicine. METHODS: One hundred patients, aged 20 - 70 years with grade 2 or 3 knee osteoarthritis were included in this study. Patients were randomly allocated into 2 groups to receive either unipolar (group U, n = 50) or bipolar (group B, n = 50) intraarticular pulsed radiofrequency (IAPRF) with a 45 V voltage, 2 Hz frequency, 42 degrees C temperature, 10 msec pulse width, and 10 minute duration. We recorded visual analog scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index LK 3.1WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index LK 3.1) scores of patients at baseline and one, 4, and 12 weeks after the procedure. The primary outcome was the percentage of patients with >= 50% reduction in knee pain at 12 weeks after the procedure. RESULTS: There was a significant difference between the groups according to VAS scores at all post-intervention time points. In group B, 84% of patients, and in the group U, 50% of patients achieved at least 50% knee pain relief from the baseline to 3 months. In group B, WOMAC scores were significantly lower than the group U at one and 3 months. LIMITATIONS: Lack of long-term clinical results and supportive laboratory tests. CONCLUSION: Bipolar IAPRF is more advantageous in reducing chronic knee pain and functional recovery compared with unipolar IAPRF. Further studies with longer follow-up times, laboratory-based tests, and different generator settings are required to establish the clinical importance and well-defined mechanism of action of PRF. This study protocol was registered at clinicaltrials.gov (identifier: NCT02141529), on May 15, 2014. Institutional Review Board (IRB) approval date: January 16, 2014, and number: 26/9Key words: Chronic pain, intraarticular, knee joint, knee osteoarthritis, pain management, pulsed radiofrequency treatment, quality of life, recovery of function. PMID- 28339434 TI - Platelet Rich Plasma in Musculoskeletal Pathology: A Necessary Rescue or a Lost Cause? AB - BACKGROUND: Platelet rich plasma (PRP) has been used for decades to facilitate surgical tissue repair; therefore, the current trend of percutaneously injecting PRP to theoretically enhance tissue regeneration and repair is a logical progression. Applications include treatment of osteoarthritis, tendinopathy, chondropathy, acute and chronic soft tissue injuries, muscle or ligament tear, as well as enhancement of healing after bone or tissue reconstruction. However, there is limited evidence to support the use of PRP in the abovementioned conditions. Variations in the preparation of PRP and its application in various conditions influence its effect on various orthopedic conditions. OBJECTIVE: To provide a basic overview of the current use of PRP in treating musculoskeletal conditions. METHODS: Studies relevant to PRP were extracted from the PubMed and Medline database within the dates ranging from 1990 through 2015. These studies included in vitro as well as in-vivo animal experiments and careful analysis of the study population, type of intervention, and outcomes was made. RESULTS: PRP has been noted to be a beneficial solution for tissue healing based on limited current literature. However a variety of factors such as method of preparation, composition, medical condition of the patient, anatomic location of the lesion, and tissue type can alter outcome. CONCLUSION: The effectiveness and potential adverse effects of this treatment require high quality studies prior to widespread clinical application.Key words: Growth factors, platelet rich plasma, regeneration, regenerative healing, tissue repair, stem cells, mesenchymal stem cells, tissue engineering. PMID- 28339433 TI - Management of Neuropathic Chronic Pain with Methadone Combined with Ketamine: A Randomized, Double Blind, Active-Controlled Clinical Trial. AB - BACKGROUND: Methadone and ketamine are used in neuropathic pain management. However, the benefits of both drugs association are uncertain in the treatment of neuropathic pain. OBJECTIVE: Our primary objective was test the hypothesis that oral methadone combined with oral ketamine is more effective than oral methadone or ketamine alone in reducing neuropathic pain. STUDY DESIGN: We conducted a randomized, double blind, active-controlled parallel-group clinical trial. METHODS: Forty-two patients with neuropathic pain refractory to conventional therapy were randomly assigned to receive oral methadone (n = 14), ketamine (n = 14), or methadone plus ketamine (n = 14) over a 3-month period. RESULTS: During these 90 days, we observed pain scores using a visual analogical scale (VAS), allodynia, burning/shooting pain, and some side effects. All treatments were effective in reducing pain scores by at least 40%. However, a significant improvement in pain was observed only in the ketamine alone group compared with both the methadone or methadone/ketamine groups. No significant differences were observed among the treatment groups for the reduction of burning or shooting pain, while ketamine alone was more effective than methadone or methadone/ketamine for the reduction of allodynia. LIMITATIONS: Formal assessment for awareness of the allocation was not performed, some co-intervention bias may have occurred, our results could be only relevant to the patient population investigated and the use of VAS as the primary outcome detect changes in pain intensity but not to assess neuropathic pain symptoms. CONCLUSION: This study indicates that ketamine was better than methadone or methadone/ketamine for treating neuropathic pain.Key words: Multimodal analgesia, refractory pain, NMDA receptor, opioid. PMID- 28339435 TI - Impact of Celiac Plexus Neurolysis on Survival in Patients with Unresectable Pancreatic Cancer: A Retrospective, Propensity Score Matching Analysis. AB - BACKGROUND: Pain caused by pancreatic cancer (PC) is difficult to control. Celiac plexus neurolysis (CPN) can effectively control the pain and reduce the use of opioids. However, the effect of CPN on survival for patients with unresectable PC remains controversial. OBJECTIVES: To determine if CPN is associated with survival benefits for these patients. STUDY DESIGN: Retrospective, observational cohort study. SETTING: National Cancer Center in Korea. METHODS: The CPN group included patients who were diagnosed with unresectable PC and underwent fluoroscopically guided bilateral CPN (10 mL dehydrated alcohol each side) once between January 1, 2006, and December 31, 2013. Patients with PC who did not undergo CPN were in the control group; for the final control group, 1:1 propensity score (PS) matching was conducted with the CPN group. The main outcome was median survival (PC diagnosis to death) after PS matching, assessed using Kaplan-Meier curves. RESULTS: For the primary overall survival analysis, the CPN and control groups included 110 and 258 patients, respectively. The median survival period was not significantly different between the CPN and control groups (278 vs. 203 days, P = 0.246), even after PS matching (278 vs. 180 days, P = 0.127), or based on time to CPN from diagnosis (<= 6 vs. > 6 months; 255 vs. 310 days, P = 0.147). LIMITATIONS: Retrospective design, small sample size, and inconsistent timing of CPN after the diagnosis date. CONCLUSION: CPN did not affect survival for patients with unresectable PC. Considering the limitations of the retrospective design, a well-designed prospective design study should be conducted.Key words: Celiac plexus, pancreatic neoplasms, survival, neurolysis, pain, propensity score matching, opioids, cancer. PMID- 28339436 TI - Pain-Related Limitations in Daily Activities Following Thoracic Surgery in a United States Population. AB - BACKGROUND: Ringsted et al created a statistically validated questionnaire to assess pain-related limitations in daily activities following thoracic surgery and translated it to English. We utilized the questionnaire to assess the impact of pain impairing certain daily activities in a United States thoracic surgery population. OBJECTIVES: Examine if the questionnaire developed and translated to English by Ringsted et al to assess the effects of chronic pain after thoracic surgery on daily activities would be applicable in a sample of thoracic surgery patients in the United States. STUDY DESIGN: Cross-sectional study by mailed questionnaire. SETTING: All patients who had thoracic surgery between 6 months and 3 years ago at a university hospital. METHODS: We sent questionnaires to patients who had undergone thoracic surgery between 6 months and 3 years ago, yielding a sample of 349 eligible patients. Questionnaire results were statistically assessed for item fit, dimensionality, and internal reliability. RESULTS: The response rate was 26.4%. Of the responders, 36% (95% CI: 26.1% to 46.5%) identified themselves as having chronic pain related to their thoracic surgery. Activities such as lying on the operated side, coughing, and carrying groceries were impaired in more than 50% of the patients who had thoracic surgery related pain (P < 0.05). Patients with chronic pain were more likely to report pain in other body locations. Few activities were limited in the patients identifying themselves as not having chronic pain. Statistical measures indicate high internal reliability. LIMITATIONS: This was a retrospective questionnaire with 26.4% response rate. CONCLUSIONS: Pain continues to impair the daily activities of a significant proportion of patients after thoracic surgery in a sample from the United States. Despite cultural differences, the Danish procedure specific questionnaire provides an applicable and similar assessment of functional impairment after thoracic surgery in American patients.Key words: Thoracic surgery, chronic pain, impairment, daily life, questionnaire. PMID- 28339437 TI - Complications of Lumbar Disc Herniation Following Full-endoscopic Interlaminar Lumbar Discectomy: A Large, Single-Center, Retrospective Study. AB - BACKGROUND: The new surgical procedure of full-endoscopic interlaminar lumbar discectomy (FILD) has achieved favorable effects in the treatment of lumbar disc herniation (LDH). Along with the wide range of applications of FILD, a series of complications related to the operation has gradually emerged. OBJECTIVE: To describe the types, incidences, and characteristics of complications following FILD and to explore preventative and treatment measures. STUDY DESIGN: Retrospective, observational study. SETTING: A spine center affiliated with a large general hospital. METHOD: In total, 479 patients with LDH underwent FILDs that were performed by a single experienced spine surgeon between January 2010 and April 2013. Data concerning the complications were recorded. RESULTS: All 479 cases successfully underwent the procedure. A total of 482 procedures were completed. The mean follow-up time was 44.3 months with a range of 24 to 60 months. The average patient age was 47.8 years with a range of 16 to 76 years. Twenty-nine (6.0%) related complications emerged, including 3 cases (0.6%) of incomplete decompression in which the symptoms gradually decreased following 3 - 6 weeks of conservative treatment, 2 cases (0.4%) of nerve root injury in which the patients recovered well following 1 - 3 months of neurotrophic drug and functional exercise treatment, 15 cases (3.1%) of paresthesia that gradually improved following 1 - 8 weeks of rehabilitation exercises and treatment with mecobalamin and pregabalin, and 9 cases of recurrent herniation (1.9%). The latter condition was controlled in 4 cases with a conservative method, and 5 of these cases underwent reoperations that included 3 traditional open surgeries and 2 FILDs. Furthermore, the complication rate for the first 100 cases was 18%. This rate decreased to 2.9% for cases 101 - 479. The incidence of L4-5 herniation (8.2%) was significantly greater than that of L5-S1 (4.5%). LIMITATIONS: This is a retrospective study, and some bias exists due to the single-center study design. CONCLUSION: FILD is a surgical approach that has a low complication rate. Incomplete decompression, nerve root injury, paresthesia, and recurrent herniation were observed in our study. Some effective measures can prevent and reduce the incidence of the complications including strict indications for surgery, a thorough action plan, and a high level of surgical skill. Key words: Complication, lumbar disc herniation, lumbar discectomy, endoscopic, inter laminar discectomy, minimally invasive spine surgery. PMID- 28339438 TI - The Role of Autonomic Function in Exercise-induced Endogenous Analgesia: A Case control Study in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Healthy People. AB - BACKGROUND: Patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) are unable to activate brain-orchestrated endogenous analgesia (or descending inhibition) in response to exercise. This physiological impairment is currently regarded as one factor explaining post-exertional malaise in these patients. Autonomic dysfunction is also a feature of ME/CFS. OBJECTIVES: This study aims to examine the role of the autonomic nervous system in exercise induced analgesia in healthy people and those with ME/CFS, by studying the recovery of autonomic parameters following aerobic exercise and the relation to changes in self-reported pain intensity. STUDY DESIGN: A controlled experimental study. SETTING: The study was conducted at the Human Physiology lab of a University. METHODS: Twenty women with ME/CFS- and 20 healthy, sedentary controls performed a submaximal bicycle exercise test known as the Aerobic Power Index with continuous cardiorespiratory monitoring. Before and after the exercise, measures of autonomic function (i.e., heart rate variability, blood pressure, and respiration rate) were performed continuously for 10 minutes and self-reported pain levels were registered. The relation between autonomous parameters and self reported pain parameters was examined using correlation analysis. RESULTS: Some relationships of moderate strength between autonomic and pain measures were found. The change (post-exercise minus pre-exercise score) in pain severity was correlated (r = .580, P = .007) with the change in diastolic blood pressure in the healthy group. In the ME/CFS group, positive correlations between the changes in pain severity and low frequency (r = .552, P = .014), and between the changes in bodily pain and diastolic blood pressure (r = .472, P = .036), were seen. In addition, in ME/CHFS the change in headache severity was inversely correlated (r = -.480, P = .038) with the change in high frequency heart rate variability. LIMITATIONS: Based on the cross-sectional design of the study, no firm conclusions can be drawn on the causality of the relations. CONCLUSIONS: Reduced parasympathetic reactivation during recovery from exercise is associated with the dysfunctional exercise-induced analgesia in ME/CFS. Poor recovery of diastolic blood pressure in response to exercise, with blood pressure remaining elevated, is associated with reductions of pain following exercise in ME/CFS, suggesting a role for the arterial baroreceptors in explaining dysfunctional exercise-induced analgesia in ME/CFS patients.Key words: Aerobic exercise, aerobic power index, autonomic nervous system, exercise-induced analgesia, exercise-induced hypoalgesia, fibromyalgia, heart rate variability, stress-induced analgesia, pain. PMID- 28339439 TI - Dezocine Antagonizes Morphine Analgesia upon Simultaneous Administration in Rodent Models of Acute Nociception. AB - BACKGROUND: Dezocine is a powerful analgesic that can be less addictive than morphine, yet how the two drugs interact in vivo is poorly understood. Here we administered dezocine alone or in combination with morphine to different acute nociception paradigms to explore the interactions of the 2 drugs upon co administration. OBJECTIVE: To evaluate how dezocine interacts with morphine in different acute nociception paradigms. STUDY DESIGN: Laboratory animal study. SETTING: Zhejiang University School of Medicine, Hangzhou, China. METHODS: Healthy mice were treated with saline, dezocine (0.625 - 2.5 ug), or a combination of dezocine with morphine (2.5 ug). Tail withdrawal latency (TWL) was analyzed prior to and 30 minutes after drug administration. Rats were treated with saline, morphine (3 mg/kg), dezocine (3 mg/kg), or a combination of both drugs. The animals were then left uninjured, subjected to plantar incision, or underwent formaldehyde-induced acute inflammation. Nociception was then analyzed in terms of mechanical threshold (MT) to von Frey stimulation and paw withdrawal latency (PWL) to thermal stimulation. Formaldehyde-induced pain score was calculated based on the duration of biting and elevating of the animal's legs. Phosphorylation of extracellular signal-regulated kinase (pERK) was also measured after plantar incision as a molecular index of nociception. RESULTS: Dezocine enhanced TWL but inhibited morphine analgesia in a dose-dependent fashion in mice. Usage of morphine or dezocine alone in uninjured rats increased MT, but co administering both drugs did not further increase MT. Usage of one drug alone, and both drugs together increased MT and PWL relative to saline at 30 minutes after incision. Usage of one drug alone, but not both drugs together, increased MT and PWL at 120 minutes after incision. Dezocine reduced formaldehyde-induced nociception but co-administering both drugs did not further reduce pain behavior. LIMITATIONS: The results were obtained from animal study; clinical investigations will be needed to clarify their interaction. CONCLUSION: Dezocine antagonizes morphine analgesia on acute nociception upon simultaneous administration.Key words: Dezocine, morphine, acute nociception, analgesia. PMID- 28339440 TI - Pulsed Radiofrequency to the Dorsal Root Ganglion in Acute Herpes Zoster and Postherpetic Neuralgia. AB - BACKGROUND: Latent varicella zoster virus reactivates mainly in sensory ganglia such as the dorsal root ganglion (DRG) or trigeminal ganglion. The DRG contains many receptor channels and is an important region for pain signal transduction. Sustained abnormal electrical activity to the spinal cord via the DRG in acute herpes zoster can result in neuropathic conditions such as postherpetic neuralgia (PHN). Although the efficacy of pulsed radiofrequency (PRF) application to the DRG in various pain conditions has been previously reported, the application of PRF to the DRG in patients with herpes zoster has not yet been studied. OBJECTIVES: The aim of the present study was to compare the clinical effects of PRF to the DRG in patients with herpes zoster to those of PRF to the DRG in patients with PHN. STUDY DESIGN: Retrospective comparative study. SETTING: University hospital pain center in Korea. METHODS: The medical records of 58 patients who underwent PRF to the DRG due to zoster related pain (herpes zoster or PHN) were retrospectively analyzed. Patients were divided into 2 groups according to the timing of PRF after zoster onset: an early PRF group (within 90 days) and a PHN PRF group (more than 90 days). The efficacy of PRF was assessed by a numeric rating scale (NRS) and by recording patient medication doses before PRF and at one week, 4 weeks, 8 weeks, and 12 weeks after PRF. RESULTS: Pain intensity was decreased after PRF in all participants. However, the degree of pain reduction was significantly higher in the early PRF group. Moreover, more patients discontinued their medication in the early PRF group, and the PRF success rate was also higher in the early PRF group. LIMITATIONS: The relatively small sample size from a single center, short duration of review of medical records, and the retrospective nature of the study. CONCLUSIONS: PRF to the DRG is a useful treatment for treatment-resistant cases of herpes zoster and PHN. Particularly in herpes zoster patients with intractable pain, application of PRF to the DRG should be considered for pain control and prevention of PHN.Key words: Pulsed radiofrequency, dorsal root ganglion, herpes zoster, postherpetic neuralgia. PMID- 28339441 TI - The Role of the Ligamentum Flavum Area as a Morphological Parameter of Lumbar Central Spinal Stenosis. AB - BACKGROUND: Hypertrophy of the ligamentum flavum (LF) has been considered as a major cause of lumbar central spinal stenosis (LCSS). Previous studies have found that ligamentum flavum thickness (LFT) is correlated with aging, disc degeneration, and lumbar spinal stenosis. However, hypertrophy is different from thickness. Thus, to evaluate hypertrophy of the whole LF, we devised a new morphological parameter, called the ligamentum flavum area (LFA). OBJECTIVES: We hypothesized that the LFA is a key morphologic parameter in the diagnosis of LCSS. STUDY DESIGN: Retrospective observational study. SETTING: The single center study in Seoul, Republic of Korea. METHODS: LF samples were collected from 166 patients with LCSS, and from 167 controls who underwent lumbar magnetic resonance imaging (MRI) as part of a routine medical examination. T1-weighted axial MR imageswere acquired at the facet joint level from individual patients. We measured the LFA and LFT at the L4-L5 intervertebral level on MRI using a picture archiving and communications system. The LFA was measured as the cross-sectional area of the whole LF at the L4-L5 stenotic level. The LFT was measured by drawing a line along the side of the ligament facing the spinal canal and along the laminar side of the ligament curve and then measuring the thickest point at the L4-L5 level. RESULTS: The average LFA was 96.56 +/- 30.74 mm2 in the control group and 132.69 +/- 32.68 mm2 in the LCSS group. The average LFT was 3.61 +/- 0.72 mm in the control group and 4.24 +/- 0.97 mm in the LCSS group. LCSS patients had significantly higher LFA (P < 0.001) and LFT (P < 0.001). Regarding the validity of both LFA and LFT as predictors of LCSS, Receiver Operator Characteristics (ROC) curve analysis showed that the best cut-off point for the LFA was 105.90 mm2, with 80.1% sensitivity, 76.0% specificity, and area under the curve (AUC) of 0.83 (95% CI, 0.78 - 0.87). The best cut off-point of the LFT was 3.74 mm, with 70.5% sensitivity, 66.5% specificity, and AUC of 0.72 (95% CI, 0.66 - 0.77). LIMITATIONS: The principal methodological limitation was the retrospective observational nature. Anatomically, degenerative lumbar spinal stenosis can involve the central canal, foramina, and lateral recess. However, we focused on LCSS only. CONCLUSIONS: Although the LFT and LFA were both significantly associated with LCSS, the LFA was a more sensitive measurement parameter. Thus, to evaluate LCSS patients, the treating doctor should more carefully analyze the LFA than LFT.Institutional Review Board (IRB) approval number: S2015-1328-0001Key words: Ligamentum flavum, ligamentum flavum area, ligamentum flavum thickness, lumbar central spinal stenosis, hypertrophy of the ligamentum flavum, morphological parameter, cross-sectional area, optimal cut-off point. PMID- 28339442 TI - Clinical Outcome of Full-endoscopic Interlaminar Discectomy for Single-level Lumbar Disc Herniation: A Minimum of 5-year Follow-up. AB - BACKGROUND: Full-endoscopic interlaminar discectomy (FEID) is widely applied for the treatment of lumbar disc herniation (LDH) and satisfactory short-term outcomes have been achieved. However, the long-term evaluation for this technique is still lacking, especially the comparison between FEID and microendoscopic discectomy (MED). OBJECTIVE: To evaluate the clinical outcome of FEID technique in comparison with MED for single-level LDH with a minimum of 5-year follow-up. STUDY DESIGN: Retrospective study. SETTING: Inpatient surgery center. METHODS: A total of 152 patients with single-level LDH located at either L4-L5 or L5-S1 who underwent either FEID or MED from August 2008 to April 2011 at our hospital were enrolled in this study. General parameters including operative time, length of hospital stay, mean time to return to work, complications, and recurrences were recorded. Clinical outcomes were evaluated using visual analog scale (VAS) for low back and leg pain, Oswestry Disability Index (ODI) for functional assessment, and modified MacNab criteria for patient satisfaction. RESULTS: At the final follow-up, the VAS of leg and back pain decreased from 7.6 +/- 1.6 and 3.1 +/- 2.2 points preoperatively to 1.6 +/- 1.2 and 1.7 +/- 0.9 at the final follow-up, respectively (P < 0.05). The ODI score was 69.5% +/- 10.5% preoperatively, and declined to 21.8% +/- 7.0% at the final follow-up (P < 0.05). VAS, ODI, and modified MacNab criteria of the FEID group were improved compared to the control group though there were no statistically significant differences between the 2 groups. LIMITATIONS: This was a retrospective study with a relatively small sample size. Additionally, this study contained only clinical outcomes, without long-term radiological outcomes. CONCLUSIONS: The application of FEID achieved similar satisfactory long-term clinical outcomes for the surgical treatment of LDH as MED. However, compared with MED, FEID exhibits advantages including less operation time, shorter hospital stay, and faster postoperative recovery.Key words: Lumbar disc herniation, full-endoscopic interlaminar discectomy, microendoscopic disectomy, long-term. PMID- 28339443 TI - Clinical Outcome of Augmentation Enterocystoplasty for Patients with Ketamine induced Cystitis. AB - BACKGROUND: Ketamine abuse has become a global phenomenon in recent years. Ketamine-induced cystitis (KC) is a new clinical syndrome which can result in severely inflamed bladder and intractable bladder pain. Currently there is no guideline for managing patients with KC. OBJECTIVES: To analyze the clinical outcome of patients with KC managed with augmentation enterocystoplasty (AE). STUDY DESIGN: Retrospective interventional study. SETTING: A tertiary teaching hospital, Hualien Tzu Chi Hospital. METHODS: We retrospectively collected and analyzed the medical records and video-urodynamic (VUD) test results of 26 patients who underwent AE as treatment for refractory KC during the period 2009 - 2014. All of these patients abused ketamine with nasal snorting, at least 3 grams per dose, twice per week for 6 months. Data from VUD studies performed before AE and 3 - 6 months after surgery that were analyzed in this study included cystometric bladder capacity (CBC), post-void residual (PVR) urine volume, maximum urinary flow rate (Qmax), voided volume, and bladder compliance. A self report questionnaire was used to assess patient satisfaction with AE. RESULTS: Patients included 14 women and 12 men aged 20 - 43 years (mean age, 28.5 years) with an average duration of ketamine abuse of 4.7 years (range, 1 - 10 years). All patients had contracted bladder, 9 had hydronephrosis, and 10 had vesicoureteral reflux (VUR). There was significant improvement in CBC (52.7 +/- 29.7 v 327 +/- 69.4 mL, P < 0.0001), Qmax (6.94 +/- 4.32 v 13.7 +/- 4.96 mL/s, P < 0.0001), PVR (8.08 +/- 19.2 v 82.6 +/- 91.5 mL, P < 0.0001), voided volume (44.1 +/- 28.3 v 250.7 +/- 133.4 mL, P < 0.0001), and bladder compliance (11.1 +/ 11.9 v 54 +/- 43, P < 0.0001) after AE. Hydronephrosis resolved in 7 patients after AE and VUR resolved in all patients who underwent AE with ureteral reimplantation. All patients who stopped using ketamine were free of bladder pain postoperatively. However, 10 patients who reused ketamine had recurrent bladder pain and recurrent urinary tract infection. LIMITATIONS: Small number of patients limits scope of study. CONCLUSIONS: AE is effective at treating KC-induced bladder pain and restoring normal lower urinary tract function. However, absolute cessation of ketamine is the key to success in KC treatment.Key words: Ketamine induced cystitis, augmentation enterocystoplasty, bladder pain, contracted bladder, inflammation, surgery. PMID- 28339444 TI - A Review of Long-Term Pain Relief after Genicular Nerve Radiofrequency Ablation in Chronic Knee Osteoarthritis. AB - BACKGROUND: Studies of radiofrequency ablation (RFA) of genicular nerves have reportedly significantly decreased pain up to 3 months post ablation, but no longer term effects have been reported. We performed an analysis of long-term pain relief of 31 RFA procedures of the genicular nerves to analyze the degree of pain relief past 3 months, culminating at 6 months. STUDY DESIGN: Chart review and study design was approved by Newark Health Sciences Institutional Review Board (IRB). Chart review and follow-up was performed on all patients who underwent genicular nerve RFA during the period of February 2014 through August of 2015. During this inclusion period 41 genicular nerve RFAs were performed on 31 patients, 5 patients received RFA procedure in both knees. Patient follow-up was performed via telephone interview or in-office visit at least 3 months and 6 months post RFA. SETTINGS: Procedures were performed in Medical Special Procedures at University Hospital in Newark, NJ, and the Pain Management Center at Overlook Medical Arts Center in Summit, NJ. METHODS: Chart review and study design was approved by Newark Health Sciences IRB. Chart review was performed from February 2014 and continued through August 2015. Patient follow-up was conducted at 3 and at least 6 months post treatment to gauge degree of pain relief (0 - none, 100% - complete), their current day's pain score, other treatment modalities tried before RFA, and the medications used. Patients were asked to quantify their satisfaction with procedure length, pre-procedure anxiety, complications, and if they would recommend this procedure to others. Primary and secondary goals were the duration of pain relief after RFA, the quality of pain relief, and the efficacy of our approach for RFA of genicular nerves versus prior published techniques. RESULTS: At 3 month follow-up, the average pain relief was 67% improvement from baseline knee pain, 0% being no relief and 100% being complete relief, and average 0 - 10 pain score was 2.9. At 6 month follow-up, of those who described pain relief at 3 months, 95% still described pain relief. This group's average percent pain relief was 64% and average day's 0 - 10 pain score 3.3. LIMITATIONS: Our study included a retrospective component in chart review followed by prospective follow-up, only 76% of patients were able to participate in the interview process. Furthermore, some patients suffered from other chronic pain ailments, most commonly chronic back pain, which at times disturbed the patient's ability to focus on solely knee pain. CONCLUSIONS: Based on patient interviews and data collection, RFA of genicular nerves can supply on average greater than 60% pain relief in our patient population for as long as 6 months.Key words: Osteoarthritis, knee osteoarthritis, chronic knee pain, radiofrequency ablation, nerve ablation, genicular nerves, long-term pain relief. PMID- 28339445 TI - Transforaminal Endoscopic Decompression for a Giant Epidural Gas-Containing Pseudocyst: A Case Report and Literature Review. AB - The isolated epidural gas-containing pseudocyst is an uncommon pathogenic factor for severe pain of the lower limb as a result of nerve root compression. After reviewing these rare cases reported in the literature, we found that the name, pathogenesis, and treatment strategy of this pathology remained controversial. The most common treatment is conservative treatment or percutaneous aspiration which might result inpoor pain relief and high recurrence rates. Moreover, the patient who received open surgery had good clinical outcome; however, he or she might experience a significant soft tissue injury.In this study, we report the first case of a patient who had a giant epidural gas-containing pseudocyst and received percutaneous endoscopic surgery. This 57-year-old man had been complaining of severe radicular pain in his right ankle for one year. According to computed tomography (CT) and magnetic resonance imaging (MRI) prior to the surgery, the results showed an isolated epidural gas-containing pseudocyst was located in the right lateral recess of S1. At the last follow-up period, postoperative CT scan showed the gas-contained pseudocyst was completely resected and this patient was free from the pain.Due to the great advances in endoscopic techniques and equipment, it is easier to perform lumbar surgery through the endoscope. With this first case of percutaneous endoscopic treatment for the symptomatic epidural gas-containing pseudocyst reported in this study, we believe that this surgical method provides an option to treat this rare condition because it provides sufficient decompression, has a low recurrence rate, and is minimally invasive. Key words: Endoscopic surgery, pseudocyst, epidural gas, intraspinal gas, radiulopathy. PMID- 28339446 TI - Pulsed Radiofrequency Ablation of Pudendal Nerve for Treatment of a Case of Refractory Pelvic Pain. AB - : Pudendal neuralgia (PN) is a result of pudendal nerve entrapment or injury, also called "Alcock syndrome." Pain that develops is often chronic, and at times debilitating. If conservative measures fail, invasive treatment modalities can be considered. The goal of this case report is to add to a small body of literature that a pulsed radiofrequency (PRF) ablation can be effectively used to treat PN and to show that high resolution MR neurography imaging can be used to detect pudendal neuropathy. CASE PRESENTATION: We present a case of a 51-year-old woman with 5 years of worsening right groin and vulva pain. Various medication trials only lead to limited improvement in pain. The first diagnostic right pudendal nerve block was done using 3 mL of 0.25% bupivacaine with 6mg of betamethasone using a transgluteal technique and a target of the right ischial spine; this procedure resulted in ~8 hours of > 50% pain relief. The patient was then referred for MR neurography of the lumbosacral plexus. This study revealed increased signal of the right pudendal nerve at the ischial spine and in the pudendal canal, findings consistent with the clinical picture of PN. Six weeks after the initial block, the patient underwent a second right transgluteal pudendal nerve block, utilizing 3 mL of 0.25% bupivacaine with 40 mg of triamcinolone acetonide; this procedure resulted in ~8 hours of 100% pain relief. Satisfied with these results the patient decided to undergo pudendal nerve PRF ablation for possible long-term relief. For this therapeutic procedure, a right transgluteal approach was again utilized. PRF ablation was performed for 240 seconds at 42 degrees Celsius. Following this ablation the patient reported at least 6 weeks of significant (> 50%) pain relief. DISCUSSION AND CONCLUSION: In this paper we presented a case of successful treatment of PN with PRF ablation and detection of pudendal neuropathy on MR neurography. We believe that transgluteal PRF ablation for PN might be an effective, minimally invasive option for those patients that have failed conservative management. MR neurography employed in this case is not only helpful in confirming the diagnosis of PN but could also be useful in ruling out other causes of pelvic pain, such as genitofemoral neuropathy, endometriosis, adenomyosis, or pelvic mass lesion. To conclude, transgluteal PRF ablation can serve as a viable treatment option for mitigating symptoms of pudendal neuropathy and MR neurography is useful in confirming a clinically suspected diagnosis of PN.Key words: Pelvic pain, pudendal neuralgia, MR neurography, pulsed radiofrequency ablation, transgluteal technique, Alcock canal syndrome. PMID- 28339447 TI - Chronic Localized Back Pain Due to Posterior Cutaneous Nerve Entrapment Syndrome (POCNES): A New Diagnosis. AB - Most patients with chronic back pain suffer from degenerative thoracolumbovertebral disease. However, the following case illustrates that a localized peripheral nerve entrapment must be considered in the differential diagnosis of chronic back pain. We report the case of a 26-year-old woman with continuous excruciating pain in the lower back area. Previous treatment for nephroptosis was to no avail. On physical examination the pain was present in a 2 x 2 cm area overlying the twelfth rib some 4 cm lateral to the spinal process. Somatosensory testing using swab and alcohol gauze demonstrated the presence of skin hypo- and dysesthesia over the painful area. Local pressure on this painful spot elicited an extreme pain response that did not irradiate towards the periphery. These findings were highly suggestive of a posterior version of the anterior cutaneous nerve entrapment syndrome (ACNES), a condition leading to a severe localized neuropathic pain in anterior portions of the abdominal wall. She demonstrated a beneficial albeit temporary response after lidocaine infiltration as dictated by an established diagnostic and treatment protocol for ACNES. She subsequently underwent a local neurectomy of the involved superficial branch of the intercostal nerve. This limited operation had a favorable outcome resulting in a pain-free return to normal activities up to this very day (follow-up of 24 months).We propose to name this novel syndrome "posterior cutaneous nerve entrapment syndrome" (POCNES). Each patient with chronic localized back pain should undergo simple somatosensory testing to detect the presence of overlying skin hypo- and dysesthesia possibly reflecting an entrapped posterior cutaneous nerve.Key words: Chronic pain, back pain, posterior cutaneous nerve entrapment, peripheral nerve entrapment, surgical treatment for pain, anterior cutaneous nerve entrapment. PMID- 28339448 TI - Efficacious Dorsal Root Ganglion Stimulation for Painful Small Fiber Neuropathy: A Case Report. AB - Small fiber neuropathy is a disorder of the peripheral nerves with typical symptoms of burning, sharp, and shooting pain and sensory disturbances in the feet. Pain treatment depends principally on the underlying etiology with concurrent administration of antidepressants, anticonvulsants, opioids, and topical treatments like capsaicin and local anesthetics. However, treatments for pain relief in these patients frequently fail. We describe the first case of intractable painful small fiber neuropathy of the foot successfully treated with spinal cord stimulation of the left L5 dorsal root ganglion.A 74-year-old man presented at our clinic with severe intractable pain, dysesthesia, and allodynia of the left foot caused by idiopathic small fiber neuropathy, confirmed by skin biopsy. His pain score was 8 on a standard 0 - 10 numeric rating scale. As the pain was not satisfactorily controlled by conventional therapy, dorsal root ganglion stimulation was proposed to the patient and, after informed consent, a specifically designed percutaneous stimulation lead was placed over the left L5 dorsal root ganglion and connected to an external neurostimulator. After a positive trial of 10 days, a permanent neurostimulator was implanted. Twenty months post-implantation the patient continued to experience stimulation-induced paresthesia covering the entire pain area and reported a pain rating of 4.Results from the case report demonstrate that the dorsal root ganglion is a promising neural stimulation target to treat neuropathic pain due to intractable small fiber neuropathy. Prospective controlled studies are warranted to confirm the efficacy of this treatment as an option for the aforementioned condition.Key words: Dorsal root ganglion stimulation, small fiber neuropathy, neuropathic pain. PMID- 28339449 TI - Reversal of Progressive Conscious Disturbance with Epidural Blood Patch for Cerebrospinal Fluid Leakage at C2 Level. AB - Intracranial hypotension syndrome (IHS) is generally caused by cerebrospinal fluid (CSF) leakage. Complications include bilateral subdural hygroma or haematoma and herniation of the cerebellar tonsils. Epidural blood patch (EBP) therapy is indicated if conservative treatment is ineffective. We reported the case of a 46-year-old man with a history of postural headache and dizziness. The patient was treated with bed rest and daily hydration with 2000 mL of fluid for 2 weeks. However, dizziness and headache did not resolve, and he became drowsy and disoriented with incomprehensible speech. Magnetic resonance imaging demonstrated diffuse dural enhancement on the postcontrast study, sagging of the midbrain, and CSF leakage over right lateral posterior thecal sac at C2 level. We performed EBP at the level of T10-T11. We injected 14 mL of autologous blood slowly in the Trendelenburg position. Within 30 minutes, he became alert and oriented to people, place, and time. We chose thoracic EBP as first line treatment in consideration of the risk of cervical EBP such as spinal cord and nerve root compression or puncture, chemical meningitis. Also we put our patient in Trendelenburg position to make blood travel towards the site of the leak. Untreated IHS may delay the course of resolution and affect the patient's consciousness. Delivery of EBP via an epidural catheter inserted from the thoracic spine is familiar with most of anesthesiologists. It can be a safe and effective treatment for patients with IHS caused by CSF leak even at C2.Key words: Anaesthetic techniques, regional, thoracic; cerebrospinal fluid leakage; epidural blood patch; heavily T2-weighted magnetic resonance myelography; intracranial hypotension syndrome; Trendelenburg position. PMID- 28339450 TI - Reliability and Safety of Contra-Lateral Oblique View for Interlaminar Epidural Needle Placement: Standardization of the Appropriate Angle. PMID- 28339451 TI - Percutaneous Vertebral Augmentation for the Treatment of Symptomatic Schmorl's Nodes: Our Viewpoint and Experience. PMID- 28339452 TI - Reply to: Percutaneous Vertebral Augmentation for the Treatment of Symptomatic Schmorl's Nodes: Our Viewpoint and Experience. PMID- 28339453 TI - Value of Examination Under Fluoroscopy for the Assessment of Sacroiliac Joint Dysfunction. PMID- 28339454 TI - Optimal Angle of Contralateral Oblique View in Cervical Interlaminar Epidural Injections: Safety or Precision? PMID- 28339456 TI - In Errata: Kratom the New 'Legal High' on the Block?: The Case of an Emerging Opioid Receptor Agonist with Substance Abuse Potential. PMID- 28339455 TI - Response to Letter: Optimal Angle of Contralateral Oblique View in Cervical Interlaminar Epidural Injection: Safety or Precision? PMID- 28339457 TI - Targeted AAV5-Smad7 gene therapy inhibits corneal scarring in vivo. AB - Corneal scarring is due to aberrant activity of the transforming growth factor beta (TGFbeta) signaling pathway following traumatic, mechanical, infectious, or surgical injury. Altered TGFbeta signaling cascade leads to downstream Smad (Suppressor of mothers against decapentaplegic) protein-mediated signaling events that regulate expression of extracellular matrix and myogenic proteins. These events lead to transdifferentiation of keratocytes into myofibroblasts through fibroblasts and often results in permanent corneal scarring. Hence, therapeutic targets that reduce transdifferentiation of fibroblasts into myofibroblasts may provide a clinically relevant approach to treat corneal fibrosis and improve long term visual outcomes. Smad7 protein regulates the functional effects of TGFbeta signaling during corneal wound healing. We tested that targeted delivery of Smad7 using recombinant adeno-associated virus serotype 5 (AAV5-Smad7) delivered to the corneal stroma can inhibit corneal haze post photorefractive keratectomy (PRK) in vivo in a rabbit corneal injury model. We demonstrate that a single topical application of AAV5-Smad7 in rabbit cornea post-PRK led to a significant decrease in corneal haze and corneal fibrosis. Further, histopathology revealed lack of immune cell infiltration following AAV5-Smad7 gene transfer into the corneal stroma. Our data demonstrates that AAV5-Smad7 gene therapy is relatively safe with significant potential for the treatment of corneal disease currently resulting in fibrosis and impaired vision. PMID- 28339458 TI - Rapid Surveillance for Vector Presence (RSVP): Development of a novel system for detecting Aedes aegypti and Aedes albopictus. AB - BACKGROUND: The globally important Zika, dengue and chikungunya viruses are primarily transmitted by the invasive mosquitoes, Aedes aegypti and Aedes albopictus. In Australia, there is an increasing risk that these species may invade highly urbanized regions and trigger outbreaks. We describe the development of a Rapid Surveillance for Vector Presence (RSVP) system to expedite presence- absence surveys for both species. METHODOLOGY/PRINCIPAL FINDINGS: We developed a methodology that uses molecular assays to efficiently screen pooled ovitrap (egg trap) samples for traces of target species ribosomal RNA. Firstly, specific real-time reverse transcription-polymerase chain reaction (RT-PCR) assays were developed which detect a single Ae. aegypti or Ae. albopictus first instar larva in samples containing 4,999 and 999 non-target mosquitoes, respectively. ImageJ software was evaluated as an automated egg counting tool using ovitrap collections obtained from Brisbane, Australia. Qualitative assessment of ovistrips was required prior to automation because ImageJ did not differentiate between Aedes eggs and other objects or contaminants on 44.5% of ovistrips assessed, thus compromising the accuracy of egg counts. As a proof of concept, the RSVP was evaluated in Brisbane, Rockhampton and Goomeri, locations where Ae. aegypti is considered absent, present, and at the margin of its range, respectively. In Brisbane, Ae. aegypti was not detected in 25 pools formed from 477 ovitraps, comprising ~ 54,300 eggs. In Rockhampton, Ae. aegypti was detected in 4/6 pools derived from 45 ovitraps, comprising ~ 1,700 eggs. In Goomeri, Ae. aegypti was detected in 5/8 pools derived from 62 ovitraps, comprising ~ 4,200 eggs. CONCLUSIONS/SIGNIFICANCE: RSVP can rapidly detect nucleic acids from low numbers of target species within large samples of endemic species aggregated from multiple ovitraps. This screening capability facilitates deployment of ovitrap configurations of varying spatial scales, from a single residential block to entire suburbs or towns. RSVP is a powerful tool for surveillance of invasive Aedes spp., validation of species eradication and quality assurance for vector control operations implemented during disease outbreaks. PMID- 28339459 TI - Functional classification of DNA variants by hybrid minigenes: Identification of 30 spliceogenic variants of BRCA2 exons 17 and 18. AB - Mutation screening of the breast cancer genes BRCA1 and BRCA2 identifies a large fraction of variants of uncertain clinical significance (VUS) whose functional and clinical interpretations pose a challenge for genomic medicine. Likewise, an increasing amount of evidence indicates that genetic variants can have deleterious effects on pre-mRNA splicing. Our goal was to investigate the impact on splicing of a set of reported variants of BRCA2 exons 17 and 18 to assess their role in hereditary breast cancer and to identify critical regulatory elements that may constitute hotspots for spliceogenic variants. A splicing reporter minigene with BRCA2 exons 14 to-20 (MGBR2_ex14-20) was constructed in the pSAD vector. Fifty-two candidate variants were selected with splicing prediction programs, introduced in MGBR2_ex14-20 by site-directed mutagenesis and assayed in triplicate in MCF-7 cells. Wild type MGBR2_ex14-20 produced a stable transcript of the expected size (1,806 nucleotides) and structure (V1 [BRCA2_exons_14-20]-V2). Functional mapping by microdeletions revealed essential sequences for exon recognition on the 3' end of exon 17 (c.7944-7973) and the 5' end of exon 18 (c.7979-7988, c.7999-8013). Thirty out of the 52 selected variants induced anomalous splicing in minigene assays with >16 different aberrant transcripts, where exon skipping was the most common event. A wide range of splicing motifs were affected including the canonical splice sites (15 variants), novel alternative sites (3 variants), the polypyrimidine tract (3 variants) and enhancers/silencers (9 variants). According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), 20 variants could be classified as pathogenic (c.7806-2A>G, c.7806-1G>A, c.7806-1G>T, c.7806-1_7806-2dup, c.7976+1G>A, c.7977-3_7978del, c.7977-2A>T, c.7977-1G>T, c.7977-1G>C, c.8009C>A, c.8331+1G>T and c.8331+2T>C) or likely pathogenic (c.7806-9T>G, c.7976G>C, c.7976G>A, c.7977-7C>G, c.7985C>G, c.8023A>G, c.8035G>T and c.8331G>A), accounting for 30.8% of all pathogenic/likely pathogenic variants of exons 17-18 at the BRCA Share database. The remaining 8 variants (c.7975A>G, c.7977-6T>G, c.7988A>T, c.7992T>A, c.8007A>G, c.8009C>T, c.8009C>G, and c.8072C>T) induced partial splicing anomalies with important ratios of the full-length transcript (>=70%), so that they remained classified as VUS. Aberrant splicing is therefore especially prevalent in BRCA2 exons 17 and 18 due to the presence of active ESEs involved in exon recognition. Splicing functional assays with minigenes are a valuable strategy for the initial characterization of the splicing outcomes and the subsequent clinical interpretation of variants of any disease-gene, although these results should be checked, whenever possible, against patient RNA. PMID- 28339461 TI - Mass elevation and lee effects markedly lift the elevational distribution of ground beetles in the Himalaya-Tibet orogen. AB - Mass elevation and lee effects markedly influence snow lines and tree lines in high mountain systems. However, their impact on other phenomena or groups of organisms has not yet been quantified. Here we quantitatively studied their influence in the Himalaya-Tibet orogen on the distribution of ground beetles as model organisms, specifically whether the ground beetle distribution increases from the outer to the inner parts of the orogen, against latitudinal effects. We also tested whether July temperature and solar radiation are predictors of the beetle's elevational distribution ranges. Finally, we discussed the general importance of these effects for the distributional and evolutionary history of the biota of High Asia. We modelled spatially explicit estimates of variables characterizing temperature and solar radiation and correlated the variables with the respective lower elevational range of 118 species of ground beetles from 76 high-alpine locations. Both July temperature and solar radiation significantly positively correlated with the elevational ranges of high-alpine beetles. Against the latitudinal trend, the median elevation of the respective species distributions increased by 800 m from the Himalayan south face north to the Transhimalaya. Our results indicate that an increase in seasonal temperature due to mass elevation and lee effects substantially impact the regional distribution patterns of alpine ground beetles of the Himalaya-Tibet orogen and are likely to affect also other soil biota there and in mountain ranges worldwide. Since these effects must have changed during orogenesis, their potential impact must be considered when biogeographic scenarios based on geological models are derived. As this has not been the practice, we believe that large biases likely exist in many paleoecological and evolutionary studies dealing with the biota from the Himalaya-Tibet orogen and mountain ranges worldwide. PMID- 28339460 TI - Evaluating implementation of a fire-prevention injury prevention briefing in children's centres: Cluster randomised controlled trial. AB - BACKGROUND: Many developed countries have high mortality rates for fire-related deaths in children aged 0-14 years with steep social gradients. Evidence-based interventions to promote fire safety practices exist, but the impact of implementing a range of these interventions in children's services has not been assessed. We developed an Injury Prevention Briefing (IPB), which brought together evidence about effective fire safety interventions and good practice in delivering interventions; plus training and facilitation to support its use and evaluated its implementation. METHODS: We conducted a cluster randomised controlled trial, with integrated qualitative and cost-effectiveness nested studies, across four study sites in England involving children's centres in disadvantaged areas; participants were staff and families attending those centres. Centres were stratified by study site and randomised within strata to one of three arms: IPB plus facilitation (IPB+), IPB only, usual care. IPB+ centres received initial training and facilitation at months 1, 3, and 8. Baseline data from children's centres were collected between August 2011 and January 2012 and follow-up data were collected between June 2012 and June 2013. Parent baseline data were collected between January 2012 and May 2012 and follow up data between May 2013 and September 2013. Data comprised baseline and 12 month parent- and staff-completed questionnaires, facilitation contact data, activity logs and staff interviews. The primary outcome was whether families had a plan for escaping from a house fire. Treatment arms were compared using multilevel models to account for clustering by children's centre. RESULTS: 1112 parents at 36 children's centres participated. There was no significant effect of the intervention on families' possession of plans for escaping from a house fire (adjusted odds ratio (AOR) IPB only vs. usual care: 0.93, 95%CI 0.58, 1.49; AOR IPB+ vs. usual care 1.41, 95%CI 0.91, 2.20). However, significantly more families in the intervention arms reported more behaviours for escaping from house fires (AOR IPB only vs. usual care: 2.56, 95%CI 01.38, 4.76; AOR IPB+ vs. usual care 1.78, 95%CI 1.01, 3.15). CONCLUSION: Our study demonstrated that children's centres can deliver an injury prevention intervention to families in disadvantaged communities and achieve changes in home safety behaviours. PMID- 28339462 TI - Safety of a topical insect repellent (picaridin) during community mass use for malaria control in rural Cambodia. AB - BACKGROUND: While community distribution of topical repellents has been proposed as an additional malaria control intervention, the safety of this intervention at the population level remains poorly evaluated. We describe the safety of mass distribution of the picaridin repellent during a cluster-randomised trial in rural Cambodia in 2012-2013. METHODS: The repellent was distributed among 57 intervention villages with around 25,000 inhabitants by a team of village distributors. Information on individual adverse events, reported by phone by the village distributors, was obtained through home visits. Information on perceived side effects, reported at the family level, was obtained during two-weekly bottle exchange. Adverse events were classified as adverse reactions (events likely linked to the repellent), cases of repellent abuse and events not related to the repellent use, and classified as per Common Terminology Criteria for Adverse Events. FINDINGS: Of the 41 adverse events notified by phone by the village distributors, there were 22 adverse reactions, 11 cases of repellent abuse (6 accidental, 5 suicide attempts) and 8 non-related events. All adverse reactions were mild, occurred in the first few months of use, and mainly manifested as skin conditions. Of the 11 cases of abuse, 2 were moderate and 2 life-threatening. All cases with adverse reactions and repellent abuse recovered completely. 20% of families reported perceived side effects, mainly itching, headache, dizziness and bad smell, but few discontinued repellent use. CONCLUSIONS: Adverse reactions and abuse during mass use of picaridin were uncommon and generally mild, supporting the safety of the picaridin repellent for malaria control. PMID- 28339463 TI - Combinations of SERPINB5 gene polymorphisms and environmental factors are associated with oral cancer risks. AB - BACKGROUND: We identified rs17071138 T/C, rs3744941 C/T, and rs8089104 T/C gene polymorphisms of SERPINB5 (mammary serine protease inhibitor) that are specific to patients with oral cancer susceptibility and their clinicopathological status. METHODOLOGY/PRINCIPAL FINDINGS: In total, 1342 participants, including 601 healthy controls and 741 patients with oral cancer, were recruited for this study. Allelic discrimination of rs17071138 T/C, rs3744941 C/T, and rs8089104 T/C of the SERPINB5 gene was assessed by a real-time PCR with a TaqMan assay. We found that individuals carrying the polymorphic rs17071138 and rs8089104 are more susceptible to oral cancer (OR, 1.57; 95% CI, 1.07~2.31 and OR, 1.58; 95% CI, 1.04~2.39, respectively). Among oral cancer-related risk factor exposures, the individuals carrying the polymorphic rs17071138 had 4.26- (95% CI: 1.65~11.01; p = 0.002), 2.34- (95% CI: 1.19~4.61; p = 0.01), and 2.34-fold (95% CI: 1.38~3.96; p = 0.001) higher risks of developing oral cancer. CONCLUSIONS: Heterozygous TC of the SERPINB5 rs17071138 polymorphism may be a factor that increases susceptibility to oral cancer. Interactions of gene-to-gene and gene-to-oral cancer-related environmental risk factors have a synergetic effect that can further enhance oral cancer development. PMID- 28339464 TI - The preservation of microbial DNA in archived soils of various genetic types. AB - This study is a comparative analysis of samples of archived (stored for over 70 90 years) and modern soils of two different genetic types-chernozem and sod podzolic soils. We revealed a reduction in biodiversity of archived soils relative to their modern state. Particularly, long-term storage in the museum exerted a greater impact on the microbiomes of sod-podzolic soils, while chernozem samples better preserved the native community. Thus, the persistence of microbial DNA in soil is largely determined by the physico-chemical characteristics that differ across soil types. Chernozems create better conditions for the long-term DNA preservation than sod-podzolic soils. This results in supposedly higher levels of biodiversity conservation in the microbiomes of chernozem with preservation of major microbial taxa dominant in the modern (control) soil samples, which makes archived chernozems a promising object for paleosoil studies. PMID- 28339465 TI - Comparative accuracy of the REBA MTB MDR and Hain MTBDRplus line probe assays for the detection of multidrug-resistant tuberculosis: A multicenter, non-inferiority study. AB - INTRODUCTION: Despite recent diagnostic advances, the majority of multidrug resistant tuberculosis (MDR-TB) cases remain undiagnosed. Line probes assays (LiPAs) hold great promise to curb the spread of MDR-TB as they can rapidly detect MDR-TB even when laboratory infrastructure is limited, yet few of these assays are currently widely available or supported by World Health Organization (WHO) policy. METHODS: The aim of this prospective, blinded, non-inferiority study was to compare the performance of YD Diagnostics REBA MTB MDR LiPA (YD) to the WHO-endorsed Hain MTBDRplus V1 LiPA (Hain V1) for the detection of rifampicin and isoniazid resistance. In phase 1, YD and Hain V1 diagnostic performance was assessed with selected culture isolates and results were compared to phenotypic drug susceptibility testing (DST) results and targeted sequencing data. In phase 2, both assays were tested on processed sputum samples and results were compared to phenotypic DST results. RESULTS: In phase 1, YD did not achieve non inferiority to Hain V1. For isoniazid resistance detection, Hain V1 had a sensitivity of 89% (95%CI 83.8-93%) and specificity of 99.4% (95%CI 96.9-100%). While YD had a similar sensitivity of 92% (95%CI 87.3-95.4%), the specificity was inferior at 92.6% (95%CI 87.6-96%). For rifampicin resistance detection, Hain V1 had a sensitivity of 90.2% (95%CI 84.8-94.2%) and specificity of 98.5% (95%CI 95.7-99.7%) while YD had an inferior sensitivity of 72.4% (95%CI 65.1-78.9%) and a comparable specificity of 98% (95%CI 95-99.5%). Similar results were observed in phase 2. For MDR-TB detection, the sensitivity and specificity of Hain V1 was 93.4% (95%CI 88.2-96.2%) and 96.2% (95%CI 88.2-96.8%), respectively, compared to 75.7% (95%CI 68-82.2%) and 92% (95%CI 88.2-94.9%) for YD. CONCLUSIONS: YD did not achieve non-inferiority with Hain V1. Further improvements and repeat evaluation of YD is necessary prior to recommending its use for clinical settings. PMID- 28339466 TI - In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis. AB - Cystic Fibrosis is the most common lethal autosomal recessive disorder in the white population, affecting among other organs, the lung, the pancreas and the liver. Whereas Cystic Fibrosis is a monogenic disease, many studies reveal a very complex relationship between genotype and clinical phenotype. Indeed, the broad phenotypic spectrum observed in Cystic Fibrosis is far from being explained by obvious genotype-phenotype correlations and it is admitted that Cystic Fibrosis disease is the result of multiple factors, including effects of the environment as well as modifier genes. Our objective was to highlight new modifier genes with potential implications in the lung, pancreatic and liver outcomes of the disease. For this purpose we performed a system biology approach which combined, database mining, literature mining, gene expression study and network analysis as well as pathway enrichment analysis and protein-protein interactions. We found that IFI16, CCNE2 and IGFBP2 are potential modifiers in the altered lung function in Cystic Fibrosis. We also found that EPHX1, HLA-DQA1, HLA-DQB1, DSP and SLC33A1, GPNMB, NCF2, RASGRP1, LGALS3 and PTPN13, are potential modifiers in pancreas and liver, respectively. Associated pathways indicate that immune system is likely involved and that Ubiquitin C is probably a central node, linking Cystic Fibrosis to liver and pancreatic disease. We highlight here new modifier genes with potential implications in Cystic Fibrosis. Nevertheless, our in silico analysis requires functional analysis to give our results a physiological relevance. PMID- 28339467 TI - A non-canonical RNA degradation pathway suppresses RNAi-dependent epimutations in the human fungal pathogen Mucor circinelloides. AB - Mucorales are a group of basal fungi that includes the casual agents of the human emerging disease mucormycosis. Recent studies revealed that these pathogens activate an RNAi-based pathway to rapidly generate drug-resistant epimutant strains when exposed to stressful compounds such as the antifungal drug FK506. To elucidate the molecular mechanism of this epimutation pathway, we performed a genetic analysis in Mucor circinelloides that revealed an inhibitory role for the non-canonical RdRP-dependent Dicer-independent silencing pathway, which is an RNAi-based mechanism involved in mRNA degradation that was recently identified. Thus, mutations that specifically block the mRNA degradation pathway, such as those in the genes r3b2 and rdrp3, enhance the production of drug resistant epimutants, similar to the phenotype previously described for mutation of the gene rdrp1. Our genetic analysis also revealed two new specific components of the epimutation pathway related to the quelling induced protein (qip) and a Sad-3 like helicase (rnhA), as mutations in these genes prevented formation of drug resistant epimutants. Remarkably, drug-resistant epimutant production was notably increased in M. circinelloides f. circinelloides isolates from humans or other animal hosts. The host-pathogen interaction could be a stressful environment in which the phenotypic plasticity provided by the epimutant pathway might provide an advantage for these strains. These results evoke a model whereby balanced regulation of two different RNAi pathways is determined by the activation of the RNAi-dependent epimutant pathway under stress conditions, or its repression when the regular maintenance of the mRNA degradation pathway operates under non-stress conditions. PMID- 28339468 TI - PBMDA: A novel and effective path-based computational model for miRNA-disease association prediction. AB - In the recent few years, an increasing number of studies have shown that microRNAs (miRNAs) play critical roles in many fundamental and important biological processes. As one of pathogenetic factors, the molecular mechanisms underlying human complex diseases still have not been completely understood from the perspective of miRNA. Predicting potential miRNA-disease associations makes important contributions to understanding the pathogenesis of diseases, developing new drugs, and formulating individualized diagnosis and treatment for diverse human complex diseases. Instead of only depending on expensive and time-consuming biological experiments, computational prediction models are effective by predicting potential miRNA-disease associations, prioritizing candidate miRNAs for the investigated diseases, and selecting those miRNAs with higher association probabilities for further experimental validation. In this study, Path-Based MiRNA-Disease Association (PBMDA) prediction model was proposed by integrating known human miRNA-disease associations, miRNA functional similarity, disease semantic similarity, and Gaussian interaction profile kernel similarity for miRNAs and diseases. This model constructed a heterogeneous graph consisting of three interlinked sub-graphs and further adopted depth-first search algorithm to infer potential miRNA-disease associations. As a result, PBMDA achieved reliable performance in the frameworks of both local and global LOOCV (AUCs of 0.8341 and 0.9169, respectively) and 5-fold cross validation (average AUC of 0.9172). In the cases studies of three important human diseases, 88% (Esophageal Neoplasms), 88% (Kidney Neoplasms) and 90% (Colon Neoplasms) of top-50 predicted miRNAs have been manually confirmed by previous experimental reports from literatures. Through the comparison performance between PBMDA and other previous models in case studies, the reliable performance also demonstrates that PBMDA could serve as a powerful computational tool to accelerate the identification of disease-miRNA associations. PMID- 28339469 TI - Non-invasive evaluation of muscle disease in the canine model of Duchenne muscular dystrophy by electrical impedance myography. AB - Dystrophin-deficient dogs are by far the best available large animal models for Duchenne muscular dystrophy (DMD), the most common lethal childhood muscle degenerative disease. The use of the canine DMD model in basic disease mechanism research and translational studies will be greatly enhanced with the development of reliable outcome measures. Electrical impedance myography (EIM) is a non invasive painless procedure that provides quantitative data relating to muscle composition and histology. EIM has been extensively used in neuromuscular disease research in both human patients and rodent models. Recent studies suggest that EIM may represent a highly reliable and convenient outcome measure in DMD patients and the mdx mouse model of DMD. To determine whether EIM can be used as a biomarker of disease severity in the canine model, we performed the assay in fourteen young (~6.6-m-old; 6 normal and 8 affected) and ten mature (~16.9-m-old; 4 normal and 6 affected) dogs of mixed background breeds. EIM was well tolerated with good inter-rater reliability. Affected dogs showed higher resistance, lower reactance and phase. The difference became more straightforward in mature dogs. Importantly, we observed a statistically significant correlation between the EIM data and muscle fibrosis. Our results suggest that EIM is a valuable objective measurement in the canine DMD model. PMID- 28339470 TI - Meiotic recombination modulates the structure and dynamics of the synaptonemal complex during C. elegans meiosis. AB - During meiotic prophase, a structure called the synaptonemal complex (SC) assembles at the interface between aligned pairs of homologous chromosomes, and crossover recombination events occur between their DNA molecules. Here we investigate the inter-relationships between these two hallmark features of the meiotic program in the nematode C. elegans, revealing dynamic properties of the SC that are modulated by recombination. We demonstrate that the SC incorporates new subunits and switches from a more highly dynamic/labile state to a more stable state as germ cells progress through the pachytene stage of meiotic prophase. We further show that the more dynamic state of the SC is prolonged in mutants where meiotic recombination is impaired. Moreover, in meiotic mutants where recombination intermediates are present in limiting numbers, SC central region subunits become preferentially stabilized on the subset of chromosome pairs that harbor a site where pro-crossover factors COSA-1 and MutSgamma are concentrated. Polo-like kinase PLK-2 becomes preferentially localized to the SCs of chromosome pairs harboring recombination sites prior to the enrichment of SC central region proteins on such chromosomes, and PLK-2 is required for this enrichment to occur. Further, late pachytene nuclei in a plk-2 mutant exhibit the more highly dynamic SC state. Together our data demonstrate that crossover recombination events elicit chromosome-autonomous stabilizing effects on the SC and implicate PLK-2 in this process. We discuss how this recombination-triggered modulation of SC state might contribute to regulatory mechanisms that operate during meiosis to ensure the formation of crossovers while at the same time limiting their numbers. PMID- 28339471 TI - Expression quantitative trait loci for PAX8 contributes to the prognosis of hepatocellular carcinoma. AB - Paired-box family member PAX8 encodes a transcription factor that has a role in cell differentiation and cell growth and may participate in the prognosis of hepatocellular carcinoma (HCC). By bioinformatics analysis, we identified several single nucleotide polymorphisms (SNPs) within a newly identified long non-coding RNA (lncRNA) AC016683.6 as expression quantitative trait loci (eQTLs) for PAX8. Hence, we hypothesized that PAX8eQTLs in lncRNA AC016683.6 may influence the HCC prognosis. We then performed a case-only study to assess the association between the two SNPs as well as the prognosis of HCC in 331 HBV-positive HCC patients without surgical treatment. Cox proportional hazard models were used for survival analysis with adjustments for the age, gender, smoking status, drinking status, Barcelona-Clinic Liver Cancer (BCLC) stage, and chemotherapy or TACE (transcatheter hepatic arterial chemoembolization) status. We found that the G allele of rs1110839 and the T allele of rs4848320 in PAX8was significantly associated with a better prognosis compared with the T allele of rs1110839 and the C allele of rs4848320 (adjusted HR = 0.74, 95% CI = 0.61-0.91, P = 0.004 for rs1110839 and adjusted HR = 0.71, 95% CI = 0.54-0.94, P = 0.015 for rs4848320 in the additive model). Furthermore, the combined effect of the variant genotypes for these two SNPs was more prominent in patients with the BCLC-C stage orpatients with chemotherapy or TACE. Although the exact biological function remains to be explored, our findings suggest a possible association of PAX8eQTLs in lncRNA AC016683.6 with the HCC prognosis inthe Chinese population. Further large and functional studies are needed to confirm our findings. PMID- 28339472 TI - Vector status of Aedes species determines geographical risk of autochthonous Zika virus establishment. AB - BACKGROUND: The 2015-16 Zika virus pandemic originating in Latin America led to predictions of a catastrophic global spread of the disease. Since the current outbreak began in Brazil in May 2015 local transmission of Zika has been reported in over 60 countries and territories, with over 750 thousand confirmed and suspected cases. As a result of its range expansion attention has focused on possible modes of transmission, of which the arthropod vector-based disease spread cycle involving Aedes species is believed to be the most important. Additional causes of concern are the emerging new links between Zika disease and Guillain-Barre Syndrome (GBS), and a once rare congenital disease, microcephaly. METHODOLOGY/PRINCIPAL FINDINGS: Like dengue and chikungunya, the geographic establishment of Zika is thought to be limited by the occurrence of its principal vector mosquito species, Ae. aegypti and, possibly, Ae. albopictus. While Ae. albopictus populations are more widely established than those of Ae. aegypti, the relative competence of these species as a Zika vector is unknown. The analysis reported here presents a global risk model that considers the role of each vector species independently, and quantifies the potential spreading risk of Zika into new regions. Six scenarios are evaluated which vary in the weight assigned to Ae. albopictus as a possible spreading vector. The scenarios are bounded by the extreme assumptions that spread is driven by air travel and Ae. aegypti presence alone and spread driven equally by both species. For each scenario destination cities at highest risk of Zika outbreaks are prioritized, as are source cities in affected regions. Finally, intercontinental air travel routes that pose the highest risk for Zika spread are also ranked. The results are compared between scenarios. CONCLUSIONS/SIGNIFICANCE: Results from the analysis reveal that if Ae. aegypti is the only competent Zika vector, then risk is geographically limited; in North America mainly to Florida and Texas. However, if Ae. albopictus proves to be a competent vector of Zika, which does not yet appear to be the case, then there is risk of local establishment in all American regions including Canada and Chile, much of Western Europe, Australia, New Zealand, as well as South and East Asia, with a substantial increase in risk to Asia due to the more recent local establishment of Zika in Singapore. PMID- 28339475 TI - Correction: The World Health Organization Fetal Growth Charts: A Multinational Longitudinal Study of Ultrasound Biometric Measurements and Estimated Fetal Weight. AB - [This corrects the article DOI: 10.1371/journal.pmed.1002220.]. PMID- 28339473 TI - Characterization of lignocellulolytic activities from fungi isolated from the deep-sea sponge Stelletta normani. AB - Extreme habitats have usually been regarded as a source of microorganisms that possess robust proteins that help enable them to survive in such harsh conditions. The deep sea can be considered an extreme habitat due to low temperatures (<5 degrees C) and high pressure, however marine sponges survive in these habitats. While bacteria derived from deep-sea marine sponges have been studied, much less information is available on fungal biodiversity associated with these sponges. Following screening of fourteen fungi isolated from the deep sea sponge Stelletta normani sampled at a depth of 751 metres, three halotolerant strains (TS2, TS11 and TS12) were identified which displayed high CMCase and xylanase activities. Molecular based taxonomic approaches identified these strains as Cadophora sp. TS2, Emericellopsis sp. TS11 and Pseudogymnoascus sp. TS 12. These three fungi displayed psychrotolerance and halotolerant growth on CMC and xylan as sole carbon sources, with optimal growth rates at 20 degrees C. They produced CMCase and xylanase activities, which displayed optimal temperature and pH values of between 50-70 degrees C and pH 5-8 respectively, together with good thermostability and halotolerance. In solid-state fermentations TS2, TS11 and TS12 produced CMCases, xylanases and peroxidase/phenol oxidases when grown on corn stover and wheat straw. This is the first time that CMCase, xylanase and peroxidase/phenol oxidase activities have been reported in these three fungal genera isolated from a marine sponge. Given the biochemical characteristics of these ligninolytic enzymes it is likely that they may prove useful in future biomass conversion strategies involving lignocellulosic materials. PMID- 28339474 TI - A decrease in intact parathyroid hormone (iPTH) levels is associated with higher mortality in prevalent hemodialysis patients. AB - BACKGROUND: The mortality of dialysis patients is 10- to 100-fold higher than in the general population. Baseline serum PTH levels, and more recently, changes in serum PTH levels (DeltaPTH) over time, have been associated to mortality in dialysis patients. METHODS: We explored the relationship between DeltaPTH over 1 year with mortality over the next year in a prospective cohort of 115 prevalent hemodialysis patients from a single center that had median baseline iPTH levels within guideline recommendations. RESULTS: Median baseline iPTH levels were 205 (116.5, 400) pg/ml. DeltaiPTH between baseline and 1 year was 85.2 +/- 57.1 pg/ml. During the second year of follow-up, 27 patients died. DeltaiPTH was significantly higher in patients who survived (+157.30 +/- 25.82 pg/ml) than in those who died (+39.03 +/- 60.95 pg/ml), while baseline iPTH values were not significantly different. The highest mortality (48%) was observed in patients with a decrease in DeltaiPTH (DeltaiPTH quartile 1, negative DeltaiPTH) and the lowest (12%) mortality in quartile 3 DeltaiPTH (DeltaiPTH increase 101-300 pg/ml). In a logistic regression model, DeltaiPTH was associated with mortality with an odds ratio (OR) of 0.998 (95% CI 0.996-0999, p = 0.038). In multivariable analysis, mortality risk was 73% and 88% lower for patients with DeltaiPTH 0-100 pg/ml and 101-300 pg/ml, respectively, than for those with a decrease in DeltaiPTH. In patients with a decrease in DeltaiPTH, the OR for death was 4.131 (1.515-11.27)(p = 0.006). CONCLUSIONS: In prevalent hemodialysis patients with median baseline iPTH values within the guideline recommended range, a decrease in DeltaiPTH was associated with higher mortality. Further studies are required to understand the mechanisms and therapeutic implications of this observation that challenges current clinical practice. PMID- 28339476 TI - Transgenic mice overexpressing desmocollin-2 (DSC2) develop cardiomyopathy associated with myocardial inflammation and fibrotic remodeling. AB - BACKGROUND: Arrhythmogenic cardiomyopathy is an inherited heart muscle disorder leading to ventricular arrhythmias and heart failure, mainly as a result of mutations in cardiac desmosomal genes. Desmosomes are cell-cell junctions mediating adhesion of cardiomyocytes; however, the molecular and cellular mechanisms underlying the disease remain widely unknown. Desmocollin-2 is a desmosomal cadherin serving as an anchor molecule required to reconstitute homeostatic intercellular adhesion with desmoglein-2. Cardiac specific lack of desmoglein-2 leads to severe cardiomyopathy, whereas overexpression does not. In contrast, the corresponding data for desmocollin-2 are incomplete, in particular from the view of protein overexpression. Therefore, we developed a mouse model overexpressing desmocollin-2 to determine its potential contribution to cardiomyopathy and intercellular adhesion pathology. METHODS AND RESULTS: We generated transgenic mice overexpressing DSC2 in cardiac myocytes. Transgenic mice developed a severe cardiac dysfunction over 5 to 13 weeks as indicated by 2D echocardiography measurements. Corresponding histology and immunohistochemistry demonstrated fibrosis, necrosis and calcification which were mainly localized in patches near the epi- and endocardium of both ventricles. Expressions of endogenous desmosomal proteins were markedly reduced in fibrotic areas but appear to be unchanged in non-fibrotic areas. Furthermore, gene expression data indicate an early up-regulation of inflammatory and fibrotic remodeling pathways between 2 to 3.5 weeks of age. CONCLUSION: Cardiac specific overexpression of desmocollin-2 induces necrosis, acute inflammation and patchy cardiac fibrotic remodeling leading to fulminant biventricular cardiomyopathy. PMID- 28339477 TI - Six degree-of-freedom knee joint kinematics in obese individuals with knee pain during gait. AB - Knee joint pain is a common symptom in obese individuals and walking is often prescribed as part of management programs. Past studies in obese individuals have focused on standing alignment and kinematics in the sagittal and coronal planes. Investigation of 6 degree-of-freedom (6DOF) knee joint kinematics during standing and gait is important to thoroughly understand knee function in obese individuals with knee pain. This study aimed to investigate the 6DOF knee joint kinematics in standing and during gait in obese patients using a validated fluoroscopic imaging system. Ten individuals with obesity and knee pain were recruited. While standing, the knee was in 7.4+/-6.3 degrees of hyperextension, 2.8+/-3.3 degrees of abduction and 5.6+/-7.3 degrees of external rotation. The femoral center was located 0.7+/-3.1mm anterior and 5.1+/-1.5mm medial to the tibial center. During treadmill gait, the sagittal plane motion, i.e., flexion/extension and anterior posterior translation, showed a clear pattern. Specifically, obese individuals with knee pain maintained the knee in more flexion and more anterior tibial translation during most of the stance phase of the gait cycle and had a reduced total range of knee flexion when compared to a healthy non-obese group. In conclusion, obese individuals with knee pain used hyperextension knee posture while standing, but maintained the knee in more flexion during gait with reduced overall range of motion in the 6DOF analysis. PMID- 28339478 TI - Morphological and morphometric specializations of the lung of the Andean goose, Chloephaga melanoptera: A lifelong high-altitude resident. AB - High altitude flight in rarefied, extremely cold and hypoxic air is a very challenging activity. Only a few species of birds can achieve it. Hitherto, the structure of the lungs of such birds has not been studied. This is because of the rarity of such species and the challenges of preparing well-fixed lung tissue. Here, it was posited that in addition to the now proven physiological adaptations, high altitude flying birds will also have acquired pulmonary structural adaptations that enable them to obtain the large amounts of oxygen (O2) needed for flight at high elevation, an environment where O2 levels are very low. The Andean goose (Chloephaga melanoptera) normally resides at altitudes above 3000 meters and flies to elevations as high as 6000 meters where O2 becomes limiting. In this study, its lung was morphologically- and morphometrically investigated. It was found that structurally the lungs are exceptionally specialized for gas exchange. Atypically, the infundibulae are well-vascularized. The mass-specific volume of the lung (42.8 cm3.kg-1), the mass-specific respiratory surface area of the blood-gas (tissue) barrier (96.5 cm2.g-1) and the mass-specific volume of the pulmonary capillary blood (7.44 cm3.kg-1) were some of the highest values so far reported in birds. The pulmonary structural specializations have generated a mass-specific total (overall) pulmonary morphometric diffusing capacity of the lung for oxygen (DLo2) of 0.119 mlO2.sec 1.mbar-1.kg-1, a value that is among some of the highest ones in birds that have been studied. The adaptations of the lung of the Andean goose possibly produce the high O2 conductance needed to live and fly at high altitude. PMID- 28339479 TI - Mouse newborn cells allow highly productive mouse cytomegalovirus replication, constituting a novel convenient primary cell culture system. AB - Mammalian cell culture is indispensable for most aspects of current biomedical research. Immortalized cell lines are very convenient, but transforming principles (e.g. oncogenic viruses or their oncogenes) can heavily influence the experimental outcome. Primary cells do not share this apparent disadvantage but are more laborious to generate. Certain viruses (e.g. mouse cytomegalovirus) do not replicate efficiently in most transformed cell lines. In the past, such viruses have been routinely propagated on primary mouse embryonic fibroblasts (MEF) established around day 17 (d17) of gestation. According to new regulations of the European Union, experiments using gravid mammals and/or their embryos in the last trimester (>d14 in the case of mice) of gestation do require explicit permission of the local authorities responsible for animal care and use. Applying for such permission is time-consuming and often inflexible. Embryonic fibroblasts could also be produced at earlier time points of pregnancy from younger and smaller embryos. Obviously, this approach consumes more pregnant mice and embryos. Newborn mice are larger thus yielding more cells per sacrificed animal and the new Directive (2010/63/EU) excludes the killing of animals solely for the use of their organs or tissues. We established a convenient protocol to generate adherent mouse newborn cells (MNC). A direct comparison of MNC with MEF revealed that MNC fully recapitulate all tested aspects of a broad panel of virological parameters (plaque size, final titers, viral replication kinetics, viral gene expression, drug and interferon susceptibility as well as species specificity). The herein described approach allows researchers the legal use of primary cells and contributes to the 3R (replace, reduce, refine) guiding principles-especially the 'reduce' aspect-for the use of animals in scientific research. Additionally, it offers the option to directly compare in vitro and in vivo experiments when MNC are generated from littermates of animals included in the in vivo experiments. PMID- 28339480 TI - A new accuracy measure based on bounded relative error for time series forecasting. AB - Many accuracy measures have been proposed in the past for time series forecasting comparisons. However, many of these measures suffer from one or more issues such as poor resistance to outliers and scale dependence. In this paper, while summarising commonly used accuracy measures, a special review is made on the symmetric mean absolute percentage error. Moreover, a new accuracy measure called the Unscaled Mean Bounded Relative Absolute Error (UMBRAE), which combines the best features of various alternative measures, is proposed to address the common issues of existing measures. A comparative evaluation on the proposed and related measures has been made with both synthetic and real-world data. The results indicate that the proposed measure, with user selectable benchmark, performs as well as or better than other measures on selected criteria. Though it has been commonly accepted that there is no single best accuracy measure, we suggest that UMBRAE could be a good choice to evaluate forecasting methods, especially for cases where measures based on geometric mean of relative errors, such as the geometric mean relative absolute error, are preferred. PMID- 28339481 TI - Proteomic analysis of injured storage roots in cassava (Manihot esculenta Crantz) under postharvest physiological deterioration. AB - Postharvest physiological deterioration (PPD) is a global challenge in the improvement of cassava value chain. However, how to reduce cassava spoilage and reveal the mechanism of injured cassava storage roots in response to PPD were poorly understood. In the present study, we investigated the activities of antioxidant enzymes of cassava injured storage roots in PPD-susceptible (SC9) and PPD-tolerant (QZ1) genotypes at the time-points from 0h to 120h, and further analyzed their proteomic changes using two-dimensional electrophoresis (2-DE) in combination with MALDI-TOF-MS/MS. Ninety-nine differentially expressed proteins were identified from SC9 and QZ1 genotypes in the pairwise comparison of 24h/0h, 48h/0h, 72h/0h and 96h/0h. Of those proteins were associated with 13 biological functions, in which carbohydrate and energy metabolism related proteins were the biggest amount differential proteins in both genotypes, followed by chaperones, DNA and RNA metabolism, and defense system. We speculated that SOD in combination with CAT activities would be the first line of defense against PPD to support PPD tolerant cassava varieties. The four hub proteins including CPN60B, LOS2, HSC70-1 and CPN20B, produced from the network of protein-protein interaction, will be the candidate key proteins linked with PPD. This study provides a new clue to improve cassava PPD-tolerant varieties and would be helpful to much better understand the molecular mechanism of PPD of cassava injured storage roots. PMID- 28339482 TI - A genome-wide identification and analysis of the DYW-deaminase genes in the pentatricopeptide repeat gene family in cotton (Gossypium spp.). AB - The RNA editing occurring in plant organellar genomes mainly involves the change of cytidine to uridine. This process involves a deamination reaction, with cytidine deaminase as the catalyst. Pentatricopeptide repeat (PPR) proteins with a C-terminal DYW domain are reportedly associated with cytidine deamination, similar to members of the deaminase superfamily. PPR genes are involved in many cellular functions and biological processes including fertility restoration to cytoplasmic male sterility (CMS) in plants. In this study, we identified 227 and 211 DYW deaminase-coding PPR genes for the cultivated tetraploid cotton species G. hirsutum and G. barbadense (2n = 4x = 52), respectively, as well as 126 and 97 DYW deaminase-coding PPR genes in the ancestral diploid species G. raimondii and G. arboreum (2n = 26), respectively. The 227 G. hirsutum PPR genes were predicted to encode 52-2016 amino acids, 203 of which were mapped onto 26 chromosomes. Most DYW deaminase genes lacked introns, and their proteins were predicted to target the mitochondria or chloroplasts. Additionally, the DYW domain differed from the complete DYW deaminase domain, which contained part of the E domain and the entire E+ domain. The types and number of DYW tripeptides may have been influenced by evolutionary processes, with some tripeptides being lost. Furthermore, a gene ontology analysis revealed that DYW deaminase functions were mainly related to binding as well as hydrolase and transferase activities. The G. hirsutum DYW deaminase expression profiles varied among different cotton tissues and developmental stages, and no differentially expressed DYW deaminase-coding PPRs were directly associated with the male sterility and restoration in the CMS D2 system. Our current study provides an important piece of information regarding the structural and evolutionary characteristics of Gossypium DYW-containing PPR genes coding for deaminases and will be useful for characterizing the DYW deaminase gene family in cotton biology and breeding. PMID- 28339483 TI - Temporal evolution of vasospasm and clinical outcome after intra-arterial vasodilator therapy in patients with aneurysmal subarachnoid hemorrhage. AB - Intra-arterial (IA) vasodilator therapy is one of the recommended treatments to minimize the impact of aneurysmal subarachnoid hemorrhage-induced cerebral vasospasm refractory to standard management. However, its usefulness and efficacy is not well established. We evaluated the effect IA vasodilator therapy on middle cerebral artery blood flow and on discharge outcome. We reviewed records for 115 adults admitted to Neurointensive Care Unit to test whether there was a difference in clinical outcome (discharge mRS) in those who received IA infusions. In a subset of 19 patients (33 vessels) treated using IA therapy, we tested whether therapy was effective in reversing the trends in blood flow. All measures of MCA blood flow increased from day -2 to -1 before infusion (maximum Peak Systolic Velocity (PSV) 232.2+/-9.4 to 262.4+/-12.5 cm/s [p = 0.02]; average PSV 202.1+/-8.5 to 229.9+/-10.9 [p = 0.02]; highest Mean Flow Velocity (MFV) 154.3+/-8.3 to 172.9+/-10.5 [p = 0.10]; average MFV 125.5+/-6.3 to 147.8+/-9.5 cm/s, [p = 0.02]) but not post-infusion (maximum PSV 261.2+/-14.6 cm/s [p = .89]; average PSV 223.4+/-11.4 [p = 0.56]; highest MFV 182.9+/-12.4 cm/s [p = 0.38]; average MFV 153.0+/-10.2 cm/s [p = 0.54]). After IA therapy, flow velocities were consistently reduced (day X infusion interaction p<0.01 for all measures). However, discharge mRS was higher in IA infusion group, even after adjusting for sex, age, and admission grades. Thus, while IA vasodilator therapy was effective in reversing the vasospasm-mediated deterioration in blood flow, clinical outcomes in the treated group were worse than the untreated group. There is need for a prospective randomized controlled trial to avoid potential confounding effect of selection bias. PMID- 28339484 TI - A high-throughput qPCR system for simultaneous quantitative detection of dairy Lactococcus lactis and Leuconostoc bacteriophages. AB - Simultaneous quantitative detection of Lactococcus (Lc.) lactis and Leuconostoc species bacteriophages (phages) has not been reported in dairies using undefined mixed-strain DL-starters, probably due to the lack of applicable methods. We optimized a high-throughput qPCR system that allows simultaneous quantitative detection of Lc. lactis 936 (now SK1virus), P335, c2 (now C2virus) and Leuconostoc phage groups. Component assays are designed to have high efficiencies and nearly the same dynamic detection ranges, i.e., from ~1.1 x 105 to ~1.1 x 101 phage genomes per reaction, which corresponds to ~9 x 107 to ~9 x 103 phage particles mL-1 without any additional up-concentrating steps. The amplification efficiencies of the corresponding assays were 100.1+/-2.6, 98.7+/-2.3, 101.0+/ 2.3 and 96.2+/-6.2. The qPCR system was tested on samples obtained from a dairy plant that employed traditional mother-bulk-cheese vat system. High levels of 936 and P335 phages were detected in the mother culture and the bulk starter, but also in the whey samples. Low levels of phages were detected in the cheese milk samples. PMID- 28339486 TI - A top-down manner-based DCNN architecture for semantic image segmentation. AB - Given their powerful feature representation for recognition, deep convolutional neural networks (DCNNs) have been driving rapid advances in high-level computer vision tasks. However, their performance in semantic image segmentation is still not satisfactory. Based on the analysis of visual mechanism, we conclude that DCNNs in a bottom-up manner are not enough, because semantic image segmentation task requires not only recognition but also visual attention capability. In the study, superpixels containing visual attention information are introduced in a top-down manner, and an extensible architecture is proposed to improve the segmentation results of current DCNN-based methods. We employ the current state of-the-art fully convolutional network (FCN) and FCN with conditional random field (DeepLab-CRF) as baselines to validate our architecture. Experimental results of the PASCAL VOC segmentation task qualitatively show that coarse edges and error segmentation results are well improved. We also quantitatively obtain about 2%-3% intersection over union (IOU) accuracy improvement on the PASCAL VOC 2011 and 2012 test sets. PMID- 28339485 TI - Chronic PARP-1 inhibition reduces carotid vessel remodeling and oxidative damage of the dorsal hippocampus in spontaneously hypertensive rats. AB - Vascular remodeling during chronic hypertension may impair the supply of tissues with oxygen, glucose and other compounds, potentially unleashing deleterious effects. In this study, we used Spontaneously Hypertensive Rats and normotensive Wistar-Kyoto rats with or without pharmacological inhibition of poly(ADP ribose)polymerase-1 by an experimental compound L-2286, to evaluate carotid artery remodeling and consequent damage of neuronal tissue during hypertension. We observed elevated oxidative stress and profound thickening of the vascular wall with fibrotic tissue accumulation induced by elevated blood pressure. 32 weeks of L-2286 treatment attenuated these processes by modulating mitogen activated protein kinase phosphatase-1 cellular levels in carotid arteries. In hypertensive animals, vascular inflammation and endothelial dysfunction was observed by NF-kappaB nuclear accumulation and impaired vasodilation to acetylcholine, respectively. Pharmacological poly(ADP-ribose)polymerase-1 inhibition interfered in these processes and mitigated Apoptosis Inducing Factor dependent cell death events, thus improved structural and functional alterations of carotid arteries, without affecting blood pressure. Chronic poly(ADP ribose)polymerase-1 inhibition protected neuronal tissue against oxidative damage, assessed by nitrotyrosine, 4-hydroxinonenal and 8-oxoguanosine immunohistochemistry in the area of Cornu ammonis 1 of the dorsal hippocampus in hypertensive rats. In this area, extensive pyramidal cell loss was also attenuated by treatment with lowered poly(ADP-ribose)polymer formation. It also preserved the structure of fissural arteries and attenuated perivascular white matter lesions and reactive astrogliosis in hypertensive rats. These data support the premise in which chronic poly(ADP-ribose)polymerase-1 inhibition has beneficial effects on hypertension related tissue damage both in vascular tissue and in the hippocampus by altering signaling events, reducing oxidative/nitrosative stress and inflammatory status, without lowering blood pressure. PMID- 28339487 TI - Nucleolar asymmetry and the importance of septin integrity upon cell cycle arrest. AB - Cell cycle arrest can be imposed by inactivating the anaphase promoting complex (APC). In S. cerevisiae this arrest has been reported to stabilize a metaphase like intermediate in which the nuclear envelope spans the bud neck, while chromatin repeatedly translocates between the mother and bud domains. The present investigation was undertaken to learn how other features of nuclear organization are affected upon depletion of the APC activator, Cdc20. We observe that the spindle pole bodies and the spindle repeatedly translocate across the narrow orifice at the level of the neck. Nevertheless, we find that the nucleolus (organized around rDNA repeats on the long right arm of chromosome XII) remains in the mother domain, marking the polarity of the nucleus. Accordingly, chromosome XII is polarized: TelXIIR remains in the mother domain and its centromere is predominantly located in the bud domain. In order to learn why the nucleolus remains in the mother domain, we studied the impact of inhibiting rRNA synthesis in arrested cells. We observed that this fragments the nucleolus and that these fragments entered the bud domain. Taken together with earlier observations, the restriction of the nucleolus to the mother domain therefore can be attributed to its massive structure. We also observed that inactivation of septins allowed arrested cells to complete the cell cycle, that the alternative APC activator, Cdh1, was required for completion of the cell cycle and that induction of Cdh1 itself caused arrested cells to progress to the end of the cell cycle. PMID- 28339488 TI - Mutations in the maize zeta-carotene desaturase gene lead to viviparous kernel. AB - Preharvest sprouting reduces the maize quality and causes a significant yield loss in maize production. vp-wl2 is a Mutator (Mu)-induced viviparous mutant in maize, causing white or pale yellow kernels, dramatically reduced carotenoid and ABA content, and a high level of zeta-carotene accumulation. Here, we reported the cloning of the vp-wl2 gene using a modified digestion-ligation-amplification method (DLA). The results showed that an insertion of Mu9 in the first intron of the zeta-carotene desaturase (ZDS) gene results in the vp-wl2 mutation. Previous studies have suggested that ZDS is likely the structural gene of the viviparous9 (vp9) locus. Therefore, we performed an allelic test using vp-wl2 and three vp9 mutants. The results showed that vp-wl2 is a novel allele of the vp9 locus. In addition, the sequences of ZDS gene were identified in these three vp9 alleles. The vp-wl2 mutant gene was subsequently introgressed into four maize inbred lines, and a viviparous phenotype was observed with yield losses from 7.69% to 13.33%. PMID- 28339490 TI - Create your own stimulus: Manipulating movements according to social categories. AB - People ascribe purposeful behaviour to the movements of artificial objects and social qualities to human body motion. We investigated how people associate simple motion cues with social categories. For a first rating-experiment we converted the body movements of speakers into stick-figure animations; for a second rating-experiment we used animations of one single dot. Rating-experiments were "reversed" because we asked participants to alter the movements (i.e., vertical amplitude, horizontal amplitude, and velocity) of the stimuli according to different instructions (e.g., create a stimulus of high dominance). Participants equipped stick figures and dot animations with expansive movements to represent high dominance. Expansive and fast movements (i.e., high velocity) were mainly associated with high aggressiveness. Fast movements were also associated with low friendliness, low trustworthiness, and low competence. Overall, patterns found for stick figure and dot animations were similar indicating that certain motion cues convey social information even when only a dot and no body form is visible. The "reverse approach" we propose here makes the impact of different components directly observable. The data generated by this method offers better insights into the interplay of these components and the ways in which they form meaningful patterns. The proposed method can be extended to other types of nonverbal cues and a variety of social categories. PMID- 28339489 TI - Human Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P) regulates cytoplasmic lipid droplet abundance: A potential target for indirect-acting anti dengue virus agents. AB - Viral hijacking and manipulation of host-cell biosynthetic pathways by human enveloped viruses are shared molecular events essential for the viral lifecycle. For Flaviviridae members such as hepatitis C virus and dengue virus (DENV), one of the key subsets of cellular pathways that undergo manipulation is the lipid metabolic pathways, underlining the importance of cellular lipids and, in particular, lipid droplets (LDs) in viral infection. Here, we hypothesize that targeting cellular enzymes that act as key regulators of lipid homeostasis and LD formation could represent a powerful approach to developing a novel class of broad-spectrum antivirals against infection associated with all DENV serotypes (1 4) circulating around the world. Using PF-429242, an active-site-directed inhibitor of SKI-1/S1P, we demonstrate that inhibition of SKI-1/S1P enzymatic activity in human hepatoma Huh-7.5.1 cells results in a robust reduction of the LD numbers and LD-positive areas and provides a means of effectively inhibiting infection by DENV (1-4). Pre-treatment of Huh-7.5.1 cells with PF-429242 results in a dose-dependent inhibition of DENV infection [median inhibitory dose (EC50) = 1.2 microM; median cytotoxic dose (CC50) = 81 microM; selectivity index (SI) = 68)] and a ~3-log decrease in DENV-2 titer with 20 microM of PF-429242. Post treatment of DENV-2 infected Huh-7.5.1 cells with PF-429242 does not affect viral RNA abundance, but it does compromise the assembly and/or release of infectious virus particles. PF-429242 antiviral activity is reversed by exogenous oleic acid, which acts as an inducer of LD formation in PF-429242-treated and non treated control cells. Collectively, our results demonstrate that human SKI-1/S1P is a potential target for indirect-acting pan-serotypic anti-DENV agents and reveal new therapeutic opportunities associated with the use of lipid-modulating drugs for controlling DENV infection. PMID- 28339491 TI - The dynamics of nitrogen derived from a chemical nitrogen fertilizer with treated swine slurry in paddy soil-plant systems. AB - A well-managed chemical nitrogen (N) fertilization practice combined with treated swine slurry (TSS) is necessary to improve sustainability and N use efficiency in rice farming. However, little is known about the fate of N derived from chemical N fertilizer with and without TSS in paddy soil-plant systems. The objectives of this study were (1) to estimate the contribution of applied N fertilizer to N turnover in rice paddy soil with different N fertilization practices that were manipulated by the quantity of treated swine slurry and chemical N fertilizer (i.e., HTSS+LAS, a high amount of TSS with a low amount of ammonium sulfate; LTSS+HAS, a low amount of TSS with a high amount of ammonium sulfate; AS, ammonium sulfate with phosphorus and potassium; C, the control) and (2) to compare the rice response to applied N derived from each N fertilization practice. Rice biomass yield, 15N recovery in both rice grain and stems, soil total N (TN), soil inorganic N, and soil 15N recovery were analyzed. Similar amounts of 15N uptake by rice in the TSS+AS plots were obtained, indicating that the effects of the different quantities of TSS on chemical fertilizer N recovery in rice during the experimental period were not significant. The soil 15N recoveries of HTSS+LAS, LTSS+HAS, and AS in each soil layer were not significantly different. For the HTSS+LAS, LTSS+HAS and AS applications, total 15N recoveries were 42%, 43% and 54%, respectively. Because the effects of reducing the use of chemical N fertilizer were attributed to enhancing soil quality and cost-effectiveness, HTSS+LAS could be an appropriate N fertilization practice for improving the long-term sustainability of paddy soil-plant systems. However, N losses, especially through the coupled nitrification-denitrification process, can diminish the benefits that HTSS+LAS offers. PMID- 28339492 TI - A preliminary study of skin ultrasound in diffuse cutaneous systemic sclerosis: Does skin echogenicity matter? AB - OBJECTIVE: To evaluate the usefulness of skin ultrasound and acoustic radiation force impulse (ARFI) quantification in diffuse cutaneous systemic sclerosis (dcSSc). PATIENTS AND METHODS: 28 patients with dcSSc, and 15 age gender matched normal controls were recruited. Skin echogenicity, thickness, and ARFI quantification were measured by ultrasound at 17 sites corresponding to the modified Rodnan skin score (mRSS) in each participant. Compared with controls, skin echogenicity of dcSSc patients was classified into isoechoic, hypoechoic, and hyperechoic. The skin thickness, ARFI quantification and mRSS were compared between isoechoic, hypoechoic, hyperechoic and controls. RESULTS: In patients with dcSSc, the skin thickness increased as the echogenicity changed on the order of isoechoic, hypoechoic and hyperechoic. ARFI quantification was significantly higher in hyperechoic than isoechoic (p<0.001). The mRSS were significantly higher in hyperechoic and/or hypoechoic than isoechoic. For isoechoic patients and healthy controls, the skin echogenicity or thickness was no significant different, however, the ARFI quantification was significantly higher in isoechoic than controls. CONCLUSION: Skin ultrasound is feasible for assessing the skin involvement in dcSSc. Skin echogenicity correlates with skin thickness, stiffness, and mRSS. ARFI quantification may be more sensitive to detect skin changes, compared with skin echogenicity and thickness. PMID- 28339494 TI - Facility type and primary care performance in sub-district health promotion hospitals in Northern Thailand. AB - BACKGROUND: Poor and middle-income Thai people rely heavily on primary care health services. These are staffed by a range of professionals. However, it is unknown whether the performance of primary care varies according to the staffing and organization of local service delivery units. Tambon (sub-district) health promotion hospitals (THPHs) were introduced in 2009 to upgrade the services offered by the previous health centres, but were faced with continuing shortages of doctors and nurses. The Ministry of Public Health (MoPH) designated three categories of THPH, defined according to whether they were regularly staffed by a medical practitioner, a qualified nurse or non-clinical public health officers. This study aimed to compare the performance of primary care offered by the three different types of primary care facilities in one public health region of Northern Thailand (Public Health Region 2). METHODS: A cross-sectional survey was undertaken in 2013. Data were collected on accessibility, continuity, comprehensiveness, co-ordination and community orientation of care from 825 patients attending 23 primary care facilities. These were selected to include the three officially-designated types of Tambon (sub-district) health promotion hospitals (THPHs) led by medical, nursing or public health personnel. Survey scores were compared in unadjusted and adjusted analyses. RESULTS: THPHs staffed only by public health officers achieved the highest performance score (Mean = 85.14, SD. = 7.30), followed by THPHs staffed by qualified nurses (Mean = 82.86, SD. = 7.06). THPHs staffed by a doctor on rotation returned the lowest scores (Mean = 81.63, SD. = 7.22). CONCLUSIONS: Differences in overall scores resulted mainly from differences in reported accessibility, continuity, and comprehensiveness of care, rather than staff skill-mix per se. Policy on quality improvement should therefore focus on improving performance in these areas. PMID- 28339493 TI - Timely meta-analysis on the efficacy of adoptive immunotherapy for hepatocellular carcinoma patients after curative therapy. AB - AIMS: The role of adoptive immunotherapy (AIT) for patients with hepatocellular carcinoma (HCC) who have received curative therapy is still not well illustrated. This timely meta-analysis aims to update the current evidence on efficacy and safety of AIT for patients with HCC who have received curative therapy. METHODS: We searched PubMed, EMBASE, Scopus and the Cochrane Library Through January 2017 for relevant studies. Mortality and tumor recurrence were compared between patients with or without adjuvant AIT. The meta-analysis was performed using Review Manager 5.3. RESULTS: Eight studies involving 1861 patients met the eligibility criteria and were meta-analyzed. Adjuvant AIT was associated with significantly lower mortality at 1 year (RR 0.64, 95%CI 0.52-0.79), 3 years (RR 0.73, 95%CI 0.65-0.81) and 5 years (RR 0.86, 95%CI 0.79-0.94). Similarly, adjuvant AIT was associated with significantly lower recurrence rate than curative therapies alone at 1 year (RR 0.64, 95%CI 0.49-0.82), 3 years (RR 0.85, 95%CI 0.79-0.91) and 5 years (RR 0.90, 95%CI 0.85-0.95). Short-term outcomes were confirmed in sensitivity analyses based on randomized trials or choice of random- or fixed-effect meta-analysis model. None of the included patients experienced grade 4 adverse events. CONCLUSIONS: This timely meta-analysis confirms the evidence that adjuvant AIT for patients with HCC after curative treatment lowers risk of mortality and tumor recurrence. PMID- 28339496 TI - Correction: The TIR Homologue Lies near Resistance Genes in Staphylococcus aureus, Coupling Modulation of Virulence and Antimicrobial Susceptibility. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006092.]. PMID- 28339495 TI - MicroRNA expression profiles identify disease-specific alterations in systemic lupus erythematosus and primary Sjogren's syndrome. AB - The discovery of microRNAs (miRNAs) and their critical role in genetic control opened new avenues in understanding of various biological processes including immune cell lineage commitment, differentiation, proliferation and apoptosis. However, a given miRNA may have hundreds of different mRNA targets and a target might be regulated by multiple miRNAs, thus the characterisation of dysregulated miRNA expression profiles could give a better insight into the development of immunological disturbances in autoimmune diseases. The aim of our study was to examine the changes in miRNA expression profiles in patients with systemic lupus erythematosus (SLE) and primary Sjogren's syndrome (pSS). Eight SLE patients, 8 pSS patients and 7 healthy subjects were enrolled in the investigation. MiRNAs were isolated from peripheral blood mononuclear cells, and expression patterns were determined with Illumina next-generation sequencing technology. Since the immunopathogenesis of pSS and SLE encompasses pronounced B cell hyperactivity along with specific autoantibody production, we paid a special attention on the association between miRNA expression levels and altered peripheral B cell distribution. In SLE patients 135, while in pSS patients 26 miRNAs showed altered expression. Interestingly, the 25 miRNAs including miR-146a, miR-16 and miR-21, which were over-expressed in pSS patients, were found to be elevated in SLE group, as well. On the contrary, we observed the down-regulation of miR-150-5p, which is a novel and unique finding in pSS. Levels of several miRNAs over expressed in SLE, were not changed in pSS, such as miR-148a-3p, miR-152, miR-155, miR-223, miR-224, miR-326 and miR-342. Expression levels of miR-223-5p, miR-150 5p, miR-155-5p and miR-342-3p, which miRNAs are potentially linked to B cell functions, showed associations with the B cell proportions within peripheral blood mononuclear cells. The observed differences in miRNA expression profiles and the better understanding of immune regulatory mechanisms of miRNAs may help to elucidate the pathogenesis of SLE and pSS. PMID- 28339497 TI - Women's knowledge and perception of male circumcision before and after its roll out in the South African township of Orange Farm from community-based cross sectional surveys. AB - The roll-out of medical male circumcision (MC) is progressing in Southern and Eastern Africa. Little is known about the effect of this roll-out on women. The objective of this study was to assess the knowledge and perceptions of women regarding MC in a setting before and after the roll-out. This study was conducted in the South African township of Orange Farm where MC prevalence among men increased from 17% to 53% in the period 2008-2010. Data from three community based cross sectional surveys conducted in 2007, 2010 and 2012 among 1258, 1197 and 2583 adult women, respectively were studied. In 2012, among 2583 women, 73.7% reported a preference for circumcised partners, and 87.9% knew that circumcised men could become infected with HIV. A total of 95.8% preferred to have their male children circumcised. These three proportions increased significantly during the roll-out. In 2007, the corresponding values were 64.4%, 82.9% and 80.4%, respectively. Among 2581 women having had sexual intercourse with circumcised and uncircumcised men, a majority (55.8%, 1440/2581) agreed that it was easier for a circumcised man to use a condom, 20.5% (530/2581) disagreed; and 23.07 (611/2581) did not know. However, some women incorrectly stated that they were fully (32/2579; 1.2%; 95%CI: 0.9% to 1.7%) or partially (233/2579; 9.0%; 95%CI: 8.0% to 10.2%) protected when having unprotected sex with a circumcised HIV-positive partner. This study shows that the favorable perception of women and relatively correct knowledge regarding VMMC had increased during the roll-out of VMMC. When possible, women should participate in the promotion of VMMC although further effort should be made to improve their knowledge. PMID- 28339499 TI - Evaluation of fusion protein cleavage site sequences of Newcastle disease virus in genotype matched vaccines. AB - Newcastle disease virus (NDV) causes a devastating poultry disease worldwide. Frequent outbreaks of NDV in chickens vaccinated with conventional live vaccines suggest a need to develop new vaccines that are genetically matched against circulating NDV strains, such as the genotype V virulent strains currently circulating in Mexico and Central America. In this study, a reverse genetics system was developed for the virulent NDV strain Mexico/01/10 strain and used to generate highly attenuated vaccine candidates by individually modifying the cleavage site sequence of fusion (F) protein. The cleavage site sequence of parental virus was individually changed to those of the avirulent NDV strain LaSota and other serotypes of avian paramyxoviruses (APMV serotype-2, -3, -4, -6, -7, -8, and -9). In general, these mutations affected cell-to-cell fusion activity in vitro and the efficiency of the F protein cleavage and made recombinant Mexico/01/10 (rMex) virus highly attenuated in chickens. When chickens were immunized with the rMex mutant viruses and challenged with the virulent parent virus, there was reduced challenge virus shedding compared to birds immunized with the heterologous vaccine strain LaSota. Among the vaccine candidates, rMex containing the cleavage site sequence of APMV-2 induced the highest neutralizing antibody titer and completely protected chickens from challenge virus shedding. These results show the role of the F protein cleavage site sequence of each APMV type in generating genotype V-matched vaccines and the efficacy of matched vaccine strains to provide better protection against NDV strains currently circulating in Mexico. PMID- 28339498 TI - Enhancement of osteogenic differentiation of rat adipose tissue-derived mesenchymal stem cells by zinc sulphate under electromagnetic field via the PKA, ERK1/2 and Wnt/beta-catenin signaling pathways. AB - Zinc ion as an essential trace element and electromagnetic fields (EMFs) has been reported to be involved in the regulation of bone metabolism. The aim of this study was to elucidate the effects of zinc sulphate (ZnSO4) on the osteogenic differentiation of adipose tissue-derived mesenchymal stem cells (ADSCs) in the presence of EMF as a strategy in osteoporosis therapy. Alkaline phophatase (ALP) activity measurement, calcium assay and expression of several osteoblastic marker genes were examined to assess the effect of ZnSO4 on the osteogenic differentiation of ADSCs under EMF. The expression of cAMP and PKA was evaluated by ELISA. The expression of beta-catenin, Wnt1, Wnt3a, low-density lipoprotein receptor-related protein 5 (LRP5) and reduced dickkopf1 (DKK1) genes were used to detect the Wnt/beta-catenin pathway. It was found that ZnSO4, in the presence of EMF, resulted in an increase in the expression of osteogenic genes, ALP activity and calcium levels. EMF, in the presence of ZnSO4, increased the cAMP level and protein kinase A (PKA) activity. Treatment of ADSCs with (MAPK)/ERK kinase 1/2 inhibitor, or PKA inhibitor, significantly inhibited the promotion of osteogenic markers, indicating that the induction of osteogenesis was dependent on the ERK and PKA signaling pathways. Real-time PCR analysis showed that ZnSO4, in the presence of EMF, increased the mRNA expressions of beta-catenin, Wnt1, Wnt3a, LRP5 and DKK1. In this study, it was shown that 0.432 MUg/ml ZnSO4, in the presence of 50 Hz, 20 mT EMF, induced the osteogenic differentiation of ADSCs via PKA, ERK1/2 and Wnt/beta-catenin signaling pathways. PMID- 28339500 TI - Detecting congenital malformations - Lessons learned from the Mpepu study, Botswana. AB - INTRODUCTION: A large and increasing number of HIV-infected women are conceiving on antiretroviral treatment (ART). While most antiretrovirals are considered safe in pregnancy, monitoring for rare pregnancy and infant adverse outcomes is warranted. METHODS: We conducted a retrospective secondary analysis nested within a clinical trial of infant cotrimoxazole vs. placebo prophylaxis in Botswana (the Mpepu Study). Infants were examined at birth, and at least every 3 months through 18 months of age. Abnormal physical findings and diagnostic testing revealing malformations were documented. Post hoc, a geneticist classified all reported malformations based on available documentation. Structural malformations with surgical, medical or cosmetic importance were classified as major malformations. We present a descriptive analysis of identified malformations. RESULTS: Between 2011 and 2014, 2,933 HIV-infected women who enrolled in the Mpepu study delivered 2,971 live-born infants. Study staff conducted 2,944 (99%) newborn exams. One thousand eighty-eight (38%) women were taking ART at conception; 1,147 (40%) started ART during pregnancy; 442 (15%) received zidovudine monotherapy; and 223 (7%) received no antiretroviral during pregnancy. Of 33 reported anomalies, 25 (76%) met congenital malformations criteria, 10 (30%) were classified as major malformations, 4 (40%) of which were identified after the birth exam. DISCUSSION: Our results highlight the importance of staff training on identification of congenital malformations, programmatic monitoring beyond the birth examination and the value of geneticist involvement in the malformations classification process in resource-limited settings. These elements will be important to fully define antiretroviral drug safety in pregnancy. SIGNIFICANCE: Surveillance systems for monitoring the safety of antiretroviral use during pregnancy among HIV-infected women in resource-limited setting are lacking. The World Health Organization's published programmatic recommendations for such surveillance systems represents the gold standard. We employed data from a clinical trial in Botswana, a country with a generalized HIV epidemic and high antiretroviral uptake by HIV-infected women, to highlight practical opportunities to strengthen congenital malformation surveillance systems in these settings where over 1 million HIV infected pregnant women reside. TRIAL REGISTRATION: Clinical Trials.gov NCT01229761. PMID- 28339501 TI - Mapping global biodiversity connections with DNA barcodes: Lepidoptera of Pakistan. AB - Sequences from the DNA barcode region of the mitochondrial COI gene are an effective tool for specimen identification and for the discovery of new species. The Barcode of Life Data Systems (BOLD) (www.boldsystems.org) currently hosts 4.5 million records from animals which have been assigned to more than 490,000 different Barcode Index Numbers (BINs), which serve as a proxy for species. Because a fourth of these BINs derive from Lepidoptera, BOLD has a strong capability to both identify specimens in this order and to support studies of faunal overlap. DNA barcode sequences were obtained from 4503 moths from 329 sites across Pakistan, specimens that represented 981 BINs from 52 families. Among 379 species with a Linnaean name assignment, all were represented by a single BIN excepting five species that showed a BIN split. Less than half (44%) of the 981 BINs had counterparts in other countries; the remaining BINs were unique to Pakistan. Another 218 BINs of Lepidoptera from Pakistan were coupled with the 981 from this study before being compared with all 116,768 BINs for this order. As expected, faunal overlap was highest with India (21%), Sri Lanka (21%), United Arab Emirates (20%) and with other Asian nations (2.1%), but it was very low with other continents including Africa (0.6%), Europe (1.3%), Australia (0.6%), Oceania (1.0%), North America (0.1%), and South America (0.1%). This study indicates the way in which DNA barcoding facilitates measures of faunal overlap even when taxa have not been assigned to a Linnean species. PMID- 28339502 TI - Histological and anatomical structure of the nasal cavity of Bama minipigs. AB - OBJECTIVE: The nasal mucosa is equipped with abundant lymphatic tissues, serving as the first line of defense against invasion by microorganisms. In this study, we characterized the features of the nasal mucosa of Bama minipigs (Sus scrofa domestica) via histological analysis. METHODS: Five cross sections (I, II, III, IV, and V) were obtained from the distal end of the nasal cavity toward the pharynx (along the cavity axis) and examined. Specifically, CD3+ T cells, immunoglobulin A (IgA)+ cells, and M cells were detected by immunohistochemistry, while dendritic cells (DCs) were detected by immunofluorescence. The distribution of goblet cells was determined by periodic acid-Schiff (PAS) staining. RESULTS: The nasal cavity of Bama minipigs can be divided into three parts: the regio vestibularis (I, II), regio respiratoria (III, IV), and regio olfactoria (V). Lymphoid tissue was present at random locations in the nasal cavity. Abundant lymphoid tissue was located in the roof of the nasopharyngeal meatus and was continuous with the lymphoid tissue of the pharynx. The distribution of CD3+ T cells, IgA+ cells, M cells, and DCs increased distally in the nasal cavity. CONCLUSIONS: The present work comprises a histological study of the nasal cavity of Bama minipigs, and will be beneficial for understanding the mechanisms of immunity in these animals after nasal vaccination. PMID- 28339503 TI - Rat retinal vasomotion assessed by laser speckle imaging. AB - Vasomotion is spontaneous or induced rhythmic changes in vascular tone or vessel diameter that lead to rhythmic changes in flow. While the vascular research community debates the physiological and pathophysiological consequence of vasomotion, there is a great need for experimental techniques that can address the role and dynamical properties of vasomotion in vivo. We apply laser speckle imaging to study spontaneous and drug induced vasomotion in retinal network of anesthetized rats. The results reveal a wide variety of dynamical patterns. Wavelet-based analysis shows that (i) spontaneous vasomotion occurs in anesthetized animals and (ii) vasomotion can be initiated by systemic administration of the thromboxane analogue U-46619 and the nitric-oxide donor S nitroso-acetylDL-penicillamine (SNAP). Although these drugs activate different cellular pathways responsible for vasomotion, our approach can track the dynamical changes they cause. PMID- 28339510 TI - 3D dentofacial photogrammetry reference values: a novel approach to orthodontic diagnosis. AB - Background: Orthodontic diagnostic standards generally use the cranial base as a reference and rely on samples selected by orthodontists. Objective: The purpose of this study was to provide male and female standards for a novel non radiographic approach for orthodontic diagnosis that utilizes 3D dentofacial photogrammetry using the eyes and natural head orientation as references instead of the cranial base. Methods: One hundred and eighty females and 200 males between the ages of 18 and 35 years from 2 modeling agencies were orthodontically screened for near ideal occlusion. Subjects that met the inclusion criteria were rated by a sample of 40 lay people for attractiveness on a visual analogue scale. The final sample that had 3D facial and dental imaging included 49 subjects 25 males and 24 females with near ideal occlusion and considered attractive by the public. Results: Inter and Intra-examiner ICC were greater than 0.8 for both landmarking and indexing. Relative to a coronal plane contacting the pupils (MC), the mean sagittal position of the alar curvature (representing the nasomaxillary complex) was 14.36 +/- 3.08 mm in males and 12.4 +/- 3.58 mm in females. The sagittal position of soft tissue pogonion relative to the pupils was 14.84 +/- 3.63 mm in males and 12.78 +/- 5.68 mm in females. The angle between the alar curvature and pogonion relative to the pupils was 9 degrees in males and 10 degrees in females. With the exception of the occlusal plane which was steeper in females, no ratios or angular facial measurements showed a significant gender difference. Relative to MC, males had more proclined upper incisors (20 degrees vs 16 degrees ) and more retroclined Lower incisors (27 degrees vs 31 degrees ; P > 0.05). A Procrustes ANOVA and permutation test showed that the shapes of males and females are different enough to be considered two distinct populations. Conclusions: 1. When using the proposed method for orthodontic diagnosis, male and female patients should be compared to their respective dentofacial standards. 2. Validation of the proposed method and standards on an orthodontic population is underway to determine the scope its use. PMID- 28339511 TI - Living alone and unplanned hospitalizations among older adults: a population based longitudinal study. AB - Background: The association of living alone with hospitalization among the general elderly population has been rarely investigated, and the influence of common disorders on this association remains unknown. Methods: We used data on participants in the Swedish National study on Aging and Care in Kungsholmen ( n = 3130). Risk and number of unplanned hospitalizations and length of hospital stays were studied over a period of 2 years. We used Cox proportional hazard models to estimate hazard ratios (HRs) of incident hospitalization and zero-inflated negative binomial regression models adjusted for potential confounders to estimate incident rate ratios (IRR) of the number of hospitalizations and total length of stay associated with living alone. Results: A total of 1768 participants (56.5%) lived alone. Five hundred and sixty-one (31.7%) of those who lived alone had at least one unplanned hospitalization. In the multivariate analyses, living alone was significantly associated with the risk of unplanned hospitalization (HR = 1.21, 95% confidence interval [CI] 1.01-1.45) and the number of hospitalizations (IRR = 1.35, 95% CI 1.04-1.76) but not with the length of hospital stays. In stratified analyses, the association between living alone and unplanned hospitalizations remained statistically significant only among men (HR = 1.52, 95% CI 1.17-1.99). Conclusions: Living alone is associated with higher risks of unplanned hospitalization in elderly, especially for men. PMID- 28339513 TI - Ultrasound Imaging of Metastatic Colon Cancer in a Case of Intractable Intercostal Neuralgia: Scan Before You Block. PMID- 28339512 TI - Effects of mulberry leaves on production performance and the potential modulation of antioxidative status in laying hens. AB - This study evaluated the antioxidant ability of Taisung No. 3 mulberry leaf extract (MLE) as well as the potential of mulberry leaf (ML)-based dietary supplementation for modulating the antioxidative status of laying hens. The results showed that the MLE had a total phenolic compound content of 7.4 +/- 0.15 mg of gallic acid equivalent/g dry weight (DW) and a total flavonoid content of 4.4 +/- 0.19 mg of quercetin equivalent/g DW. The 2, 2-diphenyl-1-picrylhydrazyl free-radical-scavenging ability was 45.9% when 0.1 mg/mL MLE was added. The lipid oxidation inhibition ability was 43.9% when 50 mg/mL MLE was added. We subjected 96 laying hens (Hendrix Genetics) to 4 treatments, namely diets supplemented with dry ML at 0 (control), 0.5, 1, or 2% for 12 weeks. Each treatment involved 8 replicates with 3 hens each. The results indicated that the 0.5% ML-supplemented group exhibited significantly higher mRNA levels of antioxidant-regulated genes, such as Nrf2, HO-1, and GST, and significantly lower ROMO1 gene expression levels at wk 12. The serum malondialdehyde level was lower and the catalase activity and superoxide dismutase activity were higher in all the ML-supplemented groups than in the control group. The egg mass and feed conversion rate significantly improved in the ML-supplemented groups compared with the control group, and, overall, 1% ML supplementation had the most favorable effects at one to 12 weeks. The egg yolk weight, shell weight, shell strength, shell thickness, yolk color, and Haugh unit were increased among all ML-supplemented groups at one to 12 weeks. On the basis of these observations, we conclude that 0.5% ML can be used as a new feed additive to potentially modulate the antioxidative status of laying hens and improve their production performance and egg quality. PMID- 28339514 TI - Social inequalities in self-rated health in Ukraine in 2007: the role of psychosocial, material and behavioural factors. AB - Background: Despite Ukraine's large population, few studies have examined social inequalities in health. This study describes Ukrainian educational inequalities in self-rated health and assesses how far psychosocial, material and behavioural factors account for the education gradient in health. Methods: Data were analyzed from the 2007 wave of the Ukrainian Longitudinal Monitoring Survey. Education was categorized as: lower secondary or less, upper secondary and tertiary. In logistic regressions of 5451 complete cases, stratified by gender, declaring less than average health was regressed on education, before and after adjusting for psychosocial, material and behavioural factors. Results: In analyses adjusted for socio-demographic characteristics, compared with those educated up to lower secondary level, tertiary education was associated with lower risk of less than average health for both men and women. Including material factors (income quintiles, housing assets, labour market status) reduced the association between education and health by 55-64% in men and 35-47% in women. Inclusion of health behaviours (physical activity, smoking, alcohol consumption and body mass index) reduced the associations by 27-30% in men and 19-27% in women; in most cases including psychosocial factors (marital status, living alone, trust in family and friends) did not reduce the size of the associations. Including all potential explanatory factors reduced the associations by 68-84% in men and 43-60% in women. Conclusions: The education gradient in self-rated health in Ukraine was partly accounted for by material and behavioural factors. In addition to health behaviours, policymakers should consider upstream determinants of health inequalities, such as joblessness and poverty. PMID- 28339516 TI - Improving a full-text search engine: the importance of negation detection and family history context to identify cases in a biomedical data warehouse. AB - Objective: The repurposing of electronic health records (EHRs) can improve clinical and genetic research for rare diseases. However, significant information in rare disease EHRs is embedded in the narrative reports, which contain many negated clinical signs and family medical history. This paper presents a method to detect family history and negation in narrative reports and evaluates its impact on selecting populations from a clinical data warehouse (CDW). Materials and Methods: We developed a pipeline to process 1.6 million reports from multiple sources. This pipeline is part of the load process of the Necker Hospital CDW. Results: We identified patients with "Lupus and diarrhea," "Crohn's and diabetes," and "NPHP1" from the CDW. The overall precision, recall, specificity, and F-measure were 0.85, 0.98, 0.93, and 0.91, respectively. Conclusion: The proposed method generates a highly accurate identification of cases from a CDW of rare disease EHRs. PMID- 28339517 TI - Omics studies: their use in diagnosis and reclassification of SLE and other systemic autoimmune diseases. AB - Omics studies of systemic autoimmune diseases (SADs) in general, and SLE in particular, have delivered isolated information from transcriptome, epigenome, genome, cytokine and metabolome analyses. Such analyses have resulted in the identification of disease susceptibility genes and the description of IFN expression signatures, allowing extensive insight into the mechanisms of disease and the development of new therapies. Access to such technologies allows the recognition of patterns of disease at a pathway level, thereby, to reclassify SLE and other SADs and to develop new therapeutics from a personalized perspective. The use of omic information allows the discovery of correlative patterns involving drugs not currently suspected to be of value in SADs. In this review, we summarize the omics findings for SLE and propose ways of using the data for the identification of new biomarkers, finding new drugs and reclassifying patients not only with SLE, but also with other SADs. PMID- 28339518 TI - Pain Interference and Incident Medical Disorders in the General Population. AB - Objective: To investigate the longitudinal relationship between pain interference and incident general medical conditions in a nationally representative sample. Methods: Secondary data analysis comprising chi-square tests and binomial logistic regression analyses were performed on data obtained from the US National Epidemiologic Survey on Alcohol and Related Conditions from 34,465 adult respondents who completed wave 1 (2000-2001) and wave 2 (2004-2005) data collection. Models were adjusted for multiple potentially confounding factors. Respondents were categorized at wave 1 according to past-month pain interference (i.e., no or low pain interference, moderate pain interference, severe pain interference). Results: In multivariate analyses, moderate or severe pain interference (as compared to no or low pain interference) was associated with the incidence of any medical condition; any heart condition, including angina, tachycardia and other heart disease; any stomach condition, including stomach ulcer and gastritis; arthritis; and hypertension (all P < 0.05). Severe (but not moderate) pain interference as compared with no or low pain interference was additionally associated with new occurrences of myocardial infarction, any liver disease, other liver disease, and arteriosclerosis (all P < 0.05). Conclusions: These findings suggest that the relationship between pain interference and general medical conditions is complex. A more complete understanding of this relationship is likely to involve further exploration of possible mechanisms, including whether it is the pain itself, the ascertainment of pain etiology, or pain treatment that is associated with incident general medical conditions. PMID- 28339520 TI - Efficacy of Bacillus subtilis and bacitracin methylene disalicylate on growth performance, digestibility, blood metabolites, immunity, and intestinal microbiota after intramuscular inoculation with Escherichia coli in broilers. AB - This experiment was conducted to evaluate the effect of Bacillus subtilis (BS) on broiler performance and health after intramuscular inoculation with E. coli and compare its effect with a growth promoter antibiotic. In a completely randomized design manner, 360 male Ross 308 chicks were divided into 6 treatments and 5 replicates of 12 chicks in each replicate. Experimental treatments included control diet, control + E. coli (0.5 mL of culture containing 108 CFU of E. coli/ml), control + 0.1% BS, control + 0.05% bacitracin methylene disalicylate (BMD), control + E. coli and BS, and control + E. coli and BMD in a factorial arrangement (3 * 2). Addition of BMD or BS to the control diet significantly (P < 0.01) increased body weight and decreased FCR, but E. coli challenge adversely reduced (P < 0.01) body weight and increased FCR, so that the addition of BMD or BS did not compensate growth reduction. E. coli challenged chicks had the lowest vaccine titers for ND, IB, AI, and IBD and the highest were observed in chicks fed BS. The E. coli challenge significantly (P < 0.01) increased albumin, globulin, cholesterol, triglyceride, LDL, ALT, and ALP indices. Addition of BMD and BS decreased albumin and globulin in challenged chick's plasma but had no effect on plasma lipid profile concentration. The E. coli challenge decreased villus height and increased crypt depth and goblet cell numbers significantly (P < 0.01). In birds subjected to BMD or BS, crypt depth decreased and villus height increased (P < 0.01), compared with the control diet. Challenge of E. coli significantly (P < 0.01) increased the bacterial population of E. coli, coliforms, and Salmonella in cecal parts of broilers' intestines. In challenged birds receiving BMD or BS, E. coli, coliform, and Salmonella populations of ceca showed a significant (P < 0.01) reduction. Both BMD and BS increased the digestibility of nutrients significantly (P < 0.01), but a reduction was observed in E. coli challenged groups. Results of the study suggest that spore-forming probiotics are partially effective in unsuitable rearing situations such as colibacillosis in which the load of harmful bacteria is high. PMID- 28339521 TI - Effect of Fibromyalgia Symptoms on Outcome of Spinal Surgery. AB - Objectives: To evaluate the effect of presurgical symptoms characteristic of fibromyalgia on the postsurgical outcome of patients undergoing spinal surgery. Methods: In this observational cohort study, participants were patients scheduled for spinal surgery, including cervical or lumbar laminectomy and foraminectomy. Presurgical evaluation included physical examination and manual dolorimetry. Questionnaires included the widespread pain index (WPI), symptom severity scale (SSS), and SF-36. Postsurgical evaluation performed at 10-12 weeks included questionnaires, physical examination, and dolorimetry. Results: Forty patients (21 male, 19 female) were recruited. Four patients (10%) fulfilled American College of Rheumatology (ACR) 1990 fibromyalgia; nine patients fulfilled 2010 criteria (22.5%). Overall, a significant 34% reduction in WPI was observed postsurgically ( P < 0.01), but no significant change was observed in SSS. Comparing outcomes for patients fulfilling and not fulfilling fibromyalgia criteria, fibromyalgia syndrome (FMS)-negative patients experienced highly significant reductions of both SSS and WPI (-50.1% and -42.9%, respectively, P < 0.01), while FMS-positive patients experienced no reduction of SSS symptoms and only a marginally significant reduction in WPI (-20.3%, P = 0.04). A significant negative correlation was observed between results of presurgical WPI and change in physical role functioning SF-36 component postsurgically. A significant negative correlation was observed between presurgical SSS and change in composite physical functioning SF-36 component. Regression analysis demonstrated a difference in trend between FMS-positive and FMS-negative patients regarding postop changes in SSS, as well as a difference in trend regarding the general health role limitation due to emotional problems and pain components of the SF 36. Conclusions: Fibromyalgia symptoms were highly prevalent among patients scheduled for spinal surgery. A negative correlation was observed between presurgical severity of fibromyalgia symptoms and components of postsurgical SF 36. Patients with symptoms typical of fibromyalgia may have a less favorable outcome after spinal surgery. The clinical utility of surgical intervention in such patients should be carefully evaluated, and treatment specific for fibromyalgia might be considered before embarking on a surgical course. PMID- 28339522 TI - Influence of postbiotic RG14 and inulin combination on cecal microbiota, organic acid concentration, and cytokine expression in broiler chickens. AB - This study examined the effects of different combinations of inulin and postbiotics RG14 on growth performance, cecal microbiota, volatile fatty acids (VFA), and ileal cytokine expression in broiler chickens. Two-hundred-and sixteen, one-day-old chicks were allocated into 6 treatment groups, namely, a basal diet (negative control, NC), basal diet + neomycin and oxytetracycline (positive control, PC), T1 = basal diet + 0.15% postbiotic RG14 + 1.0% inulin, T2 = basal diet + 0.3% postbiotic RG14 + 1.0% inulin, T3 = basal diet + 0.45% postbiotic RG14 + 1.0% inulin, and T4 = basal diet + 0.6% postbiotic RG14 + 1.0% inulin, and fed for 6 weeks. The results showed that birds fed T1 and T3 diets had higher (P < 0.05) final body weight and total weight gain than NC and PC birds. A lower (P < 0.05) feed conversion ratio was observed in birds fed T1 and T2 compared with those fed the NC diet. Birds fed PC, T1, T2, and T3 had higher (P < 0.05) cecum total bacteria and Bifidobacteria compared to the NC birds. Diet had no effect on cecum Lactobacilli, Enterococcus and Salmonella. The NC birds had higher (P < 0.05) Enterobacteria and E. coli than other treatments. Concentration of acetic acid was higher in birds fed PC, T1, and T4 compared to the NC birds. However, the concentration of butyric acid, propionic acid, and total VFA did not differ (P > 0.05) among diets. The NC birds had higher (P < 0.05) expression of interferon (IFN) and Lipopolysaccharide-induced tumor necrosis factor-alpha factor (LITAF) gene compared with those fed other diets. The mRNA expression of interluken-6 (IL-6) was up-regulated in birds fed T3 and T4 compared to the NC birds. However, the expression of interluken-8 (IL-8) gene was not influenced by diet. Postbiotic and inulin combinations are potential replacements for antibiotic growth promoters in the poultry industry. PMID- 28339523 TI - Factors affecting the quality of life of chronic dialysis patients. AB - Background: Patients on hemodialysis must adjust their life plans to the treatment. They are aware of losing their health and independence. Therefore, acceptance of illness (AI) is important and allows the patient to adjust to new situation and alleviates negative emotions. Methods: The aim of study was to assess the impact of AI and other socioclinical variables on hemodialysis patients' quality of life (QoL). The study included 100 patients aged 20-85 (M = 57), treated with hemodialysis for at least 2 years. Two validated instruments were used: the Acceptance of Illness Scale (AIS) and the World Health Organization Quality of Life questionnaire. Results: High, moderate and low level of AI was found for 15, 61 and 24 patients, respectively. The QoL increased with the AI score. In physical domain, it reached 69.8 +/- 12.4 in the high AIS group, 54.2 +/- 15.3 in the moderate AIS group and 42.7 +/- 12.3 in the low AIS group ( P < 0.001). The psychological domain scores were 70.3 +/- 12.8, 57.2 +/- 15.0 and 49.7 +/- 11.8 ( P < 0.001), respectively. The environmental domain scores were 68.8 +/- 13.3,59.0 +/- 12.6 and 53.0 +/- 11.6 ( P < 0.001), respectively. AIS scores were positively correlated with QoL in three domains: physical ( r = 0.549; P < 0.0001), psychological ( r = 0.505; P < 0.0001) and environmental ( r = 0.444; P < 0.0001). In multiple-factor analysis, AI was independent predictors in physical domains (beta = +0.210), psychological domain (beta = +0.402) and environmental domain (beta = +0.204). No correlation or predictive value was found for the social relationship domain, however. Conclusions: Patients on dialysis have moderate-to-low AI. AI is an independent predictor positively correlated with QoL in all domains except for social relationships. The social and psychological support for dialyzed patient might improve their HRQoL and illness acceptance. PMID- 28339524 TI - Chronic illness self-management: a mechanism behind the relationship between neighbourhood social capital and health? AB - Background: Neighbourhood social capital might provide resources that can benefit chronic illness self-management. Improved self-management is a possible mechanism behind the relationship between neighbourhood social capital and health of people with chronic illness. Methods: To test this mechanism, we collected data on self management and self-rated health among a sample of 2091 people with chronic illness in 2013. Data on neighbourhood social capital were collected among 69 336 people in 3425 neighbourhoods between May 2011 and September 2012. A social capital measure was estimated with ecometric measurements. We conducted mediation analyses to examine whether the relationship between neighbourhood social capital and self-rated health was mediated through chronic illness self-management. Results: We found that neighbourhood social capital is related to chronic illness self-management only for people with chronic illness and mild physical disabilities and that, for this group, self-management mediates the relationship between neighbourhood social capital and health. Conclusion: Improved self management is a mechanism behind the relationship between neighbourhood social capital and health for people with chronic illness and mild physical disabilities. It is possible that the self-management support needs of people with chronic illness with moderate or severe physical disabilities cannot be met by the resources provided in neighbourhoods, but more tailored support is necessary. More research is needed to discover mechanisms behind the relationship between neighbourhood social capital and health and elucidate which resources in neighbourhoods can benefit specific groups of people with chronic illness. PMID- 28339525 TI - Cracking the pathogenesis of cocaine-induced vasculitis. PMID- 28339526 TI - Effect of glass markings on drinking rate in social alcohol drinkers. AB - Background: The main aim of these studies was to explore the influence of volume information on glassware on the time taken to consume an alcoholic beverage. Methods: In Study 1, male and female social alcohol consumers ( n = 159) were randomised to drink 12 fl oz of either low or standard strength lager, from either a curved glass marked with yellow tape at the midpoint or an unmarked curved glass, in a between-subjects design. In Study 2, male and female social alcohol consumers ( n = 160) were randomised to drink 12 fl oz of standard strength lager from either a curved glass marked with 1/4, 1/2 and 3/4 volume points or an unmarked curved glass, in a between-subjects design. The primary outcome measure for both studies was total drinking time of an alcoholic beverage. Results: In Study 1, after removing outliers, total drinking time was slower from the glass with midpoint volume marking [mean drinking times (min): 9.98 (marked) vs. 9.55 (unmarked), mean difference = 0.42, 95% CI: -0.90, 1.44]. In Study 2, after removing outliers, total drinking time was slower from the glass with multiple volume marks [mean drinking times: 10.34 (marked) vs. 9.11 (unmarked), mean difference = 1.24, 95% CI: -0.11, 2.59]. However, in both studies confidence intervals were wide and also consistent with faster consumption from marked glasses. Conclusion: Consumption of an alcoholic beverage may be slower when served in glasses with volume information. Replication in larger studies is warranted. PMID- 28339527 TI - Microbial community mapping in intestinal tract of broiler chicken. AB - Domestic chickens are valuable sources of protein associated with producing meat and eggs for humans. The gastrointestinal tract (GIT) houses a large microbial community, and these microbiota play an important role in growth and health of chickens, contributing to the enhancement of nutrient absorption and improvement of the birds' immune systems. To improve our understanding of the chicken intestinal microbial composition, microbiota inhabiting 5 different intestinal locations (duodenum, jejunum, ileum, cecum, and colon) of 42-day-old broiler chickens were detected based on 16S rRNA gene sequence analysis. As a result, 1,502,554 sequences were clustered into 796 operational taxonomic units (OTUs) at the 97% sequence similarity value and identified into 15 phyla and 288 genera. Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, and Cyanobacteria were the major microbial groups and Firmicutes was the dominant phylum in duodenum, jejunum, ileum and colon accounting for > 60% of sequences, while Bacteroidetes was the dominant phylum in cecum (>50% of sequences), but little in the other four gut sections. At the genus level, the major microbial genera across all gut sections were Lactobacillus, Enterococcus, Bacteroides, and Corynebacterium. Lactobacillus was the predominant genus in duodenum, jejunum, and ileum (>35%), but was rarely present in cecum, and Bacteroides was the most dominant group in cecum (about 40%), but rarely present in the other 4 intestinal sections. Differences of microbial composition between the 5 intestinal locations might be a cause and consequence of gut functional differences and may also reflect host selection mediated by innate or adaptive immune responses. All these results could offer some information for the future study on the relationship between intestinal microbiota and broiler chicken growth performance as well as health. PMID- 28339529 TI - FDA Approval of Extended-Release Oxycodone for Children with Severe Pain: A Step Forward. PMID- 28339528 TI - The utility of comprehensive autoantibody testing to differentiate connective tissue disease associated and idiopathic interstitial lung disease subgroup cases. AB - Interstitial lung disease (ILD) comprises many heterogeneous disease groups, the largest being CTD-associated and those labelled as idiopathic out of necessity. The mechanisms causing ILD are poorly understood, but most CTD- and idiopathic ILD cases can respond to immunosuppression, clearly suggesting a pathological role for inflammation. By contrast, corticosteroid immunosuppression causes harm without benefit in the feared idiopathic pulmonary fibrosis, suggesting that inflammation plays little pathological role, and where ILD progresses rapidly to lethal outcome even with anti-fibrotic drug use. Given the treatment response differences apparent between ILD subgroups, and the dangers and costs of corticosteroid and anti-fibrotic drug use, respectively, it has become vital in every ILD patient to make an accurate subgroup diagnosis, to optimize treatment selections. This review discusses why differentiating CTD- and idiopathic-ILD subgroup cases remains so problematic, and why existing comprehensive CTD specific serology would, if generally available, represent an ideal biomarker tool to enhance ILD subgroup diagnostic accuracy. PMID- 28339533 TI - Pneumocystis pneumonia versus rituximab-induced interstitial lung disease in lymphoma patients receiving rituximab-containing chemotherapy. AB - It is difficult to differentiate Pneumocystis pneumonia (PCP) from rituximab induced interstitial lung disease (RILD) in lymphoma patients with diffuse pulmonary infiltrates who are receiving rituximab-containing chemotherapy. Using a clinical scoring system, we aim to differentiate PCP from RILD who are receiving rituximab-containing chemotherapy. We reviewed the medical records of lymphoma patients who had received rituximab-containing chemotherapy between 2012 and 2015 in a tertiary hospital. Among 613 lymphoma patients receiving rituximab containing chemotherapy, 97 (16%) had diffuse pulmonary infiltrates. Of these, 16 (16%) with an alternative diagnosis and 22 (23%) with an indeterminate diagnosis were excluded. Finally, 21 (22%) patients were classified as having PCP and the remaining 38 (39%) as having RILD. Fever, short duration of symptoms (<=5 days), systemic inflammatory response syndrome (SIRS), and severe extent of disease on CT scan (>75%) were more common in patients with PCP than in those with RILD. Clinical scores were determined using the following system: SIRS = score 1, symptom duration <=5 days = score 1, extent of disease on CT >75% = score 4. A score of >=2 differentiated PCP from RILD with 91% sensitivity (95% CI, 70-99) and 71% specificity (95% CI, 54-84). A clinical scoring system based on presence of SIRS, short duration of symptoms, and severe extent of disease on CT scan appears to be useful in differentiation of PCP from RILD. PMID- 28339534 TI - Inactivation of dermatophyte infection by nonthermal plasma on animal model. AB - Superficial fungal infections are a major epidemiological issue with increasing prevalence and are a common global problem. This article describes experimental therapy of superficial fungal skin infection using low-temperature plasma. Groups of guinea pigs were artificially infected with Trichophyton mentagrophytes SK 3286 dermatophyte and treated with plasma produced by a DC cometary discharge with an inserted grid. The course of infection was a week shorter and milder in animals treated by plasma than that in nontreated animals, the significant lowering of dermatophytic germs also occurred in the treated group. The exposure to plasma causes no harm to experimental animals. The results allow for the development of a new dermatophytoses therapy by low temperature plasma treatment. PMID- 28339536 TI - Successful nutrition policy: improvement of vitamin D intake and status in Finnish adults over the last decade. AB - Background: Due to vitamin D intake below recommendation (10 ug/day) and low (<50 nmol/l) serum 25-hydroxycholecalciferol (25(OH)D) concentration in Finnish population, the fortification of liquid dairy products with 0.5 ug vitamin D/100 g and fat spreads with 10 ug/100 g started in Finland in December 2002. In 2010, the fortification recommendation was doubled. The aim of this study was to investigate whether the vitamin D intake and status have improved among Finnish adults as a consequence of these nutrition policy actions. A further aim was to study the impact of vitamin supplement use to the total vitamin D intake. Methods: A cross-sectional survey was conducted every 5 years. The National FINDIET Survey was conducted in Finland as part of the National FINRISK health monitoring study. Dietary data were collected by using a computer-assisted 48-h dietary recall. In 2002, dietary data comprised 2007, in 2007, 1575 and 2012, 1295 working aged (25-64 years) Finns. Results: The mean D-vitamin intake increased from 5 ug/day to 17 ug/day in men and from 3 ug/day to 18 ug/day in women from 2002 to 2012. The most important food sources of vitamin D were milk products, fat spreads and fish dishes. The share of milk products was 39% among younger men and 38% among younger women, and 29% among older men and 28% among older women. Fat spreads covered on average 28% of vitamin D intake, except for younger men for which it covered 23%. Fish dishes provided 28% of vitamin D intake for older men and women, and approximately 18% for younger ones. In January-April 2012, the average serum 25-hydroxycholecalciferol (25(OH)D) concentration for men was 63 nmol/l for men and for women 67 nmol/l for women. Conclusions: The fortification of commonly used foods with vitamin D and vitamin D supplementation seems to be an efficient way to increase the vitamin D intake and the vitamin D status in the adult population. PMID- 28339538 TI - Thalamic Amnesia Accompanying Disruption of Pain Memory: A Case of Right Anterior Thalamic Infarction and a Subsequent Vertebral Compression Fracture. PMID- 28339539 TI - Unique aggregation of conjugated amphotericin B and its interaction with lipid membranes. AB - The purpose of this paper was to investigate the aggregation of amphotericin B (AMB) and AMB-arabinogalactan conjugate (AMB-AGC), and the interactions of these drugs with free and membrane-embedded sterols. Aggregation of AMB and AMB-AGC was studied by circular dichroic (CD) and UV absorbance spectroscopic techniques. The effect of liposomes on the spectra was utilized to investigate the interactions of aggregates with membrane-embedded sterols. Interaction with free sterols was studied by measuring sterols' effect on AMB/AMB-AGC susceptibility test. The results demonstrated that AMB-AGC forms unique aggregates in aqueous solution which differ from those formed by free AMB. Ergosterol and cholesterol embedded in liposomes, affected the CD spectra obtained for both AMB and AMB-AGC, indicating interactions of these sterols with both drugs. Interaction with both cholesterol and ergosterol resulted in an increase of AMB-AGC's minimal inhibitory concentration (MIC) in Candida albicans. In conclusion, AMB-AGC forms unique aggregates in aqueous solution; these aggregates interact with membrane embedded cholesterol and ergosterol and with free sterols. These results indicate that the selectivity of AMB-AGC to fungal cells may not occur due to inability to bind cholesterol but probably as a result of this unique aggregation. Understanding this mechanism may help to develop a safer AMB formulation for therapy. PMID- 28339540 TI - Interventional Pain Management for Sacroiliac Tumors in the Oncologic Population: A Case Series and Paradigm Approach. AB - Introduction: Tumors invading the sacrum and/or ilium often represent incurable metastatic disease, and treatment is targeted toward palliation of symptoms and control of pain. As systemic opioid therapy is frequently inadequate and limited by side effects, a variety of interventional techniques are available to better optimize analgesia. Using six patients as a paradigm for interventional approaches to pain relief, we present a therapeutic algorithm for treating sacroiliac tumor-related pain in the oncologic population. Methods: We describe the use of ultrasound-guided proximal sacroiliac joint corticosteroid injection, sacroiliac lateral branch radiofrequency ablation, percutaneous sacroplasty, and implantable neuraxial drug delivery devices to treat malignant sacroiliac pain in six patients. Pre- and postprocedure numerical rating scale (NRS) pain scores, duration of pain relief, and postprocedure pain medication requirements were studied for each patient. Results: Each patient had marked improvement in their pain based on an average postprocedure NRS difference of six points. The average duration of pain relief was eight months. In all cases, opioid requirements decreased after the intervention. Discussion: Depending on tumor location, burden of disease, and patient preference, patients suffering from metastatic disease to the sacrum may find benefit from use of ultrasound-guided proximal sacroiliac joint corticosteroid injection, sacroiliac lateral branch radiofrequency ablation, percutaneous sacroplasty, dorsal column stimulator leads, and/or implantable neuraxial drug delivery devices. We provide a paradigm for treatment in this patient population. PMID- 28339542 TI - Cervical Epidural Contrast Spread Patterns in Fluoroscopic Antero-Posterior, Lateral, and Contralateral Oblique View: A Three-Dimensional Analysis. AB - Objective: To describe and to analyze cervical epidural contrast patterns seen in antero-posterior (AP), contralateral oblique (CLO), and lateral view. To identify factors that might help in predicting contrast distribution pattern and extent. Method: Spread of contrast in the cervical epidural space was prospectively studied in AP, lateral, and three CLO views. Results: CLO view showed contrast spread of variable thickness with its posterior margin overlying the ventral interlaminar line (VILL). In the lateral view, the spread was also of variable thickness, but the posterior margin of the contrast lay on the spinolaminar line in only 10 of 24 patients. Ventral contrast spread was not visualized in any patient. In the AP view, bilateral spread was seen in 14 of 24 subjects, and nerve root spread was seen in 16 of 24 subjects. No association of the pattern of spread or dispersion was seen to patient age, volume injected, or needle location. Conclusions: The CLO view provides a consistent radiological landmark for the posterior margin of contrast in the dorsal epidural space; the lateral view fails to provide such a consistent landmark. The thickness of the spread is variable, both in the CLO and in the lateral view. Thick spread extending into the foramen in the CLO view and over the articular pillars in the lateral view is frequent and should not be misconstrued as subdural or intrathecal spread. In contradistinction to previous studies, true ventral spread was not seen in any patient. When using low volumes, contrast spread is independent of patient age, volume injected, or needle tip location in the AP view. PMID- 28339543 TI - Climatic factors and prevalence of Campylobacter in commercial broiler flocks in Thailand. AB - Campylobacter are bacteria associated with human foodborne disease worldwide. Poultry and poultry products are generally considered as a main source of these organisms. Compared to temperate zones, baseline information on Campylobacter in tropical regions is limited. Thus, the objectives of the present study were 1) to determine the prevalence of Campylobacter in Thai broiler flocks and 2) to investigate the association between climatic factors (i.e., rainfall, ambient temperature, and relative humidity) and Campylobacter colonization status of broiler flocks in Thailand. A total of 442 commercial broiler flocks reared in the central and northeastern regions of Thailand during 2012 to 2014 were investigated. Campylobacter positive status was identified in 252 examined flocks (57.01%; 95% CI 52.39 to 61.63%). Prevalence of Campylobacter in the northeastern region (54.46%; 95% CI 44.76 to 63.83%) was slightly lower than that of the central region (57.77%; 95% CI 52.47 to 62.90%). More than 65% of Campylobacter positive flocks in the central and northeastern regions had within-flock prevalence higher than 75%. Generalized estimating equations (GEE) revealed that the increased rainfall and relative humidity were associated with the increase of Campylobacter colonization in broiler flocks (P <= 0.05), while no relationship between ambient temperature and Campylobacter colonization status was identified. PMID- 28339545 TI - Left atrial anatomy, atrial fibrillation burden, and P-wave duration relationships and predictors for single-procedure success after pulmonary vein isolation. AB - Aims: Atrial fibrillation (AF) is associated with changes in left atrial (LA) volume, but the relationship between LA size, AF burden, and electrical conduction behaviour is still uncertain. The aim of this study was to quantify the association and impact of these parameters on the single-procedure outcome after circumferential antral ablation for pulmonary vein isolation. Methods and results: Left atrial assessment was performed in 129 consecutive patients using pre-procedural imaging in three dimensions (sphericity, indexed volume), two dimensions (diameters), and from echocardiography in one dimension (long axis). Atrial fibrillation burden was classified based on the clinical assessment as paroxysmal and persistent and based on a validated scoring system including frequency, duration of AF episodes, and number of cardioversions into four grades (minimal, mild, moderate, and severe). P-wave duration and PR interval was measured on the 12-lead electrocardiogram at the end of the procedure. Atrial fibrillation burden score (AFB) was minimal (2%), mild (75%), moderate (9%), and severe (14%) and 65% had paroxysmal and 35% had persistent AF. The recurrence rate was significantly higher in patients with persistent AF, with higher AFB, with prolonged P-wave, and with an indexed LA volume > 55 mL/m2. In multivariable analysis, AFB (hazard ratio: 2.018(1.383-2.945), P > 0.001) and a prolonged P-wave (hazard ratio: 2.612(1.248-5.466), P = 0.011) were identified as significant predictors for AF recurrence. Conclusions: In our cohort of patients with symptomatic AF, the AFB and the P-wave duration but none of the anatomical parameter revealed to be independent predictors for AF/AT recurrence after circumferential antral pulmonary vein isolation. PMID- 28339544 TI - Laxatives Do Not Improve Symptoms of Opioid-Induced Constipation: Results of a Patient Survey. AB - Introduction: Laxatives are commonly used to treat opioid-induced constipation, the commonest and most bothersome complication of opioids. However, laxatives have a nonspecific action and do not target underlying mechanisms of opioid induced constipation; their use is associated with abdominal symptoms that negatively impact quality of life. Objective: To assess the effects of laxatives in patients taking opioids for chronic pain. Methods: One hundred ninety-eight UK patients who had taken opioid analgesics for at least one month completed a cross sectional online or telephone survey. Questions addressed their pain condition, medication, and laxative use (including efficacy and side effects). The survey also assessed bowel function using the Bowel Function Index. Results: Since starting their current opioid, 134 of 184 patients (73%) had used laxatives at some point and 122 (91%) of these were currently taking them. The most common laxatives were osmotics and stimulants. Laxative side effects were reported in 75%, most commonly gas, bloating/fullness, and a sudden urge to defecate. Side effects were more common in patients less than 40 years of age. Approximately half of patients said laxatives interfered with work and social activities, and one-fifth needed an overnight hospital stay because of their pain condition and/or constipation. Laxatives did not improve the symptoms of constipation, as assessed by the Bowel Function Index. Constipation was not related to opioid strength, dose of opioid, or number of laxatives taken. Conclusions: Use of laxatives to treat opioid-induced constipation is often ineffective and associated with side effects. Instead of relieving the burden of opioid-induced constipation, laxative use is associated with a negative impact. PMID- 28339546 TI - Multicentre safety of adding Focal Impulse and Rotor Modulation (FIRM) to conventional ablation for atrial fibrillation. AB - Aims: Focal Impulse and Rotor Modulation (FIRM) uses 64-electrode basket catheters to identify atrial fibrillation (AF)-sustaining sites for ablation, with promising results in many studies. Accordingly, new basket designs are being tested by several groups. We set out to determine the procedural safety of adding basket mapping and map-guided ablation to conventional pulmonary vein isolation (PVI). Methods and results: We collected 30 day procedural safety data in five US centres for consecutive patients undergoing FIRM plus PVI (FIRM-PVI) compared with contemporaneous controls undergoing PVI without FIRM. A total of 625 cases were included in this analysis: 325 FIRM-PVI and 300 PVI-controls. FIRM-PVI patients were more likely than PVI-controls to be male (83% vs. 66%, P < 0.001) and have long-standing persistent AF (26% vs. 13%, P < 0.001) reflecting patients referred for FIRM. Total ablation time was greater for FIRM-PVI (62 +/- 22 min) vs. PVI-controls (52 +/- 18 min, P = 0.03). The complication rate for FIRM-PVI procedures (4.3%) was similar to controls (4.0%, P = 1) for both major and minor complications; no deaths were reported. The rate of complications potentially attributable to the basket catheter was small and did not differ between basket types (Constellation 2.8% vs. FIRMap 1.8%, P = 0.7) or between cases in which basket catheters were and were not used (P = 0.5). Complication rates did not differ between centres (P = 0.6). Conclusions: Procedural complications from the use of the basket catheters for AF mapping are low, and thus procedural safety appears similar between FIRM-PVI and PVI-controls in a large multicentre cohort. Future studies are required to determine the optimal approach to maximize the efficacy of FIRM-guided ablation. PMID- 28339547 TI - Effectiveness of the strengthening families programme 10-14 in Poland: cluster randomized controlled trial. AB - Background: : The Strengthening Families Programme for youth aged 10-14 and parents/carers (SFP10-14) is a family-based prevention intervention with positive results in trials in the United States. We assessed the effectiveness of SFP10-14 for preventing substance misuse in Poland. : Cluster randomized controlled trial with 20 communities (511 families; 614 young people) were allocated to SFP10-14 or a control arms. Primary outcomes were alcohol, smoking and other drug use. Secondary outcomes included parenting practices, parent-child relations, and child problem behaviour. Interview-based questionnaires were administered at baseline and at 12- and 24-months post-baseline, with respective 70.4 and 54.4%, follow-up rates. : In Bayesian regression models with complete case data we found no effects of SFP10-14 for any of the primary or secondary outcomes at either follow-up. For example at 24-months, posterior odds ratios and 95% credible intervals for past year alcohol use, past month binge drinking, past year smoking, and past year other drug use, were 0.83 (0.44-1.56), 0.83 (0.27-2.65), 1.94 (0.76-5.38) and 0.74 (0.15-3.58), respectively. Although moderate to high attrition rates, together with some evidence of systematic attrition bias according to parent education and family disposable income, could have biased the results, the results were supported in further analyses with propensity score matched data and 40 multiple imputed datasets. : We found no evidence for the effectiveness of SFP10-14 on the prevention of alcohol or tobacco use, parenting behaviour, parent-child relations or child problem behaviour at 12- or 24-month follow-up in a large cluster randomized controlled trial in Poland. PMID- 28339548 TI - Enhancement of the antidermatophytic activity of silver nanoparticles by Q switched Nd:YAG laser and monoclonal antibody conjugation. AB - The objective of this research was to investigate the effect of silver nanoparticles (AgNPs), free or conjugated with monoclonal antibody and mediated by Q-switched Nd:YAG laser on five dermatophytes. The laser was applied for 45 s at 532 nm and 0.8 J/cm2. The application of AgNPs combined with laser caused an increase in fungal susceptibility compared to application of AgNPs alone. The MIC50 and MIC100 recorded 3 and 9 MUg/ml in the case of E. floccosum (the most susceptible species), 10 and 19 MUg/ml for T. rubrum (the most tolerant species), respectively. A decrease in keratinase activity reaching 76.1, 67.1, and 62.4% was attained in the case of M. gypseum, T. rubrum, and T. mentagrophyte, respectively, on application of 10 MUg/ml AgNPs combined with Nd:YAG laser. Under the same conditions of application, a steady increase in leaked materials coupled with reduction in ergosterol synthesis was reached. The structural alterations occurred to the fungus were more observed on the application of AgNPs in combination with laser where the conidia and hyphae lost their cellular integrity, become flaccid, permanently destructed, and completely killed. The monoclonal antibody conjugated AgNPs did not result in significant variation in in vitro experiments compared with that produced by nonconjugated nanoparticles. However, the conjugates achieved significantly more curing of M. canis-inoculated guinea pigs compared with nonconjugated nanoparticles. PMID- 28339549 TI - Further investigation of a quantitative trait locus for ascites on chromosome 9 in broiler chicken lines. AB - Previously, we reported a genome wide association study (GWAS) that had shown association of a region between 11.8 and 13.6 Mbp on chromosome 9 with ascites phenotype in broilers. We had used microsatellite loci to demonstrate an association of particular genotypes for this region with ascites in experimental ascites lines and commercial broiler breeder lines. We identified two potential candidate genes, AGTR1 and UTS2D, within that chromosomal region for mediating the quantitative effect. We have now extended our analysis using SNPs for these genes to assess association with resistance or susceptibility to ascites in these same broiler lines. Surprisingly, in contrast to our previous GWAS and microsatellite data for this region, we find no association of the SNP genotypes or haplotypes in the region suggesting that the two genes might have limited association with the disease phenotype. PMID- 28339550 TI - The Tension-sensitive Ion Transport Activity of MSL8 is Critical for its Function in Pollen Hydration and Germination. AB - All cells respond to osmotic challenges, including those imposed during normal growth and development. Mechanosensitive (MS) ion channels provide a conserved mechanism for regulating osmotic forces by conducting ions in response to increased membrane tension. We previously demonstrated that the MS ion channel MscS-Like 8 (MSL8) is required for pollen to survive multiple osmotic challenges that occur during the normal process of fertilization, and that it can inhibit pollen germination. However, it remained unclear whether these physiological functions required ion flux through a mechanically gated channel provided by MSL8. We introduced two point mutations into the predicted pore-lining domain of MSL8 that disrupted normal channel function in different ways. The Ile711Ser mutation increased the tension threshold of the MSL8 channel while leaving conductance unchanged, and the Phe720Leu mutation severely disrupted the MSL8 channel. Both of these mutations impaired the ability of MSL8 to preserve pollen viability during hydration and to maintain the integrity of the pollen tube when expressed at endogenous levels. When overexpressed in an msl8-4 null background, MSL8I711S could partially rescue loss-of-function phenotypes, while MSL8F720L could not. When overexpressed in the wild-type Ler background, MSL8I711S suppressed pollen germination, similar to wild-type MSL8. In contrast, MSL8F720L failed to suppress pollen germination and increased pollen bursting, thereby phenocopying the msl8-4 mutant. Thus, an intact MSL8 channel is required for normal pollen function during hydration and germination. These data establish MSL8 as the first plant MS channel to fulfill previously established criteria for assignment as a mechanotransducer. PMID- 28339551 TI - Anticoagulant and Antiplatelet Management for Spinal Procedures: A Prospective, Descriptive Study and Interpretation of Guidelines. AB - Setting: Epidural hematoma rarely complicates interventional spine procedures. While anticoagulant and antiplatelet drugs increase bleeding risk, cessation may precipitate serious thromboembolic events. The Spine Intervention Society (SIS) and American Society of Regional Anesthesia and Pain Medicine (ASRA) put forth guidelines that dissent with regard to management of hemostatically active agents during commonly performed spinal injections. Objective: To validate an antiplatelet/anticoagulant management table based on modifications of the SIS 2013 and ASRA 2015 guidelines. Design: Prospective descriptive study. Subjects: Patients undergoing interventional spine injections from a interventional physiatrist's practice. Methods: A Modified SIS 2013-ASRA 2015 Antiplatelet & Anticoagulant (MSAAA) guideline table was devised and adopted. Patients undergoing interventional spine procedures were monitored for bleeding events. Results: Of 4,253 injection sites, 197 (4.6%) were performed in 74 patients on antiplatelet/anticoagulants. No clinically evident bleeding events were observed in patients on antiplatelet/anticoagulant medications for lumbar transforaminal epidural (N = 90), posterior-approach facet joint (N = 62), lumbar intradiscal (N = 11), lumbar sympathetic (N = 3), and sacroiliac (N = 5) injections or in 26 radiofrequency neurotomy procedures. One in 2,026 (0.05%, 95% confidence interval = 0.00-0.31%) interlaminar epidural injections (cervical, thoracic, lumbar, and caudal) suffered epidural hematoma. This patient was not on an antiplatelet/anticoagulant drug. No patient in 191 cervicothoracic and 723 lumbar transforaminal injections experienced bleeding complications. Conclusions: Continuing antiplatelet and anticoagulant medications for intermediate- to low risk interventional spine procedures may be advisable. The MSAAA table may be a reasonable guideline reference for managing antiplatelet and anticoagulant drugs. PMID- 28339552 TI - The effectiveness of ID readers and remote age verification in enhancing compliance with the legal age limit for alcohol. AB - Currently, two different age verification systems (AVS) are implemented to enhance compliance with legal age limits for the sale of alcohol in the Netherlands. In this study, we tested the operational procedures and effectiveness of ID readers and remote age verification technology in supermarkets during the sale of alcohol. Following a trained alcohol purchase protocol, eight mystery shoppers (both underage and in the branch's reference age) conducted 132 alcohol purchase attempts in stores that were equipped with ID readers or remote age verification or were part of a control group. In stores equipped with an ID reader, 34% of the purchases were conducted without any mistakes (full compliance). In stores with remote age verification, full compliance was achieved in 87% of the cases. The control group reached 57% compliance, which is in line with the national average. Stores with ID readers perform worse than stores with remote age verification, and also worse than stores without any AVS. For both systems, in addition to effectiveness, public support and user friendliness need to be investigated. This study shows that remote age verification technology is a promising intervention that increases vendor compliance during the sales of age restricted products. PMID- 28339554 TI - Efficacy and safety of antazoline in the rapid cardioversion of paroxysmal atrial fibrillation (the AnPAF Study). AB - Aims: The aim of the study was to assess the clinical efficacy of antazoline, a first-generation anti-histaminic agent, in the rapid conversion of paroxysmal non valvular atrial fibrillation (AF) to sinus rhythm in patients without heart failure. Methods and results: This study was a single center, randomized, double blind, placebo-controlled, superiority clinical trial. We enrolled patients with an AF episode lasting less than 43 h, in stable cardiopulmonary condition. Subjects who fulfilled the selection criteria were randomly assigned to receive intravenously either a placebo or up to 250 mg of antazoline. The primary end point was the conversion of AF to sinus rhythm confirmed in electrocardiogram (ECG). We enrolled 74 patients: 36 (48.6%) in the antazoline group and 38 (51.4%) in the control group. The mean age was 68 +/- 12 years (range 31-90 years), 39 (53.3%) patients were male. The successful conversion of AF to sinus rhythm during the observation period was achieved in 26 (72.2%) patients treated with antazoline and 4 (10.5%) in the control group: RR 6.86 (95% CI: 2.66-17.72, P < 0.0001). Median time to conversion was 16.0 min in antazoline and 72.5 min in the control group (P = 0.0246). There were no cases of atrial tachycardia/flutter in the antazoline group. Conclusion: Intravenous antazoline was effective and safe in the rapid conversion of non-valvular paroxysmal atrial fibrillation to sinus rhythm in patients without heart failure. Clinical Trial Registration number: NCT01527279. PMID- 28339556 TI - Influence of temperature and growth selection on turkey pectoralis major muscle satellite cell adipogenic gene expression and lipid accumulation. AB - p. major: Immature poults have an inefficient thermoregulatory system, and therefore extreme ambient temperatures can impact their internal body temperature. Satellite cells, the only posthatch myonuclei source, are multipotential stem cells and sensitive to temperature. Selection for faster growing, high-yielding birds has altered satellite-cell properties. The objective of the current study was to determine how temperature affects adipogenic properties of satellite cells isolated from the pectoralis major ( ) muscle of Randombred Control line ( ) and F line turkeys selected only for increased 16-wk body weight from the RBC2 line. Satellite cells were cultured at 2 degrees C incremental temperatures between 33 and 43 degrees C and compared to cells cultured at the control temperature of 38 degrees C to ascertain temperature effects on lipid accumulation and expression of adipogenic genes: CCAAT/enhancer binding protein-beta ( ), peroxisome proliferator-activated receptor-gamma ( ), and stearoyl-CoA desaturase ( ). During proliferation, the amount of quantifiable lipid in both F and RBC2 satellite cells increased at temperatures above 38 degrees C ( P < 0.01) and decreased at temperatures below 38 degrees C ( P < 0.01). Above 38 degrees C, RBC2 satellite cells had more lipid ( P = 0.02) compared to the F line, whereas there were few differences between lines below 38 degrees C. At 72 h of proliferation, expression of C/EBPbeta , PPARgamma , and SCD decreased ( P <= 0.02) as temperatures increased from 33 to 43 degrees C in both cell lines. During differentiation expression of C/EBPbeta increased ( P < 0.01) as temperatures increased from 33 to 43 degrees C in both cell lines. In F line satellite cells, PPARgamma expression decreased ( P < 0.01) with increasing temperatures during differentiation, whereas there was no linear trend in RBC2 cells. During differentiation expression of SCD increased as temperatures increased ( P < 0.01) in RBC2 cells, and there was no linear trend within the F line. Results from the current study suggest that environmental temperature can affect p. major satellite cellular fate; however, selection for increased body weight had little impact on these cellular responses. PMID- 28339555 TI - An Item Bank for Abuse of Prescription Pain Medication from the Patient-Reported Outcomes Measurement Information System (PROMIS(r)). AB - Objective: There is a need to monitor patients receiving prescription opioids to detect possible signs of abuse. To address this need, we developed and calibrated an item bank for severity of abuse of prescription pain medication as part of the Patient-Reported Outcomes Measurement Information System (PROMIS (r) ). Methods: Comprehensive literature searches yielded an initial bank of 5,310 items relevant to substance use and abuse, including abuse of prescription pain medication, from over 80 unique instruments. After qualitative item analysis (i.e., focus groups, cognitive interviewing, expert review, and item revision), 25 items for abuse of prescribed pain medication were included in field testing. Items were written in a first-person, past-tense format, with a three-month time frame and five response options reflecting frequency or severity. The calibration sample included 448 respondents, 367 from the general population (ascertained through an internet panel) and 81 from community treatment programs participating in the National Drug Abuse Treatment Clinical Trials Network. Results: A final bank of 22 items was calibrated using the two-parameter graded response model from item response theory. A seven-item static short form was also developed. The test information curve showed that the PROMIS (r) item bank for abuse of prescription pain medication provided substantial information in a broad range of severity. Conclusion: The initial psychometric characteristics of the item bank support its use as a computerized adaptive test or short form, with either version providing a brief, precise, and efficient measure relevant to both clinical and community samples. PMID- 28339557 TI - Deficiency of circulating progenitor cells associated with vascular thrombosis of hemodialysis patients. AB - Background: Hemodialysis (HD) patients have an increased risk of thrombosis. Endothelial progenitor cells (EPCs), which function in vascular repair, are deficient in HD patients. Nonetheless, the relationship between EPC deficiency and thrombosis in HD patients is unknown. Methods: From January 2010 to December 2012, circulating levels of EPCs that were positive for CD34 and kinase insert domain receptor (KDR) were measured in 269 HD patients. Patients received prospective follow-ups at 6-month intervals until May 2015. The primary outcome was the composite of HD access thrombosis and systemic vascular thrombosis. Results: There were 141 thrombotic events, 50 systemic vascular thrombotic events and 116 HD access thrombotic events. We found significantly negative associations between CD34 + KDR + tertile and overall thrombotic events (low: 61%; middle: 56%; high: 40%; P = 0.02), systemic vascular thrombotic events (low: 27%; middle: 18%; high: 10%; P = 0.03) and HD access thrombotic events (low: 52%; middle: 46%; high: 36%; P = 0.02). Univariate analysis indicated that systemic vascular thrombotic events were positively associated with age, diabetes, dyslipidemia, vascular disease history, urea clearance, albumin and C-reactive protein (CRP), and negatively associated with CD34 + KDR + cell count. HD access thrombosis was positively associated with vascular disease history and CRP, and negatively associated with CD34 + KDR + cell count. Multivariate analysis indicated that a low CD34 + KDR + cell count was an independent risk factor for both types of thrombosis. Conclusions: Our study of a population of HD patients showed that a low level of circulating EPCs is associated with thrombosis. PMID- 28339558 TI - Impact of sedation vs. general anaesthesia on percutaneous epicardial access safety and procedural outcomes. AB - Aims: Patient movement while under moderate/deep sedation may complicate percutaneous epicardial access (EpiAcc), mapping and ablation. We sought to compare procedural outcomes in patients undergoing EpiAcc under sedation vs. general anaesthesia (GA) for ablation. Methods and results: Patients undergoing EpiAcc between January 2004 and July 2014 were included. Safety, procedural, and clinical outcomes were compared between patients undergoing EpiAcc under sedation or GA for ventricular tachycardia or premature ventricular complex ablation. Between January 2004 and July 2014, 170 patients underwent EpiAcc (mean age, 53.2 +/- 15.8 years; average ejection fraction, 44.3 +/- 15.3%). The majority (122 [72%] patients) were male. GA was used in 69 (40.6%). There was no difference in route of access (more often anterior, 53.0%) or the rate of successful access (96% overall) between groups. Similarly, the site of ablation (endocardial vs. epicardial vs. combined endocardial/epicardial) was similar between groups. Complications were equally seen between groups-the most frequent event/complication was pericardial effusion, occurring in 10.6% of patients. Finally, procedural and clinical success rates between GA and sedation groups were comparable (93 vs. 91% and 44 vs. 51%, respectively, P > 0.05). Conclusions: Choice of anaesthesia for EpiAcc does not appear to significantly affect safety and procedural or clinical outcomes. For patients in whom anaesthesia may pose increased risk, it is reasonable to obtain epicardial access under sedation. PMID- 28339559 TI - Using a stakeholder-engaged approach to develop and validate electronic clinical quality measures. AB - Objective: To describe the stakeholder-engaged processes used to develop, specify, and validate 2 oral health care electronic clinical quality measures. Materials and Methods: A broad range of stakeholders were engaged from conception through testing to develop measures and test feasibility, reliability, and validity following National Quality Forum guidance. We assessed data element feasibility through semistructured interviews with key stakeholders using a National Quality Forum-recommended scorecard. We created test datasets of synthetic patients to test measure implementation feasibility and reliability within and across electronic health record (EHR) systems. We validated implementation with automated reporting of EHR clinical data against manual record reviews, using the kappa statistic. Results: A stakeholder workgroup was formed and guided all development and testing processes. All critical data elements passed feasibility testing. Four test datasets, representing 577 synthetic patients, were developed and implemented within EHR vendors' software, demonstrating measure implementation feasibility. Measure reliability and validity were established through implementation at clinical practice sites, with kappa statistic values in the "almost perfect" agreement range of 0.80-0.99 for all but 1 measure component, which demonstrated "substantial" agreement. The 2 validated measures were published in the United States Health Information Knowledgebase. Conclusion: The stakeholder-engaged processes used in this study facilitated a successful measure development and testing cycle. Engaging stakeholders early and throughout development and testing promotes early identification of and attention to potential threats to feasibility, reliability, and validity, thereby averting significant resource investments that are unlikely to be fruitful. PMID- 28339560 TI - Temporal trends in renal function and birthweight in Japanese adolescent males (1998-2015). AB - Background: Low birthweight (LBW) is a worldwide public health problem, demonstrating an increasing incidence in developed countries, including Japan. LBW is also a risk factor for later development of chronic kidney disease (CKD). To date, studies have not evaluated the population impacts of increasing LBW rates on renal function. Methods: Estimated glomerular filtration rate (eGFR) was evaluated in 3737 Japanese adolescent males (15-16 years old) using annual cross sectional data over an 18-year period (1998-2015). Results: Between the initial (1998-2003) and final (2010-15) periods of the study, the mean birthweight decreased from 3213.4 +/- 383.8 to 3116.2 +/- 382.3 g and the LBW rate increased from 2.5 to 5.5% (both P <= 0.01). Additionally, the mean eGFR decreased from 105.1 +/- 15.9 to 97.4 +/- 13.8 mL/min/1.73 m2 and the prevalence of mildly reduced renal function (eGFR <= 60- <90 mL/min/1.73 m2) increased from 16.4 to 30.0% (both P <= 0.01), most evident in the LBW group (from 10.3 to 41.7%, P <=0.01). The prevalence of proteinuria also increased significantly. Mildly reduced renal function was significantly associated with LBW [odds ratio (LBW 3000-3999 g) 1.51; 95% confidence interval 1.00-2.55; P = 0.047]. Conclusions: In this population of Japanese adolescents, the frequency of mildly reduced renal function increased as the LBW frequency increased. Our findings may have implications for the broader Japanese population as well as for other populations in which the prevalence of LBW is increasing. PMID- 28339561 TI - Computational Models Used to Assess US Tobacco Control Policies. AB - Introduction: Simulation models can be used to evaluate existing and potential tobacco control interventions, including policies. The purpose of this systematic review was to synthesize evidence from computational models used to project population-level effects of tobacco control interventions. We provide recommendations to strengthen simulation models that evaluate tobacco control interventions. Methods: Studies were eligible for review if they employed a computational model to predict the expected effects of a non-clinical US-based tobacco control intervention. We searched five electronic databases on July 1, 2013 with no date restrictions and synthesized studies qualitatively. Results: Six primary non-clinical intervention types were examined across the 40 studies: taxation, youth prevention, smoke-free policies, mass media campaigns, marketing/advertising restrictions, and product regulation. Simulation models demonstrated the independent and combined effects of these interventions on decreasing projected future smoking prevalence. Taxation effects were the most robust, as studies examining other interventions exhibited substantial heterogeneity with regard to the outcomes and specific policies examined across models. Conclusions: Models should project the impact of interventions on overall tobacco use, including nicotine delivery product use, to estimate preventable health and cost-saving outcomes. Model validation, transparency, more sophisticated models, and modeling policy interactions are also needed to inform policymakers to make decisions that will minimize harm and maximize health. Implications: In this systematic review, evidence from multiple studies demonstrated the independent effect of taxation on decreasing future smoking prevalence, and models for other tobacco control interventions showed that these strategies are expected to decrease smoking, benefit population health, and are reasonable to implement from a cost perspective. Our recommendations aim to help policymakers and researchers minimize harm and maximize overall population-level health benefits by considering the real-world context in which tobacco control interventions are implemented. PMID- 28339562 TI - Characterization of Children With Recurrent Episodes of Stevens Johnson Syndrome. AB - We performed a retrospective chart review for all cases of recurrent Stevens Johnson Syndrome (SJS) from March 2013 to March 2016. Nine children had 29 episodes of SJS or incomplete SJS; all children were male and 8 (88%) were white. Episodes affected mucus membranes with minimal skin involvement. Mycoplasma infections and HLA-B27/-B51 were common. PMID- 28339563 TI - Trauma-Informed Social Work Practice. AB - Social workers frequently encounter clients with a history of trauma. Trauma informed care is a way of providing services by which social workers recognize the prevalence of early adversity in the lives of clients, view presenting problems as symptoms of maladaptive coping, and understand how early trauma shapes a client's fundamental beliefs about the world and affects his or her psychosocial functioning across the life span. Trauma-informed social work incorporates core principles of safety, trust, collaboration, choice, and empowerment and delivers services in a manner that avoids inadvertently repeating unhealthy interpersonal dynamics in the helping relationship. Trauma-informed social work can be integrated into all sorts of existing models of evidence-based services across populations and agency settings, can strengthen the therapeutic alliance, and facilitates posttraumatic growth. PMID- 28339565 TI - Association of cardiac resynchronization therapy with the incidence of appropriate implantable cardiac defibrillator therapies in ischaemic and non ischaemic cardiomyopathy. AB - Aims: Cardiac resynchronization therapy (CRT) reduces the incidence of sudden cardiac death and the use of appropriate implantable cardioverter-defibrillator (ICD) therapies (AICDTs); however, this antiarrhythmic effect is only observed in certain groups of patients. To gain insight into the effects of CRT on ventricular arrhythmia (VA) burden, we compared the incidence of AICDT use in four groups of patients: patients with ischaemic cardiomyopathy vs. non-ischaemic dilated cardiomyopathy (NIDC) and patients implanted with an ICD vs. CRT-ICD. Methods and results: We analysed 689 consecutive patients (mean follow-up 37 +/- 16 months) included in the Umbrella registry, a multicentre prospective registry including patients implanted with ICD or CRT-ICD devices with remote monitoring capabilities in 48 Spanish Hospitals. The primary outcome was the time to first AICDT. Despite a worse clinical risk profile, NIDC patients receiving a CRT-ICD had a lower cumulative probability of first AICDT use at 2 years compared with patients implanted with an ICD [24.7 vs. 41.6%, hazard ratio (HR): 0.49, P = 0.003]; on the other hand, there were no significant differences in the incidence of first AICDT use at 2 years in ischaemic patients (22.6 vs. 21.9%, P = NS). Multivariate analysis confirmed the association of CRT with lower AICDT rates amongst NIDC patients (Adjusted HR: 0.55, CI 95% 0.35-0.87). Conclusions: These data suggest that CRT is associated with significantly lower rates of first AICDT use in NIDC patients, but not in ischaemic patients. This study suggests that ICD patients with NIDC and left bundle branch block experiencing VAs may benefit from an upgrade to CRT-ICD despite being in a good functional class. PMID- 28339566 TI - Progressive obesity alters ovarian insulin, phosphatidylinositol-3 kinase, and chemical metabolism signaling pathways and potentiates ovotoxicity induced by phosphoramide mustard in mice?. AB - Mechanisms underlying obesity-associated reproductive impairment are ill defined. Hyperinsulinemia is a metabolic perturbation often observed in obese subjects. Insulin activates phosphatidylinositol 3-kinase (PI3K) signaling, which regulates ovarian folliculogenesis, steroidogenesis, and xenobiotic metabolism. The impact of progressive obesity on ovarian genes encoding mRNA involved in insulin mediated PI3K signaling and xenobiotic biotransformation [insulin receptor (Insr), insulin receptor substrate 1 (Irs1), 2 (Irs2), and 3 (Irs3); kit ligand (Kitlg), stem cell growth factor receptor (Kit), protein kinase B (AKT) alpha (Akt1), beta (Akt2), forkhead transcription factor (FOXO) subfamily 1 (Foxo1), and subfamily 3 (Foxo3a), microsomal epoxide hydrolase (Ephx1), cytochrome P450 family 2, subfamily E, polypeptide 1 (Cyp2e1), glutathione S-transferase (GST) class Pi (Gstp1) and class mu 1 (Gstm1)] was determined in normal wild-type nonagouti (a/a; lean) and lethal yellow mice (KK.CG-Ay/J; obese) at 6, 12, 18, or 24 weeks of age. At 6 weeks, ovaries from obese mice had increased (P < 0.05) Insr and Irs3 but decreased (P < 0.05) Kitlg, Foxo1, and Cyp2e1 mRNA levels. Interestingly, at 12 weeks, an increase (P < 0.05) in Kitlg and Kit mRNA, pIRS1Ser302, pAKTThr308, EPHX1, and GSTP1 protein level was observed due to obesity, while Cyp2e1 mRNA and protein were reduced. A phosphoramide mustard (PM) challenge increased (P < 0.05) ovarian EPHX1 protein abundance in lean but not obese females. In addition, lung tissue from PM-exposed animals had increased (P < 0.05) EPHX1 protein with no impact of obesity thereon. Taken together, progressive obesity affected ovarian signaling pathways potentially involved in obesity-associated reproductive disorders. PMID- 28339567 TI - Role of biomechanical forces in hyperfiltration-mediated glomerular injury in congenital anomalies of the kidney and urinary tract. AB - Congenital anomalies of the kidney and urinary tract (CAKUT) including solitary kidney constitute the main cause of progressive chronic kidney disease (CKD) in children. Children born with CAKUT develop signs of CKD only during adolescence and do not respond to renin-angiotensin-aldosterone system blockers. Early cellular changes underlying CKD progression to end-stage renal disease by early adulthood are not well understood. The mechanism of maladaptive hyperfiltration that occurs from loss of functional nephrons, including solitary kidney, is not clear. We re-examine the phenomenon of hyperfiltration in the context of biomechanical forces with special reference to glomerular podocytes. Capillary stretch exerts tensile stress on podocytes through the glomerular basement membrane. The flow of ultrafiltrate over the cell surface directly causes fluid flow shear stress (FFSS) on podocytes. FFSS on the podocyte surface increases 1.5 to 2-fold in animal models of solitary kidney and its effect on podocytes is a subject of ongoing research. Podocytes (i) are mechanosensitive to tensile and shear forces, (ii) use prostaglandin E2, angiotensin-II or nitric oxide for mechanoperception and (iii) use specific signaling pathways for mechanotransduction. We discuss (i) the nature of and differences in cellular responses to biomechanical forces, (ii) methods to study biomechanical forces and (iii) effects of biomechanical forces on podocytes and glomeruli. Future studies on FFSS will likely identify novel targets for strategies for early intervention to complement and strengthen the current regimen for treating children with CAKUT. PMID- 28339569 TI - Acrolein Yields in Mainstream Smoke From Commercial Cigarette and Little Cigar Tobacco Products. AB - Introduction: Many carbonyls are produced from the combustion of tobacco products and many of these carbonyls are harmful or potentially harmful constituents of mainstream cigarette smoke. One carbonyl of particular interest is acrolein, which is formed from the incomplete combustion of organic matter and the most significant contributor to non-cancer respiratory effects from cigarette smoke. Sheet-wrapped cigars, also known as "little cigars," are a type of tobacco products that have not been extensively investigated in literature. Methods: This study uses standard cigarette testing protocols to determine the acrolein yields from sheet-wrapped cigars. Sheet-wrapped cigar and cigarette products were tested by derivatizing the mainstream smoke with 2,4-dinitrophenylhydrazine (DNPH) solution and then quantifying the derivatives using conventional analytical systems. Results: The results demonstrate that sheet-wrapped cigars can be tested for acrolein yields in mainstream smoke using the same methods used for the evaluation of cigarettes. The variability in the sheet-wrapped cigars and cigarettes under the International Organization for Standardization smoking regimen is statistically similar at the 95% confidence interval; however, increased variability is observed for sheet-wrapped cigar products under the Health Canada Intense (CI) smoking regimen. Conclusion: The amount of acrolein released by smoking sheet-wrapped cigars can be measured using standard smoking regimen currently used for cigarettes. The sheet-wrapped cigars were determined to yield similar quantity of acrolein from commercial cigarette products using two standard smoking regimens. Implications: This article reports on the measured quantity of acrolein from 15 commercial sheet-wrapped cigars using a validated standard smoking test method that derivatizes acrolein in the mainstream smoke with DNPH solution, and uses Liquid Chromatography/Ultra-Violet Detection (LC/UV) for separation and detection. These acrolein yields were similar to the levels found in the smoke from 35 commercial cigarette products measured in the same manner. Although sheet-wrapped cigar data were slightly more variable than those found for the cigarette data, this article reports that the production of acrolein is similar to cigarettes. The results demonstrate that sheet-wrapped cigars can be tested for acrolein yields in mainstream smoke using the same methods used for the evaluation of cigarettes. PMID- 28339568 TI - Varicella in a Previously Immune Patient With Leukemia. AB - Infection with varicella-zoster virus (VZV) in oncology patients can result in severe disease with an increased risk of morbidity and mortality [1, 2]. Among patients on cancer chemotherapy, only nonimmune persons are considered to be susceptible to varicella [1]. We present a case of varicella in a child with leukemia that occurred despite immunity as defined by 2 doses of varicella vaccine and documentation of positive VZV immunoglobulin G titer before initiation of chemotherapy. PMID- 28339570 TI - Frequency of different electrocardiographic abnormalities in a large cohort of Spanish workers. AB - Aims: Our aim was to describe the electrocardiographic findings of a large sample of Spanish workers from several different employment sectors. Methods and results: Between May 2008 and November 2010, 13 495 consecutive 12-lead resting electrocardiograms (ECGs) were obtained during health examinations of working adults aged 16-74 years in 5 cities in different regions of Spain. Of those, 13 179 ECGs suitable for interpretation were included in this study. All tracings were classified by the same cardiologist, according to the Minnesota Code criteria. The mean age of the sample was 40 years, and 73.4% were male. Frequencies of complete right bundle branch block, complete left bundle branch block, and left ventricular hypertrophy were 1.1, 0.2, and 3.6%, respectively. Major Q wave abnormalities were observed in 1.7% of the subjects, T wave abnormalities in 0.7%, early repolarization in 2.4%, and other ST segment abnormalities in 0.2%. Atrial fibrillation was present in 0.08% of the workers and atrial flutter in 0.02%. Frequencies of the Wolff-Parkinson-White pattern, Brugada pattern, long QT pattern, and short QT pattern were 0.2, 0.068, 0.038, and 0.015%, respectively. Conclusion: This study shows the electrocardiographic findings of a large sample of Spanish workers from several different employment sectors. The frequencies of many ECG patterns related to an adverse prognosis (left ventricular hypertrophy, complete left bundle branch block, T wave abnormalities, ST segment abnormalities, and atrial fibrillation) were low. PMID- 28339573 TI - Augmented H2S production via cystathionine-beta-synthase upregulation plays a role in pregnancy-associated uterine vasodilation. AB - Endogenous hydrogen sulfide (H2S) synthesized via metabolizing L-cysteine by cystathionine-beta-synthase (CBS) and cystathionine-gamma-lyase (CSE) is a potent vasodilator and angiogenic factor. The objectives of this study were to determine if human uterine artery (UA) H2S production increases with augmented expression and/or activity of CBS and/or CSE during the menstrual cycle and pregnancy and whether exogenous H2S dilates UA. Uterine arteries from nonpregnant (NP) premenopausal proliferative (pPRM) and secretory (sPRM) phases of the menstrual cycle and pregnant (P) women were studied. H2S production was measured by the methylene blue assay. CBS and CSE mRNAs were assessed by quantitative real-time PCR, and proteins were assessed by immunoblotting and semiquantitative immunofluorescence microscopy. Effects of H2S on rat UA relaxation were determined by wire myography ex vivo. H2S production was greater in NP pPRM and P than NP sPRM UAs and inhibited by the specific CBS but not CSE inhibitor. CBS but not CSE mRNA and protein were greater in NP pPRM and P than NP sPRM UAs. CBS protein was localized to endothelium and smooth muscle and its levels were in a quantitative order of P >NP UAs of pPRM>sPRM. CSE protein was localized in UA endothelium and smooth muscle with no difference among groups. A H2S donor relaxed P > NP UAs but not mesentery artery. Thus, human UA H2S production is augmented with endothelium and smooth muscle CBS upregulation, contributing to UA vasodilation in the estrogen-dominant physiological states in the proliferative phase of the menstrual cycle and pregnancy. PMID- 28339571 TI - Depression Among Non-Daily Smokers Compared to Daily Smokers and Never-Smokers in the United States: An Emerging Problem. AB - Introduction: Depression is strongly associated with daily smoking. Yet, little is known about the association between depression and non-daily smoking. The aim of this study was to investigate the prevalence of past-year depression and changes in past-year depression over time among non-daily smokers, compared to daily smokers and never-smokers, overall and stratified by age, gender, income, nicotine dependence, and cigarettes per day. Methods: Data were drawn from the National Household Survey on Drug Use (NSDUH), an annual cross-sectional study of persons aged 12 and over (total study population N = 496 805). The prevalence of past-year depression was examined annually among non-daily smokers, daily smokers, and never-smokers from 2005 to 2013 using linear trend analyses. Results: Past-year depression was common among 10.10% of non-daily smokers, common among 10.78% of daily smokers, and 5.51% of never-smokers in 2013. The prevalence of depression increased from 2005 to 2013 among non-daily smokers (9.06% vs. 10.10%; p = .034) while there was no significant change in depression over time among daily smokers. Increases in depression among non-daily smokers occurred for both men and women and appear most pronounced youth, those smoking fewer cigarettes, and those without nicotine dependence. Conclusions: The prevalence of depression among non-daily smokers was equivalent to daily smokers and nearly twice that among nonsmokers. Depression appears to be increasing over time in non-daily smokers especially among youth, those who smoke less, and those without nicotine dependence. More work on the mental health of non-daily smokers is needed as this is an increasing and understudied group. Implications: This is the first study to investigate changes in the prevalence of depression among non daily smokers compared to daily smokers and never-smokers over the past decade in a nationally representative sample of the United States. The results suggest an increase in depression among non-daily smokers over time that did not similarly occur for daily smokers. Further, there were several subgroups of non-daily smokers among whom depression has increased more rapidly. This study suggests the need for more information about the relationship between depression and non-daily smoking including the impact of depression on quit attempts and outcomes. PMID- 28339574 TI - Arm Paralysis After Routine Childhood Vaccinations: Application of Advanced Molecular Methods to the Causality Assessment of an Adverse Event After Immunization. AB - Post-licensure surveillance for adverse events following immunizations (AEFI) can identify rare complications of vaccinations and rigorous vaccine adverse event causality assessments can help to identify possible causal relationships. We report the development of arm paralysis after varicella vaccination in a 1-year old child. Paralysis was initially presumed to be due to vOka because of the temporal relationship between vaccination and onset of arm weakness; however, molecular studies identified wild-type varicella zoster virus VZV (WT-VZV) in the CSF, leading the authors to conclude that WT-VZV was the probable cause. This case illustrates the complexity of assessing AEFI causality, and the importance of careful and complete evaluations when determining the most likely cause of an AEFI. PMID- 28339575 TI - Histaminergic Neurotransmission as a Gateway for the Cognitive Effect of Oleoylethanolamide in Contextual Fear Conditioning. AB - Background: The integrity of the brain histaminergic system is necessary for the unfolding of homeostatic and cognitive processes through the recruitment of alternative circuits with distinct temporal patterns. We recently demonstrated that the fat-sensing lipid mediator oleoylethanolamide indirectly activates histaminergic neurons to exerts its hypophagic effects. The present experiments investigated whether histaminergic neurotransmission is necessary also for the modulation of emotional memory induced by oleoylethanolamide in a contextual fear conditioning paradigm. Methods: We examined the acute effect of i.p. administration of oleoylethanolamide immediately posttraining in the contextual fear conditioning test. Retention test was performed 72 hours after training. To test the participation of the brain histaminergic system in the cognitive effect of oleoylethanolamide, we depleted rats of brain histamine with an i.c.v. injection of alpha-fluoromethylhistidine (a suicide inhibitor of histidine decarboxylase) or bilateral intra-amygdala infusions of histamine H1 or H2 receptor antagonists. We also examined the effect of oleoylethanolamide on histamine release in the amygdala using in vivo microdialysis. Results: Posttraining administration of oleoylethanolamide enhanced freezing time at retention. This effect was blocked by both i.c.v. infusions of alpha fluoromethylhistidine or by intra-amygdala infusions of either pyrilamine or zolantidine (H1 and H2 receptor antagonists, respectively). Microdialysis experiments showed that oleoylethanolamide increased histamine release from the amygdala of freely moving rats. Conclusions: Our results suggest that activation of the histaminergic system in the amygdala has a "permissive" role on the memory enhancing effects of oleoylethanolamide. Hence, targeting the H1 and H2 receptors may modify the expression of emotional memory and reduce dysfunctional aversive memories as found in phobias and posttraumatic stress disorder. PMID- 28339576 TI - A Descriptive Report of Electronic Cigarette Use After Participation in a Community-Based Tobacco Cessation Trial. AB - Introduction: Smokers are using electronic cigarettes, also known as e cigarettes, as a cessation aid, despite uncertainty about their efficacy. This report describes the association between use of e-cigarettes before and after cessation treatment and tobacco abstinence at 12 months. It also presents characteristics of e-cigarette users and reasons for use. Methods: A longitudinal observational secondary analysis of self-reported e-cigarette use was conducted among adult Appalachian smokers enrolled in a community-based tobacco dependence treatment trial (n = 217). Data were collected at baseline, 3, 6, and 12 months following treatment. The primary outcome measure was biochemically-confirmed 7 day point prevalence tobacco abstinence at 12 months post-treatment. Results: One in five participants reported using e-cigarettes post-treatment. Baseline sociodemographic and tobacco-related characteristics did not differ by e cigarette use. Primary reasons for e-cigarette use included help in quitting, help in cutting down on cigarettes, and not as bad for health. At the 12 month follow-up, tobacco abstinence was significantly lower among post-treatment e cigarette users (4.7%) than nonusers (19.0%); (OR = 0.21 95% CI: 0.05-0.91, p = .021). Baseline use was not associated with 12-month abstinence. Conclusions: Among adult Appalachian smokers enrolled in community-based tobacco cessation treatment, use of e-cigarettes post-treatment was associated with lower abstinence rates at 12 months. Implications: This descriptive report of electronic cigarette use after participation in a community-based group randomized tobacco dependence treatment trial adds to the body of science examining e-cigarette use and cessation. Post-treatment e-cigarette use was associated with less success in achieving abstinence at 12 months, as compared to nonuse. At 3 months post-treatment, the majority of those who reported use of e cigarettes did so to assist with cessation. PMID- 28339577 TI - Cardiac resynchronization therapy for patients with cardiac sarcoidosis. AB - Aims: Sarcoidosis with cardiac involvement is a rare pathological condition, and therefore cardiac resynchronization therapy (CRT) for patients with cardiac sarcoidosis is even further rare. We aimed to clarify the clinical features of patients with cardiac sarcoidosis who received CRT. Methods and results: We retrospectively reviewed the clinical data on CRT at three cardiovascular centres to detect cardiac sarcoidosis patients. We identified 18 (8.9%) patients with cardiac sarcoidosis who met the inclusion criteria out of 202 with systolic heart failure who received CRT based on the guidelines. The majority of the patients were female [15 (83.3%)] and underwent an upgrade from a pacemaker or implantable cardioverter defibrillator [13 (72.2%)]. We found 1 (5.6%) cardiovascular death during the follow-up period (mean +/- SD, 4.7 +/- 3.0 years). Seven (38.9%) patients had a composite outcome of cardiovascular death or hospitalization from worsening heart failure within 5 years after the CRT. Twelve (66.7%) patients had a history of sustained ventricular arrhythmias or those occurring after the CRT. Among the overall patients, no significant improvement was found in either the end-systolic volume or left ventricular ejection fraction (LVEF) 6 months after the CRT. A worsening LVEF was, however, more likely to be seen in 5 (27.8%) patients with ventricular arrhythmias after the CRT than in those without (P = 0.04). An improved clinical composite score was seen in 10 (55.6%) patients. Conclusions: Cardiac sarcoidosis patients receiving CRT may have poor LV reverse remodelling and a high incidence of ventricular arrhythmias. PMID- 28339578 TI - Safe automatic one-lead electrocardiogram analysis in screening for atrial fibrillation. AB - Aims: Screening for atrial fibrillation (AF) using intermittent electrocardiogram (ECG) recordings can identify individuals at risk of AF-related morbidity in particular stroke. We aimed to validate the performance of an AF screening algorithm compared with manual ECG analysis by specially trained nurses and physicians (gold standard) in 30 s intermittent one-lead ECG recordings. Methods and results: The STROKESTOP study is a mass-screening study for AF using intermittent ECG recordings. All individuals in the study without known AF registered a 30-s ECG recording in Lead I two times daily for 2 weeks, and all ECGs were manually interpreted. A computerized algorithm was used to analyse 80 149 ECG recordings in 3209 individuals. The computerized algorithm annotated 87.1% (n = 69 789) of the recordings as sinus rhythm/minor rhythm disturbances. The manual interpretation (gold standard) was that 69 758 ECGs were normal, making the negative predictive value of the algorithm 99.9%. The number of ECGs requiring manual interpretation in order to find one pathological ECG was reduced from 288 to 35. Atrial fibrillation was diagnosed in 84 patients by manual interpretation, in all of whom the algorithm indicated pathology. On an ECG level, 278 ECGs were manually interpreted as AF, and of these the algorithm annotated 272 ECGs as pathological (sensitivity 97.8%). Conclusion: Automatic ECG screening using a computerized algorithm safely identifies normal ECGs in Lead I and reduces the need for manual evaluation of individual ECGs with >85% with 100% sensitivity on an individual basis. PMID- 28339579 TI - Left univentricular pacing for cardiac resynchronization therapy. AB - This review describes the rationale and published evidence for left univentricular pacing for cardiac resynchronization therapy, gives an overview of the existing optimization algorithms featuring this mode, and discusses future perspectives. PMID- 28339580 TI - The integration of orthodontic miniscrews under mechanical loading: a pre clinical study in rabbit. AB - Introduction: Orthodontic miniscrews are an increasingly popular choice to achieve absolute anchorage. The temporary use of miniscrews and their recent introduction have limited the debate over the biological aspect of the materials to that of the surface that permeates the field of dental implants. The aim of the present study was to investigate the integration of grade 5 titanium mini implants with machined or sand blasted acid etched surface (SAE) under mechanical load in a rabbit tibia model of implant integration. Methods: A total of 64 miniscrews (Ti6Al4V) of 1.5 mm diameter and 6.5 mm length were inserted in the proximal medial surface of each tibia in eight male rabbits aged 6 months. Each tibia received four miniscrews. A 100 g nickel-titanium coil spring (Neosentalloy) was applied between two miniscrews along the main axis while two miniscrews were left unloaded. The removal torque was measured for loaded and unloaded miniscrews after 12 weeks. Two miniscrews were harvested for histology. Results: Removal torque was significantly higher for SAE mini-implants than for machined screws, under both loading conditions. Although no difference in bone to implant contact was observed among the groups, cortical area significantly decreased with both surfaces under loading. Conclusions: Our data indicate that SAE miniscrews have higher bone retention than MA miniscrews, although the effects of mechanical loading of these devices on cortical bone require further investigations. PMID- 28339581 TI - Rationale and design of the BUDAPEST-CRT Upgrade Study: a prospective, randomized, multicentre clinical trial. AB - Aims: There is lack of conclusive evidence from randomized clinical trials on the efficacy and safety of upgrade to cardiac resynchronization therapy (CRT) in patients with implanted pacemakers (PM) or defibrillators (ICD) with reduced left ventricular ejection fraction (LVEF) and chronic heart failure (HF). The BUDAPEST CRT Upgrade Study was designed to compare the efficacy and safety of CRT upgrade from conventional PM or ICD therapy in patients with intermittent or permanent right ventricular (RV) septal/apical pacing, reduced LVEF, and symptomatic HF. Methods and results: The BUDAPEST-CRT study is a prospective, randomized, multicentre, investigator-sponsored clinical trial. A total of 360 subjects will be enrolled with LVEF <= 35%, NYHA functional classes II-IVa, paced QRS >= 150 ms, and a RV pacing >= 20%. Patients will be followed for 12 months. Randomization is performed in a 3:2 ratio (CRT-D vs. ICD). The primary composite endpoint is all-cause mortality, a first HF event, or less than 15% reduction in left ventricular (LV) end-systolic volume at 12 months. Secondary endpoints are all-cause mortality, all-cause mortality or HF event, and LV volume reduction at 12 months. Tertiary endpoints include changes in quality of life, NYHA functional class, 6 min walk test, natriuretic peptides, and safety outcomes. Conclusion: The results of our prospective, randomized, multicentre clinical trial will provide important information on the role of cardiac resynchronization therapy with defibrillator (CRT-D) upgrade in patients with symptomatic HF, reduced LVEF, and wide-paced QRS with intermittent or permanent RV pacing. Clinical trials.gov identifier: NCT02270840. PMID- 28339583 TI - Association of pre-ablation level of vitamin D with atrial fibrillation recurrence after catheter ablation. PMID- 28339582 TI - Hypoxia in the glioblastoma microenvironment: shaping the phenotype of cancer stem-like cells. AB - Glioblastoma is the most common and aggressive malignant primary brain tumor. Cellular heterogeneity is a characteristic feature of the disease and contributes to the difficulty in formulating effective therapies. Glioma stem-like cells (GSCs) have been identified as a subpopulation of tumor cells that are thought to be largely responsible for resistance to treatment. Intratumoral hypoxia contributes to maintenance of the GSCs by supporting the critical stem cell traits of multipotency, self-renewal, and tumorigenicity. This review highlights the interaction of GSCs with the hypoxic tumor microenvironment, exploring the mechanisms underlying the contribution of GSCs to tumor vessel dynamics, immune modulation, and metabolic alteration. PMID- 28339584 TI - Prosthesis depth and conduction disturbances after last generation balloon expandable transcatheter aortic valve implantation. AB - Aims: Preliminary data on Sapien 3 valve (S3-THV) use for transcatheter aortic valve implantation have shown an increased permanent pacemaker implantation (PPMI) rate with respect to Sapien XT valve. Aim of this study was to investigate the role of S3-THV position in the left ventricular outflow tract (LVOT) on electrocardiographic changes suggestive of atrioventricular (DeltaPR) and/or intraventricular (DeltaQRS) conduction abnormalities and 30 days PPMI rate. Methods and results: Eighty-six consecutive patients treated with S3-THV were included in the study. All patients underwent clinical and electrocardiogram evaluation. Left ventricular outflow tract prosthesis depth was assessed by fluoroscopy and expressed quantitatively (mm) and as aorto-ventricular ratio (AVR). Eight patients (9.3%) needed PPMI at 30 days. A low AVR (<=60/40) predicted PPMI (OR = 6.09, 95% CI 1.19-31.01, P = 0.030) and resulted into higher PPMI rate, compared with higher AVR (30.0 vs. 6.6%, P = 0.017). For each millimetre increase in the LVOT prosthesis depth PPMI risk increased by 1.41 times (95% CI 1.06-1.87, P = 0.017). In patients with low AVR, DeltaPR was higher than in those with higher AVR (33.4 +/- 56.7 vs. 12.1 +/- 19.4 ms, P = 0.021) and DeltaPR was associated to LVOT prosthesis depth (beta = 0.286, P = 0.009). Furthermore, DeltaPR was associated with risk of PPMI (OR = 1.03, 95% CI 1.01 1.06, P = 0.024). Conclusions: A low AVR is associated to higher DeltaPR and PPMI rates. The correlation between LVOT prosthesis depth with DeltaPR and higher PPMI rate suggests the need of a careful S3-THV implantation. PMID- 28339585 TI - Success and complication rates of lead extraction with the first- vs. the second generation Evolution mechanical sheath. AB - Aims: The Evolution sheath (Cook Medical, USA) is a power sheath frequently used for chronic lead extraction. In 2013, a novel type (bidirectional) of Evolution sheath (the RL type) was introduced. We evaluated differences in success and complication rates of the two types. Methods and results: From 2009 to 2015, all lead extractions requiring the use of an Evolution sheath were prospectively examined. According to the current guidelines, complete procedural success was defined as the removal of all targeted lead materials. Clinical success was the retention of a small portion of the lead, and failure was the inability to achieve either complete procedural or clinical success or the development of any permanently disabling complication. The Evolution sheath was used to extract 149 leads in 103 patients. The first 56 leads were extracted with the original unidirectional sheath, and 93 leads were extracted with the novel bidirectional R/L type. The median age of the lead at the time of extraction was 6.8 vs. 9.1 years (P = 0.007). Complete procedural success was higher for the Evolution R/L (80.0 vs. 98%, P = 0.0004). Clinical success rate was 98 vs. 99%. There were no major complications and 6 (12.0%) vs. 2 (3.8%) minor complications (P = 0.153). We did not observe changes in success rates or complications over time, meaning that the difference cannot be explained by learning curve. Conclusion: Use of the novel Evolution R/L sheath vs. the original Evolution sheath was associated with significant higher complete success rates, without major complications and with a trend towards the reduction of minor complications. PMID- 28339586 TI - Framing Tobacco Dependence as a "Brain Disease": Implications for Policy and Practice. AB - Introduction: Like other forms of drug dependence, tobacco dependence is increasingly being described as a "chronic brain disease." The potential consequences of this medical labelling have been examined in relation to other addictions, but the implications for tobacco control have been neglected. Some have posited that biomedical conceptions of addiction will reduce stigma and increase uptake of efficacious treatments. Others have countered that it could increase stigma, reduce treatment seeking, and deter unassisted quitting. We explored how smokers respond to the labelling of smoking as a brain disease. Methods: Semi-structured interviews with 29 Australian smokers recruited using purposive sampling. Thematic analysis was used to analyze the results. Results: Most participants questioned the accuracy of the brain disease label as applied to smoking. They believed that smoking was not a chronic disease because they perceived smoking to be an individual's choice. In addition, many believed that this label would increase the stigma that they already felt and, did not want to adopt a "sick role" in relation to their smoking. Conclusions: Describing smoking as a brain disease is more likely to alienate smokers than to engage them in quitting. The application of overly medical labels of smoking are inconsistent with smokers own conceptualizations of their smoking, and may have unintended consequences if they are widely disseminated in healthcare settings or antismoking campaigns. Implications: The participants in this project believed that biomedical labels of smoking as a "brain disease" or a "chronic disease" were discordant their existing understandings of their smoking. Explanations of addiction that downplay or ignore the role of choice and autonomy risk being perceived as irrelevant by smokers, and could lead to suspicion of health professionals or an unwillingness to seek treatment. PMID- 28339587 TI - Incisor inclination and perceived tooth colour changes. AB - Introduction: Social attractiveness is influenced by a variety of different smile related factors. We evaluated whether the degree of upper central incisor proclination can result in tooth colour change. Methods: Forty young adult subjects (20-25 years) in good health with a complete sound dentition were selected. The subjects were seated in standardized light conditions with an above directed light source. Their natural head position was stated as 0 degrees. To mimic the range of possible anterior torque movements they were asked to tilt their heads upward +15 degrees (upward tilting) and downward -15 degrees (downward tilting). Frontal macro photographs, parallel to the Frankfort plane of the patient's natural head position were taken at the three head angulations (+15, 0, and -15 degrees ). Photographs were analysed for colour differences at the centre of the incisor clinical crowns with a CIE L*a*b* colour model based software. A paired t-test was used to test for significance between each value for each inclination. Results: Differences were found between the CIE L*a*b* colour values for: upward tilting, downward tilting, and -15 to +15 degrees (total tilting) except for b* values for downward tilting. As the inclination of the subject's head changed downward, the upper incisors were retroclined and the CIE L*a*b* values indicated a darker and less green but redder colour component. As the inclination of the subject's head changed upwards the upper incisors were proclined and the L*a*b* values indicated a lighter and less green and yellow but redder and bluer colour component. Conclusions: Proclination of upper incisors caused lighter tooth colour parameters compared to retroclined incisors and colour changes. Orthodontic change of upper incisor inclination may induce alterations on how tooth colour is perceived. PMID- 28339589 TI - The clinical value of T-wave alternans derived from Holter monitoring. AB - Microvolt-level T-wave alternans (TWA) assessed by spectral method during an exercise stress test has been widely studied for risk stratification. Several studies have documented the association of a positive TWA with total mortality and arrhythmic events. Nevertheless, the need to achieve an elevated and stabilized heart rate resulting in a considerable proportion of indeterminate test results constitutes one of the main limitations of this method. It is well recognized that arrhythmic events may be triggered not only by physical but also by mental stress and are not necessarily associated with exercise. Detection of TWA in ambulatory electrocardiogram recordings during daily activities might be a valuable option in risk stratification. This review describes the modified moving average (MMA) technique for detection of TWA and summarizes the results of clinical studies on the prognostic value of MMA-TWA. So far, MMA-TWA has been studied in over 5000 patients including those evaluated during exercise as well as during daily activities with ambulatory ECG recordings. The results of these studies indicate that increased MMA-TWA is associated with higher risk of cardiac mortality and arrhythmic events. PMID- 28339588 TI - MRI features predict survival and molecular markers in diffuse lower-grade gliomas. AB - Background: Previous studies have shown that MR imaging features can be used to predict survival and molecular profile of glioblastoma. However, no study of a similar type has been performed on lower-grade gliomas (LGGs). Methods: Presurgical MRIs of 165 patients with diffuse low- and intermediate-grade gliomas (histological grades II and III) were scored according to the Visually Accessible Rembrandt Images (VASARI) annotations. Radiomic models using automated texture analysis and VASARI features were built to predict isocitrate dehydrogenase 1 (IDH1) mutation, 1p/19q codeletion status, histological grade, and tumor progression. Results: Interrater analysis showed significant agreement in all imaging features scored (k = 0.703-1.000). On multivariate Cox regression analysis, no enhancement and a smooth non-enhancing margin were associated with longer progression-free survival (PFS), while a smooth non-enhancing margin was associated with longer overall survival (OS) after taking into account age, grade, tumor location, histology, extent of resection, and IDH1 1p/19q subtype. Using logistic regression and bootstrap testing evaluations, texture models were found to possess higher prediction potential for IDH1 mutation, 1p/19q codeletion status, histological grade, and progression of LGGs than VASARI features, with areas under the receiver-operating characteristic curves of 0.86 +/- 0.01, 0.96 +/- 0.01, 0.86 +/- 0.01, and 0.80 +/- 0.01, respectively. Conclusion: No enhancement and a smooth non-enhancing margin on MRI were predictive of longer PFS, while a smooth non-enhancing margin was a significant predictor of longer OS in LGGs. Textural analyses of MR imaging data predicted IDH1 mutation, 1p/19q codeletion, histological grade, and tumor progression with high accuracy. PMID- 28339591 TI - Comparison of the force levels among labial and lingual self-ligating and conventional brackets in simulated misaligned teeth. AB - Background/objective: The aim of this study was to evaluate force levels exerted by levelling arch wires with labial and lingual conventional and self-ligating brackets. Materials/methods: The tested orthodontic brackets were of the 0.022-in slot size for labial and 0.018-in for lingual brackets and were as follows: 1. Labial brackets: (i) conventional bracket (GAC-Twin, Dentsply), (ii) passive self ligating (SL) brackets (Damon-Q(r), ORMCO; Ortho classic H4TM, Orthoclassic; FLI(r)SL, Rocky Mountain Orthodontics) and (iii) active SL brackets (GAC In Ovation(r)C, DENTSPLY and SPEEDTM, Strite). 2. Lingual brackets: (i) conventional brackets (Incognito, 3M and JoyTM, Adenta); (ii) passive SL bracket (GAC In Ovation(r)LMTM, Dentsply and (iii) active SL bracket (Evolution SLT, Adenta). Thermalloy-NiTi 0.013-in and 0.014-in arch wires (Rocky Mountain Orthodontics) were used with all brackets. The simulated malocclusion represented a maxillary central incisor displaced 2 mm gingivally (x-axis) and 2 mm labially (z-axis). Results: Lingual bracket systems showed higher force levels (2.4 +/- 0.2 to 3.8 +/- 0.2 N) compared to labial bracket systems (from 1.1 +/- 0.1 to 2.2 +/- 0.4 N). However, the differences between SL and conventional bracket systems were minor and not consistent (labial brackets: 1.2 +/- 0.1 N for the GAC Twin and 1.1 +/- 0.1 to 1.6 +/- 0.1 N for the SL brackets with 0.013-in thermalloy; lingual brackets: 2.5 +/- 0.2 to 3.5 +/- 0.1 N for the conventional and 2.7 +/- 0.3 to 3.4 +/- 0.1 N for the SL brackets with 0.013-in Thermalloy). Limitations: This is an in vitro study with different slot sizes in the labial and lingual bracket systems, results should be interpreted with caution. Conclusions/implications: Lingual bracket systems showed higher forces compared to labial bracket systems that might be of clinical concern. We recommend highly flexible nickel titanium arch wires lower than 0.013-in for the initial levelling and alignment especially with lingual appliances. PMID- 28339590 TI - Reducing Antimicrobial Use in an Academic Pediatric Institution: Evaluation of the Effectiveness of a Prospective Audit With Real-Time Feedback. AB - Introduction: Antimicrobial use is decreasing across freestanding children's hospitals, predominantly in institutions with antimicrobial stewardship programs (ASPs) in place. A highly effective ASP should effect a greater decrease in use than predicted by existing trends. Antimicrobial stewardship programs depend on clinician adherence to program recommendations, but little is known about factors associated with adherence. Methods: Parenteral antimicrobial-use data for our institution and 43 additional freestanding children's hospitals were obtained and normalized for patient census. Segmental linear regression was used to compare rates of change of parenteral antimicrobial use before and after ASP implementation. Time-series models were developed to predict use in the absence of intervention. The odds of adherence to ASP recommendations were determined based on provider characteristics and recommendation type. Results: In the 38 months before ASP implementation, parenteral antimicrobial use was decreasing at our hospital by 3.7%/year, similar to the 3.4%/year found across children's hospitals. The rate of change after implementation of the ASP at our hospital was 11.1%/year, compared to 5.6%/year for other hospitals over the same period. Of 643 interventions, teams adhered with recommendations in 495 cases (77.0%). According to adjusted analysis, primary service was not associated with adherence (P = .356). There was an association between adherence and the role of the clinician receiving a recommendation (P = .009) and the recommendation type (P = .009). Conclusions: Understanding factors associated with adherence to ASP recommendations can help those who administer such programs to strategize interventions for maximizing efficacy. Our findings reveal the value of a formal ASP in reducing use when controlling for secular trends. PMID- 28339592 TI - Active Collaboration with Clients: An Underemphasized but Vital Part of Evidence Based Practice. AB - Evidence-based practice (EBP) is a widely recognized concept in contemporary social work practice. However, recent studies have shown that social workers do not understand EBP correctly. Standardized administrative approaches to implementing EBP have led to confusion about its core practice decision-making process. This collaborative process is the heart of EBP in direct social work practice. This article explores the EBP process and addresses a vital but often underemphasized step of EBP: active collaboration with the client in decision making. Active collaboration with the client is shown to be important in that it (a) is consistent with social work's professional values and ethics, (b) is consistent with patient-centered health care in the Patient Protection and Affordable Care Act and contemporary health care approaches, (c) is consistent with culturally competent practice, and (d) has empirical support for its beneficial impact. Correctly and fully understanding EBP in direct practice is important to improving social work practice and improving client outcomes. PMID- 28339594 TI - In vivo development of fluconazole resistance in serial Cryptococcus gattii isolates from a cat. AB - Elevated fluconazole minimum inhibitory concentrations (MICs) are more frequently observed in Cryptococcus gattii compared to C. neoformans isolates; however, the development of in vivo resistance and the molecular mechanisms responsible have not been reported for this species. We report a case of Cryptococcus gattii (molecular type VGIII) that developed reduced susceptibility to fluconazole during therapy and delineate the molecular mechanisms responsible. Multilocus sequence typing and quantitative DNA analysis of the pre- and post-treatment isolates was performed using well-characterized methods. Pre- and post-treatment clinical isolates were confirmed isogenic, and no differences in ERG11 or PDR11 sequences were found. qPCR found an overexpression of ERG11 and the efflux pump PDR11 in the resistant isolate compared to the isolate collected prior to initiation of antifungal therapy. Reversion to wild-type susceptibility was observed when maintained in antifungal-free media confirming the in vivo development of heteroresistance. The in vivo development of heteroresistance to fluconazole in our patient with C. gattii is secondary to overexpression of the efflux pump PDR11 and the drug target ERG11. Additional work in other clinical isolates with elevated fluconazole MICs is warranted to evaluate the frequency of heteroresistance versus point mutations as a cause of resistance. PMID- 28339593 TI - Selective Pharmacological Augmentation of Hippocampal Activity Produces a Sustained Antidepressant-Like Response without Abuse-Related or Psychotomimetic Effects. AB - Background: Selective augmentation of hippocampal activity in ways similar to that caused by ketamine may have therapeutic advantages over ketamine, which has psychotomimetic and reinforcing effects likely due to effects outside the hippocampus (i.e., off-target effects). Methods: Here we evaluated the antidepressant-like response to a negative allosteric modulator of alpha5 subunit containing gamma aminobutyric acid subtype A receptors, L-655,708, as these receptors are expressed to a much greater extent in the hippocampus than in other brain areas. Results: Systemic administration of L-655,708 produced a sustained antidepressant-like effect in the forced swim test that was comparable with that of ketamine and was blocked by hippocampal inactivation with lidocaine. However, in contrast to ketamine, L-655,708 did not affect prepulse inhibition of startle, nor did it maintain responding in rats trained to self-administer i.v. ketamine. Conclusion: Taken together, these findings suggest that activation of the hippocampus by L-655,708 produces an antidepressant-like effect in the absence of any psychotomimetic or abuse-related effects. PMID- 28339597 TI - Compositional differences in multi-species biofilms formed on various orthodontic adhesives. AB - Objectives: To investigate the aspects of multi-species biofilm formation on various orthodontic adhesives with different surface characteristics. Methods: Multi-species biofilms using 13 bacterial species were grown on the surfaces of composite, compomer, and resin-modified glass-ionomer cement (RMGI). The changes in Streptococcus mutans (Sm), Streptococcus sobrinus (Ss), Porphyromonas gingivalis (Pg), Aggregatibacter actinomycetemcomitans (Aa), and total bacteria were determined at day 1 (T1) and day 4 (T2) using real-time polymerase chain reaction. Surface roughness (SR), surface free energy (SFE), and surface texture were analyzed to explain the differences in bacterial compositions among the adhesives. Repeated measures analysis of variance was used to determine time related changes in bacterial compositions with respect to adhesive type. The Kruskal-Wallis test was used to determine differences in SR and SFE among the adhesives. Results: There were no significant differences in the adhesion of total bacteria among the adhesives; however, the adhesion of Sm, Ss, and Pg was higher to RMGI than the other adhesives. The amount of Sm, Ss, and total bacteria increased from T1 to T2, while Pg and Aa decreased from T1 to T2. RMGI showed a rougher surface relative to composite or compomer due to the presence of micro pores and/or flaws. Compomer had the greatest SFE followed by RMGI and composite. Interestingly, SR differences were about 10 times greater than SFE differences among the adhesives. Conclusions: Considering the greater differences in SR than SFE among the adhesives, the rougher surface of RMGI may cause greater adhesion of Sm, Ss, and Pg. PMID- 28339595 TI - Does Starting to Smoke Cigars Trigger Onset of Cannabis Blunt Smoking? AB - Introduction: Among United States teens during the 1990s, increasing cigar use coincided with increasing use of tobacco cigar shells filled with cannabis, called "blunts." Cigar smokers are more likely to use cannabis, and we hypothesized that starting to smoke cigars might be a probabilistic "trigger" of blunt smoking. We turned to the case-crossover approach to evaluate this hypothesis. Methods: Within US National Surveys on Drug Use and Health, 2009 2013, we identified a nationally representative sample of newly incident blunt smokers aged 12- to 21-years-old (n = 4868) and compared month-of-onsets for smoking of cigars and blunts. Using the subjects-as-their-own-controls case crossover design, we specified the first month prior to blunt use as a "hazard interval" and the second month prior to blunt use as a "control interval." We used Mantel-Haenszel (MH) estimators to estimate the matched-pairs odds ratio (OR). Results: The MH OR estimate was 1.7 (95% CI = 1.3, 2.3), with excess odds of cigar onsets during the hazard interval relative to the control interval. Two alternative control interval specifications yielded congruent estimates (OR = 2.7 and 2.9, respectively). Conclusions: A short interval right after starting to smoke cigars may be one of increased risk of starting to smoke blunts. We discuss cigar, cigarillo, and "blunt wraps" control approaches that might reduce both tobacco and cannabis-related harms. Implications: If this evidence is correct, increased market-targeting to promote youthful cigar and cigarillo smoking might be followed by increased rates of blunt smoking in a vulnerable population. As noted by others, enhanced risk of smoking-attributable harms might be a consequence of mixed tobacco-cannabis formulations. PMID- 28339596 TI - Health Warning Labels for Smokeless Tobacco: The Impact of Graphic Images on Attention, Recall, and Craving. AB - Introduction: Little research has examined the impacts of graphic health warnings on the users of smokeless tobacco products. Methods: A convenience sample of past month, male smokeless tobacco users (n = 142; 100% male) was randomly assigned to view a smokeless tobacco advertisement with a graphic health warning (GHW) or a text-only warning. Eye-tracking equipment measured viewing time, or dwell time, in milliseconds. Following the advertisement exposure, participants self-reported smokeless tobacco craving and recalled any content in the health warning message (unaided recall). Linear and logistic regression analyses evaluated the proportion of time viewing the GHW, craving, and GHW recall. Results: Participants who viewed a GHW spent a significantly greater proportion of their ad viewing time on GHWs (2.87 seconds or 30%), compared to those viewing a text only warning (2.05 seconds or 24%). Although there were no significant differences by condition in total advertisement viewing duration, those participants viewing a GHW had increased recall of health warning messages compared to the text-only warning (76% had any warning message recall compared to 53%; p < .05). Self-reported craving after advertisement exposure was lower in the GHW compared to text-only condition, but the difference was not statistically significant (a rating of 4.4 vs. 5.3 on a 10-point scale; p = .08). Conclusions: GHWs attracted greater attention and greater recall of health warning messages compared to text-only warnings among rural male smokeless tobacco users. Implications: Among a sample of rural smokeless tobacco users, GHWs attracted more attention and recall of health warning messages compared to text-only warnings when viewed within smokeless tobacco advertising. These findings provide additional empirical support that GHWs are an effective tobacco control tool for all tobacco products and advertisements. PMID- 28339598 TI - High Postdischarge Morbidity in Ugandan Children With Severe Malarial Anemia or Cerebral Malaria. AB - Background: Cerebral malaria (CM) and severe malarial anemia (SMA) account for a substantial proportion of malaria-related deaths in sub-Saharan Africa. However, postdischarge morbidity in children with CM or SMA has not been well established. Methods: Children 18 months to 12 years of age, enrolled on admission to Mulago National Referral Hospital in Kampala, Uganda (CM, n = 162; SMA, n = 138), and healthy children recruited from the community (CC) (n = 133) were followed up for 6 months. The incidences of hospitalizations and outpatient clinic visits for illness during the follow-up period were compared between children with CM or SMA and the CC. Results: After adjustment for age, sex, and nutritional status, children with SMA had a higher incidence rate ratio (IRR) than CC for hospitalization (95% confidence interval [CI], 20.81 [2.48-174.68]), hospitalization with malaria (17.29 [95% CI, 2.02-148.35]), and clinic visits for any illness (95% CI, 2.35 [1.22-4.51]). Adjusted IRRs for children with CM were also increased for all measures compared with those for CC, but they achieved statistical significance only for clinic visits for any illness (2.24 [95% CI, 1.20-4.15]). In both groups, the primary reason for the clinic visits and hospitalizations was malaria. Conclusions: In the 6 months after initial hospitalization, children with SMA have an increased risk of repeated hospitalization, and children with CM or SMA have an increased risk of outpatient illness. Malaria is the main cause of inpatient and outpatient morbidity. Malaria prophylaxis has the potential to decrease postdischarge morbidity rates in children with SMA or CM. PMID- 28339599 TI - A single nucleotide polymorphism in COQ9 affects mitochondrial and ovarian function and fertility in Holstein cows. AB - A single missense mutation at position 159 of coenzyme Q9 (COQ9) (G->A; rs109301586) has been associated with genetic variation in fertility in Holstein cattle, with the A allele associated with higher fertility. COQ9 is involved in the synthesis of coenzyme COQ10, a component of the electron transport system of the mitochondria. Here we tested whether reproductive phenotype is associated with the mutation and evaluated functional consequences for cellular oxygen metabolism, body weight changes, and ovarian function. The mutation in COQ9 modifies predicted tertiary protein structure and affected mitochondrial respiration of peripheral blood mononuclear cells. The A allele was associated with low resting oxygen consumption and high electron transport system capacity. Phenotypic measurements for fertility were evaluated for up to five lactations in a population of 2273 Holstein cows. There were additive effects of the mutation (P < 0.05) in favor of the A allele for pregnancy rate, interval from calving to conception, and services per conception. There was no association of genotype with milk production or body weight changes postpartum. The mutation in COQ9 affected ovarian function; the A allele was associated with increased mitochondrial DNA copy number in oocytes, and there were overdominance effects for COQ9 expression in oocytes, follicle number, and antimullerian hormone concentrations. Overall, results show how a gene involved in mitochondrial function is associated with overall fertility, possibly in part by affecting oocyte quality. PMID- 28339600 TI - Tsunami in 2011 to the earthquake in 2016 in Fukushima-are we better prepared? PMID- 28339601 TI - Characterization and consistency of interactions of triggers and substrate at the onset of paroxysmal atrial fibrillation. AB - Aims: Initiating mechanisms of atrial fibrillation (AF) remain poorly understood, involving complex interaction between triggers and the atrial substrate. This study sought to classify the transitional phenomena, hypothesizing that there is consistency within and between patients in trigger-substrate interaction during transition to AF. Methods and results: Non-contact left atrial (LA) mapping was performed in 17 patients undergoing ablation for paroxysmal AF. All had spontaneous ectopy. Left atrial activation from the first ectopic to established AF was examined offline to characterize the initiating and transitional sequence of activation. In 57 fully mapped spontaneous AF initiations in 8 patients, all involved interaction of pulmonary venous/LA triggers with a septopulmonary line of block (SP-LOB) also evident in sinus rhythm, by 4 different transitional mechanisms characterized by (i) continuous focal firing: AF resulted from fragmentation of each ectopic wavefront through gaps in the SP-LOB and persisted only while focal firing continued (n = 18/32%) (ii) transient focal firing, wavefront fragmentation at the SP-LOB produced wavelet re-entry that persisted after cessation of an initiating ectopic source (n = 12/21%), (iii) of two separate interacting ectopic foci (n = 15/26%), or from (iv) transiently stable macroreentry (n = 12/21%), around the SP-LOB extending to the LA roof, resulting in progressive wavefront fragmentation. It was found that 79 +/- 22% of each of the initiations in individual patients showed the same triggering mechanism. Conclusion: Onset of paroxysmal AF can be described by discrete mechanistic categories, all involving interaction of ectopic activity with a common SP-LOB. Within/between-patient consistency of initiations suggests constancy of the interacting triggers and substrate, and supports the concept of mechanistically tailored treatment. PMID- 28339602 TI - Gonadotropin-releasing hormone, kisspeptin, and gonadal steroids directly modulate nucleobindin-2/nesfatin-1 in murine hypothalamic gonadotropin-releasing hormone neurons and gonadotropes. AB - Neuroendocrine regulation of metabolism and reproduction are tightly interlinked. Nesfatin-1 is an 82 amino acid metabolic peptide derived from nucleobindin-2 (NUCB2). NUCB2 mRNA and protein significantly increase in the hypothalamus of rats during puberty-to-adult transition. Administration of nesfatin-1 modulates circulating LH and testosterone in male rats. However, whether nesfatin-1 acts directly on neurons and gonadotropes remain unknown. In addition, whether reproductive hormones of the hypothalamo-pituitary gonadal axis modulate NUCB2/nesfatin-1 is unclear. To address these, we employed murine hypothalamic (GT1-7) and pituitary (LbetaT2) cells in vitro. Nucb2 expression, and NUCB2/nesfatin-1 immunoreactivity were observed in both GT1-7 and LbetaT2 cells, and in the hypothalamus of mice. Nesfatin-1 co-localized GnRH in GT1-7 cells, and in the hypothalamic perikarya of mice. Cells were treated with kisspeptin, GnRH, and estradiol and testosterone, as well as nesfatin-1 for 2, 6 or 24 hours. Synthetic nesfatin-1 increased Kiss1r and Gnrh expression in GT1-7 cells and Lhbeta in LbetaT2. Nesfatin-1 increased GnRH and LHbeta protein expression in GT1 7 and LbetaT2 at 6-hour post incubation respectively. Both NUCB2 mRNA and protein were increased in GT1-7 cells treated with kisspeptin. Testosterone increased NUCB2 mRNA and protein expression in GT1-7 and LbetaT2. 17beta-estradiol increased NUCB2 mRNA and protein expression in LbetaT2. Nesfatin-1 acts directly on hypothalamic neurons and gonadotropes to elicit a generally positive influence on the endocrine milieu regulating reproduction in mice. Reproductive hormones, in turn, modulate brain and pituitary NUCB2/nesfatin-1. In conclusion, we provide additional information to designate nesfatin-1 as a novel, additional factor that helps reproductive success. PMID- 28339603 TI - Optimization of STEM imaging conditions for cryo-tomography. AB - For three-dimensional analysis of cryo-specimens using tomography at low and medium magnifications, the use of STEM images has some important advantages over TEM. A clear understanding of the electron dose in STEM is essential for optimized cryo-microscopy so a dose estimation technique for STEM imaging has been developed. The STEM convergence angle was shown to have a large impact on the image quality, in particular on the signal-to-noise ratio in the acquired images. Importantly, there is a clear trade-off between good STEM spatial resolution in the images with a large convergence angle and the signal-to-noise ratio, which is improved by reducing the convergence angle as much as possible. Based on this and the effects of varying specimen thickness, image magnification and acceleration voltage which were also evaluated, we discuss the optimal conditions for cryo-STEM tomography of biological specimens. PMID- 28339604 TI - Association of pre-ablation level of vitamin D with atrial fibrillation recurrence after catheter ablation: reply. PMID- 28339605 TI - Uniparental chicken offsprings derived from oogenesis of chicken primordial germ cells (ZZ). AB - Cloning (somatic cell nuclear transfer) in avian species has proven unachievable due to the physical structure of the avian oocyte. Here, the sexual differentiation of primordial germ cells with genetic sex ZZ (ZZ PGCs) was investigated in female germline chimeric chicken hosts with the aim to produce uniparental offspring. ZZ PGCs were expanded in culture and transplanted into the same and opposite sex chicken embryos which were partially sterilized using irradiation. All tested chimeric roosters (ZZ/ZZ) showed germline transmission with transmission rates of 3.2%-91.4%. Unexpectedly, functional oogenesis of chicken ZZ PGCs was found in three chimeric hens, resulting in a transmission rate of 2.3%-27.8%. Matings were conducted between the germline chimeras (ZZ/ZZ and ZZ/ZW) which derived from the same ZZ PGCs line. Paternal uniparental chicken offspring were obtained with a transmission rate up to 28.4% and as expected, all uniparental offspring were phenotypic male (ZZ). Genotype analysis of uniparental offsprings was performed using 13 microsatellite markers. The genotype profile showed that uniparental offspring were 100% genetically identical to the donor ZZ PGC line, shared 69.2%-88.5% identity with the donor bird. Homozygosity of the tested birds varied from 61.5% to 84.6%, which was higher than the donor bird (38.5%). These results demonstrate that male avian ZZ PGCs can differentiate into functional ova in an ovary, and uniparental avian clones are possible. This technology suggests novel approaches for generating genetically similar flocks of birds and for the conservation of avian genetic resources. PMID- 28339606 TI - Testicular abnormalities in mice with Y chromosome deficiencies. AB - We recently investigated mice with Y chromosome gene contribution limited to two, one, or no Y chromosome genes in respect to their ability to produce haploid round spermatids and live offspring following round spermatid injection. Here we explored the normalcy of germ cells and Sertoli cells within seminiferous tubules, and the interstitial tissue of the testis in these mice. We performed quantitative analysis of spermatogenesis and interstitial tissue on Periodic acid Schiff and hematoxylin-stained mouse testis sections. The seminiferous epithelium of mice with limited Y gene contribution contained various cellular abnormalities, the total number of which was higher than in the males with an intact Y chromosome. The distribution of specific abnormality types varied among tested genotypes. The males with limited Y genes also had an increased population of testicular macrophages and internal vasculature structures. The data indicate that Y chromosome gene deficiencies in mice are associated with cellular abnormalities of the seminiferous epithelium and some changes within the testicular interstitium. PMID- 28339607 TI - Gross Motor Trajectories During the First Year of Life for Preterm Infants With Very Low Birth Weight. AB - Background: Early identification of motor dysfunction in preterm infants with very low birth weight (VLBW) is important in order to provide early intervention. Objective: This study was to examine the motor trajectories of preterm infants with VLBW during their first year of life and to investigate the predictive ability and influencing factors of the trajectories. Design and Methods: A total of 342 preterm infants with VLBW were prospectively assessed for motor development by the Alberta Infant Motor Scales at 4, 6, 9, and 12 months and for developmental outcomes using the Bayley Scales of Infant and Toddler Development, second edition, at 24 months. Perinatal and socio-environmental factors were collected at baseline. Growth mixture modeling was used to explore the patterns of infants' motor trajectories during their first year of life. Logistic regression analyses were applied to examine the influencing factors associated with motor trajectories and their predictability of 24-month developmental outcomes. Results: Preterm infants with VLBW showed 3 distinct motor trajectories: stably normal (55%), deteriorating (32%), and persistently delayed (13%). Furthermore, the motor trajectories were predictive of 24-month cognitive and motor outcomes. Perinatal factors including lower birth weight, male gender, moderate to severe bronchopulmonary dysplasia, stage III to IV retinopathy of prematurity, and major brain damage were associated with a risk of deteriorating and persistently delayed trajectories (all P < .05). Socio-environmental factors had no association with motor trajectories. Limitations: The small sample size of the infants with a persistently delayed trajectory may have limited the assessment of some influencing factors. Conclusion: The identified early motor trajectories, predictive values, and influencing factors provide insightful implications for early detection and prevention of motor -disorders in preterm infants with VLBW. PMID- 28339609 TI - A Commentary on Maes et al. "A Genetic Epidemiological Mega Analysis of Smoking Initiation in Adolescents". PMID- 28339608 TI - Inhibition of arachidonate 15-lipoxygenase prevents 4-hydroxynonenal-induced protein damage in male germ cells. AB - Lipid peroxidation products, such as 4-hydroxynonenal (4HNE), are causative agents responsible for extensive protein damage within the male and female germlines. Recently, we have demonstrated that 4HNE production can initiate the proteolytic degradation of the molecular chaperone Heat Shock Protein A2 (HSPA2) in male germ cells. These events may be partially responsible for HSPA2 deficiency in the spermatozoa of patients that repeatedly fail in vitro fertilization. Given this, mechanisms that limit the production of 4HNE will be highly advantageous for the preservation of male fertility. The propagation of 4HNE in somatic cells has been linked to the enzymatic actions of arachidonate 15 lipoxygenase (ALOX15), a member of the lipoxygenase family of proteins. In view of this association, this study sought to explore ALOX15 as a physiological target to manipulate the levels of 4HNE produced in the male germline. Herein, we have demonstrated that ALOX15 is markedly upregulated in response to oxidative stress in round spermatids and the GC-2 cell line. Pharmacological inhibition of ALOX15 in GC-2 cells resulted in a significant reduction in both mitochondrial and cytoplasmic reactive oxygen species, as well as a dramatic reduction in 4HNE. Importantly, the reduced bioavailability of this aldehyde appears to confer positive downstream effects to its target proteins such that HSPA2 could be protected from damage by 4HNE. Taken together, these results suggest that the actions of ALOX15 are intimately tied to the production of 4HNE. Thus, the ALOX15 protein may be a promising new target for the mitigation of germline oxidative stress. PMID- 28339610 TI - Prescription Opioid Use Among Young Parents in the United States: Results from the National Longitudinal Study of Adolescent to Adult Health. AB - Objectives: No estimates exist regarding the extent of prescription opioid use among US adults who are the primary caregivers to children. Methods: Data were from Wave IV of the National Longitudinal Study of Adolescent to Adult Health. Respondents were age 24 to 32 years. We compared the prevalence of prescription opioid use in the last four weeks and medical conditions with the potential to precipitate use among parents (i.e., one or more children living in the household) and nonparents. We then examined demographics and substance use behaviors among parents with and without recent prescription opioid use. Results: A significantly higher percentage of parents (6.7%) compared with nonparents (3.9%) had taken a prescription opioid in the last four weeks, but a significantly lower percentage of parents compared with nonparents reported medical conditions with the potential to precipitate use such as an injury in the last four weeks (2.8% vs 4.0%). A higher percentage of parents with recent prescription opioid use reported financial hardship (44.1% vs 28.2%) and met criteria for risky substance use behaviors such as prescription opioid misuse (26.3% vs 11.8%) compared with parents without recent prescription opioid use. Conclusions: Results suggest notable prescription opioid use among young parents in the United States and that parents with recent prescription opioid use are more likely to have a history of inappropriate use of substances. These results highlight the need for additional research regarding the effects of prescription opioid use on parenting behaviors. PMID- 28339611 TI - An interview with Magdalena Zernicka-Goetz. PMID- 28339612 TI - Orthodontically induced cervical root resorption in humans is associated with the amount of tooth movement. AB - Introduction: The aim of this study was to investigate the variation in the amount of the orthodontically induced cervical root resorption and the association with several factors, such as the amount of tooth displacement, location of tooth in the maxilla or mandible, and presence of an interference that may influence the amount of root resorption. Subjects and methods: This study included 30 subjects (20 females, 10 males) with an age range of 11.3 to 43.0 years. Using a standardized experimental orthodontic tooth movement, 59 premolars were moved buccaly during 8 weeks with application of 1 N force. Fifty eight contralateral premolars not subjected to orthodontic tooth movement served as controls. At the end of the experimental period the teeth were carefully extracted, scanned in a micro-computed tomography scanner with a resolution of 9 um, and the reconstructed images were processed for volumetric evaluation of resorption craters at the cervical part of the root surface. Data were analyzed using unpaired t-test and the Pearson's correlation. Results: Higher amount of cervical root resorption was detected in the orthodontically moved teeth (0.00055 mm3) compared to controls (0.00003 mm3; P < 0.001). Moderate correlation was found between root resorption in the two experimental teeth within the same individual (R = 0.421, P = 0.023). Teeth located in the mandible presented more resorption than those in the maxilla (P = 0.046). The amount of root resorption was correlated to the amount of tooth movement (R = 0.318, P = 0.016). Conclusion: Application of a 1 N force over a 2-month period provokes severe root resorption at the compression cervical sites. Resorption is correlated with the amount of tooth movement and the location of the teeth. PMID- 28339613 TI - A nonsense mutation in Ccdc62 gene is responsible for spermiogenesis defects and male infertility in repro29/repro29 mice. AB - Phenotype-driven mutagenesis is an unbiased method to identify novel genes involved in spermatogenesis and other reproductive processes. Male repro29/repro29 mice generated by the Reproductive Genomics Program at the Jackson Laboratory were infertile with deformed sperm and poor motility. Using selected exonic capture and massively parallel sequencing technologies, we identified a nonsense mutation in the exon 6 of coiled-coil domain-containing 62 gene (Ccdc62), which results in a formation of a premature stop codon and a truncated protein. Among the tissues examined, CCDC62 was found to be expressed at the highest level in mouse testis by reverse transcriptase-PCR (RT-PCR) and Western blot analysis. With immunofluorescent staining, we demonstrated that CCDC62 was expressed in the cytoplasm and the developing acrosome in the spematids of mouse testis, and was specifically localized at the acrosome in mature sperm. The complementation analysis by mating repro29/+ mice with Ccdc62 /- mice (generated by CRISPR-Cas9 strategy) further provided genetic proof that the infertility of repro29/repro29 mice was caused by Ccdc62 mutation. Finally, it was found that intracellular colocalization and interaction of CCDC62 and Golgi-associated PDZ and coiled-coil motif-containing protein may be important for acrosome formation. Taken together, this study identified a nonsense mutation in Ccdc62, which directly results in male infertility in repro29/repro29 mice. PMID- 28339614 TI - Integrin linked kinase regulates syncytialization of BeWo trophoblast cells. AB - During placental development, mononuclear villous cytotrophoblast cells differentiate and fuse with the overlying syncytiotrophoblast. This process requires the dissolution of E-cadherin (CDH1)-containing adherens junctions in cytotrophoblast. Integrin linked kinase (ILK) can downregulate CDH1 through poly (ADP-ribose) polymerase 1 (PARP1) and Snail-1 (SNAI1) during epithelial mesenchymal transition. ILK is known to be expressed in cytotrophoblast; thus, the role of a potential ILK-PARP1-SNAI1 pathway in aiding trophoblast syncytialization via the downregulation of CDH1 was examined. The spatiotemporal expression of PARP1, SNAI1, and CDH1 were determined in first and early second trimester chorionic villi, term villi, and BeWo cells by immunofluorescence analysis. PARP1 and SNAI1 were highly detectable in villous cytotrophoblast nuclei of human chorionic villi and SNAI1 expression, in particular, also persisted in syncytiotrophoblast. In BeWo cells undergoing syncytialization, PARP1 and SNAI1 increasingly localized to cell nuclei in correlation with decreased CDH1 expression. Using luciferase reporter assays, it was determined that PARP1 and SNAI1 promoter activities were significantly higher in BeWo cells during syncytialization compared to the activities in proliferating cells. Overexpression of wild type or constitutively active ILK also resulted in significantly increased PARP1 and SNAI1 promoter activities while dominant negative ILK overexpression significantly reduced promoter activities. Lastly, siRNA-mediated depletion of ILK expression in BeWo cells undergoing syncytialization resulted in significantly reduced SNAI1 expression and a significant reduction in the incidence of syncytialization correlating with increased CDH1 expression. These results demonstrate that ILK aids trophoblast syncytialization via the downregulation of CDH1, perhaps through an ILK-PARP1 SNAI1 pathway. PMID- 28339615 TI - Viable offspring after imaging of Ca2+ oscillations and visualization of the cortical reaction in mouse eggs. AB - -: During mammalian fertilization, egg Ca 2+ oscillations are known to play pivotal roles in triggering downstream events such as resumption of the cell cycle and the establishment of blocks to polyspermy. However, viable offspring have not been obtained after monitoring Ca 2+ oscillations, and their spatiotemporal links to subsequent events are still to be examined. Therefore, the development of imaging methods to avoid phototoxic damage while labeling these events is required. Here, we examined the usefulness of genetically encoded Ca 2+ indicators for optical imaging (GECOs), in combination with spinning-disk confocal imaging. The Ca 2+ imaging of fertilized mouse eggs with GEM-, G-, or R GECO recorded successful oscillations (8.19 +/- 0.31, 7.56 +/- 0.23, or 7.53 +/- 0.27 spikes in the first 2 h, respectively), similar to those obtained with chemical indicators. Then, in vitro viability tests revealed that imaging with G- or R-GECO did not interfere with the rate of development to the blastocyst stage (61.8 or 70.0%, respectively, vs 75.0% in control). Furthermore, two-cell transfer to recipient female mice after imaging with G- or R-GECO resulted in a similar birthrate (53.3 or 52.0%, respectively) to that of controls (48.7%). Next, we assessed the quality of the cortical reaction (CR) in artificially activated or fertilized eggs using fluorescently labeled Lens culinaris agglutinin fluorescein isothiocyanate. Multicolor imaging demonstrated that the first few Ca 2+ spikes are sufficient for the completion of the CR and subsequent hardening of the zona pellucida in mouse eggs. These methods provide a framework for studying Ca 2+ dynamics in mammalian fertilization. PMID- 28339616 TI - Time Trends in Smoking Onset by Sex and Race/Ethnicity Among Adolescents and Young Adults: Findings From the 2006-2013 National Survey on Drug Use and Health. AB - Introduction: During the 2000s the number of adolescents who became new smokers in the United States declined while the number of young adults who did so increased. However, we do not know among which demographic groups these changes occurred. Methods: We analyzed data from the 2006 to 2013 National Survey of Drug Use and Health (n = 180 079). Multivariate linear regression models were used to assess annual trends in smoking onset and log-binomial regression models to assess changes over time in the risk of smoking onset among young adults (18- to 25-years-old) relative adolescents (12- to 17-years-old). Results: From 2006 to 2013, the rate of onset among young adults (6.3%) was greater than among adolescents (1.9%). Time trends demonstrated that annual declines in smoking onset occurred among white young adult males and females. Rates of smoking onset increased among black and Hispanic young adult males with a lower rate of decline among black and Hispanic young adult females. There was a greater risk of smoking onset among young adults relative to adolescents that did not change over time. Conclusions: Smoking onset is becoming more concentrated in the young adult than adolescent years. Despite this trend, there were annual declines in young adult smoking onset but not uniformly across racial/ethnic groups. More effective strategies to prevent young adult smoking onset may contribute to a further decline in adult smoking and a reduction in tobacco-related health disparities. Implications: Smoking onset is becoming more concentrated in the young adult years across sex and racial/ethnic groups. The United States may be experiencing a period of increasing age of smoking onset and must develop tobacco control policies and practices informed by these changes. PMID- 28339617 TI - Searching for the Smoker's Paradox in Acute Stroke Patients Treated With Intravenous Thrombolysis. AB - Background: Inconsistent evidence supports better outcome in smokers after stroke. Our study examines this association in a large sample of ischemic stroke treated with intravenous thrombolysis. Method: Virtual International Stroke Trials Archive (VISTA) database, composed of individual patient data of multiple clinical trials, was queried. The primary outcome was functional independence at 3 months noted by modified Rankin Scale (mRS; a 7-point scale ranging from 0 [no deficit] to 6 [death]) score<= 2. The secondary outcomes were National Institutes of Health Stroke Scale (NIHSS; stroke severity measure, ranging from 0 [no deficit] to 42 [most severe]) score at 24 hours and the occurrence of symptomatic intractracranial hemorrhage. Results: A total of 5383 patients were included: 1501 current smokers and 3882 nonsmokers. Smokers were younger (60 +/- 13 vs. 71 +/- 12 years, p < .0001) and had lower median NIHSS score at baseline (12 [8-17] vs. 13 [9-18], p < .0001). The rate of favorable functional outcome (mRS <= 2) at 3 months was significantly higher among current smokers (49.7% vs. 39.5%, p < .0001) and with crude ORs of 1.52, 95% CI 1.33-1.72. The association became non significant after adjusting for age (OR 1.11, 95% CI 0.97-1.27). Subgroup analysis by age/gender strata showed that current smoking was associated with favorable outcome only in women >= 65 years. Current smoking was also associated with lower rates of symptomatic intracranial hemorrhage (adjusted OR 0.55, 95% CI 0.39-0.79). Conclusion: Smokers experience their first ever stroke 11 years younger than nonsmokers. This age difference explains the association between current smoking and favorable functional outcome. Implications: Smoking is associated with occurrence of first ever stroke at a younger age, therefore, focus should be on smoking prevention and treatment. The decision to treat ischemic stroke patients with intravenous thrombolysis should not be influenced by the patients' smoking status. PMID- 28339618 TI - Telomere Length, Oxidative Stress, Inflammation and BDNF Levels in Siblings of Patients with Bipolar Disorder: Implications for Accelerated Cellular Aging. AB - Background: Growing evidence supports the existence of neurobiological trait abnormalities in individuals at genetic risk for bipolar disorder. The aim of this study was to examine potential differences in brain-derived neurotrophic factor, cytokines, oxidative stress, and telomere length markers between patients with bipolar disorder, their siblings, and healthy controls. Methods: Thirty-six patients with bipolar disorder type I, 39 siblings, and 44 healthy controls were assessed. Serum levels of brain-derived neurotrophic factor, interleukin-6, interleukin-10, tumor necrosis factor-alpha, C-C motif chemokine 11, C-C motif chemokine 24, and 3-nitrotyrosine were measured, as were the activities of glutathione peroxidase, glutathione reductase, and glutathione S-transferase. Telomere length (T/S ratio) was measured using quantitative polymerase chain reaction. Results: Telomere length was different between the 3 groups (P = .041) with both patients and siblings showing a shorter T/S ratio compared with healthy controls. Patients showed increased levels of interleukin-6 (P = .005) and interleukin-10 (P = .002) compared with controls as well as increased levels of interleukin-6 (p = 0.014) and CCL24 (P = .016) compared with their siblings. C-C motif chemokine 11 levels were increased in siblings compared with controls (P = .015), and a similar tendency was found in patients compared with controls (P = .045). Glutathione peroxidase activity was decreased in patients compared with controls (P = .006) and siblings (P = .025). No differences were found for the other markers. Conclusions: The present results suggest that unaffected siblings may present accelerated aging features. These neurobiological findings may be considered as endophenotypic traits. Further prospective studies are warranted. PMID- 28339619 TI - Relationship of neuropeptide FF receptors with pubertal maturation of gilts. AB - Mechanisms governing the timing of puberty in pigs are poorly understood. A genome-wide association study for age at first estrus in pigs identified candidate genes including neuropeptide FF receptor 2 (NPFFR2), which is a putative receptor for RFamide-related peptides (RFRP). RFRP has been shown to negatively regulate secretion of reproductive hormones from hypothalamic and pituitary tissue of pigs in culture. Here, the porcine NPFFR2 gene was further screened and four potentially functional variants were identified to be associated with age at first estrus in pigs (1,288 gilts). The RFRP neurons in the porcine hypothalamus were localized in the paraventricular and dorsomedial nuclei with RFRP fibers in the lateral hypothalamic area. There were marked changes in expression of NPFF receptors in the anterior pituitary gland and hypothalamus of gilts beginning with the peripubertal period. The hypothesis that NPFF receptor function is related to secretion of luteinizing hormone (LH) in gilts was tested with various NPFF receptor ligands. The NPFF receptor antagonist RF9 stimulated a pulse-like release of LH in prepubertal gilts. The putative NPFF receptor agonist RFRP3 modestly suppressed LH pulses in ovariectomized (OVX) prepubertal gilts. A porcine-specific RFRP2 failed to have an effect on LH secretion in OVX prepubertal gilts despite its high degree of homology to avian gonadotropin-inhibitory hormone. Results indicate that an RFRP system is present in the pig and that NPFFR2 is important for pubertal onset in gilts. It is not clear if this regulation involves major control of LH secretion or another unknown mechanism. PMID- 28339621 TI - Routine quality care assessment of schizophrenic disorders using information systems. PMID- 28339622 TI - Augmented QRS notching and macroscopic T-wave alternans preceding polymorphic ventricular tachycardia in a patient with electrical storm. PMID- 28339620 TI - Systematic review of the effectiveness of health-related behavioral interventions using portable activity sensing devices (PASDs). AB - Background: Portable activity sensing devices (PASDs) have received significant interest as tools for objectively measuring activity-related parameters and promoting health-related outcomes. Studies of PASDs suggest the potential value of integrating them with behavioral interventions to improve intermediate and downstream clinical outcomes. Objectives: This systematic review describes and evaluates evidence from controlled studies of interventions using PASDs on their effectiveness in health-related outcomes. Study quality was also assessed. Methods: A systematic literature search was performed of MEDLINE, Cochrane Central Register of Controlled Trials, PsycINFO, EMBASE, and CINAHL databases. We included English-language papers of controlled trials through 2015 reporting the effectiveness of PASDs in improving health-related outcomes in any population. We extracted and analyzed data on study characteristics including design, target population, interventions, and findings. Results: Seventeen trials met the inclusion criteria from a total of 9553 unique records. Study objectives varied greatly, but most sought to increase physical activity. Studies with a "passive" intervention arm using a PASD with minimal behavioral support generally did not demonstrate effectiveness in improving health-related outcomes. Interventions integrating PASDs with multiple behavioral change techniques were more likely to be effective, particularly for intermediate outcomes such as physical activity and weight loss. Trials had small sample sizes but were generally free of bias, except for blinding and selection bias. Conclusion: There is insufficient evidence to draw a conclusion about the general health-related benefits of PASD interventions. PASD interventions may improve intermediate outcomes when coupled with multiple behavioral change techniques. Devices alone or with minimal behavioral change support are insufficient to change health-related outcomes. PMID- 28339623 TI - The Molecular and Clinical Epidemiology of Extended-Spectrum Cephalosporin- and Carbapenem-Resistant Enterobacteriaceae at 4 US Pediatric Hospitals. AB - Objective: In this report, we aim to describe the epidemiology of extended spectrum cephalosporin-resistant (ESC-R) and carbapenem-resistant (CR) Enterobacteriaceae infections in children. Methods: ESC-R and CR Enterobacteriaceae isolates from normally sterile sites of patients aged <22 years from 4 freestanding pediatric medical centers were collected along with the associated clinical data. Results: The overall frequencies of ESC-R and CR isolates according to hospital over the 4-year study period ranged from 0.7% to 2.8%. Rates of ESC-R or CR Escherichia coli and Klebsiella pneumoniae varied according to hospital and ranged from 0.75 to 3.41 resistant isolates per 100 isolates (P < .001 for any differences). E coli accounted for 272 (77%) of the resistant isolates; however, a higher rate of resistance was observed in K pneumoniae isolates (1.78 vs 1.27 resistant isolates per 100 same-species isolates, respectively; P = .005). One-third of the infections caused by ESC-R or CR E coli were community-associated. In contrast, infections caused by ESC-R or CR K pneumoniae were more likely than those caused by resistant E coli to be healthcare- or hospital-associated and to occur in patients with an indwelling device (P <= .003 for any differences, multivariable logistic regression). Nonsusceptibility to 3 common non-beta-lactam agents (ciprofloxacin, gentamicin, and trimethoprim-sulfamethoxazole) occurred in 23% of the ESC-R isolates. The sequence type 131-associated fumC/fimH-type 40-30 was the most prevalent sequence type among all resistant E coli isolates (30%), and the clonal group 258 associated allele tonB79 was the most prevalent allele among all resistant K pneumoniae isolates (10%). Conclusions: The epidemiology of ESC-R and CR Enterobacteriaceae varied according to hospital and species (E coli vs K pneumoniae). Both community and hospital settings should be considered in future research addressing pediatric ESC-R Enterobacteriaceae infection. PMID- 28339626 TI - A ward-based time study of paper and electronic documentation for recording vital sign observations. AB - Objective: To investigate time differences in recording observations and an early warning score using traditional paper charts and a novel e-Obs system in clinical practice. Methods: Researchers observed the process of recording observations and early warning scores across 3 wards in 2 university teaching hospitals immediately before and after introduction of the e-Obs system. The process of recording observations included both measurement and documentation of vital signs. Interruptions were timed and subtracted from the measured process duration. Multilevel modeling was used to compensate for potential confounding factors. Results: In all, 577 nurse events were observed (281 paper, 296 e-Obs). The geometric mean time to take a complete set of vital signs was 215 s (95% confidence interval [CI], 177 s-262 s) on paper, and 150 s (95% CI, 130 s-172 s) electronically. The treatment effect ratio was 0.70 (95% CI, 0.57-0.85, P < .001). The treatment effect ratio in ward 1 was 0.37 (95% CI, 0.26-0.53), in ward 2 was 0.98 (95% CI, 0.70-1.38), and in ward 3 was 0.93 (95% CI, 0.66-1.33). Discussion: Introduction of an e-Obs system was associated with a statistically significant reduction in overall time to measure and document vital signs electronically compared to paper documentation. The reductions in time varied among wards and were of clinical significance on only 1 of 3 wards studied. Conclusion: Our results suggest that introduction of an e-Obs system could lower nursing workload as well as increase documentation quality. PMID- 28339625 TI - Cystatin S-a candidate biomarker for severity of submandibular gland involvement in Sjogren's syndrome. AB - Objectives: Salivary cystatin S is a defence protein mainly produced by submandibular glands and involved in innate oral immunity. This study aimed to verify whether cystatin S was diversely expressed in different disease subsets of primary Sjogren's syndrome (pSS) patients, defined on the basis of salivary flow [unstimulated salivary flow rate (USFR)], minor salivary gland (MSG) focus score and submandibular gland ultrasonography abnormalities. We also evaluated miR-126 and miR-335-5p expression in MSG biopsies to verify whether an aberrant regulation of cystatin S at the glandular level may influence its salivary expression. Methods: Forty pSS patients and 20 sex- and age-matched healthy volunteers were included. Salivary cystatin S levels were assessed by western blot analysis using a stain-free technology. The expression of miR-126, miR-335 5p and cystatin S was assessed by quantitative PCR in 15 MSG biopsies differing for USFR and MSG focus score. Results: We found that salivary cystatin S was significantly decreased in pSS patients vs healthy volunteers ( P = 0.000), especially in those with hyposalivation. A positive correlation was observed between cystatin S and USFR ( r = 0.75, P = 0.01). Salivary cystatin S was also significantly reduced in patients with a submandibular gland ultrasonography score ?2. The expression levels of miR-126 and miR-335-5P increased in inverse proportion with USFR. The mRNA of cystatin S did not change significantly, suggesting post-transcriptional regulation. Conclusion: Cystatin S emerged as a promising biomarker for pSS, strongly correlated with glandular dysfunction. An upregulation of miR-126 and miR-335-5P might be implicated in its expression. PMID- 28339627 TI - Validity and reliability of three-dimensional palatal superimposition of digital dental models. AB - Objective: To evaluate the validity and reliability of three-dimensional (3D) landmark-based palatal superimposition of digital dental models using Ortho Mechanics Sequential Analyzer (OMSA). Methods: The sample consisted of pre- and post-treatment digital maxillary dental models of 20 orthodontic cases. For each case, the pre- and post-treatment digital models were superimposed using surface based methods utilizing 3dMD Vultus and Invivo 5 software as well as a landmark based method utilizing OMSA. The same set of parameters were measured on the superimposed 3D data by the three softwares for comparison. Agreement in the superimposition outcomes among the three superimposition methods was evaluated with intraclass correlation coefficients (ICCs), Bland-Altman plots, and repeated measures ANOVA. A P value of <= 0.05 was considered statistically significant. Results: Repeatability was acceptable for all methods based on the ICCs. Agreement as measured by the ICCs and repeated measures ANOVA was high among the three methods. Conclusion: The results indicate that OMSA offers a valid and reliable tool for 3D landmark-based digital dental models superimposition using 3 points marked along the midpalatal raphe as reference. PMID- 28339628 TI - Using digital interventions to improve the cardiometabolic health of populations: a meta-review of reporting quality. AB - Objectives: We conducted a meta-review to determine the reporting quality of user centered digital interventions for the prevention and management of cardiometabolic conditions. Materials and Methods: Using predetermined inclusion criteria, systematic reviews published between 2010 and 2015 were identified from 3 databases. To assess whether current evidence is sufficient to inform wider uptake and implementation of digital health programs, we assessed the quality of reporting of research findings using (1) endorsement of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, (2) a quality assessment framework (eg, Cochrane risk of bias assessment tool), and (3) 8 parameters of the Consolidated Standards of Reporting Trials of Electronic and Mobile HEalth Applications and onLine TeleHealth (CONSORT-eHEALTH) guidelines (developed in 2010). Results: Of the 33 systematic reviews covering social media, Web-based programs, mobile health programs, and composite modalities, 6 reported using the recommended PRISMA guidelines. Seven did not report using a quality assessment framework. Applying the CONSORT-EHEALTH guidelines, reporting was of mild to moderate strength. Discussion: To our knowledge, this is the first meta review to provide a comprehensive analysis of the quality of reporting of research findings for a range of digital health interventions. Our findings suggest that the evidence base and quality of reporting in this rapidly developing field needs significant improvement in order to inform wider implementation and uptake. Conclusion: The inconsistent quality of reporting of digital health interventions for cardiometabolic outcomes may be a critical impediment to real-world implementation. PMID- 28339629 TI - Orders on file but no labs drawn: investigation of machine and human errors caused by an interface idiosyncrasy. AB - In this report, we describe 2 instances in which expert use of an electronic health record (EHR) system interfaced to an external clinical laboratory information system led to unintended consequences wherein 2 patients failed to have laboratory tests drawn in a timely manner. In both events, user actions combined with the lack of an acknowledgment message describing the order cancellation from the external clinical system were the root causes. In 1 case, rapid, near-simultaneous order entry was the culprit; in the second, astute order management by a clinician, unaware of the lack of proper 2-way interface messaging from the external clinical system, led to the confusion. Although testing had shown that the laboratory system would cancel duplicate laboratory orders, it was thought that duplicate alerting in the new order entry system would prevent such events. PMID- 28339630 TI - MR Tractography in Short Lasting Unilateral Neuralgiform Headache Attacks with Conjunctival Injection and Tearing (SUNCT) Patients: Case Reports. AB - Background: Short-lasting unilateral neuralgiform headache attack with conjunctival injection and tearing (SUNCT) is one of the trigeminal autonomic cephalalgias where neurovascular compression was detected in neuroimaging in recent years. Case: We report two cases, a 52-year-old adult and a 69-year-old elderly patient with short-lasting and recurrent headache combined with cranial autonomic features. Diffusion tensor imaging (DTI) and magnetic resonance (MR) tractography of both patients outlined structural changes of the trigeminal nerve revealing neurovascular compression. Pain and autonomic symptoms were completely relieved in the 52-year-old patient who underwent microvascular decompression surgery. Conclusion: To our knowledge, this is the first time in the literature where MR tractography revealed structural changes in the trigeminal nerve secondary to neurovascular compression in SUNCT patients. We suggest that in SUNCT patients high-resolution magnetic resonance imaging (MRI) and/or DTI-MR tractography should be performed to exclude neurovascular compression. We propose that the compression of the trigeminal nerve could generate SUNCT symptoms and the posterior hypothalamus could be activated secondarily. With this point of view, trigeminal neuralgia and SUNCT could represent the different features of the neurovascular compression spectrum. PMID- 28339631 TI - Evidence for the involvement of the proximal copy of the MAGEA9 gene in Xq28 linked CNV67 specific to spermatogenic failure. AB - Spermatogenic failure characterized by impaired sperm production is a common multifactorial disease with molecular and cytogenetic causes for its extreme phenotype that include azoospermia and severe oliogzoospermia. Recently, a high resolution array-comparative genomic hybridization analysis of the X chromosome and a subsequent cohort study revealed three X-linked microdeletions (CNV64, CNV67, and CNV69) that were associated with decreased sperm production in a mixed group that included Spanish and Italian males. To confirm their spermatogenic effect, we examined the hemizygous deletions and copy dosage of the MAGE family member A9 (MAGEA9) gene, which is a potential X-linked candidate for the CNV67 related spermatogenic phenotype, to investigate their association with spermatogenic failure in 1722 Han males from southwest China. The individuals in this group consisted of 884 patients with idiopathic azoospermia/oliogzoospermia and 838 controls with normozoospermia. Our results showed that both CNV64 and CNV69 were more common in patients than in controls. Similar to that reported previously, the CNV67 was also identified as being specific to spermatogenic failure in our population, although it was rare. More importantly, the paralog ratio tests and sequence family variant analyses provided evidence that the CNV67 might cause a partial deletion of the proximal copy of the MAGEA9 and suggests that CNV67-related spermatogenic failure may be attributed to the functional defect of the Cancer/Testis gene. Our findings highlight the potential of the Xq linked CNV67 to serve as a novel detection target in the etiological diagnosis of spermatogenic failure and male infertility, although its pathogenic mechanism remains to be elucidated. PMID- 28339634 TI - Serratus Anterior Muscle Pain Syndrome: A Diagnostic Conundrum. PMID- 28339633 TI - Osmotic indices and kidney concentrating activity: population-based data on correlates and prognostic power. AB - Background: Research data are limited on indices of osmotic equilibrium and of kidney concentrating activity (KCA). This study investigated correlates and prognostic power of these indices in a sample of the general population. Methods: Urine osmolality (U-osm), plasma osmolality (P-osm), plasma creatinine and other variables were measured by the Gubbio Study for the 1988-92 exam (baseline). Plasma creatinine and other variables were re-measured in the 2001-07 exam (follow-up). KCA was assessed as the U-osm/P-osm ratio and kidney function as estimated glomerular filtration rate (eGFR). Results: Baseline data were complete in 4220 adults, of whom 852 died before follow-up and 2795 participated in the follow-up. At baseline, the following independent cross-sectional associations were identified: female sex and higher urine flow with lower values of U-osm, P osm and U-osm/P-osm ratio (P < 0.01); obesity with higher values of U-osm, P-osm and U-osm/P-osm ratio (P < 0.01); older age and lower eGFR with lower U-osm, lower U-osm/P-osm ratio and higher P-osm (P < 0.05); hypertension and smoking with lower U-osm and lower U-osm/P-osm ratio (P < 0.05) but not with P-osm. From baseline to follow-up, the annualized rate was 1.26% for mortality and -0.74 +/- 0.76 mL/min * 1.73 m2 for eGFR change. Mortality was independently predicted by baseline U-osm and baseline U-osm/P-osm ratio (hazard ratio for one higher standard deviation was <=0.91, 95% confidence interval was <=0.97, P < 0.01), but not by baseline P-osm. The eGFR change was not independently predicted by baseline values of U-osm, P-osm and U-osm/P-osm ratio (P >= 0.4). Conclusions: Sex, age, obesity, eGFR, urine flow, hypertension and smoking independently associated with U-osm and KCA. U-osm and KCA independently predicted mortality, but not kidney function change over time. PMID- 28339632 TI - Dosing down with biologic therapies: a systematic review and clinicians' perspective. AB - The effectiveness of biologic therapies now means that remission or low disease activity are realistic targets for treatment. However, after achieving remission/low disease activity, the next steps remain unclear. The aim of this publication was to conduct a broad systematic literature review to evaluate dosing down of biologics. After screening papers and abstracts for relevance and application of inclusion/exclusion criteria, a structured extraction process was used to collect information on the included studies. Fifty-two papers were included in the analysis across rheumatic disease. In patients who discontinue therapy, remission is not typically sustained, with reported rates of relapse and flare across early RA (48-54%), established RA (2-84%), axial spondyloarthritis (11-53%) and PsA (44.9%). In many cases, an acceptable disease activity can be regained upon retreatment. More research is needed to understand the long-term impacts of these strategies on efficacy, safety and cost. PMID- 28339635 TI - The Impact of Zonisamide on the Development and Course of Alcohol Dependence in Rabbits. A pharmaco-EEG study. AB - Aims: Zonisamide is a new anti-epileptic drug whose mechanism of action is associated with neurotransmission systems also involved in the pathogenesis of addiction. Recently, the role of memory processes and the hippocampus (Hp) is underlined in dependence. In our previous study, we determined that zonisamide decreases changes in hippocampal bioelectric activity induced by a single dose of ethanol. Methods: This study uses a pharmaco-EEG method to examine the impact of zonisamide on the development and course of alcohol dependence in rabbits. Quantitative changes in EEG were observed in the midbrain reticular formation, Hp and frontal cortex. Zonisamide was administered p.o. once a day at dose of 30 mg/kg/day during the entire experiment. Solutions with increasing concentrations of ethanol were administered for 6 weeks, followed by a 2-week period of abstinence. Results: The long-term administration of ethanol caused characteristic changes in rabbit EEG recordings, which were associated with a shift toward lower frequencies resulting in a depressive effect on the bioelectric activity of selected brain structures. Co-administration of zonisamide and ethanol caused a reduction of ethanol-induced alterations. Changes in EEG recordings were different during period of abstinence and were associated with potent shift toward the high frequencies. Zonisamide significantly decreased encephalographic features of neuronal hyperactivity when administered during the abstinence. Conclusion: Zonisamide decreases ethanol- and abstinence-induced changes in the EEG recordings. These effects may be a significant part of drug's mechanism of action in alcohol addiction therapy. Short Summary: A pharmaco-EEG method was used to determine the influence of a new anti-epileptic drug zonisamide on the development and course of alcohol dependence in rabbits. The drug co-administered with ethanol decreased alcohol-induced changes in selected brain structures. Zonisamide also decreases abstinence-induced changes in the EEG recordings. PMID- 28339636 TI - A before-after study of multidisciplinary Out-of-Hours handover: combining management and frontline efforts to create sustainable improvement. AB - Objective: The importance of implementation strategy in systems improvement is increasingly recognized and both 'bottom-up' and 'top-down' approaches have significant barriers. A trial of a combined approach involving frontline and managerial staff therefore seems merited. We attempted to improve handover using a Human Factors-based approach integrated with a combined 'top and bottom' implementation strategy. Design: A before-after study was conducted across 9 months. Setting: The study was set in a 236 bed district general hospital. Participants: Participants included any member of staff involved in Out of Hours handover. Intervention: Existing processes were analysed using Human Factors methods. Changes made were based on this analysis and developed via facilitation between management and frontline staff. These included creating a single multidisciplinary handover, changing the venue, standardizing the meeting structure, developing an standard operating procedure for identifying unwell patients for handover and creating a clinical coordinator role. Main outcome measures: Meeting attendance, duration, start time efficiency, the type of patients handed over and the transfer of important information were measured pre- and post-intervention. Results: We found improvement in handover start time (P = 0.002, r = 0) and multidisciplinary participation (P = 0.002, r = -0.534). Handover of unwell patients improved, but not significantly. Communication of plan (P < 0.001, r = 0.14) and pending tasks (P < 0.001, r = 0.30) improved, but diagnosis (P = 0.233, r = -0.05), history (P = 0.482, r = -0.03) and comorbidities (P = 0.19, r = -0.05) did not. Conclusions: The changes produced greater multidisciplinary participation, a broader focus and improved communication of plans and tasks outstanding. The 'top and bottom' implementation approach appeared valuable. Management involvement was essential for significant changes, while frontline staff involvement facilitated the design of context specific practical solutions with staff buy-in. PMID- 28339637 TI - Provider Perspectives on the Implementation of Psychosocial Risk Screening in Pediatric Cancer. AB - Objective: Psychosocial risk screening is an important initial step in delivering evidence-based care. This qualitative descriptive study identified how multidisciplinary pediatric oncology health-care providers perceive psychosocial risk screening to identify factors in uptake and implementation. Methods: A script guided digitally recorded (transcribed) interviews regarding psychosocial screening and challenges to facilitators of screening. Participants were 15 multidisciplinary staff (physicians, nurses, social workers, psychologists, physician assistant) at nine sites, three using the Psychosocial Assessment Tool(c) for research and six for clinical care. Constant comparative analysis was used to analyze the independently coded interviews. Results: Thematic content analysis identified an overarching theme - Screening is important because it facilitates clinical care - and four subthemes: Optimizing Psychosocial Care, Implementing Screening, Engaging Families, and Utilizing Clinical Pathways. Conclusions: Findings support the importance of integrating psychosocial risk screening into clinical care and offer strategies for implementation of screening across a range of settings. PMID- 28339639 TI - Comparative structural study of the zona radiata of the eggs of three Gobiobotia (Cyprinidae, Teleostei), endemic Korean freshwaters. AB - The genus Gobiobotia in Korea has only three species and all are endemic benthic freshwater fishes. Their oocytes were observed by light microscopy, scanning electron microscopy and transmission electron microscopy to investigate the characteristics of the zona radiata (ZR), a non-cellular envelope, which surrounds the egg. Various developmental cells appeared during the spawning season. During the yolk vesicles stage, which yolk vesicles are spherically developed in periphery of the cytoplasm and gradually increase in its number and size, the ZR becomes visible between its follicular layer and ooplasm. The morphological appearance of the ZR of each of the three species was unique: G. brevibarba had a ZR with villous structures, whereas that of G. macrocephala was honeycomb-like with porous structures. In contrast, G. naktongensis had a ZR with no structural modifications during oogenesis. Such differences in the same genus are not common. These results indicate that the structure of the ZR is a useful character for identification of the genus Gobiobotia and may reflect the types of microhabitats they inhabit. PMID- 28339638 TI - The Impact of Older Parents' Pain Symptoms on Adult Children. AB - Objective: Not only is persistent pain a debilitating health problem for older adults, it also may have negative effects on family relationships. Studies have documented the effects of pain on spouses and on parents of young children. However, research has not extended this line of inquiry to later life, and specifically to the impact of older parents' pain symptoms on adult children. This study addresses the question: Does older mothers' pain affect the quality of relations with offspring? Subjects and Design: Using data from a survey of 678 adult children of older mothers, this article presents two analyses examining the impact of mothers' self-reported pain on emotional closeness and on tension in the adult child-parent relationship. Results: Contrary to research conducted on younger families, multilevel models showed no effects on emotional closeness or tension in relationships with adult children when mothers experienced higher levels of persistent pain. This surprising finding suggests that mechanisms may exist that protect adult child caregivers from stressors that result from a relative's chronic pain. Conclusions: Based on the findings of this article, further exploration of the impact of chronic pain on relations between adult children and their parents is justified. Of interest is exploration of factors that may insulate later-life intergenerational relationships from the effects of pain. PMID- 28339640 TI - Response: Disseminated tuberculosis. PMID- 28339641 TI - Measuring job satisfaction among healthcare staff in the United States: a confirmatory factor analysis of the Satisfaction of Employees in Health Care (SEHC) survey. AB - Objective: To validate the Satisfaction of Employees in Health Care (SEHC) survey with multidisciplinary, healthcare staff in the United States (U.S.). Design: A cross-sectional psychometric study using confirmatory factor analysis. The original three-factor model was tested and modified using half-samples. Models were assessed using goodness-of-fit measures. Scale reliability and validity were tested with Cronbach's alpha coefficient and correlation of total SEHC score with two global satisfaction items, respectively. Setting: We administered a web-based survey from January to May 2015 to healthcare staff participating in initiatives aimed at delivering better care and reducing costs. Participants: The overall response rate was 38% (N = 1089), and respondents were from 86 healthcare projects. A total of 928 respondents completed the SEHC survey in full and were used in this study. Main Outcome Measures: Model fit of 18 SEHC items and total SEHC score. Results: The mean SEHC score was 77.6 (SD: 19.0). A one-factor model of job satisfaction had high loadings on all items, and demonstrated adequate model fit (second half-sample RMSEA: 0.069). The scale demonstrated high reliability (Cronbach's alpha = 0.942) and validity (r = 0.77 and 0.76, both P < 0.05). Conclusions: The SEHC appears to measure a single general job satisfaction construct. The scale has adequate reliability and validity to recommend its use to assess satisfaction among multidisciplinary, U.S. healthcare staff. Our findings suggest that this survey is a good candidate for reduction to a short form, and future research should validate this survey in other healthcare populations. PMID- 28339642 TI - Meaningful use of health information technology and declines in in-hospital adverse drug events. AB - Objective: Nationwide initiatives have promoted greater adoption of health information technology as a means to reduce adverse drug events (ADEs). Hospital adoption of electronic health records with Meaningful Use (MU) capabilities expected to improve medication safety has grown rapidly. However, evidence that MU capabilities are associated with declines in in-hospital ADEs is lacking. Methods: Data came from the 2010-2013 Medicare Patient Safety Monitoring System and the 2008-2013 Healthcare Information and Management Systems Society (HIMSS) Analytics Database. Two-level random intercept logistic regression was used to estimate the association of MU capabilities and occurrence of ADEs, adjusting for patient characteristics, hospital characteristics, and year of observation. Results: Rates of in-hospital ADEs declined by 19% from 2010 to 2013. Adoption of MU capabilities was associated with 11% lower odds of an ADE (95% confidence interval [CI], 0.84-0.96). Interoperability capability was associated with 19% lower odds of an ADE (95% CI, 0.67- 0.98). Adoption of MU capabilities explained 22% of the observed reduction in ADEs, or 67,000 fewer ADEs averted by MU. Discussion: Concurrent with the rapid uptake of MU and interoperability, occurrence of in-hospital ADEs declined significantly from 2010 to 2013. MU capabilities and interoperability were associated with lower occurrence of ADEs, but the effects did not vary by experience with MU. About one-fifth of the decline in ADEs from 2010 to 2013 was attributable to MU capabilities. Conclusion: Findings support the contention that adoption of MU capabilities and interoperability spurred by the Health Information Technology for Economic and Clinical Health Act contributed in part to the recent decline in ADEs. PMID- 28339643 TI - Increased Risk of Myofascial Pain Syndrome Among Patients with Insomnia. AB - Objective: The aim of this study is to evaluate the risk of developing myofascial pain syndrome among patients diagnosed with insomnia. Methods: We conducted a population-based longitudinal study of a matched cohort with 7,895 participants (1,579 patients with insomnia and 6,316 controls) who were selected from the Taiwan National Health Insurance Research Database. The patients were observed for a maximum of 10 years to determine the incidence of newly diagnosed myofascial pain syndrome. A Cox regression analysis was performed to identify the risk factors associated with myofascial pain syndrome in patients with insomnia. Results: During the 10-year follow-up period, 182 insomnia patients (14.9 per 1,000 person-years) and 379 controls (7.5 per 1,000 person-years) were diagnosed with myofascial pain syndrome. The incidence risk ratio of myofascial pain syndrome between the insomnia and control patients was 2.00 (95% confidence interval [CI] = 1.67-2.38, P < 0.001). After adjusting for age, sex, monthly income, urbanization, and comorbidities, the insomnia patients were 1.93 times more likely to develop myofascial pain syndrome (95% CI = 1.62-2.31, P < .001) than the control patients. Malignant neoplasm (hazard ratio = 3.08) and living in urban areas (hazard ratio = 3.05) were identified as independent risk factors for myofascial pain syndrome in patients with insomnia. Conclusions: Patients with insomnia had a higher risk of developing myofascial pain syndrome than controls. This study adds to the understanding of the complex relationship between sleep disturbance and pain. PMID- 28339644 TI - Development and validation of a structured query language implementation of the Elixhauser comorbidity index. AB - Objective: Comorbidity adjustment is often performed during outcomes and health care resource utilization research. Our goal was to develop an efficient algorithm in structured query language (SQL) to determine the Elixhauser comorbidity index. Materials and Methods: We wrote an SQL algorithm to calculate the Elixhauser comorbidities from Diagnosis Related Group and International Classification of Diseases (ICD) codes. Validation was by comparison to expected comorbidities from combinations of these codes and to the 2013 Nationwide Readmissions Database (NRD). Results: The SQL algorithm matched perfectly with expected comorbidities for all combinations of ICD-9 or ICD-10, and Diagnosis Related Groups. Of 13 585 859 evaluable NRD records, the algorithm matched 100% of the listed comorbidities. Processing time was ~0.05 ms/record. Discussion: The SQL Elixhauser code was efficient and computationally identical to the SAS algorithm used for the NRD. Conclusions: This algorithm may be useful where preprocessing of large datasets in a relational database environment and comorbidity determination is desired before statistical analysis. A validated SQL procedure to calculate Elixhauser comorbidities and the van Walraven index from ICD-9 or ICD-10 discharge diagnosis codes has been published. PMID- 28339645 TI - The extent of root resorption and tooth movement following the application of ascending and descending magnetic forces: a prospective split mouth, microcomputed-tomography study. AB - Objective: Various factors have been examined in the literature in an attempt to reduce the incidence and severity of root resorption. The purpose of the present investigation is to test the null hypothesis that there is no difference in relation to force level using gradually increasing (ascending) and decreasing (descending) orthodontic force generated by magnets on the severity of Orthodontically Induced Inflammatory Iatrogenic Root Resorption (OIIRR) and amount of tooth movement. Methods: Twenty maxillary first premolars from 10 patients were subjected to ascending (25-225 g, magnets in attraction) and descending (225 to 25 g, magnets in repulsion) buccal forces using a split mouth design over an 8-week period. Polyvinyl siloxane impressions were taken at week 0, 4, and 8 to record the tooth movement. After 8 weeks, the teeth were extracted, scanned, with micro-CT in 16.9 um resolution, and the root resorption craters were localized circumferentially and quantified at each level of the root. Results: The total volume of OIIRR with ascending force was 1.20 mm3, and with descending force was 1.25 mm3, and there was no statistically significant difference between them. OIIRR on the palatal surface (0.012 mm3) was significantly less than on the buccal surface (0.057 mm3) and than on the mesial surface (0.035 mm3). There is no statistically significant difference in the degree of OIIRR between different level of the root (cervical, middle, and apical) at different surfaces. Moreover, the amount of tooth movement, at 0-, 4-, and 8-week interval, secondary to an ascending and descending force application was not statistically significant. Conclusions: There is no short-term (8 weeks) statistically significant difference between orthodontic ascending and descending forces, from 25 to 225 g and from 225 to 25 g, respectively, in term of severity and location of OIIRR as well as the amount of tooth movement. The buccal surface of the root showed highest degree of OIIRR compared to other root's surfaces. PMID- 28339646 TI - Transforming growth factor beta receptor inhibition prevents ventricular fibrosis in a mouse model of progressive cardiac conduction disease. AB - Aims: Loss-of-function mutations in SCN5A, the gene encoding NaV1.5 channel, have been associated with inherited progressive cardiac conduction disease (PCCD). We have proposed that Scn5a heterozygous knock-out (Scn5a+/-) mice, which are characterized by ventricular fibrotic remodelling with ageing, represent a model for PCCD. Our objectives were to identify the molecular pathway involved in fibrosis development and prevent its activation. Methods and results: Our study shows that myocardial interstitial fibrosis occurred in Scn5a+/- mice only after 45 weeks of age. Fibrosis was triggered by transforming growth factor beta (TGF beta) pathway activation. Younger Scn5a+/- mice were characterized by a higher connexin 43 expression than wild-type (WT) mice. After the age of 45 weeks, connexin 43 expression decreased in both WT and Scn5a+/- mice, although the decrease was larger in Scn5a+/- mice. Chronic inhibition of cardiac sodium current with flecainide (50 mg/kg/day p.o) in WT mice from the age of 6 weeks to the age of 60 weeks did not lead to TGF-beta pathway activation and fibrosis. Chronic inhibition of TGF-beta receptors with GW788388 (5 mg/kg/day p.o.) in Scn5a+/- mice from the age of 45 weeks to the age of 60 weeks prevented the occurrence of fibrosis. However, current data could not detect reduction in QRS duration with GW788388. Conclusion: Myocardial fibrosis secondary to a loss of NaV1.5 is triggered by TGF-beta signalling pathway. Those events are more likely secondary to the decreased NaV1.5 sarcolemmal expression rather than the decreased Na+ current per se. TGF-beta receptor inhibition prevents age-dependent development of ventricular fibrosis in Scn5a+/- mouse. PMID- 28339647 TI - Detection of human immunodeficiency virus-1 ribonucleic acid in the peritoneal effluent of renal failure patients on highly active antiretroviral therapy. AB - Background: We evaluated the shedding of human immunodeficiency virus (HIV)-1 particles into continuous ambulatory peritoneal dialysis (CAPD) effluents of HIV positive patients with end-stage renal disease (ESRD). Methods: A total of 58 HIV positive patients with ESRD on highly active antiretroviral therapy (HAART) who had Tenckhoff catheters inserted between September 2012 and February 2015 were prospectively reviewed and followed for 18 months. Peritoneal dialysis (PD) effluent samples from functioning CAPD catheters and plasma samples were obtained at three points during regular clinic visits on days 45 +/- 37, 200 +/- 19 and 377 +/- 13 after catheter insertion. All specimens were stored at -20 degrees C, and each batch was analysed by Roche quantitative HIV-1 polymerase chain reaction assay to detect HIV-1 particles. Clustered logistic regression was used to test for independent predictors of HIV-1 detection in CAPD effluents. Results: HIV-1 RNA above 20 copies/mL assay limit was detectable in 19% (first batch), 26.3% (second batch) and 20% (third batch) of PD effluent specimens. HIV-1 RNA was detectable in PD fluid, without corresponding detection in the paired plasma in 3.4% (first batch), 5.3% (second batch) and 10% (third batch) of samples. Detection of HIV-1 in plasma sample (odds ratios 3.94; 95% confidence interval 1.14-13.55; P = 0.030), body mass index, serum albumin and HAART regimen were found to be significantly associated with HIV-1 detection in PD effluents. Conclusions: HIV particles are shed in detectable amounts into CAPD effluents even in patients with suppressed plasma viral load, raising concerns of a localized sanctuary site and potential infectivity of HIV-positive CAPD patients on a full complement of HAART. PMID- 28339648 TI - Three-dimensional testicular organoid: a novel tool for the study of human spermatogenesis and gonadotoxicity in vitro. AB - Existing methods for evaluating the potential gonadotoxicity of environmental agents and pharmaceutical compounds rely heavily on animal studies. The current gold standard in vivo functional assays in animals are limited in their human predictive capacity. In addition, existing human two-dimensional in vitro models of testicular toxicity do not accurately reflect the in vivo situation. A more reliable testicular in vitro model system is needed to better assess the gonadotoxic potential of drugs prior to progression into clinical trials. The overall goal of this study was to develop a three-dimensional (3D) in vitro human testis organoid culture system for use as both a predictive first tier drug screening tool and as a model of human testicular function. Multicellular human testicular organoids composed of Spermatogonial Stem Cells, Sertoli, Leydig and peritubular cells were created and evaluated over time for morphology, viability, androgen production and ability to support germ cell differentiation. Enzyme linked immunosorbent assay measurements confirmed that the organoids produced testosterone continuously with and without hCG stimulation. Upregulation of postmeiotic genes including PRM1 and Acrosin, detected by quantitative-PCR, digital PCR and Immunofluorescence, indicated the transition of a small percentage of diploid to haploid germ cells. As a novel screening tool for reproductive toxicity, 3D organoids were exposed to four chemotherapeutic drugs, and they responded in a dose-dependent manner and maintained IC50 values significantly higher than 2D cultures. This 3D human testis organoid system has the potential to be used as a novel testicular toxicity-screening tool and in vitro model for human spermatogenesis. PMID- 28339649 TI - LGBTQ Youth and Young Adult Perspectives on a Culturally Tailored Group Smoking Cessation Program. AB - Introduction: The prevalence of smoking among LGBTQ youth and young adults (YYAs) is much higher than that of non-LGBTQ young people. The current study explored LGBTQ YYA perceptions of a culturally tailored group smoking cessation counselling program, along with how the intervention could be improved. Methods: We conducted focus groups (n = 24) with 204 LGBTQ YYAs in Toronto and Ottawa, Canada. Open-ended questions focused on their feelings, likes and dislikes, concerns and additional ideas for a culturally tailored group cessation counselling intervention. Focus group transcripts were coded thematically and analyzed. Results: Overall, YYAs were ambivalent towards the concept of a culturally tailored, group cessation counselling program. Although several participants were attracted to the LGBTQ friendly and social benefits of such a program (eg, good support system), many also had concerns. Particularly, the possibility that other group members might trigger them to smoke was a frequently stated issue. Focus group members also noted lack of motivation to attend the group, and that the group program may be inaccessible depending on where and when the program was offered. Several suggestions were made as to how to ameliorate the expressed issues related to inaccessibility or lack of attractiveness. Conclusions: This study is among the first to gain the perspectives of LGBTQ YYAs on culturally tailored group cessation strategies in Canada. We identified components of group cessation programs that are both favored and not favored among LGBTQ YYAs, as well as suggestions as to how to make group cessation programs more appealing. Implications: This study is particularly relevant as smoking cessation programs are one of the most commonly offered and published cessation interventions for the LGBTQ community, yet little is understood in terms of preferences of LGBTQ YYA smokers. Given the disparity in the prevalence of smoking among LGBTQ young people compared to their non-LGBTQ peers, research on effective intervention strategies for this population is needed. Findings from this study can assist practitioners and researchers in designing interventions. PMID- 28339650 TI - Convenient method for better preservation of fine structures of cultured macrophages and engulfed yeast cells by freeze-substitution fixation. AB - Rapid freeze-freeze substitution after glutaraldehyde fixation (CF-FS method) obtained the natural and fine structures of macrophages and engulfed yeast cells. Culturing macrophages on single hole molybdenum grids placed in culture dishes made possible the rapid freezing of cells by the 'open sandwich method'. This method may be convenient when rapid-freezing cannot be performed immediately, or when a rapid-freezing device is not available in the lab. PMID- 28339651 TI - Comment on: Neurocognitive function varies by IDH1 genetic mutation status in patients with malignant glioma prior to surgical resection. PMID- 28339652 TI - Comments on clinical features and changes in epidemiology of infective endocarditis on pacemaker devices over a 27-year period (1987-2013): reply. PMID- 28339654 TI - Daily alcohol consumption and sickness absence in the GAZEL cohort. AB - Background: : Previous studies that examined the association between daily alcohol consumption and sickness absences (SA) were mostly retrospective and did not take into account the characteristics of SA. : A total of 9907 daily drinkers (8442 men and 1465 women) of the GAZEL prospective cohort were included. Daily alcohol consumption over the three previous years was self-reported at baseline and categorized as low, moderate, high or very high risk according to the World Health Organization. Duration of SA (short: <=7 days; moderate: 8-28; long: >28) was collected from administrative records as well as causes for long SA. Negative binomial regression models were used to estimate Risk Ratios of SA according to alcohol consumption with low-risk category as reference. : Duration of follow-up (in years) for SA was 8.4 +/- 3.7 in men and 11.2 +/- 5.4 in women. Increasing alcohol consumption predicted increasing risk of SA with a dose response relationship ( P < 0.01 for men; P = 0.01 for women). In men, strength of this association increased with SA duration [e.g. RRs from 1.41 (95% CI: 1.12 1.79) to 2.12 (95% CI: 1.49-3.00) in the very high-risk category, for short and long SA, respectively]. In men, even a moderate consumption predicted increased risk of SA whatever their duration (RR = 1.15; 95% CI: 1.07-1.23). In women, a moderate consumption predicted only long SA (RR = 1.22; 95% CI: 1.00-1.50). Daily alcohol consumption was associated with almost all causes of long SA in men, and with respiratory diseases, digestive diseases and injury in women. : We found a dose-response relationship between daily alcohol consumption and the risk of SA. Even moderate consumption could increase this risk, particularly in men. PMID- 28339655 TI - What should we do when a small pulmonary embolus is diagnosed unexpectedly? PMID- 28339656 TI - Development of a real-time wave field reconstruction TEM system (I): incorporation of an auto focus tracking system. AB - We have developed a real-time wave field reconstruction transmission electron microscope system that enables auto focus tracking at a video rate. In the developed system, a high-speed image calculation technique using a graphical processing unit was incorporated along with two techniques facilitating high speed focus control using high-voltage modulation and weighted image integration using exposure time control. By utilizing these techniques, the sample drift induced in the Z-axis direction can be measured and automatically corrected for every 1/30 of a second. The auto focus tracking system can be operated in the sample drift range of +/-150 nm with a precision of ~0.4 nm. In addition to amorphous samples, the system can be used to examine thin crystalline samples, which indicates that atomic structure analysis can be performed in real time with high reliability even when heavy drift occurs in the Z-axis direction. PMID- 28339657 TI - Comment on clinical features and changes in epidemiology of infective endocarditis on pacemaker devices over a 27-year period. PMID- 28339658 TI - Acute cell volume regulation by Janus kinase 2-mediated sodium/hydrogen exchange activation develops at the late one-cell stage in mouse preimplantation embryos. AB - Early preimplantation embryos are extremely sensitive to dysregulation of cell volume, which can lead to developmental arrest. It was previously shown that mouse embryos at the two-cell stage respond to a cell volume decrease by quickly activating Na+/H+ exchange via a signaling mechanism that involves the tyrosine kinase Janus kinase 2 (JAK2). However, it was not known whether this mechanism is active at the one-cell stage, when embryos are most sensitive to perturbed cell volume. Na+/H+ exchanger activity elicited by an induced cell volume decrease was significantly lower at the mid one-cell stage than at the late one-cell stage or during the two-cell stage. This activity could be completely blocked by the broad specificity tyrosine kinase inhibitor genistein at either stage, but only at the two-cell stage was there a substantial component of activity that was sensitive to low concentrations of the JAK2-selective inhibitors TG101348 or ruxolitinib. Western blots to detect active JAK2 phosphorylated on tyrosine Y1007/8 revealed that JAK2 became substantially phosphorylated in response to a cell volume decrease at the mid two-cell, but not mid one-cell stage. Such cell volume decrease-induced JAK2 phosphorylation appeared by the late one-cell stage. At least in part this appears to be due to an increase in total JAK2 protein at the late one-cell stage. Furthermore, TG101348 impaired maintenance of cell volume at the two-cell, but not mid one-cell, stages. Thus, cell volume homeostasis requiring Na+/H+ exchange signaled by JAK2 first becomes prominent during mouse embryonic development at the late one-cell stage. PMID- 28339659 TI - The use of guideline recommended beta-blocker therapy in primary prevention implantable cardioverter defibrillator patients: insight from Danish nationwide registers. AB - Aims: We aimed to examine the use of guideline recommended beta-blocker therapy prior to and after primary prevention implantable cardioverter defibrillator (ICD) implantation in a 'real-life' setting. Methods and results: From the Danish Pacemaker and ICD Registry we identified all 1st-time primary prevention ICD and cardiac resynchronization therapy defibrillator (CRT-D) implantations in Denmark from 2007-12 (n = 2935). Use of beta-blocker, type and dose was acquired through the Danish Prescription Registry. According to guideline recommendations, we defined target daily doses as >=50 mg carvedilol and >=200 mg metoprolol. Prior to implantation 2427 of 2935 (83%) patients received beta-blocker therapy, with 2166 patients (89%) having initiated treatment 3 months or more prior to implantation. The majority of patients was prescribed carvedilol (52%) or metoprolol (41%). Patients on carvedilol reached target dosages more frequently than patients on metoprolol, with 39% of patients on carvedilol and 26% of patients on metoprolol at the time of implantation (P < 0.001 for all time points). Increase in proportion of patients reaching target daily doses was observed for both carvedilol and metoprolol after ICD implantation. Carvedilol treatment was a strong predictor for being on target dose of BB at time of implant, as was treatment with angiotensin-converting enzyme inhibitors and/or spironolactone, no history of myocardial infarction, younger age and less pronounced heart failure symptoms. Conclusion: In a real-life setting of primary prevention ICD patients, 39% and 26% of patients were titrated to optimal target dose of carvedilol or metoprolol prior to implantation. A higher proportion of patients on carvedilol reached target dose, as compared with metoprolol. PMID- 28339661 TI - The effectiveness of current French health warnings displayed on alcohol advertisements and alcoholic beverages. AB - Background: Many countries use health warnings in an attempt to regulate alcohol consumption. However, there is a lack of conclusive evidence in the research on alcohol warnings to support decision-making on effective health policies. This study explores the effectiveness of two mandatory warnings introduced in France in 1991 and 2007: the first (Alcohol abuse is harmful) is displayed on alcohol advertisements; the second (a pictogram) on bottles. Given that advertising content regulations have been implemented in some countries to reduce the attractiveness of alcohol marketing (e.g. the Evin law in France), this research also aims to explore whether such regulations can improve the effectiveness of warnings. Methods: In-depth interviews were conducted with 26 French people aged 15-29 years. The effectiveness of health warnings was assessed in terms of recall, noticeability, credibility, comprehension, responsiveness, and ability to encourage moderate drinking and abstinence during pregnancy. Participants were shown alcohol advertisements and bottles that either followed or challenged content regulations. The data were analyzed using double manual coding and NVivo software. Results: While both warnings suffered from a lack of visibility and noticeability due to their size, location, and outdatedness and because of competition from marketing design elements, the warning on the advertisement that followed content regulations was most visible. Both warnings were considered to be informationally vague, lacking in credibility and ineffective in terms of making participants feel concerned and influencing consumption habits. Conclusions: Current French warnings are ineffective and require modification. Improvements are suggested regarding the design and content of warnings to help increase their effectiveness. PMID- 28339663 TI - Cardiac involvement in granulomatosis with polyangiitis: a magnetic resonance imaging study of 31 consecutive patients. AB - Objectives: Specific cardiac involvement in granulomatosis with polyangiitis (GPA) is probably underestimated since many of these conditions are subclinical. The objective of this study was to assess the prevalence and patterns of cardiac abnormalities detected by cardiac MRI (CMRI) in patients with GPA. Methods: Thirty-one consecutive patients with newly diagnosed or relapsing GPA underwent CMRI to assess morphological, functional, perfusion at rest and delayed enhancement abnormalities. Results: At least one abnormality was observed on CMRI for 19 of 31 patients (61%). Four patients (13%) had an impaired left ventricle ejection fraction (LVEF). LV regional wall motion abnormalities were found in 11 patients (35%). Late gadolinium enhancement (LGE) was detected in 10 of 31 patients (32%). LGE was mostly nodular ( n = 9). Myocardial early contrast enhancement was detected in 5 of the 31 patients (16%), which was systematically associated with LGE in the same territory. CMRI detected pericarditis in eight patients (26%). GPA with <18 months duration was associated with a higher LVEF ( P = 0.03), fewer CMRI abnormalities ( P = 0.04) and less LV hypokinesia ( P = 0.04) than GPA with a longer duration. Patients with recent-onset GPA had a higher LVEF ( P = 0.01) and less LV hypokinesia ( P = 0.006) than patients experiencing a relapse ( P = 0.02). Conclusion: CMR is an accurate technique for detecting heart involvement in GPA. This unique non-invasive technique may provide information with important clinical implications for the accurate early assessment of cardiac lesions in GPA patients and for detecting cumulative, irreversible damage. It may also have prognostic implications. PMID- 28339660 TI - Eculizumab in secondary atypical haemolytic uraemic syndrome. AB - Background: Complement dysregulation occurs in thrombotic microangiopathies (TMAs) other than primary atypical haemolytic uraemic syndrome (aHUS). A few of these patients have been reported previously to be successfully treated with eculizumab. Methods: We identified 29 patients with so-called secondary aHUS who had received eculizumab at 11 Spanish nephrology centres. Primary outcome was TMA resolution, defined by a normalization of platelet count (>150 * 10 9 /L) and haemoglobin, disappearance of all the markers of microangiopathic haemolytic anaemia (MAHA), and improvement of renal function, with a >=25% reduction of serum creatinine from the onset of eculizumab administration. Results: Twenty nine patients with secondary aHUS (15 drug-induced, 8 associated with systemic diseases, 2 with postpartum, 2 with cancer-related, 1 associated with acute humoral rejection and 1 with intestinal lymphangiectasia) were included in this study. The reason to initiate eculizumab treatment was worsening of renal function and persistence of TMA despite treatment of the TMA cause and plasmapheresis. All patients showed severe MAHA and renal function impairment (14 requiring dialysis) prior to eculizumab treatment and 11 presented severe extrarenal manifestations. A rapid resolution of the TMA was observed in 20 patients (68%), 15 of them showing a >=50% serum creatinine reduction at the last follow-up. Comprehensive genetic and molecular studies in 22 patients identified complement pathogenic variants in only 2 patients. With these two exceptions, eculizumab was discontinued, after a median of 8 weeks of treatment, without the occurrence of aHUS relapses. Conclusion: Short treatment with eculizumab can result in a rapid improvement of patients with secondary aHUS in whom TMA has persisted and renal function worsened despite treatment of the TMA-inducing condition. PMID- 28339662 TI - HIV-1 Proteins Influence Novelty-Seeking Behavior and Alter Region-Specific Transcriptional Responses to Chronic Nicotine Treatment in HIV-1Tg Rats. AB - Introduction: Clinical studies suggest that HIV-1-infected patients are more likely to use or abuse addictive drugs than is the general population. We hypothesized that HIV-1 proteins impact novelty-seeking behavior and enhance the transcriptional response to nicotine in genes implicated in both novelty-seeking behavior and drug addiction. Methods: We assessed the effects of HIV-1 proteins on novelty-seeking behavior by comparing baseline activity differences of HIV-1Tg and F344 control rats in the open-field test. One day after behavioral testing, all rats began daily subcutaneous injections of either nicotine (0.4 mg/kg, base) or saline (the same for each rat) for 27 days. At the end of treatment, the prefrontal cortex, nucleus accumbens, and ventral tegmental area were collected for RNA expression analysis of genes in the receptor families for dopamine, GABA, glutamate, and serotonin. Results: Significant strain difference was detected in the distance moved in the center, such that HIV-1Tg rats traveled greater distance in the center of the arena than did F344 rats. Quantitative RT-PCR analysis showed that mRNA from Drd3 and Grm2 in the prefrontal cortex and Drd5 and Gabra6 in the ventral tegmental area was significantly upregulated, whereas that of Drd5 in the nucleus accumbens was downregulated in HIV-1Tg rats compared with F344 rats. Further, more addiction-related genes were significantly modulated by nicotine in each brain region in the HIV-1Tg rats than in the control animals. Conclusions: HIV-1 proteins may affect novelty-seeking behavior and modulate the expression of genes related to drug addiction and novelty seeking behavior. Implications: HIV-1 viral proteins and chronic nicotine treatment impact the expression of genes involved in novelty-seeking behavior and addiction in three brain regions of the HIV-1 transgenic rat. These findings implicate that HIV-1 proteins may be involved in novelty-seeking behavior and in modulating the expression of genes related to drug addiction and novelty seeking. PMID- 28339664 TI - Adult Paget's disease of bone: a review. AB - Adult PD of bone is the second commonest metabolic bone condition after osteoporosis. The condition is characterized by increased bone cell activity, with bone-resorbing osteoclasts often larger and containing more nuclei than normal, and osteoblasts producing increased amounts of disorganized bone. This leads to expanded bone of poor quality possessing both sclerotic and lytic areas. PD of bone has a strong genetic element, with a family history being noted in 10 20% of cases. A number of genetic defects have been found to be associated with the condition. The most common disease-associated variants identified affect the SQSTM1 gene, providing insights into disease aetiology, with the clinical value of knowledge of SQSTM1 mutation status currently under active investigation. The diagnosis may be suggested by an isolated raised total ALP without other identifiable causes. This can be confirmed on plain X-rays and the extent determined by isotope bone scan. The mainstays of treatment are the bisphosphonates, especially i.v. zoledronate, which results in long-term suppression of bone turnover. ALP is the usual means of monitoring the condition, although more specific bone turnover markers can be helpful, especially in coincident liver disease. Patients should be followed up to monitor for biochemical relapse or development of complications, which may require medical or surgical intervention. PMID- 28339665 TI - An evaluation of a public-private partnership to reduce artificial trans fatty acids in England, 2011-16. AB - Background: The Public Health Responsibility Deal (RD) is a public-private partnership in England involving voluntary pledges between government, and business and other public organizations to improve public health. One such voluntary pledge refers to the reduction of trans fatty acids (TFAs) in the food supply in England by either pledging not to use artificial TFAs or pledging artificial TFA removal. This paper evaluates the RD's effectiveness at encouraging signatory organizations to remove artificially produced TFAs from their products. Methods: We analysed publically available data submitted by RD signatory organizations. We analysed their plans and progress towards achieving the TFAs pledge, comparing 2015 progress reports against their delivery plans. We also assessed the extent to which TFAs reductions beyond pre-2011 levels could be attributed to the RD. Results: Voluntary reformulation via the RD has had limited added value, because the first part of the trans fat pledge simply requires organizations to confirm that they do not use TFAs and the second part, that has the potential to reduce use, has failed to attract the participation of food producers, particularly those producing fast foods and takeaways, where most remaining use of artificial TFAs is located. Conclusions: The contribution of the RD TFAs pledges in reducing artificial TFAs from England's food supply beyond pre 2011 levels appears to be negligible. This research has wider implications for the growing international evidence base voluntary food policy, and offers insights for other countries currently undertaking work to remove TFAs from their food supply. PMID- 28339666 TI - Zero-fluoroscopy catheter ablation of concealed left accessory pathway in a pregnant woman. PMID- 28339667 TI - Unilateral Pulmonary Edema, Westermark's Sign and Palla's Sign in Pulmonary Embolism. PMID- 28339668 TI - Immunogenicity of a Booster Dose of Quadrivalent Meningococcal Conjugate Vaccine in Previously Immunized HIV-Infected Children and Youth. AB - Background: The US Advisory Committee on Immunization Practices recommends a booster dose of quadrivalent meningococcal conjugate vaccine (MCV4) after initial immunization for patients at high risk for meningococcal infection. Methods: The International Maternal Pediatric Adolescents AIDS Clinical Trials (IMPAACT) P1065 trial evaluated the use of MCV4 in human immunodeficiency virus (HIV)-infected children and youth. The final step of this trial was an open-label study of an MCV4 booster dose 3.5 years after primary MCV4 immunization. Antibody titers were evaluated at the time of the booster vaccine and 1, 4, and 24 weeks after the booster. Immunogenicity was measured by rabbit serum bactericidal antibody (rSBA) against each meningococcal serogroup. Immunologic memory was defined as either seroprotection (rSBA titer >=1:128) or a >=4-fold increase 1 week after the booster dose. Primary response was defined as either a >=4-fold response or seropositivity 4 weeks after the booster in the absence of immunologic memory. Adverse events were assessed for 4 weeks after the booster dose. Results: Of 174 participants with serology results at entry and 1 and 4 weeks later, the percentage with protective antibody levels at entry varied according to serogroup, ranging from a low of 26% for serogroup C to a high of 68% for serogroup A. A memory response to at least 1 serogroup occurred in 98% of the participants: 93% each for serogroups A and Y, 88% for serogroup C, and 94% for serogroup W-135; 83% had a memory response to all 4 serogroups. Overall, rates of any memory or primary response were >=90% for all serogroups. No serious adverse events were encountered. Conclusions: A booster dose of MCV4 elicited a memory response in 88% to 94% of previously immunized HIV-infected participants depending on serogroup, including those who lacked a protective titer level for that serogroup before booster vaccination. PMID- 28339669 TI - In Their Own Words: Young Adults' Menthol Cigarette Initiation, Perceptions, Experiences and Regulation Perspectives. AB - Background: Menthol cigarettes are disproportionately used by young people and have been called smoking starter products. However, limited qualitative research exists on young adults' perceptions of and experiences with these products, with much of it based on document reviews of the tobacco industry's research. Methods: We conducted six focus groups with young adult (ages 18-24) menthol smokers in New Jersey (half with black smokers) between December 2014 and March 2015. Participants were asked open-ended questions about their menthol smoking initiation, preference reasons, substitution behaviors, and perceptions of menthol cigarette risks and regulation. Results: Participants' menthol cigarette initiation and preference were influenced by their perceived popularity, brand recognition, taste, smoothness, satisfaction and access (including as "loosies," typically available for Newport). Some believed menthol cigarettes were less harmful than non-menthol cigarettes when initiating smoking. Many currently believed menthol cigarettes were more harmful because they contained extra "additives," were stronger (ie, requiring fewer cigarettes to feel satisfied), and/or based on hearsay. Many had tried new brand Camel Crush, which was perceived to be especially minty, fun, and attractive for newer smokers. While some used non-menthol cigarettes when menthols were unavailable, many said they would never or almost never substitute. Many acknowledged a menthol cigarettes ban would likely help them quit smoking, even though they did not support the idea. Conclusions: Menthol cigarette initiation is influenced by an interplay of multiple factors including their sensory properties, marketing, perceived popularity and availability. The FDA should continue to pursue closing this flavored cigarette loophole. Implications: In this first qualitative study of menthol cigarette use among young adults, we found further evidence that menthol cigarettes can act as starter products because they are perceived as easier to smoke and taste and smell better than non-menthol cigarettes. We also add to the literature in finding that menthol cigarettes are perceived by young people who smoke menthol cigarettes as delivering satisfaction with fewer cigarettes, being accessible as "loosies", and being popular among their peers. Many did not understand the reasons behind a potential menthol ban. Any future regulation of menthol cigarettes should include a public educational campaign to support buy in. PMID- 28339670 TI - Exploring the variability in Behcet's disease prevalence: a meta-analytical approach. AB - Background: Surveys of Behcet's disease (BD) have shown substantial geographic variations in prevalence, but some of these differences may result from methodological inconsistencies. This meta-analysis explored the effect of geographic location and study methodology on the prevalence of BD. Methods: We systematically searched the literature in electronic databases and by handsearching to identify population-based prevalence surveys of BD. Studies were eligible if they provided an original population-based prevalence estimate for BD with the number of prevalent cases identified in the study area. Pooled prevalence proportions across all studies were computed by using random effects models based on a Poisson normal distribution. Pre-defined subgroup analyses and meta-regression were used to investigate the effect of covariates on the prevalence proportions. Results: We included 45 reports published from 1974 to 2015 and covering worldwide areas. The pooled estimates of prevalence proportions (expressed as cases/100 000 inhabitants) were 10.3 (95% CI 6.1, 17.7) for all studies and 119.8 (59.8, 239.9) for Turkey, 31.8 (12.9, 78.4) for the Middle East, 4.5 (2.2, 9.4) for Asia and 3.3 (2.1, 5.2) for Europe. Subgroup analyses showed a strikingly greater prevalence for studies with a sample survey design than a census design [82.5 (95% CI 47.3, 143.9) vs 3.6 (2.6, 5.1)]. Metaregression identified study design as an independent covariate significantly affecting BD prevalence proportions. Conclusions: Differences in BD prevalence proportions likely reflect a combination of true geographic variation and methodological artefacts. In particular, use of a sample or census study design may strongly affect the estimated prevalence. PMID- 28339672 TI - Corrigendum. PMID- 28339671 TI - Characteristics of donor-specific anti-HLA antibodies and outcome in renal transplant patients treated with a standardized induction regimen. AB - Background: Pre-transplant donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) have been associated with antibody-mediated rejection (AMR) and early kidney allograft loss. Uncertainties remain regarding the general applicability of these findings and the optimal induction therapy in DSA-positive patients. Methods: Pre-transplant sera from 174 patients receiving a crossmatch negative kidney transplant were retrospectively analysed for DSA using Luminex technology. DSA with mean-fluorescence intensity (MFI) values above 500 were considered positive. All recipients received basiliximab induction and tacrolimus based maintenance immunosuppression. DSA were monitored post-transplantation in patients with pre-transplant DSA. Antibody results were correlated with the incidence of rejection and graft loss. Results: In total, 61/174 patients had pre transplant DSA. We found a strong correlation between the presence of DSA against class I and II HLA and DSA MFI greater than 10 000. Both DSA patterns independently predicted an increased risk of early AMR (odds ratio 4.24 and 4.75, respectively, P < 0.05). The risk for AMR in patients with intermediate MFI (3000 10 000) gradually increased with increasing MFI but group sizes were too small to allow for final conclusions. The risk for AMR was comparable to nonsensitized patients in patients with only class I or II HLA-DSA or MFI below 3000. 5-year allograft survival was lowest in patients with simultaneous presence of class I and II HLA-DSA and MFI above 10 000 (45%) but was comparable between patients with only HLA class I or II or no DSA (90.0, 90.0 and 88.1%, respectively). AMR was the only independent predictor of graft loss. Undetectable DSA 14 days post transplant predicted excellent long-term outcome. Conclusion: . The favourable outcome in the majority of DSA-positive patients despite non-depleting antibody induction and the poor outcome in patients with class I and II HLA-DSA and high DSA strength call for a differentiated therapeutic approach in this patient population. PMID- 28339674 TI - Family history of systemic lupus erythematosus and risk of autoimmune disease: Nationwide Cohort Study in Denmark 1977-2013. AB - Objective: To provide population-based estimates of relative risk of SLE and other autoimmune diseases (ADs) in relatives of SLE patients. Methods: A cohort of 5 237 319 Danish residents identified through the Civil Registration System was coupled to their relatives through the parental link and followed for SLE and other ADs between 1977 and 2013 through linkage to the National Patient Register. Twin zygosity was established through the Danish Twin Registry. Hazard ratios (HRs) with 95% CIs were calculated using Cox proportional hazards regression analyses. Results: During 117.5 million person-years of follow-up, 3612 persons were hospitalized with SLE. HRs of SLE were high among first-degree (HR = 10.3; 95% CI: 8.25, 12.9; n = 80) and second- or third-degree relatives of SLE patients (HR = 3.60; 95% CI: 2.20, 5.90; n = 16). HRs for any AD were elevated in first degree (HR = 1.51; 95% CI: 1.41, 1.62; n = 785) and second- or third-degree relatives of SLE patients (HR = 1.28; 95% CI: 1.18, 1.39; n = 582). Among individuals with SLE-affected first-degree relatives, the risk was significantly increased for RA (HR = 1.64; 95% CI: 1.35, 1.99; n = 103), IBD (HR = 1.21; 95% CI: 1.02, 1.43; n = 130) and type 1 diabetes mellitus (HR = 1.23; 95% CI: 1.01, 1.48; n = 106). Risk of other ADs was significantly increased both among SLE affected first-degree (HR = 2.08; 95% CI: 1.88, 2.31; n = 371) and second- or third-degree relatives (HR = 1.38; 95% CI: 1.23, 1.54; n = 313). Conclusion: Family history of SLE is associated with a clearly elevated risk of SLE and, to a much lesser degree, of RA and other ADs. PMID- 28339676 TI - MiR-33 regulation of stretch-induced intimal hyperplasia in vein grafts. PMID- 28339675 TI - High Reported Rates of Antimicrobial Resistance in Indian Neonatal and Pediatric Blood Stream Infections. AB - Background: There is real shortage of national data on antimicrobial resistance rates in Indian neonates and children. A descriptive review was conducted to determine the patterns of antimicrobial resistance in isolates of blood stream infection among hospitalized children in India. Methods: Published and gray literature on antibiotic resistance in children was searched using "Google Scholar", "Scopus", and "PubMed" databases between January 2000 and July 2015. Studies were included if they were original articles that reported a minimum of 10 pathogenic bacterial isolates from the bloodstream within a pediatric population in India, and studies were excluded if they reported studies done during an outbreak or epidemic. Results: A total of 1179 studies were screened, and 82 papers were identified as eligible for inclusion. Most studies (78.7%) were reported from neonatal intensive care units. Among a total of 50545 reported blood cultures, 14704 (29.1%) were positive. Staphylococcus aureus (median, 14.7%; IQR, 7.4%-25.6%) and Klebsiella pneumoniae (median, 26%; IQR, 16.7%-35.4%) were the commonest reported Gram-positive and Gram-negative pathogens, respectively. Approximately half of all S aureus isolates were reported as methicillin-resistant S aureus (median, 50%; IQR, 31.4%-65.1%). After age stratification, the median rate of resistance of common Gram-negative pathogens to ampicillin and gentamicin/amikacin were extremely high (K pneumoniae/ampicillin 95.9%; K pneumoniae/gentamicin 75%; Escherichia coli/ampicillin 92.9%; E coli/gentamicin 55.6%). Likewise, the median resistance of common Gram-negative blood stream isolates to cephalosporins were also high (K pneumoniae/cefotaxime 62.6%; E coli/cefotaxime 47.5%). Conclusions: High rates of resistance to World Health Organization-recommended first-line treatment options for neonates and children have been identified in blood stream infections across India. There is an urgent need to both enhance antibiotic stewardship and infection prevention and control measures and consider urgently how to repurpose older antibiotics back into routine care in India. PMID- 28339677 TI - Development of a Food Allergy Knowledge Test for Parents. AB - Objective: To create a measure of food allergy (FA) knowledge for parents of children with FA. Methods: The food allergy knowledge test (FAKT) was developed following rigorous test-construction guidelines. The preliminary 110-item pool content was developed in consultation with FA experts. After cognitive interviews and revisions, an 88-item preliminary version was administered to 370 parents of children with FA who were recruited online and from an allergy clinic. After item difficulty, discrimination, item-scale correlations analyses, and assessment of internal consistency, a revised 57-item version was administered to a new clinic based sample (77 parents). Results: The revised FAKT was highly reliable (alpha =.86). Validity analyses revealed positive correlations ( r = .23-.57) between FAKT scores and parent age, education, insurance status, access to FA information, and auto-injector use. Conclusions: The FAKT was determined to have strong psychometrics and be appropriately reliable and valid, with clinical and research applications. PMID- 28339679 TI - Letter in response to remote ischaemic conditioning provides humoral cross species cardioprotection through glycine receptor activation. PMID- 28339680 TI - Operations management in distribution networks within a smart city framework. AB - This article studies a vehicle routing problem with environmental constraints that are motivated by the requirements for sustainable urban transport. The empirical research presents a fleet planning problem that takes into consideration both minimum cost vehicle routes and minimum pollution. The problem is formulated as a mixed integer linear programming model and experimentally validated using data collected from a real situation: a grocery company delivering goods ordered via e-channels to customers spread in the urban and metropolitan area of Genoa smart city. The proposed model is a variant of the vehicle routing problem tailored to include environmental issues and street limitations. Its novelty regards also the use of real data instances provided by the B2C grocery company. Managerial implications are the choice of both the routes and the number and type of vehicles. Results show that commercial distribution strategies achieve better results in term of both business and environmental performance, provided the smart mobility goals and constraints are included into the distribution model from the beginning. PMID- 28339678 TI - DDX4-EGFP transgenic rat model for the study of germline development and spermatogenesis. AB - Spermatogonial stem cells (SSC) are essential for spermatogenesis and male fertility. In addition, these adult tissue stem cells can be used as vehicles for germline modification in animal models and may have application for treating male infertility. To facilitate the investigation of SSCs and germ lineage development in rats, we generated a DEAD-box helicase 4 (DDX4) (VASA) promoter-enhanced green fluorescent protein (EGFP) reporter transgenic rat. Quantitative real-time polymerase chain reaction and immunofluorescence confirmed that EGFP was expressed in the germ cells of the ovaries and testes and was absent in somatic cells and tissues. Germ cell transplantation demonstrated that the EGFP-positive germ cell population from DDX4-EGFP rat testes contained SSCs capable of establishing spermatogenesis in experimentally infertile mouse recipient testes. EGFP-positive germ cells could be easily isolated by fluorescence-activated cells sorting, while simultaneously removing testicular somatic cells from DDX4-EGFP rat pup testes. The EGFP-positive fraction provided an optimal cell suspension to establish rat SSC cultures that maintained long-term expression of zinc finger and BTB domain containing 16 (ZBTB16) and spalt-like transcription factor 4 (SALL4), two markers of mouse SSCs that are conserved in rats. The novel DDX4 EGFP germ cell reporter rat described here combined with previously described GCS EGFP rats, rat SSC culture and gene editing tools will improve the utility of the rat model for studying stem cells and germ lineage development. PMID- 28339681 TI - On tear film breakup (TBU): dynamics and imaging. AB - We report the results of some recent experiments to visualize tear film dynamics. We then study a mathematical model for tear film thinning and tear film breakup (TBU), a term from the ocular surface literature. The thinning is driven by an imposed tear film thinning rate which is input from in vivo measurements. Solutes representing osmolarity and fluorescein are included in the model. Osmolarity causes osmosis from the model ocular surface, and the fluorescein is used to compute the intensity corresponding closely to in vivo observations. The imposed thinning can be either one-dimensional or axisymmetric, leading to streaks or spots of TBU, respectively. For a spatially-uniform (flat) film, osmosis would cease thinning and balance mass lost due to evaporation; for these space dependent evaporation profiles TBU does occur because osmolarity diffuses out of the TBU into the surrounding tear film, in agreement with previous results. The intensity pattern predicted based on the fluorescein concentration is compared with the computed thickness profiles; this comparison is important for interpreting in vivo observations. The non-dimensionalization introduced leads to insight about the relative importance of the competing processes; it leads to a classification of large vs small TBU regions in which different physical effects are dominant. Many regions of TBU may be considered small, revealing that the flow inside the film has an appreciable influence on fluorescence imaging of the tear film. PMID- 28339682 TI - The effects of interleukin-2 on immune response regulation. AB - The immune system has many adaptive and dynamic components that are regulated to ensure appropriate, precise and rapid response to a foreign pathogen. A delayed or inadequate immune response can lead to prolonged disease, while an excessive or under-regulated response can lead to autoimmunity. The cytokine, interleukin-2 (IL-2) and its receptor IL-2R play an important role in maintaining this balance.The IL-2 receptor transduces pSTAT5 signal through both the intermediate and high affinity receptors, which differ from each other by the presence of CD25 chain in IL-2 receptor. We present experimental data on the kinetics of pSTAT5 signalling through both of the receptors and develop a model that captures this kinetics. We then use this model to parameterize key aspects of two additional models in which we propose and study two different mechanisms by which IL-2 receptor can transduce distinct signals leading to either an activated or a non activated cell state. We speculate that this initial state differentiation, perhaps enhanced by downstream feedbacks, may eventually lead to differential cell fates.Our result shows that non-linear dynamical models can suggest resolution of a puzzling array of seemingly contradictory experimental results on IL-2 effect on proliferation and differentiation of T-cells. PMID- 28339684 TI - Embedding Nursing Interventions into the World Health Organization's International Classification of Health Interventions (ICHI). AB - Objective: The International Classification of Health Interventions, currently being developed, seeks to span all sectors of the health system. Our objective was to test the draft classification's coverage of interventions commonly delivered by nurses, and propose changes to improve the utility and reliability of the classification for aggregating and analyzing data on nursing interventions. Materials and methods: A 2-phase content mapping method was used: (1) three coders independently applied the classification to a dataset comprising 100 high-frequency nursing interventions; (2) the coders reached consensus for each intervention and identified reasons for initial discrepancies. Results: A consensus code was found for 80 of the 100 source terms; for 34% of these, the code was semantically equivalent to the source term, and for 64% it was broader. Issues that contributed to discrepancies in Phase 1 coding results included concepts in source terms not captured by the classification, ambiguities in source terms, and uncertainty of semantic matching between "action" concepts in source terms and classification codes. Discussion: While the classification generally provides good coverage of nursing interventions, there remain a number of content gaps and granularity issues. Further development of definitions and coding guidance is needed to ensure consistency of application. Conclusion: This study has produced a set of proposals concerning changes needed to improve the classification. The novel method described here will inform future health terminology and classification content coverage studies. PMID- 28339683 TI - Addressing Beacon re-identification attacks: quantification and mitigation of privacy risks. AB - The Global Alliance for Genomics and Health (GA4GH) created the Beacon Project as a means of testing the willingness of data holders to share genetic data in the simplest technical context-a query for the presence of a specified nucleotide at a given position within a chromosome. Each participating site (or "beacon") is responsible for assuring that genomic data are exposed through the Beacon service only with the permission of the individual to whom the data pertains and in accordance with the GA4GH policy and standards.While recognizing the inference risks associated with large-scale data aggregation, and the fact that some beacons contain sensitive phenotypic associations that increase privacy risk, the GA4GH adjudged the risk of re-identification based on the binary yes/no allele presence query responses as acceptable. However, recent work demonstrated that, given a beacon with specific characteristics (including relatively small sample size and an adversary who possesses an individual's whole genome sequence), the individual's membership in a beacon can be inferred through repeated queries for variants present in the individual's genome.In this paper, we propose three practical strategies for reducing re-identification risks in beacons. The first two strategies manipulate the beacon such that the presence of rare alleles is obscured; the third strategy budgets the number of accesses per user for each individual genome. Using a beacon containing data from the 1000 Genomes Project, we demonstrate that the proposed strategies can effectively reduce re identification risk in beacon-like datasets. PMID- 28339685 TI - Information needs of generalists and specialists using online best-practice algorithms to answer clinical questions. AB - Objective: To better understand clinician information needs and learning opportunities by exploring the use of best-practice algorithms across different training levels and specialties. Methods: We developed interactive online algorithms (care process models [CPMs]) that integrate current guidelines, recent evidence, and local expertise to represent cross-disciplinary best practices for managing clinical problems. We reviewed CPM usage logs from January 2014 to June 2015 and compared usage across specialty and provider type. Results: During the study period, 4009 clinicians (2014 physicians in practice, 1117 resident physicians, and 878 nurse practitioners/physician assistants [NP/PAs]) viewed 140 CPMs a total of 81 764 times. Usage varied from 1 to 809 views per person, and from 9 to 4615 views per CPM. Residents and NP/PAs viewed CPMs more often than practicing physicians. Among 2742 users with known specialties, generalists ( N = 1397) used CPMs more often (mean 31.8, median 7 views) than specialists ( N = 1345; mean 6.8, median 2; P < .0001). The topics used by specialists largely aligned with topics within their specialties. The top 20% of available CPMs (28/140) collectively accounted for 61% of uses. In all, 2106 clinicians (52%) returned to the same CPM more than once (average 7.8 views per topic; median 4, maximum 195). Generalists revisited topics more often than specialists (mean 8.8 vs 5.1 views per topic; P < .0001). Conclusions: CPM usage varied widely across topics, specialties, and individual clinicians. Frequently viewed and recurrently viewed topics might warrant special attention. Specialists usually view topics within their specialty and may have unique information needs. PMID- 28339686 TI - Movement patterns in women at risk for perinatal depression: use of a mood monitoring mobile application in pregnancy. AB - Objectives: To examine, using a smartphone application, whether mood is related to daily movement patterns in pregnant women at risk for perinatal depression. Materials and Methods: Thirty-six women with elevated depression symptoms (PHQ-9 >= 5) in pregnancy used the application for 8 weeks. Mood was reported using application-administered surveys daily (2 questions) and weekly (PHQ-9 and GAD 7). The application measured daily mobility (distance travelled on foot) and travel radius. Generalized linear mixed-effects regression models estimated the association between mood and movement. Results: Women with milder depression symptoms had a larger daily radius of travel (2.7 miles) than women with more severe symptoms (1.9 miles), P = .04. There was no difference in mobility. A worsening of mood from the prior day was associated with a contracted radius of travel, as was being in the group with more severe symptoms. No significant relationships were found between anxiety and either mobility or radius. Discussion: We found that the association of mood with radius of travel was more pronounced than its association with mobility. Our study also demonstrated that a change in mood from the prior day was significantly associated with radius but not mood on the same day that mobility and radius were measured. Conclusion: This study lays the groundwork for future research on how smartphone mood-monitoring applications can combine actively and passively collected data to better understand the relationship between the symptoms of perinatal depression and physical activity that could lead to improved monitoring and novel interventions. PMID- 28339688 TI - An Activity-Staining Method on Filtration Paper Enables High-Throughput Screening of Temperature-Sensitive and Inactive Mutations of Rice alpha-Amylase for Improvement of Rice Grain Quality. AB - alpha-Amylase is a starch-hydrolyzing enzyme (EC 3.2.1.1) indispensable for germination of cereal seeds, but it is also expressed during the ripening stage. Previous studies demonstrated that the enzyme is activated in developing rice seeds under extremely hot weather and triggers a loss of grain quality by hindering the accumulation of storage starch in the endosperm. Since inactive or, preferably, heat-labile alpha-amylases are preferable for breeding premium rice, we developed a method for rapid screening of inactive and temperature-sensitive mutants of the enzyme by combining the random mutagenesis by error-prone PCR and an on-filter activity test of the recombinant enzyme expressed by Escherichia coli. This technique was applied to a major alpha-amylase in the developing seed, Amy3D, and the activity of the isolated mutant enzymes was verified with both the bacteria-expressed recombinant proteins and the extract from the endosperm overexpressing each of them. Then, we identified several substitutions leading to loss of the activity of amino acid residues (Leu28, Asp112, Cys149, Trp201, Asp204, Gly295, Leu300 and Cys342), as well as a variety of heat-sensitive substitutions of Asp83, Asp187 and Glu252. Furthermore, variations of the heat labile enzymes were created by combining these heat-sensitive mutations. The effects of the respective mutations and their relationship to the structure of the enzyme molecule are discussed. PMID- 28339687 TI - Extragonadal oocytes residing in the mouse ovarian hilum contribute to fertility. AB - The observation of pups born from recipient and donor mice after ovariectomy followed by ovarian transplant poses the interesting possibility of an extraovarian source of oocytes. However, whether mammalian adult oocytes reside in extragonadal tissues remains elusive. Using transgenic fluorescent reporter mice and transplantation surgeries, we demonstrate the presence of both donor- and recipient-derived corpora lutea and recovery of both donor- and recipient derived offspring from ovariectomized mice after transplantation of donor ovaries. A potential region for extraovarian oocytes is the hilum, a ligament like structure between the ovary and the reproductive tract. Immunofluorescent confocal microscopy of mouse ovaries and reproductive tracts revealed that a population of primordial follicles resides outside the ovary within the hilum. Ovariectomy-only controls confirmed that oocytes remain in the recipient hilum after surgery. These results provide evidence that the hilum is a reserve source of follicles, which likely return to the ovary for maturation and ovulation. By identifying a new follicle reservoir, our study addresses a long-standing question in reproductive biology and contributes to new conceptual knowledge about ovarian function and fertility. PMID- 28339689 TI - Genomic decision support needs in pediatric primary care. AB - Clinical genome and exome sequencing can diagnose pediatric patients with complex conditions that often require follow-up care with multiple specialties. The American Academy of Pediatrics emphasizes the role of the medical home and the primary care pediatrician in coordinating care for patients who need multidisciplinary support. In addition, the electronic health record (EHR) with embedded clinical decision support is recognized as an important component in providing care in this setting. We interviewed 6 clinicians to assess their experience caring for patients with complex and rare genetic findings and hear their opinions about how the EHR currently supports this role. Using these results, we designed a candidate EHR clinical decision support application mock up and conducted formative exploratory user testing with 26 pediatric primary care providers to capture opinions on its utility in practice with respect to a specific clinical scenario. Our results indicate agreement that the functionality represented by the mock-up would effectively assist with care and warrants further development. PMID- 28339690 TI - Automated classification of eligibility criteria in clinical trials to facilitate patient-trial matching for specific patient populations. AB - Objective: To develop automated classification methods for eligibility criteria in ClinicalTrials.gov to facilitate patient-trial matching for specific populations such as persons living with HIV or pregnant women. Materials and Methods: We annotated 891 interventional cancer trials from ClinicalTrials.gov based on their eligibility for human immunodeficiency virus (HIV)-positive patients using their eligibility criteria. These annotations were used to develop classifiers based on regular expressions and machine learning (ML). After evaluating classification of cancer trials for eligibility of HIV-positive patients, we sought to evaluate the generalizability of our approach to more general diseases and conditions. We annotated the eligibility criteria for 1570 of the most recent interventional trials from ClinicalTrials.gov for HIV-positive and pregnancy eligibility, and the classifiers were retrained and reevaluated using these data. Results: On the cancer-HIV dataset, the baseline regex model, the bag-of-words ML classifier, and the ML classifier with named entity recognition (NER) achieved macro-averaged F2 scores of 0.77, 0.87, and 0.87, respectively; the addition of NER did not result in a significant performance improvement. On the general dataset, ML + NER achieved macro-averaged F2 scores of 0.91 and 0.85 for HIV and pregnancy, respectively. Discussion and Conclusion: The eligibility status of specific patient populations, such as persons living with HIV and pregnant women, for clinical trials is of interest to both patients and clinicians. We show that it is feasible to develop a high-performing, automated trial classification system for eligibility status that can be integrated into consumer-facing search engines as well as patient-trial matching systems. PMID- 28339692 TI - Decrease in unnecessary vitamin D testing using clinical decision support tools: making it harder to do the wrong thing. AB - Objective: To evaluate the impact of clinical decision support (CDS) tools on rates of vitamin D testing. Screening for vitamin D deficiency has increased in recent years, spurred by studies suggesting vitamin D's clinical benefits. Such screening, however, is often unsupported by evidence and can incur unnecessary costs. Materials and Methods: We evaluated how rates of vitamin D screening changed after we implemented 3 CDS tools in the electronic health record (EHR) of a large health plan: (1) a new vitamin D screening guideline, (2) an alert that requires clinician acknowledgement of current guidelines to continue ordering the test (a "hard stop"), and (3) a modification of laboratory ordering preference lists that eliminates shortcuts. We assessed rates of overall vitamin D screening and appropriate vitamin D screening 6 months pre- and post-intervention. Results: Vitamin D screening rates decreased from 74.0 tests to 24.2 tests per 1000 members ( P < .0001). The proportion of appropriate vitamin D screening tests increased from 56.2% to 69.7% ( P < .0001), and the proportion of inappropriate screening tests decreased from 43.8% pre-implementation to 30.3% post implementation ( P < .0001). Discussion: To our knowledge, this is the first demonstration of how CDS can reduce rates of inappropriate vitamin D screening. We used 3 straightforward, inexpensive, and replicable CDS approaches. We know of no previous research on the impact of removing options from a preference list. Conclusion: Similar approaches could be used to reduce unnecessary care and decrease costs without reducing quality of care. PMID- 28339691 TI - Z-Guggulsterone Produces Antidepressant-Like Effects in Mice through Activation of the BDNF Signaling Pathway. AB - Background: Z-guggulsterone, an active compound extracted from the gum resin of the tree Commiphora mukul, has been shown to improve animal memory deficits via activating the brain-derived neurotrophic factor signaling pathway. Here, we investigated the antidepressant-like effect of Z-guggulsterone in a chronic unpredictable stress mouse model of depression. Methods: The effects of Z guggulsterone were assessed in mice with the tail suspension test and forced swimming test. Z-guggulsterone was also investigated in the chronic unpredictable stress model of depression with fluoxetine as the positive control. Changes in hippocampal neurogenesis as well as the brain-derived neurotrophic factor signaling pathway after chronic unpredictable stress/Z-guggulsterone treatment were investigated. The tryptophan hydroxylase inhibitor and the tyrosine kinase B inhibitor were also used to explore the antidepressant-like mechanisms of Z guggulsterone. Results: Z-guggulsterone (10, 30 mg/kg) administration protected the mice against the chronic unpredictable stress-induced increases in the immobile time in the tail suspension test and forced swimming test and also reversed the reduction in sucrose intake in sucrose preference experiment. Z guggulsterone (10, 30 mg/kg) administration prevented the reductions in brain derived neurotrophic factor protein expression levels as well as the phosphorylation levels of cAMP response element binding protein, extracellular signal-regulated kinase 1/2, and protein kinase B in the hippocampus and cortex induced by chronic unpredictable stress. Z-guggulsterone (10, 30 mg/kg) treatment also improved hippocampal neurogenesis in chronic unpredictable stress-treated mice. Blockade of the brain-derived neurotrophic factor signal, but not the monoaminergic system, attenuated the antidepressant-like effects of Z guggulsterone. Conclusions: Z-guggulsterone exhibits antidepressant activity via activation of the brain-derived neurotrophic factor signaling pathway and upregulation of hippocampal neurogenesis. PMID- 28339693 TI - Neuronal signaling repertoire in the mammalian sperm functionality. AB - The common embryonic origin has been a recurrent explanation to understand the presence of "neural receptors" in sperm. However, this designation has conditioned a bias marked by the classical neurotransmission model, dismissing the possibility that neurotransmitters can play specific roles in the sperm function by themselves. For instance, the launching of acrosome reaction, a fundamental sperm function, includes several steps that recall the process of presynaptic secretion. Unlike of postsynaptic neuron, whose activation is mediated by molecular interaction between neurotransmitter and postsynaptic receptors, the oocyte activation is not mediated by receptors, but by cytosolic translocation of sperm phospholipase (PLCzeta). Thus, the sperm has a cellular design to access and activate the oocyte and restore the ploidy of the species by an "allogenic pronuclear fusion." At subcellular level, the events controlling sperm function, particularly the capacitation process, are activated by chemical signals that trigger ion fluxes, sterol oxidation, synthesis of cyclic adenosine monophosphate, protein kinase A activation, tyrosine phosphorylations and calcium signaling, which correspond to second messengers similar to those associated with exocytosis and growth cone guidance in neurons. Classically, the sperm function associated with neural signals has been analyzed as a unidimensional approach (single ligand-receptor effect). However, the in vivo sperm are exposed to multidimensional signaling context, for example, the GABAergic, monoaminergic, purinergic, cholinergic, and melatoninergic, to name a few. The aim of this review is to present an overview of sperm functionality associated with "neuronal signaling" and possible cellular and molecular mechanisms involved in their regulation. PMID- 28339694 TI - Regional acidosis locally inhibits but remotely stimulates Ca2+ waves in ventricular myocytes. AB - Aims: Spontaneous Ca2+ waves in cardiomyocytes are potentially arrhythmogenic. A powerful controller of Ca2+ waves is the cytoplasmic H+ concentration ([H+]i), which fluctuates spatially and temporally in conditions such as myocardial ischaemia/reperfusion. H+-control of Ca2+ waves is poorly understood. We have therefore investigated how [H+]i co-ordinates their initiation and frequency. Methods and results: Spontaneous Ca2+ waves were imaged (fluo-3) in rat isolated ventricular myocytes, subjected to modest Ca2+-overload. Whole-cell intracellular acidosis (induced by acetate-superfusion) stimulated wave frequency. Pharmacologically blocking sarcolemmal Na+/H+ exchange (NHE1) prevented this stimulation, unveiling inhibition by H+. Acidosis also increased Ca2+ wave velocity. Restricting acidosis to one end of a myocyte, using a microfluidic device, inhibited Ca2+ waves in the acidic zone (consistent with ryanodine receptor inhibition), but stimulated wave emergence elsewhere in the cell. This remote stimulation was absent when NHE1 was selectively inhibited in the acidic zone. Remote stimulation depended on a locally evoked, NHE1-driven rise of [Na+]i that spread rapidly downstream. Conclusion: Acidosis influences Ca2+ waves via inhibitory Hi+ and stimulatory Nai+ signals (the latter facilitating intracellular Ca2+-loading through modulation of sarcolemmal Na+/Ca2+ exchange activity). During spatial [H+]i-heterogeneity, Hi+-inhibition dominates in acidic regions, while rapid Nai+ diffusion stimulates waves in downstream, non-acidic regions. Local acidosis thus simultaneously inhibits and stimulates arrhythmogenic Ca2+-signalling in the same myocyte. If the principle of remote H+ stimulation of Ca2+ waves also applies in multicellular myocardium, it raises the possibility of electrical disturbances being driven remotely by adjacent ischaemic areas, which are known to be intensely acidic. PMID- 28339696 TI - Reply to Freyschlag et al. PMID- 28339695 TI - Incidence and Outcomes of Infections Caused by Multidrug-Resistant Enterobacteriaceae in Children, 2007-2015. AB - Background: The escalating incidence of invasive disease caused by multidrug resistant Gram-negative enteric Enterobacteriaceae (MDR-GNE) is a global concern. Scant published studies in which the epidemiology of these infections in children is described exist; previous studies focused mainly on adults, described circumscribed populations, or lacked clinical detail. The objective of this study was to examine and describe the incidence, risk factors, and outcomes associated with MDR-GNE infection in children. Methods: In this cohort study, we used data from 48 children's hospitals maintained by the Pediatric Health Information System. We documented the proportion of MDR-GNE diagnoses among children's hospital patients aged 0 to <18 years who were diagnosed with an Enterobacteriaceae-associated infection between January 1, 2007, and March 31, 2015, and we analyzed the association between MDR-GNE infection and hospital length of stay and death before discharge. Results: During the study period, 107610 discharges included a diagnosis code for Enterobacteriaceae infection, 724 (0.7%) of which included MDR-GNE infection. The incidence of MDR-GNE, and the proportion of infections with Enterobacteriaceae organisms that were MDR-GNE increased over the study period; from 0.2% in 2007 to 1.5% by 2015 (test for trend < .001). Almost one-quarter (23%) of the infections in children hospitalized for MDR-GNE were nosocomial. Increased odds of MDR-GNE infection were associated with older age and comorbid illnesses. Lengths of stay in patients with MDR-GNE infection were increased 20% (95% confidence interval, 9.9% 30.5%; P < .001) over those without MDR-GNE infection; the increased odds for death did not reach statistical significance (1.46 [95% confidence interval, 0.98 2.18]; P = .06). Results were robust to sensitivity analyses. Conclusions: The incidence of pediatric MDR-GNE infection increased during 2007-2015. MDR-GNE infection was associated with increased length of stay, and we found a trend toward increased risk of death. Infections with Gram-negative enteric bacilli are becoming increasingly difficult to treat; considering the global burden of these antimicrobial-resistant organisms, interventions to curtail or even reverse this trend are needed urgently. PMID- 28339697 TI - Are informed policies in place to promote safe and usable EHRs? A cross-industry comparison. AB - Objective: Despite federal policies put in place by the Office of the National Coordinator (ONC) to promote safe and usable electronic health record (EHR) products, the usability of EHRs continues to frustrate providers and have patient safety implications. This study sought to compare government policies on usability and safety, and methods of examining compliance to those policies, across 3 federal agencies: the ONC and EHRs, the Federal Aviation Administration (FAA) and avionics, and the Food and Drug Administration (FDA) and medical devices. Our goal was to identify whether differences in policies exist and, if they do exist, how policies and enforcement mechanisms from other industries might be applied to optimize EHR usability. Method: We performed a qualitative study using publicly available governing documents to examine similarities and differences in usability and safety policies across agencies. Results: The policy review and analysis revealed several consistencies within each agency's usability policies. Critical differences emerged in the usability standards and policy enforcement mechanisms utilized by the 3 agencies. The FAA and FDA look at evidence of usability processes and are more prescriptive when it comes to testing final products as compared to the ONC, which relies on attestation and is less prescriptive. Discussion: A comparison of usability policies across industries illustrates key differences between the ONC and other federal agencies. These differences could be contributing to the usability challenges associated with EHRs. Conclusion: Our analysis highlights important areas of usability and safety policy from other industries that can better inform ONC policies on EHRs. PMID- 28339698 TI - Learning from errors: analysis of medication order voiding in CPOE systems. AB - Objective: Medication order voiding allows clinicians to indicate that an existing order was placed in error. We explored whether the order voiding function could be used to record and study medication ordering errors. Materials and Methods: We examined medication orders from an academic medical center for a 6-year period (2006-2011; n = 5 804 150). We categorized orders based on status (void, not void) and clinician-provided reasons for voiding. We used multivariable logistic regression to investigate the association between order voiding and clinician, patient, and order characteristics. We conducted chart reviews on a random sample of voided orders ( n = 198) to investigate the rate of medication ordering errors among voided orders, and the accuracy of clinician provided reasons for voiding. Results: We found that 0.49% of all orders were voided. Order voiding was associated with clinician type (physician, pharmacist, nurse, student, other) and order type (inpatient, prescription, home medications by history). An estimated 70 +/- 10% of voided orders were due to medication ordering errors. Clinician-provided reasons for voiding were reasonably predictive of the actual cause of error for duplicate orders (72%), but not for other reasons. Discussion and Conclusion: Medication safety initiatives require availability of error data to create repositories for learning and training. The voiding function is available in several electronic health record systems, so order voiding could provide a low-effort mechanism for self-reporting of medication ordering errors. Additional clinician training could help increase the quality of such reporting. PMID- 28339699 TI - Effects of chlorine and hydrogen peroxide sanitation in low bacterial content water on biofilm formation model of poultry brooding house waterlines. AB - An in vitro experiment was performed to determine if biofilm would develop when polyvinylchloride (PVC) test coupons (material used for poultry waterlines) were exposed to low bacterial content warm water (<=1000 cfu/mL, test water) and also to determine if biofilm development would be influenced by adding a sanitizer. PVC sections 2.54 cm long and internal diameter of 1. 90 cm were used as test coupons to grow biofilm. Two coupons were immersed in 600 mL test water in a beaker. Nine beakers were utilized similarly with a total of 18 coupons. Three beakers (T1) were treated with a chlorine (Cl) based product (targeted to produce 2 to 4 ppm residual) and the other 3 (T2) with hydrogen peroxide a (HP) based product (targeted to produce 25 to 50 ppm residual). Three untreated beakers served as controls (T3). All beakers and coupons were placed into a water bath shaker under warm and moving water conditions mimicking poultry brooding conditions. Coupons and test water were sampled for treatments for aerobic plate count (APC). Trial 1 used test water with zero cfu bacteria/mL initial APC, whereas the Trial 2 test water initial APC was 3 log10 cfu/mL. Test water samples and coupons had no bacterial growth for all treatments on sampling occasions for Trial 1. In Trial 2, T3 (control) and T2 (HP treated) had APC growth in both test water (2.5 to 3.0 log10 cfu/mL) and on coupons (2 to 2.5 log10 cfu/cm2) on sampling d with no difference (P > 0.05) between these treatments. Whereas, T1 (Cl treated) eliminated bacteria (zero cfu/mL) in test water and inhibited biofilm growth on test coupons (<=0.2 log10 cfu/cm2) during sampling d (P < 0.05). This experiment showed that biofilm can develop in minimally contaminated water even in the presence of sanitizers, yet chlorine was more effective than hydrogen peroxide in limiting this development. PMID- 28339701 TI - Comparison of three commercial knowledge bases for detection of drug-drug interactions in clinical decision support. AB - Objective: To compare 3 commercial knowledge bases (KBs) used for detection and avoidance of potential drug-drug interactions (DDIs) in clinical practice. Methods: Drugs in the DDI tables from First DataBank (FDB), Micromedex, and Multum were mapped to RxNorm. The KBs were compared at the clinical drug, ingredient, and DDI rule levels. The KBs were evaluated against a reference list of highly significant DDIs from the Office of the National Coordinator for Health Information Technology (ONC). The KBs and the ONC list were applied to a prescription data set to simulate their use in clinical decision support. Results: The KBs contained 1.6 million (FDB), 4.5 million (Micromedex), and 4.8 million (Multum) clinical drug pairs. Altogether, there were 8.6 million unique pairs, of which 79% were found only in 1 KB and 5% in all 3 KBs. However, there was generally more agreement than disagreement in the severity rankings, especially in the contraindicated category. The KBs covered 99.8-99.9% of the alerts of the ONC list and would have generated 25 (FDB), 145 (Micromedex), and 84 (Multum) alerts per 1000 prescriptions. Conclusion: The commercial KBs differ considerably in size and quantity of alerts generated. There is less variability in severity ranking of DDIs than suggested by previous studies. All KBs provide very good coverage of the ONC list. More work is needed to standardize the editorial policies and evidence for inclusion of DDIs to reduce variation among knowledge sources and improve relevance. Some DDIs considered contraindicated in all 3 KBs might be possible candidates to add to the ONC list. PMID- 28339702 TI - Subclinical chronic left ventricular systolic dysfunction resulting from phosphine poisoning. AB - We present a case of a 32-year-old male crew member of a cargo ship, accidentally exposed to phosphine, a fumigating substance. He and other crew members developed increasing fatigue and digestive disorders 24 h later; two died from acute pulmonary oedema. The patient was admitted to hospital, where bilateral pneumonia, acute nephritis, hepatopathy, electrolyte imbalance and leucopenia were diagnosed. He was discharged from hospital 3 weeks later. He was examined 4 months later for possible chronic consequences of acute phosphine poisoning, which included echocardiography showing normal heart size and cardiac function. However, on advanced quantitative analysis, using two-dimensional speckle tracking echocardiography, depressed global longitudinal strain was found. Our report extends previously published findings of phosphine-induced left ventricular (LV) dysfunction by demonstrating that subclinical myocardial dysfunction resulting from acute phosphine exposure may persist several months after the exposure in an otherwise asymptomatic patient, and potentially may not be entirely reversible. The persistence of subclinical abnormalities of LV longitudinal function can be diagnosed using the advanced quantitative echocardiographic analysis we describe. PMID- 28339700 TI - A clinical perspective on the 2016 WHO brain tumor classification and routine molecular diagnostics. AB - The 2007 World Health Organization (WHO) classification of brain tumors did not use molecular abnormalities as diagnostic criteria. Studies have shown that genotyping allows a better prognostic classification of diffuse glioma with improved treatment selection. This has resulted in a major revision of the WHO classification, which is now for adult diffuse glioma centered around isocitrate dehydrogenase (IDH) and 1p/19q diagnostics. This revised classification is reviewed with a focus on adult brain tumors, and includes a recommendation of genes of which routine testing is clinically useful. Apart from assessment of IDH mutational status including sequencing of R132H-immunohistochemistry negative cases and testing for 1p/19q, several other markers can be considered for routine testing, including assessment of copy number alterations of chromosome 7 and 10 and of TERT promoter, BRAF, and H3F3A mutations. For "glioblastoma, IDH mutated" the term "astrocytoma grade IV" could be considered. It should be considered to treat IDH wild-type grades II and III diffuse glioma with polysomy of chromosome 7 and loss of 10q as glioblastoma. New developments must be more quickly translated into further revised diagnostic categories. Quality control and rapid integration of molecular findings into the final diagnosis and the communication of the final diagnosis to clinicians require systematic attention. PMID- 28339704 TI - Cullen's sign & acute pancreatitis. PMID- 28339703 TI - Marked bradycardia elicited during pulmonary vein isolation: not a sign of success-Authors' reply. PMID- 28339705 TI - Catheter ablation for atrial flutter: a survey by the European Heart Rhythm Association and Canadian Heart Rhythm Society. PMID- 28339706 TI - Differential proliferation and metabolic activity of Sertoli cells in the testes of broiler and layer breeder chickens. AB - Decades of genetic selection have generated 2 different, highly specialized types of chickens in which 1 type, known as the layer-type chicken, expresses high laying performance while the other type, known as the broiler-type chicken, is dedicated to the production of fast-growing birds. Selected lines for the latter type often express disorders in their reproductive performance including early sexual maturation and accelerated, non-reversible seasonal decline of their semen production and mating behavior. The aim of the present study was to characterize some metabolic markers of the Sertoli cell populations. Sertoli cells are somatic cells known to support, coordinate, nourish, and protect the germ cell populations from onset to the end of their meiotic process. Comparisons of gonadal development between males of the 2 genetic types taken at their pre pubertal period indicated that the testes of layer-type chickens are significantly less developed than in broiler-type males taken at the same age. In addition, cultures of purified Sertoli cells from the 2 types revealed in vitro a higher proliferative capacity when issued from layer compared to broiler-type chickens. This was associated with a higher expression of the genes involved in the beta-oxidation of fatty acids (CPT1; PPARbeta) as well as a 4-fold increase in the Lactate Dehydrogenase-A expression and activity. In contrast, Sertoli cells from broiler-type chickens presented an elevated activity of citrate synthase and mitochondria, suggesting a better efficacy of aerobic metabolism in Sertoli cells from broiler compared to layer-type chickens. Moreover, the testis from broiler-type chickens seems to be more sensitive to oxidative stress due to the lower global antioxidant capacity compared to layer-type chickens.In conclusion, these results suggest that the metabolic activity of testicular tissues is different in the layer and broiler breeder chickens. The aerobic metabolism more prevalent in broiler-type chickens could be a factor to reduce the male fertility such as germ cell quality. PMID- 28339707 TI - Selection for pro-inflammatory mediators produces chickens more resistant to Campylobacter jejuni. AB - Campylobacter spp. are the second leading cause of bacterial-induced foodborne illnesses with an estimated economic burden of nearly $2B USD per year. Most human illness associated with campylobacteriosis is due to infection by C. jejuni and chickens are recognized as a reservoir that could lead to foodborne illness in humans resulting from handling or consuming raw or undercooked chicken. We recently developed a novel breeding strategy based on identification and selection of chickens with an inherently high and low phenotype of pro inflammatory mediators including IL-6, CXCLi2, and CCLi2, hereafter referred to as the high and low lines, respectively. We have shown the high line chickens are more resistant to the foodborne and poultry pathogens Salmonella enterica serovar Enteritidis, Eimeria tenella, and Clostridium perfringens-induced necrotic enteritis compared to the low line. The objective of this study was to determine whether the same trend of enhanced resistance in the high line birds was observed for C. jejuni. Birds were challenged at 2 d of age by oral gavage (0.5 mL) with 5 * 106 colony forming units (cfu) of C. jejuni/mL, necropsied 4 d post challenge, and cecal content collected to determine if there was a difference in C. jejuni resistance between the high and low line chickens. There were fewer (P = 0.01) chickens from the high line (28/40 = 71.8%) that were colonized by C. jejuni compared to the low line (37/39 = 94.9%). The amount of C. jejuni recovered from the ceca of infected birds was quantified; however, no differences were observed (P = 0.10). Since the high line birds were also more resistant to C. jejuni, it provides additional validation of selection based on pro-inflammatory mediators producing a line of chickens with increased natural resistance against diverse foodborne and poultry pathogens. The poultry industry is moving towards reduced therapeutics and, as such, our breeding strategy would be a viable method to incorporate into traditional poultry breeding programs. PMID- 28339708 TI - Effects of dietary methyl sulfonyl methane (MSM) supplementation on growth performance, nutrient digestibility, meat quality, excreta microbiota, excreta gas emission, and blood profiles in broilers. AB - A 29-d trial was conducted to evaluate the effects of dietary methyl sulfonyl methane (MSM) supplementation on growth performance, meat quality, nutrient digestibility, excreta microbiota, excreta gas emission, and blood profiles in broilers. A total of 816 1-day-old male Ross 308 broilers (44 +/- 0.44 g) were assigned to 4 dietary treatments, composed of 12 replicates with 17 birds per replicate. The 4 treatments were: 1) CON, basal diet; 2) S1, CON + 0.05% MSM; 3) S2, CON + 0.10% MSM; 4) S3, CON + 0.20% MSM. In the current study, body weight (BW) on d 14 and 29 showed significant improvement as dietary MSM increased from 0.05% to 0.20% (P < 0.05). During d 1 to 14 and overall, higher (P < 0.05) body weight gain (BWG) and lower feed conversion ratio (FCR) were observed in broilers fed MSM diets. Between d 15 and 29, higher (P < 0.05) BWG was observed in broilers fed MSM diets. Redness (a*) was increased linearly (P < 0.05) in broilers fed MSM diets. On d 3, 5, and 7, drip loss was decreased linearly (P < 0.05) in broilers fed MSM diets. Lactobacillus and E. coli were effected linearly (P < 0.05) in broilers fed MSM diets. Alanine aminotransferase (ALT), white blood cells (WBC) and lymphocytes were improved linearly (P < 0.05) in broilers fed MSM diets. In conclusion, dietary supplementation MSM has positive effects on growth performance, meat quality, excreta microbiota, and blood profiles in broilers. PMID- 28339709 TI - Clinicopathologic correlations of renal pathology in the adult population of Poland. AB - Background: This is the first report on the epidemiology of biopsy-proven kidney diseases in Poland. Methods: The Polish Registry of Renal Biopsies has collected information on all (n = 9394) native renal biopsies performed in Poland from 2009 to 2014. Patients' clinical data collected at the time of biopsy, and histopathological diagnoses were used for epidemiological and clinicopathologic analysis. Results: There was a gradual increase in the number of native renal biopsies performed per million people (PMP) per year in Poland in 2009-14, starting from 36 PMP in 2009 to 44 PMP in 2014. A considerable variability between provinces in the mean number of biopsies performed in the period covered was found, ranging from 5 to 77 PMP/year. The most common renal biopsy diagnoses in adults were immunoglobulin A nephropathy (IgAN) (20%), focal segmental glomerulosclerosis (FSGS) (15%) and membranous glomerulonephritis (MGN) (11%), whereas in children, minimal change disease (22%), IgAN (20%) and FSGS (10%) were dominant. Due to insufficient data on the paediatric population, the clinicopathologic analysis was limited to patients >=18 years of age. At the time of renal biopsy, the majority of adult patients presented nephrotic-range proteinuria (45.2%), followed by urinary abnormalities (38.3%), nephritic syndrome (13.8%) and isolated haematuria (1.7%). Among nephrotic patients, primary glomerulopathies dominated (67.6% in those 18-64 years of age and 62.4% in elderly patients) with leading diagnoses being MGN (17.1%), FSGS (16.2%) and IgAN (13.0%) in the younger cohort and MGN (23.5%), amyloidosis (18.8%) and FSGS (16.8%) in the elderly cohort. Among nephritic patients 18-64 years of age, the majority (55.9%) suffered from primary glomerulopathies, with a predominance of IgAN (31.3%), FSGS (12.7%) and crescentic GN (CGN) (11.1%). Among elderly nephritic patients, primary and secondary glomerulopathies were equally common (41.9% each) and pauci-immune GN (24.7%), CGN (20.4%) and IgAN (14.0%) were predominant. In both adult cohorts, urinary abnormalities were mostly related to primary glomerulopathies (66.8% in younger and 50% in elderly patients) and the leading diagnoses were IgAN (31.4%), FSGS (15.9%), lupus nephritis (10.7%) and FSGS (19.2%), MGN (15.1%) and pauci-immune GN (12.3%), respectively. There were significant differences in clinical characteristics and renal biopsy findings between male and female adult patients. Conclusions: The registry data focused new light on the epidemiology of kidney diseases in Poland. These data should be used in future follow-up and prospective studies. PMID- 28339710 TI - Productive performance and blood profiles of laying hens fed Hermetia illucens larvae meal as total replacement of soybean meal from 24 to 45 weeks of age. AB - The aim of the research was to study the effects of an insect meal from Hermetia illucens larvae (HILM) as complete replacement of soybean meal (SBM) on productive performance and blood profiles of laying hens, from 24 to 45 wk of age. A total of 108 24-week-old Lohmann Brown Classic laying hens was equally divided into 2 groups (54 hens/group, 9 replicates of 6 hens/group). From 24 to 45 wk of age, the groups were fed 2 different isoproteic and isoenergetic diets: the control group (SBM) was fed a corn-soybean meal based diet, while in the HILM group the soybean meal was completely replaced by Hermetia illucens larvae meal. Feed intake, number of eggs produced, and egg weight were recorded weekly along the trial. At 45 wk of age, blood samples were collected from 2 hens per replicate. The use of HIML led to a more favorable (P < 0.01) feed conversion ratio in hens but lay percentage, feed intake, average egg weight, and egg mass were higher (P < 0.01) in hens fed the SBM diet. Hens fed insect meal produced a higher percentage of eggs from small (S), medium (M), and extra-large (XL) classes (P < 0.01) than SBM, while the SBM group had a higher percentage of eggs from the large (L) class (P < 0.01). The levels of globulin and albumin to globulin ratio were, respectively, higher and lower (P < 0.05) in HILM than the SBM group. Cholesterol and triglycerides were higher (P < 0.05 and P < 0.01, respectively) in hens from SBM than in the HILM group. Blood levels of Ca were higher (P < 0.01) in hens fed insect meal, while creatinine was higher (P < 0.01) in blood of hens fed SBM. Hermetia illucens larvae meal can be a suitable alternative protein source for laying hens even if the complete replacement of soybean meal needs further investigation to avoid the negative effects on feed intake. PMID- 28339711 TI - Interactions of full-fat canola seed, oat hulls as an insoluble fiber source and pellet temperature for nutrient utilization and growth performance of broiler chickens. AB - The effectiveness of the addition of oat hulls (OH) as an insoluble fiber for improving nutrient digestibility and performance of birds fed diets containing full-fat canola seed (CS) was studied. A 2 * 2 * 2 factorial arrangement of treatments was used to assess the main effects of canola source (CS vs canola meal plus oil as control), OH (0 or 3%), pellet temperature (75 and 90 degrees C) and their interactions. A total of 576 male day-old Ross 308 chickens were assigned to 8 experimental treatments, each replicated 6 times (12 birds per replicate). All birds were fed a same commercial starter diet for the first 10 d of age. Canola meal and canola oil in the control diets were replaced with CS at 11.6% and 13.5% in the grower (d 10 to 24) and finisher (d 24 to 35) diets, respectively. An interaction was observed between canola source and OH led to improved body weight gain (P < 0.01) and FCR (P < 0.05) in birds fed the combination of CS and OH in grower phase. Pelleting temperature at 75 vs 90 degrees C did not affect performance of broilers. Birds fed diets containing OH had heavier gizzards at 24 and 35 d of age. Inclusion of CS in the diets depressed fat digestibility at d 24 (P < 0.001) and AME of the grower diets. At d 35, there was a significant interaction (P < 0.05) between CS and pellet temperature where birds fed CS diets pelleted at 75 degrees C had higher fat digestibility than birds fed CS pelleted at 90 degrees C. Regardless of canola source or pellet temperature, OH increased fat utilization at d 35 (P < 0.001) but had no effect on AME of the grower diets. In conclusion, CS can replace supplemental oil in broiler diets when an adequate source of insoluble fiber is included in the diet, which may help to maintain feed intake of broilers fed CS in steam-pelleted diets. PMID- 28339712 TI - Effect of Chinese herbal medicine treatment on plasma lipid profile and hepatic lipid metabolism in Hetian broiler. AB - The purpose of this study was to investigate whether adding a Chinese herbal hedicine (CHM, including astragalus membranaceus, codonopsis pilosula, poria cocos, bighead atractylodes rhizome, fructus crataegi, folium epimedii, radix saposhnikoviae, and pericarpium citri reticulatae) diet has effects on lipid metabolism in the liver of the broiler. Six-hundred-thirty Hetian broilers were divided into 3 groups including base diet (control), 0.3%, or 1% CHM diets, for 130 days. The results showed that CHM treatment significantly increased the slaughter performance. CHM treatment decreased plasma triglyceride (TG) and nonesterified fatty acid (NEFA) concentrations; up-regulated the expression of peroxisome proliferator activated receptor (PPAR), the transcription factor sterol regulatory element binding protein-1c (SREBP-1c) and its downstream proteins involved in NEFA oxidation including carnitine palmitoyltransferase-1, liver fatty acid binding protein, and PPARalpha; and it significantly decreased fatty acid synthetase, stearoyl-CoA desaturase, acyl-CoA synthetase long-chain family member 1 and acetyl-CoA carboxylase expression to inhibit NEFA synthesis. In addition, the CHM treatment increased plasma insulin (INS) levels and up regulated insulin receptors (INSR) glycerol-3-phosphate acyltransferase and mitochondrial and 1-acylglycerol-3-phosphate O-acyltransferase 6 mRNA expression to enhance TG synthesis. The protein levels of phosphatidylinositol 3-hydroxy kinase (PI3K), serine/threonine protein kinase (Akt), S6 kinase (S6K), phospho serine/threonine protein kinase (p-Akt), and phospho-S6 kinase (p-S6K) also were increased. PI3K, p-Akt, and p-S6K were significantly up-regulated in the liver. These data suggest that the CHM may be a beneficial compound to decrease plasma NEFA and TG levels by activating the INS/INSR-PI3K-Akt-SREBP1c pathway resulting in fat content reduction in the carcass. PMID- 28339713 TI - Evaluation of the effectiveness of intermittent mechanical pressure with short loading duration: new type of intermittent force for orthodontic treatment. AB - Background: Since it is difficult to precisely control the magnitude of force in orthodontic practice, controlling the duration of force is expected to prevent tissue damage. The use of an actuator as an appliance for intermittent force application is a possible solution for controlling the duration. However, effectiveness of an actuator for controlling the duration is still not clear. Aim: To determine whether a short loading duration of intermittent force has the potential to maintain a sound condition of the capillaries and induce dilation of capillaries, which is a requisite phenomenon for orthodontic tooth movement. Materials and methods: Six-week-old male hamsters with a dorsal skinfold chamber attached to an intermittent loading device were used. In three experimental groups, application of intermittent pressure that involved repetition of loading and unloading was performed. The durations of loading/unloading were 1 second/9 seconds (group T10), 1 second/19 seconds (group T20), and 1 second/29 seconds (group T30). Vessels were examined using a fluorescence microscope and a stereomicroscope for 5 days. Results: Widths of capillaries in groups T10 and T20 increased significantly (P < 0.01). In contrast, widths of capillaries in group T30 showed no significant difference from those in the control group. Only group T10 showed bleeding, obvious destruction of vessels, and a significant increase in the rate of disappearance of vessels. Conclusion: In the epidermis, although conditions are limited, a short loading duration of intermittent force maintains a sound condition of the capillaries at the tissue level and induces dilation of capillaries. PMID- 28339714 TI - Effect of whole yeast cell product supplementation (CitriStim(r)) on immune responses and cecal microflora species in pullet and layer chickens during an experimental coccidial challenge. AB - Three separate experiments were conducted to study the effects of whole yeast cell product supplementation in pullets and layer hens. Body weight gain, fecal and intestinal coccidial oocyst counts, cecal microflora species, cytokine mRNA amounts, and CD4+ and CD8+ T-cell populations in the cecal tonsils were analyzed following an experimental coccidial infection. In Experiment I, day-old Leghorn layer chicks were fed 3 experimental diets with 0, 0.1, or 0.2% whole yeast cell product (CitriStim(r), ADM, Decatur, IL). At 21 d of age, birds were challenged with 1 * 105 live coccidial oocysts. Supplementation with whole yeast cell product decreased the fecal coccidial oocyst count at 7 (P = 0.05) and 8 (P < 0.01) d post-challenge. In Experiment II, 27-week old Leghorn layer hens were fed 3 experimental diets with 0, 0.05 or 0.1% whole yeast cell product and challenged with 1 * 105 live coccidial oocysts on d 25 of whole yeast cell product feeding. Supplementation with whole yeast cell product decreased the coccidial oocyst count in the intestinal content (P < 0.01) at 5, 13, and 38 d post-coccidial challenge. Supplementation with whole yeast cell product increased relative proportion of Lactobacillus (P < 0.01) in the cecal tonsils 13 d post-coccidial challenge. Supplementation with whole yeast cell product decreased CD8+ T cell percentages (P < 0.05) in the cecal tonsils at 5 d post-coccidial challenge. In Experiment III, 32-week-old Leghorn layer hens were fed 3 experimental diets with 0, 0.1, or 0.2% whole yeast cell product and challenged with 1 * 105 live coccidial oocysts on d 66 of whole yeast cell product feeding. At 5 d post coccidial challenge, whole yeast cell product supplementation down-regulated (P = 0.01) IL-10 mRNA amount. It could be concluded that supplementing whole yeast cell product can help minimize coccidial infection in both growing pullets and layer chickens. PMID- 28339715 TI - Determination of pre-cecal phosphorus digestibility of inorganic phosphates and bone meal products in broilers. AB - A broiler study was performed to determine the pre-cecal phosphorus (P) digestibility of 5 P sources, 3 from animal (Delfos, Calfos, and porcine bone meal) and 2 of inorganic (monocalcium phosphate [MCP] and dicalcium phosphate [DCP]) origin. Delfos is processed from bones resulting in a dicalcium phosphate product, and Calfos is processed from bones in which part of the gelatin is removed but in which the hydroxy-apatite matrix is preserved. During the first 14 d, birds were housed in floor pens bedded with wood shavings and received a commercial starter diet. At d 14, broilers were randomly assigned to pens (0.9 m2, 10 birds/pen) with a slatted floor. From d 14 onwards, one of the 6 experimental diets (a basal diet, and 5 diets containing the P sources) was provided. Test diets were replicated 6 times, and the basal diet 8 times. Electron microscopy images of test products were made in order to verify whether the spatial structure of the test products could be related to the pre-cecal P digestibility of the same products. Diets met or exceeded CVB (2011) requirements for all nutrients except for P and were formulated to contain a calcium to total P ratio of between 1.4 and 1.6 and a minimal amount of phytate P. Diets contained 5 g/kg titanium oxide as a marker to determine digestibility of P. At d 24 all birds were euthanized, after which the content of the terminal part of the ileum was sampled. The P digestibility was calculated by linear regression according to World's Poultry Science Association (WPSA) protocol for determination of pre cecal P digestibility. Pre-cecal P digestibility of MCP, DCP, Delfos, Calfos, and porcine bone meal was 88.5, 82.4, 94.5, 86.9, and 78.2%, respectively. Based on visual inspection of electron microscopy images of test products, the spatial structure of the test products might be related to P digestibility. It is concluded that processing of bone meal increases the pre-cecal P digestibility in broilers. PMID- 28339717 TI - Death of the sole doctor at Takano Hospital 6 years after the Fukushima nuclear crisis-who is responsible for health care delivery in the Fukushima disaster zone? PMID- 28339716 TI - Prevalence, antimicrobial resistance and genetic diversity of Campylobacter coli and Campylobacter jejuni in Ecuadorian broilers at slaughter age. AB - Thermotolerant Campylobacter spp. are a major cause of foodborne gastrointestinal infections worldwide. The linkage of human campylobacteriosis and poultry has been widely described. In this study we aimed to investigate the prevalence, antimicrobial resistance and genetic diversity of C. coli and C. jejuni in broilers from Ecuador. Caecal content from 379 randomly selected broiler batches originating from 115 farms were collected from 6 slaughterhouses located in the province of Pichincha during 1 year. Microbiological isolation was performed by direct plating on mCCDA agar. Identification of Campylobacter species was done by PCR. Minimum inhibitory concentration (MIC) values for gentamicin, ciprofloxacin, nalidixic acid, tetracycline, streptomycin, and erythromycin were obtained. Genetic variation was assessed by RFLP-flaA typing and Multilocus Sequence Typing (MLST) of selected isolates. Prevalence at batch level was 64.1%. Of the positive batches 68.7% were positive for C. coli, 18.9% for C. jejuni, and 12.4% for C. coli and C. jejuni. Resistance rates above 67% were shown for tetracycline, ciprofloxacin, and nalidixic acid. The resistance pattern tetracycline, ciprofloxin, and nalidixic acid was the dominant one in both Campylobacter species. RFLP-flaA typing analysis showed that C. coli and C. jejuni strains belonged to 38 and 26 profiles respectively. On the other hand MLST typing revealed that C. coli except one strain belonged to CC-828, while C. jejuni except 2 strains belonged to 12 assigned clonal complexes (CCs). Furthermore 4 new sequence types (STs) for both species were described, whereby 2 new STs for C. coli were based on new allele sequences. Further research is necessary to estimate the impact of the slaughter of Campylobacter positive broiler batches on the contamination level of carcasses in slaughterhouses and at retail in Ecuador. PMID- 28339718 TI - Increased Nuclear T2 Signal Intensity and Improved Function and Pain in a Patient One Year After an Intradiscal Platelet-Rich Plasma Injection. PMID- 28339720 TI - Readying the Profession for Changing Times. AB - Regardless of your political preferences, the 2016 election will, in part, be known for its revelation of great divides in our nation. The focus of this editorial is on the importance of promoting our collective social work values and positions over the next four years. The profession engages a wide spectrum of people across economic, political, social, and educational experiences. There are many who feel a sense of fear, anger, and concern about their safety and their place in this country, particularly those who sit at the intersection of multiple forms of oppression. It is important that social workers provide spaces for diverse populations to find not only comfort, but also strong advocacy. It is now more critical than ever for social workers to be proactive, to be engaged, and to follow through to promote social and economic justice. Using the best of our profession-the integration of micro, mezzo, and macro perspectives-will ensure our impact and make a positive contribution to resolving the priority issues of the profession and society. PMID- 28339719 TI - The Pepper WPP Domain Protein, CaWDP1, Acts as a Novel Negative Regulator of Drought Stress via ABA Signaling. AB - Plants are constantly challenged by various environmental stresses, including high salinity and drought, and they have evolved defense mechanisms to counteract the deleterious effects of these stresses. The plant hormone ABA regulates plant growth and developmental processes and mediates abiotic stress responses. Here, we report the identification and characterization of a novel CaWDP1 (Capsicum annuum) protein. The expression of CaWDP1 in pepper leaves was induced by ABA, drought and NaCl treatments, suggesting its role in the abiotic stress response. CaWDP1 proteins show conserved sequence homology with other known WDP1 proteins, and they are localized in the nucleus and cytoplasm. We generated CaWDP1-silenced peppers via virus-induced gene silencing (VIGS). We evaluated the responses of these CaWDP1-silenced pepper plants and CaWDP1-overexpressing (OX) transgenic Arabidopsis plants to ABA and drought. CaWDP1-silenced pepper plants displayed enhanced tolerance to drought stress, and this was characterized by low levels of leaf water loss in the drought-treated leaves. In contrast to CaWDP1-silenced plants, CaWDP1-OX plants exhibited an ABA-hyposensitive and drought-susceptible phenotype, which was accompanied by high levels of leaf water loss, low leaf temperatures, increased stomatal pore size and low expression levels of stress responsive genes. Our results indicate that CaWDP1, a novel pepper negative regulator of ABA, regulates the ABA-mediated defense response to drought stress. PMID- 28339721 TI - Analysis of professional competencies for the clinical research data management profession: implications for training and professional certification. AB - Objective: To assess and refine competencies for the clinical research data management profession. Materials and Methods: Based on prior work developing and maintaining a practice standard and professional certification exam, a survey was administered to a captive group of clinical research data managers to assess professional competencies, types of data managed, types of studies supported, and necessary foundational knowledge. Results: Respondents confirmed a set of 91 professional competencies. As expected, differences were seen in job tasks between early- to mid-career and mid- to late-career practitioners. Respondents indicated growing variability in types of studies for which they managed data and types of data managed. Discussion: Respondents adapted favorably to the separate articulation of professional competencies vs foundational knowledge. The increases in the types of data managed and variety of research settings in which data are managed indicate a need for formal education in principles and methods that can be applied to different research contexts (ie, formal degree programs supporting the profession), and stronger links with the informatics scientific discipline, clinical research informatics in particular. Conclusion: The results document the scope of the profession and will serve as a foundation for the next revision of the Certified Clinical Data Manager TM exam. A clear articulation of professional competencies and necessary foundational knowledge could inform the content of graduate degree programs or tracks in areas such as clinical research informatics that will develop the current and future clinical research data management workforce. PMID- 28339722 TI - Prevalence and drug resistance of avian Eimeria species in broiler chicken farms of Zhejiang province, China. AB - In this study, coccidia were isolated and identified from 5 main poultry farms located in Zhejiang province, eastern China. The overall prevalence of Eimeria spp. was 30.7% (95 of 310). Five common species were observed: E. tenella, E. acervulina, E. maxima, E. necatrix, and E. mitis. Two isolates (HZ and QZ) were tested for sensitivity to 8 anticoccidial drugs using 4 indexes including anticoccidial index (ACI), percent of optimum anticoccidial activity (POAA), reduction of lesion scores (RLS), and relative oocyst production (ROP): sulfachloropyrazine, toltrazuril, diclazuril, sulfamonomethoxine/trimethoprim, and amprolium; sulfaquinoxaline/sulfadimethoxine, nicarbazin, and halofuginone. The results showed that the 2 isolates have developed various degrees of resistance to most of the tested drugs. The multi-resistance coccidia are a potential threat to local poultry farming. Rotation of anticoccidial drugs and shuttle programs are recommended to prevent further economic losses caused by coccidiosis. PMID- 28339725 TI - MiR-142-3p is a paracrine mediator between T cells and endothelium during allograft rejection. PMID- 28339723 TI - Leveraging molecular datasets for biomarker-based clinical trial design in glioblastoma. AB - Background: Biomarkers can improve clinical trial efficiency, but designing and interpreting biomarker-driven trials require knowledge of relationships among biomarkers, clinical covariates, and endpoints. We investigated these relationships across genomic subgroups of glioblastoma (GBM) within our institution (DF/BWCC), validated results in The Cancer Genome Atlas (TCGA), and demonstrated potential impacts on clinical trial design and interpretation. Methods: We identified genotyped patients at DF/BWCC, and clinical associations across 4 common GBM genomic biomarker groups were compared along with overall survival (OS), progression-free survival (PFS), and survival post-progression (SPP). Significant associations were validated in TCGA. Biomarker-based clinical trials were simulated using various assumptions. Results: Epidermal growth factor receptor (EGFR)(+) and p53(-) subgroups were more likely isocitrate dehydrogenase (IDH) wild-type. Phosphatidylinositol-3 kinase (PI3K)(+) patients were older, and patients with O6-DNA methylguanine-methyltransferase (MGMT)-promoter methylation were more often female. OS, PFS, and SPP were all longer for IDH mutant and MGMT methylated patients, but there was no independent prognostic value for other genomic subgroups. PI3K(+) patients had shorter PFS among IDH wild-type tumors, however, and no DF/BWCC long-term survivors were either EGFR(+) (0% vs 7%, P = .014) or p53(-) (0% vs 10%, P = .005). The degree of biomarker overlap impacted the efficiency of Bayesian-adaptive clinical trials, while PFS and OS distribution variation had less impact. Biomarker frequency was proportionally associated with sample size in all designs. Conclusions: We identified several associations between GBM genomic subgroups and clinical or molecular prognostic covariates and validated known prognostic factors in all survival periods. These results are important for biomarker-based trial design and interpretation of biomarker-only and nonrandomized trials. PMID- 28339724 TI - Three cis-Regulatory Motifs, AuxRE, MYCRS1 and MYCRS2, are Required for Modulating the Auxin- and Mycorrhiza-Responsive Expression of a Tomato GH3 Gene. AB - Auxin is well known to be a key regulator that acts in almost all physiological processes during plant growth, and in interactions between plants and microbes. However, to date, the regulatory mechanisms underlying auxin-mediated plant arbuscular mycorrhizal (AM) fungi symbiosis have not been well deciphered. Previously we identified a GH3 gene, SlGH3.4, strongly responsive to both auxin induction and mycorrhizal symbiosis. Here, we reported a refined dissection of the SlGH3.4 promoter activity using the beta-glucuronidase (GUS) reporter. The SlGH3.4 promoter could drive GUS expression strongly in mycorrhizal roots of soybean and rice plants, and in IAA-treated soybean roots, but not in IAA-treated rice roots. A promoter deletion assay revealed three cis-acting motifs, i.e. the auxin-responsive element, AuxRE, and two newly identified motifs named MYCRS1 and MYCRS2, involved in the activation of auxin- and AM-mediated expression of SlGH3.4. Deletion of the AuxRE from the SlGH3.4 promoter caused almost complete abolition of GUS staining in response to external IAA induction. Seven repeats of AuxRE fused to the Cauliflower mosaic virus (CaMV) 35S minimal promoter could direct GUS expression in both IAA-treated and AM fungal-colonized roots of tobacco plants. Four repeats of MYCRS1 or MYCRS2 fused to the CaMV35S minimal promoter was sufficient to drive GUS expression in arbuscule-containing cells, but not in IAA-treated tobacco roots. In summary, our results offer new insights into the molecular mechanisms underlying the potential cross-talk between the auxin and the AM regulatory pathways in modulating the expression of AM responsive GH3 genes in diverse mycorrhizal plants. PMID- 28339726 TI - Effect of feeding soybean meal and differently processed peas on the gut mucosal immune system of broilers. AB - Peas are traditionally used as a protein source for poultry. However, peas contain antinutritional factors (ANF), which are associated with the initiation of local and systemic immune reactions. The current study examined the effect of feeding raw or differently processed peas in comparison with feeding a soybean meal (SBM) based control diet (C) on the gut mucosal immune system of broilers in a 35 day feeding trial. In six replicates, a total of 360 one-day-old male broilers were randomly allocated to four different groups receiving C, or three treatment diets containing raw, fermented, and enzymatically pre-digested peas, each supplying 30% of required crude protein. After slaughtering, jejunal samples were taken for immunohistochemical, flow cytometric, and gene expression analyses. Investigations were focused on the topological distribution of intraepithelial leukocytes (villus tip, villus mid, and crypt region) as well as on the further characterization of the different intraepithelial lymphocytes (IEL) and concomitant pro- and anti-inflammatory cytokines. Broilers receiving the raw or processed pea diets had higher numbers of intraepithelial CD45+ leukocytes in the tip (P = 0.004) and mid region (P < 0.001) of villi than birds fed C. Higher numbers of intraepithelial CD3+ lymphocytes were found in the villus tip (P = 0.002) and mid region (P = 0.003) of birds fed raw or processed pea containing diets in comparison with those fed C. The flow cytometric phenotyping showed a similar relative distribution of IEL among the feeding groups. The expression of intestinal pro- and anti-inflammatory cytokines was affected by feeding the different diets only to a minor extent. To conclude, feeding of diets formulated with raw and processed peas in comparison with feeding a SBM control diet initiated mucosal immune responses in the jejunum of broilers indicated by a quantitative increase of intraepithelial T cells. Further research is needed in order to ascertain the specific factors which are responsible for observed local immune reactions and how these local reactions might affect the immune status and health of broilers. PMID- 28339727 TI - Rapid Decrease in Rates of Hospitalization Resulting From Invasive Pneumococcal Disease and Community-Acquired Pneumonia in Children Aged <60 Months After 13 Valent Pneumococcal Conjugate Vaccine Introduction in Argentina. AB - Background: In January 2012, Argentina included universal pneumococcal vaccination in the routine childhood vaccination program using a 13-valent pneumococcal conjugate vaccine (PCV13). A 2 + 1 schedule (2 doses in the first year of life and a booster dose at 12 months of age) in children aged <2 years and 2-dose catch-up immunization in children aged 13 to 24 months was administered during the first year of vaccine introduction. The purpose of this study was to assess the burdens of invasive pneumococcal disease (IPD) and/or community-acquired pneumonia (CAP) in hospitalized children younger than 5 years during the first 2 years of the program compared to those in the prevaccination period in our setting. Methods: This was a multicenter, prospective, and descriptive study. Rates of hospitalization resulting from IPD and/or CAP in 5 pediatric reference centers across the country were analyzed (every 10 000 admissions). Clinical, epidemiologic, and microbiological data were recorded. Statistical analysis using Stata 8.0 was performed. Results: A comparison of rates of hospitalization resulting from global IPD and/or CAP in the prevaccine (2009-2011) and postvaccine (2012-2013) periods revealed significant decreases of 50% (P = .003) and 51% (P < .0001), respectively. Significant decreases were also observed in number of hospitalizations resulting from empyema (39%; P = .03) and pneumococcal empyema (67.8%; P = .007); the reduction was not statistically significant for pneumococcal CAP (58%; P = .18). Hospital stays for IPD and/or CAP decreased by 56%. Conclusion: Rapid and significant decreases in the rates of hospitalization resulting from IPD and/or CAP during the first 2 years after PCV13 introduction were observed. A longer surveillance period is required to confirm these results and the effectiveness of the vaccination program. PMID- 28339729 TI - How to monitor safety and efficacy of biologic treatment in rare, therapy refractory immune-mediated inflammatory diseases? PMID- 28339730 TI - Nonne-Froin sign. PMID- 28339728 TI - Comparative expression of host defense peptides in turkey poults. AB - Host defense peptides (HDPs) are a large group of small, positively charged peptides that play an important role in innate immunity, particularly at early ages when other components of the immune system have not fully developed. There are 3 classes of avian HDPs: avian beta defensins (AvBDs), cathelicidins (Cath), and liver-expressed antimicrobial peptide 2 (LEAP-2). The objective was to compare expression of HDP mRNAs in male turkey poults at day of hatch (d 0), d 7, d 14, d 21 and d 28 from the thymus, spleen, bursa, duodenum, jejunum, and ileum. The expression of AvBD1, AvBD2, AvBD8, AvBD9, AvBD10, AvBD13, Cath2, Cath3, and LEAP-2 mRNA was measured using qPCR (n = 6 birds/tissue/age). Data were analyzed by one-way ANOVA and Tukey's test, and significance considered at P < 0.05. AvBDs and Caths exhibited greater expression in immune organs (thymus, spleen, and bursa) than intestinal tissues. In the thymus, expression of all AvBDs examined, except AvBD8, showed an increase from d 0 to d 21. In the spleen, AvBD1 and AvBD2 exhibited reduced expression from d 0 to d 7 and low expression thereafter. In the intestine, AVBD1, AVBD8, and AvBD13 increased expression from d 0 to d 28 in the duodenum, while AvBD10 showed the greatest expression at d 0 that declined to d 7 and stayed low thereafter in the duodenum, jejunum, and ileum. Cath2 and Cath3 demonstrated the highest expression in the spleen, which was greatest at d 0 then declined to d 7 through d 28. Conversely, LEAP-2 showed greater expression in the intestinal tissues than in the immune organs. LEAP-2 expression was upregulated from d 0 to d 7 and then remained elevated from d 7 through d 14 in the duodenum. In the jejunum, LEAP-2 increased from d 0 to d 21 and d 28. Understanding the differential expression of HDPs could reveal the innate immune status of turkey poults, and may subsequently allow improvement of their health through appropriate mitigation strategies. PMID- 28339731 TI - Obesity-associated cardiac pathogenesis in broiler breeder hens: Development of metabolic cardiomyopathy. AB - Feed intake is typically restricted (R) in broiler hens to avoid obesity and improve egg production and livability. To determine whether improved heart health contributes to improved livability, fully adult 45-week-old R hens were allowed to consume feed to appetite (ad libitum; AL) up to 10 wk (70 d). Mortality, contractile functions, and morphology at 70 d, and measurements of cardiac hypertrophic remodeling at 7 d and 21 d were made and compared between R and AL hens. Outcomes for cardiac electrophysiology and mortality, reported separately, found increased mortality in AL hens in association with cardiac pathological hypertrophy and contractile dysfunction. The present study aimed to delineate metabolic cardiomyopathies underlying the etiology of obesity-associated cardiac pathology. Metabolic measurements were made in hens continued on R rations or assigned to AL feeding after 7 d and 21 days. AL feeding increased plasma insulin, glucose, and non-esterified fatty acid (NEFA) concentrations by 21 d (P < 0.05). Metabolic cardiomyopathy in AL-hens was confirmed by cardiac triacylglycerol (TG) and ceramide accumulation consistent with up-regulation of related enzyme gene expressions, and by increased indices of oxidation stress (P < 0.05). In contrast to R hens, cardiac pyruvate dehydrogenase (PDH) activity and glucose transporter (GLUT) gene expressions increased progressively while carnitine palmitoyltransferase-1 (CPT-1) transcript levels in AL hens declined from 7 d to 21 d (P < 0.05), reflecting a shift from an oxidative to a more glycolytic metabolism, a typical metabolic derangement associated with cardiac hypertrophic remodeling. Cardiac pathogenesis in AL hens was further indicated by increased leukocyte infiltrates, interleukin-1beta (IL-1beta) and IL-6 production, cellular apoptosis, interstitial fibrosis, and expression of the heart failure marker myosin heavy chain (MHC-beta; cardiac muscle beta) (P < 0.05). Results support the conclusion that diabetic conditions, cardiac inflammation and lipotoxic metabolic derangements act as pathological cues to trigger pathogenic changes along cardiac hypertrophy in AL hens. PMID- 28339733 TI - A Two-phase mixture model of platelet aggregation. AB - We present a two-phase model of platelet aggregation in coronary-artery-sized blood vessels. The model tracks the number densities of three platelet populations as well as the concentration of a platelet activating chemical. Through the formation of elastic bonds, activated platelets can cohere with one another to form a platelet thrombus. Bound platelets in a thrombus move in a velocity field different from that of the bulk fluid. Stresses produced by the elastic bonds act on the bound platelet material. Movement of the bound platelet material and that of the background fluid are coupled through an interphase drag and an incompressibility constraint. The relative motion between bound platelets and the background fluid permits intraclot transport of individual platelets and activating chemical, allows the bound platelet density to reach levels much higher than the platelet density in the bulk blood, and allows thrombus formation to occur on a physiological timescale, all of which were precluded by our earlier single phase model. Computational results from the two-phase model indicate that through complicated fluid-structure interactions, the platelet thrombus can develop significant spatial inhomogeneities and that the amount of intraclot flow may greatly affect the growth, density, and stability of a thrombus. PMID- 28339734 TI - Correction. PMID- 28339732 TI - Exploring the in vivo digestion of plant proteins in broiler chickens. AB - The use of various protein sources (industry by-products, proteaginous) in poultry diets requires a greater understanding of protein digestion mechanisms. The aim of this study was to characterize the molecular actors required for protein digestion in broilers fed 4 different diets containing soybean meal, rapeseed meal, pea, or corn distiller's dried grain with solubles as the only protein source. The digesta of the digestive tract segments were collected and soluble proteins were analyzed by SDS-PAGE. SDS-PAGE analyses revealed 5 ubiquitous bands in digesta of all digestive tract segments regardless of the diet, whereas 3 bands were diet-specific. The digesta of the jejunum were further submitted to proteomic analysis. Forty-two proteins of chicken origin and 17 plant proteins were identified in digesta samples by mass spectrometry. Fifteen proteins of chicken origin were specific to one diet and 18 were common to all diets. By homology with mammals, these proteins are thought to be involved in protein, lipid, carbohydrate, and nucleic acid metabolism and also in intestinal homeostasis. Some of the 17 plant proteins were found to be not fully digested (soybean meal, rapeseed meal, and pea diets) and others were identified as protease inhibitors (soybean meal and pea diets). This study provides a comprehensive analysis of the physiological proteins involved in the digestion of 4 protein sources used in broiler diets. Such an approach, combined with the analysis of insoluble components of these different protein sources, would contribute to define whether these protein sources could be more largely used in poultry nutrition. It also would allow identifying ways to improve their digestibility in broiler chickens (feed additives such as exogenous proteases or processing to inactivate anti-nutritional factors, for instance). PMID- 28339735 TI - Triage quality control is missing tools-a new observation technique for ED quality improvement. AB - Objective: Correct assessment of patient urgency is critical to ensuring patient safety in emergency departments (EDs). Although significant time and effort have been devoted to developing triage systems, less attention has been paid to the development of quality control. The aim of this study is to introduce and test observation technique, which enables identifying of patient groups at risk of erroneous assessment in triage. The introduced technique is aimed to be less laborious to use than existing triage quality control methods. Design: The study developed an observation technique for identifying patients with possible erroneous assessments in triage. Data sample for the observation technique is carried out with survey form filled in by nurse. Setting: Hospital ED with ~74 000 patient visits annually. Participants: Consecutive adult patients in an ED for baseline study period of 14 days (1774 patients) in 2010 and control study period of 4 days (541 patients) in 2012. Intervention: Triage observation technique for continuous improvement of triage performance. Main Outcome Measures: Primary measures of triage improvement were triage accuracy and nurses' ability to predict patient admissions. Results: With the observation technique the ED staff was able to identify patient groups at risk for erroneous triage. Under-triage related mostly to patients with chest pain, shortness of breath, collapse, stomach pain and infections. Instead injures and muscular skeletal symptoms were seldom undertriaged even though they are common. Conclusions: EDs can control triage quality with simple observation technique. The usability of observation technique and triage quality improvement process were good. PMID- 28339736 TI - Extractions, retention and stability: the search for orthodontic truth. AB - Background and objectives: From the beginnings of modern orthodontics, questions have been raised about the extraction of healthy permanent teeth in order to correct malocclusions. A hundred years ago, orthodontic tooth extraction was debated with almost religious intensity by experts on either side of the issue. Sheldon Friel and his mentor Edward H. Angle both had much to say about this controversy. Today, after significant progress in orthodontic practice, similar arguments are being voiced between nonextraction expansionists and those who see the need for tooth extractions in some orthodontic patients. Furthermore, varying concepts of mechanical retention of treatment results have evolved over the years which have been misinterpreted as enhancing natural orthodontic stability. Materials and methods: In this essay, representing the Ernest Sheldon Friel Memorial Lecture presented in 2016 at the 92nd Congress of the European Orthodontic Society, a full spectrum of evidence from biology, anthropology and history is critically discussed in the search for truth among highly contested orthodontic variables: extraction versus nonextraction, fixed retention versus limited retention, and rationalized stability versus biological homeostasis. Conclusions and implications: Conscientious clinicians should try to develop individualized treatment plans for their patients, and not be influenced by treatment 'philosophies' with untested claims in clinical orthodontics. PMID- 28339737 TI - A Novel Chronic Opioid Monitoring Tool to Assess Prescription Drug Steady State Levels in Oral Fluid. AB - Objective: Interpretation limitations of urine drug testing and the invasiveness of blood toxicology have motivated the desire for the development of simpler methods to assess biologically active drug levels on an individualized patient basis. Oral fluid is a matrix well-suited for the challenge because collections are based on simple noninvasive procedures and drug concentrations better correlate to blood drug levels as oral fluid is a filtrate of the blood. Well established pharmacokinetic models were utilized to generate oral fluid steady state concentration ranges to assess the interpretive value of the alternative matrix to monitor steady state plasma oxycodone levels. Methods: Paired oral fluid and plasma samples were collected from patients chronically prescribed oxycodone and quantitatively analyzed by liquid chromatography tandem mass spectrometry. Steady state plasma concentration ranges were calculated for each donor and converted to an equivalent range in oral fluid. Measured plasma and oral fluid oxycodone concentrations were compared with respective matrix-matched steady state ranges, using each plasma steady state classification as the control. Results: A high degree of correlation was observed between matrices when classifying donors according to expected steady state oxycodone concentration. Agreement between plasma and oral fluid steady state classifications was observed in 75.6% of paired samples. This study supports novel application of basic pharmacokinetic knowledge to the pain management industry, simplifying and improving individualized drug monitoring and risk assessment through the use of oral fluid drug testing. Many benefits of established therapeutic drug monitoring in plasma can be realized in oral fluid for patients chronically prescribed oxycodone at steady state. PMID- 28339738 TI - A multi-biomarker score measuring disease activity in rheumatoid arthritis patients tapering adalimumab or etanercept: predictive value for clinical and radiographic outcomes. AB - Objective: The aim was to evaluate the predictive value of the baseline multi biomarker disease activity (MBDA) score in long-standing RA patients with low disease activity tapering TNF inhibitors (TNFi) for successful tapering or discontinuation, occurrence of flare and major flare, and radiographic progression. Methods: Dose REduction Strategies of Subcutaneous TNF inhibitors (Dutch Trial Register, NTR 3216) is an 18-month non-inferiority randomized controlled trial comparing tapering of TNFi until discontinuation or flaring with usual care (UC) in long-standing RA patients with stable low disease activity. Flare was defined as DAS28-CRP increase >1.2 or >0.6 if current DAS ?3.2; major flare was a flare lasting >3 months, despite treatment intervention. MBDA scores were measured at baseline. Radiographs were scored at baseline and 18 months using the Sharp-van der Heijde score. The area under the receiver operating characteristic (AUROC) curve was used to analyse the capability of baseline MBDA score to predict the above-mentioned outcomes. Results: Serum samples and outcomes were available for 171 of 180 patients from Dose REduction Strategies of Subcutaneous TNF inhibitors (115 tapering; 56 UC). AUROC analyses showed that baseline MBDA score was not predictive for the above-mentioned clinical outcomes in the taper group, but did predict major flare in the UC group (AUROC = 0.72, 95% CI: 0.56, 0.88). Radiographic progression was minimal and was not predicted by MDBA score. Conclusion: In this disease activity-guided strategy study of TNFi tapering in RA patients with low disease activity, baseline MBDA score was not predictive for successful tapering, discontinuation, flare, major flare or radiographic progression in patients who tapered TNFi. PMID- 28339739 TI - Unabated occupational risk in a patient with rheumatoid pulmonary fibrosis. AB - Background: This case highlights the importance of considering hypersensitivity pneumonitis (HP) in the differential diagnosis of interstitial lung disease (ILD) and of obtaining an occupational history so that remediable risk factors may be identified and managed. Aims: To report a case of a chicken sexer with severe rheumatoid arthritis (RA) who developed progressively worsening dyspnoea and restrictive lung disease associated with pulmonary fibrosis. Methods: Clinical investigation included physical examination, occupational history, pulmonary function tests (PFTs), chest imaging and bronchoalveolar lavage (BAL), as well as serological tests including standard IgE bird feather mixture and local IgG precipitin preparation to chicken excrement. Lung histopathology was examined post-mortem. Results: The patient had worked as a chicken sexer for 29 years with limited control of exposure to chicken bioaerosols. PFTs initially showed mild restriction with a moderate gas transfer defect and computerized tomography of the chest exhibited extensive interstitial infiltrates throughout with severe honeycombing at the bases. Cytology from a BAL revealed multinucleated giant cells (MNGs). Specific serologic tests for bird antigens were negative. Histopathology demonstrated diffuse interstitial fibrosis with honeycombing, poorly formed granulomas and MNGs. Conclusions: Findings were consistent with a diagnosis of HP with RA-associated ILD. The patient's history of severe RA biased the diagnosis to one of RA-associated ILD and her occupational risk had been less emphatically addressed. Obtaining a thorough occupational history can uncover exposures to workplace respiratory hazards and may create opportunities for intervention to limit morbidity from chronic lung disease. PMID- 28339740 TI - Margin estimation and disturbances of irradiation field in layer-stacking carbon ion beams for respiratory moving targets. AB - Carbon-ion therapy by layer-stacking irradiation for static targets has been practised in clinical treatments. In order to apply this technique to a moving target, disturbances of carbon-ion dose distributions due to respiratory motion have been studied based on the measurement using a respiratory motion phantom, and the margin estimation given by the square root of the summation Internal margin2+Setup margin2 has been assessed. We assessed the volume in which the variation in the ratio of the dose for a target moving due to respiration relative to the dose for a static target was within 5%. The margins were insufficient for use with layer-stacking irradiation of a moving target, and an additional margin was required. The lateral movement of a target converts to the range variation, as the thickness of the range compensator changes with the movement of the target. Although the additional margin changes according to the shape of the ridge filter, dose uniformity of 5% can be achieved for a spherical target 93 mm in diameter when the upward range variation is limited to 5 mm and the additional margin of 2.5 mm is applied in case of our ridge filter. Dose uniformity in a clinical target largely depends on the shape of the mini-peak as well as on the bolus shape. We have shown the relationship between range variation and dose uniformity. In actual therapy, the upper limit of target movement should be considered by assessing the bolus shape. PMID- 28339743 TI - Application of bacteriophages to reduce Salmonella attachment and biofilms on hard surfaces. AB - This study evaluated the effectiveness of bacteriophage treatment for reducing Salmonella attachment and biofilms on hard surfaces. Bacteriophages (n = 6) were selected for bacteriophage treatment based on host ranges against Salmonella isolates (n = 10) obtained from rendering plants. The effectiveness of bacteriophage treatment (104-108 PFU/mL) was initially evaluated against strong Salmonella biofilm formers in 96-well microplate. Then, the bacteriophage treatment (109 PFU/mL) was applied for 7 d to reduce Salmonella attached to the stainless steel surfaces under laboratory and greenhouse conditions. The inhibition of biofilm formation and reduction of pre-formed biofilm in 96-well microplate with bacteriophage treatment reached up to 90 and 66%, respectively. Under laboratory conditions, bacteriophage treatment reduced up to 2.9 and 3.0 log CFU/cm2 of attachment and slightly formed biofilm of selected top 10 Salmonella strains and an avirulent Salmonella Typhimurium strain 8243, respectively, as compared with reductions of 3.4, 1.4, and 3.0 log CFU/cm2 of S. Typhimurium strain 8243 in summer, fall/winter, and spring seasons under greenhouse conditions, respectively. Clearly, bacteriophages were effective on reducing Salmonella attachment and biofilms formed on hard surfaces under both laboratory and greenhouse conditions. The use of bacteriophages on hard surfaces may have merits in reducing the likelihood of finished rendered products being recontaminated with Salmonella in rendering plants. PMID- 28339742 TI - Topiramate modulates post-infarction inflammation primarily by targeting monocytes or macrophages. AB - Aims: Monocytes/macrophages response plays a key role in post-infarction inflammation that contributes greatly to post-infarction ventricular remodelling and cardiac rupture. Therapeutic targeting of the GABAA receptor, which is enriched in monocytes/macrophages but not expressed in the myocardium, may be possible after myocardial infarction (MI). Methods and results: After MI was induced by ligation of the coronary artery, C57BL/6 mice were intraperitoneally administered with one specific agonist or antagonist of the GABAA receptor (topiramate or bicuculline), in the setting of presence or depletion of monocytes/macrophages. Our data showed that within the first 2 weeks after MI, when monocytes/macrophages dominated, in contrast with bicuculline, topiramate treatment significantly reduced Ly-6Chigh monocyte numbers by regulating splenic monocytopoiesis and promoted foetal derived macrophages preservation and conversion of M1 to M2 or Ly-6Chigh to Ly-6Clow macrophage phenotype in the infarcted heart, though GABAAergic drugs failed to affect M1/M2 or Ly-6Chigh/Ly 6Clow macrophage polarization directly. Accordingly, pro-inflammatory activities mediated by M1 or Ly-6Chigh macrophages were decreased and reparative processes mediated by M2 or Ly-6Clow macrophages were augmented. As a result, post infarction ventricular remodelling was attenuated, as reflected by reduced infarct size and increased collagen density within infarcts. Echocardiographic indices, mortality and rupture rates were reduced. After depletion of monocytes/macrophages by clodronate liposomes, GABAAergic drugs exhibited no effect on cardiac dysfunction and surrogate clinical outcomes. Conclusion: Control of the GABAA receptor activity in monocytes/macrophages can potently modulate post-infarction inflammation. Topiramate emerges as a promising drug, which may be feasible to translate for MI therapy in the future. PMID- 28339746 TI - In vitro cytotoxic and ACE-inhibitory activities of promod 278P hydrolysate of ovotransferrin from chicken egg white. AB - Peptides released from egg proteins via enzymatic hydrolysis show various bioactivities such as antimicrobial, antioxidant, antihypertensive, and immunomodulatory properties. The objective of this study was to investigate the cytotoxic and Angiotensin Converting Enzyme (ACE)-inhibitory activities of ovotransferrin and its promod 278P enzyme hydrolysate. Ovotransferrin from egg white was hydrolyzed using promod 278P at 45 degrees C for 3 hours. Using the MTT assay, the cytotoxicity of ovotransferrin and promod 278P hydrolysate of ovotransferrin were evaluated in human cancer cell lines of various tissue origins. The ACE-inhibitory activity was determined using the cleavage of a chromogenic substrate -Hip-His-Leu. The promod 278P hydrolysate of ovotransferrin showed a potent cytotoxicity (>90%) at 20 mg/mL in all cancer cell lines tested, but ovotransferrin did not. The IC50 value of the promod 278P hydrolysate of ovotransferrin against 5 different cancer cells were 10.05 +/- 1.55, 3.45 +/- 0.94, 4.43 +/- 1.87, 4.92 +/- 0.63, and 10.43 +/- 3.91 mg/mL for MCF-7, HeLa, HepG2, HT-29, and LoVo cells, respectively. The promod 278P hydrolysate of ovotransferrin showed a strong ACE-inhibiting activity: at 10 mg/mL level, the hydrolysate showed 76.82 +/- 1.28% inhibition to ACE-inhibitory activity, and 73.33 +/- 2.56%, 56.85 +/- 1.84%, 50.32 +/- 3.71%, 17.30 +/- 0.13%, and 4.52 +/- 6.83% inhibitory activity at 5, 2.5, 1.25, 0.625, and 0.3125 mg/mL level, respectively. The IC50 value of the promod 278P hydrolysate of ovotransferrin was 1.53 +/- 0.20 mg/mL. However, ovotransferrin did not show any inhibitory effect to angiotensin-converting enzyme activity. This result indicated that the promod 278P hydrolysate of ovotransferrin has a great potential as an anticancer and antihypertension agent for humans, but the information on the peptides responsible for the functional activities is not available yet. PMID- 28339744 TI - Determining the analytical specificity of PCR-based assays for the diagnosis of IA: What is Aspergillus? AB - A wide array of PCR tests has been developed to aid the diagnosis of invasive aspergillosis (IA), providing technical diversity but limiting standardisation and acceptance. Methodological recommendations for testing blood samples using PCR exist, based on achieving optimal assay sensitivity to help exclude IA. Conversely, when testing more invasive samples (BAL, biopsy, CSF) emphasis is placed on confirming disease, so analytical specificity is paramount. This multicenter study examined the analytical specificity of PCR methods for detecting IA by blind testing a panel of DNA extracted from a various fungal species to explore the range of Aspergillus species that could be detected, but also potential cross reactivity with other fungal species. Positivity rates were calculated and regression analysis was performed to determine any associations between technical specifications and performance. The accuracy of Aspergillus genus specific assays was 71.8%, significantly greater (P < .0001) than assays specific for individual Aspergillus species (47.2%). For genus specific assays the most often missed species were A. lentulus (25.0%), A. versicolor (24.1%), A. terreus (16.1%), A. flavus (15.2%), A. niger (13.4%), and A. fumigatus (6.2%). There was a significant positive association between accuracy and using an Aspergillus genus PCR assay targeting the rRNA genes (P = .0011). Conversely, there was a significant association between rRNA PCR targets and false positivity (P = .0032). To conclude current Aspergillus PCR assays are better suited for detecting A. fumigatus, with inferior detection of most other Aspergillus species. The use of an Aspergillus genus specific PCR assay targeting the rRNA genes is preferential. PMID- 28339745 TI - Chronic nasal Staphylococcus aureus carriage identifies a subset of newly diagnosed granulomatosis with polyangiitis patients with high relapse rate. AB - Objective: The aim of this study was to evaluate whether chronic nasal carriage of Staphylococcus aureus (SA) is related to relapses in patients with newly diagnosed ANCA-associated vasculitis (AAV). Methods: In two clinical trials (n = 200), for early systemic (n = 83) and generalized (n = 117) AAV, nasal swabs were obtained monthly and at the time of a relapse. Chronic nasal SA carriage (CNSAC) was defined as ? 75% of cultures being SA positive, with non-carriers being SA negative in all cultures and remaining patients being intermittent carriers. Fifty-five of 200 (27.5%) patients received prophylactic trimethoprim/sulfamethoxazole (T/S) against Pneumocystis jirovecii . Results: Of the total AAV patients, 24/200 (12%) were chronic, 102/200 (51%) intermittent and 74/200 (37%) non-carriers. Of 65 relapsing patients, 10/24 (41.7%) were chronic, 32/102 (31.4%) intermittent and 23/74 (31.1%) non-carriers (P = 0.59). For all AAV patients, CNSAC was not associated with an increased relapse risk [odds ratio (OR) = 1.57, 95% CI: 0.66, 3.76; P = 0.31]. However, 23/24 chronic carriers had granulomatosis with polyangiitis (GPA). In the 73 patients with generalized GPA (hazard ratio = 4.10, 95% CI: 1.37, 12.25; P = 0.01) and the 78 patients with early systemic GPA during immunosuppression (hazard ratio = 2.73, 95% CI: 0.95, 7.87; P = 0.06), relapse rates were higher for chronic SA carriers. Prophylactic T/S was not associated with a reduced relapse risk (OR = 0.71, 95% CI: 0.36, 1.41; P = 0.33). Nevertheless, prophylactic T/S reduced CNSAC (OR = 0.19, 95% CI: 0.04, 0.91; P = 0.04). Conclusion: The frequency of CNSAC in newly diagnosed GPA paralleled that in the general population. This subset of GPA patients (23/151, 15.2%) has a high relapse rate despite immunosuppression and prophylactic T/S treatment, requiring further investigations on pathogenesis and therapy. PMID- 28339747 TI - Deep learning for pharmacovigilance: recurrent neural network architectures for labeling adverse drug reactions in Twitter posts. AB - Objective: Social media is an important pharmacovigilance data source for adverse drug reaction (ADR) identification. Human review of social media data is infeasible due to data quantity, thus natural language processing techniques are necessary. Social media includes informal vocabulary and irregular grammar, which challenge natural language processing methods. Our objective is to develop a scalable, deep-learning approach that exceeds state-of-the-art ADR detection performance in social media. Materials and Methods: We developed a recurrent neural network (RNN) model that labels words in an input sequence with ADR membership tags. The only input features are word-embedding vectors, which can be formed through task-independent pretraining or during ADR detection training. Results: Our best-performing RNN model used pretrained word embeddings created from a large, non-domain-specific Twitter dataset. It achieved an approximate match F-measure of 0.755 for ADR identification on the dataset, compared to 0.631 for a baseline lexicon system and 0.65 for the state-of-the-art conditional random field model. Feature analysis indicated that semantic information in pretrained word embeddings boosted sensitivity and, combined with contextual awareness captured in the RNN, precision. Discussion: Our model required no task specific feature engineering, suggesting generalizability to additional sequence labeling tasks. Learning curve analysis showed that our model reached optimal performance with fewer training examples than the other models. Conclusion: ADR detection performance in social media is significantly improved by using a contextually aware model and word embeddings formed from large, unlabeled datasets. The approach reduces manual data-labeling requirements and is scalable to large social media datasets. PMID- 28339748 TI - Genotype-based gene signature of glioma risk. AB - Background: Glioma accounts for 80% of malignant brain tumors, but its etiologic determinants remain elusive. Despite genetic susceptibility loci identified by genome-wide association study (GWAS), the agnostic approach leaves open the possibility that other susceptibility genes remain to be discovered. Here we conduct a gene-centric integrative GWAS (iGWAS) of glioma risk that combines transcriptomics and genetics. Methods: We synthesized a brain transcriptomics dataset (n = 354), a GWAS dataset (n = 4203), and an advanced glioma tumor transcriptomic dataset (n = 483) to conduct an iGWAS. Using the expression quantitative trait loci (eQTL) dataset, we built models to predict gene expression for the GWAS data, based on eQTL genotypes. With the predicted gene expression, iGWAS analyses were performed using a novel statistical method. Gene signature risk score was constructed using a penalized logistic regression model. Results: A total of 30527 transcripts were analyzed using the iGWAS approach. Four novel glioma susceptibility genes were identified with internal and external validation, including DRD5 (P = 3.0 * 10-79), WDR1 (P = 8.4 * 10-77), NOMO1 (P = 1.3 * 10-25), and PDXDC1 (P = 8.3 * 10-24). The genotype-predicted transcription pattern between cases and controls is consistent with that between tumor and its matched normal tissue. The genotype-based 4-gene signature improved the classification between glioma cases and controls based on age, gender, and population stratification, with area under the receiver operating characteristic curve increasing from 0.77 to 0.85 (P = 8.1 * 10-23). Conclusion: A new genotype based gene signature of glioma was identified using a novel iGWAS approach, which integrates multiplatform genomic data as well as different genetic association studies. PMID- 28339750 TI - Downstream overdrive pacing and intracardiac concealed fusion to guide rapid identification of atrial tachycardia after atrial fibrillation ablation. AB - Aims: Atrial tachycardia (AT) related to atrial fibrillation (AF) ablation frequently poses a diagnostic challenge. Downstream overdrive pacing (DOP) can be used to rapidly detect reentry and assess proximity of a pacing site to an AT circuit or focus. We hypothesized that systematic DOP using multielectrode catheters would facilitate AT mapping. Methods and results: DOP identified constant fusion when the post-pacing interval (PPI)-tachycardia cycle length (TCL) <40 ms and stimulus to adjacent upstream atrial electrogram interval >75% of TCL. Mapping was performed as follows: (i) CS DOP, (ii) DOP at left atrial (LA) roof, (iii) DOP at selected LA sites based on prior DOP attempts, and (iv) mapping and ablation at regions of fractionated electrograms in region of AT. Activation mapping was performed at operator discretion. AT diagnosis was confirmed by successful ablation or additional mapping when ablation was unsuccessful. Fifty consecutive patients with sustained AT underwent mapping of 68 ATs, of whom 42 (62%) were macroreentrant, 19 were locally reentrant (28%), and 7 (10%) were focal. AT was correctly identified with a median of three DOP attempts. All macroreentrant ATs were identified with <=6 DOP attempts. One AT (1.6%) was terminated by DOP, and three ATs (4.8%) required activation mapping. Intracardiac concealed fusion was seen in 26 ATs (38%), each of which was successfully ablated. Conclusion: Reentry could be demonstrated in a substantial majority of AF ablation-related AT. A stepwise diagnostic approach using DOP and recognition of intracardiac concealed fusion can be used to rapidly identify and ablate reentrant AT. PMID- 28339749 TI - Multi-generational genome wide association studies identify chromosomal regions associated with ascites phenotype. AB - Ascites is a multi-faceted disease commonly observed in fast growing broilers, which is initiated when the body is insufficiently oxygenated. A series of events follow, including an increase in pulmonary artery pressure, right ventricle hypertrophy, and accumulation of fluid in the abdominal cavity and pericardium. Advances in management practices along with improved selection programs have decreased ascites incidence in modern broilers. However, ascites syndrome remains an economically important disease throughout the world, causing estimated losses of $100 million per year. In this study, a 60 K Illumina SNP BeadChip was used to perform a series of genome wide association studies (GWAS) on the 16th and 18th generation of our relaxed (REL) line descended from a commercial elite broiler line beginning in 1995. Regions significantly associated with ascites incidence were identified on chromosome 2 around 70 megabase pairs (Mbp) and on chromosome Z around 60 Mbp. Five candidate single nucleotide polymorphisms (SNP) were evaluated as indicators for these 2 regions in order to identify association with ascites and right ventricle to total ventricle weight (RVTV) ratios. Chromosome 2 SNP showed an association with RVTV ratios in males phenotyped as ascites resistant and ascites susceptible (P = 0.02 and P = 0.03, respectively). The chromosome Z region also indicates an association with resistant female RVTV values (P = 0.02). Regions of significance identified on chromosomes 2 and Z described in this study will be used as proposed candidate regions for further investigation into the genetics of ascites. This information will lead to a better understanding of the underlying genetics and gene networks contributing to ascites, and thus advances in ascites reduction through commercial breeding schemes. PMID- 28339751 TI - Changes in Secondhand Smoke Exposure After Smoke-Free Legislation (Spain, 2006 2011). AB - Introduction: In 2011, the Spanish partial smoke-free legislation was extended to affect all enclosed settings, including hospitality venues and selected outdoor areas. This study evaluated the change in self-reported exposure to secondhand smoke among the adult, nonsmoking population. Methods: Two cross-sectional surveys were conducted on nationally representative samples of the adult (>=18 years) nonsmoking Spanish population. One was conducted in 2006 (6 months after the first ban) and the other in 2011, 6 months after the new ban was implemented. We assessed the prevalence and 95% confidence interval (CI) of self-reported exposure to secondhand smoke in various settings, and the corresponding adjusted prevalence ratios (PR) and 95% CIs. Results: Overall, the self-reported exposure to secondhand smoke fell from 71.9% (95% CI: 70.1%-73.7%) in 2006 to 45.2% (95% CI: 43.1%-47.3%) in 2011 (PR = 0.43; 95% CI: 0.39-0.47). Specifically, self reported exposure significantly decreased from 29.2% to 12.7% (PR = 0.36; 95% CI: 0.31-0.42) in the home, from 35.0% to 13.0% (PR = 0.40; 95% CI: 0.33-0.49) at work/education venues, from 56.2% to 32.2% (PR = 0.44; 95% CI: 0.39-0.48) during leisure time (mainly hospitality venues, but also venues other than work/education venues and home), and from 40.6% to 12.7% (PR = 0.24; 95% CI: 0.21 0.29) in transportation vehicles/stations. Conclusions: The prevalence of secondhand smoke exposure among nonsmokers decreased after implementation of a comprehensive smoke-free legislation in Spain. In addition to the expected reduction in exposure during leisure time, we observed reductions in settings that were not subject to the new legislation, such as homes, outdoor bus stops, and train stations. Implications: Exposure to secondhand smoke in selected outdoor settings may be further reduced by extending smoke-free legislation. PMID- 28339752 TI - Testing Shoulder Pain Mapping. AB - Objective: A previous study on shoulder pain mapping showed specific pain patterns for common shoulder disorders. This study aimed to test those patterns for accuracy, modify shoulder pain mapping as needed, and observe their reliability and validity. Methods: This prospective study used a two-step process and was undertaken to determine its potential utility in daily practice. New shoulder pain patients marked their pain, its character and severity, on a custom made mapping form. Then a researcher blinded to the diagnoses gave their estimations on the basis of previously established maps, and they were correlated with final diagnoses. Subsequently, a guide table was developed on how to read the maps, and intertester reliability was performed with three independent testers. Results: The study included 194 patients, and the overall accuracy for estimations was between 45.4% and 49.5%. The sensitivity was high, especially for instability, followed by calcific tendinitis, acromio-calvicular joint pathology, and impingement. The intertester reliability showed clinically significant agreement between testers for both disease groups (kappa = 0.70) and individual disorders (kappa = 0.52). Conclusions: This was a unique and extensive study on shoulder pain mapping. The study concluded that pain mapping could be a useful adjunct to the clinical assessment of patients with shoulder pain and can be used in the primary care setting as well as secondary care and for research. PMID- 28339753 TI - In-ovo monochromatic green light photostimulation enhances embryonic somatotropic axis activity. AB - Previous studies demonstrated that in ovo photostimulation with monochromatic green light increases body weight and accelerates muscle development in broilers. The mechanism in which in ovo photostimulation accelerates growth and muscle development is not clearly understood. The objective of the current study was to define development of the somatotropic axis in the broiler embryo associated with in ovo green light photostimulation. Two-hundred-forty fertile broiler eggs were divided into 2 groups. The first group was incubated under intermittent monochromatic green light using light-emitting diode (LED) lamps with an intensity of 0.1 W?m2 at shell level, and the second group was incubated under dark conditions and served as control. In ovo green light photostimulation increased plasma growth hormone (GH) and prolactin (PRL) levels, as well as hypothalamic growth hormone releasing hormone (GHRH), liver growth hormone receptor (GHR), and insulin-like growth factor-1 (IGF-1) mRNA levels. The in ovo photostimulation did not, however, increase embryo's body weight, breast muscle weight, or liver weight. The results of this study suggest that stimulation with monochromatic green light during incubation increases somatotropic axis expression, as well as plasma prolactin levels, during embryonic development. PMID- 28339755 TI - Assessing the impact of egg sweating on Salmonella Enteritidis penetration into shell eggs. AB - Salmonella Enteritidis (SE) prevalence in eggs is a major concern to the egg industry. Some research has shown that egg sweating can increase Salmonella penetration into egg contents when refrigerated eggs are moved to a warmer temperature. This occurs when eggs are tempered before wash, to minimize thermal cracks. The effect of egg sweating on SE penetration into shell eggs over a 6 week storage period at 4 degrees C was assessed. A 2 * 2 factorial of SE inoculation and egg sweating was utilized. Treatments included (SES) nalidixic acid (NA)-resistant SE inoculated and sweated, (SENS) NA-resistant SE inoculated and not sweated, (NSES) buffered peptone water (BPW) inoculated and sweated, and (NSENS) BPW inoculated and not sweated. Eggs were inoculated with 108 SE. Eggs formed condensation for approximately 17 min in a 32 degrees C incubator. Shell rinse, shell emulsion, and egg contents were sampled then enumerated and assessed for prevalence of SE over a 6 wk storage period at 4 degrees C. After wk 1, the SENS shell rinse had higher SE counts (0.32 log10 CFU/mL) than the other 3 treatments, where no SE was enumerated. A significant week by treatment interaction was found for the shell rinse SE detection (P < 0.05). In subsequent weeks, no SE counts were obtained from the egg shell rinse, shell emulsion, or egg contents. The SENS shell rinses had significantly higher SE prevalence than the SES rinses in weeks 1 (100% vs. 34.3%), 2 (57.6% vs. 22.2%), and 3 (38.2% vs. 11.1%) (P < 0.05). In samples from weeks 4, 5, and 6, there was no difference in SE prevalence between SES and SENS. Egg sweating did not increase SE penetration into the shell emulsion across treatment or week (P < 0.05). The decreasing trend of SE prevalence obtained over the study period indicate that refrigeration is effective at inhibiting SE growth. These results indicate that egg sweating occurring under common US egg handling practices is not harmful to egg safety. PMID- 28339754 TI - Expression of deep brain photoreceptors in the Pekin drake: a possible role in the maintenance of testicular function. AB - Several putative deep brain photoreceptors (DBPs) have been identified, such as melanopsin, opsin 5, and vertebrate ancient opsin. The aim of this study was to elucidate the role of DBPs in gonadal regulation in the Pekin drake. As previously reported, we observed opsin-like immunoreactivity (-ir) in the lateral septum (LS), melanopsin-ir in the premammillary nucleus (PMM), and opsin 5-ir in the periventricular organ. To determine the sensitivity of the DBPs to specific wavelengths of light, drakes were given an acute exposure to red, blue, or white light. Blue light stimulated an increase (P < 0.01) in the immediate early gene fra-2-ir co-expression in melanopsin-ir neurons in the PMM, and red light increased (P < 0.05) fra-2-ir co-expression in opsin-ir neurons, suggesting these neurons are blue- and red-receptive, respectively. To further investigate this photoperiodic response, we exposed drakes to chronic red, long-day white, short day white, or blue light. Blue light elicited gonadal regression, as testes weight (P < 0.001) and plasma luteinizing hormone (LH) levels (P < 0.001) were lower compared to drakes housed under long-day white light. Photo-regressed drakes experienced complete gonadal recrudescence when housed under long-day red and blue light. qRT-PCR analyses showed that gonadally regressed drakes showed reduced levels (P < 0.01) of gonadotropin releasing hormone (GnRH) mRNA but not photoreceptor or GnIH mRNAs compared to gonadally functional drakes. Our data suggest DBP in the LS may be rhodosin and multiple DBPs are required to fully maintain gonadal function in Pekin drakes. PMID- 28339757 TI - Bone characteristics, histopathology, and chondrocyte apoptosis in femoral head necrosis induced by glucocorticoid in broilers. AB - Femoral head necrosis (FHN) is a common disorder in fast-growing broilers in the poultry industry, but the pathogenesis of FHN has not been clarified completely. In the present study, glucocorticoid (GC) administration was used to induce FHN in broilers. Compared with normal birds, histopathology showed that the length of the articular cartilage of GC-induced FHN broilers was thicker while the proliferative zone and prehypertrophic zone were obviously thinner. Moreover, hematoxylin and eosin (HE) staining showed the apoptotic chondrocyte in the growth plate of the femoral head in FHN-affected birds. Bone parameters also decreased significantly in GC-induced FHN broilers. In addition, as for the mRNA expression, GC-induced FHN broilers had an apparent reduction in Col-II, Col-X, and Bcl-2 but a significant promotion of Caspase-3, Caspase-9, ASK-1, and JNK-1 when compared with the normal birds. It showed glucocorticoid induced FHN in broilers by affecting the proliferation, differentiation, and apoptosis of chondrocytes accompanying the retarding of bone growth. PMID- 28339756 TI - Molecular diagnosis of Pneumocystis pneumonia in dogs. AB - Pneumocystis pneumonia (PCP) is a life-threatening fungal disease that can occur in dogs. The aim of this study was to provide a preliminary genetic characterisation of Pneumocystis carinii f.sp.'canis' (P. canis) in dogs and thereby develop a reliable molecular protocol to definitively diagnose canine PCP. We investigated P. canis in a variety of lung specimens from dogs with confirmed or strongly suspected PCP (Group 1, n = 16), dogs with non-PCP lower respiratory tract problems (Group 2, n = 65) and dogs not suspected of having PCP or other lower respiratory diseases (Group 3, n = 11). Presence of Pneumocystis DNA was determined by nested PCR of the large and small mitochondrial subunit rRNA loci and by a real-time quantitative polymerase chain reaction (qPCR) assay developed using a new set of primers. Molecular results were correlated with the presence of Pneumocystis morphotypes detected in cytological/histological preparations. Pneumocystis DNA was amplified from 13/16 PCP-suspected dogs (Group 1) and from 4/76 dogs of control Groups 2 and 3 (combined). The latter four dogs were thought to have been colonized by P. canis. Comparison of CT values in 'infected' versus 'colonized' dogs was consistent with this notion, with a distinct difference in molecular burden between groups (CT <= 26 versus CT range (26 1-year old leads). Methods and results: Between September 2013 and June 2016, a total of 238 leads in 124 consecutive patients were removed by using the new Evolution RL rotational mechanical sheath. Indications for LE were cardiac device infection in 63 (50.8%) cases, lead malfunction in 41 (33.1%), upgrade in 1 (0.8%) case and for other reasons in the remaining 19 cases (15.3%). Ninety-one leads (38.2%) were implantable cardioverter defibrillator leads (81 dual coil vs. 10 single coil), 38 (16%) right ventricular leads, 86 (36.1%) right atrial leads, and 23 (9.7%) coronary sinus leads. The mean implant duration was 92.2 +/- 52.9 months (range 12-336). 91.6% of the leads (218/238) were extracted completely with the Evolution RL alone, with the complete success rate rising to 98.7% (235/238 leads) with combined use of a snare. Overall clinical success rate was 100%. No Evolution sheath-related complications were noted. There were no deaths or major complications. Five minor complications (4%) were encountered. In cases of companion leads no wrapping or lead damage were observed. Conclusion: On the basis of our prospective multicentre study, the new hand-powered bidirectional rotational mechanical LE sheath is an effective and safe tool for the extraction of chronically implanted leads without major complications and lead wrapping or lead damage. PMID- 28339759 TI - Performance and anticoccidial effects of nicarbazin-fed broilers reared at standard or reduced environmental temperatures. AB - A series of 4 floor pen studies was conducted to evaluate the effects of environmental temperature modification on nicarbazin (NIC) responses in broiler chickens raised to 28 d of age. Birds were reared at either standard temperatures (recommended by the primary breeder for ages zero to 28 d) or at 3 degrees C below this level. From placement to 28 d, birds were provided feeds containing zero, 100, or 125 ppm NIC, comprising a 2 * 3 factorial arrangement in each test. Two of the trials were conducted in the presence of an imposed coccidial challenge and 2 were conducted in healthy animals. At 18 and 28 d of age, performance was recorded; cloacal temperatures were measured at 7, 14, 21, and 26 days. Mortality data were collected daily and coccidial lesions were scored at 6 d post challenge. Results of these studies revealed that NIC improved coccidial lesion scores regardless of environmental temperature. In the absence of coccidial challenge, NIC depressed performance, but reductions in environmental temperature diminished the magnitude of these responses. Under conditions of coccidial challenge, NIC significantly improved body weight gains in both temperature environments. Compared to standard temperature conditions, lower environmental temperatures exerted a positive effect on feed conversion rates of NIC-fed broilers. Birds reared in the low temperature environment exhibited lower cloacal temperatures than standard environment groups throughout the test period. Irrespective of coccidial challenge, lower environmental temperatures significantly reduced nicarbazin mortality compared to standard temperature groups, resulting in a significant nicarbazin x temperature interaction. This finding indicates that temperature modification is a practical method for minimizing mortality over the course of 28-day nicarbazin usage. PMID- 28339760 TI - Ultrastructural immunohistochemical study of L-type amino acid transporter 1-4F2 heavy chain in tumor microvasculatures of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) induced rat bladder carcinoma. AB - Angiogenesis is essential for tumor growth, and an enhanced vasculature supplying nutrients and oxygen might reflect malignant potential. L-type amino acid transporter 1 (LAT1/4F2hc) comprises a major nutrient transport system responsible for the Na+-independent transport of large neutral amino acids. Seventy five to seventy eight percent N-butyl-N-(4-hydroxybutyl) nitrosamine induced rat bladder carcinoma cells showed high LAT1/4F2hc expression. While the intracarcinoma microvasculatures of fenestrated endothelial cells highly expressing LAT1/4F2hc might progressively transport essential amino acids from the microvasculatures to the extracellular matrix, non-fenestrated endothelial cells and pericytes did not. The present study revealed that the tumor angiogenesis is one of target anti-L-type amino acid transporter 1 drug. PMID- 28339761 TI - Combined modality therapy in Stage IIIA non-small cell lung cancer: clarity or confusion despite the highest level of evidence? AB - Recent years have witnessed a number of clinical trials in Stage IIIA non-small cell lung cancer (NSCLC) comparing (A) induction chemotherapy (CHT) with induction CHT and radiotherapy (RT), each followed by surgery; (B) either induction CHT or induction RT-CHT, each followed by surgery, with definitive RT CHT (no surgery). Due to the heterogeneity of patient, tumor and treatment characteristics across these trials, various meta-analyses (MAs) have been performed to define the optimal treatment approach in this setting for this clinical presentation. Six such MAs exist. In spite of the differences between MAs, it appears that RT does not add extra benefit to induction CHT administered before surgery, and that a trimodality (i.e. including surgery) regimen is not superior to definitive concurrent RT-CHT. While one can consider both induction CHT followed by surgery and exclusive concurrent RT-CHT as feasible in this setting, lack of pre-treatment predictive factors identifying patients who might preferentially benefit from a surgical approach limits its use to well-planned clinical trials. PMID- 28339762 TI - Maternal and genetic effects on broiler bone properties during incubation period. AB - In order to examine the differences in bone properties between fast-growing and slow-growing broiler embryos and to understand the effects of genotype and egg size on these differences, fast- and slow-growing hens and males were reciprocally crossed to create 4 egg groups: FST (laid by fast-growing hens, inseminated by fast-growing males), H-FST (fast-growing hens and slow-growing males), H-SLW (slow-growing hens and fast-growing males), and SLW (slow-growing hens and slow-growing males). Embryos (n = 8) from these 4 groups were sacrificed and weighed, and both tibiae were harvested on embryonic d (E) 17, 19, and 21. Left tibiae were tested for their whole-bone mechanical properties using a micromechanical device. Cortical bone structure and bone mineral density (BMD) were examined by micro-computed tomography of the left tibiae. Bone mineralization was evaluated by measuring BMD and ash content, while the rate and location of mineralization were evaluated by fluorochrome labeling. Osteoclastic activity and osteocyte density were evaluated by histological stains [TRAP (Tartrate resistant acid phosphatase) and H&E (Hematoxylin and Eosin), respectively]. Groups with larger eggs (FST and H-FST) had higher BW and tibia weight than groups with smaller eggs (SLW and H-SLW); however, they had a lower ratio of tibia weight to BW. Between groups with similar egg weight, stiffness, maximal load, and yield load of the bones were higher in the SLW than the H-SLW, while no differences were found between the FST and H-FST. Additionally, the tibiae of the SLW were stiffer and their osteocyte density higher than in the FST on E21 and their periosteal mineralization rate was higher between E19 and E21. No differences were found between the groups in cortical bone structure. This study demonstrates that faster growing hatchlings, especially those that hatch from relatively small eggs, have inferior bone mechanical properties in comparison to slower growing hatchlings, and suggests that fast-growing chicks hatching from small eggs are at a higher risk for developing bone pathologies. Accordingly, selection for increased egg size may lead to improved mechanical performance of the skeleton of fast-growing broilers. PMID- 28339765 TI - STEM moire analysis for 2D strain measurements. AB - A moire pattern is created in a scanning transmission electron microscope (STEM) when the scan step is close to a crystalline periodicity. Usually, fringes are visible in only one direction, corresponding to a single set of lattice planes, but fringes can be formed in two directions or more. Using an accurate independent calibration, the strains in silicon devices have been determined from the spacing and orientation of one-directional STEM moire fringes. In this report, we first discuss the origin of the STEM moire, and then we show how an accurate calibration of the scan step can be obtained from the STEM moire pattern itself, providing that we know initially only an approximate scan step and the planar spacing. The new calibration scheme also makes the STEM moire experiments easier, since it can be applied for the moire where the scan direction is not precisely aligned with the crystalline lattice. Finally, we show how the two dimensional strain information will be readily extracted from two one-directional moire patterns using the concept of geometric phase. PMID- 28339763 TI - Long-term care is increasingly concentrated in the last years of life: a change from 2000 to 2011. AB - Background: The use of long-term care (LTC) is common in very old age and in the last years of life. It is not known how the use pattern is changing as death is being postponed to increasingly old age. The aim is to analyze the association between the use of LTC and approaching death among old people and the change in this association from 2000 to 2011. Methods: The data were derived from national registers. The study population consists of 315 458 case-control pairs. Cases (decedents) were those who died between 2000 and 2011 at the age of 70 years or over in Finland. The matched controls (survivors) lived at least 2 years longer. Use of LTC was studied for the last 730 days for decedents and for the same calendar days for survivors. Conditional logistic regression analyses were performed to test the association of LTC use with decedent status and year. Results: The difference in LTC use between decedents and survivors was smallest among the oldest (OR 9.91 among youngest, 4.96 among oldest). The difference widened from 2000 to 2011 (OR of interaction of LTC use and year increased): use increased or held steady among decedents, but decreased among survivors. Conclusions: The use of LTC became increasingly concentrated in the last years of life during the study period. The use of LTC is also common among the oldest survivors. As more people live to very old age, the demand for LTC will increase. PMID- 28339766 TI - Higher bioavailability of doxycycline in broiler chickens with a novel in-feed pharmaceutical formulation. AB - Bioavailability of a new, long-acting (LA) pharmaceutical preparation for administering doxycycline as in-feed medication to broiler chickens was compared to the standard in-feed administration of doxycycline. A commercial poultry house harboring Ross-308 broiler chickens, weighing 450 g, was divided into 7 sections as follows: doxy-FOLA group (n = 6,000 chickens divided into 3 replicates) medicated with 10% doxycyline, long-acting pellets at a dose of 400 g of doxycycline HCl/ton of food, resulting in a calculated dose of 48 mg/kg for 5 d; doxy-ref group (n = 6,000, divided into 3 replicates) medicated as for doxy-FOLA, but using a 20% commercial preparation of doxycycline. A third group of 300 broiler chickens (divided into 3 replicates), received a single IV dose of 48 mg/kg from a 2.4% solution of doxycycline HCl under ketamine anesthesia. Blood samples were obtained at designated times, serum was harvested, and doxycycline concentrations determined by high-performance liquid chromatography (HPLC). Bioavailability values were 156% and 227% on d 1 and 5 for doxy-FOLA and 13% and 23% for doxy-ref, on the same days. Mean residence time (MRT) and elimination half-life (T1/2beta) were statistically different (P < 0.05) in doxy-FOLA group as compared to doxy-ref group (MRT: 26 h and 5.2 h; and T1/2beta: 18 h vs 3 h, on the first day for doxy-FOLA and doxy-ref, respectively). Based on 3 levels of bacterial sensitivity of E. coli derived from a small survey carried out (i.e., 1.0, 2.0, and 4.0 MUg/mL) and considering pharmacokinetic/pharmacodynamic (PK/PD) ratios required for this time-dependent antibacterial drug, it is possible to postulate that doxy-FOLA outstrips the reference preparation maintaining higher and more prolonged serum concentrations of doxycycline and consequently complying better with PK/PD ratios regarded as optimal for this drug. The advantages of using doxy-FOLA in poultry medicine include a more comprehensive use of the active principle, which in turn should have a better impact on bacterial diseases. Yet, a longer withdrawal time is anticipated based on an almost 4-fold increment in the MRT value. PMID- 28339767 TI - Accounting for overdispersion when determining primary care outliers for the identification of chronic kidney disease: learning from the National Chronic Kidney Disease Audit. AB - Background: Early diagnosis of chronic kidney disease (CKD) facilitates best management in primary care. Testing coverage of those at risk and translation into subsequent diagnostic coding will impact on observed CKD prevalence. Using initial data from 915 general practitioner (GP) practices taking part in a UK national audit, we seek to apply appropriate methods to identify outlying practices in terms of CKD stages 3-5 prevalence and diagnostic coding. Methods: We estimate expected numbers of CKD stages 3-5 cases in each practice, adjusted for key practice characteristics, and further inflate the control limits to account for overdispersion related to unobserved factors (including unobserved risk factors for CKD, and between-practice differences in coding and testing). Results: GP practice prevalence of coded CKD stages 3-5 ranges from 0.04 to 7.8%. Practices differ considerably in coding of CKD in individuals where CKD is indicated following testing (ranging from 0 to 97% of those with and glomerular filtration rate <60 mL/min/1.73 m 2 ). After adjusting for risk factors and overdispersion, the number of 'extreme' practices is reduced from 29 to 2.6% for the low-coded CKD prevalence outcome, from 21 to 1% for high-uncoded CKD stage and from 22 to 2.4% for low total (coded and uncoded) CKD prevalence. Thirty-one practices are identified as outliers for at least one of these outcomes. These can then be categorized into practices needing to address testing, coding or data storage/transfer issues. Conclusions: GP practice prevalence of coded CKD shows wide variation. Accounting for overdispersion is crucial in providing useful information about outlying practices for CKD prevalence. PMID- 28339769 TI - Incidence and potential risk factors for hospital-acquired pneumonia in an emergency department of surgery. AB - Objective: Hospital-acquired pneumonia (HAP) is associated with high mortality and is the second most common nosocomial infection. The aim of this study was to calculate the incidence and to identify potential risk factors for HAP in an emergency ward for surgical patients admitted because of acute abdomen or trauma. Design: A structured review of medical records was conducted. Patients diagnosed with pneumonia >48 h after admittance, were compared with a randomly chosen age matched reference group. Ten variables judged as potential risk factors for HAP were studied in 90 patients. Setting: An emergency ward for surgical patients with acute abdomen or trauma at an Univerity hospital in Sweden. Participants: A total of 90 patients with HAP and 120 age-matched controls were included. Main Outcome Measures: Risk factors for HAP in patients at a surgical clinic. Results: Of a total of 10 335 admitted patients, during 4.5 years the hospital stay was longer than 48 h in 4961 patients. Of these 90 (1.8%) fulfilled the strict criteria for HAP. Potential risk factors were suspected or verified aspiration (odds ratio (OR): 23.9) that was 2-fold higher than immobilization (OR: 11.2). Further, chronic pulmonary obstructive disease (COPD)/asthma, abdominal surgery and gastric retention/vomiting were risk factors for HAP. Conclusion: Verified or suspected aspiration was the dominating risk factor for HAP but also immobilization was frequently associated with HAP. Various established preventive measures should be implemented in the nursing care to reduce the frequency of HAP. PMID- 28339770 TI - Characterization of indigenous Aseel chicken breed for morphological, growth, production, and meat composition traits from India. AB - Aseel is an important native chicken breed of India, known for its martial qualities (aggressive fighting abilities), pugnacity, and majestic gait. The aim of the study is to conserve and characterize the Aseel germplasm, which is considered to be endangered. The birds were maintained on deep litter under a simulated backyard type of housing having night shelter and a free-range area. A total of 313 chicks produced in the second generation from the flock collected from native tract in Andhra Pradesh was characterized for morphological, growth, production, and meat quality parameters. Aseel birds were characterized by multicolored plumage (predominantly dark brown, black, golden, etc.) with solid feather patterns and normal distribution. Ear lobes were red (92%) and small in size, while 98% of the birds had red colored pea combs with variations in intensity of color. The shank color was yellow in the majority (65%) of the birds. The skin color was white (98%) with pinkish red coloration on exposed body parts, especially on the breast. The fertility and hatchability on total eggs were 67.2 and 41.4%, respectively. Cocks were heavier (P <= 0.05) with distinct sexual dimorphism in Aseel. The body weight of hens and cocks was 1,704.4 +/- 23.2 and 2,702.5 +/- 28.1 g at 40 wk and 2,333.7 +/- 26.1 and 3,793.7 +/- 20.8 g at 72 wk of age, respectively. The age at sexual maturity was 214.0 +/- 6.0 days. The egg production up to 40, 52, and 64 wk of age was 18.0 +/- 1, 30.0 +/- 2.0, and 47 +/- 3 eggs, respectively. The annual egg production (72 wk) was 64 +/- 6 eggs. The proximate composition of breast muscle was; protein 21.5 +/- 0.5%, fat 3.4 +/- 0.1%, ash 2.0 +/- 0.1%, and moisture 73.3 +/- 0.5%. The pH of breast muscle was 6.0 +/- 0.03 and the cholesterol content was 72.5 +/- 6.7 mg/100 g. Efforts are on for improving the productivity in the flock without compromising the original breed characteristics. PMID- 28339768 TI - The transcription factor Olig2 is important for the biology of diffuse intrinsic pontine gliomas. AB - Background: Diffuse intrinsic pontine glioma (DIPG) is a high-grade brainstem glioma of children with dismal prognosis. There is no single unifying model about the cell of origin of DIPGs. Proliferating cells in the developing human and mouse pons, the site of DIPGs, express neural stem/progenitor cell (NPC) markers, including Sox2, nestin, vimentin, Olig2, and glial fibrillary acidic protein, in an overlapping and non-overlapping manner, suggesting progenitor cell heterogeneity in the pons. It is thought that during a restricted window of postnatal pons development, a differentiation block caused by genetic/epigenetic changes leads to unrestrained progenitor proliferation and DIPG development. Nearly 80% of DIPGs harbor a mutation in the H3F3A or the related HIST1H3B gene. Supporting the impaired differentiation model, NPCs derived from human induced pluripotent stem cells expressing the H3F3A mutation showed complete differentiation block. However, the mechanisms regulating an altered differentiation program in DIPG are unknown. Methods: We established syngeneic serum-dependent and independent primary DIPG lines, performed molecular characterization of DIPG lines in vitro and in an orthotopic xenograft model, and used small hairpin RNA to examine Olig2 function in DIPG. Results: The transcription factor Olig2 is highly expressed in 70%-80% of DIPGs. Here we report that Olig2 expression and DIPG differentiation are mutually exclusive events in vitro, and only DIPG cells that retained Olig2 in vitro formed robust Olig2-positive brainstem glioma with 100% penetrance in a xenograft model. Conclusion: Our results indicate Olig2 as an onco-requisite factor in DIPG and propose investigation of Olig2 target genes as novel candidates in DIPG therapy. PMID- 28339771 TI - Implementing patient-reported outcome surveys as part of routine care: lessons from an academic radiation oncology department. AB - Patient reported outcomes (PROs) are reports of health conditions that come directly from patients. Use of PROs has been associated with improved patient outcomes, enhanced quality of life, and reduced end-of-life spending. Yet there are still outstanding questions regarding the process of implementing PRO collection in routine practice. In this article, we describe the experience of selecting and implementing PROs in a multisite, multidisease academic medical center-based radiation oncology practice and demonstrate that such large-scale rollout is feasible. We establish that PROs can be implemented with minimal to no workflow delays, are generally seen as valuable by clinicians, and can enhance patient-doctor communication. We additionally detail the challenges involved in selecting clinically relevant PRO questionnaires and the centrality of physician buy-in, easy data access, and clear workflows to successful implementation. PMID- 28339773 TI - Effects of sodium, 1,25-dihydroxyvitamin D3 and parathyroid hormone fragment on inorganic P absorption and Type IIb sodium-phosphate cotransporter expression in ligated duodenal loops of broilers. AB - Three experiments were conducted with 22-day-old Arbor Acres male broilers to study the effects of Na+, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] and parathyroid hormone fragment [PTH (1-34)] on inorganic P absorption and Type IIb sodium phosphate cotransporter (NaP-IIb) mRNA and protein expression levels in ligated duodenal loops. The duodenal loops were perfused with solutions (pH = 6) containing zero, 50, or 150 mmol/L of Na+ as NaCl in Exp. 1, containing zero, 30, or 300 pmol/L of 1,25-(OH)2D3 in Exp. 2, or containing zero, 65, or 650 pmol/L of PTH (1-34) in Exp. 3, respectively. Compared with the control, additions of 50 and 150 mmol/L of Na+, 30 and 300 pmol/L of 1,25-(OH)2D3, or 65 and 650 pmol/L of PTH (1-34) to the perfusates promoted (P < 0.02) the P absorption percentages and rates, respectively. Additions of the above-mentioned concentrations of Na+ or 1,25-(OH)2D3 to the perfusates increased (P < 0.003) NaP-IIb mRNA level in the duodenum of broilers, and a similar trend (P = 0.08) was observed for PTH (1-34). The Na+, 1,25-(OH)2D3, and PTH (1-34) had no effects (P > 0.15) on NaP-IIb protein level in the duodenum of broilers. The results indicate that increased P absorption due to perfusions of Na+, 1,25-(OH)2D3 or PTH (1-34) might be attributed to enhanced NaP-IIb expression in the duodenum of broilers. PMID- 28339774 TI - Genetic basis of leg health and its relationship with body weight in purebred turkey lines. AB - The aims of this study were to estimate the genetic parameters for leg and foot health and mobility in purebred turkey lines and their genetic correlations with BW. Traits were gait score (GS) as an overall measure of leg health, footpad dermatitis (FPD), and 2 skeletal leg health traits, namely, valgus and varus deformities (VVD) and tibial dyschondroplasia (TD). Data from 4 different lines, comprising 3 yr of phenotypic records and 4 yr of pedigree information per line, were used. The sex average BW for the lines at 18 wk ranged from 19.1 kg (line A) to 12.4 kg (line D). The prevalence of VVD ranged from 5.2 to 14.6% and for TD from 4.1 to 23.2%. The average score for FPD on a scale of 0 to 100 ranged from 48.5 to 61.1. Gait Score was scored on a scale of 1 to 5, standardized to a mean of 3 and SD of 1. Heritabilities were estimated at 0.08 to 0.13 for GS, 0.01 to 0.07 for VVD, 0.06 to 0.12 for TD, and 0.10 to 0.15 for FPD (all SE <= 0.02). Estimates of the genetic correlations between VVD and TD ranged from 0.03 to 0.21 (all SE <= 0.08), and estimates of these with GS ranged from 0.07 to 0.87 (all SE <= 0.09). The genetic correlations of FPD with GS ranged from 0.00 to 0.34 (all SE <= 0.04), and with the skeletal leg health traits from -0.06 to 0.33 (all SE <= 0.06). Body weight showed estimated genetic correlations ranging from 0.28 to 0.51 (all SE <= 0.06) with GS, -0.06 to 0.50 (all SE <= 0.13) with VVD/TD and 0.05 to 0.34 (all SE <= 0.05) with FPD. The results suggest that selection for improved leg health can be incorporated effectively in a commercial turkey breeding program using balanced breeding goals, in which production traits and leg health traits are considered simultaneously. PMID- 28339772 TI - Heterologous desensitization of cardiac beta-adrenergic signal via hormone induced betaAR/arrestin/PDE4 complexes. AB - Aims: Cardiac beta-adrenergic receptor (betaAR) signalling is susceptible to heterologous desensitization by different neurohormonal stimuli in clinical conditions associated with heart failure. We aim to examine the underlying mechanism of cross talk between betaARs and a set of G-protein coupled receptors (GPCRs) activated by hormones/agonists. Methods and results: Rat ventricular cardiomyocytes were used to determine heterologous phosphorylation of betaARs under a series of GPCR agonists. Activation of Gs-coupled dopamine receptor, adenosine receptor, relaxin receptor and prostaglandin E2 receptor, and Gq coupled alpha1 adrenergic receptor and angiotensin II type 1 receptor promotes phosphorylation of beta1AR and beta2AR at putative protein kinase A (PKA) phosphorylation sites; but activation of Gi-coupled alpha2 adrenergic receptor and activation of protease-activated receptor does not. The GPCR agonists that promote beta2AR phosphorylation effectively inhibit betaAR agonist isoproterenol induced PKA phosphorylation of phospholamban and contractile function in ventricular cardiomyocytes. Heterologous GPCR stimuli have minimal to small effect on isoproterenol-induced beta2AR activation and G-protein coupling for cyclic adenosine monophosphate (cAMP) production. However, these GPCR stimuli significantly promote phosphorylation of phosphodiesterase 4D (PDE4D), and recruit PDE4D to the phosphorylated beta2AR in a beta-arrestin 2 dependent manner without promoting beta2AR endocytosis. The increased binding between beta2AR and PDE4D effectively hydrolyzes cAMP signal generated by subsequent stimulation with isoproterenol. Mutation of PKA phosphorylation sites in beta2AR, inhibition of PDE4, or genetic ablation of PDE4D or beta-arrestin 2 abolishes this heterologous inhibitory effect. Ablation of beta-arrestin 2 or PDE4D gene also rescues beta adrenergic stimuli-induced myocyte contractile function. Conclusions: These data reveal essential roles of beta-arrestin 2 and PDE4D in a common mechanism for heterologous desensitization of cardiac betaARs under hormonal stimulation, which is associated with impaired cardiac function during the development of pathophysiological conditions. PMID- 28339775 TI - Mining non-lattice subgraphs for detecting missing hierarchical relations and concepts in SNOMED CT. AB - Objective: Quality assurance of large ontological systems such as SNOMED CT is an indispensable part of the terminology management lifecycle. We introduce a hybrid structural-lexical method for scalable and systematic discovery of missing hierarchical relations and concepts in SNOMED CT. Material and Methods: All non lattice subgraphs (the structural part) in SNOMED CT are exhaustively extracted using a scalable MapReduce algorithm. Four lexical patterns (the lexical part) are identified among the extracted non-lattice subgraphs. Non-lattice subgraphs exhibiting such lexical patterns are often indicative of missing hierarchical relations or concepts. Each lexical pattern is associated with a potential specific type of error. Results: Applying the structural-lexical method to SNOMED CT (September 2015 US edition), we found 6801 non-lattice subgraphs that matched these lexical patterns, of which 2046 were amenable to visual inspection. We evaluated a random sample of 100 small subgraphs, of which 59 were reviewed in detail by domain experts. All the subgraphs reviewed contained errors confirmed by the experts. The most frequent type of error was missing is-a relations due to incomplete or inconsistent modeling of the concepts. Conclusions: Our hybrid structural-lexical method is innovative and proved effective not only in detecting errors in SNOMED CT, but also in suggesting remediation for these errors. PMID- 28339777 TI - Support system for fine focusing and astigmatism correction using an auditory signal in scanning electron microscopy. AB - The current study describes a new support system for fine focusing and near perfect astigmatism correction for scanning electron microscopy (SEM). The signal to-noise ratio of a series of SEM images obtained from fast scan rates (TV scan) was adopted as a new metric for evaluating focus. Measured signal-to-noise ratio values were converted to an acoustic signal (sound wave frequency) using digital image processing techniques, enabling the SEM user to evaluate image focus using the auditory modality. Accurate focusing and correcting astigmatism in general purpose SEM is traditionally time-consuming and difficult. The proposed system may substantially reduce the required operation time for fine focusing. Moreover, the system is relatively immune to noise, successfully supporting focus and astigmatism correction with very noisy SEM images. Our proposed focus support system may be helpful for general-purpose SEM observation of a variety of specimens under a wide range of operating conditions. PMID- 28339776 TI - Effect of acute millimeter wave exposure on dopamine metabolism of NGF-treated PC12 cells. AB - Several forthcoming wireless telecommunication systems will use electromagnetic frequencies at millimeter waves (MMWs), and technologies developed around the 60 GHz band will soon know a widespread distribution. Free nerve endings within the skin have been suggested to be the targets of MMW therapy which has been used in the former Soviet Union. So far, no studies have assessed the impact of MMW exposure on neuronal metabolism. Here, we investigated the effects of a 24-h MMW exposure at 60.4 GHz, with an incident power density (IPD) of 5 mW/cm2, on the dopaminergic turnover of NGF-treated PC12 cells. After MMW exposure, both intracellular and extracellular contents of dopamine (DA) and 3,4 dihydroxyphenylacetic acid (DOPAC) were studied using high performance liquid chromatography. Impact of exposure on the dopamine transporter (DAT) expression was also assessed by immunocytochemistry. We analyzed the dopamine turnover by assessing the ratio of DOPAC to DA, and measuring DOPAC accumulation in the medium. Neither dopamine turnover nor DAT protein expression level were impacted by MMW exposure. However, extracellular accumulation of DOPAC was found to be slightly increased, but not significantly. This result was related to the thermal effect, and overall, no evidence of non-thermal effects of MMW exposure were observed on dopamine metabolism. PMID- 28339778 TI - Effects of an induced molt using cassava meal on body weight loss, blood physiology, ovarian regression, and postmolt egg production in late-phase laying hens. AB - This study was conducted to determine the effect of an induced molt using cassava meal on body weight, blood physiology, ovary, and postmolt performance in late phase (74 wk old) H&N Brown laying hens. Hens were randomly assigned to 3 treatments of 90 birds each: 1) Controls withno induced molt (CONT); 2) molted by full feeding with cassava meal for 3 wk (FP3); and 3) molted by full feeding with cassava meal for 4 wk (FP4). Groups 2 and 3 were fed a pullet developer diet for 3 wk following treatment. During the molt period, the birds were exposed to an 8L:16D photoperiod and had access to drinking water at all times. Thereafter, all hens were fed a layer diet (17%CP), and exposed to a 16L:8D photoperiod, and production performance was measured for 16 wk. The molt treatments resulted in total cessation of egg production within 2 wk following feeding the molt diet. BW loss of birds in the FP4 treatment was approximately 30.13%, which was significantly higher than those in the FP3 treatment (25.23%). At the termination of feeding the molt diet, an increase in hematocrit values was observed for the FP3 and FP4 treatments compared to the CONT treatment. Conversely, lower values of serum estradiol, progesterone, ionized Ca and phosphorus concentrations were found for the 2 molted treatments. Ovary weight, number of follicles, and oviduct weight and length of the FP3 and FP4 treatments were diminished as compared to the CONT treatment. No consistent differences were observed between the molted treatments. Significant (P < 0.05) improvements in postmolt feed efficiency, egg production, Haugh units, shell weight, shell thickness, shell breaking strength, and mortality rate were observed for the FP4 treatment. An improvement in those performances, except for feed efficiency and egg production, was also found for the FP3 treatment. It was concluded that feeding the cassava molt diet for 4 wk could induce molt in laying hens effectively, and produce optimum postmolt productive performance. PMID- 28339779 TI - Effect of the combination of white and red LED lighting during incubation on layer, broiler, and Pekin duck hatchability. AB - Previous research has shown that providing light during incubation can have positive effects on hatchability and chick quality; however, white light alone has been observed to improve these factors only in pigmented broiler eggs and non pigmented white layer eggs. Monochromatic red light has been shown to improve hatchability in layer eggs. Therefore the objective of this study was to utilize one light fixture that emitted both white and monochromatic red light to determine if this one light source could improve hatchability in both types of chicken eggs and pigmented Pekin duck egg. To determine this, 3 experiments were conducted, the first using White Leghorn eggs (N = 6912), the second using commercial broiler eggs (N = 4608), and the third using commercial Pekin duck eggs (N = 3564) in which eggs were incubated with 12 h of light and 12 h of darkness (LED) or complete darkness (DARK); the light level was 250 lux. Hatchability, embryo mortality, and hatchling quality were measured. In Experiment 1, LED had fewer early dead embryos (P = 0.03), less overall embryo mortality (P = 0.05), fewer chicks with unhealed navels (P < 0.001), fewer chicks with defects (P < 0.001), and a higher percentage of fertile eggs that hatched (P = 0.05) than DARK. In Experiment 2, LED had fewer chicks with unhealed navels (P = 0.003), fewer chicks with defects (P = 0.001), and a higher percentage of fertile eggs that hatched (P = 0.04) than DARK. In Experiment 3, LED had fewer early dead embryos (P = 0.05), lower overall embryo mortality (P = 0.04), and a higher percentage of fertile eggs that hatched (P = 0.05), and had ducklings with lower bodyweights at hatch (P = 0.04) than DARK. These results indicate that providing both white and red light during incubation can improve chick quality across poultry varieties. This type of fixture could be used to improve commercial hatchery efficiency and chick quality. PMID- 28339780 TI - Adverse kidney effects of epidermal growth factor receptor inhibitors. AB - The epidermal growth factor receptor (EGFR) is implicated in various malignancies. The past decade has seen the development and widespread use of EGFR inhibitors for the successful treatment of such cancers. Available EGFR inhibitors include small molecule tyrosine-kinase inhibitors and monoclonal antibodies. Class-related renal adverse events result in dual toxicity including tubular/electrolyte disorders and glomerulopathies. Tubular injury is common and mainly due to monoclonal antibodies while glomerulopathy is rare and related to various anti-EGFR agents. The exact pathogenesis of anti-EGFR agents associated with kidney disorders remains to be elucidated. PMID- 28339781 TI - Low level of Rituximab in human breast milk in a patient treated during lactation. PMID- 28339782 TI - The Adolescent HIV Disclosure Cognition and Affect Scale: Preliminary Reliability and Validity. AB - Objectives: Globally, there are 2 million HIV-positive 10-19-year-olds. One challenge for this population is sharing their HIV status with others (onward HIV disclosure). There are no multi-item, multidimensional scales of HIV disclosure cognitions and affect for young people living with HIV. An 18-item measure of HIV disclosure cognition and affect was developed, administered to 65 adolescents living with HIV (aged 12-16 years). Data were explored using principal component analysis and preliminary construct and criterion validity assessed. Three factors were revealed: negative disclosure attitudes and feelings, self-efficacy, and positive disclosure attitudes and feelings. The full scale and its subscales were internally consistent. The total score showed statistically significant positive relationships with HIV disclosure in the past 6 months, HIV disclosure intention and self-perception. Preliminary evidence of the measure's good psychometric properties suggests it may be helpful in future clinical and research work. PMID- 28339783 TI - A stochastic model for tumour control probability that accounts for repair from sublethal damage. AB - The tumour control probability (TCP) is the probability that a treatment regimen of radiation therapy (RT) eradicates all tumour cells in a given tissue. To decrease the toxic effects on healthy cells, RT is usually delivered over a period of weeks in a series of fractions. This allows tumour cells to repair sublethal damage (RSD) caused by radiation. In this article, we introduce a stochastic model for tumour response to radiotherapy which accounts for the effects of RSD. The tumour is subdivided into two cell types: 'affected' cells which have been damaged by RT and 'unaffected' cells which have not. The model is formulated as a birth-death process for which we can derive an explicit formula for the TCP. We apply our model to prostate cancer, and find that the radiosensitivity parameters and the probability of sublethal damage during radiation are the parameters to which the TCP predictions are most sensitive. We compare our TCP predictions to those given by Zaider and Minerbo's one-class model (Zaider & Minerbo, 2000) and Dawson and Hillen's two-class model (Dawson & Hillen, 2006) and find that for low doses of radiation, our model predicts a lower TCP. Finally, we find that when the probability of sublethal damage during radiation is large, the mean field assumption overestimates the TCP. PMID- 28339784 TI - Regulatory effects of autophagy on spermatogenesis. AB - Abnormal spermatogenesis is an important pathophysiological process underlying male infertility. Apoptosis of spermatogenic cells and disruption of ectoplasmic specialization (ES) have been characterized as the key biological events of this disorder. Under physiological and pathophysiological conditions (such as exposure to starvation, environmental chemicals, radiation), autophagy is activated in spermatogenic or Sertoli cells in order to maintain survival of the spermatogenic cells by inhibiting spermatogenic cell apoptosis and stabilizing the integrity of ES via degradation of PDZ and LIM domain 1 (PDLIM1), a negative regulator of cytoskeletal organization. Here, we review the most recent research progress towards understanding the pivotal effects of autophagy on spermatogenesis. PMID- 28339785 TI - A Food Debris-Like Component in the Urine Sediment From a Urostomy Pouch. AB - Microscopic examination of urine sediment is a basic, common method of detecting diseases of the urinary tract. We experienced a case involving a patient who had developed a fever after undergoing a urinary-diversion operation. Results of the microscopic examination of the urine collected from the urostomy pouch of the patient showed a food debris-like component. Based on this finding, we suspected a fistula between the urinary and intestinal tracts. However, after performing an experiment to verify the results, we determined that no fistula was present. Instead, we discovered that the food debris-like component originated from the urostomy skin barrier. To our knowledge, ours is the first report in the literature to demonstrate that the urostomy skin barrier can dissolve and mimic food debris in urine sediment, leading to incorrect assumptions regarding the presence of fistulas. We believe that it is important to derive a correct diagnosis when an unfamiliar component is observed in urinary sediment. We further believe that the findings from this case are valuable to professionals who administer clinical treatment and perform laboratory testing. PMID- 28339786 TI - Modelling original antigenic sin in dengue viral infection. AB - Cross-reactive T cell responses induced by a primary dengue virus infection may contribute to increased disease severity following heterologous infections with a different virus serotype in a phenomenon known as the original antigenic sin. In this study, we developed and analyzed in-host models of T cell responses to primary and secondary dengue virus infections that considered the effect of T cell cross-reactivity in disease enhancement. We fitted the models to published patient data and showed that the overall infected cell killing is similar in dengue heterologous infections, resulting in dengue fever and dengue hemorrhagic fever. The contribution to overall killing, however, is dominated by non-specific T cell responses during the majority of secondary dengue hemorrhagic fever cases. By contrast, more than half of secondary dengue fever cases have predominant strain-specific T cell responses with high avidity. These results support the hypothesis that cross-reactive T cell responses occur mainly during severe disease cases of heterologous dengue virus infections. PMID- 28339787 TI - Molecular characterization of Marek's disease virus in a poultry layer farm from Colombia. AB - Marek's disease (MD) is a lymphoproliferative disease caused by an Alphaherpesvirus, genus Mardivirus, serotype 1 (Gallid Herpesvirus 2, GaHV-2) that includes all known pathogenic strains. In addition to Marek's disease virus (MDV) serotype 1, the genus includes 2 distinct nonpathogenic serotypes: serotype 2 (GaHV-3) and serotype 3 (Meleagridis Herpesvirus 1, MeHV-1) which are used in commercially available vaccines against MD. As a result of vaccination, clinical signs are not commonly observed, and new cases are usually associated with emerging variant strains against which the vaccines are less effective. In this study, a commercial layer farm showing clinical signs compatible with MDV infection was evaluated. Histological lesions and positive immunohistochemistry in the sciatic nerve and thymus were compatible with cytolytic phase of MD. GaHV 2, GaHV-3 and MeHV-1 were identified by PCR and qPCR in blood samples from 17 birds with suspected MD. Analysis of the Meq gene of the Colombian GaHV-2 isolate revealed a 99% sequence identity with Asian strains, and in the phylogenetic analysis clustered with vv+ MDV. The analysis of amino acid alignments demonstrated an interruption of the proline rich region in P176A, P217A and P233L positions, which are generally associated with vv+ strains. Some of these changes, such as P233L and L258S positions have not been reported previously. In addition, primary cell cultures inoculated with lymphocytes isolated from the spleen showed typical cytopathic effect of GaHV-2 at 5 d post infection. Based on the molecular analysis, the results from this study indicate the presence of vv+ MDV infection in commercial birds for the first time in Colombia. It is recommended to perform further assays in order to demonstrate the pathotype characteristics in vivo. PMID- 28339788 TI - Intravenous dendritic cell administration enhances suppression of lung metastasis induced by carbon-ion irradiation. AB - Carbon-ion radiotherapy (CIRT) is an advanced radiotherapy and has achieved good local control, even in tumors that are resistant to conventional photon beam radiotherapy (PBRT). However, distant metastasis control is an important issue. Recently, the combination of radiotherapy and immunotherapy has attracted the attention. In immunotherapy, dendritic cells (DCs) play a pivotal role in the anti-tumor immune system. However, the mechanisms underlying the combination therapy of DCs and radiotherapy have been unclear. In the present study, we evaluated anti-metastatic effects of this combination therapy, focused on the irradiation type and the route of DC administration, using a mouse model. C3H/He mice bearing NR-S1 cells were treated with CIRT or PBRT, using biologically equivalent doses. Subsequently, DCs were administered intratumorally (IT) or intravenously (IV). IV and IT DC administrations combined with CIRT to the local tumor, but not alone, significantly suppressed pulmonary metastasis, whereas the combination of DCs with PBRT suppressed metastasis at a relatively higher dose. Additionally, the anti-metastatic effect was greater in IV DC administration compared with in IT DC administration in both CIRT and PBRT. The expression levels of CD40 and IL-12 in DCs were significantly increased after co-culturing with CIRT-treated NR-S1 cells. In addition, IV administration of those co cultured DCs significantly suppressed pulmonary metastasis. Furthermore, ecto calreticulin levels from CIRT-treated NR-S1 cells significantly increased compared with those of a PBRT-treated tumor. Taken together, these results suggest that local CIRT combined with IV DCs augments an immunogenicity of the tumor cells by ecto-calreticulin expression and the maturation of DCs to stimulate anti-tumor immunity to decrease lung metastases. PMID- 28339789 TI - Early treatment gains for antibiotic administration and within human host time series data. AB - As technological improvements continue to infiltrate and impact medical practice, it has become possible to non-invasively collect dense physiological time series data from individual patients in real time. These advances continue to improve physicians' ability to detect and to treat infections early. One important benefit of early detection and treatment of nascent infections is that it leads to earlier resolution. In response to current and anticipated advances in data capture, we introduce the Early Treatment Gain (ETG) as a measure to quantify this benefit. Roughly, we define the gain to be the limiting ratio: ETG=differential change in time of resolutiondifferential change in treatment time.We study the gain using standard dynamical models and demonstrate its use with time series data from Surgical Intensive Care Unit (SICU) patients facing ventilator associated pneumonia. The main conclusion from the mathematical modelling is that the ETG is always greater than one unless there is an effective immune response, in which case the ETG can be less than one. Using real patient time series data, we observe that the formula derived for a linear model can be applied and that this produces a ETG greater than one. PMID- 28339790 TI - Does systemic administration of casein phosphopeptides affect orthodontic movement and root resorption in rats? AB - Objectives: To assess the potential effects of casein phosphopeptides (CPPs) on orthodontically induced iatrogenic root resorption (OIIRR) and orthodontic teeth movement. Materials and methods: Forty Wistar rats (aged 11 weeks) were randomly divided into experimental group (EG; n = 20) that received a diet supplemented with CPP and control group (CG; n = 20) devoid of diet supplement. A 150 g force was applied using nickel titanium (NiTi) coil that was bonded on maxillary incisors and extended unilaterally to a maxillary first molar. At Day 28, animals in both groups were euthanized. Volumetric assessment of root resorption craters and linear measurement of maxillary first molars movement were blindly examined using a micro-computed tomography scan. Results: Nine rats were excluded from the experiment due to loss during general anesthesia or appliances' failure. Intra operator reproducibility was high in both volumetric and linear measurements, 92.8 per cent and 98.5-97.6 per cent, respectively. The results reveal that dietary CPP has statistically insignificant effect on the overall OIIRR and orthodontic movement. Conclusions: CPP seems to have statistically insignificant effect on the volume of OIIRR and orthodontic movement in rats. A long-term study with larger sample size using a different concentration of CPP is required to clarify the dentoalveolar effect of CPP. PMID- 28339791 TI - BRIDG: a domain information model for translational and clinical protocol-driven research. AB - Background: It is critical to integrate and analyze data from biological, translational, and clinical studies with data from health systems; however, electronic artifacts are stored in thousands of disparate systems that are often unable to readily exchange data. Objective: To facilitate meaningful data exchange, a model that presents a common understanding of biomedical research concepts and their relationships with health care semantics is required. The Biomedical Research Integrated Domain Group (BRIDG) domain information model fulfills this need. Software systems created from BRIDG have shared meaning "baked in," enabling interoperability among disparate systems. For nearly 10 years, the Clinical Data Standards Interchange Consortium, the National Cancer Institute, the US Food and Drug Administration, and Health Level 7 International have been key stakeholders in developing BRIDG. Methods: BRIDG is an open-source Unified Modeling Language-class model developed through use cases and harmonization with other models. Results: With its 4+ releases, BRIDG includes clinical and now translational research concepts in its Common, Protocol Representation, Study Conduct, Adverse Events, Regulatory, Statistical Analysis, Experiment, Biospecimen, and Molecular Biology subdomains. Interpretation: The model is a Clinical Data Standards Interchange Consortium, Health Level 7 International, and International Standards Organization standard that has been utilized in national and international standards-based software development projects. It will continue to mature and evolve in the areas of clinical imaging, pathology, ontology, and vocabulary support. BRIDG 4.1.1 and prior releases are freely available at https://bridgmodel.nci.nih.gov . PMID- 28339792 TI - Interference of age and supplementation of direct-fed microbial and essential oil in the activity of digestive enzymes and expression of genes related to transport and digestion of carbohydrates and proteins in the small intestine of broilers. AB - The objectives of this study were to describe alterations that age and dietary inclusion of direct-fed microbial (DFM) Bacillus subtilis (BS) and a specific essential oil (EO) blend (carvacrol, cinnamaldehyde, cineol, and pepper extract) causes in the activity of digestive enzymes (maltase: MALT; aminopeptidase-N: APN; intestinal alkaline phosphate: IAP) and expression patterns of genes related to transport (oligopeptide transporter gene: SLC15A1; Na+-dependent glucose and galactose transporter gene: SLC5A1; Na+-independent glucose, galactose, and fructose transporter gene: SLC2A2; ATPase, Na+/K+ transporting gene: ATP1A1) and digestion (aminopeptidase-N gene: ANPEP; maltase-glucoamylase gene: MGAM; Sucrase isomaltase gene: SI) of carbohydrates and proteins in the small intestine of broilers. Also, the objective was to analyze if growth performance of broilers is affected by supplementation (BS and EO blend). Day-old male broiler chicks (n = 1,320) were assigned to 5 treatments. Diets included a basal diet (BD) as a negative control (CON); experimental diets were BD + BS; BD + BS + EO; BD + EO; BD + antibiotic growth promoter (AGP) avilamycin was the positive control. Performance was evaluated between 1 to 42 d. Transcript abundance of transport related genes and digestion-related genes were assayed by RT-qPCR and determined at d 7, 21, and 42. MALT-, APN-, and IAP-specific activities were determined at d 7, 21, and 42. Broilers fed BS had greater SLC15A1 mRNA abundance compared to CON, while EO and AGP were related to higher activities of IAP and APN. Analysis over time revealed higher abundance of MGAM, SLC2A2, SLC15A1, SLC5A1 and SI mRNA at d 42 when compared to d 7. Activity of IAP decreased after d 7 and activity of MALT increased with age. The current study suggests that age had effect over carbohydrate and protein transport and carbohydrate digestion. The supplementation of BS DFM hade evident effect over protein transport and that the use of EO in the diet enhanced the activities of carbohydrate and protein digestion, reflecting improvement in digestive and transport physiology of birds. Changes performed by BS DFM and EO did not favor performance. PMID- 28339793 TI - Lameness assessment with automatic monitoring of activity in commercial broiler flocks. AB - The possibility of using automatic recordings of broiler chicken activity in commercial flocks to assess the birds? walking ability (lameness) was investigated. Data were collected from 5 commercial broiler farms in 4 European countries, using 16 flocks and 33 assessment occasions. Lameness was assessed using established gait scoring methods (Kestin et al., 1992; Welfare Quality(r), 2009) and took place at 3, 4, and 5 wk of age. Gait score (GS) was used to assess the birds' walking ability, and automatic recordings of bird activity were collected using the eYeNamicTM camera system before, during, and after an assessor walked through the house. The variables used to predict the level of GS extracted from the camera system were: baseline activity, time from assessor leaving the house to resumption of baseline activity, average activity over that period, and Delta Amplitude (difference between highest activity peak after assessor left the house and baseline level). Age (<0.001) and Delta Amplitude (P = 0.0002) were significantly related to GS, with the gait getting poorer with increased age and Delta Amplitude decreasing with declining walking ability. Both measures are thus included in a predictive equation. The results demonstrate a potential method using image analysis techniques to realize an automated assessment of the level of lameness in commercial broiler flocks. This could be of use in future animal welfare assessment schemes. PMID- 28339795 TI - Erratum. PMID- 28339794 TI - Short-term dabigatran interruption before cardiac rhythm device implantation: multi-centre experience from the RE-LY trial. AB - Aims: Cardiac implantable electronic device (CIED) surgery is commonly performed in patients with atrial fibrillation (AF). The current analysis was undertaken to compare peri-operative anticoagulation management, bleeding, and thrombotic events in AF patients treated with dabigatran vs. warfarin. Methods and results: This study included 611 patients treated with dabigatran vs. warfarin who underwent CIED surgery during the RE-LY trial. Among 201 warfarin-treated patients, warfarin was interrupted a median of 144 (inter-quartile range, IQR: 120-216) h, and 37 (18.4%) patients underwent heparin bridging. In dabigatran treated patients (216 on 110 mg bid and 194 on 150 mg bid), the duration of dabigatran interruption was a median of 96 (IQR: 61-158) h. Pocket hematomas occurred in 9 (2.20%) patients on dabigatran and 8 (3.98%) patients on warfarin (P = 0.218). The occurrence of pocket hematomas was lower with dabigatran compared with warfarin with heparin bridging (RD: -8.62%, 95% CI: -24.15 to - 0.51%, P = 0.034) but not when compared with warfarin with no bridging (P = 0.880). Ischemic stroke occurred in 2 (0.3%) patients; one in the warfarin group (without bridging) and one in the dabigatran 150 mg bid group (P = 0.735). Conclusion: In patients treated with dabigatran undergoing CIED surgery, interruption of dabigatran is associated with similar or lower incidence of pocket hematoma, when compared with warfarin interruption without or with heparin bridging, respectively. Whether uninterrupted dabigatran can reduce pocket hematoma or ischemic stroke remains to be evaluated. PMID- 28339796 TI - The identification of fungi collected from the ceca of commercial poultry. AB - Under normal conditions, fungi are ignored unless a disease/syndrome clinical signs are reported. The scientific communities are largely unaware of the roles fungi play in normal production parameters. Numerous preharvest interventions have demonstrated that beneficial bacteria can play a role in improving productions parameters; however, most researchers have ignored the impact that fungi may have on production. The goal of the present study was to record fungi recovered from commercial broiler and layer houses during production. Over 3,000 cecal samples were isolated using conventional culture methodology and over 890 samples were further characterized using an automated repetitive sequence-based PCR (rep-PCR) methodology. Eighty-eight different fungal and yeast species were identified, including Aspergillus spp., Penicillium spp., and Sporidiobolus spp, and 18 unknown genera were separated using rep-PCR. The results from the present study will provide a normal fungi background genera under commercial conditions and will be a stepping stone for investigating the impact of fungi on the gastrointestinal tract and on the health of poultry. PMID- 28339797 TI - The American Society for Clinical Pathology's 2015 Wage Survey of Medical Laboratories in the United States. AB - Objectives: To inform the pathology and laboratory field of the most recent national wage data from the American Society for Clinical Pathology (ASCP). Historically, the results of this biennial survey have served as a basis for additional research on laboratory recruitment, retention, education, marketing, certification, and advocacy. Methods: The 2015 wage survey was conducted through collaboration between the ASCP's Institute of Science, Technology, & Policy in Washington, DC, and the ASCP Board of Certification in Chicago, Illinois. Electronic survey invitations were sent to individuals who are currently practicing in the field. Results: Data reveal increased salaries since 2013 for all staff-level laboratory professionals surveyed except phlebotomists and pathologists' assistants. Laboratory assistants and phlebotomists, regardless of level, continue to have lower salaries while pathologists' assistants and administration personnel have higher salaries than the rest of the laboratory professions surveyed. Conclusions: Survey results put emphasis on strategic recruitment and retention by laboratory training programs and institutions that hire laboratory professionals. PMID- 28339798 TI - Social Work and Optometry: Interprofessional Practice Revisited. PMID- 28339799 TI - No Longer Invisible: Understanding the Psychosocial Impact of Skin Color Stratification in the Lives of African American Women. AB - This article examines how skin color stratification, termed "colorism," affects the psychological well-being of African American women. Previous research has shown that the experience of colorism is pervasive within the black community and that black women have been culturally or personally affected by intraracial discrimination. This article describes a qualitative study that used focus groups to investigate the experiences of black women that were categorized according to their self-ascribed skin tone group. The findings indicated that women of different hues have distinctive experiences based on their skin tone, and that these experiences influence how they felt about themselves and interact with others. The article concludes with a discussion of practice, research, and policy implications. PMID- 28339800 TI - The dark cloud of recreational drugs and vaping. AB - Electronic cigarettes (e-cigarettes) are increasing in popularity with 19% of UK smokers reporting to have used them. The ability to regulate the evaporation temperature in newer electronic nicotine delivery systems (ENDS) facilitates the potential for use of these devices to 'vape' cannabis, novel psychoactive substances (NPS) and other recreational drugs. Vaping cannabis does have the potential to reduce tobacco use and combustible cannabis/tobacco-related disease, but with over one-third of UK adults reporting life-time use of recreational drugs and increasing e-cigarette uptake in adolescent groups the misuse of these devices poses a serious potential public health risk. Further work is therefore urgently required to inform the appropriate treatment and primary prevention strategies for this emerging issue. PMID- 28339801 TI - Routinely measured iohexol glomerular filtration rate versus creatinine-based estimated glomerular filtration rate as predictors of mortality in patients with advanced chronic kidney disease: a Swedish Chronic Kidney Disease Registry cohort study. AB - Background: Estimated glomerular filtration rate (eGFR) becomes less reliable in patients with advanced chronic kidney disease (CKD). Methods: Using the Swedish CKD Registry (2005-11), linked to the national inpatient, dialysis and death registers, we compared the performance of plasma-iohexol measured GFR (mGFR) and urinary clearance measures versus eGFR to predict death in adults with CKD stages 4/5. Performance was assessed using survival and prognostic models. Results: Of the 2705 patients, 1517 had mGFR performed, with the remainder providing 24-h urine clearances. Median eGFR (CKD-EPI creatinine ) was 20 mL/min/1.73 m 2 [interquartile range (IQR) 14-26], mGFR 18 mL/min/1.73 m 2 (IQR 13-23) and creatinine clearance 23 mL/min (IQR 15-31). Median follow-up was 45 months (IQR 26-59), registering 968 deaths (36%). In fully adjusted Cox models, a rise in mGFR of 1 mL/min/1.73 m 2 was associated with a 5.3% fall in all-cause mortality compared with a 1.7% corresponding fall for eGFR [adjusted hazard ratio (aHR) 0.947 (95% CI, 0.930-0.964) versus aHR 0.983 (95% CI, 0.970-0.996)]. mGFR was also statistically superior in prognostic models (discrimination using logistic regression and integrated discrimination improvement). Urinary clearance measures showed a stronger aetiological relationship with death than eGFR, but were not statistically superior in the prognostic models. Conclusions: The performance of mGFR was superior to eGFR, in both aetiological and prognostic models, in predicting mortality in adults with CKD stage 4/5, demonstrating the importance of GFR per se versus non-GFR determinants of outcome. However, the relatively modest enhancement suggests that eGFR may be sufficient to use in everyday clinical practice while mGFR adds important prognostic information for those where eGFR is believed to be biased. PMID- 28339802 TI - Alterations in urinary collagen peptides in lupus nephritis subjects correlate with renal dysfunction and renal histopathology. AB - Background: The excessive accumulation of extracellular matrix (ECM) in the renal tubulointerstitium is a key component of chronic renal damage in lupus nephritis (LN) and a critical determinant of the disease progression to renal failure. Detection of fibrosis requires renal biopsy and is therefore limited by high risks associated with an invasive procedure. This study explores whether a unique LN urinary peptidome can be identified and whether LN-specific alteration reflects the underlying fibrogenic process of altered ECM turnover. Method: Urinary peptides were analyzed for 36 LN and 35 nonrenal systemic lupus erythematosus (SLE) subjects and 58 healthy volunteers (HVs). Results: In total, 70 collagen and 230 noncollagen peptides were significantly changed between LN and nonrenal SLE and between LN and HV and defined as 'LN peptides'; 14 proteases associated with observed LN collagen peptides were identified and activities in 9 proteases were significantly different between LN and nonrenal SLE; 28 collagen peptides were correlated with at least one parameter of clinical renal dysfunction or histolopathology. Conclusion: Urinary peptidomic alterations likely reflect pathogenic pathways involving ECM turnover in LN kidneys and potentially could be developed as biomarkers to monitor renal disease progression. PMID- 28339803 TI - Transcriptional comparison of myogenesis in leghorn and low score normal embryos. AB - In a previous study, we reported on a quantitative transcriptomic method which confirmed the temporal transcription of developmental fast skeletal muscle myosin heavy chain (fsMyHC) embryonic isoforms in the embryonic Pectoralis major (PM) of the Single Comb White Leghorn (SCWL). The objective of the current study was to further investigate the transcriptional events underlying embryonic PM growth in the SCWL and a genotype exhibiting partial muscular dystrophy, the Low Score Normal (LSN). We hypothesized that within the SCWL and LSN embryos, there would be differences in the temporal transcription of the fsMyHC isoforms and other myogenic regulatory genes. Samples of PM tissues were collected daily from embryonic day (ED) 6 through ED19. Total RNA was isolated from each PM tissue sample and mRNA transcripts from 28 target genes were simultaneously quantified using a probe hybridization method. Raw data counts were normalized against the geometric mean of 5 housekeeping genes and analyzed using Local Regression (LOESS) smoothing methods. Predicted estimates based on LOESS smoothing were plotted with 95% upper and lower confidence intervals, allowing for line comparisons between the SCWL and LSN. Differences (P < 0.05) were determined by non-overlapping confidence intervals between the SCWL and LSN. Among genes exhibiting line differences (P < 0.05), were the developmental fsMyHC isoforms, transcription factors, growth factors, and proteoglycans. The current study is the first to report transcription of the chicken fast skeletal adult myosin isoform (Cad) during PM myogenesis. Samples were submitted for capillary-liquid chromatography-tandem mass spectrometry analysis which confirmed the translation of all the developmental fsMyHC isoforms including Cad in both lines. The LSN exhibited altered transcription patterns of early myogenic markers (MYOD, MRF4, Cemb1, six4, and pax3) during late embryogenesis, continued transcription of Cvent, and delayed transcription of Cneo. PMID- 28339804 TI - Intra-cardiac and peripheral levels of biochemical markers of fibrosis in patients undergoing catheter ablation for atrial fibrillation. AB - Aims: Measurement of circulating biomarkers of fibrosis may have a role in selecting patients and treatment strategy for catheter ablation. Pro-collagen type III N-terminal pro-peptide (PIIINP), C-telopeptide of type I collagen (ICTP), fibroblast growth factor 23 (FGF-23), and galectin 3 (gal-3) have all been suggested as possible biomarkers for this indication, but studies assessing whether peripheral levels reflect intra-cardiac levels are scarce. Methods and results: We studied 93 patients undergoing ablation for paroxysmal atrial fibrillation (AF) (n = 63) or non-paroxysmal AF (n = 30). Femoral venous, left and right atrial, and coronary sinus blood were analysed using ELISA to determine biomarker levels. Levels were compared with control patients (n = 36) and baseline characteristics, including left atrial voltage mapping data. C telopeptide of type I collagen levels were higher in AF than in non-AF patients (P = 0.007). Peripheral ICTP levels were higher than all intra-cardiac levels (P < 0.001). Peripheral gal-3 levels were higher than left atrial levels (P = 0.001). Peripheral levels of FGF-23 and PIIINP were not significantly different from intra-cardiac levels. CS levels of ICTP were higher than right and left atrial levels (P < 0.001). gal-3 was higher in women vs. men (P <= 0.001) and with higher body mass index (P <= 0.001). ICTP levels increased with reducing ejection fraction (P <= 0.012). Conclusions: Atrial fibrillation patients have higher levels of circulating ICTP than matched non-AF controls. In AF ablation patients, intra-cardiac sampling of FGF-23 or PIIINP gives no further information over peripheral sampling. For gal-3 and ICTP, intra-cardiac sampling may be necessary to assess their association with intra-cardiac processes. None of the biomarkers is related to fibrosis assessed by left atrial voltage. PMID- 28339805 TI - Design and evaluation of a pharmacogenomics information resource for pharmacists. AB - Objective: To develop and evaluate a pharmacogenomics information resource for pharmacists. Materials and Methods: We built a pharmacogenomics information resource presenting Food and Drug Administration (FDA) drug product labelling information, refined it based on feedback from pharmacists, and conducted a comparative usability evaluation, measuring task completion time, task correctness and perceived usability. Tasks involved hypothetical clinical situations requiring interpretation of pharmacogenomics information to determine optimal prescribing for specific patients. Results: Pharmacists were better able to perform certain tasks using the redesigned resource relative to the Pharmacogenomic Knowledgebase (PharmGKB) and the FDA Table of Pharmacogenomic Biomarkers in Drug Labeling. On average, participants completed tasks in 107.5 s using our resource, compared to 188.9 s using PharmGKB and 240.2 s using the FDA table. Using the System Usability Scale, participants rated our resource 79.62 on average, compared to 53.27 for PharmGKB and 50.77 for the FDA table. Participants found the correct answers for 100% of tasks using our resource, compared to 76.9% using PharmGKB and 69.2% using the FDA table. Discussion: We present structured, clinically relevant pharmacogenomic FDA drug product label information with visualizations to help explain the relationships between gene variants, drugs, and phenotypes. The results from our evaluation suggest that user-centered interfaces for pharmacogenomics information can increase ease of access and comprehension. Conclusion: A clinician-focused pharmacogenomics information resource can answer pharmacogenomics-related medication questions faster, more correctly, and more easily than widely used alternatives, as perceived by pharmacists. PMID- 28339806 TI - Mobile digital health devices and the diagnosis in real-time of myocardial ischaemia. PMID- 28339807 TI - Differential Effects of Carbohydrates on Arabidopsis Pollen Germination. AB - Pollen germination as a crucial process in plant development strongly depends on the accessibility of carbon as energy source. Carbohydrates, however, function not only as a primary energy source, but also as important signaling components. In a comprehensive study, we analyzed various aspects of the impact of 32 different sugars on in vitro germination of Arabidopsis pollen comprising about 150 variations of individual sugars and combinations. Twenty-six structurally different mono-, di- and oligosaccharides, and sugar analogs were initially tested for their ability to support pollen germination. Whereas several di- and oligosaccharides supported pollen germination, hexoses such as glucose, fructose and mannose did not support and even considerably inhibited pollen germination when added to germination-supporting medium. Complementary experiments using glucose analogs with varying functional features, the hexokinase inhibitor mannoheptulose and the glucose-insensitive hexokinase-deficient Arabidopsis mutant gin2-1 suggested that mannose- and glucose-mediated inhibition of sucrose supported pollen germination depends partially on hexokinase signaling. The results suggest that, in addition to their role as energy source, sugars act as signaling molecules differentially regulating the complex process of pollen germination depending on their structural properties. Thus, a sugar-dependent multilayer regulation of Arabidopsis pollen germination is supported, which makes this approach a valuable experimental system for future studies addressing sugar sensing and signaling. PMID- 28339808 TI - Response: Russell's viper envenomation: acute hypopituitarism or acute primary adrenal insufficiency. PMID- 28339809 TI - Minocycline-induced hyperpigmentation. PMID- 28339810 TI - "What to eat or what not to eat-that is still the question" - Reply. PMID- 28339811 TI - Pokemon GO & driving. PMID- 28339813 TI - Microstructural observation of fuel cell catalyst inks by Cryo-SEM and Cryo-TEM. AB - In order to improve the electricity generation performance of fuel cell electric vehicles, it is necessary to optimize the microstructure of the catalyst layer of a polymer electrolyte fuel cell. The catalyst layer is formed by a wet coating process using catalyst inks. Therefore, it is very important to observe the microstructure of the catalyst ink. In this study, the morphology of carbon supported platinum (Pt/C) particles in catalyst inks with a different solvent composition was investigated by cryogenic scanning electron microscopy (cryo SEM). In addition, the morphology of the ionomer, which presumably influences the formation of agglomerated Pt/C particles in a catalyst ink, was investigated by cryogenic transmission electron microscopy (cryo-TEM). The results of a cryo-SEM observation revealed that the agglomerated Pt/C particles tended to become coarser with a higher 1-propanol (NPA) weight fraction. The results of a cryo-TEM observation indicated that the actual ionomer dispersion in a catalyst ink formed a network structure different from that of the ionomer in the solvent. PMID- 28339812 TI - Spending on Hospital Care and Pediatric Psychology Service Use Among Adolescents and Young Adults With Cancer. AB - Objective: To examine the relationship between need-based pediatric psychology service use and spending on hospital care among adolescents and young adults (AYAs) with cancer. Methods: Billing data were obtained from 48 AYAs with cancer receiving need-based pediatric psychology services and a comparison cohort of 48 AYAs with cancer not receiving services. A factorial analysis of covariance examined group differences in spending for hospital care. Pending significant findings, a multivariate analysis of covariance was planned to examine the relationship between need-based pediatric psychology service use and spending for inpatient admissions, emergency department (ED) visits, and outpatient visits. Results: Spending for hospital care was higher among AYAs receiving need-based pediatric psychology services than in the comparison cohort (p < .001, omegaPartial2 = .11). Group differences were driven by significantly higher spending for inpatient admissions and ED visits among AYAs receiving need-based pediatric psychology services. Conclusions: The behavioral and psychosocial difficulties warranting need-based pediatric psychology services may predict higher health care spending. PMID- 28339815 TI - Relationships Between Standing Frontal-Plane Knee Alignment and Dynamic Knee Joint Loading During Walking and Jogging in Youth Who Are Obese. AB - Background: Youth who are obese have high risk of poor knee health and cartilage damage. Understanding factors which may affect knee health in youth who are obese is critical for preservation of knee integrity and function. Objective: This study compared standing frontal-plane knee alignment and knee loading patterns between youth who are obese and those of healthy weight and determine the association between knee alignment and knee loading patterns during walking and jogging. Design: This study used a cross-sectional matched pair design. Methods: Twenty youth who were obese and 20 youth who were healthy-weight (ages 11-18 years) were recruited. Three-dimensional motion analysis quantified standing frontal-plane knee alignment as well as frontal- and sagittal-plane knee moments during walking and jogging. Paired t -tests, multiple analysis of covariance, and Spearman's rank correlation coefficients were used for analysis. Results: The youth who were obese demonstrated greater knee valgus in standing ( P = 0.02), lower normalized peak external knee adduction moments during walking ( P = 0.003), and greater normalized peak external knee extension moments during jogging ( P = 0.003) compared with the youth who were healthy-weight. Standing knee alignment did not correlate with knee moments in the youth who were obese. Limitations: Results are limited to small, homogeneous cohorts. The standing alignment methodology is not validated in this population and may limit interpretation of results. Conclusion: Youth who are obese stand in more knee valgus and have altered knee loading patterns during walking and jogging compared with youth who are healthy-weight. Frontal-plane knee alignment does not correlate with frontal-plane knee loading patterns in youth who are obese. A better understanding of other mechanisms related to joint loading in youth who are obese is necessary to maintain long-term joint integrity in this population. PMID- 28339816 TI - Post-mortem toxicology in young sudden cardiac death victims: a nationwide cohort study. AB - Aims: Several drugs increase the risk of ventricular fibrillation and sudden cardiac death (SCD). We aimed to investigate in detail the toxicological findings of all young SCD throughout Denmark. Methods and results: Deaths in persons aged 1-49 years were included over a 10-year period. Death certificates and autopsy reports were retrieved and read to identify cases of sudden death and establish cause of death. All medico-legal autopsied SCD were included and toxicological reports collected. Positive toxicology was defined as the presence of any substance (licit and/or illicit). All toxicological findings had previously been evaluated not to have caused the death (i.e. lethal concentrations were excluded). We identified 620 medico-legal autopsied cases of SCD, of which 77% (n = 477) were toxicologically investigated post-mortem, and 57% (n = 270) had a positive toxicology profile. Sudden cardiac death with positive toxicology had higher rates of sudden arrhythmic death syndrome (SADS), compared with SCD with negative toxicology (56% vs. 42%, P < 0.01). In total, 752 agents were detected, and polypharmacy (defined as the presence of more than one drug) was present in 61% (n = 164), all substances combined. Psychotropic drugs were the most frequent (62%, n = 467), and 82% (n = 385) were in pharmacological or subpharmacological levels. Conclusion: We found that more than half of all toxicologically investigated SCD victims have positive post-mortem toxicological findings, and polypharmacy is displayed in a considerable proportion. SCD with positive toxicology had higher rate of SADS, suggesting that the compounds may play a proarrhythmic role in these cases. PMID- 28339814 TI - Modulating Oxidative Stress Relieves Stress-Induced Behavioral and Cognitive Impairments in Rats. AB - Background: Persistent psychological stress often leads to anxiety disorders and depression. Benzodiazepines and selective serotonin reuptake inhibitors are popular treatment options but have limited efficacy, supporting the need for alternative treatment. Based on our recent preclinical work suggesting a causal link between neurobehavioral deficits and elevated oxidative stress, we hypothesized that interventions that mitigate oxidative stress can attenuate/overcome neurobehavioral deficits. Methods: Here, we employed the rat social defeat model of psychological stress to determine whether increasing antioxidant levels using grape powder would prevent and/or reverse social defeat induced behavioral and cognitive deficits. Furthermore, a hippocampal-derived HT22 cell culture model of oxidative stress was employed to identify the individual beneficial constituent(s) of grape powder and the underlying mechanism(s) of action. Results: Grape powder treatment prevented and reversed social defeat-induced behavioral and cognitive deficits and also decreased social defeat-induced increase in plasma corticosterone and 8-isoprostane (systemic and oxidative stress markers, respectively). And grape powder treatment replenished social defeat-induced depleted pool of key antioxidant enzymes glyoxalase-1, glutathione reducatse-1, and superoxide dismutase. Grape powder constituents, quercetin and resveratrol, were most effective in preventing oxidative stress induced decreased cellular antioxidant capacity. Grape powder protected oxidative stress-induced cell death by preventing calcium influx, mitochondrial dysfunction, and release of cytochrome c. Conclusions: Grape powder treatment by increasing antioxidant pool and preventing cell damage and death prevented and reversed social defeat-induced behavioral and cognitive deficits in rats. Quercetin and resveratrol are the major contributors towards beneficial effects of grape powder. PMID- 28339817 TI - BSR and BHPR guideline for the prescription and monitoring of non-biologic disease-modifying anti-rheumatic drugs. PMID- 28339818 TI - Refining success of cardiac resynchronization therapy using a simple score predicting the amount of reverse ventricular remodelling: results from the Markers and Response to CRT (MARC) study. AB - Aims: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in systolic heart failure patients with ventricular conduction delay. Variability of individual response to CRT warrants improved patient selection. The Markers and Response to CRT (MARC) study was designed to investigate markers related to response to CRT. Methods and results: We prospectively studied the ability of 11 clinical, 11 electrocardiographic, 4 echocardiographic, and 16 blood biomarkers to predict CRT response in 240 patients. Response was measured by the reduction of indexed left ventricular end-systolic volume (LVESVi) at 6 months follow-up. Biomarkers were related to LVESVi change using log-linear regression on continuous scale. Covariates that were significant univariately were included in a multivariable model. The final model was utilized to compose a response score. Age was 67 +/- 10 years, 63% were male, 46% had ischaemic aetiology, LV ejection fraction was 26 +/- 8%, LVESVi was 75 +/- 31 mL/m2, and QRS was 178 +/- 23 ms. At 6 months LVESVi was reduced to 58 +/- 31 mL/m2 (relative reduction of 22 +/- 24%), 130 patients (61%) showed >= 15% LVESVi reduction. In univariate analysis 17 parameters were significantly associated with LVESVi change. In the final model age, QRSAREA (using vectorcardiography) and two echocardiographic markers (interventricular mechanical delay and apical rocking) remained significantly associated with the amount of reverse ventricular remodelling. This CAVIAR (CRT Age-Vectorcardiographic QRSAREA -Interventricular Mechanical delay-Apical Rocking) response score also predicted clinical outcome assessed by heart failure hospitalizations and all-cause mortality. Conclusions: The CAVIAR response score predicts the amount of reverse remodelling after CRT and may be used to improve patient selection. Clinical Trials: NCT01519908. PMID- 28339819 TI - Thermal treatments prior to and during the beginning of incubation affects development of the broiler embryo and yolk sac membranes, and live performance and carcass characteristics. AB - This study evaluated temperature during preincubation and embryonic day 0 (E0) E0 to E5 of incubation on broiler embryo development and subsequent live performance. Freshly laid eggs from a single 41-wk-old Ross 708 broiler breeder flock produced on a single day were weighed individually for weight matching purposes, stored overnight, and assigned to 4 treatment combinations of 2 preincubation temperatures (23.9 or 29.4 degrees C) * 2 E0 to E5 temperatures (38.1 or 37.5 degrees C). The 29.4 degrees C preincubation temperature decreased (P <= 0.05) yolk sac membrane (YSM) vasculature at E6 and E7, and increased (P <= 0.05) embryo weight and length but decreased (P <= 0.05) yolk sac weight (YSW) at E15. No subsequent main effects were observed. The 38.1 degrees C incubation temperature increased YSM vasculature at E7, chorioallantoic membrane (CAM) vasculature at E8 and E10, and egg weight loss, embryo weight, and embryo length at E15 and chick length at E21 in the presence of reduced BW and YSW (P <= 0.05). This was followed by greater male BW at 35 d, as well as improved FCR in females 0 to 14 d and in males 15 to 35 d (P <= 0.05). Pectoralis major and minor yields were increased (P <= 0.05) at 50 d of age in males and females, respectively. There were no interactions observed with regards to broiler live performance and carcass yield, which probably negated the importance of the interactions observed for preincubation temperature by E0 to E5 incubation temperature that affected YSM vasculature, CAM vasculature area, egg weight loss, embryo weight, yolk sac weight, and chick length. PMID- 28339820 TI - Building the future of rheumatology: the role of national and international networks. PMID- 28339821 TI - Russell's viper envenomation: acute hypopituitarism or acute primary adrenal insufficiency. PMID- 28339822 TI - Can we say anything about ganglionated plexus modification during radiofrequency pulmonary vein isolation and post-ablation arrhythmia recurrence at this time? PMID- 28339823 TI - ABO blood group and risk of glioma. PMID- 28339825 TI - Glomerular filtration rate estimating equations: practical, yes, but can they replace measured glomerular filtration rate? PMID- 28339824 TI - A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study. AB - Background: Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric low-grade gliomas (LGGs). The aim of this study was to determine the recommended phase II dose (RP2D) and the dose-limiting toxicities (DLTs) of the MEK inhibitor selumetinib in children with progressive LGG. Methods: Selumetinib was administered orally starting at 33 mg/m2/dose b.i.d., using the modified continual reassessment method. Pharmacokinetic analysis was performed during the first course. BRAF aberrations in tumor tissue were determined by real-time polymerase chain reaction and fluorescence in situ hybridization. Results: Thirty-eight eligible subjects were enrolled. Dose levels 1 and 2 (33 and 43 mg/m2/dose b.i.d.) were excessively toxic. DLTs included grade 3 elevated amylase/lipase (n = 1), headache (n = 1), mucositis (n = 2), and grades 2-3 rash (n = 6). At dose level 0 (25 mg/m2/dose b.i.d, the RP2D), only 3 of 24 subjects experienced DLTs (elevated amylase/lipase, rash, and mucositis). At the R2PD, the median (range) area under the curve (AUC0-infinity) and apparent oral clearance of selumetinib were 3855 ng*h/mL (1780 to 7250 ng * h/mL) and 6.5 L * h-1 * m-2 (3.4 to 14.0 L * h-1 * m-2), respectively. Thirteen of 19 tumors had BRAF abnormalities. Among the 5 (20%) of 25 subjects with sustained partial responses, all at the RP2D, 4 had BRAF aberrations, 1 had insufficient tissue. Subjects received a median of 13 cycles (range: 1-26). Fourteen (37%) completed all protocol treatment (26 cycles [n = 13], 13 cycles [n = 1]) with at least stable disease; 2-year progression-free survival at the RP2D was 69 +/- SE 9.8%. Conclusion: Selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs. PMID- 28339826 TI - The importance of considering competing treatment affecting prognosis in the evaluation of therapy in trials: the example of renal transplantation in hemodialysis trials. AB - Background: During the follow-up in a randomized controlled trial (RCT), participants may receive additional (non-randomly allocated) treatment that affects the outcome. Typically such additional treatment is not taken into account in evaluation of the results. Two pivotal trials of the effects of hemodiafiltration (HDF) versus hemodialysis (HD) on mortality in patients with end-stage renal disease reported differing results. We set out to evaluate to what extent methods to take other treatments (i.e. renal transplantation) into account may explain the difference in findings between RCTs. This is illustrated using a clinical example of two RCTs estimating the effect of HDF versus HD on mortality. Methods: Using individual patient data from the Estudio de Supervivencia de Hemodiafiltracion On-Line (ESHOL; n = 902) and The Dutch CONvective TRAnsport STudy (CONTRAST; n = 714) trials, five methods for estimating the effect of HDF versus HD on all-cause mortality were compared: intention-to-treat (ITT) analysis (i.e. not taking renal transplantation into account), per protocol exclusion (PP excl ; exclusion of patients who receive transplantation), PP cens (censoring patients at the time of transplantation), transplantation-adjusted (TA) analysis and an extension of the TA analysis (TA ext ) with additional adjustment for variables related to both the risk of receiving a transplant and the risk of an outcome (transplantation-outcome confounders). Cox proportional hazards models were applied. Results: Unadjusted ITT analysis of all-cause mortality led to differing results between CONTRAST and ESHOL: hazard ratio (HR) 0.95 (95% CI 0.75-1.20) and HR 0.76 (95% CI 0.59-0.97), respectively; difference between 5 and 24% risk reductions. Similar differences between the two trials were observed for the other unadjusted analytical methods (PP cens, PP excl , TA) The HRs of HDF versus HD treatment became more similar after adding transplantation as a time-varying covariate and including transplantation-outcome confounders: HR 0.89 (95% CI 0.69-1.13) in CONTRAST and HR 0.80 (95% CI 0.62-1.02) in ESHOL. Conclusions: The apparent differences in estimated treatment effects between two dialysis trials were to a large extent attributable to differences in applied methodology for taking renal transplantation into account in their final analyses. Our results exemplify the necessity of careful consideration of the treatment effect of interest when estimating the therapeutic effect in RCTs in which participants may receive additional treatments. PMID- 28339827 TI - Pre-participation cardiovascular evaluation for athletic participants to prevent sudden cardiac death. PMID- 28339828 TI - Single Session of Functional Electrical Stimulation-Assisted Walking Produces Corticomotor Symmetry Changes Related to Changes in Poststroke Walking Mechanics. AB - Background: Recent research demonstrated that the symmetry of corticomotor drive with the paretic and nonparetic plantarflexor muscles was related to the biomechanical ankle moment strategy that people with chronic stroke used to achieve their greatest walking speeds. Rehabilitation strategies that promote corticomotor balance might improve poststroke walking mechanics and enhance functional ambulation. Objective: The study objectives were to test the effectiveness of a single session of gait training using functional electrical stimulation (FES) to improve plantarflexor corticomotor symmetry and plantarflexion ankle moment symmetry and to determine whether changes in corticomotor symmetry were related to changes in ankle moment symmetry within the session. Design: This was a repeated-measures crossover study. Methods: On separate days, 20 people with chronic stroke completed a session of treadmill walking either with or without the use of FES of their ankle dorsi- and plantarflexor muscles. We calculated plantarflexor corticomotor symmetry using transcranial magnetic stimulation and plantarflexion ankle moment symmetry during walking between the paretic and the nonparetic limbs before and after each session. We compared changes and tested relationships between corticomotor symmetry and ankle moment symmetry following each session. Results: Following the session with FES, there was an increase in plantarflexor corticomotor symmetry that was related to the observed increase in ankle moment symmetry. In contrast, following the session without FES, there were no changes in corticomotor symmetry or ankle moment symmetry. Limitations: No stratification was made on the basis of lesion size, location, or clinical severity. Conclusions: These findings demonstrate, for the first time (to our knowledge), the ability of a single session of gait training with FES to induce positive corticomotor plasticity in people in the chronic stage of stroke recovery. They also provide insight into the neurophysiologic mechanisms underlying improvements in biomechanical walking function. PMID- 28339829 TI - Perceived office environments and occupational physical activity in office-based workers. AB - Background: Individuals in office-based occupations have low levels of physical activity but there is little research into the socio-ecological correlates of workplace activity. Aims: To identify factors contributing to office-based workers' perceptions of the office environment and explore cross-sectional relationships between these factors and occupational physical activity. Methods: Participants in the Active Buildings study reported perceptions of their office environment using the Movement at Work Survey. A principal component analysis (PCA) was conducted on survey items. A sub-sample wore the ActivPAL3TM accelerometer for >=3 workdays to measure occupational step count, standing, sitting and sit-to-stand transitions. Linear regression analyses assessed relationships between environmental perceptions and activity. Results: There were 433 participants, with accelerometer data available for 115 participants across 11 organ izations. The PCA revealed four factors: (i) perceived distance to office destinations, (ii) perceived office aesthetics and comfort, (iii) perceived office social environment and (iv) perceived management discouragement of unscheduled breaks. Younger participants perceived office destinations as being closer to their desk. Younger and female participants perceived more positive office social environments; there were no other socio-demographic differences. Within the sub-sample with accelerometer data, perceived discouragement of breaks by management was related to occupational step count/hour (B = -64.5; 95% CI -109.7 to -19.2). No other environmental perceptions were related to activity or sitting. Conclusions: Perceived managerial discouragement of breaks could be related to meaningful decreases in occupational step count. Future research should aim to elucidate the role of the workplace socio-cultural environment in occupational walking, with a focus on the role of management. PMID- 28339832 TI - Effects of feeding Original XPCTM to broilers with a live coccidiosis vaccine under industrial conditions: Part 2. Cecal microbiota analysis. AB - Biological supplements in poultry feed are of continued interest due to the improvements in growth performance, protection from pathogen invasion, and benefits in overall host health. The fermentation metabolites of Diamond V Original XPCTM (XPC) have previously been shown to improve commercial performance and reduce Salmonella in poultry. The current study sought to characterize the cecal microbiota using culture-independent analysis based on 16S rRNA gene in Coccivac-D sprayed broilers supplemented with XPC and/or Salinomycin (SAL). Ross 708 male broilers (n = 640) were assigned to one of 4 treatments: Cocci-vaccine (T1), Cocci-vaccine + XPC (T2), Cocci-vaccine + SAL (in the grower diet only) (T3), and Cocci-vaccine + SAL (in the grower diet only) + XPC (T4). Analysis with a PCR-based denaturing gradient gel electrophoresis (DGGE) indicated a shift in the microbial populations present at the various sampling ages - 16, 28, and 42 days. Phylogenetic analysis indicated further consistency in microbial communities directly related to bird age. Identification of microbial communities present and the assessment of their respective quantities using an Illumina MiSeq indicated treatment with XPC had no significant impact on microbial diversity (Chao1 index, observed operational taxonomic unit (OTU) and phylogenetic diversity (PD) whole tree). Sampling age revealed significantly greater diversity at 16 and 28 d (P < 0.05) as compared to the 42 d for the Shannon diversity index, while showing significantly decreased richness and diversity in the 42 d sampling age (Chao1 and observed OTU; P < 0.05). The results of the current study indicate that the chicken intestinal microbiota are impacted more by temporal changes rather than by the feed additive studied. PMID- 28339834 TI - Effects of coccidiosis vaccination administered by in ovo injection on Ross 708 broiler performance through 14 days of post-hatch age. AB - Effects of the in ovo injection of a commercial coccidiosis vaccine on various hatching chick quality variables and 14 d post-hatch (dph) oocyst shedding have been previously examined. The current study was designed to examine the performance of Ross 708 broilers during the 14 dph period of oocyst shedding following the application of the coccidiosis vaccine. On each of 7 replicate tray levels of a single-stage incubator, a total of 4 treatment groups was randomly represented, with each treatment group containing 63 eggs. Treatments were administered using a commercial multi-egg injector on d 18.5 of incubation. The treatments included 3 control groups (non-injected, dry-punch, and diluent injected) and one treatment group (injected with diluent containing Inovocox EM1 vaccine). On d 21 of incubation, 20 chicks from each of the 28 treatment replicate groups were placed in corresponding wire-floored battery cages. Mortality, feed intake (FI), BW gain (BWG), and feed conversion ratio (FCR) were determined for the zero to 7, 7 to 14, and cumulative zero to 14 dph intervals. There were no significant treatment effects on mortality in any interval or on BW at zero dph. There were significant treatment effects on BW at 7 and 14 dph, on BWG and FI in the zero to 7, 7 to 14, and zero to 14 dph intervals, and on FCR in the 7 to 14 and zero to 14 dph intervals. Although the performance variables of birds belonging to the diluent-injected and vaccine-injected groups were not significantly different, the 14 dph BW, 7 to 14 dph FI, and zero to 14 dph BWG and FI of birds belonging to the vaccine treatment group were significantly higher than those in birds belonging to the non-injected control group. It was concluded that use of the Inovocox EM1 vaccine in commercial diluent has no detrimental effect on the overall post-hatch performance of broilers through 14 dph. PMID- 28339833 TI - VDAC1 is a molecular target in glioblastoma, with its depletion leading to reprogrammed metabolism and reversed oncogenic properties. AB - Background: Glioblastoma (GBM), an aggressive brain tumor with frequent relapses and a high mortality, still awaits an effective treatment. Like many cancers, GBM cells acquire oncogenic properties, including metabolic reprogramming, vital for growth. As such, tumor metabolism is an emerging avenue for cancer therapy. One relevant target is the voltage-dependent anion channel 1 (VDAC1), a mitochondrial protein controlling cell energy and metabolic homeostasis. Methods: We used VDAC1 specific short interfering (si)RNA (si-VDAC1) to treat GBM cell lines and subcutaneous or intracranial-orthotopic GBM xenograft mouse models. Tumors were monitored using MRI, immunohistochemistry, immunoblotting, immunofluorescence, quantitative real-time PCR, transcription factor expression, and DNA microarray analyses. Results: Silencing VDAC1 expression using si-VDAC1 in 9 glioblastoma related cell lines, including patient-derived cells, led to marked decreases in VDAC1 levels and cell growth. Using si-VDAC1 in subcutaneous or intracranial orthotopic GBM models inhibited tumor growth and reversed oncogenic properties, such as reprogrammed metabolism, stemness, angiogenesis, epithelial-mesenchymal transition, and invasiveness. In cells in culture, si-VDAC1 inhibits cancer neurosphere formation and, in tumors, targeted cancer stem cells, leading to their differentiation into neuronal-like cells. These VDAC1 depletion-mediated effects involved alterations in transcription factors regulating signaling pathways associated with cancer hallmarks. Conclusion: VDAC1 offers a target for GBM treatment, allowing for attacks on the interplay between metabolism and oncogenic signaling networks, leading to tumor cell differentiation into neuron- and astrocyte-like cells. Simultaneously attacking all of these processes, VDAC1 depletion overcame GBM heterogeneity and can replace several anticancer drugs that separately target angiogenesis, proliferation, or metabolism. PMID- 28339835 TI - The association between proton pump inhibitor use and the risk of adverse kidney outcomes: a systematic review and meta-analysis. AB - Background: Existing epidemiological studies illustrate that proton pump inhibitors (PPIs) may be related to adverse kidney outcomes. To date, no comprehensive meta-analysis has been conducted to evaluate and quantify this association. Methods: We performed a systematic review and meta-analysis of studies to assess the association between PPI use and the risk of adverse kidney outcomes. We searched MEDLINE, Embase, SCOPUS, Web of Science, CINAHL, Cochrane Library and grey literature with no language restrictions (through 31 October 2016). Adverse kidney outcomes were acute interstitial nephritis (AIN), acute kidney injury (AKI), chronic kidney disease (CKD) and end-stage renal disease (ESRD). The risk ratios (RRs) and confidence intervals (CIs) were pooled using a random effects model. The strength of evidence (SOE) for each outcome was assessed using the Grading of Recommended Assessment, Development and Evaluation system. Results: Of 2037 identified studies, four cohort and five case-control studies with ~2.6 million patients were included. Of these, 534 003 (20.2%) were PPI users. Compared with non-PPI users, PPI users experienced a significantly higher risk of AKI [RR 1.44 (95% CI 1.08-1.91); P = 0.013; SOE, low] and CKD [RR 1.36 (95% CI 1.07-1.72); P = 0.012; SOE, low]. Moreover, PPIs increased the risk of AIN [RR 3.61 (95% CI 2.37-5.51); P < 0.001; SOE, insufficient] and ESRD [RR 1.42 (95% CI 1.28-1.58); P < 0.001; SOE, insufficient]. Conclusion: PPI usage was associated with adverse kidney outcomes; however, these findings were based on observational studies and low-quality evidence. Additional rigorous studies are needed for further clarification. PMID- 28339836 TI - Differences in textural properties of cooked caponized and broiler chicken breast meat. AB - This study was aimed at evaluating textural properties of cooked chicken breast meats obtained from 3 production systems (conventional raising, feed modification, and caponization) and determining the relationship between instrumental parameters and sensory attributes associated with the texture of capon meat. Texture of cooked breast meats was determined using 3 instrumental methods: Warner-Bratzler Shear (WBS), texture profile analysis (TPA), and uniaxial compression (UC), and sensory analysis by trained panelists. The results indicated that cooked caponized meat showed the lowest values of WBS force, shear energy, hardness, Young's modulus of UC, and the 2 sensory attributes (firmness and number of chews) (P < 0.05). In contrast, springiness and juiciness were the highest in the caponized meat (P < 0.05), suggesting that capon meat was more tender and juicier than the others. Feed-modified chicken samples showed intermediate textural characteristics between the samples of capon and conventionally raised broiler. Pearson's correlation revealed that WBS force, shear energy, Young's modulus of UC, gumminess, and springiness were strongly correlated with 3 sensory attributes (firmness, number of chews, and juiciness). Partial least squares regression (PLSR) demonstrated that 72% of all sensory attributes for the first 2 PLSR components were explained by 36% of the instrumental parameters and the production systems. Loading and score plot illustrated that conventional raising contributed to a high degree of firmness and number of chews, and positively correlated with shear energy, WBS force, gumminess, hardness, and Young's modulus. Contrarily, caponization was negatively correlated with those sensory attributes. The univariate analysis indicated that firmness and number of chews were positively correlated with all instrumental parameters, except springiness. Juiciness was positively correlated with springiness but negatively correlated with the others. The study suggested that the cooked meat of capons could be differentiated from those of broilers raised conventionally and with feed-modified diets based on textural properties. Based on the optimized simulating equation, texture of caponized breast could be explained by WBS force, shear energy, Young's modulus, and gumminess. PMID- 28339831 TI - Safety of intravenous ferric carboxymaltose versus oral iron in patients with nondialysis-dependent CKD: an analysis of the 1-year FIND-CKD trial. AB - Background: The evidence base regarding the safety of intravenous (IV) iron therapy in patients with chronic kidney disease (CKD) is incomplete and largely based on small studies of relatively short duration. Methods: FIND-CKD (ClinicalTrials.gov number NCT00994318) was a 1-year, open-label, multicenter, prospective study of patients with nondialysis-dependent CKD, anemia and iron deficiency randomized (1:1:2) to IV ferric carboxymaltose (FCM), targeting higher (400-600 ug/L) or lower (100-200 ug/L) ferritin, or oral iron. A post hoc analysis of adverse event rates per 100 patient-years was performed to assess the safety of FCM versus oral iron over an extended period. Results: The safety population included 616 patients. The incidence of one or more adverse events was 91.0, 100.0 and 105.0 per 100 patient-years in the high ferritin FCM, low ferritin FCM and oral iron groups, respectively. The incidence of adverse events with a suspected relation to study drug was 15.9, 17.8 and 36.7 per 100 patient years in the three groups; for serious adverse events, the incidence was 28.2, 27.9 and 24.3 per 100 patient-years. The incidence of cardiac disorders and infections was similar between groups. At least one ferritin level >=800 ug/L occurred in 26.6% of high ferritin FCM patients, with no associated increase in adverse events. No patient with ferritin >=800 ug/L discontinued the study drug due to adverse events. Estimated glomerular filtration rate remained the stable in all groups. Conclusions: These results further support the conclusion that correction of iron deficiency anemia with IV FCM is safe in patients with nondialysis-dependent CKD. PMID- 28339839 TI - Recent Advances in Understanding Pelvic-Floor Tissue of Women With and Without Pelvic Organ Prolapse: Considerations for Physical Therapists. AB - Pelvic organ prolapse is a fairly common condition that imposes significant symptoms, diminished quality of life, social burden, financial expense, and surgical risk on women. As evidence supporting the benefit of pelvic-floor muscle training in nonsurgical management of pelvic organ prolapse grows, physical therapists are becoming a provider of choice interacting with women affected by pelvic organ prolapse. This perspective article will review recent research on tissue characteristics of 3 key components of pelvic organ support: skeletal muscle, ligament, and vaginal wall. This information will be summarized as implications for physical therapists. An improved understanding of pelvic-floor tissue in women with and without pelvic organ prolapse will provide a more comprehensive appreciation of the interaction of multiple systems in the disorder. PMID- 28339838 TI - The clinical epidemiology of young adults starting renal replacement therapy in the UK: presentation, management and survival using 15 years of UK Renal Registry data. AB - Background: Clinical epidemiology data for young adults on renal replacement therapy (RRT) are lacking. While mostly transplanted, they have an increased risk of graft loss during young adulthood. Methods: We combined the UK Renal Registry paediatric and adult databases to describe patient characteristics, transplantation and survival for young adults. We grouped patients 11-30 years of age starting RRT from 1999 to 2008 by age band and examined their course during 5 years of follow-up. Results: The cohort (n = 3370) was 58% male, 79% white and 29% had glomerulonephritis. Half (52%) started RRT on haemodialysis (HD). Most (78%) were transplanted (18% pre-emptive, 61% as second modality); 11% were not listed for transplant. Transplant timing varied by age group. The deceased:living donor kidney transplant ratio was 2:1 for 11-<16 year olds and 1:1 otherwise. Median deceased donor transplant waiting times ranged from 6 months if <16 years of age to 17 months if >=21 years. Overall 8% died, with being on dialysis and not transplant listed versus transplanted {hazard ratio [HR] 16.6 [95% confidence interval (CI) 10.8-25.4], P < 0.0001} and diabetes versus glomerulonephritis [HR 4.03 (95% CI 2.71-6.01), P < 0.0001] increasing mortality risk. Conclusions: This study highlights the frequent use of HD and the importance of transplant listing and diabetes for young adults. More than half the young adults in our cohort started renal replacement therapy on HD. One in 10 young adults were not listed for transplant by 5 years and were ~20 times more likely to die than those who were transplanted. Diabetes as a primary renal disease was common among young adults and associated with increased mortality. Overall, almost 1 in 10 young adults had died by 5 years from the start of RRT. PMID- 28339837 TI - Vitamin D treatment attenuates cardiac FGF23/FGFR4 signaling and hypertrophy in uremic rats. AB - Background: Vitamin D deficiency and excess of circulating fibroblast growth factor 23 (FGF23) contribute to cardiovascular mortality in patients with chronic kidney disease (CKD). FGF23 activates FGF receptor 4 and (FGFR4) calcineurin/nuclear factor of activated T cells (NFAT) signaling in cardiac myocytes, thereby causing left ventricular hypertrophy (LVH). Here, we determined if 1,25-dihydroxyvitamin D (calcitriol) inhibits FGF23-induced cardiac signaling and LVH. Methods: 5/6 nephrectomized (5/6 Nx) rats were treated with different doses of calcitriol for 4 or 10 weeks and cardiac expression of FGF23/FGFR4 and activation of calcineurin/NFAT as well as LVH were analyzed. FGFR4 activation and hypertrophic cell growth were studied in cultured cardiac myocytes that were co treated with FGF23 and calcitriol. Results: In 5/6Nx rats with LVH, we detected elevated FGF23 expression in bone and myocardium, increased cardiac expression of FGFR4 and elevated cardiac activation of calcineurin/NFAT signaling. Cardiac expression levels of FGF23 and FGFR4 significantly correlated with the presence of LVH in uremic rats. Treatment with calcitriol reduced LVH as well as cardiac FGFR4 expression and calcineurin/NFAT activation. Bone and cardiac FGF23 expression were further stimulated by calcitriol in a dose-dependent manner, but levels of intact cardiac FGF23 protein were suppressed by high-dose calcitriol. In cultured cardiac myocytes, co-treatment with calcitriol blocked FGF23-induced activation of FGFR4 and hypertrophic cell growth. Conclusions: Our data suggest that in CKD, cardioprotective effects of calcitriol stem from its inhibitory actions on the cardiac FGF23/FGFR4 system, and based on their counterbalancing effects on cardiac myocytes, high FGF23 and low calcitriol synergistically contribute to cardiac hypertrophy. PMID- 28339841 TI - Nutritive value and the maximum inclusion level of pennycress meal for broiler chickens. AB - Two experiments were conducted to evaluate the nutritive value and maximum safe level (MSL) of pennycress meal (PM) for broiler chicks. In experiment 1, a total of 480 chicks was fed either mash or crumbled diets containing zero, 5, 10, or 15% PM for 18 d (8 diets; 6 replications per diet). In experiment 2, a total of 660 chicks was fed mash diets containing zero, 3, 6, 9, 12, or 15% of either PM or canola meal (CM; a comparative reference) for 14 d (11 diets; 6 replications per diet). Analytical results show that PM is a good source of protein (~31% CP) and it is very comparable to CM (~36% CP). However, it contains higher erucic acid (~1.68 vs. < 0.021%), glucosinolates (sinigrin) (~63.5 vs. <0.163 MUmol /g), and crude fiber (18.60 vs. 9.27%) compared to CM. In experiment 1, increasing PM from zero to 15% resulted in linear reductions (P < 0.05) in FI, BWG, and FCR at 10 days. Above 10%, performance responses were affected for FI and BWG at 18 d, respectively. An estimated MSL of 10% PM based on orthogonal contrast was optimal for satisfactory FI and BWG. The MSL as estimated by broken-line linear (BLL) and broken-line quadratic (BLQ) models was 9.12 +/- 0.50 and 7.0 +/- 1.27%, respectively. In experiment 2, growth performance at 14 d was reduced above 9% due to PM inclusion. CM inclusion did not affect growth performance at 14 d, suggesting 15% to be safe. The MSL for maximum growth performance varied depending on the statistical analysis as follows: 12% by orthogonal contrast and LSD, 15% by the Scheffe test, 10.84 +/- 0.57 by BLL, and 8.61 +/- 1.29 by BLQ. In conclusion, PM can be included in broiler starter diets as a protein source but its inclusion should be limited to no more than 8.5%. Different statistical procedures give different MSL and this should be considered when interpreting the data. PMID- 28339840 TI - The Effects of Sexual Orientation on the Relationship Between Victimization Experiences and Smoking Status Among US Women. AB - Introduction: This study examined the relationships between experiences of childhood and adulthood victimization and current smoking among heterosexual and sexual minority women. The main hypothesis was that victimization experiences would predict current smoking status. Further, we hypothesized that the effect of childhood victimization on self-reported smoker status would be mediated by adult victimization. Methods: Data are from two studies conducted in the United States that used similar methods and questionnaires in order to conduct a comparative analysis of women based on sexual orientation. Data from Wave 1 (2000-2001) of the Chicago Health and Life Experiences of Women (CHLEW) study and from Wave 5 (2001) of the National Study of Health and Life Experiences of Women (NSHLEW) study were used in these analyses. Results: Twenty-eight percent of the sample reported current smoking. Victimization experiences were common, with 63.4% of participants reporting at least one type of victimization in childhood and 40.2% reporting at least one type in adulthood. Women who identified as heterosexual were less likely to be victimized during childhood than were women who identified as lesbian or bisexual. Adult victimization had a significant effect on current smoker status, and the effect of childhood victimization on smoker status was mediated by adult victimization. When examined by sexual orientation, this indirect relationship remained significant only among bisexual women in the sample. Conclusions: Study findings make a valuable contribution to the literature on victimization and health risk behaviors such as smoking. Given the negative and long-term impact of victimization on women, strategies are needed that reduce the likelihood of victimization and subsequent engagement in health risk behaviors such as smoking. Implications: The study findings make a valuable contribution to the literature on sexual minority women's health on the influence of victimization on health risk behaviors. With the goal of reducing the likelihood of adult victimization and subsequent engagement in health risk behaviors, programs and policies aimed at preventing victimization of women are warranted. Providers and community health agencies should assess and target physically and sexually abused sexual minority youth for mental health intervention with the goal of interrupting the progression from childhood victimization to adult victimization and subsequent engagement in health risk behaviors. PMID- 28339842 TI - Epicardial ablation may not be necessary in all patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy and frequent ventricular tachycardia. PMID- 28339843 TI - Availability and cost of extracorporeal treatments for poisonings and other emergency indications: a worldwide survey. AB - Background: Extracorporeal treatments (ECTRs) are used for different conditions, including replacement of organ function and poisoning. Current recommendations for ECTRs in various poisonings suggest that intermittent haemodialysis (IHD) is the most efficient technique. However, the practicality of these recommendations is poorly defined in view of limited information on availability and cost worldwide. Methods: A survey invitation to an Internet-based questionnaire was emailed between January 2014 and March 2015 to members of international societies to determine the availability, time to initiation and cost of ECTRs (including filters, dialysate, catheter, anticoagulant and nursing/physician salary). The median cost ratio of every ECTR compared with IHD performed in the same institution were presented. Results: The view rate was estimated at 28.1% (2532/9000), the participation rate was 40.1% (1015/2532) and the completion rate was 16.0% (162/1015). Respondents originated from 89 countries, and nearly three fourths practiced in a tertiary care centre. A total of 162 respondents provided sufficient data for in-depth analysis. IHD was the most available acute ECTR (96.9%), followed by therapeutic plasma exchange (TPE; 68.3%), continuous renal replacement therapy (CRRT; 62.9%), peritoneal dialysis (PD; 44.8%), haemoperfusion (HP; 30.9%) and liver support devices (LSDs; 14.7%). IHD, CRRT and HP were the shortest to initiate (median = 60 min). The median cost ratios of each ECTR compared with IHD were 1.7 for CRRT and HP, 2.8 for TPE, 6.5 for LSDs and 1.4 for PD (P < 0.001 for all). The median cost ratio of a 4-h IHD treatment compared with 1 day in the intensive care unit was 0.6 (P = 0.2). Conclusions: IHD appears to be the most widely available ECTR worldwide and is at least 30% less expensive than other ECTRs. The superior efficacy of IHD for enhanced elimination, added to its lower cost and wider availability, strengthens its preference as the ECTR of choice in most cases of acute poisoning. Keywords: costing, CRRT, EXTRIP, hemodialysis, hemoperfusion. PMID- 28339844 TI - Intensity-modulated radiotherapy using two static ports of tomotherapy for breast cancer after conservative surgery: dosimetric comparison with other treatment methods and 3-year clinical results. AB - This study investigated the differences in dose-volume parameters for the breast and normal tissues during TomoDirectTM (TD) intensity-modulated radiation therapy (IMRT), TD-3D conformal radiotherapy (3DCRT) and 3DCRT plans, all using two beams, and analyzed treatment outcomes of two-beam TD-IMRT for breast cancer after breast-conserving surgery. Between August 2011 and January 2015, 152 patients were treated using two-beam TD-IMRT with 50 Gy/25 fractions. Among them, 20 patients with left-sided breast cancer were randomly chosen, and two-beam TD IMRT, TD-3DCRT and 3DCRT plans were created for each patient. The homogeneity and conformity indices and various dose-volume parameters for the planning target volume and OARs were evaluated. Clinical outcomes were evaluated at 3 years. Toxicities were evaluated using the Common Terminology Criteria for Adverse Events version 4.0. TD-IMRT and TD-3DCRT showed better whole-breast coverage than 3DCRT (P < 0.001). Most of the mean values of dosimetric endpoints for OARs were better in TD-IMRT than in TD-3DCRT and 3DCRT. Overall survival rates were 97.7% and local control rates were 99.1% at 3 years. Regional control and distant metastasis control rates at 3 years were 98.6% and 96.8%, respectively. Twenty four of the 152 patients had Grade 2 or higher acute radiation dermatitis. Four patients (4/146 = 2.7%) had Grade 2 radiation pneumonitis. There were no late adverse events of Grade 2 or higher. Two-beam TD-IMRT appeared to yield better dose distribution for whole-breast external-beam radiation therapy than TD-3DCRT and two-beam 3DCRT. The treatment appeared to provide low skin toxicity and acceptable tumor control. PMID- 28339845 TI - Expanded spectrum beta-lactamase producing Escherichia coli isolated from chickens with colibacillosis in Egypt. AB - Throughout the world, expanded spectrum beta-lactamases (ESBL) are increasing among clinical isolates of Enterobacteriaceae, both in humans and animals. Unfortunately, there is a paucity of data on ESBL or Ampicillin class C beta lactamase (AmpC) in Egypt, although antimicrobial consumption is high in this developing country. This study aims to characterize the resistance mechanisms to expanded spectrum cephalosporins among resistant veterinary Escherichia coli isolates in Egypt. We investigated 50 clinical multi-resistant E. coli strains isolated from 20 chicken farms for production of ESBL or AmpC. Antibiotic susceptibility was tested by Clinical and Laboratory Standards Institute (CLSI) disk diffusion and ESBL confirmatory tests. PCR and sequencing were performed to screen for plasmid mediated ESBL genes and genes encoding AmpC beta-lactamases. All the isolates were phylogentically classified, investigated for harboring class 1 integrons, and genotyped by amplified fragment length polymorphism (AFLP). Three strains showed ESBL and 6 strains AmpC phenotypic patterns, respectively, with confirmed ESBL genes of blaTEM-57, blaSHV-12, blaCTX-M-14, and blaCMY-2 for AmpC producing strains. All ESBL strains belonged to phylogroup D with different clones isolated from different flocks, while most of the AmpC strains belonged to phylogroup B1 (4/6) and were assigned to the same genotype distributed in 2 different farms. Class 1 integrons were disseminated in 60% of all tested strains and in 100% of ESBL and AmpC strains. These results highlight the antimicrobial resistance problem in Egypt, caused in all probability by unwise use of antimicrobials in animal husbandry. The results call for a nationwide surveillance program to monitor antimicrobial resistance. PMID- 28339846 TI - Estimation of whole-body radiation exposure from brachytherapy for oral cancer using a Monte Carlo simulation. AB - Early stage oral cancer can be cured with oral brachytherapy, but whole-body radiation exposure status has not been previously studied. Recently, the International Commission on Radiological Protection Committee (ICRP) recommended the use of ICRP phantoms to estimate radiation exposure from external and internal radiation sources. In this study, we used a Monte Carlo simulation with ICRP phantoms to estimate whole-body exposure from oral brachytherapy. We used a Particle and Heavy Ion Transport code System (PHITS) to model oral brachytherapy with 192Ir hairpins and 198Au grains and to perform a Monte Carlo simulation on the ICRP adult reference computational phantoms. To confirm the simulations, we also computed local dose distributions from these small sources, and compared them with the results from Oncentra manual Low Dose Rate Treatment Planning (mLDR) software which is used in day-to-day clinical practice. We successfully obtained data on absorbed dose for each organ in males and females. Sex-averaged equivalent doses were 0.547 and 0.710 Sv with 192Ir hairpins and 198Au grains, respectively. Simulation with PHITS was reliable when compared with an alternative computational technique using mLDR software. We concluded that the absorbed dose for each organ and whole-body exposure from oral brachytherapy can be estimated with Monte Carlo simulation using PHITS on ICRP reference phantoms. Effective doses for patients with oral cancer were obtained. PMID- 28339847 TI - Telephone-Delivered Exercise Advice and Behavior Change Support by Physical Therapists for People with Knee Osteoarthritis: Protocol for the Telecare Randomized Controlled Trial. AB - Background: Exercise and physical activity are a core component of knee osteoarthritis (OA) care, yet access to physical therapists is limited for many people. Telephone service delivery models may increase access. Objective: Determine the effectiveness of incorporating exercise advice and behavior change support by physical therapists into an existing Australian nurse-led musculoskeletal telephone service for adults with knee OA. Design: Randomized controlled trial with nested qualitative studies. Setting: Community, Australia wide. Participants: One hundred seventy-five people >=45 years of age with knee symptoms consistent with a clinical diagnosis of knee OA. Eight musculoskeletal physical therapists will provide exercise advice and support. Intervention: Random allocation to receive existing care or exercise advice in addition to existing care. Existing care is a minimum of one phone call from a nurse for advice on OA self-management. Exercise advice involves 5-10 calls over 6 months from a physical therapist trained in behavior change support to prescribe, monitor, and progress a strengthening exercise program and physical activity plan. Measurements: Outcomes will be measured at baseline and at 6 and 12 months. Primary outcomes are knee pain and physical function. Secondary outcomes include other measures of knee pain, self-efficacy, physical activity and its mediators, kinesiophobia, health service usage, work productivity, participant-perceived change, and satisfaction. Additional measures include adherence, adverse events, therapeutic alliance, satisfaction with telephone-delivered therapy, and expectation of outcome. Semi-structured interviews with participants with knee OA and therapists will be conducted. Limitations: Physical therapists cannot be blinded. Conclusions: This study will determine if incorporating exercise advice and behavior change support by physical therapists into a nurse-led musculoskeletal telephone service improves outcomes for people with knee OA. Findings will inform development and implementation of telerehabilitation services. PMID- 28339848 TI - Left atrial and pulmonary vein flutter associated with double electrical connections after a lung transplantation. PMID- 28339850 TI - Allelic variation in TLR4 is linked to resistance to Salmonella Enteritidis infection in chickens. AB - Salmonella Enteritidis (SE) is a foodborne pathogen that negatively affects both animal and human health. Polymorphisms of the TLR4 gene may affect recognition by Toll-like receptor 4 (TLR4) of bacterial lipopolysaccharide (LPS), leading to differences in host resistance to pathogenic infections. The present study has investigated polymorphic loci of chicken TLR4 (ChTLR4) in ten chicken breeds, electrostatic potentials of mutant structures of TLR4, and a linkage analysis between allelic variation and survival ratio to infection with SE in specific pathogen-free (SPF) White Leghorns. A total of 19 Single Nucleotide Polymorphisms (SNPs), of which 10 were novel, were found in chicken breeds. Seven newly identified amino acid variants (C68G, G674A, G782A, A896T, T959G, T986A, and A1104C) and previously reported important mutations (G247A, G1028A, C1147T, and A1832G) were demonstrated in the extracellular domain of the ChTLR4 gene. Significant changes in surface electrostatic potential of the ectodomain of TLR4, built by homology modeling, were observed at the Glu83Lys (G247A), Arg298Ser (A896T), Ser368Arg (A1104C), and Gln611Arg (A1832G) substitutions. Linkage analysis showed that one polymorphic locus G247A of TLR4 gene, common in all breeds examined, was significantly associated with increased resistance to SE in SPF White Leghorns chicks (log-rank P-value = 0.04). The genotypes from A1832G SNPs did not show statistically significant survival differences. This study has provided the first direct evidence that G247A substitution in ChTLR4 is associated with increased resistance to Salmonella Enteritidis. PMID- 28339852 TI - Relationship Between Back Pain and Urinary Incontinence in the Canadian Population. AB - Background: Back problems and urinary incontinence (UI) have been found to co occur more frequently than would be predicted by chance. Objective: The aim of this study was to estimate the associations between UI and back problems in the Canadian men and women. Design: This was an observational, cross-sectional study. Methods: The 2011-2012 Statistics Canada Canadian Community Health Survey (CCHS) provided the data. The CCHS surveyed 125,645 adults, providing a representative sample of the Canadian population. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to quantify the strength of the associations among the variables. Results: Having UI increased the risk of also having back problems in both men (OR = 2.45; 95% CI = 2.06-2.91) and women (OR = 2.97; 95% CI = 2.64-3.35) compared with not experiencing UI. Among those participants with UI, men and women were at equal risk of experiencing back problems. Limitations: The CCHS data are cross-sectional and self-reported, which prevents determining causality and carries a risk of response bias. Also, various diagnoses were grouped under the back problems and UI categories, which makes it difficult to propose possible explanations for this pattern of comorbidity. Conclusions: This study provides firm evidence to support clinically observed associations between UI and back problems. The strength of the associations was essentially equal in men and women. These findings reinforce the importance of screening for these frequently coincident conditions. PMID- 28339854 TI - Prediction versus aetiology: common pitfalls and how to avoid them. AB - Prediction research is a distinct field of epidemiologic research, which should be clearly separated from aetiological research. Both prediction and aetiology make use of multivariable modelling, but the underlying research aim and interpretation of results are very different. Aetiology aims at uncovering the causal effect of a specific risk factor on an outcome, adjusting for confounding factors that are selected based on pre-existing knowledge of causal relations. In contrast, prediction aims at accurately predicting the risk of an outcome using multiple predictors collectively, where the final prediction model is usually based on statistically significant, but not necessarily causal, associations in the data at hand.In both scientific and clinical practice, however, the two are often confused, resulting in poor-quality publications with limited interpretability and applicability. A major problem is the frequently encountered aetiological interpretation of prediction results, where individual variables in a prediction model are attributed causal meaning. This article stresses the differences in use and interpretation of aetiological and prediction studies, and gives examples of common pitfalls. PMID- 28339853 TI - Prosurvival effect of cumulus prostaglandin G/H synthase 2/prostaglandin2 signaling on bovine blastocyst: impact on in vivo posthatching development. AB - Apoptotic activity is a common physiological process which culminates at the blastocyst stage in the preimplantation embryo of many mammals. The degree of embryonic cell death can be influenced by the oocyte microenvironment. However, the prognostic significance of the incidence of apoptosis remains undefined. Prostaglandin E2 (PGE2) derived from prostaglandin G/H synthase-2 (PTGS2) activity is a well-known prosurvival factor that is mainly studied in oncology. PGE2 is the predominant PTGS2-derived prostaglandin present in the oocyte microenvironment during the periconceptional period. Using an in vitro model of bovine embryo production followed by transfer and collection procedures, we investigated the impact of periconceptional PGE2 on the occurrence of spontaneous apoptosis in embryos and on subsequent in vivo posthatching development. Different periconceptional PGE2 environments were obtained using NS-398, a specific inhibitor of PTGS2 activity, and exogenous PGE2. We assessed the level of embryonic cell death in blastocysts at day 8 postfertilization by counting total cell numbers, by the immunohistochemical staining of active caspase-3, and by quantifying terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling signals and apoptosis regulator (BCL-2/BAX) mRNA expression. Morphometric parameters were used to estimate the developmental stage of the embryonic disk and the extent of trophoblast elongation on day 15 conceptuses. Our findings indicate that periconceptional PGE2 signaling durably impacts oocytes, conferring increased resistance to spontaneous apoptosis in blastocysts and promoting embryonic disk development and the elongation process during preimplantation development. PMID- 28339857 TI - Creutzfeld Jacob disease. PMID- 28339858 TI - Relationship Between Emotional Processing, Drinking Severity and Relapse in Adults Treated for Alcohol Dependence in Poland. PMID- 28339860 TI - Outcomes with single-coil versus dual-coil implantable cardioverter defibrillators: a meta-analysis. AB - Aims: Dual-coil implantable cardioverter defibrillator (ICD) leads have traditionally been used over single-coil leads due to concerns regarding high defibrillation thresholds (DFT) and consequent poor shock efficacy. However, accumulating evidence suggests that this position may be unfounded and that dual coil leads may also be associated with higher complication rates during lead extraction. This meta-analysis collates data comparing dual- and single-coil ICD leads. Methods and results: Electronic databases were systematically searched for randomized controlled trials (RCT) and non-randomized studies comparing single coil and dual-coil leads. The mean differences in DFT and summary estimates of the odds-ratio (OR) for first-shock efficacy and the hazard-ratio (HR) for all cause mortality were calculated using random effects models. Eighteen studies including a total of 138,124 patients were identified. Dual-coil leads were associated with a lower DFT compared to single coil leads (mean difference 0.83J; 95% confidence interval [CI] -1.39--0.27; P = 0.004). There was no difference in the first-shock success rate with dual-coil compared to single-coil leads (OR 0.74; 95%CI 0.45-1.21; P=0.22). There was a significantly lower risk of all-cause mortality associated with single-coil leads (HR 0.91; 95%CI 0.86-0.95; P < 0.0001). Conclusion: This meta-analysis suggests that single-coil leads have a marginally higher DFT but that this may be clinically insignificant as there appears to be no difference in first-shock efficacy when compared to dual-coil leads. The mortality benefit with single-coil leads most likely represents patient selection bias. Given the increased risk and complexity of extracting dual-coil leads, centres should strongly consider single-coil ICD leads as the lead of choice for routine new left-sided ICD implants. PMID- 28339861 TI - Constitutive luteinizing hormone receptor signaling causes sexual dysfunction and Leydig cell adenomas in male mice. AB - The luteinizing hormone receptor (LHCGR) is necessary for fertility, and genetic mutations cause defects in reproductive development and function. Activating mutations in LHCGR cause familial male-limited precocious puberty (FMPP). We have previously characterized a mouse model (KiLHRD582G) for FMPP that exhibits the same phenotype of precocious puberty, Leydig cell hyperplasia, and elevated testosterone as boys with the disorder. We observed that KiLHRD582G male mice became infertile by 6 months of age, although sperm count and motility were normal. In this study, we sought to determine the reason for the progressive infertility and the long-term consequences of constant LHCGR signaling. Mating with superovulated females showed that infertile KiLHRD582G mice had functional sperm and normal accessory gland function. Sexual behavior studies revealed that KiLHRD582G mice mounted females, but intromission was brief and ejaculation was not achieved. Histological analysis of the reproductive tract showed unique metaplastic changes resulting in pseudostratified columnar epithelial cells with cilia in the ampulla and chondrocytes in the penile body of the KiLHRD582G mice. The infertile KiLHRD582G exhibited enlarged sinusoids and a decrease in smooth muscle content in the corpora cavernosa of the penile body. However, collagen content was unchanged. Leydig cell adenomas and degenerating seminiferous tubules were seen in 1-year-old KiLHRD582G mice. We conclude that progressive infertility in KiLHRD582G mice is due to sexual dysfunction likely due to functional defects in the penis. PMID- 28339862 TI - A New Insight into the Evolution and Functional Divergence of SWEET Transporters in Chinese White Pear (Pyrus bretschneideri). AB - SWEET genes are a recently identified plant gene family that play an indispensable role in sugar efflux. However, no systematic study has been performed in pear. In this research, 18 SWEET transporters identified in pear, almost twice the number found in woodland strawberry and Japanese apricot, were divided into four clades. Conserved motifs and six exons of the SWEET transporters were found in six species. SWEET transporters contained seven transmembrane segments (TMSs) that evolved from an internal duplication of an ancestral three-TMSs unit, connected by TMS4. This is the first direct evidence identifying internal repeats through bioinformatics analysis. Whole-genome duplication (WGD) or segmental duplication and dispersed duplication represent the main driving forces for SWEET family evolution in six species, with former duplications more important in pear. Gene expression results suggested that PbSWEET15 and PbSWEET17 have no expression in any tissues because of critical lost residues and that 62.5% of PbSWEET duplicate gene pairs have functional divergence. Additionally, PbSWEET6, PbSWEET7 and PbSWEET14 were found to play important roles in sucrose efflux from leaves, and the high expression of PbSWEET1 and PbSWEET2 might contribute to unloading sucrose from the phloem in the stem. Finally, PbSWEET5, PbSWEET9 and PbSWEET10 might contribute to pollen development. Overall, our study provides important insights into the evolution of the SWEET gene family in pear and four other Rosaceae, and the important candidate PbSWEET genes involved in the development of different tissues were identified in pear. PMID- 28339863 TI - Cigarette smoking and chronic kidney disease in the general population: a systematic review and meta-analysis of prospective cohort studies. AB - Background: Cigarette smoking has been established as a major risk factor for chronic kidney disease (CKD) development in people with diabetes. Conflicting evidence exists among representative community-based studies as to whether smoking is an independent risk factor for CKD. The aim of this meta-analysis was to assess the effects of tobacco smoking on the development of CKD in adult general populations. Methods: A literature search was conducted using MEDLINE and Embase from their inception through 31 May 2016 for prospective cohort studies that reported relative risks of CKD with smoking status in the general population. Summary relative risks (SRRs) and 95% confidence intervals (CIs) were calculated using a random effects model. Results: A total of 15 prospective cohort studies, including 65 064 incident CKD cases, were included. Compared with never-smokers, the SRRs of incident CKD were 1.27 (95% CI 1.19-1.35) for ever smokers, 1.34 (95% CI 1.23-1.47) for current smokers and 1.15 (95% CI 1.08-1.23) for former smokers. The SRRs for end-stage renal disease development were 1.51 (95% CI 1.24-1.84) for ever-smokers, 1.44 (95% CI 1.00-2.09) for former smokers and 1.91 (95% CI 1.39-2.64) for current smokers. Considerable heterogeneity was observed among these studies. After combining an additional three prospective cohort studies, which involved 5747 incident proteinuria cases, a null smoking proteinuria association in the general population was observed. Conclusions: Our meta-analysis suggests evidence for cigarette smoking as an independent risk factor for incident CKD. Future studies are required to investigate whether smoking cessation can decrease incident CKD in the general adult population. PMID- 28339864 TI - Macroreentrant atrial tachycardia around the native common atrioventricular valve in a surgically corrected complete atrioventricular septal defect. PMID- 28339865 TI - Myrddin Evans: A Gentleman and a Founder of the Medical Council on Alcohol (MCA) and its Journal. PMID- 28339866 TI - Relative biological value of 1alpha-hydroxycholecalciferol to 25 hydroxycholecalciferol in broiler chicken diets. AB - This study was conducted to evaluate the relative biological value (RBV) of 1alpha-hydroxycholecalciferol (1alpha-OH-D3) to 25-hydroxycholecalciferol (25-OH D3) in one- to 21-day-old broiler chickens fed calcium (Ca)- and phosphorus (P) deficient diets. On the d of hatch, 450 male Ross 308 broiler chickens were weighed and randomly allotted to 9 treatments with 5 replicates of 10 birds per replicate. The basal diet contained 0.50% Ca and 0.25% non-phytate phosphorus (NPP) but was not supplemented with cholecalciferol (vitamin D3). The levels of Ca and NPP in basal diets were lower than those recommended by NRC (1994). 25-OH D3 was fed at zero, 1.25, 2.5, 5.0, and 10.0 MUg/kg, and 1alpha-OH-D3 was fed at 0.625, 1.25, 2.5, and 5.0 MUg/kg. The RBV of 1alpha-OH-D3 to 25-OH-D3 based on vitamin D intake was determined by the slope ratio method. Results showed that 25 OH-D3 or 1alpha-OH-D3 improved the growth performance and decreased the mortality in one- to 21-day-old broilers. A linear relationship was observed between the level of 25-OH-D3 or 1alpha-OH-D3 and mineralization of the femur, tibia, or metatarsus. The RBV of 1alpha-OH-D3 to 25-OH-D3 were 234, 253, and 202% when the weight, ash weight, and Ca percentage of femur were used as criteria. The corresponding RBV of 1alpha-OH-D3 to 25-OH-D3 were 232 to 263% and 245 to 267%, respectively, when tibia and metatarsus mineralization were used as criteria. These data indicate that when directly feeding a hormonally active form of vitamin D as 1alpha-OH-D3 proportionally less is needed than when using the precursor (25-OH-D3) in diets deficient in Ca and P. PMID- 28339869 TI - Alcohol Induces Cellular Senescence and Impairs Osteogenic Potential in Bone Marrow-Derived Mesenchymal Stem Cells. AB - Aims: Chronic and excessive alcohol consumption is a high-risk factor for osteoporosis. Bone marrow-derived mesenchymal stem cells (BM-MSCs) play an important role in bone formation; however, they are vulnerable to ethanol (EtOH). The purpose of this research was to investigate whether EtOH could induce premature senescence in BM-MSCs and subsequently impair their osteogenic potential. Methods: Human BM-MSCs were exposed to EtOH ranging from 10 to 250 mM. Senescence-associated beta-galactosidase (SA-beta-gal) activity, cell cycle distribution, cell proliferation and reactive oxygen species (ROS) were evaluated. Mineralization and osteoblast-specific gene expression were evaluated during osteogenesis in EtOH-treated BM-MSCs. To investigate the role of silent information regulator Type 1 (SIRT1) in EtOH-induced senescence, resveratrol (ResV) was used to activate SIRT1 in EtOH-treated BM-MSCs. Results: EtOH treatments resulted in senescence-associated phenotypes in BM-MSCs, such as decreased cell proliferation, increased SA-beta-gal activity and G0/G1 cell cycle arrest. EtOH also increased the intracellular ROS and the expression of senescence-related genes, such as p16INK4alpha and p21. The down-regulated levels of SIRT1 accompanied with suppressed osteogenic differentiation were confirmed in EtOH-treated BM-MSCs. Activation of SIRT1 by ResV partially counteracted the effects of EtOH by decreasing senescence markers and rescuing the inhibited osteogenesis. Conclusion: EtOH treatments induced premature senescence in BM-MSCs in a dose-dependent manner that was responsible for EtOH-impaired osteogenic differentiation. Activation of SIRT1 was effective in ameliorating EtOH-induced senescence phenotypes in BMSCs and could potentially lead to a new strategy for clinically preventing or treating alcohol-induced osteoporosis. Short summary: Ethanol (EtOH) treatments induce premature senescence in marrow-derived mesenchymal stem cells in a dose-dependent manner that is responsible for EtOH impaired osteogenic differentiation. Activation of SIRT1 is effective in ameliorating EtOH-induced senescence phenotypes, which potentially leads to a new strategy for clinically treating alcohol-induced osteoporosis. PMID- 28339876 TI - Straight-run vs. sex separate rearing for two broiler genetic lines Part 2: Economic analysis and processing advantages. AB - The objective of this analysis was to evaluate the effects of raising broilers under sex separate and straight-run conditions for 2 broiler genetic lines. One day-old Ross 308 and Ross 708 chicks (n = 1,344) were sex separated and placed in 48 pens according to rearing type: sex separate (28 males or 28 females) or straight-run (14 males + 14 females). There were 3 dietary phases: starter (zero to 17 d), grower (17 to 32 d), and finisher (32 to 48 d). Bird individual BW and group feed intakes were measured at 12, 17, 25, 32, 42, and 48 d to evaluate performance. At 33, 43, and 49 d 4 birds per pen (straight-run pens 2 males + 2 females) were sampled for carcass yield evaluation. Data were analyzed using linear and non-linear regression in order to estimate feed intake and cut-up weights at 3 separate market weights (1,700, 2,700, and 3,700 g). Returns over feed cost were estimated for a 1.8 million broiler complex for each rearing system and under 9 feed/meat price scenarios. Overall, rearing birds that were sex separated resulted in extra income that ranged from ${?$}$48,824 to ${?$}$330,300 per week, depending on the market targeted and feed and meat price scenarios. Sex separation was shown to be especially important in disadvantageous scenarios in which feed prices were high. Gains from sex separation were markedly higher for the Ross 708 than for the Ross 308 broilers. Bird variability also was evaluated at the 3 separate market ages under narrow ranges of BW that were targeted. Straight-run birds decreased the number of birds present in the desired range. Depending on market weight, straight-run rearing resulted in 9.1 to 16.6% fewer birds than sex separate rearing to meet marketing goals. It was concluded that sex separation can result in increased company profitability and have possible beneficial effects at the processing plant due to increased bird uniformity. PMID- 28339881 TI - Genetic aspects and environmental sources of microsporidia that infect the human gastrointestinal tract. AB - Enterocytozoon bieneusi and Encephalitozoon intestinalis are microsporidia that infect the human gastrointestinal (GI) tract. Each of these microsporidia has been shown to infect various non-human hosts (mammalian and avian), raising the possibility of inter-species transmission, for example, from such hosts to human subjects via waterborne dispersal of microsporidian spores. During the past two decades, genome sequencing has delineated more than 90 genotypes of Ent. bieneusi, and has led to the conclusion that not all the genotypes of this organism infect human subjects. Well documented in the HIV-infected population, GI tract microsporidiosis is also known to occur in immunocompetent, HIV negative, individuals. The prevalence of HIV-associated microsporidiosis diminished following the introduction of effective anti-retroviral therapy. PMID- 28339885 TI - Alcohol-related hospitalization is associated with increased risk of ischaemic stroke among low-risk patients with atrial fibrillation. AB - Aims: Patients with atrial fibrillation (AF) under the age of 65 and CHA2DS2-VASc risk score of 0 in men or 1 in women are considered to be at low risk for ischaemic stroke, and therefore without benefit of oral anticoagulation therapy. The objective of this study is to assess the incidence and predictors of ischaemic stroke among low-risk patients with AF identified from a National Patient Register. Methods and results: A retrospective study of 25 252 low-risk AF patients (age 18-64) out of total 345 123 AF patients identified from the Swedish Nationwide Patient Register for the period 1 January 2006 to 31 December 2012. During a median follow-up of 5.0 (interquartile range 2.9-6.8) years, ischaemic stroke occurred at an annual rate of 0.34 per 100 patient-years [95% confidence interval (CI) 0.31-0.38]. Significant predictors of stroke were age, hazard ratio (HR) 1.06 (CI 1.05-1.08) per incremental year, and previous alcohol related hospitalization HR 2.01 (CI 1.45-2.79). Intracerebral bleeding events were rare and not statistically different HR 2.05 (CI 0.76-5.56) between patients with and without alcohol-related hospitalizations. Use of oral anticoagulants was associated with lower risk for ischaemic stroke, HR 0.78 (CI 0.63-0.97). Conclusion: The presence of a previous hospitalization with an alcohol-related disease was associated with a small but significant increase in the risk of stroke among low-risk AF patients. More research about relation between alcohol use and ischaemic stroke in AF patients is warranted. PMID- 28339886 TI - Optimal method of measuring the T-peak to T-end interval for risk stratification in primary prevention. AB - Aims: Several published investigations demonstrated that a longer T-peak to T-end interval (Tpe) implies increased risk for ventricular tachyarrhythmia (VT/VF) and mortality. Tpe has been measured using diverse methods. We aimed to determine the optimal Tpe measurement method for screening purposes. Methods and results: We evaluated 305 patients with LVEF <= 35% and an implantable cardioverter defibrillator implanted for primary prevention. Tpe was measured using seven different methods described in the literature, including six manual methods and the automated algorithm '12SL', and was corrected for heart rate. Endpoints were VT/VF and death. To account for differences in the magnitude of Tpe measurements, results are expressed in standard deviation (SD) increments. We evaluated the clinical utility of each measurement method based on predictive ability, fraction of immeasurable tracings, and intra- and interobserver correlation. >Over 31 +/- 23 months, 82 (27%) patients had VT/VF, and over 49 +/- 21 months, 91 (30%) died. Several rate-corrected Tpe measurement methods predicted VT/VF (HR per SD 1.20 1.34; all P < 0.05), and nearly all methods (both corrected and uncorrected) predicted death (HR per SD 1.19-1.35; all P < 0.05). Optimal predictive ability, readability, and correlation were found in the automated 12SL method and the manual tangent method in lead V2. Conclusion: For the prediction of VT/VF, the utility of Tpe depends upon the measurement method, but for the prediction of mortality, most published Tpe measurement methods are similarly predictive. Heart rate correction improves predictive ability. The automated 12SL method performs as well as any manual measurement, and among manual methods, lead V2 is most useful. PMID- 28339887 TI - Periostin paves the way for neonatal heart regeneration. PMID- 28339883 TI - Interventions to improve immigrant health. A scoping review. AB - Background: : Disparities in health between immigrants and their host populations have been described across countries and continents. Hence, interventions for improving health targeting general populations are not necessarily effective for immigrants. To conduct a systematic search of the literature evaluating health interventions for immigrants; to map the characteristics of identified studies including range of interventions, immigrant populations and their host countries, clinical areas targeted and reported evaluations, challenges and limitations of the interventions identified. Following the results, to develop recommendations for research in the field. A scoping review approach was chosen to provide an overview of the type, extent and quantity of research available. Studies were included if they empirically evaluated health interventions targeting immigrants and/or their descendants, included a control group, and were published in English (PubMed and Embase from 1990 to 2015). Most of the 83 studies included were conducted in the USA, encompassed few immigrant groups and used a randomized controlled trial (RCT) or cluster RCT design. Most interventions addressed chronic and non-communicable diseases and attendance at cancer screening services, used individual targeted approaches, targeted adult women and recruited participants from health centres. Outcome measures were often subjective, with the exception of interventions for cardiovascular risk and diabetes. Generally, authors claimed that interventions were beneficial, despite a number of reported limitations. Recommendations for enhancing interventions to improve immigrant health are provided to help researchers, funders and health care commissioners when deciding upon the scope, nature and design of future research in this area. PMID- 28339890 TI - Pennsylvania State Core Competencies for Education on Opioids and Addiction. AB - Objective: The objective of this project was to develop core competencies for education on opioids and addiction to be used in all Pennsylvania medical schools. Methods: The Pennsylvania Physician General created a task force that was responsible for the creation of the core competencies. A literature review was completed, and a survey of graduating medical students was conducted. The task force then developed, reviewed, and approved the core competencies. Results: The competencies were grouped into nine domains: understanding core aspects of addiction; patient screening for substance use disorder; proper referral for specialty evaluation and treatment of substance use disorder; proper patient assessment when treating pain; proper use of multimodal treatment options when treating acute pain; proper use of opioids for the treatment of acute pain (after consideration of alternatives); the role of opioids in the treatment of chronic noncancer pain; patient risk assessment related to the use of opioids to treat chronic noncancer pain, including the assessment for substance use disorder or increased risk for aberrant drug-related behavior; and the process for patient education, initiation of treatment, careful patient monitoring, and discontinuation of therapy when using opioids to treat chronic noncancer pain. Specific competencies were developed for each domain. Conclusions: These competencies will be incorporated into the educational process at all Pennsylvania medical schools. It is hoped that these curriculum changes will improve student knowledge and attitudes in these areas, thus improving patient outcomes. PMID- 28339895 TI - Does Parental Health Mediate the Relationship between Parental Uninsurance and Insured Children's Health Outcomes? Evidence from a U.S. National Survey. AB - Although the United States has made great strides in ensuring near universal health care access for children, the health insurance coverage gap between children and their parents remains high. This study analyzed aggregated data from the 2006-2013 National Health Interview Survey to investigate the direct relationships between parental uninsurance and children's health outcomes. Authors explored how parental health mediates the relationship between parents' health and children's health outcomes. Results suggest that insured children of uninsured parents have worse health status and are at higher risk of asthma, attention-deficit/hyperactivity disorder, developmental delays, learning disabilities, and mental disabilities compared with insured children of insured parents. Parental health mediated this relationship. These findings illuminate the pathway between parental uninsurance and child health outcomes and suggest that policies that provide health insurance coverage to both children and their parents may improve both parental health and children's health outcomes. This study fills an important gap in the literature related to how parental uninsurance affects children's health outcomes mediated by the impact of uninsurance on parental health. PMID- 28339896 TI - What to eat or what not to eat-that is still the question. PMID- 28339898 TI - The impact of the Psychoactive Substances Act 2016 on the online availability of MDMB-CHMICA. AB - Background: In May 2016, the UK Government enacted the Psychoactive Substances Act which made it an offense to produce or supply many drugs including new psychoactive substances (NPS). Aim: We aimed to assess the impact of the Act on the availability of the synthetic cannabinoid receptor agonist methyl 2-[[1 (cyclohexylmethyl)indole-3-carbonyl]amino]-3,3-dimethylbutanoate (MDMB-CHMICA) from internet-based suppliers. Design: Internet snapshot availability study. Methods: We conducted two snapshot availability surveys looking at the number of websites offering to sell MDMB-CHMICA: the first in March prior to implementation of the Act and the second in June, 1 month post-implementation. Results: In March and June 2016, we identified 47 and 38 websites, respectively, which offered to sell MDMB-CHMICA. There were no significant differences in the price of the drug nor the forms available for purchase. In the June survey there was a significant decrease in the number of websites which openly stated they were based in the UK (from 14 down to 2), three websites stated that they did not supply customers based in the UK and two websites stated they had ceased sales of MDMB-CHMICA due to the Act. Conclusions: This study showed a small but limited reduction in the availability of MDMB-CHMICA from internet-based suppliers following implementation of the Act. PMID- 28339904 TI - Validity of Different Activity Monitors to Count Steps in an Inpatient Rehabilitation Setting. AB - Background: Commonly used activity monitors have been shown to be accurate in counting steps in active people; however, further validation is needed in slower walking populations. Objectives: To determine the validity of activity monitors for measuring step counts in rehabilitation inpatients compared with visually observed step counts. To explore the influence of gait parameters, activity monitor position, and use of walkers on activity monitor accuracy. Methods: One hundred and sixty-six inpatients admitted to a rehabilitation unit with an average walking speed of 0.4 m/s (SD 0.2) wore 16 activity monitors (7 different devices in different positions) simultaneously during 6-minute and 6-m walks. The number of steps taken during the tests was also counted by a physical therapist. Gait parameters were assessed using the GAITRite system. To analyze the influence of different gait parameters, the percentage accuracy for each monitor was graphed against various gait parameters for each activity monitor. Results: The StepWatch, Fitbit One worn on the ankle and the ActivPAL showed excellent agreement with observed step count (ICC 2,1 0.98; 0.92; 0.78 respectively). Other devices (Fitbit Charge, Fitbit One worn on hip, G-Sensor, Garmin Vivofit, Actigraph) showed poor agreement with the observed step count (ICC 2,1 0.12 0.40). Percentage agreement with observed step count was highest for the StepWatch (mean 98%). The StepWatch and the Fitbit One worn on the ankle maintained accuracy in individuals who walked more slowly and with shorter strides but other devices were less accurate in these individuals. Limitations: There were small numbers of participants for some gait parameters. Conclusions: The StepWatch showed the highest accuracy and closest agreement with observed step count. This device can be confidently used by researchers for accurate measurement of step counts in inpatient rehabilitation in individuals who walk slowly. If immediate feedback is desired, the Fitbit One when worn on the ankle would be the best choice for this population. PMID- 28339905 TI - Comment on "Perforator-Guided Drug Injection in the Treatment of Abdominal Wall Pain". PMID- 28339908 TI - Obesity-associated cardiac pathogenesis in broiler breeder hens: Pathological adaption of cardiac hypertrophy. AB - Broiler hens consuming feed to appetite (ad libitum; AL) show increased mortality. Feed restriction (R) typically improves reproductive performance and livability of hens. Rapidly growing broilers can exhibit increased mortality due to cardiac insufficiency but it is unknown whether the increased mortality of non R broiler hens is also due to cardiac compromise. To assess cardiac growth and physiology in fully mature birds, 45-week-old hens were either continued on R rations or assigned to AL feeding for 7 or 21 days. AL hens exhibited increased bodyweight, adiposity, absolute and relative heart weight, ventricular hypertrophy, and cardiac protein/DNA ratio by d 21 (P < 0.05). Increased heart weights due to hypertrophic growth was attributed to enhanced IGF-1-Akt-FoxO1 signaling and its downstream target, translation initiation factor 4E-BP1 in conjunction with down-regulation of ubiquitin ligase atrogin-1/MAFbx (P < 0.05). Reduced activation of cardiac AMPK and downstream activation of ACC-1 in parallel with increased cardiac nitric oxide levels, calcineurin activity, and MAPK activation in AL hens (P < 0.05) suggested that metabolic derangement develops along the cardiovascular remodeling. These indictors of cardiac maladaptive hypertrophic growth were further supported by uregulation of heart failure markers, BNP and MHC-beta (P < 0.05). Hens allowed AL feeding for 70 d exhibited a higher incidence of mortality (40% vs. 10%) in association with ascites, pericardial effusion, and ventricle dilation. A higher incidence of irregular ECG patterns and rhythmicity consistent with persistently elevated systolic blood pressure and ventricle fibrosis were observed in AL hens (P < 0.05). These observations support the conclusion that AL feeding in broiler hens results in maladaptive cardiac hypertrophy that progresses to overt pathogenesis in contractility and thereby increases mortality. Feed restriction provides clear physiological benefit to heart function of adult broiler hens. PMID- 28339909 TI - IL-17 and CD40 ligand synergistically stimulate the chronicity of diabetic nephropathy. AB - Background: Early stages of diabetic nephropathy (DN) are characterized by an influx of inflammatory cells. Interactions between infiltrating T cells and podocytes may play an important role in the ongoing inflammatory response and remodelling. The aim of this study was to explore the role of IL-17 and CD40 ligand (CD40L) in DN. Methods: The study design involved a case series. Kidney biopsy samples of 69 patients with type 2 diabetes were assessed for the presence of CD4+ IL-17+ T cells. The number of CD4+ IL-17+ T cells were counted and correlated with clinical and laboratory findings. Additionally, advanced glycation end-products (AGEs) were added to cultured podocytes to imitate diabetic conditions and thus to elucidate the role of CD4+ IL-17+ T cells in renal sclerosis. Results: CD80 expression was detected in early phases of DN but was absent during diffused glomerurosclerosis in DN kidney specimens. In DN samples, CD40 expression was not only observed in most of the infiltrating cells, but also increased in podocytes and tubular epithelial cells. CD40L is locally expressed on infiltrating cells. CD4+ IL-17+ T cells were found in DN, and the number of CD4+ IL-17+ T cells was positively correlated with the deterioration in glomerular filtration rate (GFR). IL-17A was the key cytokine produced by CD4+ IL 17+ T cells. IL-17A levels were elevated in DN renal tissue and were correlated with declining GFR. IL-17 and CD40L synergistically enhanced IL-6, monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T cell expressed and secreted (RANTES), transforming growth factor beta 1 (TGF-beta1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) production in vitro. AGEs induced podocyte activation with increasing expression of IL-17A, CD40 and TGF-beta1 in vitro. Blockade with an anti-IL-17 monoclonal antibody reduced the expression of CD40 and TGF-beta1, but increased the viability of cultured podocytes. Conclusions: IL-17 and CD40L synergistically mediate the inflammatory response and remodelling associated with tissue injury and glomerular sclerosis in DN. PMID- 28339907 TI - O-linked beta-N-acetylglucosamine modification of proteins is essential for foot process maturation and survival in podocytes. AB - Background: O-linked beta- N -acetylglucosamine modification O-GlcNAcylation) is a post-translational modification of intracellular proteins, serving as a nutrient sensor. Growing evidence has demonstrated its physiological and pathological importance in various mammalian tissues. This study examined the physiological role of O-GlcNAcylation in podocyte function and development. Methods: O-GlcNAc transferase (Ogt) is a critical enzyme for O-GlcNAcylation and resides on the X chromosome. To abrogate O-GlcNAcylation in podocytes, we generated congenital and tamoxifen (TM)-inducible podocyte-specific Ogt knockout mice (Podo-Ogt y/- and TM-Podo-Ogt y/- , respectively) and analyzed their renal phenotypes. Results: Podo-Ogt y/- mice showed normal podocyte morphology at birth. However, they developed albuminuria at 8 weeks of age, increasing progressively until age 32 weeks. Glomerular sclerosis, proteinuria-related tubulointerstitial lesions and markedly altered podocyte foot processes, with decreased podocin expression, were observed histologically in 32-week-old Podo Ogt y/- mice. Next, we induced adult-onset deletion of the Ogt gene in podocytes by TM injection in 8-week-old TM-Podo-Ogt y/- mice. In contrast to Podo-Ogt y/- mice, the induced TM-Podo-Ogt y/- mice did not develop albuminuria or podocyte damage, suggesting a need for O-GlcNAcylation to form mature foot processes after birth. To test this possibility, 3-week-old Podo-Ogt y/- mice were treated with Bis-T-23, which stimulates actin-dependent dynamin oligomerization, actin polymerization and subsequent foot process elongation in podocytes. Albuminuria and podocyte damage in 16-week-old Podo-Ogt y/- mice were prevented by Bis-T-23 treatment. Conclusions: O-GlcNAcylation is necessary for maturation of podocyte foot processes, particularly after birth. Our study provided new insights into podocyte biology and O-GlcNAcylation. PMID- 28339906 TI - Interstitial fibrosis scored on whole-slide digital imaging of kidney biopsies is a predictor of outcome in proteinuric glomerulopathies. AB - Background: Interstitial fibrosis (IF), tubular atrophy (TA) and interstitial inflammation (II) are known determinants of progression of renal disease. Standardized quantification of these features could add value to current classification of glomerulopathies. Methods: We studied 315 participants in the Nephrotic Syndrome Study Network (NEPTUNE) study, including biopsy-proven minimal change disease (MCD = 98), focal segmental glomerulosclerosis (FSGS = 121), membranous nephropathy (MN = 59) and IgA nephropathy (IgAN = 37). Cortical IF, TA and II were quantified (%) on digitized whole-slide biopsy images, by five pathologists with high inter-reader agreement (intra-class correlation coefficient >0.8). Tubulointerstitial messenger RNA expression was measured in a subset of patients. Multivariable Cox proportional hazards models were fit to assess association of IF with the composite of 40% decline in estimated glomerular filtration rate (eGFR) and end-stage renal disease (ESRD) and separately as well, and with complete remission (CR) of proteinuria. Results: IF was highly correlated with TA (P < 0.001) and II (P < 0.001). Median IF varied by diagnosis: FSGS 17, IgAN 21, MN 7, MCD 1 (P < 0.001). IF was strongly correlated with baseline eGFR (P < 0.001) and proteinuria (P = 0.002). After adjusting for clinical pathologic diagnosis, age, race, global glomerulosclerosis, baseline proteinuria, eGFR and medications, each 10% increase in IF was associated with a hazard ratio of 1.29 (P < 0.03) for ESRD/40% eGFR decline, but was not significantly associated with CR. A total of 981 genes were significantly correlated with IF (|r| > 0.4, false discovery rate (FDR) < 0.01), including upstream regulators such as tumor necrosis factor, interferon gamma (IFN-gamma), and transforming growth factor beta 1 (TGF-B1), and signaling pathways for antigen presentation and hepatic fibrosis. Conclusions: The degree of IF is associated with risk of eGFR decline across different types of proteinuric glomerulopathy, correlates with inflammatory and fibrotic gene expression, and may have predictive value in assessing risk of progression. PMID- 28339910 TI - Rituximab and hepatitis B reactivation in HBsAg-negative/ anti-HBc-positive kidney transplant recipients. AB - Background: Hepatitis B virus (HBV) reactivation is a well-known complication of immunosuppressive therapy. Although rituximab is increasingly used for desensitization of ABO-incompatible or positive crossmatch kidney transplantation, the risk of HBV reactivation in hepatitis B surface antigen (HBsAg)-negative/hepatitis B core antibody (anti-HBc)-positive kidney transplant patients receiving rituximab desensitization remains undetermined. Methods: We analysed 172 resolved HBV patients who underwent living donor kidney transplantation between 2008 and 2014. Patients were divided into rituximab ( n = 49) or control ( n = 123) groups. All patients were observed for HBV reactivation, which was defined as the reappearance of hepatitis B surface antigen or HBV DNA. Results: During the follow-up period (median, 58 months; range, 4-95 months), five patients (10.2%) in the rituximab group and two patients (1.6%) in the control group experienced HBV reactivation (P = 0.003). In the rituximab group, two patients experienced HBV-related severe hepatitis, and one patient died due to hepatic failure. The median time from rituximab desensitization to HBV reactivation was 11 months (range, 5-22 months). By contrast, no patients in the control group experienced severe hepatitis. The status of hepatitis B surface antibody was similar between groups. Rituximab desensitization [hazard ratio (HR), 9.18; 95% confidence interval (CI), 1.74 48.86; P = 0.009] and hepatitis B surface antibody status (HR, 4.74; 95% CI, 1.05-21.23, P = 0.04) were significant risk factors for HBV reactivation. Conclusions: Rituximab desensitization for incompatible kidney transplantation significantly increased the risk of HBV reactivation in HBsAg-negative/anti-HBc positive patients. Therefore, close monitoring of HBV DNA is required in these patients. PMID- 28339912 TI - Pharmacogenomics and Patient Treatment Parameters to Opioid Treatment in Chronic Pain: A Focus on Morphine, Oxycodone, Tramadol, and Fentanyl. AB - Objective: Opioids are one of the most commonly prescribed medicines for chronic pain. However, their use for chronic pain has been controversial. The objective of this literature review was to identify the role of genetic polymorphisms on patient treatment parameters (opioid dose requirements, response, and adverse effects) for opioids used in malignant and nonmalignant chronic pain. The opioids that this review focuses on are codeine, morphine, oxycodone, tramadol, and fentanyl. Method: A literature search of databases Medline and Embase was carried out, and studies up to April 2016 were included in this review. Studies were included based on a combination of key words: chronic pain and related terms, pharmacogenetics and related terms, and opioids and related terms. Results: Among the 1,408 individual papers retrieved from the search in Medline and Embase, 32 original articles were included in this review, with none related to codeine. The 32 papers reported various study designs, opioids, and polymorphisms being studied for associations with treatment outcomes. This literature review reveals that variants in ABCB1, OPRM1, and COMT have been replicated for opioid dosing and variants in ABCB1 have been replicated for both treatment response and adverse effects. Conclusions: Currently, there are few validated studies to form a strong evidence base to support pharmacogenomics testing when initiating opioid therapy. However, the field of pharmacogenomics in chronic pain is likely to expand over the coming years, with the increasing number of treatment options available and larger cohorts being assembled in order to identify true associations. PMID- 28339913 TI - Relative risk versus absolute risk: one cannot be interpreted without the other. AB - For the presentation of risk, both relative and absolute measures can be used. The relative risk is most often used, especially in studies showing the effects of a treatment. Relative risks have the appealing feature of summarizing two numbers (the risk in one group and the risk in the other) into one. However, this feature also represents their major weakness, that the underlying absolute risks are concealed and readers tend to overestimate the effect when it is presented in relative terms. In many situations, the absolute risk gives a better representation of the actual situation and also from the patient's point of view absolute risks often give more relevant information. In this article, we explain the concepts of both relative and absolute risk measures. Using examples from nephrology literature we illustrate that unless ratio measures are reported with the underlying absolute risks, readers cannot judge the clinical relevance of the effect. We therefore recommend to report both the relative risk and the absolute risk with their 95% confidence intervals, as together they provide a complete picture of the effect and its implications. PMID- 28339911 TI - A null variant in the apolipoprotein L3 gene is associated with non-diabetic nephropathy. AB - Background: Inheritance of apolipoprotein L1 gene (APOL1) renal-risk variants in a recessive pattern strongly associates with non-diabetic end-stage kidney disease (ESKD). Further evidence supports risk modifiers in APOL1-associated nephropathy; some studies demonstrate that heterozygotes possess excess risk for ESKD or show earlier age at ESKD, relative to those with zero risk alleles. Nearby loci are also associated with ESKD in non-African Americans. Methods: We assessed the role of the APOL3 null allele rs11089781 on risk of non-diabetic ESKD. Four cohorts containing 2781 ESKD cases and 2474 controls were analyzed. Results: Stratifying by APOL1 risk genotype (recessive) and adjusting for African ancestry identified a significant additive association between rs11089781 and ESKD in each stratum and in a meta-analysis [meta-analysis P = 0.0070; odds ratio (OR) = 1.29]; ORs were consistent across APOL1 risk strata. The biological significance of this association is supported by the finding that the APOL3 gene is co-regulated with APOL1, and that APOL3 protein was able to bind to APOL1 protein. Conclusions: Taken together, the genetic and biological data support the concept that other APOL proteins besides APOL1 may also influence the risk of non diabetic ESKD. PMID- 28339915 TI - The effect of feed supplementation with Zakarpacki zeolite (clinoptilolite) on percentages of T and B lymphocytes and cytokine concentrations in poultry. AB - The available literature lacks information on the effect of Zakarpacki zeolite (clinoptilolite) on the immune system of poultry. Therefore, the aim of this study was to determine the effect of this zeolite on selected indicators of the immune response in poultry by evaluating the expression of cluster of differentiation (CD) surface molecules on T and B lymphocytes and the concentration of IL-2 and IL-10 in the blood. Ninety one-day-old Ross 308 broiler chicks were used in the study. The birds were divided into 3 groups of 30 each. The same basic diet was used in all groups, but groups II and III received a feed additive in the form of 2% and 3% zeolite. Blood samples were collected from all birds on the 40th day of observations. Weight gain in the birds in both experimental groups was significantly higher, and no clinical symptoms of disease were observed. The percentage of CD4+CD25+ T and B lymphocytes was higher in both groups receiving zeolite, but the percentage of CD8+CD25+ T lymphocytes was higher only in the group receiving 3% zeolite. There were no differences between the groups in the percentage of cells with CD3+ and MHC Class II expression. Higher serum concentrations of IL-2 and IL-10 were noted only in group III. The use of zeolites enhances antigen presentation and leads to increased Th1 and Th2 response. Excessive supply of zeolite in the feed leads to a local inflammatory response, which may cause damage to the intestinal barrier. PMID- 28339916 TI - Antenatal Tobacco Use and Secondhand Smoke Exposure in the Home in India. AB - Introduction: Antenatal tobacco use and secondhand smoke (SHS) exposure can have grave health consequences. We estimated the prevalence of tobacco use and SHS exposure in the home among pregnant and reproductive age women in India, and identified sociodemographic risk factors. Methods: Data were from the National Family Health Survey-3 (2005-2006), a population-based cross-sectional survey. We measured current tobacco use and SHS exposure in the home, and used logistic regression analysis to identify sociodemographic risk factors. Results: Nationally, antenatal tobacco use and SHS exposure in the home were reported by 9% and 25% of women, respectively. Tobacco use rates were slightly higher in reproductive age women (11%) than in pregnant women (9%). Common risk factors for tobacco use in pregnant and reproductive age women included older age, lower education, lower socioeconomic status, Scheduled Tribe status, Muslim religion, and rural residence. Being married lowered the risk of tobacco use among pregnant women, but increased the risk among reproductive age women. Antenatal SHS exposure decreased with older age and higher socioeconomic status. Conclusions: Antenatal tobacco use and SHS exposure in the home is a significant public health problem in India. Programs should target low socioeconomic status pregnant women, including single pregnant mothers. Implications: Antenatal tobacco use and SHS exposure in the home are significant public health problems in India. Intervention strategies should target younger women, single and socioeconomically disadvantaged pregnant women. PMID- 28339914 TI - Infant Colonization With Methicillin-Resistant Staphylococcus aureus or Vancomycin-Resistant Enterococci Preceding Neonatal Intensive Care Unit Discharge. AB - Rates of colonization with methicillin-resistant Staphylococcus aureus (MRSA) and/or vancomycin-resistant enterococci (VRE) were determined for 1320 infants within 7 days of neonatal intensive care unit discharge. Overall, 4% and 1% of the infants were colonized with MRSA or VRE, respectively. Predictors identified in fixed-effects models were surgery during hospitalization (for MRSA colonization) and prolonged antimicrobial treatment (for VRE colonization). PMID- 28339918 TI - Can clinically relevant dose errors in patient anatomy be detected by gamma passing rate or modulation complexity score in volumetric-modulated arc therapy for intracranial tumors? AB - We investigated whether methods conventionally used to evaluate patient-specific QA in volumetric-modulated arc therapy (VMAT) for intracranial tumors detect clinically relevant dosimetric errors. VMAT plans with coplanar arcs were designed for 37 intracranial tumors. Dosimetric accuracy was validated by using a 3D array detector. Dose deviations between the measured and planned doses were evaluated by gamma analysis. In addition, modulation complexity score for VMAT (MCSv) for each plan was calculated. Three-dimensional dose distributions in patient anatomy were reconstructed using 3DVH software, and clinical deviations in dosimetric parameters between the 3DVH doses and planned doses were calculated. The gamma passing rate (GPR)/MCSv and the clinical dose deviation were evaluated using Pearson's correlation coefficient. Significant correlation (P < 0.05) between the clinical dose deviation and GPR was observed with both the 3%/3 mm and 2%/2 mm criteria in clinical target volume (D99), brain (D2), brainstem (D2) and chiasm (D2), albeit that the correlations were not 'strong' (0.38 < |r| < 0.54). The maximum dose deviations of brainstem were up to 4.9 Gy and 2.9 Gy for Dmax and D%, respectively in the case of high GPR (98.2% with 3%/3 mm criteria). Regarding MCSv, none of the evaluated organs showed a significant correlation with clinical dose deviation, and correlations were 'weak' or absent (0.01 < |r| < 0.21). The use of high GPR and MCSv values does not always detect dosimetric errors in a patient. Therefore, in-depth analysis with the DVH for patient-specific QA is considered to be preferable for guaranteeing safe dose delivery. PMID- 28339924 TI - The trans-Golgi Network and the Golgi Stacks Behave Independently During Regeneration After Brefeldin A Treatment in Tobacco BY-2 Cells. AB - The trans-Golgi network (TGN) plays an essential role in intracellular membrane trafficking. In plant cells, recent live-cell imaging studies have revealed the dynamic behavior of the TGN independent from the Golgi apparatus. In order to better understand the relationships between the two organelles, we examined their dynamic responses to the reagent brefeldin A (BFA) and their recovery after BFA removal. Golgi markers responded to BFA similarly over a range of concentrations, whereas the behavior of the TGN was BFA concentration dependent. The TGN formed aggregates at high concentrations of BFA; however, TGN proteins relocalized to numerous small vesicular structures dispersed throughout the cytoplasm at lower BFA concentrations. During recovery from weak BFA treatment, the TGN started to regenerate earlier than the completion of the Golgi. The regeneration of the two organelles proceeded independently of each other for a while, and eventually was completed by their association. Our data suggest that there is some degree of autonomy for the regeneration of the TGN and the Golgi in tobacco BY-2 cells. PMID- 28339925 TI - Effects of different storage time on hatching results and some egg quality characteristics of rock partridge (A. graeca) (management and production). AB - In this research, partridge eggs were stored during zero to 7, 8 to 14, 15 to 21, 22 to 28, 29 to 35 and 36 to 42 d, respectively. The effect of different egg storage periods on egg protein and moisture rates, mineral contents, and some egg quality and hatching characteristics were investigated. The extension of egg storage times didn't affect the external quality features like shell weight, shell thickness, and albumen rate, but it affected the yolk weight, yolk index, albumen index, and Haugh unit (P < 0.05). Yolk weight was increased and yolk index, albumen index, and Haugh unit values were decreased with the extension of storage time. Different storage times of partridge eggs did not have important effects on the protein rates. Protein and humidity rate of the eggs were 14.21 and 67.64%, respectively. There were some elements such as S, P, Na, K, and Ca, but Al, Cd, Co, Mo, and Pb could not be found in the partridge eggs. There is no effect of the storage time on the mineral content of the egg. Storage time had negative effect on fertility and hatchability after 21 d of storage d, but no effect on hatchability of fertile eggs. As this study showed, partridge eggs are resistant to long storage times, as partridge egg proteins can resist degradation in the optimum storage times. To determine egg degradation, the study should be focused on partridge eggshell features, which are responsible for degradation. As a result of this research, partridge eggs can be stored for 21 d under optimum storage conditions without any negative hatchability results. PMID- 28339923 TI - Measuring patient experience: a systematic review to evaluate psychometric properties of patient reported experience measures (PREMs) for emergency care service provision. AB - Purpose: Knowledge about patient experience within emergency departments (EDs) allows services to develop and improve in line with patient needs. There is no standardized instrument to measure patient experience. The aim of this study is to identify patient reported experience measures (PREMs) for EDs, examine the rigour by which they were developed and their psychometric properties when judged against standard criteria. Data sources: Medline, Scopus, CINAHL, PsycINFO, PubMed and Web of Science were searched from inception to May 2015. Study selection: Studies were identified using specific search terms and inclusion criteria. A total of eight articles, reporting on four PREMs, were included. Data extraction: Data on the development and performance of the four PREMs were extracted from the articles. The measures were critiqued according to quality criteria previously described by Pesudovs K, Burr JM, Harley C, et al. (The development, assessment, and selection of questionnaires. Optom Vis Sci 2007;84:663-74.). Results: There was significant variation in the quality of development and reporting of psychometric properties. For all four PREMs, initial development work included the ascertainment of patient experiences using qualitative interviews. However, instrument performance was poorly assessed. Validity and reliability were measured in some studies; however responsiveness, an important aspect on survey development, was not measured in any of the included studies. Conclusion: PREMS currently available for use in the ED have uncertain validity, reliability and responsiveness. Further validation work is required to assess their acceptability to patients and their usefulness in clinical practice. PMID- 28339926 TI - Study on the expression of human lysozyme in oviduct bioreactor mediated by recombinant avian adeno-associated virus. AB - Due to its antimicrobial properties and low toxicity, human lysozyme (hLYZ) has broad application in the medical field and as a preservative used by the food industry. However, limited availability hinders its widespread use. Hence, we constructed a recombinant avian adeno-associated virus (rAAAV) that would specifically express hLYZ in the chicken oviduct and harvested hLYZ from the egg whites of laying hens. The oviduct-specific human lysozyme expression cassette flanked by avian adeno-associated virus (AAAV) inverted terminal repeats (ITRs) was subcloned into the modified baculovirus transfer vector pFBX, and then the recombinant baculovirus rBac-ITRLYZ was generated. The recombinant avian adeno associated virus was produced by co-infecting Sf9 cells with rBac-ITRLYZ and the other 2 baculoviruses containing AAAV functional genes and structural genes, respectively. Electron microscopy and real-time PCR revealed that the recombinant viral particles were generated successfully with a typical AAAV morphology and a high titer. After one intravenous injection of each laying hen with 2 * 1011 viral particles, oviduct-specific expression of recombinant human lysozyme (rhLYZ) was detected by reverse transcription-PCR. The expression level of rhLYZ in the first wk increased to 258 +/- 11.5 MUg/mL, reached a maximum of 683 +/- 16.4 MUg/mL at the fifth wk, and then progressively declined during the succeeding 7 wk of the study. Western blotting indicated that the oviduct expressed rhLYZ had the same molecular weight as the natural enzyme. These results indicate that an efficient and convenient oviduct bioreactor mediated by rAAAV has been established, and it is useful for production of other recombinant proteins. PMID- 28339927 TI - Characterizing the early inflammatory contribution of the donor kidney following reperfusion. AB - Background: Donor kidneys contain a large reservoir of passenger leucocytes that contribute to acute rejection via direct alloantigen presentation and pro inflammatory cytokine secretion. However, the early contribution of these cells following revascularization has not previously been described. We performed a secondary, high-volume preservation flush following cold storage to characterize the inflammatory contribution of the donor kidney upon reperfusion. Methods: Porcine kidneys were retrieved using a protocol analogous to current UK clinical practice. Following 2 h of cold static preservation, kidneys underwent a secondary flush with Ringer's solution. The venous effluent was collected and leucocytes phenotyped via flow cytometry. Inflammatory mediators, including cytokines and cell-free DNA, were then assessed to determine the inflammatory contribution of the donor kidney. Results: Upon reperfusion, a significant population of donor-derived CD45 + leucocytes mobilized from the renal vasculature via the renal vein [mean 4.738 * 10 8 (SD 1.348 * 10 8 )]. Within this population, T cells were dominant, representing >60% of the leucocyte repertoire. Granulocytes, monocytes and natural killer cells were also identified, but in comparatively lower numbers. Significant concentrations of cytokines and cell-free DNA were also eluted upon reperfusion. Conclusions: The donor kidney contains a significant immune load that rapidly mobilizes following reperfusion. Performing a secondary preservation flush prior to implantation may reduce this inflammatory burden via diversion of donor leucocytes and inflammatory mediators from entry into the recipient circulation. This may modulate direct presentation and reduce the inflammatory contribution of the donor kidney following transplantation. PMID- 28339928 TI - Opioid Use in Chronic Pain Patients with Chronic Kidney Disease: A Systematic Review. AB - Objectives: To investigate the prevalence of chronic pain and opioid management among patients with chronic kidney disease (CKD). Design: Systematic review. Methods: A systematic search was performed, including citations from 1960 to May 2015. The review highlights methodological quality assessment of the selected studies; prevalence of pain; type, dose, and reason for opioid use; effectiveness of pain control and associated adverse effects of opioids in CKD patients. Results: Twelve of 131 articles met inclusion criteria. There were no randomized controlled trials (RCT) evaluable, and 12 were observational studies. Out of 12 studies, four were of high quality, six were of moderate quality, and the remaining two were low-quality studies. The studies were from different countries with sample size ranging from 10 to 12,782. Several studies showed a high prevalence of chronic uncontrolled pain. The effectiveness of different categories of opioids, dose, duration, and commonly prescribed opioids varied across studies. Conclusions: Based on a systematic review of the current literature, there is fair evidence for the high prevalence of chronic pain among patients with CKD, which is not being effectively managed, probably due to underprescription of analgesics or opioids in the CKD population. Clinicians are in need of additional and well-designed randomized control trials that focus on the indications for opioid therapy, appropriate opioid doses and dosing intervals, outcomes with adequacy of symptom control, and reporting on the incidence of adverse side effects. PMID- 28339930 TI - Comment on: Diagnosing and attributing neuropsychiatric events to systemic lupus erythematosus: time to untie the Gordian knot? PMID- 28339929 TI - Dietary resveratrol supplementation prevents transport-stress-impaired meat quality of broilers through maintaining muscle energy metabolism and antioxidant status. AB - This experiment was to evaluate the effect of dietary resveratrol (Res) supplementation (0, 400 mg/kg) on growth performance, meat quality, and muscle anaerobic glycolysis and antioxidant capacity of transported broilers. A total of 360 21-day-old male Cobb broilers was randomly allotted to 2 dietary treatments (Res-free group and Res group) with 12 replicates of 15 birds each. On the morning of d 42, after a 9-hour fast, 24 birds (2 birds of each replicate) were selected from the Res-free group and then equally placed into 2 crates, and the other 12 birds (one bird of each replicate) were selected from the Res group and then placed into the other crate. All birds in the 3 crates were transported according to the following protocols: 0-hour transport of birds in the Res-free group (control group), 3-hour transport of birds in the Res-free group (T group), and 3-hour transport of birds in the Res group (T + Res group). The results showed that Res not only improved feed conversion ratio (P < 0.05) but also tended to improve birds' final body weight (P < 0.10). In the Res-free group, a 3 hour transport increased serum corticosterone concentration, muscle malondialdehyde (MDA) and lactate contents, and muscle lactate dehydrogenase (LDH) activity, while it decreased muscle glycogen content, total superoxide dismutase (T-SOD), and glutathione peroxidase (GSH-PX) activities (P < 0.05), which induced decreased breast meat quality (lower pH24h and higher drip loss and L*24 h, P < 0.05). Nevertheless, compared with the T group, Res increased muscle glycogen content and T-SOD and GSH-PX activities (P < 0.05 or P < 0.10), while it decreased muscle MDA content and LDH activity (P < 0.05), which is beneficial to the meat quality maintenance of transported broilers (lower drip loss, L*24 h, and higher pH24h, P < 0.05 or P < 0.10). This study provides the first evidence that dietary resveratrol supplementation prevents transport-stress-impaired meat quality of broilers, possibly through decreasing the muscle anaerobic glycolysis metabolism and improving the muscle antioxidant capacity. PMID- 28339932 TI - Utilizing patient geographic information system data to plan telemedicine service locations. AB - Objective: To understand potential utilization of clinical services at a rural integrated health care system by generating optimal groups of telemedicine locations from electronic health record (EHR) data using geographic information systems (GISs). Methods: This retrospective study extracted nonidentifiable grouped data of patients over a 2-year period from the EHR, including geomasked locations. Spatially optimal groupings were created using available telemedicine sites by calculating patients' average travel distance (ATD) to the closest clinic site. Results: A total of 4027 visits by 2049 unique patients were analyzed. The best travel distances for site groupings of 3, 4, 5, or 6 site locations were ranked based on increasing ATD. Each one-site increase in the number of available telemedicine sites decreased minimum ATD by about 8%. For a given group size, the best groupings were very similar in minimum travel distance. There were significant differences in predicted patient load imbalance between otherwise similar groupings. A majority of the best site groupings used the same small number of sites, and urban sites were heavily used. Discussion: With EHR geospatial data at an individual patient level, we can model potential telemedicine sites for specialty access in a rural geographic area. Relatively few sites could serve most of the population. Direct access to patient GIS data from an EHR provides direct knowledge of the client base compared to methods that allocate aggregated data. Conclusion: Geospatial data and methods can assist health care location planning, generating data about load, load balance, and spatial accessibility. PMID- 28339933 TI - Effect of heat stress on amino acid digestibility and transporters in meat-type chickens. AB - The present study was conducted to investigate the effect of heat stress (HS) on performance, digestibility, and molecular transporters of amino acids in broilers. Cobb 500 chicks were raised from hatch till 13 d in floor pens. At d 14, 48 birds were randomly and equally divided between a control group (25 degrees C) and a HS treatment group (35 degrees C). Birds in both treatment classes were individually caged and fed ad libitum on a diet containing 18.7% CP and 3,560 Kcal ME/Kg. Five birds per treatment at one and 12 d post treatment were euthanized and the Pectoralis major (P. major) and ileum were sampled for gene expression analysis. At d 33, ileal contents were collected and used for digestibility analysis. Broilers under HS had reduced growth and feed intake compared to controls. Although the apparent ileal digestibility (AID) was consistently higher for all amino acids in the HS group, it was not significant except for hydroxylysine. The amino acid consumption and retention were significantly lower in the HS group when compared to the control group. Meanwhile, the retention of amino acids per BWG was higher in the HS group when compared to the control group except for hydroxylysine and ornithine. The dynamics of amino acid transporters in the P. major and ileum was influenced by HS. In P. major and ileum tissues at d one, transporters SNAT1, SNAT2, SNAT7, TAT1, and b0,+AT, were down-regulated in the HS group. Meanwhile, LAT4 and B0AT were down-regulated only in the P. major in the treatment group. The amino acid transporters B0AT and SNAT7 at d 12 post HS were down-regulated in the P. major and ileum, but SNAT2 was down-regulated only in the ileum and TAT1 was down regulated only in the P. major compared with the control group. These changes in amino acid transporters may explain the reduced growth in meat type chickens under heat stress. PMID- 28339934 TI - Designing a Patient Empowerment Program for Chinese Immigrants. PMID- 28339935 TI - Nephrotoxicity of anticancer treatment. AB - Severe adverse systemic drug events occur commonly as a result of treatment of cancer patients. Nephrotoxicity of chemotherapeutic agents remains a significant complication limiting the efficacy of the treatment. A variety of renal disease and electrolyte disorders can result from the drugs that are used to treat malignant disease. The kidneys are a major elimination pathway for many antineoplastic drugs and their metabolites. Tumour lysis syndrome, an emergency in haematooncology, occurs most often after the initiation of cytotoxic therapy in patients with high-grade lymphomas and acute lymphoblastic leukaemia. Chemotherapeutic agents can affect the glomerulus, tubules, interstitium and renal microvasculature, with clinical manifestations that range from asymptomatic elevation of serum creatinine to acute renal failure requiring dialysis. Some factors such as intravascular volume depletion, as well as concomitant use of other drugs or radiographic ionic contrast media, can potentiate or contribute to the nephrotoxicity. Cytotoxic agents can cause nephrotoxicity by a variety of mechanisms. The most nephrotoxic chemotherapeutic drug is cisplatin, which is often associated with acute kidney injury. Many other drugs such as alkylating agents, antimetabolites, vascular endothelial growth factor pathway inhibitors and epidermal growth factor receptor pathway inhibitors may have toxic effects on the kidneys. The aim of this review is to discuss the issue of nephrotoxicity associated with chemotherapy. In routine clinical practice, monitoring of kidney function is mandatory in order to identify nephrotoxicity early, allowing dosage adjustments or withdrawal of the offending drug. PMID- 28339938 TI - Optimally predicting mortality with kidney function markers is not the same as optimally determining how kidney function predicts mortality. PMID- 28339939 TI - Developmental morphology study on the stomach of African ostrich chicks. AB - This study investigates the developmental morphology changes on the proventriculus and gizzard of African ostrich chicks using gross anatomy, and light and transmission electronic microscopy. The body weight; the weight of the proventriculus and gizzard; the thickness of simple tubular glands, muscularis mucosae, compound tubular glands, and muscular layer of the proventriculus; and the thickness of the gizzard glands and muscularis mucosae were measured on postnatal d one, 45, 90, and 334. Under transmission electronic microscopy, the oxynticopeptic cells, mucous cells, and endocrine cells were observed in the proventriculus on postnatal d one, 45, and 90. Our results revealed that the weights of the proventriculus and gizzard (relative to the body weight) both peaked on d 90, respectively, and declined thereafter. The thicknesses of the simple tubular glands, muscularis mucosae, compound tubular glands, muscular layer of the proventriculus, and gizzard glands increased with increasing bird age. However, the thickness of the muscularis mucosae in the gizzard peaked on d 90 and gradually decreased thereafter. The result of transmission electron microscopy revealed that the glands in the submucosa layer of the proventriculus did not differ from other cell types, aside from an increase in cell diameter and an increase in cytoplasmic content. A significant increase in the number of mitochondria and smooth endoplasmic reticulum was noted, as well as an in granules secreted by endocrine cells. Therefore, to improve brood rates of reared African ostrich chicks, feed management ought to be enhanced between postnatal d one and day 90. PMID- 28339937 TI - Uterine artery leptin receptors during the ovarian cycle and pregnancy regulate angiogenesis in ovine uterine artery endothelial cells?. AB - Leptin regulates body weight, reproductive functions, blood pressure, endothelial function, and fetoplacental angiogenesis. Compared to the luteal phase, the follicular phase and pregnancy are physiological states of elevated estrogen, angiogenesis, and uterine blood flow (UBF). Little is known concerning regulation of uterine artery (UA) angiogenesis by leptin and its receptors. We hypothesized that (1) ex vivo expression of leptin receptors (LEPR) in UA endothelium (UAendo) and UA vascular smooth muscle (UAvsm) is elevated in pregnant versus nonpregnant (Luteal and Follicular) sheep; (2) in vitro leptin treatments differentially modulate mitogenesis in uterine artery endothelial cells from pregnant (P-UAECs) more than in nonpregnant (NP-UAECs) ewes; and (3) LEPR are upregulated in P-UAECs versus NP-UAECs in association with leptin activation of phospho-STAT3 signaling. Local UA adaptations were evaluated using a unilateral pregnant sheep model where prebreeding uterine horn isolation (nongravid) restricted gravidity to one horn. Immunolocalization revealed LEPR in UAendo and UAvsm from pregnant and nonpregnant sheep. Contrary to our hypothesis, western analysis revealed that follicular UAendo and UAvsm LEPR were greater than luteal, nongravid, gravid, and control pregnant. Compared to pregnant groups, LEPR were elevated in renal artery endothelium of follicular and luteal sheep. Leptin treatment significantly increased mitogenesis in follicular phase NP-UAECs and P-UAECs, but not luteal phase NP-UAECs. Although UAEC expression of LEPR was similar between groups, leptin treatment only activated phospho-STAT3 in follicular NP-UAECs and P-UAECs. Thus, leptin may play an angiogenic role particularly in preparation for the increased UBF during the periovulatory period and subsequently to meet the demands of the growing fetus. PMID- 28339940 TI - Restrictions on the use of e-cigarettes in public and private places-current practice and support among adults in Great Britain. AB - Background: Debates around policies regulating e-cigarette use make it important to obtain an overview of current practice, people's attitudes and correlates of policy support. Aims were to assess (i) current practices for e-cigarette use in homes and workplaces; (ii) characteristics associated with allowing e-cigarette use in the home; and (iii) level of, and characteristics associated with, support for extending smoke-free legislation to include e-cigarettes. Methods: Online survey in 2016, n = 11 389 adults in Great Britain. Descriptives for all measures; multivariable logistic regressions assessed correlates of allowing e cigarette use and support for extension of legislation. Results: Most (79%) reporting on workplace policies reported some level of restrictions on e cigarette use. Small majorities would not allow e-cigarette use in their home (58%) and supported an extension of smoke-free legislation (52%; 21% opposed). Allowing use was less likely and supporting an extension more likely among men, respondents from a higher socio-economic status, ex-smokers, never-smokers, non users of e-cigarettes and respondents with increased perceived harm of e cigarettes or nicotine (all P < 0.001). Older respondents were less likely to allow use and to support an extension and Labour voters more likely to allow use. Conclusions: In Great Britain, the majority of workplaces has policies restricting e-cigarette use. Over half of adults would not allow use of e cigarettes in their home and support prohibiting the use of e-cigarettes in smoke free places. Adjusting for socio-demographics, more restrictive attitudes are more common among never-smokers, never-users and those with increased perception of relative harms of e-cigarettes or nicotine as cause of smoking-related illness. PMID- 28339942 TI - Diospyrobezoar and a fondness for persimmons. PMID- 28339941 TI - Productive performance, egg quality, and hatching traits of Japanese quail reared under different levels of glycerin. AB - This study evaluated subsequent effects of glycerin on productive performance, egg quality, and hatching traits in Japanese quail. A total of 200 birds was arranged according to a completely randomized design into 5 treatment groups having 5 replicates of 8 birds each (6 females and 2 males). Treatments consisted 5 levels of glycerin, i.e., 2.5, 5, 7.5, and 10% and the control group. Birds were fed with different levels of glycerin during a rearing period of 6 wk and their subsequent effects on productive performance, egg quality, and hatching traits were observed. Data were collected regarding productive performance for 16 wk; however, egg quality and hatching traits were recorded during pre-peak (at fourth wk), peak (at 12th wk), and post peak (at 16th wk) phase. Productive performance, egg quality, and hatching traits did not differ significantly throughout the experimental period. It was concluded that glycerin can be used as a replacement energy source, having no effect on productive and reproductive performance in Japanese quail. PMID- 28339944 TI - Exploring Relationships between Body Appreciation and Self-Reported Physical Health among Young Women. AB - Body image, a multidimensional construct, affects women in myriad ways. Existing scholarship has established a relationship between body image and negative mental and sexual health outcomes and suggests that it may also be related to physical health outcomes. The purpose of the study reported in this article was to explore relationships between body appreciation, a multidimensional measure of body image, and self-perceived physical health among a sample of emerging adult women (N = 399). In this sample, body appreciation was positively and significantly related to self-perceived physical health. This study contributes to a growing body of literature on the consequences of body image among women and can be used to inform interventions aimed at improving the well-being of women. PMID- 28339945 TI - Single-site ventricular pacing via the coronary sinus in patients with tricuspid valve disease. AB - Aims: To evaluate coronary sinus single-site (CSSS) left ventricular pacing in adult patients with normal left ventricular ejection fraction (LVEF) when traditional right ventricular lead implantation is not feasible or is contraindicated. Methods and results: We performed a retrospective analysis of 23 patients with tricuspid valve surgery/disease who received a CSSS ventricular pacing lead to avoid crossing the tricuspid valve. Two matched control populations were obtained from patients receiving (i) conventional right ventricular single-site (RVSS) leads and (ii) coronary sinus leads for cardiac resynchronization therapy (CSCRT). Main outcomes of interest were lead stability, electrical lead parameters and change in LVEF during long-term follow-up. Successful CSSS pacing was accomplished in all 23 patients without any procedural complications. During the 5.3 +/- 2.8-year follow-up 22/23 (95.7%) leads were functional with stable pacing and sensing parameters, and 1/23 (4.3%) was extracted for unrelated reasons. Compared to CSSS leads, the lead revision/abandonment was similar with RVSS leads (Hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.03, 22.0), but was higher with CSCRT leads (HR 7.41, 95% CI 1.30, 139.0). There was no difference in change in LVEF between CSSS and RVSS groups (-2.4 +/- 11.0 vs. 1.5 +/- 12.8, P = 0.76), but LVEF improved in CSCRT group (11.2 +/- 16.5%, P = 0.002). Fluoroscopy times were longer during implantation of CSSS compared to RVSS leads (25.6 +/- 24.6 min vs. 12.3 +/- 18.6 min, P = 0.049). Conclusion: In patients with normal LVEF, single-site ventricular pacing via the coronary sinus is a feasible, safe and reliable alternative to right ventricular pacing. PMID- 28339946 TI - Pasture flock chicken cecal microbiome responses to prebiotics and plum fiber feed amendments. AB - When prebiotics and other fermentation substrates are delivered to animals as feed supplements, the typical goal is to improve weight gain and feed conversion. In this work, we examined pasture flock chicken cecal contents using next generation sequencing (NGS) to identify and understand the composition of the microbiome when prebiotics and fermentation substrates were supplemented. We generated 16S rRNA sequencing data for 120 separate cecal samples from groups of chickens receiving one of 3 prebiotics or fiber feed additives. The data indicated that respective feed additives enrich for specific bacterial community members and modulate the diversity of the microbiome. We applied synthetic learning in microbial ecology (SLiME) analysis to interpret 16S rRNA microbial community data and identify specific bacterial operational taxonomic units (OTU) that are predictive of the particular feed additives used in these experiments. The results suggest that feed can influence microbiome composition in a predictable way, and thus diet may have indirect effects on weight gain and feed conversion through the microbiome. PMID- 28339947 TI - Nitrogen-corrected apparent metabolizable energy values of barley varies by treatment and species. AB - The aim of this study was to evaluate the effects of two species of poultry (cockerel and Japanese quail), two levels of enzyme (0 and 0.5 g/kg), and 6 processing methods (control (C), gamma irradiation 25 (GI25), and 50 kGy (GI50), autoclaving (AU), fermentation without lactobacillus (F), and fermentation with lactobacillus (FL)) on the nitrogen-corrected apparent metabolizable energy (AMEn) of barley. In this experiment, each processing method was tested at two levels of enzyme (0 and 0.5 g/kg) in six replications with two cockerels or four quails per replication. The results showed that the AMEn values by barley processing methods were: C-11.45 and 12.27; GI25-11.50 and 11.30; GI50-11.49 and 11.29; AU-11.70 and 11.46; F-12.90 and 12.30; FL-1295 and 12.51 MJ/kg in cockerels and quails, respectively. The AMEn (11.49 MJ/kg) of enzyme 0 was significantly lower than that of enzyme 0.5 (12.35 MJ/kg). There was a significant difference in the AMEn of processed barley between cockerels and quails. In conclusion, the most effective processing method of barley for AMEn is fermentation with lactobacillus and enzyme. PMID- 28339948 TI - Effects of dietary coarsely ground corn and 3 bedding floor types on broiler live performance, litter characteristics, gizzard and proventriculus weight, and nutrient digestibility. AB - The effects of zero or 50% dietary coarsely ground corn (CC) in pelleted and screened grower and finisher diets on broilers reared on 3 bedding floor types (plastic net [NET], new pine wood shavings litter [NEW], or old pine wood shavings litter [OLD]) on broiler live performance, litter characteristics, gizzard and proventriculus weight, and apparent ileal digestibility (AID) were studied in a 2 * 3 factorial arrangement of treatments. Fine corn was produced with a hammermill (271 MUm) and CC with a roller mill (1145 MUm). Utilization of CC reduced milling cost by 9.47 cents per MT with similar nutrient content of screened pellets. The 50% CC treatment exhibited improved (P <= 0.05) feed intake at 42 d (2.5%) and 49 d (3.0%), and BW (5.4%) and FCR from 28 d (1.4%). Birds on NEW litter exhibited improved (P < 0.05) BW at 28 and 35 d and 42 d FCR as compared to NET and 49 d FCR compared to NET and OLD. The 50% CC treatment exhibited increased (P < 0.05) gizzard weight but decreased proventriculus weight at 49 d. NEW litter birds exhibited increased (P <= 0.05) gizzard weight at 28 d and 49 d and decreased proventriculus weight as compared to NET at 49 days. The 50% CC treatment exhibited decreased (P <= 0.05) litter moisture at 35 and 42 d, litter N at 35 and 49 d, and litter pH at 49 days. OLD litter birds exhibited greater (P < 0.05) litter N at 14, 35, and 49 d, as well as litter moisture, pH, and ammonia concentration at 49 days. The 50% CC group also exhibited improved AID of nitrogen (P < 0.05). Broilers fed pelleted and screened diets containing 50% CC exhibited improved live performance and reduced litter moisture while use of NEW litter resulted in a somewhat similar effect, which indicated that consumption of NEW litter also facilitated gastric development and function. PMID- 28339949 TI - Bone biopsy practice patterns across Europe: the European renal osteodystrophy initiative-a position paper. AB - Renal osteodystrophy (ROD) is a heterogeneous group of metabolic bone diseases complicating progressive chronic kidney disease (CKD). Bone biomarkers and bone imaging techniques may help to assess bone health and predict fractures in CKD but do have important inherent limitations. By informing on bone turnover and mineralization, a bone biopsy may help to guide prevention and treatment of ROD and its consequences. According to a recent survey conducted among European nephrologists, bone biopsies are performed rather exceptionally, both for clinical and research purposes. Obviously, clinical research in the field of ROD is threatened by vanishing clinical and pathological expertise, small patient cohorts and scientific isolation. In March 2016, the European Renal Osteodystrophy (EU-ROD) initiative was created under the umbrella of the ERA-EDTA CKD-mineral and bone disorder (MBD) Working Group to revitalize bone biopsy as a clinically useful tool in the diagnostic workup of CKD-MBD and to foster research on the epidemiology, implications and reversibility of ROD. As such, the EU-ROD initiative aims to increase the understanding of ROD and ultimately to improve outcomes in CKD patients. PMID- 28339950 TI - Improving the quality of radiological examinations: effectiveness of an internal participatory approach. AB - Quality problem or issue: To assess the quality of radiological examinations (REs) and to evaluate the effectiveness of a participatory continuous improvement approach to ensure best practices in a Portuguese hospital imaging department. Initial assessment: At baseline, we found 232 (10.2%) non-compliances, mostly related to the criteria image centering and framing in chest radiography (CXR), proper use of radiological protection equipment in other conventional RE (CR) and X-ray beam collimation (CXR/CR). Choice of solution: A baseline and three consecutive evaluations of the RE quality were conducted. Each assessment was followed by participatory focused interventions for improvement. Implementation: For each evaluation, we selected a random sample (n = 60) of cases for four types of examination (total n = 240 for each assessment, and 960 for the whole project). Both the building of quality criteria and the design of interventions for improvement were participatory, involving the radiology technicians. Estimates of criteria compliance were calculated with 95% confidence intervals. The statistical significance of absolute and relative improvements was tested using one-tail z-tests. Evaluation: After the intervention, non-compliances decreased to 48 (2.1%). Compliance estimates improved in 25 of 38 criteria assessed, with statistical significance for 5 criteria in CXR and 3 in CR and digestive examination. Lessons learned: The internal participatory approach enabled the identification of existing quality problems and, by focusing on the more frequent quality defects, was effective in improving the quality of RE. PMID- 28339951 TI - Characterization of a hypervirulent fowl adenovirus 4 with the novel genotype newly prevalent in China and establishment of reproduction infection model of hydropericardium syndrome in chickens. AB - Severe hydropericardium syndrome (HPS) has been present in layers in the northeast of China since June 2015, with mortality rates varying from 30 to 90%. Dead layers had severe hydropericardium with pericardial volumes of 5 to 20 mL, as well as inclusion body hepatitis. Laboratory investigations led to the isolation of a fowl adenovirus strain, HLJFAd15, from the liver tissue of dead layers. Natural deletions of ORF19 and ORF27 were found in this clinical strain by complete genome sequencing, which was identified with the novel genotype recently prevalent in China. The pathogenicity characterization was conducted in 35-day-old SPF chickens using HLJFAd15 with novel genotype of fowl adenovirus serotype 4 (FAdV-4). The reproduction disease cases of HPS with mortality rates of 76.9% by oral administration and 100% by intramuscular injection were induced successfully by challenging SPF chickens, respectively. Non-enveloped viral particles with a mean diameter of approximately 80 nm were found in the livers of virus-infected SPF chickens. Our study revealed that HLJFAd15 was identified with the novel genotype strains recently emerging in China by complete genome sequencing, and the strain was capable of causing HPS by the pathogenicity analysis. However, although there is currently no commercial vaccine against the novel genotype FAdV-4, the animal infection model established in this study was valuable for vaccine evaluation and development. PMID- 28339952 TI - Value of multidisciplinary reassessment in attribution of neuropsychiatric events to systemic lupus erythematosus: prospective data from the Leiden NPSLE cohort. AB - Objective: To determine the contribution of reassessment in the attribution process of neuropsychiatric (NP) events to SLE or other aetiologies in a large, prospective and multidisciplinary assessed NPSLE cohort and to compare these results with other available attribution models for NP events occurring in SLE. Methods: Three hundred and four consecutive SLE patients presenting NP events were evaluated. All subjects underwent standardized multidisciplinary medical, neuropsychological, laboratory and radiological examination on the inclusion and reassessment dates. Diagnosis was always established by multidisciplinary consensus. The final diagnosis after reassessment also took into account disease course and response to treatment. These data were compared with currently available attribution models for NP events in SLE. Results: A total of 463 NP events were established. After reassessment, attribution to SLE was discordant in 64 (13.8%) NP events when compared with the first visit. We show that 14.5% of NP events previously attributed to SLE reclassified as non-NPSLE. In 86.4% of these patients immunosuppressive therapy was started after the first visit. When reassessment and available attribution models were compared, NPSLE cases overlapped considerably. Although specificity was high for all comparisons (0.81 0.95), an important variation in sensitivity (0.39-0.83) and agreement estimates (kappa = 0.29-0.68) was observed. The Italian algorithm showed the highest sensitivity and specificity (>0.80) and moderate agreement (0.59-0.64). Conclusion: In clinical practice NP events presenting in SLE are too often attributed to an immune-mediated origin. Multidisciplinary reassessment avoids misclassification in NPSLE. Multidisciplinary reassessment is the reference standard in NP events presenting in SLE and cannot be replaced by available attribution models. PMID- 28339955 TI - Procalcitonin in Childhood Pneumonia. PMID- 28339957 TI - Effects of caponization and age on the histology, lipid localization, and fiber diameter in muscles from Greenleg Partridge cockerels. AB - The preference of modern consumers for high-quality meat has forced breeders to use native breeds to produce capons. Caponization, both chemical and surgical, leads to androgen deficiency and changes in lipid metabolism and results in the accumulation of abdominal, subcutaneous, and intramuscular lipids, which change the sensory values of the meat. The aim of this study was to histologically evaluate selected skeletal muscles from Greenleg Partridge capons and cockerels. We examined lipid localization in the muscular tissue and also assessed both fiber type and fiber diameter in the pectoral muscles. The experiment was performed on 200 Greenleg Partridge cockerels and testes were removed at 8 wk of age. At 12, 16, 20, 24, and 28 wk of age, 6 cockerels and 6 capons were slaughtered, and samples from the pectoral and thigh muscles were evaluated. Our histopathological evaluation revealed only minimal changes, and no significant differences between capons and cockerels were observed. The pectoral and thigh muscles of the capons had higher concentrations of lipids around the blood vessels, in the perimysium, in the endomysium, and in the sarcoplasm. The analysis of fiber type in the Pectoralis major muscles revealed that the fibers were all the IIB type. The diameters of the fibers of the pectoral muscles were significantly different (P < 0.05) at 20, 24, and 28 wk of age, and diameters of the giant fibers were significantly different (P < 0.05) at 24 and 28 wk of age. High concentrations of lipids in the meat of the capons is undesirable due to health-related reasons. However, the ability of adipose tissue to improve the sensory values of meat will always be a major quality of native/traditional products. PMID- 28339958 TI - Postconditioning protects renal fibrosis by attenuating oxidative stress-induced mitochondrial injury. AB - Background: Epithelial-mesenchymal transition (EMT) plays a critical role in renal fibrosis. We hypothesize that mitochondrial DNA damage and DNA deletions caused by reactive oxygen species (ROS) during renal ischemia-reperfusion injury (IRI) might lead to EMT in renal fibrosis. Methods: Rats were classified into seven groups: sham-operation, IRI, postconditioning (POC), I/R + apocynin, POC + apocynin, I/R + Mito-Tempol (Mito-T) and POC + Mito-T. These groups were monitored for up to 3 months. Serum creatinine, renal histopathology changes and mitochondrial oxidative stress were examined. We also treated NRK52E cells with 200 MUM hydrogen peroxide to evaluate the effect of ROS on EMT development, and with 400 ng/mL ethidium bromide to assess the extent of mitochondrial DNA depletion during EMT. Results: Three months after IRI injury, the IRI group showed significant renal fibrosis, increased generation of ROS and higher mitochondrial DNA damage and DNA deletions. However, the severity of renal fibrosis and mitochondrial oxidative stress were markedly attenuated in the POC group. Studies on NRK52E cells showed that mitochondrial DNA damage triggered the development of EMT. Conclusions: Mitochondrial DNA damage induced by elevated ROS production likely leads to EMT, and might further result in renal fibrosis. POC treatment might attenuate the degree of renal fibrosis by protecting mitochondria from oxidative stress-induced mitochondrial DNA damage. PMID- 28339959 TI - Increased Evoked Potentials and Behavioral Indices in Response to Pain Among Individuals with Intellectual Disability. AB - Objective: Previous studies on the sensitivity and reactivity to pain of individuals with intellectual disability (ID) are inconsistent. The inconsistency may result from the reliance on self-reports and facial expressions of pain that are subject to internal and external biases. The aim was therefore to evaluate the reactivity to pain of individuals with ID by recording pain-evoked potentials (EPs), here for the first time, and testing their association with behavioral pain indices. Subject: Forty-one healthy adults, 16 with mild-moderate ID and 25 controls. Methods: Subjects received series of phasic heat stimuli and rated their pain on self-report scales. Changes in facial expressions and in pain EPs were recorded and analyzed offline. Results: Pain self-reports, facial expressions, and the N2P2 amplitudes of the EPs exhibited stimulus-response relationship with stimulation intensity in both groups. The facial expressions and N2P2 amplitudes of individuals with ID were increased and N2P2 latency prolonged compared with controls. N2P2 amplitudes correlated with self-reports only in controls. Conclusions: Individuals with ID are hypersensitive/reactive to pain, a finding bearing clinical implications. Although pain EPs may reflect a somewhat different aspect of pain than the behavioral indices do, there is evidence to support their use to record pain in noncommunicative individuals, pending further validation. PMID- 28339962 TI - FSTL3 is increased in renal dysfunction. AB - Background: Follistatin-like 3 (FSTL3) is a novel cytokine that regulates insulin sensitivity and counteracts activin/myostatin signalling. In the present study, regulation of FSTL3 in renal dysfunction was investigated in both human chronic kidney disease (CKD) and acute kidney dysfunction (AKD). Furthermore, mFSTL3 expression was analysed in insulin-sensitive tissues in a mouse model of CKD. Methods: Circulating FSTL3 was quantified by enzyme-linked immunosorbent assay in 581 patients with CKD covering the whole spectrum of estimated glomerular filtration rate (eGFR) categories from G1 to G5. Furthermore, FSTL3 was measured in 61 patients before and within 30 h after elective unilateral nephrectomy, an established model of AKD. Moreover, mFSTL3 mRNA expression was investigated in an animal CKD model, that is, eNOS-/-db/db mice, and compared with littermate controls. Results: Median circulating FSTL3 levels significantly and continuously increased with deteriorating renal function (eGFR category G1: 6.1; G2: 8.2; G3: 12.7; G4: 18.5; G5: 32.1 ug/L; P < 0.001). In both human CKD and AKD, renal dysfunction remained the strongest independent predictor of FSTL3 serum concentrations in multivariate analyses. FSTL3 was independently associated with an adverse cardiometabolic profile. In CKD mice, hepatic mFSTL3 mRNA expression was increased more than 6-fold as compared with controls. Conclusions: Circulating FSTL3 is significantly and independently associated with renal function in both patients with CKD and AKD. Hepatic mFSTL3 mRNA upregulation might contribute to increased FSTL3 levels in CKD. Our results are in agreement with the hypothesis that FSTL3 is eliminated by the kidneys and might counteract adverse activin/myostatin signalling observed in renal dysfunction. PMID- 28339963 TI - Anti-apoptotic effects of decyl gallate on the induction of apoptosis in A549 pneumocytes by Paracoccidioides brasiliensis gp43. AB - Apoptosis is considered an escape mechanism from the host immune system for the fungus Paracoccidioides spp, and it serves as a vehicle for entry into macrophages without stimulating microbicidal activities. Recently, gp43 of P. brasiliensis was demonstrated to be involved in this process. Therefore, as a new therapeutic alternative, it is very important to study compounds that could reduce the modulation of the induction of apoptosis caused by this fungus. Decyl gallate (G14) is a known antifungal compound, and we decided to investigate its anti-apoptotic properties. Our results demonstrate that G14 was effective against apoptosis induced by gp43, as observed in epithelial cells, and led to a reduction in DNA damage, Bak down-regulation and Bcl-2 up-regulation. Together, these data show that G14 presents promising anti-apoptotic activity. PMID- 28339964 TI - Treatment strategy and IDH status improve nomogram validity in newly diagnosed GBM patients. PMID- 28339965 TI - Opioid Prescriptions by Specialty in Ohio, 2010-2014. AB - Background: The current US opioid epidemic is attributed to the large volume of prescribed opioids. This study analyzed the contribution of different medical specialties to overall opioids by evaluating the pill counts and morphine milligram equivalents (MMEs) of opioid prescriptions, stratified by provider specialty, and determined temporal trends. Methods: This was an analysis of the Ohio prescription drug monitoring program database, which captures scheduled medication prescriptions filled in the state as well as prescriber specialty. We extracted prescriptions for pill versions of opioids written in the calendar years 2010 to 2014. The main outcomes were the number of filled prescriptions, pill counts, MMEs, and extended-released opioids written by physicians in each specialty, and annual prescribing trends. Results: There were 56,873,719 prescriptions for the studied opioids dispensed, for which 41,959,581 (73.8%) had prescriber specialty type available. Mean number of pills per prescription and MMEs were highest for physical medicine/rehabilitation (PM&R; 91.2 pills, 1,532 mg, N = 1,680,579), anesthesiology/pain (89.3 pills, 1,484 mg, N = 3,261,449), hematology/oncology (88.2 pills, 1,534 mg, N = 516,596), and neurology (84.4 pills, 1,230 mg, N = 573,389). Family medicine (21.8%) and internal medicine (17.6%) wrote the most opioid prescriptions overall. Time trends in the average number of pills and MMEs per prescription also varied depending on specialty. Conclusions: The numbers of pills and MMEs per opioid prescription vary markedly by prescriber specialty, as do trends in prescribing characteristics. Pill count and MME values define each specialty's contribution to overall opioid prescribing more accurately than the number of prescriptions alone. PMID- 28339966 TI - Operational challenges and opportunities in pastured poultry operations in the United States. AB - As pastured poultry production has gained increased popularity in the United States in recent years, there is a growing need for research and outreach efforts aimed at this sector of poultry production. In order to get familiarized with American pastured poultry producers, we conducted an online questionnaire aimed primarily at evaluating what operational challenges are faced by producers and what educational opportunities should be initiated by researchers. Results showed that pastured poultry farms largely vary in total number of acres farmed and total number of birds kept. The vast majority of farms (96%) rotate their flocks on pasture and include livestock species (78%) in their rotation systems. Mobile coops are the preferred housing option provided by producers (88%). The most common source of mortality listed by respondents was predation (52%), followed by "other" (32%). However, predation was not selected as the most important challenge by the majority of respondents. Sixty-four percent of participants instead mentioned providing adequate feed at reasonable cost as the major challenge in raising poultry on pasture, followed again by "other" (52%) and lack of processing facilities for small numbers of birds (40%). Finally, the topics considered by respondents as the most helpful to learn more about were how to improve egg production rate and/or feed conversion ratio (67%), followed by how to improve pasture condition and optimum vegetative cover all year round (62%). Despite its small sample size, this study's results provide some valuable insights of challenges encountered and information needed on pastured poultry farms. PMID- 28339968 TI - Optimization of dietary zinc for egg production and antioxidant capacity in Chinese egg-laying ducks fed a diet based on corn-wheat bran and soybean meal. AB - The aim of this study was to evaluate the effect of zinc supplementation on productive performance and antioxidant status in laying ducks. Five-hundred-four laying ducks were divided into 7 treatments, each containing 6 replicates of 12 ducks. The ducks were caged individually and fed a corn-soybean meal and wheat bran basal diet (37 mg Zn/kg) or the basal diet supplemented with 15, 30, 45, 60, 75, or 90 mg Zn/kg (as zinc sulfate). During the early laying period of 10 d (daily egg production <80%), egg production, daily egg mass, and FCR increased quadratically with increasing dietary Zn levels (P < 0.05). The highest egg production and daily egg weight were obtained when 30 or 45 mg Zn/kg diet was supplemented, with lowest FCR. Similarly, the highest egg production and daily egg mass were observed in the group supplemented with 30 or 45 mg Zn/kg during the peak laying period of the subsequent 120 d (daily egg production >80%). Average egg weight and feed intake did not differ among the groups of graded Zn supplementation.The egg quality was not affected by dietary Zn, including the egg shape index, Haugh unit, yolk color score, egg composition, and shell thickness. The activities of plasma activities of total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-PX) increased in a quadratic manner (P < 0.001) with increasing supplemental Zn. Plasma concentration of Zn increased quadratically (P < 0.05) as dietary Zn increased. The hepatic activity of Cu/Zn-SOD and GSH-PX increased quadratically (P < 0.05) with increasing dietary Zn. Plasma Zn concentrations were positively correlated with activities of T-SOD (P < 0.05), and positively with plasma Cu. Plasma concentration of reduced glutathione was correlated with plasma Cu. In conclusion, supplementation of Zn at 30 or 45 mg/kg to a corn-wheat bran and soybean basal diet may improve the productive performance and enhance the antioxidant capacity. PMID- 28339967 TI - Placental transporter localization and expression in the Human: the importance of species, sex, and gestational age differences?. AB - The placenta is a critical organ during pregnancy, essential for the provision of an optimal intrauterine environment, with fetal survival, growth, and development relying on correct placental function. It must allow nutritional compounds and relevant hormones to pass into the fetal bloodstream and metabolic waste products to be cleared. It also acts as a semipermeable barrier to potentially harmful chemicals, both endogenous and exogenous. Transporter proteins allow for bidirectional transport and are found in the syncytiotrophoblast of the placenta and endothelium of fetal capillaries. The major transporter families in the human placenta are ATP-binding cassette (ABC) and solute carrier (SLC), and insufficiency of these transporters may lead to deleterious effects on the fetus. Transporter expression levels are gestation-dependent and this is of considerable clinical interest as levels of drug resistance may be altered from one trimester to the next. This highlights the importance of these transporters in mediating correct and timely transplacental passage of essential compounds but also for efflux of potentially toxic drugs and xenobiotics. We review the current literature on placental molecular transporters with respect to their localization and ontogeny, the influence of fetal sex, and the relevance of animal models. We conclude that a paucity of information exists, and further studies are required to unlock the enigma of this dynamic organ. PMID- 28339969 TI - The quality of eggs (organic and nutraceutical vs. conventional) and their technological properties. AB - The aim of the study was to compare the quality of commercially available eggs: organic (attested organic farm) - OE, nutraceutical (enriched in n-3 fatty acids) - NE, vs. conventional (cage raising system) - CE and their technological (emulsifying) properties. Their basic chemical composition (i.e., moisture, protein, fat, ash) as well as mineral (Na, K, Ca, Mg, Zn, Fe, Mn, Cu) contents were assessed, and fatty acid profiles were determined. Next, the suitability of the eggs for mayonnaise production was assessed.The yolk of organic eggs contained the highest protein (17.7 g/100 g), K (134.7 mg/kg), and Cu (0.15 mg/kg) levels. Meanwhile, the yolk of conventional eggs was the most abundant in Mg (14.6 mg/kg) and Fe (9.05 mg/kg), and the nutraceutical ones - in Ca (109.0 mg/kg) as well as Mn (0.26 mg/kg). Albumen of organic eggs contained the highest level of protein (13.0 g/100 g), whereas the nutraceutical ones contained the highest levels of - ash (1.2 g/100 g), K (150.2 mg/kg), Zn (0.11 mg/kg), and Mn (0.04 mg/kg). Nutraceutical eggs contained a higher amount of n-3 and monounsaturated fatty acids but also smaller saturated fatty acids content. This beneficial fatty acids profile is particularly important from the nutritional point of view. Despite the lack of differences in emulsifying properties among the studied eggs, the mayonnaises prepared on the basis of the nutraceutical eggs showed better stability. This attribute is very important for both the producer (during product transport) and the consumer (during dish preparation). PMID- 28339971 TI - Intracardiac echocardiography catheter-guided zero fluoroscopy transeptal puncture technique for ablation of left-sided accessory pathway in a pregnant woman. PMID- 28339972 TI - Factors associated with sickness absence among employees with chronic conditions. AB - Background: The growing prevalence of chronic conditions in the ageing workforce has been shown to have a negative impact in terms of optimal work performance and quality of life. It is therefore important to understand the factors associated with sickness absence due to health problems. Aims: To examine the socio demographics, health status indicators, barriers to self-care and social support associated with working adults missing work because of chronic conditions. Methods: We analysed data from working adults in the USA with one or more chronic conditions who completed the National Council on Aging (NCOA) Chronic Care Survey. Analyses were performed using SPSS version 22; independent sample t-tests and chi-squared tests were used to compare sample characteristics and logistic regression was used to assess factors associated with missed work as a dichotomous outcome variable. Results: Among the 250 study subjects, employees who reported poorer general health status [odd ratio (OR) = 1.62, P < 0.05], more physician visits (OR = 1.45, P < 0.01), not having enough money for their health (OR = 3.69, P < 0.01) and a higher reliance on their co-workers (OR = 1.71, P < 0.05) were significantly more likely to report sickness absence due to their chronic conditions. Conclusions: To reduce absences among employees with chronic conditions, employers need to understand the importance of factors such as employee income, resources and knowledge of disease self-care. US employers should explore opportunities for employees to offset health care costs, apply appropriate time-flexible work policies and encourage employees' participation in health knowledge enhancing interventions. PMID- 28339973 TI - Day-to-Day Variability in Self-Reported Cigarettes Per Day. AB - Background and Aims: Nicotine addiction theory predicts small day-to-day variability in cigarettes/day (CPD) whereas social learning theory predicts large variability. A description of the variability in CPD over multiple days is not available. Methods: We conducted secondary analyses of two natural history studies with daily smokers-one of smokers not intending to quit, and one of smokers intending to quit sometime in the next 3 months. In the former, smokers recorded their smoking during the day by Ecological Momentary Assessment, using a palm-top computer. In the latter, participants reported CPD nightly via a phone Interactive Voice Response system. Analyses were based on smokers who reported averaging >=10 CPD, and on days in which there was no attempt to stop or reduce smoking. Results: Across the two studies, on average, smokers had small changes in day-to-day CPD (mean changes were 2.2 and 2.9 CPD). However a minority averaged changing by >=5 CPD from one day to the next (7% and 11%), and many changed by >=5 CPD on at least 10 of the 90 days (8% and 31%). Neither smoking restrictions, dependence, stereotypy ratings, nor interest in quitting predicted variability. Conclusion: Although on average, smokers have little change day-to day CPD, a substantial minority of smokers often change by 5 CPD from day-to-day. We did not find potential causes of this variability. Implications: Across day variability in CPD is larger than implied in prior studies. Determining causes of day-to-day variability should increase our understanding of the determinants of smoking. PMID- 28339975 TI - The Pain Interprofessional Curriculum Design Model. AB - Objective: Although the University of Toronto Centre for the Study of Pain has successfully implemented an Interfaculty Pain Curriculum since 2002, we have never formalized the process in a design model. Therefore, our primary aim was to develop a model that provided an overview of dynamic, interrelated elements that have been important in our experience. A secondary purpose was to use the model to frame an interactive workshop for attendees interested in developing their own pain curricula. Methods: The faculties from Dentistry, Medicine, Nursing, Occupational Therapy, Pharmacy, and Physical Therapy met to develop the model components. Discussion focused on patient-centered pain assessment and management in an interprofessional context, with pain content being based on the International Association for the Study of Pain-Interprofessional Pain Curriculum domains and related core pain competencies. Profession-specific requirements were also considered, including regulatory/course requirements, level of students involved, type of course delivery, and pedagogic strategies. Results: The resulting Pain Interprofessional Curriculum Design Model includes components that are dynamic, competency-based, collaborative, and interrelated. Key questions important to developing curricular components guide the process. The Model framed two design workshops with very positive responses from international and national attendees. Conclusions: The Pain Interprofessional Curriculum Design Model is based on established pain curricula and related competencies that are relevant to all health science students at the prelicensure (entry-to-practice) level. The model has been developed from our experience, and the components resonated with workshop attendees from other regions. This Model provides a basis for future interventions in curriculum design and evaluation. PMID- 28339976 TI - Effects of two different broiler flooring systems on production performances, welfare, and environment under commercial production conditions. AB - Research comparing conventional litter and alternative perforated flooring (netting) systems is relatively limited under commercial production conditions. A comprehensive comparison of broiler production performances, welfare quality, and housing environment of two broiler houses with conventional litter and new perforated plastic floors was conducted over four flocks for eight months in eastern China. The two broiler houses each had 31,700 broilers per flock on average and were ventilated using a negative-pressure system. Prior to the onset of the monitoring, litter/manure in all houses was removed. The environmental conditions, gaseous concentrations, and ventilation rate were recorded continuously. Production performance and welfare quality data were collected weekly. Results showed that indoor temperature and relative humidity were not affected by the different floors when the two houses had the same ventilation configuration and management. The average ammonia concentration was lower at 10.44 ppm in the litter house compared to 15.02 ppm in the netting flooring house due to the manure accumulation under the floor. Broiler production performance including live weight, feed conversion, and mortality, was not affected by the netting floor compared to the litter system. In addition, the results suggested that birds raised in the netting floor house may increase breast blister incidence. In this study, the welfare quality parameters including hock and foot pad lesions, lameness, and fearfulness levels were similar in both for both flooring systems. PMID- 28339977 TI - Large spherical left ventricular pseudoaneurysm: a very rare long-term complication of ablation of an accessory pathway. PMID- 28339978 TI - Ozone-Sensitive Arabidopsis Mutants with Deficiencies in Photorespiratory Enzymes. AB - An ozone-sensitive mutant was isolated from T-DNA-tagged lines of Arabidopsis thaliana. The T-DNA was inserted at a locus on chromosome 3, where two genes encoding glycolate oxidases, GOX1 and GOX2, peroxisomal enzymes involved in photorespiration, reside contiguously. The amounts of the mutant's foliar transcripts for these genes were reduced, and glycolate oxidase activity was approximately 60% of that of the wild-type plants. No difference in growth and appearance was observed between the mutant and the wild-type plants under normal conditions with ambient air under a light intensity of 100 umol photons m-2 s-1. However, signs of severe damage, such as chlorosis and ion leakage from the tissue, rapidly appeared in mutant leaves in response to ozone treatment at a concentration of 0.2 ul l-1 under a higher light intensity of 350 umol photons m 2 s-1 that caused no such symptoms in the wild-type plant. The mutant also exhibited sensitivity to sulfur dioxide and long-term high-intensity light. Arabidopsis mutants with deficiencies in other photorespiratory enzymes such as glutamate:glyoxylate aminotransferase and hydroxypyruvate reductase also exhibited ozone sensitivities. Therefore, photorespiration appears to be involved in protection against photooxidative stress caused by ozone and other abiotic factors under high-intensity light. PMID- 28339980 TI - Pushing the limits: establishing an ultra-low framerate and antiscatter grid-less radiation protocol for left atrial ablations. AB - Aims: Despite the use of 3D mapping systems and new developments of non fluoroscopic options, most centres still rely at least in part on fluoroscopy for catheter visualization during catheter ablations. The purpose of this study was to assess the feasibility of using an ultra-low frame rate and antiscatter grid less radiation protocol during complex left atrial ablations to minimize radiation exposure for the patient and staff. Methods and results: A total of 150 consecutive patients undergoing left atrial ablations in our hospital were included in the analysis. The procedures were performed between January 2015 and November 2016. Of the included patients 75 (50%) underwent ablation before and 75 (50%) after the ultra-low frame rate (reduced from 4 to 2 FPS) and antiscatter grid-less radiation protocol was established. Procedures performed after the dose reduction protocol was established showed a 64% reduction of the dose area product (630.28 +/- 550.96 vs. 226.44 +/- 277.44 uGym2, P < 0.001), while fluoroscopy duration (14.22 +/- 4.47 vs. 13.62 +/- 7.11 min, P = 0.066) and procedural duration (1:48 +/- 0:28 vs. 1:53 +/- 0:34 min, P = 0.525) were not prolonged. Acute procedural success was achieved in all procedures. Two complications occurred before and one complication after the protocol was established. During four procedures, operators decided to re-introduce the antiscatter grid. This was due to impaired visibility in morbidly obese patients (n = 2) or technically difficult transseptal puncture (n = 2). Conclusion: The use of an ultra low framerate and antiscatter grid-less radiation protocol effectively reduced radiation dose for complex left atrial ablation procedures and lead to very low average patient doses. Reduced image quality did not impair procedural and fluoroscopy duration or acute procedural success. PMID- 28339981 TI - Transcriptome analysis of comb and testis from Rose-comb Silky chicken (R1/R1) and Beijing Fatty wild type chicken (r/r). AB - Rose-comb was one of the chicken comb-variants first used by Bateson and Punnet in 1902 to demonstrate Mendelian inheritance in animals. Rose-comb is a monogenic trait that has been widely described in chickens. It is caused by a large structural rearrangement that leads to mis-expression of transcription factor MNR2 on chromosome 7. Rose-comb has pleiotropic effects in homozygous roosters, which is associated with poor sperm mobility. It was postulated that this is caused by the disruption of the CCDC108 gene located at the distal inversion breakpoint. In this study, we did the transcriptional profiling of combs and testes from Rose-comb Silky (RS) (R1/R1) and Beijing Fatty (BF) wild type chickens (r/r) using RNA-seq. We obtained 68,694,797 unique mapped reads and over 80% of the chicken genes were covered for each sample. In combs, we found that differentially expressed genes (DEGs) were significantly enriched in the retinol metabolism (RPE65, CYP26A1, and CYP26C1) and hedgehog-signaling pathway (PTCH1, GLI1, and HHIP), while genes related to cell differentiation and morphogenesis were down-regulated in R1/R1 chickens, suggesting that the transient expression of MNR2 might affect the expression of these genes and influence the development of comb tissue. For testes, DEGs were significantly enriched in the GO terms of binding activates and mitochondrial oxidation-reduction reactions. Our results suggested that the CCDC108 might be functionally related with mitochondrial oxidation-reduction reactions and caused subfertility of roosters. Compared with the genome average, the degree of expression variations within the inversion region did not show significant differences. However, DEGs near the breakpoints showed greater expression variance. Our results demonstrated that the large-scale rearrangements affected the gene expression only around the breakpoint in this case. PMID- 28339983 TI - ACR11 is an Activator of Plastid-Type Glutamine Synthetase GS2 in Arabidopsis thaliana. AB - Glutamine synthetase (GS) is an important enzyme for nitrogen assimilation, and GS2, encoded by GLN2, is the only plastid-type GS in Arabidopsis thaliana. A co expression analysis suggested that the expression level of the gene encoding a uridylyltransferase-like protein, ACR11, is strongly correlated with GLN2 expression levels. Here we showed that the recombinant ACR11 protein increased GS2 activity in vitro by reducing the Km values of its substrate glutamine. A T DNA insertion mutant of ACR11 exhibited a reduced GS activity under low nitrate conditions and reduced glutamine levels. Biochemical analyses revealed that ACR11 and GS2 interacted both in vitro and in vivo. These data demonstrate that ACR11 is an activator of GS2, giving it a mechanistic role in the nitrogen assimilation of A. thaliana. PMID- 28339984 TI - The link between phenotype and fatty acid metabolism in advanced chronic kidney disease. AB - Background: The kidney plays a central role in elimination of metabolic waste products and regulation of low-molecular weight metabolites via glomerular filtration, tubular secretion and reabsorption. Disruption of these processes results in profound changes in the biochemical milieu of the body fluids, which contribute to complications of chronic kidney disease (CKD) by inducing cytotoxicity and inflammation. Insight into the changes of the composition of metabolites and dysregulation of target genes and proteins enhances the understanding of the pathophysiology of CKD and its complications, and the development of novel therapeutic strategies. Chronic interstitial nephropathy is a common cause of CKD. The present study was designed to determine the effect of chronic interstitial nephropathy on the composition of serum metabolites and regulation of oxidative, inflammatory, fibrotic and cytoprotective pathways. Methods: Male Sprague-Dawley rats were randomized to the CKD and control groups ( n = 8/group). CKD was induced by administration of adenine (200 mg/kg body weight/day) by oral gavage for 3 weeks. The control group was treated with the vehicle alone. The animals were then observed for an additional 3 weeks, at which point they were sacrificed and kidney and serum samples were collected. Serum metabolomic and lipidomic analyses were performed using ultra-performance liquid chromatography-quadrupole time-of-flight high-definition mass spectrometry. Kidney tissues were processed for histological and molecular biochemical analyses. Results: CKD rats exhibited increased plasma urea and creatinine concentrations, renal interstitial fibrosis, tubular damage and up-regulation of pro-inflammatory, pro-oxidant and pro-fibrotic pathways. Comparison of serum from CKD and control rats revealed significant differences in concentrations of amino acids and lipids including 33 metabolites and 35 lipid species. This was associated with marked abnormalities of fatty acid oxidation, and gamma-linolenic acid and linoleic acid metabolism in CKD rats. Logistic regression analysis identified tetracosanoic acid, docosatrienoic acid, PC(18:3/14:1) and l -aspartic acid, tetracosanoic acid and docosatrienoic acid as novel biomarkers of chronic interstitial nephropathy. Conclusions: Advanced CKD in rats with adenine-induced chronic interstitial nephropathy results in profound changes in the serum metabolome, activation of inflammatory, oxidative and fibrotic pathways, and suppression of cytoprotective and antioxidant pathways. PMID- 28339985 TI - Effects of dietary rapeseed meal supplementation on cecal microbiota in laying hens with different flavin-containing monooxygenase 3 genotypes. AB - To evaluate the effect of dietary rapeseed meal (RM) supplementation on cecal trimethylamine and bacteria in laying hens with different flavin-containing monooxygenase 3 (FMO3) genotypes, a 3 * 2 2-factorial arrangement was employed using FMO3 genotypes (AA, AT, and TT) and dietary RM (0 and 14% of diet) as the main effects. At 50 wk of age, 36 hens of AT genotype and 36 hens of TT genotype were randomly allotted to one of the 2 dietary treatments, and each dietary treatment consisted of 3 replicates with 6 birds each. A total of 12 hens with AA genotype were allotted to one of the 2 dietary treatments that consisted of 3 replicates with 2 hens. Hens were fed 0% RM in a corn-soybean (SM) diet for one wk before the 6-week feeding trial period. Dietary RM supplementation increased trimethylamine (TMA) concentrations in both egg yolks (P < 0.0001) and cecal chyme (P < 0.0001). Dietary RM supplementation increased bacterial abundance and diversity (P < 0.0001). Weighted UniFrac, Nonmetric Multidimensional Scaling, and analysis of similarity (R-ANOSIM = 0.1516; P-value = 0.014) indicated distinct clustering was dependent on diets rather than FMO3 genotypes. Twenty-four phyla (most dominant, Bacteroides, Firmicutes, and Proteobacteria) and 229 genera were identified in the cecal samples. Compared with the SM diets, RM diets increased the proportion of Firmicutes (P = 0.004), Proteobacteria (P = 0.006), and Firmicutes:Bacteroides (P = 0.001), and some low-abundance phyla (P < 0.01), whereas the abundance of Bacteroides was lower (P = 0.0002). The abundance of 42 genera varied with dietary types. Six phyla and 35 genera were positively correlated with TMA concentration in the cecal chyme. In conclusion, the major TMA-producing bacteria in cecal were from Firmicutes and Proteobacteria phyla. The major TMA-producing bacterial genera could be from the genera that positively correlated with TMA concentration. PMID- 28339986 TI - The National Association of Social Workers Code of Ethics and Cultural Competence: What Does Anne Fadiman's The Spirit Catches You and You Fall Down Teach Us Today? AB - This article discusses limitations in the National Association of Social Workers (NASW) Code of Ethics conceptualization of "cultural competence." It uses the case example presented in Anne Fadiman's classic (2012) work, The Spirit Catches You and You Fall Down: A Hmong Child, Her American Doctors, and the Collision of Two Cultures, to explore the conventional markers of cultural competence, as taught in contemporary graduate-level social work education curricula, and their implications for socially just practice. Furthermore, it proposes that an expanded commitment to antiracist practice is necessary to deliver care and craft policies that, in the spirit of the NASW Code of Ethics, truly respect the "dignity and worth" of the individual. PMID- 28339988 TI - Utilization of Health Care Services and Ambulatory Resources Associated with Chronic Noncancer Pain. AB - Objective: Examine traditional and uncompensated health care utilization associated with chronic noncancer pain. Design: Retrospective chart review. Setting: Tertiary academic medical center. Subjects: Internal medicine patients on long-term opioids for chronic noncancer pain with or without a pain agreement between April 1, 2014, and April 1, 2015 (N = 834). Patients without pain served as controls (N = 782). Methods: Univariate statistics were used to compare health care utilization by the presence of chronic pain, pain agreement status, opioid dose, and schedule. Logistic regression was used to assess predictors of health care utilization, with emergency room visits, hospitalizations, and after-hour calls as binary outcomes and office visits and phone/e-mail contacts as ordinal outcomes. Results: Patients with chronic pain used significantly more health care resources compared with patients without pain (all P < 0.001). Patients on a pain agreement had more telephone and secure messages than patients without an agreement ( P = 0.002). Controlling for demographics and other factors, patients with chronic pain had 2.6 (95% confidence interval [CI] = 2.1-3.4) times the odds of an emergency room visit, 5.0 (95% CI = 3.6-7.0) times the odds of a hospitalization, and 2.3 (95% CI = 1.7-3.0) times the odds of an after hour call, compared with nonpain controls. Ordinal logistic regression yield adjusted common odds ratios of 3.4 (95% CI = 2.7-4.2) and 2.9 (95% CI = 2.3-3.6) for total clinic visits and telephone or secure messages, respectively, indicating higher utilization for chronic pain patients. Conclusions: Patients with chronic noncancer pain utilized more traditional and uncompensated health care resources compared with patients without chronic pain. PMID- 28339989 TI - Pain Management Strategies and Health Care Use in Community-Dwelling Individuals Living with Chronic Pain. AB - Objective: To describe factors associated with high clinic and emergency room (ER) use among individuals with chronic pain. Design: This study is part of a larger cross-sectional survey on the epidemiology of chronic pain in Canada. The current analysis was guided by the Andersen-Newman Service Utilization Model. Methods: Respondents (N = 702) were grouped into high (top 10%) and low (bottom 90%) users based on the number of visits made to clinics and ERs over the past year. The two groups were compared on predisposing (e.g., pain self-efficacy and sociodemographic characteristics), enabling (e.g., income and education), and need (e.g., pain characteristics and number of comorbidities) factors as well as personal health behaviors (e.g., use of medications). Binary logistic regression analysis was used to identify characteristics associated with high use in each setting. Results: High users were defined as 30 or more clinic visits or one or more ER visits. The factors associated with high clinic use in the adjusted analysis were low pain self-efficacy (odds ratio [OR] = 2.60, 95% confidence interval [CI] = 1.50-4.51), two or more comorbidities (OR = 2.13, 95% CI = 1.23 3.69), five or more pain sites (OR = 2.30, 95% CI = 1.28-4.14), and having an "other" pain diagnosis (OR = 1.78, 95% CI = 1.01-3.20). Factors that increased ER use were low pain self-efficacy (OR = 2.01, 95% CI = 1.28-3.15) and two or more comorbidities (OR = 2.31, 95% CI = 1.48-3.59), while use of alternative pain management strategies reduced ER use (OR = 0.42, 95% CI = 0.21-0.84). Conclusions: Longitudinal studies are needed to confirm if modifiable factors such as pain self-efficacy and use of alternative therapies reduce health care use. PMID- 28339991 TI - Seeing Deaths Resulting from Interpersonal Violence as a Function of "State Violence": Time for a Health Disparities Paradigm Shift? PMID- 28339990 TI - Detecting thresholds for bitter, umami, and sweet tastants in broiler chicken using a 2-choice test method. AB - The sense of taste has a key role in nutrient sensing and food intake in animals. A standardized and simple method for determination of tastant-detection thresholds is required for chemosensory research in poultry. We established a 24 h, 2-alternative, forced-choice solution-consumption method and applied it to measure detection thresholds for 3 G-protein-coupled receptor-mediated taste modalities-bitter, sweet, and umami-in chicken. Four parameters were used to determine a significant response: 1) tastant-solution consumption; 2) water (tasteless) consumption; 3) total consumption (tastant and water together); 4) ratio of tastant consumption to total consumption. Our results showed that assignment of the taste solutions and a water control to 2 bottles on random sides of the pen can be reliably used for broiler chicks, even though 47% of the chicks groups demonstrated a consistently preferred side. The detection thresholds for quinine (bitter), L-monosodium glutamate (MSG) (umami), and sucrose (sweet) were determined to be 0.3 mM, 300 mM, and 1 M, respectively. The threshold results for quinine were similar to those for humans and rodents, but the chicks were found to be less sensitive to sucrose and MSG. The described method is useful for studying detection thresholds for tastants that have the potential to affect feed and water consumption in chickens. PMID- 28339992 TI - Rheumatoid arthritis-specific cardiovascular risk scores are not superior to general risk scores: a validation analysis of patients from seven countries. AB - Objectives: Cardiovascular disease (CVD) risk calculators developed for the general population do not accurately predict CVD events in patients with RA. We sought to externally validate risk calculators recommended for use in patients with RA including the EULAR 1.5 multiplier, the Expanded Cardiovascular Risk Prediction Score for RA (ERS-RA) and QRISK2. Methods: Seven RA cohorts from UK, Norway, Netherlands, USA, South Africa, Canada and Mexico were combined. Data on baseline CVD risk factors, RA characteristics and CVD outcomes (including myocardial infarction, ischaemic stroke and cardiovascular death) were collected using standardized definitions. Performance of QRISK2, EULAR multiplier and ERS RA was compared with other risk calculators [American College of Cardiology/American Heart Association (ACC/AHA), Framingham Adult Treatment Panel III Framingham risk score-Adult Treatment Panel (FRS-ATP) and Reynolds Risk Score] using c-statistics and net reclassification index. Results: Among 1796 RA patients without prior CVD [mean ( s . d .) age: 54.0 (14.0) years, 74% female], 100 developed CVD events during a mean follow-up of 6.9 years (12430 person years). Estimated CVD risk by ERS-RA [mean ( s . d .) 8.8% (9.8%)] was comparable to FRS-ATP [mean ( s . d .) 9.1% (8.3%)] and Reynolds [mean ( s . d .) 9.2% (12.2%)], but lower than ACC/AHA [mean ( s . d .) 9.8% (12.1%)]. QRISK2 substantially overestimated risk [mean ( s . d .) 15.5% (13.9%)]. Discrimination was not improved for ERS-RA (c-statistic = 0.69), QRISK2 or EULAR multiplier applied to ACC/AHA compared with ACC/AHA (c-statistic = 0.72 for all) or for FRS ATP (c-statistic = 0.75). The net reclassification index for ERS-RA was low ( 0.8% vs ACC/AHA and 2.3% vs FRS-ATP). Conclusion: The QRISK2, EULAR multiplier and ERS-RA algorithms did not predict CVD risk more accurately in patients with RA than CVD risk calculators developed for the general population. PMID- 28339993 TI - One-year efficacy and safety of the iron-based phosphate binder sucroferric oxyhydroxide in patients on peritoneal dialysis. AB - Background: Sucroferric oxyhydroxide is a noncalcium, iron-based phosphate binder that demonstrated sustained serum phosphorus control, good tolerability and lower pill burden compared with sevelamer carbonate (sevelamer) in a Phase 3 study conducted in dialysis patients. This subanalysis examines the efficacy and tolerability of sucroferric oxyhydroxide and sevelamer in the peritoneal dialysis (PD) patient population. Methods: The initial study (NCT01324128) and its extension (NCT01464190) were multicenter, Phase 3, open-label, randomized (2:1), active-controlled trials comparing sucroferric oxyhydroxide (1.0-3.0 g/day) with sevelamer (2.4-14.4 g/day) in dialysis patients over 52 weeks in total. Results: In the overall study, 84/1055 (8.1%) patients received PD and were eligible for efficacy analysis (sucroferric oxyhydroxide, n = 56; sevelamer, n = 28). The two groups were broadly comparable to each other and to the overall study population. Serum phosphorus concentrations decreased comparably with both phosphate binders by week 12 (mean change from baseline - 0.6 mmol/L). Over 52 weeks, sucroferric oxyhydroxide effectively reduced serum phosphorus concentrations to a similar extent as sevelamer; 62.5% and 64.3% of patients, respectively, were below the Kidney Disease Outcomes Quality Initiative target range (<=1.78 mmol/L). This was achieved with a lower pill burden (3.4 +/- 1.3 versus 8.1 +/- 3.7 tablets/day) with sucroferric oxyhydroxide compared with sevelamer. Treatment adherence rates were 91.2% with sucroferric oxyhydroxide and 79.3% with sevelamer. The proportion of patients reporting at least one treatment-emergent adverse event was 86.0% with sucroferric oxyhydroxide and 93.1% with sevelamer. The most common adverse events with both treatments were gastrointestinal: diarrhea and discolored feces with sucroferric oxyhydroxide and nausea, vomiting and constipation with sevelamer. Conclusions: Sucroferric oxyhydroxide is noninferior to sevelamer for controlling serum phosphorus in patients undergoing PD, while providing a relatively low pill burden and a high rate of adherence. PMID- 28339994 TI - A longitudinal cohort study of the anti-synthetase syndrome: increased severity of interstitial lung disease in black patients and patients with anti-PL7 and anti-PL12 autoantibodies. AB - Objective: The aim was to study the prevalence, rate of appearance and severity of clinical features in patients with different anti-synthetase syndrome (ASyS) autoantibodies. Methods: All Johns Hopkins Myositis Longitudinal Cohort subjects positive for any ASyS autoantibodies were included. Clinical information, including symptoms, signs, strength, creatine kinase concentrations and pulmonary function tests, were prospectively collected. The standardized mortality and cancer rates and the rate of appearance and intensity of the different organ manifestations were assessed using univariate and multivariate analysis and compared between ASyS autoantibodies. Results: One hundred and twenty-four (73.4%) patients were positive for anti-Jo1, 23 (13.6%) for anti-PL12, 16 for anti-PL7 (9.5%) and 3 (1.8%) for anti-EJ or anti-OJ, respectively. The mean length of follow-up was 4.1 years. Anti-PL12 was more frequent in black subjects. Anti-PL12 and anti-PL7 were associated with more prevalent and severe lung involvement, often without muscle involvement. Anti-Jo1 displayed more severe muscle involvement compared with anti-PL12 patients. Concurrent anti-Ro52 was more prevalent in anti-Jo1 patients and was associated with earlier development of mechanic's hands, DM-specific skin findings and arthritis. Independent of ASyS antibody status, black patients demonstrated more severe lung involvement than white patients. There was no significant increase in mortality or cancer risk in ASyS patients compared with the general US population. Conclusion: Different ASyS autoantibodies are associated with phenotypically distinct subgroups within the ASyS spectrum. Anti-PL7 and anti-PL12 are characterized by more severe lung involvement, whereas anti-Jo1 is associated with more severe muscle involvement. Black race is a major prognostic factor associated with lung disease severity. PMID- 28339996 TI - Fathers' Perceptions of Change Following Parenting Intervention: Randomized Controlled Trial of Triple P for Parents of Children With Asthma or Eczema. AB - Objective: To test whether families' participation in an evidence-based parenting program can improve health-related outcomes reported by fathers of 2- to 10-year old children with asthma and/or eczema. Methods: A 2 (Triple P-Positive Parenting Program vs. care as usual) by 3 (baseline, postintervention, 6-month follow-up) design was used, with random group assignment. Of 107 families, 51.4% (N = 55) had a father participate alongside the child's mother, who was the primary intervention target. Fathers completed questionnaires assessing illness-related child behavior problems; self-efficacy with illness management and illness related child behavior problems; and health-related quality of life. Results: Secondary intent-to-treat analyses indicated improved child behavior and self efficacy for managing eczema, but not asthma. Health-related quality of life improved for children, but not parents/families. There were no other significant intervention effects. Conclusions: Intervention outcomes were positive for eczema but not asthma, and did not depend on the extent of father participation in the intervention. PMID- 28339995 TI - Long-term flecainide therapy in type 3 long QT syndrome. AB - Aims: Type 3 long QT syndrome (LQT3) is caused by gain-of-function mutations in the cardiac sodium channel gene (SCN5A). Previous reports on the long-term use of sodium channel blockers in LQT3 are sparse. The objective of the current study was to evaluate the long-term safety and efficacy of flecainide therapy in patients with LQT3 who carry the D1790G SCN5A mutation. Methods and results: The study population comprised 30 D1790G carriers who were treated with flecainide and followed for 1-215 months (mean 145 +/- 54 months, median 140 months). The mean baseline (off-drug) QTc was 522 +/- 45 ms, and shortened to 469 +/- 36 ms with flecainide therapy, a mean decrease of 53 ms [10.1%] (P < 0.01). A QTc longer than 500 ms was evident in 53% of carriers at baseline, and only in 13% on flecainide. All carriers while being compliant with flecainide therapy had no cardiac events during an average follow up of 83 +/- 73 months. Twenty carriers stopped flecainide after an average follow up of 40 +/- 42 months without symptoms. Six of them (30%) had cardiac events 1-11 months after stopping flecainide. Flecainide induced the appearance of Brugada pattern in six carriers (20%, 5 males), was stopped in three and was not associated with arrhythmia. Sinus-node dysfunction was evident in six carriers (20%) and was fully corrected by flecainide in three. Conclusions: These data suggest that long-term flecainide therapy is relatively safe and effective among LQT3 patients who carry the D1790G SCN5A mutation. PMID- 28339997 TI - Straight-run vs. sex separate rearing for 2 broiler genetic lines Part 1: Live production parameters, carcass yield, and feeding behavior. AB - The objective of this experiment was to evaluate the effects of raising broilers under sex separate and straight-run conditions for 2 broiler strains. Day-old Ross 308 and Ross 708 chicks (n = 1,344) were separated by sex and placed in 48 pens according to the rearing type: sex separate (28 males or 28 females) or straight-run (14 males + 14 females). There were 3 dietary phases: starter (zero to 17 d), grower (17 to 32 d), and finisher (32 to 48 d). Birds' individual BW and feed intakes were measured at 12, 17, 25, 32, 42, and 48 d to evaluate performance. At 33, 43, and 49 d, 4 birds per pen were sampled for carcass yield evaluation. Additionally, from 06:00 to 06:30, 13:00 to 13:30, and 22:00 to 22:30, video records were taken to assess behavior at 45 days. Data were analyzed as CRD with a 2 * 3 factorial arrangement of treatments over time. Throughout the experiment Ross 308 were heavier than the 708, and after 17 d, male pens had the heavier birds, followed by straight-run and then females. Straight-run pens had higher BW CV in comparison with sex separate pens. Sex separate male BW was negatively impacted from 17 to 32 days. On the other hand, females raised sex separate were heavier than females raised straight-run with lower CV from 25 to 41 days. Post 25 d, FCR was the lowest in male pens whereas feed intake was the highest for these pens after 17 days. Overall, males had total carcass cut-up weights higher than straight-run and females at the 3 processing times. The Ross 708 had higher white meat yields, whereas 308 had higher yields for dark meat. Feeding behavior results were not consistent over time. However, from 13:00 to 13:30, birds in female pens spent more time eating, followed by straight-run and then males. In conclusion, raising females in a straight-run system negatively impacted performance and CV, whereas males benefited from straight-run rearing, with the differences being possibly related to feeder space competition. PMID- 28339998 TI - Executive Functioning in Pediatric Chronic Pain: Do Deficits Exist? AB - Objective: Despite ample research documenting deficits in executive functioning for adults with chronic pain, the literature on pediatric patients with chronic pain is limited and provides mixed results. The current study sought to further investigate the nature of executive dysfunction in this population and also examine the relationships between pain intensity, duration, and catastrophizing with sustained attention, working memory, and self- and parent-report of executive functioning. Settings: Pediatric pain clinic and rehabilitation program. Participants: Forty adolescents with chronic pain and their parents participated in this study. Methods: Participants completed neuropsychological measures and standardized self-report questionnaires during a 45- to 60-minute testing session. Results: Fifty percent of this sample of adolescents with chronic pain demonstrated significant difficulties on at least one measure, with nine participants indicating difficulties on multiple measures. Pain significantly increased during the testing session. Pain variables of intensity, duration, and catastrophizing are related to sustained attention and working memory. Conclusions: This study adds support to previous findings suggesting subclinical struggles with executive functioning for adolescents with chronic pain. One-half of the sample indicated difficulties in either sustained attention and/or working memory. Future studies that would more thoroughly examine more complex executive functioning skills in this population would be helpful to further guide multidisciplinary treatment of these patients, particularly regarding whether or not school accommodations are warranted. PMID- 28339999 TI - Bone curvature changes can predict the impact of treatment on cartilage volume loss in knee osteoarthritis: data from a 2-year clinical trial. AB - Objectives: Knee bone curvature assessed by MRI was associated with OA cartilage loss. A recent knee OA trial demonstrated the superiority of chondroitin sulfate over celecoxib (comparator) at reducing cartilage volume loss (CVL) in the medial compartment (condyle). The main objectives were to identify which baseline bone curvature regions of interest (BCROI) best associated with CVL and investigate whether baseline BCROI and 2-year change are correlated with the protective effect of chondroitin sulphate on CVL. Methods: This post hoc analysis of a clinical trial used the according-to-protocol population (chondroitin sulphate, n = 57; celecoxib, n = 63) baseline and 2-year MRI to assess bone curvature and CVL. Global optimum search identified the BCROI in the medial condyle using celecoxib as reference. Statistical analyses were performed with Pearson's correlation, Mann-Whitney U -test, Student's t -test and analysis of covariance. Results: The BCROI including the medial posterior condyle and lateral central condyle was found to correlate best with medial condyle CVL at 2 years ( r = 0.33, P = 0.008). In patients with a baseline BCROI value less than the median (more flattened bone), chondroitin sulphate demonstrated a protective effect on CVL compared with celecoxib in the medial compartment (P = 0.037). In patients with 2-year BCROI changes greater than the median (greater severity of bone flattening), chondroitin sulphate protected against CVL in the medial compartment, condyle and central plateau (P ? 0.030). Conclusion: This study is the first to demonstrate the feasibility and usefulness of bone curvature measurements to predict effectiveness of OA treatment on CVL. The results identify bone curvature as a potential novel biomarker for knee OA clinical trials. PMID- 28340000 TI - Effects of feeding Original XPCTM to broilers with a live coccidiosis-vaccine under industry conditions: Part 1. Growth performance and Salmonella inhibition. AB - Supplementation of poultry diets with Diamond V Original XPCTM (XPC) has been proposed as a means to ameliorate the commonly observed loss of appetite and depression of growth in birds given a live coccidiosis vaccine. A study was conducted to compare the effects on bird performance of a live coccidiosis vaccine in broilers, with and without the dietary inclusion of XPC (1.25 g/kg). Ross 708 male broilers (n = 1,280) were allocated to one of 4 feed treatments: cocci-vaccine (T1), cocci-vaccine + XPC (T2), cocci-vaccine + salinomycin in the grower diet only, (T3), and cocci-vaccine + salinomycin in the grower diet + XPC (T4). Birds consuming diets containing XPC (T2 and T4) and salinomycin (T3) exhibited increased (P < 0.05) feed intake and significantly heavier body weights at 28 d (1.70, 1.74, and 1.67 kg, respectively) and 42 d (3.29, 3.31, and 3.26 kg, respectively). Feed conversion ratio at 28 d was improved (P < 0.05) by adding XPC to diets (T2: 1.47 and T4: 1.44) compared to control diets (T1: 1.50 and T3: 1.47). Salmonella prevalence determined via selective media indicated the inclusion of XPC in the diet resulted in a significant reduction of Salmonella when compared to treatments lacking XPC. Molecular confirmation of Salmonella species indicated S. Kentucky to be present in 38 of the 39 positive samples. Results revealed the ability of XPC in reducing the prevalence of Salmonella. Results from this study also suggest that XPC could be used in conjunction with a live coccidiosis-vaccine to increase growth rate and improve feed conversion of broilers. However, further work is needed to delineate more specific effects directly attributable to XPC. PMID- 28340001 TI - Early-life origin of intestinal inflammatory disorders. AB - A growing body of evidence supports the concept of perinatal programming through which the perinatal environment affects the development of the fetus and infant, thereby modifying the risk profile for disease later in life. Increasing attention is focusing on the role of the early environment in the development of chronic intestinal disorders. Epidemiological studies have highlighted the link between perinatal factors, such as breastfeeding, cesarean delivery, and antibiotic use, and an increased risk for inflammatory bowel disease and/or celiac disease. These links are consistent with the concept of perinatal programming of intestinal inflammatory disorders. Animal models have shown that the early-life environment affects the development of the gastrointestinal tract, but further experimental studies are needed to confirm the long-term effects of the perinatal environment on susceptibility to chronic intestinal disorders later in life. Changes in the development and composition of the intestinal microbiota as well as epigenetic changes are emerging as key mechanisms through which the perinatal environment determines susceptibility to intestinal inflammatory disorders. PMID- 28340003 TI - Beighton scores and cut-offs across the lifespan: cross-sectional study of an Australian population. AB - Objectives: The primary aim of this study was to evaluate generalized joint hypermobility (GJH) according to the Beighton scoring system in an Australian population. Secondary aims were to identify whether the commonly used Beighton score cut-off of ?4 is appropriate, and to suggest age- and sex-specific Beighton score cut-offs across the lifespan. Methods: A thousand individuals aged 3-101 years were assessed for GJH with the Beighton scoring system. Differences between age, sex and ethnicity were investigated. The appropriateness of the ?4 cut-off was investigated with use of a binary logistic regression. Each Beighton score cut-off was established as the nearest Beighton score that delineated the uppermost 5% of the population. Results: Overall, females and non-Caucasians had higher Beighton scores across the lifespan (P < 0.001). Based on a binary logistic regression model, if a cut-off of ?4 was utilized, the Beighton scoring system demonstrated a sensitivity of 0.8% and a specificity of 99.3% (P < 0.001). A cut-off of ?4 was only found to be appropriate for females aged 40-59 years and males aged 8-39 years. Conclusion: Beighton scores varied across the lifespan and were significantly influenced by age, sex and ethnicity. Assessing GJH using the Beighton scoring system required age- and sex-specific cut-off scores based on the uppermost 5% values. This was confirmed by the low sensitivity, high specificity and 60% false-positive rate if a cut-off of ?4 was used for both sexes across the lifespan. To lower the risk of a false-positive diagnosis of GJH, further tests of hypermobility need to be utilized. PMID- 28340002 TI - Overexpression of the Rice SUMO E3 Ligase Gene OsSIZ1 in Cotton Enhances Drought and Heat Tolerance, and Substantially Improves Fiber Yields in the Field under Reduced Irrigation and Rainfed Conditions. AB - The Arabidopsis SUMO E3 ligase gene AtSIZ1 plays important roles in plant response to abiotic stresses as loss of function in AtSIZ1 leads to increased sensitivity to drought, heat and salt stresses. Overexpression of the AtSIZ1 rice homolog, OsSIZ1, leads to increased heat and drought tolerance in bentgrass, suggesting that the function of the E3 ligase SIZ1 is highly conserved in plants and it plays a critical role in abiotic stress responses. To test the possibility that the SUMO E3 ligase could be used to engineer drought- and heat-tolerant crops, the rice gene OsSIZ1 was overexpressed in cotton. We report here that overexpression of OsSIZ1 in cotton results in higher net photosynthesis and better growth than wild-type cotton under drought and thermal stresses in growth chamber and greenhouse conditions. Additionally, this tolerance to abiotic stresses was correlated with higher fiber yield in both controlled-environment and field trials carried out under reduced irrigation and rainfed conditions. These results suggest that OsSIZ1 is a viable candidate gene to improve crop yields under water-limited and rainfed agricultural production systems. PMID- 28340004 TI - Prevalence of malnutrition and validation of bioelectrical impedance analysis for the assessment of body composition in patients with systemic sclerosis. AB - Objectives: The aims were to assess the prevalence of malnutrition and to validate bioelectrical impedance analysis (BIA) against whole-body DXA for the assessment of body composition in patients with SSc. Methods: Malnutrition was defined as BMI <18.5 kg/m 2 or unintentional weight loss >10% in combination with a fat-free mass index (FFMI) <15 kg/m 2 for women or <17 kg/m 2 for men or BMI <20.0 kg/m 2 (age <70 years) or <22 kg/m 2 (age >70 years). Body composition was assessed in 72 patients with whole-body DXA (Hologic, Discovery A) and BIA (Bodystat Quadscan 400). The manufacturer's equation and the Geneva equation were used to estimate FFM and fat mass. The agreement between BIA and whole-body DXA was assessed with Bland-Altman analysis and intraclass correlation coefficient. Results: Malnutrition was found in 8.3% (n = 6) and low FFMI in 20.8% (n = 15) of patients. The mean difference in FFM between BIA and DXA applying the Geneva equation was 0.02 ( s . d . 2.4) kg, intraclass correlation coefficient 0.97 (95% CI: 0.95, 0.98). Limits of agreement were +/-4.6 kg. The manufacturer's equation was less adequate to predict FFM. Conclusion: This study shows a relatively low prevalence of malnutrition in comparison with other studies, but a high prevalence of low FFMI, underlining the necessity of measuring body composition in SSc patients with a standardized and validated method. A good validity of BIA in determining FFM was found at a group level, while at an individual level the FFM may vary by 4.6 kg. PMID- 28340005 TI - Inappropriate shocks in single-chamber and subcutaneous implantable cardioverter defibrillators: a systematic review and meta-analysis. AB - Aims: Single-chamber (VR-ICD) and subcutaneous (S-ICD) implantable cardioverter defibrillators are effective to protect patients against sudden death but expose them to higher risk of inappropriate shock (IS). We sought to quantify the annual rate and influencing factors of ISs in VR- and S-ICDs from the literature. Methods and results: PubMed, Embase, and Cochrane Library were searched for full text articles with IS rates. Poisson distribution estimated proportion of patients with ISs; rates were annualized based on follow-up duration. Random effects meta-analysis accounted for study-to-study variation. Out of 3264 articles, 16 qualified for the meta-analysis. Across studies, 6.4% [95% confidence interval (CI) 5.1-7.9%] of patients received an IS per year. Meta regression analyses demonstrated that IS rates were lower in more recent studies [rate ratio (RR) per year: 0.93, 95% CI: 0.87-0.98; P = 0.01] and trended lower in studies with longer follow-up (RR per year: 0.78, 95% CI: 0.60-1.01; P = 0.06). Use of S-ICDs (RR: 1.81, 95% CI: 0.86-3.81; P = 0.12) and ventricular tachycardia zone programmed on (RR: 1.13, 95% CI: 0.65-1.97; P = 0.66) were not associated with a significantly increased change in risk. The IS rate observed in one of the more recent studies was significantly lower than predicted after accounting for covariates (RR: 0.29, 95% CI: 0.14-0.60; P < 0.001). Conclusions: A comprehensive review of the literature shows that 6.4% of patients with ICDs experienced their first IS annually. One of the 16 studies was better than predicted with the lowest reported rate (1.9%) and could not be explained by timing of the study or other covariates. PMID- 28340006 TI - Benefit of biologics initiation in moderate versus severe rheumatoid arthritis: evidence from a United States registry. AB - Objectives: To compare clinical outcomes and treatment patterns among patients with moderate vs severe RA following biologic DMARD initiation. Methods: Biologics-naive patients with moderate to severe RA [Clinical Disease Activity Index (CDAI) >10] who initiated a biologic DMARD were selected from the Corrona registry (2001-13). CDAI, functional status [modified HAQ (mHAQ)] and patterns of drug use were compared at 1 and 2 years post-initiation between patients with moderate (CDAI >10?22) vs severe (CDAI >22) baseline disease activity. Results: A total of 1596 patients (817 severe, 779 moderate) had ?1 year of follow-up and 1269 (635 severe, 634 moderate) had ?2 years of follow-up. Patients with severe vs moderate baseline disease activity experienced greater improvements in disease activity [mean change in CDAI -18.9 vs -6.0 at year 1; -21.0 vs -7.1 at year 2 ( P < 0.0001)] and physical function [mean change in mHAQ -0.2 vs -0.1 ( P < 0.0001) at year 1; -0.2 vs -0.1 ( P = 0.0013) at year 2]. Greater proportions of patients with moderate vs severe disease activity achieved remission (CDAI ?2.8) [22.7 vs 15.8% ( P = 0.0003) at year 1; 25.9 vs 20.9% ( P = 0.0396) at year 2] or low disease activity (CDAI <10) [60.1 vs 41.2% at year 1; 66.7 vs 49.4% at year 2 ( P < 0.0001)]. Most patients remained on the original biologic drug (>70% at year 1; >62% at year 2). Conclusion: With biologic therapy, RA patients with higher baseline disease activity achieved greater improvements in measures of disease activity than those with lower levels of disease, but less often achieved the common targets of remission or low disease activity. PMID- 28340008 TI - Pre-treatment interleukin-6 levels strongly affect bone erosion progression and repair detected by magnetic resonance imaging in rheumatoid arthritis patients. AB - Objective: To examine the relationship between MRI structural damage and repair and plasma inflammatory cytokines in patients with RA. Methods: A total of 88 newly diagnosed, untreated RA patients were enrolled. Contrast MRI of the dominant hand and X-rays of the hands and feet were performed at baseline and 1 year later. MR images were evaluated using RA MRI scoring, and X-ray. Results: Progression of bone erosion and repair were observed more frequently in MRI than in X-rays (erosion, 52% vs 26%, P < 0.001; repair, 26% vs 15%, P = 0.003, respectively). Baseline IL-6 levels and seropositivity were independent relevant factors for MRI erosion progression, with IL-6 having stronger effect than seropositivity. A receiver operating characteristic curve identified the baseline IL-6 level of 7.6 pg/ml for predicting erosion progression during 1 year, with an area under the curve of 0.82; higher IL-6 levels resulted in more erosion progression. Baseline low IL-6 was also an independent predictor for MRI erosion repair. Conclusion: In newly diagnosed, untreated RA patients, baseline plasma IL 6 levels are responsible for 1-year MRI bone erosion progression and repair. PMID- 28340009 TI - Designing an optimal screening program for unknown atrial fibrillation: a cost effectiveness analysis. AB - Aims: The primary objective of this study was to use computer simulations to suggest an optimal age for initiation of screening for unknown atrial fibrillation and to evaluate if repeated screening will add value. Methods and results: In the absence of relevant clinical studies, this analysis was based on a simulation model. More than two billion different designs of screening programs for unknown atrial fibrillation were simulated and analysed. Data from the published scientific literature and registries were used to construct the model and estimate lifelong effects and costs. Costs and effects generated by 2 147 483 648 different screening designs were calculated and compared. Program designs that implied worse clinical outcome and were less cost-effective compared to other programs were excluded from the analysis. Seven program designs were identified, and considered to be cost effective depending on what the health-care decision makers are ready to pay for gaining a quality-adjusted life-year (QALY). Screening at the age of 75 implied the lowest cost per gained QALY (?4 800/QALY). Conclusion: In conclusion, examining the results of more than two billion simulated screening program designs for unknown atrial fibrillation, seven designs were deemed cost-effective depending on how much we are prepared to pay for gaining QALYs. Our results showed that repeated screening for atrial fibrillation implied additional health benefits to a reasonable cost compared to one-off screening. PMID- 28340010 TI - Non-proteinuric rather than proteinuric renal diseases are the leading cause of end-stage kidney disease. AB - Proteinuria is a distinguishing feature in primary and secondary forms of chronic glomerulonephritis, which contribute to no more than the 20% of the end-stage kidney disease (ESKD) population. The contribution of non-proteinuric nephropathies to the global ESKD burden is still poorly focused and scarce research efforts are dedicated to the elucidation of risk factors and mechanistic pathways triggering ESKD in these diseases. We abstracted information on proteinuria in the main renal diseases other than glomerulonephritides that may evolve into ESKD. In type 2 diabetes, non-proteinuric diabetic kidney disease (DKD) is more frequent than proteinuric DKD, and risk factors for non-proteinuric forms of DKD now receive increasing attention. Similarly, proteinuria is most often inconspicuous or absent in the most frequent cause of ESKD, i.e. hypertension-related chronic kidney disease (CKD), as well as in progressive cystic diseases like autosomal dominant polycystic kidney disease and in pyelonephritis/tubulo-interstitial diseases. Maintaining a high degree of attention in the care of CKD patients with proteinuria is fundamental to effectively retard progression toward kidney failure. However, substantial research efforts are still needed to develop treatment strategies that may help the vast majority of CKD patients who eventually develop ESKD via mechanistic pathways other than proteinuria. PMID- 28340011 TI - Evaluation of the Impact of Physical Exercise in Reducing Pain in Women Undergoing Mammography: A Randomized Clinical Trial. AB - Objective: To evaluate the efficacy of exercise prior to mammography in reducing perceived postexamination pain. Methods: An open, randomized, and controlled clinical trial was conducted. The interventions consisted of warm-up and stretching exercises of the upper or lower limbs of women who consulted at Barretos Cancer Hospital, Sao Paulo State, Brazil. The women were divided into three groups based on the intervention and its location: upper limbs (group 1), lower limbs (group 2), and no intervention (group 0). Quantitative variables were compared between and within groups using analysis of variance and Student's t test with a 5% significance level. Relative risk (RR) calculations and their derived measurements such as efficacy, number needed to treat (NNT), absolute risk reduction (ARR), and relative risk reduction (RRR) were taken. This study was approved by the Institutional Committee of Research Ethics. Results: A total of 198 (66 per group) women were evaluated. Sociodemographic data and level of physical activity were not found to be associated with perception of pain after mammogram. However, group 1 had the greatest reduction in postprocedure perception of pain compared with groups 2 (relative risk [RR] = 3.54, 95% confidence interval [CI] = 2.12-5.51, P < 0.05) and 0 (RR = 1.92 (95% CI = 1.08 3.42, P < 0.05). Conclusions: Pre-examination upper limb exercises were most effective in reducing the perception and sensation of pain. However, women who performed lower limb exercises also had a decreased perception of pain compared with the control group. PMID- 28340013 TI - Implications of Thoracic Epidural Analgesia on Hospital Charges in Rib Fracture Patients. AB - Objective: Rib fractures are present in more than 150,000 patients admitted to US trauma centers each year. Those who fracture two or more ribs are typically treated with oral analgesic drugs and are discharged with few complications. The cost of this care generally reflects its brevity. When a patient fractures three or more ribs, there is an elevated risk of complication. In response, treatments are often broadened and their durations prolonged; this affects cost. While health, function, and survival have been widely explored, patient billing has not. Thus, we evaluated the financial implications of one mode of treatment for patients with rib fractures: thoracic epidural analgesia (TEA). Methods: We retrospectively analyzed the registry of a level II trauma center. All patients who fractured one or more ribs (n = 1,344) were considered; 382 of those patients were not candidates for epidural placement and were eliminated from analyses. Epidural placement was determined by individual clinicians. We used multiple linear regressions to determine predictors of cost. Results: After eliminating patients who were not eligible to receive TEA, the average patient bill was $59,123 ($10,631 per day of treatment). The administration of TEA predicted a 25% reduction in total billing (99% CI = -$21,429.55- -$7,794.66) and a 24% reduction in per-day billing (99% CI = -$3,745.99- -$1,276.14). Conclusions: Patients who received TEA were more severely injured and required longer treatments; controlling for these variables, the use of TEA associated with reductions in the cost of receiving care. From an administrative and insurance perspective, more frequent reliance on TEA may be indicated. PMID- 28340014 TI - Association between right ventricular lead position and clinical outcomes in patients with cardiac resynchronization therapy. AB - Aims: To evaluate the association between an apical vs. non-apical right ventricular lead position (RV-LP) and clinical outcome in a large nationwide cohort of patients treated with cardiac resynchronization therapy (CRT). Methods and results: We included consecutive Danish patients receiving a CRT device from 2008 to 2012, identified from the Danish Pacemaker and ICD Register. Endpoints were mortality, mortality or hospitalization for heart failure (HF), and clinical response (improvement >=1 New York Heart Association class at follow-up). Subgroup analysis was made for ischaemic heart disease (IHD) and non-IHD. Cox and logistic regression analyses were used to calculate adjusted HR (aHR) and adjusted odds ratios with 95% confidence intervals (CI). A total of 2883 patients received a CRT device during the period. We excluded 301 patients that did not meet standard CRT indication. In 2391 (93%) of the remaining 2582 patients the RV LP was defined as apical in 647 (27%) and non-apical in 1744 (73%). After mean 3.2 +/- 2 years, 660 patients had died, 1275 patients were hospitalized for HF, and 1021 were responders. With a non-apical RV-LP the aHR for mortality was 0.93 (95% CI 0.0.79-1.10, P = 0.40) and the aHR for the combined endpoint of mortality or HF-hospitalization was 0.89 (95% CI 0.79-0.99, P = 0.03). These findings were significant only in patients with non-IHD. There was no association between clinical response and RV-LP. Conclusion: A non-apical RV-LP is associated with lower risk of meeting the combined endpoint of mortality or hospitalization for HF in patients with CRT. In subgroup analysis, this association was present only in patients with non-IHD. PMID- 28340012 TI - Assessment of muscle mass relative to fat mass and associations with physical functioning in rheumatoid arthritis. AB - Objectives: To determine whether a novel measure of appendicular lean mass relative to fat mass is associated with physical functioning in RA. Methods: In a cross-sectional design, three independent RA cohorts were retrospectively analysed. Whole-body DXA measures of appendicular lean mass index (ALMI, kg/m 2 ) and fat mass index (FMI, kg/m 2 ) were converted to age, sex and race-specific Z scores using published National Health and Nutrition Examination Survey reference ranges. Adiposity-adjusted ALMI Z-scores (ALMI FMI ) were determined using a published method to adjust for normal associations between ALMI and FMI Z-scores. Associations between ALMI Z-scores, ALMI FMI Z-scores and physical functioning were assessed after adjusting for age, sex and study. Functional outcomes assessed included the HAQ, Valued Life Activities assessment and Short Physical Performance Battery. Low lean for age was defined as a Z-score of -1 or less. Results: Our sample consisted of 442 patients with RA. The combined cohort had a mean ALMI Z-score of - 0.51 (1.08) and a mean ALMI FMI Z-score of - 0.58 (1.53), suggesting muscle mass deficits compared with a nationally representative sample. Greater ALMI FMI Z-scores demonstrated stronger associations with better functional outcomes compared with ALMI Z-scores. Associations were not attenuated with adjustment for systemic inflammation or pain. The FMI Z-score was independently associated with physical functioning, with a stronger association seen among patients with greater FMI Z-score. Adiposity-adjusted definitions of low lean mass more clearly identified those with functional impairment. Conclusion: Estimates of appendicular lean mass that are adjusted for adiposity demonstrate stronger positive associations with functional outcomes compared with unadjusted estimates. PMID- 28340015 TI - Sarcoidosis-the great masquerader. PMID- 28340016 TI - Changes in leisure-time physical activity and subsequent common mental disorders among ageing employees. AB - The aim of this study was to examine whether changes in leisure-time physical activity are associated with subsequent common mental disorders. Follow-up survey data were collected from 40 to 60-year-old employees of the City of Helsinki, Finland, at three time points: 2000-2002 (rr 67%), 2007 (rr 83%) and 2012 (rr 79%). We excluded those with common mental disorders at phase 1 (n = 1162) and in total 4681 respondents (81% women) were available for the analyses. Compared with those persistently active, those persistently inactive had an increased risk of subsequent common mental disorders. Promoting leisure-time physical activity may prove useful for preventing common mental disorders. PMID- 28340018 TI - Air embolism and CT-guided lung biopsy. PMID- 28340017 TI - Patient reporting of undesirable events: a pilot study in China. AB - Objective: To identify the frequency of undesirable events reported by patients during hospitalization and explore the relationship between undesirable events and perception of safety and satisfaction with care in China. Design: Cross sectional survey. Setting: Chinese university hospital. Participants: Adult patients (N = 341) discharged from medical and surgical departments. Interventions: Patients were interviewed post-discharge using a survey instrument to ask whether they had experienced specific undesirable events during hospitalization. Patient perception of safety and satisfaction with care received were also probed during this interview. Main outcome measures: Frequency of interpersonal problems, medical complications and healthcare process problems, and perception of safety and satisfaction with care. Results: In total, 601 undesirable events were reported (rate of 1.76 per person), including 229 interpersonal problems, 132 medical complications and 240 healthcare process problems. The most frequent event was insufficient explanation of medication side effects (22.9%). Both the perception of safety and satisfaction with care were related to the experience of undesirable events negatively. Conclusions: Many respondents experienced undesirable events during hospitalization and these experiences impacted negative on patients' feelings toward the hospital. Engaging patients as partners in reporting undesirable events is a valuable tool for identifying and monitoring problematic areas of care. In order to encourage the contribution patients could make to improving patient safety, it is necessary to develop patient incident reporting systems. PMID- 28340019 TI - Giant kissing aneurysms masquerading in the sella. PMID- 28340020 TI - Comment on: Diagnosing and attributing neuropsychiatric events to systemic lupus erythematosus: time to untie the Gordian Knot?: reply. PMID- 28340022 TI - Nicotine Content and Physical Properties of Large Cigars and Cigarillos in the United States. AB - Introduction: Cigars are combusted tobacco products consisting of filler, binder, and wrapper, which are derived from tobacco. Despite the abundance of literature on the composition of traditional combusted cigarettes, research is limited on the physical and chemical properties of cigars. Therefore, research on cigar properties may be useful to better understand their health impact. Methods: In this study, twenty large cigar and cigarillo products were characterized for physical properties (ie, weight, length, and diameter), filler nicotine content, and tobacco pH. Tobacco pH was used to calculate free nicotine content, free nicotine concentration, and percent free nicotine for all cigars using the Henderson-Hasselbach equation. An additional analysis was performed on a second batch of two large cigar and two cigarillo brands to determine within-brand consistency. All analyses were performed in triplicate. Results: The initial analysis of the twenty cigars showed that cigars exhibited wide variation in product size and nicotine content, although tobacco pH was similar across cigars. Furthermore, in the two large cigar and cigarillo brands analyzed a second time, there was considerable within-brand variance in nicotine content and concentration between the first and second analyses. Conclusions: While only a small sample of commercially-available cigars was analyzed, our data suggest there is wide variability in nicotine content and some physical properties in the domestic cigar market. The data may help to inform potential future regulatory decisions related to these products. Implications: This study reveals some of the challenges to experimental cigar research and illustrates the need to characterize cigar products (eg, nicotine and tobacco content) before use in clinical studies. Additional studies and characterization of the physical and chemical properties of cigars may be useful to further understand these products' toxicity, abuse potential, and public health impact. PMID- 28340021 TI - Phenamil, an amiloride derivative, restricts long bone growth and alters keeled sternum bone architecture in growing chickens. AB - "Broiler-type" chickens are fast-grow-ing, heavy-bodied birds with high demands on bone quality. Phenamil increased mineralization in cultured murine mesenchymal stem cells. Phenamil effects were tested in 2 groups of weight and gender matched day-old broiler chickens (n = 13). Oral administration of 30 mg phenamil/kg body weight d 1 to 13 reduced growth of chicks d 5 to 14 (P = 0.002); with phenamil treated (PT) chick body weight being 84% of vehicle-treated (VT) chicks' body weight on d 14. Tissues collected on d 15 showed that femur lengths and widths did not differ, but tibias from PT chicks were 6% shorter (P = 0.002) and 13% narrower (P = 0.012) with 18% thinner tibial cross-sections (P < 0.008) than in VT chicks. Angles of the caudal aspect of the anterior surface of keeled-sternums were 166 degrees in PT chicks, flatter than the 148 degrees found in VT chicks (P = 0.000). Total mineral content of both tibia and femur were lower in PT chicks (P = 0.005 for both). Bone Ca, P, and Mg (ppm) in ash were similar, but Ca:P was lower (1.70 vs 1.75) in PT versus VT chicks (P < 0.05). Osteocalcin was ~20% lower (P = 0.020), PINP was ~45% higher (P = 0.000) in PT chicks. Carboxy terminal telopeptide type I collagen (ICTP) and cross-linked N-telopeptide of type I collagen (NTX1) were similar in the 2 groups. Phenamil had unexpected and detrimental effects on bone formation in growing broiler chicks, reducing linear skeletal growth and markedly changing bone architecture. PMID- 28340024 TI - Opioid Overdose Risk in Low-Wage Online Workers. PMID- 28340026 TI - High rate of subcutaneous implantable cardioverter-defibrillator sensing screening failure in patients with Brugada syndrome: a comparison with other inherited primary arrhythmia syndromes. AB - Aims: Subcutaneous implantable cardioverter-defibrillator (S-ICD) can avoid important complications associated with transvenous leads in patients with inherited primary arrhythmia syndromes, who do not need pacing therapy. Few data are available on the percentage of patients with inherited arrhythmia syndromes eligible for S-ICD implantation. Aim of this study was to analyse the eligibility for S-ICD in a series of patients with Brugada syndrome (BrS), and to compare it with patients with other channelopathies. Methods and results: Patients presenting with BrS, long-QT syndrome (LQTS), early repolarization syndrome (ERS), and idiopathic ventricular fibrillation (IVF) were considered eligible for this study. ECG screening was performed by analysis of QRS complex and T wave morphology recorded in standing and supine position. Eligibility was defined when >=1 sense vector was acceptable in both supine and standing position. A total of 100 patients (72 males; mean age: 46 +/- 17 years) underwent S-ICD sensing screening. Sixty-one patients presented with BrS, 21 with LQTS, 14 with IVF, and 4 with ERS. Thirty-four patients with BrS (56%) presented with spontaneous type 1 ECG. In the other 27 patients (44%), type 1 ECG was unmasked by ajmaline. Overall, rate of screening failure was 13%. Patients with BrS had a higher rate of inappropriate morphology analysis as compared with other channelopathies (18% vs. 5%, P = 0.07) and had a lower number of suitable sensing vectors (49.6% vs. 84.7% vs. P < 0.001). Ajmaline challenge unmasked sensing failure in 14.8% of drug-induced BrS patients previously considered eligible. In all patients, the reason for sensing inappropriateness was due to the presence of high T wave voltages. Conclusion: S-ICD screening failure occurs in up to 13% of patients with inherited primary arrhythmia syndromes. Patients with BrS present a higher rate of screening failure as compared with other cardiac channelopathies. PMID- 28340027 TI - Influence of long-term in vivo exposure, debris accumulation and archwire material on friction force among different types of brackets and archwires couples. AB - Objective: The aim was to assess the influence of long-term in vivo exposure, debris accumulation and archwire material on static and kinetic friction force among different types of brackets and archwires couples. Material and Methods: Friction testing was performed among four lower incisors' brackets, conventional and self-ligating (SL), coupled with either nickel-titanium or stainless steel archwires, as-received and in vivo exposed in 18 subjects. The friction testing was performed for a sliding distance of 14 mm at a speed of 10 mm/min, with a starting force of 0.2 N. Wear and quantitative assessment of debris accumulation was performed on pictures of brackets obtained using a scanning electron microscope. Non parametric tests were used for statistical analysis. Results: Only bracket type, but not exposure duration, amount of debris accumulation, archwire material or their manufacturer, was significantly correlated with both static (rho = 0.602, P < 0.001) and kinetic (rho = 0.584, P < 0.001) friction force. Within each bracket type no significant difference was observed between as received and in vivo exposed brackets for any friction parameter except for the SL brackets in which significantly higher static and kinetic (P = 0.001, at least) friction forces were seen in in vivo exposed SL brackets (164.9 cN and 217.63 cN, respectively) in comparison with as-received SL brackets (19.69 cN and 55.72 cN, respectively). Limitation: The frictional testing was performed in the dry condition which might have influenced the results. Conclusion: A significant correlation was seen between friction force and bracket type, while treatment duration, amount of debris accumulation, archwire material or their manufacturer was not significantly correlated to it. Nevertheless, higher friction forces were measured among in vivo aged SL brackets in comparison with as-received ones. PMID- 28340028 TI - FDG PET diagnosis of primary intracranial lymphoma: radiology-pathology correlation. PMID- 28340029 TI - The proportion of errors in medical prescriptions and their executions among hospitalized children before and during accreditation. AB - Objective: To evaluate the rate of medication related errors in the pediatric ward and pediatric emergency department (PED), before and after implementing intervention strategies according to the Joint Commission International (JCI) accreditation program. Design: A retrospective cross-sectional study that included chart review. Setting: A university affiliated pediatric ward and PED. Participants: Children 0-18 years old admitted on February 2013 (before the JCI program) and February 2014 (during implementation of the JCI program). Intervention(s): A training program designed to meet the JCI official standards on medication prescribing. Main outcome measure(s): The number of prescribing and medication administration errors in the 2 years. Results: We collected 937 valid prescription orders and 924 administration orders (1861 medical orders) from February 2013, and 961 valid prescription orders and 958 administration orders (1919 medical orders) from February 2014. There was a significant reduction in prescribing errors from 6.5 to 4.2% between years 2013 and 2014 (P = 0.03). There was no significant difference in administration error rates between the two periods (104 (11.3%) in the first period and 114 (11.9%) in the second; P = 0.61). Conclusions: The errors rate we found was within the range described in the literature. Quality assurance interventions can significantly reduce medication prescribing errors. PMID- 28340030 TI - Effects of consumer-oriented health information technologies in diabetes management over time: a systematic review and meta-analysis of randomized controlled trials. AB - Objective: To reveal the effects of consumer-oriented health information technologies (CHITs) on patient outcomes in diabetes management over time through systematic review and meta-analysis. Methods: We searched 5 electronic databases (from database inception to July 2016) for studies that reported on randomized controlled trials examining the effects of CHITs on glycemic control and other patient outcomes in diabetes management. Data were analyzed using either meta analysis or a narrative synthesis approach. Results: Eighty randomized controlled trial studies, representing 87 individual trials, were identified and included for analysis. Overall, the meta-analysis showed that the use of CHITs resulted in significant improvement in glycemic control compared to usual care (standardized mean difference = -0.31%, 95% confidence interval -0.38 to -0.23, P < .001) in patients with diabetes. Specifically, improvement in glycemic control was significant at intervention durations of 3, 6, 8, 9, 12, 15, 30, and 60 months, while no significant differences were found at other time points reported. The narrative synthesis provided mixed effects of CHITs on other clinical, psychosocial, behavioral, and knowledge outcomes. Conclusions: The use of CHITs appears to be more effective than usual care in improving glycemic control for patients with diabetes. However, their effectiveness did not remain consistent over time and in other patient outcomes. Further efforts are required to examine long-term effects of CHITs and to explore factors that can moderate the effects over time. PMID- 28340031 TI - One Year Clinical Correlates of EtG Positive Urine Screening in Alcohol-Dependent Patients: A Survival Analysis. AB - Aims: Little evidence exists supporting the efficacy of regular alcohol urine screening (RAUS) in the management of alcohol dependence, despite recent improvements in urine biomarkers. In this study, we aimed at investigating 1 year, differential clinical correlates between a positive and a negative baseline urine ethyl glucuronide (EtG) screening. Methods: Alcohol-dependent outpatients participating in a previous cross-sectional study where EtG and ethanol diagnostic performances were compared in a double blind design were included. After 1 year, the presence of relapse, the number of hospitalizations and whether patients had abandoned treatment or not were assessed from electronic medical records. A survival analysis was conducted to compare time to relapse between EtG negative and positive subjects. Regression models were performed to compare the mean number of days hospitalized between groups, the risk of being lost to follow up and treatment expenses. Results: Of note, 152 patients (mean age 52, 67% males) were included. The mean time to relapse was of 163 days in EtG positive subjects, compared to 329 days in those with a negative result. In the Cox regression model, only EtG positivity yielded significant results, with a hazard ratio of 5:3 (95% CI: 3.1-9.1). EtG positive was also the only significant predictor of a greater number of hospitalization days and treatment expenses. Younger age was the only variable predicting a greater risk of treatment abandonment. Conclusion: RAUS with sensible biomarkers could improve clinicians' ability to assess patients' relapse risk. Further prospective studies will have to determine if this can be translated into a better prevention capacity. Short summary: Positive urine screenings, when conducted with highly sensible alcohol biomarkers, significantly indicate a greater risk of relapse in alcohol-dependent patients and have the capacity to predict a greater risk of hospitalization and greater treatment expenses. PMID- 28340032 TI - OsPTR7 (OsNPF8.1), a Putative Peptide Transporter in Rice, is Involved in Dimethylarsenate Accumulation in Rice Grain. AB - Rice (Oryza sativa) is a major dietary source of arsenic (As) for the population consuming rice as their staple food. Rice grain contains both inorganic As and methylated As species, especially dimethyarsinate (DMA). DMA is highly mobile in long-distance translocation in plants, but the underlying mechanism remains unknown. In the present study, we showed that OsPTR7 (OsNPF8.1), a putative peptide transporter in rice, was permeable to DMA in Xenopus laevis oocytes. Transient expression of the OsPTR7-green fluorescent protein (GFP) in tobacco protoplasts showed that OsPTR7 was localized in the cell plasma membrane. Quantitative real-time PCR analysis showed that OsPTR7 was more highly expressed in the shoots than in the roots at the seedling stage. At the flowering and grain filling stage, the OsPTR7 transcript was abundant in the leaves, node I and roots. Knockout or knockdown mutants of OsPTR7 had significantly decreased root to shoot translocation of DMA compared with wild-type plants and accumulated less As in the brown rice. In field-grown plants, DMA accounted for 35% of the total As in the brown rice of wild-type plants but was undetectable in the knockout mutant. Our study demonstrates that OsPTR7 is involved in the long-distance translocation of DMA and contributes to the accumulation of DMA in rice grain. PMID- 28340033 TI - Inappropriate inhibition of biventricular pacing due to diaphragmatic myopotentials amplified by the selectable sensing filter. PMID- 28340037 TI - Erratum. PMID- 28340034 TI - Estimating Demand and Cross-Price Elasticity for Very Low Nicotine Content (VLNC) Cigarettes Using a Simulated Demand Task. AB - Introduction: Very Low Nicotine Content (VLNC) cigarettes might be useful as part of a tobacco control strategy, but relatively little is known about their acceptability as substitutes for regular cigarettes. We compared subjective effects and demand for regular cigarettes and VLNC cigarettes, and estimated cross-price elasticity for VLNC cigarettes, using simulated demand tasks. Method: Forty New Zealand smokers sampled a VLNC cigarette and completed Cigarette Purchase Tasks to indicate their demand for regular cigarettes and VLNC cigarettes at a range of prices, and a cross-price task indicating how many regular cigarettes and VLNC cigarettes they would purchase at 0.5x, 1x, and 2x the current market price for regular cigarettes, assuming the price of VLNC cigarettes remained constant. They also rated the subjective effects of the VLNC cigarette and their usual-brand regular cigarettes. Results: Cross-price elasticity for VLNC cigarettes was estimated as 0.32 and was significantly positive, indicating that VLNC cigarettes are partially substitutable for regular cigarettes. VLNC cigarettes were rated as less satisfying and psychologically rewarding than regular cigarettes, but this was unrelated to demand or substitutability. Conclusion: VLNC cigarettes are potentially substitutable for regular cigarettes. Their availability may reduce tobacco consumption, nicotine intake and addiction; making it easier for smokers to quit. Implications: VLNC cigarettes share the behavioral and sensory components of smoking while delivering negligible levels of nicotine. Although smokers rated VLNCs as less satisfying than regular cigarettes, smokers said they would increase their consumption of VLNCs as the price of regular cigarettes increased, if VLNCs were available at a lower price. This suggests that VLNCs are partially substitutable for regular cigarettes. VLNCs can be part of an effective tobacco control strategy, by reducing nicotine dependence and improving health and financial outcomes for smokers. PMID- 28340038 TI - Coincidental coronary artery disease impairs outcome in patients with takotsubo cardiomyopathy. AB - Background and aim: Takotsubo cardiomyopathy (TC) is an important differential diagnosis of coronary artery disease (CAD), mimicking acute coronary syndrome in clinical symptoms, biomarker profiles and ST-elevation in ECG. Absence of occlusive coronary disease is an essential criterion distinguishing both diseases. The aim of the study was to explore the influence of co-existing incidental CAD on poorer clinical outcomes and all-cause mortality in TC. Design, methods and results: Our mono-centric study cohort constituted 114 consecutive patients diagnosed with TC between 2003 and 2015. The primary endpoint was the all-cause mortality. Additionally, we compared the incidence of thromboembolic events, life-threatening arrhythmias, cardiogenic shock and in-hospital death. There was no significant difference in gender distribution or mean age in both groups. Patients diagnosed with a co-existing CAD (n = 22), had a more pronounced cardiovascular risk profile. The all-cause mortality among patients with co existing CAD after a 2-year follow-up was higher than those diagnosed with lone TC (22.7 vs. 5.4 %, P = 0.07). In a multivariate cox regression analysis CAD (HR 3.5, 95 %CI 1.0-11.6; P = 0.04), LVEF <= 35% (HR 3.8, 95% CI 0.0-0.6, P = 0.01) and cardiogenic shock (HR 3.8, 95% CI 1.2-11.3; P = 0.01) were independent predictors of the primary endpoint. Conclusion: Our study reveals that co existing CAD impairs the outcome in patients with TC. The diagnostic work-up for TC should therefore not necessarily hinge on ruling out CAD. PMID- 28340040 TI - Impaired ability to grow colonies of endothelial stem cells could be the mechanism explaining the high cardiovascular morbidity and mortality of patients with depression. AB - Background: Subjects with depression are more prone to develop cardiovascular complications. Severity of depression is associated with higher rates of cardiovascular mortality and morbidity. Several mechanisms were suggested including accelerated atherosclerosis, alteration of the cardiac autonomic response with a decrease in heart rate variability. There is evidence that circulating endothelial progenitor cells (EPCs) are decreased in patients with major depression. Our hypothesis was that patients with depression would have an impaired ability to build colonies of EPCs. Methods: A prospective study enrolled twenty women with a diagnosis of major. All were not treated before for depression. Thirteen healthy age-matched women served as controls. All signed a consent form before recruitment to the study. Peripheral blood was drawn to build colonies of EPCs within 5 days. ELISA methods were used to measure levels of vascular cell adhesion molecule-1 (VCAM-1) and vascular endothelial growth factor (VEGF). Results: Twenty female patients with depression were recruited. The mean age was 43 +/- 14 years (vs. controls 41 +/- 11 years, P = 0.682), patients' average CFU-EPCs was 7 +/- 8 colonies per well (controls 31 +/- 11, P = 0.0001), VCAM-1 level was 121.7 +/- 3.0 ng/ml (controls 119.3 +/- 3.1 pg/ml, P = 0.037), VEGF level was 6.4 +/- 0.2 pg/ml (controls 5.2 +/- 0.5 pg/ml, P = 0.0001). An inverse correlation was found between VEGF level and EPCs' colonies (r = -0.547, P < 0.001) and between age and CFU-EPCs (r = -0.576, P = 0.008). Conclusions: We found that patients with major depression had high levels of VCAM-1 and VEGF. They also had a significant inhibition of EPCs' colonies. An inverse correlation was found between levels of VEGF and the ability to grow colonies of EPCs in culture. PMID- 28340039 TI - Infant birth outcomes are associated with DNA damage biomarkers as measured by the cytokinesis block micronucleus cytome assay: the DADHI study. AB - Accumulation of DNA damage in the first 1000 days may increase risk of accelerated ageing and degenerative diseases in adult life such as cancers. The extent of DNA damage in infants and the correlation of maternal factors during pregnancy with neonate birth outcomes and DNA damage is not known in infants born in Australia. Therefore, we performed a prospective cohort study to collect data on DNA damage in lymphocytes of Australian infants (aged 0, 3 and 6 months), using the cytokinesis block micronucleus cytome (CBMN-Cyt) assay. The study also explored correlation of CBMN-Cyt biomarkers with infant birth outcomes and maternal anthropometric and lifestyle variables. Peripheral blood lymphocytes were isolated from the infants at birth (cord blood) (n = 82), 3 months (n = 64) and 6 months (n = 53) after birth. DNA damage biomarkers measured ex vivo in binucleated lymphocytes (BNC) included: micronuclei (MN), nucleoplasmic bridges (NPB) and nuclear buds (NBUD). Apoptotic and necrotic lymphocytes were also scored and nuclear division index (NDI) was measured using the frequency of mono , bi- and multinucleated lymphocyte. MN and NBUD were also scored in mononucleated lymphocytes (MNC). The mean (+/- SD) frequency of MN, NPB and NBUD in BNCs at birth was 2.0 (+/- 1.2), 5.8 (+/- 3.7) and 11.1 (+/- 5.7) per 1000 BNC, respectively, and tended to decrease significantly at 3 months (P < 0.01, P < 0.0001, P < 0.001, respectively) and 6 months (P < 0.05, P < 0.0001, P < 0.0001, respectively) after birth relative to cord blood when compared with the same cohort of infants (n = 48 at birth, 48 at 3 months and 39 at 6 months). None of the CBMN cytome biomarkers measured at birth was associated with maternal smoking status, alcohol and folic acid intake during pregnancy. The mean gestation age correlated positively with MN (r = 0.38, P = 0.006), NPB (r = 0.30, P = 0.03) and negatively with NDI (r = -0.29, P = 0.03). Infant birth weight associated positively with MN, NPB and NBUD in cord blood (r = 0.24, P = 0.08; r = 0.32, P = 0.02; r = 0.28, P = 0.04, respectively), birth length associated positively with NPB (r = 0.32, P = 0.02) and NBUD (r = 0.27, P = 0.04) while head circumference associated negatively with apoptotic cells (r = -0.27, P = 0.06). APGAR score at 1 and 5 min after birth associated positively with NDI at birth (r = 0.3, P = 0.05, r = 0.28, P = 0.06, respectively). Mother's weight and body mass index (BMI) recorded at the time of recruitment associated positively with NPB (r = 0.38, P = 0.006, r = 0.32, P = 0.02, respectively) and negatively with APGAR score at 5 min (r = -0.25, P = 0.07). The significant positive associations of infant birth weight and length and maternal BMI with CBMN-Cyt biomarkers suggest the possibility of a genotoxic effect of metabolic processes that promote excessive growth and high BMI. PMID- 28340041 TI - Bleeding Complications in Patients Undergoing Intrathecal Drug Delivery System Implantation. AB - Introduction: Intrathecal drug delivery systems (IDDSs) have dramatically improved analgesia and the functional status of cancer patients and those with chronic pain states. However, given the close proximity to the neuraxis and frequent concomitant use of antiplatelet or anticoagulant medications, this intervention is not without risk. The goal of this investigation was to determine the incidence of bleeding complications following IDDS placement. Methods: This is a retrospective review from 2005 through 2014 of adult patients undergoing IDDS implantation or revision at a tertiary care center. The primary outcome was a bleeding-related neurological complication requiring emergency medicine, neurology, or neurosurgical evaluation within 31 days. Results: A total of 247 procedures were performed on 216 unique patients. Patients received aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) within seven days of needle placement for 64 procedures (25.9%). A preprocedural platelet count or international normalized ratio (INR) was available within 30 days for 138 procedures (55.9%). Of these, two patients had a platelet count lower than 100 x 109/L and one patient had an INR of 1.5 or higher at the time of the procedure. One neurological complication was identified (0.4%) that was not related to procedural bleeding. Similarly, three patients (1.2%) received a periprocedural red blood cell transfusion, none of which were related to procedural bleeding. Conclusion: No cases of bleeding-related neurological complications were identified following IDDS placement or revision, including in those receiving aspirin or NSAIDs. Future investigations with larger numbers are needed to further explore the safety of antithrombotic therapy continuation or discontinuation periprocedurally. PMID- 28340042 TI - Effects of dietary L-arginine levels on small intestine protein turnover and the expression of genes related to protein synthesis and proteolysis of layers. AB - The aim of this study was to test the effects of dietary L-arginine (Arg) levels on protein turnover in the small intestine and the expression of genes related to protein synthesis and proteolysis of laying hens. Xinyang Black commercial laying hens (n = 864, aged 217 d) were randomly distributed to 6 treatments with 4 replicates of 36 birds. The dietary treatments were corn-corn gluten meal based diets containing 0.64, 0.86, 1.03, 1.27, 1.42 and 1.66% L-Arg, respectively. Fractional protein synthesis rate (FSR) and fractional protein gain rate (FGR) in the jejunum were the highest in the 1.27% L-Arg group. The mRNA expression of target of rapamycin (TOR), ribosomal protein S6 kinase 1 (S6K1), and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) in the duodenum reached the highest in the 1.27% L-Arg group, while the mRNA expression of 20S proteasome (20S) was the lowest in the 1.27% L-Arg group. The mRNA abundances of TOR and S6K1 in the jejunum were the highest in the 1.27% L-Arg group, while the mRNA expression of 20S was the lowest in the 1.27% L-Arg group, and the protein expression and phosphorylation levels of TOR in the 1.27% L-Arg group were higher than those in the 0.64% L-Arg group. These results indicate that the action of an appropriate level of dietary L-Arg to improve the protein synthesis of the small intestine involves up-regulating the protein expression and phosphorylation level of TOR in the jejunum accompanied by inhibiting the mRNA expression of 20S of laying hens. PMID- 28340043 TI - Very long-term outcome following transcatheter ablation of atrial fibrillation. Are results maintained after 10 years of follow up? AB - Aims: Atrial fibrillation (AF) transcatheter ablation is a safe and effective procedure. However, outcome over 10 years of follow-up has never been reported. The aim of this study is to assess outcome, describe predictors of recurrences, and report on quality of life (QoL) the decade after an AF ablation. Methods and results: Patients referred for AF ablation in a single high volume centre from June 2004 to June 2006 were enrolled and followed in a prospective fashion by yearly clinical assessment and Holter monitoring. Among 255 patients (42.7% paroxysmal AF, 77% males, after a follow-up of 125 +/- 7 months), 132 (52%) were arrhythmia-free including (58, 32% after a single procedure) while 27 (10%) progressed to permanent AF. At multivariate analysis, a greater left atrium antero-posterior diameter (HR 1.05 95% CI 1.02-1.09, P = 0.02) related to arrhythmic recurrences, while no increase in blood pressure (HR 0.06 95% CI 0.02 0.20, P = 0.01), BMI (HR 0.06 95% CI 0.02-0.09, P < 0.001), and fasting glucose (HR 0.58 95% CI 0.36-0.92, P = 0.02) during follow-up were protective for arrhythmic recurrences. Overall QoL improved significantly, significantly related to the absence of recurrences, arrhythmic burden reduction and blood pressure, and BMI control (P < 0.001). Conclusion: The outcome of AF ablation over more than 10 years is characterized by a low incidence of progression towards permanent AF. Greater LA anteroposterior diameter related to arrhythmic recurrences, while blood pressure, BMI, and fasting blood glucose control emerged as predictors of sinus rhythm maintenance. Eventually, QoL improved significantly over the follow-up. PMID- 28340044 TI - Oral ghrelin receptor agonist MK-0677 increases serum insulin-like growth factor 1 in hemodialysis patients: a randomized blinded study. AB - Background: Protein-energy wasting (PEW) in end-stage renal disease (ESRD) patients is associated with increased morbidity and mortality, but options for treatment are limited. Growth hormone (GH) increases insulin-like growth factor 1 (IGF-1), with improved nutritional parameters, but must be given subcutaneously and does not provide normal GH secretion patterns. MK-0677, an oral ghrelin receptor agonist (GRA), maintains normal GH secretion and increases lean body mass in normal subjects; it has not been studied in dialysis patients, an essential step in assessing efficacy and safety prior to clinical trials. Methods: We performed a randomized crossover double-blind study in assessing the effect of MK-0677 versus placebo on IGF-1 levels, the primary outcome, in hemodialysis patients. In total, 26 subjects enrolled and 22 completed the 3 month crossover study. Results: The geometric mean IGF-1 was 1.07-fold greater [95% confidence interval (CI) 0.89-1.27; P = 0.718] after placebo. In patients receiving MK-0677, the geometric mean IGF-1 were 1.76-fold greater (95% CI 1.48 2.10; P < 0.001) following MK-0677. When the data were adjusted for preintervention IGF-1 concentration, the ratio of geometric means (MK-0677 relative to placebo) for the pre- versus postintervention change in the IGF-1 was 1.65 (95% CI 1.33-2.04; P < 0.001). These data demonstrate a 65% greater increase (95% CI 33-104%) in IGF-1 in MK-0677-dosed subjects compared with placebo. There were no serious adverse effects attributable to MK-0677. Conclusions: MK-0677 increased serum IGF-1 levels with minimal adverse effects in hemodialysis subjects. Studies are needed to evaluate whether long-term therapy with MK-0677 improves PEW, lean body mass, physical strength, quality of life and survival in CKD/ESRD patients. PMID- 28340045 TI - Age-Related Patterns in Cancer Pain and Its Psychosocial Impact: Investigating the Role of Variability in Physical and Mental Health Quality of Life. AB - Objective: Age-related patterns in cancer pain remain equivocal. Most studies ignore heterogeneity across multiple domains of well-being, and the potential role of physical (PH) and mental health (MH) quality of life (QOL) in these age related patterns is unknown. We investigated the relationships between age and cancer pain intensity, qualities, and interference, and physical and psychosocial adaptation and the interaction between age and PH and MH QOL on pain and adaptation to cancer pain. Design: In this cross-sectional study, 244 patients with advanced cancer and pain completed measures of pain, QOL, physical function, and psychosocial well-being. Pearson's correlations and ANOVAs assessed relationships between age and demographic and clinical factors, pain, and physical and psychosocial measures. Regression models tested the role of age and its interaction with PH and MH QOL on pain and physical and psychosocial adaptation. Results: Older age was associated with a lower likelihood of receiving an opioid prescription, greater likelihood of having comorbidities, and worse functional status. When we did not account for these factors, age was not associated with pain and most adaptation indices. When we did account for these factors and PH QOL, older age was associated with lower non-neuropathic and neuropathic pain and several indices of psychosocial adaptation. Most interestingly, older age was associated with lower non-neuropathic pain among those with high, but not low, MH QOL. Conclusions: This study addresses knowledge gaps about factors underlying age-related patterns in cancer pain. Impaired MH QOL may be a proxy for age-related patterns in cancer pain. Summary: This study investigated age-related patterns in the experience of cancer pain and the role of quality of life in resilience and vulnerability to pain and adaptation to pain. Older age is associated with lower non-neuropathic pain among those with high, but not low, mental health quality of life, suggesting that impaired mental health quality of life is an important indicator of vulnerability to multidimensional pain outcomes. PMID- 28340046 TI - Validation of a Screening Risk Index for Serious Prescription Opioid-Induced Respiratory Depression or Overdose in a US Commercial Health Plan Claims Database. AB - Objective: To validate a risk index that estimates the likelihood of overdose or serious opioid-induced respiratory depression (OIRD) among medical users of prescription opioids. Subjects and Methods: A case-control analysis of 18,365,497 patients with an opioid prescription from 2009 to 2013 in the IMS PharMetrics Plus commercially insured health plan claims database (CIP). An OIRD event occurred in 7,234 cases. Four controls were selected per case. Validity of the Risk Index for Overdose or Serious Opioid-induced Respiratory Depression (RIOSORD), developed previously using Veterans Health Administration (VHA) patient data, was assessed. Multivariable logistic regression was used within the CIP study population to develop a slightly refined RIOSORD. The composition and performance of the CIP-based RIOSORD was evaluated and compared with VHA-based RIOSORD. Results: VHA-RIOSORD performed well in discriminating OIRD events in CIP (C-statistic = 0.85). Additionally, re-estimation of logistic model coefficients in CIP yielded a 0.90 C-statistic. The resulting comorbidity and pharmacotherapy variables most highly associated with OIRD and retained in the CIP-RIOSORD were largely concordant with VHA-RIOSORD. These variables included neuropsychiatric and cardiopulmonary disorders, impaired drug excretion, opioid characteristics, and concurrent psychoactive medications. The average predicted probability of OIRD ranged from 2% to 83%, with excellent agreement between predicted and observed incidence across risk classes. Conclusions: RIOSORD had excellent predictive accuracy in a large population of US medical users of prescription opioids, similar to its performance in VHA. This practical risk index is designed to support clinical decision-making for safer opioid prescribing, and its clinical utility should be evaluated prospectively. PMID- 28340047 TI - A call for safety during electrophysiological procedures: US in, why not US out? Authors' reply. PMID- 28340049 TI - Cardiac troponin-I as a predictor of mortality in patients with first episode acute atrial fibrillation. AB - Background: Recent-onset atrial fibrillation (AF) is a frequent cause for presentation to the emergency department. Recent studies proposed that the addition of biomarker information might improve the prediction of clinical outcomes by enabling identification of patients at high risk. Aim: We aimed to examine the role of cardiac troponin I as a predictor of clinical outcome in patients with first episode acute AF. Design: Patients, 18 years or older, presenting to our hospital with a primary diagnosis of first episode acute AF were included in this retrospective study. Methods: The association between elevated cTnI with mortality or the composite endpoint (mortality, stroke or heart failure) was examined in a univariate Cox regression model. Results: Of the 274 study patients, 111 had elevated cTnI levels (41%). Increased cTnI was associated with older age, history of myocardial infarction, higher creatinine levels and higher heart rate (All P < 0.01). Elevated cTn was associated with an adjusted hazard ratio of 1.86 [95% confidence interval (CI) 1.17-2.96; P = 0.009] for mortality and 1.89 (95% CI 1.27-2.84; P = 0.002) for the combined endpoint. Conclusions: Elevated cardiac Troponin I is a significant predictor of mortality and a composite endpoint of mortality, stroke or heart failure in patients presenting with first episode acute AF. PMID- 28340050 TI - Naps Enhance Executive Attention in Preschool-Aged Children. AB - Objective: Executive attention is impaired following sleep loss in school-aged children, adolescents, and adults. Whether naps improve attention relative to nap deprivation in preschool-aged children is unknown. The aim of this study was to compare executive attention in preschool children following a nap and an interval of wake. Method: Sixty-nine children, 35-70 months of age, completed a Flanker task to assess executive attention following a nap and an equivalent interval of wake. Results: Overall, accuracy was greater after the nap compared with the wake interval. Reaction time(s) did not differ between the nap and wake intervals. Results did not differ between children who napped consistently and those who napped inconsistently, suggesting that naps benefit executive attention of preschoolers regardless of nap habituality. Conclusions: These results indicate that naps enhance attention in preschool children. As executive attention supports executive functioning and learning, nap promotion may improve early education outcomes. PMID- 28340051 TI - Protective factors for work ability in preschool teachers. AB - Background: Work ability (WA) describes the physical and intellectual resources on which individuals can rely to respond to work demands. While several studies have investigated the protective role of work-related psychosocial factors on WA, only a few have examined differences across age cohorts. Moreover, few studies have investigated WA in the educational context and most of those did not consider preschool teachers. Aims: To examine the role of psychosocial factors (support from colleagues, support from supervisors, work meaning, reward, skill discretion and autonomy) in sustaining WA among preschool teachers in different age cohorts. Methods: A cross-sectional study of preschool teachers employed in the municipal educational services of a city in northwest Italy. Study subjects completed a self-reported questionnaire. Results: Among the 706 study subjects, in the 35-44 age cohort, support from colleagues was positively associated with WA. In the 45-54 age cohort, WA was found to be associated with reward and skill discretion while in the 55-63 age cohort, work meaning was significantly associated with WA. Conclusions: Our findings indicate that potential protective factors for WA may differ between age cohorts. They also suggest that in order to sustain WA effectively, interventions in working populations should be tailored to employees' ages. PMID- 28340054 TI - Outcomes of atrial arrhythmia radiofrequency catheter ablation in patients with Ebstein's anomaly. AB - Aims: Atrial arrhythmias are common in patients with Ebstein's anomaly (EA) despite cardiac surgical repair and concomitant Maze procedures. We aimed to evaluate the outcome of radiofrequency catheter ablation in this group of patients. Methods and results: All patients with EA and atrial arrhythmias who underwent catheter ablation for atrial arrhythmias between 1/1999 and 1/2016 were included. Atrial arrhythmia recurrence was identified as the primary outcome; secondary outcomes included repeat ablation, need for antiarrhythmic medications after ablation, and death. Predictors of recurrence were sought using univariate analysis. 22 patients (median age 42 years, 54.5% male) were included. Atrial flutter was the most common presenting arrhythmia (n = 14 patients, 63.5%), whereas focal atrial tachycardia (FAT) and atrial fibrillation were identified in 5 (22.7%) and 2 patients (9.1%), respectively, with both atrial flutter/fibrillation evident in a single patient 1 (4.5%). 8 patients (36.4%) had a history of right-sided maze procedures. Cavotricuspid isthmus atrial flutter (CTI-AFl) was the most commonly induced arrhythmia (n = 13, 59.1%), followed by incisional intra-atrial re-entrant tachycardia (IART; n = 4, 18.2%), and FAT (n = 4, 18.2%); 3 patients also underwent left-side ablation with concomitant pulmonary vein isolation (13.6%). 1-year and 5-year atrial arrhythmia recurrence rates were 10.0% and 41.2%, respectively. 7 patients (31.8%) underwent redo ablations, and anti-arrhythmic medication was utilized in 8 patients (36.4%) post ablation. Neither ablation location nor echocardiographic parameters were found to be predictors of arrhythmia recurrence. Conclusion: Catheter ablation of atrial arrhythmias in patients with EA has a favorable outcome overall with an acceptable recurrence and safety profile; left-sided ablations are rarely necessary. Despite prior Maze and catheter ablation procedures, CTI-AFl and IART recurrences predominate. PMID- 28340053 TI - Does the Regulatory Environment for E-Cigarettes Influence the Effectiveness of E Cigarettes for Smoking Cessation?: Longitudinal Findings From the ITC Four Country Survey. AB - Introduction: To date, no studies have explored how different regulatory environments may influence the effectiveness of electronic cigarettes (ECs) as a smoking cessation aid. Objective: This study compares the real-world effectiveness of adult smokers using ECs for quitting compared with quitting unassisted or quitting with nicotine replacement therapy (NRT) and/or prescription medications in two countries with restrictive policies towards ECs (ie, Canada and Australia) versus two countries with less restrictive policies (ie, United States and United Kingdom). Methods: Data were drawn from the International Tobacco Control Four Country surveys, from the United States and Canada (2 waves, n = 318 and 380, respectively), the United Kingdom (3 waves, n = 439) and Australia (4 waves, n = 662), collected 2010-2014. Smokers at baseline wave who reported making a quit attempt at follow-up were included. The primary outcome was self-reported abstinence for at least 30 days regardless of smoking status at follow-up assessment. Data across waves were combined and analyzed using generalized estimating equations. Results: Compared to unassisted quitting (ie, no medications or ECs), smokers who used ECs for quitting from countries with less restrictive EC policy environments were more likely (OR = 1.95, 95%CI = 1.19-3.20, p < .01), whereas smokers who used ECs for quitting from countries with more restrictive EC policies were less likely (OR = 0.36, 95%CI = 0.18-0.72, p < .01), to report sustained abstinence for at least 30 days. Conclusions: Use of ECs in the real world during a quit attempt appears only effective for sustaining smoking abstinence in a less restrictive EC environment suggesting that the benefits of ECs for smoking cessation are likely highly dependent on the regulatory environment. Implications: What this study adds: This is the first study to examine the impact of regulatory environment for ECs on their real-world effectiveness for smoking cessation. This study shows that in a less restrictive EC regulatory environment, use of ECs during a quit attempt facilitates, but in a more restrictive environment, it inhibits, short-term sustained abstinence. The findings underscore the need for careful consideration on how best to regulate this emerging product so that EC benefits for smoking cessation are maximized and its risks to public health are minimized. PMID- 28340057 TI - Long-term outcome of pulmonary vein isolation in patients with paroxysmal atrial fibrillation and Brugada syndrome. AB - Aims: The therapeutical management of atrial fibrillation (AF) in the setting of Brugada syndrome (BS) might be challenging as many antiarrhythmic drugs (AADs) with sodium channel blocking properties might lead to to the development of ventricular arrhythmias. This study sought to evaluate the clinical outcome in a consecutive series of patients with BS having undergone pulmonary vein (PV) isolation by means of radiofrequency (RF) or cryoballoon (CB) ablation and the efficacy of catheter ablation for preventing inappropriate interventions delivered by implantable cardioverter defibrillators (ICD) on a 3-year follow up. Methods and results: Twenty-three consecutive patients with BS (13 males; mean age was 47 +/- 18 years) having undergone PV isolation for drug-resistant paroxysmal AF were enrolled. Eleven patients (48%) had an ICD implanted of whom four had inappropriate shocks secondary to rapid AF. Over a mean follow-up period of 35.0 +/- 25.4 months (median 36 months) the freedom from AF recurrence after the index PV isolation procedure was 74% without AADs. Patients with inappropriate ICD interventions for AF did not present futher ICD shocks after AF ablation. No major complications occurred. Conclusion: Catheter ablation is a valid therapeutic choice for patients with BS and paroxysmal AF considering the high success rates, the limitations of the AADs and the safety of the procedure, and it should be taken into consideration especially in those patients presenting inappropriate ICD shocks due to rapid AF. PMID- 28340056 TI - Neutrophil-derived mitochondrial DNA promotes receptor activator of nuclear factor kappaB and its ligand signalling in rheumatoid arthritis. AB - Objectives: Mitochondrial DNA (mtDNA) contains sequestered damage-associated molecular patterns that might be involved in osteoimmunological pathogenesis of RA. Here, we aimed to investigate the cellular source of mtDNA and its role in RANK ligand (RANKL) expression by RA SF neutrophils. Methods: The gene expression signature of SF neutrophils was examined by proteomic quantitative analysis. Levels of mtDNA in circulating and SF neutrophils from RA patients and OA control subjects were assessed by real-time PCR. Purified neutrophils were challenged in vitro with Toll-like receptor agonists as well as mtDNA. RANKL expression by neutrophils was studied by flow cytometry. Results: SF neutrophils from RA patients displayed a gene expression signature of oxidative stress. This stress signature was associated with the release of mtDNA in SF as observed by a significant increase of mtDNA in the SF of RA patients compared with OA patients. mtDNA in RA SF was correlated with systemic inflammation as assessed by CRP concentrations. We also showed that mtDNA drives neutrophil RANKL expression to the same extent as Toll-like receptor agonists. Conclusion: Our data identify SF neutrophils as a cellular source of mtDNA that leads to a subsequent expression of RANKL. This highlights the important role of neutrophils in RA osteoimmunology. PMID- 28340058 TI - Predictive modeling for monitoring egg freshness during variable temperature storage conditions. AB - The overall aim of this research was to develop egg freshness prediction models in terms of selected quality indices. Six experiments (4 constant temperatures and 2 variable temperatures) were carried out on hen eggs for a total period of 10, 21, 26, 13, and 105 d at storage temperatures of 30, 20, 20 to 10, 30 to 10, and 5 and 10 degrees C, to observe trends in the relative weight loss (RWL), Haugh unit (HU), yolk index (YI), albumin index (AI), yolk pH, and albumin pH. The results showed that there was an increasing trend in the RWL and a decreasing trend in the YI, AI, and HU for all temperature conditions. The changes in the yolk and albumin pH were not uniform. The data from the constant temperature conditions were used to determine the coefficients of the egg quality prediction models, which consisted of the primary model controlling the change rate of the quality indicator at a temperature condition in differential equation form, and the secondary model controlling the change rate with temperature, which was in quadratic polynomial form. The models were applied to the data from the fluctuating temperature conditions, and the zeroth, third, and eighth order kinetic models described the stepwise change in the RWL, HU, and YI, respectively. The accuracy and bias factor values for the RWL, HU, and YI were 1.116 and 0.940, 1.028 and 1.001, and 1.038 and 0.966, respectively. It can be concluded that the models can be used to predict egg freshness in terms of the RWL, HU, and YI at any temperature condition with in the range of 5 to 30 degrees C during storage. PMID- 28340059 TI - Topic Modeling of Smoking- and Cessation-Related Posts to the American Cancer Society's Cancer Survivor Network (CSN): Implications for Cessation Treatment for Cancer Survivors Who Smoke. AB - Introduction: Smoking is a risk factor in at least 18 cancers, and approximately two-thirds of cancer survivors continue smoking following diagnosis. Text mining of survivors' online posts related to smoking and quitting could inform strategies to reduce smoking in this vulnerable population. Methods: We identified posts containing smoking/cessation-related keywords from the Cancer Survivors Network (CSN), an online cancer survivor community of 166 000 members and over 468 000 posts since inception. Unsupervised topic model analysis of posts since 2000 using Latent Dirichlet Allocation extracted 70 latent topics which two subject experts inspected for themes based on representative terms. Posterior analysis assessed the distribution of topics within posts, and the range of themes discussed across posts. Results: Less than 1% of posts (n = 3998) contained smoking/cessation-related terms, and covered topics related to cancer diagnoses, treatments, and coping. The most frequent smoking-related topics were quit smoking methods (5.4% of posts), and the environment for quitters (2.9% of posts), such as the stigma associated with being a smoker diagnosed with cancer and lack of empathy experienced compared to nonsmokers. Smoking as a risk factor for one's diagnosis was a primary topic in only 1.7% of smoking/cessation-related posts. Conclusions: The low frequency of smoking/cessation-related posts may be due to expected criticism/stigma for smoking but may also suggests a need for health care providers to address smoking and assist with quitting in the diagnostic and treatment process. Topic model analysis revealed potential barriers that should be addressed in devising clinical or population-level interventions for cancer survivors who smoke. Implications: Although smoking is a major risk factor for cancer, little is known about cancer patients' or survivors' views or concerns about smoking and quitting. This study used text mining of posts to an online community of cancer patients and survivors to investigate contexts in which smoking or quitting is discussed. Results indicated that smoking and quitting discussions were relatively rare, but nevertheless provide insight into barriers that may need to be addressed in cessation interventions for survivors. PMID- 28340060 TI - Physician Dispensing of Oxycodone and Other Commonly Used Opioids, 2000-2015, United States. AB - Objective: An average of 91 people in the United States die every day from an opioid-related overdose (including prescription opioids and heroin). The direct dispensing of opioids from health care practitioner offices has been linked to opioid-related harms. The objective of this study is to describe the changing nature of the volume of this type of prescribing at the state level. Methods: This descriptive study examines the distribution of opioids by practitioners using 1999-2015 Automation of Reports and Consolidated Orders System data. Analyses were restricted to opioids distributed to practitioners. Amount distributed (morphine milligram equivalents [MMEs]) and number of practitioners are presented. Results: Patterns of distribution to practitioners and the number of practitioners varied markedly by state and changed dramatically over time. Comparing 1999 with 2015, the MME distributed to dispensing practitioners decreased in 16 states and increased in 35. Most notable was the change in Florida, which saw a peak of 8.94 MMEs per 100,000 persons in 2010 (the highest distribution in all states in all years) and a low of 0.08 in 2013. Discussion: This study presents the first state estimates of office-based dispensing of opioids. Increases in direct dispensing in recent years may indicate a need to monitor this practice and consider whether changes are needed. Using controlled substances data to identify high prescribers and dispensers of opioids, as well as examining overall state trends, is a foundational activity to informing the response to potentially high-risk clinical practices. PMID- 28340061 TI - Venous thrombo-embolism: thalidomide and leprosy. PMID- 28340062 TI - Exogenously Applied 24-Epibrassinolide (EBL) Ameliorates Detrimental Effects of Salinity by Reducing K+ Efflux via Depolarization-Activated K+ Channels. AB - This study has investigated mechanisms conferring beneficial effects of exogenous application of 24-epibrassinolides (EBL) on plant growth and performance under saline conditions. Barley seedlings treated with 0.25 mg l-1 EBL showed significant improvements in root hair length, shoot length, shoot fresh weight and relative water content when grown in the presence of 150 mM NaCl in the growth medium. In addition, EBL treatment significantly decreased the Na+ content in both shoots (by approximately 50%) and roots. Electrophysiological experiments revealed that pre-treatment with EBL for 1 and 24 h suppressed or completely prevented the NaCl-induced K+ leak in the elongation zone of barley roots, but did not affect root sensitivity to oxidative stress. Further experiments using Arabidopsis loss-of-function gork1-1 (lacking functional depolarization-activated outward-rectifying K+ channels in the root epidermal cells) and akt1 (lacking inward-rectifying K+ uptake channel) mutants showed that NaCl-induced K+ loss in the elongation zone of roots was reduced by EBL pre-treatment 50- to 100-fold in wild-type Col-0 and akt1, but only 10-fold in the gork1-1 mutant. At the same time, EBL treatment shifted vanadate-sensitive H+ flux towards net efflux. Taken together, these data indicate that exogenous application of EBL effectively improves plant salinity tolerance by prevention of K+ loss via regulating depolarization-activated K+ channels. PMID- 28340063 TI - Conventional (Simplicity III) and Cooled (SInergy) Radiofrequency for Sacroiliac Joint Denervation: One-Year Retrospective Study Comparing Two Devices. AB - Objective: To compare two radiofrequency (RF) devices, Simplicity III (conventional RF), and SInergy (cooled RF), which are specifically designed to denervate the sacroiliac joint (SIJ). Design: Retrospective observational study. Setting: Italian National Health Service Public Hospital. Subjects: Forty-three patients with SIJ-derived pain refractory to conservative treatment; 21 and 22 patients, respectively, received Simplicity III or SInergy to denervate the SIJ. Methods: Mean numerical rating scale (NRS) and Oswestry Disability Index (ODI) scores were determined for each study group up to 12 months postprocedure. Secondary outcomes included the average amount of time required to complete each RF procedure and the adverse events associated with each technique. Results: Average SInergy group NRS and ODI scores were consistently less than those in the Simplicity III cohort at each post-RF denervation follow-up, and such differences were statistically significant at six and 12 months. The Simplicity III procedure was completed approximately 2.5 times faster than the SInergy procedure, and one minor adverse event was reported in the SInergy group. Conclusions: The study results suggest that SInergy safely afforded patients with greater and more durable analgesia and disability relief than Simplicity III for SIJ-derived pain. The Simplicity III procedure may be more conducive than SInergy for bilateral procedures and for patients who have limited tolerance to be in an RF procedure required prone position. Randomized controlled trials are needed to confirm the implication made in this study that SInergy is the preferred RF denervation option for treating SIJ-derived pain and the disability associated with it. PMID- 28340064 TI - The Influence of State and Trait Anxiety on the Memory of Pain. AB - Objective: The study aimed to assess the accuracy of memories of both pain and the state anxiety that accompanies experimentally induced pain and to investigate the factors that influence the memory of experimental pain. Methods: Forty-nine healthy female volunteers participated in the study. The participants received three electrocutaneous pain stimuli during the first phase of the study and rated the pain intensity, pain unpleasantness, and state anxiety they felt at that moment. Trait pain anxiety was measured by the Pain Anxiety Symptoms Scale and the Fear of Pain Questionnaire. During the second phase of the study, three or six months later (depending on the experimental group), the participants were asked to rate the pain intensity, pain unpleasantness, and state anxiety they had felt during the first phase of the study. Results: Recalled pain intensity and unpleasantness and the state anxiety that accompanied the pain experience were remembered accurately, regardless of the recall delay. Both recalled pain intensity and unpleasantness were predicted by experienced pain, experienced and recalled state anxiety, and trait pain anxiety, that is, scores for physiological anxiety, cognitive anxiety, escape/avoidance, and severe pain. Conclusions: The present study demonstrates that a specific type of trait anxiety (pain anxiety) influences the memory of pain. The study is not only the first to investigate the influence of trait anxiety on the memory of experimental pain, it also is the first study to determine the effect of a specific form of anxiety (pain anxiety) on the memory of experimentally induced pain. PMID- 28340065 TI - The next three decades of the comet assay: a report of the 11th International Comet Assay Workshop. AB - The International Comet Assay Workshops are a series of scientific conferences dealing with practical and theoretical aspects of the Comet Assay (single-cell gel electrophoresis)-a simple method for detecting DNA strand breaks. The first paper describing such an assay was published over 30 years ago in 1984 by Swedish researchers O. Ostling and K. J. Johanson. Appropriately, the theme for the 2015 meeting was looking to the future: 'The Next 3 Decades of the Comet Assay'. The programme included 25 oral and 43 poster presentations depicting the latest advances in technical developments as well as applications of the comet assay in genotoxicity testing (in vitro and in vivo) and biomonitoring of both humans and the environment. Open discussion sessions based on questions from the participants allowed exchange of practical details on current comet assay protocols. This report summarises technical issues of high importance which were discussed during the sessions. We provide information on ways to improve the assay performance, by testing for cytotoxicity, by using reference samples to reduce or allow for inter-experimental variation, and by standardising quantification of the damage, including replicates and scoring enough comets to ensure statistical validity. After 30 years of experimentation with the comet assay, we are in a position to control the important experimental parameters and make the comet assay a truly reliable method with a wealth of possible applications. PMID- 28340068 TI - Demanding Competence. PMID- 28340066 TI - Diagnostic test accuracy of ultrasound for synovitis in rheumatoid arthritis: systematic review and meta-analysis. AB - Objective: To evaluate diagnostic test accuracy of US compared with MRI for the detection of synovitis in RA patients. Methods: A systematic literature search was performed in the PubMed, EMBASE, Cochrane Library and Web of Science Core Collection databases. Studies evaluating the diagnostic test accuracy of US for synovitis detected by MRI as the reference standard for wrist, MCP, PIP and knee joints were included. To assess the overall accuracy, we calculated the diagnostic odds ratio using a DerSimonian-Laird random effects model and the area under the curve (AUC) for the hierarchical summary receiver operating characteristics using Holling's proportional hazards models. The summary estimate of the sensitivity and specificity were obtained using the bivariate model. Results: Fourteen of 601 identified articles were included in the review. The diagnostic odds ratio was 11.6 (95% CI 5.6, 24; I2 = 0%), 28 (95% CI 12, 66; I2 = 11%), 23 (95% CI 6.5, 84; I2 = 19%) and 5.3 (95% CI 0.60, 48; I2 = 0%) and the AUC was 0.81, 0.91, 0.91 and 0.61 for wrist, MCP, PIP and knee joints, respectively. The summary estimates of sensitivity and specificity were 0.73 (95% CI 0.51, 0.87)/0.78 (95% CI 0.46, 0.94), 0.64 (95% CI 0.43, 0.81)/0.93 (95% CI 0.88, 0.97), 0.71 (95% CI 0.33, 0.93)/0.94 (95% CI 0.89, 0.97) and 0.91 (95% CI 0.56, 0.99)/0.60 (95% CI 0.20, 0.90) for wrist, MCP, PIP and knee joints, respectively. Conclusion: US is a valid and reproducible technique for detecting synovitis in the wrist and finger joints. It may be considered for routine use as part of the standard diagnostic tools in RA. PMID- 28340069 TI - The Association of Post-traumatic and Postmigration Stress with Pain and Other Somatic Symptoms: An Explorative Analysis in Traumatized Refugees and Asylum Seekers. AB - Objective: Post-traumatic stress disorder (PTSD) and somatic symptoms, such as pain, are frequently seen in refugees. Their relationship is poorly understood, and the treatment of these comorbid conditions can be very challenging. The current cross-sectional study examined pain and other somatic symptoms and their relationship with trauma history, PTSD symptom clusters, and current living difficulties among treatment-seeking refugees. Methods: One hundred thirty-four treatment-seeking traumatized refugees (78% male, mean age = 42 years) were assessed regarding lifetime traumatic experiences, symptoms of post-traumatic stress, overall pain and somatic symptoms, and postmigration living difficulties. Results: An exploratory factor analysis of the 12 somatic symptoms revealed two distinct factors: somatic symptoms related to bodily dysfunction ("weakness") and somatic symptoms related to increased sympathetic activity ("arousal"). DSM-5 PTSD Criteria D "alterations in cognitions and mood" and E "alterations in arousal and reactivity" were primarily related to "weakness," while PTSD Criterion E "alterations in arousal and reactivity" and postmigration living difficulties were associated with "arousal." Overall pain was associated primarily with living difficulties and PTSD Criterion D and Criterion E. Conclusions: Results indicate that somatic symptoms are of considerable concern among traumatized refugees and that different patterns of somatic symptoms are associated with different clusters of PTSD symptoms. The findings contribute to the better understanding of the symptom presentation of traumatized people who are experiencing somatization and potentially inform treatment directions and highlight the importance of screening for PTSD in refugees presenting with pain and somatic symptoms. PMID- 28340070 TI - Material Hardship and Self-Rated Mental Health among Older Black Americans in the National Survey of American Life. AB - This article examines the association between material hardships and self-rated mental health (SRMH) among older black Americans and determines whether the effect varies by race and ethnicity. Using data from the National Survey of American Life, multiple logistic regression models were specified on a sample of older white Americans (n = 289), African Americans (n = 1,135), and black Caribbean Americans (n = 377). Material hardship was measured as an index of seven items that occurred within the past year. Material hardship (odds ratio = 0.48; 95 percent confidence interval = 0.29-0.79) was associated with SRMH for both groups. None of the interactions were significant. The study concludes that material hardship may contribute to poorer SRMH among older African Americans and black Caribbean Americans. Future studies should examine these associations by using longitudinal designs, which may be better designed to confirm these results. PMID- 28340071 TI - Variable Potassium Concentrations: Which Is Right and Which Is Wrong? AB - Reverse pseudohyperkalemia is a term used to describe in vitro, falsely elevated potassium concentrations in plasma specimens that occur in association with extreme leukocytosis and are commonly associated with hematologic malignant neoplasms. Tumor lysis syndrome is an in vivo lysis of tumor cells that leads to elevated levels of potassium, uric acid, phosphate, and lactate dehydrogenase, as well as decreased calcium concentrations. Herein, we report a case of a 66-year old Caucasian man with stage IV mantle-cell lymphoma who has elevated levels of potassium, uric acid, and phosphorus, as well as a white blood cell (WBC) count greater than 100,000 cells per mm3. The patient initially was diagnosed as having tumor lysis syndrome. His subsequent potassium concentrations in whole blood remained elevated even after hemodialysis; however, his serum potassium concentrations were decreased. The patient then was diagnosed accurately as having reverse pseudohyperkalemia, and accurate potassium measurements were obtained via serum specimens. PMID- 28340072 TI - Loneliness in Children and Adolescents With Chronic Physical Conditions: A Meta Analysis. AB - Objective: This meta-analysis examines loneliness in children and adolescents with chronic physical conditions as compared with their peers. Multilevel meta analyses were performed on 43 studies (69 samples), published between 1987 and 2015. A total of 2,518 individuals with chronic physical conditions and 1,463 control peers were included in the analyses. Children and adolescents with chronic conditions are, on average, somewhat lonelier than their peers without such conditions. Moreover, the link between chronic conditions and loneliness varied according to the recruitment procedure used for participant selection. Stronger links were found for studies that recruited from patient organizations as compared with clinical registers. Findings support the link between loneliness and chronic conditions. To take into account the heterogeneity within patient groups, we advocate an alternative approach that cuts across diagnostic boundaries and focuses on illness-related variables such as illness duration and visibility of the condition. PMID- 28340073 TI - Left atrial appendage isolation in addition to pulmonary vein isolation in persistent atrial fibrillation: one-year clinical outcome after cryoballoon-based ablation. AB - Aims: In this study, we sought to evaluate the safety and efficacy of cryoballoon (CB) based empirical left atrial appendage (LAA) isolation as an adjunct to pulmonary vein isolation (PVI) compared to the PVI-only strategy in patients with persistent AF. Objectives: Clinical outcomes of catheter ablation were less beneficial for persistent atrial fibrillation (AF) than paroxysmal AF. Methods and results: A total of 100 consecutive patients with persistent AF underwent both PVI and additional LAA isolation using CB (Group II). As a control group (Group I), among persistent AF patients, we conducted a retrospective, propensity score matched cohort, in whom only PVI was performed using CB. Recurrence of atrial tachyarrhythmia (Ata) at the 12th month follow-up was the primary endpoint. Baseline demographic and clinical characteristics were similar between two groups. At the 12th month follow-up, 67 (67%) patients in Group I and 86 (86%) patients in Group II were free of ATa after the index procedure (P < 0.001). As a unique complication of LAA isolation, left circumflex artery spasm was observed in 4% of the Group II. After adjusting for several baseline variables, PVI-only strategy was found as a significant predictor for recurrence (HR: 3.37; 95% CI: 1.73-6.56; P < 0.001). Transoesophageal echocardiography examination during the follow-up revealed no thrombus in the LAA. Conclusion: Our findings indicated that LAA isolation as an adjunct to PVI improved 1-year outcomes in persistent AF compared with the PVI-only strategy using CB without an increase in thromboembolic complications. PMID- 28340076 TI - Cisplatin-induced renal inflammation is ameliorated by cilastatin nephroprotection. AB - Background: Cisplatin is a potent chemotherapeutic drug whose nephrotoxic effect is a major complication and a dose-limiting factor for antitumoral therapy. There is much evidence that inflammation contributes to the pathogenesis of cisplatin induced nephrotoxicity. We found that cilastatin, a renal dehydropeptidase-I inhibitor, has protective effects in vitro and in vivo against cisplatin-induced renal damage by inhibiting apoptosis and oxidation. Here, we investigated the potential use of cilastatin to protect against cisplatin-induced kidney injury and inflammation in rats. Methods: Male Wistar rats were divided into four groups: control, cilastatin-control, cisplatin and cilastatin-cisplatin. Nephrotoxicity was assessed 5 days after administration of cisplatin based on blood urea nitrogen, creatinine, glomerular filtration rate (GFR), kidney injury molecule (KIM)-1 and renal morphology. Inflammation was measured using the electrophoretic mobility shift assay, immunohistochemical studies and evaluation of inflammatory mediators. Results: Compared with the control rats, cisplatin administered rats were affected by significant proximal tubule damage, decreased GFR, increased production of inflammatory mediators and elevations in urea, creatinine and tissue KIM-1 levels. Cilastatin prevented these changes in renal function and ameliorated histological damage in cisplatin-administered animals. Cilastatin also reduced pro-inflammatory cytokine levels, activation of nuclear factor-kappaB and CD68-positive cell concentrations. Conclusions: Cilastatin reduces cisplatin-induced nephrotoxicity, which is associated with decreased inflammation in vivo. Although the exact role of decreased inflammation in nephroprotection has not been fully elucidated, treatment with cilastatin could be a novel strategy for the prevention of cisplatin-induced acute kidney injury. PMID- 28340078 TI - Image integration into 3-dimensional-electro-anatomical mapping system facilitates safe ablation of ventricular arrhythmias originating from the aortic root and its vicinity. AB - Aims: During ablation in the vicinity of the coronary arteries establishing a safe distance from the catheter tip to the relevant vessels is mandatory and usually assessed by fluoroscopy alone. The aim of the study was to investigate the feasibility of an image integration module (IIM) for continuous monitoring of the distance of the ablation catheter tip to the main coronary arteries during ablation of ventricular arrhythmias (VA) originating in the sinus of valsalva (SOV) and the left ventricular summit part of which can be reached via the great cardiac vein (GCV). Methods and results: Of 129 patients undergoing mapping for outflow tract arrhythmias from June 2014 till October 2015, a total of 39 patients (52.4 +/- 18.1 years, 17 female) had a source of origin in the SOV or the left ventricular summit. Radiofrequency (RF) ablation was performed when a distance of at least 5 mm could be demonstrated with IIM. A safe distance in at least one angiographic plane could be demonstrated in all patients with a source of origin in the SOV, whereas this was not possible in 50% of patients with earliest activation in the summit area. However, using the IIM a safe position at an adjacent site within the GCV could be obtained in three of these cases and successful RF ablation performed safely without any complications. Ablation was successful in 100% of patients with an origin in the SOV, whereas VAs originating from the left ventricular summit could be abolished completely in only 60% of cases. Conclusion: Image integration combining electroanatomical mapping and fluoroscopy allows assessment of the safety of a potential ablation site by continuous real-time monitoring of the spatial relations of the catheter tip to the coronary vessels prior to RF application. It aids ablation in anatomically complex regions like the SOV or the ventricular summit providing biplane angiograms merged into the three-dimensional electroanatomical map. PMID- 28340077 TI - Idiopathic non-lupus full-house nephropathy is associated with poor renal outcome. AB - Background: Full-house immunofluorescence in combination with various histopathologic lesions in the renal biopsies of patients without overt systemic lupus erythematosus (SLE) poses a diagnostic challenge. In this setting, the biopsy findings are sometimes termed non-lupus 'full-house nephropathy' (FHN). It is presently unknown whether idiopathic non-lupus FHN is clinicopathologically and prognostically distinct from lupus FHN. Methods: We included non-lupus FHN patients and lupus FHN controls (four or more American College of Rheumatology or Systemic Lupus International Collaborating Clinics criteria) who were biopsied between 1968 and 2014 at the Leiden University Medical Centre. Non-lupus FHN patients were studied for progression to SLE and/or the presence of other conditions with FHN. The clinicopathologic characteristics and prognosis of idiopathic non-lupus FHN patients were compared with those of lupus FHN patients. Results: Of 149 included patients, 32 had non-lupus FHN. During the median follow up of 20 years, no non-lupus FHN patients developed SLE. In all, 20 non-lupus FHN patients had idiopathic non-lupus FHN, and in 12 patients, secondary non-lupus FHN was considered due to membranous nephropathy (anti-PLA2R-positive, n = 1; cancer-associated, n = 3), IgA nephropathy ( n = 4), infection-related glomerulonephritis ( n = 2) or anti-neutrophil cytoplasmic antibody-associated glomerulonephritis ( n = 2). Idiopathic non-lupus FHN patients were more often male (P < 0.001) than lupus FHN patients and their renal biopsies more often showed a mesangial (P = 0.04) or membranous pattern of injury (P = 0.02) and less intense C1q staining (P = 0.002). Clinically, they presented with lower-range erythrocyturia (P = 0.04), more proteinuria (P < 0.01) and less complement consumption in the classical pathway (P < 0.001) than lupus FHN patients. By multivariable Cox regression analysis of patients with a lupus nephritis class III/IV pattern of injury, idiopathic non-lupus FHN compared with lupus FHN was an independent risk factor for end-stage renal disease [hazard ratio 5.31 (95% confidence interval 1.47-19.24)]. Conclusions: Our results show that the clinical recognition of idiopathic non-lupus FHN as a diagnostic category is critical. PMID- 28340079 TI - Measured glomerular filtration rate does not improve prediction of mortality by cystatin C and creatinine. AB - Background: Cystatin C may add explanatory power for associations with mortality in combination with other filtration markers, possibly indicating pathways other than glomerular filtration rate (GFR). However, this has not been firmly established since interpretation of associations independent of measured GFR (mGFR) is limited by potential multicollinearity between markers of GFR. The primary aim of this study was to assess associations between cystatin C and mortality, independent of mGFR. A secondary aim was to evaluate the utility of combining cystatin C and creatinine to predict mortality risk. Methods: Cox regression was used to assess the associations of cystatin C and creatinine with mortality in 1157 individuals referred for assessment of plasma clearance of iohexol. Results: Since cystatin C and creatinine are inversely related to mGFR, cystatin C - 1 and creatinine - 1 were used. After adjustment for mGFR, lower cystatin C - 1 (higher cystatin C concentration) and higher creatinine - 1 (lower creatinine concentration) were independently associated with increased mortality. When nested models were compared, avoiding the potential influence of multicollinearity, the independence of the associations was supported. Among models combining the markers of GFR, adjusted for demographic factors and comorbidity, cystatin C - 1 and creatinine - 1 combined explained the largest proportion of variance in associations with mortality risk ( R 2 = 0.61). Addition of mGFR did not improve the model. Conclusions: Our results suggest that both creatinine and cystatin C have independent associations with mortality not explained entirely by mGFR and that mGFR does not offer a more precise mortality risk assessment than these endogenous filtration markers combined. PMID- 28340080 TI - Measuring PM2.5, Ultrafine Particles, Nicotine Air and Wipe Samples Following the Use of Electronic Cigarettes. AB - Background: Few studies have examined the extent of inhalation or dermal contact among bystanders following short-term, secondhand e-cigarette exposure. Objective: Measure PM2.5 (particles < 2.5 microns), UF (ultrafine particles < 100 nm), and nicotine in air and deposited on surfaces and clothing pre-/during/post- a short-term (2-hour) e-cigarette exposure. Methods: E-cigarettes were used ad libitum by three experienced users for 2 hours during two separate sessions (disposable e-cigarettes, then tank-style e-cigarettes, or "tanks") in a 1858 ft3 room. We recorded: uncorrected PM2.5 (using SidePak); UF (using P-Trak); air nicotine concentrations (using air samplers; SKC XAD-4 canisters); ambient air exchange rate (using an air capture hood). Wipe samples were taken by wiping 100 cm2 room surfaces pre- and post- both sessions, and clean cloth wipes were worn during the exposure and collected at the end. Results: Uncorrected PM2.5 and UF were higher (p < .0001) during sessions than before or after. Median PM2.5 during exposure was higher using tanks (0.515 mg/m3) than disposables (0.035 mg/m3) (p < .0001). Median UF during exposure was higher using disposables (31 200 particles/cm3) than tanks (25 200 particles/cm3)(p < .0001). Median air nicotine levels were higher (p < .05) during both sessions (disposables = 0.697 ng/L, tanks = 1.833 ng/L) than before (disposables = 0.004 ng/L, tanks = 0.010 ng/L) or after (disposables = 0.115 ng/L, tanks = 0.147 ng/L). Median accumulation rates of nicotine on surface samples were 2.1 ng/100 cm2/h using disposables and 4.0 ng/100 cm2/h using tanks; for cloth samples, it was 44.4 ng/100 cm2/h using disposables and 69.6 ng/100 cm2/h using tanks (p < .01). Mean room ventilation rate was ~5 air changes per hour during both sessions. Conclusions: Short-term e cigarette use can produce: elevated PM2.5; elevated UF; nicotine in the air; and accumulation of nicotine on surfaces and clothing. Implications: Short-term indoor e-cigarette use produced accumulation of nicotine on surfaces and clothing, which could lead to dermal exposure to nicotine. Short-term e-cigarette use produced elevated PM2.5 and ultrafine particles, which could lead to secondhand inhalation of these particles and any chemicals associated with them by bystanders. We measured significant differences in PM2.5 and ultrafine particles between disposable e-cigarettes and tank-style e-cigarettes, suggesting a difference in the exposure profiles of e-cigarette products. PMID- 28340081 TI - Retroocular and Subdural Hemorrhage or Hemosiderin Deposits in Pediatric Autopsies. AB - The presence of hemosiderin in the optic nerve sheath and/or retina is sometimes used to estimate the timing of injury in infants or children with suspected non accidental head trauma. To determine the prevalence of hemosiderin in deaths not associated with trauma, we performed a prospective study of retroocular orbital tissue, cranial convexity, and cervical spinal cord dura mater in infants and children <2.5 years age. In 53 cases of non-traumatic death, approximately 70% had blood or hemosiderin within the orbital fat, ocular muscles, and parasagittal cranial and/or cervical spinal subdural compartment. This bleeding is likely a consequence of the birth process. None had evidence of hemorrhage within the optic nerve sheath. Premature birth was less likely associated with orbital tissue hemorrhage. Caesarean section birth (mainly nonelective) was not associated with lower prevalence. Residual hemosiderin was identifiable up to 36 weeks postnatal age, suggesting gradual disappearance after birth. Cardiopulmonary resuscitation (performed in the majority of cases) was not associated with acute hemorrhage. In 9 traumatic deaths, 6 had blood and/or hemosiderin within the optic nerve sheath. Knowledge of the potential presence and resolution of hemosiderin in these locations is important for medicolegal interpretation of childhood deaths associated with head or brain injury. PMID- 28340082 TI - Disparities in Health Care Quality among Asian Children with Special Health Care Needs. AB - There is a dearth of information on the quality of health care for Asian American children and particularly Asian children with special health care needs (CSHCN). The goal of this article was to determine whether there were disparities in quality of health care for Asian CSHCN, whose experiences have not been studied. Data were derived from the 2009-2010 National Survey of Children with Special Health Care Needs (ns = 355 non-Hispanic Asian children and 4,343 non-Hispanic white CSHCN). Bivariate and multivariate logistic regression analyses were conducted to examine the relationship between racial identity (that is, non Hispanic white and non-Hispanic Asian) and quality of health care. Racial disparities in quality of health care were substantial between Asian and white CSHCN in 2009-2010. Asian parents were significantly less likely than white parents to report that their health care provider provided the specific information they needed, helped them feel like a partner in their child's care, and was sensitive to the family's values and customs. The development and testing of specific, targeted policy and practice interventions to reduce disparities in health care quality for these children are urgently needed. PMID- 28340085 TI - Prevalence of Neuropathic Pain in Patients with Traumatic Brachial Plexus Injury: A Multicenter Prospective Hospital-Based Study. AB - Objective: Prevalence and clinical characteristics of neuropathic pain due to traumatic brachial plexus injury. Design: Observational epidemiological study. Setting: Hospital-based multicenter study. Subjects: One hundred seven prospectively enrolled patients with brachial plexus injury. Methods: All the patients underwent clinical examination and neurophysiological testing for a definitive diagnosis of the brachial plexus lesion. The DN4 questionnaire was used to identify neuropathic pain, and the Neuropathic Pain Symptom Inventory (NPSI) to evaluate the different symptoms of neuropathic pain. The SF36 questionnaire and the Beck Depression Inventory (BDI) were used to assess quality of life and mood disturbances in patients with neuropathic pain. Results: Of the 107 enrolled patients, 74 had pain (69%); neuropathic pain, as assessed by means of the DN4, was identified in 60 (56%) of these patients. According to the NPSI, the most frequent and severe pain type was the spontaneous burning pain. Clinical and neurophysiological findings showed that pain is unrelated to age but is associated with the severity of peripheral nerve damage. The SF36 questionnaire and BDI showed that neuropathic pain impairs quality of life and causes depression. Conclusions: Our study provides information on the prevalence, characteristics, and variables associated with neuropathic pain due to traumatic brachial plexus injuries that might provide a basis for improving the clinical management of this condition. PMID- 28340083 TI - Evaluating the Patterns of Aging-Related Tau Astrogliopathy Unravels Novel Insights Into Brain Aging and Neurodegenerative Diseases. AB - The term "aging-related tau astrogliopathy" (ARTAG) describes pathological accumulation of abnormally phosphorylated tau protein in astrocytes. We evaluated the correlates of ARTAG types (i.e., subpial, subependymal, white and gray matter, and perivascular) in different neuroanatomical regions. Clinical, neuropathological, and genetic (eg, APOE epsilon4 allele, MAPT H1/H2 haplotype) data from 628 postmortem brains from subjects were investigated; most of the patients had been longitudinally followed at the University of Pennsylvania. We found that (i) the amygdala is a hotspot for all ARTAG types; (ii) age at death, male sex, and presence of primary frontotemporal lobar degeneration (FTLD) tauopathy are significantly associated with ARTAG; (iii) age at death, greater degree of brain atrophy, ventricular enlargement, and Alzheimer disease (AD) related variables are associated with subpial, white matter, and perivascular ARTAG types; (iv) AD-related variables are associated particularly with lobar white matter ARTAG; and (v) gray matter ARTAG in primary FTLD-tauopathies appears in areas without neuronal tau pathology. We provide a reference map of ARTAG types and propose at least 5 constellations of ARTAG. Furthermore, we propose a conceptual link between primary FTLD-tauopathy and ARTAG-related astrocytic tau pathologies. Our observations serve as a basis for etiological stratification and definition of progression patterns of ARTAG. PMID- 28340086 TI - Real-World Massage Therapy Produces Meaningful Effectiveness Signal for Primary Care Patients with Chronic Low Back Pain: Results of a Repeated Measures Cohort Study. AB - Objective: While efficacy of massage and other nonpharmacological treatments for chronic low back pain is established, stakeholders have called for pragmatic studies of effectiveness in "real-world" primary health care. The Kentucky Pain Research and Outcomes Study evaluated massage impact on pain, disability, and health-related quality of life for primary care patients with chronic low back pain. We report effectiveness and feasibility results, and make comparisons with established minimal clinically important differences. Methods: Primary care providers referred eligible patients for 10 massage sessions with community practicing licensed massage therapists. Oswestry Disability Index and SF-36v2 measures obtained at baseline and postintervention at 12 and 24 weeks were analyzed with mixed linear models and Tukey's tests. Additional analyses examined clinically significant improvement and predictive patient characteristics. Results: Of 104 enrolled patients, 85 and 76 completed 12 and 24 weeks of data collection, respectively. Group means improved at 12 weeks for all outcomes and at 24 weeks for SF-36v2's Physical Component Summary and Bodily Pain Domain. Of those with clinically improved disability at 12 weeks, 75% were still clinically improved at 24 weeks ( P < 0.01). For SF-36v2 Physical and Mental Component Summaries, 55.4% and 43.4%, respectively, showed clinically meaningful improvement at 12 weeks, 46.1% and 30.3% at 24 weeks. For Bodily Pain Domain, 49.4% were clinically improved at 12 weeks, 40% at 24 weeks. Adults older than age 49 years had better pain and disability outcomes than younger adults. Conclusions: Results provide a meaningful signal of massage effect for primary care patients with chronic low back pain and call for further research in practice settings using pragmatic designs with control groups. PMID- 28340087 TI - Nutrigenomic point of view on effects and mechanisms of action of ruminant trans fatty acids on insulin resistance and type 2 diabetes. AB - Evidence from observational studies suggests beneficial effects of ruminant trans fatty acids (rTFA) on insulin resistance (IR) and type 2 diabetes (T2D). However, beneficial effects of rTFA are not always observed in cell, animal, and human studies. This narrative review presents potential mechanisms of action of rTFA using nutrigenomics and microRNA results in an integrative model. In addition, the review presents factors, including measures of IR and T2D, dose and duration of studies, as well as health status, ethnicity, and genotypes of subjects, that may help explain the heterogeneity in response to rTFA supplementation. Future studies should consider these factors, as well as research in nutritional genomics, to better understand the effects of rTFA on IR and T2D. PMID- 28340088 TI - Does Pain Reduction with Oral Steroids Predict Pain Reduction after a First-Time Cervical Epidural Steroid Injection in Patients with Cervical Radicular Pain? A Pilot Study. AB - Objective: Oral and injected steroids are used commonly in the treatment of cervical radicular pain despite a paucity of data demonstrating their efficacy. The purpose of this study is to assess whether the response to orally administered steroids among patients with acute cervical radicular pain who develop recurrent pain is associated with their subsequent response to cervical epidural steroid injections. Methods: Patients referred to our center were evaluated and then referred for cervical epidural steroid injections at the clinical discretion of the provider; those who met inclusion criteria were offered participation in the study. After the injection was administered, patients were contacted by telephone and asked to complete the Brief Pain Inventory Short Form at one week, one month, three months, and six months postinjection. Results: Pain reduction after cervical steroid injection was not significantly different between 49 patients who reported pain reduction with a prior course of oral steroids and 22 patients who reported no pain reduction. Average pain scores decreased over six months (P < 0.001) among 72 patients treated with epidural steroid injection for cervical radicular pain. Of the 55 who provided baseline and six-month data, 14 (25.5%) reported complete relief at six months and 20 (36.4%) reported decreased pain. Conclusions: Patients can be reassured that they may experience pain reduction after a cervical epidural steroid injection even if oral steroid therapy was not effective. The majority of patients treated for cervical radicular pain with epidural steroid injection have reduced or absent pain for at least six months after treatment. PMID- 28340089 TI - How Embryophytic is the Biosynthesis of Phenylpropanoids and their Derivatives in Streptophyte Algae? AB - The origin of land plants from algae is a long-standing question in evolutionary biology. It is becoming increasingly clear that many characters that were once assumed to be 'embryophyte specific' can in fact be found in their closest algal relatives, the streptophyte algae. One such case is the phenylpropanoid pathway. While biochemical data indicate that streptophyte algae harbor lignin-like components, the phenylpropanoid core pathway, which serves as the backbone of lignin biosynthesis, has been proposed to have arisen at the base of the land plants. Here we revisit this hypothesis using a wealth of new sequence data from streptophyte algae. Tracing the biochemical pathway towards lignin biogenesis, we show that most of the genes required for phenylpropanoid synthesis and the precursors for lignin production were already present in streptophyte algae. Nevertheless, phylogenetic analyses and protein structure predictions of one of the key enzyme classes in lignin production, cinnamyl alcohol dehydrogenase (CAD), suggest that CADs of streptophyte algae are more similar to sinapyl alcohol dehydrogenases (SADs). This suggests that the end-products of the pathway leading to lignin biosynthesis in streptophyte algae may facilitate the production of lignin-like compounds and defense molecules. We hypothesize that streptophyte algae already possessed the genetic toolkit from which the capacity to produce lignin later evolved in vascular plants. PMID- 28340090 TI - Predictive value of European Scleroderma Group Activity Index in an early scleroderma cohort. AB - Objective: To estimate the effect of disease activity, as measured by the European Scleroderma Research Group Activity Index (EScSG-AI), on the risk of subsequent organ damage in a large systemic sclerosis (SSc) cohort. Methods: Of 421 SSc patients from the Canadian Scleroderma Research Group database with disease duration of ? 3 years, 197 who had no evidence of end-stage organ damage initially and available 3 year follow-up were included. Disease activity was assessed by the EScSG-AI with two variability measures: the adjusted mean EScSG AI (the area under the curve of the EScSG-AI over the observation period) and persistently active disease/flare. Outcomes were based on the Medsger severity scale and included accrual of a new severity score (Delta ? 1) overall and within organ systems or reaching a significant level of deterioration in health status. Results: After adjustment for covariates, the adjusted mean EScSG-AI was the most consistent predictor of risk across the study outcomes over 3 years in dcSSc: disease progression defined as Delta ? 1 in any major internal organ, significant decline in forced vital capacity and diffusing capacity of carbon monoxide, severity of visceral disease and HAQ Disability Index worsening. In multivariate analysis, progression of lung disease was predicted solely by adjusted mean EScSG AI, while the severity of lung disease was predicted the adjusted mean EScSG-AI, older age, modified Rodnan skin score (mRSS) and initial severity. The EScSG-AI was associated with patient- and physician-assessed measures of health status and overpowered the mRSS in predicting disease outcomes. Conclusion: Disease activity burden quantified with the adjusted mean EScSG-AI predicted the risk of deterioration in health status and severe organ involvement in dcSSc. The EScSG AI is more responsive when done repeatedly and averaged. PMID- 28340091 TI - Effect of Antimicrobial Treatment on the Resolution of Middle-Ear Effusion After Acute Otitis Media. AB - Background: Acute otitis media (AOM) induces middle-ear effusion (MEE), which affects hearing. The effect of antimicrobial treatment on the resolution of MEE is controversial, and the factors that affect resolution are unknown. Methods: We studied the effect of antimicrobial treatment on the time to the resolution of MEE as a secondary objective in our randomized double-blind placebo-controlled trial. Children aged 6 to 35 months with stringently diagnosed AOM were allocated to receive amoxicillin-clavulanate (161 patients) or placebo (158 patients) for 7 days and closely followed for 3 months. This study was registered at ClinicalTrials.gov (identifier NCT00299455). Results: The median times to resolution of MEE were 20 days (95% confidence interval [CI], 16-24 days) and 29 days (95% CI, 26-32 days) in the amoxicillin-clavulanate and placebo groups, respectively (P = .10). The resolution of MEE was confirmed in 138 (86%) of 161 and 132 (84%) of 158 patients in the amoxicillin-clavulanate and placebo groups, respectively (P = .59). In multivariable analysis, the resolution of MEE was prolonged most significantly by at least 1 recurrence of AOM during follow-up. MEE resolved in 65 (65%) of 100 patients with a recurrence of AOM during follow up and in 205 (94%) of 219 of those without a recurrence (P < .001) (median times to resolution, 67 vs 15 days, respectively; P < .001). Conclusions: Immediate antimicrobial treatment of AOM does not significantly affect the resolution of MEE in young children. Subsequent recurrences of AOM are a major reason for the persistence of MEE. PMID- 28340092 TI - Community-Based Effectiveness Trials as a Means to Disseminate Evidence-Based and Culturally Responsive Behavioral Health Interventions. AB - This article adds to the existing knowledge about innovative community-based approaches used to reduce and eliminate behavioral health disparities. Special attention is given to culturally appropriate interventions that increase access to care and that improve the quality of behavioral health services across different geographic regions and communities. Effectiveness trials are presented as appropriate tools to translate existing efficacious interventions into real world settings. This article describes how to transition from efficacy to effectiveness, including factors essential to consider from the perspectives of university-based research teams and community-based organizations (CBOs). A case study illustrates how a university-CBO partnership mastered the complexities of transitioning an efficacious family intervention to a community setting while nurturing a new partnership. Included are implications of the study related to social work education and social work practice. Lessons learned about critical components of the community-based research collaboration and recommendations for future research are provided. PMID- 28340093 TI - The Molecular and Morphologic Structures That Make Saltatory Conduction Possible in Peripheral Nerve. AB - Saltatory conduction is the process by which action potentials are rapidly and efficiently propagated along myelinated axons. In the peripheral nervous system, saltatory conduction is made possible by a series of morphologically and molecularly distinct subdomains in both axons and their associated myelinating Schwann cells. This review briefly summarizes current knowledge on the molecular structure and physiology of the node of Ranvier and adjacent regions of the axoglial unit in peripheral nerve. PMID- 28340094 TI - NLRP2 is a suppressor of NF-kB signaling and HLA-C expression in human trophoblasts?,?. AB - During pregnancy, fetal extravillous trophoblasts (EVT) play a key role in the regulation of maternal T cell and NK cell responses. EVT display a unique combination of human leukocyte antigens (HLA); EVT do not express HLA-A and HLA B, but do express HLA-C, HLA-E, and HLA-G. The mechanisms establishing this unique HLA expression pattern have not been fully elucidated. The major histocompatibility complex (MHC) class I and class II transcriptional activators NLRC5 and CIITA are expressed neither by EVT nor by the EVT model cell line JEG3, which has an MHC expression pattern identical to that of EVT. Therefore, other MHC regulators must be present to control HLA-C, HLA-E, and HLA-G expression in these cells. CIITA and NLRC5 are both members of the nucleotide-binding domain, leucine-rich repeat (NLR) family of proteins. Another member of this family, NLRP2, is highly expressed by EVT and JEG3, but not in maternal decidual stromal cells. In this study, transcription activator-like effector nuclease technology was used to delete NLRP2 in JEG3. Furthermore, lentiviral delivery of shRNA was used to knockdown NLRP2 in JEG3 and primary EVT. Upon NLRP2 deletion, Tumor Necrosis Factor-alpha (TNFalpha)-induced phosphorylation of NF-KB p65 increased in JEG3 and EVT, and more surprisingly a significant increase in constitutive HLA C expression was observed in JEG3. These data suggest a broader role for NLR family members in the regulation of MHC expression during inflammation, thus forming a bridge between innate and adaptive immune responses. As suppressor of proinflammatory responses, NLRP2 may contribute to preventing unwanted antifetal responses. PMID- 28340095 TI - Non-laser percutaneous extraction of pacemaker and defibrillation leads: a decade of progress. AB - Aims: Non-laser-based methods are safe in lead extraction but in the past have been less effective than laser methods. In the past decade, new equipment has been introduced including the Evolution(r) Mechanical Dilator Sheath and the Evolution(r) RL. We sought to determine the impact of new equipment on outcome in mechanical lead extraction. Methods and results: We considered 288 consecutive patients (age 66 +/- 18 years) who underwent transvenous lead extraction (TLE) of 522 leads in the decade to the end of 2014. Three groups were identified: Group 1 (pre-Evolution(r) period, 76 patients, 133 leads), Group 2 (original Evolution(r) period, 115 patients, 221 leads), and Group 3 (Evolution(r) RL period, 97 patients, 168 leads). The age of leads was significantly greater in Groups 2 and 3 (6.2 +/- 4.4 and 6.1 +/- 5.4 years vs.4.7 +/- 4.5, P < 0.05) as was the proportion of implantable cardioverter defibrillator leads (27.2 and 28.9 vs. 14.3%, P < 0.05). The groups were similar in the number of leads extracted per patient. Despite the increasing complexity of the systems extracted, complete extraction was achieved in a progressively greater proportion of leads (88.0% in Group 1, 95.5% in Group 2, and 97.6% in Group 3, P < 0.05), and procedure duration was similar. The proportion of leads for which femoral access was required was greater in Group 3 (11%, 18/164) compared with Group 2 (3%, 7/211), P = 0.006. The only major complications were a post-procedure subacute tamponade in Group 1 and an oesophageal injury related to transoesophageal echocardiography in Group 3. Conclusion: With current equipment, mechanical extraction provides a good combination of efficacy and safety. PMID- 28340098 TI - Effect of fluoride-releasing resin composite in white spot lesions prevention: a single-centre, split-mouth, randomized controlled trial. AB - Introduction: The objective of this two-arm split-mouth randomized trial, was to evaluate the ability of fluoride-releasing resin composite to prevent demineralization and white spot lesion (WSL) formation, during orthodontic treatment with fixed appliances. Methods: Patients needing comprehensive orthodontic treatment were randomly allocated into two groups, according to the half split-mouth technique. This trial examined a total of 300 teeth in each group: the control group, in which brackets were fixed with a non-fluoride containing adhesive resin; and the intervention group, in which brackets were fixed with a fluoride-containing adhesive resin. Eligibility criteria included Class I malocclusion in the permanent dentition, adequate oral hygiene and no missing teeth, active caries, enamel demineralization, fluorosis staining, or heavy restorations. The primary outcome was the formation of WSLs. Randomization was achieved using a computer-generated random number table; blinding of the patients, assessor, orthodontist and data analysist were achieved. The patients were followed for twelve months, during which time their teeth were checked every three months. To investigate the differences in frequencies and ranks of demineralization and WSL formation between the two groups, odds ratios were computed using mixed modelling (to compensate for the clustered nature of the data) with intervention as a fixed effect and patient as a random effect. Results: Thirty-four patients (ages, 13-25 years; mean age, 17.6) were randomized into a 1:1 ratio, though four patients dropped out before the start of the treatment. The percentage of the teeth showing the effects of demineralization and WSL formation, increased from 6.3% to 15% for the control group after three and twelve months, respectively, and from 3% to 16.3% for the study group, after three to twelve months, respectively. There were no significant differences between the two groups and no interaction between time and treatment group in the visual inspections (OR 0.79; 95% CI 0.52, 1.21), in DIAGNOdent examinations (OR 0.68; 95% CI 0.43, 1.06), or in photographic images (OR 0.72; 95% CI 0.46, 1.11). No serious harm was observed during the trial. Limitations: This trial was a single-centre trial, and treatment was carried out by one orthodontist. Conclusions: Fluoride-containing resin adhesive does not have the desired preventive effect to prevent demineralization and WSL formation, during orthodontic treatment with fixed appliance. Registration and Protocol: This randomized trial was not registered, and the protocol was not published before patient recruitment. Funding: The University of Damascus funded this trial. PMID- 28340099 TI - Topical Gabapentin as Add-on Therapy for Trigeminal Neuralgia. A Case Report. PMID- 28340096 TI - Dual- vs. single-chamber defibrillators for primary prevention of sudden cardiac death: long-term follow-up of the Defibrillateur Automatique Implantable Prevention Primaire registry. AB - Aims: Implantable cardioverter defibrillators (ICDs) are an effective primary prevention of sudden cardiac death. We examined whether dual-chamber (DC) ICDs confer a greater benefit than single-chamber (SC) ICDs, and compared the long term outcomes of recipients of each type of device implanted for primary prevention. Methods and results: Between 2002 and 2012, the DAI-PP registry consecutively enrolled 1258 SC- and 1280 DC-ICD recipients at 12 French medical centres. The devices were interrogated at 4- to 6-month intervals during outpatient visits, with a focus on the therapies delivered. The study endpoints were incidence of appropriate therapies, ICD-related morbidity, and deaths from all and from specific causes. The mean age of the SC- and DC-ICD recipients was 59 +/- 12 and 62 +/- 11 years, respectively (P< 0.0001). The distribution of genders, New York Heart Association functional classes and glomerular filtration rates, and the rates of ischaemic vs. dilated cardiomyopathies and of defibrillation tests at implant, were similar in both study groups. The rates of periprocedural complications were 12.1% in the DC- vs. 8.8% in the SC-ICD groups (P= 0.008). Over a mean follow-up of 3.1 +/- 2.2 years, pulse generators were replaced in 21.9% of the DC- vs. 13.6% of the SC-ICD group (P< 0.0001). The proportions of patients treated with >=1 appropriate therapies (24.7 vs. 23.8%) and >=1 inappropriate shocks (8.4 vs. 7.8%), and all-cause mortality (12.4 vs. 13.2%) were similar in both groups. Conclusion: In this large registry of ICD implanted for primary prevention, DC-ICDs were associated with higher rates of peri-implant complications and generator replacements, whereas the survival and rates of inappropriate shocks were similar in both groups. Clinical trial number: NCT#01992458. PMID- 28340100 TI - Glioblastoma stem cell differentiation into endothelial cells evidenced through live-cell imaging. AB - Background: Glioblastoma cell-initiated vascularization is an alternative angiogenesis called vasculogenic mimicry. However, current knowledge on the mechanism of de novo vessel formation from glioblastoma stem cells (GSCs) is limited. Methods: Sixty-four glioblastoma samples from patients and 10 fluorescent glioma xenograft samples were examined by immunofluorescence staining for endothelial marker (CD34 and CD31) and glial cell marker (glial fibrillary acidic protein [GFAP]) expression. GSCs were then isolated from human glioblastoma tissue and CD133+/Sox2+ red fluorescent protein-containing (RFP)-GSC 1 cells were established. The ability of these cells to form vascular structures was examined by live-cell imaging of 3D cultures. Results: CD34-GFAP or CD31-GFAP coexpressing glioblastoma-derived endothelial cells (GDEC) were found in 30 of 64 (46.9%) of clinical glioblastoma samples. In those 30 samples, GDEC were found to form vessel structures in 21 (70%) samples. Among 21 samples with GDEC vessels, the CD34+ GDEC vessels and CD31+ GDEC vessels accounted for about 14.16% and 18.08% of total vessels, respectively. In the xenograft samples, CD34+ GDEC were found in 7 out of 10 mice, and 4 out of 7 mice had CD34+ GDEC vessels. CD31+ GDEC were also found in 7 mice, and 4 mice had CD31+ GDEC vessels (10 mice in total). Through live-cell imaging, we observed gradual CD34 expression when cultured with vascular endothelial growth factor in some glioma cells, and a dynamic increase in endothelial marker expression in RFP-GSC-1 in vitro was recorded. Cells expressed CD34 (9.46%) after 6 hours in culture. Conclusions: The results demonstrated that GSCs may differentiate into endothelial cells and promote angiogenesis in glioblastomas. PMID- 28340101 TI - Dietary assessment in minority ethnic groups: a systematic review of instruments for portion-size estimation in the United Kingdom. AB - Context: Dietary assessment in minority ethnic groups is critical for surveillance programs and for implementing effective interventions. A major challenge is the accurate estimation of portion sizes for traditional foods and dishes. Objective: The aim of this systematic review was to assess records published up to 2014 describing a portion-size estimation element (PSEE) applicable to the dietary assessment of UK-residing ethnic minorities. Data sources, selection, and extraction: Electronic databases, internet sites, and theses repositories were searched, generating 5683 titles, from which 57 eligible full-text records were reviewed. Data analysis: Forty-two publications about minority ethnic groups (n = 20) or autochthonous populations (n = 22) were included. The most common PSEEs (47%) were combination tools (eg, food models and portion-size lists), followed by portion-size lists in questionnaires/guides (19%) and image-based and volumetric tools (17% each). Only 17% of PSEEs had been validated against weighed data. Conclusions: When developing ethnic-specific dietary assessment tools, it is important to consider customary portion sizes by sex and age, traditional household utensil usage, and population literacy levels. Combining multiple PSEEs may increase accuracy, but such methods require validation. PMID- 28340103 TI - Diagnosis-to-ablation time as a predictor of success: early choice for pulmonary vein isolation and long-term outcome in atrial fibrillation: results from the Middelheim-PVI Registry. AB - Aims: The aim of the study is to define long-term outcome of pulmonary vein isolation (PVI) in atrial fibrillation (AF) and to determine whether time window between AF diagnosis and PVI affects outcome. Methods and results: Consecutive AF patients undergoing PVI (2006-14) were followed for 5 years. Primary outcome was clinical success, defined as freedom of documented AF without anti-arrhythmic drugs respecting a 1-month blanking period. A 1000 patients were included (age 60 +/- 10 years, CHA2DS2-VASc score 1 +/- 1). The cohort was divided in four quartiles (Q) according to the diagnosis-to-ablation time (DAT): Q1 DAT 0-11 months (N = 244), Q2 DAT 12-<=33 months (N = 254), Q3 DAT 34-<=70 months (N = 252) and Q4 DAT 71-360 months (N = 250). Mean follow-up was 44.3+/-21.0 months. At 5 years, clinical success was achieved in 45.2 +/- 2.0% of patients. Independent predictors of clinical success were AF type (HR = 0.61; 95%CI 0.50 0.74; P < 0.0001), left atrial size (HR = 1.03; 95%CI 1.02-1.05; P < 0.0001), DAT (HR = 1.00; 95%CI 1.00-1.00; P = 0.001), ablation technique (P = 0.012), and year of ablation (HR = 0.93; 95%CI 0.86-1.00; P = 0.045) in multivariable-adjusted analysis. The highest clinical success was achieved when PVI was performed within the first year, and gradually declined with increasing DAT: 55.9 +/- 4.6% for Q1, 46.9 +/- 4.0% for Q2, 45.5 +/- 3.6% for Q3, and 35.5 +/- 3.6% for Q4 (P < 0.001). Conclusion: Long-term success rate of PVI is 45.2 +/- 2.0%. Shorter diagnosis-to ablation times are associated with better clinical success. Our data advocate for early PVI following diagnosis of AF. PMID- 28340102 TI - Impact of Unrestricted Access to Pregabalin on the Use of Opioids and Other CNS Active Medications: A Cross-Sectional Time Series Analysis. AB - Objective: Access to pregabalin via Ontario's public drug insurance program was expanded to an unrestricted model on April 1, 2013, from a prior authorization model. This study aims to identify the effect of expanded access on the rate of pregabalin use by publicly insured persons and to assess the characteristics of new patients initiating pregabalin following this expanded access. Methods: We conducted a cross-sectional time series analysis using the linked health administrative records of residents of Ontario, Canada, with public drug coverage who were dispensed a prescription for pregabalin between April 1, 2006, and December 31, 2014. Results: A total of 108,047 publicly insured persons were dispensed pregabalin over the study period. The overall rate of pregabalin use increased from 1.0 per 1,000 individuals in Q1 of 2013 to 22.0 per 1,000 individuals in Q4 of 2014. Musculoskeletal (81.6%) and neurological (68.1%) conditions were the most prevalent diagnoses in patients who initiated pregabalin following the expansion of access. Past and concomitant use of opioids, nonsteroidal anti-inflammatory drugs, and antidepressants was also common in this population. Conclusions: Formulary changes in Ontario have led to expanded access to pregabalin, which may have led to an increase in off-label use of these products and potential patient risk associated with concomitant use of pregabalin with central nervous system-depressing drugs. PMID- 28340104 TI - Personalizing lung cancer risk prediction and imaging follow-up recommendations using the National Lung Screening Trial dataset. AB - Objective: To demonstrate a data-driven method for personalizing lung cancer risk prediction using a large clinical dataset. Materials and Methods: An algorithm was used to categorize nodules found in the first screening year of the National Lung Screening Trial as malignant or nonmalignant. Risk of malignancy for nodules was calculated based on size criteria according to the Fleischner Society recommendations from 2005, along with the additional discriminators of pack-years smoking history, sex, and nodule location. Imaging follow-up recommendations were assigned according to Fleischner size category malignancy risk. Results: Nodule size correlated with malignancy risk as predicted by the Fleischner Society recommendations. With the additional discriminators of smoking history, sex, and nodule location, significant risk stratification was observed. For example, men with >=60 pack-years smoking history and upper lobe nodules measuring >4 and <=6 mm demonstrated significantly increased risk of malignancy at 12.4% compared to the mean of 3.81% for similarly sized nodules (P < .0001). Based on personalized malignancy risk, 54% of nodules >4 and <=6 mm were reclassified to longer-term follow-up than recommended by Fleischner. Twenty-seven percent of nodules <=4 mm were reclassified to shorter-term follow-up. Discussion: Using available clinical datasets such as the National Lung Screening Trial in conjunction with locally collected datasets can help clinicians provide more personalized malignancy risk predictions and follow-up recommendations. Conclusion: By incorporating 3 demographic data points, the risk of lung nodule malignancy within the Fleischner categories can be considerably stratified and more personalized follow-up recommendations can be made. PMID- 28340106 TI - Erratum. PMID- 28340107 TI - Association between the application of ISO 9001:2008 alone or in combination with health-specific standards and quality-related activities in Hungarian hospitals. AB - Objective: To investigate how International Organization for Standardization (ISO) 9001 and the Hungarian Health Care Standards (HHCS) certifications are associated with quality management, patient safety, patient rights and human resource management activities. Design: A cross-sectional study was implemented using the 2009 Hungarian hospital survey's database. Setting: Hungary. Participants: Fifty-three general hospitals were included in the statistical analysis. Intervention: No intervention was carried out in the study. Main Outcome Measures: The outcomes included the percentage of compliance in the dimensions of quality management, patient safety, patient rights, human resource management and the overall score for each hospital, and they were grouped according to the hospitals' certifications. Results: Sixteen hospitals did not have either ISO 9001 or HHCS certifications, 19 had ISO 9001 certification only and 18 had both. Hospitals with ISO 9001 alone or in combination with the HHCS significantly outperformed hospitals with no certifications in terms of quality management and human resource management activities but not in terms of patient safety or patient rights activities. Combined, the two models provided the highest median levels in all cases. Nevertheless, no significant differences were observed when the hospitals with both certifications were compared with hospitals with ISO 9001 only. Conclusions: Although the combination of ISO 9001 and the HHCS showed the best results, the benefits were not decisive. Furthermore, although the HHCS include standards addressing patient safety, no direct association was found with regard to compliance. Thus, further investigation is required to understand this enigma. PMID- 28340105 TI - Morin Stain Detects Aluminum-Containing Macrophages in Macrophagic Myofasciitis and Vaccination Granuloma With High Sensitivity and Specificity. AB - Macrophagic myofasciitis (MMF) is an inflammatory condition associated with the intramuscular (i.m.) injection of aluminum adjuvant-containing vaccines. It is clinically characterized by myalgia, weakness, and chronic fatigue and histologically by aggregates of cohesive macrophages with abundant basophilic, periodic acid-Schiff (PAS)-positive, diastase-resistant granules that percolate through the peri- and endomysium without eliciting substantial myofiber damage. The definitive diagnosis of MMF requires demonstration of aluminum within these macrophages. We evaluated the Morin stain, a simple, 2-step histochemical stain for aluminum, as a confirmatory diagnostic tool for MMF. Among 2270 muscle biopsies processed at UTSW between 2010 and 2015, a total of 12 MMF cases and 1 subcutaneous vaccination granuloma case were identified (11 pediatric, 2 adults). With the Morin stain, all 13 cases showed strong granular reactivity within the cytoplasm of macrophages but not in myofibers or connective tissue. Three cases of inflammatory myopathy with abundant macrophages (IMAM), 8 cases of granulomatous inflammation and 23 other deltoid muscle biopsies used as controls were all negative. Morin stain could be used in both formalin-fixed paraffin embedded and cryostat sections. Thus, Morin stain detects aluminum with high sensitivity and specificity in human muscle and soft tissue and may improve the diagnostic yield of MMF and vaccination granuloma. PMID- 28340109 TI - MTH1, an 8-oxo-2'-deoxyguanosine triphosphatase, and MYH, a DNA glycosylase, cooperate to inhibit mutations induced by chronic exposure to oxidative stress of ionising radiation. AB - Our previous results showed that in addition to the immediate interaction of ionising radiation with DNA (direct and indirect effect), low-dose and chronic low-dose rate of irradiation induce endogenous oxidative stress. During oxidative stress, free radicals react with DNA, nucleoside triphosphates (dNTPs), proteins and lipids, and modify their structures. The MYH and MTH1 genes play important roles in preventing mutations induced by 8-hydroxy-guanine, which is an oxidised product of guanine. In this study, we used short-hairpin RNA to permanently knockdown MYH and MTH1 proteins in human lymphoblastoid TK6 cells. Knockdown and wild-type cells were chronically exposed to low dose rates of gamma-radiation (between 1.4 and 30 mGy/h). The cells were also subjected to acute doses delivered at a high-dose rate. Growth rate, extracellular 8-hydroxy-2' deoxyguanosine, clonogenic cell survival and mutant frequencies were analysed in all cell types. A reduced level of cell growth and survival as well as increased mutant frequencies were observed in cells lacking both MYH and MTH1 proteins as compared to cells lacking only MYH and wild-type cells. To sum up, our results suggest that low-dose rates elevate oxidative stress. MTH1 together with MYH plays an important role in protection against mutations induced by modified dNTPs during chronic oxidative stress. In addition, we found no dose-rate effect at the level of mutations in the wild-type TK6 and MYH-KD cells. Our data interestingly indicate a dose-rate threshold for mutation induction in MTH1/MYH double knockdown cells. PMID- 28340108 TI - Cigarette Smoking and Musculoskeletal Pain Severity Among Male and Female Afghanistan/Iraq Era Veterans. AB - Objective: Cigarette smoking and musculoskeletal pain are prevalent among Department of Veterans Affairs (VA) health care system users. These conditions frequently co-occur; however, there is limited empirical information specific to Afghanistan/Iraq era veterans. The present study sought to examine gender differences in the association between cigarette smoking and moderate to severe musculoskeletal pain in US veterans with Afghanistan/Iraq era service. Methods: A random sample of 5,000 veterans with service after November 11, 2001, participated in a survey assessing health care needs and barriers to care. One thousand ninety veterans completed the survey assessing post-traumatic stress disorder (PTSD) symptoms, depressive symptoms, and current pain severity. Multivariate logistic regression was used to examine the association between gender, cigarette smoking status, and current moderate to severe musculoskeletal pain. Results: Findings indicated a significant gender by smoking interaction on moderate/severe musculoskeletal pain, adjusting for age, self-reported race/ethnicity and weight status, combat exposure, probable PTSD, depressive symptoms, service-connected injury during deployment, and VA health care service utilization. Deconstruction of the interaction indicated that female veteran smokers, relative to female nonsmokers, had increased odds of endorsing moderate to severe musculoskeletal pain (odds ratio [OR] = 2.73, 95% confidence interval [CI] = 1.16-6.41), whereas this difference was nonsignificant for male veterans (OR = 1.03, 95% CI = 0.69-1.56). Conclusions: Survey data from Operation Enduring Freedom/Operation Iraqi Freedom veterans suggest an association between current smoking, gender, and moderate to severe musculoskeletal pain. The stronger relationship between smoking and pain in women supports the need for interventional and longitudinal research that can inform gender-based risk factors for pain in veteran cigarette smokers. PMID- 28340110 TI - Peri-mitral atrial flutter: personalized ablation strategy based on arrhythmogenic substrate. AB - Aims: The aim of this study is to characterize the arrhythmogenic substrate for peri-mitral atrial flutter (PMAFL), thereby determining a personalized ablation strategy to treat PMAFL. Methods and results: Thirty-six consecutive PMAFL patients (mean age: 63.8 +/- 11.3, 23 males) underwent detailed three-dimensional electroanatomic mapping in left atrium (LA). The LA was divided into septal anterior wall (SAW), posterior inferior wall (PIW), and mitral isthmus (MI) region, respectively. Ablation strategy was determined based on the endocardial bipolar voltage map. Based on electrophysiological substrates, 10, 17, and 9 cases were classified into iatrogenic, spontaneous, and no-substrate PMAFL, respectively. The mean voltage in SAW was significantly lower in spontaneous PMAFL (iatrogenic: 1.07 +/- 0.66 mV; spontaneous: 0.65 +/- 0.44 mV; no-substrate: 1.60 +/- 0.53 mV, P <0.001), while iatrogenic PMAFL patients had the lowest voltage in MI (0.51 +/- 0.23 mV vs. 1.55 +/- 0.78 mV, 1.61 +/- 0.56 mV, P <0.001). No low-voltage or slow conduction zone was found in the no-substrate PMAFL group. Fifteen spontaneous PMAFLs were successfully terminated by modified septal-anterior (9/10) or conventional anterior ablation line (6/7). Eight iatrogenic PMAFLs (8/10) were terminated by reinforcing the previous ablation areas. Cardioversion without PMAFL ablation was done in no-substrate PMAFL patients. After a median follow-up of 12 (7-39) months, two spontaneous PMAFL patients received redo procedures for recurrence due to "gap" conduction. Conclusions: The ablation strategy for PMAFL patients should be based on the arrhythmogenic substrate, but not the indiscriminate MI ablation. No-substrate PMAFLs during AF ablation could be monitored after cardioversion and might not need further ablation. PMID- 28340111 TI - Assessment of Patient-Reported Outcome Instruments to Assess Chronic Low Back Pain. AB - Objective: To identify patient-reported outcome (PRO) instruments that assess chronic low back pain (cLBP) symptoms (specifically pain qualities) and/or impacts for potential use in cLBP clinical trials to demonstrate treatment benefit and support labeling claims. Design: Literature review of existing PRO measures. Methods: Publications detailing existing PRO measures for cLBP were identified, reviewed, and summarized. As recommended by the US Food & Drug Administration (FDA) PRO development guidance, standard measurement characteristics were reviewed, including development history, psychometric properties (validity and reliability), ability to detect change, and interpretation of observed changes. Results: Thirteen instruments were selected and reviewed: Low Back Pain Bothersomeness Scale, Neuropathic Pain Symptom Inventory, PainDETECT, Pain Quality Assessment Scale Revised, Revised Short Form McGill Pain Questionnaire, Low Back Pain Impact Questionnaire, Oswestry Disability Index, Pain Disability Index, Roland-Morris Disability Questionnaire, Brief Pain Inventory and Brief Pain Inventory Short Form, Musculoskeletal Outcomes Data Evaluation and Management System Spine Module, Orebro Musculoskeletal Pain Questionnaire, and the West Haven-Yale Multidimensional Pain Inventory Interference Scale. The instruments varied in the aspects of pain and/or impacts that they assessed, and none of the instruments fulfilled all criteria for use in clinical trials to support labeling claims based on recommendations outlined in the FDA PRO guidance. Conclusions: There is an unmet need for a validated PRO instrument to evaluate cLBP-related symptoms and impacts for use in clinical trials. PMID- 28340112 TI - Long-Term Mortality of Patients with an Alcohol-Related Wernicke-Korsakoff Syndrome. AB - Aims: To characterize a series of contemporary patients with alcohol-related Wernicke's encephalopathy (WE) or Korsakoff's syndrome (KS) and to update the current prognosis of disease. Methods: Retrospective and prospective study of patients diagnosed with an alcohol-related WE or KS between 2002 and 2011 in a tertiary hospital. Socio-demographic, alcohol use characteristics, signs and symptoms, co-morbidity and blood parameters were obtained at admission. Patients were followed up until 2013 and causes of death were ascertained through the review of charts. Results: Sixty-one patients were included (51 with WE and 10 with KS). Among patients with WE, 78% were men and age at diagnosis was 57 years (interquartile range (IQR): 49-66). Twenty-three percent fulfilled the classic WE triad. Regarding Caine's criteria for WE, 70.6% presented with at least two out of four signs or symptoms. Median follow-up of patients with WE syndrome was 5.3 years (IQR: 2.6-8.8), the cumulated mortality was 45% and death rate of 7.4 * 100 person-years (95% confidence interval (CI): 4.8-10.9). Overall, 50% of patients would be expected to die within 8 years of WE episode and main causes of death included serious bacterial infections (44.5%) and cancer (33.3%). Conclusions: Survival of patients with an alcohol-related Wernicke-Korsakoff syndrome is poor; pursuing treatment of alcohol use disorder and early diagnosis of thiamine deficiency is a priority for improving clinical outcomes. PMID- 28340114 TI - The Pain-Related Cognitive Processes Questionnaire: Development and Validation. AB - Objective: Cognitive processes may be characterized as how individuals think, whereas cognitive content constitutes what individuals think. Both cognitive processes and cognitive content are theorized to play important roles in chronic pain adjustment, and treatments have been developed to target both. However, the evaluation of treatments that target cognitive processes is limited because extant measures do not satisfactorily separate cognitive process from cognitive content. The current study aimed to develop a self-report inventory of potentially adaptive and presumed maladaptive attentional processes that may occur when someone is experiencing pain. Methods: Scales were derived from a large item pool by successively applying confirmatory factor analysis to item data from two undergraduate samples (N = 393 and 233). Results: Items, which were generated to avoid confounding of cognitive content with cognitive processes, represented nine constructs: Suppression, Distraction, Enhancement, Dissociation, Reappraisal, Absorption, Rumination, Nonjudgment, and Acceptance. The resulting nine scales formed the Pain-Related Cognitive Process Questionnaire (PCPQ), and scale correlations produced four conceptually distinct composite scales: Pain Diversion, Pain Distancing, Pain Focus, and Pain Openness. Internal consistency reliabilities of the nine scales were adequate (alpha >= 0.70) to good, and the four composite scales had alpha values of 0.79 or higher. Correlations with pain related criterion variables were generally consistent with putative constructs. Conclusions: The developed PCPQ scales offer a comprehensive assessment of important cognitive processes specific to pain. Overall, the findings suggest that the PCPQ scales may prove useful for evaluating the role of pain-related cognitive processes in studies of chronic pain. PMID- 28340113 TI - GATA1 Is a Sensitive and Specific Nuclear Marker for Erythroid and Megakaryocytic Lineages. AB - Objectives: GATA binding factor 1 (GATA1) is a transcription factor essential for erythromegakaryocytic differentiation. Given its function in lineage specification, we sought to evaluate the immunohistochemical profile of GATA1 in normal marrow and acute leukemia and assess the use of GATA1 as a specific erythromegakaryocytic immunohistochemical marker. Methods: Immunohistochemical studies for GATA1 expression were performed on bone marrow biopsy specimens to define its role in the evaluation of acute leukemia and other hematologic disorders. Results: In normal marrows, intense nuclear reactivity is seen in immature erythroid precursors and megakaryocytes. Weak to moderate nuclear positivity is seen in eosinophils and mast cells. In marrows involved by acute leukemia, blasts of pure erythroleukemia and acute megakaryoblastic leukemia exhibit intense nuclear GATA1 positivity, while blasts of acute myeloid leukemia of other categories are negative. GATA1 is also absent in the blasts of acute lymphoblastic leukemia/lymphoma and in the neoplastic cells of metastatic carcinoma and plasma cell neoplasms. Conclusions: Intense GATA1 nuclear expression is a sensitive and specific marker for cells of erythroid and megakaryocytic lineages and is an excellent marker for neoplastic cells of pure erythroleukemia and acute megakaryoblastic leukemia. PMID- 28340115 TI - Cellular Senescence in Mouse Hippocampus After Irradiation and the Role of p53 and p21. AB - Diverse stress signals including irradiation may trigger cellular senescence. We asked whether irradiation induced senescence in mouse hippocampus, and whether p53 or p21 played a role in this response. Following whole-brain irradiation, polymerase chain reaction (PCR) arrays for senescence-associated genes showed increased expression of CDKN1A (p21) and CDKN2A (p19ARF) in mouse hippocampus at 9 weeks. Upregulation of p21 and p19ARF was confirmed using real-time PCR, which also demonstrated increased CDKN2A/p16INKa expression after irradiation. No altered regulation of another 17 senescence-associated genes was observed after irradiation. Immunohistochemistry revealed increased nuclear expression of p16INK4A, p19ARF, p53, p21, phosphorylated p38 (pp38), 4-hydroxy-2-nonenal, and interleukin-6 (IL6) in granule cells of dentate gyrus after irradiation. Increased p16 nuclear immunoreactivity was further observed in type -1 cells, the putative neural stem cells. gamma-phosphorylated-histone-2A nuclear foci were also seen in dentate gyrus 9 weeks postirradiation. In nonirradiated mice knockout of the TRP53 or p21 gene, there was increased p16INK4A, p19ARF, and IL6, but not pp38 in dentate gyrus. We conclude that irradiation induces transcript and protein expression profile alterations in mouse dentate gyrus consistent with the senescence phenotype. Absence of p53 or p21 results in increase in baseline expression of senescence markers with no further increase in expression after irradiation. PMID- 28340117 TI - An evaluation of the performance of the Dynamiker(r) Fungus (1-3)-beta-D-Glucan Assay to assist in the diagnosis of invasive aspergillosis, invasive candidiasis and Pneumocystis pneumonia. AB - Invasive fungal disease (IFD) can be caused by a range of pathogens. Conventional diagnosis has the capacity to detect most causes of IFD, but poor performance limits impact. The introduction of non-culture diagnostics, including the detection of (1-3)-beta-D-Glucan (BDG), has shown promising performance for the detection of IFD in variety of clinical settings. Recently, the Dynamiker(r) Fungus (1-3)-beta-D-Glucan assay (D-BDG) was released as an IFD diagnostic test. This article describes an evaluation of the D-BDG assay for the diagnosis of invasive aspergillosis (IA), invasive candidiasis (IC) and Pneumocystis pneumonia (PCP) across several high-risk patient cohorts and provides comparative data with the Associates of Cape Cod Fungitell(r) and BioRad PlateliaTM Aspergillus Ag (GM) assays. There were 163 serum samples from 121 patients tested, from 21 probable IA cases, 28 proven IC cases, six probable PCP cases, one probable IFD case, 14 possible IFD cases and 64 control patients. For proven/probable IFD the mean BDG concentration was 209pg/ml, significantly greater than the control population (73pg/ml; P: <.0001). The sensitivity, specificity, and diagnostic odds ratio for proven/probable IFD was 81.4%, 78.1%, and 15.5, respectively. Significant BDG false positivity (9/13) was associated post abdominal surgery. D-BDG showed fair and good agreement with the Fungitell(r), and GM assays, respectively. In conclusion, the D-BDG provides a useful adjunct test to aid the diagnosis of IFD, with technical flexibility that will assist laboratories processing low sample numbers. Further, large scale, prospective evaluation is required to confirm the clinical validity and determine clinical utility. PMID- 28340118 TI - Group Music Therapy as a Preventive Intervention for Young People at Risk: Cluster-Randomized Trial. AB - Background: Music forms an important part of the lives and identities of adolescents and may have positive or negative mental health implications. Music therapy can be effective for mental disorders such as depression, but its preventive potential is unknown. Objective: The aim of this study was to examine whether group music therapy (GMT) is an effective intervention for young people who may be at risk of developing mental health problems, as indicated via unhealthy music use. The main question was whether GMT can reduce unhealthy uses of music and increase potentials for healthy uses of music, compared to self directed music listening (SDML). We were also interested in effects of GMT on depressive symptoms, psychosocial well-being, rumination, and reflection. Methods: In an exploratory cluster-randomized trial in Australian schools, 100 students with self-reported unhealthy music use were invited to GMT (weekly sessions over 8 weeks) or SDML. Changes in the Healthy-Unhealthy Music Scale (HUMS) and mental health outcomes were measured over 3 months. Results: Both interventions were well accepted. No effects were found between GMT and SDML (all p > 0.05); both groups tended to show small improvements over time. Younger participants benefited more from GMT, and older ones more from SDML (p = 0.018). Conclusions: GMT was associated with similar changes as SDML. Further research is needed to improve the processes of selecting participants for targeted interventions; to determine optimal dosage; and to provide more reliable evidence of effects of music-based interventions for adolescents. PMID- 28340119 TI - The risk of nephrolithiasis is causally related to inactive matrix Gla protein, a marker of vitamin K status: a Mendelian randomization study in a Flemish population. AB - Background: Vitamin K (VK)-dependent gamma-glutamate carboxylation and serine phosphorylation activate matrix Gla protein (MGP) to a potent locally acting inhibitor of calcification. Nephrolithiasis represents a process of unwanted calcification associated with substantial mortality and high recurrence rates. We hypothesized that the risk of nephrolithiasis increases with VK shortage, as exemplified by higher plasma levels of desphospho-uncarboxylated MGP (dp-ucMGP). Methods: In 1748 randomly recruited Flemish individuals (51.1% women; mean age 46.8 years), we determined dp-ucMGP and the prevalence of nephrolithiasis at baseline (April 1996-February 2015) and its incidence during follow-up until March 2016. We estimated the multivariable-adjusted relative risk associated with the doubling of dp-ucMGP, using logistic or Cox regression. We did a Mendelian randomization analysis using four MGP genotypes as instrumental variables. Results: With adjustments applied for sex, age and 24-h urinary volume and calcium excretion, the odds of having prevalent nephrolithiasis [n = 144 (8.2%)] associated with dp-ucMGP was 1.31 [95% confidence interval (CI) 1.04-1.64; P = 0.022]. dp-ucMGP levels were associated (P <= 0.001) with MGP variants rs2098435, rs4236 and rs2430692. In the Mendelian analysis, the causal odds ratio was 3.82 (95% CI 1.15-12.7; P = 0.029). The incidence of nephrolithiasis over 12.0 years (median) was 37 cases (0.2%). With similar adjustments as before, the hazard ratio in relation to dp-ucMGP was 2.48 (95% CI 1.71-3.61; P < 0.001). Additional adjustment for a nephrolithiasis propensity score produced consistent results. Conclusion: Higher levels of inactive dp-ucMGP may be causally associated with the risk of nephrolithiasis. Whether or not VK deficiency plays a role in these observations remains to be firmly established. PMID- 28340120 TI - Location, Location, Location: Appraising the Pleiotropic Function of HMGB1 in Fetal Brain. PMID- 28340121 TI - Atrioventricular nodal echoes over a wide echo window as a therapeutic end point for the catheter-guided radiofrequency ablation of atrioventricular nodal reentrant tachycardia: a prospective study. AB - Aims: In previous retrospective studies, it was shown that the presence of residual single atrioventricular node (AVN) echoes with an echo zone longer than 30 ms may increase the rate of recurrence after radiofrequency ablation (RFA) of slow pathway in patients with AVN reentrant tachycardia (AVNRT). Based on that, some centres perform additional RFA in these patients. However, this opinion has never been tested prospectively and many centres do not perform re-ablation in these patients. The purpose of this study was to test whether persistence of a single AVN echo over a wide echo zone is a valid end point for RFA. Methods and results: In this prospective study, 576 patients who had a non-inducible arrhythmia post-RFA of AVNRT were divided into those with a remnant echo over a wide echo zone (case group) and those reaching classical end points (control group). The primary end point of the study was recurrence and patients were followed for 34.5 +/- 18.8 months. In the control group (n = 510), 14 patients (2.7%) had a recurrence while no recurrence was seen in the case group (n = 66) (final cure rate, 97.3 vs. 100%; difference, 2.7%; upper bound of the 98% CI, 0.0488; P < 0.0001 for non-inferiority). Two complete heart blocks (0.4%) happened in the control group and none in the case group (P = 0.784). Conclusion: Non-inducibility in the presence of a wide echo window is non-inferior to non inducibility in the presence of narrow echo window or no AVN echoes. In general, the presence of a single echo beat is not an indication for further ablation and this applies for both narrow and wide windows. PMID- 28340123 TI - Rapid Ascent From Zero Quality to International Organization for Standardization Accreditation: A Case Study of Hai Duong Preventive Medicine Center in Vietnam, 2012-2013. AB - Objectives: In 2012, the Vietnam Ministry of Health sought to improve the quality of health laboratories by introducing international quality standards. Methods: Strengthening Laboratory Management Toward Accreditation (SLMTA), a year-long, structured, quality improvement curriculum (including projects and mentorship) was piloted in 12 laboratories. Progress was measured using a standardized audit tool (Stepwise Laboratory Quality Improvement Process Towards Accreditation). Results: All 12 pilot laboratories (a mix of hospital and public health) demonstrated improvement; median scores rose from 44% to 78% compliance. The public health laboratory in Hai Duong Province entered the program with the lowest score of the group (28%) yet concluded with the highest score (86%). Five months after the completion of the program, without any additional external support, they were accredited. Laboratory management/staff describe factors key to their success: support from the facility senior management, how-to guidance provided by SLMTA, support from the site mentor, and strong commitment of laboratory staff. Conclusions: Hai Duong preventive medical center is one of only a handful of laboratories to reach accreditation after participation in SLMTA and the only laboratory to do so without additional support. Due to the success seen in Hai Duong and other pilot laboratories, Vietnam has expanded the use of SLMTA. PMID- 28340124 TI - Depressive Symptoms and Involvement in Physical Fighting among Portuguese Adolescents. AB - In this article, authors present findings on the relationship between depressive symptoms and involvement in physical fighting in late adolescence. Participants were 1,380 Portuguese adolescents initially recruited in 2003 to the EPITeen cohort. Depressive symptoms were assessed at 13 and 17 years of age using Beck Depressive Inventory II (BDI). Physical fighting was recorded at the age of 17. For girls, there was a significant association between depressive symptoms and physical fighting for those who scored BDI >13 at 17 years old and remained statistically significant after adjustment. For boys, those who scored >13 in both study waves presented higher crude odds to engage in fights that were attenuated after adjusting for grade retention. Depressive symptoms were significantly related to physical fighting involvement during adolescence, for both genders. However, whereas for female adolescents the association was significant when relevant symptoms and fighting occurred in the same period, for male adolescents such symptoms must have persisted from 13 to 17 years of age. PMID- 28340122 TI - Potential Role of Patients' CYP3A-Status in Clozapine Pharmacokinetics. AB - Background: The atypical antipsychotic clozapine is effective in treatment resistant schizophrenia; however, the success or failure of clozapine therapy is substantially affected by the variables that impact the clozapine blood concentration. Thus, elucidating the inter-individual differences in clozapine pharmacokinetics can facilitate the personalized therapy. Methods: Since a potential role in clozapine metabolism is assigned to CYP1A2, CYP2C19, CYP2D6 and CYP3A enzymes, the association between the patients' CYP status (CYP genotypes, CYP expression) and clozapine clearance was evaluated in 92 psychiatric patients. Results: The patients' CYP2C19 or CYP2D6 genotypes and CYP1A2 expression seemed to have no effect on clozapine serum concentration, whereas CYP3A4 expression significantly influenced the normalized clozapine concentration (185.53+/-56.53 in low expressers vs 78.05+/-29.57 or 66.52+/-0.25 (ng/mL)/(mg/kg) in normal or high expressers, P<.0001), in particular that the patients expressed CYP1A2 at a relatively low level. The functional CYP3A5*1 allele seemed to influence clozapine concentrations in those patients who expressed CYP3A4 at low levels. The dose requirement for the therapeutic concentration of clozapine was substantially lower in low CYP3A4 expresser patients than in normal/high expressers (2.18+/-0.64 vs 4.98+/-1.40 mg/kg, P<.0001). Furthermore, significantly higher plasma concentration ratios of norclozapine/clozapine and clozapine N-oxide/clozapine were observed in the patients displaying normal/high CYP3A4 expression than in the low expressers. Conclusion: Prospective assaying of CYP3A-status (CYP3A4 expression, CYP3A5 genotype) may better identify the patients with higher risk of inefficiency or adverse reactions and may facilitate the improvement of personalized clozapine therapy; however, further clinical studies are required to prove the benefit of CYP3A testing for patients under clozapine therapy. PMID- 28340125 TI - The Association of Lesbian, Gay, and Bisexual Identity Facets With Smoking Dependence Motives. AB - Introduction: Lesbian, gay, and bisexual (LGB) adults have higher rates of smoking than heterosexual adults. LGB individuals face unique stressors, including challenges associated with having a LGB identity. The extent to which these unique stressors are related to dependence motives in LGB adult smokers, however, has not been previously explored. The current study was conducted to redress these gaps. Methods: Participants (N = 52; Mage = 42.8; 55.8% Black/African American) were recruited from the local community. Identity facets were measured by the Lesbian, Gay, and Bisexual Identity Scale (LGBIS). Dependence motives were measured by the Brief Wisconsin Inventory of Smoking Dependence Motives. Linear multiple regressions were calculated with the predictors of seven LGBIS subscales for primary and secondary dependence motives, respectively. Results: Primary dependence motives (core nicotine dependence features) were predicted by affirmation of LGB identity (beta = 0.44). Secondary dependence motives (eg, taste, cognitive/affective enhancement) were predicted by uncertainty of LGB identity (beta = 0.43). Conclusions: LGB identity affirmation was associated with primary dependence motives, suggesting that a positive view of one's sexual orientation is a risk factor for dependence. It may be that identity affirmation is related to stronger involvement with the LGB community, which has smoking-friendly norms. Identity uncertainty was associated with secondary dependence motives; this unique identity challenge may represent a stressor contributing to smoking dependence. Findings can help explain the higher rate of smoking in LGB populations and offer avenues to better tailor smoking cessation interventions. Implications: The current study is the first to examine multidimensional aspects of LGB identity in explaining smoking dependence motives among LGB adults. Results reveal that LGB identity challenges are associated with dependence motives, suggesting that interventions targeting these challenges may be help reduce LGB smoking disparities. Specifically, reducing identity uncertainty may help reduce smoking dependence. Though identity affirmation was a smoking dependence correlate, it is counterproductive to reduce affirmation, given its association with other positive health outcomes. Rather, interventions to change LGB community norms around smoking appear warranted, given the documented high overlap between affirmation and community affiliation. PMID- 28340126 TI - Association Between Socioeconomic Status and Access to Care and Quitting Smoking With and Without Assistance. AB - Introduction: Socio-economic disparities in smoking rates persist, in Ontario, despite public health care and universal tobacco control policies. Mechanisms for continuing disparities are not fully understood. Unequal access or utilization of assistance for cessation may contribute. The objective of this research was to use longitudinal data on smokers to examine the associations between socioeconomic status (SES) and access to care measures and assisted and unassisted quit attempts. Methods: Data were taken from 3578 smokers with at least one follow-up interview participating in the Ontario Tobacco Survey (OTS). Multinomial regression models with imputed missing values were run for each measure of SES and access to care to assess the association with quitting behavior and use of assistance, unadjusted and while adjusting for smoking history and demographic covariates. Results: Adjusted analyses found smokers living in areas with the lowest ethnic concentration were more likely to make an assisted quit attempt compared to unassisted quitting (RR = 1.64; 95% CI = 1.08 2.50) or making no quit attempt (RR = 1.65; 95% CI = 1.15-2.37). Smokers who reported visiting a doctor in the previous 6 months were more likely to quit with assistance versus unassisted compared to those not visiting a doctor, whether they were advised (RR = 1.89, 95% CI = 1.43-2.48) or not advised to quit (OR = 1.32, 95% CI = 1.01-1.74). Similar results were seen when comparing assisted quit attempts with no quit attempts. Conclusions: Adjusted analyses showed that quitting with assistance was unrelated to measures of SES except ethnic concentration. Physician intervention with patients who smoke is important for increasing assisted quit attempts. Implications: For most measures of SES there were no significant associations with either assisted or unassisted quitting adjusting for demographic and smoking history. Smokers who live in areas with the lowest ethnic concentration were most likely to use assistance as were smokers who visited their doctor and were advised to quit smoking. Interventions to increase the delivery of effective quitting methods in smokers living in areas with high ethnic concentrations and to increase physician compliance with asking and advising patients to quit may increase assisted quit attempts. PMID- 28340127 TI - Do Interoceptive Sensations Provoke Fearful Responses in Adolescents With Chronic Headache or Chronic Abdominal Pain? A Preliminary Experimental Study. AB - Objective: To determine whether fear can be triggered when experiencing interoceptive sensations locally proximal to the primary pain region. Two groups of adolescents (11-18 years) with chronic headache ( n = 20) or chronic abdominal pain (CAP; n = 20) completed three muscle tensing tasks to induce proximal versus distal sensations: (1) "frown" task (proximal for chronic headache; distal for CAP), (2) "tighten stomach" task (proximal for CAP; distal for chronic headache), and (3) safe comparison task (clench fist). Fear and avoidance were assessed via self-report. Adolescents with CAP reported greater fear and avoidance after the proximal compared with the distal task, while adolescents with chronic headache did not. Both groups reported similar levels of fear and avoidance in the frown and safe comparison task. Results suggest that the perception of proximal interoceptive sensations appears to activate the fear system in adolescents with CAP. Future research is warranted. PMID- 28340128 TI - Crossing the health IT chasm: considerations and policy recommendations to overcome current challenges and enable value-based care. AB - While great progress has been made in digitizing the US health care system, today's health information technology (IT) infrastructure remains largely a collection of systems that are not designed to support a transition to value based care. In addition, the pursuit of value-based care, in which we deliver better care with better outcomes at lower cost, places new demands on the health care system that our IT infrastructure needs to be able to support. Provider organizations pursuing new models of health care delivery and payment are finding that their electronic systems lack the capabilities needed to succeed. The result is a chasm between the current health IT ecosystem and the health IT ecosystem that is desperately needed.In this paper, we identify a set of focal goals and associated near-term achievable actions that are critical to pursue in order to enable the health IT ecosystem to meet the acute needs of modern health care delivery. These ideas emerged from discussions that occurred during the 2015 American Medical Informatics Association Policy Invitational Meeting. To illustrate the chasm and motivate our recommendations, we created a vignette from the multistakeholder perspectives of a patient, his provider, and researchers/innovators. It describes an idealized scenario in which each stakeholder's needs are supported by an integrated health IT environment. We identify the gaps preventing such a reality today and present associated policy recommendations that serve as a blueprint for critical actions that would enable us to cross the current health IT chasm by leveraging systems and information to routinely deliver high-value care. PMID- 28340130 TI - Falling Down on the Job: Evaluation and Treatment of Fall Risk Among Older Adults With Upper Extremity Fragility Fractures. AB - Background: Clinical practice guidelines recommend fall risk assessment and intervention for older adults who sustain a fall-related injury to prevent future injury and mobility decline. Objective: The aim of this study was to describe how often Medicare beneficiaries with upper extremity fracture receive evaluation and treatment for fall risk. Design: Observational cohort. Methods: Participants were fee-for-service beneficiaries age 66 to 99 treated as outpatients for proximal humerus or distal radius/ulna ("wrist") fragility fractures. -Participants were studied using Carrier and Outpatient Hospital files. The proportion of patients evaluated or treated for fall risk up to 6 months after proximal humerus or wrist fracture from 2007-2009 was examined based on evaluation, treatment, and diagnosis codes. Time to evaluation and number of treatment sessions were calculated. Logistic regression was used to analyze patient characteristics that predicted receiving evaluation or treatment. Narrow (gait training) and broad (gait training or therapeutic exercise) definitions of service were used. Results: There were 309,947 beneficiaries who sustained proximal humerus (32%) or wrist fracture (68%); 10.7% received evaluation or treatment for fall risk or gait issues (humerus: 14.2%; wrist: 9.0%). Using the broader definition, the percentage increased to 18.5% (humerus: 23.4%; wrist: 16.3%). Factors associated with higher likelihood of services after fracture were: evaluation or treatment for falls or gait prior to fracture, more comorbidities, prior nursing home stay, older age, humerus fracture (vs wrist), female sex, and white race. Limitations: Claims analysis may underestimate physician and physical therapist fall assessments, but it is not likely to qualitatively change the results. Conclusions: A small proportion of older adults with upper extremity fracture received fall risk assessment and treatment. Providers and health systems must advance efforts to provide timely evidence-based management of fall risk in this population. PMID- 28340131 TI - Interobserver Variability in Histologic Evaluation of Liver Fibrosis Using Categorical and Quantitative Scores. AB - Objectives: The aim of the study was to investigate the interobserver agreement for categorical and quantitative scores of liver fibrosis. Methods: Sixty-five consecutive biopsy specimens from patients with mixed liver disease etiologies were assessed by three pathologists using the Ishak and nonalcoholic steatohepatitis Clinical Research Network (NASH CRN) scoring systems, and the fibrosis area (collagen proportionate area [CPA]) was estimated by visual inspection (visual-CPA). A subset of 20 biopsy specimens was analyzed using digital imaging analysis (DIA) for the measurement of CPA (DIA-CPA). Results: The bivariate weighted kappa between any two pathologists ranged from 0.57 to 0.67 for Ishak staging and from 0.47 to 0.57 for the NASH CRN staging. Bland-Altman analysis showed poor agreement between all possible pathologist pairings for visual-CPA but good agreement between all pathologist pairings for DIA-CPA. There was good agreement between the two pathologists who assessed biopsy specimens by visual-CPA and DIA-CPA. The intraclass correlation coefficient, which is equivalent to the kappa statistic for continuous variables, was 0.78 for visual CPA and 0.97 for DIA-CPA. Conclusions: These results suggest that DIA-CPA is the most robust method for assessing liver fibrosis followed by visual-CPA. Categorical scores perform less well than both the quantitative CPA scores assessed here. PMID- 28340132 TI - The Impact of Weight and Weight-Related Perceptions on Smoking Status Among Young Adults in a Text-Messaging Cessation Program. AB - Introduction: Weight gain and concerns about weight can influence a smoker's ability to successfully quit, and young adults are a subgroup of smokers who are particularly concerned about the impact of quitting on their body weight. This study explored the associations between body mass index, weight perceptions, and smoking status among young adults. Methods: The sample consisted of 4027 young adults between the ages of 18 and 29 who participated in a randomized control trial of the National Cancer Institute's SmokefreeTXT program. Multivariable logistic regression models were used to examine the associations between weight related variables and smoking status. Results: Obese participants had a 0.72 lower odds (95% CI: 0.62, 0.85) of reporting smoking at the end of the program than participants of normal weight, and this difference persisted over time. Weight perceptions were also associated with smoking status. Those who perceived themselves to be slightly underweight/underweight were more likely to report smoking than those who reported being just about the right weight (OR: 1.53, 95% CI: 1.20, 1.95), and those who strongly disagreed that smoking cigarettes helps people keep their weight down were less likely to report smoking at the end of treatment than those who neither agreed nor disagreed with this statement (OR: 0.69, 95% CI: 0.54, 0.87). Conclusions: Weight related factors assessed at baseline predicted smoking status at the end of treatment and through long term follow-up. Smoking cessation programs that tailor content to addresses the specific needs of weight concerned smokers may enhance effectiveness. Implications: This study explores the association between weight related factors and smoking status among young adults, a priority population for smoking cessation efforts. This study demonstrates that both actual weight and weight perceptions (eg, perception of body weight, perception of associations between smoking and weight) are associated with smoking outcomes, and thus need to be a considered in the development of smoking cessation programs. PMID- 28340133 TI - A rare case of rheumatoid pachyleptomeningitis successfully treated with rituximab. PMID- 28340134 TI - Primary Motor Cortex Organization Is Altered in Persistent Patellofemoral Pain. AB - Objective: Reorganization of the primary motor cortex (M1) may be a feature of persistent patellofemoral pain (PFP), but no studies have investigated M1 organization in this condition. Here we aimed to examine the organization of the M1 representation of the quadriceps muscles in people with PFP and healthy controls. Design: Using a cross-sectional design, the M1 representation of the rectus femoris, vastus lateralis, and vastus medialis was mapped using transcranial magnetic stimulation in 11 individuals with PFP and 11 controls. Measures of pain severity were also made. Results: Individuals with PFP had reduced map volumes (P < 0.001) and an anterior shift in the M1 representation (P = 0.03) across all three quadriceps muscles compared with controls. Greater overlap of the M1 representation (P = 0.02) and a reduction in the number of discrete cortical peaks (P = 0.009) across all three quadriceps muscles were also observed in individuals with PFP compared with controls. There was no relationship between altered M1 organization and pain in PFP. Conclusions: These findings provide evidence of altered M1 organization in individuals with PFP compared with healthy controls. Notably, no difference in M1 organization was observed for the medial and lateral heads of the quadriceps in PFP. These data have relevance for our understanding of the pathophysiology of PFP and for the design of future treatments that aim to target M1 in this condition. PMID- 28340135 TI - Modeling longitudinal data and its impact on survival in observational nephrology studies: tools and considerations. AB - Nephrologists and kidney disease researchers are often interested in monitoring how patients' clinical and laboratory measures change over time, what factors may impact these changes, and how these changes may lead to differences in morbidity, mortality, and other outcomes. When longitudinal data with repeated measures over time in the same patients are available, there are a number of analytical approaches that could be employed to describe the trends and changes in these measures, and to explore the associations of these changes with outcomes. Researchers may choose a streamlined and simplified analytic approach to examine trajectories with subsequent outcomes such as estimating deltas (subtraction of the last observation from the first observation) or estimating per patient slopes with linear regression. Conversely, they could more fully address the data complexity by using a longitudinal mixed model to estimate change as a predictor or employ a joint model, which can simultaneously model the longitudinal effect and its impact on an outcome such as survival. In this review, we aim to assist nephrologists and clinical researchers by reviewing these approaches in modeling the association of longitudinal change in a marker with outcomes, while appropriately considering the data complexity. Namely, we will discuss the use of simplified approaches for creating predictor variables representing change in measurements including deltas and patient slopes, as well more sophisticated longitudinal models including joint models, which can be used in addition to simplified models based on the indications and objectives of the study as warranted. PMID- 28340136 TI - The Effect of a "Class Smoke Free Pledge" on Breath Carbon Monoxide in Arabic Male Adolescents. AB - Introduction: Arabic male adolescents have a high smoking prevalence. Introduction of "Class smoke-free" pledges have been successful amongst European adolescents but have not been evaluated using objective valid measures. We tested the impact of adding a smoke free pledge strategy to a proven peer-led asthma and smoking prevention program on breath carbon monoxide level (BCO) in male high school students in Jordan. Methods: We enrolled male students from four high schools in Irbid, Jordan. Schools were randomly assigned to receive either TAJ (Triple A in Jordan, n = 218) or TAJ-Plus (with added class smoke-free pledge, n = 215). We hypothesized that students receiving TAJ-Plus would have greater reduction in BCO levels than those only receiving the TAJ intervention. Asthma and smoking status were assessed by self-administered questionnaires. Smoking outcomes were collected using a BCO Monitor. Results: Both groups had significant reductions in BCO levels post-intervention (p < .0001), however, decreases were greater in TAJ-Plus group (3.9 +/- 0.2 vs. 4.8 +/- 0.2, p < .0001). Intervention effects on BCO over time did not vary by smoking status (p = .085), asthma status (p = .602), or a combination of the two (p = .702). Conclusions: An added smoke free pledge strategy to a proven peer-led asthma education program appears to be a promising approach to motivate adolescents to abstain from smoking in Jordan. Future research is required to determine if these results can be extended to Jordanian adolescent females. Implications: A commitment by students via a "class smoke-free" pledge can be an added incentive to motivate adolescents in Arabic speaking countries to abstain from smoking. Social influence approaches in schools can be useful in countering the aggressive tobacco marketing campaigns targeting Jordanian and other Arabic-speaking youth. The combination of "class smoke-free" pledges and an evidence-based peer-led asthma and smoking education can be implemented in schools to influence adolescents with asthma to abstain from smoking. PMID- 28340137 TI - Questioning the preference for dual- vs. single-chamber implantable defibrillator in primary prevention implantable cardioverter-defibrillator recipients. PMID- 28340139 TI - Assessment of acute kidney injury in rhabdomyolytic mice by transcutaneous measurement of sinistrin excretion. AB - Background: Early and accurate assessment of renal function is required for the successful detection and treatment of acute kidney injury (AKI). However, only retention parameters such as plasma urea and creatinine, and the indirect estimation of glomerular filtration rate are commonly available. Methods: Here, we measured the kinetics of plasma fluorescein isothiocyanate (FITC)-sinistrin excretion to detect alterations of renal function over time in a murine model of rhabdomyolysis-induced AKI. The half-life of FITC-sinistrin was evaluated using a transcutaneous device at different time points in conscious mice, from 4 days before renal damage up to 30 days after. Retention markers were also evaluated, in parallel. Results: Evaluation of the FITC-sinistrin half-life revealed early reduction of renal filtration, observed as early as 6 h after renal damage, and maintained up to 12 h following AKI. Plasma creatinine and urea levels correlated with the transcutaneous measurements of sinistrin excretion. Evaluation of sinistrin excretion also demonstrated that glycerol-treated animals did not develop AKI. Finally, histological analysis showed the presence of renal parenchymal lesions, which developed following the reduced renal filtration and persisted over time, highlighting the causative role of vascular dysfunction and myoglobin toxicity on the subsequent induction of tissue damage. Conclusions: Taken together, the results of this study provide important insights into the pathophysiology of kidney injury in rhabdomyolytic mice, and indicate that the transcutaneous measurement of FITC-sinistrin is an efficient and simple method to assess renal function precisely. This method also allows reduction of the required number of experimental animals by monitoring the same mouse over time. PMID- 28340140 TI - Lipidomic profiling of endometrial fluid in women with ovarian endometriosis?. AB - The proteomic content of the endometrial fluid (EF) from patients with endometriosis has been investigated, but the lipidomic profile has not been analyzed yet in detail.This study is a comparative untargeted lipidomic analysis of human EF obtained from 35 patients (12 endometriosis and 23 controls). Global differential lipidomic profile was analyzed in both groups by ultrahigh performance liquid chromatography coupled to mass spectrometry. A total of 123 out of the 457 metabolites identified in the EF were found to be significantly differentially expressed between ovarian endometriosis (OE) versus controls. Univariate statistical analysis showed reduced levels of saturated diacylglycerols and saturated triacylglycerols in endometriosis patients. A predictive model was generated using the 123 differentially expressed metabolites. Using this model, we were able to correctly classify 86% of the samples. This study identified the lipidomic profile in the EF associated with OE, suggesting that EF analysis could be considered as a minimally invasive approach for the diagnosis of endometriosis. In conclusion, the lipidomic profile of the EF is different between samples from patients with OE and controls. PMID- 28340138 TI - A life without worms. AB - Worms have co-evolved with humans over millions of years. To survive, they manipulate host systems by modulating immune responses so that they cause (in the majority of hosts) relatively subtle harm. Anthelminthic treatment has been promoted as a measure for averting worm specific pathology and to mitigate subtle morbidities which may include effects on anaemia, growth, cognitive function and economic activity. With our changing environment marked by rapid population growth, urbanisation, better hygiene practices and anthelminthic treatment, there has been a decline in worm infections and other infectious diseases and a rise in non-communicable diseases such as allergy, diabetes and cardiovascular disease. This review reflects upon our age-old interaction with worms, and the broader ramifications of life without worms for vaccine responses and susceptibility to other infections, and for allergy-related and metabolic disease. We touch upon the controversy around the benefits of mass drug administration for the more subtle morbidities that have been associated with worm infections and then focus our attention on broader, additional aspects of life without worms, which may be either beneficial or detrimental. PMID- 28340141 TI - The unfinished issue of ischaemic stroke and embolic events during catheter ablation of atrial fibrillation. PMID- 28340142 TI - Multigene signature for predicting prognosis of patients with 1p19q co-deletion diffuse glioma. AB - Background: Co-deletion of 1p and 19q marks a diffuse glioma subtype associated with relatively favorable overall survival; however, heterogeneous clinical outcomes are observed within this category. Methods: We assembled gene expression profiles and sample annotation of 374 glioma patients carrying the 1p/19q co deletion. We predicted 1p/19q status using gene expression when annotation was missing. A first cohort was randomly split into training (n = 170) and a validation dataset (n = 163). A second validation set consisted of 41 expression profiles. An elastic-net penalized Cox proportional hazards model was applied to build a classifier model through cross-validation within the training dataset. Results: The selected 35-gene signature was used to identify high-risk and low risk groups in the validation set, which showed significantly different overall survival (P = .00058, log-rank test). For time-to-death events, the high-risk group predicted by the gene signature yielded a hazard ratio of 1.78 (95% confidence interval, 1.02-3.11). The signature was also significantly associated with clinical outcome in the The Cancer Genome Atlas (CGA) IDH-mutant 1p/19q wild type and IDH-wild-type glioma cohorts. Pathway analysis suggested that high risk was associated with increased acetylation activity and inflammatory response. Tumor purity was found to be significantly decreased in high-risk IDH-mutant with 1p/19q co-deletion gliomas and IDH-wild-type glioblastomas but not in IDH-wild type lower grade or IDH-mutant, non-co-deleted gliomas. Conclusion: We identified a 35-gene signature that identifies high-risk and low-risk categories of 1p/19q positive glioma patients. We have demonstrated heterogeneity amongst a relatively new glioma subtype and provided a stepping stone towards risk stratification. PMID- 28340143 TI - Protecting Pain Patients. The Evaluation of a Chronic Pain Educational Intervention. AB - Introduction: Advocacy and commercially funded education successfully reduced barriers to the provision of long-term opioid analgesia. The subsequent escalation of opioid prescribing for chronic noncancer pain has seen increasing harms without improved pain outcomes. Methods: This was a one-group pretest posttest design study. A multidisciplinary team developed a chronic pain educational package for general practitioner trainees emphasizing limitations, risk-mitigation, and deprescribing of opioids with transition to active self care. This educational intervention incorporated prereadings, a resource kit, and a 90-minute interactional video case-based workshop incorporated into an education day. Evaluation was via pre- and postintervention (two months) questionnaires. Differences in management of two clinical vignettes were tested using McNemar's test. Results: Of 58 eligible trainees, 47 (response rate = 81.0%) completed both questionnaires (36 of whom attended the workshop). In a primary analysis including these 47 trainees, therapeutic intentions of tapering opioid maintenance for pain (in a paper-based clinical vignette) increased from 37 (80.4%) pre-intervention to 44 (95.7%) postintervention (P = 0.039). In a sensitivity analysis including only trainees attending the workshop, 80.0% pre intervention and 97.1% postintervention tapered opioids (P = 0.070). Anticipated initiation of any opioids for a chronic osteoarthritic knee pain clinical vignette reduced from 35 (74.5%) to 24 (51.1%; P = 0.012) in the primary analysis and from 80.0% to 41.7% in the sensitivity analysis (P = 0.001). Conclusions: Necessary improvements in pain management and opioid harm avoidance are predicated on primary care education being of demonstrable efficacy. This brief educational intervention improved hypothetical management approaches two months subsequently. Further research measuring objective changes in physician behavior, especially opioid prescribing, is indicated. PMID- 28340144 TI - Preventive chemotherapy in one year reduces by over 80% the number of individuals with soil-transmitted helminthiases causing morbidity: results from meta analysis. AB - The morbidity due to Ascaris lumbricoides and Trichuris trichiura is caused by infections of moderate and heavy intensity while hookworm infections of all intensities are recognized to cause morbidity. This study aims to evaluate the effect of repeated rounds of preventive chemotherapy on the proportion of soil transmitted helminth (STH) infections causing morbidity. We identified studies from 17 countries, reporting changes in the proportion of STH infection causing morbidity between baseline and follow-up. In the studies identified, the average proportion of individuals with STH infections of moderate and heavy intensity was of 14% at baseline and was on average reduced to 2% by the intervention (i.e., 85% reduction). There was an average reduction of 73% after the first year of treatment, which reached almost 80% after 5 years and over 95% in 10 years of deworming interventions. The reduction in hookworm prevalence was 57% after 12 months reaching 78% after 5 years. We consider the results presented in this study especially useful for decision makers as it demonstrates the effectiveness of preventive chemotherapy in reducing STH prevalence and morbidity. We encourage the implementation of deworming programs to achieve the goal, set by WHO for 2020, to eliminate STH morbidity in children. PMID- 28340145 TI - Human Abuse Potential of the New Opioid Analgesic Molecule NKTR-181 Compared with Oxycodone. AB - Objective: Evaluate the human abuse potential, pharmacokinetics, pharmacodynamics, and safety of NKTR-181, a novel mu-opioid agonist molecule, relative to oxycodone. Design: This randomized, single-center, double-blind, active- and placebo-controlled five-period crossover study enrolled healthy, adult, non-physically dependent recreational opioid users. Setting: Inpatient clinical research site. Subjects: Forty-two randomized subjects (73.8% male, 81% white, mean age = 25 years). Methods: The primary objective was to evaluate single orally administered 100, 200, and 400 mg NKTR-181 doses in solution compared with 40 mg oxycodone and placebo solutions using the Drug Liking visual analog scale. Secondary measures included the Drug Effects Questionnaire, Addiction Research Center Inventory/Morphine Benzedrine Group Subscale, Price Value Assessment Questionnaire, Global Assessment of Overall Drug Liking, and Take Drug Again Assessment. Central nervous system mu-opioid effects were assessed using pupillometry. The study included qualifying and treatment phases. Subjects received each of the five treatments using a crossover design. Results: NKTR-181 at all dose levels had significantly lower Drug Liking Emax than oxycodone (P < 0.0001). Drug Liking scores for oxycodone increased rapidly within 15 minutes and peaked at approximately one hour postdose, whereas Drug Liking (and most secondary abuse potential measures) for all doses of NKTR-181 were comparable with placebo for at least the first hour. Only the 400 mg Drug Liking scores were minimally differentiated vs placebo from one and a half to four hours, but remained significantly lower than oxycodone (P < 0.003). NKTR-181 treatment-related adverse effects were mild and occurred at a lower rate compared with oxycodone. Conclusions: NKTR-181 demonstrated delayed onset of CNS effects and significantly lower abuse potential scores compared with oxycodone in recreational opioid users. PMID- 28340146 TI - Effect of broiler breeders fed with corn or sorghum diet and canthaxanthin supplementation on production and reproductive performance. AB - This study was designed to evaluate the effect of corn or sorghum diet and canthaxanthin (CX) supplementation on performance in broiler breeders. A total of 440 females with similar body weight (BW) (3.71 +/- 0.14 kg) and 60 roosters were placed in an open-sided house with 20 pens, randomly distributed in a factorial arrangement (2 * 2). There were 4 diets of 2 ingredients; corn (CO) or sorghum (SO) and 2 levels of CX; 6 mg/kg (CX) and 0 mg/kg (NCX) totaling 5 replicate pens of 22 females and 3 males each, from 42 to 65 wk, divided in 2 periods (from wk 42 to 53 and wk 54 to 65). Birds' BW was measured every 28 d and mortality rate was calculated at the end of trial. Egg production (%), egg specific gravity (g/cm3), egg weight (g), yolk weight (%), albumen weight (%), eggshell weight (%) and yolk colorimetric score were measured weekly. Incubation parameters were recorded in 12 incubations to evaluate hatching eggs, hatching (%), hatchability (%), fertility (%), weight of the chicks born and their quality. The BW, mortality, percentage of yolk and albumen weight, fertility and some incubation parameters were not affected (P > 0.05) by diets used. An increase in the egg production, hatching eggs, chicks born and first quality chick by hen at the second period were observed in CX breeder's diets (P = 0.0066; P = 0.0060; P = 0.0368; P = 0.0326). Egg specific gravity and eggshell weight were improved at the first period by SO+CX diet (P = 0.0138; P = 0.0209) and the same effect to egg weight, but at the second period (P = 0.0251). The CX was well absorbed from the diet and effectively transferred to the egg yolk, thereby increasing egg yolk pigmentation in the both periods (P < 0.0001). The CX supplementation in broiler breeder diets improved the productive and reproductive performance (laying% and hatchable eggs) at the second period, also to the both periods improved the egg yolk pigmentation. PMID- 28340147 TI - Evoked Pressure Pain Sensitivity Is Associated with Differential Analgesic Response to Verum and Sham Acupuncture in Fibromyalgia. AB - Objective: Fibromyalgia is a chronic pain condition with few effective treatments. Many fibromyalgia patients seek acupuncture for analgesia; however, its efficacy is limited and not fully understood. This may be due to heterogeneous pathologies among participants in acupuncture clinical trials. We hypothesized that pressure pain tenderness would differentially classify treatment response to verum and sham acupuncture in fibromyalgia patients. Design: Baseline pressure pain sensitivity at the thumbnail at baseline was used in linear mixed models as a modifier of differential treatment response to sham versus verum acupuncture. Similarly, needle-induced sensation was also analyzed to determine its differential effect of treatment on clinical pain. Methods and Patients: A cohort of 114 fibromyalgia patients received baseline pressure pain testing and were randomized to either verum (N = 59) or sham (N = 55) acupuncture. Participants received treatments from once a week to three times a week, increasing in three-week blocks for a total of 18 treatments. Clinical pain was measured on a 101-point visual analog scale, and needle sensation was measured by questionnaire throughout the trial. Results: Participants who had higher pain pressure thresholds had greater reduction in clinical pain following verum acupuncture while participants who had lower pain pressure thresholds showed better analgesic response to sham acupuncture. Moreover, patients with lower pressure pain thresholds had exacerbated clinical pain following verum acupuncture. Similar relationships were observed for sensitivity to acupuncture needling. Conclusions: These findings suggest that acupuncture efficacy in fibromyalgia may be underestimated and a more personalized treatment for fibromyalgia may also be possible. PMID- 28340148 TI - Characteristics of Hookah Tobacco Smoking Sessions and Correlates of Use Frequency Among US Adults: Findings From Wave 1 of the Population Assessment of Tobacco and Health (PATH) Study. AB - Introduction: Hookah tobacco smoking has increased in the United States. However, information on hookah use frequency and other characteristics of hookah use is limited. Methods: Investigators analyzed data from Wave 1 of the Population Assessment of Tobacco and Health (PATH) Study, a nationally representative, longitudinal cohort study of US youth and adults. Our analysis draws on baseline data from adult (ages >=18 years) ever (N = 10 624) and past year (n = 3947) hookah users. Bivariate and regression analyses were conducted to identify associations between demographics, use characteristics, and hookah use frequency. Results: Overall, 16.4% of adults reported ever smoking tobacco from a hookah. Of those, 31.9% reported smoking hookah within the past year. Among 3947 past-year hookah tobacco smokers, 10.7% were daily/weekly users, 13.7% were monthly users, 42.1% smoked every couple of months, and 33.5% smoked about once a year. Among daily/weekly hookah users, 66% were young adults (ages 18-24 years). When comparing daily/weekly hookah users to those who smoked every couple of months, more frequent hookah use was associated with younger age, male gender, a greater number of times the hookah is refilled during a session, fewer people sharing, and hookah ownership. Conclusion: Although there were few demographic differences between daily/weekly users and less frequent hookah tobacco smokers, some notable differences in use behaviors exist among use frequency groups. Unlike other tobacco products, hookah is often smoked communally, over an extended time period. A detailed understanding of hookah user characteristics and experiences could inform hookah-specific measures, messaging, and regulations. Implications: To our knowledge, this is one of the first studies to characterize hookah use frequency, session length, and other hookah use experiences using a nationally representative sample of US adult hookah smokers. Understanding characteristics of hookah tobacco smokers, their use experiences, and patterns of hookah use frequency would be useful in assessing risks for hookah tobacco dependence at the population level. Additionally, identifying variation in use behaviors of hookah tobacco smokers could be used to inform the development of strategies to reduce and prevent hookah tobacco use, such as tobacco regulations or public education efforts, particularly among young adults. PMID- 28340149 TI - Individual and Regional Determinants for Physical Therapy Utilization in Germany: Multilevel Analysis of National Survey Data. AB - Background: Physical therapy is included in many clinical guidelines and is a commonly used health service. However, access to its benefits should not strongly depend on social or demographic factors. Objective: The present study used the Andersen model to explain to what extent physical therapy utilization in Germany depends on factors beyond medical need. Methods: The German Health Interview and Examination Survey for Adults (DEGS, 2008-2011; target population, 18-79 years) is part of the German health-monitoring system. Two-stage stratified cluster sampling resulted in a sample of 8152 participants. Data were matched with district-related information on social structures and service supply. Following Andersen's Behavioral Model of Health Services Use, this study identified predisposing, enabling, and need factors for physical therapy utilization using multilevel logistic regression analyses. Results: Physical therapy was used by 23.4% (95% CI: 22.0-24.8) of the German population within one year, with a higher proportion of females (26.8%; 95% CI: 25.1-28.6) than males (19.9%; 95% CI: 18.1 21.8) and an increase with age. Beyond medical need, physical therapy utilization depended on higher education, migrant background, nonsmoking (predisposing), social support, higher income, private health insurance, and gatekeeping service contact (enabling). Variation among districts partly reflected regional supply. Limitations: Because the present study was cross-sectional, its findings provide representative information on physical therapy use but do not establish final causal links or identify whether utilization or supply in certain districts or population groups is adequate. Conclusions: Whether certain regions are under- or overserved and whether further regulations are needed is of political interest. Physicians and therapists should develop strategies to improve both adherence of hard-to-reach groups and supply in low-supply regions. PMID- 28340150 TI - Severe conduction defects requiring permanent pacemaker implantation in patients with a new-onset left bundle branch block after transcatheter aortic valve implantation. AB - Aims: Transcatheter aortic valve implantation (TAVI) is frequently associated with cardiac conduction defects (CCD) requiring permanent pacemaker implantation (PPI). Although new-onset left bundle branch block (LBBB) is often seen, the rate of progression to severe CCD is unclear. We aimed to find clinical and electrocardiographic (ECG) parameters associated with severe CCD requiring PPI in patients with a new-onset LBBB after TAVI and assess its effect on clinical outcome. Methods and results: All consecutive patients undergoing TAVI who developed a new-onset LBBB were retrospectively analysed. We excluded patients with pre-existing bundle branch block or pacemaker. Patients were divided into two groups: with or without PPI after TAVI. We included 155 patients (50% female, 80 +/- 7 years), of which 37 (24%) developed CCD requiring PPI, mainly due to a total atrioventricular block (n = 17; 46%). Cardiac conduction defects requiring PPI were associated with the following pre-existing parameters: atrial fibrillation (AF), the use of digoxin, CoreValve implantation, and left heart axis. Furthermore, it was associated with the following post-procedural parameters: left heart axis, lower mean heart rate, and prolonged PQ and QRS times. During follow-up, patients with PPI showed a lower mortality rate (11 vs. 29%, P = 0.03). In patients without PPI, mortality was lower in those with narrower QRS complex and transient LBBB. Conclusion: The severity and persistence of a new-onset LBBB after TAVI is associated with mortality. Cardiac conduction defects requiring PPI are associated with prior AF, the use of digoxin, CoreValve implantation, and a left heart axis. In these patients, PPI portends a better prognosis than no PPI. PMID- 28340151 TI - Effect of excess dietary fluoride on laying performance and antioxidant capacity of laying hens. AB - The objective of this study was to investigate the effects of excess dietary fluoride (F) on laying performance and antioxidant capacity of laying hens. A total of 576 laying hens, 51 wk old, was randomly divided into 6 groups, each of which included 6 replicates of 16 hens. Graded amounts of sodium fluoride (NaF) were added to the basal diet to achieve concentrations of 16 (control), 200, 400, 600, 800, and 1,000 mg/kg F, respectively. Dietary F at 1,000 mg/kg significantly decreased ADFI, laying rate, and average egg weight, and increased feed conversion ratio (FCR) (P < 0.05). No significant differences were observed in serum total antioxidant capacity (T-AOC) level or catalase (CAT) concentration among all the treatments, while hens fed F at 800 and 1,000 mg/kg had higher activity of serum glutathione peroxidase (GSH-PX) and concentration of malondialdehyde (MDA) (P < 0.05) as compared to the control group. Compared with the control group, dietary F at 400 mg/kg increased liver MDA concentration (P < 0.001), and decreased CAT concentration of liver (P < 0.001); 600 mg/kg F decreased liver T-AOC levels (P < 0.001); and 800 mg/kg of F decreased liver total superoxide dismutases (T-SOD) activity (P < 0.001). Compared with the control group, feeding F at 600 mg/kg decreased kidney T-AOC levels and T-SOD activity (P < 0.001), and increased MDA concentration of kidney (P < 0.001), while dietary 1,000 mg/kg of F decreased kidney GSH-PX activity (P < 0.05) and CAT concentration (P < 0.001). In conclusion, these results indicated that excessive F ingestion had an adverse effect on laying performance by inducing oxidative stress and impairing the antioxidant system of laying hens. PMID- 28340152 TI - Sarcopenia and relationships between muscle mass, measured glomerular filtration rate and physical function in patients with chronic kidney disease stages 3-5. AB - Background: Sarcopenia and poor physical function are common in patients with chronic kidney disease (CKD). Our aim was to investigate the relationships between muscle mass and measured glomerular filtration rate (GFR) and between muscle mass and strength and balance, respectively, in patients with CKD stages 3 5. Methods: This is a baseline data analysis of a randomized controlled clinical trial. A total of 148 adult patients with an estimated GFR <30 mL/min/1.72 m2, not on renal replacement therapy, irrespective of the number of comorbidities were included from the Department of Nephrology, Skane University Hospital, Lund, from 2011 to 2016. Body composition was measured by dual-energy X-ray absorptiometry (DEXA). GFR was measured by iohexol clearance. Balance was measured by functional reach and the Berg balance test and strength by handgrip strength and isometric quadriceps strength. Results: Measured GFR ranged from 8 to 55 mL/min/1.73 m2. Lean mass (P < 0.05), fat mass (P < 0.05), appendicular skeletal muscle (P < 0.001) and appendicular skeletal muscle index (P < 0.05) were associated with GFR. Functional reach was associated with leg lean mass (P < 0.05) and the Berg balance test score was associated with trunk lean mass (P < 0.05). Handgrip strength was associated with arm lean mass (P < 0.001). Isometric quadriceps strength was associated with leg lean mass (P < 0.001). More men (44%) suffered from low muscle mass than women (22%), whereas more women (36%) suffered from low muscle strength than men (26%). However, when combining both, men (16%) suffered from sarcopenia to a greater extent than women (8%). Conclusions: Among patients with CKD stages 3-5, loss of lean body mass, especially appendicular skeletal muscle, was significantly related to GFR decline. Two important markers of physical function, balance and strength, were significantly related to muscle mass. Moreover, men were more prone to sarcopenia than women during kidney function decline. PMID- 28340153 TI - Establishing a Stand-Alone Laboratory Dedicated to the Care of Patients With Ebola Virus Disease. AB - Objective: To describe the process for establishment of a stand-alone laboratory dedicated to testing for Ebola virus disease (EVD). Methods: We selected 2 neighboring rooms for the EVD unit: 1 for patient care and 1 for laboratory testing. A limited test menu was developed after consultation with the team of healthcare providers treating patients with EVD, Centers for Disease Control and Prevention (CDC) recommendations, and other sites with EVD expertise. Results: We selected several point-of-care (POC) devices and manual assays to provide necessary testing. Three new instruments were purchased to meet testing needs (Abaxis Piccolo Xpress, Sysmex pocH-100i, and Helena Cascade) and accuracy, precision and reportable range were verified and found to be consistent with the manufacturers' claims. Training was obtained for volunteering laboratory staff members before the initiation of laboratory operation, involving simulation of all procedures. Conclusions: The establishment of a stand-alone unit and laboratory dedicated to the care of patients with EVD minimizes the risk of spreading EVD among hospital patients and employees. Risk assessment, instrument validation, and employee training are major components that contribute to the success of establishing this type of laboratory. PMID- 28340154 TI - Irradiation strongly reduces tumorigenesis of human induced pluripotent stem cells. AB - Induced pluripotent stem (iPS) cells have demonstrated they can undergo self renewal, attain pluripotency, and differentiate into various types of functional cells. In clinical transplantation of iPS cells, however, a major problem is the prevention of tumorigenesis. We speculated that tumor formation could be inhibited by means of irradiation. Since the main purpose of this study was to explore the prevention of tumor formation in human iPS (hiPS) cells, we tested the effects of irradiation on tumor-associated factors such as radiosensitivity, pluripotency and cell death in hiPS cells. The irradiated hiPS cells showed much higher radiosensitivity, because the survival fraction of hiPS cells irradiated with 2 Gy was < 10%, and there was no change of pluripotency. Irradiation with 2 and 4 Gy caused substantial cell death, which was mostly the result of apoptosis. Irradiation with 2 Gy was detrimental enough to cause loss of proliferation capability and trigger substantial cell death in vitro. The hiPS cells irradiated with 2 Gy were injected into NOG mice (NOD/Shi-scid, IL-2 Rgammanull) for the analysis of tumor formation. The group of mice into which hiPS cells irradiated with 2 Gy was transplanted showed significant suppression of tumor formation in comparison with that of the group into which non-irradiated hiPS cells were transplanted. It can be presumed that this diminished rate of tumor formation was due to loss of proliferation and cell death caused by irradiation. Our findings suggest that tumor formation following cell therapy or organ transplantation induced by hiPS cells may be prevented by irradiation. PMID- 28340155 TI - Identification of Jasmonic Acid and Jasmonoyl-Isoleucine, and Characterization of AOS, AOC, OPR and JAR1 in the Model Lycophyte Selaginella moellendorffii. AB - Jasmonic acid (JA) is involved in a variety of physiological responses in seed plants. However, the detection and role of JA in lycophytes, a group of seedless vascular plants, have remained elusive until recently. This study provides the first evidence of 12-oxo-phytodienoic acid (OPDA), JA and jasmonoyl-isoleucine (JA-Ile) in the model lycophyte Selaginella moellendorffii. Mechanical wounding stimulated the accumulation of OPDA, JA and JA-Ile. These data were corroborated by the detection of enzymatically active allene oxide synthase (AOS), allene oxide cyclase (AOC), 12-oxo-phytodienoic acid reductase 3 (OPR3) and JA-Ile synthase (JAR1) in S. moellendorffii. SmAOS2 is involved in the first committed step of JA biosynthesis. SmAOC1 is a crucial enzyme for generating the basic structure of jasmonates and is actively involved in the formation of OPDA. SmOPR5, a functionally active OPR3-like enzyme, is also vital for the reduction of (+)-cis-OPDA, the only isomer of the JA precursor. The conjugation of JA to Ile by SmJAR1 demonstrates that S. moellendorffii produces JA-Ile. Thus, the four active enzymes have characteristics similar to those in seed plants. Wounding and JA treatment induced the expression of SmAOC1 and SmOPR5. Furthermore, JA inhibited the growth of shoots in S. moellendorffii, which suggests that JA functions as a signaling molecule in S. moellendorffii. This study proposes that JA evolved as a plant hormone for stress adaptation, beginning with the emergence of vascular plants. PMID- 28340156 TI - Systematic Review and Meta-Analysis: The Impact of Multicomponent Weight Management Interventions on Self-Esteem in Overweight and Obese Adolescents. AB - Objective: Building self-esteem in overweight adolescents is key to long-term weight management; yet, self-esteem is rarely a key outcome of adolescent weight management interventions. This systematic review investigates the impact of multicomponent weight management interventions on self-esteem in overweight and obese adolescents. Method: Six databases were searched in December 2014. Eligible studies met the following criteria: (1) randomized controlled trial, (2) overweight or obese participants, (3) adolescents (10-19 years), (4) multicomponent weight management intervention, (5) reported self-esteem and weight changes. Results: Thirteen studies with 1,157 overweight or obese adolescents, aged 10-19 years, were included. Meta-analyses showed no significant change in self-esteem (0.27 [-0.04, 0.59]), but body mass index z -score reduced following intervention (-0.17 [-0.22, -0.11]). Conclusion: The lack of change in self-esteem suggests weight loss alone is insufficient to improve self-esteem. Multicomponent weight management interventions require a specific focus on self esteem to improve this outcome in overweight and obese adolescents. PMID- 28340157 TI - Cervical Lateral Glide Neural Mobilization Is Effective in Treating Cervicobrachial Pain: A Randomized Waiting List Controlled Clinical Trial. AB - Background: Cervicobrachial pain (CP) is a high-incidence and prevalent condition. Cervical lateral glide (CLG) is a firstline treatment of CP. There is a current lack of enough high-quality randomized controlled double-blind clinical trials that measure the effectiveness of neural tissue mobilization techniques such as the CLG and its specific effect over CP. Objectives: The aim of the present study was to assess the effect of CLG neural mobilization in treating subjects who suffer from CP, compared with the complete absence of treatment. Study Design: This investigation was a single-center, blinded, parallel randomized controlled clinical trial (RCT). Setting: One hundred forty-seven individuals were screened in a medical center from July to November 2015. Fifty eight participants were diagnosed with CP. Methods: Participants were recruited and randomly assigned into two groups of 29 subjects. The intervention group received CLG treatment, and the control group (CG) was assigned to a six-week waiting list to receive treatment. Randomization was carried out by concealed computer software randomized printed cards. The primary outcome was pain intensity, reported through the Numeric Rating Scale for Pain (NRSP). Secondary outcomes were physical function involving the affected upper limb using the Quick DASH scale and ipsilateral cervical rotation (ICR) using a CROM device. Assessments were made at baseline and one hour after treatment. Results: The CLG group NRSP mean value was significantly (P < 0.0001) superior to those obtained by the CG. Subjects treated with CLG reported an average NRSP decrease of 2.16 points (35%). CROM device and Quick DASH outcome values also reported significant (P < 0.0001) improvements only in the CLG group. Cohen's d showed a very large effect of the CLG intervention at subject discharge. Limitations: Due to the lack of dipper subgroup analysis and additional reproductions of the applied protocol, the authors considered the generalization of the study results to be impossible. Conclusions: CLG is superior to the absence of treatment in reducing pain and increasing the affected upper limb function of subjects who suffer from CP. CLG may be considered an effective treatment in specific cases of CP. PMID- 28340158 TI - Maintenance therapy is associated with better long-term outcomes in adult patients with primary angiitis of the central nervous system. AB - Objective: We aimed to analyse the effect of maintenance therapy after induction on the outcomes of adult patients with primary angiitis of the CNS (PACNS). Methods: We analysed long-term outcomes (relapse, survival and functional status) of patients enrolled in the French multicentre PACNS cohort who achieved remission after induction treatment and with ?12 months' follow-up, according to whether or not they received maintenance therapy. Good outcome was defined as relapse-free survival and good functional status (modified Rankin scale ? 2) at last follow-up. Results: Ninety-seven patients [46 (47%) female, median age: 46 (18-78) years at diagnosis] were followed up for a median of 55 (5-198) months. Induction treatment consisted of glucocorticoids in 95 (98%) patients, combined with an immunosuppressant in 80 (83%) patients, mostly CYC. Maintenance therapy was prescribed in 48 (49%) patients, following CYC in 42 of them. Maintenance therapy was started 4 (3-18) months after glucocorticoid initiation. At last follow-up, good outcomes were observed in 32 (67%) patients who had received maintenance therapy vs 10 (20%) who had not (P < 0.0001). Thirty-two (33%) patients experienced relapse [10 (22%) had received maintenance therapy while 22 (45%) had not, P = 0.01]; four subsequently died from relapse. In the multivariate analysis, maintenance therapy was the only independent predictor of good outcome [odds ratio (OR) = 7.8 (95% CI: 3.21, 20.36), P < 0.0001]. Conclusion: The results of this long-term follow-up study suggest that maintenance therapy in adults with PACNS is associated with better functional outcomes and lower relapse rates. Further studies are needed to confirm these findings. PMID- 28340159 TI - Detection of Polish clinical Aspergillus fumigatus isolates resistant to triazoles. AB - We studied the presence of triazole resistance of 121 Aspergillus fumigatus clinical isolates collected in two Polish cities, Warsaw and Wroclaw, to determine if resistance is emerging in our country. We identified five itraconazole resistant isolates (4.13%) carrying the TR34/L98H alteration in Cyp51A gene, four of which were cross-resistant to posaconazole and one to voriconazole. One isolate was intermediate susceptible to itraconazole and harbored no Cyp51A alterations. The study confirms the presence of azole resistant A. fumigatus strains in Poland at a level that is comparative to other European countries. PMID- 28340161 TI - Organizational Benchmarks for Test Utilization Performance: An Example Based on Positivity Rates for Genetic Tests. AB - Objectives: Health care organizations are under increasing pressure to deliver value by improving test utilization management. Many factors, including organizational factors, could affect utilization performance. Past research has focused on the impact of specific interventions in single organizations. The impact of organizational factors is unknown. The objective of this study is to determine whether testing patterns are subject to organizational effects, ie, are utilization patterns for individual tests correlated within organizations. Methods: Comparative analysis of ordering patterns (positivity rates for three genetic tests) across 659 organizations. Hierarchical regression was used to assess the impact of organizational factors after controlling for test-level factors (mutation prevalence) and hospital bed size. Results: Test positivity rates were correlated within organizations. Conclusions: Organizations have a statistically significant impact on the positivity rate of three genetic tests. PMID- 28340160 TI - Safety of fluoroscopy-guided transseptal approach for ablation of left-sided arrhythmias. AB - Aims: The transseptal approach is used for left atrial access during the ablation of atrial fibrillation (AF) and other left-sided arrhythmia substrates. Transseptal puncture (TP) is commonly performed with fluoroscopic guidance, contrast injection, and pressure monitoring. In many centres, additional techniques [intracardiac echocardiography (ICE), transoesophageal echocardiography (TEE), radiofrequency needle] are used to facilitate TP but its use adds costs. In this retrospective study, we studied the safety and complication rate when TP was routinely done with fluoroscopic guidance, contrast injection, and pressure monitoring using ICE or TEE only in selected cases. Methods and results: This study analysed 4690 consecutive TP performed between 2000 and 2015: 3408 (72.6%) were ablation of AF, left-sided atrial flutter, or left-sided atrial tachycardia (non-AP group); 1153 (24.6%) were ablation of left sided accessory pathway, AP group; and 129 (2.8%) were ablation of ventricular tachycardia. Transseptal puncture was done under fluoroscopy, pressure monitoring, and commonly using contrast media injection. In 27 procedures, ICE or TEE was used to guide the TP. We found 34 tamponades (Tx) that required pericardial drainage of which 28 (0.59%) could possibly be TP related and six could not. The total complication rate for all Tx was 0.72%. A higher rate of tamponades was observed in the AF (non-AP) group than in the AP group (0.88 vs. 0.17%, P < 0.02). The highest rate of tamponades was registered during the operators 51-100 cases, 1.3%, and decreased to 0.4% in cases 101-200, P = 0.04. Conclusion: TP can safely be done under fluoroscopy and pressure monitoring without routine use of additional techniques. With experience, operators should be able to further decrease complication rate. PMID- 28340162 TI - Spina ventosa-a rare cause of sausage digit. PMID- 28340163 TI - Does Cervical Interlaminar Epidural Steroid Injection with Low-Dose Lidocaine Cause Objective Upper Extremity Weakness? A Preliminary Study. AB - Objective: Low-dose local anesthetic is often used in cervical interlaminar epidural steroid injections (CIESI), yet its effect on upper extremity strength has not been studied. The presence of consequent weakness has potential implications for postprocedure safety. This study aimed to determine whether low dose lidocaine in a C7-T1 CIESI causes objective weakness. Design: Prospective case series. Setting: Academic pain center. Subjects: Adults, cervical radicular pain. Methods: Participants underwent CIESI with 1 mL of 1% lidocaine (3 mL total injectate). Elbow flexion (EF), wrist extension (WE), elbow extension (EE), and handgrip strength were measured by dynamometry at baseline, 15 minutes, and 30 minutes postinjection. Changes in strength from baseline and the proportion of participants with a minimum perceptible change in EF, WE, EE, and handgrip strength (>=20%) and 95% confidence intervals (CIs) were calculated. Results: Twenty-seven participants were included. At 15 and 30 minutes postinjection, there was no within-participant difference in EF, WE, EE, and handgrip strength from baseline overall. Nonetheless, five (19%, 95% CI = 4-33) of the participants demonstrated a 20% or greater strength decrease in at least one myotomal distribution. A 20% or greater decrease in strength was present in left EF 4% (95% CI = 0-11%), right EF 7% (95% CI = 0-17%), left WE 4% (95% CI = 0-11%), and right WE 7% (95% CI = 0-17%). Conclusions: The present data suggest that CIESI with an injectate volume of 3 mL that includes 1 mL of 1% lidocaine may result in objective upper extremity weakness that is above the minimum threshold of perception in a subset of patients. PMID- 28340164 TI - Denervation of the extrinsic cardiac sympathetic nervous system as a treatment modality for arrhythmia. AB - Denervation of the extrinsic cardiac sympathetic nervous system is a method of altering the autonomic tone experienced by the heart and vasculature. It has been studied and employed as a therapy for cardiac disease for decades. Currently, there is a high level of interest in using cardiac denervation for treatment of arrhythmias. This review describes the anatomy and physiology of the cardiac autonomic nervous system followed by a discussion of the mechanistic studies which provide a basis for the therapeutic use of sympathetic denervation. The clinical research supporting its use in human arrhythmias is then appraised, covering the standard indications, such as long QT syndrome, as well as future possibilities. Last, a detailed account of the methods for performing surgical cardiac denervation and percutaneous stellate ganglion anesthetic block is provided, including the complications of each procedure. An understanding of the anatomy and physiology of the cardiac autonomic nervous system along with the techniques of surgical denervation and percutaneous anesthetic block will allow the clinician to effectively discuss and implement these therapies. PMID- 28340165 TI - Attitudes Toward Opioids and Risk of Misuse/Abuse in Patients with Chronic Noncancer Pain Receiving Long-term Opioid Therapy. AB - Objectives: To determine the attitudes of patients toward long-term opioid therapy (LtOT) and the potential risk of misuse/abuse in patients with chronic noncancer pain (CNCP). Design: Prospective, descriptive epidemiological study. Setting: Multidisciplinary tertiary care pain center within the Montreal University Health Center. Subjects: Patients who had had at least one visit at least one year prior to the invitation. Methods: We used four questionnaires: demographic questionnaire, the Drug Attitude Inventory Modified (DAI-M), the Opioid Risk Tool (ORT), and the Screening Tool for Addiction Risk (STAR). All questionnaires were administered in their validated French version. Results: Three hundred seventy patients completed questionnaires. The response rate was 79.26%. Of those who responded, 61.62% women and 38.38% men, the mean age was 57 years. The patients had been treated with LtOT for an average of 6.31 years, and the median dose per day in morphine equivalents was 48.21 mg. The DAI-M showed that 32.16% had a positive attitude toward opioids, 39.73% had a negative attitude, and 22.16% had a neutral attitude. The ORT questionnaire demonstrated that 86.2% of the patients were at low risk of abuse/misuse, 13.2% were at moderate risk, and only 0.54% were at high risk. The STAR questionnaire showed that 4.2% had a low risk of abuse/misuse. Conclusions: Despite public opinion, patients treated with LtOT for CNCP and followed in a tertiary care pain center are at low risk for opioid misuse/abuse. We need to refine the way of prescribing opioids, should be selective with our patients, and should relive their pain adequately. PMID- 28340166 TI - Complete Blood Count Reference Ranges from a Rural Haitian Ambulatory Care Clinic. AB - Background: At rural healthcare centers in developing countries, it is difficult to recruit healthy individuals for reference range studies. So, in this study, I evaluated complete blood count (CBC) data to determine reference ranges for a rural Haitian population. Methods: A convenience sample of laboratory records was reviewed to obtain CBC results for 157 adult patients with normal screening examination results. Central 95% reference ranges were determined for male and female subjects. Results: Relative to reference ranges obtained with United States (US)-based subjects, the hemoglobin (Hgb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and absolute neutrophil count (ANC) ranges were lower in subjects who resided in rural Haiti. The upper reference limit of the red blood cell distribution width-coefficient of variation (RDW-CV) was higher than the reference range for the US-based group. Conclusion: Locally derived CBC reference ranges were established using data from subjects who resided in rural Haiti. Ranges for Hgb, Hct, MCV, MCH, RDW-CV, and ANC differed from those established using data from US-based subjects. PMID- 28340167 TI - Factors Influencing Cognitive Impairment in Neuropathic and Musculoskeletal Pain and Fibromyalgia. AB - Objective: To assess cognitive performance of chronic pain (CP) patients diagnosed with three types of pain-neuropathic pain (NP), musculoskeletal (MSK), and fibromyalgia (FM)-and to analyze the factors influencing cognitive difficulties in each group. Methods: Two hundred fifty-four CP patients-104 NP, 99 MSK, 51 FM-and 72 pain-free subjects were included in the study. The "Test Your Memory" (TYM) scale was used to assess cognitive performance. Pain intensity was measured by means of the visual analog scale (VAS); the Hospital Anxiety and Depression scale was used to assess mental status, and the Medical Outcome Study (MOS) sleep scale to assess sleep quality. The relationships between cognitive performance and these factors were analyzed using linear regression models. Results: The mean score in the TYM was significantly lower (worse cognitive function) in CP patients than controls (40.5 vs 43.9, P < 0.001). In the separate analysis of each group, depression was observed to have a negative impact on MSK pain patients (beta = -0.37, 95% confidence interval [CI] = -0.53 to -0.2, P < 0.001) and on FM subjects (beta =-1.01, 95% CI = -1.05 to -2.38, P = 0.022). A significant interaction between pain intensity and depression was observed in the FM patients. In addition, a U-shaped association was found between the duration of pain and cognitive performance in the NP patients. Neither anxiety nor sleep impairment affected cognitive performance in any of the CP patients. Conclusions: These results highlight the importance of taking into account the type of pain when assessing cognitive performance in CP patients and demonstrate the influence of the emotional state of the patient, especially if depression is present. PMID- 28340168 TI - Young Children's Acute Stress After a Burn Injury: Disentangling the Role of Injury Severity and Parental Acute Stress. AB - Objective: Although injury severity and parental stress are strong predictors of posttraumatic adjustment in young children after burns, little is known about the interplay of these variables. This study aimed at clarifying mediation processes between injury severity and mother's, father's, and young child's acute stress. Methods: Structural equation modeling was used to examine the relationships between injury severity and parental and child acute stress. Parents of 138 burn injured children (ages 1-4 years) completed standardized questionnaires on average 19 days postinjury. Results: Sixteen children (11.7%) met Diagnostic and Statistical Manual of Mental Disorders, 5th edition, preschool criteria for posttraumatic stress disorder (excluding time criterion). The model revealed a significant mediation of maternal acute stress, with the effect of injury severity on a child's acute stress mediated by maternal acute stress. Paternal acute stress failed to serve as a mediating variable. Conclusions: Our findings confirm mothers' crucial role in the posttraumatic adjustment of young children. Clinically, mothers' acute stress should be monitored. PMID- 28340169 TI - Histamine Receptors in the Cross-Talk between Periphery and Brain. PMID- 28340170 TI - The Behcet's centres of excellence. PMID- 28340171 TI - Immunohistochemical Approach to the Differential Diagnosis of Meningiomas and Their Mimics. AB - The differential diagnosis between meningioma and others tumors can be challenging. This study aimed to evaluate different immunohistochemical markers for the differential diagnosis between meningioma and their morphological mimics. Immunohistochemistry was performed on tissue microarray with antiepithelial membrane antigen (EMA), progesterone receptor, somatostatin receptor 2A (SSTR2A), CD34, STAT6, S100, SOX10, HMB45, MelanA, GFAP, inhibin, and BCL2 antibodies. One hundred and twenty-seven meningiomas, 26 solitary fibrous tumor/hemangiopericytomas (SFT/HPC), 39 schwannomas, 17 hemangioblastomas, 21 melanomas, 9 gliosarcomas, 5 neurofibromas, 9 peripheral primitive neuroectodermal tumors, 7 synovial sarcomas, and 5 malignant peripheral nerve sheath tumors were included in the microarray. SSTR2A was the most sensitive (95.2%) and specific (92%) marker of meningiomas. In combination, SSTR2A and/or EMA positivity reached maximal sensitivity (100%). Coexpression of SSTR2A and EMA was the most specific (94.8%) for the diagnosis of meningioma, regardless of the grade or subtype, with the exception of the differential diagnosis with synovial sarcoma. All synovial sarcomas were EMA-positive and 6/7 SSTR2A-positive. STAT6 showed optimum sensitivity and specificity (100%) for SFT/HPC. SOX10 was the most sensitive (94.3%) and specific (100%) marker to discriminate meningiomas from schwannomas. In conclusion, SSTR2A, STAT6, and SOX10 were the most sensitive and specific markers to distinguish meningiomas from their morphological mimics. PMID- 28340174 TI - Application of Virtual Navigation with Multimodality Image Fusion in Foramen Ovale Cannulation. AB - Objective: Idiopathic trigeminal neuralgia (ITN) can be effectively treated with radiofrequency thermocoagulation. However, this procedure requires cannulation of the foramen ovale, and conventional cannulation methods are associated with high failure rates. Multimodality imaging can improve the accuracy of cannulation because each imaging method can compensate for the drawbacks of the other. We aim to determine the feasibility and accuracy of percutaneous foramen ovale cannulation under the guidance of virtual navigation with multimodality image fusion in a self-designed anatomical model of human cadaveric heads. Design: Five cadaveric head specimens were investigated in this study. Spiral computed tomography (CT) scanning clearly displayed the foramen ovale in all five specimens (10 foramina), which could not be visualized using two-dimensional ultrasound alone. The ultrasound and spiral CT images were fused, and percutaneous cannulation of the foramen ovale was performed under virtual navigation. After this, spiral CT scanning was immediately repeated to confirm the accuracy of the cannulation. Results: Postprocedural spiral CT confirmed that the ultrasound and CT images had been successfully fused for all 10 foramina, which were accurately and successfully cannulated. The success rates of both image fusion and cannulation were 100%. Conclusions: Virtual navigation with multimodality image fusion can substantially facilitate foramen ovale cannulation and is worthy of clinical application. PMID- 28340173 TI - F-Box Protein FBX92 Affects Leaf Size in Arabidopsis thaliana. AB - F-box proteins are part of one of the largest families of regulatory proteins that play important roles in protein degradation. In plants, F-box proteins are functionally very diverse, and only a small subset has been characterized in detail. Here, we identified a novel F-box protein FBX92 as a repressor of leaf growth in Arabidopsis. Overexpression of AtFBX92 resulted in plants with smaller leaves than the wild type, whereas plants with reduced levels of AtFBX92 showed, in contrast, increased leaf growth by stimulating cell proliferation. Detailed cellular analysis suggested that AtFBX92 specifically affects the rate of cell division during early leaf development. This is supported by the increased expression levels of several cell cycle genes in plants with reduced AtFBX92 levels. Surprisingly, overexpression of the maize homologous gene ZmFBX92 in maize had no effect on plant growth, whereas ectopic expression in Arabidopsis increased leaf growth. Expression of a truncated form of AtFBX92 showed that the contrasting effects of ZmFBX92 and AtFBX92 gain of function in Arabidopsis are due to the absence of the F-box-associated domain in the ZmFBX92 gene. Our work reveals an additional player in the complex network that determines leaf size and lays the foundation for identifying putative substrates. PMID- 28340172 TI - Repositioning disulfiram as a radiosensitizer against atypical teratoid/rhabdoid tumor. AB - Background: Atypical teratoid/rhabdoid tumor (AT/RT) is one of the most common malignant brain tumors in infants. Although cancer stem cells of AT/RT express aldehyde dehydrogenase (ALDH), effective chemotherapies against AT/RT have not been established. Here, we examined radiosensitizing effects of disulfiram (DSF), an irreversible inhibitor of ALDH against AT/RT for a novel therapeutic method. Methods: Patient-derived primary cultured AT/RT cells (SNU.AT/RT-5 and SNU.AT/RT 6) and established AT/RT cell lines (BT-12 and BT-16) were used to assess therapeutic effects of combining DSF with radiation treatment (RT). Survival fraction by clonogenic assay, protein expression, immunofluorescence, and autophagy analysis were evaluated in vitro. Antitumor effects of combining DSF with RT were verified by bioluminescence imaging, tumor volume, and survival analysis in vivo. Results: The results demonstrated that DSF at low concentration enhanced the radiosensitivity of AT/RT cells with reduction of survival fraction to 1.21-1.58. DSF increased DNA double-strand break (gamma-H2AX, p-DNA-PKcs, and p-ATM), apoptosis (cleaved caspase-3), autophagy (LC3B), and cell cycle arrest (p21) in irradiated AT/RT cells, while it decreased anti-apoptosis (nuclear factor-kappaB, Survivin, and B-cell lymphoma 2 [Bcl2]). In vivo, DSF and RT combined treatment significantly reduced tumor volumes and prolonged the survival of AT/RT mouse models compared with single treatments. The combined treatment also increased gamma-H2AX, cleaved caspase-3, and LC3B expression and decreased ALDH1, Survivin, and Bcl2 expression in vivo. Conclusions: DSF and RT combination therapy has additive therapeutic effects on AT/RT by potentiating programmed cell death, including apoptosis and autophagy of AT/RT cells. We suggest that DSF can be applied as a radiosensitizer in AT/RT treatment. PMID- 28340175 TI - FunResDB-A web resource for genotypic susceptibility testing of Aspergillus fumigatus. AB - Therapy of invasive aspergillosis is becoming more difficult due to the emergence of azole resistance in Aspergillus fumigatus. A majority of resistant strains carries mutations in the CYP51A gene. Due to a lack of sensitivity of culture based methods, molecular detection of A. fumigatus has become an important diagnostic tool. We set up the database FunResDB (www.nrz-myk.de/funresdb) to gather all available information about CYP51A-dependent azole resistance from published literature. In summary, the screening resulted in 79 CYP51A variants, which are linked to 59 nonsynonymous mutations. A tailor-made online sequence analysis tool allows for genotypic susceptibility testing of A. fumigatus. PMID- 28340176 TI - European Heart Rhythm Association Young Electrophysiology Community: introducing our National Ambassadors of Italy, Turkey, and Poland. PMID- 28340177 TI - The Significance of Internode Length for Saltatory Conduction: Looking Back at the Age of 90. AB - The development of peripheral nerve fibers involves interdependence between the timing of Schwann cell recruitment during myelination and elongation of the nerve. This adjusts the number and the length of internodes to the length of the fiber. Saltatory conduction in longer nerves involves longer saltations; this makes internode length the factor that determines conduction velocity, thereby adjusting impulse transmission in circuits of different lengths. Myelination increases conduction velocity by means of saltatory conduction but what determines the saltatory conduction is not so much the indispensable insulating adjunct of myelin as the length of the internodes that separate the excitable membrane segments. We have previously studied the development of the length and proportion of internodes in some detail. If the anatomical data are combined, the data fall in place for a revised understanding of conduction velocity and the system that adapts the conduction properties of peripheral nerves to fiber lengths and to body size. PMID- 28340178 TI - Morphometric covariation between palatal shape and skeletal pattern in Class II growing subjects. AB - Objectives: To evaluate the patterns of covariation between palatal and craniofacial morphology in Class II subjects in the early mixed dentition by means of geometric morphometrics. Methods: A cross-sectional sample of 85 Class II subjects (44 females, 41 males; mean age 8.7 years +/- 0.8) was collected retrospectively according to the following inclusion criteria: European ancestry (white), Class II skeletal relationship, Class II division 1 dental relationship, early mixed dentition, and prepubertal skeletal maturation. Pre-treatment digital 3D maxillary dental casts and lateral cephalograms were available. Landmarks and semilandmarks were digitized (239 on the palate and 121 on the cephalogram) and geometric morphometric methods (GMM) were applied. Procrustes analysis and principal component analysis (PCA) were performed to reveal the main patterns of palatal shape and craniofacial skeletal shape variation. Two-block partial least squares analysis (PLS) assessed patterns of covariation between palatal morphology and craniofacial morphology. Results: For the morphology of the palate, the first principal component (PC1) described variation in all three dimensions. For the morphology of the craniofacial complex, PC1 showed shape variation mainly in the vertical direction. Palatal shape and craniofacial shape covaried significantly (RV coefficient: 0.199). PLS1 accounted for more than 64 per cent of total covariation and related divergence of the craniofacial complex to palatal height and width. The more a Class II subject tended towards high angle divergence, the narrower and higher was the palate. Conclusions: Class II high-angle patients tended to have narrower and higher palates, while Class II low-angle patients were related to wider and more shallow palates. PMID- 28340179 TI - Open-Label Pilot Study to Compare the Safety and Immunogenicity of Pentavalent Rotavirus Vaccine (RV5) Administered on an Early Alternative Dosing Schedule with Those of RV5 Administered on the Recommended Standard Schedule. AB - This study compares the safety and immunogenicity of pentavalent rotavirus vaccine (RV5) administered on an alternative schedule (initiated at 2-5 weeks of age) with those of RV5 administered on the recommended standard schedule. Our findings support the future conduct of larger clinical trials to confirm the safety and efficacy of rotavirus vaccination in the neonatal period. PMID- 28340180 TI - Reliability Study in Five Languages of the Translation of the Pain Observational Scale Algoplus. AB - Objective: Acute pain is frequent and underestimated in older persons, especially when they suffer from cognitive impairment. Algoplus is an observational scale for acute pain evaluation, validated in French in older persons with communication disorders. We present the validation by an international expert team of the Algoplus scale in five languages: English, Spanish, Italian, Portuguese, and Turkish. Methods: A total of 181 older consecutive patients were included in five countries (Spain, Australia, Italy, Portugal, and Turkey). Test retest and inter-rater reliabilities were determined by weighted kappa coefficient for each item and internal consistency by Kuder-Richardson-20 (KD). Results: Regarding test-retest reliability, the kappa coefficient for the five items ranged from 0.68 to 0.84. Inter-rater reliability kappa values ranged from 0.64 to 0.82. Internal consistency was indicated at a KD greater than 0.6. Satisfaction was good to excellent for all teams. Results show that reliability tests are good to excellent for all items of Algoplus. Conclusions: This study shows evidence that Algoplus is an acceptable, reproducible, reliable, and easy to-use tool. It provides a unique opportunity to include the translated Algoplus scale in daily assessment of older persons with communication disorders in many countries. PMID- 28340183 TI - CRLF2-Positive B-Cell Acute Lymphoblastic Leukemia in Adult Patients: A Single Institution Experience. AB - Objectives: Cytokine receptor-like factor 2 ( CRLF2 ) rearrangement is found in approximately 50% of pediatric Ph-like B-cell acute lymphoblastic leukemia (B ALL), and around 50% of CRLF2 + cases harbor JAK mutations. We analyzed CRLF2 expression and studied its correlation with CRLF2 rearrangement in adult patients with B-ALL. Methods: Multiparameter flow cytometry (MFC) was performed consecutively in 126 patients. Results: CRLF2 overexpression was detected in 30 (27%) patients, 28 (41%) of 69 patients with B-ALL not otherwise specified, 14 (21%) of 67 untreated patients, and 16 (27%) of 59 patients with relapsed B-ALL, with the highest among Hispanic patients (25/55, 45%). Of CRLF2+ cases, 21 (100%) of 21 cases showed CRLF2 rearrangement by fluorescence in situ hybridization, preferentially involving IGH@CRLF2 (15/15). The entire coding region of JAK2 was sequenced in 14 patients with CRLF2+ B-ALL, and nine (64%) were positive for JAK2 mutations. Conclusions: MFC allows a rapid, inexpensive, and reliable detection of B-ALL with CRLF2 rearrangement that would further facilitate testing for JAK2 mutations for targetable therapy. PMID- 28340184 TI - A cross-national comparison of incident reporting systems implemented in German and Swiss hospitals. AB - Objective: This study aimed to empirically compare incident reporting systems (IRS) in two European countries and to explore the relationship of IRS characteristics with context factors such as hospital characteristics and characteristics of clinical risk management (CRM). Design: We performed exploratory, secondary analyses of data on characteristics of IRS from nationwide surveys of CRM practices. Setting: The survey was originally sent to 2136 hospitals in Germany and Switzerland. Participants: Persons responsible for CRM in 622 hospitals completed the survey (response rate 29%). Intervention(s): None. Main outcome measure(s): Differences between IRS in German and Swiss hospitals were assessed using Chi2, Fisher's Exact and Freeman-Halton-Tests, as appropriate. To explore interrelations between IRS characteristics and context factors (i.e. hospital and CRM characteristics) we computed Cramer's V. Results: Comparing participating hospitals across countries, Swiss hospitals had implemented IRS earlier, more frequently and more often provided introductory IRS training systematically. German hospitals had more frequently systematically implemented standardized procedures for event analyses. IRS characteristics were significantly associated with hospital characteristics such as hospital type as well as with CRM characteristics such as existence of strategic CRM objectives and of a dedicated position for central CRM coordination. Conclusions: This study contributes to an improved understanding of differences in the way IRS are set up in two European countries and explores related context factors. This opens up new possibilities for empirically informed, strategic interventions to further improve dissemination of IRS and thus support hospitals in their efforts to move patient safety forward. PMID- 28340181 TI - Different expression patterns of sperm motility-related genes in testis of diploid and tetraploid cyprinid fish?. AB - Sperm motility is an important standard to measure the fertility of male. In our previous study, we found that the diploid spermatozoa from allotetraploid hybrid (4nAT) had longer durations of rapid and slow progressive motility than haploid spermatozoa from common carp (COC). In this study, to explore sperm motility related molecular mechanisms, we compared the testis tissues transcriptomes from 2-year-old male COC and 4nAT. The RNA-seq data revealed that 2985 genes were differentially expressed between COC and 4nAT, including 2216 upregulated and 769 downregulated genes in 4nAT. Some differentially expressed genes, such as tubulin genes, dynein, axonemal, heavy chain(dnah) genes, mitogen-activated protein kinase(mapk) genes, tektin 4, FOX transcription factors, proteasome genes, and ubiquitin carboxyl-terminal hydrolase(uchl) genes, are involved in the regulation of cell division, flagellar and ciliary motility, gene transcription, cytoskeleton, energy metabolism, and the ubiquitin-proteasome system, suggesting that these genes were related to sperm motility of the 4nAT. We confirmed the differential expression of 12 such genes in 4nAT by quantitative PCR. By western blotting, we also confirmed increased expression of Uchl3 in 4nAT testis. In addition, we identified 1915 and 2551 predicted long noncoding RNA (lncRNA) transcripts from testis tissue transcriptomes of COC and 4nAT, respectively. Of these, 1575 lncRNAs were specifically expressed in 4nAT and 939 were specifically expressed in COC. This study provides insights into the transcriptome profile of testis tissues from diploid and tetraploid, which are useful for research on regulatory mechanisms behind sperm motility in male polyploidy. PMID- 28340185 TI - Knowledge of Opioid Overdose and Attitudes to Supply of Take-Home Naloxone Among People with Chronic Noncancer Pain Prescribed Opioids. AB - Objective: Take-home naloxone (THN) is recommended in response to pharmaceutical opioid-related mortality. Some health professionals are reluctant to discuss THN for fear of causing offense. The aims of this study were to assess knowledge of opioid overdose and attitudes toward THN for opioid overdose reversal in people with chronic noncancer pain (CNCP). Design: Prospective cohort study. Setting: Australia, September to October 2015. Subjects: A subset of participants (N = 208) from a cohort of people prescribed restricted opioids for CNCP. Methods: Questions added in the two-year telephone interviews examined knowledge of overdose symptoms and attitudes toward community supply of naloxone. Associations with overdose risk factors and naloxone supply eligibility criteria with attitudes toward naloxone were explored. Results: Fourteen percent reported ever experiencing opioid overdose symptoms. Participants correctly identified fewer than half of the overdose signs and symptoms. After receiving information on naloxone, most participants (60%), thought it was a "good" or "very good" idea. Few participants reported that they would be "a little" (N = 21, 10%) or "very" offended (N = 7, 3%) if their opioid prescriber offered them naloxone. Positive attitudes toward THN were associated with male gender (odds ratio [OR] = 1.96, 95% confidence interval [CI] = 1.09-3.50), past year cannabis use (OR = 2.52, 95% CI = 1.03-6.16), and past year nicotine use (OR = 2.11, 95% CI = 1.14-3.91). Conclusions: Most participants had positive attitudes toward THN but low knowledge about opioid overdose symptoms. Strategies for educating patients and their caregivers on opioid toxicity are needed. THN may be best targeted toward those with risk factors in terms of overdose prevention and acceptability. PMID- 28340186 TI - Monocyte-to-HDL-cholesterol ratio and left atrial remodelling in atrial fibrillation. PMID- 28340188 TI - Commentary on "Phase III randomized study of radiation and temozolomide versus radiation and nitrosourea therapy for anaplastic astrocytoma: results of NRG Oncology RTOG 9813". PMID- 28340187 TI - Biofilm, adherence, and hydrophobicity as virulence factors in Malassezia furfur. AB - Malassezia species are natural inhabitants of the healthy skin. However, under certain conditions, they may cause or exacerbate several skin diseases. The ability of this fungus to colonize or infect is determined by complex interactions between the fungal cell and its virulence factors. This study aims to evaluate "in vitro" the hydrophobicity levels, the adherence on a plastic surface and the biofilm formation of 16 clinical isolates of Malassezia furfur. Cellular surface hydrophobicity (CSH) levels were determined by two-phase system. The biofilm formation was determined by tetrazolium salt (XTT) reduction assay and by Scanning Electron Microscopy (SEM). Results showed many isolates were hydrophobic, adherent, and producers of biofilm on abiotic surfaces with different capacity. SEM observations confirmed an abundant extracellular matrix after 48 h of biofilm formation. About 63% of strains with high production of biofilm showed medium to high percentage of hydrophobicity and/or adherence. In addition, it has been demonstrated a correlation between hydrophobicity, adherence, and biofilm formation in about 60% of strains examined. These important virulence factors could be responsible of this yeast changing from a commensal to a pathogenic status. PMID- 28340189 TI - The Relationship Between Pain Severity and Alcohol Use Among School-Aged Children and Adolescents: The Moderating Role of Drinking Motives. AB - Objective: Evidence from adult samples suggests a co-occurrence between pain and alcohol abuse. However, studies in adolescents are scarce and results are inconsistent, with some studies observing heightened and others observing reduced alcohol consumption in adolescents suffering from pain. We hypothesized that in adolescents the association between pain and alcohol use will be moderated by drinking motives. Methods: Data from a large representative sample of Flemish school children and adolescents (N = 10,650, 50.8% boys, age range = 10-21 years, Mage = 14.33 years) were collected as part of the World Health Organization collaborative Health Behaviour in School-Aged Children (HBSC) survey. Pain severity was graded based on a pediatric pain classification system that accounts for both pain intensity and disability. Alcohol consumption was operationalized using two variables: frequency of drinking and drunkenness. The Drinking Motives Questionnaire-Revised was used to capture drinking motives; it assesses four motive categories (enhancement, coping, social, and conformity). Results: Findings indicated that higher pain severity was associated with greater frequency of alcohol use and drunkenness. However, drinking motives moderated this association. The positive association between pain severity and drinking frequency was stronger in case of high conformity motives. Likewise, the association between pain severity and drunkenness frequency was stronger at high levels of conformity motives and reached significance only at high levels of coping motives. Conclusions: Our findings suggest that specific drinking motives are linked to problematic alcohol use in adolescents with pain. Future studies using a longitudinal design are needed to draw conclusions about direction of effects. PMID- 28340190 TI - Systematic Review: A Systematic Review of the Interrelationships Among Children's Coping Responses, Children's Coping Outcomes, and Parent Cognitive-Affective, Behavioral, and Contextual Variables in the Needle-Related Procedures Context. AB - Objective: To conduct a systematic review of the interrelationships between children's coping responses, children's coping outcomes, and parent variables during needle-related procedures. A systematic literature search was conducted. It was required that the study examined a painful needle-related procedure in children from 3 to 12 years of age, and included a children's coping response, a children's coping outcome, and a parent variable. In all, 6,081 articles were retrieved to review against inclusion criteria. Twenty studies were included. Parent coping-promoting behaviors and distress-promoting behaviors enacted in combination are the most consistent predictors of optimal children's coping responses, and less optimal children's coping outcomes, respectively. Additional key findings are presented. Children's coping with needle-related procedures is a complex process involving a variety of different dimensions that interact in unison. Parents play an important role in this process. Future researchers are encouraged to disentangle coping responses from coping outcomes when exploring this dynamic process. PMID- 28340191 TI - Cardiac health and fitness of Colorado male/female firefighters. AB - Background: Cardiovascular disease (CVD) is documented as the leading cause of mortality in on-duty firefighters. Aims: To examine the prevalence of metabolic syndrome (MetS) components, cardiorespiratory fitness levels and the association between them in firefighters in Colorado, USA. Methods: This study included male and female Colorado firefighters. MetS was identified where three or more metabolic abnormalities were present, using Cholesterol Education Program/Adult Treatment Panel III guidelines. Cardiorespiratory fitness (indicated by VO2 max) was evaluated with the Bruce protocol. Poisson regression was conducted to examine the association between MetS components and VO2 max. Results: Among the 947 male and 76 female study subjects, MetS was present in 9% of all firefighters, in 5% of females and 10% of males. The mean age was 37 +/- 10 years. MetS prevalence increased with age (from 3% at age <30 to 17% at 50 and older, data not shown). In addition, 35% had one and 19% had two abnormal MetS components and 49% of participants did not meet the minimum recommended VO2 max of 42.0 ml/kg/min. VO2 max was negatively associated with abnormal MetS components (incident rate ratios = 0.95, 95% confidence interval 0.94-0.96, P < 0.001). Conclusions: About one in 10 of these Colorado firefighters had MetS and nearly half had insufficient cardiorespiratory fitness. Comprehensive CVD risk management and cardiorespiratory fitness improvement are essential for firefighter health and safety. PMID- 28340192 TI - Prediction equation for calculating residual kidney urea clearance using urine collections for different hemodialysis treatment frequencies and interdialytic intervals. AB - Background: The purpose of the study was to explore the precision of an equation designed to estimate residual kidney urea clearance (KRU) from interdialytic urine collection data and pre-hemodialysis (HD) serum urea nitrogen (SUN) in different hemodialysis treatment schedules. Methods: The generalizability of the proposed equation was tested in 32 731 HD treatments where urine was collected prior to a dialysis session, mostly for 24 h but sometimes longer, in patients being dialyzed 1-4 times/week. Results: The residual kidney urea clearance estimating equation predicted a KRU that matched the one computed by formal modeling within 5% in >98% of sessions analyzed. The errors in estimated versus modeled KRU for interdialytic intervals (IDIs) of 2, 3, 4 and 7 days, were 1.6 +/ 1.5%, -0.4 +/- 1.6%, 0.9 +/- 1.6%, and 1.5 +/- 1.2%, respectively. Percent errors were similar for schedules of 1-4/week with the exception of urine collection during the 2-day interval of a 2:5-day twice-weekly schedule; here error averaged 5.0 +/- 1.2%. Use of the average of the SUN values at the start and end of the collection period overestimated modeled KRU by 11.3 +/- 4.5%, whereas an equation suggested by others underestimated modeled KRU by -9.9 +/- 3.4%. Conclusions: The equation tested predicts values for KRU that are similar to those obtained from formal urea kinetic modeling, with percent errors that only rarely exceed 5%. It gives relatively precise results for a wide range of HD treatment schedules, IDIs and urine collection periods. Keywords: chronic hemodialysis, clearance, guidelines, hemodialysis, predialysis. PMID- 28340194 TI - Painful Foot Nodules and Rash in a Teenager. PMID- 28340193 TI - Addressing Structural Barriers to HIV Care among Triply Diagnosed Adults: Project Bridge Oakland. AB - People who are "triply diagnosed" with HIV, mental health issues, and substance related disorders face tremendous barriers connecting to and remaining in HIV care. Authors of this article implemented Project Bridge Oakland (PBO), an intervention based on harm reduction and trauma-informed care, to help maintain continuity of care for triply diagnosed adults through cycles of criminal justice involvement. From August 2011 to December 2014, a clinical social worker and an HIV physician provided intensive case management for 19 clients living in Oakland, California. By working with clients across a multitude of community, clinic, and correctional spaces while maintaining a low threshold for services, the social worker was able to engage a severely marginalized population in HIV care. This article details the PBO strategies for assisting with a wide range of services needed for community stabilization, navigating criminal justice involvement, and establishing a therapeutic relationship through mundane practices such as eating and waiting for appointments. This article illustrates how programs aimed at stabilizing triply diagnosed clients in the community and connecting them to HIV care require coordination among providers, outreach to engage clients, ample time to work with them, and flexibility to account for the complexities of their day-to-day lives and experiences. PMID- 28340195 TI - Nicotine Sales to Minors: Store-Level Comparison of E-Cigarette Versus Cigarette Violation Rates. AB - Introduction: In recent years, e-cigarettes overtook cigarettes as the leading tobacco product used by US adolescents. Most states, as well as federal regulations, have added e-cigarettes to laws prohibiting tobacco products sales to minors. We tested compliance with the newer regulation among Colorado urban retail businesses, speculating that violations might be more common for e cigarettes than smokable cigarettes. Methods: Supervised minors visited a random sample of urban businesses and sequentially attempted to purchase an e-cigarette product and cigarettes. The protocol prescribed that the same minor make both attempts in each business, separated by at least a day to minimize influence of the first result on the second result. Data were collected during May 2014 January 2015. Results: Among 238 businesses, more than one-fourth (26.1%; 95% confidence interval (CI), 18.9%-33.2%) sold at least one type of product, and 6.3% (CI, 1.8%-10.8%) sold both types. Violation rates were similar for e cigarette products and cigarettes (17.6% vs. 14.7%, p = n.s.). Conclusion: Enforcement to prevent retail tobacco sales to adolescents should include e cigarette products. Dual testing of stores indicates that single visits underestimate the problem of underage tobacco sales. Implications: Adolescents can buy e-cigarettes from retail stores as easily as they buy cigarettes. Enforcement of tobacco sales laws should include e-cigarettes, and test-retest protocols are needed to estimate the true extent of the problem. PMID- 28340196 TI - Erratum. PMID- 28340197 TI - The evolution and benefit of device therapy in patients listed for heart transplant. AB - Aims: The latest 2015 ESC Guidelines on the prevention of sudden cardiac death make a Class IIa recommendation for ICD implantation in patients listed for heart transplantation. This recommendation was based on expert consensus in view of the sparsity of data. Methods and results: All patients listed for heart transplantation at the University Hospitals of Leuven from 2002 until 2014 were studied retrospectively. Exclusion criteria were age <16 years, cardiac disease other than ischaemic or dilated cardiomyopathy and re-transplantation. A total of 286 patients were included, of which 140 (49.0%) received an ICD. There was a historical increase of the time on the waiting list before transplantation (P < 0.001) together with an increase of the use of ICDs (P < 0.001) and left ventricular assist devices (LVADs) (P < 0.001). The proportion of patients reaching heart transplant remained unchanged (P = 0.700). The annual appropriate shock rate in patients with ICD was 28.0%/y on the active waiting list. Patients with ICD showed a trend to improved survival (P = 0.070). Independent predictors of mortality or removal from the transplant list because of clinical deterioration were the need for LVAD (HR 4.38, 95%CI 2.11-9.01), a history of stroke (HR 2.95, 95%CI 1.61-5.40), older age (HR 1.03, 95%CI 1.01-1.05) and a worse renal function (HR 1.15, 95%CI 1.00-1.33). Conclusion: The time on the waiting list for heart transplantation significantly increased together with an increased use of device therapy in this population. The proportion of patients reaching transplant remained unchanged. This patient group is prone to life threatening arrhythmias and the use of an ICD may improve survival. PMID- 28340198 TI - Reasons to wait or to treat naive patients affected by chronic hepatitis C with low fibrosis stage and genotypes 2 or 3. AB - Background: New interferon (IFN)-free therapies are not currently available for all patients with chronic hepatitis C due to higher costs; in Italy, patients with genotype 2 (GT2) or GT3 without severe fibrosis can choose between wait or treatment with pegylated (PEG)-IFN and ribavirin. This study wants to examine the real rate of patients that accept or refused this therapy and the reasons related to decision. Methods: This prospective, observational analysis was performed at our centre between January 2014 and June 2015. Epidemiological, social and clinical data were collected in medical records; reasons for treatment acceptance/refusal were recorded through a questionnaire. Eligible patients were: naive, with genotypes 2 or 3, fibrosis stage F0-F2. Results: In total 132 patients were included: 34 with GT2, 98 with GT3. Patients with GT3 were younger, with prevalent sex male and mostly with active intravenous drug use. 53 patients accepted the treatment option (40.1%): 12 with GT2 (22%), 41 GT3 (41.8%) (P < 0.001). 79 patients refused (59.8%): 22 with GT2 (64.7%), 57 with GT3 (58.2) (P < 0.001). Fear of side-effects (OR = 1.774; 95% CI = 1.089-2.117; P = 0.016) and active alcoholism (OR = 1.144; 95% CI = 1.012-2.006; P = 0.025) were predictive factors for treatment refusal in GT3, whereas the presence of extrahepatic manifestations in GT2 (OR = 1.911; 95% CI = 1.124-2.912; P = 0.019) and the will to eradicate the infection in GT3 (OR = 2.140; 95% CI = 1.120-3.445; P = 0.008) were predictive of treatment acceptance. Conclusions: Dual therapy is the only option for these subjects; however the motivation of patients and major socio economic conditions were strictly related to decision of acceptance or refusal. PMID- 28340199 TI - Intrarenal arterial stiffness is increased in systemic sclerosis patients with anti-ribonucleic acid polymerase III antibodies. PMID- 28340200 TI - Cytokines profile in immunocompetent mice during Trichosporon asahii infection. AB - Trichosporon asahii is an opportunistic yeastlike fungus commonly associated with systemic infections in immunocompromised patients. Neutropenia is recognized as the main risk factor in infections by T. asahii; however, little is known about the cytokine response during trichosporonosis. Here, we evaluated systemic and local cytokine production and histological damage in immunocompetent mice during systemic infection with T. asahii. We found a significant increased presence of G CSF, TNF-alpha, IFN-gamma, and IL-6 in sera samples. High levels of G-CSF were found in organs (kidney, liver and spleen); meanwhile IL-10, IL-17A, IL-2, IL-4 and TNF-alpha were found in low levels. Neutrophils and fungal structures were found in early stage in analyzed organs. Our results demonstrated that T. asahii induces a systemic inflammatory response and G-CSF environment in infected organs in immunocompetent mice and neutrophil recruitment in analyzed tissue suggests the importance of these cells for fungal control. PMID- 28340201 TI - A systematic review of the relationship of physical activity and health status in adolescents. AB - Background: Reduced physical activity is a known risk factor for many illnesses. Research in adolescent populations found increased physical activity levels improves objective health outcomes, but there is conflicting evidence regarding the relationship between physical activity levels and self-reported health status. To synthesise current evidence on the association between physical activity and self-reported health status in adolescents. Secondary objectives are to assess whether the relationship is dose dependant, and the appropriateness of WHO recommendations on adolescents' physical activity. The main databases were searched using keywords for the main outcome of interest (health status, health behaviour and self-perception) and exposure of interest (motor activity, physical activity and exercise), supplemented with manual searches, secondary citation and reference searches. Quality appraisal was carried out using the Strengthening the Reporting of Observational Studies in Epidemiology checklist. Eleven studies entered this review. Nine studies reported a significant relationship between increased levels of physical activity and improved self-reported health status, however two did not. Two studies followed up participants and found that the relationship persisted over time. Two papers described a dose-response relationship. Improvements in self-perceived health can be observed even below the current recommended levels of physical activity. The review supports initiatives to encourage adolescents to engage in physical activity as it improves self-reported health status. Sub-optimal levels of physical activity can also be beneficial. Further research should use standardised measurement scales and objectively measured physical activity levels. The roles of gender, income and culture should be further investigated. PMID- 28340202 TI - Validity and Reproducibility of the STarT Back Tool (Dutch Version) in Patients With Low Back Pain in Primary Care Settings. AB - Objective: The purpose of this study was to translate and to investigate the reliability and validity of the STarT Back screening tool (SBT) in the primary care setting among patients with nonspecific low back pain (LBP). Design: The SBT was formally translated into Dutch following a multistep approach for forward and backward translation. General practitioners and physical therapists included patients with LBP. Methods: Patients completed a baseline questionnaire and a follow-up at 3 days and 3 months. The construct validity was calculated with Pearson's correlation coefficient. The reproducibility was assessed using the quadratic weighted kappa and the specific agreement. Predictive validity was assessed using relative risk ratios for persisting disability at 3 months. Content validity was analyzed using floor and ceiling effects. Results: In total, 184 patients were included; 52.2% were categorized in the "low-risk" subgroup, 38.0% "medium-risk," and 9.8% "high-risk." For the construct validity we found, as expected, a moderate to high Pearson's correlation for questions 3 to 9 and a low correlation for questions 1 and 2 with their respective reference questionnaires. The reproducibility had a quadratic weighted kappa of 0.65 and the specific agreement of 82.4% for "low-risk," 53.3% for "medium-risk," and 33.3% for "high-risk." For the predictive validity for persisting disability we found a relative risk ratio for "medium-risk" of 1.8 (95% confidence interval [CI]: 1.0-3.1) and 2.7 (95% CI: 1.4-4.9) for "high-risk" compared with "low risk." For the content validity, we found that no floor and ceiling effects were present. Limitations: There was a relatively small sample size for the retest reliability study. Patients were not compared between physical therapist and GP, as there were not enough patients in both groups. For practical reasons, the patients filled out the baseline questionnaire after receiving the first treatment/consultation; however, the questionnaire is intended to be filled in before the first consultation/treatment. Conclusion: The SBT has been successfully translated into Dutch. The psychometric analysis showed acceptable results and, therefore, the SBT is a valid screening tool for patients with LBP in Dutch primary care. PMID- 28340203 TI - Been There, Done That: The Experience of Acting as a Young Adult Mentor to Adolescents Living With Chronic Illness. AB - Objective: To explore the perceived benefits and challenges of acting as a young adult peer mentor to adolescents with chronic illness. Methods: A qualitative descriptive study, using interviews and a focus group, explored the perceptions of young adult peer mentors following participation in the iPeer2Peer program, a Skype-based peer-mentorship program for adolescents with chronic illness. Interviews and focus group data were transcribed and analyzed using inductive content analysis. Results: Ten peer mentors (20.00 +/- 1.49 years old, range 17 22 years; diagnosed with chronic pain [n = 4] or juvenile idiopathic arthritis [n = 6]) who mentored four mentees (+/-2.55 mentees, range = 1-10 mentees) participated. Four main categories were identified: social connection, personal growth, mentor role in mentee growth, and logistics of mentorship. Conclusions: Acting as a peer mentor online is a feasible and rewarding experience that supports the mentor's own illness self-management, social connection, and personal growth. PMID- 28340204 TI - Changes in Pain and Muscle Architecture in Colon Cancer Survivors After a Lumbopelvic Exercise Program: A Secondary Analysis of a Randomized Controlled Trial. AB - Objective: To investigate the efficacy of an eight-week lumbopelvic stabilization program (CO-CUIDATE) for colon cancer survivors. Design: A secondary analysis of a randomized controlled clinical trial. Settings: A blinded, trained researcher performed the end point assessments for pain (Pressure Pain Threshold and Brief Pain Inventory) and muscle architecture (ultrasound imaging measurements). Subjects: Forty-six colon cancer survivors who were assigned to the CO-CUIDATE group or usual care group. Methods: The CO-CUIDATE program was conducted for eight weeks. A trained researcher who was blinded to patient group performed the assessments. The tests were carried out with multiple observations. Intention-to treat analyses were performed. Results: The program had an adherence rate of 88.36% and two dropouts (10.5%). The participants reported some minor side effects during the first exercise sessions. The analysis revealed significant differences in the group x time interactions for the lumbar side (dominant: F = 3.1, P < 0.001; nondominant: F = 3.0, P = 0.01) and the infra-umbilical dominant side (F = 1.2, P = 0.04) after the program and at the six-month follow up and for the internal oblique thickness (F = 5.1, P = 0.030) after the program. The experimental group experienced a greater improvement in all values after the program compared with the control group. There were no significant changes in the other pressure pain threshold points, pain severity, interference of pain, or the remaining ultrasound imaging measurements. Conclusion: The CO CUIDATE program is effective for improving the musculoskeletal conditions related to the lumbopelvic area in colon cancer survivors, specifically in relation to pain and the internal oblique thickness. PMID- 28340205 TI - Ocular involvement in patients with spondyloarthritis. AB - Ocular inflammatory diseases can present as isolated conditions but also as part of systemic inflammatory diseases. Anterior uveitis is closely related to SpA and shares the common genetic background of HLA-B27. Other ocular manifestations, such as episcleritis and scleritis, may also occur, although less frequently. Therefore, ocular involvement has been included as one of the important clinical features of SpA in the recently published classification criteria for axial and peripheral disease. However, there are a wide variety of aetiologies for ocular diseases and this must be considered in assessment of SpA. PMID- 28340206 TI - Monitoring the quality of cardiac surgery based on three or more surgical outcomes using a new variable life-adjusted display. AB - Quality problem or issue: The traditional variable life-adjusted display (VLAD) is a graphical display of the difference between expected and actual cumulative deaths. The VLAD assumes binary outcomes: death within 30 days of an operation or survival beyond 30 days. Full recovery and bedridden for life, for example, are considered the same outcome. This binary classification results in a great loss of information. Initial assessment: Although there are many grades of survival, the binary outcomes are commonly used to classify surgical outcomes. Consequently, quality monitoring procedures are developed based on binary outcomes. With a more refined set of outcomes, the sensitivities of these procedures can be expected to improve. Choice of solution: A likelihood ratio method is used to define a penalty-reward scoring system based on three or more surgical outcomes for the new VLAD. The likelihood ratio statistic W is based on testing the odds ratio of cumulative probabilities of recovery R. Two methods of implementing the new VLAD are proposed. Implementation: We accumulate the statistic W-W-R to estimate the performance of a surgeon where W-R is the average of the W's of a historical data set. The accumulated sum will be zero based on the historical data set. This ensures that if a new VLAD is plotted for a future surgeon of performance similar to this average performance, the plot will exhibit a horizontal trend. Evaluation: For illustration of the new VLAD, we consider 3 outcome surgical results: death within 30 days, partial and full recoveries. In our first illustration, we show the effect of partial recoveries on surgical results of a surgeon. In our second and third illustrations, the surgical results of two surgeons are compared using both the traditional VLAD based on binary outcome data and the new VLAD based on 3-outcome data. A reversal in relative performance of surgeons is observed when the new VLAD is used. In our final illustration, we display the surgical results of four surgeons using the new VLAD based completely on 3-outcome data. Lessons learned: Full recovery and bedridden for life are two completely different outcomes. There is a great loss of information when different grades of 'successful' operations are naively classified as survival. When surgical outcomes are classified more accurately into more than two categories, the resulting new VLAD will reveal more accurately and fairly the surgical results. PMID- 28340208 TI - Health care on equal terms? Assessing horizontal equity in health care use in Northern Sweden. AB - Background: The Swedish health care system has successively moved toward increased market-orientation, which has raised concerns as to whether Sweden still offers health on equal terms. To explore this issue, this study aimed (i) to assess if the principles of horizontal equity (equal access for equal need regardless of socio-economic factors) are met in Northern Sweden 2006-14; and (ii) to explore the contribution of different factors to the inequalities in access along the same period. Methods: Data came from cross sectional surveys known in 2006, 2010 and 2014 targeting 16-84-year-old residents in the four northern-most counties in Sweden. The horizontal inequity index was calculated based on variables representing (i) the individual socioeconomic status, (ii) the health care needs, (iii) non-need factors as well as (iv) health care utilization: general practitioner (GP), specialist doctors, hospitalization. Decomposition analysis of the concentration index for need-standardized health care utilization was applied. Results: Adjusting for needs, there was a higher use of GP services by rich people during the two last surveys, a roughly equal use of specialists, and hospitalization concentrated among the poor but with a clear time trend toward equality. The pro-rich inequalities in GP use were to a large part explained by the income gap. Conclusion: While health care utilization can be considered equitable regarding specialist and hospital use, the increasing pro-rich trend in the use of GP is a concern. Further studies are required to investigate the reasons and a constant monitoring of socioeconomic differences in health care access is recommended. PMID- 28340207 TI - Effect of the 2014/2015 Ebola outbreak on reproductive health services in a rural district of Guinea: an ecological study. AB - Background: The 2014/2015 Ebola outbreak was the most sustained in history. In Guinea, we compared trends in family planning, antenatal care, and institutional deliveries over the period before, during and after the outbreak. Methods: We carried out an ecological study involving all the health facilities during pre Ebola (1 March 2013 to 28 February 2014), intra-Ebola (1 March 2014 to 28 February 2015) and post-Ebola (1 March to 31 July 2016) periods in Macenta district. Results: Utilization of family planning declined from a monthly average of 531 visits during the pre-Ebola period to 242 visits in the peak month of the Ebola outbreak (51% decline) but recovered in the post-Ebola period. From a monthly average of 2053 visits pre-Ebola, antenatal care visits declined by 41% during Ebola and then recovered to only 63% of the pre-Ebola level (recovery gap of 37%, p<0.001). From a monthly average of 1223 deliveries pre-Ebola, institutional deliveries also declined during Ebola and then recovered to only 66% of the pre-Ebola level (p<0.001). Conclusions: All services assessed were affected by Ebola. Family planning recovered post-Ebola; however, shortfalls were observed in recovery of antenatal care and institutional deliveries. We call for stronger political will, international support and generous funding to change the current state of affairs. PMID- 28340209 TI - A novel PTEN mutation associated with colonic ganglioneuromatous polyps. PMID- 28340211 TI - Familial hypercholesterolemia: xanthelesma, arcus corneae and tendon xanthomas. PMID- 28340210 TI - Clinical Significance of Isolated Myeloperoxidase Expression in Pediatric B Lymphoblastic Leukemia. AB - Objectives: Diagnosis of B-cell acute lymphoblastic leukemia (B-ALL) requires immunophenotypic evidence of B-lineage and absence of specific myeloid or T lineage markers. Rare cases of otherwise typical B-ALL express myeloperoxidase (MPO) detectable by flow cytometry with an absence of other myeloid markers, but the clinical significance of this finding is not well studied. Methods: A retrospective cohort analysis of flow cytometry and clinical data was performed to investigate the clinical outcome of this specific group of patients. Results: Twenty-nine cases of otherwise typical B-ALL that expressed MPO by flow cytometry (B-ALL-isoMPO) without expression of other myeloid markers were identified. The B ALL-isoMPO group had a significantly increased incidence of relapse (univariate log rank P = .0083; multivariate hazard ratio, 2.50; 95% confidence interval, 1.07-5.85; P = .034) and significantly worse event-free survival by univariate analysis (log rank P = .0066) compared with a reference group of patients with B ALL from the same time period (n = 264). Conclusions: To our knowledge, this is the first report to document the clinical outcomes in a group of pediatric patients with B-ALL that expresses MPO in the absence of other myeloid markers. This group had an increased rate of relapse and a worse event-free survival than the patients with B-ALL who did not express MPO. PMID- 28340213 TI - Effects of Alcohol Dependence Severity on Neural Correlates of Delay Discounting. AB - Aims: The current study examines the relationship between alcohol dependence severity and delay discounting neural activation. Methods: Participants (N = 17; 6 female) completed measures of alcohol use and severity and a functional magnetic resonance imaging version of a delay discounting task. Results: Alcohol dependence severity was negatively associated with activation in superior frontal gyrus during impulsive relative to delayed decisions, and positively associated with activation in paracingulate gyrus and frontal pole in delayed relative to impulsive decisions. Conclusions: These results indicate that alcohol dependence severity tracks closely with dysregulations in cognitive control and reward evaluation areas during impulsive and delayed decisions, respectively. Delay discounting may be a useful construct in capturing these cognitive dysregulations as alcohol use disorders become more severe. Short summary: Among alcohol dependent individuals, alcohol dependence severity is associated with overactivation of ventromedial prefrontal areas during delayed and underactivation of dorsolateral prefrontal regions during impulsive reward decisions. PMID- 28340214 TI - Knuckle pigmentation and vitamin B12 deficiency. PMID- 28340212 TI - Accelerated senescence in skin in a murine model of radiation-induced multi-organ injury. AB - Accidental high-dose radiation exposures can lead to multi-organ injuries, including radiation dermatitis. The types of cellular damage leading to radiation dermatitis are not completely understood. To identify the cellular mechanisms that underlie radiation-induced skin injury in vivo, we evaluated the time-course of cellular effects of radiation (14, 16 or 17 Gy X-rays; 0.5 Gy/min) in the skin of C57BL/6 mice. Irradiation of 14 Gy induced mild inflammation, observed histologically, but no visible hair loss or erythema. However, 16 or 17 Gy radiation induced dry desquamation, erythema and mild ulceration, detectable within 14 days post-irradiation. Histological evaluation revealed inflammation with mast cell infiltration within 14 days. Fibrosis occurred 80 days following 17 Gy irradiation, with collagen deposition, admixed with neutrophilic dermatitis, and necrotic debris. We found that in cultures of normal human keratinocytes, exposure to 17.9 Gy irradiation caused the upregulation of p21/waf1, a marker of senescence. Using western blot analysis of 17.9 Gy irradiated mice skin samples, we also detected a marker of accelerated senescence (p21/waf1) 7 days post-irradiation, and a marker of cellular apoptosis (activated caspase-3) at 30 days, both preceding histological evidence of inflammatory infiltrates. Immunohistochemistry revealed reduced epithelial stem cells from hair follicles 14-30 days post-irradiation. Furthermore, p21/waf1 expression was increased in the region of the hair follicle stem cells at 14 days post 17 Gy irradiation. These data indicate that radiation induces accelerated cellular senescence in the region of the stem cell population of the skin. PMID- 28340215 TI - Development of enzyme immunoassays (ELISA and Western blot) for the serological diagnosis of dermatophytosis in symptomatic and asymptomatic cats. AB - Dermatophytosis is the most common fungal infection in cats worldwide and plays an important role in both animal and human health due to their high zoonotic potential. Effective screening is a strong preventive measure and the fungal culture is quite useful but requires full laboratorial experience and it takes a long time to obtain the result. A rapid and accurate screening test for dermatophytosis in cats is crucial for the effective control of disease outbreaks. The aim of this study was to develop and evaluate the diagnostic efficacy of enzyme immunoassays (ELISA and Western blot [WB]) for the rapid and precise diagnosis of dermatophytosis in cats. Seventy cats of various ages were divided into three groups: S (symptomatic, n = 20), AS (asymptomatic, n = 30), and N (negative, n = 20). All animals were submitted to fungal culture and blood samples for carrying out the serological tests. A significant difference (P < 0.05) was found between IgG-specific levels of sera of Microsporum canis positive and negative animals. There was no statistic difference between groups symptomatic and asymptomatic. The ELISA test showed sensitivity of 94% and specificity of 75%. Receiver operating characteristic (ROC) analysis also showed higher diagnostic accuracy (AUC 0.925). The WB technique detected 13 bands, and the 50 kDa protein was considered the most immunogenic protein, observing reactivity in 83.3% in the symptomatic group and 66.6% in the asymptomatic group. The study concluded that ELISA and WB were useful tools to reliably detect cats that have been exposed to M. canis. PMID- 28340216 TI - Meta-analysis of statins in chronic kidney disease: who benefits? AB - Background: Attempts to reduce the burden of vascular disease in advanced chronic kidney disease (CKD) by control of lipids have not been as successful as predicted. Aim: To determine the extent to which the effectiveness of statins varies by kidney class. Design: Meta-analysis. Methods: We selected randomized trials of statin vs. placebo that gave outcomes for CKD3 (eGFR 30-59 ml/min), CKD4 (eGFR 15-29 ml/min), CKD5 (eGFR < 15 ml/min)/5D(dialysis) and transplant patients separately. Data sources were the Cholesterol Triallists' Treatment Collaboration and previously published meta-analyses. Main outcome measures were major cardiovascular events (MACE), cardiovascular death and all-cause mortality (ACM). Results: A total of 13 studies provided 19 386 participants with CKD3, 2565 with CKD4, 7051 with CKD5/5D and 2102 with a functioning renal transplant. Statins reduced MACE (pooled HR 0.72, 95% CI 0.67-0.78) and ACM (0.82, 0.73-0.91) in CKD3; probably reduced MACE (0.78, 0.62-0.99) in CKD4; and probably reduced cardiovascular death (0.62, 0.40-0.96) in renal transplants. There were no cardiovascular or ACM data in CKD4; there was no convincing evidence of benefit for any outcome in CKD5/5D; and no significant reduction in MACE or ACM in patients with a functioning transplant. Conclusions: Statins are indicated in CKD3, probably indicated in CKD4, not indicated in CKD5/5D and probably indicated in patients with a functioning transplant. Too few patients with CKD4 and renal transplants have been included in lipid lowering trials for confident conclusions to be drawn. PMID- 28340217 TI - Establishment of Reference Interval for Alkaline Phosphatase in Healthy Children of Various Ethnicities, Aged 0-12 Years. AB - Background: To establish a reference interval of alkaline phosphatase for healthy children of various ethnicities, aged 0 years to 12 years in China. Methods: According to the Clinical and Laboratory Standards Institute guideline C28-A3, blood specimens were collected in the morning after overnight fasting from 502 healthy children to determine the alkaline phosphatase (ALP) level, using the Beckman AU5800 automatic biochemical analyzer. Children were grouped by sex and age. The age groups were as follows: 0 to 1 year, 1 to 3 years, 3 to 6 years, and 6 to 12 years. Results: There were no significant differences between the sex and age groups for the age groups of 0 to 1 year, 1 to 3 years, and 3 to 6 years; as a result, we combined those groups into a single group. The reference interval of ALP is 81.9 to 350.3 U per L in the group aged 0 to 6 years and 48.8 to 445.9 U per L in the group aged 6 to 12 years. Conclusions: The results of this study establish a reference interval for ALP in healthy children, which will provide a basis for screening, diagnosing, and monitoring bone or liver-related diseases in children. PMID- 28340219 TI - Reply to letter on results of NRG Oncology RTOG 9813. PMID- 28340218 TI - User-centered design of discharge warnings tool for colorectal surgery patients. AB - Objectives: Readmission following colorectal surgery, typically due to surgery related complications, is common. Patient-centered discharge warnings may guide recognition of early complication signs after colorectal surgery. Materials and Methods: User-centered design of a discharge warnings tool consisted of iterative health literacy review and a heuristic evaluation with human factors and clinical experts as well as patient end users to establish content validity and usability. Results: Literacy evaluation of the prototype suggested >12th-grade reading level. Subsequent revisions reduced reading level to 8th grade or below. Contents were formatted during heuristic evaluation into 3 action-oriented zones (green, yellow, and red) with relevant warning lexicons. Usability testing demonstrated comprehension of this 3-level lexicon and recognition of appropriate patient actions to take for each level. Discussion: We developed a discharge warnings tool for colorectal surgery using staged user-centered design. The lexicon of surgical discharge warnings could structure communication among patients, caregivers, and clinicians to improve post-discharge care. PMID- 28340220 TI - Her2/neu Status Determination in Breast Cancer: A Single Institutional Experience Using a Dual-Testing Approach With Immunohistochemistry and Fluorescence In Situ Hybridization. AB - Objectives: According to current guidelines, either immunohistochemistry (IHC) or in situ hybridization (ISH) can be used to determine human epidermal growth factor receptor 2 (Her2/neu) status in breast carcinoma. While the guidelines explicitly delineate result interpretation, there is no consensus on the most appropriate testing algorithm. Methods: The Her2/neu statuses of 369 consecutive cases of invasive breast cancer (from 351 patients) were assessed in a dual testing algorithm that uses both IHC and fluorescence ISH (FISH). FISH was performed using dual-color HER2/ chromosome enumeration probe 17 ( CEP17 ) probes, and if equivocal results were obtained, reflex testing using HER2/lissencephaly gene 1 ( LIS1 ) probes was used. Results from both modalities were scored and reported using American Society of Clinical Oncology/College of American Pathologists 2013 criteria. Results: Sixty-one (16.5%) of the 369 tumors were found to be Her2/neu positive by at least one modality. The overall concordance between IHC and FISH results was 97.6%. Six of the 369 tumors were reclassified as Her2/neu positive after a negative IHC result. FISH was also able to identify significantly more Her2/neu-positive cases than IHC. Conclusions: The commonly used reflex strategy based on IHC results may deny potentially beneficial targeted therapy for a small cohort of patients, which should be considered as testing guidelines are formulated and the cost-benefit analyses of various testing algorithms are assessed. PMID- 28340222 TI - Success in Implementation of a Resident In-Service Examination Review Series. AB - Objectives: Primary pathology board certification has been correlated with senior resident in-service examination (RISE) performance. We describe our success with an annual, month-long review series. Methods: Aggregate program RISE performance data were gathered for 3 years prior to and 3 years following initiation of the review series. In addition, mean United States Medical Licensing Examination Step 1 and 2 Clinical Knowledge scores for residents participating in each RISE examination were obtained to control for incoming knowledge and test-taking ability. Linear models were used to evaluate differences in average RISE performance prior to and following the initiation of the review series in addition to controlling for relevant covariates. Results: Significant improvement was noted in the grand total, anatomic pathology section average, clinical pathology section average, and transfusion medicine section. Although not statistically significant, improvement was noted on the cytopathology and clinical chemistry sections. There was no significant difference in scores in hematopathology, molecular pathology, and the special topics section average. In addition, improvement in primary pathology board certification rates was also noted. Conclusions: Institution of a month-long RISE review series demonstrated improved overall performance within our training program. The success could easily be replicated in any training program without significant disruption to an annual didactic series. PMID- 28340223 TI - Implantation of cardiac resynchronization therapy devices using three leads by cephalic vein dissection approach. AB - Aims: Percutaneous subclavian, axillary, and cephalic vein access are all used in conjunction for atrial and ventricular lead implantation, though no standard approach for cardiac resynchronization therapy (CRT) device implantation has been established. We describe an effective and a safe technique for implanting three leads via cephalic vein for CRT pacemaker and/or defibrillator implantations. Methods and results: A total of 171 consecutive patients undergoing de novo implantation of CRT pacemaker or defibrillator were included. Cephalic vein access was achieved by dissection and direct visualization. If the cephalic vein was inadequate, alternate means of access was determined after outset of the procedure. Procedural success rates and complications were recorded. Of the 171 de novo CRT implant attempts, 169 (98.8%) patients had successful implantation of all 3 leads on the first attempt. Of the 171 procedural attempts, 150 (87.7%) patients had all 3 leads placed via cephalic vein. Overall, complications occurred in 6 of 171 patients (3.5%) including initial and repeat procedures. These complications included seven lead dislodgements, two cases of diaphragmatic stimulation requiring lead revision, and one coronary sinus dissection without pericardial effusion. There were no cases of pneumothorax, pocket haematoma requiring evacuation, or infection. Conclusion: The triple lead via cephalic vein technique is safe and effective when used as a first approach for CRT device implantation. PMID- 28340221 TI - Nationwide multicentre kidney biopsy study of Japanese patients with type 2 diabetes. AB - Background: The clinical and pathologic manifestations of nephropathy due to type 2 diabetes are diverse, but large-scale pathologic studies with long-term observations are limited. Methods: Kidney biopsies and clinical data of 600 patients with type 2 diabetes were collected retrospectively from 13 centres across Japan. Thirteen pathologic findings (nine glomerular lesions, two interstitial lesions and two vascular lesions) were clearly defined and scored. Results: During the observation period, there were 304 composite kidney events [dialysis, doubling of creatinine or reduction of estimated glomerular filtration rate (eGFR) by half], 31 instances of chronic kidney disease (CKD) G5D, 76 cardiovascular events and 73 deaths. The mean observation period was 72.4 months. The distribution of CKD heat map categories for the 600 patients was 103 green or yellow, 149 orange and 348 red. Even in the cases in the green and yellow category, diffuse lesions (81.6%), polar vasculosis (42.6%) and subendothelial space widening (35.1%) were commonly detected. Cox proportional hazard analysis revealed that the presence of nodular lesions [hazard ratio (HR) 21.1, 95% confidence interval (CI) 5.3-84.6], exudative lesions (HR 5.1, 95% CI 1.3-20.3) and mesangiolysis (HR 7.6, 95% CI 2.0-28.8) in cases in the green and yellow category were associated with significantly great impact on composite kidney events after adjustment for clinical risk factors. Conclusions: This nationwide study on kidney biopsy of 600 cases with type 2 diabetes revealed that pathologic findings (presence of nodular lesions, exudative lesions and mesangiolysis) were strong predictors of kidney events in low-risk patients. PMID- 28340224 TI - The association of context-specific sitting time and physical activity intensity to working memory capacity and academic achievement in young adults. AB - Background: To examine combined associations between self-reported context specific sitting time (ST) and physical activity (PA) with working memory capacity (WMC) and academic achievement in a sample of Spanish adults. Design: Undergraduate students (n = 371; 21 years +/- 3 years, 44% female) were recruited from University of Vic-Central University of Catalonia. Methods: Participants completed a 54-item survey that assessed socio-demographic variables (e.g. age, gender, academic year), min/week of light (LPA), moderate (MPA) and vigorous (VPA) intensity PA (International Physical Activity Questionnaire), min/day of domain-specific ST (Last 7 days sedentary behavior questionnaire) and academic performance (grade point average). WMC was assessed through a multiple complex span task that included: Operation Span, Symmetry Span and Rotation Span. These tasks interleave a processing task with a short list of to-be-remembered items. General linear models-adjusted by PA, ST and gender-assessed combined associations between ST and PA with WMC and academic achievement. Results: Performing more than 3 h/week of MPA was related to increases in WMC (P < 0.001). However, PA was not associated with academic performance. More than 3 h seated on a weekend day while performing non-screen leisure activities were related to reduced WMC after adjusting for PA (P = 0.012). Similarly, >3 h/weekday spent seated in these sedentary activities or in leisure-forms of screen time were inversely associated with academic performance regardless of PA (P = 0.033; P = 0.048). Conclusions: MPA may benefit working memory; however, specific domains of leisure-time sedentary behavior may have an unfavorable influence on working memory and academic performance regardless of time spent in PA. PMID- 28340225 TI - Long working hours and metabolic syndrome. PMID- 28340226 TI - Chronic total occlusion: a black-box? PMID- 28340227 TI - Transplant as a competing risk in the analysis of dialysis patients. AB - Time-to-event analyses are frequently used in nephrology research, for instance, when recording time to death or time to peritonitis in dialysis patients. Many papers have pointed out the important issue of competing events (or competing risks) in such analyses. For example, when studying one particular cause of death it can be noted that patients also die from other causes. Such competing events preclude the event of interest from occurring and thereby complicate the statistical analysis. The Kaplan-Meier approach to calculating the cumulative probability of the event of interest yields invalid results in the presence of competing risks, thus the alternative cumulative incidence competing risk (CICR) approach has become the standard. However, when kidney transplant is the competing event that prevents observing the outcome of interest, CICR may not always be the matter of interest. We discuss situations where both the Kaplan Meier and the CICR approach are not suitable for the purpose and point out alternative analysis methods for such situations. We also look at the suitability and interpretation of different estimators for relative risks. In the presence of transplant as a competing risk, one should very clearly state the research question and use an analysis method that targets this question. PMID- 28340228 TI - Dual Immunostain With SATB2 and CK20 Differentiates Appendiceal Mucinous Neoplasms From Ovarian Mucinous Neoplasms. AB - Objectives: Determination of the primary site of origin for mucinous neoplasms identified in the peritoneal and/or pelvic cavities may be challenging, with major differential diagnoses including appendiceal mucinous neoplasm (AMN) and ovarian mucinous neoplasm (OMN). Special AT-rich sequence binding protein 2 (SATB2) has been shown to be highly selectively expressed in the lower gastrointestinal tract, including the appendix. Methods: We investigated the utility of a dual stain (DS) with SATB2 or caudal type homeobox 2 (CDX2) and cytokeratin 20 (CK20) or villin in distinguishing AMNs from OMNs. Tissue microarrays with 40 AMNs and 18 OMNs were stained with SATB2 or CDX2 paired with either CK20 or villin. Results: SATB2 single stain showed a good sensitivity of 83% and the highest specificity of 78% for AMNs over OMNs among all four stains. DS with SATB2 and villin showed an identical sensitivity of 78% but specificity increased to 94%, while DS with SATB2 and CK20 showed a sensitivity of 80% and a specificity of 100%. In contrast, DS with CDX2 and CK20/villin showed slightly higher sensitivity but much lower specificity. Conclusions: DS with SATB2/CK20 shows the greatest potential clinical utility in distinguishing AMNs from OMNs and is superior to DS with CDX2/CK20. Importantly, DS could be helpful for specimens with limited tissues. PMID- 28340229 TI - Meaningful use in the safety net: a rapid ethnography of patient portal implementation at five community health centers in California. AB - Objective: US health care institutions are implementing secure websites (patient portals) to achieve federal Meaningful Use (MU) certification. We sought to understand efforts to implement portals in "safety net" health care systems that provide services for low-income populations. Materials and Methods: Our rapid ethnography involved visits at 4 California safety net health systems and in depth interviews at a fifth. Visits included interviews with clinicians and executives ( n = 12), informal focus groups with front-line staff ( n = 35), observations of patient portal sign-up procedures and clinic work, review of marketing materials and portal use data, and a brief survey ( n = 45). Results: Our findings demonstrate that the health systems devoted considerable effort to enlisting staff support for portal adoption and integrating portal-related work into clinic routines. Although all health systems had achieved, or were close to achieving, MU benchmarks, patients faced numerous barriers to portal use and our participants were uncertain how to achieve and sustain "meaningful use" as defined by and for their patients. Discussion: Health systems' efforts to achieve MU certification united clinic staff under a shared ethos of improved quality of care. However, MU's assumptions about patients' demand for electronic access to health information and ability to make use of it directed clinics' attention to enrollment and message routing rather than to the relevance and usability of a tool that is minimally adaptable to the safety net context. Conclusion: We found a mismatch between MU-based metrics of patient engagement and the priorities and needs of safety net patient populations. PMID- 28340230 TI - Determinants of Opioid Prescribing for Nonmalignant Chronic Pain in US Outpatient Settings. AB - Study Objectives: Identify prescribing trends for opioid use in non-malignant chronic pain (NMCP) from the National Ambulatory Medical Care Survey (NAMCS). Determine predictors of opioid use based on patient-specific factors. Design: This cross-sectional study analyzed NAMCS data from 2000 to 2007. Pain medications prescribed were retrieved using NAMCS drug codes. Multivariate logistic models examined determinants of opioid prescribing among NMCP patients. Subjects: Patients included in the study were age 18 years or older with NMCP diagnosis based on ICD-9 codes identified as reason for visits. Results: Approximately 690 million weighted outpatient visits related to NMCP were reported in the US between 2000 to 2007. Reported opioid use was 14.3%. Compared with patients age 18 to 34 years, patients age 35 to 49 years were 1.47 times more likely (odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.17-1.86) and patients age 65 years or older were 0.61 times less likely (OR = 0.39, 95% CI = 0.27-0.55] to receive opioids. Patient visits from primary care physicians were 1.83 times more likely to report opioids (OR = 1.83, 95% CI = 1.50-2.25) than specialty physicians. Hispanic ethnicity and patients with private insurance were less likely to receive opioids, while patients having five or more medications, publicly funded insurance, the ICD-9 code of general chronic pain, established patients, and the southern prescribing region were more likely to receive opioids. Conclusions: Differences exist between those prescribed and not prescribed opioids. Results from this study paired with increased education and further research regarding the appropriate prescribing and monitoring of opioids may help enhance awareness, diminish treatment disparities and improve safe and appropriate use of opioids in the NMCP population. PMID- 28340231 TI - Prevalence and Determinants of Premature Menopause among Indian Women: Issues and Challenges Ahead. AB - Premature menopause refers to the occurrence of menopause in women less than 40 years of age. This heterogeneous disorder affects 1 percent and 0.1 percent of women less than 40 and 30 years of age, respectively. The study reported in this article attempts to understand the prevalence and determinants of premature menopause among Indian women by studying the effects of various socioeconomic indicators, such as age, education, wealth index, rural-urban settlement, work status, religion, and caste, on women. The study analyzed the National Family Health Survey-3, which is equivalent to the Demographic Health Survey in India. Bivariate and logistic regression analyses were performed to tease out the determinants of premature menopause. Results indicate that the percentage of premature menopause is very high (5.5 percent) among Indian women. Among Indian states, Andhra Pradesh women have the highest percentage of premature menopause (14.6 percent). Smoking and the nutritional status of women are strongly associated with early menopause. Furthermore, women living in rural areas and using tobacco are at a greater risk of premature menopause. PMID- 28340232 TI - A Proposed Set of Metrics to Reduce Patient Safety Risk From Within the Anatomic Pathology Laboratory. AB - Background: Anatomic pathology laboratory workflow consists of 3 major specimen handling processes. Among the workflow are preanalytic, analytic, and postanalytic phases that contain multistep subprocesses with great impact on patient care. A worldwide representation of experts came together to create a system of metrics, as a basis for laboratories worldwide, to help them evaluate and improve specimen handling to reduce patient safety risk. Method: Members of the Initiative for Anatomic Pathology Laboratory Patient Safety (IAPLPS) pooled their extensive expertise to generate a list of metrics highlighting processes with high and low risk for adverse patient outcomes. Results: : Our group developed a universal, comprehensive list of 47 metrics for patient specimen handling in the anatomic pathology laboratory. Steps within the specimen workflow sequence are categorized as high or low risk. In general, steps associated with the potential for specimen misidentification correspond to the high-risk grouping and merit greater focus within quality management systems. Primarily workflow measures related to operational efficiency can be considered low risk. Conclusion: Our group intends to advance the widespread use of these metrics in anatomic pathology laboratories to reduce patient safety risk and improve patient care with development of best practices and interlaboratory error reporting programs. PMID- 28340233 TI - Increase in Drug Overdose Deaths Involving Fentanyl-Rhode Island, January 2012 March 2014. AB - Objective: This study identified sociodemographic, substance use, and multiple opioid prescriber and dispenser risk factors among drug overdose decedents in Rhode Island, in response to an increase in overdose deaths (ODs) involving fentanyl. Methods: This cross-sectional investigation comprised all ODs reviewed by Rhode Island's Office of the State Medical Examiners (OSME) during January 2012 to March 2014. Data for 536 decedents were abstracted from OSME's charts, death certificates, toxicology reports, and Prescription Monitoring Program (PMP) databases. Decedents whose cause of death involved illicit fentanyl (N = 69) were compared with decedents whose causes of death did not involve fentanyl (other drug decedents; N = 467). Results: Illicit-fentanyl decedents were younger than other drug decedents (P = 0.005). While more other-drug decedents than illicit fentanyl decedents had postmortem toxicological evidence of consuming heroin (31.9% vs 19.8%, P < 0.001) and various pharmaceutical substances (P = 0.002 0.027), third party reports indicated more recent heroin use among illicit fentanyl decedents (62.3% vs 45.6%, P = 0.002). Approximately 35% of decedents filled an opioid prescription within 90 days of death; of these, one-third had a mean daily dosage greater than 100 morphine milligram equivalents (MME/day). Most decedents' opioid prescriptions were filled at one to two dispensers (83.9%) and written by one to two prescribers (75.8%). Notably, 29.2% of illicit fentanyl and 10.5% of other drug decedents filled prescriptions for buprenorphine, which is used to treat opioid use disorders. Conclusions: Illicit-fentanyl deaths frequently involved other illicit drugs (e.g., cocaine, heroin). The proportion of all decedents acquiring greater than 100 MME/day prescription dosages written and/or filled by few prescribers and dispensers is concerning. To protect patients, prescribers and dispensers should review PMP records and substance abuse history prior to providing opioids. PMID- 28340234 TI - Detection of severe digital vasculopathy in systemic sclerosis by colour Doppler sonography is associated with digital ulcers. AB - Objective: Colour Doppler ultrasonography (CDUS) is very important in general vascular diagnostic procedures. Its role in determining the extent of vasculopathy in Systemic Sclerosis (SSc) needs further investigation. The aim of this study was to compare the presence of altered arteries with nailfold capillaroscopy and clinical signs of ischaemia, that is, digital ulcers or pitting scars (DU/PS). A feasible CDUS protocol is provided. Methods: Two thousand five hundred and twenty-eight arteries of the fingers, palms and wrists from 79 SSc patients (32 arteries per patient) were examined using CDUS. Furthermore, nailfold capillaroscopy, clinical and laboratory data were evaluated. Results: Narrowed or occluded lumens were seen in 39.8% of all assessable arteries (n = 2489) and 48.9% of all proper palmar digital arteries (n = 1564) but only 15.6% (P < 0.0001) of proximal arteries (n = 924). Fingerwise analyses presented significant coincidence of pathological CDUS findings and DU/PS (P = 0.0009). Pathological CDUS findings were also associated with elevated CRP concentrations, current or past smoking with ?20 pack-years, male gender and present or past DU/PS. Receiver operating characteristic curve analysis (area under the curve = 0.727) suggested a cut-off value of ?20% pathological vessels (sensitivity: 90.7%; specificity: 47.8%) for the presence of DU/PS. An examination protocol focusing on the right-hand digits II-V (proper palmar digital arteries) revealed similar results (area under the curve = 0.751; sensitivity: 93.0%; specificity: 43.5%). Conclusion: CDUS of hand and finger arteries allows measurement of the extent of SSc vasculopathy, which is associated with clinical signs of chronic malperfusion. A shortened examination protocol of CDUS (right-hand digits II-V; 15 min instead of 45 min examination time) could complement vascular diagnostics in SSc. PMID- 28340235 TI - Polymerase Chain Reaction Human Papillomavirus (HPV) Detection and HPV Genotyping in Invasive Cervical Cancers With Prior Negative HC2 Test Results. AB - Objectives: Recently, three large Chinese cohort studies showed that 7.5% to 15.5% of patients with cervical carcinoma had negative high-risk human papillomavirus (hrHPV) test results on prior cytology specimens. These studies raise the question as to whether these negative hrHPV results represent truly hrHPV-negative carcinomas or false-negative hrHPV test results due to limitations in the testing of cytology specimens. This is increasingly an important question with increasing push to use hrHPV testing alone to screen for cervical cancer. Methods: We investigated the hrHPV status on the surgical specimens from these same patients with cervical carcinoma using three polymerase chain reaction methods and a linear assay genotyping method. Results: A variety of HPV genotypes were detected in 28 (45.9%) of 61 cases, all belonging to carcinogenic or possibly carcinogenic categories. HPV 16 was the most common genotype detected in positive cases (66.7%). HPV was detected in 25 (50%) of 50 squamous cell carcinomas and two (66.7%) of three adenosquamous carcinomas and only one (12.5%) of eight endocervical adenocarcinomas. Conclusions: Our findings demonstrate that negative hrHPV testing on cervicovaginal cytology specimens in women later diagnosed with cervical carcinoma can be explained by the occurrence of truly HPV negative carcinomas in more than half of patients. These results should be considered in the development of future cervical cancer screening guidelines. PMID- 28340236 TI - Diet density during the first week of life: Effects on energy and nitrogen balance characteristics of broiler chickens. AB - This study aimed to determine effects of diet density on growth performance, energy balance, and nitrogen (N) balance characteristics of broiler chickens during the first wk of life. Effects of diet density were studied using a dose response design consisting of 5 dietary fat levels (3.5, 7.0, 10.5, 14.0, and 17.5%). The relative difference in dietary energy level was used to increase amino acid levels, mineral levels, and the premix inclusion level at the same ratio. Chickens were housed in open-circuit climate respiration chambers from d 0 to 7 after hatch. Body weight was measured on d 0 and 7, whereas feed intake was determined daily. For calculation of energy balances, O2 and CO2 exchange were measured continuously and all excreta from d 0 to 7 was collected and analyzed at d 7. Average daily gain (ADG) and average daily feed intake (ADFI) decreased linearly (P = 0.047 and P < 0.001, respectively), whereas gain to feed ratio increased (P < 0.001) with increasing diet density. Gross energy (GE) intake and metabolizable energy (ME) intake were not affected by diet density, but the ratio between ME and GE intake decreased linearly with increasing diet density (P = 0.006). Fat, N, and GE efficiencies (expressed as gain per unit of nutrient intake), heat production, and respiratory exchange ratio (CO2 to O2 ratio) decreased linearly (P < 0.001) as diet density increased. Energy retention, N intake, and N retention were not affected by diet density. We conclude that a higher diet density in the first wk of life of broiler chickens did not affect protein and fat retention, whereas the ME to GE ratio decreased linearly with increased diet density. This suggests that diet density appears to affect digestibility rather than utilization of nutrients. PMID- 28340237 TI - Pain and Cognition in Multiple Sclerosis. AB - Objective: The goal of the present study was to examine the relationship between pain and cognition in patients with multiple sclerosis. Design: Cross-sectional. Setting: Nursing home and personal environment of the investigators. Subjects: Two groups of participants were included: 91 patients with multiple sclerosis and 80 matched control participants. Methods: The level of pain was measured by the following pain scales: Number of Words Chosen-Affective, Colored Analogue Scale for pain intensity and suffering from pain, and the Faces Pain Scale. Mood was tested by administering the Beck Depression Inventory and the Symptom Check List 90 anxiety and depression subscale. Global cognitive functioning was assessed by the Mini Mental State Examination. Memory and executive functions were assessed by several neuropsychological tests. Results: Multiple sclerosis (MS) patients scored significantly lower than control participants on the majority of the neuropsychological tests. The MS patients experienced more pain compared with control participants, despite the fact that they were taking significantly more pain medication. No significant correlation was observed between cognition and pain in MS patients. Verbal working memory explained 10% of pain intensity (trend). Mood appeared to be a significant predictor of pain in patients with multiple sclerosis. Conclusion: The lack of a relationship between cognition and pain might be explained by the fact that, compared with control participants, patients with multiple sclerosis activate other non-pain-related areas to perform executive functions and memory tasks. PMID- 28340240 TI - Osteonecrosis, splenic calcification and sickle cell disease. PMID- 28340238 TI - Cigarette Smoke Exposure Worsens Endotoxin-Induced Lung Injury and Pulmonary Edema in Mice. AB - Introduction: Cigarette smoking (CS) remains a major public health concern and has recently been associated with an increased risk of developing acute respiratory distress syndrome (ARDS). Bronchoalveolar lavage (BAL) experiments in human volunteers have demonstrated that active smokers develop increased alveolar epithelial barrier permeability to protein after inhaling lipopolysaccharide (LPS). Here we tested the hypothesis that short-term whole-body CS exposure would increase LPS-induced lung edema in mice. Methods: Adult mice were exposed in a Teague TE-10 machine to CS from 3R4F cigarettes at 100 mg/m3 total suspended particulates for 12 days, then given LPS or saline intratracheally. Control mice were housed in the same room without CS exposure. Post-mortem measurements included gravimetric lung water and BAL protein, cell counts, and lung histology. Cytokines were measured in lung homogenate by ELISA and in plasma by Luminex and ELISA. Results: In CS-exposed mice, intratracheal LPS caused greater increases in pulmonary edema by gravimetric measurement and histologic scoring. CS-exposed mice also had an increase in BAL neutrophilia, lung IL-6, and plasma CXCL9, a T cell chemoattractant. Intratracheal LPS concentrated blood hemoglobin to a greater degree in CS-exposed mice, consistent with an increase in systemic vascular permeability. Conclusions: These results demonstrate that CS exposure in endotoxin injured mice increases the severity of acute lung injury. The increased lung IL-6 in CS-exposed LPS-injured mice indicates that this potent cytokine, previously shown to predict mortality in patients with ARDS, may play a role in exacerbating lung injury in smokers and may have utility as a biomarker of tobacco-related lung injury. Implications: Our results suggest that short-term CS exposure at levels that cause no overt lung injury may still prime the lung for acute inflammatory damage from a "second hit", a finding that mirrors the increased risk of developing ARDS in patients who smoke. This model may be useful for evaluating the acute pulmonary toxicity of existing and/or novel tobacco products and identifying biomarkers of tobacco-related lung injury. PMID- 28340239 TI - Hypertension in dialysis patients: a consensus document by the European Renal and Cardiovascular Medicine (EURECA-m) working group of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and the Hypertension and the Kidney working group of the European Society of Hypertension (ESH). AB - In patients with end-stage renal disease (ESRD) treated with haemodialysis or peritoneal dialysis, hypertension is common and often poorly controlled. Blood pressure (BP) recordings obtained before or after haemodialysis display a J- or U shaped association with cardiovascular events and survival, but this most likely reflects the low accuracy of these measurements and the peculiar haemodynamic setting related to dialysis treatment. Elevated BP detected by home or ambulatory BP monitoring is clearly associated with shorter survival. Sodium and volume excess is the prominent mechanism of hypertension in dialysis patients, but other pathways, such as arterial stiffness, activation of the renin-angiotensin aldosterone and sympathetic nervous systems, endothelial dysfunction, sleep apnoea and the use of erythropoietin-stimulating agents may also be involved. Non pharmacologic interventions targeting sodium and volume excess are fundamental for hypertension control in this population. If BP remains elevated after appropriate treatment of sodium and volume excess, the use of antihypertensive agents is necessary. Drug treatment in the dialysis population should take into consideration the patient's comorbidities and specific characteristics of each agent, such as dialysability. This document is an overview of the diagnosis, epidemiology, pathogenesis and treatment of hypertension in patients on dialysis, aiming to offer the renal physician practical recommendations based on current knowledge and expert opinion and to highlight areas for future research. PMID- 28340241 TI - Pragmatic (trial) informatics: a perspective from the NIH Health Care Systems Research Collaboratory. AB - Pragmatic clinical trials (PCTs) are research investigations embedded in health care settings designed to increase the efficiency of research and its relevance to clinical practice. The Health Care Systems Research Collaboratory, initiated by the National Institutes of Health Common Fund in 2010, is a pioneering cooperative aimed at identifying and overcoming operational challenges to pragmatic research. Drawing from our experience, we present 4 broad categories of informatics-related challenges: (1) using clinical data for research, (2) integrating data from heterogeneous systems, (3) using electronic health records to support intervention delivery or health system change, and (4) assessing and improving data capture to define study populations and outcomes. These challenges impact the validity, reliability, and integrity of PCTs. Achieving the full potential of PCTs and a learning health system will require meaningful partnerships between health system leadership and operations, and federally driven standards and policies to ensure that future electronic health record systems have the flexibility to support research. PMID- 28340242 TI - Insertion of miniaturized cardiac monitors outside the catheter operating room: experience and practical advice. AB - Minor surgical procedures are increasingly being performed as outpatient procedures in settings outside hospital operating rooms (ORs). In electrophysiology, the recent miniaturization of insertable cardiac monitors (ICMs) has enabled the routine insertion of the device as a minimally invasive procedure without the need of a catheter OR. However, a shift to office-based environments for minor surgical procedures is associated with some concerns, particularly with respect to patient- and procedure-related safety in the new setting. In the present document, the authors provide practical advice on facilities, practices, and adaptations necessary when performing ICM insertions in office settings, based on available recommendations as well as their own experience with the use of the novel Reveal LINQ ICM. The main differences from in-hospital implant settings are simplified requirements of room, equipment, and insertion procedures, while ensuring and maintaining an adequate, sterile environment. Patient selection is important: certain groups of patients are recommended to be treated in the catheter OR (e.g. those at increased risk for bleeding or very frail elderly individuals). Insertion in alternative positions, as is sometimes performed for cosmetic reasons, should be referred to dedicated hospitals. Quality assurance and internal quality control are critical in the new procedural landscape, and it is important not to trivialize minor surgical procedures. Operators' sharing of experiences and lessons learned, e.g. in the form of registries, should be encouraged. PMID- 28340243 TI - Finite-time parametric identification for the model representing the metabolic and genetic regulatory effects of sequential aerobic respiration and anaerobic fermentation processes in Escherichia coli. AB - Mathematical modelling applied to biological systems allows for the inferring of changes in the dynamic behaviour of organisms associated with variations in the environment. Models based on ordinary differential equations are most commonly used because of their ability to describe the mechanisms of biological systems such as transcription. The disadvantage of using this approach is that there is a large number of parameters involved and that it is difficult to obtain them experimentally. This study presents an algorithm to obtain a finite-time parameter characterization of the model used to describe changes in the metabolic behaviour of Escherichia coli associated with environmental changes. In this scheme, super-twisting algorithm was proposed to recover the derivative of all the proteins and mRNA of E. coli associated to changes in the concentration of oxygen available in the growth media. The 75 identified parameters in this study maintain the biological coherence of the system and they were estimated with no more than 20% error with respect to the real ones included in the proposed model. PMID- 28340244 TI - Bupropion Administration Increases Resting-State Functional Connectivity in Dorso Medial Prefrontal Cortex. AB - Background: Patients on the selective serotonergic reuptake inhibitors like citalopram report emotional blunting. We showed previously that citalopram reduces resting-state functional connectivity in healthy volunteers in a number of brain regions, including the dorso-medial prefrontal cortex, which may be related to its clinical effects. Bupropion is a dopaminergic and noradrenergic reuptake inhibitor and is not reported to cause emotional blunting. However, how bupropion affects resting-state functional connectivity in healthy controls remains unknown. Methods: Using a within-subjects, repeated-measures, double blind, crossover design, we examined 17 healthy volunteers (9 female, 8 male). Volunteers received 7 days of bupropion (150 mg/d) and 7 days of placebo treatment and underwent resting-state functional Magnetic Resonance Imaging. We selected seed regions in the salience network (amygdala and pregenual anterior cingulate cortex) and the central executive network (dorsal medial prefrontal cortex). Mood and anhedonia measures were also recorded and examined in relation to resting-state functional connectivity. Results: Relative to placebo, bupropion increased resting-state functional connectivity in healthy volunteers between the dorsal medial prefrontal cortex seed region and the posterior cingulate cortex and the precuneus cortex, key parts of the default mode network. Conclusions: These results are opposite to that which we found with 7 days treatment of citalopram in healthy volunteers. These results reflect a different mechanism of action of bupropion compared with selective serotonergic reuptake inhibitors. These results help explain the apparent lack of emotional blunting caused by bupropion in depressed patients. PMID- 28340246 TI - Considerations on glycaemic control in older and/or frail individuals with diabetes and advanced kidney disease. AB - The increasing prevalence of chronic kidney disease (CKD) and diabetes over the last decade has resulted in increasing numbers of frail older patients with a combination of these conditions. Current treatment guidelines may not necessarily be relevant for such patients, who are mostly excluded from the trials upon which these recommendations are based. There is a paucity of data upon which to base the management of older patients with CKD. Nearly all current guidelines recommend less-tight glycaemic control for the older population, citing the lack of proven medium-term benefits and concerns about the high short-term risk of hypoglycaemia. However, reports from large landmark trials have shown potential benefits for both microvascular and macrovascular complications, though the relevance of these findings to this specific population is uncertain. The trials have also highlighted potential alternative explanations for the hazards of intensive glycaemic control. These include depression, low endogenous insulin reserve, low body mass index and side effects of the medication. Over the last few years, newer classes of hypoglycaemic drugs with a lower risk of hypoglycaemia have emerged. This article aims to present a balanced view of advantages and disadvantages of intense glycaemic control in this group of patients, which we hope will help the clinician and patient to come to an individualized management approach. PMID- 28340245 TI - Unacceptable human leucocyte antigens for organ offers in the era of organ shortage: influence on waiting time before kidney transplantation. AB - Background: The assignment of human leucocyte antigens (HLAs) against which antibodies are detected as unacceptable antigens (UAGs) avoids allocation of HLA- incompatible allografts. There is uncertainty as to what extent UAGs decrease the probability of receiving a kidney offer. Methods: Kidney transplantations in 3264 patients on the waiting lists of six German transplant centres were evaluated for a period of at least 2 years. The proportion of excluded offers due to UAGs was calculated as virtual panel-reactive antibodies (vPRAs). Results: In the common Eurotransplant Kidney Allocation Scheme, the transplant probability was unaffected by vPRAs in exploratory univariate analyses. In the multivariable model, a 1% increase in vPRA values was outweighed by an additional waiting time of 2.5 weeks. The model was confirmed using an external validation cohort of 1521 patients from seven centres. If only patients with standard risk were considered (e.g. no simultaneous transplantation of other organs), only 1.3 weeks additional waiting time was needed. In the Eurotransplant Senior Program, patients with vPRA values >50% had a strongly reduced transplant probability in the unadjusted analyses. In the multivariable model, a 1% increase in vPRA values was outweighed by an additional waiting time of 5 weeks. Conclusions: This study demonstrates that the assignment of UAGs decreases the transplant probability in both main Eurotransplant allocation programs because of insufficient compensatory mechanisms. At present, for immunized patients, a prolonged waiting time has to be weighed against the increased immunologic risk due to donor-specific antibodies not assigned as UAGs. PMID- 28340247 TI - Usability Testing of the iPhone App to Improve Pain Assessment for Older Adults with Cognitive Impairment (Prehospital Setting): A Qualitative Study. AB - Objectives: Pain assessment in older adults with cognitive impairment is often challenging, and paramedics are not given sufficient tools/training to assess pain. The development of a mobile app may improve pain assessment and management in this vulnerable population. We conducted usability testing of a newly developed iPhone pain assessment application with potential users, in this case as a tool for clinical paramedic practice to improve pain assessment of older adults with cognitive impairment. Methods: We conducted usability testing with paramedic students and a Delphi panel of qualified paramedics. Participants studied the app and paper-based algorithm from which the app was developed. The potential use for the app was discussed. Usability testing focus groups were recorded, transcribed verbatim, and analyzed using a thematic approach. Proposed recommendations were disseminated to the Delphi panel that reviewed and confirmed them. Results: Twenty-four paramedic students from two UK ambulance services participated in the focus groups. Usability of the app and its potential were viewed positively. Four major themes were identified: 1) overall opinion of the app for use in paramedic services; 2) incorporating technological applications into the health care setting; 3) improving knowledge and governance; and 4) alternative uses for the app. Subthemes were identified and are presented. Discussion: Our results indicate that the pain assessment app constitutes a potentially useful tool in the prehospital setting. By providing access to a tool specifically developed to help identify/assess pain in a user-friendly format, paramedics are likely to have increased knowledge and confidence in assessing pain in patients with dementia. PMID- 28340248 TI - Irradiation of Red Blood Cells and Alloimmunization. AB - Background: Animal models suggest that red blood cell (RBC) damage incurred during storage can increase immunogenicity to some RBC antigens. We hypothesized that RBC irradiation, a source of oxidative damage, may result in higher RBC alloimmunization rates among transfusion recipients. Methods: Individuals receiving 1 or more gamma-irradiated RBC units, with follow-up antibody screening, were studied. We recorded diagnosis at the time of first irradiated RBC-unit transfusion, total irradiated RBCs received, and alloantibodies detected before and after irradiated RBC transfusion. Results: The alloimmunization rate for patients receiving irradiated RBCs was 1.9% (3/154); this rate was not significantly different from the rate of 2.5% (5/200) derived from a control group that had undergone transfusion with nonirradiated RBCs ( P > .99). Most of the study subjects (83/154 [53.9%]) did not harbor an immunosuppressive disorder at the time of transfusion of irradiated RBCs, with postoperative bleeding (36/83 [43.4%]) being the most common diagnosis. Conclusions: This analysis provides reassurance that irradiated RBCs are not more immunogenic in patients with immunosuppression than in patients with immunocompetence. PMID- 28340249 TI - Orthodontic strain affects the Hippo-pathway effector YAP concomitant with proliferation in human periodontal ligament fibroblasts. AB - Objectives: During orthodontic tooth movement (OTM), human periodontal ligament fibroblasts (hPDLFs) sense, and respond to mechanical forces. Since the molecular constituents involved in these processes are not fully elucidated, the objective of the present study was to identify further key molecules of the cellular strain response. Materials and Methods: Primary hPDLFs were strained with a static equiaxial strain of 2.5 per cent for 15 minutes, 1 hour, 6 hours, and 24 hours. Western blot (WB) and indirect immunofluorescence (IIF) analyses were performed to investigate the quantity and activation state of proteins involved in mechanotransduction, namely extracellular signal-regulated kinase (ERK) 1/2 and yes-associated protein (YAP). On the cell behavioural level, proliferation was assessed by the marker of proliferation KI-67. Results: In response to the applied strain, an early decline of phosphorylated and thus activated ERK1/2 was observed, followed by a mild recovery. Furthermore, both WB and IIF analyses revealed a modulation of nuclear YAP localisation. Concomitant with the modulation of YAP, the applied strain evoked an early increase in nuclear KI-67 amount, followed by a continuous decrease. Limitations: Consecutive studies will focus on scrutinising the suggested relationship between YAP and proliferation in response to static strain. Conclusions: Our findings provide evidence of ERK1/2 and YAP being biomechanically responsive molecular players in the context of OTM, among which YAP rather than ERK1/2 seems to be mechanistically interrelated with proliferation. Furthermore, the molecular and cell behavioural strain-induced early modulations may point to an involvement of the investigated molecules in the initial and the following lag phase of OTM. PMID- 28340250 TI - Improving safety culture in hospitals: Facilitators and barriers to implementation of Systemic Falls Investigative Method (SFIM). AB - Objective: The purpose of this study was to assess the facilitators and barriers to implementation of the Systemic Falls Investigative Method (SFIM) on selected hospital units. Design: A cross-sectional explanatory mixed methods design was used to converge results from a standardized safety culture survey with themes that emerged from interviews and focus groups. Findings were organized by six elements of the Ottawa Model of Research Use framework. Setting: A geriatric rehabilitation unit of an acute care hospital and a neurological unit of a rehabilitation hospital were selected purposefully due to the high frequency of falls. Participants: Hospital staff who took part in: surveys (n = 39), interviews (n = 10) and focus groups (n = 12), and 38 people who were interviewed during falls investigations: fallers, family, unit staff and hospital management. Intervention: Implementation of the SFIM to investigate fall occurrences. Main Outcome Measure(s): Percent of positive responses on the Modified Stanford Patient Safety Culture Survey Instrument converged with qualitative themes on facilitators and barriers for intervention implementation. Results: Both hospital units had an overall poor safety culture which hindered intervention implementation. Facilitators were hospital accreditation, strong emphasis on patient safety, infrastructure and dedicated champions. Barriers included heavy workloads, lack of time, lack of resources and poor communication. Conclusions: Successful implementation of SFIM requires regulatory and organizational support, committed frontline staff and allocation of resources to identify active causes and latent contributing factors to falls. System-wide adjustments show promise for promotion of safety culture in hospitals where falls happen regularly. PMID- 28340251 TI - Thermal QST Phenotypes Associated with Response to Lumbar Epidural Steroid Injections: A Pilot Study. AB - Objective: Response to lumbar epidural steroid injection in lumbar radicular pain varies. The purpose of this study is to characterize the changes in quantitative sensory testing (QST) phenotypes of subjects and compare the QST characteristics in patients who do respond to treatment of radicular pain with a lumbar epidural steroid injection (ESI). Design: Prospective, observational pilot study. Setting: Outpatient pain center. Methods: Twenty subjects with a lower extremity (LE) radicular pain who were scheduled to have an ESI were recruited. At the visit prior to and four weeks following an ESI, subjects underwent QST measurements of both the affected LE and the contralateral unaffected UE. Results: Following an ESI, nine subjects reported a greater than 30% reduction in radicular pain and 11 reported a less than 30% reduction in radicular pain. Subjects who had less than 30% pain reduction response (nonresponders) to an ESI had increased pre-injection warm sensation threshold (37.30 degrees C, SD = 2.51 vs 40.39, SD = 3.36, P = 0.03) and heat pain threshold (47.22 degrees C, SD = 1.38, vs 48.83 degrees C, SD = 2.10, P = 0.04). Further, the nonresponders also showed increased pre injection warm sensation threshold as measured in the difference of warm sensation detection threshold difference in the affected limb and the unaffected arm (2.68 degrees C, SD = 2.92 vs 5.67 degrees C, SD = 3.22, P = 0.045). Other QST parameters were not affected. Conclusions: The results show that the nonresponders to ESIs have increased detection threshold to heat pain and warm sensation, suggesting that a preexisting dysfunction in the C fibers in this group of subjects who can be detected by QST. Such altered QST characteristics may prognosticate the response to ESIs. PMID- 28340253 TI - Diagnostic Value, Prognostic Value, and Safety of Provocation Discography. PMID- 28340252 TI - Urinary tract infection: recent insight into the evolutionary arms race between uropathogenic Escherichia coli and our immune system. AB - Urinary tract infections (UTIs) are among the most common bacterial infections worldwide. Humans evolved various immune-dependent and independent defense mechanisms, while pathogens evolved multiple virulence factors to fight back. This article summarizes recent findings regarding the arms race between hosts and pathogens in UTIs. It was recently reported that macrophage subsets regulate neutrophil-mediated defense in primary UTIs but seem to subvert adaptive immunity upon re-infection. Moreover, some bacterial strains can survive inside macrophages, leading to recurrent infections. Inflammasome activation results in infected host cell death and pathogen release, facilitating the removal of intracellular bacteria. As a counteraction, some bacteria evolved mechanisms to disrupt inflammasome activation. Mucosal-associated invariant T cells are further effectors that can lyse infected epithelial cells and release intracellular bacteria. Once released, the bacteria are phagocytosed by neutrophils. However, some bacteria can inhibit neutrophil migration and deprive neutrophils of nutrients. Furthermore, the complement system, considered generally bactericidal, is exploited by the bacteria for cellular invasion. Another weapon against UTI is antimicrobial peptides, e.g. ribonuclease 7, but its production is inhibited by certain bacterial strains. Thus the arms race in UTI is ongoing, and knowing the enemy's methods can help in developing new drugs to win the race. PMID- 28340254 TI - The unfinished issue of ischaemic stroke and embolic events during ablation for atrial fibrillation: the authors' reply. PMID- 28340255 TI - Massive Gastric Juvenile Polyposis: A Clinicopathologic Study Using SMAD4 Immunohistochemistry. AB - Objectives: Juvenile polyps involving the stomach are uncommon. Massive gastric juvenile polyposis is even rarer. Methods: We describe the clinicopathologic features of nine cases of massive gastric juvenile polyposis. Results: All patients had anemia; four had hypoalbuminemia. The polyps were composed predominantly of dilated crypts lined by columnar epithelium and abundant edematous stroma with mixed inflammatory infiltrates. One patient had a poorly differentiated adenocarcinoma, arising in juvenile polyp-associated intraepithelial neoplasia. A second patient had a well-differentiated intramucosal adenocarcinoma arising in a juvenile polyp with high-grade dysplasia. Three of our cases had polyposis restricted to the stomach. Six (66.6%) had loss of SMAD4 immunoreactivity, making them subject to severe bleeding and hypoproteinemia, as well as developing severe dysplasia or adenocarcinoma. Conclusions: SMAD4 immunohistochemstry is a helpful ancillary diagnostic test in cases of suspected juvenile polyposis syndrome involving the stomach. PMID- 28340256 TI - Sleep disturbance of adults with a brain tumor and their family caregivers: a systematic review. AB - The high incidence and psychophysiological morbidities of sleep disturbance in cancer have been increasingly recognized. Yet, more detailed understanding of sleep disturbance and options for management have been neglected areas in both clinical care and research. Brain tumor patients have been particularly overlooked. A systematic search of the literature from 1990 to 2015 was performed to review sleep disturbance in adults with primary or secondary brain tumor and their family caregivers. Fifty eligible studies were identified, of which 12 focused on sleep, 37 reported sleep items within a health-related quality of life measure and 1 reported caregivers' sleep. No sleep intervention has been developed or tested for brain tumor patients. Sleep disturbance and somnolence were frequently reported as the most severely rated symptoms within health related quality of life across the disease course or treatments, along with fatigue. However, sleep-focused studies yielded inconsistent results in small samples of mostly benign brain tumors in long-term remission from total tumor resection. The research using standardized, multifaceted sleep assessments, particularly in patients with malignant brain tumor and caregivers who are undergoing treatment, is seriously lacking. A more systematic examination of sleep disturbance is warranted to inform the development of better symptom management programs in this population. PMID- 28340257 TI - CD8-Positive T-Cell Leukoencephalitis With Astrocytopathy Clinically Presenting as Neuromyelitis Optica. AB - We describe a novel disease entity with the clinical and radiologic presentation of neuromyelitis optica (NMO) and widespread CD8-positive T-cell leukoencephalitis and astrocytopathy. The 59-year-old female patient had a complex 2-year neurological history that included early changes in cognition and memory, progressive lower extremity motor dysfunction, and multimodal sensory involvement. MRI of the spinal cord showed increased T2 signal in the central cord extending from C2 through T4. MRI of the brain showed symmetric radial enhancement in periventricular deep white matter without evidence of demyelinating lesions. The constellation of findings met clinical criteria for NMO. Steroid treatment was initiated with subjective improvement but she developed urosepsis and died at age 61 years. At autopsy, the spinal cord showed typical NMO findings but no evidence of complement deposition or neutrophil infiltration. There was diffuse CD8-positive T-cell infiltration and CD68 positive macrophage activation throughout subcortical white matter, optic chiasm, brainstem, and spinal cord. This was accompanied by marked astrocytopathy in all areas. Serum was negative for aquaporin-4 autoantibodies suggesting a nonhumoral basis of astrocyte damage. This first example of CD8-positive T-cell leukoencephalitis in a patient with a clinical presentation of NMO may explain the recalcitrance of some patients to therapies targeting humoral immunity. PMID- 28340258 TI - Hydrocodone is More Effective than Morphine or Oxycodone in Suppressing the Development of Burn-Induced Mechanical Allodynia. AB - Background: Pain is the most frequent complaint of burn-injured patients. Opioids are commonly used in the course of treatment. However, there is a lack of rodent studies that examine the differential effects of various opioids on burn pain. Objective: This study compared the ability of morphine, oxycodone, and hydrocodone to suppress the development of burn-induced mechanical allodynia and reduce pain sensitivity. Methods: Mice were examined for their baseline pain sensitivity thresholds using the von Frey Filaments test. Then, they were subjected to burn or sham injury and treated orally with morphine, oxycodone, hydrocodone (20 or 40 mg/kg), or saline twice daily throughout the study. They were retested on days 4, 7, 11, 14, 21, and 28 postburn. Results: In the sham animals, morphine produced significant opioid-induced hyperalgesia (OIH). Development of OIH was minimal for hydrocodone and was not observed for oxycodone. Secondary mechanical allodynia was observed beginning four days after the burn injury and intensified with time. All opioids produced comparable antinociceptive effects. Hydrocodone was effective in suppressing the development of burn-induced mechanical allodynia and fully treated the burn-induced increase in pain sensitivity. In contrast, morphine and oxycodone had only minimal effects on the development of burn-induced mechanical allodynia and only partially treated the burn-induced increase in pain sensitivity. Conclusions: This study demonstrated that hydrocodone is effective in suppressing the development of burn induced mechanical allodynia, while both morphine and oxycodone had minimal effects. These findings underscore the need for additional studies on the differences among various opioids using clinically relevant pain models. PMID- 28340259 TI - Sedative Prescriptions Are Common at Opioid Initiation: An Observational Study in the Veterans Health Administration. AB - Background: Concurrent use of sedatives, especially anxiolytics, and opioids is associated with increased risk of medication-related harms. To the extent that multiple prescribers are involved, approaches to influence patterns of coprescribing will differ from those to influence prescribing within a single drug class. Objectives: Describe the proportion of new opioid recipients with concurrent sedative medications at opioid initiation and determine whether these medications were prescribed by the same prescriber. Methods: We used national Department of Veterans Affairs (VA) outpatient pharmacy administration data to identify veterans who received a new opioid prescription between October 20, 2010, and September 1, 2011 (FY 2011), preceded by a 365-day opioid-free period. Concurrent sedative use was defined as a skeletal muscle relaxant, benzodiazepine, atypical antipsychotic, or hypnotic filled on the opioid start date or before and after the opioid start date with a gap of less than twice the day supply of the prior fill. Results: Concurrent sedative use at opioid initiation was 21.4% (112,408/526,499) in FY 2011. The proportion of concurrent recipients who received at least one concurrent sedative prescribed by a provider other than the opioid prescriber was 61.4% (69,002/112,408). The proportion of recipients who received a sedative concurrent with opioid initiation from the same prescriber varied across sedative class. Benzodiazepines and opioids were prescribed by the same provider in 41.1% (15,520/37,750) of concurrent users. Conclusion: One in five patients newly prescribed opioids also had a sedative prescription. Less than half of patients with concurrent opioid and benzodiazepine prescriptions received these from the same provider. Efforts to reduce concurrent opioid and sedative prescribing will require addressing care coordination. PMID- 28340260 TI - A study on natural recovery of tassel fertilization and doubling method in maize haploids. AB - Doubling method is the technical barriers in maize haploid breeding. It was very important to establish the independent intellectual property rights for doubling method. In this experiment, the maize haploid inducer, TG15, was used for producing maternal haploids. Also, haploids were obtained from two kinds of maternal genotypes involved in the experiment, including high-oil type and common type. Significant differences were observed among offspring of various genotypes in the recovery of haploid fertilization. In 21 hybrid offspring haploids, the average powder rate was 8.28%, and the seed setting rate was 4.98%. The experimental results showed that when the hybrids were treated with 0.08% colchicine, the average powder rate and seed setting rate of offspring haploids were 35.53 and 20.30%, respectively, which were significantly higher than the hybrids with natural recovery ability. This study primarily established the doubling method of haploids called "bud seedling method" in China which was very practicably in maize doubled haploid breeding. PMID- 28340261 TI - Effect of a high-concentrate diet on milk components and mammary health in Holstein dairy cows. AB - In order to evaluate the milk yield, milk quality, and health of dairy cows fed a high-concentrate (HC) diet, eight lactating Holstein dairy cattle were randomly assigned to HC or low-concentrate (LC) diet groups and fed for 50 days, and the auto-control studying before and after treatment with the two diets was used. During the experiment, plasma and milk samples were collected and measured. With regard to milk component, HC feeding led to higher milk production (P < 0.05), but significantly lower milk protein percentage (P < 0.05), milk protein yield (P < 0.05), and milk fat percentage (P < 0.05) throughout the five periods than LC feeding. Milk somatic cell count and N-acetyl-D-glucosaminidase activity (P < 0.01) were higher than those observed under LC feeding. mRNA expression levels of interleukin-8 (IL-8), C-C motif chemokine ligand (CCL5), and lactalbumin alpha (alpha-LA) were investigated by qPCR and found to be significantly lower (P < 0.01) in cattle fed the HC diet. The amino acid content was analyzed by high performance liquid chromatography (HPLC), and the content of Asp (P < 0.01), Gln (P < 0.01), Ala (P < 0.05), Leu (P < 0.05), Lys (P < 0.05), and Ile (P < 0.01) was significantly lower in the HC group, whereas the content of Arg (P < 0.05) and Phe (P < 0.01) was significantly higher. These results suggest that the HC diet might have an important influence on mammary health. The amino acid content was lower, suggesting that depletion of amino acids, resulting in depleted milk protein, affects milk quality. PMID- 28340262 TI - Effect of photoperiod on serum hormone concentrations during the annual reproductive cycle in geese. AB - The poor egg-laying rate of geese hinders the development of the goose industry; therefore, the reproductive performance of geese is an important area of investigation. To evaluate the relationship between photoperiod, reproductive hormones, and reproductive activity during the egg-laying cycle in geese under natural conditions, we collected blood samples from Sichuan white geese and Xupu geese to quantify changes in prolactin (PRL), estradiol (E2), vasoactive intestinal polypeptide (VIP), follicle stimulating hormone (FSH), gonadotropin inhibitory hormone (GnIH), and luteinizing hormone (LH). We also calculated the rate of egg laying for the two populations during the egg-laying cycle. We show that the egg-laying rate and the serum concentration of some hormones (PRL, E2, VIP, FSH, GnIH, and LH) differed significantly between the two populations during the pre-laying, laying, and ceased-laying periods. Serum LH concentrations may be associated with maturation of the ovary and oviducts, whereas FSH, PRL, and GnIH play important roles in egg laying. These results provide a useful resource for future studies examining the laying rate in geese. PMID- 28340263 TI - Myrciaria dubia, an Amazonian fruit: population structure and its implications for germplasm conservation and genetic improvement. AB - Myrciaria dubia (camu-camu) is an Amazon tree that produces a tart fruit with high vitamin C content. It is probably the fruit with the highest vitamin C content among all Brazilian fruit crops and it can be used to supplement daily vitamin C dose. This property has attracted the attention of consumers and, consequently, encouraged fruit farmers to produce it. In order to identify and select potential accessions for commercial exploitation and breeding programs, M. dubia has received considerable research attention. The identification and characterization of genetic diversity, as well as identification of the population structure of accessions preserved in germplasm banks are fundamental for the success of any breeding program. The objective of this study was to evaluate the genetic variability of 10 M. dubia populations obtained from the shores of Reis Lake, located in the municipality of Caracarai, Roraima, Brazil. Fourteen polymorphic inter simple sequence repeat (ISSR) markers were used to study the population genetic diversity, which resulted in 108 identified alleles. Among the 14 primers, GCV, UBC810, and UBC827 produced the highest number of alleles. The study illustrated the suitability and efficiency of ISSR markers to study the genetic diversity of M. dubia accessions. We also revealed the existence of high genetic variability among both accessions and populations that can be exploited in future breeding programs and conservation activities of this species. PMID- 28340264 TI - Identification of 19 loci for reproductive traits in a local Chinese chicken by genome-wide study. AB - Reproductive traits have long been studied and have an important influence on chicken breeding. To identify quantitative trait loci affecting reproductive traits, a genome-wide analysis of a Chinese chicken breed was performed to analyze age at first egg body weight at first egg, first egg weight, egg weight at the age of 300 days, egg weight at the age of 462 days, egg number at the age of 300 days, egg number between the ages of 300 and 462 days and egg number at the age of 462 days. Nineteen SNPs related to reproductive traits were presented (P < 1.80E-6). Nine of the 19 SNPs had a significant effect on BWF, six SNPs were significantly associated with egg weight, and four SNPs were significantly associated with egg number. These SNPs were located near to or in 17 genes including FAM184B, HTT, KCNH7, CDC42BPA, KCNIP4, GJA5, CBFB, and GPC6. The present results may be beneficial for reproductive research and may be used in marker-assisted selection in future studies. These results could potentially benefit further breeding programs, especially in Jinghai Yellow Chicken. PMID- 28340265 TI - Association of RUNX2 and TNFSF11 genes with production traits in a paternal broiler line. AB - Intense selection for production traits has improved the genetic gain of important economic traits. However, selection for performance and carcass traits has led to the onset of locomotors problems and decreasing bone strength in broilers. Thus, genes associated with bone integrity traits have become candidates for genetic studies in order to reduce the impact of bone disorders in broilers. This study investigated the association of the RUNX2 and TNFSF11 genes with 79 traits related to performance, carcass composition, organs, and bone integrity in a paternal broiler line. Analyses of genetic association between single-nucleotide polymorphisms (SNPs) and traits were carried out using the maximum likelihood procedures for mixed models. Genetic associations (P < 0.05) were found between SNP g.124,883A>G in the RUNX2 gene and chilled femur weight (additive plus dominance deviation effects within sex) and with performance traits (additive within sex and additive effects). The SNP g.14,862T>C in the TNFSF11 gene presented genetic associations (P < 0.05) with additive plus dominance deviation effects within sex for performance traits. Suggestive genetic associations (P < 0.10) were found with abdominal fat and its yield. Selection based on SNPs g.14,862T>C in TNFSF11 and g.124,883A>G in RUNX2 could be used to improve performance and carcass quality traits in the population studied, although SNP g.14,862T>C was not in Hardy-Weinberg equilibrium because it was not undergoing a selection process. Furthermore, it is important to validate these markers in an unrelated population for use in the selection process. PMID- 28340266 TI - RNA-Seq-based transcriptome and the reproduction-related genes for the aphid Schlechtendalia chinensis (Hemiptera, Aphididae). AB - Chinese galls form on sumac plants (Rhus chinensis) and are used for medicinal and chemical purposes, due to their richness in tannins. The galls are formed by aphids, the most prominent of which is Schlechtendalia chinensis, which forms horn-shaped galls on the winged rachis of R. chinensis. S. chinensis has a complex life cycle, including both R. chinensis and certain mosses as hosts, as well as the existence of both sexual and asexual reproduction (cyclical parthenogenesis). Previous studies have shown that the alternate occurrence of sexual and asexual reproduction relies on many environmental factors, such as temperature, photoperiod, and host-plant. However, the sexual and asexual modes of reproduction are poorly understood on the molecular level. We aimed to identify genes that respond to changes in temperature that may be related to the reproduction process. We compared the transcriptome of two samples of S. chinensis, which had been reared at different temperatures. Using gene ontology analysis, a total of 51 evolutionary conserved genes related to reproduction determination in insects were identified. Of these genes, S. chinensis harbors 42 genes. When we analyzed aphids that had asexually or sexually produced offspring, eight out of these 42 genes were identified and expressed differently in two temperature conditions. This is the first report on genes associated with reproduction determination in S. chinensis, which has a complex life cycle. Genes, expressed differently in response to different temperature conditions will be helpful to understand the mechanism of aphid reproductive determination. PMID- 28340267 TI - Digital phenotyping for quantification of genetic diversity in inbred guava (Psidium guajava) families. AB - Digital image analysis of seeds has been used for the identification of cultivars, determination of seed color and mechanical damage, and classification of different seed sizes. The aim of the present study was to evaluate the efficiency of digital image analysis of seeds for the quantification of genetic diversity among genotypes of inbred guava (Psidium guajava L.) families. The SAS Mini equipment, which consists of a capture module and a software program for analysis, was employed for the capture and analysis of the seed images. Different genetic diversity quantification strategies were tested using the Ward-Modified Location Model method. The set of variables related to geometry of the seeds was the largest contributor to divergence among the guava genotypes. The use of seed descriptors obtained by digital image analysis via the SAS system was efficient at quantifying the genetic diversity among genotypes of inbred guava families associated with the use of the Ward-Modified Location Model method. PMID- 28340268 TI - Is differential expression of p16INK4a based on the classification of uterine smooth muscle tumors associated with a different prognosis? A meta-analysis. AB - We conducted a meta-analysis to examine p16INK4a expression in uterine smooth muscle tumors (USMTs). Although the prognostic value of tumor suppressor p16INK4a has been elucidated in a variety of cancers and precancerous lesions, its role in USMTs is not well established. We searched PubMed, Web of Science, and Embase for publication son p16INK4a expression in USMTs. Strict inclusion and exclusion criteria were imposed. Risk ratios (RRs) with 95% confidence intervals (95%CIs) were calculated to assess the strength of association. Publication bias was estimated using funnel plots and the Egger's regression test. Twelve eligible studies comprising 661 patients were included. Compared with leiomyoma (LM), the figures for the strength of association were as follows: LM variants (RR = 1.53, 95%CI = 1.03-2.27, P = 0.036, random effect); leiomyosarcoma (LMS) (RR = 3.20, 95%CI = 1.68-6.12, P < 0.001, random effect); and smooth muscle tumors of uncertain malignant potential (STUMP) (RR = 2.90, 95%CI = 1.17-7.21, P = 0.022, random effect). p16INK4a expression was significantly higher in LMS than in LM variants (RR = 3.74, 95%CI = 1.96-7.13, P < 0.001, random effect) or STUMP (RR = 1.67, 95%CI = 1.26-2.23, P < 0.001, fixed effect). There was a significant correlation between overexpressed p16INK4a and recurrence rates of USMTs (RR = 1.85, 95%CI = 1.11-3.10, P = 0.019, fixed effect). p16INK4a over expression is a potential biomarker for diagnosing problematic USMTs and it might indicate a worse prognosis. However, there is currently insufficient evidence to assess the prognostic value of p16INK4a in USMTs. PMID- 28340269 TI - Prevention of DNA damage and anticarcinogenic activity of Activia(r) in a preclinical model. AB - Colorectal cancer is a global public health issue. Studies have pointed to the protective effect of probiotics on colorectal carcinogenesis. Activia(r) is a lacto probiotic product that is widely consumed all over the world and its beneficial properties are related, mainly, to the lineage of traditional yoghurt bacteria combined with a specific bacillus, DanRegularis, which gives the product a proven capacity to intestinal regulation in humans. The aim of this study was to evaluate the antigenotoxic, antimutagenic, and anticarcinogenic proprieties of the Activia product, in response to damage caused by 1,2-dimethylhydrazine (DMH) in Swiss mice. Activia does not have shown antigenotoxic activity. However, the percent of DNA damage reduction, evaluated by the antimutagenicity assay, ranged from 69.23 to 96.15% indicating effective chemopreventive action. Activia reduced up to 79.82% the induction of aberrant crypt foci by DMH. Facing the results, it is inferred that Activia facilitates the weight loss, prevents DNA damage and pre cancerous lesions in the intestinal mucosa. PMID- 28340270 TI - Genetic progress estimation strategy for upright common bean plants using recurrent selection. AB - Common bean producers in Brazil tend to grow plants as upright as possible. Because the control of this trait involves a large number of genes, recurrent selection (RS) is the best approach for successful plant improvement. Because plant architecture (PA) is evaluated using scores and usually has high heritability, RS for PA is performed through visual selection in generation S0. The aim of the present study was to evaluate selection progress and investigate whether this progress varies with the number of selected progenies or the generation evaluated. In addition, the effect of RS for the upright (PA) trait on progeny grain yield (GY) was investigated. Data of progenies S0:3 and S0:4 of the fifth, eighth, and twelfth cycles were used. A combined analysis of variance was performed using the adjusted means of the 47 best progenies from each generation and cycle, using two control cultivars as reference. A joint analysis of the two generations used during the evaluation of progenies for the different cycles was also performed. The genetic progress (GP) was estimated by fitting a linear regression equation to the relationship between the adjusted mean of each cycle and the number of cycles. We found that RS was efficient and the estimated GP of the evaluated progenies was 4.5%. Based on the GY heritability estimates, in more advanced generation selection for GY can be successfully performed on progenies. Thus, the selection already done for PA in F2 could be associated to the most productive progenies. PMID- 28340272 TI - REML/BLUP and sequential path analysis in estimating genotypic values and interrelationships among simple maize grain yield-related traits. AB - Methodologies using restricted maximum likelihood/best linear unbiased prediction (REML/BLUP) in combination with sequential path analysis in maize are still limited in the literature. Therefore, the aims of this study were: i) to use REML/BLUP-based procedures in order to estimate variance components, genetic parameters, and genotypic values of simple maize hybrids, and ii) to fit stepwise regressions considering genotypic values to form a path diagram with multi-order predictors and minimum multicollinearity that explains the relationships of cause and effect among grain yield-related traits. Fifteen commercial simple maize hybrids were evaluated in multi-environment trials in a randomized complete block design with four replications. The environmental variance (78.80%) and genotype vs-environment variance (20.83%) accounted for more than 99% of the phenotypic variance of grain yield, which difficult the direct selection of breeders for this trait. The sequential path analysis model allowed the selection of traits with high explanatory power and minimum multicollinearity, resulting in models with elevated fit (R2 > 0.9 and epsilon < 0.3). The number of kernels per ear (NKE) and thousand-kernel weight (TKW) are the traits with the largest direct effects on grain yield (r = 0.66 and 0.73, respectively). The high accuracy of selection (0.86 and 0.89) associated with the high heritability of the average (0.732 and 0.794) for NKE and TKW, respectively, indicated good reliability and prospects of success in the indirect selection of hybrids with high-yield potential through these traits. The negative direct effect of NKE on TKW (r = 0.856), however, must be considered. The joint use of mixed models and sequential path analysis is effective in the evaluation of maize-breeding trials. PMID- 28340271 TI - SNP detection using RNA-sequences of candidate genes associated with puberty in cattle. AB - Fertility traits, such as heifer pregnancy, are economically important in cattle production systems, and are therefore, used in genetic selection programs. The aim of this study was to identify single nucleotide polymorphisms (SNPs) using RNA-sequencing (RNA-Seq) data from ovary, uterus, endometrium, pituitary gland, hypothalamus, liver, longissimus dorsi muscle, and adipose tissue in 62 candidate genes associated with heifer puberty in cattle. RNA-Seq reads were assembled to the bovine reference genome (UMD 3.1.1) and analyzed in five cattle breeds; Brangus, Brahman, Nellore, Angus, and Holstein. Two approaches used the Brangus data for SNP discovery 1) pooling all samples, and 2) within each individual sample. These approaches revealed 1157 SNPs. These were compared with those identified in the pooled samples of the other breeds. Overall, 172 SNPs within 13 genes (CPNE5, FAM19A4, FOXN4, KLF1, LOC777593, MGC157266, NEBL, NRXN3, PEPT-1, PPP3CA, SCG5, TSG101, and TSHR) were concordant in the five breeds. Using Ensembl's Variant Effector Predictor, we determined that 12% of SNPs were in exons (71% synonymous, 29% nonsynonymous), 1% were in untranslated regions (UTRs), 86% were in introns, and 1% were in intergenic regions. Since these SNPs were discovered in RNA, the variants were predicted to be within exons or UTRs. Overall, 160 novel transcripts in 42 candidate genes and five novel genes overlapping five candidate genes were observed. In conclusion, 1157 SNPs were identified in 62 candidate genes associated with puberty in Brangus cattle, of which, 172 were concordant in the five cattle breeds. Novel transcripts and genes were also identified. PMID- 28340273 TI - Genetic diversity and selection of common bean lines based on technological quality and biofortification. AB - The development of common bean cultivars with high technological quality that are biofortified with minerals, is required to meet the demand for food with health benefits. The objectives of this study were to evaluate whether common bean genotypes differ in terms of technological and mineral biofortification traits, to study the correlations between these characters, to analyze the genetic dissimilarity of common bean genotypes, and to select superior lines for these traits. For this, 14 common bean genotypes were evaluated in experiments conducted in three growing seasons in the Rio Grande do Sul State, Brazil. A significant genotype x environment interaction was observed for technological quality (mass of 100 grains and cooking time) and biofortification traits (concentration of potassium, phosphorus, calcium, iron, zinc, and copper). Positive correlation estimates were obtained between phosphorus and potassium (r = 0.575), iron and zinc (r = 0.641), copper and iron (r = 0.729), and copper and phosphorus (r = 0.533). In the main component cluster analysis, four groups of genotypes were formed. The following lines are recommended for selection: LP 11 363 for fast-cooking, CNFC 11 948 for high iron concentration, and LEC 03-14 for high potassium, phosphorus, and calcium concentrations in grains. Common bean lines with high phosphorus and iron concentrations in grains can be indirectly selected based on higher potassium, copper, and zinc concentrations. Controlled crossings between LP 11-363 x CNFC 11 948 and LP 11-363 x LEC 03-14 are recommended to obtain segregating lines that are fast-cooking and biofortified with minerals. PMID- 28340274 TI - Regularized quantile regression applied to genome-enabled prediction of quantitative traits. AB - Genomic selection (GS) is a variant of marker-assisted selection, in which genetic markers covering the whole genome predict individual genetic merits for breeding. GS increases the accuracy of breeding values (BV) prediction. Although a variety of statistical models have been proposed to estimate BV in GS, few methodologies have examined statistical challenges based on non-normal phenotypic distributions, e.g., skewed distributions. Traditional GS models estimate changes in the phenotype distribution mean, i.e., the function is defined for the expected value of trait-conditional on markers, E(Y|X). We proposed an approach based on regularized quantile regression (RQR) for GS to improve the estimation of marker effects and the consequent genomic estimated BV (GEBV). The RQR model is based on conditional quantiles, Qtau(Y|X), enabling models that fit all portions of a trait probability distribution. This allows RQR to choose one quantile function that "best" represents the relationship between the dependent and independent variables. Data were simulated for 1000 individuals. The genome included 1500 markers; most had a small effect and only a few markers with a sizable effect were simulated. We evaluated three scenarios according to symmetrical, positively, and negatively skewed distributions. Analyses were performed using Bayesian LASSO (BLASSO) and RQR considering three quantiles (0.25, 0.50, and 0.75). The use of RQR to estimate GEBV was efficient; the RQR method achieved better results than BLASSO, at least for one quantile model fit for all evaluated scenarios. The gains in relation to BLASSO were 86.28 and 55.70% for positively and negatively skewed distributions, respectively. PMID- 28340275 TI - Mini tomato genotypes resistant to the silverleaf whitefly and to two-spotted spider mites. AB - The mini tomato production has expanded, becoming an amazing alternative for enterprise. Despite all commercial potential, the cultivation has the occurrence of pests as main obstacle during the crop development. Nowadays, there are no researches that aimed obtaining genotypes with high acylsugar content, capable of providing a broad-spectrum resistance to pests. This study aimed the selection of mini tomato genotypes, with high acylsugar content, and checking the resistance level to the silverleaf whitefly [Bemisia tabaci (Gennadius)] and to the two spotted spider mites (Tetranychus urticae Koch). Sixteen genotypes were evaluated, from which 12 were on the generation F2BC1, originated from the interespecific cross between Solanum pennellii versus Solanum lycopersicum L. and 4 were check treatments, being three of cultivated tomatos (cv. Santa Clara, UFU 02, and UFU-73) and the wild accession LA-716 (S. pennellii). The variables analyzed were acylsugar content, repellency to the silverleaf whitefly, repellence to the two-spotted spider mites, and density of glandular trichomes. The genotypes UFU-22-F2BC1#9 and UFU-73-F2BC1#11 have high acylsugar content and both are resistant to the pests that were evaluated. New studies must be conducted seeking for inbred lines, obtained from the selected genotypes, aiming to get commercial hybrids with high acylsugar content. PMID- 28340276 TI - Multivariate diallel analysis allows multiple gains in segregating populations for agronomic traits in Jatropha. AB - Jatropha is research target worldwide aimed at large-scale oil production for biodiesel and bio-kerosene. Its production potential is among 1200 and 1500 kg/ha of oil after the 4th year. This study aimed to estimate combining ability of Jatropha genotypes by multivariate diallel analysis to select parents and crosses that allow gains in important agronomic traits. We performed crosses in diallel complete genetic design (3 x 3) arranged in blocks with five replications and three plants per plot. The following traits were evaluated: plant height, stem diameter, canopy projection between rows, canopy projection on the line, number of branches, mass of hundred grains, and grain yield. Data were submitted to univariate and multivariate diallel analysis. Genotypes 107 and 190 can be used in crosses for establishing a base population of Jatropha, since it has favorable alleles for increasing the mass of hundred grains and grain yield and reducing the plant height. The cross 190 x 107 is the most promising to perform the selection of superior genotypes for the simultaneous breeding of these traits. PMID- 28340277 TI - Immunomodulatory and neuroprotective effect of cryopreserved allogeneic mesenchymal stem cells on spinal cord injury in rats. AB - This study aimed to evaluate the immunomodulatory and neuroprotective effects of allogeneic and cryopreserved mesenchymal stem cells (MSCs) on spinal cord injury. A total of 120 rats were distributed into the following groups: negative control (NC) - without injury, positive control (PC) - with injury without treatment, and group treated with MSC (GMSC) - with injury and treated. Motor function was evaluated by the BBB test at 24, 48, and 72 h and at 8 and 21 postoperative days. Spinal cords were evaluated by histopathology and immunohistochemistry to determine the expression of CD68, NeuN, and GFAP. IL-10, TNF-alpha, IL-1beta, TGF beta, BDNF, GDNF, and VEGF expression was quantified by RT-PCR. The GMSC presented higher scores for motor function at 72 h and 8 and 21 days after injury, lower expression of CD68 at 8 days, and lower expression of GFAP at 21 days compared to the PC. In addition, higher expression of NeuN and lower degeneration of the white matter occurred at 21 days. The GMSC also showed higher expression of IL-10 24 h after injury, GDNF at 48 h and 8 days, and VEGF at 21 days. Moreover, lower expression of TNF-alpha was observed at 8 and 21 days and TGF-beta at 24 h and 21 days. There were no differences in the expression of IL 1beta and BDNF between the GMSC and PC. Thus, cryopreserved MSCs promote immunomodulatory and neuroprotective effects in rats with spinal cord injury by increasing IL-10, GDNF, and VEGF expression and reducing TNF-alpha and TGF-beta expression. PMID- 28340279 TI - Corrigendum. PMID- 28340278 TI - Path analysis and canonical correlations for indirect selection of Jatropha genotypes with higher oil yield. AB - Jatropha is a species with great potential for biodiesel production, and the knowledge on how the main agronomic traits are correlated will contribute to its improvement. Therefore, the objectives of this study were to estimate the genetic parameters of the traits: plant height at 12 and 40 months, canopy projection on the row at 12 and 40 months, canopy projection between the row at 12 and 40 months, number of branches at 40 months, grain yield, and oil yield; to verify the existence of phenotypic correlation between these traits; to verify the influence of the morphological traits on oil yield by means of path analysis; and to evaluate the relationship between the productive traits in Jatropha and the morphological traits measured at different ages. Sixty-seven half-sib families were evaluated using a completely randomized block design with two replications and five plants per plot. Analysis of variance was used to estimate the genetic value. Phenotypic correlations were given by the Pearson correlation between traits. For the canonical correlation analysis, two groups of traits were established: group I, consisting of traits of economic importance for the culture, and group II, consisting of morphological traits. Path analysis was carried out considering oil yield as the main dependent variable. Genetic variability was observed among Jatropha families. Productive traits can be indirectly selected via morphological traits due to the correlation between these two groups of traits. Therefore, canonical correlations and path analysis are two strategies that may be useful in Jatropha-breeding program when the objective is to select productive traits via morphological traits. PMID- 28340280 TI - Gap junctions in epilepsy: for better or worse. PMID- 28340281 TI - High ten-year remission rates following rituximab, fludarabine, mitoxantrone and dexamethasone (R-FND) with interferon maintenance in indolent lymphoma: Results of a randomized Study. AB - We report a single-centre, randomized study evaluating the efficacy and safety of concurrent fludarabine, mitoxantrone, dexamethasone (FND) and rituximab versus sequential FND followed by rituximab in 158 patients with advanced stage, previously untreated indolent lymphoma, enrolled between 1997 and 2002. Patients were randomized to 6-8 cycles of FND followed by 6 monthly doses of rituximab or 6 doses of rituximab given concurrently with FND. All patients who achieved at least a partial response received 12 months of interferon (IFN) maintenance. Median ages were 54 and 55 years. The two groups were comparable with the exception of a higher percentage of females (65% vs. 43%) and baseline anaemia (23% vs. 11%) in the FND followed by rituximab group. Complete response/unconfirmed complete response rates were 89% and 93%. The most frequent grade >= 3 toxicity was neutropenia (86% vs. 96%). Neutropenic fever occurred in 21% and 16%. Late toxicity included myelodysplastic syndrome (n = 3) and acute myeloid leukaemia (n = 5). With 12.5 years of follow-up, no significant differences based on treatment schedule were observed. 10-year overall survival estimates were 76% and 73%. 10-year progression-free survival estimates were 52% and 51%. FND with concurrent or sequential rituximab, and IFN maintenance in indolent lymphoma demonstrated high response rates and robust survival. PMID- 28340282 TI - Carfilzomib induces leukaemia cell apoptosis via inhibiting ELK1/KIAA1524 (Elk 1/CIP2A) and activating PP2A not related to proteasome inhibition. AB - Enhancing the tumour suppressive activity of protein phosphatase 2A (PP2A) has been suggested to be an anti-leukaemic strategy. KIAA1524 (also termed CIP2A), an oncoprotein inhibiting PP2A, is associated with disease progression in chronic myeloid leukaemia and may be prognostic in cytogenetically normal acute myeloid leukaemia. Here we demonstrated that the selective proteasome inhibitor, carfilzomib, induced apoptosis in sensitive primary leukaemia cells and in sensitive leukaemia cell lines, associated with KIAA1524 protein downregulation, increased PP2A activity and decreased p-Akt, but not with the proteasome inhibition effect of carfilzomib. Ectopic expression of KIAA1524, or pretreatment with the PP2A inhibitor, okadaic acid, suppressed carfilzomib-induced apoptosis and KIAA1524 downregulation in sensitive cells, whereas co-treatment with the PP2A agonist, forskolin, enhanced carfilzomib-induced apoptosis in resistant cells. Mechanistically, carfilzomib affected KIAA1524 transcription through disturbing ELK1 (Elk-1) binding to the KIAA1524 promoter. Moreover, the drug sensitivity and mechanism of carfilzomib in xenograft mouse models correlated well with the effects of carfilzomib on KIAA1524 and p-Akt expression, as well as PP2A activity. Our data disclosed a novel drug mechanism of carfilzomib in leukaemia cells and suggests the potential therapeutic implication of KIAA1524 in leukaemia treatment. PMID- 28340284 TI - Quality of life and paediatric stroke: the shadows of things that may be. PMID- 28340283 TI - Comparative analysis of pulmonary hypertension in patients treated with imatinib, nilotinib and dasatinib. AB - Pulmonary hypertension (PH) is a rare, but life-threatening, adverse event in patients treated with tyrosine kinase inhibitors (TKIs), such as dasatinib, but has not been fully evaluated in patients treated with imatinib or nilotinib. We used echocardiography to noninvasively assess the incidence of PH in 105 patients with chronic myeloid leukaemia (CML) treated with imatinib (n = 37), nilotinib (n = 30) or dasatinib (n = 38). The mean triscupid regurgitation peak gradient (TRPG), which reflects pulmonary arterial pressure, was 22.7 mmHg in the imatinib group, 23.1 mmHg in the nilotinib group and 23.4 mmHg for dasatinib group. These values were not significantly different, but higher than those (19.0 mmHg) in newly diagnosed CML patients. A TRPG > 31 mmHg, marking possible PH onset, was detected in 9 of 105 patients: one (2.7%) treated with imatinib, three (10.0%) with nilotinib and five (13.2%) with dasatinib. Only three patients complained of dyspnoea, whereas the other six were asymptomatic. In addition, there was a tendency toward correlation of TRPG value and age or TKI treatment duration. These results suggested that treatment with not only dasatinib, but also imatinib and nilotinib, can be associated with subclinical PH. Noninvasive echocardiography is useful for screening, especially in older patients with long term TKI treatment. PMID- 28340285 TI - The six-minute walk test in patients with AL amyloidosis: a single centre case series. AB - The six-minute walk test (6MWT) has been widely used as an objective evaluation of functional exercise capacity and response to medical intervention in cardiopulmonary diseases. However, little is known about the 6MWT in evaluating patients with AL amyloidosis. We performed a retrospective study of 120 adults with systemic AL amyloidosis (60 with cardiac involvement and 60 without cardiac involvement) who had their initial evaluation at the Amyloidosis Center between 2013 and 2015 and had undergone 6MWT as a measure of functional exercise capacity. Forty-seven patients with cardiac involvement and 41 patients without cardiac involvement were included in the final analysis. The six-minute walk distances (6MWD) were 368 +/- 105 m and 420 +/- 116 m (mean +/- SD), respectively (P = 0.03). Among AL amyloidosis patients with cardiac involvement, the 6MWD was associated with New York Heart Association class (P < 0.001), B-type natriuretic peptide (P = 0.003) and overall survival (hazard ratio 0.381, 95% confidence interval 0.215-0.676, P = 0.001). In conclusion, the 6MWT is a valuable tool in assessing functional exercise capacity in patients with AL amyloidosis. PMID- 28340286 TI - Bringing the world of child neurology together. PMID- 28340288 TI - Erratum. PMID- 28340289 TI - Remote ischaemic conditioning decreases blood flow and improves oxygen extraction in patients with early complex regional pain syndrome. AB - BACKGROUND: Remote ischaemic conditioning (RIC) is the cyclic application of non damaging ischaemia leading to an increased tissue perfusion, among others triggered by NO (monoxide). Complex regional pain syndrome (CRPS) is known to have vascular alterations such as increased blood shunting and decreased NO blood levels, which in turn lead to decreased tissue perfusion. We therefore hypothesized that RIC could improve tissue perfusion in CRPS. METHOD: In this proof-of-concept study, RIC was applied in the following groups: in 21 patients with early CRPS with a clinical history less than a year, in 20 age/sex-matched controls and in 12 patients with unilateral nerve lesions via a tourniquet on the unaffected/non-dominant upper limb. Blood flow and tissue oxygen saturation (StO2 ) were assessed before, during and after RIC via laser Doppler and tissue spectroscopy on the affected extremity. The oxygen extraction fraction was calculated. RESULTS: After RIC, blood flow declined in CRPS (p < 0.01). StO2 decreased in CRPS and healthy controls (p < 0.01). Only in CRPS, the oxygen extraction fraction correlated negatively with the decreasing blood flow (p < 0.05). CONCLUSION: Contrary to our expectations, RIC induced a decrease of blood flow in CRPS, which led to a revised hypothesis: the decrease of blood flow might be due to an anti-inflammatory effect that attenuates vascular disturbances and reduces blood shunting, thus improving oxygen extraction. Further studies could determine whether a repeated application of RIC leads to a reduced hypoxia in chronic CRPS. SIGNIFICANCE: Remote ischaemic conditioning leads to a decrease of blood flow. This decrease inversely correlates with the oxygen extraction in patients with CRPS. PMID- 28340290 TI - Nucleus accumbens dopamine receptors mediate hypothalamus-induced antinociception in the rat formalin test. AB - BACKGROUND: Lateral hypothalamus (LH) involves in modulation of tonic pain. Regarding the direct and indirect neural connections between the LH and nucleus accumbens (NAc), we aimed to examine the pain modulatory role of NAc dopamine receptors in modulation of LH-induced analgesia in the formalin test. METHODS: Vehicle-control groups received saline or DMSO into the NAc and saline into the LH. Carbachol-control groups received carbachol (250 nmol/L) into the LH, 5 min after saline or DMSO injection into the NAc. In treatment groups, intra-NAc administration of SCH-23390 or sulpiride (D1-and D2-like dopamine receptor antagonists, respectively) was performed 5 min before carbachol injection. Formalin test was done in all rats 5 min after the second injection. RESULTS: The blockade of NAc dopamine receptors reduced carbachol-induced antinociception during both phases of formalin test and reduction in LH-induced analgesia during the late phase was more than that during the early phase. Furthermore, contribution of D2-like dopamine receptors to mediation of anti-hyperalgesic effect of carbachol was greater than that of D1-like dopamine receptors during the late phase. CONCLUSIONS: The findings suggest that LH-VTA-NAc circuit is contributed to the modulation of formalin-induced pain. These findings demonstrate that transmission at D1- and D2-like dopamine receptors mediates the LH-induced analgesia. SIGNIFICANCE: Blockade of accumbal dopamine receptors attenuated analgesia induced by carbachol injection into the lateral hypothalamus during both phases of formalin test. Effect of blockade of D1- and D2-like dopamine receptors on reduction in antinociception was more during the late phase. Contribution of D2-like dopamine receptors to mediation of antinociception during the late phase was greater than the early phase. PMID- 28340291 TI - Head-to-Head Prenyl Synthases in Pathogenic Bacteria. AB - Many organisms contain head-to-head isoprenoid synthases; we investigated three such types of enzymes from the pathogens Neisseria meningitidis, Neisseria gonorrhoeae, and Enterococcus hirae. The E. hirae enzyme was found to produce dehydrosqualene, and we solved an inhibitor-bound structure that revealed a fold similar to that of CrtM from Staphylococcus aureus. In contrast, the homologous proteins from Neisseria spp. carried out only the first half of the reaction, yielding presqualene diphosphate (PSPP). Based on product analyses, bioinformatics, and mutagenesis, we concluded that the Neisseria proteins were HpnDs (PSPP synthases). The differences in chemical reactivity to CrtM were due, at least in part, to the presence of a PSPP-stabilizing arginine in the HpnDs, decreasing the rate of dehydrosqualene biosynthesis. These results show that not only S. aureus but also other bacterial pathogens contain head-to-head prenyl synthases, although their biological functions remain to be elucidated. PMID- 28340293 TI - Functional Paper-Based Platform for Rapid Capture and Detection of CeO2 Nanoparticles. AB - Development of systems for capture, sequestration, and tracking of nanoparticles (NPs) is becoming a significant focus in many aspects of nanotechnology and environmental research. These systems enable a broad range of applications for evaluating concentration, distribution, and effects of NPs for environmental, clinical, epidemiological, and occupational exposure studies. Herein, we describe the first example of a ligand-graft multifunctional platform for capture and detection of cerium oxide (CeO2 or ceria) NPs. The approach involves the use of redox-active ligands containing o-dihydroxy functionality, enabling multivalent binding, surface retention, and formation of charge transfer complexes between the grafted ligand and the NPs. Using this strategy, paper-based and microarray printed platforms with NP-capture ability involving either catechol or ascorbic acid as ligands were successfully fabricated. Surface modification was determined by infrared spectroscopy, electron microscopy, X-ray spectroscopy, and thermogravimetric analysis. Functionality was demonstrated for the rapid assessment of NPs in chemical mechanical planarization (CMP) slurries and CMP wastewaters. This novel approach can enable further development of devices and separation technologies including platforms for retention and separation of NPs and measurement tools for detection of NPs in various environments. PMID- 28340292 TI - Combined spiroergometry and 31 P-MRS of human calf muscle during high-intensity exercise. AB - Simultaneous measurements of pulmonary oxygen consumption (VO2 ), carbon dioxide exhalation (VCO2 ) and phosphorus magnetic resonance spectroscopy (31 P-MRS) are valuable in physiological studies to evaluate muscle metabolism during specific loads. Therefore, the aim of this study was to adapt a commercially available spirometric device to enable measurements of VO2 and VCO2 whilst simultaneously performing 31 P-MRS at 3 T. Volunteers performed intense plantar flexion of their right calf muscle inside the MR scanner against a pneumatic MR-compatible pedal ergometer. The use of a non-magnetic pneumotachograph and extension of the sampling line from 3 m to 5 m to place the spirometric device outside the MR scanner room did not affect adversely the measurements of VO2 and VCO2 . Response and delay times increased, on average, by at most 0.05 s and 0.79 s, respectively. Overall, we were able to demonstrate a feasible ventilation response (VO2 = 1.05 +/- 0.31 L/min; VCO2 = 1.11 +/- 0.33 L/min) during the exercise of a single calf muscle, as well as a good correlation between local energy metabolism and muscular acidification (tauPCr fast and pH; R2 = 0.73, p < 0.005) and global respiration (tauPCr fast and VO2 ; R2 = 0.55, p = 0.01). This provides improved insights into aerobic and anaerobic energy supply during strong muscular performances. PMID- 28340294 TI - A Well-Defined Osmium-Cupin Complex: Hyperstable Artificial Osmium Peroxygenase. AB - Thermally stable TM1459 cupin superfamily protein from Thermotoga maritima was repurposed as an osmium (Os) peroxygenase by metal-substitution strategy employing the metal-binding promiscuity. This novel artificial metalloenzyme bears a datively bound Os ion supported by the 4-histidine motif. The well defined Os center is responsible for not only the catalytic activity but also the thermodynamic stability of the protein folding, leading to the robust biocatalyst (Tm ~ 120 degrees C). The spectroscopic analysis and atomic resolution X-ray crystal structures of Os-bound TM1459 revealed two types of donor sets to Os center with octahedral coordination geometry. One includes trans-dioxide, OH, and mer-three histidine imidazoles (O3N3 donor set), whereas another one has four histidine imidazoles plus OH and water molecule in a cis position (O2N4 donor set). The Os-bound TM1459 having the latter donor set (O2N4 donor set) was evaluated as a peroxygenase, which was able to catalyze cis-dihydroxylation of several alkenes efficiently. With the low catalyst loading (0.01% mol), up to 9100 turnover number was achieved for the dihydroxylation of 2-methoxy-6-vinyl naphthalene (50 mM) using an equivalent of H2O2 as oxidant at 70 degrees C for 12 h. When octene isomers were dihydroxylated in a preparative scale for 5 h (2% mol cat.), the terminal alkene octene isomers was converted to the corresponding diols in a higher yield as compared with the internal alkenes. The result indicates that the protein scaffold can control the regioselectivity by the steric hindrance. This protein scaffold enhances the efficiency of the reaction by suppressing disproportionation of H2O2 on Os reaction center. Moreover, upon a simple site-directed mutagenesis, the catalytic activity was enhanced by about 3 fold, indicating that Os-TM1459 is evolvable nascent osmium peroxygenase. PMID- 28340295 TI - Response of Catalase of the Mouse Primary Hepatocytes to Sodium Dodecylbenzenesulfonate and the Underlying Molecular Mechanisms. AB - This study investigated the adverse effects of sodium dodecylbenzenesulfonates (SDBS) on mouse primary hepatocytes by conducting cell viability, intracellular oxidative stress level, and catalase (CAT) activity assays. It was shown that SDBS altered CAT activities, triggered oxidative stress, and thus exhibited cytotoxicity to the hepatocytes. Both the stimulation of intracellular CAT production and the inhibition of molecular CAT activity contributed to intracellular CAT activity change. Molecular mechanisms underlying CAT activity inhibition and structural changes were explored by isothermal titration calorimetry, multispectroscopy, and molecular docking studies. SDBS binds to CAT with 8.81 +/- 0.751 sites via electrostatic forces, resulting in structural changes with alpha-helix significantly decreasing to 9.7 +/- 1.2%. SDBS could interact with HIS 74, ASN 147, and TYR 357 around the active sites as well as TRP 185, ASP 127, and GLN 167 within the substrate channel and therefore might result in the inhibition of molecular CAT activity. PMID- 28340297 TI - Atomic-Scale Snapshots of the Formation and Growth of Hollow PtNi/C Nanocatalysts. AB - Determining the formation and growth mechanism of bimetallic nanoparticles (NPs) with atomic detail is fundamental to synthesize efficient "catalysts by design". However, an understanding of the elementary steps which take place during their synthesis remains elusive. Herein, we have exploited scanning transmission electron microscopy coupled to energy-dispersive X-ray spectroscopy, operando wide angle and small-angle X-ray scattering, and electrochemistry to unveil the formation and growth mechanism of hollow PtNi/C NPs. Such NPs, composed of a PtNi shell surrounding a nanoscale void, catalyze efficiently and sustainably the oxygen reduction reaction (ORR) in an acidic electrolyte. Our step-by-step study reveals that (i) Ni-rich/C NPs form first, before being embedded in a NixByOz shell, (ii) the combined action of galvanic displacement and the nanoscale Kirkendall effect then results in the sequential formation of Ni-rich core@Pt rich/C shell and ultimately hollow PtNi/C NPs. The electrocatalytic properties for the ORR and the stability of the different synthesis intermediates were tested and structure-activity-stability relationships established both in acidic and alkaline electrolytes. Beyond its interest for the ORR electrocatalysis, this study also presents a methodology that is capable to unravel the formation and growth mechanism of various nanomaterials including preferentially shaped metal NPs, core@shell NPs, onion-like NPs, Janus NPs, or a combination of several of these structures. PMID- 28340296 TI - Ultralow Surface Recombination Velocity in Passivated InGaAs/InP Nanopillars. AB - The III-V semiconductor InGaAs is a key material for photonics because it provides optical emission and absorption in the 1.55 MUm telecommunication wavelength window. However, InGaAs suffers from pronounced nonradiative effects associated with its surface states, which affect the performance of nanophotonic devices for optical interconnects, namely nanolasers and nanodetectors. This work reports the strong suppression of surface recombination of undoped InGaAs/InP nanostructured semiconductor pillars using a combination of ammonium sulfide, (NH4)2S, chemical treatment and silicon oxide, SiOx, coating. An 80-fold enhancement in the photoluminescence (PL) intensity of submicrometer pillars at a wavelength of 1550 nm is observed as compared with the unpassivated nanopillars. The PL decay time of ~0.3 MUm wide square nanopillars is dramatically increased from ~100 ps to ~25 ns after sulfur treatment and SiOx coating. The extremely long lifetimes reported here, to our knowledge the highest reported to date for undoped InGaAs nanostructures, are associated with a record-low surface recombination velocity of ~260 cm/s. We also conclusively show that the SiOx capping layer plays an active role in the passivation. These results are crucial for the future development of high-performance nanoscale optoelectronic devices for applications in energy-efficient data optical links, single-photon sensing, and photovoltaics. PMID- 28340298 TI - Quantum Yield of Nitrite from the Photolysis of Aqueous Nitrate above 300 nm. AB - Photolysis of nitrate (NO3-) produces reactive nitrogen and oxygen species via three different channels, forming: (1) nitrogen dioxide (NO2) and hydroxyl radical (*OH), (2) nitrite (NO2-) and oxygen atom (O(3P)), and (3) peroxynitrite (ONOO-). These photoproducts are important oxidants and reactants in surface waters, atmospheric drops, and snowpacks. While the efficiency of the first channel, to form NO2, is well documented, a large range of values have been reported for the second channel, nitrite, above 300 nm. In part, this disagreement reflects secondary chemistry that can produce or destroy nitrite. In this study, we examine factors that influence nitrite production and find that pH, nitrate concentration, and the presence of an *OH scavenger can be important. We measure an average nitrite quantum yield (Phi(NO2-)) of (1.1 +/- 0.2)% (313 nm, 50 MUM nitrate, pH >= 5), which is at the upper end of past measurements and an order of magnitude above the smallest-and most commonly cited-value reported for this channel. Nitrite production is often considered a very minor channel in nitrate photolysis, but our results indicate it is as important as the NO2 channel. In contrast, at 313 nm we observe no formation of peroxynitrite, corresponding to Phi(ONOO-) < 0.26%. PMID- 28340299 TI - Bifurcation of Regeneration and Recombination in Dye-Sensitized Solar Cells via Electronic Manipulation of Tandem Cobalt Redox Shuttles. AB - A cobalt(IV/III) redox shuttle, cobalt tris(2-(p-tolyl)pyridine), [Co(ptpy)3]+/0, was synthesized and investigated for use in dye-sensitized solar cells, DSSCs. An incredibly fast self-exchange rate constant of (9.2 +/- 3.9) * 108 M-1 s-1 was determined for [Co(ptpy)3]+/0, making it an ideal candidate for dye regeneration. To avoid fast recombination and solubility limitations, we utilized a tandem electrolyte containing [Co(ptpy)3]+/0 and cobalt tris(2,2'-bipyridine), [Co(bpy)3]3+/2+. An improved short circuit current density is achieved for DSSCs employing the tandem electrolyte, compared to electrolytes containing only [Co(bpy)3]3+/2+, consistent with superior dye regeneration expected based on predictions using Marcus theory, which is also discussed. PMID- 28340300 TI - Synthesis of 3-O-Sulfated Oligosaccharides to Understand the Relationship between Structures and Functions of Heparan Sulfate. AB - The sulfation at the 3-OH position of glucosamine is an important modification in forming structural domains for heparan sulfate to enable its biological functions. Seven 3-O-sulfotransferase isoforms in the human genome are involved in the biosynthesis of 3-O-sulfated heparan sulfate. As a rare modification present in heparan sulfate, the availability of 3-O-sulfated oligosaccharides is very limited. Here, we report the use of a chemoenzymatic synthetic approach to synthesize six 3-O-sulfated oligosaccharides, including three hexasaccharides and three octasaccharides. The synthesis was achieved by rearranging the enzymatic modification sequence to accommodate the substrate specificity of 3-O sulfotransferase 3. We studied the impact of 3-O-sulfation on the conformation of the pyranose ring of 2-O-sulfated iduronic acid using NMR, and on the correlation between ring conformation and anticoagulant activity. We identified a novel octasaccharide that interacts with antithrombin and displays anti factor Xa activity. Interestingly, the octasaccharide displays a faster clearance rate than fondaparinux, an FDA-approved pentasaccharide drug, in a rat model, making this octasaccharide a potential short-acting anticoagulant drug candidate that could reduce bleeding risk. Having access to a set of critically important 3-O-sulfated oligosaccharides offers the potential to develop new heparan sulfate-based therapeutics. PMID- 28340301 TI - Ten years of barcoding at the African Centre for DNA Barcoding. AB - The African Centre for DNA Barcoding (ACDB) was established in 2005 as part of a global initiative to accurately and rapidly survey biodiversity using short DNA sequences. The mitochondrial cytochrome c oxidase 1 gene (CO1) was rapidly adopted as the de facto barcode for animals. Following the evaluation of several candidate loci for plants, the Plant Working Group of the Consortium for the Barcoding of Life in 2009 recommended that two plastid genes, rbcLa and matK, be adopted as core DNA barcodes for terrestrial plants. To date, numerous studies continue to test the discriminatory power of these markers across various plant lineages. Over the past decade, we at the ACDB have used these core DNA barcodes to generate a barcode library for southern Africa. To date, the ACDB has contributed more than 21 000 plant barcodes and over 3000 CO1 barcodes for animals to the Barcode of Life Database (BOLD). Building upon this effort, we at the ACDB have addressed questions related to community assembly, biogeography, phylogenetic diversification, and invasion biology. Collectively, our work demonstrates the diverse applications of DNA barcoding in ecology, systematics, evolutionary biology, and conservation. PMID- 28340302 TI - Does the type of activity "break" from prolonged sitting differentially impact on postprandial blood glucose reductions? An exploratory analysis. AB - Frequent breaks in prolonged sitting are associated beneficially with glycaemic control. However, the contribution of energy expenditure to this relationship has not been well characterised. In this exploratory analysis, data from 3 laboratory trials that standardised test meals, cohort characteristics (overweight/obese, sedentary), and break frequency and duration were pooled. Higher energy expenditures of different types of breaks (standing, light- or moderate-intensity walking) were associated with lower postprandial glucose and insulin responses in a dose-dependent manner. PMID- 28340303 TI - Epidemiology and patterns of facial fractures due to road traffic accidents in Taiwan: A 15-year retrospective study. AB - OBJECTIVE: The facial region is a commonly fractured site, but the etiology varies widely by country and geographic region. To date, there are no population based studies of facial fractures in Taiwan. METHODS: We conducted a retrospective study of patients diagnosed with facial fracture and registered in the National Health Insurance Research Database of Taiwan between 1997 and 2011. The epidemiological characteristics of this cohort were analyzed, including the etiology, fracture site, associated injuries, and sex and age distributions. RESULTS: A total of 6,013 cases were identified that involved facial fractures. Most patients were male (69.8%), aged 18-29 years (35.8%), and had fractures caused by road traffic accidents (RTAs; 55.2%), particularly motorcycle accidents (31.5%). Falls increased in frequency with advancing age, reaching 23.9% among the elderly (age > 65 years). The most common sites of involvement were the malar and maxillary bones (54.0%), but nasal bone fractures were more common among those younger than 18 years. CONCLUSION: Most facial injuries in Taiwan occur in young males and typically result from RTAs, particularly involving motorcycles. However, with increasing age, there is an increase in the proportion of facial injuries due to falls. PMID- 28340304 TI - Family members' experiences of driving disruption after acquired brain injury. AB - PRIMARY OBJECTIVE: 1) To explore family members' lived experiences of driving disruption at early and later stages of the recovery continuum following acquired brain injury (ABI). 2) To describe health-related quality of life of family members of individuals with ABI who are experiencing driving disruption. RESEARCH DESIGN: Mixed methods phenomenological research approach. METHODS AND PROCEDURES: Semi-structured interviews and health-related quality of life questionnaires were conducted with 15 family members of individuals with ABI (early group: 1-12 months post-injury, n = 6; later group: >1 year post-injury, n = 9). RESULTS: Two main themes were identified: Different for everyone: how driving disruption affects families, and Making it harder: context of driving disruption. The challenges of driving disruption were reported more frequently and with a more intense focus by family members who were caring for their relative for more than 1 year post-injury. This group also reported higher caregiver strain and poorer health-related quality of life. Reduced satisfaction with life, poor mental health and affected family functioning were reported by both groups. CONCLUSIONS: Driving disruption impacts on family members and has long-lasting consequences. It is important for clinicians to work with family members to manage these challenges even years after ABI and consider individual contextual factors. PMID- 28340305 TI - The clinical application of NGS-based SNP haplotyping for PGD of Hb H disease. AB - This study investigated the usefulness of next-generation sequencing (NGS)-based single nucleotide polymorphism (SNP) haplotyping for preimplantation genetic diagnosis (PGD) of hemoglobin H (Hb H) disease. Multiple displacement amplification (MDA) was used for whole genome amplification (WGA) of biopsied trophectoderm (TE) cells. Gap-PCR and NGS-based SNP haplotyping was used to distinguish the two genotypes of -alpha3.7/alphaalpha and -SEA/alphaalpha for PGD of Hb H disease. One out of the ten blastocysts (B11) was successfully diagnosed as genotype -alpha3.7/alphaalpha by Gap-PCR, whereas the others revealed allele dropout (ADO) (B1, B2, B4, B5, B7, B8, B12, and B15) or amplification failure (B10). However, NGS-based SNP haplotyping successfully diagnosed the alpha3.7/alphaalpha and -SEA/alphaalpha genotypes from the MDA products of the biopsied TE cells. The haplotyping result showed that B4, B7, B8, B10, B11, B12, and B15 were carriers of the -alpha3.7 deletion (-alpha3.7/alphaalpha), whereas B1, B2, and B5 were carriers of the -SEA deletion (-SEA/alphaalpha). A blastocyst (B11) was transferred into the uterus in a subsequent frozen embryo transfer (FET) cycle after PGD. A healthy infant with a -alpha3.7/alphaalpha genotype weighing 2,800 g was born by cesarean section at the 38th week of gestation. This result indicates that NGS-based SNP haplotyping is a valid screening tool for the PGD of Hb H disease. PMID- 28340306 TI - The Effects of Positive End-Expiratory Pressure at Different Levels on Postoperative Respiration Parameters in Patients Undergoing Laparoscopic Cholecystectomy. AB - : Purpose/Aim of the study: We investigated the effects of different positive end expiratory pressure (PEEP) levels on postoperative respiration parameters in patients undergoing laparoscopic cholecystectomy. MATERIALS AND METHODS: One hundred and five consecutive patients were randomly divided to three groups (n = 35, for each group). Group I did not receive PEEP whereas group II received PEEP as 5 cmH2O and group III received PEEP as 8 cm H2O. Measurements with spirometer were taken 1 hour before the operation (T1) and, 1 (T2), 6 (T3), and 24 hours (T4) after extubation by an anesthetist. Forced expiratory volume (FEV1), forced vital capacity (FVC), and peak expiratory flow (PEF) were recorded. RESULTS: Group I had higher FVC values measured at T2 time point compared with other groups (p < 0.05, for both groups). There was a statistically significant difference between group I and group III in terms of the FVC values measured at T3 and T4 time points (p = 0.05 and p < 0.05, retrospectively). A statistical difference was found between group I and group II in terms of FEV1 measured at T2 time point (p < 0.05). Group I had higher FEV1 values measured at T3 and T4 time points compared to group III (p = 0.05, P<0.05; respectively). Group III had lower PEF values measured at T4 time point compared to group I and II (p < 0.05). CONCLUSIONS: We concluded that PEEP with 5 or 8 cmH2O has negative effects on lung function tests measured with spirometer during postoperative 1st, 6th, and 24th hours in patients underwent elective laparoscopic cholecystectomy. PMID- 28340307 TI - Genetic diversity analysis of Asian clam Corbicula fluminea in the Hongze Lake based on mitochondrial cytochrome b gene. AB - The Asian clam Corbicula fluminea is a small bivalve with high nutritional and medical values. However, natural resources of C. fluminea have declined in many areas of China including the Hongze Lake. In this study, 119 individuals from 10 sites of this lake and 2 outgroups were analyzed using a 456 bp mitochondrial cytochrome b (cytb) gene segment. Totally, 19 polymorphic sites were detected, which defined 16 haplotypes. Polymorphism varied among the 10 populations with those at the water inlet being more polymorphic. Most FST values among these populations were below 0.15 with the overall value of 0.060 (p < .05), meanwhile, the overall gene flow was 7.67, both of which indicated the low level of population differentiation in this lake. Neutrality test and mismatch analyses indicated that population explosion may have occurred in this lake. The results obtained in this study will provide useful information for artificial breeding and resource protection of this species in the Hongze Lake. PMID- 28340308 TI - A preliminary investigation on the effect of extracorporeal shock wave therapy as a treatment for neurogenic heterotopic ossification following traumatic brain injury. Part I: Effects on pain. AB - INTRODUCTION: Neurogenic heterotopic ossification (NHO) is a complication of a neurological injury following traumatic brain injury (TBI) and may be present around major synovial joints. It is often accompanied by severe pain, which may lead to limitation in activities of daily living. Currently, a common intervention for NHO is surgery, which has been reported to carry many additional risks. This study was designed to assess the effect of extracorporeal shock wave therapy (ESWT) on pain in patients with TBI with chronic NHO. METHODS: A series of single-case studies (n = 11) was undertaken with patients who had TBI and chronic NHO at the hip or knee. Each patient received four applications of high energy EWST delivered to the affected joint over 8 weeks. Two-weekly follow-up assessments were carried out, and final assessments were made 3 and 6 months post intervention. Pain was measured using the Faces Rating Scale, and X-rays were taken at baseline and 6-months post-intervention to physiologically measure the size of the NHO. RESULTS: The application of high-energy ESWT was associated with significant overall reduction of pain in patients with TBI and NHO (Tau-0.412, 95% confidence interval -0.672 to -0.159, p = 0.002). CONCLUSIONS: ESWT is a novel non-invasive intervention for reducing pain resulting from NHO in patients with TBI. PMID- 28340310 TI - Viruses in cystic fibrosis patients' airways. AB - Although bacteria have historically been considered to play a major role in cystic fibrosis (CF) airway damage, a strong impact of respiratory viral infections (RVI) is also now recognized. Emerging evidence confirms that respiratory viruses are associated with deterioration of pulmonary function and exacerbation and facilitation of bacterial colonization in CF patients. The aim of this review is to provide an overview of the current knowledge on respiratory viruses in CF airways, to discuss the resulting inflammation and RVI response, to determine how to detect the viruses, and to assess their clinical consequences, prevalence, and interactions with bacteria. The most predominant are Rhinoviruses (RVs), significantly associated with CF exacerbation. Molecular techniques, and especially multiplex PCR, help to diagnose viral infections, and the coming rise of metagenomics will extend knowledge of viral populations in the complex ecosystem of CF airways. Prophylaxis and vaccination are currently available only for Respiratory syncytial and Influenza virus (IV), but antiviral molecules are being tested to improve CF patients' care. All the points raised in this review highlight the importance of taking account of RVIs and their potential impact on the CF airway ecosystem. PMID- 28340309 TI - Analytical Techniques in Lipidomics: State of the Art. AB - Current studies related to lipid identification and determination, or lipidomics in biological samples, are one of the most important issues in modern bioanalytical chemistry. There are many articles dedicated to specific analytical strategies used in lipidomics in various kinds of biological samples. However, in such literature, there is a lack of articles dedicated to a comprehensive review of the actual analytical methodologies used in lipidomics. The aim of this article is to characterize the lipidomics methods used in modern bioanalysis according to the methodological point of view: (1) chromatography/separation methods, (2) spectroscopic methods and (3) mass spectrometry and also hyphenated methods. In the first part, we discussed thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), gas chromatography (GC) and capillary electrophoresis (CE). The second part includes spectroscopic techniques such as Raman spectroscopy (RS), Fourier transform infrared spectroscopy (FT-IR) and nuclear magnetic resonance (NMR). The third part is a synthetic review of mass spectrometry, matrix-assisted laser desorption/ionization (MALDI), hyphenated methods, which include liquid chromatography-mass spectrometry (LC-MS), gas chromatography-mass spectrometry (GC-MS) and also multidimensional techniques. Other aspects are the possibilities of the application of the described methods in lipidomics studies. Due to the fact that the exploration of new methods of lipidomics analysis and their applications in clinical and medical studies are still challenging for researchers working in life science, we hope that this review article will be very useful for readers. PMID- 28340311 TI - Early Clinical Efficacy Comparison Study of Gamma3 Nail, Percutaneous Compression Plate (PCCP) and Femoral Head Replacement (FHR) Treatment on Senile Unstable Intertrochanteric Fractures. AB - PURPOSE: This study aimed to analyze the early clinical efficacy of Gamma 3 nail, percutaneous compression plate (PCCP) and femoral head replacement (FHR) treatments on senile unstable intertrochanteric fractures. MATERIALS AND METHODS: Totally 116 patients were included to perform an retrospective study, which involved analysis of the operation time, intraoperative blood loss, and hemoglobin reduction on the first postoperative day compared with preoperative levels, fracture gap, neck shaft angle and tip apex distance on the first postoperative X-ray, hospital stay, time from surgery to mobilization, Harris hip scores and Barthel index six months after operation, and complications postoperative meanwhile were evaluated respectively among three groups. RESULTS: The Harris hip score and Barthel index and time from surgery to mobilization after FHR treatment were superior to another two surgical methods, but had more blood loss and greater hemoglobin reduction. The mean PCCP hemoglobin reduction was notably shorter than that of the other two groups. Gamma 3 treatment had a lower operation time and blood loss than those treated with PCCP and FHR. CONCLUSIONS: Gamma 3 and PCCP treatments are a priority for senile unstable intertrochanteric fractures if patients are in good health and perform fair activities of daily living prior to the operation, but had a significantly longer mobilization time than that in FHR. Therefore, considering the senile patients who unable to tolerate long immobilization time, FHR treatment is a considerable choice for faster recovery of independent function and achieve a good clinical efficacy as well as improve quality of life. PMID- 28340312 TI - A preliminary investigation on the effect of extracorporeal shock wave therapy as a treatment for neurogenic heterotopic ossification following traumatic brain injury. Part II: Effects on function. AB - INTRODUCTION: Neurogenic heterotopic ossification (NHO) occurs as a complication of traumatic brain injury (TBI). Management of clinically significant NHO remains variable. Complications of mature NHO include limitation of mobility. The effect of the extracorporeal shock wave therapy (ESWT) on range of motion at hip and knee, and function in patients with TBI with chronic NHO was investigated. METHODS: A series of single-case studies applying ESWT to chronic NHO at the hip or knee of 11 patients with TBI were undertaken at a rehabilitation hospital. Participants received four applications of high-energy EWST delivered to the affected hip or knee over a period of 8 weeks. Two-weekly follow- up assessments were carried out; final assessments were made 3 and 6 months post-intervention. Range of motion (ROM) and Functional Reach (FR) or Modified Functional Reach (MFR) were measured. RESULTS: Application of high-energy ESWT was associated with significant improvement in ROM (flexion) of the NHO-affected knee (Tau = 0.833, 95% CI 0.391-1.276, p = 0.002) and significant improvement of FR (Overall Tau 0.486, 95% CI 0.141-0.832, p = 0.006); no significant improvement in hip ROM or MFR. CONCLUSIONS: ESWT may improve mobility and balance of patients with TBI who have chronic NHO. PMID- 28340313 TI - Linkage between mitochondrial genome alterations, telomere length and aging population. AB - We studied telomere length (TL) and mitochondrial DNA (mtDNA) copy number variations in individuals from Latvian Caucasian population in different age groups. We showed a positive correlation between TL and mtDNA copy number in individuals of up to 90 years of age; however, this correlation was not observed in the 90-100 years age group. While TL shortened with age and mtDNA content decreased with increasing age, in this study it was observed that mtDNA copy number in nonagenarians was slightly higher than in the 60-89 years age group. The presence of heteroplasmy in the mtDNA HVS-I control region did not correlate with TL and mtDNA copy number. TL and mtDNA values also did not differ between mitochondrial haplogroups. In conclusion, while both TL and mtDNA are involved in the aging process and link between these cell components exists, nonagenarians may have differences in senescence-related pathways and systems, which may function as a protective mechanism that allows them to live longer. PMID- 28340314 TI - Ocular Manifestations in Children with Juvenile-Onset Systemic Lupus Erythematosus. AB - PURPOSE: To study the ocular manifestations of juvenile systemic lupus erythematosus (JSLE), including the ocular side-effects of the systemic medications used. METHODS: A descriptive cross-sectional study on 40 children diagnosed with JSLE was conducted. Ophthalmological and laboratory investigations as well as a calculation of the Systemic Lupus Disease Activity Index 2000 (SLEDAI-2K) were performed. RESULTS: Forty consecutive children, 32 females and 8 males, with JSLE were examined. Their mean age was 13+/-2.8 years and the mean SLEDAI-2K was 4.3+/-3.1. An abnormal Schirmer test was found in 16 patients (40%), retinal vascular changes were found in seven patients (17.5%), and one patient (2.5%) had faint posterior subcapsular cataract. CONCLUSION: Serious sight-threatening complications were not detected in our study; dry eye was the most common ocular finding, and the detected retinopathy was related to systemic hypertension and could not be correlated to either disease activity or duration. PMID- 28340315 TI - Systematic behavioural observation of executive performance after brain injury. AB - OBJECTIVE: To develop an ecologically valid measure of executive functioning (i.e. Planning and Organization, Executive Memory, Initiation, Cognitive Shifting, Impulsivity, Sustained and Directed Attention, Error Detection, Error Correction and Time Management) during a functional chocolate brownie cooking task. METHODS: In Study 1, the inter-rater reliability of a novel behavioural observation assessment method was assessed with 10 people with traumatic brain injury (TBI). In Study 2, 27 people with TBI and 16 healthy controls completed the functional task along with other measures of executive functioning to assess validity. RESULTS: Intraclass correlation coefficients for six of the nine aspects of executive functioning ranged from .54 to 1.00. Percentage agreements for the remaining aspects ranged from 70% to 90%. Significant and non significant, moderate, correlations were found between the functional cooking task and standard neuropsychological measures. The healthy control group performed better than the TBI group in six areas (d = 0.56 to 1.23). CONCLUSIONS: In this initial trial of a novel assessment method, adequate inter-rater reliability was found. The measure was associated with standard neuropsychological measures, and our healthy control group performed better than the TBI group. The measure appears to be an ecologically valid measure of executive functioning. PMID- 28340316 TI - Quality of relationship between veterans with traumatic brain injury and their family members. AB - OBJECTIVES: The quality of the relationship between patients with many illnesses and their family members has been shown to affect the well-being of both. Yet, relationship quality has not been studied in traumatic brain injury (TBI), and giving and receiving aspects have not been distinguished. The present study of veterans with TBI examined associations between relationship quality and caregiver burden, satisfaction with caregiving, and veterans' competence in interpersonal functioning, rated by veterans and family members. METHOD: In this cross-sectional study, 83 veterans and their family members were interviewed at home. Measures of quality of relationship, veterans' interpersonal competence and sociodemographics were collected for both, caregiver burden and satisfaction for family members only. RESULTS: As predicted, veteran-rated Qrel/Giving was associated with family-rated Qrel/Receiving, and veteran-rated Qrel/Receiving with family-rated Qrel/Giving. Lower caregiver burden and higher caregiving satisfaction were associated with higher Qrel/Receiving scores but not with Qrel/Giving scores. Veterans' interpersonal competence was associated with total Qrel as rated by either veterans or family members. CONCLUSIONS: Relationship quality should be included in family research in TBI, and giving and receiving aspects should be differentiated. Findings suggest that lower caregiver burden and greater satisfaction should be more achievable by increasing caregivers' sense of benefits received from the relationship. PMID- 28340317 TI - Opportunities for crash and injury reduction: A multiharm approach for crash data analysis. AB - OBJECTIVE: A multiharm approach for analyzing crash and injury data was developed for the ultimate purpose of getting a richer picture of motor vehicle crash outcomes for identifying research opportunities in crash safety. METHODS: Methods were illustrated using a retrospective analysis of 69,597 occupant cases from NASS CDS from 2005 to 2015. Occupant cases were analyzed by frequency and severity of outcome: fatality, injury by Abbreviated Injury Scale (AIS), number of cases, attributable fatality, disability, and injury costs. Comparative analysis variables included precrash scenario, impact type, and injured body region. RESULTS: Crash and injury prevention opportunities vary depending on the search parameters. For example, occupants in rear-end crash scenarios were more frequent than in any other precrash configuration, yet there were significantly more fatalities and serious injury cases in control loss, road departure, and opposite direction crashes. Fatality is most frequently associated with head and thorax injury, and disability is primarily associated with extremity injury. Costs attributed to specific body regions are more evenly distributed, dominated by injuries to the head, thorax, and extremities but with contributions from all body regions. Though AIS 3+ can be used as a single measure of harm, an analysis based on multiple measures of harm gives a much more detailed picture of the risk presented by a particular injury or set of crash conditions. CONCLUSIONS: The developed methods represent a new approach to crash data mining that is expected to be useful for the identification of research priorities and opportunities for reduction of crashes and injuries. As the pace of crash safety improvement accelerates with innovations in both active and passive safety, these techniques for combining outcome measures for insights beyond fatality and serious injury will be increasingly valuable. PMID- 28340318 TI - Is there a relationship between postural alignment and mobility for adults after acquired brain injury? A systematic review. AB - PRIMARY OBJECTIVE: To examine the relationship between postural alignment and mobility skills for adults after acquired brain injury (ABI). METHODS: Systematic review of the literature. Seven electronic databases, grey literature and reference lists of the shortlisted publications were searched. Studies were included if participants were adults with ABI, both postural alignment and mobility were measured and analysis included a relationship between alignment and mobility. Those that met the inclusion criteria were assessed with a critical appraisal tool. The review was registered with PROSPERO, registration number CRD42015019867. RESULTS: Seven observational studies were included that had examined a relationship between postural alignment and mobility after ABI. Critical appraisal scores were moderate to strong. While some studies reported that improved postural alignment was related to improved mobility after ABI, results varied and there was insufficient evidence to answer the primary question. Heterogeneous study designs did not allow meta-regression. CONCLUSIONS: A small amount of observational evidence exists for a relationship between postural alignment and mobility after ABI. Results vary, with some studies reporting that a more stable, upright trunk correlates with better mobility, and others providing conflicting or ambiguous results. Further research is needed to establish the relationship between postural alignment and mobility skills after ABI. PMID- 28340319 TI - Apigenin Reduces NF-kappaB and Subsequent Cytokine Production as Protective Effect in a Rodent Animal Model of Lung Ischemia-Reperfusion Injury. AB - PURPOSE: Lung ischemia-reperfusion injury (LIRI) can complicate lung transplantation or cardiac surgery with cardiopulmonary bypass, increasing morbidity and mortality. In LIRI, pro-inflammatory cytokines are activated, reactive oxygen species are generated and nuclear factor-kappaB (NF-kappaB) is up regulated, altering lung mechanics. We tested the effect of the flavonoid apigenin on a rodent model of LIRI. METHODS: Thirty-seven Wistar rats were subjected to LIRI with or without a single or double dose of apigenin. Induction of LIRI involved sternotomy and clamping of either the left lung hilum or the pulmonary artery alone for 30 min, followed by 60 min of reperfusion. Control groups consisted of LIRI plus NaCl, a sham group and a baseline group. At the end of the experiments, both lungs were analyzed by RT-PCR, Western blot, and light microscopy. RESULTS: In placebos, the expression levels of pro-inflammatory markers were increased in both lungs significantly, whereas NF-kappaB was markedly up-regulated. Administration of apigenin reduced the activation of NF kappaB and the expression of TNFalpha, iNOS, and IL-6. These effects were observed in total lung ischemia. Histology showed greater hemorrhage and exudation in the pulmonary periphery of all groups, whereby damage was practically absent in the central lung regions of the apigenin animals. A second dose of apigenin did not outclass a single one. CONCLUSIONS: We conclude that apigenin given intraperitoneally can reduce activation of NF-kappaB and also attenuate the expression of TNFalpha, IL-6, and iNOS in a surgical model of LIRI. The surgical procedure itself can induce significant damage to the lungs. PMID- 28340320 TI - Protective Effects of Alpha-Lipoic Acid on Methotrexate-Induced Oxidative Lung Injury in Rats. AB - OBJECTIVE: Oxidative stress is one of the major causes of methotrexate induced lung injury (MILI). Alpha-lipoic acid (ALA), which occurs naturally in human food, has antioxidative and anti-inflammatory activities. The aim of this study was to research the potential protective role of ALA on MILI in rats. METHODS: Twenty one rats were randomly subdivided into three groups: control (group I), methotrexate (MTX) treated (group II), and MTX+ALA treated (group III). Lung injury was performed with a single dose of MTX (20 mg/kg) to groups 2 and 3. On the sixth day, animals in all groups were sacrificed by decapitation and lung tissue and blood samples were removed for histological examination and also measurement the levels of interleukin-1-beta (IL-1beta), malondialdehyde (MDA), glutathione (GSH), tumour necrosis factor-alpha (TNF-alpha), myeloperoxidase (MPO), and sodium potassium-adenosine triphosphatase (Na+/K+ATPase). RESULTS: In MTX group tissue GSH, Na+/K+ATPase activities were lower, tissue MDA, MPO and plasma IL-1?, TNF-? were significantly higher than the other groups. Histopathological examination showed that lung injury was less severe in group 2 according to group 3. CONCLUSIONS: Oxidative damage of MTX in rat lung is partially reduced when combined with ALA. PMID- 28340321 TI - Exploring the relationship between cognition and functional verbal reasoning in adults with severe traumatic brain injury at six months post injury. AB - OBJECTIVE(S): This study aims to determine the association between cognitive impairment and functional verbal reasoning in adults with severe traumatic brain injury (TBI), at six months post-injury. METHOD(S): 38 participants with severe TBI were assessed using the four tasks on the Functional Assessment of Verbal Reasoning and Executive Strategies (FAVRES) [1] and a battery of neuropsychological tests at 6 months post injury in a cross-sectional observational study. RESULTS: Overall performance on the FAVRES [1] was strongly associated with overall performance on the neuropsychological battery (rho = 0.60). FAVRES Task 2 and FAVRES Task 4 had the most significant positive associations with the cognitive indices of Attention and speed of processing, Memory and Executive functions. There was one weak significant association between the Task 1 Accuracy score and the Total Cognitive index (rho = 0.46). CONCLUSIONS: Performance on the FAVRES [1] is positively associated with cognitive processes. Participants with stronger verbal reasoning skills which may be required for activities in work, home and social contexts also had higher scores on tests of cognitive functioning. These findings may inform clinical practices for speech pathologists and other health professionals, in the assessment and treatment of cognitive communication disorders during early stages of recovery in people with severe TBI. PMID- 28340323 TI - A key to the backdoor into the castle: The clinical ramifications of immunoediting driven by antigenic competition. AB - Over the last decade the field of cancer biology has gained considerable data on genomic heterogeneity. This situation creates challenges and possibly opportunities for cancer treatment. The evolution of the tumor at all stages also requires the growing malignancy to confront and avoid the immune system. What we describe here is the interaction of two immune phenomena that work together to change the characteristics of the tumor, i.e., antigenic competition and immune editing. These two systems are mutually functional and their interaction is capable of altering the characteristics of the tumor for protection and survival in an immune competent host as well as restricting the diversity of the tumor clones. Therefore, the final outcome of these interactions can also become the key to the backdoor into the castle. Through an additional immune manipulation, autologous tumor cell immunization, we can achieve prevention of disease recurrence after surgical resection and by analyzing induced human monoclonal antibodies to the neoantigens, gain in site into the restriction of diversity of the mutant clones. These findings may also open the door for a pathway to immune prevention of cancer. PMID- 28340324 TI - VPS36-Mediated plasma membrane protein turnover is critical for Arabidopsis root gravitropism. AB - The gravitropic response is an evolutionary adaptation for plants to cope with the altered gravitational field. It involves reestablishing the distribution of the phytohormone auxin by differential degradation of auxin influx and efflux carriers. This process includes the endosomal sorting complexes required for transport (ESCRT) machinery to recognize ubiquitinated proteins and deliver them to vacuoles for degradation, as evidenced by vps36-1 mutants. Here, we generated RNAi knockdown plants of Vacuolar Protein Sorting 36 (VPS36) that could survive to adulthood. VPS36-induced RNAi plants showed PIN FORMED1 (PIN1) accumulation in the intracellular compartment, reduced root length and small stature, as observed in vps36-1 mutants. After gravistimulation, the roots of VPS36-induced RNAi plants did not show the bending observed in wild-type plants. The VPS36 containing ESCRT machinery may have a role in the gravitropic response possibly associated with the degradation of auxin transporters. PMID- 28340325 TI - On doing the right science. PMID- 28340322 TI - Immunogenicity and safety of primary and booster vaccination with 2 investigational formulations of diphtheria, tetanus and Haemophilus influenzae type b antigens in a hexavalent DTPa-HBV-IPV/Hib combination vaccine in comparison with the licensed Infanrix hexa. AB - Safety and immunogenicity of 2 investigational formulations of diphtheria, tetanus and Haemophilus influenzae type b antigens of the combined diphtheria tetanus-acellular pertussis-hepatitis B-inactivated poliomyelitis-Hib vaccine (DTPa-HBV-IPV/Hib) were evaluated in a Primary (NCT01248884) and a Booster vaccination (NCT01453998) study. In the Primary study, 721 healthy infants (randomized 1:1:1) received 3 doses of DTPa-HBV-IPV/Hib formulation A (DATAPa-HBV IPV/Hib), or B (DBTBPa-HBV-IPV/Hib) or the licensed DTPa-HBV-IPV/Hib vaccine (Infanrix hexa, GSK; control group) at 2, 3, 4 months of age. Infants were planned to receive a booster dose at 12-15 months of age with the same formulation received in the Primary study; however, following high incidence of fever associated with the investigational formulations in the Primary study, the Booster study protocol was amended and all infants yet to receive a booster dose (N = 385) received the licensed vaccine. In the Primary study, non-inferiority of 3-dose vaccination with investigational formulations compared with the licensed vaccine was not demonstrated due to anti-pertactin failing to meet the non inferiority criterion. Post-primary vaccination, most infants had seroprotective levels of anti-diphtheria (100% of infants), anti-tetanus antigens (100%), against hepatitis B (>= 97.5% across groups), polyribosyl-ribitol-phosphate (>= 88.0%) and poliovirus types 1-3 (>= 90.5%). Seropositivity rates for each pertussis antigen were 100% in all groups. Higher incidence of fever (> 38 degrees C) was reported in infants receiving the investigational formulations (Primary study: 75.0% [A] and 72.1% [B] vs 58.8% [control]; Booster study, before amendment: 49.4% and 46.6% vs 37.4%, respectively). The development of the investigational formulations was not further pursued. PMID- 28340326 TI - Effects of coupling a UF membrane with a mesh screen and elevating temperature in the methanogenic digester of a two-phased anaerobic system. AB - This study was conducted to investigate coupling of UF with a mesh screen under thermophilic temperatures and compare the effectiveness of membrane filtration and temperature change in the methanogenic digester. A two-phased anaerobic digester coupled with an ultrafiltration (UF) membrane system was used for anaerobic sludge digestion. The overall average chemical oxygen demand (COD) removal efficiency achieved in the two-phased anaerobic digester coupled with the UF membrane system was 97.9 +/- 0.8%. In the methanogenic digester, 10.5% improvement of methane production rate was obtained by the increased microbial population and metabolic activity due to coupling with a UF membrane and a mesh screen and elevating the temperature from mesophilic to thermophilic conditions. The average methane production per VS loading and unit volume (m3) was 477.14 +/- 31.5 and 567.15 +/- 43.3 mL CH4g-1 VS before and after elevating the temperature, respectively. The optimal operating pressure for the UF membrane system was less than 3 kgf cm-2, and the mesh screen saved 19.0% of the operating cost and 17.3% of energy consumption. As a result, the UF membrane system enhanced the digestion of sewage sludge, where the elevation of temperature improved the methane production rate in the thermophilic methanogenic digester. PMID- 28340327 TI - Polymorphic responses of Medicago truncatula accessions to potassium deprivation. AB - Potassium (K+) is an essential macronutrient for plants and the most abundant cation in cells. Due to variable K+ availability in the environment, plants must be able to adjust their developmental, physiological and transcriptional responses. The plant development to K+ deprivation was not well studied in legumes thus far. We recently described the first adaptation mechanisms of the model legume Medicago truncatula Jemalong A17 to long-term K+ deprivation and analyzed these responses in the context of arbuscular mycorrhizal symbiosis. Here we report polymorphic growth variations of two genetically very different accessions of M. truncatula to K+-limiting conditions, Jemalong A17, and the Tunisian accession Tn11.1. The faster adaptation of Tn11.1 than A17 to K+ shortage might be due to its greater adaptation to saline soils. Examining in a more systematic way the developmental adaptation of various M. truncatula accessions to K+ deprivation will provide a better understanding of how legume evolved to cope with this stressful condition. PMID- 28340328 TI - The role of AUXIN RESPONSE FACTORs in the development and differential growth of inflorescence stems. AB - Plants react to environmental cues by altering their growth and development, which can include organ tropic responses. These differential growth responses are triggered by the hormone auxin, and AUXIN RESPONSE FACTORs (ARFs) have been implicated in numerous organ tropisms in Arabidopsis thaliana. Surprisingly, despite being critical for light capture and overall plant morphology, inflorescence stem tropic responses remain relatively understudied, with presumed direct links to ARF function yet to be established. Here, we show that the expression patterns of ARF5/MONOPTEROS and ARF7/NONPHOTOTROPIC HYPOCOTYL4 are consistent with roles in inflorescence stem tropisms. Mutation of these factors does not alter inflorescence stem responses to gravity or unilateral auxin application, meaning their participation in these processes is presumably masked by functional redundancies. Future resolution of these redundancies will likely require higher order arf mutant combinations, guided by detailed expression analyses of ARFs in the inflorescence stem. PMID- 28340329 TI - A close-up view of codon selection in eukaryotic initiation. AB - When given an option to choose among a set of alternatives and only one selection is right, one might stop and reflect over which one is best. However, the ribosome has no time to stop and make such reflections, proteins need to be produced and very fast. Eukaryotic translation initiation is an example of such a conundrum. Here, scanning for the correct codon match must be fast, efficient and accurate. We highlight our recent computational findings, which show how the initiation machinery manages to recognize one specific codon among many possible challengers, by fine-tuning the energetic landscape of base-pairing with the aid of the initiation factors eIF1 and eIF1A. Using a recent 3-dimensional structure of the eukaryotic initiation complex we have performed simulations of codon recognition in atomic detail. These calculations provide an in-depth energetic and structural view of how discrimination against near-cognate codons is achieved by the initiation complex. PMID- 28340331 TI - SUMO on CRMPs - wrestling for pain? PMID- 28340330 TI - Same same but different: The evolution of TBP in archaea and their eukaryotic offspring. AB - Transcription factors TBP and TF(II)B assemble with RNA polymerase at the promoter DNA forming the initiation complex. Despite a high degree of conservation, the molecular binding mechanisms of archaeal and eukaryotic TBP and TF(II)B differ significantly. Based on recent biophysical data, we speculate how the mechanisms co-evolved with transcription regulation and TBP multiplicity. PMID- 28340333 TI - The Randomized CRM: An Approach to Overcoming the Long-Memory Property of the CRM. AB - The primary object of a Phase I clinical trial is to determine the maximum tolerated dose (MTD). Typically, the MTD is identified using a dose-escalation study, where initial subjects are treated at the lowest dose level and subsequent subjects are treated at progressively higher dose levels until the MTD is identified. The continual reassessment method (CRM) is a popular model-based dose escalation design, which utilizes a formal model for the relationship between dose and toxicity to guide dose finding. Recently, it was shown that the CRM has a tendency to get "stuck" on a dose level, with little escalation or de escalation in the late stages of the trial, due to the long-memory property of the CRM. We propose the randomized CRM (rCRM), which introduces random escalation and de-escalation into the standard CRM dose-finding algorithm, as well as a hybrid approach that incorporates escalation and de-escalation only when certain criteria are met. Our simulation results show that both the rCRM and the hybrid approach reduce the trial-to-trial variability in the number of cohorts treated at the MTD but that the hybrid approach has a more favorable tradeoff with respect to the average number treated at the MTD. PMID- 28340332 TI - Super elongation complex promotes early HIV transcription and its function is modulated by P-TEFb. AB - Early work on the control of transcription of the human immunodeficiency virus (HIV) laid the foundation for our current knowledge of how RNA Polymerase II is released from promoter-proximal pausing sites and transcription elongation is enhanced. The viral Tat activator recruits Positive Transcription Elongation Factor b (P-TEFb) and Super Elongation Complex (SEC) that jointly drive transcription elongation. While substantial progress in understanding the role of SEC in HIV gene transcription elongation has been obtained, defining of the mechanisms that govern SEC functions is still limited, and the role of SEC in controlling HIV transcription in the absence of Tat is less clear. Here we revisit the contribution of SEC in early steps of HIV gene transcription. In the absence of Tat, the AF4/FMR2 Family member 4 (AFF4) of SEC efficiently activates HIV transcription, while gene activation by its homolog AFF1 is substantially lower. Differential recruitment to the HIV promoter and association with Human Polymerase-Associated Factor complex (PAFc) play key role in this functional distinction between AFF4 and AFF1. Moreover, while depletion of cyclin T1 expression has subtle effects on HIV gene transcription in the absence of Tat, knockout (KO) of AFF1, AFF4, or both proteins slightly repress this early step of viral transcription. Upon Tat expression, HIV transcription reaches optimal levels despite KO of AFF1 or AFF4 expression. However, double AFF1/AFF4 KO completely diminishes Tat trans-activation. Significantly, our results show that P-TEFb phosphorylates AFF4 and modulates SEC assembly, AFF1/4 dimerization and recruitment to the viral promoter. We conclude that SEC promotes both early steps of HIV transcription in the absence of Tat, as well as elongation of transcription, when Tat is expressed. Significantly, SEC functions are modulated by P-TEFb. PMID- 28340334 TI - Advances in phase plate cryo-EM imaging of DNA and nucleosomes. AB - Contrast in electron cryo-microscopy (cryo-EM) is limited by the weak phase and radiation sensitive nature of biologic samples embedded in vitrified ice. We have recently shown that a new contrast enhancement technique utilizing the Volta phase plate can be combined with single particle analysis to determine the structure of a small chromatin complex, the nucleosome core particle, at near atomic resolution. Here, we discuss advantages and limitations of the technique in terms of data collection, particle detection, and visualization of individual DNA molecules and higher-order chromatin structure. PMID- 28340335 TI - Experimental Evolution to Study Virus Emergence. AB - Understanding how viruses adapt to new environments and acquire new phenotypes is critical for developing comprehensive responses to outbreaks. By studying the emergence of vaccine-derived poliovirus outbreaks, Stern et al. describe how a combination of sequence analysis and experimental evolution can be used to reveal adaptive pathways. PMID- 28340336 TI - A DNA-Based T Cell Receptor Reveals a Role for Receptor Clustering in Ligand Discrimination. AB - A T cell mounts an immune response by measuring the binding strength of its T cell receptor (TCR) for peptide-loaded MHCs (pMHC) on an antigen-presenting cell. How T cells convert the lifetime of the extracellular TCR-pMHC interaction into an intracellular signal remains unknown. Here, we developed a synthetic signaling system in which the extracellular domains of the TCR and pMHC were replaced with short hybridizing strands of DNA. Remarkably, T cells can discriminate between DNA ligands differing by a single base pair. Single-molecule imaging reveals that signaling is initiated when single ligand-bound receptors are converted into clusters, a time-dependent process requiring ligands with longer bound times. A computation model reveals that receptor clustering serves a kinetic proofreading function, enabling ligands with longer bound times to have disproportionally greater signaling outputs. These results suggest that spatial reorganization of receptors plays an important role in ligand discrimination in T cell signaling. PMID- 28340337 TI - Structural Basis of RNA Polymerase I Transcription Initiation. AB - Transcription initiation at the ribosomal RNA promoter requires RNA polymerase (Pol) I and the initiation factors Rrn3 and core factor (CF). Here, we combine X ray crystallography and cryo-electron microscopy (cryo-EM) to obtain a molecular model for basal Pol I initiation. The three-subunit CF binds upstream promoter DNA, docks to the Pol I-Rrn3 complex, and loads DNA into the expanded active center cleft of the polymerase. DNA unwinding between the Pol I protrusion and clamp domains enables cleft contraction, resulting in an active Pol I conformation and RNA synthesis. Comparison with the Pol II system suggests that promoter specificity relies on a distinct "bendability" and "meltability" of the promoter sequence that enables contacts between initiation factors, DNA, and polymerase. PMID- 28340338 TI - A Phase Separation Model for Transcriptional Control. AB - Phase-separated multi-molecular assemblies provide a general regulatory mechanism to compartmentalize biochemical reactions within cells. We propose that a phase separation model explains established and recently described features of transcriptional control. These features include the formation of super-enhancers, the sensitivity of super-enhancers to perturbation, the transcriptional bursting patterns of enhancers, and the ability of an enhancer to produce simultaneous activation at multiple genes. This model provides a conceptual framework to further explore principles of gene control in mammals. PMID- 28340341 TI - Tridimensional Visualization and Analysis of Early Human Development. AB - Generating a precise cellular and molecular cartography of the human embryo is essential to our understanding of the mechanisms of organogenesis in normal and pathological conditions. Here, we have combined whole-mount immunostaining, 3DISCO clearing, and light-sheet imaging to start building a 3D cellular map of the human development during the first trimester of gestation. We provide high resolution 3D images of the developing peripheral nervous, muscular, vascular, cardiopulmonary, and urogenital systems. We found that the adult-like pattern of skin innervation is established before the end of the first trimester, showing important intra- and inter-individual variations in nerve branches. We also present evidence for a differential vascularization of the male and female genital tracts concomitant with sex determination. This work paves the way for a cellular and molecular reference atlas of human cells, which will be of paramount importance to understanding human development in health and disease. PAPERCLIP. PMID- 28340342 TI - Staying in Touch while on the Go. PMID- 28340339 TI - Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. AB - The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density, and renal function in both fast aging XpdTTD/TTD and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored. PMID- 28340340 TI - Selective Chemical Inhibition of PGC-1alpha Gluconeogenic Activity Ameliorates Type 2 Diabetes. AB - Type 2 diabetes (T2D) is a worldwide epidemic with a medical need for additional targeted therapies. Suppression of hepatic glucose production (HGP) effectively ameliorates diabetes and can be exploited for its treatment. We hypothesized that targeting PGC-1alpha acetylation in the liver, a chemical modification known to inhibit hepatic gluconeogenesis, could be potentially used for treatment of T2D. Thus, we designed a high-throughput chemical screen platform to quantify PGC 1alpha acetylation in cells and identified small molecules that increase PGC 1alpha acetylation, suppress gluconeogenic gene expression, and reduce glucose production in hepatocytes. On the basis of potency and bioavailability, we selected a small molecule, SR-18292, that reduces blood glucose, strongly increases hepatic insulin sensitivity, and improves glucose homeostasis in dietary and genetic mouse models of T2D. These studies have important implications for understanding the regulatory mechanisms of glucose metabolism and treatment of T2D. PMID- 28340343 TI - SnapShot: Circulating Tumor Cells. PMID- 28340344 TI - Modified mRNA Vaccines Protect against Zika Virus Infection. PMID- 28340345 TI - SnapShot: Subcellular mRNA Localization. AB - Many cells localize mRNAs to discrete locations in the cytoplasm. Coupled to local translation, this process affords precise spatial and temporal control of protein function. This SnapShot provides an overview of the key events in subcellular mRNA localization and highlights recent progress in understanding how cytoskeletal motors orchestrate mRNA trafficking. PMID- 28340347 TI - Rejuvenation by Therapeutic Elimination of Senescent Cells. AB - In this issue of Cell, Baar et al. show how FOXO4 protects senescent cell viability by keeping p53 sequestered in nuclear bodies, preventing it from inducing apoptosis. Disrupting this interaction with an all-D amino acid peptide (FOXO4-DRI) restores p53's apoptotic role and ameliorates the consequences of senescence-associated loss of tissue homeostasis. PMID- 28340346 TI - The Upsides and Downsides of Organelle Interconnectivity. AB - Interconnectivity and feedback control are hallmarks of biological systems. This includes communication between organelles, which allows them to function and adapt to changing cellular environments. While the specific mechanisms for all communications remain opaque, unraveling the wiring of organelle networks is critical to understand how biological systems are built and why they might collapse, as occurs in aging. A comprehensive understanding of all the routes involved in inter-organelle communication is still lacking, but important themes are beginning to emerge, primarily in budding yeast. These routes are reviewed here in the context of sub-system proteostasis and complex adaptive systems theory. PMID- 28340348 TI - The Evolutionary Pathway to Virulence of an RNA Virus. AB - Paralytic polio once afflicted almost half a million children each year. The attenuated oral polio vaccine (OPV) has enabled world-wide vaccination efforts, which resulted in nearly complete control of the disease. However, poliovirus eradication is hampered globally by epidemics of vaccine-derived polio. Here, we describe a combined theoretical and experimental strategy that describes the molecular events leading from OPV to virulent strains. We discover that similar evolutionary events occur in most epidemics. The mutations and the evolutionary trajectories driving these epidemics are replicated using a simple cell-based experimental setup where the rate of evolution is intentionally accelerated. Furthermore, mutations accumulating during epidemics increase the replication fitness of the virus in cell culture and increase virulence in an animal model. Our study uncovers the evolutionary strategies by which vaccine strains become pathogenic and provides a powerful framework for rational design of safer vaccine strains and for forecasting virulence of viruses. VIDEO ABSTRACT. PMID- 28340350 TI - A Viral Immunoevasin Controls Innate Immunity by Targeting the Prototypical Natural Killer Cell Receptor Family. AB - Natural killer (NK) cells play a key role in innate immunity by detecting alterations in self and non-self ligands via paired NK cell receptors (NKRs). Despite identification of numerous NKR-ligand interactions, physiological ligands for the prototypical NK1.1 orphan receptor remain elusive. Here, we identify a viral ligand for the inhibitory and activating NKR-P1 (NK1.1) receptors. This murine cytomegalovirus (MCMV)-encoded protein, m12, restrains NK cell effector function by directly engaging the inhibitory NKR-P1B receptor. However, m12 also interacts with the activating NKR-P1A/C receptors to counterbalance m12 decoy function. Structural analyses reveal that m12 sequesters a large NKR-P1 surface area via a "polar claw" mechanism. Polymorphisms in, and ablation of, the viral m12 protein and host NKR-P1B/C alleles impact NK cell responses in vivo. Thus, we identify the long-sought foreign ligand for this key immunoregulatory NKR family and reveal how it controls the evolutionary balance of immune recognition during host-pathogen interplay. PMID- 28340349 TI - Structure Reveals Mechanisms of Viral Suppressors that Intercept a CRISPR RNA Guided Surveillance Complex. AB - Genetic conflict between viruses and their hosts drives evolution and genetic innovation. Prokaryotes evolved CRISPR-mediated adaptive immune systems for protection from viral infection, and viruses have evolved diverse anti-CRISPR (Acr) proteins that subvert these immune systems. The adaptive immune system in Pseudomonas aeruginosa (type I-F) relies on a 350 kDa CRISPR RNA (crRNA)-guided surveillance complex (Csy complex) to bind foreign DNA and recruit a trans-acting nuclease for target degradation. Here, we report the cryo-electron microscopy (cryo-EM) structure of the Csy complex bound to two different Acr proteins, AcrF1 and AcrF2, at an average resolution of 3.4 A. The structure explains the molecular mechanism for immune system suppression, and structure-guided mutations show that the Acr proteins bind to residues essential for crRNA-mediated detection of DNA. Collectively, these data provide a snapshot of an ongoing molecular arms race between viral suppressors and the immune system they target. PMID- 28340351 TI - Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research. AB - Genome sequencing has revolutionized the diagnosis of genetic diseases. Close collaborations between basic scientists and clinical genomicists are now needed to link genetic variants with disease causation. To facilitate such collaborations, we recommend prioritizing clinically relevant genes for functional studies, developing reference variant-phenotype databases, adopting phenotype description standards, and promoting data sharing. PMID- 28340353 TI - Molecular Structure of the Human CFTR Ion Channel. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-binding cassette (ABC) transporter that uniquely functions as an ion channel. Here, we present a 3.9 A structure of dephosphorylated human CFTR without nucleotides, determined by electron cryomicroscopy (cryo-EM). Close resemblance of this human CFTR structure to zebrafish CFTR under identical conditions reinforces its relevance for understanding CFTR function. The human CFTR structure reveals a previously unresolved helix belonging to the R domain docked inside the intracellular vestibule, precluding channel opening. By analyzing the sigmoid time course of CFTR current activation, we propose that PKA phosphorylation of the R domain is enabled by its infrequent spontaneous disengagement, which also explains residual ATPase and gating activity of dephosphorylated CFTR. From comparison with MRP1, a feature distinguishing CFTR from all other ABC transporters is the helix-loop transition in transmembrane helix 8, which likely forms the structural basis for CFTR's channel function. PMID- 28340352 TI - Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk. AB - Multiple sclerosis (MS) is an autoimmune disorder where T cells attack neurons in the central nervous system (CNS) leading to demyelination and neurological deficits. A driver of increased MS risk is the soluble form of the interleukin-7 receptor alpha chain gene (sIL7R) produced by alternative splicing of IL7R exon 6. Here, we identified the RNA helicase DDX39B as a potent activator of this exon and consequently a repressor of sIL7R, and we found strong genetic association of DDX39B with MS risk. Indeed, we showed that a genetic variant in the 5' UTR of DDX39B reduces translation of DDX39B mRNAs and increases MS risk. Importantly, this DDX39B variant showed strong genetic and functional epistasis with allelic variants in IL7R exon 6. This study establishes the occurrence of biological epistasis in humans and provides mechanistic insight into the regulation of IL7R exon 6 splicing and its impact on MS risk. PMID- 28340356 TI - Acquiring variation in an artificial language: Children and adults are sensitive to socially conditioned linguistic variation. AB - Languages exhibit sociolinguistic variation, such that adult native speakers condition the usage of linguistic variants on social context, gender, and ethnicity, among other cues. While the existence of this kind of socially conditioned variation is well-established, less is known about how it is acquired. Studies of naturalistic language use by children provide various examples where children's production of sociolinguistic variants appears to be conditioned on similar factors to adults' production, but it is difficult to determine whether this reflects knowledge of sociolinguistic conditioning or systematic differences in the input to children from different social groups. Furthermore, artificial language learning experiments have shown that children have a tendency to eliminate variation, a process which could potentially work against their acquisition of sociolinguistic variation. The current study used a semi-artificial language learning paradigm to investigate learning of the sociolinguistic cue of speaker identity in 6-year-olds and adults. Participants were trained and tested on an artificial language where nouns were obligatorily followed by one of two meaningless particles and were produced by one of two speakers (one male, one female). Particle usage was conditioned deterministically on speaker identity (Experiment 1), probabilistically (Experiment 2), or not at all (Experiment 3). Participants were given tests of production and comprehension. In Experiments 1 and 2, both children and adults successfully acquired the speaker identity cue, although the effect was stronger for adults and in Experiment 1. In addition, in all three experiments, there was evidence of regularization in participants' productions, although the type of regularization differed with age: children showed regularization by boosting the frequency of one particle at the expense of the other, while adults regularized by conditioning particle usage on lexical items. Overall, results demonstrate that children and adults are sensitive to speaker identity cues, an ability which is fundamental to tracking sociolinguistic variation, and that children's well established tendency to regularize does not prevent them from learning sociolinguistically conditioned variation. PMID- 28340354 TI - Mechanism of Substrate Translocation in an Alternating Access Transporter. AB - Transporters shuttle molecules across cell membranes by alternating among distinct conformational states. Fundamental questions remain about how transporters transition between states and how such structural rearrangements regulate substrate translocation. Here, we capture the translocation process by crystallography and unguided molecular dynamics simulations, providing an atomic level description of alternating access transport. Simulations of a SWEET-family transporter initiated from an outward-open, glucose-bound structure reported here spontaneously adopt occluded and inward-open conformations. Strikingly, these conformations match crystal structures, including our inward-open structure. Mutagenesis experiments further validate simulation predictions. Our results reveal that state transitions are driven by favorable interactions formed upon closure of extracellular and intracellular "gates" and by an unfavorable transmembrane helix configuration when both gates are closed. This mechanism leads to tight allosteric coupling between gates, preventing them from opening simultaneously. Interestingly, the substrate appears to take a "free ride" across the membrane without causing major structural rearrangements in the transporter. PMID- 28340355 TI - The Human Immunodeficiency Virus 1 ASP RNA promotes viral latency by recruiting the Polycomb Repressor Complex 2 and promoting nucleosome assembly. AB - Various epigenetic marks at the HIV-1 5'LTR suppress proviral expression and promote latency. Cellular antisense transcripts known as long noncoding RNAs (lncRNAs) recruit the polycomb repressor complex 2 (PRC2) to gene promoters, which catalyzes trimethylation of lysine 27 on histone H3 (H3K27me3), thus promoting nucleosome assembly and suppressing gene expression. We found that an HIV-1 antisense transcript expressed from the 3'LTR and encoding the antisense protein ASP promotes proviral latency. Expression of ASP RNA reduced HIV-1 replication in Jurkat cells. Moreover, ASP RNA expression promoted the establishment and maintenance of HIV-1 latency in Jurkat E4 cells. We show that this transcript interacts with and recruits PRC2 to the HIV-1 5'LTR, increasing accumulation of the suppressive epigenetic mark H3K27me3, while reducing RNA Polymerase II and thus proviral transcription. Altogether, our results suggest that the HIV-1 ASP transcript promotes epigenetic silencing of the HIV-1 5'LTR and proviral latency through the PRC2 pathway. PMID- 28340357 TI - Ruthenium complexes with phenylterpyridine derivatives target cell membrane and trigger death receptors-mediated apoptosis in cancer cells. AB - Elucidation of the communication between metal complexes and cell membrane may provide useful information for rational design of metal-based anticancer drugs. Herein we synthesized a novel class of ruthenium (Ru) complexes containing phtpy derivatives (phtpy = phenylterpyridine), analyzed their structure-activity relationship and revealed their action mechanisms. The result showed that, the increase in the planarity of hydrophobic Ru complexes significantly enhanced their lipophilicity and cellular uptake. Meanwhile, the introduction of nitro group effectively improved their anticancer efficacy. Further mechanism studies revealed that, complex (2c), firstly accumulated on cell membrane and interacted with death receptors to activate extrinsic apoptosis signaling pathway. The complex was then transported into cell cytoplasm through transferrin receptor mediated endocytosis. Most of the intracellular 2c accumulated in cell plasma, decreasing the level of cellular ROS, inducing the activation of caspase-9 and thus intensifying the apoptosis. At the same time, the residual 2c can translocate into cell nucleus to interact with DNA, induce DNA damage, activate p53 pathway and enhance apoptosis. Comparing with cisplatin, 2c possesses prolonged circulation time in blood, comparable antitumor ability and importantly, much lower toxicity in vivo. Taken together, this study uncovers the role of membrane receptors in the anticancer actions of Ru complexes, and provides fundamental information for rational design of membrane receptor targeting anticancer drugs. PMID- 28340358 TI - Lysosomal rupture induced by structurally distinct chitosans either promotes a type 1 IFN response or activates the inflammasome in macrophages. AB - Chitosan is a family of glucosamine and N-acetyl glucosamine polysaccharides with poorly understood immune modulating properties. Here, functional U937 macrophage responses were analyzed in response to a novel library of twenty chitosans with controlled degree of deacetylation (DDA, 60-98%), molecular weight (1 to >100 kDa), and acetylation pattern (block vs. random). Specific chitosan preparations (10 or 190 kDa 80% block DDA and 3, 5, or 10 kDa 98% DDA) either induced macrophages to release CXCL10 and IL-1ra at 5-50 MUg/mL, or activated the inflammasome to release IL-1beta and PGE2 at 50-150 MUg/mL. Chitosan induction of these factors required lysosomal acidification. CXCL10 production was preceded by lysosomal rupture as shown by time-dependent co-localization of galectin-3 and chitosan and slowed autophagy flux, and specifically depended on IFN-beta paracrine activity and STAT-2 activation that could be suppressed by PGE2. Chitosan induced a type I IFN paracrine response or inflammasome response depending on the extent of lysosomal rupture and cytosolic foreign body invasion. This study identifies the structural motifs that lead to chitosan-driven cytokine responses in macrophages and indicates that lysosomal rupture is a key mechanism that determines the endogenous release of either IL-1ra or IL-1beta. PMID- 28340359 TI - Diabetic foot ulcer development risk classifications' validation: A multicentre prospective cohort study. AB - AIMS: To prospectively validate the existing classifications to stratify subjects with diabetes mellitus (DM) by their risk of diabetic foot ulcer (DFU), in high and low risk settings. METHODS: A prospective multicentre cohort study was conducted, including 446 subjects with DM without active DFU followed in the hospital or primary care setting. Demographic, clinical characterization variables, and those included in the classifications were collected at baseline. Subjects were followed for 1year, until DFU or death. RESULTS: In our sample, with a mean age of 65years, 52% were male; 32 developed a DFU, 7 required an amputation and 18 died. Differences were found between participants' characteristics and classifications' accuracy according to the setting. The great majority of the variables were associated with higher DFU risk. Globally, classifications were highly and equally valid, positive predictive values (PV) were inferior to 40%, negative PV superior to 90% and area under the receiver operating characteristic curve superior to 0.75. DISCUSSION: All the existing classifications are valid to be applied in high risk clinical context and have a very high capacity to categorize as low risk those subjects that will not develop a DFU. Further research is needed in the primary care setting. PMID- 28340360 TI - The influence of carbohydrate consumption on glycemic control in pregnant women with type 1 diabetes. AB - AIMS: To study the influence of the quantity and the quality of carbohydrate consumption on glycemic control in early pregnancy among women with type 1 diabetes. METHODS: A retrospective study of 107 women with type 1 diabetes who completed 1-3days of diet recording before first antenatal visit, as a part of routine care. The total daily carbohydrate consumption from the major sources (e.g. bread, potatoes, rice, pasta, dairy products, fruits, candy) was calculated. A dietician estimated the overall glycemic index score (scale 0-7). RESULTS: At least two days of diet recording were available in 75% of the 107 women at mean 64 (SD+/-14) gestational days. The quantity of carbohydrate consumption from major sources was 180 (+/-51)g/day. HbA1c was positively associated with the quantity of carbohydrate consumption (beta=0.41; 95% CI 0.13 0.70, P=0.005), corresponding to an increase of 0.4% in HbA1c per 100g carbohydrates consumed daily, when adjusted for insulin dose/bodyweight and use of insulin pump treatment. The median (IQR) glycemic index score was 2 (0-3). An adjusted association between HbA1c and glycemic index score was not demonstrated. The women using carbohydrate counting daily (45%) had lower HbA1c compared to the remaining women (6.4 (+/-0.5) vs. 6.8 (+/-0.9)% (47+/-6 vs. 51+/-10mmol/mol), P=0.01). CONCLUSIONS: HbA1c in early pregnancy was positively associated with the quantity of carbohydrate consumption regardless of insulin treatment. Carbohydrate counting is probably important for glycemic control in pregnant women with type 1 diabetes. PMID- 28340362 TI - Studies on neutron spectrum characterization for the Pneumatic Fast Transfer System (PFTS) of KAMINI reactor. AB - Characterization of neutron energy spectrum along with the determination of sub cadmium to epithermal neutron flux ratio (f) and the epithermal neutron flux shape factor (alpha) has been carried out at pneumatic fast transfer system (PFTS) of KAMINI reactor. The facility has been extensively used for the neutron activation analysis (NAA) studies using both k0-NAA and relative method. This paper describes the multi-foil activation method to determine the reaction rates followed by the generation of computed guess spectrum to unfold the neutron spectrum using least square minimization approach. PMID- 28340361 TI - HDL inhibits saturated fatty acid mediated augmentation of innate immune responses in endothelial cells by a novel pathway. AB - BACKGROUND AND AIMS: Peripheral insulin resistance is associated with several metabolic abnormalities, including elevated serum fatty acids that contribute to vascular injury and atherogenesis. Our goals were to examine whether saturated fatty acids can modify innate immune responses to subclinical concentrations of lipopolysaccharide (LPS) in endothelial cells, and to explore the underlying pathway and determine whether it is modified by high density lipoprotein (HDL) and other factors commonly altered in insulin resistance. METHODS: Physiologic concentrations of palmitic acid were added to human aortic endothelial cells with and without a variety of inhibitors or HDL and measures of cell inflammation and function assessed. RESULTS: Palmitic acid significantly amplified human aortic endothelial cell inflammatory responses to LPS. Similar results were obtained from lipolysis products of triglyceride rich lipoproteins. Metabolism of palmitic acid to ceramide and subsequent activation of PKC-zeta, MAPK and ATF3 appeared critical in amplifying LPS induced inflammation. The amplified response to palmitic acid/LPS was decreased by HDL, dose dependently, and this inhibition was dependent on activation of PI3K/AKT and reduction in ATF3. CONCLUSIONS: These results indicate that endothelial cell innate immune responses are modified by metabolic abnormalities commonly present in insulin resistance and provide evidence for a novel mechanism by which HDL may reduce vascular inflammation. PMID- 28340363 TI - Benchmark integral neutron experiments for Fe, Be and C with DT neutron by liquid scintillation detector. AB - The measurements of iron, beryllium and carbon sphere neutron leakage spectra using BC501A detector by DT neutron source are presented. The experiments were carried out in Institute of Nuclear Physics and Chemistry (INPC), China. Neutron leakage spectra in a wide energy range at angles of 0 degrees and 30 degrees from the direction of incident deuteron beam were obtained. The results show the leakage neutron flux decreases notably with the spherical shell increasing when neutron energy >10MeV. When neutron energy <6MeV the leakage neutron distribution tends to lower energy side with the shell increase. The total uncertainty evaluation of the neutron spectra is also provided: in the high-energy parts the uncertainty is about 5-7%, while in the low-energy parts the uncertainty is about 7-9%. In order to compare the experiment results a Monte-carlo calculation was made using the MCNP5 Code with the ENDF/B-VII.1 nuclear data files. PMID- 28340364 TI - Cervical facet force analysis after disc replacement versus fusion. AB - BACKGROUND: Cervical total disc replacement was developed to preserve motion and reduce adjacent-level degeneration relative to fusion, yet concerns remain that total disc replacement will lead to altered facet joint loading and long-term facet joint arthrosis. This study is intended to evaluate changes in facet contact force, pressure and surface area at the treated and superior adjacent levels before and after discectomy, disc replacement, and fusion. METHODS: Ten fresh-frozen human cadaveric cervical spines were potted from C2 to C7 with pressure sensors placed into the facet joints of C3-C4 and C4-C5 via slits in the facet capsules. Moments were applied to the specimens to produce axial rotation, lateral bending and extension. Facet contact force and pressure were measured at both levels for intact, discectomy at C4-C5, disc replacement with ProDisc-C (Synthes Spine, West Chester, Pennsylvania, USA) at C4-C5, and anterior discectomy and fusion with Cervical Spine Locking Plate (Synthes Spine, West Chester, Pennsylvania, USA) at C4-C5. Facet contact area was calculated from the force and pressure measurements. An analysis of variance was used to determine significant differences with P-values <0.05 indicating significance. FINDINGS: Facet contact force was elevated at the treated level under extension following both discectomy and disc replacement, while facet contact pressure and area were relatively unchanged. Facet contact force and area were decreased at the treated level following fusion for all three loading conditions. INTERPRETATION: Total disc replacement preserved facet contact force for all scenarios except extension at the treated level, highlighting the importance of the anterior disco ligamentous complex. This could promote treated-level facet joint disease. PMID- 28340365 TI - Emotion regulation strategies mediate the associations of positive and negative affect to upper extremity physical function. AB - BACKGROUND: The Gross process model of emotion regulation holds that emotion eliciting situations (e.g. musculoskeletal illness) can be strategically regulated to determine the final emotional and behavioral response. Also, there is some evidence that innate emotional traits may predispose an individual to a particular regulating coping style. METHODS: We enrolled 107 patients with upper extremity musculoskeletal illness in this cross-sectional study. They completed self-report measures of positive and negative affect, emotion regulation strategies (cognitive reappraisal and expressive suppression), upper extremity physical function, pain intensity, and demographics. We used Preacher and Hayes' bootstrapping approach to process analysis to infer the direct effect of positive and negative affect on physical function as well as their indirect effects through activation of emotion regulation strategies. RESULTS: Negative affect was associated with decreased physical function. The association was partly mediated by expressive suppression (b (SE)=-.10 (.05), 95% BCa CI [-.21, -.02]). Positive affect was associated with increased physical function. Cognitive reappraisal partially mediated this association (b (SE)=.11 (.05), 95% BCa CI [.03, .24]). After controlling for pain intensity, the ratio of the mediated effect to total effect grew even larger in controlled model comparing to uncontrolled model (33% vs. 26% for expressive suppression and 32% vs. 30% for cognitive reappraisal). CONCLUSIONS: The relationships between affect, emotion regulation strategies and physical function appear to be more dependent on the emotional response to an orthopedic condition rather than the intensity of the nociceptive stimulation of the pain. Findings support integration of emotion regulation training in skill based psychotherapy in this population to mitigate the effect of negative affect and enhance the influence of positive affect on physical function. PMID- 28340367 TI - Insulin resistance is associated with carotid intima-media thickness in non diabetic subjects. A cross-sectional analysis of the ELSA-Brasil cohort baseline. AB - BACKGROUND AND AIMS: Epidemiological studies have analyzed the association between carotid intima-media thickness (CIMT) and insulin resistance, glucose levels or glycated hemoglobin with mixed results. We aimed to evaluate the association between CIMT and homeostasis model assessment - insulin resistance (HOMA-IR), fasting and post-load plasma glucose and glycated hemoglobin in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) baseline. METHODS: We included 8028 participants (aged 35-74 years) without diabetes or overt cardiovascular disease who had complete CIMT data at baseline. We built crude and adjusted linear and binary logistic models to evaluate the association between CIMT and (a) HOMA-IR; (b) fasting plasma glucose; (c) post-load plasma glucose; and (d) glycated hemoglobin. We also built post-hoc models, stratified by sex. RESULTS: In the fully-adjusted linear models, only the association between CIMT (in mm) and HOMA-IR remained significant (beta = 0.004; 95% confidence interval [95%CI]:0.001 to 0.006). Consistent with these results, only the association between the highest age- sex- and race-specific CIMT quartile and HOMA-IR was significant in the adjusted logistic model (odds ratio [OR]:1.10; 95% CI:1.04 1.17). The association between HOMA-IR and the highest CIMT quartile remained significant in sex-specific analyses (OR:1.10; 95% CI:1.02-1.20 for men and OR:1.10; 95% CI:1.02-1.20 for women). We did not find an independent association between CIMT and glucose or glycated hemoglobin. CONCLUSIONS: We found a direct association between HOMA-IR and CIMT in a large sample of non-diabetic participants. Mechanisms unrelated to glucose homeostasis, as a direct effect of insulin on atherosclerosis, or medial hypertrophy, may be involved. PMID- 28340368 TI - Synthesis, molecular docking, antimycobacterial and antimicrobial evaluation of new pyrrolo[3,2-c]pyridine Mannich bases. AB - In this report, we describe the synthesis and biological evaluation of a new series of pyrrolo[3,2-c]pyridine Mannich bases (7a-v). The Mannich bases were obtained in good yields by one-pot three component condensation of pyrrolo[3,2 c]pyridine scaffold (6a-c) with secondary amines and excess of formaldehyde solution in AcOH. The chemical structures of the compounds were characterized by 1H NMR, 13C NMR, LC/MS and elemental analysis. Single crystal X-ray diffraction has been recorded for compound 7k ([C23H29ClN4]+2, H2O). The in vitro antimicrobial activities of the compounds were evaluated against various bacterial and fungal strains using Agar diffusion method and Broth micro dilution method. Compounds 7e, 7f, 7r, 7t, and 7u were showed good Gram-positive antibacterial activity against S. aureus, B. flexus, C. sporogenes and S. mutans. Furthermore, in vitro antimycobacterial activity was evaluated against Mycobacterium tuberculosis H37Rv (ATCC 27294) using MABA. Compounds 7r, 7t, and 7u were showed good antitubercular activity against Mtb (MIC >=6.25 MUg/mL). Among the tested compounds, 1-((4-chloro-2-(cyclohexylmethyl)-1H-pyrrolo[3,2 c]pyridin-3-yl)methyl)piperidine-3-carboxamide (7t) was showed excellent antimycobacterial activity against Mtb (MIC <0.78 MUg/mL) and low cytotoxicity against the HEK-293T cell line (SI >>25). Molecular docking of the active compounds against glutamate racemase (MurI) and Mtb glutamine synthetase were explained the structure-activity observed in vitro. PMID- 28340369 TI - Degradation of diclofenac by UV-activated persulfate process: Kinetic studies, degradation pathways and toxicity assessments. AB - Diclofenac (DCF) is the frequently detected non-steroidal pharmaceuticals in the aquatic environment. In this study, the degradation of DCF was evaluated by UV 254nm activated persulfate (UV/PS). The degradation of DCF followed the pseudo first-order kinetics pattern. The degradation rate constant (kobs) was accelerated by UV/PS compared to UV alone and PS alone. Increasing the initial PS dosage or solution pH significantly enhanced the degradation efficiency. Presence of various natural water constituents had different effects on DCF degradation, with an enhancement or inhibition in the presence of inorganic anions (HCO3- or Cl-) and a significant inhibition in the presence of NOM. In addition, preliminary degradation mechanisms and major products were elucidated using LC MS/MS. Hydroxylation, decarbonylation, ring-opening and cyclation reaction involving the attack of SO4*- or other substances, were the main degradation mechanism. TOC analyzer and Microtox bioassay were employed to evaluate the mineralization and cytotoxicity of solutions treated by UV/PS at different times, respectively. Limited elimination of TOC (32%) was observed during the mineralization of DCF. More toxic degradation products and their related intermediate species were formed, and the UV/PS process was suitable for removing the toxicity. Of note, longer degradation time may be considered for the final toxicity removal. PMID- 28340366 TI - Effect of ezetimibe on low- and high-density lipoprotein subclasses in sitosterolemia. AB - BACKGROUND AND AIMS: Sitosterolemia displays high plasma total sterols [high plant sterols (PS) + normal to high total cholesterol (TC)] with normal to moderately elevated low-density lipoprotein (LDL) levels. High LDL, intermediate density lipoprotein (IDL) and very low-density lipoprotein (VLDL) particles, low high-density lipoprotein (HDL), and increased non-HDL and the ratios of TC and triglycerides (TG) to HDL can increase the risk for atherosclerosis. Ezetimibe (EZE) can reduce plasma PS and TC levels in sitosterolemia, but its effect on lipoprotein subclasses has not been previously reported. METHODS: Sitosterolemia patients (n = 8) were taken off EZE for 14 weeks (OFF EZE) and placed on EZE (10 mg/d) for 14 weeks (ON EZE). Serum lipids were measured enzymatically and lipoprotein subclasses were assessed by polyacrylamide gel electrophoresis. RESULTS: EZE reduced (p < 0.05) total sterols (-12.5 +/- 4.1%) and LDL-sterol ( 22.7 +/- 5.7%) and its sterol mass of large VLDL (-24.4 +/- 4.5%), VLDL remnants (-21.1 +/- 7.9%) and large IDL (-22.4 +/- 7.2%) compared to OFF EZE. EZE did not affect large LDL subclasses or mean LDL particle size (273.8 +/- 0.6 vs. 274.6 +/ 0.3 A). EZE increased HDL-sterol (25.5 +/- 8.0%, p = 0.008) including intermediate (34 +/- 14%, p = 0.02) and large (33 +/- 16%, p = 0.06) HDL. EZE reduced non-HDL-sterol (-21.8+/- 5.0%), total sterols/HDL (-28.2 +/- 5.5%) and TG/HDL (-27.4 +/- 6.5%, all p < 0.01). CONCLUSIONS: EZE improves VLDL and HDL subfraction distribution, thereby reducing the atherogenic lipid profile, thus providing potential clinical benefit in sitosterolemia beyond TC and PS reduction. PMID- 28340370 TI - Validation of Comet assay in Oregon-R and Wild type strains of Drosophila melanogaster exposed to a natural radioactive environment in Brazilian semiarid region. AB - Natural radiation of geological origin is a common phenomenon in Brazil, a country where radioactive agents such as uranium may be often found. As an unstable atom, uranium undergoes radioactive decay with the generation of a series of decay by-products, including radon, which may be highly genotoxic and trigger several pathological processes, among which cancer. Because it is a gas, radon may move freely between cracks and gaps in the ground, seeping upwards into the buildings and in the environment. In this study, two Drosophila melanogaster Meigen (Diptera, Drosophilidae) strains called Oregon-R and Wild (collected in a non-radioactive environment) were exposed to atmospheric radiation in the Lajes Pintadas city, in the semiarid zone of northeastern Brazil. After six days of environmental exposure, the organisms presented genetic damage significantly higher than that of the negative control group. The genotoxic effects observed reinforce the findings of other studies carried out in the same region, which warn about the environmental risks related to natural radioactivity occurrence. The results also validate the use of the Comet assay in hemocytes of D. melanogaster as a sensitive test to detect genotoxicity caused by natural radiation, and the use of a recently collected D. melanogaster strain in the environmental of radon. PMID- 28340371 TI - Walking-adaptability assessments with the Interactive Walkway: Between-systems agreement and sensitivity to task and subject variations. AB - The ability to adapt walking to environmental circumstances is an important aspect of walking, yet difficult to assess. The Interactive Walkway was developed to assess walking adaptability by augmenting a multi-Kinect-v2 10-m walkway with gait-dependent visual context (stepping targets, obstacles) using real-time processed markerless full-body kinematics. In this study we determined Interactive Walkway's usability for walking-adaptability assessments in terms of between-systems agreement and sensitivity to task and subject variations. Under varying task constraints, 21 healthy subjects performed obstacle-avoidance, sudden-stops-and-starts and goal-directed-stepping tasks. Various continuous walking-adaptability outcome measures were concurrently determined with the Interactive Walkway and a gold-standard motion-registration system: available response time, obstacle-avoidance and sudden-stop margins, step length, stepping accuracy and walking speed. The same holds for dichotomous classifications of success and failure for obstacle-avoidance and sudden-stops tasks and performed short-stride versus long-stride obstacle-avoidance strategies. Continuous walking adaptability outcome measures generally agreed well between systems (high intraclass correlation coefficients for absolute agreement, low biases and narrow limits of agreement) and were highly sensitive to task and subject variations. Success and failure ratings varied with available response times and obstacle types and agreed between systems for 85-96% of the trials while obstacle avoidance strategies were always classified correctly. We conclude that Interactive Walkway walking-adaptability outcome measures are reliable and sensitive to task and subject variations, even in high-functioning subjects. We therefore deem Interactive Walkway walking-adaptability assessments usable for obtaining an objective and more task-specific examination of one's ability to walk, which may be feasible for both high-functioning and fragile populations since walking adaptability can be assessed at various levels of difficulty. PMID- 28340372 TI - Shotgun metagenomic sequencing reveals freshwater beach sands as reservoir of bacterial pathogens. AB - Recreational waters and adjacent beach sands harbor complex microbial communities which may contain human pathogens that cannot be detected by conventional methods. Here, we investigate the diversity of bacterial populations inhabiting four freshwater beaches of the Great Lakes region using shotgun metagenomic sequencing approach. Our analysis suggests that average taxonomic richness and alpha diversity are significantly higher (P < 0.001) in beach sands compared to the corresponding water environments. Compared to the water environments, beach sands harbored taxa from a more diverse range of phyla, including a higher proportion of sequences from unclassified phyla. Unique phyla were also identified in sand which included species from Aquificae, Candidatus Microgenomates, Latescibacteria, and Candidatus Aminicenantes. Sequences originating from pathogens were detected in both sand and water, with some pathogens enriched in both environments. Both lakes exhibited similar community composition suggesting that geographic location did not appear to have any major impact on bacterial diversity. These findings reveal the diversity of bacterial communities of freshwater beaches and highlight the importance of monitoring pathogens in recreational beaches, especially in the sand environment of these beaches. PMID- 28340373 TI - Influence of sex on cardiovascular drug responses: role of estrogen. AB - In this review we discuss the sex/estrogen-specific modulation of cardiovascular function and responses to current therapeutics. We discuss how anatomical differences such as a smaller kidney size, and lower glomerular filtration rate in females, reduce the clearance and increase the toxicity of some drugs in females. Other important sex differences include the dampening effect of estrogen on central sympathetic and renin angiotensin systems. Further, we discuss how a shift in myocardial redox status leads to paradoxical transformation of estrogen into a pro-inflammatory hormone. Finally, the review, along with cited recent publications, identify some areas that need further investigation to advance our understanding of the sex differences in cardiovascular disease outcomes to help develop female specific interventions for these anomalies. PMID- 28340374 TI - Ebola virus persistence as a new focus in clinical research. AB - Ebola virus (EBOV) causes severe acute human disease with high lethality. Viremia is typical during the acute disease phase. However, EBOV RNA can remain detectable in immune-privileged tissues for prolonged periods of time after clearance from the blood, suggesting EBOV may persist during convalescence and thereafter. Eliminating persistent EBOV is important to ensure full recovery of survivors and decrease the risk of outbreak re-ignition caused by EBOV spread from apparently healthy survivors to naive contacts. Here, we review prior evidence of EBOV persistence and explore the tools needed for the development of model systems to understand persistence. PMID- 28340375 TI - Repetitive TMS in right sensorimotor areas affects the selection and completion of contralateral movements. AB - Although the existence of directional motor deficits (DMD) associated with movement planning and/or execution seems to be widely recognized, neglect and single cell studies examining their neuroanatomical foundation have produced contradictory and inconclusive findings. The present study assessed the occurrence of DMD following the application of repetitive transcranial magnetic stimulation (rTMS) over two regions, as commonly reported in the neglect literature, namely the right middle frontal gyrus (rMFG) and the right angular gyrus (rAG). Fourteen healthy subjects underwent rTMS while performing an auditory choice task, involving pointing toward two laterally located targets, under internally (i.e., pointing side freely selected) and externally guided conditions (i.e., pointing side guided by spatial auditory cues). In order to examine whether subjects compensated for induced deficits with the help of vision, visual feedback was occluded at movement onset in half of the trials. rTMS applied to the rAG significantly increased reaction times (RTs) for leftward internally-guided movements. In contrast, rTMS applied to the rMFG reduced the likelihood to complete leftward internally-guided movements under blindfolded conditions. These effects suggest that DMD might involve cognitive processes contributing to the different stages of motor control, such as movement selection and goal maintenance. PMID- 28340376 TI - Linarin could protect myocardial tissue from the injury of Ischemia-reperfusion through activating Nrf-2. AB - OBJECTIVES: As we all know, oxidative stress was one of the most important causes of ischemia-reperfusion injury. And it was reported that Nrf-2 as an important regulator for oxidative stress could be activated by Linarin. Thus it would be interesting to find whether Linarin could inhibit ischemia-reperfusion injury through activating Nrf-2. METHODS: In this study, cell activity was detected by MTT assay and caspase-3 activity detection kit. And the expressions or activities of some signal proteins were evaluated by western-blot or activity detection kits. At last, the effect and mechanism of Linarin on heart tissues were verified in the ischemia-reperfusion model of isolated hearts. RESULTS: The proliferation activity of cell was inhibited while the apoptosis rate was increased after hypoxia-reoxygenation. However, Linarin could inhibit these two variations. It was found that these effects of Linarin were related with the activation of Nrf-2 through PI3K/Akt signaling pathway. Meanwhile, the anti-oxidative enzymes, regulated by Nrf-2, were enhanced to against the oxidative stress caused by hypoxia-reoxygenation. And with the inhibition of oxidative stress, some proliferation and apoptosis related proteins such as NF-kB and Cytochrome C were adjusted to support the viability of cells. At last, these results were verified in the ischemia reperfusion experiment of isolated hearts. CONCLUSIONS: From this study, we assured that LIN could protect myocardial tissue from ischemia reperfusion through activating Nrf-2. PMID- 28340377 TI - Possible protective effect of royal jelly against cyclophosphamide induced prostatic damage in male albino rats; a biochemical, histological and immuno histo-chemical study. AB - Almost all the chemotherapy treat many cancer types effectively, but it leads to severe side effects. Chemotherapy like cyclophosphamide (CP) not works only on the active cells, such as cancer cells, but also acts on the healthy cells. Royal jelly (RJ) was reported to have a lot of therapeutic effects besides being an anti-oxidant and anti-cancer agent. The purpose of this study was to assess the possible protective role of RJ in ameliorating the toxic effects of CP overdose in the rat prostatic tissue. The rats were separated into 4 groups; control group, RJ group, CP group and RJ with CP group. Prostatic specimens were processed for biochemical, histological and immune-histo-chemical studies. The mean area fractions of eNOS and Bax expression were measured in all groups, and statistical analysis was carried out. The results showed that in CP treated group, there were marked biological changes in the form of significant increase in prostatic malondialdehyde (MDA) and C - reactive protein (CRP). Additionally there was a significant decrease in glutathione peroxidase (GPx) in prostatic tissue if compared with the control group. Furthermore, the histological changes showed marked acinar and stromal prostatic degeneration. Most prostatic acini showed less PAS reaction and more (eNOS and Bax) expression if compared with the control group. Concomitant administration of RJ with CP revealed a noticeable amelioration of these biochemical and histological changes. In conclusion, RJ provided biochemical and histo-pathological improvement in CP induced prostatic tissue toxicity. These findings revealed that this improvement was associated with a decrease in the tissue oxidative damage and apoptosis. PMID- 28340378 TI - Current FDA-approved treatments for non-small cell lung cancer and potential biomarkers for its detection. AB - BACKGROUND: Lung cancer is the leading worldwide cancer with almost 1.5 million deaths every year. Some drugs for lung cancer treatment have been available on the market for decades, but novel drugs have emerged promising better outcomes, especially for Non-Small Cell Lung Cancer (NSCLC), which represents 75% of lung cancer cases. However, how much do drugs have evolved for NSCLC treatment? Are they sharing the same mechanism of action? AIM: In this review we analyzed how the approved drugs by Federal Drug Agency for NSCLC have advanced in the last four decades identifying shared mechanism of action of medicines against NSCLC treatment and some of the potential biomarkers for early detection. RESULTS: Cisplatin and its derivatives are still the most used therapy in combination with some other more specific drugs. However, increasing the survival rates seems to be a great challenge and research is moving into early detection through biomarkers but also trying to identify molecules such as those derived from the immune system, cell-free DNA, non-coding RNAs, but also polymorphisms to detect early tumor formation. CONCLUSIONS: Cisplatin and derivatives have been one of the most successful therapies in spite of their side effects and low specificity. Some of the drugs developed after cisplatin discovery, have been targeted the epidermal growth factor receptor, anaplastic lymphoma kinase, programmed cell death 1 ligand and vascular endothelial growth factor. Since none of the pharmacological treatments in combination with radiation/surgery have extended dramatically the survival rate, research is now focused in early cancer detection in combination with precision medicine, which attempts to treat patients individually according to their stage and tumor characteristics. PMID- 28340379 TI - Knockdown of SKA1 gene inhibits cell proliferation and metastasis in human adenoid cystic carcinoma. AB - The spindle and kinetochore-associated complex subunit 1(SKA1) is a newly discovered gene, which has been associated with mitosis and tumorigenesis. However, its role insalivary adenoid cystic carcinoma (SACC) is still unknown, and the invasive and metastatic mechanism in SACC is still unclear. To explore the molecular mechanism of SKA1 in the process of malignant proliferation and metastasis in adenoid cystic cancer (ACC) cells, we employed lentivirus-mediated short hairpin RNA to knockdown SKA1 in SACC-83 cells. The results demonstrated that the lentivirus-mediated shRNA-targeting SKA1 lead to a significant down regulation of SKA1 expression. Knockdown of SKA1 inhibited cell proliferation, cell invasion, migration and the cell cycle arrest. Furthermore, knockdown of SKA1 reduced the Ndc80, CDK4, Cyclin D1, Cyclin E1, Cyclin B1 and matrix metalloproteinase-9 (MMP-9) protein expression, but increased the p27 protein expression. These findings indicated that SKA1 might be a promising target for cancer gene therapy in human ACC. PMID- 28340380 TI - The origin and evolution of the term "clone". AB - In biology, the term "clone" is most widely used to designate genetically identical cells or organisms that are asexually descended from a common progenitor. The concept of clonality in hematology-oncology has received much attention in recent years, as the advent of next-generation sequencing platforms has provided new tools for detection of clonal populations in patients, and experiments on primary cells have provided fascinating new insights into the clonal architecture of human malignancies. The term "clone" is used more loosely by the general public to mean any close or identical copy. Cloning of humans has been a staple of science fiction films and dystopian novels since Aldous Huxley's Brave New World was published in 1932. Here I trace the origin and evolution of the word clone, from its first use as an agricultural and botanical term in 1903, to its widespread adoption in biology, adaptation by artists, and contemporary use in hematology-oncology. PMID- 28340381 TI - Studying the adsorption of DNA nanostructures on graphene in the aqueous phase using molecular dynamic simulations. AB - DNA nanostructures can undergo large structural fluctuations and deviate from their intended configurations. In this work, two model DNA nanostructures (i.e., Nan and Kai) were designed based on the shape of the two Chinese characters of the name of Nankai University, and additional single-stranded DNA fragments were added to interact with graphene. During four 50-ns molecular dynamic simulations in aqueous solution, the DNA nanostructures adsorbed onto graphene demonstrated more stable conformations with lower root mean square deviations and smaller coordinate changes in the z-axis direction than the DNA nanostructures that were not adsorbed onto graphene. The interaction analyses and energetic calculations show that pi-pi interactions between single-stranded DNA and graphene are necessary for adsorption of the DNA nanostructures. Overall, this work examined the interactions between DNA and graphene at a large spatial scale with the hope that it provides a new strategy to stabilize DNA nanostructures. PMID- 28340382 TI - The BDNFval66met polymorphism and individual differences in temperament in 4 month-old infants: A pilot study. AB - Individual differences in infants' temperament are under genetic control. We investigated the association between brain-derived-neurotrophic-factor (BDNFval66met) polymorphism and temperament in 63 full-term infants. Met-carriers (N=25) had lower Regulatory capacities compared to val-homozygotes (N=38). These findings suggest that the BDNF polymorphism affects early temperament individual differences. PMID- 28340383 TI - Infant helping in the first year of life: Parents' recollection of infants' earliest prosocial behaviors. AB - Prosocial behavior is widely thought to emerge early in the second year of life. This paper presents evidence that helping emerges early in the first year of life. Parents of 80 children asked to recollect the earliest instance of their child helping recalled help in two contexts: chores (e.g., cleaning up) and care and self-care (e.g., feeding and dressing). A subset of parents recalled helping even before eight months of age, most often in the context of self-care tasks. The presence of helping this early in the lifespan is situated in recent research, and its implications for current theories of early prosocial behavior are discussed. PMID- 28340384 TI - Effects of waste eggshells and SiC addition on specific strength and thermal expansion of hybrid green metal matrix composite. AB - Chicken eggshell waste is an industrial byproduct, and its disposal constitutes a serious environmental hazard. Chicken eggshell can be used in commercial products to produce new materials with low cost and density. Low density material which can sustain at higher temperature is a remarkable area of research. Keeping these facts in the mind, the present investigation aims to study the physical behaviour, specific strength and thermal expansion of AA2014/SiC/carbonized eggshell hybrid green metal matrix composites. Microstructure of hybrid green metal matrix shows that the reinforcement particles (SiC particulates and carbonized eggshells particles) are uniformly distributed in the matrix AA2014 alloy. Specific strength for the composites containing 2.5wt.% SiC and up to 7.5wt.% carbonized eggshell was observed to be higher than that of the other selected composites. While for the same composition (AA2014/2.5% SiC/7.5% carbonized eggshell composites), porosity was observed lower than other selected composites. The results revealed that sample of AA2014/2.5% SiC/7.5% carbonized eggshell showed minimum cross sectional area reduction after the thermal expansion at 450 degrees C among all the selected samples. Overall costs of hybrid metal matrix composites were also calculated. PMID- 28340385 TI - Experimental study of polyethylene pyrolysis and combustion over HZSM-5, HUSY, and MCM-41. AB - The effects of temperatures, catalysts, and catalyst contents on polyethylene (PE) pyrolysis were investigated by using single-photon ionization time-of-flight mass spectrometry (SPI-TOFMS). The mass spectra of pyrolyzed PE and PE/catalysts from 300 degrees C to 800 degrees C illustrate that the pyrolysis reactions were apparently promoted and varied by introducing HZSM-5, HUSY, and MCM-41. As microporous catalysts, HZSM-5 and HUSY were found to accelerate the BTX formation at 400 degrees C, which could not be observed for pure PE until 800 degrees C. With the existence of MCM-41, only alkenes were produced below 600 degrees C. The pyrolysis processes could to be accelerated by adding catalysts. Principal components analysis (PCA) was finally employed to identify the main factors with influence on the products distribution. Analytical results showed that the yield of the majority of products could be affected by different experimental conditions, that the type of catalysts makes the most significant influence. The impact of different types of catalysts on fire hazard of PE was studied by using the cone calorimeter. The results indicated that the time to ignition (TTI) and the peak heat release rate (pHRR) were changed remarkably. It is worth noting that with the addition of MCM-41, the pHRR is the minimum. PMID- 28340386 TI - Constructed ILs coated porous magnetic nickel cobaltate hexagonal nanoplates sensing materials for the simultaneous detection of cumulative toxic metals. AB - The different morphologies of magnetic nickel cobaltate (NiCo2O4) electrocatalysts, consisting of nanoparticles (NiCo2O4-N), nanoplates (NiCo2O4-P) and microspheres (NiCo2O4-S) were fabricated. It was found that the electrocatalytic properties of the sensing materials were strongly dependent on morphology and specific surface area. The porous NiCo2O4 hexagonal nanoplates coupled with ILs as modified materials (ILs@NiCo2O4-P) for the simultaneous determination of thallium (Tl+), lead (Pb2+) and copper (Cu2+), exhibited high sensitivity, long-time stability and good repeatability. The enhanced electrocatalytic activity was attributed to relatively large specific surface area, excellent electronic conductivity, and unique porous nanostructure. The analytical performance of the constructed electrode on detection of Tl+, Pb2+ and Cu2+ was examined using differential pulse anodic stripping voltammetry (DPASV). Under optimal conditions, the electrode showed a good linear response to Tl+, Pb2+and Cu2+ in the concentration range of 0.1-100.0, 0.1-100.0 and 0.05 100.0MUg/L, respectively. The detection limits (S/N=3) were 0.046, 0.034 and 0.029MUg/L for Tl+, Pb2+ and Cu2+, respectively. The fabricated sensor was successfully applied to detect trace Tl+, Pb2+ and Cu2+ in various water and soil samples with satisfactory results. Hence, this work provided a promising material for electrochemical determination of cumulative toxic metals individually and simultaneously. PMID- 28340387 TI - An exploration of the effect and interaction mechanism of bisphenol A on waste sludge hydrolysis with multi-spectra, isothermal titration microcalorimetry and molecule docking. AB - An increasing amount of bisphenol A (BPA) is being produced and used, then discharged into sewage treatment plants and accumulated in sludge or soil, when the sludge is used as fertilizer. Accumulation of BPA in sludge or soil causes poisoning to the enzyme, which affects the biological treatment of sludge and the circulation and conversion of materials in soil. In this research, effect of BPA on sludge hydrolysis is studied from the respect of concentration and components of soluble organic matter in sludge, using three-dimensional fluorescence spectra. In order to illuminate the interaction mechanism, toxic effect of BPA on alpha-Amylase (a model of hydrolase in sludge) is investigated with multi spectra, isothermal titration microcalorimetry and molecule docking at the molecular level. Results show that the secondary structure of alpha-Amylase and the microenvironment of amino acid residue in alpha-Amylase are changed. The molecular docking study and ITC results show that hydrophobic bond and hydrogen bond exist in the interaction between BPA and alpha-Amylase. Based on the above analysis and enzyme activity assay, sludge hydrolysis is inhibited due to the denaturation of alpha-Amylase with BPA exposure. PMID- 28340388 TI - Evaluation of Cr(VI) reduction mechanism and removal by Cellulosimicrobium funkei strain AR8, a novel haloalkaliphilic bacterium. AB - The present study, a novel haloalkaliphilic Cr(VI) tolerant bacterial strain, Cellulosimicrobium funkei AR8, was isolated and characterized for its high Cr(VI) reduction. In batch experiments, Cr(VI) reduction was evaluated under different parametric conditions which include different pH (5-9), temperature (25-45 degrees C), NaCl (0-3%) and Cr(VI) concentrations (100-250MUg/ml). Variations in the cell surface functional groups and morphology of the bacterial cells after Cr(VI) reduction were characterized by FT-IR and SEM-EDX. FT-IR analysis revealed that cell surface functional groups such as alkanes, amide and amines are involved in chromium biosorption and SEM-EDX results showed that biosorption and immobilization of chromium species on the cell surface. Bioconversion of Cr(VI) into Cr(III) by strain AR8 was confirmed by XRD and Raman spectroscopy analysis. Intracellular localization of reduced product (Cr(III)) was visualized by TEM analysis. Various instrumentation analysis verified that Cr(VI) removal mechanism of C. funkei AR8 strain was achieved by both extra and intracellular reducing machinery. Toxicity study revealed that the bacterially reduced product exerted less toxic effects on phenotypic, survival (91.31%), hatching (84.04%) and heart function (115+/-1.03 beats/min) of zebrafish (Danio rerio) embryos. Higher Cr(VI) reducing ability of the strain under haloalkaliphilic condition suggests the C. funkei AR8 as a novel and efficient strain for remediating Cr(VI) contaminated industrial effluents with high salinity and alkalinity. PMID- 28340389 TI - Minilaparotomy without general anesthesia for the treatment of sigmoid volvulus in high-risk patients: A case series of 4 patients. AB - BACKGROUND: Sigmoid volvulus (SV) is a common cause of large bowel obstruction worldwide. Presenting symptoms can be nonspecific and varied amongst the elderly population, making medical and surgical management challenging. This population is at markedly increase risk of complications and mortality with surgery under general anesthesia. In this case series, we describe 4 cases of sigmoid volvulus in octogenarians. GOALS: To demonstrate that sigmoid colectomy under local anesthesia, with or without intravenous conscious sedation, is feasible and can be done safely and with a low rate of converting to a general anesthetic. RESULTS: Four patients, mean age 90 years, were admitted a total of 4 times for acute sigmoid volvulus. All patients had serious comorbidities and were classified as ASA III. There was no relevant past surgical history. All patients were severely physically deconditioned but alert and able to interact meaningfully with their families and caregivers. Three patients suffered recurrent volvulus following endoscopic decompression and one patient underwent immediate surgery due to abdominal tenderness. CONCLUSION: Our experience demonstrates that minilaparotomy for sigmoid volvulus is effective and safe. The techniques and can extend the applicability of definitive surgical intervention to this high-risk population of patients. In our series postoperative outcomes were excellent, however, additional studies are needed to determine if this technique results in improved 30-day and long-term mortality and morbidity in high-risk patients and to determine the utility of extending the technique to all patients with sigmoid volvulus. PMID- 28340391 TI - Optimization of the marinelli beaker dimensions using genetic algorithm. AB - A computational code, based on the genetic algorithm and MCNPX version 2.6 code was developed and used to investigate the effects of some important parameters of HPGe detector (such as Al cap thickness, dead-layer thickness and Ge hole size) on optimum dimensions of marinelli beaker. In addition, the effects of detector material on optimal beaker dimensions were also investigated. Finally, the optimized beaker dimensions at various beaker volumes (300, 500, 700, 1000 and 1500 cm3) were determined for some conventional Ge detectors with different crystal sizes (16 sizes). These sets of data then were used to drive mathematical formulas (obtained by best fitting to data sets). The results showed that, there is no meaningful correlation between the optimum dimensions of the beaker and each of the dead-layer thickness, Al cap thickness and the Ge-crystal hole size. On the other hand, the optimum beaker radius increases with decreasing the density of the detector material while the beaker height decreases. PMID- 28340392 TI - 237Np analytical method using 239Np tracers and application to a contaminated nuclear disposal facility. AB - Environmental 237Np analyses are challenged by low 237Np concentrations and lack of an available yield tracer; we report a rapid, inexpensive 237Np analytical approach employing the short lived 239Np (t1/2 = 2.3 days) as a chemical yield tracer followed by 237Np quantification using inductively coupled plasma-mass spectrometry. 239Np tracer is obtained via separation from a 243Am stock solution and standardized using gamma spectrometry immediately prior to sample processing. Rapid digestions using a commercial, 900 W "Walmart" microwave and Parr microwave vessels result in 99.8 +/- 0.1% digestion yields, while chromatographic separations enable Np/U separation factors on the order of 106 and total Np yields of 95 +/- 4% (2sigma). Application of this method to legacy soil samples surrounding a radioactive disposal facility (the Subsurface Disposal Area at Idaho National Laboratory) reveal the presence of low level 237Np contamination within 600 m of this site, with maximum 237Np concentrations on the order of 103 times greater than nuclear weapons testing fallout levels. PMID- 28340390 TI - The association of eating performance and environmental stimulation among older adults with dementia in nursing homes: A secondary analysis. AB - BACKGROUND: Nursing home residents with dementia experience increased risk for compromised eating performance due to intrapersonal, interpersonal, and environmental factors. Environmental stimulation is physical, social, and/or sensory stimulation present in the environment that can potentially trigger individuals' emotion or motivate physical reactions. Beyond the personal factors, there is a lack of evidence on how environmental stimulation influences individuals' eating performance at mealtimes. OBJECTIVES: This study examined the association between environmental stimulation and eating performance among nursing home residents with dementia. DESIGN: This study was a secondary analysis using baseline videos selected from a communication intervention study, where videos were recorded to capture staff-resident interactions during care activities for nursing home residents with dementia. Videos were included in this study only if residents demonstrated eating activities at mealtimes. SAMPLE AND SETTING: A total of 36 videos were selected (mean length=4min). The sample included 15 residents with dementia (mean age=86), and 19 certified nursing assistants (mean age=36) in 8 nursing homes. METHODS: The dependent variable was eating performance as measured by the Level of Eating Independence scale (range: 15-36, with higher scores indicating better eating performance). The independent variables were characteristics of environmental stimulation measured by the Person-Environment Apathy Rating-Environment subscale (stimulation clarity, stimulation strength, stimulation specificity, interaction involvement, physical accessibility, and environmental feedback). Each characteristic was rated on a 1 4 scale with higher scores indicating more desirable environmental stimulation. Multilevel models were used to examine the association between eating performance and environmental stimulation, adjusting for resident characteristics (i.e., age, gender, dementia stage, function, comorbidity, psychoactive medication use) and nesting effects of residents and staff. RESULTS: Resident participants demonstrated moderate levels of eating performance (M=27.08, SD=5.16). Eating performance was significantly lower among older residents, those with more advanced dementia, and higher comorbidity. After controlling for resident characteristics, eating performance was significantly associated with stimulation specificity (how the stimulation is delivered and tailored to the resident), and was not associated with other environmental stimulation characteristics. For each 1 point increase in stimulation specificity, eating performance increased by 8.78 points (95% CI=0.59, 16.97). CONCLUSIONS: Environmental stimulation that is personally tailored to a resident' needs and preferences and directly offered to a resident contributed to better eating performance among residents with dementia. The findings will direct future development and implementation of person-directed mealtime care programs and dining environment arrangements for residents with dementia in nursing homes. PMID- 28340393 TI - When public health intervention is not successful: Cost sharing, crowd-out, and selection in Korea's National Cancer Screening Program. AB - This study investigates the impact of and behavioral responses to cost sharing in Korea's National Cancer Screening Program, which provides free stomach and breast cancer screenings to those with an income below a certain cutoff. Free cancer screening substantially increases the screening take up rate, yielding more cancer detections. However, the increase in cancer detection is quickly crowded out by cancer detection through other channels such as diagnostic testing and private cancer screening. Further, compliers are much less likely to have cancer than never takers. Crowd-out and selection help explain why the program has been unable to reduce cancer mortality. PMID- 28340394 TI - Assessment of engineered surfaces roughness by high-resolution 3D SEM photogrammetry. AB - We describe a methodology to obtain three-dimensional models of engineered surfaces using scanning electron microscopy and multi-view photogrammetry (3DSEM). For the reconstruction of the 3D models of the surfaces we used freeware available in the cloud. The method was applied to study the surface roughness of metallic samples patterned with parallel grooves by means of laser. The results are compared with measurements obtained using stylus profilometry (PR) and SEM stereo-photogrammetry (SP). The application of 3DSEM is more time demanding than PR or SP, but it provides a more accurate representation of the surfaces. The results obtained with the three techniques are compared by investigating the influence of sampling step on roughness parameters. PMID- 28340395 TI - A quint-wavelength UV spectroscopy for simultaneous determination of dichlorobenzene, chlorobenzene, and benzene in simulated water reduced by nanoscale zero-valent Fe/Ni bimetal. AB - A quint-wavelength UV spectroscopy for rapid determination of dichlorobenzene (DCB), chlorobenzene (CB) and benzene (B) was developed for the dechlorination process of DCB reduced by nanoscale zero-valent Fe/Ni bimetal. Based on the absorbance measurements at 260, 269, 277, 290 and 300nm, the equations for calculating the concentration of DCB and CB and B were established, in which the spectral interference from the nanoparticles could be effectively minimized. The results show that the present method has a good measurement precision (the relative standard deviations are within 2.0%) and accuracy (the recoveries are between 89 and 111%) in the DCB, CB and B's quantification. The present method is simple, rapid, and such a methodology is very suitable to be used for evaluating the dechlorination performance of chlorinated aromatic compounds in the presence of bimetal nanoparticle. PMID- 28340396 TI - Spectral studies on anthracene based dual sensor for Hg2+ and Al3+ ions with two distinct output modes of detection. AB - A simple and easily synthesized colorimetric and fluorescent chemosensor 1, based on aromatic OH and imine moieties as a binding and anthracene as signaling unit, has been synthesized in a one-step procedure. The chemosensor 1 is developed as a dual chemosensor for detection of Hg2+ and Al3+ ions in CH3OH, which exhibited a color change from light yellow to dark yellow with Hg2+ ions, enabling 1 a suitable "bare eye" indicator for Hg2+ ions. On the other hand, fluorescent enhancement with blue shift along with brilliant cyan fluorescence was observed upon binding with Al3+ ions. A possible sensing mechanism has been proposed by means of Job's plot and 1H NMR titration. PMID- 28340397 TI - Quantification of hydrocarbon species on surfaces by combined microbalance-FTIR. AB - Absorption coefficients for the asymmetric stretching modes of CH3 and CH2 groups formed by adsorbing alkyl chained species from the vapour phase onto two different adsorbents; a gamma-alumina support material and a supported metal catalyst have been determined using a custom made thermogravimetric-infrared cell. Results show that despite variations in the individually calculated absorption coefficients (ca. +/-20%), the ratio of the absorption coefficients (CH2:CH3) remained consistent despite employing adsorbates of varying chain length and functionality, and despite the choice of adsorbents which exhibited different surface areas and light scattering characteristics. The use of this absorption coefficient ratio has been shown to be applicable in the quantification of the average chain length of multiple adsorbed species of differing chain length. The potential for applying this to scenarios where reactions on surfaces are monitored is discussed. PMID- 28340398 TI - Proteomics analysis of maize (Zea mays L.) grain based on iTRAQ reveals molecular mechanisms of poor grain filling in inferior grains. AB - In maize, inferior grains (IG) located on the upper part of the ear have poor grain filling process compared to superior grains (SG) located on the middle and lower parts of the ear. This difference limits satisfactory yield and quality; however, the underlying molecular mechanisms remain unknown. Here, using the isobaric tag for relative and absolute quantification (iTRAQ) technology, the proteomes of IG and SG during early and middle grain filling stages were investigated. In total, 4720 proteins were identified in maize grain and 305 differentially accumulated proteins (DiAPs) were detected between IG and SG. These DiAPs were involved in diverse cellular and metabolic processes with preferred distribution in protein synthesis/destination and metabolism. Compared to SG, DiAPs related to cell growth/division and starch synthesis were lag accumulated and down-regulated in IG, respectively, resulting in smaller sink sizes and lower sink activities in IG. Meanwhile, impediment of the glycolysis pathway in IG may lead to reduce energy supply and building materials for substance synthesis. Additionally, reactive oxygen species (ROS) homeostasis and the defense system were disturbed in IG, which might lead to reduce protection against various environmental stresses. The present study provides new information on the proteomic differences between IG and SG, and explains possible molecular mechanisms for poor grain filling in IG. PMID- 28340399 TI - Metacognition in the classroom: The association between students' exam predictions and their desired grades. AB - Students are overconfident when making grade predictions, and worse, the lowest performing students are generally the most overconfident. Because metacognitive accuracy is associated with academic performance, multiple studies have attempted to improve metacognitive accuracy with mixed results. However, these studies may be of limited use because we do not understand the types of information university students use to make performance predictions. The current studies examined the possibility that university students' predictions are associated with their desires-the grade they want to receive. Studies 1-4 demonstrated that students' desired grades were strongly associated with their grade predictions across different courses, universities, and measurement strategies. Study 4 also showed that, if warned about the previous results, students could reduce their reliance on their desired grades and improve the accuracy of their predictions relative to control. Together, results demonstrated that students' exam predictions are associated with their desired grades. PMID- 28340401 TI - Clinical supervision in perioperative nursing education in Sweden - A questionnaire study. PMID- 28340400 TI - Pharmacoinformatics exploration of polyphenol oxidases leading to novel inhibitors by virtual screening and molecular dynamic simulation study. AB - Polyphenol oxidases (PPOs)/tyrosinases are metal-dependent enzymes and known as important targets for melanogenesis. Although considerable attempts have been conducted to control the melanin-associated diseases by using various inhibitors. However, the exploration of the best anti-melanin inhibitor without side effect still remains a challenge in drug discovery. In present study, protein structure prediction, ligand-based pharmacophore modeling, virtual screening, molecular docking and dynamic simulation study were used to screen the strong novel inhibitor to cure melanogenesis. The 3D structures of PPO1 and PPO2 were built through homology modeling, while the 3D crystal structures of PPO3 and PPO4 were retrieved from PDB. Pharmacophore modeling was performed using LigandScout 3.1 software and top five models were selected to screen the libraries (2601 of Aurora and 727, 842 of ZINC). Top 10 hit compounds (C1-10) were short-listed having strong binding affinities for PPO1-4. Drug and synthetic accessibility (SA) scores along with absorption, distribution, metabolism, excretion and toxicity (ADMET) assessment were employed to scrutinize the best lead hit. C4 (name) hit showed the best predicted SA score (5.75), ADMET properties and drug likeness behavior among the short-listed compounds. Furthermore, docking simulations were performed to check the binding affinity of C1-C10 compounds against target proteins (PPOs). The binding affinity values of complex between C4 and PPOs were higher than those of other complexes (-11.70, -12.1, -9.90 and 11.20kcal/mol with PPO1, PPO2, PPO3, or PPO4, respectively). From comparative docking energy and binding analyses, PPO2 may be considered as better target for melanogenesis than others. The potential binding modes of C4, C8 and C10 against PPO2 were explored using molecular dynamics simulations. The root mean square deviation and fluctuation (RMSD/RMSF) graphs results depict the significance of C4 over the other compounds. Overall, bioactivity and ligand efficiency profiles suggested that the proposed hit may be more effective inhibitors for melanogenesis. PMID- 28340402 TI - Eslicarbazepine acetate as a therapeutic option in a patient with carbamazepine induced rash and HLA-A*31:01. AB - Eslicarbazepine acetate (ESL) is an anticonvulsant drug approved for the treatment of focal epilepsies, and related to oxcarbazepine and carbamazepine (CBZ), which are also derivatives of the dibenzazepine family. ESL is contraindicated in patients with hypersensitivity reactions to CBZ.We report a patient with frontal lobe epilepsy responding to treatment with ESL without any serious adverse effects after developing a severe skin rash following treatment with CBZ. HLA testing revealed an HLA-A*31:01 haplotype, that increases the risk of CBZ-induced cutaneous reactions.This case study shows that, in clinical practice, ESL may be considered in a patient with the HLA-A*31:01 haplotype and a hypersensitivity reaction to CBZ. PMID- 28340403 TI - Micro- and macrovascular function in children with sickle cell anaemia and sickle cell haemoglobin C disease. AB - It is unclear whether vascular function is affected similarly in children with sickle cell anaemia (SS) and children with sickle haemoglobin C (SC) disease. Therefore, we compared micro and macrovascular functions in healthy (AA) children, children with SS and SC disease, and assessed their association with physical activity. Participants (24 SS, 22 SC and 16 AA), were compared in terms of 1) thermal hyperaemic response (finger pad warming to 42 degrees C) measured by Laser Doppler techniques, 2) arterial stiffness determined by pulse wave velocity, 3) daily energy expenditure related to moderate and intense physical activities estimated by questionnaire and 4) fitness level, evaluated by the six minute walk test. Response to heating differed between SS, SC and controls. Peripheral microvascular reactivity was lower and pulse wave velocity higher in SS compared to AA. SC had blunted microvascular reactivity in response to heating compared to AA but pulse wave velocity was not different within the two groups. Physical activity and fitness levels were markedly lower in sickle cell patients compared to healthy controls but no association was observed with vascular function. Microvasodilatory reserve is decreased in both SS and SC patients but only SS patients were also characterised by impaired macrovascular function. PMID- 28340404 TI - Synthesis, in vitro antiproliferative activity and kinase profile of new benzimidazole and benzotriazole derivatives. AB - Protein kinase 2 (CK2), a member of the serine/threonine kinase family, has been established as a promising target in anticancer therapy. New derivatives of known CK2 inhibitors 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi) and 4,5,6,7-tetrabromo 1H-benzotriazole (TBBt) bearing azide or substituted triazole groups were synthesized. Their influence on the activity of human recombinant CK2alpha and cytotoxicity against normal and cancer cell lines were evaluated. TBBi derivatives with triazole substituted with carboxyl substituent (7 and 10) exhibited the most potent inhibitory activity against CK2 with Ki value in the range of 1.96-0.91MUM, respectively. New TBBi derivatives 2, 3, 5 and 9 have demonstrated the EC50, in the range of 12-25MUM and 13-29MUM respectively towards CCRF-CEM and MCF-7 cells. Derivatives TBBi decreased viability of cancer cells more efficiently than BALB cells and the biggest differences were observed for the azide substituted compounds 3 and 5. The effect of the most active compounds on the activity of eight off-target kinases was evaluated. Inhibitory efficiency of CK2-mediated p65 phosphorylation was demonstrated for the TBBi and compound 12. PMID- 28340405 TI - Population pharmacokinetic modeling of furosemide in patients with hypertension and fluid overload conditions. AB - BACKGROUND: Furosemide is a loop diuretic drug frequently indicated in hypertension and fluid overload conditions such as congestive heart failure and hepatic cirrhosis. OBJECTIVE: The purpose of the study was to establish a population pharmacokinetic model for furosemide in Indian hypertensive and fluid overload patients, and to evaluate effects of covariates on the volume of distribution (V/F) and oral clearance (CL/F) of furosemide. METHODS: A total of 188 furosemide plasma sample concentrations from 63 patients with hypertension or fluid overload conditions were collected in this study. The population pharmacokinetic model for furosemide was built using Phoenix NLME 1.3 software. The covariates included age, sex, body surface area, bodyweight, height and creatinine clearance (CRCL). RESULTS: The pharmacokinetic data of furosemide was adequately explained by a two-compartment linear pharmacokinetic model with first order absorption and an absorption lag-time. The mean values of CL/F and Vd/F of furosemide in the patients were 15.054Lh-1 and 4.419L, respectively. Analysis of covariates showed that CRCL was significantly influencing the clearance of furosemide. CONCLUSION: The final population pharmacokinetic model was demonstrated to be appropriate and effective and it can be used to assess the pharmacokinetic parameters of furosemide in Indian patients with hypertension and fluid overload conditions. PMID- 28340406 TI - A local adjustment strategy for the initialization of dynamic causal modelling to infer effective connectivity in brain epileptic structures. AB - This paper addresses the question of effective connectivity in the human cerebral cortex in the context of epilepsy. Among model based approaches to infer brain connectivity, spectral Dynamic Causal Modelling is a conventional technique for which we propose an alternative to estimate cross spectral density. The proposed strategy we investigated tackles the sub-estimation of the free energy using the well-known variational Expectation-Maximization algorithm highly sensitive to the initialization of the parameters vector by a permanent local adjustment of the initialization process. The performance of the proposed strategy in terms of effective connectivity identification is assessed using simulated data generated by a neuronal mass model (simulating unidirectional and bidirectional flows) and real epileptic intracerebral Electroencephalographic signals. Results show the efficiency of proposed approach compared to the conventional Dynamic Causal Modelling and the one wherein a deterministic annealing scheme is employed. PMID- 28340407 TI - Transmission of persistent ionizing radiation-induced foci through cell division in human primary cells. AB - Unrepaired DNA double-strand breaks (DSBs) induced by ionizing radiation are associated with lethal effects and genomic instability. After the initial breaks and chromatin destabilization, a set of post-translational modifications of histones occurs, including phosphorylation of serine 139 of histone H2AX (gammaH2AX), which leads to the formation of ionizing radiation-induced foci (IRIF). DSB repair results in the disappearance of most IRIF within hours after exposure, although some remain 24h after irradiation. Their relation to unrepaired DSBs is generally accepted but still controversial. This study evaluates the frequency and kinetics of persistent IRIF and analyzes their impact on cell proliferation. We observed persistent IRIF up to 7 days postirradiation, and more than 70% of cells exposed to 5Gy had at least one of these persistent IRIF 24h after exposure. Moreover we demonstrated that persistent IRIF did not block cell proliferation definitively. The frequency of IRIF was lower in daughter cells, due to asymmetric distribution of IRIF between some of them. We report a positive association between the presence of IRIF and the likelihood of DNA missegregation. Hence, the structure formed after the passage of a persistent IRI focus across the S and G2 phases may impede the correct segregation of the affected chromosome's sister chromatids. The ensuing abnormal resolution of anaphase might therefore cause the nature of IRIF in daughter-cell nuclei to differ before and after the first cell division. The resulting atypical chromosomal assembly may be lethal or result in a gene dosage imbalance and possibly enhanced genomic instability, in particular in the daughter cells. PMID- 28340408 TI - Ongoing evolution of Pseudomonas aeruginosa PAO1 sublines complicates studies of DNA damage repair and tolerance. AB - Sublines of the major P. aeruginosa reference strain PAO1 are derivatives of the original PAO1 isolate, which are maintained in laboratories worldwide. These sublines display substantial genomic and phenotypic variation due to ongoing microevolution. Here, we examined four sublines, MPAO1, PAO1-L, PAO1-DSM and PAO1 UT, originated from different laboratories, and six DNA polymerase-deficient mutants from the P. aeruginosa MPAO1 transposon library for their employment in elucidation of DNA damage repair and tolerance mechanisms in P. aeruginosa. We found that PAO1 subline PAO1-UT carries a large deletion encompassing the DNA damage inducible imuA-imuB-imuC cassette (PA0669-PA0671), which is implied in mutagenesis in several species. Furthermore, the genetic changes leading to variation in the functionality of the MexEF-OprN efflux system contributed largely to the phenotypic discordance between P. aeruginosa PAO1 sublines. Specifically, we identified multiple mutations in the mexT gene, which encodes a transcriptional regulator of the mexEF-oprN genes, mutations in the mexF, and complete absence of these genes. Of the four tested sublines, MPAO1 was the only subline with the functional MexEF-OprN multidrug efflux system. Active efflux through MexEF-OprN rendered MPAO1 highly resistant to chloramphenicol and ciprofloxacin. Moreover, the functions of specialized DNA polymerase IV and nucleotide excision repair (NER) in 4-NQO-induced DNA damage tolerance appeared to be masked in MPAO1, while were easily detectable in other sublines. Finally, the frequencies of spontaneous and MMS-induced Rifr mutations were also significantly lower in MPAO1 in comparison to the PAO1 sublines with impaired MexEF-OprN efflux system. The MexEF-OprN-attributed differences were also observed between MPAO1 and MPAO1-derived transposon mutants from the two-allele transposon mutant collection. Thus, the accumulating mutations and discordant phenotypes of the PAO1 derivatives challenge the reproducibility and comparability of the results obtained with different PAO1 sublines and also limit the usage of the MPAO1 transposon library in DNA damage tolerance and mutagenesis studies. PMID- 28340409 TI - Mitochondrial DNA damage and oxidative damage in HL-60 cells exposed to 900MHz radiofrequency fields. AB - HL-60 cells, derived from human promyelocytic leukemia, were exposed to continuous wave 900MHz radiofrequency fields (RF) at 120MUW/cm2 power intensity for 4h/day for 5 consecutive days to examine whether such exposure is capable damaging the mitochondrial DNA (mtDNA) mediated through the production of reactive oxygen species (ROS). In addition, the effect of RF exposure was examined on 8-hydroxy-2'-dexoyguanosine (8-OHdG) which is a biomarker for oxidative damage and on the mitochondrial synthesis of adenosine triphosphate (ATP) which is the energy required for cellular functions. The results indicated a significant increase in ROS and significant decreases in mitochondrial transcription factor A, mtDNA polymerase gamma, mtDNA transcripts and mtDNA copy number in RF-exposed cells compared with those in sham-exposed control cells. In addition, there was a significant increase in 8-OHdG and a significant decrease in ATP in RF-exposed cells. The response in positive control cells exposed to gamma radiation (GR, which is also known to induce ROS) was similar to those in RF-exposed cells. Thus, the overall data indicated that RF exposure was capable of inducing mtDNA damage mediated through ROS pathway which also induced oxidative damage. Prior-treatment of RF- and GR-exposed the cells with melatonin, a well-known free radical scavenger, reversed the effects observed in RF-exposed cells. PMID- 28340411 TI - Synthesis and biological evaluation of novel chalcone derivatives as a new class of microtubule destabilizing agents. AB - A series of novel chalcone derivatives were designed and synthesized as potential antitumor agents. Structures of target molecules were confirmed by 1H NMR, 13C NMR and HR-MS, and evaluated for their in vitro anti-proliferative activities using MTT assay. Among them, compound 12k displayed potent activity against the test tumor cell lines including multidrug resistant human cancer lines, with the IC50 values ranged from 3.75 to 8.42 MUM. In addition, compound 12k was found to induce apoptosis in NCI-H460 cells via the mitochondrial pathway, including an increase of the ROS level, loss of mitochondrial membrane potential, release of cytochrome c, down-regulation of Bcl-2, up-regulation of Bax, activation of caspase-9 and caspase-3, respectively. Moreover, the cell cycle analysis indicated that 12k effectively caused cell cycle arrest at G2/M phase. The results of tubulin polymerization assay displayed that 12k could inhibit tubulin polymerization in vitro. Furthermore, molecular docking study indicated that 12k can be binding to the colchicine site of tubulin. PMID- 28340410 TI - Development of fusogenic glass surfaces that impart spatiotemporal control over macrophage fusion: Direct visualization of multinucleated giant cell formation. AB - Implantation of synthetic material, including vascular grafts, pacemakers, etc. results in the foreign body reaction and the formation of multinucleated giant cells (MGCs) at the exterior surface of the implant. Despite the long-standing premise that fusion of mononucleated macrophages results in the formation of MGCs, to date, no published study has shown fusion in context with living specimens. This is due to the fact that optical-quality glass, which is required for the majority of live imaging techniques, does not promote macrophage fusion. Consequently, the morphological changes that macrophages undergo during fusion as well as the mechanisms that govern this process remain ill-defined. In this study, we serendipitously identified a highly fusogenic glass surface and discovered that the capacity to promote fusion was due to oleamide contamination. When adsorbed on glass, oleamide and other molecules that contain long-chain hydrocarbons promoted high levels of macrophage fusion. Adhesion, an essential step for macrophage fusion, was apparently mediated by Mac-1 integrin (CD11b/CD18, alphaMbeta2) as determined by single cell force spectroscopy and adhesion assays. Micropatterned glass further increased fusion and enabled a remarkable degree of spatiotemporal control over MGC formation. Using these surfaces, we reveal the kinetics that govern MGC formation in vitro. We anticipate that the spatiotemporal control afforded by these surfaces will expedite studies designed to identify the mechanism(s) of macrophage fusion and MGC formation with implication for the design of novel biomaterials. PMID- 28340412 TI - Discovery of 2-substituted 1H-benzo[d]immidazole-4-carboxamide derivatives as novel poly(ADP-ribose)polymerase-1 inhibitors with in vivo anti-tumor activity. AB - Novel 1H-benzo[d]immidazole-4-carboxamide derivatives bearing five-membered or six-membered N-heterocyclic moieties at the 2-position were designed and synthesized as PARP-1 inhibitors. Structure-activity relationships were conducted and led to a number of potent PARP-1 inhibitors having IC50 values in the single or double digit nanomolar level. Some potent PARP-1 inhibitors also had similar inhibitory activities against PARP-2. Among all the synthesized compounds, compound 10a and 11e displayed strong potentiation effects on temozolomide (TMZ) in MX-1 cells (PF50 = 7.10, PF50 = 4.17). In vivo tumor growth inhibition was investigated using compound 10a in combination with TMZ, and it was demonstrated that compound 10a could strongly potentiate the cytotoxicity of TMZ in MX-1 xenograft tumor model. Two co-crystal structures of compounds 11b and 15e complexed with PARP-1 were achieved and demonstrated a unique binding mode of these benzo-imidazole derivatives. PMID- 28340413 TI - Design, synthesis and biological evaluation of novel coumarin-based benzamides as potent histone deacetylase inhibitors and anticancer agents. AB - Histone deacetylases (HDACs) are attractive therapeutic targets for the treatment of cancer and other diseases. It has four classes (I-IV), among them especially class I isozyme are involved in promoting tumor cells proliferation, angiogenesis, differentiation, invasion and metastasis and also viable targets for cancer therapeutics. A novel series of coumarin-based benzamides was designed and synthesized as HDAC inhibitors. The cytotoxic activity of the synthesized compounds (8a-u) was evaluated against six human cancer cell lines including HCT116, A2780, MCF7, PC3, HL60 and A549 and a single normal cell line (Huvec). We evaluated their inhibitory activities against pan HDAC and HDAC1 isoform. Four compounds (8f, 8q, 8r and 8u) showed significant cytotoxicity with IC50 in the range of 0.53-57.59 MUM on cancer cells and potent pan-HDAC inhibitory activity (consists of HDAC isoenzymes) (IC50 = 0.80-14.81 MUM) and HDAC1 inhibitory activity (IC50 = 0.47-0.87 MUM and also, had no effect on Huvec (human normal cell line) viability (IC50 > 100 MUM). Among them, 8u displayed a higher potency for HDAC1 inhibition with IC50 value of 0.47 +/- 0.02 MUM near equal to the reference drug Entinostat (IC50 = 0.41 +/- 0.06 MUM). Molecular docking studies and Molecular dynamics simulation of compound 8a displayed possible mode of interaction between this compound and HDAC1enzyme. PMID- 28340414 TI - Intersection crash prediction modeling with macro-level data from various geographic units. AB - There have been great efforts to develop traffic crash prediction models for various types of facilities. The crash models have played a key role to identify crash hotspots and evaluate safety countermeasures. In recent, many macro-level crash prediction models have been developed to incorporate highway safety considerations in the long-term transportation planning process. Although the numerous macro-level studies have found that a variety of demographic and socioeconomic zonal characteristics have substantial effects on traffic safety, few studies have attempted to coalesce micro-level with macro-level data from existing geographic units for estimating crash models. In this study, the authors have developed a series of intersection crash models for total, severe, pedestrian, and bicycle crashes with macro-level data for seven spatial units. The study revealed that the total, severe, and bicycle crash models with ZIP-code tabulation area data performs the best, and the pedestrian crash models with census tract-based data outperforms the competing models. Furthermore, it was uncovered that intersection crash models can be drastically improved by only including random-effects for macro-level entities. Besides, the intersection crash models are even further enhanced by including other macro-level variables. Lastly, the pedestrian and bicycle crash modeling results imply that several macro-level variables (e.g., population density, proportions of specific age group, commuters who walk, or commuters using bicycle, etc.) can be a good surrogate exposure for those crashes. PMID- 28340415 TI - Uncertainty analysis for effluent trading planning using a Bayesian estimation based simulation-optimization modeling approach. AB - In this study, a Bayesian estimation-based simulation-optimization modeling approach (BESMA) is developed for identifying effluent trading strategies. BESMA incorporates nutrient fate modeling with soil and water assessment tool (SWAT), Bayesian estimation, and probabilistic-possibilistic interval programming with fuzzy random coefficients (PPI-FRC) within a general framework. Based on the water quality protocols provided by SWAT, posterior distributions of parameters can be analyzed through Bayesian estimation; stochastic characteristic of nutrient loading can be investigated which provides the inputs for the decision making. PPI-FRC can address multiple uncertainties in the form of intervals with fuzzy random boundaries and the associated system risk through incorporating the concept of possibility and necessity measures. The possibility and necessity measures are suitable for optimistic and pessimistic decision making, respectively. BESMA is applied to a real case of effluent trading planning in the Xiangxihe watershed, China. A number of decision alternatives can be obtained under different trading ratios and treatment rates. The results can not only facilitate identification of optimal effluent-trading schemes, but also gain insight into the effects of trading ratio and treatment rate on decision making. The results also reveal that decision maker's preference towards risk would affect decision alternatives on trading scheme as well as system benefit. Compared with the conventional optimization methods, it is proved that BESMA is advantageous in (i) dealing with multiple uncertainties associated with randomness and fuzziness in effluent-trading planning within a multi-source, multi-reach and multi-period context; (ii) reflecting uncertainties existing in nutrient transport behaviors to improve the accuracy in water quality prediction; and (iii) supporting pessimistic and optimistic decision making for effluent trading as well as promoting diversity of decision alternatives. PMID- 28340416 TI - Nonradical oxidation from electrochemical activation of peroxydisulfate at Ti/Pt anode: Efficiency, mechanism and influencing factors. AB - Electrochemical activation of peroxydisulfate (PDS) at Ti/Pt anode was systematically investigated for the first time in this work. The synergistic effect produced from the combination of electrolysis and the addition of PDS demonstrates that PDS can be activated at Ti/Pt anode. The selective oxidation towards carbamazepine (CBZ), sulfamethoxazole (SMX), propranolol (PPL), benzoic acid (BA) rather than atrazine (ATZ) and nitrobenzene (NB) was observed in electrochemical activation of PDS process. Moreover, addition of excess methanol or tert-butanol had negligible impact on CBZ (model compound) degradation, demonstrating that neither sulfate radical (SO4-) nor hydroxyl radical (HO) was produced in electrochemical activation of PDS process. Direct oxidation (PDS oxidation alone and electrolysis) and nonradical oxidation were responsible for the degradation of contaminants. The results of linear sweep voltammetry (LSV) and chronoamperometry suggest that electric discharge may integrate PDS molecule with anode surface into a unique transition state structure, which is responsible for the nonradical oxidation in electrochemical activation of PDS process. Adjustment of the solution pH from 1.0 to 7.0 had negligible effect on CBZ degradation. Increase of either PDS concentration or current density facilitated the degradation of CBZ. The presence of chloride ion (Cl-) significantly enhanced CBZ degradation, while addition of bicarbonate (HCO3-), phosphate (PO43-) and humic acid (HA) all inhibited CBZ degradation with the order of HA >> HCO3- > PO43-. The degradation products of CBZ and chlorinated products were also identified. Electrochemical activation of PDS at Ti/Pt anode may serve as a novel technology for selective oxidation of organic contaminants in water and soil. PMID- 28340417 TI - Interfacial interactions between Skeletonema costatum extracellular organic matter and metal oxides: Implications for ceramic membrane filtration. AB - In the current study, the interfacial interactions between the high molecular weight (HMW) compounds of Skeletonema costatum (SKC) extracellular organic matter (EOM) and ZrO2 or Al2O3, were investigated by atomic force microscopy (AFM). HMW SKC-EOM was rigorously characterized and described as a hydrophilic organic compound mainly comprised of polysaccharide-like structures. Lipids and proteins were also observed, although in lower abundance. HMW SKC-EOM displayed attractive forces during approaching (i.e., leading to jump-to-contact events) and adhesion forces during retracting regime to both metal oxides at all solution conditions tested, where electrostatics and hydrogen bonding were suggested as dominant interacting mechanisms. However, the magnitude of these forces was significantly higher on ZrO2 surfaces, irrespective of cation type (Na+ or Ca2+) or concentration. Interestingly, while HMW SKC-EOM interacting forces to Al2O3 were practically insensitive to solution chemistry, the interactions between ZrO2 and HMW SKC-EOM increased with increasing cation concentration in solution. The structure, and lower charge, hydrophilicity, and density of hydroxyl groups on ZrO2 surface would play a key role on favoring zirconia associations with HMW SKC EOM. The current results contribute to advance our fundamental understanding of Algogenic Organic Matter (AOM) interfacial interactions with metal oxides (i.e., AOM membrane fouling), and would highly assist in the proper selection of membrane material during episodic algal blooms. PMID- 28340418 TI - Enantioselective reductive transformation of climbazole: A concept towards quantitative biodegradation assessment in anaerobic biological treatment processes. AB - An efficient chiral method-based using liquid chromatography-high resolution-mass spectrometry analytical method has been validated for the determination of climbazole (CBZ) enantiomers in wastewater and sludge with quantification limits below the 1 ng/L and 2 ng/g range, respectively. On the basis of this newly developed analytical method, the stereochemistry of CBZ was investigated over time in sludge biotic and sterile batch experiments under anoxic dark and light conditions and during wastewater biological treatment by subsurface flow constructed wetlands. CBZ stereoselective degradation was exclusively observed under biotic conditions, confirming the specificity of enantiomeric fraction variations to biodegradation processes. Abiotic CBZ enantiomerization was insignificant at circumneutral pH and CBZ was always biotransformed into CBZ alcohol due to the specific and enantioselective reduction of the ketone function of CBZ into a secondary alcohol function. This transformation was almost quantitative and biodegradation gave good first order kinetic fit for both enantiomers. The possibility to apply the Rayleigh equation to enantioselective CBZ biodegradation processes was investigated. The results of enantiomeric enrichment allowed for a quantitative assessment of in situ biodegradation processes due to a good fit (R2 > 0.96) of the anoxic/anaerobic CBZ biodegradation to the Rayleigh dependency in all the biotic microcosms and was also applied in subsurface flow constructed wetlands. This work extended the concept of applying the Rayleigh equation towards quantitative biodegradation assessment of organic contaminants to enantioselective processes operating under anoxic/anaerobic conditions. PMID- 28340419 TI - Photolytic degradation of the beta-blocker nebivolol in aqueous solution. AB - Nebivolol (NEB) is one of the top-sold prescription drugs belonging to the third generation of beta-blockers. However, so far, occurrence data in the environment are lacking. Within this study NEB has been found for the first time in effluent samples of wastewater treatment plants in Germany with an average concentration of 13 ng L-1. Its photodegradation behavior in the environment and in technical processes is largely unknown. To fill this gap, three different UV treatment procedures (UV-C at 254 nm, UV-B at 312 nm and UV-A at 365 nm) were investigated in three different matrices: pure water, pure water in presence of the hydroxyl radical (OH) scavenger tert.-butanol and real wastewater. No elimination was observed during UV-A treatment. In contrast, NEB degradation during UV-B and UV-C treatment followed pseudo first order reaction kinetics, with highest removal rate during UV-C treatment in pure water (k = 7.8 * 10-4 s-1). The rate constant for UV-C irradiation decreased to 2.9 * 10-4 s-1 in the presence of the OH scavenger and in the presence of the wastewater matrix. The rate constant for the UV-B lamp was 4.4 * 10-4 s-1, Three transformation products were identified after UV-B and UV-C photolytic degradation using high resolution mass spectrometry. The main photoreaction is the substitution of the fluorine atoms of NEB by hydroxyl groups. A photolytic cleavage of the CF bond can be excluded as the high bond dissociation energy of aromatic CF bonds (525 kJ mol-1), exceeds the energy of electromagnetic radiation applied in the present study (>=254 nm, i.e., max. 471 kJ E-1). The quantum yields for NEB degradation for the UV-C lamp achieved in pure water, the OH scavenged system and wastewater matrix were Phideg = 0.53, 0.19 and 0.22, respectively. For UV-B Phideg was 0.023 +/- 0.003, noticeable differences in quantum yield were not found. The photooxidation involves reactive oxygen species such as superoxide and singlet oxygen. These oxidative species may be formed upon reaction of photo-excited NEB with oxygen. PMID- 28340420 TI - Extended anaerobic conditions in the biological wastewater treatment: Higher reduction of toxicity compared to target organic micropollutants. AB - Extended anaerobic conditions during biological wastewater treatment may enhance the biodegradation of micropollutants. To explore this, we combined iron-reducing or substrate-limited anaerobic conditions and aerobic pilot-scale reactors directly at a wastewater treatment plant. To investigate the detoxification by these processes, we applied two in vitro bioassays for baseline toxicity (Microtox) and reactive toxicity (AREc32) as well as in vivo bioassays with aquatic model species in two laboratory experiments (Desmodesmus subspicatus, Daphnia magna) and two on-site, flow-through experiments (Potamopyrgus antipodarum, Lumbriculus variegatus). Moreover, we analyzed 31 commonly occurring micropollutants and 10 metabolites. The baseline toxicity of raw wastewater was effectively removed in full-scale and reactor scale activated sludge treatment (>85%), while the oxidative stress response was only partially removed (>61%). A combination of an anaerobic pre-treatment under iron reducing conditions and an aerobic nitrification significantly further reduced the residual in vitro toxicities by 46-60% and outperformed the second combination consisting of an aerobic pre-treatment and an anaerobic post-treatment under substrate-limiting conditions (27-43%). Exposure to effluents of the activated sludge treatment did not induce adverse in vivo effects in aquatic invertebrates. Accordingly, no further improvement in water quality could be observed. Compared to that, the removal of persistent micropollutants was increased. However, this observation was restricted to a limited number of compounds and the removal of the sum concentration of all target micropollutants was relative low (14-17%). In conclusion, combinations of strictly anaerobic and aerobic processes significantly enhanced the removal of specific and non-specific in vitro toxicities. Thus, an optimization of biological wastewater treatment can lead to a substantially improved detoxification. These otherwise hidden capacities of a treatment technology can only be uncovered by a complementary biological analysis. PMID- 28340422 TI - The clinicopathologic relevance of RECK gene polymorphisms in ameloblastoma. AB - OBJECTIVE: To investigate the relationship between RECK gene polymorphisms and the clinicopathologic features of ameloblastoma. DESIGN: Normal gingival mucosa specimens were obtained from 10 healthy volunteers. Ameloblastomas were surgically removed from 30 patients and part of the tumor specimens were used to detect RECK gene polymorphisms by using PCR-single-strand conformation polymorphism (PCR-SSCP) and DNA sequencing analysis. Expression of RECK and MMP-9 protein was measured using western blot. RESULTS: The overall SNP rate was 46.7% (14/30). Four polymorphisms were detected in exon 9, 11, 13, 15 of the RECK gene: two synonymous (P520P and R625R) and two missense SNPs (V275I and I395V). RECK protein expression in specimens with minor RECK SNPs was lower than that in specimens without RECK SNPs (P<0.05), and, RECK protein expression in specimens with and without RECK SNPs was lower than that in the normal gingiva specimens (P<0.05). MMP-9 protein expression in specimens with minor RECK SNPs was higher than that in specimens without RECK SNPs (P<0.05), and MMP-9 protein expression in specimens with and without RECK SNPs was higher than that in normal gingiva specimens (P<0.05). RECK gene polymorphisms were closely associated with active proliferation, capsular invasion, and clinical recurrence of ameloblastoma. CONCLUSION: The rs16932912(G/A) SNP in the RECK gene was closely associated with active proliferation, capsular invasion, and clinical recurrence of ameloblastoma. RECK protein expression was closely associated with the presence of the rs16932912(G/A) SNP. PMID- 28340421 TI - Cannabis use patterns and motives: A comparison of younger, middle-aged, and older medical cannabis dispensary patients. AB - INTRODUCTION: Medical cannabis is increasingly being used for a variety of health conditions as more states implement legislation permitting medical use of cannabis. Little is known about medical cannabis use patterns and motives among adults across the lifespan. METHODS: The present study examined data collected at a medical cannabis dispensary in San Francisco, California. Participants included 217 medical cannabis patients who were grouped into age-defined cohorts (younger: 18-30, middle-aged: 31-50, and older: 51-72). The age groups were compared on several measures of cannabis use, motives and medical conditions using one-way ANOVAs, chi-square tests and linear regression analyses. RESULTS: All three age groups had similar frequency of cannabis use over the past month; however, the quantity of cannabis used and rates of problematic cannabis use were higher among younger users relative to middle-aged and older adults. The association between age and problematic cannabis use was moderated by age of regular use initiation such that earlier age of regular cannabis use onset was associated with more problematic use in the younger users, but not among older users. Middle-aged adults were more likely to report using medical cannabis for insomnia, while older adults were more likely to use medical cannabis for chronic medical problems such as cancer, glaucoma and HIV/AIDS. Younger participants reported cannabis use when bored at a greater rate than middle-aged and older adults. CONCLUSIONS: Findings suggest that there is an age-related risk for problematic cannabis use among medical cannabis users, such that younger users should be monitored for cannabis use patterns that may lead to deleterious consequences. PMID- 28340423 TI - Carbon nanotube-impeded transport of non-steroidal anti-inflammatory drugs in Xiangjiang sediments. AB - Carbon nanotubes (CNTs), usually with a superior affinity with organic chemicals, are expected to ultimately released to the environment through their manufacturing, usage, and eventual disposal, which will influence the mobility and environmental risk of nonsteroidal anti-inflammatory drugs (NSAIDs). In this study, batch and column experiments were performed to examine the effects of two kinds of multi-walled carbon nanotubes (MWCNTs: MWCNT2040, MWCNT0815) and one kind of single-walled carbon nanotubes (SWCNTs) on the environmental fate of two NSAIDs, paracetamol (PA) and diclofenac sodium (DS), in sediments. Impact ways of CNTs including addition in inflow and mixing with sediments were investigated. The adsorption capacity of NSAIDs on sediments increased with increasing CNTs/sediments ratios and in an order of MWCNT20405%) were observed in 32%, 51% and 75% of ALS patients and 3%, 0% and 20% of CSA patients for the APB, trapezius and deltoid muscles, respectively. The sensitivity for 23 ALS patients with upper limb onset was 78% for the trapezius and 100% for the deltoid muscles. CONCLUSIONS: An abnormal decremental response in the trapezius muscle was 100% specific to ALS in comparison with CSA: abnormal decrement in this muscle would strongly suggest ALS. No decrement in the deltoid muscle might exclude ALS in patients having symptoms with upper-limb onset. SIGNIFICANCE: RNS is useful in differentiation between ALS and CSA. PMID- 28340432 TI - Reorganization of anterior and posterior hippocampal networks associated with memory performance in mesial temporal lobe epilepsy. AB - OBJECTIVE: To investigate the pattern of functional demarcation of hippocampal network and its relationship with memory performance in mesial temporal lobe epilepsy (mTLE) with unilateral hippocampal sclerosis. METHODS: Resting state fMRI data were acquired from fifteen left mTLE patients, fourteen right mTLE patients and twenty healthy subjects. We explore the hippocampal-cortical alterations and corresponding inter-hemispheric functional connectivity (FC) across anterior and posterior hippocampal networks. The association between FC and memory performance was assessed. RESULTS: Left mTLE showed increased intra hemispheric FC in anterior hippocampal networks, including left anterior hippocampal-entorhinal cortex and right anterior hippocampal-orbitofrontal cortex, and decreased inter-hemispheric FC between anterior hippocampus, entorhinal cortex and posterior cingulate cortex. Right mTLE was associated with extensive reduction in inter-hemispheric FC along the areas of anterior and posterior hippocampal networks. Intra-hemispheric FC between left anterior hippocampus and entorhinal cortex was positively correlated with verbal memory in left mTLE. Inter-hemispheric FC between posterior parahippocampal gyrus was negatively correlated with verbal memory in right mTLE. CONCLUSIONS: Our findings suggested that left and right mTLE exhibit different neural reorganization patterns of anterior and posterior hippocampal networks associated with verbal memory. SIGNIFICANCE: The findings may facilitate the characterization of mTLE associated with memory deficit. PMID- 28340433 TI - Feasibility of carbon dioxide sequestration by Spongiochloris sp microalgae during petroleum wastewater treatment in airlift bioreactor. AB - The aim of this work was to study the ability of using Hydrocabonoclastic native microbial and Spongiochloris sp microalgae in airlift bioreactors couples in order to restore hydrocarbons wastewater and develop the capacity of natural systems to reduce greenhouse effect through maximal control of CO2 gas emission in atmosphere. The kinetic parameters of CO2 gas fixation level and conversion it into biological material by microalgae as the biodegradation process effect in hydrocarbon have been evaluated. The result present that maximum specific growth rate MUmax of Spongiochloris sp was (0.87+/-0.04day-1) and the biomass productivity Pmax was attended (1.5+/-0.3gL-1day-1) with maximal CO2 biofixation rate RCO2 (2.9205gL-1day-1). At 30 degrees C and pH (7.6-7.4) the bioreactor showed a good wastewater removal efficiency (99.18%) in total hydrocarbons with COD stabilized within (1.30g/L), this result obtained suggesting that, the bioreactor applied system represented a useful strategy for maximizing CO2 bio mitigation. PMID- 28340434 TI - Potentially direct interspecies electron transfer of methanogenesis for syntrophic metabolism under sulfate reducing conditions with stainless steel. AB - Direct interspecies electron transfer (DIET) is an alternative to syntrophic metabolism in natural carbon cycle as well as in anaerobic digesters, but its function in anaerobic treatment of sulfate-containing wastewater have not yet to be described. Here, conductive stainless steel was added into anaerobic digesters for treating sulfate-containing wastewater to investigate the potential role of DIET in the response to the sulfate impact. Results showed that adding the conductive stainless steel made the anaerobic digestion less affected by the sulfate reduction than adding insulative plastic material. With adding stainless steel, methane production of the digesters increased by 7.5%-24.6%. Microbial analysis showed that the dissimilatory Fe (III) reducers like Geobacter species were enriched on the surface of the stainless steel. These results implied that the potential DIET of methanogenesis was established associating with stainless steel to outcompete the sulfate reduction. PMID- 28340435 TI - Optimization of hydrogen dispersion in thermophilic up-flow reactors for ex situ biogas upgrading. AB - This study evaluates the efficiency of four novel up-flow reactors for ex situ biogas upgrading converting externally provided CO2 and H2 to CH4, via hydrogenotrophic methanogenesis. The gases were injected through stainless steel diffusers combined with alumina ceramic sponge or through alumina ceramic membranes. Pore size, input gas loading and gas recirculation flow rate were modulated to optimize gas-liquid mass transfer, and thus methanation efficiency. Results showed that larger pore size diffusion devices achieved the best kinetics and output-gas quality converting all the injected H2 and CO2, up to 3.6L/LREACTOR.d H2 loading rate. Specifically, reactors' CH4 content increased from 23 to 96% and the CH4 yield reached 0.25LCH4/LH2. High throughput 16S rRNA gene sequencing revealed predominance of bacteria belonging to Anaerobaculum genus and to uncultured order MBA08. Additionally, the massive increase of hydrogenotrophic methanogens, such as Methanothermobacter thermautotrophicus, and syntrophic bacteria demonstrates the selection-effect of H2 on community composition. PMID- 28340436 TI - A comparative study on biochemical methane potential of algal substrates: Implications of biomass pre-treatment and product extraction. AB - Dried powdered algae (SDPA), heat treated algae (MHTA), lipid extracted algae (LEA) and protein extracted algae (PEA) were digested to determine biomethane potential. The average CH4 production rate was ~2.5-times higher for protein and lipid extracted algae than for whole algae (SDPA and MHTA) whilst the cumulative CH4 production was higher for pre-treated algae. Highest cumulative CH4 production (318.7mlCH4g-1VS) was observed for MHTA followed by SDPA (307.4mlCH4g 1VS). CH4/CO2 ratios of 1.5 and 0.7 were observed for MHTA and LEA respectively. Pre-treatment processes disrupted the algal cell wall, exposing intracellular material which remained intact as opposed to product extraction processes which broke down the intracellular compounds resulting in changes in elemental composition and decreases the cumulative gas yield and CH4/CO2 ratio. Comparative analysis determined that the most profitable route of biomass utilisation was protein extraction followed by biogas production giving ~2.5-times higher return on investment. PMID- 28340437 TI - Assessment of microalga biofilms for simultaneous remediation and biofuel generation in mine tailings water. AB - Microalgae crops can generate a biochemical profile of high energy density and may be used for remediation of contaminated waste waters. This manuscript presents a laboratory-scale investigation into the potential for growing endemic microalgae biofilms in phosphorus-enriched nickel refinery tailings water, with an emphasis on product potential and the remediation of heavy metals. The dominant species of the consortia was a Chlorella-like microalga. The growth was monitored over time, with a productivity (0.77+/-0.07gAFDW.m-2.day-1) showing promising potential. The biochemical profile of biomass had a high total carbohydrate yield (40.0%), and a potential for increased lipid yields (6.7 19.5%). Biofilms showed a significant potential for the removal of heavy metals (Ni, Co, Mn, Sr) from the waste water with 24.8%, 10.5%, 24.8% and 26.4% reduction in Ni, Co, Mn and Sr, respectively. Results highlight significant potential for large-scale biofilm biomass production using metal-laden nickel refinery waste waters. PMID- 28340438 TI - Long-term stability and nutrient removal efficiency of aerobic granules at low organic loads. AB - The feasibility of application of aerobic granular sludge cultivated with high organic loads for biological nutrient removal (BNR) from low-strength wastewater was studied. Granules obtained with high-strength (COD=1400mg/L) wastewater were fed with medium (COD=700mg/L) and then low-strength (COD=400mg/L) wastewater. The granules rapidly acclimated to the medium-strength wastewater. However, feeding with low-strength wastewater reduced the F/M ratio from 0.4 to 0.2gCOD/gVSSd and granules disintegration occurred. Re-granulation was obtained after poor settling biomass was washed out and the F/M ratio reached 0.4gCOD/gVSSd. Disintegration of granules coincided with the decrease in extracellular polymeric substances (EPS) content and protein-to-carbohydrate ratio and re-granulation was assisted with the increase in EPS and protein-to-carbohydrate ratio. The results indicated that cultivation of aerobic granules with high organic loads and its implication for BNR treatment of low-strength wastewater while balancing the F/M ratio can be an alternative to reduce start-up period. PMID- 28340439 TI - Co-production of functional xylooligosaccharides and fermentable sugars from corncob with effective acetic acid prehydrolysis. AB - A novel and green approach for the coproduction of xylooligosaccharides (XOS), in terms of a series of oligosaccharide components from xylobiose to xylohexose, and fermentable sugars was developed using the prehydrolysis of acetic acid that was fully recyclable and environmentally friendly, followed by enzymatic hydrolysis. Compared to hydrochloric acid and sulfuric acid, acetic acid hydrolysis provided the highest XOS yield of 45.91% and the highest enzymatic hydrolysis yield. More than 91% conversion of cellulose was achieved in a batch-hydrolysis using only a cellulase loading of 20FPU/g cellulose and even a high solid loading of 20% without any special strategies. The acetic acid pretreated corncob should be washed adequately before saccharification to achieve complete hydrolysis. Consequently, a mass balance analysis showed that 139.8g XOS, 328.1g glucose, 25.1g cellobiose, and 147.8g xylose were produced from 1000g oven dried raw corncob. PMID- 28340440 TI - Bioaugmentation with hydrolytic microbes to improve the anaerobic biodegradability of lignocellulosic agricultural residues. AB - Bioaugmentation with hydrolytic microbes was applied to improve the methane yield of bioreactors fed with agricultural wastes. The efficiency of Clostridium thermocellum and Melioribacter roseus to degrade lignocellulosic matter was evaluated in batch and continuously stirred tank reactors (CSTRs). Results from batch assays showed that C. thermocellum enhanced the methane yield by 34%. A similar increase was recorded in CSTR during the bioaugmentation period; however, at steady-state the effect was noticeably lower (7.5%). In contrast, the bioaugmentation with M. roseus did not promote markedly the anaerobic biodegradability, as the methane yield was increased up to 10% in batch and no effect was shown in CSTR. High-throughput 16S rRNA amplicon sequencing was used to assess the effect of bioaugmentation strategies on bacterial and archaeal populations. The microbial analysis revealed that both strains were not markedly resided into biogas microbiome. Additionally, the applied strategies did not alter significantly the microbial communities. PMID- 28340441 TI - Type D personality, stress coping strategies and self-efficacy as predictors of Facebook intrusion. AB - Recently, Facebook has become one of the most popular social networking sites. People use it more and more often. A number of studies have recently addressed the issue of excessive Facebook use, showing this phenomenon to be a spreading problem. The main aim of the present study was to examine whether Type D personality, self-efficacy and coping strategies are related to Facebook intrusion. The participants were 882 students of Polish universities, all of them Facebook users (72% women, mean age: 22.25 years, SD =2.06). We used the Facebook Intrusion Questionnaire, the Facebook Intensity Scale, the General Self-Efficacy Scale, the Coping Inventory for Stressful Situations, and the Type D Scale. We applied the pen-and-paper procedure. Our results indicate that emotion-oriented and avoidance-oriented strategies of coping in stressful situations are predictors of Facebook intrusion and Facebook intensity. The relations between both Facebook intrusion and intensity and social inhibition are significant only when emotion-oriented coping strategy is controlled. The knowledge of whether coping strategies in stressful situations, such as focus on emotions or avoidance, are related to Facebook intrusion might be useful for clinical purposes. PMID- 28340443 TI - Quantitative EEG abnormalities in major depressive disorder with basal ganglia stroke with lesions in different hemispheres. AB - BACKGROUND: This study aimed to examine the aberrant EEG oscillation in major depressive subjects with basal ganglia stroke with lesions in different hemispheres. METHODS: Resting EEG of 16 electrodes in 58 stroke subjects, 26 of whom had poststroke depression (13 with left-hemisphere lesion and 13 with right) and 32 of whom did not (18 with left lesion and 14 with right), was recorded to obtain spectral power analysis for several frequency bands. Multiple analysis of variance and receiver operating characteristic (ROC) curves were used to identify differences between poststroke depression (PSD) and poststroke non-depression (PSND), treating the different lesion hemispheres separately. Moreover, Pearson linear correlation analysis was conducted to test the severity of depressive symptoms and EEG indices. RESULTS: PSD with left-hemisphere lesion showed increased beta2 power in frontal and central areas, but PSD with right-hemisphere lesion showed increased theta and alpha power mainly in occipital and temporal regions. Additionally, for left-hemisphere lesions, beta2 power in central and right parietal regions provided high discrimination between PSD and PSND, and for right-hemisphere lesions, theta power was similarly discriminative in most regions, especially temporal regions. We also explored the association between symptoms of depression and the power of abnormal bands, but we found no such relationship. LIMITATIONS: The sample size was relatively small and included subjects with different lesions of the basal ganglia. CONCLUSIONS: The aberrant EEG oscillation in subjects with PSD differs between subjects with lesions of the left and right hemispheres, suggesting a complex association between depression and lesion location in stroke patients. PMID- 28340442 TI - Neurocognitive performance as an endophenotype for mood disorder subgroups. AB - BACKGROUND: There is growing evidence that neurocognitive function may be an endophenotype for mood disorders. The goal of this study is to examine the specificity and familiality of neurocognitive functioning across the full range of mood disorder subgroups, including Bipolar I (BP-I), Bipolar II (BP-II), Major Depressive Disorders (MDD), and controls in a community-based family study. METHODS: A total of 310 participants from 137 families with mood spectrum disorders (n=151) and controls (n=159) completed the University of Pennsylvania's Computerized Neurocognitive Battery (CNB) that assessed the accuracy and speed of task performance across five domains. Mixed effects regression models tested association and familiality. RESULTS: Compared to those without mood disorders, participants with BP-I had increased accuracy in complex cognition, while participants with MDD were more accurate in emotion recognition. There was also a significant familial association for accuracy of complex cognition. Mood disorder subgroups did not differ in performance speed in any of the domains. LIMITATIONS: The small number of BP-I cases, and family size limited the statistical power of these analyses, and the cross-sectional assessment of neurocognitive function precluded our ability to determine whether performance precedes or post dates onset of disorder. CONCLUSIONS: This is one of the few community-based family studies of potential neurocognitive endophenotypes that includes the full range of mood disorder subgroups. There were few differences in neurocognitive function except enhanced accuracy in specific domains among those with BP-I and MDD. The differential findings across specific mood disorder subgroups substantiate their heterogeneity in other biologic and endophenotypic domains. PMID- 28340444 TI - Comparative effectiveness of dual-action versus single-action antidepressants for the treatment of depression in people living with HIV/AIDS. AB - BACKGROUND: Depression is the most common psychiatric comorbidity among people living with HIV/AIDS (PLWHA). Little is known about the comparative effectiveness between different types of antidepressants used to treat depression in this population. We compared the effectiveness of dual-action and single-action antidepressants in PLWHA for achieving remission from depression. METHODS: We used data from the Centers for AIDS Research Network of Integrated Clinic Systems to identify 1175 new user dual-action or single-action antidepressant treatment episodes occurring from 2005 to 2014 for PLWHA diagnosed with depression. The primary outcome was remission from depression defined as a Patient Health Questionnaire-9 (PHQ-9) score <5. Mean difference in PHQ-9 depressive symptom severity was a secondary outcome. The main approach was an intent-to-treat (ITT) evaluation complemented with a per protocol (PP) sensitivity analysis. Generalized linear models were fitted to estimate treatment effects. RESULTS: In ITT analysis, 32% of the episodes ended in remission for both dual-action and single-action antidepressants. The odds ratio (OR) of remission was 1.02 (95%CI=0.63,1.67). In PP analysis, 40% of dual-action episodes ended in remission compared to 32% in single-action episodes. Dual-action episodes had 1.33 times the odds of remission (95%CI=0.55,3.21), however the result was not statistically significant. Non-significant differences were also observed for depressive symptom severity. LIMITATIONS: Missing data was common but was addressed with inverse probability weights. CONCLUSIONS: Results suggest that single-action and dual-action antidepressants are equally effective in PLWHA. Remission was uncommon highlighting the need to identify health service delivery strategies that aid HIV providers in achieving full remission of their patients' depression. PMID- 28340445 TI - An updated meta-analysis: Short-term therapeutic effects of repeated transcranial magnetic stimulation in treating obsessive-compulsive disorder. AB - BACKGROUND: This study was conducted to evaluate the short-term therapeutic effects of using repeated transcranial magnetic stimulation (rTMS) to treat obsessive-compulsive disorder (OCD) and to examine potential influencing factors. METHOD: We searched the PubMed, EMBASE, CENTRAL, Wanfang, CNKI, and Sinomed databases on September 18, 2016 and reviewed the references of previous meta analyses. Sham-controlled, randomized clinical trials using rTMS to treat OCD were included. Hedge's g was calculated for the effect size. Subgroup analyses and univariate meta-regressions were conducted. RESULTS: Twenty studies with 791 patients were included. A large effect size (g=0.71; 95%CI, 0.55-0.87; P<0.001) was found for the therapeutic effect. Targeting the supplementary motor area (SMA) (g=0.56; 95%CI, 0.12-1.01; P<0.001), left dorsolateral prefrontal cortex (DLPFC) (g=0.47; 95%CI, 0.02-0.93; P=0.02), bilateral DLPFC (g=0.65; 95%CI, 0.38 0.92; P<0.001) and right DLPFC (g=0.93; 95%CI, 0.70-1.15; P<0.001), excluding the orbitofrontal cortex (OFC) (g=0.56; 95%CI, -0.05-1.18; P=0.07), showed significant improvements over sham treatments. Both low-frequency (g=0.73; 95%CI, 0.50-0.96; P<0.001) and high-frequency (g=0.70; 95%CI, 0.51-0.89; P<0.001) treatments were significantly better than sham treatments, with no significant differences between the effects of the two frequencies. The subgroup analyses indicated that patients who were non-treatment resistant, lacked concurrent major depressive disorder (MDD) and received threshold-intensity rTMS showed larger therapeutic effects than the corresponding subgroups. The subgroup analysis according to sham strategy showed that tilted coils yielded larger effects than sham coils. Meta-regression analyses revealed that none of the continuous variables were significantly associated with the therapeutic effects. LIMITATIONS: Only short-term therapeutic effects were assessed in this study. CONCLUSIONS: Based on this study, the short-term therapeutic effects of rTMS are superior to those of sham treatments. The site of stimulation, stimulation frequency and intensity and sham condition were identified as potential factors modulating short-term therapeutic effects. The findings of this study may inspire future research. PMID- 28340446 TI - Mental health and behavioral weight loss: 24-month outcomes in Veterans. AB - BACKGROUND: Individuals with mental health (MH) disorders have an increased risk of being overweight/obese; however research on behavioral weight loss interventions has been limited. A priori hypothesis was that Veterans with serious mental illness (SMI) and/or affective disorders (AD) would lose significantly less weight and have a different pattern of weight loss than Veterans without these diagnoses. METHODS: Secondary data analysis of ASPIRE-VA study, three-arm randomized, effectiveness weight loss trial among Veterans (n=409) categorized by MH diagnoses: 1) SMI, 2) AD without SMI, or 3) No SMI/No AD. Linear mixed-effects model analyzed weight changes from baseline thru 24 months. RESULTS: SMI and AD were diagnosed in 10% (n=41) and 31% (n=125). Participants attended approximately 15 sessions from baseline to 24 months. On average, participants lost a modest amount of weight over 24 months regardless of MH diagnosis. Longitudinally, no statistically significant differences were found in weight loss patterns by MH diagnosis. Unadjusted average weight loss (kg) was 1.6+/-4.0 at 3 months (n=373), 1.9+/-6.5 at 12 months (n=361), 1.5+/-7.8 at 18 months (n=289), and 1.4+/-8.0 at 24 months (n=279). LIMITATIONS: ASPIRE-VA study was not designed or powered to detect weight loss differences among MH diagnostic groups. CONCLUSIONS: Veterans achieved and maintained modest weight loss, through 24 months, with the three behavioral weight loss interventions. Contrary to our hypotheses, the amount and pattern of weight loss did not differ by MH diagnosis. Greater inclusion of individuals with MH diagnoses may be warranted in behavioral weight loss interventions not specifically tailored for them. PMID- 28340447 TI - Fronto-limbic disconnection in depressed patients with suicidal ideation: A resting-state functional connectivity study. AB - BACKGROUND: Suicidal ideation (SI) is highly prevalent and a known symptom of Major Depressive Disorder (MDD), but its underlying biological mechanisms are relatively unknown. Several studies linked suicidal ideation to dysfunctional brain circuits, specifically fronto-limbic connections. The purpose of this work was to investigate fronto-limbic disconnection in MDD patients with or without SI. METHODS: MDD patients with SI (SI, n=28) or without SI (NSI, n=20), identified by the Scale for Suicide Ideation and healthy controls (HCs, n=30) underwent resting-state functional MRI scanning. The functional properties of correlations in neural activity (intrinsic functional connectivity, iFC) of the rostral anterior cingulate cortex (rACC) were analyzed among the three groups. Furthermore, correlation analyses between iFC, SI severity and depression severity were performed. RESULTS: We found that the SI group exhibited decreased iFC between the rACC, the orbitomedial prefrontal cortex and the right middle temporal pole compared to HCs and NSI groups. The NSI group showed decreased iFC between the rACC and the orbitomedial prefrontal cortex compared to HCs. In the SI group, iFC strength between the right rACC and the middle temporal pole positively correlated with SI severity. CONCLUSION: Transdiagnostic and diagnosis specific alterations of fronto-limbic iFC were found in MDD patients with or without SI. Disrupted fronto-limbic circuits may impact decision-making and emotional processing in SI. These results provide useful information about the pathophysiological mechanisms of MDD patients with SI. PMID- 28340448 TI - Structural correlates of creative thinking in patients with bipolar disorder and healthy controls-a voxel-based morphometry study. AB - BACKGROUND: This study investigated the structural correlates of creative thinking in patients with bipolar disorder (BD) to understand the possible neural mechanism of creative thinking in BD. METHODS: We recruited 59 patients with BD I or BD II (35.3+/-8.5 y) and 56 age- and sex-matched controls (HCs; 34+/-7.4 y). Each participant underwent structural magnetic resonance imaging and evaluation of creative thinking, which was assessed using two validated tools: the Chinese version of the Abbreviated Torrance Test for Adults for divergent thinking and the Chinese Word Remote Associates Test for remote association. Voxel-based morphometry was performed using SPM12. RESULTS: In patients with BD, divergent thinking positively correlated with the gray matter volume (GMV) in right medial frontal gyrus (Brodmann area [BA] 9), and remote association positively correlated with the GMV in the medial prefrontal gyrus (BA 10). In the HCs, divergent thinking negatively correlated with the GMV in left superior frontal gyrus (BA 8) and positively correlated with the GMV in the precuneus and occipital regions, and remote association positively correlated with the GMV in the hippocampus. LIMITATIONS: Patients with BD were receiving various dosages of antipsychotics, antidepressants and mood stabilizer. These medications may confound the GMV-creative thinking relationship in patients with BD. CONCLUSIONS: Our findings indicate that medial prefrontal cortex plays a major and positive role in creative thinking in patients with BD. By contrary, creative thinking involves more diverse structures, and the prefrontal cortex may have an opposite effect in HCs. PMID- 28340449 TI - Right hemisphere pitch-mismatch negativity reduction in patients with major depression: An MEG study. AB - BACKGROUND: The mismatch negativity (MMN) component of the event-related potential and its magnetic counterpart, the MMNm, are generated by a mismatch between the physical features of a deviant stimulus and a neuronal sensory-memory trace produced by repetitive standard stimuli. Deficits in the MMN/MMNm have been reported in patients with major depression; however, the results are inconsistent. The present study investigated the pitch-MMNm in patients with major depression using whole-head 306-channel magnetoencephalography (MEG). METHODS: Twenty patients with major depression and 36 healthy subjects participated in this study. Subjects were presented with two sequences of auditory stimuli. One consisted of 1000Hz standard signals (probability=90%) and 1200Hz deviant signals (probability=10%), while the other consisted of 1200Hz standard (90%) and 1000Hz deviant signals (10%). Event-related brain responses to standard tones were subtracted from responses to deviant tones. RESULTS: Major depressive patients showed significantly reduced magnetic global field power (GFP) of MMNm in the right hemisphere (p=0.02), although no significant MMNm reduction was observed in the left hemisphere (p=0.81). Additionally, patients with major depression showed significantly earlier bilateral MMNm peak latencies (p=0.004). No significant associations were observed between MMNm variables and demographic data/clinical variables within the patients. LIMITATIONS: We could not exclude the effects of antidepressants, mood stabilizers, or neuroleptics on the MMNm abnormalities found in patients with major depression. Sample size was also insufficient to permit subgroup analyses. CONCLUSIONS: Patients with major depression exhibited reduced GFP of MMNm in the right hemisphere. The present study suggested that patients with major depression may have right hemispheric dominant preattentive dysfunction. PMID- 28340450 TI - Health promotion and psychological interventions for adolescent and young adult cancer survivors: A systematic literature review. AB - BACKGROUND: The effects of cancer and treatment have severe and long lasting negative impacts on quality of life. Adolescents and Young Adults (AYA) have high survival rates but may not reach their full life potential because of these consequences. This review aims to identify, appraise and synthesise the effects of health promotion and psychological interventions for AYA after cancer treatment. METHODS: The review was undertaken using the preferred reporting items for systematic reviews and meta-analyses guidelines. Included studies were identified though a range of electronic databases through to May 2016. Studies were critically appraised using the Cochrane Risk of Bias tool. RESULTS: Seventeen studies, comprising a total of 2314 participants aged 13-39years were included in this review. Participants in 15 studies were survivors of childhood cancer, with only two studies specifically recruiting survivors of cancer diagnosed during young adulthood. Ten studies were randomised controlled trials (RCTs); the remaining seven were before and after studies. The quality of studies was variable across all appraised domains; risk of bias was evident in regards to recruitment, measures of exposure and outcomes, confounding factors, attrition and lost-to follow-up. Studies evaluated a range of health promotion and psychological interventions to improve health related and process outcomes. Eleven studies reported modest positive outcomes, with psychological and physical activity interventions achieving greater success compared to general health promotion interventions. CONCLUSION: This review highlights the lack of high quality studies for optimising the health and well-being of AYA cancer survivors. No conclusive evidence favouring specific interventions were identified, although recommendations for future studies are made. Interventions delivered face-to-face and those that facilitate peer-to-peer support hold promise. Harnessing social media and technology to deliver interventions is likely to increase and these modes of delivery require further investigations. PMID- 28340451 TI - The role of drug-drug interactions in prostate cancer treatment: Focus on abiraterone acetate/prednisone and enzalutamide. AB - Elderly patients with cancer may have comorbidities, each requiring additional pharmacologic treatment. Therefore, the occurrence of pharmacokinetic (PK) and pharmacodynamic (PD) interactions is very likely, and the risk of adverse reactions (ADRs), due to the narrow therapeutic window of anticancer drugs, is increased. Drug-drug interactions (DDIs) may occur in prostate cancer patients due to inhibition by abiraterone of liver cytochrome P450 (CYP)-dependent enzymes CYP2C8 and 2D6, which are involved in the metabolism of approximately 25% of all drugs, and induction by enzalutamide of CYP3A4, 2C9 and 2C19, which metabolize up to 50% of medications. Therefore, abiraterone may increase plasma levels of CYP2D6 substrates, including amitriptyline, oxycodone and risperidone, as well as of CYP2C8 substrates including amiodarone and carbamazepine. Since enzalutamide is extensively metabolized by CYP2C8, its plasma levels are likely to be raised if coadministered with strong CYP2C8 inhibitors such as gemfibrozil or pioglitazone. Inducers of CYP2C8 (i.e., rifampin) may reduce the effectiveness of enzalutamide and hence should be avoided. Enzalutamide may decrease plasma levels of CYP3A4, 2C9 and 2C19 substrates including disopiramide, quetiapine, quinidine and warfarin. Growing awareness of the importance of DDIs in cancer patients is now reflected in the variety of web-based sources offering information and guidance. However, the evaluation of the clinical relevance of DDIs is the result of a comprehensive evaluation of many factors, including therapeutic index, amplitude of therapeutic range and presence of comorbidities, requiring a specific expertise in clinical pharmacology. PMID- 28340452 TI - A study of photosynthetic biogas upgrading based on a high rate algal pond under alkaline conditions: Influence of the illumination regime. AB - Microalgal-bacterial processes have emerged as environmental friendly systems for the cost-effective treatment of anaerobic effluents such as biogas and nutrients laden digestates. Environmental parameters such as temperature, irradiation, nutrient concentration and pH effect the performance of the systems. In this paper, the potential of a microalgal-bacterial photobioreactor operated under high pH (~9.5) and high alkalinity to convert biogas into biomethane was evaluated. The influence of the illumination regime (continuous light supply vs 12h/12h light/dark cycles) on the synthetic biogas upgrading efficiency, biomass productivity and nutrient removal efficiency was assessed in a High-Rate Algal Pond interconnected to a biogas absorption bubble column. No significant differences in the removal efficiency of CO2 and H2S (91.5+/-2% and 99.5%+/-0.5, respectively) were recorded regardless of the illumination regime. The high fluctuations of the dissolved oxygen concentration during operation under light/dark cycles allowed to evaluate the specific growth rate and the specific partial degradation rate of the microalgae biomass by photosynthesis and respiration, respectively. The respiration reduced the net microalgae biomass productivity under light/dark cycles compared with process operation under the continuous light supply. PMID- 28340453 TI - Long-term nitrogen deposition increases heathland carbon sequestration. AB - The large increases in reactive nitrogen (N) deposition in developed countries since the Industrial Revolution have had a marked impact on ecosystem functioning, including declining species richness, shifts in species composition, and increased N leaching. A potential mitigation of these harmful effects is the action of N as a fertiliser, which, through increasing primary productivity (and subsequently, organic matter production), has the potential to increase ecosystem carbon (C) storage. Here we report the response of an upland heath to 10years of experimental N addition. We find large increases in plant and soil C and N pools, with N-driven C sequestration rates in the range of 13-138kgCkg-1. These rates are higher than those previously found in forest and lowland heath, mainly due to higher C sequestration in the litter layer. C sequestration is highest at lower N treatments (10, 20, and 40kgNha-1yr-1 above ambient), with evidence of saturation at the highest N treatment, reflecting a physiologically aged Calluna vulgaris (Calluna) canopy. To maintain these rates of sequestration, the Calluna canopy should be managed to maximise it's time in the building phase. Scaling our results across UK heathlands, this equates to an additional 0.77Mt CO2e per annum extra C sequestered into plant litter and the top 15cm of heathland soil as a result of N deposition. The bulk of this is found in the litter and organic soil horizons that hold an average of 23% and 54% of soil C, respectively. This additional C represents around 0.44% of UK annual anthropogenic GHG emissions. When considered in the context of falling biodiversity and altered species composition in heathland, policy focus should remain on reducing N emissions. PMID- 28340454 TI - Pea cultivar and wheat residues affect carbon/nitrogen dynamics in pea-triticale intercropping: A microcosms approach. AB - The underlying mechanisms by which legume cultivars contribute to nitrous oxide (N2O) generation are poorly understood. The aim of the present study was to explore the effects of two pea cultivars (Zero4 and Nitouche) intercropped with triticale, with or without wheat (Triticum aestivum) residues incorporation, on soil C and N dynamics, on bacterial community structure and their links with N2O emissions. Monocrops and bare soil (no plant) treatments were used as an additional control in order to account for the level of mineralisation between treatments. Changes in total C and N contents and in some functionally-related soil pools (microbial biomass C and N, basal respiration, KCl-exchangeable ammonium and nitrate, potentially mineralisable N, DOC, ecophysiological indexes) were followed throughout a 97-day microcosm experiment carried out on a loamy arable soil. ARISA community fingerprinting of soil extracted DNA and GHG emissions were carried out at two key stages (pea flowering and harvest). The addition of residues to the soil resulted in only small changes to the total C and N pools the Nitouche monocrop, which was found to have the highest potentially mineralisable N (13.4MUgg-128d-1) of the treatments with added residue. The different pea cultivar selectively affected N2O emissions, with highest emissions associated with the cultivar Nitouche in the absence of residues. The two intercropping treatments of triticale/pea were significantly different either with residues or without, especially the triticale/Zero4 which had the lowest values (356gN2O-Nha-1). Similar patterns were also observed in below ground data. ARISA analysis showed that monocropped legumes and the Triticale-based treatment clearly grouped on separate clusters to the added residue treatment. We hypothesize that in pea-based intercrops variations in carbon supply from different cultivars may contribute to differences in N2O emissions and thus influence the choice of suitable cultivars, to optimize nutrient cycling and sustainable crop management. PMID- 28340455 TI - Toxicological and behavioral responses as a tool to assess the effects of natural and synthetic dyes on zebrafish early life. AB - Organic dyes extracted from natural sources have been widely used to develop safety and eco-friendly dyes as an alternative to synthetic ones, since the latter are usually precursors of mutagenic compounds. Thereby, toxicity tests to non-target organisms are critical step to develop harmless dyes to environment and in this context, zebrafish early life stages are becoming an important alternative model. We aimed to assess the toxic effects of the synthetic dye Basic Red 51 (BR51, used in cosmetic industry), the natural dye erythrostominone (ERY, a potential commercial dye extracted from fungi) and its photodegradation product (DERY), using zebrafish early life assays. Developmental malformations on embryos and behavioral impairment on larvae were explored. Our results showed that embryos exposed to BR51 and ERY exhibited a large yolk sac (LOEC = 7.5 mg L 1), possibly due to a deformity or delayed resorption. ERY also induced pericardial and yolk sac edemas at high concentrations (LOEC = 15 and 30 mg L-1, respectively). Moreover, larvae swan less distance and time when exposed to ERY (LOEC = 7.5 mg L-1) and BR51 (LOEC = 1.875 mg L-1). The lowest larvae locomotion have been associated with impairment of the yolk sac, important tissue of the energy source. Interestingly, DERY did not affect neither development nor behavior of zebrafish, showing that ERY photodegradation is sufficient to prevent its toxic effects. In conclusion, both natural and synthetic dyes impaired development and behavior of zebrafish early life, therefore, a simple treatment of the natural dye can prevent the aquatic life impact. PMID- 28340456 TI - Macroscopic and microscopic investigation of adsorption and precipitation of Zn on gamma-alumina in the absence and presence of As. AB - Contaminants zinc (Zn) and arsenate (As) often coexist in soils. However, little is known concerning the impacts of coexisting As on Zn adsorption and precipitation on soil minerals. In the present study, adsorption and precipitation of Zn on gamma-alumina in the absence and presence of arsenate was investigated employing batch experiments and Extended X-ray Absorption Fine Structure (EXAFS) spectroscopy. Results indicated that Zn formed edge-sharing tetrahedral surface complexes at pH 5.5 and Zn-Al LDH-like (layered double hydroxide) precipitates at pH 7.0 on the surface of gamma-alumina. The presence of arsenate significantly enhanced Zn sorption densities, and remarkably changed its bonding environment. At pH 5.5, SR-XRD (Synchrotron Radiation-based X-ray Diffraction) and EXAFS showed that koettigite-like precipitate were formed in the cosorption of Zn and As on gamma-alumina regardless of the addition sequence of As and Zn. At pH 7.0, when Zn was preequilibrated with gamma-alumina prior to the As introduction, mixed Zn-Al LDH-like and amorphous adamite-like precipitates formed. However, when Zn and As were added simultaneously, only amorphous adamite like precipitate was observed. Zn inner-sphere complexes and surface ternary complexes gamma-alumina-As-Zn were the main outcome when As was preequilibrated firstly. Zn-arsenate precipitates could significantly decrease the concentration of Zn in aqueous solution and decrease the bioavailability and mobilization of Zn in soils. PMID- 28340457 TI - Dermal exposure of applicators to chlorpyrifos on rice farms in Ghana. AB - Studies evaluating dermal exposure to pesticides among applicators in tropical countries have largely been conducted using the patch dosimetry and hand wiping/washing techniques. This study used the more accurate whole-body dosimetry technique to evaluate dermal exposure to chlorpyrifos among applicators on rice farms in Ghana. The exposure levels were plotted as Cumulative Probability Distribution (CPD). Total Dermal Exposure (TDE) of chlorpyrifos among the median exposed and the 5% highly exposed groups during a spray event were 24 mg and 48 mg, respectively. When these were converted as a percentage of the quantity of active ingredient applied (Unit Exposure, UE), UE values of 0.03% and 0.06% were found among the median exposed and the 5% highly exposed groups, respectively. Overall, the hands were the most contaminated anatomical regions of the applicators, both in terms of proportion of TDE (39%) and skin loading (13 MUg/cm2). Also, the lower anatomical region was more contaminated (82% of TDE) compared to the upper anatomical region (18% of TDE). The levels of chlorpyrifos TDE among the applicators were found to be influenced by the quantity of insecticide applied and the height of the crops sprayed (p < 0.05). The pesticide UE data of the present study can be used to estimate the levels of dermal exposure under similar pesticide use scenarios among applicators. The findings of the present study suggest that protecting the hands and the lower anatomical regions with appropriate PPE may significantly reduce exposure among applicators. PMID- 28340458 TI - Toxic effects of environmental pollutants: Comparative investigation using Allium cepa L. and Lactuca sativa L. AB - Studies that help understand the mechanisms of action of environmental pollutants are extremely important in environmental toxicology. In this context, assays using plants as models stand out for their simplicity and low performance cost. Among the plants used for this purpose, Allium cepa L. is the model most commonly applied for cytogenotoxic tests, while Lactuca sativa L., already widely used in phytotoxic investigations, has been gaining prominence in cytotoxic analyses. The present study aimed to compare the responses of A. cepa and L. sativa via macroscopic (root growth) and microscopic analyses (cell cycle and DNA fragmentation via TdT-mediated deoxy-uracil nick and labeling (TUNEL) and comet assays) after exposure of their roots to environmental pollutants with known cytogenotoxic mechanisms. Both species presented sensitive and efficient response to the applied tests after exposure to the DNA-alkylating agent Methyl Methanesulfonate (MMS), the heavy metal Cadmium, the aluminum industry waste Spent Potliner (SPL) and the herbicide Atrazine. However, they differed regarding the responses to the evaluated endpoints. Overall, A. cepa was more efficient in detecting clastogenic changes, arising from DNA breakage, while L. sativa rather detected aneugenic alterations, related to chromosome segregation in mitosis. In the tests applied to verify DNA fragmentation (comet and TUNEL assays), A. cepa presented higher sensitivity. In conclusion, both models are efficient to evaluate toxicological risks of environmental pollutants. PMID- 28340459 TI - Transcriptional profiling of porcine granulosa cells exposed to 2,3,7,8 tetrachlorodibenzo-p-dioxin. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a toxic man-made chemical compound contaminating the environment. An exposure of living organisms to TCDD may result in numerous disorders, including reproductive pathologies. The aim of the current study was to examine the effects of TCDD on the transcriptome of porcine granulosa cell line AVG-16. By employing next-generation sequencing (NGS) we aimed to identify genes potentially involved in the mechanism of TCDD action and toxicity in porcine granulosa cells. The AVG-16 cells were treated with TCDD (100 nM) for 3, 12 or 24 h, and afterwards total cellular RNA was isolated and sequenced. In TCDD-treated cells we identified 141 differentially expressed genes (DEGs; padjusted < 0.05 and log2 fold change >=1.0). The DEGs were assigned to GO term, covering biological processes, molecular functions and cellular components. Due to the large number of genes with altered expression, in the current study we analyzed only the genes involved in follicular growth, development and functioning. The obtained results showed that TCDD may affect ovarian follicle fate by influencing granulosa cell cycle, proliferation and DNA repair. The demonstrated over-time changes in the quantity and quality of genes being affected by TCDD treatment showed that the effects of TCDD on granulosa cells changed dramatically between 3-, 12- and 24-h of cell culture. This finding indicate that timing of gene expression measurement is critical for drawing correct conclusions on detailed relationships between the TCDD-affected genes and resulting intracellular processes. These conclusions have to be confirmed and extended by research involving proteomic and functional studies. PMID- 28340460 TI - Interactions between three typical endocrine-disrupting chemicals (EDCs) in binary mixtures exposure on myocardial differentiation of mouse embryonic stem cell. AB - In recent years, various kinds of endocrine-disrupting chemicals (EDCs) have been detected in human blood and urine. Thus, it was important to investigate the combined toxicity effect of EDCs. In the present study, we evaluated the individual and combined developmental toxicities of three classic EDCs: perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and bisphenol A (BPA) by embryonic stem cell test (EST). The similarities and differences between combination of same chemical group as well as different chemical groups were investigated in this research. Our results showed that the three compounds were all classified as weak embryotoxicity. The results of co-exposure revealed that there was synergistic action in combination of PFOS and BPA on myocardial differentiation. However, in all endpoints, the combined effects between PFOA with PFOS or BPA were both additive action. Therefore, we concluded that the additive effects were found in most different EDC mixtures whether they had similar structure or not. On the other hand, synergistic action was observed in a mixture of EDCs that belonged to a different chemical groups. PMID- 28340461 TI - Tracing biomarker of PAH-exposure and susceptibility factor (GSTM-polymorphism) among cancer patients in Pakistan. AB - We studied cancer patients for possible PAH exposure, using urinary concentration of 1-hydroxypyrene (1-OHP) as a biomarker of internal dose of polycyclic aromatic hydrocarbons (PAHs). The subjects included in this study belonged to various socio-demographic backgrounds, and were diagnosed with cancer (i.e. lung, head and neck or digestive tract cancer). In general, we observed high concentration of urinary 1-OHP among digestive tract cancer patients, compared with the controls (CN) (mean 1.06, median 1.03 and mean 0.62, median 0.63 MUmol/mol-Cr in digestive tract cancer patients and controls respectively). The concentrations of urinary 1-OHP were higher than the background level of PAHs; therefore, these groups could have been exposed to PAHs. Highest urinary 1-OHP concentration was observed in digestive tract cancer patients (median 1.25 MUmol/mol-Cr) with GSTM 1 genotype. The results of PCA were consistent with qualitative and quantitative data analysis. The contribution of urinary 1-OHP eigenvector revealed a relatively high PAH-exposure among cancer patients compared with CN, while diet and age were influential parameters among cancer patients, which could have a strong link in cancer etiology in the selected exposure groups. PMID- 28340462 TI - Assessment of arsenic and fluorine in surface soil to determine environmental and health risk factors in the Comarca Lagunera, Mexico. AB - Total, bioaccessible and mobile concentrations of arsenic and fluorine are determined in polluted surface soil within the Comarca Lagunera region using standardized protocols to obtain a full description of the environmental behavior for these elements. The composition of mineral phases associated with them is evaluated with microscopic and spectroscopic techniques. Mineralogical characterizations indicate that ultra-fine particles (<1-5 MUm) including mimetite-vanadite (Pb5(AsO4)3Cl, Pb5(AsO4, VO4)3Cl)-like, lead arseniate (Pb3(AsO4)2)-like and complex arsenic-bearing compounds are main arsenic-bearing phases, while fluorite (CaF2) is the only fluorine-bearing phase. Total fluorine and arsenic concentrations in surface soil range from 89.75 to 926.63 and 2.7 78.6 mg kg-1, respectively, exceeding in many points a typical baseline value for fluorine (321 mg kg-1), and trigger level criterion for arsenic soil remediation (20 mg kg-1); whereas fluoride and arsenic concentrations in groundwater vary from 0.24 to 1.8 mg L-1 and 0.12-0.650 mg L-1, respectively. The main bioaccessible percentages of soil in the gastric phase (SBRC-G) are estimated for arsenic from 1 to 63%, and this parameter in the intestinal phase (SBRC-I) fluorine from 2 to 46%, suggesting human health risks for this region. While a negligible/low mobility is found in soil for arsenic (0.1-11%), an important mobility is determined for fluorine (2-39%), indicating environmental risk related to potential fluorine release. The environmental and health risks connected to arsenic and fluorine are discussed based on experimental data. PMID- 28340463 TI - Hypoxia and hydrogen sulfide differentially affect normal and tumor-derived vascular endothelium. AB - BACKGROUND: endothelial cells play a key role in vessels formation both under physiological and pathological conditions. Their behavior is influenced by blood components including gasotransmitters (H2S, NO and CO). Tumor cells are subjected to a cyclic shift between pro-oxidative and hypoxic state and, in this scenario, H2S can be both cytoprotective and detrimental depending on its concentration. H2S effects on tumors onset and development is scarcely studied, particularly concerning tumor angiogenesis. We previously demonstrated that H2S is proangiogenic for tumoral but not for normal endothelium and this may represent a target for antiangiogenic therapeutical strategies. METHODS: in this work, we investigate cell viability, migration and tubulogenesis on human EC derived from two different tumors, breast and renal carcinoma (BTEC and RTEC), compared to normal microvascular endothelium (HMEC) under oxidative stress, hypoxia and treatment with exogenous H2S. RESULTS: all EC types are similarly sensitive to oxidative stress induced by hydrogen peroxide; chemical hypoxia differentially affects endothelial viability, that results unaltered by real hypoxia. H2S neither affects cell viability nor prevents hypoxia and H2O2-induced damage. Endothelial migration is enhanced by hypoxia, while tubulogenesis is inhibited for all EC types. H2S acts differentially on EC migration and tubulogenesis. CONCLUSIONS: these data provide evidence for a great variability of normal and altered endothelium in response to the environmental conditions. PMID- 28340464 TI - A review on various electrochemical techniques for heavy metal ions detection with different sensing platforms. AB - Heavy metal ions are non-biodegradable and contaminate most of the natural resources occurring in the environment including water. Some of the heavy metals including Lead (Pb), Mercury (Hg), Arsenic (As), Chromium (Cr) and Cadmium (Cd) are considered to be highly toxic and hazardous to human health even at trace levels. This leads to the requirement of fast, accurate and reliable techniques for the detection of heavy metal ions. This review presents various electrochemical detection techniques for heavy metal ions those are user friendly, low cost, provides on-site and real time monitoring as compared to other spectroscopic and optical techniques. The categorization of different electrochemical techniques is done on the basis of different types of detection signals generated due to presence of heavy metal ions in the solution matrix like current, potential, conductivity, electrochemical impedance, and electrochemiluminescence. Also, the recent trends in electrochemical detection of heavy metal ions with various types of sensing platforms including metals, metal films, metal oxides, nanomaterials, carbon nano tubes, polymers, microspheres and biomaterials have been evoked. PMID- 28340465 TI - Dumbbell DNA-templated CuNPs as a nano-fluorescent probe for detection of enzymes involved in ligase-mediated DNA repair. AB - DNA repair processes are responsible for maintaining genome stability. Ligase and polynucleotide kinase (PNK) have important roles in ligase-mediated DNA repair. The development of analytical methods to monitor these enzymes involved in DNA repair pathways is of great interest in biochemistry and biotechnology. In this work, we reported a new strategy for label-free monitoring PNK and ligase activity by using dumbbell-shaped DNA templated copper nanoparticles (CuNPs). In the presence of PNK and ligase, the dumbbell-shaped DNA probe (DP) was locked and could resist the digestion of exonucleases and then served as an efficient template for synthesizing fluorescent CuNPs. However, in the absence of ligase or PNK, the nicked DP could be digested by exonucleases and failed to template fluorescent CuNPs. Therefore, the fluorescence changes of CuNPs could be used to evaluate these enzymes activity. Under the optimal conditions, highly sensitive detection of ligase activity of about 1U/mL and PNK activity down to 0.05U/mL is achieved. To challenge the practical application capability of this strategy, the detection of analyte in dilute cells extracts was also investigated and showed similar linear relationships. In addition to ligase and PNK, this sensing strategy was also extended to the detection of phosphatase, which illustrates the versatility of this strategy. PMID- 28340466 TI - A flexible and disposable battery powered by bacteria using eyeliner coated paper electrodes. AB - Herein, an environment friendly paper-based biobattery is demonstrated that yields a power of 12.5W/m3. Whatman filter papers were used not only as support for electrode fabrication but also as separator of the biobattery. To provide electrical conductivity to the paper-based cathode and anode, commercially available eyeliner containing carbon nanoparticles and Fe3O4 was directly employed as conductive ink without any binder. With an instant start-up, the as fabricated biocompatible electrodes could hold bacteria in an active form at the anode allowing chemical oxidation of organic fuel producing current. The facile process delineated here can be employed for the tailored electrode fabrication of various flexible energy harnessing devices. PMID- 28340467 TI - The clinical use of chromosomal microarray analysis in detection of fetal chromosomal rearrangements: a study from China Mainland. AB - OBJECTIVES: This study aimed to evaluate the detection rate of chromosomal microarray analysis (CMA) in prenatal fetuses compared with conventional karyotype and to assess the additional diagnostic yields of CMA in groups of different indications. STUDY DESIGN: A total of 217 fetuses were divided into seven groups according to different indications. All cases were tested by both CMA and karyotype. The detection rates of CMA and karyotype were evaluated. The increased value of CMA in each group was also calculated. RESULTS: A total of 35 cases were detected to have a pathogenic result by CMA, indicating the overall detection rate of 16.1%. Nine more cases were detected only by CMA, indicating an incremental diagnostic yield of 4.2%. The highest incremental value was observed in fetuses with structural defects (6.6%). In 11 cases with known abnormal chromosome anomalies, CMA revealed additional information over conventional karyotyping in 4 fetuses. CONCLUSIONS: The present study convincingly demonstrated the efficiency of CMA in detecting feal chromosomal rearrangements. CMA significantly improves the detection rate in fetuses with structural defects and provides helpful information for fetuses with known abnormal chromosomes but without clear diagnosis. PMID- 28340468 TI - The prevalence of HIV among women with high-grade cervical smear abnormalities in Birmingham, United Kingdom: A prospective cohort study. AB - OBJECTIVE: The aim of the study was twofold: 1. To assess the acceptance for HIV screening in women attending Colposcopy clinic 2. To determine the prevalence of HIV in women presenting with high-grade cervical smear abnormalities. DESIGN: A prospective study. SETTING: Colposcopy clinic, Birmingham Women's Hospital, UK. POPULATION: Patients attending colposcopy clinic. MAIN OUTCOME MEASURES: To determine acceptance of HIV testing and prevalence in colposcopy patients with High-grade cervical smear abnormalities. RESULTS: Of the 252 patients who were offered the HIV test, 244(96.5%) accepted the test. None of 244 cases tested for HIV were found positive. CONCLUSIONS: HIV testing is feasible and acceptable in colposcopy clinics. PMID- 28340469 TI - Characterization and expression patterns of key C4 photosynthetic pathway genes in bread wheat (Triticum aestivum L.) under field conditions. AB - Wheat is a C3 plant with relatively low photosynthetic efficiency and is a potential target for C4 photosynthetic pathway engineering. Here we reported the characterization of four key C4 pathway genes and assessed their expression patterns and enzymatic activities at three growth stages in flag leaves of 59 bread wheat genotypes. The C4-like genes homologous to PEPC, NADP-ME, MDH, and PPDK in maize were identified in the A, B, and D sub-genomes of bread wheat, located on the long arms of chromosomes 3 and 5 (TaPEPC), short arms of chromosomes 1 and 3 (TaNADP-ME), long arms of chromosomes 1 and 7 (TaMDH), and long arms of chromosome 1 (TaPPDK), respectively. All the four C4-like genes were expressed in the flag leaves at the three growth stages with considerable variations among the 59 bread wheat genotypes. Significant differences were observed between the photosynthesis rates (A) of wheat genotypes with higher expressions of TaPEPC_5, TaNADP-ME_1, and TaMDH_7 at heading and middle grain filling stages and those with intermediate and low expressions. Our results also indicated that the four C4 enzymes showed activity in the flag leaves and were obviously different among the 59 wheat genotypes. The activities of PEPcase and PPDK decreased at anthesis and slightly increased at grain-filling stage, while NADP-ME and MDH exhibited a decreasing trend at the three stages. The results of the current study could be very valuable and useful for wheat researchers in improving photosynthetic capacity of wheat. PMID- 28340470 TI - Calcifying giant cell cardiomyopathy: a possible new entity: Images in Cardiovascular Pathology. AB - We demonstrated an extremely unusual case of an 83-year-old male's sudden death secondary to characteristic myocardial necrosis and fibrosis with calcification and multinucleated giant cells infiltration, possibly due to sepsis and Stage IV pulmonary pleomorphic carcinoma-induced cachexia after postmortem study. We propose that this calcifying giant cell cardiomyopathy (CGC) would be a new entity especially from the pathological viewpoints and should be considered in the classification of noninfectious myocarditis. Further prospective studies are needed to validate the presence and significance of CGC and the association with any triggers of somewhat microvascular dysfunction and/or toxic agents, after collecting and investigating a larger number of CGC cases examined. PMID- 28340471 TI - Chemotaxonomic studies of nine Paris species from China based on ultra-high performance liquid chromatography tandem mass spectrometry and Fourier transform infrared spectroscopy. AB - Paris species, which contain steroid saponins, have been used as herb folk medicines in Asia. In the present study, a comprehensive strategy based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) and Fourier transform infrared (FT-IR) spectroscopy was firstly proposed to evaluate the chemotaxonomic relationships of nine Paris species sampled from different geographical regions in China. Principle component analysis (PCA) based on FT-IR data revealed chemical similarities in term of the nine species and geographical regions, indicating the accumulation of metabolites affected by the combination of geographical factors and species. The chemotaxonomic relationships of four species supported the morphological taxonomy and implied ancestry from P. polyphylla. After high-efficiency chromatographic separation, ions trap/time-of flight mass spectrometry (IT-TOFMS) and triple quadrupole mass spectrometry (QQQ MS) were used to identify unknown metabolites and simultaneously determine six key compounds (polyphyllin I, II, V, VI, VII and gracillin) in Paris species, respectively. The tentative identification of 22 steroid saponins was indicative of a common biosynthetic pathway in Paris species. Phytoecdysones, gracillin and open-chain steroid saponins were considered as key precursors. According to Pearson's correlation analysis, an insignificant correlation was found between diosgenin-type and pennogenin-type saponins belonging to the same biosynthetic pathways in the current stage. Our results could provide a reasonable foundation for chemotaxonomy or further studies of Paris species. PMID- 28340472 TI - Characterization of an unknown impurity in doxofylline using LC-MS and NMR. AB - During quality control of doxofylline, a novel impurity was detected, which was above the identification threshold defined by ICH. First, a liquid chromatographic method compatible with mass spectrometric (MS) detection was developed. Based on tandem multistage MS and high resolution MS data, the unknown impurity was found to consist of two theophylline groups connected by a methylene group. The structure was further confirmed by 1D and 2D nuclear magnetic resonance (NMR) experiments after semi-preparative isolation. In addition, the formation of the impurity was also discussed. PMID- 28340473 TI - Enantiomers of triclabendazole sulfoxide: Analytical and semipreparative HPLC separation, absolute configuration assignment, and transformation into sodium salt. AB - Direct HPLC separation of the enantiomers of triclabendazole sulfoxide (TCBZ-SO), which is the main metabolite of the anthelmintic drug triclabendazole, was carried out using the polysaccharide-based Chiralpak AS-H and Chiralpak IF-3 chiral stationary phases (CSPs). The chromatographic behaviour of both CSPs was evaluated and compared using normal-phase and reversed-phase eluents at different column temperatures. The eluent mixture of n-hexane-2-propanol-trifluoroacetic acid 70:30:0.1 (v/v/v) and a column temperature of 40 degrees C were identified as the best operational conditions to carry out semipreparative enantioseparations on a 1-cm I.D. AS-H column. Under these conditions, 12.5mg of racemic sample were resolved in a single chromatographic run within 15min. Comparison of calculated and experimental chiroptical properties provided the absolute configuration assignment at the sulfur atom. The salification of the isolated enantiomers of TCBZ-SO by reaction with sodium hydroxide solution produced water-soluble Na salts which are potentially useful in the development of new anthelmintic enantiomerically pure formulations. PMID- 28340474 TI - Studying the effects of natural extracts with metabolomics: A longitudinal study on the supplementation of healthy rats with Polygonum cuspidatum Sieb. et Zucc. AB - BACKGROUND: A longitudinal study was performed to evaluate the effects of Polygonum cuspidatum extract (standardized at 20% resveratrol) supplementation on healthy rats. The effects were explored by monitoring urinary metabolome changes using UPLC-HRMS and 1H NMR-based approaches. The aim of the study was to explore the effects of P. cuspidatum supplementation on a healthy animal model using metabolomics, in order to determine possible modes of action and obtain information on bioactivity. METHODS: Healthy Sprague-Dawley rats were orally supplemented with 100mg/kg of dried P. cuspidatum extract for 49days and 24-h urinary outputs were collected. Samples were analysed by untargeted UPLC-HRMS and 1H NMR approaches and the obtained data sets were modelled by an adaptation of post-transformation of PLS2 to longitudinal studies. Putative markers were discovered by a stability selection procedure and specific oxidative stress markers were monitored by a targeted HPLC-MS/MS analysis to assess the in vivo antioxidant activity of P. cuspidatum extract. RESULTS: UPLC-HRMS and 1H NMR platforms showed two different but complementary patterns of metabolites describing the changes ascribable to P. cuspidatum supplementation and using both approaches, a comprehensive resveratrol metabolism and urinary excretion could be observed. Markers of P. cuspidatum supplementation effects identified by UPLC HRMS were mainly related to its antioxidant activity and to a possible "adaptogenic" activity. Urinary changes observed by 1H NMR were mainly related to energy metabolism. UPLC-HRMS and 1H NMR metabolomics approaches allowed the effects of a prolonged supplementation with P. cuspidatum on healthy rats to be observed. The statistical models built from both data sets showed metabolic changes in urines related to rat aging. PMID- 28340475 TI - Irinotecan Upregulates Fibroblast Growth Factor Receptor 3 Expression in Colorectal Cancer Cells, Which Mitigates Irinotecan-Induced Apoptosis. AB - BACKGROUND: Irinotecan (IRI) is an integral part of colorectal cancer (CRC) therapy, but response rates are unsatisfactory and resistance mechanisms are still insufficiently understood. As fibroblast growth factor receptor 3 (FGFR3) mediates essential survival signals in CRC, it is a candidate gene for causing intrinsic resistance to IRI. METHODS: We have used cell line models overexpressing FGFR3 to study the receptor's impact on IRI response. For pathway blockade, a dominant-negative receptor mutant and a small molecule kinase inhibitor were employed. RESULTS: IRI exposure induced expression of FGFR3 as well as its ligands FGF8 and FGF18 both in cell cultures and in xenograft tumors. As overexpression of FGFR3 mitigated IRI-induced apoptosis in CRC cell models, this suggests that the drug itself activated a survival response. On the cellular level, the antiapoptotic protein bcl-xl was upregulated and caspase 3 activation was inhibited. Targeting FGFR3 signaling using a dominant-negative receptor mutant sensitized cells for IRI. In addition, the FGFR inhibitor PD173074 acted synergistically with the chemotherapeutic drug and significantly enhanced IRI induced caspase 3 activity in vitro. In vivo, PD173074 strongly inhibited growth of IRI-treated tumors. CONCLUSION: Together, our results indicate that targeting FGFR3 can be a promising strategy to enhance IRI response in CRC patients. PMID- 28340476 TI - Temporal patterns of CO2 and CH4 in a rural area in northern Spain described by a harmonic equation over 2010-2016. AB - The present paper seeks to improve our knowledge concerning the evolution of CO2 and CH4 in terms of monthly trends, growth rate and seasonal variations in the lower atmosphere. Dry continuous measurements of CO2 and the CH4 mixing ratio were carried out over five and a half years (from 15 October 2010 to 29 February 2016) by multi-point sampling at 1.8, 3.7 and 8.3m, using a Picarro analyzer at a rural site in the Low Atmosphere Research Centre (CIBA), on the upper Spanish plateau. Data were divided into diurnal and nocturnal records. The mathematical equation proposed to analyze the overall data was a harmonic one, comprising a polynomial (trend) and a series of harmonics (seasonal cycle). Amplitude was considered as a constant and variable term over time. Quite different behaviour was found between day and night measurements in both climate forcing agents. CO2 showed an accelerating trend in autumn, whereas CH4 trends were higher during the winter. Increasing growth rates were reported for CO2 and CH4 over the whole study period. Nocturnal CO2 amplitudes are higher than diurnal ones except in winter for both gases, and also in the autumn for CH4. PMID- 28340477 TI - Environmental analysis of typical antibiotic-resistant bacteria and ARGs in farmland soil chronically fertilized with chicken manure. AB - Antibiotics and the corresponding resistant bacteria and resistance genes (ARGs) are generally considered emerging pollutants. To assess the impacts of tetracycline (TC) and sulfonamide (SA) antibiotics that are eliminated with fecaluria as drug prototypes, farmland soil used to research long-term fertilization with chicken manure was collected at four sites in Shandong Province. In this study, the rates of bacterial drug resistance to the same antibiotic decreased with an increase in the concentration of that antibiotic, and the resistance rates to TCs were lower than those to SAs. PCR of ARGs revealed that the ARGs detected at the highest frequency were the TC resistance genes tetW and tetO and the SA resistance genes sul1 and sul2. Real-time qPCR showed that the quantities of ARGs in farmland soil fertilized with chicken manure were significantly greater compared with the control soil. Moreover, significant correlations (R2=0.9525, p<0.05) between the number of sul ARGs and the total SA concentration were observed in all of the soil samples. In summary, this study showed that SAs can induce the appearance of ARGs and pollute the soil environment. PMID- 28340478 TI - Different DNA damage response of cis and trans isomers of commonly used UV filter after the exposure on adult human liver stem cells and human lymphoblastoid cells. AB - 2-ethylhexyl 4-methoxycinnamate (EHMC), used in many categories of personal care products (PCPs), is one of the most discussed ultraviolet filters because of its endocrine-disrupting effects. EHMC is unstable in sunlight and can be transformed from trans-EHMC to emergent cis-EHMC. Toxicological studies are focusing only on trans-EHMC; thus the toxicological data for cis-EHMC are missing. In this study, the in vitro genotoxic effects of trans- and cis-EHMC on adult human liver stem cells HL1-hT1 and human-derived lymphoblastoid cells TK-6 using a high-throughput comet assay were studied. TK-6 cells treated with cis-EHMC showed a high level of DNA damage when compared to untreated cells in concentrations 1.56 to 25MUgmL-1. trans-EHMC showed genotoxicity after exposure to the two highest concentrations 12.5 and 25MUgmL-1. The increase in DNA damage on HL1-hT1 cells induced by cis EHMC and trans-EHMC was detected at the concentration 25MUgmL-1. The No observed adverse effect level (NOAEL, mg kg-1bwday-1) was determined using a Quantitative in vitro to in vivo extrapolation (QIVIVE) approach: NOAELtrans-EHMC=3.07, NOAELcis-EHMC=0.30 for TK-6 and NOAELtrans-EHMC=26.46, NOAELcis-EHMC=20.36 for HL1-hT1. The hazard index (HI) was evaluated by comparing the reference dose (RfD, mgkg-1bwday-1) obtained from our experimental data with the chronic daily intake (CDI) of the female population. Using comet assay experimental data with the more sensitive TK-6 cells, HIcis-EHMC was 7 times higher than HItrans-EHMC. In terms of CDI, relative contributions were; dermal exposure route>oral>inhalation. According to our results we recommend the RfDtrans EHMC=0.20 and RfDcis-EHMC=0.02 for trans-EHMC and cis-EHMC, respectively, to use for human health risk assessment. The significant difference in trans-EHMC and cis-EHMC response points to the need for toxicological reevaluation and application reassessment of both isomers in PCPs. PMID- 28340479 TI - Additive effects prevail: The response of biota to multiple stressors in an intensively monitored watershed. AB - Freshwater ecosystems are impacted by a range of stressors arising from diverse human-caused land and water uses. Identifying the relative importance of single stressors and understanding how multiple stressors interact and jointly affect biology is crucial for River Basin Management. This study addressed multiple human-induced stressors and their effects on the aquatic flora and fauna based on data from standard WFD monitoring schemes. For altogether 1095 sites within a mountainous catchment, we used 12 stressor variables covering three different stressor groups: riparian land use, physical habitat quality and nutrient enrichment. Twenty-one biological metrics calculated from taxa lists of three organism groups (fish, benthic invertebrates and aquatic macrophytes) served as response variables. Stressor and response variables were subjected to Boosted Regression Tree (BRT) analysis to identify stressor hierarchy and stressor interactions and subsequently to Generalised Linear Regression Modelling (GLM) to quantify the stressors standardised effect size. Our results show that riverine habitat degradation was the dominant stressor group for the river fauna, notably the bed physical habitat structure. Overall, the explained variation in benthic invertebrate metrics was higher than it was in fish and macrophyte metrics. In particular, general integrative (aggregate) metrics such as % Ephemeroptera, Plecoptera and Trichoptera (EPT) taxa performed better than ecological traits (e.g. % feeding types). Overall, additive stressor effects dominated, while significant and meaningful stressor interactions were generally rare and weak. We concluded that given the type of stressor and ecological response variables addressed in this study, river basin managers do not need to bother much about complex stressor interactions, but can focus on the prevailing stressors according to the hierarchy identified. PMID- 28340480 TI - Using UHPLC Q-Trap/MS as a complementary technique to in-depth mine UPLC Q-TOF/MS data for identifying modified nucleosides in urine. AB - Modified nucleosides, metabolites of RNA, are potential biomarkers of cancer before the appearance of morphological abnormalities. It is of great significance to comprehensively detect and identify nucleosides in human urine for discovery of cancer biomarkers. However, the lower abundance, the greater polarity and the matrix effects make it difficult to detect urinary nucleosides. In this paper, an integrated method consisted of sample preparation followed by ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC Q-TOF/MS) detection and primary identification, then ultra-high performance liquid chromatography coupled with hybrid triple quadrupole linear ion trap mass spectrometer (UHPLC Q-Trap/MS) further identification and validation were introduced. Firstly, to enrich the nucleosides and eliminate the urine matrix effects, different sorbent materials of solid phase extraction (SPE) and the elution conditions were screened. Secondly, UPLC Q-TOF/MS was used to acquire mass data in MSE mode. The structural formulas of nucleosides in urine sample were primarily identified according to retention time, accurate mass precursor ions and fragment ions from in-house database and online database. Thirdly, the preliminary identified nucleoside structures lacking of characteristic fragment ions were verified by UHPLC Q-Trap/MS in multiple reaction monitoring trigger enhanced product ion scan (MRM-EPI) and neutral loss scan (NL). At last, phenylboronic acid (PBA)-based SPE was utilized due to its higher MS signal and weaker matrix effects under optimized extraction conditions. Fifty-five nucleosides were primarily identified by UPLC Q-TOF/MS, among which 50 nucleosides were confirmed by UHPLC Q-Trap/MS. Five nucleosides, namely 4',5' didehydro-5'-deoxyadenosine, 4',5'-didehydro-5'-deoxyinosine, isonicotinamide riboside, peroxywybutosine and hydroxywybutosine, were found from urine for the first time. The results will expand the Human Metabolome Database (HMDB). PMID- 28340481 TI - Metabolic profiling of tyrosine, tryptophan, and glutamate in human urine using gas chromatography-tandem mass spectrometry combined with single SPE cleanup. AB - The tyrosine, tryptophan, and glutamate metabolic pathways play key roles on pathological state of neuronal functions and the change of their levels in biological systems reflects the progress degree of neuronal diseases. Comprehensive profiling of these metabolites is important to find new biomarkers for diagnosis or prognosis of various neuronal diseases. However, the overall profiling analysis of various neurochemicals in biological sample is confronted with several limitations due to their low concentration and physicochemical properties and the coexistence of matrices. We developed an efficient and feasible method using gas chromatography-tandem mass spectrometry (GC-MS/MS). Wide-bore mixed cation exchange (MCX) SPE process enables a rapid and effective cleanup of 20 neurochemicals even including acidic and basic neurochemicals in a single SPE cartridge by using different composition of eluents. Selective derivatization of various types of metabolites was applied to achieve highly chromatographic separation and sensitive mass detection. Appropriate selection of precursor and product transition ions used in multiple reaction-monitoring (MRM) mode based on the MS/MS fragmentations of the derivatized neurochemicals could be significantly minimized the matrix effects and enhanced the reliability of quantification results. The developed method was validated in terms of linearity, limits of detection, precision, accuracy, and matrix effects. The intra- and inter-assay analytical variations were less than 10%. The overall linearity for all of the targets was excellent (R2>=0.996). The detection limits ranged between 0.38 and 8.13ng/mL for the acidic neurochemicals and between 0.02 and 11.1ng/mL for the basic neurochemicals. The developed protocol will be expected to be a promising tool for the understanding of the pathological state and diagnosis of various neuronal diseases. PMID- 28340482 TI - The effect of interprofessional team-based learning among nursing students: A quasi-experimental study. AB - BACKGROUND: Although interprofessional education has received attention in recent years as a means of providing opportunities for health-care professionals to learn with, from and about other disciplines and enhance the quality of patient care, evidence of its effectiveness is limited. Interprofessional team-based learning was introduced to make it possible for students in different healthcare disciplines to interact with each other, and to prepare them to function effectively within a team in their future career. OBJECTIVES: To examine the effects of interprofessional team-based learning for undergraduate nursing students in terms of knowledge level, readiness for interprofessional learning, attitude towards various aspects of team learning, and perceived collective efficacy. DESIGN: The study employed a one-group pretest-posttest quasi experimental design. METHODS: An interprofessional education program was given to students from two universities in Hong Kong who were in different healthcare disciplines including medicine, nursing, pharmacy, biomedical science, and Chinese medicine programs. The program was based on four phases of student learning- individual readiness assessment test, ice breaking session, team readiness assessment test, and application exercise. Nursing students involved in the program were invited to complete anonymous questionnaires to evaluate their interprofessional team experience. RESULTS: A total of 40 nursing students (9 male, 31 female) participated in the study. A statistically significant improvement was identified in their knowledge level (p<0.001), attitude towards readiness for interprofessional learning, team learning, and perceived collective efficacy (p<0.001). CONCLUSION: This study suggests that interprofessional team based learning can enhance cross-disciplinary learning and outcomes resulting from team efforts. PMID- 28340483 TI - Improving the water solubility and antimicrobial activity of silymarin by nanoencapsulation. AB - The aims of this study were to improve the water solubility and antimicrobial activity of milk thistle silymarin by nanoencapsulation and to assess the functions of silymarin nanoparticle-containing film as an antimicrobial food packaging agent. Silymarin nanoparticles were prepared using water-soluble chitosan (WCS) and poly-gamma-glutamic acid (gamma-PGA). As the WCS and silymarin concentrations increased, particle size and polydispersity index (PDI) significantly increased. Nanoencapsulation significantly improved the water solubility of silymarin 7.7-fold. Antimicrobial activity of silymarin was effectively improved when silymarin was entrapped within the nanocapsule compared to when it was not entrapped. Films incorporating silymarin nanoparticles had better antimicrobial activity than films incorporating free silymarin. The results suggest that silymarin nanoparticles have applications in antimicrobial food additives and food packing. PMID- 28340484 TI - Engineering of layered, lipid-encapsulated drug nanoparticles through spray drying. AB - Drug-containing nanoparticles have been synthesized through the spray-drying of submicron droplet aerosols by using matrix materials such as lipids and biopolymers. Understanding layer formation in composite nanoparticles is essential for the appropriate engineering of particle substructures. The present study developed a droplet-shrinkage model for predicting the solid-phase formation of two non-volatile solutes-stearic acid lipid and a set of drugs, by considering molecular volume and solubility. Nanoparticle formation was simulated to define the parameter space of material properties and process conditions for the formation of a layered structure with the preferential accumulation of the lipid in the outer layer. Moreover, lipid-drug demarcation diagrams representing a set of critical values of ratios of solute properties at which the two solutes precipitate simultaneously were developed. The model was validated through the preparation of stearic acid-isoniazid nanoparticles under controlled processing conditions. The developed model can guide the selection of solvents, lipids, and processing conditions such that drug loading and lipid encapsulation in composite nanoparticles are optimized. PMID- 28340485 TI - An approach for liposome immobilization using sterically stabilized micelles (SSMs) as a precursor for bio-layer interferometry-based interaction studies. AB - Non-fluidic bio-layer interferometry (BLI) has rapidly become a standard tool for monitoring almost all biomolecular interactions in a label-free, real-time and high-throughput manner. High-efficiency screening methods which measure the kinetics of liposomes with a variety of compounds require the immobilization of liposomes. In this work, a method is described for immobilizing liposomes for interaction studies, based on the biophysical principles of this biosensor platform. The immobilization approach includes the loading of DSPE-PEG(2000) biotin containing sterically stabilized micelles (SSMs) which are restructured in a buffer change step, resulting in an accessible substrate for liposome immobilization. Liposomes in a concentration of 5mM of varying composition and fluidity were immobilized on the sensor surface by inserting the hydrophobic residues of the former loaded SSMs. This proof of principle was carried out using Cytochrome C as a membrane-interacting model protein. The binding of Cytochrome C to the immobilized liposomes was demonstrated, and the derived kinetic and affinity constants were similar to values given in the literature. In order to obtain a detailed understanding of this surface, and to show the integrity of the liposomes, confocal fluorescence microscopy was used. Images of immobilized liposomes containing calcein in the aqueous core indicated intact vesicles. A combination of this simple liposome immobilization approach, the possibility of automation on BLI systems with high throughput within an acceptable timescale and excellent reproducibility makes this assay suitable for basic research as well as for industrial and regulatory applications. PMID- 28340486 TI - Review of current nuclear fallout codes. AB - The importance of developing a robust nuclear forensics program to combat the illicit use of nuclear material that may be used as an improvised nuclear device is widely accepted. In order to decrease the threat to public safety and improve governmental response, government agencies have developed fallout-analysis codes to predict the fallout particle size, dose, and dispersion and dispersion following a detonation. This paper will review the different codes that have been developed for predicting fallout from both chemical and nuclear weapons. This will decrease the response time required for the government to respond to the event. PMID- 28340487 TI - MicroRNA-4739 regulates osteogenic and adipocytic differentiation of immortalized human bone marrow stromal cells via targeting LRP3. AB - Understanding the regulatory networks underlying lineage differentiation and fate determination of human bone marrow stromal cells (hBMSC) is a prerequisite for their therapeutic use. The goal of the current study was to unravel the novel role of the low-density lipoprotein receptor-related protein 3 (LRP3) in regulating the osteogenic and adipogenic differentiation of immortalized hBMSCs. Gene expression profiling revealed significantly higher LRP3 levels in the highly osteogenic hBMSC clone imCL1 than in the less osteogenic clone imCL2, as well as a significant upregulation of LRP3 during the osteogenic induction of the imCL1 clone. Data from functional and gene expression assays demonstrated the role of LRP3 as a molecular switch promoting hBMSC lineage differentiation into osteoblasts and inhibiting differentiation into adipocytes. Interestingly, microRNA (miRNA) expression profiling identified miR-4739 as the most under represented miRNA (-36.11 fold) in imCL1 compared to imCL2. The TargetScan prediction algorithm, combined with functional and biochemical assays, identified LRP3 mRNA as a novel target of miR-4739, with a single potential binding site for miR-4739 located in the LRP3 3' UTR. Regulation of LRP3 expression by miR-4739 was subsequently confirmed by qRT-PCR, western blotting, and luciferase assays. Over-expression of miR-4739 mimicked the effects of LRP3 knockdown on promoting adipogenic and suppressing osteogenic differentiation of hBMSCs. Hence, we report for the first time a novel biological role for the LRP3/hsa-miR-4739 axis in balancing osteogenic and adipocytic differentiation of hBMSCs. Our data support the potential utilization of miRNA-based therapies in regenerative medicine. PMID- 28340488 TI - National and sub-national age-sex specific and cause-specific mortality and disability-adjusted life years (DALYs) attributable to household air pollution from solid cookfuel use (HAP) in Iran, 1990-2013. AB - National and sub-national mortality, years of life lost due to premature mortality (YLLs), years lived with disability (YLDs) and disability-adjusted life years (DALYs) for household air pollution from solid cookfuel use (HAP) in Iran, 1990-2013 were estimated based on the Global Burden of Disease Study 2013 (GBD 2013). The burden of disease attributable to HAP was quantified by the comparative risk assessment method using four inputs: (1) exposure to HAP, (2) the theoretical minimum risk exposure level (TMREL), (3) exposure-response relationships of related causes (4) disease burden of related causes. All across the country, solid fuel use decreased from 5.26% in 1990 to 0.15% in 2013. The drastic reduction of solid fuel use leaded to DALYs attributable to HAP fell by 97.8% (95% uncertainty interval 97.7-98.0%) from 87,433 (51072-144303) in 1990 to 1889 (1016-3247) in 2013. Proportion of YLLs in DALYs from HAP decreased from 95.7% in 1990 to 86.6% in 2013. Contribution of causes in the attributable DALYs was variable during the study period and in 2013 was in the following order: ischemic heart disease for 43.4%, chronic obstructive pulmonary disease for 24.7%, hemorrhagic stroke for 9.7%, lower respiratory infections for 9.3%, ischemic stroke for 7.8%, lung cancer for 3.4% and cataract for 1.8%. Based on the Gini coefficient, the spatial inequality of the disease burden from HAP increased during the study period. The remained burden of disease was relatively scarce and it mainly occurred in seven southern provinces. Further reduction of the disease burden from HAP as well as compensation of the increasing spatial inequality in Iran could be attained through an especial plan for providing cleaner fuels in the southern provinces. PMID- 28340490 TI - A Novel Method of Neo-osseous Flap Prefabrication: Induction of Free Calvarial Periosteum with Bioactive Glass. AB - BACKGROUND: Reconstruction of craniofacial bone defects is a primary focus of craniofacial surgery. Although autogenous bone grafts remain as the gold standard, alloplastic materials have also gained widespread popularity due to their off-the-shelf availability, ease of use, and durability. In addition to replacing the missing bone, some of these alloplastic materials have also been found to induce new bone formation. OBJECTIVES: In this study, the phenomenon of neo-osseous induction with bioactive glass was investigated for different implant soft tissue configurations. MATERIALS AND METHODS: Thirty-two male, Wistar albino rats were divided into four equally numbered study groups. In group 1 (FP), adipofascial groin flaps were prefabricated with free periosteal grafts. In group 2 (FPB), adipofascial groin flaps were prefabricated with free periosteal grafts and bioactive glass. In group 3 (FB), adipofascial groin flaps were prefabricated with bioactive glass. In group 4 (control), adipofascial groin flaps were not prefabricated. Morphometric analyses of the prefabricated structures were performed using micro-CT. The histologic properties of the ectopic ossification were assessed by using a modified scoring system. RESULTS: Group 1 (FP) showed the greatest rate of mature lamellar bone formation. Group 2 (FBP) showed the greatest amount of bone density and volume. However, the addition of bioactive glass in group 2 (FBP) decreased the rate of mature lamellar bone formation when compared with group 1 (FP). Ectopic ossification was not observed in the control group. CONCLUSION: Bioactive glass can be successfully used in the prefabrication of vascularized compound structures for the reconstruction of complex bone defects. However, interference with the periosteal induction of mature lamellar bone formation should be taken into consideration, especially in pediatric bone defects, which primarily rely on spontaneous osteogenesis through periosteal induction. PMID- 28340489 TI - MiR-34a-3p alters proliferation and apoptosis of meningioma cells in vitro and is directly targeting SMAD4, FRAT1 and BCL2. AB - Micro (mi)RNAs are short, noncoding RNAs and deregulation of miRNAs and their targets are implicated in tumor generation and progression in many cancers. Meningiomas are mostly benign, slow growing tumors of the central nervous system with a small percentage showing a malignant phenotype.Following in silico prediction of potential targets of miR-34a-3p, SMAD4, FRAT1, and BCL2 have been confirmed as targets by dual luciferase assays with co-expression of miR-34a-3p and reporter gene constructs containing the respective 3'UTRs. Disruption of the miR-34a-3p binding sites in the 3'UTRs resulted in loss of responsiveness to miR 34a-3p overexpression. In meningioma cells, overexpression of miR-34a-3p resulted in decreased protein levels of SMAD4, FRAT1 and BCL2, while inhibition of miR-34a 3p led to increased levels of these proteins as confirmed by Western blotting. Furthermore, deregulation of miR-34a-3p altered cell proliferation and apoptosis of meningioma cells in vitro.We show that SMAD4, FRAT1 and BCL2 are direct targets of miR-34a-3p and that deregulation of miR-34a-3p alters proliferation and apoptosis of meningioma cells in vitro. As part of their respective signaling pathways, which are known to play a role in meningioma genesis and progression, deregulation of SMAD4, FRAT1 and BCL2 might contribute to the aberrant activation of these signaling pathways leading to increased proliferation and inhibition of apoptosis in meningiomas. PMID- 28340491 TI - Comparison of Skillful vs. Less Skilled Young Soccer Players on Anthropometric, Maturation, Physical Fitness and Time of Practice. AB - This study compared maturation, body composition and physical fitness between youth soccer athletes with different technical skills levels. Sixty-two young athletes (11-17 years) were categorized dichotomously in more skilled (n=31) and less skilled (n=31) groups based on 3 specific technical tests (Dribbling Speed Test [DST], Shuttle Dribble Test [SDT] and Slalom Dribble Test [SLDT]). Chronological and skeletal age, time of practice, body composition and 4 physical fitness tests were performed for comparisons. As expected, the 3 technical tests were correlated (r=0.47-0.54, P<0.05). More skilled subjects in DST and SDT showed (respectively) higher time of practice (effect size [ES]=0.72 and 0.90), and greater performance sit-ups (ES=1.23 and 0.81), squat jump (ES=1.10 and 1.08), countermovement jump (ES=1.11 and 1.10), and Yo-Yo test (ES=1.17 and 1.40) compared to the less skilled subjects (P<0.05). However, more skilled subjects in SLDT showed greater performance (P<0.05) only in the squat jump (ES=0.67) and Yo Yo tests (ES=0.83). The results suggest that technical performance is associated with greater time of practice and some physical capabilities. Moreover, the DST and SDT tests seem to be good options to discriminate technical performance in youth soccer athletes. PMID- 28340492 TI - Hemolysis, Elevated Liver Enzymes, Low Platelets Syndrome Superimposed on Hemolytic Uremic Syndrome. AB - A pregnancy complicated by typical hemolytic uremic syndrome (HUS) and hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome is reported. At 20 weeks of gestation, a case of HUS was diagnosed, with Shiga toxin-producing Escherichia coli identified. Plasmapheresis allowed continuation of the pregnancy for 5 weeks. Superimposed preeclampsia and HELLP syndrome were diagnosed after the establishment of nephrotic range proteinuria, hypertension and recurrence of hemolysis. This is a singular case, as it demonstrates that HELLP syndrome can superimpose upon HUS, a fact that can impact future research on reproductive immunology. It also reminds clinicians that the overlapping of clinical and laboratory findings in HELLP syndrome makes the diagnosis of other thrombotic microangiopathies during pregnancy a clinical challenge. PMID- 28340493 TI - Conservative Treatment with Octreotide to Provide Early Recovery of Children with Esophageal Perforation. AB - BACKGROUND: The effectiveness of nonoperative treatment of esophageal perforation (EP) in children with octreotide is highlighted. METHODS: Records of nine patients (seven boys and two girls with an average age of 5.83 +/- 5.35 years) with EP were reviewed. RESULTS: EP developed in six patients during dilation of esophageal stenosis (five of six caused by caustic burns). In the other three patients, EP developed after nasogastric placement, after endotracheal intubation, and during endoscopy for foreign body. The symptoms consisted of dyspnea in four patients, tachypnea in seven patients, fever in six patients, chest pain in two patients, and abdominal pain in one patient. Two patients had pneumomediastinum, four patients had pleural effusion, one patient had subcutaneous emphysema, four patients had pneumothorax, and two patients had severe sepsis. Eight of the perforations resolved spontaneously. Therapy included cessation of oral feedings, implementation of proper antibiosis, parenteral and/or enteral nutrition by gastrostomy, and drainage of pleural effusions or mediastinal abscesses if required. Though not recommended by literature, octreotide was administered to these patients. Only one patient was operated in another clinic and was lost during follow-up. The length of hospitalization stay had a median of 11 +/- 6.59 days, ranging between 5 and 28 days. If the patient who was operated and did not receive octreotide therapy is excluded, the median hospitalization was only 8 days (5 to 12 days). All patients in our series (except patient 8) survived and still have their native esophagus. CONCLUSION: The initiation of octreotide treatment in the early period after diagnosis of EP without surgical intervention leads to early improvement in children. PMID- 28340494 TI - Postoperative Care of Patients with High-grade Glioma: Is There a Real Need for the Neurocritical ICU and Early CT Scan? AB - BACKGROUND: Pressure on economic resources now requires a careful rationalization of services. For adult patients with supratentorial gliomas, there is no consensus on the real need for care in a postoperative neurocritical intensive care unit (NICU) and on the timing of a postsurgical computed tomography (CT) scan. In this retrospective nonrandomized study, we assessed if and when there is a real need for NICU and if an early CT scan could be justified in the absence of neurologic worsening. METHODS: Of 264 patients, 21 were admitted to the NICU after the procedure as planned before the surgery for their clinical features (Karnofsky performance status < 70, American Society of Anesthesiologists score > 2, or Charlson Comorbidity Index > 5). RESULTS: The mean stay in the NICU was 19.7 hours. One of these patients had developed a postoperative hematoma that was subsequently removed, and died afterward. The other 243 patients were followed clinically after the procedure: 219 underwent a cerebral CT scan 24 hours after the procedure and were discharged in good condition. The other 24 patients had a cerebral CT scan within 24 hours after the procedure. The early CT showed the presence of a local edema in five cases and a hematoma surgically treated with a subsequent admission to the NICU in two cases. CONCLUSION: Considering our data, we suggest that NICU should not always be used after craniotomy for supratentorial gliomas. Clinical observation was sufficient to predict early postoperative complications. A CT scan before 24 hours after surgery is not recommended in the absence of clinical worsening. PMID- 28340495 TI - Residents' Learning Curve of Lumbar Transforaminal Epidural Steroid Injections. AB - Background and Study Aims There is a paucity of literature on beginners' training and on its connection with patient safety for transforaminal epidural steroid injections (TFESIs). This study retrospectively assessed the learning curves and associated complications of neurosurgery residents never previously exposed to TFESI and compared them with experienced board-certified faculty neurosurgeons (BCFNs). Material and Methods Procedure time in minutes, dose-area product (DAP) in cGy*cm2, periprocedural observations, and complications in 354 TFESIs for radicular pain secondary to lumbar disk herniation or lumbar spinal stenosis were extracted from operative notes and the electronic infiltration logbook in the per injection format. Learning curves for 238 residents and 116 BCFN TFESIs in terms of procedure time and DAP were estimated using monotone regression. Results Residents' TFESI procedure time and DAP reached BCFN level (4.7 minutes and 140.2 Gy*cm2) after 67 and 68 cases, respectively. Residents' TFESIs were unsuccessful in 1.7%, mostly for severe obesity and hypertrophied facet joints, but no severe complications were noted. Obesity, however, did not result in increased procedure times or radiation exposure in general. Residents were faster and required less fluoroscopy in TFESI of the upper lumbar nerve roots than for L5 or S1 in particular. Conclusion The residents' learning curve for TFESIs in terms of procedure time and radiation exposure can be overcome safely after < 70 TFESIs. An outcome analysis correlating to the interventionalist's training level would be worth investigating in future studies. PMID- 28340496 TI - Recent developments in nanomedicine for melanoma treatment. AB - Melanoma is a most aggressive skin cancer with limited therapeutic options and its incidence is increasing rapidly in recent years. The discovery and application of new targeted therapy agents have shown significant benefits. However, adverse side-effects and resistance to chemotherapy remain formidable challenges in the clinical treatment of malignant melanoma. Nanotherapeutics offers an important prospect of overcoming these drawbacks. The anti-tumoral applications of nanomedicine are varied, including those in chemotherapy, RNA interference, photothermal therapy, and photodynamic therapy. Furthermore, nanomedicine allows delivery of the effector structures into the tumor site via passive or active targeting, thereby allowing increased therapeutic specificity and reduced side effects. In this review, we summarize the latest developments in the application of nanocarrier-mediated targeted drug delivery to melanoma and nanomedicine-related clinical trials in melanoma treatment. We also discuss existing problems and opportunities for future developments, providing direction and new thoughts for further studies. PMID- 28340497 TI - P450 inhibitor ketoconazole increased the intratumor drug levels and antitumor activity of fenretinide in human neuroblastoma xenograft models. AB - We previously reported that concurrent ketoconazole, an oral anti-fungal agent and P450 enzyme inhibitor, increased plasma levels of the cytotoxic retinoid, fenretinide (4-HPR) in mice. We have now determined the effects of concurrent ketoconazole on 4-HPR cytotoxic dose-response in four neuroblastoma (NB) cell lines in vitro and on 4-HPR activity against two cell line-derived, subcutaneous NB xenografts (CDX) and three patient-derived NB xenografts (PDX). Cytotoxicity in vitro was assessed by DIMSCAN assay. Xenografted animals were treated with 4 HPR/LXS (240 mg/kg/day) + ketoconazole (38 mg/kg/day) in divided oral doses in cycles of five continuous days a week. In one model, intratumoral levels of 4-HPR and metabolites were assessed by HPLC assay, and in two models intratumoral apoptosis was assessed by TUNEL assay, on Day 5 of the first cycle. Antitumor activity was assessed by Kaplan-Meier event-free survival (EFS). The in vitro cytotoxicity of 4-HPR was not affected by ketoconazole (p >= 0.06). Ketoconazole increased intratumoral levels of 4-HPR (p = 0.02), of the active 4-oxo-4-HPR metabolite (p = 0.04), and intratumoral apoptosis (p <= 0.0006), compared to 4 HPR/LXS-alone. Concurrent ketoconazole increased EFS in both CDX models compared to 4-HPR/LXS-alone (p <= 0.008). 4-HPR + ketoconazole also increased EFS in PDX models compared to controls (p <= 0.03). Thus, concurrent ketoconazole decreased 4-HPR metabolism with resultant increases of plasma and intratumoral drug levels and antitumor effects in neuroblastoma murine xenografts. These results support the clinical testing of concurrent ketoconazole and oral fenretinide in neuroblastoma. PMID- 28340499 TI - Pagan symbols associated with the female anatomy in the Medici Chapel by Michelangelo Buonarroti. AB - Numerous studies have shown that many works of art from the Renaissance period contain hidden symbols and codes that could have religious, mathematical and/or pagan significance and even anatomical allusions. In this context, the present manuscript offers new evidence that the great genius of anatomy, Michelangelo Buonarroti (1475-1564), included pagan symbols associated with female anatomy in the funerary monuments found in the Sagrestia Nuova/Medici Chapel (1519-1533) in Florence, Italy. The interpretation of the symbols provided in this study will interest those with a passion for the history of anatomy. Clin. Anat. 30:572-577, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28340498 TI - Academic Difficulties in Children with Prenatal Alcohol Exposure: Presence, Profile, and Neural Correlates. AB - BACKGROUND: Academic achievement was evaluated in children with heavy prenatal alcohol exposure to determine potential strengths and weaknesses, evaluate the utility of different definitions for identifying low academic performance, and explore the neural correlates that may underlie academic performance. METHODS: Children (8 to 16 years) were assessed using the WIAT-II. Patterns of performance were examined in 2 subject groups: children with heavy prenatal alcohol exposure (n = 67) and controls (n = 61). A repeated-measures MANCOVA examining group differences on academic domain (reading, spelling, math) scores was conducted. Post hoc comparisons examined within-group profiles. Numbers and percentage of children with low achievement were calculated using several criteria. In a subsample (n = 42), neural correlates were analyzed using FreeSurfer v5.3 to examine relations between cortical structure (thickness and surface area) and performance. RESULTS: The alcohol-exposed group performed worse than controls on all domains and had a unique academic profile, supported by a significant group * academic domain interaction (p < 0.001). For the alcohol-exposed group, math reasoning was significantly lower than numerical operations, which was significantly lower than spelling and word reading. Over half of the alcohol exposed group (58.2%) demonstrated low achievement on 1 or more academic domains. The number and percentage of children meeting criteria for low achievement varied based on the domain and definition used. The imaging analysis identified several surface area clusters that were differentially related to math (L superior parietal and R lateral/middle occipital) and spelling (bilateral inferior and medial temporal) performance by group, with no relations for the other academic domains. Generally, scores improved as surface area decreased in controls, whereas no relation or a positive relation was observed in the alcohol-exposed group. CONCLUSIONS: Alcohol-exposed children demonstrated deficits in academic performance across domains and definitions, with a relative weakness in math functioning. Atypical brain development may contribute to these impairments in academic achievement. Understanding academic difficulties can assist in advocating effectively for alcohol-exposed children. PMID- 28340500 TI - Advanced Practice Registered Nurses and Long-Acting Reversible Contraception. AB - INTRODUCTION: Advanced practice registered nurses (APRNs) are in an excellent position to address the high rates of unintended pregnancy in the United States by providing long-acting reversible contraceptives (LARCs). These methods are significant in their effectiveness in preventing pregnancy in individual women and in having population-level effects on unintended pregnancy. The aim of this study was to learn more about APRN practices around long-acting reversible contraception and influences on those practices. METHODS: A cross-sectional survey of APRNs who provide women's health services was conducted during the summer of 2015 using an existing adapted instrument with items on personal and patient characteristics, opinions, practices, and training around LARC methods. Zero-inflated Poisson regression models were conducted to study the factors that influenced the number of LARC insertions in the past year. RESULTS: While 84% of the 390 respondents were inserting intrauterine devices (IUDs) and 77% single-rod implants, only 16% of these were inserting more devices than 5 years earlier. The most significant predictor of placement of these contraceptives was the clinical practice of requiring only one visit for completion. DISCUSSION: National guidelines and recommendations have been in place for several years stating that women should be able to receive the contraceptive method of their choice in just one clinic visit. Women's access to LARCs from APRNs may be less than optimal. Additional research is needed to understand if the limitations in accessibility of this important reproductive health service are a function of clinician practices or clinic policies. PMID- 28340501 TI - Hepatitis C. PMID- 28340502 TI - Trends in Alcohol Consumption Among Older Americans: National Health Interview Surveys, 1997 to 2014. AB - BACKGROUND: The majority of U.S. older adults consume alcoholic beverages. The older population is projected to almost double by 2050. Substantially more drinkers are likely. PURPOSE: To describe gender-specific trends (1997 to 2014) in prevalence of drinking status (lifetime abstention, former drinking, current drinking [including average volume], and binge drinking) among U.S. adults ages 60+ by age group and birth cohort. METHODS: In the 1997 to 2014 National Health Interview Surveys, 65,303 respondents ages 60+ (31,803 men, 33,500 women) were current drinkers; 6,570 men and 1,737 women were binge drinkers. Prevalence estimates and standard errors were computed by age group (60+, 60 to 64, 65 to 69, 70 to 74, 75 to 79, 80+) and birth cohort (<1925, 1925 to 1935, 1936 to 1945, 1946 to 1954). Trends were examined using joinpoint regression and described as average annual percent change (AAPC; overall change 1997 to 2014) and annual percent change (APC; in-between infection points). Primary analyses were unadjusted. All analyses (unadjusted and adjusted for demographics/lifestyle) were weighted to produce nationally representative estimates. Statistical procedures accounted for the complex survey design. RESULTS: Among men ages 60+, unadjusted prevalence of current drinking trended upward, on average, 0.7% per year (AAPC, p = 0.02); average volume and prevalence of binge drinking remained stable. Adjusted results were similar. Among women age 60+, unadjusted prevalence of current drinking trended upward, on average, 1.6% per year (AAPC, p < 0.0001), but average volume remained stable; prevalence of binge drinking increased, on average, 3.7% per year (AAPC, p < 0.0001). Adjusted results were similar. Trends varied by age group and birth cohort. Among men born 1946 to 1954, unadjusted prevalence of current drinking trended upward, on average, 2.4% per year (AAPC, p = 0.02); adjusted results were nonsignificant. CONCLUSIONS: Our finding of upward trends in drinking among adults ages 60+, particularly women, suggests the importance of public health planning to meet future needs for alcohol-related programs. PMID- 28340504 TI - Improving the outcomes of human immunodeficiency virus/hepatitis C virus coinfected transplant recipients: The answer is Blowin' in the wind. PMID- 28340503 TI - Risk factors for lymph node metastases in women with endometrial cancer: A population-based, nation-wide register study-On behalf of the Swedish Gynecological Cancer Group. AB - The role of lymphadenectomy in the management of early endometrial cancer remains controversial. In the recent ESMO-ESGO-ESTRO guidelines, lymphadenectomy is recommended for patients with endometrioid adenocarcinoma Grade 3 with deep myometrial invasion, but complete agreement was not achieved. In Sweden, DNA aneuploidy has been included as a high-risk factor. The aim of our study was to evaluate the impact of tumor histology, FIGO grade, DNA ploidy and myometrial invasion (MI) on occurrence of lymph node metastasis (LNM) in patients with endometrial cancer. The study design is a retrospective cohort study based on prospectively recorded register data. Endometrial cancer patients registered in the Swedish Quality Registry for Gynecologic Cancer 2010-2015 with FIGO Stages I III and verified nodal status were included. Data on DNA ploidy, histology, FIGO grade and MI were included in multivariable log-binomial regression analyses with LNM as dependent variable. 1,165 cases fulfilled the inclusion criteria. The multivariable analyses revealed increased risk of LNM in patients with tumors with MI >= 50% (risk ratio [RR] = 4.1; 95% confidence interval [CI] 3.0-5.6), nonendometrioid compared to endometrioid histology (RR 1.8; CI 1.4-2.4) and FIGO Grade 3 compared to Grade 1-2 tumors (RR 1.5; CI 1.1-2.0). No statistically significant association between DNA ploidy status and LNM was detected. This population-based, nation-wide study in women with endometrial cancer confirms a strong association between MI >= 50%, nonendometrioid histology and FIGO Grade 3, respectively, and LNM. DNA ploidy should not be included in the preoperative decision making of removing nodes or not. PMID- 28340505 TI - Afferent and efferent connections of the interpeduncular nucleus with special reference to circuits involving the habenula and raphe nuclei. AB - The habenula is an epithalamic structure differentiated into two nuclear complexes, medial (MHb) and lateral habenula (LHb). Recently, MHb together with its primary target, the interpeduncular nucleus (IP), have been identified as major players in mediating the aversive effects of nicotine. However, structures downstream of the MHb-IP axis, including the median (MnR) and caudal dorsal raphe nucleus (DRC), may contribute to the behavioral effects of nicotine. The afferent and efferent connections of the IP have hitherto not been systematically investigated with sensitive tracers. Thus, we placed injections of retrograde or anterograde tracers into different IP subdivisions or the MnR and additionally examined the transmitter phenotype of major IP and MnR afferents by combining retrograde tract tracing with immunofluorescence and in situ hybridization techniques. Besides receiving inputs from MHb and also LHb, we found that IP is reciprocally interconnected mainly with midline structures, including the MnR/DRC, nucleus incertus, supramammillary nucleus, septum, and laterodorsal tegmental nucleus. The bidirectional connections between IP and MnR proved to be primarily GABAergic. Regarding a possible topography of IP outputs, all IP subnuclei gave rise to descending projections, whereas major ascending projections, including focal projections to ventral hippocampus, ventrolateral septum, and LHb originated from the dorsocaudal IP. Our findings indicate that IP is closely associated to a distributed network of midline structures that modulate hippocampal theta activity and forms a node linking MHb and LHb with this network, and the hippocampus. Moreover, they support a cardinal role of GABAergic IP/MnR interconnections in the behavioral response to nicotine. PMID- 28340506 TI - Neuromedin U alters bioenergetics and expands the cancer stem cell phenotype in HER2-positive breast cancer. AB - Neuromedin U (NmU) is a neuropeptide belonging to the neuromedin family. Recently, we reported a significant association between NmU and breast cancer, particularly correlating with increased aggressiveness, resistance to HER2 targeted therapies and overall significantly poorer outcome for patients, although the mechanism through which it exerts this effect remained unexplained. Investigating this, here we found that ectopic over-expression of NmU in HER2 positive breast cancer cells induced aberrant metabolism, with increased glycolysis, likely due to enhanced pyruvate dehydrogenase kinase activity. Similar results were observed in HER2-targeted drug-resistant cell variants, which we had previously shown to display increased levels of NmU. Overexpression of NmU also resulted in upregulation of epithelial-mesenchymal transition markers and increased IL-6 secretion which, together with aberrant metabolism, have all been associated with the cancer stem cell (CSC) phenotype. Flow cytometry experiments confirmed that NmU-overexpressing and HER2-targeted drug-resistant cells showed an increased proportion of cells with CSC phenotype (CD44+ /CD24- ). Taken together, our results report a new mechanism of action for NmU in HER2 overexpressing breast cancer that enhances resistance to HER2-targeted drugs through conferring CSC characteristics and expansion of the CSC phenotype. PMID- 28340507 TI - Understanding the contribution of disulfide bridges to the folding and misfolding of an anti-Abeta scFv. AB - ScFv-h3D6 is a single chain variable fragment that precludes Abeta peptide induced cytotoxicity by withdrawing Abeta oligomers from the amyloid pathway to the worm-like pathway. Production of scFv molecules is not a straightforward procedure because of the occurrence of disulfide scrambled conformations generated in the refolding process. Here, we separately removed the disulfide bond of each domain and solved the scrambling problem; and then, we intended to compensate the loss of thermodynamic stability by adding three C-terminal elongation mutations, previously described to stabilize the native fold of scFv h3D6. Such stabilization occurred through stabilization of the intermediate state in the folding pathway and destabilization of a different, beta-rich, intermediate state driving to worm-like fibrils. Elimination of the disulfide bridge of the less stable domain, VL , deeply compromised the yield and increased the aggregation tendency, but elimination of the disulfide bridge of the more stable domain, VH , solved the scrambling problem and doubled the production yield. Notably, it also changed the aggregation pathway from the protective worm like morphology to an amyloid one. This was so because a partially unfolded intermediate driving to amyloid aggregation was present, instead of the beta-rich intermediate driving to worm-like fibrils. When combining with the elongation mutants, stabilization of the partially unfolded intermediate driving to amyloid fibrils was the only effect observed. Therefore, the same mutations drove to completely different scenarios depending on the presence of disulfide bridges and this illustrates the relevance of such linkages in the stability of different intermediate states for folding and misfolding. PMID- 28340508 TI - Dyspareunia in a Survivor of Childhood Sexual Abuse. AB - Dyspareunia is a frequent chief concern encountered by midwives and other women's health care providers. There are many possible etiologies for dyspareunia, including a history of childhood sexual abuse, and approaching assessment in a holistic manner is necessary to identify the etiology. This case report presents evidence on the importance of screening a woman who presents with dyspareunia in a therapeutic manner to facilitate disclosure of sexual abuse. Best practices for screening for sexual violence, along with recommendations for providing gynecologic care to survivors, are offered. By understanding the long-term sequelae of sexual abuse and through screening all women, midwives and other women's health care providers can facilitate healing and treatment for survivors. PMID- 28340509 TI - Liver transplantation recipients with nonalcoholic steatohepatitis have lower risk hepatocellular carcinoma. AB - Liver transplantation (LT) is a well-established treatment for hepatocellular carcinoma (HCC) in carefully selected patients. Risk factors for tumors with poor prognostic features on explant have not been well described in a national cohort. We performed a retrospective cohort study of adult LT recipients with HCC transplanted from April 8, 2012 (when explant pathology in United Network for Organ Sharing [UNOS] became available) until September 30, 2014. We evaluated the association between listing diagnosis and other demographic factors with tumor features on explant using logistic regression. High-risk tumor features included the following: > 3 tumors, largest tumor > 5 cm, presence of vascular invasion, presence of metastases, and poor differentiation of tumor. In total, 3733 LT recipients with HCC who had complete explant data in UNOS were included. The median age was 60 years; 78% were male; and 68% were white. Of the primary non HCC listing diagnoses, 2608 (70%) had hepatitis C virus (HCV); 271 (7%) had nonalcoholic steatohepatitis (NASH); 246 (7%) had alcoholic cirrhosis; and 189 (5%) had hepatitis B virus. Also, 1140 (31%) had evidence of >= 1 high-risk explant feature(s). The presence of >= 1 high-risk explant feature(s) was associated with HCC recurrence after transplant (odds ratio [OR], 5.00; P < 0.001). Compared with HCV-associated HCC transplant recipients, individuals with NASH had lower likelihood of high-risk explant features (OR, 0.71; P = 0.02) after adjusting for covariables. Women were more likely to have high-risk explant features (OR, 1.23; P = 0.04). Diabetes mellitus (DM) was not associated with high-risk explant features. In conclusion, LT recipients with NASH-associated HCC had fewer high-risk tumor features on explant compared with HCV-associated HCC, despite having higher rates of DM and other potential risk factors for the development of HCC. Women had a higher likelihood of high-risk tumor features. Further study is warranted whether these differences are due to disease-specific or sex-specific influences on tumor biology or due to selection criteria for transplant. Liver Transplantation 23 1015-1022 2017 AASLD. PMID- 28340510 TI - The diverse family of MmpL transporters in mycobacteria: from regulation to antimicrobial developments. AB - Mycobacterial genomes contain large sets of loci encoding membrane proteins that belong to a family of multidrug resistance pumps designated Resistance-Nodulation Cell Division (RND) permeases. Mycobacterial membrane protein Large (MmpL) transporters represent a subclass of RND transporters known to participate in the export of lipid components across the cell envelope. These surface-exposed lipids with unusual structures play key roles in the physiology of mycobacteria and/or can act as virulence factors and immunomodulators. Defining the substrate specificity of MmpLs and their mechanisms of regulation helps understanding how mycobacteria elaborate their complex cell wall. This review describes the diversity of MmpL proteins in mycobacteria, emphasising their high abundance in a few opportunistic rapid-growing mycobacteria. It reports the conservation of mmpL loci between Mycobacterium tuberculosis and non-tuberculous mycobacteria, useful in predicting the role of MmpLs with unknown functions. Paradoxically, whereas MmpLs participate in drug resistance mechanisms, they represent also attractive pharmacological targets, opening the way for exciting translational applications. The most recent advances regarding structural/functional information are also provided to explain the molecular basis underlying the proton-motive force driven lipid transport. Overall, this review emphasises the Janus-face nature of MmpLs at the crossroads between antibiotic resistance mechanisms and exquisite vulnerability to drugs. PMID- 28340511 TI - Quantitative mapping reveals age and sex differences in vasopressin, but not oxytocin, immunoreactivity in the rat social behavior neural network. AB - The neuropeptides vasopressin (AVP) and oxytocin (OT) have been implicated in the regulation of numerous social behaviors in adult and juvenile animals. AVP and OT signaling predominantly occur within a circuit of interconnected brain regions known collectively as the "social behavior neural network" (SBNN). Importantly, AVP and OT signaling within the SBNN has been shown to differentially regulate diverse social behaviors, depending on the age and/or sex of the animal. We hypothesized that variation in the display of these behaviors is due in part to age and sex differences in AVP and OT synthesis within the SBNN. However, a thorough characterization of AVP and OT-immunoreactive (ir) fibers and cell bodies across age and sex within the SBNN has been lacking in rats. We therefore quantified AVP- and OT-ir fibers and cell bodies in 22 subregions of the forebrain SBNN in juvenile and adult, male and female rats. We found numerous age (16 subregions) and sex (10 subregions) differences in AVP-ir fiber fractional areas, and AVP-ir cell body numbers, which were mainly observed in the medial amygdala/bed nucleus of the stria terminalis to lateral septum circuit. In contrast to AVP, we observed no age or sex differences in OT-ir fiber fractional areas or cell bodies in any of the 22 subregions of the forebrain SBNN. Thus, unlike the static pattern observed for OT, AVP innervation of the forebrain SBNN appears to undergo developmental changes, and is highly sexually dimorphic, which likely has significant functional consequences for the regulation of social behavior. PMID- 28340512 TI - Activation mechanisms of alphaVbeta3 integrin by binding to fibronectin: A computational study. AB - Integrin alphaVbeta3 plays an important role in regulating cellular activities and in human diseases. Although the structure of alphaVbeta3 has been studied by crystallography and electron microscopy, the detailed activation mechanism of integrin alphaVbeta3 induced by fibronectin remains unclear. In this study, we investigated the conformational and dynamical motion changes of Mn2+ -bound integrin alphaVbeta3 by binding to fibronectin with molecular dynamics simulations. Results showed that fibronectin binding to integrin alphaVbeta3 caused the changes of the conformational flexibility of alphaVbeta3 domains, the essential mode of motion for the domains of alphaV subunit and beta3 subunit and the degrees of correlated motion of residues between the domains of alphaV subunit and beta3 subunit of integrin alphaVbeta3. The angle of Propeller domain with respect to the Calf-2 domain of alphaV subunit and the angle of Hybrid domain with respect to betaA domain of beta3 subunit significantly increased when integrin alphaVbeta3 was bound to fibronectin. These changes could result in the conformational change tendency of alphaVbeta3 from a bend conformation to an extended conformation and lead to the open swing of Hybrid domain relative to betaA domain of beta3 subunit, which have demonstrated their importance for alphaVbeta3 activation. Fibronectin binding to integrin alphaVbeta3 significantly decreased the relative position of alpha1 helix to betaA domain and that to metal ion-dependent adhesion site, stabilized Mn2+ ions binding in integrin alphaVbeta3 and changed fibronectin conformation, which are important for alphaVbeta3 activation. Results from this study provide important molecular insight into the "outside-in" activation mechanism of integrin alphaVbeta3 by binding to fibronectin. PMID- 28340514 TI - Elucidation of the methods used for quantitative analysis of radiolabeled sphingolipids with beta imager 2000 radiochromatoscanner in MOLT-4 leukemic cells. PMID- 28340513 TI - Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer. AB - While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP-CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20-1.79, p = 1.68 * 10-4 ). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92 1.18, p = 0.49), 0.94 (95% CI: 0.84-1.05, p = 0.27), and 0.98 (95% CI: 0.85-1.12, p = 0.75) respectively. A genetic risk score for 3-hydoxy-3-methylglutaryl coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49-0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia. PMID- 28340515 TI - Inflammatory potential of diet and risk of oral and pharyngeal cancer in a large case-control study from Italy. AB - Diet and inflammation have been suggested to be important risk factors for oral and pharyngeal cancer. We examined the association between dietary inflammatory index (DIITM) and oral and pharyngeal cancer in a large case-control study conducted between 1992 and 2009 in Italy. This study included 946 cases with incident, histologically confirmed oral and pharyngeal cancer, and 2,492 controls hospitalized for acute non-neoplastic diseases. The DII was computed based on dietary intake assessed by a valid 78-item food frequency questionnaire and was adjusted for nonalcohol energy intake using the residual approach (E-DIITM). Logistic regression models were used to estimate odds ratios (ORs), and 95% confidence intervals (CIs), adjusted for age, sex, non-alcohol energy intake, study center, year of interview, education, body mass index, tobacco smoking, and alcohol drinking. Subjects with higher DII scores (i.e., with a more pro inflammatory diet) had a higher risk of oral and pharyngeal cancer, the OR being 1.80 (95% CI 1.36-2.38) for the highest versus the lowest DII quartile and 1.17 (95% CI 1.10-1.25) for a one-unit increase (8% of the DII range). When stratified by selected covariates, a stronger association was observed among women (ORquartile4 v.1 3.30, 95% CI 1.95-5.57). We also observed a stronger association for oral cancers and a strong combined effect of higher DII score and tobacco smoking or alcohol consumption on oral and pharyngeal cancer. These results indicate that the pro-inflammatory potential of the diet, as shown by higher DII scores, is associated with higher odds of oral and pharyngeal cancer. PMID- 28340517 TI - Piecemeal Mechanism Combining Sprouting and Intussusceptive Angiogenesis in Intravenous Papillary Formation Induced by PGE2 and Glycerol. AB - Recently, we demonstrated that in human intravascular papillary endothelial hyperplasia (IPEH), vein wall vascularization occurs in association with myriad papillae, a large part of which formed in the vascularized vein wall. Previously, using an animal model, we observed that PGE2 and glycerol administration around the femoral vein originates intense vascularization of the vein wall from its intimal endothelial cells (ECs). This vascularization is similar to that in IPEH. The aim of this study is to assess the mechanism of papillary formation, using this model after demonstrating papillary development in neo-vascularized femoral vein walls. In semithin and ultrathin sections, the sequential vascular and papillary development was as follows: (a) activation of vein intimal ECs, (b) sprouting of intimal ECs towards the vein media layer and microvessel development, (c) interconnection between neighboring microvessels originated elementary loops, which encircled vein wall components and formed papillae. The encircling ECs formed the papillary cover, and the encircled component formed the core. The papillae showed a similar structure to that of folds and pillars in intussusceptive angiogenesis, and (d) origin of secondary and complex loop systems by interconnection of neighboring elementary loops and by splitting of papillae by new loops, with abundant papillary development. In conclusion, the results support a piecemeal angiogenic mechanism in papillary formation, with association of sprouting and intussusceptive types of angiogenesis. Further studies are needed to assess whether the intravascular papillae described in several pathologic processes, including vessel tumors, such as Dabska's tumor, retiform hemangioendothelioma, and angiosarcoma, follow a similar mechanism. Anat Rec, 2017. (c) 2017 Wiley Periodicals, Inc. Anat Rec, 300:1781-1792, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28340516 TI - Markers of dietary protein intake are associated with successful weight loss in the POUNDS Lost trial. AB - To assess the association of markers for dietary protein intake, measures of dietary adherence and demographic variables with weight loss in the POUNDS Lost study over the first 6 months and again between 6 and 24 months using data from those who completed each period. This is a secondary analysis of pooled data on completers assigned to one of four diets: 65%C/15%P/20%F (AP/LF), 55%C/25%P/20%F (HP/LF), 45%C/15%P/40%F (AP/HF) or 35%C/25%P40%F (HP/HF) in the POUNDS Lost study. Urinary nitrogen excretion, dietary adherence measured by 24-h recall and attendance at sessions, age (above and below 50 years), gender, race/ethnicity and activity by pedometry were analysed. Increased spread between protein intake at baseline and protein at 6 or 24 months, assessed by urinary nitrogen excretion, was associated with greater weight loss from baseline to 2 years. At 6 and 24 months, older age, male gender, body mass index > 30 kg m-2 and adherence to the fat and protein diets were associated with more weight loss. None of these variables was associated with a regain from 6 to 24 months. Weight regain for women in the highest carbohydrate (65%) group was significantly greater (-4.4 kg [95% CI: -5.9, -3.0]) than for women in the lowest carbohydrate group (-1.8 kg [95% CI: -3.2, -0.4 kg]) (P for interaction = 0.012). An increased spread in the difference between baseline and follow-up protein intake was associated with greater weight loss, consistent with the 'protein spread theory'. Women eating the highest carbohydrate diet regained more weight from 6 to 24 months. PMID- 28340518 TI - Prevalence and distribution of sesamoid bones in the hand determined using digital tomosynthesis. AB - The aim of this study was to identify the prevalence and distribution of sesamoid bones in the hand using digital tomosynthesis (DTS) in comparison to previous studies. Using conventional radiography (CR) and DTS, hand images (81 left and 100 right) taken at a tertiary hospital were retrospectively reviewed. The sesamoid bones were identified in the interphalangeal (IP) and metacarpophalangeal (MCP) joints of the thumb (I), and in the distal interphalangeal (DIP) and metacarpophalangeal (MCP) of index (II), middle (III), ring (IV), and little (V) fingers. Differences in number of sesamoid bones detected on CR and DTS were analyzed. Sesamoid bones were observed in MCP I (100%), MCP II (46%), MCP III (2%), MCP IV (2%), MCP V (53%), and IP I (53%) on CR. Using DTS, sesamoid bones were found more often in MCP I (100%), MCP II (54%), MCP III (2%), MCP IV (1%), MCP V (59%), and IP I (75%). Differences in the mean number of sesamoid bones detected on CR and DTS were statistically significant. Sesamoid bones in DIP joints were frequently observed on DTS, but rarely found on CR. Most sesamoid bones in the hand were detected in MCP I, II, V, and IP I joints, and were more often detected on DTS than CR. DTS is a reliable tool to evaluate bony structures in the hand. Clin. Anat. 30:608-613, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28340520 TI - Galangin inhibits human osteosarcoma cells growth by inducing transforming growth factor-beta1-dependent osteogenic differentiation. AB - Osteosarcoma is the most common primary malignancy of the musculoskeletal system, and is associated with excessive proliferation and poor differentiation of osteoblasts. Currently, despite the use of traditional chemotherapy and radiotherapy, no satisfactory and effective agent has been developed to treat the disease. Herein, we found that a flavonoid natural product, galangin, could significantly attenuate human osteosarcoma cells proliferation, without causing obvious cell apoptosis. Moreover, galangin enhanced the expression of osteoblast differentiation markers (collagen type I, alkaline phosphatase, osteocalcin and osteopontin) remarkably and elevated the alkaline phosphatase activity in human osteosarcoma cells. And galangin could also attenuated osteosarcoma growth in vivo. These bioactivities of galangin resulted from its selective activation of the transforming growth factor (TGF)-beta1/Smad2/3 signaling pathway, which was demonstrated by pathway blocking experiments. These findings suggested that galangin could be a promising agent to treat osteosarcoma. In addition, targeting TGF-beta1 to induce osteogenic differentiation might represent a novel therapeutic strategy to treat osteosarcoma with minimal side effects. PMID- 28340521 TI - Stable and Controllable Synthesis of Silver Nanowires for Transparent Conducting Film. AB - Silver nanowires without particles are synthesized by a solvothermal method at temperature 150 degrees C. Silver nanowires are prepared via a reducing agent of glycerol and a capping agent of polyvinylpyrrolidone (M w ~ 1,300,000). Both of them can improve the purity of the as-prepared silver nanowires. With controllable shapes and sizes, silver nanowires are grown continuously up to 10 20 MUm in length with 40-50 nm in diameter. To improve the yield of silver nanowires, the different concentrations of AgNO3 synthesis silver nanowires are discussed. The characterizations of the synthesized silver nanowires are analyzed by UV-visible absorption spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM), and atomic force microscope (AFM), and silver nanowires are pumped on the cellulose membrane and heated stress on the PET. Then, the cellulose membrane is dissolved by the steam of acetone to prepare flexible transparent conducting thin film, which is detected 89.9 of transmittance and 58 Omega/?. Additionally, there is a close loop connected by the thin film, a blue LED, a pair of batteries, and a number of wires, to determinate directly the film if conductive or not. PMID- 28340522 TI - Tin Oxide-Carbon-Coated Sepiolite Nanofibers with Enhanced Lithium-Ion Storage Property. AB - Natural sepiolite (Sep) nanofibers were coated with carbon and nanoscale SnO2 to prepare an emerging nanocomposite (SnO2-C@Sep), which exhibited enhanced electrochemical performance. Sepiolite could act as a steady skeleton, carbon coating principally led sepiolite from an isolated to an electric state, and decoration of nanoscale SnO2 was beneficial to the functionization of sepiolite. Cycling performances indicated that SnO2-C@Sep showed higher discharge capacities than commercial SnO2 after 50 cycles. The nanocomposite SnO2-C@Sep possessed enhanced lithium storage properties with stable capacity retention and low cost, which could open up a new strategy to synthesize a variety of functional hybrid materials based on the cheap and abundant clay and commercialization of lithium metal oxide batteries. PMID- 28340519 TI - Barrington's nucleus: Neuroanatomic landscape of the mouse "pontine micturition center". AB - Barrington's nucleus (Bar) is thought to contain neurons that trigger voiding and thereby function as the "pontine micturition center." Lacking detailed information on this region in mice, we examined gene and protein markers to characterize Bar and the neurons surrounding it. Like rats and cats, mice have an ovoid core of medium-sized Bar neurons located medial to the locus coeruleus (LC). Bar neurons express a GFP reporter for Vglut2, develop from a Math1/Atoh1 lineage, and exhibit immunoreactivity for NeuN. Many neurons in and around this core cluster express a reporter for corticotrophin-releasing hormone (BarCRH ). Axons from BarCRH neurons project to the lumbosacral spinal cord and ramify extensively in two regions: the dorsal gray commissural and intermediolateral nuclei. BarCRH neurons have unexpectedly long dendrites, which may receive synaptic input from the cerebral cortex and other brain regions beyond the core afferents identified previously. Finally, at least five populations of neurons surround Bar: rostral-dorsomedial cholinergic neurons in the laterodorsal tegmental nucleus; lateral noradrenergic neurons in the LC; medial GABAergic neurons in the pontine central gray; ventromedial, small GABAergic neurons that express FoxP2; and dorsolateral glutamatergic neurons that express FoxP2 in the pLC and form a wedge dividing Bar from the dorsal LC. We discuss the implications of this new information for interpreting existing data and future experiments targeting BarCRH neurons and their synaptic afferents to study micturition and other pelvic functions. PMID- 28340523 TI - Nanostructured (Co, Mn)3O4 for High Capacitive Supercapacitor Applications. AB - Nanostructured Co doped Mn3O4 spinel structure ((Co, Mn)3O4) were prepared by co precipitation under O3 oxidizing conditions and post-heat treatment. The product was composed of nanogranules with a diameter of 20-60 nm. The electrochemical performance of (Co, Mn)3O4 electrode was tested by cyclic voltammetry, impedance, and galvanostatic charge-discharge measurements. A maximum specific capacitance value of 2701.0 F g-1 at a current density of 5 A g-1 could be obtained within the potential range from 0.01 to 0.55 V versus Hg/HgO electrode in 6 mol L-1 KOH electrolyte. When at high current density of 30 A g-1, the capacitance is 1537.2 F g-1 or 56.9% of the specific capacitance at 5 A g-1, indicating its good rate capability. After 500 cycles at 20 A g-1, the specific capacitance remains 1324 F g-1 with a capacitance retention of 76.4%. PMID- 28340524 TI - Controlled Hydrothermal Synthesis and Photoluminescence of Nanocrystalline ZnGa2O4:Cr3+ Monospheres. AB - The hydrothermal synthesis of nanocrystalline ZnGa2O4:Cr3+ (ZGC) red phosphor monospheres was accomplished in this work, and the effects of system pH, reactant content, reaction time, and citrate anions (Cit3-) on the phase and morphology evolution of the product were systematically studied. Under the optimized conditions of Cit3-/M = 1.0 molar ratio (M = total cations), pH = 5.0, and 0.2 mmol of Zn2+, well-dispersed ZGC monospheres with an average diameter of ~454 +/- 56 nm (average crystallite size ~15 nm) were successfully obtained via hydrothermal reaction at 180 degrees C for 18 h. Cit3+ ions were demonstrated to be crucial to the formation of monospheres and substantially affect the pathway of phase formation. The ZGC monospheres calcined at 800 degrees C (average diameter ~353 +/- 59 nm; average crystallite size ~30 nm) have an intensity ~6 times that of the original phosphor for the 700 nm red emission of Cr3+ (the 2E > 4A2 transition) under excitation with the O2- -> Ga3+ charge transfer band at 250 nm. Fluorescence decay analysis found that the 700 nm emission has lifetime values of ~5 ms for the ZGC phosphors. PMID- 28340525 TI - Enhanced Dielectric Environment Sensitivity of Surface Plasmon-Polariton in the Surface-Barrier Heterostructures Based on Corrugated Thin Metal Films with Quasi Anticorrelated Interfaces. AB - A new approach to the formation of a 1D planar periodicity on the front of a plasmonic photodetector based on Schottky barrier is proposed. It allows forming a 1D planar periodicity with corrugation at the "metal/environment" interface by laser interference lithography using embedded chalcogenide wires, whereas the "metal/semiconductor" interface is flat that leads to reducing of surface recombination losses at Shottky barrier in contrary to the conventional technology for forming corrugated metal films on the semiconductor surface requiring chemical etching of the semiconductor substrate. In this case, the metal film interfaces are quasi-anticorrelated as opposed to correlated ones in the conventional technology. It has been theoretically predicted that the polarization sensitivity (T p /T s ) strongly depends on the cross-sectional shape of chalcogenide wires and reaches a value of 8. Furthermore, it was theoretically found that the maximum sensitivity of the signal intensity on the environment refractive index is three times larger than for an equivalent structure obtained by conventional technology. Comparison of experimental data for the photocurrent in the case of two types of correlation between metal film interfaces demonstrates good agreement with numerical simulations. PMID- 28340526 TI - An Experimental Study on Flow and Heat Transfer Characteristics of Ethanol/Polyalphaolefin Nanoemulsion Flowing Through Circular Minichannels. AB - This work experimentally studied the convective flow and heat transfer characteristics of a novel nanostructured heat transfer fluid: "ethanol/polyalphaolefin nanoemulsion" flowing through 12 circular minichannels of 1-mm diameter each. Ethanol/polyalphaolefin nanoemulsion is a thermodynamically stable system formed by dispersing ethanol into a mixture of "polyalphaolefin (PAO)" and surfactants. In this study, ethanol/PAO nanoemulsion is used as the working fluid to study the effect of ethanol nanodroplets on its convective flow and heat transfer characteristics. In addition, the effect of flow regime on its heat transfer is examined. It is found that using ethanol/PAO nanoemulsion fluids can improve convective heat transfer compared to that of pure PAO under both single- and two-phase flow regimes. For single-phase flow, there is no significant difference in Nusselt number between ethanol/PAO nanoemulsion and pure PAO in laminar flow regime. However, when entering transition flow regime, the ethanol/PAO nanoemulsion fluid showed a substantial increase in Nusselt number. Meanwhile, there is an increase in pressure drop and early onset of the laminar-turbulent transitional region for the ethanol/PAO nanoemulsion compared to pure PAO. The heat transfer coefficient of ethanol/PAO nanoemulsion can be further enhanced when the ethanol nanodroplets undergo phase change, which is hypothesized that such an effect is likely related to the enhanced interfacial thermal transport between the nanodroplets and base fluid under elevated temperature and the latent heat of phase changeable nanodroplets inside nanoemulsion. Further studies are needed to fully explore the convective heat transfer properties of nanoemulsion fluids. PMID- 28340527 TI - Synthesis and Adsorption Properties of 4-Vinylpyridine and Styrene Copolymer In Situ Immobilized on Silica Surface. AB - Copolymer of 4-vinylpyridine with styrene was in situ immobilized on silica gel surface via the heterogeneous radical polymerization. Anchorage of the copolymer on the surface layer was confirmed by IR spectroscopy. The quantity of copolymer on the silica gel surface was evaluated as 25.73 wt.% by TG and DSC-MS analysis. "Islet" location of polymer layer on the silica surface was confirmed by the scanning electron microscopy. A high adsorption activity of silica gel with immobilized copolymer towards microquantitatives of Cu(II), Cd(II), Pb(II), Fe(III), and Ni(II) ions in steady state conditions as well as of Ni(II) ions in dynamic regime was found. PMID- 28340529 TI - Effects of Rapid Thermal Annealing and Different Oxidants on the Properties of LaxAlyO Nanolaminate Films Deposited by Atomic Layer Deposition. AB - A comparative study of different sequences of two metal precursors [trimethylaluminum (TMA) and Tris(isopropylcyclopentadienyl) lanthanum (La(iPrCp)3)] for atomic layer deposition (ALD) lanthanum aluminum oxide (LaxAlyO) films is carried out. The percentage compositions of C and N impurity of LaxAlyO films were investigated using in situ X-ray photoelectron spectroscopy (XPS). The effects of different oxidants on the physical and chemical properties and electrical characteristics of LaxAlyO films are studied before and after annealing. Preliminary testing results indicate that the impurity level of LaxAlyO films grown with different oxidants can be well controlled before and after annealing. Analysis indicates the rapid thermal annealing (RTA) and kinds of oxidants have significant effects on the equivalent oxide thickness (EOT), dielectric constant, electrical properties, and stability of LaxAlyO films. Additionally, the change of chemical bond types of rapid thermal annealing effects on the properties of LaxAlyO films are grown with different oxidants also investigated by XPS. PMID- 28340528 TI - ZnFe2O4 Nanotapers: Slag Assistant-Growth and Enhanced Photoelectrochemical Efficiency. AB - In this study, ZnFe2O4 (ZFO) nanotapers are fabricated on the ZnO nanorods (NRs) by recycling rare-earth oxide (REO) slag as the iron source, which thereby exhibits dramatically enhanced photoelectrochemical (PEC) efficiency. Our studies demonstrate that the electron-hole separation and charge migration can be facilitated by the cascade band alignment of ZFO and ZnO and the branched nanotaper structures. Not only the iron source, the slag particles can also act as the passivation layers, leading to improved electron lifetime and significant PEC enhancement. The current study presents a novel REO-slag-modified PEC anode for high-efficiency PEC devices and offers a possibility of recycling industrial waste for renewable energy generation. PMID- 28340530 TI - Effect of Severe Plastic Deformation on Structure and Properties of Al-Sc-Ta and Al-Sc-Ti Alloys. AB - The comparative analysis of the effect of monotonous and non-monotonous severe plastic deformations (SPD) on the structure and properties of aluminum alloys has been carried out. Conventional hydrostatic extrusion (HE) with a constant deformation direction and equal-channel angular hydroextrusion (ECAH) with an abrupt change in the deformation direction were chosen for the cases of monotonous and non-monotonous SPD, respectively. Model cast hypoeutectic Al 0.3%Sc alloys and hypereutectic Al-0.6%Sc alloys with Ta and Ti additives were chosen for studying. It was demonstrated that SPD of the alloys resulted in the segregation of the material into active and inactive zones which formed a banded structure. The active zones were shown to be bands of localized plastic deformation. The distance between zones was found to be independent of the accumulated strain degree and was in the range of 0.6-1 MUm. Dynamic recrystallization in the active zones was observed using TEM. The dynamic recrystallization was accompanied by the formation of disclinations, deformation bands, low-angle, and high-angle boundaries, i.e., rotational deformation modes developed. The dynamic recrystallization was more intense during the non monotonous deformation as compared with the monotonous one, which was confirmed by the reduction of texture degree in the materials after ECAH. PMID- 28340531 TI - Zinc Oxide Coating Effect for the Dye Removal and Photocatalytic Mechanisms of Flower-Like MoS2 Nanoparticles. AB - Flower-like MoS2 nanoparticles (NPs) consist of ultra-thin MoS2 nanosheets are synthesized via a facile one-pot hydrothermal method. The MoS2/ZnO p-n heterostructure is formed by coating n-type ZnO on the surface of flower-like MoS2 NPs through the seed-mediate route and post-annealing treatment. The effects for the dye removal and photocatalytic performances after ZnO coating are systematically investigated. The results demonstrated that the coating of ZnO nanoparticles has a positive promotion to the photodegrading properties while negative effect on the adsorption capacity of the MoS2/ZnO heterostructures. The related mechanisms on the relationship of adsorption capacity and photocatalysis are discussed in detail. PMID- 28340533 TI - Vapor Phase Exchange of Self-Assembled Monolayers for Engineering of Biofunctional Surfaces. AB - We show that 4'-nitro-1,1'-biphenyl-4-thiol self-assembled monolayers (NBPT SAMs) on gold can be exchanged with 11-(mercaptoundecyl)triethylene glycol (C11EG3OH) SAMs via vapor deposition (VD). The pristine and the exchanged SAMs obtained by VD as well as solution method (SM) were characterized by X-ray photoelectron spectroscopy (XPS) and polarization modulation infrared reflection-absorption spectroscopy (PM-IRRAS). Using surface plasmon resonance (SPR), it is shown that C11EG3OH SAMs on gold obtained by vapor deposition exchange (VDEx) have the same protein resistivity as SAMs obtained by the direct self-assembly process. As expected, the cross-linked NBPT SAM are found to be resistive to both exchange processes, VDEx and solution method exchange (SMEx). In this way, VDEx opens up an elegant and new approach of patterning SAM surfaces in situ at vacuum conditions without using any solvents. By combining electron irradiation-induced chemical lithography of NBPT SAMs with VDEx, biofunctional patterned substrates were engineered and used for immobilization of protein arrays. PMID- 28340532 TI - A Phytochrome-Derived Photoswitch for Intracellular Transport. AB - Cells depend on the proper positioning of their organelles, suggesting that active manipulation of organelle positions can be used to explore spatial cell biology and to restore cellular defects caused by organelle misplacement. Recently, blue-light dependent recruitment of specific motors to selected organelles has been shown to alter organelle motility and positioning, but these approaches lack rapid and active reversibility. The light-dependent interaction of phytochrome B with its interacting factors has been shown to function as a photoswitch, dimerizing under red light and dissociating under far-red light. Here we engineer phytochrome domains into photoswitches for intracellular transport that enable the reversible interaction between organelles and motor proteins. Using patterned illumination and live-cell imaging, we demonstrate that this system provides unprecedented spatiotemporal control. We also demonstrate that it can be used in combination with a blue-light dependent system to independently control the positioning of two different organelles. Precise optogenetic control of organelle motility and positioning will provide a better understanding of and control over the spatial biology of cells. PMID- 28340534 TI - Raman spectroscopy enabled investigation of carbon nanotubes quality upon dispersion in aqueous environments. AB - Dispersion of high quality carbon nanotubes (CNTs) in aqueous solutions is of central importance for their potential biological and biomedical applications. Although it is now possible to obtain highly dispersed CNT solutions by means of surfactant assisted processing, organic functionalization, and mechanical mixing, a concern remains about preservation of CNTs' quality during these dispersion procedures. In this report, the authors demonstrate that by employing Raman spectroscopy, one can study changes in CNTs' quality post-dispersion. Specifically, the authors focused on mechanical mixing via sonication and quantitatively determined the effects of various parameters such as surfactants, CNTs' geometry, sonication time, and sonication method on CNTs' quality post sonication. While not addressed here, our method could be extended to monitor CNTs' quality as a function of other parameters that could potentially compromise their quality, such as chemical functionalization or doping. PMID- 28340535 TI - Continuation of Renin-Angiotensin-Aldosterone Inhibitors Does Not Impact Renal Function Among Patients Undergoing Percutaneous Nephrolithotomy. AB - OBJECTIVE: In the perioperative period, renin-angiotensin-aldosterone system (RAAS) inhibitors may result in cardiovascular and renal functional changes. We sought to determine the acute and chronic renal functional and blood pressure effects of continuing or withdrawing angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) after percutaneous nephrolithotomy (PCNL). MATERIALS AND METHODS: This was a retrospective review of all patients undergoing PCNL at our institution from 2002 to 2013. Patients on either an ACE-I and/or ARB who received an ACE-I and/or ARB during their surgical hospitalization were matched based on sex, age, and body mass index to patients who had their medication withheld during the postoperative period. The two groups were compared. RESULTS: A total of 2784 patients underwent PCNL during the study period. At the time of PCNL, 15.2% (423/2784) of patients and 6.5% (181/2784) were prescribed an ACE-I and an ARB, respectively. Fifty-nine percent (248/423) of patients on an ACE-I and 66.9% (121/181) on an ARB received their medication during their postoperative hospitalization. There was no significant difference in average length of stay (2 days vs 2 days), perioperative change in glomerular filtration rate, glomerular filtration rate (GFR) (-0.50 mL/min/1.73 m2 vs -2.34 mL/min/1.73 m2, p = 0.267), change in GFR at 1 month postoperatively (-4.63 mL/min/1.73 m2 vs -5.90 mL/min/1.73 m2, p = 0.748), or change in GFR at 1 year ( 2.08 mL/min/1.73 m2 vs -0.13 mL/min/1.73 m2, p = 0.267) between patients who received vs withheld their medication during the postoperative stay. CONCLUSION: It is safe to continue RAAS inhibitors in patients undergoing PCNL during their operative hospitalization. PMID- 28340537 TI - Study on a 3D Hydrogel-Based Culture Model for Characterizing Growth of Fibroblasts under Viral Infection and Drug Treatment. AB - Three-dimensional (3D) in vitro tissue models provide an approach for the systematic, repetitive, and quantitative study of drugs. In this study, we constructed an in vitro 3D acrylated hyaluronic acid (AHA) hydrogel model encapsulating fibroblasts, performed long-period 3D culture, and tested cellular topological changes and proliferation variation in the presence of herpes simplex virus-1 (HSV-1) as an infecting virus and acyclovir (ACV) as the treatment drug. The AHA hydrogels were formed by using Michael addition chemistry of bis-cysteine containing MMP-degradable cross-linker onto AHA prefunctionalized with cell adhesion peptides (RGD). Cellular structures of 3T3 fibroblasts in hydrogel presented different morphological evolution processes and proliferation rates between different groups, including HSV-1 treated alone, ACV treated alone, HSV-1 and ACV cotreated, and control samples. In AHA hydrogel, ACV blocked HSV-1 infection/replication on fibroblasts. Yet, the proliferation of ACV-treated fibroblasts was slower than that of the control group. A significantly longer period was required for cells in 3D AHA gel to regain a healthy status when compared with cells in two-dimensional (2D) culture. This hydrogel-based 3D culture model potentially lays a foundation for analyzing the response of self organized 3D tissues to viruses and drugs in a way that is closer to nature. PMID- 28340538 TI - Development of High-Throughput Screening Assay for Antihantaviral Therapeutics. AB - Humans acquire hantavirus infection by the inhalation of aerosolized excreta of infected rodent hosts. There is no treatment for hantavirus diseases at present. Therapeutic intervention during early stages of viral infection can improve the outcome of this zoonotic viral illness. The interaction between an evolutionary conserved sequence at the 5' terminus of hantaviral genomic RNA and hantavirus nucleocapsid protein plays a critical role in the hantavirus replication cycle. This unique interaction is a novel target for therapeutic intervention of hantavirus disease. We developed a very sensitive, tractable, and cost-effective fluorescence-based assay to monitor the interaction between the nucleocapsid protein and the target RNA sequence. The assay was optimized for high-throughput screening of chemical libraries to identify molecules that interrupt this RNA protein interaction. The assay was validated using a library of 6880 chemical compounds. This validation screen demonstrated the reproducibility and validity of required statistical criteria for high-throughput screening. The assay is ready to use for high-throughput screening of large chemical libraries to identify antihantaviral therapeutic molecules and can be amenable to similar targets in other viruses. PMID- 28340539 TI - Erratum. PMID- 28340536 TI - Comparison of Broad vs Narrow Focal Width Lithotripter Fields. AB - OBJECTIVE: To investigate the impact of lithotripter focal width on stone fragmentation. MATERIALS AND METHODS: A modified reflector was used to reduce -6 dB beam size of the HM3 lithotripter, while increasing concomitantly peak pressure. Fragmentation in vitro was assessed with modified and original reflectors using BegoStone phantoms. A membrane holder was used to mimic lithotripsy in vivo, and a matrix holder was used to assess variations of fragmentation power in the focal plane of the lithotripter field. Stone fragmentation in vivo produced by the two reflectors was further compared in a swine model. RESULTS: Stone fragmentation in vitro after 500 (or 2000) shocks was ~60% (or ~82%) vs ~40% (or ~75%) with original and modified reflector, respectively (p <= 0.0016). Fragmentation power with the modified reflector was the highest on the lithotripter axis, but dropped rapidly in the lateral direction and became insignificant at radial distances >6.0 mm. Stone fragmentation with the original reflector was lower along the lithotripter axis, but fragmentation power decayed slowly in lateral direction, with appreciable fragmentation produced at 6.0 mm. Stone fragmentation efficiency in vivo after 500 (or 2000) shocks was ~70% (or ~90%) vs ~45% (or ~80%) with original and modified reflector, respectively (p <= 0.04). CONCLUSIONS: A lithotripter field with broad beam size yields superior stone comminution when compared with narrow beam size under comparable effective acoustic pulse energy both in vivo and in vitro. These findings may facilitate future improvements in lithotripter design to maximize comminution efficiency while minimizing tissue injury. PMID- 28340540 TI - Use of the Moses Technology to Improve Holmium Laser Lithotripsy Outcomes: A Preclinical Study. AB - OBJECTIVE: To evaluate in vitro and in vivo effects of Moses technology in Holmium laser and to compare it with the Regular mode in terms of lithotripsy efficiency and laser-tissue interactions. METHODS: The Lumenis(r) PulseTM P120H holmium laser system together with Moses D/F/L fibers were used to compare the Regular mode with the Moses modes in stone retropulsion by using a high-speed camera, and stone ablation efficiency. In addition, a porcine ureteroscopy model was used to assess stone fragmentation and dusting as well as laser-tissue interaction with the ureteral wall. RESULTS: After a laser pulse, in vitro stone displacement experiments showed a significant reduction in retropulsion when using the Moses mode. The stone movement was reduced by 50 times at 0.8 J and 10 Hz (p < 0.01). The pronounced reduction of retropulsion in the Moses mode was clearly observed during fragmentation setting (high energy) and dusting (low energy, high Hz). In addition, stone fragmentation tests showed that the Moses modes resulted in a significantly higher ablation volume when compared with the Regular mode (160% higher; p < 0.001). In vivo assessment also supported the reduction in retropulsion when treating stones in the porcine kidney. Histological analysis of the porcine ureter after direct lasing in the Moses mode suggested less damage than in the Regular mode. CONCLUSIONS: The Moses technology resulted in more efficient laser lithotripsy, in addition to significantly reduced stone retropulsion, and displayed a margin of safety that may result in a shorter procedural time and safer lithotripsy. PMID- 28340541 TI - Drug Discovery Testing Compounds in Patient Samples by Automated Flow Cytometry. AB - Functional ex vivo assays that predict a patient's clinical response to anticancer drugs for guiding cancer treatment have long been a goal, but few have yet proved to be reliable. To address this, we have developed an automated flow cytometry platform for drug screening that evaluates multiple endpoints with a robust data analysis system that can capture the complex mechanisms of action across different compounds. This system, called PharmaFlow, is used to test peripheral blood or bone marrow samples from patients diagnosed with hematological malignancies. Functional assays that use the whole sample, retaining all the microenvironmental components contained in the sample, offer an approach to ex vivo testing that may give results that are clinically relevant. This new approach can help to predict the patients' response to existing treatments or to drugs under development, for hematological malignancies or other tumors. In addition, relevant biomarkers can be identified that determine the patient's sensitivity, resistance, or toxicity to a given treatment. We propose that this approach, which better recapitulates the human microenvironment, constitutes a more predictive assay for personalized medicine and preclinical drug discovery. PMID- 28340543 TI - NHANES. PMID- 28340542 TI - Expectations and Attitudes of Individuals With Type 1 Diabetes After Using a Hybrid Closed Loop System. AB - Purpose The first hybrid closed loop (HCL) system, which automates insulin delivery but requires user inputs, was approved for treatment of type 1 diabetes (T1D) by the US Food and Drug Administration in September 2016. The purpose of this study was to explore the benefits, expectations, and attitudes of individuals with T1D following a clinical trial of an HCL system. Methods Thirty two individuals with T1D (17 adults, 15 adolescents) participated in focus groups after 4 to 5 days of system use. Content analysis generated themes regarding perceived benefits, hassles, and limitations. Results Some participants felt misled by terms such as "closed loop" and "artificial pancreas," which seemed to imply a more "hands-off" experience. Perceived benefits were improved glycemic control, anticipated reduction of long-term complications, better quality of life, and reduced mental burden of diabetes. Hassles and limitations included unexpected tasks for the user, difficulties wearing the system, concerns about controlling highs, and being reminded of diabetes. Conclusion Users are willing to accept some hassles and limitations if they also perceive health and quality of-life benefits beyond current self-management. It is important for clinicians to provide a balanced view of positives and negatives to help manage expectations. PMID- 28340544 TI - Understanding Challenges, Strategies, and the Role of Support Networks in Medication Self-management Among Patients With Type 2 Diabetes. AB - Purpose The purpose of this qualitative study was to investigate the challenges and strategies of patients with type 2 diabetes mellitus (T2DM) regarding daily management of their medication regimen focusing on the role of their support networks. Methods A purposeful sample of 25 patients with T2DM was recruited from local self-help groups, general practitioner practices, and a university hospital in southwestern Germany. Four semi-structured focus groups were conducted to identify the challenges patients experienced, the strategies they used, and their collaboration with support networks to assist them in self-managing their medication regimen. Sessions were audio- and video-recorded, fully transcribed, and subjected to computer-aided qualitative content analysis, guided by the Self- and Family Management Framework (SFMF). Results Patients with T2DM experienced numerous challenges affecting medication self-management arising from their personal situation, health status and resources, characteristics of their regimen, and how health care is currently organized. Patients' self-initiated strategies included activating health care, community, social, and online resources; taking ownership of medication-related needs; and integrating medication-taking into daily life. Patients drew on self-help groups, family, and friends to discuss concerns regarding medication safety and receive experience based information and advice for navigating within the health care system as well as practical hands-on support with daily medication self-management. Conclusions Understanding the challenges and building on strategies patients with T2DM devised help diabetes educators to better address patients' needs and priorities and guide patient-centered interventions to support patients' self-management activities. Community and social support networks operating in patients' lives need to be engaged in the self-management support. PMID- 28340545 TI - A Comparison of the Use of Antidepressant Treatment Between Non-Hispanic Black and White and Mexican American Adults With Type 2 Diabetes in the United States. AB - Purpose The purpose of this study was to determine antidepressant use among Mexican Americans (MA) and non-Hispanic (NH) blacks and whites with type 2 diabetes and depressive symptoms. Methods A secondary data analysis based on National Health and Nutrition Examination Survey (NHANES) 2005-2012 cohort data included 560 noninstitutionalized civilian MA, NH black, and NH white adults with type 2 diabetes and depressive symptoms. Unadjusted and adjusted 2-way ANOVA models evaluated whether there was a difference in the use of antidepressants by depressive symptom level across race/ethnic group. Results Whites were more likely than blacks and MA to be on antidepressant treatment (whites: 41.7%, blacks: 27.1%, MA: 24.2%) and on serotonin-norepinephrine reuptake inhibitors (SNRI) (whites: 8.1%, blacks: 2.9%, MA: 2.4%). However, there was no difference in the use of other drug classes or antidepressant use by depressive symptom level across racial/ethnic group. Followed by tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRI) were the most commonly used drug class overall. Approximately 30% of subjects were on antidepressants and among those, 80% were on one antidepressant, all others on 2 or more. Conclusions Racial/ethnic differences were observed in the use of antidepressant treatment but not when depressive symptom levels were incorporated in the analyses. Further studies on the effectiveness of different antidepressants in diabetes outcomes minorities are needed. PMID- 28340546 TI - A Qualitative Study of Cognitive, Behavioral, and Psychosocial Challenges Associated With Pediatric Type 2 Diabetes in Ethnic Minority Parents and Adolescents. AB - Purpose The purpose of this descriptive qualitative study was to explore cognitive, behavioral, and psychosocial challenges associated with having and/or parenting an adolescent with pediatric type 2 diabetes (T2D) from the perspectives of ethnic minority parents and adolescents. Methods Ethnic minority (79.2% non-Hispanic black, 29.6% Hispanic) adolescents (n = 14, 78.6% female, 14.7 +/- 1.9 years) and their parents (n = 13, 100% female) participated in either individual family interviews or multifamily focus group sessions. Sessions were audio recorded, transcribed, and coded by a team of 4 raters. QSR NVivo 10 was used to perform a content analysis and to extract coded adolescent and parent responses. Results Six themes corresponding to 3 broad categories (cognitive, behavioral, and psychosocial challenges) emerged. Regarding cognitive challenges, families described difficulties learning about a new disease and managing youth knowledge deficits and/or superficial knowledge. In terms of behavioral challenges, parents and adolescents discussed ongoing difficulties with making and maintaining positive youth health behavior changes as well as with ensuring regimen adherence. Finally, managing youth emotions related to diabetes and navigating social relationships with peers and other family members around the disclosure of T2D were the primary psychosocial challenges to emerge. Conclusions Directions for future research include developing and evaluating brief family interventions and adolescent psychosocial screening measures. Recommendations for clinical practice include increasing family knowledge of T2D, enhancing parenting skills for managing youth behavior change, and conducting routine psychosocial screening during follow-up clinic visits. PMID- 28340547 TI - The Complexities of "Struggling to Live Life". AB - Purpose The purpose of the study was to explore and describe perceptions and experiences of young adults with type 1 diabetes mellitus (T1DM) living in Appalachia, Tennessee. Methods Qualitative descriptive analysis of in-depth interviews of 9 young adults (male = 3, female = 6) 18 to 30 years of age living in Appalachian counties in Tennessee provided the basis of identifying the salient concerns from the perspective of this diverse group related to living daily with T1DM. Data analysis was facilitated by using NVivo 11 Pro and consisted of iterative review of the accounts in 3 phases: immersion, reduction, and interpretation. Results Findings revealed that young Appalachian adults had some common, consistent experiences living with T1DM. Major themes included the struggle toward adulthood, the daily struggle of living with diabetes, the strong desire to live life, the supportive environment, the development of one's identity by diabetes, the disruptiveness of diabetes' demands, and the pros and cons of technological development in diabetes management. Conclusion Health vulnerabilities are multiplied for young adults living with T1DM in Appalachian Tennessee. Participants pointed to living in communities with social stigma, lack of T1DM knowledge, and lack of access to health care that compares with the quality of care they experienced when in pediatric care. They also expressed fear about pregnancy, diabetes complications, and the dangers of hypoglycemia. Individual and community-based empowerment programs focusing on T1DM accompanied by insurance reimbursement and T1DM policy reinforcement are necessary to reduce health disparities and improve quality of life in this underserved population of young adults in Appalachia. PMID- 28340549 TI - Long-Term In Vivo Monitoring of Adult-Derived Human Liver Stem/Progenitor Cells by Bioluminescence Imaging, Positron Emission Tomography, and Contrast-Enhanced Computed Tomography. AB - Adult-derived human liver stem/progenitor cells (ADHLSCs) have the potential to alleviate liver injury. However, the optimal delivery route and long-term biodistribution of ADHLSCs remain unclear. In this article, we used a triple fusion reporter system to determine the kinetic differences in the biodistribution of ADHLSCs following intrasplenic (IS) and intrahepatic (IH) administration in severe combined immunodeficiency/beige mice. ADHLSCs were transduced with a lentiviral vector expressing a triple fusion reporter comprising renilla luciferase, monomeric red fluorescent protein, and truncated HSV-1 thymidine kinase. The stability and duration of the transgenes, and the effects of transduction on the cell properties were evaluated in vitro. The acute retention and long-term engraftment in vivo were revealed by positron emission tomography and bioluminescence imaging (BLI), respectively, followed by histochemical analysis. We showed that ADHLSCs can be safely transduced with the triple fusion reporter. Radiolabeled ADHLSCs showed acute cell retention at the sites of injection. The IH group showed a confined BLI signal at the injection site, while the IS group displayed a dispersed distribution at the upper abdominal liver area, and a more intense signal. In conclusion, ADHLSCs could be monitored by BLI for up to 4 weeks with a spread out biodistribution following IS injection. PMID- 28340550 TI - High Prevalence of Vitamin D Deficiency in Patients With Bone Marrow Edema Syndrome of the Foot and Ankle. AB - BACKGROUND: Bone marrow edema syndrome (BMOS) is a phenomenon primarily affecting the lower extremity. It is characterized by a sudden onset of pain and an ill defined osseous hyperintense signal in magnetic resonance imaging. The main cause of BMOS is still largely unknown. Its pathophysiology is presumably multifactorial and it has recently been demonstrated that it usually involves an increase in bone turnover and alterations within the bone microenvironment. Vitamin D plays a pivotal role in maintaining a healthy and well-balanced bone microenvironment. However, to date only limited information has been reported on vitamin D status in patients with BMOS. Moreover, it is still uncertain whether hypovitaminosis D is associated with the etiology and course of the disease. For this reason, the aim of this study was to determine serum vitamin D levels (25(OH)D) of patients diagnosed with BMOS of the foot and ankle. METHODS: Patients were identified and laboratory results collected by retrospective review of the medical records between year 2011 and 2015. Diagnosis was based on clinical examination, the existence of prolonged foot pain, the presence of abnormal bone marrow signal intensity in T1- and T2-weighted magnetic resonance imaging, and the patient's medical history. All patients who demonstrated other concomitant diagnoses were excluded from the study. RESULTS: Overall, 31 patients were affected by BMOS with a mean age of 44.4 (range, 18-76) years. Notably, 84% of patients (26/31) had low vitamin D levels with a mean 25(OH)D level of 19.03 ng/mL. Specifically, 61% of patients (19/31) were vitamin D deficient, 23% (7/31) vitamin D insufficient, and only 5 patients (16%) had sufficient vitamin D levels. Statistical analysis showed no significant difference comparing vitamin D levels with patient age, sex, and time of diagnosis. Moreover, there was no correlation between vitamin D status and the number of bony foci or location of BMOS. CONCLUSION: We found a widespread rate of vitamin D deficiency in patients presenting with BMOS of the foot and ankle. Comparing these data to the vitamin D status of the general population in Germany and to patients living in comparable latitudes, this raises the possibility that BMOS might be associated with low vitamin D status. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 28340551 TI - Genomic prediction using subsampling. AB - BACKGROUND: Genome-wide assisted selection is a critical tool for the genetic improvement of plants and animals. Whole-genome regression models in Bayesian framework represent the main family of prediction methods. Fitting such models with a large number of observations involves a prohibitive computational burden. We propose the use of subsampling bootstrap Markov chain in genomic prediction. Such method consists of fitting whole-genome regression models by subsampling observations in each round of a Markov Chain Monte Carlo. We evaluated the effect of subsampling bootstrap on prediction and computational parameters. RESULTS: Across datasets, we observed an optimal subsampling proportion of observations around 50% with replacement, and around 33% without replacement. Subsampling provided a substantial decrease in computation time, reducing the time to fit the model by half. On average, losses on predictive properties imposed by subsampling were negligible, usually below 1%. For each dataset, an optimal subsampling point that improves prediction properties was observed, but the improvements were also negligible. CONCLUSION: Combining subsampling with Gibbs sampling is an interesting ensemble algorithm. The investigation indicates that the subsampling bootstrap Markov chain algorithm substantially reduces computational burden associated with model fitting, and it may slightly enhance prediction properties. PMID- 28340552 TI - StrAuto: automation and parallelization of STRUCTURE analysis. AB - BACKGROUND: Population structure inference using the software STRUCTURE has become an integral part of population genetic studies covering a broad spectrum of taxa including humans. The ever-expanding size of genetic data sets poses computational challenges for this analysis. Although at least one tool currently implements parallel computing to reduce computational overload of this analysis, it does not fully automate the use of replicate STRUCTURE analysis runs required for downstream inference of optimal K. There is pressing need for a tool that can deploy population structure analysis on high performance computing clusters. RESULTS: We present an updated version of the popular Python program StrAuto, to streamline population structure analysis using parallel computing. StrAuto implements a pipeline that combines STRUCTURE analysis with the Evanno Delta K analysis and visualization of results using STRUCTURE HARVESTER. Using benchmarking tests, we demonstrate that StrAuto significantly reduces the computational time needed to perform iterative STRUCTURE analysis by distributing runs over two or more processors. CONCLUSION: StrAuto is the first tool to integrate STRUCTURE analysis with post-processing using a pipeline approach in addition to implementing parallel computation - a set up ideal for deployment on computing clusters. StrAuto is distributed under the GNU GPL (General Public License) and available to download from http://strauto.popgen.org . PMID- 28340553 TI - Promoting independence, health and well-being for older people: a feasibility study of computer-aided health and social risk appraisal system in primary care. AB - BACKGROUND: With population ageing, research is needed into new low-cost, scalable methods of effective promotion of health and wellbeing for older people. We aimed to assess feasibility, reach and costs of implementing a new tailored computer-aided health and social risk appraisal system in primary care. METHODS: Design: Feasibility study. SETTING: Five General Practices in London (Ealing) and Hertfordshire, United Kingdom (UK) Participants: Random sample of patients aged 65 + years. INTERVENTION: The Multi-dimensional Risk Appraisal for Older people (MRA-O) system includes: 1) Postal questionnaire including health, lifestyle, social and environmental domains; 2) Software system generating a personalised feedback report with advice on health and wellbeing; 3) Follow-up of people with new concerning or complex needs by GPs or practice nurses. EVALUATION: Feasibility of implementation; participant wellbeing, functional ability and quality of life; social needs, health risks, potential lifestyle changes; and costs of implementation. RESULTS: Response rates to initial postal invitations were low (526/1550, 34%). Of these, 454/526 (86%) completed MRA-O assessments. Compared to local UK Census data on older people, participants were younger, more were owner-occupiers and fewer were from ethnic minority groups than expected. A range of problems was identified by participants, including pain in last week (269/438, 61.4%), low physical activity (173/453, 38.2%), sedentary lifestyle (174/447, 38.3%), falls (117/439, 26.7%), incontinence (111/441 25.2%), impaired vision 116/451 (25.7%), impaired hearing (145/431, 33.6%), depressed mood (71/451, 15.7%), impaired memory (44/444 9.9%), social isolation (46/449, 10.2%) and loneliness (31/442, 7.0%). Self-rated health was good/excellent in 312/437 (71.4%), and quality of life and well-being were slightly above age-specific population norms. Implementation costs were low. Practices reviewed medical records of 143/454 (31.5%) of participants as a consequence of their responses, and actively followed up 110/454 (24.2%) of their patients. CONCLUSIONS: A computer-aided risk appraisal system was feasible for General Practices to implement, yields useful information about health and social problems, and identifies individual needs. Participation rates were however low, particularly for the oldest old, the poorest, and ethnic minority groups, and this type of intervention may increase inequalities in access. Widespread implementation of this approach would require work to address potential inequalities. PMID- 28340554 TI - Cross disease analysis of co-functional microRNA pairs on a reconstructed network of disease-gene-microRNA tripartite. AB - BACKGROUND: MicroRNAs always function cooperatively in their regulation of gene expression. Dysfunctions of these co-functional microRNAs can play significant roles in disease development. We are interested in those multi-disease associated co-functional microRNAs that regulate their common dysfunctional target genes cooperatively in the development of multiple diseases. The research is potentially useful for human disease studies at the transcriptional level and for the study of multi-purpose microRNA therapeutics. METHODS AND RESULTS: We designed a computational method to detect multi-disease associated co-functional microRNA pairs and conducted cross disease analysis on a reconstructed disease gene-microRNA (DGR) tripartite network. The construction of the DGR tripartite network is by the integration of newly predicted disease-microRNA associations with those relationships of diseases, microRNAs and genes maintained by existing databases. The prediction method uses a set of reliable negative samples of disease-microRNA association and a pre-computed kernel matrix instead of kernel functions. From this reconstructed DGR tripartite network, multi-disease associated co-functional microRNA pairs are detected together with their common dysfunctional target genes and ranked by a novel scoring method. We also conducted proof-of-concept case studies on cancer-related co-functional microRNA pairs as well as on non-cancer disease-related microRNA pairs. CONCLUSIONS: With the prioritization of the co-functional microRNAs that relate to a series of diseases, we found that the co-function phenomenon is not unusual. We also confirmed that the regulation of the microRNAs for the development of cancers is more complex and have more unique properties than those of non-cancer diseases. PMID- 28340555 TI - RNA-Seq transcriptomics and pathway analyses reveal potential regulatory genes and molecular mechanisms in high- and low-residual feed intake in Nordic dairy cattle. AB - BACKGROUND: The selective breeding of cattle with high-feed efficiencies (FE) is an important goal of beef and dairy cattle producers. Global gene expression patterns in relevant tissues can be used to study the functions of genes that are potentially involved in regulating FE. In the present study, high-throughput RNA sequencing data of liver biopsies from 19 dairy cows were used to identify differentially expressed genes (DEGs) between high- and low-FE groups of cows (based on Residual Feed Intake or RFI). Subsequently, a profile of the pathways connecting the DEGs to FE was generated, and a list of candidate genes and biomarkers was derived for their potential inclusion in breeding programmes to improve FE. RESULTS: The bovine RNA-Seq gene expression data from the liver was analysed to identify DEGs and, subsequently, identify the molecular mechanisms, pathways and possible candidate biomarkers of feed efficiency. On average, 57 million reads (short reads or short mRNA sequences < ~200 bases) were sequenced, 52 million reads were mapped, and 24,616 known transcripts were quantified according to the bovine reference genome. A comparison of the high- and low-RFI groups revealed 70 and 19 significantly DEGs in Holstein and Jersey cows, respectively. The interaction analysis (high vs. low RFI x control vs. high concentrate diet) showed no interaction effects in the Holstein cows, while two genes showed interaction effects in the Jersey cows. The analyses showed that DEGs act through certain pathways to affect or regulate FE, including steroid hormone biosynthesis, retinol metabolism, starch and sucrose metabolism, ether lipid metabolism, arachidonic acid metabolism and drug metabolism cytochrome P450. CONCLUSION: We used RNA-Seq-based liver transcriptomic profiling of high- and low-RFI dairy cows in two breeds and identified significantly DEGs, their molecular mechanisms, their interactions with other genes and functional enrichments of different molecular pathways. The DEGs that were identified were the CYP's and GIMAP genes for the Holstein and Jersey cows, respectively, which are related to the primary immunodeficiency pathway and play a major role in feed utilization and the metabolism of lipids, sugars and proteins. PMID- 28340556 TI - Innovative substance 2250 as a highly promising anti-neoplastic agent in malignant pancreatic carcinoma - in vitro and in vivo. AB - BACKGROUND: Former studies already revealed the anti-neoplastic properties of the anti-infective agent Taurolidine (TRD) against many tumor species in vitro and in vivo. Its anti-proliferative and cell death inducing capacity is largely due to its main derivative Taurultam (TRLT). In this study it could be demonstrated, that substance 2250 - a newly defined innovative structural analogue of TRLT - exhibits an anti-neoplastic effect on malignant pancreatic carcinoma in vitro and in vivo. METHODS: The anti-neoplastic potential of substance 2250 as well as its mode of action was demonstrated in extensive in vitro analysis, followed by successful and effective in vivo testings, using xenograft models derived from established pancreatic cancer cell lines as well as patient derived tissue. RESULTS: Our functional analysis regarding the role of oxidative stress (ROS) and caspase activated apoptosis showed, that ROS driven programmed cell death (PCD) is the major mechanisms induced by substance 2250 in pancreatic carcinoma. What is strongly relevant towards clinical practice is especially the observed inhibition of patient derived pancreatic cancer tumor growth in mice treated with this new substance in combination with its sharply higher metabolic stability. CONCLUSION: These encouraging results provide new therapeutical opportunities in pancreatic cancer treatment and build the basis for further functional analysis as well as first clinical studies for this promising agent. PMID- 28340557 TI - Development of selective medium for IMP-type carbapenemase-producing Enterobacteriaceae in stool specimens. AB - BACKGROUND: Identification of carbapenemase-producing Enterobacteriaceae (CPE) in faecal specimens is challenging. This fact is particularly critical because low level carbapenem-resistant organisms such as IMP-producing CPE are most prevalent in Japan. We developed a modified selective medium more suitable for IMP-type CPE. METHODS: Fifteen reference CPE strains producing different types of beta lactamases were used to evaluate the commercially available CHROMagar KPC and chromID CARBA as well as the newly prepared MC-ECC medium (CHROMagar ECC supplemented with meropenem, cloxacillin, and ZnSO4) and M-ECC medium (CHROMagar ECC supplemented with meropenem and ZnSO4). A total of 1035 clinical samples were then examined to detect CPE using chromID CARBA and M-ECC medium. RESULTS: All tested strains producing NDM-, KPC-, and OXA-48-carbapenemases were successfully cultured in the media employed. Although most of the IMP-positive strains did not grow in CHROMagar KPC, chromID CARBA, or MC-ECC, all tested strains grew on M ECC. When faecal samples were applied to the media, M-ECC medium allowed the best growth of IMP-type CPE with a significantly higher sensitivity (99.3%) than that of chromID CARBA (13.9%). CONCLUSIONS: M-ECC medium was determined as the most favourable selective medium for the detection of IMP-type CPE as well as other types of CPE. PMID- 28340558 TI - A novel real-time PCR assay for specific detection of Brucella melitensis. AB - BACKGROUND: Brucellosis is a zoonosis that occurs worldwide. The disease has been completely eradicated in livestock in Sweden in 1994, and all cases of confirmed human brucellosis are imported into Sweden from other countries. However, due to an increase in the number of refugees and asylum seekers from the middle-east to Sweden, there is a need to improve the current diagnostic methodology for Brucella melitensis. Whilst culture of Brucella species can be used as a diagnostic tool, real-time PCR approaches provide a much faster result. The aim of this study was to set up a species-specific real-time PCR for the detection of all biovars of Brucella melitensis, which could be used routinely in diagnostic laboratories. METHODS: A Brucella melitensis real-time PCR assay was designed using all available genomes in the public database of Brucella (N = 96) including all complete genomes of Brucella melitensis (N = 17). The assay was validated with a collection of 37 Brucella species reference strains, 120 Brucella melitensis human clinical isolates, and 45 clinically relevant non-Brucella melitensis strains. RESULTS: In this study we developed a single real-time PCR for the specific detection of all biovars of Brucella melitensis. CONCLUSIONS: This new real-time PCR method shows a high specificity (100%) and a high sensitivity (1.25 GE/MUl) and has been implemented in the laboratories of four governmental authorities across Sweden. PMID- 28340559 TI - Association of general psychological factors with frequent attendance in primary care: a population-based cross-sectional observational study. AB - BACKGROUND: Whereas several studies have examined the association between frequent attendance in primary care and illness-specific psychological factors, little is known about the relation between frequent attendance and general psychological factors. Thus, the aim of this study was to investigate the association between being a frequent attender in primary care and general psychological factors. METHODS: Data were used from a large, population-based sample of community-dwelling individuals aged 40 and above in Germany in 2014 (n = 7,446). Positive and negative affect, life satisfaction, optimism, self-esteem, self-efficacy, and self-regulation were included as general psychological factors. The number of self-reported GP visits in the past twelve months was used to quantify frequency of attendance; individuals with more than 9 visits (highest decile) were defined as frequent attenders. RESULTS: Multiple logistic regressions showed that being a frequent attender was positively associated with less life satisfaction [OR: 0.79 (0.70-0.89)], higher negative affect [OR: 1.38 (1.17-1.62)], less self-efficacy [OR: 0.74 (0.63-0.86)], less self-esteem [OR: 0.65 (0.54-0.79)], less self-regulation [OR: 0.74 (0.60-0.91)], and higher perceived stress [OR: 1.46 (1.28-1.66)], after adjusting for sociodemographic factors, morbidity and lifestyle factors. However, frequent attendance was not significantly associated with positive affect and self-regulation. CONCLUSIONS: The present study highlights the association between general psychological factors and frequent attendance. As frequent GP visits produce high health care costs and are potentially associated with increased referrals and use of secondary health care services, this knowledge might help to address these individuals with high needs. PMID- 28340560 TI - A novel pore-region mutation, c.887G > A (p.G296D) in KCNQ4, causing hearing loss in a Chinese family with autosomal dominant non-syndromic deafness 2. AB - BACKGROUND: Hereditary non-syndromic hearing loss is the most common inherited sensory defect in humans. The KCNQ4 channel belongs to a family of potassium ion channels that play crucial roles in physiology and disease. Mutations in KCNQ4 underlie deafness non-syndromic autosomal dominant 2, a subtype of autosomal dominant, progressive, high-frequency hearing loss. METHODS: A six-generation Chinese family from Hebei Province with autosomal dominantly inherited, sensorineural, postlingual, progressive hearing loss was enrolled in this study. Mutation screening of 129 genes associated with hearing loss was performed in five family members by next-generation sequencing (NGS). We also carried out variant analysis on DNA from 531 Chinese individuals with normal hearing as controls. RESULTS: This family exhibits postlingual, progressive, symmetrical, bilateral, non-syndromic sensorineural hearing loss. NGS, bioinformatic analysis, and Sanger sequencing confirmed the co-segregation of a novel mutation [c.887G > A (p.G296D)] in KCNQ4 with the disease phenotype in this family. This mutation leads to a glycine-to-aspartic acid substitution at position 296 in the pore region of the KCNQ4 channel. This mutation affects a highly conserved glutamic acid. NGS is a highly efficient tool for identifying gene mutations causing heritable disease. CONCLUSIONS: Progressive hearing loss is common in individuals with KCNQ4 mutations. NGS together with Sanger sequencing confirmed that the five affected members of this Chinese family inherited a missense mutation, c.887G > A (p.G296D), in exon 6 of KCNQ4. Our results increase the number of identified KCNQ4 mutations. PMID- 28340561 TI - Ascorbic acid ameliorates renal injury in a murine model of contrast-induced nephropathy. AB - BACKGROUND: Contrast induced nephropathy (CIN) is the commonest cause of iatrogenic renal injury and its incidence has increased with the advent of complex endovascular procedures. Evidence suggests that ascorbic acid (AA) has a nephroprotective effect in percutaneous coronary interventions when contrast media are used. A variety of biomarkers (NGAL, NGAL:creatinine, mononuclear cell infiltration, apoptosis and RBP-4) in both the urine and kidney were assayed using a mouse model of CIN in order to determine whether AA can reduce the incidence and/or severity of renal injury. METHODS: Twenty-four BALB/c mice were divided into 4 groups. Three groups were exposed to high doses of contrast media (omnipaque) in a well-established model of CIN, and then treated with low or high dose AA or placebo (saline). CIN severity was determined by measurement of urinary neutrophil gelatinase-associated lipocalin (NGAL):creatinine at specific time intervals. Histological analysis was performed to determine the level of mononuclear inflammatory infiltration as well as immunohistochemistry to determine apoptosis in the glomeruli by staining for activated caspase-3 and DNA nicking (TUNEL assays). Reverse transcriptase PCR (rtPCR) of mRNA transcripts prepared from mRNA extracted from mouse kidneys was also performed for both lipocalin-2 (Lcn2) encoding NGAL and retinol binding protein-6 (RBP4) genes. NGAL protein expression was also confirmed by ELISA analysis of kidney lysates. RESULTS: Urinary NGAL:creatinine ratio was significantly lower at 48 h with a 44% and 62% (204.3MUg/mmol versus 533.6MUg/mmol, p = 0.049) reduction in the low and high dose AA groups, respectively. The reduced urinary NGAL:creatinine ratio remained low throughout the time period assessed (up to 96 h) in the high dose AA group. In support of the urinary analysis ELISA analysis of NGAL in kidney lysates also showed a 57% reduction (12,576 ng/ml versus 29,393 ng/ml) reduction in the low dose AA group. Immunohistochemistry for apoptosis demonstrated decreased TUNEL and caspase-3 expression in both low and high dose AA groups. CONCLUSIONS: Ascorbic acid reduced the frequency and severity of renal injury in this murine model of CIN. Further work is required to establish whether AA can reduce the incidence of CIN in humans undergoing endovascular procedures. PMID- 28340562 TI - Drug-induced liver injury from antituberculous treatment: a retrospective study from a large TB centre in the UK. AB - BACKGROUND: We describe drug-induced liver injury (DILI) secondary to antituberculous treatment (ATT) in a large tuberculosis (TB) centre in London; we identify the proportion who had risk factors for DILI and the timing and outcome of DILI. METHODS: We identified consecutive patients who developed DILI whilst on treatment for active TB; patients with active TB without DILI were selected as controls. Comprehensive demographic and clinical data, management and outcome were recorded. RESULTS: There were 105 (6.9%) cases of ATT-associated DILI amongst 1529 patients diagnosed with active TB between April 2010 and May 2014. Risk factors for DILI were: low patient weight, HIV-1 co-infection, higher baseline ALP, and alcohol intake. Only 25.7% of patients had British or American Thoracic Society defined criteria for liver test (LT) monitoring. Half (53%) of the cases occurred within 2 weeks of starting ATT and 87.6% occurred within 8 weeks. Five (4.8%) of seven deaths were attributable to DILI. CONCLUSIONS: Only a quarter of patients who developed DILI had British or American Thoracic Society defined criteria for pre-emptive LT monitoring, suggesting that all patients on ATT should be considered for universal liver monitoring particularly during the first 8 weeks of treatment. PMID- 28340564 TI - Erratum to: Schrodinger's scat: a critical review of the currently available tiger (Panthera Tigris) and leopard (Panthera pardus) specific primers in India, and a novel leopard specific primer. PMID- 28340563 TI - Genome evolutionary dynamics followed by diversifying selection explains the complexity of the Sesamum indicum genome. AB - BACKGROUND: Whole genome duplication (WGD) and tandem duplication (TD) provide two critical sources of raw genetic material for genome complexity and evolutionary novelty. Little is known about the complexity of the Sesamum indicum genome after it diverged from a common ancestor with the paleodiploid Vitis vinifera and further experienced WGD and TD events. RESULTS: Here, we analyzed the functional divergence of different classes of inter- and intra-genome gene pairs from ancestral events to uncover multiple-layers of evolutionary dynamics acting during the process of forming the modern S. indicum genome. Comprehensive inter-genome analyses revealed that 60% and 70% of syntenic orthologous gene pairs were retained among the two subgenomes in S. indicum compared to V. vinifera, although there was no evidence of significant differences under selection pressure. For the intra-genomic analyses, 5,932 duplicated gene pairs experienced fractionation, with the remaining 1,236 duplicated gene pairs having undergone functional divergence under diversifying selection. Analysis of the TD events indicated that 2,945 paralogous gene pairs, from 1,089 tandem arrays of 2 16 genes, experienced functional divergence under diversifying selection. Sequence diversification of different classes of gene pairs revealed that most of TD events occurred after the WGD event, with others following the ancestral gene order indicating ancient TD events at some time prior to the WGD event. Our comparison-of-function analyses for different classes of gene pairs indicated that the WGD and TD evolutionary events were both responsible for introducing genes that enabled exploration of novel and complementary functionalities, whilst maintaining individual plant ruggedness. CONCLUSIONS: In this study, we first investigated functional divergence of different classes of gene pairs to characterize the dynamic processes associated with each evolutionary event in S. indicum. The data demonstrated massive and distinct functional divergence among different classes of gene pairs, and provided a genome-scale view of gene function diversification explaining the complexity of the S. indicum genome. We hope this provides a biological model to study the mechanism of plant species formation, particularly in the context of the evolutionary history of flowering plants, and offers novel insights for the study of angiosperm genomes. PMID- 28340565 TI - u-PAR expression in cancer associated fibroblast: new acquisitions in multiple myeloma progression. AB - BACKGROUND: Multiple Myeloma (MM) is a B-cell malignancy in which clonal plasma cells progressively expand within the bone marrow (BM) as effect of complex interactions with extracellular matrix and a number of microenvironmental cells. Among these, cancer-associated fibroblasts (CAF) mediate crucial reciprocal signals with MM cells and are associated to aggressive disease and poor prognosis. A large body of evidence emphasizes the role of the urokinase plasminogen activator (u-PA) and its receptor u-PAR in potentiating the invasion capacity of tumor plasma cells, but little is known about their role in the biology of MM CAF. In this study, we investigated the u-PA/u-PAR axis in MM associated fibroblasts and explore additional mechanisms of tumor/stroma interplay in MM progression. METHODS: CAF were purified from total BM stromal fraction of 64 patients including monoclonal gammopathy of undetermined significance, asymptomatic and symptomatic MM, as well as MM in post-treatment remission. Flow cytometry, Real Time PCR and immunofluorescence were performed to investigate the u-PA/u-PAR system in relation to the level of activation of CAF at different stages of the disease. Moreover, proliferation and invasion assays coupled with silencing experiments were used to prove, at functional level, the function of u-PAR in CAF. RESULTS: We found higher activation level, along with increased expression of pro-invasive molecules, including u-PA, u-PAR and metalloproteinases, in CAF from patients with symptomatic MM compared to the others stages of the disease. Consistently, CAF from active MM as well as U266 cell line under the influence of medium conditioned by active MM CAF, display higher proliferative rate and invasion potential, which were significantly restrained by u-PAR gene expression inhibition. CONCLUSIONS: Our data suggest that the stimulation of u-PA/u-PAR system contributes to the activated phenotype and function of CAF during MM progression, providing a biological rationale for future targeted therapies against MM. PMID- 28340567 TI - Improving the provision of services to young people from refugee backgrounds with comorbid mental health and substance use problems: addressing the barriers. AB - BACKGROUND: South Australia (SA) has resettled 151,134 refugees in the last ten years (Department of Immigration and Border Protection, Settlement reporting facility, 2014). Northern metropolitan Adelaide, an area which experiences significant social disadvantage, has received a significant number of (predominantly young) refugees. Research indicates that refugee youth are at elevated risk of mental health (MH) and alcohol and other drug (AOD) problems. These factors, along with the low socio-economic status of northern Adelaide, the number of refugee youth residing there, and the added complexity of treating comorbid MH and AOD problems (comorbidity) prompted this research. We investigated the barriers and facilitators to culturally responsive comorbidity care for these youth and whether the MH and AOD services were equipped to provide such support. METHODS: This mixed-methods study employed semi-structured interviews with refugee youth and service providers and an online survey with managers of services. Thirty participants (15 refugee youth, 15 service providers) took part in the semi-structured interviews and 56 (40 complete, 16 partially-complete) in the survey. RESULTS: Thematic analysis of the interview data revealed the most commonly reported barriers related to four broad areas: (1) organisational and structural, (2) access and engagement, (3) treatment and service delivery, and (4) training and resources. Survey data supported the barriers identified in the qualitative findings. CONCLUSIONS: This research highlights significant gaps in the response of MH and AOD services to refugee youth with comorbidity. Based on the findings, ways of overcoming the barriers are discussed, and are of particular relevance to policy makers, organisations and clinicians. PMID- 28340566 TI - A critical review of manual therapy use for headache disorders: prevalence, profiles, motivations, communication and self-reported effectiveness. AB - BACKGROUND: Despite the expansion of conventional medical treatments for headache, many sufferers of common recurrent headache disorders seek help outside of medical settings. The aim of this paper is to evaluate research studies on the prevalence of patient use of manual therapies for the treatment of headache and the key factors associated with this patient population. METHODS: This critical review of the peer-reviewed literature identified 35 papers reporting findings from new empirical research regarding the prevalence, profiles, motivations, communication and self-reported effectiveness of manual therapy use amongst those with headache disorders. RESULTS: While available data was limited and studies had considerable methodological limitations, the use of manual therapy appears to be the most common non-medical treatment utilized for the management of common recurrent headaches. The most common reason for choosing this type of treatment was seeking pain relief. While a high percentage of these patients likely continue with concurrent medical care, around half may not be disclosing the use of this treatment to their medical doctor. CONCLUSIONS: There is a need for more rigorous public health and health services research in order to assess the role, safety, utilization and financial costs associated with manual therapy treatment for headache. Primary healthcare providers should be mindful of the use of this highly popular approach to headache management in order to help facilitate safe, effective and coordinated care. PMID- 28340568 TI - Chronic lymphocytic leukemia skin infiltration mimicking an ICD pocket infection: a case report. AB - BACKGROUND: We are presenting a case report on an unreported and unusual cutaneous manifestation of chronic lymphocytic leukemia in a patient with an implantable cardioverter-defibrillator (ICD). CASE PRESENTATION: A 65-year-old man with a history of chronic lymphocytic leukemia (CLL), previously treated with chlorambucil, was referred in October 2013 for extraction of a single chamber ICD due to a suspected device-related infection in the pulse generator area (left hand side of Fig. 1). The ICD system (Current VR, St. Jude Medical, USA) had been implanted in November 2009. The patient complained of painless erythema with pruritus in the pocket area. Inflammatory blood parameters were C-reactive protein 17.3 mg/L and leucocytes 29.0 * 109/L. Due to the atypical appearance of the pocket area we did not extract the device. Instead, we created an exploratory excision in the skin induration, which had been present for approximately 6 weeks, and conducted a microbiological and histological examination. All cultivation examinations were negative. However, we did histologically show skin infiltration by CD-5 positive low-grade B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL). Re-initiation of chemotherapy was not necessary and the skin induration completely disappeared within 2 months (right-hand side of Fig. 1). CONCLUSIONS: Complete removal of an ICD system carries considerable risk. In patients with a history of hematological disease, it is crucial to exclude cutaneous manifestations of the disease prior to device removal. PMID- 28340570 TI - The therapeutic HIV Env C5/gp41 vaccine candidate Vacc-C5 induces specific T cell regulation in a phase I/II clinical study. AB - BACKGROUND: Levels of non-neutralising antibodies (AB) to the C5 domain of HIV Env gp120 are inversely related to progression of HIV infection. In this phase I/II clinical study we investigated safety of Vacc-C5, a peptide-based therapeutic vaccine candidate corresponding to C5/gp41732-744 as well as the effects on pre-existing AB levels to C5/gp41732-744, immune activation and T cell responses including exploratory assessments of Vacc-C5-induced T cell regulation. Our hypothesis was that exposure of the C5 peptide motif may have detrimental effects due to several of its HLA-like features and that enhancement of non neutralising anti-C5 AB by vaccination could reduce C5 exposure and thereby chronic immune activation. METHODS: Thirty-six HIV patients on effective antiretroviral therapy were randomised to one of three dose levels of Vacc-C5 administered intramuscularly with Alhydrogel or intradermally with GM-CSF as adjuvant through initial immunisation and two booster periods over 26 weeks. Vacc C5-specific AB were measured by ELISA and T cell responses by both IFN-gamma ELISPOT and proliferative assays analysed by flow cytometry. Immune regulation was assessed by functional blockade of the two inhibitory cytokines IL-10 and TGF beta in parallel cultures. Non-parametric statistical tests were applied. RESULTS: Vacc-C5 was found safe and well tolerated in all patients. Only marginal changes in humoral and cellular responses were induced, without any effect on immune activation. Overall, anti-Vacc-C5 AB levels seemed to decrease compared to pre-existing levels. Whereas Vacc-C5-specific CD8+ T cell proliferative responses increased after the first booster period (p = 0.020; CD4+, p = 0.057), they were reduced after the second. In contrast, Vacc-C5-induced T cell regulation increased after completed vaccination (p <= 0.027) and was lower at baseline in the few AB responders identified (p = 0.027). CONCLUSIONS: The therapeutic HIV vaccine candidate Vacc-C5 safely induced only marginal immune responses, whereas Vacc-C5-induced T cell regulation markedly increased. Our data support further attention on immune regulation during therapeutic HIV vaccination studies. TRIAL REGISTRATION: NCT01627678 . PMID- 28340569 TI - An immunohistochemical, enzymatic, and behavioral study of CD157/BST-1 as a neuroregulator. AB - BACKGROUND: Recent rodent and human studies provide evidence in support of the fact that CD157, well known as bone marrow stromal cell antigen-1 (BST-1) and a risk factor in Parkinson's disease, also meaningfully acts in the brain as a neuroregulator and affects social behaviors. It has been shown that social behaviors are impaired in CD157 knockout mice without severe motor dysfunction and that CD157/BST1 gene single nucleotide polymorphisms are associated with autism spectrum disorder in humans. However, it is still necessary to determine how this molecule contributes to the brain's physiological and pathophysiological functions. METHODS: To gain fresh insights about the relationship between the presence of CD157 in the brain and its enzymatic activity, and aberrant social behavior, CD157 knockout mice of various ages were tested. RESULTS: CD157 immunoreactivity colocalized with nestin-positive cells and elements in the ventricular zones in E17 embryos. Brain CD157 mRNA levels were high in neonates but low in adults. Weak but distinct immunoreactivity was detected in several areas in the adult brain, including the amygdala. CD157 has little or no base exchange activity, but some ADP-ribosyl cyclase activity, indicating that CD157 formed cyclic ADP-ribose but much less nicotinic acid adenine dinucleotide phosphate, with both mobilizing Ca2+ from intracellular Ca2+ pools. Social avoidance in CD157 knockout mice was rescued by a single intraperitoneal injection of oxytocin. CONCLUSIONS: CD157 may play a role in the embryonic and adult nervous systems. The functional features of CD157 can be explained in part through the production of cyclic ADP-ribose rather than nicotinic acid adenine dinucleotide phosphate. Further experiments are required to elucidate how the embryonic expression of CD157 in neural stem cells contributes to behaviors in adults or to psychiatric symptoms. PMID- 28340571 TI - DIRProt: a computational approach for discriminating insecticide resistant proteins from non-resistant proteins. AB - BACKGROUND: Insecticide resistance is a major challenge for the control program of insect pests in the fields of crop protection, human and animal health etc. Resistance to different insecticides is conferred by the proteins encoded from certain class of genes of the insects. To distinguish the insecticide resistant proteins from non-resistant proteins, no computational tool is available till date. Thus, development of such a computational tool will be helpful in predicting the insecticide resistant proteins, which can be targeted for developing appropriate insecticides. RESULTS: Five different sets of feature viz., amino acid composition (AAC), di-peptide composition (DPC), pseudo amino acid composition (PAAC), composition-transition-distribution (CTD) and auto correlation function (ACF) were used to map the protein sequences into numeric feature vectors. The encoded numeric vectors were then used as input in support vector machine (SVM) for classification of insecticide resistant and non resistant proteins. Higher accuracies were obtained under RBF kernel than that of other kernels. Further, accuracies were observed to be higher for DPC feature set as compared to others. The proposed approach achieved an overall accuracy of >90% in discriminating resistant from non-resistant proteins. Further, the two classes of resistant proteins i.e., detoxification-based and target-based were discriminated from non-resistant proteins with >95% accuracy. Besides, >95% accuracy was also observed for discrimination of proteins involved in detoxification- and target-based resistance mechanisms. The proposed approach not only outperformed Blastp, PSI-Blast and Delta-Blast algorithms, but also achieved >92% accuracy while assessed using an independent dataset of 75 insecticide resistant proteins. CONCLUSIONS: This paper presents the first computational approach for discriminating the insecticide resistant proteins from non-resistant proteins. Based on the proposed approach, an online prediction server DIRProt has also been developed for computational prediction of insecticide resistant proteins, which is accessible at http://cabgrid.res.in:8080/dirprot/ . The proposed approach is believed to supplement the efforts needed to develop dynamic insecticides in wet-lab by targeting the insecticide resistant proteins. PMID- 28340572 TI - Does sevoflurane add to outpatient procedural sedation in children? A randomised clinical trial. AB - BACKGROUND: There is little evidence concerning the effect of sevoflurane in outpatient procedural sedation, especially in children. We hypothesised that the addition of sevoflurane to a sedation regimen improves children's behaviour with minimal adverse events. METHODS: This is a randomised, triple-blind clinical trial conducted on an outpatient basis. Participants were 27 healthy children aged 4 to 6 years, who previously refused dental treatment with non-pharmacologic methods. All participants received oral midazolam (0.5 mg/kg, maximum 20 mg) and oral ketamine (3 mg/kg, maximum 50 mg) and, in addition: Group MK - 100% oxygen; Group MKS - inhalational sevoflurane at a sedative dose (final expired concentration between 0.3 and 0.4%). Dental appointments were video recorded for assessment of the children's sleep patterns, crying, movements, and overall behaviour during the procedure with the Houpt scale. Intra- and post-operative adverse events were systematically reported. Data were analysed by bivariate analyses in the IBM SPSS v. 19, at a significance level of 5%. RESULTS: MK (n = 13) and MKS (n = 14) did not differ regarding the Houpt scores (P > 0.05), but 53.8% of children in the MK group showed hysterical and continuous crying at the time of the local anaesthesia injection, compared to 7.1% of children in the MKS group (P = 0.01; phi = 0.5). There was a trend toward less crying and movement over time during the dental appointment in the MKS group (P = 0.48). Minor adverse events were observed in 10 MK children and 4 MKS children (P = 0.01). CONCLUSIONS: The addition of sevoflurane to oral midazolam-ketamine improved the children's crying behaviour during local anaesthetic administration, and did not increase the occurrence of adverse events. TRIAL REGISTRATION: Clinical Trials NCT02284204 . Registered 5 October 2014. PMID- 28340573 TI - A questionnaire measuring staff perceptions of Lean adoption in healthcare: development and psychometric testing. AB - BACKGROUND: During the past decade, the concept of Lean has spread rapidly within the healthcare sector, but there is a lack of instruments that can measure staff's perceptions of Lean adoption. Thus, the aim of the present study was to develop a questionnaire measuring Lean in healthcare, based on Liker's description of Lean, by adapting an existing instrument developed for the service sector. METHODS: A mixed-method design was used. Initially, items from the service sector instrument were categorized according to Liker's 14 principles describing Lean within four domains: philosophy, processes, people and partners and problem-solving. Items were lacking for three of Liker's principles and were therefore developed de novo. Think-aloud interviews were conducted with 12 healthcare staff from different professions to contextualize and examine the face validity of the questionnaire prototype. Thereafter, the adjusted questionnaire's psychometric properties were assessed on the basis of a cross-sectional survey among 386 staff working in primary care. RESULTS: The think-aloud interviews led to adjustments in the questionnaire to better suit a healthcare context, and the number of items was reduced. Confirmatory factor analysis of the adjusted questionnaire showed a generally acceptable correspondence with Liker's description of Lean. Internal consistency, measured using Cronbach's alpha, for the factors in Liker's description of Lean was 0.60 for the factor people and partners, and over 0.70 for the three other factors. Test-retest reliability measured by the intra-class correlation coefficient ranged from 0.77 to 0.88 for the four factors. CONCLUSIONS: We designed a questionnaire capturing staff's perceptions of Lean adoption in healthcare on the basis of Liker's description. This Lean in Healthcare Questionnaire (LiHcQ) showed generally acceptable psychometric properties, which supports its usability for measuring Lean adoption in healthcare. We suggest that further research focus on verifying the usability of LiHcQ in other healthcare settings, and on adjusting the instrument if needed. PMID- 28340574 TI - Myocyte enhancer factor 2D provides a cross-talk between chronic inflammation and lung cancer. AB - BACKGROUND: Lung cancer is the leading cause of cancer-related morbidity and mortality worldwide. Patients with chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD), are exposed to a higher risk of developing lung cancer. Chronic inflammation may play an important role in the lung carcinogenesis among those patients. The present study aimed at identifying candidate biomarker predicting lung cancer risk among patients with chronic respiratory diseases. METHODS: We applied clinical bioinformatics tools to analyze different gene profile datasets with a special focus on screening the potential biomarker during chronic inflammation-lung cancer transition. Then we adopted an in vitro model based on LPS-challenged A549 cells to validate the biomarker through RNA-sequencing, quantitative real time polymerase chain reaction, and western blot analysis. RESULTS: Bioinformatics analyses of the 16 enrolled GSE datasets from Gene Expression Omnibus online database showed myocyte enhancer factor 2D (MEF2D) level significantly increased in COPD patients coexisting non-small-cell lung carcinoma (NSCLC). Inflammation challenge increased MEF2D expression in NSCLC cell line A549, associated with the severity of inflammation. Extracellular signal-regulated protein kinase inhibition could reverse the up-regulation of MEF2D in inflammation-activated A549. MEF2D played a critical role in NSCLC cell bio-behaviors, including proliferation, differentiation, and movement. CONCLUSIONS: Inflammatory conditions led to increased MEF2D expression, which might further contribute to the development of lung cancer through influencing cancer microenvironment and cell bio-behaviors. MEF2D might be a potential biomarker during chronic inflammation-lung cancer transition, predicting the risk of lung cancer among patients with chronic respiratory diseases. PMID- 28340575 TI - NOX2 deficiency alters macrophage phenotype through an IL-10/STAT3 dependent mechanism: implications for traumatic brain injury. AB - BACKGROUND: NADPH oxidase (NOX2) is an enzyme system that generates reactive oxygen species (ROS) in microglia and macrophages. Excessive ROS production is linked with neuroinflammation and chronic neurodegeneration following traumatic brain injury (TBI). Redox signaling regulates macrophage/microglial phenotypic responses (pro-inflammatory versus anti-inflammatory), and NOX2 inhibition following moderate-to-severe TBI markedly reduces pro-inflammatory activation of macrophages/microglia resulting in concomitant increases in anti-inflammatory responses. Here, we report the signaling pathways that regulate NOX2-dependent macrophage/microglial phenotype switching in the TBI brain. METHODS: Bone marrow derived macrophages (BMDMs) prepared from wildtype (C57Bl/6) and NOX2 deficient (NOX2-/-) mice were treated with lipopolysaccharide (LPS; 10 ng/ml), interleukin 4 (IL-4; 10 ng/ml), or combined LPS/IL-4 to investigate signal transduction pathways associated with macrophage activation using western immunoblotting and qPCR analyses. Signaling pathways and activation markers were evaluated in ipsilateral cortical tissue obtained from adult male wildtype and NOX2-/- mice that received moderate-level controlled cortical impact (CCI). A neutralizing anti-IL-10 approach was used to determine the effects of IL-10 on NOX2-dependent transitions from pro- to anti-inflammatory activation states. RESULTS: Using an LPS/IL-4-stimulated BMDM model that mimics the mixed pro- and anti-inflammatory responses observed in the injured cortex, we show that NOX2-/- significantly reduces STAT1 signaling and markers of pro-inflammatory activation. In addition, NOX2-/- BMDMs significantly increase anti-inflammatory marker expression; IL-10 mediated STAT3 signaling, but not STAT6 signaling, appears to be critical in regulating this anti-inflammatory response. Following moderate-level CCI, IL-10 is significantly increased in microglia/macrophages in the injured cortex of NOX2 /- mice. These changes are associated with increased STAT3 activation, but not STAT6 activation, and a robust anti-inflammatory response. Neutralization of IL 10 in NOX2-/- BMDMs or CCI mice blocks STAT3 activation and the anti-inflammatory response, thereby demonstrating a critical role for IL-10 in regulating NOX2 dependent transitions between pro- and anti-inflammatory activation states. CONCLUSIONS: These studies indicate that following TBI NOX2 inhibition promotes a robust anti-inflammatory response in macrophages/microglia that is mediated by the IL-10/STAT3 signaling pathway. Thus, therapeutic interventions that inhibit macrophage/microglial NOX2 activity may improve TBI outcomes by not only limiting pro-inflammatory neurotoxic responses, but also enhancing IL-10-mediated anti inflammatory responses that are neuroprotective. PMID- 28340576 TI - Polysaccharides from Ganoderma lucidum attenuate microglia-mediated neuroinflammation and modulate microglial phagocytosis and behavioural response. AB - BACKGROUND: Ganoderma lucidum (GL) has been widely used in Asian countries for hundreds of years to promote health and longevity. The pharmacological functions of which had been classified, including the activation of innate immune responses, suppression of tumour and modulation of cell proliferations. Effective fractions of Ganoderma lucidum polysaccharides (GLP) had already been reported to regulate the immune system. Nevertheless, the role of GLP in the microglia mediated neuroinflammation has not been sufficiently elucidated. Further, GLP effect on microglial behavioural modulations in correlation with the inflammatory responses remains to be unravelled. The aim of this work was to quantitatively analyse the contributions of GLP on microglia. METHODS: The BV2 microglia and primary mouse microglia were stimulated by lipopolysaccharides (LPS) and amyloid beta42 (Abeta42) oligomer, respectively. Investigation on the effect of GLP was carried by quantitative determination of the microglial pro- and anti inflammatory cytokine expressions and behavioural modulations including migration, morphology and phagocytosis. Analysis of microglial morphology and phagocytosis modulations was confirmed in the zebrafish brain. RESULTS: Quantitative results revealed that GLP down-regulates LPS- or Abeta-induced pro inflammatory cytokines and promotes anti-inflammatory cytokine expressions in BV 2 and primary microglia. In addition, GLP attenuates inflammation-related microglial migration, morphological alterations and phagocytosis probabilities. We also showed that modulations of microglial behavioural responses were associated with MCP-1 and C1q expressions. CONCLUSIONS: Overall, our study provides an insight into the GLP regulation of LPS- and Abeta-induced neuroinflammation and serves an implication that the neuroprotective function of GLP might be achieved through modulation of microglial inflammatory and behavioural responses. PMID- 28340579 TI - Obstacles and opportunities in Chinese pharmaceutical innovation. AB - BACKGROUND: Global healthcare innovation networks nowadays have expanded beyond developed countries with many developing countries joining the force and becoming important players. China, in particular, has seen a significant increase in the number of innovative firms and research organizations stepping up to the global network in recent years. Nevertheless, the intense Research and Development input has not brought about the expectable output. While China is ascending at a great speed to a leading position worldwide in terms of Research and Development investment, scientific publications and patents, the innovation capabilities in the pharmaceutical sector remain weak. DISCUSSION: This study discusses the challenges and opportunities for pharmaceutical innovation in China. One hand, academic, industrial, institutional and financial constraints were found to be the major and inevitable barriers hindering the development of drug innovation. On the other hand, unique advantages had been observed which included growing pharmaceutical market, Research and Development funding, distinctive source, and international cooperation. The most important thing for China's pharmaceutical sector to leap forward is to break though innovation barriers and integrate own advantages into global value-chain of healthcare product development. PMID- 28340577 TI - Gene and protein analysis reveals that p53 pathway is functionally inactivated in cytogenetically normal Acute Myeloid Leukemia and Acute Promyelocytic Leukemia. AB - BACKGROUND: Mechanisms that inactivate the p53 pathway in Acute Myeloid Leukemia (AML), other than rare mutations, are still not well understood. METHODS: We performed a bioinformatics study of the p53 pathway function at the gene expression level on our collection of 1153 p53-pathway related genes. Publically available Affymetrix data of 607 de-novo AML patients at diagnosis were analyzed according to the patients cytogenetic, FAB and molecular mutations subtypes. We further investigated the functional status of the p53 pathway in cytogenetically normal AML (CN-AML) and Acute Promyelocytic Leukemia (APL) patients using bioinformatics, Real-Time PCR and immunohistochemistry. RESULTS: We revealed significant and differential alterations of p53 pathway-related gene expression in most of the AML subtypes. We found that p53 pathway-related gene expression was not correlated with the accepted grouping of AML subtypes such as by cytogenetically-based prognosis, morphological stage or by the type of molecular mutation. Our bioinformatic analysis revealed that p53 is not functional in CN AML and APL blasts at inducing its most important functional outcomes: cell cycle arrest, apoptosis, DNA repair and oxidative stress defense. We revealed transcriptional downregulation of important p53 acetyltransferases in both CN-AML and APL, accompanied by increased Mdmx protein expression and inadequate Chk2 protein activation. CONCLUSIONS: Our bioinformatic analysis demonstrated that p53 pathway is differentially inactivated in different AML subtypes. Focused gene and protein analysis of p53 pathway in CN-AML and APL patients imply that functional inactivation of p53 protein can be attributed to its impaired acetylation. Our analysis indicates the need in further accurate evaluation of p53 pathway functioning and regulation in distinct subtypes of AML. PMID- 28340578 TI - ABCB1 and ABCG2 drug transporters are differentially expressed in non-small cell lung cancers (NSCLC) and expression is modified by cisplatin treatment via altered Wnt signaling. AB - BACKGROUND: Lung cancer (LC) is still the most common cause of cancer related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of all LC cases but is not a single entity. It is now accepted that, apart from the characteristic driver mutations, the unique molecular signatures of adeno- (AC) and squamous cell carcinomas (SCC), the two most common NSCLC subtypes should be taken into consideration for their management. Therapeutic interventions, however, frequently lead to chemotherapy resistance highlighting the need for in depth analysis of regulatory mechanisms of multidrug resistance to increase therapeutic efficiency. METHODS: Non-canonical Wnt5a and canonical Wnt7b and ABC transporter expressions were tested in primary human LC (n = 90) resections of AC and SCC. To investigate drug transporter activity, a three dimensional (3D) human lung aggregate tissue model was set up using differentiated primary human lung cell types. Following modification of the canonical, beta-catenin dependent Wnt pathway or treatment with cisplatin, drug transporter analysis was performed at mRNA, protein and functional level using qRT-PCR, immunohistochemistry, immune fluorescent staining and transport function analysis. RESULTS: Non-canonical Wnt5a is significantly up-regulated in SCC samples making the microenvironment different from AC, where the beta-catenin dependent Wnt7b is more prominent. In primary cancer tissues ABCB1 and ABCG2 expression levels were different in the two NSCLC subtypes. Non-canonical rhWnt5a induced down-regulation of both ABCB1 and ABCG2 transporters in the primary human lung aggregate tissue model recreating the SCC-like transporter pattern. Inhibition of the beta-catenin or canonical Wnt pathway resulted in similar down-regulation of both ABC transporter expression and function. In contrast, cisplatin, the frequently used adjuvant chemotherapeutic agent, activated beta-catenin dependent signaling that lead to up-regulation of both ABCB1 and ABCG2 transporter expression and activity. CONCLUSIONS: The difference in the Wnt microenvironment in AC and SCC leads to variations in ABC transporter expression. Cisplatin via induction of canonical Wnt signaling up-regulates ABCB1 and ABCG2 drug transporters that are not transporters for cisplatin itself but are transporters for drugs that are frequently used in combination therapy with cisplatin modulating drug response. PMID- 28340580 TI - Toll-like receptors genes polymorphisms and the occurrence of HCMV infection among pregnant women. AB - BACKGROUND: Human cytomegalovirus (HCMV) is the most common cause of intrauterine infections worldwide. The toll-like receptors (TLRs) have been reported as important factors in immune response against HCMV. Particularly, TLR2, TLR4 and TLR9 have been shown to be involved in antiviral immunity. Evaluation of the role of single nucleotide polymorphisms (SNPs), located within TLR2, TLR4 and TLR9 genes, in the development of human cytomegalovirus (HCMV) infection in pregnant women and their fetuses and neonates, was performed. METHODS: The study was performed for 131 pregnant women, including 66 patients infected with HCMV during pregnancy, and 65 age-matched control pregnant individuals. The patients were selected to the study, based on serological status of anti-HCMV IgG and IgM antibodies and on the presence of viral DNA in their body fluids. Genotypes in TLR2 2258 A > G, TLR4 896 G > A and 1196 C > T and TLR9 2848 G > A SNPs were determined by self-designed nested PCR-RFLP assays. Randomly selected PCR products, representative for distinct genotypes in TLR SNPs, were confirmed by sequencing. A relationship between the genotypes, alleles, haplotypes and multiple variants in the studied polymorphisms, and the occurrence of HCMV infection in pregnant women and their offsprings, was determined, using a logistic regression model. RESULTS: Genotypes in all the analyzed polymorphisms preserved the Hardy-Weinberg equilibrium in pregnant women, both infected and uninfected with HCMV (P > 0.050). GG homozygotic and GA heterozygotic status in TLR9 2848 G > A SNP decreased significantly the occurrence of HCMV infection (OR 0.44 95% CI 0.21-0.94 in the dominant model, P <= 0.050). The G allele in TLR9 SNP was significantly more frequent among the uninfected pregnant women than among the infected ones (chi2 = 4.14, P <= 0.050). Considering other polymorphisms, similar frequencies of distinct genotypes, haplotypes and multiple SNP variants were observed between the studied groups of patients. CONCLUSIONS: TLR9 2848 G > A SNP may be associated with HCMV infection in pregnant women. PMID- 28340581 TI - Does psychological functioning mediate the relationship between bullying involvement and weight loss preoccupation in adolescents? A two-stage cross sectional study. AB - BACKGROUND: Adolescent bullying is associated with a range of adversities for those who are bullied i.e., victims and bully-victims (e.g., those who bully others and get victimised), including reduced psychological functioning and eating disorder symptoms. Bullies are generally well-adjusted psychologically, but previous research suggests that bullies may also engage in problematic diet behaviours. This study investigates a) whether adolescents involved in bullying (bullies, victims, bully-victims) are at increased risk of weight loss preoccupation, b) whether psychological functioning mediates this relationship and c) whether sex is a key moderator. METHOD: A two-stage design was used. In stage 1, adolescents (n = 2782) from five UK secondary schools were screened for bullying involvement using self and peer reports. In stage 2, a sample of bullies, victims, bully-victims and uninvolved adolescents (n = 767) completed a battery of assessments. The measures included the eating behaviours component of the Child and Adolescent Psychiatric Assessment, which was reduced to one factor (weight loss preoccupation) and used as the outcome variable. Measures of self esteem, body-esteem and emotional problems were reduced to a latent (mediator) variable of psychological functioning. Multi-group analysis examined the effects of sex and all models were adjusted for covariates (BMI, pubertal stage, age, parental education and ethnicity). RESULTS: Bullies, victims and bully-victims were at increased risk of weight loss preoccupation compared to adolescents uninvolved in bullying. The mechanism by which bullying involvement related to increased weight loss preoccupation varied by bullying role: in bullies the effect was direct, in victims the effect was indirect (via reduced psychological functioning) and in bully-victims the effect was both direct and indirect. Sex significantly moderated the relationship in bullies: weight loss preoccupation was only statistically significant in bullies who were boys. CONCLUSION: Bullying involvement during adolescence is associated with weight loss preoccupation. Bullies are likely driven by a desire to increase attractiveness and social status; whereas weight loss preoccupation in bullied adolescents may have maladaptive influences on diet and exercise behaviours due to its association with reduced psychological functioning. Future research should consider peer victimisation as a potential modifiable risk factor for reduced psychological functioning and weight loss preoccupation, which if targeted, may help to prevent maladaptive diet and exercise behaviours. PMID- 28340582 TI - Optimisation of an exemplar oculomotor model using multi-objective genetic algorithms executed on a GPU-CPU combination. AB - BACKGROUND: Parameter optimisation is a critical step in the construction of computational biology models. In eye movement research, computational models are increasingly important to understanding the mechanistic basis of normal and abnormal behaviour. In this study, we considered an existing neurobiological model of fast eye movements (saccades), capable of generating realistic simulations of: (i) normal horizontal saccades; and (ii) infantile nystagmus - pathological ocular oscillations that can be subdivided into different waveform classes. By developing appropriate fitness functions, we optimised the model to existing experimental saccade and nystagmus data, using a well-established multi objective genetic algorithm. This algorithm required the model to be numerically integrated for very large numbers of parameter combinations. To address this computational bottleneck, we implemented a master-slave parallelisation, in which the model integrations were distributed across the compute units of a GPU, under the control of a CPU. RESULTS: While previous nystagmus fitting has been based on reproducing qualitative waveform characteristics, our optimisation protocol enabled us to perform the first direct fits of a model to experimental recordings. The fits to normal eye movements showed that although saccades of different amplitudes can be accurately simulated by individual parameter sets, a single set capable of fitting all amplitudes simultaneously cannot be determined. The fits to nystagmus oscillations systematically identified the parameter regimes in which the model can reproduce a number of canonical nystagmus waveforms to a high accuracy, whilst also identifying some waveforms that the model cannot simulate. Using a GPU to perform the model integrations yielded a speedup of around 20 compared to a high-end CPU. CONCLUSIONS: The results of both optimisation problems enabled us to quantify the predictive capacity of the model, suggesting specific modifications that could expand its repertoire of simulated behaviours. In addition, the optimal parameter distributions we obtained were consistent with previous computational studies that had proposed the saccadic braking signal to be the origin of the instability preceding the development of infantile nystagmus oscillations. Finally, the master-slave parallelisation method we developed to accelerate the optimisation process can be readily adapted to fit other highly parametrised computational biology models to experimental data. PMID- 28340583 TI - Inflammatory signature of cerebellar neurodegeneration during neonatal hyperbilirubinemia in Ugt1 -/- mouse model. AB - BACKGROUND: Severe hyperbilirubinemia is toxic during central nervous system development. Prolonged and uncontrolled high levels of unconjugated bilirubin lead to bilirubin-induced neurological damage and eventually death by kernicterus. Bilirubin neurotoxicity is characterized by a wide array of neurological deficits, including irreversible abnormalities in motor, sensitive and cognitive functions, due to bilirubin accumulation in the brain. Despite the abundant literature documenting the in vitro and in vivo toxic effects of bilirubin, it is unclear which molecular and cellular events actually characterize bilirubin-induced neurodegeneration in vivo. METHODS: We used a mouse model of neonatal hyperbilirubinemia to temporally and spatially define the response of the developing cerebellum to the bilirubin insult. RESULTS: We showed that the exposure of developing cerebellum to sustained bilirubin levels induces the activation of oxidative stress, ER stress and inflammatory markers at the early stages of the disease onset. In particular, we identified TNFalpha and NFKbeta as key mediators of bilirubin-induced inflammatory response. Moreover, we reported that M1 type microglia is increasingly activated during disease progression. Failure to counteract this overwhelming stress condition resulted in the induction of the apoptotic pathway and the generation of the glial scar. Finally, bilirubin induced the autophagy pathway in the stages preceding death of the animals. CONCLUSIONS: This study demonstrates that inflammation is a key contributor to bilirubin damage that cooperates with ER stress in the onset of neurotoxicity. Pharmacological modulation of the inflammatory pathway may be a potential intervention target to ameliorate neonatal lethality in Ugt1 -/- mice. PMID- 28340584 TI - Validation of the German version of two scales (RIS, RCS-HCP) for measuring regret associated with providing healthcare. AB - BACKGROUND: The regret intensity scale (RIS) and the regret coping scale for healthcare professionals (RCS-HCP) working in hospitals assess the experience of care-related regrets and how healthcare professional deal with these negative events. The aim of this study was to validate a German version of the RIS and the RCS-HCP. METHODS: The RIS and RCS-HCP in German were first translated into German (forward- and backward translations) and then pretested with 16 German-speaking healthcare professionals. Finally, two surveys (test and 1-month retest) administered the scales to a large sample of healthcare professionals from two different hospitals. RESULTS: Of the 2142 eligible healthcare professionals, 494 (23.1%) individuals (108 physicians) completed the cross-sectional web based survey and 244 completed the retest questionnaire. Participants (n = 165, 33.4% of the total sample) who reported not having experienced a regret in the last 5 years, had significantly more days of sick leave during the last 6 months. These participants were excluded from the subsequent analyses. The structure of the scales was similar to the French version with a single dimension for the regret intensity scale (Cronbach's alpha: 0.88) and three types of coping strategies for the regret coping scale (alphas: 0.69 for problem-focused strategies, 0.67 for adaptive strategies and 0.86 for the maladaptive strategies). Construct validity was good and reproduced the findings of the French study, namely that higher regret intensity was associated with situations that entailed more consequences for the patients. Furthermore, higher regret intensity and more frequent use of maladaptive strategies were associated with more sleep difficulties and less work satisfaction. CONCLUSIONS: The German RIS and RCS-HCP scales were found valid for measuring regret intensity and regret coping in a population of healthcare professionals working in a hospital. Reporting no regret, which corresponds to the coping strategy of suppression, seems to be a maladaptive strategy because it was associated with more frequent sick day leaves. PMID- 28340585 TI - Analytical sensitivity of current best-in-class malaria rapid diagnostic tests. AB - BACKGROUND: Rapid diagnostic tests (RDTs) are today the most widely used method for malaria diagnosis and are recommended, alongside microscopy, for the confirmation of suspected cases before the administration of anti-malarial treatment. The diagnostic performance of RDTs, as compared to microscopy or PCR is well described but the actual analytical sensitivity of current best-in-class tests is poorly documented. This value is however a key performance indicator and a benchmark value needed to developed new RDTs of improved sensitivity. METHODS: Thirteen RDTs detecting either the Plasmodium falciparum histidine rich protein 2 (HRP2) or the plasmodial lactate dehydrogenase (pLDH) antigens were selected from the best performing RDTs according to the WHO-FIND product testing programme. The analytical sensitivity of these products was evaluated using a range of reference materials including P. falciparum and Plasmodium vivax whole parasite samples as well as recombinant proteins. RESULTS: The best performing HRP2-based RDTs could detect all P. falciparum cultured samples at concentrations as low as 0.8 ng/mL of HRP2. The limit of detection of the best performing pLDH-based RDT specifically detecting P. vivax was 25 ng/mL of pLDH. CONCLUSION: The analytical sensitivity of P. vivax and Pan pLDH-based RDTs appears to vary considerably from product to product, and improvement of the limit-of-detection for P. vivax detecting RDTs is needed to match the performance of HRP2 and Pf pLDH-based RDTs for P. falciparum. Different assays using different reference materials produce different values for antigen concentration in a given specimen, highlighting the need to establish universal reference assays. PMID- 28340586 TI - Development and validation of a condition-specific diary to measure severity, bothersomeness and impact on daily activities for patients with acute urinary tract infection in primary care. AB - BACKGROUND: Urinary tract infection (UTI) is a common condition in primary care. Patient-reported outcome measures (PROMs) are crucial in the evaluation of interventions to improve diagnosis, treatment and prognosis of UTI. The aim of this study was to identify an existing condition-specific PROM to measure symptom severity, bothersomeness and impact on daily activities for adult patients with suspected urinary tract infection in primary care; or, in the absence of such a PROM, to test items identified from existing PROMs for coverage and relevance in single and group interviews and to psychometrically validate the resulting PROM. METHODS: The literature was searched for existing PROMs covering the three domains. Items from the identified PROMs were tested in single and group interviews. The resulting symptom diary was psychometrically validated using the partial credit Rasch model for polytomous items in a cohort of 451 women participating in two studies regarding UTI. RESULTS: No existing PROM fulfilled the inclusion criteria. Content validation resulted in one domain concerning symptom severity (18 items), one concerning bothersomeness (18 items), and one concerning impact on daily activities (7 items). Psychometrical validation resulted in four dimensions in each of the first two domains and one dimension in the third domain. CONCLUSIONS: Domains were not unidimensional, which meant that we identified dimensions of patient-experienced UTI that differed substantially from those previously found. We recommend that future studies on UTI, in which PROMs are to be used, should ensure high content validity of their outcome measures and unidimensionality of the included dimensions. PMID- 28340587 TI - Lymphocytes have a role in protection, but not in pathogenesis, during La Crosse Virus infection in mice. AB - BACKGROUND: La Crosse Virus (LACV) is a primary cause of pediatric viral encephalitis in the USA and can result in severe clinical outcomes. Almost all cases of LACV encephalitis occur in children 16 years or younger, indicating an age-related susceptibility. This susceptibility is recapitulated in a mouse model where weanling (3 weeks old or younger) mice are susceptible to LACV-induced disease, and adults (greater than 6 weeks) are resistant. Disease in mice and humans is associated with infiltrating leukocytes to the CNS. However, what cell types are infiltrating into the brain during virus infection and how these cells influence pathogenesis remain unknown. METHODS: In the current study, we analyzed lymphocytes recruited to the CNS during LACV-infection in clinical mice, using flow cytometry. We analyzed the contribution of these lymphocytes to LACV pathogenesis in weanling mice using knockout mice or antibody depletion. Additionally, we studied at the potential role of these lymphocytes in preventing LACV neurological disease in resistant adult mice. RESULTS: In susceptible weanling mice, disease was associated with infiltrating lymphocytes in the CNS, including NK cells, CD4 T cells, and CD8 T cells. Surprisingly, depletion of these cells did not impact neurological disease, suggesting these cells do not contribute to virus-mediated damage. In contrast, in disease-resistant adult animals, depletion of both CD4 T cells and CD8 T cells or depletion of B cells increased neurological disease, with higher levels of virus in the brain. CONCLUSIONS: Our current results indicate that lymphocytes do not influence neurological disease in young mice, but they have a critical role protecting adult animals from LACV pathogenesis. Although LACV is an acute virus infection, these studies indicate that the innate immune response in adults is not sufficient for protection and that components of the adaptive immune response are necessary to prevent virus from invading the CNS. PMID- 28340588 TI - Comparison of the COM-FCP inclination angle and other mediolateral stability indicators for turning. AB - BACKGROUND: Studies have shown that turning is associated with more instability than straight walking and instability increases with turning angles. However, the precise relationship of changes in stability with the curvature and step length of turning is not clear. The traditional center of mass (COM)-center of pressure (COP) inclination angle requires the use of force plates. A COM-foot contact point (FCP) inclination angle derived from kinematic data is proposed in this study as a measure of the stability of turning. METHODS: In order to generate different degrees of stability, we designed an experiment of walking with different curvatures and step lengths. Simultaneously, a novel method was proposed to calculate the COM-FCP inclination angles of different walking trajectories with different step lengths for 10 healthy subjects. The COM-FCP inclination angle, the COM acceleration, the step width and the COM-ankle inclination angles were statistically analyzed. RESULTS: The statistical results showed that the mediolateral (ML) COM-FCP inclination angles increased significantly as the curvature of the walking trajectories or the step length in circular walking increased. Changes in the ML COM acceleration, the step width and the ML COM-ankle inclination angle verified the feasibility and reliability of the proposed method. Additionally, the ML COM-FCP inclination angle was more sensitive to the ML stability than the ML COM-ankle inclination angle. CONCLUSIONS: The work suggests that it is more difficult to keep balance when walking in a circular trajectory with a larger curvature or in a larger step length. Essentially, turning with a larger angle in one step leads to a lower ML stability. A novel COM-FCP inclination angle was validated to indicate ML stability. This method can be applied to complicated walking tasks, where the force plate is not applicable, and it accounts for the variability of the base of support (BOS) compared to the COM-ankle inclination angle. PMID- 28340589 TI - Critical race theory as a tool for understanding poor engagement along the HIV care continuum among African American/Black and Hispanic persons living with HIV in the United States: a qualitative exploration. AB - BACKGROUND: African American/Black and Hispanic persons living with HIV (AABH PLWH) in the U.S. evidence insufficient engagement in HIV care and low uptake of HIV antiretroviral therapy, leading to suboptimal clinical outcomes. The present qualitative study used critical race theory, and incorporated intersectionality theory, to understand AABH-PLWH's perspectives on the mechanisms by which structural racism; that is, the macro-level systems that reinforce inequities among racial/ethnic groups, influence health decisions and behaviors. METHODS: Participants were adult AABH-PLWH in New York City who were not taking antiretroviral therapy nor well engaged in HIV care (N = 37). Participants were purposively sampled for maximum variation from a larger study, and engaged in semi-structured in-depth interviews that were audio-recorded and professionally transcribed verbatim. Data were analyzed using a systematic content analysis approach. RESULTS: We found AABH-PLWH experienced HIV care and medication decisions through a historical and cultural lens incorporating knowledge of past and present structural racism. This contextual knowledge included awareness of past maltreatment of people of color in medical research. Further, these understandings were linked to the history of HIV antiretroviral therapy itself, including awareness of the first HIV antiretroviral regimen; namely, AZT (zidovudine) mono-therapy, which was initially prescribed in unacceptably high doses, causing serious side effects, but with only modest efficacy. In this historical/cultural context, aspects of structural racism negatively influenced health care decisions and behavior in four main ways: 1) via the extent to which healthcare settings were experienced as overly institutionalized and, therefore, dehumanizing; 2) distrust of medical institutions and healthcare providers, which led AABH-PLWH to feel pressured to take HIV antiretroviral therapy when it was offered; 3) perceptions that patients are excluded from the health decision making process; and 4) an over-emphasis on antiretroviral therapy compared to other non-HIV related priorities. We found that although participants were located at the intersection of multiple social categories (e.g., gender, social class, AABH race/ethnicity), race/ethnicity and social class were described as primary factors. CONCLUSIONS: Critical race theory proved useful in uncovering how macro-level structural racism affects individual-level health decisions and behaviors. HIV clinical settings can counter-balance the effects of structural racism by building "structural competency," and interventions fostering core self determination needs including autonomy may prove culturally appropriate and beneficial for AABH-PLWH. PMID- 28340590 TI - Comparison of angle, shape, and position of articular processes in Dobermans and Great Danes with and without cervical spondylomyelopathy. AB - BACKGROUND: Cervical spondylomyelopathy (CSM), also known as wobbler syndrome, affects mainly large and giant-breed dogs, causing compression of the cervical spinal cord and/or nerve roots. Structural and dynamic components seem to play a role in the development of CSM; however, pathogenesis is not yet fully understood. Physiologic and pathologic movements of the cervical spine depend on the morphology and morphometry of articular processes, as well as on intervertebral discs and vertebral column ligaments. Moreover, the characteristics of the articular processes affect motion and stability of the vertebral column. The goal of this study was to investigate the angle, shape, and position of the articular surfaces within the articular processes and compare them between Doberman Pinschers and Great Danes with and without cervical spondylomyelopathy. RESULTS: Magnetic resonance images were obtained for 60 dogs: 15 clinically normal Dobermans (Dob-N), 15 CSM-affected Dobermans (Dob-CSM), 15 clinically normal Great Danes (GD-N), and 15 CSM-affected Great Danes (GD-CSM). Angle, shape, and position (lateral distance) of the articular surfaces from the articular processes were analyzed from C2-3 to C7-T1. Results indicate that the mean angle was different between Dob-CSM and GD-CSM at C4-5, C5-6, and C6-7, and between GD-N and GD-CSM at C6-7. There were differences between Dob-N and GD-N, and between Dob-CSM and GD-CSM for the lateral distance at most locations, except C2-3. Compared with Great Danes, Dobermans generally had a greater proportion of concave caudal surfaces at C4-5, C5-6, and C6-7. Concave articular surfaces have been associated with greater axial rotation. This may explain the high proportion of disc-associated CSM in Dobermans compared to Great Danes. The differences between breeds suggest they may have different motion patterns in the caudal cervical vertebral column. CONCLUSIONS: Considering that no differences in angle, shape, or position of the articular surfaces within the articular processes were found between normal and CSM-affected dogs, their relevance appears to have a secondary role in the pathogenesis of CSM. PMID- 28340591 TI - Altered mTOR and Beclin-1 mediated autophagic activation during right ventricular remodeling in monocrotaline-induced pulmonary hypertension. AB - BACKGROUND: Right ventricular structure and function is a major predictor of outcomes in pulmonary hypertension (PH), yet the underlying mechanisms remain poorly understood. Growing evidence suggests the importance of autophagy in cardiac remodeling; however, its dynamics in the process of right ventricle(RV) remodeling in PH has not been fully explored. We sought to study the time course of cardiomyocyte autophagy in the RV in PH and determine whether mammalian target of rapamycin (mTOR) and Beclin-1 hypoxia-related pro-autophagic pathways are underlying mechanisms. METHODS: Rats were studied at 2, 4, and 6 weeks after subcutaneous injection of 60 mg/kg monocrotaline (MCT) (MCT-2 W, 4 W, 6 W) or vehicle (CON-2 W, 4 W, 6 W). Cardiac hemodynamics and RV function were assessed in rats. Autophagy structures and markers were assessed using transmission electron microscope, RT-qPCR, immunohistochemistry staining, and western blot analyses. Western blot was also used to quantify the expression of mTOR and Beclin-1 mediated pro-autophagy signalings in the RV. RESULTS: Two weeks after MCT injection, pulmonary artery systolic pressure increased and mild RV hypertrophy without RV dilation was observed. RV enlargement presented at 4 weeks with moderately decreased function, whereas typical characteristics of RV decompensation and failure occurred at 6 weeks thus demonstrating the progression of RV remodeling in the MCT model. A higher LC3 (microtubule- associated protein light chain 3) II/I ratio, upregulated LC3 mRNA and protein levels, as well as accumulation of autophagosomes in RV of MCT rats indicated autophagy induction. Autophagy activation was coincident with increased pulmonary artery systolic pressure. Pro-autophagy signaling pathways were activated in a RV remodeling stage-dependent manner since phospho-AMPK (adenosine monophosphate-activated protein kinase)-alpha were primarily upregulated and phospho-mTOR suppressed in the RV at 2 and 4 weeks post-MCT injection, whearas, BNIP3 (Bcl2-interacting protein 3) and beclin-1 expression were relatively low during these stages, they were significantly upregulated after 6 weeks in this model. CONCLUSIONS: Our findings provide evidence of sustained activation of autophagy in RV remodeling of MCT induced PH model, while pro-autophagic signaling pathways varied depending on the phase. PMID- 28340593 TI - Erratum to: Aryl hydrocarbon receptor/cytochrome P450 1A1 pathway mediates breast cancer stem cells expansion through PTEN inhibition and beta-Catenin and Akt activation. PMID- 28340592 TI - The Impact of the Share 35 Policy on Racial and Ethnic Disparities in Access to Liver Transplantation for Patients with End Stage Liver Disease in the United States: An Analysis from UNOS Database. AB - BACKGROUND: The Share 35 policy was instituted in June 2013 by the United Network for Organ Sharing (UNOS) in order to reduce death on liver transplant waiting list. The effect of this policy on racial and ethnic disparities in access to liver transplantation has not been examined. METHODS: A total of 14,585 adult patients registered for liver transplantation between 2012 and 2015 were identified from UNOS database. Logistic and proportional hazards models were used to model the effects of race and ethnicity on access to liver transplantation. Stratification on pre- and post-Share 35 periods was performed to compare the first 18 months of Share 35 policy to an equivalent time period before. RESULTS: Comparison of the pre- and post-Share 35 periods showed significantly decreased time on waiting list and increased numbers of minorities having access to liver transplantation. Hispanic recipients still experienced significantly longer waiting time (HR: 0.69, 95% CI: 0.53-0.88) before they received liver transplantation after Share 35 policy took effect. CONCLUSION: The Share 35 policy did not lead to improved access to liver transplantation among minorities but eliminated the previously observed racial and ethnic disparities in transplant rates as well as shortened the waiting time. PMID- 28340594 TI - Species-specific ecological niche modelling predicts different range contractions for Lutzomyia intermedia and a related vector of Leishmania braziliensis following climate change in South America. AB - BACKGROUND: Before 1996 the phlebotomine sand fly Lutzomyia neivai was usually treated as a synonym of the morphologically similar Lutzomyia intermedia, which has long been considered a vector of Leishmania braziliensis, the causative agent of much cutaneous leishmaniasis in South America. This report investigates the likely range changes of both sand fly species in response to a stabilisation climate change scenario (RCP4.5) and a high greenhouse gas emissions one (RCP8.5). METHODS: Ecological niche modelling was used to identify areas of South America with climates currently suitable for each species, and then the future distributions of these climates were predicted based on climate change scenarios. Compared with the previous ecological niche model of L. intermedia (sensu lato) produced using the GARP algorithm in 2003, the current investigation modelled the two species separately, making use of verified presence records and additional records after 2001. Also, the new ensemble approach employed ecological niche modelling algorithms (including Maximum Entropy, Random Forests and Support Vector Machines) that have been widely adopted since 2003 and perform better than GARP, as well as using a more recent climate change model (HadGEM2) considered to have better performance at higher resolution than the earlier one (HadCM2). RESULTS: Lutzomyia intermedia was shown to be the more tropical of the two species, with its climatic niche defined by higher annual mean temperatures and lower temperature seasonality, in contrast to the more subtropical L. neivai. These different latitudinal ranges explain the two species' predicted responses to climate change by 2050, with L. intermedia mostly contracting its range (except perhaps in northeast Brazil) and L. neivai mostly shifting its range southwards in Brazil and Argentina. This contradicts the findings of the 2003 report, which predicted more range expansion. The different findings can be explained by the improved data sets and modelling methods. CONCLUSIONS: Our findings indicate that climate change will not always lead to range expansion of disease vectors such as sand flies. Ecological niche models should be species specific, carefully selected and combined in an ensemble approach. PMID- 28340596 TI - Clinical treatment considerations in the intensity-modulated radiotherapy era for patients with N0-category nasopharyngeal carcinoma and enlarged neck lymph nodes. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) shows a high proportion of lymph node metastasis, and treatment guidelines have been developed for positive nodes. However, no irradiation guidelines have been proposed for patients with enlarged neck lymph nodes (ENLNs) that do not meet the radiological criteria of 10 mm in diameter for positive lymph nodes. This study aimed to determine the prognostic value and radiation dose for ENLNs in N0-category NPC patients treated with intensity-modulated radiotherapy (IMRT). METHODS: We reviewed the medical data of 251 patients with non-metastatic, N0-category NPC treated with IMRT. Receiver operating characteristic curves were used to calculate the cut-off value of the ENLN diameter for the prediction of disease failure. The biological equivalent dose (BED) for ENLNs was calculated. Patient survival was compared between the small and large ENLN groups. Independent prognostic factors were identified using the Cox proportional hazards model. RESULTS: The estimated 4-year regional relapse-free survival rate was higher in patients with ENLNs >=5.5 mm than in those with ENLNs <5.5 mm (100% vs. 98.8%, P = 0.049), whereas disease-free, overall, and distant metastasis-free survival rates were similar between the two groups. After adjusting for various factors, ENLN diameter was not identified as an independent prognostic factor (P > 0.05 for all survival rates). In the subgroup analysis, patients receiving BED >=72 Gy had a similar prognosis as patients receiving BED <72 Gy in both the small and large ENLN groups. The multivariate analysis also confirmed that BED >=72 Gy was not associated with significantly improved prognosis in patients with N0-category NPC. CONCLUSIONS: A BED of 72 Gy to ENLNs is considerably sufficient to provide a clinical benefit to patients with N0-category NPC. Prospective studies are warranted to validate the findings in the present study. PMID- 28340595 TI - The risk associated with spinal manipulation: an overview of reviews. AB - BACKGROUND: Spinal manipulative therapy (SMT) is a widely used manual treatment, but many reviews exist with conflicting conclusions about the safety of SMT. We performed an overview of reviews to elucidate and quantify the risk of serious adverse events (SAEs) associated with SMT. METHODS: We searched five electronic databases from inception to December 8, 2015. We included reviews on any type of studies, patients, and SMT technique. Our primary outcome was SAEs. Quality of the included reviews was assessed using a measurement tool to assess systematic reviews (AMSTAR). Since there were insufficient data for calculating incidence rates of SAEs, we used an alternative approach; the conclusions regarding safety of SMT were extracted for each review, and the communicated opinion were judged by two reviewers independently as safe, harmful, or neutral/unclear. Risk ratios (RRs) of a review communicating that SMT is safe and meeting the requirements for each AMSTAR item, were calculated. RESULTS: We identified 283 eligible reviews, but only 118 provided data for synthesis. The most frequently described adverse events (AEs) were stroke, headache, and vertebral artery dissection. Fifty-four reviews (46%) expressed that SMT is safe, 15 (13%) expressed that SMT is harmful, and 49 reviews (42%) were neutral or unclear. Thirteen reviews reported incidence estimates for SAEs, roughly ranging from 1 in 20,000 to 1 in 250,000,000 manipulations. Low methodological quality was present, with a median of 4 of 11 AMSTAR items met (interquartile range, 3 to 6). Reviews meeting the requirements for each of the AMSTAR items (i.e. good internal validity) had a higher chance of expressing that SMT is safe. CONCLUSIONS: It is currently not possible to provide an overall conclusion about the safety of SMT; however, the types of SAEs reported can indeed be significant, sustaining that some risk is present. High quality research and consistent reporting of AEs and SAEs are needed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015030068 . PMID- 28340597 TI - Temporal dynamics of the gut microbiota in people sharing a confined environment, a 520-day ground-based space simulation, MARS500. AB - BACKGROUND: The intestinal microbial communities and their temporal dynamics are gaining increasing interest due to the significant implications for human health. Recent studies have shown the dynamic behavior of the gut microbiota in free living, healthy persons. To date, it is not known whether these dynamics are applicable during prolonged life sharing in a confined and controlled environment. RESULTS: The MARS500 project, the longest ground-based space simulation ever, provided us with a unique opportunity to trace the crew microbiota over 520 days of isolated confinement, such as that faced by astronauts in real long-term interplanetary space flights, and after returning to regular life, for a total of 2 years. According to our data, even under the strictly controlled conditions of an enclosed environment, the human gut microbiota is inherently dynamic, capable of shifting between different steady states, typically with rearrangements of autochthonous members. Notwithstanding a strong individuality in the overall gut microbiota trajectory, some key microbial components showed conserved temporal dynamics, with potential implications for the maintenance of a health-promoting, mutualistic microbiota configuration. CONCLUSIONS: Sharing life in a confined habitat does not affect the resilience of the individual gut microbial ecosystem, even in the long term. However, the temporal dynamics of certain microbiota components should be monitored when programming future mission simulations and real space flights, to prevent breakdowns in the metabolic and immunological homeostasis of the crewmembers. PMID- 28340598 TI - Myelin-specific multiple sclerosis antibodies cause complement-dependent oligodendrocyte loss and demyelination. AB - Intrathecal immunoglobulin G (IgG) synthesis, cerebrospinal fluid (CSF) oligoclonal IgG bands and lesional IgG deposition are seminal features of multiple sclerosis (MS) disease pathology. Both the specific targets and pathogenic effects of MS antibodies remain poorly characterized. We produced IgG1 monoclonal recombinant antibodies (rAbs) from clonally-expanded plasmablasts recovered from MS patient CSF. Among these were a subset of myelin-specific MS rAbs. We examined their immunoreactivity to mouse organotypic cerebellar slices by live binding and evaluated tissue injury in the presence and absence of human complement. Demyelination, glial and neuronal viability, and complement pathway activation were assayed by immunofluorescence microscopy and compared to the effects of an aquaporin-4 water channel (AQP4)-specific rAb derived from a neuromyelitis optica (NMO) patient. MS myelin-specific rAbs bound to discrete surface domains on oligodendrocyte processes and myelinating axons. Myelin specific MS rAbs initiated complement-dependent cytotoxicity to oligodendrocytes and induced rapid demyelination. Demyelination was accompanied by increased microglia activation; however, the morphology and survival of astrocytes, oligodendrocyte progenitors and neurons remained unaffected. In contrast, NMO AQP4-specific rAb initiated complement-dependent astrocyte damage, followed by sequential loss of oligodendrocytes, demyelination, microglia activation and neuronal death. Myelin-specific MS antibodies cause oligodendrocyte loss and demyelination in organotypic cerebellar slices, which are distinct from AQP4 targeted pathology, and display seminal features of active MS lesions. Myelin specific antibodies may play an active role in MS lesion formation through complement-dependent mechanisms. PMID- 28340599 TI - DNA methylation changes at infertility genes in newborn twins conceived by in vitro fertilisation. AB - BACKGROUND: The association of in vitro fertilisation (IVF) and DNA methylation has been studied predominantly at regulatory regions of imprinted genes and at just thousands of the ~28 million CpG sites in the human genome. METHODS: We investigated the links between IVF and DNA methylation patterns in whole cord blood cells (n = 98) and cord blood mononuclear cells (n = 82) from newborn twins using genome-wide methylated DNA immunoprecipitation coupled with deep sequencing. RESULTS: At a false discovery rate (FDR) of 5%, we identified one significant whole blood DNA methylation change linked to conception via IVF, which was located ~3 kb upstream of TNP1, a gene previously linked to male infertility. The 46 most strongly associated signals (FDR of 25%) included a second region in a gene also previously linked to infertility, C9orf3, suggesting that our findings may in part capture the effect of parental subfertility. Using twin modelling, we observed that individual-specific environmental factors appear to be the main overall contributors of methylation variability at the FDR 25% IVF associated differentially methylated regions, although evidence for methylation heritability was also obtained at several of these regions. We replicated previous findings of differential methylation associated with IVF at the H19/IGF2 region in cord blood mononuclear cells, and we validated the signal at C9orf3 in monozygotic twins. We also explored the impact of intracytoplasmic sperm injection on the FDR 25% signals for potential effects specific to male or female infertility factors. CONCLUSIONS: To our knowledge, this is the most comprehensive study of DNA methylation profiles at birth and IVF conception to date, and our results show evidence for epigenetic modifications that may in part reflect parental subfertility. PMID- 28340600 TI - An evaluation of the comparative effectiveness of geriatrician-led comprehensive geriatric assessment for improving patient and healthcare system outcomes for older adults: a protocol for a systematic review and network meta-analysis. AB - BACKGROUND: Comprehensive geriatric assessment (CGA) is an integrated model of care involving a geriatrician and an interdisciplinary team and can prioritize and manage complex health needs of older adults with multimorbidity. CGAs differ across healthcare settings, ranging from shared care conducted in primary care settings to specialized inpatient units in acute care. Models of care involving geriatricians vary across healthcare settings, and it is unclear which CGA model is most effective. Our objective is to conduct a systematic review and network meta-analysis (NMA) to examine the comparative effectiveness of various geriatrician-led CGAs and to identify which models improve patient and healthcare system level outcomes. METHODS: An integrated knowledge translation approach will be used and knowledge users (KUs) including patients, caregivers, geriatricians, and healthcare policymakers will be involved throughout the review. Electronic databases including MEDLINE, EMBASE, Cochrane library, and Ageline will be searched from inception to November 2016 to identify relevant studies. Randomized controlled trials of older adults (>=65 years of age) that examine geriatrician led CGAs compared to any intervention will be included. Primary and secondary outcomes will be selected by KUs to ensure the results are relevant to their decision-making. Two reviewers will independently screen the search results, extract data, and assess risk of bias. Data will be synthesized using an NMA to allow for multiple comparisons using direct (head-to-head) as well as indirect evidence. Interventions will be ranked according to their effectiveness using surface under the cumulative ranking curve (SUCRA). DISCUSSION: As the proportion of older adults grows worldwide, the demand for specialized geriatric services that help manage complex health needs of older adults with multimorbidity will increase in many countries. Results from this systematic review and NMA will enhance decision-making and the efficient allocation of scarce geriatric resources. Moreover, active involvement of KUs throughout the review process will ensure the results are relevant to different levels of decision-making. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014014008. PMID- 28340601 TI - RANTES levels in peripheral blood, CSF and contused brain tissue as a marker for outcome in traumatic brain injury (TBI) patients. AB - BACKGROUND: Traumatic brain injury (TBI) causes activation of several neurochemical and physiological cascades, leading to neurological impairment. We aimed to investigate the level of novel chemokine RANTES in plasma, cerebrospinal fluid (CSF) and contused brain tissue in traumatic brain injury patients and to correlate the expression of this chemokine with the severity of head injury and neurological outcome. METHODS: This longitudinal case control study was performed on 70 TBI patients over a period of 30 months. Glasgow coma scale (GCS) and Glasgow outcome score were used to assess the severity of head injury and clinical outcome. Level of RANTES was quantified in plasma (n = 60), CSF (N = 10) and contused brain tissue (n = 5). Alterations in the plasma levels on 1st and 5th day following TBI were assessed. Patients were categorized as severe (GCS < 8) (SHI), moderate and mild Head injury (GCS > 8-14). 15 healthy volunteers were taken as the control group. RESULTS: The median plasma RANTES levels were 971.3 (88.40-1931.1); 999.2 (31.2-2054.9); 471.8 (370.9-631.9) for SHI, MHI and healthy control respectively and showed statistically significant variation (p = 0.005). There was no statistical difference in the mean 1st and 5th day RANTES levels for the SHI group. However, admission RANTES levels were significantly higher in patients who died than those who survived (p = 0.04). Also, RANTES levels were significantly higher in plasma as compared to contused brain tissue and CSF (p = 0.0001). CONCLUSION: This is the first study of its kind which shows that there is significant correlation of admission RANTES levels and early mortality. Another interesting finding was the significant upregulated in the expression of RANTES in plasma, compared to CSF and contused brain tissue following severe TBI. PMID- 28340602 TI - Clinical application prospect of umbilical cord-derived mesenchymal stem cells on clearance of advanced glycation end products through autophagy on diabetic wound. AB - Nowadays, wound healing delay due to diabetes is considered to be closely related to the accumulation of advanced glycation end products (AGEs). Although mesenchymal stem cells (MSCs) exhibit positive effects on diabetic wound healing, related mechanisms are still not fully elucidated. It has been reported that MSCs can improve the activity of autophagy in injured tissues, thereby playing an important role in wound healing. The autophagy induced by MSCs may be beneficial to diabetic wound healing via removing AGEs, which provide new ideas for clinical treatment of diabetic wounds with the potential of broad application prospects. In this study, the current research situation and application prospect of umbilical cord-derived MSCs on the clearance of AGEs in diabetic wound were reviewed. PMID- 28340603 TI - Blunt cardiac injury due to trauma associated with snowboarding: a case report. AB - BACKGROUND: Cardiac trauma is associated with a much higher mortality rate than injuries to other organ systems, even though cardiac trauma is identified in less than 10% of all trauma admissions. Here we report blunt trauma of the left atrium due to snowboarding trauma. CASE PRESENTATION: A 45-year-old Asian man collided with a tree while he was snowboarding and drinking. He lost consciousness temporarily. An air ambulance was requested and he was transported to an advanced critical care center. On arrival, a pericardial effusion was detected by a focused assessment with sonography for trauma. His presenting electrocardiogram revealed normal sinus rhythm and complete right bundle branch block. Laboratory findings included a white blood cell count of 13.5 * 103/MUl, serum creatine kinase level of 459 IU/l, and creatine kinase-myocardial band level of 185 IU/l. Enhanced computed tomography showed a large pericardial effusion and bleeding from his left adrenal gland. There were no pelvic fractures. A diagnosis of cardiac tamponade due to blunt cardiac injury and left adrenal injury due to blunt trauma was made. Subsequently, emergency thoracic surgery and transcatheter arterial embolization of his left adrenal artery were performed simultaneously. A laceration of the left atrial appendage in the lateral wall of his left ventricle was detected intraoperatively and repaired. His postoperative course progressed favorably, although a pericardial effusion was still detected on chest computed tomography on hospital day 35. His electrocardiogram showed normal sinus rhythm and the complete right bundle branch block pattern changed to a narrow QRS wave pattern. He was discharged on hospital day 40. CONCLUSIONS: The present case report illustrates two points: (1) severe injuries resulted from snowboarding, and (2) complete right bundle branch block was caused by blunt cardiac injury. The present report showed blunt trauma of the left atrium with complete right bundle branch block as an electrocardiogram change due to snowboarding trauma. To detect cardiac trauma in snowboarding accidents, an examination of an electrocardiogram is required in all patients who might have a bruised chest. PMID- 28340604 TI - The conclusion of a comparative efficacy study of fluralaner and sarolaner against the tick Amblyomma americanum on dogs is based on results obtained at study times that are outside the fluralaner label recommendations. AB - The only fluralaner-related conclusion presented in a study comparing the efficacy of fluralaner and sarolaner for control of the tick Amblyomma americanum on dogs is based on study times that are outside the label administration recommendations. Label recommendations for fluralaner treatment of A. americanum on dogs in the USA require re-administration at 56 days. This 56 day re administration was not conducted in the study; therefore, all assessed time points following 56 days post-treatment in the study present comparisons that are not consistent with fluralaner administration recommendations. The only comparative time point assessed prior to 56 days showing a difference between treatments was at 42 days post-administration, a time point when methodological problems were identified by the investigators. Therefore, the only comparative study conclusion that a difference was shown between fluralaner and sarolaner beyond 6 weeks (42 days) after treatment is not based on recommended product use. Furthermore, if the study does not show that there is a difference between the treatments at times when the products are used as recommended, then there also can be no comparative discussion of the risk of tick-borne pathogen transmission risk between treatments. PMID- 28340605 TI - Diagnostic value of urinary tissue inhibitor of metalloproteinase-2 and insulin like growth factor binding protein 7 for acute kidney injury: a meta-analysis. AB - BACKGROUND: Tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7), inducers of G1 cell cycle arrest, are two recently discovered good biomarkers for early diagnosis of acute kidney injury (AKI). To obtain a more robust performance measurement, the present meta analysis was performed, pooling existing studies. METHODS: Literature in the MEDLINE (via PubMed), Ovid, Embase, and Cochrane Library databases was systematically searched from inception to 12 October 2016. Studies that met the set inclusion and exclusion criteria were identified by two independent investigators. The diagnostic value of urinary [TIMP-2] * [IGFBP7] for AKI was evaluated by pooled sensitivity, specificity, likelihood ratio (LR), diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) curve analyses. The causes of heterogeneity were explored by sensitivity and subgroup analyses. RESULTS: A total of nine published and eligible studies assessing 1886 cases were included in this meta-analysis. Early diagnostic value of urinary [TIMP-2] * [IGFBP7] for AKI was assessed using a random-effects model. Pooled sensitivity and specificity with corresponding 95% CIs were 0.83 (95% CI 0.79 0.87, heterogeneity I 2 = 68.8%) and 0.55 (95% CI 0.52-0.57, I 2 = 92.9%), respectively. Pooled positive LR, negative LR, and DOR were 2.37 (95% CI 1.87 2.99, I 2 = 82.6%), 0.30 (95% CI 0.21-0.41, I 2 = 43.4%), and 9.92 (95% CI 6.09 16.18, I 2 = 38.5%), respectively. The AUC estimated by SROC was 0.846 (SE 0.027) with a Q* value of 0.777 (SE 0.026). Sensitivity analysis indicated that one study significantly affected the stability of pooled results. Subgroup analysis showed that population setting and AKI threshold were the key factors causing heterogeneity in pooled sensitivity and specificity. CONCLUSIONS: On the basis of recent evidence, urinary [TIMP-2] * [IGFBP7] is an effective predictive factor of AKI. TRIAL REGISTRATION: PROSPERO registration number: CRD42016051186 . Registered on 10 November 2016. PMID- 28340607 TI - Randomised, double-blind, placebo-controlled trials of non-individualised homeopathic treatment: systematic review and meta-analysis. AB - BACKGROUND: A rigorous systematic review and meta-analysis focused on randomised controlled trials (RCTs) of non-individualised homeopathic treatment has not previously been reported. We tested the null hypothesis that the main outcome of treatment using a non-individualised (standardised) homeopathic medicine is indistinguishable from that of placebo. An additional aim was to quantify any condition-specific effects of non-individualised homeopathic treatment. METHODS: Literature search strategy, data extraction and statistical analysis all followed the methods described in a pre-published protocol. A trial comprised 'reliable evidence' if its risk of bias was low or it was unclear in one specified domain of assessment. 'Effect size' was reported as standardised mean difference (SMD), with arithmetic transformation for dichotomous data carried out as required; a negative SMD indicated an effect favouring homeopathy. RESULTS: Forty-eight different clinical conditions were represented in 75 eligible RCTs. Forty-nine trials were classed as 'high risk of bias' and 23 as 'uncertain risk of bias'; the remaining three, clinically heterogeneous, trials displayed sufficiently low risk of bias to be designated reliable evidence. Fifty-four trials had extractable data: pooled SMD was -0.33 (95% confidence interval (CI) -0.44, 0.21), which was attenuated to -0.16 (95% CI -0.31, -0.02) after adjustment for publication bias. The three trials with reliable evidence yielded a non significant pooled SMD: -0.18 (95% CI -0.46, 0.09). There was no single clinical condition for which meta-analysis included reliable evidence. CONCLUSIONS: The quality of the body of evidence is low. A meta-analysis of all extractable data leads to rejection of our null hypothesis, but analysis of a small sub-group of reliable evidence does not support that rejection. Reliable evidence is lacking in condition-specific meta-analyses, precluding relevant conclusions. Better designed and more rigorous RCTs are needed in order to develop an evidence base that can decisively provide reliable effect estimates of non-individualised homeopathic treatment. PMID- 28340608 TI - Molecular evidence of Rickettsia spp. in ixodid ticks and rodents in suburban, natural and rural habitats in Slovakia. AB - BACKGROUND: Natural foci of tick-borne spotted fever group (SFG) rickettsiae of public health concern have been found in Slovakia, but the role of rodents in their circulation is unclear. Ticks (Ixodes ricinus, Ixodes trianguliceps, Dermacentor marginatus, Dermacentor reticulatus, Haemaphysalis concinna and Haemaphysalis inermis) and tissues of rodents (Apodemus flavicollis, Apodemus sylvaticus, Myodes glareolus, Microtus arvalis, Microtus subterraneus and Micromys minutus) were examined for the presence of SFG rickettsiae and Coxiella burnetii by molecular methods. Suburban, natural and rural habitats were monitored to acquire information on the role of ticks and rodents in the agents' maintenance in various habitat types of Slovakia. RESULTS: The overall prevalence of rickettsial infection in questing I. ricinus and D. marginatus was 6.6% and 21.4%, respectively. Rickettsia helvetica, R. monacensis and non-identified rickettsial species were detected in I. ricinus, whereas R. slovaca and R. raoultii were identified in D. marginatus. Rickettsia spp.-infected I. ricinus occurred during the whole tick questing period. Rickettsia helvetica dominated (80.5%) followed by R. monacensis (6.5%). The species were present in all studied habitats. Rickettsia slovaca (66.7%) and R. raoultii (33.3%) were identified in D. marginatus from the rural habitat. Apodemus flavicollis was the most infested rodent species with I. ricinus, but My. glareolus carried the highest proportion of Rickettsia-positive I. ricinus larvae. Only 0.5% of rodents (A. flavicollis) and 5.2% of engorged I. ricinus removed from My. glareolus, A. flavicollis and M. arvalis were R. helvetica- and R. monacensis-positive. Coxiella burnetii was not detected in any of the tested samples. We hypothesize that rodents could play a role as carriers of infected ticks and contribute to the maintenance of rickettsial pathogens in natural foci. CONCLUSIONS: Long-term presence of SFG Rickettsia spp. was confirmed in questing ticks from different habitat types of Slovakia. The results suggest a human risk for infection with the pathogenic R. helvetica, R. monacensis, R. slovaca and R. raoultii. PMID- 28340606 TI - Validating a self-report measure of HIV viral suppression: an analysis of linked questionnaire and clinical data from the Canadian HIV Women's Sexual and Reproductive Health Cohort Study. AB - BACKGROUND: We assessed the validity of a self-report measure of undetectable viral load (VL) among women with HIV in British Columbia (BC), Canada. Questionnaire data from the Canadian HIV Women's Sexual and Reproductive Health Cohort Study was linked with population-based clinical data from the BC Centre for Excellence in HIV/AIDS. Self-reported undetectable VL was assessed by the question: "What was your most recent VL, undetectable (i.e. <50 copies/mL) or detectable (i.e. >=50 copies/mL)?" Laboratory measurements of VL <50 copies/mL (closest to/before study visit) were the criterion for validity analyses. We measured positive and negative predictive values (PPV, NPV) and likelihood ratios (LR+, LR-). RESULTS: Of 356 participants, 99% were linked to clinical data. Those unlinked (n = 1), missing self-report VL (n = 18), or missing self-report and laboratory VL (n = 1) were excluded. Among the remaining 336: median age was 44 (IQR 37-51); 96% identified as cis-gender; 84% identified as heterosexual; and 45% identified as Indigenous, 40% White, 8% African, Caribbean, or Black, and 8% other/multiple ethnicities. Overall, 85% self-reported having an undetectable VL while 82% had clinical data indicating viral suppression. The PPV was 93.7 (95% CI 90.2-96.2) indicating that 94% of women who self-reported being undetectable truly were. The NPV was 80.4 (95% CI 66.9-90.2). LR+ was 3.2 (2.1-4.6) and LR- was 0.05 (0.03-0.10). CONCLUSIONS: Our self-report measure assessing undetectable VL strongly predicted true viral suppression among Canadian women with HIV. This measure can be used in research settings without laboratory data in regions with high rates of VL testing and suppression. PMID- 28340609 TI - A systematic review of screening instruments for depression for use in antenatal services in low resource settings. AB - BACKGROUND: In low resource settings, short, valid and reliable instruments with good high sensitivity and specificity are essential for the screening of depression in antenatal care. A review of published evidence on screening instruments for depression for use in antenatal services in low resource settings was conducted. The aim of this review was to appraise the best available evidence on screening instruments suitable for detecting depression in antenatal care in low resource settings. METHODS: Searching, selection, quality assessment, and data abstraction was done by two reviewers. ScienceDirect, CINAHL, MEDLINE, PubMed, SABINET and PsychARTICLES databases were searched using relevant search terms. Retrieved studies were evaluated for relevancy (whether psychometric data were reported) and quality. Data were synthesised and sensitivity and specificity of instruments were pooled using forest plots. RESULTS: Eleven articles were included in the review. The methodological quality ranged from adequate to excellent. The review found 7 tools with varying levels of accuracy, sensitivity and specificity, including the Edinburgh Postnatal Depression Scale, Beck Depression Index, Centre for Epidemiologic Studies Depression Scale 20, Hamilton Rating Scale for Depression, Hopkins Symptoms Checklist-25, Kessler Psychological Distress Scale and Self-Reporting Questionnaire. The Edinburgh Postnatal Depression Scale was most common and had the highest level of accuracy (AUC = .965) and sensitivity. CONCLUSION: This review suggests that the Edinburgh Postnatal Depression Scale can be a suitable instrument of preference for screening antenatal depression in low resource settings because of the reported level of accuracy, sensitivity and specificity. PROSPERO REGISTRATION: CRD42015020316 . PMID- 28340610 TI - The importance of informational, clinical and personal support in patient experience with total knee replacement: a qualitative investigation. AB - BACKGROUND: Total knee arthroplasty (TKA) is the most frequently performed joint replacement surgery in North America. Patient perspectives on TKA have been investigated in various ways, including finding as many as 20% of TKA patients are dissatisfied with their surgical outcomes. Understanding the patient experience with TKA broadly and in relation to patient satisfaction is a key gap in existing literature. METHODS: We report on the qualitative component of a mixed methods prospective cohort study examining patient experience and satisfaction post-TKA for adults in British Columbia, Canada. Data collection consisted of 45 in-depth interviews about individuals' knee surgery experiences conducted eight months after surgery. Analysis consisted of thematic coding by multiple coders. RESULTS: Participants' descriptions of their TKA experiences were primarily concerned with support, or the provision of aid and assistance. Support was insufficient when their expectations of support were not met; unmet support expectations led to an overall negative TKA experience. Support operated in three key domains: (1) informational support, (2) clinical support, and (3) personal support. Key sources of informational and clinical support included pre optimisation clinics, surgeons, and physiotherapists. Key topics for informational support included pain, pain management, and recovery trajectories. Personal support was provided by family, friends, other TKA patients, employers, and themselves. CONCLUSIONS: Patient needs and expectations for support are shaped both before and after TKA surgery. Patients with an overall positive TKA experience had improvement in their knee pain, stiffness or functioning post-TKA, had their major expectations and needs for support met during their TKA recovery, and believed that any significant future expectations or needs for ongoing support would be adequately met. In contrast, patients with an overall negative TKA experience had at least one major expectation or need for support not met during their TKA recovery, even in cases where they had good TKA outcomes. Suggested interventions to improve the experience of persons receiving TKA include an expanded patient navigator model, revised pre-surgery educational materials, particularly around pain expectations and management, and comprehensive sharing of other patients' TKA experience. PMID- 28340611 TI - An exploratory cross-sectional study on the impact of education on perception of stigma by Chinese patients with schizophrenia. AB - BACKGROUND: Stigma is a major issue across various society and cultures, and few studies focus on the perception of stigma by Chinese patients with schizophrenia. In the current cross-sectional study, we sought to assess the extent of internalized stigma among outpatients with schizophrenia in China and to investigate whether education level correlated with the experience of stigma. METHODS: Outpatients with schizophrenia were evaluated using the brief psychosis rating scale (BPRS), the positive and negative syndrome scale (PANSS), the clinical global impression-severity of illness (CGI-SI) scale and the Stigma Scale for Mental Illness (SSMI 2C). Patients were categorized into the high education and low education group according to their educational levels. RESULTS: One hundred thirty-three subjects were included in the study. Their mean course of illness was 4.32 +/- 6.14 years (range, 1 month to 15 years). Their mean BPRS score was 19.87 +/- 5.46, their mean PANSS score was 44.11 +/- 13.1, and their mean CGI-SI score was 2.22 +/- 0.81. In addition, the mean SSMI 2C score of the high education group (7.15 +/- 0.98) was markedly higher than that of the low education group (5.75 +/- 0.79, P < 0.05). The mean domain I score of the high education group (2.30 +/- 0.76) was comparable to that of the low education group (2.07 +/- 0.78, P > 0.05). The mean domain II score of the high education group (2.42 +/- 0.96) was markedly higher than that of the low education group (2.01 +/ 0.79, P < 0.05). Moreover, the mean domain III score of the high education group (2.43 +/- 0.79) was significantly higher than that of the low education group (1.67 +/- 0.77, P < 0.05). CONCLUSIONS: Education level impacts on the perception of stigma by patients with schizophrenia and more psycho-education should be done to improve patients' knowledge about schizophrenia. PMID- 28340612 TI - The singular epidemiology of HPV infection among French Guianese women with normal cytology. AB - BACKGROUND: In French Guiana, cervical cancer is the second most frequent cancer in females. The objective of the present study was to describe the prevalence of HPV infections in women with normal cervical cytology living in the remote villages of French Guiana. METHODS: Before the study, the study team communicated in the remote villages on the importance of screening. All women from the target population were offered to participate. They signed informed consent during inclusion and then had a concomitant HPV-test and cervical smear. Only women with normal cytology and a good quality smear were analyzed. The detection of HPV-DNA was performed using the GREINER-BIO-ONE kit. RESULTS: Overall, 27.2% of women with normal cervical cytology had a positive HPV-test. There was a U-shaped evolution of prevalence with women over 50 years having the highest HPV prevalence, followed by the 20 to 29 years group. The most prevalent HPV genotypes were HPV 53(3.52%), 68(3.33%), 52(2.59%), 31(2.22%) and 16 (1.85%). The proportion of HPV 16 among HPV-infected women was 6.8%. CONCLUSIONS: HPV prevalence in cytologically normal women was very high. The most prevalent genotypes were very different from what is usually described in the world, and notably in South America. PMID- 28340613 TI - Adherence to and factors associated with self-care behaviours in type 2 diabetes patients in Ghana. AB - BACKGROUND: Previous research has failed to examine more than one self-care behaviour in type 2 diabetes patients in Ghana. The purpose of this study is to investigate adult Ghanaian type 2 diabetes patients' adherence to four self-care activities: diet (general and specific), exercise, self-monitoring of blood glucose (SMBG) and foot care. METHODS: Consenting type 2 diabetes patients attending diabetes outpatient clinic appointments at three hospitals in the Tamale Metropolis of Ghana completed a cross-sectional survey comprising the Summary of Diabetes Self-Care Activities Measure, and questions about demographic characteristics and diabetes history. Height and weight were also measured. Multiple linear regression analyses were conducted to identify the factors associated with adherence to each of the four self-care behaviours. RESULTS: In the last 7 days, participants exercised for a mean (SD) of 4.78 (2.09) days and followed diet, foot care and SMBG for a mean (SD) of 4.40 (1.52), 2.86 (2.16) and 2.15 (0.65) days, respectively. More education was associated with a higher frequency of reported participation in exercise (r = 0.168, p = 0.022), following a healthy diet (r = 0.223, p = 0.002) and foot care (r = 0.153, p = 0.037) in the last 7 days. Males reported performing SMBG (r = 0.198, p = 0.007) more frequently than their female counterparts. CONCLUSION: Adherence to diet, SMBG and checking of feet were relatively low. People with low education and women may need additional support to improve adherence to self-care behaviours in this type 2 diabetes population. PMID- 28340614 TI - Family-focused practice within a recovery framework: practitioners' qualitative perspectives. AB - BACKGROUND: Family-focused practice (FFP) is an effective approach to supporting individuals with mental illness. 'Recovery' is also central to contemporary mental health care. However, there is a dearth of evidence about how the two concepts are related and subsequently implemented in practice. The aim of this study was to explore practitioners' understandings and practices of FFP within a recovery framework. METHODS: Purposive/snowball sampling was used to recruit and conduct qualitative interviews with 11 mental health practitioners in rural Australia. Concurrent sampling and data collection were informed by thematic analysis and continued until data saturation was reached. RESULTS: Participants found it difficult to articulate their understandings of FFP within a recovery framework. Nonetheless they were able to describe practices that embodied family focused recovery. Barriers to such practices included medical models of care, where there are often a shortage of skilled staff and high demands for care. Stigma (self and from others) and confidentiality were also identified as barriers to involving family members in recovery focused care. CONCLUSIONS: Family-focused recovery care is a priority in many high-income countries. A family-focused recovery framework is needed to assist service planners, practitioners, family members and those with mental health needs and ensure such care is embedded within practice guidelines. PMID- 28340615 TI - Glucocorticoids induce production of reactive oxygen species/reactive nitrogen species and DNA damage through an iNOS mediated pathway in breast cancer. AB - BACKGROUND: Psychological stress increases the circulating levels of the stress hormones cortisol and norepinephrine (NE). Chronic exposure to elevated stress hormones has been linked to a reduced response to chemotherapy through induction of DNA damage. We hypothesize that stress hormone signalling may induce DNA damage through the production of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and interference in DNA repair processes, promoting tumourigenesis. METHODS: Breast cancer cell lines were incubated with physiological levels of cortisol and NE in the presence and absence of receptor antagonists and inducible nitric oxide synthase (iNOS) inhibitors and DNA damage measured using phosphorylated gamma-H2AX. The rate of DNA repair was measured using comet assays and electrochemical sensors were used to detect ROS/RNS in the cell lysates from cells exposed to stress hormones. A syngeneic mouse model was used to assess the presence of iNOS in mammary tumours in stressed versus control animals and expression of iNOS was examined using western blotting and qRT-PCR. RESULTS: Acute exposure to cortisol and NE significantly increased levels of ROS/RNS and DNA damage and this effect was diminished in the presence of receptor antagonists. Cortisol induced DNA damage and the production of RNS was further attenuated in the presence of an iNOS inhibitor. An increase in the expression of iNOS in response to psychological stress was observed in vivo and in cortisol treated cells. Inhibition of glucocorticoid receptor-associated Src kinase also produced a decrease in cortisol-induced RNS. CONCLUSION: These results demonstrate that glucocorticoids may interact with iNOS in a non-genomic manner to produce damaging levels of RNS, thus allowing an insight into the potential mechanisms by which psychological stress may impact breast cancer. PMID- 28340616 TI - Lacking of palladin leads to multiple cellular events changes which contribute to NTD. AB - BACKGROUND: The actin cytoskeleton-associated protein palladin plays an important role in cell motility, morphogenesis and adhesion. In mice, Palladin deficient embryos are lethal before embryonic day (E) 15.5, and exhibit severe cranial neural tube and body wall closure defects. However, the mechanism how palladin regulates the process of cranial neural tube closure (NTC) remains unknown. METHODS: In this paper, we use gene knockout mouse to elucidate the function of palladin in the regulation of NTC process. RESULTS: We initially focuse on the expression pattern of palladin and found that in embryonic brain, palladin is predominantly expressed in the neural folds at E9.5. We further check the major cellular events in the neural epithelium that may contribute to NTC during the early embryogenesis. Palladin deficiency leads to a disturbance of cytoskeleton in the neural tube and the cultured neural progenitors. Furthermore, increased cell proliferation, decreased cell differentiation and diminished apical cell apoptosis of neural epithelium are found in palladin deficient embryos. Cell cycle of neural progenitors in Palladin -/- embryos is much shorter than that in wt ones. Cell adhesion shows a reduction in Palladin -/- neural tubes. CONCLUSIONS: Palladin is expressed with proper spatio-temporal pattern in the neural folds. It plays a crucial role in regulating mouse cranial NTC by modulating cytoskeleton, proliferation, differentiation, apoptosis, and adhesion of neural epithelium. Our findings facilitate further study of the function of palladin and the underlying molecular mechanism involved in NTC. PMID- 28340617 TI - The efficacy of pregabalin for the management of postoperative pain in primary total knee and hip arthroplasty: a meta-analysis. AB - OBJECTIVE: A systematic review of randomized controlled trials (RCTs) was conducted to evaluate the efficacy of pregabalin for the management of postoperative pain in patients undergoing primary total knee arthroplasty (TKA) and primary total hip arthroplasty (THA). METHOD: The PubMed, Embase, Cochrane Central Register of Controlled Trials, and Google Scholar databases were searched for related articles using search strategy. RevMan 5.3 software was selected to conduct the meta-analysis. RESULTS: Seven RCTs were included in our meta analysis. There were significant differences in visual analogue scale (VAS) at 24 and 48 h with rest, knee flexion degree, mean morphine consumption, and postoperative side effects (nausea, vomiting, pruritus, and dizziness) when comparing the pregabalin group to the placebo group after TKA and THA. However, the differences in VAS at 72 h with rest and at 24 h on movement were not significant between the two groups. CONCLUSIONS: Pregabalin was found to improve pain control at 24 and 48 h with rest, reduce morphine consumption, improve the knee flexion degree, decrease the incident rate of nausea, vomiting, and pruritus, and increase the incident rate of dizziness after TKA and THA but could not improve the pain control at 72 h with rest. In summary, the use of pregabalin may be a valuable asset in pain management within the first 48 h after TKA and THA. However, future studies regarding doses and pregabalin medication are required. PMID- 28340618 TI - Are cells from a snowman realistic? Cryopreserved tissues as a source for single cell RNA-sequencing experiments. AB - A recently published study in Genome Biology shows that cells isolated from cryopreserved tissues are a reliable source of genetic material for single-cell RNA-sequencing experiments.Please see related Method article: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1171-9. PMID- 28340619 TI - Operational and implementation research within Global Fund to Fight AIDS, Tuberculosis and Malaria grants: a situation analysis in six countries. AB - BACKGROUND: Operational/implementation research (OR/IR) is a key activity to improve disease control programme performance. We assessed the extent to which malaria and tuberculosis (TB) grants from the Global Fund to Fight AIDS, Tuberculosis and Malaria ("Global Fund") include support for OR/IR, and discuss the implications of the current Global Fund operating mechanisms for OR/IR support. METHODS: The situation analysis focussed on malaria and TB, while HIV was excluded. Stakeholder interviews were conducted at the Global Fund secretariat and in six purposefully selected high disease burden countries, namely the Democratic Republic of the Congo, Ethiopia, India, Indonesia, Myanmar and Zimbabwe. Interviewed in-country stakeholders included the relevant disease control programme managers, project implementation partners, representatives from international organisations with a stake in global health, academic and governmental research institutions, and other relevant individuals such as members of the country coordination mechanism. Additionally, documentation of grants and OR/IR obtained from the Global Fund was reviewed. RESULTS: The Global Fund provides substantial resources for malaria and TB surveys, and supports OR/IR if such support is requested and the application is well justified. We observed considerable variations from one country to another and between programmes with regards to need, demand, absorption capacity and funding for OR/IR related to malaria and TB. Important determinants for the extent of such funding are the involvement of national research coordination bodies, established research agendas and priorities, human and technical research capacity, and involvement of relevant stakeholders in concept note development. Efforts to disseminate OR/IR findings were generally weak, and the Global Fund does not maintain a central OR/IR database. When faced with a need to choose between procurement of commodities for disease control and supporting research, countries tend to seek research funding from other donors. The Global Fund is expected to issue more specific guidance on the conditions under which it supports OR/IR, and to adapt administrative procedures to facilitate research. CONCLUSIONS: The importance of OR/IR for optimising disease control programmes is generally accepted but countries vary in their capacity to demand and implement studies. Countries expect guidance on OR/IR from the Global Fund. Administrative procedures specifically related to the budget planning should be modified to facilitate ad-hoc OR/IR funding. More generally, several countries expressed a need to strengthen capacity for planning, negotiating and implementing research. PMID- 28340620 TI - Stable high-level expression of factor VIII in Chinese hamster ovary cells in improved elongation factor-1 alpha-based system. AB - BACKGROUND: Recombinant factor VIII (FVIII), used for haemophilia A therapy, is one of the most challenging among the therapeutic proteins produced in heterologous expression systems. Deletion variant of FVIII, in which the entire domain B is replaced by a short linker peptide, was approved for medical use. Efficacy and safety of this FVIII deletion variant are similar to full-length FVIII preparations while the level of production in CHO cells is substantially higher. Typical levels of productivity for CHO cell lines producing deletion variant FVIII-BDD SQ, described elsewhere, are 0.5-2 IU/ml, corresponding to the concentration of FVIII of about 0.2 MUg/ml. Using standard vectors based on the cytomegalovirus promoter (CMV) and the dihydrofolate reductase cDNA we have previously obtained the cell line secreting 0.5 IU/ml of FVIII-BDD, which roughly corresponds to the previously published data. RESULTS: An expression system based on CHO genomic sequences including CHO-EEF1A promoter and Epstein-Barr virus terminal repeat fragment allowed us to achieve 80-fold increase in the production level as compared with the conventional expression system based on the CMV promoter. Immediately after the primary selection FVIII -producing cells secreted 5-10 IU/ml of FVIII-BDD, and after multi-stage methotrexate-driven amplification a stable clonal line 11A4H was selected, secreting 39 IU/ml of FVIII-BDD in the simple batch culturing conditions, which considerably exceeds known indicators for industrial producers of this protein. In contrast to other FVIII-BDD producing lines 11A4H accumulates low proportion of the secreted FVIII on the membrane. Its productivity may be further increased approximately two-fold by adding sodium butyrate and butylated hydroxyanisol to the culture medium. A five stage purification process for the factor VIII was employed. It allowed isolation of the intact FVIII-BDD as was confirmed by mass spectrometry. Purified FVIII-BDD has a specific activity of 11,000 IU/mg, similar to known recombinant FVIII drugs. CONCLUSIONS: The recombinant FVIII-BDD was produced in CHO cells without addition of any animal-derived materials, purified and characterized. Novel genetic constructions for the expression of heterologous proteins combined with optimized cultivation method allowed to obtain the secretion level of biologically active recombinant FVIII increased by almost ten times as compared with the previously published analogues. PMID- 28340621 TI - Antibacterial and antibiotic resistance modulatory activities of leaves and bark extracts of Recinodindron heudelotii (Euphorbiaceae) against multidrug-resistant Gram-negative bacteria. AB - BACKGROUND: Recinodindron heudelotii (Euphorbiaceae) is a plant used in Africa, particularly in Cameroon to treat various ailments including bacterial infections. In this study, we evaluated the extracts of the leaves (RHL) and bark (RHB) of R. heudelotii for their antibacterial and antibiotic resistance modulating activities against 29 Gram-negative bacteria, including multidrug resistant (MDR) phenotypes. METHODS: The broth micro-dilution assay was used to evaluate the antibacterial activity, and the antibiotic resistance modulating effects of the plant extracts. RESULTS: RHL displayed the most important spectrum of activity with minimal inhibitory concentrations (MICs) values ranging from 256 to 1024 MUg/mL against 75.86% of the 29 tested bacteria strains while RHB was not active. RHL also showed killing effects with minimal bactericidal concentrations (MBCs) ranging from 256 to 1024 MUg/mL. The activities of tetracycline and kanamycin associated with RHL were improved on 88.89% and 77.78% of the tested MDR bacteria, at MIC/2 at MIC/4 respectively, with 2 to 16-folds decreasing of MIC. This suggests the antibiotic resistance modulating effects of these antibiotics. CONCLUSION: The present study provides data indicating a possible use of the leaves extract of Recinodindron heudelotii alone or in association with common antibiotics in the fight against bacterial infections including those involving MDR bacteria. PMID- 28340622 TI - Anti-plasmodial activity of Norcaesalpin D and extracts of four medicinal plants used traditionally for treatment of malaria. AB - BACKGROUND: Malaria is an old life-threatening parasitic disease that is still affecting many people, mainly children living in sub-Saharan Africa. Availability of effective antimalarial drugs played a significant role in the treatment and control of malaria. However, recent information on the emergence of P. falciparum parasites resistant to one of the artemisinin-based combination therapies suggests the need for discovery of new drug molecules. Therefore, this study aimed to evaluate the antiplasmodial activity of extracts, fractions and isolated compound from medicinal plants traditionally used in the treatment of malaria in Tanzania. METHODS: Dry powdered plant materials were extracted by cold macerations using different solvents. Norcaesalpin D was isolated by column chromatography from dichloromethane root extract of Caesalpinia bonducella and its structure was assigned based on the spectral data. Crude extracts, fractions and isolated compound were evaluated for antiplasmodial activity against chloroquine-sensitive P. falciparum (3D7), chloroquine-resistant P. falciparum (Dd2, K1) and artemisinin-resistant P. falciparum (IPC 5202 Battambang, IPC 4912 Mondolkiri) strains using the parasite lactate dehydrogenase assay. RESULTS: The results indicated that extracts of Erythrina schliebenii, Holarrhena pubescens, Dissotis melleri and C. bonducella exhibited antiplasmodial activity against Dd2 parasites. Ethanolic root extract of E. schliebenii had an IC50 of 1.87 MUg/mL while methanolic and ethanolic root extracts of H. pubescens exhibited an IC50 = 2.05 MUg/mL and IC50 = 2.43 MUg/mL, respectively. Fractions from H. pubescens and C. bonducella roots were found to be highly active against K1, Dd2 and artemisinin-resistant parasites. Norcaesalpin D from C. bonducella root extract was active with IC50 of 0.98, 1.85 and 2.13 MUg/mL against 3D7, Dd2 and IPC 4912 Mondolkiri parasites, respectively. CONCLUSIONS: Antiplasmodial activity of norcaesalpin D and extracts of E. schliebenii, H. pubescens, D. melleri and C. bonducella reported in this study requires further attention for the discovery of antimalarial lead compounds for future drug development. PMID- 28340623 TI - Changes in clinical symptoms and functional disability in patients with coexisting patellofemoral and tibiofemoral osteoarthritis: a 1-year prospective cohort study. AB - BACKGROUND: This 1-year prospective cohort study aimed to compare the changes in clinical symptoms and functional disability between patients with coexisting patellofemoral (PF) and tibiofemoral (TF) osteoarthritis (OA) and those with isolated TFOA. METHODS: Seventy-two patients with medial knee OA were enrolled. Knee pain and functional disability were assessed at baseline and at 1-year follow-up using the Japanese Knee Osteoarthritis Measure (JKOM) and a visual analog scale (VAS). We performed two-way analysis of covariance for the clinical outcome variables to examine, time (baseline and follow-up), group (coexisting PFOA and isolated TFOA), and time-group interaction effects. Furthermore, we conducted post-hoc exploratory analysis to address the possibility that dividing patients according to location of PFOA (i.e., isolated lateral, isolated medial, and mixed [bilateral]) may identify a distinct subgroup with different changes in clinical outcomes at 1-year follow-up. RESULTS: We detected group effects only in scores of the JKOM pain subscale (P = 0.012) and VAS (P = 0.033), adjusted for age, sex, and body mass index. Patients with coexisting PFOA have stable moderate level knee pain and functional disability throughout the year which is significantly worse than that in those with isolated TFOA. Post-hoc subgroup analysis demonstrated that change of knee pain likely varied with location of PFOA. Patients with isolated lateral PFOA had mild/moderate level knee pain, and their VAS scores were likely to improve, whereas those with mixed PFOA exhibited stable to worsening moderate/severe knee pain. CONCLUSIONS: Although we did not detect differences in changes in clinical symptoms and functional disability between patients with coexisting PFOA and those with isolated TFOA, our findings indicate that patients with coexisting PFOA had worse clinical symptoms and functional disability than those with isolated TFOA. The results of the exploratory analysis suggested that patients with coexisting PFOA might have heterogeneous clinical outcomes, and presence of mixed PFOA might be an indicator of severe clinical knee OA. PMID- 28340624 TI - MeDeCom: discovery and quantification of latent components of heterogeneous methylomes. AB - It is important for large-scale epigenomic studies to determine and explore the nature of hidden confounding variation, most importantly cell composition. We developed MeDeCom as a novel reference-free computational framework that allows the decomposition of complex DNA methylomes into latent methylation components and their proportions in each sample. MeDeCom is based on constrained non negative matrix factorization with a new biologically motivated regularization function. It accurately recovers cell-type-specific latent methylation components and their proportions. MeDeCom is a new unsupervised tool for the exploratory study of the major sources of methylation variation, which should lead to a deeper understanding and better biological interpretation. PMID- 28340625 TI - Habit training versus habit training with direct visual biofeedback in adults with chronic constipation: study protocol for a randomised controlled trial. AB - BACKGROUND: Constipation affects up to 20% of adults. Chronic constipation (CC) affects 1-2% of adults. Patient dissatisfaction is high; nearly 80% feel that laxative therapy is unsatisfactory and symptoms have significant impact on quality of life. There is uncertainty about the value of specialist investigations and whether equipment-intensive therapies using biofeedback confer additional benefit when compared with specialist conservative advice. METHODS/DESIGN: A three-arm, parallel-group, multicentre randomised controlled trial. OBJECTIVES: to determine whether standardised specialist-led habit training plus pelvic floor retraining using computerised biofeedback is more clinically effective than standardised specialist-led habit training alone; to determine whether outcomes are improved by stratification based on prior investigation of anorectal and colonic pathophysiology. Primary outcome measure is response to treatment, defined as a 0.4-point (10% of scale) or greater reduction in Patient Assessment of Constipation-Quality of Life (PAC-QOL) score 6 months after the end of treatment. Other outcomes up to 12 months include symptoms, quality of life, health economics, psychological health and qualitative experience. HYPOTHESES: (1) habit training (HT) with computer-assisted direct visual biofeedback (HTBF) results in an average reduction in PAC-QOL score of 0.4 points at 6 months compared to HT alone in unselected adults with CC, (2) stratification to either HT or HTBF informed by pathophysiological investigation (INVEST) results in an average 0.4-point reduction in PAC-QOL score at 6 months compared with treatment not directed by investigations (No-INVEST). Inclusion: chronic constipation in adults (aged 18-70 years) defined by self-reported symptom duration of more than 6 months; failure of previous laxatives or prokinetics and diet and lifestyle modifications. Consenting participants (n = 394) will be randomised to one of three arms in an allocation ratio of 3:3:2: [1] habit training, [2] habit training and biofeedback or [3] investigation-led allocation to one of these arms. Analysis will be on an intention-to-treat basis. DISCUSSION: This trial has the potential to answer some of the major outstanding questions in the management of chronic constipation, including whether costly invasive tests are warranted and whether computer-assisted direct visual biofeedback confers additional benefit to well-managed specialist advice alone. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number: ISRCTN11791740. Registered on 16 July 2015. PMID- 28340628 TI - Auf dem Weg zu einer okologischen Abfallwirtschaft Auf dem Weg zu einer okologischen Abfallwirtschaft. PMID- 28340629 TI - Ruckgewinnung von CKW aus Destillationsruckstanden Ruckgewinnung von CKW aus Destillationsruckstanden. PMID- 28340630 TI - Umdenken in der Abfallwirtschaft: Volkswirtschaftliche Aspekte des Materialrecycling Umdenken in der Abfallwirtschaft: Volkswirtschaftliche Aspekte des Materialrecycling. PMID- 28340627 TI - The contribution of dietary restriction to extended longevity in the malaria vector Anopheles coluzzii. AB - BACKGROUND: Variation in longevity has long been of interest in vector biology because of its implication in disease transmission through vectorial capacity. Recent studies suggest that Anopheles coluzzii adults persist during the ~7 month dry season via aestivation. Recently there has been a growing body of evidence linking dietary restriction and low ratio of dietary protein to carbohydrate with extended longevity of animals. Here, we evaluated the effects of dietary restriction and the protein : carbohydrate ratio on longevity of An. coluzzii. RESULTS: In our experiment, we combined dietary regimes with temperature and relative humidity to assess their effects on An. coluzzii longevity, in an attempt to simulate aestivation under laboratory conditions. Our results showed significant effects of both the physical and the dietary variables on longevity, but that diet regimen had a considerably greater effect than those of the physical conditions. Higher temperature and lower humidity reduced longevity. At 22 degrees C dietary protein (blood) shortened longevity when sugar was not restricted (RH = 85%), but extended longevity when sugar was restricted (RH = 50%). CONCLUSIONS: Dietary restriction extended longevity in accord with predictions, but protein : carbohydrate ratio had a negligible effect. We identified conditions that significantly extend longevity in malaria vectors, however, the extent of increase in longevity was insufficient to simulate aestivation. PMID- 28340631 TI - Behandlung der gasformigen Abgange Sondermulldeponie Kolliken Behandlung der gasformigen Abgange Sondermulldeponie Kolliken. PMID- 28340632 TI - Abfallprobleme bei Sandoz Abfallprobleme bei Sandoz. PMID- 28340626 TI - Decision making for breast cancer prevention among women at elevated risk. AB - Several medical management approaches have been shown to be effective in preventing breast cancer and detecting it early among women at elevated risk: 1) prophylactic mastectomy; 2) prophylactic oophorectomy; 3) chemoprevention; and 4) enhanced screening routines. To varying extents, however, these approaches are substantially underused relative to clinical practice recommendations. This article reviews the existing research on the uptake of these prevention approaches, the characteristics of women who are likely to use various methods, and the decision-making processes that underlie the differing choices of women. It also highlights important areas for future research, detailing the types of studies that are particularly needed in four key areas: documenting women's perspectives on their own perceptions of risk and prevention decisions; explicit comparisons of available prevention pathways and their likely health effects; the psychological, interpersonal, and social processes of prevention decision making; and the dynamics of subgroup variation. Ultimately, this research could support the development of interventions that more fully empower women to make informed and values-consistent decisions, and to move towards favorable health outcomes. PMID- 28340633 TI - PLASMOX(r), ein Plasma-Ultrahochtemperaturverfahren zur umweltgerechten Entsorgung von Sonderabfallen, mit Stoff- und Energieruckgewinnungs-potentialen, sowie endlagerfahiger Schlackenproduktion PMID- 28340635 TI - Abfallminderung, ein zentrales Anliegen der chemischen Industrie Abfallminderung, ein zentrales Anliegen der chemischen Industrie. PMID- 28340634 TI - Methodik und Problemlosungskonzepte der Bodensanierung Methodik und Problemlosungskonzepte der Bodensanierung. PMID- 28340636 TI - 1st Entsorgung Aufgabe des Herstellers? 1st Entsorgung Aufgabe des Herstellers? PMID- 28340638 TI - Abfall, Materie am falschen Ort Abfall, Materie am falschen Ort. PMID- 28340637 TI - Reststoffentsorgung bei Kehrichtverbrennungsanlagen Reststoffentsorgung bei Kehrichtverbrennungsanlagen. PMID- 28340639 TI - Control of Metal-Catalyzed Reactions by Organic Ligands: From Corrinoid and Porphinoid Metal Complexes to Tailor-Made Catalysts for Asymmetric Synthesis. AB - Corrinoid and porphinoid metal complexes playa fundamental role in nature as catalysts for a variety of biochemical transformations. The properties of the metal ion in these complexes are strongly influenced by the macrocyclic ligand. In this way, the reactivity of the metal complex is adjusted to the specific requirements of enzymatic catalysis. This is illustrated in the first part of this article, which is centered on the structure and properties of coenzyme F430, a hydroporphinoid nickel complex involved in the methane-producing step of the energy metabolism of methanogenic bacteria. A different group of metal complexes, which exemplify the concept of ligand-based selectivity control, is discussed in the second part, summarizing our work on enantioselective catalysis. Inspired by the structure of corrinoid and hydroporphinoid compounds, we have developed a route to chiral C2-symmetric semicorrins, a particular class of bidentate nitrogen ligands specifically designed for the stereocontrol of metal-catalyzed reactions. Semicorrins were found to induce remarkable enantioselectivities in the cobalt-catalyzed conjugate reduction of alpha,beta-unsaturated carboxylic esters and amides and in the copper-catalyzed cyclopropanation of olefins with diazo compounds. PMID- 28340640 TI - New Solid-State Contact for lon-Selective Liquid Membrane Electrodes. AB - A new kind of solid-state contact for ion-selective electrodes based on solvent polymeric membranes is described. These electrodes show similar electrochemical behaviour to conventional ion-selective membranes in contact with an internal filling solution. They exhibit no significant interference with oxygen, nitrogen or carbon dioxide. PMID- 28340642 TI - Otto Isler: On the Occasion of his 80th Birthday. PMID- 28340641 TI - Herstellung von (S)-4-Methyloxetan-2-on(beta-Butyrolacton) durch Lactonisierung von (R)-3-Hydroxy-buttersaure mit Orthoessigsaure-triethylester AB - The readily available (R)-3-hydroxybutanoic acid (1) was treated with triethyl orthoacetate, with azeotropic removal of ethanol, to yield (6R)-2-ethoxy-2,6 dimethyl-1,3-dioxan-4-one (3a). Pyrolysis of 3a led to the beta-Lactone of (S)-3 hydroxybutanoic acid and other products. The influence of pressure, temperature, solvents, and some additives has been tested. A procedure for preparing (S)-4 methyloxetan-2-one (4) in a 0.25-mol scale is described. PMID- 28340643 TI - Markt: Apparate, Chemikalien und Dienstleistungen Markt: Apparate, Chemikalien und Dienstleistungen. PMID- 28340644 TI - Sweet success: will sugar taxes improve health? PMID- 28340645 TI - Transgender hormone therapy: understanding international variation in practice. PMID- 28340646 TI - Essential Anatomy and Evaluation for Functional Rhinoplasty. AB - The nose, a prominent facial feature in defining facial beauty, is responsible for the fundamental physiologic functions of heating, humidifying, and filtering inspired air. When the normal balance of laminar and turbulent airflow become disturbed due to anatomic abnormalities, nasal obstruction may result. To successfully restore these basic physiologic functions, the surgeon must have a detailed understanding of the nasal anatomy and be able to successfully identify the specific cause of the nasal obstruction. This article discusses the fundamental surgical anatomy and the various diagnostic techniques and instruments at the surgeon's disposal. PMID- 28340647 TI - Septoplasty: Basic and Advanced Techniques. AB - Nasal septal deviation is a prevalent problem that can have significant quality of life ramifications. Septoplasty is commonly performed to provide qualitative and quantitative benefit to those with nasal obstruction owing to septal deviation. Although a standard, basic technique is often adequate for individuals with mild to moderate mid to posterior septal deviation, unique challenges arise with caudal septal deviation. Herein, multiple strategies that attempt to address anterior septal deviation are discussed. Anterior septal reconstruction has been shown to be a safe and effective means by which to address severe caudal septal deviation and long-term reduction in preoperative symptoms. PMID- 28340648 TI - The Inferior Turbinate in Rhinoplasty. AB - There is controversy regarding optimum treatment of the hypertrophied inferior turbinate. Patients undergoing rhinoplasty will likely need treatment of bony hypertrophy as well as possibly soft tissue hypertrophy. Although inferior turbinate hypertrophy is a heterogeneous entity, future studies should standardize outcome measures and compare treatment methods with rigorous clinical trials. PMID- 28340649 TI - The External Nasal Valve. AB - The external nasal valve is a complex entity comprised of multiple structures and tissue types. As such, there is no single operation that can address all problems of the external valve. This article reviews the relevant anatomy, pathologic conditions, and treatments for external nasal valve dysfunction, including a detailed review of the nasal muscles and their contribution to external nasal valve patency. Surgical and nonsurgical options for treatment and the evidence supporting the importance of proper external nasal valve function on quality-of life measures are discussed. PMID- 28340650 TI - Functional Rhinoplasty. AB - Understanding nasal anatomy and physiology are the most important points for successful functional rhinoplasty. Anatomic structures playing major roles in nasal breathing functions include the septum, and internal and external nasal valves, so physical examination of these regions is essential. Planning for functional rhinoplasty involves the identification of the sites of nasal airway obstruction or old trauma, and addressing those regions during the operation with a number of different techniques that have been described. PMID- 28340651 TI - Osteotomies Demystified. AB - Osteotomies are critical techniques in rhinoplasty. There are a variety of approaches, trajectories, and tools used with no widely standardized classification or nomenclature. Percutaneous osteotomies are gaining in popularity, and picture framing the nasomaxillary bone is crucial for predictable fracture and reproducible results. This is best accomplished with medial, lateral, and transverse osteotomies. Intermediate osteotomies are used less frequently, but provide more mobility. With a detailed understanding of anatomy and a thorough approach to nasal osteotomies, the contour and function of the bony vault can be reshaped with a successful outcome for both the surgeon and patient. PMID- 28340652 TI - Management of Pediatric Nasal Surgery (Rhinoplasty). AB - Nasal surgery in children, most often performed after trauma, can be performed safely in selected patients with articulate, deliberate, and conscientious operative plan. All nasal surgery in children seeks to avoid disruption of the growth centers, preserving and optimizing nasal growth while improving the form and function of the nose. A solid appreciation of long-term outcomes and effects on growth remain elusive. PMID- 28340654 TI - The Saddle Deformity: Camouflage and Reconstruction. AB - This article presents a comprehensive review of past and present modalities in the surgical management of saddle nose deformities. Various surgical techniques, including allograft materials, are systematically reviewed. The senior author's surgical experience and current management approach are highlighted. PMID- 28340653 TI - Cleft Septorhinoplasty: Form and Function. AB - Nasal deformity associated with typical cleft lip can cause aesthetic and functional issues that are difficult to address. The degree of secondary nasal deformity is based on the extent of the original cleft deformity, growth over time, and any prior surgical correction to the nose or lip. Repair and reconstruction of these deformities require comprehensive understanding of embryologic growth, the cleft anatomy, as well as meticulous surgical technique and using a spectrum of structural grafting. This article reviews cleft lip nasal deformity, presurgical care, primary cleft rhinoplasty, and definitive cleft septorhinoplasty with a focus on aesthetics and function. PMID- 28340655 TI - Revision Functional Surgery: Salvaging Function. AB - Reduction rhinoplasty techniques include maneuvers that weaken the nasal osseocartilaginous framework. The structurally compromised anatomy remaining after reductive surgery may be left with inadequate strength to withstand postoperative contractile forces. Significant aesthetic and functional deformities requiring revision rhinoplasty may develop. This article reviews common causes of nasal obstruction after primary rhinoplasty. The discussion of etiology is based on both the anatomic description of nasal subsites (middle vault and lateral walls) as well as an explanation of why certain techniques lead to functional problems in these areas. Revision rhinoplasty techniques for correcting these problems are discussed in detail. PMID- 28340656 TI - Advances in Technology for Functional Rhinoplasty: The Next Frontier. AB - Advances in computer modeling and simulation technologies have the potential to provide facial plastic surgeons with information and tools that can aid in patient-specific surgical planning for rhinoplasty. Finite element modeling and computational fluid dynamics are modeling technologies that have been applied to the nose to study structural biomechanics and nasal airflow. Combining these technologies with patient-specific imaging data and symptom measures has the potential to alter the future landscape of nasal surgery. PMID- 28340657 TI - Crafting a Functional Nose. PMID- 28340658 TI - A Global View of Digital Replantation and Revascularization. AB - Survival rates of digital replantation vary in different regions and countries, and Asian surgeons see more challenging cases and have developed some unique methods. Replantation of multiple digits in one or both hands can follow a structure-by-structure method or a digit-by-digit method. For replanting all 10 digits, 3 or 4 teams should be organized. Flow-through flaps, often venous flaps, can be taken from the distal forearm or lower extremity to repair defects of soft tissues and arteries. A pedicled digital artery flap from the adjacent digit can also repair tissue defects and supply blood to the replanted digit. PMID- 28340659 TI - Exploring New Frontiers of Microsurgery: From Anatomy to Clinical Methods. AB - This article presents the authors' understanding and experience concerning anatomic studies and clinical methods in microsurgical hand reconstruction. The 4 parts of this article include anatomic study of the hand for developing new flaps; application of miniflaps from the hand, including clinical experience with 8 unique flaps in the hand; anatomic and clinical considerations concerning several flaps from other parts of the human body; And our experience with vascularized free toe joint transfer. PMID- 28340660 TI - Severe Crush Injury to the Forearm and Hand: The Role of Microsurgery. AB - The main goals of treating severe crush injuries are debriding away devitalized tissue and filling any resultant dead space with vascularized tissue. In the authors' experience, the most ideal methods for soft tissue coverage in treating crush injuries are the iliac flap, the adipofascial lateral arm flap, and the gracilis flap. Accompanying bone defects respond very well to free corticoperiosteal flaps. Digital defects often require the use of complete or subtotal toe transfer to avoid amputation and restore function to the hand. PMID- 28340661 TI - Medial Femoral Trochlea Osteochondral Flap: Applications for Scaphoid and Lunate Reconstruction. AB - Vascularized osteochondral flaps are a new technique described for the reconstruction of challenging articular defects of the carpus. The medial femoral trochlea osteochondral flap is supplied by the descending geniculate artery. This osteochondral flap has shown promise in the treatment of recalcitrant scaphoid proximal pole nonunions and advanced avascular necrosis of the lunate. The anatomy, surgical technique, and results are discussed, with clinical cases provided. PMID- 28340662 TI - Vascularized Small-Bone Transfers for Fracture Nonunion and Bony Defects. AB - Vascularized small-bone grafting is an efficient and often necessary surgical approach for nonunion or necrosis of several bones in particular sites of the body, including scaphoid, lunate, distal ulna, and clavicle. The medial femoral condyle is an excellent graft source that can be used in treating scaphoid, ulna, clavicle, or lower-extremity bone defects, including nonunion. Vascularized bone grafting to the small bones, particularly involving reconstruction of damaged cartilage surfaces, should enhance subchondral vascular supply and help prevent cartilage regeneration. Vascularized osteoperiosteal and corticoperiosteal flaps are useful for treating nonunion of long bones. PMID- 28340663 TI - Compound or Specially Designed Flaps in the Lower Extremities. AB - Novel and combined tissue transfers from the lower extremity provide new tools to combat soft tissue defects of the hand, foot, and ankle, or fracture nonunion. Flaps can be designed for special purposes, such as providing a gliding bed for a grafted or repaired tendon or for thumb or finger reconstruction. Propeller flaps can cover soft tissue defects of the leg and foot. In repairing severe bone and soft tissue defects of the lower extremity, combined approaches, including external fixators, one-stage vascularized bone grafting, and skin or muscle flap coverage of the traumatized leg and foot, have become popular. PMID- 28340664 TI - Complex Microsurgical Reconstruction After Tumor Resection in the Trunk and Extremities. AB - Reconstruction of soft tissue defects following tumor ablation procedures in the trunk and extremities can challenge the microsurgeon. The goal is not just to provide adequate soft tissue coverage but also to restore form and function and minimize donor site morbidity. Although the principles of the reconstructive ladder still apply in the trunk and extremities, free tissue transfer is used in many cases to optimally restore form and function. Microsurgery has changed the practice in soft tissue tumors, and amputation is less frequently necessary. PMID- 28340665 TI - Pediatric Microsurgery: A Global Overview. AB - As microsurgical expertise has improved, allowing for the safe transfer of smaller and more refined flaps, free tissue transfer has continued to gain popularity for the management of pediatric soft tissue and bony defects. For the past 2 decades pediatric microsurgery has been shown to be technically feasible and reliable. The major advantage of free tissue transfer in children is the ability to reconstruct defects in a single stage, avoiding the historic treatments of skin grafting, tissue expansion, and pedicled flaps. This article reviews the present state-of-the-art in pediatric microsurgery. PMID- 28340666 TI - Innovations and Future Directions in Head and Neck Microsurgical Reconstruction. AB - Head and neck reconstructive microsurgery is constantly innovating because of a combination of multidisciplinary advances. This article examines recent innovations that have affected the field as well as presenting research leading to future advancement. Innovations include the use of virtual surgical planning and three-dimensional printing in craniofacial reconstruction, advances in intraoperative navigation and imaging, as well as postoperative monitoring, development of minimally invasive reconstructive microsurgery techniques, integration of regenerative medicine and stem cell biology with reconstruction, and the dramatic advancement of face transplant. PMID- 28340667 TI - Microsurgical Tissue Transfer in Breast Reconstruction. AB - Autologous breast reconstructions have grown in popularity because of their durability, aesthetic outcomes, symmetry, increase in external beam radiotherapy use, and potential aesthetic enhancement at the donor site. Increasing patient expectations for predictable high aesthetic outcomes with minimal complications or need for further procedures has been met by refinement in the use of flaps. The authors' microsurgical breast reconstruction center aims to provide this while delivering efficient service. The deep inferior epigastric flaps form 85% and transverse upper gracilis and profunda artery perforator flaps account for 10%; lumbar artery perforator flaps are a new addition to the authors' armamentarium. PMID- 28340668 TI - Anastomosis of the Superficial Inferior Epigastric Vein to the Internal Mammary Vein to Augment Deep Inferior Artery Perforator Flaps. AB - Use of the retrograde limb of the internal mammary vein has been described previously as a lifeboat for venous congestion but not prophylactically. Maximizing the length of the deep inferior artery perforator (DIEP) flap pedicle, identifying and dissecting the superficial inferior epigastric vein proximally in every patient, and taking advantage of the retrograde internal mammary vein are all technical details that facilitate the additional venous anastomosis and flap inset. Performing a second venous anastomosis routinely using the superficial inferior epigastric vein to the retrograde internal mammary vein helps with flap inset. PMID- 28340669 TI - Maximizing the Utility of the Pedicled Anterolateral Thigh Flap for Locoregional Reconstruction: Technical Pearls and Pitfalls. AB - The pedicled anterolateral thigh (PALT) flap is an underutilized flap for locoregional reconstruction largely because methods to maximize its reach are neither universally implemented nor fully understood. In addition, most of the available literature has focused on the utility of the free anterolateral thigh flap with less emphasis on the PALT flap. Moreover, flap design concepts to maximize its utility and reach and optimize outcomes have not been comprehensively described. In an effort to address this knowledge gap, the authors sought to review their institution's experience with the PALT flap for locoregional reconstruction. PMID- 28340670 TI - Keystone and Pedicle Perforator Flaps in Reconstructive Surgery: New Modifications and Applications. AB - Pedicle perforator flaps and keystone perforator island flaps are additional tools for reconstructive surgeons. Advances in understanding of vascular anatomy, the dynamic nature of perforator perfusion, inter-perforator flow and the hot spot principle have led to reconstructive techniques that allow innovative autologous tissue transfer while limiting donor site morbidity. Further modifications of the pedicle perforator flap have led to a multitude of freestyle pedicle perforator flap options, as well as freestyle free flaps for soft tissue reconstruction. Modifications in the keystone perforator island flap have increased the degrees of freedom for soft tissue coverage of large defects, with reliable and aesthetically pleasing results. PMID- 28340671 TI - Unique Techniques or Approaches in Microvascular and Microlymphatic Surgery. AB - Several methods can be used for identifying tissues for transfer in donor-site depleted patients. A fillet flap can be temporarily stored in other parts of the body and transferred back to the site of tissue defect, including covering the amputated stump of the lower extremity. Human arm transplant is rare and has some unique concerns for the surgery and postsurgical treatment. Cosmetics of the narrow neck of transferred second toes can be improved with insertion of a flap. Lymphedema of the breast after cancer treatment can be diagnosed with several currently available imaging techniques and treated surgically with lymphaticovenous anastomosis. PMID- 28340672 TI - New Frontiers in Robotic-Assisted Microsurgical Reconstruction. AB - Robotic surgery has revolutionized minimally invasive surgery. Owing to its unique features and key advantages, robotic surgery is being used for complex cases across surgical specialties. It has been introduced into reconstructive surgery, and is being applied in microsurgery. Robotic surgery combines properties of conventional microsurgery, endoscopic surgery, and telesurgery. It holds great promise in expanding the boundaries of reconstructive microsurgery. However, there are constraints that limit its widespread use. We present the different clinical applications of robotic microsurgery, highlighting its advantages over conventional microsurgery, and outlining the main limitations that might prevent its widespread use. PMID- 28340673 TI - The Advent of Vascularized Composite Allotransplantation. AB - Modern microsurgical techniques have made possible a broad spectrum of novel means for the reconstruction of complex bone and soft tissue defects. These techniques, in combination with developments in transplant immunology, have led to successful hand and facial allotransplantation and achievement of the highest rung in the reconstructive ladder - truly replacing like with like. The utilization of contemporary microsurgical technique in the context of vascularized composite allotransplantation (VCA) (1) permits successful technical execution and feasibility of VCA, (2) facilitates the study of immunologic tolerance in VCA preclinical models, and (3) optimizes functional VCA outcomes. PMID- 28340674 TI - Microsurgery Half a Century After Establishment: Global Perspectives. PMID- 28340675 TI - Development and Historical Evolution Half a Century Ago at the Dawn of Microsurgery. PMID- 28340676 TI - Erratum. PMID- 28340677 TI - Microsurgical Technical Training: Differences Between China and the United States. PMID- 28340678 TI - Biomedical Research as a Team Sport. PMID- 28340680 TI - Heat-Induced Editing of HPV Genes to Clear Mucocutaneous Warts? AB - Hyperthermia increases expression of the antiviral cellular factors APOBEC3A and APOBEC3G and induces G-to-A or C-to-T mutations in human papilloma virus cervical cell lines and genital warts. This unexpected effect of heat treatment correlated with regression of genital warts in a subset of patients, including at distant sites, suggesting that this effect may be mediated in part by antiviral as well as immunological mechanisms. PMID- 28340679 TI - Insights into Pathomechanisms and Treatment Development in Heritable Ectopic Mineralization Disorders: Summary of the PXE International Biennial Research Symposium-2016. AB - Pseudoxanthoma elasticum is a prototype of heritable ectopic mineralization disorders, with phenotypic overlap with generalized arterial calcification of infancy and arterial calcification due to CD73 deficiency. Recent observations have suggested that the reduced inorganic pyrophosphate/phosphate ratio is the cause of soft connective tissue mineralization in these disorders. PXE International, a patient advocacy organization, supports research in part by sponsoring biennial research symposia on these disorders; the latest meeting was held in September 2016 at Thomas Jefferson University, Philadelphia. This report summarizes the progress in pseudoxanthoma elasticum and other ectopic mineralization disorders, as presented in the symposium, with focus on translational aspects of precision medicine toward improved diagnostics and treatment development for these currently intractable disorders. PMID- 28340682 TI - SCFAs Control Skin Immune Responses via Increasing Tregs. AB - We are surrounded by billions of microbes, and our immune system is substantially affected by the commensal bacteria on the surface of our body. Schwarz et al. describe the immune-suppressive effect of sodium butyrate, a bacterial metabolite that is categorized as one of the short-chain fatty acids, during skin inflammatory responses. PMID- 28340681 TI - Seeking Standards for the Detection of Merkel Cell Polyomavirus and its Clinical Significance. AB - Merkel cell carcinoma is a rare skin cancer associated with Merkel cell polyomavirus in most cases. Prior studies associating Merkel cell carcinoma viral status with prognosis have inconsistent findings. Moshiri et al. used multimodal virus detection to determine that the 81% of patients with virus-positive Merkel cell carcinoma tumors had earlier stage disease and better outcomes relative to virus-negative cases. PMID- 28340683 TI - TRPV4 Moves toward Center-Fold in Rosacea Pathogenesis. AB - Mascarenhas et al. report that TRPV4 expression is upregulated in mast cells in response to the proteolytic cathelicidin fragment LL37 in a murine rosacea model and that TRPV4 loss of function attenuates mast cell degranulation. These findings render TRPV4 a translational-medical target in rosacea. However, signaling mechanisms causing increased expression of TRPV4 await elucidation. Moreover, we ask whether TRPV4-mediated Ca++-influx evokes mast cell degranulation. PMID- 28340684 TI - Do the Side Effects of BRAF Inhibitors Mimic RASopathies? AB - Recent advances in targeted anticancer therapies have substantially improved the prognosis of several cancers. Such targeted therapies are not, however, free of side effects, and these side effects are clearly distinct from those induced by classical cytotoxic chemotherapies. This is likely so because targeted therapies are designed to interfere with specific oncogenic signaling pathways rather than to inhibit cell proliferation in general. In fact, interference with specific signaling pathways may lead to effects that mimic those associated with genetic disorders due to alterations in the corresponding signaling pathways. Here, we compare the clinical effects of treatment with BRAF inhibitors with those of genetic RASopathies and find a striking overlap between the inhibitor-induced, iatrogenic dermatoses with the genodermatoses seen in patients with corresponding congenital RASopathies. We hope that such comparisons lead to a better understanding of the side effects of targeted therapies. PMID- 28340685 TI - Research Techniques Made Simple: Experimental Methodology for Single-Cell Mass Cytometry. AB - Growing recognition of the complexity of interactions within cellular systems has fueled the development of mass cytometry. The precision of time-of-flight mass spectrometry combined with the labeling of specific ligands with mass tags enables detection and quantification of more than 40 markers at a single-cell resolution. The 135 available detection channels allow simultaneous study of additional characteristics of complex biological systems across millions of cells. Cutting-edge mass cytometry by time-of-flight (CyTOF) can profoundly affect our knowledge of cell population heterogeneity and hierarchy, cellular state, multiplexed signaling pathways, proteolysis products, and mRNA transcripts. Although CyTOF is currently scarcely used within the field of investigative dermatology, we aim to highlight CyTOF's utility and demystify the technique. CyTOF may, for example, uncover the immunological heterogeneity and differentiation of Langerhans cells, delineate the signaling pathways responsible for each phase of the hair cycle, or elucidate which proteolysis products from keratinocytes promote skin inflammation. However, the success of mass cytometry experiments depends on fully understanding the methods and how to control for variations when making comparisons between samples. Here, we review key experimental methods for CyTOF that enable accurate data acquisition by optimizing signal detection and minimizing background noise and sample-to-sample variation. PMID- 28340688 TI - Rho-associated kinase 1 inhibition is synthetically lethal with von Hippel-Lindau deficiency in clear cell renal cell carcinoma. Thompson JM, Nguyen QH, Singh M, Pavesic MW, Nesterenko I, Nelson LJ, Liao AC, Razorenova OV. PMID- 28340689 TI - Basic/Translational Science Survey Section: Kidney Cancer. PMID- 28340690 TI - Basic/Translational Science Survey: Kidney Cancer. PMID- 28340691 TI - Fabry disease: A fundamental genetic modifier of cardiac function. AB - Fabry disease (FD) is an inherited X-linked metabolic storage disorder triggered by abnormalities in the GLA gene at Xq22, which leads to a deficiency in alpha galactosidase A and massive accumulation of intralysosomal glycosphingolipids. Cardiac complications are very common in FD and are the main cause of late morbidity, as well as early mortality in both hemizygous men and heterozygous women. There is a need for a multidisciplinary approach to evaluation and management of FD patients as there is a wide range of presentation of FD, which varies with mutation and other organ involvement/dysfunction. An overview of common cardiac involvement and clinical characteristics in FD including: left ventricular hypertrophy (LVH), conduction abnormalities and arrhythmias, coronary artery disease and valvular infiltrative myopathy are provided in this review. Current therapeutic approaches such as enzyme replacement therapy as well as the emergence of novel therapeutic options such as gene therapy to optimize disease outcomes in FD patients will be highlighted in this paper. PMID- 28340692 TI - CALR gene mutational profile in myeloproliferative neoplasms with non-mutated JAK2 in Moroccan patients: A case series and germline in-frame deletion. AB - BACKGROUND: The discovery of somatic mutations within the gene encoding calreticulin (CALR) in 2013 represented a major milestone in the molecular diagnosis of BCR-ABL negative myeloproliferative neoplasms (MPN). In fact, exome sequencing revealed that most patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF) lacking JAK2 or MPL mutations, harbor somatic insertion and/or deletion in exon 9 of CALR gene. In this study, we identified the first CALR gene mutational landscape in Moroccan patients with MPN nonmutated for the JAK2 gene. METHODS: We performed Sanger sequencing of exon 9 of CALR gene in blood samples obtained from 33 Moroccan patients with ET or PMF non-mutated for JAK2. RESULTS: Of the 33 patients analyzed, we detected eight distinct variants in 15 patients (45.4%); six indel mutations, five with type 1 recurrent 52bp deletion, four with type 2 recurrent 5bp insertion and one in frame deletion which was found to be a germline variant suggesting a very rare condition in MPN. CONCLUSION: This is the first cohort reported in CALR gene mutation analysis in Morocco. Our results were concordant with studies reported up to date and very encouraging in promoting the molecular diagnosis of myeloproliferative neoplasms in Moroccan patients. Moreover, the presence of a germline in frame deletion in a symptomatic patient should undermine the effectiveness of sizing assays without DNA sequencing in the diagnosis of CALR mutations. PMID- 28340693 TI - Protective effects of bezafibrate against elaidic acid-induced accumulation of lipid droplets in monocytic cells. AB - Some factors related to diet, such as trans fatty acids (TFA), are known to be involved in the progression of atherosclerosis in humans. Thus, the aim of our study was (i) to evaluate the effects of three dietary free fatty acids (FFA) (elaidic (EA), oleic (OA) and palmitic acid (PA)) on U937 human monocytes, and (ii) to study the eventual benefits of bezafibrate (BZF), a pan-agonist for PPAR isoforms (alpha, gamma and delta) in U937 cells treated with FFA. Morphologic and functional changes were investigated by microscopic and flow cytometric methods. Cellular lipid content, lipid droplets and FA composition were identified and studied. All analyses were also realized in association with or without BZF. Contrary to OA and PA, EA slightly induced both propidium iodide-positive cells and mitochondrial depolarization. In addition, in contrast to OA and PA, EA induced only a slight increase in superoxide anion production. However, EA and OA promoted cytoplasmic lipid droplets accumulation. Only EA and OA significantly increased CD36 expression. It is noteworthy that BZF had a more or less pronounced protective effect against EA-, OA- and PA-induced side effects: BZF attenuated the impaired cell viability and inflammatory response, decreased superoxide anion production and prevented the accumulation of neutral and polar lipids. The effects were less pronounced with OA and PA than with EA. Altogether, our data revealed a benefit of BZF on the side effects induced especially with EA. It may thus be of interest in preventing the early stages of atherosclerotic plaque formation. PMID- 28340694 TI - Composition and organization of the pancreatic extracellular matrix by combined methods of immunohistochemistry, proteomics and scanning electron microscopy. AB - The epidemic expansion of diabetes is a major concern of public health. A promising treatment is the transplantation of islets of Langerhans isolated from the whole pancreas but the yields of islets isolation and the rates of successful engraftments still have to be improved to make this therapy effective. The extracellular matrix (ECM) of the pancreatic tissue is partially lost during the isolation process and a comprehensive knowledge of the pancreatic ECM composition and organization could identify targets to improve islets isolation and transplantation or highlight new therapeutics for pancreatic diseases. The organization, composition and three-dimensional architecture of the pancreatic ECM were analysed in mouse and pig by three different techniques. Laminin alpha-4 and beta-2 chains are localized by immunohistochemistry in the exocrine tissue and inside islets of mouse pancreas but not around islets that are surrounded by an ECM made of collagen type IV and type V. Collagen type I, III, and VI were identified by proteomics as specific constituents of the pig pancreatic ECM along with the low-abundance isoforms alpha3(IV) alpha4(IV) alpha5(IV) and alpha1(V) alpha2(V) alpha3(V) of collagen type IV and type V respectively. The three dimensional ECM architecture is analysed on decellularized mouse pancreas by scanning electron microscopy and is organized in honeycomb structures made of thin ECM fibers assembled in thicker bundles. The combination of immunohistochemistry, proteomics and scanning electron microscopy gives complementary perspective on the pancreatic ECM composition and organization. It represents a valuable toolbox for deeper investigations of ECMs and proposes clues in tissue engineering of the pancreas. PMID- 28340695 TI - Long-term follow-up after autologous adipose-derived stromal vascular fraction injection into fingers in systemic sclerosis patients. AB - INTRODUCTION: Hand involvement confers a substantial handicap in work and daily activities in patients with Systemic sclerosis (SSc). Autologous adipose-derived stromal vascular fraction is as an easily accessible source of cells with regenerative effects. We previously performed a phase I open-label clinical trial (NTC01813279) assessing the safety of subcutaneous injection of autologous adipose-derived stromal vascular fraction. Six and 12-month data have been reported. As patients were followed in our medical centre, we report their longer term outcome beyond the end of the trial. PATIENTS AND METHOD: Twelve females, mean age 54.5+/-10.3 years, initially enrolled in the clinical trial were assessed during a scheduled medical care, which took place between 22 and 30months after treatment. RESULTS: Multiple patient-reported outcomes showed sustained improvement, in comparison with the assessment performed just before surgery: 62.5% in the Cochin Hand Function Scale, 51.1% in the Scleroderma Health Assessment Questionnaire, 33.1% in hand pain, and 88.3% in the Raynaud Condition Score. A decrease in the number of digital ulcers number was noted. Mobility, strength and fibrosis of the hand also showed improvement. None of the 8 patients who had previously received iloprost infusion required new infusion. CONCLUSION: Despite the limits of an open label study, the data are in favour of the long term safety of the adipose-derived stromal vascular fraction injection. Two randomized double blind, placebo-controlled trials of this therapeutic agent are ongoing in the USA (NCT02396238) and in France (NCT02558543) and will help determine the place of this innovative therapy for SSc patients. PMID- 28340696 TI - Comments on the history of medical-biological studies of aging, the birth of scientific gerontology. AB - Recent books (Immunity. How Elie Metchnikoff changed the course of modern medicine and Expectations of Life) reviewed the important contribution of Metchnikoff to the emergence of gerontology as a new branch of biomedical sciences. Here, we insist on Metchnikoff's contribution and pivotal role in the emergence of nutrition as a science and its importance for health and longevity. The discovery of phagocytosis by Metchnikoff and of its evolutionary ancestry are at the origin of the emergence of cellular immunity as an independent science besides humoral immunity. The longevity of Metchnikoff (71years) at a time when average life expectancy of men did hardly pass 50years certainly contributed to the acceptance of his teachings. The recent increase of the senior population in most advanced countries is a good opportunity to review the contributions of nutrition to longevity. PMID- 28340697 TI - Hypoxia inducible factor one alpha and human viral pathogens. AB - If the oxygen tension level is 21% in ambient air, it is only between 14% and 1% in vivo. Consequently, viral pathogens are exposed and must adapt to these fluctuating oxygen levels to colonize the host and cause diseases. The problem is that for many years, the virological studies have been performed at 21% oxygen levels and consequently this is a real handicap to have a correct view of the mechanistic aspects of human viral infections. In this brief review, we describe for some selected examples the interactions of human viruses with this relative hypoxia observed in vivo. PMID- 28340698 TI - Determination of Pd(II) using an antimony film coated on a screen-printed electrode by adsorptive stripping voltammetry. AB - The use of an antimony film coated on a screen-printed carbon electrode (ex-situ SbSPCE) is proposed for the determination of Pd(II) at ppb levels in natural samples by adsorptive stripping voltammetry using dimethylglyoxime as chelating agent. Ex-situ SbSPCE produces a better analytical performance as compared to a commercially sputtered bismuth screen-printed electrode (BispSPE). The detection and quantification limits were 2.7 and 9.0ugL-1 respectively with a good linear behaviour in the wide examined concentration range (from 1ugL-1 up to 100.0ugL-1, R2=0.998). The proposed ex-situ SbSPCE showed an excellent repeatability with a relative standard deviation of 0.5% for ten successive measurements and a very good reproducibility (1.6% for three different ex-situ SbSPCE units within series of ten repetitive assays). Moreover, the ex-situ SbSPCE was successfully applied for the determination of low concentration levels of Pd(II) in spiked tap water with a very high reproducibility (0.2%) and providing equivalent results to those achieved by ICP-MS measurements. PMID- 28340699 TI - A LED-based fiber-optic sensor integrated with lab-on-valve manifold for colorimetric determination of free chlorine in water. AB - In this work, a colorimetric methodology was developed for free chlorine determination by constructing a fiber-optic sensor (FOS) which was designed by using a small LED as light source and two silica fibers as light transmission elements. Then the FOS was integrated with the sequential injection lab-on-valve (SI-LOV) manifold to fabricate a FOS-SI-LOV system for free chlorine detection. The colorimetric determination was based on the reaction between N,N-diethyl-p phenylenediamine (DPD) reagent and free chlorine, which would produce a chromophore showing maximum absorbance at 511 and 551nm and detected by a micro spectrometer detector. By choosing a green LED with emission wavelength at 520nm as light source, the chlorine concentration could be simply evaluated according to Beer's law. The developed FOS-SI-LOV system showed improved performances of wide linear range (10-400MUgL-1), low detection limit (3.5MUgL-1, 3sigma), fast analysis (6.85s) and excellent repeatability (0.0083 RSD, n=8) for chlorine determination. The proposed FOS-SI-LOV system has been applied to on-line and real-time chlorine determination in different water samples with excellent selectivity. Furthermore, this FOS-SI-LOV methodology provided a colorimetric and fluorescence detection platform for other hazardous species monitoring in water environment based on Beer's law and Stern-Volmer relationship, respectively. PMID- 28340701 TI - Development of nitrogen-enriched carbonaceous material coated titania nanotubes array as a fiber coating for solid-phase microextraction of ultraviolet filters in environmental water. AB - A novel solid-phase microextraction (SPME) fiber was fabricated by direct electrodeposition of polyaniline (PANI) coated the titania nanotube arrays in situ grown on the titanium wire followed by carbonization at 500 degrees C under nitrogen atmosphere. The resulting titanium-based fiber with nitrogen-enriched carbonaceous material coated titania nanotubes (N-C/TiO2NTs/Ti) showed better extraction performance for ultraviolet (UV) filters among model aromatic compounds compared with common PANI as well as commercial polydimethylsiloxane and polyacrylate coatings. The influence of various experimental parameters on the extraction efficiency of UV filters were investigated and optimized. The calibration curves were linear from 0.2 to 200MUgL-1 for each analyte with correlation coefficients above 0.9980. Limits of detection (LODs) and limits of quantitation (LOQs) ranged from 0.03 to 0.05MUgL-1 and from 0.11 to 0.18MUgL-1 for UV filters, respectively. Relative standard deviations (RSDs) for single fiber repeatability ranged from 3.3% to 4.1% (n=5) and RSDs for fiber-to-fiber reproducibility (n=3) varied from 5.7% to 7.7%. The proposed method was successfully applied to the preconcentration and determination of target UV filters in river water and wastewater samples with good recoveries from 86.2% to 113%. Moreover this novel Ti-based fiber is mechanically and chemically stable, and can be easily prepared in a highly reproducible manner. PMID- 28340700 TI - Highly photosensitive colorimetric immunoassay for tumor marker detection based on Cu2+ doped Ag-AgI nanocomposite. AB - Visual detection of tumor markers with accuracy and selectivity exhibits significant advantages for cancer early diagnosis due to its low-cost and simple analytical instruments. Herein, a highly photosensitive colorimetric immunoassay for carcino embryonie antigen (CEA, as a model) detection based on Cu2+ doped Ag AgI nanocomposite was constructed. First, Cu2+ doped Ag-AgI nanocomposite (Cu2+/Ag-AgI) owned the ability of oxidization of TMB was synthesized by impregnation method, which was characterized by transmission electron microscope (TEM), scanning electron microscope (SEM), energy-dispersive X-ray spectroscopy (EDX), X-ray powder diffraction (XRD), UV-Vis diffuse reflectance spectroscopy (DRS) and X-ray photoelectron spectroscopy (XPS). Second, based on sandwich-type immunoassay, the immunocomplex was built on the surface of magnetic bead by utilizing Cu2+/Ag-AgI as labels. The blue color of TMBox was obtained under visible irradiation and ultraviolet spectrum scanning was carried out in ABS buffer solution. Under optimal conditions, the absorbance values increased with the increasing of CEA concentrations in sample with the linearity range of 1.0pgmL-1-5.0ngmL-1. The detection limit was 0.13pgmL-1. More importantly, the developed colorimetric immunoassay exhibited good selectivity, repeatability, stability and possible applications in the real serum sample analysis. PMID- 28340702 TI - Selective solid phase extraction of JWH synthetic cannabinoids by using computationally designed peptides. AB - The objective of the present work is to demonstrate a rational way to prepare selective sorbents able to extract simultaneously several structural analogs. For this purpose the binding specificity of two hexapeptides computationally designed (VYWLVW and YYIGGF) versus four synthetic cannabinoids Naphthalen-1-yl-(1 pentylindol-3-yl)methanone (JWH 018), naphthalen-1-yl-(1-butylindol-3 yl)methanone (JWH 073), (R)-(1-((1-methylpiperidin-2-yl)methyl)-1H-indol-3 yl)(naphthalen-1-yl)methanone (AM 1220) and (R)-(+)-[2,3-Dihydro-5-methyl-3-(4 morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone (WIN 55) was computationally studied and then experimentally tested by solid phase extraction (SPE) clean-up and ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) analysis. The two peptides were chosen using a semi combinatorial virtual technique by generating 4 cycles of peptide libraries (around 2.3*104 elements). To select the two peptides, the simulated binding scores between synthetic cannabinoids and peptides was used by maximizing the recognition properties of amino acid motif between the two JWH and the other synthetic cannabinoids. In particular, the peptide YYIGGF, having also affinity for AM 120, was selected as control because it was the only one without tryptophan residues within the best peptides obtained from simulation. Experimentally, the two hexapeptides were tested as SPE sorbent using nanomolar solutions of the four drugs. After optimization of best retentions the binding constants were calculated by loading synthetic cannabinoids solutions at different concentrations. The results indicated a strong interaction between hexapeptide VYWLVW and JWH 018 (15.58+/-2.03*106M-1), 3-fold and 40-fold larger compared to the analog JWH 073 and both AM 1220 and the WIN 55. Similar trend was observed for the hexapeptide YYIGGF but the binding constants were at least three times lower highlighting the key role of the tryptophan. To demonstrate the hexapeptides specific interaction with only synthetic cannabinoids, a cross reactivity study was carried out using other drugs (cocaine, morphine, phencyclidine and methamphetamine) in the same SPE condition. Finally the practical utility of these peptide modified sorbent materials was further demonstrated by detecting the synthetic cannabinoids in real samples using hair matrix. PMID- 28340703 TI - A ratiometric two-photon fluorescent probe for imaging hydrogen sulfide in lysosomes. AB - Hydrogen sulfide (H2S) is a kind of gaseous signalling molecule that plays pivotal role in various biological processes. So far, it is still a challenge to develop convenient and reliable methods for H2S detection in lysosomes. Herein, we developed a novel ratiometric two-photon fluorescent probe LR-H2S for imaging H2S in lysosomes. Upon the addition of H2S (using Na2S as a donor) to LR-H2S in buffer solution, the azide group is reduced to amino group and subsequently the carbamate ester is cleaved by 1,6-elimination, resulting in a fluorescence emission increase at 541nm and a concomitant emission decrease at 475nm. Under two-photon excitation of 840nm, an 80-fold fluorescence ratio (F541/F475) enhancement was observed with a wide linear range of 25-2500MUM. The detection limit was calculated to be 0.70MUM based on 3sigma/k method, indicating that the probe can detect H2S with a high sensitivity. The probe also shows excellent selectivity toward H2S among other biological interference species and features with low cytotoxicity and favorable two-photon properties. Furthermore, LR-H2S can easily localize in lysosomes and vividly illuminate endogenous/exogenous H2S level and distribution in lysosomes of living SGC-7901 cells. PMID- 28340704 TI - Sub-attomolar electrochemical measurement of DNA hybridization based on the detection of high coverage biobarcode latex labels at PNA-modified screen printed electrodes. AB - We have constructed biobarcode labels based on 468nm diameter latex spheres. Modification with polyallylamine and then glutaraldehyde was used to attach a high DNA loading, consisting of aminated probe DNA (approx. 1.01*102 molecules per sphere) and biobarcode DNA (approx. 1.66*104 molecules per sphere). Detection of the biobarcodes was performed by application of a Ag enhancer solution, causing association of the Ag+ ions with the phosphate groups of the DNA. The deposited Ag was detected by differential pulse voltammetry. A 30 mer sequence from the BL21 strain of E. coli was detected with an LOD of 2.6fM (calibration range 10 aM to 0.1pM, r2=0.91, n=45). The LOD was lowered to 0.56aM (calibration range 100zM to 0.1nM, r2=0.991, n=50) by utilizing a sandwich assay with PNA modified screen printed electrodes, which lowered the Ag background current. The sandwich assay platform was used to calibrate E. coli strain BL2(DE3) with an LOD of 17.0 CFU mL-1 (calibration range 10 to 106 CFU mL-1, r2=0.99, n=33) with good discrimination against Salmonella. PMID- 28340705 TI - Towards automation in protein digestion: Development of a monolithic trypsin immobilized reactor for highly efficient on-line digestion and analysis. AB - Reducing experimental variability, limiting contamination and increasing automation are essential goals in the development of reliable analytical platforms for mass spectrometry (MS)-based proteomics. In this work novel trypsin based monolithic immobilized enzyme reactors (tryp-IMERs), obtained by covalent immobilization on convective interaction media (CIMacTM) analytical columns (5mm*5.2mm I.D.), were developed. Notwithstanding the small dimensions, column format allowed the insertion in common high performance liquid chromatography (HPLC) systems, thus avoiding the use of expensive micro- or nano-platforms. Monolith pore diameter and surface chemistry were optimized to achieve high digestion efficiency even with high molecular weight proteins and to avoid protein/peptide adsorption, peak broadening and sample loss. A full characterization of the tryp-IMERs was undertaken to select the best protocol for preparation and type of trypsin. Optimization of the operational and storage conditions was carried out by an off-line approach. On-line studies were performed by setting a multidimensional analytical platform, which included the tryp-IMER, a trapping column, an analytical C4 column and a high resolution hybrid mass spectrometer (ESI-Q-TOF). In the optimized conditions rapid protein digestion (90+/-9s), high protein coverage (>=60%) and high score values were achieved for five selected sample proteins (cytochrome c, myoglobin and albumins from different sources) differing in molecular size, isoelectric point and accessibility to cleavage sites as well as for a protein mixture of 200ng. The best performing tryp-IMERs showed high sensitivity down to the pmole level. The platform also resulted suitable for the analysis of high-molecular weight proteins such as a pool of human immunoglobulins G (hIgG) and for the high molecular weight fraction of human plasma proteins, which were digested in less than two minutes to an extent similar to that achieved by overnight incubation in a classical in solution protocol. Finally, underestimated key procedural issues were also highlighted during the study. Such aspects are of general interest both for tryp-IMER users and tryp-IMER developers. PMID- 28340706 TI - Layer-by-layer self-assembly of gold nanoparticles/thiols beta-cyclodextrin coating as the stationary phase for enhanced chiral differentiation in open tubular capillary electrochromatography. AB - The popularity of capillary electrochromatography (CEC) has led to an increasing number of studies on the development and evaluation of enantioselective CEC systems. Herein, a novel, simple, and economical method for the preparation of chiral stationary phases for enantioselective open tubular capillary electrochromatography (OTCEC) was reported for the first time. This novel capillary column was fabricated through layer-by-layer self-assembly of GNPs on a 3-mercaptopropyl-trimethoxysilane (MPTMS)-modified fused-silica capillary and subsequent surface functionalization of the GNPs through self-assembly of thiols beta-cyclodextrin (SH-beta-CD). With this method, monolayer and multilayer GNPs film capillary columns were prepared and evaluated using meptazinol and its three intermediate enantiomers as templates. Consequently, the three-layer GNPs capillary column was found to exhibit favorable enantioseparation performance. Factors that influence the chiral separation resolution were examined. Under the optimized conditions, enantioselectivity was obtained for meptazinol and its three intermediate enantiomers (intermediates II, III and IV) in less than 20min with resolutions of 2.05, 0.36, 1.67, 1.53, respectively. The proposed column revealed adequate repeatability concerning run-to-run and day-to-day. In brief, these results confirmed the use of GNPs as the electrochromatographic support can enhance the phase ratio of OTC column in capillary electrochromatography (CEC). Then, this proposed method was well validated with good linearity (>=0.999), recovery (92.0-94.5%) and repeatability, and was successfully used for enantioseparation of meptazinol in spiked urine samples, which indicated the new column's potential usage in biological analysis. PMID- 28340707 TI - Sequential determination of multi-nutrient elements in natural water samples with a reverse flow injection system. AB - An integrated system was developed for automatic and sequential determination of NO2-, NO3-, PO43-, Fe2+, Fe3+ and Mn2+ in natural waters based on reverse flow injection analysis combined with spectrophotometric detection. The system operation was controlled by a single chip microcomputer and laboratory-programmed software written in LabVIEW. The experimental parameters for each nutrient element analysis were optimized based on a univariate experimental design, and interferences from common ions were evaluated. The upper limits of the linear range (along with detection limit, umolL-1) of the proposed method was 20 (0.03), 200 (0.7), 12 (0.3), 5 (0.03), 5 (0.03), 9 (0.2) umolL-1, for NO2-, NO3-, PO43-, Fe2+, Fe3+ and Mn2+, respectively. The relative standard deviations were below 5% (n=9-13) and the recoveries varied from 88.0+/-1.0% to 104.5+/-1.0% for spiked water samples. The sample throughput was about 20h-1. This system has been successfully applied for the determination of multi-nutrient elements in different kinds of water samples and showed good agreement with reference methods (slope 1.0260+/-0.0043, R2=0.9991, n=50). PMID- 28340708 TI - Phosphoserine imprinted nanosensor for detection of Cancer Antigen 125. AB - Cancer antigen 125 (CA 125) is widely used as diagnostic biomarker for ovarian cancer. Change in the concentration level of CA 125 is associated with disease progression or regression. CA 125 posseses a phosphorylation site and protein backbone is phosphorylated on serine, before secretion. In this study, we have developed an imprinting method for CA 125 recognition and determination. In this method, methacryloyl antipyrine europium (III) [(MAAP)2-Eu(III)] and methacryloyl antipyrine terbium (III) [(MAAP)2-Tb(III)] have been used as new metal-chelating monomers via metal coordination-chelation interactions. Phosphoserine (PS) has been used as a template for the detection of CA 125. PS imprinted carbon nanotube (CNT) and Fe2O3 nanoparticle (SPN) have cavities that are selective for CA 125. The binding affinity of the PS imprinted CNT and SPN nanosensor has been investigated using Langmuir adsorption isotherms and affinity constants (Kaffinity) have found to be 1.85 105M-1 for PS and 13.5 10-3 mLU-1 and 7.73 10-3 mLU-1 for CA 125 (for CNT and SPN, respectively). Detection limit of PS imprinted CNT nanosensor for PS and CA 125 have been found to be 1.77 10-10M and 0.49 UmL 1, respectively. Human serum samples have been spiked with different concentrations of CA 125 (in pH 7.4 PBS) to investigate the feasibility of the nanosensors for clinical applications. Experimental results have been revealed that prepared nanosensors have been exhibited better sensivity, recovery and reproducibility. PMID- 28340709 TI - An overview on forensic analysis devoted to analytical chemists. AB - The present article has as main aim to show analytical chemists interested in forensic analysis the world they will face if decision in favor of being a forensic analytical chemist is adopted. With this purpose, the most outstanding aspects of forensic analysis in dealing with sampling (involving both bodily and no bodily samples), sample preparation, and analytical equipment used in detection, identification and quantitation of key sample components are critically discussed. The role of the great omics in forensic analysis, and the growing role of the youngest of the great omics -metabolomics- are also discussed. The foreseeable role of integrative omics is also outlined. PMID- 28340710 TI - Selective colorimetric analysis of spermine based on the cross-linking aggregation of gold nanoparticles chain assembly. AB - A selective colorimetric assay for spermine was proposed in this work. In a weak alkaline medium, the conformational structure of double-stranded calf thymus DNA (ctDNA) was loosened to install gold nanoparticles (AuNPs) into chains. While, the chain assembly of AuNPs could form cross-linking aggregates when spermine was present, which was attributed to the electrostatic interaction between the positive change of spermine and negative change both of AuNPs and ctDNA, as well as the groove binding between ctDNA and spermine. Under the optimum conditions, the aggregation degree of AuNPs was proportional to the concentration of spermine in the range of 0.1-2.0MUM with a limit of detection of 11.6nM. More interestingly, AuNPs changed from red to purple and even to blue depending on the concentration of spermine, which could be developed as the colorimetric analysis of spermine. ctDNA-AuNPs assembly was demonstrated as a novel visual probe for the specific sensing of spermine with high specificity and sensitivity. PMID- 28340711 TI - Non-enzymatic sensors based on in situ laser-induced synthesis of copper-gold and gold nano-sized microstructures. AB - The synthesis of conductive gold and copper-gold microstructures with high developed surface based on the method of laser-induced metal deposition from solution was developed. The topology and crystallization phase of these structures were observed by means of scanning electron microscopy and X-ray diffraction, respectively. The electrochemical properties of the synthesized materials were investigated using cyclic voltamperometry and amperometry. According to the obtained results, it was found out that copper-gold microstructures demonstrate a linear dependence of Faraday current vs. concentration from 0.025 to 5uM for D-glucose and from 0.025 to 10uM for hydrogen peroxide. In turn, gold deposit exhibits a linear dependence of Faraday current vs. concentration from 0.025 to 50uM for D-glucose and from 0.025 to 1uM for hydrogen peroxide. Moreover, the synthesized materials reveal low detection limits (0.025uM) with respect to the aforementioned analytes, which is quite promising for their potential application in design and fabrication of new non enzymatic biosensors. PMID- 28340712 TI - A double-mediator based whole cell electrochemical biosensor for acute biotoxicity assessment of wastewater. AB - This work investigates the feasibility and sensitivity of a double-mediator based whole cell electrochemical biosensor to detect the acute biotoxicity of wastewater. The lipophilic mediator menadione was used to mediate the intracellular metabolic activities whereas hydrophilic potassium ferricyanide was employed as extracellular electron acceptor to transport the electron from the menadiol to anode. A chitosan hydrogel polymer film with boron-doped nanocrystalline diamond (BND) particles was electrodeposited onto a glassy carbon (GC) electrode to immobilize Saccharomyces cerevisiae cells and the mediators. The feasibility of the as-prepared biosensor was verified by determine the acute biotoxicity of four heavy metal ions(Cu2+, Cd2+, Ni2+, Pb2+), three phenol pollutants (3,5-dichlorophenol, 4-chlorophenol, phenol) and three real wastewater samples. The IC50 values for Cu2+, Cd2+, Ni2+, Pb2+ are 10.12mg/L,13.88mg/L, 17.06mg/L and 34.56mg/L. And the IC50 value is 16.48mg/L, 34.40mg/L and 44.55mg/L for 3,5-dichlorophenol, 4-chlorophenol and phenol, respectively. The results of this work indicate that the double-mediator based whole cell electrochemical biosensor could be applied into the acute toxicity assessment of real wastewater samples with excellent performance and highlight their merit as portable and sensitive, which may providing a reasonable and reliable way for wastewater toxicity online detection. PMID- 28340713 TI - Tunable diode laser absorption spectroscopy as method of choice for non-invasive and automated detection of microbial growth in media fills. AB - Tunable diode laser absorption spectroscopy (TDLAS) was evaluated on its potential to detect bacterial growth of contaminated media fill vials. The target was a replacement/ automation of the traditional visual media fill inspection. TDLAS was used to determine non-invasively O2 and/or CO2 changes in headspaces of such vials being induced by metabolically active microorganisms. Four different vial formats, 34 microorganisms (inoculation volume<10 cells) and two different media (TSB/FTM) were tested. Applying parallel CO2 and O2 headspace measurements all format-organism combinations were detected within <11 days reliably with reproducible results. False negatives were exclusively observed for samples that were intentionally breached with syringes of 0.3mm in diameter. Overall it was shown that TDLAS functionality for a replacement of the visual media fill inspection is given and that investing in further validation and implementation studies is valuable. Nevertheless, some small but vincible challenges remain to have this technology in practical use. PMID- 28340714 TI - Critical evaluation of strategies for single and simultaneous determinations of As, Bi, Sb and Se by hydride generation inductively coupled plasma optical emission spectrometry. AB - A systematic study of hydride generation (HG) of As, Bi, Sb and Se from solutions containing As(III), As(V), Bi(III), Sb(III), Sb(V), Se(IV) and Se(VI) was presented. Hydrides were generated in a gas-liquid phase separation system using a continuous flow vapor generation accessory (VGA) by mixing acidified aqueous sample, HCl and sodium borohydride reductant (NaBH4) solutions on-line. For detection, a simultaneous axially viewed inductively coupled plasma optical emission spectrometer (ICP-OES) was applied. Effects of the HCl concentration (related to sample and additional acid solutions) and type of the pre-reducing agents used for reduction of As(V), Sb(V) and Se(VI) into As(III), Sb(III) and Se(IV) on the analytical responses of As, Bi, Sb and Se were studied and discussed. Two compromised HG reaction conditions for simultaneous measurements of As+Bi+Sb (CC1) or As+Sb+Se (CC2) were established. It was found that choice of the pre-reductant prior to formation of the hydrides is critical in obtaining the dependable results of the analysis. Accordingly, for a As(III)+As(V)+Bi(III)+Sb(III)+Sb(V) mixture and using CC1, thiourea/thiourea ascorbic acid interfered in Bi determination and hence, total As+Sb could be measured. If L-cysteine/L-cysteine-ascorbic acid were used, measurements of total Bi+Sb was possible in these HG reaction conditions. For a As(III)+As(V)+Sb(III)+Sb(V)+Se(IV)+Se(VI) mixture and using CC2, thiourea/thiourea-ascorbic acid and L-cysteine/L-cysteine-ascorbic acid influenced HG of Se but ensured total As+Sb determination. In contrast, heating a sample solution with HCl, although did not pre-reduce As(V) and Sb(V), assured quantitative reduction of Se(VI) to Se(IV). Finally, considering all favorable pre-reducing and HG conditions, methodologies for reliable determination of total As, Bi, Sb and Se by HG-ICP-OES were proposed. Strategies for single-, two- and three-element measurements were evaluated and validated, obtaining the detection limits (DLs) below 0.1ngg-1 and precision typically in the range of 1.4-3.9% RSD. PMID- 28340715 TI - Short wave infrared chemical imaging as future tool for analysing gunshot residues patterns in targets. AB - This work used chemical imaging in the short-wave infrared region for analysing gunshot residues (GSR) patterns in cotton fabric targets shot with conventional and non-toxic ammunition. It presents a non-destructive, non-toxic, highly visual and hiperspectral-based approach. The method was based on classical least squares regression, and was tested with the ammunition propellants and their standard components' spectra. The propellants' spectra were satisfactorily used (R2 >0.966, and CorrCoef >0.982) for identifying the GSR irrespective of the type of ammunition used for the shooting. In a more versatile approach, nitrocellulose, the main component in the ammunition propellants, resulted an excellent standard for identifying GSR patterns (R2>0.842, and CorrCoef >0.908). In this case, the propellants' stabilizers (diphenilamine and centralite), and its nitrated derivatives as well as dinitrotoluene, showed also high spectral activity. Therefore, they could be recommended as complementary standards for confirming the GSR identification. These findings establish the proof of concept for a science-based evidence useful to support expert reports and final court rulings. This approach for obtaining GSR patterns can be an excellent alternative to the current and traditional chemical methods, which are based in presumptive and invasive colour tests. PMID- 28340716 TI - High sensitive detection of penicillin G residues in milk by surface-enhanced Raman scattering. AB - The antibiotic residue in animal source foods (milk, meat, etc.) is threatening people's health due to its abusing in livestock breeding more and more seriously. In this study, a simple and sensitive SERS method coupled with a two-step pretreatment process of sample was proposed for the residue detection of penicillin G (PENG) in real milk sample. It can be found that the two-step pretreatment process of sample is an essential procedure for the successful detection of PENG residue in milk, which can effectively avoid interference from other components in the sample and achieve the trace-level detection of PENG residue by SERS. Under the optimal test conditions, the limit of detection of PENG residue is 2.54*10-9mol/L (equal to 0.85MUg/kg), which is lower than the standard of the European Union (4MUg/kg). And, there is a good linear relationship (R2=0.9902) in the concentration range of 1.0*10-8~1.0*10-3mol/L. By this method, the recovery of PENG residue ranges from 76% to 97% with relative standard deviation between 4.8% and 2.1%. The proposed SERS method can be effectively applied for determination of PENG residue in milk. PMID- 28340717 TI - A rapid, accurate and sensitive method with the new stable isotopic tags based on microwave-assisted dispersive liquid-liquid microextraction and its application to the determination of hydroxyl UV filters in environmental water samples. AB - A rapid, accurate and sensitive method, using the stable isotope labeling (SIL), microwave-assisted dispersive liquid-liquid micro extraction (MADLLME) and the ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC MS/MS), was developed and validated for the determination of hydroxyl UV Filters in environmental water samples. A pair of new isotopic tags D0-/D3-1-methylindole 3-acetic acid (D0-/D3-MIAA) is synthesized, with which a simple yet efficient pretreatment MADLLME-SIL is developed. Under the optimized conditions (80C, 240W, 180s), the sample pretreatment including analyte extraction, pre-concentration and isotope labeling can be finished conveniently in only 9min. D0-/D3-MIAA labeling improves the chromatographic retention by strengthening the hydrophobicity and enhances the MS response for 3-4 orders of magnitude. Excellent linearity is established by the H/D ratios of 1/10-10/1 with the correlation coefficients >0.9990. The quite low detection limits (0.54-1.79ng/L) are achieved, ensuring the trace detection. This method is successfully applied to a series of environmental water samples. The recoveries (93.2%~103.5%) are significantly improved and the analysis time is largely reduced (<15min). The excellent sensitivity, accuracy, recovery, and efficiency demonstrate this MADLLME-SIL-LC-MS/MS method a superior alternative for the analysis of UV filters in water samples. PMID- 28340718 TI - Metal-to-ligand charge-transfer: Applications to visual detection of beta galactosidase activity and sandwich immunoassay. AB - In this work, we report a novel use of the distinctive metal-to-ligand charge transfer (MLCT) absorption properties of the chromogenic Fe(BPDS)34- (BPDS=bathophenanthroline disulfonic acid) reporter for the visual detection of beta-galactosidase (beta-Gal) activity and sandwich immunoassay. The enzymatic hydrolysis of the substrate p-aminophenyl-beta-D-galactopyranoside can switch on the reduction of Fe3+ to Fe2+ and the subsequent complexation of Fe2+ with the BPDS ligand to generate the Fe(BPDS)34- reporter, leading to the appearance of the intense MLCT absorption band at 535nm and the colorless-to-red color change of the solution. Simply through a single step, the activity of beta-Gal can be sensitively and selectively detected within the dynamic range of 0-220mUmL-1, with a limit of detection (LOD) of 1.69mUmL-1. This approach is applicable for the visual detection of beta-Gal activities in the presence of complex human serum samples. Besides, when integrated with the sandwich immunoassay of carcinoembryonic antigen, a LOD of 1.16ngmL-1 can be achieved. In light of its prominent simplicity and practicality, our MLCT-based approach holds great potential in diagnostic and analytical applications. PMID- 28340719 TI - Application of a rapid MU-SPE clean-up for multiclass quantitative analysis of sixteen new psychoactive substances in whole blood by LC-MS/MS. AB - Europe is an important market for illegal drugs, and nowadays a lot of new different psychoactive substances (NPS) are widespread. This work reports the development of a method to determine simultaneously different classes of NPS, as synthetic cannabinoids (SC) and their metabolites, cathinones and phenetylamines, directly on whole blood (WB) without anti-coagulants and using miniaturized solid phase extraction (MU-SPE). In order to demonstrate the feasibility of the method 16 different NPS belonging to the mentioned classes were selected for the analysis. Recoveries ranged from 21% to 70% while matrix effect was lower than 15% for all the analytes. LOQ values were 5ngmL-1 for cathinones and phenetylamines, between 0.25 and 1ngmL-1 for SCs and up to 2.5ngmL-1 for SC metabolites. The performance of MU-SPE was compared with different clean-up strategies (i.e. protein precipitation (PPT), liquid liquid extraction, PPT/SPE hybrid) in term of recovery, matrix effect and suitability for multi-class analysis. The developed method was validated according to SWGTOX guidelines. The validation data demonstrated that this approach is potentially very useful as confirmation method for multiclass analysis in WB and post mortem specimens. In fact only 100MUL of human WB are used, sample preparation involves few rapid steps and the method is easily implementable for the determination of other NPS. PMID- 28340720 TI - Headspace single drop microextraction versus dispersive liquid-liquid microextraction using magnetic ionic liquid extraction solvents. AB - A headspace single drop microextraction (HS-SDME) method and a dispersive liquid liquid microextraction (DLLME) method were developed using two tetrachloromanganate ([MnCl42-])-based magnetic ionic liquids (MIL) as extraction solvents for the determination of twelve aromatic compounds, including four polyaromatic hydrocarbons, by reversed phase high-performance liquid chromatography (HPLC). The analytical performance of the developed HS-SDME method was compared to the DLLME approach employing the same MILs. In the HS-SDME approach, the magnetic field generated by the magnet was exploited to suspend the MIL solvent from the tip of a rod magnet. The utilization of MILs in HS-SDME resulted in a highly stable microdroplet under elevated temperatures and long extraction times, overcoming a common challenge encountered in traditional SDME approaches of droplet instability. The low UV absorbance of the [MnCl42-]-based MILs permitted direct analysis of the analyte enriched extraction solvent by HPLC. In HS-SDME, the effects of ionic strength of the sample solution, temperature of the extraction system, extraction time, stir rate, and headspace volume on extraction efficiencies were examined. Coefficients of determination (R2) ranged from 0.994 to 0.999 and limits of detection (LODs) varied from 0.04 to 1.0MUgL-1 with relative recoveries from lake water ranging from 70.2% to 109.6%. For the DLLME method, parameters including disperser solvent type and volume, ionic strength of the sample solution, mass of extraction solvent, and extraction time were studied and optimized. Coefficients of determination for the DLLME method varied from 0.997 to 0.999 with LODs ranging from 0.05 to 1.0MUgL-1. Relative recoveries from lake water samples ranged from 68.7% to 104.5%. Overall, the DLLME approach permitted faster extraction times and higher enrichment factors for analytes with low vapor pressure whereas the HS-SDME approach exhibited better extraction efficiencies for analytes with relatively higher vapor pressure. PMID- 28340721 TI - Sensitive determination of Hg together with Mn, Fe, Cu by combined photochemical vapor generation and pneumatic nebulization in the programmable temperature spray chamber and inductively coupled plasma optical emission spectrometry. AB - Continuous photo-induced generation of mercury cold vapor has been successfully coupled with conventional pneumatic nebulization in programmable temperature spray chamber (PCVG-PN-PTSC) allowing fast, sensitive and easy multi-element analysis. The applied technique enabled simultaneous determination of non volatile forming elements (Fe, Cu, Mn) and volatile Hg, while 15%v/v formic acid is present in the sample. PTSC elevated temperature (40 degrees C) causes partial conversion of sample matrix into vapor form, thus improving plasma robustness. The efficiency of Hg vapor generation and its transport to the plasma is close to 100%. Moreover, spray chamber temperature stabilization improved the precision of the measurements (Hg signal RSD below 0.5%). The achieved limit of detection for Hg (90pgmL-1) at 194.23nm with no monochromator purge is better by almost two orders of magnitude than that obtained by conventional PN-ICP-OES. On the other hand, LODs for non-vapor forming elements are comparable to those obtained with pneumatic nebulization. The linear dynamic ranges for all examined elements are at least three orders of magnitude up to 1000ngmL-1. None mutual interference between examined analytes (Hg, Fe, Cu, Mn) has been observed. The method was validated by the analysis of two CRM materials of different matrix composition (waste water ERM CA713 and estuarine sediment ERM CC580) giving satisfactory results. As low as 2 ppb of Hg can he directly determined in waste water. The proposed procedure uses mild reagents and allows for fast multi-element analysis, and matches green chemistry requirements. PMID- 28340722 TI - Amperometric biosensors based on carboxylated multiwalled carbon nanotubes-metal oxide nanoparticles-7,7,8,8-tetracyanoquinodimethane composite for the determination of xanthine. AB - A comparison of the analytical performances of two xanthine biosensors, based on the use of different metal oxide nanoparticles (MONPs: Co3O4 or Fe3O4)-modified carboxylated multiwalled carbon nanotubes (c-MWCNTs)-7,7',8,8' tetracyanoquinodimethane (TCNQ)-chitosan (CHIT) composite, is discussed. Xanthine oxidase (XOD) enzyme was covalently attached to c-MWCNTs/MONPs/TCNQ/CHIT/GCE via N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxy succinimide (NHS) chemistry and the electrode surface was further modified with Nafion in order to minimize the effect of possible interfering substances. The results showed that analytical performance of the Fe3O4 based biosensor was better than the Co3O4 based biosensor. The linear working range, limit of detection and sensitivity were found to be 1.9*10-6-2.3*10-4M, 0.20MUM (S/N=3), 25.07MUAmM-1cm 2 for the Fe3O4 based biosensor and 1.9*10-6-1.2*10-4M, 0.36MUM (S/N=3), 13.24MUAmM-1cm-2 for the Co3O4 based biosensor, respectively. The purposed biosensors were applied in the determination of xanthine in coffee samples, and satisfactory results were obtained. PMID- 28340723 TI - An electrochemical sensor device for measuring blood ammonia at the point of care. AB - The level of ammonia in blood is relevant in a number of medical conditions. While ammonia is a marker of dysfunction, elevated ammonia is itself a serious medical emergency and can lead to significant and permanent neurological impairment if not addressed quickly. Blood ammonia testing is typically performed in the central laboratory. While a number of point of care devices have been developed, these are based on classical enzymatic or colorimetric principles and have not been widely adopted. In this work, an electrochemical sensor device was developed for measuring blood ammonia. The device was based on the deposition of polyaniline nanoparticle films onto screen printed interdigitated electrodes using inkjet printing and their integration into a polymer microfabricated device with a polytetrafluoroethylene membrane. The device required a 52uL serum sample and measured the change in impedance of the sensor with respect to air at 1kHz, 5mV rms. The device was capable of the measurement of ammonia in serum across the physiologically relevant range of 25-200uM (r2 =0.9984) and had a limit of detection of 12uM (n =3). The device showed no significant issues with common electrochemical interferences in blood. The device was also validated against a commercial spectrophotometric assay which resulted in excellent correlation (r =0.9699, p<0.0001) between both methods (n =3). When stored under desiccation, devices displayed minimal variation over time (0.64%) with respect to their impedance in air (n =12) and could be stored in desiccant for at least five months. PMID- 28340724 TI - Mass spectrometry and metallomics: A general protocol to assess stability of metallodrug-protein adducts in bottom-up MS experiments. AB - The bottom-up mass spectrometry approach is today one of the best tools of Metallomics to characterize the binding of metal-based drugs to proteins. Yet, the stability of metal-protein coordination bonds along the whole process may be a critical issue. This led us to build up a general protocol to test metallodrug protein adduct stability under the typical conditions of the filter-aided sample preparation (FASP)/bottom-up procedure, ranging from the analysis of solutions containing metal-protein adducts to tandem mass spectrometry experiments. More in detail, we identified nine critical situations, either during the sample manipulations or instrumental, as a potential source of metal-protein bond impairment when using FASP operative conditions and a nano high performance liquid chromatography-nanoelectrospray ionization-LTQ-Orbitrap (nanoLC-nanoESI LTQ-Orbitrap) mass spectrometer system, equipped with a preconcentration/purification device. These are: 1) sample permanence in the ammonium bicarbonate buffer; 2) denaturation with urea; 3) reduction with dithiothreitol; 4) alkylation with iodoacetamide; 5) sample permanence in the loading mobile phase; 6) sample permanence in the elution mobile phase; 7) the nanoESI process; 8) the transfer of the adduct through ion transfer tube and tube lens; 9) collision induced dissociation in the ion trap. Accordingly, an ad hoc experimental protocol was developed and applied to the adducts formed between cytochrome c (Cyt c) and two different metallodrugs, i.e. cisplatin (cis diamminedichloridoplatinum(II), CDDP) and RAPTA-C, a well-known ruthenium(II) arene compound [Ru(eta6-p-cymene)Cl2(pta)] (pta=1,3,5-triaza-7 phosphaadamantane), used here as models. Notably, Cyt c-CDDP adducts were stable through all the above conditions while Cyt c-RAPTA-C adducts turned out unstable in the ammonium bicarbonate buffer. This latter finding supports the need to perform a test-protocol of this kind when starting any extensive bottom-up MS investigation of protein-metallodrug systems. PMID- 28340726 TI - A flow-batch manipulated Ag NPs based SPR sensor for colorimetric detection of copper ions (Cu2+) in water samples. AB - Using flow-batch analysis, a highly sensitive and selective method for automatic colorimetric detection of copper ions (Cu2+) was produced on the basis of the surface plasma resonance (SPR) of silver nanoparticles (Ag NPs). The Ag NPs were catalytically etched by thiosulfate in the presence of Cu(NH3)42+, resulting in a color change of the solution induced by the absorbance decrease at 401nm of the SPR peak of Ag NPs. The proposed method showed high selectivity for Cu2+ over various metallic ions, including Fe3+, Mn2+, Co2+, Ni2+, Zn2+, Pb2+, Ba2+, Cd2+, Bi3+, Sb2+, As3+, Hg2+, Cr3+ and K+. The linear range was 0.5-35MUg/L with a coefficient of 0.9954. The limit of detection was as low as 0.24MUg/L. The relative standard deviation (RSD, n=7) for the determination of Cu2+ spiked samples at concentrations of 10MUg/L was 1.21% and for 25MUg/L was 1.03%. The proposed method was successfully applied to analyze Cu2+ in lake water, tap water, rainwater and bottled water samples, as well as leaf samples for food packaging. The results were in good agreement with those obtained by graphite furnace atomic absorption spectrometry, the classical technique. PMID- 28340725 TI - Biomonitored UHPLC-ESI-QTOF-MS2 and HPLC-UV thermostability study of the aerial parts of Sphagneticola trilobata (L.) Pruski, Asteraceae. AB - As the temperature of extraction and processing could impact the biological effects of herbal extracts, which have wide chemical diversity, the aim of this work were to investigate the thermostability of herbal derivatives of the aerial parts of Sphagneticola trilobata, a reputed medicinal plant; to biomonitor its oral anti-hyperalgesic effect; and to elucidate the degradation pathways of the major components by UHPLC-ESI-QTOF-MS. The lipophilic markers (kaurenoic acid-KA) and hydrophilic markers [chlorogenic acids; measured as total phenolic compounds (PC), expressed in caffeic acid] were also monitored through a validated HPLC-UV methodology, suitable for quality control and stability studies. The soft extract (drug:solvent ratio of 1:10, ethanol 60% v/v) was exposed to high temperatures (50-180 degrees C). PC showed high thermolability (27.4% of degradation at 150 degrees C), compared to KA (16.5%, at 180 degrees C). These results suggest that the loss of oral anti-hyperalgesic activity observed in the spray-dried extracts (dried at 170 degrees C), compared with the soft and the lyophilized extract may be related to degradation of the active components, especially the polar compounds, i.e. chlorogenic acid derivatives and the four oleanane type triterpenoid saponins. These latter degraded at temperatures above 150 degrees C and vanished at 180 degrees C, as demonstrated in the UHPLC-ESI-QTOF-MS analyses. These results provide a relevant guide for the extraction process of S. trilobata, aimed at preserving the antinociceptive effect. PMID- 28340727 TI - A quantitative approach for Cd, Cu, Fe and Mn through laser ablation imaging for evaluating the translocation and accumulation of metals in sunflower seeds. AB - The uptake and accumulation of Cd in sunflower seeds represents an important pathway for imputing potentially toxic metals into human and animal food. In this way, bioimaging of Cd and micronutrients (Cu, Fe and Mn) in the seeds of sunflower grown in soil contaminated with Cd are performed. For this task, laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) is used in quantitative approach, considering four groups: precursor, control, Cd-low (50mg) and Cd-high (700mg). For attaining our proposals, ICP-MS (nebulizer and auxiliary flow rates and radiofrequency power) and LA (laser intensity, frequency and spot size) parameters were optimized, and the analytical signal improved to 197%, 217%, 232%, and 283%, for 57Fe, 112Cd, 55Mn and 63Cu, respectively. The accuracy of proposed method using LA-ICP-MS is evaluated comparing the CRM results (Tomato leaves, NIST SRM 1573a). No difference is found at 95% confidence level. Regarding Cd accumulation in sunflower seeds, the results indicated that cadmium is translocated to seeds, and the cotyledons showed the highest concentration (Cd high group), ranging from 10 to 20ugg-1. Considering both total concentration and the distribution in the seeds, Cd uptake is responsible to the homeostasis misbalance of micronutrients, which play an essential role in the sunflower metabolism. Such results highlight the importance of bioimaging evaluation, in the translocation and accumulation of metals, contributing to expand the information available of this culture. PMID- 28340728 TI - Ferrocene-graphene sheets for high-efficiency quenching of electrochemiluminescence from Au nanoparticles functionalized cadmium sulfide flower-like three dimensional assemblies and sensitive detection of prostate specific antigen. AB - A signal-switchable electrochemiluminescence (ECL) aptasensor was presented for sensitive prostate specific antigen (PSA) assay using ferrocene-graphene sheets (Fc-GNs) for high-efficiency quenching of ECL from Au nanoparticles functionalized cadmium sulfide flower-like three dimensional (3D) assemblies (Au CdS flower-like 3D assemblies). Au-CdS flower-like 3D assemblies were synthesized and employed as luminophore, exhibiting strong and stable ECL intensity, and followed by assembling captured DNA (cDNA) and hybridizing it with half of base sequence of PSA aptamer on the Au-CdS flower-like 3D assemblies modified electrode. The remaining part of the non-complementary base of the aptamer could preferentially adsorb GN with the signal switched "off" state. While in the presence of the PSA, the binding of PSA with aptamer caused desorption of aptamer from the surface of Fc-GNs and was then released from electrode surface, thus allowing the ECL signal enhancement. With the transformation of luminescence signal from "off" to "on", the aptasensor displays high sensitivity for PSA detection with a linear range from 1pgmL-1 to 25ngmL-1 and a detection limit of 0.38pgmL-1S/N=3). Moreover, this developed method could be successfully applied to the determination of PSA in human serum samples with recoveries of 85.8 104.0%, suggesting great potential applications in biochemical analysis. PMID- 28340729 TI - Development, validation and comparison of near infrared and Raman spectroscopic methods for fast characterization of tablets with amlodipine and valsartan. AB - The objective of this study was to develop, validate and compare NIR and Raman spectroscopic methods for fast characterization in terms of API content and tensile strength of fixed-dose combination tablets containing amlodipine and valsartan. For the APIs assay NIR-transmittance and Raman-reflectance methods were considered, whereas for the tensile strength assay Raman spectra were recorded in reflectance configuration and NIR spectra were recorded in both reflectance and transmittance. Multivariate calibration models (PLS) were built by applying different pre-processing methods (SNV, MSC, SD+SNV) on certain spectral regions. Correlating pre-processed spectral data with tablet properties resulted in highly predictive models except in the case of NIR-transmittance spectra for tensile strength estimation. The best models selected by cross validation were further validated on independent samples in terms of linearity, trueness, accuracy and precision. Using Bland and Altman analysis the analytical performance of the NIR and Raman methods were compared, demonstrating their similarity considering the investigated applications. The two spectroscopic methods can be used in association to confirm each others results for at-line characterization of the pharmaceutical product. PMID- 28340730 TI - Identification and determination of synthetic cannabinoids in herbal products by dry film attenuated total reflectance-infrared spectroscopy. AB - A new procedure has been developed for the identification and quantitative determination of synthetic cannabinoids in illicit herbal preparations. The methodology is based on the use of attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) measurement of sample extracts with 2-propanol drying 5uL of the extracts onto the ATR crystal. The qualitative identification was carried out on the 2-propanol extract after identification of the herbal matrix, followed by its subtraction and using a cut-off criterion of 75%. Quantitative determination was made by univariate calibration using the absorbance of the band located at 1520cm-1 of the spectrum. Four different cannabinoids, RCS-4, JWH-210, UR-144 and JWH-081 were used as test analytes and the ATR-FTIR method provided limits of quantification from 14 till 79mgL-1. Sized blank market samples were successfully identified and UR-144 quantified. PMID- 28340731 TI - Prediction of organic carbon and total nitrogen contents in organic wastes and their composts by Infrared spectroscopy and partial least square regression. AB - Middle and near infrared (MIR and NIR) were employed to determine organic carbon (OC) and total nitrogen (TN) in different soil organic amendments including wastes, composts and mixtures of composts and organic wastes. Prediction models based on partial least squares (PLS) regression from the spectra of untreated samples were built. Different spectra preprocessing strategies were adopted and the best number of latent variable was evaluated using leave-one-out cross validation. Attenuated total reflectance (PLS-ATR-MIR) and diffuse reflectance (PLS-DR-NIR) models were built and evaluated from root mean square error of cross validation and prediction (RMSECV and RMSEP), coefficients of determination for prediction (R2 pred) and residual predictive deviation (RPD). ATR-MIR provided a better prediction capability than DR-NIR with RMSEP, R2pred and RPD values of 2.2%, 0.76 and 2.0 for OC and values of 0.2%, 0.82 and 2.4 for TN, respectively. PMID- 28340732 TI - Glycine post-synthetic modification of MIL-53(Fe) metal-organic framework with enhanced and stable peroxidase-like activity for sensitive glucose biosensing. AB - A facile and rapid post-synthetic strategy was proposed to prepare a glycine functionalized MIL-53(Fe), namely glycine-MIL-53(Fe), by a simple mixing of water dispersible MIL-53(Fe) and glycine. The FT-IR, SEM, XRD and zeta potential were used to characterize the glycine-MIL-53(Fe). The result showed that glycine post synthetic modification of MIL-53(Fe) did not change in the morphology and crystal structure of MIL-53(Fe). Interestingly, compared with MIL-53(Fe), the glycine-MIL 53(Fe) exhibits an enhanced peroxidase-like activity, which could catalyze the oxidation of TMB by H2O2 to produce an intensive color reaction. Kinetic analysis indicated that the Km of glycine-MIL-53(Fe) for TMB was one-tenth of that of MIL 53(Fe). The glycine-MIL-53(Fe) as peroxidase mimetic displays better stability under alkaline or acidic conditions than MIL-53(Fe). The good performance of glycine-MIL-53(Fe) over MIL-53(Fe) may be attributed to the increase of affinity between TMB and the glycine-MIL-53(Fe). With these characteristics, a simple and sensitive method was developed for the detection of H2O2 and glucose. The linear detection range for H2O2 is 0.10-10MUM with a detection limit of 49nM, and glucose could be linearly detected in the range from 0.25 to 10MUM with a detection limit of 0.13MUM. The proposed method was successfully used for glucose detection in human serum samples. PMID- 28340734 TI - Novel immunochromatographic assay on cotton thread based on carbon nanotubes reporter probe. AB - In this article, a novel immunochromatographic assay method on cotton thread based on carbon nanotubes (CNTs) as reporter probe was successfully prepared for visual and rapid detection of a lung cancer related biomarker, human ferritin antigen. A model system comprising ferritin as an analyte was used to demonstrate the protocol of the cotton thread immunoassay device. The device can detect at least 50ng/mL human ferritin antigen, which improved the sensitivity approximately by 500 folds comparing with previous point-of-care test report based on carbon nanotubes as reporter probe. The CNTs reporter probe combined with cotton thread device based biosensor provided an alternative path for clinical diagnosis of other protein or nucleic acid biomarkers. PMID- 28340733 TI - Migration test of Bisphenol A from polycarbonate cups using excitation-emission fluorescence data with parallel factor analysis. AB - Bisphenol A (BPA) is one of the most largely produced chemical in the world; it is used to make plastics and epoxy resins. The endocrine disruptor potential of BPA is well known, but recent researches suggest a relationship between chronic exposure to BPA, genotoxic activity and epigenetic modifications. The main source of exposure to BPA includes food contact materials (FCM). Thus simple and robust test methods are needed to improve the migration test of BPA. In this work, a non separative, easy, fast and inexpensive spectrofluorimetric method based on the second order calibration of excitation-emission fluorescence matrices (EEMs) was proposed for the determination of BPA. For the first time, molecular fluorescence was used to identify unequivocally and quantify BPA. Trilinearity of the data tensor guarantees the uniqueness of the solution obtained through parallel factor analysis (PARAFAC), so one factor of the decomposition matches up with BPA even if other fluorophores are in the test sample. The effect of four experimental factors of the procedure on the figures of merit and the unequivocally identification was investigated by means of a D-optimal design and PARAFAC calibration. The method is linear and accurate in the range 0-720ugL-1. The decision limit CCalpha and detection capability CCbeta are 6.63ugL-1 and 18.85ugL 1 respectively (with probabilities of false positive and false negative fixed at 0.05). Finally the proposed method was applied to carry out a migration test from two polycarbonate cups, using 3% (w/v) acetic acid in aqueous solution as food simulant. The migrated amount of BPA was found to be 688.7ugL-1 (n=5) for the first cup and 710.5ugL-1 (n=4) for the second one, above the specific migration limit set by EFSA (European Food Safety Authority). PMID- 28340735 TI - Facile visual colorimetric sensor based on iron carbide nanoparticles encapsulated in porous nitrogen-rich graphene. AB - Herein, via one-step pyrolysis of glucose, dicyandiamide (DCDA) and Fe containing metal-organic framework (Fe-MOF), small Fe3C nanoparticles were in-situ decorated in 3D porous network of N-rich graphene (NGr). The Fe-MOF served as size regulating precursor, layered g-C3N4 (derived from pyrolysis of DCDA) acted as not only a template to guide the growth of small Fe3C nanoparticles, but also the carbon source for 3D porous NGr network. The intrinsic peroxidase-like catalytic activity of Fe3C/NGr was unpredictably discovered, by taking the oxidation reaction of 3,3',5,5'-tetramethylbenzidine (TMB) with H2O2 as a protocol. Fast and distinguished color change, improved stability in exposure to extreme H2O2 concentration and high temperature were obtained. The Michaelis-Menten kinetics was investigated. The detection of glucose was accomplished over a wide concentration range of 2.0~500.0MUM with a detection limit lower than most of other similar systems. The reliability of the present sensor was further evaluated by practical monitoring glucose in diluted serum samples. Low cost and simple preparation, fast and distinguished color change, high tolerance to extreme H2O2 concentration and high temperature, endow Fe3C/NGr as one of the promising materials for fast visual colorimetry. PMID- 28340736 TI - Highly sensitive electrochemical sensor for chloramphenicol based on MOF derived exfoliated porous carbon. AB - Benefit from the advantages in costless, simplicity and efficiency, solvent exfoliation has been widely used in preparation of two-dimensional nanosheets with enhanced performances in electronics, photonics, and catalysis. In this work, solvent exfoliation was first applied to prepare exfoliated porous carbon (EPC) from an isoreticular metal-organic framework-8 (IRMOF-8) derived porous carbon (DPC). The obtained EPC with high surface area (1854m2g-1) and improved dispersibility was used as electrode modifier for glassy carbon electrode (GCE) in square wave voltammetry (SWV) detection of chloramphenicol (CAP). The sensitivity of EPC modified GCE (EPC/GCE) was greatly improved in compare with that of the DPC modification. The corresponding linear ranges are 1*10-8-1*10 6molL-1 and 1*10-6-4*10-6molL-1. The detection limit was calculated to be 2.9*10 9molL-1 (at a signal-to-noise ratio of 3, S/N=3). In addition, the proposed sensor was successfully applied in the analysis of CAP in honey and achieved satisfying recovery. PMID- 28340737 TI - Efficient extraction of low-abundance peptides from digested proteins and simultaneous exclusion of large-sized proteins with novel hydrophilic magnetic zeolitic imidazolate frameworks. AB - Zeolitic imidazolate frameworks (ZIFs) are composed of tetrahedral transition metal ions and imidazolate type organic linkers. This kind of metal organic frameworks (MOFs) combines the unique properties of both zeolites and MOFs. Furthermore, ZIFs can be assembled under mild biocompatible conditions. These advantages make them be primarily studied for biochemical analysis. In this work, polydopamine-modified hydrophilic magnetic ZIFs were synthesized in a simple and mild way for the efficient extraction of low-abundance peptides. Thanks to the low-coordinated Zn2+ ions, the Fe3O4@PDA@ZIF-8 composites showed strong affinity towards low-abundance peptides, especially those with histidine residues. After enrichment, the sequence coverage of BSA and HSA tryptic digest got a significant increase. The solid phase method based on the magnetic ZIFs exhibited size exclusion effect towards large-sized proteins, and proved to be effective even under the 200-fold dilution with BSA protein solution. PMID- 28340738 TI - 226Ra dynamic lixiviation from phosphogypsum samples by an automatic flow-through system with integrated renewable solid-phase extraction. AB - The release of 226Ra from phosphogypsum (PG) was evaluated by developing a novel tool for fully automated 226Ra lixiviation from PG integrating extraction/pre concentration using a renewable sorbent format. Eight leached fractions (30mL each one) and a residual fraction were analyzed allowing the evaluation of dynamic lixiviation of 226Ra. An automatic system allows this approach coupling a homemade cell with a 226Ra extraction/pre-concentration method, which is carried out combining two procedures: Ra adsorption on MnO2 and its posterior co precipitation with BaSO4. Detection was carried out with a low-background proportional counter, obtaining a minimum detectable activity of 7Bqkg-1. Method was validated by analysis of a PG reference material (MatControl CSN-CIEMAT 2008), comparing the content found in fractions (sum of leached fractions + residual fraction) to the reference value. PG samples from Huelva (Spain) were studied. 226Ra average activity concentration of the sum of leached fractions with artificial rainwater at pH 5.4+/-0.2 was 105+/-3Bqkg-1d.w. representing a 226Ra lixiviation of 37%; while at pH 2.0+/-0.2, it was 168+/-3Bqkg-1 d.w., which represents a 50%. Also, static lixiviation, maintaining the same experimental conditions, was carried out indicating that, for both considered pH, the 226Ra release from PG is up to 50% higher in a dynamic leaching that in a static one, may have both environmental and reutilization implications. PMID- 28340739 TI - Optimization and validation of the methods for the total mercury and methylmercury determination in breast milk. AB - The objective of the work was to develop and validate methods for the total Hg and methylmercury (MeHg) in breast milk that could be further used to obtain first data on chemical contamination of French breast milk. For total Hg determination, the potential of two techniques, namely Advanced Mercury Analyzer (AMA) and ICP MS, was compared. For MeHg determination, ICP MS detection associated to a quantification by isotopic dilution was used and the potential of a preliminary separation by gas or liquid chromatography was evaluated and discussed. The optimization studies have shown that AMA for total Hg determination and HPLC - ID - ICP MS, after a preconcentration step by freeze drying, for MeHg quantification were the most relevant methods to use for epidemiologic studies. The figures of merit for both methods were evaluated by means of accuracy profiles in terms of limits of quantification (1.82 and 1.35ug Hg/kg dry weight, corresponding to 0.22 and 0.16ug Hg/kg wet basis for total Hg and MeHg, respectively), repeatability (2-11% and 3-8% for total Hg and MeHg respectively), intermediate precision reproducibility (4-12% and 4-8% for total Hg and MeHg respectively) and trueness bias (-0.1-9% and -4-0% for total Hg and MeHg respectively). The methods were then applied to 180 breast milk samples. Total Hg concentrations ranged from 3 times since 2005, and the number of private transplantation centers has increased 9 times for the same period. We also found that the number of brain deaths, donors after brain death in hospitals, and number of brain deaths and donors after brain death per hospital had varied throughout the study years. CONCLUSIONS: Although the number of transplantation centers has increased since 2005, the number of brain deaths and donors after brain death has not increased to the same extent for this period in these hospitals that have transplantation units. PMID- 28340798 TI - Effect of Interviews Done by Intensive Care Physicians on Organ Donation. AB - In this study, we examined the correspondence between intensive care unit physicians and the relatives of potential brain-dead donors regarding the decision to donate or the reasons for refusing organ donation. A total of 12 consecutive cases of potential brain-dead patients treated in intensive care units of Marmara University Pendik Education and Research Hospital in 2013 were evaluated. For each of the cases, the Potential Donor Questionnaire, and Family Notification, Brain Death Criteria Fulfilment and Organ Donation Conversation Questionnaires were used to collect the required data. Statistically, descriptive analyses were performed. We concluded that honestly, regularly, and sufficiently informed relatives of the potential brain-dead donor more readily donate organs, with a positive contribution from the intensive care physician. PMID- 28340799 TI - Is There a Long-Term Risk for Donors With Heterozygous MEFV Mutation After Kidney Donation? AB - BACKGROUND: Familial Mediterranean fever (FMF) is an autosomal-recessive autoinflammatory disorder manifested severely by systemic amyloidosis. It has been hypothesized that heterozygous carriers may also have susceptibility to certain symptoms or even diseases. Because the living kidney donors of patients with FMF are generally relatives of the kidney recipients, there is a high possibility that the donors will have a heterozygous mutation of the FMF gene. The goal of this study was to investigate the long-term kidney function of donors who are carriers of the Mediterranean fever (MEFV) gene. METHODS: The medium- to long-term outcomes of 12 asymptomatic donors were compared with MEFV gene carriers and 24 non-FMF recipients' donors. RESULTS: Heterozygous carriers and the control group were similar with respect to age, sex, and follow-up period. The preoperative estimated glomerular filtration rate and 24-hour urine proteinuria levels were similar in the MEFV carrier and control groups. Four years after the donation, both groups had similar estimated glomerular filtration rates, but the change in 24-hour urine protein was statistically higher in the MEFV carrier group, and no significant change was observed in the control group (P = .004). At the end of the follow-up period, neither overt proteinuria nor kidney failure was seen in either group. CONCLUSIONS: This study showed that the medium- to long-term results of the kidney donors who are carriers of the MEFV gene seem to be safe. However, there was more of a tendency for an increase in proteinuria in the MEFV gene carriers compared with control subjects, which necessitated further long-term care for these donors. PMID- 28340800 TI - Long-term Results of Living Donors in Simultaneous Kidney and Liver Transplantations. AB - INTRODUCTION: Because of the shortage of organs available for transplantation, living related sequential transplantation with the use of liver and a kidney from the same donor has emerged as a reasonable therapeutic alternative. However, there is insufficient literature about the complications that living donors experience after simultaneous kidney and liver transplantations. METHODS: From December 2001 to October 2009, 5 living donors provided simultaneous donation of livers and kidneys and 1 living donor donated first her kidney and then her liver. Demographic data of the donors and information concerning the surgery and postoperative observation were collected prospectively. RESULTS: All of the donors were female. The median age was 27.5 (range, 19-36) years. Indications requiring the simultaneous transplantation of livers and kidneys were primary hyperoxaluria type 1 (PH1) in 5 potential recipients and cirrhosis due to chronic hepatitis B infection and idiopathic chronic renal insufficiency in 1 potential recipient. Four recipients underwent right hepatectomy (segments 5-8) and right nephrectomy; 1 recipient underwent left hepatectomy (segments 2-4) and right nephrectomy; and 1 recipient underwent left lobectomy (segments 2-3) and right nephrectomy. There were no complications except in 1 donor (postoperative ileus). No donor developed hypertension or microalbuminuria. CONCLUSIONS: With the right indications, appropriate preoperative evaluation, meticulous surgical technique, proper postoperative care, and long-term close monitoring to minimize morbidity and mortality risks, liver and kidney donation from the same donor can be considered for simultaneous kidney and liver transplantation. PMID- 28340801 TI - Increased Oxidative Stress in Living Kidney Donors: Correlation of Renal Functions With Antioxidant Capacity. AB - BACKGROUND: Substantial attention has recently been paid to the possibility of an increased risk of chronic kidney disease (CKD) in living kidney donors. It has been demonstrated that CKD patients suffer from increased oxidative stress, which have been reported to show a strong association with several clinical problems such as accelerated atherosclerosis. The purpose of the current cross-sectional, single-center study was to evaluate the relationship between renal functions of living kidney donors and systemic oxidative stress. METHODS: A total of 55 living kidney donors operated at least 1 year ago and 40 age- and sex-matched healthy individuals were enrolled in this study. Plasma malondialdehyde (MDA) levels were determined as oxidative stress marker. Superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were measured as antioxidants. Renal function parameters and proteinuria were also assessed. RESULTS: Mean serum creatinine levels were higher (P = .022) and 24-hour creatinine clearance was lower (P = .016) in living kidney donors compared with healthy controls. Serum MDA levels were higher (P = .034), and SOD and GPx activities were lower (P = .023 and P < .001, respectively). There was a significant positive correlation between serum GPx activity and 24-hour creatinine clearance levels (r = 0.524, P < .01). A linear regression analysis showed that serum GPx activity was still significantly and positively correlated with creatinine clearance (regression coefficient = 0.416, P < .001). CONCLUSION: Our data demonstrated that living kidney donors exhibit slightly reduced kidney function, increased oxidative stress, and decreased antioxidant activity. We propose that 24-hour creatinine clearance is positively correlated with antioxidant enzyme GPx. To our knowledge, this is the first study to demonstrate the association between renal functions and antioxidant activity in kidney donors. PMID- 28340802 TI - Comparison of Two Different Laparoscopic Donor Nephrectomy With Vaginal Extraction Techniques-A Single-Center Experience. AB - OBJECTIVE: The aim of this study was to compare the results of standard laparoscopic donor nephrectomy with vaginal extraction (SLDN-VE) and laparoendoscopic single-site donor nephrectomy with vaginal extraction (LESSDN VE). METHODS: We analyzed the data of 95 female donors who underwent SLDN-VE (group I; n = 87) and LESSDN-VE (group II; n = 8) in our center. Parameters regarding donor age, body mass index (BMI), length of hospitalization, duration of surgical procedure, amount of blood loss, warm and cold ischemia times, side of graft nephrectomy, number of renal arteries and veins, postoperative visual analog pain scores at 6th and 12th hours (VAS6, VAS12), peri-and postoperative complications of donors and recipients, and graft function at discharge and follow-up were compared between the 2 groups. RESULTS: No significant difference regarding donor age, mean operative time, amount of blood loss, or warm ischemia time was observed between the 2 groups. However, BMI (P = .018) and pain scores (VAS6: P = .047; VAS12: P = .009) were lower and length of hospitalization (P = .005) shorter in group II. On the other hand, cold ischemia time (P = .047) was lower in group I. No peri- or postoperative complications occurred for donors and recipients in both groups. Graft function at discharge and during follow-up were similar in both groups. CONCLUSIONS: Because our first priority is to minimize the morbidity of donors, LESSDN-VE can be chosen in selected female donors for not only decreased pain and hospital stay, but also for better cosmetic outcomes. PMID- 28340803 TI - Evaluation of Ureteral Stent Colonization in Live-Donor Renal Transplant Recipients. AB - BACKGROUND: Ureteral stent insertion during kidney transplantation is a matter of debate. Stenting has been proven to reduce the risk of surgical complications. In addition, it has been reported to increase risks such as urinary tract infections especially after operation. Ureteral stent colonization (USC) is known to play a role in the pathogenesis of stent related-infections. The aim of this study was (1) to assess the frequency of USC and values of urine cultures in identifying colonizing bacteria; (2) to assess the importance of indwelling time for USC in live-donor renal transplant recipients; and (3) to evaluate the biomarker role of neutrophil-to-lymphocyte ratio (NLR) on USC. METHODS: A total of 107 live-donor kidney transplant patients were included in the study (76 men and 31 women). The mean age was 43.7 years, and average indwelling time of the ureteral stent was 24.7 days. Patients were divided into three groups according to indwelling stent time as group 1: 15 to 21 days (3rd week), group 2: 22 to 28 days (4th week), and group 3: 29 to 35 days (5th week). The decision to remove the stent was primarily based on clinical judgment. Ureteral stents were removed with the use of flexible cystoscopy. Midstream urine for urine culture and blood samples for NLR were taken prior to stent removal. The removed stents were divided into three parts and taken for bacteriological investigation. RESULTS: Of 107 patients, USC was detected in 24 (22.4%) patients, whereas urinary proliferation was observed in 8 (7.4%) patients. The most common microorganisms found in USC was the Enterecoccus species. The most common microorganisms in urinary culture were Enterecoccus spp. and Klebsiella pnemoniae. All patients with isolated microorganisms in the urine had USC (P < .001). On the other hand, proliferation in urinary culture was observed only in 30% of patients. Urine culture was not significant in identification of USC (P = .063). The three patient groups that were determined according to indwelling stent time were compared in terms of USC, proliferation in urine culture, and NLR. The highest incidence of USC was found in group 3 (44%) and the least in group 2 (11%) (P < .05). No significant difference was found between the groups in terms of urine culture (P = .546). Although no significant difference was found between groups 1 and 2 in NLR values (P = .755), NLR was significantly higher in group 3 (P = .026). CONCLUSIONS: Colonization is common in ureteral stents inserted in live-donor kidney transplant patients, although routine urine culture is insufficient in identfying this colonization. The most common microorganism detected in ureteral stent colonization was Enterecoccus spp. The 4th week was the most convenient time for stent removal time in terms of USC among the 3rd, 4th, and 5th weeks. In addition, increased NLR might have value as a biomarker for USC. PMID- 28340804 TI - Preliminary Screening Results of Fabry Disease in Kidney Transplantation Patients: A Single-Center Study. AB - Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by the deficiency of alfa-galactosidase A (AGALA) and leads to progressive impairment of renal function in almost all male patients and in a significant proportion of female patients. FD is underdiagnosed or even misdiagnosed in patients undergoing kidney transplantation. We initiated a selective screening study for FD among kidney transplant patients in our center. In this study, 1095 male and female patients were included. Dried blood samples on Guthrie papers were used to analyze galactosidase A enzyme for male patients. Genetic analyses were performed in all female and male patients with low enzyme activity. In total, 648 female and 447 male patients with functioning grafts were evaluated. Among 1095 patients, 5 male patients had AGALA activity below threshold and 3 female patients had galactosidase alpha gene DNA variations. One male patient had a disease-causing mutation. The other 4 patients had polymorphisms causing low enzyme activity. All the 3 female patients had mutations that were associated with FD according to Human Gene Mutation Database (ID: CM025441). In contrast, these mutations were reported as unknown clinical significance in Clinvar (rs149391489). The patients with clinical findings suggesting FD were planned to be analyzed for Lyso Gb3. In our selective screening study, 8 variations were found among 1095 kidney transplantation patients, which needs further investigation to determine causes of FD. Clinical findings, physical examination, and family history are also necessary to evaluate the genetic changes as a mutation in this selected population. PMID- 28340805 TI - Association Between HLA Antibodies and Different Sensitization Events in Renal Transplant Candidates. AB - BACKGROUND: Human leukocyte antigen (HLA) allo-immunization is caused by various events such as blood transfusions, pregnancies, or organ transplantations, which can lead to sensitization. In this retrospective study, we evaluated different sensitization models and their effects on panel-reactive antibody (PRA) profiles of renal transplantation candidates. METHODS: Anti-HLA class I/II antibody screening tests were performed in 906 renal transplantation candidates with the use of a microbead-based assay (Luminex). RESULTS: Two hundred ninety-seven (32.8%) of the patients were determined as positive in terms of PRA, and 609 (67.2%) were negative. Sensitized and non-sensitized patients were compared separately in terms of each sensitization type. The anti-HLA class I, II, and I+II positivity rates in patients sensitized only by blood transfusion were 13.1%, 6.3%, and 14.1%, the rates with pregnancy sensitization were 35.5%, 29%, and 45.2%, and rates with previous transplantation sensitization were 15.6%, 34.4%, and 38.9%, respectively. Prevalence of PRA positivity was significantly higher in patients with previous pregnancy than with transplantation and transfusion (odds ratio, 1.003; 95% confidence interval, 0.441-2.281; P = .031). The risk of developing HLA class I antibodies was higher in pregnancies (P < .001), and the risk of developing anti-HLA class II antibodies was higher in patients who had undergone a previous transplantation (P < .001). The rate of developing HLA-B antibodies in patients sensitized by pregnancy were significantly higher compared with sensitization after transfusion (P = .015), as was the rate of developing HLA-DQ antibodies in patients sensitized by previous transplantation compared with sensitization through pregnancy (P = .042). CONCLUSIONS: In patients who are waiting for kidney transplantation, sensitization by pregnancy and transplantation have a significant impact on development of HLA class I and class II antibodies. PMID- 28340806 TI - Average Tacrolimus Trough Level in the First Month After Transplantation May Predict Acute Rejection. AB - BACKGROUND: Although tacrolimus is one of the essential drugs used for the prevention of rejection in kidney recipients, target trough levels are not well established. In this study, we aimed to investigate the association between average tacrolimus trough levels (TTLs) of the first month after transplantation and biopsy-proven acute rejection (BPAR) during the first 12 months after transplant. METHODS: A total of 274 patients who underwent kidney-alone transplantation between 2002 and 2014 were enrolled in the study. Average TTLs of the first month were assessed by means of receiver operating characteristic (ROC) curve analysis to discriminate patients with and those without BPAR. Univariate and multivariate Cox proportional hazards models were used to determine the effect of average TTLs of the first month on BPAR. RESULTS: According to ROC curve analysis, the highest area under the curve (AUC) was obtained from 8 ng/mL (AUC = 0.73 +/- 0.11; 95% confidence interval [CI], 0.62-0.84). Forty-two (31.8%) of the 132 patients with average TTLs <8 ng/mL and 13 (9.1%) of 142 patients with >=8 ng/mL had BPAR during the first 12 months after transplant (P < .001). In univariable analysis, average TTLs of the first month <8 ng/mL were associated with higher risk of BPAR (P < .001), and the significance remained in Cox multivariable analysis (hazard ratio, 2.79; 95% CI, 1.76-3.82; P = .001). No significant differences were observed in the glomerular filtration rate, cytomegalovirus, BK viremia, or BK nephropathy between groups at post-transplant month 12. CONCLUSIONS: Keeping the average TTLs of the first month after transplantation at >=8 ng/mL not only prevents BPAR occurrence but also minimizes the toxic effects of the use of a single-trough level. PMID- 28340807 TI - Prevalence of Human Herpesvirus-8 and BK Polyoma Virus Infections in End-stage Renal Disease and the Influence of Renal Transplantation. AB - Viral infections lead to significant morbidity and mortality in kidney transplant recipients. We evaluated 49 kidney transplant recipients for human herpesvirus 8 (HHV-8) and BK polyomavirus infections in conjunction with data obtained from 43 donors. The seroprevalence of HHV-8 was 6.9% in donors and 12.2% in recipients. HHV-8 DNA was detected below the limit of quantification (<5000 copies/mL) in a recipient with HHV-8 seropositivity at the pretransplant period and was undetectable at month 3 after transplantation. Transient viruria with BK polyomavirus was recorded in 10.2% of recipients without viremia. Multiple factors contribute to viral reactivation, particularly immunosuppressive treatment. Reduction in maintenance immunosuppression seems beneficial in terms of viral reactivation. At our center, routine use of valganciclovir for antiviral prophylaxis may be effective for the prevention of HHV-8 reactivation. PMID- 28340808 TI - Cytotoxic Antibody Detection by Means of Flow-Cytometric Cross-Match. AB - BACKGROUND: Complement-dependent lymphocytotoxicity (CDC-XM) and flow-cytometric (FCXM) cross-match are analyzed individually for each donor and recipient pair, because these techniques have fundamental differences for the evaluation of histocompatibility. Lately, cytotoxic flow-cytometric cross-match (cFCXM) has been developed as an alternative to both CDC-XM and FCXM techniques. We evaluated the limits of cFCXM with the use of different positive serum dilutions. METHODS: CDC-XM, FCXM, and cFCXM tests were performed with the use of commercially available negative and positive serum samples and lymphocytes from healthy donors. RESULTS: Complement-dependent cell death was successfully detected with the use of cFCXM. Complement-dependent cell death ratios in cFCXM were similar those in CDC-XM. With cFCXM, not only complement-dependent cell death but also IgG binding could be detected within a single assay. At higher concentrations of the positive serum, IgG-fluorescein isothiocyanate (FITC) mean fluorescent intensity (MFI) values detected with the use of cFCXM were less than those of conventional FCXM. Correspondingly, for dead cells, MFI values of IgG-FITC were less than those of live cells in higher positive serum concentrations in the cFCXM assay. Moreover, our results demonstrated that in cFCXM analysis, the decreasing ratio of dead cells at increasing positive serum dilutions was not in parallel with the same decrease in IgG-FITC MFI values. CONCLUSIONS: The cFCXM technique detects complement-mediated cytotoxic cell death with the additional ability to show IgG binding in the same tube and therefore may reduce the necessary bench time and workload. PMID- 28340809 TI - Corrected Panel-Reactive Antibody Positivity Rates for Hypersensitized Patients in Turkish Population With Calculated Panel-Reactive Antibody Software. AB - INTRODUCTION: High rates of panel-reactive antibody (PRA) may decrease the chance of kidney transplantation and may result in long waiting periods before transplantation. The calculated PRA (cPRA) is performed based on unacceptable HLA antigens. These antigens are identified by a program that was created based on the antibodies that developed against the HLA antigens circulating in serum and on the risk of binding of these antibodies to antigens. The antigen profile of the population and antigen frequencies can be measured, and more realistic cPRA positivity rates may be obtained using this method. MATERIALS AND METHODS: We developed a program based on the HLA antigens of 494 blood donors in 2 European Federation for Immunogenetics-accredited Tissue Typing Laboratories in Turkey. Next-generation sequencing-based tissue typing (HLA-A, -B, -C, -DR, -DQ, 4 digits) of the samples was performed. The PRA screening test was performed on 380 patients who were waiting for organ transplant from a cadaver in Istanbul Faculty of Medicine. The single antigen bead assay testing was performed to identify the antibody profiles on 48 hypersensitized patients. RESULTS: The PRA testing results using the current methods were 44.6% +/- 18.5%, and the cPRA rate was 86.2% +/- 5.1%. The mean PRA positivity of the sensitized patients using the current methods was 44.6%; however, the rate was 86.2% using the cPRA. DISCUSSION: cPRA shows the rate of the rejected donors according to all unacceptable antigens. The need for a list of unacceptable antigens in place of the PRA positivity rate is a real change in the sensitization-dependent calculation as cPRA positivity rate. CONCLUSION: In principal, implementation of cPRA will encourage many centers and laboratories to adopt a standard measurement of sensitization in Turkey. It will increase the chances of better donor match, particularly for hypersensitized patients, by the creation of an unacceptable mismatch program using cPRA software. PMID- 28340811 TI - Tac-MMF Versus CsA-MMF/CsA-AZA-Based Regimens in Development of De Novo Complement-Binding Anti-HLA Antibodies After Kidney Transplantation. AB - BACKGROUND: Immunosuppressive regimens with tacrolimus or cyclosporine A (CsA) were compared for graft-related outcomes in conjunction with complement-binding de novo donor-specific antibodies (DSAs). METHODS: Non-sensitized adult patients without rejection episodes within 3 months after transplantation were screened for the presence of de novo DSAs and C1q binding. Clinical and biopsy data were retrospectively obtained. RESULTS: The analysis included 118 patients (68 tacrolimus, 50 CsA), with mean age and follow-up of 36.1 +/- 11.4 and 7.2 +/- 4.8 years, respectively. As compared with tacrolimus, the CsA group had higher rates of both class II DSAs and C1q-binding DSAs (20% vs 4.4%, P = .008, and 18% vs 0%, P = .003, respectively). Rates of chronic antibody-mediated rejection (cAMR), proteinuria >500 mg/g, and levels of creatinine both at last visits were also higher in the CsA group (20% vs 0%, P = .002, 30% vs 5.9%, P = .005, 1.67 +/- 1.31 vs 1.18 +/- 0.45 mg/dL, P = .019, respectively).Class II DSAs and C1q binding class II DSAs were significantly correlated with the clinical outcomes (creatinine levels, proteinuria, and cAMR). CONCLUSIONS: Compared with tacrolimus, CsA appears to pose a higher risk for the development of de novo anti HLA antibodies with C1q-binding properties and, consequently, adverse graft related outcomes. PMID- 28340810 TI - Comparison of Two Different Inhalation Anesthetics on Grafted Kidney Function in Patients Undergoing Renal Transplantation Surgery: Desflurane or Sevoflurane? AB - BACKGROUND: Anesthetic management of patients during renal transplantation is vitally important for ensuring proper functioning of kidneys that have undergone ischemia-reperfusion damage. The goal of this prospective study was to compare the effects of 2 different inhalation agents (sevoflurane and desflurane) on grafted kidney function in renal transplantation surgery. METHODS: Sixty-five patients who were scheduled for living donor renal transplantation were enrolled in the study. General anesthesia was performed on all patients. Thirty-five pairs of recipients and donors were anesthetized with sevoflurane (group S) and 30 pairs of recipients and donors were anesthetized with desflurane (group D). Each patient's demographic characteristics, immunologic and clinical data, and hemodynamic parameters were recorded. The estimated glomerular filtration rate was calculated in the preoperative period and on postoperative days 1 and 7. The blood samples were collected before the operation and on postoperative days 1 and 7 for measurement of serum creatinine, neutrophil gelatinase-associated lipocalin, and interleukin 18. RESULTS: There were no significant differences in demographic characteristics or immunologic data between group D and group S. Intraoperative heart rate and mean arterial blood pressure were the same between groups. Creatinine, estimated glomerular filtration rate, neutrophil gelatinase associated lipocalin, and interleukin 18 values did not differ between groups (P > .05) in the preoperative period and postoperative days 1 and 7. CONCLUSIONS: Sevoflurane and desflurane had no adverse effects on grafted kidney functions according to short-term graft outcomes in patients undergoing living donor renal transplantation. PMID- 28340812 TI - Outcomes of Kidney Transplantations From the Same Deceased Donor to Two Different Recipients: A Single-Center Experience. AB - BACKGROUND: Kidney transplantation is the best treatment method for end-stage renal disease. Technically, left kidney transplantation is easier than right kidney, and the complication rates in the right are higher than the left kidney. We performed 28 kidney transplantations from 14 deceased donors between November 2010 and May 2016. Our aim was to share our outcomes and experiences about these 28 patients. METHODS: We performed 182 kidney transplantations between November 2010 and May 2016. Fifty-four kidney transplantations were performed from deceased donors. Thirty-two of these were performed from 16 of the same donors. These 32 recipients' data were collected and retrospectively analyzed. We excluded the transplantations from two same-donors to their four recipients in this study. The remaining 28 recipients were included in the study. RESULTS: The left and right kidney recipients' numbers were equal (14:14). The left kidney:right kidney rate was 11:3 in the first kidney transplantation recipient group; in the second kidney transplantation recipient group, the rate was 3:11. The difference was statistically significant (P = .002). We found no statistical differences for sex, mean age, and body mass index of recipients, total ischemic time of grafts, hospitalization times, creatinine levels at discharge time, and current ratio of postoperative complications of recipients (P > .05). CONCLUSIONS: There were no differences in the left or the right kidneys or in the first and the second kidney transplantations during the long follow-up period. PMID- 28340813 TI - Comparison of Anti-HLA Antibody Production According to Gestational Periods in Pregnant Women. AB - BACKGROUND: To evaluate paternal anti-HLA antibody profiles, sera samples were collected from pregnant women in different trimesters and the panel-reactive antibody (PRA) specificities were identified. METHODS: From 2013 to 2015, serum samples were obtained from 41 pregnant women who had registered at the Izmir Tepecik Education and Research Hospital Gynecology Clinic. Anti-HLA antibodies were screened by using the panel reactive antibody screening and identification tests. Sera samples were obtained at the first, second, and third trimesters. The primary outcome was to determine the anti-HLA antibody production term during pregnancy; the secondary outcome was identification of anti-HLA antibodies. RESULTS: None of the women had a sensitization history except during pregnancy. We observed that 54% of the women produced paternal antibodies, either class I or II. Class I PRA positivity of the women who had a first or second pregnancy was the same in all 3 trimesters, whereas class II positivity was increased in the third trimester. Class II and both class I and II positivity increased in the third trimester; class I positivity was decreased in the third trimester. PRA positivity could be affected by the history of pregnancy and could be raised, but no impact was observed from the history of abortion and miscarriage (odds ratios, 1.9, 0.4, and 0.5 [95% confidence intervals, 0.5-7.8, 0.1-2.0, and 0.3-0.7], respectively; P > .05). The most frequently detected antibodies were A2, B7, DR7, DR4, DR11, DR13, DQ2, and DQ8. CONCLUSIONS: Anti-HLA antibodies against paternal HLA antigens were detected more in multiparous women than in primiparous women. Anti-HLA antibody detection ratios did not change until the third trimester and were followed by a specific increase in class II anti-HLA antibody production. PMID- 28340814 TI - Evaluation of TH17 and TH1 Immune Response Profile in Patients After Renal Transplant. AB - BACKGROUND: Renal transplantation (RT) is the best treatment option for patients with end-stage renal disease (ESRD) because it improves both quality of life and survival. However, allograft rejection remains the most important barrier to successful transplantation. Underlying immunologic mechanisms should be understood to develop appropriate treatment strategies. METHODS: In this prospective study, we followed renal transplant recipients for 6 months. The study population comprised 50 recipients of renal transplants, and these were divided into 2 groups: 44 patients with stable graft function (SGF) and 6 patients with rejection (RX). Peripheral blood samples were drawn from patients on the pre-RT day, at post-RT day 7, month 1, and month 6, and on the day of rejection for analysis of the percentages of cytokines interleukin (IL) 17 and interferon (IFN) gamma with the use of flow cytometry and enzyme-linked immunosorbent assay. RESULTS: The percentages of intracellular IFN-gamma were not significant in the group with RX compared with SGF. Levels of intracellular IL-17 obtained at the 6th month after RT were significantly higher in the RX group than in the SGF group. Plasma levels of pre-RT IL-17 were also higher in the RX group; therefore, it may be a predictive biomarker of acute rejection of renal transplants. CONCLUSIONS: The present study provides information about pre-RT and post-RT cytokine profiles of Turkish patients with ESRD. We consider cytokine analysis to be a valuable biomarker panel in the prevention of rejection and in assisting with new treatment strategies for patients undergoing renal transplant. PMID- 28340815 TI - Expression Profile of MicroRNA Biogenesis Components in Renal Transplant Patients. AB - BACKGROUND: MicroRNAs (miRNAs) and the miRNA biogenesis components are potential biomarkers of some prevalent diseases, such as cancer and diabetes. In light of this information, we aimed to investigate the expression profiles of miRNA biogenesis components in renal transplant patients before and after transplantation and how these profiles are related to immunosuppressive treatment and clinical outcomes of these patients. METHODS: In this study, gene and protein expression profiles of Dicer, Drosha, Pasha (DGCR8), Exportin5 (XPO5), and Argonaute2 (AGO2) in peripheral blood mononuclear cells (PBMCs) of renal transplant patients were evaluated by means of real-time quantitative polymerase chain reaction and Western blot methods before and 3 months after transplantation. Patients who had transplant procedures for the first time were included in the study. RESULTS: Gene expressions were significantly reduced after transplantation. The reduction rate of expressions in 1 patient undergoing chronic rejection was higher. In addition, in patients under everolimus treatment, gene expression of Dicer did not change and gene expression of AGO2 increased. Dicer, Drosha, DGCR8, and AGO2 protein expressions were reduced in all patients, but no change was observed in XPO5 protein expression in nonrejecting patients. Interestingly, in the patient undergoing chronic rejection, protein expression profiles other than Dicer were distinctive from nonrejecting patients. However, XPO5 protein expression was higher in that patient. CONCLUSIONS: Our study shows the importance of the global effect of immunosuppressive treatment on the miRNA biogenesis pathway. miRNA biogenesis components are potential biomarkers indicative of graft outcome and pharmacologic target molecules. PMID- 28340816 TI - Relevance of Flow Cytometric Auto-Crossmatch to the Post-transplant Course of Kidney Transplant Recipients. AB - INTRODUCTION: The crossmatch test is essential prior to kidney transplantation (tx) to confirm compatibility between the donor and the recipient. However, its results can be misleading due to "undetectable antibodies" in the recipient's serum. To establish if undetectable autoantibodies are responsible for a positive result, an auto-crossmatch test can be performed. In this study, we aim to determine the long-term prognostic value of auto-flow cytometric auto-crossmatch (FCXM) test on kidney survival in kidney tx recipients. MATERIALS AND METHODS: The primary outcome variable was reduced renal function. Secondary endpoints were incidence of biopsy-confirmed chronic antibody-mediated rejection (CAMR) and recurrent glomerulonephritis (GN). RESULTS: There were no differences regarding initial serum creatinine levels between the study and control groups (P = .441). Patients who had positive auto-B FCXM had a significantly reduced renal function compared with the control group (P = .016). Four patients developed biopsy confirmed CAMR in the study group and 1 patient in the control group (P = .047). Five patients had biopsy-confirmed recurrent GN in the GN study group, and only 1 patient had recurrent GN in the GN control group (P = .026). DISCUSSION: Kidney transplant recipients with positive auto-FCXM test had significantly reduced renal function and a higher incidence of recurrent GN and CAMR compared with the control group. The findings of this study suggest a potential role of auto antibody causing positive auto-FCXM test result, meanwhile increasing the risk of CAMR, recurrent GN, and new-onset diabetes after tx. PMID- 28340817 TI - Efficacy and Safety of ATG-Fresenius as an Induction Agent in Living-Donor Kidney Transplantation. AB - BACKGROUND: Induction therapy is mostly recommended for deceased-donor transplantation, whereas it has some controversies in live-donor transplantation. In this study, we described the outcomes of live-donor renal transplant recipients who received ATG-Fresenius (ATG-F) induction. METHODS: Live-donor transplantations in patients over 18 years old with ATG-F induction between 2009 and 2015 were included. All patients received quadruple immunosuppression, one of which was ATG-F induction. Biopsies after the artery anastomosis (zero hour) and protocol biopsies at the 6th month and at the 1st first year were obtained. Acute graft dysfunction was defined as a 20% to 25% increase in creatinine level from baseline. All acute rejection episodes were biopsy-confirmed. All episodes were initially treated with intravenous methyl prednisolone (MP) or ATG-F if resistant to MP. Four hundred twenty-two patients with live-donor transplantation were evaluated. The mean age was 40 +/- 13 (18-73) years. The mean panel-reactive antibody levels were 42% +/- 30% and 45% +/- 30% for class I and II, respectively. RESULTS: The mean mismatch number for living unrelated donors (n = 112) was 4.6 +/- 1.0. Acute rejection rate was 29.1% (123 patients) within the first year. The mean cumulative ATG-F doses for per patient and per kilogram were 344 +/- 217 mg and 5.1 +/- 2.7 mg, respectively. Patient survival rates were 98.3% and 96.7% for 12 months and 60 months, respectively. Death-censored graft survival rates were 97.6% and 92.1% for 12 months and 60 months, respectively. CONCLUSIONS: ATG-F induction provided excellent graft and patient survival rates without any significantly increased side effects. Increasing sensitized patient numbers, more unrelated donors, increasing re-transplantation numbers, and more desensitization protocols make ATG-F more favorable in an induction regimen. PMID- 28340818 TI - Use of ATG-Fresenius as an Induction Agent in Deceased-Donor Kidney Transplantation. AB - BACKGROUND: Anti-T-lymphocyte globulins (ATG) are most commonly used as induction agents in kidney transplantation (KT). In this study, we investigated the use of ATG as induction therapy in deceased-donor KT. METHODS: Among 152 deceased-donor KT recipients transplanted between January 2009 and December 2003, 147 with exact data were enrolled in this study. Delayed graft function was defined as dialysis requirement after KT. Greater than 10% panel-reactive antibody (PRA) was considered as positive. Total ATG (rATG-Fresenius) dosage and induction duration was evaluated. Mean age was 45 +/- 10 years; 91 patients were male and 56 patients were female. Class I and class II PRA-positive patient numbers were 20 (13.6%) and 17 (11.5%), respectively. Pre-transplant dialysis vintage was 108 +/- 63 months. Mean donor age was 42 +/- 17, and cold ischemia time was 16 +/- 5 hours. Eighty-nine patients (60%) had delayed graft function and needed at least one session of hemodialysis after transplantation. Cumulative ATG-F dosage was 676 +/- 274 mg. The mean ATG-F cumulative dosage was 10.6 +/- 3.8 mg/kg. At the end of first year, mean creatinine and proteinuria levels were 1.4 +/- 1.0 mg/dL and 0.3 +/- 0.4 g/d, respectively. RESULTS: Mean follow-up time was 32 +/- 20 months. During follow-up, there were 14 graft failures and 11 patients died. Patient survival for 1 and 2 years were 93% and 92.3%, respectively. Death censored graft survival rates for 1 and 2 years were 94.8% and 90.8%, respectively. CONCLUSIONS: ATG-F induction provides acceptable graft and patient survival in deceased-donor KT. ATG-F infusion is well tolerated. Infection rates seem to be acceptable compared with all transplantation populations. PMID- 28340819 TI - Influence of Proton Pump Inhibitors on Mycophenolic Acid Pharmacokinetics in Patients With Renal Transplantation and the Relationship With Cytochrome 2C19 Gene Polymorphism. AB - BACKGROUND: Most patients have serious digestive complications after renal transplantation. Therefore, it is important to protect gastrointestinal function to improve the survival rate of transplant patients. Proton pump inhibitors (PPIs) such as lansoprazole and rabeprazole are widely administered to renal transplant patients with mycophenolic acid (MPA) in the perioperative period. PPIs are metabolized by cytochrome (CYP) 2C19 enzymes. Mycophenolate sodium (MYF) and mycophenolate mofetil (MMF) have been used in immunosuppression. Clinically relevant drug-drug interactions have been described between immunosuppressive drugs. In the present study, we investigated the drug interaction between MPA and lansoparazole or rabeprazole and the impact of CYP2C19 polymorphisms on these drug interactions after renal transplantation. MATERIALS AND METHODS: A total of 125 renal transplant patients taking MPA derivatives between 2012 and 2016 were included in this study. The 125 patients were divided into 6 groups: MMF/tacrolimus/steroid together with lansoprazole or rabeprazole; MYF/tacrolimus/steroid together with lansoprazole or rabeprazole and without PPI. The single nucleotide polymorphisms of CYP2C19 were determined by the polymerase chain reaction-restriction fragment length polymorphism. Plasma concentrations of MPA were measured by cloned enzyme donor immunoassay. Clinical parameters such as incidence of delayed graft function and acute rejection, the rate of change of serum creatinine, toxicity, and gastrointestinal adverse effects were analyzed retrospectively. RESULTS: The mean concentrations of MPA in the MYF group were higher than those in the MMF group. The mean dose-adjusted blood concentration of MPA coadministered with lansoprazole was lower than that of MPA with rabeprazole or without PPI in MMF and MYF groups (P < .05). In patients with the CYP2C19*2/*2 genotype, the mean concentrations of MMF with lansoprazole were significantly lower than those with rabeprazole with MMF or without PPI (P < .05). Gastrointestinal side effects were significantly higher in MMF with lansoprazole group than in MYF with lansoprazole group (P < .05). However, no differences were found according to genotype distribution in all groups (P > .05). CONCLUSION: Polymorphisms in CYP2C19 are related to the metabolic oxidation of drugs to varying degrees. Both genetic and clinical factors in pharmacokinetics may help to make further progress toward individualized therapy to yield maximum efficacy with minimal side effects. PMID- 28340820 TI - Role of Everolimus on Cardiac Functions in Kidney Transplant Recipients. AB - BACKGROUND: Kidney transplantation is known to increase the survival of dialysis patients by ameloriating cardiac status, including both systolic and diastolic functions. We aimed to evaluate the role of immunosuppressive drug regimens on cardiac functions of kidney transplant recipients (KTRs). METHODS: We prospectively evaluated 120 KTRs immediately before and 1 year after the kidney transplantation, using tissue Doppler echocardiography. A triple immunosuppressive therapy including tacrolimus, mycophenoloic acid (MPA), and prednisolone was started for all patients. After 3 to 6 months, the tacrolimus dose was lowered to achieve target serum levels of 5 to 8 ng/mL in both groups. MPA was switched to everolimus, with target levels of 4 to 6 ng/mL, in group 1 (n = 58), whereas group 2 (n = 62) continued with MPA. RESULTS: No differences in age, sex, or dialysis duration existed between the groups. The prevalence of diabetic or hypertensive nephropathy as the etiology of chronic kidney disease was similar. Blood pressure was strictly controlled. The number of acute rejection episodes was not different in both groups, and no graft loss was observed in either group. Improvement in cardiac parameters including ejection fraction, left ventricular diastolic diameter, posterior wall thickness, and left ventricular hypertrophy was significantly better before and 1 year after transplantation. Interestingly, when compared with group 2, ameloriation of all of the parameters mentioned above was even better in group 1 patients (P = .02, P = .03, P = .04, and P = .04, respectively). Multivariate analysis of the significant variables determined by univariate analysis identified albumin (relative risk [RR] = 1.05, P = .02) and everolimus (RR = 1.07, P = .01) as two independent factors of improving cardiovascular function. CONCLUSIONS: Better ameloriation of cardiovascular functions with everolimus may favor the choice of this drug in KTRs. PMID- 28340821 TI - Incidence, Management, and Risk Factors for Lower Gastrointestinal Bleeding in Renal Transplant Recipients. AB - BACKGROUND: There are limited convincing data regarding management and outcomes of lower gastrointestinal bleeding (LGB) in renal transplant recipients (RTR). The aim of this study was to evaluate incidence, management strategies, and risk factors associated with LGB in RTR. METHODS: Between January 2004 and December 2013, RTR with LGB were analyzed. LGB was defined as having clinical evidence of hemorrhage after upper gastrointestinal etiology was ruled out. RESULTS: There were 1578 RTR with a mean age of 50 +/- 14 years at the time of transplantation. Mean follow-up time after transplantation was 57 +/- 45 months. Forty-five (2.9%) patients had a documented site of LGB. The most common causes of bleeding were colitis and angiodysplasia (n = 17). Mean time to LGB after transplantation was 43 +/- 36 months. Twelve patients with LGB required intervention. Three underwent colectomy, endoscopic treatment was utilized in 8, and 1 patient had angiographic embolization to control bleeding. Recurrent LGB developed in 11 patients of 42 patients who did not have surgery at the time of index bleeding. Surgical (n = 1) or endoscopic intervention (n = 4) was required in 5 of recurrent bleeders. LGB was more commonly seen in RTRs who had development of a nonfunctioning kidney (P < .0001). RTR who had an LGB had an increased overall mortality rate (not directly related to the bleeding episode) compared with those who did not have a LGB (P = .001). We did not observe any increased risk of LGB bleeding among patients who were receiving anticoagulant or anti-aggregant treatment agents (P = .76). CONCLUSIONS: Nonfunctioning kidney after transplant is a risk factor for LGB. Overall mortality rates increased after LGB in RTR. Strategies aiming to prolong transplanted kidney function may reduce the incidence of LGB and improve life expectancy in RTR. PMID- 28340822 TI - Risk Factors of Hyperuricemia After Renal Transplantation and Its Long-term Effects on Graft Functions. AB - BACKGROUND: Hyperuricemia is a common complication in renal transplant recipients. Recent studies have suggested that hyperuricemia may contribute to the deterioration of graft function. METHODS: In this study, we aimed to investigate the risk factors related to hyperuricemia and the effects of hyperuricemia on graft dysfunction, graft survival, cardiovascular events, and mortality rates. Between the years 2005 and 2016, 141 renal transplantation patients with at least 5 years of follow-up were included in this retrospective cohort study. Multi-linear regression analysis was used to determine the relationship between mean serum uric acid level and estimated glomerular filtration rate (eGFR). RESULTS: The average transplant age was 37.1 +/- 12.1 years and the average follow-up time was 83.09 +/- 20.30 months; the prevalence of patients with hyperuricemia was 39 (27.6%). The mean uric acid levels were higher in women (P < .001) in the condition of dyslipidemia (P = .026), beta blocker usage (P = .002), and thiazide diuretics (P = .020). Patients with hyperuricemia (P < .001), new-onset hypertension (P = .027), beta-blocker usage (P = .005), and thiazide diuretics (P = .040) had statistically different eGFR levels than other recipients. Multivariant regression analyses showed that eGFR levels after transplantation were correlated with mean uric acid levels (beta = 0.46, P = .001), donor age (beta = -0.18, P = .048), recipient age (beta = -0.28, P = .0003), and mean hemoglobin levels (beta = 0.31, P = .003). CONCLUSIONS: There was no difference in graft loss, general mortality, and cardiovascular events between normo-uricemic and hyperuricemic groups. Increased uric acid levels contribute to eGFR decline in patients with renal transplantation. On the other hand, effects of uric acid levels on graft survival, cardiovascular events, and general mortality are still controversial. PMID- 28340823 TI - Evaluation of Bone Disease in Kidney Transplant Recipients. AB - BACKGROUND: Kidney transplant recipients are known to have bone disease, specifically osteoporosis. In this descriptive clinical study we aimed to evaluate the incidence of osteoporosis and to determine the risk factors among our transplant recipients. METHODS: A total of 109 patients (82 males and 27 females) aged from 19 to 70 years, who had undergone kidney transplantation 12 to 69 months previously, were included in the study. Bone mineral densitometry was performed using dual-energy X-ray absorptiometry. The correlation between femur and lumbar spine T-scores with age, gender, post-transplantation duration, serum 25 hydroxy vitamin D, parathyroid hormone, calcium, phosphorus, creatinine, and hemoglobin values were investigated. RESULTS: The incidence of osteoporosis was 22% (24 of 109 patients). The most common sites of osteoporosis were the femur (osteoporotic in 17 patients [15.5%] and osteopenic in 57 [52.2%]) and the lumbar spine (osteoporotic in 24 patients [22%] and osteopenic in 50 [45.8%]). Osteoporosis was found to have no relationship with age and gender. There was a significant negative correlation between serum parathyroid hormone levels with both femur and lumbar spine T-scores (P = .013 and .033, respectively). However, serum phosphorus levels were negatively correlated with only femur T-scores (P = .037). A positive correlation of hemoglobin with lumbar T-scores and a negative correlation with post-transplantation duration (P = .038 and .012, respectively) were also observed. CONCLUSION: Bone disease after transplantation is a frequent complication, which may decrease the quality of life, so we believe it is important to reduce the morbidity; it is required to detect and correct the risk factors of this complex pathophysiological situation. PMID- 28340824 TI - Comparison of Surgical Correction Techniques for Post-Renal Transplantation Vesicoureteral Reflux. AB - BACKGROUND: Symptomatic urinary tract infection (UTI) after renal transplantation (RT) is an important morbidity in transplant recipients and may cause pyelonephritis and sepsis. Surgical correction of high-grade vesicoureteral reflux (VUR) after RT is suggested, performing ureteral reimplantation or pyelo ureteral/uretero-ureteral anastomosis. Recently, extravesical seromuscular tunnel lengthening techniques have been reported with favorable results and low complication rates. METHODS: We retrospectively reviewed the charts of 38 patients with post-transplantation VUR who underwent reflux correction surgery. Patient characteristics were analyzed to compare our extravesical seromuscular tunnel lengthening technique with uretero-ureteral and pyelo-ureteral anastomosis techniques. RESULTS: Twenty patients were treated with the extravesical approach (group I) and 18 patients by pyelo-ureteral or uretero-ureteral anastomosis with the use of native ureter (group II). Mean operative time was significantly shorter in group I than in group II (64.8 vs 110.1 min; P < .05), and mean duration of hospital stay after the operation also was shorter in group I (1.5 vs 5.1 d; P < .05). We determined persistent VUR in postoperative voiding cystouretrography in 2 patients (10%) in group I, but there was regression in VUR grades of all of the patients. There was no significant difference in postoperative number of UTI episodes and serum creatinine levels between the 2 groups. CONCLUSIONS: Extravesical seromuscular tunnel lengthening is an effective and safe technique for post-transplantation VUR management. PMID- 28340825 TI - Should Interventional Radiology or Open Surgery Be the First Choice for the Management of Ureteric Stenosis After Transplantation? Dual-Center Study. AB - BACKGROUND: Ureteric stenosis (US) is the most common urologic complication after kidney transplantation. In this dual-center retrospective study we compared the efficacy and safety of open surgery versus interventional radiology for the management of US. METHODS: From 2009 to January 2016, US was treated by surgical revision in 22 (7.8%) out of 281 recipients at one center (group 1) and managed by percutaneous nephrostomy with antegrade nephroureteral stenting (PNAS) in 22 (14.2%) out of 155 recipients at the other center (group 2). RESULTS: Three patients in group 1 required reintervention and again were treated with open surgery. With a mean follow-up of 42.1 +/- 38.7 months, graft function improved in all but one patients (95%). Three patients in group 2 were admitted with relapse of US not amenable to 2nd PNAS, and 2 of them were managed with surgery. These 3 and 2 other cases with improved graft function after PNAS lost their grafts and returned to hemodialysis. The remaining 17 patients (77%) still have functioning grafts. There was no statistically significant difference between the efficacy of PNAS and open surgery for the management of post-transplantation US. However; a benefit in favor of open surgery existed for type 2 urinary tract obstruction in terms of decreased reintervention rate and much better protection of the graft function and survival. CONCLUSIONS: Both interventional radiology and open surgery have acceptable efficacy rates in the management of ureteric complications after renal transplantation. Open surgery is a better treatment option for type 2 obstruction. PMID- 28340826 TI - Optimal Timing for Removal of the Double-J Stent After Kidney Transplantation. AB - BACKGROUND: Urologic complications (UC) have gradually decreased in recent years after advanced surgical experience. The incidence of urologic complications varies between 0.22% and 30% in different medical studies. There is no routine usage of double-J stenting (DJS) during renal transplantation (RT) in the literature. It is a necessity, and optimal timing for stent removal is an important question for many transplantation centers. METHODS: This study includes 818 renal transplant patients whose ureteroneocystostomy anastomoses were completed by use of the Lich-Gregorie procedure during a 2-year period at a transplantation center. We performed 926 renal transplantations at Antalya Medical Park Hospital Renal Transplantation Center between January 2014 and January 2016. The patients were divided into four groups according to the timing of DJS removal. RESULTS: For group 1, removal time for DJS was between 5 and 7 days; group 2, Removal time for DJS was between 8 and 14 days; group 3, removal time for DJS was between 15 and 21 days; and group 4, removal time for DJS was later than 22 days. The patients were divided into two groups according to removal time of stent as 5 to 14 days and >15 days. DJS was performed again in the patients whose urine output was reduced during the first 5 days after removal of the DJS, whose creatine level increased, and whose graft ureter and collecting tubules were extended as an ultrasonographic finding. CONCLUSIONS: There is no declared optimal time for the removal of DJS. The removal time was reported between postoperative first week and 3 months in some of the reports of RT centers, according to their protocols. We emphasize that the optimal time for the removal of DJS is 14 to 21 days after RT, based on the findings of our large case report study. PMID- 28340827 TI - End-To-Side Versus End-to-End Uretero-Ureteral Anastomosis in Kidney Transplant Recipients With Disused Atrophic Bladder. AB - BACKGROUND: Extravesical Lich-Gregoir ureteroneocystostomy (UC) is the most widely used method for urinary reconstruction during kidney transplantation. Sometimes it is difficult to perform UC in cases with disused atrophic bladder. Pyelo-ureteral anastomosis (PUA) and uretero-ureteral anastomosis (UUA) may be preferred to UC for these patients. METHODS: We retrospectively reviewed the charts of 833 kidney transplant recipients operated on by our transplantation team between July 2010 and November 2014. The patients were divided into two groups: Group I consisted of 16 patients who underwent end-to-side UUA and Group II consisted of 20 patients who underwent end-to-end UUA. The two groups were compared in terms of efficacy, safety, and graft function. RESULTS: As we performed end-to-side UUA as a relatively new technique compared with end-to-end UUA, the post-transplantation follow-up period of Group II was significantly longer than Group I (P = .000), but all the patients in both groups had at least 1 year of follow-up. Because the first two patients in Group II, who underwent native ureteral ligation without nephrectomy, developed hydronephrosis in their native kidneys, requiring nephrectomy in the post-transplantation period, we performed native nephrectomy in all of the remaining patients in this group. That is why the mean operative time was significantly longer in Group II compared with Group I (P = .000). There was no significant difference between the two groups in terms of postoperative surgical complications, post-transplantation urinary infections, and graft function. CONCLUSION: End-to-side UUA without native ureteral ligation is a safe surgical technique for urinary tract reconstruction during kidney transplantation in patients with disused atrophic bladder. PMID- 28340828 TI - Prevalence and Risk Factors of BK Viremia in Patients With Kidney Transplantation: A Single-Center Experience From Turkey. AB - BACKGROUND: BK virus is the cause of nephropathy, which can progress to graft loss after kidney transplantation. In this study, we aimed to investigate the prevalence and risk factors of BK viremia in patients with kidney transplantation at our center. METHODS: This was a retrospective single-center study. We included recipients transplanted between 2010 and 2015. Patients were stratified according to BK virus DNA follow-up values into three groups (0-999 copies/mL, 1000-9999 copies/mL and >=10,000 copies/mL). The parametric t test and the non-parametric chi2 test were used to detect differences between groups. Multivariate analysis was used to identify risk factors for BK viremia. RESULTS: One hundred eighty three patients were included in the study, with mean follow-up time of 33.6 +/- 14.9 months. BK viremia prevalence was found 15.8% (n = 29), and time to detection of viremia was 7.6 months. Cadaveric transplantation and matching human leukocyte antigen (HLA) A24 and HLA B55 subgroups were found to be independent risk factors for BK viremia [odds ratio (OR), 3.65; 95% confidence interval (CI), 1.42-9.39; P < .001; OR, 4.94; 95% CI, 1.84-13.2; P < .001 and OR, 14.03; 95% CI, 1.07-183.5; P = .04, respectively]. Risk factors for BKV level >=10,000 copies/mL cadaveric transplantation, male sex, and HLA A24 matching (OR, 4.53; 95% CI, 1.49 13.7; P < .001; OR, 3.47; 95% CI, 1.11-10.86; P = .03 and OR, 3.63; 95% CI, 1.08 12.1; P = .03, respectively). CONCLUSIONS: Patients should be followed more carefully for BK viremia who have cadaveric transplantation, are male, and have matching in certain HLA groups, which were independent risk factors in the present study. Our results are important to individualize screening methods and provide early diagnosis in our country. PMID- 28340829 TI - Impact of Prophylaxis vs Pre-emptive Approach for Cytomegalovirus Infection in Kidney Transplant Recipients. AB - Cytomegalovirus (CMV) is the most common viral infection during the post transplant period, and it is one of the major causes of morbidity and mortality in kidney transplantation. In this study, the incidence and impact of pre-emptive and prophylactic approaches and long-term effects on graft and patient survival of CMV infection were investigated. Among 493 adult kidney transplant recipients, pretransplant CMV IgG-negative patients and patients with a follow-up shorter than a month were excluded. The patients were divided into 2 groups: pre-emptive group (n = 187, regular screening and acyclovir 400 mg twice daily for 6 months), and prophylaxis group (n = 275, valganciclovir 450 mg/d for 3 months). The pre emptive group was screened for CMV with either pp65 antigenemia or CMV DNA. There were 462 patients, and mean follow-up was 37.7 months. There were more CMV infections in the pre-emptive group than in the prophylaxis group (n = 56, 30.1% vs n = 12, 4.4%, respectively; P < .001). Late CMV infections were significantly more frequent in the prophylaxis group (10 of 12, 83.3%) than in the pre-emptive group (8 of 56, 14.3%, P < .001). In multivariate analysis, valganciclovir prophylaxis was associated with a lower CMV infection (relative risk [RR]: 0.18, 95% confidence interval [CI] 0.08 to 0.39, P < .001). Delayed graft function was the only independent risk factor for graft loss during the follow-up on multivariate Cox regression analysis (RR: 2.66, 95% GA 1.17 to 6.04, P = .02). Valganciclovir prophylaxis was more protective against CMV infection than the pre emptive approach. Neither prophylaxis/pre-emptive approaches nor CMV infection had negative effect on graft and patient survival. PMID- 28340830 TI - A Novel Biomarker for Post-Transplant Recurrent IgA Nephropathy. AB - BACKGROUND: The serum levels of galactose-deficient immunoglobulin (Ig)A1 (Gd IgA1) represent the most promising candidate biomarker for IgA nephropathy (IgAN). The aim of this study was to evaluate the serum levels of Gd-IgA1 as a novel noninvasive biomarker for post-transplant IgAN recurrence. METHODS: Serum Gd-IgA1 levels of 18 patients with recurrent IgAN were compared with control renal transplant recipients (n = 23) with non-recurrent IgAN and control non transplant IgAN patients (n = 44) and healthy relatives (n = 11). Serum Gd-IgA1 levels of patients were measured with the use of KM55 enzyme-linked immunosorbent assay (ELISA). The effects of serum Gd-IgA1 concentrations on IgAN recurrence, post-transplant events, and graft survival were evaluated. RESULTS: All recurrent IgAN patients presented with renal dysfunction (mean serum creatinine, 1.62 +/- 0.39 mg/dL) and detectable proteinuria at the time of diagnosis. Serum Gd-IgA1 levels of recurrent IgAN patients (8735 +/- 10854 ng/mL [log10: 3.71 +/- 0.45]) were significantly higher than those of non-recurrent IgAN patients (4790 +/- 6089 ng/MUL [log10: 3.31 +/- 0.64]) (P = .027). Serum Gd-IgA1 levels of non transplant IgAN patients were significantly higher (8791 +/- 8700 ng/MUL [log10: 3.79 +/- 0.36]) than those of non-recurrent IgAN patients (4790 +/- 6089 ng/MUL [log10: 3.31 +/- 0.64]) and healthy relatives (2615 +/- 1611 ng/MUL [log10: 3.34 +/- 0.27]) (P < .001 and P = .021, respectively). Receiver-operating characteristic curve analysis revealed that the area under the curve for recurrence of IgAN was 0.69 (0.53-0.85) for serum Gd-IgA1 (P = .038). Biopsy confirmed allograft rejection rates were similar in the recurrent IgAN group [3 (17%)] compared with the non-recurrent IgAN [6 (26%)] group (P = .47). Graft failure rate was not also significantly different in the recurrent IgAN group [4 (22.2%)] compared with the non-recurrent IgAN group [2 (8.7%)] (P = .224). CONCLUSIONS: This novel lectin-independent Gd-IgA1 ELISA that can detect serum Gd IgA1 in patients with recurrent IgAN can be used as a biomarker for diagnosis and activity assessment of post-transplant recurrent IgAN. PMID- 28340831 TI - Pregnancy and Delivery in the Sequel of Kidney Transplantation: Single-Center Study of 8 Years' Experience. AB - BACKGROUND: Depending on hyphothalamic, hyphophyseal, and gonadal axis dysfunction, anovulatory irregular cycles occur and the probability of pregnancy decreases in the patients with chronic kidney disease (CKD). Maternal mortality and morbidity rates are increased in CKD patients; the risk of premature delivery is 70% and the risk of preeclampsia is 40% more than normal among those with a creatine level of >2.5 mg/dL. METHODS: If a pregnancy is expected in the sequel of kidney transplantation (KT), a multidisciplinary team approach should be adopted and both the gynecologist and the nephrologist should follow the patient simultaneously. Among 3883 patients who underwent KT at Antalya Medical Park Hospital Transplantion Department between November 2009 and October 2016, the records of 550 female patients between the ages of 18 and 40 years were examined retrospectively; 31 patients who complied with these criteria were included in the study group. In 6 of these patients who had an unplanned pregnancy, medical abortion was performed after the families were informed about the possible fetal anomalies caused by the use of everolimus in the first trimester, and they were excluded from the study (pregnant group). The control group consisted of 43 patients who had a KT and became pregnant, and of those who had recently undergone KT and shared similarities regarding age, CKD etiology, duration of dialysis, and number of transplants. RESULTS: In both groups, the ages of the patients, their follow-up span and dialysis duration, tissue compatibility, age of the donor, and time elapsed until the pregnancy was analyzed, whereas in the control group, creatinine levels in the first, second, third, and fourth years after the KT were reviewed. Additionally, in the pregnant group, creatinine levels of the first, second, and third trimesters; delivery week; birth weight of the baby; APGAR scores of the first minute; postnatal creatinine levels of first, second, and third years; and prenatal, maternal, and postnatal acute rejections were reviewed. We measured the creatine clearance by use of the Cockcroft-Gault formula in the pregnancy group before pregnancy and during delivery [Cockcroft Gault formula: (140 - age) * body weight (kg)/72 * plasma creatine level (mg/dL) * 0.85]. CONCLUSIONS: Pregnancy after KT is risky both for the mother and the baby; however, if planned and followed in coordination within an experienced center, both the pregnancy period and the birth process can occur without distress. PMID- 28340832 TI - The Most Frequently Cited 100 Articles in Liver Transplantation Literature. AB - INTRODUCTION: We investigated the liver transplantation literature since 1975 and found the most frequently cited 100 articles and assessed the distribution of authors and journals of these articles. METHOD: Using the advanced mode of the Institute for Scientific Information (ISI) Web of Science (WOS) search engine, the words "SU = transplantation AND TI = liver OR SU = transplantation AND TS = liver" were used to scan articles and determine the most-cited 100 articles on July 18, 2016. RESULTS: From 1975 to date, it appears a total of 43,369 articles were published in the field of liver transplantation in the WOS. Although the most cited article had 677 citations, the least cited article had 180 citations. The mean citation number for the 100 articles was 252.31 +/- 96.75. The mean annual citation number for the articles varied from 61.55 to 5 and the mean was 15.31 +/- 8.63. The most cited article was by Feng et al "Characteristics Associated With Liver Graft Failure: The Concept of a Donor Risk Index" published in the American Journal of Transplantation (677 citations). CONCLUSION: Bibliometric analysis highlights the key topics and publications that have shaped the understanding and management of liver transplantation. According to our research, this is the first study to investigate articles with most citations in the field of liver transplantation. In our study the article with the most citations was cited 677 times, whereas the 100th article was cited 180 times with a mean citation number for the 100 articles of 252.31 +/- 96.75. PMID- 28340833 TI - Telescopic Biliary Reconstruction in Patients Undergoing Liver Transplantation With 1-Year Follow-up. AB - BACKGROUND: Biliary complications are important during liver transplantation because of their effect on recipient and graft survival, incidence, and the long treatment period. These complications are associated with 50% morbidity and 30% mortality rates in recent studies. One of the most important reasons for biliary anastomosis complications is arterial ischemia. We present the results of our telescopic biliary anastomosis technique performed on the mucosa of the main biliary duct. PATIENTS AND METHODS: Fifty-six cases of telescopic biliary reconstruction were performed in 203 patients during 2015. Fifty cases and 52 patients who underwent standard reconstruction were chosen and compared. All patients had been scanned retrospectively. Statistical analyses were conducted with chi2 and Mann-Whitney U tests for the complications that occurred during the first 3 months. A P value <.05 was considered significant. RESULTS: No clinical or demographic differences were detected between the groups. About 90% of both groups were living donor liver transplantation cases. Five (10%) anastomotic leaks occurred in telescopic reconstruction group (n = 50), and 13 (25%) occurred in the standard reconstruction group (n = 52; P < .05). CONCLUSION: The arterial blood supply is better if the biliary anastomosis is made on the mucosal side of the main biliary duct. Early period anastomotic leaks may decrease significantly. PMID- 28340834 TI - Hepatic Artery Reconstruction With Autologous Inferior Mesenteric Artery Graft in Living Donor Liver Transplant Recipients. AB - INTRODUCTION: In living donor liver transplantation (LDLT), hepatic arterial continuity is crucial to avoid biliary leakage, biliary stricture, cholangitis, and graft and patient loss. Sometimes there exist factors making anastomosis difficult or even impossible. In these cases, a vascular graft may be needed to bridge the two arteries for revascularization. METHOD: Medical records of 297 patients who underwent LDLT between June 2000 and July 2016 at the Hepatopancreatobiliary Surgery and Liver Transplantation Unit of Dokuz Eylul University Hospital were reviewed retrospectively. Twenty-eight (9%) patients younger than the age of 18 were excluded from the study. The remaining 269 patients were included in the study. We analyzed data of patients who developed hepatic arterial complications during or after LDLT and underwent revascularization using autologous interposed inferior mesenteric artery (IMA) grafts. RESULTS: In 8 (2.9%) of the 269 patients who underwent LDLT and were included in the study, autologous interposed IMA grafts were used for the hepatic artery revascularization. All of the patients were males. Their mean age was 42 (range, 25-57). The mean duration of follow-up was 83.25 months (range, 3-144 months). One patient developed intraoperative hepatic arterial thrombosis (HAT) after autologus IMA reconstruction and this patient needed retransplantation. No arterial complications developed in the other 7 patients. CONCLUSION: Autologous interposed IMA graft could be used as an alternative vascular graft in hepatic artery revascularization to provide tension-free hepatic arterial continuity. PMID- 28340835 TI - Can Patients Who Develop Cerebral Death in Fulminant Liver Failure Despite Liver Transplantation Be Previously Forseen? AB - BACKGROUND: The outcome of medical treatment is worse in fulminant liver failure (FLF) developing on acute or chronic ground. Recently, liver transplantations with the use of living and cadaveric donors have been performed in these diseases and good results obtained. In this study, we aimed to present the factors affecting the recovery of cerebral functions after liver transplantation in hepatic encephalopathy (HE) developing in FLF, to identify irreversible patient groups and to prevent unnecessary liver transplantation. METHODS: In Inonu University's Liver Transplant Institute, 69 patients who made an emergency notice to the National Coordination Center for liver transplantation owing to FLF from January 2012 to December 2015 were included in the study. Patients were divided into 2 groups. Group 1 consisted of 52 patients who underwent liver transplantation and recovered normal brain function, and group 2 had 17 patients who underwent liver transplantation and did not recover normal brain function and had cerebral death. All patients were evaluated before surgery for clinical encephalopathy stage, light reflex, and convulsions. Groups were compared and assessed according to age (>40, 10-40 and <10 years), body mass index, etiologic factor, preoperative laboratory values, transplantation type, mortality, and encephalopathy level. Multivariate analysis was done for specific parameters. RESULTS: Prothrombin time (PT), international normalized ratio (INR), and total bilirubin values were significantly different between the groups. There was no significant difference between the groups regarding ammonia and lactate levels. There was a statistically significant difference between the groups regarding sodium and potassium levels from serum electrolytes. However, the averages of both groups were within normal limits. pH and total bilirubin levels were meaningful for multivariate analysis. CONCLUSIONS: HE reversibility, mortality, and morbidity are important in patients with HE who undergo liver transplantation. Therefore, West Haven clinical staging and serum INR, PT, and total bilirubin level may be helpful in predicting the reversibility of FLF patients with HE before liver transplantation. It was determined that West Haven encephalopathy grading is important in determining the reversibility of HE after transplantation in FLF; especially the probability of reversibility of stage 4 HE decreases significantly. High PT and INR levels, hyperbilirubinemia, and serum sodium and potassium concentrations were risk factors for the reversibility of HE in this study. PMID- 28340836 TI - Effect of Dosage and Type of Hepatitis B Immunoglobulin on Hepatitis Antibody Levels in Liver Transplant Recipients. AB - BACKGROUND: The current study aimed to evaluate the effect of dosage and type (intramuscular [IM] vs intravenous [IV]) of hepatitis B immunoglobulin (HBIG) on hepatitis antibody level in liver transplant recipients. METHODS: Between September 2000 and August 2016, patients who underwent orthotropic liver transplantation for chronic liver failure or hepatocellular carcinoma secondary to chronic hepatitis B virus (HBV) were retrospectively reviewed from a prospectively maintained database. The analyses of risk factors for postoperative short- and long-term anti-hepatitis B surface antibody levels (as classified level I: 0 to 100 U; II: 100 to 500 U; III: 500 to 1000 U; IV: >1000 U) were performed based on demographic characteristics, hepatitis B envelope antigen, hepatitis B core antibody, HBV DNA, delta antigen, HBIG administration dosage during unhepatic phase (5000 or 10,000 I/U; IM or IV), and type of administration in post-transplant period. Patients who were followed for less than 12 months were excluded from long-term analysis. RESULTS: The mean follow-up of 58 orthotropic liver transplant patients was 72 (+/-45) months. No adverse events were observed during both IM and IV type of administration. Compared with IM type, IV administration was associated with a significantly higher HBV antibody level in the short term (for IM and IV: level I: 24% vs 6%; II: 49% vs 18%; III: 12% vs 35%; IV: 15% vs 41%, respectively, P = .007). In the long term, IV administration of hepatitis B immunoglobulin (HBIG) was reported as the sole factor causing higher antibody level (P = .002). Longer follow-up was associated with decreased levels of anti-hepatitis B surface antibody. CONCLUSION: IV HBIG administration in preoperative anhepatic phase and postoperative prophylaxis is associated with higher antibody level both the short and long term without any adverse event. PMID- 28340837 TI - Complications in Donors Using Right Liver Graft: Analysis of 280 Consecutive Cases. AB - INTRODUCTION: Living donor liver transplantation (LDLT) is performed with increasing frequency worldwide due to the shortage of donated organs. It is a life-saving procedure for the recipient, but, on the other hand, a major surgical procedure for healthy donors and it may cause morbidity and even mortality. PATIENTS AND METHODS: This research was completed at Dokuz Eylul University Faculty of Medicine Hospital General Surgery Department Liver Transplant Unit and included 280 cases (4 with simultaneous liver and kidney transplants from living donors) who underwent donor right hepatectomy for LDLT from June 2000 to June 2016. We analyzed the data of patients retrospectively. RESULTS: Of 280 donor right hepatectomies for LDLT, 181 were male (M; 64.6%) and 99 were female (F; 35.4%) (M/F: 1.82). Mean donor age was 31.2 +/- 0.9 years (range, 18-56). Mean donor monitoring duration was 45 +/- 2.4 months (range, 3-192 months). Mean body mass index (BMI) was 24.28 +/- 2.96 kg/m2 (range, 18.1-32.42 kg/m2). In our study 72 cases (25.7%) developed postoperative complications. There were 17 Clavien grade 3A, 1 grade 3B, and 5 grade 4A complications and also 1 death due to pulmonary embolism. CONCLUSION: Together with the increase in living donor surgery, the morbidity and mortality of these cases are becoming controversial. Full donor safety is only possible with appropriate donor choice requiring very detailed studies, a problem-free hepatectomy process, and close postoperative donor monitoring. PMID- 28340838 TI - Anesthetic Management for Left Ventricular Assist Device Implantation Through Left Thoracotomy: Evaluation of On-Pump Versus Off-Pump. AB - BACKGROUND: Ventricular assist devices (VADs) are alternative approaches to medical treatment in patients with acute or chronic heart failure. The goal of this study was to compare an anesthetic approach in patients undergoing implantation of a VAD with (on-pump) or without (off-pump) cardiopulmonary bypass (CPB) through left thoracotomy. METHODS: A total of 32 patients were divided into 2 groups: on-pump (group 1) and off-pump (group 2). A standard anesthesia protocol was used in all patients. Baseline characteristics of the patients, intraoperative hemodynamic and respiratory variables, anesthetic agents and vasoactive drugs administered, the amount of blood products, extubation, length of hospital stay and intensive care unit stay, and postoperative complications were recorded. RESULTS: Patients' mean age was 54.7 +/- 13.3 years (range, 18-74 years). Eighteen patients underwent surgery with CPB. Demographic data of the patients, preoperative characteristics, intraoperative use of blood products, intraoperative complications, and anesthetic drugs used were similar between groups (P > .05). The duration of surgery (219 +/- 23 vs 273 +/- 56 minutes) and anesthesia (274 +/- 38 vs 323 +/- 57 minutes) were shorter in group 2; there was no difference between the 2 groups in terms of mechanical ventilation time, length of stay in the intensive care unit, and length of hospital stay. There was no decrease in postoperative oxygen parameters and an increase in patient lactate levels with the use of CPB. The use of fresh frozen plasma and platelet suspension in the postoperative period was significantly higher in group 1 (P < .05). The rate of complications and mortality rate were comparable between the 2 groups (P > .05). CONCLUSIONS: Our study results show that the use of CPB during VAD implantation via left thoracotomy increases operation time and use of blood products, while causing no change in the rate of complications. PMID- 28340839 TI - Incidence of Early Acute Kidney Injury in Lung Transplant Patients: A Single Center Experience. AB - BACKGROUND: Acute kidney injury (AKI) is a common complication in the early period of lung transplantation (LTx). We aimed to describe the incidence and perioperative risk factors associated with AKI following LTx. METHODS: Clinical data of 30 patients who underwent LTx were retrospectively reviewed. Primary outcomes were development of AKI and patient mortality within 30 postoperative days. Postoperative AKI is determined based on creatinine criteria from Acute Kidney Injury Network (AKIN) classification. Secondary outcomes included the association between AKI and demographic and clinical parameters of patients and treatment modalities in the pre- and postoperative periods. RESULTS: Of the 30 LTx recipients included, AKI occurred in 16 patients (53.4%) within the first 30 days. Length of intensive care unit (P = .06) and hospital stay (P = .008) and mechanical ventilation duration (P = .03) were significantly higher in patients with AKI compared with patients without AKI. Factors independently associated with AKI were intraoperative hypotension (odds ratio [OR] 0.500; 95% confidence interval [CI], 1.145 to 26.412, P = .02), longer duration of mechanical ventilation (OR 1.204; 95% CI 0.870 to 1.665, P = .03), and systemic infection (OR 8.067; 95% CI 1.538 to 42.318, P = .014) in the postoperative period. Short term mortality was similar in patients with and patients without AKI. CONCLUSION: By the AKIN definition, AKI occurred in half of the patients following LTx. Several variables including intraoperative hypotension, longer duration of mechanical ventilation, and systemic infection in the postoperative period independently predict AKI in LTx recipients. PMID- 28340840 TI - Short-term Results of Heartmate 3 Ventricular Assist Device Implantation for End Stage Heart Failure. AB - OBJECTIVE: To report our initial experience with Heartmate 3 ventricular assist device (HM3) in cases with end-stage heart failure (ESHF). METHODS: Charts of 8 ESHF patients who underwent HM3 implantation in our clinic from January to June 2016 (group 1) and 16 patients who underwent HM2 implantation during 2015 (group 2) were reviewed retrospectively. Demographics as well as pre- and early postoperative medical data were noted and statistically analyzed between the 2 groups. RESULTS: No statistical difference was found in age or sex distribution between groups (P > .05). Mean Interagency Registry for Mechanically Assisted Circulatory Support scores were 2.13 +/- 0.99 and 3.38 +/- 0.72 in groups 1 and 2, respectively (P = .020). Mean cardiopulmonary bypass time, and chest tube drainage fluid volume and blood product requirement during intensive care unit (ICU) stay were 64.0 +/- 13.9 minutes, 1,112.5 +/- 516.7 mL, and 318.8 +/- 271.2 mL, respectively, in group 1 and 89.0 +/- 33.3 minutes, 2,081.3 +/- 1,696.0 mL, and 1,118.8 +/- 1,010.8 mL in group 2 (P = .027, P = .019, and P = .040, respectively). Need for surgical revision and early mortality were not evident for group 1, although 4 cases (25.0%) required revision surgery, and early mortality was seen in 3 cases (18.8%) in group 2 (P = .121 and P = .190, respectively). Mean durations of ICU stay and total postoperative hospitalization were 5.9 +/- 2.0 and 18.3 +/- 5.5 days, respectively in group 1 and 6.2 +/- 4.3 and 18.0 +/- 6.9 days in the surviving 13 patients of the group 2 (P = .645 and P = .697, respectively). CONCLUSIONS: With its shorter implantation time and reduced blood product requirement in the early postoperative period, the HM3 system was found to be safe and effective in ESHF treatment. PMID- 28340841 TI - Liver Transplantation for Polycystic Liver Disease Due to Huge Liver With Related Complications: A Case Report. AB - Polycystic liver disease is characterized by multiple cystic lesions on the liver. It is an uncommon autosomal dominant disease. The cysts' diameters range from 20 to 30 cm to small microscopic nodules. Generally, more than half of the liver parenchyma is covered. The mass effect of the liver created by the large cysts can cause life-threatening symptoms such as weight loss, reduction of oral intake, and malnutrition. Liver transplantation is the best treatment option in symptomatic patients. We present a patient who had polycystic liver and kidney disease, and we performed liver transplantation because of his life-threatening symptoms. PMID- 28340842 TI - Surgical Treatment of Portal Vein Thrombosis With the Use of Cadaveric Venous Patch After Donor Hepatectomy: A Case Report. AB - Live donors should be the priority of transplant professionals to prevent surgery related morbidity and mortality during living-donor liver transplantation. Portal vein thrombosis after donor hepatectomy is an important complication which can be prevented by careful preoperative as well as perioperative evaluation. If portal vein thrombus occurs after donor hepatectomy, anticoagulation and surgical thrombectomy and even portal vein reconstruction should be kept in mind. Cadaveric venous patches can be used for the reconstruction of narrowed and angulated portal veins. Here we report the surgical treatment of a donor with a cadaveric venous patch who developed portal vein thrombosis after donor hepatectomy. PMID- 28340843 TI - Acquired Acrodermatitis Enteropathica Syndrome in a Kidney Transplant Receipt: A Case Report. AB - Acrodermatitis enteropathica syndrome (AE) is a clinical entity that results in severe zinc deficiency. It can be genetic or acquired. Acquired AE has been reported in patients with chronic liver disease, malabsorption syndrome, sickle cell anemia, and chronic renal failure. We present a kidney transplant recipient with skin rash and watery diarrhea. The patient had low serum zinc levels, which quickly resolved after zinc supplementation. Skin biopsy showed cytoplasmic pallor and vacuolization and ballooning degeneration of keratinocytes within the superficial epidermis, which may have led to confluent necrosis of keratinocytes. Large amounts of keratinosome-derived lamellae were found in the intercellular spaces in the keratinized area, probably related to disturbance of keratinosome metabolism due to zinc deficiency. PMID- 28340844 TI - Anatomic Diversity Encountered During Laparoscopic Hand-Assisted Transperitoneal Donor Nephrectomy: A Case Report of Complete Caval Duplication. AB - INTRODUCTION: Laparoscopic donor nephrectomy is widely used to retrieve a kidney for transplantation. Preoperative evaluation of the donor is of crucial importance to the recipient. In particular, vascular anatomy should be assessed with the help of modern imaging modalities. We present a hand-assisted laparoscopic nephrectomy of a kidney donor with a complete duplex vena cava. CASE REPORT: A 40-year-old male patient was admitted to our clinic as a kidney donor for his 20-year-old son. After the preliminary tests, further imaging with the use of computerized tomographic angiography showed a complete duplex vena cava. He had no morbidities or previous surgeries. A hand-assisted transperitoneal laparoscopic left nephrectomy was performed as the kidney removal technique commonly used in our center. There was minimal blood loss, and the warm ischemia time was 66 minutes. Operation time was 265 minutes. After transplantation had been performed, graft functions were good with normal urine output. Blood sample tests were in normal ranges. The live donor was discharged on the 7th day after the procedure without any complications. CONCLUSIONS: Although renal vascular anomalies are rarely seen, they have a significant impact on the outcomes of the renal transplantation. Knowing the vascular anatomy minimizes the complications risk and increases the success rate. Laparoscopic live-donor nephrectomy can be performed safely, even in patients with vascular anomalies. PMID- 28340845 TI - Erratum. PMID- 28340846 TI - Erratum. PMID- 28340847 TI - Erratum. PMID- 28340848 TI - Preeclampsia and the Long-term Risk of Kidney Failure. PMID- 28340849 TI - The Interaction of Dialysis Prescription and Residual Kidney Function: Yet Another Layer of Complexity. PMID- 28340850 TI - From Static to Dynamic Risk Prediction: Time Is Everything. PMID- 28340851 TI - In Reply to 'Kidney Disease of Unknown Cause in Agricultural Laborers (KDUCAL) Is a Better Term to Describe Regional and Endemic Kidney Diseases Such as Uddanam Nephropathy'. PMID- 28340852 TI - Kidney Disease of Unknown Cause in Agricultural Laborers (KDUCAL) Is a Better Term to Describe Regional and Endemic Kidney Diseases Such as Uddanam Nephropathy. PMID- 28340853 TI - Quiz: Acute Kidney Injury in a Patient on a TNF-alpha Blocking Agent. PMID- 28340854 TI - AJKD Atlas of Renal Pathology: IgG4-Related Tubulointerstitial Nephritis. PMID- 28340855 TI - No mediating effects of glycemic control and inflammation on the association between vitamin D and lung function in the general population. AB - BACKGROUND: Vitamin D deficiency is discussed to be associated with lung health. While former studies focused on subjects suffering from pulmonary diseases, we aimed to investigate the association of 25-hydroxy vitamin D [25(OH)D] with lung function in the general population and examined whether mediating effects of inflammation, glycemic control or renal function exist. METHODS: 1404 participants from the Study of Health in Pomerania with pulmonary function testing assessed by expiratory volume in 1 s (FEV1), forced vital capacity (FVC), total lung capacity and Krogh index were used. Adjusted analysis of variance, linear regression models and mediation analyses were performed. RESULTS: Significant positive associations between 25(OH)D levels and FEV1, FVC and Krogh index were found. Mediator analyses revealed no mediating effect of inflammation (fibrinogen), glycemic control (HbA1c) or renal function (eGFR) on associations with FEV1 or FVC. With respect to Krogh-Index, the association to 25(OH)D was slightly mediated by fibrinogen with a proportion mediated of 9.7%. CONCLUSION: Significant positive associations of 25(OH)D with lung function were revealed in a general population. The proposed mediating effects of inflammation, glycemic control and renal function on these relations were not confirmed. Further studies examining the causality of the association between 25(OH)D and lung function are necessary. PMID- 28340856 TI - Changes in the prevalence of COPD in Korea between 2001 and 2011 in the KNHANES data. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a serious public health problem. Understanding the longitudinal trend in prevalence is important for characterizing the burden of COPD and planning health services. METHODS: We analyzed the prevalence of airflow obstruction between 2001 and 2011 using data from Korean National Health and Nutritional Examination Surveys (2001, n = 2217; 2011, n = 3101). Participants >40 years of age with an FEV1/FVC <0.7 were defined as having COPD. We used data from the Population and Housing Census, which was conducted by Statistics Korea in 2010, to compare the prevalence of COPD after standardizing by age. RESULTS: The crude prevalence of COPD was not significantly different between 2001 and 2011 (2001, 13.0%; 2011, 13.2%), but the age standardized prevalence of COPD decreased significantly over the 10-year period (2001, 15.7%; 2011, 12.4%). While significant decreases were observed for ex smokers and current smokers, significant increases were noted for subjects who smoked <20 pack-years and those with a BMI <=18.5 kg/m2. The prevalence of mild and severe COPD decreased (2001, mild 8.5%, severe 1.4%; 2011, mild 5.4%, severe 0.5%), while the prevalence of moderate COPD increased (2001, 5.7%; 2011, 6.4%) after age standardization. CONCLUSIONS: We report a reduction in the age standardized prevalence of COPD in Korea from 2001 to 2011. Continued surveillance and early prevention are required because the socioeconomic burden of COPD remains substantial. PMID- 28340857 TI - Reducing socioeconomic inequalities in COPD care in the hospital outpatient setting - A nationwide initiative. AB - OBJECTIVE: Socioeconomic differences in quality of care have been suggested to contribute to inequality in clinical prognosis of COPD. We examined socioeconomic differences in the quality of COPD outpatient care and the potential of a systematic quality improvement initiative in reducing potential socioeconomic differences. METHODS: A mandatory national quality improvement initiative has since 2008 monitored the quality of COPD care at all national pulmonary specialized outpatient clinics in Denmark using six evidence-based process performance measures. We followed patients aged >=30 years with a first-ever outpatient contact for COPD during 2008-2012 (N = 23,741). Adjusted year-specific relative risks (RR) of fulfilling all relevant process performance measures was compared according to ethnicity, education, income, employment, and cohabitation using Poisson regression. RESULTS: Quality of care improved following the implementation of the clinical improvement initiative with 11% of COPD patients receiving optimal care in 2008 compared to 57% in 2012. Substantial socioeconomic differences were observed the first year: immigrants (RR 0.41, 95% CI 0.21-0.82), the unemployed (RR 0.37, 95% CI 0.18-0.74), disability pensioners (RR 0.63, 95% CI 0.46-0.87) and patients living alone (RR 0.80, 95% CI 0.60-0.97) were less likely to receive all relevant care processes, whereas those with highest education (RR 1.22, 95% CI 0.92-1.63) were more likely to receive these processes. These differences were eliminated during the study period. CONCLUSION: A systematic quality improvement initiative including regular audits, knowledge sharing, and detailed disease-specific recommendations for care improvement may increase the overall quality of care and considerably modify the substantial socioeconomic inequalities in COPD management. PMID- 28340858 TI - Corrigendum to "Analysis of discrepant results between the Genotype(r) MTBDRplus assay and an antimicrobial-susceptibility test for isoniazid-resistant tuberculosis'"[Respiratory Med. 122 (January 2017) 12-17]. PMID- 28340859 TI - Heterogeneity of obesity-asthma association disentangled by latent class analysis, the SAPALDIA cohort. AB - Although evidence for the heterogeneity of asthma accumulated, consensus for definitions of asthma phenotypes is still lacking. Obesity may have heterogeneous effects on various asthma phenotypes. We aimed to distinguish asthma phenotypes by latent class analysis and to investigate their associations with different obesity parameters in adults using a population-based Swiss cohort (SAPALDIA). We applied latent class analysis to 959 self-reported asthmatics using information on disease activity, atopy, and age of onset. Associations with obesity were examined by multinomial logistic regression, after adjustments for age, sex, smoking status, educational level, and study centre. Body mass index, percent body fat, waist hip ratio, waist height ratio, and waist circumference were used as obesity measure. Four asthma classes were identified, including persistent multiple symptom-presenting asthma (n = 122), symptom-presenting asthma (n = 290), symptom-free atopic asthma (n = 294), and symptom-free non-atopic asthma (n = 253). Obesity was positively associated with symptom-presenting asthma classes but not with symptom-free ones. Percent body fat showed the strongest association with the persistent multiple symptom-presenting asthma. We observed heterogeneity of associations with obesity across asthma classes, indicating different asthma aetiologies. PMID- 28340860 TI - Association of pre-hospital theophylline use and mortality in chronic obstructive pulmonary disease patients with sepsis. AB - BACKGROUND: Although theophylline has been shown to have anti-inflammatory effects, the therapeutic use of theophylline before sepsis is unknown. The aim of our study was to determine the effect of theophylline on COPD patients presenting with sepsis. METHODS: This nationwide, population-based, propensity score-matched analysis used data from the linked administrative databases of Taiwan's National Health Insurance program. Patients with COPD who were hospitalized for sepsis between 2000 and 2011 were divided into theophylline users and non-users. The primary outcome was 30-day mortality. The secondary outcome was in-hospital death, intensive care unit admission, and need for mechanical ventilation. Cox proportional hazard model and conditional logistic regression were used to calculate the risk between groups. RESULTS: A propensity score-matched cohort of 51,801 theophylline users and 51,801 non-users was included. Compared with non users, the 30-day (HR 0.931, 95% CI 0.910-0.953), 180-day (HR 0.930, 95% CI 0.914 0.946), 365-day (HR 0.944, 95% CI 0.929-0.960) and overall mortality (HR 0.965, 95% CI 0.952-0.979) were all significantly lower in theophylline users. Additionally, the theophylline users also had lower risk of in-hospital death (OR 0.895, 95% CI 0.873-0.918) and need for mechanical ventilation (OR 0.972, 95% CI 0.949-0.997). CONCLUSIONS: Theophylline use is associated with a lower risk of sepsis-related mortality in COPD patients. Pre-hospital theophylline use may be protective to COPD patients with sepsis. PMID- 28340861 TI - A randomised double-blind, placebo-controlled, long-term extension study of the efficacy, safety and tolerability of fixed-dose combinations of aclidinium/formoterol or monotherapy in the treatment of chronic obstructive pulmonary disease. AB - INTRODUCTION: Aclidinium bromide/formoterol fumarate (AB/FF) 400/12 MUg efficacy and safety was demonstrated in two 6-month Phase III studies (AUGMENT and ACLIFORM) and a 12-month study in patients with moderate to severe chronic obstructive pulmonary disease (COPD). This Phase III, double-blind, placebo controlled, 6-month AUGMENT extension investigated the long-term safety and tolerability of AB/FF 400/12 MUg (NCT01572792). METHODS: Patients were randomised in AUGMENT (1:1:1:1:1) to twice-daily AB/FF 400/12 MUg, AB/FF 400/6 MUg, AB 400 MUg, FF 12 MUg or placebo. Patients completing AUGMENT were invited to continue the same treatment in the extension. Adverse events (AEs), major adverse cardiovascular events (MACE), laboratory tests, electrocardiograms and vital signs were recorded. Efficacy was assessed. RESULTS: Of 1322 patients completing AUGMENT, 921 enrolled and 780 completed the extension. AE incidence was low and comparable across treatment groups; most common were nasopharyngitis (range 4.8% 9.3%), urinary tract infection (range 4.1%-8.8%) and upper respiratory tract infection (range 2.7%-5.5%). Serious AEs (SAEs) and MACE were low (ranges 6.8% 7.7% and 0.5%-1.5%, respectively). Significant improvements in bronchodilation and dyspnoea were maintained over 52 weeks versus placebo. Trends towards improvements in other symptoms and health status were observed versus placebo and monotherapies. AB/FF combinations increased the time to first exacerbation by approximately 30% versus placebo (p < 0.05). CONCLUSION: AB/FF 400/12 MUg was well tolerated over 52 weeks with low incidences of AEs, SAEs and MACE that were comparable across treatment groups. Improvements in bronchodilation, symptoms and health status were maintained across 52 weeks. PMID- 28340862 TI - Symptom variability and control in COPD: Advantages of dual bronchodilation therapy. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder characterized by usually progressive development of airflow obstruction that is not fully reversible. While most patients will experience symptoms throughout the day or in the morning upon awakening, many patients do not experience their symptoms as constant but report variability in symptoms during the course of the day or over time. Symptom variability adversely affects patients' health status and increases the risk of COPD exacerbations. METHODS: We examined data from the literature on symptom variability and control in patients with COPD, with focus on the use of inhaled bronchodilator therapy with long acting muscarinic antagonist agents (LAMA) plus long-acting beta2-agonists (LABA); in particular twice-daily fixed-dose combination LAMA/LABA therapy with aclidinium/formoterol. RESULTS: Correct diagnosis and assessment of COPD requires comprehensive clinical and functional evaluation and consideration of individual needs to support the clinical decisions necessary for effective long-term management. Combining bronchodilators from different and complementary pharmacological classes with distinct mechanisms of action can increase the magnitude of bronchodilation as opposed to increasing the dose of a single bronchodilator. CONCLUSIONS: The use of inhaled bronchodilator therapy with LAMA/LABA fixed-dose combinations in patients with stable COPD is supported by current evidence. This treatment approach provides robust effects on lung function and symptom control and may improve patients' adherence to treatment. Administration of the long-acting bronchodilators aclidinium and formoterol as twice daily fixed-dose aclidinium/formoterol 400/12 MUg has the potential to control symptoms throughout the 24 h in patients with stable moderate-to-severe COPD. PMID- 28340863 TI - Serum cytokine profiles as predictors of asthma control in adults from the EGEA study. AB - BACKGROUND: To which extent serum cytokines may predict asthma control in adults remains understudied. OBJECTIVES: We investigated cross-sectional and longitudinal associations between cytokine profiles and asthma outcomes. METHODS: Serum interleukin (IL)-1Ra, IL-5, IL-7, IL-8, IL-10, IL-13 and TNF-alpha levels were determined in 283 adults with current asthma from the 2nd survey of the Epidemiological Study on the Genetics and Environment of Asthma (EGEA2). Participants were followed-up seven years later. Asthma symptom control was assessed according to GINA 2015 guidelines. Cytokine profiles were identified by principal component (PC) analyses, and expressed as above/below the median. RESULTS: The first two PCs captured 82.5% of the variability. While all seven cytokines scored high on PC1, only IL-1Ra and IL-10 scored high on PC2. At EGEA2, neither PC1 nor PC2 were related to exacerbations, asthma attacks, asthma symptom control, lung function, or allergic diseases. High level of PC1 (above the median) was associated with higher blood neutrophil counts (P = 0.02), while high level of PC2 was associated with lower IgE levels (P = 0.04). High level of PC2 at EGEA2 was associated with lower bronchial hyperresponsiveness (adjusted(a) OR[95%CI] = 0.46[0.23; 0.91]) and with subsequent lower risk of worsening asthma control and attacks (aOR[95%CI] = 0.24[0.09; 0.60]; 0.31[0.11; 0.85] respectively). CONCLUSIONS: Serum cytokine profiles with high levels of IL-1Ra and IL-10 were associated with lower subsequent risks of worsening asthma control and attacks in adults. This study adds new findings for the role of serum cytokine profiles to help identifying adults with subsequent risk of asthma burden that could be targeted for specific therapies. PMID- 28340864 TI - Multi-dimensional scores to predict mortality in patients with idiopathic pulmonary fibrosis undergoing lung transplantation assessment. AB - BACKGROUND: The heterogeneous progression of idiopathic pulmonary fibrosis (IPF) makes prognostication difficult and contributes to high mortality on the waitlist for lung transplantation (LTx). Multi-dimensional scores (Composite Physiologic index [CPI], [Gender-Age-Physiology [GAP]; RIsk Stratification scorE [RISE]) demonstrated enhanced predictive power towards outcome in IPF. The lung allocation score (LAS) is a multi-dimensional tool commonly used to stratify patients assessed for LTx. We sought to investigate whether IPF-specific multi dimensional scores predict mortality in patients with IPF assessed for LTx. METHODS: The study included 302 patients with IPF who underwent a LTx assessment (2003-2014). Multi-dimensional scores were calculated. The primary outcome was 12 month mortality after assessment. LTx was considered as competing event in all analyses. RESULTS: At the end of the observation period, there were 134 transplants, 63 deaths, and 105 patients were alive without LTx. Multi dimensional scores predicted mortality with accuracy similar to LAS, and superior to that of individual variables: area under the curve (AUC) for LAS was 0.78 (sensitivity 71%, specificity 86%); CPI 0.75 (sensitivity 67%, specificity 82%); GAP 0.67 (sensitivity 59%, specificity 74%); RISE 0.78 (sensitivity 71%, specificity 84%). A separate analysis conducted only in patients actively listed for LTx (n = 247; 50 deaths) yielded similar results. CONCLUSIONS: In patients with IPF assessed for LTx as well as in those actually listed, multi-dimensional scores predict mortality better than individual variables, and with accuracy similar to the LAS. If validated, multi-dimensional scores may serve as inexpensive tools to guide decisions on the timing of referral and listing for LTx. PMID- 28340866 TI - Epidemiology of clinical trials of medicines in respiratory diseases in Europe and Italy. AB - BACKGROUND: Clinical trials play a key role in advancing medical knowledge, improving patient care and promoting economic growth in Europe. We have assessed the clinical trial activity in any respiratory diseases in Europe, with a specific focus on Italy. METHODS: Information from public sources (EFPIA, clinicaltrials.gov, clinicaltrialsregister. eu, AIFA) was used to describe clinical trial activity of in respiratory diseases in Europe and by country. RESULTS: In 2015, 3908 clinical trials were reported in Europe, 386 in respiratory diseases (9.9%). Germany was the first country both as absolute number (76 trials) and as percentage within country trials (14%), followed by Poland. Spain, Italy and France were the countries with the lowest number and percentage of trials in respiratory diseases. In 2013, the Italian Drug Agency reported 9 trials with respiratory compounds in Italy (2.1% of overall trials, 12^ position in the therapeutic area rank), 33% in phase 2 and 66% in phase 3. No phase 1 or phase 4 trials were reported for respiratory trials. Prevalence of respiratory trials by non-profit sponsors (28.3%) was below the average for the country (38.3%). CONCLUSIONS: Europe has a greater potential for clinical research on drugs for respiratory diseases, particularly in countries with less activity, such as Spain, France and Italy, that should identify and implement actions to increase attractiveness for clinical trials of drugs. PMID- 28340865 TI - Association of systemic inflammation, adiposity, and metabolic dysregulation with asthma burden among Hispanic adults. AB - RATIONALE: Obesity-related asthma is associated with higher disease burden than normal-weight asthma among Hispanics. Adiposity, metabolic dysregulation, and inflammation are all implicated in pathogenesis of obesity-related asthma, but their independent contributions are poorly understood. OBJECTIVE: To examine the independent contributions of body fat distribution, metabolic abnormalities and inflammation on asthma symptoms and pulmonary function among Hispanics. METHODS: Participants of the Hispanic Community Health Study/Study of Latinos with doctor diagnosed asthma who completed an asthma symptom questionnaire and performed a valid spirometry were included in the analysis (n = 1126). Multivariate analysis was used to examine the independent association of general adiposity (assessed using body mass index), truncal adiposity (assessed by waist circumference), metabolic dysregulation (presence of insulin resistance and low HDL) and inflammation (high-sensitivity C-Reactive Protein>=3 mg/L) with reported asthma symptoms or pulmonary function measures (FEV1, and FVC) while adjusting for demographic and clinical covariates. RESULTS: Of the 1126 participants, 334 (29.5%) were overweight, and 648 (57.8%) were obese. FEV1 and FVC were lower in obese compared to normal-weight asthmatics. In analyses controlling for metabolic and adiposity factors, high hs-CRP (>7 mg/L) was associated with more symptoms (prevalence-ratio 1.27 (95%CI 1.05, 1.54), and lower FVC (beta -138 ml (95%CI -27 ml, -249 ml)) and FEV1 (beta -155 ml (95% CI -38 ml, -272 ml). Low HDL was also associated with lower FVC (beta -111 ml (-22 ml, -201 ml) and FEV1 (beta -100 ml (-12 ml, -188 ml)). Results were similar in men and women. CONCLUSIONS: Our findings suggest that hs-CRP and low HDL, rather than general and truncal adiposity, are associated with asthma burden among overweight and obese Hispanic adults. PMID- 28340868 TI - Suicidal Ideation and Alcohol Use: Understanding Developmental Trajectories. PMID- 28340867 TI - Comparative prevalence of co-morbidities in smoking and non-smoking asthma patients with incomplete reversibility of airway obstruction, non-smoking asthma patients with complete reversibility of airway obstruction and COPD patients. AB - BACKGROUND: Asthma with incomplete reversibility of airway obstruction (IRAO) may often be associated to smoking-induced changes. Nevertheless, a high proportion of patients showing IRAO have never smoked. These patients with IRAO often share features of patients with chronic obstructive pulmonary disease (COPD). Although IRAO is still a poorly defined condition, it has been associated with a higher morbidity and mortality than asthma with complete reversibility of airway obstruction (CRAO) or even COPD alone. A high prevalence of comorbidities could contribute to the reported poorer clinical outcome in IRAO, in comparison to CRAO or COPD alone. AIM: To determine the prevalence of past and current comorbidities in IRAO patients compared to patients with CRAO or COPD. METHODS: This was a retrospective, cross-sectional study. Demographic data, clinical characteristics and 36 predetermined comorbidities documented from self-report and chart review, were recorded from smoking-associated IRAO (S-IRAO), non-smoking IRAO (NS-IRAO), CRAO and COPD patients. RESULTS: A total of 199 patients were included in the final analysis (111F/88M, mean (+/-SD) age of 63 +/- 10 years). The CRAO group had more comorbidities than the three other groups, but this difference was significant only with the NS-IRAO group (P = 0.04). For most comorbidities, the prevalence of comorbidities in both IRAO sub-groups was intermediate between CRAO and COPD, with significant differences between S-IRAO and NS-IRAO only for hypertension (P = 0.03), nasal polyps (P = 0.002) and pneumonia (P = 0.04). Typical asthma-associated comorbidities tended to be more prevalent in NS-IRAO patients and COPD-associated comorbidities in S-IRAO patients. CONCLUSION: In this study, the prevalence of comorbidities was not superior in patients with IRAO, compared to those with CRAO or COPD alone. The prevalence of comorbidities in the two main types of IRAO patients reflects exposure to cigarette smoke and asthma-related mechanisms. PMID- 28340869 TI - Young People: Understanding the Links Between Satisfaction With Services and Their Health Outcomes in Primary Care. PMID- 28340871 TI - Improving Knowledge About, Access to, and Utilization of Long-Acting Reversible Contraception Among Adolescents and Young Adults. PMID- 28340870 TI - Collaboration Is Key for Successful Treatment of Youth-Onset Type 2 Diabetes. AB - Type 2 diabetes (T2D) is increasing in U.S. adolescents, particularly those of ethnic and racial minority groups. Risk factors for youth-onset T2D include obesity, family history of T2D, poor diet, lack of exercise, and poverty. The onset of diabetes-related complications is accelerated in adolescents with T2D compared to adults, and knowledge regarding the optimal way to prevent and slow complications is lacking. Existing treatment options are limited, and research into novel pharmacologic treatments is hindered by lack of sufficient patient population for clinical trials. Health care providers and investigators should collaborate both with each other, and with patients and their communities to build networks that will allow comprehensive evaluation of this disease in order to offer optimal, comprehensive care for these adolescents. PMID- 28340872 TI - Establishing an Immunization Platform for 16-Year-Olds in the United States. PMID- 28340873 TI - Peripheral T-Cell Lymphoma, Not Otherwise Specified: A Review of Current Disease Understanding and Therapeutic Approaches. AB - Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), corresponds with a heterogeneous group of mature T-cell lymphomas. Recent gene expression profiling studies have identified at least two molecular subgroups (GATA3 and TBX2). Standard treatment and outcomes remain poor. High-dose chemotherapy with autologous stem cell transplantation is incorporated into primary therapy for young fit patients but remains ineffective for most and has not been tested in a randomized study. Several novel agents have been approved for use in relapsed/refractory PTCLs, and although response rates are modest for most, durable remissions have been reported. Selecting rationale combinations and incorporating predictive biomarkers will be important moving forward to improve outcomes in patients with PTCL. PMID- 28340874 TI - Management of Anaplastic Large Cell Lymphoma. AB - Anaplastic large cell lymphoma (ALCL) is one of the most common peripheral T-cell lymphomas, and the incidence is higher in blacks than non-Hispanic whites. ALK positive and ALK-negative ALCL are distinct subtypes that have different characteristics and clinical outcomes. Breast implant-associated ALCL is a rare lymphoma that has a good survival outcome, and a recent study showed that total capsulectomy is essential for treatment. Brentuximab vedotin (BV) is a standard treatment for relapsed/refractory ALCL. The response rate is high at 80-90%; however, once the disease progresses in patients on BV, survival outcome is very poor, with a median overall survival of less than two months. PMID- 28340875 TI - Angioimmunoblastic T-Cell Lymphoma. AB - Angioimmunoblastic T-cell lymphoma is a follicular T-helper-derived neoplasm displaying a peculiar morphologic appearance and biological complexity. New mutations have been described that contribute to elucidating the underlying pathogenetic events. The disease behaves aggressively and typically affects elderly patients. The outcomes reported with anthracycline-containing regimens are poor; therefore autologous transplantation in first remission should be offered whenever possible. Newer approaches are urgently needed for relapsed and refractory patients. Newly approved agents show activity in pretreated patients but response durations are short. Innovative induction strategies (CHOP + biologic agent) should be designed to enhance response quality, facilitate transplantation, and prolong survival. PMID- 28340876 TI - Clinical Features and Current Optimal Management of Natural Killer/T-Cell Lymphoma. AB - Extranodal natural killer/T-cell lymphoma, nasal type (ENKL), is a rare subtype of non-Hodgkin lymphoma, and its treatment outcome was previously poor. Novel treatment strategies have improved the outcomes of ENKL remarkably in the last decade. Nowadays, patients with localized nasal ENKL are recommended treatment with concurrent chemoradiotherapy, and their 5-year overall survival rate is approximately 70%. In patients with advanced or relapsed/refractory disease, the efficacy of l-asparaginase-containing therapy has been confirmed. However, there still remain unmet needs in the treatment of ENKL. Continued efforts should be made to further improvements in the treatment of ENKL. PMID- 28340878 TI - T-cell Prolymphocytic Leukemia. AB - T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive T-cell malignancy. T-PLL can be distinguished from other lymphoid diseases by the evaluation and integration of clinical features, morphology, immunophenotyping, cytogenetics, and molecular features. The current therapeutic approach relies on immunotherapy followed by a hematopoietic stem cell transplant in selected cases. Clinical outcomes are generally poor, although insights from genomic and molecular studies may increase our understanding of this disease, with the promise of additional effective therapeutic options. PMID- 28340877 TI - Adult T-cell Leukemia/Lymphoma: A Problem Abroad and at Home. AB - Adult T-cell leukemia/lymphoma (ATLL) is a rare T-cell disorder that is etiologically linked to chronic infection with human T-cell lymphotropic virus type 1. ATLL is divided into four subtypes: acute, lymphomatous, chronic, and smoldering. The acute and lymphomatous variants are often described clinically as the aggressive types of ATLL. Treatment strategies traditionally have focused on antiviral therapy with zidovudine and interferon-alpha and combination chemotherapy. Novel therapeutic approaches include the use of monoclonal antibodies, anti-CCR4 therapy, immunomodulatory therapy, and anti-TAX vaccines. Future research must focus on multi-institutional clinical trial participation because of the rarity of this deadly hematologic malignancy. PMID- 28340879 TI - Uncommon Variants of T-Cell Lymphomas. AB - Peripheral T-cell lymphomas represent 10% to 15% of non-Hodgkin lymphomas and comprise more than 20 different entities. Treatment of very rare T-cell lymphomas can be challenging because there are no large or randomized studies to guide clinical decision making, and treatment paradigms are often based on small series or imperfect data. Although a strict algorithm cannot be written with certainty, through the literature that exists and clinical experience, themes and principles of approaches do emerge that when coupled with clinical judgment allow reasonable and logical decisions. PMID- 28340880 TI - Mycosis Fungoides and Sezary Syndrome. AB - Mycosis fungoides and the Sezary syndrome (SS) are rare lymphomas of CD4+ helper T cells. There is stagewise progression from patch/plaques to thicker tumor lesions/diffuse erythroderma. Blood involvement is a characteristic of SS. Outcomes are related to the extent of skin, blood, lymph node, and visceral organ involvement. Patients with limited patch and plaque disease are treated with skin directed therapies. More advanced/refractory disease is treated with skin directed therapies and oral or systemic immunomodulatory agents. Single-agent chemotherapies are used against tumors, refractory plaques, and lymph node and visceral involvement. Allogeneic stem cell transplantation is a potentially curative strategy for advanced/resistant disease. PMID- 28340882 TI - Autologous and Allogeneic Hematopoietic Cell Transplantation in Peripheral T/NK cell Lymphomas: A Histology-Specific Review. AB - Peripheral T-cell lymphoma and natural killer/T-cell lymphomas (PT/NKCL) make up a diverse subgroup of non-Hodgkin's lymphomas characterized by an aggressive clinical course. The use of hematopoietic stem cell transplantation (HSCT) in the treatment of PT/NKCL remains controversial because of the absence of randomized controlled trials. The best available data suggest that certain subtypes of PT/NKCL may benefit more from the application of HSCT than other subtypes and that this benefit results from their unique clinical characteristics and underlying biology. Ultimately, however, prospective randomized controlled trials are needed to clarify the optimal type and timing of HSCT in patients with PT/NKCL. PMID- 28340883 TI - Novel Agents in the Treatment of Relapsed or Refractory Peripheral T-Cell Lymphoma. AB - Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of mature T-cell malignancies associated with exceptionally poor prognoses. Currently, chemotherapy remains the standard of care, but outcomes are suboptimal, with 5 year survival rates ranging from 15% to 25%. In recent years, several novel agents, including pralatrexate, romidepsin, belinostat, and brentuximab vedotin, have been approved for the treatment of relapsed/refractory PTCL. In addition, numerous other therapies with different mechanisms of action and targets are currently under investigation. This article discusses in detail agents currently available, those currently under investigation, and active combination trials. PMID- 28340881 TI - CD30+ Lymphoproliferative Disorders of the Skin. AB - Primary cutaneous CD30+ lymphoproliferative disorders encompass lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (pcALCL), and indeterminate cases. LyP is a benign disorder characterized by recurrent crops of red or violaceous papulonodules. Patients with LyP are at an increased risk of a secondary malignancy. pcALCL is characterized by a solitary red to violaceous nodule or tumor larger than 20 mm. LyP is benign, is limited to the skin, and self-resolves, with a 5-year survival rate of 100%; pcALCL is limited to the skin and responsive to directed therapies, with a 5-year survival rate of over 95%. Aggressive chemotherapeutic regimens should be avoided. PMID- 28340884 TI - Peripheral T-Cell Lymphoma: The Beginning of the End of the Beginning. PMID- 28340885 TI - Immunosuppression for kidney transplantation: Where are we now and where are we going? AB - Advances in immunosuppression have propelled kidney transplantation from a scientific curiosity to the optimal treatment for patients with end stage kidney disease. Declining rates of acute rejection have led to improvements in short term kidney transplant survival, culminating in incrementally better long term patient and allograft outcomes. Contextualized around established immune suppressing drug targets, this review summarizes the history of the clinical science and highlights the pivotal trials that have led to present-day treatment standards at the level of both individual agents and multidrug regimens for kidney recipients. Finally, recently approved and emerging therapies are discussed, with an emphasis on challenges faced by clinicians managing this increasingly complex patient population. PMID- 28340886 TI - Diagnostic Imaging of Reproductive Tract Disorders in Reptiles. AB - Diagnostic imaging of the reproductive tract in reptiles is used for gender determination, evaluation of breeding status, detection of pathologic changes, and supervising treatment. Whole-body radiographs provide an overview and support detection of mineralized egg shells. Sonography is used to evaluate follicles, nonmineralized eggs, and the salpinx in all reptiles. Computed tomography is able to overcome imaging limitations in chelonian species. This article provides detailed information about the performance of different imaging techniques. Multiple images demonstrate the physiologic appearance of the male and female reproductive tract in various reptile species and pathologic changes. Advantages and disadvantages of radiography, sonography, and computed tomography are described. PMID- 28340887 TI - Reproductive Disorders in Snakes. AB - Reproduction of snakes is one of the challenging aspects of herpetology medicine. Due to the complexity of reproduction, several disorders may present before, during, or after this process. This article describes the physical examination, and radiographic, ultrasonographic, and endoscopic findings associated with reproductive disorders in snakes. Surgical techniques used to resolve reproductive disorders in snakes are described. Finally, common reproductive disorders in snakes are individually discussed. PMID- 28340888 TI - Veterinary Aspects of Bird of Prey Reproduction. AB - Captive breeding has contributed to successful restoration of many species of birds of prey. Avicultural techniques pioneered by raptor breeders include double clutching, direct fostering, cross-fostering, hatch and switch, hacking, imprinting male and female falcons for semen collection, and artificial insemination techniques. However, reproductive failure occurs related to management problems, including hygiene measures, food quality issues, breeding flock structure, or individual health issues of breeding birds. These may result in non-egg laying females, low-quality eggs, or infertile eggs caused by male infertility. Veterinary care of breeding collections is extremely important. This article provides an overview of veterinary involvement in raptor breeding projects. PMID- 28340889 TI - Disorders of the Reproductive Tract of Rabbits. AB - Disorders of the reproductive tract are common in rabbits. Conditions are different in rabbits that are farmed for their meat or fur and those that are kept as pets. Farmed rabbits suffer from infections and diseases associated with pregnancy. Congenital abnormalities are more likely to be recognized and treated in pet rabbits. Pet rabbits suffer from age-related changes to their genital tract (hyperplasia, neoplasia, or hernias). Neutering is an important part of prevention and treatment of reproductive disorders. Knowledge of normal male and female reproductive anatomy is essential to prevent complications. These are described and illustrated. PMID- 28340890 TI - Reproductive Disorders in Pet Rodents. AB - Reproduction diseases are common presentations in small rodents. Some can be presented to the clinician as an emergency where a fast and effective treatment is required. This article presents an overview of reproductive disorders in these species. Diseases affecting the ovary, uterus, testicles, and mammary gland are developed in rats, mice, hamsters, and gerbils: inflammatory, infectious, and neoplasia. Clinical signs, diagnosis, and treatment information are included. Some specific indications about the surgical reproduction procedures are described. Literature regarding reproductive disorders exists for squirrels and prairie dogs. Brief information about the normal anatomy of the reproductive system is given. PMID- 28340891 TI - Reproductive Medicine in Guinea Pigs, Chinchillas and Degus. AB - Guinea pigs, chinchillas, and degus are hystricomorph rodents originating from South America. They are commonly presented as exotic pets in veterinary practice. Reviewing the anatomy and physiology of their reproductive tract helps to offer better client education about preventive medicine and helps to act faster in emergency situations. Choosing the right anesthetic protocol helps to prevent complications. This article should aid as a guideline on the most common reproductive problems of these 3 species and help in making decisions regarding the best treatment options. PMID- 28340893 TI - Reproductive Medicine in Exotic Animal Species. PMID- 28340892 TI - Reproductive Medicine in Ferrets. AB - In the United States, desexing is performed routinely in ferrets at the age of 6 weeks, therefore reproductive tract diseases are not so common. However, in Europe most ferrets are desexed when they are several months old, or they are kept as intact animals. For this reason, diseases of the reproductive organs and a prolonged estrus are far more frequent in Europe than in the United States. This article summarizes and reviews the anatomy, reproductive physiology, management of reproduction (including surgical and hormonal contraception) and reproductive tract diseases in male and female ferrets. PMID- 28340894 TI - Wenckebach pattern in right bundle branch block - benign or not? AB - A Mobitz type I block (Wenckebach phenomenon) with narrow QRS complex is almost always due to a lesion in the AV node. In a type I block with wide QRS complex (>0.12sec), the block can be in the His-Purkinje system in 60-70% of the cases. Even though the progressive PR prolongation with every conducted beat suggests Wenckebach phenomenon, one needs to pay attention to the accompanying QRS complex. In the setting of persistent right bundle branch block, axis change of subsequent conducted beat before an unconducted p suggests alternating fascicular block, giving clue to unreliable infra-Hisian conduction; and in the setting of symptoms, a pacemaker should be implanted. Infra-Hisian Wenckebach block is rare with only sparse literature reports. The present case report adds to these, suggesting that wide QRS with Wenckebach block on surface ECG may indicate infra Hisian conduction abnormalities. PMID- 28340895 TI - Post-operative consequences of hemodynamic optimization. AB - Hemodynamic optimization begins with a medical assessment to identify the high risk patients. This stratification is needed to customize the choice of hemodynamic support that is best adapted to the patient's level of risk, integrating the use of the least invasive procedures. The macro-circulatory hemodynamic approach aims to maintain a balance between oxygen supply (DO2) and oxygen demand (VO2). Volume replacement plays a crucial role based on the titration of fluid boluses according to their effect on measured stroke volume or indices of preload dependency. Good function of the microcirculatory system is the best guarantee to achieve this goal. An assessment of the DO2/VO2 ratio is needed for guidance in critical situations where tissue hypoxia may occur. Overall, all of these strategies are based on objective criteria to guide vascular replacement and/or tissue oxygenation in order to improve the patient's post-operative course by decreasing morbidity and hospital stay. PMID- 28340896 TI - Bioactive constituents from transformed root cultures of Nepeta teydea. AB - A phytochemical study of an extract from transformed root cultures of Nepeta teydea, induced by Agrobacterium rhizogenes, led to the isolation of the following new compounds: the sesquiterpene (-)-cinalbicol, the diterpene teydeadione (6,11,14-trihydroxy-12-methoxy-abieta-5,8,11,13,15-penten-7-one), a degraded C23-triterpene (teydealdehyde) and three fatty acid esters of lanosta 7,24-dien-3beta-ol. The propyl ester of rosmarinic acid was also isolated for the first time from a natural source. In addition, two dehydroabietane diterpenes, eight triterpenes and eighteen known phenolic compounds were obtained. The antifeedant, cytotoxic and phytotoxic activities of the isolated compounds have also been investigated. PMID- 28340897 TI - Response to "DHEA as marker of good surgical homeostasis". PMID- 28340898 TI - Proctologic surgery done by residents: Who is the surgeon in real life? PMID- 28340899 TI - [When will cardiology care be tailored to the specific needs of women?] PMID- 28340900 TI - [Radial approach in women]. AB - Since the first series of coronary angiographies through the radial approach reported by Campeau in 1989, the radial route has become a major approach, used in up to 95 % of PCIs in some centers. As documented by this clinical case, and although registries show that the radial approach is underused in women compared to men, women benefit from the radial approach mainly by reducing the bleeding risk. Indeed, despite more frequent difficulties encountered by using this approach in women, the radial approach has to be preferred because it reduces haemorrhagic complications and death in comparison to the femoral route. PMID- 28340901 TI - Predictive validity of an observer-rated adherence protocol for multisystemic therapy with juvenile drug offenders. AB - OBJECTIVE: Multisystemic therapy (MST) is perhaps the best validated treatment for youth who engage in serious and chronic antisocial behavior (Henggeler, Schoenwald, Borduin, Rowland, & Cunningham, 2009). Despite evidence suggesting that high treatment adherence is needed to achieve optimal MST outcomes, this research is limited because past studies have relied on adherence reports derived solely from treatment participants (i.e., caregivers, youth, and therapists). To address this gap in the literature, the present study assessed the reliability and predictive validity of an observational protocol for rating adherence to MST. METHOD: The sample was drawn from a randomized clinical trial of juvenile drug offenders (77.5% male, 65% African American) referred to one of four treatment conditions (Henggeler et al., 2006). Audiotaped sessions of youth and their families were selected from the first month of MST and trained undergraduate students independently rated therapist adherence to the nine MST treatment principles. We assessed the validity of MST adherence in predicting outcomes at post-recruitment and 12-month follow-up. RESULTS: Good interrater reliability (ICC=0.642) was found across all raters for our composite index of adherence. High adherence to MST during the first month of therapy predicted decreases in externalizing behavior at post-recruitment and decreases in youth alcohol consumption at 12-month follow-up. CONCLUSIONS: These results provide independent support for the link between treatment fidelity and behavioral outcomes in the context of MST. Further, this study demonstrates the feasibility of using novice, undergraduate judges to reliably code therapist adherence. PMID- 28340903 TI - Erratum to "Heterogeneity in pathways to abstinence among women in treatment for alcohol use disorder" [Journal of Substance Abuse Treatment 75 (2017) 1-9]. PMID- 28340902 TI - Quality of care measures for the management of unhealthy alcohol use. AB - There is a paucity of quality measures to assess the care for the range of unhealthy alcohol use, ranging from risky drinking to alcohol use disorders. Using a two-phase expert panel review process, we sought to develop an expanded set of quality of care measures for unhealthy alcohol use, focusing on outpatient care delivered in both primary care and specialty care settings. This process generated 25 candidate measures. Eight measures address screening and assessment, 11 address aspects of treatment, and six address follow-up. These quality measures represent high priority targets for future development, including creating detailed technical specifications and pilot testing them to evaluate their utility in terms of feasibility, reliability, and validity. PMID- 28340904 TI - A group-based motivational interviewing brief intervention to reduce substance use and sexual risk behavior among homeless young adults. AB - Homeless young adults ages 18-25 exhibit high rates of alcohol and other drug (AOD) use, and sexual risk behaviors such as unprotected sex. Yet few programs exist for this population that are both effective and can be easily incorporated into settings serving this population. This pilot cluster cross-over randomized controlled trial evaluates AWARE, a voluntary four session group-based motivational interviewing (MI) intervention to reduce AOD use and sexual risk behavior. We evaluated AWARE with 200 homeless young adults using drop-in center services in Los Angeles County (mean age=21.8years; 73% male; 79% heterosexual; 31% non-Hispanic White, 25% African American, 24% Hispanic, 21% multiracial/other). Surveys were completed at baseline and three months after program completion. Retention in the AWARE program was excellent (79% attended multiple sessions) and participants reported high levels of satisfaction with the program. AWARE participants self-reported positive change in their past 3month and past 30day alcohol use (ps<=0.05), motivation to change drug use (ps<0.05), and condom use self-efficacy (p=0.05) compared to the control group. Among those with multiple sex partners, AWARE participants showed a decrease in unprotected sexual events (p<0.05), whereas the control group did not. Results from this pilot evaluation are promising, suggesting that a brief group-MI risk reduction intervention can be effective in helping homeless young adults make positive changes in their alcohol and condom use. Further work is needed to more fully evaluate the efficacy of AWARE on AOD behavior and sexual risk behavior outcomes. PMID- 28340905 TI - Searching objective criteria for patient assignment in addiction treatment. AB - The main aim of this study was to objectify the treatment assignment criteria used in a clinical centre for addiction treatment in Spain. A sample of 162 patients (87 inpatients and 75 outpatients) who sought treatment between 2010 and 2012 was assessed. Clinical characteristics (addiction severity, psychopathological symptoms, impulsiveness and maladjustment) of the two treatment groups (inpatient and outpatient) into which patients were assigned according to the clinical criteria of therapists were analysed to identify which variables were more relevant for patient placement. Moreover, the therapeutic progression of patients who met and did not meet the assignment criteria received was studied. According to the results, a score above 4 in the family/social support area of the European Addiction Severity Index (EuropASI), or, in cases of a score between 2 and 4 in the family/social area of EuropASI, a score above 2 in the partner subscale of the Maladjustment Scale correctly classified 73.5% of cases (96.6% of inpatients and 46.7% of outpatients). Comparisons of therapeutic results depending on matching or mismatching these assignment criteria showed a larger effect size in mismatching patient assignment criteria for outpatient treatment. The results obtained in this study provide an objective criterion for addicted patient placement. Moreover, from a cost-effective perspective, they question the necessity of inpatient treatment in most cases, demonstrating that outpatient treatment is a sufficient level of care. This study addresses the approach to assigning patients to the treatment modality that best fits them, implementing the least expensive level of care needed to achieve treatment success. PMID- 28340907 TI - Pervious concrete reactive barrier for removal of heavy metals from acid mine drainage - column study. AB - This paper presents a column study conducted to investigate the potential use of pervious concrete as a reactive barrier for treatment of water impacted by mine waste. The study was done using acid mine drainage (AMD) collected from a gold mine (WZ) and a coalfield (TDB). Pervious concrete mixtures consisting of Portland cement CEM I 52.5R with or without 30% fly ash (FA) were prepared at a water-cementitious ratio of 0.27 then used to make cubes which were employed in the reactor columns. It was found that the removal efficiency levels of Al, Fe, Mn, Co and Ni were 75%, 98%, 99%, 94% and 95% for WZ; 87%, 96%, 99%, 98% and 90% for TDB, respectively. The high rate of acid reduction and metal removal by pervious concrete is attributed to dissolution of portlandite which is a typical constituent of concrete. The dominant reaction product in all four columns was gypsum, which also contributed to some removal of sulphate from AMD. Formation of gypsum, goethite, and Glauber's salt were identified. Precipitation of metal hydroxides seems to be the dominant metal removal mechanism. Use of pervious concrete offers a promising alternative treatment method for polluted or acidic mine water. PMID- 28340906 TI - Veterans treatment courts: A case study of their efficacy for Veterans' needs. AB - Veterans Treatment Courts (VTCs) were created to: (1) address issues unique to U.S. Military Veterans; and, (2) where possible, avoid punishing veterans for crimes that may have been committed as a direct result of their mental conditions (e.g., Posttraumatic Stress Disorder (PTSD) and/or Traumatic Brain Injury (TBI)). Little research has been undertaken to ascertain whether VTCs are accomplishing their intended goals. To that end, the present case study examined three operating VTCs in order to determine if they are meeting their objectives. The research provides further information about VTC operations and recidivism rates. The research further reveals that, while the three VTCs examined are arguably benefitting veterans, they are not reaching a greater part of the population due largely to the gatekeeping role of VTC prosecutors, and the rigid eligibility requirements established by the three VTCs for veteran participation. Consequently, it's possible that the low recidivism rates reported by the three VTCs examined are inflated or constitute false positives. PMID- 28340908 TI - Preparing the United States for Zika Virus: Pre-emptive Vector Control and Personal Protection. AB - Discovered in 1947 in a monkey in the Zika forest of Uganda, Zika virus was dismissed as a cause of a mild illness that was confined to Africa and Southeast Asia and transmitted by Aedes mosquitoes. In 2007, Zika virus appeared outside of its endemic borders in an outbreak on the South Pacific Island of Yap. In 2013, Zika virus was associated with a major neurological complication, Guillain-Barre syndrome, in a larger outbreak in the French Polynesian Islands. From the South Pacific, Zika invaded Brazil in 2015 and caused another severe neurological complication, fetal microcephaly. The mosquito-borne transmission of Zika virus can be propagated by sexual transmission and, possibly, by blood transfusions, close personal contacts, and organ transplants, like other flaviviruses. Since these combined mechanisms of infectious disease transmission could result in catastrophic incidences of severe neurological diseases in adults and children, the public should know what to expect from Zika virus, how to prevent infection, and what the most likely failures in preventive measures will be. With federal research funding stalled, a Zika vaccine is far away. The only national strategies to prepare the United States for Zika virus invasion now are effective vector control measures and personal protection from mosquito bites. In addition to a basic knowledge of Aedes mosquito vectors and their biting behaviors, an understanding of simple household vector control measures, and the selection of the best chemical and physical mosquito repellents will be required to repel the Zika threat. PMID- 28340909 TI - Investigation of bias related to differences between case and control interview dates in five INTERPHONE countries. AB - PURPOSE: Associations between cellular telephone use and glioma risk have been examined in several epidemiological studies including the 13-country INTERPHONE study. Although results showed no positive association between cellular telephone use and glioma risk overall, no increased risk for long-term users, and no exposure-response relationship, there was an elevated risk for those in the highest decile of cumulative call time. However, results may be biased as data were collected during a period of rapidly increasing cellular telephone use, and as controls were usually interviewed later in time than cases. METHODS: Further analyses were conducted in a subset of five INTERPHONE study countries (Australia, Canada, France, Israel, New Zealand) using a post hoc matching strategy to optimize proximity of case-to-control interview dates and age. RESULTS: Although results were generally similar to the original INTERPHONE study, there was some attenuation of the reduced odds ratios and stronger positive associations among long-term users and those in the highest categories for cumulative call time and number of calls (eighth-ninth and 10th decile). CONCLUSIONS: Proximity and symmetry in timing of case-to-control interviews should be optimized when exposure patterns are changing rapidly with time. PMID- 28340910 TI - Birth seasonality in rural areas of Iran, analysis of 5,536,262 births from 1992 to 2007. AB - PURPOSE: We conducted this study to investigate birth seasonality in rural parts of Iran. METHODS: In this study, patterns of 5,536,262 live births in rural parts of Iran between 1992 and 2007 were studied. Information about birth numbers, environmental factors, and sociocultural status of participants was obtained from previous works. Visually inspecting the seasonal variation of birth, studying its trend using autocorrelation analysis, examining the trend of birth seasonality using the seasonality coefficient, a newly introduced index, studying correlations between birth seasonality and possible associated factors, and analyzing associations between these variables and birth seasonality using multiple regression model were performed in this study. RESULTS: In this study, we showed birth seasonality in rural parts of Iran, with the highest births in the first two seasons, winter and spring, mostly before the year of 2002. Latitude and mean temperature of districts, wealth status of families, education of women, and mothers' ages were associated with birth seasonality. However, latitude, temperature, and mothers' ages lost their associations after adjusting for sociocultural factors in the regression model. CONCLUSIONS: Birth numbers in rural areas of Iran follow a rhythmic seasonal pattern; however, the ordering of seasons changes in the last years of the study period. PMID- 28340911 TI - Ultrasound-guided vascular cannulation in critical care patients: A practical review. AB - Vascular cannulation is common practice in critical care, and is traditionally performed using the landmark technique - though failures and complications are not uncommon. In this regard, ultrasound guided vascular cannulation (USGVC) has been shown to improve the procedure success rate and reduce its associated complications. This review addresses the fundamental aspects of USGVC and discusses some training issues related to this technique which is currently regarded as essential for intensivists. PMID- 28340912 TI - Autophagy and the invisible line between life and death. AB - For a considerable time cell death has been considered to represent mutually exclusive states with cell death modalities that are governed by their inherent and unique mode of action involving specific molecular entities and have therefore been studied primarily in isolation. It is now, however, becoming increasingly clear that these modalities are regulated by similar pathways and share a number of initiator and effector molecules that control both cell death as well as cell survival mechanisms, demanding a newly aligned and integrative approach of cell death assessment. Frequently cell death is triggered through a dual action that incorporates signaling events associated with more than one death modality. Apoptosis and necrosis regularly co-operate in a tightly balanced interplay that involves autophagy to serve context dependently either as a pro survival or a pro-death mechanism. In this review we will assess current cell death modalities and their molecular overlap with the goal of clarifying the controversial role of autophagy in the cell death response. By dissecting the key molecular pathways and their positioning within a network of regulatory signalling hubs and checkpoints we discuss a distinct approach that integrates autophagy with a resultant cell death manifestation. In doing so, former classifications of cell death modalities fade and reveal the intricate molecular proportions and complexities of the cell death response that may contribute towards an enhanced means of cell death control. PMID- 28340913 TI - Synthesis, activity and docking studies of phenylpyrimidine-carboxamide Sorafenib derivatives. AB - Two series of Sorafenib derivatives bearing phenylpyrimidine-carboxamide moiety (16a-g and 17a-p) were designed, synthesized and evaluated for the IC50 values against three cancer cell lines (A549, MCF-7 and PC-3). Two selected compounds (17f and 17n) were further evaluated for the activity against VEGFR2/KDR kinase. More than half of the synthesized compounds showed moderate to excellent activity against three cancer cell lines. Compound 17f showed equal activity to Sorafenib against MCF-7 cell line, with the IC50 values of 6.35+/-0.43MUM. Meanwhile, compound 17n revealed more active than Sorafenib against A549 cell line, with the IC50 values of 3.39+/-0.37MUM. Structure-activity relationships (SARs) and docking studies indicated that the second series (17a-p) showed more active than the first series (16a-g). What's more, the introduction of fluoro atom to the phenoxy part played no significant impact on activity. In addition, the presence of electron-donating on aryl group was benefit for the activity. PMID- 28340914 TI - Editorial overview: Cell reprogramming, regeneration and repair. PMID- 28340915 TI - Quality improvement program reduces perioperative dental injuries - A review of 64,718 anesthetic patients. AB - BACKGROUND: Perioperative dental injury (PDI) is a common adverse event associated with anesthesia that can easily lead to medicolegal litigation. A quality improvement program was conducted with the electronic, standardized dental chart to document dentition before anesthesia and dentist consultation when necessary. This study aimed to reduce PDIs through execution of a quality improvement program. METHODS: We reviewed the 42-month interval anesthetic records of 64,718 patients who underwent anesthesia. A standardized electronic dental chart was designed to identify any dental prosthetics, fixed and removable dentures, and degree of loose teeth. The incidence of dental injuries associated with anesthesia was separated into three time periods: baseline, initiative (Phase I), and execution (Phase II). Primary outcome measurement was the incidence of PDIs related to anesthesia. RESULTS: The overall incidence of dental injury related to anesthesia was 0.059% (38/64,718 patients). During the baseline period, the dental injury rate was 0.108% (26/24,137 patients), and it decreased from 0.051% in the initiative period (10/19,711 patients) to 0.009% in the execution period (2/20,870 patients) during implementation of the quality improvement program. Most dental injuries were associated with laryngeal mask airway (42.1%) and laryngoscopy (28.9%). The most commonly involved teeth were the upper incisors. CONCLUSION: Dental injury incidence was significantly reduced and remained at low levels after implementation of the quality improvement program. We suggest the implementation of a standardized dental examination into the preoperative evaluation system adding pathologic teeth fixed or protected devices to minimize dental injury associated with anesthesia. PMID- 28340916 TI - Erratum to "Head and neck adenoid cystic carcinoma: A prospective multicenter REFCOR study of 95 cases" [Eur. Ann. Otorhinolaryngol. Head Neck Dis. 133 (1) (2016) 13-7]. PMID- 28340918 TI - A Challenging Case of Colitis in a Young Man. PMID- 28340919 TI - An Unusual Case of an Extremely Large alpha-Fetoprotein-Producing Tumor. PMID- 28340920 TI - Rapidly Progressing Liver Failure in an Adult Female. PMID- 28340921 TI - A Rash and a Mass: What's the Link? PMID- 28340922 TI - Derivation and Validation of a Panel of Exhaled Volatile Organic Compounds in Differentiating Irritable Bowel Syndrome From Health. PMID- 28340923 TI - Nonalcoholic Fatty Liver Disease-Related Hepatocellular Carcinoma: A Potential New Challenge for Hepatocellular Carcinoma Surveillance. PMID- 28340924 TI - Hippocampal-Sparing Whole-Brain Radiotherapy for Lung Cancer. AB - Brain metastases occur in 20% to 40% of lung cancer patients. Whole-brain radiotherapy (WBRT) has long been considered the treatment of choice for many patients with lung cancer, because of its wide availability, ease of delivery, and effectiveness in prolonging survival. However, WBRT is also associated with several side effects, such as decline in memory and other cognitive functions. There exists significant preclinical and clinical evidence that radiation-induced injury to the hippocampus correlates with neurocognitive decline of patients who receive WBRT. Technological advances in treatment planning and delivery facilitate the use of hippocampal-sparing (HS) WBRT as prophylactic cranial irradiation or the primary treatment modality for lung cancer patients with brain metastases. In this review, we provide a detailed and comprehensive discussion of the safety profile, techniques for hippocampus-sparing, and the clinical evidence of HS-WBRT for lung cancer patients. PMID- 28340925 TI - Duration of Twice-Daily Thoracic Radiotherapy and Time From the Start of Any Treatment to the End of Chest Irradiation as Significant Predictors of Outcomes in Limited-Disease Small-Cell Lung Cancer. AB - BACKGROUND: The hypothesis of this retrospective study was that the duration of twice-daily (BID) thoracic radiotherapy (TRT) and time from the start of any treatment to the end of chest irradiation (SER) would predict outcomes in limited disease small-cell lung cancer. MATERIALS AND METHODS: All 81 patients received 45 Gy in 30 fractions BID with a >= 6-hour interval and concurrent chemotherapy of platinum and etoposide. RESULTS: The median radiotherapy duration was 25 days (range, 21-38 days). The 5-year overall survival rates were 26.2% (95% confidence interval [CI], 14.3%-38.0%), and the median survival time was 30 months (95% CI, 15.5-44.5 months). Using multivariate regression analysis, the significant predictors of survival were the sum of the diameters of the primary tumor and metastatic lymph nodes, male gender, age >= 60 years, and the duration of BID-TRT (hazard ratio [HR], 1.15; 95% CI, 1.06-1.25; HR, 2.38; 95% CI, 1.13-5.02; HR, 2.38; 95% CI, 1.10-5.17; and HR, 1.08; 95% CI, 1.01-1.15, respectively). A total of 70 of 81 patients (86%) received radiotherapy during the first chemotherapy cycle. The median SER was 29 days (range, 21-109 days). The 5-year local control rate was 48.7% (95% CI, 33.9%-63.6%). The significant predictors of local control were the sum of the diameters of the primary tumor and metastatic lymph nodes, age >= 60 years, and SER (HR, 1.18; 95% CI, 1.06-1.31; HR, 4.18; 95% CI, 1.23 14.24; and HR, 1.02; 95% CI, 1-1.04, respectively). CONCLUSIONS: The duration of BID-TRT and SER were identified as one of the significant predictors of survival and local control in limited-disease small-cell lung cancer treated with concurrent chemoradiotherapy at 45 Gy in 30 fractions, respectively. PMID- 28340926 TI - Impact of obesity on postoperative 30-day outcomes in emergent open ventral hernia repairs. AB - BACKGROUND: Anecdotally, obese patients experience increased morbidity with emergent ventral hernia repair (VHR). We hypothesized obese patients are over represented in emergent VHRs and experience increased 30-day morbidity. METHODS: American College of Surgeons National Surgical Quality Improvement Program database (2011 to 2013) was queried for patients undergoing open VHR. Patients were stratified by body mass index (BMI) categories: underweight, normal weight, overweight, and obesity classes I, II, and III; 30-day postoperative complications (surgical site infections, return to operating room, dehiscence, death) were evaluated across BMI for elective vs emergent VHR. RESULTS: In all, 39,822 patients were included: 7.3% emergent. Obese classes I to III represented higher percent of emergent VHRs (55.8% vs 68.9%). Complication rate doubled for emergent group (7.2% vs 14.5%), and likelihood of at least one complication increased with BMI for emergent vs normal weight-elective VHR (overweight odds ratio, 2.2; 95% confidence interval, 1.4 to 3.4; class III odds ratio, 4.0; 95% confidence interval, 2.9 to 5.5). CONCLUSIONS: Selection bias exists with obese patients and ventral hernias. Emergent VHR have increased complications. Elective BMI cutoffs require re-evaluation. PMID- 28340927 TI - Resuscitative endovascular balloon occlusion of the aorta for control of noncompressible truncal hemorrhage in the abdomen and pelvis. AB - BACKGROUND: Noncompressible truncal hemorrhage is a leading cause of potentially preventable death in trauma and acute care surgery patients. These patients are at high risk of exsanguination before potentially life-saving surgical intervention may be performed. Temporary aortic occlusion is an effective means of augmenting systolic blood pressure and perfusion of the heart and brain in these patients. Aortic occlusion temporarily controls distal bleeding until permanent hemostasis can be achieved. The traditional method for temporary aortic occlusion is via resuscitative thoracotomy with cross clamping of the descending aorta. While effective, resuscitative thoracotomy is highly invasive and may worsen blood loss, hypothermia, and coagulopathy by opening an otherwise uninjured body cavity. Resuscitative endovascular balloon occlusion of the aorta (REBOA) achieves temporary aortic occlusion using an occlusive balloon catheter that is introduced into the aorta via endovascular access of the common femoral artery. For this reason it is thought that REBOA could provide a less-invasive method for temporary aortic occlusion. Our purpose is to describe our experience with the implementation of REBOA at our Level 1 trauma center. METHODS: A retrospective case series describing all cases of REBOA performed at a prominent level 1 trauma center between October 2011 and September 2015. The study inclusion criteria were any patient that received a REBOA procedure in the acute phases after injury. There were no exclusion criteria. Data were collected from electronic medical records and the hospital's trauma registry. RESULTS: A total of 31 patients underwent REBOA during the study period. The median age of REBOA patients was 47 (interquartile range [IQR] = 27 to 63) and 77% were male. A majority (87%) of patients sustained blunt trauma. The median injury severity score was 34 (IQR = 22 to 42). The overall survival rate was 32% but varied greatly between subgroups. Balloon inflation resulted in a median increase in systolic blood pressure of 55-mm Hg (IQR 33 to 60), in cases where the data were available (n = 20). A return to spontaneous circulation was noted in 60% of patients who had arrested before REBOA (n = 10). Overall, early death by hemorrhage was 28% with only 2 deaths in the emergency department before reaching the operating room. CONCLUSIONS: REBOA is an effective method for achieving temporary aortic occlusion in trauma patients with noncompressible truncal hemorrhage. Balloon inflation correlated with increased blood pressure and temporary hemorrhage control in a vast majority of patients. PMID- 28340928 TI - The difficult gall bladder: Outcomes following laparoscopic cholecystectomy and the need for open conversion. AB - INTRODUCTION: Surgery for the difficult gallbladder (DGB) is associated with increased risk compared to more routine laparoscopic cholecystectomies (LC). Laparoscopic "damage control" methods including cholecystostomy, fundus-down approach and subtotal cholecystectomy (SC) have been proposed to avoid conversion to open. We hypothesized that a Total LC (TLC) for DBG can be completed safely with an acceptably low conversion rate. MATERIAL AND METHODS: All patients that underwent LC from January 2005-June 2015 were retrospectively reviewed. Cases met criteria for DGB if they were necrotic/gangrenous, involved Mirizzi syndrome, had extensive adhesions, were converted to open, lasted more than 120 min, had prior tube cholecystostomy or known GB perforation. RESULTS: A total of 2212 patients underwent LC during the study time period, of which 351 (15.8%) met criteria for DGB. Of these cases, 213 (60.7%) were admitted from the emergency department and 67 (19.1%) underwent urgent/emergent cholecystectomy (within 24 h). Additionally 18 (5.1%) had pre-operative tube cholecystostomies. Seventy patients (19.9%) were converted to open. Indications for conversion included severe inflammation/adhesion (n = 31, 46.3%), difficult anatomy (n = 14, 20.9%) and bleeding (n = 6, 9.0%). Predictors for conversion included urgent/emergent intervention (OR, 0.80; 95% CI 0.351-0.881, p = 0.032), previous abdominal surgery (OR, 2.18; 95% CI, 1.181-4.035, p = 0.013) and necrotic/gangrenous cholecystitis (OR, 1.92; 95% CI, 1.356-4.044, p = 0.033). Comparing the TLC and the conversion groups, mean operative time and length of hospital stay were significantly different; 147 +/- 47 min vs 185 +/- 71 min; p < 0.005 and 3 +/- 2 days vs 5 +/- 3 days; p = 0.011, respectively. There was no significant difference in postoperative hemorrhage, subhepatic collection, cystic duct leak, wound infection, reoperation and 30 day mortality. There was no bile duct injury in either group. CONCLUSION: Total laparoscopic cholecystectomy can be safely performed in difficult gallbladder situations with a lower conversion rate than previously reported. Possible predictors of conversion include urgency, necrotic gallbladder and history of prior abdominal surgeries. For patients converted to open, similar morbidity and mortality can be expected. PMID- 28340929 TI - Pattern transition phenomena in spatial modeling of infectious diseases: Comment on "Pattern transitions in spatial epidemics: Mechanisms and emergent properties" by Gui-Quan Sun et al. PMID- 28340930 TI - Transition from stationary pattern to patch invasion in infectious diseases with space: Comment on "Pattern transitions in spatial epidemics: Mechanisms and emergent properties" by Gui-Quan Sun et al. PMID- 28340931 TI - Time delay induces pattern transition in spatial epidemics: Comment on "Pattern transitions in spatial epidemics: Mechanisms and emergent properties" by Gui-Quan Sun et al. PMID- 28340933 TI - Financial compensation of oocyte donors: an Ethics Committee opinion. AB - Financial compensation of women donating oocytes for infertility therapy or for research is justified on ethical grounds and should acknowledge the time, inconvenience, and discomfort associated with screening, ovarian stimulation, and oocyte retrieval, and not vary according to the planned use of the oocytes, the number or quality of oocytes retrieved, the number or outcome of prior donation cycles, or the donor's ethnic or other personal characteristics. This document replaces the document of the same name, last published in 2007 (Fertil Steril 2007;88:305-9). PMID- 28340932 TI - Predicting first trimester pregnancy outcome: derivation of a multiple marker test. AB - OBJECTIVE: To predict first trimester pregnancy outcome using biomarkers in a multicenter cohort. DESIGN: Case-control study. SETTING: Three academic centers. PATIENT(S): Women with pain and bleeding in early pregnancy. INTERVENTION(S): Sera from women who were 5-12 weeks' gestational age with ectopic pregnancy (EP), viable intrauterine pregnancy (IUP), and miscarriage/spontaneous abortion (SAB) was analyzed by ELISA and immunoassay for activin A, inhibin A, P, A Disintegrin And Metalloprotease-12, pregnancy-associated plasma protein A (PAPP-A), pregnancy specific B1-glycoprotein (SP1), placental-like growth factor, vascular endothelial growth factor, glycodelin (Glyc), and hCG. Classification trees were developed to optimize sensitivity/specificity for pregnancy location and viability. MAIN OUTCOME MEASURE(S): Area under receiver operating characteristic curve, sensitivity, specificity, and accuracy of first trimester pregnancy outcome. RESULT(S): In 230 pregnancies, the combination of trees to maximize sensitivity and specificity resulted in 73% specificity (95% confidence interval (CI) 0.65-0.80) and 31% sensitivity (95% CI 0.21-0.43) for viability. Similar methods had 21% sensitivity (95% CI 0.12-0.32) and 33% specificity (95% CI 0.26 0.41) for location. Activin A, Glyc, and A Disintegrin And Metalloprotease-12 definitively classified pregnancy location in 29% of the sample with 100% accuracy for EP. Progesterone and PAPP-A classified the viability in 61% of the sample with 94% accuracy. CONCLUSION(S): Multiple marker panels can distinguish pregnancy location and viability in a subset of women at risk for early pregnancy complications. This strategy of combining markers to maximize sensitivity and specificity results in high accuracy in a subset of subjects. Activin A, ADAM12, and Glyc are the most promising markers for pregnancy location; P and PAPP-A for viability. PMID- 28340934 TI - [Iris metastasis presenting as monocular diplopia]. PMID- 28340935 TI - Individual and hospital-related determinants of potentially inappropriate admissions emerging from administrative records. AB - INTRODUCTION: The appropriate use of health care is an important issue in developed countries. The purpose of this study was to ascertain the extent of potentially inappropriate hospital admissions and their individual, clinical and hospital-related determinants. METHODS: Medical records were analyzed for the year 2014 held by the Local Heath Unit n. 13 in the Veneto Region of north-east Italy (19,000 records). The outcomes calculated were: admissions for conditions amenable to day hospital care; brief medical admissions; outlier lengths of stay for elderly patients' medical admissions; and medical admissions to surgical wards. Univariate analyses and logistic regression models were used to test associations with demographic, clinical and hospital ward covariates, including organizational indicators. RESULTS: Inappropriate reliance on acute care beds ranged from 6% to 28%, depending on the type of quality indicator analyzed. Some individual features, and wards' specific characteristics were associated with at least one of the phenomena of inappropriate hospital resource usage. In particular, male gender, younger age and transferals seemed to affect inappropriate admissions to surgical wards. Potentially avoidable admissions featuring inpatients amenable to day hospital care were associated with subjects with fewer comorbidities and lower case-mix wards, while inappropriately short medical stays were influenced by patients' higher functional status and local residency and by lower bed occupancy rates. In conclusion, inappropriately long hospital stays for elderly cases were associated with patients with multiple pathologies in wards with a low bed-occupancy. Education level and citizenship did not seem to influence inappropriate admissions. CONCLUSIONS: Some individual, clinical ad structural characteristics of patients and wards emerging from administrative records could be associated with inappropriate reliance on acute hospital beds. Analyzing the indicators considered in this study could generate inexpensive real-time data for identifying what determines potentially inappropriate hospital resource usage, and thus orient auditing activities and health care policy-making. PMID- 28340936 TI - Population ageing and healthcare demand: The case of Slovenia. AB - The aim of this paper is to explore the consequences of demographic ageing on healthcare demand in Slovenia for primary care, secondary care, hospital day-care treatments, and hospitalisations. In the paper, we develop a model for making projections of the total number of treatments using the age-group projection method with the scenario approach. The model allows the number of treatments to be observed with respect to medical services, age groups and main disease groups. The results are presented for the cross-section years 2015, 2025 and 2035. The smallest increase in the number of treatments occurs in primary care, a larger one for secondary care, and the largest for hospital day-care services and hospitalisations (up to 29.9%). The structure of demand will also change. Demand for healthcare services for children and infants will decrease while demand for diseases associated with older age groups will increase, particularly for diseases of the circulatory system, eye and adnexa, and diseases of the blood and blood-forming organs. The results presented in this paper can help improve understanding of similar processes in other countries for total healthcare demand and for changes in the structure of demand. The results show that the healthcare system in Slovenia will face a major additional burden in the next 20 years. PMID- 28340938 TI - Guest Editorial: Sociology, environment and public health. PMID- 28340937 TI - Sirtuin 5 protects mitochondria from fragmentation and degradation during starvation. AB - During starvation, intra-mitochondrial sirtuins, NAD+ sensitive deacylating enzymes that modulate metabolic homeostasis and survival, directly adjust mitochondrial function to nutrient availability; concomitantly, mitochondria elongate to escape autophagic degradation. However, whether sirtuins also impinge on mitochondrial dynamics is still uncharacterized. Here we show that the mitochondrial Sirtuin 5 (Sirt5) is essential for starvation induced mitochondrial elongation. Deletion of Sirt5 in mouse embryonic fibroblasts increased levels of mitochondrial dynamics of 51kDa protein and mitochondrial fission protein 1, leading to mitochondrial accumulation of the pro-fission dynamin related protein 1 and to mitochondrial fragmentation. During starvation, Sirt5 deletion blunted mitochondrial elongation, resulting in increased mitophagy. Our results indicate that starvation induced mitochondrial elongation and evasion from autophagic degradation requires the energy sensor Sirt5. PMID- 28340941 TI - Brown dog tick, Rhipicephalus sanguineus sensu lato, infestation of susceptible dog hosts is reduced by slow release of semiochemicals from a less susceptible host. AB - Domestic dog breeds are hosts for the brown dog tick, Rhipicephalus sanguineus sensu lato, but infestation levels vary among breeds. Beagles are less susceptible to tick infestations than English cocker spaniels due to enhanced production of 2-hexanone and benzaldehyde that act as volatile tick repellents. We report the use of prototype slow-release formulations of these compounds to reduce the burden of R. sanguineus s. l. on English cocker spaniel dogs. Twelve dogs were randomly assigned to two groups with six dogs each. The treated group received collars with slow-release formulations of the compounds attached, while the control group received collars with clean formulations attached. Five environmental infestations were performed, with the number of ticks (at all stages) on the dogs being counted twice a day for 45days. The counts on the number of tick stages found per dog were individually fitted to linear mixed effects models with repeated measures and normal distribution for errors. The mean tick infestation in the treated group was significantly lower than in the control group. For larvae and nymphs, a decrease in tick infestation was observed at the fifth count, and for adults, lower average counts were observed in all counts. The compounds did not interfere with the distribution of the ticks on the body of the dogs, as a similar percentage of ticks was found on the anterior half of the dogs (54.5% for the control group and 56.2% for the treated group). The biological and reproductive parameters of the ticks were not affected by the repellents. This study highlights for the first time the potential use of a novel allomone (repellent)-based formulation for reduction of tick infestation on susceptible dogs. PMID- 28340940 TI - Axially-modified paddlewheel diruthenium(II,III)-ibuprofenato metallodrugs and the influence of the structural modification on U87MG and A172 human glioma cell proliferation, apoptosis, mitosis and migration. AB - The metallodrug chloridotetrakis(ibuprofenato)diruthenium(II,III) ([Ru2(Ibp)4Cl] or RuIbpCl (1), Ibp=carboxylate anion derived from the non-steroidal anti inflammatory drug ibuprofen) has shown promising results in vitro and in vivo, which point to its potential as an inhibitor of glioma tumour growth in vivo. In order to get insight into the influence of structural changes on the biological response of the metallodrug, the [Ru2(Ibp)4] metal-metal multiply bonded paddlewheel unit was modified for the axial ligand. Two new analogues, [Ru2(Ibp)4(CF3SO3)] (2) and [Ru2(Ibp)4(EtOH)2]PF6 (3), were synthesized and fully characterized by elemental analysis, ESI-MS, vibrational (FTIR, Raman) and electronic (UV/VIS/NIR) spectroscopy, magnetic susceptibility, molar conductivity measurements, and thermal analysis. RuIbpCl was re-prepared and complementary characterization to previous work was performed. The three axially-modified RuIbp metallodrugs were compared for their effects on U87MG and A172 human glioma cell proliferation, apoptosis, mitosis, and cell migration in vitro. The results provide evidence that the chloride ligand in RuIbpCl may play key role in the mode of action of the metallodrug, since the best results for antiproliferative activity were found for (1) in both types of human glioma cells. All the metallodrugs, (1), (2) and (3), were uptaken by the cells, and were shown to cause increase on number of apoptotic cells and decrease on number of mitotic cells. Additionally, the RuIbp metallodrugs were capable of inhibiting cell migration process in both human glioma cell lines. These data are extremely promising as drugs which can inhibit both cell proliferation/mitosis and inhibit cell migration could target two major chemotherapeutic targets in high grade gliomas. PMID- 28340942 TI - Where is the true location of the femoral piriform fossa? AB - OBJECTIVE: To analyze knowledge of the anatomic location of the piriform fossa using a questionnaire with anatomic figures. MATERIALS AND METHODS: Participants taking AO Trauma Brasil courses were requested to complete a questionnaire containing a photograph of the superior surface and a photograph of the lateral surface of the femur and answer a question asking which of four numbered points corresponded to the piriform fossa. RESULTS: Just 4.5% of respondents correctly chose point 2 (the piriform fossa) in both images, while 75.4% of respondents chose point 4 (the trochanteric fossa) as the correct anatomic structure. The subset of 4th-year residents' answers was significantly different from those of the other subsets, with 7.5% of correct answers. CONCLUSIONS: The low rate of correct answers indicates a tendency for the respondents to be influenced by illustrations in text books or examples in scientific publications that indicate the site of the piriform fossa incorrectly. Interest in the specialty of traumatology is possibly the reason why the subset of 4th-year residents had a better- than-average rate of correct answers. PMID- 28340943 TI - Femoral neck collapse after internal fixation of an intracapsular hip fracture: Does it indicate a poor outcome? AB - The degree of femoral neck collapse that occurred after 519 patients with an intracapsular hip fracture treated by internal fixation with a Targon FN implant was measured. Mean femoral neck collapse was 8.0mm and this was increased for displaced fractures in comparison to undisplaced fractures (9.5mm versus 5.9mm, p<0.0001) and for those patients that subsequently developed fracture healing complications (11.6mm versus 7.1mm, p<0.0001). At one year from injury femoral neck collapse in excess of 15mm was associated with an increase in the degree of residual pain (p=0.01). A clear relationship between increased collapse and increased loss of mobility was demonstrated (P<0.0001). This study confirms previous smaller studies that excessive femoral neck collapse (of more than 15mm) is more common for displaced fractures and presents new data to demonstrate that excessive femoral neck collapse is associated with an increased risk of fracture healing complications and increased loss of function. Future studies are now justified that consider methods to reduce fracture collapse. PMID- 28340944 TI - Snapping knee syndrome caused by semitendinosus and semimembranosus tendons. A case report. AB - We report the case of a 24-year-old female triathlon athlete with a snapping syndrome of both the distal semimembranosus and the semitendinosus tendon which has not been described so far. The semitendinosus tendon was harvested whereupon snapping has diminished. Tenoscopy and digital palpation showed the semimembranosus tendon to cause the snapping, as well. A careful step-by-step release of the anterior insertion of the tendon was performed with the result of a snapping-free range of motion of the patient's knee. PMID- 28340945 TI - Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review. AB - Dementia is one of the major causes of disability in later life, and ischemic heart disease is a leading cause of morbidity and mortality. Apolipoprotein E (apoE) plays a pivotal role in lipoprotein metabolism in the brain and in the periphery, and is implicated in both dementia and ischemic heart disease. Peripherally, liver-derived apoE is the main source of plasma apoE. Approximately half of plasma apoE is associated with triglyceride-rich lipoproteins, where apoE serves as the main ligand for the low density lipoprotein (LDL) receptor and the LDL receptor Related Protein (LRP). In the brain, apoE is produced mainly by astrocytes. Astrocyte-derived apoE is pivotal for cerebral cholesterol metabolism and clearance of beta-amyloid, a major pathological hallmark of Alzheimer disease. Plasma levels of apoE and other lipids and lipoproteins are under strong genetic influence by the APOE polymorphism, and the epsilon4 allele is a strong genetic risk factor for Alzheimer disease. The characteristics of the APOE polymorphism thus suggest the qualitative importance of apoE, whereas studies of familial absolute apoE deficiency suggest a quantitative importance of plasma apoE levels in lipid metabolism. Whether plasma levels of apoE are associated with increased risk of dementia and ischemic heart disease, and whether these associations are independent of the APOE polymorphism and of lipids and lipoproteins has only recently been established. The aim of this review is to summarize and discuss the current epidemiological and biological evidence for an association of plasma levels of apoE with risk of dementia and ischemic heart disease. PMID- 28340946 TI - Fifty Shades of Stigma: Exploring the Health Care Experiences of Kink-Oriented Patients. AB - INTRODUCTION: The term kink describes sexual behaviors and identities encompassing bondage, discipline, domination and submission, and sadism and masochism (collectively known as BDSM) and sexual fetishism. Individuals who engage in kink could be at risk for health complications because of their sexual behaviors, and they could be vulnerable to stigma in the health care setting. However, although previous research has addressed experiences in mental health care, very little research has detailed the medical care experiences of kink oriented patients. AIM: To broadly explore the health care experiences of kink oriented patients using a community-engaged research approach. METHODS: As part of the Kink Health Project, we gathered qualitative data from 115 kink-oriented San Francisco area residents using focus groups and interviews. Interview questions were generated in collaboration with a community advisory board. Data were analyzed using a thematic analysis approach. MAIN OUTCOME MEASURES: Themes relating to kink-oriented patients' experience with health and healthcare. RESULTS: Major themes included (i) kink and physical health, (ii) sociocultural aspects of kink orientation, (iii) the role of stigma in shaping health care interactions, (iv) coming out to health care providers, and (v) working toward a vision of kink-aware medical care. The study found that kink-oriented patients have genuine health care needs relating to their kink behaviors and social context. Most patients would prefer to be out to their health care providers so they can receive individualized care. However, fewer than half were out to their current provider, with anticipated stigma being the most common reason for avoiding disclosure. Patients are often concerned that clinicians will confuse their behaviors with intimate partner violence and they emphasized the consensual nature of their kink interactions. CONCLUSION: Like other sexual minorities, kink oriented patients have a desire to engage with their health care providers in meaningful discussions about their health risks, their identities, and their communities without fear of being judged. Additional research is needed to explore the experiences of kink-oriented patients in other areas of the country and internationally. PMID- 28340947 TI - Ultrasonic assisted formation and stability of mustard oil in water nanoemulsion: Effect of process parameters and their optimization. AB - The present work reports the ultrasound assisted preparation of mustard oil in water nanoemulsion stabilized by Span 80 and Tween 80 at different operating conditions. Effects of various operating parameters such as HLB (Hydrophilic Lipophilic Balance) value, surfactant volume fraction (phiS), oil volume fraction (phiO) and power amplitude were investigated and optimized on the basis of droplet size and stability of nanoemulsions. It was observed that minimum droplet size of about 87.38nm was obtained within 30min of ultrasonication at an optimum HLB value of 10, phiS of 0.08 (8%, v/v), phiO of 0.1 (10%, v/v) and ultrasonic power amplitude of 40%. The stability of the nanoemulsion was measured through visual observation and it was found that the unstable emulsions got separated within 24h whereas, stable emulsions never showed any separation until 90days. In addition to that, the kinetic stability of the prepared nanoemulsions was also assessed under centrifuge and thermal stress conditions. The emulsion stability was found to be unaffected by these forces as the droplet size remained unchanged. The ultrasound prepared emulsion was found to be long term stable even after 3months of storage at ambient conditions without any visual evidence of creaming and phase separation and also remained kinetically stable. FTIR analysis of the emulsions at different sonication conditions was carried out to examine the possible impact of ultrasonically induced chemical effects on oil structure during emulsification and it was found that the oil molecular structure was unaffected by ultrasonication process. The present work illustrates the formation and stability of mustard oil in water nanoemulsion using ultrasound cavitation which may be useful in food and cosmetic based applications. PMID- 28340948 TI - Application of ultrasound-aided method for the synthesis of CdS-incorporated three-dimensional TiO2 photocatalysts with enhanced performance. AB - In this study, an ultrasound-aided hydrothermal-impregnation method was used to synthesize three-dimensional (3D) urchin-like CdS-TiO2 nanostructures (UCTs) with variable CdS content. The photocatalytic efficiencies (for degrading limonene and toluene vapor) of UCTs synthesized using the ultrasound-aided process were greater than those of UCTs fabricated without ultrasound treatment. In addition, the photocatalytic efficiencies of ultrasound-treated UCTs were greater than those of zero-dimensional ultrasound-treated CdS-TiO2 particles, which, in turn, were greater than those of untreated 3D TiO2. These results indicate that ultrasonication is an amicable process for the synthesis of UCTs with high photocatalytic activity. The enhanced activity of ultrasound-treated photocatalysts is ascribed to the greater charge carrier efficiency, adsorption capacity, and light absorption efficiency of these materials. The photocatalytic efficiencies of ultrasound-treated UCTs increased as the CdS loading was increased from 0.1% to 0.3%, gradually dropping as the loading was further increased to 3.0%, which indicated the existence of an optimum CdS loading. UCT photocatalytic efficiencies depended on the input concentration of target pollutants, relative humidity, and air flow rate. The photocatalytic efficiency for the decomposition of limonene mixed with 2-propanol was lower than that for limonene alone, likely due to the radical scavenging properties of 2-propanol. However, the photocatalytic degradation efficiency of the latter alcohol was not changed upon admixture. Toluene exhibited the same behavior. The mineralization ratios of both target compounds were lower than their decomposition ratios, indicating formation of byproducts due to incomplete oxidation. In addition to CO, three organic compounds were observed as photocatalytic decomposition byproducts of limonene (acetic acid, limonene oxide, and methacrolein) and toluene (benzene, benzaldehyde, and p-xylene). UCTs synthesized by the ultrasound aided hydrothermal-impregnation method could be used to decompose organic vapors with an efficiency of up to 98%, depending on operating conditions. PMID- 28340949 TI - Genetic variants in IL-6 and IL-10 genes and susceptibility to hepatocellular carcinoma in HCV infected patients. AB - BACKGROUND: Hepatitis C virus (HCV) infection is the major cause of hepatocellular carcinoma (HCC), a common primary liver malignancy, and the third leading cause of cancer-related death. The HCC risk increases with the severity of liver inflammation, and the clinical course of HCV infection depends on a balance between pro- and anti-inflammatory cytokines. The former includes interleukin (IL)-6, while the latter includes IL-10. However, the exact pathogenic mechanisms underlying IL-6 and IL-10 effects remain unclear. METHODS: The present study evaluated 174 chronic HCV Tunisian patients. Polymorphisms of IL-6 (rs1880242, rs1474847, rs2069840, rs1800797, rs1800796, rs2069845, rs2069827, rs1474348, rs1800795), and IL-10 (rs1800896, rs1800871, rs1800872, rs1554286, rs1878672, rs1518111) were determined by real-time PCR. RESULTS: Notable differences between chronic HCV-infected patients and HCC patients were observed for the three IL-10 SNPs; rs1800871 (-819T/C), rs1800872 (-592A/C), and rs1878672. Carriage of IL-6 rs1800796 G/G genotype, IL-6 rs1474358 C-allele, and IL-6 rs1800797 A-allele was more frequent in chronic HCV-infected patients than in HCC patients. On the other hand, IL-6 rs1474358 GG genotype had a favourable factor for HCC establishment. CONCLUSION: IL-10 and IL-6 SNPs markedly influence the clinical outcomes of HCV infection. These SNPs could be used as biomarkers for early detection and molecular therapy for preventing HCC, and prognostic factors for predicting the clinical outcomes of HCC. PMID- 28340950 TI - Pharmacokinetics and bioavailability of oral single-dose maleic acid in biofluids of Sprague-Dawley rats. AB - Maleic acid (MA) was purposefully adulterated in an array of starch-based foods in Taiwan, inciting a food safety incident. Due to limited data on the pharmacokinetics and bioavailability of ingested MA, we studied pharmacokinetic (PK) parameters in serum and urine of Sprague Dawley rats. Three groups of male and female rats were given three doses of MA by oral gavage; biofluid samples were collected accordingly. Data demonstrated that a non-compartment model best described MA's linear kinetic behavior upon ingestion. The mean residence life of maleic acid in serum was 17.58 h and 9.84 h for low-dosed male and female rats, whereas 8.24 h and 4.17 h for high-dosed male and female rats, respectively. Our results revealed oral bioavailability ranged from 30.8 to 41.0% for males and 32.2-39.1% for females. The data confirmed that ingested MA is absorbed and metabolized rapidly, along with low bioavailability. Future pathological studies may determine whether prolonged and low-level exposures of MA produce nephrotoxicity. These data provide additional contribution to current understanding of the kinetics of MA in a rat model and enable the development of a physiologically based model, which is essential to form the basis of evidenced based food safety guidelines. PMID- 28340951 TI - Epstein barr virus hemophagocytic lymphohistiocytosis related to rituximab use and immunopathogenetic insights. AB - Anti-CD20-based chemo-immunotherapeutic regimens have been suggested to assist in the management of Epstein-Barr virus (EBV)-induced hemophagocytic lymphohistiocytosis (HLH) and EBV-associated post-transplant lymphoproliferative disorders (EBV-PTLD), by reducing EBV viral load and EBV-induced inflammation. Herein we report a fatal EBV-related HLH in the context of Hodgkin lymphoma (HL) like Richter's transformation of B chronic lymphocytic leukemia (B-CLL), two months after rituximab treatment. The complex balance between EBV driven T-cell stimulation and immunosuppressive therapy in the context of multiple immune deficits is discussed. PMID- 28340952 TI - Lack of association of mortalin (HSPA9) and other mitochondria-related genes with risk of Parkinson's and Alzheimer's diseases. AB - We investigated the role of mortalin (HSPA9) and its interaction with other mitochondria-related genes (parkin, PINK1, DJ1, and COQ2) as a risk factor for Parkinson's disease (PD) and Alzheimer's disease (AD) in 500 PD, 400 AD, and 500 control subjects. The HSPA9 variants identified by direct sequencing or its interaction with other genes assessed by genetic risk scores did not show a significant association with PD or AD risk. Our findings did not provide a strong evidence for the role of HAPA9 and its interaction with other mitochondria related genes as a genetic risk factor for PD or AD. PMID- 28340953 TI - Clinical features of Chinese patients with Gerstmann-Straussler-Scheinker identified by targeted next-generation sequencing. AB - Gerstmann-Straussler-Scheinker (GSS) is an autosomal dominant neurodegenerative disease due to mutations within prion protein (PRNP) gene. Clinically, it is not easy to distinguish GSS from spinocerebellar ataxia (SCA), especially in the early stage of disease. We aimed to identify genetic mutations in 8 Chinese pedigrees with dominant ataxia but excluded dynamic mutations of SCA genes. Targeted next-generation sequencing was performed in the 8 probands. A customized panel was designed to capture 24 known causative genes, including 15 autosomal dominant SCA genes and 9 dementia-related genes. A 2-year follow-up was performed in these patients who harbored mutation. Of the 8 probands, 5 were identified to harbor the p.P102L mutation within PRNP. All these 5 cases had progressive ataxia with age at onset ranging from 48 to 52 years (49.5 +/- 4.51). Remarkable phenotypic heterogeneity was observed in them. Cognitive decline was found in 4/5 probands. The average duration from initial symptoms to cognitive decline is 32.5 months, ranging from 22 to 48 months. In this study, we presented the detailed clinical features of 5 GSS pedigrees with PRNP p.P102L mutation. The variable phenotypes among these GSS patients indicated other genetic or environmental factors might be involved in the phenotypic heterogeneity of GSS. Our findings also support the proposal that screening of PRNP mutations should be performed for the patients with dominant ataxia if dynamic mutations of SCA genes were excluded. PMID- 28340954 TI - Professor Peter York-A Distinguished Career in Powders, Processing, and Particle Design. PMID- 28340955 TI - A Practical Framework Toward Prediction of Breaking Force and Disintegration of Tablet Formulations Using Machine Learning Tools. AB - Enabling the paradigm of quality by design requires the ability to quantitatively correlate material properties and process variables to measureable product performance attributes. Conventional, quality-by-test methods for determining tablet breaking force and disintegration time usually involve destructive tests, which consume significant amount of time and labor and provide limited information. Recent advances in material characterization, statistical analysis, and machine learning have provided multiple tools that have the potential to develop nondestructive, fast, and accurate approaches in drug product development. In this work, a methodology to predict the breaking force and disintegration time of tablet formulations using nondestructive ultrasonics and machine learning tools was developed. The input variables to the model include intrinsic properties of formulation and extrinsic process variables influencing the tablet during manufacturing. The model has been applied to predict breaking force and disintegration time using small quantities of active pharmaceutical ingredient and prototype formulation designs. The novel approach presented is a step forward toward rational design of a robust drug product based on insight into the performance of common materials during formulation and process development. It may also help expedite drug product development timeline and reduce active pharmaceutical ingredient usage while improving efficiency of the overall process. PMID- 28340956 TI - Stability Orders of Acetaminophen and Theophylline Co-crystals Determined by Co crystal Former Exchange Reactions and Their Correlation With In Silico and Thermal Parameters. AB - The aim of this study was to determine the thermodynamic stability order of co crystals using co-crystal former exchange reactions and to validate 2 in silico parameters for predicting co-crystal formation. Co-crystal former exchange reactions were performed using acetaminophen (AC) co-crystals of oxalic acid (OX), maleic acid (MA), and theophylline (TH). The addition of TH to an AC-MA co crystal (AC-MA) afforded AC-TH, suggesting that AC-TH was more stable than AC-MA. The stability order among the other co-crystals was determined in the same manner. The stability order of the AC co-crystals was determined to be AC-TH > AC MA ~ AC-OX. Interestingly, the addition of TH to AC-OX afforded TH-OX. The stability order of the TH co-crystals was also determined (OX-TH > AC-TH ~ MA TH). Although the stability order of the AC co-crystals was consistent with the differences in their hydrogen bond energy (DeltaE), an in silico parameter for predicting co-crystal formation, it showed no relationship to the excess enthalpy (Hex). These results suggest that co-crystal formation can be predicted with greater accuracy using DeltaE rather than Hex for AC co-crystals. The stability orders of the AC and TH co-crystals also correlated well with their melting points and disintegration temperatures. PMID- 28340957 TI - The perils of rivaroxaban in younger patients. PMID- 28340958 TI - Metabolism and acetylation in innate immune cell function and fate. AB - Innate immunity is the first line of defense against invading pathogens. Changes in both metabolism and chromatin accessibility contribute to the shaping of these innate immune responses, and we are beginning to appreciate that cross-talk between these two systems plays an important role in determining innate immune cell differentiation and function. In this review we focus on acetylation, a post translational modification important for both regulating chromatin accessibility by modulating histone function, and for functional regulation of non-histone proteins, which has many links to both immune signaling and metabolism. We discuss the interactions between metabolism and acetylation, including the requirement for metabolic intermediates as substrates and co-factors for acetylation, and the regulation of metabolic proteins and enzymes by acetylation. Here we highlight recent findings, which demonstrate the role that the metabolism acetylation axis has in coordinating the responses of innate immune cells to the availability of nutrients and the microenvironment. PMID- 28340959 TI - Molecular detection of Clostridium difficile on inert surfaces from a Costa Rican hospital during and after an outbreak. AB - BACKGROUND: Hospital transmission of Clostridium difficile is fostered by contamination of surfaces and medical equipment with spores highly resistant to disinfectants and regular cleaning procedures. Despite the outbreaks and fatalities that C difficile causes, its epidemiology has not been studied in hospitals from middle- and low-income countries. To tackle this knowledge gap, the detection frequency of C difficile DNA on inert surfaces of a major Costa Rican hospital during and after an outbreak was compared. METHODS: We used a presence-absence real-time polymerase chain reaction to detect a fragment of the tpi gene of C difficile on 21 surface samples collected during an outbreak and 54 surface samples taken 2 years later at the same hospital. RESULTS: C difficile DNA was detected in 40% of the 75 environmental samples analyzed. Whereas 71% of the samples collected during the outbreak were positive, only 28% of the samples obtained 2 years after the outbreak gave the same result. This 2.5* ratio was maintained when the comparison was restricted to the wards that were sampled both during and after the outbreak (72% vs 35%, P = .016). CONCLUSIONS: Our results show that environmental surfaces in the hospital analyzed are continuously being contaminated with C difficile DNA and that their level of contamination is higher during an outbreak than after it. PMID- 28340962 TI - The reliability of measuring the density of the L1 vertebral body on CT imaging as a predictor of bone mineral density. AB - AIM: To determine whether the density of the L1 vertebra measured on computed tomography (CT) images correlates with the bone mineral density (BMD) as measured by quantitative computed tomography (QCT), and to determine the reliability of L1 density measurements by different observers to see if this measure could help identify patients who would benefit from formal BMD assessment. MATERIALS AND METHODS: Non-contrast CT along with a phantom for determination of BMD was performed on 30 healthy patients. The L1 density was measured by 3 observers at two time-points separated by at least 2 weeks. RESULTS: L1 density was well correlated to the QCT BMD (correlation coefficient 0.83; 95% confidence interval [CI]: 0.67-0.92). There was excellent intra- and interobserver agreement in L1 density measurements. There were excellent intra-class correlation coefficients for each observer's measurements at two separate time points with a coefficient for observer 1 of 0.94 (95% CI: 0.88-0.97) and for observer 2 and 3 of 0.99 (95% CI: 0.98-1). The interobserver measurements had an intra-class correlation coefficient of 0.98 (95% CI: 0.96-0.99). CONCLUSION: L1 vertebral density can be reliably measured on CT images and might be used as an indicator of BMD for opportunistic screening of patients with osteoporosis. Low bone density detected incidentally on CT imaging could be used to identify patients who should be further investigated and treated for osteoporosis. PMID- 28340963 TI - Pioglitazone in patients with insulin resistance after ischemic stroke or transient ischemic attack: A comment on the IRIS trial. PMID- 28340964 TI - Higher parity is associated with increased risk of Type 2 diabetes mellitus in women: A linear dose-response meta-analysis of cohort studies. AB - AIM: The goal of this study is to investigate the association between higher parity and the risk of occurrence of type 2 diabetes mellitus (T2DM) in women and to quantify the potential dose-response relation. METHODS: We searched MEDLINE, and EMBASE electronic databases for related cohort studies up to March 10th, 2016. Summary rate ratios (RRs) and 95% confidence intervals (CIs) for T2DM with at least 3 categories of exposure were eligible. A random-effects dose-response analysis procedure was used to study the relations between them. RESULTS: After screening a total of 13,647 published studies, only 7 cohort studies (9,394 incident cases and 286,840 female participants) were found to be eligible for this meta-analysis. In the category analysis, the pooled RR for the highest number of parity vs. the lowest one was 1.42 (95% CI: 1.17-1.72, I2=71.5%, Pheterogeneity=0.002, Power=0.99). In the dose-response analysis, a noticeable linear dose-risk relation was found between parity and T2DM (Pfor nonlinearity test=0.942). For every live birth increase in parity, the combined RR was 1.06 (95% CI: 1.02-1.09, I2=84.3%, Pheterogeneity=0.003, Power=0.99). Subgroup and sensitivity analyses yielded similar results. No publication bias was found in the results. CONCLUSION: This meta-analysis suggests that higher parity and the risk of T2DM show a linear relationship in women. PMID- 28340965 TI - Identification and quantification of microplastics using Nile Red staining. AB - We investigated the applicability of Nile Red (NR), a fluorescent dye, for microplastic analysis, and determined the optimal staining conditions. Five mg/L NR solution in n-hexane effectively stained plastics, and they were easily recognized in green fluorescence. The NR staining method was successfully applied to micro-sized polyethylene, polypropylene, polystyrene, polycarbonate, polyurethane, and poly(ethylene-vinyl acetate), except for polyvinylchloride, polyamide and polyester. The recovery rate of polyethylene (100-300MUm) spiked to pretreated natural sand was 98% in the NR stating method, which was not significantly (p<0.05) different with FT-IR identification. The NR staining method was suitable for discriminating fragmented polypropylene particles from large numbers of sand particles in laboratory weathering test samples. The method is straightforward and quick for identifying and quantifying polymer particles in the laboratory controlled samples. Further studies, however, are necessary to investigate the application of NR staining to field samples with organic remnants. PMID- 28340966 TI - Recognition memory is selectively impaired in adult rats exposed to binge-like doses of ethanol during early postnatal life. AB - Exposure to alcohol in utero can induce a variety of physical and mental impairments, collectively known as fetal alcohol spectrum disorders (FASD). This study explores the persistent cognitive consequences of ethanol administration in rat pups over postnatal days (PD) 4-9, modeling human third trimester consumption. Between PD65-70, ethanol-exposed (5E) and control rats were evaluated in two variants of recognition memory, the spontaneous novel object recognition (NOR) task, using 20 and 240 min sample-to-test delays, and the associative object-in-context (OIC) task, using a 20 min delay. No treatment group differences were observed in object exploration during the sample session for any task. In the 20 min NOR test session the 5E rats explored the novel object significantly less than controls, relative to the total time exploring both objects. Postnatal ethanol exposure is hypothesized to impede object memory consolidation in the perirhinal cortex of 5E rats, hindering their ability to discriminate between familiar and novel objects at short delays. The 5E rats performed as well or better than control rats in the 240 min NOR and the 20 min OIC tasks, indicating developmental ethanol exposure selectively impairs the retention and expression of recognition memories in young adult rats. PMID- 28340967 TI - [Age and cardiopulmonary resuscitation wishes of patients with heart disease]. PMID- 28340968 TI - Genetics of triple-negative breast cancer: Implications for patient care. AB - Patients with triple-negative breast cancer (TNBC), defined as lacking expression of the estrogen and progesterone receptors (ER/PR) and amplification of the HER2 oncogene, often have a more aggressive disease course than do patients with hormone receptor-positive breast cancer, including higher rates of visceral and central nervous system metastases, early cancer recurrences and deaths. Triple negative breast cancer is associated with a young age at diagnosis and both African and Ashkenazi Jewish ancestry, the latter due to three common founder mutations in the highly penetrant cancer susceptibility genes BRCA1 and BRCA2 (BRCA1/2). In the past decade, there has been a surge both in genetic testing technology and in patient access to such testing. Advances in genetic testing have enabled more rapid and less expensive commercial sequencing than could be imagined only a few years ago. Massively parallel, next-generation sequencing allows the simultaneous analysis of many different genes. Studies of TNBC patients in the current era have revealed associations of TNBC with mutations in several moderate penetrance breast cancer susceptibility genes, including PALB2, BARD1, BRIP1, RAD51C and RAD51D. Interestingly, many of these genes, like BRCA1/2, are involved in homologous recombination DNA double-stranded repair. In this review, we summarize the current understanding of pathogenic germline gene mutations associated with TNBC and the early detection and prevention strategies for women at risk of developing this high-risk breast cancer subtype. Furthermore, we discuss recent the advances in targeted therapies for TNBC patients with a hereditary predisposition, including the role of poly (ADP ribose) polymerase (PARP) inhibitors in BRCA1/2 mutation-associated breast cancers. PMID- 28340969 TI - Effect of different rates of spent coffee grounds (SCG) on composting process, gaseous emissions and quality of end-product. AB - The use of spent coffee grounds (SCG) in composting for organic farming is a viable way of valorising these agro-industrial residues. In the present study, four treatments with different amounts of spent coffee grounds (SCG) were established, namely, C0 (Control), C10, C20 and C40, containing 0, 10, 20 and 40% of SCG (DM), respectively; and their effects on the composting process and the end-product quality characteristics were evaluated. The mixtures were completed with Acacia dealbata L. shoots and wheat straw. At different time intervals during composting, carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O) emissions were measured and selected physicochemical characteristics of the composts were evaluated. During the composting process, all treatments showed a substantial decrease in total phenolics and total tannins, and an important increase in gallic acid. Emissions of greenhouse gases were very low and no significant difference between the treatments was registered. The results indicated that SCG may be successfully composted in all proportions. However C40, was the treatment which combined better conditions of composting, lower GHG emissions and better quality of end product. PMID- 28340971 TI - Glutathione species and metabolomic prints in subjects with liver disease as biological markers for the detection of hepatocellular carcinoma. AB - BACKGROUND: The incidence of liver disease is increasing in USA. Animal models had shown glutathione species in plasma reflects liver glutathione state and it could be a surrogate for the detection of hepatocellular carcinoma (HCC). METHODS: The present study aimed to translate methods to the human and to explore the role of glutathione/metabolic prints in the progression of liver dysfunction and in the detection of HCC. Treated plasma from healthy subjects (n = 20), patients with liver disease (ESLD, n = 99) and patients after transplantation (LTx, n = 7) were analyzed by GC- or LC/MS. Glutathione labeling profile was measured by isotopomer analyzes of 2H2O enriched plasma. Principal Component Analyzes (PCA) were used to determined metabolic prints. RESULTS: There was a significant difference in glutathione/metabolic profiles from patients with ESLD vs healthy subjects and patients after LTx. Similar significant differences were noted on patients with ESLD when stratified by the MELD score. PCA analyses showed myristic acid, citric acid, succinic acid, l-methionine, d-threitol, fumaric acid, pipecolic acid, isoleucine, hydroxy-butyrate and glycolic, steraric and hexanoic acids were discriminative metabolites for ESLD-HCC+ vs ESLD-HCC- subject status. CONCLUSIONS: Glutathione species and metabolic prints defined liver disease severity and may serve as surrogate for the detection of HCC in patients with established cirrhosis. PMID- 28340975 TI - A Case of Apples and Oranges. PMID- 28340974 TI - Herpes Zoster Vaccine Coverage in Older Adults in the U.S., 2007-2013. AB - INTRODUCTION: This study aimed to assess the coverage of herpes zoster (HZ) vaccine among a large cohort of insured individuals aged >=50 years from 2007 to 2013, and to determine the factors associated with being vaccinated for adults aged >=60 years. METHODS: This was a retrospective, observational study using the MarketScan(r) database conducted in 2015. The study population was U.S. adults aged >=60 years during 2007-2013 and 50-59 years during 2011-2013. The claims of each eligible subject were evaluated post-index date to assess HZ vaccine uptake. Multivariate analyses were performed to understand factors associated with receiving HZ vaccine. RESULTS: A total of 6,746,476 adults aged >=60 years and 6,770,294 adults aged 50-59 years were identified. By 2013, 1.7% of adults aged 50-59 years, 23.9% of adults aged 60-64 years, and 14.5% of adults aged >=65 years received HZ vaccine. Adults aged >=65 years were less likely to receive HZ vaccine than those aged 60-64 years (hazard ratio [HR]=0.543; 95% CI=0.539, 0.547). Adults who were female, immunocompetent, and had more outpatient hospital, doctor office, and pharmacy visits were more likely to receive HZ vaccine. Adults who received influenza vaccine were more likely to receive HZ vaccine (HR=1.841; 95% CI=1.830, 1.853). CONCLUSIONS: Estimated HZ vaccine coverage is 19.5% in adults aged >=60 years, which is lower than the Healthy People 2020 target of 30%. Providers should identify every opportunity for HZ vaccination to assure that older adults are protected from HZ, a vaccine preventable disease. PMID- 28340973 TI - Multilevel Interventions Targeting Obesity: Research Recommendations for Vulnerable Populations. AB - INTRODUCTION: The origins of obesity are complex and multifaceted. To be successful, an intervention aiming to prevent or treat obesity may need to address multiple layers of biological, social, and environmental influences. METHODS: NIH recognizes the importance of identifying effective strategies to combat obesity, particularly in high-risk and disadvantaged populations with heightened susceptibility to obesity and subsequent metabolic sequelae. To move this work forward, the National Heart, Lung, and Blood Institute, in collaboration with the NIH Office of Behavioral and Social Science Research and NIH Office of Disease Prevention convened a working group to inform research on multilevel obesity interventions in vulnerable populations. The working group reviewed relevant aspects of intervention planning, recruitment, retention, implementation, evaluation, and analysis, and then made recommendations. RESULTS: Recruitment and retention techniques used in multilevel research must be culturally appropriate and suited to both individuals and organizations. Adequate time and resources for preliminary work are essential. Collaborative projects can benefit from complementary areas of expertise and shared investigations rigorously pretesting specific aspects of approaches. Study designs need to accommodate the social and environmental levels under study, and include appropriate attention given to statistical power. Projects should monitor implementation in the multiple venues and include a priori estimation of the magnitude of change expected within and across levels. CONCLUSIONS: The complexity and challenges of delivering interventions at several levels of the social-ecologic model require careful planning and implementation, but hold promise for successful reduction of obesity in vulnerable populations. PMID- 28340976 TI - Population genetic data for 12 X-STR loci in the Northern Han Chinese and StatsX package as tools for population statistics on X-STR. AB - The X-chromosomal short tandem repeat (X-STR) has the advantage in female traces identification against male contamination and in complex kinship cases. In this study, a total of 516 Northern Han Chinese were genotyped using the Investigator(r) Argus X-12 QS Kit and pairwise genetic distances (FST) were measured between Northern Han Chinese and 35 published populations using the same 12 X-STR loci in four presumed linkage groups (LG). Meanwhile, the StatsX package was compiled to aid the analysis of population statistics on X-STR. Off-ladder alleles were investigated by Sanger sequencing or next generation sequencing (NGS). The results showed that high combined PDM, PDF, MECKruger, MECKishida, MECDesmarais and MECDesmarais Duo based on allele frequencies were achieved as 0.999999998, >0.999999999, 0.999996425, 0.999999993, 0.999999993 and 0.999998732, respectively, so did they based on haplotype frequencies. Averaged FST and multidimensional scaling (MDS) plot generally mirrored with the biogeography distribution of the studied populations and their historical relationships. A total of 16 unique off-ladder alleles were observed in this experiment, four of which have not been reported yet. The StatsX package could obtain full concordance with established software. Overall, the Investigator(r) Argus X-12 QS Kit may provide high polymorphic information for forensic identification and kinship analysis in the Northern Han Chinese population, and the StatsX package can make the workflow smoother for researchers to do population statistical analysis on X-STR. PMID- 28340977 TI - Commentary to 'Management of undescended testes: European Association of Urology/European Society for Paediatric Urology Guidelines'. PMID- 28340979 TI - Delirium in heart failure. PMID- 28340978 TI - Adult congenital heart disease nurse coordination: Essential skills and role in optimizing team-based care a position statement from the International Society for Adult Congenital Heart Disease (ISACHD). AB - BACKGROUND: Founded in 1992, the International Society for Adult Congenital Heart Disease (ISACHD) is the leading global organization of professionals dedicated to pursuing excellence in the care of adults with congenital heart disease (CHD) worldwide. Among ISACHD's objectives is to "promote a holistic team-based approach to the care of the adult with CHD that is comprehensive, patient centered, and interdisciplinary" (http://www.isachd.org). This emphasis on team based care reflects the fact that adults with CHD constitute a heterogeneous population with a wide spectrum of disease complexity, frequent association with other organ involvement, and varied co-morbidities and psychosocial issues. METHODS: Recognizing the vital role of the adult CHD (ACHD) nurse coordinator (ACHD-NC) in optimizing team-based care, ISACHD established a task force to elucidate and provide guidance on the roles and responsibilities of the ACHD-NC. Acknowledging that nursing roles can vary widely from region to region based on factors such as credentials, scopes of practice, regulations, and local culture and tradition, an international panel was assembled with experts from North America, Europe, East Asia, and Oceania. The writing committee was tasked with reviewing key aspects of the ACHD-NC's role in team-based ACHD care. RESULTS/CONCLUSION: The resulting ISACHD position statement addresses the ACHD NC's role and skills required in organizing, coordinating, and facilitating the care of adults with CHD, holistic assessment of the ACHD patient, patient education and counseling, and support for self-care management and self-advocacy. PMID- 28340980 TI - Comments on the letter to the editor by Farjadmand et al., on "Galen's book on sphygmology" [Int. J. Cardiol. 221 (2016) 333-334]. PMID- 28340981 TI - Is mean platelet volume a prognostic marker for hemodialysis patients? PMID- 28340982 TI - Corrigendum to "Untangling the relatedness among correlations, Part I: Nonparametric approaches to inter-subject correlation analysis at the group level" [Neuroimage (in press)]. PMID- 28340983 TI - Sonographer preference of ballistic gelatin concentration used to create DVT training phantoms. PMID- 28340984 TI - An unusual etiology for acquired long QT syndrome and torsade de pointes. PMID- 28340986 TI - Design and synthesis of affinity chromatography ligands for the purification of 5 hydroxyeicosanoid dehydrogenase. AB - Arachidonic acid (AA) is converted to biologically active metabolites by different pathways, one of the most important of which is initiated by 5 lipoxygenase (5-LO). 5-Hydroxyeicosatetraenoic acid (5-HETE), although possessing only weak biological activity itself, is oxidized to 5-oxo-6,8,11,14 eicosatetraenoic acid (5-oxo-ETE), a potent chemoattractant for eosinophils and neutrophils. Our main goal is to determine how the biosynthesis of 5-oxo-ETE is regulated and to determine its pathophysiological roles. To achieve this task, we designed and synthesized affinity chromatography ligands for the purification of 5-hydroxyeicosanoid dehydrogenase (5-HEDH), the enzyme responsible for the formation of 5-oxo-ETE. PMID- 28340985 TI - Autoimmunity, Autoantibodies, and Autism Spectrum Disorder. AB - Auism spectrum disorder (ASD) now affects one in 68 births in the United States and is the fastest growing neurodevelopmental disability worldwide. Alarmingly, for the majority of cases, the causes of ASD are largely unknown, but it is becoming increasingly accepted that ASD is no longer defined simply as a behavioral disorder, but rather as a highly complex and heterogeneous biological disorder. Although research has focused on the identification of genetic abnormalities, emerging studies increasingly suggest that immune dysfunction is a viable risk factor contributing to the neurodevelopmental deficits observed in ASD. This review summarizes the investigations implicating autoimmunity and autoantibodies in ASD. PMID- 28340987 TI - Discovery of novel curcumin derivatives targeting xanthine oxidase and urate transporter 1 as anti-hyperuricemic agents. AB - A series of curcumin derivatives as potent dual inhibitors of xanthine oxidase (XOD) and urate transporter 1 (URAT1) was discovered as anti-hyperuricemic agents. These compounds proved efficient effects on anti-hyperuricemic activity and uricosuric activity in vivo. More importantly, some of them exhibited proved efficient effects on inhibiting XOD activity and suppressing uptake of uric acid via URAT1 in vitro. Especially, the treatment of 4d was demonstrated to improve uric acid over-production and under-excretion in oxonate-induced hyperuricemic mice through regulating XOD activity and URAT1 expression. Docking study was performed to elucidate the potent XOD inhibition of 4d. Compound 4d may serve as a tool compound for further design of anti-hyperuricemic drugs targeting both XOD and URAT1. PMID- 28340988 TI - Rational design, synthesis, and structure-activity relationships of 5-amino-1H pyrazole-4-carboxylic acid derivatives as protein tyrosine phosphatase 1B inhibitors. AB - A series of novel amino-carboxylic based pyrazole as protein tyrosine phosphatase 1B (PTP1B) inhibitors were designed on the basis of structure-based pharmacophore model and molecular docking. Compounds containing different hydrophobic tail (1,2 diphenyl ethanone, oxdiadizole and dibenzyl amines) were synthesized and evaluated in PTP1B enzymatic assay. Structure-activity relationship based optimization resulted in identification of several potent, metabolically stable and cell permeable PTP1B inhibitors. PMID- 28340989 TI - Bio-Electron-Fenton (BEF) process driven by microbial fuel cells for triphenyltin chloride (TPTC) degradation. AB - The intensive use of triphenyltin chloride (TPTC) has caused serious environmental pollution. In this study, an effective method for TPTC degradation was proposed based on the Bio-Electron-Fenton process in microbial fuel cells (MFCs). The maximum voltage of the MFC with graphite felt as electrode was 278.47% higher than that of carbon cloth. The electricity generated by MFC can be used for in situ generation of H2O2 to a maximum of 135.96MUmolL-1 at the Fe@Fe2O3(*)/graphite felt composite cathode, which further reacted with leached Fe2+ to produce hydroxyl radicals. While 100MUmolL-1 TPTC was added to the cathodic chamber, the degradation efficiency of TPTC reached 78.32+/-2.07%, with a rate of 0.775+/-0.021MUmolL-1h-1. This Bio-Electron-Fenton driving TPTC degradation might involve in SnC bonds breaking and the main process is probably a stepwise dephenylation until the formation of inorganic tin and CO2. This study provides an energy saving and efficient approach for TPTC degradation. PMID- 28340990 TI - Identification of sulfonylurea biodegradation pathways enabled by a novel nicosulfuron-transforming strain Pseudomonas fluorescens SG-1: Toxicity assessment and effect of formulation. AB - Nicosulfuron is a selective herbicide belonging to the sulfonylurea family, commonly used on maize culture. A bacterial strain SG-1 was isolated from an agricultural soil previously treated with nicosulfuron. This strain was identified as Pseudomonas fluorescens and is able to quantitatively dissipate 77.5% of nicosulfuron (1mM) at 28 degrees C in the presence of glucose within the first day of incubation. Four metabolites were identified among which ASDM (2 (aminosulfonyl)-N,N-dimethyl-3-pyridinecarboxamide) and ADMP (2-amino-4,6 dimethoxypyrimidine) in substantial proportions, corresponding to the hydrolytic sulfonylurea cleavage. Two-phase dissipation kinetics of nicosulfuron by SG-1 were observed at the highest concentrations tested (0.5 and 1mM) due to biosorption. The extend and rate of formulated nicosulfuron transformation were considerably reduced compared to those with the pure active ingredient (appearance of a lag phase, 30% dissipation after 10days of incubation instead of 100% with the pure herbicide) but the same metabolites were observed. The toxicity of metabolites (standardized Microtox(r) test) showed a 20-fold higher toxicity of ADMP than nicosulfuron. P. fluorescens strain SG-1 was also able to biotransform two other sulfonylureas (metsulfuron-methyl and tribenuron-methyl) with various novel pathways. These results provide new tools for a comprehensive picture of the sulfonylurea environmental fate and toxicity of nicosulfuron in the environment. PMID- 28340991 TI - SERS-based ultrasensitive detection of organophosphorus nerve agents via substrate's surface modification. AB - Highly efficient detection of the organicphosphor nerve agents such as sarin and soman, based on surface enhanced Raman scattering (SERS) effect, has been in challenge due to their weak adsorption property on coin metals. In this paper, a new strategy is presented to achieve the SERS-based ultrasensitive detection of sarin-simulated agent methanephosphonic acid (MPA) via the surface modification of SERS-substrates. The Au-coated Si nanocone array is surface-modified with 2 aminoethanethiol and used as SERS-substrate for detection of MPA. It has been shown that the modified substrate could preferentially capture MPA molecules in the solution with coupling agent and induce amidation reaction. The reaction products are still bound or anchor on the substrate's surface. The MPA molecules can thus be detected by Raman spectral measurement of the solution-soaked SERS substrate. The minimum detection level is down to ~1ppb. The Raman peak intensity versus the MPA concentration is subject to a linear double logarithmic relation from ~1ppb to ~1000ppm, which is attributed to Freundlich adsorption of MPA on the surface-modified SERS substrate. This study provides a new way for the highly efficient SERS-based detection of the organophosphorus nerve agents and some other target molecules weakly interacted with metal substrates. PMID- 28340992 TI - Hierarchical structured MnO2@SiO2 nanofibrous membranes with superb flexibility and enhanced catalytic performance. AB - Constructing nanostructured catalyst-embedded ceramic fibrous membranes would facilitate the remediation or preliminary treatment of dyeing wastewater, however, most of such membranes are brittle with low deformation resistance, thus, restricting their widely applications. Herein, the flexible and hierarchical nanostructured MnO2-immobilized SiO2 nanofibrous membranes (MnO2@SiO2 NFM) were fabricated by combining the electrospinning technique with hydrothermal method. The morphologies of membranes could be regulated from nanowires and nanoflower to mace-like structure via varying concentration of reactants. The resultant MnO2@SiO2 NFM could cooperate with hydrogen peroxide to form a Fenton-like reagent for the degradation of methylene blue (MB). The resultant membrane exhibited prominent catalytic performance towards MB, including high degradation degree of 95% within 40min, fast degradation rate of 0.0865min-1, and excellent reusability in 5 cycles. Moreover, the membranes could be used in a wide pH range of 0 to 14 and the degradation degree reached 76% during dynamic filtration process with a flux of 490,000Lm-2h-1. The successful fabricating of such membrane with extraordinary catalytic performance would provide a platform for preparing high-performance catalysts for remediation of dyeing wastewater. PMID- 28340993 TI - Antimony speciation as geochemical tracer for anthropogenic emissions of atmospheric particulate matter. AB - The chemical composition of atmospheric particulate matter (PM) has been studied at the cities of Cordoba and Granada (South of Spain) between 2007 and 2013, considering urban background, traffic and industrial monitoring stations. The results of Principal Component Analysis (PCA) indicated that geochemical anomalies observed in the ambient air of Cordoba (mainly Cu, Zn, Pb and Cd) are closely related to the geochemical profile obtained from fugitive metallurgy emissions of brass industries. These findings have been confirmed performing an Sb speciation analysis of PM10 samples, which allowed to distinguish between Sb(III) and Sb(V). The percentage of Sb(V) in PM10 found in the traffic station of Granada was 64-69%. At Cordoba, the percentage of Sb(V) was found to be higher (73-77%) at both urban background and traffic stations, indicating a possible second source of Sb in the PM of this city. The PM10 samples from the industrial station of Cordoba showed a 85-86% of Sb(V). A similar percentage (84-88%) of Sb(V) was found for the fugitive emissions of the brass industries, confirming this industrial source of Sb. These results show that Sb speciation can be a useful geochemical tracer to identify anthropogenic sources (traffic and industrial) emissions of PM. PMID- 28340994 TI - Biological effect of aqueous C60 aggregates on Scenedesmus obliquus revealed by transcriptomics and non-targeted metabolomics. AB - This work evaluated biological effect of nC60 on Scenedesmus obliquus. The cells were exposed to various concentrations of nC60 for 7days. Low-dose of nC60 was found to have a minor growth inhibitory effect. The transcriptomics and metabolomics were integrated to examine intricate molecular and cellular effects of nC60 on Scenedesmus obliquus. We found that Scenedesmus obliquus cells exposed to nC60 had several significant alterations in cellular transcription and biochemical processes. During the 7-day exposure to nC60, 2234 and 2,448 unigenes were differentially expressed by 0.1mg/L and 1mg/L nC60-treated groups compared with the control, including 2085 or 2247 up-regulated genes and 149 or 201 down regulated genes, respectively. We successfully identified 22 metabolites, including 6 significantly changed metabolites, such as sucrose, d-glucose, and malic acid. The citrate cycle (TCA cycle) (ko00020) was the main target of both differentially expressed genes and metabolic change. However, accumulation of sucrose (end-product) could have induced feedback inhibition of photosynthesis in Scenedesmus obliquus, explaining the slight growth inhibition observed. The results provided a mechanistic understanding of the growth inhibition of nC60 toxicity. These genes and metabolites are useful biomarkers for future studies and offer new insights into the early detectable changes in Scenedesmus obliquus with nC60 exposure. PMID- 28340995 TI - An overview of advanced reduction processes for bromate removal from drinking water: Reducing agents, activation methods, applications and mechanisms. AB - Bromate (BrO3-) is a possible human carcinogen regulated at a strict standard of 10MUg/L in drinking water. Various techniques to eliminate BrO3- usually fall into three main categories: reducing bromide (Br-) prior to formation of BrO3-, minimizing BrO3- formation during the ozonation process, and removing BrO3- from post-ozonation waters. However, the first two approaches exhibit low degradation efficiency and high treatment cost. The third workaround has obvious advantages, such as high reduction efficiency, more stable performance and easier combination with UV disinfection, and has therefore been widely implemented in water treatment. Recently, advanced reduction processes (ARPs), the photocatalysis of BrO3-, have attracted much attention due to improved performance. To increase the feasibility of photocatalytic systems, the focus of this work concerns new technological developments, followed by a summary of reducing agents, activation methods, operational parameters, and applications. The reaction mechanisms of two typical processes involving UV/sulfite homogeneous photocatalysis and UV/titanium dioxide heterogeneous photocatalysis are further summarized. The future research needs for ARPs to reach full-scale potential in drinking water treatment are suggested accordingly. PMID- 28340996 TI - Diabetes for Cardiologists: Practical Issues in Diagnosis and Management. AB - Diabetes mellitus (DM), a chronic metabolic disease characterized by hyperglycemia, is a profound cardiovascular (CV) risk factor. It compounds the effects of all other risk factors, leads to premature micro- and macrovascular disease, facilitates development of heart failure, worsens the clinical course of all CV diseases, and shortens life expectancy. Established DM, unrecognized DM, and dysglycemia that may progress to DM are all commonly present at the time of presentation of overt CV disease. Thus, CV specialists and trainees frequently treat patients with dysglycemia. The traditional and proven role of cardiologists in reducing the risk of macrovascular events in this population is through aggressive lipid and blood pressure treatment. However, a more proactive role in the detection and management of DM is likely to become increasingly important as the prevalence continues to increase and therapies continue to improve. The latter include antihyperglycemic therapies with proven cardiovascular safety profiles and CV event reduction properties not yet fully elucidated and not necessarily related to glycemic control. Accordingly, the purpose of this article is to (1) expand the interest of cardiologists in earlier stages of the natural history of DM, when prevention or early detection might help achieve greatest benefit; (2) highlight principles of optimal glycemic management, with an emphasis on add-on choices showing promising reduction of CV events and lacking CV adverse effects; and (3) encourage cardiologists to become proactive partners in the multidisciplinary care needed to ensure optimal lifelong vascular health in patients with, or who are at risk of, DM. PMID- 28340997 TI - Association between Nutrition Risk in Critically Ill score and mortality may be mediated by nutritional therapy. PMID- 28340998 TI - Theophylline increases diaphragmatic contractility in mechanically ventilated newborns. PMID- 28340999 TI - Emergent vs. elective stenting of carotid stenosis with intraluminal carotid thrombus. AB - BACKGROUND AND PURPOSE: Carotid stenosis (CS) with intraluminal carotid artery thrombus (ICAT) is rare but ominous finding. The optimal treatment modality is unclear. The aim of this study was to analyze the feasibility and outcome of acute endovascular intervention and delayed elective endovascular therapy after initial anticoagulation in these delicate cases. Moreover, both treatment points were compared and several parameters discussed to facilitate the determination of the optimal time modality in future cases. MATERIALS AND METHODS: A series of 11 consecutive cases with acute symptomatic CS with ICAT that received endovascular treatment was retrospectively analyzed. General patient data, pre and post interventional symptoms and imaging were evaluated in an overall mean follow-up of 84 weeks. RESULTS: Urgent stenting and mechanical thrombectomy was performed in 6 patients. In the remaining 5 cases, elective endovascular treatment was planned after initial anticoagulation therapy with thrombus resolution. One case received secondary urgent treatment due to clinical deterioration. Overall outcome at three months follow-up was excellent (Modified Ranking Scale [mRS] 0 1) in 5 cases, good (mRS 2) in 4 and unfavorable in the remaining 2. Important differences between the two treatment arms were seen in 3 parameters (stenosis degree, thrombus length, and NIHSS score). CONCLUSIONS: This is one of the largest studies analysing endovascular treatment in patients with acute symptomatic CS and additional ICAT only. Both endovascular treatment strategies seem feasible. Parameters such as size of intraluminal thrombus and clinical symptoms should be included in the decision-making process regarding the optimal individual treatment time. PMID- 28341000 TI - Arterial spin-labeling perfusion imaging of children with subdural hemorrhage: Perfusion abnormalities in abusive head trauma. AB - BACKGROUND AND PURPOSE: Perfusion abnormalities have not been well described in children with subdural hemorrhage (SDH). We investigated whether patients with abusive head trauma (AHT+) had more perfusion abnormalities than those without (AHT-). MATERIALS AND METHODS: We reviewed the perfusion MR studies of 12 infants with SDH and 21 controls. The perfusion images were obtained using a pseudo continuous arterial spin-labeling sequence with volumetric fast spin-echo readout. An MR perfusion scoring system (0-6 points) was devised to facilitate appraisal of the extent of abnormalities. An asymmetry index (AI) was calculated for each region of perfusion abnormality. Comparison of perfusion scores across the AHT+, AHT-, and control groups was performed. The AIs of the hypoperfused lesions and hyperperfused lesions in patients were separately compared with those of the controls. The neurological outcomes of the patients were associated with imaging abnormalities. RESULTS: Perfusion abnormalities were found in five (83%) of six AHT+ patients and in one (17%) of six AHT- patients. The AHT+ group recorded a significantly higher perfusion score than did both the AHT- group and the controls. Four patients with hypoperfused lesions exhibited significantly lower AI (P=.002) than did the controls, and three patients with hyperperfused lesions had significantly higher AI (P=.006) than did the controls. Of the four patients with hypoperfused lesions, two expired and one experienced hemiparesis. CONCLUSIONS: Patients with AHT have higher perfusion abnormality scores than patients with other causes of SDH and controls. Moreover, hypoperfusion may suggest a poor clinical outcome. PMID- 28341001 TI - Atypical intracranial artifacts caused by dreadlocks during brain Magnetic Resonance Imaging: Keep calm and recognize them. PMID- 28341002 TI - Seroprevalence survey of selective anti-neuronal autoantibodies in patients with first-episode schizophrenia and chronic schizophrenia. AB - Autoimmune encephalopathy caused by autoantibodies against neuronal cell-surface proteins in the brain is a newly discovered disease category associated with psychiatric disorders. Correct diagnosis of this condition relies on the detection of specific autoantibodies in the blood or cerebral spinal fluid in addition to the clinical presentations. The study aimed to understand the seroprevalence of selective anti-neuronal autoantibodies in our patients with schizophrenia. First, we screened for six anti-neuronal autoantibodies in an archived blood sample collected from patients with the first-episode schizophrenia. The six autoantibodies including antibodies against N-methyl-d aspartate (NMDA) receptor, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors 1 and 2, gamma-butyric acid receptor type B1 (GABARB1), leucine-rich glioma inactivated-1 (LGI1) protein, and contactin-associated protein-like 2 (CASPR2) protein. A total of 78 plasma samples (46 males and 32 females) were investigated; however, no positive case was identified. In this second study, we screened anti-NMDA receptor autoantibodies in a blood sample of 234 patients with chronic schizophrenia (133 females and 101 males) including 48 patients defined as treatment resistance. None of this sample was detected as positive. The negative findings in this study suggest that the seroprevalence of autoantibodies against neuronal surface proteins might be low in patients diagnosed with schizophrenia. PMID- 28341004 TI - Correction. PMID- 28341003 TI - [Can venous iron and tranexamic acid reduce the transfusion need? Report on a non randomized, case control study]. AB - OBJECTIVES: To evaluate if the association of injectable iron and tranexamic acid allows a significant saving in transfusion, in cases of myomectomies and hysterectomies. PATIENTS AND METHOD: This is a prospective, non randomized study done over 8 months (from January 2013 to August 2013). Were included, patients undergoing hysterectomy or myomectomy who had a hemoglobin level greater than or equal to 8g/dl and less than 12g/dl. Two groups were compared: group A consisting of patients for whom a pack red cells was ordered and the group B which patients received intravenous iron preoperatively and tranexamic acid perioperatively. The level of hemoglobin, pre- and postoperative, the average number of blood units per patient and estimated blood loss was compared. The transfusion economy was evaluated. RESULTS: During this period, 87 patients with a mean age of 40+/-9 years (range: 23 and 70years) were included according to our criteria: 44 patients in group A and 43 patients in group B. Initial mean hemoglobin in both groups was 9.1+/-0.7g/dl. In group B, after iron administration, the mean hemoglobin was 11.3+/-0.7g/dl. The average number of red blood cells received intraoperative patient in group A was 1.54+/-0.51. The estimated blood loss was significant greater (P=0.0002) in group A (571.6+/-237.1ml) than in group B (213.7+/-131.7ml). No transfusion was performed in group B. CONCLUSION: The association intravenous iron and tranexamic acid resulted in the reduction of transfusion requirements in our setting. It could be integrated in the strategy for sparing blood transfusion in scheduled surgery with hemorrhagic risks. PMID- 28341005 TI - An Industry/Academia Collaborative to Support Smoking-Cessation Grants. PMID- 28341006 TI - An unusual case of sudden unexpected death due to massive hemopericardium from primary mediastinal seminoma. AB - It is well-known that cardiovascular disease is the most common cause of sudden unexpected death, especially in the young. However complete postmortem investigation performed by qualified forensic pathologists is crucial in establishing the exact cause and manner of death. Sudden death caused by a cardiac tamponade occurring secondarily to a primary mediastinal tumor is extremely unusual. An autopsy on a 25-year-old man who died unexpectedly discovered a massive hemopericardium in association with an anterosuperior mediastinal mass. The tumor had invaded the pericardium and an ulcerative surface with hemorrhagic necrosis on the cut surfaces of the intrapericardial tumor was revealed. All cardiac chambers and intrathoracic great vessels were intact and both testes were normal. Histologic examination confirmed the diagnosis of primary mediastinal pure cell seminoma. Diffuse pulmonary edema, as well as generalized congestion of internal organs, was observed as evidence of acute decompensated heart failure. To our knowledge, this is the first reported case of unexpected death due to massive hemopericardium as a result of primary mediastinal seminoma. PMID- 28341007 TI - On the mishandling of probabilities in Lamotte & Wells' commentary on J.P. Michaud, G. Moreau, Predicting the visitation of carcasses by carrion-related insects under different rates of degree-day accumulation. AB - LaMotte and Wells re-analyzed and criticized one of our articles in which we proposed a novel statistical test for predicting postmortem interval from insect succession data. Using simple mathematical examples, we demonstrate that LaMotte and Wells erred because their analyses are based on an erroneous interpretation of the nature of probabilities that disregards more than 300 years of scientific literature on probability combination. We also argue that the methods presented in our article, more specifically the use of degree-day-based logistic regression analysis to model succession, was a positive contribution to the fields of forensic entomology and carrion ecology, which LaMotte and Wells forgot to mention by instead focusing on issues that were either trivial or did not exist. PMID- 28341008 TI - Serum vitamin D level in Egyptian children with Familial Mediterranean fever. AB - BACKGROUND: The aim of the study is to measure plasma vitamin D levels in a group of Egyptian children with familial Mediterranean fever (FMF) compared to healthy children. METHODS: The study enrolled 52 children with FMF and 40 apparently healthy controls. Serum vitamin D level was measured by enzyme-linked immunosorbent assay. RESULTS: The mean serum vitamin D level was significantly lower in children with FMF than control group (12.3+/-3.4 and 21.2+/-3.5ng/mL, respectively, p<0.001). Vitamin D level was significantly lower in female patients than males (11.3+/-2.9, 13.2+/-3.6, respectively p=0.04). No statistically significant relations were detected between vitamin D level and different clinical, laboratory and genetic variables. CONCLUSION: Vitamin D levels were lower in Egyptian FMF children than healthy controls. There is a speculation that vitamin D deficiency in FMF patients may be related to inflammation. Further studies with larger number of patients before and after Vitamin D, therapy may be needed. Supplementation with high doses of vitamin D seems appropriate for children with FMF. PMID- 28341009 TI - Gardnerella vaginalis diversity and ecology in relation to vaginal symptoms. AB - Gardnerella vaginalis was first described in 1953, and subsequently identified as the causative agent of a cluster of vaginal symptoms currently known as vaginosis. Research has so far failed to confirm whether and by which mechanism G. vaginalis initiates vaginosis, with, consequently, poor diagnostics and treatment outcomes. Recent molecular analyses of protein-coding genes demonstrate that the taxon G. vaginalis consists of at least four distinct species. This development may represent a critical turning point in clarifying ecological interactions and virulence factors contributing to symptoms and/or sequelae of vaginosis. PMID- 28341010 TI - History and development of ophthalmology in Taiwan. AB - Western medicine was first introduced to Taiwan by medical missionaries in the mid-19th century. Modernization of medicine was systematically transplanted to Taiwan in the Japanese colonial period, and ophthalmology was established third among hospital departments, following internal medicine and surgery. Dr Hidetaka Yamaguchi, an ophthalmologist, was the first head of the Taihoku Hospital, later known as National Taiwan University Hospital (NTUH; Taipei, Taiwan). Ophthalmologists during the colonial period conducted studies on tropical and infectious eye diseases. After World War II, ophthalmologists at NTUH played an important role in medical education, residency training, studies, and teaching. Dr Yan-Fei Yang established the Taiwan Ophthalmological Society in 1960 and instituted its official journal in 1962. Dr Ho-Ming Lin established the Department of Ophthalmology at the Tri-Service General Hospital in the 1950s and the Veterans General Hospital in the 1960s. Taiwan ophthalmologists eradicated trachoma by 1971. Cataract surgery and penetrating keratoplasty were initially performed in the 1960s. Currently, there are about 1600 ophthalmologists in Taiwan conducting an estimated 120,000 cataract surgeries and 600 corneal transplantations annually. Many subspecialty societies have been established recently that serve to educate Taiwanese ophthalmologists and to connect with international ophthalmic societies. Taiwan ophthalmologists continue to contribute to the advancement of ophthalmic knowledge globally. PMID- 28341011 TI - Interstitial high-dose-rate brachytherapy as salvage treatment for locally recurrent prostate cancer after definitive radiation therapy: Toxicity and 5-year outcome. AB - PURPOSE: We report our results with interstitial high-dose-rate brachytherapy (HDR-BT) as a salvage therapy option after external beam therapy with or without BT. Emphasis was put on toxicity and 5-year outcome. METHODS AND MATERIALS: From 2003 to 2011, 29 patients with local failure after previous radiotherapy for prostate cancer were treated with salvage interstitial HDR-BT. The diagnosis of local recurrence was made on the basis of choline positron emission tomography. Salvage HDR-BT was given in three fractions with a single dose of 10 Gy per fraction and weekly. The target volume covered the peripheral zone of the prostate and the positron emission tomography-positive area. Acute and late toxicities were documented according to common terminology criteria for adverse events (CTCAE v 4.0). RESULTS: Twenty-two patients with minimum followup of 60 months were analyzed. The 5-year overall survival was 95.5% with a disease specific survival of 100%. The 5-year biochemical control was 45%. Late grade 2 gastrointestinal toxicities were observed in two patients (9%). No grade 3 or higher gastrointestinal late toxicities were observed. Urinary incontinence found in 2 patients (9%) and grade 2 obstruction of urinary tract occurred in one patient (4%). CONCLUSIONS: Interstitial HDR-BT was feasible and effective in the treatment of locally recurrent prostate cancer after definitive radiotherapy. The long-term toxicity was low and acceptable. PMID- 28341014 TI - Live pertussis vaccines: will they protect against carriage and spread of pertussis? AB - Pertussis is a severe respiratory disease that can be fatal in young infants. Its main aetiological agent is the Gram-negative micro-organism Bordetella pertussis. Vaccines against the disease have been in use since the 1950s, and global vaccination coverage has now reached more than 85%. Nevertheless, the disease has not been controlled in any country, and has even made a spectacular come-back in the industrialized world, where the first-generation whole-cell vaccines have been replaced by the more recent, less reactogenic, acellular vaccines. Several hypotheses have been proposed to explain these observations, including the fast waning of acellular vaccine-induced protection. However, recent mathematical modelling studies have indicated that asymptomatic transmission of B. pertussis may be the main reason for the current resurgence of pertussis. Recent studies in non-human primates have shown that neither whole-cell, nor acellular vaccines prevent infection and transmission of B. pertussis, in contrast to prior exposure. New vaccines that can be applied nasally to mimic natural infection without causing disease may therefore be useful for long-term control of pertussis. Several vaccine candidates have been proposed, the most advanced of which is the genetically attenuated B. pertussis strain BPZE1. This vaccine candidate has successfully completed a first-in-man phase I trial and was shown to be safe in young male volunteers, able to transiently colonize the nasopharynx and to induce antibody responses to B. pertussis antigens in all colonized individuals. Whether BPZE1 will indeed be useful to ultimately control pertussis obviously needs to be assessed by carefully conducted human efficacy trials. PMID- 28341015 TI - Impairment of Social Function in Young Females With Recent-Onset Anorexia Nervosa and Recovered Individuals. AB - PURPOSE: A subgroup of individuals with anorexia nervosa (AN) displays social difficulties; however, it is not clear if individuals with comorbid autism spectrum disorders account for these difficulties. METHODS: We compared social function using the Autism Diagnostic Observation Schedule in 43 young females with first-episode AN who did not have comorbid autism spectrum disorder, 28 individuals recovered from adolescent-onset AN, and 41 healthy comparison individuals (age range 14-22 years). We measured adaptive behavior with the Vineland-II parent questionnaire, and aspects of social cognition with psychological tests, such as the Reading-the-Mind-in-the-Eyes test, Profile of Nonverbal Sensitivity short version, The Awareness of Social Inference Test, Animated Triangles, and the CANTAB Affective Go/No-go task. RESULTS: Participants with first-episode AN and those recovered from AN displayed difficulties in social function, which were not associated with body mass index or other state factors of the disorder in those with first-episode AN. Mood problems and anxiety were not associated with these difficulties. Parents rated participants with first-episode AN lower than recovered and control participants on the Socialization Domain of Vineland-II. Finally, only participants recovered from AN demonstrated deficits in specific domains of social cognition: perceiving nonverbal bodily gesture and vocal prosody. CONCLUSIONS: Young females with first episode AN and those recovered from AN displayed impairments in social function, which may represent more stable traits of the disorder. Only participants recovered from AN demonstrated deficits in social cognition. PMID- 28341016 TI - The Role of Alcohol Expectancies in Sexual Risk Behaviors Among Adolescents and Young Adults in the Democratic Republic of the Congo. AB - PURPOSE: Considering the increased risk of HIV among alcohol users, we explored the role of individual alcohol expectancies in risk behaviors among youth in the Democratic Republic of the Congo. METHODS: We surveyed 1,396 adolescents (ages 15 19) and young adults (ages 20-24) on alcohol and sexual behaviors in May, 2010. We assessed expectancies of alcohol use (1) leading to sex or positive sexual experiences; (2) diminishing one's ability to resist unwanted sex; and (3) diminishing one's ability to use or negotiate use of condoms. Adjusted logistic regression models assessed the association between alcohol use and alcohol expectancies with unprotected sex and multiple sex partners (MSP). RESULTS: Participants reporting alcohol use (36.8%) were more likely to have engaged in unprotected sex and MSP than nondrinkers (adjusted odds ratio [AOR]: 2.87, 95% confidence interval [CI]: 2.29-3.60; AOR: 3.73 95% CI: 2.94-4.72, respectively). Among alcohol users, after adjusting for drinking quantity, moderate expectancies of alcohol leading to positive sexual experiences were significantly associated with MSP among adolescent boys (AOR: 4.20, 95% CI: 1.49-11.86) and girls (AOR: 3.97, 95% CI: 1.36-11.60), whereas high expectancies were significant among young adult men (AOR: 2.70, 95% CI: 1.19-6.10). Among adolescent girls who used alcohol, adjusted odds of unprotected sex were elevated among those with expectancies of diminished ability to refuse unwanted sex (AOR: 5.13, 95% CI: 1.41-16.64) or to negotiate condom use (AOR: 16.22; 2.08-126.8). CONCLUSIONS: HIV prevention efforts for youth should acknowledge the role of alcohol expectancies in sexual risk behaviors and tailor programs to address different roles of expectancies in males and females. PMID- 28341017 TI - Family Meals and Adolescent Emotional Well-Being: Findings From a National Study. AB - OBJECTIVE: To describe the relationship between family meals and adolescent mental health and determine whether the relationship differs by sex. DESIGN: Secondary analyses of a cross-sectional survey. PARTICIPANTS: A total of 8,500 nationally representative students. MAIN OUTCOME MEASURES: Reynolds Adolescent Depression Scale; Strengths and Difficulties Questionnaire; World Health Organization Well-being Index. ANALYSIS: Multiple regression models determined the relationships between family meals and mental health indicators; sociodemographic variables and family connection were included as covariates. RESULTS: Approximately 60% of adolescents shared family meals >=5 times in the previous week, whereas 22% reported that they shared <=2 meals in the previous week. Greater frequency of family meals was associated with fewer depressive symptoms (P < .001), fewer emotional difficulties (P < .001) and better emotional well-being (<.001). These relationships between family meals and depressive symptoms were attenuated by sex; the relationship was stronger for females than for males. CONCLUSIONS AND IMPLICATIONS: Frequent family meals may have a protective effect on the mental health of adolescents, particularly for depressive symptoms in girls. Interventions that aim to increase the frequency of family meals are needed to evaluate whether family meals alone can have an emotional benefit for adolescents. PMID- 28341018 TI - Using Skin Carotenoids to Assess Dietary Changes in Students After 1 Academic Year of Participating in the Shaping Healthy Choices Program. AB - OBJECTIVE: To determine whether fourth-grade students participating in the Shaping Healthy Choices Program (SHCP), a school-based nutrition intervention, would change vegetable and carotenoid intake measured by skin carotenoids and dietary intake. METHODS: Single-group pretest-posttest with a self-selected, convenience sample of students (n = 30) participating in the SHCP, which lasted 1 academic year (9 months). Dietary intake of vegetables and carotenoids as measured by Block food frequency questionnaire and skin carotenoids as measured by Raman spectroscopy were collected at the school preintervention and postintervention. RESULTS: Reported carotenoid intake decreased by 1.5 mg (P = .05) and skin carotenoids decreased by 2,247.9 RRS intensity units (P = .04). Change in reported intake correlated with change in skin carotenoids (r = .43; P = .02). CONCLUSIONS AND IMPLICATIONS: The reported decrease in vegetable and carotenoid intake was unanticipated; nevertheless, the RRS measurements confirmed this. RRS data can help evaluate changes in fruit and vegetable intake. PMID- 28341019 TI - Re: Lead diagnostic testing and maxillofacial gunshot wounds. PMID- 28341020 TI - Editorial Comment. PMID- 28341021 TI - Author Reply. PMID- 28341023 TI - Molecular characterization of invasive Streptococcus dysgalactiae subsp. equisimilis. Multicenter study: Argentina 2011-2012. AB - Streptococcus dysgalactiae subsp. equisimilis (SDSE) has virulence factors similar to those of Streptococcus pyogenes. Therefore, it causes pharyngitis and severe infections indistinguishable from those caused by the classic pathogen. The objectives of this study were: to know the prevalence of SDSE invasive infections in Argentina, to study the genetic diversity, to determine the presence of virulence genes, to study antibiotic susceptibility and to detect antibiotic resistance genes. Conventional methods of identification were used. Antibiotic susceptibility was determined by the disk diffusion and the agar dilution methods and the E-test. Twenty eight centers from 16 Argentinean cities participated in the study. Twenty three isolates (16 group G and 7 group C) were obtained between July 1 2011 and June 30 2012. Two adult patients died (8.7%). Most of the isolates were recovered from blood (60.9%). All isolates carried speJ and ssa genes. stG62647, stG653 and stG840 were the most frequent emm types. Nineteen different PFGE patterns were detected. All isolates were susceptible to penicillin and levofloxacin, 6 (26.1%) showed resistance or reduced susceptibility to erythromycin [1 mef(A), 3 erm(TR), 1 mef(A)+erm(TR) and 1 erm(TR)+erm(B)] and 7 (30.4%) were resistant or exhibited reduced susceptibility to tetracycline [2 tet(M), 5 tet(M)+tet(O)]. The prevalence in Argentina was of at least 23 invasive infections by SDSE. A wide genetic diversity was observed. All isolates carried speJ and ssa genes. Similarly to other studies, macrolide resistance (26.1%) was mainly associated to the MLSB phenotype. PMID- 28341024 TI - [Biochemical basis of tolerance to osmotic stress in phytopathogenic fungus: The case of Macrophomina phaseolina (Tassi) Goid.] AB - Fungus Macrophomina phaseolina (Tassi) Goid. is the causative agent of charcoal rot disease which causes significant yield losses in major crops such as maize, sorghum, soybean and common beans in Mexico. This fungus is a facultative parasite which shows broad ability to adapt itself to stressed environments where water deficits and/or high temperature stresses commonly occur. These environmental conditions are common for most cultivable lands throughout Mexico. Here we describe some basic facts related to the etiology and epidemiology of the fungus as well as to the importance of responses to stressed environments, particularly to water deficits, based on morphology and growth traits, as well as on physiology, biochemistry and pathogenicity of fungus M. phaseolina. To conclude, we show some perspectives related to future research into the genus, which emphasize the increasing need to improve the knowledge based on the application of both traditional and biotechnological tools in order to elucidate the mechanisms of resistance to environmental stress which can be extrapolated to other useful organisms to man. PMID- 28341025 TI - Standardizing Care and Parental Training to Improve Training Duration, Referral Frequency, and Length of Stay: Our Quality Improvement Project Experience. AB - OBJECTIVES: At our institution, there is a six bed Pediatric Respiratory Care Unit for technology dependent infants and children with a tracheostomy tube. A lack of consistency in patient care and parent/guardian education prompted our group to critically evaluate the services we provided by revisiting our teaching protocol and instituting a new model of care in the Unit. The aims of this quality improvement (QI) project were to standardize care and skills proficiency training to parents of infants with a tracheostomy tube in preparation for discharge to home. METHODS: After conducting a current state survey of key unit stakeholders, we initiated a multidisciplinary, QI project to answer the question: 'could a standardized approach to care and training lead to a decrease in parental/guardian training time, a decrease in length of stay, and/or an increase in developmental interventions for infants with tracheostomy tubes'? A convenience sample of infants with a tracheostomy tube admitted to the Pediatric Respiratory Care Unit were included in the study. Descriptive statistics were used to analyze the results. RESULTS: Through this QI approach, we were able to decrease the time required by parents to achieve proficiency in the care of a technology dependent infant, the length of stay for these infants, and increase referral of the infants for developmental assessment. CONCLUSIONS: These outcomes have implications for how to approach deficiencies in patient care and make changes that lead to sustained improvements. PMID- 28341026 TI - Dimethyl sulfoxide but not indomethacin is efficient for healing in hydrofluoric acid eye burns. AB - INTRODUCTION: In this study, we aimed to investigate the effect of indomethacin and dimethyl sulfoxide (DMSO), well-known antioxidant and anti-inflammatory agents, to heal eye burns induced with hydrofluoric acid in rabbits. METHODS: After general anesthesia, the right eye of 72 male New Zealand rabbits were burned by instillation of 2% hydrofluoric acid for 60s. Following this, the eyes were irrigated with 500 cc normal saline. The rabbits were then divided into four groups of 18 rabbits each. Group D was instilled dimethyl sulfoxide 40%, Group I indomethacin 0.1%, and Group DI dimethyl sulfoxide together with indomethacin for 2, 7, and 14 treatment days, respectively. Group C received no instilled drug as control. Treatment efficacies were evaluated as clinical (corneal haziness, conjunctival status, conjunctivitis, corneal erosion area, and intraocular pressure) and histopathological (inflammatory cell infiltration, vascularization, stromal thickness, reepithelization, proliferating cell nuclear antigen [PCNA], apoptosis, and inducible nitric oxide synthases [iNOS]). RESULTS: In terms of corneal haziness and erosion area at days 7 and 14, group D showed the best result statistically as compared to the other groups. This group also showed the best result statistically for reepithelization rate, stromal thickness, and inflammatory cell end at day 14 as compared to the other groups. CONCLUSIONS: Dimethyl sulfoxide (40%) was efficient to induce reepithelization on mild hydrofluoric acid eye burns, whereas 0.1% indomethacin both alone and along with DMSO poorly induced reepithelization and exacerbated inflammation. Thus, 40% DMSO could be used for the treatment of corneal disorders. PMID- 28341027 TI - Thinking under Pressure. PMID- 28341031 TI - Surveillance of women with a personal history of breast cancer by tumour subtype. AB - AIM: To determine if the rate and timing of a second breast cancer event (SBCE) in women with a personal history of breast cancer varies by disease subtype or breast imaging method. MATERIALS AND METHODS: A retrospective review was performed of women with a SBCE from January 2006 to December 2010 at a single institution. Data analysed included oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status of the primary and second breast cancers; mammographic and ultrasound (US) features from SBCE; and the time interval between both events. RESULTS: Of 207 patients diagnosed with a SBCE, the median age at first diagnosis was 50.6 years, range 24.8 to 80.2; at second diagnosis was 56.2 years, range 25.8 to 87.9. Eleven percent of SBCE were diagnosed >10 years after the primary cancer diagnosis. The median time between the first and second diagnosis for ER-positive patients was 2.7 years (range 0.7-17.4 years); and 1.9 years for ER-negative patients, (range 0.4-23.4 years; p<0.002). Patients with triple-negative breast cancer (TNBC) had a shorter time between diagnoses than others (p=0.0003). At 3, 5, and 10 years, 85%, 92%, and 97% of ER-negative and 54%, 81%, and 95% of ER-positive tumours, respectively, had recurred. ER-negative tumours and TNBC were more likely to be visible at US. CONCLUSION: There may be a role for customised imaging surveillance of women with a personal history of breast cancer (PHBC) after 10 years. Further studies are necessary to determine if US may be valuable in the surveillance of patients with ER-negative and TNBC tumours. PMID- 28341030 TI - The clinical value of hepatic extracellular volume fraction using routine multiphasic contrast-enhanced liver CT for staging liver fibrosis. AB - AIM: To investigate the value of hepatic extracellular volume fractions (fECVs) measured using routine liver computed tomography (CT) evaluating liver fibrosis (LF). MATERIALS AND METHODS: A total of 60 patients (male:female ratio, 39:21; mean age, 42.4 years) histologically diagnosed with LF underwent routine liver CT. Absolute enhancement (in Hounsfield units) of the liver parenchyma (Eliver) and aorta (Eaorta) 3 minutes after contrast medium administration was calculated using precontrast and equilibrium phase scans. The fECV was calculated using the following equation: fECV (%)=Eliver* (100 - haematocrit [%])/Eaorta. Correlation between fECV and LF stage was evaluated using the Spearman correlation coefficient. The fECVs were compared between each stage of LF. The diagnostic performance of fECV was assessed using receiver operating characteristic (ROC) curve analysis. RESULTS: The difference among the groups was statistically significant (p<0.05). The fECVs were significantly different (p<0.05) between F0 versus F4, F1 versus F4, and F2 versus F4. The fECVs showed a significant correlation with pathological LF staging (r=0.468, p=0.001). The sensitivity and specificity were 0.76 and 0.68 for severe LF (F>=3); and 0.89 and 0.63 for cirrhosis (F=4). The areas under the ROC curve (AUCs) for F>=3 and F=4 were 0.757 and 0.775, respectively. CONCLUSIONS: Calculation of fECV during routine contrast enhanced liver CT may provide a non-invasive means of assessing LF. PMID- 28341032 TI - Normal Ranges of Left Atrial Strain by Speckle-Tracking Echocardiography: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Recent advances in the assessment of myocardial function have facilitated the direct measurement of atrial function using speckle-tracking echocardiography. Currently, normal reference ranges for atrial function using speckle-tracking echocardiography are based on a few initial studies, with variations among modestly sized (n = 100-350) studies. METHODS: The authors searched the PubMed, Embase, and Scopus databases for the key terms "left atrial/atrial/atrium" and "strain/function/deformation/stiffness" and "speckle tracking/Velocity Vector Imaging/edge tracking." Studies of global left atrial function using speckle-tracking were selected if they involved >30 normal or healthy participants without any cardiac risk factors. Normal ranges for reservoir strain, conduit strain, and contractile strain were computed using a random-effects model. Meta-regression and subgroup analysis was performed to explore between-study heterogeneity. RESULTS: Forty studies (2,542 healthy subjects) satisfied the inclusion criteria. Meta-analysis revealed a normal reference range for reservoir strain of 39% (95% CI, 38%-41%, from 40 articles), for conduit strain of 23% (95% CI, 21%-25%, from 14 articles), and for contractile strain of 17% (95% CI, 16%-19%, from 18 articles). Meta-regression identified heart rate (P = .02) and body surface area (P = .003) as contributors to this heterogeneity. Subgroup analyses revealed heterogeneity due to sample size (n > 100 vs N < 100, P = .02). CONCLUSIONS: The normal reference ranges for the three components of left atrial function are demonstrated. The between-study heterogeneity is explained partly by heart rate, body surface area, and sample size. PMID- 28341033 TI - Stress Echocardiographic Evaluation for D-Transposition of the Great Arteries after Atrial Redirection: Unmasking Early Signs of Myocardial Dysfunction and Baffle Stenosis. AB - BACKGROUND: The authors used semisupine cycle ergometry stress echocardiography to assess cardiac function and unmask baffle stenosis in patients with d transposition of the great arteries after atrial redirection surgery. METHODS: This was a retrospective review of semisupine cycle ergometry stress echocardiography performed in 53 patients (64% male; mean age, 24.0 years; 90% Mustard procedure) and 56 healthy control subjects. Incremental exercise to volitional fatigue was performed. Hemodynamic data, echocardiographic cardiac dimensions, area change, tissue Doppler velocities, strain, ventricular synchronization, and superior vena cava flow velocities before and immediately after exercise are reported. RESULTS: Patients had lower exercise capacity (870 vs 1,854 J/kg, P < .001) and peak heart rates (132 vs 167 beats/min, P < .001). Stroke volume index did not increase with exercise (45 vs 47 mL/m2, P = .400). Cardiac index increased in both groups with exercise (3.0 vs 6.1 and 2.9 vs 7.0 L/min/m2, P < .001) and was higher in control subjects (P = .006). Right ventricular diastolic and systolic areas decreased significantly with exercise in both the short-axis and four-chamber views. Right and left ventricular contraction time shortened with exercise (405 vs 247 and 338 vs 217 msec, P < .001) and remained synchronous (ratio of right ventricular to left ventricular contraction time = 0.080). Doppler velocities in patients with baffle obstruction were higher in the lower superior vena cava with exercise compared with nonobstructed patients (1.87 vs 1.46 m/sec, P = .020) and normalized after catheter intervention (1.49 vs 1.46 m/sec, P = .800). CONCLUSIONS: Patients with d-transposition of the great arteries have lower exercise capacity and peak heart rates. The systemic right ventricle presents a lesser but qualitatively normal systolic response and decreased diastolic filling. Semisupine cycle ergometry stress echocardiography unmasked SVC obstruction. PMID- 28341034 TI - Outcome Assessment in Total Knee Arthroplasty: A Systematic Review and Critical Appraisal. AB - BACKGROUND: The Outcome Measures in Rheumatology (OMERACT) initiative developed a core outcome set (COS) of domains to assess effectiveness of interventions for knee osteoarthritis. These domains (pain, physical function, patient global assessment, imaging at 1 year) should be assessed in every trial to make research evidence meaningful and comparable. We systematically evaluated and critically appraised the use of measurement instruments and outcome domains in prospective studies evaluating patients with knee osteoarthritis undergoing total knee arthroplasty (TKA) and assessed their accordance with the OMERACT COS. METHODS: Literature search was performed until August 26, 2014, in Medline and Embase. Clinical trials and prospective observational studies with >=50 participants and a follow-up of >=1 year were included. We collected general study characteristics, comprehensive information on measurement instruments, and corresponding domains used. RESULTS: This systematic review identified low accordance of used outcome domains with the OMERACT COS of domains published in 1997. Only 4 of 100 included studies included all recommended core domains. Pain (85% of studies) and physical function (86%) were assessed frequently, whereas patient global assessment (21%) and joint imaging (>=1 year; 27%) were rarely assessed. There was substantial heterogeneity in the use of measurement instruments (n = 111) investigating TKA. CONCLUSION: More efforts are required to implement the existing COS. In addition, a more consistent use of adequate measurement instruments is important to make research evidence on TKA more relevant, better comparable, and thus more useful for guideline developers and clinical decision makers. PMID- 28341036 TI - Advanced Methodologies in High-Throughput Sequencing of Immune Repertoires. AB - In recent years, major efforts have been made to develop sophisticated experimental and bioinformatic workflows for sequencing adaptive immune repertoires. The immunological insight gained has been applied to fields as varied as lymphocyte biology, immunodiagnostics, vaccines, cancer immunotherapy, and antibody engineering. In this review, we provide a detailed overview of these advanced methodologies, focusing specifically on strategies to reduce sequencing errors and bias and to achieve high-throughput pairing of variable regions (e.g., heavy-light or alpha-beta chains). In addition, we highlight recent technologies for single-cell transcriptome sequencing that can be integrated with immune repertoires. Finally, we provide a perspective on advanced immune repertoire sequencing and its ability to impact basic immunology, biopharmaceutical drug discovery and development, and cancer immunotherapy. PMID- 28341037 TI - Influenza virus infection exacerbates experimental autoimmune encephalomyelitis disease by promoting type I T cells infiltration into central nervous system. AB - Multiple sclerosis starts with increased migration of auto-reactive lymphocytes across the blood-brain barrier, resulting in persistent neurodegeneration. Clinical and epidemiological studies indicated upper respiratory viral infections are associated with clinical exacerbation of multiple sclerosis. However, so far there is no any direct evidence to support it. Using the experimental autoimmune encephalomyelitis mice as the model for multiple sclerosis, we demonstrated that mice experienced with influenza virus infection were unable to recover from experimental autoimmune encephalomyelitis with a long-term exacerbation. The exacerbated disease was due to more type I T cells, such as CD45highCD4+CD44high, CD45highCD4+CCR5+, CD45high IFNgamma+CD4+, MOG35-55-specific IFNgamma+CD4+ and influenza virus-specific IFNgamma+CD4+ T cells, infiltrating central nervous system in mice with prior influenza virus infection. Influenza virus infection created a notable inflammatory environment in lung and mediastinal lymph node after influenza virus inoculation, suggesting the lung may constitute an inflammatory niche in which auto-aggressive T cells gain the capacity to enter CNS. Indeed, the early stage of EAE disease was accompanied by increased CCR5+CD4+, CXCR3+CD4+ T cell and MOG35-55 specific CD4+ T cells localized in the lung in influenza virus-infected mice. CCL5/CCR5 might mediate the infiltration of type I T cells into CNS during the disease development after influenza infection. Administration of CCR5 antagonist could significantly attenuate the exacerbated disease. Our study provided the evidence that the prior influenza virus infection may promote the type I T cells infiltration into the CNS, and subsequently cause a long-term exacerbation of experimental autoimmune encephalomyelitis. PMID- 28341038 TI - Acute Gout Following Dermofasciectomy in a Patient With Dupuytren Disease. AB - A 62-year-old man underwent uncomplicated dermofasciectomy of the right little finger. In the week after surgery, he presented with erythema, tenderness, reduced range of movement, and a chalklike discharge from the suture line. Investigations revealed a raised serum urate level accompanied with a borderline rise in inflammatory markers. A diagnosis of acute gout was made. The patient was managed with nonsteroidal anti-inflammatory drugs. Clinicians should consider the diagnosis of gout when patients present after surgery with redness, pain, and swelling and also consider measuring urate levels before surgery and initiating colchicine prophylaxis when there is a known diagnosis of gout before surgery. Accurate diagnosis may prevent unnecessary antibiotic use. PMID- 28341039 TI - Cognitive impairment and BDNF serum levels. AB - BACKGROUND/AIMS: To investigate the alterations of brain-derived neurotrophic factor (BNDF) serum levels in subjects with different intensity of cognitive impairment and different neurodegenerative processes. MATERIAL AND METHODS: Serum BDNF levels were analyzed by ELISA kit in 378 subjects: 134 Alzheimer's disease (AD) patients, 115 amnestic mild cognitive impairment (MCI) patients, and 129 controls divided into two groups: neurodegenerative control group (ND), consisting of 49 Parkinson's disease patients without any cognitive complaints, and cognitively normal control group (CN), consisting of 80 subjects without any neurological disorders. RESULTS: AD patients had significantly lower (p<0.001) BDNF serum levels compared to MCI, CN and ND controls. Age and education had significant influence on BDNF serum levels regardless the diagnosis or group assignment. We have found no influence of depression on BDNF serum levels either in our group as a whole, or in each group assessed separately. We found significant correlation between BDNF serum levels and cognitive impairments. After multiple comparisons between the groups, we found that, after adjustment for confounding factors (age, gender, education, depression, cognitive impairment), BDNF serum levels were the lowest in AD group (p=0.05). CONCLUSIONS: Advanced age and low educational level are associated with decreased BDNF serum levels. Decreased BDNF serum levels correspond to the severity of cognitive impairment. There is no correlation between BDNF serum levels and depressive symptoms. PMID- 28341040 TI - Hyperdense middle cerebral artery sign as the only radiological manifestation of hyperacute ischemic stroke in computed tomography. AB - OBJECTIVES: The main aim of the study was to find the effect of hyperdense middle cerebral artery sign (HMCAS), as the only admission computed tomography (CT) manifestation of ischemic stroke involving middle cerebral artery (MCA) region, on the extent of stroke measured by Alberta Stroke Program Early CT score (ASPECTS) in the follow-up CT. The secondary aim was to determine the correlation between length of hyperdense MCA segment on admission CT and ASPECTS in follow-up CT. METHODS: The group analyzed consisted of 118 patients with ischemic MCA region stroke, with no early signs of brain tissue ischemia on admission CT, but infarcts confirmed in follow-up CT, with extent evaluated using ASPECTS. For the subgroups: 66 patients with HMCAS present and 52 with HMCAS absent, median ASPECTS values were compared. In the subgroup with HMCAS present, length of hyperdense segment was measured and correlation with ASPECTS was determined. RESULTS: The median ASPECTS 6 (min. 0, max. 9) in the subgroup with HMCAS present was significantly lower, compared to the score 8.5 (min. 0, max. 9) in the subgroup with HMCAS absent. Moderate correlation between the length of hyperdense segment and ASPECTS was found (R=-0.45). CONCLUSION: In patients with ischemic stroke involving MCA region and no early signs of brain tissue ischemia on the admission CT, HMCAS is associated with significantly lower ASPECTS in the follow up CT. There is moderate correlation between the length of hyperdense MCA segment and ASPECTS. PMID- 28341041 TI - Invited review: A systematic literature review and meta-analysis of mortality and culling in dairy cattle. AB - Dairy industries and individual farmers are concerned about mortality and culling of dairy animals. This is because the timing and fates of animals that exit dairy farms have important animal welfare and economic consequences that reflect the conditions under which they are farmed and the efficiency of their production systems. Reports from a few countries have indicated increased incidence of mortality, and occasionally culling, of dairy animals in recent decades, and these changes have been associated with intensification of production systems. Dairy industries and farmers need benchmarks for culling and mortality against which they can compare themselves, as well as improved understanding of the extent of any change and of any associated factors. We reasoned that a systematic literature review and meta-analysis of scientific articles published between 1989 and 2014 would allow us to determine whether these reports were universal, to quantify any change over time, and to investigate whether production systems or study factors were associated with culling and mortality. From 3,275 articles retrieved from databases and manual searching of cited articles, 118 articles were appraised independently by 2 assessors, and 51 articles representing 54 studies were determined to be eligible for review and meta-analysis. We estimated that both the annual incidence risk (IR) and incidence density of mortality of cows had increased significantly from 0.02 per cow and 2.32 per 100 cow-years, to 0.04 per cow and 3.75 per 100 cow-years, an increase per decade of 0.02 per cow and 1.42 per 100 cow-years, respectively. We also estimated that the annual IR of culling attributed to low production had declined significantly from 0.07 to 0.05 and that the IR of perinatal, but not neonatal, mortality had increased significantly from 0.04 to 0.06 per decade. We found no evidence of change in overall annual IR of culling of cows over time or any association between study design factors and the IR or incidence density of culling or mortality. These findings provide benchmarks for describing culling and mortality, and should encourage farmers and researchers in countries with modern dairy industries to discover and implement management strategies to reduce the animal welfare and economic costs associated with these changes. PMID- 28341042 TI - Effect of forage to concentrate ratio with sorghum silage as a source of forage on rumen fermentation, N balance, and purine derivative excretion in limit-fed dairy heifers. AB - Sorghum silage has been shown to be a good alternative to corn silage for dairy cows; however, studies regarding heifers are insufficiently explored. Therefore, the objective of this study was to evaluate effects of changing forage to concentrate ratio (FOR:CON) in diets based on sorghum silage on N digestibility, rumen fermentation, N balance, C excretion, and microbial N yield in limit-fed dairy heifers. A split-plot 4*4 Latin square design with 19-d periods (15 d of adaptation and 4 d of sampling) was conducted with 8 rumen cannulated dairy heifers (age 13.7+/-0.6mo and weight 364.8+/-17.6kg). Heifers were fed sorghum silage-based diets with 4 FOR:CON (85:15, 75:25, 65:35, and 55:45) balanced for similar metabolizable energy intake per unit of body weight and crude protein concentration. Diets were fed to allow 900 to 1,000g/d body weight gain and were fed once daily. Total collection of feces and urine was completed on d 15 to 19 to determine N, C, urea N, allantoin, uric acid, and creatinine excretion. Rumen contents were sampled on d 19 at 0, 1.5, 3, 4.5, 6, 9, 13, 17, 21, and 23h after feeding to measure pH, volatile fatty acid (VFA), ammonia-N, and free AA concentrations. The pH decreased linearly while ammonia-N and free AA levels increased linearly with decreasing FOR:CON of diets. Although mean total VFA did not differ among treatment diets, molar proportions of VFA did. Acetate proportion decreased while propionate and butyrate increased with decreasing FOR:CON. Intake of N and urea N excretion decreased with decreasing forage proportion in diets while total N excretion, apparent N digestibility, and N retention were not different. Intake of C and excretion in feces (g/d) decreased linearly with decreasing FOR:CON in diets. Creatinine, allantoin, and uric acid excretion were not affected by FOR:CON; however, microbial N yield tended to increase linearly with greater concentrate in diets. Heifers limit fed diets based on sorghum silage demonstrated the effect of available ammonia-N and readily fermentable carbohydrates with subsequent effects on nutrient utilization when different FOR:CON were applied. Based on the presented results, FOR:CON 65:35 had the most suitable balance of available ammonia-N and readily fermentable carbohydrates for the most optimal results. PMID- 28341043 TI - Sorghum forage in precision-fed dairy heifer diets. AB - Sorghum forage is an alternative crop that is more adapted to drier conditions and more resistant than corn to drought conditions. Thus, sorghum forage maximizes water utilization. The objective of this study was to evaluate sorghum silage (SS), including digestibility and fermentation parameters, in precision fed dairy heifers. Eight Holstein heifers (13.7+/-0.6mo of age and 364.8+/ 17.64kg of body weight) fitted with rumen cannulas were used in a replicated 4*4 Latin Square design; treatments were 4 levels of forage to concentrate ratios (85:15, 75:25, 65:35, and 55:45). Rumen contents were sampled at various times to determine pH and volatile fatty acid concentrations. Dry matter (DM) and neutral detergent fiber (NDF) in situ degradation kinetics were compared between SS and corn silage (CS) diets. Fecal total collection was used to estimate apparent total-tract digestibility. Fecal grab samples at 0, 6, 12, and 18h after feeding were used to estimate total-tract starch digestibility. Amount of concentrate in the diet affected the time that heifers spent eating as well as rumen pH. When the concentrate proportion of the diet increased, eating time and rumen pH decreased linearly. Total volatile fatty acid concentrations were not affected by treatment, but butyrate increased as the proportion of concentrate increased in the diet. Digestibility of DM and starch were higher in diets with lower forage to concentrate ratio, but NDF, acid detergent fiber, and hemicellulose digestibility were not affected. Corn silage had greater DM and NDF digestibility than SS. Also, fractional rate of digestion was faster for CS than SS (2.78 vs. 2.42% per hour, respectively). We conclude that fecal grab samples are suitable for predicting starch digestibility in heifers given the starch levels studied. In addition, SS was an adequate alternative forage in precision-fed dairy heifers with outcomes very similar to CS-based rations. PMID- 28341044 TI - Decreasing the pH of milk replacer containing soy flour affects nutrient digestibility, digesta pH, and gastrointestinal development of preweaned calves. AB - We evaluated the effect of feeding soy flour-containing milk replacer (MR) with a lower than normal pH on growth, nutrient digestibility, digesta pH, and gastrointestinal development of preweaned calves. The study consisted of 48 neonatal calves, allocated to 8 treatments in a 2-factor 4*2 randomized design. The calves received 2 types of MR containing soy flour. The proportion of soy crude protein (CP) to total CP (SP/CP) in MR was 50% (MR50 treatment) or 80% (MR80 treatment), respectively. The pH of the reconstituted MR was decreased by 1 N HCl from to 6.2 to 5.5, 5.0, or 4.5. We measured body weight and dry matter intake and calculated feed conversion rate in the MR50 treatment. We monitored urinary and fecal pH consecutively for 5h when calves were 25d old. We also conducted a digestion trial to determine nutrient digestibility from 49 to 55d of age. At 63d old, calves were slaughtered, and gastrointestinal pH, mass index, and morphology were evaluated. Reducing the pH of MR containing soy flour improved average daily gain and feed conversion rate, increased Ca digestibility, and reduced urinary, fecal, and digesta pH in the rumen, reticulum, and omasum. Although treatments had no effect on gastrointestinal mass index, the pH 5.0 treatment led to favorable ruminal epithelium growth, and the pH 5.5 treatment led to better intestinal epithelium growth. Increasing SP/CP from 50 to 80% decreased P digestibility and fecal and digesta pH in rumen, reticulum, and omasum. Moreover, the MR80 treatment reduced the mass index of the abomasums and jejunum. In conclusion, decreasing the pH of MR containing soy flour to a pH of 5.0 to 5.5 improved the digestive tract of preweaned calves. A pH reduction to 4.5 had adverse effects on intestinal epithelium growth. PMID- 28341045 TI - Exogenous beta-mannanase improves feed conversion efficiency and reduces somatic cell count in dairy cattle. AB - Exogenous fibrolytic enzymes have been shown to be a promising way to improve feed conversion efficiency (FCE). beta-Mannanase is an important enzyme digesting the polysaccharide beta-mannan in hemicellulose. Supplementation of diets with beta-mannanase to improve FCE has been more extensively studied in nonruminants than in ruminants. The objective of this study was to investigate the effects of beta-mannanase supplementation on nutrient digestibility, FCE, and nitrogen utilization in lactating Holstein dairy cows. Twelve post-peak-lactation multiparous Holstein cows producing 45.5+/-6.6kg/d of milk at 116+/-19.0d in milk were randomly allotted to 1 of 3 treatments in a 3*3 Latin square design with 3 periods of 18d (15d for adaptation plus 3d for sample collection). All cows were fed the same basal diet and the 3 treatments differed only by the beta-mannanase dose: 0% dry matter (DM; control), 0.1% of DM (low supplement, LS), and 0.2% of DM (high supplement, HS) supplemented to the basal diet. Supplementation of beta mannanase enzyme at the LS dose reduced dry matter intake (DMI) but did not affect milk yield or milk composition. Cows receiving LS produced 90g more milk per kg of DMI compared with control cows. Somatic cell count (SCC) in milk was lower for cows fed the LS diet compared with cows fed control diets. Cows fed LS diet had lower DM, organic matter and crude protein digestibility compared with cows fed control diets. Starch, neutral detergent fiber, and acid detergent fiber digestibility were not affected by LS. Milk yield, DMI, SCC, and nutrient digestibility did not change for HS. Despite the reduced crude protein digestibility, reduced N intake led to similar fecal N excretions in LS cows and control cows (234 vs. 235g/cow per day). Urinary N excretions remained similar between enzyme-fed and control cows (~190g/cow per day), although the percentage of N intake partitioned to urinary N tended to be greater in LS than in control cows (31 vs. 27%). Cows fed LS significantly improved the percentage of apparently absorbed N partitioned to milk protein N (42 vs. 38%). When supplemented at 0.1% of dietary DM, beta-mannanase can improve FCE and lower the SCC of dairy cows without affecting milk yield, milk composition, or total manure N excretions of dairy cows. PMID- 28341046 TI - Relationship between residual feed intake and digestibility for lactating Holstein cows fed high and low starch diets. AB - We determined if differences in digestibility among cows explained variation in residual feed intake (RFI) in 4 crossover design experiments. Lactating Holstein cows (n=109; 120+/-30d in milk; mean +/- SD) were fed diets high (HS) or low (LS) in starch. The HS diets were 30% (+/-1.8%) starch and 27% (+/-1.2%) neutral detergent fiber (NDF); LS diets were 14% (+/-2.2%) starch and 40% (+/-5.3%) NDF. Each experiment consisted of two 28-d treatment periods, with apparent total tract digestibility measured using indigestible NDF as an internal marker during the last 5d of each period. Individual cow dry matter (DM) intake and milk yield were recorded daily, body weight was measured 3 to 5 times per week, and milk components were analyzed 2 d/wk. Individual DM intake was regressed on milk energy output, metabolic body weight, body energy gain, and fixed effects of parity, experiment, cohort (a group of cows that received treatments in the same sequence) nested within experiment, and diet nested within cohort and experiment, with the residual being RFI. High RFI cows ate more than expected and were deemed less efficient. Residual feed intake correlated negatively with digestibility of starch for both HS (r=-0.31) and LS (r=-0.23) diets, and with digestibilities of DM (r=-0.30) and NDF (r=-0.23) for LS diets but was not correlated with DM or NDF digestibility for HS diets. For each cohort within an experiment, cows were classified as high RFI (HRFI; >0.5 SD), medium RFI (MRFI; +/-0.5 SD), and low RFI (LRFI; <-0.5 SD). Digestibility of DM was similar (~66%) among HRFI and LRFI for HS diets but greater for LRFI when fed LS diets (64 vs. 62%). For LS diets, digestibility of DM could account for up to 31% of the differences among HRFI and LRFI for apparent diet energy density, as determined from individual cow performance, indicating that digestibility explains some of the between-animal differences for the ability to convert gross energy into net energy. Some of the differences in digestibility between HRFI and LRFI were expected because cows with high RFI eat at a greater multiple of maintenance, and greater intake is associated with increased passage rate and digestibility depression. Based on these data, we conclude that a cow's digestive ability explains none of the variation in RFI for cows eating high starch diets but 9 to 31% of the variation in RFI when cows are fed low starch diets. Perhaps differences in other metabolic processes, such as tissue turnover, heat production, or others related to maintenance, can account for more variation in RFI than digestibility. PMID- 28341047 TI - Short communication: Effects of prill size of a palmitic acid-enriched fat supplement on the yield of milk and milk components, and nutrient digestibility of dairy cows. AB - The objective of our experiment was to evaluate the effects of prill size of a palmitic acid-enriched fatty acid supplement (PA; 85% C16:0) on feed intake, nutrient digestibility, and production responses of dairy cows. Twenty-four primiparous and multiparous Holstein cows were assigned based on parity and production level to replicated 4*4 Latin squares balanced for carryover effects with 21-d periods. Treatments were a control diet (no added PA), or 2.0% PA added as a small prill size (PA-SM; 284+/-12.4um), a medium prill size (PA-MD; 325+/ 14.7um), or a large prill size (PA-LG; 600+/-17.4um) supplement. Overall, PA treatments increased milk fat content (4.25 vs. 3.99%), milk fat yield (1.48 vs. 1.39kg/d), 3.5% fat-corrected milk (39.2 vs. 37.7kg/d), and improved feed efficiency (fat-corrected milk:dry matter intake; 1.51 vs. 1.42) compared with control. Compared with control, PA treatments did not affect dry matter intake, body weight, body condition score, or yields of milk, protein, and lactose. The PA treatments increased neutral detergent fiber digestibility (44.8 vs. 42.4%) and reduced the digestibility of 16-carbon fatty acids (72.3 vs. 79.1%) and total fatty acids (76.6 vs. 80.3%). Compared with control, PA treatments reduced the contents of de novo synthesized milk fatty acids (23.0 vs. 25.8g/100g of fatty acids) and preformed milk fatty acids (36.3 vs. 39.1g/100g of fatty acids), but did not affect their yields. In contrast, PA treatments increased the content (40.8 vs. 35.1g/100g of fatty acids) and yield (570 vs. 436g/d) of 16-carbon milk fatty acids compared with control. The PA prill size had no effect on dry matter intake, yield of milk and milk components, or feed efficiency. However, PA-LG tended to increase milk fat content compared with PA-SM (4.28 vs. 4.22%), and it increased 16-carbon fatty acid digestibility compared with PA-MD (74.2 vs. 71.0%) and PA-SM (74.2 vs. 71.7%). Additionally, PA-LG increased total fatty acid digestibility compared with PA-MD (78.1 vs. 75.6%) and PA-SM (78.1 vs. 76.0%). Results demonstrate that PA increased milk fat content and yield, and feed efficiency. Reducing prill size decreased fatty acid digestibility, but it had no effect on animal performance under the dietary conditions and prill sizes evaluated. PMID- 28341048 TI - Genetic analysis of coagulation properties, curd firming modeling, milk yield, composition, and acidity in Sarda dairy sheep. AB - Sheep milk is an important source of food, especially in Mediterranean countries, and is used in large part for cheese production. Milk technological traits are important for the sheep dairy industry, but research is lacking into the genetic variation of such traits. Therefore the aim of this study was to estimate the heritability of traditional milk coagulation properties and curd firmness modeled on time t (CFt) parameters, and their genetic relationships with test-day milk yield, composition (fat, protein, and casein content), and acidity in Sarda dairy sheep. Milk samples from 1,121 Sarda ewes from 23 flocks were analyzed for 5 traditional coagulation properties by lactodynamographic tests conducted for up to 60min: rennet coagulation time (min), curd-firming time (k20, min), and 3measures of curd firmness (a30, a45, and a60, mm). The 240 curd firmness observations (1 every 15 s) from each milk sample were recorded, and 4 parameters for each individual sample equation were estimated: rennet coagulation time estimated from the equation (RCTeq), the asymptotic potential curd firmness (CFP), the curd firming instant rate constant (kCF), and the syneresis instant rate constant (kSR). Two other derived traits were also calculated (CFmax, the maximum curd firmness value; and tmax, the attainment time). Multivariate analyses using Bayesian methodology were performed to estimate the genetic relationships of milk coagulation properties and CFt with the other traits; statistical inference was based on the marginal posterior distributions of the parameters of concern. The marginal posterior distribution of heritability estimates of milk yield (0.16+/-0.07) and composition (0.21+/-0.11 to 0.28+/ 0.10) of Sarda ewes was similar to those often obtained for bovine species. The heritability of rennet coagulation time as a single point trait was also similar to that frequently obtained for cow milk (0.19+/-0.09), whereas the same trait calculated as an individual equation parameter exhibited larger genetic variation and a higher heritability estimate (0.32+/-0.11). The other curd firming and syneresis traits, whether as traditional single point observations or as individual equation parameters and derived traits, were characterized by heritability estimates lower than for coagulation time and for the corresponding bovine milk traits (0.06 to 0.14). Phenotypic and additive genetic correlations among the 11 technological traits contribute to describing the interdependencies and meanings of different traits. The additive genetic relationships of these technological traits with the single test-day milk yield and composition were variable and showed milk yield to have unfavorable effects on all measures of curd firmness (a30, a45, a60, CFP, and CFmax) and tmax, but favorable effects on both instant rate constants (kCF and kSR). Milk fat content had a positive effect on curd firmness traits, especially on those obtained from CFt equations, whereas the negative effects on both coagulation time traits were attributed to the milk protein and casein contents. Finally, in view of the estimated heritabilities and additive genetic correlations, enhancement of technological traits of sheep milk through selective breeding could be feasible in this population. PMID- 28341049 TI - Accuracy of breeding values in small genotyped populations using different sources of external information-A simulation study. AB - Genetically linked small and large dairy cattle populations were simulated to test the effect of different sources of information from foreign populations on the accuracy of predicting breeding values for young animals in a small population. A large dairy cattle population (PL) with >20 generations was simulated, and a small subpopulation (PS) with 3 generations was formed as a related population, including phenotypes and genomic information. Predicted breeding values for young animals in the small population were calculated using BLUP and single-step genomic BLUP (ssGBLUP) in 4 different scenarios: (S1) 3,166 phenotypes, 22,855 pedigree animals, and 1,000 to 6,000 genotypes for PS; (S2) S1 plus genomic estimated breeding value (GEBV) for 4,475 sires from PL as external information; (S3) S1 plus 221,580 phenotypes, 402,829 pedigree animals, and 53,558 genotypes for PL; and (S4) single nucleotide polymorphism (SNP) effects calculated based on PL data. The ability to predict true breeding value was assessed in the youngest third of the genotyped animals in the small population. When data only from the small population were used and 1,000 animals were genotyped, the accuracy of GEBV was only 1 point greater than the estimated breeding value accuracy (0.32 vs. 0.31). Adding external GEBV for sires from PL did not considerably increase accuracy (0.33 vs. 0.32 in S1). Combining phenotypes, pedigree, and genotypes for PS and PL was beneficial for predicting accuracy of GEBV in the small population, and the prediction accuracy of GEBV in this scenario was 0.38 compared with 0.31 from estimated breeding values. When SNP effects from PL were used to predict GEBV for young genotyped animals from PS, accuracy was greatest (0.56). With 6,000 genotyped animal in PS, accuracy was greatest (0.61) with the combined populations. In a small population with few genotypes, the highest accuracy of evaluation may be obtained by using SNP effects derived from a related large population. PMID- 28341050 TI - Development of genetic and genomic evaluation for wellness traits in US Holstein cows. AB - In March 2016, Zoetis Genetics offered the first commercially available evaluation for wellness traits of Holstein dairy cattle. Phenotypic data on health events, pedigree, and genotypes were collected directly from producers upon obtaining their permission. Among all recorded health events, 6 traits were chosen to be included in the evaluation: mastitis, metritis, retained placenta, displaced abomasum, ketosis, and lameness. Each trait was defined as a binary event, having a value of 1 if a cow has been recorded with a disorder at any point during the lactation and zero otherwise. The number of phenotypic records ranged from 1.8 million for ketosis to 4.1 million for mastitis. Over 14 million pedigree records and 114,216 genotypes were included in the evaluation. All traits were analyzed using univariate threshold animal model with repeated observations, including fixed effect of parity and random effects of herd by year by season of calving, animal, and permanent environment. A total of 45,425 single nucleotide polymorphisms were used in the genomic analyses. Animals genotyped with low-density chips were imputed to the required number of single nucleotide polymorphisms. All analyses were based on the single-step genomic BLUP, a method that combines phenotype, pedigree, and genotype information. Predicted transmitting abilities were expressed in percentage points as a difference from the average estimated probability of a disorder in the base population. Reliabilities of breeding values were obtained by approximation based on partitioning of a function of reliability into contributions from records, pedigree, and genotypes. Reliabilities of genomic predicted transmitting abilities for young genotyped and pedigreed females without recorded health events had average values between 50.2% (displaced abomasum) and 51.9% (mastitis). Genomic predictions for wellness traits can provide new information about an animal's genetic potential for health and new selection tools for dairy wellness improvement. PMID- 28341051 TI - Whey protein-derived exosomes increase protein synthesis and hypertrophy in C2 C12 myotubes. AB - We sought to examine potential amino acid independent mechanisms whereby hydrolyzed whey protein (WP) affects muscle protein synthesis (MPS) and anabolism in vitro. Specifically, we tested (1) whether 3-h and 6-h treatments of WP, essential amino acids, or l-leucine (Leu) affected MPS, and whether 6-h treatments with low-, medium-, or high doses of WP versus Leu affected MPS; (2) whether knockdown of the primary Leu transporter affected WP- and Leu-mediated changes in MPS, mammalian target of rapamycin (mTOR) signaling responses, or both, following 6-h treatments; (3) whether exosomes isolated from WP (WP-EXO) affected MPS, mTOR signaling responses, or both, compared with untreated (control) myotubes, following 6-h, 12-h, and 24-h treatments, and whether they affected myotube diameter following 24-h and 48-h treatments. For all treatments, 7-d post-differentiated C2C12 myotubes were examined. In experiment 1, 6-h WP treatments increased MPS compared with control (+46%), Leu (+24%), and essential amino acids (+25%). Moreover, the 6-h low-, medium-, and high WP treatments increased MPS by approximately 40 to 50% more than corresponding Leu treatments. In experiment 2 (LAT short hairpin RNA-transfected myotubes), 6-h WP treatments increased MPS compared with control (+18%) and Leu (+19%). In experiment 3, WP EXO treatments increased MPS over controls at 12h (+18%) and 24h (+45%), and myotube diameters increased with 24-h (+24%) and 48-h (+40%) WP-EXO treatments compared with controls. The WP-EXO treatments did not appear to operate through mTOR signaling; instead, they increased mRNA and protein levels o eukaryotic initiation factor 4A. Bovine-specific microRNA following 24-h WP-EXO treatments were enriched in myotubes (chiefly miR-149-3p, miR-2881), but were not related to hypertrophic gene targets. To summarize, hydrolyzed WP-EXO increased skeletal MPS and anabolism in vitro, and this may be related to an unknown mechanism that increases translation initiation factors rather than enhancing mTOR signaling or the involvement of bovine-specific microRNA. PMID- 28341052 TI - Factors associated with intramammary infection in dairy cows caused by coagulase negative staphylococci, Staphylococcus aureus, Streptococcus uberis, Streptococcus dysgalactiae, Corynebacterium bovis, or Escherichia coli. AB - The aim of this study was to determine risk factors for bovine intramammary infection (IMI) associated with the most common bacterial species in Finland. Large databases of the Finnish milk-recording system and results of microbiological analyses of mastitic milk samples from Valio Ltd. (Helsinki, Finland) were analyzed. The study group comprised 29,969 cows with IMI from 4,173 dairy herds. A cow with a quarter milk sample in which DNA of target species was detected in the PathoProof Mastitis PCR Assay (Thermo Fisher Scientific, Waltham, MA) was determined to have IMI. Only cows with IMI caused by the 6 most common pathogens or groups of pathogens, coagulase-negative staphylococci (CNS), Staphylococcus aureus, Streptococcus uberis, Streptococcus dysgalactiae, Corynebacterium bovis, and Escherichia coli, were included. The control group comprised 160,176 IMI-free cows from the same herds as the study group. A multilevel logistic regression model was used to study herd- and cow-specific risk factors for incidence of IMI. Pathogen-specific results confirmed those of earlier studies, specifically that increasing parity increases prevalence of IMI regardless of causative pathogen. Holsteins were more susceptible to IMI than Nordic Reds except when the causative pathogen was CNS. Occurrence of IMI caused by C. bovis was not related to milk yield, in contrast to IMI caused by all other pathogens investigated. Organic milk production was associated with IMI only when the causative pathogen of IMI was Staph. aureus; Staph. aureus IMI was more likely to occur in conventional than in organic production. Cows in older freestall barns with parlor milking had an increased probability of contracting an IMI compared with cows in tiestall barns or in new freestall barns with automatic milking. This was the case for all IMI, except those caused by CNS, the prevalence of which was not associated with the milking system, and IMI caused by Staph. aureus, which was most common in cows housed in tiestall barns. A better breeding index for milk somatic cell count was associated with decreased occurrence of IMI, indicating that breeding for improved udder health has been successful in reducing the incidence of IMI caused by the most common pathogens in Finland. In the Finnish dairy sector, the importance of other measures to control IMI will increase as the Holstein breed progressively takes the place of the Nordic Red breed. Attention should be paid to hygiene and cleanliness, especially in old freestall barns. Based on our results, the increasing prevalence of automatic milking is not a reason for special concern. PMID- 28341053 TI - Water use on nonirrigated pasture-based dairy farms: Combining detailed monitoring and modeling to set benchmarks. AB - Water use in intensively managed, confinement dairy systems has been widely studied, but few reports exist regarding water use on pasture-based dairy farms. The objective of this study was to quantify the seasonal pattern of water use to develop a prediction model of water use for pasture-based dairy farms. Stock drinking, milking parlor, and total water use was measured on 35 pasture-based, seasonal calving dairy farms in New Zealand over 2 yr. Average stock drinking water was 60 L/cow per day, with peak use in summer. We estimated that, on average, 26% of stock drinking water was lost through leakage from water distribution systems. Average corrected stock drinking water (equivalent to voluntary water intake) was 36 L/cow per day, and peak water consumption was 72 L/cow per day in summer. Milking parlor water use increased sharply at the start of lactation (July) and plateaued (August) until summer (February), after which it decreased with decreasing milk production. Average milking parlor water use was 58 L/cow per day (between September and February). Water requirements were affected by parlor type, with rotary milking parlor water use greater than herringbone parlor water use. Regression models were developed to predict stock drinking and milking parlor water use. The models included a range of climate, farm, and milk production variables. The main drivers of stock drinking water use were maximum daily temperature, potential evapotranspiration, radiation, and yield of milk and milk components. The main drivers for milking parlor water use were average per cow milk production and milking frequency. These models of water use are similar to those used in confinement dairy systems, where milk yield is commonly used as a variable. The models presented fit the measured data more accurately than other published models and are easier to use on pasture-based dairy farms, as they do not include feed and variables that are difficult to measure on pasture-based farms. PMID- 28341054 TI - Corrigendum to "The lipoxygenase pathway in zebrafish. Expression and characterization of zebrafish ALOX5 and comparison with its human ortholog" [Biochim. Biophys. Acta 1861/1, (2016) 1-11]. PMID- 28341055 TI - Obstetric care for women with thalassemia. AB - Thalassemia is the commonest monogenic disease and manifests as severe anemia. It is increasingly encountered outside the Mediterranean region, Africa, Middle East, and Southeast Asia because of immigration. Pregnancy, previously uncommon in patients with homozygous beta-thalassemia, is encountered increasingly because of improved management and assisted reproduction technology; however, preconceptional problems that include anemia, iron overload, cardiac dysfunction, thromboembolism, alloimmunization, infections, and endocrine and bone disorders, could influence maternal and obstetric outcome. Although, successful pregnancy in thalassemia trait carriers and women with hemoglobin H disease is more common, there is still increased risk of obstetric and perinatal complications. Prenatal diagnosis to exclude fetal homozygous thalassemia and other congenital anomalies, together with close monitoring of the pregnancy, would optimize outcome. Further research is warranted to elucidate the fetal safety of iron chelation therapy and potential effect of pregnancy on long-term maternal health outcome, especially following occurrence of maternal complications. PMID- 28341056 TI - Temporal changes in plasma markers of oxidative stress following laparoscopic sleeve gastrectomy in subjects with impaired glucose regulation. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is an effective treatment for obesity and associated metabolic complications. Obesity and type 2 diabetes are associated with increased oxidative stress. Previous studies have examined changes in plasma oxidative stress after laparoscopic Roux-en-Y gastric bypass, but there is limited evidence of the effects of LSG. OBJECTIVES: To examine the effects of LSG on plasma thiobarbituric acid reactive substances (TBARS) and total antioxidant status (TAOS) at 1 and 6 months after LSG in patients with obesity and impaired glucose regulation. SETTING: University hospital, United Kingdom. METHODS: Twenty-two participants with impaired glucose homeostasis undergoing LSG (body mass index 50.1 kg/m2, glycated hemoglobin 53 mmol/mol) were studied. Measurements of fasting and 120-minute TBARS and TAOS were performed during an oral glucose tolerance test preoperatively and postoperatively. RESULTS: Compared with preoperative levels, significant decreases were seen 6 months postoperatively in fasting TBARS (61.0+/-17.9 versus 39.4+/-13.8 ng/mL, P = .04) and 120-minute TBARS (76.0+/-29.5 versus 46.5+/-16.3 ng/mL, P = .02). No significant changes were observed in plasma TAOS. No significant association was observed between changes in TBARS and other clinical or biochemical measures. CONCLUSION: We observed a significant reduction in TBARS, a global measure of lipid peroxidation 6 months after LSG in participants with obesity and impaired glucose regulation. PMID- 28341057 TI - Histone deacetylase inhibitors suppress immature dendritic cell's migration by regulating CC chemokine receptor 1 expression. AB - The modulation of immature dendritic cells (iDCs), which involves processes such as phagocytosis, migration, and maturation, is considered a beneficial research theme. Once activated by an antigen, iDCs turn to mature DCs (mDCs) and migrate towards secondary lymphoid organs, and initiate the progress of cellular immunity. Histone deacetylase inhibitors (HDACis) are also thought to be a major modulator of cellular immunity. Herein, we demonstrate that HDACis (trichostatin A (TSA), sodium butylate (SB), scriptaid (ST)) play a central regulatory role in the migratory activity of iDCs. In our results, TSA, SB and ST showed the potent inhibitory effect on the migration of iDCs stimulated by MIP-1alpha. The inhibitory activities of HDACis were found to be caused by reduction of CCR1 expression on the cell surface, and by the inhibition of phosphorylation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases 1 and 2 (ERK 1/2), and c-Jun N-terminal kinase (JNK). PMID- 28341058 TI - Anti-fibrotic effects of soluble guanylate cyclase stimulators and activators: A review of the preclinical evidence. AB - It is now well established that the NO-sGC-cGMP signal transduction system mediates many different physiological functions in almost every conceivable organ system; this has been best characterized in the cardiovascular system where NO driven cGMP production exerts a plethora of cytoprotective and anti-atherogenic effects, including dilatation, inhibition of vascular smooth muscle proliferation, blockade of leukocyte recruitment, and anti-platelet activity. Accordingly, dysfunctional NO-sGC-cGMP mediated signaling is perceived as the underlying pathophysiological cause of many cardiovascular and non-cardiovascular diseases. Due to the fundamental role of sGC in the signaling pathways triggered by NO, novel sGC 'modulators' have been identified that directly stimulate both heme-containing as well as heme-free sGC, the so-called 'sGC activators' and 'sGC stimulators', respectively. The beneficial effects of this new family of sGC 'modulators' extend beyond vasodilation, and their potential in other cardiovascular diseases aside from pulmonary arterial hypertension is promising. In animal models of hypertension and heart failure, reno-protective effects, attenuated cardiac fibrosis, and attenuated hypertrophy independent of hemodynamic effects have been shown. During recent years it has become obvious that cGMP increase by sGC modulators exerts direct antifibrotic efficacy in various organs as well as the skin. This review will provide an overview of the preclinical in vitro and in vivo studies for different fibrotic disorders including chronic renal, cardiac, liver, and lung fibrosis, as well as sclerosis and wound healing. Moreover, this review provides evidence for a new mode of action of sGC 'modulators' and its implication for clinical investigations in the treatment of fibrotic disorders such as pulmonary fibrosis and skin fibrosis. PMID- 28341059 TI - Masking properties of ceramics for veneer restorations. AB - STATEMENT OF PROBLEM: The translucency and opacity of ceramics play a significant role in emulating the natural color of teeth, but studies of the masking properties and limitations of dental ceramics when used as monolayer restorations are lacking. PURPOSE: The purpose of this in vitro study was to determine the translucency of 6 materials used for veneer restorations by assessing their translucency parameters (TPs), contrast ratios (CRs), and potential to mask dark tooth colors. MATERIAL AND METHODS: Ten square- or disk-shaped specimens (0.5-mm thickness, shade A2) were fabricated from Vitablocks Mark II (VMII; Vita Zahnfabrik), IPS e.max CAD LT (EMXC LT; Ivoclar Vivadent AG), IPS e.max CAD HT (EMXC HT; Ivoclar Vivadent AG), IPS Empress CAD LT (EMP LT; Ivoclar Vivadent AG), IPS e.max Press LT (EMXP LT; Ivoclar Vivadent AG), and CZR (CZR; Kuraray Noritake Dental Inc). Their luminance (Y) values over black and over white tiles were measured, followed by their color (CIELab) over black tiles and white tiles and shaded A2 (control group), A3.5, A4, and B4 acrylic resin blocks. All measurements were performed using a spectrophotometer in 2 different areas on each specimen. Then CRs, TPs, and color differences (over shaded backgrounds) were determined. Data were subjected to 1-way and 2-way ANOVA (alpha=.05) for analysis. RESULTS: Mean CR values of EMXP LT were significantly higher than those of the other tested materials, whereas VMII and EMXC HT had the lowest values (P<.001). Mean TP values over black and over white backgrounds of VMII and EMXC HT were significantly higher than those of the other tested materials, while EMXP LT and EMXC LT revealed the lowest values (P<.001). Background shade A4 displayed the highest mean effect (expressed in DeltaE* values) on the color of the ceramic materials, whereas shade B4 demonstrated the lowest mean background effect (P<.001). CONCLUSIONS: Significant differences in translucency among the tested ceramics were revealed (P<.001). The EMXC LT and EMXP LT groups were the least translucent under the conditions of this study (P<.001). All tested ceramics exhibited poor masking properties against the A4 background. The color differences of most tested ceramics were more acceptable when tested against the B4 background (DeltaE*<=3.3). PMID- 28341060 TI - Dose dependent treatment with isotretinoin induces more changes in the ileum than in the duodenum and jejunum in Wistar rats. AB - Acne is the most common skin disorder and can directly affect the patients' self esteem. Systemic treatment has been indicated for nodular, cystic or persistent acne rather than another type of treatment, such as a topic one. Isotretinoin is an analogue of vitamin A and by suppressing the sebaceous glands the disease can be controlled. This study was designed to mimic the treatment performed in young patients using the dosage of 1mg/kg, and a higher one of 10mg/kg, for 60days in young male Wistar rats. 24 Wistar rats were divided into four groups: control(water), D0(soybean oil, control group), D1(1mg/kg of Isotretinoin solution), D10(10mg/kg of Isotretinoin solution). Using the morphometry tool and histochemical techniques we evaluated the villus, intestinal crypts, and goblet cells to find signs of possible alterations of the duodenum, jejunum and ileum segments of the small intestine. We found no signs of changes in the jejunum mucosa after 60 days of treatment with 1mg/kg and 10mg/kg. The duodenum is also less affected, whereas significant modifications were found in the ileum. The goblet cell frequency was altered, indicating a proliferative potential for the substance. Although some patients have described intestinal symptoms, no important alterations were found with this protocol, reaffirming the security involved in the treatment with this substance. PMID- 28341061 TI - VMAT plus a few computer-optimized non-coplanar IMRT beams (VMAT+) tested for liver SBRT. AB - PURPOSE: To propose a novel treatment approach, designated VMAT+, involving addition of <5 IMRT beams with computer-optimized non-coplanar orientations to VMAT, and evaluate it for liver Stereotactic Body Radiation Therapy (SBRT). VMAT+ is investigated as an alternative for (1) coplanar VMAT and (2) multi-beam non coplanar treatment. METHODS/MATERIALS: For fifteen patients with liver metastases, VMAT+ plans were compared with (1) dual-arc VMAT and (2) 25-beam, non coplanar treatment with computer-optimized beam orientations (25-NCP). All plans were generated fully automatically for delivery of the highest feasible tumor Biologically Effective Dose (BED). OAR doses, intermediate-dose-spillage, dose compactness, and measured delivery times were evaluated. RESULTS: With VMAT+ the maximum achievable tumor BED was equal to that of 25-NCP. Conversely, VMAT resulted in a lower tumor BED in 5 patients. Compared to VMAT, VMAT+ yielded significant dose reductions in OARs. Intermediate-dose-spillage and dose compactness were significantly improved by 9.8% and 17.3% (p<=0.002), respectively. Treatment times with VMAT+ were only enhanced by 4.1min on average, compared to VMAT (8.4min). Improvements in OAR sparing with 25-NCP, compared to VMAT+, were generally modest and/or statistically insignificant, while delivery times were on average 20.5min longer. CONCLUSIONS: For liver SBRT, VMAT+ is equivalent to time-consuming treatment with 25 non-coplanar beams in terms of achievable tumor BED. Compared to VMAT, OAR sparing and intermediate-dose spillage are significantly improved, with minor increase in delivery time. PMID- 28341062 TI - The effect of post-mastectomy radiation in women with one to three positive nodes enrolled on the control arm of BCIRG-005 at ten year follow-up. AB - BACKGROUND AND PURPOSE: We evaluated the effect of post-mastectomy radiation (PMRT) in 1-3 positive lymph nodes (LN) in patients who received uniform modern systemic therapy. MATERIALS AND METHODS: Cohort study using individual data collected for 1,649 node-positive women who received doxorubicin/cyclophosphamide with sequential docetaxel in 2000-2003 on the control arm of BCIRG-005. All women underwent mastectomy or lumpectomy and axillary LN dissection. PMRT was given at investigator's discretion. RESULTS: A total of 523 women with 1-3 positive LN underwent mastectomy and 39% (206/523) received PMRT. With a median follow-up of 10years, PMRT improved loco-regional control (LRC) from 91% to 98% (p=0.001) but had no effect on overall survival (OS) (84% vs. 86%, p=0.9). On multivariate analysis, PMRT improved local control (LC) (hazard ratio, 0.14; 95% CI, 0.03 0.62; p=0.01) and LRC (hazard ratio, 0.15; 95% CI, 0.04-0.50; p=0.002). PMRT did not significantly impact OS on multivariate analysis (hazard ratio, 0.91; 95% CI, 0.55-1.51; p=0.7). Results remained consistent with the use of propensity score analysis. CONCLUSIONS: In this cohort of patients with N1 disease treated with modern systemic therapy, PMRT improves LRC but has no effect on OS. The rates of OS were excellent, irrespective of adjuvant radiation. PMID- 28341063 TI - The personnel's experiences with the implementation of an activity program for men in municipal health services. AB - The aim of this study was to explore the personnel's experiences with the implementation of an activity program for male residents in municipal care services. The design was inspired by a grounded theory approach. The data were collected by means of two focus group interviews with 11 participants in total. The findings showed that the personnel experienced that continuity was a prerequisite to being and remaining motivated when taking part in the activity program. Therefore, a lack of continuity was an obstacle. The categories 'to be prepared', 'to be responsible for a sense of fellowship', and 'to gain new perspectives' illuminate the personnel's experiences. Different conditions had an impact on how the personnel experienced the implementation of the activity program and whether they stayed motivated for being a part of the program in the future. More attention should be given to ward routines that, with only minor changes, may strengthen the activity leader role. PMID- 28341064 TI - A qualitative study to examine older adults' perceptions of health: Keys to aging successfully. AB - Older adult health is often defined in clinical terms. Research has demonstrated that many older adults self-report aging successfully regardless of clinical health status. This qualitative study used claims data to identify older adults on three levels of health status: healthy and active, managing diseases, or very sick, to better understand how health is defined and maintained. In total, 32 participants from two cities were interviewed. Interviews were audio- and video recorded and then transcribed. Thematic analysis identified five themes: disconnectedness between objective and subjective health; health defined to include psychological and social components; resilience and coping mechanisms indicative of successful aging; social support systems integral to health; and the goal of maintaining functioning. These results indicate the importance of individual perceptions of health rather than just counts of chronic diseases. Health management programs should provide holistic approaches to maximize health outcomes and to promote successful aging. PMID- 28341065 TI - Recommendations for CSF AD biomarkers in the diagnostic evaluation of dementia. AB - This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-beta1-42, tau, and phosphorylated tau in the diagnostic evaluation of patients with dementia. The recommendations were developed by a multidisciplinary working group based on the available evidence and consensus from focused discussions for (i) identification of Alzheimer's disease (AD) as the cause of dementia, (ii) prediction of rate of decline, (iii) cost-effectiveness, and (iv) interpretation of results. The working group found sufficient evidence to support a recommendation to use CSF AD biomarkers as a supplement to clinical evaluation, particularly in uncertain and atypical cases, to identify or exclude AD as the cause of dementia. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Operational recommendations for the interpretation of ambiguous CSF biomarker results were also provided. PMID- 28341067 TI - Treatment of Recurrent Dupuytren Contracture in Joints Previously Effectively Treated With Collagenase Clostridium histolyticum. AB - PURPOSE: Collagenase Clostridium histolyticum (CCH) is approved for the treatment of adults with Dupuytren contracture with a palpable cord. This open-label, phase 4 study evaluated the safety and efficacy of CCH for the retreatment of recurrent contractures in joints that were previously effectively treated with CCH. METHODS: Patients participating in a long-term follow-up study who had contracture recurrence (increased >= 20 degrees with a palpable cord) after successful treatment in the previous study were eligible. Recurrent joint contractures were treated with up to 3 CCH injections (~ 1 month apart). Patients were followed for 1 year to evaluate safety. Assessments included change in joint contracture, range of motion, and the percentage of joints that achieved contracture of 5 degrees or less at day 30 after the last injection. RESULTS: The efficacy analysis included 51 patients with 1 treated joint per patient (31 metacarpophalangeal, 20 proximal interphalangeal). A total of 35 joints (69%) received 1 injection, 12 (24%) received 2 injections, and 4 (8%) received 3 injections. Fifty-seven percent of joints achieved contracture of 5 degrees or less (29 of 51). Overall, 86% (43 of 50) patients had a 20 degrees or greater increase in range of motion. The adverse event profile was consistent with previous studies. One ligament injury was reported. CONCLUSIONS: At a short-term follow-up of 1 year, recurrent contracture in joints previously successfully treated with CCH may be effectively retreated with up to 3 injections of CCH. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 28341066 TI - Recommendations for cerebrospinal fluid Alzheimer's disease biomarkers in the diagnostic evaluation of mild cognitive impairment. AB - This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-beta1-42, tau, and phosphorylated tau in the diagnostic evaluation of patients with mild cognitive impairment (MCI). The recommendations were developed by a multidisciplinary working group and based on the available evidence and consensus from focused group discussions for 1) prediction of clinical progression to Alzheimer's disease (AD) dementia, 2) cost effectiveness, 3) interpretation of results, and 4) patient counseling. The working group recommended using CSF AD biomarkers in the diagnostic workup of MCI patients, after prebiomarker counseling, as an add-on to clinical evaluation to predict functional decline or conversion to AD dementia and to guide disease management. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Furthermore, the working group provided recommendations for interpretation of ambiguous CSF biomarker results and for pre and post-biomarker counseling. PMID- 28341068 TI - Clinical Characteristics of Pyogenic Flexor Tenosynovitis in Pediatric Patients. AB - PURPOSE: To characterize the clinical presentation, common pathogens, antimicrobial susceptibility, and treatment methods associated with pyogenic flexor tenosynovitis (PFT) in pediatric patients. METHODS: Patients who underwent surgical treatment for PFT at a large tertiary-care children's hospital between 2001 and 2015 were identified. Descriptive summary statistics were reported on patient demographics, presenting symptoms and clinical examination features, culture results, treatment strategies, and early complications. RESULTS: Thirty two patients (71.9% male) with a mean age of 9.5 +/- 5.5 years (range, 0.8-19 years) were included. At least 3 Kanavel signs were present on presentation in 62% of the cohort, with all 4 signs identified in 34%. Three children (9%) presented with 0 to 1 Kanavel signs, with semiflexed posturing of the digit as the least commonly (41%) manifested sign. The most frequently cultured organisms were methicillin-resistant Staphylococcus aureus (MRSA) (38%), methicillin sensitive S. aureus (22%), and Pasteurella multocida (13%). Multiple organisms were cultured in 19% of cases. Intravenous antibiotics were administered for a median duration of 4 days (range, 1-16 days) in all cases. Organisms were sensitive to the initial antibiotic regimen in 81% of cases. All methicillin resistant S. aureus infections were sensitive to vancomycin and trimethroprim sulfamethoxazole, and 83% were sensitive to clindamycin. Incision and drainage (I&D) was performed in all cases, with 18% of patients requiring repeat I&D. Surgical approaches included limited incision (80%), midaxial incision (13%), and Bruner incision (7%). The average length of hospitalization was 5.1 days. Infection resolved in all cases without readmission. No neurovascular complications were identified. CONCLUSIONS: The presence of Kanavel signs at presentation are a meaningful indicator of PFT, but are not uniformly present on examination in children and adolescents. Owing to the prevalence of antimicrobial resistance and polymicrobial infection, empirical antibiotic therapy using broad spectrum agents with MRSA coverage is essential. In our cohort of pediatric patients with PFT of sufficient severity to warrant surgical management, prompt I&D along with culture-guided antibiotics predictably resolves infection. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 28341069 TI - Open Surgery Versus Ultrasound-Guided Corticosteroid Injection for Trigger Finger: A Randomized Controlled Trial With 1-Year Follow-up. AB - PURPOSE: Trigger finger is a common condition with a lifetime prevalence of 2%. Corticosteroid injection is a treatment often considered as a first-line intervention with reported cure rates between 60% and 90% in observational cohorts. Nevertheless, open surgery remains the most effective treatment with reported cure rates near 100%. Head-to-head trials on these treatments are limited. We investigated the efficacy of open surgery compared with ultrasound guided corticosteroid injections. METHODS: The study was performed as a single center, randomized, controlled trial with a 1-year follow-up. A total of 165 patients received either open surgery (n = 81) or ultrasound-guided corticosteroid injection (n = 84). Follow-up was conducted at 3 and 12 months. If the finger had normal movement or normal movement with discomfort at latest follow-up, the outcome was considered a success. Secondary outcomes were postprocedural pain and complications. RESULTS: The groups were similar at baseline except for lower alcohol consumption in the open surgery group. At 3 months, 86% and 99% were successfully treated after corticosteroid injection and open surgery, respectively. At 12 months, 49% and 99% were considered successfully treated after corticosteroid injection and open surgery, respectively. The pain score at latest follow-up was significantly higher in the corticosteroid injection group. Complications after open surgery were more severe and included 3 superficial infections and 1 iatrogenic nerve lesion. After corticosteroid injection 11 patients experienced a steroid flare and 2 had fat necrosis at the site of injection. CONCLUSIONS: Open surgery is superior to ultrasound-guided corticosteroid injections. Complications after open surgery are more severe; this must be taken into account when advising patients with regard to treatment. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic I. PMID- 28341070 TI - Severe Hand Injuries From Fireworks: Injury Patterns, Outcomes, and Fireworks Types. AB - PURPOSE: The purpose of this study was to characterize injury patterns and outcomes of fireworks-related hand injuries and determine if there was an association with certain fireworks types. METHODS: A retrospective cohort study was conducted on patients treated at a trauma center between 2005 and 2015. A total of 105 patients sustaining operative hand injuries due to fireworks were identified. Medical records were reviewed to identify injury patterns, treatment outcomes, and fireworks types. RESULTS: Eighty-eight patients (84%) sustained 92 thumb and/or first web space injuries. There were 12 thumb soft tissue-only injuries (13%) and 80 thumb fractures/dislocations (87%). Of these, there were 52 thumb carpometacarpal (CMC) joint dislocations (57%) and 36 thumb fractures outside the thumb CMC joint (39%). Fifteen hands (16%) sustained both thumb CMC joint dislocations and additional thumb fractures. Twenty-three hands (25%) required thumb revision amputation. The number of surgeries for acute reconstruction ranged from 1 to 7, with 17 patients (19%) requiring 3 or more. Sixty-three hands had deep first web space injuries, and 11 (17%) required flaps acutely for first web space reconstruction. Six hands required secondary reconstruction of a first web space contracture. An external fixator was applied to 6 hands to maintain the first web space; none of these required secondary web reconstruction. Excluding isolated pin removals and dressing changes under anesthesia, 19 patients (22%) required later-stage surgeries. Shells/mortars (59%) were the most common fireworks type causing injury. CONCLUSIONS: Among operative hand injuries, fireworks most commonly fracture the thumb, destabilize the thumb CMC joint, and deeply damage the first web space. The first web space requires particular consideration because deep injury may result in adduction contracture and require secondary reconstruction if not prevented. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 28341071 TI - Comparative study of 2 oral care protocols in intensive care units. AB - BACKGROUND: The quality of oral care is important in limiting the emergence of ventilator-associated pneumonia (VAP) in intubated patients. Our main objective was to measure the quality improvement in oral care following the implementation of a new oral care protocol. We also monitored VAP rates. MATERIAL/METHODS: This was a cohort study of patients in 5 adult ICUs covering different specialties. During period 1, caregivers used a foam stick for oral care and during period 2 a stick and tooth brushing with aspiration. Oral chlorhexidine was used during both periods. The caregivers rated improvement in oral health on the basis of 4 criteria (tongue, mucous membranes, gingivae, and teeth). Caregiver satisfaction was also assessed. The incidence of VAP was monitored. RESULTS: A total of 2,030 intubated patients admitted to intensive care units benefited from oral care. The patient populations during the 2 periods were similar with regard to demographic data and VAP potential risk factors. Oral health was significantly better from the third day of oral care in period 2 onward (period 1, 6.4 +/- 2.1; period 2, 5.6 +/- 1.8; P = .043). Caregivers found the period 2 protocol easier to implement and more effective. VAP rates decreased significantly between the 2 periods (period 1, 12.8%; period 2, 8.5%; P = .002). CONCLUSIONS: Our study showed that the implementation of a simple strategy improved the quality of oral care of patients in intensive care units, and decreased VAP rates. PMID- 28341074 TI - Long-Term Prognosis in Ischemic Stroke Patients Treated with Intravenous Thrombolytic Therapy. AB - BACKGROUND AND PURPOSE: It remains unclear if intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator has an impact on the survival and maintenance of a favorable effect on functional recovery over a long follow-up period. The aim of this study was to assess whether or not IVT treatment has a favorable effect on functional recovery and survival less than 1 year after a stroke. METHODS: This matched cohort study included 259 patients with acute ischemic stroke (IS) who were treated with IVT and standard care and 259 patients treated with standard care alone in the stroke unit between February 2006 and January 2013. RESULTS: After a median follow-up period of 3 years (range, 1-7 years), survival did not differ significantly between the groups; specifically, 56 patients (21.6%) in the thrombolysed group died versus 62 patients (23.94%) in the nonthrombolysed group (log-rank, .240, P = .624). Based on a multivariate Cox proportional hazards regression model, older age (>70 years), stroke severity (National Institutes of Health Stroke Scale score >= 15), diabetes mellitus, and a history of atrial fibrillation were independent predictors of long-term mortality after stroke. After the follow-up period, 144 patients (55.6%) in the IVT-treated group versus 112 patients (43.2%) in the control group had an excellent outcome, with a modified Rankin Scale score of 0-1 (hazard ratio [HR] = 1.64, 95% confidence interval [CI] = 1.16-2.32). Based on a multivariate Cox proportional hazards regression model, an excellent 3-month functional recovery was a strong predictor of favorable outcome (HR = 11.27, 95% CI = 6.45-19.63). CONCLUSION: The results suggest that IVT for acute IS has a favorable effect on functional recovery more than 1 year after stroke. PMID- 28341077 TI - First Report of Arg587Cys Mutation of Notch3 Gene in Two Chinese Families with CADASIL. AB - OBJECTIVE: To explore Notch3 mutation sites of Chinese patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). METHODS: Direct sequencing of all exons in Notch3 gene was performed on 12 unrelated suspected CADASIL cases from mainland China. RESULT: A missense p.Arg587Cys (1759C>T) mutation in exon 11 was identified in 2 patients through genetic analysis. CONCLUSION: Chinese patients with CADASIL of R587C mutation in exon 11 was firstly reported. PMID- 28341078 TI - Isolation, molecular characterization, and in vitro differentiation of bovine Wharton jelly-derived multipotent mesenchymal cells. AB - Extrafetal tissues are a noncontroversial and inexhaustible source of mesenchymal stem cells that can be harvested noninvasively at low cost. In the veterinary field, as in man, stem cells derived from extrafetal tissues express plasticity, reduced immunogenicity, and have high anti-inflammatory potential making them promising candidates for treatment of many diseases. Umbilical cord mesenchymal cells have been isolated and characterized in different species and have recently been investigated as potential candidates in regenerative medicine. In this study, cells derived from bovine Wharton jelly (WJ) were isolated for the first time by enzymatic methods, frozen/thawed, cultivated for at least 10 passages, and characterized. Wharton jelly-derived cells readily attached to plastic culture dishes displaying typical fibroblast-like morphology and, although their proliferative capacity decreased to the seventh passage, these cells showed a mean doubling time of 34.55 +/- 6.33 hours and a mean frequency of one colony forming unit fibroblast like for every 221.68 plated cells. The results of molecular biology studies and flow cytometry analyses revealed that WJ-derived cells showed the typical antigen profile of mesenchymal stem cells and were positive for CD29, CD44, CD105, CD166, Oct-4, and c-Myc. They were negative for CD34 and CD14. Remarkably, WJ-derived cells showed differentiation ability. After culture in induced media, WJ-derived cells were able to differentiate into osteogenic, adipogenic, chondrogenic, and neurogenic lines as shown by positive staining and expression of specific markers. On polymerase chain reaction analysis, these cells were negative for MHC-II and positive for MHC-I, thus reinforcing the role of extrafetal tissue as an allogenic source for bovine cell based therapies. These results provide evidence that bovine WJ-derived cells may have the potential to differentiate to repair damaged tissues and reinforce the importance of extrafetal tissues as stem cell sources in veterinary regenerative medicine. A more detailed evaluation of their immunologic properties is necessary to better understand their potential role in cellular therapy. PMID- 28341079 TI - Monitoring of nociception, reality or fiction? AB - There are currently various projects underway that attempt to monitor the nociceptive responses caused by surgical stress and ensure patients the best analgesic conditions. The systemic response to surgical stress has repercussions in the postoperative period, such as worse pain control, delayed recovery, greater complications, longer stay in resuscitation and hospital units, and increased healthcare costs. However, treatment with higher doses of opioids than necessary may lead to slower awakening, increased drowsiness and adverse effects, as well as situations of postoperative opioid-induced hyperalgesia. There are 2 large groups of nociceptive monitoring according to the origin of the theoretical objective of monitoring response to the stimulus, that may derive from changes in the electroencephalogram or the response of the autonomic nervous system. PMID- 28341080 TI - Residual neuromuscular blockade in the postanesthesia care unit. A secondary analysis of the ReCuSS. Observational cross-sectional study of a multicenter cohort. PMID- 28341081 TI - Is albumin a real alternative to starches in septic patients? PMID- 28341082 TI - Perioperative management of liver transplantation in Spanish hospitals: Results of a survey. PMID- 28341083 TI - Scientific publications in gastroenterology and hepatology in Taiwan: An analysis of Web of Science from 1993 to 2013. AB - BACKGROUND: Scientific publications are important for evaluating the achievements of a medical specialty or discipline. Gastroenterology and Hepatology is a medical specialty in great demand in Taiwan, therefore, this study aimed to analyze the Gastroenterology and Hepatology publications from 1993 to 2013 in Taiwan, using the Web of Science (WoS) database. METHODS: Scientific publications from departments/institutes of gastroenterology and hepatology were retrieved and analyzed from the WoS database, which included articles published in the Science Citation Index Expanded and Social Science Citation Index journals from 1993 to 2013. RESULTS: Among 229,030 articles published from departments/institutes of gastroenterology and hepatology worldwide during 1993-2013, 5061 (2.21%) were published in Taiwan, ranking the country 13th in the world. In total, 4759 articles from Taiwan were selected for further analysis, excluding meeting abstracts and corrections. During these two decades, the number of gastroenterology and hepatology publications increased rapidly. There were 440 articles published during 1993-1997, 646 articles during 1998-2002, 1211 articles during 2003-2007, and up to 2462 articles during 2008-2013. However, the mean number of articles cited decreased from 25.35 to 27.25 to 20.64 to 7.28, and the mean impact factor of publishing journals decreased from 5.0 to 4.20 to 4.13 to 4.03 during 1993-1997, 1998-2002, 2003-2007, and 2008-2013, respectively. Most of those publications belong to the subject category gastroenterology and hepatology (2346 articles, 49.30%), followed by surgery (677 articles, 14.23%), medicine, general and internal (358 articles, 7.52%), oncology (316 articles, 6.64%), and pharmacology pharmacy (286 articles, 6.01%). The Journal of Gastroenterology and Hepatology published the most papers (326 articles, 6.9%), followed by World Journal of Gastroenterology (201 articles, 4.2%), Hepato-Gastroenterology (165 articles, 3.5%), Gastrointestinal Endoscopy (159 articles, 3.3%), and Hepatology (146 articles, 3.1%). CONCLUSION: Scientific publications from departments/institutes of gastroenterology and hepatology in Taiwan increased rapidly from 1993 to 2013. However, there were decreasing trends in the number of articles cited and journal impact factors. PMID- 28341084 TI - Corrigendum to "Sense of life worth living (ikigai) and incident functional disability in elderly Japanese: The Tsurugaya Project" [J. Psychosom. Res. 95 (2017) 62-67]. PMID- 28341085 TI - Faculty Evaluations Correlate Poorly with Medical Student Examination Performance in a Fourth-Year Emergency Medicine Clerkship. AB - BACKGROUND: Clerkship directors routinely evaluate medical students using multiple modalities, including faculty assessment of clinical performance and written examinations. Both forms of evaluation often play a prominent role in final clerkship grade. The degree to which these modalities correlate in an emergency medicine (EM) clerkship is unclear. OBJECTIVE: We sought to correlate faculty clinical evaluations with medical student performance on a written, standardized EM examination of medical knowledge. METHODS: This is a retrospective study of fourth-year medical students in a 4-week EM elective at one academic medical center. EM faculty performed end of shift evaluations of students via a blinded online system using a 5-point Likert scale for 8 domains: data acquisition, data interpretation, medical knowledge base, professionalism, patient care and communication, initiative/reliability/dependability, procedural skills, and overall evaluation. All students completed the National EM M4 Examination in EM. Means, medians, and standard deviations for end of shift evaluation scores were calculated, and correlations with examination scores were assessed using a Spearman's rank correlation coefficient. RESULTS: Thirty-nine medical students with 224 discrete faculty evaluations were included. The median number of evaluations completed per student was 6. The mean score (+/-SD) on the examination was 78.6% +/- 6.1%. The examination score correlated poorly with faculty evaluations across all 8 domains (rho 0.074-0.316). CONCLUSION: Faculty evaluations of medical students across multiple domains of competency correlate poorly with written examination performance during an EM clerkship. Educators need to consider the limitations of examination score in assessing students' ability to provide quality patient clinical care. PMID- 28341086 TI - Recurrent Priapism Gone Wrong: ST-Elevation Myocardial Infarction and Cardiogenic Shock After Penile Corporal Phenylephrine Irrigation. AB - BACKGROUND: Recurrent priapism secondary to sickle cell trait in an African American male has been reported in the literature. A common treatment for these low-flow priapism cases is aspiration and injection of the corpus cavernosum with a sympathomimetic agent. We report a rare complication not described previously in the literature of ST-elevation myocardial infarction (STEMI) and cardiogenic shock in a 29-year-old male with sickle cell trait undergoing a routine detumescence procedure. CASE REPORT: A 29-year-old African-American male with a history of sickle cell trait and recurrent low-flow/ischemic priapism presented with a painful erection for 8 h. Corporal aspiration and irrigation with phenylephrine was performed. After phenylephrine injection, the patient experienced hypertensive emergency, flash pulmonary edema, STEMI, and subsequent cardiogenic shock. He required intubation, ionotropic support, cardiac catheterization, and admission to the cardiac care unit. History taken from the patient's wife on the following day revealed that he was taking high doses of pseudoephedrine at home to treat symptoms. The patient was subsequently discharged after 3 days with normalization of ejection fraction and negative troponin. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Intracavernosal injection of phenylephrine is a common emergency department treatment utilized in management of priapism, but emergency physicians should be aware of the potential severe systemic complications resulting from this procedure. Providers should take a careful history, including over-the-counter medication use; consider comorbid medical history; standardize phenylephrine mixing instructions with pharmacy; and perform the procedure in a monitored setting with a brief observation after complete detumescence. PMID- 28341087 TI - The Impact of a Pediatric Emergency Department Facility Verification System on Pediatric Mortality Rates in Arizona. AB - BACKGROUND: The Emergency Medical Services for Children State Partnership Program, as well as the Institute of Medicine report on pediatric emergency care, encourages recognition of emergency departments (EDs) through categorization and verification systems. Although pediatric verification programs are associated with greater pediatric readiness, clinical outcome data have been lacking to track the effects and patient-centered outcomes by implementing such programs. OBJECTIVE: To describe pediatric mortality rates prior to and after implementation of a pediatric emergency facility verification system in Arizona. METHODS: This was a cross-sectional study conducted using data from ED visits between 2011 and 2014 recorded in the Arizona Hospital Discharge Database. The primary outcome measure was the mortality rate for ED visits by patients under 18 years old. Rates were compared prior to and after facility certification by the Arizona Pediatric Prepared Emergency Care program. RESULTS: The total number of ED visits by children during the study period was 1,928,409. Of these, 1,127,294 were at facilities undergoing certification. For hospitals becoming certified, overall ED mortality rates were 35.2 deaths/100,000 ED visits (95% confidence interval [CI] 29.5-41.7) in the precertification analysis and 34.4 deaths/100,000 ED visits (95% CI 30.4-38.9) in the postcertification analysis. The injury related ED visit mortality rate for certified hospitals showed a decrease from 40.0 injury-related deaths/100,000 ED visits (95% CI 28.6-54.4) in the precertification analysis to 25.8 injury-related deaths/100,000 ED visits (95% CI 18.7-34.8) in the postcertification analysis. CONCLUSION: The implementation of the Arizona pediatric ED verification system was associated with a trend toward lower mortality. These results offer a platform for further research on pediatric ED preparedness efforts and their effects on improved patient outcomes. PMID- 28341088 TI - The latest treatment strategy for the rheumatoid hand deformity. AB - With a remarkable improvement in the pharmacotherapy of rheumatoid arthritis (RA), severely handicapped patients are very rare to see. Healing, repair and drug-free, and toward radical cure are coming to be possible. In the clinical practice, more than 50% of the patients are in remission. However, some patients are still difficult to reach remission due to comorbidities and economic burden. In the patient with clinical remission, smoldering synovitis so called "silent destructor" is often detected by ultrasonograpy or by synovial histology in the small joints of the hand. In recent years, over use with "no pain" increases the risk of deformity, osteoarthrosis, tendon rupture and entrapment neuropathy. Highly motivated patients, who concern about the appearance of the hand, hope to get a higher level of activities of daily living and quality of life (QOL). A prospective cohort study was performed for the purpose of knowing whether rheumatoid hand surgery affects the patient's QOL and mental health as well as upper extremity function. A primary hand surgery was scheduled in 119 patients with RA. Synovectomy and Darrach procedure, radiolunate arthrodesis, reconstruction of the extensor tendons, arthroplasty at the metacarpophalangeal (MP) using Swanson implant, fusion at the proximal interphalangeal (PIP) joint, suspensionplasty at the carpometacarpal (CM) joint of the thumb (Thompson method) et al. were performed. As a result, Japanese version of the Stanford Health Assessment Questionnaire (J-HAQ:physical function,QOL), EuroQOL-5 dimension (EQ 5D:QOL), Beck Depression Inventory-II (BDI-II:depression, mentality) at 6 months and at 12 months after surgery improved significantly compared to those just before surgery (p < 0.01). Disease activity score 28- C reactive protein 4 (DAS28 CRP (4)) decreased significantly (p < 0.01). Latest hand surgery with tight medical control is possible to raise QOL and to provide mental wellness for the patient with RA. PMID- 28341089 TI - Corrigendum to "malignant transformation of keratocystic odontogenic tumor: Two case reports" [American journal of otolaryngology 34 (2013) 357-361]. PMID- 28341090 TI - Transient Isolated Lower Bulbar Palsy With Elevated Serum Anti-GM1 and Anti-GD1b Antibodies During Aripiprazole Treatment. AB - BACKGROUND: Transient bulbar palsy without involvement of the facial or extraocular muscles is a rare presentation. It is considered a form of cranial polyneuropathy, a variant of Guillain-Barre syndrome that is related to the autoimmune mechanisms induced by preceding infections or vaccinations. However, drug-induced cranial polyneuropathy has not previously been reported. We describe a boy with isolated bulbar palsy and positive serum antiganglioside antibodies during aripiprazole treatment. PATIENT DESCRIPTION: This 12-year-old boy was admitted with a seven-day history of dysarthria, tongue discomfort, and tinnitus. Three weeks before symptom onset, aripiprazole was added to the patient's medications for attention-deficit hyperactivity disorder. On examination, he showed curtaining of the pharyngeal wall, tongue fasciculation and deviation, and a weak gag reflex. Cranial magnetic resonance imaging suggested lower cranial nerve involvement. Serum anti-GM1 IgG and anti-GD1b IgG antibodies were positive. After stopping aripiprazole, his bulbar symptoms improved. However, on readministration of aripiprazole seven weeks later, dysarthria recurred and again resolved after stopping the drug. CONCLUSION: We describe the first patient with anti-GM1 IgG and anti-GD1b IgG antibodies-associated transient cranial polyneuropathy presenting as isolated bulbar palsy. These findings could be an adverse effect of aripiprazole treatment. PMID- 28341091 TI - Predictors of moderate to severe fatigue 12 months following admission to hospital for burn: Results from the Burns Registry of Australia and New Zealand (BRANZ) Long Term Outcomes project. AB - INTRODUCTION: Fatigue has been identified as an outcome of concern following burn but is rarely captured in outcomes studies. We aimed to: (i) describe the prevalence, and predictors, of moderate to severe fatigue in the first 12 months following burn, and (ii) establish the association between fatigue and health related quality of life and work outcomes. METHODS: Adult burns patients, admitted >24h, were recruited from five BRANZ sites. Participants were followed up at 1-, 6-, and 12-months after injury using the Brief Fatigue Inventory (BFI), 36-item Short Form Health Survey (SF-36) and the Sickness Impact Profile (SIP) work scale. Moderate to severe fatigue was defined as a global BFI score of 4-10. Multivariable mixed effects regression modelling was used to identify demographic, socioeconomic, burn size and severity predictors of moderate/severe fatigue at follow-up. RESULTS: The mean+/-SD age of the 328 participants was 42.1+/-16.7years, 70% were male, 47% were flame burns, and the mean+/-SD %TBSA was 8.7+/-11.2. The prevalence of moderate/severe fatigue decreased from 37% at 1 month, to 32% at 6-months and 26% at 12-months. The adjusted odds of moderate/severe fatigue were 2.62 (95% CI: 1.27, 5.42) times higher for women compared to men, and 2.64 (95% CI: 1.03, 6.79) times higher in patients with a %TBSA>=20. Compared to patients in major cities, the adjusted odds of reporting moderate/severe fatigue were 2.48 fold higher (95% CI: 1.17, 5.24) for patients residing in inner regional areas, and 3.60 fold (95% CI: 1.43, 9.05) higher for patients living in remote/very remote areas. At each time point, the physical and mental health summary scores, and each sub-scale score, of the SF-36 were significantly lower in patients reporting moderate/severe fatigue. Patients experiencing moderate to severe fatigue reported higher work-related disability on the SIP work scale at each time point after injury. DISCUSSION AND CONCLUSION: More than a quarter of participants reported moderate to severe fatigue on the BFI at 12-months and fatigue was strongly associated with poorer health-related quality of life and greater work-related disability. PMID- 28341092 TI - Repigmentation or stimulated skin physiology? Medical needling in combination with non-cultured skin cell transplantation-The way of the melanocyte. PMID- 28341093 TI - Response to Letter to the Editor: 'Repigmentation or stimulated skin physiology? Medical needling in combination with non-cultured skin cell transplantation-The way of the melanocyte'. PMID- 28341094 TI - Association between exposure to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers prior to septic shock and acute kidney injury. AB - OBJECTIVE: To evaluate the association between angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) use prior to a septic shock episode and the development, prognosis and long-term recovery from acute kidney injury (AKI). DESIGN: A single-centre, prospective observational study was carried out between September 2005 and August 2010. SCOPE: Patients admitted to the ICU of a third level hospital. PATIENTS: A total of 386 septic shock patients were studied. INTERVENTIONS: None. VARIABLES OF INTEREST: Use of ACEIs/ARBs, AKI development, recovery of previous creatinine levels and time to recovery. RESULTS: A total of 386 patients were included, of which 312 (80.8%) developed AKI during ICU stay and 23% were receiving ACEIs/ARBs. The percentage of patients on ACEIs/ARBs increased significantly in relation to more severe stages of AKI irrespective of the kind of AKI score. After adjusting for confounders, the development of AKI was independently associated to the use of ACEIs/ARBs (OR 2.19; 95%CI 1.21-3.84; p=.04). With respect to the recovery of kidney function, the group of patients on ACEIs/ARBs had significantly higher creatinine levels at ICU discharge and needed hemodialysis more frequently thereafter. However, use of ACEIs/ARBs affected neither recovery of previous creatinine levels nor significantly delayed recovery. CONCLUSIONS: The use of ACEIs/ARBs before septic shock episodes was correlated to AKI development and severity, but did not affect the recovery of kidney function after sepsis resolution. PMID- 28341095 TI - Nano-graphene induced positive effects on methanogenesis in anaerobic digestion. AB - The effects of nano-graphene on methanogenesis in anaerobic digestion was investigated. Short-term results showed that graphene (30 and 120mg/L) had significantly positive effects on methane production rate, which increased by 17.0% and 51.4%. Further investigation indicated that acetate-consuming methanogenesis was enhanced. The failure of quinones to replicate graphene stimulation effects on methanogenesis suggested that graphene did not function as electron shuttles. After 55 day's operation at room temperature (from 20 to 10 degrees C, the methane production rate with 30mg/L graphene was 14.3% higher than that of the control, while 120mg/L graphene showed a slight inhibition on methane yield. Illumina sequencing data showed that the archaeal community structure remained fairly constant as the incubated sludge with graphene at low temperature, in which Methanoregula, Methanosaeta and Methanospirillum were the dominant species. Besides, Geobacter enrichment was observed with graphene, suggesting that the direct interspecies electron transfer might be promoted. PMID- 28341096 TI - Anoxic oscillating MBR for photosynthetic bacteria harvesting and high salinity wastewater treatment. AB - In this study, photosynthetic bacteria (PSB) were first harvested by MBR with pendulum type oscillation (PTO) hollow fiber module in succession and on a large scale. Based on unique properties of PSB, PSB/MBR was successfully applied for high-salinity wastewater treatment. Compared with control PSB-MBR (CMBR), PSB/PTO MBR exhibited more excellent organics removal, which was mainly attributed to much higher biomass production for utilization. Meanwhile, the influence of light irradiation and aeration on activity of PSB was investigated in detail. Results showed that PTO-MBR with 12h light irradiation proved to be a promising and economical alternative. The cycle of dark/light and anoxic had a positive effect on PSB cultivating. Moreover, PTO-MBR exhibited much higher flux than CMBR even if large amounts of biomass existed, which demonstrated that the strong shear stress on interface of liquid-membrane played important roles on membrane fouling reduction. PMID- 28341097 TI - First report of OXA-232-producing Klebsiella pneumoniae strains in Tunisia. AB - Eleven carbapenem-resistant Klebsiella pneumoniae isolates were recovered from the military hospital of Tunis, Tunisia. Three of these isolates carried the carbapenemase blaOXA-232 gene recently identified in France. These isolates were clonally related and co-expressed the extended-spectrum beta-lactamase, CTX-M-15. This work identified the occurrence of OXA-232 producers in North-African countries. PMID- 28341098 TI - Antimicrobial activity of tigecycline and cefoperazone/sulbactam tested against 18,386 Gram-negative organisms from Europe and the Asia-Pacific region (2013 2014). AB - A total of 18,386 organisms, including 13,224 Enterobacteriaceae, 3536 Pseudomonas aeruginosa, 1254 Acinetobacter spp., and 372Stenotrophomonas maltophilia were collected from Western Europe (WEU; n=10,021), Eastern Europe (EEU; n=4957), and the Asia-Pacific region (APAC; n=3408 [1052 from China]) in 2013-2014 as part of the SENTRY Antimicrobial Surveillance Program and tested by a reference broth microdilution method for susceptibility against tigecycline, cefoperazone/sulbactam, and comparator agents. Overall, 95.3% of Enterobacteriaceae were susceptible (<=1MUg/mL; EUCAST) to tigecycline (MIC50/90, 0.12/1MUg/mL) with regional EUCAST susceptibility rates of 94.8-97.8% (98.9-99.6% inhibited at <=2MUg/mL [US FDA]). Among Acinetobacter spp., 66.1% (EEU) and 79.5% (WEU) were inhibited at <=1MUg/mL of tigecycline (94.9% and 97.3% inhibited at <=2MUg/mL; pan-European MIC50/90, 1/2MUg/mL). For S. maltophilia, 65.4% (China) to 88.9% (EEU) of the isolates were inhibited at <=1MUg/mL of tigecycline. Cefoperazone/sulbactam inhibited 94.6/83.5/91.5% of Enterobacteriaceae at <=16MUg/mL in WEU/EEU/APAC, respectively. PMID- 28341099 TI - Invitro Apramycin Activity against multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa. AB - The in vitro activity of apramycin was compared to that of amikacin, gentamicin, and tobramycin against multidrug-resistant, extensively drug-resistant, and pandrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa. Apramycin demonstrated an MIC50/MIC90 of 8/32MUg/ml for A. baumannii and 16/32MUg/ml for P. aeruginosa. Only 2% of A. baumannii and P. aeruginosa had an MIC greater than an epidemiological cutoff value of 64MUg/ml. In contrast, the MIC50/MIC90 for amikacin, gentamicin, and tobramycin were >=64/>256MUg/ml for A. baumannii with 57%, 95%, and 74% of isolates demonstrating resistance, respectively, and the MIC50/MIC90 were >=8/256MUg/ml for P. aeruginosa with 27%, 50%, and 57% of strains demonstrating resistance, respectively. Apramycin appears to offer promising in vitro activity against highly resistant pathogens. It therefore may warrant further pre-clinical study to assess potential for repurposing as a human therapeutic and relevance as a scaffold for further medicinal chemistry exploration. PMID- 28341100 TI - The ubiquitin-proteasome system: A potential therapeutic target for heart failure. AB - The rising incidence of heart failure (HF) is one of the biggest challenges in cardiovascular medicine. The persistent shortage of donor organs for transplantation has led to an expanding application of left ventricular assist devices as a bridge to recovery. Accumulating evidence suggests that the ubiquitin-proteasome system (UPS), which is responsible for protein degradation, plays a direct role in cardiac hypertrophy and HF and is impacted by mechanical unloading. The UPS system also plays a role in the cardiac regulation of apoptosis, cell mass, and sarcomere quality control. Furthermore, it is a key regulator of beta2-adrenergic signaling, cell excitability, and conductance. In this review, we discuss the roles of the UPS in cardiac health and disease, including its roles in the pathologic hypertrophy associated with HF and its reversal during mechanical unloading. Finally, we suggest future areas of research, including possible therapeutic strategies for reversing cardiac remodeling by targeting the UPS. PMID- 28341101 TI - Crucial residue Trp158 of lipoprotein PiaA stabilizes the ferrichrome-PiaA complex in Streptococcus pneumoniae. AB - The pathogenic Streptococcus pneumoniae (S. pneumoniae) has evolved a special mechanism such as pneumococcal iron acquisition ATP binding cassette (PiaABC) to take up siderophore-iron from its host. The cell-surface lipoprotein PiaA, a key component of PiaABC, is the primary receptor to bind ferrichrome (Fc). To study the structure-function relationship of PiaA, three conservative amino-acid residues, Trp63, Trp158 and Phe255, in the hydrophobic barrel of the metal binding site of PiaA, were individually and collectively mutated to alanine; and the resulted single-point mutants, W63A, W158A and F255A, and triple mutant W63A/W158A/F255A were characterized by using biochemical and biophysical methods. Experiments showed that wild-type PiaA (WT-PiaA) and the single-point mutant proteins bound Fc with a similar kinetics mode, but the reaction rate of W158A was lower than that for WT-PiaA. The binding affinity of W158A toward Fc was significantly weaker than that of the WT-PiaA-Fc (wild-type PiaA bound with Fc) interaction. Furthermore, the absence of Trp158 in the protein led to a significant impact on the secondary structure of PiaA, resulting in a labile conformational structure of W158A, with impaired resistance to thermal and chemical denaturation. Collectively, Trp158 is a crucial residue for binding Fc, playing an important role in stabilizing the PiaA-Fc complex. This study revealed the critical role of the conserved tryptophan residues in Fc-binding protein PiaA, and provided valuable information for understanding the Fc transport mechanism mediated by PiaA or its homologous proteins in bacteria. PMID- 28341102 TI - Bicolumnar 90-90 plating of AO 13C type fractures. AB - OBJECTIVE: The aim of this study was to evaluate functional results and complication rate of patients who underwent medial-dorsolateral plating for intra articular distal humeral fracture (Muller AO type 13C). METHODS: Twenty-four patients (14 men, 10 women; mean age: 47 years) with AO type 13C distal humerus fracture were included in the study. Mean follow-up time was 28 months. Nine patients were in 13C1 subgroup, according to AO classification system, 11 patients were categorized as 13C2, and 4 patients were 13C3. Final follow-up assessment of outcomes included Broberg and Morrey radiological criteria; Mayo Elbow Performance Score, disabilities of the Arm, Shoulder and Hand (DASH) Outcome Measure, score based on Jupiter criteria; and range of motion (ROM) values. RESULTS: The mean carrying angle of operated elbows was 11.37 degrees (range: 0-20 degrees ). According to Broberg and Morrey radiological criteria, 14 patients, had radiologically normal elbow, 4 patients had mild change, 3 patients had moderate change, and 3 patients had severe radiological change. Mean DASH score was 21.91 (range: 0-50), and mean Mayo rating was 83.37 (range: 55-100). Jupiter criteria evaluation revealed excellent results in 10 cases, good in 12, and fair results in 2. One patient with fair result had open fracture, and the other had previous hemiparesis in the same extremity. There was no instance of nonunion observed at follow-up. CONCLUSION: Osteosynthesis with medial dorsolateral plating is a safe and effective method for the treatment of intra articular fractures of distal humerus. LEVEL OF EVIDENCE: Level IV, Therapeutic study. PMID- 28341103 TI - Reply to: Non invasive ventilation for relieving dyspnea in severe COPD: Some key practical insights from lung physiology. PMID- 28341104 TI - Assessment of the adult patient presenting with knee pain: A review article. PMID- 28341105 TI - Commentary on: "Reduced burden of childhood diarrheal diseases through increased access to water and sanitation in India: A modelling analysis". PMID- 28341106 TI - The APPLE Trial: Feasibility and Activity of AZD9291 (Osimertinib) Treatment on Positive PLasma T790M in EGFR-mutant NSCLC Patients. EORTC 1613. AB - The AZD9291 (Osimertinib) Treatment on Positive PLasma T790M in EGFR-mutant NSCLC Patients (APPLE) trial is a randomized, open-label, multicenter, 3-arm, phase II study in advanced, epidermal growth factor receptor (EGFR)-mutant and EGFR tyrosine kinase inhibitor (TKI)-naive non-small-cell lung cancer (NSCLC) patients, to evaluate the best strategy for sequencing gefitinib and osimertinib treatment. Advanced EGFR-mutant NSCLC patients, with World Health Organization performance status 0-2 who are EGFR TKI treatment-naive and eligible to receive first-line treatment with EGFR TKI will be randomized to: In all arms, a plasmatic ctDNA T790M test will be performed by a central laboratory at the Medical University of Gdansk (Poland) but will be applied as a predictive marker for making treatment decisions only in arm B. The primary objective is to evaluate the best strategy for sequencing of treatment with gefitinib and osimertinib in advanced NSCLC patients with common EGFR mutations, and to understand the value of liquid biopsy for the decision-making process. The progression-free survival rate at 18 months is the primary end point of the trial. The activity of osimertinib versus gefitinib to prevent brain metastases will be evaluated. PMID- 28341107 TI - Comparison of clinical effects of epidural levobupivacaine morphine versus bupivacaine morphine in dogs undergoing elective pelvic limb surgery. AB - OBJECTIVE: To evaluate the efficacy, in terms of the amount of rescue analgesia required, and the clinical usefulness of epidural injection of morphine with bupivacaine or levobupivacaine for elective pelvic limb surgery in dogs during a 24-hour perioperative period. STUDY DESIGN: Prospective, blinded, randomized clinical study. ANIMALS: A group of 26 dogs weighing 31.7 +/- 14.2 (mean +/- standard deviation) kg and aged 54 +/- 36 months. METHODS: All dogs were premedicated with methadone intravenously (0.2 mg kg-1) and anaesthesia induced with diazepam (0.2 mg kg-1) and propofol intravenously to effect. After induction of anaesthesia, dogs randomly received a lumbosacral epidural injection of morphine 0.1 mg kg-1 with either levobupivacaine 0.5% (1 mg kg-1; group LevoBM) or bupivacaine 0.5% (1 mg kg-1; group BM). Cardiovascular, respiratory and temperature values were recorded during the intra- and postoperative period. A visual analogue scale, subjective pain scale, sedation scale and the short form of the Glasgow pain scale were assessed every 6 hours after epidural injection during 24 hours. The ability to stand and walk, neurological deficits and other side effects were assessed at the same time points. The amount of rescue analgesia (sufentanil intraoperatively and methadone postoperatively) was recorded. RESULTS: No statistically significant differences were found between groups for any of the recorded data, with the exception of the incidence of spontaneous urination and postoperative rescue analgesia requirement. In group LevoBM four dogs spontaneously urinated at recovery while none of the dogs in group BM did (p = 0.03) and seven dogs of group LevoBM required postoperative rescue analgesia versus none of the dogs in the BM group (p = 0.005). CONCLUSIONS: and clinical relevance Epidural LevoBM is a suitable alternative to BM in healthy dogs during elective pelvic limb surgery. Epidural BM produced more urinary retention but better pain control compared to the same concentration and dose of LevoBM in dogs. PMID- 28341108 TI - Treatment Rationale and Design for J-AXEL: A Randomized Phase 3 Study Comparing Nab-Paclitaxel With Docetaxel in Patients With Previously Treated Advanced Non Small-Cell Lung Cancer. AB - BACKGROUND: Nanoparticle albumin-bound (nab) paclitaxel is a promising new therapeutic agent for all histologic types of non-small-cell lung cancer (NSCLC). We recently performed a phase 2 study of weekly nab-paclitaxel in patients with previously treated advanced NSCLC, finding promising activity and acceptable toxicity for this regimen. We have now designed a randomized phase 3 intergroup study (J-AXEL, UMIN000017487) to examine the clinical benefit and safety of nab paclitaxel compared to docetaxel in patients with previously treated advanced NSCLC. PATIENTS AND METHODS: Patients are randomized to receive either docetaxel (60 mg/m2 on day 1 every 3 weeks, control arm) or nab-paclitaxel (100 mg/m2 on days 1, 8, and 15 every 3 weeks, experimental arm), with each drug being administered until disease progression or unacceptable toxicity. The study will evaluate the noninferiority of nab-paclitaxel relative to docetaxel for the primary end point of overall survival. CONCLUSION: If the primary objective is achieved, this study will provide evidence for a new alternative treatment option for patients with previously treated advanced NSCLC. PMID- 28341109 TI - Phase 1/2 Study of the CD56-Targeting Antibody-Drug Conjugate Lorvotuzumab Mertansine (IMGN901) in Combination With Carboplatin/Etoposide in Small-Cell Lung Cancer Patients With Extensive-Stage Disease. AB - INTRODUCTION: This trial assessed the safety and efficacy of LM in combination with carboplatin/etoposide therapy compared to carboplatin/etoposide treatment alone in patients with previously untreated extensive-disease small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS: A run-in phase 1 stage was used to determine the recommended phase 2 dose and characterize the dose-limiting toxicities of LM in combination with carboplatin/etoposide followed by LM alone in patients with CD56-positive solid tumors. In phase 2, chemotherapy-naive ED SCLC patients were randomized 2:1 to carboplatin AUC (area under the plasma concentration vs. time curve) of 5 day 1 + etoposide 100 mg/m2 days 1 to 3 plus LM (arm 1) or alone (arm 2). RESULTS: In the phase 1 study (n = 33), a dose of LM at 112 mg/m2 with carboplatin/etoposide was identified as the recommended phase 2 dose. However, because of an increased incidence of peripheral neuropathy events during early phase 2, this dose was reduced to 90 mg/m2. In phase 2, a total of 94 and 47 evaluable patients were assigned to arms 1 and 2, respectively. No difference in median progression-free survival was observed between arms 1 and 2 (6.2 vs. 6.7 months). The most common treatment-emergent adverse event leading to discontinuation was peripheral neuropathy (29%). A total of 21 patients had a treatment-emergent adverse event leading to death (18 in arm 1 and 3 in arm 2); for 10 individuals, this was an infection (pneumonia or sepsis) deemed to be related to the study drug. CONCLUSION: The combination of LM plus carboplatin/etoposide did not improve efficacy over standard carboplatin/etoposide doublet therapy in ED-SCLC patients and showed increased toxicity, including a higher incidence of serious infections with fatal outcomes. PMID- 28341110 TI - Clinical Response to Everolimus of EGFR-Mutation-Positive NSCLC With Primary Resistance to EGFR TKIs. PMID- 28341111 TI - Generation, characterization and immunogenicity of a novel chimeric recombinant protein based on Plasmodium vivax AMA-1 and MSP119. AB - Plasmodium vivax is the most widely distributed malaria species and the most prevalent species of malaria in America and Asia. Vaccine development against P. vivax is considered a priority in the global program for the eradication of malaria. Earlier studies have characterized the Apical Membrane Antigen 1 (AMA-1) ectodomain and the C-terminal region (19kDa) of the Merozoite Surface Protein 1 (MSP-1) of P. vivax as immunodominant antigens. Based on this characterization, we designed a chimeric recombinant protein containing both merozoite immunodominant domains (PvAMA166-MSP119). The recombinant PvAMA166-MSP119 was successfully expressed in Pichia pastoris and used to immunize two different mouse strains (BALB/c and C57BL/6) in the presence of the Poly (I:C) as an adjuvant. Immunization with the chimeric protein induced high antibody titers against both proteins in both strains of mice as detected by ELISA. Antisera also recognized the native proteins expressed on the merozoites of mature P. vivax schizonts. Moreover, this antigen was able to induce IFN-gamma-secreting cells in C57BL/6 mice. These findings indicate that this novel yeast recombinant protein containing PvAMA166 and PvMSP119 is advantageous, because of improved antibody titers and cellular immune response. Therefore, this formulation should be further developed for pre-clinical trials in non-human primates as a potential candidate for a P. vivax vaccine. PMID- 28341112 TI - Off-label use of vaccines. AB - This article reviews the off-label recommendations and use of vaccines, and focuses on the differences between the labelled instructions on how to use the vaccine as approved by the regulatory authorities (or "label"1), and the recommendations for use issued by public health advisory bodies at national and international levels. Differences between public health recommendations and the product label regarding the vaccine use can lead to confusion at the level of vaccinators and vaccinees and possibly result in lower compliance with national vaccination schedules. In particular, in many countries, the label may contain regulatory restrictions and warnings against vaccination of specific population groups (e.g. pregnant women) due to a lack of evidence of safety from controlled trials at the time of initial licensure of the vaccine, while public health authorities may recommend the same vaccine for that group, based on additional post-marketing data and benefit risk analyses. We provide an overview of the different responsibilities between regulatory authorities and public health advisory bodies, and the rationale for off-label use2 of vaccines, the challenges involved based on the impact of off-label use in real-life. We propose to reduce off-label use of vaccines by requiring the manufacturer to regularly adapt the label as much as possible to the public health needs as supported by new evidence. This would require manufacturers to collect and report post-marketing data, communicate them to all stakeholders and regulators to extrapolate existing evidence (when acceptable) to other groups or to other brands of a vaccine (class effect3). Regulatory authorities have a key role to play by requesting additional post-marketing data, e.g. in specific target groups. When public health recommendations for vaccine use that are outside labelled indications are considered necessary, good communication between regulatory bodies, public health authorities, companies and health care providers or vaccinators is crucial. Recommendations as well as labels and label changes should be evidence-based. The rationale for the discrepancy and the recommended off-label use of a vaccine should be communicated to providers. PMID- 28341113 TI - Dynamics of African horse sickness virus nucleic acid and antibody in horses following immunization with a commercial polyvalent live attenuated vaccine. AB - African horse sickness (AHS) is a fatal disease of equids relevant to the global equine industry. Detection of AHS virus (AHSV) during outbreaks has become more rapid and efficient with the advent of group specific reverse transcriptase quantitative polymerase chain reaction (GS RT-qPCR) assays to detect AHSV nucleic acid. Use of GS RT-qPCR together with recently described type specific (TS RT qPCR) assays cannot only expedite diagnosis of AHS but also facilitate further evaluation of the dynamics of AHSV infection in the equine host. A potential limitation to the application of these assays is that they detect viral nucleic acid originating from any AHS live attenuated vaccine (LAV), which is the vaccine type routinely administered to horses in South Africa. The aim of this study was to contrast the dynamics and duration of the RNAaemia to the serological responses of horses following immunization with a commercial polyvalent AHSV-LAV using GS and TS RT-qPCR assays and serum neutralisation tests. The results of the study showed extended RNAemia in vaccinated horses, and that more horses tested positive on GS RT-qPCR with lower Cq values after receiving the AHSV-LAV containing types 1, 3 and 4 prior to the vaccine containing types 2, 6, 7 and 8, rather than when the vaccine combinations were reversed. Furthermore, lower Cq values were obtained when vaccines were administered 4weeks apart as compared with a longer interval or 12weeks apart. These findings are of particular relevance in regions where AHSV-LAVs are used as the use of these vaccines may complicate the accurate interpretation of diagnostic testing results. PMID- 28341114 TI - Measuring maternal Tdap and influenza vaccination rates: Comparison of two population-based methods. AB - Pregnant women are routinely recommended to receive Tdap and influenza vaccines to prevent disease and complications among mothers and newborns. Monitoring population trends in maternal vaccination is important in order to evaluate the implementation of these recommendations and to identify pockets of need. We present two methods for measuring maternal vaccination among a state population and discuss the strengths and drawbacks of each method. First, we matched maternal information from records of Wisconsin births during 2013-2015 with maternal vaccination records in the Wisconsin Immunization Registry. Second, we used an all-payer health insurance claims database to identify Wisconsin women with deliveries during 2013-2015 and vaccinations received during pregnancy. Both methods produced similar trends and indicated a substantial increase in the percentage of women receiving Tdap during pregnancy, and lower vaccination rates among women who were Medicaid-insured. When available and timely, both methods are useful for monitoring maternal vaccination. PMID- 28341115 TI - Fewer out-of-sequence vaccinations and reduction of child mortality in Northern Ghana. AB - BACKGROUND: Studies suggest that diphtheria-tetanus-pertussis (DTP) vaccine administered simultaneously with measles vaccine (MV) or DTP administered after MV are associated with higher child mortality than having MV-after-DTP3 as most recent vaccination. We tested this in Northern Ghana where the prevalence of such out-of-sequence vaccinations has declined. METHODS: Using annual cohort data of children aged 12-23months from 1996 to 2012 and Cox proportional hazards models, we assessed survival in relation to the most recent vaccination status within the next 12months and until five years of age. We assessed whether mortality in children aged 12-59months was higher when the most recent vaccine was non-live (DTP) rather than live (MV or OPV). RESULTS: Out-of-sequence vaccinations with DTP-containing vaccines and MV declined from 86% in 1989 to 24% in 1996 and 0.7% in 2012. Between 1996 and 2012, 38 070 children had their vaccinations status assessed: the adjusted hazard ratio (HR) for out-of-sequence vaccinations (DTP>=MV) compared with the recommended sequence of MV-after-DTP3 was 1.42(1.06 1.90) during the first 12months after assessment of vaccination status and 1.29(1.03-1.60) with follow-up to five years of age; the HR was 2.58(1.14-5.84) before OPV or MV campaigns and 1.37(1.02-1.85) after the campaigns. CONCLUSION: Out-of-sequence vaccinations with DTP and MV are associated with higher mortality than MV as most recent vaccination; the effect is unlikely to be due to confounding. Hence, the reduction in out-of-sequence vaccinations may have lowered child mortality. It is recommended not to give DTP with MV or DTP after MV. PMID- 28341116 TI - Management and outcomes of acute pancreatitis patients over the last decade: A US tertiary-center experience. AB - BACKGROUND/OBJECTIVES: Acute pancreatitis (AP) management remains largely supportive and can be challenging in patients with severe disease. This study aims to describe a ten-year US tertiary-center experience in managing AP patients. METHODS: Clinical management and outcomes of 400 prospectively enrolled AP patients stratified by the Revised Atlanta Classification were analyzed; trends in management between early (2004-2008) and late enrollment phase (2009 2014) were assessed. RESULTS: Fifty-two% of patients were classified as mild AP (MAP); moderately severe (MoAP) and severe (SAP) grades contained 23.5% and 24.5% of participants. Intravenous fluid administration during the first 24 h (MAP 3.7, MoAP 4.7, and SAP 4.8 L), need for ICU (6%, 23%, 93%), and nutritional support (7%, 51%, 90%) increased significantly with greater AP severity (p < 0.001). One hundred fifty five (39%) patients developed necrotizing AP, of which 41% received prophylactic antibiotics, and 44% underwent pancreatic drainage/debridement. Prophylactic antibiotics (58% vs. 27%) and interventions (63% vs. 27%) were noted more frequently in SAP than MoAP (p < 0.001). Enteral nutrition (18% vs. 30%) and minimally invasive pancreatic interventions (19% vs. 41%) were more commonly used in the late phase (p < 0.05). The overall median length of hospitalization was 7 days reaching 29 days in SAP group. Mortality was 5%; all deaths occurred in SAP group. CONCLUSIONS: This study provides an extensive report on clinical management of AP and its trends overtime. Pancreatic intervention is required in less than 50% of patients with necrotizing pancreatitis. Utilization of enteral nutrition and minimally invasive pancreatic interventions has been increasing over time. PMID- 28341118 TI - Efficacy of emergency transarterial embolization in acute lower gastrointestinal bleeding: A single-center experience. AB - PURPOSE: The purpose of this study was to assess the safety and efficacy of transcatheter arterial embolization (TAE) in the treatment of acute lower gastrointestinal bleeding (LGIB) and to determine the potential factors that influence treatment outcome. MATERIAL AND METHODS: A total of 38 patients with acute LGIB who were treated by TAE were retrospectively included. There were 24 men and 14 women, with a mean age of 61 years (range: 9-84 years). Patient characteristics, laboratory findings, treatments, causes of bleeding, angiographic findings, and outcomes were reviewed. RESULTS: Active contrast extravasation was observed in 26/38 patients (68.4%) and was the most frequent angiographic finding, followed by abnormal mucosal staining (8/38; 21.1%) and tumor staining (4/38; 10.5%). Technical success of TAE was obtained in 35/38 patients (92%) whereas technical failure was observed in 3/38 patients (8%). Clinical success rate following TAE was 63%. Bowel ischemia occurred in 5/38 patients (13%) following TAE; mild ischemia without sequelae was observed in 3 patients and severe ischemias with bowel perforation requiring surgery in 2 patients. No variables were identified as significant predictive factors of failed TAE. CONCLUSION: TAE is a safe and effective treatment to control massive acute LGIB, especially in the emergency setting with a clinical success rate of 63%. PMID- 28341117 TI - Progress and challenges in maternal health in western China: a Countdown to 2015 national case study. AB - BACKGROUND: China is one of the few Countdown countries to have achieved Millennium Development Goal 5 (75% reduction in maternal mortality ratio between 1990 and 2015). We aimed to examine the health systems and contextual factors that might have contributed to the substantial decline in maternal mortality between 1997 and 2014. We chose to focus on western China because poverty, ethnic diversity, and geographical access represent particular challenges to ensuring universal access to maternal care in the region. METHODS: In this systematic assessment, we used data from national census reports, National Statistical Yearbooks, the National Maternal and Child Health Routine Reporting System, the China National Health Accounts report, and National Health Statistical Yearbooks to describe changes in policies, health financing, health workforce, health infrastructure, coverage of maternal care, and maternal mortality by region between 1997 and 2014. We used a multivariate linear regression model to examine which contextual and health systems factors contributed to the regional variation in maternal mortality ratio in the same period. Using data from a cross-sectional survey in 2011, we also examined equity in access to maternity care in 42 poor counties in western China. FINDINGS: Maternal mortality declined by 8.9% per year between 1997 and 2014 (geometric mean ratio for each year 0.91, 95% CI 0.91 0.92). After adjusting for GDP per capita, length of highways, female illiteracy, the number of licensed doctors per 1000 population, and the proportion of ethnic minorities, the maternal mortality ratio was 118% higher in the western region (2.18, 1.44-3.28) and 41% higher in the central region (1.41, 0.99-2.01) than in the eastern region. In the rural western region, the proportion of births in health facilities rose from 41.9% in 1997 to 98.4% in 2014. Underpinning such progress was the Government's strong commitment to long-term strategies to ensure access to delivery care in health facilities-eg, professionalisation of maternity care in large hospitals, effective referral systems for women medically or socially at high risk, and financial subsidies for antenatal and delivery care. However, in the poor western counties, substantial disparity by education level of the mother existed in access to health facility births (44% of illiterate women vs 100% of those with college or higher education), antenatal care (17% vs 69%) had at least four visits), and caesarean section (8% vs 44%). INTERPRETATION: Despite remarkable progress in maternal survival in China, substantial disparities remain, especially for the poor, less educated, and ethnic minority groups in remote areas in western China. Whether China's highly medicalised model of maternity care will be an answer for these populations is uncertain. A strategy modelled after China's immunisation programme, whereby care is provided close to the women's homes, might need to be explored, with township hospitals taking a more prominent role. FUNDING: Government of Canada, UNICEF, and the Bill & Melinda Gates Foundation. PMID- 28341119 TI - Atypical presentation of symptomatic accessory soleus muscle: Imaging findings. PMID- 28341120 TI - Voice Quality Following Unilateral Vocal Fold Paralysis: A Randomized Comparison of Therapeutic Modalities. AB - In this work, a study on the efficacy of different therapeutic modalities in patients with unilateral vocal fold paralysis (UVFP) was carried out. The study included 20 patients with UVFP, divided into two groups. The objective of this work is to evaluate the voice quality in these patients and to compare the voice following surgery and voice therapy. Group I received voice therapy and group II underwent thyroplasty type I and type IV. The voice was assessed pretreatment and 1 and 3 months posttreatment. Different parameters, such as habitual fundamental frequency (F0), signal-to-noise ratio, jitter, shimmer, maximum phonation duration, s/z ratio, and objective and subjective ratings of dysphonia, were analyzed. It was observed that in group I, all the parameters in seven out of ten patients improved significantly, except for shimmer. In group II, voice quality improved in 70% of the patients with all the parameters. As per previous studies, jitter and shimmer improved after a rehabilitation procedure. However, in this work, it is observed that shimmer did not improve in patients receiving voice therapy. The present study is the first of its type documenting and comparing the efficacy of voice therapy and thyroplasty type I and type IV in patients with UVFP. PMID- 28341121 TI - Activation of EphA1-Epha receptor axis attenuates diabetic nephropathy in mice. AB - The Eph family of receptor tyrosine kinases serves as key modulators of various cellular functions, including inflammation, hypertrophy and fibrosis. Recent analyses have revealed that a member of the Eph family, EphA1, plays a pivotal role in regulating insulin metabolism and kidney injury. However, the importance of EphA1 in diabetic nephropathy has not been recognized. We established a diabetic nephropathy mouse model using a high-fat diet and streptozotocin (STZ) injection. Then, the recombinant adeno-associated virus type 9 (AAV9) overexpressing EphA1 or a negative control was injected locally into the kidney. Metabolite testing and histopathological analyses of kidney fibrosis, pancreatic islet function and signaling pathways were evaluated. Our study showed that hyperglycemia, insulin resistance, and renal fibrosis accompanied the deterioration of kidney function in diabetic mice. The overexpression of EphA1 in the kidney attenuated renal fibrosis and improved kidney function but did not affect systemic glucose metabolism and pancreatic islet function. Furthermore, the overexpression of EphA1 decreased the phosphorylation of ERK1/2, JNK and MYPT1 (a substrate of Rho kinase). The overexpression of EphA1 can be therapeutically targeted to inhibit diabetic renal fibrosis, which suggests that the EphA1-Epha receptor axis may be a novel therapy target for diabetic nephropathy. Mechanistically, the overexpression of EphA1 could inhibit MAPK and the Rho pathway in diabetic kidneys. PMID- 28341122 TI - Molecular dynamics simulations of Zika virus NS3 helicase: Insights into RNA binding site activity. AB - America is still suffering with the outbreak of Zika virus (ZIKV) infection. Congenital ZIKV syndrome has already caused a public health emergency of international concern. However, there are still no vaccines to prevent or drugs to treat the infection caused by ZIKV. The ZIKV NS3 helicase (NS3h) protein is a promising target for drug discovery due to its essential role in viral genome replication. NS3h unwinds the viral RNA to enable the replication of the viral genome by the NS5 protein. NS3h contains two important binding sites: the NTPase binding site and the RNA binding site. Here, we used molecular dynamics (MD) simulations to study the molecular behavior of ZIKV NS3h in the presence and absence of ssRNA and the potential implications for NS3h activity and inhibition. Although there is conformational variability and poor electron densities of the RNA binding loop in various apo flaviviruses NS3h crystallographic structures, the MD trajectories of NS3h-ssRNA demonstrated that the RNA binding loop becomes more stable when NS3h is occupied by RNA. Our results suggest that the presence of RNA generates important interactions with the RNA binding loop, and these interactions stabilize the loop sufficiently that it remains in a closed conformation. This closed conformation likely keeps the ssRNA bound to the protein for a sufficient duration to enable the unwinding/replication activities of NS3h to occur. In addition, conformational changes of this RNA binding loop can change the nature and location of the optimal ligand binding site, according to ligand binding site prediction results. These are important findings to help guide the design and discovery of new inhibitors of NS3h as promising compounds to treat the ZIKV infection. PMID- 28341123 TI - Acetaminophen analog N-acetyl-m-aminophenol, but not its reactive metabolite, N acetyl-p-benzoquinone imine induces CYP3A activity via inhibition of protein degradation. AB - Cytochrome P450 (CYP) 3A subfamily members are known to metabolize various types of drugs, highlighting the importance of understanding drug-drug interactions (DDI) depending on CYP3A induction or inhibition. While transcriptional regulation of CYP3A members is widely understood, post-translational regulation needs to be elucidated. We previously reported that acetaminophen (APAP) induces CYP3A activity via inhibition of protein degradation and proposed a novel DDI concept. N-Acetyl-p-benzoquinone imine (NAPQI), the reactive metabolite of APAP formed by CYP, is known to cause adverse events related to depletion of intracellular reduced glutathione (GSH). We aimed to inspect whether NAPQI rather than APAP itself could cause the inhibitory effects on protein degradation. We found that N-acetyl-l-cysteine, the precursor of GSH, and 1-aminobenzotriazole, a nonselective CYP inhibitor, had no effect on CYP3A1/23 protein levels affected by APAP. Thus, we used APAP analogs to test CYP3A1/23 mRNA levels, protein levels, and CYP3A activity. We found N-acetyl-m-aminophenol (AMAP), a regioisomer of APAP, has the same inhibitory effects of CYP3A1/23 protein degradation, while p acetamidobenzoic acid (PAcBA), a carboxy-substituted form of APAP, shows no inhibitory effects. AMAP and PAcBA cannot be oxidized to quinone imine forms such as NAPQI, so the inhibitory effects could depend on the specific chemical structure of APAP. PMID- 28341124 TI - Tenascin-C is a potential cancer-associated fibroblasts marker and predicts poor prognosis in prostate cancer. AB - Tenascin-C (TNC), as a member of the extracellular matrix (ECM), plays an important role in cancer cell proliferation and migration and tumor invasion in various types of cancer. Here, we attempted to investigate the role of TNC as a prognostic factor in prostate cancer. We studied TNC expression via immunohistochemistry in 145 prostate cancer tissue samples. The clinicopathological relevance of TNC expression was examined, as well as other cancer-associated fibroblasts (CAFs)-related factors. Our results showed that the high levels of TNC expression in prostate cancer stroma was significantly associated with lymph node metastasis (P = 0.024) and clinical stage (P = 0.032). Furthermore, TNC was positively correlated with increased micro-vessel density (MVD) (P = 0.017) and tumor associated macrophage (TAM) population (P = 0.025). In both univariate and multivariate Cox regression analyses, TNC (P < 0.001) was an independent poor prognostic factor for overall survival in prostate cancer patients. Moreover, over-expression of TNC (P < 0.001), SMA (P = 0.042) and vimentin (P = 0.010) were significantly correlated with the lower overall survival. In addition, TNC expression in prostate cancer stroma was significantly associated with FSP1 (P = 0.011), SMA (P = 0.021), and vimentin (P = 0.002). In conclusion, our study revealed that high level of TNC as a potential biomarker of CAFs was significantly correlated with the poor prognosis for prostate cancer patients. PMID- 28341125 TI - Corrigendum to "Reduction of dioxin-like toxicity in effluents by additional wastewater treatment and related effects in fish" [Ecotoxicol. Environ. Saf. 132 (2016) 47-58]. PMID- 28341126 TI - Rasmussen and the boundaries of empirical evaluation. AB - In this special issue, many of the papers focus on Rasmussen's analytic contributions to the understanding of work in complex sociotechnical systems. Work is analysed for the purpose of developing new designs that can improve the nature of that work. The evaluation of such designs was a key part of Rasmussen's program, yet he was often sceptical of the claims made for the generalizability of empirical studies. To tackle this problem, he extended his work analysis framework to provide a way of thinking about empirical evaluation. As authors of this paper, we come from two different backgrounds-systems engineering in the case of Burns, and engineering psychology in the case of Sanderson-and over the decades of our respective research programs, we have both performed many empirical investigations: field investigations, simulation studies, and behavioural laboratory experiments. Rasmussen's scepticism-and his writings on the issue-have stimulated and shaped our own research. In this brief paper we present our interpretation of Rasmussen's perspective, we provide examples how our research sits within Rasmussen's framework of constraints defining boundary conditions for experiments, and we draw conclusions for the future. PMID- 28341127 TI - Effects of coal contamination on early life history processes of a reef-building coral, Acropora tenuis. AB - Successful reproduction and larval dispersal are important for the persistence of marine invertebrate populations, and these early life history processes can be sensitive to marine pollution. Coal is emerging as a contaminant of interest due to the proximity of ports and shipping lanes to coral reefs. To assess the potential hazard of this contaminant, gametes, newly developed embryos, larvae and juveniles of the coral Acropora tenuis were exposed to a range of coal leachate, suspended coal, and coal smothering treatments. Fertilisation was the most sensitive reproductive process tested. Embryo survivorship decreased with increasing suspended coal concentrations and exposure duration, effects on larval settlement varied between treatments, while effects on juvenile survivorship were minimal. Leachate exposures had negligible effects on fertilisation and larval settlement. These results indicate that coral recruitment could be affected by spills that produce plumes of suspended coal particles which interact with gametes and embryos soon after spawning. PMID- 28341128 TI - [A bronchial mucous gland adenoma resected by endoscopic procedure]. AB - INTRODUCTION: Surgical resection is usually performed for the treatment of endobronchial tumors. This case describes the use of endoscopic resection as an initial treatment, allowing to spare lung parenchyma. CASE REPORT: A patient was admitted to the emergency unit with right lower lobe pneumonia. A thoracic CT scan and subsequent bronchoscopy revealed an intrabronchial tumor between the right main and intermediate bronchus. Biopsies were non-diagnostic and a PET scanner did not find any abnormalities. Surgical resection was initially proposed but would have required a right upper lobectomy. The patient had stage 2 (moderate) chronic obstructive pulmonary disease (GOLD classification). Because of this, we decided to perform an endoscopic resection to obtain further histology and hopefully achieve total removal. Under conscious sedation, the resection by argon plasma coagulation with a flexible bronchoscope was realized without any complication. The histological diagnosis was a bronchial mucous gland adenoma. CONCLUSION: This case emphasizes the role of multidisciplinary discussion when considering suitability of local resection of tumors by an endobronchial procedure rather than a surgical resection. PMID- 28341129 TI - Optimal hand washing technique to minimize bacterial contamination before neuraxial anesthesia: a randomized control trial. AB - INTRODUCTION: Infectious complications related to neuraxial anesthesia may result in adverse outcomes. There are no best practice guidelines regarding hand sanitizing measures specifically for these procedures. The objective of this study was to compare the growth of microbial organisms on the operator's forearm between five common techniques of hand washing for labor epidurals. METHODS: In this single blind randomized controlled trial, all anesthesiologists performing labor epidurals in a tertiary care hospital were randomized into five study groups: hand washing with alcohol gel only up to elbows (Group A); hand washing with soap up to elbows, sterile towel to dry, followed by alcohol gel (Group B); hand washing with soap up to elbows, non-sterile towel to dry, followed by alcohol gel (Group C); hand washing with soap up to elbows, non-sterile towel to dry (Group D) or hand washing with soap up to elbows, sterile towel to dry (Group E). The number of colonies for each specimen/rate per 100 specimens on one or both arms per group was measured. RESULTS: The incidence of colonization was 2.5, 23.0, 18.5, 114.5, and 53.0 in Groups A, B, C, D and E, respectively. Compared to Group A, the odds ratio of bacterial growth for Group B was 1.52 (P=0.519), Group C 5.44 (P=0.003), Group D 13.82 (P<0.001), and Group E 8.65 (P<0.001). CONCLUSION: Alcohol-based antiseptic solutions are superior in terms of reducing the incidence of colonization. The results will enable us to develop guidelines to standardize and improve hand-sanitizing practices among epidural practitioners. PMID- 28341131 TI - Neural evidence that inhibition is linked to the affective devaluation of distractors that match the contents of working memory. AB - Stimuli appearing as visual distractors subsequently receive more negative affective evaluations than novel items or prior targets of attention. Leading accounts question whether this distractor devaluation effect occurs through evaluative codes that become associated with distractors as a mere artefact of attention-task instructions, or through affective consequences of attentional inhibition when applied to prevent distractor interference. Here we test opposing predictions arising from the evaluative-coding and devaluation-by-inhibition hypotheses using an electrophysiological marker of attentional inhibition in a task that requires participants to avoid interference from abstract-shape distractors presented while maintaining a uniquely-colored stimulus in memory. Consistent with prior research, distractors that matched the colour of the stimulus being held in memory elicited a Pd component of the event-related potential waveform, indicating that their processing was being actively suppressed. Subsequent affective evaluations revealed that memory-matching distractors also received more negative ratings than non-matching distractors or previously-unseen shapes. Moreover, Pd magnitude was greater on trials in which the memory-matching distractors were later rated negatively than on trials preceding positive ratings. These results support the devaluation-by-inhibition hypothesis and strongly suggest that fluctuations in stimulus inhibition are closely associated with subsequent affective evaluations. In contrast, none of the evaluative-coding based predictions were confirmed. PMID- 28341132 TI - Stochastic modeling and numerical simulation of gene regulatory networks with protein bursting. AB - Gene expression is inherently stochastic. Advanced single-cell microscopy techniques together with mathematical models for single gene expression led to important insights in elucidating the sources of intrinsic noise in prokaryotic and eukaryotic cells. In addition to the finite size effects due to low copy numbers, translational bursting is a dominant source of stochasticity in cell scenarios involving few short lived mRNA transcripts with high translational efficiency (as is typically the case for prokaryotes), causing protein synthesis to occur in random bursts. In the context of gene regulation cascades, the Chemical Master Equation (CME) governing gene expression has in general no closed form solution, and the accurate stochastic simulation of the dynamics of complex gene regulatory networks is a major computational challenge. The CME associated to a single gene self regulatory motif has been previously approximated by a one dimensional time dependent partial integral differential equation (PIDE). However, to the best of our knowledge, multidimensional versions for such PIDE have not been developed yet. Here we propose a multidimensional PIDE model for regulatory networks involving multiple genes with self and cross regulations (in which genes can be regulated by different transcription factors) derived as the continuous counterpart of a CME with jump process. The model offers a reliable description of systems with translational bursting. In order to provide an efficient numerical solution, we develop a semilagrangian method to discretize the differential part of the PIDE, combined with a composed trapezoidal quadrature formula to approximate the integral term. We apply the model and numerical method to study sustained stochastic oscillations and the development of competence, a particular case of transient differentiation attained by certain bacterial cells under stress conditions. We found that the resulting probability distributions are distinguishable from those characteristic of other transient differentiation processes. In this way, they can be employed as markers or signatures that identify such phenomena from bacterial population experimental data, for instance. The computational efficiency of the semilagrangian method makes it suitable for purposes like model identification and parameter estimation from experimental data or, in combination with optimization routines, the design of gene regulatory networks under molecular noise. PMID- 28341133 TI - Sperm cryopreservation in the spermcasting Australian flat oyster Ostrea angasi by a programmable freezing method. AB - Cryopreservation offers long-term storage of gametes without constraint from seasonal gamete maturation, provides opportunities to improve the efficiency of breeding and genetic programs, and protects endangered species from extinction due to epidemic diseases and natural disasters. In this study, a protocol for cryopreserving sperm of the spermcasting Australian flat oyster Ostrea angasi was developed by optimizing key factors influencing the quality of cryopreserved sperm. Dimethyl sulfoxide (DMSO) was non-toxic to sperm within the concentration and duration assessed in the toxicity experiment whereas 10% methanol or a higher concentration was toxic to sperm from the exposure duration of 30 min onwards. DMSO produced higher post-thaw sperm motility among the treatments with a single cryoprotectant. The inclusion of trehalose or glucose with DMSO further increased the post-thaw sperm motility (%) and plasma membrane integrity (PMI). Sperm equilibrated for 30 min showed higher post-thaw motility and PMI than those for 10 or 50 min. Higher post-thaw sperm motility and PMI were achieved at the freezing rate of -3 degrees C/min than at -7 degrees C/min. Sperm packaged in 0.5 ml straws had a higher post-thaw motility and PMI than those packaged in 0.25 ml straws. In this study, 44.4% post-thaw sperm motility and 49.2% PMI were achieved when sperm were equilibrated in 10% DMSO +0.45 M trehalose for 30 min, packaged in 0.5 ml straws, frozen at -3 degrees C/min from 4 degrees C to -80 degrees C, and thawed at 40 degrees C for 8 s. The availability of viable cryopreserved sperm would open an option for future breeding and genetic improvement programs for the spermcasting Australian flat oyster. PMID- 28341134 TI - Metabolic changes in droplet vitrified semen of wild endangered Persian sturgeon Acipenser persicus (Borodin, 1997). AB - Comparative quantitative metabolite profiling can be used for better understanding of cell functions and dysfunctions in particular circumstances such as sperm banking which is an important approach for cryopreservation of endangered species. Cryopreservation techniques have some deleterious effects on spermatozoa which put the obtained results in controversy. Therefore, in the present study, quantitative 1H NMR (Nuclear Magnetic Resonance) based metabolite profiling was conducted to evaluate metabolite changes related to energetics and some other detected metabolites in vitrified semen of critically endangered wild Acipenser persicus. The semen was diluted with extenders containing 0, 5, 10, and 15 MUM of fish antifreeze protein (AFP) type III as a cryoprotectant. Semen extenders were vitrified and stored for two days. Based on post-thaw motility duration and motility percentage assessments, two treatments with 10 MUM and 0 MUM of AFP had the highest and the lowest motility percentages respectively and they were objected to 1H NMR spectroscopy investigations in order to reveal the extremes of the metabolites dynamic range. Univariate (ANOVA) and multivariate (PCA) analysis of the resulting metabolic profiles indicated significant changes (P > 0.05) in metabolites. The level of some metabolites including acetate, adenine, creatine, creatine phosphate, lactate, betaine, sarcosine, beta-alanine and trimethylamine N-oxide significantly decreased in vitrified semen while some others such as creatinine, guanidinoacetate, N, N-dimethylglycine, and glycine significantly increased. There were also significant differences between vitrified treatments in levels of creatine, creatine phosphate, creatinine, glucose, guanidinoacetate, lactate, N, N-dimethylglycine, and glycine, suggesting how fish AFP type III can be effective as a cryoprotectant. PMID- 28341135 TI - Methamphetamine induces hepatotoxicity via inhibiting cell division, arresting cell cycle and activating apoptosis: In vivo and in vitro studies. AB - Methamphetamine (METH) resulted in acute hepatic injury. However, the underlying mechanisms have not been fully clarified. In the present study, rats were treated with METH (15 mg/kg B.W.) for 8 injections (i.p.), and the levels of alanine transaminase, asparatate transaminase and ammonia in serum were significantly elevated over those in the control group, suggesting hepatic injury, which was evidenced by histopathological observation. Analysis of the liver tissues with microarray revealed differential expressions of a total of 332 genes in METH treated rats. According to the GO and KEGG annotations, a large number of down regulated cell cycle genes were screened out, suggesting that METH induced cell cycle arrest and deficient of cell cycle checkpoint. Related genes and proteins were confirmed by RT-qPCR and western blotting in rat livers, respectively. Moreover, treatment of Brl-3A cells with METH caused significant cytotoxic response and marked cell cycle arrest. Furthermore, overexpressions of Cidea, cleaved caspase 3 and PARP 1 in METH-treated rats indicated activation of apoptosis, while its inhibition alleviated cell death in Brl-3A cells, suggesting that activation of apoptosis took an important role in METH-induced hepatotoxicity. Taken together, the present study demonstrates that METH induced hepatotoxicity via inducing cell cycle arrest and activating apoptosis. PMID- 28341136 TI - Criteria for the evidence-based categorisation of skin sensitisers. PMID- 28341137 TI - Targeting hepatocellular carcinoma with piperine by radical-mediated mitochondrial pathway of apoptosis: An in vitro and in vivo study. AB - Redox mediated cancer therapeutics are of immense interest in the recent decade due to their anticancer activity. Piperine is the principal alkaloid of black and long pepper. Although its anticancer activity has been reported in number of cancers , the precise molecular mechanism of action remains to be unravelled. Hence, in this study, for the first time, we delineated the mechanistic insight into the effect of piperine against hepatocellular carcinoma (HCC).MTT analysis determined the dose and time dependent cytotoxicity of piperine against Hep G2 cells. Further molecular studies evidenced the prooxidant property of piperine by inducing H2O2 driven mitochondria-mediated apoptosis in Hep G2 cells by inhibiting the peroxide detoxifying enzyme Catalase. Molecular docking and western blotting analysis uncovered the piperine mediated receptor tyrosine kinase inhibition and mitigation of HCC progression. In addition, histological investigations of piperine - treated, DEN-induced HCC rats showed significant prognosis with apoptotic cell death. Whereas,co-treatment of an antioxidant EUK 134 significantly abrogated its chemotherapeutic activity substantiating its radical-mediated anticancer property. Altogether, this study shows that the piperine may be a promising prooxidant drug for the amelioration of hepatocellular carcinoma. PMID- 28341138 TI - Depression is Associated with Increased Risk for Metabolic Syndrome in Latinos with Type 2 Diabetes. AB - OBJECTIVE: Latino adults are 66% more likely to have diabetes relative to non Latino white adults. Prior research identifies depression as a significant risk factor for metabolic syndrome (MetS), but research examining this among Latinos is lacking. This study sought to examine the links between depression and MetS and clinically significant elevations in cardiovascular disease risk markers of MetS in a sample of community-dwelling older Latinos with type 2 diabetes. METHODS: Participants were 332 community-dwelling older (>=60 years) Latinos with type 2 diabetes who completed the nine-item Patient Health Questionnaire and received a health checkup assessing body mass index (BMI), triglyceride and high density lipoprotein (HDL) cholesterol levels, and blood pressure. Logistic regression analysis compared MetS rates of those meeting criteria for depression with those who did not. Secondary analyses examined the associations between depression and individual MetS components. All analyses controlled for demographic (e.g., income, age) and other potential MetS risk factors (e.g., smoking status, physical activity, alcohol level consumption). RESULTS: Depression was significantly associated with an increased risk of MetS (OR: 5.79; 95% CI: 1.32-25.42) and clinically significant elevations in triglycerides (OR: 2.71; 95% CI: 1.15-6.42) and reduced (HDL) cholesterol (OR: 2.46; 95% CI: 1.11 5.45). A significant association was not observed between depression and either BMI or hypertension. CONCLUSION: Depression is significantly linked to MetS, and most notably dyslipidemia, in older Latinos with diabetes. Causation, however, cannot be inferred from these analyses given the cross-sectional nature of the study. Future research should prospectively examine the directionality of this effect. PMID- 28341140 TI - A meta-analysis of the efficacy of prophylactic alpha-blockade for the prevention of urinary retention following primary unilateral inguinal hernia repair. AB - BACKGROUND: Urinary retention following inguinal hernia surgery is common and is believed to be associated with adrenergic over-stimulation of the smooth muscle in the bladder neck and prostate. The efficacy of prophylactic alpha-blockade in the prevention of urinary retention following elective inguinal hernia repair in males is unknown. METHODS: A comprehensive literature search was performed adhering to PRISMA guidelines. Each study was reviewed and data were extracted. Random-effects models were used to combine data. RESULTS: Five randomized studies describing 456 patients were identified. General or spinal anaesthetic were used. Prophylactic alpha-blockade decreases the risk of urinary retention requiring catheterisation following elective unilateral inguinal hernia repair compared to control groups (OR:0.179, 95% CI:0.043-0.747, p:0.018). Rates of urinary retention between treatment and control groups are reduced by 20.6%. No serious complications relating to alpha blockade occurred. CONCLUSIONS: Prophylactic alpha-blockade reduces urinary retention following elective inguinal hernia surgery under general or spinal anaesthetic. PMID- 28341139 TI - Comparison of topical mupirocin and gentamicin in the prevention of peritoneal dialysis-related infections: A systematic review and meta-analysis. AB - BACKGROUND: Topical antibiotics have been shown to reduce exit-site infection and peritonitis. The aim of this study was to compare infection rates between mupirocin and gentamicin. METHODS: Multiple comprehensive databases were searched systematically to include relevant randomized controlled trials and observational studies. Pooled risk ratios (RRs) and 95% confidence intervals were calculated for the incidences of exit-site infection and peritonitis. RESULTS: Seven studies (mupirocin group n = 458, gentamicin group n = 448) were analyzed for exit-site infection. The risk of gram-positive exit-site infection was similar between the groups. Gram-negative exit-site infection rate was higher in the mupirocin group (RR = 2.125, P = 0.037). Six studies were assessed the peritonitis risk. There was no difference in the gram-positive and -negative peritonitis rate. CONCLUSIONS: Topical use of gentamicin is associated with fewer exit-site infections caused by gram-negative organisms. Gentamicin has comparable efficacy to mupirocin for peritonitis and gram-positive exit-site infection. PMID- 28341143 TI - Corrigendum to "Multiple inhibitory factor removal from an Escherichia coli cell extract improves cell-free protein synthesis" [J Biosci Bioeng 108 (2009) 30-35]. PMID- 28341141 TI - Efficacy and safety of tocilizumab in neuro-Behcet's disease: A case report. PMID- 28341142 TI - Mitochondrial DNA G13708A variation and multiple sclerosis: Is there an association? AB - BACKGROUND: Multiple sclerosis (MS) is considered a pathogenetic enigma. Recently, efforts to implicate genetics in human susceptibility to MS have identified an important role of mitochondrial DNA (mtDNA). G13708A is a common mtDNA variation associated with MS in specific populations. This study tested the hypothesis that the mtDNA G13708A variation is associated with MS in an Iranian population. MATERIALS AND METHODS: Blood samples were collected from 100 MS patients and 100 unrelated healthy controls. DNA was extracted using a salting out method, followed by polymerase chain reaction (PCR) amplification. For assessment of restriction fragment length polymorphism (RFLP), PCR products were restricted by restriction enzyme Mva I. Thereafter, the restriction products were assessed by means of an ultraviolet (UV) transilluminator following electrophoresis with 3% agarose gel. Accuracy of the genotyping procedure was assessed by direct sequencing. RESULTS: The mtDNA G13708A variation was found in 17 cases (17%) and 19 controls (19%) (P=0.7, OR: 0.8, 95% CI: 0.3-1.9). CONCLUSION: The findings of the present study fail to support the hypothesis that the G13708A mtDNA variation is associated with MS in the selected Iranian population. PMID- 28341144 TI - A subjective domestic cat (Felis silvestris catus) temperament assessment results in six independent dimensions. AB - The study of personality or temperament is well developed in many species, but in domestic cats (Felis silvestris catus) it has lagged behind. We applied one common methodology, subjective surveys, performed by their owners, to investigate the dimensions of cat temperament. To do this, we developed an eighteen question survey covering common behavioral traits of cats, and had the evaluators rank their cat on a seven point Likert scale for trait. The responses were analyzed with factor analysis, and resulted in six significant dimensions of temperament across the 251 surveys. The six dimensions, in order of importance, are: Cat Social, Active, Human Nonsocial, Human Aggressive, and Intense. Supplemental questions were also included in all the surveys, and MANOVA analysis of these showed that outdoor usage, feeding style (ad-lib vs. meal fed), living with other cats, sex, duration of ownership, and previous history as a stray all had effects on at least one of the dimensions of cat temperament. Future work is clearly needed to fully validate our model and to further investigate our findings. PMID- 28341145 TI - Facial correlates of emotional behaviour in the domestic cat (Felis catus). AB - Leyhausen's (1979) work on cat behaviour and facial expressions associated with offensive and defensive behaviour is widely embraced as the standard for interpretation of agonistic behaviour in this species. However, it is a largely anecdotal description that can be easily misunderstood. Recently a facial action coding system has been developed for cats (CatFACS), similar to that used for objectively coding human facial expressions. This study reports on the use of this system to describe the relationship between behaviour and facial expressions of cats in confinement contexts without and with human interaction, in order to generate hypotheses about the relationship between these expressions and underlying emotional state. Video recordings taken of 29 cats resident in a Canadian animal shelter were analysed using 1-0 sampling of 275 4-s video clips. Observations under the two conditions were analysed descriptively using hierarchical cluster analysis for binomial data and indicated that in both situations, about half of the data clustered into three groups. An argument is presented that these largely reflect states based on varying degrees of relaxed engagement, fear and frustration. Facial actions associated with fear included blinking and half-blinking and a left head and gaze bias at lower intensities. Facial actions consistently associated with frustration included hissing, nose licking, dropping of the jaw, the raising of the upper lip, nose wrinkling, lower lip depression, parting of the lips, mouth stretching, vocalisation and showing of the tongue. Relaxed engagement appeared to be associated with a right gaze and head turn bias. The results also indicate potential qualitative changes associated with differences in intensity in emotional expression following human intervention. The results were also compared to the classic description of "offensive and defensive moods" in cats (Leyhausen, 1979) and previous work by Gourkow et al. (2014a) on behavioural styles in cats in order to assess if these observations had replicable features noted by others. This revealed evidence of convergent validity between the methods However, the use of CatFACS revealed elements relating to vocalisation and response lateralisation, not previously reported in this literature. PMID- 28341146 TI - [Construction of a diagnostic prediction model of severe bacterial infection in febrile infants under 3 months old]. AB - INTRODUCTION: Fever is a common cause of paediatric admissions in emergency departments. An aetiological diagnosis is difficult to obtain in those less than 3 months of age, as they tend to have a higher rate of serious bacterial infection (SBI). The aim of this study is to find a predictor index of SBI in children under 3 months old with fever of unknown origin. METHODS: A study was conducted on all children under 3 months of age with fever admitted to hospital, with additional tests being performed according to the clinical protocol. Rochester criteria for identifying febrile infants at low risk for SBI were also analysed. A predictive model for SBI and positive cultures was designed, including the following variables in the maximum model: C-reactive protein (CRP), procalcitonin (PCT), and meeting not less than four of the Rochester criteria. RESULTS: A total of 702 subjects were included, of which 22.64% had an SBI and 20.65% had positive cultures. Children who had SBI and a positive culture showed higher values of white cells, total neutrophils, CRP and PCT. A statistical significance was observed with less than 4 Rochester criteria, CRP and PCT levels, an SBI (area under the curve [AUC] 0.877), or for positive cultures (AUC 0.888). Using regression analysis a predictive index was calculated for SBI or a positive culture, with a sensitivity of 87.7 and 91%, a specificity of 70.1 and 87.7%, an LR+ of 2.93 and 3.62, and a LR- of 0.17 and 0.10, respectively. CONCLUSIONS: The predictive models are valid and slightly improve the validity of the Rochester criteria for positive culture in children less than 3 months admitted with fever. PMID- 28341147 TI - Cadmium stimulates myofibroblast differentiation and mouse lung fibrosis. AB - Increasing evidence suggests that Cd at levels found in the human diet can cause oxidative stress and activate redox-sensitive transcription factors in inflammatory signaling. Following inflammation, tissue repair often involves activation of redox-sensitive transcription factors in fibroblasts. In lungs, epithelial barrier remodeling is required to restore gas exchange and barrier function, and aberrant myofibroblast differentiation leads to pulmonary fibrosis. Contributions of exogenous exposures, such as dietary Cd, to pulmonary fibrosis remain incompletely defined. In the current study, we tested whether Cd activates fibrotic signaling in human fetal lung fibroblasts (HFLF) at micromolar and submicromolar Cd concentrations that do not cause cell death. Exposure of HFLF to low-dose Cd (<=1.0MUM) caused an increase in stress fibers and increased protein levels of myofibroblast differentiation markers, including alpha-smooth muscle actin (alpha-SMA) and extra-domain-A-containing fibronectin (ED-A-FN). Assay of transcription factor (TF) activity using a 45-TF array showed that Cd increased activity of 12 TF, including SMAD2/3/4 (mothers against decapentaplegic homolog) signaling differentiation and fibrosis. Results were confirmed by real-time PCR and supported by increased expression of target genes of SMAD2/3/4. Immunocytochemistry of lungs of mice exposed to low-dose Cd (0.3 and 1.0mg/L in drinking water) showed increased alpha-SMA protein level with lung Cd accumulation similar to lung Cd in non-smoking humans. Together, the results show that relatively low Cd exposures stimulate pulmonary fibrotic signaling and myofibroblast differentiation by activating SMAD2/3/4-dependent signaling. The results indicate that dietary Cd intake could be an important variable contributing to pulmonary fibrosis in humans. PMID- 28341149 TI - Docetaxel-loaded RIPL peptide (IPLVVPLRRRRRRRRC)-conjugated liposomes: Drug release, cytotoxicity, and antitumor efficacy. AB - We previously synthesized the RIPL peptide (IPLVVPLRRRRRRRRC) to facilitate selective delivery into hepsin-expressing cancer cells and showed that RIPL peptide-conjugated liposomes (RIPL-L) enhanced the intracellular delivery of fluorescent probes in vitro. In this study, docetaxel-loaded RIPL-L (DTX-RIPL-L) were prepared and evaluated for in vitro drug release, cytotoxicity, and in vivo antitumor efficacy. DTX was successfully encapsulated by pre-loading, with an average encapsulation efficiency and drug loading capacity of 32.4% and 21.39+/ 2.05 (MUg/mg), respectively. A DTX release study using dialysis showed a biphasic release pattern, i.e., rapid release for 6h, followed by sustained release up to 72h. The first-order equation provided the best fit for drug release (r2=0.9349). In vitro cytotoxicity was dose-dependent, resulting in IC50 values of 36.10 (SK OV-3) and 48.62ng/mL (MCF-7) for hepsin-positive, and 61.12 (DU145) and 53.04ng/mL (PC-3) for hepsin-negative cell lines. Live/dead cell imaging was carried out to visualize the proportion of viable and nonviable SK-OV-3 cells. Compared to DTX solution, DTX-RIPL-L significantly inhibited tumor growth and prolonged survival time in BALB/c nude mice with SK-OV-3 cell tumors. We suggest that DTX-RIPL-L is a good candidate for efficient drug targeting to hepsin expressing cancer cells. PMID- 28341148 TI - Lipidomics: Prospects from a technological perspective. AB - Over the last two decades, lipidomics has evolved into an 'omics' technology pari passu with benchmarking 'omics' technologies, such as genomics or proteomics. The driving force behind this development was a constant advance in mass spectrometry and related technologies. The aim of this opinion article is to give the interested reader a concise but still comprehensive overview about the technological state of the art in lipidomics, current challenges and perspectives for future development. As such, this article guides through the whole workflow of lipidomics, from sampling to data analysis. This article is part of a Special Issue entitled: BBALIP_Lipidomics Opinion Articles edited by Sepp Kohlwein. PMID- 28341150 TI - In vitro and in silico characterization of fibrous scaffolds comprising alternate colistin sulfate-loaded and heat-treated polyvinyl alcohol nanofibrous sheets. AB - A multilayer mat for dispensing colistin sulfate through a body surface was prepared by electrospinning. The fabricated system comprised various polyvinyl alcohol fibrous layers prepared with or without the active ingredient. One of the electrospun layers contained water-soluble colistin sulfate and the other was prepared from the same polymer type and composition without the active drug and was finally heat-treated. The heat treatment modified the supramolecular structure and conferred the polymer nanofibre with the rate-controlling function. The microstructure of different layers was tracked by positron annihilation lifetime spectroscopy, and detailed morphological analysis of the fibre mats was performed using a scanning electron microscope. The drug-release profiles of various layer arrangements were studied in relation to their antimicrobial activity. The finite element method was applied to overcome the challenge of diffusion-controlled drug release from multilayer polymer scaffolds. The finite element method was first verified using analytical solutions for a simple arrangement (one drug-loaded swellable fibre and one rate-controlling nonswellable fibre) under perfect sink conditions and in a well-stirred finite volume. The effect of alternate layer arrangements on the drug-release profiles was also investigated to plan for controlled topical drug release from fibrous scaffolds. This design is expected to aid in increasing local effectiveness, thus reducing the systemic loading and the consequent side effects of colistin. PMID- 28341151 TI - Mice heterozygous for an inactivated allele of the schizophrenia associated Brd1 gene display selective cognitive deficits with translational relevance to schizophrenia. AB - Schizophrenia is a debilitating brain disorder characterized by disturbances of emotion, perception and cognition. Cognitive impairments predict functional outcome in schizophrenia and are detectable even in the prodromal stage of the disorder. However, our understanding of the underlying neurobiology is limited and procognitive treatments remain elusive. We recently demonstrated that mice heterozygous for an inactivated allele of the schizophrenia-associated Brd1 gene (Brd1+/- mice) display behaviors reminiscent of schizophrenia, including impaired social cognition and long-term memory. Here, we further characterize performance of these mice by following the preclinical guidelines recommended by the 'Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS)' and 'Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS)' initiatives to maximize translational value. Brd1+/- mice exhibit relational encoding deficits, compromised working and long term memory, as well as impaired executive cognitive functioning with cognitive behaviors relying on medial prefrontal cortex being particularly affected. Akin to patients with schizophrenia, the cognitive deficits displayed by Brd1+/- mice are not global, but selective. Our results underline the value of Brd1+/- mice as a promising tool for studying the neurobiology of cognitive deficits in schizophrenia. PMID- 28341152 TI - Identification of genotoxic compounds in crude oil using fractionation according to distillation, polarity and Kow. AB - We examined the degree of DNA damage caused by fractions of crude oil in accordance with the boiling points, polarity and log Kow. Relatively high DNA damage was observed in the aromatic fraction (290-330 degrees C) and resin and polar fraction (350-400 degrees C). The resin and polar fraction showed relatively high genotoxicity compared with the aliphatic and aromatic fraction at the 1-4 log Kow range. At the 6-7 log Kow range, the aromatic fraction showed relatively high DNA damage compared with the aliphatic and resin and polar fraction. In particular, every detailed fraction in accordance with the log Kow values (aliphatic and aromatic (310-320 degrees C) and resins and polar fractions (370-380 degrees C)) showed one or less than one DNA damage. However, the fractions before separation in accordance with log Kow values (aliphatic and aromatic (310-320 degrees C) and resin and polar (370-380 degrees C) fractions) showed high DNA damage. Thus, we confirm the synergistic action between the detailed compounds. PMID- 28341153 TI - Elemental distribution and trace metal contamination in the surface sediment of south east coast of India. AB - Spatial distribution and potential ecological risk of trace metals in the surface sediment of south east coast of India covering eight different ecosystems was studied. The concentration of major elements viz. Ca, Mg, K, Ti and trace metals viz. Cr, Mn, Co, Al, Fe, Ni, Cu, Zn, Cd and Pb were analysed by energy dispersive X-ray fluorescence technique. Contamination factor, geo-accumulation index, probable effect level, enrichment factor and pollution load index were calculated to evaluate the pollution status. Except cadmium, CF values for all the metals ranged between 1<=CF<=3 indicating moderate metal contaminations along the coast. Mean PEL quotient (Qm-PEL) indicated toxicity probability to be below 21%. Fe, Cu, Zn and Co showed significant positive correlation (p<0.01) with clay. Chromium was the only metal that demonstrated strong negative correlation with clay (p<0.01) and positive correlation (p<0.01) with sand content. PMID- 28341154 TI - The short-term effects of farmed fish food consumed by wild fish congregating outside the farms. AB - We simulated in the laboratory the possible effects on fatty acids and immune status of wild fish arriving for the first time in the vicinity of a sea-cage fish farm, shifting their natural diet to commercial feed consumption, rich in fatty acids of vegetable origin. The flesh fatty acid profile of golden mullet specimens was altered after 2weeks of commercial feed consumption, showing an increase in fatty acids of vegetable origin. The serum peroxidase and bactericidal activities, and head-kidney leucocyte phagocytic capacity, increased after eight weeks of the new diet, while the respiratory burst activity decreased. The extent of these changes cannot be considered large enough to regard them as compromising the health status of fish. More research is needed in order to elucidate whether the rapid assimilation of the dietary fatty acids could harm the immune status of fish when feeding for longer periods than two months. PMID- 28341155 TI - Anthropogenic debris in the nests of kelp gulls in South Africa. AB - Anthropogenic debris results in detrimental interactions with many marine species. Several seabirds include debris items in their nests, which can lead to entanglement of chicks and adults, resulting in injury or death. Anthropogenic debris was found in 4-67% of kelp gull Larus dominicanus nests in seven colonies in the Western Cape, South Africa. Nests contained two types of litter: items included in the nest structure during construction (mainly ropes and straps), and regurgitated items (mainly bags and food wrappers) that probably accumulate primarily during the chick-rearing period. Debris used in nest construction was more likely to injure gulls, and was found mainly at coastal sites where there was little natural vegetation for construction. Distance to the nearest urban waste landfill significantly affected the occurrence of debris items in nests, especially dietary-derived items. The amount of debris in kelp gull nests highlights the need for improved debris management in South Africa. PMID- 28341156 TI - Long-range interactions between protein-coated particles and POEGMA brush layers in a serum environment. AB - Hydrophilic poly[oligo(ethylene glycol) methyl methacrylate] (POEGMA) brush layers with different thickness and graft densities were prepared by surface initiated atom transfer radical polymerization (SI-ATRP) to construct a model surface to examine protein-surface interactions in a serum environment. The thickness of the POEGMA brush layers could be well controlled by the polymerization time and density of the immobilized initiators. The interactions between these brush-modified surfaces and the protein-coated polystyrene (PS) particles in newborn calf serum (NBCS) environment were then measured by total internal reflection microscopy (TIRM). In addition, protein adsorption properties onto the polymer brush surface layers were examined by atomic force microscopy (AFM). Relatively large amounts of protein adsorbed to short (4nm and 9nm-thick) POEGMA-coated surfaces or surfaces grafted with a low density of polymer chains. It was considered that shorter polymer chains or chains with low grafted density cannot fully cover the surfaces, proteins in serum could directly interact with the material surface and then deposited to form an adsorbed layer. The TIRM measurements showed that such adsorbed protein layer could mediate the interactions between the two surfaces by generating steric or bridging forces, resulting in different interaction potentials. Some particles were freely diffusing, some experienced intermittent diffusion and more than 50% of particles were irreversibly deposited to the surfaces covered by short polymer brushes. However, for longer (17 and 30nm-thick) POEGMA brush layer surfaces, material surface would be sufficiently covered by the dense coating and the first step of protein adsorption on surface was avoided. TIRM measurements showed that around 95% of the protein-coated particles could freely move in the serum and no attractive force between two surfaces was detected. The steric repulsion generated from the long POEGMA brush layer in the swollen state was long-range and strong so that the protein adsorption is very unlikely. These results concluded that the adsorbed protein layer on POEGMA surfaces plays an important role in regulating the interaction between protein-coated particles and POEGMA surfaces which are highly repellent toward protein adsorption. PMID- 28341157 TI - Answer to UCB letter to the editor concerning "cancer risk in women exposed to diethylstilbestrol in utero". PMID- 28341158 TI - Letter to the editor concerning the cancer risk in women exposed to diethylstilbestrol in utero. PMID- 28341159 TI - [Effectiveness of preventive treatment by Influenzinum in the winter period against the onset of influenza-like illnesses]. AB - AIM: In vitro Influenzinum induce a cellular change. We present the results of the first study examining the effectiveness of Influenzinum against influenza like illnesses. METHOD: Retrospective cohort study during winter 2014-2015. After influenza epidemic, a self-assessment questionnaire was offered to patients presenting for a consultation. The primary endpoint was the declaration of an influenza-like illness. The exposed patients (treated by Influenzinum) were matched to two non-exposed patients (untreated) with a propensity score. A conditional logistic model expressed influenza-like illness risk reduction provided by the Influenzinum. RESULTS: The cohort included 3514 patients recruited from 46 general practitioners. After matching, the treated group (n=2041) and the untreated group (n=482) did not differ on variables collected. Influenzinum preventive therapy does not significantly alter the likelihood of influenza-like illness (adjusted odds ratio=0,91 [0,62 to 1,35], p=0,64). CONCLUSION: Influenzinum preventive therapy did not appear effective in preventing influenza-like illness. PMID- 28341161 TI - Predictive position computations mediated by parietal areas: TMS evidence. AB - When objects move or the eyes move, the visual system can predict the consequence and generate a percept of the target at its new position. This predictive localization may depend on eye movement control in the frontal eye fields (FEF) and the intraparietal sulcus (IPS) and on motion analysis in the medial temporal area (MT). Across two experiments we examined whether repetitive transcranial magnetic stimulation (rTMS) over right FEF, right IPS, right MT, and a control site, peripheral V1/V2, diminished participants' perception of two cases of predictive position perception: trans-saccadic fusion, and the flash grab illusion, both presented in the contralateral visual field. In trans-saccadic fusion trials, participants saccade toward a stimulus that is replaced with another stimulus during the saccade. Frequently, predictive position mechanisms lead to a fused percept of pre- and post-saccade stimuli (Paeye et al., 2017). We found that rTMS to IPS significantly decreased the frequency of perceiving trans saccadic fusion within the first 10min after stimulation. In the flash grab illusion, a target is flashed on a moving background leading to the percept that the target has shifted in the direction of the motion after the flash (Cavanagh and Anstis, 2013). In the first experiment, the reduction in the flash grab illusion after rTMS to IPS and FEF did not reach significance. In the second experiment, using a stronger version of the flash grab, the illusory shift did decrease significantly after rTMS to IPS although not after rTMS to FEF or to MT. These findings suggest that right IPS contributes to predictive position perception during saccades and motion processing in the contralateral visual field. PMID- 28341162 TI - Structural laterality is associated with cognitive and mood outcomes: An assessment of 105 healthy aged volunteers. AB - The human brain presents multiple asymmetries that dynamically change throughout life. These phenomena have been associated with cognitive impairments and psychiatric disorders although possible associations with specific patterns of cognitive aging are yet to be determined. We have therefore mapped and quantified morphological asymmetries in a heterogeneous and aged population (65.2+/-8.0 years old, 52 male and 53 female) to explore potential associations between the asymmetries in specific brain regions and cognitive performance. The sample was characterized in a battery of neuropsychological tests and in terms of brain structural asymmetries using a ROI-based approach. A substantial number of brain areas presented some degree of asymmetry. Such biases survived a stringent statistical correction and were largely confirmed in a voxel-based analysis. In specific brain areas, like the thalamus and insula, asymmetry was correlated with cognition and mood descriptors as the Stroop words/colors test or depressive mood scale, respectively. Curiously in the latter, the association was independent of its left/right direction. Altogether, results reveal that asymmetry is widespread in the aged brain and that area-specific biases (degree and direction) associate with the functional profile of the individual. PMID- 28341163 TI - Factor analysis linking functions for simultaneously modeling neural and behavioral data. AB - A growing number of researchers have advocated for the advancement of cognitive neuroscience by blending cognitive models with neurophysiology. The recently proposed joint modeling framework is one way to bridge the gap between the abstractions assumed by cognitive models and the neurophysiology obtained by modern methods in neuroscience. Despite this advancement, the current method for linking the two domains is hindered by the dimensionality of the neural data. In this article, we present a new linking function based on factor analysis that allows joint models to grow linearly in complexity with increases in the number of neural features. The new linking function is then evaluated in two simulation studies. The first simulation study shows how the model parameters can be accurately recovered when there are many neural features, that mimics real-world applications. The second simulation shows how the new linking function can (1) properly recover a representation of the data generating model, even in the case of model misspecification, and (2) outperform the previous linking function in a cross-validation test. We close by applying a model equipped with the new linking function to real-world data from a perceptual decision making task. The model allows us to understand how differences in the model parameters emerge as a function of differences in brain function across speed and accuracy instruction. PMID- 28341160 TI - Metabolic network failures in Alzheimer's disease: A biochemical road map. AB - INTRODUCTION: The Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer's disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance. METHODS: Fasting serum samples from the Alzheimer's Disease Neuroimaging Initiative (199 control, 356 mild cognitive impairment, and 175 AD participants) were analyzed using the AbsoluteIDQ-p180 kit. Performance was validated in blinded replicates, and values were medication adjusted. RESULTS: Multivariable-adjusted analyses showed that sphingomyelins and ether-containing phosphatidylcholines were altered in preclinical biomarker-defined AD stages, whereas acylcarnitines and several amines, including the branched-chain amino acid valine and alpha-aminoadipic acid, changed in symptomatic stages. Several of the analytes showed consistent associations in the Rotterdam, Erasmus Rucphen Family, and Indiana Memory and Aging Studies. Partial correlation networks constructed for Abeta1-42, tau, imaging, and cognitive changes provided initial biochemical insights for disease related processes. Coexpression networks interconnected key metabolic effectors of disease. DISCUSSION: Metabolomics identified key disease-related metabolic changes and disease-progression-related changes. Defining metabolic changes during AD disease trajectory and its relationship to clinical phenotypes provides a powerful roadmap for drug and biomarker discovery. PMID- 28341165 TI - The left intraparietal sulcus adapts to symbolic number in both the visual and auditory modalities: Evidence from fMRI. AB - A growing body of evidence from functional Magnetic Resonance Imaging adaptation (fMRIa) has implicated the left intraparietal sulcus (IPS) as a crucial brain region representing the semantic of number symbols. However, it is currently unknown to what extent the left IPS brain activity can be generalized across modalities (e.g., Arabic digits and spoken number words) and how robust and reproducible numerical adaptation effects are. In two separate fMRIa experiments we habituated the brain response of 20 native English-speaking (Experiment 1) and 34 native German-speaking (Experiment 2) adults to Arabic digits or spoken number words. Consistent with previous findings, experiment 1 revealed numerical ratio dependent adaptation to Arabic numerals in the left IPS using both conventional and cortex-based alignment techniques. Experiment 2 revealed numerical ratio dependent signal recovery in the left IPS following adaptation to both Arabic numerals and spoken number words using both conventional and cortex-based alignment techniques. Together, these findings suggest that the left IPS is involved in symbolic number processing across modalities. PMID- 28341166 TI - [Identification of neurodegenerative diseases in administrative databases in France: A systematic review of the literature]. AB - BACKGROUND: Given the health, social and economic burden of neurodegenerative diseases (ND), the development of epidemiologic studies is required. Administrative databases, such as the French national health insurance database (SNIIRAM) could represent an opportunity for researchers. ND could be presumed from drug reimbursement data, hospital stays or registration of a chronic condition. The aim of this study was to describe, in French administrative databases, algorithms used to identify Alzheimer's disease and associated disorders (ADAD), Parkinson's disease and associated disorders (PDAD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). METHODS: A systematic literature review was performed in Medline and gray literature through December 31th, 2015. French studies focusing on ADAD, PDAD, MS or ALS as a primary health outcome, conducted among one of the SNIIRAM data sources (outpatient reimbursements, chronic condition registration, hospital discharge) were included. RESULTS: Thirty-four studies were included (ADAD, n=18, PDAD, n=9, MS, n=4, ALS, n=3), leading to 36 algorithms. For each studied ND, there was an important variability in the algorithms, concerning (i) the type of criteria used (administrative database versus multi-source systems); (ii) the number of criteria used; (iii) the definition used for each criteria. The extent and level of drug exposure highly varied. Identification through hospitalizations showed variations in terms of type of stay (short stay, long-term stay, psychiatric ward...), extent of diagnosis codes used, diagnosis type (principal, related, associated diagnosis) and period used. A validation study was conducted for 2 out of 36 algorithms (PDAD), and criteria completeness was estimated for 3 algorithms (MS, ALS). CONCLUSION: Despite the increase in ND identification among French administrative databases, few algorithms have been validated. Validation studies should be encouraged. PMID- 28341164 TI - Expectation violation and attention to pain jointly modulate neural gain in somatosensory cortex. AB - The neural processing and experience of pain are influenced by both expectations and attention. For example, the amplitude of event-related pain responses is enhanced by both novel and unexpected pain, and by moving the focus of attention towards a painful stimulus. Under predictive coding, this congruence can be explained by appeal to a precision-weighting mechanism, which mediates bottom-up and top-down attentional processes by modulating the influence of feedforward and feedback signals throughout the cortical hierarchy. The influence of expectation and attention on pain processing can be mapped onto changes in effective connectivity between or within specific neuronal populations, using a canonical microcircuit (CMC) model of hierarchical processing. We thus implemented a CMC within dynamic causal modelling for magnetoencephalography in human subjects, to investigate how expectation violation and attention to pain modulate intrinsic (within-source) and extrinsic (between-source) connectivity in the somatosensory hierarchy. This enabled us to establish whether both expectancy and attentional processes are mediated by a similar precision-encoding mechanism within a network of somatosensory, frontal and parietal sources. We found that both unexpected and attended pain modulated the gain of superficial pyramidal cells in primary and secondary somatosensory cortex. This modulation occurred in the context of increased lateralized recurrent connectivity between somatosensory and fronto parietal sources, driven by unexpected painful occurrences. Finally, the strength of effective connectivity parameters in S1, S2 and IFG predicted individual differences in subjective pain modulation ratings. Our findings suggest that neuromodulatory gain control in the somatosensory hierarchy underlies the influence of both expectation violation and attention on cortical processing and pain perception. PMID- 28341168 TI - Lies, damned lies and statistics: Clinical importance versus statistical significance in research. AB - Correctly performed and interpreted statistics play a crucial role for both those who 'produce' clinical research, and for those who 'consume' this research. Unfortunately, however, there are many misunderstandings and misinterpretations of statistics by both groups. In particular, there is a widespread lack of appreciation for the severe limitations with p values. This is a particular problem with small sample sizes and low event rates - common features of many published clinical trials. These issues have resulted in increasing numbers of false positive clinical trials (false 'discoveries'), and the well-publicised inability to replicate many of the findings. While chance clearly plays a role in these errors, many more are due to either poorly performed or badly misinterpreted statistics. Consequently, it is essential that whenever p values appear, these need be accompanied by both 95% confidence limits and effect sizes. These will enable readers to immediately assess the plausible range of results, and whether or not the effect is clinically meaningful. PMID- 28341167 TI - Procalcitonin as a potential predicting factor for prognosis in bacterial meningitis. AB - We investigated the potential role of serum procalcitonin in differentiating bacterial meningitis from viral meningitis, and in predicting the prognosis in patients with bacterial meningitis. This was a retrospective study of 80 patients with bacterial meningitis (13 patients died). In addition, 58 patients with viral meningitis were included as the disease control groups for comparison. The serum procalcitonin level was measured in all patients at admission. Differences in demographic and laboratory data, including the procalcitonin level, were analyzed between the groups. We used the mortality rate during hospitalization as a marker of prognosis in patients with bacterial meningitis. Multiple logistic regression analysis showed that high serum levels of procalcitonin (>0.12ng/mL) were an independently significant variable for differentiating bacterial meningitis from viral meningitis. The risk of having bacterial meningitis with high serum levels of procalcitonin was at least 6 times higher than the risk of having viral meningitis (OR=6.76, 95% CI: 1.84-24.90, p=0.004). In addition, we found that high levels of procalcitonin (>7.26ng/mL) in the blood were an independently significant predictor for death in patients with bacterial meningitis. The risk of death in patients with bacterial meningitis with high serum levels of procalcitonin may be at least 9 times higher than those without death (OR=9.09, 95% CI: 1.74-47.12, p=0.016). We found that serum procalcitonin is a useful marker for differentiating bacterial meningitis from viral meningitis, and it is also a potential predicting factor for prognosis in patients with bacterial meningitis. PMID- 28341170 TI - Amoxicillin challenge without penicillin skin testing in evaluation of penicillin allergy in a cohort of Marine recruits. PMID- 28341169 TI - Evaluation of basophil activation test in the management of immediate hypersensitivity reactions to gadolinium-based contrast agents: a five-year experience. PMID- 28341171 TI - Chronic granulomatous disease caused by maternal uniparental isodisomy of chromosome 16. PMID- 28341172 TI - Comparison of Pediatric and Adult Systemic Reactions to Subcutaneous Immunotherapy. AB - BACKGROUND: Subcutaneous immunotherapy (SCIT) has been used to treat allergic rhinitis for over a century, and current regimens have wide variability with an array of practice styles and dosing strategies. Although there are some statements about contraindications and cautions, no specific formal age- or weight-based dosing guidelines are utilized when administering SCIT. OBJECTIVE: The primary objective of this study was to estimate the overall incidence rate of any reaction to SCIT and to consider the severity of the reaction by grade in children and adults. METHODS: A retrospective chart review was conducted to document the number and severity of episodes of systemic reactions (SRs) in pediatric and adult subjects. Crude incidence rates were estimated as the number of SRs relative to the total injections administered. Adjusted incidence rate ratios were generated using a generalized estimating equation approach, which accounted for multiple visits within subjects. RESULTS: The incidence rate for any SR was 0.2%. The unadjusted incidence rate of any SR was significantly higher in children compared with adults (P < .001), although not significant when adjusted for asthma, gender, and phase of SCIT (P < .054). However, the incidence rate for grade 1 and 2 SRs in children was 1.89 times the incidence rate for adults, adjusting for these variables (P < .015). CONCLUSIONS: These results suggest that current SCIT practices are associated with a higher rate of SRs, specifically of grade 1 and 2 SRs, in children than adults. Further studies are necessary to evaluate if changes in dosing strategies for children, such as a lower starting dose, a decrease in target maintenance dose, or a slower build-up phase, are warranted. PMID- 28341173 TI - Preparation and characterization of reinforced papers using nano bacterial cellulose. AB - The main goal of this work was to reinforce softwood pulp (SP) with bacterial cellulose (BC) to generate a sustainable biocomposite. BC is a nanocellulose, which was anticipated to increase interfacial adhesion between the cellulosic fibers and BC. The organism used was Gluconacetobacter xylinus, which was incubated in a static Hestrin-Schramm culture at 28 degrees C for 14days. The specimens of BC, SP and the reinforced SP with BC were characterized using X-ray diffraction (XRD), FT-IR, FESEM, and physico-mechanical testing. The crystallinity index was found to be 83 and 54% for BC and SP, respectively. FT-IR spectra showed that the composition of BC was fully different from that of SP fibers. Based on FESEM images, one can conclude that BC and softwood fibers do form a good combination with a nonporous structure. BC fibers fill in among the softwood fibers in the sheet. The physical and mechanical properties showed that as the dosage of BC increased, the properties of tensile index, tear index, and burst index greatly improved, while the porosity and the elongation decreased. The reason for the improved mechanical properties can be attributed to the increase of interfibrillar bonding which reduced porosity. This would be due to the high aspect ratio of BC that is capable of connecting between the cellulosic fibers and BC nanofibers, enhancing a large contact surface and therefore producing excellent coherence. This study suggests that BC could be a promising material for reinforcing composites at low loading. PMID- 28341174 TI - Insights into the mechanism of how Morin suppresses amyloid fibrillation of hen egg white lysozyme. AB - This communication describes the inhibitory effect of Morin on the fibrillation of Hen Egg White Lysozyme (HEWL), a generic amyloid-forming model protein. This effect was dose-dependent and stronger than other small molecules we have tested previously. Spectrofluorometric and computational studies support a model suggesting that Morin inhibits amyloid fibril formation of HEWL by binding to the aggregation prone cleft region of the beta-domain of HEWL, thereby stabilizing the molecule in its native-like state. Interestingly, transmission electron microscopy observations suggest that, along with increases in Morin concentration, the observed amorphous aggregates became larger and morphologically different. We propose that following occupation of the binding cleft, excess Morin adheres and coats the HEWL protein surface, thereby minimizing the interaction between the protein surface and water molecules. PMID- 28341175 TI - Enhanced mechanical and thermal properties of poly (vinyl alcohol)/corn starch blends by nanoclay intercalation. AB - Poly (vinyl alcohol) (PVA)/corn starch blend films with enhanced properties were fabricated by melt processing and montmorillonite (MMT) reinforcing. It was revealed that strong hydrogen bonding occurred between the abundant OH groups of the matrix and polar SiOSi and OH groups of MMT. The highly exfoliated MMT nanolayers were randomly dispersed in the matrix containing MMT lower than 10wt%, whereas the intercalated structure was predominant with MMT content higher than 10wt%. With the increase of MMT, the glass transition temperature as well as equilibrium torque increased. The water sorption decreased and water resistant properties were improved with the incorporation of MMT due to the restricted swelling of the matrix by MMT nanolayers. Significant improvement in strength and flexibility were observed due to the fine dispersion of the MMT layers and the strong interaction between MMT and the matrix. The thermal stability was also improved. The MMT nanolayers could act as the heat and mass transport barriers and retard the thermal decomposition of the composites. PMID- 28341176 TI - Effect of dual modification of sonication and gamma-irradiation on physicochemical and functional properties of lentil (Lens culinaris L.) starch. AB - Starch isolated from lentil was subjected to two treatments namely sonication and, a dual treatment of sonication and irradiation at a dose of 5kGy. Lentil yielded 26.12+/-1.56g starch/100g of lentil. Chemical composition of native starch revealed 7.83+/-0.28% moisture, 0.23+/-0.30% protein, 0.35+/-0.05% fat and 0.10+/-0.00% ash. The results revealed that pasting properties of lentil starch were not affected upon sonication. However, these decreased significantly (p<=0.05) upon dual treatments. Amylose content of native starch was 31.16+/ 1.80g/100g which showed a decrease upon sonication and dual treatments. Sonication and dual treatments (sonication and irradiation) decreased hunter 'L' value while 'a' and 'b' values showed an increase. Syneresis decreased more or less insignificantly upon sonication. However, a significant decrease in syneresis was observed after 120h storage following dual treatments. Sonication did not decrease the functional properties significantly while as dual treatment induced a significant decrease in functional properties. FT-IR analysis revealed a decrease in the intensities of OH, CH and OC stretches and CH2 bending upon sonication and dual treatments. PMID- 28341177 TI - Changes in physicochemical properties and in vitro starch digestion of native and extruded maize flours subjected to branching enzyme and maltogenic alpha-amylase treatment. AB - Extrusion is an increasingly used type of processing which combined with enzymatic action could open extended possibilities for obtaining clean label modified flours. In this study, native and extruded maize flours were modified using branching enzyme (B) and a combination of branching enzyme and maltogenic alpha-amylase (BMA) in order to modulate their hydrolysis properties. The microstructure, pasting properties, in vitro starch hydrolysis and resistant starch content of the flours were investigated. Whereas BMA treatment led to greater number of holes on the granule surface in native samples, B and BMA extruded samples showed rougher surfaces with cavities. A reduction in the retrogradation trend was observed for B and BMA native flours, in opposition to the flat pasting profile of their extruded counterparts. The glucose release increased gradually for native flours as the time of reaction did, whereas for extruded flours a fast increase of glucose release was observed during the first minutes of reaction, and kept till the end, indicating a greater accessibility to their porous structure. These results suggested that, in enzymatically treated extruded samples, changes produced at larger hierarchical levels in their starch structure could have masked a slowdown in the starch digestion properties. PMID- 28341179 TI - The use of non-steroidal anti-inflammatory drugs in neurological diseases. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) have been in use for many years and constitute a large part of prescriptions issued in daily practice. Although NSAIDs are used for many diseases in neurology, they have also been tested as a new therapeutic option for various other diseases. While their effects on headache and cerebrovascular diseases are well known, little is known about their impact on neurodegenerative diseases. This review discusses the use, effects and safety of NSAIDs in neurological diseases. PMID- 28341180 TI - Morphological and morphometrical maturation of ventral cochlear nucleus in human foetus. AB - Auditory impulses perceived by the hair cells of the organ of corti are relayed in the cochlear nucleus, the first relay station in the brainstem, by the cochlear nerve. The human foetus is well known to respond to sound during the last trimester of gestation. On the contrary, studies conducted in rat, cat and mouse have shown that these mammals have an immature auditory system at the time of birth. There are very few reports available regarding the morphological and functional maturation of the cochlear nucleus in human. Although the human cochlear nucleus neurons attain adult morphological characters by mid-gestation, there are hardly any studies discussing the functional maturation of the cochlear nucleus. Hence the present study was aimed at observing the morphological as well as functional maturation of the human foetal cochlear nuclei at various gestational ages. Morphological maturation was observed qualitatively while stereological estimation of the volume of well defined ventral cochlear nucleus (VCN) was calculated by the Cavalieri principle; neuronal count and density was estimated by dissector principle. The functional maturation was assessed by observing the expression of synaptophysin, a synaptic marker, at different gestational ages and by the presence of parvalbumin, a calcium binding functional neuronal marker by immunohistochemistry. Neurons showed coarse Nissl's substance and well developed cell processes and gradual increase in cell size by the 24th 30th gestational week. Synaptophysin labeling in the complete cochlear nucleus was observed at 20 weeks of gestation. Adult pattern of synaptophysin labeling was observed finally at37weeks of gestation. Earliest presence of parvalbumin expression was detected at 16 weeks of gestation and a distinct adult pattern was seen at 37 weeks of gestation. This study concluded that morphological and functional maturation of the human cochlear nuclei occurs simultaneously during mid-gestation which represents the critical period of development and continues up to term. PMID- 28341178 TI - Mechanisms underlying sodium nitroprusside-induced tolerance in the mouse aorta: Role of ROS and cyclooxygenase-derived prostanoids. AB - AIMS: To determine the role of reactive oxygen species (ROS) on sodium nitroprusside (SNP)-induced tolerance. Additionally, we evaluated the role of ROS on NF-kappaB activation and pro-inflammatory cytokines production during SNP induced tolerance. MAIN METHODS: To induce in vitro tolerance, endothelium-intact or -denuded aortic rings isolated from male Balb-c mice were incubated for 15, 30, 45 or 60min with SNP (10nmol/L). KEY FINDINGS: Tolerance to SNP was observed after incubation of endothelium-denuded, but not endothelium-intact aortas for 60min with this inorganic nitrate. Pre-incubation of denuded rings with tiron (superoxide anion (O2-) scavenger), and the NADPH oxidase inhibitors apocynin and atorvastatin reversed SNP-induced tolerance. l-NAME (non-selective NOS inhibitor) and l-arginine (NOS substrate) also prevented SNP-induced tolerance. Similarly, ibuprofen (non-selective cyclooxygenase (COX) inhibitor), nimesulide (selective COX-2 inhibitor), AH6809 (prostaglandin PGF2alpha receptor antagonist) or SQ29584 [PGH2/thromboxane TXA2 receptor antagonist] reversed SNP-induced tolerance. Increased ROS generation was detected in tolerant arteries and both tiron and atorvastatin reversed this response. Tiron prevented tolerance-induced increase on O2- and hydrogen peroxide (H2O2) levels. The increase onp65/NF-kappaB expression and TNF-alpha production in tolerant arteries was prevented by tiron. The major new finding of our study is that SNP-induced tolerance is mediated by NADPH-oxidase derived ROS and vasoconstrictor prostanoids derived from COX-2, which are capable of reducing the vasorelaxation induced by SNP. Additionally, we found that ROS mediate the activation of NF-kappaB and the production of TNF alpha in tolerant arteries. SIGNIFICANCE: These findings identify putative molecular mechanisms whereby SNP induces tolerance in the vasculature. PMID- 28341181 TI - Transcription factor SP1 mediates hyperglycemia-induced upregulation of roundabout4 in retinal microvascular endothelial cells. AB - Roundabout4 (Robo4) is a gene that is expressed specifically in vasculature and is involved in the angiogenesis and integrity of blood vessels. The expression level of Robo4 increases gradually along with the development of diabetic retinopathy (DR). In this study, we explored the mechanism of transcriptional regulation of Robo4 in retinal endothelial cells, and investigated the effects of this regulation on cellular functions under hyperglycemic conditions. Human retinal endothelial cells (HREC) exposed to hyperglycemia were used to detect the expression levels of specificity protein 1 (SP1) and Robo4 by RT-qPCR and western blotting. Small interfering RNA (SiRNA) transfection technology was used to analyze the regulatory relationship between SP1 and Robo4. The effect of transcription factor SP1 on Robo4 promoter activity and the location of SP1 binding sites were investigated using chromatin immunoprecipitation (ChIP) and luciferase assay. Cell migration, monolayer permeability and tube formation assays were performed to demonstrate the role of SP1/Robo4 in regulating HREC functions in hyperglycemic conditions. The results showed that hyperglycemia upregulated the mRNA and protein levels of SP1 and Robo4 in HREC. Depletion of SP1 by siRNA transfection inhibited the hyperglycemia induced overexpression of Robo4. ChIP combined with luciferase assay showed that under hyperglycemic conditions, SP1 significantly increased the transcriptional level of Robo4 via an additional SP1 binding site at -1912/-1908 in the Robo4 promoter. Repressing the SP1/Robo4 pathway effectively mitigated the abnormity in HREC migration, permeability and angiogenesis induced by hyperglycemia. All these findings indicate that hyperglycemia-induced upregulation of Robo4 is mediated by enhanced transcription of SP1. The SP1/Robo4 signaling pathway can regulate the migratory ability, monolayer permeability and angiogenesis of HREC under hyperglycemic conditions, suggesting that it may play an important role in microvascular dysfunction during DR. PMID- 28341182 TI - Systematic identification of key genes and pathways in the development of invasive cervical cancer. AB - BACKGROUND: Cervical cancer progresses through different stages: a long stage of precancerous lesions, then high-grade squamous intraepithelial lesion (HSIL) stage in which precancerous lesions transform into invasive cervical carcinoma, and finally invasive squamous cell carcinomas (SCC) which is difficult to be treated and can be deadly. METHODS AND RESULTS: To identify critical genes for the development and progression of cervical cancer development, we analyzed an online database comprised of normal squamous cervical epithelia samples, HSIL samples and SCC of cervix. Dysregulated genes were identified in both early stage (from normal to HSIL stage) and late stage (from HSIL stage to SCC stage) of cervical cancer. By overlapping these dysregulated genes, we found that three genes, including CDKN2A, IL1R2 and RFC4, were not only changed in HSIL, but also significantly changed in SCC, indicating that their dysregulation may contribute to cervical cancer development. Several altered pathways during tumor progression were also discovered, including those involved in cell proliferation, cell cycle and cell division. CONCLUSIONS: Our findings suggest that dysregulations of CDKN2A, IL1R2 and RFC4 may contribute to cervical cancer progression and they might be potential diagnostic markers and therapeutic drug targets. PMID- 28341183 TI - Transfer of extensor digiti minimi and extensor carpi ulnaris nerve branches to the intrinsic motor nerve branches: A histological study on cadaver. AB - BACKGROUND: In cases of high ulnar and median nerve palsy, result of nerve repair in term of intrinsic muscle recovery is unsatisfactory. Distal nerve transfer can alleviate the regeneration time and improve the results. Transfer of the extensor digiti minimi (EDM) and extensor carpi ulnaris (ECU) nerve branches to the deep branch of ulnar nerve (DBUN)/recurrent branch of median nerve (RMN) at wrist had been used to restore intrinsic hand function but, incomplete recovery occurred. The axon count at the donor nerve has a strong influence on the final results. HYPOTHESIS: This cadaveric study aims to analyses the histology of this nerve transfer to evaluate whether these donor nerves are suitable for this transfer or another donor nerve may be considered. MATERIALS AND METHODS: Ten cadaveric upper limbs dissected to identify the location of the EDM, ECU, RMN and DBUN. Surface area, fascicle count, and axon number was determined by histological methods. RESULTS: The mean of axon number in the EDM, ECU, RMN and DBUN branches was 5931, 7355, 30960 and 35426, respectively. In this study, the number of axons in the EDM and ECU branches was 37% (13281/35426) of that in the DBUN. Also, the number of axons in the EDM and ECU branches was 42% (13281/30960) of that in the RMN. CONCLUSION: The axon count data showed an unfavorable match between the EDM, ECU and DBUN/RMN. Therefore, it is suggested that another donor nerve with higher axon number to be considered. TYPE OF STUDY: Cadaver study (histological study). PMID- 28341184 TI - Global fit concept in revision hip arthroplasty for cementless press-fit femoral stems. AB - A revision stem may be required after a femoral extended trochanteric osteotomy (ETO) is made during revision hip arthroplasty. The two main complications of straight cementless femoral stems are subsidence due to inadequate osteointegration and stress-shielding. We will describe an original revision method with ETO that uses a straight cementless stem. The goal of this method was to achieve the most extensive press-fit possible during stem implantation to improve the transmission of stresses to the bone and to prevent reduction in bone density. The intramedullary preparation was done after closure and fixation of the ETO, which allows impaction of the revision stem with metaphyseal and diaphyseal press-fit. We report encouraging results with preservation of periprosthetic bone stock and good osteointegration of these revision stems at the final follow-up. Pronounced sagittal curvature or large bone defects are contraindications for this technique. PMID- 28341185 TI - C-MAC compared with direct laryngoscopy for intubation in patients with cervical spine immobilization: A manikin trial. AB - INTRODUCTION: The aim of this study was to compare C-MAC videolaryngoscopy with direct laryngoscopy for intubation in simulated cervical spine immobilization conditions. METHODS: The study was designed as a prospective randomized crossover manikin trial. 70 paramedics with <5years of medical experience participated in the study. The paramedics attempted to intubate manikins in 3 airway scenarios: normal airway without cervical immobilization (Scenario A); manual inline cervical immobilization (Scenario B); cervical immobilization using cervical extraction collar (Scenario C). RESULTS: Scenario A: Nearly all participants performed successful intubations with both MAC and C-MAC on the first attempt (95.7% MAC vs. 100% C-MAC), with similar intubation times (16.5s MAC vs. 18s C MAC). Scenario B: The results with C-MAC were significantly better than those with MAC (p<0.05) for the time of intubation (23 s MAC vs. 19 s C-MAC), success of the first intubation attempt (88.6% MAC vs. 100% C-MAC), Cormack-Lehane grade, POGO score, severity of dental compression, device difficulty score, and preferred airway device. Scenario C: The results with C-MAC were significantly better than those with MAC (p<0.05) for all the analysed variables: success of the first attempt (51.4% MAC vs. 100% C-MAC), overall success rate, intubation time (27 s MAC vs. 20.5 s C-MAC), Cormack-Lehane grade, POGO score, dental compression, device difficulty score and the preferred airway device. CONCLUSION: The C-MAC videolaryngoscope is an excellent alternative to the MAC laryngoscope for intubating manikins with cervical spine immobilization. PMID- 28341186 TI - Problem-based learning discussion on advanced life support training for perioperative interprofessional education. PMID- 28341187 TI - Persistent hyperlactatemia-high central venous-arterial carbon dioxide to arterial-venous oxygen content ratio is associated with poor outcomes in early resuscitation of septic shock. AB - OBJECTIVE: Several studies reported Pv-aCO2/Ca-vO2 ratio as a surrogate of VCO2/VO2 to detect global tissue hypoxia. The present study aimed to evaluate the prognostic value of Pv-aCO2/Ca-vO2 ratio combined with lactate levels during the early phases of resuscitation in septic shock. METHODS: A retrospective study was conducted in 144 septic shock patients in a 30-bed mixed ICU. A Pv-aCO2/Ca-vO2 ratio>1.4 was considered abnormal. Patients were classified into four predefined groups according to lactate levels and Pv-aCO2/Ca-vO2 ratio after the first 6h of resuscitation. Sequential Organ Failure Assessment (SOFA) score at day 3 was assessed. A Kaplan-Meier curve showed the survival probabilities at day 28 using a log-rank test to evaluate the differences between groups. A receiver operating characteristics (ROC) curve evaluated the ability of lactate, Pv-aCO2/Ca-vO2 ratio and Pv-aCO2/Ca-vO2 ratio combined with lactate to predict mortality at day 28. RESULTS: Combination of hyperlactatemia and high Pv-aCO2/Ca-vO2 ratio was associated with poor SOFA scores and low survival rates at day 28 (P<0.001). The Cox multivariate survival analysis demonstrated that Pv-aCO2/Ca-vO2 ratio and lactate at T6 were independent predictors of mortality at day 28. The area under the ROC curve of the Pv-aCO2/Ca-vO2 ratio combined with lactate for predicting mortality at day 28 was highest and superior to that of lactate and Pv-aCO2/Ca vO2 ratios. CONCLUSION: Combination of Pv-aCO2/Ca-vO2 ratio and lactate at early stages of resuscitation of septic shock can better predict the prognosis of patients. The Pv-aCO2/Ca-vO2 ratio may become a useful parameter supplementary to lactate in the resuscitation of septic shock. PMID- 28341188 TI - Features of hospital and emergency medical service in out-of-hospital cardiac arrest patients with shockable rhythm. AB - OBJECTIVE: Predicting the outcome of out-of-hospital cardiac arrest (OHCA) patients is crucial. We examined hospital characteristics and parameters of emergency medical service (including scene time interval and direct ambulance delivery to intensive heart hospitals) as survival or outcome predictors. STUDY DESIGN: Data from 546 consecutive OHCA shockable patients treated between January 2012 and December 2015 in Taoyuan City (Taiwan, ROC) were collected. In addition to demographic data, location of arrest, initial rhythm, availability of a hospital with or without 24/7 percutaneous coronary intervention (PCI), emergency medical service (EMS) time, provision of cardiopulmonary resuscitation by a bystander, presence of a witness at collapse, and level of life support were analysed. RESULTS: Multivariate analysis showed that hospitalisation with immediate PCI availability was an independent predictor (OR: 4.32; 95% CI: 1.27 14.70) solely for the outcome of survival until discharge. The presence of a witness while collapsing (OR: 3.52; 95% CI: 1.03-11.98), EMS response time (OR: 0.83; 95% CI: 0.70-0.98), and scene time interval (STI; OR: 0.89; 95% CI: 0.81 0.99) were valuable for predicting the neurological outcome. CONCLUSIONS: Direct ambulance delivery to intensive heart hospitals that had 24/7 PCI availability was associated with a higher probability of surviving until discharge in OHCA patients with shockable rhythms. Similarly, a witnessed collapse was correlated with being discharged alive from hospital and recovering with good cerebral performance. In addition, longer response time and scene time interval indicated poorer survival and neurological outcome. PMID- 28341189 TI - Cost savings and the HEART pathway: The author responds. PMID- 28341190 TI - Evolving cutoff values of "hyperlactatemia" and the role of infection. PMID- 28341191 TI - [Bacillus cereus endocarditis and a probable cutaneous gateway]. AB - BACKGROUND: Bacillus cereus is a ubiquitous telluric organism. B. cereus endocarditis is a rare condition seen mostly in prosthetic heart valves and among intravenous drug users. We report a new case of a patient without risk factors and with a good clinical outcome not requiring valve replacement. CASE REPORT: In October 2014, a 50-year-old woman was referred to the dermatology department of Lille University Hospital for lower-limb wounds developing 6 months earlier. She presented fever without clinical signs of infection, except for the lower-limbs wounds. Blood cultures revealed the presence of B. cereus. Transesophageal echocardiography was performed and revealed two foci of aortic valve vegetation with a diameter of 5mm. After bacterial sensitivity testing, rifampicin and levofloxacin treatment was given for six weeks, with complete remission. A skin graft was performed and good improvement was seen. DISCUSSION: Nineteen cases of B. cereus endocarditis have been described previously, only one of which was without risk factors. We described a case of complete remission after a 6-week course of antibiotics. Our case demonstrates that BC should not be considered as a blood culture contamination, and that treatment may be complex due to antibiotic resistance. PMID- 28341192 TI - Potential Infection Control Risks Associated with Ultrasound Equipment - A Bacterial Perspective. AB - Ultrasound equipment used in trans-abdominal (TA) and trans-vaginal (TV) examination may carry bacterial contamination and pose risks to infection control during ultrasound examination. We aimed to describe the prevalence of bacterial contamination on ultrasound probes, gel, machine keyboard and cords and examined the effectiveness of low- and high-level disinfection techniques. This study was performed at a public hospital and a private practice. A total of 171 swabs were analyzed and bacterial species were identified using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) analysis and polymerase chain reaction (PCR). Sixty percent of TA probes and 14% of TV probes had evidence of bacterial contamination after an ultrasound examination. Low-level disinfection was partially effective, but 4% of probes were still contaminated by spore forming species. Some heated gel samples were highly contaminated with the environmental bacterium Brevundimonas aurantiaca, suggesting the gel was conducive to bacterial growth. Ultrasound machines, probe cords and gels were identified as potential sources of bacterial contamination and need to be cleaned and changed regularly to minimize risks of infection. PMID- 28341193 TI - Is Grey Level a Suitable Alternative to Low-Contrast Penetration as a Serial Measure of Sensitivity in Computerised Ultrasound Quality Assurance? AB - The aim of this study was to test the hypothesis that grey levels are a suitable alternative measure of sensitivity in ultrasound imaging quality assurance, as there are several caveats in the use of penetration depth. In a primary cohort of nine probes, where measurements had been made for 6 to 34 mo, both penetration depth and mean grey level fell below tolerance for six probes; both penetration depth and mean grey level remained within tolerance for three probes. In a secondary cohort where a measurement programme had been in place for a shorter period, grey level and/or penetration depth fell below tolerance in 15 of 66 probes; the sensitivity and specificity of at least 10% loss of grey level in predicting >5% loss in penetration depth were 91% and 93%, respectively. A loss of grey level accompanies a loss of penetration and provides a suitable alternative measure of sensitivity. PMID- 28341194 TI - Outcomes of open staged corrective surgery in the setting of adult spinal deformity. AB - BACKGROUND CONTEXT: Adult spinal deformity (ASD) represents a constellation of complex malalignments affecting the spinal column. Corrective surgical procedures aimed at improving ASD can be equally challenging, and commonly require multiple index procedures and potential revisions before definitive management. There is a paucity of data comparing the outcomes of same-day(simultaneous [SIM]) and 2-day (staged [STA]) procedures for long spinal fusions for ASD. Using a large patient cohort with surgeon- and patient-reported outcomes will be particularly useful in determining the utility and effect of staging long spinal fusions for ASD. PURPOSE: This study aimed to compare intraoperative, perioperative, and 2-year outcomes of STA and SIM procedures correcting ASD. STUDY DESIGN: This is a retrospective analysis of a prospective multicenter database. PATIENT SAMPLE: A total of 142 patients (71 STA, 71 SIM) were included. OUTCOME MEASURES: Primary outcome measures were intra- and perioperative (6 weeks) complication rates. Secondary outcome measures were 2-year thoracolumbar and spinopelvic radiographic parameters, 2-year health-related quality of life (HRQoL) changes (Oswestry Disability Index [ODI] and Short Form-36 [SF-36]), and 2-year complication rates. METHODS: Inclusion criteria included patients with ASD >=18 years with 6-week and 2-year follow-up. Propensity score matching identified similar patients undergoing STA or SIM long spinal fusions based on surgical invasiveness, pelvic tilt, and sagittal vertical axis (SVA). Complications, HRQoL scores (Scoliosis Research Society-22 Patient Questionnaire [SRS-22r], SF-36, ODI), and patient characteristics were compared across and within treatment groups at follow-up with analysis of variance (ANOVA) and paired t tests at three surgical stages: intraoperatively, perioperatively (6 weeks), and postoperatively (>6 weeks). RESULTS: A total of 142 patients were included (71 STA, 71 SIM). Matching STA and SIM groups based on degree of deformity and surgical invasiveness created two groups similar in overall correction of the surgery. Patients undergoing STA underwent more anterior lumbar interbody fusion (ALIF) and lateral lumbar interbody fusion (LLIF) procedures, whereas patients undergoing SIM had longer fusions. Charlson comorbidity index and revision status were similar between groups (p>.05). Staging procedures had significantly more complications causing reoperation (STA: 47% vs. SIM: 8%, p=.021), and had a greater number of perioperative complications requiring a return to the operating room (OR) (STA: 9.9% vs. SIM: 1.4%, p=.029). There was no difference in intraoperative complications, mortality, or perioperative infection or wound complications (p>.05) between the two procedures. At 2-year follow-up, incidence of revision surgery was higher in STA (STA: 21.1% vs. SIM: 8.5%, p=.033). CONCLUSION: Staged spinal fusions, which add ALIFs and LLIFs to the procedure, compared with similar correction SIM procedures, result in similar intraoperative complication incidence, but significantly higher rates of peri- and postoperative complications leading to revision. Functional outcomes, radiographic parameters, and mortality were similar. This will aid surgeons in their determination of the optimal treatment for such complex procedures. PMID- 28341195 TI - Methylenetetrahydrofolate Reductase (MTHFR) (C677T and A1298C) Polymorphisms and Vascular Complications in Patients with Type 2 Diabetes. AB - OBJECTIVES: To assess whether 2 polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, are risk factors for vascular complications in Tunisian patients with type 2 diabetes mellitus. METHODS: The MTHFR polymorphisms were genotyped, and plasma homocysteine levels were evaluated in 160 Tunisian patients with type 2 diabetes mellitus. RESULTS: Prevalence of the 2 heterozygous polymorphisms of the thermolabile MTHFR gene (CT and AC) was encountered more commonly in patients with diabetes mellitus than in the healthy controls (p<10-3). Subjects with diabetes had significantly higher homocysteine (Hcy) levels than the control subjects; however, there was no statistical difference in plasma Hcy values between carriers of mutant genotypes (CT/TT for C677T and AC/CC for A1298C) and wild types (CC and AA) in patients with diabetes. Retinopathy was found to be a vascular complication in patients with either the 677CT or the 1298(AC+CC) genotype more commonly than in those with the wild-type genotypes (p=0.003; OR=3.2, 95% CI, 1.4 to 7.4; p<10-3; OR=5.9, 95% CI, 2.7 to 13). Only patients who carry the A1298C mutation (AC+CC) are at risk for at least 1 complication (p=0.002). Double heterozygous mutants were at the greatest risk for retinopathy and for suffering at least 1 complication (p<10-3). CONCLUSIONS: Studies involving a larger study population and various ethnic groups are required before ruling out the role of MTHFR gene in type 2 diabetes mellitus and in vascular complications. PMID- 28341196 TI - The use of intraosseous needles for injection of contrast media for computed tomographic angiography of the thoracic aorta. AB - BACKGROUND: The objective of this study is to evaluate the safety and quality of computed tomographic angiography of the thoracic aorta (CTA-TA) exams performed using intraosseous needle intravenous access (ION-IVA) for contrast media injection (CMI). METHODS: All CTA-TA exams at the study institution performed between 1/1/2013 and 8/14/2015 were reviewed retrospectively to identify those exams which had been performed using ION-IVA (ION-exams). ION-exams were then analyzed to determine aortic attenuation and contrast-to-noise ratio (CNR). Linear regression was used to determine how injection rate and other variables affected image quality for ION-exams. Patient electronic medical records were reviewed to identify any adverse events related to CTA-TA or ION-IVA. RESULTS: 17 (~0.2%) of 7401 exams were ION-exams. ION-exam CMI rates varied between 2.5 and 4 ml/s. Mean attenuation was 312 HU (SD 88 HU) and mean CNR was 25 (SD 9.9). A strong positive linear association between attenuation and injection rate was found. No immediate or delayed complications related to the ION-exams, or intraosseous needle use in general, occurred. CONCLUSION: For CTA-TA, ION-IVA appears to be a safe and effective route for CMI at rates up to 4 ml/s. PMID- 28341197 TI - Label-free quantitative proteomics unravels the importance of RNA processing in glioma malignancy. AB - Glioma, one of the most common cancers in human, is classified to different grades according to the degrees of malignancy. Glioblastoma (GBM) is known to be the most malignant (Grade IV) whereas low-grade astrocytoma (LGA, Grade II) is relatively benign. The mechanism underlying the pathogenesis and progression of glioma malignancy remains unclear. Here we report a quantitative proteomic study to elucidate the differences between GBM and LGA using liquid chromatography and tandem mass spectrometry followed by label-free quantification. A total of 136 proteins were differentially expressed in GBM for at least five folds in comparison with LGA. Ontological analysis revealed a close correlation between GBM-associated proteins and RNA processing. Interaction network analysis indicated that the GBM-associated proteins in the RNA processing were linked to crucial signaling transduction modulators including epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 1 (STAT1), and mitogen-activated protein kinase 1 (MAPK1), which were further connected to the proteins important for neuronal structural integrity, development and functions. Upregulation of 40S ribosomal protein S5 (RPS5), Ferritin Heavy chain (FTH1) and STAT1, and downregulation of tenascin R (TNR) were validated as representatives by immune assays. In summary, we revealed a panel of GBM-associated proteins and the important modulators centered at the RNA-processing network in glioma malignancy that may become novel biomarkers and help elucidate the underlying mechanism. PMID- 28341199 TI - Quantitative Magnetic Resonance Diffusion-Weighted Imaging Evaluation of the Supratentorial Brain Regions in Patients Diagnosed with Brainstem Variant of Posterior Reversible Encephalopathy Syndrome: A Preliminary Study. AB - BACKGROUND AND PURPOSE: Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiologic entity with several causes, characterized by rapid onset of symptoms and typical neuroimaging features, which usually resolve if promptly recognized and treated. Brainstem variant of PRES presents with vasogenic edema in brainstem regions on magnetic resonance (MR) images and there is sparing of the supratentorial regions. Because PRES is usually caused by a hypertensive crisis, which would likely have a systemic effect and global manifestations on the brain tissue, we thus proposed that some microscopic abnormalities of the supratentorial regions could be detected with diffusion-weighted imaging (DWI) using apparent diffusion coefficient (ADC) analysis in brainstem variant of PRES and hypothesized that "normal-looking" supratentorial regions will increase water diffusion. METHODS: We retrospectively identified patients with PRES who underwent brain magnetic resonance imaging studies. We identified 11 brainstem variants of PRES patients, who formed the study cohort, and 11 typical PRES patients and 20 normal control subjects as the comparison cohorts for this study. Nineteen regions of interest were drawn and systematically placed. The mean ADC values were measured and compared among these 3 groups. RESULTS: ADC values of the typical PRES group were consistently elevated compared with those in normal control subjects. ADC values of the brainstem variant group were consistently elevated compared with those in normal control subjects. ADC values of the typical PRES group and brainstem variant group did not differ significantly, except for the pons area. CONCLUSIONS: Quantitative MR DWI may aid in the evaluation of supratentorial microscopic abnormalities in brainstem variant of PRES patients. PMID- 28341200 TI - Clinical Characteristics of Stroke Occurring while Bathing. AB - BACKGROUND: Stroke can occur during any human activity. Although cardiac arrests or drowning accidents while bathing have been studied extensively, there are few studies focusing on stroke occurring while bathing. The objectives of this study were to evaluate the clinical characteristics of stroke occurring while bathing and the association between stroke and drowning accidents. METHODS: Clinical data prospectively acquired between January 2011 and December 2015 on 1939 patients with stroke (1224 cerebral infarctions [CIs], 505 intracerebral hemorrhages [ICHs], and 210 subarachnoid hemorrhages [SAHs]) were reviewed to identify patients who sustained a stroke while bathing. The ratio of bathing-related strokes to strokes occurring during other activities was evaluated. Moreover, the demographics of these 2 groups were compared in each stroke type. RESULTS: Among the 1939 patients, 78 (CI, 32; ICH, 28; and SAH, 18) sustained a stroke while bathing. The ratio of bathing to other activities in the SAH group was the highest (8.6%), followed by the ICH group (5.5%), whereas that in the CI group was the lowest (2.6%). Regardless of stroke type, only a minority of patients were found to have collapsed inside the bathtub. CONCLUSIONS: The higher ratio of bathing in hemorrhagic strokes may indicate that there is a small risk of hemorrhagic stroke while bathing in vulnerable subjects. This retrospective study did not establish a causal relationship between bathing and stroke nor identify risk factors, which means that future prospective studies are warranted. The finding that the great majority of bathing-related stroke patients were found to have collapsed outside the bathtub suggests that the involvement of stroke in drowning accidents in the bathtub may be small. PMID- 28341201 TI - The ATM kinase inhibitor KU-55933 provides neuroprotection against hydrogen peroxide-induced cell damage via a gammaH2AX/p-p53/caspase-3-independent mechanism: Inhibition of calpain and cathepsin D. AB - The role of the kinase ataxia-telangiectasia mutated (ATM), a well-known protein engaged in DNA damage repair, in the regulation of neuronal responses to oxidative stress remains unexplored. Thus, the neuroprotective efficacy of KU 55933, a potent inhibitor of ATM, against cell damage evoked by oxidative stress (hydrogen peroxide, H2O2) has been studied in human neuroblastoma SH-SY5Y cells and compared with the efficacy of this agent in models of doxorubicin (Dox)- and staurosporine (St)-evoked cell death. KU-55933 inhibited the cell death induced by H2O2 or Dox but not by St in undifferentiated (UN-) and retinoic acid differentiated (RA)-SH-SY5Y cells, with a more pronounced effect in the latter cell phenotype. Furthermore, this ATM inhibitor attenuated the Dox- but not H2O2 induced caspase-3 activity in both UN- and RA-SH-SY5Y cells. Although KU-55933 inhibited the H2O2- and Dox-induced activation of ATM, it attenuated the toxin induced phosphorylation of the proteins H2AX and p53 only in the latter model of cell damage. Moreover, the ATM inhibitor prevented the H2O2-evoked increases in calpain and cathepsin D activity and attenuated cell damage to a similar degree as inhibitors of calpain (MDL28170) and cathepsin D (pepstatin A). Finally, we confirmed the neuroprotective potential of KU-55933 against the H2O2- and Dox evoked cell damage in primary mouse cerebellar granule cells and in the mouse hippocampal HT-22 cell line. Altogether, our results extend the neuroprotective portfolio of KU-55933 to a model of oxidative stress, with this effect not involving inhibition of the gammaH2AX/p-p53/caspase-3 pathway and instead associated with the attenuation of calpain and cathepsin D activity. PMID- 28341202 TI - Tumor necrosis factor-alpha did not enhance alpha-smooth muscle actin expression in fibroblastic cell cultures derived from healthy donors. PMID- 28341203 TI - Nosocomial nontuberculous mycobacteria infections associated with heater-cooler devices. PMID- 28341204 TI - The economic cost of respiratory disease in the UK. PMID- 28341205 TI - Autism-like behavior in the BTBR mouse model of autism is improved by propofol. AB - Autism spectrum disorder (ASD) is a developmental disorder that is characterized by symptoms of impaired social interactions, restricted interests and repetitive behaviors. Recent studies in humans and animal-models suggest that reduced GABAergic neurotransmission in the brain may underlie autism-related behavioral symptoms. It has been shown that propofol, a commonly used anesthetic, facilitates gamma-aminobutyric acid-mediated inhibitory synaptic transmission. The present study investigated whether propofol improved autistic phenotypes in BTBR T + Itpr3tf/J (BTBR) mice, a model of idiopathic autism. We found that i.p. injection of propofol in BTBR mice significantly improved aspects of social approach and repetitive behaviors without affecting reciprocal social interactions and without any detrimental effects in C57BL/6J mice. The ability of propofol to improve autistic phenotypes in BTBR mice through GABAergic neurotransmission suggests a potential pharmacological target for interventions to treat symptoms of autism. PMID- 28341207 TI - Transcriptome analysis of airborne PM2.5-induced detrimental effects on human keratinocytes. AB - Ambient air pollution is becoming more severe worldwide, posing a serious threat to human health. Fine airborne particles of particulate matter (PM2.5) show higher cytotoxicity than other coarse fractions. Indeed, PM2.5 induces cardiovascular or respiratory damage; however, few studies have evaluated the detrimental effect of PM2.5 to normal human skin. We used a next-generation sequencing-based (RNA-Seq) method with transcriptome and Gene Ontology (GO) enrichment analysis to determine the harmful influences of PM2.5 on human normal epidermal keratinocytes. DAVID analysis showed that the most significantly enriched GO terms were associated with epidermis-related biological processes such as "epidermis development (GO: 0008544)" and "keratinocyte differentiation (GO: 0030216)", suggesting that PM2.5 has some deleterious effects to the human epidermis. In addition, Ingenuity Pathway Analysis predicted inflammation-related signaling as one of the major PM2.5-induced signaling pathways, and pro inflammatory cytokines as upstream regulators with symptoms similar to psoriasis as downstream effects. PM2.5 caused considerable changes in the expression of pro inflammatory cytokines and psoriatic skin disease-related genes, might lead to epidermal dysfunctions. Our results might help to understand the mechanism of air pollution-induced skin barrier perturbation and contribute to the development of a new strategy for the prevention or recovery of the consequent damage. PMID- 28341208 TI - Geometry of carbon nanotubes and mechanisms of phagocytosis and toxic effects. AB - A review of in vivo and in vitro toxicological studies of the potential toxic effects of carbon nanotubes is presented along with the analysis of experimental data and a hypothesis about the nanotube-asbestos similarity. Developments of the structure-activity paradigm have been reviewed along with the size effects and the classification of carbon nanotubes into eleven distinct classes (e.g., the high aspect ratio nanotubes, thick multi-wall nanotubes and short nanotubes). Scaling analysis of similarities between different classes of carbon nanotubes and asbestos fibers in the context of their potential toxicity and the efficiency of phagocytosis has been reviewed. The potential toxic effects of carbon nanotubes have been characterized by their normalized length, their aspect ratio and other parameters related to their inhalability, engulfment by macrophages and the effectiveness of phagocytosis. Geometric scaling parameters and the classification of carbon nanotubes are used to develop an updated parametric map for the extrapolation of the potential toxic effects resulting from the inhalation of long and short carbon nanotubes. An updated parametric map has been applied to the evaluation of the efficiency of phagocytosis involving distinct classes of carbon nanotubes. A critical value of an important nondimensional parameter characterizing the efficiency of phagocytosis for different nanotubes is presented along with its macrophage-based normalization. The present evaluation of the potential toxicological effects of the high aspect ratio carbon nanotubes is found to be in the agreement with other available studies and earlier scaling analyses. PMID- 28341209 TI - A non-zero variance of Tajima's estimator for two sequences even for infinitely many unlinked loci. AB - The population-scaled mutation rate, theta, is informative on the effective population size and is thus widely used in population genetics. We show that for two sequences and n unlinked loci, the variance of Tajima's estimator (theta^), which is the average number of pairwise differences, does not vanish even as n >infinity. The non-zero variance of theta^ results from a (weak) correlation between coalescence times even at unlinked loci, which, in turn, is due to the underlying fixed pedigree shared by gene genealogies at all loci. We derive the correlation coefficient under a diploid, discrete-time, Wright-Fisher model, and we also derive a simple, closed-form lower bound. We also obtain empirical estimates of the correlation of coalescence times under demographic models inspired by large-scale human genealogies. While the effect we describe is small (Vartheta^/theta2~ONe-1), it is important to recognize this feature of statistical population genetics, which runs counter to commonly held notions about unlinked loci. PMID- 28341198 TI - Cholesterol Levels Are Associated with 30-day Mortality from Ischemic Stroke in Dialysis Patients. AB - BACKGROUND: We investigated the impact of serum cholesterol levels on 30-day mortality after ischemic stroke in dialysis patients. METHODS: From the Taiwan Stroke Registry data, we identified 46,770 ischemic stroke cases, including 1101 dialysis patients and 45,669 nondialysis patients from 2006 to 2013. RESULTS: Overall, the 30-day mortality was 1.46-fold greater in the dialysis group than in the nondialysis group (1.75 versus 1.20 per 1000 person-days). The mortality rates were 1.64, .62, 2.82, and 2.23 per 1000 person-days in dialysis patients with serum total cholesterol levels of <120 mg/dL, 120-159 mg/dL, 160-199 mg/dL, and >=200 mg/dL, respectively. Compared to dialysis patients with serum total cholesterol levels of 120-159 mg/dL, the corresponding adjusted hazard ratios of mortality were 4.20 (95% confidence interval [CI] = 1.01-17.4), 8.06 (95% CI = 2.02-32.2), and 6.89 (95% CI = 1.59-29.8) for those with cholesterol levels of <120 mg/dL, 160-199 mg/dL, and >=200 mg/dL, respectively. CONCLUSIONS: Dialysis patients with serum total cholesterol levels of >=160 mg/dL or <120 mg/dL on admission are at an elevated hazard of 30-day mortality after ischemic stroke. PMID- 28341213 TI - Lung Cancer Screening Practices in North Carolina CT Facilities. AB - BACKGROUND: The burden of lung cancer in the United States is staggering, with more Americans dying from lung cancer than the next four most common cancers combined. With endorsement of lung cancer screening by the United States Preventive Services Task Force and reimbursement by CMS, the number screened for lung cancer with low-dose CT (LDCT) is anticipated to rise in the near future. METHODS: In 2015, we conducted a cross-sectional study of mailed surveys to 112 ACR CT facilities across North Carolina to examine recommended guidelines for lung cancer screening, referral patterns, and patient tracking methods. We describe the survey results and compare findings with surveys of academic medical centers. RESULTS: Among 48 respondents (response rate = 42.9%), 54.2% offer lung cancer screening with LDCT (93.1% community and 6.9% academic settings); of these, 70.8% use ACR/CMS guidelines. In lung cancer screening facilities, reported patient volumes are low (average eight patients screened per month, range: 0-30) and patient tracking occurs in 72% of facilities. CONCLUSIONS: Among our predominately community-based sample of facilities, we found variation in lung cancer screening guideline usage, number of patients screened, and tracking methods. PMID- 28341214 TI - The Long Arms of Radiology: Emergence of Radiologists as Public Health Practitioners. PMID- 28341206 TI - Alcohol and basal ganglia circuitry: Animal models. AB - Brain circuits that include the cortex and basal ganglia make up the bulk of the forebrain, and influence behaviors related to almost all aspects of affective, cognitive and sensorimotor functions. The learning of new actions as well as association of existing action repertoires with environmental events are key functions of this circuitry. Unfortunately, the cortico-basal ganglia circuitry is also the target for all drugs of abuse, including alcohol. This makes the circuitry susceptible to the actions of chronic alcohol exposure that impairs circuit function in ways that contribute to cognitive dysfunction and drug use disorders. In the present review, we describe the connectivity and functions of the associative, limbic and sensorimotor cortico-basal ganglia circuits. We then review the effects of acute and chronic alcohol exposure on circuit function. Finally, we review studies examining the roles of the different circuits and circuit elements in alcohol use and abuse. We attempt to synthesize information from a variety of studies in laboratory animals and humans to generate hypotheses about how the three circuits interact with each other and with the other brain circuits during exposure to alcohol and during the development of alcohol use disorders. This article is part of the Special Issue entitled "Alcoholism". PMID- 28341210 TI - Chronic Kidney Disease and Subclinical Brain Infarction Increase the Risk of Vascular Cognitive Impairment: The Sefuri Study. AB - BACKGROUND AND PURPOSE: The purpose of this study was to determine the complex associations among chronic kidney disease (CKD), subclinical brain infarction (SBI), and cognitive impairment. METHODS: We used structural equation modeling (SEM) to examine the complex relationships among CKD, SBI, and cognitive function with Mini-Mental State Examination (MMSE; global function) and modified Stroop test (executive function) in a population-based cohort of 560 non-demented elderly subjects. RESULTS: Path analysis based on SEM revealed that the direct paths from estimated glomerular filtration rate (eGFR) to SBI and from SBI to executive function were significant (beta = -.10, P = .027, and beta = .16, P < .001, respectively). Furthermore, the direct path from eGFR to executive function was also significant (beta = -.12, P = .006), indicating that the effects of CKD on executive function are independent of SBI. The direct paths from age and education to global cognitive function were highly significant (beta = -.17 and .22, respectively, P < .001), whereas the direct path from eGFR to MMSE was not significant. CONCLUSIONS: Our findings indicate that CKD confers a risk of vascular cognitive impairment or executive dysfunction through mechanisms dependent and independent of SBI. Treating CKD may be a potential strategy to protect against vascular cognitive impairment or executive dysfunction in healthy elderly subjects. PMID- 28341215 TI - Identification and molecular characterization of cytochrome P450 (CYP450) family genes in the marine ciliate Euplotes crassus: The effect of benzo[a]pyrene and beta-naphthoflavone. AB - Marine ciliate Euplotes crassus, a single-cell eukaryote, and has been considered as a model organism for monitoring of environmental pollutions in sediments. Cytochrome P450 (CYP450) monooxygenase are phase I enzyme involved in detoxification of environmental pollutants, such as polycyclic aromatic hydrocarbons (PAHs). However, little information on CYP450 family genes in ciliate is available. In the present study, acute toxicity of PAH, benzo[a]pyrene (B[a]P) and PAH-like model compound, beta-naphthoflavone (beta-NF), was investigated; full-length cDNA sequences and genomic structure of five CYP450 genes (CYP5680A1, CYP5681A1, CYP5681B1, CYP5682A1, and CYP5683A1) were analyzed; and finally their activities and transcriptional changes were measured after exposure to PAHs for 48h. According to the results, B[a]P exposure showed a negative effect on E. crassus survival, whereas beta-NF exposure showed no significant effect. The 8h-LC50 value of B[a]P was determined to be 2.449MUM (95% C.L., 7.726-3.619MUM). Five genes belonging to the CYP450 family had conserved domains and clustered with those of ciliate group, as revealed in phylogenetic analysis. CYP activity did not change after exposure to B[a]P, whereas it was slightly, but significantly, induced after exposure to beta-NF. The mRNA expression of five CYP450 genes was significantly modulated in a concentration- and time-dependent manner after exposure to both the chemicals. Our findings suggest that CYP450 genes in E. crassus may be involved in detoxification of B[a]P and beta-NF. This study would give a better understanding about the mode of action of B[a]P and beta-NF in marine ciliates at the molecular level. PMID- 28341216 TI - Effects of methimazole on Drosophila glucolipid metabolism in vitro and in vivo. AB - Methimazole (MMI) is an antithyroid agent widely used in the treatment of hyperthyroidism, and metabolized by cytochrome P450 enzymes and flavin-containing monooxygenases in mammals. However, drug overdose and the inadequate detoxification of the metabolite(s) are responsible for hepatocellular damage and organ dysfunction. Depending on the desired properties, Drosophila melanogaster has recently emerged as an ideal model organism for the study of human diseases. Here we investigated the changes in metabolic profiles and mRNA expressions related to glucolipid metabolism in response to treatment with MMI in Drosophila. Remarkable loss of lifespan occurred in fruit flies fed on the diets containing 10 or 30mM MMI compared to unsupplemented controls. To examine whether MMI affects glucolipid metabolism in vitro and in vivo, fruit flies were fed diets containing 30mM MMI for two weeks and Drosophila S2 cells were incubated with 300MUM MMI for 48h. Measurements of metabolites showed that triglyceride content dramatically decreased (30.56% in vivo and 18.13% in vitro), and glycogen content significantly increased (10.7% in vivo and 126.8% in vitro). Quantitative analyses indicated that mRNA expression levels of Dmfmo1, s6k, dilp2, acc and dilp5 genes involved in metabolic homeostasis were remarkably down-regulated in vivo and in vitro. Meanwhile, the addition of MMI could significantly reduce the lipid droplet content in S2 cells by approximately 25% compared to control subjects. These data may provide a biological basis for the study of MMI on disease symptoms and complications, and discovery of therapeutic treatments. PMID- 28341217 TI - Lemmel's syndrome: Obstructive jaundice secondary to a duodenal diverticulum. PMID- 28341218 TI - [A Third nerve palsy that reveals a diffuse large B cell lymphoma in an octogenarian patient]. PMID- 28341219 TI - [Patients with cognitive impairment and falls in a psychogeriatric clinic]. PMID- 28341220 TI - National Academy of Medicine Social and Behavioral Measures: Associations With Self-Reported Health. AB - INTRODUCTION: Social and behavioral factors play important roles in physical and mental health; however, they are not routinely assessed in the healthcare system. A brief panel of measures of social and behavioral determinants of health (SBDs) were recommended in a National Academy of Medicine report for use in electronic health records. Initial testing of the panel established feasibility of use and robustness of the measures. This study evaluates their convergent and divergent validity in relation to self-reported physical and mental health and social desirability bias. METHODS: Adults, aged >=18 years, were recruited through Qualtrics online panel survey platform in 2015 (data analyzed in 2015-2016). Participants completed the (1) panel of SBD measures; (2) 12-Item Short Form Health Survey to assess associations with global physical and mental health; and (3) Marlowe-Crowne Social Desirability Scale short form to assess whether social desirability influenced associations between SBD measures and self-reported health. RESULTS: The sample included 513 participants (mean age, 47.9 [SD=14.2] years; 65.5% female). Several SBD domain measures were associated with physical and mental health. Adjusting for age, poorer physical and mental health were observed among participants reporting higher levels of financial resource strain, stress, depression, physical inactivity, current tobacco use, and a positive score for intimate partner violence. These associations remained significant after adjustment for social desirability bias. CONCLUSIONS: SBD domains were associated with global measures of physical and mental health and were not impacted by social desirability bias. The panel of SBD measures should now be tested in clinical settings. PMID- 28341221 TI - A Systematic Review of Obesity Disparities Research. AB - CONTEXT: A review of interventions addressing obesity disparities could reveal gaps in the literature and provide guidance on future research, particularly for populations with a high prevalence of obesity and obesity-related cardiometabolic risk. EVIDENCE ACQUISITION: A systematic review of clinical trials in obesity disparities research that were published in 2011-2016 in PubMed/MEDLINE resulted in 328 peer-reviewed articles. Articles were excluded if they had no BMI, weight, or body composition measure as primary outcome or were foreign (n=201); were epidemiologic or secondary data analyses of clinical trials (n=12); design or protocol papers (n=54); systematic reviews (n=3); or retracted or duplicates (n=9). Forty-nine published trials were summarized and supplemented with a review of ongoing obesity disparities grants being funded by the National, Heart, Lung and Blood Institute. EVIDENCE SYNTHESIS: Of the 49 peer-reviewed trials, 27 targeted adults and 22 children only or parent-child dyads (5 of 22). Interventions were individually focused; mostly in single settings (e.g., school or community); of short duration (mostly <=12 months); and primarily used behavioral modification (e.g., self-monitoring) strategies. Many of the trials had small sample sizes and moderate to high attrition rates. A meta-analysis of 13 adult trials obtained a pooled intervention effect of BMI -1.31 (95% CI=-2.11, -0.52, p=0.0012). Institutional review identified 140 ongoing obesity-related health disparities grants, but only 19% (n=27) were clinical trials. CONCLUSIONS: The reviews call for cardiovascular-related obesity disparities research that is long term and includes population research, and multilevel, policy, and environmental, or "whole of community," interventions. PMID- 28341222 TI - The science and ethics of cell-based therapies for Parkinson's disease. AB - Parkinson's Disease (PD) is an age-related, disabling neurodegenerative disorder. Although sufferers usually respond to dopamine agonists for extended periods, the disease remains progressive and adverse drug effects can compromise effective long term treatment. Cell-based therapies have been the subject of much hype and optimism with regard to PD. Proof of principle was provided in the 1980s with fetal tissue transplantation trials demonstrating successful graft survival. Embryonic stem cells and reprogrammed or transdifferentiated somatic cells may provide alternative sources of tissue with the potential to overcome the material shortages and technical difficulties that have hindered fetal neural transplants. This article will review the state of the science for cell based therapies and examine the ethical issues that societies must negotiate regarding their clinical use. PMID- 28341223 TI - A novel mutation of CHCHD2 p.R8H in a sporadic case of Parkinson's disease. PMID- 28341224 TI - Palliative care and its emerging role in Multiple System Atrophy and Progressive Supranuclear Palsy. AB - Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) are sporadic, neurodegenerative conditions and belong to a group known as the atypical Parkinsonian disorders. The atypical Parkinsonian (AP) disorders have some features of idiopathic Parkinson's disease (PD) but often with poor or transient levodopa response [1], distinct symptom profiles, more rapid progression and reduced survival. They have significant symptom burden [2]. It is beginning to be appreciated that AP disorders not only carry a heavy symptom burden equivalent to that of patients with advanced cancer but that AP patients experience significant morbidity for an extended period of time. PSP and MSA patients reach clinical milestones such as wheelchair-dependence or frequent falls early in the course of their disease and can live with these accumulating burdens for some years [3]. The acknowledgement of the benefits of emphasizing quality of life in progressive disorders and the growing evidence for palliative care need in non-malignant conditions suggests that MSA and PSP would benefit from an integrated palliative approach. Studies to determine palliative need and possibility of benefit from intervention are beginning to yield results in Parkinsonian conditions. This review aims to discuss the trajectory of disease in MSA and PSP, explore significant symptoms and summarize some evidence which exists for palliative care need and quality of life in these conditions. The challenges of a palliative approach with this group including advance care planning will also be discussed. PMID- 28341225 TI - Improved Outcomes with Modern Lung-Sparing Trimodality Therapy in Patients with Malignant Pleural Mesothelioma. AB - INTRODUCTION: Higher target conformity and better sparing of organs at risk with modern radiotherapy (RT) may result in higher tumor control and less toxicity. In this study, we compare our institutional multimodality therapy experience of adjuvant chemotherapy and hemithoracic intensity-modulated pleural RT (IMPRINT) with previously used adjuvant conventional RT (CONV) in patients with malignant pleural mesothelioma (MPM) treated with lung-sparing pleurectomy/decortication (P/D). METHODS: We analyzed 209 patients who underwent P/D and adjuvant RT (131 who received CONV and 78 who received IMPRINT) for MPM between 1974 and 2015. The primary end point was overall survival (OS). The Kaplan-Meier method and Cox proportional hazards model were used to calculate OS; competing risks analysis was performed for local failure-free survival and progression-free survival. Univariate analysis and multivariate analysis were performed with relevant clinical and treatment factors. RESULTS: The median age was 64 years, and 80% of the patients were male. Patients receiving IMPRINT had significantly higher rates of the epithelial histological type, advanced pathological stage, and chemotherapy treatment. OS was significantly higher after IMPRINT (median 20.2 versus 12.3 months, p = 0.001). Higher Karnofsky performance score, epithelioid histological type, macroscopically complete resection, and use of chemotherapy/IMPRINT were found to be significant factors for longer OS in multivariate analysis. No significant predictive factors were identified for local failure or progression. Grade 2 or higher esophagitis developed in fewer patients after IMPRINT than after CONV (23% versus 47%). CONCLUSIONS: Trimodality therapy including adjuvant hemithoracic IMPRINT, chemotherapy, and P/D is associated with promising OS rates and decreased toxicity in patients with MPM. Dose constraints should be applied vigilantly to minimize serious adverse events. PMID- 28341227 TI - Corrigendum to "Design and methods of a double blind randomized placebo controlled trial of extended-release naltrexone for alcohol dependent and hazardous drinking prisoners with HIV who are transitioning to the community" [Contemp. Clin. Trials (2014) 209-218]. PMID- 28341226 TI - Lung Adenocarcinoma and Squamous Cell Carcinoma Gene Expression Subtypes Demonstrate Significant Differences in Tumor Immune Landscape. AB - INTRODUCTION: Molecular subtyping of lung adenocarcinoma (AD) and lung squamous cell carcinoma (SCC) reveal biologically diverse tumors that vary in their genomic and clinical attributes. METHODS: Published immune cell signatures and several lung AD and SCC gene expression data sets, including The Cancer Genome Atlas, were used to examine immune response in relation to AD and SCC expression subtypes. Expression of immune cell populations and other immune related genes, including CD274 molecule gene (CD274) (programmed death ligand 1), was investigated in the tumor microenvironment relative to the expression subtypes of the AD (terminal respiratory unit, proximal proliferative, and proximal inflammatory) and SCC (primitive, classical, secretory, and basal) subtypes. RESULTS: Lung AD and SCC expression subtypes demonstrated significant differences in tumor immune landscape. The proximal proliferative subtype of AD demonstrated low immune cell expression among ADs whereas the secretory subtype showed elevated immune cell expression among SCCs. Tumor expression subtype was a better predictor of immune cell expression than CD274 (programmed death ligand 1) in SCC tumors but was a comparable predictor in AD tumors. Nonsilent mutation burden was not correlated with immune cell expression across subtypes; however, major histocompatibility complex class II gene expression was highly correlated with immune cell expression. Increased immune and major histocompatibility complex II gene expression was associated with improved survival in the terminal respiratory unit and proximal inflammatory subtypes of AD and in the primitive subtype of SCC. CONCLUSIONS: Molecular expression subtypes of lung AD and SCC demonstrate key and reproducible differences in immune host response. Evaluation of tumor expression subtypes as potential biomarkers for immunotherapy should be investigated. PMID- 28341230 TI - Intraoperative cryoanalgesia for managing pain after the Nuss procedure. AB - BACKGROUND: Cryoanalgesia prevents pain by freezing the affected peripheral nerve. We report the use of intraoperative cryoanalgesia during the Nuss procedure for pectus excavatum and describe our initial experience, modifications of technique, and lessons learned. MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients who received cryoanalgesia during the Nuss procedure between June 1, 2015, and April 30, 2016, at our institutions and analyzed modifications in surgical technique during this early adoption period. RESULTS: Eight male and two female patients underwent the Nuss procedure with cryoanalgesia. The mean postoperative length of stay (LOS) was 2days (range 1-3). Average inpatient pain scores were 3.4, 3.2, and 4.6 on postoperative days 1-3, respectively (N=10, 7, and 2). At a 1-week postoperative visit, mean pain score was 1.1 (N=6). Compared to the preceding 15 Nuss patients at our institution, who were treated with a thoracic epidural, postoperative LOS was significantly shorter with cryoanalgesia (2.0+/-0.82 vs. 6.3+/-1.3days, P<0.001). We modified our technique for patient habitus and adopted single-lung ventilation for improved visualization. CONCLUSIONS: Cryoanalgesia may be the ideal pain management strategy for Nuss patients because it is effective and long lasting. Intraoperative application is easily integrated into the Nuss procedure. STUDY TYPE: Treatment study: case series; Evidence level IV. PMID- 28341228 TI - Use of the ROLL technique for lumpectomy in non-palpable breast lesions. AB - OBJECTIVE: To evaluate the efficiency of radioguided occult lesion localising in non-palpable breast lesions (NPBL) compared to the surgical wire technique. METHOD: A prospective study was conducted on 161 women with NPBL, of whom 80 marked with the wire (group 1), whereas 81 women were marked with an intratumour injection of 99mTc-nanocoloid (group 2). The NPBL were located by ultrasound or stereotactic guidance. The lumpectomies were performed following the wire direction in group 1, and with the aid of a gamma-probe in group 2. Surgical margins were then checked, determining the need of extension if the margin was less than 5mm in the intra-surgical study, and less than 2mm in the deferred study. Data were collected on the mean number detected by surgery, surgical margins, number of extensions, presence of residual tumour in the extension, second surgeries, lumpectomy volume, as well as total resected volume, volume/tumour ratio, and complications. RESULTS: No significant differences were observed between the two groups in the mean number detected, surgical margins, number of extensions, presence of residual tumour in the extension, second surgeries, lumpectomy volume, total resected volume, volume/tumour ratio or complications. The multivariate analysis showed the determining factors of the resected volume were the radiological guidance technique, as well as the surgeon. CONCLUSIONS: The radioguided occult lesion localising technique helps in the detection and resection of NPBL with the same efficiency as the surgical wire, and adds the possibility of sentinel node detection in the same surgery. The determining factors of the resected volume were the radiological guidance technique and the surgeon. PMID- 28341229 TI - Assessment of the extension of pressure ulcers into soft tissue and osteomyelitis diagnosis using 18F-FDG PET/CT. AB - The precise assessment of pressure ulcer extension in patients with neurological diseases has crucial therapeutic implications, especially in the early detection of fistula to interior structures and osteomyelitis. Two case reports are presented on patients with a similar ischial ulcer, in whom an 18F-FDG PET/CT study enabled a precise assessment of infectious complications in underlying tissues. These cases support the implementation of 18F-FDG PET/CT as a first-line technique in their management. PMID- 28341231 TI - Rectal suction biopsy with calretinin immunohistochemistry in patients suspected with residual aganglionosis after operation for Hirschsprung disease. AB - INTRODUCTION: This study investigates the use of rectal suction biopsy (RSB) with calretinin immunohistochemical staining (CIS) in patients suspected of having abnormally innervated bowel after pull through operation for Hirschsprung disease (HD). METHOD: This study was conducted in Children's Hospital 2, Ho Chi Minh City from January 2015 through June 2016. Patients suspected with abnormally innervated bowel after pull through operation for HD were submitted for a RSB with CIS. Following histological results, the patients underwent an appropriate treatment (redo pull through operation or non-operative medical management) and followed up at least 6 months to evaluate their outcomes. RESULTS: Ten patients were enrolled in our study. The median age was 5.6 (range 1.4-20) years. The diagnosis of normally innervated bowel was made in five patients by showing positive reactivity of CIS on RSB, whereas five others were diagnosed with abnormally innervated bowel. Final diagnosis of the five latter patients was confirmed by analyses of the resected bowel after a redo pull through operation (including 4 cases with residual aganglionosis and one case with transition zone bowel). CONCLUSIONS: RSB with CIS is a reliable and simple method for diagnosis of abnormally innervated bowel after pull through operation for HD. LEVEL OF EVIDENCE: III TYPE OF STUDY: Study of diagnostic test (evaluate the effectiveness of a diagnostic test or outcome assessment). PMID- 28341232 TI - Lower urinary tract symptoms and sexual functions after endorectal pull-through for Hirschsprung disease: controlled long-term outcomes. AB - BACKGROUND/PURPOSE: To define the prevalence of lower urinary tract symptoms (LUTS) and outcomes for sexual function after endorectal pull-through (EPT) for Hirschsprung disease (HD) compared to controls. To date, similar controlled studies are lacking. METHODS: Patients aged >=4years (n=123) operated on for HD at our center between 1987 and 2011 were invited to answer questionnaires on LUTS and sexual function (aged >=16years). Patients with an intellectual disability and patients with a definitive endostomy were excluded. Patients were matched to three controls and also invited to a clinical follow-up for urological investigations including urine flow measurement, renal tract ultrasound, and urinalysis. RESULTS: Altogether, 59 responses concerning LUTS and 24 responses concerning sexual functions were analyzed. No significant differences were demonstrated in the overall prevalence of LUTS between patients (67%) and controls (80%), nor in the prevalence of frequent LUTS (14% vs. 16%; P=NS for both). One patient (2%) had a urethral stricture after laparotomy-assisted EPT. Male patients reported sexual satisfaction and erectile function similar to controls (P>0.10). Female patients were currently less in stable relationships compared to controls (25% vs. 83%, P=0.005). CONCLUSIONS: Our results support the safety of EPT in patients with HD with regard to preservation of the integrity and functioning of the genitourinary tract. PMID- 28341233 TI - Neonatal reflexes and behavior in hypertensive rats of ISIAH strain. AB - Hypertension is one of the most common diseases in humans, and there is a special concern on the consequences of maternal hypertensive conditions for the health of newborns. An inherited stress-induced arterial hypertension (ISIAH) rat strain has been selected but only a few studies have addressed behavior in these rats. Body weight, neurodevelopmental reflexes, and neuronal density in the hippocampus were compared in ISIAH and normotensive WAG rats during their suckling period. Systolic and diastolic blood pressure (SBP, DBP), adult rat performance in the open field (OF), elevated plus maze (EPM), and novel object recognition (NOR) tests were evaluated at the age of 12-14weeks old. Body weight in pups did not differ significantly during the suckling period, while adult ISIAH rats were heavier than age-matched WAG rats and possessed the increased SBP and DBP. ISIAH pups were developmentally more advanced than WAG as indicated by grasp reflex and negative geotaxis reaction scores. This was associated with higher neuronal density in CA1 and CA3 hippocampal areas in ISIAH pups on postnatal day 6 as compared to WAG rats. Adult ISIAH rats demonstrated an increased locomotor and exploratory activity in the OF and EPM tests as well as low levels of anxiety. The NOR test revealed no significant difference in recognition but confirmed higher exploratory activity in ISIAH rats compared to WAG rats. The results indicate that hypertensive ISIAH rats feature accelerated development during their suckling period, and as adults, they are more active and less anxious than normotensive WAG rats. PMID- 28341234 TI - Radioprotective effect of ursolic acid in radiation-induced impairment of neurogenesis, learning and memory in adolescent BALB/c mouse. AB - The effect of acute irradiation with 5Gy or fractionated exposure with 0.5Gy continuously for 10days (a total dose of 5Gy) was evaluated in an immature BALB/c mouse model. Radioprotective effect of ursolic acid (at 25mg/kg/daily administered 1h after acute or each of fractionated irradiations, and continuously for 30days) was also investigated. We found that both acute and fractionated irradiation at a total dose of 5Gy did not induce any mortality within 30days after exposure to postnatal day 26 (P26) BALB/c mice, but reduced animal weigh gain in the first few weeks. At 90days after irradiation, the weight of animals with acute irradiation was still significantly lower than the control group; no significant difference though was observed for those fractionatedly exposed mice compared to the control group. Behavioral tests indicated that acute irradiation at 5Gy induced deficits in learning and memory in the contextual fear conditioning test. The memory for novel object recognition was also impaired. Similar changes were not observed in mice with fractionated irradiation. Immunohistochemical study demonstrated clearly that acute and fractionated irradiations induced impairment of neurogenesis in the subgranular zone (SGZ) of the dentate gyrus although fractionated exposure induced much lesser loss of newly generated neurons. Ursolic acid administered at 25mg/kg/daily for 30days after irradiation greatly improved acute irradiation-induced deficits in contextual learning and memory and in novel object recognition memory although it exacerbated radiation-induced reduction of neurogenesis in SGZ. PMID- 28341236 TI - Use of behaviour change techniques in lifestyle change interventions for people with intellectual disabilities: A systematic review. AB - BACKGROUND: People with intellectual disabilities (ID) experience more health problems and have different lifestyle change needs, compared with the general population. AIMS: To improve lifestyle change interventions for people with ID, this review examined how behaviour change techniques (BCTs) were applied in interventions aimed at physical activity, nutrition or physical activity and nutrition, and described their quality. METHODS AND PROCEDURES: After a broad search and detailed selection process, 45 studies were included in the review. For coding BCTs, the CALO-RE taxonomy was used. To assess the quality of the interventions, the Physiotherapy Evidence Database (PEDro) scale was used. Extracted data included general study characteristics and intervention characteristics. OUTCOMES AND RESULTS: All interventions used BCTs, although theory-driven BCTs were rarely used. The most frequently used BCTs were 'provide information on consequences of behaviour in general' and 'plan social support/social change'. Most studies were of low quality and a theoretical framework was often missing. CONCLUSION AND IMPLICATIONS: This review shows that BCTs are frequently applied in lifestyle change interventions. To further improve effectiveness, these lifestyle change interventions could benefit from using a theoretical framework, a detailed intervention description and an appropriate and reliable intervention design which is tailored to people with ID. PMID- 28341237 TI - ACTIVLIM-CP a new Rasch-built measure of global activity performance for children with cerebral palsy. AB - OBJECTIVE: Children with cerebral palsy (CP) often have upper extremity (UE) and lower extremity (LE) impairments. While tools measuring separately UE and LE abilities are currently used, activities in which UE and LE are used in combination - numerous in everyday life - cannot be assessed because no instrument allows capturing global activity performance in children with CP. This study aimed to develop a clinical tool for measuring their global activity performance using the Rasch model. STUDY DESIGN: The caregivers of 226 children with CP (2-18 years old) answered a 154-item experimental questionnaire. Within 4 6 weeks, 129 of them filled in the questionnaire a second time. Responses were analyzed using the Rasch RUMM2020 software. RESULTS: The final 43 item scale presented a high reliability (R=0.98) and reproducibility (R=0.97). The item difficulty hierarchy was consistent over time and did not vary according to age, gender, or clinical form, allowing the follow-up of children from 2 to 18 years old. CONCLUSIONS: ACTIVLIM-CP is a unidimensional scale specifically developed to measure global activity performance in children with CP providing a reliable tool to follow children's evolution and document changes related to neurorehabilitation, especially where a combination of UE and LE is targeted. Its responsiveness is still to be tested. PMID- 28341235 TI - Physiological Markers of Motor Inhibition during Human Behavior. AB - Transcranial magnetic stimulation (TMS) studies in humans have shown that many behaviors engage processes that suppress excitability within the corticospinal tract. Inhibition of the motor output pathway has been extensively studied in the context of action stopping, where a planned movement needs to be abruptly aborted. Recent TMS work has also revealed markers of motor inhibition during the preparation of movement. Here, we review the evidence for motor inhibition during action stopping and action preparation, focusing on studies that have used TMS to monitor changes in the excitability of the corticospinal pathway. We discuss how these physiological results have motivated theoretical models of how the brain selects actions, regulates movement initiation and execution, and switches from one state to another. PMID- 28341239 TI - Calcineurin inhibitors block sodium-chloride cotransporter dephosphorylation in response to high potassium intake. AB - Dietary potassium intake is inversely related to blood pressure and mortality. Moreover, the sodium-chloride cotransporter (NCC) plays an important role in blood pressure regulation and urinary potassium excretion in response to potassium intake. Previously, it was shown that NCC is activated by the WNK4-SPAK cascade and dephosphorylated by protein phosphatase. However, the mechanism of NCC regulation with acute potassium intake is still unclear. To identify the molecular mechanism of NCC regulation in response to potassium intake, we used adult C57BL/6 mice fed a 1.7% potassium solution by oral gavage. We confirmed that acute potassium load rapidly dephosphorylated NCC, which was not dependent on the accompanying anions. Mice were treated with tacrolimus (calcineurin inhibitor) and W7 (calmodulin inhibitor) before the oral potassium loads. Dephosphorylation of NCC induced by potassium was significantly inhibited by both tacrolimus and W7 treatment. There was no significant difference in WNK4, OSR1, and SPAK expression after high potassium intake, even after tacrolimus and W7 treatment. Another phosphatase, protein phosphatase 1, and its endogenous inhibitor I-1 did not show a significant change after potassium intake. Hyperkaliuria, induced by high potassium intake, was significantly suppressed by tacrolimus treatment. Thus, calcineurin is activated by an acute potassium load, which rapidly dephosphorylates NCC, leading to increased urinary potassium excretion. PMID- 28341241 TI - High Dose Rate Brachytherapy as Monotherapy for Localised Prostate Cancer: Review of the Current Status. AB - The aim of this article is to review and present the published data on high dose rate (HDR) brachytherapy as monotherapy in the treatment of localised prostate cancer. A search and review of the literature was carried out on PubMed and MedLine using the medical subject headings 'high-dose-rate, brachytherapy, prostate cancer, monotherapy' as search terms. The search yielded more than 100 articles and abstracts published between 2000 and 2016. Only original clinical data on HDR monotherapy reporting oncological outcomes were included. When more than one series from the same institution were identified, the most recent one encompassing the largest patient number was considered for analysis. For citation crosscheck, the ISI web of science database was used employing the same search terms. Data tables were generated and summary descriptions created. The main outcome parameters used were biochemical control and toxicity scores. Fifteen articles comprising 3546 patients reported clinical outcome and toxicity, with follow-up ranging from median 1.4 to 8.0 years. A variety of dose and fractionation schedules were described, including 19.0 Gy as a single fraction to 54.0 Gy in nine fractions. Biochemical control rates ranged from 66 to 100% in low-risk, 63 to 98% in intermediate-risk and 81-93% in high-risk patients. Late grade 3 genitourinary and gastrointestinal toxicity was 0-16% and 0-2%, respectively. The reported potency preservation rates ranged from 60 to 90%. In conclusion, high biochemical control and low complication rates are reported with HDR monotherapy. It is a safe and effective local treatment modality for organ confined prostate cancer with reproducible high-quality dosimetry. PMID- 28341240 TI - Overexpression of exogenous kidney-specific Ngal attenuates progressive cyst development and prolongs lifespan in a murine model of polycystic kidney disease. AB - Neutrophil gelatinase-associated lipocalin (Ngal) is a biomarker for acute and chronic renal injuries, including polycystic kidney disease (PKD). However, the effect of Ngal on PKD progression remains unexplored. To study this, we generated 3 strains of mice with different expression levels of Ngal within an established PKD model (Pkd1L3/L3): Pkd1L3/L3 (with endogenous Ngal), Pkd1L3/L3; NgalTg/Tg (with endogenous and overexpression of exogenous kidney-specific Ngal) and Pkd1L3/L3; Ngal-/- mice (with Ngal deficiency). Knockout of endogenous Ngal had no effect on phenotypes, cystic progression, or survival of the PKD mice. However, the transgenic mice had a significantly longer lifespan, smaller (but not fewer) renal cysts, and less interstitial fibrosis than the mice without or with endogenous Ngal. Western-blot analyses showed significant increases in Ngal and cleaved caspase-3 and decreases in alpha-smooth muscle actin, hypoxia inducible factor 1-alpha, pro-caspase 3, proliferating cell nuclear antigen, Akt, mammalian target of rapamycin, and S6 Kinase in the transgenic mice as compared with the other 2 strains of PKD mice. Thus, overexpression of exogenous kidney specific Ngal reduced cystic progression and prolonged the lifespan in PKD mice, was associated with reductions in interstitial fibrosis and proliferation, and augmented apoptosis. PMID- 28341242 TI - Adjuvant Chemotherapy for Stage II and III Colon Cancer Following Complete Resection: A Cancer Care Ontario Systematic Review. AB - The objective of this systematic review was to provide current evidence regarding the use of adjuvant systemic chemotherapy for stage II and III colon cancer following curative intent surgery. MEDLINE and EMBASE databases and proceedings of American Society for Clinical Oncology and European Society of Medical Oncology/European Cancer Congress were searched through to August 2015. Systematic reviews (with or without meta-analyses) and randomised controlled trials were included. Patients with completely resected stage III colon cancer have an overall survival benefit from adjuvant chemotherapy. Combination chemotherapy (5-fluorouracil/leucovorin/oxaliplatin or capecitabine/oxaliplatin) provides a larger benefit than monotherapy but with additional toxicity. For stage II colon cancer, a clear overall survival benefit has not been shown. However, based on the subgroup analysis available, patients with high-risk stage II disease may benefit from adjuvant chemotherapy. Patients younger than 70 years of age may derive greater disease-free survival and overall survival benefit from adjuvant chemotherapy (in combination with oxaliplatin) compared with those older than 70 years. Stage II patients with microsatellite instability may have an overall survival detriment if given adjuvant chemotherapy. PMID- 28341243 TI - Variation of clearance considering viscosity of the solution used in the reservoir and following scleral lens wear over time. AB - PURPOSE: This study aims to evaluate the settling of a scleral lens and if this process is influenced by the nature of the fluid layer. METHODS: A prospective, non-randomized control study was performed using an 18mm scleral lens. They were fitted with a central clearance of 400 um at insertion. One eye was randomly assigned to be fitted with a non-preserved gel solution of carboxymethylcellulose, while the other was inserted with non-preserved saline. Measurements of clearance in 3 locations were taken (OCT) at baseline, every 30min up to 1h30 post insertion and every 2h thereafter up to 6h00 of wear. A two way repeated measure analysis of variance (liquids*times) was used to test central, nasal and temporal fluid thickness. RESULTS: Following 6h of wear, the 18mm lens had a mean central settling of 70.0+/-9.8MUm, 36.7+/-9.8MUm of which occurred within the first 30min of wear. There was no significant difference between lenses filled with non-preserved saline to those with non-preserved gel. However, a paired comparison concluded to a significant difference between mean nasal settling (41.4MUm) and temporal settling (20.4MUm). CONCLUSION: With respect to the lens studied, current results suggest that practitioners can evaluate the lens 30min post insertion and can estimate the amount of fluid that will remain after lens stabilization by doubling the value obtained initially. The use of non-preserved saline or non-preserved more viscous solution to fill the lens does not influence its settling. PMID- 28341244 TI - Imperatorin suppresses proliferation and angiogenesis of human colon cancer cell by targeting HIF-1alpha via the mTOR/p70S6K/4E-BP1 and MAPK pathways. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Angelica dahurica is a commonly used traditional Chinese medicine to treat migraine headache, toothache and cancer. Imperatorin is an active natural furocoumarin component originating from Angelica dahurica and has been shown to exhibit multiple bioeffector functions, including anti-cancer activity. However, the mechanism by which imperatorin inhibits tumor growth is not fully understood. AIM OF THE STUDY: The aim of this study was to investigate the effectiveness of imperatorin as a treatment of cancer and to identify the underlying mechanisms of its anticancer activity. MATERIALS AND METHODS: HCT116, HeLa, and Hep3B cells were used in this study. Major assays were promoter reporter gene assay, MTT, western blot analysis, immunofluorescence assay, reverse transcription-PCR (RT-PCR), flow cytometric analysis, clonogenic assay, EdU labeling and immunofluorescence, xenografted assay, and VEGF ELISA. RESULTS: We here demonstrated the effect of imperatorin on hypoxia-inducible factor-1 (HIF 1) activation. Imperatorin showed a potent inhibitory activity against HIF-1 activation induced by hypoxia in various human cancer cell lines. This compound markedly decreased the hypoxia-induced accumulation of HIF-1alpha protein dose dependently, whereas it did not affect the expressions of HIF-1beta and topoisomerase-I (Topo-I). Further analysis revealed that imperatorin inhibited HIF-1alpha protein synthesis, without affecting the expression level of HIF 1alpha mRNA or degradation of HIF-1alpha protein. Moreover, the phosphorylation levels of mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase (p70S6K), eIF4E binding protein-1 (4E-BP1), eukaryotic initiation factor 4E (eIF4E), extracellular signal-regulated kinase-1/2 (ERK1/2), SAPK/JNK and p38 were significantly suppressed by imperatorin. Furthermore, imperatorin prevented hypoxia-induced expression of HIF-1 target genes and flow cytometric analysis indicated that imperatorin induced G1 phase arrest in human colon cancer cell (HCT116). We found that imperatorin administration inhibits tumor growth and blocks tumor angiogenesis in a xenograft tumor model. CONCLUSIONS: These results show that imperatorin inhibited HIF-1alpha protein synthesis by downregulating the mTOR/p70S6K/4E-BP1 and MAPK pathways. These conclusions suggest that imperatorin is an effective inhibitor of HIF-1 and provide new perspectives into the mechanism of its anticancer activity. PMID- 28341245 TI - In vitro anti-diabetic activity of flavonoids and pheophytins from Allophylus cominia Sw . on PTP1B, DPPIV, alpha-glucosidase and alpha-amylase enzymes. AB - BACKGROUND: Ethno-botanical information from diabetic patients in Cuba led to the identification of Allophylus cominia as a possible source of new drugs for the treatment of type 2 diabetes mellitus (T2-DM). EXPERIMENTAL: Chemical characterization of the extracts from A. cominia was carried out using chromatographic and spectroscopic methods. The extracts were tested for their activity on PTP1B, DPPIV, alpha-glucosidase enzymes and alpha-amylase. RESULTS: The flavonoid rich fractions from A. cominia inhibited DPPIV enzyme (75.3+/ 2.33%) at 30ug/ml and produced a concentration-dependent inhibition against DPPIV with a Ki value of 2.6ug/ml. At 30ug/ml, flavonoids and pheophytins extracts significantly inhibited PTP1B enzyme (100+/-2.6% and 68+/-1% respectively). The flavonoids, pheophytin A and pheophytin B fractions showed significant concentration-dependent inhibition against PTP1B with Ki values of 3ug/ml, 0.64ug/ml and 0.88ug/ml respectively. At 30ug/ml, the flavonoid fraction significantly inhibited alpha-glucosidase enzyme (86+/-0.3%) in a concentration dependent pattern with a Ki value of 2ug/ml. None of the fractions showed significant effects on alpha-amylase. Fatty acids, tannins, pheophytins A and B, and a mixture of flavonoids were detected in the methanolic extract from A. cominia. The identified flavonoids were mearnsitrin, quercitrin, quercetin-3 alloside, and naringenin-7-glucoside. CONCLUSION: The pharmacological effects of the extracts from A. cominia earlier observed in experimental diabetic models was confirmed in this study. Thus a new drug or formulation for the treatment of T2 DM could be developed from A. cominia. PMID- 28341246 TI - Anemone rivularis inhibits pyruvate dehydrogenase kinase activity and tumor growth. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Anemone rivularis Buch.-Ham. ex DC. (Ranunculaceae) have been used as a traditional remedy for treatment of inflammation and cancer. However, there is no report demonstrating experimental evidence on anti-tumor action of A. rivularis. AIM OF STUDY: The Warburg's effect, preference of aerobic glycolysis rather than oxidative phosphorylation (OXPHOS) even in oxygen rich condition, is focused as one of major characteristics of malignant tumor. Thus, we investigated the effect of A. rivularis on the Pyruvate dehydrogenase (PDH) kinases (PDHKs), a major molecular targets for reducing aerobic glycolysis. MATERIALS AND METHODS: The ethanol extract of whole plant of A. rivularis (ARE), fingerprinted by high performance liquid chromatography (HPLC), was applied to in vitro and cell-based PDHK activity assays. The effect of ARE on cell viabilities of several tumor cells was estimated by MTT assay. The expression of phosphor-PDH, PDH and PDHK1 were measured by Western blot analysis. The production of reactive oxygen species (ROS) and apoptosis was measured by fluorescence-activated cell sorting analysis, using 5-(and-6)-carboxy-2',7'-dichlorodihydrofluorescein diacetate (carboxy H2DCFDA) and Annexin V/propidium iodide (PI) staining, respectively. Mitochondrial membrane potential was examined by tetramethylrhodamine methyl ester (TMRM) staining. In vivo anti-tumor efficacy of ARE was estimated by means of tumor volume and weight using allograft injection of murine Lewis lung carcinoma (LLC) cells to dorsa of C57BL/6 mice. RESULTS: ARE inhibited the viabilities of several cancer cells, including MDA-MB321, K562, HT29, Hep3B, DLD 1, and LLC. ARE suppressed PDHK activity in in vitro kinase assay, and also inhibited aerobic glycolysis by reducing phosphorylation of PDHA in human DLD-1 colon cancer and murine LLC cells. The expression of PDHK1, a major isoform of PDHKs in cancer, was not affected by ARE treatment. Moreover, ARE increased the both ROS production and mitochondrial damage. In addition, ARE suppressed the in vitro tumor growth through mitochondria-mediated apoptosis. The growth rates of allograft LLC cells were also reduced by ARE treatment. CONCLUSIONS: Here, we firstly report that ARE inhibits PDHK activity and growth of tumor in both in vitro and in vivo experiments. Therefore, we suggest ARE as a potential candidate for developing anti-cancer drugs. PMID- 28341247 TI - Toxicological evaluation of Oviductus ranae: Acute, sub-acute and genotoxicity studies in mice and rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Oviductus ranae (OR) is a traditional animal based Chinese medicine, which has been listed in the Chinese Pharmacopoeia since 1985 edition. Although its medicinal application has been widely acknowledged, there is little available information on its potential toxicity. AIM OF THE STUDY: The aim of this study was to investigate the acute, sub-acute, and genetic toxicities of OR. MATERIALS AND METHODS: In acute toxicity evaluation, OR was administered orally to mice at doses of 2.5, 5.0, 10.0, and 20.0g/kg BW for one time. Mortality, clinical signs, and body weight were observed for 14 days after treatment. In sub-acute toxicity evaluation, OR was administered orally to rats once a day for 28 consecutive days at doses of 1.75, 3.50, and 7.00g/kg BW. Animals were observed for general behaviors, mortality, food intake, and body weight changes. At the end of treatment, relative organ weight, pathology, hematological and biochemical parameters were monitored. In genotoxicity evaluation, bacterial reverse mutation assay (Ames test) was performed by treating OR with four different Salmonella typhimurium strains at doses of 8, 40, 200, 1000, and 5000MUg/plate without or with S-9 mix, respectively. The genotoxicity of OR was also evaluated by micronucleus and sperm malformation assays in mice at doses of 2.5, 5.0, and 10.0g/kg BW, respectively. RESULTS: The results of acute toxicity study showed that the LD50 value of OR is higher than 20.0g/kg BW in mice. Death and abnormal clinical symptoms were not found during the period of experiment. In sub-acute toxicity, we found that the no-observed adverse-effect levels (NOAEL) of OR in rats is up to 7.00g/kg BW. No statistically significant or toxicologically relevant defferences in body weight, food intake, relative organ weight, pathology, hematological and biochemical parameters were observed, when compared with control group. Results of Ames test, micronucleus and sperm malformation assays indicated that OR has no mutagenicity in vitro at a limited dose of 5000MUg/plate, and dose not induce micronuclei and sperm malformation in mice at the dose of up to 10.0g/kg BW in mice. CONCLUSIONS: In conclusion, OR is a tranditional Chinese medicine with high safety. PMID- 28341249 TI - How many tumor indications should be initially screened in development of next generation immunotherapies? AB - An experimental oncology immunotherapy may have the potential to be effective in a large number of tumor indications. We have considered a staggered approach for efficacy screening in subjects with an unmet medical need. A cohort of tumor indications is selected for the first wave investigation and the second wave investigation in a different cohort of tumor indications is initiated only after the drug has been demonstrated to be effective in the first wave. The effectiveness of an experimental immunotherapy is unknown at the planning stage, and the assumptions at the planning stage are subject to revision later on. How many tumor indications should be investigated in the first wave for the development program to be cost-effective amid the uncertainties? We attempt to answer this question by maximizing a benefit-cost ratio, defined to be the expected number of effective tumor indications correctly identified in the two waves (benefit) divided by the expected total sample size in the two waves and the subsequent trials for more definitive testing triggered by those with a positive outcome in the first wave (cost). It is found from the benefit-cost ratio analyses that, depending on resource availability, three to five tumor indications may be initiated in the first wave to properly balance the risk and benefit, and adequate investment is important to maintain the quality of statistical design. PMID- 28341248 TI - Abnormal lipid/lipoprotein metabolism and high plasma testosterone levels in male but not female aromatase-knockout mice. AB - Sex steroid hormones, such as estrogen and testosterone, are believed to play important roles in lipid metabolism. To elucidate the effects of estrogen depletion on lipid metabolism in male and female mice, we used aromatase-knockout (ArKO) mice, in which Cyp19 gene disruption prevented estrogen synthesis in vivo. These mice were divided into the following 4 groups: male and female ArKO mice and male and female wild-type (WT) mice. These mice were fed a normal-fat diet (13.6% fat) ad libitum. At 159 days after birth, the mice were tested for liver and plasma lipid content and hepatic hormone receptor- and lipid/lipoprotein metabolism-related gene expression. Interestingly, we found that hepatic steatosis was accompanied by markedly elevated plasma testosterone levels in male ArKO mice but not in female ArKO mice. Plasma lipoprotein profiles exhibited concurrent decreases in LDL- and small dense LDL-triglyceride (TG) levels in male ArKO mice. Moreover, male mice, but not female mice, exhibited marked elevations in androgen receptor (AR), sterol regulatory element-binding protein 1 (SREBP1), and CD36 expression. These results strongly suggest that Cyp19 gene disruption, which induces a sexually dimorphic response and high plasma testosterone levels in male mice, also induces hepatic steatosis. PMID- 28341250 TI - Modulation of LILRB2 protein and mRNA expressions in septic shock patients and after ex vivo lipopolysaccharide stimulation. AB - Septic patients develop immune dysfunctions, the intensities and durations of which are associated with deleterious outcomes. LILRB2 (leukocyte immunoglobulin like receptors subfamily B, member 2), an inhibitory member of the LILR family of receptors, is known for its immunoregulatory properties. In a microarray study, we identified LILRB2 as an upregulated gene in septic shock patients. On monocytes primed with LPS ex vivo, LILRB2 mRNA and protein expressions were dose dependently downregulated and subsequently highly upregulated versus non stimulated cells. This is concordant with clinical data, since both LILRB2 mRNA and protein expressions were significantly increased in septic shock patients at day 3. In a cohort of more than 700 patients, only after septic shock were LILRB2 mRNA levels increased compared with non-infected or less severely infected patients. This was preceded by a phase of downregulated mRNA expression during the first hours after septic shock. Interestingly, the intensity of this decrease was associated with increased risk of death after septic shock. LILRB2 protein and mRNA expressions are deregulated on monocytes after septic shock and this can be reproduced ex vivo after LPS challenge. Considering LILRB2 inhibitory properties, we can hypothesize that LILRB2 may participate in the altered immune response after septic shock. PMID- 28341251 TI - Vitamin D and muscle function. AB - Muscle weakness is a hallmark of severe vitamin D deficiency, but the effect of milder vitamin D deficiency or insufficiency on muscle mass and performance and risk of falling is uncertain. In this presentation, I review the evidence that vitamin D influences muscle mass and performance, balance, and risk of falling in older adults. Special consideration is given to the impact of both the starting 25-hydroxyvitamin D [25(OH)D] level and the dose administered on the clinical response to supplemental vitamin D in older men and women. Based on available evidence, older adults with serum 25(OH)D levels <40nmol/L appear most likely to improve their muscle performance with supplementation. The vitamin D dose range of 800-1000 IU per day has been effective in many studies; lower doses have generally been ineffective and several doses above this range have increased the risk of falls. In conclusion, older adults with serum 25(OH)D levels <40nmol/L are likely to have fewer falls if supplemented with 800-1000 IU per day of vitamin D. PMID- 28341252 TI - Correlation between digital epiluminescence microscopy parameters and histopathological changes in lentigo maligna and solar lentigo: A dermoscopic index for the diagnosis of lentigo maligna. AB - BACKGROUND: The clinical and dermoscopic differentiation between lentigo maligna (LM) and solar lentigo (SL)/initial seborrheic keratosis (SK) may be difficult. OBJECTIVE: Our aim was to identify digital epiluminescence microscopy (DELM) specific criteria that can be helpful in distinguishing LM from SL/SK and to propose a new model of LM dermoscopic progression based on a study of DELM histopathological correlation. METHODS: A total of 167 consecutive doubtful pigmented lesions of the head (105 LM and 62 SL/SK) were studied. DELM assessment was based on the presence or absence of 15 DELM parameters that were subsequently examined histologically. Statistical analysis was performed to determine which DELM parameters were most strongly associated with LM. RESULTS: The finding of at least 1 of 4 parameters (ie, brown globules, a "necklace" pigment network, an atypical pigment network, and dark-brown/blue-gray ribbonlike structures) showed to be an extremely sensitive (99%) and specific (83.9%) DELM criterion to discriminate between LM and SL/SK. LIMITATIONS: Our findings were obtained by examining medium-high magnification DELM images. CONCLUSIONS: The finding of 1 or more among the 4 above-mentioned DELM parameters allows for the correct identification of 99.0% of the LM lesions, and - when the score is 0 - the correct classification as non-LM, of 83.9% of the SL/SK lesions. PMID- 28341253 TI - Digital workflow for a dental prosthesis that considers lateral mandibular relation. AB - Most digital prosthesis designs consider only the maximal intercuspal position (MIP) and not the lateral movement. During the computer-aided design and computer aided manufacture (CAD-CAM) prosthesis delivery process, the clinician has to adjust the prosthesis to avoid occlusal interference during lateral excursion. The novel digital workflow described in this report can be divided into 2 steps. After obtaining interocclusal records for the MIP and the lateral excursion position, the crown CAD data were designed using a general digital workflow considering only the MIP. The previous crown CAD data were then adjusted in the lateral excursion state before manufacturing the prosthesis. This process using information for 2 occlusal positions means that the definitive prosthesis design reflects not only static occlusion but also lateral mandibular relation. PMID- 28341255 TI - Damage-associated molecular patterns (DAMPs) released after burn are associated with inflammation and monocyte activation. AB - Burns are associated with activation of the innate immunity that can contribute to complications. Damage-associated molecular patterns (DAMPs) released after tissue injury play a critical role in the activation of the innate immunity, which appears to be mediated via toll-like receptors (TLRs). Previous findings have shown that TLRs and TLR-mediated responses are up-regulated after burn. Nonetheless, it is unclear what impact burn has on circulating levels of DAMPs. To study this, male C57BL/6 mice were subjected to a major burn or sham procedure. Three hours to 7days thereafter, plasma was collected and assayed for the representative DAMPs (i.e., HMGB1, cytochrome C, DNA and S100A) and extracellular cleavage products (fibronectin and hyaluronan). HMGB1, cytochrome C, fibronectin and hyaluronan levels were elevated in a time-dependent manner after burn as compared to sham levels. A significant elevation in TNF-alpha, IL-6 and IL-10 cytokine plasma levels was also found after burn. All cytokine levels were increased as early as 3h and remained elevated up to 24h. Circulating CD11b+ monocytes were increased at 24h after burn and showed increased expression of TLR 2. In conclusion, these findings support the concept that burn-induced elevations in circulating DAMPs are in part responsible for monocyte activation and the development of inflammatory complications under such conditions and warrants further investigation. PMID- 28341256 TI - The ability of selected plant essential oils to enhance the action of recommended antibiotics against pathogenic wound bacteria. AB - The aim of this work was to characterize the ability of essential oils to support antibiotics against pathogenic bacteria in wounds. Gram-positive and Gram negative bacteria obtained from wound infections were identified according to standard microbiological methods. Essential oils were analysed by GC-FID-MS. The susceptibility of bacteria to antibiotics, essential oils and their combination was assessed using the disc-diffusion method. The Minimal Inhibitory Concentration and Minimum Bactericidal Concentration of the essential oils were established by the micro-dilution broth method. Although cinnamon, clove, thyme and lavender essential oils were found to have the greatest antibacterial activity when used alone, the greatest additive and synergistic effects against pathogenic wound bacteria in combination with recommended antibiotics were demonstrated by basil, clary sage and rosemary oils. PMID- 28341257 TI - Our initial learning curve in the enzymatic debridement of severely burned hands Management and pit falls of initial treatments and our development of a post debridement wound treatment algorithm. AB - INTRODUCTION: Excisional surgical debridement (SD) is still the gold standard in the treatment of deeply burned hands, though the intricate anatomy is easily damaged. Previous studies demonstrated that enzymatic debridement with the bromelain debriding agent NexoBrid(r) (EDNX) is more selective and thus can preserve viable tissue with excellent outcome results. So far no method paper has been published presenting different treatment algorithms in this new field. Therefore our aim was to close this gap by presenting our detailed learning curve in EDNX of deeply burned hands. METHODS: We conducted a single-center prospective observational clinical trial treating 20 patients with deeply burned hands with EDNX. Different anaesthetic procedures, debridement and wound treatment algorithms were compared and main pitfalls described. RESULTS: EDNX was efficient in 90% of the treatments though correct wound bed evaluation was challenging and found unusual compared to SD. Post EDNX surprisingly the majority of the burn surface area was found overestimated (18 wounds). Finally we simplified our process and reduced treatment costs by following a modified treatment algorithm and treating under plexus anaesthesia bedside through a single nurse and one burn surgeon solely. Suprathel(r) could be shown to be an appropriate dressing for wound treatment after EDNX. Complete healing (less 5% rest defect) was achieved at an average of day 28. CONCLUSION: EDNX in deep burned hands is promising regarding handling and duration of the treatment, efficiency and selectivity of debridement, healing potential and early rehabilitation. Following our treatment algorithm EDNX can be performed easily and even without special knowledge in burn wound depth evaluation. PMID- 28341258 TI - Treatment costs of burn victims in a university hospital. AB - OBJECTIVES: To analyze the direct costs of treating critically ill patients in the intensive care unit of a center specializing in treating burns. METHODS: This is a prospective cohort study of 180 patients from May 2011 to May 2013. Clinical and demographic data were collected in addition to data for the calculation of severity scores. The costs related to daily clinical and surgical treatment were evaluated until hospital outcome. The costs were grouped into five blocks: Clinical support, Drugs and blood products, Medical procedures, Specific burn procedures and Hospital fees. The level of significance was set at 5%. RESULTS: There was a predominance of males, 131 (72.8%). The mean age of the patients was 42.0+/-15.3years and the mean burned body surface area was 27.9+/-17%. The median length of stay in intensive care beds was 15.0 (interquartile range IQR: 7.0 24.8) days and the median hospital stay was 23.0 (IQR: 14.0-34.0) days. The mean daily cost was US$ 1330.48 (standard error of the mean SE=38.36) and the mean total cost of hospitalization was US$ 39,594.90 (SE: 2813.11). The drugs and blood products block accounted for the largest fraction of the total costs (US$ 18,086.09; SE 1444.55). There was a difference in the daily costs of survivors and non survivors (US$ 1012.89; SE: 29.38 and US$ 1866.11, SE: 36.43, respectively, P<0.001). CONCLUSION: The direct costs of the treatment of burn patients at the study center were high. The drugs and blood products block presented the highest mean total and daily costs. Non surviving patients presented higher costs. PMID- 28341259 TI - Effect of vitamin D supplementation and isokinetic training on muscle strength, explosive strength, lean body mass and gait in severely burned children: A randomized controlled trial. AB - OBJECTIVE: To determine the effects of vitamin D (VD) supplementation and isokinetic training on muscle strength, explosive strength (counter movement jump) (ES), lean body mass (LBM) and gait parameters in severe pediatric burn. METHODS: Forty-eight burned children with circumferential lower extremity burns covering 40-55% of the total body surface area (TBSA), aged 10-16 years (Mean+/ SD 13.01+/-1.75), were randomized into the standard of care (n=16), isokinetic (n=17) and VD (n=15) groups. Unburned children (n=20) served as matched controls. All burned children received 12 weeks of routine physical therapy program (RPTP). In addition, the isokinetic group received isokinetic training for the quadriceps dominant limb 3 times per week at angular velocity 150 degrees /s, and the VD group received the isokinetic training plus an oral daily dose of vitamin D3 1000 IU (Cholecalciferol). The primary measures, assessed at baseline and 12 weeks, included quadriceps strength by isokinetic dynamometer, ES, LBM by dual-energy X ray absorptiometry (DEXA) and gait parameters by GAITRite system. RESULTS: The VD and isokinetic groups showed significant improvement in quadriceps strength, ES, LBM and gait parameters compared with the standard of care, and VD group show significant improvement in the VD level as compared with the other groups. The outcome measures (and percent of improvement where applicable) for the VD, isokinetic and standard of care are as follows: quadriceps strength, 85.25+/ 0.93Nm (85%), 64.25+/-0.93 (36%) and 51.88+/-1.31Nm (12%); stride length, 94.00+/ 2.69 (7%), 110.60+/-2.87 (25%) and 139.56+/-2.57 (60%); step length, 67.26+/-2.45 (72%), 55.25+/-2.49 (43%) and 43.76+/-1.34 (18%); velocity, 133.94+/-1.65 (82%), 99.94+/-1.65 (35%) and 80.11+/-1.91 (9%); and cadence, 140.63+/-1.36 (68%), 132.63+/-1.36 (58%) and 90.35+/-1.32 (9%), VD level 43.33+/-7.48 (75%), 24.77+/ 7.38 (5%) and 25.63+/-8.39 (4%) respectively. CONCLUSIONS: VD supplementation combined with exercise training significantly increased muscle strength, ES, LBM, gait and VD level in severely burned children. PMID- 28341260 TI - The effect of preexisting respiratory co-morbidities on burn outcomes. AB - INTRODUCTION: Burns cause physiologic changes in multiple organ systems in the body. Burn mortality is usually attributable to pulmonary complications, which can occur in up to 41% of patients admitted to the hospital after burn. Patients with preexisting comorbidities such as chronic lung diseases may be more susceptible. We therefore sought to examine the impact of preexisting respiratory disease on burn outcomes. METHODS: A retrospective analysis of patients admitted to a regional burn center from 2002-2012. Independent variables analyzed included basic demographics, burn mechanism, presence of inhalation injury, TBSA, pre existing comorbidities, smoker status, length of hospital stay, and days of mechanical ventilation. Bivariate analysis was performed and Cox regression modeling using significant variables was utilized to estimate hazard of progression to mechanical ventilation and mortality. RESULTS: There were a total of 7640 patients over the study period. Overall survival rate was 96%. 8% (n=672) had a preexisting respiratory disease. Chronic lung disease patients had a higher mortality rate (7%) compared to those without lung disease (4%, p<0.01). The adjusted Cox regression model to estimate the hazard of progression to mechanical ventilation in patients with respiratory disease was 21% higher compared to those without respiratory disease (HR=1.21, 95% CI=1.01-1.44). The hazard of progression to mortality is 56% higher (HR=1.56, 95% CI=1.10-2.19) for patients with pre-existing respiratory disease compared to those without respiratory disease after controlling for patient demographics and injury characteristics. CONCLUSION: Preexisting chronic respiratory disease significantly increases the hazard of progression to mechanical ventilation and mortality in patients following burn. Given the increasing number of Americans with chronic respiratory diseases, there will likely be a greater number of individuals at risk for worse outcomes following burn. PMID- 28341261 TI - Occlusive drainage system for split-thickness skin graft: A prospective randomized controlled trial. AB - BACKGROUND: Split-thickness skin grafts are widely used in reconstruction of large area defects. Conventional postoperative recipient site care includes saline-moistened gauze with a protective layer of petroleum gauze and splints for immobilization. This method causes pain while changing the dressing. We designed a better occlusive drainage system for split-thickness skin grafts. We compared the treatment effect and subjective evaluation of our occlusive drainage system with that of the conventional method for coverage of split-thickness skin grafts. METHODS: A randomized controlled trial was carried out in patients who received split-thickness skin grafts. Patients aged 24-76 years were randomly assigned to the occlusive drainage system or the conventional indirect wet dressing method. The status of graft take, pain, and subjective evaluations were compared. RESULTS: Twenty-eight participants were enrolled, with 14 in each group. The percentage of graft take was no difference between the 2 groups. No wound infection developed. Patients in the occlusive drainage system group experienced less pain and greater satisfaction. All patients followed up for at least 3 months, and no hypertrophic scar formation was noted. CONCLUSION: Comparing with the indirect wet dressing method, this new method is practical for covering split thickness skin grafts, causes less pain, and provides a better experience for patients. PMID- 28341262 TI - Pulsed-xenon ultraviolet light disinfection in a burn unit: Impact on environmental bioburden, multidrug-resistant organism acquisition and healthcare associated infections. AB - Portable pulsed xenon ultraviolet disinfection (PPX-UVD) may reduce healthcare associated infections (HAI). There is limited data to inform use in burn intensive care units (BICU), where multidrug-resistant organisms (MDRO), especially gram negative rods (GNR), commonly cause disease. We evaluated PPX-UVD effects on environmental bioburden and rates of HAI and MDRO acquisition in a BICU. PPX-UVD was used for 3 months after standard cleaning of patient and operating rooms (ORs). Settle and touch plates in patient rooms and ORs were obtained after standard cleaning, pre-and post-PPX-UVD. HAI and MDRO acquisition were evaluated 1year prior to and for 3 month periods before, during, and after PPX-UVD. 110 touch and settle plates (33 pre- and 30 post-PPX-UVD) were obtained after standard cleaning, pre- and post-PPX-UVD. After PPX-UVD, environmental samples with any growth decreased (48% vs 31%, p=0.02), as did mean colony count/sample (2.8 pre- vs 1.6 post-, p=0.03). The 379 colonies largely represented skin commensals, without identified MDRO. Following PPX-UVD, no changes in device-associated infections, overall MDRO, or MDR GNR were seen, though a prolonged interval without healthcare-associated Clostridium difficile infection was observed. PPX-UVD in a BICU reduced overall environmental bioburden, without a statistically significant impact on HAI or MDRO. PMID- 28341263 TI - Living with burn scars caused by self-immolation among women in Iraqi Kurdistan: A qualitative study. AB - Patients with burns have to live with a variety of long-term physical and psychosocial consequences. Burns lead to prolonged hospital stay, disfiguring scars, disability, and even death. Since self-immolation is common in women of Iraqi Kurdistan, the present study sought to explore the experiences of women living with scars caused by self-immolation. This paper was part of a qualitative research study. A purposive sample of 18 female self-immolation survivors from Iraqi Kurdistan was selected, and 21 individual interviews were conducted and analyzed using conventional content analysis. Four categories emerged during the data analysis: (1) feelings of disbelief, regret, and anger caused by post-burn scars; (2) desperately seeking solutions; (3) grief due to disappointment and surrender to despair; and (4) rejection and isolation. In conclusion, individuals with scars and disfigurements sometimes adopted inappropriate measures to deal with the psychological problems caused by others' behaviors and wrong perceptions. Educational and support programs are hence indicated to promote awareness levels of self-immolation survivors, their families, and the whole society. PMID- 28341264 TI - Total hip arthroplasty survival in femoral head avascular necrosis versus primary hip osteoarthritis: Case-control study with a mean 10-year follow-up after anatomical cementless metal-on-metal 28-mm replacement. AB - BACKGROUND: Total hip arthroplasty is the most widely used procedure to treat avascular necrosis (AVN) of the femoral head. Few studies have compared the outcomes of THA in femoral head AVN and primary hip osteoarthritis. Therefore we performed a case-control study to compare THA for femoral head AVN vs. primary hip osteoarthritis in terms of: (1) prosthesis survival, (2) complication rates, (3) functional outcomes and radiographic outcomes, (4) and to determine whether specific risk factors for THA failure exist in femoral head AVN. HYPOTHESIS: THA survival is similar in femoral head AVN and primary hip osteoarthritis. MATERIAL AND METHODS: We compared two prospective cohorts of patients who underwent THA before 65 years of age, one composed of cases with femoral head AVN and the other of controls with primary hip osteoarthritis. In both cohorts, a cementless metal on-metal prosthesis with a 28-mm cup and an anatomical stem was used. Exclusion criteria were THA with other types of prosthesis, posttraumatic AVN, and secondary osteoarthritis. With alpha set at 5%, to obtain 80% power, 246 patients were required in all. Prosthesis survival was assessed based on time to major revision (defined as replacement of at least one implant fixed to bone) and time to aseptic loosening. The other evaluation criteria were complications, Postel Merle d'Aubigne (PMA) score, and the Engh and Agora Radiographic Assessment (ARA) scores for implant osseointegration. RESULTS: The study included 282 patients, 149 with AVN and 133 with osteoarthritis. Mean age was 47.8+/-10.2 years (range, 18.5-65) and mean follow-up was 11.4+/-2.8 years (range, 4.5-18.3 years). The 10 year survival rates were similar in the two groups: for major revision, AVN group, 92.5% (95% confidence interval [95% CI], 90.2-94.8) and osteoarthritis group, 95.3% (95% CI, 92.9-97.7); for aseptic loosening, AVN group, 98.6% (95% CI, 97.6-98.6) and osteoarthritis, 99.2% (95% CI, 98.4-100). The AVN group had higher numbers of revision for any reason (19 vs. 6, P=0.018) and for dislocation (8 vs. 1, P=0.031). Mean PMA scores at last follow-up were comparable in the AVN group (17.65+/-1.27 [range, 10-18]) and osteoarthritis group (17.59+/-1.32 [range, 14-18]) (P=0.139). Osseointegration was also similar in the two groups: global Engh score, 26.51+/-1.81 (range, 14-27) for AVN and 26.84+/-0.91 (range, 19.5-27) for osteoarthritis (P=0.065); femoral ARA score, 5.83+/-0.46 (range, 3 6) for AVN and 5.90+/-0.42 (range, 3-6) for osteoarthritis (P=0.064); and cup ARA score, 5.74+/-0.67 (range, 3-6) for AVN and 5.78+/-0.66 (range, 3-6) for osteoarthritis (P=0.344). DISCUSSION: Survival in this study was good and consistent with recent data on AVN, with no difference between AVN and osteoarthritis. Revisions for any cause or for dislocation were more common after THA for AVN. Functional outcomes were similar in the AVN and osteoarthritis groups. An anatomical cementless prosthesis combined with metal-on-metal 28-mm bearing provides durable good outcomes. LEVEL OF EVIDENCE: III, non-randomized comparison of two prospective cohorts. PMID- 28341265 TI - Does a titanium sleeve reduce the frequency of pseudotumors in metal-on-metal total hip arthroplasty at 5-7years follow-up? AB - INTRODUCTION: Little is known about pseudotumor frequency and risk factors for pseudotumor formation among different types of metal-on-metal (MoM) hip arthroplasties. A lower release of chromium and cobalt have been reported in MoM hip arthroplasties with a titanium sleeve compared to MoM designs without a titanium sleeve, but yet it is unknown whether a titanium sleeve reduces the pseudotumor frequency. We conducted a cross-sectional study to investigate: 1) pseudotumor frequency, 2) risk factors of pseudotumor formation 3) and correlations between pseudotumors, serum metal-ions, implant position, and clinical symptoms. HYPOTHESIS: We expected a lower pseudotumor frequency in MoM hip articulation with a titanium sleeve than reported in MoM hip articulation designs using chromium-cobalt sleeve. MATERIALS AND METHOD: A consecutive series of 41 patients/49 hips (31 males), mean age 52 (28-68) years, participated in a 5.5+/-0.5 (4-6.5) year follow-up study of their M2a_Magnum hip articulation (Biomet Inc., Warsaw, Indiana, USA). Patients were evaluated with magnetic resonance imaging (MRI), measurements of serum metal-ions, plain radiographs, and clinical outcome measures of Harris Hip Score (HHS) and Oxford Hip Score (OHS). RESULTS: Eighteen of 47 hips (38%) had MRI-verified pseudotumors, all cystic, with a mean dimension of 10.6*25.6*41mm. Digital measurements on plain radiographs revealed a higher cup anteversion in patients with a pseudotumor of mean 28.4 degrees +/-5.05 degrees compared to mean 23.5 degrees +/-6.5 degrees in patients without a pseudotumor (P=0.009). Serum metal-ion concentrations, acetabular cup inclination and measures of HHS and OHS were similar between patients with and without a pseudotumor (P>0.46). CONCLUSION: At 5.5+/-0.5years after surgery, MRI-verified cystic pseudotumors were frequently observed in M2a_Magnum hip articulations despite the use of titanium sleeves. The pseudotumors were related to high cup anteversion angles but not related to high serum metal-ions or clinical symptoms. LEVEL OF EVIDENCE: IV: cross-sectional study. PMID- 28341266 TI - Influence of fixation point of latissimus dorsi tendon transfer for irreparable rotator cuff tear on glenohumeral external rotation: A cadaver study. AB - : Latissimus dorsi tendon transfer is a surgical option for treating irreparable posterosuperior rotator cuff tears, notably when attempting to reconstruct active external rotation. We hypothesized that the positioning of the transfer's point of fixation would differ depending on the desired elbow-to-body external rotation or external rotation with the elbow abducted. MATERIAL AND METHODS: Seven shoulders from four whole frozen cadavers were used. We created two systems to install the subject in a semi-seated position to allow external rotation elbow to body and the arm abducted 90 degrees . Traction sutures were positioned on the latissimus dorsi muscle and a massive tear of the rotator cuff was created. We tested six different transfer positions. Muscle contraction of the latissimus dorsi was stimulated using 10-N and 20-N suspended weights. RESULTS: The point of fixation of the latissimus dorsi on the humeral head had an influence on the elbow-to-body external rotation and with 90 degrees abduction (P<0.001). The fixation point for a maximum external rotation with the elbow to the body was the anterolateral position (P<0.016). The fixation point for a maximum external rotation at 90 degrees abduction was the position centered on the infraspinatus footprint (P<0.078). CONCLUSION: The optimal point of fixation differs depending on whether external rotation is restored at 0 degrees or 90 degrees abduction. LEVEL OF EVIDENCE: Fundamental study, anatomic study. PMID- 28341267 TI - In vivo clinical and radiological effects of platelet-rich plasma on interstitial supraspinatus lesion: Case series. AB - BACKGROUND: Rotator cuff tear (RCT) is a frequent condition of clinical relevance that can be managed with a symptomatic conservative treatment, but surgery is often needed. Biological components like leukocytes and platelet rich plasma (L PRP) could represent an alternative curative method for interstitial RCT. HYPOTHESES: It has been hypothesized that an ultrasound guided L-PRP injection in supraspinatus interstitial RCT could induce radiological healing. MATERIAL AND METHODS: A prospective case series including 25 patients was performed in order to assess the effect of L-PRP infiltration into supraspinatus interstitial RCTs. Primary outcome was tear size change determined by magnetic resonance imaging arthrogram (MRA) before and 6 months after L-PRP infiltration. Secondary outcomes were Constant score, SANE score, and pain visual analog scale (VAS) after L-PRP infiltration. RESULTS: Tear volume diminution was statistically significant (P=.007), and a >50% tear volume diminution was observed in 15 patients. A statistically significant improvement of Constant score (P<.001), SANE score (P=.001), and VAS (P<.001) was observed. In 21 patients, Constant score improvement reached the minimal clinical important difference of 10.4 points. DISCUSSION: We observed a statistically significant and clinically relevant effect on RCT size and clinical parameters after L-PRP infiltration. Such an important improvement of supraspinatus interstitial RCT with conservative management is uncommon, therefore intratendinous L-PRP infiltrations could have been beneficial. This encouraging result could pave the way for future randomized studies in order to formally determinate whether L-PRP infiltrations are a possible alternative to surgical treatment of interstitial RCT. LEVEL OF EVIDENCE: Prospective observational study; Level of evidence II. PMID- 28341268 TI - Social is special: A normative framework for teaching with and learning from evaluative feedback. AB - Humans often attempt to influence one another's behavior using rewards and punishments. How does this work? Psychologists have often assumed that "evaluative feedback" influences behavior via standard learning mechanisms that learn from environmental contingencies. On this view, teaching with evaluative feedback involves leveraging learning systems designed to maximize an organism's positive outcomes. Yet, despite its parsimony, programs of research predicated on this assumption, such as ones in developmental psychology, animal behavior, and human-robot interaction, have had limited success. We offer an explanation by analyzing the logic of evaluative feedback and show that specialized learning mechanisms are uniquely favored in the case of evaluative feedback from a social partner. Specifically, evaluative feedback works best when it is treated as communicating information about the value of an action rather than as a form of reward to be maximized. This account suggests that human learning from evaluative feedback depends on inferences about communicative intent, goals and other mental states-much like learning from other sources, such as demonstration, observation and instruction. Because these abilities are especially developed in humans, the present account also explains why evaluative feedback is far more widespread in humans than non-human animals. PMID- 28341269 TI - Ultrasonic, bipolar, and integrated energy devices: comparing heat spread in collateral tissues. AB - BACKGROUND: Integrated devices incorporating ultrasonic and bipolar technology have been used in laparoscopic surgery, however, are not yet incorporated into open operations. Here, we compare thermal spread and recurrent laryngeal nerve (RLN) functional data of the integrated THUNDERBEAT Open Fine Jaw device, the bipolar Ligasure Small Jaw, and the ultrasonic Harmonic Focus for open thyroidectomy. MATERIALS AND METHODS: The three energy devices were compared in a live porcine model using three tissue types including liver, muscle, and thyroid. The devices were fired three times on each energy setting, and the thermal spread was measured by thermocouples that were inserted in surrounding tissues at 1-mm intervals. To determine RLN injury, devices were fired at successive 1-mm increments from the RLN until the monitor signal was lost. RESULTS: When comparing heat generated across these devices at 1 mm, the peak temperature (Celsius) reached in liver tissue was observed with the ultrasonic device (115.4 +/- 86.7), in muscle tissue with the integrated device (104.2 +/- 82.1), and in thyroid with the bipolar device (81.4 +/- 41.3). Temperatures generated at individual settings on each device were similar (P = 0.11-0.81). RLN injury occurred after firing on manually approximated tissue 1-mm away from the RLN for all devices; however, there was no signal loss at >=2 mm. CONCLUSIONS: Heat transfer was similar among all devices with the exception of the ultrasonic device when used in the liver, which showed higher temperatures. Liver tissue showed the most consistent results. RLN injury did not occur if the devices were fired on manually approximated tissue >=2 mm from the nerve. PMID- 28341270 TI - Age-Dependent Gender Disparities in Post Lung Transplant Survival Among Patients With Idiopathic Pulmonary Fibrosis. AB - BACKGROUND: The influence of age and gender on survival after lung transplant in patients with idiopathic pulmonary fibrosis (IPF) is not well defined. METHODS: The United Network for Organ Sharing database was queried to identify IPF patients receiving lung transplant between 2005 and 2015. RESULTS: There were 6,677 patients receiving lung transplant between May 2015 and June 2015 who met the inclusion criteria, predominantly males (n = 4,769, 71%). Within 1 year posttransplant, the survival curves of male and female recipients diverged, with male recipients having significantly worse survival (log-rank test p = 0.008). Univariate Cox proportional hazards regressions demonstrated no gender difference in survival below age 65 years (HR = 1.051; 95% CI = 0.945, 1.168; p = 0.362) but a significant increase in mortality hazard associated with male gender among patients age 65 years and older (HR = 1.161; 95% CI = 1.000, 1.347; p = 0.049). Multivariable Cox regression accounting for age modulation of the gender effect further demonstrated the emergence of a male disadvantage in post-transplant survival above age 65 years at transplantation. CONCLUSIONS: In patients with IPF receiving lung transplant at greater than 65 years of age, male gender is associated with significantly increased risk for death, so referral for lung transplant in IPF should be considered early in the disease course. PMID- 28341271 TI - Obesity and kidney disease: from population to basic science and the search for new therapeutic targets. AB - The global burden of kidney disease is increasing strikingly in parallel with increases in obesity and diabetes. Indeed, chronic kidney disease (CKD) and end stage renal disease (ESRD) coupled with comorbidities such as obesity, diabetes, and hypertension cost the health care system hundreds of billions of dollars in the US alone. The progression to ESRD in patients with obesity and diabetes continues despite widespread use of inhibitors of the renin-angiotensin aldosterone system (RAAS) along with aggressive blood pressure and glycemic control in these high-risk populations. Thereby, it is increasingly important to better understand the underlying mechanisms involved in obesity-related CKD in order to develop new strategies that prevent or interrupt the progression of this costly disease. In this context, a key mechanism that drives development and progression of kidney disease in obesity is endothelial dysfunction and associated tubulointerstitial fibrosis. However, the precise interactive mechanisms in the development of aortic and kidney endothelial dysfunction and tubulointerstitial fibrosis remain unclear. Further, strategies specifically targeting kidney fibrosis have yielded inconclusive benefits in human studies. While clinical data support the benefits derived from inhibition of the RAAS, there is a tremendous amount of residual risk for the progression of kidney disease in individuals with obesity and diabetes. There is promising experimental data to suggest that exercise, targeting inflammation and oxidative stress, lowering uric acid, and targeting the mineralocorticoid receptor signaling and/or sodium channel inhibition could improve tubulointerstitial fibrosis and mitigate progression of kidney disease in persons with obesity and diabetes. PMID- 28341272 TI - Kidney fibroblast growth factor 23 does not contribute to elevation of its circulating levels in uremia. AB - Fibroblast growth factor 23 (FGF23) secreted by osteocytes is a circulating factor essential for phosphate homeostasis. High plasma FGF23 levels are associated with cardiovascular complications and mortality. Increases of plasma FGF23 in uremia antedate high levels of phosphate, suggesting a disrupted feedback regulatory loop or an extra-skeletal source of this phosphatonin. Since induction of FGF23 expression in injured organs has been reported we decided to examine the regulation of FGF23 gene and protein expressions in the kidney and whether kidney-derived FGF23 contributes to the high plasma levels of FGF23 in uremia. FGF23 mRNA was not detected in normal kidneys, but was clearly demonstrated in injured kidneys, already after four hours in obstructive nephropathy and at 8 weeks in the remnant kidney of 5/6 nephrectomized rats. No renal extraction was found in uremic rats in contrast to normal rats. Removal of the remnant kidney had no effect on plasma FGF23 levels. Well-known regulators of FGF23 expression in bone, such as parathyroid hormone, calcitriol, and inhibition of the FGF receptor by PD173074, had no impact on kidney expression of FGF23. Thus, the only direct contribution of the injured kidney to circulating FGF23 levels in uremia appears to be reduced renal extraction of bone-derived FGF23. Kidney-derived FGF23 does not generate high plasma FGF23 levels in uremia and is regulated differently than the corresponding regulation of FGF23 gene expression in bone. PMID- 28341273 TI - Branched-chain amino acids enhance cyst development in autosomal dominant polycystic kidney disease. AB - Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney and liver cysts. The mammalian target of rapamycin (mTOR) cascade is one of the important pathways regulating cyst growth in ADPKD. Branched-chain amino acids (BCAAs), including leucine, play a crucial role to activate mTOR pathway. Therefore, we administered BCAA dissolved in the drinking water to Pkd1flox/flox:Mx1-Cre (cystic) mice from four to 22 weeks of age after polyinosinic-polycytidylic acid-induced conditional Pkd1 knockout at two weeks of age. The BCAA group showed significantly greater kidney/body weight ratio and higher cystic index in both the kidney and liver compared to the placebo-treated mice. We found that the L-type amino acid transporter 1 that facilitates BCAA entry into cells is strongly expressed in cells lining the cysts. We also found increased cyst-lining cell proliferation and upregulation of mTOR and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathways in the BCAA group. In vitro, we cultured renal epithelial cell lines from Pkd1 null mice with or without leucine. Leucine was found to stimulate cell proliferation, as well as activate mTOR and MAPK/ERK pathways in these cells. Thus, BCAA accelerated disease progression by mTOR and MAPK/ERK pathways. Hence, BCAA may be harmful to patients with ADPKD. PMID- 28341275 TI - Current thinking about the management of dysfunction of the temporomandibular joint: a review. AB - Increasingly the management of TMJ pathology is becoming a subspecialist interest. The number of patients having TMJ joint replacement had steadily increased over the last decade and there is now NICE guidance on this matter. Whilst the evidence of the management of TMJ disease is limited and there are few randomised controlled trials, the incidence of TMJ pathology has not changed and there is a requirement for guidance on the management. Whilst previously patients with TMJ pain were managed surgically, this is changing, and the vast bulk of initial management is non-surgical/medical. This paper will review the literature on TMD and provide guidance for management. PMID- 28341274 TI - Oxford Classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group. AB - Since the Oxford Classification of IgA nephropathy (IgAN) was published in 2009, MEST scores have been increasingly used in clinical practice. Further retrospective cohort studies have confirmed that in biopsy specimens with a minimum of 8 glomeruli, mesangial hypercellularity (M), segmental sclerosis (S), and interstitial fibrosis/tubular atrophy (T) lesions predict clinical outcome. In a larger, more broadly based cohort than in the original Oxford study, crescents (C) are predictive of outcome, and we now recommend that C be added to the MEST score, and biopsy reporting should provide a MEST-C score. Inconsistencies in the reporting of M and endocapillary cellularity (E) lesions have been reported, so a web-based educational tool to assist pathologists has been developed. A large study showed E lesions are predictive of outcome in children and adults, but only in those without immunosuppression. A review of S lesions suggests there may be clinical utility in the subclassification of segmental sclerosis, identifying those cases with evidence of podocyte damage. It has now been shown that combining the MEST score with clinical data at biopsy provides the same predictive power as monitoring clinical data for 2 years; this requires further evaluation to assess earlier effective treatment intervention. The IgAN Classification Working Group has established a well-characterized dataset from a large cohort of adults and children with IgAN that will provide a substrate for further studies to refine risk prediction and clinical utility, including the MEST-C score and other factors. PMID- 28341276 TI - Lung metastasectomy in adenoid cystic cancer: Is it worth it? AB - BACKGROUND AND PURPOSE: Adenoid cystic carcinoma (ACC) of salivary glands is characterized by long-term distant metastasis, most commonly in lungs. No agreement has been reached about the role of surgical treatment of pulmonary lesions. We evaluated the long-term results of lung metastasectomy for ACC in order to identify factors that should be taken into account in selecting patients eligible for surgery and treatment planning. PATIENTS AND METHODS: A retrospective study was conducted on 109 patients selected from our institutional experience and from the International Registry of Lung Metastases. Survival was calculated by Kaplan-Meier estimate and prognostic factors endowed with a predictive power for most other metastatic cancers were investigated. RESULTS: The cumulative survival was 66.8% at 5years and 40.5% at 10years. In patients with a disease-free interval (DFI) greater than 36months, the overall survival was 76.5% at 5years. Survival in case of complete surgical resection was 69.5% at 5years. Multivariate analysis confirmed DFI and completeness of resection resulted in the best prognostic variables. DISCUSSION: Lung metastasectomy should be considered as a therapeutic option to achieve local control of disease when 2 conditions are met: (1) complete surgical resection is feasible and (2) the time to pulmonary relapse after primary tumor treatment is greater than 36months. Symptomatic benefits of an incomplete lung resection in slow-growing tumors such as ACC remain uncertain. The turning point in the management of disseminated cancers will be clarified with biological profiling of ACC and the development of targeted therapies. PMID- 28341277 TI - Seasonality of Periprosthetic Femur Fractures in 12,700 Primary and Revision Total Hip Arthroplasties. AB - BACKGROUND: Periprosthetic femur fractures after primary and revision total hip arthroplasty (THA) are one of the most common long-term reasons for reoperation after THA. Previous investigations have analyzed the incidence and risk factors of these fractures. No previous study, however, has analyzed a variation in periprosthetic femur fractures between meteorologic seasons. The aim of this study was to compare the incidence of periprosthetic femur fractures after primary and revision THAs depending on the meteorologic season. METHODS: We identified 8920 patients (10,672 hips) who underwent primary THAs and 1830 patients (1998 hips) who underwent revision THAs at our institution between 1995 and 2011. All patients resided in the Upper Midwest at the time of surgery. Patients who experienced periprosthetic femur fractures were identified and categorized based on the meteorologic season. A Cox model was used to assess the association of seasonality with the risk of fracture. RESULTS: During the study period, 165 primary THAs and 80 revision THAs sustained a periprosthetic femur fracture. Using winter as a reference, the risk of a periprosthetic femur fracture after primary THA was not statistically higher in the spring (hazard ratio [HR] = 1.3; P = .2), autumn (HR = 1.4; P = .2), and summer (HR = 1.415; P = .1). Similarly, the risk of periprosthetic femur fracture after revision THA was not statistically higher in the spring (HR = 0.9; P = .6), autumn (HR = 0.6; P = .1), and summer (HR = 0.9; P = 1.0). CONCLUSION: The risk of periprosthetic femur fracture after primary and revision THA does not significantly differ between meteorologic seasons. PMID- 28341278 TI - Early Outcomes of Kinematic Alignment in Primary Total Knee Arthroplasty: A Meta Analysis of the Literature. AB - BACKGROUND: Kinematic alignment in total knee arthroplasty (TKA) seeks to more anatomically align the knee prosthesis to promote more physiological kinematics. However, there are questions about the durability, function, and complication rate of a non-mechanically aligned TKA. Therefore, the purpose of this study is to perform a systematic review and meta-analysis to evaluate early outcomes after kinematic alignment. METHODS: Two independent reviewers performed a systematic review of the English literature using both the MEDLINE and Embase databases searching for studies on kinematic TKA. Of the initial 839 published reports, 9 studies were included in the review. Four randomized, controlled trials comparing outcomes of kinematic and conventional alignment TKA were identified. Data were extracted and aggregated using inverse variance and Mantel-Haenszel fixed effects meta-analysis. RESULTS: Of an aggregated 877 kinematic TKAs, the cumulative survivorship was 97.4% at a weighted mean follow-up of 37.9 months. The most common reasons for revision were patellofemoral problems in 8 patients (1.2%). We found no difference in the complication rate between the 229 kinematic and 229 conventional TKA patients (3.9% vs 4.4%; P = .83). The kinematic TKA group had a higher combined postoperative Knee Society Score than the conventional TKA group (mean difference, 9.1 points; 95% confidence interval, 5.2-13.0 points; P < .001). CONCLUSION: Small deviations from the traditional mechanical axis alignment in TKA do not appear to impact overall survivorship or complication rates at short-term follow-up. Functional outcome as measured by the Knee Society Score favored kinematic alignment. These preliminary results illustrate the concept that there may be more than a single alignment target for all patients undergoing primary TKA. PMID- 28341279 TI - Letter to the Editor on 'The Prevalence of Positive Findings on Metal Artifact Reduction Sequence Magnetic Resonance Imaging in Metal-on-Metal Total Hip Arthroplasty': Part 1. PMID- 28341280 TI - Cost-Effectiveness of Staphylococcus aureus Decolonization Strategies in High Risk Total Joint Arthroplasty Patients. AB - BACKGROUND: The risk of prosthetic joint infection increases with Staphylococcus aureus colonization. The cost-effectiveness of decolonization is controversial. We evaluated cost-effectiveness decolonization protocols in high-risk arthroplasty patients. METHODS: An analytical model evaluated risk under 3 protocols: 4 swabs, 2 swabs, and nasal swab alone. These were compared to no screening and universal decolonization strategies. Cost-effectiveness was evaluated from the hospital, patient, and societal perspective. RESULTS: Under base case conditions, universal decolonization and 4-swab strategies were most effective. The 2-swab and universal decolonization strategy were most cost effective from patient and societal perspectives. From the hospital perspective, universal decolonization was the dominant strategy (much less costly and more effective). CONCLUSION: S aureus decolonization may be cost-effective for reducing prosthetic joint infections in high-risk patients. These results may have important implications for treatment of patients and for cost containment in a bundled payment system. PMID- 28341281 TI - Uncemented Metal-Backed Tantalum Patellar Components in Total Knee Arthroplasty Have a High Fracture Rate at Midterm Follow-Up. AB - BACKGROUND: There is interest in uncemented total knee arthroplasty due to the hope for long-term biologic fixation, but limited data are available regarding uncemented tantalum patellar components. The purpose of this study was to evaluate the radiographic outcomes of uncemented tantalum patellar implants at midterm follow-up. METHODS: We retrospectively reviewed a consecutive series of 30 knees in 29 patients who underwent cementless total knee arthroplasty with an uncemented metal-backed tantalum patella between September 2006 and April 2009. Patients were required to have a minimum radiographic follow-up of 2 years. Anteroposterior and lateral radiographs of the knee were evaluated for signs of implant fracture or gross loosening. Clinical follow-up was obtained by reviewing each patient's most recent orthopedic record. RESULTS: Thirty knees in 29 patients met inclusion criteria. The mean age of the cohort was 59.1 years with a mean body mass index of 31.9 kg/m2. Mean postoperative radiographic follow-up time was 5.5 years. Six fractures of the patellar component were noted. This represented a fracture rate of 20% among the entire cohort and 35% among the 17 knees with visible patellae on anteroposterior radiograph. All fractures had a transverse pattern. No gross patellar component loosening was noted. Among patients with component fractures, 2 required revisions for instability and 1 revision was for infection. CONCLUSION: Our results suggest a minimum 20% rate of component fracture at midterm follow-up. Although many of these patellar component fractures were asymptomatic, they have the potential to impact revision rates in the longer term. PMID- 28341282 TI - The state of the surgical workforce in Brazil. AB - BACKGROUND: A critical insufficiency of surgeons, anesthesiologists, and obstetricians exists around the world, leaving billions of people without access to safe operative care. The distribution of the surgical workforce in Brazil, however, is poorly described and rarely assessed. Though the surgical workforce is only one element in the surgical system, this study aimed to map and characterize the distribution of the surgical workforce in Brazil in order to stimulate discussion on future surgical policy reforms. METHODS: The distribution of the surgical workforce was extracted from the Brazilian Federal Medical Board registry as of July 2014. Included in the surgical workforce were surgeons, anesthesiologists, and obstetricians. RESULTS: There are 95,169 surgeons, anesthesiologists, and obstetricians in the surgical workforce of Brazil, creating a surgical workforce density of 46.55/100,000 population. This varies from 20.21/100,000 population in the North Region up to 60.32/100,000 population in the South Region. A total of 75.2% of the surgical workforce is located in the 100 biggest cities in Brazil, where only 40.4% of the population lives. The average age of a physician in the surgical workforce is 46.6 years. Women make up 30.0% of the surgical workforce, 15.8% of surgeons, 36.6% of anesthesiologists, and 53.8% of obstetricians and gynecologists. CONCLUSION: Brazil has a substantial surgical workforce, but inequalities in its distribution are concerning. There is an urgent need for increased surgeons, anesthesiologists, and obstetricians in states like Para, Amapa, and Maranhao. Female surgeons and anesthesiologists are particularly lacking in the surgical workforce, and incentives to recruit these physicians are necessary. Government policies and leadership from health organizations are required to ensure that the surgical workforce will be more evenly distributed in the future. PMID- 28341283 TI - Are antimicrobial peripherally inserted central catheters associated with reduction in central line-associated bloodstream infection? A systematic review and meta-analysis. AB - BACKGROUND: Antimicrobial peripherally inserted central catheters (PICCs) may reduce the risk of central line-associated bloodstream infection (CLABSI). However, data regarding efficacy are limited. We aimed to evaluate whether antimicrobial PICCs are associated with CLABSI reduction. METHODS: MEDLINE, EMBASE, CINHAL, and Web of Science were searched from inception to July 2016; conference proceedings were searched to identify additional studies. Study selection and data extraction were performed independently by 2 authors. RESULTS: Of 597 citations identified, 8 studies involving 12,879 patients met eligibility criteria. Studies included adult and pediatric patients from intensive care, long term care, and general ward settings. The incidence of CLABSI in patients with antimicrobial PICCs was 0.2% (95% confidence interval [CI], 0.0%-0.5%), and the incidence among nonantimicrobial catheters was 5.3% (95% CI, 2.6%-8.8%). Compared with noncoated PICCs, antimicrobial PICCs were associated with a significant reduction in CLABSI (relative risk [RR], 0.29; 95% CI, 0.10-0.78). Statistical heterogeneity (I2, 71.6%; T2 = 1.07) was resolved by publication type, with peer reviewed articles showing greater reduction in CLABSI (RR, 0.21; 95% CI, 0.06 0.74). Twenty-six patients (95% CI, 21-75) need to be treated with antimicrobial PICCs to prevent 1 CLABSI. Studies of adults at greater baseline risk of CLABSI experienced greater reduction in CLABSI (RR, 0.20; P = .003). CONCLUSIONS: Available evidence suggests that antimicrobial PICCs may reduce CLABSI, especially in high-risk subgroups. Randomized trials are needed to assess efficacy across patient populations. PMID- 28341284 TI - Prospective microbiologic evaluation of the forceps elevator in closed-channel duodenoscopes after reprocessing. AB - BACKGROUND: Endoscopes are well-known sources of bacterial transmission in health care facilities offering endoscopy services. The association between multidrug resistant bacterial infections in patients who had undergone an endoscopic retrograde cholangiopancreatography procedure with reprocessed duodenoscopes has been much discussed. Bacterial contamination of duodenoscopes has been attributed to difficulties with reprocessing these devices, specifically the distal end of the scope, which features a movable forceps elevator. In light of a recent Food and Drug Administration warning letter to Olympus regarding their closed-channel duodenoscope model TJF-Q180V, the aim of our study was to prospectively evaluate the efficacy and safety of our current reprocessing procedures with regard to the TJF-Q180V duodenoscope models used in our hospital. METHODS: From August 2015 March 2016, we prospectively collected microbiologic surveillance samples from 6 TJF-Q180V model duodenoscopes in routine use at the Division of Gastroenterology and Hepatology using the ESwab collection system (COPAN Diagnostics Inc, Murrieta, CA). RESULTS: A total of 237 microbiologic samples from the forceps elevator were obtained during the survey period. None of the samples yielded microorganism growth. CONCLUSION: These findings suggest that when following a diligent and validated reprocessing standard in accordance with manufacturer's recommendations, closed-channel endoscope models can still be used. Nevertheless, validated adaptions of current closed-channel duodenoscope models are needed to allow for simple and safe reprocessing. Furthermore, comprehensive postmarket surveillance needs to be established. PMID- 28341287 TI - Outcomes of the retrograde approach through epicardial versus non-epicardial collaterals in chronic total occlusion percutaneous coronary intervention. AB - BACKGROUND: The retrograde approach through epicardial collaterals (EC) for chronic total occlusion (CTO) percutaneous coronary intervention (PCI) is a challenging procedure. Our study aim was to evaluate the outcomes of patients undergoing CTO PCI using a retrograde approach through epicardial versus non epicardial collaterals (NEC). METHODS: We collected data from our single-center registry of consecutive patients undergoing retrograde CTO PCI, performed by an experienced operator through EC and NEC (septals and bypass grafts). Clinical, angiographic and procedural data were recorded. The primary endpoint (major adverse cardiac events, MACE) was a composite of cardiac death, target-vessel myocardial infarction (MI) and target-vessel revascularization (TVR) on follow up. RESULTS: During the study period, 318 CTO PCIs were performed. Of these, 81 procedures (25%) were performed retrogradely in 75 patients (38 using NEC [31 septals, 7 bypass grafts], 37 through EC [34 contralateral, 3 ipsilateral]). Clinical characteristics were balanced between EC and NEC. J-CTO score was 2.1+/ 1.1 and 2.2+/-1.2, respectively (p=0.92). Collateral tortuosity was more marked in EC. Technical and procedural success was lower in EC (35% vs. 76%, p<0.001; 30% vs. 76%, p<0.001; respectively). There were two perforations (5%) with need for intervention in EC, and none in NEC (p=0.15). After a median follow-up of 443 (331-744) days, MACE were observed in 12.9% (n=4) of EC vs. 5.4% (n=2) in NEC patients (p=0.28). CONCLUSIONS: In our experience, retrograde CTO PCI through EC was associated with lower success rate, and a numerically higher rate of perforation, as compared with NEC. Clinical outcomes on follow-up were similar. PMID- 28341288 TI - Establishing the structures within populations of models. AB - As computational biology matures as a field, increasing attention is being paid to the relation of computational models to their target. One aspect of this is addressing how computational models can appropriately reproduce the variation seen in experimental data, with one solution being to use populations of models united by a common set of equations (the framework), with each individual member of the population (each model) possessing its own unique set of equation parameters. These model populations are then calibrated and validated against experimental data, and as a whole reproduce the experimentally observed variation. The primary focus of validation thus becomes the population, with the individual models' validation seemingly deriving from their membership of this population. The role of individual models within the population is not clear, with uncertainty regarding the relationship between individual models and the population they make up. This work examines the role of models within the population, how they relate to the population they make up, and how both can be said to be validated in this context. PMID- 28341289 TI - Long-term culture with lipopolysaccharide induces dose-dependent cytostatic and cytotoxic effects in THP-1 monocytes. AB - Monocytes act as a first line of defence against invading pathogens and their dysfunctions seem to be a key factor in many immune disorders. However, the data on mechanisms underlying these dysfunctions remain elusive. In this study, we evaluated the effects of long-term (168h) lipopolysaccharide exposure on monocytes at low density cultures (1*105cells/ml). Treatment with low dose LPS (<=5MUg/ml) resulted in oxidative stress induction followed by p21 pathway activation, permanent cell cycle arrest and SASP development. Furthermore, high dose LPS (>=10MUg/ml) induced cell death involving mitochondrial pathways, death receptors as well as p21-dependent DNA damage response activation mediated by ROS generation and TNF-alpha release. Additionally, exposure to high dose of LPS resulted in THP-1 monocytes differentiation to macrophages. In conclusion, long term culture with LPS exerts in low density monocytes cytostatic/cytotoxic effects in a dose-dependent manner by inducing senescence associated with chronic inflammation at low doses and initiation of cell death at higher doses. These findings shed new light on understanding of monocytes dysfunction, an issue relevant to chronic inflammation and many immune disorders. PMID- 28341290 TI - The cessation of breathing in the chicken embryo during cold-hypometabolism. AB - The avian embryo toward end-incubation combines gas exchange through the chorioallantoic membrane (CAM) and pulmonary ventilation (VE). The main experiments examined breathing activity during cold-hypometabolism. Chicken embryos close to hatching were prepared for simultaneous measurements of oxygen consumption ( [Formula: see text] ) and carbon dioxide production ( [Formula: see text] ; open-flow methodology) and breathing frequency (f; barometric technique). As ambient (Ta) and egg temperature (Tegg) dropped, breathing eventually ceased at ~18 degrees C, when [Formula: see text] and [Formula: see text] were 22-28% of the normothermic values. With the eggshell experimentally covered to reduce CAM gas exchange breathing ceased at slightly lower [Formula: see text] and [Formula: see text] (17-18% of normothermia). Once breathing had stopped, egg exposure to hypoxia (10% or 5% O2) or hypercapnia (3% or 8% CO2) did not resume breathing, which recovered with re-warming. In normothermia, 10% O2 caused hypometabolism and tachypnea; differently, in 5% O2 [Formula: see text] dropped as much as with hypothermia and breathing stopped, to recover upon return in air. Correlation analysis among Ta, Tegg, [Formula: see text] , [Formula: see text] and f during cooling and re-warming indicated that f followed more closely the changes in [Formula: see text] and, especially, in [Formula: see text] than the changes in Ta or Tegg. Some considerations suggest that in this experimental model the cessation of breathing in hypothermia or severe hypoxia may be due to hypometabolism, while the lack of chemo-responses may have a different mechanistic basis. PMID- 28341291 TI - Attitudes of students of a health sciences university towards the extension of smoke-free policies at the university campuses of Barcelona (Spain). AB - OBJECTIVE: To assess attitudes towards the extension of outdoor smoke-free areas on university campuses. METHODS: Cross-sectional study (n=384) conducted using a questionnaire administered to medical and nursing students in Barcelona in 2014. Information was obtained pertaining to support for indoor and outdoor smoking bans on university campuses, and the importance of acting as role models. Logistic regression analyses were performed to examine agreement. RESULTS: Most of the students agreed on the importance of health professionals and students as role models (74.9% and 64.1%, respectively) although there were statistically significant differences by smoking status and age. 90% of students reported exposure to smoke on campus. Students expressed strong support for indoor smoke free policies (97.9%). However, only 39.3% of participants supported regulation of outdoor smoking for university campuses. Non-smokers (OR=12.315; 95% CI: 5.377 28.204) and students >=22 years old (OR=3.001; 95% CI: 1.439-6.257) were the strongest supporters. CONCLUSIONS: The students supported indoor smoke-free policies for universities. However, support for extending smoke-free regulations to outdoor areas of university campuses was limited. It is necessary to educate students about tobacco control and emphasise their importance as role models before extending outdoor smoke-free legislation at university campuses. PMID- 28341292 TI - Antioxidant response to metal pollution in Phragmites australis from Anzali wetland. AB - This research was conducted to examine variations of antioxidant enzyme activity in Phragmites australis as a biomarker for metals such as As, Pb, Cu, and Cd. Samples of sediment and plants were collected from 7 stations located in Anzali wetland. Biochemical parameters including Catalase, Peroxidase and Ascorbate Peroxidase activity were analyzed in the roots, stems and leaves of P. australis. The obtained results indicated that there were significant differences among activities of antioxidant enzymes in three organs (p<0.05). Antioxidant enzyme activities in the organs for all studied stations were as the following order: stem94.5%). Especially, via pumping the fabric rolled into a multilayered tube, various types of oils on water surface can be continuously separated in situ without any water uptake. Furthermore, the superhydrophobic fabrics show excellent superhydrophobic stability, and can resist different chemicals, such as salty, acidic, and alkaline solutions, oils, and hot water. After the abrasion of 400cycles, the broken fabric still possesses highly hydrophobicity with water contact angle of 145 degrees . Therefore, due to simple fabrication steps, low cost, and scalable process, the as-prepared fabrics can be applied in the separation of oils and other organic solvents from water. PMID- 28341296 TI - Ocean acidification increases larval swimming speed and has limited effects on spawning and settlement of a robust fouling bryozoan, Bugula neritina. AB - Few studies to date have investigated the effects of ocean acidification on non reef forming marine invertebrates with non-feeding larvae. Here, we exposed adults of the bryozoan Bugula neritina and their larvae to lowered pH. We monitored spawning, larval swimming, settlement, and post-settlement individual sizes at two pHs (7.9 vs. 7.6) and settlement dynamics alone over a broader pH range (8.0 down to 6.5). Our results show that spawning was not affected by adult exposure (48h at pH7.6), larvae swam 32% faster and the newly-settled individuals grew significantly larger (5%) at pH7.6 than in the control. Although larvae required more time to settle when pH was lowered, reduced pH was not lethal, even down to pH6.5. Overall, this fouling species appeared to be robust to acidification, and yet, indirect effects such as prolonging the pelagic larval duration could increase predation risk, and might negatively impact population dynamics. PMID- 28341297 TI - GEANT4 models for the secondary radiation flux in the collimation system of a 300MeV proton microbeam. AB - In Harbin, we are developing a 300MeV proton microbeam for many applications in space science including upset studies in microelectronic devices, radiation hardness of materials for satellites and radiation effects in human tissues. There are also applications of this facility proposed for proton therapy. The microbeam system will employ a purpose-built proton synchrotron to provide the beam. However there are many challenges to be addressed in the design, construction and operation of this facility. Here we address two important design aspects for which we apply GEANT4 modeling. First, the high energy proton beam interacts strongly with beam line materials, especially the collimation slits, to produce showers of secondary particles which could introduce significant background signals and degrade the resolution of the proton microbeam. Second, the beam transport within the residual vacuum of the beam line may also introduce undesirable background radiation. In both cases mitigation strategies need to be incorporated during the design phase of the new system. We study the use of a dipole magnet following the aperture collimator to reduce the flux of secondary particles incident on the analysis chamber. Monte Carlo simulations are performed using GEANT4 and SRIM. By inserting the dipole magnet, we find as expected a significant reduction in the scattering of protons and other particles, such as neutrons and gamma rays, at the collimation system exit position. Secondary radiation from the residual gas pressure within the beam line vacuum system are also modelled and found to be negligible under the standard operating conditions. PMID- 28341298 TI - Providing hope. PMID- 28341299 TI - Adopting a public health approach to addressing child sexual abuse and exploitation. PMID- 28341301 TI - Disease Modeling in Stem Cell-Derived 3D Organoid Systems. AB - Organoids are 3D in vitro culture systems derived from self-organizing stem cells. They can recapitulate the in vivo architecture, functionality, and genetic signature of original tissues. Thus, organoid technology has been rapidly applied to understanding stem cell biology, organogenesis, and various human pathologies. The recent development of human patient-derived organoids has enabled disease modeling with precision, highlighting their great potential in biomedical applications, translational medicine, and personalized therapy. In light of recent breakthroughs using organoids, it is only apt that we appreciate the advantages and shortcomings of this technology to exploit its full potential. We discuss recent advances in the application of organoids in studying cancer and hereditary diseases, as well as in the examination of host cell-microorganism interactions. PMID- 28341300 TI - A phase I pharmacokinetic study of intraperitoneal bortezomib and carboplatin in patients with persistent or recurrent ovarian cancer: An NRG Oncology/Gynecologic Oncology Group study. AB - PURPOSE: Intraperitoneal (IP) therapy improves survival compared to intravenous (IV) treatment for women with newly diagnosed, optimally cytoreduced, ovarian cancer. However, the role of IP therapy in recurrent disease is unknown. Preclinical data demonstrated IP administration of the proteasome inhibitor, bortezomib prior to IP carboplatin increased tumor platinum accumulation resulting in synergistic cytotoxicity. We conducted this phase I trial of IP bortezomib and carboplatin in women with recurrent disease. METHODS: Women with recurrent ovarian cancer were treated with escalating doses of IP bortezomib - in combination with IP carboplatin (AUC 4 or 5) every 21days for 6cycles. Pharmacokinetics of both agents were evaluated in cycle 1. RESULTS: Thirty-three women participated; 32 were evaluable for safety. Two patients experienced dose limiting toxicity (DLT) at the first dose level (carboplatin AUC 5, bortezomib 0.5mg/m2), prompting carboplatin reduction to AUC 4 for subsequent dose levels. With carboplatin dose fixed at AUC 4, bortezomib was escalated from 0.5 to 2.5mg/m2 without DLT. Grade 3/4 related toxicities included abdominal pain, nausea, vomiting, and diarrhea which were infrequent. The overall response rate in patients with measurable disease (n=21) was 19% (1 complete, 3 partial). Cmax and AUC in peritoneal fluid and plasma increased linearly with dose, with a favorable exposure ratio of the peritoneal cavity relative to peripheral blood plasma. CONCLUSION: IP administration of this novel combination was feasible and showed promising activity in this phase I trial of heavily pre-treated women with ovarian cancer. Further evaluation of this IP combination should be conducted. PMID- 28341302 TI - Health systems in the Republic of Congo: challenges and opportunities for implementing tuberculosis and HIV collaborative service, research, and training activities. AB - The Republic of Congo is on the World Health Organization (WHO) list of 'high burden' countries for tuberculosis (TB) and HIV. TB is the leading cause of death among HIV-infected patients in the Republic of Congo. In this viewpoint, the available data on TB and HIV in the Republic of Congo are reviewed, and the gaps and bottlenecks that the National TB Control Program (NTCP) faces are discussed. Furthermore, priority requirements for developing and implementing TB and HIV collaborative service activities are identified. HIV and TB control programs operate as distinct entities with separate case management plans. The implementation of collaborative TB/HIV activities to evaluate and monitor the management of TB/HIV co-infected individuals remains inefficient in most regions, and these activities are sometimes non-existent. This reveals major challenges that require definition in order to improve the delivery of healthcare. The NTCP lacks adequate resources for optimal implementation of control measures of TB and HIV compliance and outcomes. The importance of aligning and integrating TB and HIV treatment services (including follow-up) and adherence support services through coordinated and collaborative efforts between individual TB and HIV programs is discussed. Aligning and integrating TB and HIV treatment services through coordinated and collaborative efforts between individual TB and HIV programs is required. However, the WHO recommendations are generic, and health services in the Republic of Congo need to tailor their TB and HIV programs according to the availability of resources and operational feasibility. This will also open opportunities for synergizing collaborative TB/HIV research and training activities, which should be prioritized by the donors supporting the TB/HIV programs. PMID- 28341303 TI - Changing Perceptions of Harm of E-Cigarettes Among U.S. Adults, 2012-2015. AB - INTRODUCTION: Although the impact of long-term use of electronic cigarettes (e cigarettes) on health is still unknown, current scientific evidence indicates that e-cigarettes are less harmful than combustible cigarettes. The study examined whether perceived relative harm of e-cigarettes and perceived addictiveness have changed during 2012-2015 among U.S. adults. METHODS: Data were from Tobacco Products and Risk Perceptions surveys of probability samples representative of U.S. adults in 2012, 2014, and 2015. Changes over time in perceived harmfulness of e-cigarettes were examined using pairwise comparisons of proportions and multinomial logistic regression analysis. Analyses were conducted in January 2016. RESULTS: Whereas 11.5% and 1.3% of adults perceived e-cigarettes to have about the same level of harm and to be more harmful than cigarettes, respectively, in 2012, 35.7% and 4.1% did so in 2015. The proportion of adults who thought e-cigarettes were addictive more than doubled during 2012-2015 (32.0% in 2012 vs 67.6% in 2015). Compared with 2012, the odds of perceiving e cigarettes to be equally or more harmful (than to be less harmful) doubled (95% CI=1.64, 2.41) in 2014, and tripled (95% CI=2.60, 3.81) in 2015. CONCLUSIONS: There is an increase in the proportion of U.S. adults who misperceive the harm of e-cigarettes and consider them to be as harmful as combustible cigarettes. The study highlights the need to design public health messages that accurately interpret the scientific data on the potential harm of e-cigarettes and clearly differentiate the absolute from the relative harm of e-cigarettes. PMID- 28341304 TI - The normal variants in the left bundle branch system. AB - This article reviewed the main anatomic and physiopathological aspects of the left bundle branch from its origin in the His bundle and its intraventricular distribution on the left endocardial surface. The results are based on the relevant literature and on personal observations executed on 206 hearts distributed as follows: 67 dogs, 60 humans, 45 sheep, 22 pigs, 10 cows, 2 monkeys, 1 guanaco, and 1 sea lion. The main anatomical features of the His Purkinje conducting system may be summarized as follows: The bundle of His is composed by two segments: the penetrating and branching portions. LBB originates in the branching portion located underneath the membranous septum. There is no true bifurcation of the bundle of His in a human heart. Short after its origin the LBB gives rise to its two main fascicles, anterior and posterior, both heading the anterior and posterior papillary muscles, respectively. The anterior division is thinner and longer than the posterior one. The RBB and the most anterior fibers of the LBB arise at the end of the branching portion. In some cases a well-defined left septal fascicle can be identified, usually arising from the posterior division. Each division gives off small fibers and false tendons crossing the left ventricular cavity connecting the papillary between them or the papillary muscles with the septal surface. From each division of the LBB, their corresponding Purkinje networks emerge covering the subendocardium of the septum and the free wall of the left ventricles. There are critical relationships of the proximal segments of the His-Purkinje system with the surrounding cardiac structures whose pathologic processes may damage the conducting tissue. PMID- 28341305 TI - Welcome to The Residents and Fellows Corner. PMID- 28341306 TI - High-frequency QRS analysis in the evaluation of chest pain in the emergency department. AB - OBJECTIVES: High frequency QRS (HFQRS) analysis has been shown to be an accurate marker for myocardial ischemia. Our objective was to test the use of HFQRS in diagnosing ACS in the emergency department. METHODS: 324 patients presenting to the ED with chest pain were enrolled. Resting ECG was recorded and later analyzed by an HFQRS algorithm. Results were compared to the conventional ECG diagnosis by 3 independent interpretations: treating physician, expert cardiologist and an automated computer program. RESULTS: The HFQRS analysis demonstrated improved sensitivity (67.5%) for the NSTE-ACS group compared to the human interpreters (59.7% and 53.2% for the treating physician and cardiologist respectively) with similar specificity. The automatic program had significantly lower sensitivity (31%) with a higher specificity (77%). CONCLUSIONS: HFQRS which has shown great promise in diagnosing stable CAD may also be helpful in the ED for diagnosing ACS. PMID- 28341307 TI - The efficacy advantage of evolocumab (AMG 145) dosed at 140mg every 2weeks versus 420mg every 4weeks in patients with hypercholesterolemia: Evidence from a meta analysis. AB - BACKGROUND: Evolocumab (AMG 145), a PCSK9 inhibitor, has been shown to decrease low-density lipoprotein cholesterol (LDL-C) levels. Doses of 140mg administered every 2weeks (Q2W) and 420mg administered every 4weeks (Q4W) are widely used, and both dosing schedules were effective in clinical trials. However, some researchers have speculated that 140mg Q2W administration has equal or even greater efficacy. This meta-analysis was performed to assess the differences in efficacy and safety between the two doses. METHODS: We searched the PubMed, EMBASE, and Web of Science databases to identify relevant clinical trials published before January 2016. A total of 2403 patients from 8 randomized controlled trials were identified and included in the analysis. RESULTS: Evolocumab administered at 140mg Q2W resulted in a greater percent change from baseline in LDL-C concentration (-7.27; 95% confidence interval (CI), -10.36 to 4.18) and had greater efficacy in achieving the treatment goal of LDL-C <=1.8mmol/L with an relative risk (RR) of 1.09 (95% CI, 1.00 to 1.18) compared with 420mg Q4W in patients who were concomitantly treated with statins. These findings were not significantly different between the 140mg Q2W and 420mg Q4W groups when evolocumab was administered as monotherapy. There was no difference in the rate of occurrence of the main treatment-related adverse events between the two doses. CONCLUSIONS: Evolocumab administered at 140mg Q2W was more effective than the 420mg Q4W dosage at lowering lipid concentrations, especially in patients who concomitantly received stable statin therapy. PMID- 28341308 TI - Biochemical characterization and stability of immune globulin intravenous 10% liquid (Panzyga(r)). AB - Panzyga(r) is a new glycine-formulated immune globulin intravenous 10% liquid for the treatment of patients suffering from immunodeficiencies and autoimmune diseases. Panzyga(r) is a high purity, native and functional IgG product with an IgG subclass distribution equivalent to normal plasma. The levels of hemagglutinins and accompanying plasma proteins (including IgA and IgM) are low. Potential procoagulant activity is not detectable. Functional activity of the IgG was demonstrated by opsonophagocytosis and receptor binding assays. Dynamic light scattering measurements and fluorescent dye binding were used to characterize the integrity of the IgG molecule. Panzyga(r) is stable under refrigerated storage for at least two years regarding all assessed physicochemical and functional parameters; it can also be stored at room temperature for at least twelve months within its total shelf-life. PMID- 28341309 TI - Polymorphic distribution of proteins in solution by mass spectrometry: The analysis of insulin analogues. AB - The characterization of conformational and oligomeric distribution of proteins is of paramount importance for the understanding of the correlation between structure and function. Among the bioanalytical approaches currently available, the electrospray ionization-mass spectrometry (ESI-MS) coupled to ion mobility spectrometry (IMS) is the best suited for high resolution identification with high sensitivity, allowing the in situ separation of oligomeric and conformational species. We tested the performance of the ESI-MS technique along with the IMS separation approach on a broad variety of insulin and insulin analogues with distinct oligomeric distribution pattern. The measurement of commercial insulin allowed the identification of species ranging from monomers to hexamers and their complexes with zinc ions. Dissimilar distribution profile for regular insulin as a function of formulation component and among the insulin analogues were observed by ESI-IMS-MS but not by ESI-MS along, crystallographic assays or size-exclusion chromatography. These data suggest the additional suitability of ESI-IMS-MS in conformational and oligomeric profiling of biomacromolecules and biopharmaceuticals. The easiness of the technique provides further motivation for its application in the characterization of both raw and formulated protein biopharmaceuticals in routine and comparability exercises. PMID- 28341310 TI - Women in Leadership: Why So Few and What to Do About It. AB - The numbers of women in medical school and in medical training have increased dramatically and are near 50% overall, but the number of women who advance to senior and leadership positions is not nearly this high. There are many reasons why the number of women in leadership roles in academic medicine has not kept pace with the number of women entering the field of medicine. Two popular themes are the glass ceiling (referring to an invisible barrier to advancement) and the leaky pipeline (the loss of women faculty along the path, or pipeline, to advancement). I believe that both come into play. Glass ceiling issues tend to be of two types: those related to the institutional culture and those related to problems of bias, especially unconscious bias. Leaky pipeline issues include the challenges of work-life integration and the need for leadership development for women. There are solutions to all of these challenges. These include improving institutional culture; making sure women advance as quickly as men and are paid equitably; ensuring that there are resources to help with work-life balance, related not only to family but to all aspects of life; and providing adequate mentoring and leadership training. These measures will help all faculty, as factors that hamper women's advancement may hamper men as well. Although these themes are broadly applicable, there are strategies that can address them all. We just need to be aware, and be proactive, and we will succeed in breaking the glass ceiling and patching the leaky pipeline. PMID- 28341311 TI - R-SCAN: Imaging for Headache. PMID- 28341312 TI - Evaluation of methods for the assessment of attention while driving. AB - The ability to assess the current attentional state of the driver is important for many aspects of driving, not least in the field of partial automation for transfer of control between vehicle and driver. Knowledge about the driver's attentional state is also necessary for the assessment of the effects of additional tasks on attention. The objective of this paper is to evaluate different methods that can be used to assess attention, first theoretically, and then empirically in a controlled field study and in the laboratory. Six driving instructors participated in all experimental conditions of the study, delivering within-subjects data for all tested methods. Additional participants were recruited for some of the conditions. The test route consisted of 14km of motorway with low to moderate traffic, which was driven three times per participant per condition. The on-road conditions were: baseline, driving with eye tracking and self-paced visual occlusion, and driving while thinking aloud. The laboratory conditions were: Describing how attention should be distributed on a motorway, and thinking aloud while watching a video from the baseline drive. The results show that visual occlusion, especially in combination with eye tracking, was appropriate for assessing spare capacity. The think aloud protocol was appropriate to gain insight about the driver's actual mental representation of the situation at hand. Expert judgement in the laboratory was not reliable for the assessment of drivers' attentional distribution in traffic. Across all assessment techniques, it is evident that meaningful assessment of attention in a dynamic traffic situation can only be achieved when the infrastructure layout, surrounding road users, and intended manoeuvres are taken into account. This requires advanced instrumentation of the vehicle, and subsequent data reduction, analysis and interpretation are demanding. In conclusion, driver attention assessment in real traffic is a complex task, but a combination of visual occlusion, eye tracking and thinking aloud is a promising combination of methods to come further on the way. PMID- 28341313 TI - Perioperative Topical Nonsteroidal Anti-inflammatory Drugs for Macular Edema Prophylaxis Following Cataract Surgery. PMID- 28341314 TI - Fretting and Corrosion at the Backside of Modular Cobalt Chromium Acetabular Inserts: A Retrieval Analysis. AB - BACKGROUND: Adverse local tissue reaction formation has been suggested to occur with the Modular Dual Mobility (MDM) acetabular design. Few reports in the literature have evaluated fretting and corrosion damage between the acetabular shell and modular metal inserts in this modular system. We evaluated a series of 18 retrieved cobalt chromium MDM inserts for evidence of fretting and corrosion. METHODS: We assessed the backsides of 18 MDM components for evidence of fretting and corrosion in polar and taper regions based on previously established methods. We collected and assessed 30 similarly designed modular inserts retrieved from metal-on-metal (MoM) total hip arthroplasties as a control. RESULTS: No specific pattern of fretting or corrosion was identified on the MDM inserts. Both fretting and corrosion were significantly greater in the MoM cohort than the MDM cohort, driven by higher fretting and corrosion scores in the engaged taper region of the MoM inserts. CONCLUSION: MoM components demonstrated more fretting and corrosion than MDM designs, specifically at the taper region, likely driven by differences in the taper engagement mechanism and geometry among the insert designs. The lack of significant fretting and corrosion observed in the MDM inserts are inconsistent with recent claims that this interface may produce clinically significant metallosis and adverse local tissue reactions. PMID- 28341315 TI - Initial clinical experience of postmastectomy intensity modulated proton therapy in patients with breast expanders with metallic ports. AB - PURPOSE: The feasibility of proton postmastectomy radiation therapy in patients reconstructed with expanders has not been previously reported, limiting treatment options. We analyzed the dosimetric impact of the metallic port contained within expanders on intensity modulated proton therapy (IMPT) and report our techniques and quality control for treating patients in this setting. METHODS AND MATERIALS: Twelve patients with the same expander model underwent 2-field IMPT as part of a prospective registry. All planning dosimetry was checked with an in-house graphic processing unit--based Monte Carlo simulation. Proton ranges through the expander were validated using a sample implant. Dosimetric impact of setup metallic port position uncertainty was evaluated. Pre- and posttreatment photographs were obtained and acute toxicity was graded using the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Nine patients had bilateral skin-sparing mastectomy with bilateral tissue expander reconstruction, and 3 patients had unilateral skin-sparing mastectomy and reconstruction. The left side was treated in 10 patients and the right side in 2. Target coverage and normal tissue dose uncertainties resulting from the expander were small and clinically acceptable. The maximum physician-assessed acute radiation dermatitis was grade 3 in 1 patient, grade 2 in 5 patients, and grade 1 in 6 patients. CONCLUSIONS: Postmastectomy IMPT in breast cancer patients with expanders is feasible and associated with favorable clinical target volume coverage and normal tissue sparing, even when taking into account treatment uncertainties; therefore, these patients should be eligible to participate in clinical trials studying the potential role of proton therapy in breast cancer. We caution, however, that institutions should carry out similar analyses of the physical properties and dosimetric impact of the particular expanders used in their practice before considering IMPT. PMID- 28341316 TI - What are appropriate physics manuscripts for submission to the Practical Radiation Oncology journal? PMID- 28341317 TI - Target volume and artifact evaluation of a new data-driven 4D CT. AB - PURPOSE: Four-dimensional computed tomography (4D CT) is often used to define the internal gross target volume (IGTV) for radiation therapy of lung cancer. Traditionally, this technique requires the use of an external motion surrogate; however, a new image, data-driven 4D CT, has become available. This study aims to describe this data-driven 4D CT and compare target contours created with it to those created using standard 4D CT. METHODS AND MATERIALS: Cine CT data of 35 patients undergoing stereotactic body radiation therapy were collected and sorted into phases using standard and data-driven 4D CT. IGTV contours were drawn using a semiautomated method on maximum intensity projection images of both 4D CT methods. Errors resulting from reproducibility of the method were characterized. A comparison of phase image artifacts was made using a normalized cross correlation method that assigned a score from +1 (data-driven "better") to -1 (standard "better"). RESULTS: The volume difference between the data-driven and standard IGTVs was not significant (data driven was 2.1 +/- 1.0% smaller, P = .08). The Dice similarity coefficient showed good similarity between the contours (0.949 +/- 0.006). The mean surface separation was 0.4 +/- 0.1 mm and the Hausdorff distance was 3.1 +/- 0.4 mm. An average artifact score of +0.37 indicated that the data-driven method had significantly fewer and/or less severe artifacts than the standard method (P = 1.5 * 10-5 for difference from 0). CONCLUSIONS: On average, the difference between IGTVs derived from data-driven and standard 4D CT was not clinically relevant or statistically significant, suggesting data-driven 4D CT can be used in place of standard 4D CT without adjustments to IGTVs. The relatively large differences in some patients were usually attributed to limitations in automatic contouring or differences in artifacts. Artifact reduction and setup simplicity suggest a clinical advantage to data-driven 4D CT. PMID- 28341318 TI - Online palliative care and oncology patient education resources through Google: Do they meet national health literacy recommendations? AB - PURPOSE: The Google search engine is a resource commonly used by patients to access health-related patient education information. The American Medical Association and National Institutes of Health recommend that patient education resources be written at a level between the third and seventh grade reading levels. We assessed the readability levels of online palliative care patient education resources using 10 readability algorithms widely accepted in the medical literature. METHODS AND MATERIALS: In October 2016, searches were conducted for 10 individual terms pertaining to palliative care and oncology using the Google search engine; the first 10 articles written for the public for each term were downloaded for a total of 100 articles. The terms included palliative care, hospice, advance directive, cancer pain management, treatment of metastatic disease, treatment of brain metastasis, treatment of bone metastasis, palliative radiation therapy, palliative chemotherapy, and end-of-life care. We determined the average reading level of the articles by readability scale and Web site domain. RESULTS: Nine readability assessments with scores equivalent to academic grade level found that the 100 palliative care education articles were collectively written at a 12.1 reading level (standard deviation, 2.1; range, 7.6 17.3). Zero articles were written below a seventh grade level. Forty-nine (49%) articles were written above a high school graduate reading level. The Flesch Reading Ease scale classified the articles as "difficult" to read with a score of 45.6 of 100. The articles were collected from 62 Web site domains. Seven domains were accessed 3 or more times; among these, www.mskcc.org had the highest average reading level at a 14.5 grade level (standard deviation, 1.4; range, 13.4-16.1). CONCLUSIONS: Most palliative care education articles readily available on Google are written above national health literacy recommendations. There is need to revise these resources to allow patients and their families to derive the most benefit from these materials. PMID- 28341319 TI - Improving patient safety and workflow efficiency with standardized pretreatment radiation therapist chart reviews. AB - PURPOSE: Radiation therapists play a critical role in ensuring patient safety; however, they are sometimes given insufficient time to perform quality assurance (QA) of a patient's treatment chart and documentation before the start of treatment. In this work, we show the benefits of introducing a formal therapist prestart QA checklist, completed in a quiet space well in advance of treatment, into our workflow. METHODS AND MATERIALS: A therapist prestart QA checklist was created by analyzing in-house variance reports and treatment unit delays over 6 months. Therapists were then given dedicated time and workspace to perform their checks within the dosimetry office of our department. The effectiveness of the checklist was quantified by recording the percentage of charts that underwent QA before treatment, the percentage of charts with errors needing intervention, and treatment unit delays during a nearly 2-year period. The frequency and types of errors found by the prestart QA were also recorded. RESULTS: Through the use of therapist prestart QA, instances of treatment unit delays were reduced by up to a factor of 9 during the first year of the program. At the outset of this new initiative, nearly 40% of charts had errors requiring intervention, with the majority being scheduling related. With upstream workflow changes and automation, this was reduced over the period of a year to about 10%. CONCLUSIONS: The number of treatment unit delays was dramatically reduced by using a formal therapist prestart QA checklist completed well in advance of treatment. The data collected via the checklist continue to be used for further quality improvement efforts. PMID- 28341320 TI - Gallbladder toxicity and high-dose ablative-intent radiation for liver tumors: Should we constrain the dose? AB - PURPOSE: Little is known about the risk of gallbladder toxicity from hypofractionated (HFXRT) and stereotactic body radiation therapy (SBRT). We report on gallbladder toxicity and attribution to treatment in a prospective series of patients with primary and metastatic liver tumors receiving ablative intent HFXRT and SBRT with protons. METHODS AND MATERIALS: We evaluated 93 patients with intact gallbladders enrolled in either of 2 trials investigating proton HFXRT and SBRT for primary and metastatic liver tumors from 2009 to 2014. Patients received 45 to 67.5 GyE in 15 fractions for primary liver tumors (n = 45) and 30 to 50 GyE in 5 fractions for metastatic tumors (n = 48). No gallbladder dose constraints were used at treatment, and gallbladder volumes and dose-volume histograms were created retrospectively. Attributable toxicity was defined as cholecystitis or perforation without preexisting gallbladder disease. Baseline factors were evaluated using Fisher exact test and the nonparametric K sample test. RESULTS: At baseline, 25 patients had preexisting cholelithiasis and 15 underwent biliary stenting before or after RT. Median follow-up after treatment was 11.8 months (range, 0.1-59.2 months). Despite maximum gallbladder doses >70 GyE in 41%, >80 GyE in 31%, and >90 GyE in 13% (equieffective dose at 2 Gy [EQD2], alpha/beta = 3), there were no attributable cases of gallbladder toxicity. Two patients developed grade 3 and 4 cholecystitis 16 and 2 months after treatment, respectively, and both had a strong history of preexisting cholelithiasis and biliary stenting. These patients received relatively low gallbladder doses with mean doses of 0.02 GyE and 5.1 GyE (EQD2, alpha/beta = 3), well below the 17.1 GyE mean for the remaining cohort (range, 0-81.1 GyE, EQD2). CONCLUSIONS: We identified no relationship between gallbladder dose and toxicity and did not reach the maximum tolerated gallbladder dose in this cohort treated with high-dose radiation. We recommend not constraining dose to the gross tumor volume to protect the gallbladder during ablative HFXRT and SBRT. PMID- 28341321 TI - Reprint of "Repeated adolescent activity-based anorexia influences central estrogen signaling and adulthood anxiety-like behaviors in rats". AB - Anorexia nervosa (AN) typically presents in adolescence and is highly comorbid with anxiety and depression, which often persist after elimination of AN symptomology. The activity-based anorexia (ABA) paradigm allows for evaluation of behavioral and neuroendocrine consequences of AN-like behaviors, including voluntary anorexia, hyperactivity, and disruption of the hypothalamic-pituitary gonadal (HPG) and the hypothalamic pituitary adrenal (HPA) axis. Because ABA in adolescent females results in increased anxiety-like behavior in adulthood and the estrogen signaling system has been shown to play a role in anxiety and food intake, we investigated the role of ovarian hormones in adolescent ABA-treated rats, and long-term effects of mid- and late adolescent ABA exposure on behavior and estrogen signaling. While previous research demonstrated that two bouts of ABA during adolescence resulted in decreased time in the open arm of the elevated plus maze (EPM) and increased activity of the HPA axis in response to a novel stressor, here we show that one bout of ABA in mid-or late-adolescence did not result in the same behavioral outcome. Two exposures to ABA during adolescence were necessary to produce long-term anxiety-like behavior on the EPM. Finally, removal of ovarian hormones by ovariectomy (OVX) prior to puberty did not attenuate long-term behavioral consequences of ABA in adolescence, and estrogen receptor beta (ERbeta) expression level in the amygdala of ABA rats was significantly lower than control subjects. Taken together, these studies identify enduring effects of ABA in adolescent females that may be mediated by ABA-induced changes to CNS ERbeta signaling that increase anxiety-like behaviors. PMID- 28341322 TI - Re: Clonal Evolution of Chemotherapy-resistant Urothelial Carcinoma. PMID- 28341323 TI - Experts' perspective on a definition for delayed return-to-work after surgery for nontraumatic upper extremity disorders: Recommendations and implications. AB - STUDY DESIGN: Descriptive study. INTRODUCTION: A delayed return to work (RTW) is often associated with poorer outcomes after a workplace injury but is ill defined. PURPOSE OF THE STUDY: To define delayed RTW after surgery for nontraumatic upper extremity conditions. METHODS: Experts were consulted to define delayed RTW and whether a universal time point can determine the transition from early to delayed RTW. RESULTS: Forty-two experts defined a delayed RTW as either a worker not returning to preinjury (or similar) work within the expected time frame (45%); not returning to any type of work (36%); or recovering slower than expected (12%). Two-thirds of experts believed that universal time points to delineate delayed RTW should be avoided. DISCUSSION: Multiple factors complicate a uniform definition of delayed RTW. CONCLUSION: Defining delayed RTW should be individualized with due consideration to the type of work. Time-based cutoffs for outcome measurement may not be appropriate with continuous measures more appropriate in research. LEVEL OF EVIDENCE: Decision analysis V. PMID- 28341324 TI - The suitcase packing activity: A new evaluation of hand function. AB - STUDY DESIGN: Prospective, repeated-measures study. INTRODUCTION: Understanding individual hand function can assist therapists with the process of determining relevant treatment approaches and realistic therapeutic outcomes. At this point in time, a composite test that assesses both unilateral and bimanual hand function in relation to a functional activity is not available. PURPOSE OF THE STUDY: To establish the reliability and validity of the suitcase packing activity (SPA). METHODS: An expert panel established face and content validity. Eighty healthy, English-speaking volunteers aged between 18 and 45 years were randomly assigned to either 1 or 2 sessions (test-retest reliability). Relative agreement between 2 examiners using an intraclass correlation coefficient (ICC)3,1 determined interrater reliability. Test-retest reliability was determined by using a repeated-measures analysis of variance and an ICC3,2. Concurrent validity was evaluated against 2 well-established hand evaluations using separate tests of correlational coefficients. RESULTS: Face and content validity were established across 4 focus groups. Our results demonstrate good to excellent interrater reliability (ICC3,1 >= 0.93) and good to excellent test-retest reliability (ICC3,2 >= 0.83). SPA scores were moderately correlated with the 2-hand evaluations. DISCUSSION: Through evaluating hand function during participation in a goal-directed activity (eg, packing a suitcase), the SPA exhibits promise in usefulness as a future viable outcome measure that can be used to assess functional abilities following a hand injury. CONCLUSION: The SPA is a valid and reliable tool for assessing bimanual and unilateral hand function in healthy subjects. LEVELS OF EVIDENCE: Diagnostic level II. PMID- 28341325 TI - Relevance of grasp types to assess functionality for personal autonomy. AB - STUDY DESIGN: Cross-sectional research design. INTRODUCTION: Current assessment of hand function is not focused on evaluating the real abilities required for autonomy. PURPOSE OF THE STUDY: To quantify the relevance of grasp types for autonomy to guide hand recovery and its assessment. METHODS: Representative tasks of the International Classification of Functioning, Disability and Health activities in which the hands are directly involved were recorded. The videos were analyzed to identify the grasps used with each hand, and their relevance for autonomy was determined by weighting time with the frequency of appearance of each activity in disability and dependency scales. Relevance is provided globally and distinguished by hand (right-left) and bimanual function. Significant differences in relevance are also checked. RESULTS: The most relevant grasps are pad-to-pad pinch (31.9%), lumbrical (15.4%), cylindrical (12%), and special pinch (7.3%) together with the nonprehensile (18.6%) use of the hand. Lumbrical grasp has higher relevance for the left hand (19.9% vs 12%) while cylindrical grasp for the right hand (15.3% vs 7.7%). Relevancies are also different depending on bimanual function. DISCUSSION: Different relative importance was obtained when considering dependency vs disability scales. Pad-to-pad pinch and nonprehensile grasp are the most relevant grasps for both hands, whereas lumbrical grasp is more relevant for the left hand and cylindrical grasp for the right one. The most significant difference in bimanual function refers to pad-to-pad pinch (more relevant for unimanual actions of the left hand and bimanual actions of the right). CONCLUSIONS: The relative importance of each grasp type for autonomy and the differences observed between hand and bimanual action should be used in medical and physical decision-making. LEVEL OF EVIDENCE: N/A. PMID- 28341326 TI - A novel XRF method to measure environmental release of copper and zinc from antifouling paints. AB - The release of copper (Cu) and zinc (Zn) from vessels and leisure crafts coated with antifouling paints can pose a threat to water quality in semi-enclosed areas such as harbors and marinas as well as to coastal archipelagos. However, no reliable, practical and low-cost method exists to measure the direct release of metals from antifouling paints. Therefore, the paint industry and regulatory authorities are obliged to use release rate measurements derived from either mathematical models or from laboratory studies. To bridge this gap, we have developed a novel method using a handheld X-Ray Fluorescence spectrometer (XRF) to determine the cumulative release of Cu and Zn from antifouling paints. The results showed a strong linear relationship between XRF Kalpha net intensities and metal concentrations, as determined by ICP-MS. The release of Cu and Zn were determined for coated panels exposed in harbors located in the Baltic Sea and in Kattegat. The field study showed salinity to have a strong impact on the release of Cu, i.e. the release increased with salinity. Contrary, the effect of salinity on Zn was not as evident. As exemplified in this work, the XRF method also makes it possible to identify the governing parameters to the release of Cu and Zn, e.g. salinity and type of paint formulation. Thus, the XRF method can be used to measure environmentally relevant releases of metallic compounds to design more efficient and optimized antifouling coatings. PMID- 28341327 TI - Importance of the structure and nanoporosity of organic matter on the desorption kinetics of benzo[a]pyrene in sediments. AB - The desorption kinetics and mechanism were investigated using a Tenax extraction technique on different sediments spiked with radiocarbon-labeled benzo[a]pyrene (BaP). Five sedimentary fractions were sequentially fractionated, and the only nonhydrolyzable organic carbon fractions (NHC) were characterized using advanced solid-state 13C nuclear magnetic resonance spectroscopy (NMR), improved six end member model, and a CO2 gas adsorption technique. The sediments contained high percentages of algaenan and/or sporopollenin but low percentages of black carbon and lignin. A first-order, two-compartment kinetics model described the desorption process very well (R2 > 0.990). Although some of the organic carbon fractions were significantly related to the desorption kinetics parameters, the NHC fractions showed the highly significant correlation. Moreover, the nanoporosity or specific surface area (SSA) of the NHC fractions was highly related to their OC contents and aliphatic C (R2 = 0.960, p < 0.01). The multiple regression equations among the desorption kinetics parameters, structural parameters, and nanoporosity were well established (R2=>0.999). Nanoporosity and aromatic C were the dominant contributors. Furthermore, the enhanced percentages of desorbed BaP at elevated temperatures significantly showed a linear regression with the structure and nanoporosity. To our knowledge, the above evidence demonstrates for the first time that the transfer (or diffusion) of BaP in the nanopores of condensed aromatic components is the dominant mechanism of the desorption kinetics of BaP at organic matter particle scale. PMID- 28341328 TI - Assessment of bioavailability of selenium in different plant-soil systems by diffusive gradients in thin-films (DGT). AB - Uptake of selenium (Se) by plants largely depend on the availability of Se in soil. Soils and plants were sampled four times within 8 weeks of plant growth in pot experiments using four plant species. Sequential extraction and diffusive gradients in thin-films (DGT) method were employed to measure Se concentrations in potted soils in selenite- or selenate-amended soils. Results showed that DGT measured Se concentrations (CDGT-Se) were generally several folds higher for selenate than selenite amended soils, which were obviously affected by the plant species and the duration of their growth. For example, the folds in soil planted with mustard were 1.49-3.47 and those in soils planted with purple cabbage and broccoli, which grew for 3 and 4 weeks after sowing, were 1.06-2.14 and only 0.15 0.62 after 6 weeks of growth. The selenate-amended soil planted with wheat showed an extremely high CDGT-Se compared with selenite-amended soil, except the last harvest. Furthermore, minimal changes in CDGT-Se and soluble Se(IV) were found in selenite-amended soils during plant growth, whereas significant changes were observed in selenate-amended soils (p < 0.05). Additionally, Se distribution in various fractions of soil remarkably changed; the soils planted with purple cabbage and broccoli showed the most obvious change followed by wheat and mustard. Soluble Se(VI) and exchangeable Se(VI) were likely the major sources of CDGT-Se in selenate-amended soils, and soluble Se(IV) was the possible source of CDGT-Se in selenite-amended soils. In selenate-amended soils, soluble Se(VI) and exchangeable Se(VI) were significantly correlated with Se concentrations in purple cabbage, broccoli, and mustard; in wheat, Se concentration was significantly correlated only with soluble Se(VI) but not with exchangeable Se. CDGT-Se eventually became positively correlated with Se concentrations accumulated by different plants, indicating that DGT is a feasible method in predicting plant uptake of selenate but not of selenite. PMID- 28341329 TI - Body mass index and insulin-like growth factor 1 as risk factors for discordant growth hormone and insulin-like growth factor 1 levels following pituitary surgery in acromegaly. AB - BACKGROUND: Growth hormone (GH)-secreting pituitary adenoma is a chronic disease characterized by excess levels of GH and insulin-like growth factor 1 (IGF-1). Based on our clinical experience and observations, we identified discordant GH and IGF-1 levels after surgery. The risk factors for this phenomenon are unclear, and individualized cure, control criteria, and management after surgery should be considered. PURPOSE: This study aims to investigate the factors affecting the discordant GH and IGF-1 levels after pituitary surgery in acromegalic patients. METHODS: We retrospectively analyzed 146 patients diagnosed with acromegaly caused by GH-secreting pituitary adenoma who had undergone trans-sphenoidal adenectomy (TSA) at Peking Union Medical College Hospital in 2013. Medical histories were obtained for all patients. Hormone levels, biochemical measurements of liver and renal function, and tumor size were recorded before and 3 months after surgery. RESULTS: Among the GH-cured patients who had normal GH levels after TSA, 39.2% (20 of 51) had elevated IGF-1. Acromegalic patients with elevated IGF-1 and normal GH levels after TSA had a significantly higher mean body mass index and percentage of upper limit of normal range IGF-1 than the cured patients (p < 0.05). A body mass index greater than >25.0 kg/m2 and a percentage of upper limit of normal range IGF-1 higher than 141.5 before TSA might predict the occurrence of hormone-level discordance after surgery. CONCLUSION: Body mass index and percentage of upper limit of normal range IGF-1 before TSA might constitute prognostic risk factors for discordance in IGF-1 and GH levels in acromegaly. Additional attention should be devoted to potential risk factors for this phenomenon, and methods for modifying the cure and control criteria for acromegaly should be developed. PMID- 28341331 TI - How sonochemistry contributes to green chemistry? AB - Based on the analyses of papers from the literature, and especially those published in Ultrasonics Sonochemistry journal, the contribution of sonochemistry to green chemistry area has been discussed here. Important reminders and insights on the good practices and considerations have been made to understand and demonstrate how sonochemistry can continue to efficiently contribute to green chemistry area in the further studies. PMID- 28341330 TI - Community perspectives on the use of regulation and law for obesity prevention in children: A citizens' jury. AB - INTRODUCTION: Childhood obesity is a significant challenge for public health internationally. Regulatory and fiscal measures propagated by governments offer a potentially effective response to this issue. Fearing public criticism, governments are often reluctant to use such measures. In this study we asked a descriptively representative and informed group of Australians their views on the use of legislation and fiscal measures by governments to address childhood obesity. METHODS: A citizens' jury, held in South Australia in April 2015, was asked to consider the question: What laws, if any, should we have in Australia to address childhood obesity? RESULTS: The jury agreed that prevention of obesity was complex requiring multifaceted government intervention. Recommendations fell into the areas of health promotion and education (n=4), regulation of food marketing (n=3), taxation/subsidies (n=2) and a parliamentary enquiry. School based nutrition education and health promotion and mandatory front-of-pack interpretive labelling of food and drink were ranked 1 and 2 with taxation of high fat, high sugar food and drink third. CONCLUSION: The recommendations were similar to findings from other citizens' juries held in Australia suggesting that the reticence of decision makers in Australia, and potentially elsewhere, to use legislative and fiscal measures to address childhood obesity is misguided. Supporting relevant informed public discussion could facilitate a politically acceptable legislative approach. PMID- 28341332 TI - The viral innate immune antagonism and an alternative vaccine design for PRRS virus. AB - Porcine reproductive and respiratory syndrome (PRRS) remains one of the most economically significant diseases in the swine industry worldwide. The current vaccines are less satisfactory to confer protections from heterologous infections and long-term persistence, and the need for better vaccines are urgent. The immunological hallmarks in PRRSV-infected pigs include the unusually poor production of type I interferons (IFNs-alpha/beta) and the aberrant and delayed adaptive immune responses, indicating that PRRSV has the ability to suppress both innate and adaptive immune responses in the host. Type I IFNs are the potent antiviral cytokines and recent studies reveal their pleiotropic functions in the priming of expansion and maturation of adaptive immunity. Thus, IFN antagonism negative PRRSV is hypothesized to be attenuated and to build effective and broad- spectrum innate and adaptive immune responses in pigs. Such vaccines are promising alternatives to traditional vaccines for PRRSV. PMID- 28341333 TI - Hinfinity control for a class of singular systems with state time-varying delay. AB - This paper is concerned with the Hinfinity control problem for a class of singular systems. The systems under consideration involve state time-varying delay. The aim of this paper is to design a dynamic feedback controller such that the resultant closed-loop system is regular, impulse-free and stable with given Hinfinity performance index. By using the Lyapunov-Krasovskii functional method, some delay-dependent sufficient criteria which guarantee the existence of the dynamic feedback controller and determine explicitly the parameters of the dynamic feedback controller are presented. Finally, some numerical examples are provided to show the effectiveness of the presented approaches. PMID- 28341334 TI - Hinfinity output-feedback fuzzy proportional-integral control of fully delayed input/output systems. AB - This paper presents the output-feedback fuzzy proportional-integral (PI) controller design for uncertain nonlinear systems with both fully delayed input and output. Based on the Takagi-Sugeno (T-S) fuzzy model representation, the output-feedback PI control is realized via parallel distributed PI compensation and novel LMI gain design. Although the T-S fuzzy PI controller is simple, asymptotic output regulation is assured to overcome the effect of uncertainty, state delay, and full input/output delays. When considering disturbance and measurement noise, the control performance is achieved by robust gain design. Furthermore, state observers and bilinear matrix inequality conditions are removed in this paper. Finally, time-delay Chua's circuit system and a continuous time stirred tank reactor are taken as applications to show the expected performance. PMID- 28341335 TI - Robust control of a spin-stabilized spacecraft via a 1DoF gimbaled-thruster and two reaction wheels. AB - In impulsive orbital maneuvers, thrust vector misalignment from the center of mass (C.M) results in a large disturbance torque. In this paper a thrusting maneuver system is proposed and studied which is based on the combination of a one degree of freedom (1DoF) gimbaled-thruster, two reaction wheels (RWs) and spin-stabilization. The main goals are disturbance rejection and thrust vector stabilization without using reaction control systems (RCS). The nonlinear two body dynamics of the proposed system is formulated. The controller design is formulated as a multi-objective optimization problem where the peak-value of the control input and Hinfinity performance are the cost functions. Based on the peak to-peak gain minimization, the accuracy of the linearized model can be guaranteed. The optimization results give many optimal controllers which are acceptable for a thrusting maneuver. The simulation results illustrate the applicability of the proposed method in presence of the sampling effects of the control inputs. PMID- 28341336 TI - Valproic acid malabsorption in 30 year-old female patient - Case study. AB - AIM: Valproic acid (VPA) is used in epilepsy treatment and as a stabilizer in bipolar affective disorder for over 40 years. Although, the pharmacokinetic properties of valproic acid are well known, it is often forgotten that the formulation of the drug significantly influences its gastrointestinal absorption. CASE: We are describing the case of 30 year-old female patient, diagnosed at the age of 13 with juvenile myoclonic epilepsy. Complete ineffectiveness of the treatment was caused by malabsorption of sodium valproate and valproic acid in the patient. The change of the drug formulation resulted in a several times higher bioavailability of the drug and a partial improvement of the patient's clinical condition. COMMENTARY: Low concentration of valproic acid after administration the slow-released tablets are usually observed. However, a low bioavailability beside the bad compliance should be considered when the minimal level is extremely low during therapy. It is known that form of the drug, beside presence of food and its components, as well as gastrointestinal tract condition or interactions with other drugs can influence the drug level. Modification of the formulation of the drug may lead to improvement of absorption and increase its effectiveness. PMID- 28341338 TI - Response to the Letter to the Editor regarding "Comparison of temporalis fascia muscle and full-thickness cartilage grafts in type 1 pediatric tympanoplasties" by Yegin et al. (Braz J Otorhinolaryngol. 2016;82:695-701). PMID- 28341339 TI - The Uterine-shaped Intrauterine Device. PMID- 28341337 TI - Anti-inflammatory effects of hyperbaric oxygen on irradiated laryngeal tissues. AB - INTRODUCTION: To manage the complications of irradiation of head and neck tissue is a challenging issue for the otolaryngologist. Definitive treatment of these complications is still controversial. Recently, hyperbaric oxygen therapy is promising option for these complications. OBJECTIVE: In this study, we used biochemical and histopathological methods to investigate the efficacy of hyperbaric oxygen against the inflammatory effects of radiotherapy in blood and laryngeal tissues when radiotherapy and hyperbaric oxygen are administered on the same day. METHODS: Thirty-two Wistar Albino rats were divided into four groups. The control group was given no treatment, the hyperbaric oxygen group was given only hyperbaric oxygen therapy, the radiotherapy group was given only radiotherapy, and the radiotherapy plus hyperbaric oxygen group was given both treatments on the same day. RESULTS: Histopathological and biochemical evaluations of specimens were performed. Serum tumor necrosis factor-alpha, interleukin-1beta, and tissue inflammation levels were significantly higher in the radiotherapy group than in the radiotherapy plus hyperbaric oxygen group, whereas interleukin-10 was higher in the radiotherapy plus hyperbaric oxygen group. CONCLUSION: When radiotherapy and hyperbaric oxygen are administered on the same day, inflammatory cytokines and tissue inflammation can be reduced in an early period of radiation injury. PMID- 28341340 TI - ? PMID- 28341341 TI - The High Prevalence of Vitamin D Insufficiency in Cord Blood in Calgary, Alberta (APrON-D Study). AB - OBJECTIVE: Vitamin D is important in promoting healthy pregnancy and fetal development. We undertook this study to measure 25-hydroxyvitamin D in maternal and cord blood and to identify maternal factors related to vitamin D status in Calgary. METHODS: Blood samples collected at the time of delivery from the Alberta Pregnancy Outcomes and Nutrition study cohort (ApronStudy.ca) participants were processed for plasma and assayed using liquid chromatography mass spectrometry methodology for 25(OH)D3. RESULTS: Ninety-two pairs of maternal and cord blood samples were obtained. The prevalence of 25(OH)D3 insufficiency 25(OH)D3 <75 nmol/L-was 38% and 80% in women and neonates, respectively. Vitamin D supplementation was the only clinical factor associated with 25(OH)D3 sufficiency, and the odds of sufficiency were 3.75 (95% CI 1.00 to 14.07) higher for women and 5.27 (95% CI 1.37 to 20.27) when over 2000 IU/day were used. CONCLUSION: Using liquid chromatography mass spectrometry, we demonstrated a very high prevalence of vitamin D insufficiency in cord blood and that the use of high dose vitamin D was associated with greater odds of sufficiency in pregnant women and cord blood in Alberta. PMID- 28341342 TI - A Parasitic Leiomyoma of the Small Bowel. PMID- 28341343 TI - Leiomyome parasitaire dans l'intestin grele. PMID- 28341344 TI - Propofol affinity to mitochondrial membranes does not alter mitochondrial function. AB - The molecular mechanisms of hepatotoxicity after propofol anaesthesia have not been fully elucidated, although there is a relation with mitochondrial dysfunction. The action of propofol on mitochondrial hepatic functions in a rat model was evaluated by infusion for 4h with 25 and 62.5mg/kg/h propofol or 3.125ml/kg/h (vehicle). Liver mitochondrial respiratory rates were evaluated as well as mitochondrial transmembrane potential (DeltaPsi), calcium fluxes, mitochondrial enzymatic activities (Complex I-V) and oxidative stress biomarkers (superoxide dismutase, catalase, glutathione reductase, glutathione S transferase, lipid peroxidation and the oxidised/reduced glutathione ratio). Biophysical interactions with membrane models were also performed. The mitochondrial transmembrane potential was decreased and the opening time of the mitochondrial permeability transition pore was slightly reduced for the highest dose. The activity of complex II was stimulated by propofol, which also causes fluctuations on some respiratory parameters, whereas the antioxidant system was affected in a nonspecific manner. Fluorescence quenching studies suggested that propofol is preferably located in deeper regions of the bilayer and has a high affinity to mitochondrial membranes. It is suggested that propofol interacts with liver mitochondrial membranes with mild modification in mitochondrial function. PMID- 28341345 TI - The signaling signature of the neurotensin type 1 receptor with endogenous ligands. AB - The human neurotensin 1 receptor (hNTS1) is a G protein-coupled receptor involved in many physiological functions, including analgesia, hypothermia, and hypotension. To gain a better understanding of which signaling pathways or combination of pathways are linked to NTS1 activation and function, we investigated the ability of activated hNTS1, which was stably expressed by CHO-K1 cells, to directly engage G proteins, activate second messenger cascades and recruit beta-arrestins. Using BRET-based biosensors, we found that neurotensin (NT), NT(8-13) and neuromedin N (NN) activated the Galphaq-, Galphai1-, GalphaoA , and Galpha13-protein signaling pathways as well as the recruitment of beta arrestins 1 and 2. Using pharmacological inhibitors, we further demonstrated that all three ligands stimulated the production of inositol phosphate and modulation of cAMP accumulation along with ERK1/2 activation. Interestingly, despite the functional coupling to Galphai1 and GalphaoA, NT was found to produce higher levels of cAMP in the presence of pertussis toxin, supporting that hNTS1 activation leads to cAMP accumulation in a Galphas-dependent manner. Additionally, we demonstrated that the full activation of ERK1/2 required signaling through both a PTX-sensitive Gi/o-c-Src signaling pathway and PLCbeta DAG-PKC-Raf-1-dependent pathway downstream of Gq. Finally, the whole-cell integrated signatures monitored by the cell-based surface plasmon resonance and changes in the electrical impedance of a confluent cell monolayer led to identical phenotypic responses between the three ligands. The characterization of the hNTS1-mediated cellular signaling network will be helpful to accelerate the validation of potential NTS1 biased ligands with an improved therapeutic/adverse effect profile. PMID- 28341346 TI - Stimulation of MU-opioid receptors dilates retinal arterioles by neuronal nitric oxide synthase-derived nitric oxide in rats. AB - Opioids contribute to the regulation of cerebral vascular tone. The purpose of this study was to examine the effects of herkinorin, a non-opioid MU-opioid receptor agonist derived from salvinorin A, on blood vessels in the rat retina and to investigate the mechanism underlying the herkinorin-induced retinal vasodilatory response. Ocular fundus images were captured using an original high resolution digital fundus camera in vivo. The retinal vascular responses were evaluated by measuring the diameter of retinal arterioles in the fundus images. Both systemic blood pressure and heart rate were continuously recorded. Herkinorin increased the retinal arteriolar diameter without significantly changing mean blood pressure and heart rate. The retinal vasodilator response to herkinorin was almost completely prevented following treatment with naloxone, a nonselective opioid receptor antagonist and H-D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr NH2 (CTOP), a selective MU-opioid receptor antagonist. Nomega-nitro-L-arginine methyl ester, a nonselective nitric oxide (NO) synthase inhibitor, or indomethacin, a cyclooxygenase inhibitor, significantly attenuated the herkinorin induced retinal vasodilator responses. In addition, Nomega-propyl-L-arginine, an inhibitor of neuronal NO synthase, diminished the herkinorin-induced retinal vasodilator responses. Seven days after an intravitreal injection of N-methyl-D aspartic acid, loss of inner retinal neurons and abolishment of the retinal vasodilator response to herkinorin were observed. These results suggest that herkinorin dilates rat retinal arterioles through stimulation of retinal MU opioid receptors. The MU-opioid receptor-mediated retinal vasodilator response is likely mediated by NO generated by neuronal NO synthase. Retinal neurons play an important role in the retinal vasodilator mechanism involving MU-opioid receptors in rats. PMID- 28341347 TI - Remote limb ischemic post conditioning during early reperfusion alleviates cerebral ischemic reperfusion injury via GSK-3beta/CREB/ BDNF pathway. AB - Remote limb ischemic post conditioning (RIPOC) has been reported to attenuate cerebral ischemic reperfusion (I/R) injury, while the molecular mechanisms remain elusive. Various studies have highlighted the involvement of glycogen synthase kinase (GSK-3beta) in cerebral I/R injury and cognitive disorders. Hence, the present study was designed to explore the role of GSK-3beta and its downstream regulators in RIPOC mediated neuroprotection against cerebral I/R injury and associated cognitive impairment. Male Wistar rats are randomly assigned into four groups: Sham, bilateral common carotid arteries occlusion (BCCAO), RIPOC and BCCAO+RIPOC. BCCAO was achieved by transient occlusion of bilateral common carotid arteries for 20min, followed by reperfusion. Non-invasive RIPOC was induced by 3 cycles each of 10min occlusion and reperfusion of both femoral arteries by using tourniquets, during early reperfusion phase. A battery of behavioral and cognitive tests were performed. Biochemical estimation of oxidative markers, anti-oxidants and pro-inflammatory markers were estimated. Levels of GSK-3beta, CREB and BDNF were estimated to confirm the molecular mechanism. Hippocampal structural abnormalities were confirmed by H and E staining. The neurobehavioral analysis revealed that neurological and cognitive deficits caused by BCCAO, were reduced by RIPOC intervention. Meanwhile, the results of biochemical tests suggested that RIPOC attenuates the BCCAO induced oxidative damage, neuroinflammation and hippocampal structural abnormalities. Further, RIPOC prevented the elevation of BCCAO induced GSK-3beta. RIPOC exerts neuroprotective effect against I/R injury, putatively by attenuating GSK-3beta expression and upregulating the levels of CREB and BDNF. PMID- 28341348 TI - The impact of oral Polypodium leucotomos extract on ultraviolet B response: A human clinical study. AB - BACKGROUND: There is a rationale for adding systemic photoprotective agents to the current photoprotection regimen. OBJECTIVE: This study was designed to objectively evaluate the molecular and photobiologic effects of oral administration of Polypodium leucotomos extract (PLE). METHODS: In all, 22 subjects with Fitzpatrick skin phototype I to III were enrolled. On day 1, subjects were irradiated with visible light, ultraviolet (UV) A1, and UVB (using 308-nm excimer laser). Evaluation was done immediately and 24 hours after irradiation. On days 3 and 4, irradiation and evaluation process was repeated after ingestion of PLE. RESULTS: Clinical assessments and colorimetry data showed a decrease in UVB-induced changes in 17 of 22 subjects post-PLE administration; histology findings demonstrated such a decrease in all 22 subjects. LIMITATIONS: Only 2 doses of PLE were given. Furthermore, subjects with skin phototypes I to III only were studied. CONCLUSION: The results suggest that PLE can potentially be used as an adjunctive agent to lessen the negative photobiologic effects of UVB. PMID- 28341349 TI - Implementing a standard internal telephone number 2222 for cardiac arrest calls in all hospitals in Europe. PMID- 28341350 TI - Deadly business, the usefulness of ETCO2. PMID- 28341351 TI - Should we still be teaching the recovery position? PMID- 28341352 TI - Volumetric analysis of the maxillary, sphenoid and frontal sinuses: A comparative computerized tomography based study. AB - OBJECTIVE: To study volume characteristics of the maxillary, sphenoid and frontal sinuses among healthy Caucasians adults, using computed tomography (CT) scans. METHODS: A retrospective, case series study in a single academic center, CT scans of 201 consecutive adult subjects, performed between January and September 2014, were reviewed for the volume and dimensions of the paranasal sinuses. Patients with documented sinus pathology or lack of pneumatization were excluded. The study population was subdivided by gender and age (50 men age 25-64; 51 men age >=65; 50 women age 25-64, and 50 women age >=65). RESULTS: The mean volume of maxillary, sphenoid and frontal sinuses in the four groups were 12.75+/-4.38 cc; 4.00+/-1.99 cc and 2.92+/-2.57 cc, respectively. In both genders, older patients demonstrated a significantly lower volume of the maxillary and sphenoid sinuses (14.81+/-3.96 cc vs. 11.82+/-4.28 cc and 4.84+/-1.97 vs. 3.84+/-1.89 cc respectively; p<0.001). No age related difference was found in the frontal sinus. Males had significantly larger sinus volumes than females (p<0.001): maxillary 14.38+/-(4.64) vs. 12.23+/-(3.82) cc, sphenoid 4.74+/-(2.06) vs. 3.55+/-(1.73) cc, frontal 3.74+/-(2.97) vs. 3.21+/-(2.79) cc. No synergistic effect of age and gender was found. CONCLUSION: Volumes of the paranasal sinuses correlates with age and gender. Age related volume degeneration is expected in the maxillary and sphenoid sinuses. This volume reduction may influence future surgical and therapeutic approaches in the geriatric population. PMID- 28341353 TI - The NCK and ABI adaptor genes in catfish and their involvement in ESC disease response. AB - Adaptor proteins non-catalytic region of tyrosine kinase (NCK) and Abelson interactor (ABI) are crucial for disease response. NCK1 was identified to be a candidate gene for enteric septicemia of catfish (ESC) disease resistance, and was speculated to play similar roles during ESC and enteropathogenic Escherichia coli (EPEC) pathogenicity. ABI1 was reported as a positional candidate gene for bacterial cold water disease (BCWD) resistance in rainbow trout. In this study, three NCK genes and six ABI genes were identified in the channel catfish (Ictalurus punctatus) genome and blue catfish (I. furcatus) transcriptome, and annotated by domain structures, phylogenetic and syntenic analyses. Their expression patterns were examined in the intestine and liver of catfish after challenge with Edwardsiella ictaluri. In the intestine, NCK1, ABI2a, ABI2b, ABI3a were differentially expressed after E. ictaluri infection. In the liver, NCK2a, NCK2b, ABI1b, ABI2a, ABI2b were significantly upregulated in ESC susceptible fish. In general, the NCK and ABI genes, with exception of ABI3a gene and NCK1 gene, were expressed at higher levels in susceptible fish after infection than in control fish, but were expressed at lower levels in resistant fish than in the control fish. Taken together, these results support the notion that NCK and ABI genes are involved in disease processes facilitating pathogenesis of the E. ictaluri bacteria. PMID- 28341354 TI - Comparison of Propensity Score-Matched Analysis of Acute Kidney Injury After Percutaneous Coronary Intervention With Transradial Versus Transfemoral Approaches. AB - Transradial percutaneous coronary intervention (TR-PCI) may be associated with reduced rates of acute kidney injury (AKI). There is limited data from real-world registries about AKI rates stratified by PCI access. Our aim was to evaluate AKI rates and correlates in TR-PCI versus transfemoral PCI (TF-PCI) in a propensity score-matched analysis of patient data from a large, single-center registry. We performed a 1:1 propensity score-matched analysis on consecutive patients who underwent PCI from January 2011 to June 2016, excluding those on dialysis. A multivariate logistic regression model was adjusted to variables found to be significant in univariate models. AKI was defined by creatinine increase of >=0.3 mg/dL post-PCI during hospitalization. During the study period, 6,743 patients underwent PCI (TR-PCI n = 1,119). Initial univariate models revealed significant differences between patients with TF-PCI and TR-PCI. Contrast amount and procedure duration were both increased with TR-PCI versus TF-PCI (162 vs 154 ml, p = 0.003; and 86 vs 79 minutes, p <0.001, respectively). Multivariate propensity score analysis matched 536 pairs of patients. In this matched cohort, TR-PCI was associated with a reduced risk for AKI compared with TF-PCI in univariate (4.3% vs 10.4%, p <0.001) and multivariate adjusted models (odds ratio 0.28, 95% confidence interval 0.19 to 0.59, p <0.001). PMID- 28341355 TI - Comparison of Clinical and Electrocardiographic Predictors of Ischemic and Nonischemic Cardiomyopathy During the Initial Evaluation of Patients With Reduced (<=40%) Left Ventricular Ejection Fraction. AB - Invasive coronary angiography is routinely performed during the initial evaluation of patients with suspected cardiomyopathy with reduced left ventricular function. Clinical and electrocardiographic (ECG) data may accurately predict ischemic cardiomyopathy (IC). Medical records of adults referred for coronary angiography for evaluation of left ventricular ejection fraction <=40% from 2010 to 2014 were retrospectively reviewed. Patients with myocardial infarction (MI), previous coronary revascularization, cardiac surgery, or left sided valvular disease were excluded. IC was defined as >=70% diameter stenosis of the left main, proximal left anterior descending, or involvement of >=2 epicardial coronary arteries. A risk model was developed from logistic regression coefficients, with a dichotomous cut-point based on the maximal Youden's index from the receiver-operating characteristic curve. A total of 273 patients met study inclusion criteria. Mean age was 56.8 +/- 11.6 and 68.1% were men. IC was identified in 41 patients (15%). Patients with IC were more likely to have ECG evidence of Q-wave MI (34% vs 13%, p <0.001) and less likely to have left bundle branch block (2% vs 15%, p = 0.03) than non-IC. A model including age, hypertension, diabetes mellitus, tobacco use, ECG evidence of ST or T-wave abnormalities concerning for ischemia, and previous Q-wave MI, yielded a 95% negative predictive value for IC. In conclusion, at an urban referral hospital, the prevalence of IC was low. Left bundle branch block on electrocardiography was rarely associated with IC. A risk score incorporating clinical and ECG abnormalities identified patients at a low likelihood for IC. PMID- 28341356 TI - Mortality Risk Stratification in Fontan Patients Who Underwent Heart Transplantation. AB - The number of patients who require orthotopic heart transplantation (OHT) for failing Fontan physiology continues to grow; however, the methods and tools to evaluate risk of OHT are limited. This study aimed to identify a set of preoperative variables and characteristics that were associated with a greater risk of postoperative mortality in patients who received OHT for failing Fontan physiology. Thirty-six Fontan patients were identified as having undergone OHT at University of California-Los Angeles Medical Center from 1991 to 2014. Data were collected retrospectively and analyzed. The primary end point was designated as postoperative mortality. After an average follow-up time of 3.5 years, 17 (44%) patients suffered postoperative mortality. Patient characteristics including (1) age <18 years at the time of OHT, (2) Fontan-OHT interval of <10 years, (3) systemic ventricular ejection fraction <20%, (4) moderate-to-severe atrioventricular valve insufficiency, (5) an elevated Model of End-stage Liver Disease, eXcluding INR score, or (6) need for advanced mechanical support before surgery were associated with an increased incidence of postoperative mortality. Using these risk factors, we present a theoretical framework to stratify risk of postoperative death in failing Fontan patients after OHT. In conclusion, a method such as this may aid in the transplantation evaluation and listing process of patients with failing Fontan physiology. PMID- 28341357 TI - Prognostic Significance of Early Rehospitalization After Takotsubo Cardiomyopathy. AB - Short-term complications, particularly rehospitalization, after a diagnosis of takotsubo cardiomyopathy (TTC) are poorly described. We sought to characterize the rates, causes, clinical associations, and prognostic implications of early rehospitalization in this patient population. We performed a retrospective observational study of all adult subjects diagnosed with TTC at an academic tertiary care hospital from 2005 to 2015. The primary outcome was rehospitalization within 30 days of index discharge. Multivariable logistic regression was used to test for association between clinical variables and rehospitalization. Association between rehospitalization and survival after index discharge was assessed as a secondary outcome using a multivariable Cox proportional hazard model. Two hundred sixty-three subjects met the inclusion criteria for the study. There were 38 rehospitalizations among 32 subjects (12%). Ninety-five percent of rehospitalizations were due to nonheart failure causes, and 76% were related to noncardiovascular complaints. In multivariable analysis, recent hospitalization before TTC diagnosis and increased length of index hospitalization were associated with greater risk of rehospitalization (odds ratio 4.58, 95% CI 1.97 to 10.65, p <0.001 and odds ratio 1.05, 95% CI 1.01 to 1.10, p = 0.026, respectively). Early rehospitalization after TTC was associated with decreased survival (hazard ratio 3.17, 95% CI 1.53 to 6.56, p = 0.002). PMID- 28341358 TI - Meta-Analysis of the Optimal Percutaneous Revascularization Strategy in Patients With Acute Myocardial Infarction, Cardiogenic Shock, and Multivessel Coronary Artery Disease. AB - The optimal percutaneous coronary intervention (PCI) revascularization strategy in patients with multivessel (MV) coronary artery disease (CAD) who present with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) has not been systematically addressed. Accordingly, we performed a study-level meta analysis comparing 2 PCI strategies in these patients-infarct-related artery (IRA) only versus MV revascularization. Studies including patients with AMI and MV CAD complicated with CS who received primary PCI were searched from 2000 to 2016. The primary end points were in-hospital/30-day and mid- to long-term (>=6 month) mortality. Fixed and random effects models were used for analysis. Ten studies (9 prospective and 1 retrospective) involving 6,068 patients met our inclusion criteria. IRA-only PCI was the most frequently used revascularization strategy (4,872 patients, 80%), while MV PCI was performed in 1,196 patients (20%). The MV PCI strategy was associated with higher short-term mortality compared with the IRA-only PCI strategy (odds ratio 1.41, 95% confidence interval 1.15 to 1.71, p = 0.008). There was no difference in mid- to long-term mortality between MV PCI and IRA-only strategies (odds ratio 1.02, 95% confidence interval 0.65 to 1.58, p = 0.94). In conclusion, in patients with AMI and MV CAD complicated by CS, the IRA-only PCI strategy seems to be associated with lower short-term, but not mid- to long-term mortality compared with MV PCI. This finding is different from the revascularization strategy recommended by current professional guidelines and suggests the need for dedicated randomized clinical trials. PMID- 28341359 TI - Prognostic Value of the Clinical SYNTAX Score on 2-Year Outcomes in Patients With Acute Coronary Syndrome Who Underwent Percutaneous Coronary Intervention. AB - This prospective, single-center, observational study evaluated prognostic value of clinical SYNTAX score (CSS) on 2-year outcomes in patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI). The SYNTAX score (SS) is a scoring system based on the complexity and severity of coronary lesions and is thought to be a prognostic tool to predict long-term outcomes. However, SS was a sole angiographic grading tool only with no consideration for clinical factors. There are few studies investigating the prognostic value of CSS in patients with ACS who underwent PCI. From January 2013 to December 2013, 6,099 consecutive patients with ACS admitted to FuWai hospital and underwent PCI were enrolled in this study. Based on CSS, patients were divided into low CSS group (CSS <= 6.5; 2,012 patients), mid-CSS group (6.5 < CSS < 13.8; 2,056 patients), and high CSS group (CSS >= 13.8; 2,031 patients). At 2-year follow-up, rates of cardiac death and major adverse cardiac events (MACE) were significantly higher in the high CSS group. Compared with baseline SS, CSS demonstrated significantly improved performance for 2-year cardiac death (receiver-operating characteristic curve C-statistic: 0.74 vs 0.62, p <0.001) but not for MACE (receiver-operating characteristic curve C-statistic: 0.60 vs 0.59, p = 0.29). By multivariable analysis, the CSS combined with PCI history and hypertension were strong predictors for cardiac death and CSS, intra-aortic balloon pump support, diabetes, and successful PCI were independent predictors for MACE. In conclusion, compared with the anatomic SS, CSS was suitable in risk stratifying and predicting 2-year clinical outcome among ACS population. PMID- 28341360 TI - Use of Antiarrhythmic Medications in Medicare Part D Patients With an Implantable Cardioverter-Defibrillator and Ventricular Tachycardia. AB - Ventricular tachycardia (VT) is common in cardiomyopathy patients with an implantable cardioverter-defibrillator. This analysis evaluated antiarrhythmic medication use and change in use over time in patients with VT and structural heart disease. Query of Medicare claims identified patients with an implantable cardioverter-defibrillator and VT. Patients with atrial fibrillation or supraventricular tachycardia were excluded. Two cohorts were created of patients enrolled in Medicare Part D for the 12 months before 2007 and 2012. Patients were identified through a search for antiarrhythmic medication fills with a supply covering January 1 of the cohort year. Adjusted logistic regression modeling evaluated the association between patient characteristics and antiarrhythmic medication use. The 2007 (n = 2,334) and 2012 (n = 3,892) Medicare Part D cohorts had similar demographics: median age 76 years, 64%-67% male, and 87%-89% white. Of the 2007 cohort, 1,380 (59%) patients were on a beta blocker, and 484 (20.7%) were on an antiarrhythmic medication (70% amiodarone and 20% sotalol). Between 2007 and 2012, there was a statistically significant higher use of any antiarrhythmic medication (p = 0.014), beta blockers (p <0.0001), mexiletine (p = 0.005), and ranolazine (p <0.0001), while amiodarone use remained unchanged (p = 0.53). After multivariable adjustment, male gender and renal disease were associated with higher antiarrhythmic medication use. In conclusion, although antiarrhythmic medication and beta blocker use in patients with VT increased over time, <1 in 4 patients were on an antiarrhythmic medication and only 65% of the patients were on a beta blocker. PMID- 28341361 TI - Frequency of Left Ventricular End-Diastolic Volume-Mediated Declines in Ejection Fraction in Patients Receiving Potentially Cardiotoxic Cancer Treatment. AB - We sought to determine the frequency by which decreases in left ventricular (LV) end-diastolic volume (LVEDV) with and without increases in end-systolic volume (LVESV) influenced early cancer treatment-associated declines in LV ejection fraction (LVEF) or LV mass. One hundred twelve consecutively recruited subjects (aged 52 +/- 14 years) with cancer underwent blinded cardiovascular magnetic resonance measurements of LV volumes, mass, and LVEF before and 3 months after initiating potentially cardiotoxic chemotherapy (72% of participants received anthracyclines). Twenty-six participants developed important declines in LVEF of >10% or to values <50% at 3 months, in whom 19% versus 60%, respectively, experienced their decline in LVEF due to isolated declines in LVEDV versus an increase in LVESV; participants who dropped their LVEF due to decreases in LVEDV lost more LV mass than those who dropped their LVEF due to an increase in LVESV (p = 0.03). Nearly one fifth of subjects experience marked LVEF declines due to an isolated decline in LVEDV after initiating potentially cardiotoxic chemotherapy. Because reductions in intravascular volume (which could be treated by volume repletion) may account for LVEDV-related declines in LVEF, these data indicate that LV volumes should be reviewed along with LVEF when acquiring imaging studies for cardiotoxicity during the treatment for cancer. PMID- 28341362 TI - Sinus Bradycardia in Habitual Cocaine Users. AB - Common physiological manifestations of cocaine are related to its adrenergic effects, due to inhibition of dopamine and norepinephrine uptake at the postsynaptic terminal. Few studies have documented bradycardia secondary to cocaine use, representing the antithesis of its adrenergic effects. We assessed the prevalence of sinus bradycardia (SB) in habitual cocaine users and postulated a mechanism for this effect. One hundred sixty-two patients with a history of cocaine use were analyzed and compared with age- and gender-matched controls. SB was defined as a rate of <60 beats/min and habitual cocaine use as 2 or more documented uses >30 days apart. Propensity score-matching analysis was applied to balance covariates between cocaine users and nonusers and reduce selection bias. Patients with a history of bradycardia, hypothyroidism, or concomitant beta blocker use were excluded. Mean age of study patients was 44 +/- 8 years. SB was observed in 43 of 162 (27%) cocaine users and in 9 of 149 (6%) nonusers (p = 0.0001). Propensity score-matching analysis matched 218 patients from both groups. Among matched patients SB was observed in 25 of 109 (23%) cocaine users and in 5 of 109 (5%) nonusers (p = 0.0001). Habitual cocaine use was an independent predictor of SB and associated with a sevenfold increase in the risk of SB (95% CI 2.52 to 19.74, p = 0.0002). In conclusion, habitual cocaine use is a strong predictor of SB and was unrelated to recency of use. A potential mechanism for SB may be related to cocaine-induced desensitization of the beta adrenergic receptor secondary to continuous exposure. Symptomatic SB was not observed; thus, pacemaker therapy was not indicated. PMID- 28341364 TI - Decreased access to bariatric care: an analysis of referral practices to bariatric specialists. AB - BACKGROUND: Substantial evidence reveals tolerability and co-morbid disease resolution after bariatric surgery; however, few physicians refer morbidly obese patients for bariatric consultation. OBJECTIVE: To evaluate morbidly obese patient access to bariatric surgical consultation. SETTING: A multidisciplinary, private, bariatric center of excellence. METHODS: Patient surveyed in person regarding preconsultation co-morbidities, physician discussion and support for bariatric surgery, and physician referral practices. RESULTS: The patients' (n = 388) co-morbid profile was 27.0% diabetes, 54.1% hypertension, 30.1% hyperlipidemia, and 37.1% obstructive sleep apnea. It was reported that 71.1% of patients stated that their primary care physician did not initiate a discussion about bariatric surgery. Among this group, 59.7% of patients initiated a conversation about bariatric surgery, with 80.6% of physicians supporting the decision and 18.4% referring to a bariatric practice. Overall referring specialty profile was 14.4% primary care, 4.4% cardiology, and 3.6% endocrinology. Diabetes and obstructive sleep apnea were more likely to prompt a referral (P = .008 and P = .014, respectively). CONCLUSION: Most primary care and subspecialists do not discuss bariatric surgical options, resulting in decreased access to bariatric care. The main barrier to referral is noncommunication by the primary care physician or subspecialist, despite the vast majority of physicians having positive attitudes about bariatric surgery. Co-morbidities of diabetes and obstructive sleep apnea are more likely to prompt a referral. Primary care physicians are most likely to refer, while endocrinologists are least likely. Improved familiarity with nationally recognized obesity management algorithms could contribute to improved referral rates. PMID- 28341365 TI - Sham surgical procedures for pain intervention result in significant improvements in pain: systematic-review and meta-analysis: Metaepidemiologic research requires reporting requirements. PMID- 28341366 TI - Transforming intraclass correlation coefficients with the Spearman-Brown formula. AB - OBJECTIVES: De Vet, Mokkink, Mosmuller, and Terwee (2017) discovered that the Spearman-Brown formula (SB formula) can be used to transform certain intraclass correlation coefficients (ICCs) for single measurements into the corresponding ICCs for average measurements, without knowledge of the variance components. RESULTS: A formal proof of the discovery by De Vet et al. is presented. It is also proved that, vice versa, the SB formula can be used to transform certain ICCs for average measurements into the corresponding ICCs for single measurements. Furthermore, it is specified to which type of ICC the transformations can be applied. Finally, several illustrations of the transformations are presented. CONCLUSION: The discovery by De Vet et al. is quite remarkable because ICCs and the SB formula come from quite different scientific disciplines. PMID- 28341367 TI - Embedding researchers in health service organizations improves research translation and health service performance: the Australian Hunter New England Population Health example. PMID- 28341368 TI - Acute necrotizing pancreatitis after transarterial chemoembolization in candidates for a liver transplant. PMID- 28341369 TI - Muscular and heart adaptations of execise in hypoxia. Is training in slow hypoxy healthy? PMID- 28341363 TI - A gene regulatory program controlling early Xenopus mesendoderm formation: Network conservation and motifs. AB - Germ layer formation is among the earliest differentiation events in metazoan embryos. In triploblasts, three germ layers are formed, among which the endoderm gives rise to the epithelial lining of the gut tube and associated organs including the liver, pancreas and lungs. In frogs (Xenopus), where early germ layer formation has been studied extensively, the process of endoderm specification involves the interplay of dozens of transcription factors. Here, we review the interactions between these factors, summarized in a transcriptional gene regulatory network (GRN). We highlight regulatory connections conserved between frog, fish, mouse, and human endodermal lineages. Especially prominent is the conserved role and regulatory targets of the Nodal signaling pathway and the T-box transcription factors, Vegt and Eomes. Additionally, we highlight network topologies and motifs, and speculate on their possible roles in development. PMID- 28341370 TI - Management of smoldering myeloma: Recommendations of the Spanish Myeloma Group. PMID- 28341371 TI - Erratum to "Prognostic value of interleukin 6 for death of patients with sepsis" [Med Clin (Barc). 147 (7) (2016) 281-286]. PMID- 28341372 TI - Evaluation of remote dielectric sensing (ReDS) technology-guided therapy for decreasing heart failure re-hospitalizations. AB - OBJECTIVE: We tested whether remote dielectric sensing (ReDS)-directed fluid management reduces readmissions in patients recently hospitalized for heart failure (HF). BACKGROUND: Pulmonary congestion is the most common cause of worsening HF leading to hospitalization. Accurate remote monitoring of lung fluid volume may guide optimal treatment and prevent re-hospitalization. ReDS technology is a quantitative non-invasive method for measuring absolute lung fluid volume. METHODS: Patients hospitalized for acute decompensated HF were enrolled during their index admission and followed at home for 90days post discharge. Daily ReDS readings were obtained using a wearable vest, and were used as a guide to optimizing HF therapy, with a goal of maintaining normal lung fluid content. Comparisons of the number of HF hospitalizations during ReDS-guided HF therapy were made, both to the 90days prior to enrollment and to the 90days following discontinuation of ReDS monitoring. RESULTS: Fifty patients were enrolled, discharged, and followed at home for 76.9+/-26.2days. Patients were 73.8+/-10.3years old, 40% had LVEF above 40%, and 38% were women. Compared to the pre- and post-ReDS periods, there were 87% and 79% reductions in the rate of HF hospitalizations, respectively, during ReDS-guided HF therapy. The hazard ratio between the ReDS and the pre-ReDS period was 0.07 (95% CI [0.01-0.54] p=0.01), and between the ReDS and the post-ReDS period was 0.11 (95% CI [0.014-0.88] p=0.037). CONCLUSIONS: These findings suggest that ReDS-guided management has the potential to reduce HF readmissions in acute decompensated HF patients recently discharged from the hospital. PMID- 28341373 TI - Drugs to prevent sudden cardiac death. AB - Sudden cardiac death (SCD) remains a major public health burden despite enormous advances in post-resuscitation care, management of structural heart diseases, and antiarrhythmic treatment modalities. Primary and secondary prevention of sudden cardiac death require understanding of the underlying substrate causing ventricular arrhythmias and its modification by pharmacological (i.e. heart failure therapy) or interventional (catheter ablation) methods. Antiarrhythmic drug therapy has experienced ups and downs during the last 30years balancing high antiarrhythmic potential, toxic side effects and pro-arrhythmic potency. Therefore, the implantable cardioverter-defibrillator (ICD) remains irreplaceable in primary and secondary prevention of SCD. Hybrid therapy combing antiarrhythmic drugs (predominantly amiodarone) with ICD therapy represents an often-used treatment option. This short review provides an overview of current pharmacological therapy aiming to prevent SCD. PMID- 28341374 TI - Cardiorenal disease connection during post-menopause: The protective role of estrogen in uremic toxins induced microvascular dysfunction. AB - Female gender, post-menopause, chronic kidney disease (CKD) and (CKD linked) microvascular disease are important risk factors for developing heart failure with preserved ejection fraction (HFpEF). Enhancing our understanding of the interrelation between these risk factors could greatly benefit the identification of new drug targets for future therapy. This review discusses the evidence for the protective role of estradiol (E2) in CKD-associated microvascular disease and related HFpEF. Elevated circulating levels of uremic toxins (UTs) during CKD may act in synergy with hormonal changes during post-menopause and could lead to coronary microvascular endothelial dysfunction in HFpEF. To elucidate the molecular mechanism involved, published transcriptome datasets of indoxyl sulfate (IS), high inorganic phosphate (HP) or E2 treated human derived endothelial cells from the NCBI Gene Expression Omnibus database were analyzed. In total, 36 genes overlapped in both IS- and HP-activated gene sets, 188 genes were increased by UTs (HP and/or IS) and decreased by E2, and 572 genes were decreased by UTs and increased by E2. Based on a comprehensive in silico analysis and literature studies of collected gene sets, we conclude that CKD-accumulated UTs could negatively impact renal and cardiac endothelial homeostasis by triggering extensive inflammatory responses and initiating dysregulation of angiogenesis. E2 may protect (myo)endothelium by inhibiting UTs-induced inflammation and ameliorating UTs-related uremic bleeding and thrombotic diathesis via restored coagulation capacity and hemostasis in injured vessels. PMID- 28341375 TI - Risk factors for mortality in patients undergoing hemodialysis: A systematic review and meta-analysis. AB - BACKGROUND: No consensus exists regarding the factors influencing mortality in patients undergoing hemodialysis (HD). This meta-analysis aimed to evaluate the impact of various patient characteristics on the risk of mortality in such patients. METHODS: PubMed, Embase, and Cochrane Central were searched for studies evaluating the risk factors for mortality in patients undergoing HD. The factors included age, gender, diabetes mellitus (DM), body mass index (BMI), previous cardiovascular disease (CVD), HD duration, hemoglobin, albumin, white blood cell, C-reactive protein (CRP), parathyroid hormone, total iron binding capacity (TIBC), iron, ln ferritin, adiponectin, apolipoprotein A1 (ApoA1), ApoA2, ApoA3, high-density lipoprotein (HDL), total cholesterol, hemoglobin A1c (HbA1c), serum phosphate, troponin T (TnT), and B-type natriuretic peptide (BNP). Relative risks with 95% confidence intervals were derived. Data were synthesized using the random-effects model. RESULTS: Age (per 1-year increment), DM, previous CVD, CRP (higher versus lower), ln ferritin, adiponectin (per 10.0MUg/mL increment), HbA1c (higher versus lower), TnT, and BNP were associated with an increased risk of all cause mortality. BMI (per 1kg/m2 increment), hemoglobin (per 1d/dL increment), albumin (higher versus lower), TIBC, iron, ApoA2, and ApoA3 were associated with reduced risk of all-cause mortality. Age (per 1-year increment), gender (women versus men), DM, previous CVD, HD duration, ln ferritin, HDL, and HbA1c (higher versus lower) significantly increased the risk of cardiac death. Albumin (higher versus lower), TIBC, and ApoA2 had a beneficial impact on the risk of cardiac death. CONCLUSIONS: Multiple markers and factors influence the risk of mortality and cardiac death in patients undergoing HD. PMID- 28341376 TI - Decreased frequency and duration of tooth brushing is a risk factor for endothelial dysfunction. AB - BACKGROUND: Periodontal disease is associated with endothelial dysfunction, leading to cardiovascular disease. The effect of detailed tooth brushing behavior, not only frequency but also duration of tooth brushing, on endothelial function is unclear. The purpose of this study was to evaluate the relationships of detailed methods of tooth brushing with vascular function. METHODS: We evaluated flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation, and frequency and duration of tooth brushing in 896 subjects. We divided the subjects into three groups according to the frequency and duration of tooth brushing: low frequency and short duration group (=twice/day and >=2min/procedure). RESULTS: FMD in the low frequency and short duration group was significantly lower than FMD in the low frequency or short duration group and FMD in the non-low frequency and non-short duration group [3.1 (2.7)% vs. 4.2 (3.1)% and 4.7 (3.1)%, P=0.001 and <0.001, respectively]. Nitroglycerine-induced vasodilation was similar in the three groups. Using the non-low frequency and non short duration group as the reference, the low frequency and short duration of tooth brushing group was significantly associated with an increased odds ratio of a low FMD tertile after adjustment for conventional risk factors (OR: 2.25, 95% CI: 1.39-3.59; P<0.001). CONCLUSIONS: These findings suggest that low frequency and short duration of tooth brushing are associated with endothelial dysfunction. CLINICAL TRIAL REGISTRATION INFORMATION: URL for clinical trial: http://UMIN; registration number for clinical trial: UMIN000003409. PMID- 28341377 TI - LRP5: From bedside to bench to bone. AB - A role for low-density lipoprotein-related receptor 5 (LRP5) in human bone was first established by the identification of genetic alterations that led to dramatic changes in bone mass. Shortly thereafter, mutations that altered the function of the sclerostin (SOST) gene were also associated with altered human bone mass. Subsequent studies of LRP5 and sclerostin have provided important insights into the mechanisms by which these proteins regulate skeletal homeostasis. Sclerostin normally binds to LRP5 and the related LRP6 protein and prevents their activation by Wnts, the LRP5/LRP6 ligands. The interaction of sclerostin with LRP5 or LRP6 is facilitated by the LRP4 protein. Loss of LRP5 leads to defective osteoblast function and low bone mass, while loss of SOST or mutations in LRP5, which produce a protein that can no longer be bound by SOST, result in high bone mass. Insights gained from the use of genetically engineered mouse models are presented, as well as a brief summary of the status of antibodies in clinical trials that block the function of SOST as a mechanism to increase bone mass. PMID- 28341378 TI - Pilot scale intensification of rubber seed (Hevea brasiliensis) oil via chemical interesterification using hydrodynamic cavitation technology. AB - Chemical interesterification of rubber seed oil has been investigated for four different designed orifice devices in a pilot scale hydrodynamic cavitation (HC) system. Upstream pressure within 1-3.5bar induced cavities to intensify the process. An optimal orifice plate geometry was considered as plate with 1mm dia hole having 21 holes at 3bar inlet pressure. The optimisation results of interesterification were revealed by response surface methodology; methyl acetate to oil molar ratio of 14:1, catalyst amount of 0.75wt.% and reaction time of 20min at 50 degrees C. HC is compared to mechanical stirring (MS) at optimised values. The reaction rate constant and the frequency factor of HC were 3.4-fold shorter and 3.2-fold higher than MS. The interesterified product was characterised by following EN 14214 and ASTM D 6751 international standards. PMID- 28341379 TI - The rapid adsorption-microbial reduction of perchlorate from aqueous solution by novel amine-crosslinked magnetic biopolymer resin. AB - The aim of this work was to study the adsorption characters of resin, microbial reduction of perchlorate and combined process of perchlorate removal in aqueous solution. Study demonstrated the adsorption equilibrium was achieved in 120min, which based on ion exchange reaction. Dissolved perchlorate (100mg/L) can be completely removed by acclimated anaerobic sludge in 15h, and the concentrated perchlorate (~200mg/g) on the surface of resin would be effectively microbial reduced after 3days. Neutral environment (pH=7.4), higher biomass and additional electron donor can apparently improve the biological reduction efficiency of concentrated perchlorate. Addition of many co-anions showed the competition adsorption towards perchlorate, especially in the presence of NO3-. This study provides an effective method for perchlorate reduction by the adsorption microbial process. PMID- 28341380 TI - Low energy single-staged anaerobic fluidized bed ceramic membrane bioreactor (AFCMBR) for wastewater treatment. AB - An aluminum dioxide (Al2O3) ceramic membrane was used in a single-stage anaerobic fluidized bed ceramic membrane bioreactor (AFCMBR) for low-strength wastewater treatment. The AFCMBR was operated continuously for 395days at 25 degrees C using a synthetic wastewater having a chemical oxygen demand (COD) averaging 260mg/L. A membrane net flux as high as 14.5-17L/m2h was achieved with only periodic maintenance cleaning, obtained by adding 25mg/L of sodium hypochlorite solution. No adverse effect of the maintenance cleaning on organic removal was observed. An average SCOD in the membrane permeate of 23mg/L was achieved with a 1h hydraulic retention time (HRT). Biosolids production averaged 0.014+/-0.007gVSS/gCOD removed. The estimated electrical energy required to operate the AFCMBR system was 0.039kWh/m3, which is only about 17% of the electrical energy that could be generated with the methane produced. PMID- 28341381 TI - Potential of Brachiaria mutica (Para grass) for bioethanol production from Loktak Lake. AB - The aim of present study was to evaluate feasibility of using the Para grass as feedstock for production of bioethanol. Process involved the pretreatment with dilute acid or alkali and followed by enzymatic saccharification with commercial cellulase. Maximum sugar release of 696mg/g was obtained from 10% biomass loading and 0.5% w/v of alkali whereas in the case of acid pretreatment maximum sugar of 660mg/g was obtained from 20% biomass loading and 2% w/v acid loading. Results showed that Para grass utilization as a biorefinery feedstock can be a potential strategy to address the sustainable utilization of this invasive grass thereby keeping its population in check in the Loktak Lake. PMID- 28341382 TI - Assisting cultivation of photosynthetic microorganisms by microbial fuel cells to enhance nutrients recovery from wastewater. AB - Spirulina was cultivated in cathodic compartments of photo-microbial fuel cells (P-MFC). Anodic compartments were fed with swine-farming wastewater, enriched with sodium acetate (2.34gCODL-1). Photosynthetic oxygen generation rates were sufficient to sustain cathodic oxygen reduction, significantly improving P-MFC electrochemical performances, as compared to water-cathode control experiments. Power densities (0.8-1Wm-2) approached those of air-cathode MFCs, run as control. COD was efficiently removed and only negligible fractions leaked to the cathodic chamber. Spirulina growth rates were comparable to those of control (MFC-free) cultures, while pH was significantly (0.5-1unit) higher in P-MFCs, due to cathodic reactions. Alkaliphilic photosynthetic microorganisms like Spirulina might take advantage of these selective conditions. Electro-migration along with diffusion to the cathodic compartment concurred for the recovery of most nutrients. Only P and Mg were retained in the anodic chamber. A deeper look into electro-osmotic mechanisms should be addressed in future studies. PMID- 28341384 TI - Field demonstration of polymer-amended in situ chemical oxidation (PA-ISCO). AB - The methods and results of the first field-scale demonstration of polymer-amended in situ chemical oxidation (PA-ISCO) are presented. The demonstration took place at MCB CAMLEJ (Marine Corps Base, Camp Lejeune) Operable Unit (OU) 15, Site 88, in Camp Lejeune, North Carolina between October and December 2010. PA-ISCO was developed as an alternative treatment approach that utilizes viscosity-modified fluids to improve the in situ delivery and distribution (i.e. sweep-efficiency) of chemical oxidants within texturally heterogeneous contaminated aquifers. The enhanced viscosity of the fluid mitigates the effects of preferential flows, improving sweep-efficiency and enhancing the subsurface contact between the injected oxidant and the target contamination within the treatment zone. The PA ISCO fluid formulation used in this demonstration included sodium permanganate as oxidant, xanthan gum biopolymer as a shear-thinning viscosifier, and sodium hexametaphosphate (SHMP) as an anti-coagulant. It was the goal of this demonstration to validate the utility of PA-ISCO within a heterogeneous aquifer. An approximate 100% improvement in sweep-efficiency was achieved for the PA-ISCO fluid, as compared to a permanganate-only injection within an adjacent control plot. PMID- 28341385 TI - Imaging of Intracranial and Orbital Complications of Sinusitis and Atypical Sinus Infection: What the Radiologist Needs to Know. AB - Sinusitis is a common disease. Complications, however, are less common and can be life threatening. Major complications occur from extension of disease into the orbit and intracranial compartment and often require emergent treatment with intravenous (IV) antibiotics or operative intervention. Immunocompromised patients with acute sinusitis are susceptible to atypical infections, such as invasive fungal sinusitis, which is a surgical emergency. Therefore, it is important to accurately and promptly identify potentional complications of acute sinusitis to ensure appropriate treatment and minimize negative outcomes. This article reviews the imaging features of a spectrum of complications associated with acute sinusitis and atypical infections. PMID- 28341383 TI - Utilization of gynecologic services in women with breast cancer receiving hormonal therapy. AB - BACKGROUND: The selective estrogen receptor modulator tamoxifen is now widely used for the treatment and prevention of breast cancer. Tamoxifen use has been associated with a variety of gynecologic problems. Despite the frequency with which hormonal therapy is used for the treatment of breast cancer, limited population-level data are available to describe the occurrence of gynecologic conditions and the use of surveillance testing in women receiving tamoxifen and aromatase inhibitors. OBJECTIVE: We performed a population-based analysis among women with breast cancer receiving hormonal therapy with tamoxifen, a drug commonly used in premenopausal and sometimes postmenopausal women, to determine the frequency of gynecologic abnormalities and use of diagnostic and surveillance testing. We compared these findings to women treated with aromatase inhibitors, agents commonly used in postmenopausal women. STUDY DESIGN: The MarketScan database was used to identify women diagnosed with breast cancer from 2009 through 2013 who underwent mastectomy or lumpectomy. Women receiving tamoxifen (age <50 vs >=50 years) were compared to women >=50 years of age treated with aromatase inhibitors. We examined the occurrence of gynecologic symptoms and diseases (vaginal bleeding, endometrial polyps, endometrial hyperplasia, and endometrial cancer) and gynecologic procedures and interventions (transvaginal ultrasound, endometrial biopsy, hysteroscopy/dilation and curettage, and hysterectomy). Time-dependent analyses were performed to examine symptoms and testing. RESULTS: A total of 75,170 women, including 15,735 (20.9%) age <50 years treated with tamoxifen, 13,827 (18.4%) age >=50 years treated with tamoxifen, and 45,608 (60.7%) age >=50 years treated with aromatase inhibitors were identified. The cumulative incidence of any gynecologic symptom or pathologic diagnosis during the study period was 20.2%, 12.3%, and 3.5%, respectively (P < .001), while the cumulative incidence of any gynecologic procedure or intervention during the study period was 34.2%, 20.9%, and 9.0%, respectively (P < .0001). Among women without symptoms or pathology, interventions were performed in 20.0%, 11.0%, and 6.8%, respectively (P < .0001). CONCLUSION: Compared to women taking aromatase inhibitors, gynecologic symptoms, procedures, and pathology are higher for both premenopausal and postmenopausal women with breast cancer on tamoxifen. Increased efforts to curb use of gynecologic interventions in asymptomatic women are needed. PMID- 28341386 TI - Follicular output rate can predict clinical pregnancy in women with unexplained infertility undergoing IVF/ICSI: a prospective cohort study. AB - This study aimed to determine whether follicular output rate (FORT) can predict the clinical pregnancy rate in women with unexplained infertility undergoing IVF/ICSI. This was a prospective study conducted at Dar El Teb subfertility centre in Cairo between June 2014 and July 2016. A total of 303 women with unexplained infertility, who were undergoing IVF/ICSI, were divided into three groups according to FORT tertile values. FORT was calculated as pre-ovulatory follicle count/antral follicle count * 100. There was a progressive and significant increase from the low to the high FORT groups in the clinical pregnancy rate (29.9%, 43.3% and 57.8%; P < 0.001), number of retrieved oocytes (5.4 +/- 1.5, versus 6.8 +/- 2.8, and 7.4 +/- 2.1; P < 0.001), and fertilization rate (48.4 +/- 21.8 versus 55.3 +/- 20.3 and 57.4 +/- 19.2; P = 0.006). Multivariate logistic regression analysis revealed that the correlation between FORT and pregnancy was independent of potential confounding factors (P = 0.008). We concluded that FORT is an independent variable affecting the clinical pregnancy rate in IVF/ICSI cycles. Higher FORT values had better oocyte yield and clinical pregnancy rates in women with unexplained infertility undergoing IVF/ICSI with potentially normal ovarian response. PMID- 28341387 TI - [New-onset preseptal cellulitis secondary to group B Streptococcus agalactiae bacteremia in a 12-day-old boy]. PMID- 28341388 TI - [Real life visual and anatomic outcomes of aflibercept treatment for treatment naive patients with exudative age-related macular degeneration]. AB - : Anti-VEGF therapies have revolutionized the treatment of neovascular age related macular degeneration (AMD). PURPOSE: The goal of this study was to evaluate the "real life" visual and anatomical outcomes of aflibercept treatment for treatment-naive patients with exudative AMD. METHODS: This was a retrospective study of patients treated with aflibercept in the department of Ophthalmology at the University Hospital of Bordeaux between November 2013 and July 2015. The follow-up period varied from 3months to 2years. All patients received an induction phase with 3monthly intravitreal injections (IVT) followed by personalized monitoring. ETDRS best-corrected visual acuity (BCVA), fundus examination and OCT were performed at each visit. Data were collected at day 0, 3 months, 6, 9, 12months, 18 and 24months. RESULTS: Forty-three eyes of forty patients, mean age 77.7years, were included, with a minimum of 3months follow-up. Twenty-five eyes were followed for 1year; 5 eyes for two years. At baseline, the mean BCVA was 55.7 letters. Patients received 7.5 injections on average the first year and 2.6 the 2nd year. The mean gain of visual acuity was +7.3 letters at 3 months, +6.2 letters at 12 months, and +6.8 letters at 2years. Anatomically, the OCT data showed a decline of all parameters. The central macular thickness decreased by 118.3MUm at 3months, 136.4MUm at 12months and 65.5MUm at 2years. CONCLUSION: Aflibercept can achieve effective visual and anatomical outcomes with results, which approach the pivotal studies, despite the use of personalized protocols and longer monitoring intervals. PMID- 28341389 TI - Visual outcomes and complications of cataract surgery with primary implantation in infants. AB - PURPOSE: To describe the visual results and postoperative complications of cataract surgery with primary intraocular lens (IOL) implantation performed in infants and to determine possible predictive factors related to poor visual outcome. METHODS: A retrospective consecutive case series of cataract surgeries with primary IOL implantation in infants was performed. Visual outcome and postoperative complications were recorded. A final visual acuity>0.5 logMAR was considered as a poor visual outcome. RESULTS: Sixty-one consecutive procedures were evaluated in 43 infants. Eighteen infants (42%) had bilateral cataract surgery and 25 (58%) had monocular surgery. The median age at primary surgery was 5.7 months (range: 4 weeks-24 months). The median follow-up was 47 months (range: 14-60 months). The median best-corrected visual acuity in logarithm of the minimum angle of resolution (logMAR) at the last follow-up examination was 1.00 in the case of unilateral surgery and 0.40 in the case of bilateral surgery. The overall visual result in all eyes was 0.50 logMAR. A better visual result was achieved when the infants were younger than 6 months or older than 12 months of age when surgery was performed. Opacification in the visual axis requiring secondary surgery occurred in 54% of the eyes (33/61). Postoperative inflammation occurred in 41% of the eyes (25/61) but was not associated with poor visual outcome (P=0.39). Glaucoma affected 11.5% of the eyes (7/61) and was significantly associated with poorer visual function (OR: 15.36, 95% CI 1.02 230.35, P=0.05). Compared with the unilateral cataract group, the OR of poor visual acuity was 0.06 (95% CI 0.01-0.35, P<0.01) in the bilateral cataract group. No statistical association was observed between final visual acuity>0.5 logMAR and leukocoria at time of diagnosis, IOL-related complications and postoperative strabismus. CONCLUSIONS: Primary IOL implantation is associated with an overall satisfactory visual outcome, especially when surgery is performed before 6 months or after 12 months of age and in bilateral cases. Glaucoma is the main complication associated with poor visual outcome. PMID- 28341390 TI - Pulmonary MR angiography and perfusion imaging-A review of methods and applications. AB - The pulmonary vasculature and its role in perfusion and gas exchange is an important consideration in many conditions of the lung and heart. Currently the mainstay of imaging of the vasculature and perfusion of the lungs lies with CT and nuclear medicine perfusion scans, both of which require ionizing radiation exposure. Improvements in MRI techniques have increased the use of MRI in pulmonary vascular imaging. Here we review MRI methods for imaging the pulmonary vasculature and pulmonary perfusion, both using contrast enhanced and non contrast enhanced methodology. In many centres pulmonary MR angiography and dynamic contrast enhanced perfusion MRI are now well established in the routine workflow of patients particularly with pulmonary hypertension and thromboembolic disease. However, these imaging modalities offer exciting new directions for future research and clinical use in other respiratory diseases where consideration of pulmonary perfusion and gas exchange can provide insight in to pathophysiology. PMID- 28341392 TI - Novel synthesis of gold nanoparticles using Artemisia vulgaris L. leaf extract and their efficacy of larvicidal activity against dengue fever vector Aedes aegypti L. AB - The Aedes aegypti L. mosquito transmits dengue and yellow fever, which cause millions of death every year. Dengue is a mosquito-borne viral disease that has rapidly spread worldwide particularly in countries with tropical and subtropical climates areas. The present study denotes a simple and eco-friendly biosynthesis of gold nanoparticles using Artemisia vulgaris L. leaf extract as reducing agent. The synthesized gold nanoparticles were characterized by UV-Visible Spectroscopy, X-Ray Diffraction (XRD), Fourier Transform Infrared Spectroscopy (FT-IR), Dynamic Light Scattering (DLS), Zeta Potential (ZP), Transmission Electron Microscopy (TEM) and Energy Dispersive X-ray Spectroscopy (EDX). Solid state 13C NMR was utilized to confirm the presence of larvicidal compound Beta caryophyllene in the synthesized AuNPs. Larvicidal activity of the synthesized AuNPs was measured against A. aegypti over 12 and 24h exposure periods and compared with essential oil in various concentrations (25ppm, 50ppm, 100ppm, 200ppm and 400ppm). After a 12h exposure period, the larvicidal activity of 3rd instar larva by AuNPs showed LC50=156.55ppm and LC90=2506.21ppm, while and essential oil displayed LC50=128.99ppm and LC90=1477.08ppm. Larvicidal activity of 4th instar larva by AuNPs showed LC50=97.90ppm and LC90=1677.36ppm, while essential oil displayed LC50=136.15ppm and LC90=2223.55ppm. After a 24h of exposure period, larvicidal activity of 3rd instar larva by AuNPs showed LC50=62.47ppm and LC90=430.16ppm and essential oil showed LC50=111.15ppm and LC90=1441.51ppm. The larvicidal activity of 4th instar larva and AuNPs displayed LC50=43.01ppm and LC90=376.70ppm and for essential oil LC50=74.42ppm, LC90=858.36ppm. Histopathology of A. aegypti with AuNPs for 3rdand 4th stage larvae after 24h exposure at the highest mortality concentration (400ppm) showed that the area of the midgut, epithelial cells and cortex were highly affected. The present findings demonstrate that the biosynthesis of AuNPs using A. vulgaris leaf extracts could be an eco-friendly, safer nanobiopesticide and treatment against A. aegypti which could be used to combat of dengue fever. PMID- 28341393 TI - Cell-specific immuno-localization of progesterone receptor alpha in the rabbit ovary during pregnancy and after parturition. AB - Progesterone receptor alpha (PRA) has a central coordinator role in the ovarian functions in mammals. The aim of this study was to investigate the immunolocalization of PRA in the rabbit ovary during pregnancy and after parturition. The rabbit ovary during pregnancy and after parturition had moderate cytoplasmic and moderate to intense nuclear PRA immunostaining in the ovarian surface epithelial cells, stromal cells and interstitial gland cells. The PRA was also present in granulosa cells and theca interna cells of the growing, small antral and mature Graafian follicles. Theca interna cells of the atretic antral follicle in addition to endothelial and fibroblast cells had PRA immunoreactivity. The PRA were also observed in the theca externa smooth muscle like cells of the growing and antral follicles and in the telocytes. In the present study, the corpora haemorrhagica and early developing corpora lutea had, slight cytoplasmic and nuclear PRA immunostaining in the large lutein and small lutein cells. The endothelial cells of the corpora haemorrhagica and corpora lutea had an intense nuclear PRA immune signal. The corpora lutea at an advanced stage of development had moderate cytoplasmic and nuclear PRA immunostaining in the large lutein cells and intense nuclear PRA immunostaining in the small lutein cells. The regressed corpora lutea did not have PRA immunostaining in the apoptotic large lutein cells and moderate cytoplasmic and intense nuclear PRA immunostaining in the small lutein cells. PMID- 28341394 TI - Serum biochemical profile and molecular detection of pathogens in semen of infertile male dromedary camels (Camelus dromedarius). AB - Detection of pathogens in the semen of camels has not been completely elucidated. Therefore, the current study aimed to determine the association of some economically important pathogens with infertility in 94 male infertile camels through molecular detection and estimation of selected biochemical parameters in serum of these animals compared with a control non infected fertile animals (n=40). PCR analysis of semen samples of infertile camels indicated that, four potential pathogens namely Mycoplasma spp., Leptospira spp., Brucella melitensis, and Bovine viral diarrhea virus (BVDV) were detected in 50 semen samples of infertile camels whereas, 44 semen samples of infertile camels were free of pathogens and all tested semen samples were negative for bovine herpes virus 1, Salmonella spp. and Trypanosoma evansi. Single and mixed infection was detected in 88% and 12% of the infected semen samples, respectively. Mycoplasma spp., Leptospira spp., Brucella and Bovine viral diarrhea virus infection represented 66%, 27.2%, 4.5% and 2.3% of the single infected semen samples. Mycoplasma spp.+Leptospira spp. and Mycoplasma spp.+Brucella spp. were detected in 83.3% and 16.7% of mixed infected semen samples, respectively. Testosterone concentration decreased significantly in infertile infected camels compare to both control and infertile non infected animals that remained comparable. The current findings reported the molecular detection of mixed infection in camel semen for the first time. Mycoplasma spp. is the most widely recognized microorganism in the present study and together with Leptospira spp., Brucella spp. and Bovine viral diarrhea virus, might be associated with infertility in dromedary camels. PMID- 28341391 TI - Mice lacking liver-specific beta-catenin develop steatohepatitis and fibrosis after iron overload. AB - BACKGROUND & AIMS: Iron overload disorders such as hereditary hemochromatosis and iron loading anemias are a common cause of morbidity from liver diseases and increase risk of hepatic fibrosis and hepatocellular carcinoma (HCC). Treatment options for iron-induced damage are limited, partly because there is lack of animal models of human disease. Therefore, we investigated the effect of iron overload in liver-specific beta-catenin knockout mice (KO), which are susceptible to injury, fibrosis and tumorigenesis following chemical carcinogen exposure. METHODS: Iron overload diet was administered to KO and littermate control (CON) mice for various times. To ameliorate an oxidant-mediated component of tissue injury, N-Acetyl-L-(+)-cysteine (NAC) was added to drinking water of mice on iron overload diet. RESULTS: KO on iron diet (KO +Fe) exhibited remarkable inflammation, followed by steatosis, oxidative stress, fibrosis, regenerating nodules and occurrence of occasional HCC. Increased injury in KO +Fe was associated with activated protein kinase B (AKT), ERK, and NF-kappaB, along with reappearance of beta-catenin and target gene Cyp2e1, which promoted lipid peroxidation and hepatic damage. Addition of NAC to drinking water protected KO +Fe from hepatic steatosis, injury and fibrosis, and prevented activation of AKT, ERK, NF-kappaB and reappearance of beta-catenin. CONCLUSIONS: The absence of hepatic beta-catenin predisposes mice to hepatic injury and fibrosis following iron overload, which was reminiscent of hemochromatosis and associated with enhanced steatohepatitis and fibrosis. Disease progression was notably alleviated by antioxidant therapy, which supports its chemopreventive role in the management of chronic iron overload disorders. LAY SUMMARY: Lack of animal models for iron overload disorders makes it hard to study the disease process for improving therapies. Feeding high iron diet to mice that lack the beta-catenin gene in liver cells led to increased inflammation followed by fat accumulation, cell death and wound healing that mimicked human disease. Administration of an antioxidant prevented hepatic injury in this model. PMID- 28341395 TI - Gonocytes-to-spermatogonia transition initiates prior to birth in murine testes and it requires FGF signaling. AB - Spermatogenesis is a continuous and highly coordinated process of spermatozoa production. In mice, this process is believed to initiate shortly after birth with the emergence of nascent spermatogonia in the testes. However, because the nascent spermatogonia originated from the gonocytes are morphologically indistinguishable from their predecessors and there is no clear definition for the gonocytes-to-spermatogonia transition (GST), it remains unclear when and how spermatogenesis is initiated in the mouse testes. To address these questions, we characterized the emergence of nascent spermatogonia in ICR mice. We found that GST is initiated in a subset of gonocytes as early as E18.5. These nascent spermatogonia express markers typical of undifferentiated spermatogonia residing in testes of adult mice. In addition to markers expression, we identified FOXO1 nuclear-to-cytoplasmic translocation as a novel feature of GST distinguishing nascent spermatogonia from the gonocytes. Using those criteria, we demonstrated that GST requires FGF signaling. When FGF signaling was inhibited pharmacologically, gonocytes retained nuclear FOXO1 expression, did not express spermatogonial markers and failed to proliferate. We found that FGF signaling acts upstream of GDNF and RA signalings for the activation of the MEK/ERK and PI3K/Akt pathways in germ cells during GST. Taken together, we defined the precise timing of GST and revealed FGF signaling as a master regulator of GST in the perinatal mouse testes. PMID- 28341396 TI - Beyond D'Arcy Thompson: Future challenges for quantitative biology. AB - The centennial of "On Growth and Form" is a good opportunity to reflect on the progress of the quantitative study of living systems and where we would like to see it heading. The era of the physical sciences being a mere vehicle for tool building for biological investigations is over. The approaches taken nowadays are analogous to those that physical scientists have taken within their respective fields for centuries, only that now they ask them about biological phenomena and function. Here I give a brief reflection on where we are and where we should direct our focus next, both from the perspective of the research endeavor as a whole, but also with respect to teaching the next generation of scientists joining the field. PMID- 28341398 TI - Further enhancement of FR901469 productivity by co-overexpression of cpcA, a cross-pathway control gene, and frbF in fungal sp. No. 11243. AB - FR901469 is a secondary metabolite with antifungal activity, produced by fungal sp. No. 11243. In our previous study, we constructed the frbF overexpression mutant (TFH2-2) from the wild-type strain. FR901469 productivity of TFH2-2 was 3.4 times higher than that of the wild-type strain. To further enhance FR901469 productivity in TFH2-2, we attempted to find genes from the genome that limited the productivity as bottlenecks in this study. Based on both correlation analysis of gene expression level against FR901469 productivity and genome annotation information, the cross-pathway control gene A (cpcA) was most predicted as the bottleneck. The cpcA and frbF co-overexpression mutant named TFCH3 was then constructed from TFH2-2. As a result, FR901469 productivity of TFCH3 was enhanced at 1.8 times higher than that of TFH2-2. Transcriptome analysis revealed that many genes involved in amino acid biosynthesis and encoding tRNA ligases were significantly upregulated in TFCH3, which implied increase of amino acids as the substrates of FR901469 would be a reason of further productivity enhancement. PMID- 28341397 TI - Degradation of textile dyes by cyanobacteria. AB - Dyes are recalcitrant compounds that resist conventional biological treatments. The degradation of three textile dyes (Indigo, RBBR and Sulphur Black), and the dye-containing liquid effluent and solid waste from the Municipal Treatment Station, Americana, Sao Paulo, Brazil, by the cyanobacteria Anabaena flos-aquae UTCC64, Phormidium autumnale UTEX1580 and Synechococcus sp. PCC7942 was evaluated. The dye degradation efficiency of the cyanobacteria was compared with anaerobic and anaerobic-aerobic systems in terms of discolouration and toxicity evaluations. The discoloration was evaluated by absorption spectroscopy. Toxicity was measured using the organisms Hydra attenuata, the alga Selenastrum capricornutum and lettuce seeds. The three cyanobacteria showed the potential to remediate textile effluent by removing the colour and reducing the toxicity. However, the growth of cyanobacteria on sludge was slow and discoloration was not efficient. The cyanobacteria P. autumnale UTEX1580 was the only strain that completely degraded the indigo dye. An evaluation of the mutagenicity potential was performed by use of the micronucleus assay using Allium sp. No mutagenicity was observed after the treatment. Two metabolites were produced during the degradation, anthranilic acid and isatin, but toxicity did not increase after the treatment. The cyanobacteria showed the ability to degrade the dyes present in a textile effluent; therefore, they can be used in a tertiary treatment of effluents with recalcitrant compounds. PMID- 28341400 TI - The breath of life. Patients' experiences of breathing during and after mechanical ventilation. AB - INTRODUCTION: Breathlessness is a prevalent and distressing symptom in intensive care, underestimated by nurses and physicians. Therefore, to develop a more comprehensive understanding of this problem, the study had two aims: to compare patients' self-reported scores of breathlessness obtained during mechanical ventilation (MV) with experiences of breathlessness later recalled by patients and: to explore the lived experience of breathing during and after MV. METHOD: A qualitatively driven sequential mixed method design combining prospective observational breathlessness data at the end of a spontaneous breathing trial (SBT) and follow up data from 11 post-discharge interviews. FINDINGS: Four out of six patients who reported breathlessness at the end of an SBT did not remember being breathless in retrospect. Experiences of breathing intertwined with the whole illness experience and were described in four themes: existential threat; the tough time; an amorphous and boundless body and getting through. CONCLUSION: Breathing was not always a clearly separate experience, but intertwined with the whole illness experience. This may explain the poor correspondence between patients' and clinicians assessments of breathlessness. The results suggest patients' own reports of breathing should form part of nursing interventions and follow-up to support patients' quest for meaning. PMID- 28341399 TI - Early postoperative blood pressure and blood loss after cardiac surgery: A retrospective analysis. AB - BACKGROUND: Increased blood loss after cardiac surgery is a risk factor for patient morbidity and mortality. Guidelines for postoperative haemodynamics management recommend normotensive blood pressure to avoid increased chest drain volumes. The aim of this study was to verify the correlation of early postoperative hypertension and blood loss in patients after cardiac surgery during the early postoperative period. METHODS: Postoperative mean blood pressure values and chest drain volumes of 431 patients were registered by an intensive care monitoring system during first 60minutes after intensive care admission. Correlation between blood pressure and blood loss was calculated by linear regression analysis. RESULTS: In the entire patient cohort and in various subgroup analyses (body-mass-index, type of surgery, comorbidity, emergency surgery, preoperative anticoagulation therapy) no association between early mean blood pressure >80mmHg and increased blood loss was evident in simple regression analysis. Merely, after aortic surgery a correlation of hypertension and blood loss was found. Multiple regression revealed postoperative INR values >1.5 and thrombocyte counts <100.000/nL to impact blood loss in contrast to postoperative hypertension. CONCLUSION: Evidence for strict blood pressure management to reduce blood loss after cardiac surgery is scarce. Instead, in face of higher INR and low thrombocytes increasing postoperative blood loss, achieving and maintaining a physiological coagulation is essential. PMID- 28341401 TI - Discovery of (2-aminophenyl)methanol as a new molecular chaperone that rescues the localization of P123S mutant pendrin stably expressed in HEK293 cells. AB - Pendred syndrome is the most common form of syndromic deafness. It is associated with a mutation in the SLC26A4 gene that encodes pendrin, which is thought to maintain the ion concentration of endolymph in the inner ear most likely by acting as a chloride/bicarbonate transporter. Mutations in the SLC26A4 gene are responsible for sensorineural hearing loss. In this study, we established a stable HEK293 cell line expressing P123S mutant pendrin and developed screening methods for compounds that show pharmacological chaperone activity by image analysis using CellInsightTM. Morphological analysis of stained cells in each well of 96-well plates yielded six compounds in the compound library. Furthermore, fluorescence intensity analysis of the intracellular localization of P123S mutant pendrin in HEK293 cells using FLUOVIEWTM and cytotoxicity experiments revealed that (2-aminophenyl)methanol 8 is the most promising molecular chaperone to rescue P123S mutant pendrin: the plasma membrane (M)/cytoplasm (C) ratios are 1.5 and 0.9 at the concentrations of 0.3 and 0.1mM, respectively, and a sustained effect was observed 12h after removal of the compound from the cell medium. Because the M/C ratio of salicylate, which was previously discovered as a molecular chaperone of P123S mutant pendrin, was approximately 1 at 10mM concentration and a sustained effect was not observed even at 6h, (2-aminophenyl)methanol 8 was 100 times more potent and exhibited a longer sustained effect than salicylate. These findings suggest that (2 aminophenyl)methanol 8 is an attractive candidate for therapeutic agent for Pendred syndrome patients. PMID- 28341402 TI - Inhibitors of protein arginine deiminases and their efficacy in animal models of multiple sclerosis. AB - Protein arginine deiminases (PAD) are implicated in a variety of inflammatory and neurodegenerative diseases including multiple sclerosis (MS). Following the discovery of an in silico hit containing hydantoin and a piperidine moiety, we hypothesized that a 2-carbon linker on the hydantoin would be necessary for a 5 membered heterocycle for optimal PAD inhibitory activity. We designed thirteen compounds as potential inhibitors of PAD2 and PAD4 enzymes-two important PAD enzymes implicated in MS. Two compounds, one with an imidazole moiety (22) and the other with a tetrazole moiety (24) showed good inhibition of PAD isozymes in vitro and in the EAE mouse model of MS in vivo. Further experiments suggested that compound 22, a non-covalent inhibitor of PAD2 and PAD4, exhibits dose dependent efficacy in the EAE mouse model and in the cuprizone-mediated demyelination model. PMID- 28341404 TI - Corrigendum to "Synthesis and biological activity of 2,5-diaryl-3 methylpyrimido[4,5-c]quinolin-1(2H)-one derivatives" [Bioorg. Med. Chem. 15 (2007) 2434-2440]. PMID- 28341403 TI - Thiazolidine derivatives as potent and selective inhibitors of the PIM kinase family. AB - The PIM family of serine/threonine kinases have become an attractive target for anti-cancer drug development, particularly for certain hematological malignancies. Here, we describe the discovery of a series of inhibitors of the PIM kinase family using a high throughput screening strategy. Through a combination of molecular modeling and optimization studies, the intrinsic potencies and molecular properties of this series of compounds was significantly improved. An excellent pan-PIM isoform inhibition profile was observed across the series, while optimized examples show good selectivity over other kinases. Two PIM-expressing leukemic cancer cell lines, MV4-11 and K562, were employed to evaluate the in vitro anti-proliferative effects of selected inhibitors. Encouraging activities were observed for many examples, with the best example (44) giving an IC50 of 0.75MUM against the K562 cell line. These data provide a promising starting point for further development of this series as a new cancer therapy through PIM kinase inhibition. PMID- 28341405 TI - Synthesis of novel C-9 carbon substituted derivatives of artemisinin. AB - Several artemisinin derivatives carrying several groups (alkyl, hydroxyalkyl, allyl or azide) at position 9 have been synthesized starting from artemisinin via enolate formation and subsequent reaction with appropriate electrophiles. PMID- 28341406 TI - Sweet New Roles for Protein Glycosylation in Prokaryotes. AB - Long-held to be a post-translational modification unique to Eukarya, it is now clear that both Bacteria and Archaea also perform protein glycosylation, namely the covalent attachment of mono- to polysaccharides to specific protein targets. At the same time, many of the roles assigned to this protein-processing event in eukaryotes, such as guiding protein folding/quality control, intracellular trafficking, dictating cellular recognition events and others, do not apply or are even irrelevant to prokaryotes. As such, protein glycosylation must serve novel functions in Bacteria and Archaea. Recent efforts have begun to elucidate some of these prokaryote-specific roles, which are addressed in this review. PMID- 28341407 TI - Comparison of endoscopic laser therapy and self expanding metal stents for palliation in patients with non-resectable oesophageal carcinoma. AB - BACKGROUND: There are currently limited data on the comparative success of endoscopic laser therapy (NLT) and self expanding metal stents (SEMS) as palliative measures in patients with non-resectable oesophageal cancer. This study aims to assess and compare the outcomes of these methods of endoscopic palliation. METHODS: Patients with non-curative oesophageal/gastro-oesophageal cancers with dysphagia were identified prospectively and consented to swallow assessment and follow-up. Patients underwent SEMS or NLT at the discretion of the treating endoscopist. Initial standardised swallow scores (0-4) were assessed. All subsequent interventions were recorded as well as survival. RESULTS: 31 patients were recruited (30M vs 8F, mean age 70.8). There was no significant difference in age, sex or chemotherapy treatment between groups. 19(61%)patients underwent NLT as primary procedure. 20(64.5%) patients required subsequent intervention(s) (median 1, range 0-8). Primary NLT patients were more likely to require subsequent therapy (p = 0.004) and multiple procedures (p = 0.001). 8(42.1%)patients initially undergoing NLT subsequently required SEMS, while no SEMS patients underwent subsequent NLT. Swallow scores of 1 or 2 were more likely to be maintained with NLT while scores of 3 or 4 were more likely to progress to SEMS (p = 0.039). Time to repeat procedure was greater in the SEMS group (p = 0.001). Median survival was 133 days for NLT vs 60 days for SEMS (p = 0.412). CONCLUSION: In this series, patients selected for NLT had a trend towards longer survival, but were more likely to require repeated procedures. Those with lower early initial dysphagia scores were more likely to be maintained by NLT alone. PMID- 28341408 TI - The Effect of 3-Dimensional Simulation on Neurosurgical Skill Acquisition and Surgical Performance: A Review of the Literature. AB - OBJECTIVE: In recent years, 3-dimensional (3D) simulation of neurosurgical procedures has become increasingly popular as an addition to training programmes. However, there remains little objective evidence of its effectiveness in improving live surgical skill. This review analysed the current literature in 3D neurosurgical simulation, highlighting remaining gaps in the evidence base for improvement in surgical performance and suggests useful future research directions. DESIGN: An electronic search of the databases was conducted to identify studies investigating 3D virtual reality (VR) simulation for various types of neurosurgery. Eligible studies were those that used a combination of metrics to measure neurosurgical skill acquisition on a simulation trainer. Studies were excluded if they did not measure skill acquisition against a set of metrics or if they assessed skills that were not used in neurosurgical practice. This was not a systematic review however, the data extracted was tabulated to allow comparison between studies RESULTS: This study revealed that the average overall quality of the included studies was moderate. Only one study assessed outcomes in live surgery, while most other studies assessed outcomes on a simulator using a variety of metrics. CONCLUSIONS: It is concluded that in its current state, the evidence for 3D simulation suggests it as a useful supplement to training programmes but more evidence is needed of improvement in surgical performance to warrant large-scale investment in this technology. PMID- 28341410 TI - Emotional Wellness of Current Musculoskeletal Radiology Fellows. AB - RATIONALE AND OBJECTIVES: Burnout is a psychological syndrome composed of emotional exhaustion, depersonalization, and sense of lack of personal accomplishment, as a result of prolonged occupational stress. The purpose of our study was to determine the prevalence of burnout among current musculoskeletal radiology fellows and to explore causes of emotional stress. MATERIALS AND METHODS: A 24-item survey was constructed on SurveyMonkey using the Maslach Burnout Inventory. We identified 82 musculoskeletal radiology fellowship programs. We recruited subjects indirectly through the program director or equivalent. RESULTS: Fifty-eight respondents (48 male, 10 female) identified themselves as current musculoskeletal radiology fellows and completed the survey. Comparison of the weighted subscale means in our data to the Maslach normative subscale thresholds for medical occupations indicates that musculoskeletal radiology fellows report relatively high levels of burnout with regard to lack of personal accomplishment and depersonalization, whereas emotional exhaustion levels in our sample are within the average range reported by Maslach. Although male musculoskeletal radiology fellows experience relatively high levels in two of the three dimensions of burnout (depersonalization and personal accomplishment), female musculoskeletal radiology fellows experience relatively high burnout across all three dimensions. Job market-related stress and the effort required providing care for dependents significantly affect personal accomplishment. Conversely, imbalances in the work-life relationship and feelings of powerlessness are significantly associated with depersonalization and emotional exhaustion. CONCLUSIONS: Musculoskeletal radiology fellows report relatively high levels of burnout. Because the consequences of burnout can be severe, early identification and appropriate intervention should be a priority. PMID- 28341409 TI - Glottis Closure Influences Tracheal Size Changes in Inspiratory and Expiratory CT in Patients with COPD. AB - RATIONALE AND OBJECTIVES: The opened or closed status of the glottis might influence tracheal size changes in inspiratory and expiratory computed tomography (CT) scans. We investigated if the glottis status makes the tracheal collapse differently correlate with lung volume difference between inspiratory and expiratory CT scans. MATERIALS AND METHODS: Forty patients with chronic obstructive pulmonary disease whose glottis was included in the acquired scanned volume for lung CT were divided into two groups: 16 patients with the glottis closed in both inspiratory and expiratory CT, and 24 patients with the glottis open in at least one CT acquisition. Lung inspiratory (Vinsp) and expiratory (Vexp) volumes were automatically computed and lung DeltaV was calculated using the following formula: (Vinsp - Vexp)/Vinsp * 100. Two radiologists manually measured the anteroposterior diameter and cross-sectional area of the trachea 1 cm above the aortic arch and 1 cm above the carina. Tracheal collapse was then calculated and correlated with lung DeltaV. RESULTS: In the 40 patients, the correlations between tracheal Deltaanteroposterior diameter and Deltacross sectional area at each level and lung DeltaV ranged between 0.68 and 0.74 (rho) at Spearman rank correlation test. However, in the closed glottis group, the correlations were higher for all measures at the two levels (rho range: 0.84 0.90), whereas in the open glottis group, correlations were low and not statistically significant (rho range: 0.29-0.34) at the upper level, and moderate at the lower level (rho range: 0.51-0.55). CONCLUSIONS: A closed or open glottis influences the tracheal size change in inspiratory and expiratory CT scans. With closed glottis, the tracheal collapse shows a stronger correlation with the lung volume difference between inspiratory and expiratory CT scans. PMID- 28341411 TI - Oligoprogression: What Radiologists Need to Know About This Emerging Concept in Cancer Therapeutic Decision-making. PMID- 28341413 TI - A Response to Skerl et al. (2016). PMID- 28341412 TI - Dorsal Muscle Attenuation May Predict Failure to Respond to Interleukin-2 Therapy in Metastatic Renal Cell Carcinoma. AB - RATIONALE AND OBJECTIVES: To explore whether the sarcopenia body type can help predict response to interleukin-2 (IL-2) therapy in metastatic renal cell carcinoma (RCC). MATERIALS AND METHODS: Institutional review board approval was obtained for this Health Insurance Portability and Accountability Act-compliant retrospective cohort study of 75 subjects with metastatic RCC who underwent pretreatment contrast-enhanced computed tomography within 1 year of initiating IL 2 therapy. Cross-sectional area and attenuation of normal-density (31-100 Hounsfield units [HU]) and low-density (0-30 HU) dorsal muscles were obtained at the T11 vertebral level. The primary outcome was partial or complete response to IL-2 using RECIST 1.1 criteria at 6 weeks. A conditional inference tree was used to determine an optimal HU cutoff for predicting outcome. Bonferroni-adjusted multivariate logistic regression was conducted to investigate the independent associations between imaging features and response after controlling for demographics, doses of IL-2, and RCC prognostic scales (eg, Heng and the Memorial Sloan Kettering Cancer Center [MSKCC]). RESULTS: Most subjects had intermediate prognosis by Heng (65% [49 of 75]) and the MSKCC (63% [47 of 75]) criteria; 7% had complete response and 12% had partial response. Mean attenuation of low density dorsal muscles was a significant univariate predictor of IL-2 response after Bonferroni correction (P = 0.03). The odds of responding to treatment were 5.8 times higher for subjects with higher-attenuation low-density dorsal muscles (optimal cutoff: 18.1 HU). This persisted in multivariate analysis (P = 0.02). Body mass index (P = 0.67) and the Heng (P = 0.22) and MSKCC (P = 0.08) clinical prognostic scales were not significant predictors of response. CONCLUSIONS: Mean cross-sectional attenuation of low-density dorsal muscles (ie, sarcopenia) may predict IL-2 response in metastatic RCC. Clinical variables are poor predictors of response. PMID- 28341414 TI - Myocardial Extracellular Volume Is Not Associated With Malignant Ventricular Arrhythmias in High-risk Hypertrophic Cardiomyopathy. AB - INTRODUCTION AND OBJECTIVES: Myocardial interstitial fibrosis, a hallmark of hypertrophic cardiomyopathy (HCM), has been proposed as an arrhythmic substrate. Fibrosis is associated with increased extracellular volume (ECV), which can be quantified by computed tomography (CT). We aimed to analyze the association between CT-determined ECV and malignant ventricular arrhythmias. METHODS: A retrospective case-control observational study was conducted in HCM patients with implantable cardioverter-defibrillator, undergoing a CT-protocol with continuous iodine contrast infusion to determine equilibrium ECV. Left ventricular septal and lateral CT-determined ECV was compared between prespecified cases (malignant arrhythmia any time before CT scan) and controls (no prior malignant arrhythmias) and among ECV tertiles. RESULTS: A total of 78 implantable cardioverter defibrillator HCM patients were included; 24 were women, with a mean age of 52.1 +/- 15.6 years. Mean ECV +/- standard deviation in the septal left ventricular wall and was 29.8% +/- 6.3% in cases (n = 24) vs 31.9% +/- 8.5% in controls (n = 54); P = .282. Mean ECV in the lateral wall was 24.5% +/- 6.8% in cases vs 28.2% +/- 7.4% in controls; P = .043. On comparison of the entire population according to septal ECV tertiles, no significant differences were found in the number of patients receiving appropriate shocks. Conversely, we found a trend (P = .056) for a higher number of patients receiving appropriate shocks in the lateral ECV lowest tertile. CONCLUSIONS: Extracellular volume was not increased in implantable cardioverter-defibrillator HCM patients with malignant ventricular arrhythmias vs those without arrhythmias. Our findings do not support the use of ECV (a surrogate of diffuse fibrosis) as a predictor of arrhythmias in high-risk HCM patients. PMID- 28341416 TI - A physiologically-oriented transcriptomic analysis of the midgut of Tenebrio molitor. AB - Physiological data showed that T. molitor midgut is buffered at pH 5.6 at the two anterior thirds and at 7.9 at the posterior third. Furthermore, water is absorbed and secreted at the anterior and posterior midgut, respectively, driving a midgut counter flux of fluid. To look for the molecular mechanisms underlying these phenomena and nutrient absorption as well, a transcriptomic approach was used. For this, 11 types of transporters were chosen from the midgut transcriptome obtained by pyrosequencing (Roche 454). After annotation with the aid of databanks and manual curation, the sequences were validated by RT-PCR. The expression level of each gene at anterior, middle and posterior midgut and carcass (larva less midgut) was evaluated by RNA-seq taking into account reference sequences based on 454 contigs and reads obtained by Illumina sequencing. The data showed that sugar and amino acid uniporters and symporters are expressed along the whole midgut. In the anterior midgut are found transporters for NH3 and NH4+ that with a chloride channel may be responsible for acidifying the lumen. At the posterior midgut, bicarbonate-Cl- antiporter with bicarbonate supplied by carbonic anhydrase may alkalinize the lumen. Water absorption caused mainly by an anterior Na+-K+-2Cl- symporter and water secretion caused by a posterior K+-Cl- may drive the midgut counter flux. Transporters that complement the action of those described were also found. PMID- 28341417 TI - Poor knowledge of age-related fertility decline and assisted reproduction among healthcare professionals. AB - Reproduction is a matter of concern for individuals and society due to the postponement of childbearing, and healthcare professionals are the main source of information and counselling. This study aims to evaluate how knowledgeable healthcare professionals are about fertility and assisted reproduction, and to explore attitudes towards social oocyte freezing. A cross-sectional study was performed with 201 professionals (gynaecologists, physicians and nurses) from four public centres in Spain. Participants completed a survey about fertility, IVF, oocyte donation (OD) and social oocyte freezing, between May 2013 and March 2014. Reported mean age limits for pregnancy were 39.5 +/- 4.5 (spontaneously), 43.7 +/- 5.2 (IVF) and 49.0 +/- 6.5 (OD). Gynaecologists reported a younger limit for spontaneous and IVF pregnancies (P < 0.001); 36.1% reported a limit for a spontaneous pregnancy >39, compared with 77.3% of other physicians and 72.9% of nurses. Regarding social oocyte freezing, 41.8% of gynaecologists thought it should be offered to every young woman, versus 62.7% of other physicians and 48.9% of nurses (P = 0.041). In conclusion, gynaecologists are more knowledgeable about fertility and assisted reproduction, while more restrictive towards social oocyte freezing. Knowledge and attitudes could influence the quality of information and counselling given to patients. PMID- 28341415 TI - Diuretic Strategies in Acute Heart Failure and Renal Dysfunction: Conventional vs Carbohydrate Antigen 125-guided Strategy. Clinical Trial Design. AB - INTRODUCTION AND OBJECTIVES: The optimal treatment of patients with acute heart failure (AHF) and cardiorenal syndrome type 1 (CRS-1) is far from being well defined. Arterial hypoperfusion in concert with venous congestion plays a crucial role in the pathophysiology of CRS-I. Plasma carbohydrate antigen 125 (CA125) has emerged as a surrogate of fluid overload in AHF. The aim of this study was to evaluate the clinical usefulness of CA125 for tailoring the intensity of diuretic therapy in patients with CRS-1. METHODS: Multicenter, open-label, parallel clinical trial, in which patients with AHF and serum creatinine >= 1.4mg/dL on admission will be randomized to: a) standard diuretic strategy: titration-based on conventional clinical and biochemical evaluation, or b) diuretic strategy based on CA125: high dose if CA125 > 35 U/mL, and low doses otherwise. The main endpoint will be renal function changes at 24 and 72hours after therapy initiation. Secondary endpoints will include: a) clinical and biochemical changes at 24 and 72hours, and b) renal function changes and major clinical events at 30 days. RESULTS: The results of this study will add important knowledge on the usefulness of CA125 for guiding diuretic treatment in CRS-1. In addition, it will pave the way toward a better knowledge of the pathophysiology of this challenging situation. CONCLUSIONS: We hypothesize that higher levels of CA125 will identify a patient population with CRS-1 who could benefit from the use of a more intense diuretic strategy. Conversely, low levels of this glycoprotein could select those patients who would be harmed by high diuretic doses. PMID- 28341418 TI - A novel Y chromosome microdeletion potentially associated with defective spermatogenesis identified by custom array comparative genome hybridization. AB - Male infertility is a major health problem worldwide. Oligospermia and azoospermia are the most common symptoms of this disorder. Despite recent advances, the aetiopathogenesis of defective spermatogenesis remains largely uncertain. The aim of this study is to discover unknown or novel chromosome aberrations associated with male reproductive failure. We developed a high resolution custom array comparative genomic hybridization for initial screening of copy number variations in 10 patients with idiopathic oligozoospermia and azoospermia and eight normal fertile men. We found that deletions were mainly located in the deleted-in-azoospermia subregion and were confined to patients. More importantly, an interesting microdeletion of the Y chromosome designated as D01 was detected in four out of 10 patients with oligozoospermia and azoospermia. We validated this recurrent deletion in nine out of 100 additional infertile men using polymerase chain reaction assays, whereas, it was not present in 100 proven fertile controls(P = 0.002). Furthermore, a bioinformatics analysis demonstrated that the 5' terminal of D01 is situated proximal to several conserved transcription factor binding sites within the Y chromosome. Our study indicated that this newly identified Y chromosome deletion might be potentially associated with impaired spermatogenesis and it is worthy of further investigations in larger cohorts. PMID- 28341420 TI - Brain metastasization of breast cancer. AB - Central nervous system metastases have been reported in 15-25% of breast cancer patients, and the incidence is increasing. Moreover, the survival of these patients is generally poor, with reports of a 1-year survival rate of 20%. Therefore, a better knowledge about the determinants of brain metastasization is essential for the improvement of the clinical outcomes. Here, we summarize the current data about the metastatic cascade, ranging from the output of cancer cells from the primary tumour to their colonization in the brain, which involves the epithelial-mesenchymal transition, invasion of mammary tissue, intravasation into circulation, and homing into and extravasation towards the brain. The phenotypic change in malignant cells, and the importance of the microenvironment in the formation of brain metastases are also inspected. Finally, the importance of genetic and epigenetic changes, and the recently disclosed effects of microRNAs in brain metastasization of breast cancer are highlighted. PMID- 28341421 TI - Mutations, evolution and the central role of a self-defined fitness function in the initiation and progression of cancer. AB - The origin and progression of cancer is widely viewed as "somatic evolution" driven by the accumulation of random genetic changes. This theoretical model, however, neglects fundamental conditions for evolution by natural selection, which include competition for survival and a local environmental context. Recent observations that the mutational burden in different cancers can vary by 2 orders of magnitude and that multiple mutations, some of which are "oncogenic," are observed in normal tissue suggests these neglected Darwinian dynamics may play a critical role in modifying the evolutionary consequences of molecular events. Here we discuss evolutionary principles in normal tissue focusing on the dynamical tension between different evolutionary levels of selection. Normal somatic cells within metazoans do not ordinarily evolve because their survival and proliferation are governed by tissue signals and internal controls (e.g. telomere shortening) that maintain homeostatic function. The fitness of each cell is, thus, identical to the whole organism, which is the evolutionary level of selection. For a cell to evolve, it must acquire a self-defined fitness function so that its survival and proliferation is determined entirely by its own heritable phenotypic properties. Cells can develop independence from normal tissue control through randomly accumulating mutations that disrupt its ability to recognize or respond to all host signals. A self-defined fitness function can also be gained non-genetically when tissue control signals are lost due to injury, inflammation, or infection. Accumulating mutations in cells without a self-defined fitness function will produce no evolution - consistent with reports showing mutations, including some that would ordinarily be oncogenic, are present in cells from normal tissue. Furthermore, once evolution begins, Darwinian forces will promote mutations that increase fitness and eliminate those that do not. Thus, cancer cells will typically have a mutational burden similar to adjacent normal cells and many (perhaps most) mutations observed in cancer cells occurred prior to somatic evolution and may not contribute to the cell's malignant phenotype. This article is part of a Special Issue entitled: Evolutionary principles - heterogeneity in cancer?, edited by Dr. Robert A. Gatenby. PMID- 28341422 TI - Pyrolysis of waste tires: A modeling and parameter estimation study using Aspen Plus(r). AB - This paper presents a simulation flowsheet model of a waste tire pyrolysis process with feed capacity of 150kg/h. A kinetic rate-based reaction model is formulated in a form implementable in the simulation package Aspen Plus, giving the flowsheet model the capability to predict more than 110 tire pyrolysis products as reported in experiments by Laresgoiti et al. (2004) and Williams (2013) for the oil and gas products respectively. The simulation model is successfully validated in two stages: firstly against experimental data from Olazar et al. (2008) by comparing the mass fractions for the oil products (gas, liquids (non-aromatics), aromatics, and tar) at temperatures of 425, 500, 550 and 610 degrees C, and secondly against experimental results of main hydrocarbon products (C7 to C15) obtained by Laresgoiti et al. (2004) at temperatures of 400, 500, 600, and 700 degrees C. The model was then used to analyze the effect of pyrolysis process temperature and showed that increased temperatures led to chain fractions from C10 and higher to decrease while smaller chains increased; this is attributed to the extensive cracking of the larger hydrocarbon chains at higher temperatures. The utility of the flowsheet model was highlighted through an energy analysis that targeted power efficiency of the process determined through production profiles of gasoline and diesel at various temperatures. This shows, through the summation of the net power gain from the plant for gasoline plus diesel that the maximum net power lies at the lower temperatures corresponding to minimum production of gasoline and maximum production of diesel. This simulation model can thus serve as a robust tool to respond to market conditions that dictate fuel demand and prices while at the same time identifying optimum process conditions (e.g. temperature) driven by process economics. PMID- 28341424 TI - Swedish infant VUR trial. PMID- 28341425 TI - Proximal hypospadias repair with bladder mucosal graft: Our 10 years experience. AB - INTRODUCTION AND OBJECTIVE: A great variety of different surgical techniques has been described for proximal hypospadias repair and an ideal tissue has not been determined yet. We present our 10 years of surgical experience using a bladder mucosal graft for urethroplasty. STUDY DESIGN: Bladder mucosal graft urethroplasty was performed between 2005 and 2015 in 50 patients with severe proximal hypospadias. The mean age of patients was 45.1 months (range 24-164 months). Hypospadias were perineal in 18 patients, scrotal in 22, and penoscrotal in 10. In all cases a chordee correction was performed and median time between the first and the second stages was 12 months (mean 17 months, range 4-68 months). Both foley catheter and a suprapubic cystostomy were positioned and maintained for 2-4 weeks. Follow-up was performed at 1-3 and 6-12 months after surgery, and afterwards annually with clinical examination and flowmetry test. RESULTS: Mean follow-up was 5.3 years (median 5, range 1-10 years). Mean graft length was 57.4 mm (median 55 mm, range 35-85 mm). Among all the only early complication registered was a postoperative infection in one patient (2%) at the site of anastomosis. The long-term complications observed were urethrocutaneous fistula in nine patients (18%), urethral stricture in 15 patients (30%), meatal stricture in four patients (8%), and prolapse of meatus in seven patients (14%). The mean time of complication occurrence was 15 months (median 15.5 months, range 1-96 months). The functional and cosmetic appearance after surgery was satisfactory in 42/50 patients (84%) during the follow-up period. DISCUSSION: There is still an open debate regarding the optimal surgical approach for management of severe proximal hypospadias. Compared with other approaches, our technique showed acceptable results even though encumbered by slightly higher complication rates. CONCLUSION: Our results show that bladder mucosal graft for primary severe proximal hypospadias in selected patients is a possible alternative to other commonly used techniques, with the aim of restoring recovery of the normal continuity of the distal urinary tract see figure below. PMID- 28341426 TI - Corrigendum to "Management of undescended testes: European Association of Urology/European Society for Paediatric Urology Guidelines" [J Pediatr Urol 12 (2016) 335-343]. PMID- 28341427 TI - Community-onset carbapenem-resistant Klebsiella pneumoniae urinary tract infections in infancy following NICU hospitalisation. AB - INTRODUCTION: Urinary tract infection (UTI) is a common bacterial infection in childhood with favourable outcome. However, the recent emergence of UTI caused by multidrug-resistant pathogens, such as carbapenem-resistant Enterobacteriaceae (CRE), has become a great concern worldwide. CRE are mainly responsible for nosocomial infections and community-onset CRE infections in healthy individuals are rare. OBJECTIVES: In this study, we report a series of infants without substantial genitourinary abnormalities that were admitted with community-onset urinary tract infections (UTIs) caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) and we discuss their aetiology. METHODS: We retrospectively reviewed the medical records of nine infants who presented from community to the paediatric ward with CRKP urinary tract infections, as well as all affected neonates of a concomitant CRKP outbreak that occurred in the neonatal intensive care unit (NICU) in a tertiary hospital (period from April 2009 to July 2012). We further retrieved all culture-proven CRKP infections of any site from 2007 to 2015 in our paediatric department. RESULTS: Over a 33-month period, nine infants, all males, aged 0.9-19.3 (median 4.0) months, were admitted to the Department of Paediatrics with UTI caused by CRKP. Three of them were diagnosed with urinary tract abnormalities but only one had vesicoureteral reflux (VUR), which was a UTI associated one. History revealed that they had all been hospitalised in the same NICU during a concurrent long-lasting CRKP outbreak for a median of 17 (2-275) days and thereafter presented with CRKP UTI 15 to 207 (median 41) days after NICU discharge. The antibiotic susceptibility and phenotypic characteristics were identical among all isolates in NICU and the paediatric ward. The summary Figure shows a timeline of NICU hospitalisation indicative of its duration and subsequent CRKP UTI of study participants is presented. CONCLUSIONS: These cases illustrate that UTI caused by multidrug-resistant pathogens does not necessarily imply an underlying urinary track anomaly. Hospital acquisition of CRKP may well provoke community-onset multidrug-resistant UTI in infants months later, and this highlights the value of detailed history in patients with unusual pathogens. Cautious use of broad-spectrum antibiotics in NICUs and infection control measures would minimise the spread of multidrug-resistant pathogens in infants in the community. PMID- 28341428 TI - Renal papillary necrosis in patients with sickle cell disease: How to recognize this 'forgotten' diagnosis. AB - INTRODUCTION: Renal papillary necrosis is not commonly seen in daily practice, but can have severe consequences when it is not diagnosed in time. It is known to be associated with sickle cell hemoglobinopathies; however a wide range of etiologies are possible, and it is therefore not the first diagnosis clinicians consider in patients with sickle cell disease who present with hematuria. METHODS: A literature search was performed to summarize the current knowledge about renal papillary necrosis associated with sickle cell disease. These findings are illustrated with a case of a 9-year old girl with sickle cell disease who was referred with painless gross hematuria. RESULTS: Typical radiologic signs for renal papillary necrosis are necrotic cavities that fill with contrast, small collections of contrast peripheral to the calyces in the papillary region (ball-on-tee sign), calcification of the papillary defect, filling defects, hydronephrosis, blunted papillary tip, clefts in the renal medulla filled with contrast, hyperattenuated medullary calcifications, non enhanced lesions surrounded by rings of excreted contrast, and clubbed calyces. DISCUSSION: This study focuses on the pathophysiology of renal papillary necrosis associated with sickle cell disease, the possible symptoms, as well as the diagnostic steps, with a special interest in particular presentation on old (retrograde pyelography) and new (computed tomography) gold standard in radiologic imaging, and the management for this pathology. CONCLUSION: This study aims to remind clinicians of this "forgotten" diagnosis and what signs to look for in pediatric patients with sickle cell disease who present with hematuria. In pediatric cases radiation protection is important, therefore knowing what radiologic signs can be found on retrograde pyelography can lead to early identification of this pathology without having to proceed to computed tomography. PMID- 28341429 TI - Survival following redo hepatectomy vs radiofrequency ablation for recurrent hepatocellular carcinoma: a systematic review and meta-analysis. AB - BACKGROUND: Redo hepatic resection (RHR) and radiofrequency ablation (RFA) are salvage treatment choices for recurrent hepatocellular carcinoma (RHCC). As yet, it is unclear as to which treatment modality is superior in terms of long term survival. The aim of this study was to compare the survival benefits and treatment efficacy of RHR and RFA for recurrent HCC. METHODS: A literature review using the EMBASE, Medline, Google scholar, and Cochrane databases was performed. Meta-analyses were performed using an inference of variance, random effects model for 1, 3 and 5-year Disease Free Survival (DFS) and Overall Survival (OS). Secondary outcomes were major morbidity and mortality. RESULTS: Five retrospective studies including 639 patients were eligible. Overall, there were no differences in 1, 3 and 5-year DFS or OS for patients undergoing RHR or RFA for recurrent HCC. Comparison between the two groups demonstrated similar 5-year DFS (HR 0.86, 95% CI 0.67-1.11, p = 0.250) and 5-year OS (HR 1.03, 95% CI 0.83 1.27, p = 0.082). However, RFA had a lower morbidity rate (2%) compared with RHR (17%, p < 0.001). CONCLUSION: This study demonstrates, neither RHR nor RFA appeared to be superior in terms of DFS and OS. Well-constructed, randomised, multicenter trials will be required to determine if a true difference exists. PMID- 28341433 TI - Minimizing the impact of Joule heating as a prerequisite for the reliable analysis of metal-protein complexes by capillary electrophoresis. AB - Herein we report on a drastic release of metal ions from the Fe-bound transferrin, and Fe- or Mn-bound lactoferrin, observed upon the increase in the separation voltage during CE-based analysis. To verify whether this process is caused directly by electric field, we developed an Isothermal Voltage Increase approach (IVI), which is the extension of methods reported by Krylov et al. IVI ensures isothermal conditions while increasing separation voltage by a hydrodynamic pushing of the injected sample to the actively cooled capillary section, combined with a rationale choice of cooling temperature, dependent on the value of current. Interestingly, the application of IVI revealed that the previously observed effect was caused solely by the insufficient dissipation of Joule heating - the saturation of each protein remained unchanged despite a significant rise in the electric field. This outcome demonstrates how crucial is to ensure an effective temperature control for preventing systematic errors in the analysis of biomolecular complexes. IVI seems also to be a simple and useful tool for discovering new potential processes that may be stimulated directly by electric field. PMID- 28341432 TI - Development, validation and evaluation of an analytical method for the determination of monomeric and oligomeric procyanidins in apple extracts. AB - There is a lack of data for individual oligomeric procyanidins in apples and apple extracts. Our aim was to develop, validate and evaluate an analytical method for the separation, identification and quantification of monomeric and oligomeric flavanols in apple extracts. To achieve this, we prepared two types of flavanol extracts from freeze-dried apples; one was an epicatechin-rich extract containing ~30% (w/w) monomeric (-)-epicatechin which also contained oligomeric procyanidins (Extract A), the second was an oligomeric procyanidin-rich extract depleted of epicatechin (Extract B). The parameters considered for method optimisation were HPLC columns and conditions, sample heating, mass of extract and dilution volumes. The performance characteristics considered for method validation included standard linearity, method sensitivity, precision and trueness. Eight laboratories participated in the method evaluation. Chromatographic separation of the analytes was best achieved utilizing a Hilic column with a binary mobile phase consisting of acidic acetonitrile and acidic aqueous methanol. The final method showed linearity for epicatechin in the range 5-100MUg/mL with a correlation co-efficient >0.999. Intra-day and inter-day precision of the analytes ranged from 2 to 6% and 2 to 13% respectively. Up to dp3, trueness of the method was >95% but decreased with increasing dp. Within laboratory precision showed RSD values <5 and 10% for monomers and oligomers, respectively. Between laboratory precision was 4 and 15% (Extract A) and 7 and 30% (Extract B) for monomers and oligomers, respectively. An analytical method for the separation, identification and quantification of procyanidins in an apple extract was developed, validated and assessed. The results of the inter laboratory evaluation indicate that the method is reliable and reproducible. PMID- 28341434 TI - Trends in maxillofacial imaging. AB - Maxillofacial imaging encompasses radiology of the teeth and jaws, including the temporomandibular joints. Modalities used include intra-oral radiographs, panoramic tomography, cephalograms, cone-beam computed tomography, computed tomography, magnetic resonance imaging, ultrasound, and radionuclide imaging. Common indications for imaging are impacted and supernumerary teeth, dental implants, inflammatory dental disease, and fibro-osseous lesions, cysts, and masses of the jaws. Osteonecrosis of the jaws may follow radiotherapy or the use of bisphosphonates and other drugs. Imaging of the temporomandibular joints and the potential role of imaging in obstructive sleep apnoea are also discussed. PMID- 28341435 TI - The visceral brain: Bipolar disorder and microbiota. PMID- 28341436 TI - Optimal dosage and duration of pivmecillinam treatment for uncomplicated lower urinary tract infections: a systematic review and meta-analysis. AB - OBJECTIVE: To compare the efficacy and safety of different pivmecillinam (PIV) regimes for uncomplicated lower urinary tract infections (UTIs). METHODS: The MEDLINE, Embase, and Cochrane Library databases were searched. Randomized controlled clinical trials (RCTs) involving adults or children with symptoms suggestive of uncomplicated UTI and that compared different PIV regimes or PIV versus other antibiotics were included. Meta-analyses were conducted to obtain direct and indirect efficacy estimates. PIV regimes were categorized into high total dosage, moderate total dosage, and low total dosage. The risk of bias was evaluated using the Cochrane tool. RESULTS: Twenty-four RCTs were identified. No difference in clinical cure was found for the high vs. moderate (short-term: risk ratio (RR) 1.01, p=0.813; long term: RR 1.09, p=0.174) or high vs. low dosage comparisons (mean difference 0, 95% confidence interval -0.44 to 0.45, p=1). For bacteriological cure, comparisons of high vs. moderate dosage (short term: RR 1.05, p=0.056; long term: RR 1.05, p=0.131) and high vs. low dosage (short term: RR 1.02, p=0.759; long term: RR 1.13, p=0.247) showed a trend in favor of the high dosage treatment. Results for relapse, re-infection, and failure were inconclusive and not statistically significant. Patients treated with high dosages were 40% (p=0.062) and 44% (p=0.293) more likely to report mild to moderate adverse events. CONCLUSIONS: There is insufficient evidence to support the use of an optimal combination of dosage, frequency, and duration of PIV therapy for the treatment of uncomplicated lower UTI. Evidence is limited due to the high risk of bias, poor reporting, and heterogeneous study data. PMID- 28341440 TI - Optimization and testing of dried antibody tube: The EuroFlow LST and PIDOT tubes as examples. AB - Within EuroFlow, we recently developed screening tubes for hematological malignancies and immune deficiencies. Pipetting of antibodies for such 8-color 12 marker tubes however is time-consuming and prone to operational mistakes. We therefore evaluated dried formats of the lymphocytosis screening tube (LST) and of the primary immune deficiency orientation tube (PIDOT). Both tubes were evaluated on normal and/or on patient samples, comparing the mean fluorescence intensity of specific lymphocyte populations. Our data show that the dried tubes and liquid counterparts give highly comparable staining results, particularly when analyzed in multidimensional plots. In addition, the use of dried tubes may result in a reduced staining variability between different samples and thereby contributes to the generation of more robust data. Therefore, by using ready-to use reagents in a dried single test tube format, the laboratory efficiency and quality will be improved. PMID- 28341439 TI - Restoring pulmonary surfactant membranes and films at the respiratory surface. AB - Pulmonary surfactant is a complex of lipids and proteins assembled and secreted by the alveolar epithelium into the thin layer of fluid coating the respiratory surface of lungs. There, surfactant forms interfacial films at the air-water interface, reducing dramatically surface tension and thus stabilizing the air exposed interface to prevent alveolar collapse along respiratory mechanics. The absence or deficiency of surfactant produces severe lung pathologies. This review describes some of the most important surfactant-related pathologies, which are a cause of high morbidity and mortality in neonates and adults. The review also updates current therapeutic approaches pursuing restoration of surfactant operative films in diseased lungs, mainly through supplementation with exogenous clinical surfactant preparations. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escriba. PMID- 28341437 TI - Lipid functions in skin: Differential effects of n-3 polyunsaturated fatty acids on cutaneous ceramides, in a human skin organ culture model. AB - Ceramides are important for skin health, with a multitude of species found in both dermis and epidermis. The epidermis contains linoleic acid-Ester-linked Omega-hydroxylated ceramides of 6-Hydroxy-sphingosine, Sphingosine and Phytosphingosine bases (CER[EOH], CER[EOS] and CER[EOP], respectively), that are crucial for the formation of the epidermal barrier, conferring protection from environmental factors and preventing trans-epidermal water loss. Furthermore, a large number of ceramides, derivatives of the same sphingoid bases and various fatty acids, are produced by dermal and epidermal cells and perform signalling roles in cell functions ranging from differentiation to apoptosis. Supplementation with the n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have shown promise as therapeutic agents in a number of inflammatory skin conditions, altering the lipid profile of the skin and production of bioactive lipids such as the eicosanoids, docosanoids and endocannabinoids. In this study we wished to investigate whether EPA and DHA could also affect the ceramide profile in epidermis and dermis, and, in this way, contribute to formation of a robust lipid barrier and ceramide-mediated regulation of skin functions. Ex vivo skin explants were cultured for 6days, and supplemented with EPA or DHA (50MUM). Liquid chromatography coupled to tandem mass spectrometry with electrospray ionisation was used to assess the prevalence of 321 individual ceramide species, and a number of sphingoid bases, phosphorylated sphingoid bases, and phosphorylated ceramides, within the dermis and epidermis. EPA augmented dermal production of members of the ceramide families containing Non-hydroxy fatty acids and Sphingosine or Dihydrosphingosine bases (CER[NS] and CER[NDS], respectively), while epidermal CER[EOH], CER[EOS] and CER[EOP] ceramides were not affected. DHA did not significantly affect ceramide production. Ceramide-1-phosphate levels in the epidermis, but not the dermis, increased in response to EPA, but not DHA. This ex vivo study shows that dietary supplementation with EPA has the potential to alter the ceramide profile of the skin, and this may contribute to its anti-inflammatory profile. This has implications for formation of the epidermal lipid barrier, and signalling pathways within the skin mediated by ceramides and other sphingolipid species. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escriba. PMID- 28341442 TI - Risk factors for postoperative delirium after colorectal operation. AB - BACKGROUND: A clear understanding of risk factors for postoperative delirium helps in the selection of individuals who might benefit from targeted perioperative intervention. The aim of this study was to identify risk factors for postoperative delirium after colorectal operation for malignancy. METHODS: All consecutive patients who underwent elective or emergency operation because of malignancy of the colon, sigmoid, or rectum between 2009 and 2012 were included in this study. Potential risk factors for postoperative delirium were selected based on previous studies. These candidate factors were analyzed using univariate and multivariate logistic regression analysis. Based on this analysis, odds ratios and 95% confidence intervals were estimated. RESULTS: A total of 436 patients underwent an oncologic resection of the colon, sigmoid, or rectum. Postoperative delirium was observed in 45 (10.3%) patients. Patients with a delirium had a greater in-hospital mortality rate (8.9% vs 3.6%, P = .09), spent more days in the intensive care unit, and had a longer total hospital stay. Variables associated with postoperative delirium in univariate analyses were age, American Society of Anesthesiologists classification, blood transfusion, history of psychiatric disease, history of cerebrovascular disease, postoperative pain management, postoperative renal impairment, C-reactive protein levels, leukocyte blood count, and postoperative complications. Independent risk factors were history of psychiatric disease (odds ratio 8.38, 95% confidence interval: 1.50 46.82), age (odds ratio 4.01, 95% confidence interval; 1.55-10.37), and perioperative blood transfusion (odds ratio 2.37, 95% confidence interval; 1.11 5.06). CONCLUSION: This study shows that postoperative delirium is a frequently encountered complication after colorectal operation. Three independent risk factors for postoperative delirium were identified (history of psychiatric disease, age, and perioperative transfusion) that may contribute to risk estimation in this patient population. PMID- 28341438 TI - Engineering a Novel Porin OmpGF Via Strand Replacement from Computational Analysis of Sequence Motif. AB - beta-Barrelmembrane proteins (betaMPs) form barrel-shaped pores in the outer membrane of Gram-negative bacteria, mitochondria, and chloroplasts. Because of the robustness of their barrel structures, betaMPs have great potential as nanosensors for single-molecule detection. However, natural betaMPs currently employed have inflexible biophysical properties and are limited in their pore geometry, hindering their applications in sensing molecules of different sizes and properties. Computational engineering has the promise to generate betaMPs with desired properties. Here we report a method for engineering novel betaMPs based on the discovery of sequence motifs that predominantly interact with the cell membrane and appear in more than 75% of transmembrane strands. By replacing beta1-beta6 strands of the protein OmpF that lack these motifs with beta1-beta6 strands of OmpG enriched with these motifs and computational verification of increased stability of its transmembrane section, we engineered a novel betaMP called OmpGF. OmpGF is predicted to form a monomer with a stable transmembrane region. Experimental validations showed that OmpGF could refold in vitro with a predominant beta-sheet structure, as confirmed by circular dichroism. Evidence of OmpGF membrane insertion was provided by intrinsic tryptophan fluorescence spectroscopy, and its pore-forming property was determined by a dye-leakage assay. Furthermore, single-channel conductance measurements confirmed that OmpGF function as a monomer and exhibits increased conductance than OmpG and OmpF. These results demonstrated that a novel and functional betaMP can be successfully engineered through strand replacement based on sequence motif analysis and stability calculation. PMID- 28341441 TI - Neoadjuvant therapy versus upfront surgery for resected pancreatic adenocarcinoma: A nationwide propensity score matched analysis. AB - BACKGROUND: Neoadjuvant therapy is an emerging paradigm in pancreatic cancer care; however, its role for resectable disease remains controversial in the absence of conclusive randomized controlled trials. The purpose of the present study is to assess the impact of neoadjuvant therapy on survival in resected pancreatic cancer patients by clinical stage. METHODS: A retrospective cohort study using the National Cancer Data Base from 2004 to 2012 including nonmetastatic pancreatic adenocarcinoma patients who underwent pancreatectomy and initiated chemotherapy. Propensity score matching within each stage was used to account for potential selection bias between patients undergoing neoadjuvant therapy and upfront surgery. Overall survival was compared by the Kaplan-Meier method. RESULTS: In the study, 1,541 and 7,159 patients received neoadjuvant therapy followed by surgery and upfront surgery succeeded by adjuvant therapy, respectively. In clinical stage III pancreatic cancer (n = 486), neoadjuvant therapy was associated with significant survival benefit after matching (median survival 22.9 vs 17.3 months; log-rank P < .0001) compared with conventional upfront surgery followed by adjuvant therapy; however, no survival difference was found between the 2 treatment sequences in patients with clinical stage I (n = 3,149; median survival, 26.2 vs 25.7 months; P = .4418) and II (n = 5,065; median survival, 23.5 vs 23.0 months; P = .7751) disease after matching. CONCLUSION: The survival impact of neoadjuvant therapy is stage-dependent. Neoadjuvant therapy does not disadvantage survival compared with conventional upfront surgery followed by adjuvant therapy in any stage, and is associated with a significant survival advantage in stage III pancreatic cancer. PMID- 28341443 TI - High serum soluble tumor necrosis factor receptor 1 predicts poor treatment response in acute-stage schizophrenia. AB - Inflammation may be involved in the pathophysiology of schizophrenia. However, few cross-sectional or longitudinal studies have examined changes in biomarker expression to evaluate diagnostic and prognostic efficacy in acute-stage schizophrenia. We compared serum inflammatory biomarker concentrations in 87 patients with acute-stage schizophrenia on admission to 105 age-, sex-, and body mass index (BMI)-matched healthy controls. The measured biomarkers were soluble tumor necrosis factor receptor 1 (sTNFR1) and adiponectin, which are associated with inflammatory responses, and pigment epithelium-derived factor (PEDF), which has anti-inflammatory properties. We then investigated biomarker concentrations and associations with clinical factors in 213 patients (including 42 medication free patients) and 110 unmatched healthy controls to model conditions typical of clinical practice. Clinical symptoms were assessed using the Brief Psychiatric Rating Scale and Global Assessment of Function. In 121 patients, biomarker levels and clinical status were evaluated at both admission and discharge. Serum sTNFR1 was significantly higher in patients with acute-stage schizophrenia compared to matched controls while no significant group differences were observed for the other markers. Serum sTNFR1 was also significantly higher in the 213 patients compared to unmatched controls. The 42 unmedicated patients had significantly lower PEDF levels compared to controls. Between admission and discharge, sTNFR1 levels decreased significantly; however, biomarker changes did not correlate with clinical symptoms. The discriminant accuracy of sTNFR1 was 93.2% between controls and patients, showing no symptom improvement during care. Inflammation and a low level anti-inflammatory state may be involved in both schizophrenia pathogenesis and acute-stage onset. High serum sTNFR1 in the acute stage could be a useful prognostic biomarker for treatment response in clinical practice. PMID- 28341444 TI - The importance of TCF4 gene in the etiology of recurrent depressive disorders. AB - BACKGROUND: A recurrent depressive disorder is one of the most commonly diagnosed disease entities among psychiatric disorders. The prevalence and morbidity of depression are constantly increasing. Numerous studies have demonstrated the role of genetic factors in the etiology of depressive disorders. Many studies are being conducted to identify genes that predispose to depression. The purpose of this study was to investigate the role of TCF4 gene in the etiology of recurrent depressive disorders and, in particular, to assess expression of the TCF4 gene at the mRNA and protein level in patients with recurrent depressive disorders versus healthy individuals. MATERIAL AND METHODS: The examined population consisted of 170 individuals suffering from depression and 90 healthy individuals. The expressions of the TCF4 gene at the mRNA and protein level were assessed. RESULTS: Decreased TCF4 expression at the mRNA and protein level was found in patients with depressive disorder versus healthy individuals. Expression of the studied gene was not affected by the patients' sex and age. The statistical analysis also showed no correlation between the expression of TCF4 at the mRNA and protein level and the number of episodes or the severity of symptoms. Among the clinical manifestations of depression, only the duration of the illness correlated with the expression of TCF4 at the mRNA level. CONCLUSIONS: Expression of TCF4 at the mRNA and protein level may be significant in the pathomechanism of recurrent depressive disorder and it is not dependent on sex and age. PMID- 28341445 TI - Insulin promotes cell migration by regulating PSA-NCAM. AB - Cellular interactions with the extracellular environment are modulated by cell surface polysialic acid (PSA) carried by the neural cell adhesion molecule (NCAM). PSA-NCAM is involved in cellular processes such as differentiation, plasticity, and migration, and is elevated in Alzheimer's disease as well as in metastatic tumour cells. Our previous work demonstrated that insulin enhances the abundance of cell surface PSA by inhibiting PSA-NCAM endocytosis. In the present study we have identified a mechanism for insulin-dependent inhibition of PSA-NCAM turnover affecting cell migration. Insulin enhanced the phosphorylation of the focal adhesion kinase leading to dissociation of alphav-integrin/PSA-NCAM clusters, and promoted cell migration. Our results show that alphav-integrin plays a key role in the PSA-NCAM turnover process. alphav-integrin knockdown stopped PSA-NCAM from being endocytosed, and alphav-integrin/PSA-NCAM clusters co labelled intracellularly with Rab5, altogether indicating a role for alphav integrin as a carrier for PSA-NCAM during internalisation. Furthermore, inhibition of p-FAK caused dissociation of alphav-integrin/PSA-NCAM clusters and counteracted the insulin-induced accumulation of PSA at the cell surface and cell migration was impaired. Our data reveal a functional association between the insulin/p-FAK-dependent regulation of PSA-NCAM turnover and cell migration through the extracellular matrix. Most importantly, they identify a novel mechanism for insulin-stimulated cell migration. PMID- 28341446 TI - PKR induces the expression of NLRP3 by regulating the NF-kappaB pathway in Porphyromonas gingivalis-infected osteoblasts. AB - The double-stranded RNA-dependent kinase (PKR), which is activated by double stranded RNA, induces inflammation by regulating NF-kappaB signaling. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome also modulates inflammation in response to infection. Porphyromonas gingivalis (P.gingivalis) is an oral bacterium which is implicated in the pathogenesis of periodontal diseases. We previously reported that PKR is a key modulator of bone metabolism and inflammation in the periodontal tissue. PKR was also reported to induce inflammation in response to microbes by regulating the NLRP3 inflammasome, suggesting that PKR could affect inflammation along with NLRP3 in periodontal diseases. In this study, we investigated the effects of PKR on NLRP3 expression and NF-kappaB activity in P. gingivalis infected osteoblasts. We first constructed a SNAP26b-tagged P.gingivalis (SNAP-P. g.) and traced its internalization into the cell. SNAP-P. g. increased the activity of PKR and NF kappaB and also induced NLRP3 expression in osteoblasts. Inhibition of NF-kappaB attenuated SNAP-P. g.-induced NLRP3 expression. The knockdown of PKR using shRNA decreased both the activity of NF-kappaB and the expression of NLRP3 induced by SNAP-P.g.. We therefore concluded that in osteoblasts, P. gingivalis activated PKR, which in turn increased NLRP3 expression by activating NF-kappaB. Our results suggest that PKR modulates inflammation by regulating the expression of the NLRP3 inflammasome through the NF-kappaB pathway in periodontal diseases. PMID- 28341447 TI - Macrophage heterogeneity and energy metabolism. AB - Macrophages are versatile and multifunctional cell types present in most vertebrate tissues. They are the first line of defense against pathogens through phagocytosis of microbial infections, particles and dead cells. Macrophages harbor additional functions besides immune protection by participating in essential homeostatic and tissue development functions. The immune response requires a concomitant and coordinated regulation of the energetic metabolism. In this review, we will discuss how macrophages influence metabolic tissues and in turn how metabolic pathways, particularly glucose and lipid metabolism, affect macrophage phenotypes. PMID- 28341448 TI - The Drosophila DOCK family protein Sponge is required for development of the air sac primordium. AB - Dedicator of cytokinesis (DOCK) family genes are known as DOCK1-DOCK11 in mammals. DOCK family proteins mainly regulate actin filament polymerization and/or depolymerization and are GEF proteins, which contribute to cellular signaling events by activating small G proteins. Sponge (Spg) is a Drosophila counterpart to mammalian DOCK3/DOCK4, and plays a role in embryonic central nervous system development, R7 photoreceptor cell differentiation, and adult thorax development. In order to conduct further functional analyses on Spg in vivo, we examined its localization in third instar larval wing imaginal discs. Immunostaining with purified anti-Spg IgG revealed that Spg mainly localized in the air sac primordium (ASP) in wing imaginal discs. Spg is therefore predicted to play an important role in the ASP. The specific knockdown of Spg by the breathless-GAL4 driver in tracheal cells induced lethality accompanied with a defect in ASP development and the induction of apoptosis. The monitoring of ERK signaling activity in wing imaginal discs by immunostaining with anti-diphospho ERK IgG revealed reductions in the ERK signal cascade in Spg knockdown clones. Furthermore, the overexpression of D-raf suppressed defects in survival and the proliferation of cells in the ASP induced by the knockdown of Spg. Collectively, these results indicate that Spg plays a critical role in ASP development and tracheal cell viability that is mediated by the ERK signaling pathway. PMID- 28341450 TI - Oral Surgery in Patients With Glanzmann Thrombasthenia: A Case Series. AB - Glanzmann thrombasthenia is a severe defect of platelet function caused by an inherited deficiency or dysfunction of the glycoprotein IIb/IIIa complex, the platelet fibrinogen receptor. Patients with Glanzmann thrombasthenia experience lifelong spontaneous and post-traumatic mucocutaneous bleeding diathesis. Surgery is usually very challenging, requiring close cooperation among surgeons, hematologists, and anesthesiologists. For anatomic reasons, oral surgery is particularly difficult owing to the inherent risk of hemorrhage and the difficulty in achieving local hemostasis. In the present report, we describe 3 successful cases of oral surgery in patients with Glanzmann thrombasthenia and report the surgical and hematologic management of each case. PMID- 28341449 TI - Do Antibiotics Decrease the Risk of Inflammatory Complications After Third Molar Removal in Community Practices? AB - PURPOSE: The role of antibiotic use in third molar (M3) surgery is controversial. The purpose of this study was to measure the association between antibiotic use and postoperative inflammatory complications after M3 surgery in the community office-based ambulatory private practice setting. MATERIALS AND METHODS: The authors designed and implemented a prospective cohort study and enrolled a sample composed of patients who had at least one M3 removed in a private practice setting by oral and maxillofacial surgeons participating in a practice-based research collaborative from June 2011 through May 2012. The predictor variable was antibiotic use of any type, categorized as yes or no. The primary outcome variable was the presence or absence of an inflammatory complication, specifically surgical site infection (SSI) or alveolar osteitis (AO), after M3 removal. Descriptive, bivariate, and multiple logistic regression statistics were computed to measure the association between antibiotic use and inflammatory complications after M3 removal, with statistical significance set at a P value less than or equal to .05. RESULTS: The study sample was composed of 2,954 patients. Three fourths (75.2%) of the sample received antibiotics in some form. The overall inflammatory complication (AO or SSI) frequencies in the antibiotic and nonantibiotic groups were 5.0 and 7.5%, respectively (P = .012). After adjusting for differences between the two groups, statistical significance between the groups persisted. CONCLUSIONS: The results of this study suggest that antibiotic therapy, regardless of type, dose, frequency, or pattern of delivery, is associated with a decreased risk of inflammatory complications after M3 removal. PMID- 28341451 TI - Is Treating Oral and Maxillofacial Trauma Profitable? An Analysis of Hospital and Surgeon Reimbursement at an Academic Medical Center. AB - PURPOSE: During the past 2 decades, there has been a marked decrease in the willingness of community-based oral and maxillofacial surgeons to participate in trauma call. Although many factors can influence the decision not to take trauma call, 1 primary disincentive is the perception that managing facial trauma might be profitable for the hospital, but not profitable for the surgeon. The purpose of this study was to compare the profitability of facial trauma management for the hospital and the surgeon at the Virginia Commonwealth University (VCU) Medical Center (Richmond, VA). MATERIALS AND METHODS: In this retrospective cohort study, records were collected for patients who were seen for primary trauma management by the Department of Oral and Maxillofacial Surgery at VCU (VCUOMS) from June 2011 through July 2014. Cost and reimbursement data were analyzed for these patients from the VCU Health System (VCUHS) and the VCUOMS. For the hospital, actual cost data were provided; for the surgeon, cost was calculated based on an average overhead of 50%. For uniformity, patients were excluded if they remained in the hospital for longer than a 23-hour observation period. Patients younger than 18 years also were excluded. RESULTS: In total, 169 patients met the inclusion criteria. There was a statistically relevant difference in the percentage of costs recouped and the actual profit. The average percentage of costs recouped was 230% for the VCUHS versus 47% for the VCUOMS. This amounts to an average profit per case of $3,461 for the hospital versus a loss of $1,162 for the surgeon. CONCLUSIONS: The results of this study indicate that in the VCU Medical Center, maxillofacial trauma yields a net profit for the hospital and a net loss for the operating surgeon. Although the results are limited to outpatient management at 1 academic institution, they suggest that hospitals in some settings might be in a position to incentivize surgeons for trauma management. PMID- 28341456 TI - Two distinct CXC chemokine receptors (CXCR3 and CXCR4) from the big-belly seahorse Hippocampus abdominalis: Molecular perspectives and immune defensive role upon pathogenic stress. AB - CXC chemokine receptor 3 (CXCR3) and 4 (CXCR4) are members of the seven transmembrane G protein coupled receptor family, involved in pivotal physiological functions. In this study, seahorse CXCR3 and CXCR4 (designated as HaCXCR3 and HaCXCR4) cDNA sequences were identified from the transcriptome library and subsequently molecularly characterized. HaCXCR3 and HaCXCR4 encoded 363 and 373 amino acid long polypeptides, respectively. The HaCXCR3 and HaCXCR4 deduced proteins have typical structural features of chemokine receptors, including seven transmembrane domains and a G protein coupled receptors family 1 profile with characteristic DRY motifs. Amino acid sequence comparison and phylogenetic analysis of these two CXC chemokine receptors revealed a close relationship to their corresponding teleost counterparts. Quantitative real time PCR analysis revealed that HaCXCR3 and HaCXCR4 were ubiquitously expressed in all the tested tissues, with highest expression levels in blood cells. The seahorse blood cells and kidney HaCXCR3 and HaCXCR4 mRNA expressions were differently modulated when challenged with Edwardsiella tarda, Streptococcus iniae, lipopolysaccharide, and polyinosinic:polycytidylic acid, confirming their involvement in post immune responses. PMID- 28341457 TI - Thyroid hormone transport across L-type amino acid transporters: What can molecular modelling tell us? AB - Thyroid hormones (THs) and their derivatives require transmembrane transporters (TTs) to mediate their translocation across the cell membrane. Among these TTs, the L-type amino acid transporters (LAT) not only transport amino acids (AAs) but also certain THs and their derivatives. This review summarizes available knowledge concerning structure function patterns of the TH transport by LAT1 and LAT2. For example, LAT2 imports 3,3'-T2 and T3, but not rT3 and T4. In contrast to amino acids, THs are not at all exported by LAT2. Homology modelling of LAT1 and LAT2 is based on available crystal structures from the same superfamily the amino acid/polyamine/organocation transporter (APC). Molecular model guided mutagenesis has been used to predict substrate interaction sites. A common recognition feature for amino acid- and TH-derivatives has been suggested in an interior cavity of LAT1 and LAT2. Therein additional distinct molecular determinants that are responsible for the bidirectional AA transport but allowing only unidirectional import of particular THs have been confirmed for LAT2 by mutagenesis. Characterized substrate features that are needed for TH translocation and distinct LAT2 properties will be highlighted to understand the molecular import and export mechanisms of this transporter in more detail. PMID- 28341458 TI - Not just a woman's business! Understanding men and women's knowledge of HPV, the HPV vaccine, and HPV-associated cancers. AB - Few studies have included men when assessing differences in knowledge about HPV, and HPV-associated cancers. We examined gender differences in knowledge about HPV, HPV vaccine, and HPV-associated cancers. Multivariable logistic regression models were used to analyze data of 3,677 survey respondents aged 18 years and older from the 2014 Health Information National Trends Survey. Covariates included age, race/ethnicity, marital status, education, income level, regular provider, general health, internet use, and family structure aged 9 to 27 years. Analyses were conducted in 2015. Sixty-four percent of respondents had heard of HPV and the HPV vaccine. Seventy-eight percent of respondents knew HPV causes cervical cancer, but only 29% knew it causes penile cancer, 26% knew it causes anal cancer, and 30% knew it causes oral cancer. In multivariable analyses, males were less likely to have heard of HPV (aOR: 0.33; 95% CI: 0.25-0.45), and less likely to have heard of the HPV vaccine (aOR: 0.24; 95% CI: 0.18-0.32) compared to females. No differences existed between males and females regarding knowledge about HPV-associated cancers. In conclusion, knowledge of HPV, the vaccine, and HPV-associated cancers in both males and females in the United States remains very low, especially among men. PMID- 28341459 TI - Does where you shop or who you are predict what you eat?: The role of stores and individual characteristics in dietary intake. AB - Interventions to address diet, a modifiable risk factor for diabetes, cancer, and cardiovascular disease, have increasingly emphasized the influence of the physical environment on diet, while more traditional approaches have focused on individual characteristics. We examined environmental and individual influences on diet to understand the role of both. Household interviews were conducted in 2011 with 1372 individuals randomly selected from two low-income, predominantly African American neighborhoods in Pittsburgh, PA. Participants reported their sociodemographic characteristics, food shopping behavior, and dietary intake. Both food shopping frequency at different types of food stores and sociodemographic characteristics showed significant associations with diet in adjusted regression models. More frequent shopping at convenience and neighborhood stores and being younger, male, without a college degree, and receiving SNAP benefits were associated with greater intake of sugar-sweetened beverages (SSBs), added sugars, and discretionary fats. Being older, male, and having a college degree were associated with greater intake of fruits and vegetables. However, while food shopping behavior and sociodemographic characteristics accounted for similar amounts of nonoverlapping variance in fruit and vegetable intake, food shopping behavior accounted for much less variance, and little unique variance, in SSBs, added sugars, and discretionary fats in models with sociodemographic characteristics. The current study reinforces the need for policies and interventions at both the environmental and individual levels to improve diet in food desert residents. Individual interventions to address food choices associated with certain sociodemographic characteristics might be particularly important for curbing intake of SSBs, added sugars, and discretionary fats. PMID- 28341461 TI - Sequential therapy of anti-Nogo-A antibody treatment and treadmill training leads to cumulative improvements after spinal cord injury in rats. AB - Intense training is the most clinically successful treatment modality following incomplete spinal cord injuries (SCIs). With the advent of plasticity enhancing treatments, understanding how treatments might interact when delivered in combination becomes critical. Here, we investigated a rational approach to sequentially combine treadmill locomotor training with antibody mediated suppression of the fiber growth inhibitory protein Nogo-A. Following a large but incomplete thoracic lesion, rats were immediately treated with either anti-Nogo-A or control antibody (2weeks) and then either left untrained or step-trained starting 3weeks after injury for 8weeks. It was found that sequentially combined therapy improved step consistency and reduced toe dragging and climbing errors, as seen with training and anti-Nogo-A individually. Animals with sequential therapy also adopted a more parallel paw position during bipedal walking and showed greater overall quadrupedal locomotor recovery than individual treatments. Histologically, sequential therapy induced the greatest corticospinal tract sprouting caudally into the lumbar region and increased the number of serotonergic synapses onto lumbar motoneurons. Increased primary afferent sprouting and synapse formation onto lumbar motoneurons observed with anti-Nogo-A antibody were reduced by training. Animals with sequential therapy also showed the highest reduction of lumbar interneuronal activity associated with walking (c fos expression). No treatment effects for thermal nociception, mechanical allodynia, or lesion volume were observed. The results demonstrate that sequential administration of anti-Nogo-A antibody followed in time with intensive locomotor training leads to superior recovery of lost locomotor functions, which is probably mediated by changes in the interaction between descending sprouting and local segmental networks after SCI. PMID- 28341460 TI - Cortical adrenoceptor expression, function and adaptation under conditions of cannabinoid receptor deletion. AB - A neurochemical target at which cannabinoids interact to have global effects on behavior is brain noradrenergic circuitry. Acute and repeated administration of a cannabinoid receptor synthetic agonist is capable of increasing multiple indices of noradrenergic activity. This includes cannabinoid-induced 1) increases in norepinephrine (NE) release in the medial prefrontal cortex (mPFC); 2) desensitization of cortical alpha2-adrenoceptor-mediated effects; 3) activation of c-Fos in brainstem locus coeruleus (LC) noradrenergic neurons; and 4) increases in anxiety-like behaviors. In the present study, we sought to examine adaptations in adrenoceptor expression and function under conditions of cannabinoid receptor type 1 (CB1r) deletion using knockout (KO) mice and compare these to wild type (WT) controls. Electrophysiological analysis of alpha2 adrenoceptor-mediated responses in mPFC slices in WT mice showed a clonidine induced alpha2-adrenoceptor-mediated increase in mPFC cell excitability coupled with an increase in input resistance. In contrast, CB1r KO mice showed an alpha2 adrenoceptor-mediated decrease in mPFC cell excitability. We then examined protein expression levels of alpha2- and beta1-adrenoceptor subtypes in the mPFC as well as TH expression in the locus coeruleus (LC) of mice deficient in CB1r. Both alpha2- and beta1-adrenoceptors exhibited a significant decrease in expression levels in CB1r KO mice when compared to WT in the mPFC, while a significant increase in TH was observed in the LC. To better define whether the same cortical neurons express alpha2A-adrenoceptor and CB1r in mPFC, we utilized high-resolution immunoelectron microscopy. We localized alpha2A-adrenoceptors in a knock-in mouse that expressed a hemoagglutinin (HA) tag downstream of the alpha2A-adrenoceptor promoter. Although the alpha2A-adrenoceptor was often identified pre-synaptically, we observed co-localization of CB1r with alpha2 adrenoceptors post-synaptically in the same mPFC neurons. Finally, using receptor binding, we confirmed prior results showing that alpha2A-adrenoceptor is unchanged in mPFC following acute or chronic exposure to the synthetic cannabinoid receptor agonist, WIN 55,212-2, but is increased, following chronic treatment followed by a period of abstinence. Taken together, these data provide convergent lines of evidence indicating cannabinoid regulation of the cortical adrenergic system. PMID- 28341462 TI - Asthma management in a specialist setting: Results of an Italian Respiratory Society survey. AB - BACKGROUND: Asthma considerably impairs patients' quality of life and increases healthcare costs. Severity, morbidity, and degree of disease control are the major drivers of its clinical and economic impact. National scientific societies are required to monitor the application of international guidelines and to adopt strategies to improve disease control and better allocate resources. AIM: to provide a detailed picture of the characteristics of asthma patients and modalities of asthma management by specialists in Italy and to develop recommendations for the daily management of asthma in a specialist setting. METHOD: A quantitative research program was implemented. Data were collected using an ad hoc questionnaire developed by a group of specialists selected by the Italian Pneumology Society/Italian Respiratory Society. RESULTS: The records of 557 patients were analyzed. In the next few years, specialists are expected to focus their activity patients with more severe disease and will be responsible for selection of patients for personalized biological therapy; however, only 20% of patients attending Italian specialist surgery can be considered severe. In 84.4% of cases, the visit was a follow-up visit requested in 82.2% of cases by the specialist him/herself. The Asthma Control Test is used only in 65% of patients. When available, a significant association has been observed between the test score and asthma control as judged by the physician, although concordance was only moderate (kappa = 0.68). Asthma was considered uncontrolled by the specialist managing the case in 29.1% of patients; nevertheless, treatment was not stepped up in uncontrolled or partly controlled patients (modified in only 37.2% of patients). CONCLUSIONS: The results of this survey support re-evaluation of asthma management by Italian specialists. More resources should be made available for the initial visit and for more severely ill patients. In addition, more extensive use should be made of validated tools, and available drugs should be used more appropriately. PMID- 28341463 TI - Increasing trends in rainfall-runoff erosivity in the Source Region of the Three Rivers, 1961-2012. AB - As the head source of the two longest rivers in China and the longest river in Southeast Asia, the East Qinghai-Tibetan Plateau (QTP) is experiencing increasing thaw snowmelt and more heavy precipitation events under global warming, which might lead to soil erosion risk. To understand the potential driving force of soil erosion and its relationship with precipitation in the context of climate change, this study analyzed long-term variations in annual rainfall-runoff erosivity, a climatic index of soil erosion, by using the Mann-Kendall statistical test and Theil and Sen's approach in the Source Region of the Three Rivers during 1961-2012. The results showed the followings: (i) increasing annual rainfall-runoff erosivity was observed over the past 52years, with a mean relative trend index (RT1) value of 12.1%. The increasing trend was more obvious for the latest two decades: RT1 was nearly three times larger than that over the entire period; (ii) more precipitation events and a higher precipitation amount were the major forces for the increasing rainfall-runoff erosivity; (iii) similar rising trends in sediment yields, which corresponded to rainfall-runoff erosivity under slightly increasing vegetation coverage in the study area, implied a large contribution of rainfall-runoff erosivity to the increasing sediment yields; and (iv) high warming rates increased the risk of soil destruction, soil erosion and sediment yields. Conservation measures, such as enclosing grassland, returning grazing land to grassland and rotation grazing since the 1980s, have maintained vegetation coverage and should be continued and strengthened. PMID- 28341464 TI - Reproductive effects of oestrogenic endocrine disrupting chemicals in Astyanax rivularis inhabiting headwaters of the Velhas River, Brazil. AB - The Velhas River is the most polluted river in the state of Minas Gerais, south eastern Brazil. Due to its historical and environmental relevance, the aim of this study was to evaluate the effects of oestrogenic endocrine disruptors on the reproduction of the lambari Astyanax rivularis, a small-sized species found in headwaters of the Sao Francisco River basin. Quarterly field samplings were carried out during a reproductive cycle in three streams of the upper Velhas River: S1 (reference site) and S2 and S3 (sites contaminated by untreated sewage). The main oestrogenic compounds were evaluated in water using HPLC/MS. Molecular, histological and reproductive biomarkers were assessed in liver and gonad. The results showed higher average concentrations of oestradiol (>200ng/l) in S2 and S3, oestrone (>250ng/l) in S2 as well as oestriol (>200ng/l), bisphenol A (>190ng/l), and nonylphenol (>600ng/l) in S3 compared to S1 (<70ng/l for all compounds). In S2 and S3, there was an increase in the proportion of females, higher ELISA levels of vitellogenin (Vtg) and proteins of the zona radiata (Zrp) in liver males. Insulin-like growth factor (IGF-I) levels were lower in S2 males, which also had a smaller body size, a smaller seminiferous tubule diameter, a higher proportion of spermatogonia, and lower proportion of spermatozoa in relation to S1. Histopathological analyses detected an increase in yolk deficient oocytes and over-ripening in the contaminated sites, and these alterations were associated to a reduction of hepatic Vtg levels and a delay in spawning, respectively. Intersex specimens with perinucleolar follicles in a multifocal distribution in the testis were detected in S2 and S3. These results indicate that chronic exposure to oestrogenic compounds induced endocrine disruption that may affect wild populations of A. rivularis in the Velhas River. PMID- 28341465 TI - Influences of removing linear and nonlinear trends from climatic variables on temporal variations of annual reference crop evapotranspiration in Xinjiang, China. AB - Reference crop evapotranspiration (ETo) is a key parameter in field irrigation scheduling, drought assessment and climate change research. ETo uses key prescribed (or fixed or reference) land surface parameters for crops. The linear and nonlinear trends in different climatic variables (CVs) affect ETo change. This research aims to reveal how ETo responds after the related CVs were linearly and nonlinearly detrended over 1961-2013 in Xinjiang, China. The ETo-related CVs included minimum (Tmin), average (Tave), and maximum air temperatures (Tmax), wind speed at 2m (U2), relative humidity (RH) and sunshine hour (n). ETo was calculated using the Penman-Monteith equation. A total of 29 ETo scenarios, including the original scenario, 14 scenarios in Group I (ETo was recalculated after removing linear trends from single or more CVs) and 14 scenarios in Group II (ETo was recalculated after removing nonlinear trends from the CVs), were generated. The influence of U2 was stronger than influences of the other CVs on ETo for both Groups I and II either in northern, southern or the entirety of Xinjiang. The weak influences of increased Tmin, Tave and Tmax on increasing ETo were masked by the strong effects of decreased U2 &n and increased RH on decreasing ETo. The effects of the trends in CVs, especially U2, on changing ETo were clearly shown. Without the general decreases of U2, ETo would have increased in the past 53years. Due to the non-monotone variations of the CVs and ETo, the results of nonlinearly detrending CVs on changing ETo in Group II should be more plausible than the results of linearly detrending CVs in Group I. The decreasing ETo led to a general relief in drought, which was indicated by the recalculated aridity index. Therefore, there would be a slightly lower risk of water utilization in Xinjiang, China. PMID- 28341466 TI - Limited role of biochars in nitrogen fixation through nitrate adsorption. AB - Nitrate cycling is essential in sustaining soil systems. Excessive application of N-fertilizers and the associated underground water contamination have attracted a great deal of research attention. Sorption is efficient and environmentally friendly in nitrate fixation. A debate was noted in literature regarding whether biochars have potential to fix nitrate through sorption. In this study, biochars produced from different biomasses as well as biomass compositions were chosen as the absorbents to evaluate their potential efficiencies in nitrate fixation. Increased sorption to nitrate was observed for biochars with increased pyrolysis temperature, but the increasing extent varied with biomass. The surface base functional groups and surface charges of biochars could not well explain nitrate sorption. The significant positive correlation between nitrate sorption and biochar surface areas suggested that surface area was the controlling parameter for nitrate sorption. The pre-coating of tannic acid (TA) on biochars decreased but did not completely inhibit nitrate sorption. This observation suggested that nitrate sorption on biochars may be further decreased after their interactions with natural organic matter. Nitrate sorption was compared among various adsorbents, including biochars, soil particles, clay minerals, engineered particles, as well as humic substances. Soil particles generally showed high sorption to nitrate over biochars. This result suggested that biochars investigated in this work may play a limited role in nitrate fixation through sorption after their massive application. Nitrogen fixation through nitrate adsorption on biochars should be carefully evaluated taking into consideration of biochar feedstocks and properties. PMID- 28341467 TI - Prediction of soil organic carbon in an intensively managed reclamation zone of eastern China: A comparison of multiple linear regressions and the random forest model. AB - Organic carbon is a key component of soils and plays a fundamental role in soil fertility and climate change. Determining the importance of potential drivers of soil organic carbon (SOC) and thus predicting the distribution of SOC are important for measuring carbon sequestration or emissions. Coastal wetlands are precious land resources that are currently undergoing rapid reclamation in China. The alternations in soil physicochemical conditions caused by reclamation can strongly impact the cycle of organic carbon. However, identification of the important drivers of SOC dynamics and prediction of SOC using the potential drivers remain largely unclear. In this study, we used classification and regression tree (CART) to identify the importance of the potential drivers of SOC at 241 sites from an intensively managed reclamation zone of eastern China. Multiple linear regressions (MLR) and random forest (RF) models were applied to predict the distribution of SOC using continuous variables, such as the contents of Cl, CaO, Fe2O3, Al2O3, SiO2, clay, silt, and sand as well as the soil pH, along with categorical variables, such as land use and reclamation duration. The results indicate that the soil/sediment pH was the most important variable impacting SOC, followed by the Cl and silt contents. The RF and MLR involving all predictor variables produced much higher R2 and lower error indices than the RF and MLR models involving independent variables (pH and CaO). RF performed much better than MLR as it revealed much lower error indices (ME, MSE, and RMSE) and a higher R2 than MLR. The superiority of RF in predicting SOC is related to its capability to deal with non-linear and hierarchical relationships between SOC and predictors. Analyses of land use effects on SOC dynamics indicated that paddy soils were superior in sequestering SOC than other land use types, which is likely ascribed to the rapid desalination and dealkalization of paddy field management. Therefore, paddy field management is recommended as an environment friendly approach for managing newly reclaimed lands. PMID- 28341468 TI - Cause and predictability for the severe haze pollution in downtown Beijing in November-December 2015. AB - Based on the hourly PM2.5 concentrations, meteorological variable records and ERA Interim reanalysis data, a series of diagnostic analyses were conducted to explore the possible meteorological causes for the severe haze pollution that occurred in Beijing in November-December 2015. Using the online-coupled WRF-Chem model and GFS data, the predictability of hourly and daily PM2.5 concentrations was evaluated. The results showed that, in the context of pollutant emission, the severe haze pollution in downtown Beijing in November-December 2015 was primarily attributed to anomalous local meteorological conditions, which were caused and strengthened by anomalous large-scale atmospheric circulations. The abnormal changes in the upper troposphere appeared to trigger the anomalies in the middle lower troposphere and the local conditions. The numerical simulations can capture the spatial distribution patterns of the PM2.5 concentrations for predictions of 1 to 10days in advance. The PM2.5 concentration trends in downtown Beijing were generally consistent with the predictions on both daily and hourly time-scales, although the predictability decreased gradually as the lead times prolonged. The predictability of the daily mean PM2.5 concentration was slightly higher than that of the hourly concentration. The statistical indices suggested that the predictions of daily and hourly mean PM2.5 concentrations were generally skillful and reliable for maximum lead times of 8 and 5days, respectively. PMID- 28341469 TI - Long-term survival after the Fontan operation: Twenty years of experience at a single center. AB - OBJECTIVE: Existing studies of patients palliated with the Fontan operation are limited by heterogeneous patient populations and incomplete follow-up. This study aimed to describe long-term post-Fontan survival in a modern patient cohort. METHODS: All 773 patients who underwent a first Fontan operation at our institution between 1992 and 2009 were reviewed. The primary outcome was the composite endpoint of Fontan takedown, heart transplantation, or death before 2013. RESULTS: Follow-up rate was 99.2%. Survival with intact Fontan circulation was 94% at 1 year (95% confidence interval [95% CI], 92%-95%), 90% at 10 years (95% CI, 88%-92%), 85% at 15 years (95% CI, 82%-88%), and 74% at 20 years (95% CI, 67%-80%). Distinct risk factors were identified for early (<=1 year) and late composite outcomes. Independent risk factors for early outcome included prolonged pleural drainage (hazard ratio [HR], 4.4; P < .001), intensive care unit stay >1 week (HR, 2.4; P < .001), Fontan before 1997 (HR, 3.3; P < .001), preoperative atrioventricular valve regurgitation (HR, 2.0; P < .001), and longer crossclamp time (HR, 1.3 per 10 minutes; P < .001). Late outcome was predicted by atrioventricular valve regurgitation prior to Fontan (HR, 2.0; P <= .001), and post-Fontan ICU stay >1 week (HR, 2.4; P < .001). CONCLUSIONS: Long-term mortality after Fontan operation remains substantial. Risk factors for death or loss of Fontan circulation differ between the early and late postoperative periods. Long-term survival has not improved appreciably over the last decade, suggesting that alternatives to the Fontan are warranted. PMID- 28341471 TI - Discussion. PMID- 28341470 TI - History of The Journal of Thoracic and Cardiovascular Surgery. PMID- 28341472 TI - Indices and scores, or how to simplify complexity. PMID- 28341473 TI - Pneumonia after cardiac surgery: Experience of the National Institutes of Health/Canadian Institutes of Health Research Cardiothoracic Surgical Trials Network. AB - RATIONALE: Pneumonia remains the most common major infection after cardiac surgery despite numerous preventive measures. OBJECTIVES: To prospectively examine the timing, pathogens, and risk factors, including modifiable management practices, for postoperative pneumonia and estimate its impact on clinical outcomes. METHODS: A total of 5158 adult cardiac surgery patients were enrolled prospectively in a cohort study across 10 centers. All infections were adjudicated by an independent committee. Competing risk models were used to assess the association of patient characteristics and management practices with pneumonia within 65 days of surgery. Mortality was assessed by Cox proportional hazards model and length of stay by a multistate model. MEASUREMENTS AND MAIN RESULTS: The cumulative incidence of pneumonia was 2.4%, 33% of which occurred after discharge. Older age, lower hemoglobin level, chronic obstructive pulmonary disease, steroid use, operative time, and left ventricular assist device/heart transplant were risk factors. Ventilation time (24-48 vs <=24 hours; hazard ratio [HR], 2.83; 95% confidence interval [95% CI], 1.72-4.66; >48 hours HR, 4.67; 95% CI, 2.70-8.08), nasogastric tubes (HR, 1.80; 95% CI, 1.10-2.94), and each unit of blood cells transfused (HR, 1.16; 95% CI, 1.08-1.26) increased the risk of pneumonia. Prophylactic use of second-generation cephalosporins (HR, 0.66; 95% CI, 0.45-0.97) and platelet transfusions (HR, 0.49, 95% CI, 0.30-0.79) were protective. Pneumonia was associated with a marked increase in mortality (HR, 8.89; 95% CI, 5.02-15.75) and longer length of stay of 13.55 +/- 1.95 days (bootstrap 95% CI, 10.31-16.58). CONCLUSIONS: Pneumonia continues to impose a major impact on the health of patients after cardiac surgery. After we adjusted for baseline risk, several specific management practices were associated with pneumonia, which offer targets for quality improvement and further research. PMID- 28341474 TI - Anti-Vascular Endothelial Growth Factor Therapy for Primary Treatment of Type 1 Retinopathy of Prematurity: A Report by the American Academy of Ophthalmology. AB - PURPOSE: To review the available evidence on the ocular safety and efficacy of anti-vascular endothelial growth factor (VEGF) agents for the treatment of retinopathy of prematurity (ROP) compared with laser photocoagulation therapy. METHODS: A literature search of the PubMed and Cochrane Library databases was conducted last on September 6, 2016, with no date restrictions and limited to articles published in English. This search yielded 311 citations, of which 37 were deemed clinically relevant for full-text review. Thirteen of these were selected for inclusion in this assessment. The panel methodologist assigned ratings to the selected articles according to the level of evidence. RESULTS: Of the 13 citations, 6 articles on 5 randomized clinical trials provided level II evidence supporting the use of anti-VEGF agents, either as monotherapy or in combination with laser therapy. The primary outcome for these articles included recurrence of ROP and the need for retreatment (3 articles), retinal structure (2 articles), and refractive outcome (1 article). Seven articles were comparative case series that provided level III evidence. The primary outcomes included the effects of anti-VEGF treatment on development of peripheral retinal vessels (1 article), refractive outcomes (1 article), or both structural and refractive or visual outcomes (5 articles). CONCLUSIONS: Current level II and III evidence indicates that intravitreal anti-VEGF therapy is as effective as laser photocoagulation for achieving regression of acute ROP. Although there are distinct ocular advantages to anti-VEGF pharmacotherapy for some cases (such as eyes with zone I disease or aggressive posterior ROP), the disadvantages are that the ROP recurrence rate is higher, and vigilant and extended follow-up is needed because retinal vascularization is usually incomplete. After intravitreal injection, bevacizumab can be detected in serum within 1 day, and serum VEGF levels are suppressed for at least 8 to 12 weeks. The effects of lowering systemic VEGF levels on the developing organ systems of premature infants are unknown, and there are limited long-term data on potential systemic and neurodevelopmental effects after anti-VEGF use for ROP treatment. Anti-VEGF agents should be used judiciously and with awareness of the known and unknown or potential side effects. PMID- 28341476 TI - Panel-Based Clinical Genetic Testing in 85 Children with Inherited Retinal Disease. AB - PURPOSE: To assess the clinical usefulness of genetic testing in a pediatric population with inherited retinal disease (IRD). DESIGN: Single-center retrospective case series. PARTICIPANTS: Eighty-five unrelated children with a diagnosis of isolated or syndromic IRD who were referred for clinical genetic testing between January 2014 and July 2016. METHODS: Participants underwent a detailed ophthalmic examination, accompanied by electrodiagnostic testing (EDT) and dysmorphologic assessment where appropriate. Ocular and extraocular features were recorded using Human Phenotype Ontology terms. Subsequently, multigene panel testing (105 or 177 IRD-associated genes) was performed in an accredited diagnostic laboratory, followed by clinical variant interpretation. MAIN OUTCOME MEASURES: Diagnostic yield and clinical usefulness of genetic testing. RESULTS: Overall, 78.8% of patients (n = 67) received a probable molecular diagnosis; 7.5% (n = 5) of these had autosomal dominant disease, 25.4% (n = 17) had X-linked disease, and 67.2% (n = 45) had autosomal recessive disease. In a further 5.9% of patients (n = 5), a single heterozygous ABCA4 variant was identified; all these participants had a spectrum of clinical features consistent with ABCA4 retinopathy. Most participants (84.7%; n = 72) had undergone EDT and 81.9% (n = 59) of these patients received a probable molecular diagnosis. The genes most frequently mutated in the present cohort were CACNA1F and ABCA4, accounting for 14.9% (n = 10) and 11.9% (n = 8) of diagnoses respectively. Notably, in many cases, genetic testing helped to distinguish stationary from progressive IRD subtypes and to establish a precise diagnosis in a timely fashion. CONCLUSIONS: Multigene panel testing pointed to a molecular diagnosis in 84.7% of children with IRD. The diagnostic yield in the study population was significantly higher compared with that in previously reported unselected IRD cohorts. Approaches similar to the one described herein are expected to become a standard component of care in pediatric ophthalmology. We propose the introduction of genetic testing early in the diagnostic pathway in children with clinical and/or electrophysiologic findings, suggestive of IRD. PMID- 28341475 TI - Genotypic and Phenotypic Characteristics of CRB1-Associated Retinal Dystrophies: A Long-Term Follow-up Study. AB - PURPOSE: To describe the phenotype, long-term clinical course, clinical variability, and genotype of patients with CRB1-associated retinal dystrophies. DESIGN: Retrospective cohort study. PARTICIPANTS: Fifty-five patients with CRB1 associated retinal dystrophies from 16 families. METHODS: A medical record review of 55 patients for age at onset, medical history, initial symptoms, best corrected visual acuity, ophthalmoscopy, fundus photography, full-field electroretinography (ffERG), Goldmann visual fields (VFs), and spectral-domain optical coherence tomography. MAIN OUTCOME MEASURES: Age at onset, visual acuity survival time, visual acuity decline rate, and electroretinography and imaging findings. RESULTS: A retinitis pigmentosa (RP) phenotype was present in 50 patients, 34 of whom were from a Dutch genetic isolate (GI), and 5 patients had a Leber congenital amaurosis phenotype. The mean follow-up time was 15.4 years (range, 0-55.5 years). For the RP patients, the median age at symptom onset was 4.0 years. In the RP group, median ages for reaching low vision, severe visual impairment, and blindness were 18, 32, and 44 years, respectively, with a visual acuity decline rate of 0.03 logarithm of the minimum angle of resolution per year. The presence of a truncating mutation did not alter the annual decline rate significantly (P = 0.75). Asymmetry in visual acuity was found in 31% of patients. The annual VF decline rate was 5% in patients from the genetic isolate, which was significantly faster than in non-GI patients (P < 0.05). Full-field electroretinography responses were extinguished in 50% of patients, were pathologically attenuated without a documented rod or cone predominance in 30% of patients, and showed a rod-cone dysfunction pattern in 20% of RP patients. Cystoid fluid collections in the macula were found in 50% of RP patients. CONCLUSIONS: Mutations in the CRB1 gene are associated with a spectrum of progressive retinal degeneration. Visual acuity survival analyses indicate that the optimal intervention window for subretinal gene therapy is within the first 2 to 3 decades of life. PMID- 28341477 TI - Melatonin reduces hypoxic-ischaemic (HI) induced autophagy and apoptosis: An in vivo and in vitro investigation in experimental models of neonatal HI brain injury. AB - Melatonin has neuroprotective effects in many diseases, including neonatal hypoxic-ischaemic (HI) brain injury. The purpose of this study was to evaluate the neuroprotective effects of melatonin both in vivo and in vitro and associated molecular mechanisms behind these effects. Postnatal day 7 male and female rat pups were subjected to unilateral HI, melatonin was injected intraperitoneally 1h before HI and an additional six doses were administered at 24h intervals. The pups were sacrificed at 24h and 7 d after HI. Pre-treatment with melatonin significantly reduced brain damage at 7 d after HI, with 15mg/kg melatonin achieving over 30% recovery in tissue loss compared to vehicle-treated animals. Autophagy and apoptotic cell death as indicated by autophagy associated proteins, cleaved caspase 3 and Tunel staining, was significantly inhibited after melatonin treatment in vivo as well as in PC12 cells. Melatonin treatment also significantly increased the GAP43 in the cortex. In conclusion, melatonin treatment reduced neonatal rat brain injury after HI, and this appeared to be related to inhibiting autophagy as well as reducing apoptotic cell death. PMID- 28341478 TI - Importance of major histocompatibility complex of class I (MHC-I) expression for astroglial reactivity and stability of neural circuits in vitro. AB - MHC-I molecules are involved in the antigenic presentation of cytosol-derived peptides to CD8T lymphocytes. In the nervous system, MHC-I expression is low to absent, occurring only during certain phases of development and aging or after injuries. The involvement of MHC-I in synaptic plasticity has been reported and, following lesion, astrocytes become reactive, limiting tissue damage. Such cells also attempt to restore homeostasis by secreting cytokines and neurotrophic factors. Moreover, astrocytes modulate synapse function, by taking up and releasing neurotransmitters and by limiting the synaptic cleft. Thus, the aim of the present study was to evaluate if astrocyte activation and reactivity are related to MHC I expression and if astrogliosis can be downregulated by silencing MHC-I mRNA synthesis. Given that, we evaluated astrocyte reactivity and synaptogenesis in co-cultures of astrocytes and spinal neurons under MHC-I RNA interference. For that, the MHC-I beta2-microglobulin subunit (beta2m) was knocked-down by siRNA in co-cultures (beta2m expression <60%, p<0.001). As measured by qRT-PCR, silencing of beta2m decreased expression of the astrocytic marker GFAP (<60%, p<0.001), as well as neurotrophic factors (BDNF and GDNF) and pro-inflammatory cytokines (TNF-alpha, IL-1, IL-6, IL-12 and IL-17). No significant changes in synaptic stability indicate that neuron-neuron interaction was preserved after beta2m silencing. Overall, the present data reinforce the importance of MHC-I expression for generation of astrogliosis, what may, in turn, become a target for future CNS/PNS therapies following injury. PMID- 28341479 TI - A method for independent modelling in support of regulatory review of dose assessments. AB - Several countries consider geological disposal facilities as the preferred option for spent nuclear fuel due to their potential to provide isolation from the surface environment on very long timescales. In 2011 the Swedish Nuclear Fuel & Waste Management Co. (SKB) submitted a license application for construction of a spent nuclear fuel repository. The disposal method involves disposing spent fuel in copper canisters with a cast iron insert at about 500 m depth in crystalline basement rock, and each canister is surrounded by a buffer of swelling bentonite clay. SKB's license application is supported by a post-closure safety assessment, SR-Site. SR-Site has been reviewed by the Swedish Radiation Safety Authority (SSM) for five years. The main method for review of SKB's license application is document review, which is carried out by SSM's staff and supported by SSM's external experts. The review has proven a challenging task due to its broad scope, complexity and multidisciplinary nature. SSM and its predecessors have, for several decades, been developing independent models to support regulatory reviews of post-closure safety assessments for geological repositories. For the review of SR-Site, SSM has developed a modelling approach with a structured application of independent modelling activities, including replication modelling, use of alternative conceptual models and bounding calculations, to complement the traditional document review. This paper describes this scheme and its application to biosphere and dose assessment modelling. SSM's independent modelling has provided important insights regarding quality and reasonableness of SKB's rather complex biosphere modelling and has helped quantifying conservatisms and highlighting conceptual uncertainty. PMID- 28341480 TI - Multiplex platform technology and bioinformatics are essential for development of biomarkers in atopic dermatitis. PMID- 28341481 TI - Reply. PMID- 28341485 TI - Modulation of gut microbiota contributes to curcumin-mediated attenuation of hepatic steatosis in rats. AB - BACKGROUND: Structural disruption of gut microbiota contributes to the development of non-alcoholic fatty liver disease (NAFLD) and modulating the gut microbiota represents a novel strategy for NAFLD prevention. Although previous studies have demonstrated that curcumin alleviates hepatic steatosis, its effect on the gut microbiota modulation has not been investigated. METHODS: Next generation sequencing and multivariate analysis were utilized to evaluate the structural changes of gut microbiota in a NAFLD rat model induced by high fat diet (HFD) feeding. RESULTS: We found that curcumin attenuated hepatic ectopic fat deposition, improved intestinal barrier integrity, and alleviated metabolic endotoxemia in HFD-fed rats. More importantly, curcumin dramatically shifted the overall structure of the HFD-disrupted gut microbiota toward that of lean rats fed a normal diet and altered the gut microbial composition. The abundances of 110 operational taxonomic units (OTUs) were altered by curcumin. Seventy-six altered OTUs were significantly correlated with one or more hepatic steatosis associated parameters and designated 'functionally relevant phylotypes'. Thirty six of the 47 functionally relevant OTUs that were positively correlated with hepatic steatosis associated parameters were reduced by curcumin. CONCLUSION: These results indicate that curcumin alleviates hepatic steatosis in part through stain-specific impacts on hepatic steatosis associated phylotypes of gut microbiota in rats. GENERAL SIGNIFICANCE: Compounds with antimicrobial activities should be further investigated as novel adjunctive therapies for NAFLD. PMID- 28341484 TI - RUVBL1-ITFG1 interaction is required for collective invasion in breast cancer. AB - BACKGROUND: The mechanisms of breast cancer collective invasion are poorly understood limiting the metastasis therapy. The ATPase RUVBL1 is frequently overexpressed in various cancers and plays a crucial role in oncogenic process. We further investigated the role of RUVBL1 in promoting collective invasion and uncovered that targeting RUVBL1 could inhibit metastatic progression. METHODS: The expression levels of RUVBL1 and ITFG1 were examined by Western blot and qRT PCR. Co-localization and interaction of RUVBL1 and ITFG1 were determined by immunofluorescence and co-immunoprecipitation. The invasive ability was examined by transwell assay and microfluidic assay. The metastatic and tumorigenic abilities of breast cancer cells were revealed in BALB/c nude mice by xenograft and tail vein injection. RESULTS: ATPase RUVBL1 is highly expressed in breast cancer and predicts the poor prognosis. Elevated expression of RUVBL1 is found in high metastatic breast cancer cells. Silencing RUVBL1 suppresses cancer cell expansion and invasion in vitro and in vivo. RUVBL1 interacts with a conserved transmembrane protein ITFG1 in cytoplasm and plasma membrane to promote the collective invasion. Using a microfluidic model, we demonstrated that silencing RUVBL1 or ITFG1 individually compromises collective invasion of breast cancer cells. CONCLUSION: RUVBL1 is a vital regulator for collective invasion. The interaction between RUVBL1 and ITFG1 is required for breast cancer cell collective invasion and progression. GENERAL SIGNIFICANCE: Targeting collective invasion promoted by RUVBL1-ITFG1 complex provides a novel therapeutic strategy to improve the prognosis of invasive breast cancer. PMID- 28341487 TI - Fever in an elderly patient unmasks Brugada syndrome. PMID- 28341486 TI - Polo-like kinase 1 expression is suppressed by CCAAT/enhancer-binding protein alpha to mediate colon carcinoma cell differentiation and apoptosis. AB - BACKGROUND: Human polo-like kinase 1 (PLK1), a highly conserved serine/threonine kinase is a key player in several essential cell-cycle events. PLK1 is considered an oncogene and its overexpression often correlates with poor prognosis of cancers, including colorectal cancer (CRC). However, regulation of PLK1 expression in colorectal cells was never studied earlier and it is currently unknown if PLK1 regulates differentiation and apoptosis of CRC. METHODS: PLK1 expression was analyzed by real-time PCR and western blotting. Transcriptional regulation was studied by reporter assay, gene knock-down, EMSA and ChIP. RESULTS: PLK1 expression was down-regulated during butyrate-induced differentiation of HT-29 and other CRC cells. Also, PLK1 down-regulation mediated the role of butyrate in CRC differentiation and apoptosis. We report here a novel transcriptional regulation of PLK1 by butyrate. Transcription factors CCAAT/enhancer-binding protein alpha (C/EBPalpha) and Oct-1 share an overlapping binding site over the PLK1 promoter. Elevated levels of C/EBPalpha by butyrate treatment of CRC cells competed out the activator protein Oct-1 from binding to the PLK1 promoter and sequestered it. Binding of C/EBPalpha was associated with increased deacetylation near the transcription start site (TSS) of the PLK1 promoter, which abrogated transcription through reduced recruitment of RNA polymerase II. We also found a synergistic role between the synthetic PLK1 inhibitor SBE13 and butyrate on the apoptosis of CRC cells. CONCLUSION: This study offered a novel p53-independent regulation of PLK1 during CRC differentiation and apoptosis. GENERAL SIGNIFICANCE: Down-regulation of PLK1 is one of the mechanisms underlying the anti-cancer role of dietary fibre-derived butyrate in CRC. PMID- 28341488 TI - What would be the fate of the association between saxagliptin and heart failure admission in the SAVOR-TIMI 53 trial if appropriate statistical methods should have been applied? PMID- 28341489 TI - Automatic Evaluation of Scan Adequacy and Dysplasia Metrics in 2-D Ultrasound Images of the Neonatal Hip. AB - Ultrasound (US) imaging of an infant's hip joint is widely used for early detection of developmental dysplasia of the hip. In current US-based diagnosis of developmental dysplasia of the hip, trained clinicians acquire US images and, if they judge them to be adequate (i.e., to contain relevant hip joint structures), analyze them manually to extract clinically useful dysplasia metrics. However, both the scan adequacy classification and dysplasia metrics extraction steps exhibit significant variability within and between both clinicians and institutions, which can result in significant over- and undertreatment rates. To reduce the subjectivity resulting from this variability, we propose a computational image analysis technique that automatically identifies adequate images and subsequently extracts dysplasia metrics from these 2-D US images. Our automatic method uses local phase symmetry-based image measures to robustly identify intensity-invariant geometric features of bone/cartilage boundaries from the US images. Using the extracted geometric features, we trained a random forest classifier to classify images as adequate or inadequate, and in the adequate images we used a subset of the geometric features to calculate key dysplasia metrics. We validated our method on a data set of 693 US scans collected from 35 infants. Our approach produces excellent agreement with clinician adequacy classifications (area under the receiver operating characteristic curve = 0.985) and in reducing variability in the measured developmental dysplasia of the hip metrics (p < 0.05). The automatically computed dysplasia metrics appear to be slightly biased toward higher Graf categories than the manually estimated metrics, which could potentially reduce missed early diagnoses. PMID- 28341490 TI - Validation of Shear Wave Elastography Cutoff Values on the Supersonic Aixplorer for Practical Clinical Use in Liver Fibrosis Staging. AB - The purpose of this study was to determine the validity of previously established ultrasound shear wave elastography (SWE) cut-off values (>=F2 fibrosis) on an independent cohort of patients with chronic liver disease. In this cross sectional study, approved by the institutional review board and compliant with the Health Insurance Portability and Accountability Act, 338 patients undergoing liver biopsy underwent SWE using an Aixplorer ultrasound machine (SuperSonic Imagine, Aix-en-Provence, France). Median SWE values were calculated from sets of 10 elastograms. A single blinded pathologist evaluated METAVIR fibrosis staging as the gold standard. The study analyzed 277 patients with a mean age of 48 y. On pathologic examination, 212 patients (76.5%) had F0-F1 fibrosis, whereas 65 (23.5%) had >=F2 fibrosis. Spearman's correlation of fibrosis with SWE was 0.456 (p < 0.001). A cut-off value of 7.29 kPa yielded sensitivity of 95.4% and specificity of 50.5% for the diagnosis of METAVIR stage >=F2 liver fibrosis in patients with liver disease using the SuperSonic Imagine Aixplorer SWE system. PMID- 28341491 TI - One-year follow-up optical coherence tomography after endovascular treatment with a new-generation zotarolimus-eluting stent for chronic mesenteric ischemia. PMID- 28341492 TI - Understanding antibiotic decision making in surgery-a qualitative analysis. AB - OBJECTIVE: To investigate the characteristics and culture of antibiotic decision making in the surgical specialty. METHODS: A qualitative study including ethnographic observation and face-to-face interviews with participants from six surgical teams at a teaching hospital in London was conducted. Over a 3-month period: (a) 30 ward rounds (WRs) (100 h) were observed, (b) face-to-face follow up interviews took place with 13 key informants, (c) multidisciplinary meetings on the management of surgical patients and daily practice on wards were observed. Applying these methods provided rich data for characterizing the antibiotic decision making in surgery and enabled cross-validation and triangulation of the findings. Data from the interview transcripts and the observational notes were coded and analysed iteratively until saturation was reached. RESULTS: The surgical team is in a state of constant flux with individuals having to adjust to the context in which they work. The demands placed on the team to be in the operating room, and to address the surgical needs of the patient mean that the responsibility for antibiotic decision making is uncoordinated and diffuse. Antibiotic decision making is considered by surgeons as a secondary task, commonly delegated to junior members of their team and occurs in the context of disjointed communication. CONCLUSION: There is lack of clarity around medical decision making for treating infections in surgical patients. The result is sub optimal and uncoordinated antimicrobial management. Developing the role of a perioperative clinician may help to improve patient-level outcomes and optimize decision making. PMID- 28341493 TI - Procalcitonin as a Biomarker for Predicting Amputation Level in Lower Extremity Infections. AB - Inflammatory markers are essential tools in the decision-making process for lower extremity infections. When coupled with objective findings, clinicians can more accurately diagnose and treat these entities. Typically, markers such as the white blood cell count, erythrocyte sedimentation rate, and C-reactive protein are used to initially assess these patients or monitor the progression of medical or surgical therapy. Procalcitonin is a newer inflammatory marker that is specific for an infectious process. Originally, procalcitonin was used to monitor antibiotic therapy and sepsis for patients in the intensive care setting, but it has now been expanded to other facets of medicine. The utility of procalcitonin has been described for diagnosing infection or osteomyelitis in diabetic foot ulcers. However, limited research has compared inflammatory marker levels and the level of amputation. A retrospective inpatient medical record review was performed of 156 consecutive patient occurrences during 25 months in which surgical intervention was required for a lower extremity infection and an initial procalcitonin level had been obtained. This initial procalcitonin value was then compared with the level of amputation at the final surgical intervention. A highly statistically significant difference was found when comparing those who underwent a below-the-knee or above-the-knee amputation (median procalcitonin 1.72 ng/mL) and those who did not (median procalcitonin 0.105 ng/mL; p < .001). Therefore, patients with higher initial procalcitonin values were more likely to undergo below-the-knee or above-the-knee amputation or require aggressive surgical intervention. Thus, the procalcitonin level can provide valuable initial information to the clinician. PMID- 28341494 TI - How do patients choose between active surveillance, radical prostatectomy, and radiotherapy? The effect of a preference-sensitive decision aid on treatment decision making for localized prostate cancer. AB - PURPOSE: To determine the effect of a decision aid (DA) on treatment preferences and to investigate which patient preferences are important for final treatment preferences. We also determined if the patient's treatment decision was influenced by the urologist's treatment preference. PATIENTS AND METHODS: Between August 2014 and July 2015, newly diagnosed patients with low-/intermediate-risk prostate cancer were offered to use a web-based DA after diagnosis. Treatment preferences and patient's values were extracted from the DA. Urologists' treatment preferences were indicated at the time of inclusion. RESULTS: We included 181 patients, of whom 21% preferred active surveillance, 33% radical prostatectomy, 10% brachytherapy, 3% external beam radiotherapy, and 34% did not indicate a specific preferred treatment option after DA use (missing N = 6). Among 67%, treatment preference before DA use did not change after DA use. In men who chose active surveillance after DA use, 97% (37/38) preferred to postpone unnecessary treatment. For radical prostatectomy, 91% (52/57) of the patients valued tumor removal, and for brachytherapy, 88% (15/17) valued incontinence worse than bowel complaints. For 64% (missing N = 21) of the patients, urologists indicated one specific preferred treatment option as most suitable for the patient concerned. Agreement between final treatment decision and urologist's preference was lower (kappa = 0.68) than between final treatment decision and preferred treatment after DA use (kappa = 0.82). CONCLUSION: Most patients with prostate cancer chose the treatment in accordance with the post-DA preference and to a lesser extent the urologists preference; implications of this are prospectively investigated in an ongoing study. PMID- 28341495 TI - A phase 2 study of TMX-101, intravesical imiquimod, for the treatment of carcinoma in situ bladder cancer. AB - PURPOSE: Imiquimod is a toll-like receptor agonist with proven antitumor activity as a topical treatment for skin cancer. TMX-101 (Vesimune) is a novel liquid formulation of imiquimod optimized for intravesical delivery. The agent demonstrated safety as an intravesical treatment for non-muscle-invasive bladder cancer in a phase 1 clinical trial. We report the results of a phase 2 prospective multicenter clinical trial assessing the safety and activity of TMX 101. MATERIALS AND METHODS: Patients with non-muscle-invasive bladder cancer containing carcinoma in situ were eligible for inclusion. Enrolled patients received 6 weekly intravesical administrations of 200mg/50ml TMX-101 0.4%. End points included rate of adverse events, changes in urinary cytokine levels following treatment, and clinical response at 6 weeks following final instillation, defined as negative posttreatment bladder biopsy and urine cytology results. RESULTS: A total of 12 patients were enrolled, with 10 available for efficacy analysis. Half of the patients (6/12) had received>=2 prior induction courses of bacillus Calmette-Guerin. All patients received all 6 doses of TMX-101 per protocol. Overall, 75% of patients experienced treatment-related adverse events, only 1 of which was>grade 2 (urinary tract infection). Furthermore, 2 patients demonstrated a negative cytology and biopsy result at 6 weeks following treatment. Significant increases in urinary cytokines, including IL-6 and IL-18, were seen following treatment. CONCLUSION: In this phase 2 pilot study in patients with carcinoma in situ bladder cancer, intravesical TMX-101 was safe and well tolerated with common, mild genitourinary adverse effects. Clinical activity was suggested by the increase in posttreatment urinary cytokines. Complete responders were seen. Further investigation of the agent is warranted. PMID- 28341496 TI - Prospective assessment and histological analysis of adherent perinephric fat in partial nephrectomies. AB - OBJECTIVES: The complexity of partial nephrectomy (PN) is partly anticipated by morphometric tumor-based scores that do not consider patient-related issues such as adherent perinephric fat (APF). Also, the objective is to prospectively assess the predictive factors of APF during PN, its effect on complications, and to correlate it to the histological reality. METHODS: A total of 125 consecutive patients undergoing robotic or open PN were prospectively included. The Mayo adhesive probability score (MAP score) was compared to the peroperative presence of APF defined by a score>=2. Adipose tissue was analyzed histologically for fibrosis and inflammatory infiltrate of CD68+macrophages. Univariate and multivariate logistic regression analyses were performed to evaluate predictive factors of APF, and outcomes were compared using chi-square and Kruskal-Wallis tests. RESULTS: APF was present in 51 patients (40.8%) and associated with slight longer operating time and increased blood loss. Warm ischemia time, margins, transfusion, and the Clavien-Dindo score were not different. In multivariate analysis, only male sex, age, waist circumference, fat density on computed tomography, and MAP score were significant predictors of APF. A radioclinical score was more predictive of APF than MAP score alone. Histologically, there was no macrophage infiltration but larger adipocytes in APF without significant differences in fibrosis. CONCLUSIONS: APF can be accurately predicted using radioclinical data as the MAP score, combined with sex, age, and waist circumference. APF is associated with increased operative time and blood loss without postoperative complications. Histological analysis finds larger adipocytes in APF without inflammatory infiltrate, and no difference in fibrosis. PMID- 28341497 TI - Congenital pseudarthrosis of the clavicle: a report on 27 cases. AB - HYPOTHESIS: We aimed to report our experience in treating congenital pseudarthrosis of the clavicle (CPC). MATERIALS AND METHODS: A retrospective search of the archive of our institute was performed; 27 cases (12 male and 15 female patients) affected by CPC were recorded. Among these patients, 19 underwent surgical intervention for cosmetic appearance between 1960 and 2015. Of 19 patients, 18 were treated by pseudarthrosis resection and stabilization with a Kirschner wire, whereas in 1 case, the osteosynthesis was performed with a plate. Iliac crest bone autograft was used in 15 patients, whereas 4 patients were treated with a fibular allograft. RESULTS: The mean follow-up period was 36.3 +/- 49.1 months. Bone healing was achieved in 14 of 19 operated cases (74%); none of the patients had complaints regarding cosmetic abnormalities or unesthetic appearance. All the operated patients were pain free, range of motion was complete, and no other subjective anomalies were found. No vascular or neurologic complications were observed. However, the use of allograft was associated with high rates of nonunion in this case series (P = .037). CONCLUSION: CPC can be satisfactorily treated by K-wire fixation and autologous iliac crest bone grafting, which showed better results in terms of functional and cosmetic outcome. PMID- 28341498 TI - Natural History of Iatrogenic Pediatric Femoral Artery Injury. AB - BACKGROUND: Iatrogenic femoral artery trauma complicates the course of critically ill neonates and children. Complications from persistent arterial occlusion may include claudication and limb length discrepancies. Data supporting risk factors for such and need for revascularization are lacking. METHODS: Review of a prospectively maintained database at a tertiary institution of iatrogenic pediatric femoral artery injuries incurred between 2013 and 2014 was performed. Additional injuries were identified by review of pediatric arterial duplex performed between 2008 and 2013. Demographics, risk factors, and outcomes were queried. Data analysis utilized Fischer's exact t-test and logistic regression. RESULTS: Seventy-six patients were identified of which 68 presented with acute limb ischemia (ALI) and 8 with chronic iliofemoral arterial occlusion resulting in claudication (n = 6) or limb length discrepancy (n = 2). Mean weight at injury was 6.3 kg; mean age at injury was 49 weeks (50% aged <3 months). Mean follow-up was 14 months (out to 11 years). Six patients required surgery for ALI, and 6 required delayed operation for limb length discrepancy (n = 4) or for persistent external iliac artery (EIA) occlusion. Mean age at delayed revascularization was 6 years (range: 2-13 years). Vasopressor use, mechanism/location of injury, and concomitant venous thrombosis were not significantly correlated with need for operation; trends suggested that cardiac catheterization and EIA thrombosis may correlate with chronic disease. Increased age at injury was associated with need for operation. CONCLUSIONS: Although a majority of children with ALI may be successfully treated medically, 9% will require operation for ALI and 16% ultimately required revascularization during follow-up. Persistent iliofemoral arterial thrombosis is a likely risk factor for limb length discrepancy with growth; identifying risk factors for this and improved methods for surveillance requires ongoing investigation. PMID- 28341499 TI - Renal Arteriovenous Malformations: A Rare Vascular Cause of Back Pain. AB - BACKGROUND: Renal arteriovenous malformation (AVM) is a very rare phenomenon (fewer than 200 cases in the literature), most commonly (75%) presenting with hematuria in young women. Renal AVMs may be cirsoid (multibranched) or cavernous, with cirsoid morphology predominating 3:1. The historical treatment is partial nephrectomy. Best endovascular therapy is divided among many options. We present 2 cases of large renal AVMs treated with single Amplatzer plugs. METHODS: During a 2-year period (2014-15), 2 patients presented for vascular evaluation of renal AVMs found incidentally on workup for nonspecific abdominal and back pain. Both were the less common cavernous-type AVM. Each noted back pain ipsilateral to the AVM. Neither had a history of trauma or renal procedures. Each underwent angiography and Amplatzer plug placement to occlude flow while preserving parenchyma. RESULTS: Each patient successfully underwent occlusion of the arterial feeding branch of the AVM with immediate angiographic success. Each patient subsequently underwent follow-up imaging that demonstrated absence of filling of the AVM with preservation of healthy renal parenchyma. CONCLUSIONS: Renal AVMs, although very rare, do present to vascular surgeons and may be managed successfully via an endovascular approach with standard techniques. Although renal AVMs are often managed with cyanoacrylate embolization, careful selective arterial catheterization allows for single plug embolization with excellent results and without requiring venous intervention. PMID- 28341500 TI - Effect of 2% Chlorhexidine Gluconate-Impregnated Cloth on Surgical Site Infections in Vascular Surgery. AB - BACKGROUND: Surgical site infections (SSIs) are a significant burden to patients and health care systems. This retrospective study evaluates the observed rates of SSI after our institution implemented chlorhexidine gluconate-impregnated (CHG) cloth as a preoperative antiseptic preparation in elective vascular surgery. METHODS: Between March 2011 and January 2012, we reviewed 250 patients who underwent elective vascular surgery who used the CHG cloth preoperatively. Their rate of SSIs was compared with 252 control patients who received the CHG shower preoperatively during the preintervention period. Urgent and emergent cases were excluded. The primary outcome measured was SSI within 30 days of index operation. RESULTS: There was no baseline difference in mean age, gender distribution, smoking status, diabetes, chronic obstructive pulmonary disease, and the number of patients with body mass index >40 between the cohorts. There was no difference in the overall rate (5.6% vs. 5.6%, P = 1.00) and type of SSIs between the 2 groups, but the control group trended toward deeper infections (4 deep incisional and 2 organ space vs. none and 1, respectively). The control group also had more dirty or infected wound categories (10 vs. 21.4%, P < 0.01) and more perioperative antibiotic errors and hypothermia (P < 0.02). CONCLUSIONS: There was no observed difference in SSI rates before and after implementation of the CHG as the preoperative method of skin decontamination in our retrospective case control cohorts. PMID- 28341501 TI - Normal Lower Extremity Duplex Findings in Patients with Left Ventricular Assist Devices: A Basis for Vascular Laboratory Interpretation. AB - BACKGROUND: Left ventricular assist devices (LVADs) have been shown to cause changes in carotid artery duplex-derived flow velocity waveforms; however, possible effects on lower extremity arterial duplex (LEAD) findings have not been characterized. We sought to characterize LEAD findings in patients with LVADs to establish a basis for vascular laboratory interpretation of LEAD in patients with LVADs. METHODS: Retrospective single institution review of all patients with LEAD performed after LVAD implantation from 2003 to 2014. Peak systolic velocity (PSVs) of common femoral (CFA), superficial femoral (SFA), popliteal, and posterior tibial arteries (PTA) in asymptomatic extremities in patients with LVADs were compared to a control group of patients at our institution without LVADs who underwent LEAD for nonischemic indications. Arterial brachial index (ABIs) and CFA waveform acceleration times (ATs) and end diastolic velocity (EDV) were also measured. RESULTS: There were 248 LVAD patients, 29 had LEAD of at least 1 lower extremity (34 extremities, 22 asymptomatic, and 12 symptomatic) during the study period and 136 control limbs. Mean PSVs (cm/s) in the control CFA, mid SFA, popliteal, and PTA were 137 +/- 4.8, 104.2 +/- 4.5, 65.2 +/- 2.8, and 64.6 +/-3.2. Mean PSVs were significantly decreased in the LVAD patients: 49.5 +/- 4.9, 40.6 +/- 3.7, 27.2 +/- 2.2, and 25.5 +/- 2.3, P < 0.001 for each comparison. Average ABI for control limbs was 0.91 +/- 0.05 compared to 1.17 +/- 0.35 in LVAD extremities (P < 0.001). Mean CFA AT was 97 ms in the controls and 207 ms in LVAD patients, P < 0.001. Mean CFA EDV was 14.7 cm/s in the controls and 18.6 cm/s in the LVAD patients, P = 0.011. CONCLUSIONS: This is the first study characterizing LEAD in lower extremity arteries in LVAD patients. PSV is significantly decreased throughout lower extremity vessels, and common femoral artery acceleration time increased. Results can serve as a basis for identifying normal LEAD findings in LVAD patients. PMID- 28341502 TI - Significance of Blunted Venous Waveforms Seen on Upper Extremity Ultrasound. AB - BACKGROUND: Current guidelines recommend vascular mapping ultrasound (US) prior to arteriovenous fistula creation. Blunted venous waveforms (BVWs) suggest central venous stenosis; however, this relationship and one between BVWs and the presence of a central venous catheter (CVC) remain unclear. METHODS: All patients who received upper extremity vascular mapping US between January 2013 and October 2014 at a single institution were retrospectively reviewed. Patient demographics, comorbidities, US results, pacemaker history, and CVC status were collected. Waveforms were assessed at the proximal subclavian vein/distal axillary vein and interpreted by radiologists. Patients were determined to have central venous stenosis (CVS) if detected by venography within 6 months of US. RESULTS: There were 342 patients, of which 165 (48%) had a current CVC and 29 (8.5%) had BVW of at least 1 arm. Right-sided BVW were associated with a history of a prior ipsilateral CVC (odds ratio [OR] = 4.5, 95% confidence interval [CI] = 1.6-12.6, P = 0.009). Of the 342 patients, 69 (20%) had a venogram within 6 months. Seventeen (25%) of the 69 patients had CVS, with 7 involving the left subclavian vein, 8 the right subclavian vein, and 3 the superior vena cava (one patient had tandem stenoses). A BVW on the left side was not associated with any CVS. A BVW on the right side was associated with an ipsilateral CVS (OR = 5.8, 95% CI = 1.2 27.4, P = 0.04). This association persisted in the setting of a prior CVC (relative risk = 1.3, 95% CI = 0.9-2, P = 0.01). CONCLUSIONS: There are associations between right-sided BVW and an ipsilateral subclavian vein stenosis. We recommend that hemodialysis access planning includes venography to rule out central vein stenosis in patients with BVW, especially if right-sided and in the setting of a prior CVC. PMID- 28341503 TI - Endovascular Repair of a Large Abdominal Aortic Aneurysm in a Patient Presenting with Lower Extremity Edema as a Result of Inferior Vena Cava Thrombosis. AB - PURPOSE: Abdominal aortic aneurysm (AAA) can present with symptoms because of aneurysmal compression of adjacent organ systems. This condition has always been treated by open surgical repair. Here, we report a case of an AAA complicated by inferior vena cava (IVC) thrombosis and deep venous thrombosis (DVT) due to IVC compression by aneurysm successfully treated by endovascular aneurysm repair (EVAR). CASE REPORT: A 50-year-old man was presented with 3-day right lower extremity edema. He was diagnosed with acute DVT and IVC thrombosis initially. Anticoagulation therapy and catheter-directed thrombolysis under the protection of IVC filter were performed. Subsequent imaging revealed a 9.5-cm infrarenal AAA compressing the IVC. The patient was transferred to our hospital and underwent EVAR successfully. CONCLUSIONS: EVAR is a viable treatment option for patients with an AAA complicated by IVC thrombosis and DVT due to IVC compression by aneurysm. PMID- 28341504 TI - The Management of Superior Mesenteric Artery Aneurysm: Experience with 16 Cases in a Single Center. AB - BACKGROUND: Superior mesenteric artery aneurysm (SMAA) represents a rare but potentially fatal condition. This study aimed to present the individual management protocol of SMAA in our center and to discuss a potential preliminary treatment algorithm. METHODS: SMAA patients treated in our center between January 2007 and December 2014 were retrospectively reviewed on January 2015. RESULTS: Sixteen patients with SMAA were identified, including 1 female and 15 males, with a mean age of 48.9 +/- 12.9 years. Three patients (3/16, 18.8%) were treated by multiple overlapping bare stents and one (1/16, 6.3%) initially by a single bare stent. Two cases (2/16, 12.5%) were treated by a covered stent implantation, but one of those suffered from SMAA rupture 7 days later, whereas the other had inner stent thrombosis one month after discharge and died from multiple organ dysfunction syndrome. Nine patients (9/16, 56.2%) received conservative therapy, one of who received multiple overlapping bare stents implantations for persistent abdominal pain. One patient underwent open surgery. There were 2 major complications, with no death during hospitalization and 1 death during follow-up. CONCLUSIONS: SMAA treatment needs to be individually prescribed, based on clinical manifestation, anatomy, and etiology. Multiple overlapping bare stents are safe and effective in selective patients with SMAA, and covered stents should be used with caution to avoid covering proximal branches; open surgery should be reserved for patients with suspected intestinal necrosis. PMID- 28341505 TI - Secondary Aortoenteric Erosion Followed by Recurrent Lower Extremity Abscesses. AB - A secondary aortoenteric fistula (SAEF) is a relatively rare complication of aortoiliac reconstructive surgery, often involving relatively fixed duodenal third portion and a vascular anastomosis. We observed a 52-year-old man with a recurrent right lower leg abscess following the erosion between ipsilateral bifurcated prosthetic graft limb and nonfixed jejunum. In situ graft-sparing surgical treatment with aggressive debridement was successfully performed. A SAEF may occur even at a nonvascular anastomosis site, or in nonfixed small bowel, and may become a source of a septic embolus. A high index of suspicion for SAEF is required for early diagnosis and treatment of this life-threatening complication. PMID- 28341506 TI - A Case of Acute Ischemic Monomelic Neuropathy and Review of the Literature. AB - Ischemia monomelic neuropathy is rare and underrecognized complication of hemodialysis access (HA), characterized by diffuse multiple mononeuropathies in the absence of significant clinical ischemia. It is important to diagnose this syndrome early because ligation of the HA is the most accepted treatment to prevent or at least halt irreversible neural dysfunction and therefore, chronic pain and disability. Literature describing this fistulae-related pathology is rare, and we attempt to increase its awareness. PMID- 28341507 TI - Endovascular Aortic Repair for Progressive Chronic Thoracoabdominal Aortic Dissections. AB - BACKGROUND: Ascending and thoracic aortic dissections progress into thoracoabdominal aneurysms 20-40% of the time, due to the initial aortic injury with associated weakness of the aortic wall. The increased firmness of the intimal flap usually results in a collapsed true lumen that does not spontaneously reexpand even with progressive dilatation of the aorta. In an effort to identify a safe and effective treatment path for this complex disease process, we present 4 cases illustrating successful sequential thoracic endovascular aortic repair (TEVAR) and fenestrated endovascular aortic repair (FEVAR). The treatment of these patients with endovascular techniques is less invasive than open conventional operations. However, multiple procedures are required using various complex novel techniques. METHODS: Institutional review board approval was obtained to identify 4 cases between January 2010 and May 2015 of patients with pretreatment hypertension, who initially presented with an aortic dissection. All patients subsequently developed a descending aortic aneurysm and were treated by TEVAR and FEVAR. Monthly and yearly outcomes were analyzed. RESULTS: All procedures concluded with branched visceral vessel patency and no type I endoleaks. One patient required extraction of the retrograde superior mesenteric artery stent placed during the acute phase for visceral reperfusion. Another patient developed acute thromboembolic occlusion of the right common femoral artery requiring emergent revascularization in the immediate postoperative period. CONCLUSIONS: Aortic dissection is the most common cause of death related to aortic pathology. Treatment of type B aortic dissections has traditionally been initially medical therapy unless complications develop. The treatment of subsequent complications has been associated with a high morbidity and mortality rate. However, the advent of evolving endovascular therapies has resulted in the reassessment of how these patients might be handled. This case series illustrates the treatment of expanding chronic thoracoabdominal aortic dissecting aneurysms with a total endovascular approach using various novel techniques. PMID- 28341508 TI - Efficacy of Endovascular Radiofrequency Ablation for Thromboangiitis Obliterans (Buerger's Disease). AB - BACKGROUND: This study aimed to evaluate the efficacy of endovascular radiofrequency ablation (RFA) for the treatment of thromboangiitis obliterans (TAO). METHODS: Total 30 males (median age: 46.00 years, interquartile range: 42.00-51.25 years) with unilateral TAO in the lower extremity underwent RFA were retrospectively enrolled from January 2013 and October 2013. The pre-operative and post-operative digital subtraction angiographic (DSA) images were recorded. Pain scores preoperatively and postoperatively were assessed according to the World Health Organization Pain Guideline. The values of ankle brachial index (ABI) at pre-operation, post-operation, 2 weeks and 2 years after surgery were all recorded and analyzed. Additionally, a 2-year follow up was performed by a computed tomographic angiography (CTA) image. RESULTS: The DSA images indicated that occlusion of femoral artery was improved after surgery. Moreover, there was no recurrence of TAO at 2 years of follow-up based on the CTA images. The pain score (P < 0.001) was significantly deceased after surgery. The values of ABI at postoperation, 2 weeks after surgery, and 2 years after surgery were all significantly higher than the preoperative ABI (P < 0.001). Furthermore, the values of ABI at 2 weeks after surgery and 2 years after surgery were all significantly higher than the postoperative ABI (P < 0.001). CONCLUSIONS: These results supported the application of endovascular RFA for treating TAO. PMID- 28341509 TI - Dialysis Access Hemorrhage: Access Rescue from a Surgical Emergency. AB - BACKGROUND: Hemorrhage from a dialysis access can be a life-threatening condition. This study details our experience using access rescue strategies, including in situ graft replacement, primary repair, or conversion to an autogenous fistula, coupled with treatment of central vein occlusion to maintain access usage in patients presenting with conduit hemorrhage. METHODS: During a 3 year period (2012-2014), 26 patients (14 women, 12 men) on chronic hemodialysis were treated for access conduit bleeding (n = 18) or life-threatening hemorrhage (n = 8), located in the upper extremity (n = 23) or thigh (n = 3). All patients had developed bleeding from a skin eschar/ulcer over a bovine (n = 9) or polytetrafluoroethylene (n = 9) bridge graft, or aneurysmal autogenous fistula (n = 8). A retrospective review of outcome relative to clinical signs, etiology of conduit bleeding (infection, wall erosion), and the type of rescue procedure(s) was performed. Duplex ultrasound testing was used to guide therapy based on the presence of aneurysmal degeneration, perigraft fluid, or access flow pattern indicative of venous outflow obstruction. RESULTS: One-half of the patients were taken emergently to the operating room for hemorrhage control or impending rupture of an infected false aneurysm, the remaining repaired on an urgent basis. In 18 patients, emergency room personnel attempted control of access site bleeding by suturing (n = 14) or tourniquet (n = 4). Dialysis access salvage was achieved in 22 (85%) of 26 patients by in situ conduit replacement using a rifampin-soaked polytetrafluoroethylene conduit (n = 19) or primary repair (n = 3). Two patients with sepsis and ruptured, infected false aneurysm were treated by ligation, and 2 patients with nonsalvable access had conversion to an autogenous fistula. One-third of rescued accesses (n = 7) had staged endovascular treatment of central vein stenosis. One patient died within 30 days. All dialysis access revisions remained patent and used for immediate dialysis (n = 5), within 4-5 weeks (n = 19), or after vein maturation (n = 2). One replaced graft was revised for infection. Positive blood or bleeding site cultures were obtained from 9 (45%) of 20 patients tested. CONCLUSIONS: Salvage of a functional dialysis access is possible in the majority of patients presenting with conduit hemorrhage. Loss of wall integrity, infection, and venous hypertension were etiologic factors. Application of in situ graft replacement strategies known to be effective in the treatment of graft infection should be considered in the management of this surgical emergency. PMID- 28341510 TI - Endovascular Stenting of Portal Vein for Graft Rescue after a Pancreas Transplant Venous Graft Thrombosis: A Case Report. AB - Venous thrombosis of pancreas transplant allografts often leads to graft loss. It is an worrisome complication and difficult to treat, forming the most common nonimmunological cause of graft loss. Multiple risk factors have been implicated in the development of venous thrombosis of pancreas transplant. Color Doppler ultrasonography enables early diagnosis of venous thrombosis, thus increasing the possibility of graft-rescue treatments. Endovascular management of pancreatic transplant vascular complications is scant and in the form of case reports. We report a case of early detection of pancreatic graft venous thrombosis that was treated successfully by catheter-directed thrombolysis mechanical thrombectomy, percutaneous transluminal angioplasty, and stenting of portal vein. PMID- 28341511 TI - Open and Endovascular Abdominal Aortic Injury Repair Outcomes in Polytrauma Patients. AB - INTRODUCTION: The management of patients with abdominal aortic injury (AAI) remains challenging. Open repair of AAI is still the standard of care although it is associated with high mortality. In past few years, endovascular surgery has evolved as a less invasive alternative to open surgery in emergency settings. The objective of this study was to compare outcomes after open repair versus endovascular repair of AAI in polytrauma patients. METHODS: The National Trauma Data Bank, from 2008 to 2012, was queried to identify trauma patients undergoing open and endovascular repair of AAI using International Classification of Diseases, ninth Edition, and Clinical Modification codes. Data reviewed included demographics, type of associated injury, type of operative management, and complications. Factors independently associated with mortality were evaluated using multivariate logistic regression model. RESULTS: Of 325 injured patients with AAI, 91 patients underwent endovascular repair and 234 patients underwent open repair. Of these, 80.6% were male, with a mean age of 35.70 years, and a mean injury severity score (ISS) was 30.59 for patients undergoing open repair and 31.56 for endovascular repair. Associated traumatic injuries included bowel injuries 57.5%, liver-pancreas injuries 36.6%, splenic injuries 14.8%, renal injuries 15.7%, and retroperitoneal injuries 19.1%. In-patient mortality for patients undergoing the open repair cohort was 63.7% and 20.9% for patients in the endovascular cohort (P < 0.001). The endovascular repair cohort patients had a higher incidence of pneumonia 17.6% as compared to open repair cohort 5.1% (P < 0.001). Similarly, patients in the endovascular repair cohort also had a higher abdominal compartment syndrome (4.4% vs. 0.4% in the open repair cohort, P = 0.009), postoperative acute kidney injury (9.9% endovascular repair cohort vs. 6.4% in the open repair cohort, P = 0.281), and acute mesenteric ischemia (1.1%). After controlling for associated injuries, acidosis, blood pressure at presentation, age, and ISS, patients in the open repair cohort had 6.58 times higher odds (confidence interval: 3.25-13.33; P < 0.001) of mortality as compared to the endovascular repair cohort. CONCLUSIONS: Endovascular repair of abdominal aorta in polytrauma patients seems to be feasible and may improve survivorship in appropriately selected patients. More research is needed to understand to identify indications for endovascular repair versus open repair. PMID- 28341512 TI - Change in Aortic Neck Diameter after Endovascular Aortic Aneurysm Repair. AB - BACKGROUND: Implications of aortic neck dilatation following endovascular aneurysm repair (EVAR) are unclear. Previous studies are limited to comparisons of individual, early generation devices. We compared aortic neck dilatation among contemporary stent grafts. METHODS: We reviewed preoperative and postoperative computed tomographic angiograms for EVARs performed from 2008-2014. Images were analyzed using 3-dimensional centerline reconstructions. Aortic neck diameter was measured in orthogonal planes at and 10 mm below the lowest renal artery. Device type and main body graft diameter were obtained from operative reports. RESULTS: Eighty-six patients were analyzed with a median radiologic follow-up of 21.9 months (range: 4-64). Stent grants implanted included 26 Cook Zenith, 26 Gore Excluder, 22 Medtronic Endurant, 10 Endologix Powerlink, and 2 Trivascular Ovation devices. Mean device oversizing was 13.6 +/- 11.5% and did not vary by device type (P = 0.54). Most patients (86.0%) experienced increases in aortic neck diameter during follow-up, with a mean increase of 1.3 +/- 2.2 mm (5.9 +/- 9.3%) and 3.3 +/- 0.6 mm (8.9 +/- 2.5%) at 30 day and latest follow-up scans, respectively. Repeated-measures analysis further demonstrated a significant increase in mean neck dilatation during follow-up (P < 0.001). Neck dilatation was not significantly different across different devices (P = 0.233). However, there was a moderate positive correlation between percent change in neck diameter and degree of oversizing, which was statistically significant (rs = 0.41, P < 0.001). Type Ia endoleak was observed in 2 patients and was associated with greater mean neck dilatation (8.8 +/- 3.3 mm vs. 3.35 +/- 2.71, P = 0.041). There was no relationship between changes in neck diameter and sac regression/expansion. CONCLUSIONS: Aortic neck diameter increases consistently over time following EVAR. The degree of neck dilatation correlates with degree of device oversize but not with device type. PMID- 28341513 TI - Impact of Inferior Vena Cava Filter Placement on Short-Term Outcomes in Patients with Acute Pulmonary Embolism. AB - BACKGROUND: Inferior vena cava filters (IVCFs) have been associated with improved survival in patients with acute pulmonary embolism (PE) in some studies. However, without randomization, those with early mortality who did not receive an IVCF might have died prior to treatment decision about filter placement, falsely contributing a survival advantage to those receiving IVCF and biasing the results of previous observational studies. The objective of this study is to evaluate the impact of IVCF on in-hospital mortality after adjusting for this survivor treatment selection. METHODS: National Inpatient Sample data sets from 2009 to 2012 were analyzed to assess the impact of IVCF placement on in-hospital mortality in all patients with acute PE. Subgroup analyses were performed in those with high-risk PE (hemodynamic shock) and also for those with both shock and concomitant thrombolysis. Inverse propensity-score weighting was used to balance clinical and comorbid differences between filter and nonfilter groups. To account for survivor treatment selection bias, an extended Cox model was fitted with IVCF placement as a time-dependent covariate. RESULTS: We identified 263,955 patients with acute PE over this period; 36,702 (13.9%) received IVCF. Those receiving IVCF in the unadjusted cohort were older (IVCF: 66.3 +/- 15.9 vs. non IVCF: 62.4 +/- 17.4; P < 0.001) with higher rates of shock (6.8% vs. 3.8%; P < 0.001), deep venous thrombosis (32.8% vs. 13.9%; P < 0.001), thrombolytic therapy (5.9% vs. 1.6%; P < 0.001), and lower crude mortality (6.0% vs. 6.7%; P < 0.001). Propensity weighted extended Cox analysis showed that IVCF placement did not significantly decrease mortality hazard compared to an untreated patient (hazard ratio [HR]: 0.93, 95% confidence interval [CI]: 0.89-1.01). Similar results were seen in the combined high-risk and thrombolysis (HR: 0.85, 95% CI: 0.60-1.21) subgroup and associated with worse outcomes in the high-risk (HR: 1.2, 95% CI 1.11-1.38) subgroup. CONCLUSIONS: Placement of IVCF in all patients with acute PE, in high-risk patients, or in high-risk patients concurrently treated with thrombolysis is not significantly associated with improvement of in-hospital mortality when accounting for survivor treatment selection bias. PMID- 28341514 TI - The INFANT study-a flawed design foreseen. PMID- 28341516 TI - Computerised cardiotocography-study design hampers findings. PMID- 28341515 TI - Computerised interpretation of fetal heart rate during labour (INFANT): a randomised controlled trial. AB - BACKGROUND: Continuous electronic fetal heart-rate monitoring is widely used during labour, and computerised interpretation could increase its usefulness. We aimed to establish whether the addition of decision-support software to assist in the interpretation of cardiotocographs affected the number of poor neonatal outcomes. METHODS: In this unmasked randomised controlled trial, we recruited women in labour aged 16 years or older having continuous electronic fetal monitoring, with a singleton or twin pregnancy, and at 35 weeks' gestation or more at 24 maternity units in the UK and Ireland. They were randomly assigned (1:1) to decision support with the INFANT system or no decision support via a computer-generated stratified block randomisation schedule. The primary outcomes were poor neonatal outcome (intrapartum stillbirth or early neonatal death excluding lethal congenital anomalies, or neonatal encephalopathy, admission to the neonatal unit within 24 h for >=48 h with evidence of feeding difficulties, respiratory illness, or encephalopathy with evidence of compromise at birth), and developmental assessment at age 2 years in a subset of surviving children. Analyses were done by intention to treat. This trial is completed and is registered with the ISRCTN Registry, number 98680152. FINDINGS: Between Jan 6, 2010, and Aug 31, 2013, 47 062 women were randomly assigned (23 515 in the decision-support group and 23 547 in the no-decision-support group) and 46 042 were analysed (22 987 in the decision-support group and 23 055 in the no-decision support group). We noted no difference in the incidence of poor neonatal outcome between the groups-172 (0.7%) babies in the decision-support group compared with 171 (0.7%) babies in the no-decision-support group (adjusted risk ratio 1.01, 95% CI 0.82-1.25). At 2 years, no significant differences were noted in terms of developmental assessment. INTERPRETATION: Use of computerised interpretation of cardiotocographs in women who have continuous electronic fetal monitoring in labour does not improve clinical outcomes for mothers or babies. FUNDING: National Institute for Health Research. PMID- 28341517 TI - Enhancement of bactericidal activity against group B streptococci with reduced penicillin susceptibility by uptake of gentamicin into cells resulting from combination with beta-lactam antibiotics. AB - Combined effects of penicillin (PEN) and gentamicin (GM) against Streptococcus agalactiae, i.e. group B streptococci (GBS), are known to occur, but synergy has not been examined in strains with reduced PEN susceptibility, usually called PEN resistant GBS (PRGBS). We therefore studied combined effects of beta-lactam antibiotics and GM in cultures of 3 PRGBS strains belonging to serotype Ia or III that were isolated from Japanese adults with invasive infections. Killing kinetics were determined at 2-h intervals from 0 to 6 h after exposure to ampicillin (AMP) or cefotaxime (CTX) combined with GM. Concentrations of GM in bacterial cells were measured by liquid chromatography-tandem mass spectrometry. Morphologic changes after exposure to agents were observed by transmission electron microscopy. Combining AMP or CTX with GM synergistically increased bactericidal activity against PRGBS beyond that of either beta-lactam alone. GM concentrations in bacterial cells increased 5- to 8-fold when GM was combined with AMP or CTX. Electron microscopically, bacterial cells showed aggregates of strands and ribosomal damage most likely reflecting enhanced GM uptake into bacterial cells. This uptake appeared to result from cell wall damage caused by beta-lactam antibiotics. This study suggests that combining beta-lactam antibiotics with GM might be useful against severe PRGBS infection. PMID- 28341518 TI - Evaluation of the implementation rate of primary antifungal prophylaxis and the prognosis of invasive fungal disease in acute leukemia patients in China. AB - BACKGROUND: Invasive fungal disease (IFD) is a major complication of acute leukemia, thus primary antifungal prophylaxis (PAP) is recommended by guidelines. Nevertheless, guidelines might not be commonly followed in developing countries due to economic factors. The primary objectives were to evaluate the implementation rate of PAP in acute leukemia patients in China and to compare the prognosis of IFD with and without PAP. The secondary objectives were to investigate the safety of PAP, clinical characteristics of IFDs and risk factors of breakthrough. METHODS: This was a retrospective observational single-center study, including non-M3 acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) patients receiving uniform induction or salvage chemotherapy between 2012 and 2016. RESULTS: There were 29.4% of patients without PAP among a total of 248 cases. The incidence of breakthrough proven/probable/possible IFDs was 24.7%, 6.5%, 5.5%, 5.4% and 5.3% in control (no prophylaxis), fluconazole, itraconazole, voriconazole and posaconazole group respectively (P = 0.007), while the percentage of patients requiring empirical or pre-emptive therapy was 54.8%, 45.7%, 23.3%, 18.9%, 10.5% respectively (P < 0.001). PAP could also significantly improve IFD-free survival (P < 0.001) and reduce 90-day overall mortality in patients on AML salvage regimen (P = 0.021). There were no statistical differences in PAP-related adverse events. Past history of IFD (OR 9.5, P = 0.006) was confirmed to be independent risk factors. CONCLUSIONS: There are a considerable number of acute leukemia patients without PAP in China, who have higher IFD incidence, increased empiric/pre-emptive antifungal drug use and worse IFD-free survival. PMID- 28341519 TI - Rett Syndrome-Current Status and Future Directions. PMID- 28341520 TI - In silico prediction of the effects of mutations in the human triose phosphate isomerase gene: Towards a predictive framework for TPI deficiency. AB - Triose phosphate isomerase (TPI) deficiency is a rare, but highly debilitating, inherited metabolic disease. Almost all patients suffer severe neurological effects and the most severely affected are unlikely to live beyond early childhood. Here, we describe an in silico study into well-characterised variants which are associated with the disease alongside an investigation into 79 currently uncharacterised TPI variants which are known to occur in the human population. The majority of the disease-associated mutations affected amino acid residues close to the dimer interface or the active site. However, the location of the altered amino acid residue did not predict the severity of the resulting disease. Prediction of the effect on protein stability using a range of different programs suggested a relationship between the degree of instability caused by the sequence variation and the severity of the resulting disease. Disease-associated variations tended to affect well-conserved residues in the protein's sequence. However, the degree of conservation of the residue was not predictive of disease severity. The majority of the 79 uncharacterised variants are potentially associated with disease since they were predicted to destabilise the protein and often occur in well-conserved residues. We predict that individuals homozygous for the corresponding mutations would be likely to suffer from TPI deficiency. PMID- 28341521 TI - Periodic leg movements during sleep: phenotype, neurophysiology, and clinical significance. AB - Periodic leg movements during sleep (PLMS) are the most important objective finding in restless legs syndrome (RLS). During the last decade, PLMS have been very important for the assessment and comprehension of their pathophysiological correlates, which have been paralleled by the emergence of new computer-assisted and data-driven rules for their identification, scoring, and analysis. The present article focused on the most relevant PLMS-related findings of the last decade, and sought to provide a coherent and comprehensive overview on this enigmatic motor phenomenon. First, a clear description was made on the identification, quantification, and scoring of PLMS and their associated events. This was followed by a description of the current knowledge of their neurophysiologic aspects. Then, the typical phenotype of genuine PLMS in RLS and other clinical conditions was described, allowing for their careful separation from other sleep leg motor activities. In addition, the most recent findings on the genetics of PLMS were briefly summarized, followed by the current evidence on their clinical correlates, which is another rapidly advancing field of research. The description of the specific aspects of PLMS in children was also carefully reported, with important clues on their evaluation in this age group. Finally, further research was proposed, which may lead to consideration of PLMS as a clinically significant concern, independent of the association with RLS. PMID- 28341522 TI - Cognitive Schemas in Placebo and Nocebo Responding: Role of Autobiographical Memories and Expectations. AB - PURPOSE: Placebo effects are presumed to be based on one's expectations and previous experience with regard to a specific treatment. The purpose of this study was to investigate the role of the specificity and valence of memories and expectations with regard to itch in experimentally induced placebo and nocebo itch responses. It was expected that cognitive schemas with more general and more negative memories and expectations with regard to itch contribute to less placebo itch responding. METHODS: Validated memory tasks (ie, the Autobiographical Memory Test and the Self-referential Endorsement and Recall Task) and expectation tasks (ie, Future Event Task and the Self-referential Endorsement and Recall Task) were modified for physical symptoms, including itch. Specificity and valence of memories and expectations were assessed prior to a placebo experiment in which expectations regarding electrical itch stimuli were induced in healthy participants. FINDINGS: Participants who were more specific in their memories regarding itch and who had lesser negative itch-related expectations for the future were more likely to be placebo itch responders. There were no significant differences in effects between the nocebo responders and nonresponders. IMPLICATIONS: The adapted tasks for assessing cognitive (memory and expectations) schemas on itch seem promising in explaining interindividual differences in placebo itch responding. Future research should investigate whether similar mechanisms apply to patients with chronic itch. This knowledge can be used for identifying patients who will benefit most from the placebo component of a treatment. PMID- 28341523 TI - Intracranial stents in the endovascular treatment of acute ischemic stroke. AB - OBJECTIVE: To evaluate the efficacy and safety of intracranial stenting as a rescue therapy after failed mechanical thrombectomy in patients with acute ischemic stroke. MATERIAL AND METHODS: We retrospectively studied 42 patients treated with intracranial stenting after failed mechanical thrombectomy between December 2008 and January 2016. We compared outcomes before and after the incorporation of stentrievers. We assessed the degree of recanalization in the carotid and basilar territories (modified TIMI score), prognostic factors, and outcome (modified Rankin Score at 3 months). Safety was evaluated in function of the appearance of symptomatic intracranial hemorrhage (SICH). RESULTS: Median NIHSS was 17 in patients with carotid territory strokes and 26 in those with vertebrobasilar territory strokes. Median time from onset of symptoms to treatment was 225minutes in carotid territory strokes and 390minutes in vertebrobasilar territory strokes. A total of 10 patients underwent intravenous fibrinolytic therapy before treatment with stentrievers. Two patients developed SICH; both had undergone intravenous fibrinolytic therapy (p=0.0523). Recanalization was effective in 30 (71.4%) in the entire series: in 7 (50%) of 14 patients treated before the incorporation of stentrievers and in 23 (82.1%) of 28 treated after the incorporation of stentrievers (p=0.0666). Outcome at 3 months was good in 2 (14.3%) patients in the earlier group and in 14 (50%) patients in the later group (p=0.042). We found significant associations between recanalization and outcome (p=0.0415) and between shorter time to treatment and outcome (p=0.002). Outcome was good in 14 (48.3%) of the 29 patients with carotid territory strokes and in 2 (15.4%) of the 13 patients with vertebrobasilar territory strokes (p=0.078). CONCLUSIONS: Intracranial stenting is the rescue treatment when the usual treatment fails. Stentrievers must be used to eliminate the clot burden before stenting. In our study, antiplatelet treatment did not seem to increase the risk of SICH except in patients with prior intravenous fibrinolytic treatment. PMID- 28341524 TI - A Clinical Care Algorithmic Toolkit for Promoting Screening and Next-Level Assessment of Pediatric Depression and Anxiety in Primary Care. AB - With a documented shortage in youth mental health services, pediatric primary care (PPC) providers face increased pressure to enhance their capacity to identify and manage common mental health problems among youth, such as anxiety and depression. Because 90% of U.S. youth regularly see a PPC provider, the primary care setting is well positioned to serve as a key access point for early identification, service provision, and connection to mental health services. In the context of task shifting, we evaluated a quality improvement project designed to assist PPC providers in overcoming barriers to practice-wide mental health screening through implementing paper and computer-assisted clinical care algorithms. PPC providers were fairly successful at changing practice to better address mental health concerns when equipped with screening tools that included family mental health histories, next-level actions, and referral options. Task shifting is a promising strategy to enhance mental health services, particularly when guided by computer-assisted algorithms. PMID- 28341525 TI - Two-Year Follow-Up Outcomes of Premature Infants Enrolled in the Phase I Trial of Mesenchymal Stem Cells Transplantation for Bronchopulmonary Dysplasia. AB - OBJECTIVE: To determine the long-term safety and outcomes of mesenchymal stem cells (MSCs) for bronchopulmonary dysplasia in premature infants enrolled in a previous phase I clinical trial up to 2 years of corrected age (CA). STUDY DESIGN: We assessed serious adverse events, somatic growth, and respiratory and neurodevelopmental outcomes at visit 1 (4-6 months of CA), visit 2 (8-12 months of CA), and visit 3 (18-24 months of CA) in a prospective longitudinal follow-up study up to 2 years' CA of infants who received MSCs (MSC group). We compared these data with those from a historical case-matched comparison group. RESULTS: One of 9 infants in the MSC group died of Enterobacter cloacae sepsis at 6 months of CA, the remaining 8 infants survived without any transplantation-related adverse outcomes, including tumorigenicity. No infant in the MSC group was discharged with home supplemental oxygen compared with 22% in the comparison group. The average rehospitalization rate in the MSC group was 1.4/patient because of respiratory infections during 2 years of follow-up. The mean body weight of the MSC group at visit 3 was significantly higher compared with that of the comparison group. No infant in the MSC group was diagnosed with cerebral palsy, blindness, or developmental delay; in the comparison group, 1 infant was diagnosed with cerebral palsy and 1 with developmental delay. CONCLUSIONS: Intratracheal transplantation of MSCs in preterm infants appears to be safe, with no adverse respiratory, growth, and neurodevelopmental effects at 2 years' CA. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01632475. PMID- 28341526 TI - Getting Published: A Primer on Manuscript Writing and the Editorial Process. PMID- 28341528 TI - Molecular diagnosis of allergy to Anisakis simplex and Gymnorhynchus gigas fish parasites. AB - BACKGROUND: There has been an increase in the prevalence of hypersensitivity to Anisakis simplex. There are fish parasites other than Anisakis simplex whose allergenicity has not yet been studied. OBJECTIVE: To assess IgE hypersensitivity caused by fish parasite allergens in patients with gastro-allergic symptoms after consumption of fish, shellfish or cephalopods, compared with healthy subjects, pollen allergic individuals and children with digestive symptoms after eating marine food. METHODS: We carried out in vivo tests (skin prick) and in vitro tests (specific IgE determination, Western blot) and component resolved diagnostics (CRD) using microarray analysis in all patients. RESULTS: CRD better detected sensitisation to allergens from marine parasites than skin prick tests and determination of specific IgE by CAP. Sensitisation to Gymnorhynchus gigas was detected in 26% of patients measured by skin prick tests and 36% measured by IgE. CONCLUSIONS: The prevalence of hypersensitivity to marine parasite allergens other than Anisakis simplex should be studied, and the most appropriate technique for this is CRD. PMID- 28341529 TI - Radiation enteritis diagnosed through capsule endoscopy, an uncommon cause of iron-deficiency anemia. PMID- 28341530 TI - Thoracic Endovascular Aortic Repair for Type B Acute Aortic Dissection Complicated by Descending Thoracic Aneurysm. AB - OBJECTIVES: To analyse the results and review the literature about thoracic aortic endovascular repair (TEVAR) for type B acute aortic dissection (TBAAD) complicated by descending thoracic aortic aneurysm (DTA) in the hyperacute or acute phases. METHODS: This was a multicentre, observational descriptive study. Inclusion criteria were TBAAD with a DTA of >=50 mm, TBAAD on an already known aneurysmal descending thoracic aorta, and TBAAD presenting with an enlarged aorta with a total diameter <50 mm, but with >50% diameter increase compared with a previous computed tomography angiography (CTA) showing a non-dissected aorta with normal sizing. Primary endpoints were early and long-term survival, freedom from TEVAR and aortic related mortality (ARM), and freedom from re-intervention. RESULTS: Twenty-two patients were included in the analysis. The mean aortic diameter was 66 +/- 26 mm (range 42-130; IQR 51-64). The in hospital TEVAR related mortality was 14% (n = 3). The mean radiological follow-up was 56 +/- 45 months (range 6-149; IQR 12-82), and the follow-up index 0.97 +/- 0.1. All surviving patients were available for follow-up. During follow-up the cumulative mortality was 26% (n = 5) and TEVAR related mortality was 5% (n = 1). Overall the estimate of survival was 82% (95%CI: 61.5-93) at 1 year, and 64% at 5 years. Ongoing primary clinical success was 79% (re-intervention n = 4). Freedom from aortic related mortality was 86% (95%CI: 66-95) at 1 and 5 year, while freedom from re-intervention was 95% (95%CI: 75.5-95) at 1 year, and 77% (95%CI: 50-92) at 5 years. CONCLUSIONS: In our experience, DTA is a frequent complication from the very beginning of the clinical onset of TBAAD. In this high-risk cohort, TEVAR showed satisfactory results, better than those predicted by the risk score for open repair, with favourable stability of the aortic diameter and no aortic related adverse events during follow-up. PMID- 28341527 TI - The Relationship of Maternal Prepregnancy Body Mass Index and Pregnancy Weight Gain to Neurocognitive Function at Age 10 Years among Children Born Extremely Preterm. AB - OBJECTIVE: To assess the association between maternal prepregnancy body mass index and adequacy of pregnancy weight gain in relation to neurocognitive function in school-aged children born extremely preterm. STUDY DESIGN: Study participants were 535 ten-year-old children enrolled previously in the prospective multicenter Extremely Low Gestational Age Newborns cohort study who were products of singleton pregnancies. Soon after delivery, mothers provided information about prepregnancy weight. Prepregnancy body mass index and adequacy of weight gain were characterized based on this information. Children underwent a neurocognitive evaluation at 10 years of age. RESULTS: Maternal prepregnancy obesity was associated with increased odds of a lower score for Differential Ability Scales-II Verbal IQ, for Developmental Neuropsychological Assessment-II measures of processing speed and visual fine motor control, and for Wechsler Individual Achievement Test-III Spelling. Children born to mothers who gained an excessive amount of weight were at increased odds of a low score on the Oral and Written Language Scales Oral Expression assessment. Conversely, children whose mother did not gain an adequate amount of weight were at increased odds of a lower score on the Oral and Written Language Scales Oral Expression and Wechsler Individual Achievement Test-III Word Reading assessments. CONCLUSION: In this cohort of infants born extremely preterm, maternal obesity was associated with poorer performance on some assessments of neurocognitive function. Our findings are consistent with the observational and experimental literature and suggest that opportunities may exist to mitigate risk through education and behavioral intervention before pregnancy. PMID- 28341532 TI - The Importance of Peer Review. PMID- 28341531 TI - Urease activity as an index for assessing the maturity of cow manure and wheat residue vermicomposts. AB - The establishment of a reliable index is an essential need to assess the degree of stability and maturity of solid wastes vermicomposts. The objective of this study was to investigate the effects of vermicomposting process on some chemical (pH, EC, OC, TN, lignin and C:N ratio) and biochemical properties of the cow manure (CM) and wheat residue (WR). Results demonstrated that during vermicomposting process of CM and WR urease activity was highly correlated with the time of vermicomposting (r=-0.97** for CM and r=-0.99** for WR), and well able to show the stability of organic waste. The urease activity showed significant correlations with the C:N ratio during the vermicomposting of CM and WR (r=0.89* and r=0.93** respectively) therefore it can be considered as a reliable indicator for determining the maturity and stability of organic wastes during vermicomposting process. PMID- 28341533 TI - Epidemiology of infectious encephalitis causes in 2016. AB - We performed a literature search in the Medline database, using the PubMed website. The incidence of presumably infectious encephalitis is estimated at 1.5 7 cases/100,000 inhabitants/year, excluding epidemics. Infectious encephalitis and immune-mediated encephalitis share similar clinical signs and symptoms. The latter accounts for a significant proportion of presumably infectious encephalitis cases without any established etiological diagnosis; as shown from a prospective cohort study where 21% of cases were due to an immune cause. Several infectious agents are frequently reported in all studies: Herpes simplex virus (HSV) is the most frequent pathogen in 65% of studies, followed by Varicella zoster virus (VZV) in several studies. Enteroviruses are also reported; being the most frequent viruses in two studies, and the 2nd or 3rd viruses in five other studies. There are important regional differences, especially in case of vector borne transmission: Asia and the Japanese encephalitis virus, Eastern and Northern Europe/Eastern Russia and the tick-borne encephalitis virus, Northern America and Flavivirus or Alphavirus. Bacteria can also be incriminated: Mycobacterium tuberculosis and Listeria monocytogenes are the most frequent, after HSV and VZV, in a French prospective study. The epidemiology of encephalitis is constantly evolving. Epidemiological data may indicate the emergence and/or dissemination of new causative agents. The dissemination and emergence of causative agents are fostered by environmental, social, and economical changes, but prevention programs (vaccination, vector controls) help reduce the incidence of other infectious diseases and associated encephalitis (e.g., measles). PMID- 28341534 TI - The Declaration of Rabat: An update. PMID- 28341535 TI - As a Nucleus Enters a Small Pore, Chromatin Stretches and Maintains Integrity, Even with DNA Breaks. AB - As a cell pushes or pulls its nucleus through a small constriction, the chromatin must distort and somehow maintain genomic stability despite ever-present double strand breaks in the DNA. Here we visualize within a living cell the pore-size dependent deformation of a specific locus engineered into chromosome-1 and cleaved. An mCherry-tagged nuclease targets the submicron locus, causing DNA cleavage and recruiting repair factors such as GFP-53BP1 to a large region around the locus. Aspiration of a cell and its nucleus into a micropipette shows that chromatin aligns and stretches parallel to the pore. Extension is largest in small pores, increasing >10-fold but remaining 30-fold shorter than the DNA contour length in the locus. Brochard and de Gennes' blob model for tube geometry fits the data, with a simple modification for chromatin crowding. Continuity of the highly extended, cleaved chromatin is also maintained, consistent with folding and cross bridging of the DNA. Surprisingly, extensional integrity is unaffected by an inhibitor of the DNA repair scaffold. PMID- 28341536 TI - The role of cPLA2 in Methylglyoxal-induced cell apoptosis of HUVECs. AB - Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is mainly formed as a byproduct of glycolysis. Elevated MGO level is known to induce apoptosis of vascular endothelial cells, which is implicated with progression of atherosclerosis and diabetic complications. However, the underlying mechanisms have not been exhaustively investigated yet. Here, we further characterized the mechanisms how MGO induced apoptosis in human umbilical vein endothelial cells (HUVECs). Our data revealed that cytosolic phospholipase A2 (cPLA2) played an important role in MGO-induced cell apoptosis. It was found that MGO could increase both the activity and expression of cPLA2. Inhibition of cPLA2 by Pyrrophenone (PYR) or siRNA significantly attenuated the MGO-induced apoptosis. Additionally, MGO time-dependently decreased the phosphorylation of nuclear factor kappaB (NF-kappaB). Pretreatment of the cells with NF-kappaB inhibitor, BAY11-7082, further increased MGO-induced apoptosis of HUVECs, indicating that NF kappaB played a survival role in this MGO-induced apoptosis. Furthermore, in the presence of si-cPLA2 or PYR, MGO no longer decreased NF-kappaB phosphorylation. Beyond that, the antioxidant N-acetyl cysteine (NAC) could reverse the changes of both cPLA2 and NF-kappaB caused by MGO. p38, the upstream of cPLA2, was also significantly phosphorylated by MGO. However, p38 inhibitor failed to reverse the apoptosis induced by MGO. This study gives an important insight into the downstream signaling mechanisms of MGO, cPLA2-NF-kappaB, in endothelial apoptosis. PMID- 28341537 TI - Interleukin-6 expression in disc derangement of human temporomandibular joint and association with osteoarthrosis. AB - The inflammatory process is a coordinated response that protects host after infection or trauma, involving several molecular reactions. Once the inflammation is closely linked to the process of destruction of the temporomandibular joint, this study aims to examine, by immunohistochemistry, the expression of interleukin-6 (IL-6), an important inflammatory marker, in temporomandibular articular discs of patients with anterior disc displacement with (ADDwR) and without reduction (ADDwoR) and its association with osteoarthrosis (OA). Thirty eight (n = 38) articular discs were divided into two cutoffs: 1) analysis 1: 4 control (acute pathology), 17 ADDwR, 17 ADDwoR; and 2) analysis 2: without OA (n = 21) and with OA (n = 17). The area of immunostaining was compared statistically between groups (p < 0.05). In the disc samples, no significant differences were observed between the groups ADDwR and ADDwoR, and with and without OA, in respect to the expression of IL-6 by immunohistochemical examination. Future studies should be conducted with a larger sample size, which could clarify the association of the inflammatory mediator IL-6 with temporomandibular joint dysfunction. PMID- 28341538 TI - The differential impact of oxytocin receptor gene in violence-exposed boys and girls. AB - Childhood violence exposure is a prevalent public health problem. Understanding the lasting impact of violence requires an enhanced appreciation for the complex effects of violence across behavioral, physiologic, and molecular outcomes. This subject matched, cross-sectional study of 80 children explored the impact of violence exposure across behavioral, physiologic, and cellular outcomes. Externalizing behavior, diurnal cortisol rhythm, and telomere length (TL) were examined in a community recruited cohort of Black youth. Given evidence that genetic variation contributes to individual differences in response to the environment, we further tested whether a polymorphism in the oxytocin receptor gene (OXTR rs53576) moderated associations between violence and youth outcomes. Exposure to violence was directly associated with increased externalizing behavior, but no direct association of violence was found with cortisol or TL. Oxytocin genotype, however, moderated the association between violence and both cortisol and TL, suggesting that pathways linked to oxytocin may contribute to individual differences in the physiologic and molecular consequences of violence exposure. Sex differences with OXTR in cortisol and TL outcomes were also detected. Taken together, these findings suggest that there are complex pathways through which violence exposure impacts children, and that these pathways differ by both genetic variation and the sex of the child. PMID- 28341539 TI - Functional results in endoscopic Zenker's diverticulum surgery. AB - OBJECTIVES: The main objective of this retrospective study was to assess functional results in endoscopic Zenker's diverticulum surgery. The secondary objectives were to assess safety, identify recurrence risk factors, and determine optimal management of recurrence. MATERIAL AND METHODS: From 2000 to 2014, 50 patients underwent endoscopic surgery for marsupialization of Zenker's diverticulum. Regurgitation and dysphagia were assessed on the FOIS scale, pre- and post-operatively. Recurrences and complications rates were determined retrospectively at a minimum 18 months' follow-up. RESULTS: Regurgitation and dysphagia improved in respectively 96% and 86% of patients. There was a 12% rate of complications, mostly minor. Mean hospital stay and time to return to oral feeding were 2.0 and 1.3 days respectively. Nine patients (18%) showed recurrence of symptoms, requiring revision surgery at a mean 2.7 years, performed endoscopically in the majority of cases. Only one recurrence risk factor was identified: small diverticulum size. CONCLUSION: Endoscopic Zenker's diverticulum surgery provided functional improvement in most cases. Safe and effective, it is currently the treatment of choice for Zenker's diverticulum. PMID- 28341540 TI - Clinical meaningfulness of Alzheimer's Disease Assessment Scale-Cognitive subscale change in relation to goal attainment in patients on cholinesterase inhibitors. AB - INTRODUCTION: The clinical meaningfulness of Alzheimer's Disease Assessment Scale Cognitive subscale (ADAS-Cog) subscale change is disputed. We compared 2- to 4 point ADAS-Cog changes with changes in Goal Attainment Scaling (GAS) and everyday function across initial ADAS-Cog scores and treatment responses. METHODS: This exploratory analysis evaluated mild-moderate Alzheimer's disease patients treated with donepezil (12 months) or galantamine (8 months). Clinical meaningfulness was defined as concomitant ADAS-Cog and GAS changes of +/-3 points and/or functional improvement. RESULTS: Patients with >=3-point ADAS-Cog improvement significantly improved on GAS but not on standard tests of everyday function. ADAS-Cog "no change" (<=+/-3 points) was seen with mean GAS improvement. Initial ADAS-Cog improvement made endpoint improvement (ADAS-Cog 3 points and GAS 1 point) more likely (odds ratio = 6.9; 95% confidence interval = 2.5-19.5). In contrast, initial deterioration made endpoint improvement unlikely (0.33; 0.14-0.64). DISCUSSION: ADAS-Cog improvement and no change were each associated with GAS improvement. Initial ADAS-Cog worsening was unlikely to result in later improvement. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN26167328. PMID- 28341541 TI - Pro-resolving actions of SPM in adipose tissue biology. AB - White adipose tissue plays an important endocrine role in balancing metabolic homeostasis. During conditions of nutrient excess, as occurs in obesity, there is an expansion of adipose tissue mass associated with a state of "low-grade" inflammation in this tissue. This chronic, unresolved inflammation of adipose tissue is deleterious and leads to many pathological sequelae associated with obesity including insulin resistance, type 2 diabetes and non-alcoholic fatty liver disease. Recently, a novel genus of anti-inflammatory and pro-resolving lipid mediators endogenously generated from membrane phospholipid-derived polyunsaturated fatty acids has been identified during the resolution phase of acute inflammation. These molecules have been termed specialized pro-resolving mediators and act not only as "stop-signals" of inflammatory response but also as facilitators of timely resolution of inflammation. In this review, we provide a comprehensive description of the role of these specialized pro-resolving mediators as endogenous counter-regulators of the persistent inflammatory status present in white adipose tissue of obese individuals. In addition, we discuss the potentiality of these molecules as a novel therapy for the prevention of metabolic co-morbidities associated with obesity. PMID- 28341542 TI - QT spatial dispersion and sudden cardiac death in hypertrophic cardiomyopathy: Time for reappraisal. AB - BACKGROUND: The 12-lead surface electrocardiographic (ECG) analysis is able to provide independent predictors of prognosis in several cardiovascular settings, including hypertrophic cardiomyopathy (HCM). The present single-center study investigated the possible ability of several ECG-derived variables in stratifying sudden cardiac death (SCD) risk and, possibly, in improving the accuracy of the 2014 European Society of Cardiology guidelines. METHODS: A total of 221 consecutive HCM outpatients were recruited and prospectively followed. All of them underwent a full clinical and instrumental examination, including a 12-lead surface ECG to calculate the dispersion for the following intervals: QRS, Q-Tend (QT), Q-Tpeak (QTp), Tpeak-Tend (TpTe), J-Tpeak (JTp), and J-Tend (JT). The study composite end-point was SCD, aborted SCD, and appropriate implantable cardioverter defibrillator (ICD) interventions. RESULTS: During a median follow up of 4.4 years (25th-75th interquartile range: 2.4-9.4 years), 23 patients reached the end-point at 5-years (3 SCD, 3 aborted SCD, 17 appropriate ICD interventions). At multivariate analysis, the spatial QT dispersion corrected according to Bazett's formula (QTcd) remains independently associated to the study endpoint over the HCM Risk-SCD score (C-index 0.737). A QTcd cut-off value of 93ms showed the best accuracy in predicting the SCD endpoint within the entire HCM study cohort (sensitivity 56%, specificity 75%, positive predictive value 22%, negative predictive value 97%). CONCLUSION: Our data suggest that the QTcd might be helpful in SCD risk stratification, particularly in those HCM categories classified at low-intermediate SCD risk according to the contemporary guidelines. PMID- 28341543 TI - Long-term prognostic impact of the Great East Japan Earthquake in patients with cardiovascular disease - Report from the CHART-2 Study. AB - BACKGROUND: We and others have previously reported that the Great East Japan Earthquake (GEJE) caused a significant but transient increase in cardiovascular diseases and deaths in the disaster area. However, it remains to be examined whether the GEJE had a long-term prognostic influence in large-scale cohort studies. This point is important when analyzing the data before and after the GEJE in the cohort studies in the disaster area. METHODS: We examined 8676 patients registered in our Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study (N=10,219) between 2006 and 2010 and were alive after March 10, 2011. RESULTS: There were 48 GEJE-related deaths, causing a sharp and transient increase in all-cause death within a month after the GEJE. However, after excluding the GEJE-related deaths, the cubic polynomial spline smoothing showed no significant increase in all-cause death, heart failure admission, non fetal acute myocardial infarction, or non-fetal stroke during the median 3-year follow-up after the GEJE. The extrapolation curves beyond the GEJE, which were obtained by the parametric survival models based on the survival data censored on the GEJE, were not significantly different from the Kaplan-Meier curves estimating the survival functions of deaths and cardiac events during the total follow-up period without considering the impacts of the GEJE. Furthermore, the multivariate Cox proportional hazard model applied to the matched cohort of the baseline data and the data after the GEJE showed no significant differences in the impacts of prognostic factors on all-cause mortality before and after the GEJE. CONCLUSIONS: These results indicate that the GEJE had no significant long term prognostic impact after the earthquake in cardiovascular patients in the disaster area. PMID- 28341544 TI - Echocardiographic assessment of right ventricular function in routine practice: Which parameters are useful to predict one-year outcome in advanced heart failure patients with dilated cardiomyopathy? AB - BACKGROUND: Right ventricular (RV) function has recently gained attention as a prognostic predictor of outcome even in patients who have left-sided heart failure. Since several conventional echocardiographic parameters of RV systolic function have been proposed, our aim was to determine if any of these parameters (tricuspid annular plane systolic excursion: TAPSE, tissue Doppler derived systolic tricuspid annular motion velocity: S', fractional area change: FAC) are associated with outcome in advanced heart failure patients with dilated cardiomyopathy (DCM). METHODS: We retrospectively enrolled 68 DCM patients, who were New York Heart Association (NYHA) Class III or IV and had a left ventricular (LV) ejection fraction <35%. All patients were undergoing evaluation for heart transplantation or management of heart failure. Primary outcomes were defined as LV assist device implantation or cardiac death within one year. RESULTS: Thirty nine events occurred (5 deaths, 32 LV assist devices implanted). Univariate analysis showed that age, systolic blood pressure, heart rate, NYHA functional class IV, plasma brain natriuretic peptide concentration, intravenous inotrope use, left atrial volume index, and FAC were associated with outcome, whereas TAPSE and S' were not. Receiver-operating characteristic curve analysis showed that the optimal FAC cut-off value to identify patients with an event was <26.7% (area under the curve=0.74). The event-free rate determined by Kaplan-Meier analysis was significantly higher in patients with FAC>=26.7% than in those with FAC<26.7% (log-lank, p=0.0003). Moreover, the addition of FAC<26.7% improved the prognostic utility of a model containing clinical variables and conventional echocardiographic indexes. CONCLUSIONS: FAC may provide better prognostic information than TAPSE or S' in advanced heart failure patients with DCM. PMID- 28341545 TI - Novel putative Bluetongue virus in healthy goats from Sardinia, Italy. AB - In recent years, novel Bluetongue virus (BTV) serotypes have been isolated and/or sequenced by researchers within the field. During Bluetongue surveillance activities, we identified a putative novel BTV serotype in healthy goats from Sardinia, Italy. RNAs purified from blood and serum samples were positive for BTV by a generic real time RT-PCR and c-ELISA, respectively, whereas genotyping and serotyping were unsuccessful. By NGS, the whole genome sequence was obtained from two blood samples (BTV-X ITL2015 strains 34200 and 33531). Overall, Seg 2 of BTV X ITL2015 shows the highest identity (75.3-75.5% nt/77.4-78.1% aa) with recently isolated BTV-27s from Corsica and with the last discovered BTV XJ1407 from China (75.9% nt /78.2% aa), whereas it is less related with BTV-25 from Switzerland (73.0% nt/75.0% aa) and BTV-26 from Kuwait (62.0% nt/60.5% aa). A specific RT qPCR targeting Seg 2 of BTV-X ITL2015 was assessed in this study. Considering the Seg 2/VP2 identity of BTV-X ITL2015 with BTV-25, 26, 27s and BTV XJ1407 and that serum of BTV-X ITL2015 infected goats failed to neutralize all tested extant serotypes, we propose the existence of a novel BTV serotype circulating in goats in Sardinia. Isolation was so far unsuccessful thus hampering proper antigenic characterization. PMID- 28341546 TI - Co-circulation of two Usutu virus strains in Northern Italy between 2009 and 2014. AB - Usutu virus is an arbovirus closely related to West Nile virus (genus Flavivirus), which circulates between mosquitoes and wild birds. This virus has been increasingly reported in Europe, raising concerns for its possible pathogenic potential for wild birds and humans. This study reports the whole genome sequences of 15 strains of USUV, isolated between 2010 and 2014 from mosquitoes and wild birds in the course of West Nile virus surveillance in the Emilia-Romagna and Lombardy regions of Northern Italy. Both whole and 656 partial genome sequences, obtained from isolated viruses and field samples (mosquitoes and wild birds), were analyzed to describe the temporal and geographical spread of USUV in the surveyed area. The detected sequences belonged to two groups, with one circulating primarily in the northwestern part of the area and the other in the southeastern part. This pattern is likely the result of different routes of introduction from the North (over the Alps) and from the East, respectively. The phylogenetic analysis of obtained sequences and other European sequences demonstrated that the majority of European strains belonged to one main clade, while less common strains, mainly from Western Europe, fell in other two clades. This analysis strongly suggested an autochthonous evolution process of strains of the main clade from a common ancestor with an estimated time of arrival in Europe at the beginning of the 1990s. In addition to causing mass mortality in wild birds, Usutu virus can infect humans and can sporadically cause disease. These factors and the endemization of the Usutu virus in a large area of Europe, sustained by the obtained data, strongly support the need to adequately survey Usutu virus in areas in which its circulation is detected. PMID- 28341547 TI - Evaluation and rational design of guide RNAs for efficient CRISPR/Cas9-mediated mutagenesis in Ciona. AB - The CRISPR/Cas9 system has emerged as an important tool for various genome engineering applications. A current obstacle to high throughput applications of CRISPR/Cas9 is the imprecise prediction of highly active single guide RNAs (sgRNAs). We previously implemented the CRISPR/Cas9 system to induce tissue specific mutations in the tunicate Ciona. In the present study, we designed and tested 83 single guide RNA (sgRNA) vectors targeting 23 genes expressed in the cardiopharyngeal progenitors and surrounding tissues of Ciona embryo. Using high throughput sequencing of mutagenized alleles, we identified guide sequences that correlate with sgRNA mutagenesis activity and used this information for the rational design of all possible sgRNAs targeting the Ciona transcriptome. We also describe a one-step cloning-free protocol for the assembly of sgRNA expression cassettes. These cassettes can be directly electroporated as unpurified PCR products into Ciona embryos for sgRNA expression in vivo, resulting in high frequency of CRISPR/Cas9-mediated mutagenesis in somatic cells of electroporated embryos. We found a strong correlation between the frequency of an Ebf loss-of function phenotype and the mutagenesis efficacies of individual Ebf-targeting sgRNAs tested using this method. We anticipate that our approach can be scaled up to systematically design and deliver highly efficient sgRNAs for the tissue specific investigation of gene functions in Ciona. PMID- 28341548 TI - Cos2/Kif7 and Osm-3/Kif17 regulate onset of outer segment development in zebrafish photoreceptors through distinct mechanisms. AB - Zebrafish morphants of osm-3/kif17, a kinesin-2 family member and intraflagellar transport motor, have photoreceptor outer segments that are dramatically reduced in number and size. However, two genetic mutant lines, osm-3/kif17sa0119 and osm 3/kif17sa18340, reportedly lack any observable morphological outer segment defects. In this work, we use TALENs to generate an independent allele, osm 3/kif17mw405, and show that both osm-3/kif17sa0119 and osm-3/kif17mw405 have an outer segment developmental delay in both size and density that is fully recovered by 6 days post-fertilization. Additionally, we use CRISPRs to generate cos2/kif7mw406, a mutation in the kinesin-4 family member cos2/kif7 that has been implicated in controlling ciliary architecture and Hedgehog signaling to test whether it may be functioning redundantly with osm-3/kif17. We show that cos2/kif7mw406 has an outer segment developmental delay similar to the osm 3/kif17 mutants. Using a three-dimensional mathematical model of outer segments, we show that while cos2/kif7mw406 and osm-3/kif17mw405 outer segments are smaller throughout the first 6 days of development, the volumetric rates of outer segment morphogenesis are not different among wild-type, cos2/kif7mw406, and osm 3/kif17mw405 after 60hpf. Instead, our model suggests that cos2/kif7mw406 and osm 3/kif17mw405 impact outer segment morphogenesis through upstream events that that are different for each motor. In the case of cos2/kif7mw406 mutants, we show that early defects in Hedgehog signaling lead to a general, non-photoreceptor-specific delay of retinal neurogenesis, which in turn causes the secondary phenotype of delayed outer segment morphogenesis. In contrast, the osm-3/kif17mw405 outer segment morphogenesis delays are linked specifically to initial disc morphogenesis of photoreceptors rather than an upstream event. Further, we show that osm-3/kif17 mutant mice also exhibit a similarly delayed outer segment development, suggesting a role for osm-3/kif17 in early outer segment development that is conserved across species. In conclusion, we show that both osm-3/kif17 and cos2/kif7 have comparable outer segment developmental delays, although through independent mechanisms. PMID- 28341550 TI - Sphingosine's role in epithelial host defense: A natural antimicrobial and novel therapeutic. AB - Sphingosine is a natural sphingolipid found in membranes of all eukaryotic cells. In addition to its functions in cell signaling, sphingosine has broad-spectrum antimicrobial properties. Sphingosine's role as an antimicrobial is important in tissues such as the skin and respiratory epithelium. Reduction in the normal sphingosine level is associated with problems related to infection susceptibility. Therefore, exogenous sphingosine may be an effective antimicrobial therapeutic. Inhaled nebulized sphingosine has been shown to be effective at both preventing and treating pneumonia in multiple mouse models. We now show that inhaled sphingosine has low toxicity to the respiratory system, strengthening its case as an excellent candidate for a novel inhaled antimicrobial drug. PMID- 28341549 TI - A quantitative method for screening and identifying molecular targets for nanomedicine. AB - Identifying a molecular target is essential for tumor-targeted nanomedicine. Current cancer nanomedicines commonly suffer from poor tumor specificity, "off target" toxicity, and limited clinical efficacy. Here, we report a method to screen and identify new molecular targets for tumor-targeted nanomedicine based on a quantitative analysis. In our proof-of-principle study, we used comparative flow cytometric screening to identify ICAM-1 as a potential target for metastatic melanoma (MM). We further evaluated ICAM-1 as a MM targeting moiety by characterizing its (1) tumor specificity, (2) expression level, (3) cellular internalization, (4) therapeutic function, and (5) potential clinical impact. Quantitation of ICAM-1 protein expression on cells and validation by immunohistochemistry on human tissue specimens justified the synthesis of antibody-functionalized drug delivery vehicles, which were benchmarked against appropriate controls. We engineered ICAM-1 antibody conjugated, doxorubicin encapsulating immunoliposomes (ICAM-Dox-LPs) to selectively recognize and deliver doxorubicin to MM cells and simultaneously neutralize ICAM-1 signaling via an antibody blockade, demonstrating significant and simultaneous inhibitory effects on MM cell proliferation and migration. This paper describes a novel, quantitative metric system that identifies and evaluates new cancer targets for tumor-targeting nanomedicine. PMID- 28341551 TI - Augmenting the cytotoxicity of oleic acid-protein complexes: Potential of target specific antibodies. AB - HAMLET (Human Alpha-Lactalbumin Made LEthal to Tumor cells), a complex of oleic acid (OA) with partially unfolded human alpha-lactalbumin, shows remarkable toxicity towards a spectrum of tumor cells as well as few differentiated cells including mammalian erythrocytes. Human erythrocytes, for this reason, have been used as convenient model cells to study toxic properties of the OA complexes. The toxicity of HAMLET-like complexes, prepared using immunoglobulin gamma (IgG) isolated from the sera of rabbits immunized with human erythrocytes as well as those unimmunized, towards the red cells was investigated. The OA complex of the IgG prepared by the heat-treatment procedure comprised of protein monomers and oligomers with bound OA. The IgG in the complexes retained most secondary but only partial tertiary structure and complex formation with OA did not abolish the ability of anti-erythrocyte IgG to bind to the erythrocytes. Anti-erythrocyte IgG OA complexes were remarkably more hemolytic than those prepared using non specific IgG, while complexes prepared using affinity purified anti-erythrocyte IgG were most effective in hemolyzing the cells. The work suggests that antibodies that exhibit affinity towards target cells may be useful in the preparation of selective and highly toxic OA complexes for the cells. PMID- 28341553 TI - Spin polarisation with electron Bessel beams. AB - The theoretical possibility to use an electron microscope as a spin polarizer is studied. It turns out that a Bessel beam passing a standard magnetic objective lens is intrinsically spin polarized when post-selected on-axis. In the limit of infinitely small detectors, the spin polarisation tends to 100%. Increasing the detector size, the polarisation decreases rapidly, dropping below 10-4 for standard settings of medium voltage microscopes. For extremely low voltages, the Figure of Merit increases by two orders of magnitude, approaching that of existing Mott detectors. Our findings may lead to new desings of spin filters, an attractive option in view of its inherent combination with the electron microscope, especially at low voltage. PMID- 28341552 TI - Identification of a molecular signaling gene-gene regulatory network between GWAS susceptibility genes ADTRP and MIA3/TANGO1 for coronary artery disease. AB - Coronary artery disease (CAD) is the leading cause of death worldwide. GWAS have identified >50 genomic loci for CAD, including ADTRP and MIA3/TANGO1. However, it is important to determine whether the GWAS genes form a molecular network. In this study, we have uncovered a novel molecular network between ADTRP and MIA3/TANGO1 for the pathogenesis of CAD. We showed that knockdown of ADTRP expression markedly down-regulated expression of MIA3/TANGO1. Mechanistically, ADTRP positively regulates expression of PIK3R3 encoding the regulatory subunit 3 of PI3K, which leads to activation of AKT, resulting in up-regulation of MIA3/TANGO1. Both ADTRP and MIA3/TANGO1 are involved in endothelial cell (EC) functions relevant to atherosclerosis. Knockdown of ADTRP expression by siRNA promoted oxidized-LDL-mediated monocyte adhesion to ECs and transendothelial migration of monocytes, inhibited EC proliferation and migration, and increased apoptosis, which was reversed by expression of constitutively active AKT1 and MIA3/TANGO1 overexpression, while the over-expression of ADTRP in ECs blunted these processes. Knockdown of MIA3/TANGO1 expression also promoted monocyte adhesion to ECs and transendothelial migration of monocytes, and vice versa for overexpression of MIA3/TANGO1. We found that ADTRP negatively regulates the levels of collagen VII and ApoB in HepG2 and endothelial cells, which are downstream regulatory targets of MIA3/TANGOI. In conclusion, we have uncovered a novel molecular signaling pathway for the pathogenesis of CAD, which involves a novel gene-gene regulatory network. We show that ADTRP positively regulates PIK3R3 expression, which leads to activation of AKT and up-regulation of MIA3/TANGO1, thereby regulating endothelial cell functions directly relevant to atherosclerosis. PMID- 28341554 TI - Structure and chemistry of epitaxial ceria thin films on yttria-stabilized zirconia substrates, studied by high resolution electron microscopy. AB - We have applied aberration-corrected transmission electron microscopy (TEM) imaging and electron energy loss spectroscopy (EELS) to study the structure and chemistry of epitaxial ceria thin films, grown by pulsed laser deposition onto (001) yttria-stabilized zirconia (YSZ) substrates. There are few observable defects apart from the expected mismatch interfacial dislocations and so the films would be expected to have good potential for applications. Under high electron beam dose rate (above about 6000 e-/A2s) domains of an ordered structure appear and these are interpreted as being created by oxygen vacancy ordering. The ordered structure does not appear at lower lose rates (ca. 2600 e-/A2s) and can be removed by imaging under 1 mbar oxygen gas in an environmental TEM. EELS confirms that there is both oxygen deficiency and the associated increase in Ce3+ versus Ce4+ cations in the ordered domains. In situ high resolution TEM recordings show the formation of the ordered domains as well as atomic migration along the ceria thin film (001) surface. PMID- 28341555 TI - Enhanced thermal stability of a polymer solar cell blend induced by electron beam irradiation in the transmission electron microscope. AB - We show by in situ microscopy that the effects of electron beam irradiation during transmission electron microscopy can be used to lock microstructural features and enhance the structural thermal stability of a nanostructured polymer:fullerene blend. Polymer:fullerene bulk-heterojunction thin films show great promise for use as active layers in organic solar cells but their low thermal stability is a hindrance. Lack of thermal stability complicates manufacturing and influences the lifetime of devices. To investigate how electron irradiation affects the thermal stability of polymer:fullerene films, a model bulk-heterojunction film based on a thiophene-quinoxaline copolymer and a fullerene derivative was heat-treated in-situ in a transmission electron microscope. In areas of the film that exposed to the electron beam the nanostructure of the film remained stable, while the nanostructure in areas not exposed to the electron beam underwent large phase separation and nucleation of fullerene crystals. UV-vis spectroscopy shows that the polymer:fullerene films are stable for electron doses up to 2000kGy. PMID- 28341556 TI - Advanced electron holography techniques for in situ observation of solid-state lithium ion conductors. AB - Advanced techniques for overcoming problems encountered during in situ electron holography experiments in which a voltage is applied to an ionic conductor are reported. The three major problems encountered were 1) electric-field leakage from the specimen and its effect on phase images, 2) high electron conductivity of damage layers formed by the focused ion beam method, and 3) chemical reaction of the specimen with air. The first problem was overcome by comparing experimental phase distributions with simulated images in which three-dimensional leakage fields were taken into account, the second by removing the damage layers using a low-energy narrow Ar ion beam, and the third by developing an air-tight biasing specimen holder. PMID- 28341557 TI - Cathodoluminescence in the scanning transmission electron microscope. AB - Cathodoluminescence (CL) is a powerful tool for the investigation of optical properties of materials. In recent years, its combination with scanning transmission electron microscopy (STEM) has demonstrated great success in unveiling new physics in the field of plasmonics and quantum emitters. Most of these results were not imaginable even twenty years ago, due to conceptual and technical limitations. The purpose of this review is to present the recent advances that broke these limitations, and the new possibilities offered by the modern STEM-CL technique. We first introduce the different STEM-CL operating modes and the technical specificities in STEM-CL instrumentation. Two main classes of optical excitations, namely the coherent one (typically plasmons) and the incoherent one (typically light emission from quantum emitters) are investigated with STEM-CL. For these two main classes, we describe both the physics of light production under electron beam irradiation and the physical basis for interpreting STEM-CL experiments. We then compare STEM-CL with its better known sister techniques: scanning electron microscope CL, photoluminescence, and electron energy-loss spectroscopy. We finish by comprehensively reviewing recent STEM-CL applications. PMID- 28341558 TI - Biomethane: The energy storage, platform chemical and greenhouse gas mitigation target. AB - Results in three areas of anaerobic microbiology in which methane formation and utilization plays central part are reviewed. a.) Bio-methane formation by reduction of carbon dioxide in the power-to-gas process and the various possibilities of improvement of the process is a very intensively studied topic recently. From the numerous potential methods of exploiting methane of biological origin two aspects are discussed in detail. b.) Methane can serve as a platform chemical in various chemical and biochemical synthetic processes. Particular emphasis is put on the biochemical conversion pathways involving methanotrophs and their methane monooxygenase-catalyzed reactions leading to various small molecules and polymeric materials such as extracellular polysaccharides, polyhydroxyalkanoates and proteins. c.) The third area covered concerns methane consuming reactions and methane emission mitigation. These investigations comprise the anaerobic microbiology of ruminants and approaches to diminishing methane emissions from ruminant animals. PMID- 28341559 TI - [Moyamoya disease associated with kidney angiodysplasia in a child]. AB - INTRODUCTION: Moyamoya disease is a progressive, chronic occlusive vascular disease of the circle of Willis arteries leading to the development of collateral circulation to compensate the occlusion. CASE REPORT: An 11-year-old girl presented an abrupt loss of consciousness and a right-sided motor deficit. Clinical examination found hypertension with 220/120mmHg arterial blood pressure. Brain magnetic resonance imaging showed a large left hemispheric ischemic lesion. Cerebral arteriography demonstrated an abnormal anastomotic vascular network with fine arteriolar ends in several territories, with a "wisp of smoke" aspect arguing in favor of moyamoya disease. Renal arteriography revealed dysplasia of the upper polar branches of the right kidney. CONCLUSION: Moyamoya disease is a rare cause of stroke in children. Its association with renal angiodysplasia is unusual and may be responsible for malignant hypertension. Cognitive impairment and social dependence have recently been recognized as an important unresolved social issue. Affected children require medical-surgical, social, and psychological care. PMID- 28341560 TI - Showcasing Clinical Development and Production of Cellular Therapies. PMID- 28341561 TI - Duvoglustat HCl Increases Systemic and Tissue Exposure of Active Acid alpha Glucosidase in Pompe Patients Co-administered with Alglucosidase alpha. AB - Duvoglustat HCl (AT2220, 1-deoxynojirimycin) is an investigational pharmacological chaperone for the treatment of acid alpha-glucosidase (GAA) deficiency, which leads to the lysosomal storage disorder Pompe disease, which is characterized by progressive accumulation of lysosomal glycogen primarily in heart and skeletal muscles. The current standard of care is enzyme replacement therapy with recombinant human GAA (alglucosidase alfa [AA], Genzyme). Based on preclinical data, oral co-administration of duvoglustat HCl with AA increases exposure of active levels in plasma and skeletal muscles, leading to greater substrate reduction in muscle. This phase 2a study consisted of an open-label, fixed-treatment sequence that evaluated the effect of single oral doses of 50 mg, 100 mg, 250 mg, or 600 mg duvoglustat HCl on the pharmacokinetics and tissue levels of intravenously infused AA (20 mg/kg) in Pompe patients. AA alone resulted in increases in total GAA activity and protein in plasma compared to baseline. Following co-administration with duvoglustat HCl, total GAA activity and protein in plasma were further increased 1.2- to 2.8-fold compared to AA alone in all 25 Pompe patients; importantly, muscle GAA activity was increased for all co-administration treatments from day 3 biopsy specimens. No duvoglustat related adverse events or drug-related tolerability issues were identified. PMID- 28341562 TI - Deformable Discoidal Polymeric Nanoconstructs for the Precise Delivery of Therapeutic and Imaging Agents. AB - Over the last 15 years, a plethora of materials and different formulations have been proposed for the realization of nanomedicines. Yet drug-loading efficiency, sequestration by phagocytic cells, and tumor accumulation are sub-optimal. This would imply that radically new design approaches are needed to propel the clinical integration of nanomedicines, overcoming well-accepted cliches. This work briefly reviews the use of deformable discoidal nanoconstructs as a novel delivery strategy for therapeutic and imaging agents. Inspired by blood cell behavior, these nanoconstructs are designed to efficiently navigate the circulatory system, minimize sequestration by phagocytic cells, and recognize the tortuous angiogenic microvasculature of neoplastic masses. This article discusses the notion of nanoparticle margination and vascular adhesion, as well as advantages associated with deformable particles. Finally, details on the synthesis, physico-chemical properties, and in vivo characterization of discoidal polymeric nanoconstructs are provided, with particular emphasis on their ability to independently control size, shape, surface properties, and mechanical stiffness. These nanoconstructs could help in gaining a deeper understanding of the mechanisms regulating the behavior of nanomedicines and identifying optimal delivery strategies for patient-specific therapeutic interventions. PMID- 28341563 TI - Avoidance of On-Target Off-Tumor Activation Using a Co-stimulation-Only Chimeric Antigen Receptor. AB - Chimeric antigen receptors (CARs) combine T cell activation with antibody mediated tumor antigen specificity, bypassing the need for T cell receptor (TCR) ligation. A limitation of CAR technology is on-target off-tumor toxicity caused by target antigen expression on normal cells. Using GD2 as a model cancer antigen, we hypothesized that this could be minimized by using T cells expressing Vgamma9Vdelta2 TCR, which recognizes transformed cells in a major histocompatibility complex (MHC)-unrestricted manner, in combination with a co stimulatory CAR that would function independently of the TCR. An anti-GD2 CAR containing a solitary endodomain derived from the NKG2D adaptor DAP10 was expressed in Vgamma9Vdelta2+ T cells. Differential ligation of the CAR and/or TCR using antibody-coated beads showed that pro-inflammatory cytokine response depended on activation of both receptors. Moreover, in killing assays, GD2 expressing neuroblastoma cells that engaged the Vgamma9Vdelta2 TCR were efficiently lysed, whereas cells that expressed GD2 equivalently but did not engage the Vgamma9Vdelta2 TCR were untouched. Differentiation between X-on tumor and X-off tumor offers potential for safer immunotherapy and broader target selection. PMID- 28341564 TI - Systemic AAV Gene Therapy Close to Clinical Trials for Several Neuromuscular Diseases. PMID- 28341565 TI - Single pulse electrical stimulation and high-frequency oscillations, a complicated marriage. PMID- 28341566 TI - Vibration-induced nystagmus in patients with vestibular schwannoma: Characteristics and clinical implications. AB - OBJECTIVE: To investigate the clinical significance of vibration-induced nystagmus (VIN) in unilateral vestibular asymmetry and vestibular schwannoma. METHODS: Thirteen patients with vestibular schwannoma underwent the VIN test, in which stimulation was applied to the mastoid processes and sternocleidomastoid (SCM) muscles on the ipsilateral and contralateral sides of lesions. Preoperative VIN was measured, and changes in VIN were followed up for 6months after tumor removal. Significance of VIN was determined by evaluation of its sensitivity, correlation with vestibular function tests and tumor volume, and postoperative changes. RESULTS: The overall pre and postoperative sensitivities of VIN were 92.3% and 100%, respectively, considering stimulation at all four sites. Maximum slow-phase velocity (MSPV) of VIN was linearly correlated with caloric weakness and tumor volume, especially when stimulation was applied to the SCM muscle. Postoperative MSPV of VIN exhibited stronger linear correlation with postoperative changes in canal paresis value and inverse correlation with tumor size upon stimulation of the ipsilateral SCM muscle than upon stimulation of other sites. During the 6-month follow-up period, persistence of VIN without changes in MSPV was observed even after vestibular compensation. CONCLUSIONS: Evoking VIN by stimulation of the mastoid processes and SCM muscles is effective for detecting vestibular asymmetry. It could also help determine the degree of vestibular asymmetry and volume of vestibular schwannoma if stimulation is applied to the SCM muscle. SIGNIFICANCE: The results of this study could provide clues for the basic application of VIN in patients with vestibular loss and vestibular schwannoma. PMID- 28341567 TI - Can epileptiform abnormalities predict delayed cerebral ischemia in subarachnoid hemorrhage? PMID- 28341568 TI - A mathematical method for precisely calculating the radiographic angles of the cup after total hip arthroplasty. PMID- 28341569 TI - Oral exposure of pregnant rats to toxic doses of methylmercury alters fetal accumulation. AB - Methylmercury (CH3Hg+) is an environmental toxicant that may lead to significant pathologies in exposed individuals. The current study assessed the disposition and toxicological effects of 2.5 or 7.5mgkg-1 CH3Hg+, conjugated to cysteine (Cys; Cys-S-CH3Hg) and administered orally to pregnant and non-pregnant Wistar and TR- rats. Rats were euthanized on gestational day 20 and the content of mercury in each fetus, amniotic sac, and placenta was determined. The brain, liver, and kidneys were removed from each fetus for estimation of mercury content. From the dams, a sample of blood, kidneys, liver, and brain were removed at the time of euthanasia. The findings from this study indicate that pregnancy leads to significant changes in the handling of mercuric ions, particularly in the liver. Furthermore, there are significant differences in the handling of non nephrotoxic and nephrotoxic doses of Cys-S-CH3Hg by maternal and fetal organs. PMID- 28341570 TI - A study of the age-related effects of lactational atrazine exposure. AB - A growing number of reports have demonstrated that the widely-used herbicide Atrazine (ATR) can cause injury to dopamine (DA) neurons, but the exact mechanism remains unclear. In this study, we examined the effects of lactational ATR exposure in Sprague-Dawley rats on dopaminergic neuron health later in life. Compared with control rats, rats exposed to ATR during a critical period of neural development showed decreased striatal DA content and increased rates of DA turnover. The expression of Monoamine oxidase (MAO), which is associated with DA degradation, was up-regulated, and the expression of Vesicular Monoamine Transporter 2 (VMAT2), which is associated with DA transport, was down-regulated. The expression of transcription factor Nuclear Receptor Related Factor 1 (Nurr1), which is associated with DA neuron development, was down-regulated. Increased age (6-12 months old) increased the statistical significance of the differences of the above indicators in the ATR-treated rats compared to the control rats (P<0.05). Taken together, our results indicate that ATR exposure during the critical neural development period causes a down-regulation of Nurr1, which in turn affects Nurr1 target genes, including MAO, VMAT2 and DAT, which are involved in DA degradation and transport. Reduced expression of these genes impairs the capacity for vesicular storage or reuptake of DA, causing decreased levels of striatal DA, which can ultimately lead to DA neuron injury. DA neuron injuries become more severe over time, which suggests that aging can synergistically promote the ATR-associated DA neuron injuries. PMID- 28341571 TI - Alterations in prostate morphogenesis in male rat offspring after maternal exposure to Di-n-butyl-phthalate (DBP). AB - Prostate morphogenesis is regulated by androgens hormones and modulated by morphogenetic proteins such as Bone Morphogenetic Proteins (BMPs). This study aims to investigate the effects on prostate development in male offspring and differentiation after gestational and lactational maternal exposure to Di-n-butyl phthalate (DBP), an important environmental contamination. Pregnant Wistar rats received 100 or 500mg/kg of DBP (DBP100 and DBP500), by gavage, from gestation day 15 (GD15) until postnatal day 21 (PND21). The pups were euthanized on PND1 and PND21. Anogenital distance and testosterone levels decreased in animals from exposed mothers (DBP100 and 500) on PND1. A three-dimensional reconstruction model of the prostatic urethra showed reduction in the prostatic buds in the DBP500 group. AR expression and alpha-actin immunoreactivity decreased, and BMP-4 expression was lower on PND1 for DBP500. These results showed that DBP exposure, especially at a higher dose, delayed prostate morphogenesis by reducing the testosterone/AR axis and BMP-4 expression. PMID- 28341574 TI - Homozygous familial hypercholesterolaemia - Early recognition and early treatment improve outcomes. PMID- 28341573 TI - Quercetin alters uterine fluid volume and aquaporin (AQP) subunits (AQP-1, 2, 5 & 7) expression in the uterus in the presence of sex-steroids in rats. AB - : Effects of quercetin on uterine fluid volume and aquaporin (AQP) expression in the uterus were investigated. Estradiol (E) or estradiol followed by progesterone (E+P) were given to ovariectomised rats with or without quercetin (10, 50 or 100mg/kg/day) treatment. Uteri were harvested and its inner/outer circumference ratio was determined. AQP-1, 2, 5 and 7 mRNA and protein levels in uterus were quantified by Real-time PCR and Western blotting respectively. Protein distribution was observed by immunohistochemistry. Administration of quercetin in E-treated rats decreased the uterine fluid volume and uterine AQP-2 expression. In E+P-treated rats, administration of 100mg/kg/day quercetin increased uterine fluid volume, AQP-1 and 2 expression but decreased AQP-7 expression in uterus. AQP-1 was distributed in stromal blood vessels while AQP-2, 5 and 7 were distributed in uterine epithelium. CONCLUSIONS: Quercetin-induced changes in uterine fluid volume and AQP subunits expression in uterus could affect the uterine reproductive functions under different sex-steroid influence. PMID- 28341572 TI - Cell and region specificity of Aryl hydrocarbon Receptor (AhR) system in the testis and the epididymis. AB - Aryl hydrocarbon receptor (AhR) plays multiple important functions in adaptive responses. Exposure to AhR ligands may produce an altered metabolic activity controlled by the AhR pathways, and consequently affect drug/toxin responses, hormonal status and cellular homeostasis. This research revealed species-, cell- and region-specific pattern of the AhR system expression in the rat and human testis and epididymis, complementing the existing knowledge, especially within the epididymal segments. The study showed that AhR level in the rat and human epididymis is higher than in the testis. The downregulation of AhR expression after TCDD treatment was revealed in the spermatogenic cells at different stages and the epididymal epithelial cells, but not in the Sertoli and Leydig cells. Hence, this basic research provides information about the AhR function in the testis and epididymis, which may provide an insight into deleterious effects of drugs, hormones and environmental pollutants on male fertility. PMID- 28341575 TI - The use of a Colapinto TIPS Needle under cone-beam computed tomography guidance for true lumen re-entry in subintimal recanalization of chronic iliac artery occlusion. AB - BACKGROUND: To report the technique and clinical outcome of subintimal re-entry in chronic iliac artery occlusion by using a Colapinto transjugular intrahepatic portosystemic shunt (TIPS) needle under rotational angiography (cone-beam computed tomography; CT) imaging guidance. METHODS: Patients with chronic iliac artery occlusion with earlier failed attempts at conventional percutaneous recanalization during the past 5 years were enrolled in our study. In these patients, an ipsilateral femoral access route was routinely utilized in a retrograde fashion. A Colapinto TIPS Needle was used to aid the true lumen re entry after failed conventional intraluminal or subintimal guidewire and catheter based techniques. The puncture was directed under rotational angiography cone beam CT guidance to re-enter the abdominal aorta. Bare metallic stents 8-10 mm in diameter were deployed in the common iliac artery, and followed by balloon dilation. RESULTS: Ten patients (9 male; median age, 75 years) were included in our investigation. The average occlusion length was 10.2 cm (range, 4-15 cm). According to the Trans-Atlantic Inter-Society Consensus (TASC) II classification, there were five patients each with Class B and D lesions. Successful re-entry was achieved in all patients without procedure-related complications. The ankle brachial index (ABI) values increased from 0.38-0.79 to 0.75-1.28 after the procedure. Imaging follow-up (> 6 months) was available in six patients with patency of all stented iliac artery. Thereafter, no complaints of recurrent clinical symptoms occurred during the follow-up period. CONCLUSION: The use of Colapinto TIPS needle, especially under cone-beam CT image guidance, appears to be safe and effective to re-enter the true lumen in a subintimal angioplasty for a difficult chronic total iliac occlusion. PMID- 28341576 TI - Effectiveness of interventions to reduce household air pollution and/or improve health in homes using solid fuel in low-and-middle income countries: A systematic review and meta-analysis. AB - BACKGROUND: Cookstove intervention programs have been increasing over the past two (2) decades in Low and Middle Income Countries (LMICs) across the globe. However, there remains uncertainty regarding the effects of these interventions on household air pollution concentrations, personal exposure concentrations and health outcomes. OBJECTIVES: The primary objective was to determine if household air pollution (HAP) interventions were associated with improved indoor air quality (IAQ) in households in LMICs. Given the potential impact of HAP interventions on health, a secondary objective was to evaluate the effectiveness of HAP interventions to improve health in populations receiving these interventions. DATA SOURCES: OVID Medline, Ovid Embase, SCOPUS and PubMED were searched from their inception until December 2015 with no restrictions on study design. The WHO Global database of household air pollution measurements and Members' archives were also reviewed together with the reference lists of identified reviews and relevant articles. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTION: We considered randomized controlled trials, or non randomized control trials, or before-and-after studies; original studies; studies conducted in a LMIC (based on the United Nations Human Development Report released in March 2013 (World Bank, 2013); interventions that were explicitly aimed at improving IAQ and/or health from solid fuel use; studies published in a peer-reviewed journal or student theses or reports; studies that reported on outcomes which was indicative of IAQ or/and health. There was no restriction on the type of comparator (e.g. household receiving plancha vs. household using traditional cookstove) used in the intervention study. STUDY APPRAISAL AND SYNTHESIS METHODS: Five review authors independently used pre-designed data collection forms to extract information from the original studies and assessed risk of bias using the Effective Public Health Practice Project (EPHPP). We computed standardized weighted mean difference (SMD) using random-effects models. Heterogeneity was computed using the Q and I2-statistics. We examined the influence of various characteristics on the study-specific effect estimates by stratifying the analysis by population type, study design, intervention type, and duration of exposure monitoring. The trim and fill method was used to assess the potential impact of missing studies. RESULTS: Fifty-five studies met our a priori inclusion criteria and were included in the systematic review. Fifteen studies provided 43 effect estimates for our meta-analysis. The largest improvement in HAP was observed for average particulate matter (PM) (SMD=1.57) concentrations in household kitchens (1.03), followed by daily personal average concentrations of PM (1.18), and carbon monoxide (CO) concentrations in kitchens. With respect to personal PM, significant improvement was observed in studies of children (1.26) and studies monitoring PM for >=24h (1.32). This observation was also noted in terms of studies of kitchen concentrations of CO. A significant improvement was also observed for kitchen levels of PM in both adult populations (1.56) and in RCT/cohort designs (1.59) involving replacing cookstoves without chimneys. Our findings on health outcomes were inconclusive. LIMITATIONS, CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: We observed high statistical between study variability in the study-specific estimate. Thus, care should be taken in concluding that HAP interventions - as currently designed and implemented - support reductions in the average kitchen and personal levels of PM and CO. Further, there is limited evidence that current stand-alone HAP interventions yield any health benefits. Post-intervention levels of pollutants were generally still greatly in excess of the relevant WHO guideline and thus a need to promote cleaner fuels in LMICs to reduce HAP levels below the WHO guidelines. SYSTEMATIC REVIEW REGISTRATION NUMBER: The review has been registered with PROSPERO (registration number CRD42014009768). PMID- 28341577 TI - Re: Zacho et al.: Unexplained Bone Pain Is an Independent Risk Factor for Bone Metastases in Newly Diagnosed Prostate Cancer: A Prospective Study (Urology 2017;99:148-154). PMID- 28341578 TI - The Utility of the Kidneys-ureters-bladder Radiograph as the Sole Imaging Modality and Its Combination With Ultrasonography for the Detection of Renal Stones. AB - OBJECTIVE: To investigate the efficacy of plain radiography and ultrasonography, each as the sole imaging tool as well as combined, for detecting renal stones using unenhanced computed tomography as a standard reference. Ultrasonography and plain radiography of the kidneys, ureters, and bladder are often used for urinary tract stone detection, but the effectiveness of each method used alone, or the 2 methods used together, remains controversial. MATERIALS AND METHODS: From January 2012 to September 2014, 822 patients underwent plain radiography, ultrasonography, and unenhanced computed tomography on the same day. The sensitivity and specificity of the 2 modalities to detect stones were evaluated. We compared the sizes of stones on plain radiography and ultrasonography with their size on unenhanced computed tomography. RESULTS: Of 1644 kidneys, unenhanced computed tomography detected at least 1 stone in 994 kidneys. Ultrasonography and plain radiography detected at least 1 stone in 882 and 488 kidneys, yielding a sensitivity of 88.7% and 49.1% and a specificity of 68.3% and 99.1%, respectively. Of 488 stones detected by plain radiography, 476 stones were also detected by ultrasound, with a sensitivity of 89.9% and specificity of 68.1% for the combination of the 2 modalities. The detection rate for plain radiography for stones <5 mm was low. Stone sizes measured by the 2 modalities positively correlated with those obtained by computed tomography, and the concordance rate based on size was similar. CONCLUSION: Plain radiography is of limited value for detecting small renal stones <5 mm. PMID- 28341579 TI - Beware the Looping Vas Deferens in Orchidopexy. AB - A looping vas deferens may be present in up to 20% of undescended testes located within or proximal to the inguinal canal. This associated abnormality is vulnerable to transection during orchidopexy. We present an example of a very long looping vas to emphasize the importance of inspection for this anomaly, and demonstrate the extreme extent that a looping vas may extend. Identification of the vas among cord structures may provide false reassurance of normal ductal anatomy. Examination for a looping vas by inspecting structures caudal to the testis should occur at an early opportunity during orchidopexy to avoid inadvertent transection. PMID- 28341580 TI - Efficacy and Safety of Sildenafil in Men With Sexual Dysfunction and Spinal Cord Injury. AB - INTRODUCTION: Spinal cord injury (SCI) is estimated to affect approximately 276,000 individuals in the United States. Since 2010, the mean age of individuals at the time of the SCI has been 42 years, with nearly 80% of cases involving men. This means that individuals with SCI generally are young men who typically place a great deal of importance on normal sexual and reproductive function. AIM: To assess the effect of sildenafil treatment on erectile function and the frequency of ejaculation in men with SCI. METHODS: This study was a post hoc analysis of pooled data from two randomized, double-blinded, placebo-controlled, flexible dose, crossover sildenafil trials conducted in Europe, Australia, and Turkey. Two hundred forty-eight men at least 18 years old with traumatic SCI of at least 6 months' duration, with erectile dysfunction solely attributed to SCI, and in a stable heterosexual relationship were treated sequentially with sildenafil and placebo. Exclusion criteria included taking nitrate therapy, severe cardiac failure, and recent stroke or myocardial infarction. The starting sildenafil dose was 50 mg, taken approximately 1 hour before sexual activity, with subsequent dose adjustment to 100 or 25 mg based on efficacy and safety during treatment. There was a 2-week washout between 6-week treatments. MAIN OUTCOME MEASURES: Change from baseline in International Index of Erectile Function question 3 (frequency of penetration), question 4 (maintaining erection after penetration), question 9 (frequency of ejaculation), and erectile function domain scores; intercourse success; and treatment preference. RESULTS: All International Index of Erectile Function outcomes, including achieving and maintaining erections and ejaculation frequency, were statistically significantly greater with sildenafil vs placebo, including the subgroup with complete SCI (P < .01 for all comparisons). The percentage of successful intercourse attempts with sildenafil (53% vs 12%) and preference for sildenafil (96% vs 4%) vs placebo were significant (P < .001), including the subgroup with complete SCI. The most common all-cause adverse events with sildenafil were headache (16.1%) and urinary tract infection (11.6%). CONCLUSION: Sildenafil significantly improves erections, intercourse success, and ejaculation frequency vs placebo, including in men with complete SCI. Sildenafil is an effective and well-tolerated treatment for sexual dysfunction in men with SCI. The increase in frequency of ejaculation could allow the possibility of having children without medical intervention in this patient population. Ohl DA, Carlsson M, Stecher VJ, Rippon GA. Efficacy and Safety of Sildenafil in Men With Sexual Dysfunction and Spinal Cord Injury. Sex Med Rev 2017;5:521-528. PMID- 28341581 TI - The Graham Jackson Memorial Lecture ISSM 2016-"The Man Who Knew Too Much": Time to Recognize Erectile Dysfunction and Low Testosterone as Independent Risk Factors for Cardiovascular Disease. AB - INTRODUCTION: Graham Jackson introduced the concept that erectile dysfunction (ED) is a marker for undiagnosed cardiovascular (CV) disease and future events. In the Princeton 3 guidelines, he recognized the important impact of testosterone deficiency (TD) on all-cause and CV mortality. Recent evidence suggests that testosterone therapy to target levels and for sufficient duration decreases CV events. Unfortunately, this had a modest impact on CV disease management because ED is not incorporated into current risk calculators. This report is based on the Graham Jackson Memorial Lecture presented at the International Society for Sexual Medicine (ISSM) in Beijing in 2016. AIM: To examine recent evidence as to whether ED should be upgraded to a risk factor, especially with the high predictive value in younger men, and to develop a case for TD to be considered an independent risk factor based on a large number of long-term studies during the past 5 years. METHODS: A Medline search was undertaken to include articles on ED and TD and related terms from 1998 to 2016 during the preparation of ISSM guidelines on ED and TD. MAIN OUTCOME MEASURES: A rational justification for ED and low testosterone to be considered risk factors for CV disease and be included in risk calculators. RESULTS: The evidence for inclusion of ED and TD might be stronger than for accepted risk factors and have the advantages of being easily assessed, quantitative, symptomatic, and clinically relevant, especially in younger men. Because important studies are often published in endocrine, sexual medicine, urology, and cardiology journals, a multidisciplinary approach is needed. CONCLUSION: There is strong evidence that ED and low testosterone might be of more practical relevance to programs that decrease CV risk than some current recognized risk factors. Hackett G. The Graham Jackson Memorial Lecture ISSM 2016 "The Man Who Knew Too Much": Time to Recognize Erectile Dysfunction and Low Testosterone as Independent Risk Factors for Cardiovascular Disease. Sex Med Rev 2017;5:256-265. PMID- 28341583 TI - A story of birth and death: Insights into the formation and dynamics of the microglial population. AB - Microglia are the main resident immunocompetent cells of the brain with key roles in brain development, homeostasis and function. Here we briefly review our current knowledge of the homeostatic mechanisms regulating the composition and turnover of the microglial population under physiological conditions from development to ageing. A greater understanding of these mechanisms may inform understanding of how dysregulation of microglial dynamics could contribute to the pathogenesis and/or progression of neurological disorders. PMID- 28341582 TI - Sex differences in microglial phagocytosis in the neonatal hippocampus. AB - Microglia regulate brain development through many processes, such as promoting neurogenesis, supporting cell survival, and phagocytizing progenitor, newly-born, and dying cells. Many of these same developmental processes show robust sex differences, yet very few studies have assessed sex differences in microglia function during development. Hormonally-induced sexual differentiation of the brain occurs during the perinatal period, thus we examined sex differences in microglial morphology, phagocytosis, and proliferation in the hippocampus during the early postnatal period. We found that the neonatal female hippocampus had significantly more microglia with phagocytic cups than the male hippocampus. We subsequently found that female microglia phagocytized more neural progenitor cells and healthy cells compared to males, but there were no sex differences in the number of newly-born or dying cells targeted by microglial phagocytosis. We found that the number of phagocytic microglia in females was reduced to male typical levels by treatment with estradiol, the hormone responsible for masculinizing the rodent brain. Females also had higher expression of several phagocytic pathway genes in the hippocampus compared to males. In contrast to robust sex differences in phagocytic microglia, we found no sex differences in the number of microglia with amoeboid, transitioning, or ramified morphologies or differences in three-dimensional reconstructions of microglial morphology. While we did not find a baseline sex difference in microglial proliferation during or following the prenatal gonadal hormone surge in males, we found that estradiol treatment increased microglia proliferation in females. Overall, these data show that there are important sex differences in microglia function in the hippocampus during the early neonatal period. PMID- 28341584 TI - Development of videogrammetry as a tool for gas-particle fluidization research. AB - Many industries use fluidization of solid particles for energy efficiency or environmental friendly process development, and this paper introduces research techniques developed for investigating gas-particle systems At present there is plenty of room for refining gas-particle fluidization process. With the rapidly rising application of mathematical modelling, real time visualization of processes will be widely used for validation of those models in the near future. In presented research, photogrammetry, as a part of close range vision metrology, has been expanded to allow dynamic space and time analysis of the phase concentration distribution inside fluidization devices. A novel videogrammetry method was created with additional stochastic process analysis for detailed frequency and amplitude characteristics. Videogrammetry was used for the assessment of flow regimes, which were held in various types of fluidization apparatuses. Classic bubbling, jet-spouted and fast circulating fluidization processes were explored under the investigation. Videogrammetry is non-invasive flow regime recognition method, which enables detailed research of gas-particle fluidization phenomena. Until now, there were no comparative studies for three different types of fluidization processes with the use of one complex approach. Developed videogrammetric method consists of the flow structure visualization and dynamic image analysis. The analysed feature is the grey level of the image in time domain, and grey level signals were analysed with the use of autocorrelation function and power density function. The results are presented as images, plots and a flow map. Efficiency of the method was tested by comparison of real observed flow structures to the reconstructed flow structures and the recognition accuracy reached 92%. PMID- 28341585 TI - The experiences of last-year student midwives with High-Fidelity Perinatal Simulation training: A qualitative descriptive study. AB - BACKGROUND: Simulation training is a powerful and evidence-based teaching method in healthcare. It allows students to develop essential competences that are often difficult to achieve during internships. High-Fidelity Perinatal Simulation exposes them to real-life scenarios in a safe environment. Although student midwives' experiences need to be considered to make the simulation training work, these have been overlooked so far. AIM: To explore the experiences of last-year student midwives with High-Fidelity Perinatal Simulation training. METHODS: A qualitative descriptive study, using three focus group conversations with last year student midwives (n=24). Audio tapes were transcribed and a thematic content analysis was performed. The entire data set was coded according to recurrent or common themes. To achieve investigator triangulation and confirm themes, discussions among the researchers was incorporated in the analysis. FINDINGS: Students found High-Fidelity Perinatal Simulation training to be a positive learning method that increased both their competence and confidence. Their experiences varied over the different phases of the High-Fidelity Perinatal Simulation training. Although uncertainty, tension, confusion and disappointment were experienced throughout the simulation trajectory, they reported that this did not affect their learning and confidence-building. CONCLUSION: As High Fidelity Perinatal Simulation training constitutes a helpful learning experience in midwifery education, it could have a positive influence on maternal and neonatal outcomes. In the long term, it could therefore enhance the midwifery profession in several ways. The present study is an important first step in opening up the debate about the pedagogical use of High-Fidelity Perinatal Simulation training within midwifery education. PMID- 28341586 TI - Less Exercise and More Drugs: How a Low-Income Population Manages Chronic Pain. AB - OBJECTIVES: To evaluate chronic pain management in a multistate, low-income Hispanic population, and to examine predictors of exercising and prescription pain medication (PPM) use. DESIGN: Online survey administered to a representative sample of Hispanic adults in June 2015. SETTING: Five southwestern states. PARTICIPANTS: Among all online panel members who were Hispanic (N=1007), aged 35 to 75 years from 5 states, representing 11,016,135 persons, the survey was completed by 516 members (51%). Among these, 102 participants were identified with chronic noncancer pain representing 1,140,170 persons. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Exercising or using PPM for chronic pain in past year. RESULTS: Most participants reported using PPM (58%) and exercise (54%) to manage pain. Compared with annual household incomes >$75,000, adjusted odds ratios [AORs] for exercising were .20 for <$10,000 (P=.12); .40 for $10,000 to $34,999 (P=.22); and .15 for $35,000 to $74,999 (P=.015). Conversely, AORs for PPM were over 4-fold higher for lower-income groups as follows: 14.2, 4.79, and 4.85, respectively (all P<.065). PPM users rated the importance of accessing a gym to manage pain lower (P=.01), while exercisers rated the feasibility of gym access to manage pain higher (P=.001). CONCLUSIONS: In a Hispanic population based sample with chronic pain, lower-income groups tended to exercise less but use PPM more. Barriers to gym access and use may play a role in these disparities. PMID- 28341587 TI - Impact of Rapid Molecular Respiratory Virus Testing on Real-Time Decision Making in a Pediatric Emergency Department. AB - Acute respiratory illnesses (ARIs) are usually viral [influenza, respiratory syncytial virus (RSV)] and account for 25% of emergency department (ED) peak season visits. Laboratory PCR testing is accurate albeit slow, whereas rapid antigen testing is inaccurate. We determined the impact of bedside PCR (molecular point-of-care test; mPOCT) on pediatric ARI management. This was a prospective cohort study of consecutive pediatric patients with ED-ordered respiratory PCR test, enrolled over 9 weeks during peak flu season. On ordering, ED physicians were interviewed to ascertain real-time plans if given immediate influenza/RSV PCR results for the current patient. Two groups were compared: actual management and management adjusted for mPOCT results. We compared ED length of stay (LOS), tests ordered, and antibiotic/antiviral ordering. One-hundred thirty-six respiratory PCR panels were ordered, 71 by admitting team, 61 for ED management. Of 61 ED-initiated tests, physicians indicated in 39 cases (64%) they would change patient management were bedside viral results available. Physicians would have decreased ED LOS by 33 minutes, ordered fewer tests (18%; P < 0.001) with average patient charge savings of $669, fewer antibiotics among discharged patients (17%; P = 0.043), and increased appropriate antiviral use (13%; P = 0.023). Rapid bedside ARI mPOCT PCR has the potential to decrease ED LOS, reduce diagnostic tests and patient charges, and increase appropriate use of antibiotics and antiviral agents. PMID- 28341588 TI - Targeted Next-Generation Sequencing of 51 Genes Involved in Primary Electrical Disease. AB - Primary electrical disease (PED) is characterized by cardiac arrhythmias, which can lead to sudden cardiac death in the absence of detectable structural heart disease. PED encompasses a diversity of inherited syndromes, predominantly Brugada syndrome, early repolarization syndrome, long QT syndrome, short QT syndrome, arrhythmogenic right ventricular cardiomyopathy, and catecholaminergic polymorphic ventricular tachycardia. To overcome the diagnostic challenges imposed by the clinical and genetic heterogeneity of PED, we developed a targeted gene panel for next-generation sequencing of 51 PED genes. The amplified samples were sequenced on MiSeq. To validate the panel, 20 Human Polymorphism Study Center samples and 19 positive control samples were used, with a total of 1479 variants. An analytical sensitivity and specificity of 100% and 99.9% were obtained. After validation, we applied the assay to 114 PED patients. We identified 107 variants in 36 different genes, 18 of which were classified as pathogenic or likely pathogenic, 54 variants were of unknown significance, and 35 were classified as likely benign. We can conclude that the PED Multiplex Amplification of Specific Targets for Resequencing Plus assay is a proficient and highly reliable test to routinely screen patients experiencing primary arrhythmias. PMID- 28341590 TI - Guidelines for Validation of Next-Generation Sequencing-Based Oncology Panels: A Joint Consensus Recommendation of the Association for Molecular Pathology and College of American Pathologists. AB - Next-generation sequencing (NGS) methods for cancer testing have been rapidly adopted by clinical laboratories. To establish analytical validation best practice guidelines for NGS gene panel testing of somatic variants, a working group was convened by the Association of Molecular Pathology with liaison representation from the College of American Pathologists. These joint consensus recommendations address NGS test development, optimization, and validation, including recommendations on panel content selection and rationale for optimization and familiarization phase conducted before test validation; utilization of reference cell lines and reference materials for evaluation of assay performance; determining of positive percentage agreement and positive predictive value for each variant type; and requirements for minimal depth of coverage and minimum number of samples that should be used to establish test performance characteristics. The recommendations emphasize the role of laboratory director in using an error-based approach that identifies potential sources of errors that may occur throughout the analytical process and addressing these potential errors through test design, method validation, or quality controls so that no harm comes to the patient. The recommendations contained herein are intended to assist clinical laboratories with the validation and ongoing monitoring of NGS testing for detection of somatic variants and to ensure high quality of sequencing results. PMID- 28341589 TI - Comprehensive Determination of Prostate Tumor ETS Gene Status in Clinical Samples Using the CLIA Decipher Assay. AB - ETS family gene fusions are common in prostate cancer and molecularly define a tumor subset. ERG is the most commonly rearranged, leading to its overexpression, followed by ETV1, ETV4, and ETV5, and these alterations are generally mutually exclusive. We validated the Decipher prostate cancer assay to detect ETS alterations in a Clinical Laboratory Improvement Amendments-accredited laboratory. Benchmarking against ERG immunohistochemistry and ETV1/4/5 RNA in situ hybridization, we examined the accuracy, precision, and reproducibility of gene expression ETS models using formalin-fixed, paraffin-embedded samples. The m ERG model achieved an area under curve of 95%, with 93% sensitivity and 98% specificity to predict ERG immunohistochemistry status. The m-ETV1, -ETV4, and ETV5 models achieved areas under curve of 98%, 88%, and 99%, respectively. The models had 100% robustness for ETS status, and scores were highly correlated across sample replicates. Models predicted 41.5% of a prospective radical prostatectomy cohort (n = 4036) to be ERG+, 6.3% ETV1+, 1% ETV4+, and 0.4% ETV5+. Of prostate tumor biopsy samples (n = 509), 41.2% were ERG+, 8.6% ETV1+, 0.4% ETV4+, and none ETV5+. Higher Decipher risk status tumors were more likely to be ETS+ (ERG or ETV1/4/5) in the radical prostatectomy and the biopsy cohorts (P < 0.05). These results support the utility of microarray-based ETS status prediction models for molecular classification of prostate tumors. PMID- 28341591 TI - Report of Morinda citrifolia chronic toxicity not applicable to commercial noni juice. PMID- 28341592 TI - Comparison of two cadaveric acellular dermal matrices for immediate breast reconstruction: A prospective randomized trial. AB - AlloDerm RTU(r) and AlloMaxTM are two acellular dermal matrices (ADMs) used in implant-based breast reconstruction. In this study, we examined whether different processing methods for the ADMs lead to a disparity in histologic, clinical, and financial outcomes after breast reconstruction. Thirty patients undergoing implant-based breast reconstruction were randomized into AlloMax or AlloDerm arms (n = 15, each). ADM was placed at the time of immediate reconstruction. Patients were evaluated for complications on postoperative days 7, 14, and 30. During implant exchange, ADM biopsies were taken and compared histologically for vascular and cellular infiltration. Patient satisfaction was evaluated using the BRECON-31 questionnaire 1 year after implant exchange. A cost analysis was performed comparing the two ADMs. Patient demographics and complication rates were similar between the two groups (p > 0.05). Histologically, vessel density and fibroblast/inflammatory cell infiltrate were greater on the dermal side than on the implant side (p < 0.01) in both ADMs, suggesting greater vascular and cellular in-growth from the dermal side. Vessel density in the middle portion of the Allomax biopsies was significantly higher than the same site in the Alloderm biopsies (p < 0.05). The extent of fibroblast/inflammatory cell infiltration was similar in both arms (p > 0.05). The BRECON-31 satisfaction questionnaire yielded similar responses across all metrics between the two study arms. The negotiated price was slightly different when comparing the two ADMs, with no significant difference in ADM reimbursement. In this study, AlloDerm RTU and AlloMax were successfully used for implant-based breast reconstruction with comparable outcomes. PMID- 28341593 TI - Correction of tuberous breast deformity: A retrospective study comparing lipofilling versus breast implant augmentation. AB - Breast implants and, more recently, autologous fat grafting are the two most common treatments used to correct tuberous breast deformity (TBD). The post surgical quality of life between the two techniques is not well demonstrated. This study aimed to compare satisfaction and health-related quality of life in patients affected by TBD between these two techniques. All TBD patients operated between January 2008 and May 2015 were retrospectively identified, and only those treated with implants or lipofilling were included. Satisfaction was evaluated at least 6 months after surgery with the postoperative Breast-Q(r) augmentation module. From January 2008 to May 2015, 62 patients were recruited in our study, and 37 patients were evaluated using a Breast-Q questionnaire after at least 6 months of follow-up. Breast implant-augmented patients were significantly more satisfied concerning the "satisfaction with breasts" module (p = 0.002) and the "satisfaction with outcome" module (p = 0.00008). A question-by-question analysis revealed several interesting and significant differences, showing higher scores in most of the questions in the breast implant group. Patients in the lipofilling group, interestingly, had a mean of 1.6 interventions compared to the mean 1.36 interventions in the implant group (p = 0.23). This reflects the need to perform more surgical sessions in the lipofilling group to achieve a satisfactory result. Our study demonstrated that tuberous breast correction with implants can achieve better satisfaction along with good outcomes than lipofilling usually does. PMID- 28341594 TI - iTRAQ-based proteomics analysis of hippocampus in spatial memory deficiency rats induced by simulated microgravity. AB - : It has been demonstrated that simulated microgravity (SM) may lead to cognitive dysfunction. However, the underlying mechanism remains unclear. In present study, tail-suspension (30 degrees ) rat was employed to explore the effects of 28 days of SM on hippocampus-dependent learning and memory capability and the underlying mechanisms. We found that 28-day tail-suspension rats displayed decline of learning and memory ability in Morris water maze (MWM) test. Using iTRAQ-based proteomics analysis, a total of 4774 proteins were quantified in hippocampus. Of these identified proteins, 147 proteins were differentially expressed between tail-suspension and control group. Further analysis showed these differentially expressed proteins (DEPs) involved in different molecular function categories, and participated in many biological processes. Based on the results of PANTHER pathway analysis and further western blot verification, we observed the expression of glutamate receptor 1 (GluR1) and glutamate receptor 4 (GluR4) which involved in metabotropic glutamate receptor group III pathway and ionotropic glutamate receptor pathway were significantly induced by SM. Moreover, an increased concentration of glutamic acid (Glu) was also found in hippocampus while the concentrations of 5-hydroxytryptamine (5-HT), dopamine (DA), gamma amino acid butyric acid (GABA) and epinephrine (E) were decreased. Our finding confirms that 28-day SM exposure can cause degrading of the spatial learning and memory capability and the possible mechanisms might be related with glutamate excitotoxicity and imbalances in specific neurotransmitters. BIOLOGICAL SIGNIFICANCE: The goal of sending astronauts farther into space and extending the duration of spaceflight missions from months to years will challenge the current capabilities of bioastronautics. The investigation of the physiological and pathological changes induced by spaceflight will be critical in developing countermeasures to ensure astronauts to complete spaceflight mission accurately and effectively and return to earth safely. It has been demonstrated that spaceflight may lead to impairments in cognitive function which is crucial for mission success. Here we show that long-term simulated microgravity, the most potent environment risk factor during spaceflight, impairs the spatial learning and memory of rats and the underlying mechanism may be involved in glutamate excitotoxicity and imbalances in specific neurotransmitters release in hippocampus, which may provide new insight for the countermeasures of cognitive impairment during spaceflight. PMID- 28341596 TI - Application of an NLME-Stochastic Deconvolution Approach to Level A IVIVC Modeling. AB - Stochastic deconvolution is a parameter estimation method that calculates drug absorption using a nonlinear mixed-effects model in which the random effects associated with absorption represent a Wiener process. The present work compares (1) stochastic deconvolution and (2) numerical deconvolution, using clinical pharmacokinetic (PK) data generated for an in vitro-in vivo correlation (IVIVC) study of extended release (ER) formulations of a Biopharmaceutics Classification System class III drug substance. The preliminary analysis found that numerical and stochastic deconvolution yielded superimposable fraction absorbed (Fabs) versus time profiles when supplied with exactly the same externally determined unit impulse response parameters. In a separate analysis, a full population PK/stochastic deconvolution was applied to the clinical PK data. Scenarios were considered in which immediate release (IR) data were either retained or excluded to inform parameter estimation. The resulting Fabs profiles were then used to model level A IVIVCs. All the considered stochastic deconvolution scenarios, and numerical deconvolution, yielded on average similar results with respect to the IVIVC validation. These results could be achieved with stochastic deconvolution without recourse to IR data. Unlike numerical deconvolution, this also implies that in crossover studies where certain individuals do not receive an IR treatment, their ER data alone can still be included as part of the IVIVC analysis. PMID- 28341595 TI - Systems characterization of differential plasma metabolome perturbations following thrombotic and non-thrombotic myocardial infarction. AB - : Myocardial infarction (MI) is an acute event characterized by myocardial necrosis. Thrombotic MI is caused by spontaneous atherosclerotic plaque disruption that results in a coronary thrombus; non-thrombotic MI occurs secondary to oxygen supply-demand mismatch. We sought to characterize the differential metabolic perturbations associated with these subtypes utilizing a systems approach. Subjects presenting with thrombotic MI, non-thrombotic MI and stable coronary artery disease (CAD) were included. Whole blood was collected at two acute time-points and at a time-point representing the quiescent stable disease state. Plasma metabolites were analyzed by untargeted UPLC-MS/MS and GC MS. A weighted network was constructed, and modules were determined from the resulting topology. To determine perturbed modules, an enrichment analysis for metabolites that demonstrated between-group differences in temporal change across the disease state transition was then conducted. BIOLOGICAL SIGNIFICANCE: We report evidence of metabolic perturbations of acute MI and determine perturbations specific to thrombotic MI. Specifically, a module characterized by elevated glucocorticoid steroid metabolites following acute MI showed greatest perturbation following thrombotic MI. Modules characterized by elevated pregnenolone metabolites, monoacylglycerols, and acylcarnitines were perturbed following acute MI. A module characterized by a decrease in plasma amino acids following thrombotic MI was differentially perturbed between MI subtypes. PMID- 28341597 TI - Effect of Isopropyl Myristate on Transdermal Permeation of Testosterone From Carbopol Gel. AB - The objective of the present study was to investigate the effect of isopropyl myristate (IPM) on the in vitro permeation of testosterone through human cadaver skin from carbopol gels. Six testosterone gel formulations were prepared using different IPM contents of 0%, 0.4%, 0.7%, 1%, 2%, and 3%. The gels were characterized for drug permeation, matrix morphology, pH, kinetics of ethanol evaporation, and viscosity. Mass balance studies were performed to estimate testosterone distribution among the compartments of diffusion cells. All formulations exhibited pH values of 5.1 and viscosities of 1.25-1.75 Pa.s depending on IPM contents. Under occlusive condition, testosterone flux was found to increase significantly (p < 0.05) by increasing IPM content. Gels containing 2% IPM exhibited 11-fold increase in flux compared with formulation devoid of IPM. Ethanol was found to have a synergistic effect with IPM in enhancing testosterone flux. Mass balance analysis showed that testosterone was in a saturated state in the skin. Conducting permeation experiments under nonocclusive condition was nondiscriminating because of the evaporation of alcohol and consequent precipitation of drugs. Based on demonstrated effect of IPM on product performance, the final IPM concentration should be controlled with minimal variation during manufacturing and shelf life of drug product. PMID- 28341598 TI - Lyophilized Drug Product Cake Appearance: What Is Acceptable? AB - Cake appearance is an important attribute of freeze-dried products, which may or may not be critical with respect to product quality (i.e., safety and efficacy). Striving for "uniform and elegant" cake appearance may continue to remain an important goal during the design and development of a lyophilized drug product. However, "sometimes" a non-ideal cake appearance has no impact on product quality and is an inherent characteristic of the product (due to formulation, drug product presentation, and freeze-drying process). This commentary provides a summary of challenges related to visual appearance testing of freeze-dried products, particularly on how to judge the criticality of cake appearance. Furthermore, a harmonized nomenclature and description for variations in cake appearance from the ideal expectation of uniform and elegant is provided, including representative images. Finally, a science and risk-based approach is discussed on establishing acceptance criteria for cake appearance. PMID- 28341599 TI - Nucleo-cytoplasmic transport of estrogen receptor alpha in breast cancer cells. AB - Approximately 70% cases of breast cancers exhibit high expression and activity levels of estrogen receptor alpha (ERalpha), a transcription regulator that induces the expression of genes associated with cellular proliferation and survival. These nuclear functions of the receptor are associated with the development of breast cancer. However, ERalpha localization is not static, but rather, dynamic with continuous shuttling between the nucleus and the cytoplasm. Interestingly, both the nuclear import and export of ERalpha are modulated by several stimuli that include estradiol, antiestrogens, and growth factors. As ERalpha nuclear accumulation is critical to the regulation of gene expression, nuclear export of this receptor modulates the intensity and duration of its transcriptional activity. Thus, the subcellular spatial distribution of ERalpha ensures tight modulation of its concentration in cellular compartments, as well as of its nuclear and extranuclear functions. In this review, we will discuss current findings regarding the biological importance of molecular mechanisms of, and proteins responsible for, the nuclear import and export of ERalpha in breast cancer cells. PMID- 28341602 TI - Cytosolic YB-1 and NSUN2 are the only proteins recognizing specific motifs present in mRNAs enriched in exosomes. AB - Exosomes, membranous vesicles secreted by various cells, are involved in intercellular communication and carry vast repertoires of RNAs and proteins. Processes mediating RNA sorting into exosomes are currently poorly understood. Using bioinformatics approaches, three structural motifs ACCAGCCU, CAGUGAGC and UAAUCCCA have been discovered as enriched in exosomal mRNAs and long noncoding RNAs. Here, utilizing short RNA hairpins, each containing one of the motifs, in a pull-down assay of cytosolic extract of human embryonic kidney 293 (HEK293) cells, we prove that multifunctional RNA-binding protein YB-1 specifically interacts with all three motifs, whereas methyltransferase NSUN2 recognizes only the motif CAGUGAGC. RNA hairpins other than those mentioned above pull out neither YB-1 nor NSUN2. Both these proteins are found in exosomes secreted by HEK293 cells. YB-1 for all that is detected as a form having a slightly higher electrophoretic mobility than that of YB-1 associated with the above RNA hairpins, assuming changes in posttranslational modifications of the protein during its transfer from cytoplasm into exosomes. Next generation sequencing of total exosomal RNA (eRNA) reveals a large representative set of RNA species, including mRNAs containing the above-mentioned motifs. The degree of enrichment in exosomes with this kind of mRNAs strongly depends on the locations of eRNA specific motifs within the mRNA sequences. Altogether, our findings point to YB-1 and NSUN2 as possible mediators of the process of transfer of specific mRNAs into exosomes, allowing us to speculate on an involvement of these proteins in the mRNA sorting via the recognition of the above motifs. PMID- 28341601 TI - Advances in MALDI imaging mass spectrometry of proteins in cardiac tissue, including the heart valve. AB - Significant progress has been made for tissue imaging of proteins using matrix assisted laser desorption ionization imaging mass spectrometry (MALDI IMS). These advancements now facilitate mapping of a wide range of proteins, peptides, and post-translational modifications in a wide variety of tissues; however, the use of MALDI IMS to detect proteins from cardiac tissue is limited. This review discusses the most recent advances in protein imaging and demonstrates application to cardiac tissue, including the heart valve. Protein imaging by MALDI IMS allows multiplexed histological mapping of proteins and protein components that are inaccessible by antibodies and should be considered an important tool for basic and clinical cardiovascular research. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann. PMID- 28341603 TI - Different desmin peptides are distinctly deposited in cytoplasmic aggregations and cytoplasm of desmin-related cardiomyopathy patients. AB - Desmin-related cardiomyopathy is a heterogeneous group of myofibrillar myopathies characterized by aggregates of desmin and related proteins in myocytes. It has been debated how the expression and protein structure are altered in the aggregates and other parts of myocytes in patients. To address this question, we investigated the proteome quantification as well as localization in formalin fixed and paraffin-embedded specimens of the heart of patients by imaging mass spectrometry and liquid chromatography-mass spectrometry analyses. Fifteen tryptic peptide signals were enriched in the desmin-related cardiomyopathy myocardium, twelve of which were identified as desmin peptides with 14.3- to 27.3 fold increase compared to normal hearts. High-intensity signals at m/z 1032.5 and 1002.5, which were desmin peptides 59-70 at the head portion and 213-222 at the 1B domain, were with infrequent colocalization distributed not only in desmin positive intracytoplasmic aggregates but also in histologically normal cytoplasm, indicating that desmin protein is fragmented and different types of naturally occurring truncated proteins ectopically assemble throughout the heart of patients. Thus, in addition to conventional histological identification of protein aggregates, specific desmin peptides show a marked difference in quantity and localization in a tissue section of desmin-related cardiomyopathy and differentiate from other cardiomyopathies. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann. PMID- 28341605 TI - Patient-Reported Spectacle Independence Questionnaire (PRSIQ): Development and Validation. AB - PURPOSE: To develop a questionnaire quantifying spectacle independence following cataract surgery. DESIGN: Questionnaire design and validation study. METHODS: A literature review, expert clinical interviews, and patient interviews were undertaken to develop a patient-reported questionnaire assessing spectacle independence. Draft items were assessed and revised in a series of cognitive interviews where the instructions, recall period, and response categories were evaluated for understandability and consistency. The final draft items were evaluated in 2 quantitative studies. Confirmatory factor analyses, including item response theory calibration, were performed; reliability estimates were obtained; and validity analyses of the resulting scores were carried out. RESULTS: Qualitative research demonstrated that patients often considered themselves spectacle independent yet, when probed, it was determined that the respondent actually wore correction for certain activities. Moreover, despite what the respondents claimed about needing to wear correction and their actual use of correction, there were various levels of function reported when carrying out activities at several different distances without the use of correction. Using the qualitative results, the Patient-Reported Spectacle Independence Questionnaire (PRSIQ) was developed to assess spectacle independence via items that assess what patients say and do, and how they function at various distances. All quantitative analyses (eg, discriminant and convergent validity correlations, known-groups analyses) conform to predictions and support the use of the PRSIQ as a measure of spectacle independence. CONCLUSIONS: The PRSIQ is a patient-reported measure assessing spectacle independence following cataract surgery. The analyses conducted provide evidence for the use of the PRSIQ total score as a measure of spectacle independence. PMID- 28341604 TI - Analysis of FDA-approved imaging agents. AB - The development of imaging agents was initially driven following the discovery of X-ray technologies, but quickly evolved and expanded to include radiolabeling of cells and tissues to assist disease diagnosis and progression. The first imaging agents preceded the Great War but the field did not gain momentum until the 1950s. The approval rate for imaging NMEs continued at a high level for the remainder of the 20th century, but substantially decreased thereafter. This decline in approval rates corresponds with industry consolidation. Such losses have stabilized, but could have important implications for a field that has conveyed direct benefits to medicine and that could ensure the future of the wider biopharmaceutical industry. PMID- 28341607 TI - Do emotion regulation difficulties when upset influence the association between dietary restraint and weight gain among college students? AB - Obesity is a significant public health concern that affects more than one-fifth of adolescents aged 12-19 in the United States. Theoretical models suggest that prolonged dietary restraint leads to binge-eating behaviors, which in turn increases individuals' risk for weight gain or obesity. Results from the literature indicate a potential role for negative urgency (the tendency to act rashly when distressed) as a mediating variable that explains the link between dietary restraint and binge-eating episodes. The current study tested short-term, prospective longitudinal associations among dietary restraint, binge eating, negative urgency, and weight gain among college students - a population at increased risk for the development of overweight and obesity. We hypothesized that dietary restraint and weight gain would be mediated by negative urgency and binge eating, but only among participants with overweight and obesity. College students (N = 227) completed the Eating Pathology Symptoms Inventory, UPPS-P Impulsivity Scale, and self-reported weight and height to calculate body mass index. Results showed that the association between dietary restraint and weight gain was mediated by negative urgency and binge eating, but only among participants with overweight and obesity. Our findings indicated that negative urgency might represent a mechanism that explains why dietary restraint leads to future binge-eating episodes and weight gain among college students with overweight and obesity. Results suggest that future treatment and prevention programs for overweight and obesity may benefit from incorporating strategies to improve emotion regulation as a way to reduce binge eating and to prevent additional weight gain among 'at-risk' populations. PMID- 28341606 TI - Safety and Efficacy of Sequential Intracorneal Ring Segment Implantation and Cross-linking in Pediatric Keratoconus. AB - PURPOSE: To evaluate the safety and visual outcome of intracorneal ring segment (ICRS) implantation followed by cross-linking in pediatric keratoconus patients. DESIGN: Retrospective interventional case series. METHODS: This retrospective study included pediatric patients (aged <=14 years) with keratoconus and poor corrected distance visual acuity (CDVA) that underwent ICRS implantation and cross-linking (CXL). ICRS were inserted under topical anesthesia after creating a corneal tunnel with a femtosecond laser. Cross-linking was performed 1 month subsequently. Records were reviewed and data collected preoperatively and at 6 months, 1 year, 2 years, and 4 years postoperatively. RESULTS: Twelve patients (17 eyes; 10 male, 2 female) aged 9-14 years (mean age 12.3 years) received ICRS implantation followed by CXL. Follow-up times ranged from 6 months to 4 years after surgery. At the 6-month follow-up all eyes were evaluated; at the 1-year, 2 year, and 4-year follow-up 11, 10, and 7 eyes were evaluated, respectively. At the 6-month follow-up, mean CDVA in comparison to preoperative levels improved significantly (P = .001) from 0.30 +/- 0.19 logMAR to 0.12 +/- 0.1 logMAR; mean uncorrected distance visual acuity (UDVA) also improved significantly from 0.90 +/- 0.50 logMAR to 0.43 +/- 0.31 logMAR. A significant decrease in both keratometry readings and spherical equivalent (from -4.0 to -1.56 diopters) was also noted after ICRS insertion. At the 1-year, 2-year, and 4-year follow-up refractive values remained relatively stable in comparison to the 6-month follow up, except for a minor but significant improvement in cylinder and, at 4 years, in UDVA. All patients tolerated the surgery well and no intraoperative or postoperative complications were reported, except for 1 ring segment that had to be removed after 2 years owing to vascularization and corneal thinning. CONCLUSION: ICRS implantation is a safe and effective procedure for visual rehabilitation in children with keratoconus and poor CDVA. PMID- 28341600 TI - Metabolic Dysfunction in Parkinson's Disease: Bioenergetics, Redox Homeostasis and Central Carbon Metabolism. AB - The loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of protein inclusions (Lewy bodies) are the pathological hallmarks of Parkinson's disease (PD). PD is triggered by genetic alterations, environmental/occupational exposures and aging. However, the exact molecular mechanisms linking these PD risk factors to neuronal dysfunction are still unclear. Alterations in redox homeostasis and bioenergetics (energy failure) are thought to be central components of neurodegeneration that contribute to the impairment of important homeostatic processes in dopaminergic cells such as protein quality control mechanisms, neurotransmitter release/metabolism, axonal transport of vesicles and cell survival. Importantly, both bioenergetics and redox homeostasis are coupled to neuro-glial central carbon metabolism. We and others have recently established a link between the alterations in central carbon metabolism induced by PD risk factors, redox homeostasis and bioenergetics and their contribution to the survival/death of dopaminergic cells. In this review, we focus on the link between metabolic dysfunction, energy failure and redox imbalance in PD, making an emphasis in the contribution of central carbon (glucose) metabolism. The evidence summarized here strongly supports the consideration of PD as a disorder of cell metabolism. PMID- 28341608 TI - The dual-pathway model of binge eating: Is there a need for modification? AB - The dual-pathway model proposes that body dissatisfaction might lead to binge eating (BE) through restraint eating and negative affect. Both pathways have been confirmed longitudinally, but there is evidence that the affect-pathway might rather be found in the short-term, whereas other variables might be involved over longer periods. Research suggests that self-esteem represents a key-factor in the etiology of BE in adolescent girls and might serve as a mediator between body dissatisfaction and eating pathology. Based on these findings, the aim of this study was to investigate the original dual-pathway model across 20 months and to evaluate a modified version of the model with self-esteem instead of negative affect as a mediator in the affect-pathway. We assessed eating pathology, negative affect and self-esteem by self-report in a sample of 523 adolescent girls at two time points separated by 20 months. Data were analyzed using a cross lagged panel design. Both, the original and the modified model provided good fit to the data, but results yielded limited support for the assumptions of the original model. Neither restraint eating nor negative affect mediated the link between body dissatisfaction and BE. The modified model fit the data slightly better and results indicated that low self-esteem mediated the relationship between body dissatisfaction and BE. Notably, our results indicated that restraint eating might even reduce the risk for BE through the enhancement of self-esteem. Results suggest that the dual-pathway model could benefit from the inclusion of a more trait-like variable such as self-esteem when evaluated across the long-term. Furthermore, our findings indicate that healthy restraint eating might have positive effects on self-esteem, thereby reducing risk for BE in adolescent girls, who are dissatisfied with their bodies. PMID- 28341609 TI - Effects of chronic restraint stress on the global DNA methylation profile of rat lung cells: Modulation by physical exercise. AB - The potential of behavioral stress to affect epigenetic mechanisms of non encephalic tissues is still underestimated. In the present study we evaluated the effects of chronic behavioral stress on the DNA methylation profile of rat lung cells. Furthermore, we evaluated the potential of physical exercise to modulate the changes evoked by behavioral stress in lung cells. Male Wistar rats were divided into four experimental groups: (1) animals submitted to chronic restraint stress (CRS) (ST group) during the period of the 67th-80th postnatal day (PND); (2) animals submitted to physical exercise (EX group) during the 53rd-79th PND; (3) animals submitted to swimming during the 53rd-79th PND and to CRS during the 67th-80th PND (EX-ST group); and (4) animals not submitted to stress or swimming protocols (CTL). Global DNA methylation was quantified using an ELISA-based approach and gene expression was evaluated by real time PCR. A decreased global DNA methylation profile was observed in the ST group, however physical exercise demonstrated protection of lung cells from this stress-related hypomethylation. Increased expression of the Dnmt1 gene was evidenced in the ST group, whereas physical exercise was shown to protect lung cells from this stress-related effect in the EX-ST group. Comparative analysis of the ST and EX groups revealed opposite effects on the expression of Dnmt3a and Dnmt3b; however, a stress related increase in expression of Dnmt3a and Dnmt3b was not seen in the EX-ST group. Our data showed that behavioral stress induced significant changes in the DNA methylation profile of rat lung cells and that this could be modulated by physical exercise. PMID- 28341612 TI - Impact of beta-lactam antibiotic therapeutic drug monitoring on dose adjustments in critically ill patients undergoing continuous renal replacement therapy. AB - The objective of this study was to describe the effect of therapeutic drug monitoring (TDM) and dose adjustments of beta-lactam antibiotics administered to critically ill patients undergoing continuous renal replacement therapy (CRRT) in a 30-bed tertiary intensive care unit (ICU). beta-Lactam TDM data in our tertiary referral ICU were retrospectively reviewed. Clinical, demographic and dosing data were collected for patients administered beta-lactam antibiotics while undergoing CRRT. The target trough concentration range was 1-10* the minimum inhibitory concentration (MIC). A total of 111 TDM samples from 76 patients (46 male) with a mean +/- standard deviation age of 56.6 +/- 15.9 years and weight of 89.1 +/- 25.8 kg were identified. The duration of antibiotic therapy was between 2 days and 42 days. TDM identified a need for dose modification of beta-lactam antibiotics in 39 (35%) instances; in 27 (24%) samples, TDM values resulted in decreasing the prescribed dose of beta-lactam antibiotic whereas an increase in the prescribed dose occurred in 12 (11%) cases. In patients treated for hospital acquired pneumonia and primary or secondary bacteraemia, the dose was required to be decreased in 10/25 (40%) and 7/46 (15%) cases, respectively, to attain target concentrations. beta-Lactam TDM is a useful tool for guiding drug dosing in complex patients such as those receiving CRRT. Although over one-third of patients manifested concentrations outside the therapeutic range, most of these CRRT patients had excessive beta-lactam concentrations. PMID- 28341610 TI - Differential effects of social and novelty enrichment on individual differences in impulsivity and behavioral flexibility. AB - Early life experience profoundly impacts behavior and cognitive functions in rats. The present study investigated how the presence of conspecifics and/or novel objects, could independently influence individual differences in impulsivity and behavioral flexibility. Twenty-four rats were reared in an isolated condition, an isolated condition with a novel object, a pair-housed social condition, or a pair-housed social condition with a novel object. The rats were then tested on an impulsive choice task, a behavioral flexibility task, and an impulsive action task. Novelty enrichment produced an overall increase in impulsive choice, while social enrichment decreased impulsive choice in the absence of novelty enrichment and also produced an overall increase in impulsive action. In the behavioral flexibility task, social enrichment increased regressive errors, whereas both social and novelty enrichment reduced never reinforced errors. Individual differences analyses indicated a significant relationship between performance in the behavioral flexibility and impulsive action tasks, which may reflect a common psychological correlate of action inhibition. Moreover, there was a relationship between delay sensitivity in the impulsive choice task and performance on the DRL and behavioral flexibility tasks, suggesting a dual role for timing and inhibitory processes in driving the interrelationship between these tasks. Overall, these results indicate that social and novelty enrichment produce distinct effects on impulsivity and adaptability, suggesting the need to parse out the different elements of enrichment in future studies. Further research is warranted to better understand how individual differences in sensitivity to enrichment affect individuals' interactions with and the resulting consequences of the rearing environment. PMID- 28341611 TI - Extinction memory is facilitated by methylphenidate and regulated by dopamine and noradrenaline receptors. AB - Extinction is defined as the learned inhibition of retrieval and is the mainstay of exposure therapy, which is widely used to treat drug addiction, phobias and fear disorders. The psychostimulant, methylphenidate (MPH) is known to increase extracellular levels of noradrenaline and dopamine by blocking their reuptake and studies have demonstrated that MPH can modulate hippocampal physiology and/or functions including long-term potentiation (LTP), learning and memory. However, the influence of MPH on fear extinction memory has been insufficiently studied. Here we investigate the effect of MPH infused into the CA1 region of the hippocampus on extinction memory in animals normally incapable of showing contextual fear conditioning (CFC) extinction because of weak training, and the possible mechanisms through which it acts during this process. For this, male Wistar rats with infusion cannulae stereotaxically implanted in the CA1 region were submitted to a weak extinction protocol in a CFC apparatus. Animals that received intra-CA1 infusion of MPH (12.5MUg/side) 20min before the extinction training (Ext Tr) expressed less freezing behavior than Veh-treated animals during both Ext Tr and extinction retention Test (Ext Test). Additionally, the administration of MPH+Timolol (1MUg/side) or MPH+SCH23390 (1.5MUg/side) intra-CA1 20min before the Ext Tr blocked the enhancing effect of the MPH on extinction learning. These results suggest that MPH in the CA1 region of the hippocampus is able to induce the consolidation of extinction memory and this process occurs through both beta-adrenergic and D1/D5 dopaminergic receptors. PMID- 28341613 TI - Development and photoprotective effect of a sunscreen containing the antioxidants Spirulina and dimethylmethoxy chromanol on sun-induced skin damage. AB - The literature claims that incorporation of antioxidants into sunscreens provides additional skin photoprotection by scavenging free radicals formed due to sun radiation, but there are limited in vivo studies that support this hypothesis. This study aims to examine whether addition of antioxidants to a broad-spectrum sunscreen increases its photoprotective effect in real-use conditions. Sunscreen formulations composed of stable UV filters (Tinosorb(r) S, Tinosorb(r) M, Uvinul(r) APlus, and Uvinul(r) T150) alone or in combination with antioxidants (Spirulina and dimethylmethoxy chromanol-loaded solid lipid nanoparticles) were developed and their appearance, odor, rheological behavior, Sun Protection Factor (SPF), and UVA protection were analyzed. Next, it was conducted a 3-month, single blind clinical study with 44 healthy subjects (30-50years). Before and 28, 54, and 84days after twice-daily self application of the sunscreens on the face, the stratum corneum water content, transepidermal water loss, dermis echogenicity, and skin elasticity and pigmentation were measured. At the end of the study period, the volunteers answered a questionnaire containing terms related to sensory characteristics of the formulations. All formulations were stable and exhibited non-Newtonian and pseudoplastic behavior, in vivo SPF 30, and good UVA protection. Antioxidant supplementation to the sunscreen formulation significantly improved the skin pigmentation, the collagen degradation on the dermis and thereby the skin net elasticity after 84days of treatment compared to the sunscreen alone. Concerning safety, all formulations were considered non irritant according to the sensorial analyses, whose results agreed with the clinical study findings. PMID- 28341614 TI - Anti-tubercular drug discovery: in silico implications and challenges. AB - Tuberculosis (TB) has been reported as a major public health concern, especially in the developing countries. WHO report on tuberculosis 2016 shows a high mortality rate caused by TB leading to 1.8 million deaths worldwide (including deaths due to TB in HIV positive individuals), which is one of the top 10 causes of mortality in 2015. However, the main therapy used for the treatment of TB is still the Direct Observed Therapy Short-course (DOTS) that consists of four main first-line drugs. Due to the prolonged and unorganized use of these drugs, Mycobacterium tuberculosis (Mtb) has developed drug-resistance against them. To overcome this drug-resistance, efforts are continuously being made to develop new therapeutics. New drug-targets of Mtb are pursued by the researchers to develop their inhibitors. For this, new methodologies that comprise of the computational drug designing techniques are vigorously applied. A major limitation that is found with these techniques is the inability of the newly identified target-based inhibitors to inhibit the whole cell bacteria. A foremost factor for this limitation is the inability of these inhibitors to penetrate the bacterial cell wall. In this regard, various strategies to overcome this limitation have been discussed in detail in this review, along with new targets and new methodologies. A bunch of in silico tools available for the prediction of physicochemical properties that need to be explored to deal with the permeability issue of the Mtb inhibitors has also been discussed. PMID- 28341615 TI - Design and Usability of a Heart Failure mHealth System: A Pilot Study. AB - BACKGROUND: Despite the advances in mobile health (mHealth) systems, little is known about patients' and providers' experiences using a new mHealth system design. OBJECTIVE: This study aimed to understand challenges and provide design considerations for a personalized mHealth system that could effectively support heart failure (HF) patients after they transition into the home environment. METHODS: Following exploratory interviews with nurses and preventive care physicians, an mHealth system was developed. Patients were asked to measure their weight, blood pressure, and blood glucose (if they had diabetes). They were also instructed to enter symptoms, view notifications, and read messages on a mobile app that we developed. A Bluetooth-enabled weight scale, blood pressure monitor, glucometer, and mobile phone was provided after an introductory orientation and training session. HF nurses used a dashboard to view daily measurements for each patient and received text and email alerts when risk was indicated. Observations of usage, cases of deterioration, readmissions, and metrics related to system usability and quality of life outcomes were used to determine overall effectiveness of the system, whereas focus group sessions with patients were conducted to elicit participants' feedback on the system's design. RESULTS: A total of 8 patients with HF participated over a 6-month period. Overall, the mean users' satisfaction with the system ranked 73%, which was above average. Quality of life improvement was 3.6. Patients and nurses used the system on a regular basis and were able to successfully identify and manage 8 health deteriorations, of which 5 were completely managed remotely. Focus groups revealed that, on one hand, the system was beneficial and helped patients with: recording and tracking readings; receiving encouragement and reassurance from nurses; spotting and solving problems; learning from past experiences; and communication. On the other hand, findings also highlighted design issues and recommendations for future systems such as the need to communicate via other media, personalize symptom questions and messages, integrate other health tracking technologies, and provide additional methods to analyze and visualize their data. CONCLUSIONS: Understanding users' experiences provides important design considerations that could complement existing design recommendations from the literature, and, when combined with physician and nurse requirements, have the potential to yield a feasible telehealth system that is effective in supporting HF self-care. Future studies will include these guidelines and use a larger sample size to validate the outcomes. PMID- 28341616 TI - Cloudy with a Chance of Pain: Engagement and Subsequent Attrition of Daily Data Entry in a Smartphone Pilot Study Tracking Weather, Disease Severity, and Physical Activity in Patients With Rheumatoid Arthritis. AB - BACKGROUND: The increasing ownership of smartphones provides major opportunities for epidemiological research through self-reported and passively collected data. OBJECTIVE: This pilot study aimed to codesign a smartphone app to assess associations between weather and joint pain in patients with rheumatoid arthritis (RA) and to study the success of daily self-reported data entry over a 60-day period and the enablers of and barriers to data collection. METHODS: A patient and public involvement group (n=5) and 2 focus groups of patients with RA (n=9) supported the codesign of the app collecting self-reported symptoms. A separate "capture app" was designed to collect global positioning system (GPS) and continuous raw accelerometer data, with the GPS-linking providing local weather data. A total of 20 patients with RA were then recruited to collect daily data for 60 days, with entry and exit interviews. Of these, 17 were loaned an Android smartphone, whereas 3 used their own Android smartphones. RESULTS: Of the 20 patients, 6 (30%) withdrew from the study: 4 because of technical challenges and 2 for health reasons. The mean completion of daily entries was 68% over 2 months. Patients entered data at least five times per week 65% of the time. Reasons for successful engagement included a simple graphical user interface, automated reminders, visualization of data, and eagerness to contribute to this easily understood research question. The main barrier to continuing engagement was impaired battery life due to the accelerometer data capture app. For some, successful engagement required ongoing support in using the smartphones. CONCLUSIONS: This successful pilot study has demonstrated that daily data collection using smartphones for health research is feasible and achievable with high levels of ongoing engagement over 2 months. This result opens important opportunities for large-scale longitudinal epidemiological research. PMID- 28341618 TI - Can Gaming Increase Antibiotic Awareness in Children? A Mixed-Methods Approach. AB - BACKGROUND: e-Bug is a pan-European educational resource for junior and senior school children, which contains activities covering prudent antibiotic use and the spread, treatment, and prevention of infection. Teaching resources for children aged 7-15 years are complemented by a student website that hosts games and interactive activities for the children to continue their learning at home. OBJECTIVE: The aim of this study was to appraise young people's opinions of 3 antibiotic games on the e-Bug student website, exploring children's views and suggestions for improvements, and analyzing change in their knowledge around the learning outcomes covered. The 3 games selected for evaluation all contained elements and learning outcomes relating to antibiotics, the correct use of antibiotics, and bacteria and viruses. METHODS: A mixed methodological approach was undertaken, wherein 153 pupils aged 9-11 years in primary schools and summer schools in the Bristol and Gloucestershire area completed a questionnaire with antibiotic and microbe questions, before and after playing 3 e-Bug games for a total of 15 minutes. The after questionnaire also contained open-ended and Likert scale questions. In addition, 6 focus groups with 48 students and think-aloud sessions with 4 students who had all played the games were performed. RESULTS: The questionnaire data showed a significant increase in knowledge for 2 out of 7 questions (P=.01 and P<.001), whereas all questions showed a small level of increase. The two areas of significant knowledge improvement focused around the use of antibiotics for bacterial versus viral infections and ensuring the course of antibiotics is completed. Qualitative data showed that the e-Bug game "Body Busters" was the most popular, closely followed by "Doctor Doctor," and "Microbe Mania" the least popular. CONCLUSIONS: This study shows that 2 of the e-Bug antibiotic educational games are valuable. "Body Busters" effectively increased antibiotic knowledge in children and had the greatest flow and enjoyment. "Doctor Doctor" also resulted in increased knowledge, but was less enjoyable. "Microbe Mania" had neither flow nor knowledge gain and therefore needs much modification and review. The results from the qualitative part of this study will be very important to inform future modifications and improvements to the e-Bug games. PMID- 28341617 TI - Internet-Delivered Health Interventions That Work: Systematic Review of Meta Analyses and Evaluation of Website Availability. AB - BACKGROUND: Due to easy access and low cost, Internet-delivered therapies offer an attractive alternative to improving health. Although numerous websites contain health-related information, finding evidence-based programs (as demonstrated through randomized controlled trials, RCTs) can be challenging. We sought to bridge the divide between the knowledge gained from RCTs and communication of the results by conducting a global systematic review and analyzing the availability of evidence-based Internet health programs. OBJECTIVES: The study aimed to (1) discover the range of health-related topics that are addressed through Internet delivered interventions, (2) generate a list of current websites used in the trials which demonstrate a health benefit, and (3) identify gaps in the research that may have hindered dissemination. Our focus was on Internet-delivered self guided health interventions that did not require real-time clinical support. METHODS: A systematic review of meta-analyses was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO Registration Number CRD42016041258). MEDLINE via Ovid, PsycINFO, Embase, Cochrane Database of Systematic Reviews, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched. Inclusion criteria included (1) meta-analyses of RCTs, (2) at least one Internet-delivered intervention that measured a health-related outcome, and (3) use of at least one self-guided intervention. We excluded group-based therapies. There were no language restrictions. RESULTS: Of the 363 records identified through the search, 71 meta-analyses met inclusion criteria. Within the 71 meta-analyses, there were 1733 studies that contained 268 unique RCTs which tested self-help interventions. On review of the 268 studies, 21.3% (57/268) had functional websites. These included evidence-based Web programs on substance abuse (alcohol, tobacco, cannabis), mental health (depression, anxiety, post-traumatic stress disorder [PTSD], phobias, panic disorders, obsessive compulsive disorder [OCD]), and on diet and physical activity. There were also evidence-based programs on insomnia, chronic pain, cardiovascular risk, and childhood health problems. These programs tended to be intensive, requiring weeks to months of engagement by the user, often including interaction, personalized and normative feedback, and self monitoring. English was the most common language, although some were available in Spanish, French, Portuguese, Dutch, German, Norwegian, Finnish, Swedish, and Mandarin. There were several interventions with numbers needed to treat of <5; these included painACTION, Mental Health Online for panic disorders, Deprexis, Triple P Online (TPOL), and U Can POOP Too. Hyperlinks of the sites have been listed. CONCLUSIONS: A wide range of evidence-based Internet programs are currently available for health-related behaviors, as well as disease prevention and treatment. However, the majority of Internet-delivered health interventions found to be efficacious in RCTs do not have websites for general use. Increased efforts to provide mechanisms to host "interventions that work" on the Web and to assist the public in locating these sites are necessary. PMID- 28341620 TI - Caesarean section is associated with offspring obesity in childhood and young adulthood. PMID- 28341619 TI - Assessing Feasibility and Acceptability of Web-Based Enhanced Relapse Prevention for Bipolar Disorder (ERPonline): A Randomized Controlled Trial. AB - BACKGROUND: Interventions that teach people with bipolar disorder (BD) to recognize and respond to early warning signs (EWS) of relapse are recommended but implementation in clinical practice is poor. OBJECTIVES: The objective of this study was to test the feasibility and acceptability of a randomized controlled trial (RCT) to evaluate a Web-based enhanced relapse prevention intervention (ERPonline) and to report preliminary evidence of effectiveness. METHODS: A single-blind, parallel, primarily online RCT (n=96) over 48 weeks comparing ERPonline plus usual treatment with "waitlist (WL) control" plus usual treatment for people with BD recruited through National Health Services (NHSs), voluntary organizations, and media. Randomization was independent, minimized on number of previous episodes (<8, 8-20, 21+). Primary outcomes were recruitment and retention rates, levels of intervention use, adverse events, and participant feedback. Process and clinical outcomes were assessed by telephone and Web and compared using linear models with intention-to-treat analysis. RESULTS: A total of 280 people registered interest online, from which 96 met inclusion criteria, consented, and were randomized (49 to WL, 47 to ERPonline) over 17 months, with 80% retention in telephone and online follow-up at all time points, except at week 48 (76%). Acceptability was high for both ERPonline and trial methods. ERPonline cost approximately L19,340 to create, and L2176 per year to host and maintain the site. Qualitative data highlighted the importance of the relationship that the users have with Web-based interventions. Differences between the group means suggested that access to ERPonline was associated with: a more positive model of BD at 24 weeks (10.70, 95% CI 0.90 to 20.5) and 48 weeks (13.1, 95% CI 2.44 to 23.93); increased monitoring of EWS of depression at 48 weeks (-1.39, 95% CI -2.61 to -0.163) and of hypomania at 24 weeks (-1.72, 95% CI -2.98 to -0.47) and 48 weeks (-1.61, 95% CI -2.92 to -0.30), compared with WL. There was no evidence of impact of ERPonline on clinical outcomes or medication adherence, but relapse rates across both arms were low (15%) and the sample remained high functioning throughout. One person died by suicide before randomization and 5 people in ERPonline and 6 in WL reported ideas of suicide or self-harm. None were deemed study related by an independent Trial Steering Committee (TSC). CONCLUSIONS: ERPonline offers a cheap accessible option for people seeking ongoing support following successful treatment. However, given high functioning and low relapse rates in this study, testing clinical effectiveness for this population would require very large sample sizes. Building in human support to use ERPonline should be considered. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 56908625; http://www.isrctn.com/ISRCTN56908625 (Archived by WebCite at http://www.webcitation.org/6of1ON2S0). PMID- 28341621 TI - Cancer cachexia-induced muscle atrophy: evidence for alterations in microRNAs important for muscle size. AB - Muscle atrophy is a hallmark of cancer cachexia resulting in impaired function and quality of life and cachexia is the immediate cause of death for 20-40% of cancer patients. Multiple microRNAs (miRNAs) have been identified as being involved in muscle development and atrophy; however, less is known specifically on miRNAs in cancer cachexia. The purpose of this investigation was to examine the miRNA profile of skeletal muscle atrophy induced by cancer cachexia to uncover potential miRNAs involved with this catabolic condition. Phosphate buffered saline (PBS) or Lewis lung carcinoma cells (LLC) were injected into C57BL/6J mice at 8 wk of age. LLC animals were allowed to develop tumors for 4 wk to induce cachexia. Tibialis anterior muscles were extracted and processed to isolate small RNAs, which were used for miRNA sequencing. Sequencing results were assembled with mature miRNAs, and functions of miRNAs were analyzed by Ingenuity Pathway Analysis. LLC animals developed tumors that contributed to significantly smaller tibialis anterior muscles (18.5%) and muscle cross-sectional area (40%) compared with PBS. We found 371 miRNAs to be present in the muscle above background levels. Of these, nine miRNAs were found to be differentially expressed. Significantly altered groups of miRNAs were categorized into primary functionalities including cancer, cell-to-cell signaling, and cellular development among others. Gene network analysis predicted specific alterations of factors contributing to muscle size including Akt, FOXO3, and others. These results create a foundation for future research into the sufficiency of targeting these genes to attenuate muscle loss in cancer cachexia. PMID- 28341622 TI - Abortion care in Canada is decided between a woman and her doctor, without recourse to criminal law. PMID- 28341623 TI - Twenty miles per hour speed limits: a sustainable solution to public health problems in Wales. AB - BACKGROUND: Prevention, rather than treatment, is the key to longer healthier lives. Identifying interventions that will impact positively on road traffic injuries, air quality and encourage active travel is a significant public health challenge. This paper aimed to explore whether 20 mph limits could be useful in achieving this. METHODS: Research evidence was reviewed to identify the effect of 20 mph zones and limits on health and well-being. The evidence was then used to estimate the effect of a change to a 20 mph limit on road traffic casualties and air pollution. It was then mapped against the seven goals of the Well-being of Future Generations Act (2015). RESULTS: If all current 30 mph limit roads in Wales became 20 mph limits, it is estimated that 6-10 lives would be saved and 1200-2000 casualties avoided each year, at a value of prevention of L58M-L94M. In terms of air pollution, deaths attributed to nitrogen dioxide (NO2) may increase by 63, and years of life lost by 753. However, deaths attributed to particulates (PM2.5) may decrease by 117 and years of life lost by 1400. Evidence review suggests benefits in terms of road traffic casualties, air quality, active travel, noise pollution, greater social inclusion, greater community cohesion and local business viability. CONCLUSIONS: Road traffic injuries, air pollution and obesity are an inter-related, interdependent triad. The challenge facing public health today is identifying robust interventions that will have positive effects on all three as a minimum; default 20 mph limits is the solution to increasing public health problems in Wales. PMID- 28341624 TI - Compliance affects success of ultrasound for bone healing. PMID- 28341625 TI - Non-cardiac surgery in patients with continuous-flow left ventricular assist devices: a single institutional experience. AB - With improvements in life expectancy for patients with continuous-flow left ventricular assist devices (LVADs), non-cardiac surgeons will increasingly encounter surgical problems in this population. 209 patients underwent LVAD placement between 10/1/2007 and 6/1/2015 at a single institution. Survival was compared between patients who had non-cardiac surgery (NCS) during the initial LVAD implantation hospitalization (n=36) and those who had NCS only in subsequent hospitalizations (n=33). Postoperative complication rates were examined. Index admission NCS was associated with lower 5-year survival compared with subsequent admission NCS (27.1% vs 39.4%, p=0.017). In subsequent admissions, the risks of bleeding and infectious complications were the same for elective or urgent NCS, but the risk of death was higher in the urgent surgery group. We conclude that elective NCS can be performed with low risk of death or LVAD dysfunction after sufficient recovery of patients from LVAD implantation. PMID- 28341626 TI - Phenotypic effects of allotetraploidization of wild Arachis and their implications for peanut domestication. AB - PREMISE OF THE STUDY: Several species of Arachis have been cultivated for their edible seeds, historically and to the present day. The diploid species that have a history of cultivation show relatively small signatures of domestication. In contrast, the tetraploid species A. hypogaea evolved into highly domesticated forms and became a major world crop, the cultivated peanut. It seems likely that allotetraploidization (hybridity and/or tetraploidization) in some way enhanced attractiveness for cultivation. Here we investigate this using six different hybridization and tetraploidization events, from distinct Arachis diploid species, including one event derived from the same wild species that originated peanut. METHODS: Twenty-six anatomical, morphological, and physiological traits were examined in the induced allotetraploid plants and compared with their wild diploid parents. KEY RESULTS: Nineteen traits were transgressive (showed strong response to hybridization and chromosome duplication): allotetraploids had larger leaves, stomata and epidermal cells than did their diploid parents. In addition, allotetraploids produced more photosynthetic pigments. These traits have the same trend across the different hybrid combinations, suggesting that the changes are more likely due to ploidy rather than hybridity. In contrast, seed dimensions and seed mass did not significantly change in response to hybridization or tetraploidization. CONCLUSIONS: We suggest that the original allotetraploid that gave rise to cultivated peanut may have been attractive because of an increase in plant size, different transpiration characteristics, higher photosynthetic capacity, or other characteristics, but contrary to accepted knowledge, increased seed size was unlikely to have been important in the initial domestication. PMID- 28341628 TI - Species richness and endemism in the native flora of California. AB - PREMISE OF THE STUDY: California's vascular flora is the most diverse and threatened in temperate North America. Previous studies of spatial patterns of Californian plant diversity have been limited by traditional metrics, non-uniform geographic units, and distributional data derived from floristic descriptions for only a subset of species. METHODS: We revisited patterns of sampling intensity, species richness, and relative endemism in California based on equal-area spatial units, the full vascular flora, and specimen-based distributional data. We estimated richness, weighted endemism (inverse range-weighting of species), and corrected weighted endemism (weighted endemism corrected for richness), and performed a randomization test for significantly high endemism. KEY RESULTS: Possible biases in herbarium data do not obscure patterns of high richness and endemism at the spatial resolution studied. High species richness was sometimes associated with significantly high endemism (e.g., Klamath Ranges) but often not. In Stebbins and Major's (1965) main endemism hotspot, Southwestern California, species richness is high across much of the Peninsular and Transverse ranges but significantly high endemism is mostly localized to the Santa Rosa and San Bernardino mountains. In contrast, species richness is low in the Channel Islands, where endemism is significantly high, as also found for much of the Death Valley region. CONCLUSIONS: Measures of taxonomic richness, even with greater weighting of range-restricted taxa, are insufficient for identifying areas of significantly high endemism that warrant conservation attention. Differences between our findings and those in previous studies appear to mostly reflect the source and scale of distributional data, and recent analytical refinements. PMID- 28341629 TI - Persistent homology and the branching topologies of plants. PMID- 28341630 TI - Flexibility of resource allocation in a hermaphroditic-gynomonoecious herb through deployment of female and male resources in perfect flowers. AB - PREMISE OF THE STUDY: It has been hypothesized that two flower types permit flexible allocation of resources to female and male functions, yet empirical evidence for the sex-allocation hypothesis remains scarce in gynomonoecious species. To characterize resource allocation to pistillate and perfect flowers and allocation of perfect flowers between gynomonoecious and hermaphroditic individuals, we examined the flexibility and whether female-biased allocation increases with plant size in the hermaphroditic-gynomonoecious herb Eremurus anisopterus. METHODS: Frequency of gynomonoecious individuals, flower production, and plant size were investigated in different populations. Floral allocation was compared among the three flower types of E. anisopterus. KEY RESULTS: Frequency of gynomonoecious plants varied from 2-17% in nine populations. Only larger plants produced female flowers at the bottom of racemes. Both female and perfect flower production tended to increase proportionately with plant size in gynomonoecious individuals. Female flowers did not produce less biomass than perfect flowers from hermaphroditic or gynomonoecious plants. However, both female and perfect flowers from gynomonoecious individuals had lighter stamen mass, but larger pistil mass, than perfect flowers from hermaphrodites. CONCLUSIONS: Although the prediction of an increase in female flower number with plant size was not observed in E. anisopterus, the flexibility of sex allocation in gynomonoecious species was confirmed in that gynomonoecious individuals had a female-biased floral allocation compared to hermaphroditic individuals. Such comparisons of gynomonoecious to hermaphroditic individuals permit us to unveil a sexual adjustment strategy: flexibility of sexual investments within plants. PMID- 28341631 TI - Effects of soil type and light on height growth, biomass partitioning, and nitrogen dynamics on 22 species of tropical dry forest tree seedlings: Comparisons between legumes and nonlegumes. AB - PREMISE OF THE STUDY: The seedling stage is particularly vulnerable to resource limitation, with potential consequences for community composition. We investigated how light and soil variation affected early growth, biomass partitioning, morphology, and physiology of 22 tree species common in tropical dry forest, including eight legumes. Our hypothesis was that legume seedlings are better at taking advantage of increased resource availability, which contributes to their successful regeneration in tropical dry forests. METHODS: We grew seedlings in a full-factorial design under two light levels in two soil types that differed in nutrient concentrations and soil moisture. We measured height biweekly and, at final harvest, biomass partitioning, internode segments, leaf carbon, nitrogen, delta13C, and delta15N. KEY RESULTS: Legumes initially grew taller and maintained that height advantage over time under all experimental conditions. Legumes also had the highest final total biomass and water-use efficiency in the high-light and high-resource soil. For nitrogen-fixing legumes, the amount of nitrogen derived from fixation was highest in the richer soil. Although seed mass tended to be larger in legumes, seed size alone did not account for all the differences between legumes and nonlegumes. Both belowground and aboveground resources were limiting to early seedling growth and function. CONCLUSIONS: Legumes may have a different regeneration niche, in that they germinate rapidly and grow taller than other species immediately after germination, maximizing their performance when light and belowground resources are readily available, and potentially permitting them to take advantage of high light, nutrient, and water availability at the beginning of the wet season. PMID- 28341632 TI - Microvascular leakage in acute myocardial infarction: characterization by histology, biochemistry, and magnetic resonance imaging. AB - Cardiac microvascular obstruction (MVO) after ischemia-reperfusion (I/R) has been well studied, but microvascular leakage (MVL) remains largely unexplored. We characterized MVL in the mouse I/R model by histology, biochemistry, and cardiac magnetic resonance (CMR) imaging. I/R was induced surgically in mice. MVL was determined by administrating the microvascular permeability tracer Evans blue (EB) and/or gadolinium-diethylenetriaminepentaacetic acid contrast. The size of MVL, infarction, and MVO in the heart was quantified histologically. Myocardial EB was extracted and quantified chromatographically. Serial CMR images were acquired from euthanized mice to determine late gadolinium enhancement (LGE) for comparison with MVL quantified by histology. I/R resulted in MVL with its severity dependent on the ischemic duration and reaching its maximum at 24-48 h after reperfusion. The size of MVL correlated with the degree of left ventricular dilatation and reduction in ejection fraction. Within the risk zone, the area of MVL (75 +/- 2%) was greater than that of infarct (47 +/- 4%, P < 0.01) or MVO (36 +/- 4%, P < 0.01). Contour analysis of paired CMR-LGE by CMR and histological MVL images revealed a high degree of spatial colocalization (r = 0.959, P < 0.0001). These data indicate that microvascular barrier function is damaged after I/R leading to MVL. Histological and biochemical means are able to characterize MVL by size and severity while CMR-LGE is a potential diagnostic tool for MVL. The size of ischemic myocardium exhibiting MVL was greater than that of infarction and MVO, implying a role of MVL in postinfarct pathophysiology.NEW & NOTEWORTHY We characterized, for the first time, the features of microvascular leakage (MVL) as a consequence of reperfused myocardial infarction. The size of ischemic myocardium exhibiting MVL was significantly greater than that of infarction or no reflow. We made a proof-of-concept finding on the diagnostic potential of MVL by cardiac magnetic resonance imaging. PMID- 28341633 TI - Increased hypoxia-inducible factor-1alpha in striated muscle of tumor-bearing mice. AB - Cancer cachexia is a progressive wasting disease resulting in significant effects on the quality of life and high mortality. Most studies on cancer cachexia have focused on skeletal muscle; however, the heart is now recognized as a major site of cachexia-related effects. To elucidate possible mechanisms, a proteomic study was performed on the left ventricles of colon-26 (C26) adenocarcinoma tumor bearing mice. The results revealed several changes in proteins involved in metabolism. An integrated pathway analysis of the results revealed a common mediator in hypoxia-inducible factor-1alpha (HIF-1alpha). Work by other laboratories has shown that extensive metabolic restructuring in the C26 mouse model causes changes in gene expression that may be affected directly by HIF 1alpha, such as glucose metabolic genes. M-mode echocardiography showed progressive decline in heart function by day 19, exhibited by significantly decreased ejection fraction and fractional shortening, along with posterior wall thickness. Using Western blot analysis, we confirmed that HIF-1alpha is significantly upregulated in the heart, whereas there were no changes in its regulatory proteins, prolyl hydroxylase domain-containing protein 2 (PHD2) and von Hippel-Lindau protein (VHL). PHD2 requires both oxygen and iron as cofactors for the hydroxylation of HIF-1alpha, marking it for ubiquination via VHL and subsequent destruction by the proteasome complex. We examined venous blood gas values in the tumor-bearing mice and found significantly lower oxygen concentration compared with control animals in the third week after tumor inoculation. We also examined select skeletal muscles to determine whether they are similarly affected. In the diaphragm, extensor digitorum longus, and soleus, we found significantly increased HIF-1alpha in tumor-bearing mice, indicating a hypoxic response, not only in the heart, but also in skeletal muscle. These results indicate that HIF-1alpha may contribute, in part, to the metabolic changes that occur during cancer cachexia.NEW & NOTEWORTHY We used proteomics and metadata analysis software to identify contributors to metabolic changes in striated muscle during cancer cachexia. We found increased expression of hypoxia inducible factor-1alpha in the heart and skeletal muscle, suggesting a potential target for the therapeutic treatment of cancer cachexia. PMID- 28341635 TI - Sept7b is required for the subcellular organization of cardiomyocytes and cardiac function in zebrafish. AB - Myofibrils made up of actin, myosin, and associated proteins generate the contractile force in muscle, and, consequently, mutations in these proteins may lead to heart failure. Septins are a conserved family of small GTPases that associate with actin filaments, microtubules, and cellular membranes. Despite the importance of septins in cytoskeleton organization, their role in cardiomyocyte organization and function is poorly characterized. Here, we show that septin 7 is expressed in both embryonic and adult zebrafish hearts and elucidate the physiological significance of sept7b, the zebrafish ortholog of human septin 7, in the heart in embryonic and larval zebrafish. Knockdown of sept7b reduced F actin and alpha-cardiac actin expression in the heart and caused disorganization of actin filaments. Electron microscopy of sept7b-depleted larvae showed disorganization of heart myofibrils and partial detachment from Z-disks. Functional studies revealed that knockdown of sept7b leads to reduced ventricular dimensions, contractility, and cardiac output. Furthermore, we found that depletion of sept7b diminished the expression of retinaldehyde dehydrogenase 2, which catalyzes the synthesis of retinoic acid necessary for heart morphogenesis. We further observed that the sept7b and retinoic acid signaling pathways converge to regulate cardiac function. Together, these results specify an essential role for sept7b in the contractile function of the heart.NEW & NOTEWORTHY Knockdown of the zebrafish ortholog of human septin 7 (sept7b) destabilizes cardiac actin and reduces ventricular dimensions, contractility, and cardiac output in larval zebrafish, indicating that sept7b is essential for cardiac function. We further found that sept7b and retinoic acid signaling pathways converge to regulate cardiac function. These data prompt further studies defining the role of sept7b in cardiomyopathies. PMID- 28341634 TI - Contribution of two-pore K+ channels to cardiac ventricular action potential revealed using human iPSC-derived cardiomyocytes. AB - Two-pore K+ (K2p) channels have been described in modulating background conductance as leak channels in different physiological systems. In the heart, the expression of K2p channels is heterogeneous with equivocation regarding their functional role. Our objective was to determine the K2p expression profile and their physiological and pathophysiological contribution to cardiac electrophysiology. Induced pluripotent stem cells (iPSCs) generated from humans were differentiated into cardiomyocytes (iPSC-CMs). mRNA was isolated from these cells, commercial iPSC-CM (iCells), control human heart ventricular tissue (cHVT), and ischemic (iHF) and nonischemic heart failure tissues (niHF). We detected 10 K2p channels in the heart. Comparing quantitative PCR expression of K2p channels between human heart tissue and iPSC-CMs revealed K2p1.1, K2p2.1, K2p5.1, and K2p17.1 to be higher expressed in cHVT, whereas K2p3.1 and K2p13.1 were higher in iPSC-CMs. Notably, K2p17.1 was significantly lower in niHF tissues compared with cHVT. Action potential recordings in iCells after K2p small interfering RNA knockdown revealed prolongations in action potential depolarization at 90% repolarization for K2p2.1, K2p3.1, K2p6.1, and K2p17.1. Here, we report the expression level of 10 human K2p channels in iPSC-CMs and how they compared with cHVT. Importantly, our functional electrophysiological data in human iPSC-CMs revealed a prominent role in cardiac ventricular repolarization for four of these channels. Finally, we also identified K2p17.1 as significantly reduced in niHF tissues and K2p4.1 as reduced in niHF compared with iHF. Thus, we advance the notion that K2p channels are emerging as novel players in cardiac ventricular electrophysiology that could also be remodeled in cardiac pathology and therefore contribute to arrhythmias.NEW & NOTEWORTHY Two-pore K+ (K2p) channels are traditionally regarded as merely background leak channels in myriad physiological systems. Here, we describe the expression profile of K2p channels in human-induced pluripotent stem cell-derived cardiomyocytes and outline a salient role in cardiac repolarization and pathology for multiple K2p channels. PMID- 28341637 TI - The Tax Exclusion for Employer-Sponsored Insurance Is Not Regressive-But What Is It? AB - Conventional wisdom says that the tax exclusion for employer-sponsored health insurance (ESI) is "regressive and therefore unfair." Yet, by the standard definition of regressive tax policy, the conventional view is almost certainly false. It confuses the absolute size of the tax exclusion with its proportional effect on income. The error results from paying attention only to the marginal tax rate applied to ESI benefits as a portion of income and ignoring the fact that benefits are normally a much larger share of income for people with lower wages. This article explains the difference and then considers other distributional effects of ESI. It suggests that ESI-for those who receive it further redistributes toward those with lesser means or greater need. The most evident effect is by need, favoring employees with families over those without. Yet there is good reason to believe there is also a redistribution by income, with the package of wages plus benefits being less unequal than wages alone would be. Therefore reformers should be much more careful before criticizing either ESI or its subsidy through the tax code as "unfair," especially as the likelihood of enacting something better in the United States seems quite low. PMID- 28341636 TI - Relief from neuropathic pain by blocking of the platelet-activating factor-pain loop. AB - Neuropathic pain resulting from peripheral neuronal damage is largely resistant to treatment with currently available analgesic drugs. Recently, ATP, lysophosphatidic acid, and platelet-activating factor (PAF) have been reported to play important inductive roles in neuropathic pain. In the present study, we found that pain-like behaviors resulting from partial sciatic nerve ligation (PSL) were largely attenuated by deficiency of lysophosphatidylcholine acyltransferase (LPCAT)2, which is one of the PAF biosynthetic enzymes. By contrast, deficiency of the other PAF biosynthetic enzyme, LPCAT1, did not ameliorate neuropathic pain. With regard to the mechanism of the observed effects, LPCAT2 was detected in wild-type spinal cord microglia, and the absence of LPCAT2 expression precluded spinal PAF expression in LPCAT2-knockout mice. Furthermore, ATP-stimulated PAF biosynthesis in macrophages was decreased by pretreatment with the PAF receptor antagonist ABT-491, indicating the existence of a positive feedback loop of PAF biosynthesis, which we designated the PAF-pain loop. In conclusion, LPCAT2 is a novel therapeutic target for newly categorized analgesic drugs; in addition, our data call for the re-evaluation of the clinical utility of PAF receptor antagonists.-Shindou, H., Shiraishi, S., Tokuoka, S. M., Takahashi Y., Harayama, T., Abe, T., Bando, K., Miyano, K., Kita, Y., Uezono, Y., Shimizu, T. Relief from neuropathic pain by blocking of the platelet-activating factor-pain loop. PMID- 28341638 TI - TET1 exerts its tumour suppressor function by regulating autophagy in glioma cells. AB - DNA methylation and demethylation play a critical role in the regulation of the molecular pathogenesis of gliomas. Tet methylcytosine dioxygenase 1 (TET1) catalyses the sequential oxidation of 5-methylcytosine (5mC) to 5 hydroxymethylcytosine, (5hmC) leading to eventual DNA demethylation. It has been reported that TET1 is a tumour suppressor in several cancers. However, whether TET1 plays a role in glioma development is largely unclear. Different glioma specimens and corresponding normal controls were collected to analyse the expression of TET1. At the same time, TET1 of glioma U251 cells was knocked down or overexpressed to observe its effect on glioma cell proliferation and invasion as well as autophagy level. Here, we reported that the expression of TET1 in glioma tissue was significantly lower than the corresponding non-tumour normal tissues, and the concentration of TET1 is negatively correlated with the glioma WHO classification. When TET1 gene in glioma U251 cells was knocked down by CRISPR/Caspase-9 system, the proliferation and invasive ability of U251 increased remarkably. But when TET1 was overexpressed in U251 cells, the proliferation and invasion were impaired. Following the down-expression of TET1, the level of autophagy in U251 cells decreased accordingly.However, when TET1 was overexpressed in U251 cells, the level of autophagy incraesed. Furthermore, bafilomycin A1 (Baf-A1) but not 3-methyladenine (3-MA) could decrease the autophagy level of TET1-/- U251 cells as the wild-type controls. It suggests that the tumour suppressor effect of TET1 seems to be mediated by regulating the level of autophagy, and the regulation of TET1 on autophagy is at an early stage. PMID- 28341639 TI - Indian doctors take to streets to demand better security. PMID- 28341640 TI - Impaired B cell function during viral infections due to PTEN-mediated inhibition of the PI3K pathway. AB - Transient suppression of B cell function often accompanies acute viral infection. However, the molecular signaling circuitry that enforces this hyporesponsiveness is undefined. In this study, experiments identify up-regulation of the inositol phosphatase PTEN (phosphatase and tensin homolog) as primarily responsible for defects in B lymphocyte migration and antibody responses that accompany acute viral infection. B cells from mice acutely infected with gammaherpesvirus 68 are defective in BCR- and CXCR4-mediated activation of the PI3K pathway, and this, we show, is associated with increased PTEN expression. This viral infection-induced PTEN overexpression appears responsible for the suppression of antibody responses observed in infected mice because PTEN deficiency or expression of a constitutively active PI3K rescued function of B cells in infected mice. Conversely, induced overexpression of PTEN in B cells in uninfected mice led to suppression of antibody responses. Finally, we demonstrate that PTEN up regulation is a common mechanism by which infection induces suppression of antibody responses. Collectively, these findings identify a novel role for PTEN during infection and identify regulation of the PI3K pathway, a mechanism previously shown to silence autoreactive B cells, as a key physiological target to control antibody responses. PMID- 28341642 TI - Feasibility and accuracy of teleconcussion for acute evaluation of suspected concussion. AB - OBJECTIVE: To assess the feasibility and accuracy of telemedical concussion evaluations (teleconcussion) for real-time athletic sideline assessment of concussion, as such assessment may address the gap in access some populations of athletes have to providers with expertise in concussion evaluation. METHODS: A cohort of 11 consecutive male collegiate football players with suspected concussion was assessed using Standardized Assessment of Concussion (SAC), King Devick test (K-D), and modified Balance Error Scoring System (mBESS). A remote neurologist assessed each athlete using a telemedicine robot with real-time, 2 way audiovisual capabilities, while a sideline provider performed a simultaneous face-to-face assessment. After the assessment, a remove-from-play (RFP) determination was made. The remote and the face-to-face providers were blinded to each other's examination findings and RFP decision until the end of the assessment. RESULTS: The teleconcussion and face-to-face SAC were in agreement 100% of the time (6/6; 95% confidence interval [CI] 54%-100%). The mean (SD) difference between remote and sideline K-D times was 0.7 (1.4) seconds. Remote and sideline K-D times were within a 3-second difference 100% of the time (11/11; 95% CI 72%-100%). Remote and sideline mBESS scores were within 3 points 100% of the time (6/6; 95% CI 54%-100%). RFP decisions were in agreement 100% of the time (11/11; 95% CI 72%-100%). CONCLUSIONS: The aim of this study was to investigate the feasibility of teleconcussion for sideline concussion assessments. These data suggest a high level of agreement between remote and face-to-face providers with regard to examination findings and RFP determinations. PMID- 28341641 TI - Proliferation of latently infected CD4+ T cells carrying replication-competent HIV-1: Potential role in latent reservoir dynamics. AB - A latent reservoir for HIV-1 in resting CD4+ T lymphocytes precludes cure. Mechanisms underlying reservoir stability are unclear. Recent studies suggest an unexpected degree of infected cell proliferation in vivo. T cell activation drives proliferation but also reverses latency, resulting in productive infection that generally leads to cell death. In this study, we show that latently infected cells can proliferate in response to mitogens without producing virus, generating progeny cells that can release infectious virus. Thus, assays relying on one round of activation underestimate reservoir size. Sequencing of independent clonal isolates of replication-competent virus revealed that 57% had env sequences identical to other isolates from the same patient. Identity was confirmed by full-genome sequencing and was not attributable to limited viral diversity. Phylogenetic and statistical analysis suggested that identical sequences arose from in vivo proliferation of infected cells, rather than infection of multiple cells by a dominant viral species. The possibility that much of the reservoir arises by cell proliferation presents challenges to cure. PMID- 28341643 TI - Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: A systematic review. AB - OBJECTIVE: To systematically assess the effect of pharmacologic treatments of diabetic peripheral neuropathy (DPN) on pain and quality of life. METHODS: We searched PubMed and Cochrane Database of Systematic Reviews for systematic reviews from 2011 to October 12, 2015, and PubMed, Embase, and the Cochrane Central Register of Controlled Trials for primary studies from January 1, 2013, to May 24, 2016. We searched Clinicaltrials.gov on March 9, 2016. Two reviewers independently evaluated studies for eligibility, serially abstracted data, and independently evaluated risk of bias and graded strength of evidence (SOE). RESULTS: We updated a recently completed systematic review of 57 eligible studies with 24 additional published studies and 25 unpublished studies. For reducing neuropathy-related pain, the serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine (moderate SOE), the anticonvulsants pregabalin and oxcarbazepine (low SOE), the drug classes tricyclic antidepressants (low SOE) and atypical opioids (low SOE), and botulinum toxin (low SOE) were more effective than placebo. We could not draw conclusions about quality of life due to incomplete reporting. All studies were short-term (less than 6 months), and all effective drugs had more than 9% dropouts from adverse effects. CONCLUSIONS: For reducing pain, duloxetine and venlafaxine, pregabalin and oxcarbazepine, tricyclic antidepressants, atypical opioids, and botulinum toxin were more effective than placebo. However, quality of life was poorly reported, studies were short-term, drugs had substantial dropout rates, and opioids have significant risks. Future studies should evaluate longer-term outcomes, use methods and measures recommended by pain organizations, and assess patients' quality of life. PMID- 28341644 TI - Nerve ultrasound: A useful screening tool for peripheral nerve sheath tumors in NF1? AB - OBJECTIVE: To determine ultrasonographic peripheral nerve involvement in patients with asymptomatic neurofibromatosis type 1 (NF1). METHODS: Thirteen asymptomatic and 4 minimally symptomatic patients with NF1 were included in this cross sectional pilot study to detect asymptomatic abnormalities of the brachial plexus and upper and lower extremity nerves. Patients underwent clinical examination, nerve conduction studies (NCS), and high-resolution ultrasonography (HRUS). RESULTS: HRUS showed abnormalities in 16 patients (94.1%). Neurofibromas were identified in 10 patients (58.8%): localized neurofibromas were found in 3 patients (17.6%), plexiform neurofibromas in 3 (17.6%), and both in 4 (23.5%). In 6 patients (35.3%), only nerve enlargement without an abnormal fascicular pattern was observed. Severe involvement of the peripheral nervous system with multiple plexiform neurofibromas was observed in 7 patients (41.2%), while 4 patients (23.5%) had no or only minor involvement. Both NCS and HRUS were performed on 73 individual nerve segments. In 5.5%, abnormalities were found with both tests; in 50.7%, only with HRUS; and in 1.4%, only with NCS. CONCLUSIONS: HRUS frequently showed subclinical involvement of the peripheral nerves in NF1, also when NCS were normal. HRUS findings ranged from normal to widespread peripheral nerve involvement. Because the presence of plexiform neurofibromas and the benign tumor load are risk factors for the development of a malignant peripheral nerve sheath tumor, HRUS may be a useful tool to identify a subgroup of patients who could benefit from regular follow-up. PMID- 28341645 TI - Paroxysmal eye-head movements in Glut1 deficiency syndrome. AB - OBJECTIVE: To describe a characteristic paroxysmal eye-head movement disorder that occurs in infants with Glut1 deficiency syndrome (Glut1 DS). METHODS: We retrospectively reviewed the medical charts of 101 patients with Glut1 DS to obtain clinical data about episodic abnormal eye movements and analyzed video recordings of 18 eye movement episodes from 10 patients. RESULTS: A documented history of paroxysmal abnormal eye movements was found in 32/101 patients (32%), and a detailed description was available in 18 patients, presented here. Episodes started before age 6 months in 15/18 patients (83%), and preceded the onset of seizures in 10/16 patients (63%) who experienced both types of episodes. Eye movement episodes resolved, with or without treatment, by 6 years of age in 7/8 patients with documented long-term course. Episodes were brief (usually <5 minutes). Video analysis revealed that the eye movements were rapid, multidirectional, and often accompanied by a head movement in the same direction. Eye movements were separated by clear intervals of fixation, usually ranging from 200 to 800 ms. The movements were consistent with eye-head gaze saccades. These movements can be distinguished from opsoclonus by the presence of a clear intermovement fixation interval and the association of a same-direction head movement. CONCLUSIONS: Paroxysmal eye-head movements, for which we suggest the term aberrant gaze saccades, are an early symptom of Glut1 DS in infancy. Recognition of the episodes will facilitate prompt diagnosis of this treatable neurodevelopmental disorder. PMID- 28341646 TI - Cardiorespiratory fitness alters the influence of a polygenic risk score on biomarkers of AD. AB - OBJECTIVE: To examine whether a polygenic risk score (PRS) derived from APOE4, CLU, and ABCA7 is associated with CSF biomarkers of Alzheimer disease (AD) pathology and whether higher cardiorespiratory fitness (CRF) modifies the association between the PRS and CSF biomarkers. METHODS: Ninety-five individuals from the Wisconsin Registry for Alzheimer's Prevention were included in these cross-sectional analyses. They were genotyped for APOE4, CLU, and ABCA7, from which a PRS was calculated for each participant. The participants underwent lumbar puncture for CSF collection. beta-Amyloid 42 (Abeta42), Abeta40, total tau (t-tau), and phosphorylated tau (p-tau) were quantified by immunoassays, and Abeta42/Abeta40 and tau/Abeta42 ratios were computed. CRF was estimated from a validated equation incorporating sex, age, body mass index, resting heart rate, and self-reported physical activity. Covariate-adjusted regression analyses were used to test for associations between the PRS and CSF biomarkers. In addition, by including a PRS*CRF term in the models, we examined whether these associations were modified by CRF. RESULTS: A higher PRS was associated with lower Abeta42/Abeta40 (p < 0.001), higher t-tau/Abeta42 (p = 0.012), and higher p tau/Abeta42 (p = 0.040). Furthermore, we observed PRS * CRF interactions for Abeta42/Abeta40 (p = 0.003), t-tau/Abeta42 (p = 0.003), and p-tau/Abeta42 (p = 0.001). Specifically, the association between the PRS and these CSF biomarkers was diminished in those with higher CRF. CONCLUSIONS: In a late-middle-aged cohort, CRF attenuates the adverse influence of genetic vulnerability on CSF biomarkers. These findings support the notion that increased cardiorespiratory fitness may be beneficial to those at increased genetic risk for AD. PMID- 28341647 TI - Estimating Seven Coefficients of Pairwise Relatedness Using Population-Genomic Data. AB - Population structure can be described by genotypic-correlation coefficients between groups of individuals, the most basic of which are the pairwise relatedness coefficients between any two individuals. There are nine pairwise relatedness coefficients in the most general model, and we show that these can be reduced to seven coefficients for biallelic loci. Although all nine coefficients can be estimated from pedigrees, six coefficients have been beyond empirical reach. We provide a numerical optimization procedure that estimates all seven reduced coefficients from population-genomic data. Simulations show that the procedure is nearly unbiased, even at 3* coverage, and errors in five of the seven coefficients are statistically uncorrelated. The remaining two coefficients have a negative correlation of errors, but their sum provides an unbiased assessment of the overall correlation of heterozygosity between two individuals. Application of these new methods to four populations of the freshwater crustacean Daphnia pulex reveal the occurrence of half siblings in our samples, as well as a number of identical individuals that are likely obligately asexual clone mates. Statistically significant negative estimates of these pairwise relatedness coefficients, including inbreeding coefficients that were typically negative, underscore the difficulties that arise when interpreting genotypic correlations as estimations of the probability that alleles are identical by descent. PMID- 28341648 TI - DNA Damage Tolerance Pathway Choice Through Uls1 Modulation of Srs2 SUMOylation in Saccharomyces cerevisiae. AB - DNA damage tolerance and homologous recombination pathways function to bypass replication-blocking lesions and ensure completion of DNA replication. However, inappropriate activation of these pathways may lead to increased mutagenesis or formation of deleterious recombination intermediates, often leading to cell death or cancer formation in higher organisms. Post-translational modifications of PCNA regulate the choice of repair pathways at replication forks. Its monoubiquitination favors translesion synthesis, while polyubiquitination stimulates template switching. Srs2 helicase binds to small ubiquitin-related modifier (SUMO)-modified PCNA to suppress a subset of Rad51-dependent homologous recombination. Conversely, SUMOylation of Srs2 attenuates its interaction with PCNA Sgs1 helicase and Mus81 endonuclease are crucial for disentanglement of repair intermediates at the replication fork. Deletion of both genes is lethal and can be rescued by inactivation of Rad51-dependent homologous recombination. Here we show that Saccharomyces cerevisiae Uls1, a member of the Swi2/Snf2 family of ATPases and a SUMO-targeted ubiquitin ligase, physically interacts with both PCNA and Srs2, and promotes Srs2 binding to PCNA by downregulating Srs2-SUMO levels at replication forks. We also identify deletion of ULS1 as a suppressor of mus81Delta sgs1Delta synthetic lethality and hypothesize that uls1Delta mutation results in a partial inactivation of the homologous recombination pathway, detrimental in cells devoid of both Sgs1 and Mus81 We thus propose that Uls1 contributes to the pathway where intermediates generated at replication forks are dismantled by Srs2 bound to SUMO-PCNA. Upon ULS1 deletion, accumulating Srs2-SUMO unable to bind PCNA-takes part in an alternative PCNA-independent recombination repair salvage pathway(s). PMID- 28341649 TI - F-Box Protein XREP-4 Is a New Regulator of the Oxidative Stress Response in Caenorhabditis elegans. AB - The transcription factor SKN-1 (Skinhead family member-1) in Caenorhabditis elegans is a homolog of the mammalian Nrf-2 protein and functions to promote oxidative stress resistance and longevity. SKN-1 mediates protection from reactive oxygen species (ROS) via the transcriptional activation of genes involved in antioxidant defense and phase II detoxification. Although many core regulators of SKN-1 have been identified, much remains unknown about this complex signaling pathway. We carried out an ethyl methanesulfonate (EMS) mutagenesis screen and isolated six independent mutants with attenuated SKN-1-dependent gene activation in response to acrylamide. All six were found to contain mutations in F46F11.6/xrep-4 (xenobiotics response pathways-4), which encodes an uncharacterized F-box protein. Loss of xrep-4 inhibits the skn-1-dependent expression of detoxification genes in response to prooxidants and decreases survival of oxidative stress, but does not shorten life span under standard culture conditions. XREP-4 interacts with the ubiquitin ligase component SKR-1 and the SKN-1 principal repressor WDR-23, and knockdown of xrep-4 increases nuclear localization of a WDR-23::GFP fusion protein. Furthermore, a missense mutation in the conserved XREP-4 F-box domain that reduces interaction with SKR-1 but not WDR-23 strongly attenuates SKN-1-dependent gene activation. These results are consistent with XREP-4 influencing the SKN-1 stress response by functioning as a bridge between WDR-23 and the ubiquitin ligase component SKR-1. PMID- 28341650 TI - Bivariate Analysis of Age-Related Macular Degeneration Progression Using Genetic Risk Scores. AB - Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world. While many AMD susceptibility variants have been identified, their influence on AMD progression has not been elucidated. Using data from two large clinical trials, Age-Related Eye Disease Study (AREDS) and AREDS2, we evaluated the effects of 34 known risk variants on disease progression. In doing so, we calculated the eye-level time-to-late AMD and modeled them using a bivariate survival analysis approach, appropriately accounting for between-eye correlation. We then derived a genetic risk score (GRS) based on these 34 risk variants, and analyzed its effect on AMD progression. Finally, we used the AREDS data to fit prediction models of progression based on demographic and environmental factors, eye-level AMD severity scores and the GRS and tested the models using the AREDS2 cohort. We observed that GRS was significantly associated with AMD progression in both cohorts, with a stronger effect in AREDS than in AREDS2 (AREDS: hazard ratio (HR) = 1.34, P = 1.6 * 10-22; AREDS2: HR = 1.11, P = 2.1 * 10-4). For prediction of AMD progression, addition of GRS to the demographic/environmental risk factors considerably improved the prediction performance. However, when the baseline eye-level severity scores were included as the predictors, any other risk factors including the GRS only provided small additional predictive power. Our model for predicting the disease progression risk demonstrated satisfactory performance in both cohorts, and we recommend its use with baseline AMD severity scores plus baseline age, education level, and smoking status, either with or without GRS. PMID- 28341651 TI - A Cre Transcription Fidelity Reporter Identifies GreA as a Major RNA Proofreading Factor in Escherichia coli. AB - We made a coupled genetic reporter that detects rare transcription misincorporation errors to measure RNA polymerase transcription fidelity in Escherichia coli Using this reporter, we demonstrated in vivo that the transcript cleavage factor GreA, but not GreB, is essential for proofreading of a transcription error where a riboA has been misincorporated instead of a riboG. A greA mutant strain had more than a 100-fold increase in transcription errors relative to wild-type or a greB mutant. However, overexpression of GreB in DeltagreA cells reduced the misincorporation errors to wild-type levels, demonstrating that GreB at high concentration could substitute for GreA in RNA proofreading activity in vivo. PMID- 28341652 TI - Exploring Evolutionary Relationships Across the Genome Using Topology Weighting. AB - We introduce the concept of topology weighting, a method for quantifying relationships between taxa that are not necessarily monophyletic, and visualizing how these relationships change across the genome. A given set of taxa can be related in a limited number of ways, but if each taxon is represented by multiple sequences, the number of possible topologies becomes very large. Topology weighting reduces this complexity by quantifying the contribution of each taxon topology to the full tree. We describe our method for topology weighting by iterative sampling of subtrees (Twisst), and test it on both simulated and real genomic data. Overall, we show that this is an informative and versatile approach, suitable for exploring relationships in almost any genomic dataset. Scripts to implement the method described are available at http://github.com/simonhmartin/twisst. PMID- 28341654 TI - Rapid Adaptation of a Polygenic Trait After a Sudden Environmental Shift. AB - Although a number of studies have shown that natural and laboratory populations initially well adapted to their environment can evolve rapidly when conditions suddenly change, the dynamics of rapid adaptation are not well understood. Here a population genetic model of polygenic selection is analyzed to describe the short term response of a quantitative trait after a sudden shift of the phenotypic optimum. We provide explicit analytical expressions for the timescales over which the trait mean approaches the new optimum. We find that when the effect sizes are small relative to a scaled mutation rate, small to moderate allele frequency changes occur in the short-term phase in a synergistic fashion. In contrast, selective sweeps, i.e., dramatic changes in the allele frequency, may occur provided the size of the effect is sufficiently large. Applications of our theoretical results to the relationship between QTL and selective sweep mapping and to tests of fast polygenic adaptation are discussed. PMID- 28341653 TI - Locomotion Behavior Is Affected by the GalphaS Pathway and the Two-Pore-Domain K+ Channel TWK-7 Interacting in GABAergic Motor Neurons in Caenorhabditis elegans. AB - Adjusting the efficiency of movement in response to environmental cues is an essential integrative characteristic of adaptive locomotion behavior across species. However, the modulatory molecules and the pathways involved are largely unknown. Recently, we demonstrated that in Caenorhabditis elegans, a loss-of function of the two-pore-domain potassium (K2P) channel TWK-7 causes a fast, coordinated, and persistent forward crawling behavior in which five central aspects of stimulated locomotion-velocity, direction, wave parameters, duration, and straightness-are affected. Here, we isolated the reduction-of-function allele cau1 of the C. elegans gene kin-2 in a forward genetic screen and showed that it phenocopies the locomotor activity and locomotion behavior of twk-7(null) animals. Kin-2 encodes the negative regulatory subunit of protein kinase A (KIN 1/PKA). Consistently, we found that other gain-of-function mutants of the GalphaS KIN-1/PKA pathway resemble kin-2(cau1) and twk-7(null) in locomotion phenotype. Using the powerful genetics of the C. elegans system in combination with cell type-specific approaches and detailed locomotion analyses, we identified TWK-7 as a putative downstream target of the GalphaS-KIN-1/PKA pathway at the level of the gamma-aminobutyric acid (GABA)ergic D-type motor neurons. Due to this epistatic interaction, we suggest that KIN-1/PKA and TWK-7 may share a common pathway that is probably involved in the modulation of both locomotor activity and locomotion behavior during forward crawling. PMID- 28341656 TI - Why can't hospital trusts recruit home grown talent? PMID- 28341655 TI - Accuracy of Demographic Inferences from the Site Frequency Spectrum: The Case of the Yoruba Population. AB - Some methods for demographic inference based on the observed genetic diversity of current populations rely on the use of summary statistics such as the Site Frequency Spectrum (SFS). Demographic models can be either model-constrained with numerous parameters, such as growth rates, timing of demographic events, and migration rates, or model-flexible, with an unbounded collection of piecewise constant sizes. It is still debated whether demographic histories can be accurately inferred based on the SFS. Here, we illustrate this theoretical issue on an example of demographic inference for an African population. The SFS of the Yoruba population (data from the 1000 Genomes Project) is fit to a simple model of population growth described with a single parameter (e.g., founding time). We infer a time to the most recent common ancestor of 1.7 million years (MY) for this population. However, we show that the Yoruba SFS is not informative enough to discriminate between several different models of growth. We also show that for such simple demographies, the fit of one-parameter models outperforms the stairway plot, a recently developed model-flexible method. The use of this method on simulated data suggests that it is biased by the noise intrinsically present in the data. PMID- 28341658 TI - Authors' reply to Farrar. PMID- 28341657 TI - Effect of fixation time on breast biomarker expression: a controlled study using cell line-derived xenografted (CDX) tumours. AB - AIMS: Altering the length of time specimens are placed in fixative without compromising analytical testing accuracy is a continuous challenge in the anatomical pathology lab. The aim of this study was to determine under controlled conditions the effects of variable fixation time on breast biomarker expression in human breast cancer cell line-derived xenografted (CDX) tumours. METHODS: CDX tumours using strong oestrogen receptor (ER)-positive, Her2-negative (MCF7) and weak ER-positive, Her2 equivocal (T47D) breast cancer cell lines were fixed for various times ranging from 1 to 336 hours in 10% neutral buffered formalin. CDX tumours were processed according to routine biomarker testing protocols and stained for ER and Her2 immunohistochemistry (IHC) and processed for HER2 fluorescence in situ hybridisation (FISH). The tumours were evaluated using Allred scoring for ER and current ASCO/CAP guidelines for Her2, and by objective cell counting methodology. RESULTS: No differences were found in expression of ER in either MCF7 or T47D CDX tumours under variable fixation. T47D tumours displayed equivocal Her2 staining when fixed for 24 hours, but fixation for <=8 hours resulted in consistently negative staining while tumours fixed for >72 hours demonstrated consistent equivocal staining (p<0.01). Cell counting assays revealed only a significant increase in sensitivity in tumours fixed for >72 hours (p<0.01). As expected, FISH results were unaffected by variable fixation. CONCLUSIONS: Neither shortened nor prolonged fixation affects ER expression, consistent with previous findings. In equivocal Her2-expressing tumours, however, increasing fixation increased the sensitivity of Her2 IHC reporting while not affecting FISH. PMID- 28341659 TI - Chronic microaspiration of bile acids induces lung fibrosis through multiple mechanisms in rats. AB - Gastroesophageal reflux (GER) and microaspiration of duodenogastric refluxate have been recognized as a risk factor for pulmonary fibrosis. Recent evidence suggests that bile acid microaspiration may contribute to the development of lung fibrosis. However, the molecular evidence is scarce and the underlying mechanisms remain to be elucidated. We have recently demonstrated that bile acids induce activation of alveolar epithelial cells (AECs) and lung fibroblasts in vitro In the present study, a rat model of bile acid microaspiration was established by weekly intratracheal instillation of three major bile acids including chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), and lithocholic acid (LCA). Repeated microaspiration of CDCA, DCA, and LCA caused fibrotic changes, including alveolar wall thickening and extensive collagen deposition, in rat lungs. Bile acid microaspiration also induced alveolar epithelial-mesenchymal transition (EMT), as indicated by up-regulation of mesenchymal markers alpha-smooth muscle actin (alpha-SMA) and vimentin, as well as down-regulaton of epithelial markers E cadherin and cytokeratin in alveolar epithelium of rat lungs. The expression of fibrogenic mediators, including transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and periostin, was significantly elevated in rat lungs exposed to microaspiration of bile acids. Furthermore, microaspiration of bile acids also induced p-Smad3 and farnesoid X receptor (FXR) expression in rat lungs. Our findings suggest that microaspiration of bile acids could promote the development of pulmonary fibrosis in vivo, possibly via stimulating fibrogenic mediator expression and activating TGF-beta1/Smad3 signaling and FXR. PMID- 28341660 TI - The noncoding RNA linc-ADAMTS5 cooperates with RREB1 to protect from intervertebral disc degeneration through inhibiting ADAMTS5 expression. AB - Previous studies have indicated the important roles of ADAMTS5 in intervertebral disc degeneration (IDD). However, the mechanisms that regulate ADAMTS5 expression in nuclear pulposus (NP) cells remain largely unknown. Evidence suggests that intergenic transcription may be associated with genes that encode transcriptional regulators. Here, we identified a long intergenic noncoding RNA, linc-ADAMTS5, which was transcribed in the opposite direction to ADAMTS5. In the present study, through mining computational algorithm programs, and publicly available data sets, we identified Ras-responsive element-binding protein 1 (RREB1) as a crucial transcription factor regulating the expression of ADAMTS5 in NP cells. RNA pull down, RNA immunoprecipitation (RIP), in vitro binding assays, and gain- and loss of-function studies indicated that a physical interaction between linc-ADAMTS5 and splicing factor proline/glutamine-rich (SFPQ) facilitated the recruitment of RREB1 to binding sites within the ADAMTS5 promoter to induce chromatin remodeling. This resulted in subdued ADAMTS5 levels in cultured NP cells involving histone deacetylases (HDACs). In clinical NP tissues, linc-ADAMTS5 and RREB1 were correlated negatively with ADAMTS5 expression. Taken together, these results demonstrate that RREB1 cooperates with noncoding RNA linc-ADAMTS5 to inhibit ADAMTS5 expression, thereby affecting degeneration of the extracellular matrix (ECM) of the intervertebral disc (IVD). PMID- 28341662 TI - Extreme polarisation sensitivity in the retina of the corn borer moth Ostrinia. AB - The visual system of the European corn borer (Ostrinia nubilalis) was analysed with microscopy and electrophysiological methods (electroretinograms and single cell recordings). Ostrinia nubilalis has a pair of mainly ultraviolet-sensitive ocelli and a pair of compound eyes, maximally sensitive to green light. The ommatidia contain a tiered, fused rhabdom, consisting of the rhabdomeres of 9-12 photoreceptor cells with sensitivity peak wavelengths at 356, 413, 480 and 530 nm. The photoreceptors in a large dorsal rim area have straight rhabdomeres and high polarisation sensitivity (PS1,2=3.4, 14). Elsewhere, in the main retina, the majority of photoreceptors have non-aligned microvilli and negligible PS, but each ommatidium contains one or two blue-sensitive distal photoreceptors with straight microvilli parallel to the dorsoventral axis, yielding extremely high PS (PS1,2,3=56, 63, 316). Rhabdoms containing distal cells with potentially high PS have evolved at least twice: in moths (Crambidae, Noctuidae, Saturniidae), as well as in dung beetles (Scarabaeidae). The distal photoreceptors with high PS, sensitive to vertically polarised light, represent a monopolatic system, which is unsuitable for the proper analysis of electric field vector (e-vector) orientation. However, the distal photoreceptors might be used in conjunction with polarisation-insensitive photoreceptors to detect objects that reflect polarised light with stereotyped orientation. PMID- 28341663 TI - Muscle-tendon mechanics explain unexpected effects of exoskeleton assistance on metabolic rate during walking. AB - The goal of this study was to gain insight into how ankle exoskeletons affect the behavior of the plantarflexor muscles during walking. Using data from previous experiments, we performed electromyography-driven simulations of musculoskeletal dynamics to explore how changes in exoskeleton assistance affected plantarflexor muscle-tendon mechanics, particularly for the soleus. We used a model of muscle energy consumption to estimate individual muscle metabolic rate. As average exoskeleton torque was increased, while no net exoskeleton work was provided, a reduction in tendon recoil led to an increase in positive mechanical work performed by the soleus muscle fibers. As net exoskeleton work was increased, both soleus muscle fiber force and positive mechanical work decreased. Trends in the sum of the metabolic rates of the simulated muscles correlated well with trends in experimentally observed whole-body metabolic rate (R2=0.9), providing confidence in our model estimates. Our simulation results suggest that different exoskeleton behaviors can alter the functioning of the muscles and tendons acting at the assisted joint. Furthermore, our results support the idea that the series tendon helps reduce positive work done by the muscle fibers by storing and returning energy elastically. We expect the results from this study to promote the use of electromyography-driven simulations to gain insight into the operation of muscle-tendon units and to guide the design and control of assistive devices. PMID- 28341664 TI - Monitoring Resistance, Recurrence in NSCLC. AB - Two studies indicate the importance of serial biopsies in monitoring patients with non-small cell lung cancer. In one, heterogeneous resistance mechanisms to EGFR-targeted therapy were observed, often varying between biopsies for individual patients. In another, circulating tumor cells detected recurrence 6 months earlier, on average, than conventional imaging. PMID- 28341661 TI - Vascular endothelial growth factor-A165b ameliorates outer-retinal barrier and vascular dysfunction in the diabetic retina. AB - Diabetic retinopathy (DR) is one of the leading causes of blindness in the developed world. Characteristic features of DR are retinal neurodegeneration, pathological angiogenesis and breakdown of both the inner and outer retinal barriers of the retinal vasculature and retinal pigmented epithelial (RPE) choroid respectively. Vascular endothelial growth factor (VEGF-A), a key regulator of angiogenesis and permeability, is the target of most pharmacological interventions of DR. VEGF-A can be alternatively spliced at exon 8 to form two families of isoforms, pro- and anti-angiogenic. VEGF-A165a is the most abundant pro-angiogenic isoform, is pro-inflammatory and a potent inducer of permeability. VEGF-A165b is anti-angiogenic, anti-inflammatory, cytoprotective and neuroprotective. In the diabetic eye, pro-angiogenic VEGF-A isoforms are up regulated such that they overpower VEGF-A165b. We hypothesized that this imbalance may contribute to increased breakdown of the retinal barriers and by redressing this imbalance, the pathological angiogenesis, fluid extravasation and retinal neurodegeneration could be ameliorated. VEGF-A165b prevented VEGF-A165a and hyperglycaemia-induced tight junction (TJ) breakdown and subsequent increase in solute flux in RPE cells. In streptozotocin (STZ)-induced diabetes, there was an increase in Evans Blue extravasation after both 1 and 8 weeks of diabetes, which was reduced upon intravitreal and systemic delivery of recombinant human (rh)VEGF-A165b. Eight-week diabetic rats also showed an increase in retinal vessel density, which was prevented by VEGF-A165b. These results show rhVEGF A165b reduces DR-associated blood-retina barrier (BRB) dysfunction, angiogenesis and neurodegeneration and may be a suitable therapeutic in treating DR. PMID- 28341670 TI - Prime-Boost Immunization Eliminates Metastatic Colorectal Cancer by Producing High-Avidity Effector CD8+ T Cells. AB - Heterologous prime-boost immunization with plasmid DNA and viral vector vaccines is an emerging approach to elicit CD8+ T cell-mediated immunity targeting pathogens and tumor Ags that is superior to either monotherapy. Yet, the mechanisms underlying the synergy of prime-boost strategies remain incompletely defined. In this study, we examine a DNA and adenovirus (Ad5) combination regimen targeting guanylyl cyclase C (GUCY2C), a receptor expressed by intestinal mucosa and universally expressed by metastatic colorectal cancer. DNA immunization efficacy was optimized by i.m. delivery via electroporation, yet it remained modest compared with Ad5. Sequential immunization with DNA and Ad5 produced superior antitumor efficacy associated with increased TCR avidity, whereas targeted disruption of TCR avidity enhancement eliminated GUCY2C-specific antitumor efficacy, without affecting responding T cell number or cytokine profile. Indeed, functional TCR avidity of responding GUCY2C-specific CD8+ T cells induced by various prime or prime-boost regimens correlated with antitumor efficacy, whereas T cell number and cytokine profile were not. Importantly, although sequential immunization with DNA and Ad5 maximized antitumor efficacy through TCR avidity enhancement, it produced no autoimmunity, reflecting sequestration of GUCY2C to intestinal apical membranes and segregation of mucosal and systemic immunity. Together, TCR avidity enhancement may be leveraged by prime-boost immunization to improve GUCY2C-targeted colorectal cancer immunotherapeutic efficacy and patient outcomes without concomitant autoimmune toxicity. PMID- 28341671 TI - Lipopolysaccharide-Elicited TSLPR Expression Enriches a Functionally Discrete Subset of Human CD14+ CD1c+ Monocytes. AB - Thymic stromal lymphopoietin (TSLP) is a cytokine produced mainly by epithelial cells in response to inflammatory or microbial stimuli and binds to the TSLP receptor (TSLPR) complex, a heterodimer composed of TSLPR and IL-7 receptor alpha (CD127). TSLP activates multiple immune cell subsets expressing the TSLPR complex and plays a role in several models of disease. Although human monocytes express TSLPR and CD127 mRNAs in response to the TLR4 agonist LPS, their responsiveness to TSLP is poorly defined. We demonstrate that TSLP enhances human CD14+ monocyte CCL17 production in response to LPS and IL-4. Surprisingly, only a subset of CD14+ CD16- monocytes, TSLPR+ monocytes (TSLPR+ mono), expresses TSLPR complex upon LPS stimulation in an NF-kappaB- and p38-dependent manner. Phenotypic, functional, and transcriptomic analysis revealed specific features of TSLPR+ mono, including higher CCL17 and IL-10 production and increased expression of genes with important immune functions (i.e., GAS6, ALOX15B, FCGR2B, LAIR1). Strikingly, TSLPR+ mono express higher levels of the dendritic cell marker CD1c. This evidence led us to identify a subset of peripheral blood CD14+ CD1c+ cells that expresses the highest levels of TSLPR upon LPS stimulation. The translational relevance of these findings is highlighted by the higher expression of TSLPR and CD127 mRNAs in monocytes isolated from patients with Gram-negative sepsis compared with healthy control subjects. Our results emphasize a phenotypic and functional heterogeneity in an apparently homogeneous population of human CD14+ CD16- monocytes and prompt further ontogenetic and functional analysis of CD14+ CD1c+ and LPS-activated CD14+ CD1c+ TSLPR+ mono. PMID- 28341672 TI - Activation of Myeloid TLR4 Mediates T Lymphocyte Polarization after Traumatic Brain Injury. AB - Traumatic brain injury (TBI) is a major public health issue, producing significant patient mortality and poor long-term outcomes. Increasing evidence suggests an important, yet poorly defined, role for the immune system in the development of secondary neurologic injury over the days and weeks following a TBI. In this study, we tested the hypothesis that peripheral macrophage infiltration initiates long-lasting adaptive immune responses after TBI. Using a murine controlled cortical impact model, we used adoptive transfer, transgenic, and bone marrow chimera approaches to show increased infiltration and proinflammatory (classically activated [M1]) polarization of macrophages for up to 3 wk post-TBI. Monocytes purified from the injured brain stimulated the proliferation of naive T lymphocytes, enhanced the polarization of T effector cells (TH1/TH17), and decreased the production of regulatory T cells in an MLR. Similarly, elevated T effector cell polarization within blood and brain tissue was attenuated by myeloid cell depletion after TBI. Functionally, C3H/HeJ (TLR4 mutant) mice reversed M1 macrophage and TH1/TH17 polarization after TBI compared with C3H/OuJ (wild-type) mice. Moreover, brain monocytes isolated from C3H/HeJ mice were less potent stimulators of T lymphocyte proliferation and TH1/TH17 polarization compared with C3H/OuJ monocytes. Taken together, our data implicate TLR4-dependent, M1 macrophage trafficking/polarization into the CNS as a key mechanistic link between acute TBI and long-term, adaptive immune responses. PMID- 28341673 TI - Differential Impacts of Land-Based Sources of Pollution on the Microbiota of Southeast Florida Coral Reefs. AB - Coral reefs are dynamic ecosystems known for decades to be endangered due, in large part, to anthropogenic impacts from land-based sources of pollution (LBSP). In this study, we utilized an Illumina-based next-generation sequencing approach to characterize prokaryotic and fungal communities from samples collected off the southeast coast of Florida. Water samples from coastal inlet discharges, oceanic outfalls of municipal wastewater treatment plants, treated wastewater effluent before discharge, open ocean samples, and coral tissue samples (mucus and polyps) were characterized to determine the relationships between microbial communities in these matrices and those in reef water and coral tissues. Significant differences in microbial communities were noted among all sample types but varied between sampling areas. Contamination from outfalls was found to be the greatest potential source of LBSP influencing native microbial community structure among all reef samples, although pollution from inlets was also noted. Notably, reef water and coral tissue communities were found to be more greatly impacted by LBSP at southern reefs, which also experienced the most degradation during the course of the study. The results of this study provide new insights into how microbial communities from LBSP can impact coral reefs in southeast Florida and suggest that wastewater outfalls may have a greater influence on the microbial diversity and structure of these reef communities than do contaminants carried in runoff, although the influences of runoff and coastal inlet discharge on coral reefs are still substantial.IMPORTANCE Coral reefs are known to be endangered due to sewage discharge and to runoff of nutrients, pesticides, and other substances associated with anthropogenic activity. Here, we used next-generation sequencing to characterize the microbial communities of potential contaminant sources in order to determine how environmental discharges of microbiota and their genetic material may influence the microbiomes of coral reef communities and coastal receiving waters. Runoff delivered through inlet discharges impacted coral microbial communities, but impacts from oceanic outfalls carrying treated wastewater were greater. Geographic differences in the degree of impact suggest that coral microbiomes may be influenced by the microbiological quality of treated wastewater. PMID- 28341674 TI - Interbacterial Adhesion Networks within Early Oral Biofilms of Single Human Hosts. AB - Specific interbacterial adhesion, termed coaggregation, is well established for three early colonizers of the plaque biofilm: streptococci, actinomyces, and veillonellae. However, little is known about interactions of other early colonizers and about the extent of interactions within the bacterial community from a single host. To address these gaps, subject-specific culture collections from two individuals were established using an intraoral biofilm retrieval device. Molecular taxonomy (Human Oral Microbe Identification Microarray [HOMIM]) analysis of biofilm samples confirmed the integrity and completeness of the collections. HOMIM analysis verified the isolation of Streptococcus gordonii and S. anginosus from only one subject, as well as isolation of a previously uncultivated streptococcal phylotype from the other subject. Strains representative of clonal diversity within each collection were further characterized. Greater than 70% of these streptococcal strains from each subject coaggregated with at least one other coisolate. One-third of the strains carry a known coaggregation mediator: receptor polysaccharide (RPS). Almost all nonstreptococcal isolates coaggregated with other coisolates. Importantly, certain Rothia strains demonstrated more coaggregations with their coisolated bacteria than did any Streptococcus or Actinomyces strain, and certain Haemophilus isolates participated in twice as many. Confocal microscopy of undisturbed biofilms showed that Rothia and Haemophilus each occur in small multispecies microcolonies. However, in confluent high-biomass regions, Rothia occurred in islands whereas Haemophilus was distributed throughout. Together, the data demonstrate that coaggregation networks within an individual's oral microflora are extensive and that Rothia and Haemophilus can be important initiators of cell-cell interactions in the early biofilm.IMPORTANCE Extensive involvement of specific interbacterial adhesion in dental plaque biofilm formation has been postulated based on in vitro coaggregation between oral bacteria from culture collections that are not subject specific. In the present study, subject-specific culture collections were obtained from early plaque biofilm of two volunteers, and coaggregations within each culture collection were assayed. Coaggregations, several of which involved a coaggregation-mediating cell surface molecule known from well-studied streptococci, were widespread. Unexpectedly, the little-studied organisms Haemophilus and Rothia participated in the greatest numbers of interactions with community members; these two organisms showed different distributions within the undisturbed biofilm. The data show that coaggregation networks encompass most organisms within the biofilm community of each individual, and they indicate prominent participation of organisms such as Haemophilus and Rothia in early plaque biofilm formation. PMID- 28341675 TI - Enterobius vermicularis as a Novel Surrogate for the Presence of Helminth Ova in Tertiary Wastewater Treatment Plants. AB - Significant effort has gone into assessing the fate and removal of viruses, bacteria, and protozoan parasites during wastewater treatment to provide data addressing potential health risks associated with reuse options. Comparatively less is known about the fate of parasitic worm species ova in these complex systems. It is largely assumed that these helminths settle, are removed with the sludge, and consequently represent a relatively low risk for wastewater reuse applications. However, helminths are a highly diverse group of organisms that display a wide range of physical properties that complicate the application of a single treatment for helminth reduction during wastewater treatment. Moreover, their diverse biological and physical properties make some ova highly resistant to both disinfection (i.e., with chlorine or UV treatment) and physical removal (settling) through the wastewater treatment train, indicating that there may be reason to broaden the scope of our investigations into whether parasitic worm eggs can be identified in treated wastewater. The ubiquitous human parasitic nematode Enterobius vermicularis (pinworm) produces small, buoyant ova. Utilizing a novel diagnostic quantitative PCR (qPCR), this study monitored E. vermicularis presence at two full-scale wastewater treatment plants over the course of 8 months and demonstrated incomplete physical removal of E. vermicularis ova through tertiary treatment, with removal efficiencies approximating only 0.5 and 1.6 log10 at the two wastewater treatment plants based on qPCR. These findings demonstrate the need for more-diverse surrogates of helminthic ova to fully assess treatment performance with respect to reclaimed wastewaters.IMPORTANCE Helminths, despite being a diverse and environmentally resistant class of pathogens, are often underestimated and ignored when treatment performance at modern wastewater treatment plants is considered. A one-size-fits-all surrogate for removal of helminth ova may be inappropriate to adequately assess risk and ensure public safety when treated and partially treated wastewaters are encountered. This study argues for the use of human pinworm as a conservative indicator of the presence of helminth ova due to its small size, buoyancy, prevalence in humans, and environmental resistance. PMID- 28341677 TI - A Newly Determined Member of the meso-Diaminopimelate Dehydrogenase Family with a Broad Substrate Spectrum. AB - meso-Diaminopimelate dehydrogenase (meso-DAPDH) from Symbiobacterium thermophilum (StDAPDH) is the first member of the meso-DAPDH family known to catalyze the asymmetric reductive amination of 2-keto acids to produce d-amino acids. It is important to understand the catalytic mechanisms of StDAPDH and other enzymes in this family. In this study, based on an evolutionary analysis and examination of catalytic activity, the meso-DAPDH enzymes can be divided into two types. Type I showed highly preferable activity toward meso-diaminopimelate (meso-DAP), and type II exhibited obviously reversible amination activity with a broad substrate spectrum. StDAPDH belongs to type II. A quaternary structure analysis revealed that insertions/deletions (indels) and a loss of quaternary structure resulted in divergence among members of the meso-DAPDH family. A structure alignment of StDAPDH with a representative of type I, the meso-DAPDH from Corynebacterium glutamicum (CgDAPDH), indicated that they had the same folding. Based on sequence and conservation analyses, two amino acid residues of StDAPDH, R35 and R71, were found to be highly conserved within type II while also distinct from each other between the subtypes. Site mutagenesis studies identified R71 as a substrate preference-related residue of StDAPDH, which may serve as an indicator of the amination preference of type II. These results deepen the present understanding of the meso-DAPDH family and provide a solid foundation for the discovery and engineering of meso-DAPDH for d-amino acid biosynthesis.IMPORTANCE The l-form of amino acids is typically more abundant than the d-form. However, the d-form has many important pharmaceutical applications. meso-Diaminopimelate dehydrogenase (meso-DAPDH) from Symbiobacterium thermophilum (StDAPDH) was the first member of meso-DAPDH known to catalyze the amination of 2-keto acids to produce d-amino acids. Accordingly, we analyzed the evolution of meso-DAPDH proteins and found that they form two groups, i.e., type I proteins, which show high preference toward meso-diaminopimelate (meso-DAP), and type II proteins, which show a broad substrate spectrum. We examined the differences in sequence, ternary structure, and quaternary structure to determine the mechanisms underlying the functional differences between the type I and type II lineages. These results will facilitate the identification of additional meso-DAPDHs and may provide guidance to protein engineering studies for d-amino acid biosynthesis. PMID- 28341676 TI - Anaerobic Methane Oxidation Driven by Microbial Reduction of Natural Organic Matter in a Tropical Wetland. AB - Wetlands constitute the main natural source of methane on Earth due to their high content of natural organic matter (NOM), but key drivers, such as electron acceptors, supporting methanotrophic activities in these habitats are poorly understood. We performed anoxic incubations using freshly collected sediment, along with water samples harvested from a tropical wetland, amended with 13C methane (0.67 atm) to test the capacity of its microbial community to perform anaerobic oxidation of methane (AOM) linked to the reduction of the humic fraction of its NOM. Collected evidence demonstrates that electron-accepting functional groups (e.g., quinones) present in NOM fueled AOM by serving as a terminal electron acceptor. Indeed, while sulfate reduction was the predominant process, accounting for up to 42.5% of the AOM activities, the microbial reduction of NOM concomitantly occurred. Furthermore, enrichment of wetland sediment with external NOM provided a complementary electron-accepting capacity, of which reduction accounted for ~100 nmol 13CH4 oxidized . cm-3 . day-1 Spectroscopic evidence showed that quinone moieties were heterogeneously distributed in the wetland sediment, and their reduction occurred during the course of AOM. Moreover, an enrichment derived from wetland sediments performing AOM linked to NOM reduction stoichiometrically oxidized methane coupled to the reduction of the humic analogue anthraquinone-2,6-disulfonate. Microbial populations potentially involved in AOM coupled to microbial reduction of NOM were dominated by divergent biota from putative AOM-associated archaea. We estimate that this microbial process potentially contributes to the suppression of up to 114 teragrams (Tg) of CH4 . year-1 in coastal wetlands and more than 1,300 Tg . year-1, considering the global wetland area.IMPORTANCE The identification of key processes governing methane emissions from natural systems is of major importance considering the global warming effects triggered by this greenhouse gas. Anaerobic oxidation of methane (AOM) coupled to the microbial reduction of distinct electron acceptors plays a pivotal role in mitigating methane emissions from ecosystems. Given their high organic content, wetlands constitute the largest natural source of atmospheric methane. Nevertheless, processes controlling methane emissions in these environments are poorly understood. Here, we provide tracer analysis with 13CH4 and spectroscopic evidence revealing that AOM linked to the microbial reduction of redox functional groups in natural organic matter (NOM) prevails in a tropical wetland. We suggest that microbial reduction of NOM may largely contribute to the suppression of methane emissions from tropical wetlands. This is a novel avenue within the carbon cycle in which slowly decaying NOM (e.g., humic fraction) in organotrophic environments fuels AOM by serving as a terminal electron acceptor. PMID- 28341678 TI - Defining the Core Citrus Leaf- and Root-Associated Microbiota: Factors Associated with Community Structure and Implications for Managing Huanglongbing (Citrus Greening) Disease. AB - Stable associations between plants and microbes are critical to promoting host health and productivity. The objective of this work was to test the hypothesis that restructuring of the core microbiota may be associated with the progression of huanglongbing (HLB), the devastating citrus disease caused by Liberibacter asiaticus, Liberibacter americanus, and Liberibacter africanus The microbial communities of leaves (n = 94) and roots (n = 79) from citrus trees that varied by HLB symptom severity, cultivar, location, and season/time were characterized with Illumina sequencing of 16S rRNA genes. The taxonomically rich communities contained abundant core members (i.e., detected in at least 95% of the respective leaf or root samples), some overrepresented site-specific members, and a diverse community of low-abundance variable taxa. The composition and diversity of the leaf and root microbiota were strongly associated with HLB symptom severity and location; there was also an association with host cultivar. The relative abundance of Liberibacter spp. among leaf microbiota positively correlated with HLB symptom severity and negatively correlated with alpha diversity, suggesting that community diversity decreases as symptoms progress. Network analysis of the microbial community time series identified a mutually exclusive relationship between Liberibacter spp. and members of the Burkholderiaceae, Micromonosporaceae, and Xanthomonadaceae This work confirmed several previously described plant disease-associated bacteria, as well as identified new potential implications for biological control. Our findings advance the understanding of (i) plant microbiota selection across multiple variables and (ii) changes in (core) community structure that may be a precondition to disease establishment and/or may be associated with symptom progression.IMPORTANCE This study provides a comprehensive overview of the core microbial community within the microbiomes of plant hosts that vary in extent of disease symptom progression. With 16S Illumina sequencing analyses, we not only confirmed previously described bacterial associations with plant health (e.g., potentially beneficial bacteria) but also identified new associations and potential interactions between certain bacteria and an economically important phytopathogen. The importance of core taxa within broader plant-associated microbial communities is discussed. PMID- 28341679 TI - Industrial Relevance of Chromosomal Copy Number Variation in Saccharomyces Yeasts. AB - Chromosomal copy number variation (CCNV) plays a key role in evolution and health of eukaryotes. The unicellular yeast Saccharomyces cerevisiae is an important model for studying the generation, physiological impact, and evolutionary significance of CCNV. Fundamental studies of this yeast have contributed to an extensive set of methods for analyzing and introducing CCNV. Moreover, these studies provided insight into the balance between negative and positive impacts of CCNV in evolutionary contexts. A growing body of evidence indicates that CCNV not only frequently occurs in industrial strains of Saccharomyces yeasts but also is a key contributor to the diversity of industrially relevant traits. This notion is further supported by the frequent involvement of CCNV in industrially relevant traits acquired during evolutionary engineering. This review describes recent developments in genome sequencing and genome editing techniques and discusses how these offer opportunities to unravel contributions of CCNV in industrial Saccharomyces strains as well as to rationally engineer yeast chromosomal copy numbers and karyotypes. PMID- 28341682 TI - The Royal College of Emergency Medicine composite pain scale for children: level of inter-rater agreement. AB - OBJECTIVE: To assess the inter-rater agreement of the Royal College of Emergency Medicine (RCEM) Composite Pain Scale. METHODS: A prospective, observational study of 117 children who presented to the ED with pain due to a limb injury. Pain severity was assessed by the triage nurse, doctor and child (depending on their age) using indicators of the RCEM Composite Pain Scale. This pain scale comprises a modified Wong-Baker FACES Pain Rating Scale (FACES Scale), a Behaviour scale and a numerical rating scale (Ladder). Comparisons were made between scores from individual scales and raters. RESULTS: 117 children (26 aged 0-8 years (group 1) and 91 aged >8-16 years (group 2)) were enrolled in the study. Pain in group 1 was assessed by the nurse and doctor using the FACES Scale and the Behaviour scale. The FACES Scale demonstrated greater inter-rater agreement than the Behaviour scale. Pain in group 2 was assessed by the nurse and doctor using the Behaviour scale and by the child using the FACES Scale and Ladder. The Ladder demonstrated poor inter-rater agreement in comparison with the Behaviour Score. CONCLUSION: The Ladder score could be omitted from this composite tool as it has poor inter-rater agreement in comparison with the other indicators. PMID- 28341680 TI - PhaR, a Negative Regulator of PhaP, Modulates the Colonization of a Burkholderia Gut Symbiont in the Midgut of the Host Insect, Riptortus pedestris. AB - Five genes encoding PhaP family proteins and one phaR gene have been identified in the genome of Burkholderia symbiont strain RPE75. PhaP proteins function as the surface proteins of polyhydroxyalkanoate (PHA) granules, and the PhaR protein acts as a negative regulator of PhaP biosynthesis. Recently, we characterized one phaP gene to understand the molecular cross talk between Riptortus insects and Burkholderia gut symbionts. In this study, we constructed four other phaP gene depleted mutants (DeltaphaP1, DeltaphaP2, DeltaphaP3, and DeltaphaP4 mutants), one phaR gene-depleted mutant, and a phaR-complemented mutant (DeltaphaR/phaR mutant). To address the biological roles of four phaP family genes and the phaR gene during insect-gut symbiont interaction, these Burkholderia mutants were fed to the second-instar nymphs, and colonization ability and fitness parameters were examined. In vitro, the DeltaphaP3 and DeltaphaR mutants cannot make a PHA granule normally in a stressful environment. Furthermore, the DeltaphaR mutation decreased the colonization ability in the host midgut and negatively affected the host insect's fitness compared with wild-type Burkholderia-infected insects. However, other phaP family gene-depleted mutants colonized well in the midgut of the fifth-instar nymph insects. However, in the case of females, the colonization rate of the DeltaphaP3 mutant was decreased and the host's fitness parameters were decreased compared with the wild-type-infected host, suggesting that the environment of the female midgut may be more hostile than that of the male midgut. These results demonstrate that PhaR plays an important role in the biosynthesis of PHA granules and that it is significantly related to the colonization of the Burkholderia gut symbiont in the host insects' midgut.IMPORTANCE Bacterial polyhydroxyalkanoate (PHA) biosynthesis is a complex process requiring several enzymes. The biological roles of PHA granule synthesis enzymes and the surface proteins of PHA granules during host-gut symbiont interactions are not fully understood. Here, we report the effects on colonization ability in the host midguts and the fitness of host insects after feeding Burkholderia mutant cells (four phaP-depleted mutants and one phaR depleted mutant) to the host insects. Analyses of both synthesized PHA granule amounts and CFU numbers suggest that the phaR gene is closely related to synthesis of the PHA granule and the colonization of the Burkholderia gut symbiont in the host insect's midgut. Like our previous report, this study also supports the idea that the environment of the host midgut may not be favorable to symbiotic Burkholderia cells and that PHA granules may be required to adapt in the host midgut. PMID- 28341681 TI - Chromosome-Encoded Hemolysin, Phospholipase, and Collagenase in Plasmidless Isolates of Photobacterium damselae subsp. damselae Contribute to Virulence for Fish. AB - Photobacterium damselae subsp. damselae is a pathogen of marine animals, including fish of importance in aquaculture. The virulence plasmid pPHDD1, characteristic of highly hemolytic isolates, encodes the hemolysins damselysin (Dly) and phobalysin (PhlyP). Strains lacking pPHDD1 constitute the vast majority of the isolates from fish outbreaks, but genetic studies to identify virulence factors in plasmidless strains are scarce. Here, we show that the chromosome I encoded hemolysin PhlyC plays roles in virulence and cell toxicity in pPHDD1 negative isolates of this pathogen. By combining the analyses of whole genomes and of gene deletion mutants, we identified two hitherto uncharacterized chromosomal loci encoding a phospholipase (PlpV) and a collagenase (ColP). PlpV was ubiquitous in the subspecies and exerted hemolytic activity against fish erythrocytes, which was enhanced in the presence of lecithin. ColP was restricted to a fraction of the isolates and was responsible for the collagen-degrading activity in this subspecies. Consistent with the presence of signal peptides in PlpV and ColP sequences, mutants for the type II secretion system (T2SS) genes epsL and pilD exhibited impairments in phospholipase and collagenase activities. Sea bass virulence experiments and cell culture assays demonstrated major contributions of PhlyC and PlpV to virulence and toxicity.IMPORTANCE This study constitutes genetic and genomic analyses of plasmidless strains of an emerging pathogen in marine aquaculture, Photobacterium damselae subsp. damselae To date, studies on the genetic basis of virulence were restricted to the pPHDD1 plasmid encoded toxins Dly and PhlyP. However, the vast majority of the recent isolates of this pathogen from fish farm outbreaks lack this plasmid. Here we demonstrate that the plasmidless strains produce two hitherto uncharacterized ubiquitous toxins encoded in chromosome I, namely, the hemolysin PhlyC and the phospholipase PlpV. We report the main roles of these two toxins in fish virulence and in cell toxicity. Our results constitute the basis for a better understanding of the virulence of a widespread marine pathogen. PMID- 28341683 TI - Total volume and composition of fluid intake and mortality in older women: a cohort study. AB - OBJECTIVES: The health benefits of 'drinking at least 8 glasses of water a day" in healthy individuals are largely unproven. We aimed to examine the relationship between total fluid and the sources of fluid consumption, risk of rapid renal decline, cardiovascular disease (CVD) mortality and all-cause mortality in elderly women. DESIGN, SETTING AND PARTICIPANTS: We conducted a longitudinal analysis of a population-based cohort study of 1055 women aged >=70 years residing in Australia. MAIN OUTCOME MEASURES: The associations between total daily fluid intake (defined as total volume of beverage excluding alcohol and milk) and the types of fluid (water, black tea, coffee, milk and other fluids) measured as cups per day and rapid renal decline, CVD and all-cause mortality were assessed using adjusted logistic and Cox regression analyses. RESULTS: Over a follow-up period of 10 years, 70 (6.6%) experienced rapid renal decline and 362 (34.4%) died, of which 142 (13.5%) deaths were attributed to CVD. The median (IQR) intake of total fluid was 10.4 (8.5-12.5) cups per day, with water (median (IQR) 4 (2-6) cups per day) and black tea (median (IQR) 3 (1-4) cups per day) being the most frequent type of fluid consumed. Every cup per day higher intake of black tea was associated with adjusted HRs of 0.90 (95% CI 0.81 to 0.99) and 0.92 (95% CI 0.86 to 0.98) for CVD mortality and all-cause mortality, respectively. There were no associations between black tea intake and rapid renal decline, or between the quantity or type of other fluids, including water intake, and any clinical outcomes. CONCLUSIONS: Habitual higher intake of black tea may potentially improve long-term health outcomes, independent of treating traditional CVD risk factors, but validation of our study findings is essential. PMID- 28341684 TI - Association between physical activity and body fat percentage, with adjustment for BMI: a large cross-sectional analysis of UK Biobank. AB - OBJECTIVES: The objective of this study was to examine if, in the general population, physically active adults have less body fat after taking body mass index (BMI) into account. DESIGN: A cross-sectional analysis of participants recruited into UK Biobank in 2006-2010. SETTING: UK Biobank assessment centres throughout the UK. PARTICIPANTS: 119 230 men and 140 578 women aged 40-69 years, with complete physical activity information, and without a self-reported long term illness, disability or infirmity. EXPOSURES: Physical activity measured as excess metabolic equivalent (MET)-hours per week, estimated from a combination of walking, and moderate and vigorous physical activity. BMI from measured height and weight. MAIN OUTCOME MEASURE: Body fat percentage estimated from bioimpedance. RESULTS: BMI and body fat percentage were highly correlated (r=0.85 in women; r=0.79 in men), and both were inversely associated with physical activity. Compared with <5 excess MET-hours/week at baseline, >=100 excess MET hours/week were associated with a 1.1 kg/m2 lower BMI (27.1 vs 28.2 kg/m2) and 2.8 percentage points lower body fat (23.4% vs 26.3%) in men, and 2.2 kg/m2 lower BMI (25.6 vs 27.7 kg/m2) and 4.0 percentage points lower body fat (33.9% vs 37.9%) in women. For a given BMI, greater physical activity was associated with lower average body fat percentage (for a BMI of 22.5-24.99 kg/m2: 2.0 (95% CI 1.8 to 2.2), percentage points lower body fat in men and 1.8 (95% CI 1.6 to 2.0) percentage points lower body fat in women, comparing >=100 excess MET-hours per week with <5 excess MET-hours/week). CONCLUSIONS: In this sample of middle-aged adults, drawn from the general population, physical activity was inversely associated with BMI and body fat percentage. For people with the same BMI, those who were more active had a lower body fat percentage. PMID- 28341685 TI - Use of a computerised decision aid (DA) to inform the decision process on adjuvant chemotherapy in patients with stage II colorectal cancer: development and preliminary evaluation. AB - OBJECTIVES: To develop a computerised decision aid (DA) to inform the decision process on adjuvant chemotherapy in patients with stage II colorectal cancer, and examine perceived usefulness, acceptability and areas for improvement of the DA. DESIGN: Mixed methods. SETTING: Single outpatient oncology department in central London. PARTICIPANTS: Consecutive recruitment of 13 patients with stage II colorectal cancer, 12 of whom completed the study. Inclusion criteria were: age >18 years; complete resection for stage II adenocarcinoma of the colon or rectum; patients within 14-56 days after surgery; no contraindication to adjuvant chemotherapy; able to give written informed consent. Exclusion criterion: previous chemotherapy. PRIMARY OUTCOMES: Patient perceived usefulness (assessed by the PrepDM questionnaire) and acceptability of the DA. RESULTS: PrepDM scores, measuring the perceived usefulness of the DA in preparing the patient to communicate with their doctor and make a health decision, were above those reported in other patient groups. Patient acceptability scores were also high; however, interviews showed that there was evidence of a lack of understanding of key information among some patients, in particular their baseline risk of recurrence, the net benefit of combination chemotherapy and the rationale for having chemotherapy when cancer had apparently gone. CONCLUSIONS: Patients found the DA acceptable and useful in supporting their decision about whether or not to have adjuvant chemotherapy. Suggested improvements for the DA include: sequential presentation of treatment options (eg, no treatment vs 1 drug, 1 drug vs 2 drugs) to enhance patient understanding of the difference between combination and single therapy, diagrams to help patients understand the rationale for chemotherapy to prevent a recurrence and inbuilt checks on patient understanding of baseline risk of recurrence and net benefit of chemotherapy. PMID- 28341687 TI - Perspectives on procedure-based assessments: a thematic analysis of semistructured interviews with 10 UK surgical trainees. AB - OBJECTIVES: The introduction of competency-based training has necessitated development and implementation of accompanying mechanisms for assessment. Procedure-based assessments (PBAs) are an example of workplace-based assessments that are used to examine focal competencies in the workplace. The primary objective was to understand surgical trainees' perspective on the value of PBA. DESIGN: Semistructured interviews with 10 surgical trainees individually interviewed to explore their views. Interviews were audio-recorded and transcribed; following this, they were open and axial coded. Thematic analysis was then performed. RESULTS: Semistructured interviews yielded several topical and recurring themes. In trainees' experience, the use of PBAs as a summative tool limits their educational value. Trainees reported a lack of support from seniors and variation in the usefulness of the tool based on stage of training. Concerns related to the validity of PBAs for evaluating trainees' performance with reports of 'gaming' the system and trainees completing their own assessments. Trainees did identify the significant value of PBAs when used correctly. Benefits included the identification of additional learning opportunities, standardisation of assessment and their role in providing a measure of progress. CONCLUSIONS: The UK surgical trainees interviewed identified both limitations and benefits to PBAs; however, we would argue based on their responses and our experience that their use as a summative tool limits their formative use as an educational opportunity. PBAs should either be used exclusively to support learning or solely as a summative tool; if so, further work is needed to audit, validate and standardise them for this purpose. PMID- 28341686 TI - Incidental findings on brain MRI of cognitively normal first-degree descendants of patients with Alzheimer's disease: a cross-sectional analysis from the ALFA (Alzheimer and Families) project. AB - OBJECTIVES: To describe the prevalence of brain MRI incidental findings (IF) in a cohort of cognitively normal first-degree descendants of patients with Alzheimer's disease (AD). DESIGN: Cross-sectional observational study. SETTING: All scans were obtained with a 3.0 T scanner. Scans were evaluated by a single neuroradiologist and IF recorded and categorised. The presence of white matter hyperintensities (WMH) was determined with the Fazekas scale and reported as relevant if >=2. PARTICIPANTS: 575 participants (45-75 years) underwent high resolution structural brain MRI. Participants were cognitively normal and scored over the respective cut-off values in all the following neuropsychological tests: Mini-Mental State Examination (>=26), Memory Impairment Screen (>=6), Time Orientation Subtest of the Barcelona Test II (>=68), verbal semantic fluency (naming animals >=12). Clinical Dementia Rating (CDR) had to be 0. RESULTS: 155 participants (27.0%) presented with at least one IF. Relevant WMH were present in 7.8% of the participants, and vascular abnormalities, cyst and brain volume loss in 10.7%, 3.1% and 6.9% of the study volunteers, respectively. Neoplastic brain findings were found in 2.4% of participants and within these, meningiomas were the most common (1.7%) and more frequently found in women. A positive correlation between increasing age and the presence of IF was found. Additionally, brain atrophy greater than that expected by age was significantly more prevalent in participants without a parental history of AD. CONCLUSIONS: Brain MRIs of healthy middle-aged participants show a relatively high prevalence of IF even when study participants have been screened for subtle cognitive alterations. Most of our participants are first-degree descendants of patients with AD, and therefore these results are of special relevance for novel imaging studies in the context of AD prevention in cognitively healthy middle-aged participants. TRIAL REGISTRATION NUMBER: NCT02198586. PMID- 28341688 TI - Global cardiovascular risk assessment in the primary prevention of cardiovascular disease in adults: systematic review of systematic reviews. AB - OBJECTIVE: To identify, critically appraise and summarise existing systematic reviews on the impact of global cardiovascular risk assessment in the primary prevention of cardiovascular disease (CVD) in adults. DESIGN: Systematic review of systematic reviews published between January 2005 and October 2016 in The Cochrane Library, EMBASE, MEDLINE or CINAHL databases, and post hoc analysis of primary trials. PARTICIPANTS, INTERVENTIONS, OUTCOMES: Systematic reviews of interventions involving global cardiovascular risk assessment relative to no formal risk assessment in adults with no history of CVD. The primary outcomes of interest were CVD-related morbidity and mortality and all-cause mortality; secondary outcomes were systolic blood pressure (SBP), cholesterol and smoking. RESULTS: We identified six systematic reviews of variable but generally of low quality (mean Assessing the Methodological Quality of Systematic Reviews 4.2/11, range 0/11 to 7/11). No studies identified by the systematic reviews reported CVD related morbidity or mortality or all-cause mortality. Meta-analysis of reported randomised controlled trials (RCTs) showed small reductions in SBP (mean difference (MD) -2.22 mm Hg (95% CI -3.49 to -0.95); I2=66%; n=9; GRADE: very low), total cholesterol (MD -0.11 mmol/L (95% CI -0.20 to -0.02); I2=72%; n=5; GRADE: very low), low-density lipoprotein cholesterol (MD -0.15 mmol/L (95% CI 0.26 to -0.05), I2=47%; n=4; GRADE: very low) and smoking cessation (RR 1.62 (95% CI 1.08 to 2.43); I2=17%; n=7; GRADE: low). The median follow-up time of reported RCTs was 12 months (range 2-36 months). CONCLUSIONS: The quality of existing systematic reviews was generally poor and there is currently no evidence reported in these reviews that the prospective use of global cardiovascular risk assessment translates to reductions in CVD morbidity or mortality. There are reductions in SBP, cholesterol and smoking but they may not be clinically significant given their small effect size and short duration. Resources need to be directed to conduct high-quality systematic reviews focusing on hard patient outcomes, and likely further primary RCTs. TRIAL REGISTRATION NUMBER: CRD42015019821. PMID- 28341689 TI - Designing a physical activity intervention for children with asthma: a qualitative study of the views of healthcare professionals, parents and children with asthma. AB - OBJECTIVES: Qualitative methods were used to examine: (1) the attitudes of health professionals to promoting physical activity for children with asthma; (2) reasons why children with asthma are less active and (3) how a physical activity programme for children with asthma could be designed. DESIGN: Semistructured interviews were conducted with health professionals, children with asthma and their parents between October 2015 and March 2016. Interviews were transcribed verbatim and thematically analysed. SETTING: Primary and secondary care in Bristol (UK). PARTICIPANTS: Interviews were held with 8 primary care practitioners (5 general practitioners, 2 nurse practitioners and 1 practice nurse), 9 parent-child dyads (2 fathers, 7 mothers, 6 sons, 3 daughters) of children aged 6-7 who had asthma and 4 secondary care professionals (2 respiratory consultants, 2 specialist nurses). RESULTS: Health professionals reported that physical activity was beneficial for children with asthma and if managed appropriately, children with asthma could be as active as children without asthma. Current promotion of physical activity for children with asthma was limited and restricted by NHS staff time, access to inhalers at school and a lack of parental knowledge. Potentially important components of a new programme include parental education on the possibilities of activity for children with asthma and the difference between exercise-induced breathlessness and asthma symptoms. Other important elements include how to use inhalers as a preventive measure, coping with exacerbations and practical solutions (such as clearing sputum), managing transitions from warm to cold climates and general symptom control. CONCLUSIONS: There is a need to build on current asthma programmes to increase the support for children with asthma to be physically active. Future programmes could consider working more closely with schools, increasing parental knowledge and providing children with practical support to help be physically active. PMID- 28341690 TI - Qualitative study to explore the health and well-being impacts on adults providing informal support to female domestic violence survivors. AB - OBJECTIVES: Domestic violence (DV) is hazardous to survivors' health, from injuries sustained and from resultant chronic physical and mental health problems. Support from friends and relatives is significant in the lives of DV survivors; research shows associations between positive support and the health, well-being and safety of survivors. Little is known about how people close to survivors are impacted. The aim of this study was exploratory, with the following research question: what are the health and well-being impacts on adults who provide informal support to female DV survivors? DESIGN: A qualitative study using semistructured interviews conducted face to face, by telephone or using Skype. A thematic analysis of the narratives was carried out. SETTING: Community based, across the UK. PARTICIPANTS: People were eligible to take part if they had had a close relationship (either as friend, colleague or family member) with a woman who had experienced DV, and were aged 16 or over during the time they knew the survivor. Participants were recruited via posters in community venues, social media and radio advertisement. 23 participants were recruited and interviewed; the majority were women, most were white and ages ranged from mid-20s to 80. RESULTS: Generated themes included: negative impacts on psychological and emotional well-being of informal supporters, and related physical health impacts. Some psychological impacts were over a limited period; others were chronic and had the potential to be severe and enduring. The impacts described suggested that those providing informal support to survivors may be experiencing secondary traumatic stress as they journey alongside the survivor. CONCLUSIONS: Friends and relatives of DV survivors experience substantial impact on their own health and well-being. There are no direct services to support this group. These findings have practical and policy implications, so that the needs of informal supporters are legitimised and met. PMID- 28341691 TI - Evaluating CollaboRATE in a clinical setting: analysis of mode effects on scores, response rates and costs of data collection. AB - BACKGROUND: Shared decision-making (SDM) has become a policy priority, yet its implementation is not routinely assessed. To address this gap we tested the delivery of CollaboRATE, a 3-item patient reported experience measure of SDM, via multiple survey modes. OBJECTIVE: To assess CollaboRATE response rates and respondent characteristics across different modes of administration, impact of mode and patient characteristics on SDM performance and cost of administration per response in a real-world primary care practice. DESIGN: Observational study design, with repeated assessment of SDM performance using CollaboRATE in a primary care clinic over 15 months of data collection. Different modes of administration were introduced sequentially including paper, patient portal, interactive voice response (IVR) call, text message and tablet computer. PARTICIPANTS: Consecutive patients >=18 years, or parents/guardians of patients <18 years, visiting participating primary care clinicians. MAIN MEASURES: CollaboRATE assesses three core SDM tasks: (1) explanation about health issues, (2) elicitation of patient preferences and (3) integration of patient preferences into decisions. Responses to each item range from 0 (no effort was made) to 9 (every effort was made). CollaboRATE scores are calculated as the proportion of participants who report a score of nine on each of the three CollaboRATE questions. KEY RESULTS: Scores were sensitive to mode effects: the paper mode had the highest average score (81%) and IVR had the lowest (61%). However, relative clinician performance rankings were stable across the different data collection modes used. Tablet computers administered by research staff had the highest response rate (41%), although this approach was costly. Clinic staff giving paper surveys to patients as they left the clinic had the lowest response rate (12%). CONCLUSIONS: CollaboRATE can be introduced using multiple modes of survey delivery while producing consistent clinician rankings. This may allow routine assessment and benchmarking of clinician and clinic SDM performance. PMID- 28341693 TI - Minocycline-induced skin hyperpigmentation. PMID- 28341692 TI - 'We both just wanted to be normal parents': a qualitative study of the experience of maternity care for women with learning disability. AB - BACKGROUND: More women with learning disability (LD) are becoming mothers. Women with LD have rights to equal access to maternity care that meets their needs, however, many have poor pregnancy and birth outcomes compared to other women in the UK. Research is limited in this area. OBJECTIVES: The aim of the study was to explore the lived experiences of pregnancy, childbirth, prenatal and postnatal care and services received by this group of women in the UK, including their expressed information and support needs relating to maternity care. METHODS: A qualitative study in which data were generated using in-depth semistructured interviews with learning disabled women who were pregnant or had given birth within the last 3 years in the UK; data were analysed using interpretative phenomenological analysis. RESULTS: 9 women with varying levels of cognitive impairment took part. 4 super-ordinate themes were identified: 'I hate being treated differently', 'I find it harder to understand than other people', 'We've had to prove ourselves' and 'Make sure you've got very good support around you'. Subthemes included: 'Negative attitudes and denial of choice', 'Understanding of normal care', 'Written information' and 'Being judged by professionals'. CONCLUSIONS: With support from family and services, learning disabled women can become confident and successful parents. Maternity services should make reasonable adjustments when providing care to this group, including adapting to their individual communication and learning needs: allowing sufficient time in appointments, offering clear explanations of each aspect of care and sensitive support for autonomy and fully informed choice. Mothers who will be subject to a social care assessment of their parenting skills need clear information about the process, their choices and the level of skill they must demonstrate, as well as access to sufficient antenatal and postnatal support to give them the best possible chance of passing the assessment. PMID- 28341694 TI - 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor and NaCl transport mechanisms in the renal distal nephron. AB - A key role of aldosterone and mineralocorticoid receptor is to regulate fluid volume and K+ homeostasis in the body by acting on the renal distal nephron. Global responses of the kidney to elevated aldosterone levels are determined by the coordinate action of different constituent tubule cells, including principal cells, intercalated cells and distal convoluted tubule cells. Recent studies on genetic mutations causing aldosterone overproduction have identified the molecules involved in aldosterone biosynthesis in the adrenal gland, and there is also increasing evidence for mechanisms and signaling pathways regulating the balance between renal NaCl reabsorption and K+ secretion, the two major effects of aldosterone. In particular, recent studies have demonstrated that mineralocorticoid receptor in intercalated cells is selectively regulated by phosphorylation, which prevents ligand binding and activation. Moreover, the ubiquitin ligase complex composed of Kelch-like 3 and Cullin 3 acts downstream of angiotensin II and plasma K+ alterations, regulating Na-Cl cotransporter independently of aldosterone in distal convoluted tubule cells. These and other effects are integrated to produce appropriate kidney responses in a high aldosterone state, and are implicated in fluid and electrolyte disorders in humans. This review summarizes the current knowledge on mechanisms modulating mineralocorticoid receptor and its downstream effectors in the distal nephron. PMID- 28341695 TI - Cancer-associated epiphora: a retrospective analysis of referrals to a tertiary oculoplastic practice. AB - AIM: To report the underlying causes and treatment outcome of lacrimal drainage obstruction in patients with cancer-associated epiphora. METHODS: A single-centre retrospective review was performed for consecutive referrals to an oculoplastic surgeon for cancer-associated epiphora between 2010 and 2016. Charts were reviewed for underlying neoplastic conditions, pharmacy records, radiotherapy records, levels of obstruction of the lacrimal drainage apparatus and treatment methods and outcome. RESULTS: Forty-three patients (70 eyes) were included in this study. The most common cause of epiphora was radiotherapy on the head and neck (35%), followed by oral S-1 (33%) and docetaxel (23%). The nasolacrimal duct was the most common obstruction site in patients who underwent radiotherapy (59%), whereas the punctum or canaliculus was mostly affected in patients treated with S-1 (94%) or docetaxel (100%). S-1-treated patients showed severe obstruction of the entire canaliculus (11/24 (46%)) with the lowest success rate at 58% (S-1 vs radiotherapy: p=0.012; S-1 vs docetaxel: p=0.002). Moreover, the patients treated within 1 year after the first symptom showed a significantly higher proportion of symptom improvement (85%) than did those treated after 1 year (27%) in the S-1 group (p=0.011). CONCLUSIONS: Cancer-associated epiphora can have various causes. The level of obstruction and treatment outcome vary according to underlying causes, and S-1-associated epiphora and delayed treatment are related to unsatisfactory results. Given the importance of early intervention, oncologists should be alert to tearing symptoms and cooperate with ophthalmologists in the early stages to improve patients' quality of life. PMID- 28341697 TI - Risk factors for persistence of lower respiratory symptoms among community members exposed to the 2001 World Trade Center terrorist attacks. AB - OBJECTIVES: We studied the course of lower respiratory symptoms (LRS; cough, wheeze or dyspnoea) among community members exposed to the 9/11/2001 World Trade Center (WTC) attacks during a period of 12-13 years following the attacks, and evaluated risk factors for LRS persistence, including peripheral airway dysfunction and post-traumatic stress disorder (PTSD). METHODS: Non-smoking adult participants in a case-control study of post-9/11-onset LRS (exam 1, 2008-2010) were recruited for follow-up (exam 2, 2013-2014). Peripheral airway function was assessed with impulse oscillometry measures of R5 and R5-20. Probable PTSD was a PTSD checklist score >=44 on a 2006-2007 questionnaire. RESULTS: Of 785 exam 1 participants, 545 (69%) completed exam 2. Most (321, 59%) were asymptomatic at all assessments. Among 192 participants with initial LRS, symptoms resolved for 110 (57%) by exam 2, 55 (29%) had persistent LRS and 27 (14%) had other patterns. The proportion with normal spirometry increased from 65% at exam 1 to 85% at exam 2 in the persistent LRS group (p<0.01) and was stable among asymptomatic participants and those with resolved LRS. By exam 2, spirometry results did not differ across symptom groups; however, R5 and R5-20 abnormalities were more common among participants with persistent LRS (56% and 46%, respectively) than among participants with resolved LRS (30%, p<0.01; 27%, p=0.03) or asymptomatic participants (20%, p<0.001; 8.2%, p<0.001). PTSD, R5 at exam 1, and R5-20 at exam 1 were each independently associated with persistent LRS. CONCLUSIONS: Peripheral airway dysfunction and PTSD may contribute to LRS persistence. Assessment of peripheral airway function detected pulmonary damage not evident on spirometry. Mental and physical healthcare for survivors of complex environmental disasters should be coordinated carefully. PMID- 28341698 TI - Schizosaccharomyces pombe MutSalpha and MutLalpha Maintain Stability of Tetra Nucleotide Repeats and Msh3 of Hepta-Nucleotide Repeats. AB - Defective mismatch repair (MMR) in humans is associated with colon cancer and instability of microsatellites, that is, DNA sequences with one or several nucleotides repeated. Key factors of eukaryotic MMR are the heterodimers MutSalpha (Msh2-Msh6), which recognizes base-base mismatches and unpaired nucleotides in DNA, and MutLalpha (Mlh1-Pms1), which facilitates downstream steps. In addition, MutSbeta (Msh2-Msh3) recognizes DNA loops of various sizes, although our previous data and the data presented here suggest that Msh3 of Schizosaccharomyces pombe does not play a role in MMR. To test microsatellite stability in S. pombe and hence DNA loop repair, we have inserted tetra-, penta-, and hepta-nucleotide repeats in the ade6 gene and determined their Ade+ reversion rates and spectra in wild type and various mutants. Our data indicate that loops with four unpaired nucleotides in the nascent and the template strand are the upper limit of MutSalpha- and MutLalpha-mediated MMR in S. pombe Stability of hepta-nucleotide repeats requires Msh3 and Exo1 in MMR-independent processes as well as the DNA repair proteins Rad50, Rad51, and Rad2FEN1 Most strikingly, mutation rates in the double mutants msh3 exo1 and msh3 rad51 were decreased when compared to respective single mutants, indicating that Msh3 prevents error prone processes carried out by Exo1 and Rad51. We conclude that Msh3 has no obvious function in MMR in S. pombe, but contributes to DNA repeat stability in MMR independent processes. PMID- 28341699 TI - Genomic Comparison of Indigenous African and Northern European Chickens Reveals Putative Mechanisms of Stress Tolerance Related to Environmental Selection Pressure. AB - Global climate change is increasing the magnitude of environmental stressors, such as temperature, pathogens, and drought, that limit the survivability and sustainability of livestock production. Poultry production and its expansion is dependent upon robust animals that are able to cope with stressors in multiple environments. Understanding the genetic strategies that indigenous, noncommercial breeds have evolved to survive in their environment could help to elucidate molecular mechanisms underlying biological traits of environmental adaptation. We examined poultry from diverse breeds and climates of Africa and Northern Europe for selection signatures that have allowed them to adapt to their indigenous environments. Selection signatures were studied using a combination of population genomic methods that employed FST , integrated haplotype score (iHS), and runs of homozygosity (ROH) procedures. All the analyses indicated differences in environment as a driver of selective pressure in both groups of populations. The analyses revealed unique differences in the genomic regions under selection pressure from the environment for each population. The African chickens showed stronger selection toward stress signaling and angiogenesis, while the Northern European chickens showed more selection pressure toward processes related to energy homeostasis. The results suggest that chromosomes 2 and 27 are the most diverged between populations and the most selected upon within the African (chromosome 27) and Northern European (chromosome 2) birds. Examination of the divergent populations has provided new insight into genes under possible selection related to tolerance of a population's indigenous environment that may be baselines for examining the genomic contribution to tolerance adaptions. PMID- 28341700 TI - asymptoticMK: A Web-Based Tool for the Asymptotic McDonald-Kreitman Test. AB - The McDonald-Kreitman (MK) test is a widely used method for quantifying the role of positive selection in molecular evolution. One key shortcoming of this test lies in its sensitivity to the presence of slightly deleterious mutations, which can severely bias its estimates. An asymptotic version of the MK test was recently introduced that addresses this problem by evaluating polymorphism levels for different mutation frequencies separately, and then extrapolating a function fitted to that data. Here, we present asymptoticMK, a web-based implementation of this asymptotic MK test. Our web service provides a simple R-based interface into which the user can upload the required data (polymorphism and divergence data for the genomic test region and a neutrally evolving reference region). The web service then analyzes the data and provides plots of the test results. This service is free to use, open-source, and available at http://benhaller.com/messerlab/asymptoticMK.html We provide results from simulations to illustrate the performance and robustness of the asymptoticMK test under a wide range of model parameters. PMID- 28341701 TI - From Pine Cones to Read Clouds: Rescaffolding the Megagenome of Sugar Pine (Pinus lambertiana). AB - We investigate the utility and scalability of new read cloud technologies to improve the draft genome assemblies of the colossal, and largely repetitive, genomes of conifers. Synthetic long read technologies have existed in various forms as a means of reducing complexity and resolving repeats since the outset of genome assembly. Recently, technologies that combine subhaploid pools of high molecular weight DNA with barcoding on a massive scale have brought new efficiencies to sample preparation and data generation. When combined with inexpensive light shotgun sequencing, the resulting data can be used to scaffold large genomes. The protocol is efficient enough to consider routinely for even the largest genomes. Conifers represent the largest reference genome projects executed to date. The largest of these is that of the conifer Pinus lambertiana (sugar pine), with a genome size of 31 billion bp. In this paper, we report on the molecular and computational protocols for scaffolding the P. lambertiana genome using the library technology from 10* Genomics. At 247,000 bp, the NG50 of the existing reference sequence is the highest scaffold contiguity among the currently published conifer assemblies; this new assembly's NG50 is 1.94 million bp, an eightfold increase. PMID- 28341705 TI - Leading anaesthetist praises NHS response to Westminster attacks. PMID- 28341703 TI - Niacin ameliorates ulcerative colitis via prostaglandin D2-mediated D prostanoid receptor 1 activation. AB - Niacin, as an antidyslipidemic drug, elicits a strong flushing response by release of prostaglandin (PG) D2 However, whether niacin is beneficial for inflammatory bowel disease (IBD) remains unclear. Here, we observed niacin administration-enhanced PGD2 production in colon tissues in dextran sulfate sodium (DSS)-challenged mice, and protected mice against DSS or 2,4,6 trinitrobenzene sulfonic acid (TNBS)-induced colitis in D prostanoid receptor 1 (DP1)-dependent manner. Specific ablation of DP1 receptor in vascular endothelial cells, colonic epithelium, and myeloid cells augmented DSS/TNBS-induced colitis in mice through increasing vascular permeability, promoting apoptosis of epithelial cells, and stimulating pro-inflammatory cytokine secretion of macrophages, respectively. Niacin treatment improved vascular permeability, reduced apoptotic epithelial cells, promoted epithelial cell update, and suppressed pro-inflammatory gene expression of macrophages. Moreover, treatment with niacin-containing retention enema effectively promoted UC clinical remission and mucosal healing in patients with moderately active disease. Therefore, niacin displayed multiple beneficial effects on DSS/TNBS-induced colitis in mice by activation of PGD2/DP1 axis. The potential efficacy of niacin in management of IBD warrants further investigation. PMID- 28341704 TI - Structural landscape of base pairs containing post-transcriptional modifications in RNA. AB - Base pairs involving post-transcriptionally modified nucleobases are believed to play important roles in a wide variety of functional RNAs. Here we present our attempts toward understanding the structural and functional role of naturally occurring modified base pairs using a combination of X-ray crystal structure database analysis, sequence analysis, and advanced quantum chemical methods. Our bioinformatics analysis reveals that despite their presence in all major secondary structural elements, modified base pairs are most prevalent in tRNA crystal structures and most commonly involve guanine or uridine modifications. Further, analysis of tRNA sequences reveals additional examples of modified base pairs at structurally conserved tRNA regions and highlights the conservation patterns of these base pairs in three domains of life. Comparison of structures and binding energies of modified base pairs with their unmodified counterparts, using quantum chemical methods, allowed us to classify the base modifications in terms of the nature of their electronic structure effects on base-pairing. Analysis of specific structural contexts of modified base pairs in RNA crystal structures revealed several interesting scenarios, including those at the tRNA:rRNA interface, antibiotic-binding sites on the ribosome, and the three-way junctions within tRNA. These scenarios, when analyzed in the context of available experimental data, allowed us to correlate the occurrence and strength of modified base pairs with their specific functional roles. Overall, our study highlights the structural importance of modified base pairs in RNA and points toward the need for greater appreciation of the role of modified bases and their interactions, in the context of many biological processes involving RNA. PMID- 28341706 TI - Partner abundance controls mutualism stability and the pace of morphological change over geologic time. AB - Mutualisms that involve symbioses among specialized partners may be more stable than mutualisms among generalists, and theoretical models predict that in many mutualisms, partners exert reciprocal stabilizing selection on traits directly involved in the interaction. A corollary is that mutualism breakdown should increase morphological rates of evolution. We here use the largest ant-plant clade (Hydnophytinae), with different levels of specialization for mutualistic ant symbionts, to study the ecological context of mutualism breakdown and the response of a key symbiosis-related trait, domatium entrance hole size, which filters symbionts by size. Our analyses support three predictions from mutualism theory. First, all 12 losses apparently only occur from a generalist symbiotic state. Second, mutualism losses occurred where symbionts are scarce, in our system at high altitudes. Third, domatium entrance hole size barely changes in specialized symbiotic species, but evolves rapidly once symbiosis with ants has broken down, with a "morphorate map" revealing that hotspots of entrance hole evolution are clustered in high-altitude areas. Our study reveals that mutualistic strategy profoundly affects the pace of morphological change in traits involved in the interaction and suggests that shifts in partners' relative abundances may frequently drive reversions of generalist mutualisms to autonomy. PMID- 28341702 TI - NRAS destines tumor cells to the lungs. AB - The lungs are frequently affected by cancer metastasis. Although NRAS mutations have been associated with metastatic potential, their exact role in lung homing is incompletely understood. We cross-examined the genotype of various tumor cells with their ability for automatic pulmonary dissemination, modulated NRAS expression using RNA interference and NRAS overexpression, identified NRAS signaling partners by microarray, and validated them using Cxcr1- and Cxcr2 deficient mice. Mouse models of spontaneous lung metastasis revealed that mutant or overexpressed NRAS promotes lung colonization by regulating interleukin-8 related chemokine expression, thereby initiating interactions between tumor cells, the pulmonary vasculature, and myeloid cells. Our results support a model where NRAS-mutant, chemokine-expressing circulating tumor cells target the CXCR1 expressing lung vasculature and recruit CXCR2-expressing myeloid cells to initiate metastasis. We further describe a clinically relevant approach to prevent NRAS-driven pulmonary metastasis by inhibiting chemokine signaling. In conclusion, NRAS promotes the colonization of the lungs by various tumor types in mouse models. IL-8-related chemokines, NRAS signaling partners in this process, may constitute an important therapeutic target against pulmonary involvement by cancers of other organs. PMID- 28341707 TI - Epigenetic contribution to diversification. PMID- 28341708 TI - Rapid evolution of resistance to parasitism in biological control. PMID- 28341709 TI - Magnetization dynamics and its scattering mechanism in thin CoFeB films with interfacial anisotropy. AB - Studies of magnetization dynamics have incessantly facilitated the discovery of fundamentally novel physical phenomena, making steady headway in the development of magnetic and spintronics devices. The dynamics can be induced and detected electrically, offering new functionalities in advanced electronics at the nanoscale. However, its scattering mechanism is still disputed. Understanding the mechanism in thin films is especially important, because most spintronics devices are made from stacks of multilayers with nanometer thickness. The stacks are known to possess interfacial magnetic anisotropy, a central property for applications, whose influence on the dynamics remains unknown. Here, we investigate the impact of interfacial anisotropy by adopting CoFeB/MgO as a model system. Through systematic and complementary measurements of ferromagnetic resonance (FMR) on a series of thin films, we identify narrower FMR linewidths at higher temperatures. We explicitly rule out the temperature dependence of intrinsic damping as a possible cause, and it is also not expected from existing extrinsic scattering mechanisms for ferromagnets. We ascribe this observation to motional narrowing, an old concept so far neglected in the analyses of FMR spectra. The effect is confirmed to originate from interfacial anisotropy, impacting the practical technology of spin-based nanodevices up to room temperature. PMID- 28341696 TI - A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk. AB - To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2. PMID- 28341710 TI - Reply to Baveye and Darnault: Useful models are simple and extendable. PMID- 28341711 TI - A cardiac-enriched microRNA, miR-378, blocks cardiac hypertrophy by targeting Ras signaling. PMID- 28341712 TI - Deficiency of cardiomyocyte-specific microRNA-378 contributes to the development of cardiac fibrosis involving a transforming growth factor beta (TGFbeta1) dependent paracrine mechanism. PMID- 28341713 TI - Substrate recognition by the Cdh1 destruction box receptor is a general requirement for APC/CCdh1-mediated proteolysis. PMID- 28341714 TI - Quantitative Assessment of Variation in CT Parameters on Texture Features: Pilot Study Using a Nonanatomic Phantom. AB - Our aim was to evaluate changes in texture features based on variations in CT parameters on a phantom. Scans were performed with varying milliampere, kilovolt, section thickness, pitch, and acquisition mode. Forty-two texture features were extracted by using an in-house-developed Matlab program. Two-tailed t tests and false-detection analyses were performed with significant differences in texture features based on detector array configurations (Q values = 0.001-0.006), section thickness (Q values = 0.0002-0.001), and acquisition mode (Q values = 0.003 0.006). Variations in milliampere and kilovolt had no significant effect. PMID- 28341715 TI - Can MRI Visual Assessment Differentiate the Variants of Primary-Progressive Aphasia? AB - BACKGROUND AND PURPOSE: Primary-progressive aphasia is a clinically and pathologically heterogeneous condition. Nonfluent, semantic, and logopenic are the currently recognized clinical variants. The recommendations for the classification of primary-progressive aphasia have advocated variant-specific patterns of atrophy. The aims of the present study were to evaluate the sensitivity and specificity of the proposed imaging criteria and to assess the intra- and interrater reporting agreements. MATERIALS AND METHODS: The cohort comprised 51 patients with a root diagnosis of primary-progressive aphasia, 25 patients with typical Alzheimer disease, and 26 matched control participants. Group-level analysis (voxel-based morphometry) confirmed the proposed atrophy patterns for the 3 syndromes. The individual T1-weighted anatomic images were reported by 3 senior neuroradiologists. RESULTS: We observed a dichotomized pattern of high sensitivity (92%) and specificity (93%) for the proposed atrophy pattern of semantic-variant primary-progressive aphasia and low sensitivity (21% for nonfluent-variant primary-progressive aphasia and 43% for logopenic-variant primary-progressive aphasia) but high specificity (91% for nonfluent-variant primary-progressive aphasia and 95% for logopenic-variant primary-progressive aphasia) in other primary-progressive aphasia variants and Alzheimer disease (sensitivity 43%, specificity 92%). MR imaging was least sensitive for the diagnosis of nonfluent-variant primary-progressive aphasia. Intrarater agreement analysis showed mean kappa values above the widely accepted threshold of 0.6 (mean, 0.63 +/- 0.16). Pair-wise interobserver agreement outcomes, however, were well below this threshold in 5 of the 6 possible interrater contrasts (mean, 0.41 +/- 0.09). CONCLUSIONS: While the group-level results were in precise agreement with the recommendations, semantic-variant primary-progressive aphasia was the only subtype for which the proposed recommendations were both sensitive and specific at an individual level. PMID- 28341717 TI - Regarding "Embolization of Intracranial Dural Arteriovenous Fistulas Using PHIL Liquid Embolic Agent in 26 Patients: A Multicenter Study". PMID- 28341716 TI - Multiparametric Evaluation in Differentiating Glioma Recurrence from Treatment Induced Necrosis Using Simultaneous 18F-FDG-PET/MRI: A Single-Institution Retrospective Study. AB - BACKGROUND AND PURPOSE: Differentiating glioma recurrence from treatment-induced necrosis can be a challenge on conventional imaging. This study aimed to assess the diagnostic performance of each functional MR imaging and PET parameter derived by using simultaneous FDG-PET/MR imaging individually and in combination in the evaluation of suspected glioma recurrence. MATERIALS AND METHODS: Thirty five treated glioma patients with 41 enhancing lesions (World Health Organization grade II = 9, III = 13, IV = 19) on MR imaging after an operation followed by radiation therapy and/or chemotherapy formed part of this study. Using PET/MR imaging, we calculated the normalized mean relative CBV, mean ADC, Cho/Cr, and maximum and mean target-to-background ratios. Statistical analysis was performed to determine the diagnostic performance of each parameter by receiver operating characteristic analysis individually and in combination with multivariate receiver operating characteristic analysis for the detection of glioma recurrence. Histopathology or clinicoradiologic follow-up was considered the criterion standard. RESULTS: Of 35 patients, 25 (30 lesions) were classified as having a recurrence and 10 (11 lesions) patients as having treatment-induced necrosis. Parameters like rCBVmean (mean relative CBV), ADCmean, Cho/Cr, and maximum and mean target-to-background ratios were statistically significant in the detection of recurrent lesions with an accuracy of 77.5%, 78.0%, 90.9%, 87.8%, and 87.8%, respectively. On multivariate receiver operating characteristic analysis, the combination of all 3 MR imaging parameters resulted in an area under the curve of 0.913 +/- 0.053. Furthermore, an area under the curve of 0.935 +/- 0.046 was obtained when MR imaging parameters (ADCmean and Cho/Cr) were combined with the PET parameter (mean target-to-background ratio), demonstrating an increase in diagnostic accuracy. CONCLUSIONS: Simultaneous PET/MR imaging with FDG offers correlative and synergistic multiparametric assessment of glioma recurrence with increased accuracy and clinical utility. PMID- 28341718 TI - Relationships among Cortical Glutathione Levels, Brain Amyloidosis, and Memory in Healthy Older Adults Investigated In Vivo with 1H-MRS and Pittsburgh Compound-B PET. AB - BACKGROUND AND PURPOSE: Oxidative stress has been implicated as an important pathologic mechanism in the development of Alzheimer disease. The purpose of this study was to assess whether glutathione levels, detected noninvasively with proton MR spectroscopy, are associated with brain amyloidosis and memory in a community-dwelling cohort of healthy older adults. MATERIALS AND METHODS: Fifteen cognitively healthy subjects were prospectively enrolled in this study. All subjects underwent 1H-MR spectroscopy of glutathione, a positron-emission tomography scan with an amyloid tracer, and neuropsychological testing by using the Repeatable Battery for the Assessment of Neuropsychological Status. Associations among glutathione levels, brain amyloidosis, and memory were assessed by using multivariate regression models. RESULTS: Lower glutathione levels were associated with greater brain amyloidosis in the temporal (P = .03) and parietal (P = .05) regions, adjusted for apolipoprotein E epsilon4 carrier status. There were no significant associations between glutathione levels and cognitive scores. CONCLUSIONS: This study found an association between cortical glutathione levels and brain amyloidosis in healthy older adults, suggesting a potential role for 1H-MR spectroscopy measures of glutathione as a noninvasive biomarker of early Alzheimer disease pathogenesis. PMID- 28341721 TI - Increased pathogenicity in rabbit haemorrhagic disease virus type 2 (RHDV2). PMID- 28341719 TI - Brain Perivascular Spaces as Biomarkers of Vascular Risk: Results from the Northern Manhattan Study. AB - BACKGROUND AND PURPOSE: Dilated perivascular spaces in the brain are associated with greater arterial pulsatility. We hypothesized that perivascular spaces identify individuals at higher risk for systemic and cerebral vascular events. MATERIALS AND METHODS: Stroke-free participants in the population-based Northern Manhattan Study had brain MR imaging performed and were followed for myocardial infarction, any stroke, and death. Imaging analyses distinguished perivascular spaces from lesions presumably ischemic. Perivascular spaces were further subdivided into lesions with diameters of <=3 mm (small perivascular spaces) and >3 mm (large perivascular spaces). We calculated relative rates of events with Poisson models and hazard ratios with Cox proportional models. RESULTS: The Northern Manhattan Study participants who had MR imaging data available for review (n = 1228; 59% women, 65% Hispanic; mean age, 71 +/- 9 years) were followed for an average of 9 +/- 2 years. Participants in the highest tertile of the small perivascular space score had a higher relative rate of all deaths (relative rate, 1.38; 95% CI, 1.01-1.91), vascular death (relative rate, 1.87; 95% CI, 1.12-3.14), myocardial infarction (relative rate, 2.08; 95% CI, 1.01 4.31), any stroke (relative rate, 1.79; 95% CI, 1.03-3.11), and any vascular event (relative rate, 1.74; 95% CI, 1.18-2.56). After we adjusted for confounders, there was a higher risk of vascular death (hazard ratio, 1.06; 95% CI, 1.01-1.11), myocardial infarction (hazard ratio, 2.22; 95% CI, 1.12-4.42), and any vascular event (hazard ratio, 1.04; 95% CI, 1.01-1.08) with higher small perivascular space scores. CONCLUSIONS: In this multiethnic, population-based study, participants with a high burden of small perivascular spaces had increased risk of vascular events. By gaining pathophysiologic insight into the mechanism of perivascular space dilation, we may be able to propose novel therapies to better prevent vascular disorders in the population. PMID- 28341722 TI - Sciatic and femoral nerve blockade using bupivacaine alone, or in combination with dexmedetomidine or buprenorphine in cats. AB - The aim of this study was to determine the onset and offset of antinociception after sciatic (ScN) and femoral (FN) nerve blocks. Six healthy adult cats (4.8+/ 1.3years; 4.3+/-0.4 kg) were included in a randomised, crossover, blinded and controlled study. Following sedation with dexmedetomidine (25 ug/kg, intramuscular), each ScN and FN injection was performed using 0.1 ml/kg of saline (CONTROL), bupivacaine (0.46 per cent, 0.46 mg/kg; BUPI), bupivacaine and dexmedetomidine (1 ug/kg; BUPI-DEX) or bupivacaine and buprenorphine (2.5 ug/kg; BUPI-BUPRE). Atipamezole (250 ug/kg) was administered after injections. Paw withdrawal thresholds (PWT) and motor blockade were evaluated before sedation and up to 24 hours. The PWT were significantly increased at half an hour in CONTROL, from two to four hours in BUPI and BUPI-DEX when compared with baseline. Motor blockade was observed between one and three hours in treatments using bupivacaine. Ability to walk was significantly impaired in BUPI at half an hour to two hours, BUPI-DEX at one to two hours and BUPI-BUPRE at two hours. Antinociception was observed in BUPI between one and eight hours, and in BUPI-DEX and BUPI-BUPRE between one and four hours. This study could not demonstrate a benefit of administering bupivacaine with dexmedetomidine or buprenorphine in cats. Results in BUPI-DEX may have been biased by the administration of atipamezole. PMID- 28341723 TI - Supervisor descriptions of veterinary student performance in the clinical workplace: a qualitative interview study. AB - This qualitative study investigated the qualities of veterinary student performance that inform a supervisor's impression of their competency. Semi structured interviews were conducted with a purposive sample of 15 supervisors from different veterinary subdisciplines, to elicit descriptions of excellent, weak and marginal students. Thematic analysis of transcriptions revealed 12 themes, of which engagement was frequently discussed and of stated importance, and trustworthiness was a differentiator of weak and marginal students from excellent students. Other themes were knowledge, application of knowledge, technical and animal handling skills, communication, social interaction, personal functioning, caring for animals, impact, prospects and the difficulty in judging competency. Patterns of association of themes were found, however themes were also used independently in unique combinations for most students described. The findings show the range of abilities, behaviours, attitudes and personal characteristics of students that are considered by supervisors and how these are weighted and balanced. The key contribution of engagement and trustworthiness to the overall impression aligns with research indicating their importance for success in clinical practice, as both contributors to competency and indicators of it. The findings may inform future design and investigation of workplace-based learning and in-training evaluation, as well as conceptions of veterinary competency. PMID- 28341724 TI - Less than half of new mothers in England breast feed after two months. PMID- 28341726 TI - Rest and treatment/rehabilitation following sport-related concussion: a systematic review. AB - AIM OR OBJECTIVE: The objective of this systematic review was to evaluate the evidence regarding rest and active treatment/rehabilitation following sport related concussion (SRC). DESIGN: Systematic review. DATA SOURCES: MEDLINE (OVID), CINAHL (EbscoHost), PsycInfo (OVID), Cochrane Central Register of Controlled Trials (OVID), SPORTDiscus (EbscoHost), EMBASE (OVID) and Proquest DissertationsandTheses Global (Proquest) were searched systematically. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies were included if they met the following criteria: (1) original research; (2) reported SRC as the diagnosis; and (3) evaluated the effect of rest or active treatment/rehabilitation. Review articles were excluded. RESULTS: Twenty-eight studies met the inclusion criteria (9 regarding the effects of rest and 19 evaluating active treatment). The methodological quality of the literature was limited; only five randomised controlled trials (RCTs) met the eligibility criteria. Those RCTs included rest, cervical and vestibular rehabilitation, subsymptom threshold aerobic exercise and multifaceted collaborative care. SUMMARY/CONCLUSIONS: A brief period (24-48 hours) of cognitive and physical rest is appropriate for most patients. Following this, patients should be encouraged to gradually increase activity. The exact amount and duration of rest are not yet well defined and require further investigation. The data support interventions including cervical and vestibular rehabilitation and multifaceted collaborative care. Closely monitored subsymptom threshold, submaximal exercise may be of benefit. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2016:CRD42016039570. PMID- 28341725 TI - Paraneoplastic endocrine syndromes. AB - The majority of neoplasms are responsible for symptoms caused by mass effects to surrounding tissues and/or through the development of metastases. However, occasionally neoplasms, with or without endocrine differentiation, acquire the ability to secrete a variety of bioactive substances or induce immune cross reactivity with the normal tissues that can lead to the development of characteristic clinical syndromes. These syndromes are named endocrine paraneoplastic syndromes when the specific secretory components (hormones, peptides or cytokines) are unrelated to the anticipated tissue or organ of origin. Endocrine paraneoplastic syndromes can complicate the patient's clinical course, response to treatment, impact prognosis and even be confused as metastatic spread. These syndromes can precede, occur concomitantly or present at a later stage of tumour development, and along with the secreted substances constitute the biological 'fingerprint' of the tumour. Their detection can facilitate early diagnosis of the underlying neoplasia, monitor response to treatment and/or detect early recurrences following successful initial management. Although when associated with tumours of low malignant potential they usually do not affect long-term outcome, in cases of highly malignant tumours, endocrine paraneoplastic syndromes are usually associated with poorer survival outcomes. Recent medical advances have not only improved our understanding of paraneoplastic syndrome pathogenesis in general but also enhanced their diagnosis and treatment. Yet, given the rarity of endocrine paraneoplastic syndromes, there is a paucity of prospective clinical trials to guide management. The development of well-designed prospective multicentre trials remains a priority in the field in order to fully characterise these syndromes and provide evidence-based diagnostic and therapeutic protocols. PMID- 28341727 TI - Fractures associated with ACL injury need to be taken seriously. PMID- 28341728 TI - Appraising the exercise oncology literature: a reminder of the rigour needed in systematic reviews. PMID- 28341729 TI - Vitamin D deficiency and diabetes. AB - Vitamin D deficiency has been linked to the onset of diabetes. This review summarizes the role of Vitamin D in maintaining the normal release of insulin by the pancreatic beta cells (beta-cells). Diabetes is initiated by the onset of insulin resistance. The beta-cells can overcome this resistance by releasing more insulin, thus preventing hyperglycaemia. However, as this hyperactivity increases, the beta-cells experience excessive Ca2+ and reactive oxygen species (ROS) signalling that results in cell death and the onset of diabetes. Vitamin D deficiency contributes to both the initial insulin resistance and the subsequent onset of diabetes caused by beta-cell death. Vitamin D acts to reduce inflammation, which is a major process in inducing insulin resistance. Vitamin D maintains the normal resting levels of both Ca2+ and ROS that are elevated in the beta-cells during diabetes. Vitamin D also has a very significant role in maintaining the epigenome. Epigenetic alterations are a feature of diabetes by which many diabetes-related genes are inactivated by hypermethylation. Vitamin D acts to prevent such hypermethylation by increasing the expression of the DNA demethylases that prevent hypermethylation of multiple gene promoter regions of many diabetes-related genes. What is remarkable is just how many cellular processes are maintained by Vitamin D. When Vitamin D is deficient, many of these processes begin to decline and this sets the stage for the onset of diseases such as diabetes. PMID- 28341730 TI - Combination of ibrutinib and chemotherapy produced a durable remission in multiply relapsed diffuse large B-cell lymphoma leg type with mutant MYD88 and wildtype CD79. PMID- 28341731 TI - Targeting the 5T4 oncofetal glycoprotein with an antibody drug conjugate (A1mcMMAF) improves survival in patient-derived xenograft models of acute lymphoblastic leukemia. AB - Outcome in childhood acute lymphoblastic leukemia is prognosticated from levels of minimal residual disease after remission induction therapy. Higher levels of minimal residual disease are associated with inferior results even with intensification of therapy, thus suggesting that identification and targeting of minimal residual disease cells could be a therapeutic strategy. Here we identify high expression of 5T4 in subclonal populations of patient-derived xenografts from patients with high, post-induction levels of minimal residual disease. 5T4 positive cells showed preferential ability to overcome the NOD-scidIL2Rgammanull mouse xenograft barrier, migrated in vitro on a CXCL12 gradient, preferentially localized to bone marrow in vivo and displayed the ability to reconstitute the original clonal composition on limited dilution engraftment. Treatment with A1mcMMAF (a 5T4-antibody drug conjugate) significantly improved survival without overt toxicity in mice engrafted with a 5T4-positive acute lymphoblastic leukemia cell line. Mice engrafted with 5T4-positive patient-derived xenograft cells were treated with combination chemotherapy or dexamethasone alone and then given A1mcMMAF in the minimal residual disease setting. Combination chemotherapy was toxic to NOD-scidIL2Rgammanull mice. While dexamethasone or A1mcMMAF alone improved outcomes, the sequential administration of dexamethasone and A1mcMMAF significantly improved survival (P=0.0006) over either monotherapy. These data show that specifically targeting minimal residual disease cells improved outcomes and support further investigation of A1mcMMAF in patients with high-risk B-cell precursor acute lymphoblastic leukemia identified by 5T4 expression at diagnosis. PMID- 28341732 TI - Novel recurrent chromosomal aberrations detected in clonal plasma cells of light chain amyloidosis patients show potential adverse prognostic effect: first results from a genome-wide copy number array analysis. AB - Immunoglobulin light chain (AL) amyloidosis is a rare plasma cell dyscrasia characterized by the deposition of abnormal amyloid fibrils in multiple organs, thus impairing their function. In the largest cohort studied up to now of 118 CD138-purified plasma cell samples from previously untreated immunoglobulin light chain amyloidosis patients, we assessed in parallel copy number alterations using high-density copy number arrays and interphase fluorescence in situ hybridization (iFISH). We used fluorescence in situ hybridization probes for the IgH translocations t(11;14), t(4;14), and t(14;16) or any other IgH rearrangement as well as numerical aberrations of the chromosome loci 1q21, 8p21, 5p15/5q35, 11q22.3 or 11q23, 13q14, 15q22, 17p13, and 19q13. Recurrent gains included chromosomes 1q (36%), 9 (24%), 11q (24%), as well as 19 (15%). Recurrent losses affected chromosome 13 (29% monosomy) and partial losses of 14q (19%), 16q (14%) and 13q (12%), respectively. In 88% of patients with translocation t(11;14), the hallmark chromosomal aberration in AL amyloidosis, a concomitant gain of 11q22.3/11q23 detected by iFISH was part of the unbalanced translocation der(14)t(11;14)(q13;q32) with the breakpoint in the CCND1/MYEOV gene region. Partial loss of chromosome regions 14q and 16q were significantly associated to gain 1q. Gain 1q21 detected by iFISH almost always resulted from a gain of the long arm of chromosome 1 and not from trisomy 1, whereas deletions on chromosome 1p were rarely found. Overall and event-free survival analysis found a potential adverse prognostic effect of concomitant gain 1q and deletion 14q as well as of deletion 1p. In conclusion, in the first whole genome report of clonal plasma cells in AL amyloidosis, novel aberrations and hitherto unknown potential adverse prognostic effects were uncovered. PMID- 28341733 TI - Effect of antithymocyte globulin source on outcomes of bone marrow transplantation for severe aplastic anemia. AB - For treatment of severe aplastic anemia, immunosuppressive therapy with horse antithymocyte globulin results in superior response and survival compared with rabbit antithymocyte globulin. This relative benefit may be different in the setting of transplantation as rabbit antithymocyte globulin results in more profound immunosuppression. We analyzed 833 severe aplastic anemia transplants between 2008 and 2013 using human leukocyte antigen (HLA)-matched siblings (n=546) or unrelated donors (n=287) who received antithymocyte globulin as part of their conditioning regimen and bone marrow graft. There were no differences in hematopoietic recovery by type of antithymocyte globulin. Among recipients of HLA matched sibling transplants, day 100 incidence of acute (17% versus 6%, P<0.001) and chronic (20% versus 9%, P<0.001) graft-versus-host disease were higher with horse compared to rabbit antithymocyte globulin. There were no differences in 3 year overall survival, 87% and 92%, P=0.76, respectively. Among recipients of unrelated donor transplants, acute graft-versus-host disease was also higher with horse compared to rabbit antithymocyte globulin (42% versus 23%, P<0.001) but not chronic graft-versus-host disease (38% versus 32%, P=0.35). Survival was lower with horse antithymocyte globulin after unrelated donor transplantation, 75% versus 83%, P=0.02. These data support the use of rabbit antithymocyte globulin for bone marrow transplant conditioning for severe aplastic anemia. PMID- 28341735 TI - Venous thromboembolism is associated with graft-versus-host disease and increased non-relapse mortality after allogeneic hematopoietic stem cell transplantation. AB - Although venous thromboembolism rates and risk factors are well described in patients with cancer, there are limited data on the incidence, risk factors and outcomes of thrombosis after allogeneic stem cell transplantation, a curative therapy for patients with hematologic malignancies. We aimed to determine the incidence and risks associated with venous thrombosis in allogeneic stem cell transplants. We studied 2276 recipients of first transplant between 2002-2013 at our institution with a median follow up of 50 months (range 4-146). Using pharmacy records and subsequent chart reviews, 190 patients who received systemic anticoagulation for venous thrombosis were identified. The 1-and 2-year cumulative incidence of all venous thrombotic events were 5.5% (95% confidence interval (CI) 4.6-6.5%) and 7.1% (95% CI 6.1-8.2%), respectively. There was no difference in age, sex, body mass index, diagnosis, disease risk index, conditioning intensity, donor type or graft source between transplant recipients with and without subsequent thrombosis. In multivariable models, both acute and chronic graft-versus-host disease were independently associated with thrombosis occurrence (Hazard ratio (HR)=2.05, 95% CI 1.52-2.76; HR=1.71, 95% CI 1.19-2.46, respectively). Upper extremity thrombosis differed from all other thromboses in terms of timing, risk factors and clinical impact, and was not associated with non-relapse mortality (HR=1.15; 95% CI 0.69-1.90), unlike all other thromboses which did increase non-relapse mortality (HR=1.71; 95% CI 1.17-2.49). In subgroup analysis evaluating conventional thrombosis predictors by comparing patients with and without thrombosis, a history of prior venous thrombosis was the only significant predictor. Venous thromboembolism has a high incidence after allogeneic stem cell transplant and is associated with graft-versus-host disease and non-relapse mortality. PMID- 28341736 TI - Molecular landscape of acute promyelocytic leukemia at diagnosis and relapse. PMID- 28341734 TI - Development of a modified prognostic index for patients with aggressive adult T cell leukemia-lymphoma aged 70 years or younger: possible risk-adapted management strategies including allogeneic transplantation. AB - Adult T-cell leukemia-lymphoma is a distinct type of peripheral T-cell lymphoma caused by human T-cell lymphotropic virus type I. Although allogeneic stem cell transplantation after chemotherapy is a recommended treatment option for patients with aggressive adult T-cell leukemia-lymphoma, there is no consensus about indications for allogeneic stem cell transplantation because there is no established risk stratification system for transplant eligible patients. We conducted a nationwide survey of patients with aggressive adult T-cell leukemia lymphoma in order to construct a new, large database that includes 1,792 patients aged 70 years or younger with aggressive adult T-cell leukemia-lymphoma who were diagnosed between 2000 and 2013 and received intensive first-line chemotherapy. We randomly divided patients into two groups (training and validation sets). Acute type, poor performance status, high soluble interleukin-2 receptor levels (> 5,000 U/mL), high adjusted calcium levels (>= 12 mg/dL), and high C-reactive protein levels (>= 2.5 mg/dL) were independent adverse prognostic factors used in the training set. We used these five variables to divide patients into three risk groups. In the validation set, median overall survival for the low-, intermediate , and high-risk groups was 626 days, 322 days, and 197 days, respectively. In the intermediate- and high-risk groups, transplanted recipients had significantly better overall survival than non-transplanted patients. We developed a promising new risk stratification system to identify patients aged 70 years or younger with aggressive adult T-cell leukemia-lymphoma who may benefit from upfront allogeneic stem cell transplantation. Prospective studies are warranted to confirm the benefit of this treatment strategy. PMID- 28341737 TI - An abnormal bone marrow microenvironment contributes to hematopoietic dysfunction in Fanconi anemia. AB - Fanconi anemia is a complex heterogeneous genetic disorder with a high incidence of bone marrow failure, clonal evolution to acute myeloid leukemia and mesenchymal-derived congenital anomalies. Increasing evidence in Fanconi anemia and other genetic disorders points towards an interdependence of skeletal and hematopoietic development, yet the impact of the marrow microenvironment in the pathogenesis of the bone marrow failure in Fanconi anemia remains unclear. Here we demonstrated that mice with double knockout of both Fancc and Fancg genes had decreased bone formation at least partially due to impaired osteoblast differentiation from mesenchymal stem/progenitor cells. Mesenchymal stem/progenitor cells from the double knockout mice showed impaired hematopoietic supportive activity. Mesenchymal stem/progenitor cells of patients with Fanconi anemia exhibited similar cellular deficits, including increased senescence, reduced proliferation, impaired osteoblast differentiation and defective hematopoietic stem/progenitor cell supportive activity. Collectively, these studies provide unique insights into the physiological significance of mesenchymal stem/progenitor cells in supporting the marrow microenvironment, which is potentially of broad relevance in hematopoietic stem cell transplantation. PMID- 28341738 TI - Higher HOPX expression is associated with distinct clinical and biological features and predicts poor prognosis in de novo acute myeloid leukemia. AB - Homeodomain-only protein homeobox (HOPX) is the smallest homeodomain protein. It was regarded as a stem cell marker in several non-hematopoietic systems. While the prototypic homeobox genes such as the HOX family have been well characterized in acute myeloid leukemia (AML), the clinical and biological implications of HOPX in the disease remain unknown. Thus we analyzed HOPX and global gene expression patterns in 347 newly diagnosed de novo AML patients in our institute. We found that higher HOPX expression was closely associated with older age, higher platelet counts, lower white blood cell counts, lower lactate dehydrogenase levels, and mutations in RUNX1, IDH2, ASXL1, and DNMT3A, but negatively associated with acute promyelocytic leukemia, favorable karyotypes, CEBPA double mutations and NPM1 mutation. Patients with higher HOPX expression had a lower complete remission rate and shorter survival. The finding was validated in two independent cohorts. Multivariate analysis revealed that higher HOPX expression was an independent unfavorable prognostic factor irrespective of other known prognostic parameters and gene signatures derived from multiple cohorts. Gene set enrichment analysis showed higher HOPX expression was associated with both hematopoietic and leukemia stem cell signatures. While HOPX and HOX family genes showed concordant expression patterns in normal hematopoietic stem/progenitor cells, their expression patterns and associated clinical and biological features were distinctive in AML settings, demonstrating HOPX to be a unique homeobox gene. Therefore, HOPX is a distinctive homeobox gene with characteristic clinical and biological implications and its expression is a powerful predictor of prognosis in AML patients. PMID- 28341739 TI - Modifiers of prion protein biogenesis and recycling identified by a highly parallel endocytosis kinetics assay. AB - The cellular prion protein, PrPC, is attached by a glycosylphosphatidylinositol anchor to the outer leaflet of the plasma membrane. Its misfolded isoform PrPSc is the causative agent of prion diseases. Conversion of PrPC into PrPSc is thought to take place at the cell surface or in endolysosomal organelles. Understanding the intracellular trafficking of PrPC may, therefore, help elucidate the conversion process. Here we describe a time-resolved fluorescence energy transfer (FRET) assay reporting membrane expression and real-time internalization rates of PrPC The assay is suitable for high-throughput genetic and pharmaceutical screens for modulators of PrPC trafficking. Simultaneous administration of FRET donor and acceptor anti-PrPC antibodies to living cells yielded a measure of PrPC surface density, whereas sequential addition of each antibody visualized the internalization rate of PrPC (Z' factor >0.5). RNA interference assays showed that suppression of AP2M1 (AP-2 adaptor protein), RAB5A, VPS35 (vacuolar protein sorting 35 homolog), and M6PR (mannose 6-phosphate receptor) blocked PrPC internalization, whereas down-regulation of GIT2 and VPS28 increased PrPC internalization. PrPC cell-surface expression was reduced by down regulation of RAB5A, VPS28, and VPS35 and enhanced by silencing EHD1. These data identify a network of proteins implicated in PrPC trafficking and demonstrate the power of this assay for identifying modulators of PrPC trafficking. PMID- 28341740 TI - Nanomolar nitric oxide concentrations quickly and reversibly modulate astrocytic energy metabolism. AB - Nitric oxide (NO) is an intercellular messenger involved in multiple bodily functions. Prolonged NO exposure irreversibly inhibits respiration by covalent modification of mitochondrial cytochrome oxidase, a phenomenon of pathological relevance. However, the speed and potency of NO's metabolic effects at physiological concentrations are incompletely characterized. To this end, we set out to investigate the metabolic effects of NO in cultured astrocytes from mice by taking advantage of the high spatiotemporal resolution afforded by genetically encoded Forster resonance energy transfer (FRET) nanosensors. NO exposure resulted in immediate and reversible intracellular glucose depletion and lactate accumulation. Consistent with cytochrome oxidase involvement, the glycolytic effect was enhanced at a low oxygen level and became irreversible at a high NO concentration or after prolonged exposure. Measurements of both glycolytic rate and mitochondrial pyruvate consumption revealed significant effects even at nanomolar NO concentrations. We conclude that NO can modulate astrocytic energy metabolism in the short term, reversibly, and at concentrations known to be released by endothelial cells under physiological conditions. These findings suggest that NO modulates the size of the astrocytic lactate reservoir involved in neuronal fueling and signaling. PMID- 28341742 TI - pH regulation in early endosomes and interferon-inducible transmembrane proteins control avian retrovirus fusion. AB - Enveloped viruses infect host cells by fusing their membranes with those of the host cell, a process mediated by viral glycoproteins upon binding to cognate host receptors or entering into acidic intracellular compartments. Whereas the effect of receptor density on viral infection has been well studied, the role of cell type-specific factors/processes, such as pH regulation, has not been characterized in sufficient detail. Here, we examined the effects of cell extrinsic factors (buffer environment) and cell-intrinsic factors (interferon inducible transmembrane proteins, IFITMs), on the pH regulation in early endosomes and on the efficiency of acid-dependent fusion of the avian sarcoma and leukosis virus (ASLV), with endosomes. First, we found that a modest elevation of external pH can raise the pH in early endosomes in a cell type-dependent manner and thereby delay the acid-induced fusion of endocytosed ASLV. Second, we observed a cell type-dependent delay between the low pH-dependent and temperature dependent steps of viral fusion, consistent with the delayed enlargement of the fusion pore. Third, ectopic expression of IFITMs, known to potently block influenza virus fusion with late compartments, was found to only partially inhibit ASLV fusion with early endosomes. Interestingly, IFITM expression promoted virus uptake and the acidification of endosomal compartments, resulting in an accelerated fusion rate when driven by the glycosylphosphatidylinositol anchored, but not by the transmembrane isoform of the ASLV receptor. Collectively, these results highlight the role of cell-extrinsic and cell intrinsic factors in regulating the efficiency and kinetics of virus entry and fusion with target cells. PMID- 28341743 TI - Adductome-based identification of biomarkers for lipid peroxidation. AB - Lipid peroxidation is an endogenous source of aldehydes that gives rise to covalent modification of proteins in various pathophysiological states. In this study, a strategy for the comprehensive detection and comparison of adducts was applied to find a biomarker for lipid peroxidation-modified proteins in vivo This adductome approach utilized liquid chromatography with electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) methods designed to detect the specific product ions from positively ionized adducts in a selected reaction monitoring mode. Using this procedure, we comprehensively analyzed lysine and histidine adducts generated in the in vitro oxidized low-density lipoproteins (LDL) and observed a prominent increase in several adducts, including a major lysine adduct. Based on the high resolution ESI-MS of the adduct and on the LC-ESI-MS/MS analysis of the synthetic adduct candidates, the major lysine adduct detected in the oxidized LDL was identified as Nepsilon-(8-carboxyoctanyl)lysine (COL). Strikingly, a significantly higher amount of COL was detected in the sera from atherosclerosis-prone mice and from patients with hyperlipidemia compared with the controls. These data not only offer structural insights into protein modification by lipid peroxidation products but also provide a platform for the discovery of biomarkers for human diseases. PMID- 28341741 TI - Endogenous prostaglandin E2 amplifies IL-33 production by macrophages through an E prostanoid (EP)2/EP4-cAMP-EPAC-dependent pathway. AB - When activated through toll-like receptors (TLRs), macrophages generate IL-33, an IL-1 family member that induces innate immune responses through ST2 signaling. LPS, a TLR4 ligand, induces macrophages to generate prostaglandin E2 (PGE2) through inducible COX-2 and microsomal PGE2 synthase 1 (mPGES-1) (1). We demonstrate that IL-33 production by bone marrow-derived murine macrophages (bmMFs) requires the generation of endogenous PGE2 and the intrinsic expression of EP2 receptors to amplify NF-kappaB-dependent, LPS-induced IL-33 expression via exchange protein activated by cAMP (EPAC). Compared with WT cells, bmMFs lacking either mPGES-1 or EP2 receptors displayed reduced LPS-induced IL-33 levels. A selective EP2 agonist and, to a lesser extent, EP4 receptor agonist potentiated LPS-induced IL-33 generation from both mPGES-1-null and WT bmMFs, whereas EP1 and EP3 receptor agonists were inactive. The effects of PGE2 depended on cAMP, were mimicked by an EPAC-selective agonist, and were attenuated by EPAC-selective antagonism and knockdown. LPS-induced p38 MAPK and NF-kappaB activations were necessary for both IL-33 production and PGE2 generation, and exogenous PGE2 partly reversed the suppression of IL-33 production caused by p38 MAPK and NF kappaB inhibition. Mice lacking mPGES-1 showed lower IL-33 levels and attenuated lung inflammation in response to repetitive Alternaria inhalation challenges. Cumulatively, our data demonstrate that endogenous PGE2, EP2 receptors, and EPAC are prerequisites for maximal LPS-induced IL-33 expression and that exogenous PGE2 can amplify IL-33 production via EP2 and EP4 receptors. The ubiquitous induction of mPGES-1-dependent PGE2 may be crucial for innate immune system activation during various IL-33 driven pathologic disorders. PMID- 28341744 TI - beta-Arrestin 1 has an essential role in neurokinin-1 receptor-mediated glioblastoma cell proliferation and G2/M phase transition. AB - Glioblastoma is the most common malignant brain tumor and has a poor prognosis. Tachykinin receptor neurokinin-1 (NK1R) is a promising target in glioblastoma therapy because of its overexpression in human glioblastoma. NK1R agonists promote glioblastoma cell growth, whereas NK1R antagonists efficiently inhibit cell growth both in vitro and in vivo However, the molecular mechanisms involved in these effects are incompletely understood. beta-Arrestins (ARRBs) serve as scaffold proteins and adapters to mediate intracellular signal transduction. Here we show that the ARRB1-mediated signaling pathway is essential for NK1-mediated glioblastoma cell proliferation. ARRB1 knockdown significantly inhibited NK1 mediated glioblastoma cell proliferation and induced G2/M phase cell cycle arrest. ARRB1 knockdown cells showed remarkable down-regulation of CDC25C/CDK1/cyclin B1 activity. We also demonstrated that ARRB1 mediated prolonged phosphorylation of ERK1/2 and Akt in glioblastoma cells induced by NK1R activation. ERK1/2 and Akt phosphorylation are involved in regulating CDC25C/CDK1/cyclin B1 activity. The lack of long-term ERK1/2 and Akt activation in ARRB1 knockdown cells was at least partly responsible for the delayed cell cycle progression and proliferation. Moreover, we found that ARRB1-mediated ERK1/2 and Akt phosphorylation regulated the transcriptional activity of both NF kappaB and AP-1, which were involved in cyclin B1 expression. ARRB1 deficiency increased the sensitivity of glioblastoma cells to the treatment of NK1R antagonists. Taken together, our results suggest that ARRB1 plays an essential role in NK1R-mediated cell proliferation and G2/M transition in glioblastoma cells. Interference with ARRB1-mediated signaling via NK1R may have potential significance for therapeutic strategies targeting glioblastoma. PMID- 28341745 TI - Phospholipase C-related, but catalytically inactive protein (PRIP) up-regulates osteoclast differentiation via calcium-calcineurin-NFATc1 signaling. AB - Phospholipase C-related, but catalytically inactive protein (PRIP) was previously identified as a novel inositol 1,4,5-trisphosphate-binding protein with a domain organization similar to that of phospholipase C-delta but lacking phospholipase activity. We recently showed that PRIP gene knock-out (KO) in mice increases bone formation and concomitantly decreases bone resorption, resulting in increased bone mineral density and trabecular bone volume. However, the role of PRIP in osteoclastogenesis has not yet been fully elucidated. Here, we investigated the effects of PRIP on bone remodeling by investigating dynamic tooth movement in mice fitted with orthodontic devices. Morphological analysis indicated that the extent of tooth movement was smaller in the PRIP-KO mice than in wild-type mice. Histological analysis revealed fewer osteoclasts on the bone-resorption side in maxillary bones of PRIP-KO mice, and osteoclast formation assays and flow cytometry indicated lower osteoclast differentiation in bone marrow cells isolated from these mice. The expression of genes implicated in bone resorption was lower in differentiated PRIP-KO cells, and genes involved in osteoclast differentiation, such as the transcription factor NFATc1, exhibited lower expression in immature PRIP-KO cells initiated by M-CSF. Moreover, calcineurin expression and activity were also lower in the PRIP-KO cells. The PRIP-KO cells also displayed fewer M-CSF-induced changes in intracellular Ca2+ and exhibited reduced nuclear localization of NFATc1. Up-regulation of intracellular Ca2+ restored osteoclastogenesis of the PRIP-KO cells. These results indicate that PRIP deficiency impairs osteoclast differentiation, particularly at the early stages, and that PRIP stimulates osteoclast differentiation through calcium calcineurin-NFATc1 signaling via regulating intracellular Ca2. PMID- 28341746 TI - Leveraging sequence-based faecal microbial community survey data to identify a composite biomarker for colorectal cancer. AB - OBJECTIVE: Colorectal cancer (CRC) is the second leading cause of cancer associated mortality in the USA. The faecal microbiome may provide non-invasive biomarkers of CRC and indicate transition in the adenoma-carcinoma sequence. Re analysing raw sequence and metadata from several studies uniformly, we sought to identify a composite and generalisable microbial marker for CRC. DESIGN: Raw 16S rRNA gene sequence data sets from nine studies were processed with two pipelines, (1) QIIME closed reference (QIIME-CR) or (2) a strain-specific method herein termed SS-UP (Strain Select, UPARSE bioinformatics pipeline). A total of 509 samples (79 colorectal adenoma, 195 CRC and 235 controls) were analysed. Differential abundance, meta-analysis random effects regression and machine learning analyses were carried out to determine the consistency and diagnostic capabilities of potential microbial biomarkers. RESULTS: Definitive taxa, including Parvimonas micra ATCC 33270, Streptococcus anginosus and yet-to-be cultured members of Proteobacteria, were frequently and significantly increased in stools from patients with CRC compared with controls across studies and had high discriminatory capacity in diagnostic classification. Microbiome-based CRC versus control classification produced an area under receiver operator characteristic (AUROC) curve of 76.6% in QIIME-CR and 80.3% in SS-UP. Combining clinical and microbiome markers gave a diagnostic AUROC of 83.3% for QIIME-CR and 91.3% for SS-UP. CONCLUSIONS: Despite technological differences across studies and methods, key microbial markers emerged as important in classifying CRC cases and such could be used in a universal diagnostic for the disease. The choice of bioinformatics pipeline influenced accuracy of classification. Strain-resolved microbial markers might prove crucial in providing a microbial diagnostic for CRC. PMID- 28341747 TI - Gut symbiotic microbes imprint intestinal immune cells with the innate receptor SLAMF4 which contributes to gut immune protection against enteric pathogens. AB - BACKGROUND: Interactions between host immune cells and gut microbiota are crucial for the integrity and function of the intestine. How these interactions regulate immune cell responses in the intestine remains a major gap in the field. AIM: We have identified the signalling lymphocyte activation molecule family member 4 (SLAMF4) as an immunomodulator of the intestinal immunity. The aim is to determine how SLAMF4 is acquired in the gut and what its contribution to intestinal immunity is. METHODS: Expression of SLAMF4 was assessed in mice and humans. The mechanism of induction was studied using GFPtg bone marrow chimaera mice, lymphotoxin alpha and TNLG8A-deficient mice, as well as gnotobiotic mice. Role in immune protection was revealed using oral infection with Listeria monocytogenes and Cytobacter rodentium. RESULTS: SLAMF4 is a selective marker of intestinal immune cells of mice and humans. SLAMF4 induction occurs directly in the intestinal mucosa without the involvement of the gut-associated lymphoid tissue. Gut bacterial products, particularly those of gut anaerobes, and gut resident antigen-presenting cell (APC) TNLG8A are key contributors of SLAMF4 induction in the intestine. Importantly, lack of SLAMF4 expression leads the increased susceptibility of mice to infection by oral pathogens culminating in their premature death. CONCLUSIONS: SLAMF4 is a marker of intestinal immune cells which contributes to the protection against enteric pathogens and whose expression is dependent on the presence of the gut microbiota. This discovery provides a possible mechanism for answering the long-standing question of how the intertwining of the host and gut microbial biology regulates immune cell responses in the gut. PMID- 28341749 TI - Suppression of interferon-mediated anti-HBV response by single CpG methylation in the 5'-UTR of TRIM22. AB - OBJECTIVE: Interferons (IFNs) mediate direct antiviral activity. They play a crucial role in the early host immune response against viral infections. However, IFN therapy for HBV infection is less effective than for other viral infections. DESIGN: We explored the cellular targets of HBV in response to IFNs using proteome-wide screening. RESULTS: Using LC-MS/MS, we identified proteins downregulated and upregulated by IFN treatment in HBV X protein (HBx)-stable and control cells. We found several IFN-stimulated genes downregulated by HBx, including TRIM22, which is known as an antiretroviral protein. We demonstrated that HBx suppresses the transcription of TRIM22 through a single CpG methylation in its 5'-UTR, which further reduces the IFN regulatory factor-1 binding affinity, thereby suppressing the IFN-stimulated induction of TRIM22. CONCLUSIONS: We verified our findings using a mouse model, primary human hepatocytes and human liver tissues. Our data elucidate a mechanism by which HBV evades the host innate immune system. PMID- 28341750 TI - Mortality associated with the treatment of HCV with direct-acting antivirals. PMID- 28341748 TI - Drug-induced liver injury: recent advances in diagnosis and risk assessment. AB - Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially severe adverse drug reaction that should be considered in patients who develop laboratory criteria for liver injury secondary to the administration of a potentially hepatotoxic drug. Although currently used liver parameters are sensitive in detecting DILI, they are neither specific nor able to predict the patient's subsequent clinical course. Genetic risk assessment is useful mainly due to its high negative predictive value, with several human leucocyte antigen alleles being associated with DILI. New emerging biomarkers which could be useful in assessing DILI include total keratin18 (K18) and caspase-cleaved keratin18 (ccK18), macrophage colony-stimulating factor receptor 1, high mobility group box 1 and microRNA-122. From the numerous in vitro test systems that are available, monocyte-derived hepatocytes generated from patients with DILI show promise in identifying the DILI-causing agent from among a panel of coprescribed drugs. Several computer-based algorithms are available that rely on cumulative scores of known risk factors such as the administered dose or potential liabilities such as mitochondrial toxicity, inhibition of the bile salt export pump or the formation of reactive metabolites. A novel DILI cluster score is being developed which predicts DILI from multiple complimentary cluster and classification models using absorption-distribution-metabolism-elimination-related as well as physicochemical properties, diverse substructural descriptors and known structural liabilities. The provision of more advanced scientific and regulatory guidance for liver safety assessment will depend on validating the new diagnostic markers in the ongoing DILI registries, biobanks and public-private partnerships. PMID- 28341751 TI - Low Recombination Proficiency Score (RPS) Predicts Heightened Sensitivity to DNA Damaging Chemotherapy in Breast Cancer. AB - Purpose: Molecular-based cancer tests have been developed to augment the standard clinical and pathologic features used to tailor treatments to individual breast cancer patients. Homologous recombination (HR) repairs double-stranded DNA breaks and promotes tolerance to lesions that disrupt DNA replication. Recombination Proficiency Score (RPS) quantifies HR efficiency based on the expression of four genes involved in DNA damage repair. We hypothesized low RPS values can identify HR-deficient breast cancers most sensitive to DNA-damaging chemotherapy.Experimental Design: We collected pathologic tumor responses and tumor gene expression values for breast cancer patients that were prospectively enrolled on clinical trials involving preoperative chemotherapy followed by surgery (N = 513). We developed an algorithm to calculate breast cancer-specific RPS (RPSb) values on an individual sample basis.Results: Low RPSb tumors are approximately twice as likely to exhibit a complete pathologic response or minimal residual disease to preoperative anthracycline-based chemotherapy as compared with high RPSb tumors. Basal, HER2-enriched, and luminal B breast cancer subtypes exhibit low RPSb values. In addition, RPSb predicts treatment responsiveness after controlling for clinical and pathologic features, as well as intrinsic breast subtype.Conclusions: Overall, our findings indicate that low RPS breast cancers exhibit aggressive features at baseline, but they have heightened sensitivity to DNA-damaging chemotherapy. Low RPSb values in basal, HER2 enriched, and luminal B subtypes provide a mechanistic explanation for their clinical behaviors and genomic instability. RPSb augments standard clinical and pathologic features used to tailor treatments, thereby enabling more personalized treatment strategies for individual breast cancer patients. Clin Cancer Res; 23(15); 4493-500. (c)2017 AACR. PMID- 28341753 TI - Aspirin and Risk of Subarachnoid Hemorrhage: Systematic Review and Meta-Analysis. AB - BACKGROUND AND PURPOSE: Recent studies have suggested that the use of low-dose aspirin may reduce the risk of aneurysmal subarachnoid hemorrhage (aSAH). We aimed to evaluate any association between aspirin use and risk of aSAH based on the literature, and whether this is influenced by duration or frequency of aspirin use. METHODS: A search of electronic databases was done from inception to September 2016. For each study, data on risk of aSAH in aspirin versus nonaspirin users were used to generate odds ratios and 95% confidence intervals, and combined using inverse variance-weighted averages of logarithmic odds ratios in a random-effects models. RESULTS: From 7 included studies, no significant difference was noted between aspirin use of any duration or frequency and nonaspirin users (odds ratio, 1.00; 95% confidence interval, 0.81-1.24; P=0.99). We found a significant association between short-term use of aspirin (<3 months) and the risk of aSAH (odds ratio, 1.61; 95% confidence interval, 1.20-2.18; P=0.002). No significant difference was found in terms of risk of aSAH for 3 to 12 months, 1 to 3 years, and >3 years of durations of use. No significant association was found between infrequent aspirin use (<=2* per week) or frequent use (>=3* per week) with risk of aSAH. CONCLUSIONS: Current evidence suggests that short-term (<3 months) use of aspirin is associated with increased risk of aSAH. Limitations include substantial heterogenity of the included studies. The role of long-term aspirin in reducing risk of aSAH remains unclear and ideally should be addressed by an appropriately designed randomized controlled trial. PMID- 28341752 TI - The Promise of Targeting Macrophages in Cancer Therapy. AB - Cancer therapy has developed around the concept of killing, or stopping the growth of, the cancer cells. Molecularly targeted therapy is the modern expression of this paradigm. Increasingly, however, the realization that the cancer has co-opted the normal cells of the stroma for its own survival has led to the concept that the tumor microenvironment (TME) could be targeted for effective therapy. In this review, we outline the importance of tumor-associated macrophages (TAM), a major component of the TME, in the response of tumors to cancer therapy. We discuss the normal role of macrophages in wound healing, the major phenotypes of TAMs, and their role in blunting the efficacy of cancer treatment by radiation and anticancer drugs, both by promoting tumor angiogenesis and by suppressing antitumor immunity. Finally, we review the many preclinical studies that have shown that the response of tumors to irradiation and anticancer drugs can be improved, sometimes markedly so, by depleting TAMs from tumors or by suppressing their polarization from an M1 to an M2 phenotype. The data clearly support the validity of clinical testing of combining targeting TAMs with conventional therapy. Clin Cancer Res; 23(13); 3241-50. (c)2017 AACR. PMID- 28341754 TI - Proportional Recovery From Lower Limb Motor Impairment After Stroke. AB - BACKGROUND AND PURPOSE: In people with preserved corticospinal tract (CST) function after stroke, upper limb impairment resolves by ~70% within 3 months. This is known as the proportional recovery rule. Patients without CST function do not fit this rule and have worse upper limb outcomes. This study investigated resolution of motor impairment in the lower limb (LL). METHODS: Patients with stroke and LL weakness were assessed 3 days and 3 months after stroke with the LL Fugl-Meyer. CST integrity was determined in a subset of patients using transcranial magnetic stimulation to test for LL motor-evoked potentials and magnetic resonance imaging to measure CST lesion load. Linear regression analyses were conducted to predict resolution of motor impairment (DeltaFugl-Meyer) including factors initial impairment, motor-evoked potential status, CST lesion load, and LL therapy dose. RESULTS: Thirty-two patients completed 3-month follow up and recovered 74% (95% confidence interval, 60%-88%) of initial LL motor impairment. Initial impairment was the only significant predictor of resolution of motor impairment. There was no identifiable cluster of patients who did not fit the proportional recovery rule. Measures of CST integrity did not predict proportional LL recovery. CONCLUSIONS: LL impairment resolves by ~70% within 3 months after stroke. The absence of a nonfitter group may be because of differences in the neuroanatomical organization of descending motor tracts to the upper limb and LL. Proportional recovery of the LL is not influenced by therapy dose providing further evidence that it reflects a fundamental biological process. PMID- 28341755 TI - Pathogenic variants in the healthy elderly: unique ethical and practical challenges. AB - : : Genetic research into ageing, longevity and late-onset disease is becoming increasingly common. Yet, there is a paucity of knowledge related to clinical actionability and the return of pathogenic variants to otherwise healthy elderly individuals. Whether or not genetic research in the elderly should be managed differently from standard practices adapted for younger populations has not yet been defined. In this article, we provide an overview of ethical and practical challenges in preparing for a genetic study of over 14 000 healthy Australians aged 70 years or older enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) Healthy Ageing Biobank. At the time of consent, all participants in this study were free of life-threatening illness, cardiovascular disease or cognitive impairment. ASPREE is thus a cohort of healthy elderly individuals with seemingly minimal burden of genetic disease recruited without ascertainment bias. The cohort presents a unique opportunity to address the penetrance of known pathogenic variants in a population without disease symptoms; however, it also raises a number of ethical concerns regarding the interpretation and disclosure of variants with known clinical actionability. Some of the challenges include (a) how to manage the interpretation, disclosure and actioning of pathogenic variants found in otherwise healthy elderly adults without disease symptoms, (b) whether or not to disclose findings for the benefit of family members rather than elderly consented donors themselves, (c) how to manage the return of genetic findings to the elderly individuals who are now in severe cognitive decline or terminal illness, (d) how to ensure quality of information and clinical service upon disclosure of results to this demographic and (e) how to prepare for the insurance implications of disclosing genetic information under Australian law. We discuss these and other dilemmas and propose a defensible plan of management. TRIAL REGISTRATION NUMBER: ISRCTN83772183. PMID- 28341756 TI - Distress, disease, desire: perspectives on the medicalisation of premature ejaculation. AB - The discovery that certain selective serotonin reuptake inhibitors delay ejaculation and the later development and approval of dapoxetine as an on-demand treatment option has led to a dramatic increase in medical interest in premature ejaculation. This paper analyses the diagnostic criteria and the discussion within the medical community about suitable treatments against the backdrop of theories of science, sex and gender. Our conclusion is that the diagnosis itself and the suggested treatments contribute to normative models of sexual conduct and therefore reinforce the norms that cause patients' distress over ejaculating 'too soon'. PMID- 28341757 TI - Elevated Serum Levels of sCD30 and IL6 and Detectable IL10 Precede Classical Hodgkin Lymphoma Diagnosis. AB - Background: We investigated whether an immune system environment characterized by elevated serum levels of B-cell activation molecules was associated with the subsequent development of classical Hodgkin lymphoma (cHL).Methods: We measured serum levels of B-cell-stimulatory cytokines, IL6 and IL10, soluble CD30 (sCD30), and total IgE prior to cHL diagnosis in 103 cases and 206 matched controls with archived specimens in the DoD Serum Repository.Results: Prediagnosis serum sCD30 and IL6 levels had strong positive associations with risk of a cHL diagnosis 0 to 1 year prior to diagnosis [sCD30 OR = 5.5; 95% confidence interval (CI), 3.4-9.0; IL6 OR = 4.6; 95% CI, 2.9-7.5] and >1 year to 2 years pre-cHL diagnosis (sCD30 OR = 3.3; 95% CI, 1.6-6.7; IL6 OR = 2.9; 95% CI, 1.3-6.5). We observed similar, albeit not consistently significant positive associations, over 4 or more years preceding diagnosis. We did not observe a clear association with IgE levels. Of note, detectable IL10 levels were significantly associated with Epstein-Barr virus (EBV)-positive cHL cases compared with EBV-negative cases.Conclusion: In this prospective analysis, elevated sCD30 and IL6 levels and detectable IL10 preceded cHL diagnosis.Impact: The associations of these cytokines with cHL risk may reflect the production of these molecules by proliferating nascent cHL tumor cells, or by immune cells responding to their presence, prior to clinical detection. The stable elevation in cHL risk, 4 or more years prediagnosis, also suggests that a B-cell-stimulatory immune system milieu precedes, and may promote, lymphomagenesis. Cancer Epidemiol Biomarkers Prev; 26(7); 1114-23. (c)2017 AACR. PMID- 28341758 TI - High Salt Intake Is Associated with Atrophic Gastritis with Intestinal Metaplasia. AB - Background: Although several studies have investigated excessive salt intake as a risk factor for gastric precancerous lesions, such as atrophic gastritis and intestinal metaplasia, the evidence is insufficient to make a conclusion. We evaluated the association between gastric precancerous lesions and salt intake.Methods: From 2008 to 2015, the medical records of 728 subjects who underwent upper gastrointestinal endoscopy and sodium excretion in 24-hour urine tests were retrospectively reviewed. Sixty-six subjects were excluded due to diuretics use (n = 55), diagnosis with a gastric neoplasm (n = 4), or the cases of intestinal metaplasia in the absence of atrophy (n = 7), so 662 subjects were included. Atrophic gastritis and intestinal metaplasia were diagnosed by endoscopic findings. The subjects were grouped into three levels by tertiles of 24-hour urine sodium excretion.Results: A total of 192 (29.0%) had atrophic gastritis without intestinal metaplasia and 112 (16.9%) had atrophic gastritis with intestinal metaplasia. A total of 276 subjects (61.5%) were infected with Helicobacter pylori (H. pylori). In multivariate analyses, H. pylori infection [OR = 14.17; 95% confidence interval (CI), 7.12-28.22) was associated with atrophic gastritis without intestinal metaplasia. Highest levels of sodium excretion (OR = 2.870; 95% CI, 1.34-6.14), heavy smoking (>=20 pack-years) (OR = 2.75; 95% CI, 1.02-7.39), and H. pylori infection (OR = 3.96; 95% CI, 2.02-7.76) were associated with atrophic gastritis with intestinal metaplasia.Conclusions: Our endoscopy-based study suggested that high salt intake could be associated with an increased risk of atrophic gastritis with intestinal metaplasia.Impact: Low salt diet might be helpful to prevent gastric carcinogenesis. Cancer Epidemiol Biomarkers Prev; 26(7); 1133-8. (c)2017 AACR. PMID- 28341760 TI - Intratumoral Heterogeneity in Breast Cancer: A Comparison of Primary and Metastatic Breast Cancers. AB - Intratumoral heterogeneity presents challenges in the management of cancer. To gain deeper insight in intratumoral heterogeneity at different levels and tumor sites for common biomarkers in breast cancers, this report examines seven cases of invasive breast cancer with multiple axillary nodal metastases and/or recurrences for immunohistochemical expression of estrogen receptors, progesterone receptors, human epidermal growth receptor 2, and Ki67 on all tissue blocks in both primary and metastatic tumors. The Oncologist 2017;22:487-490. PMID- 28341759 TI - A Phase Ib Study of Sorafenib (BAY 43-9006) in Patients with Kaposi Sarcoma. AB - LESSONS LEARNED: Oral targeted agents are desirable for treatment of Kaposi sarcoma (KS); however, in patients with HIV, drug-drug interactions must be considered. In this study to treat KS, sorafenib was poorly tolerated at doses less than those approved by the U.S. Food and Drug Administration for hepatocellular carcinoma and other cancers, and showed only modest activity.Sorafenib's metabolism occurs via the CYP3A4 pathway, which is inhibited by ritonavir, a commonly used antiretroviral agent used by most patients in this study. Strong CYP3A4 inhibition by ritonavir may contribute to the observed sorafenib toxicity.Alternate antiretroviral agents without predicted interactions are preferred for co-administration in patients with HIV and cancers for which sorafenib is indicated. BACKGROUND: We conducted a phase Ib study of sorafenib, a vascular epithelial growth factor receptor (VEGFR), c-kit, and platelet derived growth factor receptor (PDGFR)-targeted treatment in Kaposi sarcoma (KS). We evaluated drug-drug interactions between sorafenib and ritonavir, an HIV medication with strong CYP3A4 inhibitory activity. METHODS: Two cohorts were enrolled: HIV-related KS on ritonavir (Cohort R) and HIV-related or classical KS not receiving ritonavir (Cohort NR). Sorafenib dose level 1 in cohort R (R1) was 200 mg daily and 200 mg every 12 hours in cohort NR (NR1). Steady-state pharmacokinetics were evaluated at cycle 1, day 8. KS responses and correlative factors were assessed. RESULTS: Ten patients (nine HIV+) were enrolled: R1 (eight), NR1 (two). Median CD4+ count (HIV+) was 500 cells/uL. Dose-limiting toxicities (DLTs) were grade 3 elevated lipase (R1), grade 4 thrombocytopenia (R1), and grade 3 hand-foot syndrome (NR1). Two of seven evaluable patients had a partial response (PR; 29%; 95% CI 4%-71%). Steady-state area under the curve of the dosing interval (AUCTAU) of sorafenib was not significantly affected by ritonavir; however, a trend for decreased AUCTAU of the CYP3A4 metabolite sorafenib-N-oxide (3.8-fold decrease; p = .08) suggests other metabolites may be increased. CONCLUSION: Sorafenib was poorly tolerated, and anti-KS activity was modest. Strong CYP3A4 inhibitors may contribute to sorafenib toxicity, and ritonavir has previously been shown to be a CYP3A4 inhibitor. Alternate antiretroviral agents without predicted interactions should be used when possible for concurrent administration with sorafenib. The Oncologist 2017;22:505-e49. PMID- 28341761 TI - Cardiac Safety of Dual Anti-HER2 Therapy in the Neoadjuvant Setting for Treatment of HER2-Positive Breast Cancer. AB - BACKGROUND: Trastuzumab and pertuzumab are approved for the neoadjuvant treatment of human epidermal growth receptor 2 (HER2)-positive breast cancer, but cardiac safety data is limited. We report the cardiac safety of dose-dense doxorubicin and cyclophosphamide (AC) followed by paclitaxel, trastuzumab, and pertuzumab (THP) in the neoadjuvant setting followed by adjuvant trastuzumab-based therapy. METHODS: Fifty-seven patients treated with neoadjuvant dose-dense AC-THP followed by adjuvant trastuzumab-based therapy between September 1, 2013, and March 1, 2015, were identified. The primary outcome was cardiac event rate, defined by heart failure (New York Heart Association [NYHA] class III/IV) or cardiac death. Patients underwent left ventricular ejection fraction (LVEF) monitoring at baseline, after AC, and serially during 1 year of anti-HER2 therapy. RESULTS: The median age was 46 years (range 26-68). Two (3.5%) patients developed NYHA class III/IV heart failure 5 and 9 months after initiation of trastuzumab-based therapy, leading to permanent discontinuation of anti-HER2 treatment. Seven (12.3%) patients developed a significant LVEF decline (without NYHA class III/IV symptoms). The median LVEF was 65% (range 55%-75%) at baseline and 64% (range 53% 72%) after AC, and decreased to 60% (range 35%-70%), 60% (range 23%-73%), 61% (range 25%-73%), and 58% (range 28%-66%) after 3, 6, 9, and 12 months (+/- 6 weeks) of trastuzumab-based therapy. CONCLUSION: The incidence of NYHA class III/IV heart failure after neoadjuvant AC-THP (followed by adjuvant trastuzumab based therapy) is comparable to rates reported in trials of sequential doxorubicin and trastuzumab. Our findings do not suggest an increased risk of cardiotoxicity from trastuzumab plus pertuzumab following a doxorubicin-based regimen. IMPLICATIONS FOR PRACTICE: Dual anti-human epidermal growth receptor 2 (HER2) therapy with trastuzumab and pertuzumab combined with standard chemotherapy has received accelerated approval for the neoadjuvant treatment of stage II-III HER2-positive breast cancer. Cardiac safety data for trastuzumab and pertuzumab in this setting are limited to clinical trials that utilized epirubicin-based chemotherapy. Formalized investigations into the cardiac safety of trastuzumab and pertuzumab with doxorubicin- (rather than epirubicin) based regimens are important because these regimens are widely used for the adjuvant and neoadjuvant treatment of breast cancer. The known role of HER2 signaling in the physiological adaptive responses of the heart provides further rationale for study on the potential cardiotoxicity of dual anti-HER2 blockade. Findings from this retrospective study provide favorable preliminary data on the cardiac safety of trastuzumab and pertuzumab in combination with a regimen of neoadjuvant doxorubicin and cyclophosphamide followed by paclitaxel, one of the preferred breast cancer treatment regimens, according to the National Comprehensive Cancer Network. PMID- 28341766 TI - Recommendations to the European Commission implementing a priority list of additives that should have more stringent reporting requirements: the opinion of the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR). PMID- 28341765 TI - Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate. AB - BACKGROUND: Patients with rheumatoid arthritis (RA) who take methotrexate (MTX) are advised to limit their alcohol intake due to potential combined hepatotoxicity. However, data are limited to support this. The aim of this study was to quantify the risk of developing abnormal liver blood tests at different levels of alcohol consumption, using routinely collected data from primary care. METHODS: Patients with RA in the Clinical Practice Research Datalink starting MTX between 1987 and 2016 were included. Hepatotoxicity was defined as transaminitis: alanine transaminase or aspartate aminotransferase more than three times the upper limit of normal. Crude rates of transaminitis were calculated per 1000 person-years, categorised by weekly alcohol consumption in units. Cox proportional hazard models tested the association between alcohol consumption and transaminitis univariately, then age and gender adjusted. RESULTS: 11 839 patients were included, with 530 episodes of transaminitis occurring in 47 090 person-years follow-up. Increased weekly alcohol consumption as a continuous variable was associated with increased risk of transaminitis, adjusted HR (95% CI) per unit consumed 1.01 (1.00 to 1.02); consuming between 15 and 21 units was associated with a possible increased risk of hepatotoxicity, while drinking >21 units per week significantly increased rates of transaminitis, adjusted HR (95% CI) 1.85 (1.17 to 2.93). CONCLUSIONS: Weekly alcohol consumption of <14 units per week does not appear to be associated with an increased risk of transaminitis. PMID- 28341762 TI - A Prospective Observational Study on Effect of Short-Term Periodic Steroid Premedication on Bone Metabolism in Gastrointestinal Cancer (ESPRESSO-01). AB - BACKGROUND: A multicenter prospective observational study evaluated the effect of gastrointestinal cancer chemotherapy with short-term periodic steroid premedication on bone metabolism. PATIENTS AND METHODS: Seventy-four patients undergoing chemotherapy for gastrointestinal cancer were studied. The primary endpoints were changes in bone mineral densities (BMDs) and metabolic bone turnover 16 weeks after initiation of chemotherapy. BMDs, measured by dual-energy x-ray absorptiometry, and serum cross-linked N-telopeptides of type I collagen (sNTX), and bone alkaline phosphatase (sBAP) were assessed for evaluation of bone resorption and formation, respectively. RESULTS: In 74.3% (55/74) of the patients, BMDs were significantly reduced at 16 weeks relative to baseline. The percent changes of BMD were -1.89% (95% confidence interval [CI], -2.67% to 1.11%: p < .0001) in the lumbar spine, -2.24% (95% CI, -3.59% to -0.89%: p = .002) in the total hip, and -2.05% (95% CI, -3.11% to -0.99%: p < .0001) in the femoral neck. Although there was no significant difference in sNTX levels during 16 weeks (p = .136), there was a significant increase in sBAP levels (p = .010). Decreased BMD was significantly linked to number of chemotherapy cycles (p = .02). There were no significant correlations between changes in BMDs and the primary site of malignancy, chemotherapy regimens, total cumulative steroid dose, steroid dose intensity, and additive steroid usage. CONCLUSION: Gastrointestinal cancer chemotherapy with periodic glucocorticoid premedication was associated with reduced BMD and increased sBAP levels, which were linked to number of chemotherapy cycles but independent of primary site, chemotherapy regimen, duration, and additive steroid usage. The Oncologist 2017;22:592-600 IMPLICATIONS FOR PRACTICE: Bone health and the management of treatment-related bone loss are important for cancer care. The present study showed that a significant decrease in bone mineral density (BMD) and an increase in serum bone alkaline phosphatase levels occurred in gastrointestinal cancer patients receiving chemotherapy, which were linked to number of chemotherapy cycles but were independent of primary site, chemotherapy regimen, total steroid dose, and steroid dose intensity. Surprisingly, it seems that the decreasing BMD levels after only 16 weeks of chemotherapy for gastrointestinal cancer were comparable to that of 12-month adjuvant aromatase inhibitor therapy for early-stage breast cancer patients. PMID- 28341767 TI - The effect of excise tax increases on cigarette prices in South Africa. AB - INTRODUCTION: The effectiveness of excise tax increases as a tool for reducing tobacco consumption depends largely on how the tax increases impact the retail price. We estimate this relationship in South Africa for 2001-2015. DATA: Statistics South Africa provided disaggregated cigarette price data, used in the calculation of the Consumers' Price Index. Data on the excise tax per cigarette were obtained from Budget Reviews prepared by the National Treasury of South Africa. METHODS: Regression equations were estimated for each month. The month-on month change in cigarette prices in February through April was regressed against March's excise tax change to estimate the pass-through coefficient. For the other 9 months, the month-on-month change in cigarette price was regressed against monthly dummy variables to determine the size of the non-tax-related price increase in each of these months. The analysis was performed in both nominal and real (inflation-adjusted) terms. FINDINGS: Expressed in real terms, the excise tax was undershifted. A R1.00 (one rand) increase in the excise tax is associated with an increase in the retail price of cigarettes of R0.90 in the pre-2010 period, and R0.49 in the post-2010 period. In the pre-2010 period, the tobacco industry increased the retail price of cigarettes in July/August, independent of the excise tax increase. The discretionary July/August price increases largely disappeared after 2010, primarily because the market became more competitive. CONCLUSION: The degree of excise tax pass-through, and the magnitude of discretionary increases in cigarette prices, is significantly determined by the competitive environment in the cigarette market. PMID- 28341768 TI - Public reactions to e-cigarette regulations on Twitter: a text mining analysis. AB - BACKGROUND: In May 2016, the Food and Drug Administration (FDA) issued a final rule that deemed e-cigarettes to be within their regulatory authority as a tobacco product. News and opinions about the regulation were shared on social media platforms, such as Twitter, which can play an important role in shaping the public's attitudes. We analysed information shared on Twitter for insights into initial public reactions. METHODS: A text mining approach was used to uncover important topics among reactions to the e-cigarette regulations on Twitter. SAS Text Miner V.12.1 software was used for descriptive text mining to uncover the primary topics from tweets collected from May 1 to May 17 2016 using NUVI software to gather the data. RESULTS: A total of nine topics were generated. These topics reveal initial reactions to whether the FDA's e-cigarette regulations will benefit or harm public health, how the regulations will impact the emerging e-cigarette market and efforts to share the news. The topics were dominated by negative or mixed reactions. CONCLUSIONS: In the days following the FDA's announcement of the new deeming regulations, the public reaction on Twitter was largely negative. Public health advocates should consider using social media outlets to better communicate the policy's intentions, reach and potential impact for public good to create a more balanced conversation. PMID- 28341770 TI - An Integrated Hydraulic-Hormonal Model of Conifer Stomata Predicts Water Stress Dynamics. PMID- 28341769 TI - Stomatal Defense a Decade Later. PMID- 28341771 TI - Small chromosomal regions position themselves autonomously according to their chromatin class. AB - The spatial arrangement of chromatin is linked to the regulation of nuclear processes. One striking aspect of nuclear organization is the spatial segregation of heterochromatic and euchromatic domains. The mechanisms of this chromatin segregation are still poorly understood. In this work, we investigated the link between the primary genomic sequence and chromatin domains. We analyzed the spatial intranuclear arrangement of a human artificial chromosome (HAC) in a xenospecific mouse background in comparison to an orthologous region of native mouse chromosome. The two orthologous regions include segments that can be assigned to three major chromatin classes according to their gene abundance and repeat repertoire: (1) gene-rich and SINE-rich euchromatin; (2) gene-poor and LINE/LTR-rich heterochromatin; and (3) gene-depleted and satellite DNA-containing constitutive heterochromatin. We show, using fluorescence in situ hybridization (FISH) and 4C-seq technologies, that chromatin segments ranging from 0.6 to 3 Mb cluster with segments of the same chromatin class. As a consequence, the chromatin segments acquire corresponding positions in the nucleus irrespective of their chromosomal context, thereby strongly suggesting that this is their autonomous property. Interactions with the nuclear lamina, although largely retained in the HAC, reveal less autonomy. Taken together, our results suggest that building of a functional nucleus is largely a self-organizing process based on mutual recognition of chromosome segments belonging to the major chromatin classes. PMID- 28341772 TI - Diurnal regulation of RNA polymerase III transcription is under the control of both the feeding-fasting response and the circadian clock. AB - RNA polymerase III (Pol III) synthesizes short noncoding RNAs, many of which are essential for translation. Accordingly, Pol III activity is tightly regulated with cell growth and proliferation by factors such as MYC, RB1, TRP53, and MAF1. MAF1 is a repressor of Pol III transcription whose activity is controlled by phosphorylation; in particular, it is inactivated through phosphorylation by the TORC1 kinase complex, a sensor of nutrient availability. Pol III regulation is thus sensitive to environmental cues, yet a diurnal profile of Pol III transcription activity is so far lacking. Here, we first use gene expression arrays to measure mRNA accumulation during the diurnal cycle in the livers of (1) wild-type mice, (2) arrhythmic Arntl knockout mice, (3) mice fed at regular intervals during both night and day, and (4) mice lacking the Maf1 gene, and so provide a comprehensive view of the changes in cyclic mRNA accumulation occurring in these different systems. We then show that Pol III occupancy of its target genes rises before the onset of the night, stays high during the night, when mice normally ingest food and when translation is known to be increased, and decreases in daytime. Whereas higher Pol III occupancy during the night reflects a MAF1 dependent response to feeding, the rise of Pol III occupancy before the onset of the night reflects a circadian clock-dependent response. Thus, Pol III transcription during the diurnal cycle is regulated both in response to nutrients and by the circadian clock, which allows anticipatory Pol III transcription. PMID- 28341773 TI - PML protein organizes heterochromatin domains where it regulates histone H3.3 deposition by ATRX/DAXX. AB - Maintenance of chromatin homeostasis involves proper delivery of histone variants to the genome. The interplay between different chaperones regulating the supply of histone variants to distinct chromatin domains remains largely undeciphered. We report a role of promyelocytic leukemia (PML) protein in the routing of histone variant H3.3 to chromatin and in the organization of megabase-size heterochromatic PML-associated domains that we call PADs. Loss of PML alters the heterochromatic state of PADs by shifting the histone H3 methylation balance from K9me3 to K27me3. Loss of PML impairs deposition of H3.3 by ATRX and DAXX in PADs but preserves the H3.3 loading function of HIRA in these regions. Our results unveil an unappreciated role of PML in the large-scale organization of chromatin and demonstrate a PML-dependent role of ATRX/DAXX in the deposition of H3.3 in PADs. Our data suggest that H3.3 loading by HIRA and ATRX-dependent H3K27 trimethylation constitute mechanisms ensuring maintenance of heterochromatin when the integrity of these domains is compromised. PMID- 28341774 TI - RNA-DNA hybrid (R-loop) immunoprecipitation mapping: an analytical workflow to evaluate inherent biases. AB - The impact of R-loops on the physiology and pathology of chromosomes has been demonstrated extensively by chromatin biology research. The progress in this field has been driven by technological advancement of R-loop mapping methods that largely relied on a single approach, DNA-RNA immunoprecipitation (DRIP). Most of the DRIP protocols use the experimental design that was developed by a few laboratories, without paying attention to the potential caveats that might affect the outcome of RNA-DNA hybrid mapping. To assess the accuracy and utility of this technology, we pursued an analytical approach to estimate inherent biases and errors in the DRIP protocol. By performing DRIP-sequencing, qPCR, and receiver operator characteristic (ROC) analysis, we tested the effect of formaldehyde fixation, cell lysis temperature, mode of genome fragmentation, and removal of free RNA on the efficacy of RNA-DNA hybrid detection and implemented workflows that were able to distinguish complex and weak DRIP signals in a noisy background with high confidence. We also show that some of the workflows perform poorly and generate random answers. Furthermore, we found that the most commonly used genome fragmentation method (restriction enzyme digestion) led to the overrepresentation of lengthy DRIP fragments over coding ORFs, and this bias was enhanced at the first exons. Biased genome sampling severely compromised mapping resolution and prevented the assignment of precise biological function to a significant fraction of R-loops. The revised workflow presented herein is established and optimized using objective ROC analyses and provides reproducible and highly specific RNA DNA hybrid detection. PMID- 28341775 TI - Diarrhea in a Long-Term Kidney-Pancreas Recipient. PMID- 28341777 TI - Respiratory Compromise as a New Paradigm for the Care of Vulnerable Hospitalized Patients. AB - Acute respiratory compromise describes a deterioration in respiratory function with a high likelihood of rapid progression to respiratory failure and death. Identifying patients at risk for respiratory compromise coupled with monitoring of patients who have developed respiratory compromise might allow earlier interventions to prevent or mitigate further decompensation. The National Association for the Medical Direction of Respiratory Care (NAMDRC) organized a workshop meeting with representation from many national societies to address the unmet needs of respiratory compromise from a clinical practice perspective. Respiratory compromise may arise de novo or may complicate preexisting lung disease. The group identified distinct subsets of respiratory compromise that present similar opportunities for early detection and useful intervention to prevent respiratory failure. The subtypes were characterized by the pathophysiological mechanisms they had in common: impaired control of breathing, impaired airway protection, parenchymal lung disease, increased airway resistance, hydrostatic pulmonary edema, and right-ventricular failure. Classification of acutely ill respiratory patients into one or more of these categories may help in selecting the screening and monitoring strategies that are most appropriate for the patient's particular pathophysiology. Standardized screening and monitoring practices for patients with similar mechanisms of deterioration may enhance the ability to predict respiratory failure early and prevent its occurrence. PMID- 28341778 TI - Use of a Metered-Dose Inhaler Compared With a Vibrating Mesh Nebulizer During Mechanical Ventilation: Does It Really Matter? PMID- 28341776 TI - An NPPB Promoter Polymorphism Associated With Elevated N-Terminal pro-B-Type Natriuretic Peptide and Lower Blood Pressure, Hypertension, and Mortality. AB - BACKGROUND: Elevated B-type natriuretic peptide (BNP) levels are associated with heart failure and increased mortality in the general population. We investigated rs198389, a functional variant in the promoter region of the BNP gene (NPPB), in patients from the Atherosclerosis Risk in Communities Study to investigate associations with N-terminal pro-BNP (NT-proBNP) levels and outcomes. METHODS AND RESULTS: A total of 11 361 black and white patients with rs198389 genotyping attended visit 1 (aged 45-64 years; 1987-1989), with follow-up visits occurring every 3 years (visit 2-visit 4, 1990-1999), followed by visit 5 (2011-2013). NT proBNP levels were measured at visits 2, 4, and 5. At visit 2, the GG genotype (frequency 18%) was associated with a 41% higher mean plasma level of NT-proBNP compared with the AA genotype (frequency 34%), with intermediate values observed in AGs (P=4.2*10-52). The GG genotype was associated with reduced systolic blood pressure (-1.6 mm Hg, P=0.006), diastolic blood pressure (-1 mm Hg, P=0.003), antihypertension medication use (odds ratio, 0.85; 95% CI, 0.74-0.97 [P=0.02]), and hypertension (odds ratio, 0.81; 95% CI, 0.72-0.92 [P=0.002]) compared with the AA genotype with intermediate values in AGs. These relationships persisted throughout subsequent visits. After a median follow-up of 23 years, there were 4031 deaths. With and without covariate adjustment, the GG genotype was associated with modestly lower mortality (hazard ratio, 0.86; 95% CI, 0.78-0.95), primarily reflective of cardiovascular death (hazard ratio, 0.75; 95% CI, 0.61 0.92), and increased residual lifespan of 8 months from 50 years of age (P=0.02) versus AAs. CONCLUSIONS: The rs198389 G allele in the NPPB promoter is associated with elevated levels of NT-proBNP throughout adult life, reduced blood pressure, hypertension and cardiovascular mortality, and increased lifespan. PMID- 28341779 TI - CPAP Adherence: A Matter of Perfect Airflow Curves? PMID- 28341783 TI - Erratum. Psychosocial Care for People With Diabetes: A Position Statement of the American Diabetes Association. Diabetes Care 2016;39:2126-2140. PMID- 28341782 TI - Predictive Properties of Biomarkers GDF-15, NTproBNP, and hs-TnT for Morbidity and Mortality in Patients With Type 2 Diabetes With Nephropathy. AB - OBJECTIVE: Although patients with type 2 diabetes (T2D) with nephropathy are at high risk for renal and cardiovascular complications, relevant biomarkers have been poorly identified. Because renal impairment may increase biomarker levels, this potentially confounds associations between biomarker levels and risk. To investigate the predictive value of a biomarker in such a setting, we examined baseline levels of growth differentiation factor-15 (GDF-15), N-terminal prohormone of B-type natriuretic peptide (NTproBNP), and high-sensitivity troponin T (hs-TnT) in relation to renal and cardiovascular risk in T2D patients with nephropathy. RESEARCH DESIGN AND METHODS: Eight hundred sixty-one T2D patients from the sulodexide macroalbuminuria (Sun-MACRO) trial were included in our post hoc analysis. Prospective associations of baseline serum GDF-15, NTproBNP, and hs-TnT with renal and cardiovascular events were determined by Cox multiple regression and C-statistic analysis. Renal base models included albumin to-creatinine ratio (ACR), serum creatinine, hemoglobin, age, and sex. Cardiovascular base models included diastolic blood pressure, ACR, cholesterol, age, and sex. RESULTS: The mean (+/-SD) estimated glomerular filtration rate was 33 +/- 9 mL/min/1.73 m2, and the median serum concentration for GDF-15 was 3,228 pg/mL (interquartile range 2,345-4,310 pg/mL), for NTproBNP was 380 ng/L (155-989 ng/L), and for hs-TnT was 30 ng/L (20-47 ng/L). In multiple regression analysis, GDF-15 (hazard ratio [HR] 1.83, P = 0.04), NTproBNP (HR 2.34, P = 0.004), and hs TnT (HR 2.09, P = 0.014) were associated with renal events, whereas NTproBNP (HR 3.45, P < 0.001) was associated with cardiovascular events. The C-statistic was improved by adding NTproBNP and hs-TNT to the renal model (0.793 vs. 0.741, P = 0.04). For cardiovascular events, the C-statistic was improved by adding NTproBNP alone (0.722 vs. 0.658, P = 0.018). CONCLUSIONS: Biomarkers GDF-15, NTproBNP, and hs-TnT associate independently with renal risk, whereas NTproBNP independently predicts cardiovascular risk. PMID- 28341784 TI - Should US doctors mourn for Obamacare? PMID- 28341785 TI - Commentary. PMID- 28341781 TI - Genotype-Phenotype Correlation of SCN5A Mutation for the Clinical and Electrocardiographic Characteristics of Probands With Brugada Syndrome: A Japanese Multicenter Registry. AB - BACKGROUND: The genotype-phenotype correlation of SCN5A mutations as a predictor of cardiac events in Brugada syndrome remains controversial. We aimed to establish a registry limited to probands, with a long follow-up period, so that the genotype-phenotype correlation of SCN5A mutations in Brugada syndrome can be examined without patient selection bias. METHODS: This multicenter registry enrolled 415 probands (n=403; men, 97%; age, 46+/-14 years) diagnosed with Brugada syndrome whose SCN5A gene was analyzed for mutations. RESULTS: During a mean follow-up period of 72 months, the overall cardiac event rate was 2.5%/y. In comparison with probands without mutations (SCN5A (-), n=355), probands with SCN5A mutations (SCN5A (+), n=60) experienced their first cardiac event at a younger age (34 versus 42 years, P=0.013), had a higher positive rate of late potentials (89% versus 73%, P=0.016), exhibited longer P-wave, PQ, and QRS durations, and had a higher rate of cardiac events (P=0.017 by log-rank). Multivariate analysis indicated that only SCN5A mutation and history of aborted cardiac arrest were significant predictors of cardiac events (SCN5A (+) versus SCN5A (-): hazard ratio, 2.0 and P=0.045; history of aborted cardiac arrest versus no such history: hazard ratio, 6.5 and P<0.001). CONCLUSIONS: Brugada syndrome patients with SCN5A mutations exhibit more conduction abnormalities on ECG and have higher risk for cardiac events. PMID- 28341786 TI - Effectiveness of foot fasciotomies in foot and ankle trauma. AB - BACKGROUND: Foot compartment syndrome (FCS) has been reported to cause neuropathic pain, claw or hammer toes, and motor and sensory disturbances. The optimal treatment of FCS is controversial. The purpose of this study was to determine if foot fasciotomies improve patient outcomes in high-energy, combat related lower extremity trauma. METHODS: Medical records of patients with documented FCS from May 2007 to January 2009 were retrospectively reviewed. Consecutive, matched control patients were identified based on similar hindfoot, mid-foot and/or forefoot injuries who did not undergo foot fasciotomy during the same period. The primary outcomes analysed were the development of claw or hammer toes and neuropathic pain. RESULTS: 19 patients with foot fasctiotomies were identified and matched with 19 controls. Median follow-up was 19.5 months (range, 3.5-47.5 months) for the combined cohorts. The most common mechanism of injury was an explosive blast. Nine fasciotomy and nine control patients sustained open foot fractures. Significantly more patients with foot fasciotomies developed claw toes (50% vs 17%, p=0.03). There were no significant differences in the development of neuropathic pain, sensory deficits, motor deficits, chronic pain, stiffness or infection. The fasciotomy patients underwent an average of 5.5 surgeries per patient versus 4 surgeries per patient in the control group. CONCLUSIONS: Fasciotomy of the foot did not prevent neuropathic pain and deformities in patients with FCS in this study. PMID- 28341787 TI - Potential new treatment for non-freezing cold injury: is Iloprost the way forward? AB - INTRODUCTION: Non-freezing cold injury (NFCI) remains largely under-reported, and is of particular importance in the armed forces where its prevalence is greatest. Iloprost, a synthetic prostaglandin I2 analogue, has previously been used with some success in the treatment of vasospastic and freezing cold injuries, although its role in NFCI remains unclear. CASE REPORT: An Iloprost infusion was used to treat the long-term sequelae of an ex-soldier suffering with ongoing pedal pain and loss of function 20 years after the initial NFCI insult sustained on military exercise. Following 5 days of iloprost infusion, he reported 4 weeks of markedly reduced pain and increased mobility before symptom relapse. A second infusion was thus given 3 months later, which resulted in increased pain and analgesic requirements. DISCUSSION: The use of iloprost in the treatment of NFCI is discussed and its use in a condition which physicians consistently struggle to treat effectively is considered. Careful counselling is recommended as symptoms may be worsened. PMID- 28341788 TI - Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor. AB - Fibroblast growth factor (FGF) signaling plays critical roles in key biological processes ranging from embryogenesis to wound healing and has strong links to several hallmarks of cancer. Genetic alterations in FGF receptor (FGFR) family members are associated with increased tumor growth, metastasis, angiogenesis, and decreased survival. JNJ-42756493, erdafitinib, is an orally active small molecule with potent tyrosine kinase inhibitory activity against all four FGFR family members and selectivity versus other highly related kinases. JNJ-42756493 shows rapid uptake into the lysosomal compartment of cells in culture, which is associated with prolonged inhibition of FGFR signaling, possibly due to sustained release of the inhibitor. In xenografts from human tumor cell lines or patient derived tumor tissue with activating FGFR alterations, JNJ-42756493 administration results in potent and dose-dependent antitumor activity accompanied by pharmacodynamic modulation of phospho-FGFR and phospho-ERK in tumors. The results of the current study provide a strong rationale for the clinical investigation of JNJ-42756493 in patients with tumors harboring FGFR pathway alterations. Mol Cancer Ther; 16(6); 1010-20. (c)2017 AACR. PMID- 28341791 TI - Organ donation in the emergency department. PMID- 28341789 TI - MET Tyrosine Kinase Inhibition Enhances the Antitumor Efficacy of an HGF Antibody. AB - Receptor tyrosine kinase therapies have proven to be efficacious in specific cancer patient populations; however, a significant limitation of tyrosine kinase inhibitor (TKI) treatment is the emergence of resistance mechanisms leading to a transient, partial, or complete lack of response. Combination therapies using agents with synergistic activity have potential to improve response and reduce acquired resistance. Chemoreagent or TKI treatment can lead to increased expression of hepatocyte growth factor (HGF) and/or MET, and this effect correlates with increased metastasis and poor prognosis. Despite MET's role in resistance and cancer biology, MET TKI monotherapy has yielded disappointing clinical responses. In this study, we describe the biological activity of a selective, oral MET TKI with slow off-rate and its synergistic antitumor effects when combined with an anti-HGF antibody. We evaluated the combined action of simultaneously neutralizing HGF ligand and inhibiting MET kinase activity in two cancer xenograft models that exhibit autocrine HGF/MET activation. The combination therapy results in additive antitumor activity in KP4 pancreatic tumors and synergistic activity in U-87MG glioblastoma tumors. Pharmacodynamic characterization of biomarkers that correlate with combination synergy reveal that monotherapies induce an increase in the total MET protein, whereas combination therapy significantly reduces total MET protein levels and phosphorylation of 4E-BP1. These results hold promise that dual targeting of HGF and MET by combining extracellular ligand inhibitors with intracellular MET TKIs could be an effective intervention strategy for cancer patients who have acquired resistance that is dependent on total MET protein. Mol Cancer Ther; 16(7); 1269 78. (c)2017 AACR. PMID- 28341790 TI - Tumor-Associated Macrophages Can Contribute to Antitumor Activity through FcgammaR-Mediated Processing of Antibody-Drug Conjugates. AB - The primary mechanism of antibody-drug conjugates (ADC) is targeted delivery of a cytotoxic payload to tumor cells via cancer-associated membrane receptors. However, the tumor microenvironment likely plays a role in ADC penetration, distribution, and processing and thus impacts the overall antitumor activity. Here, we report on the potential contribution of Fc-FcgammaR interactions between ADCs and tumor-associated macrophages (TAM) to the preclinical antitumor activities of ADCs. In the CD30+ L-428 Hodgkin lymphoma model, anti-CD30-vcMMAE and a non-binding control (hIgG-vcMMAE) demonstrated similar antitumor activity as well as similar payload release in the tumors. IHC analysis revealed L-428 tumors contained highly abundant TAMs, which were confirmed to bind ADCs by IHC and flow cytometry. The infiltration of TAMs was further found to correlate with the antitumor activity of the non-binding hIgG-vcMMAE in five additional xenograft models. hIgG1V1-vcMMAE, bearing a mutation in the Fc region which ablates Fc gamma receptor (FcgammaR) binding, lost antitumor activity in three TAM-high xenograft models, suggesting Fc-FcgammaR interactions modulate the TAM ADC interaction. Our results suggest that TAMs can contribute to ADC processing through FcgammaR interaction in preclinical tumor models and may represent an important additional mechanism for drug release from ADCs. Correlative studies in clinical trials will further shed light on whether TAMs play a role in patients' response to ADC therapies. Mol Cancer Ther; 16(7); 1347-54. (c)2017 AACR. PMID- 28341792 TI - Severe chest pain in an elderly woman. PMID- 28341796 TI - Abstracts from international Emergency Medicine journals. AB - Editor's note: EMJ has partnered with the journals of multiple international emergency medicine societies to share from each a highlighted research study, as selected by their editors. This edition will feature an abstract from each publication. PMID- 28341793 TI - BET 1: IN PATIENTS WITH SUSPECTED ACUTE CORONARY SYNDROME, DOES WELLENS' SIGN ON THE ELECTROCARDIOGRAPH IDENTIFY CRITICAL LEFT ANTERIOR DESCENDING ARTERY STENOSIS? AB - Wellens' syndrome consists of a history suggestive of an acute coronary syndrome and biphasic or deeply inverted T waves in ECG leads V2-V3. A shortcut review was carried out to establish whether this ECG pattern identifies patients with a critical left anterior descending artery stenosis. Six relevant papers were found. The clinical bottom line is that biphasic T-wave inversion in lead V2-V3 should alert the clinician to a probable critical stenosis of the left anterior descending artery. PMID- 28341795 TI - BET 2: LASER THERAPY IN THE TREATMENT OF ACUTE HAMSTRING MUSCLE INJURIES. AB - Local laser therapy has been suggested as a promising treatment for acute hamstring muscle tears. We carried out a shortcut systematic review to establish whether therapeutic lasers are beneficial for patients with acute hamstring tears. Despite a comprehensive literature search, no studies that were directly relevant to the question could be identified. The clinical bottom line is therefore that there is currently no evidence for the use of any form of laser therapy in the treatment of acute hamstring muscle tears. PMID- 28341797 TI - Painful skin reaction. PMID- 28341798 TI - Daily use of high-potency cannabis is associated with an increased risk of admission and more intervention after first-episode psychosis. PMID- 28341799 TI - Use of Traumatic Brain Injury Prediction Rules With Clinical Decision Support. AB - OBJECTIVES: We determined whether implementing the Pediatric Emergency Care Applied Research Network (PECARN) traumatic brain injury (TBI) prediction rules and providing risks of clinically important TBIs (ciTBIs) with computerized clinical decision support (CDS) reduces computed tomography (CT) use for children with minor head trauma. METHODS: Nonrandomized trial with concurrent controls at 5 pediatric emergency departments (PEDs) and 8 general EDs (GEDs) between November 2011 and June 2014. Patients were <18 years old with minor blunt head trauma. Intervention sites received CDS with CT recommendations and risks of ciTBI, both for patients at very low risk of ciTBI (no Pediatric Emergency Care Applied Research Network rule factors) and those not at very low risk. The primary outcome was the rate of CT, analyzed by site, controlling for time trend. RESULTS: We analyzed 16 635 intervention and 2394 control patients. Adjusted for time trends, CT rates decreased significantly (P < .05) but modestly (2.3%-3.7%) at 2 of 4 intervention PEDs for children at very low risk. The other 2 PEDs had small (0.8%-1.5%) nonsignificant decreases. CT rates did not decrease consistently at the intervention GEDs, with low baseline CT rates (2.1%-4.0%) in those at very low risk. The control PED had little change in CT use in similar children (from 1.6% to 2.9%); the control GED showed a decrease in the CT rate (from 7.1% to 2.6%). For all children with minor head trauma, intervention sites had small decreases in CT rates (1.7%-6.2%). CONCLUSIONS: The implementation of TBI prediction rules and provision of risks of ciTBIs by using CDS was associated with modest, safe, but variable decreases in CT use. However, some secular trends were also noted. PMID- 28341800 TI - Variability in Very Preterm Stillbirth and In-Hospital Mortality Across Europe. AB - BACKGROUND AND OBJECTIVE: Stillbirth and in-hospital mortality rates associated with very preterm births (VPT) vary widely across Europe. International comparisons are complicated by a lack of standardized data collection and differences in definitions, registration, and reporting. This study aims to determine what proportion of the variation in stillbirth and in-hospital VPT mortality rates persists after adjusting for population demographics, case-mix, and timing of death. METHODS: Standardized data collection for a geographically defined prospective cohort of VPTs (22+0-31+6 weeks gestation) across 16 regions in Europe. Crude and adjusted stillbirth and in-hospital mortality rates for VPT infants were calculated by time of death by using multinomial logistic regression models. RESULTS: The stillbirth and in-hospital mortality rate for VPTs was 27.7% (range, 19.9%-35.9% by region). Adjusting for maternal and pregnancy characteristics had little impact on the variation. The addition of infant characteristics reduced the variation of mortality rates by approximately one fifth (4.8% to 3.9%). The SD for deaths <12 hours after birth was reduced by one quarter, but did not change after risk adjustment for deaths >=12 hours after birth. CONCLUSIONS: In terms of the regional variation in overall VPT mortality, over four-fifths of the variation could not be accounted for by maternal, pregnancy, and infant characteristics. Investigation of the timing of death showed that these characteristics only accounted for a small proportion of the variation in VPT deaths. These findings suggest that there may be an inequity in the quality of care provision and treatment of VPT infants across Europe. PMID- 28341801 TI - Photo Quiz: Is Gardening Dangerous? PMID- 28341802 TI - The Brief Case: Benign Rectal Polyp with Schistosoma mansoni. PMID- 28341803 TI - Closing the Brief Case: Benign Rectal Polyp with Schistosoma mansoni. PMID- 28341804 TI - Answer to April 2017 Photo Quiz. PMID- 28341805 TI - CORRECTION. PMID- 28341806 TI - Polar Localization of the NIP5;1 Boric Acid Channel Is Maintained by Endocytosis and Facilitates Boron Transport in Arabidopsis Roots. AB - Boron uptake in Arabidopsis thaliana is mediated by nodulin 26-like intrinsic protein 5;1 (NIP5;1), a boric acid channel that is located preferentially on the soil side of the plasma membrane in root cells. However, the mechanism underlying this polar localization is poorly understood. Here, we show that the polar localization of NIP5;1 in epidermal and endodermal root cells is mediated by the phosphorylation of Thr residues in the conserved TPG (ThrProGly) repeat in the N terminal region of NIP5;1. Although substitutions of Ala for three Thr residues in the TPG repeat did not affect lateral diffusion in the plasma membrane, these substitutions inhibited endocytosis and strongly compromised the polar localization of GFP-NIP5;1. Consistent with this, the polar localization was compromised in u subunit mutants of the clathrin adaptor AP2. The Thr-to-Ala substitutions did not affect the boron transport activity of GFP-NIP5;1 in Xenopus laevis oocytes but did inhibit the ability to complement boron translocation to shoots and rescue growth defects in nip5;1-1 mutant plants under boron-limited conditions. These results demonstrate that the polar localization of NIP5;1 is maintained by clathrin-mediated endocytosis, is dependent on phosphorylation in the TPG repeat, and is necessary for the efficient transport of boron in roots. PMID- 28341807 TI - The human cancer cell active toxin Cry41Aa from Bacillus thuringiensis acts like its insecticidal counterparts. AB - Understanding how certain protein toxins from the normally insecticidal bacterium Bacillus thuringiensis (Bt) target human cell lines has implications for both the risk assessment of products containing these toxins and potentially for cancer therapy. This understanding requires knowledge of whether the human cell active toxins work by the same mechanism as their insecticidal counterparts or by alternative ones. The Bt Cry41Aa (also known as Parasporin3) toxin is structurally related to the toxins synthesised by commercially produced transgenic insect-resistant plants, with the notable exception of an additional C terminal beta-trefoil ricin domain. To better understand its mechanism of action, we developed an efficient expression system for the toxin and created mutations in regions potentially involved in the toxic mechanism. Deletion of the ricin domain did not significantly affect the activity of the toxin against the human HepG2 cell line, suggesting that this region was not responsible for the mammalian specificity of Cry41Aa. Various biochemical assays suggested that unlike some other human cell active toxins from Bt Cry41Aa did not induce apoptosis, but that its mechanism of action was consistent with that of a pore forming toxin. The toxin induced a rapid and significant decrease in metabolic activity. Adenosine triphosphate depletion, cell swelling and membrane damage were also observed. An exposed loop region believed to be involved in receptor binding of insecticidal Cry toxins was shown to be important for the activity of Cry41Aa against HepG2 cells. PMID- 28341810 TI - Correction for Rhodes et al., Evaluation of Vancomycin Exposures Associated with Elevations in Novel Urinary Biomarkers of Acute Kidney Injury in Vancomycin Treated Rats. PMID- 28341811 TI - Erratum for Rutter et al., Nephrotoxicity during Vancomycin Therapy in Combination with Piperacillin-Tazobactam or Cefepime. PMID- 28341808 TI - Protein CoAlation: a redox-regulated protein modification by coenzyme A in mammalian cells. AB - Coenzyme A (CoA) is an obligatory cofactor in all branches of life. CoA and its derivatives are involved in major metabolic pathways, allosteric interactions and the regulation of gene expression. Abnormal biosynthesis and homeostasis of CoA and its derivatives have been associated with various human pathologies, including cancer, diabetes and neurodegeneration. Using an anti-CoA monoclonal antibody and mass spectrometry, we identified a wide range of cellular proteins which are modified by covalent attachment of CoA to cysteine thiols (CoAlation). We show that protein CoAlation is a reversible post-translational modification that is induced in mammalian cells and tissues by oxidising agents and metabolic stress. Many key cellular enzymes were found to be CoAlated in vitro and in vivo in ways that modified their activities. Our study reveals that protein CoAlation is a widespread post-translational modification which may play an important role in redox regulation under physiological and pathophysiological conditions. PMID- 28341809 TI - Structural basis of molecular recognition of helical histone H3 tail by PHD finger domains. AB - The plant homeodomain (PHD) fingers are among the largest family of epigenetic domains, first characterized as readers of methylated H3K4. Readout of histone post-translational modifications by PHDs has been the subject of intense investigation; however, less is known about the recognition of secondary structure features within the histone tail itself. We solved the crystal structure of the PHD finger of the bromodomain adjacent to zinc finger 2A [BAZ2A, also known as TIP5 (TTF-I/interacting protein 5)] in complex with unmodified N terminal histone H3 tail. The peptide is bound in a helical folded-back conformation after K4, induced by an acidic patch on the protein surface that prevents peptide binding in an extended conformation. Structural bioinformatics analyses identify a conserved Asp/Glu residue that we name 'acidic wall', found to be mutually exclusive with the conserved Trp for K4Me recognition. Neutralization or inversion of the charges at the acidic wall patch in BAZ2A, and homologous BAZ2B, weakened H3 binding. We identify simple mutations on H3 that strikingly enhance or reduce binding, as a result of their stabilization or destabilization of H3 helicity. Our work unravels the structural basis for binding of the helical H3 tail by PHD fingers and suggests that molecular recognition of secondary structure motifs within histone tails could represent an additional layer of regulation in epigenetic processes. PMID- 28341813 TI - Microbial competition and evolution in natural porous environments: Not that simple. PMID- 28341815 TI - TGF-beta1 Transduced Mesenchymal Stem Cells Have Profound Modulatory Effects on DCs and T Cells. AB - BACKGROUND: Mesenchymal stem cells (MSCs) and transforming growth factor-beta1 (TGF-beta1) molecules are well known for their immunomodulatory properties and their function in tissue regeneration and remodeling. OBJECTIVES: To evaluate the interaction of TGF-beta1 engineered MSCs with T cells and dendritic cells (DCs) and their modulatory effect on the immune response. METHODS: MSCs and DCs were generated from bone marrow of Balb/c mice and T cells were generated from mice lymph nodes. TGF-beta1 expressing lentiviruses were used for MSCs transduction, and then these engineered MSCs were co-cultured with T cells and DCs. T cells proliferation and cytokines release and also DCs maturation, TNF-alpha release, and stimulation of allogeneic T cells were evaluated. RESULTS: T cells proliferation and IFN-gamma release were suppressed by TGF-beta1/MSCs while IL-4 secretion was enhanced. Co-cultured DCs with TGF-beta1/MSCs showed reduced expression of CD40, CD86, and MHC II and also lower level of TNF-alpha secretion. Co-cultured DCs could also induce lower levels of allogeneic T cells proliferation and IFN-gamma release in comparison to control DCs. CONCLUSION: Engineered TGF-beta1/MSC cells showed collaborative immune suppressive functions between TGF-beta1 and MSCs to modulate T cells and DCs immune responses. We therefore suggest that TGF-beta1/MSC cells could provide a promising tool for treatment of clinical conditions such as organ transplantation, GVHD, and autoimmune disorders. PMID- 28341814 TI - The Effect of Monophosphoryl Lipid A on Maturation of DCs from Patients with Acute Myeloid Leukaemia. AB - BACKGROUND: Generation of monocyte-derived dendritic cells (MDDC) is induced in the presence of GM-CSF and IL-4, and a maturation stimulus is added to the monocyte culture to obtain mature Dendritic Cells (DCs) suitable for therapy. TNF alpha is the most common cytokine used for activating DCs and generating mature MDDC either alone or in combination with other cytokines. OBJECTIVE: To compare effects of traditional cytokine cocktail (TNF-alpha + IL-1beta) versus TLR4 agonist monophosphoryl lipid A on the viability, phenotype, cytokine profile and functionality of MDDC. METHODS: The study included 32 individuals; twenty Acute Myeloid Leukaemia (AML) cases in complete remission and 12 healthy volunteers. They were divided into 3 groups: Group 1: control group: 12 subjects to measure the baseline levels of all markers in the monocytic preparation. Group 2: cytokine cocktail (TNF-alpha) group, which included 10 AML subjects. Group 3: MPLA group which included 10 AML subjects. RESULTS: TNF-alpha group showed higher expression of CD83 than MPLA group indicating higher capacity to induce DC maturation but both were similar in CD86, CCR7 and IL-10 expression. Preparation of dendritic cells from AML cases in remission and loading them with tumor peptides was successful. CONCLUSION: MPLA effect in DC maturation is comparable with traditional DC maturation cocktail. PMID- 28341812 TI - Parkinson's disease-associated receptor GPR37 is an ER chaperone for LRP6. AB - Wnt/beta-catenin signaling plays a key role in embryonic development, stem cell biology, and neurogenesis. However, the mechanisms of Wnt signal transmission, notably how the receptors are regulated, remain incompletely understood. Here we describe that the Parkinson's disease-associated receptor GPR37 functions in the maturation of the N-terminal bulky beta-propellers of the Wnt co-receptor LRP6. GPR37 is required for Wnt/beta-catenin signaling and protects LRP6 from ER associated degradation via CHIP (carboxyl terminus of Hsc70-interacting protein) and the ATPase VCP GPR37 is highly expressed in neural progenitor cells (NPCs) where it is required for Wnt-dependent neurogenesis. We conclude that GPR37 is crucial for cellular protein quality control during Wnt signaling. PMID- 28341816 TI - Increased Expression of Toll-Like Receptors 2 and 4 in Renal Transplant Recipients that Develop Allograft Dysfunction: A Cohort Study. AB - BACKGROUND: The incidence of ischemic reperfusion injury (IRI) in early phase post-transplantation and activation of toll-like receptor (TLR-2) and TLR-4 remarkably impact the outcome of a renal allograft. OBJECTIVE: To investigate whether the expression of TLRs in peripheral blood mononuclear cells (PBMCs) can predict the clinical outcome of kidney allografts. METHODS: We obtained blood samples from 52 renal transplant patients before transplant, and 2, 90, and 180 days post-transplantation in order to analyze the surface expressions of TLR-2 and TLR-4 on peripheral blood monocytes. The expression patterns of TLR-2 and TLR 4 were compared between patients with graft dysfunction (GD) and those with well functioning graft (WFG). RESULTS: Significantly different mean dynamic changes in surface expression of TLR-2 according to percentage of TLR-2+ cells between (the GD and WFG) groups existed at most time-points before and after renal transplantation (p=0.007) with the exception of day 2 post-transplantation. We observed significantly higher mean fluorescence intensities of TLR-2 and TLR-4 on CD14+ cells in the GD group compared to the WFG group. This finding was particularly observed 180 days post-transplantation (p=0.001). Based on TLR-2 and TLR-4 protein expression for each step, multiple logistic regression and ROC curve analysis revealed that an increase in CD14+ TLR-2+ monocytes within the 90 days post-transplantaton was associated with increased risk of GD at 180 and 365 days post-transplantation [odds ratio (OR)=1.27, p=0.005)]. CONCLUSION: Sequential monitoring of TLR-2 and TLR-4 expression patterns in peripheral blood monocytes appear to be prognostic and predictive biomarkers for early and late kidney allograft outcomes. PMID- 28341817 TI - Impairment of Macrophage Presenting Ability and Viability by Echinococcus granulosus Antigens. AB - BACKGROUND: Despite advances toward an improved understanding of the evasive mechanisms leading to the establishment of cystic echinococcosis, the discovery of specific immunosuppressive mechanisms and related factors are of great interest in the development of an immunotherapeutic approach. OBJECTIVE: To elucidate immunosuppressive effects of bioactive factors contained in chromatographic fractions from hydatid cystic fluid (HCF) of Echinococcus granulosus. METHODS: Hydatid cystic fluid was fractionated by reverse phase chromatography. Non-specific Concanavalin A-driven proliferation of spleen cells was used to determine specific inhibitory fractions. Trypan blue exclusion test and flowcytometry analysis were performed to check whether highly inhibitory fractions of HCF have apoptotic effect on peritoneal macrophages. Western blot analysis was used to determine proteolytic effects of parasitic antigens on major histocompatibility complex (MHC) class II (I-a) contained in membrane proteins extract from macrophages. RESULTS: High concentrations of HCF and few of chromatographic fractions suppressed spleen cells proliferation. Fractions 7 and 35 were the highest inhibitory fractions. Specifically fraction 35 and to a lesser extent HCF induced apoptosis in peritoneal naive macrophages. However, HCF and the fraction 7 proteolytically altered the expression of MHC class II molecules on peritoneal macrophages. The proteolytic molecule was identified to be a serine protease. Macrophages taken at the chronic and end phase from cystic echinococcosis-infected mice were able to uptake and process C-Ovalbumine-FITC. These cells expressed a drastically reduced level of (I-a) molecules. CONCLUSION: Our study present new aspects of immune suppression function of E. granulosus. Further molecular characterization of apoptotic and proteolytic factors might be useful to develop immunotherapeutic procedure to break down their inhibitory effects. PMID- 28341818 TI - Clinical Relevance of Cytokines Gene Polymorphisms and Protein Levels in Gingival Cervical Fluid from Chronic Periodontitis Patients. AB - BACKGROUND: Cytokines are suggested to play a role in periodontitis. OBJECTIVES: To determine and compare the levels of Interleukin-1 beta (IL-1beta) and Tumor necrosis factor alpha (TNF-alpha) in gingival crevicular fluid (GCF) samples amongst healthy individuals and those with chronic periodontitis. Further to compare the GCF cytokine levels in three genotype classes defined by the respective gene polymorphisms. METHODS: The study was conducted on 41 chronic periodontitis patients and 40 healthy volunteers. IL-1beta and TNF-alpha were quantified in GCF by cytometric bead array. DNA was extracted from peripheral blood samples and genotyping of IL1B +3954C/T (rs1143634) IL1B -511G/A (rs16944), TNFA -1031T/C (rs1799964) and TNFA -863C/A (rs1800630) polymorphisms were performed using Sanger sequencing and Taqman SNP genotyping assays methods. RESULTS: Both IL-1beta and TNF-alpha levels were significantly higher in chronic periodontitis group compared to the controls. IL-1beta and TNF-alpha levels did not significantly differ in genotype classes of the respective polymorphism (IL1B -511G/A, TNFA -1031T/C and TNFA -863C/A). However, individuals with CT genotype of IL1B +3954C/T showed higher levels of IL-1beta in the gingival crevicular fluid (ANOVA p<0.05). CONCLUSION: The results of this study revealed the presence of higher levels of IL-1beta and TNF-alpha in subjects with periodontitis and genetic control of IL-1beta levels in our samples of Indians. PMID- 28341819 TI - Interleukin-23 Receptor Gene Variants in Acute Lymphoblastic Leukemia and Their Relation to Prognostic Factors. AB - BACKGROUND: Interleukin (IL)-23 has an important role in tumor immune regulation. OBJECTIVE: To investigate the possible association of interleukin-23 receptor (IL23R) gene variants rs1884444, rs10889677 and rs11209026 with development of acute lymphoblastic leukemia (ALL). METHODS: The IL23R variants were studied in 164 ALL patients and compared to 175 healthy controls by polymerase chain reaction-restriction fragment length polymorphism. The relationship between these variants and clinical and laboratory features of the patients and response to therapy were evaluated. RESULTS: No significant differences in genotype and allele frequencies existed between patients and controls. The rs1884444TG genotype was significantly lower in patients who relapsed (24.2%) compared to those without relapse (55.9%, p=0.006). Fewer patients who relapsed had evidence of the G allele (p=0.034). The TG genotype was associated with a longer complete remission at 1804+/-116 days compared to other genotypes (<1217 days, p=0.028), however, this result was not significant in multivariate analysis. The rs10889677 AA genotype and A allele were associated with age (p<0.041) and platelet number (p=0.03) in precursor-B cell ALL (B-ALL) patients. Both occurred more frequently in patients aged 2-10 years (63.6% and 66%, respectively) and in those with platelets >100*10^3 MUL (68.4% and 52.4%, respectively). CONCLUSION: Our findings showed a lack of association of the studied polymorphisms with the risk of ALL. The influence of the rs1884444 polymorphism on relapse rate and association of rs10889677 AA genotype with favorable prognostic factors suggest the effect of the studied polymorphisms on ALL response to therapy and prognosis. PMID- 28341820 TI - IL-23 Gene and Protein Expression in Childhood Asthma. AB - BACKGROUND: Asthma is the chronic inflammation of airways characterized by eosinophilic infiltration, mucus overproduction, airway hyper-responsiveness and airway remodeling. These changes are induced mostly by cytokines which are produced by T helper (Th) 2 cells. Recently, the role of interleukin-23 (IL-23) in the pathogenesis of adult allergic asthma has been studied. OBJECTIVE: To explore IL-23 serum levels and its expression in persistent asthma compared with healthy children younger than five years old. METHOD: Blood samples of 40 children with mild and severe persistent asthma were compared to 34 healthy children regarding IL-23 serum levels and gene expression using enzyme-linked immunosorbentassay (ELISA) and real time quantitative polymerase chain reaction (PCR). RESULTS: The IL-23 gene expression level was significantly different in the 25 children with mild persistent asthma and the 15 children with severe persistent asthma compared to the control group (p=0.001). There was no significant difference in IL-23 gene expression level between the two groups of patients with mild and severe persistent asthma. A significant difference was seen in IL-23 serum levels between the 25 children with persistent asthma and control group (p=0.002). CONCLUSION: For pre-school children with history and physical exam in favor of asthma which cannot be tested by spirometry, IL-23 serum levels may be an auxiliary biomarker for the diagnosis of asthma. PMID- 28341821 TI - Salicylate Food Intolerance and Aspirin Hypersensitivity in Nasal Polyposis. AB - BACKGROUND: A clear association between allergy and nasal polyposis (NP) is not determined and the role of food intolerance in patients with NP is not investigated by oral food challenge (OFC). OBJECTIVE: To investigate the relation of salicylate food intolerance and atopy in patients with NP according to recurrence and aspirin sensitivity. METHODS: A cross sectional multicenter study was done in two tertiary centers for allergy in Iran. Adult patients with NP were selected for the study that had been referred to allergy clinics. The oral aspirin challenge (OAC) test was performed to identify aspirin exacerbated respiratory disease (AERD) and the OFC test was used to investigate food intolerance. Atopic evaluation was performed by skin-prick tests, nasal smear and blood eosinophil count as well as serum total IgE. RESULTS: One hundred and nineteen Iranian patients (female to male ratio 1.05) with NP were enrolled (mean age, 38 +/- 11 years). Recurrence of nasal polyposis was 64.7%. OAC was performed in all cases; 43.79% cases had aspirin hypersensitivity. In addition, OFC tests determined that 69.9% of patients had salicylate food allergy. Salicylate food intolerance was significantly higher in NP cases with AERD than in aspirin tolerant patients (p<0.05). Yet, positive skin prick test was not associated with NP recurrence and AERD. CONCLUSION: Atopy and NSAID exacerbated respiratory disease; therefore, they can both be considered as predictors of NP recurrence. Our study also showed that salicylate food intolerance was associated with AERD in nasal polyposis. PMID- 28341822 TI - Berberine Restricts Coxsackievirus B Type 3 Replication via Inhibition of c-Jun N Terminal Kinase (JNK) and p38 MAPK Activation In Vitro. AB - BACKGROUND At present, the treatment of coxsackievirus-induced myocarditis remains difficult. Berberine (BBR), an isoquinoline alkaloid isolated from traditional medicine herbs, exhibits significant anti-viral efficacy against various viruses. However, the underlying mechanism by which BBR controls CVB3 infection has not yet been reported. The purpose of this study was to investigate the anti-viral efficacy of BBR against CVB3 infection and its mechanism. MATERIAL AND METHODS In our experiments, the protein levels of VP1 and MAPKs signal pathway were measured by Western blot. The mRNA level of VP1 was measured by RT PCR. The virus titers were determined by TCID50 assay. RESULTS We found that BBR treatment significantly decreased CVB3 replication in HeLa cells. In addition, the BBR treatment reduced the phosphorylation levels of JNK and p38 MAPK upon CVB3 infection in both HeLa cells and primary rat myocardial cells. CONCLUSIONS Taken together, these results suggest that BBR inhibits CVB3 replication through the suppression of JNK and p38 MAPK activation, shedding new light on the investigation of therapeutic strategies against CVB3-induced viral myocarditis. PMID- 28341823 TI - A Case with Serrated Polyposis Syndrome Controlled by Multiple Applications of Endoscopic Mucosal Resection and Endoscopic Submucosal Dissection. AB - BACKGROUND Serrated polyposis syndrome (SPS) is characterized by numerous hyperplastic polyps and sessile serrated adenoma/polyp (SSA/P) in the large intestine. SSA/P is known to transform into malignant lesions through the serrated pathway instead of the adenoma-carcinoma sequence. Early diagnosis with lower gastrointestinal endoscopy and early treatment are now considered to be essential. CASE REPORT We had an experience with a case of SPS to which endoscopic treatment was applied in multiple sessions. Endoscopic treatment was performed for 16 lesions in total, and the pathological findings were SSA/P for 15 and adenoma for the other lesion. We intend to continue performing endoscopic surveillance for any newly developing lesions. CONCLUSIONS SPS has a potential for malignant transformation, and issues, such as long-term prognosis and optimal therapeutic strategies, await resolution. However, multiple endoscopic treatments are useful for cases with lesions that are controllable employing this modality. PMID- 28341824 TI - Posterior cingulate cross-hemispheric functional connectivity predicts the level of consciousness in traumatic brain injury. AB - Previous studies have demonstrated that altered states of consciousness are related to changes in resting state activity in the default-mode network (DMN). Anatomically, the DMN can be divided into anterior and posterior regions. The anterior DMN includes the perigenual anterior cingulate cortex and other medial prefrontal cortical regions, whereas the posterior DMN includes regions such as the posterior cingulate cortex (PCC) and the temporal parietal junction (TPJ). Although differential roles have been attributed to the anterior and posterior DMN regions, their exact contributions to consciousness levels remain unclear. To investigate the specific role of the posterior DMN in consciousness levels, we investigated 20 healthy controls (7 females, mean age = 33.6 years old) and 20 traumatic brain injury (TBI) patients (5 females, mean age = 43 years old) whose brain lesions were mainly restricted to the bilateral frontal cortex but retained a well-preserved posterior DMN (e.g., the PCC and the TPJ) and who exhibited varying levels of consciousness. We investigated the intra- and cross-functional connectivity strengths (FCSs) between the right/left PCC and the right/left TPJ and their correlation with consciousness levels. Significant reductions in both the intra- and cross-hemispheric FCSs were observed in patients compared with controls. A significant correlation with consciousness levels was observed only for the cross-hemispheric PCC-TPJ FCS but not for the intra-hemispheric PCC-TPJ FCS. Taken together, our results show that the cross-hemispheric posterior DMN is related to consciousness levels in a specific group of patients without posterior structural lesions. We therefore propose that the PCC may be central in maintaining consciousness through its cross-hemispheric FC with the TPJ. PMID- 28341825 TI - Transcriptomic profile of tobacco in response to Phytophthora nicotianae infection. AB - Black shank, caused by Phytophthora nicotianae (P. nicotianae), is a serious disease of cultivated tobacco (Nicotiana tabacum) worldwide. The interactions between tobacco and P. nicotianae are complex and the outcomes of the interactions depend on the tobacco genotype, P. nicotianae strain, and environmental conditions. In this study, we used RNA-sequencing (RNA-Seq) to investigate and compare transcriptional changes in the stems of tobacco upon inoculation with P. nicotianae strain race 0. We used two tobacco varieties: RBST (named from resistance to black shank and tobacco mosaic virus), which was resistant to the P. nicotianae strain race 0, and Honghuadajinyuan (HD), which was susceptible to P. nicotianae race 0. Samples were collected 12 and 72-hour post inoculation (hpi). Analysis of differentially expressed genes (DEGs) and significantly enriched GO terms indicated that several basic defense mechanisms were suppressed in both varieties, which included response to wounding (GO: 0009611), and defense response to fungus (GO: 0050832). We also found some genes that may especially be related to mechanisms of resistance in RBST, such as the one encoding a chitinase. These results will provide a valuable resource for understanding the interactions between P. nicotianae and tobacco plants. PMID- 28341826 TI - Poly(ethylmethacrylate-co-diethylaminoethyl acrylate) coating improves endothelial re-population, bio-mechanical and anti-thrombogenic properties of decellularized carotid arteries for blood vessel replacement. AB - Decellularized vascular scaffolds are promising materials for vessel replacements. However, despite the natural origin of decellularized vessels, issues such as biomechanical incompatibility, immunogenicity risks and the hazards of thrombus formation, still need to be addressed. In this study, we coated decellularized vessels obtained from porcine carotid arteries with poly (ethylmethacrylate-co-diethylaminoethylacrylate) (8g7) with the purpose of improving endothelial coverage and minimizing platelet attachment while enhancing the mechanical properties of the decellularized vascular scaffolds. The polymer facilitated binding of endothelial cells (ECs) with high affinity and also induced endothelial cell capillary tube formation. In addition, platelets showed reduced adhesion on the polymer under flow conditions. Moreover, the coating of the decellularized arteries improved biomechanical properties by increasing its tensile strength and load. In addition, after 5 days in culture, ECs seeded on the luminal surface of 8g7-coated decellularized arteries showed good regeneration of the endothelium. Overall, this study shows that polymer coating of decellularized vessels provides a new strategy to improve re endothelialization of vascular grafts, maintaining or enhancing mechanical properties while reducing the risk of thrombogenesis. These results could have potential applications in improving tissue-engineered vascular grafts for cardiovascular therapies with small caliber vessels. PMID- 28341828 TI - Variants in the host genome may inhibit tumour growth in devil facial tumours: evidence from genome-wide association. AB - Devil facial tumour disease (DFTD) has decimated wild populations of Tasmanian devils (Sarcophilus harrisii) due to its ability to avoid immune detection and pass from host to host by biting. A small number of devils have been observed to spontaneously recover from the disease which is otherwise fatal. We have sequenced the genomes of these rare cases and compared them to the genomes of devils who succumbed to the disease. Genome-wide association, based on this limited sampling, highlighted two key genomic regions potentially associated with ability to survive DFTD. Following targeted genotyping in additional samples, both of these loci remain significantly different between cases and controls, with the PAX3 locus retaining significance at the 0.001 level, though genome-wide significance was not achieved. We propose that PAX3 may be involved in a regulatory pathway that influences the slowing of tumour growth and may allow more time for an immune response to be mounted in animals with regressed tumours. This provides an intriguing hypothesis for further research and could provide a novel route of treatment for this devastating disease. PMID- 28341827 TI - Neural basis of negativity bias in the perception of ambiguous facial expression. AB - Negativity bias, which describes the tendency to interpret ambiguous stimuli or events as negative, is often observed in patients with depression and may prevent psychological well-being. Here, we used ambiguous facial stimuli, with negative (sad) and positive (happy) emotions simultaneously accessible, to examine neural activation during perceptual decision-making in healthy participants. The negativity bias was positively correlated with the activity of the bilateral pregenual anterior cingulate cortex (pgACC) when ambiguous faces were perceived as sad versus happy. Additionally, the strength of the functional connectivity between the bilateral pgACC and the right dorsal ACC (dACC)/right thalamus was positively correlated with hopelessness, one of the core characteristics of depression. Given the role of the pgACC as a major site of depressive affect and the roles of the dACC and thalamus in conflict monitoring and vigilance, respectively, our results reveal valid and important neuroanatomical correlates of the association between negativity bias and hopelessness in the healthy individuals. PMID- 28341829 TI - USP9X deubiquitylating enzyme maintains RAPTOR protein levels, mTORC1 signalling and proliferation in neural progenitors. AB - USP9X, is highly expressed in neural progenitors and, essential for neural development in mice. In humans, mutations in USP9X are associated with neurodevelopmental disorders. To understand USP9X's role in neural progenitors, we studied the effects of altering its expression in both the human neural progenitor cell line, ReNcell VM, as well as neural stem and progenitor cells derived from Nestin-cre conditionally deleted Usp9x mice. Decreasing USP9X resulted in ReNcell VM cells arresting in G0 cell cycle phase, with a concomitant decrease in mTORC1 signalling, a major regulator of G0/G1 cell cycle progression. Decreased mTORC1 signalling was also observed in Usp9x-null neurospheres and embryonic mouse brains. Further analyses revealed, (i) the canonical mTORC1 protein, RAPTOR, physically associates with Usp9x in embryonic brains, (ii) RAPTOR protein level is directly proportional to USP9X, in both loss- and gain-of function experiments in cultured cells and, (iii) USP9X deubiquitlyating activity opposes the proteasomal degradation of RAPTOR. EdU incorporation assays confirmed Usp9x maintains the proliferation of neural progenitors similar to Raptor-null and rapamycin-treated neurospheres. Interestingly, loss of Usp9x increased the number of sphere-forming cells consistent with enhanced neural stem cell self renewal. To our knowledge, USP9X is the first deubiquitylating enzyme shown to stabilize RAPTOR. PMID- 28341830 TI - X-ray Dark-field Radiography - In-Vivo Diagnosis of Lung Cancer in Mice. AB - Accounting for about 1.5 million deaths annually, lung cancer is the prevailing cause of cancer deaths worldwide, mostly associated with long-term smoking effects. Numerous small-animal studies are performed currently in order to better understand the pathogenesis of the disease and to develop treatment strategies. Within this letter, we propose to exploit X-ray dark-field imaging as a novel diagnostic tool for the detection of lung cancer on projection radiographs. Here, we demonstrate in living mice bearing lung tumors, that X-ray dark-field radiography provides significantly improved lung tumor detection rates without increasing the number of false-positives, especially in the case of small and superimposed nodules, when compared to conventional absorption-based imaging. While this method still needs to be adapted to larger mammals and finally humans, the technique presented here can already serve as a valuable tool in evaluating novel lung cancer therapies, tested in mice and other small animal models. PMID- 28341833 TI - Large-Scale Crustal-Block-Extrusion During Late Alpine Collision. AB - The crustal-scale geometry of the European Alps has been explained by a classical subduction-scenario comprising thrust-and-fold-related compressional wedge tectonics and isostatic rebound. However, massive blocks of crystalline basement (External Crystalline Massifs) vertically disrupt the upper-crustal wedge. In the case of the Aar massif, top basement vertically rises for >12 km and peak metamorphic temperatures increase along an orogen-perpendicular direction from 250 degrees C-450 degrees C over horizontal distances of only <15 km (Innertkirchen-Grimselpass), suggesting exhumation of midcrustal rocks with increasing uplift component along steep vertical shear zones. Here we demonstrate that delamination of European lower crust during lithosphere mantle rollback migrates northward in time. Simultaneously, the Aar massif as giant upper crustal block extrudes by buoyancy forces, while substantial volumes of lower crust accumulate underneath. Buoyancy-driven deformation generates dense networks of steep reverse faults as major structures interconnected by secondary branches with normal fault component, dissecting the entire crust up to the surface. Owing to rollback fading, the component of vertical motion reduces and is replaced by a late stage of orogenic compression as manifest by north-directed thrusting. Buoyancy-driven vertical tectonics and modest late shortening, combined with surface erosion, result in typical topographic and metamorphic gradients, which might represent general indicators for final stages of continent-continent collisions. PMID- 28341831 TI - The relationship between retinal nerve fibre layer thickness profiles and CorvisST tonometry measured biomechanical properties in young healthy subjects. AB - We previously reported that a shallow circumpapillary retinal nerve fiber layer (cpRNFL) peak angle as measured by optical coherence tomography (OCT) suggests the temporal retina is stretched around the optic disc from the papillo-macular bundle (Yamashita T et al. Investigative Ophthalmol Vis Sci 2013). The purpose of the current study was to investigate the relationship between CorvisST tonometry (CST) corneal measurements, axial length (AL) and the change in OCT-measured cpRNFL peak angle, in young healthy subjects. OCT and CST measurements were carried out in 97 eyes of 97 young healthy volunteers. The relationship between cpRNFL peak angle and 12 CST parameters, adjusted for AL, was investigated using linear modelling. The mean +/- standard deviation cpRNFL peak angle of the 97 healthy volunteers was 130.6 +/- 25.4 (range: 77.8 to 207.0) degrees. The optimal linear model to explain cpRNFL peak angle (chosen from 216 different models) included three CST variables related to the speed and size of energy absorption (namely, A1 time, A1 length and A2 time), in addition to AL. In eyes with longer AL and shorter energy absorption in CST measurement, temporal retina is stretched around the optic disc from the papillo-macular bundle, as suggested by a shallow cpRNFL peak angle. PMID- 28341832 TI - MiR-2425-5p targets RAD9A and MYOG to regulate the proliferation and differentiation of bovine skeletal muscle-derived satellite cells. AB - Our group previously identified miR-2425-5p, a unique bovine miRNA; however, its biological function and regulation in muscle-derived satellite cells (MDSCs) remain unclear. Herein, stem-loop RT-PCR results showed that miR-2425-5p increased during MDSCs proliferation, but decreased during differentiation. Cell proliferation was examined using EdU assays, cyclin B1 (CCNB1) and proliferating cell nuclear antigen (PCNA) western blot (WB) and flow cytometry analysis. These results showed that miR-2425-5p mimics (miR-2425-M) enhanced MDSCs proliferation, whereas, miR-2425-5p inhibitor (miR-2425-I) had opposite effect. Conversely, cell differentiation studies by desmin (DES) immunofluorescence, myotubes formation, and myosin heavy chain 3 (MYH3) WB analyses revealed that miR-2425-M and miR-2425 I blocked and promoted MDSCs differentiation, respectively. Moreover, luciferase reporter, RT-PCR, and WB assays showed that miR-2425-5p directly targeted the 3' UTR of RAD9 homolog A (RAD9A) and myogenin (MYOG) to regulate their expression. Rescue experiment showed RAD9A inhibited the proliferation of MDSCs through miR 2425-5p. In addition, we found that miR-2425-5p expression was regulated by its host gene NCK associated protein 5-like (NCKAP5L) rather than being transcribed independently as a separate small RNA. Collectively, these data indicate that miR 2425-5p is a novel regulator of bovine MDSCs proliferation and differentiation and provides further insight into the biological functions of miRNA in this species. PMID- 28341834 TI - Grating chips for quantum technologies. AB - We have laser cooled 3 * 106 87Rb atoms to 3 MUK in a micro-fabricated grating magneto-optical trap (GMOT), enabling future mass-deployment in highly accurate compact quantum sensors. We magnetically trap the atoms, and use Larmor spin precession for magnetic sensing in the vicinity of the atomic sample. Finally, we demonstrate an array of magneto-optical traps with a single laser beam, which will be utilised for future cold atom gradiometry. PMID- 28341835 TI - Investigation and manipulation of metabolically active methanogen community composition during rumen development in black goats. AB - This study was performed to investigate the initial colonization of metabolically active methanogens and subsequent changes in four fractions: the rumen solid phase (RS), liquid-phase (RL), protozoa-associated (RP), and epithelium associated (RE) from 1 to 60 d after birth, and manipulate methanogen community by early weaning on 40 d and supplementing rhubarb from 40 to 60 d in black goats. The RNA-based real-time quantitative PCR and 16S rRNA amplicon sequencing were employed to indicate the metabolically active methanogens. Results showed that active methanogens colonized in RL and RE on 1 d after birth. RP and RE contained the highest and lowest density of methanogens, respectively. Methanobrevibacter, Candidatus Methanomethylophilus, and Methanosphaera were the top three genera. The methanogen communities before weaning differed from those post weaning and the structure of the methanogen community in RE was distinct from those in the other three fractions. The discrepancies in the distribution of methanogens across four fractions, and various fluctuations in abundances among four fractions according to age were observed. The addition of rhubarb significantly (P < 0.05) reduced the abundances of Methanimicrococcus spp. in four fractions on 50 d, but did not change the methanogen community composition on 60 d. PMID- 28341836 TI - FAM46C is critical for the anti-proliferation and pro-apoptotic effects of norcantharidin in hepatocellular carcinoma cells. AB - Norcantharidin (NCTD), a demethylated analog of cantharidin derived from Chinese traditional medicine blister beetle, has been currently used as an anticancer drug for various cancers including hepatocellular carcinoma (HCC). In this study, for a more comprehensive understanding of the targets of NCTD in HCC, next generation RNA-Seq was utilized. We revealed that the expression of FAM46C, which has been reported as a tumor suppressor for multiple myeloma, was enhanced after NCTD treatment. Re-analysis of TCGA (The Cancer Genome Atlas) LIHC (liver hepatocellular carcinoma) dataset demonstrated that FAM46C expression was significantly lower in HCC tissues than in normal liver tissues. NCTD injection or FAM46C overexpression could mitigate diethylnitrosamine (DEN)-initiated HCC in mice. Ectopic expression of FAM46C in two HCC cell lines, SMCC-7721 and SK-Hep-1, significantly repressed cell proliferation, and increased cells population in G2/M phase and cell apoptotic rate. We also found that FAM46C overexpression caused a notable decrease in Ras expression, MEK1/2 phosphorylation and ERK1/2 phosphorylation. More importantly, FAM46C knockdown significantly weakened the biological effects of NCTD on HCC cells, which suggested NCTD exerted the anticancer functions partially through up-regulating FAM46C. In conclusion, FAM46C, a tumor suppressor for HCC, is important for the anti-proliferation and proapoptotic effects of NCTD. PMID- 28341837 TI - Enhancement of CCL2 expression and monocyte migration by CCN1 in osteoblasts through inhibiting miR-518a-5p: implication of rheumatoid arthritis therapy. AB - Cysteine-rich 61 (Cyr61 or CCN1), a secreted protein from the CCN family, is an important proinflammatory cytokine. Migration and infiltration of mononuclear cells to inflammatory sites play a critical role in the pathogenesis of rheumatoid arthritis (RA). Monocyte chemoattractant protein-1 (MCP-1/CCL2) is the key chemokine that regulates migration and infiltration of monocytes. Here, we examined the role of CCN1 in monocyte migration, and CCL2 expression in osteoblasts. We found higher levels of CCN1 and CCL2 in synovial fluid from RA patients compared with levels from non-RA controls. We also found that the CCN1 induced increase in CCL2 expression is mediated by the MAPK signaling pathway and that miR-518a-5p expression was negatively regulated by CCN1 via the MAPK cascade. In contrast, inhibition of CCN1 expression with lentiviral vectors expressing short hairpin RNA ameliorated articular swelling, cartilage erosion, and infiltration of monocytes in the ankle joints of mice with collagen-induced arthritis. Our study describes how CCN1 promotes monocyte migration by upregulating CCL2 expression in osteoblasts in RA disease. CCN1 could serve as a potential target for RA treatment. PMID- 28341838 TI - Occlusion and Disocclusion Time Changes in Single Unit Crowns Designed by Functional Generated Path Technique: A Randomised Clinical Trial. AB - Although it is believed that implementation of the functional generated path (FGP) technique can facilitate occlusal surface design for restorations, it has not been objectively compared in situ with the conventional fabrication yet. Therefore, in the present study, a single-blind crossover clinical trial was conducted using T-scan to compare changes in occlusion time (OT) and disocclusion time (DT) of single posterior artificial crowns designed differently using FGP technique (FGP), average-value FGP technique (AVR) and conventional fabrication (CON). Each of the 10 participants took part in the study tried three artificial crowns in different sequences according to a computer generated randomization list. The results objectively revealed that changes in OT and DT were significantly smaller for FGP than CON (P < 0.05) and considerably smaller for AVR than CON, respectively. The subjective feedback and the occlusal adjusting time were better and shorter for FGP and AVR than CON (P < 0.05). No harm to the participants occurred. Overall, FGP is an efficient technique showing more physiological harmonious relationship with the articulating system. PMID- 28341839 TI - Therapeutic efficacy of neural stem cells originating from umbilical cord-derived mesenchymal stem cells in diabetic retinopathy. AB - The aim of this study was to evaluate the effects of intravitreal injection of neural stem cells (NSCs) originating from human umbilical cord-derived mesenchymal stem cells (UC-MSCs) on neurodegeneration of diabetic retinopathy (DR) in rats. UC-MSCs were isolated and passaged, followed by induction to NSCs in neural differentiation medium. Four weeks following NSC transplantation, treatment attenuated retinal vascular dysfunction compared with non-treated rats, and BDNF and Thy-1 expression was significantly higher in the treated group than in the control group. Treatment of diabetic rats with NSCs prevented the decrease in BDNF levels caused by diabetes. The average leakage of Evans Blue (EB) dye in the treated group was significantly less than that in the control group. These morphological improvements were accompanied by a restoration of vision, as documented by F-ERG. NSCs originating from MSCs demonstrated a neuroprotective effect by increasing the number of surviving RGCs and significantly reducing the progression of DR. Thus, transplantation of NSCs could be a novel strategy for the treatment of neurodegeneration in DR. PMID- 28341840 TI - Comparison of Two Massively Parallel Sequencing Platforms using 83 Single Nucleotide Polymorphisms for Human Identification. AB - The potential of Massively Parallel Sequencing (MPS) technology to vastly expand the capabilities of human identification led to the emergence of different MPS platforms that use forensically relevant genetic markers. Two of the MPS platforms that are currently available are the MiSeq(r) FGxTM Forensic Genomics System (Illumina) and the HID-Ion Personal Genome Machine (PGM)TM (Thermo Fisher Scientific). These are coupled with the ForenSeqTM DNA Signature Prep kit (Illumina) and the HID-Ion AmpliSeqTM Identity Panel (Thermo Fisher Scientific), respectively. In this study, we compared the genotyping performance of the two MPS systems based on 83 SNP markers that are present in both MPS marker panels. Results show that MiSeq(r) FGxTM has greater sample-to-sample variation than the HID-Ion PGMTM in terms of read counts for all the 83 SNP markers. Allele coverage ratio (ACR) values show generally balanced heterozygous reads for both platforms. Two and four SNP markers from the MiSeq(r) FGxTM and HID-Ion PGMTM, respectively, have average ACR values lower than the recommended value of 0.67. Comparison of genotype calls showed 99.7% concordance between the two platforms. PMID- 28341841 TI - Regulation of membrane ruffling by polarized STIM1 and ORAI1 in cortactin-rich domains. AB - Cell motility and migration requires the reorganization of the cortical cytoskeleton at the leading edge of cells and extracellular Ca2+ entry is essential for this reorganization. However the molecular nature of the regulators of this pathway is unknown. This work contributes to understanding the role of STIM1 and ORAI1 in the promotion of membrane ruffling by showing that phospho STIM1 localizes at the leading edge of cells, and that both phospho-STIM1 and ORAI1 co-localize with cortactin (CTTN), a regulator of the cytoskeleton at membrane ruffling areas. STIM1-KO and ORAI1-KO cell lines were generated by CRISPR/Cas9 genome editing in U2OS cells. In both cases, KO cells presented a notable reduction of store-operated Ca2+ entry (SOCE) that was rescued by expression of STIM1-mCherry and ORAI1-mCherry. These results demonstrated that SOCE regulates membrane ruffling at the leading edge of cells. Moreover, endogenous ORAI1 and overexpressed ORAI1-GFP co-immunoprecipitated with endogenous CTTN. This latter result, in addition to the KO cells' phenotype, the preservation of ORAI1-CTTN co-localization during ruffling, and the inhibition of membrane ruffling by the Ca2+-channel inhibitor SKF96365, further supports a functional link between SOCE and membrane ruffling. PMID- 28341842 TI - A scoring system to predict breast cancer mortality at 5 and 10 years. AB - : Although predictive models exist for mortality in breast cancer (BC) (generally all cause-mortality), they are not applicable to all patients and their statistical methodology is not the most powerful to develop a predictive model. Consequently, we developed a predictive model specific for BC mortality at 5 and 10 years resolving the above issues. This cohort study included 287 patients diagnosed with BC in a Spanish region in 2003-2016. MAIN OUTCOME VARIABLE: time to-BC death. Secondary variables: age, personal history of breast surgery, personal history of any cancer/BC, premenopause, postmenopause, grade, estrogen receptor, progesterone receptor, c-erbB2, TNM stage, multicentricity/multifocality, diagnosis and treatment. A points system was constructed to predict BC mortality at 5 and 10 years. The model was internally validated by bootstrapping. The points system was integrated into a mobile application for Android. Mean follow-up was 8.6 +/- 3.5 years and 55 patients died of BC. The points system included age, personal history of BC, grade, TNM stage and multicentricity. Validation was satisfactory, in both discrimination and calibration. In conclusion, we constructed and internally validated a scoring system for predicting BC mortality at 5 and 10 years. External validation studies are needed for its use in other geographical areas. PMID- 28341843 TI - Multistructure index characterization of heart rate and systolic blood pressure reveals precursory signs of syncope. AB - Recurrent syncope - abrupt loss of consciousness - can have a serious impact on patients' quality of life, comparable with chronic illnesses. Vasovagal syncope (VVS) is a specific reflex syncope, in which an inappropriate reaction of the autonomic nervous system (ANS) plays a key role in the pathophysiology. In syncope diagnosis, an ideal diagnostic method should positively identify vasovagal sensitive patients, without the need to perform a specialised head-up tilt table (HUTT) test. We apply a novel methodology of multistructure index (MI) statistics for seamlessly evaluating the size spectrum of the asymmetry properties of magnitudes of neural reflexes responsible for maintaining the homeostatic dynamics of autonomic control. Simultaneous evaluation using the MI of the effects on heart rate and blood pressure involved in achieving homeostasis of contrasting properties of the dynamics of slow and fast neural regulation reveals a clear distinction between vasovagal patients and healthy subjects, who are/are not susceptible to spontaneous fainting. Remarkably, a healthy cardiovascular response to the HUTT test is indeed evident prior to the test, making the MI a robust novel indicator, clearly distinguishing the cardiovascular autonomic regulation of healthy people from that of vasovagal patients without the need to perform an actual HUTT test. PMID- 28341844 TI - Relevance of the dietary glycemic index, glycemic load and genetic predisposition for the glucose homeostasis of Chinese adults without diabetes. AB - Type 2 diabetes (T2DM) and pre-diabetes have become a major public health problem in China. We examined whether a higher dietary glycemic index (GI) or glycemic load (GL) was associated with a less favorable glucose homeostasis among Chinese adults and whether these associations were modified by their genetic predisposition or whether combined effects exist with their cereal fiber intake. Multivariable regression analyses were performed in 3918 adults aged 23-69 years for whom three 24-hour dietary recalls and information on glucose homeostasis, genetic background and potential confounders was available. Adults in the highest GI (GL) tertile had an approximately 9% (5%) higher fasting plasma glucose, 11% (3%) higher glycated haemoglobin, 12% (7%) higher insulin level, and 28% (22%) higher hepatic insulin resistance compared to those in the lowest tertile (adjusted pfor-trend <= 0.04). Moreover, a higher dietary GI or GL was associated with higher odds of pre-diabetes (pfor-trend = 0.03). These associations were more pronounced among persons with a high T2DM genetic risk score (pfor interaction <= 0.06) or a low cereal fiber intake (pfor-interaction <= 0.05). In conclusion, our study indicates that the dietary GI or GL is of relevance for glucose homeostasis among Chinese adults, particularly among individuals genetically predisposed to T2DM. PMID- 28341845 TI - The trimer interface in the quaternary structure of the bifunctional prokaryotic FAD synthetase from Corynebacterium ammoniagenes. AB - Bifunctional FAD synthetases (FADSs) fold in two independent modules; The C terminal riboflavin kinase (RFK) catalyzes the RFK activity, while the N-terminal FMN-adenylyltransferase (FMNAT) exhibits the FMNAT activity. The search for macromolecular interfaces in the Corynebacterium ammoniagenes FADS (CaFADS) crystal structure predicts a dimer of trimers organization. Within each trimer, a head-to-tail arrangement causes the RFK and FMNAT catalytic sites of the two neighboring protomers to approach, in agreement with active site residues of one module influencing the activity at the other. We analyze the relevance of the CaFADS head-to-tail macromolecular interfaces to stabilization of assemblies, catalysis and ligand binding. With this aim, we evaluate the effect of point mutations in loop L1c-FlapI, loop L6c, and helix alpha1c of the RFK module (positions K202, E203, F206, D298, V300, E301 and L304), regions at the macromolecular interface between two protomers within the trimer. Although none of the studied residues is critical in the formation and dissociation of assemblies, residues at L1c-FlapI and helix alpha1c particularly modulate quaternary architecture, as well as ligand binding and kinetic parameters involved with RFK and FMNAT activities. These data support the influence of transient oligomeric structures on substrate accommodation and catalysis at both CaFADS active sites. PMID- 28341846 TI - Risk factors of post-operative severe hyperlactatemia and lactic acidosis following laparoscopic resection for pheochromocytoma. AB - Severe hyperlactatemia (SH)/lactic acidosis (LA) after laparoscopic resection of pheochromocytoma is an infrequently reported complication. The study aims to investigate the incidence of this complication and to determine the clinical risk factors. Patients who underwent laparoscopic resection for pheochromocytoma between 2011 and 2014 at Peking Union Medical College Hospital were enrolled. LA was defined as pH < 7.35, bicarbonate <20 mmol/L, and serum lactate >=5 mmol/L; SH as lactate >=5 mmol/L; and moderate hyperlactatemia (MH) as lactate 2.5-5.0 mmol/L without evidence of acidosis (pH > 7.35 and/or bicarbonate >20 mmol/L). Data concerning patient demographics, clinical history, and laboratory results were collected and statistical analyses were performed. Out of 145 patients, 59 (40.7%) developed post-operative hyperlactatemia. The incidences of MH and SH/LA were 25.5% and 15.2%, respectively. Multivariate analysis demonstrated that body mass index (BMI) (odds ratio [OR], 1.204; 95% confidence interval [CI], 1.016 1.426), 24-hour urine epinephrine concentration (OR, 1.012; 95% CI, 1.002-1.022), and tumor size (OR, 1.571; 95% CI, 1.102-2.240) were independent predictors of post-operative SH/LA. The data show that post-operative SH/LA is not a rare complication after pheochromocytoma resection and may be closely associated with higher BMI, larger tumor size, and higher levels of urine epinephrine. PMID- 28341847 TI - APOE Genotype Effects on Intrinsic Brain Network Connectivity in Patients with Amnestic Mild Cognitive Impairment. AB - Whether and how the apolipoprotein E (APOE) epsilon4 genotype specifically modulates brain network connectivity in patients with amnestic mild cognitive impairment (aMCI) remain largely unknown. Here, we employed resting-state ('task free') functional MRI and network centrality approaches to investigate local (degree centrality, DC) and global (eigenvector centrality, EC) functional integrity in the whole-brain connectome in 156 older adults, including 66 aMCI patients (27 epsilon4-carriers and 39 non-carriers) and 90 healthy controls (45 epsilon4-carriers and 45 non-carriers). We observed diagnosis-by-genotype interactions on DC in the left superior/middle frontal gyrus, right middle temporal gyrus and cerebellum, with higher values in the epsilon4-carriers than non-carriers in the aMCI group. We further observed diagnosis-by-genotype interactions on EC, with higher values in the right middle temporal gyrus but lower values in the medial parts of default-mode network in the epsilon4-carriers than non-carriers in the aMCI group. Notably, these genotype differences in DC or EC were absent in the control group. Finally, the network connectivity DC values were negatively correlated with cognitive performance in the aMCI epsilon4 carriers. Our findings suggest that the APOE genotype selectively modulates the functional integration of brain networks in patients with aMCI, thus providing important insight into the gene-connectome interaction in this disease. PMID- 28341849 TI - Quantitative profiling of glycerophospholipids during mouse and human macrophage differentiation using targeted mass spectrometry. AB - Macrophage lipid metabolism plays a pivotal role in innate and adaptive immune responses. Previous studies have shown that this process plays a role in infections and contributes to the pathogenesis of diabetes, atherosclerosis, and other immunometabolic diseases. M1 macrophages, or classically activated macrophages, are key players in the defense against bacterial infections. M2 macrophages, or alternatively activated macrophages, are involved in anti inflammatory responses. Using the multiple reaction monitoring method, we identified changes in lipid composition during the differentiation of human and murine macrophages. We detected over 300 lipid molecules in mammalian macrophages, and we observed a striking shift in the composition of glycerophospholipids (GLs) from saturated and monounsaturated to polyunsaturated during human macrophage polarization. Moreover, M2 macrophages showed a higher level of lysophospholipids (lysoGLs) than did M1 macrophages. The lysoPI species increased in human and mouse M2 macrophages, suggesting that they may be involved in M2 macrophage polarization and anti-inflammatory processes. Collectively, these results indicate that lipids may play a role in the pro- and anti inflammatory activities of macrophages and may be markers of the macrophage activation state. PMID- 28341850 TI - The effects of symmetrical arrangement on quantum metrology. AB - An obstacle for precision improvement in quantum metrology is the information loss causing by the unavoidable interaction between probe system and environment. Quantum fluctuations are environment no system can be isolated from and it will make the precision of initial parameter estimation of the probe atom decrease with time. After the typical time of the spontaneous decay of the probe atom, the precision is greatly damaged. However, quantum fluctuations can be modified. Our results show that if we put several ancillary atoms beside the probe atom in symmetrical arrangement, the probe atom will be affected by the ancillary atoms indirectly and the information loss of the probe atom causing by the quantum fluctuations will be partially avoided. We find that the retained precision after long time evolution can approaches to [Formula: see text] times of the initial precision in condition that the probe atom and three ancillary atoms are located in the vertex of regular tetrahedron. PMID- 28341848 TI - Role of p62 in the suppression of inflammatory cytokine production by adiponectin in macrophages: Involvement of autophagy and p21/Nrf2 axis. AB - Adiponectin possesses potent anti-inflammatory properties. p62, an adaptor protein composed of multi-functional domain, is known to play a role in controlling inflammatory responses. In the present study, we examined the role of p62 in suppressing inflammatory cytokines produced by globular adiponectin (gAcrp) and the potential underlying mechanisms in macrophages. We demonstrated that gAcrp significantly increased p62 expression. Knockdown of p62 abrogated the suppressive effects of gAcrp on LPS-stimulated TNF-alpha and IL-1beta expression and TRAF6/p38 MAPK pathway, indicating that p62 signaling is critical for suppressing inflammatory cytokines production by gAcrp. We next examined the role of p62 in gAcrp-induced autophagy activation, because autophagy has been shown to play a pivotal role in suppressing TNF-alpha. Herein, we observed that gene silencing of p62 prevented gAcrp-induced increases in autophagy-related genes and autophagosome formation. In addition, we found that Nrf2 knockdown prevented gAcrp-induced p62 expression, and p21 knockdown prevented Nrf2 induction, suggesting the role of p21/Nrf2 axis in gAcrp-induced p62 expression. Taken together, these findings imply that p62 signaling plays a crucial role in suppressing inflammatory cytokine production by globular adiponectin in macrophages, at least in part, through autophagy induction. Furthermore, the p21/Nrf2 signaling cascade contributes to p62 induction by globular adiponectin. PMID- 28341851 TI - Respiratory Microbiome of Endangered Southern Resident Killer Whales and Microbiota of Surrounding Sea Surface Microlayer in the Eastern North Pacific. AB - In the Salish Sea, the endangered Southern Resident Killer Whale (SRKW) is a high trophic indicator of ecosystem health. Three major threats have been identified for this population: reduced prey availability, anthropogenic contaminants, and marine vessel disturbances. These perturbations can culminate in significant morbidity and mortality, usually associated with secondary infections that have a predilection to the respiratory system. To characterize the composition of the respiratory microbiota and identify recognized pathogens of SRKW, exhaled breath samples were collected between 2006-2009 and analyzed for bacteria, fungi and viruses using (1) culture-dependent, targeted PCR-based methodologies and (2) taxonomically broad, non-culture dependent PCR-based methodologies. Results were compared with sea surface microlayer (SML) samples to characterize the respective microbial constituents. An array of bacteria and fungi in breath and SML samples were identified, as well as microorganisms that exhibited resistance to multiple antimicrobial agents. The SML microbes and respiratory microbiota carry a pathogenic risk which we propose as an additional, fourth putative stressor (pathogens), which may adversely impact the endangered SRKW population. PMID- 28341852 TI - Profiling of long non-coding RNAs identifies LINC00958 and LINC01296 as candidate oncogenes in bladder cancer. AB - Aberrant expression of long non-coding RNAs (lncRNAs) has been regarded as a critical component in bladder cancer (BC) and lncRNAs have been associated with BC development and progression although their overall expression and functional significance is still unclear. The aim of our study was to identify novel lncRNAs with a functional role in BC carcinogenesis. RNA-sequencing was used to identify aberrantly expressed lncRNAs in 8 normal and 72 BC samples. We identified 89 lncRNAs that were significantly dys-regulated in BC. Five lncRNAs; LINC00958, LINC01296, LINC00355, LNC-CMC1-1 and LNC-ALX1-2 were selected for further analyses. Silencing of LINC00958 or LINC01296 in vitro reduced both cell viability and migration. Knock-down of LINC00958 also affected invasion and resistance to anoikis. These cellular effects could be linked to direct/indirect regulation of protein coding mRNAs involved in cell death/survival, proliferation and cellular movement. Finally, we showed that LINC00958 binds proteins involved in regulation and initiation of translation and in post-transcriptional modification of RNA, including Metadherin, which has previously been associated with BC. Our analyses identified novel lncRNAs in BC that likely act as oncogenic drivers contributing to an aggressive cancerous phenotype likely through interaction with proteins involved in initiation of translation and/or post transcriptional modification of RNA. PMID- 28341854 TI - Gliding locomotion of manta rays, killer whales and swordfish near the water surface. AB - The hydrodynamic performance of the locomotive near the water surface is impacted by its geometrical shape. For marine animals, their geometrical shape is naturally selective; thus, investigating gliding locomotion of marine animal under the water surface may be able to elucidate the influence of the geometrical shape. We investigate three marine animals with specific geometries: the killer whale is fusiform shaped; the manta ray is flat and broad-winged; and the swordfish is best streamlined. The numerical results are validated by the measured drag coefficients of the manta ray model in a towing tank. The friction drag of the three target models are very similar; the body shape affected form drag coefficient is order as swordfish < killer whale < manta ray; the induced wave breaking upon the body of the manta ray performs different to killer whale and swordfish. These bio-inspired observations provide a new and in-depth understanding of the shape effects on the hydrodynamic performances near the free surface. PMID- 28341853 TI - Non cell-autonomous role of DCC in the guidance of the corticospinal tract at the midline. AB - DCC, a NETRIN-1 receptor, is considered as a cell-autonomous regulator for midline guidance of many commissural populations in the central nervous system. The corticospinal tract (CST), the principal motor pathway for voluntary movements, crosses the anatomic midline at the pyramidal decussation. CST fails to cross the midline in Kanga mice expressing a truncated DCC protein. Humans with heterozygous DCC mutations have congenital mirror movements (CMM). As CMM has been associated, in some cases, with malformations of the pyramidal decussation, DCC might also be involved in this process in human. Here, we investigated the role of DCC in CST midline crossing both in human and mice. First, we demonstrate by multimodal approaches, that patients with CMM due to DCC mutations have an increased proportion of ipsilateral CST projections. Second, we show that in contrast to Kanga mice, the anatomy of the CST is not altered in mice with a deletion of DCC in the CST. Altogether, these results indicate that DCC controls CST midline crossing in both humans and mice, and that this process is non cell-autonomous in mice. Our data unravel a new level of complexity in the role of DCC in CST guidance at the midline. PMID- 28341856 TI - Autoassociative Memory and Pattern Recognition in Micromechanical Oscillator Network. AB - Towards practical realization of brain-inspired computing in a scalable physical system, we investigate a network of coupled micromechanical oscillators. We numerically simulate this array of all-to-all coupled nonlinear oscillators in the presence of stochasticity and demonstrate its ability to synchronize and store information in the relative phase differences at synchronization. Sensitivity of behavior to coupling strength, frequency distribution, nonlinearity strength, and noise amplitude is investigated. Our results demonstrate that neurocomputing in a physically realistic network of micromechanical oscillators with silicon-based fabrication process can be robust against noise sources and fabrication process variations. This opens up tantalizing prospects for hardware realization of a low-power brain-inspired computing architecture that captures complexity on a scalable manufacturing platform. PMID- 28341855 TI - MiR-503 Promotes Bone Formation in Distraction Osteogenesis through Suppressing Smurf1 Expression. AB - Distraction osteogenesis (DO) is a unique technique for promoting bone formation in clinical practice. However the underlying mechanism remains elusive. As epigenetic mediators, microRNAs have been reported to play important roles in regulating osteogenesis. In this study, after successfully established the DO model of rats, a microRNA microarray was performed to find molecular targets for DO. Total 100 microRNAs were identified as differently expressed, with miR-503 being one of the most significantly up-regulated miRNAs in DO. The further investigation also showed that miR-503 was upregulated during osteogenesis in mesenchymal stem cells of rats, and overexpression of miR-503 significantly promoted osteogenesis in vitro and accelerated mineralization in DO process in vivo. By using bioinformatic investigations and luciferase activities, we successfully demonstrated that Smurf1, a negative regulator of osteogenesis, was a real target of miR-503. Furthermore, Smurf1 knockdown promoted osteogenesis and antagomir-503 abolished the promotive effect, suggesting that miR-503 mediated osteogenic differentiation via suppressing Smurf1 expression. To sum up, these findings indicated that miR-503 promoted osteogenesis and accelerated bone formation, which may shed light on the development for a potential therapeutic target for bone repair. PMID- 28341858 TI - Visualization of weak interactions between quantum dot and graphene in hybrid materials. AB - The mechanisms of the weak interactions within hybrid materials such as quantum dot (QD) and graphene (GR) have important implications for the design of related optoelectronic devices. We characterize the weak interactions in hybrid QD-GR systems using a non-covalent interactions approach. For a single Cd13Se13 QD with a core-cage structure, the intensity of the steric repulsive strain in every Cd Se spatial four-atom ring of the cage surface is stronger than that of the inter core-cage structure. Van der Waals (vdW) interactions occur within the cavity of the cage and within the six-atom rings of the cage surface. The spatial repulsion strain and attractive interactions play a key role in stabilizing the structure of the monolayer graphene. Interestingly, the spatial six-atom ring of the single QD change into spatial four-atom rings of the QD in the hybrid system, accompanied by the translation of vdW interactions into steric repulsive interactions. We conclude that the vdW interactions with pi extensions and the weak attractive interactions within local areas between the QD and graphene together stabilize the integral structure of the hybrid QD-GR system. These results explain of the formation mechanism and the stabilization of the components in QD-GR hybrid materials. PMID- 28341857 TI - Embryonic defence mechanisms against glucose-dependent oxidative stress require enhanced expression of Alx3 to prevent malformations during diabetic pregnancy. AB - Oxidative stress constitutes a major cause for increased risk of congenital malformations associated to severe hyperglycaemia during pregnancy. Mutations in the gene encoding the transcription factor ALX3 cause congenital craniofacial and neural tube defects. Since oxidative stress and lack of ALX3 favour excessive embryonic apoptosis, we investigated whether ALX3-deficiency further increases the risk of embryonic damage during gestational hyperglycaemia in mice. We found that congenital malformations associated to ALX3-deficiency are enhanced in diabetic pregnancies. Increased expression of genes encoding oxidative stress scavenging enzymes in embryos from diabetic mothers was blunted in the absence of ALX3, leading to increased oxidative stress. Levels of ALX3 increased in response to glucose, but ALX3 did not activate oxidative stress defence genes directly. Instead, ALX3 stimulated the transcription of Foxo1, a master regulator of oxidative stress-scavenging genes, by binding to a newly identified binding site located in the Foxo1 promoter. Our data identify ALX3 as an important component of the defence mechanisms against the occurrence of developmental malformations during diabetic gestations, stimulating the expression of oxidative stress scavenging genes in a glucose-dependent manner via Foxo1 activation. Thus, ALX3 deficiency provides a novel molecular mechanism for developmental defects arising from maternal hyperglycaemia. PMID- 28341859 TI - Refractive index variation in a free-standing diamond thin film induced by irradiation with fully transmitted high-energy protons. AB - Ion irradiation is a widely employed tool to fabricate diamond micro- and nano structures for applications in integrated photonics and quantum optics. In this context, it is essential to accurately assess the effect of ion-induced damage on the variation of the refractive index of the material, both to control the side effects in the fabrication process and possibly finely tune such variations. Several partially contradictory accounts have been provided on the effect of the ion irradiation on the refractive index of single crystal diamond. These discrepancies may be attributable to the fact that in all cases the ions are implanted in the bulk of the material, thus inducing a series of concurrent effects (volume expansion, stress, doping, etc.). Here we report the systematic characterization of the refractive index variations occurring in a 38 um thin artificial diamond sample upon irradiation with high-energy (3 MeV and 5 MeV) protons. In this configuration the ions are fully transmitted through the sample, while inducing an almost uniform damage profile with depth. Therefore, our findings conclusively identify and accurately quantify the change in the material polarizability as a function of ion beam damage as the primary cause for the modification of its refractive index. PMID- 28341860 TI - High Plasma Lipid Levels Reduce Efficacy of Adenovirus-Mediated Gene Therapy. AB - Adenoviruses are very efficient vectors for delivering therapeutic genes in preclinical and clinical trials. However, randomized controlled human trials have often been lacking clear clinically relevant results. We hypothesized that high lipid levels and specific lipoproteins could significantly decrease adenoviral transduction efficiency in vivo. Here we demonstrate that mice on a high fat diet have lower transgene expression compared to mice on a regular chow. In addition, on a high fat diet, ApoE-/- mice have much higher plasma transgene levels compared to LDLR-deficient mice. We also found that specific lipoprotein receptors play an important role in adenoviral transduction. These findings suggest that high plasma lipid levels, especially apoE-containing lipoproteins, reduce efficacy of adenoviral transduction in mice, which implies that high cholesterol levels in humans could be protective against viral infections and also lead to insufficient transgene expression in clinical trials using adenoviral vectors. PMID- 28341861 TI - Minimum Vertex-type Sequence Indexing for Clusters on Square Lattice. AB - An effective indexing scheme for clusters that enables fast structure comparison and congruence check is desperately desirable in the field of mathematics, artificial intelligence, materials science, etc. Here we introduce the concept of minimum vertex-type sequence for the indexing of clusters on square lattice, which contains a series of integers each labeling the vertex type of an atom. The minimum vertex-type sequence is orientation independent, and it builds a one-to one correspondence with the cluster. By using minimum vertex-type sequence for structural comparison and congruence check, only one type of data is involved, and the largest amount of data to be compared is n pairs, n is the cluster size. In comparison with traditional coordinate-based methods and distance-matrix methods, the minimum vertex-type sequence indexing scheme has many other remarkable advantages. Furthermore, this indexing scheme can be easily generalized to clusters on other high-symmetry lattices. Our work can facilitate cluster indexing and searching in various situations, it may inspire the search of other practical indexing schemes for handling clusters of large sizes. PMID- 28341862 TI - Follistatin like-1 aggravates silica-induced mouse lung injury. AB - Occupational inhalation of dust, such as crystalline silica, for prolonged periods in the workplace leads to fibrotic lung diseases worldwide. The mechanisms underlying the diseases are unknown, so that no effective treatment exists for these conditions. We found elevated levels of follistatin like 1 (FSTL1) in serum from patients with silicosis and in lungs from silica-induced mouse model. The induced Fstl1 regulated inflammation response via activation of nod-like receptor family, pyrin domain containing 3v (NLRP3) inflammasome mediated IL-1beta production from macrophages. Meanwhile, Fstl1 promoted fibrosis via positive regulation of TGF-beta1 signaling. Haploinsufficiency of Fstl1 or blockage of FSTL1 with a neutralizing antibody was protective from silica-induced lung injury in mice in vivo. Our data suggest that Fstl1 plays an important role in lung fibrosis, and may serve as a novel therapeutic target for treatment of silicosis. PMID- 28341863 TI - The feature-specific propagation of orientation and direction adaptation from areas 17 to 21a in cats. AB - Adaptation plays a key role in visual information processing, and investigations on the adaptation across different visual regions will be helpful to understand how information is processed dynamically along the visual streams. Recent studies have found the enhanced adaptation effects in the early visual system (from LGN to V1) and the dorsal stream (from V1 to MT). However, it remains unclear how adaptation effect propagates along the form/orientation stream in the visual system. In this study, we compared the orientation and direction adaptation evoked by drifting gratings and stationary flashing gratings, as well as moving random dots, in areas 17 and 21a simultaneously of cats. Recorded by single-unit and intrinsic signal optical imaging, induced by both top-up and biased adaptation protocols, the orientation adaptation effect was greater in response decline and preferred orientation shifts in area 21a compared to area 17. However, for the direction adaptation, no difference was observed between these two areas. These results suggest the feature-specific propagation of the adaptation effect along the visual stream. PMID- 28341864 TI - MicroRNA-140-5p regulates osteosarcoma chemoresistance by targeting HMGN5 and autophagy. AB - Chemotherapy is an important treatment modality for osteosarcoma. However, it often fails because of chemoresistance, especially multidrug resistance. Previously, we found several genes were involved in chemoresistance development. In this report, we used high-throughput microRNA (miRNA) expression analysis to reveal that expression of miR-140-5p was associated with chemosensitivity in osteosarcoma. The exact roles of miR-140-5p in the chemoresistance of osteosarcoma were then investigated, we found that knockdown of miR-140-5p enhanced osteosarcoma cells resistance to multiple chemotherapeutics while overexpression of miR-140-5p sensitized tumors to chemotherapy in vitro. Moreover, in vivo, knockdown of miR-140-5p also increased the osteosarcoma cells resistance to chemotherapy. Luciferase assay and Western blot analysis showed that HMGN5 was the direct target of miR-140-5p which could positively regulated autophagy. Silencing these target genes by siRNA or inhibition of autophagy sensitized osteosarcoma cells to chemotherapy. These findings suggest that a miR 140-5p/HMGN5/autophagy regulatory loop plays a critical role in chemoresistance in osteosarcoma. In conclusion, our data elucidated that miR-140-5p promoted autophagy mediated by HMGN5 and sensitized osteosarcoma cells to chemotherapy. These results suggest a potential application of miR-140-5p in overall survival, chemoresistance prognosis and treatment. PMID- 28341865 TI - Radioablation of adrenal gland malignomas with interstitial high-dose-rate brachytherapy : Efficacy and outcome. AB - PURPOSE: To assess the efficacy, safety, and outcome of image-guided high-dose rate (HDR) brachytherapy in patients with adrenal gland metastases (AGM). MATERIALS AND METHODS: From January 2007 to April 2014, 37 patients (7 female, 30 male; mean age 66.8 years, range 41.5-82.5 years) with AGM from different primary tumors were treated with CT-guided HDR interstitial brachytherapy (iBT). Primary endpoint was local tumor control (LTC). Secondary endpoints were time to untreatable progression (TTUP), time to progression (TTP), overall survival (OS), and safety. In a secondary analysis, risk factors with an influence on survival were identified. RESULTS: The median biological equivalent dose (BED) was 37.4 Gy. Mean LTC after 12 months was 88%; after 24 months this was 74%. According to CTCAE criteria, one grade 3 adverse event occurred. Median OS after first diagnosis of AGM was 18.3 months. Median OS, TTUP, and TTP after iBT treatment were 11.4, 6.6, and 3.5 months, respectively. Uni- and multivariate Cox regression analyses revealed significant influences of synchronous disease, tumor diameter, and the total number of lesions on OS or TTUP or both. CONCLUSION: Image-guided HDR-iBT is safe and effective. Treatment- and primary tumor independent features influenced survival of patients with AGM after HDR-iBR treatment. PMID- 28341867 TI - A safe procedure for connecting a continuous renal replacement therapy device into an extracorporeal membrane oxygenation circuit. AB - Patients receiving extracorporeal membrane oxygenation (ECMO) often require continuous renal replacement therapy (CRRT). The intra-circuit pressure of adult ECMO usually deviates from the physiological range. We investigated the use of CRRT connected to an ECMO circuit with physiological intra-circuit pressures (0 150 mmHg, defined as the "safety range") using an in vitro experiment involving a water-filled ECMO circuit. The intra-circuit pressure pre-pump, post-pump, and post-oxygenator were measured while varying the height of the pump or ECMO flow. The bypass conduit pressure and distance from the post-oxygenator port were measured to find the "safety point", where the bypass pressure remained within the safety range. Both drainage and return limbs of the CRRT machine were connected to the safety point and the inlet and outlet pressures of the hemofilter were recorded while varying the ECMO and CRRT flow. The pre-pump pressure only remained within the safety range for heights >75 cm (ECMO flow = 4 L/min) or ECMO flow <3.5 L min (height = 50 cm). The post-pump and post oxygenator pressure was generally outside of the safety range. The bypass pressure decreased according to the distance from the post-oxygenator port and the safety point was found at 60 or 75 cm (in a 90-cm length conduit) regardless of ECMO flow. The hemofilter inlet and outlet pressures remained within the safety range for all conditions of ECMO and CRRT flow, findings validated in clinical cases. The bypass conduit within an ECMO circuit can be connected to a CRRT machine safely under physiological pressures in adult patients receiving ECMO. PMID- 28341866 TI - Mapping brain structure and function: cellular resolution, global perspective. AB - A comprehensive understanding of the brain requires analysis, although from a global perspective, with cellular, and even subcellular, resolution. An important step towards this goal involves the establishment of three-dimensional high resolution brain maps, incorporating brain-wide information about the cells and their connections, as well as the chemical architecture. The progress made in such anatomical brain mapping in recent years has been paralleled by the development of physiological techniques that enable investigators to generate global neural activity maps, also with cellular resolution, while simultaneously recording the organism's behavioral activity. Combination of the high-resolution anatomical and physiological maps, followed by theoretical systems analysis of the deduced network, will offer unprecedented opportunities for a better understanding of how the brain, as a whole, processes sensory information and generates behavior. PMID- 28341868 TI - Risk Factors of Reoperation After Pancreatic Resection. AB - BACKGROUND: Pancreatic resection is associated with a high incidence of postoperative complications, some of which require reoperation. AIMS: To analyze the incidence of and risk factors for reoperation following pancreatectomy. METHODS: Pre- and postoperative information and procedure characteristics of 15,549 patients having undergone pancreatectomy in 435 hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program from 2011 to 2014 were analyzed. RESULTS: A total of 773 (5.0%) patients required reoperation within 30 days of their index pancreatectomy. Patients requiring reoperation were more likely to be younger (mean +/- standard deviation, 62.6 +/- 13.2 vs. 64.1 +/- 12.2 years, p < 0.001), male (60 vs. 49%, p < 0.001), to have respiratory comorbidities, lower preoperative serum albumin (3.7 +/- 0.68 vs. 3.8 +/- 0.62 mg/dl, p < 0.001), higher total bilirubin (1.7 +/- 2.7 vs. 1.5 +/- 2.4 mg/dl, p = 0.02), and higher American Society of Anesthesiologists (ASA) class than those who did not undergo reoperation. Other factors associated with increased incidence of reoperation included longer mean operative duration at the index procedure, postoperative transfusion requirement, wound complications, and cardiorespiratory, renal, thromboembolic, and infectious events. Multivariate regression analysis identified male sex, preoperative serum albumin <3.5 mg/dl, ASA class of 3 or 4, pancreaticoduodenectomy, and total pancreatectomy as the strongest predictors for reoperation after index pancreatic resection. Complication and readmission rates were significantly higher for those undergoing reoperation. CONCLUSION: Patient characteristics and procedural factors contribute to reoperation after pancreatectomy in this largest and most diverse sample to date. Further investigation to identify perioperative strategies for mitigating this risk is required to improve the safety of pancreatic resection. PMID- 28341871 TI - Erratum to: Considering total intracranial volume and other nuisance variables in brain voxel based morphometry in idiopathic PD. PMID- 28341869 TI - The Profile of Serum microRNAs Predicts Prognosis for Resected Gastric Cancer Patients Receiving Platinum-Based Chemotherapy. AB - BACKGROUND AND AIM: Adjuvant chemotherapy is an important component in the treatment of gastric cancer (GC) patients; however, some patients do not respond to the drugs. We aimed to develop a practical profile based on serum microRNAs (miRNAs) that can be used to predict patients likely to respond to treatment. METHODS: Microarrays were used to screen cisplatin-resistant SGC7901/DDP GC cells and the parental SGC7901 cell lines for miRNAs related to chemotherapy sensitivity. The correlation between the expression patterns of identified serum miRNAs and overall survival was confirmed in 68 GC patients. Furthermore, we also validated the signature of the serum miRNAs in an independent cohort of 50 GC patients. RESULTS: From the screening microarrays, we focused on miR-15a, miR-15b and miR-93 as downregulated miRNAs in the SGC7901/DDP cells and miR-27a, miR-106a and miR-664 as upregulated miRNAs. Only serum miR-106, miR-15a, miR-93 and miR 664 were useful in predicting the prognosis of patients who received adjuvant chemotherapy. We identified a signature of four serum miRNAs (miR-106, miR-15a, miR-93 and miR-664) that, when combined, can be used as a risk score for overall survival. Patients with a higher risk score had worse prognosis (p < 0.05). For the independent cohort of patients, the signature of the four miRNAs predicted prognosis well. CONCLUSION: Our data showed that the risk score derived from the four serum miRNAs was closely associated with the overall survival in GC patients who received adjuvant chemotherapy. PMID- 28341872 TI - Childhood adversity associated with white matter alteration in the corpus callosum, corona radiata, and uncinate fasciculus of psychiatrically healthy adults. AB - Diffusion tensor imaging studies report childhood adversity (CA) is associated with reduced fractional anisotropy (FA) in multiple white matter tracts in adults. Reduced FA may result from changes in tissue, suggesting myelin/axonal damage, and/or from increased levels of extracellular free-water, suggesting atrophy or neuroinflammation. Free-water imaging can separately identify FA in tissue (FAT) and the fractional volume of free-water (FW). We tested whether CA was associated with altered FA, FAT, and FW in seven white matter regions of interest (ROI), in which FA changes had been previously linked to CA (corona radiata, corpus callosum, fornix, cingulum bundle: hippocampal projection, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, uncinate fasciculus). Tract-based spatial statistics were performed in 147 psychiatrically healthy adults who had completed a self-report questionnaire on CA primarily stemming from parental maltreatment. ROI were extracted according to the protocol provided by the ENIGMA-DTI working group. Analyses were performed both treating CA as a continuous and a categorical variable. CA was associated with reduced FA in all ROI (although categorical analyses failed to find an association in the fornix). In contrast, CA was only associated with reduced FAT in the corona radiata, corpus callosum, and uncinate fasciculus (with the continuous measure of CA finding evidence of a negative relation between CA and FAT in the fornix). There was no association between CA on FW in any ROI. These results provide preliminary evidence that childhood adversity is associated with changes to the microstructure of white matter itself in adulthood. However, these results should be treated with caution until they can be replicated by future studies which address the limitations of the present study. PMID- 28341870 TI - Influences of the Gut Microbiota on DNA Methylation and Histone Modification. AB - The gut microbiota is a vast ensemble of microorganisms inhabiting the mammalian gastrointestinal tract that can impact physiologic and pathologic processes. However, our understanding of the underlying mechanism for the dynamic interaction between host and gut microbiota is still in its infancy. The highly evolved epigenetic modifications allow hosts to reprogram the genome in response to environmental stimuli, which may play a key role in triggering multiple human diseases. In spite of increasing studies in gut microbiota and epigenetic modifications, the correlation between them has not been well elaborated. Here, we review current knowledge of gut microbiota impacts on epigenetic modifications, the major evidence of which centers on DNA methylation and histone modification of the immune system. PMID- 28341873 TI - Exploring the plasmatic platelet-activating factor acetylhydrolase activity in patients with anti-phospholipid antibodies. AB - PURPOSE: To explore the role of plasmatic platelet-activating factor acetylhydrolase (PAF-AH), a marker of cardiovascular risk, in patients with anti phospholipid antibodies (aPL). METHODS: PAF-AH activity was assessed in a series of 167 unselected patients screened for aPL in a context of thrombotic events, risk of thrombosis or obstetric complications and in 77 blood donors. RESULTS: 116/167 patients showed positive results for at least one aPL among IgG/IgM anti prothrombin/phosphatidylserine (aPS/PT), anti-cardiolipin (aCL), anti-beta2 glycoprotein I (abeta2GPI) or lupus anticoagulant (LAC), while 51/167 patients resulted aPL-negative. LAC+ patients disclosed higher PAF-AH than LAC-negative (22.1 +/- 6.4 nmol/min/ml vs. 19.5 +/- 4.1 nmol/min/ml; p = 0.0032), and aPL negative patients (p = 0.03). Patients presenting positive IgG abeta2GPI disclosed higher PAF-AH than patients with only IgM abeta2GPI-positive antibodies (23.1 +/- 7.2 nmol/min/ml vs. 20.1 +/- 5.3 nmol/min/ml; p = 0.035), as well as than patients showing only isolated LAC, aCL or aPS/PT (16.9 +/- 3.8 nmol/min/ml; p = 0.003). CONCLUSIONS: PAF-AH plasmatic activity is particularly up-regulated in LAC+ and in abeta2GPI IgG+ patients, possibly representing an alternative prognostic biomarker for the therapeutic management of APS patients. PMID- 28341874 TI - The multi-faceted potential of CD38 antibody targeting in multiple myeloma. AB - CD38, an adenine dinucleotide phosphate (ADP) ribose cyclase and a cyclic ADP ribose hydrolase, is widely expressed on the surface of multiple myeloma (MM) cells. It is known to play a pivotal role in the downstream pathways that mediate MM cell growth, signal transduction, and adhesion. The clinical use of CD38 monoclonal antibodies (MoAbs), such as daratumumab, either as monotherapy or in combination with other anti-MM agents, has produced impressive results in patients who have failed standard MM therapy. CD38 MoAbs exhibit several cytotoxic mechanisms on MM cells. In addition to the classical effector mechanisms associated with antibody therapy, CD38 MoAbs induce MM apoptosis and clonal T-cell expansion. Here, we summarize the results of some pivotal clinical studies using a human CD38 MoAb, daratumumab, in patients with MM, discuss the anti-MM effector mechanisms induced by CD38 MoAbs, and review the potential tumor antigens that may be suitable targets for immunotherapy of MM. Finally, we present a paradigm of immunotherapy for MM patients using CD38 MoAbs followed by GM-CSF and an immune checkpoint inhibitor in patients who have undergone high dose chemotherapy and autologous stem cell transplant. CD38 MoAbs have emerged as a novel and ultimately very promising immunotherapeutic agent for MM because of its ability to induce MM cytotoxicity through both arms of the adaptive immune responses. PMID- 28341875 TI - PD-L1 overexpression is partially regulated by EGFR/HER2 signaling and associated with poor prognosis in patients with non-small-cell lung cancer. AB - Immunocheckpoint inhibitors targeting the programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) axis have shown promising results in patients with non-small cell lung cancer (NSCLC). Recent research has shown that epidermal growth factor receptor (EGFR) signaling affects PD-L1 expression in NSCLC cells; however, the mechanism regulating PD-L1 expression in tumor cells remains unclear. Using immunohistochemistry, we evaluated the impact of expression of PD-L1 and EGF family receptors EGFR and human epidermal growth factor receptor 2 (HER2) in tumor cells from 91 patients with pathological Stage IA-IIIA NSCLC. Overexpression of PD-L1 was observed in 14% of the resected tumors, and associated with poor recurrence-free survival (p = 0.021) and overall survival (p = 0.033). PD-L1 expression is positively correlated with EGFR expression and inversely correlated with HER2. NSCLC cell lines were treated in vitro with the EGFR ligand EGF with or without inhibition of EGFR or HER2, after which PD-L1 expression was evaluated using flow cytometry. Consistent with previous reports, PD-L1 expression was clearly enhanced by EGF. EGFR-tyrosine kinase inhibitors or EGFR small interfering RNA (siRNA) blocked EGF-induced PD-L1 overexpression in NSCLC cell lines, but HER2 siRNA did not. Moreover, our findings suggest that PD L1 expression could be partially regulated via the PI3K/AKT and JAK/STAT pathways. We conclude that PD-L1 overexpression is associated with poor prognosis and is positively correlated with EGFR expression but inversely correlated with HER2 expression in NSCLC. We also showed that EGFR and HER2 have different effects on EGF-induced PD-L1 expression in NSCLC cell lines. PMID- 28341876 TI - Consumption of green tea epigallocatechin-3-gallate enhances systemic immune response, antioxidative capacity and HPA axis functions in aged male swiss albino mice. AB - The present investigation assessed the potential of green tea phytochemical epigallocatechin-3-gallate (EGCG) in alleviating age-associated aberrations in immunity, hypothalamus-pituitary-adrenal (HPA) axis and redox homeostasis using 16 months old male Swiss albino mice. Four groups of animals (n = 6 per group) were supplemented with either aqueous EGCG at 25, 50 and 100 mg/kg/animal or vehicle control for 6 weeks. A concurrent analysis of CD4+ and CD8+ lymphocytes in splenocytes, differential leucocyte population, T cell differentiation markers in peripheral blood mononuclear cells (PBMCs), neutrophil functions, immunoglobulins profile in intestine, circulatory HPA axis hormonal levels as well as inflammatory and oxidative stress in the liver was performed. We observed a remarkable increase in plasma dehydroepiandrosterone (DHEA) levels of 100 mg EGCG fed animals while eosinophils and monocytes counts in blood increased. EGCG consumption increased the fraction of CD3+CD8+ cells in splenocytes and CD28 expression on PBMCs. The immunoglobulins profile revealed decreased production of secretory IgA, IgE and IgG1/IgG2a ratio. Liver extracts showed increase in superoxide dismutase activity and total antioxidant capacity while lipid peroxidation along with inflammatory markers (IL-6 and TNF-alpha) decreased. Our results collectively show that EGCG consumption during aging strengthens systemic immunity by enhancing cellular immune response and simultaneously attenuating antibody response aided by an increase in adrenal DHEA production. Thus, consumption of green tea may be beneficial in alleviating some of the deleterious aspects of aging and immunosenescence in elderly. PMID- 28341877 TI - Short courses of daily prednisolone during upper respiratory tract infections reduce relapse frequency in childhood nephrotic syndrome. AB - BACKGROUND: Relapses of childhood nephrotic syndrome (NS) are frequently precipitated by viral upper respiratory tract infections (URTIs). A review of the literature reveals that in patients with steroid-dependent NS on alternate day corticosteroids, a short course of daily corticosteroid therapy during the course of an URTI may reduce relapse frequency. OBJECTIVE: To assess the effect of a short course of low-dose corticosteroid therapy during the course of an URTI on relapse frequency in patients with steroid-sensitive NS who have not been taking any treatment for a minimum period of 3 months. METHODS: A double-blind placebo controlled crossover trial was conducted on 48 patients with idiopathic NS who had not been receiving corticosteroid therapy for a minimum of 3 months. Patients were randomized into two groups. Group A received 5 days of daily prednisolone at 0.5 mg/kg at the onset of an URTI while group B received 5 days of placebo. Both groups were followed up for 1 year and the URTI-induced relapse frequency was noted. A crossover was performed during the next year, with group A receiving placebo and group B receiving prednisolone. RESULTS: Thirty-three patients completed the study. In the treatment group, 115 episodes of URTI led to 11 relapses while in the control group 101 episodes of URTI led to 25 relapses. There was no significant difference between the mean number of URTIs between the treatment and control groups. The treatment group had significantly less relapses compared to the control group (p = 0.014). Within the treatment group, 65.6% did not relapse, while the remainder had a single relapse. In contrast, only 40.6% of the control group remained in remission while 40.6% suffered a single relapse and 18.8% had two or more relapses. CONCLUSIONS: Prescribing a short course of daily corticosteroids during an URTI significantly reduces the frequency of URTI induced relapse in patients with steroid-responsive NS who are off corticosteroid therapy. PMID- 28341878 TI - Sports activity is maintained or increased following total knee arthroplasty. AB - PURPOSE: The purpose of this study was to investigate sports activities and functional abilities in patients following total knee arthroplasty (TKA). It was hypothesized that patients who had undergone TKA would return to a higher activity level as that experienced preoperatively. METHODS: Two hundred patients were included in this prospective single-cohort study. All the patients completed subjective questionnaires (Tegner Activity Level, Oxford Knee Score, Visual Analog Scale for pain) prior to surgery as well as at 6, 12, and 24 months postoperatively. Additionally, sports behaviour was evaluated. Sports frequency was divided into four categories: more than 5 times a week, 2-3 times a week, occasionally, and no sports activities. Additionally, the patients were asked to state their three favourite summer and winter sports. RESULTS: All patient reported outcome scores improved significantly over time (p <= 0.005). The Tegner Activity Level increased significantly from the preoperative state to 24 months postsurgery (p = 0.005). Six months after surgery, 43% of the patients returned to the same and 35% to a higher Tegner Activity Level than prior to surgery. Gender-related differences were observed for the Tegner Activity Level showing a higher activity level for the male than for the female patients. Overall, 24 months postsurgery 83% of the patients practiced sports in comparison with 79% prior to surgery. CONCLUSIONS: Following TKA, the patients were able to increase sports performance, while pain was reduced. Therefore, patients who want to continue their desired sports may safely consider TKA. LEVEL OF EVIDENCE: II. PMID- 28341880 TI - Long-term skeletal and dental effects of facemask versus chincup treatment in Class III patients : A retrospective study. AB - OBJECTIVES: To investigate the skeletal and dental changes during chincup versus facemask treatment, to compare the long-term effects of the two appliances, and to document the impact of each on treatment success. METHODS: In all, 61 patients with Class III syndrome were retrospectively analyzed at three examination times: 7.8 +/- 1.7 years of age (T0, pretreatment), 9.6 +/- 2.4 years of age (T1, posttreatment), and around 15-20 years later (T2, long-term follow-up). RESULTS: Significant changes of specific cephalometric parameters for all treatment times: T0-T1 (SNA, interbase and gonial angle, Bjork's sum angle, maxillomandibular differential, and distance of upper lip to esthetic line), T1-T2 (NL-NSL, SNB, mandibular-body length, effective mandibular length, and effective maxillary length), and T0-T2 (mandibular-body length, effective mandibular length, effective maxillary length, maxillomandibular differential, SNB, ANB, gonial angle, Bjork's sum angle, and Wits appraisal). The T1-T2 results illustrate that in both treatment groups the typical Class III growth pattern often reappeared after treatment, including gains in SNB angle, condylion-gnathion length, and gonion-menton distance. CONCLUSIONS: Either a facemask or a chincup may be effectively used to treat Class III malocclusion. There were differences in long term stability. Maxillary development was similarly favorable in both groups of patients with successful outcome. The subgroup in whom chincup treatment had failed were mainly characterized by excessive mandibular growth, or lack of maxillary catch-up growth, with deterioration of the maxillomandibular relationship notably in the initial phase of treatment. Early chincup treatment did not have an adverse impact on the temporomandibular joints. PMID- 28341879 TI - Intra-articular findings in symptomatic minor instability of the lateral elbow (SMILE). AB - PURPOSE: Lateral epicondylitis is generally considered an extra-articular condition. The role of minor instability in the aetiology of lateral elbow pain has rarely been considered. The aim of this study was to evaluate the correlation of lateral ligamentous laxity with aspects of intra-articular lateral elbow pathology and investigate the role of minor instability in lateral elbow pain. METHODS: Thirty-five consecutive patients aged between 20 and 60 years with recalcitrant lateral epicondylitis who had failed conservative therapy and had no previous trauma or overt instability, were included. The presence of three signs of lateral ligamentous patholaxity and five intra-articular findings were documented during arthroscopy. The relative incidence of each of these was calculated, and the correlation between patholaxity and intra-articular pathology was evaluated. RESULTS: At least one sign of lateral ligamentous laxity was observed in 48.6% of the studied cohort, and 85.7% demonstrated at least one intra-articular abnormal finding. Radial head ballottement was the most common sign of patholaxity (42.9%). Synovitis was the most common intra-articular aspect of pathology (77.1%), followed by lateral capitellar chondropathy (40.0%). A significant correlation was found between the presence of lateral ligamentous patholaxity signs and capitellar chondropathy (p = 0.0409), as well as anteromedial synovitis (p = 0.0408). CONCLUSIONS: Almost one half of patients suffering from recalcitrant lateral epicondylitis display signs of lateral ligamentous patholaxity, and over 85% demonstrate at least one intra-articular abnormality. The most frequent intra-articular findings are synovitis and lateral capitellar chondropathy, which correlate significantly with the presence of lateral ligamentous patholaxity. The fact that several patients demonstrated multiple intra-articular findings in relation to laxity provides support to a sequence of pathologic changes that may result from a symptomatic minor instability of the lateral elbow (SMILE) condition. LEVEL OF EVIDENCE: III. PMID- 28341881 TI - Birmingham vasculitis activity score at diagnosis is a significant predictor of relapse of polyarteritis nodosa. AB - The objective of this study was to investigate whether clinical and laboratory data, Birmingham vasculitis activity score (BVAS) and five factor scores (FFS) at diagnosis could predict relapse in 30 patients with polyarteritis nodosa (PAN) having the follow-up duration for over 12 months. We reviewed the medical charts of 30 patients with PAN. We obtained clinical and laboratory data at diagnosis, and we compared them between the two groups based on relapse. The optimal cut-off values of BVAS and FFS (1996) at diagnosis to predict relapse were extrapolated. The mean age of patients (15 men) was 50.8 years, and the mean follow-up duration was 64.1 months. Nine patients (30.0%) had experience relapse after remission. Patients having relapse showed the higher frequency of weight loss and ocular symptoms and the less frequency of diastolic hypertension than those having not (p < 0.005 for all). On multivariate logistic regression analysis, weight loss was the only independent predictor of relapse, but on Cox Hazard model analysis, its statistical significance disappeared. The mean initial BVAS and FFS (1996) of patients in relapse group were higher than those of patients in no relapse group (p < 0.005 for all). Patients having initial BVAS over 13.5 and FFS (1996) over 1 exhibited significantly higher risk of relapse than those having not (RR 40.0 and RR 7.0, respectively). However, initial BVAS over 13.5 only remained significant in Kaplan-Meier survival analysis. In conclusion, BVAS over 13.5 at diagnosis was the only independent predictor of relapse of PAN. PMID- 28341883 TI - Conformational dynamics play important roles upon the function of N acetylglutamate kinase. AB - N-acetylglutamate kinase (NAGK) catalyzes the phosphorylation of N acetylglutamate. In many bacteria, NAGK catalysis is the rate controlling step in the L-arginine biosynthesis pathway from glutamate to L-arginine and is allosterically inhibited by L-arginine. Many data show that conformational dynamics of NAGKs are essential for their function. The demonstration of the conformational mechanism provides a potential way to improve the yield of arginine. Due to the lack of NAGK catalysis step in arginine synthesis route of mammals, the elucidation of the dynamic mechanism can also provide a way to design a new antivirus drug. This paper reviews how the dynamics affect the activity of NAGKs and are controlled by the effectors. X-ray crystallography and modeling data have shown that in NAGKs, the structural elements required for inhibitor and substrate binding, catalysis and product release, are highly mobile. It is possible to eliminate the inhibition of the arginine and/or block the synthesis of arginine by disturbing the flexibility of the NAGKs. Amino acid kinase family is thought to share some common dynamic features; the flexible structural elements of NAGKs have been identified, but the details of the dynamics and the signal transfer pathways are yet to be elucidated. PMID- 28341882 TI - Lifetime allergic rhinitis prevalence among US primary farm operators: findings from the 2011 Farm and Ranch Safety survey. AB - PURPOSE: Allergic rhinitis is associated with decreased quality of life, and reduced workplace performance and productivity. This study investigated the prevalence of lifetime allergic rhinitis and factors associated with allergic rhinitis among US primary farm operators. METHODS: The 2011 Farm and Ranch Safety Survey data collected from 11,210 active farm operators were analyzed. Survey respondents were determined to have lifetime allergic rhinitis based on a "yes" response to the question: "Have you ever been told by a doctor, nurse, or other health professional that you had hay fever, seasonal allergies, or allergic rhinitis?" Data were weighted to produce nationally representative estimates. RESULTS: An estimated 30.8% of the 2.1 million active farm operators had lifetime allergic rhinitis in 2011. The allergic rhinitis prevalence varied by demographic and farm characteristics. Farm operators with allergic rhinitis were 1.38 (95% CI 1.22-1.56) times more likely to be exposed to pesticides compared with operators with no allergic rhinitis. The association with pesticide exposure for allergic rhinitis and current asthma, and allergic rhinitis alone was statistically significant and greater than that for current asthma alone. CONCLUSION: Certain groups of farm operators may be at increased risk of allergic rhinitis. Studies should further investigate the association of allergic rhinitis with specific pesticide exposure. PMID- 28341884 TI - Mitochondrial genome of the nematode endoparasitic fungus Hirsutella vermicola reveals a high level of synteny in the family Ophiocordycipitaceae. AB - Ophiocordycipitaceae is a diverse fungal family comprising multiple ecologically, economically, medicinally, and culturally important fungal species; however, only four species of the family have available mitochondrial genomes (mitogenomes). In this study, the complete mitogenome of the nematode endoparasitic fungus Hirsutella vermicola in Ophiocordycipitaceae was sequenced, and a comparative mitogenomic analysis of Ophiocordycipitaceae was performed. We found that the 53,793-bp circular mitogenome of H. vermicola, except for standard fungal mitochondrial genes, harbors seven introns acquired possibly through lateral transfer from other fungi and three free-standing open reading frames (ORFs) coding for hypothetical proteins. Phylogenetic analysis based on concatenated mitochondrial protein sequences confirmed its placement in Ophiocordycipitaceae. Comparison on five mitogenomes of Ophiocordycipitaceae revealed great variation on their sizes, from 35.2 kb in Tolypocladium ophioglossoides to 157.5 kb in Ophiocordyceps sinensis, mainly due to variable numbers of introns (from 7 to 54) as well as variable lengths of intergenic regions. The five mitogenomes, however, are highly syntenic to each other in terms of gene order, the presence of an intronic ORF encoding ribosomal protein S3 within rnl, and the nad2/nad3 joining pattern. Our study is the first report of the mitogenome of H. vermicola and has facilitated the understanding of mitogenome evolution of Ophiocordycipitaceae. PMID- 28341885 TI - Transcriptomic profiling and its implications for the H2 production of a non methanogen deficient in the frhAGB-encoding hydrogenase. AB - The F420-reducing hydrogenase of methanogens functions in methanogenesis by providing reduced coenzyme F420 (F420H2) as an electron donor. In non methanogens, however, their physiological function has not been identified yet. In this study, we constructed an DeltafrhA mutant, whose frhA gene encoding the hydrogenase alpha subunit was deleted, in the non-methanogenic Thermococcus onnurineus NA1 as a model organism. There was no significant difference in the formate-dependent growth between the mutant and the wild-type strains. Interestingly, the mutation in the frhA gene affected the expression of genes involved in various cellular functions such as H2 oxidation, chemotactic signal transduction, and carbon monoxide (CO) metabolism. Among these genes, the CO oxidation gene cluster, enabling CO-dependent growth and H2 production, showed a 2.8- to 7.0-fold upregulation by microarray-based whole transcriptome expression profiling. The levels of proteins produced by this gene cluster were also significantly increased not only under the formate condition but also under the CO condition. In a controlled bioreactor, where 100% CO was continuously fed, the DeltafrhA mutant exhibited significant increases in cell growth (2.8-fold) and H2 production (3.4-fold). These findings strongly imply that this hydrogenase is functional in non-methanogens and is related to various cellular metabolic processes through an unidentified mechanism. An understanding of the mechanism by which the frhA gene deletion affected the expression of other genes will provide insights that can be applied to the development of strategies for the enhancement of H2 production using CO as a substrate. PMID- 28341886 TI - Industrial robustness linked to the gluconolactonase from Zymomonas mobilis. AB - The physiological characteristics and the potential gluconolactone production of the gluconolactonase-deficient strain, Zymomonas mobilis ZM4 gnlDelta, were investigated via growth inhibitory assay and biotransformation of glucose and fructose into gluconolactone and sorbitol, respectively. The results of ethanol fermentation studies performed in the presence of high concentration of glucose (>200 g l-1) under fermentative or aerobic conditions indicated that a significant reduction of volumetric ethanol productivity from the strain of ZM4 gnlDelta was noticeable due to the reduced rates of specific growth, sugar uptake, and biomass yield as compared with those of the parental strain ZM4. The biotransformation prepared at pH 6.0 using the permeabilized cell indicated that gluconic acid from ZM4 gnlDelta was still produced as a major product (67 g l-1) together with sorbitol (65 g l-1) rather than gluconolactone after 24 h. Only small amount of gluconolactone was transiently overproduced up to 9 g l-1, but at the end of biotransformation, all gluconolactone were oxidized into gluconic acid. This indicated that autolysis of gluconolactone at the pH led to such results despite under gluconolactonase inactivation conditions. The physiological characteristics of ZM4 gnlDelta was further investigated under various stress conditions, including suboptimal pH (3.5~6.0), temperature (25~40 degrees C), and presence of growth inhibitory molecules including hydrogen peroxide, ethanol, acetic acid, furfural, and so forth. The results indicated that ZM4 gnlDelta was more susceptible at high glucose concentration, low pH of 3.5, and high temperature of 40 degrees C and in the presence of 4 mM H2O2 comparing with ZM4. Therefore, the results were evident that gluconolactonase in Z. mobilis contributed to industrial robustness and anti-stress regulation. PMID- 28341887 TI - Understanding the biological activity of high rate algae ponds through the calculation of oxygen balances. AB - Microalgae culture in high rate algae ponds (HRAP) is an environmentally friendly technology for wastewater treatment. However, for the implementation of these systems, a better understanding of the oxygenation potential and the influence of climate conditions is required. In this work, the rates of oxygen production, consumption, and exchange with the atmosphere were calculated under varying conditions of solar irradiance and dilution rate during six months of operation in a real scale unit. This analysis allowed determining the biological response of these dynamic systems. The rates of oxygen consumption measured were considerably higher than the values calculated based on the organic loading rate. The response to light intensity in terms of oxygen production in the bioreactor was described with one of the models proposed for microalgae culture in dense concentrations. This model is based on the availability of light inside the culture and the specific response of microalgae to this parameter. The specific response to solar radiation intensity showed a reasonable stability in spite of the fluctuations due to meteorological conditions. The methodology developed is a useful tool for optimization and prediction of the performance of these systems. PMID- 28341888 TI - The respiratory control of carbon dioxide in children and adolescents referred for treatment of psychogenic non-epileptic seizures. AB - Psychogenic non-epileptic seizures (PNES) are a common problem in paediatric neurology and psychiatry that can best be understood as atypical responses to threat. Threats activate the body for action by mediating increases in arousal, respiration, and motor readiness. In previous studies, a range of cardiac, endocrine, brain-based, attention-bias, and behavioral measures have been used to demonstrate increases in arousal, vigilance, and motor readiness in patients with PNES. The current study uses respiratory measures to assess both the motor readiness of the respiratory system and the respiratory regulation of CO2. Baseline respiratory rates during clinical assessment and arterial CO2 levels during the hyperventilation component of routine video electroencephalogram were documented in 60 children and adolescents referred for treatment of PNES and in 50 controls. Patients showed elevated baseline respiratory rates [t(78) = 3.34, p = .001], with 36/52 (69%) of patients [vs. 11/28 (39%) controls] falling above the 75th percentile (chi 2 = 6.7343; df = 1; p = .009). Twenty-eight (47%) of patients [vs. 4/50 (8%) controls] showed a skewed hyperventilation-challenge profile-baseline PCO2 <36 mmHg, a trough PCO2 <= 20 mmHg, or a final PCO2 <36 mmHg after 15 min of recovery-signaling difficulties with CO2 regulation (chi 2 = 19.77; df = 1; p < .001). Children and adolescents with PNES present in a state of readiness-for-action characterized by high arousal coupled with activation of the respiratory motor system, increases in ventilation, and a hyperventilation challenge profile shifted downward from homeostatic range. Breathing interventions that target arousal, decrease respiratory rate, and normalize ventilation and arterial CO2 may help patients shift brain-body state and avert PNES episodes. PMID- 28341890 TI - Syndemic Conditions Reinforcing Disparities in HIV and Other STIs in an Urban Sample of Behaviorally Bisexual Latino Men. AB - Syndemics research has made great contributions to understanding sexual risk among Latino men who have sex with men. However, such work often combines data for behaviorally bisexual men with data for men with exclusively same-sex partners. Using cross-sectional data from 148 behaviorally bisexual Latino men, this study explored the impact of syndemic factors-polydrug use, childhood sexual abuse, and depression-on sexual risk behaviors and STI incidence. Approximately one-third of participants reported polydrug use, 22% reported childhood sexual abuse, and 26% screened for clinically significant depressive symptoms. An increase in syndemic factors was associated with increased odds of lifetime STI incidence and condomless receptive anal intercourse with men; however, the model did not predict condomless insertive anal intercourse with men or condomless vaginal intercourse. More efforts are needed to explore the varying mechanisms, including but not restricted to the combined impact of syndemic conditions, that influence sexual risk in this population. PMID- 28341891 TI - Homecoming of Citizen Soldiers: Postdeployment Problems and Service Use Among Army National Guard Soldiers. AB - The present study described the types and amount of problems and services sought among returned deployed Army National Guard soldiers (4568 soldiers in 50 units). The study responds to gaps in the research literature to better understand community intervention needs of reservists. About half (48%) of the soldiers reported one or two problems, mostly those of psychological well-being, such as feelings of anger and frustration, upsetting memories, and troubled sleep (34% of the study sample), followed by problems of social support (18%), alcohol use (17%), feelings of isolation including suicidal thoughts (13%), and financial difficulties (11%). Having engaged in direct combat and having wounded or killed someone showed positive relationships with reported problems. One-third (35%) of soldiers who reported having used services went to one service and, generally, soldiers went to services related to their expressed problems. Variance in self reported problems explained by service use was low, suggesting unsought postdeployment services. PMID- 28341889 TI - Complement regulation and kidney diseases: recent knowledge of the double-edged roles of complement activation in nephrology. AB - The complement activation system plays important roles to maintain homeostasis in the host and to fight foreign invaders to protect the host. Therefore, the complement system is considered a core part of innate immunity which also cross talks to acquired immunity. In the history of nephrology, the complement system is familiar to us, because complement protein or fragment deposition, including C3, C4, C1q, and/or C4d, is routinely estimated by immunohistochemistry to diagnose renal pathologies. The relationships between pathological mechanisms and complement activation have been investigated for renal diseases such as post infectious glomerulonephritis, lupus nephritis, and primary membranoproliferative glomerulonephritis, which are usually accompanied by hypocomplementemia. However, unregulated complement activation in local areas might be associated with progression of various renal injuries even in the normocomplementemic patient. Recently, attention has focused on dysfunction of complement regulation in various diseases including renal diseases such as atypical hemolytic uremic syndrome and C3 glomerulopathy. Some mechanisms associated with complement activation in these diseases were clarified. In addition, lots of anti-complement agents were developed and some of the agents have become clinically available. Now, anti-complement therapies represent a realistic choice of therapeutic approaches for complement-related diseases. Research on roles of complement activation is proceeding into new stages in the field of nephrology and in other fields involving both basic and clinical research. We herein summarize relationships between the complement activation and regulation systems, their physiological effects and roles in maintenance of homeostasis in the host, and how dysregulation of the complement system triggers disease, especially renal disease. PMID- 28341892 TI - Aquaporin 4 Forms a Macromolecular Complex with Glutamate Transporter 1 and Mu Opioid Receptor in Astrocytes and Participates in Morphine Dependence. AB - The water channel aquaporin 4 (AQP4) is abundantly expressed in astrocytes and provides a mechanism by which water permeability of the plasma membrane can be regulated. Evidence suggests that AQP4 is associated with glutamate transporter-1 (GLT-1) for glutamate clearance and contributes to morphine dependence. Previous studies show that AQP4 deficiency changed the mu opioid receptor expression and opioid receptors' characteristics as well. In this study, we focused on whether AQP4 could form macromolecular complex with GLT-1 and mu opioid receptor (MOR) and participates in morphine dependence. By using immunofluorescence staining, fluorescence resonance energy transfer, and co-immunoprecipitation, we demonstrated that AQP4 forms protein complexes with GLT-1 and MOR in both brain tissue and primary cultured astrocytes. We then showed that the C-terminus of AQP4 containing the amino acid residues 252 to 323 is the site of interaction with GLT-1. Protein kinase C, activated by morphine, played an important role in regulating the expression of these proteins. These findings may help to reveal the mechanism that AQP4, GLT-1, and MOR form protein complex and participate in morphine dependence, and deeply understand the reason that AQP4 deficiency maintains extracellular glutamate homeostasis and attenuates morphine dependence, moreover emphasizes the function of astrocyte in morphine dependence. PMID- 28341895 TI - Capsule Commentary on Egede et al., Telephone-Delivered Behavioral Skills Intervention for African American Adults with Type 2 Diabetes: A Randomized Controlled Trial. PMID- 28341893 TI - Single-Prolonged-Stress-Induced Changes in Autophagy-Related Proteins Beclin-1, LC3, and p62 in the Medial Prefrontal Cortex of Rats with Post-traumatic Stress Disorder. AB - Autophagy, or type II programmed cell death, plays a crucial role in many nervous system diseases. However, few studies have examined the role of autophagy in post traumatic stress disorder (PTSD), and the mechanisms underlying PTSD are poorly understood. The objective of this research was to explore the expression of three important autophagy-related proteins, Beclin-1, microtubule-associated protein 1 light chain 3 (LC3), and p62/SQSTM1 (p62), in the medial prefrontal cortex (mPFC) of an animal model of PTSD to identify changes in autophagic activity during PTSD pathogenesis. PTSD was induced in rats by exposure to a single-prolonged stress (SPS). The Morris water maze was used to assess cognitive changes in rats from the SPS and control groups. Transmission electron microscopy (TEM) was employed to observe mPFC morphological changes. Immunohistochemistry, immunofluorescence, and Western blotting techniques were used to detect expression of Beclin-1, LC3, and p62 in the mPFC. The Morris water maze test results showed that the escape latency time was increased and that the percent time in the target quadrant was decreased in the SPS group compared with that in the control group. Numerous visible autolysosomes in mPFC neurons were observed using TEM after SPS stimulation. Compared with that in the control group, the expression of Beclin-1 and the LC3-II/I ratio significantly decreased at 1 day, then increased and peaked at 7 days, and slightly decreased at 14 days after SPS stimulation, whereas the converse was found for p62 expression. In conclusion, dysregulation of autophagic activity in the mPFC may play a crucial role in PTSD pathogenesis. PMID- 28341894 TI - Using a Self-Reported Global Health Measure to Identify Patients at High Risk for Future Healthcare Utilization. AB - BACKGROUND: Research studies have shown that patient-reported outcome measures (PROMs) that assess global health are helpful for predicting health care utilization, but less evidence exists that collection of PROMs in routine care can identify patients with high health care needs. OBJECTIVE: To investigate the association between the PROMIS Global Health (PGH) scores and subsequent health care utilization among patients in a large accountable care organization (ACO). DESIGN: Retrospective cohort study of individuals in the Partners HealthCare ACO who completed at least one PGH during a primary care visit. PARTICIPANTS: A total of 2639 individuals who completed at least one PGH and who also had 12 months of ACO membership and/or claims data prior to the PROM completion and at least one month of claims data post-PGH completion. MAIN MEASURES: The main outcomes were the rates of emergency department (ED) visits and hospitalizations by quartile of PGH physical and mental health scores. We also compared the predictive accuracy of administrative data models with and without the PGH scores to identify the highest utilizers. KEY RESULTS: The group with the worst (lowest) physical and mental health scores had significantly higher rates of hospitalization (RR 5.14, 95% CI 2.37, 11.15; and 2.27, 95% CI 1.06, 4.85, respectively) than those with higher scores. After adjustment for demographic and clinical factors, only the group with lower physical health scores had higher rates of hospitalization (RR 3.15, 95% CI 1.30, 7.90). The addition of the physical health subscore to administrative data increased the sensitivity to detect the top 5% of hospital utilizers compared with administrative data alone (44.0% vs. 36.0% respectively). CONCLUSIONS: Worse self-reported physical health, measured during routine primary care, is associated with significantly higher rates of hospitalization. It is not associated with increased rates of ED visits. Self-reported physical health modestly increases the sensitivity to detect the highest hospital utilizers. PMID- 28341896 TI - Role of conservative management in tubercular abdominal cocoon: a case series. AB - BACKGROUND: Sclerosing encapsulating peritonitis (Abdominal cocoon) is an uncommon cause of intestinal obstruction and tuberculosis is an important etiology. Appropriate management of this entity is still uncertain. METHODS: We did a retrospective analysis of patients with abdominal cocoon who were seen over a two year period at a tertiary care center in North India. We included patients with tubercular abdominal cocoon (TAC) who were managed primarily with antitubercular therapy in the present report. The diagnosis of TAC was made using combination of criteria (radiological or surgical findings of cocoon with evidence of tuberculosis in form of microbiological, histological or biochemical evidence). The clinical presentation, outcome and need for surgery for these patients were retrieved from the records of these cases maintained in a database. RESULTS: Of 18 patients with abdominal cocoon, 15 patients had underlying tuberculosis. The median age was 28 years (interquartile range 24) and 12 (80%) were males. Three patients had confirmed tuberculosis on basis of microbiological evidence. All had abdominal pain for 1-9 months, and 11 had intestinal obstruction. Twelve patients had positive Mantoux test, none had HIV. Pulmonary tuberculosis was noted in four patients, pleural in five, splenic and intestinal in two each, hepatic and mediastinal lymph-nodal in one each. Thirteen patients were started on usual 4-drug anti-tubercular therapy (ATT) while two cirrhotics needed modified ATT. Three patients were on steroids with ATT and all three improved. One patient was lost to follow up. Of the rest 14 patients, 2 underwent surgery, 1 at initial presentation while another after 4 months of ATT. Overall five patients developed intestinal obstruction while on ATT, one needed surgery and one died of liver failure while others improved with conservative means. CONCLUSION: TAC can be managed conservatively in a subset of patients. PMID- 28341897 TI - Researcher readiness for participating in community-engaged dissemination and implementation research: a conceptual framework of core competencies. AB - Participating in community-engaged dissemination and implementation (CEDI) research is challenging for a variety of reasons. Currently, there is not specific guidance or a tool available for researchers to assess their readiness to conduct CEDI research. We propose a conceptual framework that identifies detailed competencies for researchers participating in CEDI and maps these competencies to domains. The framework is a necessary step toward developing a CEDI research readiness survey that measures a researcher's attitudes, willingness, and self-reported ability for acquiring the knowledge and performing the behaviors necessary for effective community engagement. The conceptual framework for CEDI competencies was developed by a team of eight faculty and staff affiliated with a university's Clinical and Translational Science Award (CTSA). The authors developed CEDI competencies by identifying the attitudes, knowledge, and behaviors necessary for carrying out commonly accepted CE principles. After collectively developing an initial list of competencies, team members individually mapped each competency to a single domain that provided the best fit. Following the individual mapping, the group held two sessions in which the sorting preferences were shared and discrepancies were discussed until consensus was reached. During this discussion, modifications to wording of competencies and domains were made as needed. The team then engaged five community stakeholders to review and modify the competencies and domains. The CEDI framework consists of 40 competencies organized into nine domains: perceived value of CE in D&I research, introspection and openness, knowledge of community characteristics, appreciation for stakeholder's experience with and attitudes toward research, preparing the partnership for collaborative decision-making, collaborative planning for the research design and goals, communication effectiveness, equitable distribution of resources and credit, and sustaining the partnership. Delineation of CEDI competencies advances the broader CE principles and D&I research goals found in the literature and facilitates development of readiness assessments tied to specific training resources for researchers interested in conducting CEDI research. PMID- 28341898 TI - Functional block of IL-17 cytokine promotes bone healing by augmenting FOXO1 and ATF4 activity in cortical bone defect model. AB - : We determine the effect of interleukin (IL)-17 neutralizing antibody on new bone regeneration. Anti-IL-17 antibody promoted new bone regeneration in cortical bone defect model by augmenting FOXO1 and ATF4 activity thereby decreasing oxidative stress. Our study demonstrates the bone healing and regeneration potential of neutralizing IL-17antibody in osteoporotic fractures. INTRODUCTION: The immune system plays important role in the fracture healing process. However, fracture healing is prolonged in disorders associated with systemic inflammation. Fracture healing is decelerated in osteoporosis, condition linked with systemic inflammation. Bone regeneration therapies like recombinant human BMP2 are associated with serious side effects. Studies have been carried out where agents like denosumab and infliximab enhance bone regeneration in osteoporotic conditions. Our previous studies show the osteoprotective and immunoprotective effects of neutralizing IL-17 antibody. Here, we determine the effect of IL-17 neutralizing antibody on new bone regeneration and compare its efficacy with known osteoporotic therapies. METHODS: For the study, female BALB/c mice were ovariectomized or sham operated and left for a month followed by a 0.6-mm drill hole injury in femur mid-diaphysis. The treatment was commenced next day onwards with anti-IL-17, anti-RANKL (Receptor activator of nuclear factor kappa-B ligand), parathyroid hormone (PTH), or alendronate for a period of 3, 10, or 21 days. Animals were then autopsied, and femur bones were dissected out for micro CT scanning, confocal microscopy, and gene and protein expression studies. RESULTS: Micro-CT analysis showed that anti-IL-17 antibody promoted bone healing at days 10 and 21, and the healing effect observed was significantly better than Ovx, anti-RANKL antibody, and ALN, and equal to PTH. Anti-IL-17 also enhanced new bone regeneration as assessed by calcein-labeling studies. Additionally, anti-IL 17 therapy enhanced expression of osteogenic markers and decreased oxidative stress at the injury site. CONCLUSION: Overall, our study demonstrates bone healing and regeneration potential of neutralizing IL-17 antibody in osteoporotic fractures. PMID- 28341899 TI - Cortical microstructure compensates for smaller bone size in young Caribbean Hispanic versus non-Hispanic white men. AB - : Hispanic men have smaller bone size but thicker and denser cortices compared to white men, leading to similar mechanical competence. INTRODUCTION: The purpose of this study was to assess differences in vBMD and microarchitecture in young Caribbean Hispanic (n = 30) and non-Hispanic Caucasian (n = 30) men. METHODS: We measured areal bone mineral density (aBMD) at the spine, total hip (TH), femoral neck (FN), and forearm by dual-energy X-ray absorptiometry (DXA) and bone geometry, mass, microarchitecture, and mechanical competence by high-resolution peripheral quantitative computed tomography (HRpQCT), individual trabecula segmentation (ITS), and finite element analysis (FEA). RESULTS: Hispanic men were slightly older, shorter, and heavier and had higher BMI compared with white men. aBMD, measured by DXA, did not differ at the spine, TH, or forearm before or after adjustment for age, height, weight, and the interaction of height and weight. At the FN, marginally significant higher BMD in Hispanics prior to adjustment was attenuated and no longer differed after adjustment for covariates. Adjusted HRpQCT indices indicated smaller total and trabecular area at the radius but greater total volumetric density and cortical thickness in Hispanic versus white men. The adjusted difference in cortical density at the radius was of borderline significance. Trabecular and ITS microstructure tended not to differ at the radius. At the tibia, results were similar. Bone size tended to be smaller and covariate-adjusted cortical density and cortical thickness were greater in Hispanic versus white men. Additionally, cortical porosity was lower at the tibia in Hispanic compared to white men. Stiffness and failure load did not differ at either skeletal site by ethnicity. CONCLUSION: In conclusion, greater cortical thickness and density as well as lower cortical porosity tend to compensate for smaller bone size in Hispanic men, leading to similar mechanical competence compared with white men. PMID- 28341900 TI - Tumor-induced osteomalacia: experience from a South American academic center. AB - : The majority of tumor-induced osteomalacia cases have been reported in the Northern Hemisphere and Asia. In this first series of South American patients, we show that the clinical presentation and sensitivity of plasmatic fibroblast growth factor 23 and somatostatin analog-based imaging are similar to those described in other populations. INTRODUCTION: Describe the experience of clinical presentation, diagnostic study, and treatment of patients with tumor-induced osteomalacia (TIO) in a South American academic center in comparison to literature. METHODS: Analysis of the records of patients diagnosed with TIO. The clinical presentation, diagnostic studies, and treatment were analyzed. Fibroblast growth factor 23 (FGF23) was measured by ELISA. RESULTS: Six patients were diagnosed with TIO during the studied period. The patients' median age was 53 years (range 22-64). All patients presented with weakness and pain in the extremities. Four experienced fractures during their evolution. The median time to diagnosis was 4.5 years (1-20). Biochemical studies showed hypophosphatemia, median of 1.4 mg/dL (1.2-1.6), with low maximum rates of tubular reabsorption of phosphate adjusted for glomerular filtration rate. FGF23 was elevated in 4/6 patients and inappropriately normal in the other two. In three patients, the location of the tumor was clinically evident and confirmed with anatomical imaging. In the remaining patients, two tumors were located with 68Ga DOTATATE PET/CT and one with OctreoScan. The causal tumors were located in the lower extremities in five patients and invading the frontal sinus in one patient. In all patients, tumors were successfully removed. Within 14 days, there was normalization of phosphate and FGF23 levels and resolution of clinical symptoms in all patients. In all cases, the histopathology was compatible with a phosphaturic mesenchymal tumor. CONCLUSIONS: The clinical presentation, delay time to diagnosis, FGF23 diagnostic sensitivity and histopathology in this first series of South American patients is similar to those described in other populations. The success of localization by somatostatin analog-based imaging, suggests this may the optimal imaging modality. PMID- 28341901 TI - Hypoplastic Left Heart Syndrome is not Associated with Worse Clinical or Neurodevelopmental Outcomes Than Other Cardiac Pathologies After the Norwood-Sano Operation. AB - There is evidence to suggest that patients undergoing a Norwood for non-HLHS anatomy may have lower mortality than classic HLHS, but differences in neurodevelopmental outcome have not been assessed. Our objective was to compare survival and neurodevelopmental outcome during the same surgical era in a large, well-described cohort. All subjects who underwent a Norwood-Sano operation between 2005 and 2014 were included. Follow-up clinical, neurological, and developmental data were obtained from the Western Canadian Complex Pediatric Therapies Follow-up Program database. Developmental outcomes were assessed at 2 years of age using the Bayley Scales of Infant and Toddler Development (Bayley III). Survival was assessed using Kaplan-Meier analysis. Baseline characteristics, survival, and neurodevelopmental outcomes were compared between those with HLHS and those with non-HLHS anatomy (non-HLHS). The study comprised 126 infants (75 male), 87 of whom had HLHS. Five-year survival was the same for subjects with HLHS and those with non-HLHS (HLHS 71.8%, non-HLHS 76.9%; p = 0.592). Ninety-three patients underwent neurodevelopmental assessment including Bayley-III scores. The overall mean cognitive composite score was 91.5 (SD 14.6), language score was 86.6 (SD 16.7) and overall mean motor composite score was 85.8 (SD 14.5); being lower than the American normative population mean score of 100 (SD 15) for each (p-value for each comparison, <0.0001). None of the cognitive, language, or motor scores differed between those with HLHS and non-HLHS (all p > 0.05). In the generalized linear models, dominant right ventricle anatomy (present in 117 (93%) of patients) was predictive of lower language and motor scores. Comparative analysis of the HLHS and non-HLHS groups undergoing single ventricle palliation including a Norwood-Sano, during the same era, showed comparable 2-year survival and neurodevelopmental outcomes. PMID- 28341903 TI - Exercise increases lactoferrin, but decreases lysozyme in salivary granulocytes. AB - INTRODUCTION: Intracellular lactoferrin (Lac) and lysozyme (Lys) content play an important role in regulating inflammation and promoting host protection. While exercise has demonstrated an increase in Lac and Lys concentration in exocrine solutions, little is known regarding intracellular concentration changes in response to exercise. PURPOSE: To quantify intracellular Lac and Lys concentration before and after exercise in salivary CD45+CD15+ cells. METHODS: 11 males (20.3 +/- 0.8 years, 57.2 +/- 7.6 mL/kg/min VO2pk, 11.1 +/- 3.9% body fat) ran for 45 min at 75% of VO2pk. 12 mL of stimulated saliva were collected pre and immediately post exercise. Saliva was filtered through a 30-um filter before analysis of leukocytes (CD45+) and granulocytes (CD45+CD15+) using flow cytometry. RESULTS: Median fluorescent intensity (MFI) of Lac increased from pre (64,268 +/- 46,036 MFI) to post (117,134 +/- 88,115 MFI) exercise (p <0.05). Lys MFI decreased with exercise (pre: 16,933 +/- 8249; post: 11,616 +/- 6875) (p <0.05). CONCLUSION: Acute running resulted in an increased Lac concentration which could lead to a decrease in inflammation, adding further evidence of the anti-inflammatory effects of exercise. Conversely, the exercise-associated decrease of intracellular Lys content could be the cause of increased Lys in exocrine solutions. PMID- 28341904 TI - Association between cultural distance and migrant self-rated health. AB - We study whether migrant health in Europe is associated with the cultural distance between their host country and country of origin. To this end, we run multilevel regression models on data merging self-rated health and social background of >=3800 migrants from the European Social Survey with an index of cultural distance based on country differences in values, norms and attitudes measured in the World Values Survey. We find that higher levels of cultural distance are associated with worse migrant health. This association is comparable in size with the negative association between health and female (compared with male) gender but less important than the association between health and education level. In addition, this association is less significant among second-generation than first-generation migrants. PMID- 28341902 TI - Red Flags for Maltese Adults with Congenital Heart Disease: Poorer Dental Care and Less Sports Participation Compared to Other European Patients-An APPROACH-IS Substudy. AB - Studies in recent years have explored lifestyle habits and health-risk behaviours in adult congenital heart disease (ACHD) patients when compared to controls. The aim of this study was to investigate differences in lifestyle habits between Maltese and other European ACHD patients. Data on alcohol consumption, cigarette smoking, substance misuse, dental care and physical activity collected in 2013 2015 during "Assessment of Patterns of Patient-Reported Outcomes in Adults with Congenital Heart disease-International Study" (APPROACH-IS) were analysed. Responses from 119 Maltese participants were compared to those of 1616 participants from Belgium, France, Italy, Norway, Sweden, Switzerland and the Netherlands. Significantly fewer Maltese patients with simple (Maltese 84.1% vs. European 97.5%, p < 0.001) and moderately complex CHD (Maltese 83.6% vs. European 97.4%, p < 0.001) brushed their teeth daily. Only 67.2% of Maltese with moderately complex disease had dental reviews in the previous year compared to 80.3% of Europeans (p = 0.02). Maltese patients with simple (Maltese 31.8% vs. European 56.1%, p = 0.002) and moderately complex lesions (Maltese 30.0% vs. European 59.2%, p < 0.001) performed less regular sport activities. Comparison by country showed Maltese patients to have significantly poorer tooth brushing and sports participation than patients from any other participating country. Alcohol consumption, cigarette smoking and substance misuse were not significantly different. This study highlights lifestyle aspects that Maltese ACHD patients need to improve on, which might not be evident upon comparing patients to non-CHD controls. These findings should also caution researchers against considering behaviours among patients in one country as necessarily representative of patients on the larger scale. PMID- 28341905 TI - Emotions and scope effects in the monetary valuation of health. AB - This study presents evidence on the role of emotions in the monetary evaluation of health technologies, namely, drug-eluting stents (DES) in our case. It is shown that subjects who are very afraid of having to undergo an angioplasty are: (a) less sensitive to the size of the risk reduction provided by DES and (b) willing to pay more. The lack of scope sensitivity questions the normative validity of the responses of highly emotional subjects. We provide evidence of this effect using what we call the cognitive-emotional random utility model and the responses of a face-to-face, computer-assisted personal interview survey conducted in a representative sample of the Spanish general population (n = 1663). PMID- 28341906 TI - South Brazilian wines: culturable yeasts associated to bottled wines produced in Rio Grande do Sul and Santa Catarina. AB - A comprehensive understanding of the presence and role of yeasts in bottled wines helps to know and control the organoleptic quality of the final product. The South Region of Brazil is an important wine producer, and the state of "Rio Grande do Sul" (RS) accounts for 90% of Brazilian wines. The state of "Santa Catarina" (SC) started the production in 1975, and is currently the fifth Brazilian producer. As there is little information about yeasts present in Brazilian wines, our main objective was to assess the composition of culturable yeasts associated to bottled wines produced in RS and SC, South of Brazil. We sampled 20 RS and 29 SC bottled wines produced between 2003 and 2011, and we isolated culturable yeasts in non-selective agar plates. We identified all isolates by sequencing of the D1/D2 domain of LSU rDNA or ITS1-5.8 S-ITS2 region, and comparison with type strain sequences deposited in GenBank database. Six yeast species were shared in the final product in both regions. We obtained two spoilage yeast profiles: RS with Zygosaccharomyces bailii and Pichia membranifaciens (Dekkera bruxellensis was found only in specific table wines); and SC with Dekkera bruxellensis and Pichia manshurica. Knowledge concerning the different spoilage profiles is important for winemaking practices in both regions. PMID- 28341908 TI - Lactic acid production from submerged fermentation of broken rice using undefined mixed culture. AB - The present work aimed to characterize and optimize the submerged fermentation of broken rice for lactic acid (LA) production using undefined mixed culture from dewatered activated sludge. A microorganism with amylolytic activity, which also produces LA, Lactobacillus amylovorus, was used as a control to assess the extent of mixed culture on LA yield. Three level full factorial designs were performed to optimize and define the influence of fermentation temperature (20-50 degrees C), gelatinization time (30-60 min) and broken rice concentration in culture medium (40-80 g L-1) on LA production in pure and undefined mixed culture. LA production in mixed culture (9.76 g L-1) increased in sixfold respect to pure culture in optimal assessed experimental conditions. The optimal conditions for maximizing LA yield in mixed culture bioprocess were 31 degrees C temperature, 45 min gelatinization time and 79 g L-1 broken rice concentration in culture medium. This study demonstrated the positive effect of undefined mixed culture from dewatered activated sludge to produce LA from culture medium formulated with broken rice. In addition, this work establishes the basis for an efficient and low-cost bioprocess to manufacture LA from this booming agro-industrial by product. PMID- 28341907 TI - Utilization of inulin-containing waste in industrial fermentations to produce biofuels and bio-based chemicals. AB - Inulins are polysaccharides that belong to an important class of carbohydrates known as fructans and are used by many plants as a means of storing energy. Inulins contain 20 to several thousand fructose units joined by beta-2,1 glycosidic bonds, typically with a terminal glucose unit. Plants with high concentrations of inulin include: agave, asparagus, coffee, chicory, dahlia, dandelion, garlic, globe artichoke, Jerusalem artichoke, jicama, onion, wild yam, and yacon. To utilize inulin as its carbon and energy source directly, a microorganism requires an extracellular inulinase to hydrolyze the glycosidic bonds to release fermentable monosaccharides. Inulinase is produced by many microorganisms, including species of Aspergillus, Kluyveromyces, Penicillium, and Pseudomonas. We review various inulinase-producing microorganisms and inulin feedstocks with potential for industrial application as well as biotechnological efforts underway to develop sustainable practices for the disposal of residues from processing inulin-containing crops. A multi-stage biorefinery concept is proposed to convert cellulosic and inulin-containing waste produced at crop processing operations to valuable biofuels and bioproducts using Kluyveromyces marxianus, Yarrowia lipolytica, Rhodotorula glutinis, and Saccharomyces cerevisiae as well as thermochemical treatments. PMID- 28341909 TI - Metagenomic analyses of bacterial endophytes associated with the phyllosphere of a Bt maize cultivar and its isogenic parental line from South Africa. AB - Genetic modification of maize with Bacillus thuringiensis (Bt) cry proteins may predispose shifts in the bacterial endophytes' community associated with maize shoots. In this study, the diversity of bacterial endophytes associated with a Bt maize genotype (Mon810) and its isogenic non-transgenic parental line were investigated at pre-flowering (50 days) and post-flowering (90 days) developmental stages. PCR-DGGE and high throughput sequencing on the Illumina MiSeq sequencer were used to characterize bacterial 16S rRNA gene diversity in leaves, stems, seeds and tassels. PCR-DGGE profile revealed similarity as well as differences between bacterial communities of shoots in both cultivars and at both developmental stages. A total of 1771 operational taxonomic units (OTUs) were obtained from the MiSeq and assigned into 14 phyla, 27 classes, 58 orders, 116 families and 247 genera. Differences in alpha and beta diversity measures of OTUs between the phyllospheres of both genotypes were not significant (P > .05) at all developmental stages. In all cultivars, OTU diversity reduced with plant development. OTUs belonging to the phyla Proteobacteria were dominant in all maize phyllospheres. The class Gammaproteobacteria was dominant in Bt maize while, Alphaproteobacteria and Actinobacteria were dominant in non-Bt maize phyllospheres. Differences in the abundance of some genera, including Acidovorax, Burkerholderia, Brachybacterium, Enterobacter and Rhodococcus, whose species are known beneficial endophytes were observed between cultivars. Hierarchical cluster analysis further suggests that the bacterial endophyte communities of both maize genotypes associate differently (are dissimilar). Overall, the results suggest that bacterial endophytes community differed more across developmental stages than between maize genotypes. PMID- 28341910 TI - Effectiveness and Cost-benefit Evaluation of a Comprehensive Workers' Health Surveillance Program for Sustainable Employability of Meat Processing Workers. AB - Objective To evaluate the effectiveness of a comprehensive workers' health surveillance (WHS) program on aspects of sustainable employability and cost benefit. Methods A cluster randomized stepped wedge trial was performed in a Dutch meat processing company from february 2012 until march 2015. In total 305 workers participated in the trial. Outcomes were retrieved during a WHS program, by multiple questionnaires, and from company registries. Primary outcomes were sickness absence, work ability, and productivity. Secondary outcomes were health, vitality, and psychosocial workload. Data were analyzed with linear and logistic multilevel models. Cost-benefit analyses from the employer's perspective were performed as well. Results Primary outcomes sickness absence (OR = 1.40), work ability (B = -0.63) and productivity (OR = 0.71) were better in the control condition. Secondary outcomes did not or minimally differ between conditions. Of the 12 secondary outcomes, the only outcome that scored better in the experimental condition was meaning of work (B = 0.18). Controlling for confounders did not or minimally change the results. However, our stepped wedge design did not enable adjustment for confounding in the last two periods of the trial. The WHS program resulted in higher costs for the employer on the short and middle term. Conclusions Primary outcomes did not improve after program implementation and secondary outcomes remained equal after implementation. The program was not cost-beneficial after 1-3 year follow-up. Main limitation that may have contributed to absence of positive effects may be program failure, because interventions were not deployed as intended. PMID- 28341912 TI - Ralstonia eutropha as a biocatalyst for desulfurization of dibenzothiophene. AB - The potential of Ralstonia eutropha as a biocatalyst for desulfurization of dibenzothiophene (DBT) was studied in growing and resting cell conditions. The results of both conditions showed that sulfur was removed from DBT which accompanied by the formation of 2-hydroxybiphenyl (2-HBP). In growing cell experiments, glucose was used as an energy supplying substrate in initial concentrations of 55 mM (energy-limited) and 111 mM (energy-sufficient). The growing cell behaviors were quantitatively described using the logistic equation and maintenance concept. The results indicated that 2-HBP production was higher for the energy-sufficient cultures, while the values of the specific growth rate and the maintenance coefficient for these media were lower than those of the energy-limited cultures. Additionally, the kinetic studies showed that the half saturation constant for the energy-limited cultures was 2 times higher than the energy-sufficient ones where the inhibition constant (0.08 mM) and the maximum specific DBT desulfurization rate (0.002 mmol gcell-1 h-1) were almost constant. By defining desulfurizing capacity (D DBT) including both the biomass concentration and time to reach a particular percentage of DBT conversion, the best condition for desulfurizing cell was determined at 23% gcell L-1 h-1 which corresponded with the resting cells that were harvested at the mid-exponential growth phase. PMID- 28341911 TI - Nutlin-3, an Antagonist of MDM2, Enhances the Radiosensitivity of Esophageal Squamous Cancer with Wild-Type p53. AB - Murine double minute 2 (MDM2) negatively regulates the activity of the p53 protein and plays a vital role in cell cycle arrest, apoptosis, and senescence mediated by p53. Nutlin-3, an antagonist of MDM2, is frequently used in anti cancer studies. In many human tumors, nutlin-3 stabilizes p53 status and enhances p53 expression in cells with wild-type p53. However, the effect of nutlin-3 combined with radiotherapy on esophageal squamous cancer (ESCC) has not been reported. In this study, we examined whether nutlin-3 increases the radiosensitivity of ESCC in vitro and in vivo.We chose two cell lines, ECA-109 (wild-type p53) and TE-13 (p53 mutated), for the following experiments. Cell proliferation and clonogenic survival experiments showed that nutlin-3 inhibits the cell growth and colony formation of ECA-109 cells in a dose-dependent manner. Flow cytometry analysis showed that the apoptosis rate of ECA-109 cells co treated with nutlin-3 and irradiation(IR) was significantly increased compared with cells treated with irradiation or nutlin-3 alone. Western blotting detected the expression of apoptosis-associated proteins in ECA-109 cells in response to nutlin-3 and irradiation. These effects were not evident in TE-13 cells. Xenograft mouse models indicated that nutlin-3 suppresses tumor growth and promotes radiosensitivity in the ESCC cell line ECA-109 in vivo. We have demonstrated that co-treatment of nutlin-3 with irradiation can significantly inhibit the growth and improve the radiosensitivity of ESCC cells with wild-type p53. The study suggests that nutlin-3 may be a potent therapeutic agent in conjunction with radiotherapy in ESCC. PMID- 28341913 TI - Medium-chain-length poly-3-hydroxyalkanoates-carbon nanotubes composite anode enhances the performance of microbial fuel cell. AB - Insufficient power generation from a microbial fuel cell (MFC) hampers its progress towards utility-scale development. Electrode modification with biopolymeric materials could potentially address this issue. In this study, medium-chain-length poly-3-hydroxyalkanoates (PHA)/carbon nanotubes (C) composite (CPHA) was successfully applied to modify the surface of carbon cloth (CC) anode in MFC. Characterization of the functional groups on the anodic surface and its morphology was carried out. The CC-CPHA composite anode recorded maximum power density of 254 mW/m2, which was 15-53% higher than the MFC operated with CC-C (214 mW/m2) and pristine CC (119 mW/m2) as the anode in a double-chambered MFC operated with Escherichia coli as the biocatalyst. Electrochemical impedance spectroscopy and cyclic voltammetry showed that power enhancement was attributed to better electron transfer capability by the bacteria for the MFC setup with CC CPHA anode. PMID- 28341914 TI - The Injury Tolerance of the Tibia Under Off-Axis Impact Loading. AB - During a frontal collision, there are a range of lower extremity postures that the vehicle's occupant may assume, potentially changing the way load is transmitted to this region of the body. While most experimental studies on the tibia's injury tolerance assume that load is directed along the leg's long axis, the effects of off-axis loading due to non-standard postures have not been well quantified, and commonly-cited injury criteria such as the Tibia Index do not directly account for posture. Therefore, twelve cadaveric tibias (paired from six donors) were subjected to off-axis impact loading in a custom-built test apparatus. One specimen from each pair was held at an angle of 15 degrees relative to the direction of loading, while the contralateral was held at an angle of 30 degrees , with these angles representing ankle plantarflexion and corresponding knee extension in a vehicle occupant. Specimens held at 30 degrees fractured at lower forces than the specimens held at 15 degrees (mean force = 5.8 vs. 7.5 kN). This indicates that posture should be incorporated into injury criteria for the tibia in future safety assessments instead of using a single force value based on axial impacts. PMID- 28341915 TI - In vivo system for analyzing the function of the PsbP protein using Chlamydomonas reinhardtii. AB - The PsbP protein is an extrinsic subunit of photosystem II (PSII) specifically developed in green-plant species including land plants and green algae. The protein-protein interactions involving PsbP and its effect on oxygen evolution have been investigated in vitro using isolated PSII membranes. However, the importance of those interactions needs to be examined at the cellular level. To this end, we developed a system expressing exogenous PsbP in the background of the Chlamydomonas BF25 mutant lacking native PsbP. Expression of His-tagged PsbP successfully restored the oxygen-evolving activity and photoautotrophic growth of the mutant, while PsbP-?15 lacking the N-terminal 15 residues, which are crucial for the oxygen-evolving activity of spinach PSII in vitro, only partially did. This demonstrated the importance of N-terminal sequence of PsbP for the photosynthetic activity in vivo. Furthermore, the PSII-LHCII supercomplex can be specifically purified from the Chlamydomonas cells having His-tagged PsbP using a metal affinity chromatography. This study provides a platform not only for the functional analysis of PsbP in vivo but also for structural analysis of the PSII LHCII supercomplex from green algae. PMID- 28341916 TI - Long-Term Results Following Antibiotic Treatment of Acute Appendicitis in Adults. AB - BACKGROUND: Antibiotic treatment of acute appendicitis has gained interest and inquiries. Reports have demonstrated both safety and high resolution of symptoms and inflammation following antibiotic treatment of appendicitis, but information on long-term results is required. Our present aim was therefore to evaluate long term recurrence rate of initial antibiotics-alone treatment for suspected acute appendicitis. METHODS: Patients with favourable response to antibiotics in earlier randomized (RCT, n = 97) and population-based (PBT, n = 342) studies as well as subsequently treated non-randomized (Non-R, n = 271) patients are evaluated for long-term risk to relapse demanding surgical appendectomy; altogether 710 patients. RESULTS: Clinical characteristics among randomized and non-randomized patients were similar without any statistical difference according to abdominal symptoms and degree of systemic inflammation (CRP, WCC) when antibiotic treatment started. Females and males showed the same results. The median follow-up time was 2162 days (5.92 years), and the range across highest and lowest follow-up was 3495 days (range 2-3497) for the entire group, without significant differences among subgroups (RCT, PBT, Non-R). The cumulative probability for relapse of appendicitis demanding appendectomy was: 0.09, 0.12, 0.12 and 0.13 at 1-, 2-, 3- and 5-year follow-up, with a probability of 0.86 +/- 0.013 without appendectomy after 8 years. This may imply an overall benefit of 60 70% by antibiotics during expected 10-year follow-up accounting for initial treatment failures at 10-23% in our published reports. CONCLUSION: Antibiotic treatment is safe and effective as a first-line therapy in unselected adults with acute appendicitis with a risk around 15% for long-term relapse following favourable initial treatment response. PMID- 28341917 TI - The Effect of Parathyroidectomy on Risk of Hip Fracture in Secondary Hyperparathyroidism. AB - BACKGROUND: Secondary hyperparathyroidism increases the risk for fractures. Despite improvement in medical therapy, surgical parathyroidectomy (PTX) often becomes necessary, but its effect on risk of fractures is not clear. Our aim was to study the effect of parathyroidectomy on the risk of hip fractures in patients on dialysis or with a functioning renal graft at time of parathyroidectomy. DESIGN: In a cohort of 20,056 patients on dialysis or with functioning renal allograft, we identified 590 patients who underwent parathyroidectomy between 1991 and 2009. Of these, 579 were matched with 1970 non-PTX patients on age, sex, cause of renal disease and functioning renal allograft or not at the time of PTX or at the corresponding time for non-PTX patients (t). We calculated the risk for hip fracture after PTX using crude and adjusted Cox proportional hazards regressions, adjusting for time in renal replacement therapy before t, time with functioning renal allograft before and after t, comorbidity at t and a hip fracture before t. RESULTS: The adjusted hazard ratio (95% confidence interval) for hip fracture was 0.40 (0.18-0.88) for PTX patients, compared to non-PTX patients. When analyses were performed separately for sex, only women had a lower risk of hip fracture after PTX compared to non-PTX patients. The risk of hip fracture after PTX was similar in patients with or without functioning renal allograft at time for PTX. CONCLUSION: Parathyroidectomy is associated with a lower risk of hip fracture in female patients with secondary hyperparathyroidism. PMID- 28341918 TI - Dasatinib versus imatinib in Japanese patients with newly diagnosed chronic phase chronic myeloid leukemia: a subanalysis of the DASISION 5-year final report. AB - The international phase III DASISION trial demonstrated improved efficacy of dasatinib versus imatinib in treatment-naive patients with chronic myeloid leukemia in the chronic phase (CML-CP). We report efficacy and safety outcomes in a Japanese population from the final, 5-year follow-up of DASISION. At the end of the study, 77% (20/26) of dasatinib-treated and 61% (14/23) of imatinib-treated patients remained on initial therapy. Improved responses were observed in Japanese patients who received dasatinib versus imatinib (complete cytogenetic response: 96 vs 87%; major molecular response: 88 vs 74%; BCR-ABL1 <=0.0032% International Scale [MR4.5]: 58 vs 52%). In patients who achieved BCR-ABL1 <=10% at 3 months, 5-year progression-free survival and overall survival rates were high with dasatinib (96 and 96%) and imatinib (88 and 100%). The majority of adverse events were grade 1/2 in Japanese patients. Pleural effusion occurred more frequently in dasatinib-treated Japanese patients versus all patients (42 vs 28%), with no treatment discontinuations. Overall, in Japanese patients, dasatinib maintained its safety profile and had higher or comparable response and survival outcomes compared with imatinib or with all patients in DASISION. These findings demonstrate the long-term efficacy and tolerability of dasatinib and support frontline treatment of Japanese patients with CML-CP with dasatinib. PMID- 28341920 TI - Rhythmic Modulation of Entrained Auditory Oscillations by Visual Inputs. AB - Temporal structure is ubiquitous in sensory signals, and the brain has been shown to robustly represent information about temporal structure in the phase of low frequency neural oscillations. In a related construct, the integration of information across the different senses has been proposed to be at least partly due to the phase resetting of these low frequency oscillations. As a consequence, oscillations represent a potential contributor to the encoding of complex multisensory signals with informative temporal structures. Here we investigated these interactions using electroencephalography (EEG). We entrained low frequency (3 Hz) delta oscillations using a repetitive auditory stimulus-broadband amplitude modulated noise. Following entrainment, we presented auditory and audiovisual stimuli at variable delays. We examined whether the power of oscillations at the entrained frequency was dependent on the delay (and thus, potentially, phase) at which subsequent stimulation was delivered, and whether this relationship was different for subsequent multisensory (i.e., audiovisual) stimuli when compared with auditory stimuli alone. Our findings demonstrate that, when the subsequent stimuli are solely auditory, the power of oscillations at the entrained frequency is rhythmically modulated by when the stimulus was delivered. For audiovisual stimuli, however, no such dependency is present, yielding consistent power modulations. These effects indicate that reciprocal oscillatory mechanisms may be involved in the continuous encoding of complex temporally structured multisensory inputs such as speech. PMID- 28341919 TI - Intraoperative hydroxyethyl starch 70/0.5 administration may increase postoperative bleeding: a retrospective cohort study. AB - PURPOSE: Studies evaluating the safety of hydroxyethyl starch with a molecular weight of 70 kDa and a molar substitution ratio of 0.5 (HES 70/0.5) are scarce in the literature. In this study, we investigated the relationship between intraoperative HES 70/0.5 administration and postoperative bleeding. METHODS: This is a single-center, retrospective cohort study. Subjects were postoperative adult patients who stayed in the intensive care unit (ICU) for more than 24 h during the period from January 1, 2010 to December 31, 2012. We compared postoperative adult patients with and without intraoperative HES 70/0.5 administration. The primary outcome was the drainage volume from surgical sites during the first 24 h after ICU admission. We conducted propensity score matching between the control group and the HES group. RESULTS: We analyzed data for 769 patients who met our inclusion criteria. Using propensity score matching, we successfully created 119 matched pairs from the HES group and control group, with no significant differences in patient characteristics. The drainage volume during the first 24 h after ICU admission was greater in the HES group than in the control group (400 +/- 479 vs. 260 +/- 357 mL, p < 0.003). CONCLUSION: Our retrospective cohort study suggests that intraoperative HES 70/0.5 administration is associated with increased postoperative bleeding. PMID- 28341921 TI - Selection methods in healthcare professions: where are we now and where next? PMID- 28341922 TI - Have admissions committees considered all the evidence? PMID- 28341923 TI - A research agenda for establishing the validity of non-academic assessments of medical school applicants. PMID- 28341924 TI - Effect of rhythm control on sleep disordered breathing in patients with atrial fibrillation or flutter: a systematic review and meta-analysis. PMID- 28341925 TI - Relationship between serum adiponectin and bone mineral density in male patients with obstructive sleep apnea syndrome. AB - PURPOSE: Obstructive sleep apnea syndrome (OSAS) is reported to have an association with bone mineral density (BMD). However, the underlying mechanism is far from clear. The aim of this study was to investigate the relationship between OSAS, bone turnover markers, and BMD and to evaluate the effect of adiponectin on BMD in patients with OSAS. METHODS: Seventy-one male patients with OSAS and 13 male control subjects were enrolled in this study. Serum adiponectin, calcium, phosphorus, 25-hydroxyvitamin-D3, beta-isomerized form C-terminal telopeptide of type I collagen, osteocalcin, and procollagen type 1 N-propeptide were measured in all subjects, and BMD was evaluated by dual-energy X-ray absorptiometry (DEXA) in the lumbar spine (L1-L4), the femoral neck, and the hip total. RESULTS: No statistically significant differences were found between the studied groups in terms of demographic data and bone turnover markers. Serum adiponectin significantly decreased with the aggravation of OSAS. Compared with subjects without OSAS, those with OSAS had a higher hip total BMD and t scores (p = 0.027 and p = 0.028). The significant negative association was found between serum adiponectin levels and hip total BMD. After adjusting for confounders, adiponectin as well as oxygen desaturation index (ODI) significantly predicted the hip total BMD (beta = -0.232, p = 0.005 and beta = 0.226, p = 0.037). CONCLUSIONS: In male subjects, the presence of obstructive sleep apnea syndrome is associated with higher bone mineral density of the hip. These findings suggest that serum adiponectin may be an underlying mediator for BMD in OSAS. PMID- 28341927 TI - Optimal Network for Patients with Severe Mental Illness: A Social Network Analysis. AB - It is still unclear what the optimal structure of mental health care networks should be. We examine whether certain types of network structure have been associated with improved continuity of care and greater social integration. A social network survey was carried out, covering 954 patients across 19 mental health networks in Belgium in 2014. We found continuity of care to be associated with large, centralized, and homophilous networks, whereas social integration was associated with smaller, centralized, and heterophilous networks. Two important goals of mental health service provision, continuity of care and social integration, are associated with different types of network. Further research is needed to ascertain the direction of this association. PMID- 28341928 TI - Description of a new species of Ixodes Latreille, 1795 (Acari: Ixodidae) and redescription of I. lasallei Mendez & Ortiz, 1958, parasites of agoutis and pacas (Rodentia: Dasyproctidae, Cuniculidae) in Central and South America. AB - Ixodes bocatorensis n. sp. (Acari: Ixodidae), is described based on adults ex agoutis (Rodentia: Dasyproctidae), pacas (Rodentia: Cuniculidae) and "tapir and sloth" (Perissodactyla: Tapiridae and Pilosa) from Colombia, Panama and Venezuela. Adults of I. bocatorensis n. sp. are similar to those of I. lasallei Mendez & Ortiz, 1958 but can be distinguished by the scutum dimensions, punctation pattern, gnathosoma and palpi measurements and their ratios, basis capituli anterior angle and shape of the spur of palpal segment I ventrally. For comparative purposes the female of I. lasallei is redescribed and the true male of this species is described for the first time. Studied adults of I. lasallei were found on agoutis, pacas and ocelot (Carnivora: Felidae) in Colombia, Peru and Venezuela. PMID- 28341926 TI - Risks associated with antiretroviral treatment for human immunodeficiency virus (HIV): qualitative analysis of social media data and health state utility valuation. AB - PURPOSE: Despite benefits of antiretroviral therapies (ART), people with HIV infection have increased risk of cardiovascular disease, kidney disease, and low bone mineral density. Some ARTs increase risk of these events. The purpose of this study was to examine patients' perspectives of these risks and estimate health state utilities associated with these risks for use in cost-utility models. METHODS: Qualitative thematic analysis was conducted to examine messages posted to the POZ/AIDSmeds Internet community forums, focusing on bone, kidney, and cardiovascular side effects and risks of HIV/AIDS medications. Then, health state vignettes were drafted based on this qualitative analysis, literature review, and clinician interviews. The health states (representing HIV, plus treatment-related risks) were valued in time trade-off interviews with general population participants in the UK. RESULTS: Qualitative analysis of the Internet forums documented patient concerns about ART risks, as well as treatment decisions made because of these risks. A total of 208 participants completed utility interviews (51.4% female; mean age 44.6 years). The mean utility of the HIV health state (virologically suppressed, treated with ART) was 0.86. Adding a description of risk resulted in statistically significant disutility (i.e., utility decreases): renal risk (disutility = -0.02), bone risk (-0.03), and myocardial infarction risk (-0.05). CONCLUSIONS: Patient concerns and treatment decisions were documented via qualitative analysis of Internet forum discussions, and the impact of these concerns was quantified in terms of health state utilities. The resulting disutilities may be useful for differentiating among ARTs in economic modeling of treatment for patients with HIV. PMID- 28341929 TI - Molecular characterisation of four echinostomes (Digenea: Echinostomatidae) from birds in New Zealand, with descriptions of Echinostoma novaezealandense n. sp. and Echinoparyphium poulini n. sp. AB - Morphological and molecular characterisation of echinostome specimens (Digenea: Echinostomatidae) recovered in one Anas platyrhynchos L. and one Cygnus atratus (Latham) (Anseriformes: Anatidae) from New Zealand revealed the presence of two known species, Echinostoma miyagawai Ishii, 1932 and Echinoparyphium ellisi (Johnston & Simpson, 1944) and two species new to science. Comparative morphological and phylogenetic analyses supported the distinct species status of Echinostoma novaezealandense n. sp. ex Branta canadensis (L.), A. platyrhynchos and C. atratus, and Echinoparyphium poulini n. sp. ex C. atratus. Echinostoma novaezealandense n. sp., a species of the "revolutum" species complex characterised by the possession of a head collar armed with 37 spines, keyed down to E. revolutum but was distinguished from the latter in having a much narrower body with almost parallel margins, longer oesophagus, wider cirrus-sac, larger seminal vesicle, much smaller ventral sucker, ovary, Mehlis' gland and testes, more anteriorly located ovary and testes, and distinctly smaller eggs (81-87 * 42 53 vs 106-136 * 55-70 um). This new species appears similar to Echinostoma acuticauda Nicoll, 1914 described in Australia but differs in having a longer forebody, more posteriorly located ovary and testes, and much smaller eggs (81-87 * 42-53 vs 112-126 * 63-75 um). Echinoparyphium poulini n. sp. is differentiated from the four species of Echinoparyphium possessing 37 collar spines considered valid as follows: from E. chinensis Ku, Li & Chu, 1964 in having a much smaller body, four (vs five) angle spines and simple seminal vesicle (vs bipartite); from E. schulzi Matevosyan, 1951 in having a less robust body at a comparable body length, much smaller ventral sucker, ovary and testes, and longer but narrower eggs (87-109 * 50-59 vs 70-85 * 60-84 um); and from the two smaller forms, E. serratum Howell, 1968 and E. aconiatum Dietz, 1909, in a number of additional metrical features correlated with body size and especially in the possession of much larger collar spines. Partial fragments of the mitochondrial nad1 and 28S rRNA genes were amplified for representative isolates of the four species and analysed together with sequences for Echinostoma spp. and Echinoparyphium spp. available on GenBank. Phylogenetic analyses based on the mitochondrial nad1 gene revealed congruence between the molecular data and species identification/delineation based on morphology; this was corroborated by the 28S rDNA sequence data. PMID- 28341930 TI - Clinical Utility of Cxbladder for the Diagnosis of Urothelial Carcinoma. AB - INTRODUCTION: This study aimed to demonstrate the clinical utility of non invasive multigene Cxbladder urine tests in reducing the overall number of diagnostic tests and invasive procedures used in the clinical evaluation of patients presenting with microhematuria, a key symptom of urothelial carcinoma (UC). There is a belief that using non-invasive molecular diagnostic tests in patients with hematuria may lead to patients undergoing unnecessary and costly invasive procedures that can cause adverse events and decrease patient quality of life. The objective of this study was to determine whether or not this was the case, using Cxbladder. METHODS: Data from 396 patient-by-urologist interactions generated 792 decision points from a standardized cohort of 33 patients evaluated by 12 urologists. Participant physicians recommended a selection of tests and procedures based on referral data, then reviewed and amended their recommendations in the context of diagnostic information from Cxbladder used in the Triage and Triage and Detect clinical modalities. RESULTS: All urologists changed their diagnostic behavior in at least one patient case with the addition of Cxbladder results. The total number of diagnostic procedures was reduced by 5% and 25% following disclosure of results from Cxbladder in the Triage and the Triage and Detect modalities, respectively. The total number of requested invasive procedures was reduced from 425 at referral to 379 (-11%) and 292 (-31%) following disclosure of Cxbladder information in the Triage and Triage and Detect modalities, respectively. CONCLUSIONS: Urologists made compelling changes to their clinical decision-making when they were provided with Cxbladder results for patients presenting with hematuria. Cxbladder provides an increase in clinical utility by focusing the use of invasive diagnostic procedures to appropriate patients, reducing both the total number and number of invasive procedures used in the clinical management of patients with hematuria, thereby improving the diagnostic experience and outcomes for patients. FUNDING: Pacific Edge Ltd. PMID- 28341931 TI - A Case Series of Dacryoendoscopy in Childhood: A Diagnostic and Therapeutic Alternative for Complex Congenital Nasolacrimal Duct Obstruction Even in the First Year of Life. AB - INTRODUCTION: Congenital nasolacrimal duct obstruction (CNLDO) is the most common cause of epiphora in infancy. Spontaneous resolution occurs in the majority of the cases by 1 year of age. Nevertheless, obstruction has a negative impact on the outcome of conservative or surgical therapy, especially in cases of complex CNLDO. When the condition persists beyond several months, early intervention with dacryoendoscopy (DE) around the age of 1 year could yield good results. The objective of the study is to analyze the success rate and effectiveness of early DE for complex CNLDO in the first year of life. METHODS: A retrospective, non comparative case series is presented. DE was performed under general anesthesia in patients between the age of 1 and 12 months with severe recurrent acute or chronic dacryocystitis. The medical histories, intraoperative and postoperative results after 3 months as well as via parents' interviews were analyzed to investigate the success rate. RESULTS: A total of 18 consecutive DE in 16 patients between the age of 1 and 12 months (mean 7.3 +/- 3.4 months) were studied. Nine lacrimal ducts were diagnosed with persistent chronic dacryocystitis refractory to probing/syringing. The remaining 9 presented recurrent acute dacryocystitis. Diagnostic DE was performed in 18 cases. A therapeutic DE was conducted in 15 lacrimal ducts (83.3%) with simultaneous correction of the associated stenosiswith the tip of the endoscope. A visual controlled opening of the stenosis was impossible in 3 cases due to a too narrow presaccal anatomy (n = 1), an osseous duct stenosis (n = 1), and a bulging membrane of Hasner into the inferior nasal meatus (n = 1). Postoperative findings were classified into four categories: poor, fair, good and excellent. Good results were documented in 16.7% (n = 3) and excellent results in 77.7% (n = 14). The bony obstruction was treated with dacryocystorhinostomy. A minimum follow-up of 3 months was considered for final clinical analysis. Ten patients' parents (12 surgeries) were interviewed by telephone (mean follow-up 24.8 months). No recurrence of stenosis and no further postoperative complications were observed. CONCLUSION: DE is a diagnostic and therapeutic option for complex CNLDO in patients before the age of 1 year. The outcome of DE in the 3 months follow-up is highly indicative of positive final results in terms of patency of the lacrimal duct. PMID- 28341932 TI - [Cross-sectional field pain medicine Q14 - the Mainz model : Development of the pain medicine curriculum in the standard study course at the University Medical School of the Johannes Gutenberg University Mainz]. AB - BACKGROUND AND OBJECTIVES: Following the amendment of the Medical Licensure Act (AAppO) in 2012, pain medicine was introduced as a mandatory subject for students during undergraduate medical training. Medical schools were required to define and to implement adequate curricular and formal teaching structures based on interdisciplinary and multiprofessional requirements according to the curriculum for pain medicine of the German Pain Society. These aspects were considered in the new interdisciplinary curriculum for pain medicine, the so-called Mainz model. STUDY DESIGN AND METHODS: A new curriculum based on the Kern cycle was developed and implemented at the Medical Center of the Johannes Gutenberg University in Mainz. Different teaching methods (lectures, interprofessional tutorials and bedside coaching in small groups) were used to impart professional expertise in pain medicine to medical students in an interdisciplinary clinical context. RESULTS: The new curriculum was put into practice and evaluated starting from the winter semester 2014/2015. Before and after the first implementation, medical students were asked about the relevance of pain medicine and their perception of personal competence. CONCLUSION: The interdisciplinary course in pain medicine was successfully introduced into the degree program based on the curriculum of the German Pain Society and the Kern cycle. With educational support, interdepartmental and multiprofessional collaboration the process of implementation of new interdisciplinary courses can be facilitated. In the future, the question how to increase the amount of practical lessons without increasing the load on teaching resources has to be resolved. Blended learning modules, such as a combination of E-learning and practical lessons are currently being studied in smaller cohorts. PMID- 28341933 TI - Masturbation and Partnered Sex: Substitutes or Complements? AB - Drawing upon a large, recent probability sample of American adults ages 18-60 (7648 men and 8090 women), we explored the association between sexual frequency and masturbation, evaluating the evidence for whether masturbation compensates for unavailable sex, complements (or augments) existing paired sexual activity, or bears little association with it. We found evidence supporting a compensatory relationship between masturbation and sexual frequency for men, and a complementary one among women, but each association was both modest and contingent on how content participants were with their self-reported frequency of sex. Among men and women, both partnered status and their sexual contentment were more obvious predictors of masturbation than was recent frequency of sex. We conclude that both hypotheses as commonly evaluated suffer from failing to account for the pivotal role of subjective sexual contentment in predicting masturbation. PMID- 28341935 TI - A Natural Triterpenoid Saponin as Multifunctional Stabilizer for Drug Nanosuspension Powder. AB - The objective of this study is to prepare a novel drug nanosuspension modified by a natural triterpenoid saponin (glycyrrhizin (GZ)) and evaluate its stability and redispersibility. A poorly soluble drug (andrographolide (AGE)) was used as a model drug. AGE nanosuspensions (AGE-NS) using GZ as natural stabilizer with mean particle size of 487 nm were firstly prepared by homogenization and converted into dried AGE nanosuspension powder (AGE-NP) by freeze-drying. It was found that GZ was able to prevent the aggregation of AGE nanocrystals and the freeze-dried AGE-NP could easily redisperse back to AGE-NS. It was related with special properties of GZ that possessed the interfacial property (37.02 +/- 0.29 N/m) and electrostatic effect (-43.6 +/- 0.9 mV) and could entrap AGE nanocrystals into its network structure. The freeze-dried AGE-NP/GZ exhibited excellent performance, compared with those combined with trehalose as matrix formers. The powder X-ray diffraction result demonstrated that GZ did not alter the AGE crystal state. The dissolution of AGE-NP/GZ (99.87%) was significantly enhanced, compared with the coarse AGE (42.35%). This study demonstrated that GZ could be used as a novel multifunctional stabilizer for production of drug nanosuspensions and provided a promising basis for further formulation development of poorly soluble drug. PMID- 28341934 TI - Molecular chaperone Jiv promotes the RNA replication of classical swine fever virus. AB - The nonstructural protein 2 (NS2) of classical swine fever virus (CSFV) is a self splicing ribozyme wherein the precursor protein NS2-3 is cleaved, and the cleavage efficiency of NS2-3 is crucial to the replication of viral RNA. However, the proteolytic activity of NS2 autoprotease may be achieved through a cellular chaperone called J-domain protein interacting with viral protein (Jiv) or its fragment Jiv90, as evidence suggests that Jiv is required for the proper functioning of the NS2 protein of bovine viral diarrhea virus. Hence, the expression of Jiv may be correlated with the replication efficiency of CSFV RNA. We investigated the expression levels of Jiv and viral RNA in CSFV-infected cells and tissues using Real-time RT-PCR or Western blot analysis. The obtained results show that Jiv90 possibly plays an important role in the lifecycle of CSFV because the distribution of Jiv90 protein shows a positive correlation with the viral load of CSFV. Furthermore, the overexpression or knockdown of Jiv90 in swine cells can also significantly promote or decrease the viral load, respectively. The detection of Flow cytometry shows that the overexpression of Jiv90 prolongs the G1 phase of cell cycles but has no effect on apoptosis. These findings are likely to be of benefit in clarifying the pathogenesis of the CSFV. PMID- 28341936 TI - Erratum to: White Matter Microstructure and Subcortical Gray Matter Structure Volumes in Aspartylglucosaminuria; a 5-Year Follow-up Brain MRI Study of an Adolescent with Aspartylglucosaminuria and His Healthy Twin Brother. PMID- 28341938 TI - Erratum to Current status of immunologic approaches to treating tobacco dependence: Vaccines and nicotine-specific antibodies. PMID- 28341937 TI - Percutaneous needle biopsy of mediastinal masses under C-arm conebeam CT guidance: diagnostic performance and safety. AB - The aim of this study is to evaluate the feasibility of percutaneous needle biopsy of mediastinal masses under conebeam computed tomography (CBCT) and "XperGuide" navigation guidance. From September 2013 to April 2016, 40 patients (25 men and 15 women; mean age 52.5 years; range 18.7-86.4 years) with 40 mediastinal masses underwent CBCT-/"XperGuide"-guided percutaneous needle biopsies. Technical success, sensibility, specificity, positive predictive value (ppv), negative predictive value (npv) and complications rate were evaluated. Technical success evaluated as the correct positioning of the needle inside the lesion was 100%. Based on histopathological diagnosis, 2 of 40 biopsies (5%) resulted a false negative. Diagnostic accuracy was 95%, sensitivity was 95%, specificity was 100%, ppv was 100%, and npv was 33%. The mean total procedure time was 32 min (range 15-60 min) revealing a reduction in time comparing the first group of 20 patients (mean time 45 min) with the last group of 20 patients (mean time 17 min). No major complications were recorded. Only three patients (7.5%) had mild pneumothorax as demonstrated by post-procedural CBCT, resolved spontaneously. CBCT/"XperGuide" navigation system is a new, safe and accurate technique that can be used as guidance for mediastinal mass biopsies. It also permits the use of CT machines for diagnostic examinations relieving them from interventional procedures burden. PMID- 28341942 TI - Integrating NIMH Research Domain Criteria (RDoC) into PTSD Research. AB - Three and a half decades of research on posttraumatic stress disorder (PTSD) has produced substantial knowledge on the pathobiology of this frequent and debilitating disease. However, despite all research efforts, so far no drug that has specifically targeted PTSD core symptoms progressed to clinical use. Instead, although not overly efficient, serotonin re-uptake inhibitors continue to be considered the gold standard of PTSD pharmacotherapy. The psychotherapeutic treatment and symptom-oriented drug therapy options available for PTSD treatment today show some efficacy, although not in all PTSD patients, in particular not in a substantial percent of those suffering from the detrimental sequelae of repeated childhood trauma or in veterans with combat related PTSD. PTSD has this in common with other psychiatric disorders - in particular effective treatment for incapacitating conditions such as resistant major depression, chronic schizophrenia, and frequently relapsing obsessive-compulsive disorder as well as dementia has not yet been developed through modern neuropsychiatric research.In response to this conundrum, the National Institute of Mental Health launched the Research Domain Criteria (RDoC) framework which aims to leave diagnosis-oriented psychiatric research behind and to move on to the use of research domains overarching the traditional diagnosis systems. To the best of our knowledge, the paper at hand is the first that has systematically assessed the utility of the RDoC system for PTSD research. Here, we review core findings in neurobiological PTSD research and match them to the RDoC research domains and units of analysis. Our synthesis reveals that several core findings in PTSD such as amygdala overactivity have been linked to all RDoC domains without further specification of their distinct role in the pathophysiological pathways associated with these domains. This circumstance indicates that the elucidation of the cellular and molecular processes ultimately decisive for regulation of psychic processes and for the expression of psychopathological symptoms is still grossly incomplete. All in all, we find the RDoC research domains to be useful but not sufficient for PTSD research. Hence, we suggest adding two novel domains, namely stress and emotional regulation and maintenance of consciousness. As both of these domains play a role in various if not in all psychiatric diseases, we judge them to be useful not only for PTSD research but also for psychiatric research in general. PMID- 28341939 TI - The Basic Pharmacology of Opioids Informs the Opioid Discourse about Misuse and Abuse: A Review. AB - Morphine and other opioids are widely used to manage moderate to severe acute pain syndromes, such as pain associated with trauma or postoperative pain, and they have been used to manage chronic pain, even chronic nonmalignant pain. However, recent years have seen a renewed recognition of the potential for overuse, misuse, and abuse of opioids. Therefore, prescribing opioids is challenging for healthcare providers in that clinical effectiveness must be balanced against negative outcomes-with the possibility that neither are achieved perfectly. The current discourse about the dual 'epidemics' of under-treatment of legitimate pain and the over-prescription of opioids is clouded by inadequate or inaccurate understanding of opioid drugs and the endogenous pain pathways with which they interact. An understanding of the basic pharmacology of opioids helps inform the clinician and other stakeholders about these simultaneously under- and over-used agents. PMID- 28341944 TI - Discriminative Stimulus Effects of Psychostimulants. AB - Numerous drugs elicit locomotor stimulant effects at appropriate doses; however, we typically reserve the term psychostimulant to refer to drugs with affinity for monoamine reuptake transporters. This chapter comprises select experiments that have characterized the discriminative stimulus effects of psychostimulants using drug discrimination procedures. The substitution profiles of psychostimulants in laboratory rodents are generally consistent with those observed in human and nonhuman primate drug discrimination experiments. Notably, two major classes of psychostimulants can be distinguished as those that function as passive monoamine reuptake inhibitors (such as cocaine) and those that function as substrates for monoamine transporters and stimulate monoamine release (such as the amphetamines). Nevertheless, the discriminative stimulus effects of both classes of psychostimulant are quite similar, and drugs from different classes will substitute for one another. Most importantly, for both the cocaine-like and amphetamine-like psychostimulants, dopaminergic mechanisms most saliently determine discriminative stimulus effects, but these effects can be modulated by alterations in noradrenergic and serotonergic neurotransmission as well. Thusly, the drug discrimination assay is useful for characterizing the interoceptive effects of psychostimulants and determining the mechanisms that contribute to their subjective effects in humans. PMID- 28341943 TI - Cross-Species Translational Findings in the Discriminative Stimulus Effects of Ethanol. AB - The progress on understanding the pharmacological basis of ethanol's discriminative stimulus effects has been substantial, but appears to have plateaued in the past decade. Further, the cross-species translational efforts are clear in laboratory animals, but have been minimal in human subject studies. Research findings clearly demonstrate that ethanol produces a compound stimulus with primary activity through GABA and glutamate receptor systems, particularly ionotropic receptors, with additional contribution from serotonergic mechanisms. Further progress should capitalize on chemogenetic and optogenetic techniques in laboratory animals to identify the neural circuitry involved in mediating the discriminative stimulus effects of ethanol. These infrahuman studies can be guided by in vivo imaging of human brain circuitry mediating ethanol's subjective effects. Ultimately, identifying receptors systems, as well as where they are located within brain circuitry, will transform the use of drug discrimination procedures to help identify possible treatment or prevention strategies for alcohol use disorder. PMID- 28341945 TI - Translational Value of Drug Discrimination with Typical and Atypical Antipsychotic Drugs. AB - This chapter focuses on the translational value of drug discrimination as a preclinical assay for drug development. In particular, the importance of two factors, i.e., training dose and species, for drug discrimination studies with the atypical antipsychotic clozapine is examined. Serotonin receptors appear to be an important pharmacological mechanism mediating clozapine's discriminative cue in both rats and mice, although differences are clearly evident as antagonism of cholinergic muscarinic receptors is important in rats at a higher training dose (5.0 mg/kg) of clozapine, but not at a lower training dose (1.25 mg/kg). Antagonism of alpha1 adrenoceptors is a sufficient mechanism in C57BL/6 and 129S2 mice to mimic clozapine's cue, but not in DBA/2 and B6129S mice, and only produces partial substitution in low-dose clozapine discrimination in rats. Dopamine antagonism produces partial substitution for clozapine in DBA/2, 129S2, and B6129S mice, but not in C57BL/6 mice, and partial substitution is seen with D4 antagonism in low-dose clozapine drug discrimination in rats. Thus, it is evident that clozapine has a complex mixture of receptor contributions towards its discriminative cue based on the data from the four mouse strains that have been tested that is similar to the results from rat studies. A further examination of antipsychotic stimulus properties in humans, particularly in patients with schizophrenia, would go far in evaluating the translational value of the drug discrimination paradigm for antipsychotic drugs. PMID- 28341946 TI - Surgical Masculinization of the Breast: Clinical Classification and Surgical Procedures. AB - INTRODUCTION: Aesthetic breast area improvements for gynecomastia and gender dysphoria patients who seek a more masculine appearance have increased recently. We present our clinical experience in breast masculinization and a classification for these patients. METHODS AND MATERIALS: From July 2003 to May 2014, 68 patients seeking a more masculine thorax underwent surgery. They were divided into five groups depending on three factors: excess fatty tissue, breast tissue, and skin. A specific surgical treatment was assigned according to each group. The surgical treatments included thoracic liposuction, subcutaneous mastectomy, periareolar skin resection in one or two stages, and mastectomy with a nipple areola complex graft. The evaluation was performed 6 months after surgery to determine the degree of satisfaction and presence of complications. RESULTS: Surgery was performed on a total of 68 patients, 45 male and 22 female, with ages ranging from 18 to 49 years, and an average age of 33 years. Liposuction alone was performed on five patients; subcutaneous mastectomy was performed on eight patients; subcutaneous mastectomy combined with liposuction was performed on 27 patients; periareolar skin resection was performed on 11 patients; and mastectomy with NAC free grafts was performed on 16 patients. The surgical procedure satisfied 94% of the patients, with very few complications. CONCLUSIONS: All patients who wish to obtain a masculine breast shape should be treated with only one objective regardless patient's gender: to obtain a masculine thorax. We recommend a simple mammary gland classification for determining the best surgical treatment for these patients LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28341947 TI - The Versatile Posterior Auricular Fascia in Secondary Rhinoplasty Procedures. AB - BACKGROUND: Secondary rhinoplasty often involves the addition of autogenous graft material to add volume, structure, support and to camouflage cartilage and bone grafts. A variety of fascias have been used to camouflage, wrap and give "fill" in secondary rhinoplasty. The posterior auricular fascia is a source of material ideal for such purposes, and its quantity, anatomical structure and ease of harvest with minimal donor site morbidity make it a versatile and attractive autogenous graft. METHODS: The clinical records of patients receiving autogenous posterior auricular fascial grafts were reviewed. There were two main uses of this graft material, one was to cover the tip reconstruction in secondary rhinoplasties under thin tip skin. This is a camouflage graft. The second use is for fill and augmentation, especially for the nasal dorsum and as an interpostitional graft between the dorsum and the tip. CONCLUSION: The posterior auricular fascial graft has many potential uses in secondary rhinoplasties and is readily harvested as a generous graft concurrent to conchal cartilage harvest and with a concealed scar behind the ear. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28341948 TI - Author Commentary: Objective Outcome Measurement After Upper Blepharoplasty: An Analysis of Different Operative Techniques. PMID- 28341949 TI - Complications and Outcomes After Gynecomastia Surgery: Analysis of 204 Pediatric and 1583 Adult Cases from a National Multi-center Database. AB - BACKGROUND: Gynecomastia is a common disease that is prevalent across all age groups of boys and men. Although benign in nature, it can lead to psychological and social distress, prompting affected patients to seek medical attention. Management strategies include observation and drug therapy, yet surgical procedures remain the hallmark of treatment. The goal of this study was to analyze patient demographics, outcomes, and complication rates of gynecomastia surgery in a large multi-institutional cohort. METHODS: We performed a retrospective analysis of the American College of Surgeons National Surgical Quality Improvement Program adult and pediatric databases to produce two cohorts that underwent gynecomastia surgical repair. The two populations were compared for comorbidities, perioperative details, and complication rates. Multivariate analyses helped detect risk factors associated with adverse events. RESULTS: A total of 204 pediatric and 1583 adult male patients were identified in our analysis. Mean ages were 15.8 and 39.6 years, respectively. A BMI of 28.2 in the latter cohort revealed an overweight adult population. Preoperative comorbidities (0.0-4.9% in children, 0.0-6.4% in adults) and American Society of Anesthesiologists scores (ASA 1 + 2: 98.5 and 82.7%) symbolized a healthy population. Procedures were subsequently performed mostly as outpatient (84.3 and 93.9%) and with short hospitalization durations (0.27 and 0.06 days). Our results demonstrated low surgical (3.9 and 1.9%) and medical (0.0 and 0.3%) complications within the standardized 30-day postoperative period. Children and adolescents, however, required double mean operative times compared to adults (111.3 vs 56.7 min). CONCLUSION: Operative gynecomastia treatment remains a safe treatment modality across all age groups. Patients with known preoperative medical or surgical comorbidities necessitate more extensive perioperative assessment and monitoring. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28341950 TI - Frontal Changes in the Lower Face After Clockwise Rotation of the Maxillomandibular Complex Without Perisurgical Orthodontic Treatment in Angle Class I and Skeletal Class III Women. AB - BACKGROUND: Orthognathic surgery has become more popular to slenderize a wide lower face and to improve facial esthetics in Asian patients with normal occlusion. Clockwise rotation (CR) of the maxillomandibular complex (MMC) steepens the mandibular plane. This study performed a quantitative analysis on the influence of CR on slenderness of the lower face from the frontal view. PATIENTS AND METHODS: This retrospective study included 36 female patients with Angle Class I occlusion and skeletal Class III pattern. The subjects underwent CR of the MMC without perioperative orthodontic treatment and change in the occlusion only for the purpose of esthetic improvement. Linear and angular variables were measured on a cephalogram and three-dimensional computed tomography (3D CT) obtained before and at least 6 months after surgery. Data were analyzed using paired t tests and Spearman correlations. Univariate regression analysis was used to predict the postoperative change according to the amount of posterior impaction. RESULTS: The mean posterior impaction was 3.81 mm. All mandibular plane angle (MPA) measurements were increased (ranged from 5.69 degrees to 13.12 degrees , p < 0.001), exhibiting a significant correlation with the amount of posterior impaction. Bigonial width measurements were decreased after surgery (ranged from 4.97 to 5.51 mm, p < 0.001). Among the MPAs derived from the 3D CT, the coronal projection from the frontal view exhibited a discrepancy between right and left side. CONCLUSIONS: The changes in linear and angular measurements in this study indicate that the lower face becomes narrower and more slender as the MMC rotates in a clockwise direction. Orthognathic surgery with CR has the advantage of increasing the MPAs and obtaining natural soft tissue contouring while minimizing the amount of bone resection. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266c . PMID- 28341951 TI - Discussion: Surgical Management of Gynecomastia: Subcutaneous Mastectomy and Liposuction. PMID- 28341952 TI - Septal Deviation Treatment Using Bone or Cartilage Grafts Fixed with Cyanoacrylate Tissue Adhesive. AB - BACKGROUND: This paper presents a method in which bone or cartilage grafts are fixed to the septal cartilage with cyanoacrylate-based tissue adhesive for the treatment of septal deviation. A prospective study was designed to show the effectiveness of the technique. METHODS: Cyanoacrylate-based tissue adhesive was used to fix the cartilage or bone grafts onto the septal cartilage to straighten deviated septal cartilage in 77 patients. Regarding the patients' preoperative and postoperative nasal respiration, the following were assessed: (1) Nasal Obstruction Symptom Evaluation (NOSE) scales, (2) patient satisfaction with postoperative nasal respiration using visual analog scoring, and (3) computerized tomographic images. RESULTS: The patients were followed up for 29 months on average. Patients' respiration-related problems resulting from septal deviation were relieved in all but four patients. Clinically and radiologically, the straightened septums preserved their new forms, and it was detected with computerized tomography that the bone grafts had acquired permanency. In addition, the NOSE scores improved significantly compared to their preoperative levels. CONCLUSIONS: In cases in which the use of bone or cartilage grafts is chosen to straighten the deviated septal cartilage, fixation of grafts with cyanoacrylate (CA) tissue adhesive is a quick, instantly effective, and reliable method. CA, which enables the subsurface of the graft to have complete contact with the septal cartilage, provides extra benefit by transferring all of the reformative forces of the grafts to the septal cartilage. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28341953 TI - Giant Rhinophyma: A Rare Case of Total Nasal Obstruction and Restitutio Ad Integrum. AB - Rhinophyma is considered the end stage in the development of rosacea, accompanied by hypertrophy of the sebaceous glands, which causes an enlargement of the nose. It is an uncommon condition that often results in both functional and cosmetic impairment. A large variety of surgical and nonsurgical treatments have been published to treat it. Closure is usually obtained by wound granulating in by secondary intention, skin grafting or local flaps. Rarely these lesions can attain a giant size and pose a challenge in surgical treatment. We present a 63 year-old male with the necessity for tracheostomy at the ICU due to total nasal obstruction and recurrent episodes of pneumonia caused by a huge giant rhinophyma, which had undergone extreme growth in the last five years. The tumor was removed under general anesthesia by decortication with an electrosurgical wire loop to recreate the aesthetic units of the nose preserving the alar cartilage as well as the pilosebaceous appendages. The wounds healed in by secondary intention with a very pleasant cosmetic and improved functional result. The relevant literature is discussed. Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28341955 TI - Osteoplasty in Crooked Nose Deformity: A Novel Approach. AB - BACKGROUND: Crooked nose deformity is one of the most difficult issues to correct by rhinoplasty, as it can result in undesired late sequelae. Revision rates are often high, and numerous operational techniques have been tested. This study describes a crooked nose rhinoplasty technique that reduces the need for a double osteotomy in the long nasal bone. METHODS: This study included 26 patients with an I-shaped crooked nose deformity. In the surgical correction of the crooked nose deformity, previously defined techniques were applied to the cartilage identically. However, the traditional double osteotomy of the long nasal bone was not performed. Instead, the bone protruding laterally from the long nasal bone was narrowed by rasping with a file or burr, and this section was delivered to the maxilla accordingly. Angle values were measured preoperatively and postoperatively. Two lines were used to measure the angle: The first was drawn from the midpoint of the glabella to the midpoint of the upper lip, while the second, representing the nasal dorsal axis, consisted of both the osseous and cartilaginous parts from the nasion to the anterior nasal spine. The angle between these two lines was taken as the angle of deviation from the median line. RESULTS: Postoperatively, patients' angle values were significantly smaller than preoperatively. After 1 year, no persistence was observed. CONCLUSION: In crooked nose deformity surgery, the osteoplasty technique applied to the lateral protrusion of the long nasal bone described here was as successful as a double osteotomy. Thus, certain complications of a double osteotomy can be avoided. In addition, as no greenstick fractures were induced, the long-term persistence risk was also reduced. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28341954 TI - Reversible Alopecia with Localized Scalp Necrosis After Accidental Embolization of the Parietal Artery with Hyaluronic Acid. AB - Hyaluronic acid (HA) filler injection is widely used for soft-tissue augmentation. Complications associated with HA filling are not uncommon; however, HA-induced alopecia is a rarely reported complication that could result in severe secondary psychological trauma. The etiology, clinical traits, treatment strategies, outcomes, and possible reversibility of HA-induced alopecia have not been characterized. Here, we report a case in which bilateral temple injections of 6.5 mL of HA led to persistent pain over the left scalp for several days. Although the pain was relieved at day 9 after 600 U of hyaluronidase were injected in the left temple, the patient developed localized alopecia at the left temporoparietal region with central skin necrosis at day 15. After topical applications of recombinant bovine basic fibroblast growth factor gel and 2% minoxidil spay, the necrotic skin wound was healed at day 42. Hair regrowth and normal hair density were restored at day 74. Analyses of Doppler ultrasound examinations and histopathology of the skin biopsy suggested that mild ischemia of the left temporoparietal region led to reversible alopecia, while the permanent hair loss in the left parietal area was associated with severe skin ischemia. Therefore, the key to treatment would be to focus on the effective correction of severe ischemia-induced skin necrosis to prevent permanent hair loss. Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28341956 TI - Improvement on the Neo-umbilicoplasty Technique and Review of the Literature. AB - INTRODUCTION: The umbilicus is an important component of body esthetics, and its absence or dysmorphia may give rise to psychological discomfort, making it a common concern in surgical planning. Many techniques of umbilicus reconstruction have been proposed, each with its own limitations in terms of esthetics, risk of stenosis or final positioning. Reconstruction techniques may involve skin grafting, cartilage, purse-string suture and flaps. One of the most promising approaches is scarless neo-umbilicoplasty. OBJECTIVE: To improve the technique of neo-umbilicoplasty, creating a deeper and more natural-looking umbilicus, and propose a reoperation technique for shallow umbilici. PATIENTS AND METHODS: The sample consisted of 108 patients aged 25-67 years submitted to abdominoplasty and scarless neo-umbilicoplasty under epidural anesthesia performed by the same surgeon and at the same hospital between July 2013 and October 2015. RESULTS: Follow-up lasted from 6 to 24 months. The new umbilici were scarless. DISCUSSION: Many different techniques may be used to reconstruct the umbilicus. The main purpose is to create an adequately localized structure with a natural, youthful appearance and minimal scarring. To do so, we used ten (rather than six) attachment stitches and mobilized the adipose tissue toward the center of the new umbilicus to achieve greater depth, even in lean patients. Techniques which involve suturing the umbilical stalk onto the incised skin of the abdominal flap tend to produce unesthetic results, such as visible scars and umbilical skin islands of varying size. Scarless neo-umbilicoplasty does not require suture removal and poses no risk of dehiscence, secretion or umbilical stenosis, as observed with other techniques. CONCLUSION: The localization of the new umbilicus in the space between the rectus abdominis muscles, the use of ten rather than six stitches and the mobilization of the adipose tissue toward the periumbilical area constitute an improvement on the neo-umbilicoplasty technique. The resulting umbilici were scarless and very natural-looking. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28341957 TI - Phase Ib dose-finding trial of lapatinib plus pegylated liposomal doxorubicin in advanced HER2-positive breast cancer. AB - PURPOSE: Combination of anthracyclines with trastuzumab is hampered by cardiotoxicity. Pegylated liposomal doxorubicin and lapatinib could represent a safer alternative to combination therapy. METHODS: In this phase Ib study with 3 + 3 dose escalation design, patients with HER2-positive advanced breast cancer received pegylated liposomal doxorubicin 30 mg/m2 intravenously on day 1 plus lapatinib 1250 (level 1) or 1500 (level 2) mg/day orally on days 1-21 of each 21 day cycle. The aims were to establish the maximum tolerated dose at first cycle, and the activity and safety of multiple cycles. RESULTS: Nine patients out of 11 enrolled were evaluable: 3 at level 1 and 6 at level 2. No dose-limiting toxicities occurred at dose level 1, while 1 (grade 3 diarrhea) occurred at dose level 2, leading to the expansion of this cohort to 6 patients, with no further dose-limiting toxicities. Main grade 1-2 toxicities at first cycle were leucopenia, diarrhea, elevated transaminases, mucositis. Three patients had grade 3 toxicities at subsequent cycles, including colitis, anorexia, stomatitis plus hand-foot syndrome. One partial response, 5 disease stabilizations, and 3 disease progressions were reported. CONCLUSIONS: Combination of pegylated liposomal doxorubicin and lapatinib is feasible and potentially active in pretreated HER2 positive advanced breast cancer patients. TRIAL REGISTRATION: NCT02131506 (ClinicalTrials.gov identifier). PMID- 28341958 TI - Randomized phase II study comparing weekly docetaxel-cisplatin vs. gemcitabine cisplatin in elderly or poor performance status patients with advanced non-small cell lung cancer. AB - BACKGROUND: Docetaxel/cisplatin (DP) and gemcitabine/cisplatin (GP) are standard treatment regimens for advanced non-small cell lung cancer (NSCLC). In spite of potent efficacy, the conventional 1-day DP is regarded as having more toxicity as compared with GP. There is increasing interest in a biweekly split administration of DP to reduce its toxicity. Hypothesis was that first-line biweekly DP is as safe as GP in the elderly or poor performance status (PS) patients. METHODS: Chemotherapy-naive patients with advanced NSCLC (IIIB/IV) who were elderly (65<) or PS (ECOG 2) were randomized to DP or GP arm by balancing for ECOG (0-1 vs. 2) and stage (IIIB vs. IV). DP comprised docetaxel (35 mg/m2)/cisplatin (30 mg/m2) iv on days 1 and 8, every 3 weeks. GP comprised gemcitabine (1000 mg/m2)/cisplatin (30 mg/m2) iv on days 1 and 8, every 3 weeks. Chemotherapy lasted up to 4-6 cycles or until progression. Primary endpoint was safety (proportion of grade 3/4 toxicities). Planned sample size was 49 patients in each arm. RESULTS: From November 2009 to August 2012, a total of 99 patients were randomized (DP 50/GP 49) from nine institutions. Adenocarcinoma and squamous cell carcinoma were observed in 62% and 33% of patients, respectively. Toxicity profiles were comparable for both arms and the differences were not statistically significant except for anemia and leucocytopenia. Any grade of anemia (86 vs. 98%) and of leucocytopenia (18 vs. 43%) was more common in the GP arm with statistical significance. Oral mucositis tended to be predominant in the DP arm. Patients in the DP arm (51%) suffered grade 3 or higher toxicities as did 47% in the GP arm (47%). The most common grade 3 or higher toxicities were as follows: In the DP arm, neutropenia (8%), leucopenia (8%), anemia (4%), pneumonia with normal ANC (4%) and febrile neutropenia (2%) were observed. In the GP arm, anemia (15%), neutropenia (15%), pneumonia with normal ANC (4%), thrombocytopenia (4%) and leucopenia (2%) were observed. The best overall response rates (CR + PR) for the DP and GP arms were 20.0 and 21% with no CR, respectively, and disease control rates (CR + PR + SD) were 70.0 and 76%, respectively. Median progression free survival and median overall survival were 3.7 and 14.9 months in the DP arm and 5.6 and 20.8 months in the GP arm, respectively. CONCLUSION: This study showed that DP is similar to GP in terms of efficacy and toxicity in treatment of elderly or poor performance patients. Both regimens showed similar grade 3/4 toxicities with different profiles. PMID- 28341959 TI - A randomized, single-blind, single-dose study evaluating the pharmacokinetic equivalence of proposed biosimilar ABP 980 and trastuzumab in healthy male subjects. AB - PURPOSE: This study compared the pharmacokinetic (PK) profiles of the proposed biosimilar ABP 980 and trastuzumab in healthy males. METHODS: In this single blind study, 157 healthy males were randomized 1:1:1 to a single 6 mg/kg intravenous infusion of ABP 980, FDA-licensed trastuzumab [trastuzumab (US)], or EU-authorized trastuzumab [trastuzumab (EU)]. Primary endpoints were area under the serum concentration-time curve from time 0 to infinity (AUCinf) and maximum observed serum concentration (C max). To establish equivalence, the geometric mean ratio (GMR) and 90% confidence interval (CI) for C max and AUCinf had to be within the equivalence criteria of 0.80-1.25. RESULTS: The GMRs and 90% CIs for C max and AUCinf, respectively, were: 1.04 (0.99-1.08) and 1.06 (1.00-1.12) for ABP 980 versus trastuzumab (US); 0.99 (0.95-1.03) and 1.00 (0.95-1.06) for ABP 980 versus trastuzumab (EU); and 0.96 (0.92-1.00) and 0.95 (0.90-1.01) for trastuzumab (US) versus trastuzumab (EU). All comparisons were within the equivalence criteria of 0.80-1.25. Treatment-emergent adverse events (TEAEs) were reported in 84.0, 75.0, and 78.2 of subjects in the ABP 980, trastuzumab (US), and trastuzumab (EU) groups, respectively. There were no deaths or TEAEs leading to study discontinuation and no binding or neutralizing anti-drug anti-bodies were detected. CONCLUSIONS: This study demonstrated the PK similarity of ABP 980 to both trastuzumab (US) and trastuzumab (EU), and of trastuzumab (US) to trastuzumab (EU). No differences in safety and tolerability between treatments were noted; no subject tested positive for binding anti-bodies. PMID- 28341960 TI - Relationship between healthy lifestyle behaviors and cardiovascular risk factors in Chinese patients with type 2 diabetes mellitus: a subanalysis of the CCMR-3B STUDY. AB - AIMS: This subanalysis of a cross-sectional, nationwide study was undertaken to assess the relationship between healthy lifestyle behaviors and multiple cardiovascular risk factors among people with type 2 diabetes mellitus (T2DM). METHODS: Data collected from 25,454 participants, including demographics, lifestyle behaviors and cardiovascular risk profiles, were analyzed. Blood pressure control as well as blood glucose and blood lipid (3Bs) levels were measured as multi-risk factors for cardiovascular disease. Healthy lifestyle behaviors included regular exercise, nonsmoking status and no alcohol consumption. The relationship between the healthy lifestyle behavior(s) and control of 3B(s) was calculated. RESULTS: Of the 25,454 eligible participants, 4171 (16.4%) were current smokers, 2011 (7.9%) currently consumed alcohol, and 11,174 (43.9%) did not exercise. In total, 654 (2.6%) reported all three unhealthy lifestyle behaviors. Most participants (71.1%) had received at least a high school education and were more likely to smoke and drink as compared to those with lower education. Unhealthy lifestyle behaviors were commonly found in participants with low atherosclerosis risk, such as non-elderly people and those with an above-college education level. Unhealthy lifestyle is associated with poor 3B control and worse medication adherence. CONCLUSIONS: Unhealthy lifestyles are common in Chinese people with T2DM, especially in people who are non-elderly and above-college educated. Interventions aimed at changing risky lifestyle behaviors are required for improved outcomes for Chinese patients with T2DM. PMID- 28341961 TI - From smooth to rough, from water to air: the intertidal habitat of Northern clingfish (Gobiesox maeandricus). AB - The Northern clingfish is a small, Eastern North Pacific fish that can attach to rough, fouled rocks in the intertidal. Their ability to attach to surfaces has been measured previously in the laboratory, and in this study, we show the roughness and fouling of the natural habitat of these fish. We introduce a new method for measuring surface roughness of natural substrates with time-limited accessibility. We expect this method to be broadly applicable in studies of animal/substrate surface interactions in habitats difficult to characterize. Our roughness measurements demonstrate that the fish's ability to attach to very coarse roughness is required in its natural environment. Some of the rocks showed even coarser roughness than the fish could attach to in the lab setting. We also characterized the clingfish's preference for other habitat descriptors such as the size of the rocks, biofilm, and Aufwuchs (macroalgae, encrusting invertebrates) cover, as well as grain size of underlying substrate. Northern clingfish seek shelter under rocks of 15-45 cm in size. These rocks have variable Aufwuchs cover, and gravel is the main underlying substrate type. In the intertidal, environmental conditions change with the tides, and for clingfish, the daily time under water (DTUW%) was a key parameter explaining distribution. Rather than location being determined by intertidal zonation, an 80% DTUW, a finer scale concept of tidal inundation, was required by the fish. We expect that this is likely because the mobility of the fish allows them to more closely track the ideal inundation in the marine intertidal. PMID- 28341963 TI - Is drug-induced sedation endoscopy surgical decision-making process objective and systematic? PMID- 28341964 TI - 'Conservative' approach to periocular necrotising fasciitis with paranasal sinus involvement. PMID- 28341962 TI - Tumour suppressor EP300, a modulator of paclitaxel resistance and stemness, is downregulated in metaplastic breast cancer. AB - PURPOSE: We have previously described a novel pathway controlling drug resistance, epithelial-to-mesenchymal transition (EMT) and stemness in breast cancer cells. Upstream in the pathway, three miRs (miR-106b, miR-93 and miR-25) target EP300, a transcriptional activator of E-cadherin. Upregulation of these miRs leads to the downregulation of EP300 and E-cadherin with initiation of an EMT. However, miRs regulate the expression of many genes, and the contribution to EMT by miR targets other than EP300 cannot be ruled out. METHODS: We used lentiviruses expressing EP300-targeting shRNA to downregulate its expression in MCF-7 cells as well as an EP300-knocked-out colon carcinoma cell line. An EP300 expression plasmid was used to upregulate its expression in basal-like CAL51 and MDA-MB-231 breast cancer cells. Drug resistance was determined by short-term proliferation and long-term colony formation assays. Stemness was determined by tumour sphere formation in both soft agar and liquid cultures as well as by the expression of CD44/CD24/ALDH markers. Gene expression microarray analysis was performed in MCF-7 cells lacking EP300. EP300 expression was analysed by immunohistochemistry in 17 samples of metaplastic breast cancer. RESULTS: Cells lacking EP300 became more resistant to paclitaxel whereas EP300 overexpression increased their sensitivity to the drug. Expression of cancer stem cell markers, as well as tumour sphere formation, was also increased in EP300-depleted cells, and was diminished in EP300-overexpressing cells. The EP300-regulated gene signature highlighted genes associated with adhesion (CEACAM5), cytoskeletal remodelling (CAPN9), stemness (ABCG2), apoptosis (BCL2) and metastasis (TGFB2). Some genes in this signature were also validated in a previously generated EP300 depleted model of breast cancer using minimally transformed mammary epithelial cells. Importantly, two key genes in apoptosis and stemness, BCL2 and ABCG2, were also upregulated in EP300-knockout colon carcinoma cells and their paclitaxel resistant derivatives. Immunohistochemical analysis demonstrated that EP300 expression was low in metaplastic breast cancer, a rare, but aggressive form of the disease with poor prognosis that is characterized by morphological and physiological features of EMT. CONCLUSIONS: EP300 plays a major role in the reprogramming events, leading to a more malignant phenotype with the acquisition of drug resistance and cell plasticity, a characteristic of metaplastic breast cancer. PMID- 28341965 TI - Reliability of a laryngo-pharyngeal esthesiometer and a method for measuring laryngo-pharyngeal mechano-sensitivity in a prospectively recruited cohort of patients. AB - BACKGROUND: There are not reliable methods for measuring laryngo-pharyngeal mechano-sensitivity (LPMS). We aimed to determine the reliability of a new method for measuring LPMS using a new laryngo-pharyngeal esthesiometer (LPEER) in a prospective cohort of dysphagic stroke and non-dysphagic patients. The patients underwent clinical and endoscopic evaluations of swallowing (FESSST). The LPMS assessments consisted of measurements by an expert and a novel rater of the laryngeal-adductor reflex threshold (LART), cough reflex threshold (CRT) and gag reflex threshold (GRT) using the LPEER. We assessed the Bland-Altman limits of agreement, the intraclass correlation coefficients (ICCs) and Spearman correlation coefficients (SCCs). For the inter-rater comparisons, we contrasted the expert and novel raters. A total of 1608 measurements were obtained from 34 dysphagic stroke patients and 33 non-dysphagic patients. The intra-rater ICCs for all reflex thresholds were >0.90. The inter-rater ICCs were 0.87 for the LART, 0.79 for the CRT and 0.70 for the GRT. The intra-rater SCCs for all reflex thresholds were above 0.88 (P < 0.0001). The inter-rater SCC were 0.80 for the LART, 0.79 for the CRT and 0.70 for the GRT (all P < 0.0001). The Bland-Altman plots revealed good agreement for the LART and CRT and moderate agreement for the GRT. The median normal value was 0.14 mN for the LART, 4.4 mN for the CRT and 11.9 mN for the GRT. The median thresholds values in patients with aspiration were LART: 1.31 mN; CRT: 32.9 mN and GRT: 32.9 mN (all P < 0.006 vs normal thresholds). The LPEER exhibited substantial to excellent intra- and inter-rater reliability. PMID- 28341967 TI - New organ-based tube current modulation method to reduce the radiation dose during computed tomography of the head: evaluation of image quality and radiation dose to the eyes in the phantom study. AB - A new organ-based tube current modulation (NOB-TCM) method was designed with the intent to decrease tube current by 30% over a prescribed 90 degrees radial arc across the anterior aspect of the radiosensitive organ, without increasing tube current in the remaining radial arc. We compared a reference scan and five other dose-reducing methods with regard to effects on dose, practicality, and image quality to determine the most effective method for the reduction of the radiation dose to the eyes during CT examinations of the head. We compared the radiation doses to the eyes and physical image quality in different regions of interest for TCM and shielding scans. Three types of TCM scans were performed: longitudinal TCM, angular TCM, and NOB-TCM. A bismuth sheet and lead goggles were each applied for the shielding scan. Relative to the reference scan, the dose to the eye was reduced to 25.88% with NOB-TCM, 44.53% with lead goggles, and 36.91% with a bismuth shield. Relative to the reference scan, the mean signal-to-noise ratio (SNR) was decreased to 8.02% with NOB-TCM, 28.36% with lead goggles, and 32.95% with the bismuth shield. The SNR of the anterior region of interest was decreased to 11.89% with NOB-TCM and 87.89% with the bismuth shield. The average figure of merit was increased by 11.7% with longitudinal TCM and 13.39% with NOB-TCM, compared with the reference scan. NOB-TCM is a superior solution for head CT, including the orbital area, due to the reduction in radiation exposure without significant loss in image quality. PMID- 28341966 TI - Efficacy of single-dose gonadotropin-releasing hormone agonist administration prior to magnetic resonance-guided focused ultrasound surgery for symptomatic uterine fibroids. AB - PURPOSE: To investigate the effects of a single-dose GnRHa on the thermal ablation of MRgFUS in women with symptomatic fibroids. MATERIALS AND METHOD: In this pilot study, a single-dose GnRHa was administered in 17 patients with a total of 20 fibroids. Volume and scaled signal intensity (SSI) as an objective marker of fluid contents were prospectively followed up with serial MR scans. The control group of 17 patients with 19 fibroids were retrospectively enrolled and compared with GnRHa group in terms of non-perfused volume (NPV) and thermal dosimetry to assess the efficiency of thermal ablation. RESULTS: About 29 days after GnRHa administration, SSI and volume of fibroids were reduced by 55.1 and 10.6%, respectively (p < 0.05) but no adverse events were reported. NPV per unit energy (0.046 cm3/J +/- 0.026 vs. 0.031 cm3/J +/- 0.018, p = 0.041) was larger and SSI (8.4 +/- 8.0 vs. 13.9 +/- 12.0, p = 0.053) was lower in GnRHa group. Linear regression analysis showed that these two parameters were in a reverse correlation (p = 0.011). CONCLUSION: GnRHa is supposed to reduce the fluid contents of fibroids including blood vessels and enhance the tissue responsiveness to thermal energy. A single dose prior to MRgFUS has the potential to improve treatment efficiency, while avoiding the side effects of multiple doses of GnRHa. PMID- 28341969 TI - Computed tomographic analysis of the internal structure of the metacarpals and its implications for hand use, pathology, and surgical intervention. AB - The variation of bone structure and biomechanics between the metacarpals is not well characterized. It was hypothesized that their structure would reflect their common patterns of use (i.e., patterns of hand grip), specifically that trabecular bone density would be greater on the volar aspect of all metacarpal bases, that this would be most pronounced in the thumb, and that the thumb diaphysis would have the greatest bending strength. Cross-sections at basal and mid-diaphyseal locations of 50 metacarpals from 10 human hands were obtained by peripheral quantitative computed tomography. The volar and dorsal trabecular densities of each base were measured and characterized using the volar/dorsal density ratio. The polar stress-strain index (SSIp), a surrogate measure of torsional/bending strength, was measured for each diaphysis and standardized for bone length and mass. Comparisons were made using mixed-model analyses of variance (ANOVAs) and post hoc tests. Volar/dorsal trabecular density ratios showed even distribution in all metacarpal bases except for the thumb, which showed greater values on the volar aspect. The thumb, second, and third metacarpals all had high bending strength (SSIp), but the thumb's SSIp relative to its length and trabecular mass was much higher than those of the other metacarpals. Trabecular density of the metacarpal bases was evenly distributed except in the thumb, which also showed higher bending strength relative to its length and mass. Understanding of how these indicators of strength differ across metacarpals may improve both fracture diagnosis and treatment and lays the groundwork for investigating changes with age, hand dominance, and occupation. PMID- 28341970 TI - Impact of dyspnea on advanced cancer patients referred to a palliative radiotherapy clinic. AB - PURPOSE: Dyspnea is a debilitating symptom commonly experienced by advanced cancer patients that can lead to negative effects on function and quality of life (QOL). The present study aims to determine the relationship between dyspnea and other Edmonton Symptom Assessment System (ESAS) symptoms in palliative cancer patients referred to a radiotherapy clinic. METHODS: The presence and severity of dyspnea was measured using the ESAS. All patients that visited a palliative radiotherapy clinic between 1999 to 2002 and 2006 to 2009 and completed the ESAS were included. ESAS scores and other demographic and clinical information were extracted from a prospectively collected database. Statistical tests including chi-squared tests, Spearman correlations, and multivariate analysis were conducted to explore the relationship between dyspnea, other ESAS items, and other demographic factors. Kaplan-Meier overall survival curves were generated based on dyspnea severity. RESULTS: One thousand three hundred forty-four patients were included in the dyspnea analysis; reported moderate or severe dyspnea. Dyspnea severity was significantly associated with eight other ESAS interference severities (p < 0.001). Upon multivariate analysis, greater severity of dyspnea was significantly related to higher ESAS scores for tiredness, nausea, depression, anxious, drowsiness, and poor appetite (p < 0.05). The actuarial median survival time was 6.57 months (95% CI 5.91-7.29 months). There were highly significant differences in overall survival between those with none, mild, and moderate dyspnea (p < 0.0001). CONCLUSION: Cancer patients often experience dyspnea along with a multitude of other symptoms. Moderate and severe dyspnea should be assessed and optimally managed to reduce functional and QOL debilitations. As presence of increased dyspnea severity is associated with worse overall survival, interventions should occur at the end of life to reduce symptom burden in palliative patients. PMID- 28341968 TI - The complex interrelations between two paroxysmal disorders: headache and epilepsy. AB - The interrelations between headache/migraine and epileptic seizures are an interesting topic, still lacking a systematization, which is the objective of the present revision. We organize the general setting on: (a) a distinction between pre-ictal, ictal, post-ictal and inter-ictal headaches, assuming "ictal" as epileptic seizure, and (b) the kind of headache, if it is of migraine type or not. Concerning pre-ictal migraine/headache, the necessity of its differentiation from an epileptic headache presenting as an aura of a seizure is stressed; this is connected with the indefiniteness of the term "migralepsy". The term "migraine aura-triggered seizure" should be used only in front of a proven triggering effect of migraine. Epileptic headache (called also "ictal epileptic headache") is a well-characterized entity, in which different types of head pain may occur and an ictal EEG is necessary for the diagnosis. It may present as an isolated event ("isolated epileptic headache"), requiring a differential diagnosis from other kinds of headache, or it may be uninterruptedly followed by other epileptic manifestations being in this case easily identifiable as an epileptic aura. Hemicrania epileptica is a very rare variant of epileptic headache, characterized by the ipsilaterality of head pain and EEG paroxysms. Ictal non-epileptic headache needs to be differentiated from epileptic headache. Post-ictal headaches are a frequent association of headache with seizures, particularly in patients suffering also from inter-ictal headache-migraine. The reported systematization of the topic led us to suggest a classification which is shown in Appendix. PMID- 28341971 TI - A prospective, observational, multicenter study on risk factors and prophylaxis for low emetic risk chemotherapy-induced nausea and vomiting. AB - PURPOSE: The incidence of and the risk factors for nausea and vomiting in patients undergoing low emetic risk chemotherapy (LEC) are unclear. The aim of the study was to provide information on these topics by performing a multicenter, observational, prospective study. METHODS: The study consisted of patients who were administered first-time LEC that was consistent or inconsistent with current guidelines. Using the visual analog scale, patients recorded their daily food intake and the occurrence and severity of nausea over a 5-day treatment period. RESULTS: The overall incidence of chemotherapy-induced nausea and vomiting did not differ significantly between patients undergoing guideline-consistent (n = 89) or guideline-inconsistent (n = 121) prophylaxis (30.3 vs. 22.3%, respectively; P = 0.19). Logistic regression analysis identified a history of nausea and LEC other than taxanes as independent risk factors associated with nausea and vomiting in patients undergoing LEC. The mean daily visual analog scale scores for nausea severity and a decrease in food intake were <25 mm throughout the entire observation period. CONCLUSIONS: Guideline-consistent prophylaxis appeared to control nausea and vomiting effectively in patients undergoing LEC. However, patients with a history of nausea and receiving LEC other than taxanes should be carefully observed and treatment should be adjusted according to their symptoms. PMID- 28341972 TI - A prospective study of aromatase inhibitor therapy initiation and self-reported side effects. AB - PURPOSE: The objective of this study was to examine the associations between aromatase inhibitors (AIs) and side effects less frequently reported in the literature, including difficulty concentrating, forgetfulness, hair loss, and numbness in the extremities. METHODS: Data were analyzed from a cohort of 146 breast cancer patients initiating AI therapy and followed for 1 year and a cohort of 144 postmenopausal women without a history of cancer followed for 6 months. At baseline (prior to AI therapy for breast cancer patients), and at 3 months, 6 months, and 1 year (for breast cancer patients only), a comprehensive questionnaire was administered that ascertained data on symptoms. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using logistic regression for new onset of symptoms among the breast cancer patients compared to the women without a history of cancer. RESULTS: Among the breast cancer patients, 34.2% were treated with chemotherapy prior to AI treatment. Over the first 6 months of AI treatment, breast cancer patients had significantly higher odds of reporting new onset of forgetfulness (OR 4.00; 95% CI 1.67, 9.59), difficulty concentrating (OR 2.73; 95% CI 1.29; 5.78), hair loss (OR 4.12; 95% CI 1.86, 9.17), and numbness/tingling in the extremities (OR 2.47; 95% CI 1.09, 5.62) compared to women without a history of cancer. Similar increases in odds were observed for the subgroup of women not treated with chemotherapy versus the comparison group. CONCLUSIONS: AI-related symptoms should be monitored and addressed so that adherence to therapy is maintained. PMID- 28341973 TI - Counting the cost of cancer: out-of-pocket payments made by colorectal cancer survivors. AB - PURPOSE: Cancer places a significant cost burden on health services. There is increasing recognition that cancer also imposes a financial and economic burden on patients but this has rarely been quantified outside North America. We investigate out-of-pocket costs (OOPCs) incurred by colorectal (CRC) survivors in Ireland. METHODS: CRC survivors (ICD10 C18-20) diagnosed 6-30 months previously were identified from the National Cancer Registry Ireland and invited to complete a postal questionnaire. Cancer-related OOPC for tests, procedures, drugs, allied medications and household management in approximately the year following diagnosis were calculated. Robust regression was used to identify predictors of OOPC; this was done for all survivors combined and stratified by age (<70 and >=70 years) and employment status (working and not working) at diagnosis. RESULTS: Four hundred ninety-seven CRC survivors completed questionnaires (response rate = 39%). Almost all (90%) respondents reported some cancer-related OOPC. The average total OOPC was ?1589. Stage III at diagnosis was associated with significantly higher OOPCs than other stages in the all-survivor model, in those not working in the employment model and in those under 70 years in the age stratified model. In all-survivor model, those under 70 also had higher OOPCs, as did those in employment. Having one or more children was associated with significantly lower OOPCs in those under 70 years. CONCLUSIONS: Almost all CRC survivors incur cancer-related OOPCs; for some, these are not insignificant. Greater attention should be paid to the development of services to help survivors manage the financial and economic burden of cancer. PMID- 28341975 TI - Longitudinal volumetric and 2D assessment of cerebellar atrophy in a large cohort of children with phosphomannomutase deficiency (PMM2-CDG). AB - OBJECTIVE: We aim to delineate the progression of cerebellar atrophy (the primary neuroimaging finding) in children with phosphomannomutase-deficiency (PMM2-CDG) by analyzing longitudinal MRI studies and performing cerebellar volumetric analysis and a 2D cerebellar measurement. METHODS: Statistical analysis was used to compare MRI measurements [midsagittal vermis relative diameter (MVRD) and volume] of children with PMM2-CDG and sex- and age-matched controls, and to determine the rate of progression of cerebellar atrophy at different ages. RESULTS: Fifty MRI studies of 33 PMM2-CDG patients were used for 2D evaluation, and 19 MRI studies were available for volumetric analysis. Results from a linear regression model showed that patients have a significantly lower MVRD and cerebellar volume compared to controls (p < 0.001 and p < 0.001 respectively). There was a significant negative correlation between age and MVRD for patients (p = 0.014). The rate of cerebellar atrophy measured by the loss of MVRD and cerebellar volume per year was higher at early ages (r = -0.578, p = 0.012 and r = -0.323, p = 0.48 respectively), particularly in patients under 11 years (p = 0.004). There was a significant positive correlation between MVRD and cerebellar volume in PMM2-CDG patients (r = 0.669, p = 0.001). CONCLUSIONS: Our study quantifies a progression of cerebellar atrophy in PMM2-CDG patients, particularly during the first decade of life, and suggests a simple and reliable measure, the MVRD, to monitor cerebellar atrophy. Quantitative measurement of MVRD and cerebellar volume are essential for correlation with phenotype and outcome, natural follow-up, and monitoring in view of potential therapies in children with PMM2-CDG. PMID- 28341976 TI - Development and Evaluation of User-Friendly Single Vial DOTA-Peptide Kit Formulations, Specifically Designed for Radiolabelling with 68Ga from a Tin Dioxide 68Ge/68Ga Generator. AB - PURPOSE: This study was aimed to develop single vial 1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-peptide kits to be used with fractionated eluates from a SnO2-based 68Ge/68Ga generator. PROCEDURES: Kits were formulated with 35 MUg DOTA-Tyr3-Thre8-octreotide, DOTA-[Tyr3]-octreotide and DOTA-[NaI3]-octreotide (DOTATATE, DOTATOC and DOTANOC) and sodium acetate powder, vacuum-dried and stored at -20 degrees C for up to 12 months. Labelling of the kits was carried out with 2 ml 68Ga eluate. Comparative labelling was carried out using aqueous DOTA-peptide stock solutions kept frozen at -20 degrees C for up to 12 months. RESULTS: The quality of the kits was found to be suitable over a 1-year storage period (pH, sterility, endotoxin content, radiolabelling efficiency and radiochemical yields of 68Ga-labelled DOTA peptides). Radiochemical yields ranged from 73 to 83 %, while those obtained from stock solutions from 64 to 79 %. No significant decline in kit labelling yields was observed over a 12-month storage period. CONCLUSION: The single vial kit formulations met the quality release specifications for human administration and appear to be highly advantageous over using peptide stock solutions in terms of stability and user-friendliness. PMID- 28341974 TI - Free radical and superoxide reactivity detection in semen quality assessment: past, present, and future. AB - Oxidative stress is a well-established cause of male infertility, with reactive oxygen species (ROS) impairing sperm production, motility, membrane, and DNA integrity. Currently, most clinics do not test infertile patients for the imbalance between ROS generation and the ability of the antioxidants to scavenge them, although there is a clear need for andrology laboratories to be able to identify and/or quantify seminal oxidative stress. As such there is a clinical urgency for an inexpensive and easy-to-perform assay able to identify oxidative stress in semen. The aim of this review is to provide information on the currently available methods to assess and quantify ROS and particularly superoxide in male reproductive cells, tissues, and fluids which may have a significant clinical utility in identifying men with impaired fertility associated with oxidative stress. Through a deeper understanding of oxidative stress and its assessment options, clinical andrology labs may better assist patients to achieve increased rates of fertility and pregnancy. PMID- 28341978 TI - Antegrade thoracic endovascular aortic repair using an ascending aortofemoral through-and-through wire technique for a severely tortuous aorta associated with rickets. AB - BACKGROUND: Severe aortic tortuosity of the access route often prevents successful complete exclusion of an aneurysm in thoracic endovascular aortic repair (TEVAR). CASE PRESENTATION: We performed antegrade TEVAR on a 79-year-old man with right hemiparesis. We deployed the stent graft from the ascending aorta with a tube graft conduit to treat a descending thoracic aortic aneurysm associated with rickets and multiple comorbidities. Although the application of a ministernotomy diminished the potential advantages of endovascular treatment in view of less invasive surgery, antegrade TEVAR using an ascending aortofemoral through-and-through wire technique was a good option in this patient because a conventional retrograde approach was not feasible due to his severely tortuous aorta. CONCLUSIONS: To avoid device-related complications, it is crucial to make a prudent preoperative decision on a patient-by-patient basis, taking into account the appropriate access site, adjuvant guidewire technique, and adjunctive surgical interventions. PMID- 28341977 TI - Genetic Analysis of FBXO2, FBXO6, FBXO12, and FBXO41 Variants in Han Chinese Patients with Sporadic Parkinson's Disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder and has an elusive etiology. It is likely multifactorial, and genetic defects contribute to its pathogenesis. At least 25 genetic loci and 20 monogenic genes have been identified in monogenic PD. Recessive F-box protein 7 gene (FBXO7) mutations reportedly cause hereditary parkinsonism. To explore the roles of four paralogs (FBXO2, FBXO6, FBXO12, and FBXO41) in PD development, their variants (rs9614, rs28924120, rs6442117, and rs61733550, respectively) were analyzed in 502 Han Chinese patients with PD and 556 age, gender, and ethnicity-matched normal participants in mainland China. Statistically significant differences in genotypic and allelic frequencies were detected only in the FBXO2 variant rs9614 (P = 0.001 and 0.023, respectively; odds ratio 0.819, 95% confidence interval 0.690-0.973) between patients and controls. These results suggest that the FBXO2 variant rs9614 C allele may decrease the PD risk in mainland Han Chinese and may be a biomarker for PD. PMID- 28341980 TI - Implementation and evaluation of a paediatric nurse-driven sedation protocol in a paediatric intensive care unit. AB - BACKGROUND: Optimal sedation and analgesia is a challenge in paediatric intensive care units (PICU) because of difficulties in scoring systems and specific metabolism inducing tolerance and withdrawal. Excessive sedation is associated with prolonged mechanical ventilation and hospitalisation. Adult and paediatric data suggest that goal-directed sedation algorithms reduce the duration of mechanical ventilation. We implemented a nurse-driven sedation protocol in a PICU and evaluated its impact. METHODS: We conducted a before and after protocol implementation study in a population of children aged 0-18 years who required mechanical ventilation for at least 24 h between January 2013 and March 2015. After the protocol implementation in January 2014, nurses managed analgesia and sedation following an algorithm that included the COMFORT behaviour scale (COMFORT-B). Duration of mechanical ventilation was the primary outcome; secondary outcomes were total doses and duration of medications, PICU length of stay, incidence of ventilator-associated pneumonia, and occurrence of withdrawal symptoms. Pre-post analysis followed with segmented regression analysis of interrupted time series was used to assess the effect of protocol. RESULTS: A total of 200 children were analysed, including 107 before implementation and 93 children after implementation of the protocol. After implementation of the protocol, the total number of COMFORT-B scores per day of mechanical ventilation significantly increased from 3.9 +/- 2.5 times during the pre-implementation period to 6.6 +/- 3.5 times during the post-implementation period (p < 10-3). Mean duration of mechanical ventilation tended to be lower in the post implementation period (8.3 +/- 7.3 vs 6.6 +/- 5.6 days, p = 0.094), but changes in either the trend per trimester from pre-implementation to post-implementation (p = 0.933) or the immediate change after implementation (p = 0.923) were not significant with segmented regression analysis. No significant change between pre and post-implementation was shown for total dose of sedatives, withdrawal symptoms, agitation episodes, or unplanned endotracheal extubations. CONCLUSIONS: These results were promising and suggested that implementation of a nurse-driven sedation protocol in a PICU was feasible. Evaluation of sedation and analgesia was better after the protocol implementation; duration of mechanical ventilation and occurrence of withdrawal symptoms tended to be reduced. PMID- 28341979 TI - Are third-generation cephalosporins unavoidable for empirical therapy of community-acquired pneumonia in adult patients who require ICU admission? A retrospective study. AB - BACKGROUND: Third-generation cephalosporins (3GCs) are recommended for empirical antibiotic therapy of community-acquired pneumonia (CAP) in patients requiring ICU admission. However, their extensive use could promote the emergence of extended-spectrum beta-lactamases-producing Enterobacteriaceae. Our aim was to assess whether the use of 3GCs in patients with CAP requiring ICU admission was justified. METHODS: We assessed all patients with CAP who required ICU admission during a 7-year period. We recorded empirical and definitive antibiotic therapies and susceptibility of causative pathogens. Amoxicillin, amoxicillin/clavulanate (A/C) susceptibilities as well as amikacin susceptibility of A/C-resistant strains were recorded. RESULTS: From January 2007 to March 2014, 391 patients were included in the study. Empirical 3GCs were used in 215 patients (55%). Among 267 patients with microbiologically documented CAP (68%), 241 received a beta lactam as definitive therapy, and of those, 3CGs were chosen for 43 patients (18%). Amoxicillin or A/C was active against isolated pathogens in 159 patients (66%), while 39 patients (16%) required a beta-lactam with a broader spectrum than 3GCs. Ninety-four per cent of A/C-resistant strains were amikacin susceptible. CONCLUSIONS: In ICU patients with CAP, 3GCs given on an empirical basis are changed, according to microbiological documentation, for another beta lactam in 82% of cases especially to A/C in the absence of resistance risk factor. In patients evidencing risk factors for A/C-resistant strains infection, 3GCs or antipseudomonal beta-lactams including carbapenem associated with amikacin in the most severe patients seem a relevant empirical antibiotic therapy. This strategy could decrease 3GCs' use. PMID- 28341981 TI - Meta-analysis of Fontan procedure : Extracardiac conduit vs. intracardiac lateral tunnel. AB - This meta-analysis was designed to determine the effect of an intracardiac lateral tunnel (ILT) versus an extracardiac conduit (ECC) on patients undergoing a Fontan procedure. A search of the literature in PubMed, Embase, China Academic Literature, and Wanfang databases yielded 23 studies comprising approximately 1000 patients for analysis. There were statistically significant differences between ILT and ECC in the frequency of early sinus node dysfunction, early total arrhythmias, late supraventricular tachycardia, late sinus node dysfunction, late total arrhythmias, and need for pacemaker. By contrast, no statistically significant differences between the two methods were found in takedown, protein losing enteropathy, thromboembolic events, early supraventricular tachycardia, early mortality, and total mortality. We conclude that an ECC confers some advantages over an ILT, although the underlying mechanism remains unclear. PMID- 28341982 TI - Pocket-sized point-of-care cardiac ultrasound devices : Role in the emergency department. AB - BACKGROUND: Acute breathlessness accounts for 8% of accident and emergency attendances. Point-of-care cardiac ultrasound (US) effectively reduces time to diagnosis. Fast and practical information via pocket-sized cardiac US devices may better the diagnosis in this complex patient group. METHODS: We prospectively enrolled 40 consecutive patients presenting with shortness of breath at the emergency department (ED). Divided into two groups were all adult patients over 18 with acute breathing difficulties (triage category 1-3): 21 patients received a short focused cardiac US scan using a pocket-sized Vscan and 19 patients received no scan. Data were obtained regarding the time taken for diagnosis and treatment, patient length of stay, inpatient mortality and 30-day mortality. RESULTS: In the scanned group 33% of patients had significantly abnormal Vscan results that had the potential to aid diagnosis and guide management. The difference of 20 min between the means of the time to diagnosis between the groups was not significant. DISCUSSION: The individual knowledge of UK emergency physicians regarding basic echocardiography varies greatly. An intuitive approach following a brief tutorial on pocket-size echocardiography was shown to improve diagnostic accuracy in addition to history taking and physical examination by medical students and junior doctors with no previous exposure to echocardiography. Increasing evidence shows the feasibility and benefit of FOCUS echo in the ED and the pocket-sized devices could play a large role. CONCLUSION: The Vscan is a practical, portable device that provides rapid diagnostic information. One third of patients had significant findings on the scans to possibly aid diagnosis and prevent misdiagnosis. This has the potential to reduce time to diagnosis in the ED. PMID- 28341983 TI - [Management of different cardiovascular risk factors with a combination tablet (polypill)]. AB - BACKGROUND: The multifactorial origin of cardiovascular diseases has led to polypharmacy in primary and secondary prophylaxis with evidence-based medications, such as statins, antihypertensive drugs and platelet aggregation inhibitors. The number of prescribed drugs correlates inversely to adherence and can lead to treatment failure. Fixed-dose combination drugs (polypills) could increase the medication adherence of patients, reduce risks and prevent cardiovascular events. METHODS: This review is based on publications that were retrieved from Medline (via PubMed) and The Cochrane Library. The clinical database ClinicalTrials.gov. was also considered. RESULTS: In the studies on primary prevention conducted to date, fixed-dose combinations showed a superior control of risk factors, e.g. hypertension and low-density lipoprotein (LDL) cholesterol compared to placebo and at least non-inferiority compared to usual care. In secondary prevention, the effect of the polypill is mostly on the reduction of blood pressure and LDL cholesterol in non-adherent patients; however, evidence that fixed-drug combinations reduce cardiovascular morbidity and mortality compared to standard therapy is lacking. CONCLUSION: The polypill can be considered as an alternative to polypharmacy after a risk-benefit assessment, especially in non-adherent patients. Ongoing studies are investigating the effect of the polypill on cardiovascular events. Current polypills are limited by the lack of sufficient dosages of the individual components to avoid overtreatment and undertreatment at the individual treatment level. PMID- 28341985 TI - Non-invasive identification of organic materials in historical stringed musical instruments by reflection infrared spectroscopy: a methodological approach. AB - The analysis of historical musical instruments is becoming more relevant and the interest is increasingly moving toward the non-invasive reflection FTIR spectroscopy, especially for the analysis of varnishes. In this work, a specific infrared reflectance spectral library of organic compounds was created with the aim of identifying musical instrument materials in a totally non-invasive way. The analyses were carried out on pure organic compounds, as bulk samples and laboratory wooden models, to evaluate the diagnostic reflection mid-infrared (MIR) bands of proteins, polysaccharides, lipids, and resins by comparing reflection spectra before and after the KK correction. This methodological approach was applied to real case studies represented by four Stradivari violins and a Neapolitan mandolin. PMID- 28341984 TI - Combinatorial requirement of W- and WT-boxes in microbe-associated molecular pattern-responsive synthetic promoters. AB - KEY MESSAGE: The WT-box GGACTTTC belongs to a novel class of MAMP-responsive cis regulatory sequences that are part of combinatorial elements. Microbe-associated molecular pattern (MAMP)-responsive synthetic promoters were generated with two cis-regulatory modules (CRM1 and CRM2) from the Arabidopsis thaliana WRKY30 promoter. Both modules harbour two W-boxes and one WT-box. Mutation analysis of the synthetic promoters and transient gene expression analysis in parsley protoplasts underline the importance of the W- and WT-boxes for MAMP-responsive gene expression and reveal the combinatorial requirement of at least two boxes for full MAMP responsivity. In the context of the native promoter, CRM1 is required for MAMP responsivity, while CRM2 alone is not sufficient. Yeast one hybrid screenings using CRM1 with a transcription factor (TF) only prey library select only WRKY factors. Selection of WRKY26, 40, 41, and 70 requires the W boxes. The WT-box is also required for selection of WRKY26 and 41 in yeast. In plant cells, WRKY26, 40, and 41 act as repressors of MAMP-responsive gene expression, whereas WRKY70 is an activator. To investigate whether the WT-box is also required for WRKY26 and 41 mediated gene expression in plant cells, both were converted into transcriptional activators by adding the GAL4 activating domain (AD). In contrast to yeast, transient gene expression in parsley protoplasts shows that only the W-boxes from CRM1 are required for WRKY41AD activated reporter gene activity but not the WT-box. In addition, WRKY70 activated reporter gene activity in parsley cells does not require the WT-box of CRM1. The results demonstrate the importance of the WT-box as a new cis regulatory sequence for MAMP-responsive gene expression. Based on these and earlier results, two types of WT-boxes are proposed. PMID- 28341986 TI - Enhancing effectiveness of capillary electrophoresis as an analytical tool in the supramolecular acidity modification. AB - A strategic modification of acidity (pK a values) by the non-covalent host-guest interactions is one of the most promising concepts in current supramolecular chemistry. This work is aimed at enhancing the effectiveness of capillary electrophoresis (CE) in determination of pK a shifts caused by such interactions and their thermal dependencies crucial in a deep thermodynamic description. We show how to (i) minimize the systematic errors related to Joule heating, (ii) minimize the influence of a voltage ramp time, (iii) speed up pK a shift identification and estimation, (iv) interpret thermal effects related to two overlapped dynamic equilibria, and (v) determine pK a shifts by an alternative spectrophotometric method (CE-DAD). The proposed solutions were implemented to examine the supramolecular pK a shifts of several coumarin derivatives, caused by a variety of structurally different cyclodextrins. It was revealed that a specific host substitution pattern determines the magnitude of apparent pK a shifts. Accordingly, heptakis(2,6-di-O-methyl)-beta-cyclodextrin induces the much stronger shifts than both non-methylated-beta-cyclodextrin and heptakis(2,3,6-tri O-methyl)-beta-cyclodextrin applied at the same concentration. We also show that insofar as the complexation of 4-hydroxycoumarin and its derivative (coumatetralyl) are similarly exothermic, the thermal effects accompanying the deprotonation process are remarkably different for both molecules. The pK a shift induced by complexation with calixarene was also for the first time determined by a CE method. These observations throw a new light on the background of acidity modification and confirm the applicability of CE as an analytical tool. PMID- 28341987 TI - A facile synthesis of novel three-dimensional magnetic imprinted polymers for rapid extraction of bovine serum albumin in bovine calf serum. AB - A novel three-dimensional (3D) magnetic imprinted polymer was prepared with bovine serum albumin as the template molecule, dopamine as the functional monomer, and a graphene oxide and carbon nanotube hybrid 3D nanocomposite as the carrier. The preparation conditions for the 3D magnetic molecularly imprinted polymers were optimized. The 3D magnetic molecularly imprinted polymers were characterized in detail by scanning electron microscopy, Fourier transform infrared spectroscopy, and vibrating sample magnetometry. The 3D magnetic molecularly imprinted polymers possessed a fast adsorption rate and excellent adsorption performance toward bovine serum albumin, with a maximum adsorption capacity of 78.12 mg g-1. The extraction conditions, including the washing solvent, the pH of the eluent, and the desorption time, were also optimized. Combined with high-performance liquid chromatography, the 3D magnetic molecularly imprinted polymers were successfully applied to enrich and separate bovine serum albumin from bovine calf serum samples with recoveries of 84.0-94.5%. Graphical Abstract ?. PMID- 28341988 TI - Unexpected differences between planar and column liquid chromatographic retention of 1-acenaphthenol enantiomers controlled by supramolecular interactions involving beta-cyclodextrin at subambient temperatures. AB - We report the results of experimental work focusing on host-guest supramolecular complex creation between macrocyclic compound (beta-cyclodextrin) and 1 acenaphthenol enantiomers (racemic mixture) in liquid phase composed of 35% acetonitrile in water (v/v) at different temperatures ranging from 0 to 90 degrees C. Experimental setup involved several analytical protocols based on classical non-forced flow planar chromatography (RP-18 TLC plates), micro-TLC (RP 18 W HPTLC plates), column chromatography (HPLC with C-18 and C-30 stationary phases), as well as UV-Vis spectrophotometry and optical microscopy. It has been found that under various planar chromatographic conditions (stationary plates type, chamber shape and volume, development mode, and saturation) non-typical retention properties (extremely high retention) of 1-acenaphthenol at subambient temperatures can be observed. To our knowledge, reported experimental results are in opposition to currently described retention models based on column chromatographic investigation of host-guest complexes (where in case of strong interaction of given analyte with macrocyclic mobile phases additive, which itself is non strongly retarded by stationary phase-close to the retention of dead volume marker, the retention of target compounds is shortened at low temperatures). To explain this TLC phenomenon that may have in our opinion a number of practical applications, especially for selective high throughput separation involving microchromatographic and/or microfluidic devices as well fractionation and extraction protocols (using, e.g., bar extraction systems), several experiments were conducted focusing on (i) acenaphthenol chromatography under different instrumental conditions, (ii) cyclodextrin retention measured as analyte or mobile phase additive, (iii) plate development time under different mobile phases and temperature settings, (iv) various column chromatographic conditions including C-30 and two C-18 stationary phases, (v) UV-Vis spectrophotometry, and (vi) microscopy inspection of precipitated CD acenaphthenol crystals. Analysis of collected data has revealed that the most probable reasons for TLC retention behavior of 1-acenaphthenol under beta cyclodextrin additive conditions can be associated with (i) solubility changes of created host-guest complex, (ii) kinetics of solid complex precipitation, and (iii) differences in analysis time between planar and column chromatography. Because precipitation phenomenon may have a massive impact on analytes quantification involving macrocycles as the mobile phase additives, our previously reported data concerning a number of low-molecular compounds (mainly steroids and non steroidal endocrine disrupting chemicals) using HPLC methodology based on binary mobile phases without and with beta-cyclodextrin and its hydroxypropyl derivative were re-examined and results discussed. Considering these data and the whole data set reported presently, the enhanced model of chromatographic retention driven by host-guest interaction was proposed. PMID- 28341989 TI - A fully validated bioanalytical method using an UHPLC-MS/MS system for quantification of DNA and RNA oxidative stress biomarkers. AB - A new, rapid and effective ultra-high-performance liquid chromatography method with mass spectrometry detection is described for the separation and quantification of 8-hydroxy-2-deoxyguanosine, 8-hydroxyguanosine and creatinine in human urine. The present study uses an isotope-labelled internal standard ([15N]5-8-hydroxy-2-deoxyguanosine), a BIO core-shell stationary phase and an isocratic elution of methanol and water. Sample preparation of human urine was performed by solid-phase extraction (SPE) on Oasis HLB cartridges with methanol/water 50:50 (v/v) elution. Extraction recoveries ranged from 98.1% to 109.2%. Biological extracts showed high short-term stability. Several aspects of this procedure make it suitable for both clinical and research purposes: a short elution time of less than 3.2 min, an intra-day precision of 2.5-8.9%, an inter day precision of 3.4-8.7% and low limits of quantification (27.7 nM for 8 hydroxyguanosine, 6.0 nM for 8-hydroxy-2-deoxyguanosine). Finally, simultaneous analysis of DNA and RNA oxidative stress biomarkers is a useful tool for monitoring disease progression in neurodegenerative disorders and cancer. Graphical abstract UHPLC-MS/MS analysis of DNA and RNA oxidative stress biomarkers. PMID- 28341990 TI - [Rare complication of a chronic perianal fistula]. PMID- 28341991 TI - Altered interhemispheric functional connectivity in patients with anisometropic and strabismic amblyopia: a resting-state fMRI study. AB - PURPOSE: Altered brain functional connectivity has been reported in patients with amblyopia by recent neuroimaging studies. However, relatively little is known about the alterations in interhemispheric functional connectivity in amblyopia. The present study aimed to investigate the functional connectivity patterns between homotopic regions across hemispheres in patients with anisometropic and strabismic amblyopia under resting state. METHODS: Nineteen monocular anisometropic amblyopia (AA), 18 strabismic amblyopia (SA), and 20 normal-sight controls (NC) were enrolled in this study. After a comprehensive ophthalmologic examination, resting-state fMRI scanning was performed in all participants. The pattern of the interhemispheric functional connectivity was measured with the voxel-mirrored homotopic connectivity (VMHC) approach. VMHC values differences within and between three groups were compared, and correlations between VMHC values and each the clinical variable were also analyzed. RESULTS: Altered VMHC was observed in AA and SA patients in lingual gyrus and fusiform gyrus compared with NC subjects. The altered VMHC of lingual gyrus showed a pattern of AA > SA > NC, while the altered VMHC of fusiform gyrus showed a pattern of AA > NC > SA. Moreover, the VMHC values of lingual gyrus were positively correlated with the stereoacuity both in AA and SA patients, and the VMHC values of fusiform gyrus were positively correlated with the amount of anisometropia just in AA patients. CONCLUSION: These findings suggest that interhemispheric functional coordination between several homotopic visual-related brain regions is impaired both in AA and SA patients under resting state and revealed the similarities and differences in interhemispheric functional connectivity between the anisometropic and strabismic amblyopia. PMID- 28341993 TI - A Method for Preparing Silver Nanoparticle Suspensions in Bulk for Ecotoxicity Testing and Ecological Risk Assessment. AB - Methods are needed to prepare stable suspensions of engineered nanoparticles in aqueous matrixes for ecotoxicity testing and ecological risk assessments. We developed a novel method of preparing large volumes of silver nanoparticles (AgNP) in suspension using a commercially available rotor-stator dispersion mill. AgNP in powder form (PVP capped, 30-50 nm) was suspended in deionized water and natural lake water at 1 g/L and the addition of 0.025% (w/v) gum arabic (GA) increased stability over 2 weeks after preparation. The concentrations of total and dissolved Ag in the suspensions did not change significantly over this period. Analysis of hydrodynamic diameters of the major peaks in suspension using dynamic light scattering showed that suspensions prepared with GA were stable, and this was confirmed by single-particle ICP-MS analysis. This method for dispersing AgNPs provides an inexpensive, yet reliable method for preparing suspensions for toxicity testing and ecosystem level studies of the fate and biological effects of AgNPs in aquatic ecosystems. PMID- 28341992 TI - A semi-automated volumetric software for segmentation and perfusion parameter quantification of brain tumors using 320-row multidetector computed tomography: a validation study. AB - PURPOSE: We developed a semi-automated volumetric software, NPerfusion, to segment brain tumors and quantify perfusion parameters on whole-brain CT perfusion (WBCTP) images. The purpose of this study was to assess the feasibility of the software and to validate its performance compared with manual segmentation. METHODS: Twenty-nine patients with pathologically proven brain tumors who underwent preoperative WBCTP between August 2012 and February 2015 were included. Three perfusion parameters, arterial flow (AF), equivalent blood volume (EBV), and Patlak flow (PF, which is a measure of permeability of capillaries), of brain tumors were generated by a commercial software and then quantified volumetrically by NPerfusion, which also semi-automatically segmented tumor boundaries. The quantification was validated by comparison with that of manual segmentation in terms of the concordance correlation coefficient and Bland Altman analysis. RESULTS: With NPerfusion, we successfully performed segmentation and quantified whole volumetric perfusion parameters of all 29 brain tumors that showed consistent perfusion trends with previous studies. The validation of the perfusion parameter quantification exhibited almost perfect agreement with manual segmentation, with Lin concordance correlation coefficients (rho c) for AF, EBV, and PF of 0.9988, 0.9994, and 0.9976, respectively. On Bland-Altman analysis, most differences between this software and manual segmentation on the commercial software were within the limit of agreement. CONCLUSIONS: NPerfusion successfully performs segmentation of brain tumors and calculates perfusion parameters of brain tumors. We validated this semi-automated segmentation software by comparing it with manual segmentation. NPerfusion can be used to calculate volumetric perfusion parameters of brain tumors from WBCTP. PMID- 28341994 TI - Exploring the effect of confinement on water clusters in carbon nanotubes. AB - Using armchair-type single-walled carbon nanotubes (SWCNTs) of different sizes as model compounds for lignite, the effect of water molecule confinement on the water-holding capacity of lignite pores was investigated. Results indicated that the water-holding capacity of pores with diameters of <10 nm was eight times larger than that of pores with diameters of 100 nm. The configuration of the cluster of water molecules in each SWCNT and the binding energy between each SWCNT and the water molecules within it were calculated by means of density functional theory using a hybrid functional: M06-2X/6-311+G**, 6-31G*. The results prove that the configurations of the water molecules in the SWCNTs are very different to their configuration in the unconfined state. In vacuum, the cluster of three water molecules adopted a trimer configuration, while they presented a linear configuration in the 6.78 A SWCNT. Similarly, in vacuum, the cluster of five water molecules formed a five-membered ring, while they favored a linear configuration in the 6.78 A SWCNT, a zigzag configuration in the 8.14 A SWCNT, and a trimer + 1 + 1 configuration (i.e., a trimer plus two isolated water molecules) in the 9.49 A, 10.85 A, and 13.75 A SWCNTs. There was found to be a degree of competition between the coupling energy of the water molecules with the SWCNT and the hydrogen bonding among the water molecules. When the diameter of the SWCNT was >1 nm, the hydrogen bonding among the water molecules dominated, while the coupling energy of the water molecules with the SWCNT amounted to only 30-40% of the total interaction energy of the water molecules. Graphical Abstract Computed equilibrium structures of five water molecules confined in SWCNTs with diameters of 6.78 A, 8.14 A, 9.49 A, 10.85 A, and 13.75 A, and in vacuum. PMID- 28341995 TI - Performance of wave function and density functional methods for water hydrogen bond spin-spin coupling constants. AB - Spin-spin coupling constants in water monomer and dimer have been calculated using several wave function and density functional-based methods. CCSD, MCSCF, and SOPPA wave functions methods yield similar results, specially when an additive approach is used with the MCSCF. Several functionals have been used to analyze their performance with the Jacob's ladder and a set of functionals with different HF exchange were tested. Functionals with large HF exchange appropriately predict 1 J O H , 2 J H H and 2h J O O couplings, while 1h J O H is better calculated with functionals that include a reduced fraction of HF exchange. Accurate functionals for 1 J O H and 2 J H H have been tested in a tetramer water model. The hydrogen bond effects on these intramolecular couplings are additive when they are calculated by SOPPA(CCSD) wave function and DFT methods. Graphical Abstract Evaluation of the additive effect of the hydrogen bond on spin-spin coupling constants of water using WF and DFT methods. PMID- 28341996 TI - Structural insights into ligand binding of PGRP1 splice variants in Chinese giant salamander (Andrias davidianus) from molecular dynamics and free energy calculations. AB - Peptidoglycan (PGN) recognition proteins (PGRPs) are important pattern recognition receptors of the innate immune system. A number of PGRP splicing variants produced by alternative splicing of PGRP genes have been reported. However, several important aspects of interactions between PGRP splice variants and their ligands are still unclear. In the present study, three dimensional models of salamander PGRP1 (adPGRP1) and its splice variant (adPGRP1a) were constructed, and their key amino acids involved in interacting with PGNs were analyzed. The results revealed that adPGRP1a has a typical PGRPs structure containing five beta-sheets and four alpha-helices, while adPGRP1 contained five beta-sheets and only one alpha-helix due to the lack of 51 amino acids at its C terminus. Molecular docking revealed that van der Waals and Coulombic interactions contributed to interactions in the protein-ligand complex. Further binding energy of adPGRP-PGNs computed by the MM-PBSA method revealed that adPGRP1a and adPGRP1 might selectively bind to different PGNs; the former might selectively bind Dap-type PGNs and the latter both types of PGNs. In addition, the binding energy of each residue of adPGRP1a and adPGRP1 was also calculated, revealing that residues involved in the interaction of protein-ligand complexes were different in adPGRP1a and adPGRP1. These results provided a first insight into the potential basis for interaction between PGRPs generated by alternative splicing and PGN derivatives. PMID- 28341998 TI - IRE1 signaling exacerbates Alzheimer's disease pathogenesis. AB - Altered proteostasis is a salient feature of Alzheimer's disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress and abnormal protein aggregation. ER stress triggers the activation of the unfolded protein response (UPR), a signaling pathway that enforces adaptive programs to sustain proteostasis or eliminate terminally damaged cells. IRE1 is an ER-located kinase and endoribonuclease that operates as a major stress transducer, mediating both adaptive and proapoptotic programs under ER stress. IRE1 signaling controls the expression of the transcription factor XBP1, in addition to degrade several RNAs. Importantly, a polymorphism in the XBP1 promoter was suggested as a risk factor to develop AD. Here, we demonstrate a positive correlation between the progression of AD histopathology and the activation of IRE1 in human brain tissue. To define the significance of the UPR to AD, we targeted IRE1 expression in a transgenic mouse model of AD. Despite initial expectations that IRE1 signaling may protect against AD, genetic ablation of the RNase domain of IRE1 in the nervous system significantly reduced amyloid deposition, the content of amyloid beta oligomers, and astrocyte activation. IRE1 deficiency fully restored the learning and memory capacity of AD mice, associated with improved synaptic function and improved long-term potentiation (LTP). At the molecular level, IRE1 deletion reduced the expression of amyloid precursor protein (APP) in cortical and hippocampal areas of AD mice. In vitro experiments demonstrated that inhibition of IRE1 downstream signaling reduces APP steady-state levels, associated with its retention at the ER followed by proteasome-mediated degradation. Our findings uncovered an unanticipated role of IRE1 in the pathogenesis of AD, offering a novel target for disease intervention. PMID- 28342000 TI - Efficacy and safety of percutaneous ultrasound guided radiofrequency ablation for treating cervical metastatic lymph nodes from papillary thyroid carcinoma. AB - PURPOSE: The aim of this study was to assess the effectiveness and safety of ultrasound guided percutaneous radiofrequency ablation (RFA) of cervical metastatic lymph nodes (LNs) from papillary thyroid carcinoma. METHODS: 54 metastatic LNs confirmed by percutaneous biopsy in 33 patients with previous total thyroidectomy and radioiodine therapy were enrolled in this retrospective study. US and contrast-enhanced ultrasound (CEUS) examinations were performed before ablation. Follow-up consisted of conventional US, CEUS, thyroglobulin (Tg) level at 1, 3, 6, and 12 months and every 6 months thereafter. In 3 months after ablation, US-guided core needle biopsy (CNB) was performed in the center, at the edge of the ablation area to exclude recurrence. RESULTS: Technical success was obtained in all 54 lymph nodes (100%) without immediate or later major complications occurred. With a mean follow-up of 21 +/- 4 months (range 12-24 months), there were no evidence of recurrence at ablated sites. After RFA, 33 metastatic LNs completely disappeared (33/54, 61.1%) and 21 metastatic lymph nodes remained as small scarlike lesions (21/54, 38.9%) at the last follow-up visit. The mean volume reduction ratio (VRR) was 32.7 +/- 8.6% (range 21.2 59.3%), 46.8 +/- 9.7% (range 33.6-68.1%), 62.5 +/- 12.1% (range 42.5-95.4%), 77.1 +/- 10.6% (range 54.3-100.0%), 89.2 +/- 8.3% (range 68.7-100.0%) and 94.9 +/- 5.3% (range 78.2-100.0%) at 1, 3, 6, 12, 18 and 24 months after RFA respectively. Significant differences in the VRR were found between every two follow-up visits (P < 0.001). At the last follow-up visit, the mean serum Tg level decreased from 10.2 +/- 5.1 ng/ml (range 0.8-16.2 ng/ml) to 1.1 +/- 0.8 ng/ml (range 0.2-3.1 ng/ml) (P < 0.001). CONCLUSIONS: Ultrasound guided percutaneous RFA for cervical metastatic LNs from papillary thyroid carcinoma is a feasible, effective and safe therapy. This procedure shows a nonsurgical therapeutic option that can eradicate the lesions with a very low complication rate. PMID- 28341999 TI - Immunological memory to hyperphosphorylated tau in asymptomatic individuals. AB - Several reports have described the presence of antibodies against Alzheimer's disease-associated hyperphosphorylated forms of tau in serum of healthy individuals. To characterize the specificities that can be found, we interrogated peripheral IgG+ memory B cells from asymptomatic blood donors for reactivity to a panel of phosphorylated tau peptides using a single-cell screening assay. Antibody sequences were recovered, cloned, and expressed as full-length IgGs. In total, 52 somatically mutated tau-binding antibodies were identified, corresponding to 35 unique clonal families. Forty-one of these antibodies recognize epitopes in the proline-rich and C-terminal domains, and binding of 26 of these antibodies is strictly phosphorylation dependent. Thirteen antibodies showed inhibitory activity in a P301S lysate seeded in vitro tau aggregation assay. Two such antibodies, CBTAU-7.1 and CBTAU-22.1, which bind to the proline rich and C-terminal regions of tau, respectively, were characterized in more detail. CBTAU-7.1 recognizes an epitope that is similar to that of murine anti PHF antibody AT8, but has different phospho requirements. Both CBTAU-7.1 and CBTAU-22.1 detect pathological tau deposits in post-mortem brain tissue. CBTAU 7.1 reveals a similar IHC distribution pattern as AT8, immunostaining (pre)tangles, threads, and neuritic plaques. CBTAU-22.1 shows selective detection of neurofibrillary changes by IHC. Taken together, these results suggest the presence of an ongoing antigen-driven immune response against tau in healthy individuals. The wide range of specificities to tau suggests that the human immune repertoire may contain antibodies that can serve as biomarkers or be exploited for therapy. PMID- 28342001 TI - GLI-mediated Keratin 17 expression promotes tumor cell growth through the anti apoptotic function in oral squamous cell carcinomas. AB - PURPOSE: Keratin 17 (KRT17) has been suggested as a potential diagnostic marker of squamous cell carcinoma including oral squamous cell carcinoma (OSCC). The current study was conducted to clarify the function of KRT17 and its expression mechanism in OSCC. METHODS: Immunohistochemical analyses were carried out to examine the expression of KRT17, GLI family zinc finger (GLI)-1, GLI-2, or cleaved caspase-3 in OSCCs. The expression of KRT17, GLI-1, or GLI-2 was investigated among OSCC cell lines, and the effects of loss-of-function of KRT17 or GLI, using siRNA or inhibitor, on the cell growth of the OSCC cell line HSC-2 particularly with respect to apoptosis were examined. RESULTS: Immunohistochemical analyses of tissue specimens obtained from 78 OSCC patients revealed that KRT17 was not observed in non-tumor regions but was strongly expressed at high frequencies in tumor regions. Knockdown of KRT17 increased the number of cleaved caspase-3-positive cells, leading to the reduction of cell number. Loss-of-function of GLI-1 or GLI-2 also increased the cell numbers of apoptotic cells positive for staining of Annexin-V and propidium iodide (PI) and the terminal deoxynucleotidyl transferase dUTP-biotin nick-end labeling (TUNEL) method, and induced DNA fragmentation. This inhibitory effect on cell growth was partially rescued by exogenous KRT17 expression. In the KRT17-positive regions in OSCCs, GLI-1 or GLI-2 was frequently detected, and the number of cells with cleaved caspase-3 positive was decreased. CONCLUSIONS: KRT17 promotes tumor cell growth, at least partially, through its anti-apoptotic effect as a result of the KRT17 overexpression by GLIs in OSCC. PMID- 28342002 TI - A retrospective study comparing the outcomes and toxicities of intensity modulated radiotherapy versus two-dimensional conventional radiotherapy for the treatment of children and adolescent nasopharyngeal carcinoma. AB - PURPOSE: To compare the clinical outcomes and toxicities of two-dimensional conventional radiotherapy (2D-CRT) and intensity-modulated radiotherapy (IMRT) for the treatment of children and adolescent nasopharyngeal carcinoma (NPC). METHODS: A total of 176 children with non-metastatic NPC treated at Sun Yat-sen University Cancer Center between October 2003 and September 2013 were included in this study. Of the 176 patients, 74 received 2D-CRT and 102 were treated with IMRT. The clinical outcomes and acute and late toxicities were determined and compared. RESULTS: The IMRT group achieved significantly higher overall survival (OS) (90.4% vs. 76.1% at 5 year, P = 0.007) and disease-free survival (DFS) (85.7% vs. 71.2%, P = 0.029) mainly due to an improvement in locoregional relapse free survival (LRRFS) (97.9 vs. 88.3%, P = 0.049). After stratification by disease stage, IMRT provided significant benefits for patients with stage III-IV disease in terms of OS, LRRFS and DFS. Multivariate analyses indicated that the treatment group (2D-CRT vs. IMRT) was a prognostic factor for OS, LRRFS and DFS. A significant reduction in Grade 2-4 xerostomia (52.7 vs. 34.3%, P = 0.015) and hearing loss (40.5 vs. 22.5%, P = 0.010) was observed in patients treated by IMRT. CONCLUSION: IMRT provides better locoregional relapse-free survival and overall survival, especially in late-stage children and adolescent NPC patients, and is associated with a lower incidence of Grade 2-4 xerostomia as well as hearing loss compared with 2D-CRT. Distant metastasis remains a challenge in the treatment of children and adolescent NPC. PMID- 28342003 TI - Lung carcinoma progression and survival versus amino- and carboxyl-parathyroid hormone-related protein expression. AB - PURPOSE: Expression of the carboxyl PTHrP region of parathyroid hormone-related protein (PTHrP) is a positive prognostic indicator in women with lung cancer, but amino PTHrP is a negative indicator in other lung cancer patients. This project investigated whether PTHrP could be expressed as predominantly amino PTHrP or carboxyl PTHrP in individual lung carcinomas. It also assessed domain-specific effects on cancer progression and patient survival. METHODS: PTHrP immunoreactivities were analyzed versus survival in a human lung cancer tissue microarray (TMA). Growth was compared in athymic mice for isogenic lung carcinoma xenografts differing in expression of amino and carboxyl PTHrP domains. RESULTS: In the TMA, 33 of 99 patient tumors expressed only one PTHrP domain, while 54 expressed both. By Cox regression, the hazard ratio for cancer-specific mortality (95% confidence interval) was 2.6 (1.28-5.44) for amino PTHrP (P = 0.008) and 0.6 (0-2.58) for carboxyl PTHrP (P = 0.092). Xenografts of H358 lung adenocarcinoma cells that overexpressed amino PTHrP grew twice as fast as isogenic low PTHrP tumors in athymic mice, but growth of tumors expressing amino plus carboxyl PTHrP was not significantly different than growth of the control tumors. In summary, the presence of amino PTHrP signifies worse prognosis in lung cancer patients. In mouse xenografts, this effect was abrogated if carboxyl PTHrP was also present. CONCLUSION: Amino PTHrP and carboxyl PTHrP can vary independently in different lung carcinomas. Carboxyl PTHrP may temper the stimulatory effect of amino PTHrP on cancer progression. PMID- 28342004 TI - Modulatory effects of Terminalia arjuna against domoic acid induced toxicity in Caco-2 cell line. AB - Domoic acid is a potent marine algal toxin produced by diatomic genus of Pseudo nitzschia causing amnesic shell fish poisoning. Domoic acid toxicosis mainly involves excitotoxic effects coupled with oxidative stress. The present study was aimed to evaluate the protective effects of hydro-alcoholic extract of Terminalia arjuna (TA) against domoic acid induced toxic effects in Caco-2 cell line. It was observed that the toxicity induced by domoic acid in Caco-2 cells was mediated by oxidative insult leading to morphological changes, DNA damage and apoptosis. In our study pre-treatment of the cells with TA (10, 20 and 30 MUg/ml) showed significant protection against domoic acid induced morphological, oxidative and apoptotic damages in a dose dependent manner. The effect of phytocompounds present in TA viz., kaempferol and arjungenin showed significant protection against domoic acid induced toxicity in Caco-2 cell line. Hence, it could be inferred that the protective effect of TA extract against domoic acid induced toxicity could be due to the individual or synergistic effects of kaempferol and argungenin. However, further clinical studies are warranted to consider TA as a natural remedy to prevent amnesic shell fish poisoning. PMID- 28342005 TI - Genetic polymorphisms for 19 autosomal STR loci of Chongqing Han ethnicity and phylogenetic structure exploration among 28 Chinese populations. AB - The allele frequencies and forensic statistical parameters of 19 autosomal short tandem repeat (STR) loci (D8S1179, D21S11, D7S820, CSF1P0, D3S1358, THOl, D13S317, D16S539, D2S1338, D19S433, vWA, TPOX, D18S51, D5S818, FGA, D6S1043, Penta D, Penta E, and D12S391) included in the GoldeneyeTM DNA ID system 20A kit were obtained in 671 Chinese Han individuals residing in Chongqing, Southwest China. All 19 STR loci were identified in agreement with the Hardy-Weinberg equilibrium. A total of 238 alleles were observed with corresponding allele frequencies that varied from 0.0007 to 0.5119. The combined power of discrimination and the combined probability of exclusion for 19 STR loci in the Chongqing Han population were 0.99999999999999999999998954 and 0.99999998387, respectively. The findings indicated that the 19 autosomal STR loci were highly polymorphic in the Chongqing Han population and can be used as a powerful tool in personal identification and parentage testing. Our genetic study enriched the Chinese local forensic reference database. Population comparisons and phylogenetic analyses revealed that genetic heterogeneity widely existed among the Chongqing Han, Xinjiang Uyghur, and Kazakh populations as well as demonstrated that genetic similarity was tightly associated with those of close geographic origin or of the same ethnic origin. PMID- 28342006 TI - Potential synergistic effects of a mixture of mineral trioxide aggregate (MTA) cement and Bacillus subtilis in dental caries treatment. AB - Bacillus subtilis is nonpathogenic in humans and produces a number of useful substances and, therefore, this bacterium is used in probiotic therapy. There have been trials of B. subtilis for patients with periodontitis, but not for patients with caries. Similarly, mineral trioxide aggregate (MTA) cement has been widely used for endodontic treatment, but there are few reports of its use for caries. Therefore, examinations were performed regarding the benefits of addition of B. subtilis to MTA cement for treatment of dental caries. Indirect pulp capping with a mixture of MTA cement and B. subtilis spore powder is effective for avoiding pulpectomy or tooth extraction in such cases (personal communication). This study was planned to examine the scientific basis of this clinical finding, with examination of possible synergistic effects of MTA cement and B. subtilis. From these experiments, the following five results were obtained: (1) B. subtilis did not proliferate in liquid-culture media at pH >=10. (2) B. subtilis proliferated when mixed with MTA cement. (3) There was no significant difference in proliferation of B. subtilis under aerobic and microaerobic conditions. (4) B. subtilis exhibited antibacterial effects on Staphylococcus aureus and Lactobacillus casei. (5) MTA cement exhibited antibacterial effects on S. aureus and Streptococcus mutans, but not on B. subtilis. These results support the hypothesis that a combination of B subtilis and MTA cement is likely to be clinically useful for treatment of dental caries. PMID- 28342007 TI - The effect of LED on blood microcirculation during chronic wound healing in diabetic and non-diabetic patients-a prospective, double-blind randomized study. AB - Chronic wounds, especially in diabetic patients, represent a challenging health issue. Since standard treatment protocols often do not provide satisfactory results, additional treatment methods-like phototherapy using low-level light therapy-are being investigated. The aim of our study was to evaluate the effect of phototherapy with light-emitting diodes on chronic wound treatment in diabetic and non-diabetic patients. Since a sufficient blood supply is mandatory for wound healing, the evaluation of microcirculation in the healthy skin at a wound's edge was the main outcome measure. Forty non-diabetic patients and 39 diabetics with lower limb chronic wounds who were referred to the University Medical Center Ljubljana between October 2012 and June 2014 were randomized to the treated and control groups. The treated group received phototherapy with LED 2.4 J/cm2 (wavelengths 625, 660, 850 nm) three times a week for 8 weeks, and the control group received phototherapy with broadband 580-900 nm and power density 0.72 J/cm2. Microcirculation was measured using laser Doppler. A significant increase in blood flow was noted in the treated group of diabetic and non-diabetic patients (p = 0.040 and p = 0.033), while there was no difference in the control groups. Additional Falanga wound bed score evaluation showed a significant improvement in both treated groups as compared to the control group. According to our results, phototherapy with LED was shown to be an effective additional treatment method for chronic wounds in diabetic and non-diabetic patients. PMID- 28342009 TI - Severe Aspergillus Pneumonia and Pulmonary Artery Hypertension in a Child with Autosomal Recessive Chronic Granulomatous Disease and Selective IgA Deficiency. PMID- 28342010 TI - Aridity promotes bet hedging via delayed hatching: a case study with two temporary pond crustaceans along a latitudinal gradient. AB - Climate change does affect not only average rainfall and temperature but also their variation, which can reduce the predictability of suitable conditions for growth and reproduction. This situation is problematic for inhabitants of temporary waters whose reproductive success depends on rainfall and evaporation that determine the length of the aquatic phase. For organisms with long-lived dormant life stages, bet hedging models suggest that a fraction of these should stay dormant during each growing season to buffer against the probability of total reproductive failure in variable environments. Thus far, however, little empirical evidence supports this prediction in aquatic organisms. We study geographic variation in delayed hatching of dormant eggs in natural populations of two crustaceans, Branchinella longirostris and Paralimnadia badia, that occur in temporary rock pools along a 725 km latitudinal aridity gradient in Western Australia. Consistent with bet hedging theory, populations of both species were characterised by delayed hatching under common garden conditions and hatching fractions decreased towards the drier end of the gradient where the probability of reproductive success was shown to be lower. This decrease was most pronounced in the species with the longer maturation time, presumably because it is more sensitive to the higher prevalence of short inundations. Overall, these findings illustrate that regional variation in climate can be reflected in differential investment in bet hedging and hints at a higher importance of delayed hatching to persist when the climate becomes harsher. Such strategies could become exceedingly relevant as determinants of vulnerability under climate change. PMID- 28342008 TI - Alterations of the oxidative status in rat hippocampus and prodepressant effect of chronic testosterone enanthate administration. AB - In a last few decades, anabolic-androgenic steroids (AASs) abuse has become serious health concern especially among adolescents. AASs abuse has been reported to be involved in pathogenesis of various mood disorders, including depression. In order to evaluate the effects of chronic (6 weeks) testosterone enanthate (TE) treatment in supraphysiological dose and exercise on depression-like behavior in rats, 32 male rats were divided into four groups: control (C), testosterone enanthate (T, 20 mg/kg/w, s.c.), exercise (E, swimming for 1 h/day), and combined group-testosterone enanthate plus exercise (T + E). TE produced prodepressant effect in tail suspension test (TST) parameters compared to the control and exercise groups, while exercise induced the opposite effect. Simultaneous TE administration along with exercise attenuated the antidepressant effect of exercise reversing the parameters of TST to the control values. Oxidative stress markers in rat hippocampus were significantly altered following applied protocols. TE administration increased index of lipid peroxidation (TBARS) and decreased superoxide dismutase activity (SOD), while exercise induced the opposite effect, with no change in glutathione (GSH) levels. Our results indicate that TE chronic treatment resulted in clear depressive-like behavior, even abolishing beneficial antidepressant effects of exercise in TST that was accompanied with increased oxidative damage in rat hippocampus. The antidepressant effect of exercise correlated with the improvement of redox status in hippocampal tissue. Behavioral parameters obtained in TST significantly correlated with the levels of oxidative stress markers. PMID- 28342011 TI - Acquiring nutrients from tree leaves: effects of leaf maturity and development type on a generalist caterpillar. AB - The rapid growth and prolific reproduction of many insect herbivores depend on the efficiencies and rates with which they acquire nutrients from their host plants. However, little is known about how nutrient assimilation efficiencies are affected by leaf maturation or how they vary between plant species. Recent work showed that leaf maturation can greatly decrease the protein assimilation efficiency (PAE) of Lymantria dispar caterpillars on some tree species, but not on species in the willow family (Salicaceae). One trait of many species in the Salicaceae that potentially affects PAE is the continuous (or "indeterminate") development of leaves throughout the growing season. To improve our understanding of the temporal and developmental patterns of nutrient availability for tree feeding insects, this study tested two hypotheses: nutrients (protein and carbohydrate) are more efficiently assimilated from immature than mature leaves, and, following leaf maturation, nutrients are more efficiently assimilated from indeterminate than determinate tree species. The nutritional physiology and growth of a generalist caterpillar (L. dispar) were measured on five determinate and five indeterminate tree species while their leaves were immature and again after they were mature. In support of the first hypothesis, caterpillars that fed on immature leaves had significantly higher PAE and carbohydrate assimilation efficiency (CAE), as well as higher protein assimilation rates and growth rates, than larvae that fed on mature leaves. Contrary to the second hypothesis, caterpillars that fed on mature indeterminate tree leaves did not have higher PAE than those that fed on mature determinate leaves, while CAE differed by only 3% between tree development types. Instead, "high-PAE" and "low-PAE" tree species were found across taxonomic and development categories. The results of this study emphasize the importance of physiological mechanisms, such as nutrient assimilation efficiency, to explain the large variation in host plant quality for insect herbivores. PMID- 28342012 TI - Predation risk influences feeding rates but competition structures space use for a common Pacific parrotfish. AB - In terrestrial systems it is well known that the spatial patterns of grazing by herbivores can influence the structure of primary producer communities. On coral reefs, the consequences of varied space use by herbivores on benthic community structure are not well understood, nor are the relative influences of bottom-up (resource abundance and quality), horizontal (competition), and top-down (predation risk) factors in affecting spatial foraging behaviors of mobile herbivorous fishes. In the current study we quantified space use and feeding rates of the parrotfish, Chlorurus spilurus, across a strong gradient of food resources and predator and competitor abundance across two islands with drastically different fisheries management schemes. We found evidence that while feeding rates of this species are affected by direct interference competition and chronic predation risk, space use appears to be primarily related to exploitative competition with the surrounding herbivore community. We found no evidence that predation risk influences diurnal foraging space use in this small bodied parrotfish species. Additionally, we found the influence of chronic predation risk on feeding rates of this species to be less dramatic than the results of recent studies that used model predators to measure acute behavioral responses of other species of herbivorous fishes. Our results indicate that the non consumptive effects of predators on the foraging behaviors of coral reef herbivores may be less dramatic than previously thought. PMID- 28342015 TI - A Prognostic Model for Predicting Overall Survival in Patients with Peritoneal Surface Malignancy of an Appendiceal Origin Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy. AB - INTRODUCTION: Our aim was to develop a prognostic model for predicting overall survival following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with appendiceal adenocarcinoma and peritoneal metastasis. METHODS: A retrospective analysis of a prospectively maintained database for all patients treated for appendiceal adenocarcinoma with peritoneal metastasis from 1989 to 2012 was conducted. RESULTS: Overall, 734 (50.7%) males and 715 (49.3%) females, with a mean age at presentation of 48.6 years, were included. Prognostic variables identified in a univariate Cox analysis included sex, tumor recurrence, tumor histology, Peritoneal Carcinomatosis Index, age at diagnosis, lesion size, completeness of cytoreduction (CC) score, distant metastasis, lymph node status, and use of HIPEC. A multivariate Cox analysis identified distant metastasis, CC score, tumor histology, HIPEC use, and sex as independently predictive of survival. A prognostic index was derived and four risk groups were categorized (<=1, 2-4, 5-10, and >=10). Median survival for the four risk groups differed significantly: 240 months for patients with a prognostic score <=1 versus 235, 78.4, and 19.4 months for the cohort of patients with a prognostic score of 2-4, 5-10 and >=10, respectively (p = 0.000). An internal validation of our prognostic model was carried out on a series of 379 randomly selected patients from our data, which provided corresponding estimates. CONCLUSIONS: Our prognostic model demonstrated a significant difference in overall survival for patients stratified by our derived prognostic scores. External validation of this model in other cohorts of patients is needed. PMID- 28342013 TI - The Evaluation of Folic Acid-Deficient or Folic Acid-Supplemented Diet in the Gestational Phase of Female Rats and in Their Adult Offspring Subjected to an Animal Model of Schizophrenia. AB - Although folic acid (FA) supplementation is known to influence numerous physiological functions, especially during pregnancy, little is known about its direct effects on the mothers' health. However, this vitamin is essential for the health of the mother and for the normal growth and development of the fetus. Thus, the aim of this study was (1) to evaluate the cognitive effects and biochemical markers produced by the AIN-93 diet (control), the AIN-93 diet supplemented with different doses of FA (5, 10, and 50 mg/kg), and a FA-deficient diet during pregnancy and lactation in female mother rats (dams) and (2) to evaluate the effect of maternal diets on inflammatory parameters in the adult offspring which were subjected to an animal model of schizophrenia (SZ) induced by ketamine (Ket). Our study demonstrated through the Y-maze test that rats subjected to the FA-deficient diet showed significant deficits in spatial memory, while animals supplemented with FA (5 and 10 mg/kg) showed no deficit in spatial memory. Our results also suggest that the rats subjected to the FA-deficient diet had increased levels of carbonylated proteins in the frontal cortex and hippocampus and also increased plasma levels of homocysteine (Hcy). Folate was able to prevent cognitive impairments in the rats supplemented with FA (5 and 10 mg/kg), data which may be attributed to the antioxidant effect of the vitamin. Moreover, FA prevented protein damage and elevations in Hcy levels in the rats subjected to different doses of this vitamin (5, 10, and 50 mg/kg). We verified a significant increase of the anti-inflammatory cytokine (interleukin-4 (IL-4)) and a reduction in the plasma levels of proinflammatory cytokines (interleukin-6 (IL 6)) and TNF-alpha) in the dams that were subjected to the diets supplemented with FA (5, 10, and 50 mg/kg), showing the possible anti-inflammatory effects of FA during pregnancy and lactation. In general, we also found that in the adult offspring that were subjected to an animal model of SZ, FA had a protective effect in relation to the levels of IL-4, IL-6, and TNF-alpha, which indicates that the action of FA persisted in the adult offspring, since FA showed a lasting effect on the inflammatory response, which was similar in both the dams and their offspring. In conclusion, the importance of supplementation with FA during pregnancy and lactation should be emphasized, not only for the benefit of the offspring but also for the health of the mother. All this is due to the considerable protective effect of this vitamin against oxidative damage, cognitive impairment, hyperhomocysteinemia, immune function, and also its ability in preventing common processes in post-pregnancy stages, as well as in reducing the risks of neurodevelopmental disorders and enhancing fetal immune development. PMID- 28342014 TI - Serum Hepcidin and Soluble Transferrin Receptor in the Assessment of Iron Metabolism in Children on a Vegetarian Diet. AB - The aim of this study was to assess the effect of vegetarian diet on iron metabolism parameters paying special attention to serum hepcidin and soluble transferrin receptor (sTfR) concentrations in 43 prepubertal children (age range 4.5-9.0 years) on vegetarian and in 46 children on omnivorous diets. There were no significant differences according to age, weight, height, and body mass index (BMI) between vegetarian and omnivorous children. Vegetarians had similar intake of iron and vitamin B12 and a significantly higher intake of vitamin C (p < 0.05) compared with non-vegetarians. Hematologic parameters and serum iron concentrations were within the reference range in both groups of children. Serum transferrin levels were similar in all subjects; however, ferritin concentrations were significantly (p < 0.01) lower in vegetarians than in omnivores. In children on a vegetarian diet, median hepcidin levels were lower (p < 0.05) but sTfR concentrations significantly higher (p < 0.001) compared with omnivorous children. In the multivariate regression model, we observed associations between hepcidin level and ferritin concentration (beta = 0.241, p = 0.05) in the whole group of children as well as between hepcidin concentration and CRP level (beta = 0.419, p = 0.047) in vegetarians. We did not find significant associations with concentration of sTfR and selected biochemical, anthropometric, and dietary parameters in any of the studied groups of children. As hematologic parameters and iron concentrations in vegetarians and omnivores were comparable and ferritin level was lower in vegetarians, we suggest that inclusion of novel markers, in particular sTfR (not cofounded by inflammation) and hepcidin, can better detect subclinical iron deficiency in children following vegetarian diets. PMID- 28342016 TI - Severity of Psoriasis Differs Between Men and Women: A Study of the Clinical Outcome Measure Psoriasis Area and Severity Index (PASI) in 5438 Swedish Register Patients. AB - BACKGROUND: Psoriasis is a common skin disease and moderate to severe psoriasis is associated with a dose-dependent risk for metabolic and cardiovascular morbidity. It has previously been speculated that women have less severe psoriasis, as men are overrepresented in psoriasis registers and consume more care. OBJECTIVE: The objective of this study was to investigate, for the first time, the sex differences in the severity of psoriasis using the gold standard of severity measurement, the Psoriasis Area and Severity Index (PASI), and the distinct elements of the PASI score. DESIGN, SETTING AND PARTICIPANTS: This was a cross-sectional study based on the national registry for systemic treatment of psoriasis in Sweden (PsoReg), with 5438 patients experiencing moderate to severe psoriasis. Differences in the PASI score and its elements at enrolment were tested by multivariable ordinal logistic regressions. MAIN OUTCOME MEASURES: The different components of the PASI score were used to analyze the assessment of disease severity. For each body area (head, arms, trunk, and legs), the score of the plaque characteristics and degree of skin involvement were used as outcomes. RESULTS: Women had statistically significantly lower median PASI scores (5.4) than men (7.3) [p < 0.001], which was consistent across all ages. The difference remained statistically significant in a multivariable linear regression. The itemized PASI analyses from the Mann-Whitney-Wilcoxon tests and the adjusted ordinal logistic regressions confirmed that women had significantly lower scores than men in all areas of the body, except for the head. No differences in the use of medications prior to enrolment could be found that may cause this difference between the sexes. CONCLUSIONS: As the PsoReg contains the detailed disease measurement PASI, which was traditionally used for selected participants in clinical studies only, a nationwide unselected population could be investigated. The fact that women have less severe psoriasis can explain the dominance of males in the systemic treatment of psoriasis. These findings motivate a gender perspective in the management of psoriasis and in the prevention and management of its comorbidities. PMID- 28342017 TI - Primary Localized Cutaneous Amyloidosis: A Systematic Treatment Review. AB - BACKGROUND: Primary localized cutaneous amyloidosis (PLCA) is characterized by extracellular deposition of heterogenic amyloid proteins in the skin without systemic involvement. Lichen amyloidosis, macular amyloidosis, and (primary localized cutaneous) nodular amyloidosis are different subtypes of PLCA. OBJECTIVE: The aim of this study was to review the current reported treatment options for PLCA. METHODS: This systematic review was based on a search in the PubMed database for English and German articles from 1985 to 2016. RESULTS: Reports on the treatment of PLCA were limited predominantly to case reports or small case series. There were a few clinical trials but these lacked control groups. A variety of treatment options for PLCA were reported including retinoids, corticosteroids, cyclophosphamide, cyclosporine, amitriptyline, colchicine, cepharanthin, tacrolimus, dimethyl sulfoxide, vitamin D3 analogs, capsaicin, menthol, hydrocolloid dressings, surgical modalities, laser treatment, and phototherapy. CONCLUSION: No definitive recommendation of preferable treatment procedures can be made based on the analyzed literature. Randomized controlled trials are needed to offer patients an evidence-based therapy with high-quality standardized treatment regimens for PLCA. PMID- 28342019 TI - Dopa-responsive dystonia presenting with predominant hemifacial dystonia. PMID- 28342020 TI - Idiopathic orbital myositis presenting as cluster headache: a case report. PMID- 28342018 TI - Overexpression of OsGATA12 regulates chlorophyll content, delays plant senescence and improves rice yield under high density planting. AB - Agronomic traits controlling the formation, architecture and physiology of source and sink organs are main determinants of rice productivity. Semi-dwarf rice varieties with low tiller formation but high seed production per panicle and dark green and thick leaves with prolonged source activity are among the desirable traits to further increase the yield potential of rice. Here, we report the functional characterization of a zinc finger transcription factor, OsGATA12, whose overexpression causes increased leaf greenness, reduction of leaf and tiller number, and affects yield parameters. Reduced tillering allowed testing the transgenic plants under high density which resulted in significantly increased yield per area and higher harvest index compared to wild-type. We show that delayed senescence of transgenic plants and the corresponding longer stay green phenotype is mainly due to increased chlorophyll and chloroplast number. Further, our work postulates that the increased greenness observed in the transgenic plants is due to more chlorophyll synthesis but most significantly to decreased chlorophyll degradation, which is supported by the reduced expression of genes involved in the chlorophyll degradation pathway. In particular we show evidence for the down-regulation of the STAY GREEN RICE gene and in vivo repression of its promoter by OsGATA12, which suggests a transcriptional repression function for a GATA transcription factor for prolonging the onset of senescence in cereals. PMID- 28342021 TI - Establishment of immortalized mouse intestinal epithelial cells line and study of effects of Arg-Arg on inflammatory response. AB - Primary mouse intestinal epithelial cells (MIEs) are not ideal models for long term culture in vitro and a limited amount of approximate three generations. In addition, the mechanism that arginine-arginine dipeptide (Arg-Arg) regulates mouse intestinal inflammatory response remains unknown. Therefore, the aim of this study was to establish immortal MIEs and study the effects of Arg-Arg on inflammatory response after challenging the MIEs with lipopolysaccharide (LPS) or staphylococcal enterotoxin C (rSEC). Our data showed that immortalized MIEs could be cultured over 100 generations. The immortalized MIEs showed positive reaction against cytokeratine 18 antigen, E-cadherin, and peptide transporters (Pept1) using indirect immunofluorescence. Cytokeratine 18 and Pept1 can be expressed in immortalized MIEs by immunoblotting. Fatty acid-binding proteins (FABPs) and villin known as intestinal epithelial cell functional protein were constitutively expressed in immortalized MIEs. For inflammatory response, these results showed that Arg-Arg can decrease the LPS-induced expression of IL-1beta and the rSEC induced expression of TNF-alpha; however, it can upregulate the LPS-induced expression of IL-6 and TNF-alpha and the rSEC-induced expression level of IL 1beta. In addition, in the MAPK signaling pathway, pSAPK/JNK and p-Erk1/2 in LPS with Arg-Arg treatment were upregulated than that in LPS treatment. p-p38 in LPS with Arg-Arg treatment was attenuated than that in LPS treatment. pSAPK/JNK and p p38 in rSEC with Arg-Arg treatment were enhanced than that in rSEC treatment. Conversely, p-Erk1/2 in rSEC with Arg-Arg treatment was attenuated than that in rSEC treatment. These novel findings suggest that Arg-Arg dipeptide plays an important role for regulation of the immunologic balance in mouse intestinal inflammatory response. PMID- 28342022 TI - Identifying connexin expression and determining gap junction intercellular communication in rainbow trout cells. AB - Gap junctions are groups of membrane-bound channels that allow the passage of small molecules and ions between cells, permitting cell-cell communication. Because of their importance in cell homeostasis, gap junction presence and function were characterized in three commonly studied rainbow trout cell lines, namely RTgill-W1, RTgutGC, and RTG-2. Firstly, gap junction presence was determined by screening for gap junction protein alpha 7 and alpha 1 (GJA7 and GJA1) presence at the transcript level and GJA7 at the protein level. GJA7 was successfully identified at both the transcript and protein levels, and GJA1 was detected at the transcript level in all three cell lines. This is the first report of a GJA7 full-length transcript sequence in rainbow trout cells. Gap junction function, as determined by gap junction intercellular communication (GJIC), was examined using Lucifer yellow dye migration with the scrape and load technique; visualized by fluorescence microscopy. Phorbol 12-myristate 13-acetate (PMA), a gap junction inhibitor, was used to confirm the presence of functional gap junctions. Effects of serum deprivation on GJIC were also monitored; 24-h serum deprivation resulted in greater dye migration compared with 30-min serum deprivation. Both RTG-2 and RTgill-W1 showed significant dye migration that was inhibited by PMA while RTgutGC did not. Human foreskin fibroblast (HFF-1) cells were used as a positive control for gap junction presence and function. Taken together, our study shows that rainbow trout cells express connexin transcripts and proteins, and RTG-2 and, to a lesser extent, RTgill-W1 cells are able to perform GJIC. PMID- 28342023 TI - Biogenic synthesis of Marsilea quadrifolia gold nanoparticles: a study of improved glucose utilization efficiency on 3T3-L1 adipocytes. AB - This study aims mainly to provide an insight and understanding of the effect of glucose utilization efficiency of biogenic gold nanoparticles (GNPs) synthesized through the mediation of Marsilea quadrifolia (M. quadrifolia) methanol extract on 3T3-L1 adipocytes. The biosynthesized GNPs were characterized by UV visible spectrophotometry and FTIR. Simultaneously, the nature, stability, and morphological characteristics were analyzed by XRD, TG-DTA, SEM-EDS, HRTEM, and SAED. The results of characterization studies were used to assess the properties of GNPs. The in vitro cytotoxicity screening indicates that 100 MUM of biogenic GNPs were displayed 71.23 +/- 1.56% of cellular viability in 3T3-L1 adipocyte cells. Subsequently, increased glucose utilization of biosynthesized GNPs based on a dose-dependent manner on 3T3-L1 has also been demonstrated. The effect of GNPs (30 MUg) on glucose uptake was higher than that of insulin and metformin. Moreover, the observed results clearly highlight that the biogenic GNPs have higher efficiency of glucose utilization and cellular viability in 3T3-L1 adipocytes with lower toxicity. PMID- 28342025 TI - Social media: physicians-to-physicians education and communication. AB - PURPOSE OF REVIEW: Physician to physician communication is essential for the transfer of ideas, surgical experience, and education. Social networks and online video educational contents have grown exponentially in recent years changing the interaction among physicians. RECENT FINDINGS: Social media platforms can improve physician-to-physician communication mostly through video education and social networking. There are several online video platforms for orthopedic surgery with educational content on diagnosis, treatment, outcomes, and surgical technique. Social networking instead is mostly centered on sharing of data, discussion of confidential topics, and job seeking. Quality of educational contents and data confidentiality represent the major drawbacks of these platforms. Orthopedic surgeons must be aware that the quality of the videos should be better controlled and regulated to avoid inaccurate information that may have a significant impact especially on trainees that are more prone to use this type of resources. Sharing of data and discussion of confidential topics should be extremely secure according the HIPAA regulations in order to protect patients' confidentiality. PMID- 28342024 TI - Towards optimization of odonto/osteogenic bioengineering: in vitro comparison of simvastatin, sodium fluoride, melanocyte-stimulating hormone. AB - Tissue engineering has emerged as a potential therapeutic option for dental problems in recent years. One of the policies in tissue engineering is to use both scaffolds and additive factors for enhancing cell responses. This study aims to evaluate and compare the effect of three types of biofactors on poly caprolactone-poly-ethylene glycol-poly caprolactone (PCL-PEG-PCL) nanofibrous scaffold on human dental pulp stem cell (hDPSCs) engineering. The PCL-PEG-PCL copolymer was synthesized with ring opening polymerization method, and its nanofiber scaffold was prepared by electrospinning method. Nanofibrous scaffold seeded hDPSCs were treated with sodium fluoride (NaF), melanocyte-stimulating hormone (MSH), or simvastatin (SIM). Non-treated nanofiber seeded cells were utilized as control. The viability, biocompatibility, adhesion, proliferation rate, morphology, osteo/odontogenic potential, and the expression of tissue specific genes were studied. The results showed that significant higher results demonstrated significant higher adhesive behavior, viability, alizarin red activity, and dentin specific gene expression in MSH- and SIM-treated cells (p < 0.05). This study is unique; in that, it compares the effects of different treatments for optimization of dental tissue engineering. PMID- 28342026 TI - High dose rate brachytherapy source measurement intercomparison. AB - This work presents a comparison of air kerma rate (AKR) measurements performed by multiple radiotherapy centres for a single HDR 192Ir source. Two separate groups (consisting of 15 centres) performed AKR measurements at one of two host centres in Australia. Each group travelled to one of the host centres and measured the AKR of a single 192Ir source using their own equipment and local protocols. Results were compared to the 192Ir source calibration certificate provided by the manufacturer by means of a ratio of measured to certified AKR. The comparisons showed remarkably consistent results with the maximum deviation in measurement from the decay-corrected source certificate value being 1.1%. The maximum percentage difference between any two measurements was less than 2%. The comparisons demonstrated the consistency of well-chambers used for 192Ir AKR measurements in Australia, despite the lack of a local calibration service, and served as a valuable focal point for the exchange of ideas and dosimetry methods. PMID- 28342027 TI - A comparative evaluation of Ac225 vs Bi213 as therapeutic radioisotopes for targeted alpha therapy for cancer. AB - The Ac225:Bi213 generator is the mainstay for preclinical and clinical studies of targeted alpha therapy for cancer. Both Ac225 (four alpha decays) and Bi213 (one alpha decay) are being used to label targeting vectors to form the alpha immunoconjugate for cancer therapy. This paper considers the radiobiological and economic aspects of Ac225 vs Bi213 as the preferred radioisotope for preclinical and clinical TAT. The in vitro and in vivo evidence and the role of DNA repair processes is examined. The maximum tolerance dose and therapeutic gain are endpoints for comparison. Ac225 has the higher therapeutic gain, when normalised to equal alpha production. However, the slow repair of double strand breaks reduces this advantage. Comparisons are made for the specific energy deposition in targeted and non-targeted cells, for endothelial cells by direct or indirect targeting, the need for sparing agents to save critical organs and cost considerations for preclinical and clinical trials and clinical use. Overall, Ac225 is found to have the better or equal performance to Bi213 at a much lower cost. PMID- 28342028 TI - Disparities in Knee and Hip Arthroplasty Outcomes: an Observational Analysis of the ACS-NSQIP Clinical Registry. AB - BACKGROUND: Disparities in total joint arthroplasty (TJA) have largely been studied in single center studies and using administrative data. Our objective was to investigate differences in TJA outcomes in white men, black men, white women, and black women using a large international registry. METHODS: We used 2010-2013 data from the ACS-NSQIP to identify four groups of adults (white men, black men, white women, black women) who underwent primary total knee arthroplasty (TKA) or total hip arthroplasty (THA). We compared differences in (1) surgical complications (mortality, pulmonary embolism, wound infection, sepsis, blood loss requiring transfusion, myocardial infarction, pneumonia, acute renal failure, and a composite representing occurrence of one or more adverse outcomes) and (2) discharge to a nursing home. RESULTS: We identified 62,075 TKA and 39,334 THA patients. For TKA, 35.3% were white men, 57.2% white women, 1.9% black men, and 5.6% black women. White and black women were significantly more likely to experience our composite outcome when compared to their male counterparts (16.5 and 14.1% for white women and white men; P < .001) (18.3 and 14.3% for black women and black men; P = .002); higher complications for women were explained by higher transfusion rates in women (14.9 vs 12.2% for white women and men, 16.4 vs 11.7% for black; P < .001 for both). For TKA, blacks (compared to whites) and women (compared to men) were significantly more likely to be discharged to a nursing home. Results were similar for THA. CONCLUSIONS: In contrast to prior studies, we found that complications after primary TJA were generally similar among white and black men and women with the exception of markedly higher transfusion rates among women of both racial groups. PMID- 28342030 TI - Time Pattern of Exercise-Induced Changes in Type I Collagen Turnover after Prolonged Endurance Exercise in Humans. AB - Type I collagen is known to adapt to physical activity, and biomarkers of collagen turnover indicate that synthesis can be influenced by a single intense exercise bout, but the exact time pattern of these latter changes are largely undescribed. In the present study, 17 healthy young males had their plasma concentrations of the carboxyterminal propeptide of type I procollagen (PICP), a marker of collagen formation, and the immunoactive carboboxyterminal cross-linked telopeptide (ICTP), a marker of collagen resorption, measured before and immediately postexercise, as well as 1, 2, 3, 4, 5, and 6 days after completion of a marathon run (42 km). Serum concentrations of creatine kinase (S-CK) were measured as an indicator of muscular breakdown in response to the exercise bout. After a transient decrease in collagen formation immediately after exercise (plasma PICP concentration: 176 +/- 17 MUg/liter to 156 +/- 9 MUg/liter)(P < 0.05), concentrations rose in the days following the marathon, peaked 72 hours after exercise (197 +/- 8 MUg/liter)(P < 0.05 versus basal), and returned to basal values similar to those 5 days postexercise (170 +/- 10 MUg/liter). Apart from a short increase immediately after exercise, collagen resorption did not change from basal levels throughout the remaining period (P > 0.05). Muscle breakdown was elevated during the days following the exercise and peaked 24 hours after the exercise (S-CK concentration: 3133 +/- 579 U/liter). The findings in the present study indicate that type I collagen synthesis is accelerated in response to prolonged strenuous exercise, reaching a peak after 3 days and returning to preexercising levels 5 days after the completion of a marathon run. PMID- 28342029 TI - Self-Awareness and Cultural Identity as an Effort to Reduce Bias in Medicine. AB - In response to persistently documented health disparities based on race and other demographic factors, medical schools have implemented "cultural competency" coursework. While many of these courses have focused on strategies for treating patients of different cultural backgrounds, very few have addressed the impact of the physician's own cultural background and offered methods to overcome his or her own unconscious biases. In hopes of training physicians to contextualize the impact of their own cultural background on their ability to provide optimal patient care, the authors created a 14-session course on culture, self reflection, and medicine. After completing the course, students reported an increased awareness of their blind spots and that providing equitable care and treatment would require lifelong reflection and attention to these biases. In this article, the authors describe the formation and implementation of a novel medical school course on self-awareness and cultural identity designed to reduce unconscious bias in medicine. Finally, we discuss our observations and lessons learned after more than 10 years of experience teaching the course. PMID- 28342031 TI - Ibrutinib in CLL: a focus on adverse events, resistance, and novel approaches beyond ibrutinib. AB - Bruton's tyrosine kinase (BTK), a mediator in B cell receptor signaling has been successfully exploited as a therapeutic target in treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Ibrutinib is a BTK inhibitor that has shown excellent efficacy in treatment-naive, heavily pre treated, and high-risk CLL/SLL. With remarkable efficacy, good oral bioavailability, and modest adverse events profile, ibrutinib use is likely to continue to increase. As data with ibrutinib use in CLL matures, concerns regarding adverse events and drug resistance have emerged. New insights into mechanisms of ibrutinib resistance in CLL have uncovered potential therapeutic targets. Several promising novel agents are currently in early phases of development for overcoming ibrutinib resistance in CLL/SLL. We provide a comprehensive analysis of emerging adverse events profile of ibrutinib, summarize our current understanding of ibrutinib resistance in CLL, and review promising novel therapeutic tools to overcome this challenge. PMID- 28342032 TI - Densoviruses in oyster Crassostrea ariakensis. AB - Densoviruses have short ssDNA genomes and mainly infect arthropods. To characterize viral nucleic acid in shellfish, oysters (Crassostrea ariakensis) were analyzed using viral metagenomics. Two large de novo assembled contigs, CaaDV1 and CaaDV2, consisting of nearly complete densovirus genomes (5860 nucleotides (nt) and 4034 nt) with two major ambisense protein coding regions were identified. Several potential non-structural proteins and capsid proteins were encoded by these genomes, but these were divergent from the existing densoviral species. The NS1 protein of the two CaaDVs shared 43.3%~61.5% amino acid identities with the sea star-associated densovirus and cherax quadricarinatus densovirus, with the four species clustering by phylogenetic analysis. This is the first report of densovirus detection in shellfish, increasing the potential host range of densoviruses and the genetic diversity of the genus Ambidensovirus. PMID- 28342033 TI - Sequencing and phylogenetic analysis of tobacco virus 2, a polerovirus from Nicotiana tabacum. AB - The complete genome sequence of a new virus, provisionally named tobacco virus 2 (TV2), was determined and identified from leaves of tobacco (Nicotiana tabacum) exhibiting leaf mosaic, yellowing, and deformity, in Anhui Province, China. The genome sequence of TV2 comprises 5,979 nucleotides, with 87% nucleotide sequence identity to potato leafroll virus (PLRV). Its genome organization is similar to that of PLRV, containing six open reading frames (ORFs) that potentially encode proteins with putative functions in cell-to-cell movement and suppression of RNA silencing. Phylogenetic analysis of the nucleotide sequence placed TV2 alongside members of the genus Polerovirus in the family Luteoviridae. To the best our knowledge, this study is the first report of a complete genome sequence of a new polerovirus identified in tobacco. PMID- 28342034 TI - Molecular characterization of a new begomovirus infecting Mirabilis jalapa in northern India. AB - Begomoviruses are whitefly-transmitted single-stranded DNA viruses that are responsible for considerable economic losses. A begomovirus, alphasatellite and betasatellite were characterized in a Mirabilis jalapa plant exhibiting severe leaf curling and mottling symptoms. The complete viral genome shared highest sequence identity of 87% with pedilanthus leaf curl virus (AM712436), reported from Pakistan. Additionally, the viral genome was 84% identical to that of chilli leaf curl India virus (KX951415) and 83% identical to that of tobacco curly shoot virus (GU1999584), which were previously reported to infect M. jalapa in India and China, respectively. Based on the ICTV criterion for begomovirus species demarcation (>=91% sequence identity for the complete genome), the virus represents a new species, for which we propose the name Mirabilis leaf curl virus. The alphasatellite and betasatellite sequences were similar to the corresponding sequences of ageratum yellow vein India alphasatellite (KU852743; 99% identity) and tomato leaf curl Patna betasatellite (HQ180394; 86% identity) sequences, respectively. This report describes a new begomovirus-satellite disease complex in M. jalapa. PMID- 28342035 TI - Prediction of cortical bone porosityIn Vitro by microcomputed tomography. AB - The high importance of intracortical porosity for mechanical strength of cortical bone has been established. The contribution of other parameters of microstructure such as osteon dimensions for strength is in discussion. The aim of this study was to evaluate the predictive value of microcomputed tomography (uCT) for porosity and other microstructural parameters of cortical bone in cortical bone biopsies. Femoral cortical bone specimens from the middiaphysis of 24 patients were harvested during the procedure of total hip replacement at the location where normally one hole (O 4.5 mm) for the relief of the intramedullary pressure is placed.In vitro intracortical porosity and bone mineral density (BMD) measurements by uCT were compared with structural parameters assessed in histological sections of the same specimens. A strong correlation was found between intracortical porosity measured by uCT and histological porosity (r=0.95,P<0.0001). Porosity measured by uCT was also a strong predictor for other parameters describing dimensions of porous structures. BMD-1 was associated with osteonal area (r=-0.76,P<0.0001). We consider the measurement of porosity by uCT as a very potent procedure for assessing intracortical porosity and parameters related to porous structures of cortical bone nondestructivelyin vitro. PMID- 28342039 TI - Italian Spine Society National Congress SICV&GIS Naples, Italy May 11-13, 2017 ABSTRACTS. PMID- 28342038 TI - Coronary artery calcium in breast cancer survivors after radiation therapy. AB - The purpose of the current study is to investigate whether breast cancer survivors after radiation therapy have a higher burden of coronary artery calcium as a potential surrogate of radiation-induced accelerated coronary artery disease. 333 patients were included. 54 patients underwent chest CT >= 6 months after the start of radiation therapy (radiation therapy group), while 279 patients had a CT scan either prior to or without undergoing radiation therapy (RT). Coronary artery calcium was quantified from CT by applying a threshold based automated algorithm. Mean age at diagnosis was similar (p = 0.771) between RT (57.4 +/- 13.1 years) and NoRT (58.0 +/- 11.9 years). Median time between radiation therapy and CT was 2 years. The groups showed no significant differences in race, smoking history, cancer laterality, or cancer stage. 39 (72.2%) of RT patients had a coronary artery calcium score of 0, compared to 201 (72.0%) in patients without radiation therapy. Median coronary artery calcium burden for both groups was not significantly different (p = 0.982), nor when comparing patients who underwent left- versus right-sided radiation therapy (p = 0.453). When adjusting for the time between diagnosis and CT, radiation therapy patients had a significantly lower risk of a positive coronary artery calcium score. In conclusion, breast cancer survivors after radiation therapy are not more likely to show coronary artery calcium on follow-up CT imaging. Our results thus do not support radiation-induced accelerated coronary artery disease as an explanation for higher rates of heart disease in this group. PMID- 28342041 TI - Utility of MR imaging in the evaluation of colon cancer. PMID- 28342040 TI - Ancient parasites from endemic deer from "CUEVA PARQUE DIANA" archeological site, Patagonia, Argentina. AB - The narrow Andean-Patagonian temperate rainforest strip in the west of southern South America is inhabited by two endemic species of cervids, the southern pudu (Pudu puda) and the huemul (Hippocamelus bisulcus), both cataloged as near threatened and threatened species, respectively. One of the possible causes of their declined number is the susceptibility to livestock diseases. Significant zooarchaeological records of both deer have been found throughout the Holocene from Patagonia. The present contribution reports the first paleoparasitological results obtained from coprolites of endemic deer from the archeological site "Cueva Parque Diana," Neuquen Province, Argentina, and discusses the possible diseases found in ancient times. Thirty-four coprolites were fully processed, rehydrated, homogenized, sieved, subjected to spontaneous sedimentation, and examined by light microscopy. Thirty samples contained parasite remains. The presence of diverse parasitic diseases such as trematodioses, metastrongylosis, trichuriosis, strongylida gastroenteritis, dioctophymosis, and coccidiosis which could cause diseases in deer previous to the arrival of European livestock and the presence of zoonotic diseases in the hunters-gatherers and fishermen are discussed. PMID- 28342042 TI - Genetic variant of BNC2 gene is functionally associated with adolescent idiopathic scoliosis in Chinese population. AB - Adolescent idiopathic scoliosis (AIS) is a structural curvature of the spine that was estimated to affect millions of children worldwide. Recent study shows that the functional variant rs10738445 could add to the risk of AIS through the regulation of BNC2 gene. This study aims to investigate whether the rs10738445 of BNC2 gene is a functional susceptible locus for AIS in the Chinese population and to further clarify the association of the BNC2 expression with the curve severity. SNP rs10738445 was genotyped in 1952 patients and 2492 controls, and further replicated in 693 patients and 254 controls. We found that patients have a significantly higher frequency of CC than the controls (21.9 vs. 17.7%, p = 0.004 for stage 1; 12.6 vs. 7.9%, p = 0.03 for stage 2). Allele C can significantly add to the risk of AIS with an OR of 1.14-1.24. AIS patients were found to have significantly higher BNC2 expression than the controls. The BNC2 expression was significantly correlated with the curve severity (r = 0.316, p = 0.02). In conclusion, our study suggests a functional role of BNC2 in the development and progression of the spinal deformity in AIS. PMID- 28342043 TI - Accuracy Validation of an Automated Method for Prostate Segmentation in Magnetic Resonance Imaging. AB - Three dimensional (3D) manual segmentation of the prostate on magnetic resonance imaging (MRI) is a laborious and time-consuming task that is subject to inter observer variability. In this study, we developed a fully automatic segmentation algorithm for T2-weighted endorectal prostate MRI and evaluated its accuracy within different regions of interest using a set of complementary error metrics. Our dataset contained 42 T2-weighted endorectal MRI from prostate cancer patients. The prostate was manually segmented by one observer on all of the images and by two other observers on a subset of 10 images. The algorithm first coarsely localizes the prostate in the image using a template matching technique. Then, it defines the prostate surface using learned shape and appearance information from a set of training images. To evaluate the algorithm, we assessed the error metric values in the context of measured inter-observer variability and compared performance to that of our previously published semi-automatic approach. The automatic algorithm needed an average execution time of ~60 s to segment the prostate in 3D. When compared to a single-observer reference standard, the automatic algorithm has an average mean absolute distance of 2.8 mm, Dice similarity coefficient of 82%, recall of 82%, precision of 84%, and volume difference of 0.5 cm3 in the mid-gland. Concordant with other studies, accuracy was highest in the mid-gland and lower in the apex and base. Loss of accuracy with respect to the semi-automatic algorithm was less than the measured inter observer variability in manual segmentation for the same task. PMID- 28342044 TI - 3D Histopathology-a Lung Tissue Segmentation Workflow for Microfocus X-ray Computed Tomography Scans. AB - Lung histopathology is currently based on the analysis of 2D sections of tissue samples. The use of microfocus X-ray-computed tomography imaging of unstained soft tissue can provide high-resolution 3D image datasets in the range of 2-10 MUm without affecting the current diagnostic workflow. Important details of structural features such as the tubular networks of airways and blood vessels are contained in these datasets but are difficult and time-consuming to identify by manual image segmentation. Providing 3D structures permits a better understanding of tissue functions and structural interrelationships. It also provides a more complete picture of heterogeneous samples. In addition, 3D analysis of tissue structure provides the potential for an entirely new level of quantitative measurements of this structure that have previously been based only on extrapolation from 2D sections. In this paper, a workflow for segmenting such 3D images semi-automatically has been created using and extending the ImageJ open source software and key steps of the workflow have been integrated into a new ImageJ plug-in called LungJ. Results indicate an improved workflow with a modular organization of steps facilitating the optimization for different sample and scan properties with expert input as required. This allows for incremental and independent optimization of algorithms leading to faster segmentation. Representation of the tubular networks in samples of human lung, building on those segmentations, has been demonstrated using this approach. PMID- 28342045 TI - Effects of an alveolar recruitment maneuver on subdural pressure, brain swelling, and mean arterial pressure in patients undergoing supratentorial tumour resection: a randomized crossover study. AB - PURPOSE: Although recruitment maneuvers have been advocated as part of a lung protective ventilation strategy, their effects on cerebral physiology during elective neurosurgery are unknown. Our objectives were to determine the effects of an alveolar recruitment maneuver on subdural pressure (SDP), brain relaxation score (BRS), and cerebral perfusion pressure among patients undergoing supratentorial tumour resection. METHODS: In this prospective crossover study, patients scheduled for resection of a supratentorial brain tumour were randomized to undergo either a recruitment maneuver (30 cm of water for 30 sec) or a "sham" maneuver (5 cm of water for 30 sec), followed by the alternative intervention after a 90-sec equilibration period. Subdural pressure was measured through a dural perforation following opening of the cranium. Subdural pressure and mean arterial pressure (MAP) were recorded continuously. The blinded neurosurgeon provided a BRS at baseline and at the end of each intervention. During each treatment, the changes in SDP, BRS, and MAP were compared. RESULTS: Twenty-one patients underwent the study procedure. The increase in SDP was higher during the recruitment maneuver than during the sham maneuver (difference, 3.9 mmHg; 95% confidence interval [CI], 2.2 to 5.6; P < 0.001). Mean arterial pressure decreased further in the recruitment maneuver than in the sham maneuver (difference, -9.0 mmHg; 95% CI, -12.5 to -5.6; P < 0.001). Cerebral perfusion pressure decreased 14 mmHg (95% CI, 4 to 24) during the recruitment maneuver. The BRS did not change with either maneuver. CONCLUSION: Our results suggest that recruitment maneuvers increase subdural pressure and reduce cerebral perfusion pressure, although the clinical importance of these findings is thus far unknown. This trial was registered with ClinicalTrials.gov, NCT02093117. PMID- 28342047 TI - Blood toxic metals and hemoglobin levels in Mexican children. AB - Metal toxicity can cause hematologic abnormalities and hemolysis. To evaluate the relationship of anemia with metal contamination in children, the following elements were quantified in dry blood: silicon, chromium, lead, titanium, vanadium, nickel, arsenic, manganese, and cadmium. A total of 88 samples of anemic children and 208 of non-anemic children aged 6-12 years were analyzed. Lead (35.1%), chromium (24.3%), vanadium (24.3%), nickel (45.6%), and silicon (48.6%) were identified in the samples, with titanium only detected in anemic children. The average level of arsenic was higher in anemic than non-anemic children (0.041 +/- 0.11 wt% vs 0.014 +/- 0.05 wt%, p < 0.05) and correlated with the concentration of hemoglobin (r = -0.441, p < 0.01). In conclusion, heavy metals, which confer a health risk, were detected in the dry blood of the children evaluated, and the levels of arsenic and titanium were found to be related to anemia. PMID- 28342046 TI - Sources, mechanisms, and fate of steroid estrogens in wastewater treatment plants: a mini review. AB - Steroid estrogens, such as estrone (E1), 17beta-estradiol (E2), estriol (E3), and 17alpha-ethinylestradiol (EE2), are natural and synthetic hormones released into the environment through incomplete sewage discharge. This review focuses on the sources of steroid estrogens in wastewater treatment plants (WWTPs). The mechanisms and fate of steroid estrogens throughout the entire wastewater treatment system are also discussed, and relevant information on regulatory aspects is given. Municipal, pharmaceutical industry, and hospitals are the main sources of steroid estrogens that enter WWTPs. A typical WWTP comprises primary, secondary, and tertiary treatment units. Sorption and biodegradation are the main mechanisms for removal of steroid estrogens from WWTPs. The fate of steroid estrogens in WWTPs depends on the types of wastewater treatment systems. Steroid estrogens in the primary treatment unit are removed by sorption onto primary sludge, followed by sorption onto micro-flocs and biodegradation by microbes in the secondary treatment unit. Tertiary treatment employs nitrification, chlorination, or UV disinfection to improve the quality of the secondary effluent. Activated sludge treatment systems for steroid estrogens exhibit a removal efficiency of up to 100%, which is higher than that of the trickling filter treatment system (up to 75%). Moreover, the removal efficiency of advance treatment systems exceeds 90%. Regulatory aspects related to steroid estrogens are established, especially in the European Union. Japan is the only Asian country that implements a screening program and is actively involved in endocrine disruptor testing and assessment. This review improves our understanding of steroid estrogens in WWTPs, proposes main areas to be improved, and provides current knowledge on steroid estrogens in WWTPs for sustainable development. PMID- 28342048 TI - Assessing knowledge, performance, and efficiency for hospital waste management-a comparison of government and private hospitals in Pakistan. AB - Proper management of healthcare waste is a critical concern in many countries of the world. Rapid urbanization and population growth rates pose serious challenges to healthcare waste management infrastructure in such countries. This study was aimed at assessing the situation of hospital waste management in a major city of Pakistan. Simple random sampling was used to select 12 government and private hospitals in the city. Field visits, physical measurements, and questionnaire survey method were used for data collection. Information was obtained regarding hospital waste generation, segregation, collection, storage, transportation, and disposal. Data envelopment analysis (DEA) was used to classify the hospitals on the basis of their relative waste management efficiencies. The weighted average total waste generation at the surveyed hospitals was discovered to be 1.53 kg/patient/day of which 75.15% consisted of general waste and the remaining consisted of biomedical waste. Of the total waste, 24.54% came from the public hospital and the remaining came from the private hospitals. DEA showed that seven of the surveyed hospitals had scale or pure technical inefficiencies in their waste management activities. The public hospital was relatively less efficient than most of the private hospitals in these activities. Results of the questionnaire survey showed that none of the surveyed hospitals was carrying out waste management in strict compliance with government regulations. Moreover, hospital staff at all the surveyed hospitals had low level of knowledge regarding safe hospital waste management practices. The current situation should be rectified in order to avoid environmental and epidemiological risks. PMID- 28342049 TI - Safety assessment of chromafenozide residue level with decline study on tomato in Egypt. AB - The objective of this study is to perform a safety assessment of chromafenozide residue level on tomato at the Egyptian national level. An open field decline study of chromafenozide on tomato was performed. The theoretical maximum daily intake (TMDI) of chromafenozide was calculated for assessing the chronic dietary exposure indicating that the ADI value of chromafenozide (0.27 mg/kg bw/day) was not exceeded. As a result, the safety assessment of chromafenozide residue levels was attained. A validated method of the QuEChERS approach followed by HPLC-DAD analysis was used to determine the chromafenozide residues. The recoveries ranged from 70 to 88% with relative standard deviations ranging from 2.0 to 9.0%. The limit of quantitation was 0.01 mg/kg. The half-life of chromafenozide on tomatoes was 3.5 days. PMID- 28342050 TI - Sewage pollution: genotoxicity assessment and phytoremediation of nutrients excess with Hydrocotyle ranunculoides. AB - The discharge of sewage effluents into low-order streams has negative effects on water quality. Macrophytes can be efficient in the treatment of this wastewater due to the removal of the main pollutants. The genotoxicity of sewage-polluted water discharging into La Choza stream was evaluated by testing with Allium cepa. Also, a phytoremediation assay with continuous recirculation of the residual water was conducted for 12 days. Three treatments were carried out. One treatment (Hr) was performed with a macrophyte (Hydrocotyle ranunculoides), and two treatments were conducted without macrophytes: with lighting (Ai) and without lighting (Ao). The wastewater was toxic according to all the evaluated indexes (mitotic index, frequency of chromosomal aberrations and micronucleus). High concentrations of ammonium, dissolved inorganic nitrogen (DIN), total (TP) and soluble reactive phosphorous (SRP) and indicators of faecal contamination were determined in the wastewater. The ammonium, DIN, SRP and TP loads at the end of the assay were significantly lower in the treatments with light (Hr and Ai). So, the nutrient removal was due to their absorption and adsorption by the periphyton and H. ranunculoides. Our results lead us to recommend the maintenance and planting of macrophytes in lowland streams subject to sewage pollution. PMID- 28342051 TI - Appraisal of nutrient distribution in the surface water and bed sediments of a small mountainous river. AB - A total of 42 (21 surface water and 21 bed sediments) samples were collected from upstream to downstream stretches of Meenachil river during pre-monsoon (PRM), monsoon (MON) and post monsoon (POM) seasons. DOC in water showed increasing trend spatially while temporal study illustrates high mean value during PRM (1.58 ppm) followed by POM (0.97) and MON (0.36). Spatial assessment of elements such as Ca, Mg, K and Na in sediments reveals erratic trend during different seasons, while total phosphorous showed escalating trend signifying abrupt addition from anthropogenic sources. Based on characteristic carbon to nitrogen ratio, the study demonstrates significant control of macrophyte in terrestrial organic matter accumulation along downstream stations. PMID- 28342052 TI - Arsenic concentrations in local aromatic and high-yielding hybrid rice cultivars and the potential health risk: a study in an arsenic hotspot. AB - The presence of high levels of arsenic (As) in rice fields has negative effects on the health of those consuming rice as their subsistence food. This study determined the variation in total As concentration in local aromatic rice (LAR) (kalijira) and two high-yielding varieties (HYVs) (BRRI dhan 32 and BRRI dhan 28) grown in paddy fields in Matlab, Bangladesh, an As hotspot with elevated As levels in groundwater. Mature rice grain samples and soil samples were collected from different paddy fields, and the As concentrations in both the de-husked grains and the husks of the three rice cultivars were analysed to identify the safest of the three cultivars for human consumption. The results showed that the total As concentration was higher (0.09-0.21 mg As kg-1) in the de-husked grains of LAR than in the husks, while the opposite was found for the HYV rice. Moreover, the As concentration in soil samples was 2 to 5-fold higher for the LAR than for the HYVs, but the As accumulation factor (AF) was lower in the LAR (0.2 0.4%) than in the HYVs (0.9-1%). Thus, LAR can be considered the safest of the three cultivars for human consumption owing to its low AF value. Furthermore, due to the low AF, growing LAR instead of HYVs in soils with slightly elevated As levels could help improve the food safety level in the food chain. PMID- 28342053 TI - An increasing problem in publication ethics: Publication bias and editors' role in avoiding it. AB - Publication bias is defined as "the tendency on the parts of investigators, reviewers, and editors to submit or accept manuscripts for publication based on the direction or the strength of the study findings."Publication bias distorts the accumulated data in the literature, causes the over estimation of potential benefits of intervention and mantles the risks and adverse effects, and creates a barrier to assessing the clinical utility of drugs as well as evaluating the long term safety of medical interventions. The World Medical Association, the International Committee of Medical Journals, and the Committee on Publication Ethics have conferred responsibilities and ethical obligations to editors concerning the avoidance of publication bias. Despite the explicit statements in these international documents, the editors' role in and ability to avoid publication bias is still being discussed. Unquestionably, all parties involved in clinical research have the ultimate responsibility to sustain the research integrity and validity of accumulated general knowledge. Cooperation and commitment is required at every step of a clinical trial. However, this holistic approach does not exclude effective measures to be taken at the editors' level. The editors of major medical journals concluded that one precaution that editors can take is to mandate registration of all clinical trials in a public repository as a precondition to submitting manuscripts to journals. Raising awareness regarding the value of publishing negative data for the scientific community and human health, and increasing the number of journals that are dedicated to publishing negative results or that set aside a section in their pages to do so, are positive steps editors can take to avoid publication bias. PMID- 28342054 TI - Tube task hand preference in captive hylobatids. AB - The link between laterality in humans and other primates is still hotly debated. Hylobatids have been rather neglected in this research area, yet they can provide important insights because: (1) they share with humans a complex vocal repertoire, which in humans is thought to be associated with brain hemispheric specialization and lateralized behaviors; (2) their adaptation to arboreality has produced unique postural constraints; (3) the little that is known about laterality in gibbons is contradictory (captive studies have provided conflicting results, while a field study on siamangs reported a population-level left-hand preference). To clarify this, we investigated hand preference in captive hylobatids [n = 42; 22 siamangs (Symphalangus syndactylus) and 20 gibbons (Hylobates sp., Nomascus leucogenys)] in nine Japanese facilities. We had a large sample size, controlled for possible confounds (posture, enclosure limitations) and used a well-established testing protocol (tube task). Handedness indices calculated from raw frequencies and bouts were highly correlated and showed a significant left-hand skew, which is consistent with data from wild siamangs. Major differences between captive and wild siamangs were a larger number of ambiguously handed individuals, and no significant age-related variation in captivity. The use of the index finger elicited a much more strongly lateralized response than the thumb. These results confirmed a left-hand preference in siamangs, but were equivocal in other hylobatids, and suggest selective pressures that may have acted on the highly arboreal hylobatids to favor handedness. Our study also indicates factors that might explain the discrepancy in the literature between handedness studies on captive and wild primate populations. PMID- 28342055 TI - The analysis of lncRNA HOTAIR rs12826786 C>T polymorphism and gastric cancer susceptibility in a Turkish population: lack of any association in a hospital based case-control study. AB - BACKGROUND: The HOX transcript antisense intergenic RNA (HOTAIR), a well-known long noncoding RNA (lncRNA), has been widely identified to participate in pathogenesis of multiple cancers. An aberrant up-regulation and biological functions have been observed in gastric cancer (GC). A common single nucleotide polymorphism (SNP) (rs12826786 C>T) at the HOTAIR has been reported to influence HOTAIR expression, but its association with GC has yet to be investigated in Turkish population. AIM: The aim of the present study was to investigate whether HOTAIR rs12826786 C>T polymorphism could be involved in the risk of GC susceptibility in Turkish population. METHODS: We genotyped HOTAIR rs12826786 C>T polymorphism in 312 Turkish individuals including 105 GC patients and 207 healthy controls matched on age and gender by a Real-Time Polymerase Chain Reaction (PCR) with the TaqMan assay. RESULTS: No statistically significant differences were found in the allele or genotype distributions of the HOTAIR rs12826786 C>T polymorphism among GC and healthy control subjects (P > 0.05). CONCLUSIONS: Our results demonstrate that the HOTAIR rs12826786 C>T polymorphism has not been in any major role in genetic susceptibility to gastric carcinogenesis, at least in the population studied here. Independent studies are needed to validate our findings in a larger series, as well as in patients of different ethnic origins. PMID- 28342057 TI - Preparation of Drug-Loaded PLGA-PEG Nanoparticles by Membrane-Assisted Nanoprecipitation. AB - PURPOSE: The aim of this work is to develop a scalable continuous system suitable for the formulation of polymeric nanoparticles using membrane-assisted nanoprecipitation. One of the hurdles to overcome in the use of nanostructured materials as drug delivery vectors is their availability at industrial scale. Innovation in process technology is required to translate laboratory production into mass production while preserving their desired nanoscale characteristics. METHODS: Membrane-assisted nanoprecipitation has been used for the production of Poly[(D,L lactide-co-glycolide)-co-poly ethylene glycol] diblock) (PLGA-PEG) nanoparticles using a pulsed back-and-forward flow arrangement. Tubular Shirasu porous glass membranes (SPG) with pore diameters of 1 and 0.2 MUm were used to control the mixing process during the nanoprecipitation reaction. RESULTS: The size of the resulting PLGA-PEG nanoparticles could be readily tuned in the range from 250 to 400 nm with high homogeneity (PDI lower than 0.2) by controlling the dispersed phase volume/continuous phase volume ratio. Dexamethasone was successfully encapsulated in a continuous process, achieving an encapsulation efficiency and drug loading efficiency of 50% and 5%, respectively. The dexamethasone was released from the nanoparticles following Fickian kinetics. CONCLUSIONS: The method allowed to produce polymeric nanoparticles for drug delivery with a high productivity, reproducibility and easy scalability. PMID- 28342059 TI - Dental Traits of Congenital Syphilis Revisited in Dental Outpatient Department (OPD). PMID- 28342058 TI - Galician consensus on management of cardiotoxicity in breast cancer: risk factors, prevention, and early intervention. AB - This Galician consensus statement is a joint oncologists/cardiologists initiative indented to establish basic recommendations on how to prevent and to manage the cardiotoxicity in breast cancer with the aim of ensuring an optimal cardiovascular care of these patients. A clinical screening of the patients before treatment is recommended to stratify them into a determined risk group based on their intrinsic cardiovascular risk factors and those extrinsic arose from breast cancer therapy, thereby providing individualized preventive and monitoring measures. Suitable initial and ongoing assessments for patients with low and moderate/high risk and planned treatment with anthracyclines and trastuzumab are given; also, measures aimed at preventing and correcting any modifiable risk factor are pointed out . PMID- 28342056 TI - Formulation, Delivery and Stability of Bone Morphogenetic Proteins for Effective Bone Regeneration. AB - Bone morphogenetic proteins (BMPs) are responsible for bone formation during embryogenesis and bone regeneration and remodeling. The osteoinductive action of BMPs, especially BMP-2 and BMP-7, has led to their use in a range of insurmountable treatments where intervention is required for effective bone regeneration. Introduction of BMP products to the market, however, was not without reports of multiple complications and side effects. Aiming for optimization of the therapeutic efficacy and safety, efforts have been focused on improving the delivery of BMPs to lower the administered dose, localize the protein, and prolong its retention time at the site of action. A major challenge with these efforts is that the protein stability should be maintained. With this review we attempt to shed light on how the stability of BMPs can be affected in the formulation and delivery processes. We first provide a short overview of the current standing of the complications experienced with BMP products. We then discuss the different delivery parameters studied in association with BMPs, and their influence on the efficacy and safety of BMP treatments. In particular, the literature addressing the stability of BMPs and their possible interactions with components of the delivery system as well as their sensitivity to conditions of the formulation process is reviewed. In summary, recent developments in the fields of bioengineering and biopharmaceuticals suggest that a good understanding of the relationship between the formulation/delivery conditions and the stability of growth factors such as BMPs is a prerequisite for a safe and effective treatment. PMID- 28342061 TI - Cost-Effectiveness Analysis of Obinutuzumab for Previously Untreated Chronic Lymphocytic Leukaemia in Portuguese Patients who are Unsuitable for Full-Dose Fludarabine-Based Therapy. AB - BACKGROUND: Chronic lymphocytic leukaemia (CLL) mostly affects patients with comorbidities and limited therapeutic options. Obinutuzumab in combination with chlorambucil (GClb) is a new therapeutic option for previously untreated CLL patients who are unsuitable for full-dose fludarabine-based therapy. This combination delays disease progression but incurs additional costs; thus, an assessment of its value for money is relevant. OBJECTIVE: To estimate the incremental cost-utility ratio of GClb in comparison with (i) rituximab in combination with chlorambucil (RClb), and (ii) chlorambucil alone (Clb) from the perspective of the Portuguese National Health Service (NHS). METHODS: A Markov model was used to predict disease progression. Pre-progression clinical data were based on the latest CLL11 trial data, and post-progression clinical data were obtained from CLL5 trial data. Utility values are from Kosmas et al. (Leuk Lymphoma 56:1320-1326, 14). Only direct medical costs were included. The resource consumption was estimated by a panel of Portuguese experts, and the unit costs were obtained from official sources. A discount rate of 5% was applied to costs and consequences. RESULTS: GClb and RClb were associated with an increase of 1.06 and 0.39 quality-adjusted life-years (QALY) at an additional cost of ?21,720 and ?9836 when compared to Clb, respectively. The cost-utility ratio of GClb versus Clb was ?20,397/QALY, while RClb was extendedly dominated. CONCLUSIONS: The use of GClb for previously untreated CLL patients who are unsuitable for full-dose fludarabine-based therapy incurs an incremental cost per QALY that is generally accepted in Portugal. Therefore, although there is some uncertainty, obinutuzumab is probably a cost-effective therapy in the Portuguese setting. PMID- 28342062 TI - [New challenges for medical rehabilitation]. PMID- 28342063 TI - ? PMID- 28342060 TI - Glycogen-Rich Clear Cell Squamous Cell Carcinoma Originating in the Oral Cavity. AB - Clear cell squamous cell carcinoma (CCSCC) is a rare histological subtype of squamous cell carcinoma (SCC) that was originally described in the skin. Here, we report a case of a 66-year-old female patient who presented with a fungating ulcerative mass of the left lateral tongue extending anteriorly to the floor of the mouth, and posteriorly to the left retromolar fossa and the oropharynx. The patient had a history of SCC of the left posterior tongue that was treated with partial glossectomy and adjuvant radiotherapy. Representative biopsies were obtained from the floor of the mouth, tongue and retromolar fossa. The examined biopsies showed various degrees of dysplastic surface epithelium with transition into infiltrating epithelial tumor nests and cords with clear cytoplasm and malignant cellular features. Pancytokeratin, CK5/6, and p63 were all diffusely positive. S-100, Calponin, and smooth muscle actin (SMA) were negative. PAS stain was diffusely positive and diastase labile in the tumor clear cells. Sparse areas of mucicarmine positivity were noted. Based on these findings a final diagnosis of a glycogen-rich CCSCC was given. This case represents a very rare histological variant of oral SCC, which is significant for the histological differential diagnosis of clear cell tumors of the oral cavity. PMID- 28342065 TI - Pharmacokinetics of linezolid in plasma and cerebrospinal fluid in patients with cerebral hemorrhage post-surgical intervention. PMID- 28342066 TI - Antidepressant use in suicides: a case-control study from the Friuli Venezia Giulia Region, Italy, 2005-2014. AB - PURPOSE: To compare the use of antidepressant (AD) classes and compounds in individuals who committed suicide and in controls from the general population and to assess to what extent adherence and current use of different AD classes can affect the risk of committing suicide. METHODS: Individual data on suicide, diagnoses and AD use in Friuli Venezia Giulia from 2005 to 2014 were obtained from the Regional Social and Health Information System. All suicides that had at least one prescription of AD in the 730 days before death (N = 876) were included as cases. Each case was matched with regard to age and sex with five controls from the general population. The association between suicide and AD use was assessed using conditional logistic regression analysis. RESULTS: Almost 70% of all suicides occurring in the10-year period had been prescribed AD. Selective serotonin reuptake inhibitors (SSRIs) accounted for more than the 90% of the prescriptions, with paroxetine the most prescribed AD. All AD compounds and classes were not associated with a higher suicide risk, with the exception of SSRI (OR = 1.6). A decreasing trend in suicide risk was observed when adherent subjects or current AD users were compared to the others. CONCLUSIONS: AD treatment is an important factor for preventing suicide, since the use of AD at adequate dosage and for a proper duration was associated with a lower suicide risk. The proper use of AD should be ascertained by physicians, particularly in a primary care context. PMID- 28342068 TI - Erratum to: The influence of memory on indoor environment exploration: A numerical study. PMID- 28342067 TI - The incidence of post-transplant cancer among kidney transplant recipients is associated with the level of tacrolimus exposure during the first year after transplantation. AB - PURPOSE: Immunosuppressive therapy plays a major role in the development of post transplant cancer. In this nested case-control study of kidney transplant recipients (KTRs), we investigated whether the incidence of post-transplant cancer is associated with the level of tacrolimus exposure over time. METHODS: We screened the Rabin Medical Center database for adults who received kidney transplants between 2001 and 2014 and developed post-transplant cancer (excluding basal and squamous cell skin cancers). They were matched against KTRs without cancer. All patients received a maintenance immunosuppressive treatment with tacrolimus, mycophenolate mofetil and corticosteroids. The degree of exposure to tacrolimus was estimated as the time-weighted average (tTWA) value of tacrolimus blood levels. The tTWA was calculated as the area under the curve divided by time at 1, 6, and 12 months after transplantation and at time of cancer diagnosis. RESULTS: Thirty-two cases were matched against 64 controls. tTWA values above 11 ng/mL at 6 and 12 months after transplantation were associated with odds ratio (OR) of 3.1 (95% CI 1.1-9) and 11.7 (95% CI = 1.3-106), respectively, for post transplant cancer; and with OR of 5.2 (95% CI 1.3-20.5) and 14.1 (95% CI = 1.5 134.3), respectively, for cancer diagnosed more than 3 years after transplantation. CONCLUSION: Exposure to a tacrolimus time-weighted average level above 11 ng/mL at 6 or 12 months after kidney transplantation is associated with an increased risk of developing cancer. PMID- 28342069 TI - Erratum to: Measuring sequences of keystrokes with jsPsych: Reliability of response times and interkeystroke intervals. PMID- 28342064 TI - HDL cholesterol: reappraisal of its clinical relevance. AB - BACKGROUND: While several lines of evidence prove that elevated concentrations of low-density lipoproteins (LDL) causally contribute to the development of atherosclerosis and its clinical consequences, high-density lipoproteins are still widely believed to exert atheroprotective effects. Hence, HDL cholesterol (HDL-C) is in general still considered as "good cholesterol". Recent research, however, suggests that this might not always be the case and that a fundamental reassessment of the clinical significance of HDL-C is warranted. METHOD: This review article is based on a selective literature review. RESULTS: In individuals without a history of cardiovascular events, low concentrations of HDL-C are inversely associated with the risk of future cardiovascular events. This relationship may, however, not apply to patients with metabolic disorders or manifest cardiovascular disease. The classical function of HDL is to mobilise cholesterol from extrahepatic tissues for delivery to the liver for excretion. These roles in cholesterol metabolism as well as many other biological functions of HDL particles are dependent on the number as well as protein and lipid composition of HDL particles. They are poorly reflected by the HDL-C concentration. HDL can even exert negative vascular effects, if its composition is pathologically altered. High serum HDL-C is therefore no longer regarded protective. In line with this, recent pharmacological approaches to raise HDL-C concentration have not been able to show reductions of cardiovascular outcomes. CONCLUSION: In contrast to LDL cholesterol (LDL-C), HDL-C correlates with cardiovascular risk only in healthy individuals. The calculation of the ratio of LDL-C to HDL-C is not useful for all patients. Low HDL-C should prompt examination of additional metabolic and inflammatory pathologies. An increase in HDL-C through lifestyle change (smoking cessation, physical exercise) has positive effects and is recommended. However, HDL-C is currently not a valid target for drug therapy. PMID- 28342070 TI - Normative data for Chinese compound remote associate problems. AB - The Remote Associates Test (RAT) is a well-known measure of creativity, with each item on the RAT is composed of three unrelated stimulus words. The participant's task is to find an answer in the form of a word that could combine with each of the stimulus words, thus forming three new actual nouns. Researchers have modified the RAT to develop compound remote associate problems that emphasize combining vocabulary to form compound words. In the field of creativity research for Mandarin speakers, the Chinese RAT has been widely applied for over 10 years. The original RAT, compound remote associate problems, and Chinese RAT have various common advantages, such as being convenient to use and having objective scoring; additionally, the development of items for certain tests is easy and satisfies the requirements of psychological assessments in terms of the quantity of items. Currently, many language editions of the RAT and compound remote associate problems already exist. In particular, the English and Italian versions of these tests already have derived normative data. Because approximately 20% of the world's population are native Mandarin speakers, and because increasing numbers of people are choosing Mandarin as a second language, the need to increase Mandarin-language resources is growing; however, normative data for the Chinese RAT still do not exist. To address this issue, in the present study we developed Chinese compound remote associate problems and analyzed the passing rates by items, problem solving times, and various normative data, using the responses of 253 subjects in three experiments. PMID- 28342071 TI - Estimating psychological networks and their accuracy: A tutorial paper. AB - The usage of psychological networks that conceptualize behavior as a complex interplay of psychological and other components has gained increasing popularity in various research fields. While prior publications have tackled the topics of estimating and interpreting such networks, little work has been conducted to check how accurate (i.e., prone to sampling variation) networks are estimated, and how stable (i.e., interpretation remains similar with less observations) inferences from the network structure (such as centrality indices) are. In this tutorial paper, we aim to introduce the reader to this field and tackle the problem of accuracy under sampling variation. We first introduce the current state-of-the-art of network estimation. Second, we provide a rationale why researchers should investigate the accuracy of psychological networks. Third, we describe how bootstrap routines can be used to (A) assess the accuracy of estimated network connections, (B) investigate the stability of centrality indices, and (C) test whether network connections and centrality estimates for different variables differ from each other. We introduce two novel statistical methods: for (B) the correlation stability coefficient, and for (C) the bootstrapped difference test for edge-weights and centrality indices. We conducted and present simulation studies to assess the performance of both methods. Finally, we developed the free R-package bootnet that allows for estimating psychological networks in a generalized framework in addition to the proposed bootstrap methods. We showcase bootnet in a tutorial, accompanied by R syntax, in which we analyze a dataset of 359 women with posttraumatic stress disorder available online. PMID- 28342073 TI - A Web-based interface to calculate phonotactic probability for words and nonwords in Modern Standard Arabic. AB - A number of databases (Storkel Behavior Research Methods, 45, 1159-1167, 2013) and online calculators (Vitevitch & Luce Behavior Research Methods, Instruments, and Computers, 36, 481-487, 2004) have been developed to provide statistical information about various aspects of language, and these have proven to be invaluable assets to researchers, clinicians, and instructors in the language sciences. The number of such resources for English is quite large and continues to grow, whereas the number of such resources for other languages is much smaller. This article describes the development of a Web-based interface to calculate phonotactic probability in Modern Standard Arabic (MSA). A full description of how the calculator can be used is provided. It can be freely accessed at http://phonotactic.drupal.ku.edu/ . PMID- 28342072 TI - Statistical properties of four effect-size measures for mediation models. AB - This project examined the performance of classical and Bayesian estimators of four effect size measures for the indirect effect in a single-mediator model and a two-mediator model. Compared to the proportion and ratio mediation effect sizes, standardized mediation effect-size measures were relatively unbiased and efficient in the single-mediator model and the two-mediator model. Percentile and bias-corrected bootstrap interval estimates of ab/s Y , and ab(s X )/s Y in the single-mediator model outperformed interval estimates of the proportion and ratio effect sizes in terms of power, Type I error rate, coverage, imbalance, and interval width. For the two-mediator model, standardized effect-size measures were superior to the proportion and ratio effect-size measures. Furthermore, it was found that Bayesian point and interval summaries of posterior distributions of standardized effect-size measures reduced excessive relative bias for certain parameter combinations. The standardized effect-size measures are the best effect size measures for quantifying mediated effects. PMID- 28342074 TI - Evaluation of 'SAEFVIC', A Pharmacovigilance Surveillance Scheme for the Spontaneous Reporting of Adverse Events Following Immunisation in Victoria, Australia. AB - INTRODUCTION: Australia is traditionally an early adopter of vaccines, therefore comprehensive and effective post-licensure vaccine pharmacovigilance is critical to maintain confidence in immunisation, both nationally and internationally. With adverse event following immunisation (AEFI) surveillance the responsibility of Australian jurisdictions, Victoria operates an enhanced passive AEFI surveillance system integrated with clinical services, called 'SAEFVIC' (Surveillance of Adverse Events Following Vaccination In the Community). OBJECTIVE: The aim of this study was to evaluate Victoria's current AEFI surveillance system 'SAEFVIC' and inform ongoing quality improvement of vaccine pharmacovigilance in Victoria and Australia. METHODS: We conducted a retrospective structured desktop evaluation of AEFI reporting received by SAEFVIC from 2007 to 2014, to evaluate the system according to its stated objectives, i.e. to improve AEFI reporting; provide AEFI signal detection; and to maintain consumer confidence in vaccination. RESULTS: AEFI reporting has tripled since SAEFVIC commenced (incidence risk ratio [IRR] 3.04, 95% confidence interval [CI] 2.35-3.93), raising Victoria to be the lead jurisdiction by AEFI reporting volume and to rank third by population reporting rate nationally. The largest increase was observed in children. Data were utilised to investigate potential signal events and inform vaccine policy. Signal detection required clinical suspicion by surveillance nurses, or prior vaccine-specific concerns. Subsequent vaccination post-AEFI was documented for 56.2% (95% CI 54.1-58.4) of reports, and the proportion of children due or overdue for vaccination was 2.3% higher for those reporting AEFI compared with the general population. CONCLUSION: SAEFVIC has improved AEFI surveillance, facilitates signal investigation and validation, and supports consumer confidence in immunisation. Expansion of the system nationally has the potential to improve capacity and capability of vaccine pharmacovigilance, particularly through data consistency and jurisdictional comparability in Australia. PMID- 28342075 TI - Evaluation of Pre-marketing Factors to Predict Post-marketing Boxed Warnings and Safety Withdrawals. AB - INTRODUCTION: An important goal in drug regulation is understanding serious safety issues with new drugs as soon as possible. Achieving this goal requires us to understand whether information provided during the Food and Drug Administration (FDA) drug review can predict serious safety issues that are usually identified after the product is approved. However, research on this topic remains understudied. In this paper, we examine whether any pre-marketing drug characteristics are associated with serious post-marketing safety actions. METHODS: We study this question using an internal FDA database containing every new small molecule drug submitted to the FDA's Center for Drug Evaluation and Research (CDER) on or after November 21, 1997, and approved and commercially launched before December 31, 2009. Serious post-marketing safety actions include whether these drugs ever experienced either a post-marketing boxed warning or a withdrawal from the market due to safety concerns. A random effects logistic regression model was used to test whether any pre-marketing characteristics were associated with either post-marketing safety action. RESULTS: A total of 219 new molecular entities were analyzed. Among these drugs, 11 experienced a safety withdrawal and 30 received boxed warnings by July 31, 2016. Contrary to prevailing hypotheses, we find that neither clinical trial sample sizes nor review time windows are associated with the addition of a post-marketing boxed warning or safety withdrawal. However, we do find that new drugs approved with either a boxed warning or priority review are more likely to experience post marketing boxed warnings. Furthermore, drugs approved with boxed warnings tend to receive post-marketing boxed warnings resulting from new safety information that are unrelated to the original warning. Drugs approved with a boxed warning are 3.88 times more likely to receive a post-marketing boxed warning, while drugs approved with a priority review are 3.51 times more likely to receive a post marketing boxed warning. CONCLUSION: Although drugs approved with a boxed warning or priority review are more likely to experience serious post-marketing safety events, other information provided during the FDA drug review that is easy to quantify is generally not associated with post-marketing safety events. It appears that these post-marketing events are not discernible during a pre marketing review and therefore might not be avoidable using current review data. PMID- 28342076 TI - Schizosaccharomyces pombe rsv1 Transcription Factor and its Putative Homologues Preserved their Functional Homology and are Evolutionarily Conserved. AB - Environmental glucose is an important regulator of biological processes, as it can launch different cell processes depending on its concentration. Thus, low glucose concentration can induce entry into quiescence, which ensures long-term viability for the cells or in other cases mycelial growth in the dimorphic species, which, in turn, provides the cells with fresh nutrients. Several genes, such as the genes of cAMP cascade, are involved in glucose sensing and response. Since this signal transduction pathway seemed to be an evolutionarily conserved process, we assumed that its genes were also conserved and preserved their functional homology. To obtain evidence, Schizosaccharomyces pombe rsv1 and its orthologous genes were investigated using in silico and experimental approaches. Our results supported that the Rsv1 zinc-finger transcription factors of Schizosaccharomyces japonicus and Schizosaccharomyces octosporus and the Candida albicans cas5p were really functional homologues of the S. pombe Rsv1. Namely, the homologous proteins were able to restore mutant phenotype of the S. pombe rsv1-deleted cells. Bioinformatic anaysis revealed that the most conserved parts of the proteins always contained the C2H2 domains and the complementation abilities of the counterpart genes were not uniform regarding the investigated features, which can be in connection with the conserved regions outside C2H2. PMID- 28342077 TI - The Influences of Bacillus subtilis on the Virulence of Aeromonas hydrophila and Expression of luxS Gene of Both Bacteria Under Co-cultivation. AB - The aim of this study was to explore the influence of Bacillus subtilis CH9 on Aeromonas hydrophila SC2005. The transcription level of virulence genes of A. hydrophila SC2005 and its hemolysin activity as well as its cytotoxicity were analyzed when B. subtilis CH9 and A. hydrophila SC2005 were co-cultured. The results indicated that the transcription levels of four virulence genes of A. hydrophila, including aer, ahyB, hcp, and emp, decreased when A. hydrophila was cultured with B. subtilis CH9. Furthermore, the extracellular products of A. hydrophila showed attenuated hemolysin activity as well as cytotoxicity when A. hydrophila was cultured with B. subtilis CH9. Finally, the transcriptional levels of luxS genes of B. subtilis CH9 and A. hydrophila SC2005 were determined when these two species were co-cultured. RT-qPCR results suggested that the transcription level of A. hydrophila was down-regulated significantly. On the contrary, the transcription level of B. subtilis CH9 was up-regulated significantly. These results suggested that the probiotic role of B. subtilis CH9 is related to the inhibition of growth and virulence of A. hydrophila SC2005, and quorum sensing may be involved. PMID- 28342078 TI - An anoxic-aerobic system for simultaneous biodegradation of phenol and ammonia in a sequencing batch reactor. AB - A laboratory-scale sequencing batch reactor (SBR) was investigated to treat artificial pretreated coal gasification wastewater that was mainly contained of ammonia and phenol. The efficiency of SBR fed with increasing phenol concentrations (from 150 to 300 mg l-1) and the relationship among phenol, nitrogen removal, and the microbial community structure were evaluated. When the phenol feeding concentration was increased to about 300 mg l-1, the removal efficiency was above 99.0%, demonstrating the robustness of phenol removal capacity. The study showed that most phenol was degraded in anoxic stage. The average removal efficiencies of ammonia and total nitrogen were 98.4 and 81.9%, respectively, with average NH4+-N concentration of 107.5 mg l-1 and COD/N 7.5. Low temperature caused sludge loss that led to the decreased performance. Increasing the temperature could not recover the performance effectively. The data from bacterial analysis revealed that Delftia, Hydrogenophaga, and unclassified Xanthomonadaceae played a significant role in phenol degradation before the temperature increase, while uncultured Syntrophococcus sp. and unclassified Rhodocyclaceae were responsible for phenol degradation after the temperature increase. These results imply that the SBR holds potential for the simultaneous removal of phenolic compounds and nitrogen through aerobic ammonia oxidation and anoxic denitrification with phenol as the co-organic carbon source. PMID- 28342079 TI - Remediation of PCB-contaminated soil using a combination of mechanochemical method and thermal desorption. AB - The combination of mechanochemical method and thermal desorption for remediating polychlorinated biphenyls (PCBs) in contaminated soil was tested in this study. The effects of grinding time and heating time on PCB removal efficiency were investigated. The contaminated soil, mixed with CaO powder at a weight ratio of 1:1, was first ground using a planetary ball mill. After 4 h of grinding, the total PCB concentration and its toxic equivalence quantity (TEQ) decreased by 74.6 and 75.8%, respectively. Then, after being heated at 500 degrees C for 60 min, the residual PCBs in mechanochemical + thermal treated soil decreased to 247 ng/g, resulting in a removal efficiency of 99.95%. The removal effect can be promoted by longer grinding time and heating time; however, increased energy consumption was inevitable. The combination of grinding time and heating time should be optimized in a practical remediation process. PMID- 28342080 TI - Heavy metals bioconcentration from soil to vegetables and appraisal of health risk in Koka and Wonji farms, Ethiopia. AB - Heavy metal accumulation in agricultural crops has grown a major concern globally as a result of a significant health impact on human. The quantification of heavy metals (Cd, Pb, Cr, Zn, Cu, and Ni) in the soil and vegetables at two sites (Koka and Wonji Gefersa) was done using flame atomic absorption spectrophotometer. The mean concentrations of heavy metals in vegetable fields' soil samples obtained from Koka were higher for Pb, Cr, Zn, Cu, and Ni. The overall results of soil samples ranged 0.52-0.93, 13.6-27.3, 10.0-21.8, 44.4-88.5, 11.9-30.3, and 14.7 34.5 mg kg-1 for Cd, Pb, Cr, Zn, Cu, and Ni, respectively. The concentrations of heavy metals were maximum for Cd (0.41 +/- 0.03 mg kg-1), Pb (0.54 +/- 0.11 mg kg 1), Zn (14.4 +/- 0.72 mg kg-1), Cu (2.84 +/- 0.27 mg kg-1), and Ni (1.09 +/- 0.11 mg kg-1) in Cabbage and for Cr (2.63 +/- 0.11 mg kg-1) in green pepper. The result indicated that Cd has high transfer factor value and Pb was the lowest. The transfer pattern for heavy metals in different vegetables showed a trend in the order: Cd > Zn > Cu > Cr > Ni > Pb. Among different vegetables, cabbage showed the highest value of metal pollution index and bean had the lowest value. Hazard index of all the vegetables was less than unity; thus, the consumption of these vegetables is unlikely to pose health risks to the target population. PMID- 28342081 TI - Characterization of polycyclic aromatic hydrocarbons in soil close to secondary copper and aluminum smelters. AB - A total of 35 surface soil samples around two secondary copper smelters and one secondary aluminum smelter were collected and analyzed for 16 USEPA priority polycyclic aromatic hydrocarbons (PAHs). The concentrations of PAHs were highest when the soil sample sites were closest to the secondary copper smelters. And, a level gradient of PAHs was observed in soil samples according to the distance from two secondary copper smelters, respectively. The results suggested that PAH concentrations in surrounding soils may be influenced by secondary copper smelters investigated, whereas no such gradient was observed in soils around the secondary aluminum smelter. Further analysis revealed that PAH patterns in soil samples also showed some difference between secondary copper and aluminum smelter, which may be attributed to the difference in their fuel and smelting process. PAH patterns and diagnostic ratios indicated that biomass burning may be also an important source of PAHs in the surrounding soil in addition to the emissions from the plants investigated. PMID- 28342082 TI - Quantitative characterization of pore structure of several biochars with 3D imaging. AB - Pore space characteristics of biochars may vary depending on the used raw material and processing technology. Pore structure has significant effects on the water retention properties of biochar amended soils. In this work, several biochars were characterized with three-dimensional imaging and image analysis. X ray computed microtomography was used to image biochars at resolution of 1.14 MUm and the obtained images were analysed for porosity, pore size distribution, specific surface area and structural anisotropy. In addition, random walk simulations were used to relate structural anisotropy to diffusive transport. Image analysis showed that considerable part of the biochar volume consist of pores in size range relevant to hydrological processes and storage of plant available water. Porosity and pore size distribution were found to depend on the biochar type and the structural anisotopy analysis showed that used raw material considerably affects the pore characteristics at micrometre scale. Therefore, attention should be paid to raw material selection and quality in applications requiring optimized pore structure. PMID- 28342084 TI - The transplantation of mesenchymal stem cells derived from unconventional sources: an innovative approach to multiple sclerosis therapy. AB - In recent years, in the effort to find a potential innovative therapy for multiple sclerosis (MS), researchers focused on transplantation of mesenchymal stem cells (MSCs) due to their well-recognized ability to suppress inflammatory/autoimmune responses and exert neuroregenerative properties. MSCs are a heterogeneous subset of pluripotent non-hematopoietic stromal cells that can be isolated from many different adult tissues, characterized by the capability to differentiate into various cell lineages, and to translocate into damaged areas, providing immunomodulatory effects. To date, several encouraging results were obtained mainly from the use of MSCs derived from the bone marrow (BM-MSCs) in experimental models of MS as well as in clinical trials. However, their use in clinic is limited due to the invasive collecting procedure and the low yield of viable stem cells. Consequently, these restrictions have prompted researchers to look for alternative tissue sources for stem cells such as adipose tissue, fetal annexes, and dental tissues that could represent a novel therapeutic option for MS treatment. Here, we provide an overview of the current knowledge about the most explored BM-MSCs in MS treatment in experimental and clinical studies. Moreover, we propose that unconventional sources of stem cells, which show characteristics similar to that of BM-MSCs, and being less invasive for removal, could be considered an excellent alternative to BM-MSCs and thus could be a promising innovative approach for MS treatment. PMID- 28342083 TI - Classification of advanced stages of Parkinson's disease: translation into stratified treatments. AB - Advanced stages of Parkinson's disease (advPD) still impose a challenge in terms of classification and related stage-adapted treatment recommendations. Previous concepts that define advPD by certain milestones of motor disability apparently fall short in addressing the increasingly recognized complexity of motor and non motor symptoms and do not allow to account for the clinical heterogeneity that require more personalized approaches. Therefore, deep phenotyping approaches are required to characterize the broad-scaled, continuous and multidimensional spectrum of disease-related motor and non-motor symptoms and their progression under real-life conditions. This will also facilitate the reasoning for clinical care and therapeutic decisions, as neurologists currently have to refer to clinical trials that provide guidance on a group level; however, this does not always account for the individual needs of patients. Here, we provide an overview on different classifications for advPD that translate into critical phenotypic patterns requiring the differential therapeutic adjustments. New concepts refer to precision medicine approaches also in PD and first studies on genetic stratification for therapeutic outcomes provide a potential for more objective treatment recommendations. We define novel treatment targets that align with this concept and make use of emerging device-based assessments of real-life information on PD symptoms. As these approaches require empowerment of patients and integration into treatment decisions, we present communication strategies and decision support based on new technologies to adjust treatment of advPD according to patient demands and safety. PMID- 28342085 TI - Concerns about the long-term safety of live kidney donors are justified. PMID- 28342086 TI - Motivational and Volitional Correlates of Physical Activity in Participants Reporting No, Past, and Current Hypertension: Findings from a Cross-Sectional Observation Study. AB - PURPOSE: The study investigated differences in motivational and volitional correlates of physical activity in persons who reported currently having hypertension, had hypertension in the past, or had no hypertension by using the health action process approach as a theoretical background. METHOD: Self-reported data from 512 participants (71.9% women; M age = 46.83 years; SD age = 13.77; M BMI = 24.89; SD BMI = 4.71) were analyzed using multivariate analysis of variance (MANOVA), analysis of variance (ANOVA), and post hoc comparisons of groups to determine differences in motivational and volitional correlates for physical activity between groups followed by analysis of covariance (ANCOVA). Additionally, chi 2 statistic was used to analyze differences in the distribution of behavioral stages between groups. RESULTS: Participants with hypertension reported a higher perceived vulnerability (d = 0.99) and lower action planning (d = 0.32) and self-efficacy (d = 0.30) compared to those who indicated no hypertension. Their perceived vulnerability was also higher compared to those who indicated past hypertension on the mean level (d = 0.60). Significant main effects for all independent variables were found when controlling for gender and HAPA stages with main effects for perceived vulnerability, action planning, and self-efficacy. Participants with current hypertension were more prominent in the intender stage, whereas participants with past hypertension were more likely to be in the actor stage. Participants with no hypertension at all were equally distributed across the intender and actor stages. CONCLUSION: The study contributes to the understanding of differences in motivational and volitional correlates of physical activity in persons who reported different hypertension statuses. PMID- 28342087 TI - Pelvic inflammatory disease and the risk of ovarian cancer: a meta-analysis. AB - PURPOSE: Previous studies on pelvic inflammatory disease (PID) and the risk of ovarian cancer have found inconsistent results. We performed an updated meta analysis to summarize the evidence of this association. METHODS: PubMed, Embase, and ISI web of science databases were searched through October 2016 for studies that investigated the PID and ovarian cancer association. Summary risk estimates were calculated using random-effects meta-analysis. RESULT: Thirteen studies were eligible for analysis, which included six cohort studies and seven case-control studies. PID was associated with an increased risk of ovarian cancer overall [relative risk (RR) 1.24, 95% CI 1.06-1.44; I 2 = 58.8%]. In analyses stratified by race, a significant positive association was observed in studies conducted among Asian women (RR 1.69, 95% CI 1.22-2.34; I 2 = 0%), but marginally significant among Caucasians (RR 1.18, 95% CI 1.00-1.39; I 2 = 60.7%).Risk estimates were elevated in both cohort (RR1.32; 95% CI 1.05-1.66; I 2 = 64.7%) and case-control studies (RR 1.17; 95% CI 0.93-1.49; I 2 = 57.6%), albeit not statistically significant in case-control studies. CONCLUSIONS: Our results suggested that PID might be a potential risk factor of ovarian cancer, with pronounced associations among Asian women. Large and well-designed studies with objective assessment methods, such as hospital records, are needed to confirm the findings of this meta-analysis. PMID- 28342090 TI - The effect of varenicline and nicotine patch on smoking rate and satisfaction with smoking: an examination of the mechanism of action of two pre-quit pharmacotherapies. AB - OBJECTIVES: In recent years, there has been growing research interest in using nicotine replacement medications to aid smoking reduction prior to a quit attempt. Gaining a better understanding of how treatments influence smoking reduction may allow for better tailoring of treatments and, ultimately, better cessation outcomes. The objective of the current study was to test the effects of the pre-quit use of varenicline and nicotine patch on smoking rate and satisfaction with smoking. METHODS: All participants were required to attend up to five study visit sections. Participants (n = 213) who were interested in quitting were randomised (open-label) to receive either pre-quit patch or varenicline (both treatments started 2 weeks prior to an assigned quit day, followed by 10 weeks post-quit) or standard patch (10 weeks starting from an assigned quit day). Participants used modified smartphones to monitor their smoking in real time for 4 weeks. RESULTS: Participants in the two pre-quit treatment groups reported significant reductions in both their satisfaction with smoking (p < 0.001) and smoking rate (p < 0.001) from baseline to the end of pre quit period; participants in the standard patch group did not. The observed reduction of smoking rate was associated with the satisfaction with smoking (p < 0.01), although the mediation effect of satisfaction was small. CONCLUSIONS: Pre quit treatment caused reductions in satisfaction with smoking and smoking rate. Satisfaction was associated with changes in smoking rate, but the relationship was weak. As such, monitoring reductions in satisfaction do not appear to be a viable method of evaluating responsiveness to treatment. PMID- 28342089 TI - Voluntary induction and maintenance of alcohol dependence in rats using alcohol vapor self-administration. AB - RATIONALE: A major issue in the addiction field is the limited number of animal models of the voluntary induction and maintenance of alcohol dependence in outbred rats. OBJECTIVES: To address this issue, we developed a novel apparatus that vaporizes alcohol for 2-10 min after an active nosepoke response. METHODS: Male Wistar rats were allowed to self-administer alcohol vapor for 8 h/day every other day for 24 sessions (escalated) or eight sessions (non-escalated). Escalated and non-escalated rats were then tested for progressive ratio responding. Anxiety-like behavior, somatic signs of withdrawal, and hyperalgesia were assessed during acute withdrawal. RESULTS: The results showed that rats exhibited excellent discrimination between the active and inactive operanda (>85%), and the escalated rats quickly increased their blood alcohol levels from ~50 to >200 mg% in ~6 weeks. Compared with non-escalated rats, escalated rats exhibited severe addiction-like behavior, including somatic signs of withdrawal, anxiety-like behavior, hyperalgesia, and higher responding on a progressive ratio schedule of reinforcement. CONCLUSIONS: These results demonstrate that outbred rats will voluntarily self-administer alcohol vapor to the point of dependence without the use of forced alcohol administration, sweeteners, food/water restriction, operant pretraining, or behavioral/genetic selection. This novel animal model may be particularly useful for medication development to help unveil the neuronal circuitry that underlies the voluntary induction of alcohol addiction and identify novel molecular targets that are specifically recruited after the voluntary induction and maintenance of alcohol dependence. PMID- 28342091 TI - Both nicotine reward and withdrawal are enhanced in a rodent model of diabetes. AB - RATIONALE: It is presently unclear whether diabetic rats experience greater rewarding effects of nicotine and/or negative affective states produced by nicotine withdrawal. OBJECTIVE: The present study utilized a rodent model of diabetes to examine the rewarding effects of nicotine and negative affective states and physical signs produced by withdrawal. METHODS: Separate groups of rats received systemic administration of either vehicle or streptozotocin (STZ), which destroys insulin-producing beta cells in the pancreas and elevates glucose levels. Place conditioning procedures were utilized to compare the rewarding effects of nicotine (conditioned place preference; CPP) and negative affective states produced by withdrawal (conditioned place aversion; CPA) in vehicle- and STZ-treated rats. CPA and physical signs of withdrawal were compared after administration of the nicotinic receptor antagonist mecamylamine to precipitate withdrawal in nicotine-dependent rats. A subsequent study utilized elevated plus maze (EPM) procedures to compare anxiety-like behavior produced by nicotine withdrawal in vehicle- and STZ-treated rats. RESULTS: STZ-treated rats displayed greater rewarding effects of nicotine and a larger magnitude of aversive effects and physical signs produced by withdrawal as compared to vehicle-treated controls. STZ-treated rats also displayed higher levels of anxiety-like behavior on the EPM during nicotine withdrawal as compared to controls. CONCLUSION: The finding that both nicotine reward and withdrawal are enhanced in a rodent model of diabetes implies that the strong behavioral effects of nicotine promote tobacco use in persons with metabolic disorders, such as diabetes. PMID- 28342093 TI - Achieving value in mobile health applications for cancer survivors. AB - PURPOSE: This study aimed to identify appropriate development and testing strategies for mobile health applications for cancer survivors. METHODS: In January of 2016, we conducted a PubMed search for mobile applications for cancer survivors. A total of 32 articles were selected for inclusion, including 13 review articles, and 19 articles describing an mHealth application or intervention. We assessed mobile app development and testing strategies and standards as described in these articles. RESULTS: We identified seven elements of patient empowerment applications for cancer survivors, strategies for application development that take advantage of smartphone capabilities, issues for consideration in developing new applications, and steps for creating user centered mobile health applications that provide meaningful value for cancer survivors. However, few mobile health apps implemented empowerment elements, underwent rigorous design approaches, or included assessment of use in the cancer survivor population. CONCLUSIONS: There is tremendous potential for mobile health apps to benefit cancer survivors. However, there are specific issues for consideration in developing new applications and steps for creating user-centered applications which are not routinely used. This diminishes the value for the cancer survivor population but could be easily addressed through standardized development and testing procedures. IMPLICATIONS FOR CANCER SURVIVORS: Smartphone applications have the potential to improve the cancer survivorship experience, but users should look for evidence that the application was appropriately developed and tested. PMID- 28342092 TI - Evaluation of structural connectivity changes in betel-quid chewers using generalized q-sampling MRI. AB - RATIONALE: Betel quid (BQ) is a common addictive substance in many Asian countries. However, few studies have focused on the influences of BQ on the brain. It remains unclear how BQ can affect structural brain abnormalities in BQ chewers. OBJECTIVES: We aimed to use generalized q-sampling imaging (GQI) to evaluate the impact of the neurological structure of white matter caused by BQ. METHODS: The study population comprised 16 BQ chewers, 15 tobacco and alcohol controls, and 17 healthy controls. We used GQI with voxel-based statistical analysis (VBA) to evaluate structural brain and connectivity abnormalities in the BQ chewers compared to the tobacco and alcohol controls and the healthy controls. Graph theoretical analysis (GTA) and network-based statistical (NBS) analysis were also performed to identify the structural network differences among the three groups. RESULTS: Using GQI, we found increases in diffusion anisotropy in the right anterior cingulate cortex (ACC), the midbrain, the bilateral angular gyrus, the right superior temporal gyrus (rSTG), the bilateral superior occipital gyrus, the left middle occipital gyrus, the bilateral superior and inferior parietal lobule, and the bilateral postcentral and precentral gyrus in the BQ chewers when compared to the tobacco and alcohol controls and the healthy controls. In GTA and NBS analyses, we found more connections in connectivity among the BQ chewers, particularly in the bilateral anterior cingulum. CONCLUSIONS: Our results provided further evidence indicating that BQ chewing may lead to brain structure and connectivity changes in BQ chewers. PMID- 28342094 TI - Comparison of the use of rhBMP-7 versus iliac crest autograft in single-level lumbar fusion: a meta-analysis of randomized controlled trials. AB - The aim of this study was to evaluate the safety and clinical effectiveness of rhBMP-7 (or osteogenic protein-1) versus that of autogenous iliac crest bone graft (ICBG) in single-level posterolateral fusion (PLF) of the lumbar spine. A systematic search of all articles published through July 1, 2016 was conducted in databases such as PubMed, EMBASE, Scopus, and the Cochrane Collaboration Library. Randomized controlled trials (RCTs) that compared rhBMP-7 with ICBG for the treatment of single-level degenerative spondylolisthesis, provided the fusion rate, clinical success rate, safety and adverse events report, operation time, and hospital stay durations as the outcome were assessed. As a result, a total of five RCTs involving 539 patients met the inclusion criteria. The outcomes of subgroup analysis demonstrated that when compared with autogenous ICBG, rhBMP-7 appear to yield lower fusion rates in instrumented posterolateral fusion patients (RR = 0.76, 95% CI [0.60, 0.98], P = 0.03), despite the test for overall fusion rates suggested that there was no significant difference between the two groups (RR = 0.89, 95% CI [0.78, 1.02], P = 0.09). Patients treated with OP-1 had shorter operation times versus those treated with ICBG (WMD = -16.70,95% CI [ 25.83, -7.57], P = 0.0003). Additionally, the outcomes demonstrated a lack of significant differences between rhBMP-7 and ICBG in terms of clinical success of ODI, overall adverse events, revision rates and duration of hospitalization. In conclusion, with the exception of reducing the operation time, our review suggests that the use of the rhBMP-7 instead of ICBG produce no any additional beneficial effect on the fusion rates, clinical success of ODI, overall adverse events, revision rates and duration of hospitalization in single level PLF. On the contrary, it appeared to yield lower fusion rate in the instrumented posterolateral fusion patients and cannot be recommended as an effective tool for this set of patients. PMID- 28342095 TI - [Advances in diagnostic microbiology : Opportunities and limitations]. AB - In the light of ever increasing problems related to the emergence of multidrug resistant bacteria, rapid microbiological diagnostics are of growing importance. Timely pathogen detection and availability of susceptibility data are essential for optimal treatment, but are even more crucial for de-escalation of broad spectrum empiric therapies. Medical microbiology is, thus, an integral part of antimicrobial stewardship programs. Traditional microbiological techniques for species identification and susceptibility testing rely on bacterial growth and are, thus, characterized by inherent slowness. Time-to-report is usually 48 h or longer, and typically delays optimization of therapeutic regimens. Constant improvement of available techniques (e. g., molecular methods) and introduction of novel methods (e. g., matrix-assisted laser desorption ionization time-of flight [MALDI-ToF] mass spectrometry) have fundamentally changed diagnostic procedures. As a consequence, sensitivity and specificity as well as time-to report have been dramatically improved. In this manuscript, key methodological advances in medical microbiology are discussed, emphasizing consequences for daily management of infectious disease patients. PMID- 28342096 TI - [Emergency treatment of tachycardias]. AB - The treatment of symptomatic tachycardia is a key challenge in intensive care medicine and emergency care. Making a quick and authoritative diagnosis on an ECG and applying adequate emergency treatment requires a structured approach to analyzing and treating arrhythmias. This CME article offers a practical categorization of the multitude of tachycardias, with medical and electrical treatment options and ECG examples. Appropriate first- and second-line treatment options are presented for most common tachyarrhythmias. PMID- 28342097 TI - A systematic review of propensity score methods in the acute care surgery literature: avoiding the pitfalls and proposing a set of reporting guidelines. AB - BACKGROUND: Propensity score methods are techniques commonly employed in observational research to account for confounding when estimating the effects of treatments and exposures. These methods have been increasingly employed in the acute care surgery literature in an attempt to infer causality; however, the adequacy of reporting and the appropriateness of statistical analyses when using propensity score matching remain unclear. OBJECTIVES: The goal of this systematic review is to assess the adequacy of reporting of propensity score methods, with an emphasis on propensity score matching (to assess balance and the use of appropriate statistical tests), in acute care surgery (ACS) studies and to provide suggestions for improvement for junior investigators. METHODS: We searched three databases, and other relevant literature (from January 2005 to June 2015) to identify observational studies within the ACS literature using propensity score methods (PROSPERO No: CRD42016036432). Two reviewers extracted data and assessed the quality of the studies retrieved by reviewing the adequacy of both overall reporting and of the propensity score matching methods used. RESULTS: A total of 49/71 (69%) of studies adequately reported propensity score methods overall. Matching was the most common propensity score method used in 46/71 (65%) studies, with 36/46 (78%) studies reporting matching methods adequately. Only 19/46 (41%) of matching studies reported the balance of baseline characteristics between treated and untreated subjects while 6/46 (13%) used correct statistical methods to assess balance. There were 35/46 (76%) of matching studies that explicitly used statistical methods appropriate for the analysis of matched data when estimating the treatment effect and its statistical significance. CONCLUSION: We have proposed reporting guidelines for the use of propensity score methods in the acute care surgery literature. This is to help investigators improve the adequacy of reporting and statistical analyses when using observational data to estimate effects of treatments and exposures. PMID- 28342100 TI - Erratum to: Yolk sac tumour: a rare cause of raised serum alpha-foetoprotein in a young child with a large liver mass. PMID- 28342098 TI - Expression of cell cycle regulators and biomarkers of proliferation and regrowth in human pituitary adenomas. AB - PURPOSE: The pathogenesis of pituitary adenomas (PA) is complex. Ki-67, pituitary tumour transforming gene (PTTG), vascular endothelial growth factor (VEGF), cyclin D1, c-MYC and pituitary adenylate cyclase-activating peptide (PACAP) protein expression were analysed and correlated with tumour and patient characteristics. METHODS: 74 pituitary tumour samples (48 non-functional PA, 26 functional PAs); Immunohistochemical analysis of protein expression, retrospective analysis of MR images and in vitro analysis of octreotide treatment was carried out on GH3 cells. RESULTS: PTTG expression was negatively associated with age and positively with PA size, regrowth and Ki-67 index. Cyclin D1 correlated with Ki-67 and tumour size. c-MYC negatively correlated with size of tumour and age; and correlated with PTTG expression. Somatostatin analogue treatment was associated with lower Ki-67, PTTG and Cyclin D1 expression while T2 hypointense PAs were associated with lower PTTG, cyclin D1, c-MYC and Ki-67. In vitro analyses confirmed the effect of somatostatin analogue treatment on Pttg and Cyclin D1 expression. CONCLUSIONS: Interesting and novel observations on the differences in expression of tumour markers studied are reported. Correlation between Ki-67 expression, PTTG nuclear expression and recurrence/regrowth of PAs, emphasizes the role that Ki-67 and PTTG expression have as markers of increased proliferation. c-MYC and PTTG nuclear expression levels were correlated providing evidence that PTTG induces c-MYC expression in PAs and we propose that c-MYC might principally have a role in early pituitary tumorigenesis. Evidence is shown that the anti-proliferative effect of somatostatin analogue treatment in vivo occurs through regulation of the cell cycle. PMID- 28342099 TI - Optimized decellularization protocol including alpha-Gal epitope reduction for fabrication of an acellular porcine annulus fibrosus scaffold. AB - Recent advances in tissue engineering have led to potential new strategies, especially decellularization protocols from natural tissues, for the repair, replacement, and regeneration of intervertebral discs. This study aimed to validate our previously reported method for the decellularization of annulus fibrosus (AF) tissue and to quantify potentially antigenic alpha-Gal epitopes in the decellularized tissue. Porcine AF tissue was decellularized using different freeze-thaw temperatures, chemical detergents, and incubation times in order to determine the optimal method for cell removal. The integrity of the decellularized material was determined using biochemical and mechanical tests. The alpha-Gal epitope was quantified before and after decellularization. Decellularization with freeze-thaw in liquid nitrogen, an ionic detergent (0.1% SDS), and a 24 h incubation period yielded the greatest retention of GAG and collagen relative to DNA reduction when tested as single variables. Combined, these optimal decellularization conditions preserved more GAG while removing the same amount of DNA as the conditions used in our previous study. Components and biomechanical properties of the AF matrix were retained. The decellularized AF scaffold exhibited suitable immune-compatibility, as evidenced by successful in vivo remodeling and a decrease in the alpha-Gal epitope. Our study defined the optimal conditions for decellularization of porcine AF tissues while preserving the biological composition and mechanical properties of the scaffold. Under these conditions, immunocompatibility was evidenced by successful in vivo remodeling and reduction of the alpha-Gal epitope in the decellularized material. Decellularized AF scaffolds are potential candidates for clinical applications in spinal surgery. PMID- 28342101 TI - Myocardial segmentation based on coronary anatomy using coronary computed tomography angiography: Development and validation in a pig model. AB - OBJECTIVES: To validate a method for performing myocardial segmentation based on coronary anatomy using coronary CT angiography (CCTA). METHODS: Coronary artery based myocardial segmentation (CAMS) was developed for use with CCTA. To validate and compare this method with the conventional American Heart Association (AHA) classification, a single coronary occlusion model was prepared and validated using six pigs. The unstained occluded coronary territories of the specimens and corresponding arterial territories from CAMS and AHA segmentations were compared using slice-by-slice matching and 100 virtual myocardial columns. RESULTS: CAMS more precisely predicted ischaemic area than the AHA method, as indicated by 95% versus 76% (p < 0.001) of the percentage of matched columns (defined as percentage of matched columns of segmentation method divided by number of unstained columns in the specimen). According to the subgroup analyses, CAMS demonstrated a higher percentage of matched columns than the AHA method in the left anterior descending artery (100% vs. 77%; p < 0.001) and mid- (99% vs. 83%; p = 0.046) and apical-level territories of the left ventricle (90% vs. 52%; p = 0.011). CONCLUSIONS: CAMS is a feasible method for identifying the corresponding myocardial territories of the coronary arteries using CCTA. KEY POINTS: * CAMS is a feasible method for identifying corresponding coronary territory using CTA * CAMS is more accurate in predicting coronary territory than the AHA method * The AHA method may underestimate the ischaemic territory of LAD stenosis. PMID- 28342102 TI - The value of gadoxetic acid-enhanced MRI for differentiation between hepatic microabscesses and metastases in patients with periampullary cancer. AB - OBJECTIVES: We aimed to identify features that differentiate hepatic microabscess from hepatic metastasis on gadoxetic acid-enhanced MRI in patients with periampullary cancer. METHODS: We included 72 patients (31 patients with 83 hepatic microabscesses and 41 patients with 71 hepatic metastases) who had a history of periampullary cancer and underwent gadoxetic acid-enhanced MRI. Image analysis was performed for margin, signal intensity, rim enhancement, perilesional hyperaemia, pattern on DWI and dynamic phases, and size discrepancy between sequences by consensus of two observers. RESULTS: Multivariate analysis revealed that the following significant parameters favour microabscess: a history of bile duct cancer, perilesional hyperaemia, persistent arterial rim enhancement through the transitional phase (TP), and size discrepancy between T1WI and T2WI and between T1WI and hepatobiliary phase image (HBPI). The diagnostic accuracy for microabscess was highest (90.9%) when showing a size discrepancy >=30% between T1WI and HBPI or persistent arterial rim enhancement through the TP. When the lesion was positive for both these variables, specificity reached 100%. CONCLUSION: The combination of a size discrepancy between T1WI and HBPI and persistent arterial rim enhancement through the TP represents a reliable MRI feature for distinguishing between hepatic microabscess and metastasis in patients with periampullary cancer. KEY POINTS: * Gadoxetic acid-enhanced MRI is useful for distinguishing hepatic microabscess from metastasis. * Hepatic microabscess showed significant size discrepancy >=30% between T1WI and HBPI. * Arterial rim enhancement persistent through the TP indicates hepatic microabscess. PMID- 28342103 TI - Survival and prognostic factors after adjuvant 131iodine-labeled lipiodol for hepatocellular carcinoma: a retrospective analysis of 106 patients over 20 years. AB - OBJECTIVE: Hepatocellular carcinoma (HCC) has high recurrence rate after curative treatment. The aim of the present study was to report our experience with adjuvant use of 131I-lipiodol after curative treatment of HCC in terms of recurrence and survival in a large cohort of patients with a long follow-up. METHODS: All patients treated with 131I-lipiodol after curative treatment of HCC in two French centers from 1991 to 2009 were included in a retrospective cohort study. RESULTS: One hundred and six patients were included. The median (range) follow-up was 6 years (0.3-22). Forty-three patients (41%) had cirrhosis. Recurrence-free survival rates at 1, 2, 5, 10, and 20 years were 73, 57, 40, 30, and 14%, respectively. Cirrhosis was an independent predictive factor of recurrence [RR = 1.18, 95% CI (1.11-3.02), p = 0.019]. Overall, survival rates at 1, 2, 5, 10, and 20 years were 90, 83, 59, 37, and 23%, respectively. Prognostic factors were recurrence [RR = 2.73, 95% CI (1.35-5.54); p = 0.005], age over 60 years (RR = 1.91, 95% CI [1.02-3.61]; p = 0.044), and tumor number over 3 [RR = 3.31, 95% CI (1.25-8.77); p = 0.016]. CONCLUSION: Our results suggest that the effect of 131I-lipiodol after curative treatment of HCC could be related to a beneficial impact on risk factors of early tumor recurrence. This could be evaluated in further studies using modern radioembolization methods. PMID- 28342104 TI - A comprehensive review of paediatric low-grade diffuse glioma: pathology, molecular genetics and treatment. AB - Gliomas are the most common central nervous system neoplasms affecting children and can be both high- and low-grade. Paediatric low-grade glioma may be either World Health Organization grade I or grade II. Despite being classified as grade II diffuse astrocytoma, these neoplasms arising in children are distinct clinically and molecularly from their adult counterparts. They do not tend to progress to higher grade lesions and only rarely harbour an IDH mutation. Here, we review the clinical, histologic and molecular features of paediatric grade II diffuse glioma, highlighting their diagnostic criteria, prevalence across brain locations, their most common molecular features and how to test for them, and lastly the current status of therapeutic options available for their treatment. PMID- 28342105 TI - Real-time surgical tool tracking and pose estimation using a hybrid cylindrical marker. AB - PURPOSE: To provide an integrated visualisation of intraoperative ultrasound and endoscopic images to facilitate intraoperative guidance, real-time tracking of the ultrasound probe is required. State-of-the-art methods are suitable for planar targets while most of the laparoscopic ultrasound probes are cylindrical objects. A tracking framework for cylindrical objects with a large work space will improve the usability of the intraoperative ultrasound guidance. METHODS: A hybrid marker design that combines circular dots and chessboard vertices is proposed for facilitating tracking cylindrical tools. The circular dots placed over the curved surface are used for pose estimation. The chessboard vertices are employed to provide additional information for resolving the ambiguous pose problem due to the use of planar model points under a monocular camera. Furthermore, temporal information between consecutive images is considered to minimise tracking failures with real-time computational performance. RESULTS: Detailed validation confirms that our hybrid marker provides a large working space for different tool sizes (6-14 mm in diameter). The tracking framework allows translational movements between 40 and 185 mm along the depth direction and rotational motion around three local orthogonal axes up to [Formula: see text]. Comparative studies with the current state of the art confirm that our approach outperforms existing methods by providing nearly 100% detection rates and accurate pose estimation with mean errors of 2.8 mm and 0.72[Formula: see text]. The tracking algorithm runs at 20 frames per second for [Formula: see text] image resolution videos. CONCLUSION: Experiments show that the proposed hybrid marker can be applied to a wide range of surgical tools with superior detection rates and pose estimation accuracies. Both the qualitative and quantitative results demonstrate that our framework can be used not only for assisting intraoperative ultrasound guidance but also for tracking general surgical tools in MIS. PMID- 28342106 TI - Extraction of skin lesions from non-dermoscopic images for surgical excision of melanoma. AB - PURPOSE: Computerized prescreening of suspicious moles and lesions for malignancy is of great importance for assessing the need and the priority of the removal surgery. Detection can be done by images captured by standard cameras, which are more preferable due to low cost and availability. One important step in computerized evaluation is accurate detection of lesion's region, i.e., segmentation of an image into two regions as lesion and normal skin. METHODS: In this paper, a new method based on deep neural networks is proposed for accurate extraction of a lesion region. The input image is preprocessed, and then, its patches are fed to a convolutional neural network. Local texture and global structure of the patches are processed in order to assign pixels to lesion or normal classes. A method for effective selection of training patches is proposed for more accurate detection of a lesion's border. RESULTS: Our results indicate that the proposed method could reach the accuracy of 98.7% and the sensitivity of 95.2% in segmentation of lesion regions over the dataset of clinical images. CONCLUSION: The experimental results of qualitative and quantitative evaluations demonstrate that our method can outperform other state-of-the-art algorithms exist in the literature. PMID- 28342107 TI - Interactive segmentation in MRI for orthopedic surgery planning: bone tissue. AB - PURPOSE: Planning orthopedic surgeries is commonly performed in computed tomography (CT) images due to the higher contrast of bony structure. However, soft tissues such as muscles and ligaments that may determine the functional outcome of a procedure are not easy to identify in CT, for which fast and accurate segmentation in MRI would be desirable. To be usable in daily practice, such method should provide convenient means of interaction for modifications and corrections, e.g., during perusal by the surgeon or the planning physician for quality control. METHODS: We propose an interactive segmentation framework for MR images and evaluate the outcome for segmentation of bones. We use a random forest classification and a random walker-based spatial regularization. The latter enables the incorporation of user input as well as enforcing a single connected anatomical structures, thanks to which a selective sampling strategy is proposed to substantially improve the supervised learning performance. RESULTS: We evaluated our segmentation framework on 10 patient humerus MRI as well as 4 high resolution MRI from volunteers. Interactive humerus segmentations for patients took on average 150 s with over 3.5 times time-gain compared to manual segmentations, with accuracies comparable (converging) to that of much longer interactions. For high-resolution data, a novel multi-resolution random walker strategy further reduced the run time over 20 times of the manual segmentation, allowing for a feasible interactive segmentation framework. CONCLUSIONS: We present a segmentation framework that allows iterative corrections leading to substantial speed gains in bone annotation in MRI. This will allow us to pursue semi-automatic segmentations of other musculoskeletal anatomy first in a user-in the-loop manner, where later less user interactions or perhaps only few for quality control will be necessary as our annotation suggestions improve. PMID- 28342108 TI - Fine mapping of a quantitative resistance gene for gray leaf spot of maize (Zea mays L.) derived from teosinte (Z. mays ssp. parviglumis). AB - KEY MESSAGE: In this study we mapped the QTL Qgls8 for gray leaf spot (GLS) resistance in maize to a ~130 kb region on chromosome 8 including five predicted genes. In previous work, using near isogenic line (NIL) populations in which segments of the teosinte (Zea mays ssp. parviglumis) genome had been introgressed into the background of the maize line B73, we had identified a QTL on chromosome 8, here called Qgls8, for gray leaf spot (GLS) resistance. We identified alternate teosinte alleles at this QTL, one conferring increased GLS resistance and one increased susceptibility relative to the B73 allele. Using segregating populations derived from NIL parents carrying these contrasting alleles, we were able to delimit the QTL region to a ~130 kb (based on the B73 genome) which encompassed five predicted genes. PMID- 28342109 TI - Sensitivity to Enterocins of Biogenic Amine-Producing Faecal Enterococci from Ostriches and Pheasants. AB - Enterococci are widespread bacteria forming the third largest genus among lactic acid bacteria. Some possess probiotic properties or they can produce beneficial proteinaceous antimicrobial substances called enterocins. On the other hand, some enterococci produce biogenic amines (BAs), so this study is focused on the sensitivity to enterocins of biogenic amine-producing faecal enterococci from ostriches and pheasants. Altogether, 60 enterococci isolated from faeces of ostriches and pheasants were tested for production of BAs. This target of the identified enterococci involved 46 strains selected from 140 ostriches and 17 from 60 pheasants involving the species Enterococcus hirae, E. faecium, E. faecalis, and E. mundtii. Although BAs histamine, cadaverine, putrescine, and tryptamine were not detected in the enterococci tested, in general high BA production by the tested enterococci was noted. The species E. hirae formed the majority of the enterococcal strains from ostrichs faeces (34 strains). High production of tyramine (TYM) was measured with an average amount of 958.16 +/- 28.18 mg/ml. Among the enterococci from pheasants, the highest was production of TYM compared to phenylethylamine, spermidine, and spermine. Enterococci featured high BA production; however, they were sensitive to seven enterocins with inhibition activity ranging from 100 up to 25,600 AU/ml. PMID- 28342110 TI - Electroconvulsive therapy enhances endocannabinoids in the cerebrospinal fluid of patients with major depression: a preliminary prospective study. AB - Despite the lack of clinical data about the role of the endocannabinoid system (ECS) in affective disorders, preclinical work suggests that the ECS is relevant in both with regard to the etiology of depression as well as the mediation of antidepressant effects. We measured the intraindividual levels of the endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2 AG) in the cerebrospinal fluid of 12 patients suffering from a major depressive episode before and after the antidepressant treatment by electroconvulsive therapy (ECT). AEA was significantly elevated after ECT as compared to baseline. The AEA increase positively correlated with the number of individually performed ECT sessions. Although the sample size was small and confounders were not rigorously controlled for, our finding corroborates preclinical work and should encourage further exploration of the involvement of the ECS in depressive disorder. PMID- 28342112 TI - An Investigation of the Overlap Between the ICECAP-A and Five Preference-Based Health-Related Quality of Life Instruments. AB - BACKGROUND: The ICEpop CAPability measure for Adults (ICECAP-A) is a measure of capability wellbeing developed for use in economic evaluations. It was designed to overcome perceived limitations associated with existing preference-based instruments, where the explicit focus on health-related aspects of quality of life may result in the failure to capture fully the broader benefits of interventions and treatments that go beyond health. The aim of this study was to investigate the extent to which preference-based health-related quality of life (HRQoL) instruments are able to capture aspects of capability wellbeing, as measured by the ICECAP-A. METHODS: Using data from the Multi Instrument Comparison project, pairwise exploratory factor analyses were conducted to compare the ICECAP-A with five preference-based HRQoL instruments [15D, Assessment of Quality of Life 8-dimension (AQoL-8D), EQ-5D-5L, Health Utilities Index Mark 3 (HUI-3), and SF-6D]. RESULTS: Data from 6756 individuals were used in the analyses. The ICECAP-A provides information above that garnered from most commonly used preference-based HRQoL instruments. The exception was the AQoL-8D; more common factors were identified between the ICECAP-A and AQoL-8D compared with the other pairwise analyses. CONCLUSION: Further investigations are needed to explore the extent and potential implications of 'double counting' when applying the ICECAP-A alongside health-related preference-based instruments. PMID- 28342111 TI - CKB1 is involved in abscisic acid and gibberellic acid signaling to regulate stress responses in Arabidopsis thaliana. AB - Casein kinase II (CK2), an evolutionarily well-conserved Ser/Thr kinase, plays critical roles in all higher organisms including plants. CKB1 is a regulatory subunit beta of CK2. In this study, homozygous T-DNA mutants (ckb1-1 and ckb1-2) and over-expression plants (35S:CKB1-1, 35S:CKB1-2) of Arabidopsis thaliana were studied to understand the role of CKB1 in abiotic stress and gibberellic acid (GA) signaling. Histochemical staining showed that although CKB1 was expressed in all organs, it had a relatively higher expression in conducting tissues. The ckb1 mutants showed reduced sensitivity to abscisic acid (ABA) during seed germination and seedling growth. The increased stomatal aperture, leaf water loss and proline accumulation were observed in ckb1 mutants. In contrast, the ckb1 mutant had increased sensitivity to polyaluminum chloride during seed germination and hypocotyl elongation. We obtained opposite results in over-expression plants. The expression levels of a number of genes in the ABA and GA regulatory network had changed. This study demonstrates that CKB1 is an ABA signaling-related gene, which subsequently influences GA metabolism, and may play a positive role in ABA signaling. PMID- 28342113 TI - Crizotinib for Untreated Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. AB - As part of the National Institute for Health and Care Excellence (NICE) single technology appraisal process, the manufacturer of crizotinib submitted evidence on the clinical and cost effectiveness of crizotinib in untreated anaplastic lymphoma kinase-positive (ALK-positive) non-small-cell lung cancer (NSCLC). Crizotinib has previously been assessed by NICE for patients with previously treated ALK-positive NSCLC (TA 296). It was not approved in this previous appraisal, but had been made available through the cancer drugs fund. As part of this new appraisal, the company included a price discount patient access scheme (PAS). The Centre for Reviews and Dissemination and Centre for Health Economics Technology Appraisal Group at the University of York was commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company's submission and the ERG's review and summarises the resulting NICE guidance issued in August 2016. The main clinical-effectiveness data were derived from a multicentre randomised controlled trial-PROFILE 1014-that compared crizotinib with pemetrexed chemotherapy in combination with carboplatin or cisplatin in patients with untreated non-squamous ALK-positive NSCLC. In the trial, crizotinib demonstrated improvements in progression-free survival (PFS) and overall survival (OS). The company's economic model was a three-state 'area under the curve' Markov model. The base-case incremental cost-effectiveness ratio (ICER) was estimated to be greater than L50,000 per quality-adjusted life-year (QALY) gained (excluding the PAS discount). The ERG assessment of the evidence submitted by the company raised a number of concerns. In terms of the clinical evidence, the OS benefit was highly uncertain due to the cross-over permitted in the trial and the immaturity of the data; only 26% of events had occurred by the data cut-off point. In the economic modelling, the most significant concerns related to the analysis of OS and assumptions made regarding the duration of therapy. The ERG exploratory re-analysis of the OS data relaxed the assumption of proportional hazards made in the company submission, which demonstrated significant uncertainty regarding the OS gains from crizotinib. The ERG reconfigured the economic model so that duration of therapy was based on the area under the curve analysis of the PROFILE 1014 trial, dramatically increasing the cost associated with implementing crizotinib and consequently, substantially increasing the ICER. At the first appraisal meeting, the NICE Appraisal Committee concluded that crizotinib, while clinically effective, was not sufficiently cost effective for use in the UK NHS. Following the consultation, the company offered a revised PAS and conducted extensive re-analysis, resulting in a revised base case ICER of L47,291 per QALY gained. The NICE Appraisal Committee concluded that crizotinib was likely to be a cost-effective use of NHS resources, despite the uncertainty that persisted around a number of factors, namely the long-term survival benefit of crizotinib. Crizotinib was therefore recommended as an option for untreated ALK-positive advanced NSCLC in adults. PMID- 28342114 TI - Using Parameter Constraints to Choose State Structures in Cost-Effectiveness Modelling. AB - BACKGROUND: This article addresses the choice of state structure in a cost effectiveness multi-state model. Key model outputs, such as treatment recommendations and prioritisation of future research, may be sensitive to state structure choice. For example, it may be uncertain whether to consider similar disease severities or similar clinical events as the same state or as separate states. Standard statistical methods for comparing models require a common reference dataset but merging states in a model aggregates the data, rendering these methods invalid. METHODS: We propose a method that involves re-expressing a model with merged states as a model on the larger state space in which particular transition probabilities, costs and utilities are constrained to be equal between states. This produces a model that gives identical estimates of cost effectiveness to the model with merged states, while leaving the data unchanged. The comparison of state structures can be achieved by comparing maximised likelihoods or information criteria between constrained and unconstrained models. We can thus test whether the costs and/or health consequences for a patient in two states are the same, and hence if the states can be merged. We note that different structures can be used for rates, costs and utilities, as appropriate. APPLICATION: We illustrate our method with applications to two recent models evaluating the cost effectiveness of prescribing anti-depressant medications by depression severity and the cost effectiveness of diagnostic tests for coronary artery disease. CONCLUSIONS: State structures in cost-effectiveness models can be compared using standard methods to compare constrained and unconstrained models. PMID- 28342116 TI - Constantin von Monakow (1853-1930) and his legacy to science. AB - Constantin von Monakow was a Russian-born Swiss neurologist. Monakow was an outstanding scientist of his time. He will be remembered by his important contributions to our knowledge on the organization, location, and direction of tracts of the nervous system. PMID- 28342115 TI - SSh versus TSE sequence protocol in rapid MR examination of pediatric patients with programmable drainage system. AB - PURPOSE: A low radiation burden is essential during diagnostic procedures in pediatric patients due to their high tissue sensitivity. Using MR examination instead of the routinely used CT reduces the radiation exposure and the risk of adverse stochastic effects. Our retrospective study evaluated the possibility of using ultrafast single-shot (SSh) sequences and turbo spin echo (TSE) sequences in rapid MR brain imaging in pediatric patients with hydrocephalus and a programmable ventriculoperitoneal drainage system. METHODS: SSh sequences seem to be suitable for examining pediatric patients due to the speed of using this technique, but significant susceptibility artifacts due to the programmable drainage valve degrade the image quality. Therefore, a rapid MR examination protocol based on TSE sequences, less sensitive to artifacts due to ferromagnetic components, has been developed. Of 61 pediatric patients who were examined using MR and the SSh sequence protocol, a group of 15 patients with hydrocephalus and a programmable drainage system also underwent TSE sequence MR imaging. The susceptibility artifact volume in both rapid MR protocols was evaluated using a semiautomatic volumetry system. RESULTS: A statistically significant decrease in the susceptibility artifact volume has been demonstrated in TSE sequence imaging in comparison with SSh sequences. Using TSE sequences reduced the influence of artifacts from the programmable valve, and the image quality in all cases was rated as excellent. In all patients, rapid MR examinations were performed without any need for intravenous sedation or general anesthesia. CONCLUSIONS: Our study results strongly suggest the superiority of the TSE sequence MR protocol compared to the SSh sequence protocol in pediatric patients with a programmable ventriculoperitoneal drainage system due to a significant reduction of susceptibility artifact volume. Both rapid sequence MR protocols provide quick and satisfactory brain imaging with no ionizing radiation and a reduced need for intravenous or general anesthesia. PMID- 28342117 TI - Otto Mennicke (1876-) and the first description of skull base anomalies causing cerebellar tonsillar ectopia: one of the first mentions of the Chiari I malformation. AB - INTRODUCTION: Although Hans Chiari made significant and meaningful contributions to our understanding and classification of hindbrain herniations, others have also contributed to this knowledge. One figure who has been lost to history is Otto Mennicke. Herein, we discuss his role in our understanding of tonsillar ectopia and his life and connection to Hans Chiari. CONCLUSIONS: Our knowledge of what is now known as the Chiari malformations has been shaped by several clinicians including Otto Mennicke. PMID- 28342119 TI - Returns to Operating Room After Colon and Rectal Surgery in a Tertiary Care Academic Medical Center: a Valid Measure of Surgical Quality? AB - INTRODUCTION: Returns to the operating room (ROR) have been suggested as a marker of surgical quality. Increasingly, quality and value metrics are utilized for reimbursement as well as public reporting to inform health care consumers. We sought to understand the etiology of ROR and assess the validity of simple ROR as a quality metric. METHODS: This was a single referral center retrospective review of all colon and rectal operations between January 1, 2014 and December 31, 2014. Surgical Systems Nurse + was constructed and validated at our institution for classifying ROR as either an unplanned return to the OR, planned return due to complications, planned staged return, or an unrelated return. The primary outcome was the classification of ROR and total number of ROR within 30 days. RESULTS: Of the 2389 colorectal patients who underwent surgery between January 1, 2014 and December 31, 2014; 214 returned to the operating room within 30 days (9.0%). Among the 214 patients, there were a total of 232 ROR with an average of 1.1 ROR per patient (range 1-4); 90 (38.8%) were unplanned ROR, 49 (21.1%) were planned returns due to complications, 92 (39.7%) were planned staged returns, and 1 (0.4%) were unrelated ROR. The most common reason for an unplanned ROR was an anastomotic leak (n = 21; 9.1%). Overall, unplanned reoperations were rare events (n = 90/2389; 3.8%), largely comprised of patients experiencing an anastomotic abscess or leak (n=21/2389; 0.9%). CONCLUSIONS: In a high volume and complexity academic colon and rectal surgery practice, RORs within 30 days occurred after 10.4% of cases. Unplanned ROR were relatively rare and most commonly associated with an anastomotic leak. Since the majority of ROR were planned-staged returns, overall rate of ROR should be questioned as a metric of surgical quality. Perhaps, the anastomotic leak rate may be a better metric to monitor for quality improvement efforts. PMID- 28342118 TI - Somatosensory evoked potentials as a screening tool for diagnosis of spinal pathologies in children with treatment refractory overactive bladder. AB - PURPOSE: To evaluate the usefulness of somatosensory evoked potential as a screening tool for spinal pathologies in patients with treatment refractory overactive bladder. METHODS: This prospective study was performed between January 2011 and January 2014. Children >5 years old with treatment refractory overactive bladder were enrolled after exclusion of anatomical and neurological causes of incontinence. All patients underwent urodynamic studies, spinal MRI, and somatosensory evoked potential (SEP). Sensitivity, specificity, PPV, and NPV were calculated for SEP. RESULTS: Thirty-one children (average age 8.3 +/- 2.9 years) were included in the study. SEP was abnormal in 13 (41.9%), and MRI was abnormal in 8 (25.8%) patients. SEP was found to have a sensitivity of 87.5%, a specificity of 73.9%, positive predictive value of 53.85%, and negative predictive value (NPV) of 94.4%. CONCLUSION: In patients with treatment refractory OAB, SEP is an important tool for the screening of tethered cord/spinal pathologies. Our results suggest that a child with a normal SEP study in this group of patients may not require further investigation with MRI. PMID- 28342120 TI - The Impact of Hepaticojejunostomy Leaks After Pancreatoduodenectomy: a Devastating Source of Morbidity and Mortality. AB - INTRODUCTION: Hepaticojejunostomy leaks are less frequent than pancreatic leaks after pancreatoduodenectomy, and the current literature suggests comparable outcomes. The purpose of this study was to determine if the hepaticojejunostomy leak adversely affected patient outcomes. METHODS: Consecutive cases of pancreatoduodenectomy (n = 924) were reviewed at a single high-volume institution over an 8-year period (2006-2014). RESULTS: Pancreaticojejunostomy leaks were identified in 217 (23%) patients and hepaticojejunostomy leaks were identified in 24 patients (3%); combined hepaticojejunostomy/pancreaticojejunostomy leaks were identified in 31 patients (3%). Those with hepaticojejunostomy leaks or combined leaks had a significantly increased risk of morbidity when compared to pancreaticojejunostomy leaks or no leak (54 and 58 vs. 34 and 24%, respectively, p < 0.05). The median length of stay was significantly greater for hepaticojejunostomy leaks or combined leaks when compared to pancreatojejunostomy leaks (17 or 14 vs. 9 days, p = 0.001) and those with no leak (17 or 14 vs. 7 days, p = 0.001). Ninety-day mortality for all patients was 3.6%. Hepaticojejunostomy leaks and combined leaks significantly increased 90-day mortality rate (17 and 32%, respectively, p < 0.05). CONCLUSIONS: Hepaticojejunostomy and combined leaks after pancreatoduodenectomy are rarer than pancreaticojejunostomy leaks; these patients are at a significantly increased risk of major morbidity and mortality. PMID- 28342121 TI - Can Comprehensive Imaging Analysis with Analytic Morphomics and Geriatric Assessment Predict Serious Complications in Patients Undergoing Pancreatic Surgery? AB - We aimed to determine whether comprehensive imaging analysis with analytic morphomics (AM) enhances or replaces geriatric assessment (GA) in risk stratifying pancreatic surgery patients. One hundred thirty-four pancreatic surgery patients were identified from a prospective cohort. Sixty-three patients in the cohort had preoperative CT scans in addition to comprehensive geriatric assessments. CT scans were processed using AM. Associations with National Surgical Quality Improvement Program (NSQIP) serious complications were evaluated using univariate analysis and robust elastic net modeling to obtain AUROC curves by adding AM and GA measures to our previously defined clinical base risk model (age, body mass index, American Society of Anesthesiologists classification, and Charlson comorbidity index). NSQIP serious complications were associated with low psoas Hounsfield units (HUs) (p = 0.002), low-density (0 to 30 HU) psoas area (p = 0.01), visceral fat HU (p <= 0.001), visceral fat area (p = 0.009), subcutaneous fat HU (p = 0.023), and total body area (p = 0.012) on univariate analysis. Elastic net models incorporating the base model with geriatric assessment and psoas HU (AUC = 0.751), and AM alone (AUC = 0.739) have greater predictive value than the base model alone (AUC = 0.601). The model utilizing AM and GA in combination had the highest predictive value (AUC = 0.841). When combined, AM and GA improve prediction of NSQIP serious complications compared to either technique alone. The additive nature of these two modalities suggests they likely capture unique aspects of a patient's fitness for surgery. PMID- 28342122 TI - Impact of Secreted Protein Acidic and Rich in Cysteine (SPARC) Expression on Prognosis After Surgical Resection for Biliary Carcinoma. AB - BACKGROUND: Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that influences chemotherapy effectiveness and prognosis. The aim of this study was to investigate whether SPARC expression correlates with the postoperative survival of patients treated with surgical resection for biliary carcinoma. METHODS: SPARC expression in resected biliary carcinoma specimens was investigated immunohistochemically in 175 patients. The relationship between SPARC expression and prognosis after surgery was evaluated using univariate and multivariate analyses. RESULTS: High SPARC expression in peritumoral stroma was found in 61 (35%) patients. In all patients, stromal SPARC expression was significantly associated with overall survival (OS) (P = 0.006). Multivariate analysis revealed that high stromal SPARC expression was an independent risk factor for poor OS (HR 1.81, P = 0.006). Moreover, high stromal SPARC expression was independently associated with poor prognosis in a subset of 118 patients treated with gemcitabine-based adjuvant chemotherapy (HR 2.04, P = 0.010) but not in the 57 patients who did not receive adjuvant chemotherapy (P = 0.21). CONCLUSIONS: Stromal SPARC expression correlated with the prognosis of patients with resectable biliary carcinoma, and its significance was enhanced in patients treated with adjuvant gemcitabine-based chemotherapy. PMID- 28342123 TI - Clinical case of cfr-positive MRSA CC398 in Belgium. PMID- 28342124 TI - Laparoscopic image-based navigation for microwave ablation of liver tumors-A multi-center study. AB - BACKGROUND: Stereotactic navigation technology has been proposed to augment accuracy in targeting intrahepatic lesions for local ablation therapy. This retrospective study evaluated accuracy, efficacy, and safety when using laparoscopic image-guided microwave ablation (LIMA) for malignant liver tumors. METHODS: All patients treated for malignant liver lesions using LIMA at two European centers between 2013 and 2015 were included for analysis. A landmark based registration technique was applied for intraoperative tumor localization and positioning of ablation probes. Intraoperative efficiency of the procedure was measured as number of registration attempts and time needed to achieve sufficient registration accuracy. Technical accuracy was assessed as Fiducial Registration Error (FRE). Outcome at 90 days including mortality, postoperative morbidity, rates of incomplete ablations, and early intrahepatic recurrences were reported. RESULTS: In 34 months, 54 interventions were performed comprising a total of 346 lesions (median lesions per patient 3 (1-25)). Eleven patients had concomitant laparoscopic resections of the liver or the colorectal primary tumor. Median time for registration was 4:38 min (0:26-19:34). Average FRE was 8.1 +/- 2.8 mm. Follow-up at 90 days showed one death, 24% grade I/II, and 4% grade IIIa complications. Median length of hospital stay was 2 days (1-11). Early local recurrence was 9% per lesion and 32% per patient. Of these, 63% were successfully re-ablated within 6 months. CONCLUSIONS: LIMA does not interfere with the intraoperative workflow and results in low complication and early local recurrence rates, even when simultaneously targeting multiple lesions. LIMA may represent a valid therapy option for patients with extensive hepatic disease within a multimodal treatment approach. PMID- 28342125 TI - Underwater endoscopic mucosal resection is associated with fewer recurrences and earlier curative resections compared to conventional endoscopic mucosal resection for large colorectal polyps. AB - BACKGROUND: Studies comparing the efficacy and safety of conventional saline assisted piecemeal endoscopic mucosal resection (EMR) to underwater EMR (UEMR) without submucosal lifting of colorectal polyps are lacking. The objective of this study was to compare the efficacy and safety of EMR to UEMR of large colorectal polyps. METHODS: Two hundred eighty-nine colorectal polyps were removed by a single endoscopist from 7/2007 to 2/2015 using EMR or UEMR. 135 polyps (EMR: 62, UEMR: 73) that measured >=15 mm and had not undergone prior attempted polypectomy were evaluated for rates of complete macroscopic resection and adverse events. 101 of these polyps (EMR: 46, UEMR: 55) had at least 1 follow up colonoscopy and were studied for rates of recurrence and the number of procedures required to achieve curative resection. RESULTS: The rate of complete macroscopic resection was higher following UEMR compared to EMR (98.6 vs. 87.1%, p = 0.012). UEMR had a lower recurrence rate at the first follow-up colonoscopy compared to EMR (7.3 vs. 28.3%, OR 5.0 for post-EMR recurrence, 95% CI: [1.5, 16.5], p = 0.008). UEMR required fewer procedures to reach curative resection than EMR (mean of 1.0 vs. 1.3, p = 0.002). There was no significant difference in rates of adverse events. CONCLUSIONS: UEMR appears superior to EMR for the removal of large colorectal polyps in terms of rates of complete macroscopic resection and recurrent (or residual) abnormal tissue. Compared to conventional EMR, UEMR may offer increased procedural effectiveness without compromising safety in the removal of large colorectal polyps without prior attempted resection. PMID- 28342126 TI - Learning curve takes 65 repetitions of totally extraperitoneal laparoscopy on inguinal hernias for reduction of operating time and complications. AB - BACKGROUND: Inguinal hernia repair is one of the most frequently conducted surgical procedures worldwide. Totally extraperitoneal (TEP) hernioplasty has shown many advantages over traditional open surgery. However, because of increased surgical complexity, it requires more practice to achieve optimal results. OBJECTIVES: The aim of this study is to evaluate the learning curve for TEP hernioplasty, analysing parameters related to the mean operating time. The secondary objective is to assess the complications and early discharge rates related to this procedure. METHODS: A prospective study of 238 consecutive patients undergoing TEP hernioplasty from the same practitioner between May 2009 and May 2014, in a specialised centre for abdominal hernias in Sao Paulo, Brazil, was conducted. All data were obtained through medical records. RESULTS: The study included 137 patients undergoing a total of 157 TEP hernia repairs. Bilaterality and complications can influence the operating time and so were excluded. Patients with unilateral surgery and without complications were included. Patients were chronologically divided into four groups. Groups 1-3 were composed of 35 patients and group 4 of 32. There were no significant variations in clinical characteristics between the groups. The plateau of the learning curve was reached on the 65 th repetition of the surgery, with a mean operating time of 28 min (p < 0,05). Complications were only observed in the first group of 35 patients. 97% of patients were discharged early, defined as patient leaving hospital less than 12 h after surgery. CONCLUSION: After an initial reduction, the mean operating time stabilised after 65 cases. A reduction in the rate of complications was observed after 35 cases, and a rate of 97% of early discharge was achieved. PMID- 28342127 TI - Robotic single-site plus ONE port distal pancreatectomy. AB - Laparoscopic distal pancreatectomy is regarded as safe and effective surgical approach in benign and low-grade malignant tumor of the pancreas. With the advances of laparoscopic techniques and instruments, many efforts to reduce the number of the trocar site has been made. There are a few available surgical techniques of laparoscopic single-site (single port or reduced port) distal pancreatectomy, suggesting its safety and feasibility. However, it is true that laparoscopic single-site distal pancreatectomy is difficult and technically quite demanding. Robotic surgical system was introduced to overcome the limitation of conventional laparoscopic surgery. Recently, we experienced robotic single-site plus ONE port distal pancreatectomy in benign and low-grade malignant tumor of the pancreas. A 45-year-old male patient was incidentally found to have pancreatic mass in tail of the pancreas. October 6th 2015, robotic distal pancreatectomy was performed using the Da Vinci single-site surgical platform (DVSSP) with one additional port. Additional robotic 12-mm-port was placed left side of DVSSP, and robotic 3rd arm was used through this site. Usual robotic instruments such as hook, bipolar, vessel sealer, and endo-GIA with endo-wrist function could be used to facilitate effective surgical procedure. The general operation procedure was based on modified Lasso technique (isolation and ligation of splenic artery prior to Lasso technique). Resected specimen was delivered through umbilicus and drains were inserted through additional port site. Five consecutive clinical experiences were reviewed. This study was approved by institutional review board. Two patients were male and three were female with median age, 38 years (range 21-56). The distribution of the pathological diagnosis was 2 solid pseudopapillary tumors, 1 serous cystic neoplasm, 1 chronic pancreatitis, and 1 neuroendocrine tumor. Median operation time was 165 min (range 120-270 min), and intraoperative-estimated blood loss were median 5 ml (range 0-50 ml). One patient could preserve spleen by Warshaw procedure. One patient converted to conventional multi-port robotic distal pancreatectomy due to inter-arms collisions. There was no clinically relevant postoperative pancreatic fistula. Length of hospital stay was median 6 days after surgery (range 5-8 days). Robotic single-site plus ONE port distal pancreatectomy is safe and feasible with acceptable perioperative outcomes. Although, certain patients such as those with a hard pancreas need an amount of care due to the features of robotic GIA, currently available robotic single-site plus ONE port surgical system was thought to have potential role to make laparoscopic single-site distal pancreatectomy much easier and ergonomics, providing some room to expand more minimally invasive surgery. Further experiences are mandatory. PMID- 28342128 TI - Efficacy and safety of endoscopic submucosal dissection in elderly patients with esophageal squamous cell carcinoma. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) has been widely applied in superficial esophageal squamous cell carcinoma (SESCC) as a minimally invasive treatment, which has advantages over surgery, especially in the elderly who have high risk of surgery. This study elucidated the efficacy and safety of ESD for SESCC in the elderly. METHODS: Between April 2007 and June 2016, a total of 176 patients with SESCC treated with ESD were analyzed. Clinical outcomes including En bloc, complete, and curative resection rates, procedure-related complication rates, and cumulative recurrence rates were compared between the elderly (n = 46, >=70 years of age) and the non-elderly groups (n = 130, <70 years of age). RESULTS: Between the two groups, sex, past medical history (hypertension and diabetes), body mass index, tumor characteristics (number, location, shape, maximal and circumferential size of the tumor and the resected specimen, and depth), and use of stricture prevention except for age (elderly vs non-elderly; 74.1 +/- 2.78 vs. 61.1 +/- 6.06 years, p < 0.001) did not differ. En bloc resection (elderly vs. non-elderly; 93.5 vs. 93.8%, p = 1.000), complete resection (elderly vs. non-elderly; 69.6 vs. 76.2%, p = 0.433), and curative resection rates (elderly vs. non-elderly; 54.3 vs. 60.0%, p = 0.602) did not differ significantly between the two groups. Procedure time and hospital stay were also similar between the two groups. Complications of ESD such as stricture (17.4 vs. 10.8%, p = 0.299) and perforation (13.0 vs. 6.2%, p = 0.083) occurred at a similar rate in the elderly and non-elderly groups. After curative ESD, cumulative recurrence rate of the elderly group (0%) did not differ significantly to that of the non-elderly group (5.1%) by the log-rank test (p = 0.307). CONCLUSION: ESD for SESCC is effective and safe in elderly patients as in non elderly patients. PMID- 28342129 TI - Comparison of two specimen retrieval techniques in laparoscopic sleeve gastrectomy: what is the role of endobag? AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has become a popular stand alone treatment for morbid obesity. However, removal of the gastric specimen could be a challenging step due to its large size relative to the width of the trocar site. OBJECTIVES: We aimed to compare a simplified retrieval technique for extraction of the gastric specimen without an endobag with conventionally performed specimen retrieval using an endobag. METHODS: A case-control study was conducted recruiting patients undergoing LSG. Patient's demographics, preoperative characteristics, intra-operative, and postoperative variables were compared between the two groups according to the technique of gastric specimen removal. RESULTS: A total of 193 patients (60.6% female) were enrolled into case (n = 100) and control groups (n = 93). Mean +/- SD age and BMI of patients were 35.64 +/- 11.84 years and 47.28 +/- 8.22 Kg/m2, respectively with no significant difference between groups. Median (25th, 75th inter-quartile), extraction time was significantly reduced in the non-endobag group compared to the endobag group (3.5 [2.5-4.5] min vs. 6.5 [3.4-8.2] min, p = 0.03).Patients of both groups had similar intra-operative and trocar site complications (hernia and wound infection) (3% for endobag group and 3.3 % for non-endobag group). The median (25 75% [IQR]) LOS was also comparable between endobag and non-endobag patients (3[2 3] vs. 3[2-4] days, p = 0.84). No difference was observed between the two groups for weight loss and comorbidity resolution. CONCLUSION: Non-endobag technique for gastric specimen retrieval is safe and feasible with substantial saving in operative time and comparable intra-operative and postoperative outcomes to the conventional retrieval technique. PMID- 28342130 TI - Laparoscopic proximal gastrectomy with double tract reconstruction is superior to laparoscopic total gastrectomy for proximal early gastric cancer. AB - BACKGROUND: Laparoscopic proximal gastrectomy (LPG) with double tract reconstruction (DTR) is known to reduce reflux symptoms, which is a major concern after proximal gastrectomy. The aim of this study is to compare retrospectively the clinical outcomes of patients undergoing LPG with DTR with those treated by laparoscopic total gastrectomy (LTG). METHODS: Ninety-two and 156 patients undergoing LPG with DTR and LTG for proximal stage I gastric cancer were retrospectively analyzed for short- and long-term clinical outcomes. RESULTS: There were no significant differences in the demographics, T-stage, N-stage, and complications between the groups. The LPG with DTR group had a shorter operative time and lower estimated blood loss than the LTG group (198.3 vs. 225.4 min, p < 0.001; and 84.7 vs. 128.3 mL p = 0.001). The incidence of reflux symptoms >= Visick grade II did not significantly differ between the groups during a mean follow-up period of 37.2 months (1.1 vs. 1.9%, p = 0.999). The hemoglobin change was significantly lower in the LPG with DTR group compared to in the LTG group in the first and second postoperative years (5.03 vs. 9.18% p = 0.004; and 3.45 vs. 8.30%, p = 0.002, respectively), as was the mean amount of vitamin B12 supplements 2 years after operation (0.1 vs. 3.1 mg, p < 0.001). The overall survival rate was similar between the groups. CONCLUSIONS: LPG with DTR maintained comparable oncological safety and anastomosis-related late complications compared to LTG and is preferred over LTG in terms of preventing postoperative anemia and vitamin B12 deficiency. PMID- 28342131 TI - Volume and outcomes relationship in laparoscopic diaphragmatic hernia repair. AB - BACKGROUND: There is no published data regarding the relationship between hospital volume and outcomes in patients undergoing laparoscopic diaphragmatic hernia repair. We hypothesize that hospitals performing high case volume have improved outcomes compared to low-volume hospitals. MATERIALS AND METHODS: We reviewed the National Inpatient Sample (NIS) database between 2008 and 2012 for adults with the diagnosis of diaphragmatic hernia who underwent elective laparoscopic repair of diaphragmatic Hernia and/or Nissen fundoplication. Pediatric, emergent, and open cases were excluded. Main outcome measures included logistic regression analysis of factors predictive of in-hospital mortality and outcomes according to annual hospital case volume. RESULTS: A total of 31,228 laparoscopic diaphragmatic hernia operations were analyzed. The overall in hospital mortality was 0.14%. Risk factors for higher in-hospital mortality included renal failure (AOR: 6.26; 95% CI: 2.48-15.78; p < 0.001), age>60 years (AOR: 5.06; 95% CI: 2.38-10.76; p < 0.001), and CHF (AOR: 3.80; 95% CI: 1.39 10.38; p = 0.009) while an incremental increase in volume of 10 cases/year (AOR: 0.89; 95% CI: 0.81-0.98; p = 0.019) and diabetes (AOR: 0.34; 95% CI: 0.12-0.93; p = 0.036) decreases mortality. There was a small but significant inverse relationship between hospital case volume and mortality with a 10% reduction in adjusted odds of in-hospital mortality for every increase in 10 cases per year. Using 10 cases per year as the volume threshold, low-volume hospitals (<=10 cases/year) had almost a twofold higher mortality compared to high-volume hospitals (0.23 vs. 0.12%, respectively, p = 0.02). CONCLUSIONS: There was a small but significant inverse relationship between the hospitals' case volume and mortality in laparoscopic diaphragmatic hernia repair. PMID- 28342132 TI - Endoscopic mucosal resection versus esophagectomy for intramucosal adenocarcinoma in the setting of barrett's esophagus. AB - BACKGROUND: Esophagectomy has been the standard of care for patients with intramucosal adenocarcinoma (IMC) in the setting of Barrett's esophagus. It is, however, associated with significant post-operative morbidity and mortality. Endoscopic mucosal resection (EMR) offers a minimally invasive approach with lesser morbidity. This study investigates the transition from esophagectomy to EMR for IMC with respect to eradication rates, post-operative morbidity, and long term survival. METHODS: Patients diagnosed with IMC from 2005 to 2013 were identified retrospectively. Beginning in 2009, preferred initial therapy for IMC transitioned from esophagectomy to EMR. Esophagectomy was performed either through a transthoracic or transhiatal technique. EMR was repeated until resolution of IMC on pathology or progression of disease. Continuous data are expressed as mean (SD) and analyzed using Student's t test. Categorical data are presented as number (%) and analyzed using Fisher's exact test. RESULTS: We identified 23 patients; 12 patients underwent esophagectomy and 11 patients underwent EMR as initial therapy. Patients were similar with respects to age, gender, and comorbidity index. Most tumors arose from short segment (vs long segment) Barrett's (esophagectomy: 9 (75%) vs. EMR: 10 (91%), p = 0.59) and one patient in each group had superficial invasion into the submucosa (T1sm1), the remainder having mucosal disease. Esophagectomy was associated with 7 (58%) minor complications and 2 (17%) major complications (respiratory failure, anastomotic leak), whereas there were no complications related to EMR (p < 0.01). EMR successfully eradicated IMC in 10 patients (91%) with one progressing to esophagectomy. Patients required 2 (1) endoscopies to achieve eradication. There was one mortality in each group on long-term follow-up (log-rank test, p = 0.62). CONCLUSIONS: EMR was successful in eradicating IMC in 10/11 patients with similar long-term recurrence and mortality to esophagectomy patients. Patients with IMC may benefit from EMR as initial therapy by obviating the need for a complex and morbid operation. PMID- 28342133 TI - Is old age a contraindication to elective ventral hernia repair? AB - BACKGROUND: Ventral hernia repair (VHR) is a frequent problem in the expanding aging population. However, advanced age is often viewed as a contraindication to elective hernia surgery. We aimed to analyze outcomes of VHR in a large cohort of elderly patients. We hypothesized that elective VHR is safe and effective even in patients over 70 years old. METHODS: We conducted a retrospective review of consecutive patients over the age of 70 who underwent VHR at a at a tertiary care hospital. Main outcome measures included postoperative complications and recurrence rate. RESULTS: Between 2006 and 2015, 263 elderly patients who underwent elective VHR were included. Major comorbidities included diabetes, COPD, and smoking history. The majority of the patients underwent open repairs. Surgical site events occurred in 54 patients (21%). Postoperative complications included 17 venous thromboembolism occurrences, 2 myocardial infarctions, 41 patients who required postoperative critical care, and 1 mortality. Readmission within 90 days postoperatively occurred in 34 patients (13%). At a mean follow-up of 25.6 months, 17 patients in the open group and 6 patients in the laparoscopic group had a recurrence. CONCLUSION: We demonstrated that VHR can be performed reasonably safely and effectively even in this potentially risky cohort. The use of laparoscopy might be associated with further reduction in morbidity. Overall, age should not be a contraindication to elective VHR, even in patients over 70 years old. PMID- 28342134 TI - Dopaminergic Neuron-Specific Deletion of p53 Gene Attenuates Methamphetamine Neurotoxicity. AB - p53 plays an essential role in the regulation of cell death in dopaminergic (DA) neurons and its activation has been implicated in the neurotoxic effects of methamphetamine (MA). However, how p53 mediates MA neurotoxicity remains largely unknown. In this study, we examined the effect of DA-specific p53 gene deletion in DAT-p53KO mice. Whereas in vivo MA binge exposure reduced locomotor activity in wild-type (WT) mice, this was significantly attenuated in DAT-p53KO mice and associated with significant differences in the levels of the p53 target genes BAX and p21 between WT and DAT-p53KO. Notably, DA-specific deletion of p53 provided protection of substantia nigra pars reticulata (SNpr) tyrosine hydroxylase (TH) positive fibers following binge MA, with DAT-p53KO mice having less decline of TH protein levels in striatum versus WT mice. Whereas DAT-p53KO mice demonstrated a consistently higher density of TH fibers in striatum compared to WT mice at 10 days after MA exposure, DA neuron counts within the substantia nigra pars compacta (SNpc) were similar. Finally, supportive of these results, administration of a p53-specific inhibitor (PFT-alpha) provided a similarly protective effect on MA binge-induced behavioral deficits. Neither DA specific p53 deletion nor p53 pharmacological inhibition affected hyperthermia induced by MA binge. These findings demonstrate a specific contribution of p53 activation in behavioral deficits and DA neuronal terminal loss by MA binge exposure. PMID- 28342135 TI - PACAP Protects Against Ethanol and Nicotine Toxicity in SH-SY5Y Cells: Implications for Drinking-Smoking Co-morbidity. AB - The detrimental effects of heavy drinking and smoking are multiplied when the two are combined. Treatment modalities for each and especially for the combination are very limited. Although in low concentration, alcohol and nicotine, each may have beneficial effects including neuroprotection, their combination, instead of providing additive protection, may actually lead to toxicity in cell cultures. Pituitary adenylate cyclase-activating polypeptide (PACAP) is an endogenous 38 amino-acid peptide with demonstrated protection against neuronal injury, trauma as well as various endogenous and exogenous toxic agents. The aim of this study was to investigate whether PACAP may also protect against toxicity induced by high alcohol, high nicotine, or the combination of low alcohol and nicotine concentrations, and if so, whether this effect was mediated via PAC1 receptor. We used the neuroblastoma-derived SH-SY5Y cells and applied various colorimetric assays for determination of cell viability or toxicity. Results indicate that PACAP blocks toxicity induced by high alcohol and high nicotine as well as their combination at low concentrations. The effects of PACAP in turn were blocked by the PACAP antagonist (PACAP 6-38), indicating involvement of the PACAP receptor PAC1 and possibly vasoactive intestinal peptide (VIP) receptors in PACAP's protection. Moreover, no combined toxicity of low alcohol and low nicotine could be detected in calcium-free medium. These findings suggest possible beneficial effects of PACAP in preventing alcohol and nicotine toxicity and that calcium contributes to the damage induced by combination of low alcohol and nicotine in SH-SY5Y cells. PMID- 28342136 TI - Molecular basis of P450 OleTJE: an investigation of substrate binding mechanism and major pathways. AB - Cytochrome P450 OleTJE has attracted much attention for its ability to catalyze the decarboxylation of long chain fatty acids to generate alkenes, which are not only biofuel molecule, but also can be used broadly for making lubricants, polymers and detergents. In this study, the molecular basis of the binding mechanism of P450 OleTJE for arachidic acid, myristic acid, and caprylic acid was investigated by utilizing conventional molecular dynamics simulation and binding free energy calculations. Moreover, random acceleration molecular dynamics (RAMD) simulations were performed to uncover the most probable access/egress channels for different fatty acids. The predicted binding free energy shows an order of arachidic acid < myristic acid < caprylic acid. Key residues interacting with three substrates and residues specifically binding to one of them were identified. The RAMD results suggest the most likely channel for arachidic acid, myristic acid, and caprylic acid are 2e/2b, 2a and 2f/2a, respectively. It is suggested that the reaction is easier to carry out in myristic acid bound system than those in arachidic acid and caprylic acid bound system based on the distance of Hbeta atom of substrate relative to P450 OleTJE Compound I states. This study provided novel insight to understand the substrate preference mechanism of P450 OleTJE and valuable information for rational enzyme design for short chain fatty acid decarboxylation. PMID- 28342137 TI - Skewed Exposure to Environmental Antigens Complements Hygiene Hypothesis in Explaining the Rise of Allergy. AB - The Hygiene Hypothesis has been recognized as an important cornerstone to explain the sudden increase in the prevalence of asthma and allergic diseases in modernized culture. The recent epidemic of allergic diseases is in contrast with the gradual implementation of Homo sapiens sapiens to the present-day forms of civilization. This civilization forms a gradual process with cumulative effects on the human immune system, which co-developed with parasitic and commensal Helminths. The clinical manifestation of this epidemic, however, became only visible in the second half of the twentieth century. In order to explain these clinical effects in terms of the underlying IgE-mediated reactions to innocuous environmental antigens, the low biodiversity of antigens in the domestic environment plays a pivotal role. The skewing of antigen exposure as a cumulative effect of reducing biodiversity in the immediate human environment as well as in changing food habits, provides a sufficient and parsimonious explanation for the rise in allergic diseases in a highly developed and helminth-free modernized culture. Socio-economic tendencies that incline towards a further reduction of environmental biodiversity may provide serious concern for future health. This article explains that the "Hygiene Hypothesis", the "Old Friends Hypothesis", and the "Skewed Antigen Exposure Hypothesis" are required to more fully explain the rise of allergy in modern societies. PMID- 28342138 TI - Does Removal of Subchondral Cortical Bone Provide Sufficient Resection Depth for Treatment of Cam Femoroacetabular Impingement? AB - BACKGROUND: Residual impingement resulting from insufficient resection of bone during the index femoroplasty is the most-common reason for revision surgery in patients with cam-type femoroacetabular impingement (FAI). Development of surgical resection guidelines therefore could reduce the number of patients with persistent pain and reduced ROM after femoroplasty. QUESTIONS/PURPOSES: We asked whether removal of subchondral cortical bone in the region of the lesion in patients with cam FAI could restore femoral anatomy to that of screened control subjects. To evaluate this, we analyzed shape models between: (1) native cam and screened control femurs to observe the location of the cam lesion and establish baseline shape differences between groups, and (2) cam femurs with simulated resections and screened control femurs to evaluate the sufficiency of subchondral cortical bone thickness to guide resection depth. METHODS: Three-dimensional (3 D) reconstructions of the inner and outer cortical bone boundaries of the proximal femur were generated by segmenting CT images from 45 control subjects (29 males; 15 living subjects, 30 cadavers) with normal radiographic findings and 28 nonconsecutive patients (26 males) with a diagnosis of cam FAI based on radiographic measurements and clinical examinations. Correspondence particles were placed on each femur and statistical shape modeling (SSM) was used to create mean shapes for each cohort. The geometric difference between the mean shape of the patients with cam FAI and that of the screened controls was used to define a consistent region representing the cam lesion. Subchondral cortical bone in this region was removed from the 3-D reconstructions of each cam femur to create a simulated resection. SSM was repeated to determine if the resection produced femoral anatomy that better resembled that of control subjects. Correspondence particle locations were used to generate mean femur shapes and evaluate shape differences using principal component analysis. RESULTS: In the region of the cam lesion, the median distance between the mean native cam and control femurs was 1.8 mm (range, 1.0-2.7 mm). This difference was reduced to 0.2 mm (range, -0.2 to 0.9 mm) after resection, with some areas of overresection anteriorly and underresection superiorly. In the region of resection for each subject, the distance from each correspondence particle to the mean control shape was greater for the cam femurs than the screened control femurs (1.8 mm, [range, 1.1-2.9 mm] and 0.0 mm [range, -0.2-0.1 mm], respectively; p < 0.031). After resection, the distance was not different between the resected cam and control femurs (0.3 mm; range, -0.2-1.0; p > 0.473). CONCLUSIONS: Removal of subchondral cortical bone in the region of resection reduced the deviation between the mean resected cam and control femurs to within a millimeter, which resulted in no difference in shape between patients with cam FAI and control subjects. Collectively, our results support the use of the subchondral cortical-cancellous bone margin as a visual intraoperative guide to limit resection depth in the correction of cam FAI. CLINICAL RELEVANCE: Use of the subchondral cortical-cancellous bone boundary may provide a method to guide the depth of resection during arthroscopic surgery, which can be observed intraoperatively without advanced tooling, or imaging. PMID- 28342140 TI - Correlates of the Third Victim Phenomenon. AB - The third victim phenomenon refers to a system-wide organizational response to a serious untoward event in health care settings. The objective of this report is to describe possible measurable correlates of this phenomenon. A serious incident on one unit in the hospital is described. Utilization of constant observation and rate of discharge in the aftermath throughout the hospital were assessed. There was a hospital-wide uptick in conservative decision making following the serious incident, exemplified by an increase in the utilization of constant observation and decreased rate of discharges. These findings lend support to the validity of the concept of the third victim phenomenon and underscore the imperative for a coherent leadership response to prevent damage to institutional core values, morale, and reputation. Systematic investigation of this phenomenon and its potential effects on clinical practice in the aftermath of serious incidents is warranted. PMID- 28342139 TI - Exploring the Link Between Posttraumatic Stress Disorder and inflammation-Related Medical Conditions: An Epidemiological Examination. AB - There have been few epidemiological studies exploring the link between PTSD and inflammation using population-based samples. This study examined the relation between posttraumatic stress disorder (PTSD) and inflammation-related medical conditions using data from the 2013-2014 New York City Health and Nutrition Examination Survey. Using a representative sample of 1,527 residents in New York City, the association between PTSD and 17 inflammation-related medical conditions were examined. Bivariate and multivariable analyses were conducted, adjusting for demographic characteristics and lifetime depression. PTSD was strongly associated with increased odds for hypercholesterolemia, insulin resistance, angina, heart attack, and emphysema with the greatest odds observed for heart attack (OR= 3.94) and emphysema (OR= 4.06). But PTSD was also associated with lower odds for hypertension, type 1 diabetes, asthma, coronary heart disease, stroke, osteoporosis, and a failing kidney with the lowest odds observed for type 1 diabetes (OR= 0.43). These findings suggest a complex link between PTSD and inflammation-related medical conditions. PMID- 28342141 TI - Total Tau and Phosphorylated Tau Protein Serum Levels in Patients with Schizophrenia Compared with Controls. AB - Tau protein is located in the axons of neurons and in Alzheimer Disease, is abnormally phosphorylated and aggregates into paired helical filaments (neurofibrillary tangles) reflecting the degree of neurofibrillary pathology and neurodegeneration. Although tau and phosphorylated tau (p-Tau) pathology is a hallmark for dementia, few studies were performed in patients of schizophrenia. This preliminary serum study was designed to compare serum total tau and p-Tau levels of schizophrenia patients with healthy controls. The study was included 42 patients diagnosed with schizophrenia and 42 healthy control subjects. Sociodemographic form was applied to both groups and PANSS was applied to patient group. Serum total tau and p-Tau levels were measured by ELISA method. Total tau and p-Tau levels of patients were significantly lower than healthy controls. There was a positive correlation between amount of past electroconvulsive therapies and total tau level. However total tau and p-Tau levels were positively correlated. Our study results showed that serum total tau and p-Tau levels of patients with schizophrenia were significantly lower than healthy controls. PMID- 28342142 TI - Smoking Prevalence Among Users of Primary Healthcare Units in Brazil: The Role of Religiosity. AB - The objective of this cross-sectional study is to examine the association between religious involvement and tobacco use in a large representative sample of users of primary healthcare units of Ribeirao Preto, Southeast Brazil. Current and past smoking habits were determined among 1055 users of primary healthcare units. Participants' religiosity was measured using the DUREL questionnaire. The prevalence of smoking among men was 16.8% [95% confidence interval (CI) 12.0 22.5] and among women was 12.6% (95% CI 10.4-15.0). Among the current smokers, 40.9% were light smokers, 24.6% were moderate smokers, and 34.5% were heavy smokers. The mean number of cigarettes smoked per day was 13.5. Respondents who have a religion had a lower smoking prevalence than people who had no religion. Current smoking prevalence tended to be higher among people who do not practice their religion than people who practice their religion. Smoking status is also associated with self-reported religiosity, organizational religious activity and some aspects of intrinsic religiosity. Religiosity is an important factor in influencing the smoking behavior in Brazilian users of the public health services. PMID- 28342143 TI - "One Big Family": Pastoral Care and Treatment Seeking in an Egyptian Coptic Church in England. AB - Little is known about Coptic migrants' chronic disease health beliefs and treatment-seeking behaviours. Interviews to explore these issues and their relationship with church membership were conducted with 15 Coptic migrants in Southern England. Obesity and cardiovascular disease (CVD) were most frequently identified as health risks for Coptic migrants. CVD was ascribed to stress and considered amenable to spiritual healing. Lay referral to medical practitioners who were church members was common but may devalue perceptions of family medicine. The Coptic Church functions as a community that addresses members' wider vulnerability. Central to this is the "parish nurse" role of the priest. PMID- 28342144 TI - Transformational Analysis and Religious Experience. AB - The therapeutic process, which taps into the individual's most vulnerable inner experience, can always reach a radical reversal of one's perception of religion and God, which may be askew due to deep trauma. This transformation caused by the therapeutic relationship can reciprocally help to resolve one's deep and complicated issues, while at the same time radically altering their relationship to religion. This is especially apparent among those who were cruelly and traumatically abused in their earliest stages of development. PMID- 28342145 TI - Spiritual Experiences of Muslim Critical Care Nurses. AB - The purpose of this study was to determine the experiences and perceptions of intensive care nurses (ICNs) about spirituality and spiritual care, as well as the effective factors, and increase the sensitivity to the subject. In this study, we examined spiritual experiences, using McSherry et al. (Int J Nurs Stud 39:723-734, 2002) Spirituality and spiritual care rating scale (SSCRS), among 145 ICNs. 44.8% of the nurses stated that they received spiritual care training and 64.1% provided spiritual care to their patients. ICNs had a total score average of 57.62 +/- 12.00 in SSCRS. As a consequence, it was determined that intensive care nurses participating in the study had insufficient knowledge about spirituality and spiritual care, but only the nurses with sufficient knowledge provided the spiritual care to their patients. PMID- 28342146 TI - Religious Practice and Health-Related Quality of Life in Iranian Adolescent Girls. AB - This study aimed to determine the relationship between religious practice and health-related quality of life in adolescent girls in Tabriz, Iran, 2014-2015. This cross-sectional study was conducted on 520 female students who were selected using the random sampling method. Religious practice and health-related quality of life questionnaires were used for data collection. Multivariate linear regression analysis showed a significant relationship between health-related quality of life and received religious support, religiosity, father's and mother's education, father's occupation, family economic status, and the number of children. It is necessary to find ways to further promote religious practices in adolescents and ultimately their quality of life. PMID- 28342147 TI - Meaning-Making Coping Among Cancer Patients in Sweden and South Korea: A Comparative Perspective. AB - The present study compared meaning-making coping among cancer patients in Sweden and South Korea, with a focus on the sociocultural context. Semi-structured interviews were conducted with 51 Swedes and 33 Koreans. The results showed significant differences between the two countries as well as similarities in existential, spiritual, and religious coping. For example, Swedes primarily used meaning-making coping as a means of meditation or relaxation, whereas Koreans relied on coping with prayer and using healthy foods as a means to survive. The present study confirms the significance of investigating cultural context when we explore the use of meaning-making coping among people who have experienced cancer. PMID- 28342148 TI - Further characterization and independent validation of a DNA aptamer-quantum dot based magnetic sandwich assay for Campylobacter. AB - Previously reported DNA aptamers developed against surface proteins extracted from Campylobacter jejuni were further characterized by aptamer-based Western blotting and shown to bind epitopes on proteins weighing ~16 and 60 kD from reduced C. jejuni and Campylobacter coli lysates. Proteins of these approximate weights have also been identified in traditional antibody-based Western blots of Campylobacter spp. Specificity of the capture and reporter aptamers from the previous report was further validated by aptamer-based ELISA-like (ELASA) colorimetric microplate assay. Finally, the limit of detection of the previously reported plastic-adherent aptamer-magnetic bead and aptamer-quantum dot sandwich assay (PASA) was validated by an independent food safety testing laboratory to lie between 5 and 10 C. jejuni cells per milliliter in phosphate buffered saline and repeatedly frozen and thawed chicken rinsate. Such ultrasensitive and rapid (30 min) aptamer-based assays could provide alternative or additional screening tools to enhance food safety testing for Campylobacter and other foodborne pathogens. PMID- 28342149 TI - Identification and Preparation of a Novel Chemokine Receptor-Binding Domain in the Cytoplasmic Regulator FROUNT. AB - FROUNT is a cytoplasmic protein that binds to the membrane-proximal C-terminal regions (Pro-Cs) of chemokine receptors, CCR2 and CCR5. The FROUNT-chemokine receptor interactions play a pivotal role in the migration of inflammatory immune cells, indicating the potential of FROUNT as a drug target for inflammatory diseases. To provide the foundation for drug development, structural information of the Pro-C binding region of FROUNT is desired. Here, we defined the novel structural domain (FNT-CB), which mediates the interaction with the chemokine receptors. A recombinant GST-tag-fused FNT-CB protein expression system was constructed. The protein was purified by affinity chromatography and then subjected to in-gel protease digestion of the GST-tag. The released FNT-CB was further purified by anion-exchange and size-exclusion chromatography. Purified FNT-CB adopts a helical structure, as indicated by CD. NMR line-broadening indicated that weak aggregation occurred at sub-millimolar concentrations, but the line-broadening was mitigated by using a deuterated sample in concert with transverse relaxation-optimized spectroscopy. The specific binding of FNT-CB to CCR2 Pro-C was confirmed by the fluorescence-based assay. The improved NMR spectral quality and the retained functional activity of FNT-CB support the feasibility of further structural and functional studies targeted at the anti inflammatory drug development. PMID- 28342150 TI - Expression and Characterization of Human beta-1, 4-Galactosyltransferase 1 (beta4GalT1) Using Silkworm-Baculovirus Expression System. AB - Baculovirus expression vector system (BEVS) is widely known as a mass-production tool to produce functional recombinant glycoproteins except that it may not be always suitable for medical practice due to the differences in the structure of N linked glycans between insects and mammalian. Currently, various approaches have been reported to alter N-linked glycan structures of glycoproteins derived from insects into terminally sialylated complex-type N-glycans. In the light of those studies, we also proposed in vitro maturation of N-glycan with mass-produced and purified glycosyltransferases by silkworm-BEVS. beta-1,4-Galactosyltransferase 1 (beta4GalT1) is known as one of type II transmembrane enzymes that transfer galactose in a beta-1, 4 linkage to accepter sugars, and a key enzyme for further sialylation of N-glycans. In this study, we developed a large-scale production of recombinant human beta4GalT1 (rhbeta4GalT1) with N- or C-terminal tags in silkworm-BEVS. We demonstrated that rhbeta4GalT1 is N-glycosylated and without mucin-type glycosylation. Interestingly, we found that purified rhbeta4GalT1 from silkworm serum presented higher galactosyltransferase activity than that expressed from cultured mammalian cells. We also validated the UDP-galactose transferase activity of produced rhbeta4GalT1 proteins by using protein subtracts from silkworm silk gland. Taken together, rhbeta4GalT1 from silkworms can become a valuable tool for producing high-quality recombinant glycoproteins with mammalian-like N-glycans. PMID- 28342152 TI - Association of 86 bp variable number of tandem repeat (VNTR) polymorphism of interleukin-1 receptor antagonist (IL1RN) with susceptibility and clinical activity in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic, systemic disease of unknown etiology. Several studies have reported a variable number of tandem repeat (VNTR) 86 bp (rs2234663) in the intron 2 of IL1RN gene with RA risk. The present study was designed to determine the frequencies of this polymorphism in patients with RA and control subjects (CS) and its association with RA in a western Mexican population. An analytical cross-sectional study was performed, in which 350 patients with RA and 307 CS were included. The identification of IL1RN VNTR polymorphism was carried out by polymerase chain reaction (PCR), and genotypes were associated with clinical variables (DAS28 and CRP). The presence of A1/A2 genotype was associated with RA risk (p = 0.03, OR = 1.45, 95% CI = 1.02-2.05). Also, results indicate that the presence of heterozygote genotypes which include A2 was associated with RA risk (p = 0.01, OR = 1.5, 95% CI = 1.07-2.11). Patients carrier of A2/A2 genotype have a higher score of DAS28 (5.64 [4.49-6.70]). A-/A- has higher level of CRP (2.30 [0.62-9.10]) in comparison with A2/A- (1.06 [0.37 2.82]). A1/A2 genotype was associated with susceptibility to RA in a western Mexican population. The presence of the A2/A2 genotype in RA is associated with increased disease activity. PMID- 28342154 TI - Aluminum fractionation in acidic soils and river sediments in the Upper Mero basin (Galicia, NW Spain). AB - This study aims to determine aluminum fractions in the fine earth of acidic soils under different land uses (forest, pasture and cultivation) and in the river bed sediments of the headwater of the Mero River in order to identify and quantify Al bearing phases to assess Al mobility and potential bioavailability (environmental availability) in the monitoring area. Sequential extraction is used to evaluate the Al partitioning into six fractions operationally defined: soluble/exchangeable/specifically adsorbed, bound to manganese oxides, associated with amorphous compounds, aluminum bound to oxidizable organic matter, associated with crystalline iron oxides, and residual fraction (aluminum within the crystal lattices of minerals). The mean concentration of total aluminum (24.01 g kg-1) was similar for the three considered uses. The mean percentage of the aluminum fractions, both in soils and sediments, showed the following order: residual fraction ? amorphous compounds ~ crystalline iron oxides > water soluble/exchangeable/specifically adsorbed > bound to oxidizable organic matter ~ Mn oxides. However, in the soils, the amorphous compounds and water soluble/exchangeable/specifically adsorbed fraction showed considerable differences between some types of uses, the percentage of aluminum linked to amorphous compounds being higher in forest soils (16% of total Al) compared to other uses (mean about 8% of total Al). The highest values of water soluble/exchangeable/specifically adsorbed Al were also found in forest soils (mean 8.6% of the total Al versus about 4% of pasture and cultivation), which is consistent with the lower pH and higher organic matter content in forest soils. Nevertheless, the potentially bioavailable fraction (sum of the first three fractions) is low, suggesting very low geoavailability of this element in both soils and sediments; hence, the possibility to affect the crops and water quality is minimal. PMID- 28342153 TI - Response to "Vaccine-related serious adverse events might have been under recognized in the pivotal HPV vaccine randomized trial". PMID- 28342155 TI - [Benefits of zoster vaccination in older patients]. PMID- 28342151 TI - Cardiovascular disease in rheumatoid arthritis: medications and risk factors in China. AB - This study aims to assess the risk factors of cardiovascular disease (CVD) and to determine the association of traditional and biologic disease-modifying anti rheumatic drugs (DMARDs) with risk for CVD in Chinese rheumatoid arthritis (RA) patients. A cross-sectional cohort of 2013 RA patients from 21 hospitals around China was established. Medical history of CVD was documented. The patients' social background, clinical manifestations, comorbidities, and medications were also collected. Of the 2013 patients, 256 had CVD with an incidence of 12.7%. Compared with non-CVD controls, RA patients with CVD had a significantly advanced age, long-standing median disease duration, more often male and more deformity joints. Patients with CVD also had higher rates of smoking, rheumatoid nodules, interstitial lung disease, and anemia. The prevalence of comorbidities, including hypothyroidism, diabetes mellitus (DM), hypertension, and hyperlipidemia, was also significant higher in the CVD group. In contrast, patients treated with methotrexate, hydroxychloroquine (HCQ), and TNF blockers had lower incidence of CVD. The multivariate analysis showed that the use of HCQ was a protective factor of CVD, while hypertension, hyperlipidemia, and interstitial lung disease were independent risk factors of CVD. Our study shows that the independent risk factors of CVD include hypertension, hyperlipidemia, and interstitial lung disease. HCQ reduces the risk of CVD in patients with RA. PMID- 28342157 TI - Recto-vaginal fistula after pessary therapy. PMID- 28342158 TI - The incidence of and risk factors for a repeat obstetric anal sphincter injury (OASIS) in the vaginal birth subsequent to a first episode of OASIS: a hospital based cohort study. AB - PURPOSE: To identify the incidence of and risk factors for a repeat obstetric anal sphincter injury (OASIS) in women who sustained an OASIS in their first vaginal delivery and have a subsequent vaginal birth. METHODS: Data were collected retrospectively for women having had singleton cephalic presentation vaginal deliveries between 2007 and 2015. Women with breech deliveries, stillbirths, foetal congenital abnormalities and multiple pregnancies were excluded. RESULTS: Over the study period, we identified 11,191 women who had a first vaginal birth, of which 603 (5.4%) sustained a first episode of OASIS. Of these women, 243 (40.2%) had a subsequent pregnancy with 190 (78.1%) having a second vaginal birth, 13 (5.4%) an emergency caesarean section (CS) delivery while in labour and 40 (16.5%) an elective CS delivery. In those who delivered vaginally, 16 (8.4%) women had a repeat OASIS. After adjusting for several confounding factors, it was found that the risk of a repeat OASIS was associated with the use of epidural analgesia (OR = 3.66; 95% CI: 1.14-11.71) and an episiotomy in the first delivery (OR = 3.93; 95% CI:1. 03-15.02) and a short labour (<2.8 h) in the second delivery (OR = 14.55; 95% CI: 1.83-115.75). The time interval between the two vaginal births was not associated with any increased risk of a repeat OASIS. CONCLUSION: We found that 8.4% of women sustained a repeat OASIS in a subsequent vaginal birth with this risk being associated with the presence of a short second labour and certain features from the first labour. PMID- 28342156 TI - Diet Change After Sleeve Gastrectomy Is More Effective for Weight Loss Than Surgery Only. AB - BACKGROUND: Bariatric surgery with or without diet change has become one of the most effective treatments for obesity. The objective of this study was to observe the effects of vertical sleeve gastrectomy (VSG) and diet change in Sprague Dawley rats on both body and tissue weights. METHODS: Eighteen rats were fed with a standard chow diet (SCD) (C group), and 36 rats were fed with a high-fat diet (HFD) (diet-induced obesity (DIO) group). After 8 weeks, the animals underwent VSG, sham surgery or no surgery (NS). After surgery, a third of the rats fed with the HFD changed to the SCD (DIO + C group). Body weight, food and energy intake were recorded daily during the experiment (12 weeks). Food efficiency (%) (FE) was determined from weekly weight gain and weekly kilocalorie consumed measurements. RESULTS: The DIO group had higher and significant weight gain than the C group at the time of surgery (p < 0.001). The major weight loss (WL) was observed in the DIO + C-VSG group, during the 4 weeks after surgery. Adipose tissues in the DIO + C-VSG group were drastically reduced and had a weight similar to those in the C-VSG group. CONCLUSION: VSG and the diet change combination led to a greater WL, which was maintained during the 4 weeks post surgery, leading to a normalization of body weight. VSG and diet change also affected most of the tissues, not only adipose, showing a global change in whole body composition. PMID- 28342159 TI - Genetic aspects of feed efficiency and reduction of environmental footprint in broilers: a review. AB - Currently, optimization of feed efficiency is one of the main challenges in improvement programs of livestock and poultry genetics. The objective of this review is to present the genetic aspects of feed efficiency related traits in meat-type chicken and possible ways to reduce the environmental impact of poultry meat production with effective breeding. Basic measures of feed efficiency are defined and the genetic background of these traits, including a review of heritabilities is described. Moreover, a number of genomic regions and candidate genes determining feed efficiency traits of broilers that were detected over the past decades are described. Classical and genomic selection strategies for feed efficiency in the context of its relationships with other performance traits are discussed as well. Finally, future strategies to improve feed digestibility are described as it is expected that they will decrease wastes and greenhouse gas emission. Further genetic improvement of feed efficiency, should be examined jointly with appropriate feeding strategies in broilers. PMID- 28342160 TI - Dogs demonstrate perspective taking based on geometrical gaze following in a Guesser-Knower task. AB - Currently, there is still no consensus about whether animals can ascribe mental states (Theory of Mind) to themselves and others. Showing animals can respond to cues that indicate whether another has visual access to a target or not, and that they are able to use this information as a basis for whom to rely on as an informant, is an important step forward in this direction. Domestic dogs (Canis familiaris) with human informants are an ideal model, because they show high sensitivity towards human eye contact, they have proven able to assess the attentional state of humans in food-stealing or food-begging contexts, and they follow human gaze behind a barrier when searching for food. With 16 dogs, we not only replicated the main results of Maginnity and Grace (Anim Cogn 17(6):1375 1392, 2014) who recently found that dogs preferred to follow the pointing of a human who witnessed a food hiding event over a human who did not (the Guesser Knower task), but also extended this finding with a further, critical control for behaviour-reading: two informants showed identical looking behaviour, but due to their different position in the room, only one had the opportunity to see where the food was hidden by a third person. Preference for the Knower in this critical test provides solid evidence for geometrical gaze following and perspective taking in dogs. PMID- 28342161 TI - Granulocyte and monocyte adsorptive apheresis ameliorates sepsis in rats. AB - BACKGROUND: Overwhelming activation of granulocytes and monocytes is central to inflammatory responses during sepsis. Granulocyte and monocyte adsorptive apheresis (GMA) is an extracorporeal leukocyte apheresis device filled with cellulose acetate beads and selectively adsorbs granulocytes and monocytes from the peripheral blood. METHODS: In this study, septic rats received the GMA treatment for 2 h at 18 h after cecal ligation and puncture. RESULTS: GMA selectively adsorbed activated neutrophils and monocytes from the peripheral blood, reduced serum inflammatory cytokine expression, and seemed to improve organ injuries and animal survival. GMA potentially reduced lung injury by alleviating the infiltration of inflammatory cells and the secretion of cytokines. CONCLUSIONS: This study showed that selective granulocyte and monocyte adsorption with cellulose acetate beads might ameliorate cecal ligation and puncture (CLP)-induced sepsis and improve survival and organ function. PMID- 28342162 TI - Brief Report: Estimated Prevalence of a Community Diagnosis of Autism Spectrum Disorder by Age 4 Years in Children from Selected Areas in the United States in 2010: Evaluation of Birth Cohort Effects. AB - We compared early-diagnosed autism spectrum disorder (ASD) (defined as diagnosis by age 4 years) between the 2002 and 2006 birth cohorts, in five sites of the Autism and Developmental Disabilities Monitoring Network. In the 2002 cohort, the prevalence/1000 of early-diagnosed ASD was half the 8-year-old prevalence (7.2 vs. 14.7, prevalence ratio [PR] 0.5 [0.4-0.6]). Overall, the prevalence of early diagnosed ASD did not differ between birth cohorts (PR 1.1 [0.9-1.3]). However, in three sites with complete case ascertainment, the prevalence of early diagnosed ASD was higher for those born in 2006 versus 2002 (PR 1.3 [1.1-1.5]), suggesting possible improvement in early identification. The lack of change in two sites may reflect less complete case ascertainment. Studies in more recent cohorts are needed. PMID- 28342163 TI - Brief Report: Sexual Attraction and Relationships in Adolescents with Autism. AB - Past research suggests more variation in sexual attraction in Autism Spectrum Disorder (ASD) using clinical samples. This study utilised a population representative group of 14/15 year olds from the Longitudinal Study of Australian Children. Ninety-four adolescents (73 males, 21 females) with ASD and 3454 (1685 males, 1675 females) without self-reported on sexual attraction and past sexual relationships. Females with ASD reported lower rates of heterosexual preference (adjusted odds ratio: 0.14, p < .001), higher rates of bisexuality (adjusted odds ratio: 6.05, p < .001) and uncertainty in attraction (adjusted odds ratio: 10.44, p < .001) compared with non-ASD females. ASD males reported fewer prior boyfriends/girlfriends. Findings confirm female adolescents with ASD have differences in sexual attraction compared with non-ASD females. PMID- 28342164 TI - Attempting to "Increase Intake from the Input": Attention and Word Learning in Children with Autism. AB - Previous work has demonstrated that social attention is related to early language abilities. We explored whether we can facilitate word learning among children with autism by directing attention to areas of the scene that have been demonstrated as relevant for successful word learning. We tracked eye movements to faces and objects while children watched videos of a woman teaching them new words. Test trials measured participants' recognition of these novel word-object pairings. Results indicate that for children with autism and typically developing children, pointing to the speaker's mouth while labeling a novel object impaired performance, likely because it distracted participants from the target object. In contrast, for children with autism, holding the object close to the speaker's mouth improved performance. PMID- 28342165 TI - Formal Thought Disorder and Executive Functioning in Children and Adolescents with Autism Spectrum Disorder: Old Leads and New Avenues. AB - Formal thought disorder (FTD) is a disruption in the flow of thought and a common feature in psychotic disorders and autism spectrum disorder (ASD). Executive dysfunction has often been associated with FTD, yet for ASD convincing evidence is lacking. This study investigated FTD and three core executive functions in 50 young children and adolescents with high-functioning ASD and 56 matched controls. Higher overall levels of FTD marked ASD compared to controls. Furthermore, in ASD decreased performance on verbal working memory was correlated with increased FTD ratings and explained a significant amount of variance of objective and subjective FTD. Verbal working memory is currently the most promising target executive function for understanding the development of idiosyncratic thought disorders in ASD. PMID- 28342166 TI - Second Language Exposure, Functional Communication, and Executive Function in Children With and Without Autism Spectrum Disorder (ASD). AB - Parents and professionals are concerned that second language exposure may delay communication in children with ASD. In this study 174 youth (6-16 years) with and without ASD, exposed to a second language, were compared on executive function (EF) and functional communication (FC) with their peers without exposure. There were no significant differences between groups on age, IQ, and socioeconomic status. Parents reported on language exposure and rated EF and FC skills within everyday social contexts. The findings indicated that second language exposure in children with ASD is not associated with delay in cognitive and functional communication skills rather there was evidence of a reduced clinical impact as indexed by a lower percentage of children whose FC and EF ratings fell within the clinical range. PMID- 28342169 TI - Erratum to: Diet and Diabetic Kidney Disease: Plant Versus Animal Protein. PMID- 28342167 TI - How Children with Autism Reason about Other's Intentions: False-Belief and Counterfactual Inferences. AB - We examine false belief and counterfactual reasoning in children with autism with a new change-of-intentions task. Children listened to stories, for example, Anne is picking up toys and John hears her say she wants to find her ball. John goes away and the reason for Anne's action changes-Anne's mother tells her to tidy her bedroom. We asked, 'What will John believe is the reason that Anne is picking up toys?' which requires a false-belief inference, and 'If Anne's mother hadn't asked Anne to tidy her room, what would have been the reason she was picking up toys?' which requires a counterfactual inference. We tested children aged 6, 8 and 10 years. Children with autism made fewer correct inferences than typically developing children at 8 years, but by 10 years there was no difference. Children with autism made fewer correct false-belief than counterfactual inferences, just like typically developing children. PMID- 28342168 TI - Bone Mass in Boys with Autism Spectrum Disorder. AB - To examine bone mass in children and adolescents with autism spectrum disorders (ASD). Risperidone-treated 5 to 17 year-old males underwent anthropometric and bone measurements, using dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. Multivariable linear regression analysis models examined whether skeletal outcomes differed among participants with (n = 30) versus without ASD (n = 156). After adjusting for potential covariates, having ASD was associated with significantly lower trabecular bone mineral density and bone strength at the radius, and with marginally lower total body less head bone mineral content (p < 0.09). No differences at the lumbar spine were observed. ASD are associated with lower bone mass. Future studies should investigate interventions to optimize skeletal health in ASD. PMID- 28342170 TI - Importance of stress-response genes to the survival of airborne Escherichia coli under different levels of relative humidity. AB - Other than the needs for infection control to investigate the survival and inactivation of airborne bacterial pathogens, there has been a growing interest in exploring bacterial communities in the air and the effect of environmental variables on them. However, the innate biological mechanism influencing the bacterial viability is still unclear. In this study, a mutant-based approach, using Escherichia coli as a model, was used to prove the concept that common stress-response genes are important for airborne survival of bacteria. Mutants with a single gene knockout that are known to respond to general stress (rpoS) and oxidative stress (oxyR, soxR) were selected in the study. Low relative humidity (RH), 30-40% was more detrimental to the bacteria than high RH, >90%. The log reduction of ?rpoS was always higher than that of the parental strain at all RH levels but the ?oxyR had a higher log reduction than the parental strain at intermediate RH only. ?soxR had the same viability compared to the parental strain at all RH levels. The results hint that although different types and levels of stress are produced under different RH conditions, stress-response genes always play a role in the bacterial viability. This study is the first reporting the association between stress-response genes and viability of airborne bacteria. PMID- 28342172 TI - Rheumatoid neutrophilic dermatitis in a patient taking tocilizumab for treatment of rheumatoid arthritis. PMID- 28342171 TI - Expressing anti-HIV VRC01 antibody using the murine IgG1 secretion signal in Pichia pastoris. AB - The use of the recombinant expression platform Pichia pastoris to produce pharmaceutically important proteins has been investigated over the past 30 years. Compared to mammalian cultures, expression in P. pastoris is cheaper and faster, potentially leading to decreased costs and process development times. Product yields depend on a number of factors including the secretion signal chosen for expression, which can influence the host cell response to recombinant protein production. VRC01, a broadly neutralising anti-HIV antibody, was expressed in P. pastoris, using the methanol inducible AOX1 promoter for both the heavy and light chains. Titre reached up to 3.05 MUg mL-1 in small scale expression. VRC01 was expressed using both the alpha-mating factor signal peptide from Saccharomyces cerevisiae and the murine IgG1 signal peptide. Surprisingly, using the murine IgG1 signal peptide resulted in higher yield of antibody capable of binding gp140 antigen. Furthermore, we evaluated levels of secretory stress compared to the untransformed wild-type strain and show a reduced level of secretory stress in the murine IgG1 signal peptide strains versus those containing the alpha-MF signal peptide. As bottlenecks in the secretory pathway are often the limiting factor in protein secretion, reduced levels of secretory stress and the higher yield of functional antibody suggest the murine IgG1 signal peptide may lead to better protein folding and secretion. This work indicates the possibilities for utilising the murine IgG1 signal peptide for a range of antibodies, resulting in high yields and reduced cellular stress. PMID- 28342174 TI - Did you know? Modelling vision: computational science for understanding human visual perception. PMID- 28342173 TI - Metal ions-binding T4 lysozyme as an intramolecular protein purification tag compatible with X-ray crystallography. AB - Phage T4 lysozyme is a well folded and highly soluble protein that is widely used as an insertion tag to improve solubility and crystallization properties of poorly behaved recombinant proteins. It has been used in the fusion protein strategy to facilitate crystallization of various proteins including multiple G protein-coupled receptors, lipid kinases, or sterol binding proteins. Here, we present a structural and biochemical characterization of its novel, metal ions binding mutant (mbT4L). We demonstrate that mbT4L can be used as a purification tag in the immobilized-metal affinity chromatography and that, in many respects, it is superior to the conventional hexahistidine tag. In addition, structural characterization of mbT4L suggests that mbT4L can be used as a purification tag compatible with X-ray crystallography. PMID- 28342175 TI - Black Swan - the sacrifice of a prima ballerina: Psychosexual (self-)injuries as the legacy of archaic experiences of violence. PMID- 28342176 TI - Investigating the physiological effects of 10.5 Tesla static field exposure on anesthetized swine. AB - PURPOSE: In this work, we investigated the relative effects of static magnetic field exposure (10.5 Tesla [T]) on two physiological parameters; blood pressure (BP) and heart rate (HR). METHODS: In vivo, we recorded both BP and HR in 4 swine (3 female, 1 male) while they were positioned within a 10.5T magnet. All measurements were performed invasively within these anesthetized animals by the placement of pressure catheters into their carotid arteries. RESULTS: We measured average increases of 2.0 mm Hg (standard deviation [SD], 6.9) in systolic BP and an increase of 4.5 mm Hg (SD, 13.7) in the diastolic BPs: We also noted an average increase of 1.2 beats per minute (SD, 2.5) in the HRs during such. CONCLUSION: Data regarding changes in BP and HR in anesthetized swine attributed to whole-body 10.5T exposure are reported. Magn Reson Med 79:511-514, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28342177 TI - Career Development Awards in Emergency Medicine: Resources and Challenges. AB - OBJECTIVES: In the United States, emergency medicine (EM) researchers hold proportionately fewer federal career development awards than researchers in other specialties. Others hypothesize that this deficit may partly be attributed to lack of mentors, departmental resources, and qualified applicants. Our objectives were to examine the association between departmental and institutional resources and career development awards and to describe the barriers to conducting research and btaining grants in EM. METHODS: We conducted an online, cross-sectional survey study of vice chairs for research and research directors at academic emergency departments in the United States in January and February 2016. Participants provided quantitative information regarding their department's demographics, available research resources, number of funded independent investigators, and number of career development awards. They were also asked about the perceived adequacy of departmental and institutional resources and perceived barriers to research and grant success. Data were analyzed using descriptive statistics and multivariable linear regression, as appropriate. RESULTS: Of 178 eligible participants, 103 (58%) completed the survey. Most departments reported some infrastructure for research and grant submission, including research coordinator(s) (n = 75/99; 76%, 95% confidence interval [CI] = 66%-84%), research associates (69/99; 70%, 95% CI = 60%-79%), and administrative/secretarial research support (79/101; 78%, 95% CI = 69%-86%). The majority of departments (56/103; 49%, 95% CI = 44%-64%) had no R01-funded researchers, and only 15 (15%, 95% CI = 8%-23%) had three or more R01-funded researchers. The most frequently reported challenge to junior faculty applying for grants was low motivation for applying (62/103; 60%, 95% CI = 50%-70%), followed closely by insufficient mentorship (50/103; 49%, 95% CI = 39%-59%) and discouragement from low funding rates (50/103; 49%, 95% CI = 39%-59%). In the multivariable model, only the number of departmental R-level-funded researchers was associated with the number of departmental career development awards (coefficient = 0.75, 95% CI = 0.39-1.11; R2 = 0.57). CONCLUSIONS: While more multiple departmental and institutional resources correlated with a greater number of funded career development awards, the single greatest predictor was the number of R-level-funded researchers in the department. Low motivation and insufficient mentorship were the most frequently reported barriers to junior faculty applying for career development awards. Further studies are needed to describe junior faculty perspectives on these issues and to explore strategies for overcoming these barriers. PMID- 28342178 TI - Return of the lysergamides. Part III: Analytical characterization of N6 -ethyl-6 norlysergic acid diethylamide (ETH-LAD) and 1-propionyl ETH-LAD (1P-ETH-LAD). AB - The psychoactive properties of lysergic acid diethylamide (LSD) have fascinated scientists across disciplines and the exploration of other analogues and derivatives has been motivated by deepening the understanding of ligand-receptor interactions at the molecular level as well as by the search for new therapeutics. Several LSD congeners have appeared on the new psychoactive substances (NPS) market in the form of blotters or powders. Examples include 1 propionyl-LSD (1P-LSD), AL-LAD, and LSZ. The absence of analytical data for novel compounds is a frequent challenge encountered in clinical and toxicological investigations. Two newly emerging lysergamides, namely N6 -ethyl-6-norlysergic acid diethylamide (ETH-LAD) and 1P-ETH-LAD, were characterized by gas chromatography-mass spectrometry (GC-MS), low and high mass accuracy electrospray MS(/MS), GC solid-state infrared analysis, high performance liquid chromatography diode array detection as well as nuclear magnetic resonance spectroscopy. Limited analytical data for ETH-LAD were previously available, whereas information about 1P-ETH-LAD has not previously been encountered in the scientific literature. This study extends the characterization of lysergamides distributed on the NPS market, which will help to make analytical data available to clinicians, toxicologists, and other stakeholders who are likely to encounter these substances. The analysis of a test incubation of 1P-ETH-LAD with human serum at 37 degrees C by LC single quadrupole MS at various time points (0-6 h, once per hour and one measurement after 24 h) revealed the formation of ETH-LAD, suggesting that 1P-ETH-LAD might serve as a pro-drug. 1P-ETH-LAD was still detectable in serum after 24 h. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28342179 TI - Common polymorphisms of chemokine (C-X3-C motif) receptor 1 gene modify amyotrophic lateral sclerosis outcome: A population-based study. AB - INTRODUCTION: In the brain, the chemokine (C-X3-C motif) receptor 1 (1CX3CR1) gene is expressed only by microglia, where it acts as a key mediator of the neuron-microglia interactions. We assessed whether the 2 common polymorphisms of the CX3CR1 gene (V249I and T280M) modify amyotrophic lateral sclerosis (ALS) phenotype. METHODS: The study included 755 ALS patients diagnosed in Piemonte between 2007 and 2012 and 369 age-matched and sex-matched controls, all genotyped with the same chips. RESULTS: Neither of the variants was associated with an increased risk of ALS. Patients with the V249I V/V genotype had a 6-month-shorter survival than those with I/I or V/I genotypes (dominant model, P = 0.018). The T280M genotype showed a significant difference among the 3 genotypes (additive model, P = 0.036). Cox multivariable analysis confirmed these findings. DISCUSSION: We found that common variants of the CX3CR1 gene influence ALS survival. Our data provide further evidence for the role of neuroinflammation in ALS. Muscle Nerve 57: 212-216, 2018. PMID- 28342181 TI - Reply. PMID- 28342180 TI - Metabolic syndrome in patients on first-line antiretroviral therapy containing zidovudine or tenofovir in rural Lesotho, Southern Africa. AB - OBJECTIVE: To assess the prevalence of metabolic syndrome (MetS) among patients in rural Lesotho who are taking first-line antiretroviral therapy (ART) containing either zidovudine or tenofovir disoproxil. METHODS: Cross-sectional survey in 10 facilities in Lesotho among adult (>=16 years) patients on non nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line ART for >=6 months. MetS was defined according to the International Diabetes Federation criteria. RESULTS: Among 1166 patients (65.8% female), 22.2% (95% CI: 19.3-25.3) of women and 6.3% (4.1-9.1) of men met the IDF definition of MetS (P < 0.001). In both sexes, there was no significant difference in MetS prevalence between NNRTIs. However, in women taking zidovudine as nucleoside reverse transcriptase inhibitor (NRTI), MetS prevalence was 27.9%, vs. 18.8% in those taking tenofovir. In the multivariate logistic regression allowing for socio-demographic and clinical covariates, ART containing zidovudine was associated with MetS in women (aOR 2.17 (1.46-3.22), P < 0.001) but not in men. CONCLUSION: In this study, taking ART containing zidovudine instead of tenofovir disoproxil was an independent predictor of MetS in women but not in men. This finding endorses WHO's recommendation of tenofovir as preferred NRTI. PMID- 28342182 TI - At first sight or second glance: clinical presentation of mosaic manifestations of autosomal dominant skin disorders - a case series. AB - BACKGROUND: Several autosomal dominant disorders may manifest in mosaic patterns with cutaneous involvement. Genomic mosaicism results from postzygotic autosomal mutations, giving rise to clonal proliferation of two genetically distinct cell groups, which clinically present as lesions following the lines of Blaschko. OBJECTIVE: To increase the awareness of the clinical variability of mosaic manifestations in autosomal dominant skin disorders in order to avoid delayed diagnosis. METHODS: Clinicopathologic correlation in a case series including three patients with mosaic manifestations of different autosomal dominant skin diseases. RESULTS: Here, we describe a patient with type 1 segmental mosaicism of epidermolytic ichthyosis (case 1) and two patients with either type 1 (case 2) or type 2 (case 3) segmental neurofibromatosis 1 (NF1). CONCLUSION: Dermatologists should be familiar with mosaic manifestations of autosomal dominant skin diseases to ensure appropriate guidance of the affected patient. Genetic counselling is mandatory as even limited forms of mosaicism may involve the patient's germline with a moderately increased risk to transmit the mutation to their offspring, resulting in a more severe, generalized form of the respective disease. PMID- 28342183 TI - Results of a multicentre UK-wide compassionate use programme evaluating the efficacy of idelalisib monotherapy in relapsed, refractory follicular lymphoma. PMID- 28342184 TI - The lipid-lowering effect of levothyroxine in patients with subclinical hypothyroidism: A systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVES: Dyslipidaemia is common in patients with subclinical hypothyroidism (SCH). To date, there is no universal agreement regarding the lipid-lowering effect of substitution treatment with L-T4 in patients with SCH. We aimed to clarify the effect by conducting this systematic review and meta-analysis of randomized controlled trials (RCTs). DESIGN: We systematically searched PubMed, the Cochrane Library, ClinicalTrials.gov and EMBASE for RCTs comparing substitution treatment to placebo treatment or observation. We focused on the primary outcomes of changes from baseline of total, low-density lipoprotein and high-density lipoprotein cholesterol (TC, LDL-C and HLD-C) and triglycerides. Subgroup analyses were performed, assessing the effect of treatment duration, disease severity and ethnicity on the occurrence of discrepancy. RESULTS: Twelve trials, with 940 participants, were eligible for analysis. Compared with the control group, levothyroxine substitution yielded a mean reduction in TC (-0.29 mmol/L, [-0.42 to -0.16]) and LDL-C (-0.22 mmol/L, [-0.36 to -0.09]), with no significant effects on HDL-C (-0.04 mmol/L, [-0.08 to 0.01]) or triglycerides ( 0.04 mmol/L, [-0.08 to 0.00]). Trials in which only patients with mild SCH (thyrotropin <10 mIU/L) were enrolled showed equivalent effects. The lowering effects were weaker, but still significant, in long-term treatment (>6 months) compared with short-term treatment (<=6 months) for TC (-0.19 mmol/L [-0.35, 0.03] vs -0.50 mmol/L [-0.68, -0.31], P=.047) and LDL-C (-0.09 mmol/L [-0.16, 0.02] vs -0.46 mmol/L [-0.68, -0.25], P=.006). CONCLUSIONS: Levothyroxine treatment has clear benefits on TC and LDL-C in SCH patients, including those with mild SCH. PMID- 28342185 TI - A Spotlight on the Compatibility between XFEL and Ab Initio Structures of the Oxygen Evolving Complex in Photosystem II. AB - The Mn4 CaO5 cluster of photosystem II promotes a crucial step in the oxygenic photosynthesis, namely, the water-splitting reaction. The structure of such cluster in the S1 state of the Kok-Joliot's cycle has been recently resolved by femtosecond X-ray free-electron laser (XFEL) measurements. However, the XFEL results are characterized by appreciable discrepancies with previous X-ray diffraction (XRD), as well as with S1 models based on ab initio calculations. We provide here a unifying picture based on a combined set of DFT-based structures and molecular dynamics simulations of the S0 and S1 states. Our findings indicate that the XFEL results cannot be interpreted on the grounds of a single structure. A combination of two S1 stable isomers together with a minority contribution of the S0 state is necessary to reproduce XFEL results within 0.16 A. PMID- 28342186 TI - Simplifying oral misoprostol protocols for the induction of labour. PMID- 28342188 TI - Haemorrhagic onychomadesis: a cutaneous clue to chronic selenosis - case series. PMID- 28342187 TI - Effect of adverse environmental conditions and protective clothing on temperature rise in a human body exposed to radiofrequency electromagnetic fields. AB - This study considers the computationally determined thermal profile of a finely discretized, heterogeneous human body model, simulating a radiofrequency electromagnetic field (RF-EMF) worker wearing protective clothing subject to RF EMF exposure, and subject to various environmental conditions including high ambient temperature and high humidity, with full thermoregulatory mechanisms in place. How the human body responds in various scenarios was investigated, and the information was used to consider safety limits in current international RF-EMF safety guidelines and standards. It was found that different environmental conditions had minimal impact on the magnitude of the thermal response due to RF EMF exposure, and that the current safety factor of 10 applied in international RF-EMF safety guidelines and standards for RF-EMF workers is generally conservative, though it is only narrowly so when workers are subjected to the most adverse environmental conditions. Bioelectromagnetics. 38:356-363, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28342189 TI - Straight-to-test colonoscopy for 2-week-wait referrals improves time to diagnosis of colorectal cancer and is feasible in a high-volume unit. AB - AIM: We have introduced 'straight-to-test' (STT) colonoscopy as part of our 2 week-wait (2WW) pathway to address increasing numbers of urgent referrals for colorectal cancer (CRC) within the National Health Service. In this study we evaluated the ability of this initiative to shorten the time to diagnosis of CRC. METHOD: We amended our 2WW referral form to include performance status and comorbidities. General practitioners were asked to provide data on estimated glomerular filtration rate and full blood count/ferritin. Our 2WW referrals were screened by a colorectal consultant and a nurse specialist. Those deemed unsuitable for STT were offered outpatient assessment (OPA). RESULTS: Of 553 2WW referrals screened, 352 were considered suitable, 65 of whom failed a telephone assessment or were uncontactable, and accordingly 287 were offered the STT pathway. The STT group was significantly younger than the OPA group (median 65.9 years vs 78.7 years; P < 0.0001). STT colonoscopy significantly reduced the time to first test (13 days vs 22 days; P < 0.0001) and tissue diagnosis from the referral date (17 days vs 24.5 days; P < 0.0001). Thirty-seven (6.8%) CRCs were detected. Proportionately fewer patients in the STT pathway were managed with 'best supportive care only' compared with patients attending OPA (one of 15 vs six of 22, respectively). STT colonoscopy obviated the need for clinic attendance before testing in 287 patients, representing a potential net cost benefit of at least L48 500 in 4 months. CONCLUSION: STT colonoscopy was safe and effective for selecting out a group of symptomatic patients who could proceed straight to endoscopic examination and receive a diagnosis more rapidly. PMID- 28342190 TI - Expanded Medicaid dental coverage under the Affordable Care Act: an analysis of Minnesota emergency department visits. AB - OBJECTIVES: Hospital emergency departments (EDs) function as the safety net for patients with non-traumatic dental conditions (NTDCs). With the implementation of Medicaid expansion under the Affordable Care Act (ACA) many adults became eligible for dental benefits. We examined the impact of "early" Medicaid expansion in Minnesota on ED visits for NTDCs from 2008 (prereform) to 2014 (postreform). METHODS: Data from the State Emergency Department Databases for Minnesota were analyzed for 2 years: 2008 and 2014. All individuals who presented to the ED with a dental problem were identified based on the International Classification of Diseases, Ninth Revision, Clinical Modification with a primary diagnosis of 520.0-529.9. Demographic variables including patient age, gender, and primary payer were examined. RESULTS: Between 2008 and 2014 there was a 18.8 percent increase in the number of all non-dental ED visits and a 9.7 percent decrease in the number of NTDC visits. In that time period, young adults 18-26 years old showed a significant decrease (19.3 percent, P < 0.001) in the number of NTDC visits. CONCLUSIONS: The Minnesota experience suggests that the increase in Medicaid dental benefits through the ACA has significantly decreased NTDC visits, especially among young adults who were eligible for a dependent coverage policy that extends parents' health insurance to age 26. To our knowledge, no previous study has reported on the impact of early Medicaid expansion on the rate of ED use for NTDCs. PMID- 28342191 TI - Exploiting multicompartment effects in triple-echo steady-state T2 mapping for fat fraction quantification. AB - PURPOSE: To investigate and exploit the effect of intravoxel off-resonance compartments in the triple-echo steady-state (TESS) sequence without fat suppression for T2 mapping and to leverage the results for fat fraction quantification. METHODS: In multicompartment tissue, where at least one compartment is excited off-resonance, the total signal exhibits periodic modulations as a function of echo time (TE). Simulated multicompartment TESS signals were synthesized at various TEs. Fat emulsion phantoms were prepared and scanned at the same TE combinations using TESS. In vivo knee data were obtained with TESS to validate the simulations. The multicompartment effect was exploited for fat fraction quantification in the stomach by acquiring TESS signals at two TE combinations. RESULTS: Simulated and measured multicompartment signal intensities were in good agreement. Multicompartment effects caused erroneous T2 offsets, even at low water-fat ratios. The choice of TE caused T2 variations of as much as 28% in cartilage. The feasibility of fat fraction quantification to monitor the decrease of fat content in the stomach during digestion is demonstrated. CONCLUSIONS: Intravoxel off-resonance compartments are a confounding factor for T2 quantification using TESS, causing errors that are dependent on the TE. At the same time, off-resonance effects may allow for efficient fat fraction mapping using steady-state imaging. Magn Reson Med 79:423 429, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28342192 TI - Intravenous Versus Nonintravenous Benzodiazepines for the Cessation of Seizures: A Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - BACKGROUND: The acquisition of intravenous (IV) access in the actively convulsing patient is difficult. This often delays the administration of the IV benzodiazepine (BDZ) necessary for seizure cessation. Delays in seizure cessation are associated with increased pharmacoresistance, increased risk of neuronal injury, worse patient outcomes, and increased morbidity. OBJECTIVE: The objective was to assess whether the delay imposed by IV access acquisition is justified by improved outcomes. We compared IV versus non-IV BDZ efficacy in the real world with regard to failure rates (primary outcome), interval to seizure control, and observed complications (secondary outcomes). METHODS: A systematic review was performed using Medline, Embase, and the Cochrane Library. All studies published or in press from the inception of the respective database to July 2016 were included. Only randomized and quasi-randomized controlled trials directly comparing IV to non-IV (buccal, rectal, intranasal, or intramuscular) BDZ were included. RESULTS: Our search strategy retrieved 2,604 citations for review. A total of 11 studies were finally included in qualitative synthesis and 10 in quantitative analysis. Only one was of high quality. For treatment failure, non IV BDZ was superior to IV BDZ (odd ratio [OR] = 0.72; 95% confidence interval [CI] = 0.56-0.92). However, no significant difference was found between the two treatments in the pediatric subgroup (OR = 1.16; 95% CI = 0.74-1.81). Non-IV BDZ was administered faster than IV BDZ and therefore controlled seizures faster (mean difference = 3.41 minutes; 95% CI = 1.69-5.13 minutes) despite a longer interval between drug administration and seizure cessation (mean difference = 0.74 minutes; 95% CI = 0.52-0.95 minutes). Respiratory complications requiring intervention were similar between non-IV BDZ and IV BDZ, regardless of administration route (risk difference = 0.00; 95% CI = -0.02 to 0.01). CONCLUSION: Non-IV BDZ, compared to IV BDZ, terminate seizures faster and have a superior efficacy and side effect profile. Higher-quality studies and further evaluation in different age groups are warranted. PMID- 28342193 TI - Metabolism of the tryptamine-derived new psychoactive substances 5-MeO-2-Me-DALT, 5-MeO-2-Me-ALCHT, and 5-MeO-2-Me-DIPT and their detectability in urine studied by GC-MS, LC-MSn , and LC-HR-MS/MS. AB - Many N,N-dialkylated tryptamines show psychoactive properties and were encountered as new psychoactive substances. The aims of the presented work were to study the phase I and II metabolism and the detectability in standard urine screening approaches (SUSA) of 5-methoxy-2-methyl-N,N-diallyltryptamine (5-MeO-2 Me-DALT), 5-methoxy-2-methyl-N-allyl-N-cyclohexyltryptamine (5-MeO-2-Me-ALCHT), and 5-methoxy-2-methyl-N,N-diisopropyltryptamine (5-MeO-2-Me-DIPT) using gas chromatography-mass spectrometry (GC-MS), liquid chromatography coupled with multistage accurate mass spectrometry (LC-MSn ), and liquid chromatography-high resolution tandem mass spectrometry (LC-HR-MS/MS). For metabolism studies, urine was collected over a 24 h period after administration of the compounds to male Wistar rats at 20 mg/kg body weight (BW). Phase I and II metabolites were identified after urine precipitation with acetonitrile by LC-HR-MS/MS. 5-MeO-2-Me DALT (24 phase I and 12 phase II metabolites), 5-MeO-2-Me-ALCHT (24 phase I and 14 phase II metabolites), and 5-MeO-2-Me-DIPT (20 phase I and 11 phase II metabolites) were mainly metabolized by O-demethylation, hydroxylation, N dealkylation, and combinations of them as well as by glucuronidation and sulfation of phase I metabolites. Incubations with mixtures of pooled human liver microsomes and cytosols (pHLM and pHLC) confirmed that the main metabolic reactions in humans and rats might be identical. Furthermore, initial CYP activity screenings revealed that CYP1A2, CYP2C19, CYP2D6, and CYP3A4 were involved in hydroxylation, CYP2C19 and CYP2D6 in O-demethylation, and CYP2C19, CYP2D6, and CYP3A4 in N-dealkylation. For SUSAs, GC-MS, LC-MSn , and LC-HR-MS/MS were applied to rat urine samples after 1 or 0.1 mg/kg BW doses, respectively. In contrast to the GC-MS SUSA, both LC-MS SUSAs were able to detect an intake of 5 MeO-2-Me-ALCHT and 5-MeO-2-Me-DIPT via their metabolites following 1 mg/kg BW administrations and 5-MeO-2-Me-DALT following 0.1 mg/kg BW dosage. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28342194 TI - Analysis of mobile phone use among young patients with brain tumors in Japan. AB - The purpose of this study was to clarify ownership and usage of mobile phones among young patients with brain tumors in Japan. The subjects of this study were patients with brain tumors diagnosed between 2006 and 2010 who were between the ages of 6 and 18 years. The target population for the analysis was 82 patients. Patients were divided into two groups: 16 patients who were mobile phone owners 1 year before diagnosis, and 66 patients who did not own mobile phones (non owners). Using data on the mobile phone ownership rate obtained from three general-population surveys, we calculated the expected number of mobile phone owners. The three age-adjusted standardized ownership ratios were 0.83 (95% confidence interval [CI]: 0.56-1.22), 0.51 (95% CI: 0.24-1.04), and 0.75 (95% CI: 0.42-1.32). The mobile phone ownership prevalence among the young Japanese patients with brain tumors in the current study does not differ from available estimates for the general population of corresponding age. However, since the use of mobile phones among children is increasing annually, investigations into the health effects of mobile phone use among children should continue. Bioelectromagnetics. 38:349-355, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28342195 TI - A simple self-diagnosis tool to assess the prevalence of dermatoporosis in France. AB - IMPORTANCE: The term dermatoporosis has been proposed to describe clinical signs and functional consequences of age-related extreme skin fragility. OBJECTIVE: To create a simple dermatoporosis self-diagnosis tool (IDA: Index Dermatoporosis Assessment) and to use this tool to estimate the prevalence of dermatoporosis in France. DESIGN, SETTING AND PARTICIPANTS: A specific dermatoporosis questionnaire was developed with the help of senior dermatologists and survey experts. This questionnaire was submitted to consecutive individuals aged >=65 years who consulted a dermatologist. At the end of the consultation, the dermatologist was asked to assess 'whether or not' dermatoporosis was present. In a second step, the final questionnaire was mailed to a representative sample of the French population aged >=65 years in order to estimate the prevalence of dermatoporosis. RESULTS: The initial questionnaire, consisting of two modules (24 questions), was validated in 173 individuals aged >=65 years) during a dermatologist consultation. Dermatologists diagnosed 46% of the individuals with dermatoporosis. The final validated questionnaire consisted of 14 items, 12 consisting in presence or absence of clinical signs and two items consisting of the self-assessment by individuals of skin ageing on neckline and hands (none/moderate/significant/very significant). A scoring system was generated to quote quantitatively dermatoporosis (from 0 if no sign of dermatoporosis to 20 maximal dermatoporosis). The area under the receiver operator curve was 0.8535, indicating a very good ability of the questionnaire to differentiate between individuals. A cut-off value of 11 was linked to positive and negative predictive values of 0.78 and 0.81, respectively. In a second step, using the questionnaire in a representative sample of the French population (n = 533), the estimated overall prevalence of dermatoporosis was 37.5% in French subjects aged >=65 years [27.5% (males) vs. 43.9% (females); P < 0.05]. The estimated prevalence of dermatoporosis was twice higher in subjects with eczema or atopic dermatitis during childhood than in the population without dermatoporosis (60.6% vs. 33.4%, P < 0.001). Individuals with dermatoporosis also reported a higher prevalence of itching, long-term corticosteroid use, anticoagulant use and prior sun exposure. CONCLUSIONS AND RELEVANCE: Using a new simple dermatoporosis self-diagnosis tool, this study provides a previously unprecedented insight into the high prevalence of dermatoporosis in elderly individuals. IDA questionnaire is a short (14-item) and easy to use tool for evaluating dermatoporosis in adults and may allow an easy evaluation of each subject. PMID- 28342196 TI - A DNA Logic Gate Automaton for Detection of Rabies and Other Lyssaviruses. AB - Immediate activation of biosensors is not always desirable, particularly if activation is due to non-specific interactions. Here we demonstrate the use of deoxyribozyme-based logic gate networks arranged into visual displays to precisely control activation of biosensors, and demonstrate a prototype molecular automaton able to discriminate between seven different genotypes of Lyssaviruses, including Rabies virus. The device uses novel mixed-base logic gates to enable detection of the large diversity of Lyssavirus sequence populations, while an ANDNOT logic gate prevents non-specific activation across genotypes. The resultant device provides a user-friendly digital-like, but molecule-powered, dot matrix text output for unequivocal results read-out that is highly relevant for point of care applications. PMID- 28342197 TI - Clinicopathological analysis of primary central nervous system NK/T cell lymphoma: rare and localized aggressive tumour among extranasal NK/T cell tumours. AB - AIMS: The central nervous system (CNS) is a rare primary site of non-Hodgkin lymphoma. Although direct invasion of nasal natural killer (NK)/T cell tumours into CNS is reported occasionally, primary CNS NK/T cell lymphoma is extremely rare, and the clinicopathological features of primary CNS NK/T cell lymphoma remain largely unknown. METHODS AND RESULTS: We identified four cases from our consultation files and analysed the clinicopathological features. Three were immunocompetent and one was immunosuppressed. There were three males and one female and their ages ranged from 21 to 77 years (median: 46 years). Radiotherapy was rendered for all patients, and methotrexate was administered to two patients. The overall survival was 4-29 months (median, 19 months) for the three immunocompetent patients. Neoplastic cells exhibited medium to large atypical nuclei. Angiocentric growth and necrosis were observed. The immunophenotype was typical of NK cell tumours: CD3epsilon, 100%; CD56, 67%; CD5, 50%; cytotoxic molecules, 100%; Epstein-Barr virus encoded small RNA (EBER), 100% and T cell receptor (TCR)-beta or gamma, 0%. No TCR-gene rearrangements were detected. Reviewing 10 additional cases from the literature and comparing with extranasal NK/T cell lymphoma of the more frequent origins (skin or gastrointestinal tract), primary CNS NK/T cell lymphoma was diagnosed at an earlier stage without B symptoms but exhibited aggressive clinical behaviours. CONCLUSIONS: Although extremely rare, primary CNS NK/T cell lymphoma does occur and should always be included in the differential diagnosis and we should apply relevant markers routinely in conjunction with exploring the patient background. The accumulation of cases is indispensable to establish an effective treatment strategy for this rare and aggressive malignancy. PMID- 28342198 TI - An Isolable Diboron-Centered Diradical with a Triplet Ground State. AB - Two new diboranes, 2,6-bis(BMes2 )mesitylene (1) and 3,3'-bis(BMes2 )bimesitylene (3), were synthesized. Two-electron reduction of 1 with elemental potassium afforded the C-H activation product [(18-c-6)K(THF)2 ]2+ ?22- bearing a BC3 four membered ring as colorless crystals, whereas the reduction of 3 with potassium led to the isolation of [(18-c-6)K(THF)2 ]2+ ?32-.. as dark blue crystals. Both reduction products were characterized by structural and spectroscopic methods. Electron paramagnetic resonance (EPR) spectroscopy and theoretical calculations revealed that the electron spin density of 32-.. mainly resides on the two boron nuclei and features a triplet ground state, which was confirmed by superconducting quantum interference device (SQUID) measurements as well as theoretical calculations. 32-.. represents the first structurally characterized boron-centered diradical with a triplet ground state. In addition, the reactivity of [(18-c-6)K(THF)2 ]2+ ?32-.. toward PhSeSePh and nBu3 SnH was investigated, which is consistent with its radical character. PMID- 28342199 TI - Overexpression of Drosha, DiGeorge syndrome critical region gene 8 (DGCR8), and Dicer mRNAs in the pathogenesis of psoriasis. AB - INTRODUCTION: Psoriasis is a complex autoimmune inflammatory disease that occurs in genetically susceptible individuals and presents with the development of inflammatory plaques on the skin. Recent studies have indicated that microRNAs (miRNAs) play important roles in psoriasis. OBJECTIVE: To investigate whether expression of Drosha, DGCR8, and Dicer mRNAs is involved in the pathogenesis of psoriasis. METHODS: Biopsies were obtained from involved psoriatic skin (PP), noninvolved psoriatic skin (PN), and healthy skin (NN). Expression of Drosha, Dicer, and DGCR8 was assessed with real-time quantitative real-time PCR in 25 patients with psoriasis and 25 healthy volunteers. RESULTS: We observed that expression levels of Drosha, Dicer, and DGCR8 were upregulated in patients with psoriasis compared to the control group. However, the Drosha and Dicer expression levels were higher in PP tissues and PN tissues compared to NN tissues, but they were more upregulated in PP tissues compared to PN tissues (P<.001). Although the DGCR8 expression was higher in PP tissues and PN tissues compared to NN tissues, it was more upregulated in PN tissues compared to PP tissues (P<.001). CONCLUSION: Our data demonstrate that upregulated expression of Drosha, DGCR8, and Dicer mRNAs may be involved in the pathogenesis of psoriasis. PMID- 28342200 TI - Telomere length is a critical determinant for survival in multiple myeloma. AB - The variable clinical outcomes of Multiple Myeloma (MM) patients are incompletely defined by current prognostication tools. We examined the clinical utility of high-resolution telomere length analysis as a prognostic marker in MM. Cohort stratification, using a previously determined length threshold for telomere dysfunction, revealed that patients with short telomeres had a significantly shorter overall survival (P < 0.0001; HR = 3.4). Multivariate modelling using forward selection identified International Staging System (ISS) stage as the most important prognostic factor, followed by age and telomere length. Importantly, each ISS prognostic subset could be further risk-stratified according to telomere length, supporting the inclusion of this parameter as a refinement of the ISS. PMID- 28342202 TI - Treatment of chronic venous ulcers: experience in six patients treated with terminal interruption of the reflux source (TIRS) TIRS: effective option for the treatment of venous ulcers. PMID- 28342201 TI - Expression of oxysterol pathway genes in oestrogen-positive breast carcinomas. AB - OBJECTIVE: This study investigated whether gene expression levels of key modulators of the oxysterol signalling pathway modify the prognosis of patients with oestrogen receptor-positive (ER+) breast carcinomas via interaction with endocrine therapy. CONTEXT: The prognosis of patients with ER+ breast carcinoma depends on several factors. Previous studies have suggested that some oxygenated forms of cholesterol (oxysterols) bind to oestrogen receptor and anti-oestrogen binding site which may deregulate cholesterol homoeostasis and influence effect of therapy. DESIGN: The expression levels of 70 oxysterol pathway genes were evaluated in a test set of breast carcinomas differing in ER expression. The genes differentially expressed in ER+ tumours were assessed in a comprehensive set of ER+ tumours to evaluate their clinical significance. PATIENTS: A total of 193 primary patients with breast carcinoma were included. MEASUREMENTS: The transcript levels were determined by quantitative real-time polymerase chain reaction. RESULTS: The expression levels of 23 genes were found to be specifically dysregulated in ER+ tumours compared to ER- tumours of the test set. The expression levels of ABCG2, CYP7B1, CYP24A1, CYP39A1 and CH25H genes were found to be strongly associated with disease stage; however, none of the gene expression levels were associated with disease-free survival in patients treated with endocrine therapy. CONCLUSIONS: The expression of a number of oxysterol pathway genes is significantly modulated by ER expression and associated with the clinical stage of patients. However, the expression of oxysterol pathway genes was not found to modify the prognosis of ER+ patients with breast carcinoma treated with endocrine therapy. PMID- 28342203 TI - GPU accelerated implementation of NCI calculations using promolecular density. AB - The NCI approach is a modern tool to reveal chemical noncovalent interactions. It is particularly attractive to describe ligand-protein binding. A custom implementation for NCI using promolecular density is presented. It is designed to leverage the computational power of NVIDIA graphics processing unit (GPU) accelerators through the CUDA programming model. The code performances of three versions are examined on a test set of 144 systems. NCI calculations are particularly well suited to the GPU architecture, which reduces drastically the computational time. On a single compute node, the dual-GPU version leads to a 39 fold improvement for the biggest instance compared to the optimal OpenMP parallel run (C code, icc compiler) with 16 CPU cores. Energy consumption measurements carried out on both CPU and GPU NCI tests show that the GPU approach provides substantial energy savings. (c) 2017 Wiley Periodicals, Inc. PMID- 28342204 TI - The EP4 antagonist, L-161,982, induces apoptosis, cell cycle arrest, and inhibits prostaglandin E2-induced proliferation in oral squamous carcinoma Tca8113 cells. AB - BACKGROUND: Recent studies suggest that cyclooxygenase 2 (COX-2) inhibitors may enhance the toxic effects of anticancer drugs on tumor cells, including oral squamous cell carcinoma (OSCC), but its long-term use can cause side effects such as stomach ulcers and myocardial infarction. Our aim was to investigate proliferative effects of a downstream product of COX-2, prostaglandin E2 (PGE2), in human oral squamous carcinoma cell line Tca8113 and explore the effects of PGE2 receptors, especially EP4 receptor, on the growth of Tca8113 cells. METHODS: To evaluate the effects of PGE2 and EP receptors on Tca8113 cells, CCK8 assay, Western blotting, cell cycle analysis, and apoptosis assay were performed. RESULTS: We found that the EP4 receptor agonist, PGE1-OH, could mimick PGE2 rescued the inhibitory effect of celecoxib and induced cell growth via ERK phosphorylation, and the EP4 receptor antagonist, L-161,982, completely blocked PGE2-stimulated ERK phosphorylation and proliferation of Tca8113 cells. Furthermore, L-161,982 may induce apoptosis and block cell cycle progression at s phase by upregulating Bax and p21 protein levels and by downregulating Bcl-2, CDK2, and cyclin A2 protein levels. CONCLUSIONS: Our results indicate that EP4 receptor mediates PGE2-induced cell proliferation through ERK signaling, and inhibition of EP4 receptor may represent an alternative therapeutic strategy for the prevention and treatment of OSCC. PMID- 28342205 TI - Superficial herpes simplex virus wound infection following lung transplantation. AB - Surgical site infections (SSIs) are infections of tissues, organs, or spaces exposed by surgeons during performance of an invasive procedure. SSIs are classified into superficial, which are limited to skin and subcutaneous tissues, and deep. The incidence of deep SSIs in lung transplant (LTx) patients is estimated at 5%. No reports have been published as to the incidence of superficial SSIs specifically in LTx patients. Common sense would dictate that the majority of superficial SSIs would be bacterial. Uncommonly, fungal SSIs may occur, and we believe that no reports exist as to the incidence of viral wound infections in LTx patients, or in any solid organ transplant patients. We report a de novo superficial wound infection with herpes simplex virus following lung transplantation, its possible source, treatment, and resolution. PMID- 28342206 TI - Case of lupus miliaris disseminatus faciei associated with marked formation of cysts, successfully treated with intralesional injections of triamcinolone acetonide. PMID- 28342207 TI - Genetic effect of MTHFR C677T polymorphism on the structural covariance network and white-matter integrity in Alzheimer's disease. AB - The 677 C to T transition in the MTHFR gene is a genetic determinant for hyperhomocysteinemia. We investigated whether this polymorphism modulates gray matter (GM) structural covariance networks independently of white-matter integrity in patients with Alzheimer's disease (AD). GM structural covariance networks were constructed by 3D T1-magnetic resonance imaging and seed-based analysis. The patients were divided into two genotype groups: C homozygotes (n = 73) and T carriers (n = 62). Using diffusion tensor imaging and white-matter parcellation, 11 fiber bundle integrities were compared between the two genotype groups. Cognitive test scores were the major outcome factors. The T carriers had higher homocysteine levels, lower posterior cingulate cortex GM volume, and more clusters in the dorsal medial lobe subsystem showing stronger covariance strength. Both posterior cingulate cortex seed and interconnected peak cluster volumes predicted cognitive test scores, especially in the T carriers. There were no between-group differences in fiber tract diffusion parameters. The MTHFR 677T polymorphism modulates posterior cingulate cortex-anchored structural covariance strength independently of white matter integrities. Hum Brain Mapp 38:3039-3051, 2017. (c) 2017 The Authors Human Brain Mapping Published Wiley by Periodicals, Inc. PMID- 28342209 TI - From somatic pain to psychic pain: The body in the psychoanalytic field. AB - The integration of psyche and soma begins with a baby's earliest contact with his or her parents. With the help of maternal empathy and reverie, beta-elements are transformed into alpha-elements. While we understand this to be the case, we would like to enquire what actually happens to those parts of the affect which have not been transformed? For the most part they may be dealt with by evacuation, but they can also remain within the body, subsequently contributing to psychosomatic symptoms. This paper describes how the body serves as an intermediate store between the psychic (inner) and outer reality. The authors focuses on the unconscious communicative process between the analyst and the analysand, and in particular on how psychosomatic symptoms can spread to the analyst's body. The latter may become sensitive to the analysand's psychosomatic symptoms in order to better understand the psychoanalytical process. Sensory processes (visual and auditory) and psychic mechanisms such as projective identification can serve as a means for this communication. One of the first analysts to deal with this topic was Wilhelm Reich. He described one kind of psychosomatic defence like a shell, the character armour, comparing the armour formed by muscle tension with another, more psychical type of armour. This concept can be linked to Winnicott's contribution of the false self and later on to Feldman's concept of compliance as a defence. The authors links further details of the clinical material with theoretical concepts from Joyce McDougall, Piera Aulagnier, and Ricardo Rodulfo and Marilia Aisenstein. With the aid of the complex concept of projective identification, as described by Heinz Weiss, the authors discusses the important question of how the analyst gets in touch with the patient's current psychosomatic state, and describes a specific communication between the body of the psychoanalyst and the body of the patient. A vignette illustrates in greater detail the relationship between this theoretical understanding and an actual clinical example. In the session described, the analyst reacts to the patient with an intense body-countertransference, taking on the patient's symptoms for a short time. The patient, who had been unable to integrate psyche and soma (whose psyche did not indwell (Winnicott) in his body), projected the untransformed beta-elements into his body, where they emerged as bodily symptoms. The body became a kind of intermediate store between inner and outer reality. By internalizing the patient's symptoms in his own body, the analyst created a bodily communication - something in between concerning the inner and the outer reality of both participants of the analytic dyad. The analyst was able to recognize his psychosomatic experience as the fear of dying, and to work through his bodily countertransference. This is described in detail. The emerging understanding of the countertransference helped the analyst to contribute to the patient's process of transforming his symptoms. The analyst was able to help the patient get in touch emotionally with many traumatic situations experienced during his life. The function of the psychosomatic symptoms was to contain the patient's fear of death. These frightening feelings could now be worked through on a psychical level; they could enter into a process of symbol formation so that the psychosomatic symptoms were no longer necessary and disappeared. PMID- 28342208 TI - Serogroups and genotypes of Leptospira spp. strains from bovine aborted foetuses. AB - Leptospirosis is a global disease of animals, with potential major economic impact on livestock industry and important zoonotic capacities. The disease represents a major challenge in the developing countries as humans and animals frequently live in close association. The serovar Hardjo of Leptospira whose primary host is cattle has been studied extensively, but few data exist on other current circulating or emerging serotypes. To better understand the disease in cattle and how to prevent and/or control it, it is necessary to identify the genotype and the serotype of circulating Leptospira. This study presents results of several investigations performed on a historical Belgian collection of congenital jaundice in bovine aborted foetuses coming from the leptospirosis emerging episode of 2014 (Delooz et al., Transboundary and Emerging Diseases, 62, 2015, 124). The results revealed that L. Grippotyphosa and L. Australis were the most prevalent serogroups with, respectively, 17/42 and 13/42 positive microscopic agglutination test (MAT) during this emerging event associated with the same clinical pattern. The study also confirms that congenital jaundice is associated with L. kirscheneri and L. interrogans and provides the genotyping of DNA obtained from these two species. PMID- 28342210 TI - Does the turgor loss point characterize drought response in dryland plants? AB - The water potential at turgor loss point (Psitlp ) has been suggested as a key functional trait for determining plant drought tolerance, because of its close relationship with stomatal closure. Psitlp may indicate drought tolerance as plants, which maintain gas exchange at lower midday water potentials as soil water availability declines also have lower Psitlp . We evaluated 17 species from seasonally dry habitats, representing a range of life-forms, under well-watered and drought conditions, to determine how Psitlp relates to stomatal sensitivity (pre-dawn water potential at stomatal closure: Psigs0 ) and drought strategy (degree of isohydry or anisohydry; DeltaPsiMD between well-watered conditions and stomatal closure). Although Psigs0 was related to Psitlp , Psigs0 was better related to drought strategy (DeltaPsiMD ). Drought avoiders (isohydric) closed stomata at water potentials higher than their Psitlp ; whereas, drought tolerant (anisohydric) species maintained stomatal conductance at lower water potentials than their Psitlp and were more dehydration tolerant. There was no significant relationship between Psitlp and DeltaPsiMD . While Psitlp has been related to biome water availability, we found that Psitlp did not relate strongly to stomatal closure or drought strategy, for either drought avoiders or tolerators. We therefore suggest caution in using Psitlp to predict vulnerability to drought. PMID- 28342211 TI - The molecular behavior of a single beta-amyloid inside a dipalmitoylphosphatidylcholine bilayer at three different temperatures: An atomistic simulation study: Abeta interaction with DPPC: Atomistic simulation. AB - The behavior of a single Abeta40 molecule within a dipalmitoylphosphatidylcholine (DPPC) bilayer was studied by all-atom molecular dynamics simulations. The effect of membrane structure was investigated on Abeta40 behavior, secondary structure, and insertion depth. Simulations were performed at three temperatures (323, 310, and 300 K) to probe three different bilayer fluidities. Results show that at all above temperatures, the peptide contains two short helices, coil, bend, and turn structures. At 300 K, the peptide contains a region with beta structure in C terminal region. Our results also show that Abeta decreases the bilayer thickness and the order of lipids in its vicinity which leads to water insertion into the bilayer and concomitant increase in the local fluidity. The peptide remains embedded in the bilayer at all temperatures, and become inserted into the bilayer up to several residues at 323 and 310 K. At 310 and 300 K, the dominant interaction energy between Abeta and bilayer changes from electrostatic to van der Waals. It can be proposed that at higher temperatures (e.g., 323 K), Lys28 and the C-terminal region of the peptide play the role of two anchors that keep Abeta inside the top leaflet. This study demonstrates that Abeta molecule can perturb the integrity of cellular membranes. Proteins 2017; 85:1298-1310. (c) 2017 Wiley Periodicals, Inc. PMID- 28342213 TI - Reply. PMID- 28342212 TI - High-speed whole-brain oximetry by golden-angle radial MRI. AB - PURPOSE: To determine whole-brain cerebral metabolic rate of oxygen (CMRO2 ), an improved imaging approach, based on radial encoding, termed radial OxFlow (rOxFlow), was developed to simultaneously quantify draining vein venous oxygen saturation (SvO2 ) and total cerebral blood flow (tCBF). METHODS: To evaluate the efficiency and precision of the rOxFlow sequence, 10 subjects were studied during a paradigm of repeated breath-holds with both rOxFlow and Cartesian OxFlow (cOxFlow) sequences. CMRO2 was calculated at baseline from OxFlow-measured data assuming an arterial O2 saturation of 97%, and the SvO2 and tCBF breath-hold responses were quantified. RESULTS: Average neurometabolic-vascular parameters across the 10 subjects for cOxFlow and rOxFlow were, respectively: SvO2 (%) baseline: 64.6 +/- 8.0 versus 64.2 +/- 6.6; SvO2 peak: 70.5 +/- 8.5 versus 72.6 +/- 5.4; tCBF (mL/min/100 g) baseline: 39.2 +/- 3.8 versus 40.6 +/- 8.0; tCBF peak: 53.2 +/- 5.1 versus 56.1 +/- 11.7; CMRO2 (umol O2 /min/100 g) baseline: 111.5 +/- 26.8 versus 120.1 +/- 19.6. The above measures were not significantly different between sequences (P > 0.05). CONCLUSION: There was good agreement between the two methods in terms of the physiological responses measured. Comparing the two, rOxFlow provided higher temporal resolution and greater flexibility for reconstruction while maintaining high SNR. Magn Reson Med 79:217 223, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28342214 TI - Real-time fMRI neurofeedback in adolescents with attention deficit hyperactivity disorder. AB - Attention Deficit Hyperactivity Disorder (ADHD) is associated with poor self control, underpinned by inferior fronto-striatal deficits. Real-time functional magnetic resonance neurofeedback (rtfMRI-NF) allows participants to gain self control over dysregulated brain regions. Despite evidence for beneficial effects of electrophysiological-NF on ADHD symptoms, no study has applied the spatially superior rtfMRI-NF neurotherapy to ADHD. A randomized controlled trial tested the efficacy of rtfMRI-NF of right inferior prefrontal cortex (rIFG), a key region that is compromised in ADHD and upregulated with psychostimulants, on improvement of ADHD symptoms, cognition, and inhibitory fMRI activation. To control for region-specificity, an active control group received rtfMRI-NF of the left parahippocampal gyrus (lPHG). Thirty-one ADHD boys were randomly allocated and had to learn to upregulate their target brain region in an average of 11 rtfMRI NF runs over 2 weeks. Feedback was provided through a video-clip of a rocket that had to be moved up into space. A transfer session without feedback tested learning retention as a proximal measure of transfer to everyday life. Both NF groups showed significant linear activation increases with increasing number of runs in their respective target regions and significant reduction in ADHD symptoms after neurotherapy and at 11-month follow-up. Only the group targeting rIFG, however, showed a transfer effect, which correlated with ADHD symptom reductions, improved at trend level in sustained attention, and showed increased IFG activation during an inhibitory fMRI task. This proof-of-concept study demonstrates for the first time feasibility, safety, and shorter- and longer-term efficacy of rtfMRI-NF of rIFG in adolescents with ADHD. Hum Brain Mapp 38:3190 3209, 2017. (c) 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. PMID- 28342215 TI - Efficacy and safety of nivolumab in Japanese patients with previously untreated advanced melanoma: A phase II study. AB - Treating advanced or recurrent melanoma remains a challenge. Cancer cells can evade the immune system by blocking T-cell activation through overexpression of the inhibitory receptor programmed death 1 (PD-1) ligands. The PD-1 inhibitor nivolumab blocks the inhibitory signal in T cells, thus overcoming the immune resistance of cancer cells. Nivolumab has shown promising anticancer activity in various cancers. We carried out a single-arm, open-label, multicenter, phase II study to investigate the efficacy and safety of nivolumab in previously untreated Japanese patients with advanced melanoma. Twenty-four patients with stage III/IV or recurrent melanoma were enrolled and received i.v. nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was overall response rate evaluated by an independent radiology review committee. The independent radiology review committee-assessed overall response rate was 34.8% (90% confidence interval, 20.8-51.9), and the overall survival rate at 18 months was 56.5% (90% confidence interval, 38.0-71.4). Treatment-related adverse events (AEs) of grade 3 or 4 only occurred in three patients (12.5%). Two patients discontinued nivolumab because of AEs, but all AEs were considered manageable by early diagnosis and appropriate treatment. Subgroup analyses showed that nivolumab was clinically beneficial and tolerable regardless of BRAF genotype, and that patients with treatment-related select AEs and with vitiligo showed tendency for better survival. In conclusion, nivolumab showed favorable efficacy and safety profiles in Japanese patients with advanced or recurrent melanoma, with or without BRAF mutations. (Trial registration no. JapicCTI 142533.). PMID- 28342217 TI - The Sacral Autonomic Outflow Is Spinal, but Not "Sympathetic". AB - A recent article published in a high-profile journal proposed to reclassify the sacral autonomic outflow as being part of the sympathetic system. In this commentary, arguments against this erroneous proposal are provided. Anat Rec, 300:1369-1370, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28342218 TI - Histological assessment of regenerative endodontic treatment in animal studies with different scaffolds: A systematic review. AB - BACKGROUND/AIM: The concept of regenerative endodontic procedures remains controversial. The aim of this study was to evaluate the histology of the tissues formed in immature animal teeth with necrotic and infected pulps after attempted endodontic regeneration procedures using different scaffolds. DESIGN: A systematic electronic literature search was performed in PubMed, Web of Science, Scopus, EMBASE, DOSS, and Cochrane Library databases. The terms used were a combination of the following: "immature permanent necrotic tooth or teeth" or "open apex or apices" and "regeneration or revitalization or revascularization" and "histology." The inclusion criteria comprised animal studies with histological examination following regenerative endodontics in immature necrotic infected permanent teeth. RESULTS: From 123 screened studies, 13 met the inclusion criteria. Formation of dentin-like tissue on the dentinal walls was reported in only 4% of teeth treated with blood clot scaffold and 2% treated with blood clot with additional materials. Cementum-like hard tissue was found in 64% of teeth with blood clot, 80% treated with blood clot with additional materials, 50% treated with alternative scaffolds, and 5% that were left empty. Bone-like tissue was reported in 10% of teeth treated with blood clot, 2% treated with blood clot with additional materials, and 4% treated with alternative scaffolds. The tissues in the canal space were found to be connective tissue with infiltration of fibroblast-like cells and blood vessels. Forty-six percent of the studies reported formation of periodontal ligament-like tissues. CONCLUSIONS: None of the regeneration protocols resulted in the predictable formation of a true pulp-dentin complex. PMID- 28342216 TI - Case of bullous pemphigoid coexisting with anti-desmoglein autoantibodies. AB - A 79-year-old Japanese woman had clinical and histopathological features of bullous pemphigoid, while direct immunofluorescence test revealed C3 and immunoglobulin G depositions in the lower cell surfaces of the epidermis in addition to those in the dermoepidermal junction. Chemiluminescent enzyme immunoassays were positive for desmoglein-1 and -3 antibodies in addition to anti BP180 antibodies. In an immunoblotting study, antibodies against both 180-kDa bullous pemphigoid antigen and 130-kDa pemphigus vulgaris antigen were detected. Based on these results, bullous pemphigoid coexisting with anti-desmoglein autoantibodies was diagnosed in this case. PMID- 28342219 TI - Combining two antifungal agents does not enhance survival of Galleria mellonella larvae infected with Madurella mycetomatis. AB - OBJECTIVE: To determine whether combination therapy would improve therapeutic outcome in eumycetoma caused by Madurella mycetomatis. METHODS: Survival, colony forming units (CFU), melanisation and histopathology in M. mycetomatis-infected Galleria mellonella larvae treated with amphotericin B, itraconazole, terbinafine or combinations thereof were determined. RESULTS: Compared to larvae treated with 5% glucose, enhanced survival was obtained when M. mycetomatis-infected larvae were treated with amphotericin B, but not when they were treated with itraconazole or terbinafine. Combination therapy did not increase survival compared to 5% glucose-treated larvae, itraconazole-treated larvae or terbinafine treated larvae. Compared to amphotericin B monotreatment, a significant decrease in survival was noted when this therapy was combined with either itraconazole or terbinafine. CFU, melanisation and histopathology did not differ between monotherapy, combination therapy or 5% glucose-treated larvae. CONCLUSIONS: Combining different classes of antifungal agents did not enhance the survival of M. mycetomatis-infected G. mellonella larvae. Instead of improving the therapeutic outcome, combining either itraconazole or terbinafine with amphotericin B resulted in significantly lower survival rates of infected larvae than amphotericin B monotherapy. This experimental study does not provide support for the use of combined amphotericin B and itraconazole, combined itraconazole and terbinafine or combined terbinafine and amphotericin B and should be confirmed in other animal models. PMID- 28342220 TI - Prenatal course of metaphyseal anadysplasia associated with homozygous mutation in MMP9 identified by exome sequencing. AB - Metaphyseal anadysplasia (MANDP) is a rare autosomal recessive form of skeletal dysplasia characterized by normal length at birth and transitory bowing of the legs. Although several families with MANDP have been reported, homozygous mutations in the matrix metalloproteinase type 9 (MMP9) gene have been described in only one consanguineous family, and thus the pre and postnatal phenotypic spectrum is still obscure. A clinically similar but more severe type is caused by autosomal-dominant inheritance and is caused by mutations in matrix metalloproteinase type 13 gene (MMP13). Here, we report the prenatal and early postnatal course of two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes. Whole-exome sequencing revealed homozygous mutation in MMP9 in both fetuses suggesting a diagnosis of MANDP. We propose that MANDP should be considered in pregnancies with early prenatal shortening of the long bones without associated finding of lethal skeletal dysplasias. In addition, the finding of homozygous mutation in non-consanguineous parents of Jewish-Caucasus ancestry may suggest unawareness of such relation or the occurrence of a founder mutation in this gene. PMID- 28342221 TI - p53 immunohistochemistry in high-grade urothelial carcinoma of the bladder is prognostically significant. AB - AIMS: TP53 mutations are characteristic of the high-grade pathway in the dual pathway of urothelial carcinogenesis. These mutations have been correlated with aberrant accumulation of p53 protein; however the definition and significance of this vary in the literature. The aim of this study was to assess p53 immunostaining in a cohort of high-grade urothelial carcinomas by using standard published cut-offs and a novel binarized method that included assessment of the null phenotype. Each scoring method was correlated with oncological outcome. METHODS AND RESULTS: A triplicate core tissue microarray was constructed from 207 cases of high-grade urothelial carcinoma treated by cystectomy, and was stained with p53. The percentage nuclear staining was recorded for each core and averaged for every case (206 cases were evaluable). Cases were categorized as positive/negative according to published cut-offs (10%, 40%) or by binarizing them as abnormal (null phenotype or >50% positivity) and wild type (1-49% positivity). Correlation with disease-specific survival was not significant according to standard definitions of p53 positivity. When a 40% cut-off was used, a correlation with relapse-free survival was significant on univariate analysis (P = 0.038) but not on multivariate analysis (P = 0.079). Abnormal p53 expression showed a near-significant trend for association with disease-specific survival (P = 0.052) and was a significant predictor for relapse-free survival on both univariate analysis (P = 0.047) and multivariate analysis (P = 0.035). CONCLUSIONS: Prior to this study, the p53 null phenotype was not well described in urothelial carcinoma of the bladder. Abnormal p53 immunoexpression (null staining pattern or staining in >50% of cells) is prognostic in terms of oncological outcome. PMID- 28342222 TI - The H3 loop of antibodies shows unique structural characteristics. AB - The H3 loop in the Complementarity Determining Region of antibodies plays a key role in their ability to bind the diverse space of potential antigens. It is also exceptionally difficult to model computationally causing a significant hurdle for in silico development of antibody biotherapeutics. In this article, we show that most H3s have unique structural characteristics which may explain why they are so challenging to model. We found that over 75% of H3 loops do not have a sub Angstrom structural neighbor in the non-antibody world. Also, in a comparison with a nonredundant set of all protein fragments over 30% of H3 loops have a unique structure, with the average for all of other loops being less than 3%. We further observed that this structural difference can be seen at the level of four residue fragments where H3 loops present numerous novel conformations, and also at the level of individual residues with Tyrosine and Glycine often found in energetically unfavorable conformations. Proteins 2017; 85:1311-1318. (c) 2017 Wiley Periodicals, Inc. PMID- 28342225 TI - Japanese version of the Family Dermatology Life Quality Index: Translation and validation. AB - Skin conditions affect the quality of life (QoL) of patients and their family. To assess family members' QoL, a questionnaire uniquely designed for family members is necessary. We translated the Family Dermatology Life Quality Index (FDLQI), originally created and validated by Basra et al., into Japanese, and evaluated its reliability and validity. For psychometric evaluations, 150 dermatology patients and their family members were included. The Japanese version of the FDLQI showed high test-retest reliability (intraclass correlation coefficient = 0.95) and internal consistency reliability (Cronbach's alpha = 0.86). FDLQI scores significantly correlated with DLQI scores (r = 0.58, P < 0.01, Spearman's rho) and global question (GQ) which measured the patient's skin condition on a visual analog scale (r = 0.36, P < 0.01). Family members of patients with inflammatory skin diseases showed higher FDLQI scores than those with isolated lesions, but the difference was not statistically significant (P = 0.062, Mann Whitney U-test). Responsiveness to change was demonstrated in a group in which the patient's skin condition was assessed as improved (n = 37, r = 0.46, P < 0.01) but not in that in which it became worse. The difference of the change between the two groups was statistically significant (P < 0.01). Additionally, the change in FDLQI scores and GQ were significantly correlated (r = 0.40, P < 0.01). Exploratory factor analysis suggested essential unidimensionality of the instrument. We showed acceptable validity and responsiveness of this Japanese version of FDLQI. Further clinical epidemiological studies are required to confirm this. PMID- 28342224 TI - Interleukin-18 activates Vgamma9Vdelta2+ T cells from HIV-positive individuals: recovering the response to phosphoantigen. AB - The study aimed to identify an immunoregulatory factor that restores the phosphoantigen response of Vgamma9Vdelta2+ T cells from HIV-positive individuals on antiretroviral therapy. It was designed to characterize the effects of interleukin-18 (IL-18) on proliferation and effector function in Vgamma9Vdelta2 T cells from HIV-negative individuals and test whether exogenous IL-18 reconstitutes the Vgamma9Vdelta2 T-cell response to phosphoantigen from HIV positive donors. Vgamma9Vdelta2 T cells from HIV-negative individuals responded strongly to phosphoantigen or aminobisphosphonate stimulation of peripheral blood mononuclear cells (PBMC), whereas cells with similar T-cell receptor profiles from HIV-positive individuals only responded to aminobisphosphonate. Interleukin 18 was higher after aminobisphosphonate stimulation due to activation of the inflammasome pathway. Both IL-18 and IL-18 receptor levels were measured and the activity of exogenous IL-18 on HIV-negative and HIV-positive PBMC was evaluated in terms of Vgamma9Vdelta2 T-cell proliferation, memory subsets, cytokine expression and CD107a expression. Interleukin-18 stimulation increased proliferation, enhanced the accumulation of effector memory cells, and increased expression of cytotoxic markers in HIV-negative controls. When Vgamma9Vdelta2 T cells from HIV-positive individuals were stimulated with isopentenyl pyrophosphate in the presence of IL-18, there was increased proliferation, accumulation of memory cells, and higher expression of CD56, NKG2D and CD107a (markers of cytotoxic effector phenotype). Interleukin-18 stimulation specifically expanded the Vgamma9-JgammaP+ subset of Vgamma9Vdelta2 T cells, as was expected for normal responses to phosphoantigen. Interleukin-18 is a potent stimulator of Vgamma9Vdelta2 T-cell proliferation and effector function. Therapies directed at reconstituting Vgamma9Vdelta2 T-cell activity in HIV positive individuals should include stimulators of IL-18 or direct cytokine supplementation. PMID- 28342223 TI - Ritonavir and ixazomib kill bladder cancer cells by causing ubiquitinated protein accumulation. AB - There is no curative treatment for advanced bladder cancer. Causing ubiquitinated protein accumulation and endoplasmic reticulum stress is a novel approach to cancer treatment. The HIV protease inhibitor ritonavir has been reported to suppress heat shock protein 90 and increase the amount of unfolded proteins in the cell. If the proteasome functions normally, however, they are rapidly degraded. We postulated that the novel proteasome inhibitor ixazomib combined with ritonavir would kill bladder cancer cells effectively by inhibiting degradation of these unfolded proteins and thereby causing ubiquitinated proteins to accumulate. The combination of ritonavir and ixazomib induced drastic apoptosis and inhibited the growth of bladder cancer cells synergistically. The combination decreased the expression of cyclin D1 and cyclin-dependent kinase 4, and increased the sub-G1 fraction significantly. Mechanistically, the combination caused ubiquitinated protein accumulation and endoplasmic reticulum stress. The combination-induced apoptosis was markedly attenuated by the protein synthesis inhibitor cycloheximide, suggesting that the accumulation of ubiquitinated proteins played an important role in the combination's antineoplastic activity. Furthermore, the combination induced histone acetylation cooperatively and the decreased expression of histone deacetylases was thought to be one mechanism of this histone acetylation. The present study provides a theoretical basis for future development of novel ubiquitinated-protein-accumulation-based therapies effective against bladder cancer. PMID- 28342226 TI - Psychopathology and personality traits associated with driving while intoxicated in Beijing, China: Implications for interventions. AB - BACKGROUND AND OBJECTIVES: Driving while intoxicated (DWI) represents an area of grave concern in China, yet little research has focused on it or on the personality traits and psychiatric disorders among these drivers. METHODS: We enrolled 325 of 382 residents charged with DWI in a compulsory detention center in Beijing, China. And 351 male drivers who had never had any alcohol arrests as control participants. All were screened for Axis I disorders using the Chinese version of the Structured Clinical Interview for the Diagnostic Statistical Manual of Mental Disorders IV-TR (SCID), the Minnesota Multiphasic Personality Inventory (MMPI-2), and the Sixteen Personality Factor Questionnaire (16PF). RESULTS: The subjects were all males with a mean (+/-SD) age of 34.41 +/- 8.48 years, and almost 30% met DSM-IV criteria for alcohol abuse or dependence (n = 92). Compared to normal controls they showed greater Social Boldness, Abstractedness, Apprehension, Liveliness and Tension, and poorer Reasoning, Vigilance, Openness to Change, and Self-reliance. On the MMPI-2, DWI subjects showed greater Hypochondriasis, Psychopathic Deviate, Paranoia, Psychasthenia, Schizophrenia and Hypomania; and lower Social introversion. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Severe alcohol problems are more common in Beijing's drunk drivers than in the Chinese general population. These DWI drivers also have a broad variety of traits that increase their tendency to be venturesome and socially bold while enjoying excitement and risk-taking. (Am J Addict 2017;26:374 378). PMID- 28342227 TI - Treatment of adenoviral keratoconjunctivitis with a combination of povidone iodine 1.0% and dexamethasone 0.1% drops: a clinical prospective controlled randomized study. AB - PURPOSE: To determine the efficacy of combination povidone-iodine (PVP-I) 1.0% eyedrops and dexamethasone 0.1% eyedrops in the treatment of adenoviral keratoconjunctivitis. MATERIALS AND METHODS: In a prospective, randomized, controlled, double-blinded clinical trial patients with recent adenoviral keratoconjunctivitis (diagnosed clinically and confirmed by PCR), we randomly divided into three treatment groups: study group - received PVP-I 1.0% and dexamethasone 0.1%, control 1 group - received dexamethasone 0.1% and control 2 group - received lubricating eyedrops (hypromellose 0.3%). The treatment was administered four times a day in each group. All patients were examined and filled a questionnaire before treatment and on the 3rd, 5th and 7th days of treatment. RESULTS: We included in the study 78 eyes (26 in each group). Adenovirus type 8 was the most common pathogen (83% of cases). The fastest improvement in patients red eyes, discharge, superficial punctate keratitis and pseudomembranes was observed in the study group (p < 0.001). Those patients reached a near complete recovery in 5-7 days, which was also confirmed by reduction in Adenovirus titres by PCR. The slowest improvement was in the control 2 group. Subepithelial infiltrates (SEI) were observed in 44% of the control 1 group, 20% of the control 2 group and in 0% of the study group. The rate of reduction in Adenovirus titres was the slowest in the control 1 group. CONCLUSION: The combination of PVP-I 1.0% and dexamethasone 0.1% four times a day can reduce symptoms and expedite recovery in epidemic keratoconjunctivitis patients. PMID- 28342228 TI - Coevolutionary constraints in the sequence-space of macromolecular complexes reflect their self-assembly pathways. AB - Is the order in which biomolecular subunits self-assemble into functional macromolecular complexes imprinted in their sequence-space? Here, we demonstrate that the temporal order of macromolecular complex self-assembly can be efficiently captured using the landscape of residue-level coevolutionary constraints. This predictive power of coevolutionary constraints is irrespective of the structural, functional, and phylogenetic classification of the complex and of the stoichiometry and quaternary arrangement of the constituent monomers. Combining this result with a number of structural attributes estimated from the crystal structure data, we find indications that stronger coevolutionary constraints at interfaces formed early in the assembly hierarchy probably promotes coordinated fixation of mutations that leads to high-affinity binding with higher surface area, increased surface complementarity and elevated number of molecular contacts, compared to those that form late in the assembly. Proteins 2017; 85:1183-1189. (c) 2017 Wiley Periodicals, Inc. PMID- 28342230 TI - Self-Assembled Chiral Nanostructures as Scaffolds for Asymmetric Reactions. AB - The asymmetric reaction is one of the most important reactions in organic synthesis. While a large number of efficient molecular catalysts have been developed and applied, recently, supramolecular and nanostructured catalysts have been attracting interest. In this Minireview, we focus on self-assembled chiral nanostructures and review their possibility and feasibility as enantioselective catalysts. The design concept and the requirement of the chiral scaffold as the catalysts are discussed. Based on the chirality and catalytic performance of the building molecules and the supramolecular nanostructures, the nanocatalyst is divided into chiral nanostructure driven (CND) and chiral nanostructure enhanced (CNE) enantioselective catalysts. Then, several typical self-assembled chiral nanostructures such as nanocages, nanotubes, nanorods, micelles and vesicles are selected as the chiral scaffold and their catalytic behaviors for the asymmetric reactions were demonstrated. Finally, the future developments of the field are also discussed. PMID- 28342229 TI - Real-world experience with the all-oral, interferon-free regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir for the treatment of chronic hepatitis C virus infection in the German Hepatitis C Registry. AB - Real-world studies are relevant to complement clinical trials on novel antiviral therapies against chronic hepatitis C; however, clinical practice data are currently limited. This study investigated effectiveness and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r)+/-dasabuvir (DSV)+/-ribavirin (RBV) for treatment of HCV genotype (GT) 1 and GT4 infection in a large real-world cohort. The German Hepatitis C Registry is an observational cohort study prospectively collecting clinical practice data on direct-acting antiviral therapies. Patients with GT1/4 infection treated with OBV/PTV/r+/-DSV+/-RBV were analysed. Effectiveness was assessed by sustained virologic response in 558 patients who reached post-treatment week 12 (SVR12). Safety is reported in 1017 patients who initiated treatment. Of the patients, 892 (88%) had GT1 and 125 (12%) had GT4 infection. Prior treatment experience and cirrhosis were reported in 598 (59%) and 228 (22%) patients, respectively. Overall, SVR12 (mITT) was 96% (486/505) in GT1- and 100% (53/53) in GT4 patients. SVR12 rates were high across subgroups including patients with cirrhosis (95%, 123/129), patients with moderate to severe renal impairment (100%, 34/34), and subgroups excluded from registrational trials like patients >=70 years (96%, 64/67) and failures to prior protease inhibitor treatment (96%, 46/48). Adverse events (AEs) and serious AEs were reported in 52% (525/1017) and 2% (21/1017) of patients, respectively, and led to treatment discontinuation in 1.5% (15/1017) of patients. OBV/PTV/r+/-DSV+/ RBV was effective and generally well tolerated for treatment of HCV infection in clinical practice. PMID- 28342231 TI - Exploring the hypothesis of differential care for African immigrant and native women in France with hypertensive disorders during pregnancy: a qualitative study. AB - OBJECTIVE: To analyse whether prenatal care trajectories among women with hypertensive disorders during pregnancy in France differ between immigrants from sub-Saharan Africa (SSA) and native French women. DESIGN: Qualitative interview study. SETTING: Three public maternity units in the Paris region. POPULATION: Women born in SSA or in France of French parents and treated for hypertension or pre-eclampsia during their pregnancy. METHODS: A sociologist conducted semi structured in-depth interviews of 33 women during their postpartum hospitalisation and collected data from their medical files. n'vivo 10 (QSR International) was used for line-by-line coding of the transcriptions, to identify emerging themes. Strauss's concept of illness trajectories was then applied to these data. MAIN OUTCOME MEASURES: Themes derived from interviews. RESULTS: Women reported during the interviews that the blood pressure measurement procedures used by hospital staff varied between the two groups, and their medical records supported this finding. Repeated urinary dipstick testing of proteinuria before laboratory testing was more frequent for African women, as was the failure to further test proteinuria levels requiring additional action. The two groups received similar standardised care after severe complications. Other findings showed that African women were less likely to rely on healthcare services. CONCLUSIONS: These results suggest non-medically justified differential prenatal care between African and native women that may have helped delay the diagnosis of hypertension or pre-eclampsia. This study suggests hypotheses for further quantitative studies to explore the potential involvement of this differential care in the higher frequency of severe complications in this subgroup, concordantly reported in European countries hosting SSA migrants. TWEETABLE ABSTRACT: Differential prenatal care may delay diagnosis of pre eclampsia among African compared with native French women. PMID- 28342232 TI - Immune modulator-induced changes in the gastrointestinal tract. PMID- 28342233 TI - Extraneural findings during peripheral nerve ultrasound: Prevalence and further assessment. AB - INTRODUCTION: In this study we evaluated the frequency and further assessment of extraneural findings encountered during peripheral nerve ultrasound (US). METHODS: Our retrospective review identified 278 peripheral nerve US examinations of 229 patients performed between December 2014 and December 2015. Reports were reviewed to assess the number of studies without peripheral nerve abnormalities and the frequency and further assessment of extraneural findings. RESULTS: A total of 107 peripheral nerve US examinations of 90 patients (49 men and 41 women, mean age 55 +/- 16 years) did not report peripheral nerve abnormalities. Extraneural findings were observed in 24 of 107 (22.4%) studies. Fifteen of the 278 [5.4% (95% confidence interval 2.7%-8.1%)] studies led to a recommendation for additional imaging or clinical evaluation of an extraneural finding. DISCUSSION: At least 5.4% (15 of 278) of peripheral nerve US studies led to additional clinical or imaging assessment. Muscle Nerve 57: 65-69, 2018. PMID- 28342234 TI - Critical contribution of the interleukin-6/signal transducer and activator of transcription 3 axis to vasculopathy associated with systemic sclerosis. AB - Reflecting the critical role of interleukin (IL)-6 in systemic sclerosis (SSc), tocilizumab, an anti-IL-6 receptor antibody, is currently under a global phase III trial against skin sclerosis of this disease. We here demonstrate that the IL 6/signal transducer and activator of transcription 3 axis is broadly activated in various cell types in the lesional skin of SSc patients irrespective of disease subtypes, especially in endothelial cells. Importantly, 12 monthly infusions of tocilizumab improved nailfold capillary changes as well as skin sclerosis in a patient with diffuse cutaneous SSc. The present findings suggest a potential disease-modifying effect of tocilizumab on SSc vasculopathy. PMID- 28342235 TI - The inactivation of rfaP, rarA or sspA gene improves the viability of the Escherichia coli DNA polymerase III holD mutant. AB - The Escherichia coli holD mutant is poorly viable because the stability of holoenzyme polymerase III (Pol III HE) on DNA is compromised. Consequently, the SOS response is induced and the SOS polymerases DinB and Pol II further hinder replication. Mutations that restore the holD mutant viability belong to two classes, those that stabilize Pol III on DNA and those that prevent the deleterious effects of DinB over-production. We identified a dnaX mutation and the inactivation of rfaP and sspA genes as belonging to the first class of holD mutant suppressors. dnaX encodes a Pol III clamp loader subunit that interacts with HolD. rfaP encodes a lipopolysaccharide kinase that acts in outer membrane biogenesis. Its inactivation improves the holD mutant growth in part by affecting potassium import, previously proposed to stabilize Pol III HE on DNA by increasing electrostatic interactions. sspA encodes a global transcriptional regulator and growth of the holD mutant in its absence suggests that SspA controls genes that affect protein-DNA interactions. The inactivation of rarA belongs to the second class of suppressor mutations. rarA inactivation has a weak effect but is additive with other suppressor mutations. Our results suggest that RarA facilitates DinB binding to abandoned forks. PMID- 28342236 TI - Resolving protein structure-function-binding site relationships from a binding site similarity network perspective. AB - Functional annotation is seldom straightforward with complexities arising due to functional divergence in protein families or functional convergence between non homologous protein families, leading to mis-annotations. An enzyme may contain multiple domains and not all domains may be involved in a given function, adding to the complexity in function annotation. To address this, we use binding site information from bound cognate ligands and catalytic residues, since it can help in resolving fold-function relationships at a finer level and with higher confidence. A comprehensive database of 2,020 fold-function-binding site relationships has been systematically generated. A network-based approach is employed to capture the complexity in these relationships, from which different types of associations are deciphered, that identify versatile protein folds performing diverse functions, same function associated with multiple folds and one-to-one relationships. Binding site similarity networks integrated with fold, function, and ligand similarity information are generated to understand the depth of these relationships. Apart from the observed continuity in the functional site space, network properties of these revealed versatile families with topologically different or dissimilar binding sites and structural families that perform very similar functions. As a case study, subtle changes in the active site of a set of evolutionarily related superfamilies are studied using these networks. Tracing of such similarities in evolutionarily related proteins provide clues into the transition and evolution of protein functions. Insights from this study will be helpful in accurate and reliable functional annotations of uncharacterized proteins, poly-pharmacology, and designing enzymes with new functional capabilities. Proteins 2017; 85:1319-1335. (c) 2017 Wiley Periodicals, Inc. PMID- 28342237 TI - An ecosystem services approach to the ecological effects of salvage logging: valuation of seed dispersal. AB - Forest disturbances diminish ecosystem services and boost disservices. Because post-disturbance management intends to recover the greatest possible value, selling timber often prevails over other considerations. Ecological research has shown diverse effects of salvage logging, yet such research has focused on the biophysical component of post-disturbance ecosystems and lacks the link with human well-being. Here we bridge that gap under the ecosystem services framework by assessing the impact of post-fire management on a non-timber value. By employing the replacement cost method, we calculated the value of the post-fire natural regeneration of Holm oaks in southern Spain under three post-fire management options by considering the cost of planting instead. The value of this ecosystem service in non-intervention areas doubled that of salvage-logged stands due to the preference for standing dead trees by the main seed disperser. Still, most of the value resulted from the resprouting capacity of oaks. The value of this and other ecosystem services should be added to traditional cost/benefit analyses of post-disturbance management. We thus call for a more holistic approach to salvage logging research, one that explicitly links ecological processes with human well-being through ecosystem services, to better inform decision-makers on the outcomes of post-disturbance management. PMID- 28342238 TI - A peel-off facial mask comprising myoinositol and trehalose-loaded liposomes improves adult female acne by reducing local hyperandrogenism and activating autophagy. AB - BACKGROUND: Hyperandrogenism and reduced skin autophagy have been implicated in the pathogenesis of adult female acne (AFA). Here, we tested whether a ready-to use peel-off facial mask containing myoinositol (an androgen inhibitor) and trehalose-loaded liposomes (as activators of cutaneous autophagy) applied overnight every other day for 60 days can improve AFA. We also sought to investigate the molecular mechanisms underlying the clinical effects. OBJECTIVES: We conducted an uncontrolled, open-label clinical study in 40 cases of AFA to investigate the effect of the facial mask on lesion count, sebum production (measured with the Sebutape(r) technique), and Global Acne Grading System (GAGS) scale. We also investigated the changes from baseline to the end of treatment in androgen and beclin-1 levels (as a marker of authophagy) in skin biopsy supernatants. METHODS: Forty Caucasian patients with AFA were enrolled. Changes in clinical and molecular endpoints before and after treatment were investigated. RESULTS: The mean counts of comedones, papules, pustules, and nodular lesions decreased significantly (all P<.001). The mean Sebutape(r) score was reduced from 3.4+/-0.6 to 1.8+/-0.2 (P<.001), whereas the mean GAGS scale score decreased from 16.8+/-5.3 at baseline to 9.8+/-4.6 after treatment (P<.001). A significant decrease in testosterone and dehydroepiandrosterone sulfate in skin biopsy supernatants was observed, whereas beclin-1 levels increased significantly (P<.001). CONCLUSION: A ready-to-use peel-off facial mask containing myoinositol and trehalose-loaded liposomes improved the cosmetic appearance of AFA by reducing cutaneous androgen content and promoting skin autophagy. PMID- 28342239 TI - Cultural Differences in Visual Search for Geometric Figures. AB - While some studies suggest cultural differences in visual processing, others do not, possibly because the complexity of their tasks draws upon high-level factors that could obscure such effects. To control for this, we examined cultural differences in visual search for geometric figures, a relatively simple task for which the underlying mechanisms are reasonably well known. We replicated earlier results showing that North Americans had a reliable search asymmetry for line length: Search for long among short lines was faster than vice versa. In contrast, Japanese participants showed no asymmetry. This difference did not appear to be affected by stimulus density. Other kinds of stimuli resulted in other patterns of asymmetry differences, suggesting that these are not due to factors such as analytic/holistic processing but are based instead on the target detection process. In particular, our results indicate that at least some cultural differences reflect different ways of processing early-level features, possibly in response to environmental factors. PMID- 28342240 TI - Combination of growth pattern and tumor regression identifies a high-risk group in neoadjuvant treated rectal cancer patients. AB - OBJECTIVE: To analyze the prognostic effect of E-cadherin expression, the growth pattern of the tumor and the regression grade in a rectal cancer cohort treated with neoadjuvant radiochemotherapy (RCT). METHODS: A total of 223 patients with rectal cancer treated with neoadjuvant RCT followed by surgery were included. Altogether 88 biopsies prior to RCT and 213 tumor resections in an average of 55 days post-RCT were investigated. Protein expression of E-cadherin and tumor growth pattern (solid glandular vs single-cell pattern) was assessed by staining tissue microarrays. The regression grade at the invasion front was determined according to the Dworak scale. RESULTS: There was a significant decrease of E cadherin expression (P = 0.002) and a significant increased single-cell growth (P < 0.001) at the invasion front in tumor samples after RCT compared with primary biopsies of the tumor. A low E-cadherin expression in the biopsy was related to a longer metastasis-free survival (P = 0.033) and tumor-specific survival (P = 0.030). Post-RCT single-cell growth at the tumor invasion front was a prognostic factor for longer tumor-specific survival (P = 0.021). A combination of growth pattern and the Dworak regression grade was an independent prognostic parameter for tumor-specific survival (P = 0.015). CONCLUSIONS: Loss of E-cadherin protein expression in the pretreatment biopsy of rectal cancer is associated with fewer metastases and improved survival. Furthermore, the growth pattern in the post-RCT resection specimen has a prognostic value for survival. A combination of growth pattern and tumor regression score (the RegPat score) showed the highest discriminatory power to identify high-risk patients. PMID- 28342241 TI - Overt and occult hepatitis B virus infection among community children in Northwest China. AB - Although a universal newborn hepatitis B (HB) immunization programme has been implemented in China, hepatitis B virus (HBV) breakthrough infection, including HB surface antigen (HBsAg)-positive infection and occult HBV infection (OBI), still occurs during infancy or childhood. Obtaining the actual prevalence of HBV infection in general children is important for preventing and controlling the spread of HB. Accordingly, we investigated the prevalence of overt infection and OBI in community children and compared the serological and virological characteristics of OBI and HBsAg carrier children to clarify the mechanisms related to OBI. In total, 6 706 community children <12 years of age were included from a population-based HBV seroepidemiological investigation in Northwest China. The HBsAg carrier rate in community children was 1.60% (107/6706), and the anti HBs positive rate was 57.35% (3846/6706). Additionally, 1192 HBsAg-negative children were examined for OBI using nested PCR. The prevalence of OBI in local children was 1.26% (15/1192), and the predominant OBI genotypes were C and D. The 15 OBI children and 29 HBsAg-positive children from the same population did not have a statistical significant difference in age, gender, alanine aminotransferase (ALT), proportion of anti-HBs or anti-HBc, viral genotypes or mutations. Children with chronic overt infection had higher viral loads than OBI children (P=.004). These results suggested that HBV overt and occult infection of children was more serious in underdeveloped north-west regions. HBV neonatal immunization and catch-up programmes should be strengthened and supplemented. None of specific viral mutations or genotypes related to OBI were found. OBI may be a specific stage of HBV infection. PMID- 28342242 TI - A systematic analysis of scoring functions in rigid-body protein docking: The delicate balance between the predictive rate improvement and the risk of overtraining. AB - Protein-protein interactions play fundamental roles in biological processes including signaling, metabolism, and trafficking. While the structure of a protein complex reveals crucial details about the interaction, it is often difficult to acquire this information experimentally. As the number of interactions discovered increases faster than they can be characterized, protein protein docking calculations may be able to reduce this disparity by providing models of the interacting proteins. Rigid-body docking is a widely used docking approach, and is often capable of generating a pool of models within which a near native structure can be found. These models need to be scored in order to select the acceptable ones from the set of poses. Recently, more than 100 scoring functions from the CCharPPI server were evaluated for this task using decoy structures generated with SwarmDock. Here, we extend this analysis to identify the predictive success rates of the scoring functions on decoys from three rigid body docking programs, ZDOCK, FTDock, and SDOCK, allowing us to assess the transferability of the functions. We also apply set-theoretic measure to test whether the scoring functions are capable of identifying near-native poses within different subsets of the benchmark. This information can provide guides for the use of the most efficient scoring function for each docking method, as well as instruct future scoring functions development efforts. Proteins 2017; 85:1287 1297. (c) 2017 Wiley Periodicals, Inc. PMID- 28342243 TI - COPD: Lessons learned, forging a fantastic future. PMID- 28342244 TI - The utility of pap cell block preparations with liqui-PREPTM cell pellets to clarify the cytological diagnosis of atypical squamous cells of undetermined significance and atypical glandular cells. AB - OBJECTIVE: Atypical squamous cells of undetermined significance (ASCUS) and atypical glandular cells (AGC) reflect cellular abnormalities insufficient for clear diagnosis. We used cell pellets obtained from liquid-based cytology (LBC) to prepare cell blocks (CB) and clarify the initial diagnosis of ASCUS and AGC. STUDY DESIGN: A total of 393 CBs with initial diagnosis of ASCUS or AGC were processed. Of those, 305 of the ASCUS and 20 of the AGC had adequate specimens. We compared results of CBs prepared from ASCUS and AGC to determine which had higher frequencies of higher-grade lesions. RESULTS: A majority of specimens (83%) were adequate for evaluation. Compared with the initial diagnosis, 14% (42/305) of ASCUS were diagnosed with low-grade squamous intraepithelial lesion (LSIL) in CB, while 10% (2/20) of AGC were diagnosed with LSIL or adenocarcinoma. No statistical relationship between the initial diagnosis of ASCUS and AGC and results of higher-grade lesions in CB is evident as determined by p value greater than 0.05 (p = 0.228). CONCLUSIONS: CBs prepared from Liqui-PREP cell pellets are, in most cases, assessable and can be useful as an adjunctive test to help clarify the initial diagnosis of ASCUS and AGC. Diagn. Cytopathol. 2017;45:520 525. (c) 2017 Wiley Periodicals, Inc. PMID- 28342245 TI - Cutaneous spindle cell adenolipoma on the nose: A rare variant of lipoma. PMID- 28342246 TI - Hypohidrosis and metal allergy: Trigger factors for unilateral lichen planus. AB - Unilateral lichen planus (LP) is a rare clinical variant of LP. The etiology of unilateral LP has not been clarified, although various causes have been reported because of the characteristic distribution. We focused on the contribution of metal allergy and sweating in the development of unilateral LP in this case. To confirm the presence of metal allergy, patch tests with metal allergens were performed. To investigate the cause of the unilateral distribution in unilateral LP, the function of sweating and sweat leaking in the dermis was assessed by a thermoregulatory sweat test and immunohistochemical staining of dermcidin. The patch tests with SnCl2 , H2 PtCl6 , ZnCl2 and MnCl2 were positive. The thermoregulatory sweat test using the starch-iodine method (Minor test) with sweating provoked by heat stimulation revealed hypohidrosis of the affected area, whereas no skin lesions were observed on the dorsal hand and wrist where sweating was normal. Histopathological examination showed keratin plugging of the acrosyringium and lymphocytic infiltrations in the papillary and subpapillary dermis around the intraepidermal and intradermal eccrine duct in the affected area. The immunohistochemical staining of dermcidin confirmed sweat leakage in the subpapillary dermis in the affected area. The symptoms refractory to the topical steroids were markedly improved after removal of the dental metals. The coexistence of metal allergy and sweat leakage in the hypohidrotic area may be involved in the development of unilateral LP. PMID- 28342247 TI - Closing the gap. PMID- 28342248 TI - Therapeutic Intervention for Pulmonary Embolism: Show me the data! PMID- 28342249 TI - "Cognitive" radial access. PMID- 28342251 TI - Radiation attenuating hand cream: Better than bare. PMID- 28342250 TI - Does the removal of the temporary pacer wire for BAV and TAVR really simplify the procedure? PMID- 28342253 TI - Ipsilateral vs. contralateral vs. no collateral (antegrade only) chronic total occlusion percutaneous coronary interventions: What is the right choice for your practice? PMID- 28342252 TI - The arm has it: Adventures in right heart and radial approaches. PMID- 28342254 TI - Women and men, the same and different. PMID- 28342255 TI - Low rate fluoroscopy in cardiac catheterization: Toward a new standard? PMID- 28342256 TI - Patent ductus arteriosus and pulmonary arterial hypertension: Is it closer to closure? PMID- 28342257 TI - Transcatheter aortic valve replacement by a minimalist approach: A breath of fresh air for patients with chronic obstructive pulmonary disease. PMID- 28342258 TI - Non-cardiac surgery after PCI: Watch out for complex lesions. PMID- 28342260 TI - Neural decoding of visual stimuli varies with fluctuations in global network efficiency. AB - Functional magnetic resonance imaging (fMRI) studies have shown that neural activity fluctuates spontaneously between different states of global synchronization over a timescale of several seconds. Such fluctuations generate transient states of high and low correlation across distributed cortical areas. It has been hypothesized that such fluctuations in global efficiency might alter patterns of activity in local neuronal populations elicited by changes in incoming sensory stimuli. To test this prediction, we used a linear decoder to discriminate patterns of neural activity elicited by face and motion stimuli presented periodically while participants underwent time-resolved fMRI. As predicted, decoding was reliably higher during states of high global efficiency than during states of low efficiency, and this difference was evident across both visual and nonvisual cortical regions. The results indicate that slow fluctuations in global network efficiency are associated with variations in the pattern of activity across widespread cortical regions responsible for representing distinct categories of visual stimulus. More broadly, the findings highlight the importance of understanding the impact of global fluctuations in functional connectivity on specialized, stimulus driven neural processes. Hum Brain Mapp 38:3069-3080, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28342261 TI - Diagnostic performance of confocal laser endomicroscopy for atrophy and gastric intestinal metaplasia: A meta-analysis. AB - OBJECTIVE: To systematically evaluate the diagnostic efficacy of confocal laser endomicroscopy (CLE) for gastric atrophy (GA) and gastric intestinal metaplasia (GIM). METHODS: Literature search was performed in PubMed and the Cochrane Library for CLE, GA and GIM. The sensitivity, specificity and diagnostic odds ratio (DOR) in diagnosing GA and GIM were pooled for analysis. A summary receiver operating curve (SROC) was documented and the area under the curve was calculated. RESULTS: Of the 10 studies included in this current analysis, the pooled sensitivity, specificity and DOR of CLE to diagnose GA and GIM were found to be 88%, 98% and 330.85, and 93%, 98% and 439.97, respectively. The area under the SROC were 0.9491 and 0.9812 for the diagnosis of GA and GIM, respectively. Higher sensitivity and specificity of this technique in diagnosing GA and GIM were found in patients without representative disease spectrum and those received pCLE by subgroup analysis. CONCLUSION: CLE is of great value and may be considered an alternative modality for the early diagnosis of GA and GIM. PMID- 28342262 TI - Migration time shift of analytes in micellar electrokinetic chromatography induced by stacking. AB - A significant shift of migration time of nonretained compounds (ascorbic acid and cysteine) in micellar electrokinetic chromatography was observed under variation of sample matrix composition. The shift was affected by borate buffer concentration in sample matrix, sample injection time, and pH of BGE (80 mM SDS, Tris/HCl). Surprisingly, longer migration time of analyte was recorded at higher pH of separation buffer. These observations were linked to transient isotachophoresis process. Computer simulation with Simul5 software was conducted to support this hypothesis. The manuscript documents rarely reported in the literature phenomenon of isotachophoresis in micellar electrokinetic chromatography. The analytical potential of described observations was also discussed. PMID- 28342259 TI - Rodent age-related impairments in discriminating perceptually similar objects parallel those observed in humans. AB - The ability to accurately remember distinct episodes is supported by high-level sensory discrimination. Performance on mnemonic similarity tasks, which test high level discrimination, declines with advancing age in humans and these deficits have been linked to altered activity in hippocampal CA3 and dentate gyrus. Lesion studies in animal models, however, point to the perirhinal cortex as a brain region critical for sensory discriminations that serve memory. Reconciliation of the contributions of different regions within the cortical-hippocampal circuit requires the development of a discrimination paradigm comparable to the human mnemonic similarity task that can be used in rodents. In the present experiments, young and aged rats were cross-characterized on a spatial water maze task and two variants of an object discrimination task: one in which rats incrementally learned which object of a pair was rewarded and different pairs varied in their similarity (Experiment 1), and a second in which rats were tested on their ability to discriminate a learned target object from multiple lure objects with an increasing degree of feature overlap (Experiment 2). In Experiment 1, aged rats required more training than young to correctly discriminate between similar objects. Comparably, in Experiment 2, aged rats were impaired in discriminating a target object from lures when the pair shared more features. Discrimination deficits across experiments were correlated within individual aged rats, though, for the cohort tested, aged rats were not impaired overall in spatial learning and memory. This could suggest discrimination deficits emerging with age precede declines in spatial or episodic memory, an observation that has been made in humans. Findings of robust impairments in object discrimination abilities in the aged rats parallel results from human studies, supporting use of the developed tasks for mechanistic investigation of cortical-hippocampal circuit dysfunction in aging and disease. PMID- 28342264 TI - PDGFRA mRNA is overexpressed in oral cancer patients as compared to normal subjects with a significant trend of overexpression among tobacco users. AB - BACKGROUND: Platelet-derived growth factors alpha (PDGFA) is a tyrosine kinase receptor activator which is known to be amplified in the malignancies, and their expression levels are correlated to tumor progression and reduced overall survival. The expression of PDGFRA is different among the tumors and normal tissues; furthermore, their expression level is site specific. Under a physiological condition, PDGFRA and its ligand are expressed in distinct cell populations and activated in a paracrine manner. Nevertheless, heterodimer characteristic of PDGFRA allows it to be trans-activated by non-specific ligands or via autocrine manner. The future of cancer therapy can be based on PDGFRA receptor blockade and therefore warrants further investigation to determine the differing expression of PDGFRA between controls and patients with oral squamous cell carcinoma (OSCC). METHODS: We performed a case-control study of 111 patients with newly diagnosed tongue squamous cell carcinoma and 111 control subjects without a cancer diagnosis, matched for age and gender, to evaluate the association between PDGFRA expression levels in oral mucosa. We then performed smoking stratification in each cohort. Independent t test analysis was applied for case-control comparisons. RESULTS: Mean value of PDGFRA mRNA level (-DeltaCt) for normal cohort is -30.242, whereas mean value of PDGFRA mRNA level for patients with OSCC is -11.516. PDGFRA mRNA level (-DeltaCt) was significantly higher in oral cancer cohort, P<.001. Smokers have a significantly higher PDGFRA mRNA expression in comparison with non-smokers (P=.002) among the non-cancer group. Likewise, this trend is observed in cancer cohort too, P=.044. CONCLUSION: PDGFRA expression is significantly higher in oral cancer cohort with or without the establishment of tobacco risk factor. PMID- 28342263 TI - Surgical pitfalls of jejunal vein anatomy in pancreaticoduodenectomy. AB - BACKGROUND: Pancreaticoduodenectomy (PD) is the standard surgical procedure for treating pancreatic head cancers. Considerable knowledge of proximal jejunal and pancreatic vein anatomy is a prerequisite for performing PD surgery safely, yet there appear to be no detailed descriptions of first and second jejunal vein (J1V, J2V) anatomy available in the literature. STUDY DESIGN: Adults with hepatobiliary-pancreatic disease underwent multidetector-row computed tomography with intravenous contrast (n = 155), and SYNAPSE 3D (Fujifilm Medical, Tokyo, Japan) was used to generate 3D-CT images. RESULTS: In 84% of patients, J1V and J2V formed a common trunk (FJT). There were three patterns of branches, related to the presence or absence of FJT formation and the anatomical relationships between the superior mesenteric artery (SMA) and the jejunal veins, as follows: Type 1 (n = 98, 63%) characterized by an FJT located dorsal to SMA; Type 2 (n = 32, 21%), where the FJT was located ventral to the SMA; and Type 3 (n = 25, 16%), where J1V and J2V each drained separately into the SMV. CONCLUSIONS: J1V and J2V usually formed an FJT, and separate J1V and J2V drainage into the SMV was uncommon. Preoperative information on individual patient venous anatomy would increase the safety of the PD procedure. PMID- 28342265 TI - Efficacy and safety of edoxaban for treatment of portal vein thrombosis following danaparoid sodium in patients with liver cirrhosis. AB - AIM: To compare the efficacy and safety of edoxaban and warfarin for treatment of portal vein thrombosis (PVT) following danaparoid sodium in patients with liver cirrhosis. METHODS: Fifty cirrhotic patients with PVT treated initially for 2 weeks with danaparoid sodium were enrolled in this retrospective cohort study. Treatment was later switched to either edoxaban (n = 20) or warfarin (n = 30). We compared the efficacy and safety of edoxaban and warfarin for up to 6 months. The PVT volume was measured by dynamic computed tomography before treatment, at 2 weeks, and at 1, 3, and 6 months. RESULTS: There were no significant differences in the clinical characteristics of patients in the two groups. Treatment with edoxaban reduced the volume of PVT from 1.42 cm3 at 2 weeks to 0.42 cm3 at 6 months, and prevented exacerbation of PVT at 6 months after treatment with danaparoid sodium (P = 0.016). In contrast, treatment with warfarin resulted in increased PVT volume from 1.73 cm3 at 2 weeks to 2.85 cm3 at 6 months, despite the control of the international normalized ratio in 57% of the patients (P = 0.005). Multivariate regression analysis identified edoxaban therapy as the single significant and independent determinant of PVT reduction at 6 months (P = 0.0014, hazard ratio 6.400). Clinically significant gastrointestinal bleeding was encountered in 3 of 20 (15%) patients of the edoxaban group and 2 of 30 (7%) of the warfarin group (P = 0.335). CONCLUSION: Edoxaban following danaparoid sodium is an effective anticoagulant and could be potentially considered as one of the treatment options for PVT in cirrhotic patients. PMID- 28342266 TI - Increased number of mast cells in the dermis in actinic keratosis lesions effectively treated with imiquimod. AB - Actinic keratosis (AK) is a cutaneous cancer in situ which develops as a result of excessive exposure to ultraviolet (UV). Toll-like receptor (TLR)7 agonist imiquimod is a topical immune response modifier and is effective for the treatment of non-melanoma skin cancers. Recently, the diagnostic role of the dermatoscope has been reported in the course of treatment of AK. In addition, mast cells are now considered to contribute to both the innate and adaptive immune systems in topical imiquimod therapy. We assessed the effect of imiquimod treatment by dermatoscopic and immunohistochemical findings in 14 patients with a total of 21 AK lesions. With the dermatoscope, though the mean erythema score was not significantly different between the cured lesions and the unresponsive lesions, the erythema/red pseudo-network ("strawberry") pattern was decreased significantly in the cured lesions. By immunohistochemistry, the number of Ki-67 positive proliferative cells in the epidermis was decreased and that of CD117 positive mast cells in the dermis was increased in the responding lesions. To the best of our knowledge, this is the first study demonstrating that the number of mast cells in the dermis was increased in AK lesions effectively treated with imiquimod. Our present result suggests that mast cells may contribute an antitumor effect in human skin treated with topical imiquimod. PMID- 28342267 TI - The chaperone toolbox at the single-molecule level: From clamping to confining. AB - Protein folding is well known to be supervised by a dedicated class of proteins called chaperones. However, the core mode of action of these molecular machines has remained elusive due to several reasons including the promiscuous nature of the interactions between chaperones and their many clients, as well as the dynamics and heterogeneity of chaperone conformations and the folding process itself. While troublesome for traditional bulk techniques, these properties make an excellent case for the use of single-molecule approaches. In this review, we will discuss how force spectroscopy, fluorescence microscopy, FCS, and FRET methods are starting to zoom in on this intriguing and diverse molecular toolbox that is of direct importance for protein quality control in cells, as well as numerous degenerative conditions that depend on it. PMID- 28342269 TI - Acral lentiginous melanoma versus other melanoma: A single-center analysis in Japan. AB - We summarize herein our 14-year experience of conventional treatment outcomes before the era of molecular-targeted therapy and immunotherapy. Specifically, we conducted a retrospective review of our 252 patients with primary cutaneous melanoma (acral lentiginous melanoma [ALM], n = 121; non-acral lentiginous melanoma [non-ALM], n = 131), and compared the prognostic factors between ALM and non-ALM. Melanoma-specific survival and disease-free survival were estimated using the Kaplan-Meier method. Regarding the results, all patients were Japanese (106 male and 146 female), with a mean age of 60.1 years. Among ALM patients, age was elder and primary tumor size was larger than non-ALM. As for tumor thickness, in situ lesions were more frequently observed in ALM. There was no significant difference in the distribution of tumor thickness between the two groups when excluding the in situ lesions. For treatment of the primary melanoma, 248 patients (98.4%) had undergone curative surgical excision and 120 patients with more than 1 mm or ulcerated melanoma had undergone sentinel lymph node biopsy. Patients with systemic metastasis primarily underwent dacarbazine-based chemotherapy. The Kaplan-Meier survival curves revealed no significant difference in melanoma-specific survival and disease-free survival between those with ALM and non-ALM. The results also showed that both ALM and non-ALM, when they initially metastasize, first affect the regional lymph nodes. Incisional biopsy was not an adverse prognostic factor. These results suggest that ALM does not differ in its biological behavior from non-ALM, so we can consider ALM as being equivalent to non-ALM. The initial treatment for ALM and non-ALM can involve the same strategy. PMID- 28342268 TI - The susceptible HLA class II alleles and their presenting epitope(s) in Goodpasture's disease. AB - Goodpasture's disease is closely associated with HLA, particularly DRB1*1501. Other susceptible or protective HLA alleles are not clearly elucidated. The presentation models of epitopes by susceptible HLA alleles are also unclear. We genotyped 140 Chinese patients and 599 controls for four-digit HLA II genes, and extracted the encoding sequences from the IMGT/HLA database. T-cell epitopes of alpha3(IV)NC1 were predicted and the structures of DR molecule-peptide-T-cell receptor were constructed. We confirmed DRB1*1501 (OR = 4.6, P = 5.7 * 10-28 ) to be a risk allele for Goodpasture's disease. Arginine at position 13 (ARG13) (OR = 4.0, P = 1.0 * 10-17 ) and proline at position 11 (PRO11) (OR = 4.0, P = 2.0 * 10 17 ) on DRbeta1, encoded by DRB1*1501, were associated with disease susceptibility. alpha134-148 (HGWISLWKGFSFIMF) was predicted as a T-cell epitope presented by DRB1*1501. Isoleucine137 , tryptophan140 , glycine142 , phenylalanine143 and phenylalanine145 , were presented in peptide-binding pockets 1, 4, 6, 7 and 9 of DR2b, respectively. ARG13 in pocket 4 interacts with tryptophan140 and forms a hydrogen bond. In conclusion, we propose a mechanism for DRB1*1501 susceptibility for Goodpasture's disease through encoding ARG13 and PRO11 on MHC-DRbeta1 chain and presenting T-cell epitope, alpha134-148 , with five critical residues. PMID- 28342270 TI - Marital adjustment in the context of female breast cancer: A systematic review. AB - OBJECTIVE: Breast cancer (BC) diagnosis and subsequent treatments present significant challenges and distress for both patients and their partners. This can lead to difficulties in marital relationships and, consequently, decreases in marital adjustment and psychosocial adaptation to BC for both partners. Our objective was to systematically review studies assessing marital adjustment in the context of female BC to understand which factors are associated with marital adjustment in both patients and partners and characterize the measures used to assess marital adjustment within these studies. METHODS: This systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. English, peer-reviewed articles exploring factors associated with marital adjustment in the context of female BC were considered for inclusion. RESULTS: Fourteen studies were included. Results evidenced that psychosocial variables play an important role on marital adjustment. Specifically, open and constructive communication, more social support, and supportive dyadic coping were found to be associated with higher levels of marital adjustment. Other variables such as self-efficacy, sexual functioning, and psychological adjustment were also positively associated with marital adjustment. CONCLUSIONS: Most studies evidenced an association between psychosocial variables and marital adjustment for both women and their partners. Some important dimensions such as communication patterns, coping strategies, and social support dynamics were identified as potential targets for psychological interventions. Some variables, however, were explored only in a few studies, which limit our conclusions. Future studies should explore the role these variables and other relational and emotional variables play in promoting marital adjustment after BC. PMID- 28342271 TI - More bark than bite: Comparative studies are needed to determine the importance of canine zoonoses in Aboriginal communities. A critical review of published research. AB - The objective of this review was to identify and critique over forty years of peer-reviewed literature concerned with the transmission of canine zoonoses to Aboriginal people and determine the zoonotic organisms documented in dogs in Australian Aboriginal communities. A systematic literature search of public health, medical and veterinary databases identified 19 articles suitable for critical appraisal. Thirteen articles documented the occurrence of recognized zoonotic organisms in dogs in Aboriginal communities, including Toxocara canis, Dirofilaria immitis, Streptococcus dysgalactiae, Rickettsia felis, Sarcoptes scabiei and Giardia. Currently, there is definitive evidence indicating that dogs act as a reservoir for human scabies in Aboriginal communities. However, there is a need for large-scale, high-quality, comparative studies of dogs and humans from the same household to assess the occurrence and importance of transmission of S. scabiei and other diseases between dogs and humans. These studies should use current genetic and molecular techniques along with traditional techniques to identify and type organisms in order to better understand their epidemiology. This review has revealed that there is a lack of high-quality comparative studies to determine whether dogs are contributing to human disease by transmitting zoonoses. Our recommendations differ significantly from current public health policy and may have substantial implications for human and dog health. PMID- 28342272 TI - MACRA May or May Not: The Information Bare Necessities for Clinicians. PMID- 28342273 TI - Characteristics of compatible pair participants in kidney paired donation at a single center. AB - Compatible pairs of living kidney donors and their intended recipients can enter into kidney paired donation (KPD) and facilitate additional living donor kidney transplants (LDKTs). We examined 11 compatible pairs (the intended recipients and their intended, compatible donors) who participated in KPD, along with the recipients' 11 matched, exchange donors. The 11 pairs participated in 10 separate exchanges (three were multicenter exchanges) that included 33 total LDKTs (22 additional LDKTs). All the intended donors were blood group O and female, with a mean living kidney donor profile index (LKDPI) of 27.6 (SD 16.8). The matched donors had a mean LKDPI of 9.4 (SD 31.7). Compatible pairs entered KPD for altruistic reasons (N=2) or due to mismatch of age (N=7) or body/kidney size (N=2) between the recipient and intended donor. In four cases, retrospective calculation of the LKDPI revealed that the matched donor had a higher LKDPI than the intended donor. Of the 22 recipients of LDKTs enabled by the compatible pairs, three were highly sensitized, with PRA >80%. In conclusion, most compatible pairs entered into KPD so that the recipient could receive a LDKT transplant from a donor whose age or body/kidney size were more favorable to post transplant outcomes. PMID- 28342275 TI - Use of liquid chromatography hybrid triple-quadrupole mass spectrometry for the detection of emodin metabolites in rat bile and urine. AB - Emodin is the representative form of rhubarb, which is widely used in traditional Chinese medicine for the treatment of purgative, anti-inflammatory, antioxidative and antiviral, etc. Previous reports demonstrated that emodin glucuronide was the major metabolite in plasma. Owing to the extensive conjugation reactions of polyphenols, the aim of this study was to identify the metabolites of emodin in rat bile and urine. Neutral loss and precursor ion scan methods of triple quadrupole mass spectrometer revealed 13 conjugated metabolites in rat bile and 22 metabolites in rat urine, which included four phase I and 18 phase II metabolites. The major metabolites in rat biosamples were emodin glucuronoconjugates. Moreover, rhein monoglucuronide, chrysophanol monoglucuronide and rhein sulfate were proposed for the first time after oral administration of emodin. Overall, liquid chromatography hybrid triple-quadrupole mass spectrometry analysis leads to the discovery of several novel emodin metabolites in rat bile and urine and underscores that conjugated with glucuronic acid is the main metabolic pathway. PMID- 28342274 TI - A feasibility study for enrichment of highly aggressive cancer subpopulations by their biophysical properties via dielectrophoresis enhanced with synergistic fluid flow. AB - A common problem with cancer treatment is the development of treatment resistance and tumor recurrence that result from treatments that kill most tumor cells yet leave behind aggressive cells to repopulate. Presented here is a microfluidic device that can be used to isolate tumor subpopulations to optimize treatment selection. Dielectrophoresis (DEP) is a phenomenon where particles are polarized by an electric field and move along the electric field gradient. Different cell subpopulations have different DEP responses depending on their bioelectrical phenotype, which, we hypothesize, correlate with aggressiveness. We have designed a microfluidic device in which a region containing posts locally distorts the electric field created by an AC voltage and forces cells toward the posts through DEP. This force is balanced with a simultaneous drag force from fluid motion that pulls cells away from the posts. We have shown that by adjusting the drag force, cells with aggressive phenotypes are influenced more by the DEP force and trap on posts while others flow through the chip unaffected. Utilizing single-cell trapping via cell-sized posts coupled with a drag-DEP force balance, we show that separation of similar cell subpopulations may be achieved, a result that was previously impossible with DEP alone. Separated subpopulations maintain high viability downstream, and remain in a native state, without fluorescent labeling. These cells can then be cultured to help select a therapy that kills aggressive subpopulations equally or better than the bulk of the tumor, mitigating resistance and recurrence. PMID- 28342276 TI - Primary cutaneous anaplastic large cell lymphoma. AB - Primary cutaneous anaplastic large cell lymphoma (PC-ALCL) is a CD30+ lymphoproliferative disorder (LPD) of the skin with a relatively good prognosis in the absence of high-stage disease. CD30+ LPDs comprise approximately 25%-30% of primary cutaneous lymphomas and as a group represent the second most common clonal T-cell neoplasm of the skin behind mycosis fungoides. Diagnosis of PC-ALCL relies strongly on clinicopathologic correlation given the potential morphologic, clinical and molecular overlap with the other cutaneous CD30+ LPD, lymphomatoid papulosis, and more aggressive hematolymphoid neoplasms. PMID- 28342277 TI - Climatic variation modulates the indirect effects of large herbivores on small mammal habitat use. AB - Large mammalian herbivores (LMH) strongly shape the composition and architecture of plant communities. A growing literature shows that negative direct effects of LMH on vegetation frequently propagate to suppress the abundance of smaller consumers. Indirect effects of LMH on the behaviour of these consumers, however, have received comparatively little attention despite their potential ecological significance. We sought to understand (i) how LMH indirectly shape small-mammal habitat use by altering the density and distribution of understorey plants; (ii) how these effects vary with climatic context (here, seasonality in rainfall); and (iii) the extent to which behavioural responses of small mammals are contingent upon small-mammal density. We tested the effects of a diverse LMH community on small-mammal habitat use using 4 years of spatially explicit small-mammal trapping and vegetation data from the UHURU Experiment, a replicated set of LMH exclosures in semi-arid Kenyan savanna. Small-mammal habitat use was positively associated with tree density and negatively associated with bare (unvegetated) patches in all plots and seasons. In the presence of LMH, and especially during the dry season, small mammals consistently selected tree cover and avoided bare patches. In contrast, when LMH were excluded, small mammals were weakly associated with tree cover and did not avoid bare patches as strongly. These behavioural responses of small mammals were largely unaffected by changes in small-mammal density associated with LMH exclusion. Our results show that LMH indirectly affect small-mammal behaviour, and that these effects are influenced by climate and can arise via density-independent mechanisms. This raises the possibility that anthropogenic LMH declines might interact with changing patterns of rainfall to alter small-mammal distribution and behaviour, independent of numerical responses by small mammals to these perturbations. For example, increased rainfall in East Africa (as predicted in many recent climate-model simulations) may relax constraints on small-mammal distribution where LMH are rare or absent, whereas increased aridity and/or drought frequency may tighten them. PMID- 28342278 TI - Simultaneous pancreas and kidney transplantation: Incidence and risk factors for amputation after 10-year follow-up. AB - INTRODUCTION: The incidence of amputation after simultaneous pancreas and kidney (SPK) transplantation ranges from 9.5% to 23% after 5 years of follow-up. The objective of this study was to investigate the incidence and risk factors for amputation in SPK transplant patients compared to kidney transplantation alone (KTA) after a minimum follow-up of 10 years. METHODS: An analysis was performed on a prospectively maintained database of 81 SPK transplants and 43 KTA consecutively performed in one center for insulin-dependent diabetes mellitus between December 1992 and January 2006. Primary outcome variables were incidence of amputation per patient, total number of amputations, and type of amputation performed. Data are presented as a mean +/- standard deviation. RESULTS: Seven patients (9%) in the SPK cohort and one patient (2%) in the KTA cohort underwent amputation (P<.001). One amputee had pancreas allograft failure prior to amputation. Fifteen amputations were performed in total and four patients required >=2 amputations. The latency period between transplantation and amputation was 133.57+/-49.43 months in the SPK cohort and 168 months in the KTA group. CONCLUSIONS: The incidence of amputation after SPK transplantation is approximately 9% after 10-year follow-up. Patients are at a significantly greater risk of amputation after SPK transplantation compared to KTA for type 1 diabetes despite insulin independence. PMID- 28342279 TI - Learning effect on perinatal post-mortem magnetic resonance imaging reporting: single reporter diagnostic accuracy of 200 cases. AB - OBJECTIVE: The objective of the study is to compare diagnostic accuracy of perinatal post-mortem magnetic resonance (PMMR) imaging against conventional autopsy, when reported by a single-blinded observer for all organ systems following a period of initial experience. METHODS: We compared pre-autopsy PMMR with conventional autopsy for the detection of (1) major pathological abnormalities related to the cause of death and (2) all diagnostic findings in five different body organ systems. PMMR was reported blinded to autopsy findings. RESULTS: In 201 cases, 123/146 (84.2%) of major abnormalities were identified by PMMR. Overall diagnostic accuracy of PMMR was 89.6% [95% confidence interval (CI): 84.3, 93.2%] across all cases, with high concordance 91.8% (95% CI: 89.9, 93.4%) across most organ systems. Our study showed higher concordance than single reporter statistics previously reported in neurological [92.2% vs 73.8%; diff 18.4% (95% CI: 11.0, 25.4%) p < 0.01] and thoracic systems [93.7% vs 81.2%; diff 12.5% (95% CI: 6.3, 18.4%) p < 0.01] and slightly better overall [91.8% vs 87.1%; diff 4.7% (95% CI: 2.1, 7.3%) p < 0.01]. CONCLUSION: The PMMR examinations can be reliably reported by a single radiologist, following a period of experience and training with this specific modality, with high-diagnostic accuracy for all organ systems. (c) 2017 John Wiley & Sons, Ltd. PMID- 28342280 TI - Clinical and histopathological features of cutaneous manifestations of adult onset Still disease. AB - Adult-onset Still disease (AOSD) is a rare autoinflammatory syndrome characterized by recurring fevers, arthralgia, and consistent laboratory abnormalities that include leukocytosis and hyperferritinemia. Skin findings accompany the disease in nearly 90% of the cases. Early reports described evanescent, pruritic, salmon-pink or urticarial lesions, referred to as the typical eruption of AOSD. Histopathologic findings consist of superficial perivascular dermatitis with varying number of interstitial neutrophils. Later reports described a more persistent rash that tended to be photodistributed, hyperpigmented, often in a linear configuration, sometimes in a rippled pattern, referred to as the atypical eruption of AOSD. The presence of individual necrotic keratinocytes in the upper spinous layer has been the consistent histopathologic finding. The persistent rash may not represent an atypical presentation of AOSD as recent reports indicate a high prevalence of the rash. Emerging data also suggest that patients with persistent eruption have a worse prognosis. The recognition of the clinical and histopathological findings of skin eruptions of AOSD may facilitate an earlier diagnosis, potentially improving disease outcome. Herein, clinical and histopathological features of cutaneous manifestation of AOSD in 2 Asian women are highlighted accompanied by a relevant review of the disease. PMID- 28342281 TI - Incorporating in situ habitat patchiness in site selection models reveals that site fidelity is not always a consequence of animal choice. AB - Understanding site fidelity is important in animal ecology, but evidence is lacking that this behaviour is due to an animal choosing a specific location. To discern site selection behaviour, it is necessary to consider the spatial distribution of habitats that animals can occupy within a landscape. Tracking animals and defining clear habitat boundaries, however, is often difficult. We use in situ habitat distribution data and animal movement simulations to investigate behavioural choice in site fidelity patterns. We resolved the difficulty of gathering data by working with intertidal rock pool systems, which are of manageable size and where boundaries are easy to define. Movements of the intertidal starfish Parvulastra exigua were quantified to test the hypotheses that (1) this species displays fidelity to a particular rock pool and that (2) rock pool fidelity is due to site selection behaviour. Observed patterns of individuals (n = 10 starfish) returning to a previously occupied rock pool (n = 5 pools per location) were tested against an expected null distribution generated through simulations of random movements within their natural patchy environment. Starfish exhibited site selection behaviour at only one location even though site fidelity was high (av. 7.4 starfish out of 10 found in test pools) in two of the three locations. The random chance of a starfish returning to a pool increased 67% for each metre further a rock pool was from the original pool, and 120% for each square metre increase in surface area of an original pool. The decision of returning to an original rock pool was influenced by food availability. When microalgal cover was >60%, there was a c. 50% chance of animals staying faithful to that pool. Our results show the importance to consider spatial distribution of habitats in understanding patterns of animal movement associated with animal choices and site fidelity. Returning to a particular place does not necessarily mean that an animal is homing; it may be the only place to go. PMID- 28342282 TI - Pharmacokinetic and pharmacogenetic analysis of immunosuppressive agents after laparoscopic sleeve gastrectomy. AB - BACKGROUND: Severe obesity has been shown to limit access to renal transplantation in patients with end-stage renal disease (ESRD). Laparoscopic sleeve gastrectomy (LSG) has been performed in the ESRD population to assist in achieving waitlist and transplant eligibility. Little is known about how LSG impacts the bioequivalence of tacrolimus products and immunosuppression pharmacokinetics. METHODS: This was a prospective, open-label, single-dose, crossover, two-period pharmacokinetic (PK) study. The purpose of this study was to assess single-dose PK of immediate-release tacrolimus (IR-TAC), extended release tacrolimus (ER-TAC), and mycophenolic acid (MPA) in adult ESRD patients post-LSG. RESULTS: Twenty-three subjects were included in the 24-hour PK assessments. The ratio of geometric means between ER-TAC and IR-TAC was 103.5% (90% CI; 89.6%-119.6%) for AUC0-24 and 92.5% (90% CI; 80.4%-106.4%) for Cmax . PK parameters were similar between ER-TAC and IR-TAC, except for Cmin (P=.004) and Cmax (P=.04). MPA AUC0-24 was similar when given with either ER-TAC or IR-TAC (P=.32). Patients expressing CYP3A5*1 genotypes had lower tacrolimus AUC0-24 values vs those with CYP3A5*3/*3 (IR-TACP<.001; ER-TACP=.008). Genotype did not impact MPA PK. CONCLUSION: Dose modification of immunosuppressants post-LSG may not be necessary aside from standard therapeutic drug monitoring. PMID- 28342283 TI - Effects of predatory ants within and across ecosystems in bromeliad food webs. AB - Predation is one of the most fundamental ecological processes affecting biotic communities. Terrestrial predators that live at ecosystem boundaries may alter the diversity of terrestrial organisms, but they may also have cross-ecosystem cascading effects when they feed on organisms with complex life cycles (i.e. organisms that shift from aquatic juvenile stages to terrestrial adult stages) or inhibit female oviposition in the aquatic environment. The predatory ant Odontomachus hastatus establishes its colonies among roots of Vriesea procera, an epiphytic bromeliad species with water-filled tanks that shelters many terrestrial and aquatic organisms. Ants may impact terrestrial communities and deter adult insects from ovipositing in the water of bromeliads via consumptive and non-consumptive effects. Ants do not forage within the aquatic environment; thus, they may be more efficient predators on terrestrial organisms. Therefore, we predict that ants will have stronger effects on terrestrial than aquatic food webs. However, such effects may also be site contingent and depend on the local composition of food webs. To test our hypothesis, we surveyed bromeliads with and without O. hastatus colonies from three different coastal field sites in the Atlantic Forest of southeast Brazil, and quantified the effect of this predatory ant on the composition, density and richness of aquatic and terrestrial metazoans found in these bromeliads. We found that ants changed the composition and reduced the overall density of aquatic and terrestrial metazoans in bromeliad ecosystems. However, effects of ants on species diversity were contingent on site. In general terms, the effects of the ant on aquatic and terrestrial metazoan communities were similar in strength and magnitude. Ants reduced the density of virtually all aquatic functional groups, especially detritivore insects as well as metazoans that reach bromeliads through phoresy on the skin of terrestrial animals (i.e. Ostracoda and Helobdella sp.). Our results suggest that the cross-ecosystem effect of this terrestrial predator on the aquatic metazoans was at least as strong as its within-ecosystem effect on the terrestrial ecosystem, and demonstrates that the same predator can simultaneously initiate cascades in multiple ecosystems. PMID- 28342284 TI - Survey of body donation programs in the US concerning the use of donor personal information with medical students. AB - Body donor programs need to balance ethical concerns and educational needs. Among donor programs in the US, there is variability in the amount of donor personal information that is provided to medical students. This study assesses this variability and investigates the reasons for the variability among donor programs. Telephone interviews and email surveys were used to collect information concerning the provision and use of donor personal information with medical students. One hundred fifty-one donor programs in the US were contacted via email or telephone interview or both. Fifty-three donor programs responded to the survey or participated in the telephone interview. The survey results show variation, not only in the amount of donor personal information provided to medical students, but also in the attitudes and beliefs of the donor program personnel concerning donor personal information. This research documents the variability of the educational use of donor personal information. It is hoped that this description of the various approaches to using donor information will encourage the ethical use of donor information within the context of medical education. Clin. Anat. 30:445-449, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28342285 TI - Development of a human cadaver model for training in laparoscopic donor nephrectomy. AB - BACKGROUND: The organ procurement network recommends a surgeon record 15 cases as surgeon or assistant for laparoscopic donor nephrectomies (LDN) prior to independent practice. The literature suggests that the learning curve for improved perioperative and patient outcomes is closer to 35 cases. In this article, we describe our development of a model utilizing fresh tissue and objective, quantifiable endpoints to document surgical progress, and efficiency in each of the major steps involved in LDN. MATERIALS AND METHODS: Phase I of model development focused on the modifications necessary to maintain visualization for laparoscopic surgery in a human cadaver. Phase II tested proposed learner-based metrics of procedural competency for multiport LDN by timing procedural steps of LDN in a novice learner. RESULTS: Phases I and II required 12 and nine cadavers, with a total of 35 kidneys utilized. The following metrics improved with trial number for multiport LDN: time taken for dissection of the gonadal vein, ureter, renal hilum, adrenal and lumbrical veins, simulated warm ischemic time (WIT), and operative time. CONCLUSION: Human cadavers can be used for training in LDN as evidenced by improvements in timed learner-based metrics. This simulation-based model fills a gap in available training options for surgeons. PMID- 28342286 TI - Switching Aurora-A kinase on and off at an allosteric site. AB - Protein kinases are central players in the regulation of cell cycle and signalling pathways. Their catalytic activities are strictly regulated through post-translational modifications and protein-protein interactions that control switching between inactive and active states. These states have been studied extensively using protein crystallography, although the dynamic nature of protein kinases makes it difficult to capture all relevant states. Here, we describe two recent structures of Aurora-A kinase that trap its active and inactive states. In both cases, Aurora-A is trapped through interaction with a synthetic protein, either a single-domain antibody that inhibits the kinase or a hydrocarbon-stapled peptide that activates the kinase. These structures show how the distinct synthetic proteins target the same allosteric pocket with opposing effects on activity. These studies pave the way for the development of tools to probe these allosteric mechanisms in cells. PMID- 28342287 TI - Longitudinal evaluation of perfusion changes in acute and chronic renal allograft rejection using arterial spin labeling in translational mouse models. AB - PURPOSE: To examine the longitudinal changes of renal perfusion due to acute and chronic renal allograft rejection by using arterial spin labeling (ASL) MRI in translational mouse models of isogenic and allogenic kidney transplantation (ktx). MATERIALS AND METHODS: Acute rejection was induced by allogenic ktx of C57BL/6 (B6)-kidney grafts to BALB/c-recipients with prolonged cold ischemia (CIT) of 60 minutes (n = 13). To induce chronic rejection BALB/c-kidneys were transplanted into B6-recipients with short CIT of 30 minutes (n = 22). Isogenic grafts without rejection (n = 14 with prolonged, n = 9 with short CIT) and normal kidneys (n = 22) were used for comparison. Perfusion was measured on a 7T small animal magnetic resonance imaging (MRI) scanner using flow-sensitive alternating inversion recovery (FAIR) ASL-sequences at day 1 and 6 (acute) or at week 3 and 6 (chronic) after surgery. Histological analyses of grafts included inflammation, vascular changes, and fibrosis. RESULTS: In the acute ktx model, ASL showed perfusion impairment in isogenic and allogenic kidney grafts. Perfusion of allografts further decreased until day 6 and remained stable in isografts without rejection (allogenic ktx 62 +/- 21 vs. isogenic ktx 181 +/- 39 ml/min/100g, P < 0.01). In the chronic ktx model, perfusion in isografts was similar to normal kidneys over the entire observation period. Perfusion was severely reduced in allografts compared to isografts (week 3: 28 +/- 7 vs. 310 +/- 46 ml/min/100g, P < 0.001, week 6: 32 +/- 5 vs. 367 +/- 72 ml/min/100g, P < 0.001). Histological analysis revealed severe inflammation, vascular occlusion, and rejection in allografts. Chronic rejection grafts showed endothelialitis, peritubular capillaritis, interstitial fibrosis, and tubular atrophy. CONCLUSION: ASL allows longitudinal assessment of renal perfusion impairment due to acute and chronic renal allograft rejection in translational mouse models. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017;46:1664-1672. PMID- 28342288 TI - The role of acute and chronic respiratory colonization and infections in the pathogenesis of COPD. AB - COPD is a major global concern, increasingly so in the context of ageing populations. The role of infections in disease pathogenesis and progression is known to be important, yet the mechanisms involved remain to be fully elucidated. While COPD pathogens such as Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae are strongly associated with acute exacerbations of COPD (AECOPD), the clinical relevance of these pathogens in stable COPD patients remains unclear. Immune responses in stable and colonized COPD patients are comparable to those detected in AECOPD, supporting a role for chronic colonization in COPD pathogenesis through perpetuation of deleterious immune responses. Advances in molecular diagnostics and metagenomics now allow the assessment of microbe-COPD interactions with unprecedented personalization and precision, revealing changes in microbiota associated with the COPD disease state. As microbial changes associated with AECOPD, disease severity and therapeutic intervention become apparent, a renewed focus has been placed on the microbiology of COPD and the characterization of the lung microbiome in both its acute and chronic states. Characterization of bacterial, viral and fungal microbiota as part of the lung microbiome has the potential to reveal previously unrecognized prognostic markers of COPD that predict disease outcome or infection susceptibility. Addressing such knowledge gaps will ultimately lead to a more complete understanding of the microbe-host interplay in COPD. This will permit clearer distinctions between acute and chronic infections and more granular patient stratification that will enable better management of these features and of COPD. PMID- 28342290 TI - Verapamil treatment induces cytoprotective autophagy by modulating cellular metabolism. AB - Verapamil, an L-type calcium channel blocker, has been used successfully to treat cardiovascular diseases. Interestingly, we have recently shown that treatment of cancer cells with verapamil causes an effect on autophagy. As autophagy is known to modulate chemotherapy responses, this prompted us to explore the impact of verapamil on autophagy and cell viability in greater detail. We report here that verapamil causes an induction of autophagic flux in a number or tumor cells and immortalized normal cells. Moreover, we found that inhibition of autophagy in COLO 205 cells, via treatment with the chloroquine (CQ) or by CRISPR/Cas9 mediated disruption of the autophagy genes Atg7 and Atg5, causes an upregulation of apoptotic markers in response to verapamil. In search of a mechanism for this effect and because autophagy can often mitigate metabolic stress, we examined the impact of verapamil on cellular metabolism. This revealed that in normal prostate cells, verapamil diminishes glucose and glycolytic intermediate levels leading to adenosine 5'-triphosphate (ATP) depletion. In contrast, in COLO 205 cells it enhances aerobic glycolysis and maintains ATP. Importantly, we found that the autophagic response in these cells is related to the activity of l-lactate dehydrogenase A (LDHA, EC 1.1.1.27), as inhibition of LDHA reduces both basal and verapamil-induced autophagy and consequently decreases cell viability. In summary, these findings not only identify a novel mechanism of cytoprotective autophagy induction but they also highlight the potential of using verapamil together with inhibitors of autophagy for the treatment of malignant disease. ENZYMES: l-lactate dehydrogenase (LDHA, EC 1.1.1.27). PMID- 28342291 TI - Advances in MRI around metal. AB - : The prevalence of orthopedic metal implants is continuously rising in the aging society. Particularly the number of joint replacements is increasing. Although satisfying long-term results are encountered, patients may suffer from complaints or complications during follow-up, and often undergo magnetic resonance imaging (MRI). Yet metal implants cause severe artifacts on MRI, resulting in signal loss, signal-pileup, geometric distortion, and failure of fat suppression. In order to allow for adequate treatment decisions, metal artifact reduction sequences (MARS) are essential for proper radiological evaluation of postoperative findings in these patients. During recent years, developments of musculoskeletal imaging have addressed this particular technical challenge of postoperative MRI around metal. Besides implant material composition, configuration and location, selection of appropriate MRI hardware, sequences, and parameters influence artifact genesis and reduction. Application of dedicated metal artifact reduction techniques including high bandwidth optimization, view angle tilting (VAT), and the multispectral imaging techniques multiacquisition variable-resonance image combination (MAVRIC) and slice-encoding for metal artifact correction (SEMAC) may significantly reduce metal-induced artifacts, although at the expense of signal-to-noise ratio and/or acquisition time. Adding advanced image acquisition techniques such as parallel imaging, partial Fourier transformation, and advanced reconstruction techniques such as compressed sensing further improves MARS imaging in a clinically feasible scan time. This review focuses on current clinically applicable MARS techniques. Understanding of the main principles and techniques including their limitations allows a considerate application of these techniques in clinical practice. Essential orthopedic metal implants and postoperative MR findings around metal are presented and highlighted with clinical examples. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2017;46:972-991. PMID- 28342289 TI - TGFbeta-TAZ/SRF signalling regulates vascular smooth muscle cell differentiation. AB - Vascular smooth muscle cells (VSMCs) do not terminally differentiate; they modulate their phenotype between proliferative and differentiated states, which is a major factor contributing to vascular diseases. TGFbeta signalling has been implicated in inducing VSMC differentiation, although the exact mechanism remains largely unknown. Our goal was to assess the network of transcription factors involved in the induction of VSMC differentiation, and to determine the role of TAZ in promoting the quiescent VSMC phenotype. TGFbeta robustly induces VSMC marker genes in 10T1/2 mouse embryonic fibroblast cells and the potent transcriptional regulator TAZ has been shown to retain Smad complexes on DNA. Thus, the role of TAZ in regulation of VSMC differentiation was studied. Using primary aortic VSMCs coupled with siRNA-mediated gene silencing, our studies reveal that TAZ is required for TGFbeta induction of smooth muscle genes and is also required for the differentiated VSMC phenotype; synergy between TAZ and SRF, and TAZ and Myocardin (MyoC856), in regulating smooth muscle gene activation was observed. These data provide evidence of components of a novel signalling pathway that links TGFbeta signalling to induction of smooth muscle genes through a mechanism involving regulation of TAZ and SRF proteins. In addition, we report a physical interaction of TAZ and MyoC856. These observations elucidate a novel level of control of VSMC induction which may have implications for vascular diseases and congenital vascular malformations. PMID- 28342292 TI - Ultra-fast liquid chromatography with tandem mass spectrometry determination of eight bioactive components of Kai-Xin-San in rat plasma and its application to a comparative pharmacokinetic study in normal and Alzheimer's disease rats. AB - A method of ultra-fast liquid chromatography with tandem mass spectrometry was developed and validated for the simultaneous quantitation of eight bioactive components, including polygalaxanthone III, sibiricaxanthone B, tenuifolin, sibiricose A5, sibiricose A6, tenuifoliside A, ginsenoside Re and ginsenoside Rb1 in rat plasma after oral administration of Kai-Xin-San. The plasma samples were extracted by liquid-liquid extraction using digoxin as an internal standard. Chromatographic separation was performed on a Venusil MP C18 column (100 mm * 2.1 mm, 3 MUm) with methanol and 0.05% acetic acid in water as mobile phase. The tandem mass spectrometric detection was performed in the multiple reaction monitoring with turbo ion spray source in the negative ionization. Validation parameters were within acceptable ranges. The established method has been successfully applied to compare the pharmacokinetic profiles of the analytes between normal and Alzheimer's disease rats. The results indicated that there were significant differences in pharmacokinetic parameters of some components between two groups, which may be due to the mechanisms of Alzheimer's disease and pharmacological effects of the analytes. The pharmacokinetic research in the pathological state might provide more useful information to guide the clinical usage of herbal medicine. PMID- 28342294 TI - Benzylphenylpyrrolizinones with Anti-amyloid and Radical Scavenging Effects, Potentially Useful in Alzheimer's Disease Treatment. AB - Herein we describe the drug design steps developed to increase the radical scavenging and beta-amyloid aggregation inhibitory activities of a previously described series of benzylidenephenylpyrrolizinones. Among the newly synthesized derivatives, some benzylphenylpyrrolizinones exhibited interesting results in regard to those activities. Initial druggability parameters were measured, and suggest these compounds as a suitable starting point for potential alternatives in treating Alzheimer's disease. PMID- 28342293 TI - Ribosomal protein L7/L12 is required for GTPase translation factors EF-G, RF3, and IF2 to bind in their GTP state to 70S ribosomes. AB - Ribosomal protein L7/L12 is associated with translation initiation, elongation, and termination by the 70S ribosome. The guanosine 5' triphosphate hydrolase (GTPase) activity of elongation factor G (EF-G) requires the presence of L7/L12, which is critical for ribosomal translocation. Here, we have developed new methods for the complete depletion of L7/L12 from Escherichia coli 70S ribosomes to analyze the effect of L7/L12 on the activities of the GTPase factors EF-G, RF3, IF2, and LepA. Upon removal of L7/L12 from ribosomes, the GTPase activities of EF-G, RF3, and IF2 decreased to basal levels, while the activity of LepA decreased marginally. Upon reconstitution of ribosomes with recombinant L12, the GTPase activities of all GTPases returned to full activity. Moreover, ribosome binding assays indicated that EF-G, RF3, and IF2 require L7/L12 for stable binding in the GTP state, and LepA retained > 50% binding. Lastly, an EF-G?G' truncation mutant possessed ribosome-dependent GTPase activity, which was insensitive to L7/L12. Our results indicate that L7/L12 is required for stable binding of ribosome-dependent GTPases that harbor direct interactions to the L7/L12 C-terminal domains, either through a G' domain (EF-G, RF3) or a unique N terminal domain (IF2). Furthermore, we hypothesize this interaction is concomitant with counterclockwise ribosomal intersubunit rotation, which is required for translocation, initiation, and post-termination. PMID- 28342296 TI - Control of osmotic pressure to improve cell viability in cell-laden tissue engineering constructs. AB - Design of tissue engineering strategies deals with the need to balance both biomaterials characteristics and techniques specificities, often resulting in cell-compromising processing conditions. One important factor often disregarded is the osmotic pressure to which cells are exposed. An in-house microfluidic system was used to prove that addition of an osmotic regulator significantly benefits the generation of viable cell-laden hydrogels under harsh processing conditions. Human adipose-derived stem cells were resuspended in 1.5% alginate and 1% gellan gum (GG; w/v) solutions containing different concentrations (0.12 m, 0.25 m and 1.5 m) of sucrose as osmotic regulator. GG (in water) and alginate (in water or phosphate-buffered saline) solutions were used to vary the conditions under which cells were kept prior processing. Independently of the polymer, addition of sucrose did not affect the processing conditions or the viscosity of the solutions, except at 1.5 m. The obtained results clearly demonstrate that inclusion of 0.25 m sucrose during processing of the cell-laden hydrogels allowed to keep cell viability around 80%, in opposition to the 20% observed in its absence, both for GG and alginate-derived hydrogels prepared in water. Impressively, the level of cell viability observed with the inclusion of 0.25 m sucrose, 76% for GG and 86% for alginate, was similar to that obtained with the standard alginate solution prepared in phosphate-buffered saline (82%). The beneficial effect of sucrose was observed within the first 5 min of processing and was maintained for prolonged experimental setups with viability values above 50%, even after a 2-h time-frame and independently of the material. PMID- 28342297 TI - High-performance liquid chromatographic determination of multi-mycotoxin in cereals and bean foodstuffs using interference-removal solid-phase extraction combined with optimized dispersive liquid-liquid microextraction. AB - A novel pre-treatment was proposed for the simultaneous determination of aflatoxins, ochratoxin A and zearalenone in foodstuffs using high-performance liquid chromatography with fluorescence detection. The analytical procedure was based on a first step using a quick, easy, cheap, effective, rugged, and safe based extraction procedure, followed by salting out and purification with a C18 solid-phase extraction column as interference removal clean-up. Subsequently, collected supernatant was subjected to dispersive liquid-liquid microextraction. Response surface methodology based on central composite design was employed to optimize conditions in the microextraction procedure. Under the optimum conditions, satisfactory analytical performance with recoveries ranging from 63.22 to 107.6% were achieved in different types of cereals and beans, as well as desirable precisions (0.81-8.13%). Limits of detections and quantifications for these six mycotoxins ranging from 0.03 to 13 MUg/kg and 0.22 to 44 MUg/kg, respectively, were obtained. Finally, the established method was successfully validated by four certified reference materials (P = 0.897 > 0.05) and applied to 79 samples from local markets. PMID- 28342298 TI - Low-frequency vibrational spectroscopy of proteins with different secondary structures. AB - Fourier transform infrared (FTIR) and Raman spectra of proteins with significantly different structures are measured in a spectral interval of 50 to 500 ?? cm ? 1 and noticeable spectral differences are revealed. Intensities of several spectral bands correlate with contents of secondary structure elements. FTIR spectra of superhelical proteins exhibit developed spectral features that are absent in the spectra of globular proteins. Significant differences of the Raman spectra of proteins that are not directly related to the difference of the secondary structures can be due to differences of tertiary and/or quaternary structure of protein molecules. PMID- 28342299 TI - Plasma MicroRNA signature predicting weight gain among Mexican-American women. AB - OBJECTIVE: There is growing evidence that circulating microRNAs (miRNAs) play an important role in obesity. However, whether they can contribute to adult weight gain is still unclear. METHODS: In the training set with 40 nonsmoking, healthy women identified from the Mano-A-Mano Mexican American Cohort study, global circulating miRNA profiles in plasma samples were assessed. Cox proportional hazard regression was used to assess the effects of plasma miRNAs on significant weight gain during a 5-year follow-up. Plasma miRNAs associated with significant weight gain were further validated in two testing sets (N = 160 and 100, respectively). RESULTS: A total of 23 significant plasma miRNAs were identified in the training set. Among them, eight were validated in two testing sets. They were miR-142, miR-122, miR-125b, miR-15b, miR-130b, miR222, miR-519d, and miR-31. Using those eight miRNAs, a risk score for significant weight gain was created. Study participants with a high risk score had 3.01-fold increased risk of having significant weight gain in the whole study population (hazard ratio: 3.01, 95% confidence interval: 1.70-5.47). CONCLUSIONS: The findings provide evidence that circulating miRNAs play important roles in obesity and weight gain and suggest new targets for understanding the mechanisms of weight gain and developing weight loss intervention strategies. PMID- 28342300 TI - Hypofractionated re-irradiation to the brainstem in children with recurrent brain tumors. AB - To characterize radiation necrosis following hypofractionated brainstem re irradiation in pediatric patients, we reviewed 23 cases with 28 tumors invading or abutting brainstem and treated with hypofractionated re-irradiation from 2004 to 2014. Re-irradiation delivered total doses of 16-30 Gy in two to five fractions. The most commons regimens used were 24 Gy in three fractions and 25 Gy in five fractions. At median follow-up of 12.8 months, median overall survival was 14.7 months and eight in-field recurrences were detected (median time 10.5 months). Five patients experienced symptomatic brainstem necrosis, and all having received 24 Gy in three fractions. Hypofractionated brainstem re-irradiation may be safer in five fractions. PMID- 28342301 TI - Retraction Statement: "Overexpression of miR-708 and its targets in the childhood common precursor B-cell ALL" by Xue Li, MMed, Dong Li, PhD, Yong Zhuang, MMed, Qing Shi, BSc, Wei Wei, MMed, and Xiuli Ju, MD, PhD. AB - The above article, published online 23 August 2013 in Pediatric Blood and Cancer, Volume 60, Issue 12, December 2013, Pages 2060-2067, has been retracted by agreement among the authors, the journal's Editor-in-Chief, Peter E. Newburger, M.D., and Wiley Periodicals, Inc. The decision to retract was agreed upon following notification that the paper substantially duplicates a prior study already published in Chinese https://www.ncbi.nlm.nih.gov/pubmed/23611221. The authors were not aware that publication in another language would constitute a duplicate publication and, upon being informed of this fact, have agreed to withdraw the paper from Pediatric Blood and Cancer. Reference Li X, Li D, Zhuang Y, Shi Q, Wei W and Ju X. Overexpression of miR-708 and its targets in the childhood common precursor B-cell ALL. Pediatr Blood Cancer. 2013; 60: 2060-2067. doi:10.1002/pbc.24583. PMID- 28342295 TI - Intraflagellar transport: mechanisms of motor action, cooperation, and cargo delivery. AB - Intraflagellar transport (IFT) is a form of motor-dependent cargo transport that is essential for the assembly, maintenance, and length control of cilia, which play critical roles in motility, sensory reception, and signal transduction in virtually all eukaryotic cells. During IFT, anterograde kinesin-2 and retrograde IFT dynein motors drive the bidirectional transport of IFT trains that deliver cargo, for example, axoneme precursors such as tubulins as well as molecules of the signal transduction machinery, to their site of assembly within the cilium. Following its discovery in Chlamydomonas, IFT has emerged as a powerful model system for studying general principles of motor-dependent cargo transport and we now appreciate the diversity that exists in the mechanism of IFT within cilia of different cell types. The absence of heterotrimeric kinesin-2 function, for example, causes a complete loss of both IFT and cilia in Chlamydomonas, but following its loss in Caenorhabditis elegans, where its primary function is loading the IFT machinery into cilia, homodimeric kinesin-2-driven IFT persists and assembles a full-length cilium. Generally, heterotrimeric kinesin-2 and IFT dynein motors are thought to play widespread roles as core IFT motors, whereas homodimeric kinesin-2 motors are accessory motors that mediate different functions in a broad range of cilia, in some cases contributing to axoneme assembly or the delivery of signaling molecules but in many other cases their ciliary functions, if any, remain unknown. In this review, we focus on mechanisms of motor action, motor cooperation, and motor-dependent cargo delivery during IFT. PMID- 28342302 TI - Reply to iManage: A novel self-management app for sickle cell disease. PMID- 28342303 TI - Cell adaptation upon stress: the emerging role of membrane-less compartments. AB - Cells under stress transition from a growth to a quiescent state. The conventional thinking is that this is achieved through transcriptional programs, translational regulation, protein degradation, and post-translational modifications. However, there is an increasing realization that stress adaptation also goes along with dramatic changes in the architecture and organization of cells. In particular, it seems to involve the formation of membrane-less compartments and macromolecular assemblies. We propose that cells make widespread use of this ability to change macromolecular organization to adapt to stress conditions and protect themselves. Here, we address what triggers the formation of these assemblies under stress conditions. We present examples illustrating that in some cases, sophisticated signaling pathways transmit environmental fluctuations from the outside to the inside and in others, that external fluctuations directly affect the internal conditions in cells. We further argue that changes in the organization of the cytoplasm and the formation of membrane less compartments have many advantages over other ways of altering protein function, such as protein degradation, translation or transcription. Furthermore, membrane-less compartments may act as protective devices for key cellular components. PMID- 28342304 TI - Rapid profiling and pharmacokinetic studies of major compounds in crude extract from Polygonum multiflorum by UHPLC-Q-TOF-MS and UPLC-MS/MS. AB - A reliable, rapid analytical method was established for characterization of constituents in the ethanol extract of Polygonum multiflorum by combining an ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS). 131 constituents which including phenolic acids, stilbenes, flavones, anthraquinones, naphthalenes and their derivatives were identified or tentatively identified by using characteristic diagnostic fragment ions and references. The established method was further applied to analyze blood samples, and successfully identified 41 compounds which were absorbed through the gastrointestine in rats after administration the extract of P. multiflorum. Moreover, the pharmacokinetic studies of some major compounds in blood were investigated by using ultra performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) method. This study showed a comprehensive research of P. multiflorum, which could provide a meaningful basis for further quality control, pharmacological as well as toxicological researches. PMID- 28342305 TI - Metabolic profiling of nuciferine in rat urine, plasma, bile and feces after oral administration using ultra-high performance liquid chromatography-diode array detection-quadrupole time-of-flight mass spectrometry. AB - Nuciferine, a major alkaloid found in Nelumbinis Folium, exhibits a broad spectrum of bioactivities, such as antiobesity, anti-diabetes and anti inflammatory. However, many research regarding nuciferine focused on the extraction, isolation and biological activity, the metabolism is not comprehensively explained in vivo. Thence, the present of this paper is to establish a simple method for speculating metabolites of nuciferine. A total of 15 metabolites were detected and tentatively identified through ultra high performance liquid chromatography-diode array detection-quadrupole time-of-flight mass spectrometry (UHPLC-DAD-QTOF-MS), including 7 new metabolites. Among them, we also discovered a previously unmentioned metabolically active site at the C1 OCH3 position. These metabolites suggested that demethylation, oxidation, glucuronidation and sulfation were major metabolic pathways. This study provided significant experiment basis for its safety estimate and valuable information about the metabolism of nuciferine, which will be advantageous for new drug development. PMID- 28342306 TI - Rotigotine may control drooling in patients with Parkinson's Disease: Preliminary findings. AB - OBJECTIVE: To evaluate the efficacy of rotigotine in controlling the drooling of Parkinson's Disease (PD) patients. PATIENTS AND METHODS: We assessed 7 PD patients (Hoehn and Yahr scale >2.5) with three different clinical scores (Drooling Severity and Frequency Scale - DSFS, Drooling Rating Scale - DRS and Sialorrhea Clinical Scale for PD - SCS) before and after 4 weeks of therapy. Statistical differences were analyzed with Wilcoxon signed-rank test. RESULTS: We observed that rotigotine significantly improves drooling as measured by the lowering of the three scores (p<0.05). CONCLUSIONS: Among non-motor symptoms of PD, drooling is one of the most embarrassing and disabling for patients. Current treatments are unsatisfactory and novel approaches are thus desirable. In this open-label pilot study we demonstrated on a small sample of patients that up to 4mg/24h of rotigotine, a non-ergolinic dopamine agonist with continuous transdermal delivery, may be helpful in the management of drooling in advanced PD. PMID- 28342307 TI - Simple fabrication of pineapple root-like palladium-gold catalysts as the high efficiency cathode in direct peroxide-peroxide fuel cells. AB - Pd-Au/TiC electrodes with various three-dimensional structures are obtained by the pulsed potential electro-deposition in PdCl2/HAuCl4 electrolytes. The morphologies of Pd-Au/TiC composite catalysts are significantly dependent on the component of deposited solutions. The surface appearance of Pd-Au catalysts changes from rime-shaped structure, to feather-like construction, then to pineapple root-like structure and finally to flower-like configuration with the increase of PdCl2 content in electrolytes. These particular three-dimensional structures may be very suitable for H2O2 electro-reduction, which assures a high utilization of Pd-Au catalysts and provides a large specific surface area. The electro-catalytic activities of H2O2 reduction on the Pd-Au/TiC electrodes improve as increasing the Pd content in Pd-Au alloy catalysts. The pineapple root like Pd5Au1/TiC electrode reveals remarkably excellent electrochemical property and desirable stability for catalyzing H2O2 reduction in acid media. The direct peroxide-peroxide fuel cells with a 10 cm3 min-1 flow rate display the open circuit voltage (OCV) of 0.85V and the peak power density of 56.5mWcm-2 at 155mAcm-2 with desirable cell stability, which is much higher than those previously reported. PMID- 28342308 TI - Shape-selective catalysis and surface enhanced Raman scattering studies using Ag nanocubes, nanospheres and aggregated anisotropic nanostructures. AB - Three morphologies of silver nanoparticles (Ag NPs) such as nanocubes, aggregated anisotropic Ag NPs, and nanospheres were prepared using polystyrene sulfonate (PSS) and citrate as stabilizing agents utilizing a simple wet-chemical and microwave heating route respectively. Ag nanocubes were prepared within one min through microwave heating whereas anisotropic Ag NPs and spherical Ag NPs via 5 and 30min of normal stirring at room temperature (RT) respectively. The shape effect of three different morphologies of Ag NPs were examined in catalysis reaction and in surface enhanced Raman scattering (SERS) studies. For catalysis experiments, reduction of various nitroaromatics was done taking excess NaBH4 in presence of those morphologically different Ag NPs as catalyst and the corresponding catalytic activity is ordered as: Ag nanospheres>aggregated anisotropic Ag NPs>Ag nanocubes. The highest catalytic rate of ~1.34*10-1min-1 was observed with citrate capped Ag nanospheres. SERS study was done taking methylene blue (MB) as the Raman probe where a highest enhancement factor (EF) of ~1.05*107 was observed with Ag nanospheres and the order of EF values is as follows: Ag nanospheres>Ag nanocubes>aggregated anisotropic Ag NPs. The highest catalytic and SERS activity of citrate stabilized spherical Ag NPs are attributed due to the fast electron transfer in catalysis and creation of more number of surface active 'hot spots' in SERS studies. In future, the overall process we highlighted here might found potential application for the preparation of other varieties of nanomaterials applicable to catalysis reaction and in SERS-based trace analysis of various biologically important molecules and fine chemicals. PMID- 28342309 TI - Hierarchical assembly of In2O3 nanoparticles on ZnO hollow nanotubes using carbon fibers as templates: Enhanced photocatalytic and gas-sensing properties. AB - A novel hollow hierarchical nano-heterostructure consisting of ZnO nanorods coated with In2O3 nanoparticles was prepared using a hydrothermal method combined with an annealing treatment via carbon fiber (CF) templates. Experimental results reveal that the In2O3/ZnO hierarchical composite has a tubular structure with an average diameter of ~6MUm and In2O3 nanoparticles distribute uniformly on the ZnO nanorods. Significantly, the obtained heterostructure shows enhanced visible light photoactivity to methyl orange (MO) degradation and good selectivity and response toward ethanol even at a low detection limit (1ppm). This outstanding performance is a result of the one-dimensional tubular structure and the heterostructure formation between In2O3 and ZnO, advantageous for the adsorption and diffusion and the separation of electrons and holes. In addition, the excellent performance is greatly improved by virtue of the evenly decorated In2O3 nanoparticles on the ZnO nanorod surfaces, which provide more active sites for pollutants and gases. PMID- 28342310 TI - Silver nanoparticles synthesized and coated with pectin: An ideal compromise for anti-bacterial and anti-biofilm action combined with wound-healing properties. AB - The synthesis of Ag nanoparticles from Ag+ has been investigated, with pectin acting both as reductant and coating.~100% Ag+ to Ag(0) one-pot conversion was obtained, yielding p-AgNP, i.e. an aqueous solution of pectin-coated spherical Ag nanoparticles (d=8.0+/-2.6nm), with a<1ppm concentration of free Ag+ cation. Despite the low free Ag+ concentration and low Ag+ release with time, the nature of the coating allows p-AgNP to exert excellent antibacterial and antibiofilm actions, comparable to those of ionic silver, tested on E. coli (Gram-) and S. epidermidis (Gram+) both on planctonic cells and on pre- and post-biofilm formation conditions. Moreover, p-AgNP were tested on fibroblasts: not only p AgNP were found to be cytocompatible but also revealed capable of promoting fibroblasts proliferation and to be effective for wound healing on model cultures. The antibacterial activity and the wound healing ability of silver nanoparticles are two apparently irreconcilable properties, as the former usually requires a high sustained Ag+ release while the latter requires low Ag+ concentration. p-AgNP represents an excellent compromise between opposite requirements, candidating as an efficient medication for repairing wounds and/or to treat vulnerable surgical site tissues, including the pre-treatment of implants as an effective prophylaxis in implant surgery. PMID- 28342311 TI - Lengthy one-dimensional magnetite (Fe3O4) sub-microfibers with excellent electrochemical performance. AB - One dimensional Fe3O4 sub-microfibers with an average diameter of about 920nm and length of about 25MUm were prepared by hydrothermal synthesis in the presence of sodium citrate (Na3cit). The physicochemical properties were characterized by X ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), and scanning electron microscopy (SEM). It was found that Fe3O4 crystal nuclei were generated from different Fe2+-citrate complexes under hydrothermal conditions and Na3cit as a capping agent promoted the formation of Fe3O4 microfibers. The Fe3O4 nanocrystals grew along the (110) axis on the exposed (111) facet, and then further formed microfibers via an oriented attachment mechanism during the collisions. Polyvinylpyrrolidine (PVP) was more conducive to microfibers growth in comparison to polyethyleneglycol 4000 (PEG-4000), cetyltrimethylammonium bromide (CTAB) and sodium dodecyl sulfate (SDS). The electrochemical measurements show that the Fe3O4 sub-microfibers had a specific capacitance of 117.6Fg-1 with good cycling performance. PMID- 28342312 TI - ZnO nanorods array based field-effect transistor biosensor for phosphate detection. AB - A promising field-effect transistor (FET) biosensor has been fabricated based on pyruvate oxidase (PyO) functionalized ZnO nanorods (ZnO NRs) array grown on seeded SiO2/Si substrate. The direct and vertically grown ZnO NRs on the seeded SiO2/Si substrate offers high surface area for enhanced PyO immobilization, which further helps to detect phosphate with higher specificity. Under optimum conditions, the fabricated FET biosensor provided a convenient method for phosphate detection with high sensitivity (80.57MUAmM-1cm-2) in a wide-linear range (0.1uM-7.0mM). Additionally, it also showed very low effect of electroactive species, stability and good reproducibility. Encouraging results suggest that this approach presents a promising method to be used for field measurements to detect phosphate. PMID- 28342313 TI - The glyoxylate pathway contributes to enhanced extracellular electron transfer in yeast-based biofuel cell. AB - This study provides a new insight into our understanding of yeast response to starvation conditions (sole acetate as carbon source) and applied polarization and offers important information about the role of the glyoxylate cycle in the carbohydrate synthesis and extracellular charge transfer processes in biofuel cells. The biosynthetic capabilities of yeast C. melibiosica 2491 and the up/down regulation of the glyoxylate cycle are evaluated by modifying the cellular metabolism by feedback inhibition or carbohydrate presence and establishing the malate dehydrogenase activity and carbohydrate content together with the electric charge passed through bioelectrochemical system. 10mM malate leads to a decrease of the produced quantity of electricity with ca. 55%. At the same time, 24-times lower intracellular malate dehydrogenase activity is established. At polarization conditions the glyoxylate pathway is up-regulated and huge amount of malate is intra-converted into oxaloacetate. The yeasts are able to synthesize carbohydrates from acetate and a part of them is used for the electricity generation. It is recognized that the enhanced charge transfer in acetate fed yeast-based biofuel cell is implemented by secreted endogenous mediator and changes in the cellular surface redox activity depending on the addition of carbohydrate in the medium. PMID- 28342314 TI - Electrochemical DNA sandwich biosensor based on enzyme amplified microRNA-21 detection and gold nanoparticles. AB - In this work, a novel electrochemical biosensor for miRNA-21 determination, involving a sandwich hybridization assay onto gold nanoparticles modified pencil graphite electrode (PGE) and enzyme signal amplification was reported. The thiol terminated capture probe 1 (SH-P1) was immobilized on the electrode through AuS interaction. In the presence of target miRNA-21, SH-P1 hybridized with the first part of the target, however, the second part hybridizes with a biotinylated probe P2 (B-P2). Then, a streptavidin-conjugated alkaline phosphatase was immobilized by a specific binding of avidin-B-P2. The enzyme catalyzed the electro-inactive alpha-naphtyl phosphate to an electro-active alpha-naphtol. The miRNA-21 detection was achieved through the changes of alpha-naphtol oxidation signals observed at +0.12V vs Ag/AgCl with Differential Pulse Voltammetry. Under the optimal detection conditions, the biosensor exhibited selective and sensitive detection with a linear range from 200pM to 388nM and the detection limit was 100pM (10fmol in 100MUL). PMID- 28342315 TI - Inclusions or bystanders? CMV PCR sensitivity and specificity in tissue samples. PMID- 28342316 TI - Comparison of cytomegalovirus (CMV)-specific neutralization capacity of hyperimmunoglobulin (HIG) versus standard intravenous immunoglobulin (IVIG) preparations: Impact of CMV IgG normalization. AB - BACKGROUND: Based on a non-randomized study of Nigro et al. (2005) the intravenous administration of hyperimmunoglobulins (HIGs) is applied frequently to women with primary CMV-infection as "off-label use" in Germany. OBJECTIVES: In order to describe their CMV-specific neutralization-capacity in vitro, we analyzed the HIG preparations Cytotect(r), and Cytogam(r) as well as the standard intravenous immunoglobulins (IVIG) Octagam(r), Gamunex(r), Kiovig(r). STUDY DESIGN: We performed short-term cell-free CMV neutralization assays (CFNT) and long-term cell-adapted neutralization-plaque-reduction assays (PRANT). Human retinal epithelial cells (ARPE-19) were used as target cells. A clinical CMV primary-isolate from amnion fluid propagated in epithelial cells without any initial fibroblast adaption was used. For calibration we previously generated serum-pools (N=100) from two cohorts of mothers at birth: seronegative and latently CMV-infected mothers. Biochemical analysis included total protein, albumin, Ig-class, and IgG-subclasses. Additionally, CMV antibody-reactivity was checked using recombinant immunoblotting. RESULTS: HIG and IVIG preparations showed differences in levels and patterns of protein, Ig-class and CMV-specific antibody concentrations. All IgG-preparations showed high in vitro NT-capacity and high IgG-avidity. The NT90-values for HIGs and IVIGs and our seropositive reference-pool showed similar NT-capacity at a dilution of (1:100) which corresponded well to 4.1 PEI-Units/ml. CONCLUSION: All HIG- and IVIG-preparations showed similar NT-capacity following CMV IgG-normalization. Our in vitro results are in strong contrast to former findings suggesting higher functional CMV NT titers in IVIG-preparations compared to HIGs. PMID- 28342317 TI - High Androgen Receptor mRNA Expression Is Independently Associated with Prolonged Cancer-Specific and Recurrence-Free Survival in Stage T1 Bladder Cancer. AB - INTRODUCTION: High-risk non-muscle-invasive bladder cancer (NMIBC) remains challenging given the high probability of progression. Given that the androgen receptor (AR) has been discussed as a possible factor in the development and progression of bladder cancer, we investigated the predictive value of AR in stage pT1 NMIBC. MATERIALS AND METHODS: We retrospectively analyzed the clinical data and AR mRNA expression in 296 patients with stage pT1 NMIBC who underwent a transurethral resection of the bladder. The mRNA expression of the AR transcript variants 1 (AR1) and 2 (AR2) was measured by reverse transcription quantitative real-time polymerase chain reaction. AR expression was also correlated to KRT5 and KRT20 mRNA expression. RESULTS: Kaplan-Meier analysis indicated that high AR1 mRNA expression >=35.47 is associated with statistically significant better recurrence-free survival (RFS) (P=.0007), progression-free survival (PFS) (P=.0420), and cancer-specific survival (CSS) (P=.0050). Multivariate Cox regression analysis revealed that high AR1 mRNA expression is an independent prognostic marker for RFS (P=.0029) and CSS (P=.0119). Spearman rank correlation revealed a significant positive association between mRNA expression of AR1 and KRT5 (rs: 0.3171, P<.0001) as well as a negative association with multifocal tumors (rs: 0.1478, P<.0109). No association was noted between AR1 expression and tumor grade, concomitant CIS, gender, tumor size, and KRT20 in patients with stage T1 NMIBC. CONCLUSIONS: AR mRNA expression can predict RFS and CSS in patients with stage T1 NMIBC. Further studies are necessary to refine the relevance of AR mRNA expression compared with immunohistochemically detectable AR expression. PMID- 28342318 TI - Distinct Patterns of Stromal and Tumor Expression of ROR1 and ROR2 in Histological Subtypes of Epithelial Ovarian Cancer. AB - OBJECTIVE: The ROR1 and ROR2 receptor tyrosine kinases have both been implicated in ovarian cancer progression and have been shown to drive migration and invasion. There is an increasing importance of the role of stroma in ovarian cancer metastasis; however, neither ROR1 nor ROR2 expression in tumor or stromal cells has been analyzed in the same clinical cohort. AIM: To determine ROR1 and ROR2 expression in ovarian cancer and surrounding microenvironment and examine associations with clinicopathological characteristics. METHODS: Immunohistochemistry for ROR1 and ROR2 was used to assess receptor expression in a cohort of epithelial ovarian cancer patients (n=178). Results were analyzed in relation to clinical and histopathological characteristics and survival. Matched patient sample case studies of normal, primary, and metastatic lesions were used to examine ROR expression in relation to ovarian cancer progression. RESULTS: ROR1 and ROR2 are abnormally expressed in malignant ovarian epithelium and stroma. Higher ROR2 tumor expression was found in early-stage, low-grade endometrioid carcinomas. ROR2 stromal expression was highest in the serous subtype. In matched patient case studies, metastatic samples had higher expression of ROR2 in the stroma, and a recurrent sample had the highest expression of ROR2 in both tumor and stroma. CONCLUSION: ROR1 and ROR2 are expressed in tumor-associated stroma in all histological subtypes of ovarian cancer and hold potential as therapeutic targets which may disrupt tumor and stroma interactions. PMID- 28342319 TI - Absolute spike frequency as a predictor of surgical outcome in temporal lobe epilepsy. AB - PURPOSE: Frequent interictal epileptiform abnormalities may correlate with poor prognosis after temporal lobe resection for refractory epilepsy. To date, studies have focused on limited resections such as selective amygdalohippocampectomy and apical temporal lobectomy without hippocampectomy. However, it is unclear whether the frequency of spikes predicts outcome after standard anterior temporal lobectomy. METHOD: Preoperative scalp video-EEG monitoring data from patients who subsequently underwent anterior temporal lobectomy over a three year period and were followed for at least one year were reviewed for the frequency of interictal epileptiform abnormalities. Surgical outcome for those patients with frequent spikes (>60/h) was compared with those with less frequent spikes. Additionally, spike frequency was evaluated as a continuous variable and correlated with outcome to determine if increased spike frequency correlated with worse outcome, as assessed by modified Engel Class outcome. RESULTS: Forty-seven patients (18 men, 29 women; mean age 40 years at surgery) were included. Forty-six patients had standard anterior temporal lobectomy (24 right, 22 left) and one had a modified left temporal lobectomy. There was no significant difference in seizure outcome between those with frequent (57% Class I) vs. those with less frequent (58% Class I) spikes. Increased spike frequency did not correlate with worse outcome. Greater than 20 complex partial seizures/month and generalized tonic clonic seizures within one year of surgery correlated with worse outcome. CONCLUSIONS: This study suggests that absolute spike frequency does not predict seizure outcome after anterior temporal lobectomy unlike in selective procedures, and should not be used as a prognostic factor in this population. PMID- 28342322 TI - Ultrasonic field modeling in anisotropic materials by distributed point source method. AB - DPSM (distributed point source method) is a modeling technique which is based on the concept of Green's function. First, a collection of source and target points are distributed over the solution domain based on the problem description and solution requirements. Then, the effects from all source points are superimposed at the location of every individual target point. Therefore, a successful implementation of DPSM entails an effective evaluation of Green's function between many pairs of source and target points. For homogeneous and isotropic media, the Green's function is available as a closed-form analytical expression. But for anisotropic solids, the evaluation of Green's function is more complicated and needs to be done numerically. Nevertheless, important applications such as defect detection in composite materials require anisotropic analysis. In this paper, the DPSM is used for ultrasonic field modeling in anisotropic materials. Considering the prohibitive computational cost of evaluating Green's function numerically for a large number of points, a technique called "windowing" is suggested which employs the repetitive pattern of points in DPSM in order to considerably reduce the number of evaluations of Green's function. In addition, different resolutions of numerical integration are used for computing Green's function corresponding to different distances in order to achieve a good balance between time and accuracy. The developed anisotropic DPSM model equipped with windowing technique and multi-resolution numerical integration is then applied to the problem of ultrasonic wave modeling in a plate immersed in a fluid. The transducers are placed in the fluid on both sides of the plate. First an isotropic plate is considered for the sake of verification and rough calibration of numerical integration. Then a composite plate is considered to demonstrate applicability and effectiveness of the developed model for simulating ultrasonic wave propagation in anisotropic media. PMID- 28342321 TI - Improvement of paracellular transport in the Caco-2 drug screening model using protein-engineered substrates. AB - The Caco-2 assay has achieved wide popularity among pharmaceutical companies in the past two decades as an in vitro method for estimation of in vivo oral bioavailability of pharmaceutical compounds during preclinical characterization. Despite its popularity, this assay suffers from a severe underprediction of the transport of drugs which are absorbed paracellularly, that is, which pass through the cell-cell tight junctions of the absorptive cells of the small intestine. Here, we propose that simply replacing the collagen I matrix employed in the standard Caco-2 assay with an engineered matrix, we can control cell morphology and hence regulate the cell-cell junctions that dictate paracellular transport. Specifically, we use a biomimetic engineered extracellular matrix (eECM) that contains modular protein domains derived from two ECM proteins found in the small intestine, fibronectin and elastin. This eECM allows us to independently tune the density of cell-adhesive RGD ligands presented to Caco-2 cells as well as the mechanical stiffness of the eECM. We observe that lower amounts of RGD ligand presentation as well as decreased matrix stiffness results in Caco-2 morphologies that more closely resemble primary small intestinal epithelial cells than Caco-2 cells cultured on collagen. Additionally, these matrices result in Caco-2 monolayers with decreased recruitment of actin to the apical junctional complex and increased expression of claudin-2, a tight junction protein associated with higher paracellular permeability that is highly expressed throughout the small intestine. Consistent with these morphological differences, drugs known to be paracellularly transported in vivo exhibited significantly improved transport rates in this modified Caco-2 model. As expected, permeability of transcellularly transported drugs remained unaffected. Thus, we have demonstrated a method of improving the physiological accuracy of the Caco-2 assay that could be readily adopted by pharmaceutical companies without major changes to their current testing protocols. PMID- 28342320 TI - Mitigating hypoxic stress on pancreatic islets via in situ oxygen generating biomaterial. AB - A major obstacle in the survival and efficacy of tissue engineered transplants is inadequate oxygenation, whereby unsupportive oxygen tensions result in significant cellular dysfunction and death within the implant. In a previous report, we developed an innovative oxygen generating biomaterial, termed OxySite, to provide supportive in situ oxygenation to cells and prevent hypoxia-induced damage. Herein, we explored the capacity of this biomaterial to mitigate hypoxic stress in both rat and nonhuman primate pancreatic islets by decreasing cell death, supporting metabolic activity, sustaining aerobic metabolism, preserving glucose responsiveness, and decreasing the generation of inflammatory cytokines. Further, the impact of supplemental oxygenation on in vivo cell function was explored by the transplantation of islets previously co-cultured with OxySite into a diabetic rat model. Transplant outcomes revealed significant improvement in graft efficacy for OxySite-treated islets, when transplanted within an extrahepatic site. These results demonstrate the potency of the OxySite material to mitigate activation of detrimental hypoxia-induced pathways in islets during culture and highlights the importance of in situ oxygenation on resulting islet transplant outcomes. PMID- 28342323 TI - Computer-aided tumor diagnosis using shear wave breast elastography. AB - The shear wave elastography (SWE) uses the acoustic radiation force to measure the stiffness of tissues and is less operator dependent in data acquisition compared to strain elastography. However, the reproducibility of the result is still interpreter dependent. The purpose of this study is to develop a computer aided diagnosis (CAD) method to differentiate benign from malignant breast tumors using SWE images. After applying the level set method to automatically segment the tumor contour and hue-saturation-value color transformation, SWE features including average tissue elasticity, sectional stiffness ratio, and normalized minimum distance for grouped stiffer pixels are calculated. Finally, the performance of CAD based on SWE features are compared with those based on B-mode ultrasound (morphologic and textural) features, and a combination of both feature sets to differentiate benign from malignant tumors. In this study, we use 109 biopsy-proved breast tumors composed of 57 benign and 52 malignant cases. The experimental results show that the sensitivity, specificity, accuracy and the area under the receiver operating characteristic ROC curve (Az value) of CAD are 86.5%, 93.0%, 89.9%, and 0.905 for SWE features whereas they are 86.5%, 80.7%, 83.5% and 0.893 for B-mode features and 90.4%, 94.7%, 92.3% and 0.961 for the combined features. The Az value of combined feature set is significantly higher compared to the B-mode and SWE feature sets (p=0.0296 and p=0.0204, respectively). Our results suggest that the CAD based on SWE features has the potential to improve the performance of classifying breast tumors with US. PMID- 28342324 TI - Short bursts of cyclic mechanical compression modulate tissue formation in a 3D hybrid scaffold. AB - Among the cues affecting cells behaviour, mechanical stimuli are known to have a key role in tissue formation and mineralization of bone cells. While soft scaffolds are better at mimicking the extracellular environment, they cannot withstand the high loads required to be efficient substitutes for bone in vivo. We propose a 3D hybrid scaffold combining the load-bearing capabilities of polycaprolactone (PCL) and the ECM-like chemistry of collagen gel to support the dynamic mechanical differentiation of human embryonic mesodermal progenitor cells (hES-MPs). In this study, hES-MPs were cultured in vitro and a BOSE Bioreactor was employed to induce cells differentiation by mechanical stimulation. From day 6, samples were compressed by applying a 5% strain ramp followed by peak-to-peak 1% strain sinewaves at 1Hz for 15min. Three different conditions were tested: unloaded (U), loaded from day 6 to day 10 (L1) and loaded as L1 and from day 16 to day 20 (L2). Cell viability, DNA content and osteocalcin expression were tested. Samples were further stained with 1% osmium tetroxide in order to investigate tissue growth and mineral deposition by micro-computed tomography (uCT). Tissue growth involved volumes either inside or outside samples at day 21 for L1, suggesting cyclic stimulation is a trigger for delayed proliferative response of cells. Cyclic load also had a role in the mineralization process preventing mineral deposition when applied at the early stage of culture. Conversely, cyclic load during the late stage of culture on pre-compressed samples induced mineral formation. This study shows that short bursts of compression applied at different stages of culture have contrasting effects on the ability of hES-MPs to induce tissue formation and mineral deposition. The results pave the way for a new approach using mechanical stimulation in the development of engineered in vitro tissue as replacement for large bone fractures. PMID- 28342325 TI - Development of a rapid matrix digestion technique for ultrastructural analysis of elastic fibers in the intervertebral disc. AB - Collagen and elastic fibers are two major fibrous constituents of the annulus fibrosus (AF) in the disc that contribute to its mechanical and viscoelastic properties. It was thought that elastic fibers play no substantial role in the function and properties of the disc as these fibers were irregularly distributed. Studies that have revealed highly organized elastic fibers with different regional orientation and distribution, while being strongly crosslinked with matrix, suggesting their contribution to disc structure-function properties. These studies that were performed by light microscopic analysis of histologically prepared samples, have not been able to reveal the fine-scale architectural details of the elastic fiber network. Since elastic fibers are intermingled with other fibrous components of the disc and mostly obscured by the extracellular matrix, it is difficult to demonstrate their ultra-structural organization using scanning electron microscopy (SEM). Therefore the aim of this study was to develop a rapid matrix digestion technique for ultrastructural analysis of the disc elastic fibers. This study provides a new method for fundamental visualization of elastic fibers and their architecture in the disc. Through the ultra-structural analysis, the relationship between structure and function, as well as the role of elastic fibers on AF mechanical properties can be studied. This method may be used to develop a three-dimensional map of elastic fibers distribution within the disc, which would provide valuable information for designing tissue engineered scaffolds for AF repair and replacement. PMID- 28342326 TI - Sex dependent mechanical properties of the human mandibular condyle. AB - The mandibular condyle consists of articular cartilage and subchondral bone that play an important role in bearing loads at the temporomandibular joint (TMJ) during static occlusion and dynamic mastication. The objective of the current study was to examine effects of sex and cartilage on 1) static and dynamic mechanical analysis (DMA) based dynamic energy storage and dissipation for the cartilage-subchondral bone construct of the human mandibular condyle, and 2) their correlations with the tissue mineral density and trabecular morphological parameters of subchondral bone. Cartilage-subchondral bone constructs were obtained from 16 individual human cadavers (9 males, 7 females, 79.00+/-13.10 years). After scanning with micro-computed tomography, the specimens were subjected to a non-destructive compressive static loading up to 7N and DMA using a cyclic loading profile (-5+/-2N at 2Hz). After removing the cartilage from the same specimen, the series of loading experiments were repeated. Static stiffness (K) and energy dissipation (W), and dynamic storage (K'), loss (K'') stiffness, and energy dissipation (tan delta) were assessed. Gray values, which are proportional to degree of bone mineralization, and trabecular morphological parameters of the subchondral bone were also measured. After removal of the cartilage, static energy dissipation significantly decreased (p<0.009) but dynamic energy dissipation was not influenced (p>0.064). Many subchondral bone properties were significantly correlated with the overall mechanical behavior of the cartilage-subchondral bone constructs for males (p<0.047) but not females (p>0.054). However, after removal of cartilage from the constructs, all of the significant correlations were no longer found (p>0.057). The current findings indicate that the subchondral bone is responsible for bearing static and dynamic loading in males but not in females. This result indicates that the female condyle may have a mechanically disadvantageous TMJ loading environment. PMID- 28342327 TI - Influence of terrestrial radionuclides on environmental gamma exposure in a uranium deposit in Paraiba, Brazil. AB - One of the main natural uranium deposits in Brazil is located in the municipality of Espinharas, in the State of Paraiba. This area may present high levels of natural radioactivity due to the presence of these radionuclides. Since this is a populated area, there is need for a radioecological dosimetry assessment to investigate the possible risks to the population. Based on this problem, the objective of this study was to estimate the environmental effective dose outdoors in inhabited areas influenced by the uranium deposit, using the specific activities of equivalent uranium, equivalent thorium and 40K and conversion factors. The environmental assessment was carried using gamma spectroscopy in sixty-two points within the municipality, with a high-resolution gamma spectrometer with HPGe semiconductor detector and Be window. The results obtained ranged from 0.01 to 19.11 mSv y-1, with an average of 2.64 mSv y-1. These levels are, on average, 23 times higher than UNSCEAR reference levels and up to 273 times the reference value of the earth's crust for primordial radionuclides. Therefore, given the high radioactivity levels found, we conclude that there is need for further investigation to evaluate the levels of radioactivity in indoor environments, which will reflect more closely the risks of the local population. PMID- 28342328 TI - Reproductive toxicity of beta-diketone antibiotic mixtures to zebrafish (Danio rerio). AB - So far, few data are available on the reproductive toxicological assessment of beta-diketone antibiotics (DKAs), a class of ubiquitous pseudo-persistent pollutant, in zebrafish (Danio rerio). Herein, we reported the reproductive effects of DKAs by means of transcriptome analysis (F1-zebrafish), changes in a series of reproductive indices (F0-zebrafish) and histopathological observations. A total of 1170, 983 and 1399 genes were found to be differentially expressed when compared control vs. 6.25mg/L, control vs. 12.5mg/L and 6.25 vs. 12.5mg/L DKA-exposure treatments, respectively. Among three comparison groups, 670, 569 and 821 genes were respectively assigned for GO analyses based on matches with sequences of known functions. In 149 KEGG-noted metabolic pathways, the preferential one was the MAPK (mitogen-activated protein kinase) signaling pathway, followed by oxidative phosphorylation, neuroactive ligand-receptor interaction and so on. By qPCR verification, 6 genes (c6ast4, igfbp1b, mrpl42, tnnc2, emc4 and ddit4) showed consistent gene expression with those identified by transcriptome sequencing. Due to DKA-exposure, the concentrations of plasma estradiol and testosterone, and the gonado-somatic index were significantly dose dependently declined. Also, DKA-exposure led to declining in zebrafish reproductive capacity, reflecting in fertilization, hatchability and egg production. Histopathological observations demonstrated that zebrafish ovary and testis suffered serious damage after DKA-exposure. The 4-oxo-TEMP signals increased obviously with increasing DKA-exposed concentrations, implying disruption of balance between generation and clearance of 1O2. In summary, DKAs not only produce reproductive toxicological effects on F0-zebrafish, but also result in adverse consequences for growth and development of F1-zebrafish. PMID- 28342329 TI - Cheese powder as an ingredient in emulsion sausages: Effect on sensory properties and volatile compounds. AB - Different types of cheese powder were added to meat emulsion sausages in order to address its influence on chemical composition, volatile compounds profile and sensory properties, and its potential to reduce salt content through boosting saltiness. Addition of cheese powder to emulsion sausages modified their profile of volatile compounds. Blue cheese increased some ketones, alcohols, and esters, while brown cheese brought typical Maillard reaction compounds. Overall, addition of cheese powders to sausages enhanced the intensity of flavour traits. A mixture of hard and blue cheese powder showed the highest effect on boosting saltiness, while brown cheese powder showed the strongest umami and meat flavour boosting effect, and sausages with added blue cheese powder showed a more intense aftertaste. Hardness significantly increased due to the addition of blue cheese powder. Addition of cheese powder to emulsion sausages might be an interesting tool to boost flavour and reduce salt content in cooked sausages with no negative effect on saltiness or overall flavour. PMID- 28342330 TI - Probing the magnocellular and parvocellular visual pathways in facial emotion perception in schizophrenia. AB - Schizophrenia patients have well-established deficits in facial emotion perception, which contribute to their poor social functioning. A number of studies have related these deficits to a differential dysfunction in the magnocellular (M) versus parvocellular (P) visual pathway. We assessed 35 schizophrenia patients and 35 healthy individuals on an emotion identification task, in which facial stimuli were either unaltered (broad spatial frequency, BSF) or manipulated to contain only high (HSF) or low (LSF) spatial frequencies, thereby respectively biasing the visual system toward the P- or M- pathways. As expected, patients were less accurate and slower in recognizing emotions across all conditions, relative to controls. Performance was best in the BSF condition followed by the HSF and finally the LSF condition, in both groups. A significant group by spatial frequency interaction reflected a smaller magnitude of impairment in the HSF condition, compared to the other two conditions that preferentially engage the M-system. These findings are consistent with studies showing a differential M-pathway abnormality in schizophrenia with a less pronounced impairment in P-function. The current study suggests that patients have less difficulty extracting emotional content from faces when LSFs are attenuated and supports the need to remediate basic visual processing deficits in schizophrenia. PMID- 28342331 TI - Drought stress obliterates the preference for ammonium as an N source in the C4 plant Spartina alterniflora. AB - The C4 grass Spartina alterniflora is known for its unique salt tolerance and strong preference for ammonium (NH4+) as a nitrogen (N) source. We here examined whether Spartina's unique preference for NH4+ results in improved performance under drought stress. Manipulative greenhouse experiments were carried out to measure the effects of variable water availability and inorganic N sources on plant performance (growth, photosynthesis, antioxidant, and N metabolism). Drought strongly reduced leaf number and area, plant fresh and dry weight, and photosynthetic activity on all N sources, but the reduction was most pronounced on NH4+. Indeed, the growth advantage seen on NH4+ in the absence of drought, producing nearly double the biomass compared to growth on NO3-, was entirely obliterated under both intermediate and severe drought conditions (50 and 25% field capacity, respectively). Both fresh and dry weight became indistinguishable among N sources under drought. Major markers of the antioxidant capacity of the plant, the activities of the enzymes superoxide dismutase, catalase, ascorbate peroxidase, and glutathione reductase, showed higher constitutive levels on NH4+. Catalase and glutathione reductase were specifically upregulated in NH4+-fed plants with increasing drought stress. This upregulation, however, failed to protect the plants from drought stress. Nitrogen metabolism was characterized by lower constitutive levels of glutamine synthetase in NH4+-fed plants, and a rise in glutamate dehydrogenase (GDH) activity under drought, accompanied by elevated proline levels in leaves. Our results support postulates on the important role of GDH induction, and its involvement in the synthesis of compatible solutes, under abiotic stress. We show that, despite this metabolic shift, S. alterniflora's sensitivity to drought does not benefit from growth on NH4+ and that the imposition of drought stress equalizes all N-source-related growth differences observed under non-drought conditions. PMID- 28342332 TI - Steady state and dynamic behaviors of a methane biofilter under periodic addition of ethanol vapors. AB - Ethanol was added to a methane (CH4) biofilter with inorganic packing materials over three cycles based on increasing the gas flow rates from 3 to 6 and finally to 12 L min-1 corresponding to empty bed residence times (EBRT) of 6, 3 and 1.5 min. The steady state performance of the CH4 biofilter was studied for CH4 inlet loads (ILs) of 33, 66 and 132 gCH4 m-3 h-1 prior and after each ethanol cycle. In addition, the steady state removal of a mixture of CH4 and ethanol for a CH4/ethanol mass ratio of around 7.5 gCH4 g -1ethanol was evaluated over three cycles (EBRTs of 6, 3 and 1.5 min). In the absence of ethanol, the CH4 removal efficiency (RE) dropped from 35 to 7% due to an EBRT decrease from 6 to 1.5 min. In addition, the presence of ethanol resulted in a CH4 RE reduction at a constant EBRT in every cycle. The CH4 REs dropped from 35 to 29%, 17 to 13% and 7 to 0% for corresponding ethanol ILs of 4.5, 9 and 18 gethanol m-3 h-1 over the cycles. Moreover, the periodic presence of ethanol in the CH4 biofilter allowed the study of transient behaviors of the biofilter during ethanol addition and the biofilter recovery after each cycle. The CH4 RE reduction as a result of ethanol addition in each cycle was instantaneous. However, the CH4 RE recovery after completion of ethanol addition took 10, 14 and 25 days for ethanol ILs of 4.5, 9 and 18 gethanol m-3 h-1 respectively. The recovery time was related to the ethanol concentration in the leachate which were 1100 +/- 200, 1100 +/- 350 and 2500 +/- 400 gethanol m-3leachate for corresponding ethanol ILs of 4.5, 9 and 18 gethanol m-3 h-1, respectively. Based on steady state and dynamic process conditions of the biofilter, the lowest gas flow rate of 3 L min-1 (EBRT of 6 min) produced the best performance when both pollutants were present (CH4 IL of 33 gCH4 m-3 h-1 and ethanol IL of 4.5 gethanol m-3 h-1). PMID- 28342333 TI - Evidence for the involvement of heme oxygenase-1 in the antidepressant-like effect of zinc. AB - BACKGROUND: Considering that heme oxygenase-1 (HO-1) and the brain-derived neurotrophic factor (BDNF)-mediated pathway are involved in the pathophysiology of depression and that zinc has been shown to exert beneficial effects in the management of depression, this study investigated the influence of these targets on the antidepressant-like effect of zinc. METHODS: Mice were treated with sub effective or effective doses of zinc chloride (ZnCl2, 10mg/kg, po), and 45min later, they received intracerebroventricular (icv) injections of sub-effective doses of either zinc protoporphyrin IX (ZnPP, 10MUg/mouse, HO-1 inhibitor), cobalt protoporphyrin IX (CoPP, 0.01MUg/mouse, HO-1 inducer) or K-252a (1MUg/mouse, TrkB receptor antagonist). Immobility time and locomotor activity were evaluated through the tail suspension test (TST) and open-field test (OFT), respectively. HO-1 immunocontents were evaluated in the prefrontal cortex and hippocampus 60min after ZnCl2 (10mg/kg, po) treatment. RESULTS: The antidepressant-like effect of ZnCl2 was prevented by the treatment with ZnPP and K-252a. Furthermore, sub-effective doses of CoPP and ZnCl2 produced a synergistic antidepressant-like effect in the TST. None of the treatments altered locomotor activity. ZnCl2 administration increased HO-1 immunocontents only in the prefrontal cortex. CONCLUSIONS: The results indicate that the antidepressant-like effect of ZnCl2 in the TST may depend on the induction of HO-1, and activation of TrkB receptor. PMID- 28342335 TI - Enhanced antimicrobial efficacy of thermal-reduced silver nanoparticles supported by titanium dioxide. AB - The antimicrobial efficacy of silver nanoparticles (AgNPs) is influenced by many factors, including the particle size, AgNP oxidation state and support materials. In this study, AgNPs are synthesized and supported by two types of TiO2 powders (P25 and Merck TiO2) using two heat-treatment temperatures (120 and 200 degrees C). The formation of well-dispersed AgNPs with diameters ranging from 3.2 to 5.7nm was confirmed using transmission electron microscopy. X-ray photoelectron spectroscopy and X-ray diffraction indicated that the majority of the AgNPs were reduced from Ag+ to Ag0 at 200 degrees C. The AgNP antimicrobial activity was determined by the zone of inhibition against three fungi, A. niger, P. spinulosum and S. chartarum, and two bacteria, E. coli (Gram-negative) and S. epidermidis (Gram-positive). The antimicrobial activity of metallic AgNPs was more pronounced than that of silver nitrate and some antimicrobial drugs. The AgNPs exhibited optimal antimicrobial efficacy when the AgNP dispersion on the surface of TiO2 was in the region between 0.2 and 0.7MUg-Ag/m2. The minimum (critical) AgNP concentrations needed to inhibit the growth of bacteria (E. coli) and fungi (A. niger) were 13.48 and 25.4MUg/mL, respectively. The results indicate that AgNPs/TiO2 nanocomposites are a promising disinfectant against both bacteria and fungi. PMID- 28342334 TI - Oncogene addiction in non-small cell lung cancer: Focus on ROS1 inhibition. AB - Detection of molecular aberrations driving the biology and the clinical behavior of advanced non-small cell lung cancer (NSCLC) allows the adoption of specific therapeutic strategies dramatically impacting disease courses. Among these, ROS1 rearrangements are present in 1-2% of lung adenocarcinomas. Thanks to similarities between ALK and ROS1 oncogenes, lessons inferred from ALK can be applied to ROS1-positive NSCLC; nevertheless, disparities exist between diseases mastered by these two fusion genes. In the absence of more common genetic alterations detected in NSCLC (e.g. EGFR and KRAS mutations, ALK gene fusions), seeking for ROS1 rearrangements is crucial. Dedicated molecular diagnostics should be standardized, hopefully relying upon practical and efficient algorithms, comprehending immunohistochemistry and fluorescence in situ hybridisation. The major clinical impact exerted by crizotinib represents the main reason for which not even a sole ROS1-positive tumor should be undetected. The recent approval of the inhibitor by both American and European health agencies would hopefully boost the widespread testing for ROS1, eventually increasing the absolute number of positive cases, potential further source of information regarding molecular and clinical resistance. In vitro and clinical evidence have already been generated concerning crizotinib resistance and strategies to maintain patients under specific driver-inhibition are being successfully developed. Gathering data concerning diagnostics, preclinical evidence, clinical practice and ongoing studies, the present review depicts the current scenario of ROS1 inhibition in NSCLC. PMID- 28342336 TI - Clinical implications of acute pelvicaliceal hematoma formation during percutaneous catheter nephrostomy insertion. AB - PURPOSE: To determine the clinical implications of acute pelvicaliceal hematoma formation during percutaneous catheter nephrostomy (PCN) insertion. METHODS: Collecting system hematoma burden was retrospectively assessed for 694 PCN insertions in 502 patients. RESULTS: Pelvicaliceal hematoma formation occurred in 146 kidneys (21%) in 136 patients. Clinically significant blood loss occurred in 3 patients with hematomas within one week compared to 4 patients without hematomas (p=0.39). Twenty-four patients with hematomas underwent catheter exchange within one week, compared to 55 patients without hematomas (p=0.49). CONCLUSION: Pelvicaliceal hematoma formation after PCN insertion is not uncommon and is associated with very rare clinical sequelae. PMID- 28342337 TI - Nice guys: Homozygocity for the TPH2 -703G/T (rs4570625) minor allele promotes low aggressiveness and low anxiety. AB - BACKGROUND: Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin. We examined whether the TPH2 polymorphism -703G/T (rs4570625) is associated with aggressiveness and impulsivity, and the prevalence of psychiatric disorders, in a population-representative sample. METHODS: We used self and proxy reports on aggressive behaviour in the younger birth cohort of the longitudinal Estonian Children Personality, Behaviour and Health Study collected at age 25, and earlier collected impulsivity and related data of both ECPBHS cohorts. RESULTS: The TT homozygous males reported less aggressive behaviour in the Life History of Aggression interview at age 25. They also had significantly lower scores in Illinois Bully Scale peer reports, and less ADHD symptoms rated by teachers both at ages 9 and 15. The TT homozygotes of both sexes had the lowest Maladaptive Impulsivity at ages 18 and 25, and the highest Adaptive Impulsivity at age 25. The TT homozygotes also had low depressiveness and trait anxiety by age 25, and the odds ratio for the prevalence of anxiety disorders was 9.38 for the G-allele carriers. LIMITATIONS: The main limitation of the study is the naturally occurring low number of subjects with the TT genotype. CONCLUSIONS: Subjects with the TPH2 rs4570625 TT genotype, especially males, exhibit less aggression and a favourable impulsivity profile, and develop anxiety disorders by young adulthood less often. PMID- 28342338 TI - Antidepressants and risk of cataract development: A population-based, nested case control study. AB - BACKGROUND: Previous studies demonstrated increased risk of cataract development among users of selective serotonin reuptake inhibitors (SSRIs). However, it remains unknown whether this risk also prevails with the use of other types of antidepressants. The aim of this study was to investigate whether use of antidepressants is associated with an increased risk of cataract development. Moreover, the relationship between binding affinities of serotonin transporter (SERT) of antidepressant and the risk of cataracts is examined. METHODS: We conducted a nested case-control study using National Health Insurance Research Database in Taiwan. A total of 14,288 patients were included; 7651 in the cataract group and 6637 in the control group. Antidepressant exposure was categorized by type, duration of use, and binding affinities of SERT. The association between antidepressant exposure and cataract development was assessed using conditional logistic regression analysis. RESULTS: The adjusted odds ratios (AORs) for developing cataracts among continuous users of SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), and other antidepressants were 1.26 (95% confidence interval (CI): 1.12-1.41, p<0.001), 1.21 (95% CI: 1.02-1.43, p=0.027), and 1.18 (95% CI: 1.04-1.34, p=0.009) respectively. Specifically, continuous uses of fluoxetine (AOR: 1.21; 95% CI: 1.01-1.46, p=0.042), fluvoxamine (AOR: 1.47; 95% CI: 1.01-2.12, p=0.043), venlafaxine (AOR: 1.44; 95% CI: 1.19-1.74, p<0.001) significantly increased the risk of cataract development. Moreover, continuous users of antidepressants with intermediate SERT binding affinities (AOR: 1.68; 95% CI: 1.10-2.56, p=0.017) were significantly associated with increased risks of cataract development. LIMITATIONS: Several confounding factors such as obesity, multiple drug users, family history of cataracts, substance use, and environmental factors (such as sunlight or radiation exposure) were acquired. CONCLUSIONS: We found increased risk of cataract development in patients continuously using antidepressants. Regular ocular evaluations in these patients are warranted. PMID- 28342339 TI - A novel hybrid strategy for PM2.5 concentration analysis and prediction. AB - The analysis and prediction of air pollutants are of great significance in environmental research today since airborne pollution is a substantial threat, especially in urban agglomerations of China. To develop more effective warning systems and management advice, the authorities and city dwellers need more accurate forecasts of the air pollution. Most previous analysis systems were based on costly observation apparatus at fixed sites, forecasting models were usually built on observations within a certain range, and some observations contained biases. In this paper, a novel and effective framework, termed HML AFNN, was successfully developed to analyse and forecast the concentration of particular matter (PM2.5) for a selected number of forward time steps. In a simulation of the trajectory of air pollutants, the high-dimension association rules (HDAR) approach considered the tempo-spatial relations, as well as the meteorological and geographical factors of the ambient regions, as parameters. In addition, the learning vector quantization (LVQ) network was adopted to select the appropriate inputs to improve the efficiency of the training process. Moreover, an adaptive fuzzy neural network (AFNN), a combination of neural and fuzzy logic, was utilized to analyse and predict the PM2.5 concentration. The experiment results of our study on two major urban agglomerations of China, the Jing-Jin-Ji area and Pearl River Delta, over a period of more than one year demonstrated that the developed hybrid HML-AFNN model outperforms a plain AFNN, an HM-AFNN model without LVQ and the least squares support vector machines (LS SVM); this superior performance can be determined from the values of several error indexes, including MAE, MAPE and band errors. This hybrid model, which has robust and accurate results, shows the potential to be a political and administrative method to issue effective early warnings and to design suitable abatement strategies. PMID- 28342341 TI - Evaluation of heavy crude oil from a water-oil model system as starting material for the preparation of adsorbents type NaY zeolite-templated carbon. AB - In this work, NaY zeolite is explored as a possible "template" to obtain porous materials type ZTC from the adsorption of heavy crude oil in a water-oil model system (emulsion). In order to produce the adsorbents, a cationic surfactant is selected to facilitate the adsorption of the crude oil into the pores of the zeolite and to get the composite, which was activated with controlled thermal treatments (T: 700-800 degrees C and t: 0.5-1 h) in inert conditions (N2 gaseous). The starting materials, composite and porous carbons were characterized using structural/surface analysis techniques (API Gravity, SARA, IR, XRD, XRF, TGA, Langmuir isotherms, BET and SEM). The results showed that four types of mesoporous carbons were produced with specific surface areas between 70 +/- 1 m2/g and 220 +/- 3 m2/g, average pore volumes between 0.144 cm3/g and 0.40 cm3/g and average pore widths between 4.9 nm and 8.3 nm. The activation conditions of 800 degrees C and 1 h allowed to make the carbonaceous material with the best surface characteristics (220 +/- 3 m2/g, 0.27 cm3/g, and 4.9 nm). Therefore, it is concluded that under assay conditions employed, the heavy crude oil, as a mixed model (water-oil), from an aqueous environment is a starting material suitable for preparation of "mesoporous" carbons. PMID- 28342340 TI - Cellulose decomposition and larval biomass production from the co-digestion of dairy manure and chicken manure by mini-livestock (Hermetia illucens L.). AB - World trends toward the modern dairies intensification on large production units cause massive animal manure production and accumulation. Improper handling of manure produced by industrial farm operation greatly deteriorates the major environmental media including air, water and soil. The black soldier fly utilizes organic waste and converts it into larvae biomass to be used as livestock feed and into residues to be used as bio-fertilizer. However, due to the high ratio of cellulose, hemicellulose and lignin in dairy manure, this conversion is difficult. Therefore, dairy manure treated with chicken manure was digested by Hermetia illucens. In this paper, we found that the co-digestion process significantly enhanced the larval production, waste mass reduction, rate of larvae conversion, feed conversion ratio, nutrient reduction and fibers utilization. Whereas 40% dairy manure and 60% chicken manure group show better results than other manure mixtures and had a significantly increased the cellulose consumption by 61.19%, hemicellulose consumption by 53.22% and lignin consumption by 42.23% compared with 49.89%, 49.77% and 31.95%, respectively, in the dairy-only manure group. Finally, scanning electron microscopy was used to analyze the structural changes of dairy manure, chicken manure and their co digestion mixtures. The scan electron microscopy showed the deterioration in the structure of dairy and chicken manure fibers by Hermetia illucens. Moreover, the carbon-nitrogen ratio was decreased in all end products of post vermicomposting. The results suggest that the co-digestion of 40% dairy manure with 60% chicken manure is an appropriate proportion for dairy manure management with the black soldier fly. PMID- 28342342 TI - Radon concentration distributions in shallow and deep groundwater around the Tachikawa fault zone. AB - Groundwater radon concentrations around the Tachikawa fault zone were surveyed. The radon concentrations in shallow groundwater samples around the Tachikawa fault segment are comparable to previous studies. The characteristics of the radon concentrations on both sides of the segment are considered to have changed in response to the decrease in groundwater recharge caused by urbanization on the eastern side of the segment. The radon concentrations in deep groundwater samples collected around the Naguri and the Tachikawa fault segments are the same as those of shallow groundwater samples. However, the radon concentrations in deep groundwater samples collected from the bedrock beside the Naguri and Tachikawa fault segments are markedly higher than the radon concentrations expected from the geology on the Kanto plane. This disparity can be explained by the development of fracture zones spreading on both sides of the two segments. The radon concentration distribution for deep groundwater samples from the Naguri and the Tachikawa fault segments suggests that a fault exists even at the southern part of the Tachikawa fault line. PMID- 28342343 TI - Plant uptake of 238U, 235U, 232Th, 226Ra, 210Pb and 40K from a coal ash and slag disposal site and control soil under field conditions: A preliminary study. AB - The aim of this study was to investigate the uptake of 238U, 235U, 232Th, 226Ra, 210Pb and 40K by plants that grow on a coal ash and slag disposal site known for its higher content of naturally occurring radionuclides. Plant species that were sampled are common for the Mediterranean flora and can be divided as follows: grasses & herbs, shrubs and trees. To compare the activity concentrations and the resultant concentration ratios of the disposal site with those in natural conditions, we used control data specific for the research area, obtained for plants growing on untreated natural soil. Radionuclide activity concentrations were determined by high resolution gamma-ray spectrometry. Media parameters (pH, electrical conductivity and organic matter content) were also analysed. We confirmed significantly higher activity concentrations of 238U, 235U, 226Ra and 210Pb in ash and slag compared to control soil. However, a significant increase in the radionuclide activity concentration in the disposal site's vegetation was observed only for 226Ra. On the contrary, a significantly smaller activity concentration of 40K in ash and slag had no impact on its activity concentration in plant samples. The calculated plant uptake of 238U, 235U, 226Ra and 210Pb is significantly smaller in comparison with the uptake at the control site, while it is vice versa for 40K. No significant difference was observed between the disposal site and the control site's plant uptake of 232Th. These results can be the foundation for further radioecological assessment of this disposal site but also, globally, they can contribute to a better understanding of nature and long term management of such disposal sites. PMID- 28342344 TI - Water hardness determines 226Ra uptake in the tropical freshwater mussel. AB - Chemical data for freshwater mussels (Velesunio spp.) and water from 15 sampling sites in the Alligator Rivers Region and Rum Jungle uranium provinces in tropical Northern Australia were analysed to develop a predictive model of radium-226 (226Ra) bioaccumulation for variable water calcium (Ca) and magnesium (Mg) concentrations. Application of the model as a 226Ra screening approach for freshwater mussels in tropical waterbodies potentially impacted by operational or remediated uranium mine sites is discussed in relation to Mudginberri Billabong, located approximately 12 km downstream of Ranger uranium mine in the Alligator Rivers Region. PMID- 28342345 TI - Use of exhaled air as an improved biomonitoring method to assess perchloroethylene short-term exposure. AB - This paper shows the use of exhaled air as a biomonitoring method to assess perchloroethylene (PERC) environmental and occupational exposure. A sensitive, fast, and solvent free analytical method was developed to determine PERC in ambient and exhaled air of individuals occupationally exposed. The developed method used cold fiber solid phase microextraction (CF-SPME) as the sampling technique, and a standard permeation method to simulation of air matrix. The analysis were conducted by gas chromatography coupled to mass spectrometry (GC/MS). The methods were validated and were found to be precise, linear and sensitive for environmental and biological monitoring. The developed methods were applied to twenty-seven sampling points spread across Belo Horizonte city, Brazil, twenty four dry cleaners, an electroplating industry, a research laboratory, and an automotive paint preparation shop. The results of ambient air analyses ranging from 14.0 to 3205.0ugm-3 with median concentration of 599.0ugm 3. Furthermore, sampling of exhaled air of individuals occupationally exposed presented results ranging from 6.0 to 2635.0ugm-3 with median concentration of 325.0ugm-3. The strong correlation observed between ambient and exhaled air (r =0.930) demonstrates that exhaled air is a suitable biomarker for evaluating occupational exposure to PERC. PMID- 28342346 TI - Can wastewater-based epidemiology be used to evaluate the health impact of temperature? - An exploratory study in an Australian population. AB - Ambient temperature is known to have impact on population health but assessing its impact by the traditional cohort approach is resource intensive. Wastewater based epidemiology (WBE) could be an alternative for the traditional approach. This study was to provide the first evaluation to see if WBE can be used to assess the impact of temperature exposure to a population in South East Queensland, Australia using selected pharmaceuticals and personal care products (PPCPs) as biomarkers. Daily loads of eight PPCPs in wastewater collected from a wastewater treatment plant were measured from February 2011 to June 2012. Corresponding daily weather data were obtained from the closest weather station. Missing data of PPCPs were handled using the multiple imputation (MI) method, then we used a one-way between-groups analysis of variance to examine the seasonal effect on daily variation of PPCPs by seasons. Finally, an MI estimate was performed to evaluate the continuous relationship between daily average temperature and each multiply-imputed PPCP using time-series regression analysis. The results indicated that an increase of 1 degrees C in average temperature associated with decrease at 1.3g/d (95% CI: -2.2 to (-0.4), p<0.05) for atenolol, increase at 36.5g/d (95% CI: 25.2-47.8, p<0.01) for acesulfame, and increase at 0.8g/d (95% CI: 0.02-1.55, p=0.05) for naproxen. No significant association was observed between temperature and the remaining PPCPs, comprising: caffeine, carbamazepine, codeine, hydrochlorothiazide, and salicylic acid. The findings suggested that consumption of sweetened drinks, risk of worsening cardiovascular conditions and pains are associated with variation in ambient temperature. WBE can thus be used as a complementary method to traditional cohort studies in epidemiological evaluation of the association between environmental factors and health outcomes provided that specific biomarkers of such health outcomes can be identified. PMID- 28342347 TI - Assumed non-persistent environmental chemicals in human adipose tissue; matrix stability and correlation with levels measured in urine and serum. AB - The aim of this study was to (1) optimize a method for the measurement of parabens and phenols in adipose tissue, (2) evaluate the stability of chemical residues in adipose tissue samples, and (3) study correlations of these compounds in urine, serum, and adipose tissue. Samples were obtained from adults undergoing trauma surgery. Nine phenols and seven parabens were determined by isotope diluted TurboFlow-LC-MS/MS. The analytical method showed good accuracy and precision. Limits of detection (LOD) for parabens and phenols ranged from 0.05 to 1.83ng/g tissue. Good recovery rates were found, even when biological samples remained defrosted up to 24h. Benzophenone-3 (BP-3; range of values: 70% of adipose tissue samples, while bisphenol-A (BPA; 40% of adipose tissue samples. In general, levels were similar between adipose tissue and serum, while a correlation between adipose tissue and urine was only found for BP-3. In conclusion, adipose tissue samples in this study were found to contain environmental chemicals considered to be non-persistent, whose levels were weakly or not at all correlated with the urine burden. Therefore, adipose tissue may potentially provide additional information to that obtained from other biological matrices. Further investigations are warranted to explore whether adipose tissue might be a suitable matrix for assessment of the consequences for human health of mid/long-term exposure to these chemicals. PMID- 28342348 TI - Circulating thyroid hormones and associated metabolites in white whales (Delphinapterus leucas) determined using isotope-dilution mass spectrometry. AB - Blood was sampled from nine free-ranging white whales (beluga whale, Delphinapterus leucas) from Svalbard, Norway during the summers of 2013 and 2014. Total concentrations of eleven thyroid hormones and metabolites were measured in serum using a novel liquid chromatography tandem mass spectrometry analytical method. Measurements of these compounds in plasma gave the same results as in serum. The three hormones found in highest concentrations were 3,3',5 triiodothyronine (T3), 3,3',5'-triiodothyronine (rT3) and thyroxine (T4). Traces of associated metabolites were also found. PMID- 28342350 TI - Challenges for tree officers to enhance the provision of regulating ecosystem services from urban forests. AB - Urbanisation and a changing climate are leading to more frequent and severe flood, heat and air pollution episodes in Britain's cities. Interest in nature based solutions to these urban problems is growing, with urban forests potentially able to provide a range of regulating ecosystem services such as stormwater attenuation, heat amelioration and air purification. The extent to which these benefits are realized is largely dependent on urban forest management objectives, the availability of funding, and the understanding of ecosystem service concepts within local governments, the primary delivery agents of urban forests. This study aims to establish the extent to which British local authorities actively manage their urban forests for regulating ecosystem services, and identify which resources local authorities most need in order to enhance provision of ecosystem services by Britain's urban forests. Interviews were carried out with staff responsible for tree management decisions in fifteen major local authorities from across Britain, selected on the basis of their urban nature and high population density. Local authorities have a reactive approach to urban forest management, driven by human health and safety concerns and complaints about tree disservices. There is relatively little focus on ensuring provision of regulating ecosystem services, despite awareness by tree officers of the key role that urban forests can play in alleviating chronic air pollution, flood risk and urban heat anomalies. However, this is expected to become a greater focus in future provided that existing constraints - lack of understanding of ecosystem services amongst key stakeholders, limited political support, funding constraints - can be overcome. Our findings suggest that the adoption of a proactive urban forest strategy, underpinned by quantified and valued urban forest-based ecosystem services provision data, and innovative private sector funding mechanisms, can facilitate a change to a proactive, ecosystem services approach to urban forest management. PMID- 28342351 TI - The impact of well-field configuration and permeability heterogeneity on contaminant mass removal and plume persistence. AB - The purpose of this study is to investigate the effects of well-field hydraulics and permeability heterogeneity on mass-removal efficiency for systems comprising large groundwater contaminant plumes. A three-dimensional (3D) numerical model was used to simulate the impact of different well-field configurations on pump and-treat mass removal for heterogeneous domains. The relationship between reduction in contaminant mass discharge (CMDR) and mass removal (MR) was used as the metric to examine remediation efficiency. The impacts of well-field configuration on mass removal behavior are attributed to mass-transfer constraints related to regions of low flow associated with the well field, which can be muted by the influence of permeability heterogeneity. These impacts are reflected in the associated CMDR-MR profiles. Systems whose CDMR-MR profiles are below the 1:1 relationship line are associated with more efficient well-field configurations. The impact of domain heterogeneity on mass-removal effectiveness was investigated in terms of both variance and correlation scale of the random permeability distributions and indexed by the CMDR-MR relationship. Data collected from pump-and-treat operations conducted in a section of the Tucson International Airport Area (TIAA) federal Superfund site were used as a case study. The comparison between simulated and measured site data supports the general validity of the numerical model, and results from the case study are consistent with the conclusions of the theoretical study. These results illustrate that the CMDR-MR relationship can be an effective way to quantify the impacts of different factors on mass-removal efficiency. PMID- 28342352 TI - Mechanochemical mechanism of rapid dechlorination of hexachlorobenzene. AB - Recent researches indicate that mechanochemical treatment (MCT) is a promising method to degrade the environmental hazards, especially in the area of persistent organic pollutants (POPs) disposal. However, the mechanochemical dechlorination mechanism of POPs still needs to be further verified. In this mechanochemical process, hexachlorobenzene (HCB) was chosen as a model pollutant with aluminum and alumina (Al+Al2O3) powders as the co-milling regents. Both of the intermediate analysis and quantum chemical calculations were adopted to elucidate the free radical dechlorination mechanism of HCB. The solid residues were characterized by electron spin-resonance (ESR) spectroscopy, Fourier transform infrared (FTIR) spectra and X-ray photoelectron (XPS) spectra, which proposed that the radicals formed in the mechanochemical process were chlorinated phenoxyl radicals (CB-O). Four quantum chemical descriptors were selected in predicting the intermediates and reaction pathway: (i) atomic charge, (ii) electrostatic potential (ESP), (iii) frontier molecular orbitals (FMO) theory and (iv) dual descriptor. Then, a stepwise dechlorination mechanism based on CB-O was proposed. It was found that the intermediates and radical-related reactions in the mechanochemical dechlorination of HCB are quite different from that happen in a typical photocatalytic dechlorination process. Impacts of different radical reactions on the dechlorination of HCB were also compared at last. PMID- 28342349 TI - Evaluation of individual and area-level factors as modifiers of the association between warm-season temperature and pediatric asthma morbidity in Atlanta, GA. AB - INTRODUCTION: Previous studies have found associations between respiratory morbidity and high temperatures; however, few studies have explored associations in potentially sensitive sub-populations. METHODS: We evaluated individual and area-level factors as modifiers of the association between warm-season (May Sept.) temperature and pediatric respiratory morbidity in Atlanta. Emergency department (ED) visit data were obtained for children, 5-18 years old, with primary diagnoses of asthma or respiratory disease (diagnoses of upper respiratory infections, bronchiolitis, pneumonia, chronic obstructive pulmonary disease, asthma, or wheeze) in 20-county Atlanta during 1993-2012. Daily maximum temperature (Tmax) was acquired from the automated surface observing station at Atlanta Hartsfield International Airport. Poisson generalized linear models were used to estimate rate ratios (RR) between daily Tmax and asthma or respiratory disease ED visits, controlling for time and meteorology. Tmax effects were estimated for single-day lags of 0-6 days, for 3-, 5-, and 7-day moving averages and modeled with cubic terms to allow for non-linear relationships. Effect modification by individual factors (sex, race, insurance status) and area-level socioeconomic status (SES; ZIP code levels of poverty, education, and the neighborhood deprivation index) was examined via stratification. RESULTS: Estimated RRs for Tmax and pediatric asthma ED visits were positive and significant for lag days 1-5, with the strongest single day association observed on lag day 2 (RR=1.06, 95% CI: 1.03, 1.09) for a change in Tmax from 27 degrees C to 32 degrees C (25th to 75th percentile). For the moving average exposure periods, associations increased as moving average periods increased. We observed stronger RRs between Tmax and asthma among males compared to females, non-white children compared to white children, children with private insurance compared to children with Medicaid, and among children living in high compared to low SES areas. Associations between Tmax and respiratory disease ED visits were weak and non-significant (p-value>0.05). CONCLUSIONS: Results suggest socio-demographic factors (race/ethnicity, insurance status, and area-level SES) may confer vulnerability to temperature-related pediatric asthma morbidity. Our findings of weaker associations among children with Medicaid compared to other health insurance types and among children living in low compared to high SES areas run counter to our belief that children from disadvantaged households or ZIP codes would be more vulnerable to the respiratory effects of temperature. The potential reasons for these unexpected results are explored in the discussion. PMID- 28342353 TI - Preparation of a surface-grafted imprinted ceramic membrane for selective separation of molybdate anion from water solutions. AB - A surface-grafted imprinted ceramic membrane (IIP-PVI/CM) for recognizing molybdate (Mo(VI)) anion was prepared by surface-initiated graft-polymerization. Firstly, raw alumina ceramic membrane (CM) was deposited with SiO2 active layer by situ hydrolysis deposition method. Subsequently, gamma-methacryloxy propyl trimethoxyl silane (MPS) was used as a coupling agent to introduce double bonds onto the SiO2 layer (MPS-CM). Then, 1-vinylimidazole (VI) was employed as a functional monomer to graft-polymerization onto the MPS-CM (PVI-CM). During the graft-polymerization, the influence factors of grafting degree of PVI were investigated in detail. Under optimum conditions (monomer concentration 20wt%, temperature 70 degrees C, initiator amount 1.1wt% and reaction time 8h), the grafting degree of 20.39g/100g was obtained. Further, Mo(VI) anion was used as a template to imprint in the PVI-CM by employing 1,6-dibromohexane as a cross linking agent, and then Mo(VI) was removed, obtaining the IIP-PVI/CM with many imprinted cavities for Mo(VI). Thereafter, static adsorption and dynamic separation properties of IIP-PVI/CM for Mo(VI) were studied. Results indicate that IIP-PVI/CM shows a specific selectivity for Mo(VI) with the adsorption capacity of 0.69mmol/100g, and the selectivity coefficient of IIP-PVI/CM is 7.48 for molybdate to tungstate anions. During the dynamic separation, IIP-PVI/CM has also good selectivity for separation of Mo(VI) and W(VI) anions. PMID- 28342354 TI - Integrated ion imprinted polymers-paper composites for selective and sensitive detection of Cd(II) ions. AB - Paper-based sensor is a new alternative technology to develop a portable, low cost, and rapid analysis system in environmental chemistry. In this study, ion imprinted polymers (IIPs) using cadmium ions as the template were directly grafted on the surface of low-cost print paper based on the reversible addition fragmentation chain transfer polymerization. It can be applied as a recognition element to selectively capture the target ions in the complex samples. The maximum adsorption capacity of IIPs composites was 155.2mgg-1 and the imprinted factor was more than 3.0. Then, IIPs-paper platform could be also applied as a detection element for highly selective and sensitive detection of Cd(II) ions without complex sample pretreatment and expensive instrument, due to the selective recognition, formation of dithizone-cadmium complexes and light transmission ability. Under the optimized condition, the linear range was changed from 1 to 100ngmL-1 and the limit of detection was 0.4ngmL-1. The results were in good agreement with the classic ICP-MS method. Furthermore, the proposed method can also be developed for detection of other heavy metals by designing of new IIPs. PMID- 28342355 TI - Pd nanospheres decorated reduced graphene oxide with multi-functions: Highly efficient catalytic reduction and ultrasensitive sensing of hazardous 4 nitrophenol pollutant. AB - We illustrate a facile approach for in situ synthesis of Pd-gum arabic/reduced graphene oxide (Pd-GA/RGO) using GA as the reducing agent, which favors the instantaneous reduction of both Pd ions and GO into Pd nanoparticles (NPs) and RGO. From the morphological analysis of Pd-GA/RGO, we observed highly dispersed spherical 5nm Pd NPs decorated over RGO. The as-synthesized Pd-GA/RGO composite was employed for the catalytic reduction and the electrochemical detection of 4 nitrophenol (4-NP), respectively. The catalytic reduction of 4-NP was highly pronounced for Pd-GA/RGO (5min) when compared to Pd NPs (140min) and Pd/RGO (36min). This enhanced catalytic activity was attributed to the synergistic effect of Pd NPs and the presence of various functional groups of GA. Significantly, the fabricated sensor offered a low detection limit (9fM) with a wider linear range (2-80 pM) and long-term stability. The simple construction technique, high sensitivity, and long-term stability with acceptable accuracy in wastewater samples were the main advantages of the developed sensor. The results indicated that the as-prepared Pd-GA/RGO exhibited better sensing ability than the other graphene-based modified electrodes. Therefore, the proposed sensor can be employed as a more convenient sensing platform for environmental and industrial pollutants. PMID- 28342356 TI - Heterogeneous oxidative desulfurization of diesel fuel catalyzed by mesoporous polyoxometallate-based polymeric hybrid. AB - In this work, the simple preparation of novel polymer supported polyoxometallates (POMs) catalysts has been reported. Soluble task-specific cross-linked poly (ionic liquid) (PIL) was prepared with N,N-dimethyl-dodecyl-(4-vinylbenzyl) ammonium chloride and divinylbenzene as co-monomers. The as-prepared cationic PILs were assembled with different commercial POMs to form the interlinked mesoporous catalysts, and the formation mechanism was provided. The catalytic oxidation activities of the catalysts were closely related to the formation pathway of their corresponding peroxide active species. The catalyst with H2W12O4210- as counterion, which exhibited the best activity in the oxidation of benzothiophene (BT) and dibenzothiophene (DBT) to sulfones in model oil with hydrogen peroxide (H2O2, 30wt%) as oxidant, was characterized by different techniques and systematically studied for its sulfur removal performance. As for the oxidative desulfurization of a real diesel, it was observed that almost all of the original sulfur compounds could be completely converted, and the catalyst could be reused for at least eight cycles without noticeable changes in both catalytic activity and chemical structure. In the end, a catalytic mechanism was put forward with the assistant of Raman analysis. PMID- 28342357 TI - Potential impact of methyl isobutyl ketone (MIBK) on phenols degradation in an UASB reactor and its degradation properties. AB - Methyl isobutyl ketone (MIBK) as a solvent is extensively used for the phenols extraction from the wastewater, so it is unavoidable to expose in the effluent due to the solubility and leakage problem. The present study evaluated the impact of MIBK on phenols degradation in an UASB reactor and analyzed its degradation properties. The results indicated that the continuous dosing (0.1gL-1) and impact (10gL-1) of MIBK had limited effect on phenols removal (1-2% reduction) in the UASB reactor, but the specific methanogenic activity (SMA) values of sludge decreased by 45-75% after MIBK exposure. Anaerobic degradation rate of MIBK fitted well to a pseudo-first-order kinetic equation with respect to the initial concentration of 35mgL-1 (k=0.0115h-1, R2=0.9664). Furthermore, the relative methane generation rate constants of MIBK were 0.00816, 0.00613, 0.00273, and 0.00207d-1 at the initial concentrations of 0.1, 0.5, 5, and 10gL-1, respectively. MIBK showed higher inhibitory effect on the methanogenesis than on phenols degradation. This study pointed out that the industrial installations should consider the influence of solvent on anaerobic treatment of phenolic wastewater. PMID- 28342358 TI - Insight into highly efficient co-removal of p-nitrophenol and lead by nitrogen functionalized magnetic ordered mesoporous carbon: Performance and modelling. AB - Highly efficient simultaneous removal of Pb(II) and p-nitrophenol (PNP) contamination from water was accomplished by nitrogen-functionalized magnetic ordered mesoporous carbon (N-Fe/OMC). The mutual effects and inner mechanisms of their adsorption onto N-Fe/OMC were systematically investigated by sole and binary systems, and thermodynamic, sorption isotherm and adsorption kinetics models. The liquid-film diffusion step might be the rate-limiting step for PNP and Pb(II). The fitting of experimental data with Temkin model indicates that the adsorption process of PNP and Pb(II) involve physisorption and chemisorption. There exist site competition and enhancement of PNP and Pb(II) on the sorption to N-Fe/OMC. Moreover, N-Fe/OMC could be regenerated effectively and recycled by using dilute NaOH and acetone. These demonstrated superior properties of N-Fe/OMC indicate that it could be applied to treatment of wastewaters containing both lead and PNP. PMID- 28342359 TI - Synergetic effect between adsorption and photodegradation on nanostructured TiO2/activated carbon fiber felt porous composites for toluene removal. AB - The low quantum efficiency and limited adsorption efficiency of TiO2 makes it only fit for the removal of VOCs with low concentrations. Herein, we for the first time fabricated nanostructured TiO2/activated carbon fiber felt (TiO2/ACFF) porous composites by the in situ deposition of TiO2 microspheres on the carbon fibers in ACFF. Interestingly, the TiO2 microspheres exhibit hierarchical nanostructures constructed by nanocrystals as building blocks. The TiO2/ACFF porous composites possess excellent adsorption and photodegradation properties for toluene because of the synergetic effects between the nanostructured TiO2 and ACFF. The adsorption efficiencies of the TiO2/ACFF porous composites reach approximately 98% at the toluene concentration (<1150ppm) and approximately 77% even at the high concentration of 6900ppm. Moreover, the ACFF in the TiO2/ACFF porous composites significantly enhances photocatalytic property for toluene by hindering the recombination of electron-hole pairs, reducing the TiO2 band gap energy (Eg) to 2.95eV and accelerating toluene adsorption. At the toluene concentrations of 230ppm and 460ppm, the photocatalytic oxidation efficiency of toluene into CO2 arrives at 100% and 81.5%, respectively. Therefore, the TiO2/ACFF porous composites with synergetic adsorption and photocatalytic activities have great potentials for toluene removal. PMID- 28342360 TI - Ensemble-based release estimation for accidental river pollution with known source position. AB - Dispersion model is an important tool for decision makers to accurately assess risks and effectively plan countermeasures during river pollution accidents, but their applications suffer from significant modeling uncertainties, primarily due to the scarce information of the source. A fully sequential inverse estimation method is proposed to reconstruct the temporal release for accidental river pollution. The method is based on a one-dimensional advection-dispersion model in conjunction with the augmented ensemble Kalman filter method. Detailed analysis of the ensemble background error covariance (BEC) matrix is conducted to elucidate the "flow-dependent" mechanism, which enables the inversion method to simultaneously take into account the uncertainties in the hydrological parameters (mean flow velocity and longitudinal dispersion coefficient). The method is evaluated with six field tracer experiments with various mean flow velocities, ranging from 0.085 to 0.889ms-1, and also compared with the commonly used Tikhonov regularization inverse estimation method to demonstrate its performance improvement. The results indicate that it successfully reconstructs the temporal release and reduces the relative errors of the total release estimation by about 12.4% on average compared with the Tikhonov method, since the errors caused by the uncertainties in mean flow velocity and longitudinal dispersion coefficient are effectively alleviated. PMID- 28342362 TI - The only thing that is constant is change: The 2016 revision to the World Health Organisation classification of myelodysplastic syndrome. PMID- 28342361 TI - Giant leiomyosarcoma of the rectum with lymph node metastasis: A case report and review of the literature. AB - INTRODUCTION: Leiomyosarcoma of the gastrointestinal tract is very rare, with a reported frequency of less than 0.1% of all malignancies of the colorectum. It is important to diagnose leiomyosarcoma definitively by immunohistochemical profiling of smooth muscle actin, desmin, and CD34. True leiomyosarcoma of the colorectum diagnosed by immunnohistochemical profiling is extremely rare that only 13 reports have been published in reviews of resected gastrointestinal mesenchymal tumors after 1998. In addition, lymph node involvement is rare in patients with leiomyosarcoma. Herein we report an aggressive case of LMS in a rectosigmoid lesion with lymph node metastasis. CASE PRESENTATION: A 76-year-old woman visited our hospital complaining of intermittent anal bleeding that had lasted 5 months. Image studies aiming at examining the cause of her anal bleeding revealed a tumor located between the right ovary, uterus, and the rectosigmoid. Histopathology of biopsied materials from the colonoscopy suggested a malignant tumor of mesenchymal origin. Surgical resection was performed with curative intent. The tumor was diagnosed as leiomyosarcoma by pathological examination. Moreover, one of the 31 regional lymph nodes retrieved was metastasized by leiomyosarcoma. Eight months later, follow-up CT scans revealed multiple recurrent lesions in the liver and peritoneum. Despite systematic chemotherapy, she deceased 12 months after the surgery. CONCLUSION: It is crucial to diagnose leioyosarcoma precisely based on immunohistochemistry, and thereby distinguish it from GIST. Although lymph node metastasis is rare, lymphadenectomy appears to be important for high-risk LMSs to perform R0 resection. Further investigation on leiomyosarcoma cases so far is required to establish standard treatment strategies. PMID- 28342363 TI - War during childhood: The long run effects of warfare on health. AB - This paper estimates the causal long-term consequences of an exposure to war in utero and during childhood on the risk of obesity and the probability of having a chronic health condition in adulthood. Using the plausibly exogenous city-by cohort variation in the intensity of WWII destruction as a unique quasi experiment, I find that individuals who were exposed to WWII destruction during the prenatal and early postnatal periods have higher BMIs and are more likely to be obese as adults. I also find an elevated incidence of chronic health conditions such as stroke, hypertension, diabetes, and cardiovascular disorder in adulthood among these wartime children. PMID- 28342364 TI - Therapeutic effect of quercetin in collagen-induced arthritis. AB - Quercetin, a bioactive flavonoid with anti-inflammatory, immunosuppressive, and protective properties, is a potential agent for the treatment of rheumatoid arthritis (RA). Collagen-induced arthritis (CIA) is the most commonly used animal model for studying the pathogenesis of RA. This study analysed the therapeutic role of quercetin in collagen-induced arthritis in C57BL/6 mice. The animals were allocated into five groups that were subjected to the following treatments: negative (untreated) control, positive control (arthritis-induced), arthritis+methotrexate, arthritis+quercetin, and arthritis+methotrexate+quercetin. Assessments of weight, oedema, joint damage, and cytokine production were used to determine the therapeutic effect of quercetin. This study demonstrated for the first time the anti-inflammatory and protective effects of quercetin in vivo in CIA. The results also showed that the concurrent administration of quercetin and methotrexate did not offer greater protection than the administration of a single agent. The use of quercetin as a monotherapeutic agent resulted in the lowest degree of joint inflammation and the highest protection. The reduced severity of the disease in animals treated with quercetin was associated with decreased levels of TNF-alpha, IL-1beta, IL-17, and MCP-1. In conclusion, this study determined that quercetin, which was non-toxic, produced better results than methotrexate for the protection of joints from arthritic inflammation in mice. Quercetin may be an alternative treatment for RA because it modulates the main pathogenic pathways of RA. PMID- 28342365 TI - The effects of propofol on the growth behavior of hepatoma xenografts in Balb/c mice. AB - OBJECTIVE: Studies on the effects of propofol on the growth of hepatoma xenografts in Balb/c mice. METHODS: In an effort to establish a hepatoma xenograft model of BALB/C mice, human hepatocellular carcinoma cells SMMC-7721 were inoculated subcutaneously into BALB/C mice. Forty mice were randomly divided into five different groups (n=8): control group (C group), Intralipid group (Y group), low dose (50mg/kg) propofol group (P1 group), medium dose (100mg/kg) propofol group (P2 group) and high dose (150mg/kg) propofol group (P3 group). The tumor volume was measured before treatment and every 3days after treatment (T0d T18d, T0 represents time point before treatment, T3d-T18d represent time points every 3days after treatment for a total of 18 days). All mice were sacrificed 19days after drug withdrawal. The tumor masses were extracted, weighed, and the tumor inhibition rate of propofol was calculated. The protein levels of matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) in the xenografted tumors were analyzed by immunohistochemistry staining. RESULTS: No statistical significance in the tumor volume at T0d (before treatment), T3d (3days after treatment), and T6d (6days after treatment) among the five groups (P>0.05) could be determined. Compared to group C, the tumor volumes in the P1, P2, and P3 groups were found to be significantly decreased in size upon increasing the propofol dosages (P<0.05). There was no statistical significance at time points T9d-T18d in group Y compared to group C (P>0.05). The tumor weights in the P1, P2, and P3 groups were found to be significantly lower as the propofol dosages increased (P<0.05), with no statistical significance determined in group Y (P>0.05). MMP-2 and VEGF protein levels were found to be significantly lower in the P1, P2, and P3 groups as the propofol dosages increased (P<0.05), with no statistical significance in group Y (P>0.05). CONCLUSION: Within a certain range, propofol was found to inhibit tumor growth and expression of MMP-2 and VEGF proteins in hepatoma xenografts in BALB/C mice in a dose-dependent manner. PMID- 28342367 TI - Optimization of surface electrodes location for H-reflex recordings in soleus muscle. AB - The Hoffmann reflex (H reflex) is extensively used to investigate the spinal motor neuron excitability in healthy and pathological subjects. Obtaining a representative and robust amplitude estimation of the H reflex is of marked relevance in clinical as well as in research applications. As for the motor responses, this issue is strictly related to the electrode positioning, especially for large, pinnate muscles such as the triceps surae. In this study we investigated the effect of electrode position on soleus H-reflex amplitude. A grid of 96 electrodes was used to identify maximal H reflexes (Hmax) across the whole soleus region available for surface recording. The spatial distribution of Hmax amplitude detected in monopolar and single-differential derivations was used to determine where greatest reflex responses were detected from soleus. For both derivations and for all participants, largest Hmax were detected consistently over the central soleus region, in correspondence of the muscle superficial aponeurosis. Indeed, the amplitude of Hmax provided by conventional electrodes (1cm2 area, 2cm apart) located centrally was significantly greater (median: 35% for monopolar and 79% for single-differential derivations) than that obtained medially, where surface electromyograms are typically recorded from soleus. Computer simulations, used to assist in the interpretation of results, suggest the soleus pinnate architecture was the key determinant of the medio-lateral variability observed for the experimental Hmax. The presented results provide a clear indication for electrode positioning, of crucial relevance in applied studies aimed at eliciting H reflexes. PMID- 28342368 TI - Set up of cutoff thresholds for kinship determination using SNP loci. AB - The usefulness of single nucleotide polymorphism (SNP) loci for kinship testing has been demonstrated in many case works, and suggested as a promising marker for relationship identification. For interpreting results based on the calculation of the likelihood ratio (LR) in kinship testing, it is important to prepare cutoffs for respective relatives which are dependent on genetic relatedness. For this, analysis using true pedigree data is significant and reliable as it reflects the actual frequencies of markers in the population. In this study, the kinship index was explored through 1209 parent-child pairs, 1373 full sibling pairs, and 247 uncle-nephew pairs using 136 SNP loci. The cutoffs for LR were set up using different numbers of SNP loci with accuracy, sensitivity, and specificity. It is expected that this study can support the application of SNP loci-based kinship testing for various relationships. PMID- 28342366 TI - Discovery of new dual PPARgamma-GPR40 agonists with robust antidiabetic activity: Design, synthesis and in combo drug evaluation. AB - The design of compounds 1 and 2 was based on the similar scaffold of pharmacophoric groups for PPARgamma and GPR40 agonists. In order to find new compounds with improved biological activity, the current manuscript describes a new dual PPARgamma-GPR40 agonist. We synthesized two compounds, which were prepared following a multistep synthetic route, and the relative mRNA expression levels of PPARgamma, GLUT4, and GPR40 were quantified in cell culture, as well as insulin secretion and [Ca2+] intracellular levels. Compound 1 showed a 7-times increase in the mRNA expression of PPARgamma, which in turn enhanced the expression levels of GLUT4 respect to control and pioglitazone. It also showed an increase of 2-fold in the [Ca2+]i level allowing an increment on insulin release, being as active as the positive control (glibenclamide), causing also an increase of 2-fold in mRNA expression of GPR40. Furthermore, the compound 2 showed lower activity than the compound 1. The ester of 1 showed antidiabetic activity at a 50mg/kg single dose in streptozotocin-nicotinamide-induced diabetic mice model. In addition, we achieved a molecular docking study of compound 1 on PPARgamma and GPR40 receptors, showing a great affinity for both targets. We observed important polar interactions between the carboxylic group and main residues into the binding pocket. Therefore, the compound 1 has a potential for the development of antidiabetic agents with newfangled dual action. PMID- 28342369 TI - Sensing properties of monolayer borophane nanosheet towards alcohol vapors: A first-principles study. AB - The electronic properties of borophane nanosheet and adsorption behavior of three distinct alcohol vapors namely methanol, ethanol and 1-propanol on borophane nanosheet is studied using density functional theory method for the first time. The state-of-the-art provides insights on to the development of new two dimensional materials with the surface passivation on boron nanostructures. The density of states spectrum provides a clear perception on charge transfer upon adsorption of alcohol vapors on borophane nanosheets. The monolayer of borophane band gap widens upon adsorption of alcohol vapors, which can be used for the detection for volatile organic vapors. The adsorption properties of alcohol vapors on borophane base material are analyzed in terms of natural bond orbital, average energy gap variation, adsorption energy and energy gap. The most suitable adsorption sites of methanol, ethanol and 1-propanol molecules on borophane nanosheet are investigated in atomistic level. The adsorption of alcohol molecules on borophane nanosheet is found to be more favorable. The findings suggest that the monolayer borophane nanosheet can be utilized to detect the presence of alcohol vapors in the atmosphere. PMID- 28342370 TI - Fabrication and tribological properties of nanogrids on CVD-grown graphene. AB - We have used atomic force microscopy (AFM) combined with an external sourcemeter to make patterns on CVD-grown graphene, and regular nanogrids have been fabricated on graphene by AFM tip-induced local oxidation. The friction and adhesion properties of graphene with the nanogrids have been characterized by the lateral mode of AFM and the results show that the friction force on the borders of nanogrid is higher than that on the normal area of graphene, yet the adhesion force on the nanogrids decrease slightly due to the change of surface roughness. PMID- 28342371 TI - Contrast enhancement with uranyl acetate allows quantitative analysis of the articular cartilage by microCT: Application to mandibular condyles in the BTX rat model of disuse. AB - Microcomputed tomography (microCT) is well adapted to quantitative analysis of calcified tissues but soft tissues (such as cartilage) are radiolucent and need a contrast enhancement procedure for microCT. We developed a "staining" method allowing microCT imaging of articular cartilage using uranyl acetate (UA). The method was used to see whether adult rats with a botulinum toxin (BTX) injection in masticatory muscles present a change at the condylar cartilage of the mandible in association with a localized trabecular bone loss. Human femoral head samples were used to develop the enhanced contrast method using UA or lanthanides (recently proposed as a substitute for UA). The method was then applied to the condylar cartilage of rat mandibles. Mature male rats (n=11) were randomized into 2 groups: control (CTRL; n=4) and BTX group (n=7). Rats of the BTX group received a single injection of BTX into the right M. Masseter and M. Temporalis. Rats of the CTRL group were similarly injected with saline. Rats were sacrificed 4 weeks after injection. Condyles were harvested, fixed in formalin and immersed in UA. MicroCT was performed for bone and cartilage measurements. After UA impregnation, articular cartilage of human femoral head samples was clearly seen on its full thickness whereas lanthanides produced a much less pronounced contrast, with a faint labeling at the upper layer. In BTX rats, microCT analysis showed a significant bone loss at the right condyles. After UA, the whole thickness of articular cartilage was clearly evidenced. Cartilage thickness measurement showed no difference when comparing the right with the left sides of the BTX group nor between the two sides of the CTRL group. Contrast enhancement with UA is a simple technique allowing quantitative analysis of cartilage by microCT.290 words. PMID- 28342372 TI - Comparison of three sequential extraction procedures for arsenic fractionation in highly polluted sites. AB - Three sequential extraction procedures (SEPs) including Tessier, Rauret, and Shiowatana SEPs, were compared for arsenic fractionation using highly polluted soils. In the definition context of exchangeable, reducible, oxidizable and residual fractions, with similar arsenic recovery and reproducibility, Tessier and Rauret SEPs were comparable to each other, whereas Shiowatana SEP showed higher extraction efficiency in all the first three arsenic fractions, although it might overestimate the reducible arsenic. Pot experiment indicated three SEPs all could provide an estimation of the most bioavailable arsenic fraction, and the application of Shiowatana SEP should be preferred. Accordingly, a case study with Shiowatana SEP for a site near a realgar mine area is conducted. The results show that although arsenic in this area presents predominantly in the stable fractions, the sum of most bioavailable fractions was accounted around 11% of total arsenic, and moreover, about another 10% of the total arsenic, the fourth fraction in Shiowatana SEP is likely to be transferred into bioavailable species under suitable conditions, such as strong acid impact, revealing a real major risk source being formed. The study indicated that Shiowatana should be more suitable for arsenic fractionation to provide valuable information in the framework of risk assessment. PMID- 28342373 TI - Using quantum chemical modeling and calculations for evaluation of cellulose potential for estrogen micropollutants removal from water effluents. AB - This paper is devoted to investigate the suitability of cellulose for estrogens micropollutants removal from water effluent. For this purpose, the sorption of eight estrogens including Estradiol, Estrone, Testosterone, Progesterone, Estriol, Mestranol, Ethinylestradiol and Diethylstilbestrol were investigated. The charge density profiles and sorption curves were obtained and discussed using quantum chemical calculations where the Accelrys Materials Studio software and COSMO-SAC model were employed. The geometry optimization of compound molecule and energy minimizations was performed using the Dmol3 Module and density functional theory of generalized gradient approximate and Volsko-Wilk-Nusair functional. We found that cellulose cannot be a reliable choice of sorbent for removal of Estrone and Estradiol, but it is a poor choice of sorbent for removal of Estriol, Ethinylestradiol. Cellulose can be used for Diethylstilbestrol, Mestranol, Testosterone and Progesterone removal from estrogens containing effluents. PMID- 28342375 TI - Nanozyme-based bio-barcode assay for high sensitive and logic-controlled specific detection of multiple DNAs. AB - Since HCV and HIV share a common transmission path, high sensitive detection of HIV and HCV gene is of significant importance to improve diagnosis accuracy and cure rate at early stage for HIV virus-infected patients. In our investigation, a novel nanozyme-based bio-barcode fluorescence amplified assay is successfully developed for simultaneous detection of HIV and HCV DNAs with excellent sensitivity in an enzyme-free and label-free condition. Here, bimetallic nanoparticles, PtAuNPs, present outstanding peroxidase-like activity and act as barcode to catalyze oxidation of nonfluorescent substrate of amplex red (AR) into fluorescent resorufin generating stable and sensitive "Turn On" fluorescent output signal, which is for the first time to be integrated with bio-barcode strategy for fluorescence detection DNA. Furthermore, the provided strategy presents excellent specificity and can distinguish single-base mismatched mutant from target DNA. What interesting is that cascaded INHIBIT-OR logic gate is integrated with biosensors for the first time to distinguish individual target DNA from each other under logic function control, which presents great application in development of rapid and intelligent detection. PMID- 28342374 TI - Accumulation of alpha-hexabromocyclododecane (alpha-HBCDD) in tissues of fast- and slow-growing broilers (Gallus domesticus). AB - The aim of the current study was to describe the fate of ingested alpha hexabromocyclododecane (alpha-HBCDD) in fast-growing (FG) and slow-growing (SG) broilers, through an exposure to a dietary concentration of 50 ng alpha-HBCDD g-1 feed during 42 and 84 days, respectively. Depuration parameters were assessed in SG broilers successively exposed during 42 days and depurated during 42 days. At market age, SG broilers had ingested 42% more feed than FG broilers, while their body weight gain per g of feed ingested was 34% lower. No isomerization of alpha- to beta- or gamma-HBCDD forms occurred, while OH-HBCDD was identified as a product of alpha-HBCDD metabolism. Irrespective of the strain, abdominal fat displayed the highest alpha-HBCDD concentration on a lipid weight basis, followed leg muscles and then breast muscle, liver and plasma. The accumulation ratios of alpha-HBCDD were slightly higher in SG (6.7, 2.1, 2.6 and 9.9 in leg muscles, breast muscle, liver and abdominal fat, respectively) than in FG broilers (5.2, 2.2, 1.1 and 8.4, respectively). The elimination half-lives in SG broilers were 20, 12 and 19 d in leg muscles, breast muscle and abdominal fat, respectively, to which dilution through growth contributed for around 50%. The overall assimilation efficiency of alpha-HBCDD was estimated at 58 and 50% in FG and SG broilers, respectively, while 22 and 17% of alpha-HBCDD ingested were estimated to be eliminated in excreta as metabolites. PMID- 28342376 TI - Label-free silicon nanodots featured ratiometric fluorescent aptasensor for lysosomal imaging and pH measurement. AB - The homeostasis of lysosomal pH is crucial in cell physiology. Developing small fluorescent nanosensors for lysosome imaging and ratiometric measurement of pH is highly demanded yet challenging. Herein, a pH-sensitive fluorescein tagged aptamer AS1411 has been utilized to covalently modify the label-free fluorescent silicon nanodots via a crosslinker for construction of a ratiometric pH biosensor. The established aptasensor exhibits the advantages of ultrasmall size, hypotoxicity, excellent pH reversibility and good photostability, which favors its application in an intracellular environment. Using human breast MCF-7 cancer cells and MCF-10A normal cells as the model, this aptasensor shows cell specificity for cancer cells and displays a wide pH response range of 4.5-8.0 in living cells. The results demonstrate that the pH of MCF-7 cells is 5.1, which is the expected value for acidic organelles. Lysosome imaging and accurate measurement of pH in MCF-7 cells have been successfully conducted based on this nanosensor via fluorescent microscopy and flow cytometry. PMID- 28342377 TI - Live cell biosensing platforms using graphene-based hybrid nanomaterials. AB - A novel strategy to precisely detect or monitor various biomaterials in living cells poses paramount importance in understanding cellular processes. Graphene, a newly emerged two-dimensional carbon material, has been widely utilized for biosensors owing to its multifarious characteristics including mechanical, electrical, and optical properties (e.g. stability, conductivity, fluorescence quenching and photoluminescence). In addition, graphene derivatives and their innate characteristics, such as biocompatibility low cytotoxicity and water solubility have facilitated the use of graphene-based materials for live cell biosensing, wherein graphene is utilized as a core material by itself or in combination with other functional nanomaterials to load target-specific probes, fluorescent dyes, and other signaling molecules. Such graphene-based hybrid nanomaterials have been employed to detect various cellular entities in living cells, including ions, biomolecules, genetic molecules, proteins, enzymes, and even whole cells. The following review will discuss a number of previous studies in which graphene-based hybrid constructs were used for live cell biosensing, and their potential applications in cancer research and stem cell therapy. PMID- 28342378 TI - Elevated triglyceride levels are associated with cognitive impairments among patients with major depressive disorder. AB - BACKGROUND: Cognitive deficits have been identified as one of core clinical symptoms of major depressive disorder (MDD). Accumulating evidence indicated that triglycerides (TG) might be associated with MDD and cognitive decline. OBJECTIVE: This study examined whether patients with MDD had poorer cognitive functions than healthy controls, and further investigate whether TG levels were involved in MDD, and its cognitive impairments in a Han Chinese population. METHOD: 115 patients with MDD and 119 healthy controls were enrolled. Cognitive functions were assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and serum TG levels were examined using enzymatic colorimetry. RESULTS: TG levels were higher in patients with MDD than healthy controls after controlling for the variables. Cognitive test scores were lower in patients with MDD than healthy controls except for visuospatial/constructional index after controlling for the variables. TG levels were negatively correlated with visuospatial/constructional score, delayed memory score and RBANS total score of MDD. Further multivariate regression analysis showed that TG levels were negatively associated with visuospatial/constructional score, attention score, delayed memory score and RBANS total score of MDD. CONCLUSIONS: Our findings supported that serum TG levels might be involved in MDD, and play an important role in cognitive impairments of MDD, especially in delayed memory. Moreover, patients with MDD experienced greater cognitive impairments than healthy controls except for visuospatial/constructional index. PMID- 28342379 TI - Association of social support and quality of life among people with schizophrenia receiving community psychiatric service: A cross-sectional study. AB - OBJECTIVE: To understand the needs of patients with schizophrenia for recovery, this study examined the type and level of social support and its association with quality of life (QOL) among this group of patients in the city of Kuala Lumpur. METHOD: A cross-sectional study was conducted on 160 individuals with schizophrenia receiving community psychiatric services in Hospital Kuala Lumpur (HKL). The WHOQOL-BREF, Brief Psychiatric Rating Scale (BPRS) and Multidimensional Scale of Perceived Social Support (MSPSS) were used to assess QOL, severity of symptoms and social support, respectively. The study respondents were predominantly Malay, aged less than 40, males, single, unmarried, had lower education levels and unemployed. RESULTS: About 72% of the respondents had poor perceived social support, with support from significant others being the lowest, followed by friends and family. From multiple regression analysis, social support (total, friend and family) significantly predicted better QOL in all domains; [B=0.315 (p<0.001), B=0.670 (p<0.001), B=0.257 (p<0.031)] respectively in Physical Domain; [B=0.491 (p<0.001), B=0.735 (p<0.001), B=0.631 (p<0.001)] in Psychological Domain; [B=1.065 (p<0.001), B=0.670 (p<0.017), B=2.076 (p<0.001)] in Social Domain and; [B=0.652 (p<0.001), B=1.199 (p<0.001), B=0.678 (p<0.001)] in Environmental Domain. Being married and having shorter duration of illness, lower BPRS (total) scores, female gender and smoking, were also found to significantly predict higher QOL. CONCLUSION: Social support is an important missing component among people with schizophrenia who are already receiving formal psychiatric services in Malaysia. PMID- 28342380 TI - Optimization of the Compton camera for measuring prompt gamma rays in boron neutron capture therapy. AB - Optimization of the Compton camera for measuring prompt gamma rays (0.478MeV) emitted during boron neutron capture therapy (BNCT) was performed with Geant4. The parameters of the Compton camera were determined as follows: 3cm thick - 10cm wide scatter detector (Silicon), 10cm thick - 10cm wide absorber detector (Germanium), and 1cm distance between the scatter and absorber detectors. For a typical brain tumor treatment, the overall detection efficiency of the optimized Compton camera was approximately 0.1425% using the Snyder's head phantom with a sphere tumor (4cm diameter and ~1cm depth). PMID- 28342381 TI - Dosimetry verification of radioactive seed implantation for malignant tumors assisted by 3D printing individual templates and CT guidance. AB - OBJECTIVE: We compared the dose distributions of postoperative plans with preoperative plans for 3D printing template-assisted radioactive seed implantations. METHODS: A total of 14 patients with malignant tumors enrolled in the study. The dose parameters included D90, minimum peripheral dose, V100, V150, and V200. The statistical method was the paired t-test. RESULTS: There was no significant difference in P values between the two groups for all parameters except for V100. CONCLUSIONS: The 3D printing guide template can provide good accuracy for radioactive seed implantation. PMID- 28342382 TI - Words cluster phonetically beyond phonotactic regularities. AB - Recent evidence suggests that cognitive pressures associated with language acquisition and use could affect the organization of the lexicon. On one hand, consistent with noisy channel models of language (e.g., Levy, 2008), the phonological distance between wordforms should be maximized to avoid perceptual confusability (a pressure for dispersion). On the other hand, a lexicon with high phonological regularity would be simpler to learn, remember and produce (e.g., Monaghan et al., 2011) (a pressure for clumpiness). Here we investigate wordform similarity in the lexicon, using measures of word distance (e.g., phonological neighborhood density) to ask whether there is evidence for dispersion or clumpiness of wordforms in the lexicon. We develop a novel method to compare lexicons to phonotactically-controlled baselines that provide a null hypothesis for how clumpy or sparse wordforms would be as the result of only phonotactics. Results for four languages, Dutch, English, German and French, show that the space of monomorphemic wordforms is clumpier than what would be expected by the best chance model according to a wide variety of measures: minimal pairs, average Levenshtein distance and several network properties. This suggests a fundamental drive for regularity in the lexicon that conflicts with the pressure for words to be as phonologically distinct as possible. PMID- 28342383 TI - Own attractiveness and perceived relationship quality shape sensitivity in women's memory for other men on the attractiveness dimension. AB - Although recent work suggests that opposite-sex facial attractiveness is less salient in memory when individuals are in a committed romantic relationship, romantic relationship quality can vary over time. In light of this, we tested whether activating concerns about romantic relationship quality strengthens memory for attractive faces. Partnered women were exposed briefly to faces manipulated in shape cues to attractiveness before either being asked to think about a moment of emotional closeness or distance in their current relationship. We measured sensitivity in memory for faces as the extent to which they recognized correct versions of studied faces over versions of the same person altered to look either more or less-attractive than their original (i.e., studied) version. Contrary to predictions, high relationship quality strengthened hit rate for faces regardless of the sex or attractiveness of the face. In general, women's memories were more sensitive to attractiveness in women, but were biased toward attractiveness in male faces, both when responding to unfamiliar faces and versions of familiar faces that were more attractive than the original male identity from the learning phase. However, findings varied according to self-rated attractiveness and a psychometric measure of the quality of their current relationship. Attractive women were more sensitive to attractiveness in men, while their less-attractive peers had a stronger bias to remember women as more-attractive and men as less-attractive than their original image respectively. Women in better-quality romantic relationships had stronger positive biases toward, and false memories for, attractive men. Our findings suggest a sophisticated pattern of sensitivity and bias in women's memory for facial cues to quality that varies systematically according to factors that may alter the costs of female mating competition ('market demand') and relationship maintenance. PMID- 28342384 TI - Utility and diagnostic accuracy of bedside lung ultrasonography during medical emergency team (MET) activations for respiratory deterioration. AB - PURPOSE: We investigated the feasibility and diagnostic accuracy of lung ultrasonography during medical emergency team (MET) activations for respiratory deterioration. MATERIAL AND METHODS: We performed a prospective study of inpatients requiring MET evaluation for respiratory decompensation. A blinded investigator recorded videos of lung and lower extremity ultrasonography. The videos were reviewed by blinded investigators to determine a ultrasonography diagnosis. The accuracy of MET diagnosis and ultrasonography diagnosis were compared to the final diagnosis determined by retrospective chart review. RESULTS: The ultrasound exam was completed in 49/50 (98%) patients enrolled in the study with a mean duration of 13+/-4min. When excluding six cases that were not amenable to diagnosis by our algorithm, we report a lung ultrasonography diagnostic accuracy of 84% (37/44) which is similar to the accuracy of the MET clinical diagnosis of 75% (33/44) (p=0.29). Furthermore, we report in 28/37 (76%) of cases where the lung ultrasonography diagnosis was correct, patients may have received inappropriate therapies. CONCLUSIONS: Lung ultrasonography can be rapidly performed in the majority of patients with MET activation for respiratory deterioration. As an independent diagnostic test, lung ultrasonography is non inferior to the MET clinical assessment and may prevent unnecessary treatments if used simultaneously. PMID- 28342385 TI - Follow-up at two years of age and early predictors of non-compliance in a cohort of very preterm infants. AB - AIM: To examine the rates of follow-up at two years of age and perinatal factors associated with non-compliance in an observational population-based cohort of very preterm children enrolled in a routine follow-up program. METHOD: Data review of infants born between 2008 and 2012 in the Observatoire de La Grande Prematurite, Reunion Island cohort. All singletons born alive before 33weeks of gestational age and resident on the island at two years of age were included. Patients were considered compliant if they were timely evaluated between 20 28months of age, or non-compliant if they were not evaluated or evaluated after 28months of age. RESULTS: Of the 802 survivors (mean gestational age of 30.3+/ 2.0months, mean birthweight of 1364+/-396g), 468 (58.4%) were examined between 20 28months, 119 (14.8%) after 28months of age, and 215 (26.8%) were never evaluated, respectively. In multivariate analysis, factors associated with non compliance were higher parity (>2), past history of preterm delivery, maternal diabetes (preexisting or gestational), appropriate for gestational status, and centre of birth. CONCLUSION: Sustainable follow-up of vulnerable neonates remains a challenge in clinical practice. Early predictors of non-compliance can be used to define individualized and local follow-up strategies in these infants at high risk for developmental disabilities. PMID- 28342386 TI - Association between environmental factors and emergency hospital admissions due to Alzheimer's disease in Madrid. AB - INTRODUCTION: There are scarce studies of time series that analysed the short term association between emergency hospital admissions due to Alzheimer's disease (AD) and environmental factors. The objective is to analyse the effect of heat waves, noise and air pollutants on urgent hospital admissions due to AD in Madrid. METHODS: Longitudinal ecological time series study was performed. The dependent variable was the emergency AD hospital admissions occurred in Madrid during the period 2001-2009. Independent variables were: Daily mean concentrations (MUg/m3) of air pollutants (PM2.5 and PM10; O3 and NO2); maximum daily temperature ( degrees C) and daily and night noise levels (dB(A)). Relative Risk (RR) for an increment in interquartile range, and Attributable Risk (AR) values were calculated through GLM with Poisson link. RESULTS: Our findings indicated that only PM2.5 concentrations at lag 2 with a RR: 1.38 (95% CI: 1.15 1.65); AR 27.5% (95% CI: 13.0-39.4); and heat wave days at lag 3 with a RR: 1.30 (95% CI: 1.12-1.52); AR 23.1% (95% CI: 10.7-34.2) were associated with AD hospital admissions. CONCLUSION: A reduction in AD patients' exposure levels to PM2.5 and special care of such patients during heat wave periods could result in a decrease in both emergency AD admissions and the related health care costs. PMID- 28342387 TI - Isolation and characterization of a novel putative human polyomavirus. AB - The small double-stranded DNA polyomaviruses (PyVs) form a family of 73 species, whose natural hosts are primarily mammals and birds. So far, 13 PyVs have been isolated in humans, and some of them have clearly been associated with several diseases, including cancer. In this study, we describe the isolation of a novel PyV in human skin using a sensitive degenerate PCR protocol combined with next generation sequencing. The new virus, named Lyon IARC PyV (LIPyV), has a circular genome of 5269 nucleotides. Phylogenetic analyses showed that LIPyV is related to the raccoon PyV identified in neuroglial tumours in free-ranging raccoons. Analysis of human specimens from cancer-free individuals showed that 9 skin swabs (9/445; 2.0%), 3 oral gargles (3/140; 2.1%), and one eyebrow hair sample (1/439; 0.2%) tested positive for LIPyV. Future biological and epidemiological studies are needed to confirm the human tropism and provide insights into its biological properties. PMID- 28342388 TI - Insights into the molecular and biological features of the dUTPase-related gene of bovine immunodeficiency virus. AB - This study was stimulated by our previous research of the dUTPase-related protein from bovine immunodeficiency virus (BIV) (Voronin et al., 2014). Despite the lack of detectable enzymatic BIV dUTPase activity (both of the recombinant protein and in virions), mutating the dUTPase gene was deleterious to viral production. However, cDNA synthesis and integration were apparently unaffected. Consequently, we have studied here two important issues. First, we showed that in cDNA produced by the dUTPase-mutated virions, the incidence of mutations was not higher than that found in wild-type BIV-infected cells. Second, single mutations, introduced in preserved dUTPase residues Asp48 and Asn57 (in the putative dUTPase active site or close to it), have led to abortive BIV infections (except for the conservative Asp48Glu mutation). Therefore, we postulate that the BIV dUTPase related protein has a critical role in retroviral replication at steps that take place after viral cDNA synthesis and integration. PMID- 28342389 TI - Pilot randomised controlled trial comparing the risk of neonatal respiratory distress in elective caesarean section at 38 weeks' gestation following a course of corticosteroids versus caesarean at 39 weeks. AB - INTRODUCTION: The objective of this study was to compare neonatal respiratory morbidity and rate of emergency caesarean section between elective caesarean sections at 38 gestational weeks following a course of corticosteroids and planned caesarean sections at 39 gestational weeks. MATERIAL AND METHODS: This was a multicentre randomised controlled trial. The study was conducted between 2007 and 2013 in level 2 and 3 maternity units in France. A total of 208 women with an indication for elective caesarean section were enrolled and 200 analysed in per-protocol analysis. Women were randomised to either elective caesarean section at 38 gestational weeks after a course of corticosteroids (trial group) or elective caesarean section at 39 weeks (control group). The primary outcome was the rate of admission to the neonatal intensive care unit for respiratory distress. RESULTS: Two (2.1%) newborn in the tested group were admitted because of respiratory distress versus four (3.8%) in the control group. The relative risk was 0.54 in favour of the corticosteroid group (95% CI: 0.10; 2.86). There were fewer emergency caesareans in the trial group than in the control group: 12 (12.69%) versus 28 (26.67%), p=0.01. CONCLUSIONS: Our study suggests that planning caesarean sections at 38 gestational weeks after a course of corticosteroids would enable a significant reduction in the number of emergency caesareans without increasing the risk of neonatal respiratory distress. Limitations of this study include difficulties in patient recruitment and the small number of subjects. PMID- 28342390 TI - Lidocaine gel versus plain lubricating gel for pain reduction during transrectal sonography (LIPS): A randomized controlled trial. AB - OBJECTIVE: To compare the efficacy and safety of lidocaine gel and plain lubricating gel in relieving pain during transrectal sonography (TRS) in patients with gynecologic problems. METHODS: A randomized controlled trial was conducted in 80 participants who were scheduled to undergo TRS. The participants were allocated into the lidocaine gel group and the aqueous gel group at a 1:1 ratio. The intensity of pain during TRS based on the visual analogue scale (0-10 points) and the adverse events were assessed and compared between the two groups. RESULTS: The two groups had similar demographic characteristics. Between the lidocaine and aqueous gel groups, there was no significant difference in the pain score at probe manipulation (4.04+/-2.14 vs. 4.21+/-2.79; P=0.868), as well as at baseline, probe insertion, and 5min after probe removal. The degree of acceptability of the sonographer also did not differ between the two groups. No acute and delayed adverse events was occurred. CONCLUSION: Intrarectal lidocaine gel for TRS provides no analgesic benefit compared with aqueous gel. PMID- 28342391 TI - Bartholin gland abscess during pregnancy: Report on 40 patients. AB - OBJECTIVE(S): To study the clinical and bacterial characteristic of Bartholin gland abscesses during pregnancy and the obstetric and neonatal outcomes. STUDY DESIGN: Retrospective cohort study of all patients with surgical treatment of Bartholin gland abscesses between 2004 and 2015 in our university center. Clinical and bacterial characteristics between pregnant and non-pregnant women were compared. RESULTS: During the period study, 156 patients were included (40 pregnant and 116 non pregnant). The incidence of Bartholin gland abscesses during pregnancy was 0.13%. Eight (20%) abscesses occurred in the first, 18 (45%) in the second, 11 (47.5%) in the third trimester and 3 (7.5%) in the post-partum course. No severe perineal and neonatal infections occurred during pregnancy. One late miscarriage and one preterm delivery were observed. We found more multiparity in the pregnant woman group than in non-pregnant women (62.5% versus 45%, p<0.05). A history of Bartholin gland abscesses were also more frequent in pregnant women (55% versus 30.1%, p<0.05). First line antibiotic therapy was more frequent in non-pregnant women (20% versus 45%, p<0.05). The rate of positive culture did not differ between the two groups (70% versus 55.2%). Among negative pus cultures, no patient in the pregnant woman group had received a first line antibiotic therapy, in contrast with non-pregnant women (0% versus 25%, p<0.05). E. coli was the most common pathogen in the two groups (48.9% of positive cultures and 28.2% of the overall population). The distribution of bacterial taxa was not different between the two groups. CONCLUSION: Bacterial characteristics did not differ from non pregnant women. Pregnancy could increase the occurrence of Bartholin gland abscesses in patients with previous surgical treatment of abscesses. When appropriate management is applied, maternal and neonatal outcomes are favorable, and severe infections are not to be expected. PMID- 28342392 TI - Value of the 68Ga-DOTATATE PET-CT in the diagnosis of endometriosis. A pilot study. AB - OBJECTIVE: The non-invasive diagnosis of endometriosis remains challenging. Recent data suggested that somatostatin might be involved in its pathogenesis. High sensitive visualization of somatostatin receptors expression is possible using PET-CT imaging after the administration of a 68Ga-labeled somatostatin analog (DOTATATE) that will bind to the somatostatin receptor sub-types 2 and 5. The aim of the present study was to assess the usefulness of 68Ga-DOTATATE PET-CT in the diagnosis of endometriosis. STUDY DESIGN: This is a prospective, single center pilot study. A pre operative 68Ga-DOTATATE PET-CT was performed in all of the patients who presented with suspected endometriosis and who were scheduled for a laparoscopy. Surgical endometriosis staging and histopathological analysis, including somatostatin receptors SST1, 2 and 5 immunohistochemistry (IHC) of removed specimens, were confronted to the results of the 68Ga-DOTATATE PET-CT. RESULTS: 12 patients were included in this study. 68Ga-DOTATATE PET-CT performed pre operatively showed increased pathologic uptake in four patients with a deep infiltrating endometriosis (DIE) recto-vaginal lesion and in another patient with an adenomyoma. Expression of SST1, 2 and 5 receptors in surgical specimens was confirmed by IHC in these five lesions. Neither superficial peritoneal endometriosis, nor ovarian endometrioma were found to show an increased pathologic uptake on 68Ga-DOTATATE PET-CT. IHC analysis confirmed that SST1, 2, and 5 receptors were not present in these lesions. CONCLUSION: The results observed in this small size series of patients seem to confirm expression of somatostatin receptors only in recto-vaginal DIE and focal adenomyosis lesions. The usefulness of 68Ga-DOTATATE PET-CT in the diagnosis of this entity is uncertain. Future research should concentrate on studying the role of somatostatin in the pathogenesis of DIE. PMID- 28342393 TI - Embryo transfer day does not affect the initial maternal serum beta-hCG levels: A retrospective cohort study. AB - The aim of this study is to compare the serum beta-hCG values post transfer of a cleavage stage embryo versus a blastocyst stage embryo at equal time intervals post oocyte retrieval (OR) in clinically pregnant patients, and to ascertain a beta-hCG value to predict pregnancy outcomes. This is a retrospective cohort study of 560 women with clinical pregnancy who underwent an embryo transfer performed at either the cleavage stage or the blastocyst stage of embryo development between January 2003 and June 2014 at the Center for Assisted Reproduction (CARE), Singapore General Hospital. The serum beta-hCG level was measured on day 17 post OR. The beta-hCG values were not significantly different in the cleavage stage versus the blastocyst stage embryos (mean+/-SD: 387+/ 486IU/L D3 vs. 352+/-268IU/L D5, p=0.96, median value 297 in both groups). Our study suggests that the initial maternal serum beta-hCG values were not affected by the day of transfer of the embryos since assessing the beta-hCG at equivalent points after transfer should not lead to a significant difference assuming the progress and development of the embryos occurred as expected. PMID- 28342394 TI - Transvaginal laparoscopy: A minimally invasive approach to obtain brush cytology of the Fallopian tube. AB - OBJECTIVE: To evaluate in a prospective pilot study the feasibility of cytobrushing of the fimbrial end using a transvaginal endoscopic access. STUDY DESIGN: Prospective feasibility study. The procedure was performed in a consecutive series of 15 infertile women referred for a transvaginal laparoscopy as part of their fertility investigation. Tubal cells were collected using a 5Fr cytobrush. Cytology and immunocytochemistry was done. RESULTS: In all patients enough cell material was obtained for analysis, without traumatizing the fimbrial end. Specimens showed the presence of a sufficient amount of cells enabling standard cytologic examinations and immunocytochemistry (Ki 67, p53). CONCLUSION: Fimbrial cytobrushing using the transvaginal approach is an easy and minimally invasive procedure. The easy accessibility of the fimbrial end and the distal ampullary part at TVL allows an accurate collection of tubal epithelial cells. In view of the recent data reporting the Fallopian tube and more specifically the fimbrial end as a possible origin of ovarian carcinoma, further research is needed to evaluate the potential of this technique as a possible screening method for patients at risk for ovarian cancer. PMID- 28342395 TI - Longitudinal progression of fetal short-term variation and average acceleration and deceleration capacity after antenatal maternal betamethasone application. AB - OBJECTIVE: To analyze the effect of maternal betamethasone given for fetal lung maturation on fetal short-term variation (STV) and average acceleration and deceleration capacity (AAC/ADC). Both of these factors are calculated by phase rectified signal averaging (PRSA) and represent new parameters to assess the fetal autonomic nervous system. STUDY DESIGN: A longitudinal prospective study including 26 pregnant women at risk for preterm delivery was performed. Two injections of 12mg betamethasone were administered intramuscularly at a 24h interval for lung maturation. Cardiotocography recordings were performed at defined time intervals: day 0 (before the first injection) and days 1, 2, 4 after the first corticosteroid administration. AAC/ADC and STV were calculated. RESULTS: An increase of all parameters (STV, AAC and ADC) was documented between day 0 and day 1. Between day 1 and day 2, all three indices were significantly reduced (p<0.05). STV declined by 19.8%, AAC by 10.1% and ADC by 14.8%. A normalization of these values was seen after 96h. CONCLUSION: Similar to STV, AAC/ADC shows significant changes after maternal betamethasone administration. The corticosteroid-induced transient decrease of the levels needs to be taken into account in the assessment of the fetal status to avoid misinterpretation of these parameters. PMID- 28342396 TI - High-resolution cryo-EM: the nuts and bolts. AB - Cryogenic electron microscopy (cryo-EM) and single-particle analysis now enables the determination of high-resolution structures of macromolecular assemblies that have resisted X-ray crystallography and other approaches. Successful high resolution structure determination by cryo-EM always depends on the quality of the protein sample. While structural heterogeneity remains a key challenge for cryo-EM, it also represents a rare opportunity to study the intrinsic conformational flexibility of macromolecular assemblies. Here, we review the key technological advancements that have made this 'resolution revolution' possible and give a concise overview of the technical challenges that needed to be overcome to allow high-resolution structure determination. PMID- 28342397 TI - Conflict adaptation in positive and negative mood: Applying a success-failure manipulation. AB - Conflict adaptation is a cognitive mechanism denoting increased cognitive control upon detection of conflict. This mechanism can be measured by the congruency sequence effect, indicating the reduction of congruency effects after incongruent trials (where response conflict occurs) relative to congruent trials (without response conflict). Several studies have reported increased conflict adaptation under negative, as compared to positive, mood. In these studies, sustained mood states were induced by film clips or music combined with imagination techniques; these kinds of mood manipulations are highly obvious, possibly distorting the actual mood states experienced by the participants. Here, we report two experiments where mood states were induced in a less obvious way, and with higher ecological validity. Participants received success or failure feedback on their performance in a bogus intelligence test, and this mood manipulation proved highly effective. We largely replicated previous findings of larger conflict adaptation under negative mood than under positive mood, both with a Flanker interference paradigm (Experiment 1) and a Stroop-like interference paradigm (Experiment 2). Results are discussed with respect to current theories on affective influences on cognitive control. PMID- 28342398 TI - Novel phosphonate analogs of sulforaphane: Synthesis, in vitro and in vivo anticancer activity. AB - A library of over forty, novel, structurally diverse phosphonate analogs of sulforaphane (P-ITCs) were designed, synthesized and fully characterized. All compounds were evaluated for antiproliferative activity in vitro on Lovo and LoVo/DX colon cancer cell lines. All compounds exhibited high antiproliferative activity, comparable or higher to the activity of naturally occurring benzyl isothiocyanate and sulforaphane. Assessment of the mechanisms of action of selected compounds revealed their potential as inducers of G2/M cell cycle arrest and apoptosis. Further antiproliferative studies for selected compounds with the use of a set of selected cell lines derived from colon, lung, mammary gland and uterus as well as normal murine fibroblasts were performed. In vivo studies of the analyzed phosphonate analogs of sulforaphane showed lower activity in comparison with those of benzyl isothiocyanate. Our studies demonstrated that newly synthesized P-ITCs can be used for as a starting point for the synthesis of novel isothiocyanates with higher anticancer activity in the future. PMID- 28342399 TI - Design, synthesis and biological evaluation of PEGylated Xenopus glucagon-like peptide-1 derivatives as long-acting hypoglycemic agents. AB - In order to develop novel long-acting GLP-1 derivatives, a peptide hybrid (1a) from human GLP-1 and Xenopus GLP-1 discovered in our previous research was selected as the lead compound. Exendin-4 inspired modification resulted in peptide 1b with enhanced glucose-lowering activity. Cysteine mutated 1b derivatives with reserved bioactivity were further site-specifically connected with mPEG2000-MAL to provide conjugates 3a-h, among which 3d and 3e were found to have significantly improved hypoglycemic activity and insulinotropic ability than GLP-1. The hypoglycemic durations of 3d and 3e were remarkably prolonged to ~20 h in type 2 diabetic db/db mice, compared with the 5.3 h of exendin-4 in the same test. Finally, chronic in vivo studies revealed that a once-daily treatment of 3d or 3e for five weeks resulted in recovered glucose-controlling ability of type 2 diabetic db/db mice, along with other benefits, such as reduced body weight gains, food intake amounts and HbA1c values. Collectively, our results suggest 3d and 3e as potential long-acting glucose-lowering agents for treating type 2 diabetes. PMID- 28342400 TI - Using gene expression database to uncover biology functions of 1,4-disubstituted 1,2,3-triazole analogues synthesized via a copper (I)-catalyzed reaction. AB - We have synthesized bioactive 1,4-disubstituted 1,2,3-triazole analogues containing 2H-1,4-benzoxazin-3-(4H)-one derivatives via 1,3-dipolar cycloaddition in the presence of CuI. All the reactions proceeded smoothly and afforded its desired products in excellent yields. Among these analogues, 3y exhibited a better cytotoxic effect on human hepatocellular carcinoma (HCC) Hep 3B cells and displayed less cytotoxicity on normal human umbilical vein endothelial cells, compared with Sorafenib, a targeted therapy for advanced HCC. 3y also induced stronger apoptosis and autophagy. Addition of curcumin enhanced 3y-induced cytotoxicity by further induction of autophagy. Using gene expression signatures of 3y to query Connectivity Map, a glycogen synthase kinase-3 inhibitor (AR A014418) was predicted to display similar molecular action of 3y. Experiments further demonstrate that AR-A014418 acted like 3y, and vice versa. Overall, our data suggest the chemotherapeutic potential of 3y on HCC. PMID- 28342401 TI - Sudden gains in exposure therapy for obsessive-compulsive disorder. AB - Prior research in the treatment of depression and anxiety has demonstrated that a sudden reduction in symptoms between two consecutive sessions (sudden gain) is related to lower post-treatment symptom severity (e.g. Hofmann, Schulz, Meuret, Moscovitch, & Suvak, 2006; Tang & DeRubeis, 1999). However, only one study has examined sudden gains in the treatment of obsessive compulsive disorder (OCD). In that study, one-third of the patients with OCD experienced a sudden gain (Aderka et al., 2012). Further, patients who had a sudden gain had lower clinician-rated OCD symptom severity post-treatment (Aderka et al., 2012). In replication, the current study examined the frequency, characteristics, and clinical impact of sudden gains in 27 OCD patients during exposure and response prevention (ERP) therapy. Fifty two percent of patients experienced a sudden gain. The mean magnitude of a sudden gain represented, on average, 61.4% of total symptom reduction. Following treatment, individuals who had experienced a sudden gain were rated as less severe on the clinical global impression scale, but they did not experience a greater reduction in OCD symptoms (pre-to post-treatment) than those without a sudden gain. None of the pre-treatment characteristics tested were found to significantly predict whether a patient would have a sudden gain. Additional research examining predictors of, and patterns of, change in OCD symptoms is warranted. PMID- 28342402 TI - The effects of mindful learning on pro-environmental behavior: A self-expansion perspective. AB - This current article explores the differential effects of mindful learning on pro environmental behavior from the perspective of self-expansion. A total of 253 participants were recruited for four experiments. In Study 1, the mindful learning group reported greater levels of pro-environmental behavioral intentions compared to a randomized control. In Study 2, we utilized different learning materials focusing on self, humans, or the biosphere in three sub-experiments. Study 2a manipulated mindsets by a self-related focus and revealed participants in a mindfulness condition had lower pro-environmental behavioral intentions than those in the mindlessness group. Study 2b centered on "humans" and results showed that participants in a mindfulness group reported higher levels of pro environmental behavioral intentions. Finally, Study 2c induced mindsets with a biospheric focus, showing participants in the mindful-learning condition had greater pro-environmental behavioral intentions. Combined, the studies provide empirical evidence that mindful learning could influence self-reported pro environmental behavioral intentions both positively and negatively. PMID- 28342403 TI - Fitting MAS NMR spectra in crystals with local disorder: Czjzek's vs. Maurer's model for 11B and 71Ga in polycrystalline gallium borate. AB - A comparative analysis of the Czjzek's and Maurer's models of the joint distribution density of NMR quadrupole parameters has been carried out in view of their application to account for spectra broadening induced by local disorder in crystals. As an example of such an application, we have considered Magic Angle Spinning NMR of 11B and 71Ga isotopes in polycrystalline gallium borate. Computer simulations carried out using both models unambiguously show that in the case of low local disorder the Maurer's model, in contrast to the Czjzek's model, provides satisfactory fits to experimental NMR spectra. PMID- 28342404 TI - Cognitive behavioural therapy and mindfulness based stress reduction may be equally effective in reducing anxiety and depression in adults with autism spectrum disorders. AB - Anxiety and depression co-occur in 50-70% of adults with autism spectrum disorder (ASD) but treatment methods for these comorbid problems have not been systematically studied. Recently, two ASD-tailored protocols were published: mindfulness based stress reduction (MBSR) and cognitive behavioural therapy (CBT). We wanted to investigate if both methods are equally effective in reducing anxiety and depression symptoms among adults with ASD. 59 adults with ASD and anxiety or depression scores above 7 on the Hospital Anxiety and Depression Scale, gave informed consent to participate; 27 followed the CBT protocol, and 32 the MBSR treatment protocol. Anxiety and depression scores, autism symptoms, rumination, and global mood were registered at the start, at the end of the 13 week treatment period, and at 3-months follow-up. Irrational beliefs and mindful attention awareness were used as process measures during treatment and at follow up. Results indicate that both MBSR and CBT are associated with a reduction in anxiety and depressive symptoms among adults with ASD, with a sustained effect at follow-up, but without a main effect for treatment group. A similar pattern was seen for the reduction of autistic symptoms, rumination and the improvement in global mood. There are some indications that MBSR may be preferred over CBT with respect to the treatment effect on anxiety when the scores on measures of irrational beliefs or positive global mood at baseline are high. Mindfulness and cognitive behavioral therapies are both promising treatment methods for reducing comorbid anxiety and depression in adults with ASD. PMID- 28342405 TI - Validation of the baking process as a kill-step for controlling Salmonella in muffins. AB - This research investigates the potential risk of Salmonella in muffins when contamination is introduced via flour, the main ingredient. Flour was inoculated with a 3-strain cocktail of Salmonella serovars (Newport, Typhimurium, and Senftenberg) and re-dried to achieve a target concentration of ~8logCFU/g. The inoculated flour was then used to prepare muffin batter following a standard commercial recipe. The survival of Salmonella during and after baking at 190.6 degrees C for 21min was analyzed by plating samples on selective and injury recovery media at regular intervals. The thermal inactivation parameters (D and z values) of the 3-strain Salmonella cocktail were determined. A >=5logCFU/g reduction in Salmonella population was demonstrated by 17min of baking, and a 6.1logCFU/g reduction in Salmonella population by 21min of baking. The D-values of Salmonella serovar cocktail in muffin batter were 62.2+/-3.0, 40.1+/-0.9 and 16.5+/-1.7min at 55, 58 and 61 degrees C, respectively; and the z-value was 10.4+/-0.6 degrees C. The water activity (aw) of the muffin crumb (0.928) after baking and 30min of cooling was similar to that of pre-baked muffin batter, whereas the aw of the muffin crust decreased to (0.700). This study validates a typical commercial muffin baking process utilizing an oven temperature of 190.6 degrees C for at least 17min as an effective kill-step in reducing a Salmonella serovar population by >=5logCFU/g. PMID- 28342406 TI - Phase change heat transfer during cryosurgery of lung cancer using hyperbolic heat conduction model. AB - The paper reports a numerical study of phase change heat transfer process in lung cancer undergoing cryosurgery. A two dimensional hyperbolic bio-heat model with non-ideal property of tissue, blood perfusion and metabolism is used to analyze the problem. The governing equations are solved by finite difference method based on enthalpy formulation. Effects of relaxation time of heat flux in hyperbolic model on freezing process have been examined. A comparative investigation of two different models (hyperbolic and parabolic bio-heat models) is also presented. PMID- 28342407 TI - Music and natural sounds in an auditory steady-state response based brain computer interface to increase user acceptance. AB - Patients with total locked-in syndrome are conscious; however, they cannot express themselves because most of their voluntary muscles are paralyzed, and many of these patients have lost their eyesight. To improve the quality of life of these patients, there is an increasing need for communication-supporting technologies that leverage the remaining senses of the patient along with physiological signals. The auditory steady-state response (ASSR) is an electro physiologic response to auditory stimulation that is amplitude-modulated by a specific frequency. By leveraging the phenomenon whereby ASSR is modulated by mind concentration, a brain-computer interface paradigm was proposed to classify the selective attention of the patient. In this paper, we propose an auditory stimulation method to minimize auditory stress by replacing the monotone carrier with familiar music and natural sounds for an ergonomic system. Piano and violin instrumentals were employed in the music sessions; the sounds of water streaming and cicadas singing were used in the natural sound sessions. Six healthy subjects participated in the experiment. Electroencephalograms were recorded using four electrodes (Cz, Oz, T7 and T8). Seven sessions were performed using different stimuli. The spectral power at 38 and 42Hz and their ratio for each electrode were extracted as features. Linear discriminant analysis was utilized to classify the selections for each subject. In offline analysis, the average classification accuracies with a modulation index of 1.0 were 89.67% and 87.67% using music and natural sounds, respectively. In online experiments, the average classification accuracies were 88.3% and 80.0% using music and natural sounds, respectively. Using the proposed method, we obtained significantly higher user-acceptance scores, while maintaining a high average classification accuracy. PMID- 28342408 TI - Finite element method-based study for effect of adult degenerative scoliosis on the spinal vibration characteristics. AB - Finite element analysis was used to investigate the responses of five healthy subjects and five adult degenerative scoliosis (ADS) subjects to cyclic vibration. The dynamic responses of the healthy and scoliotic spines to the sinusoidal cyclic vibrations have been investigated in previous studies by simulation or experimental approaches. However, no simulation or experimental results were available for the ADS subjects. The effect of the ADS on the vibrational characteristics of spines remained unknown. The objective of this study was to compare differences of the dynamic responses to the cyclic vibration input between the healthy subjects and subjects with ADS. Based on the simulations results in this study, the scoliotic spines are more sensitive to the cyclic vibrations than the healthy spines. More resonant frequencies were predicted in the scoliotic spines than the healthy spines. The scoliotic deformity in the spine was to make the vibrational response of the spine significantly more complex at the apical scoliotic region. This study suggested that ADS could severely increase spinal response to the cyclic vibrations, which could potentially lead to further scoliotic deformity in the spine. PMID- 28342409 TI - Perceived health and alcohol use in individuals with HIV and Hepatitis C who use drugs. AB - BACKGROUND: Individuals who use illicit drugs are at heightened risk for HIV and/or Hepatitis C Virus (HCV). Despite the medical consequences of drinking for drug-using individuals with these infections, many do drink. In other studies, how individuals perceive their health relates to their engagement in risk behaviors such as drinking. However, among drug-using individuals with HIV and HCV, whether perceived health relates to drinking is unknown. OBJECTIVE: We examine the association between perceived health and drinking among drug-using individuals with HIV and/or HCV. METHODS: In a large, cross-sectional study, we utilized samples of individuals with HIV (n=476), HCV (n=1145), and HIV/HCV co infection (n=180), recruited from drug treatment centers from 2005 to 2013. In each sample, we investigated the relationship between perceived health and drinking, using ordinal logistic regressions. We present uncontrolled models as well as models controlled for demographic characteristics. RESULTS: Among samples of drug using individuals with HIV and with HCV, poorer perceived health was associated with risky drinking only when demographic characteristics were taken into account (Adjusted Odds Ratios: 1.32 [1.05, 1.67] and 1.16 [1.00, 1.34], respectively). In the smaller HIV/HCV co-infected sample, the association of similar magnitude was not significant (AOR=1.32 [0.90, 1.93]). CONCLUSIONS: Drug using patients with HIV or HCV with poor perceived health are more likely to drink heavily, which can further damage health. However, when demographics are not accounted for, these effects can be masked. Patients' reports of poor health should remind providers to assess for health risk behaviors, particularly heavy drinking. PMID- 28342410 TI - Transition to manual: Comparing simulator with on-road control transitions. AB - BACKGROUND: Whilst previous research has explored how driver behaviour in simulators may transfer to the open road, there has been relatively little research showing the same transfer within the field of driving automation. As a consequence, most research into human-automation interaction has primarily been carried out in a research laboratory or on closed-circuit test tracks. OBJECTIVE: The aim of this study was to assess whether research into non-critical control transactions in highly automated vehicles performed in driving simulators correlate with road driving conditions. METHOD: Twenty six drivers drove a highway scenario using an automated driving mode in the simulator and twelve drivers drove on a public motorway in a Tesla Model S with the Autopilot activated. Drivers were asked to relinquish, or resume control from the automation when prompted by the vehicle interface in both the simulator and on road condition. RESULTS: Drivers were generally faster to resume control in the on-road driving condition. However, strong positive correlations were found between the simulator and on road driving conditions for drivers transferring control to and from automation. No significant differences were found with regard to workload, perceived usefulness and satisfaction between the simulator and on road drives. CONCLUSION: The results indicate high levels of relative validity of driving simulators as a research tool for automated driving research. PMID- 28342411 TI - A simple reason explains why it is so difficult to assess groundwater ages and contamination ages. PMID- 28342412 TI - Bacterial community responses during a possible CO2 leaking from sub-seabed storage in marine polluted sediments. AB - Carbon capture and storage (CCS) is a viable option to reduce high concentrations of CO2 and mitigate their negative effects. This option has associated risks such as possible CO2 leakage from the storage sites. So far, negative effects deriving from a CO2 release have been reported for benthic macrofauna in both polluted and nonpolluted sediments. However, bacterial communities has no considered. In this work, risk assessment was carried out in order to evaluate the possible effects in a contaminated area considering bacterial responses (total number of cells, respiring activity, changes in the bacterial community composition and diversity). Four microcosms were placed into an integrated CO2 injection system with a non-pressurized chamber to simulate four different pH treatments (pH control 7.8, 7, 6.5 and 6). Results showed an impact on bacterial communities because of the CO2 treatment. Changes in respiring activity, community composition groups and diversity were found. This study highlights the use of respiring bacteria activity not only as bioindicator for environmental risk assessment and monitoring purposes but also as a bioindicador during a CO2 leakage event or CO2 enrichment process among all the responses studied. PMID- 28342413 TI - Efficacies of biochar and biochar-based amendment on vegetable yield and nitrogen utilization in four consecutive planting seasons. AB - Biochar has been suggested as a potential tailored technology for mediating soil conditions and improving crop yields. However, the efficacies of biochar and biochar-based amendments (e.g., composted biochar) in agricultural soils under a rotation system remain uncertain. In this study, an arable soil was subjected to peanut shell biochar (PBC) and biochar-based amendment (PAD) combined with or without nitrogen (N) fertilizer to evaluate their effects on vegetable yield, N bioavailability, and their relative contribution to vegetable biomass in four consecutive planting seasons. PBC alone or in co-application with N fertilizer had little effect on vegetable yield, while PAD co-application with N fertilizer decreased vegetable biomass because of the inhibition of root morphology by excessive nutrient supply. PBC and PAD applications increased rhizosphere soil pH due to OH- and HCO3- release and NO3--N uptake. Although the addition of PAD increased soil N contents due to its high contents in PAD, it had little effects on N utilization efficiency (NUE) in the four seasons. The relative contribution of PBC, PAD, and their interaction with N fertilizer to biomass yield was maintained at a low level. Our results indicated that a biochar-based amendment (e.g., PAD) was a potential alternative to N fertilizer, but the ratio of biochar to additives should be managed carefully to generate optimal benefits. Notably, the efficacy of PAD on plant growth was closely associated with plant species, and further related research on different plants is encouraged. PMID- 28342414 TI - Impacts of soil incorporation of pre-incubated silica-rich rice residue on soil biogeochemistry and greenhouse gas fluxes under flooding and drying. AB - Incorporation of silica-rich rice husk residue into flooded paddy soil decreases arsenic uptake by rice. However, the impact of this practice on soil greenhouse gas (GHG) emissions and elemental cycling is unresolved particularly as amended soils experience recurrent flooding and drying cycles. We evaluated the impact of pre-incubated silica-rich rice residue incorporation to soils on pore water chemistry and soil GHG fluxes (i.e., CO2, CH4, N2O) over a flooding and drying cycle typical of flooded rice cultivation. Soils pre-incubated with rice husk had 4-fold higher pore water Si than control and 2-fold higher than soils pre incubated with rice straw, whereas the pore water As and Fe concentrations in soils amended with pre-incubated straw and husk were unexpectedly similar (maximum ~0.85MUM and ~450MUM levels, respectively). Pre-incubation of residues did not affect Si but did affect the pore water levels of As and Fe compared to previous studies using fresh residues where straw amended soils had higher As and Fe in pore water. The global warming potential (GWP) of soil GHG emissions decreased in the order straw (612+/-76g CO2-eqm-2)>husk (367+/-42gCO2-eqm 2)>ashed husk=ashed straw (251+/-26 and 278+/-28gCO2-eqm-2)>control (186+/-23gCO2 eqm-2). The GWP increase due to pre-incubated straw amendment was due to: a) larger N2O fluxes during re-flooding; b) smaller contributions from larger CH4 fluxes during flooded periods; and c) higher CH4 and CO2 fluxes at the onset of drainage. In contrast, the GWP of the husk amendment was dominated by CO2 and CH4 emissions during flooded and drainage periods, while ashed amendments increased CO2 emissions particularly during drainage. This experiment shows that ashed residues and husk addition minimizes GWP of flooded soils and enhances pore water Si compared to straw addition even after pre-incubation. PMID- 28342415 TI - Initial report on methane and carbon dioxide emission dynamics from sub-Antarctic freshwater ecosystems: A seasonal study of a lake and a reservoir. AB - The sub-Antarctic Magellanic ecoregion is a part of the world where ecosystems have been understudied and where the CH4 cycling and emissions in lakes has not ever been reported. To fill that knowledge gap, a lake and a reservoir located at 53 degrees S were selected and studied during three campaigns equally distributed over one year. Among the parameters measured were CH4 and CO2 emissions, as well their dissolved concentrations in the water column, which were determined with high spatial resolution. No ebullition was observed and the CH4 flux ranged from 0.0094 to 4.47mmolm-2d-1 while the CO2 flux ranged from -22.95 to 35.68mmolm-2d 1. Dissolved CH4 concentrations varied over more than four orders of magnitude (0.025-128.75MUmolL-1), and the dissolved carbon dioxide ranged from below the detection limit of our method (i.e., 0.15MUmolL-1) to 379.09MUmolL-1. The high spatial resolution of the methods used enabled the construction of bathymetric maps, surface contour maps of CH4 and CO2 fluxes, and transect contour maps of dissolved oxygen, temperature, and dissolved greenhouse gases. Overall, both lakes were net greenhouse gas producers and were not significantly different from temperate lakes located at a similar northern latitudes (53 degrees N), except that ebullition was never observed in the studied sub-Antarctic lakes. PMID- 28342416 TI - Joint carbon footprint assessment and data envelopment analysis for the reduction of greenhouse gas emissions in agriculture production. AB - Operations management tools are critical in the process of evaluating and implementing action towards a low carbon production. Currently, a sustainable production implies both an efficient resource use and the obligation to meet targets for reducing greenhouse gas (GHG) emissions. The carbon footprint (CF) tool allows estimating the overall amount of GHG emissions associated with a product or activity throughout its life cycle. In this paper, we propose a four step method for a joint use of CF assessment and Data Envelopment Analysis (DEA). Following the eco-efficiency definition, which is the delivery of goods using fewer resources and with decreasing environmental impact, we use an output oriented DEA model to maximize production and reduce CF, taking into account simultaneously the economic and ecological perspectives. In another step, we stablish targets for the contributing CF factors in order to achieve CF reduction. The proposed method was applied to assess the eco-efficiency of five organic blueberry orchards throughout three growing seasons. The results show that this method is a practical tool for determining eco-efficiency and reducing GHG emissions. PMID- 28342417 TI - The protective roles of TiO2 nanoparticles against UV-B toxicity in Daphnia magna. AB - Aquatic environments are increasingly under environmental stress due to ultraviolet (UV) radiation and potential inputs of nanoparticles with intense application of nanotechnology. In this study, we investigated the interaction between UV-B radiation and titanium nanoparticles (TiO2-NPs) in a model freshwater cladoceran Daphnia magna. UV-B toxicity to Daphnia magna was examined when the daphnids were exposed to a range of TiO2-NPs concentrations with an initial 5 or 10min of 200MUW/cm2 UV-B radiation. In addition, UV-B toxicity was also examined in the presence of TiO2-NPs in the body of daphnids. Our results demonstrated that the daphnid mortality under UV-B radiation decreased significantly in the presence of TiO2-NPs both in the water and in the body, indicating that TiO2-NPs had some protective effects on D. magna against UV-B. Such protective effect was mainly caused by the blockage of UV-B by TiO2-NPs adsorption. UV-B produced reactive oxygen species (ROS) in the water and in the daphnids, which was not sufficient to cause mortality of daphnids over short periods of radiation. Previous studies focused on the effects of TiO2-NPs on the toxicity of total UV radiation, and did not attempt to differentiate the potential diverse roles of UV-A and UV-B. Our study indicated that TiO2-NPs may conversely protect the UV-B toxicity to daphnids. PMID- 28342418 TI - Dynamics of runoff and sediment trapping performance of vegetative filter strips: Run-on experiments and modeling. AB - Vegetative filter strips (VFSs) are a labor-saving and cost-effective agricultural best management practice to trap water runoff and sediment from the source areas. They also provide forage and/or fuel and are therefore potentially profitable for land owners. VFSs are however a dynamic system: the runoff delivery ratio (RDR) and sediment delivery ratio (SDR) vary with growth stage and vegetation types. The impacts of vegetation characteristics as well as soil physical properties modified by vegetation growth, on the RDR and SDR of VFS were evaluated by a flume experiment. Two plant species (cocksfoot (Dactylis glomerata L.) and white clover (Trifolium repens L.)) were tested at three stages in the growing season of 2016 (May, July, and August). The measured RDR and SDR were compared with the simulated results from Vegetative Filter Strip Modeling System (VFSMOD). In the early stages of the growing season, the cocksfoot formed a dense network of stems with high strip Manning's roughness faster than white clover. The runoff and sediment trapping effects of the white clover VFS were greater than that of cocksfoot VFS in all the three stages (lower RDR and SDR). This is likely attributed to strongly tillering, creeping stem posture and high infiltration capacity of the white clover VFS. VFSMOD simulated the RDR and SDR reliably except under low vegetation coverage conditions (white clover in May). The results suggested that (1) both soil physical properties and vegetation characteristics should be considered for the species-specific, temporally variable performance of VFS; and (2) when using VFSMOD inform the VFS design, modelers should take the dynamics of vegetation, mainly through vertical saturated hydraulic conductivity, stem spacing and strip Manning's roughness into account, and select parameters that reflect the actual field conditions. PMID- 28342419 TI - Incorporating denitrification-decomposition method to estimate field emissions for Life Cycle Assessment. AB - This study focuses on a detailed Life Cycle Assessment (LCA) for flax cultivation in Northern France. Nitrogen related field emissions are derived both from a process-oriented DeNitrification-DeComposition (DNDC) method and the generic Intergovernmental Panel on Climate Change (IPCC) method. Since the IPCC method is synthesised from field measurements at sites with various soil types, climate conditions, and crops, it contains significant uncertainties. In contrast, the outputs from the DNDC method are considered as more site specific as it is built according to complex models of soil science. As it is demonstrated in this paper the emission factors from the DNDC method and the recommended values from the IPCC method exhibit significant variations for the case of flax cultivation. The DNDC based emission factor for direct N2O emission, which is a strong greenhouse gas, is 0.25-0.5%, significantly lower than the recommend 1% level derived from the IPCC method. The DNDC method leads to a reduction of 17% in the impact category of climate change per kg retted flax straw production from the level obtained from the IPCC method. Much higher reductions are recorded for particulate matter formation, terrestrial acidification, and marine eutrophication impact categories. Meanwhile, based on the DNDC and IPCC methods, a comparative LCA per kg flax straw is presented. For both methods sensitivity analysis as well as comparison of uncertainties parameterisation of the N2O estimates via Monte-Carlo analysis are performed. The DNDC method incorporates more relevant field emissions from the agricultural life cycle phase, which can also improve the quality of the Life Cycle Inventory as well as allow more precise uncertainty calibration in the LCA inventory. PMID- 28342420 TI - Mapping vulnerability of multiple aquifers using multiple models and fuzzy logic to objectively derive model structures. AB - Driven by contamination risks, mapping Vulnerability Indices (VI) of multiple aquifers (both unconfined and confined) is investigated by integrating the basic DRASTIC framework with multiple models overarched by Artificial Neural Networks (ANN). The DRASTIC framework is a proactive tool to assess VI values using the data from the hydrosphere, lithosphere and anthroposphere. However, a research case arises for the application of multiple models on the ground of poor determination coefficients between the VI values and non-point anthropogenic contaminants. The paper formulates SCFL models, which are derived from the multiple model philosophy of Supervised Committee (SC) machines and Fuzzy Logic (FL) and hence SCFL as their integration. The Fuzzy Logic-based (FL) models include: Sugeno Fuzzy Logic (SFL), Mamdani Fuzzy Logic (MFL), Larsen Fuzzy Logic (LFL) models. The basic DRASTIC framework uses prescribed rating and weighting values based on expert judgment but the four FL-based models (SFL, MFL, LFL and SCFL) derive their values as per internal strategy within these models. The paper reports that FL and multiple models improve considerably on the correlation between the modeled vulnerability indices and observed nitrate-N values and as such it provides evidence that the SCFL multiple models can be an alternative to the basic framework even for multiple aquifers. The study area with multiple aquifers is in Varzeqan plain, East Azerbaijan, northwest Iran. PMID- 28342421 TI - Seasonal and soil-type dependent emissions of nitrous oxide from irrigated desert soils amended with digested poultry manures. AB - Expansion of dryland agriculture requires intensive supplement of organic fertilizers to improve the fertility of nutrient-poor desert soils. The environmental impact of organic supplements in hot desert climates is not well understood. We report on seasonal emissions of nitrous oxide (N2O) from sand and loess soils, amended with limed and non-limed anaerobic digestate of poultry manure in the Israeli Negev desert. All amended soils had substantially higher N2O emissions, particularly during winter applications, compared to unammended soils. Winter emissions from amended loess (10-175mgN2Om-2day-1) were markedly higher than winter emissions from amended sand (2-7mgN2Om-2day-1). Enumeration of marker genes for nitrification and denitrification suggested that both have contributed to N2O emissions according to prevailing environmental conditions. Lime treatment of digested manure inhibited N2O emissions regardless of season or soil type, thus reducing the environmental impact of amending desert soils with manure digestate. PMID- 28342422 TI - Synergistic desalination of potash brine-impacted groundwater using a dual adsorbent. AB - The impact of saline mining effluent has been a significant environmental concern. Natural and modified clay-mineral adsorbents have been receiving increasing attention for salinity reduction of brine-impacted water, especially for natural resource extraction sites and surrounding environments. In this study, a dual-adsorbent treatment based on the sequential application of calcined layered double hydroxide (CLDH) and acid-treated zeolite was developed, evaluated and characterized for the desalination of potash brine-impacted groundwater. Potash brine produced by conventional potash mining in Saskatchewan (Canada) contains a large amount of Na+, K+ and Cl-. The CLDH and acid-treated clinoptilolite zeolites were combined to sequentially remove Cl- and Na+. A series of batch adsorption experiments were conducted for synthetic saline water and potash brine-spiked groundwater using various combinations of adsorbents: natural zeolites (NZ) or acid-treated zeolites (AZ) with or without the CLDH pretreatment. The experiment revealed that the Na+ removal percentage was synergistically increased by the dechlorination pretreatment using CLDH, and further improved by AZ. The CLDH-AZ dual adsorbent achieved a Langmuir Na+ adsorption capacity of 24.4mg/g, a significant improvement over conventional approaches to zeolite-based desalination. Using the brine-impacted groundwater with a high sodium adsorption ratio (SAR) of 13.3+/-0.1, the CLDH-AZ dual adsorbent decreased the concentrations of Na+, K+, and Cl- by 87, 97, and 87%, respectively (below drinking water standards). It also exhibited the additional advantages of neutralizing the effluent pH and decreasing the hardness, SAR, and total dissolved sulfur concentration. This study addresses the removal mechanisms, which are associated with the structural memory effect, dealumination, protonic exchanges, and zeolite porosity changes. Synchrotron based scanning transmission X-ray microscopy analyses provided visual evidence of sodium adsorption sites (SiONa and AlONa) associated with dealumination in the acid-treated zeolites. This study is the first report that demonstrates the synergy of the CLDH-AZ dual adsorbent treatment for potash brine-impacted water. PMID- 28342423 TI - A Bioinformatics approach to designing a Zika virus vaccine. AB - The Zika virus infections have reached epidemic proportions in the Latin American countries causing severe birth defects and neurological disorders. While several organizations have begun research into design of prophylactic vaccines and therapeutic drugs, computer assisted methods with adequate data resources can be expected to assist in these measures to reduce lead times through bioinformatics approaches. Using 60 sequences of the Zika virus envelope protein available in the GenBank database, our analysis with numerical characterization techniques and several web based bioinformatics servers identified four peptide stretches on the Zika virus envelope protein that are well conserved and surface exposed and are predicted to have reasonable epitope binding efficiency. These peptides can be expected to form the basis for a nascent peptide vaccine which, enhanced by incorporation of suitable adjuvants, can elicit immune response against the Zika virus infections. PMID- 28342424 TI - End-of-Life care in a community garden: Findings from a Participatory Action Research project in regional Australia. AB - This article presents findings from research that explored how a community garden might function as a place of end-of-life and bereavement support. Adopting Participatory Action Research (PAR) methods, and informed by Third Place theory and notions of therapeutic landscape, creative consultations were held in the Garden and people's homes. The findings provide insights into the nature of informal care as it is played out in the liminal garden space, between home and institution. The results illuminate the therapeutic landscape of community gardens, and contribute new understandings to the fields of PAR, health geography and end-of-life care. PMID- 28342425 TI - How Neighborhoods Influence Health: Lessons to be learned from the application of political ecology. AB - AIM: This paper articulates how political ecology can be a useful tool for asking fundamental questions and applying relevant methods to investigate structures that impact relationship between neighborhood and health. Through a narrative analysis, we identify how political ecology can develop our future agendas for neighborhood-health research as it relates to social, political, environmental, and economic structures. Political ecology makes clear the connection between political economy and neighborhood by highlighting the historical and structural processes that produce and maintain social inequality, which affect health and well-being. These concepts encourage researchers to examine how people construct neighborhood and health in different ways that, in turn, can influence different health outcomes and, thus, efforts to address solutions. PMID- 28342426 TI - Optical and electrochemical dual channel sensing of Cu2+ using functionalized furo[2,3-d]pyrimidines-2,4[1H,3H]-diones. AB - Owing to their easy accessibility and high degree of structural and functional diversity, many multicomponent reactions (MCRs) have been a rich source of conjugate pi-systems, functionalised chromophores (or fluorophore) and redox active molecules. Despite their high explorative potential and practical benefits, only a few MCR products have been so far investigated for their metal sensing abilities. In the present report, two furopyrimidinones (FPys) based molecular systems have been synthesized by [4+1] cycloaddition based MCR sequence. Designed chemosensors displayed optic (absorption spectra) as well as electroanalytical (ion selective electrode) response toward Cu2+ ion in solution and membrane phase respectively (dual channel sensing). Different aspects of both the sensing phenomena such as selectivity, association constants, detection limit, membrane composition etc. were studied in detail using UV-Vis spectroscopy, NMR titration and cell assembly. Both the compounds showed excellent performance characteristics such as high selectivity, acceptable affinity and low detection limits (10-7M) in both sensing assays with potential utility in the area of sample monitoring. PMID- 28342427 TI - Spectroscopic studies of the interaction mechanisms between mono-caffeoylquinic acids and transferrin. AB - Transferrin (Tf) is an important protein responsible for circulating and transporting iron into cytoplasm. Tf can be taken into cells through endocytosis mediated by Tf receptor, which usually overexpresses in cancer cells. The Tf-Tf receptor pathway opens a possible avenue for novel targeted cancer therapy by utilizing Tf-binding active compounds. Among which, anti-cancer active caffeoylquinic acids (CQAs) were recently found to be promising Tf-binders by our group. For better understanding the anti-cancer activities of CQAs, it is important to unveil the binding mechanisms between CQAs and Tf. In this study, the fluorescence quenching, surface plasmon resonance (SPR), circular dichroism (CD) and molecular docking were used to investigate the interactions between CQA and Tf. The results showed that the calculated apparent association constants of interactions between 1-, 3-, 4- and 5-CQA and Tf at 298K were 7.97*105M-1, 4.36*107M-1, 6.58*105M-1 and 4.42*106M-1, respectively. The thermodynamic parameters indicated that the interaction between 1-, 3-, 5-CQA and Tf is due to H-bonding, and electrostatic interactions were likely involved in the binding of 4-CQA and Tf. The CD results indicated that bindings of 1-CQA, 4-CQA and 5-CQA with Tf resulted in more stretched beta-turn and random coil translated from beta sheet. In contrast, 3-CQA led to more stable a-helix conformation. Molecular docking studies of CQAs with Tf further displayed that CQAs were able to interact with residues near Fe3+ binding site. The spectroscopic studies revealed the action mechanisms, thermodynamics and interacting forces between CQAs and Tf, and thus are helpful for future design and discovery of Tf-binders for targeted cancer therapy applying Tf-Tf receptor pathway. PMID- 28342428 TI - Revealing the influence of glucocorticoid treatment on the excretion of anabolic androgenic steroids in horses through in vitro digestive simulations and an in vivo case study. AB - Anabolic-androgenic steroids (AAS) are strictly forbidden in equine sports because of their stimulating effect on muscle growth and performance. Nevertheless, low levels of AAS have been found in some horses, untreated with AAS. Glucocorticoids (GC), used as an anti-inflammatory therapy and structurally related to AAS, might play a role in this phenomenon. In order to unravel this possible correlation the influence of glucocorticoid treatment on the excretion of AAS was studied both in vivo and in vitro. In vivo effects were investigated by analysing urine samples collected from a gelding treated with betamethasone. Additionally, multiple in vitro digestion simulations were set up, according to a previously validated protocol, to study the possibility of a direct biotransformation of glucocorticoids to AAS, by the microbiota of the equine hindgut. Urine and in vitro digestion samples were extracted and analysed with UHPLC-MS/MS and UHPLC-Orbitrap-HRMS analytical methods. A significant influence on the urinary excretion of alpha-testosterone (alphaT), beta-testosterone (betaT) and androsta-1,4-diene-3,17-dione (ADD) was seen. alphaT-concentrations up to 20ng/mL were detected. ADD was not found before treatment but could be detected post-treatment. Cortisone and cortisol also peaked (>30ng/mL) between day 37 and 48 post-treatment. The in vitro digestion results however revealed no direct biotransformation of glucocorticoids to AAS by the microbiota of the equine hindgut. This study shows that a glucocorticoid treatment can disrupt the synthesis and excretion of AAS, not by direct biotransformation upon gastrointestinal digestion, but more likely by influencing the hypothalamic pituitary-adrenal axis. PMID- 28342429 TI - Non-parasitic life cycle of the cattle tick Rhipicephalus (Boophilus) microplus in Panicum maximum pastures in northern Argentina. AB - The aim of this work was to study the non-parasitic phase of the Rhipicephalus microplus life cycle in Panicum maximum grasses from northern Argentina, in order to provide ecological information for designing methods of tick control. Four localities were chosen as replicates. The biological parameters measured were proportion of females ovipositing, the pre-oviposition period, the proportion of egg clusters hatching, the incubation period of eggs, larval longevity, and the total non-parasitic period (time from the exposure of the female to the date of death of the last larva) (TNPP)). The following general trends were observed: I) a longer TNPP occurred when female ticks were exposed in mid- and late summer and early spring; II) the shortest TNPP occurred when female ticks were exposed from late winter to late spring; III) larvae that were active in early and mid-summer had the shortest longevity; IV) incubation periods of eggs, which originated from females exposed in late summer, early autumn and mid-spring, were longer than the incubation period of eggs produced by females exposed in late spring and early summer; V) eggs did not hatch when the engorged females were exposed in the pastures in mid- and late autumn and winter. The spelling period of the P. maximum grasses that is needed to ensure total control of R. microplus consists of 19-20weeks if the spelling starts in late spring and early summer, and 27 28weeks if the spelling begins in mid- and late summer or in autumn. PMID- 28342431 TI - [Considerations for the Definition of a Interval of Vulnerability/Possibility in Adolescence]. AB - This article explores the hypothesis that while maturation related cognitive abilities reaches maturity around the age of fifteen, maturation related social skills is delayed until well into the twenties. Our goal is to try to define what is the window of opportunity/vulnerability and what is the maturational status of the young in this interval. In this context, we argue how the maturational time of the closing of adolescence has an impact on the valuation of autonomy in decision-making of the person. Particularly, we figure out implications for the assessment of the autonomy of youth in health issues, and also criminal liability. In the conclusion, we offer some educational criteria that may provide guidance for implementing both social policy and educational programs. PMID- 28342430 TI - Exposure to a magnetic field or laser radiation ameliorates effects of Pb and Cd on physiology and growth of young wheat seedlings. AB - Lead (Pb) and cadmium (Cd) contamination of soils pose significant problems for successful seed germination and establishment. We compared effects of subjecting wheat seeds either to a magnetic field (MF: 0-800 millitesla) or laser radiation (LR: 0-8min at 20mW/mm2) on wheat seed germination and on physiology and growth of young seedlings exposed to these two heavy metals as seeds and as 2-day-old seedlings. Intermediate levels of either MF or LR increased germination. In seeds untreated by MF or LR, exposure to Cd and Pb resulted in: significant increases in the concentrations of malondialdehyde ([MDA]) and superoxide anion radical ([O2-]), and in the conductivity of electrolyte leakage (CEL); significant decreases in catalase (CAT), superoxide dismutase (SOD), and glutathione reductase (GR) activity; a significant decrease in glutathione concentration ([GSH]); and a significant decrease in shoot biomass relative to seeds exposed to these heavy metals following MF or LR treatments. Although both MF and LR ameliorated physiological effects of Cd and Pb exposure on young seedlings, only LR decreased Cd and Pb concentrations in the wheat shoot itself. Our results suggest that in agricultural sites contaminated by these two heavy metals, that LR could improve production and counter heavy metals accumulation. PMID- 28342432 TI - [Ethical Dilemmas in Practice of Medicine Child]. AB - After reviewing the existing bibliography in the last 20 years, we concluded that there is a lack of information regarding the ethical conflicts that affect to pediatrics in their daily practice. It produces certain degree of uncertainty in these professionals at the time of solving these problems. We made a systematic search in the main data bases, finding more than 150 articles related, of which 80 were considered outstanding. After studying them, we have found 40 ethical dilemmas, related to some principle of solution and that we described in this article. Through them we can find such important dilemmas as those related to physical disability, palliative care or consent from children. PMID- 28342433 TI - [Evaluation of the Degree of Patient Information to be Included in the Home-Based Palliative Care Program]. AB - The fact of communicating to a patient his or her diagnosis when it is unfavourable, this becomes a really human issue. The bioethics and the legislation protect this right of information. The aim of this study is to evaluate the degree of information of patients when they are included in the home palliative care program. This is a quantitative, descriptive, retrospective and transversal study. The year of the study is 2012 in patients diagnosed with advanced terminal illnesses processes valued by the Team of Home Palliative Attention Support, of the North Welfare Direction of the Community of Madrid. The sample size was 184 patients. Analysing the relationship between the degree of information and the age, existing differences statistically significant (p <0.01)being the group in which there are more patients correctly informed the one were the age is <=65 years old with a percentage of 95,3%. The patients with a Pfeiffer<4 in the 89,3% of the cases (p <0.01) were more informed. More than half the patients had received some information about their illness and within that half there is higher proportion of people who received complete information. The more frequent were male patients with age between 76 and 85 with oncologic pathology, showing a bad functional condition but didn't present cognitive deterioration. The information received by the family was more complete that the one the own patient knew. The factors related with a better degree of information were being younger than 65 and a lack of cognitive deterioration. The predominant place of the decease in the monitoring of the patient was the their home. PMID- 28342435 TI - [Therapeutic Aggressiveness and Liquid Oncology]. AB - Aggressiveness criteria proposed in the scientific literature a decade ago provide a quality judgment and are a reference in the care of patients with advanced cancer, but their use is not generalized in the evaluation of Oncology Services. In this paper we analyze the therapeutic aggressiveness, according to standard criteria, in 1.001 patients with advanced cancer who died in our Institution between 2010 and 2013. The results seem to show that aggressiveness at the end of life is present more frequently than experts recommend. About 25% of patients fulfill at least one criterion of aggressiveness. This result could be explained by a liquid Oncology which does not prioritize the patient as a moral subject in the clinical appointment. Medical care is oriented to necessities and must be articulated in a model focused on dignity and communication. Its implementation through Advanced Care Planning, consideration of patient's values and preferences, and Limitation of therapeutic effort are ways to reduce aggressiveness and improve clinical practice at the end of life. We need to encourage synergic and proactive attitudes, adding the best of cancer research with the best clinical care for the benefit of human being, moral subject and main goal of Medicine. PMID- 28342434 TI - [Mothers Talk. Part Unless Told of Voluntary Abortion]. AB - The aim of the study was to investigate the experiences linked to the post abortion syndrome in mothers who have had a voluntary abortion. A phenomenological qualitative approach to collect the experiences of mothers who had voluntarily interrupted their pregnancy was used. The research technique was the semistructured interviews with women who had contacted different association's help of the Murcia region for support after experiencing symptoms consistent with post-abortion syndrome. The testimonies show feminist or utilitarian arguments to justify the decision to abort, they talk about a system, to some extent, mercantilist that has no real intention of giving real life choices. Experience shows that far from lived as an act of female freedom is experienced traumatically, developed symptoms following the sense of loss. In this context, the resource spiritual becomes the best tool to expiate guilt. The experience of abortion does not improve the lives of women; far from it is a trauma that can be avoided with proper advice to avoid the tragedy of abortion. PMID- 28342436 TI - [Vulnerations of Human Dignity At The End of Life]. AB - Death is constitutive of human nature and therefore it must happen naturally. But there are mainly two ways that falsify it: euthanasia and therapeutic obstinacy. Two wrong choices that do not accept the human reality of death (the first, anticipates death and the second, delays it). From the philosophical and ethical point of view, both options are rejected, because they are against human dignity at the end of life. Aside from these, this article also rejects the different names which are given to refer to euthanasia, that also go against human nature at the end of life. On the other hand, do not confuse euthanasia with sedation. Both have a common goal to prevent the patient from feeling pain and suffering. To achieve this goal, both options administer "drugs" to the patient. But in the administration of drugs in euthanasia involves ending patient's life. The administration of drugs in sedation aims for the patient's death to occur naturally. Finally, we briefly discuss the basic care necessary in these situations. The absence of basic care cannot become a covert euthanasia. The patient must die from his/her illness, never from a lack of care. All human actions (euthanasia, sedation, therapeutic obstinacy and basic care) should be an expression and manifestation of what human dignity demands. Such dignity is expressed in the actions performed by human beings. PMID- 28342437 TI - [The Dignity of the Vulnerable Is Priceless What You Can Do Biolaw To Save Us From the Economistic Trap]. AB - This article proposes a reflection on the exclusion of particularly vulnerable human beings as a condition for the success of economistic culture and social organization. This fragility can depend on the body side as well as the social aspect: the effects of discrimination are identical. To react to a situation of injustice less and less tolerable, the biolaw touches -as in general the right, if it has a meaning and a specific function, and is not reduced to mere legitimization of the balance of forces or interest of the individuals or the groups better organized and represented- defend the fragility of all violence in the name of equality among human beings which depend on the universal condition of vulnerability, held in its positive aspects by philosophers such as MacIntyre and Nussbaum and many literary geniuses of all times. PMID- 28342438 TI - [Use of the Term "Pre-Embryo" In the Biomedical Literature From Its Origin to the Present]. AB - In this article, we present a review about the use of the term "preembryo" in the scientific literature as well as Bioethics from its origin, back in June 1979, to the end of the year 2014. We analyze their evolution along the time comparing with other terms commonly used in embryology. Also, we show the relevant journals in which this term appears, (offering the impact index within their specific field), and the authors who use it the most. The term "preembryo" arose in the scientific literature in 1979, remaining for about 6 years without reappearing in the scientific literature. Then, after an increase of articles, that covers the 90's decade, began to decrease its use without having disappeared altogether. Our study also shows that the use of the word "preembryo" has not increased with the passage of time; on the contrary, it is becoming less used in the biomedical literature. This does not occur with other terms that name the embryo before implantation, which have not ceased to increase during these years, both referring to the human species and other animal species. Finally, the term "pre embryo" appears very little in journals related to the reproduction biology area, but it does so in obstetrics and gynecology, where many articles on assisted reproduction are published. Our findings suggest that, instead of replacing classical embryological terms, the word "preembryo" does not seem to affect the use of them. Likewise, this word has a hypertrophied use in humans without an apparent reason, which would support the artificial nature of this term. Finally, the term "pre-embryo" appears very little in journals of reproduction biology area, but it does so in obstetrics and gynecology, where many articles on assisted reproduction are published. In conclusion, instead of substituting classical embryological terms, the word "pre-embryo" does not seem to affect the use of them and in the current discussions about the human condition of the embryo this term is no longer used. PMID- 28342440 TI - [Commentary on the Case: Second Opinion, Compassionate Use, and Clinical Trial]. PMID- 28342439 TI - [Second Opinion, Compassionate Use, and Clinical Trial]. PMID- 28342441 TI - Building a community of practice in rural medical education: growing our own together. AB - CONTEXT: This article chronicles the rise, decline, and recent resurgence of rural training track residency programs (RTTs) in the USA over the past 30 years and the emergence of a healthy community of practice in rural medical education. This has occurred during a time in the USA when federal and state funding of graduate medical education has been relatively stagnant and the rules around finance and accreditation of rural programs have been challenging. ISSUE: Many of the early family residency programs developed in the 1970s included a curricular focus on rural practice. However, by the 1980s, these programs were not yet producing the desired numbers of rural physicians. In response, in 1986, Maudlin and others at the family medicine residency in Spokane developed the first 1-2 RTT in Colville, Washington. In the 1990s, and by 2000, early news of success led to a peak of 35 active programs. However, over the next decade these programs experienced significant hardship due to a lack of funding and a general decline in student interest in family medicine. By 2010, only 25 programs remained. In 2010, in an effort to sustain the 1-2 RTT as a national strategy in training physicians for rural practice, a federally funded consortium of individuals and programs established the RTT Technical Assistance program (RTT TA). Building on the pattern of peer support and collaboration set by earlier groups, the RTT TA consortium expanded the existing community of practice in rural medical education in support of RTTs. In-person meetings, peer consultation and visitation, coordinated efforts at student recruitment, and collaborative rural medical education research were all elements of the consortium's strategy. Rather than anchoring its efforts in medical schools or hospitals, this consortium engaged as partners a wider variety of stakeholders. This included physician educators still living and practicing in rural communities ('local experts'), rural medical educator peers, program directors, professional groups, academic units, governmental entities such as state offices of rural health, and national associations with a stake in rural medical education. The consortium has succeeded in (1) supporting established and new RTTs, (2) increasing medical student interest in these programs, and (3) demonstrating the effectiveness of this strategy through a minimum dataset and registry of RTT trainees. From a low of 21 programs in 2012, the number has grown to 32, accounting for a total of 68 positions in each year of training. The RTT Collaborative, the non-profit that has emerged as the sustainable product of that federal funding, is now supported by a national cooperative of participating rural programs and continues the work. LESSONS LEARNED: Growing a community of practice in this fashion requires the organic building of relationships over time. The RTT TA consortium, and now the RTT Collaborative as a sustainable successor, have laid a strong foundation for community-engaged rural health professions education into the future - from each growing their own, to 'growing our own ... together. PMID- 28342442 TI - Comparison of qSOFA and SIRS for predicting adverse outcomes of patients with suspicion of sepsis outside the intensive care unit. AB - BACKGROUND: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) Task Force recently introduced a new clinical score termed quick Sequential (Sepsis-related) Organ Failure Assessment (qSOFA) for identification of patients at risk of sepsis outside the intensive care unit (ICU). We attempted to compare the discriminatory capacity of the qSOFA versus the Systemic Inflammatory Response Syndrome (SIRS) score for predicting mortality, ICU-free days, and organ dysfunction-free days in patients with suspicion of infection outside the ICU. METHODS: The Weill Cornell Medicine Registry and Biobank of Critically Ill Patients is an ongoing cohort of critically ill patients, for whom biological samples and clinical information (including vital signs before and during ICU hospitalization) are prospectively collected. Using such information, qSOFA and SIRS scores outside the ICU (specifically, within 8 hours before ICU admission) were calculated. This study population was therefore comprised of patients in the emergency department or the hospital wards who had suspected infection, were subsequently admitted to the medical ICU and were included in the Registry and Biobank. RESULTS: One hundred fifty-two patients (67% from the emergency department) were included in this study. Sixty-seven percent had positive cultures and 19% died in the hospital. Discrimination of in-hospital mortality using qSOFA [area under the receiver operating characteristic curve (AUC), 0.74; 95% confidence intervals (CI), 0.66-0.81] was significantly greater compared with SIRS criteria (AUC, 0.59; 95% CI, 0.51-0.67; p = 0.03). The qSOFA performed better than SIRS regarding discrimination for ICU-free days (p = 0.04), but not for ventilator-free days (p = 0.19), any organ dysfunction-free days (p = 0.13), or renal dysfunction-free days (p = 0.17). CONCLUSIONS: In patients with suspected infection who eventually required admission to the ICU, qSOFA calculated before their ICU admission had greater accuracy than SIRS for predicting mortality and ICU-free days. However, it may be less clear whether qSOFA is also better than SIRS criteria for predicting ventilator free-days and organ dysfunction-free days. These findings may help clinicians gain further insight into the usefulness of qSOFA. PMID- 28342443 TI - Incidental metastatic mediastinal atypical carcinoid in a patient with parathyroid adenoma: a case report. AB - BACKGROUND: Atypical carcinoid arising from the mediastinal tissue is a rare neuroendocrine tumor and an association with parathyroid adenoma is very unusual. We report an unusual case of atypical carcinoid of mediastinum with metastasis in a patient presenting with parathyroid adenoma, which is the first case to be reported from Pakistan. CASE PRESENTATION: A 51-year-old Pakistani man was seen in postoperative intensive care after right parathyroidectomy and mediastinal mass resection for the management of postoperative hypocalcaemia. He had a background history of dyspnea. Examination was unremarkable. Preoperative laboratory evaluation revealed a calcium level of 12.7 mg/dl, phosphate of 1.9 mg/dl, serum albumin of 4.8 g/dl, alkaline phosphate of 94 U/L, and serum intact parathyroid hormone level 413.8 pg/ml. A technetium-99m sestamibi parathyroid scan showed right parathyroid increased tracer uptake. Further workup revealed a large mediastinal mass which was diagnosed as atypical carcinoid after Tru-Cut biopsy. He underwent right-sided parathyroidectomy and resection of the mediastinal mass. The histopathology confirmed it to be a parathyroid adenoma and atypical carcinoid tumor of his mediastinum with metastasis in his lymph node and parathyroid gland. Somatostatin receptor scintigraphy revealed a well-defined focus in his left hypochondriac region consistent with a somatostatin receptor scintigraphy-avid tumor. He was started on everolimus and planned for octreotide therapy. CONCLUSIONS: We describe an incidental finding of atypical carcinoid of the mediastinum in a patient diagnosed as having parathyroid adenoma. Clinical manifestations of neuroendocrine syndromes are challenging. Some tumors cluster in a non-classic description with other common neoplasms. They rarely present in isolation, remain clinically silent, and need aggressive workup with the aid of imaging and histopathology. PMID- 28342446 TI - Corrections. PMID- 28342445 TI - Corrections. PMID- 28342447 TI - Corrections. PMID- 28342444 TI - Acid Ceramidase Deficiency in Mice Results in a Broad Range of Central Nervous System Abnormalities. AB - Farber disease is a rare autosomal recessive disorder caused by acid ceramidase deficiency that usually presents as early-onset progressive visceral and neurologic disease. To understand the neurologic abnormality, we investigated behavioral, biochemical, and cellular abnormalities in the central nervous system of Asah1P361R/P361R mice, which serve as a model of Farber disease. Behaviorally, the mutant mice had reduced voluntary locomotion and exploration, increased thigmotaxis, abnormal spectra of basic behavioral activities, impaired muscle grip strength, and defects in motor coordination. A few mutant mice developed hydrocephalus. Mass spectrometry revealed elevations of ceramides, hydroxy ceramides, dihydroceramides, sphingosine, dihexosylceramides, and monosialodihexosylganglioside in the brain. The highest accumulation was in hydroxy-ceramides. Storage compound distribution was analyzed by mass spectrometry imaging and morphologic analyses and revealed involvement of a wide range of central nervous system cell types (eg, neurons, endothelial cells, and choroid plexus cells), most notably microglia and/or macrophages. Coalescing and mostly perivascular granuloma-like accumulations of storage-laden CD68+ microglia and/or macrophages were seen as early as 3 weeks of age and located preferentially in white matter, periventricular zones, and meninges. Neurodegeneration was also evident in specific cerebral areas in late disease. Overall, our central nervous system studies in Asah1P361R/P361R mice substantially extend the understanding of human Farber disease and suggest that this model can be used to advance therapeutic approaches for this currently untreatable disorder. PMID- 28342448 TI - Editorial for the special issue on "Golgi-related human disorders". PMID- 28342449 TI - A systematic review and meta-analysis of the association between long non-coding RNA polymorphisms and cancer risk. AB - It has been suggested that long non-coding RNA (lncRNA) gene polymorphisms are associated with cancer risk. In this article, we conducted a systematic review related to studies on the association between lncRNA single-nucleotide polymorphisms (SNPs) and the overall risk of cancer. A total 17 SNPs in four common lncRNA genes were included in the meta-analysis. In the lncRNA H19, the rs2735971 A/G, rs2839698C/T, and rs3024270 G/C polymorphisms, but not rs217727C/T, were correlated with overall cancer risk. The results also suggested that other SNPs were correlated with overall cancer risk, namely, two in HOTAIR (HOX transcript antisense RNA: rs920778C/T and rs7958904 G/C) and two in PRNCR1 (rs1016343C/T and rs16901946 A/G). No association was found between the three ZNRD1-AS1 (ZNRD1 antisense RNA 1) SNPs and the risk of cancer. In summary, our findings suggest that quite a few studied lncRNA SNPs are associated with overall cancer risk; therefore, they are potential predictive biomarkers for the risk of cancer. Moreover, other lncRNA SNPs investigated were also relevant to cancer but studies on them are limited, and they were also briefly reviewed as candidate cancer markers. PMID- 28342450 TI - Scientific feuds, polemics, and ad hominem arguments in basic and special interest genetics. AB - Scientific disputes are commonly presented and settled in journal publications. Most are resolved by a weighing of evidence and new findings. In some cases the arguments are personal and in the form of ad hominem attacks on the personality or integrity of an author of a journal article. Many famous scientists (e.g., Galileo, Newton, and Hooke) used ad hominem arguments in responding to their critics. William Bateson, W.F.R. Weldon, William Castle, and H.J. Muller used ad hominem arguments in their publications until the end of World War I, when editorial policy of journals changed. Motivating some of the attacks are philosophic differences (such as holistic or reductionist approaches to science), ideological differences (such as Marxist or Capitalist outlooks), politics (such as Cold War depictions by East and West on fallout from nuclear testing), or conflicts of interest (which can be professional or financial such as the debates over nontraditional and orthodox medicine or over tobacco smoking and health). Most of the time, the disputes are motivated by honest disagreements over the interpretation of the data. A recent surge (2009-2016) of ad hominem attacks by Edward Calabrese has appeared disparaging H. J. Muller, E. B. Lewis, other twentieth-century contributors to radiation genetics, and the National Academy of Sciences. They address the mutational effects of low-dose radiation exposure. Calabrese's attacks have led to responses by geneticists in the field of mutagenesis, by agencies criticized by Calabrese, and by students and colleagues of those who have been accused of deception by Calabrese. This article reviews some of the history of ad hominem arguments in science and the background to the attacks by Calabrese. I argue that Calabrese's characterization of Muller and his supporters is unjust, misleading, and hurtful. I also propose some methods for dealing with or preventing ad hominem attacks in professional journals. PMID- 28342451 TI - TERT promoter mutations in telomere biology. AB - Telomere repeats at chromosomal ends, critical to genome integrity, are maintained through an elaborate network of proteins and pathways. Shelterin complex proteins shield telomeres from induction of DNA damage response to overcome end protection problem. A specialized ribonucleic protein, telomerase, maintains telomere homeostasis through repeat addition to counter intrinsic shortcomings of DNA replication that leads to gradual sequence shortening in successive mitoses. The biogenesis and recruitment of telomerase composed of telomerase reverse transcriptase (TERT) subunit and an RNA component, takes place through the intricate machinery that involves an elaborate number of molecules. The synthesis of telomeres remains a controlled and limited process. Inherited mutations in the molecules involved in the process directly or indirectly cause telomeropathies. Telomerase, while present in stem cells, is deactivated due to epigenetic silencing of the rate-limiting TERT upon differentiation in most of somatic cells with a few exceptions. However, in most of the cancer cells telomerase reactivation remains a ubiquitous process and constitutes one of the major hallmarks. Discovery of mutations within the core promoter of the TERT gene that create de novo binding sites for E-twenty-six (ETS) transcription factors provided a mechanism for cancer-specific telomerase reactivation. The TERT promoter mutations occur mainly in tumors from tissues with low rates of self renewal. In melanoma, glioma, hepatocellular carcinoma, urothelial carcinoma and others, the promoter mutations have been shown to define subsets of patients with adverse disease outcomes, associate with increased transcription of TERT, telomerase reactivation and affect telomere length; in stem cells the mutations inhibit TERT silencing following differentiation into adult cells. The TERT promoter mutations cause an epigenetic switch on the mutant allele along with recruitment of pol II following the binding of GABPA/B1 complex that leads to mono-allelic expression. Thus, the TERT promoter mutations hold potential as biomarkers as well as future therapeutic targets. PMID- 28342452 TI - Contribution of genetic factors to platinum-based chemotherapy sensitivity and prognosis of non-small cell lung cancer. AB - Although platinum-based chemotherapy remains the standard treatment for advanced NSCLC patients, clinical outcomes are poor and most patients develop high-grade toxicities. Genetic factors, such as single nucleotide polymorphisms (SNPs) involved in platinum pharmacodynamics, metabolism and mechanism of action, may account for inter-individual differences shown in effectiveness and toxicity. Polymorphisms in genes involved in DNA repair and others such as PI3K/PTEN/AKT and TGF-beta pathways have been demonstrated to be associated with response, survival and toxicity in advanced NSCLC patients treated with platinum-based chemotherapy. Other cellular processes, like DNA methylation and proliferation have been connected with clinical outcome for platinum-based chemotherapy regimens through folate metabolism and cytokine signaling. The influence of gene polymorphisms in the NER pathway on clinical outcome has been extensively investigated in advanced NSCLC patients treated with platinum-based chemotherapy but contradictory results have been reported. The most recent and thorough meta analyses have failed to show an association between ERCC1 C118T/C8092A and ERCC5 rs1047768 polymorphisms and response to platinum based chemotherapy. However, other polymorphisms in ERCC2 (Lys751Gln and Asp312Asn) and ERCC5 (rs2094258 and rs2296147) and have been related with overall survival (OS) and progression-free survival (PFS), respectively. The Arg194Trp and Gln399Arg polymorphisms in XRCC1, have also been extensively investigated. Their effects seem to be dependent on ethnicity, and recent meta-analyses have confirmed an association with response in Asian but not in Caucasian patients. The influence on overall response rate (ORR) of the rs861539 polymorphism in XRCC3, part of (DSB) repair pathway, has also been confirmed in a meta-analysis. Finally, SNPs in genes coding proteins of the p53, PI3K, TGF-beta, membrane transporters, gluthatione metabolism enzymes and cytokine pathways have been less extensively investigated. Some polymorphisms have been reported to be associated with toxicity or clinical outcome, but data generally come from a limited number of studies and need to be confirmed. PMID- 28342453 TI - Ionizing radiation biomarkers in epidemiological studies - An update. AB - Recent epidemiology studies highlighted the detrimental health effects of exposure to low dose and low dose rate ionizing radiation (IR): nuclear industry workers studies have shown increased leukaemia and solid tumour risks following cumulative doses of <100mSv and dose rates of <10mGy per year; paediatric patients studies have reported increased leukaemia and brain tumours risks after doses of 30-60mGy from computed tomography scans. Questions arise, however, about the impact of even lower doses and dose rates where classical epidemiological studies have limited power but where subsets within the large cohorts are expected to have an increased risk. Further progress requires integration of biomarkers or bioassays of individual exposure, effects and susceptibility to IR. The European DoReMi (Low Dose Research towards Multidisciplinary Integration) consortium previously reviewed biomarkers for potential use in IR epidemiological studies. Given the increased mechanistic understanding of responses to low dose radiation the current review provides an update covering technical advances and recent studies. A key issue identified is deciding which biomarkers to progress. A roadmap is provided for biomarker development from discovery to implementation and used to summarise the current status of proposed biomarkers for epidemiological studies. Most potential biomarkers remain at the discovery stage and for some there is sufficient evidence that further development is not warranted. One biomarker identified in the final stages of development and as a priority for further research is radiation specific mRNA transcript profiles. PMID- 28342454 TI - Fate of micronuclei and micronucleated cells. AB - The present review describes available evidence about the fate of micronuclei and micronucleated cells. Micronuclei are small, extranuclear chromatin bodies surrounded by a nuclear envelope. The mechanisms underlying the formation of micronuclei are well understood but not much is known about the potential fate of micronuclei and micronucleated cells. Many studies with different experimental approaches addressed the various aspects of the post-mitotic fate of micronuclei and micronucleated cells. These studies are reviewed here considering four basic possibilities for potential fates of micronuclei: degradation of the micronucleus or the micronucleated cell, reincorporation into the main nucleus, extrusion from the cell, and persistence in the cytoplasm. Two additional fates need to be considered: premature chromosome condensation/chromothripsis and the elimination of micronucleated cells by apoptosis, yielding six potential fates for micronuclei and/or micronucleated cells. The available data is still limited, but it can be concluded that degradation and extrusion of micronuclei might occur in rare cases under specific conditions, reincorporation during the next mitosis occurs more frequently, and the majority of the micronuclei persist without alteration at least until the next mitosis, possibly much longer. Overall, the consequences of micronucleus formation on the cellular level are still far from clear, but they should be investigated further because micronucleus formation may contribute to the initial and later steps of malignant cell transformation, by causing gain or loss of genetic material in the daughter cells and by the possibility of massive chromosome rearrangement in chromosomes entrapped within a micronucleus by the mechanisms of chromothripsis and chromoanagenesis. PMID- 28342455 TI - Repair of oxidatively induced DNA damage by DNA glycosylases: Mechanisms of action, substrate specificities and excision kinetics. AB - Endogenous and exogenous reactive species cause oxidatively induced DNA damage in living organisms by a variety of mechanisms. As a result, a plethora of mutagenic and/or cytotoxic products are formed in cellular DNA. This type of DNA damage is repaired by base excision repair, although nucleotide excision repair also plays a limited role. DNA glycosylases remove modified DNA bases from DNA by hydrolyzing the glycosidic bond leaving behind an apurinic/apyrimidinic (AP) site. Some of them also possess an accompanying AP-lyase activity that cleaves the sugar-phosphate chain of DNA. Since the first discovery of a DNA glycosylase, many studies have elucidated the mechanisms of action, substrate specificities and excision kinetics of these enzymes present in all living organisms. For this purpose, most studies used single- or double-stranded oligodeoxynucleotides with a single DNA lesion embedded at a defined position. High-molecular weight DNA with multiple base lesions has been used in other studies with the advantage of the simultaneous investigation of many DNA base lesions as substrates. Differences between the substrate specificities and excision kinetics of DNA glycosylases have been found when these two different substrates were used. Some DNA glycosylases possess varying substrate specificities for either purine derived lesions or pyrimidine-derived lesions, whereas others exhibit cross activity for both types of lesions. Laboratory animals with knockouts of the genes of DNA glycosylases have also been used to provide unequivocal evidence for the substrates, which had previously been found in in vitro studies, to be the actual substrates in vivo as well. On the basis of the knowledge gained from the past studies, efforts are being made to discover small molecule inhibitors of DNA glycosylases that may be used as potential drugs in cancer therapy. PMID- 28342457 TI - Response to the letter to the Editor. PMID- 28342456 TI - Letter to the Editor: Rejuvenate eggs or regenerate ovary? PMID- 28342458 TI - Novelties in the therapeutic scene of rheumatoid arthritis. PMID- 28342459 TI - ? PMID- 28342460 TI - [A personalised support programme for patients with diabetes]. AB - On the initiative of the Federation francaise des diabetiques, a personalised support project has been set up for people with diabetes. They are invited to talks and to take part in individual interviews led by specially trained volunteer expert patients. The aim is to give them an opportunity to talk with peers and to learn how to live with the disease. PMID- 28342461 TI - [The infection risk assessment visit in haemodialysis, a new tool]. AB - Haemodialysis is a speciality with a high risk of infection, due in part to the frailty of the patients (immunosuppressed, high prevalence of carriers of multi drug resistant bacteria), as well as to the invasive procedures carried out (inserting central venous catheters, using these catheters and arteriovenous fistulas). The infection risk assessment visit in haemodialysis is a tool which contributes to the safety of care. PMID- 28342462 TI - ? PMID- 28342463 TI - [Simulation in health care, an overview and framework for development]. AB - Following the example of Anglo-Saxon countries, which have been using it for some thirty years, simulation in health care is growing rapidly in France. The development of this challenging pedagogical method is guided by several documents published by the French National Health Authority. PMID- 28342464 TI - [Training through simulation in multi-professional groups]. AB - The effective management of an emergency situation requires optimal collaboration between the different players present. Training through simulation in multi professional groups is an apposite way of developing collaborative competencies. PMID- 28342465 TI - [Simulation in health care, a partnership between a training institute and a health care facility]. AB - A system of collaboration around simulation, between a health care facility and a training institute, has been put in place. It has enabled the challenges for both institutions to be identified, thereby confirming the need to continue this project. In this context, interprofessionalality and intergenerationality are key elements. PMID- 28342466 TI - [Challenges, benefits and limits of high-fidelity simulation in emergency medicine]. AB - Combining in-situ behaviour and reflexive practice during the debriefing, simulation is a powerful pedagogical tool. It enables a team to co-construct shared knowledge in a context of experiential learning and in a safe and reassuring environment. PMID- 28342467 TI - [Design and creation of a simulation centre]. AB - The design of a simulation centre must be based on a well thought out pedagogical project which meets the training needs of health professionals. Beyond the architectural design, the organisational and financial aspects of the centre are fundamental elements to be taken into consideration. PMID- 28342468 TI - [Simulation of approaching with a family of a deceased patient concerning organ donation]. AB - The simulation of approaching relating to organ donation consists in reproducing such an interview in conditions similar to those encountered in the intensive care unit. It includes the preparation of the discussion, the way the family is approached, the announcement of the death of their relative, the dialogue with them concerning the donation. Simulation is one of the best ways of training hospital organ donation coordinators in this approach. PMID- 28342469 TI - [Simulation for the announcement of health care-associated harm]. AB - A participative pedagogical tool, simulation aids the transfer of competencies in relation to the complex situation of announcing health care-associated harm. The aim is to reinforce patient safety and to improve the quality of communication with patients and between health professionals. PMID- 28342470 TI - [Simulation in health care and inter-professionality in initial training]. AB - In a context aiming to improve risk management through effective team communication, the development of inter-professional pedagogical sessions is a lever to be developed in order to construct collective competency during initial training. PMID- 28342471 TI - [Teaching simulation to trainers]. AB - Many trainers wish to integrate simulation into their teaching. Aside from the learning difficulties associated with some simulators, this practice requires the trainer to receive specific training, in order to avoid any risk of a negative or even harmful, learning experience. PMID- 28342472 TI - [The room of errors, a fun learning tool]. AB - Simulation in health care, a source of innovative pedagogical developments, is particularly well-suited to the training of nursing teams. It enables them to acquire or reinforce their knowledge, without any risk for the patients, in a calm and reassuring environment. In psychiatry in particular, the use of a room of errors constitutes a useful learning tool for professionals. PMID- 28342474 TI - ? PMID- 28342473 TI - [Ethics and medical simulation]. AB - Simulation in health care helps to raise health professionals' awareness of medical ethics and to understand the mechanisms involved in a difficult situation. They can thereby adopt a suitable form of behaviour and communication. PMID- 28342475 TI - ? PMID- 28342476 TI - Long-term Clinical Outcome of Teeth Obturated with Resilon. AB - INTRODUCTION: Although Resilon has been in clinical use as an endodontic obturation material for more than a decade, there is a lack of long-term clinical outcome studies. The purpose of this retrospective case-control study was to compare long-term clinical outcomes in teeth obturated with Resilon/RealSeal SE (RS) and GP/AH Plus (GP). METHODS: One hundred teeth treated at Texas A&M University College of Dentistry between 2007 and 2012 were included; 50 teeth were obturated with RS and 50 with GP. All cases were initial treatments without preoperative periapical radiolucencies. Success and failure were assessed on the basis of clinical signs and symptoms and/or the presence of periapical radiolucency. Chi-square test and odds ratio were used to determine the association between the obturation material and outcome. Potential prognostic factors were evaluated including age, sex, tooth location, preoperative diagnosis, and one versus multiple visits. RESULTS: The average recall time for RS was 5.8 years and 6.6 years for GP. Fifty-six percent of RS-obturated teeth were classified as successful at recall compared with 88% of GP-obturated teeth. RS had 5.7 times greater odds of failure compared with GP (P < .001). When periapical radiolucencies were present, they tended to be larger and involve multiple roots in the RS group compared with GP group. None of the prognostic factors examined were found to have any significant effect on outcome. CONCLUSIONS: Within the limitations of this study, teeth obturated with RS had 5.7 times greater chance of failure compared with teeth obturated with GP. PMID- 28342477 TI - Effect of Different Irrigation Systems on Sealer Penetration into Dentinal Tubules. AB - INTRODUCTION: Different irrigation systems have been developed to improve the efficacy and distribution of the irrigants. The aim of this study was to compare the effect of conventional endodontic needle irrigation with other irrigant delivery and/or agitation systems on sealer penetration into dentinal tubules. METHODS: Fifty single-rooted teeth with round-shaped root canals were distributed in 5 homogeneous groups characterized by the different cleansing system used: conventional endodontic needle irrigation, EndoActivator, Irrisafe, Self Adjusting File, and EndoVac. After instrumentation, all teeth were filled by Thermafil obturators and rhodamine B dye labeled TopSeal sealer. Teeth were transversally sectioned at 2-, 5-, and 7-mm levels from the apex and observed under confocal laser scanning microscope. Maximum, mean, and percentage of sealer penetration inside tubules around the root canal were measured. Moreover, the integrity of the sealer layer perimeter was evaluated. RESULTS: No significant differences both in mean (p > .05) and in maximum penetration depth (p > .05) were observed among groups, whereas both parameters showed an increased trend within each group from the 2- to the 7-mm level from apex. Similarly, the percentage of penetration around the root canal wall did not differ among groups (p > .05) and showed an increasing trend within each group from the apical to the coronal portion of the canal. CONCLUSIONS: Sealer penetration into dentinal tubules is not affected by the irrigant delivery and/or agitation systems studied. Thermafil with TopSeal technique achieves complete sealer perimeter integrity in all groups. PMID- 28342478 TI - Interactions between the Tetrasodium Salts of EDTA and 1-Hydroxyethane 1,1 Diphosphonic Acid with Sodium Hypochlorite Irrigants. AB - INTRODUCTION: A clinically useful all-in-one endodontic irrigant with combined proteolytic and decalcifying properties is still elusive. In this study, the chemical effects of dissolving the tetrasodium salts of 1-hydroxyethane 1,1 diphosphonic acid (Na4HEDP) or Na4EDTA directly in sodium hypochlorite (NaOCl) irrigants in polypropylene syringes were assessed during the course of 1 hour. METHODS: The solubility of the salts in water was determined. Their compatibility with 1% and 5% NaOCl was measured by iodometric titration and in a calcium complexation experiment by using a Ca2+-selective electrode. RESULTS: The salts dissolved within 1 minute. The dissolution maximum of Na4HEDP in water (wt/total wt) was 44.6% +/- 1.6%. The corresponding dissolution maximum of Na4EDTA was 38.2% +/- 0.8%. Na4HEDP at 18% in 5% NaOCl caused a mere loss of 16% of the initially available chlorine during 1 hour. In contrast, a corresponding mixture between NaOCl and the Na4EDTA salt caused 95% reduction in available chlorine after 1 minute. Mixtures of 3% Na4EDTA with 1% NaOCl were more stable, but only for 30 minutes. Na4HEDP lost 24% of its calcium complexation capacity after 60 minutes. The corresponding loss for Na4EDTA was 34%. CONCLUSIONS: The compatibility and solubility of particulate Na4HEDP with/in NaOCl solutions are such that these components can be mixed and used for up to 1 hour. In contrast, short-term compatibility of the Na4EDTA salt with NaOCl solutions was considerably lower, decreasing at higher concentrations of either compound. Especially for Na4HEDP but also for Na4EDTA, the NaOCl had little effect on calcium complexation. PMID- 28342479 TI - Corrigendum. PMID- 28342480 TI - Corrigendum. PMID- 28342481 TI - Preface to the special issue. PMID- 28342483 TI - Erratum. PMID- 28342482 TI - Treatment outcomes in veterans with HPV-positive head and neck cancer. AB - OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) caused by the human papilloma virus (HPV) has an improved prognosis relative to HPV-negative tumors. Patients with HPV-positive disease may benefit from different treatment modalities in order to optimize survival and quality of life. We sought to investigate HPV-positive HNSCC within the military veteran population, and analyze the role of treatment modality in outcomes of patients with HPV-positive and HPV-negative tumors. METHODS: Patients diagnosed with HNSCC between January 1, 2010 and December 31, 2014 at one regional veterans health center were retrospectively examined. Pathologic specimens underwent testing for HPV subtype and p16 expression. Demographic and clinical factors, including treatment modality, were analyzed for their impact on the primary outcome of overall survival. RESULTS: There were 209 patients with primary tumor sites including larynx (25.4%), oral tongue (19.6%), oral cavity (13.4%), oropharynx (17.2%), tonsil (17.2%), unknown primary (2.9%), nasopharynx (1.9%), and multiple sites (2.4%). Patients had HPV-positive (n=82, 39.2%), HPV-negative (n=89, 42.6%) or unknown HPV status (n=38, 18.2%). Primary treatment modalities were chemoradiation (n=124, 59.3%), surgery (n=39, 18.7%), radiation therapy (n=37, 17.7%), or no treatment (n=9, 4.3%). Survival analysis with Cox proportional hazards model demonstrated significant associations with T classification (T4 3.61, P=0.005), N classification (N3 3.52, P=0.0159), M classification (M1 2.8, P=0.0209), and HPV status (HPV-positive 0.43, P=0.0185), but no relation with primary treatment modality (primary surgery vs. primary chemoradiation 1.01, P=0.9718). CONCLUSION: HPV-positive HNSCC in the veteran population has a significantly improved prognosis relative to similarly staged patients with HPV negative disease. This study demonstrates that the primary treatment modality - chemoradiation, radiation therapy, or surgery - does not impact overall survival among veterans with HPV-positive HNSCC. PMID- 28342484 TI - Biventricular endomyocardial biopsy in patients with suspected myocarditis: Methodological issue on diagnostic value to avoid misinterpretation. PMID- 28342485 TI - Biventricular endomyocardial biopsy in patients with suspected myocarditis. PMID- 28342486 TI - Antithrombotic therapy and vascular access site: A choice not mutually exclusive. PMID- 28342487 TI - Reply: Anthithrombotic therapy and vascular access site: A choice not mutually exclusive. PMID- 28342488 TI - Prognostic factors in the heart failure with reduced ejection fraction. PMID- 28342489 TI - Answer to Dr. Eyuboglu. PMID- 28342490 TI - Renal denervation in patients with chronic kidney disease. PMID- 28342491 TI - Response to Letter to the Editor by Drs. Yang and Yu entitled: Renal denervation in patients with chronic kidney disease. PMID- 28342492 TI - Circadian variation in acute myocardial infarction size: Likely involvement of the melatonin and suprachiasmatic nuclei. PMID- 28342493 TI - Reply to "Circadian variation in acute myocardial infarction size: Likely involvement of the melatonin and suprachiasmatic nuclei". PMID- 28342494 TI - Elevated fibroblast growth factor-23 and risk for cardiovascular disease or mortality in the general population: A meta-analysis. PMID- 28342495 TI - Reply to letter to the editor: Elevated fibroblast growth factor-23 and risk for cardiovascular disease or mortality in the general population. PMID- 28342496 TI - Ivabradine in acute decompensated systolic heart failure. PMID- 28342497 TI - Ivabradine in acute decompensated systolic heart failure. PMID- 28342498 TI - Vitamin K and direct oral anticoagulants in patients with major bleeding: Risk assessment. PMID- 28342499 TI - Risk of death in patients with major bleedings while on treatment with oral anticoagulants. PMID- 28342500 TI - Is hybrid subcutaneous implantable cardioverter-defibrillator and leadless pacemaker the future of device therapy? PMID- 28342501 TI - Reply to the letter to Editor "Is hybrid subcutaneous implantable cardioverter defibrillator and leadless pacemaker the future of device therapy?" PMID- 28342502 TI - Utility of the Controlling Nutritional Status (CONUT) score in patients admitted due to acute heart failure. PMID- 28342503 TI - Letter to editor in response to Formiga et al. "Utility of the Controlling Nutritional Status (CONUT) score in patients admitted due to acute heart failure". PMID- 28342504 TI - Retraction notice to "Long-Term Trends (1986-2003)in the Use of Coronary Reperfusion Strategies in Patients Hospitalized With Acute Myocardial Infarction in Central Massachusetts" [Int. J Cardiol. 131 (2008) (83-89)]. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief and Author. This article is a duplicate of a paper that has already been published in the Journal of Thrombosis and Thrombolysis, 23 (2007) 163-71. http://dx.doi.org/10.1007/s11239-006-9029-0. One of the conditions of submission of a paper for publication is that authors declare explicitly that the paper is not under consideration for publication elsewhere. As such this article represents a severe abuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process. PMID- 28342505 TI - Erratum to "Traditional acupuncture and myocardial ischemia" [Int. J. Cardiol. 189 (2015) 281]. PMID- 28342506 TI - Invited commentary. PMID- 28342507 TI - Invited commentary. PMID- 28342508 TI - Gender, smoking, body size, and aneurysm geometry influence the biomechanical rupture risk of abdominal aortic aneurysms as estimated by finite element analysis. AB - OBJECTIVE: Finite element analysis (FEA) has been suggested to be superior to maximal diameter measurements in predicting rupture of abdominal aortic aneurysms (AAAs). Our objective was to investigate to what extent previously described rupture risk factors were associated with FEA-estimated rupture risk. METHODS: One hundred forty-six patients with an asymptomatic AAA of a 40- to 60-mm diameter were retrospectively identified and consecutively included. The patients' computed tomography angiograms were analyzed by FEA without (neutral) and with (specific) input of patient-specific mean arterial pressure (MAP), gender, family history, and age. The maximal wall stress/wall strength ratio was described as a rupture risk equivalent diameter (RRED), which translated this ratio into an average aneurysm diameter of corresponding rupture risk. RESULTS: In multivariate linear regression, RREDneutral increased with female gender (3.7 mm; 95% confidence interval [CI], 0.13-7.3) and correlated with patient height (0.27 mm/cm; 95% CI, 0.11-0.43) and body surface area (BSA, 16 mm/m2; 95% CI, 8.3 24) and inversely with body mass index (BMI, -0.40 mm/kg m-2; 95% CI, -0.75 to 0.054) in a wall stress-dependent manner. Wall stress-adjusted RREDneutral was raised if the patient was currently smoking (1.1 mm; 95% CI, 0.21-1.9). Age, MAP, family history, and patient weight were unrelated to RREDneutral. In specific FEA, RREDspecific increased with female gender, MAP, family history positive for AAA, height, and BSA, whereas it was inversely related to BMI. All results were independent of aneurysm diameter. Peak wall stress and RRED correlated with aneurysm diameter and lumen volume. CONCLUSIONS: Female gender, current smoking, increased patient height and BSA, and low BMI were found to increase the mechanical rupture risk of AAAs. Previously described rupture risk factors may in part be explained by patient characteristic-dependent variations in aneurysm biomechanics. PMID- 28342509 TI - Invited commentary. PMID- 28342510 TI - Arterial protocol including prophylactic distal perfusion catheter decreases limb ischemia complications in patients undergoing extracorporeal membrane oxygenation. AB - OBJECTIVE: Venoarterial extracorporeal membrane oxygenation (ECMO) is a salvage therapy in patients with severe cardiopulmonary failure. Owing to the large size of the cannulas inserted via the femoral vessels (<=24-F) required for adequate oxygenation, this procedure could result in significant limb ischemic complications (10%-70%). This study evaluates the results of a distal limb perfusion arterial protocol designed to reduce associated complications. METHODS: We conducted a retrospective institutional review board-approved review of consecutive patients requiring ECMO via femoral cannulation (July 2010-January 2015). To prevent arterial ischemia, a distal perfusion catheter (DPC) was placed antegrade into the superficial femoral artery and connected to the ECMO circuit. Limb perfusion was monitored via near-infrared spectroscopy (NIRS) placed on both calves. Decannulation involved open repair, patch angioplasty, and femoral thrombectomy as needed. RESULTS: A total of 91 patients were placed on ECMO via femoral arterial cannula (16-F to 24-F) for a mean duration of 9 days (range, 1 40 days). A percutaneous DPC was inserted prophylactically at the time of cannulation in 55 of 91 patients, without subsequent ischemia. Of the remaining 36 patients without initial DPC placement, 12 (33% without DPC) developed ipsilateral limb ischemia related to arterial insufficiency, as detected by NIRS and clinical findings. In these patients, the placement of a DPC (n = 7) with or without a fasciotomy, or with a fasciotomy alone (n = 4), resulted in limb salvage; only one patient required subsequent amputation. After decannulation (n = 7), no patients had further evidence of limb ischemia. Risk factors for the development of limb ischemia identified by categorical analysis included lack of DPC at time of cannulation and ECMO cannula size of less than 20-Fr. There was a trend toward younger patient age. Overall ECMO survival rate was 42%, whereas survival in patients with limb ischemia was only 25%. CONCLUSIONS: Limb ischemia complications from ECMO may be decreased by prophylactic placement of an antegrade DPC. Without DPC, continuous monitoring using NIRS may identify limb ischemia, which can be treated subsequently with DPC and or fasciotomy. PMID- 28342511 TI - Invited commentary. PMID- 28342512 TI - Invited commentary. PMID- 28342513 TI - Mycotic aortic pseudoaneurysms in a patient with active Mycobacterium kansasii infection. PMID- 28342514 TI - Angiosome-directed revascularization in patients with critical limb ischemia. AB - OBJECTIVE: Direct revascularization (DR), according to the angiosome concept, provides direct blood flow to the site of tissue loss in patients with critical limb ischemia (CLI). DR may lead to improved outcomes; however, evidence for this is controversial. This systematic review and meta-analysis investigated the outcomes of surgical and endovascular DR compared with indirect revascularization (IR) in patients with CLI. METHODS: A systematic review was undertaken using the Cochrane Collaboration specified tool, and a meta-analysis was done according to the MOOSE (Meta-analysis of Observational Studies in Epidemiology) criteria. The electronic databases of MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were systematically searched for studies of DR compared with IR in patients with CLI with tissue loss. All articles were critically assessed for relevance, validity, and availability of data regarding patient and lesion characteristics and outcomes. When possible, data were systematically pooled, and a meta-analysis was performed for wound healing, major amputation, amputation free survival, and overall survival. RESULTS: Of 306 screened abstracts, 19 cohort studies with 3932 patients were included. Nine scored 7 or higher on the Newcastle-Ottawa score. DR significantly improved wound healing (risk ratio [RR], 0.60; 95% confidence interval [CI], 0.51-0.71), major amputation (RR, 0.56; 95% CI, 0.47-0.67), and amputation-free survival rates (RR, 0.83; 95% CI, 0.69-1.00) compared with IR. This significance was lost in major amputation on sensitivity analysis for bypass studies. No significant difference was found in overall survival. In studies stratifying for collaterals, no differences between DR and IR were found in wound healing or major amputations in the presence of collaterals. CONCLUSIONS: DR significantly improves wound healing and major amputation rates after endovascular treatment in patients with CLI, supporting the angiosome theory. In the presence of collaterals, outcomes after IR are similar to outcomes after DR. Alternatively, patients without collaterals may benefit even more from DR as a primary treatment strategy. The angiosome theory is less applicable in bypass surgery, because bypasses are generally anastomosed to the least affected artery, with runoff passing the ankle to maintain bypass patency. PMID- 28342515 TI - Transluminal balloon angioplasty bundling for 2017. PMID- 28342516 TI - Medicare's new quality payment program for physicians: An overview. PMID- 28342517 TI - Regarding "Incidence of and risk factors for bowel ischemia after abdominal aortic aneurysm repair". PMID- 28342518 TI - Regarding "Effectiveness and outcome of endovascular therapy for late-onset postpancreatectomy hemorrhage using covered stents and embolization". PMID- 28342519 TI - Evidence of use of multilayer flow modulator stents in treatment of thoracoabdominal aortic aneurysms and dissections. PMID- 28342520 TI - Duplex velocity criteria for carotid endarterectomy. PMID- 28342522 TI - Invited commentary. PMID- 28342521 TI - Endovascular management of chronic symptomatic aortic dissection with the Streamliner Multilayer Flow Modulator: Twelve-month outcomes from the global registry. AB - OBJECTIVE: Reported are initial 12-month outcomes of patients with chronic symptomatic aortic dissection managed by the Streamliner Multilayer Flow Modulator (SMFM; Cardiatis, Isnes, Belgium). Primary end points were freedom from rupture- and aortic-related death, and reduction in false lumen index. Secondary end points were patency of great vessels and visceral branches, and freedom of stroke, paraplegia, and renal failure. METHODS: Out of 876 SMFM implanted globally, we have knowledge of 542. To date, 312 patients are maintained in the global registry, of which 38 patients were identified as having an aortic dissection (12.2%). Indications included 35 Stanford type B dissections, two Stanford type A and B dissections, and one mycotic Stanford type B dissection. RESULTS: There were no reported ruptures or aortic-related deaths. All cause survival was 85.3% Twelve-month freedom from neurologic events was 100%, and there were no incidences of end-organ ischemia, paraplegia or renal insult. Morphologic analysis exhibited dissection remodeling by a reduction in longitudinal length of the dissected aorta, and false lumen volume. A statistically significant reduction in false lumen index (P = .016) at 12 months, and a borderline significant increase in true lumen volume (P = .053) confirmed dissection remodeling. CONCLUSIONS: The SMFM is an option in management of complex pan-aortic dissection. Results highlight SMFM implantation leads to dissection stabilization with no further aneurysm progression, and no retrograde type A dissection. Thoracic endovascular aneurysm repair by SMFM ensued in freedom from aortic rupture, neurologic stroke, paraplegia and renal failure. Further analysis of the global registry data will inform long-term outcomes. PMID- 28342523 TI - Early experience with a modified preloaded system for fenestrated endovascular aortic repair. AB - OBJECTIVE: Preloaded endovascular delivery systems expand the anatomic eligibility for complex aortic repair by requiring only one iliac access vessel and providing a stable platform for guiding sheaths into challenging target vessels. This article reports the lessons learned and early clinical outcomes using a modified preloaded delivery system for fenestrated endovascular aneurysm repair (FEVAR) in three aortic centers in Europe. METHODS: From October 2015 to March 2016, consecutive patients presenting with extensive aortic aneurysm treated with a modified preloaded FEVAR were prospectively enrolled from three high volume European aortic centers. The new design is a modification of previous designs of preloaded fenestrated stent grafts and of the p-branch device platform. The technical details of implantation are described and perioperative outcomes, including the learning curve, are collected and reported. RESULTS: All patients (30 patients; 80% men; 70.2 years old) presented for nonurgent repair of either a type Ia endoleak (3/30; 10%), a type I-II-III thoracoabdominal (8/30; 27%), or a type IV thoracoabdominal or pararenal (19/30; 63.%) aneurysm repair of a mean size of 64 +/- 13 mm using a custom made device. Primary technical success was achieved in 28 of 30 patients (93%) and assisted primary technical success in 29 of 30 patients (97%). The two technical failures included open conversion to repair a ruptured iliac artery and restenting of a dissected superior mesenteric artery which was recognized hours after the index procedure had finished. The mean procedure time was 277 +/- 153 minutes, fluoroscopy time 79 +/- 36 minutes, dose area product 112 +/- 90 Gy cm2, and contrast volume 87 +/- 46 mL. All renal fenestrations were successfully stented without type III endoleak on completion angiogram; the preloaded guiding sheaths were used for 53 of 58 renal arteries (91%). Challenges related to learning to the use of the modified preloaded system were experienced early and had no clinical consequences. Major complications occurred in seven cases (23%), including two perioperative deaths because of stroke and sepsis following primary conversion attributable to iliac rupture. There were no target vessel occlusions or type I/III endoleaks found on postoperative imaging. CONCLUSIONS: Based on early experience, the modified preloaded system can be safely and effectively used during FEVAR, with good technical result and a short period of learning. This device expands treatment to patients with compromised iliac access, thus, additional patients and more follow up will be required to determine unique risks of operating in this patient population. PMID- 28342524 TI - Short-Communication: Revisiting conclusions of the report titled, "The impact of psychological factors on self-reported sleep disturbance among people living in the vicinity of wind turbines," by Leila Jalali, Mohammad-Reza Nezhad-Ahmadi, Mahmood Gohari, Philip Bigelow, & Stephen McColl, published in environmental research, volume 148, July 2016, 401-410. AB - The research report concluded, "It appears that self-reported sleep reported of participants may be associated to the indirect effects of visual and attitudinal cue and concern about property devaluation rather than distance to the nearest WT's or noise as itself." Careful reading of the report shows that the conclusions presented are not supported by the data provided in the report. PMID- 28342525 TI - [Cardiac hydatid cyst. Which imaging modality for an accurate diagnosis?] AB - Cardiac echinococcosis is rare. Its spontaneous course is serious because of the risk of rupture. Its clinical manifestations are variable, often latent and misleading. The diagnosis is sometimes referred to by chest radiography. It is much facilitated by non-invasive imaging techniques in particular transesophageal and transthoracic echocardiography, CT scan and magnetic resonance imaging. The latter through a morphological and topographical analysis accurate diagnosis of hydatid cyst and its relationship to cardiac muscle and surrounding tissue. Through functional analysis in cine cyst movements relative to the heart wall, it confirms its free or fixed character in the heart chambers, determines its insertion area, its deformability, the risk of rupture and its impact on myocardial contraction. Our case illustrates the relative contribution of these different imaging techniques and their respective contributions to the identification of hydatid cyst of its wall, its contents, its relationship with the various tunics and heart chambers and its relations with the lungs and mediastinum. PMID- 28342526 TI - Use of the cumulative sum method (CUSUM) to assess the learning curves of ultrasound-guided continuous femoral nerve block. AB - BACKGROUND: Although ultrasound is a basic competence for anaesthesia residents (AR) there is few data available on the learning process. This prospective observational study aims to assess the learning process of ultrasound-guided continuous femoral nerve block and to determine the number of procedures that a resident would need to perform in order to reach proficiency using the cumulative sum (CUSUM) method. METHODS: We recruited 19 AR without previous experience. Learning curves were constructed using the CUSUM method for ultrasound-guided continuous femoral nerve block considering 2 success criteria: a decrease of pain score>2 in a [0-10] scale after 15minutes, and time required to perform it. RESULTS: We analyse data from 17 AR for a total of 237 ultrasound-guided continuous femoral nerve blocks. 8/17 AR became proficient for pain relief, however all the AR who did more than 12 blocks (8/8) became proficient. As for time of performance 5/17 of AR achieved the objective of 12minutes, however all the AR who did more than 20 blocks (4/4) achieved it. CONCLUSIONS: The number of procedures needed to achieve proficiency seems to be 12, however it takes more procedures to reduce performance time. The CUSUM methodology could be useful in training programs to allow early interventions in case of repeated failures, and develop competence-based curriculum. PMID- 28342527 TI - Development of a decentralized multi-axis synchronous control approach for real time networks. AB - The message scheduling and the network-induced delays of real-time networks, together with the different inertias and disturbances in different axes, make the synchronous control of the real-time network-based systems quite challenging. To address this challenge, a decentralized multi-axis synchronous control approach is developed in this paper. Due to the limitations of message scheduling and network bandwidth, error of the position synchronization is firstly defined in the proposed control approach as a subset of preceding-axis pairs. Then, a motion message estimator is designed to reduce the effect of network delays. It is proven that position and synchronization errors asymptotically converge to zero in the proposed controller with the delay compensation. Finally, simulation and experimental results show that the developed control approach can achieve the good position synchronization performance for the multi-axis motion over the real time network. PMID- 28342528 TI - "Recredicinal" Marijuana. PMID- 28342529 TI - Reply. PMID- 28342530 TI - Reply. PMID- 28342531 TI - Sensitivity of medial and lateral knee contact force predictions to frontal plane alignment and contact locations. AB - Musculoskeletal models are increasingly used to estimate medial and lateral knee contact forces, which are difficult to measure in vivo. The sensitivity of contact force predictions to modeling parameters is important to the interpretation and implication of results generated by the model. The purpose of this study was to quantify the sensitivity of knee contact force predictions to simultaneous errors in frontal plane knee alignment and contact locations under different dynamic conditions. We scaled a generic musculoskeletal model for N=23 subjects' stature and radiographic knee alignment, then perturbed frontal plane alignment and mediolateral contact locations within experimentally-possible ranges of 10 degrees to -10 degrees and 10 to -10mm, respectively. The sensitivity of first peak, second peak, and mean medial and lateral knee contact forces to knee adduction angle and contact locations was modeled using linear regression. Medial loads increased, and lateral loads decreased, by between 3% and 6% bodyweight for each degree of varus perturbation. Shifting the medial contact point medially increased medial loads and decreased lateral loads by between 1% and 4% bodyweight per millimeter. This study demonstrates that realistic measurement errors of 5mm (contact distance) or 5 degrees (frontal plane alignment) could result in a combined 50% BW error in subject specific contact force estimates. We also show that model sensitivity varies between subjects as a result of differences in gait dynamics. These results demonstrate that predicted knee joint contact forces should be considered as a range of possible values determined by model uncertainty. PMID- 28342532 TI - Shear-scaling-based approach for irreversible energy loss estimation in stenotic aortic flow - An in vitro study. AB - Today, the functional and risk assessment of stenosed arteries is mostly based on ultrasound Doppler blood flow velocity measurements or catheter pressure measurements, which rely on several assumptions. Alternatively, blood velocity including turbulent kinetic energy (TKE) may be measured using MRI. The aim of the present study is to validate a TKE-based approach that relies on the fact that turbulence production is dominated by the flow's shear to determine the total irreversible energy loss from MRI scans. Three-dimensional particle tracking velocimetry (3D-PTV) and phase-contrast magnetic resonance imaging (PC MRI) simulations were performed in an anatomically accurate, compliant, silicon aortic phantom. We found that measuring only the laminar viscous losses does not reflect the true losses of stenotic flows since the contribution of the turbulent losses to the total loss become more dominant for more severe stenosis types (for example, the laminar loss is 0.0094+/-0.0015W and the turbulent loss is 0.0361+/ 0.0015W for the Remax=13,800 case, where Remax is the Reynolds number based on the velocity in the vena-contracta). We show that the commonly used simplified and modified Bernoulli's approaches overestimate the total loss, while the new TKE-based method proposed here, referred to as "shear scaling" approach, results in a good agreement between 3D-PTV and simulated PC-MRI (mean error is around 10%). In addition, we validated the shear scaling approach on a geometry with post-stenotic dilatation using numerical data by Casas et al. (2016). The shear scaling-based method may hence be an interesting alternative for irreversible energy loss estimation to replace traditional approaches for clinical use. We expect that our results will evoke further research, in particular patient studies for clinical implementation of the new method. PMID- 28342533 TI - Eosinophilic Dermatosis of Hematologic Malignancy. AB - Dermatosis characterized by tissue eosinophilia arising in the context of hematologic disease is known as eosinophilic dermatosis of hematologic malignancy. The most commonly associated malignancy is chronic lymphocytic leukemia. Eosinophilic dermatosis of hematologic malignancy is a rare condition with a wide variety of clinical presentations, ranging from papules, erythematous nodules, or blisters that simulate arthropod bites, to the formation of true plaques of differing sizes. Histology reveals the presence of abundant eosinophils. We present 4 new cases seen in Hospital Arnau de Vilanova, Valencia, during the past 7 years. Three of these cases were associated with chronic lymphocytic leukemia and 1 with mycosis fungoides. It is important to recognize this dermatosis as it can indicate progression of the underlying disease, as was the case in 3 of our patients. PMID- 28342536 TI - Pop! Goes the weasel. PMID- 28342535 TI - [Professional stressors and common mental health disorders: Causal links?] AB - : According to the World Health Organization, depression has become the leading cause of disability in the world, contributing significantly to the burden of health issues especially in the industrialized countries. This is a major public health problem, with potential impact on work climates, productivity at work and the continued existence of the organizations. Some recent studies have examined potential links between professional factors and common mental health disorders, but none have demonstrated a direct causal link. OBJECTIVE: In the present study, we explored possible links between work-related stressors and common mental health disorders, with the objective of determining priority mental health prevention axes. METHOD: The study used a life trajectory method. We compared professional stressors and difficulties present in other spheres of life in the last five years between two groups: a group of 29 participants with common mental health disorders during the last five years (depression, anxiety disorders, eating disorders, substance use disorders, pathological gambling), and a group of 29 participants who have not experienced a mental health disorder in the last five years. Data were collected from semi-structured interviews with the participants using a life course analysis method. Each participant was interviewed during two or three meetings of two to three hour duration. Questions regarding difficulties in different spheres of life and mental health were asked. More precisely, data were collected with regards to the presence or absence of mental health disorders in the last five years and the nature of mental health disorders and difficulties. Moreover, we collected data pertaining to the most important positive and negative events in different spheres of life that were present in the last five years, including family life, romantic relationships, social life, academic difficulties, losses and separations, episodes of personal difficulties, financial difficulties as well as protective factors. Regarding professional difficulties present in the last five years, data were collected on different kinds of adversities such as difficulties in finding a job, periods of unemployment, frequent job changes, difficult working conditions, discrimination, difficult working relationships with colleagues and with employers, moral harassment and family-work conflicts. RESULTS: Participants with common mental health disorders are more concerned about having general professional difficulties at work and about having difficult working relationships with employers. However, difficulties related to other spheres of life do not differentiate the two groups. CONCLUSION: It is possible that the work environment is linked to common mental health disorders. In particular, having general professional stressors at the work place and having difficult relationships with employers can impact the occurrence of common mental health disorders. Inversely, these stressors at work can be the consequence of a common mental health disorder. Complementary studies are of interest. Professional stressors can constitute an essential part in the occurrence of common mental health disorders. Thus, the workplace seems a priority environment for deploying effective mental health prevention strategies. Moreover, this can be a strategy for organizations to improve the work climate and to increase productivity. PMID- 28342537 TI - Nonsyndromic proximal aortic aneurysms: What size matters? PMID- 28342534 TI - Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis: Subgroup analysis of Latin American patients in the phase 3 randomized UNCOVER-3 study. AB - BACKGROUND AND OBJECTIVES: Ixekizumab demonstrated greater efficacy than placebo and etanercept in UNCOVER-3. Subgroup analysis of Latin American patients was performed. We report 12-week and 60-week data. PATIENTS AND METHODS: Analysis included 102 Latin American patients randomized to receive placebo (n=14), etanercept 50mg twice weekly (n=30), or ixekizumab 160-mg starting dose followed by 80mg every 2 weeks (Q2W; n=29) or every 4 weeks (Q4W; n=29). At week 12, patients maintaining efficacy response and adequate overall safety were assigned, at the discretion of the investigator, to long-term extension with ixekizumab Q4W. RESULTS: At week 12, Psoriasis Area and Severity Index (PASI) 100 scores were 0%, 20.0% (p=0.075 vs placebo), 62.1% (p<0.001 vs placebo; p=0.001 vs etanercept), and 48.3% (p=0.002 vs placebo; p=0.023 vs etanercept) for placebo, etanercept, ixekizumab Q2W, and ixekizumab Q4W, respectively. Among patients who continued therapy up to week 60 (n=97), PASI 100 scores were 71.4%, 60.0%, 77.8%, and 57.7% for patients who received induction placebo, etanercept, ixekizumab Q2W, and ixekizumab Q4W, respectively (non-responder imputation). By week 60, >=1 serious adverse event was experienced by 7.1% (n=1/14), 3.3% (n=1/30), 14.8% (n=4/27), and 0% (n=0/26) of patients who received induction placebo, etanercept, ixekizumab Q2W, and ixekizumab Q4W, respectively. There were no cases of active tuberculosis with ixekizumab treatment through 60 weeks. CONCLUSIONS: In Latin American patients, both ixekizumab dosing regimens demonstrated greater efficacy than etanercept for treating psoriasis over 12 weeks. The safety profile of ixekizumab through 60 weeks was well tolerated and consistent with the overall profile. PMID- 28342538 TI - The value of a challenge. PMID- 28342539 TI - Beyond public reporting. PMID- 28342540 TI - Corrigendum to "The neuroscience of depression: Implications for assessment and intervention" [Behav. Res. Ther. 62 (2014) 60-73]. PMID- 28342541 TI - Continuous gradient temperature Raman spectroscopy and differential scanning calorimetry of N-3DPA and DHA from -100 to 10 degrees C. AB - Docosahexaenoic acid (DHA, 22:6n-3) is exclusively utilized in fast signal processing tissues such as retinal, neural and cardiac. N-3 docosapentaenoic acid (n-3DPA, 22:5n-3), with just one less double bond, is also found in the marine food chain yet cannot substitute for DHA. Gradient temperature Raman spectroscopy (GTRS) applies the temperature gradients utilized in differential scanning calorimetry (DSC) to Raman spectroscopy, providing a straightforward technique to identify molecular rearrangements that occur near and at phase transitions. Herein we apply GTRS and both conventional and modulated DSC to n-3DPA and DHA from -100 to 20 degrees C. Three-dimensional data arrays with 0.2 degrees C increments and first derivatives allowed complete assignment of solid, liquid and transition state vibrational modes. Melting temperatures n-3DPA (-45 degrees C) and DHA (-46 degrees C) are similar and show evidence for solid-state phase transitions not seen in n-6DPA (-27 degrees C melt). The C6H2 site is an elastic marker for temperature perturbation of all three lipids, each of which has a distinct three dimensional structure. N-3 DPA shows the spectroscopic signature of saturated fatty acids from C1 to C6. DHA does not have three aliphatic carbons in sequence; n-6DPA does but they occur at the methyl end, and do not yield the characteristic signal. DHA appears to have uniform twisting from C6H2 to C12H2 to C18H2 whereas n-6DPA bends from C12 to C18, centered at C15H2. For n-3DPA, twisting is centered at C6H2 adjacent to the C2-C3-C4-C5 aliphatic moiety. These molecular sites are the most elastic in the solid phase and during premelting. PMID- 28342542 TI - Determinants of Late Tricuspid Regurgitation After Aortic-Mitral Double Valve Replacement. AB - The aims of this study are to evaluate the long-term outcomes of double valve replacement (aortic and mitral valves) and to investigate the determinants of late tricuspid regurgitation (TR). A total of 239 consecutive patients who underwent double valve replacement were enrolled. Valve pathology was rheumatic in 86.6% (207/239) and degenerative in 13.4% (32/239) of patients. Among these patients, 116 patients underwent concomitant tricuspid annuloplasty, and follow up was completed for all 239 patients (mean = 7.3 +/- 4.1, maximum = 15.9 years). We used propensity score matching to match 67 patients without tricuspid annuloplasty to the 114 patients who underwent annuloplasty. There was 1 in hospital death and 9.7% (23/238) of patients experienced late cardiac-related mortality. Analysis of aortic valves indicated that the transprosthetic mean pressure gradient increased with time (13.4 +/- 5.2 vs 15.4 +/- 9.0 mm Hg, p = 0.002). Aortic transprosthetic mean pressure gradient increased more notably in woman and was associated with late TR (odds ratio 1.1, p = 0.010). In patients with mild TR, those who underwent tricuspid valve repair were less likely to experience a cardiac-related death within 10 years of surgery (hazards ratio 6.1, p = 0.036). PMID- 28342543 TI - Overview of the Robert Wood Johnson Foundation Nurse Faculty Scholars program: A Commentary. PMID- 28342544 TI - Mentees on mentoring: A commentary on mentor relationships and paying it forward. PMID- 28342545 TI - Distal tibial nonunion using a contralateral anterior L-shaped locking compression plate through a posterior-lateral approach: A retrospective case series. AB - BACKGROUND: Distal tibial nonunion is usually due to severe open distal tibial fractures with high energy injury. The best surgical treatment is not well established because of the poor soft tissue condition. We retrospectively analyzed a series of patients with distal tibial nonunion after severe open distal tibial fractures; our purpose was to introduce a treatment using a contralateral anterior L-shaped locking compression plate through a posterior lateral approach with Iliac crest bone graft and evaluate the outcomes of patients. METHODS: All patients with distal tibial nonunion who received a contralateral anterior L-shaped locking compression plate fixation through the posterior-lateral approach with Iliac crest bone graft by a single surgeon from 2014 to 2016 were reviewed. 9 patients met the criteria. Five of nine patients had varus deformities (range, 9-40 degrees ) and 4 patients had valgus deformities (range, 5-30 degrees ). Postoperative radiographs, Postoperative complications, limb alignment and limb functional outcome information of AOFAS ankle-hindfoot score were recorded. RESULTS: All patients were followed up for at least 8 months (range, 8-16 months). Union was achieved in all patients after the index surgery without postoperative wound complications while one patient came up with checkrein deformity. Average time to radiographic union was 16 weeks (range, 12-24 weeks). All patients had correction to neutral alignment in both coronal and sagittal planes. The average AOFAS ankle-hindfoot score was 90 (range, 77 100) at the last follow-up of patients. CONCLUSIONS: Using a contralateral anterior L-shaped locking compression plate fixation through a posterior-lateral approach with Iliac crest bone graft to reconstruct the distal tibial nonunion is a safe and reliable method that can successfully treat patients with poor soft tissue condition of anterior portion of leg because of its adequate exposure, both tibia and fibula rigid fixation and plenty of bone graft. We believe the application of this method resulting in a high union and low complication rate. PMID- 28342546 TI - tDCS reactivation of dormant adaptation circuits. PMID- 28342547 TI - Corrigendum to "Altered functional connectivity of interoception in illness anxiety disorder" [Cortex 86 (2017) 22-32]. PMID- 28342548 TI - In situ reactive zone with modified Mg(OH)2 for remediation of heavy metal polluted groundwater: Immobilization and interaction of Cr(III), Pb(II) and Cd(II). AB - Mg(OH)2 dissolves slowly and can provide a long-term source of alkalinity, thus a promising alternative reagent for the in situ remediation of heavy metal polluted groundwater. However, the application of Mg(OH)2 on in situ reactive zone (IRZ) for heavy metal polluted groundwater has never been investigated. In this study, the behaviors of heavy metals in a Mg(OH)2 IRZ were monitored for 45d. The heavy metals show a sequential precipitation by modified Mg(OH)2 due to the difference of Ksp. Column tests were conducted to investigate the temporal and spatial distribution of heavy metals in Mg(OH)2 IRZ and evaluate the stabilization effect for multi-heavy metal polluted groundwater. Experimental results indicate that there exist interactions between different heavy metals, and their zoning distribution is attributed either to the competitive adsorption onto porous media (control column) or to the sequential precipitation of heavy metal ions (IRZ column). In contrast with the control column, heavy metal contaminated area in Mg(OH)2 IRZ significantly shrinks. According to the chemical speciation analysis, when water containing Pb(II), Cd(II) and Cr(III) flows through Mg(OH)2 IRZ, exchangeable fraction of total concentration significantly reduce and the proportion of carbonate and Fe/Mn oxides fraction increase, indicating the decrease of their mobility and toxicity. PMID- 28342549 TI - Stream-aquifer and in-stream processes affecting nitrogen along a major river and contributing tributary. AB - This study assesses the spatio-temporal patterns of water and nutrient mass exchange in a stream-riparian system of a major river and a contributing tributary in an irrigated semi-arid region. Field monitoring is performed along reaches of the Arkansas River (4.7km) and Timpas Creek (2.0km) in southeastern Colorado during the 2014 growing season, with water quantity and water quality data collected using a network of in-stream sampling sites and groundwater monitoring wells. Mass balance approaches were used to identify temporal and spatial trends in flow, nitrogen (N), and salinity in stream-aquifer exchange. In the Arkansas River, percent decrease of N concentration along the study reach averaged 36% over the period, with results from a stochastic mass balance simulation indicating a 90% probability that 44% to 50% of NO3-N mass in the study reach (109-124kg/day/km) was removed by in-stream processes between 1 September and 8 November. Results suggest that contact with organic-rich river bed sediments has a strong impact on N removal. A greater decrease in concentrations of NO3-N along the reach during the low flow period suggests the effect of both in-stream processes and dilution by inflowing groundwater that undergoes denitrification as it flows through the riparian and hyporheic zones into the river. In contrast, N concentration decreases in the smaller Timpas Creek were negligible. Results for the Arkansas River also are in contrast with other large agriculturally-influenced rivers, which have not exhibited capacity to remove N at significant rates. Results provide important insights across spatial and temporal scales and point to the need for investigating nutrient dynamics in large streams draining agriculturally-dominated watersheds. PMID- 28342550 TI - The effects of endothelin-1 on satellite glial cells in peripheral ganglia. AB - Endothelins (ET) are a family of highly active neuropeptides with manifold influences via ET receptors (ETR) in both the peripheral and central nervous systems. We have shown previously that satellite glial cells (SGCs) in mouse trigeminal ganglia (TG) are extremely sensitive to ET-1 in evoking [Ca2+]in increase, apparently via ETBR activation, but there is no functional information on ETR in SGCs of other peripheral ganglia. Here we tested the effects of ET-1 on SGCs in nodose ganglia (NG), which is sensory, and superior cervical ganglia (Sup CG), which is part of the sympathetic nervous system, and further investigated the influence of ET-1 on SGCs in TG. Using calcium imaging we found that SGCs in intact, freshly isolated NG and Sup-CG are highly sensitive to ET-1, with threshold concentration at 0.1nM. Our results showed that [Ca2+]in elevation in response to ET-1 was partially due to Ca2+ influx from the extracellular space and partially to Ca2+ release from intracellular stores. Using receptor selective ETR agonists and antagonists, we found that the responses were mediated by mixed ETAR/ETBR in SGCs of NG and predominantly by ETBR in SGCs of Sup-CG. By employing intracellular dye injection we examined coupling among SGCs around different neurons in the presence of 5nM ET-1 and observed coupling inhibition in all the three ganglion types. In summary, our work showed that SGCs in mouse sensory and sympathetic ganglia are highly sensitive to ET-1 and that this peptide markedly reduces SGCs coupling. We conclude that ET-1, which may participate in neuron glia communications, has similar functions in wide range of peripheral ganglia. PMID- 28342551 TI - Bilateral haemorrhagic papilloedema secondary to carboplatin use. PMID- 28342552 TI - "Code stroke" activation in a patient with an external ventricular assist device. PMID- 28342553 TI - Myelin changes in Alexander disease. AB - INTRODUCTION: Alexander disease (AxD) is a type of leukodystrophy. Its pathological basis, along with myelin loss, is the appearance of Rosenthal bodies, which are cytoplasmic inclusions in astrocytes. Mutations in the gene coding for GFAP have been identified as a genetic basis for AxD. However, the mechanism by which these variants produce the disease is not understood. DEVELOPMENT: The most widespread hypothesis is that AxD develops when a gain of function mutation causes an increase in GFAP. However, this mechanism does not explain myelin loss, given that experimental models in which GFAP expression is normal or mutated do not exhibit myelin disorders. This review analyses other possibilities that may explain this alteration, such as epigenetic or inflammatory alterations, presence of NG2 (+) - GFAP (+) cells, or post translational modifications in GFAP that are unrelated to increased expression. CONCLUSIONS: The different hypotheses analysed here may explain the myelin alteration affecting these patients, and multiple mechanisms may coexist. These theories raise the possibility of designing therapies based on these mechanisms. PMID- 28342554 TI - Ischaemic stroke as the predecessor event of an episode of thrombotic thrombocytopenic purpura. PMID- 28342555 TI - Use of Thudichum nasal speculum for retraction during insertion of dental implants. PMID- 28342556 TI - On constraints and affordances in motor development and learning - The case of DCD. A commentary on Wade & Kazeck (2017). AB - This commentary to the recent article by Wade & Kazeck discusses the role of constraints as a key concept in the understanding of the limitations in DCD. The concept of constraints is linked to affordances and is useful in the understanding of changes due to development and learning and the limitations of DCD, irrespective of theoretical point of view. PMID- 28342557 TI - [Cataract induced by hypoparathyroidism: A case report]. PMID- 28342558 TI - High intensity focused ultrasound as first line treatment in patients with chronic angle closure glaucoma at risk for malignant glaucoma. AB - PURPOSE: Evaluation of high intensity focused ultrasound (HIFU) transscleral cyclocoagulation as an alternative to trabeculectomy in the treatment of refractory chronic angle closure glaucoma (CACG). METHODS: This prospective one armed single center pilot study was conducted on patients with medically uncontrolled CACG who underwent high intensity focused ultrasound (HIFU) cyclocoagulation as first line surgical treatment, using the Eye-OP1 HIFU device (Eyetechcare-Rillieux-la-Pape, France) driven by ultrasound biomicroscopic (UBM) ciliary body localization. All patients had documented progression of their glaucoma despite conventional medical and laser therapy. The primary efficacy outcome was intraocular pressure (IOP) reduction; secondary outcomes included changes in number of glaucoma medications and complications after cyclocoagulation. RESULTS: The study involved 8 eyes of 7 patients between May 2013 and September 2014. The average follow-up was 5.6+/-2.1 months. The mean IOP was reduced from 18.4+/-3.5mmHg preoperatively to 14.8+/-4.1mmHg 6 months postoperatively. The average number of glaucoma medications decreased from 3.4+/ 1.1 at baseline to 3.3+/-0.7 after 6 months. Visual acuity remained stable (median 0.17 log MAR preoperatively and 0.19 log MAR at last follow-up visit). No significant side effect occurred during the 6 months follow-up period. CONCLUSIONS: HIFU cyclocoagulation appears to be a safe and reliable alternative to filtering surgery in the management of chronic angle closure glaucoma among patients with a high risk of malignant glaucoma. PMID- 28342560 TI - Evaluation of the influence of surfactants in the bioaccumulation kinetics of sulfamethoxazole and oxazepam in benthic invertebrates. AB - The potential ecotoxicological effects of mixtures of contaminants in the aquatic environment are generating a global concern. Benthic invertebrates, such as the crustacean Gammarus fossarum, are key in the functioning of aquatic ecosystems, and are frequently used as sentinel species of water quality status. The aim of this work was to study the effects of a mixture of the most frequently detected surfactants in the bioconcentration kinetics of two pharmaceuticals in G. fossarum, evaluating their potential enhancing or suppressing effects. Laboratory exposure experiments for both pharmaceuticals and surfactants (concentration ratio 1:25) were set up for two individual compounds, the anxiolytic oxazepam and the antibiotic sulfamethoxazole. Gammarid samples were processed using microQuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) extraction. Pharmaceuticals concentration in the organisms was followed-up by means of nanoliquid chromatography coupled to tandem mass spectrometry (nanoLC-MS/MS). Results indicated a similar mode of action of the surfactants in the bioconcentration kinetics of both drugs, decreasing the accumulation rate in the organism. Oxazepam showed a higher accumulation potential than sulfamethoxazole in all cases. Depuration experiments for oxazepam also demonstrated the high depurative capacity of gammarids, eliminating >50% of the concentration of oxazepam in <6h. PMID- 28342559 TI - [Senegalese experience with acute viral conjunctivitis]. AB - PURPOSE: To study the epidemiological and clinical aspects of acute enteroviral and adenoviral conjunctivitis. PATIENTS AND METHODS: A prospective study was conducted between January 1st and October 31st, 2015, jointly between two Ophthalmology services and a virology laboratory, which identified 51 patients. Were included all patients who presented a painful red eye without loss of visual acuity associated with secretions,evolving for less than 4weeks RESULTS: The mean age was 32 years, and the sex ratio 1:1. Over half of our patients (61%) came from populous districts. A history of the virus "going around" was reported by 30 patients (59% of cases). Virological testing was positive in 35 patients (68.7% of cases). Over 90% of samples collected during the first week of clinical signs were positive. CONCLUSION: Viral conjunctivitis is a contagious condition, the spread of which is favored by promiscuity. Adenovirus and enterovirus are the main causative agents. They are present on an endemic scale in Senegal; thus, the need for better epidemiological surveillance in order to limit spread. PMID- 28342561 TI - A strategic document as a tool for implementing change. Lessons from the merger creating the South-East Health region in Norway. AB - In 2007, the Norwegian Parliament decided to merge the two largest health regions in the country: the South and East Health Regions became the South-East Health Region (SEHR). In its resolution, the Parliament formulated strong expectations for the merger: these included more effective hospital services in the Oslo metropolitan area, freeing personnel to work in other parts of the country, and making treatment of patients more coherent. The Parliamentary resolution provided no specific instructions regarding how this should be achieved. In order to fulfil these expectations, the new health region decided to develop a strategy as its tool for change; a change "agent". SINTEF was engaged to evaluate the process and its results. We studied the strategy design, the tools that emerged from the process, and which changes were induced by the strategy. The evaluation adopted a multimethod approach that combined interviews, document analysis and (re)analysis of existing data. The latter included economic data, performance data, and work environment data collected by the South-East Health Region itself. SINTEF found almost no effects, whether positive or negative. This article describes how the strategy was developed and discusses why it failed to meet the expectations formulated in the Parliamentary resolution. PMID- 28342562 TI - Tackling racism as a "wicked" public health problem: Enabling allies in anti racism praxis. AB - Racism is a "wicked" public health problem that fuels systemic health inequities between population groups in New Zealand, the United States and elsewhere. While literature has examined racism and its effects on health, the work describing how to intervene to address racism in public health is less developed. While the notion of raising awareness of racism through socio-political education is not new, given the way racism has morphed into new narratives in health institutional settings, it has become critical to support allies to make informing efforts to address racism as a fundamental cause of health inequities. In this paper, we make the case for anti-racism praxis as a tool to address inequities in public health, and focus on describing an anti-racism praxis framework to inform the training and support of allies. The limited work on anti-racism rarely articulates the unique challenges or needs of allies or targets of racism, but we seek to help fill that gap. Our anti-racism praxis for allies includes five core elements: reflexive relational praxis, structural power analysis, socio-political education, monitoring and evaluation and systems change approaches. We recognize that racism is a modifiable determinant of health and racial inequities can be eliminated with the necessary political will and a planned system change approach. Anti-racism praxis provides the tools to examine the interconnection and interdependence of cultural and institutional factors as a foundation for examining where and how to intervene to address racism. PMID- 28342563 TI - Type 2 Diabetes Mellitus Treatment Patterns Across Europe: A Population-based Multi-database Study. AB - PURPOSE: The aim of this study was to determine the similarities and differences of type 2 diabetes mellitus (T2DM) treatment patterns in daily practice in 5 European countries and whether these reflect differences in guidelines. METHODS: Prescriptions for drugs used in diabetes treatment during a 5-year study period were obtained from electronic databases. Patients initiating T2DM treatment during the study period were included. An SAS analysis tool was developed to create episodes of use of drug classes, which resulted in treatment patterns. FINDINGS: A total of 253,530 patients initiating T2DM treatment during the study period were included; 52% to 55% were male, and the mean age ranged from 62 to 67 years. Metformin was the most common initial treatment in all countries. After initial therapy, most patients in the Netherlands, Spain, and the United Kingdom switched to a combination of metformin + a sulfonylurea derivative (SU). In Italy, metformin in combination with an SU was outnumbered by "other treatment," mainly because of repaglinide use. In France, treatments including dipeptidyl peptidase-4 inhibitors were most frequent as second- and fourth-line treatment. Metformin monotherapy was again most commonly observed as the third line of treatment in all countries. Fourth treatment was a combination of metformin + an SU in the Netherlands and Spain; in the United Kingdom and France, dipeptidyl peptidase-4 inhibitors were the most frequently used fourth line of treatment. IMPLICATIONS: This study provides a comprehensive overview of T2DM treatment patterns among patients initiating T2DM treatment in 5 European countries. There were differences, especially regarding the uptake of newer incretin-based treatments, which are usually prescribed as a second and/or third treatment in agreement with local guidelines. These variations reflect the differences between the national guidelines of these countries. PMID- 28342565 TI - Mini review: New pathogen profiles: Elizabethkingia anophelis. AB - Within a little more than 5 years since its taxonomic description in 2011, from the midgut of mosquitoes, Elizabethkingia anophelis has emerged as an important causes of sepsis in adults and children and in cases of neonatal meningitis. At least 3 moderate- to large-scale outbreaks of disease have been caused by this bacterium, the largest 2 occurring in the Midwest United States in 2015-2016. Several studies suggest that E. anophelis, and not E. meningoseptica, is the predominant human pathogen of this genus; identification to species is difficult. Little is presently known regarding its epidemiology, modes of transmission, and pathogenicity as it relates to virulence-associated factors. PMID- 28342564 TI - Implementation of a violence risk assessment tool on a safety-net inpatient psychiatry unit. PMID- 28342566 TI - Mechanical and Biological Effects of Ultrasound: A Review of Present Knowledge. AB - Ultrasound is widely used for medical diagnosis and increasingly for therapeutic purposes. An understanding of the bio-effects of sonography is important for clinicians and scientists working in the field because permanent damage to biological tissues can occur at high levels of exposure. Here the underlying principles of thermal mechanisms and the physical interactions of ultrasound with biological tissues are reviewed. Adverse health effects derived from cellular studies, animal studies and clinical reports are reviewed to provide insight into the in vitro and in vivo bio-effects of ultrasound. PMID- 28342567 TI - Ocular ultrasound in a patient with vitreous haemorrhage caused by a retinal tear. PMID- 28342568 TI - Erratum to: "Availability of resources for patients with wet age-related macular degeneration. Optimal study" [Arch Soc Esp Oftalmol 88 (8) (2013) 307-312]. PMID- 28342569 TI - Corrigendum to "An emerging evidence base for the management of neonatal hypoglycemia" [Early Hum. Dev. 2017; 104: 51-56]. PMID- 28342570 TI - Body Mass Index Is Associated With Differential Rates of Coronary Revascularization After Cardiac Catheterization. AB - BACKGROUND: The association of obesity with coronary revascularization procedures is not clear. We examined rates of coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) associated with obesity while accounting for the severity of coronary disease and diabetes status. METHODS: Patients who underwent cardiac catheterization were stratified according to coronary anatomy risks and diabetes status. Within each stratum, using normal body mass index (BMI) (18.5-24.9 kg/m2) as a reference, the associations of overweight (25.0-29.9 kg/m2), obese class I (30.0-34.9 kg/m2), obese class II (35.0-39.9 kg/m2), and obese class III (>= 40.0 kg/m2) with the likelihood of receiving CABG and PCI were assessed while adjusting for clinical covariates. RESULTS: Of 56,722 patients analyzed, overall use of revascularization was higher in the overweight, obese class I, and obese class II groups (overweight: adjusted hazard ratio [aHR], 1.10; 95% confidence interval [CI], 1.06-1.13; obese class I: aHR, 1.08; 95% CI, 1.05-1.12; obese class II: aHR,1.05; 95% CI, 1.01-1.10), whereas it was lower in the obese class III group (aHR, 0.91; 95% CI, 0.85-0.97) compared with normal BMI. In the subgroup with high-risk coronary anatomy and diabetes, all obese classes had higher rates of PCI (obese class I: aHR,1.24; 95% CI, 1.08 1.42; obese class II: aHR,1.27; 95% CI, 1.07-1.49, obese class III: aHR,1.37; 95% CI, 1.12-1.67) than the normal BMI group. CONCLUSIONS: Our results showed that BMI is associated with differential rates of coronary revascularization. In patients with high-risk coronary anatomy and diabetes, clinical appropriateness of higher rates of PCI associated with obesity warrants further investigation. PMID- 28342571 TI - Identification of gastric outlet obstruction using point-of-care ultrasound. PMID- 28342572 TI - Exploring the atomic structure of 1.8nm monolayer-protected gold clusters with aberration-corrected STEM. AB - Monolayer-protected (MP) Au clusters present attractive quantum systems with a range of potential applications e.g. in catalysis. Knowledge of the atomic structure is needed to obtain a full understanding of their intriguing physical and chemical properties. Here we employed aberration-corrected scanning transmission electron microscopy (ac-STEM), combined with multislice simulations, to make a round-robin investigation of the atomic structure of chemically synthesised clusters with nominal composition Au144(SCH2CH2Ph)60 provided by two different research groups. The MP Au clusters were "weighed" by the atom counting method, based on their integrated intensities in the high angle annular dark field (HAADF) regime and calibrated exponent of the Z dependence. For atomic structure analysis, we compared experimental images of hundreds of clusters, with atomic resolution, against a variety of structural models. Across the size range 123-151 atoms, only 3% of clusters matched the theoretically predicted Au144(SR)60 structure, while a large proportion of the clusters were amorphous (i.e. did not match any model structure). However, a distinct ring-dot feature, characteristic of local icosahedral symmetry, was observed in about 20% of the clusters. PMID- 28342573 TI - Capnography-Assisted Nasotracheal Intubation Using Cuff Inflation and Gum-Elastic Bougie. PMID- 28342574 TI - Ultrasound Findings in Tension Pneumothorax: A Case Report. AB - BACKGROUND: Delayed recognition of tension pneumothorax can lead to a mortality of 31% to 91%. However, the classic physical examination findings of tracheal deviation and distended neck veins are poorly sensitive in the diagnosis of tension pneumothorax. Point-of-care ultrasound is accurate in identifying the presence of pneumothorax, but sonographic findings of tension pneumothorax are less well described. CASE REPORT: We report the case of a 21-year-old man with sudden-onset left-sided chest pain. He was clinically stable without hypoxia or hypotension, and the initial chest x-ray study showed a large pneumothorax without mediastinal shift. While the patient was awaiting tube thoracostomy, a point-of-care ultrasound demonstrated findings of mediastinal shift and a dilated inferior vena cava (IVC) concerning for tension physiology, even though the patient remained hemodynamically stable. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case demonstrates a unique clinical scenario of ultrasound evidence of tension physiology in a clinically stable patient. Although this patient was well appearing without hypotension, respiratory distress, tracheal deviation, or distended neck veins, point-of-care ultrasound revealed mediastinal shift and a plethoric IVC. Given that the classic clinical signs of tension pneumothorax are not uniformly present, this case shows how point-of-care ultrasound may diagnose tension pneumothorax before clinical decompensation. PMID- 28342575 TI - Performance of a novel baffled osmotic membrane bioreactor-microfiltration hybrid system under continuous operation for simultaneous nutrient removal and mitigation of brine discharge. AB - The present study investigated the performance of an integrated osmotic and microfiltration membrane bioreactor system for wastewater treatment employing baffles in the reactor. Thus, this reactor design enables both aerobic and anoxic processes in an attempt to reduce the process footprint and energy costs associated with continuous aeration. The process performance was evaluated in terms of water flux, salinity build up in the bioreactor, organic and nutrient removal and microbial activity using synthetic reverse osmosis (RO) brine as draw solution (DS). The incorporation of MF membrane was effective in maintaining a reasonable salinity level (612-1434mg/L) in the reactor which resulted in a much lower flux decline (i.e. 11.48-6.98LMH) as compared to previous studies. The stable operation of the osmotic membrane bioreactor-forward osmosis (OMBR-FO) process resulted in an effective removal of both organic matter (97.84%) and nutrient (phosphate 87.36% and total nitrogen 94.28%), respectively. PMID- 28342576 TI - Biological CO2 mitigation from coal power plant by Chlorella fusca and Spirulina sp. AB - CO2 biofixation by microalgae and cyanobacteria is an environmentally sustainable way to mitigate coal burn gas emissions. In this work the microalga Chlorella fusca LEB 111 and the cyanobacteria Spirulina sp. LEB 18 were cultivated using CO2 from coal flue gas as a carbon source. The intermittent flue gas injection in the cultures enable the cells growth and CO2 biofixation by these microorganisms. The Chlorella fusca isolated from a coal power plant could fix 2.6 times more CO2 than Spirulina sp. The maximum daily CO2 from coal flue gas biofixation was obtained with Chlorella fusca (360.12+/-0.27mgL-1d-1), showing a specific growth rate of 0.17+/-<0.01d-1. The results demonstrated the Chlorella fusca LEB 111 and Spirulina sp. LEB 18 potential to fix CO2 from coal flue gas, and sequential biomass production with different biotechnological destinations. PMID- 28342577 TI - Corrigendum to 'Nutrient recycle from defatted microalgae (Aurantiochytrium) with hydrothermal treatment for microalgae cultivation' [Bioresour. Technol. 228 (2017) 186-192]. PMID- 28342578 TI - Efficacy and safety of aripiprazole lauroxil in schizophrenic patients presenting with severe psychotic symptoms during an acute exacerbation. AB - Aripiprazole lauroxil (AL), a new long-acting injectable antipsychotic, demonstrated safety and efficacy in treating acute exacerbation symptoms of schizophrenia in a 12-week placebo-controlled trial of two doses of AL (441mg and 882mg) administered every 4weeks. We performed a post hoc analysis of this trial to evaluate the efficacy of AL in the subgroup of patients with severe psychotic symptoms, defined as those with baseline Positive and Negative Syndrome Scale (PANSS) Total score above the median score of 92 (n=309). Change from baseline to Day 85 in PANSS Total score; Positive, Negative, and General Psychopathology subscale scores; and overall response rate were assessed. Statistically significant and clinically meaningful improvements in PANSS Total score were demonstrated with AL 441mg and AL 882mg, with placebo-adjusted differences of 14.7 (p<0.0001) and -16.6 (p<0.0001), respectively. Significant and clinically meaningful findings with both doses of AL were also demonstrated for the PANSS subscales and responder rates. Overall responder rates at Day 85 were significantly greater for AL 441mg (49%; p<0.001) and 882 mg (61%; p<0.001) groups vs. placebo (18%). Common adverse events (>5%) were schizophrenia, akathisia, headache, insomnia, and anxiety. AL demonstrated robust efficacy in treatment of the subgroup of patients experiencing severe psychotic symptoms. Both doses (441mg and 882mg) were effective, with numerically greater improvement in symptoms and proportion of responders favoring the higher dose arm. Both doses had a side effect profile consistent with the known safety profile of aripiprazole. PMID- 28342579 TI - Magnetic Mini-Mover Procedure for pectus excavatum IV: FDA sponsored multicenter trial. AB - PURPOSE: The Magnetic Mini-Mover Procedure (3MP) is a minimally invasive treatment for prepubertal patients with pectus excavatum. This multicenter trial sought to supplement safety and efficacy data from an earlier pilot trial. METHODS: Fifteen patients with pectus excavatum had a titanium-enclosed magnet implanted on the sternum. Externally, patients wore a custom-fitted magnetic brace. Patients were monitored closely for safety. Efficacy was determined by the Haller Index (HI) and satisfaction surveys. After 2 years, the implant was removed. RESULTS: Mean patient age was 12 years (range 8-14), and mean pretreatment HI was 4.7 (range 3.6-7.4). The device was successfully implanted in all patients. Mean treatment duration was 25 months (range 18-33). Posttreatment chest imaging in 13 patients indicated that HI decreased in 5, remained stable in 2, and increased in 6. Seven out of 15 patients had breakage of the implant's titanium cables because of fatigue fracture. Eight out of 13 patients were satisfied with their chest after treatment. CONCLUSION: The 3MP is a safe, minimally invasive, outpatient treatment for prepubertal patients with pectus excavatum. However, the magnetic implant design led to frequent device breakage, confounding analysis. The HI indicated mixed efficacy, although surveys indicated most patients perceived a benefit. STUDY TYPE/LEVEL OF EVIDENCE: Case series, treatment study. Level IV. PMID- 28342580 TI - Evidence-based management of chylothorax in infants. AB - PURPOSE: Management guidelines for infants with chylothorax lack substantial evidence. We sought to identify variables that impact outcomes in these patients in order to develop an evidence-based management algorithm. METHODS: We retrospectively reviewed the medical records of all infants diagnosed with chylothorax from June 2005 to December 2014 at our institution. Data collected included demographics, chest tube output (CTO), medical and dietary interventions, surgical procedures, and absolute lymphocyte count (ALC). Outcomes analyzed included death, sepsis, necrotizing enterocolitis (NEC), requiring surgery, and success of therapy, defined as CTO decrease by >50% within 7days. RESULTS: Of 178 neonates with chylothorax, initial therapy was high medium chain triglyceride (MCT) feedings in 106 patients, nothing by mouth (NPO), total parenteral nutrition (TPN) in 21, and NPO/TPN plus octreotide in 45. Octreotide use in addition to NPO/TPN revealed no significant differences in any outcome including success (47% vs. 43%, p=0.77). Initial CTO and ALC correlated with needing surgery (p=0.002 and p=0.006, respectively), and with death (p=0.028 and p=0.043, respectively). ALC also correlated with sepsis (p<0.001). CONCLUSIONS: Octreotide has no advantage over NPO/TPN alone in infants with chylothorax. CTO and ALC predict requiring surgery. We propose a management guideline based on CTO and ALC without a role for octreotide. TYPE OF STUDY: Retrospective case-control study. LEVEL OF EVIDENCE: 3. PMID- 28342581 TI - Neurodevelopmental outcomes in infants undergoing general anesthesia. AB - PURPOSE: Preclinical data strongly suggest that all agents used for general anesthesia (GA) have detrimental effects on the developing brain. However, clinical data are unclear. The purpose of this study was to use a cohort of infants who underwent GA and understand their neurodevelopmental outcomes. METHODS: A cohort of infants who underwent GA was selected between 2010 and 2011, and a control group was created. Data regarding GA, procedures, and outcomes were collected in 2015. The cohort was divided into controls, GA without surgery, GA and surgery once, and multiple general anesthetics. Both univariate and multivariate analysis were performed, and a p value of less than 0.05 was considered significant. RESULTS: 457 patients, 121 controls, and 336 cases were included. Median follow-up was 5.1years. While developmental delay and the need for speech therapy were higher with GA, this did not correlate with the duration of GA. Patients having GA for MRI had the poorest outcomes. Multivariate analysis using combined binary outcome measures for psychiatric and neurologic outcomes did not show any significant difference for duration of anesthesia, age at anesthesia, or induction and maintenance agents. CONCLUSIONS: These data suggest that GA during the first year of life may have few significant neurodevelopmental effects compared to controls. Additionally, the duration of GA did not correlate with neurodevelopmental outcomes. TYPE OF STUDY: Retrospective Case Control Cohort Study. LEVEL OF EVIDENCE: 3 b (according to Oxford Center for EBM Levels of Evidence, March 2009, http://www.cebm.net/oxford-centre-evidence-based medicine-levels-evidence-march-2009/). PMID- 28342582 TI - Simultaneous determination of nitrated and oligomerized proteins by size exclusion high-performance liquid chromatography coupled to photodiode array detection. AB - Chemical modifications such as nitration and cross-linking may enhance the allergenic potential of proteins. The kinetics and mechanisms of the underlying chemical processes, however, are not yet well understood. Here, we present a size exclusion chromatography/spectrophotometry method (SEC-HPLC-DAD) that allows a simultaneous detection of mono-, di-, tri-, and higher protein oligomers, as well as their individual nitration degrees (NDs). The ND results of proteins from this new method agree well with the results from an alternative well-established method, for the analysis of tetranitromethane (TNM)- and nitrogen dioxide and ozone (NO2/O3)-nitrated protein samples. Importantly, the NDs for individual oligomer fractions can be obtained from the new method, and also, we provide a proof of principle for the calculation of the concentrations for individual protein oligomer fractions by their determined NDs, which will facilitate the investigation of the kinetics and mechanism for protein tyrosine nitration and cross-linking. PMID- 28342583 TI - Affinity chromatographic methodologies based on immobilized voltage dependent anion channel isoform 1 and application in protein-ligand interaction analysis and bioactive compounds screening from traditional medicine. AB - Voltage dependent anion channel isoform 1 (VDAC-1) serves as an attractive target of anti-cancer drugs by mediating the entry and exit of metabolites between cytoplasm and mitochondria. This work reports on the preparation of a VDAC-1 based bioaffinity chromatographic stationary phase by linking the protein on lecithin modified microspheres. An assay of chromatographic methods including frontal analysis, zonal elution, injection dependent analysis and nonlinear chromatography were utilized to investigate the bindings of ATP, NADH and NADPH to VDAC-1. Electrostatic interactions were found to be main forces during these bindings. The calculated association constants of the three ligands to VDAC-1 showed good agreements between diverse chromatographic methods. Validated application of the stationary phase was performed by screening anti-cancer compounds of Rheum officinale Baill. using high performance affinity chromatography coupled with electrospray ionization-quadrupole time of flight mass spectrometry. Chrysophanol, emodin, rhein, aloe-emodin and catechin were identified as the bioactive components of the herb. These compounds targeted VDAC 1 through Thr207 and the N-terminal region of the protein. Taken together, the current stationary phase was possible to become a promising tool for protein ligand interaction analysis and anti-cancer drug screening from complex matrices. PMID- 28342584 TI - Dispersive liquid-liquid microextraction and injection-port derivatization for the determination of free lipophilic compounds in fruit juices by gas chromatography-mass spectrometry. AB - A method consisting of dispersive liquid-liquid microextraction (DLLME) followed by injection-port derivatization and gas chromatography-mass spectrometry (GC-MS) for the analysis of free lipophilic compounds in fruit juices is described. The method allows the analysis of several classes of lipophilic compounds, such as fatty acids, fatty alcohols, phytosterols and triterpenes. The chromatographic separation of the compounds was achieved in a chromatographic run of 25.5min. The best conditions for the dispersive liquid-liquid microextraction were 100MUL of CHCl3 in 1mL of acetone. For the injection-port derivatization, the best conditions were at 280 degrees C, 1min purge-off, and a 1:1 sample:derivatization reagent ratio (v/v) using N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA):pyridine (1:1) as reagent. Quality parameters were assessed for the target compounds, giving a limits of detection (LODs) ranging from 1.1 to 5.7ng/mL and limits of quantification (LOQs) from 3.4 to 18.7ng/mL for linoleic and stearic acid, respectively. Repeatability (%RSD, n=5) was below 11.51% in all cases. In addition, the method linearity presented an r2 >=0.990 for all ranges applied. Finally, the method was used to test the lipophilic fraction of various samples of commercial fruit juice. PMID- 28342585 TI - Response to "obesity paradox in chronic obstructive pulmonary disease: A result of airflow obstruction over-grading?" PMID- 28342586 TI - Biomechanical analysis of the fixation systems for anterior column and posterior hemi-transverse acetabular fractures. AB - OBJECTIVE: The aim of this study was to evaluate the biomechanical properties of common fixation systems for complex acetabular fractures. METHODS: A finite element (FE) pelvic model with anterior column and posterior hemi-transverse acetabular fractures was created. Three common fixation systems were used to fix the posterior wall acetabular fractures: 1. Anterior column plate combined with posterior column screws (group I), 2. Anterior column plate combined with quadrilateral area screws (group II) and 3. Double-column plates (group III). And 600 N, representing the body weight, was loaded on the upper surface of the sacrum to simulate the double-limb stance. The amounts of total and relative displacements were compared between the groups. RESULTS: The total amount of displacement was 2.76 mm in group II, 2.81 mm in group III, and 2.83 mm in group I. The amount of relative displacement was 0.0078 mm in group II, 0.0093 mm in group III and 0.014 mm in group I. CONCLUSION: Our results suggested that all fixation systems enhance biomechanical stability significantly. Anterior column plate combined with quadrilateral area screws has quite comparable results to double column plates, they were superior to anterior column plate combined with posterior screws. PMID- 28342587 TI - Highly oxygenated antiausterity agents from the leaves of Uvaria dac. AB - From the chloroform extract of the leaves of Uvaria dac, four new highly oxygenated cyclohexene derivatives named uvaridacols I-L (1-4) were isolated together with nine previously reported compounds (5-13). Their structures were determined based on the extensive NMR spectroscopic data and circular dichroism spectroscopic analysis. Among the new compounds, uvaridacol L (4) displayed strong preferential cytotoxicity in the nutrient deprived medium against five different tested pancreatic cancer cell lines, PANC-1 (PC50, 20.1MUM), PSN-1 (PC50, 9.7MUM), MIA PaCa-2 (PC50, 29.1MUM), Capan-1 (73.0MUM) and KLM-1 (25.9MUM). PMID- 28342588 TI - Corrigendum to "Fluorescent molecularly imprinted nanogels for the detection of anticancer drugs in human plasma" [Biosens. Bioelectron. 86 (2016) 913-919]. PMID- 28342589 TI - Energy consumption by forward osmosis treatment of landfill leachate for water recovery. AB - Forward osmosis (FO) is an alternative approach for treating landfill leachate with potential advantages of reducing leachate volume and recovering high quality water for direct discharge or reuse. However, energy consumption by FO treatment of leachate has not been examined before. Herein, the operational factors such as recirculation rates and draw concentrations were studied for their effects on the quantified energy consumption by an FO system treating actual leachate collected from two different landfills. It was found that the energy consumption increased with a higher recirculation rate and decreased with a higher draw concentration, and higher water recovery tended to reduce energy consumption. The highest energy consumption was 0.276+/-0.033kWhm-3 with the recirculation rate of 110mLmin-1 and 1-M draw concentration, while the lowest of 0.005+/-0.000kWhm-3 was obtained with 30mLmin-1 recirculation and 3-M draw concentration. The leachate with lower concentrations of the contaminants had a much lower requirement for energy, benefited from its higher water recovery. Osmotic backwashing appeared to be more effective for removing foulants, but precise understanding of membrane fouling and its controlling methods will need a long-term study. The results of this work have implied that FO treatment of leachate could be energy efficient, especially with the use of a suitable draw solute that can be regenerated in an energy efficient way and/or through combination with other treatment technologies that can reduce contaminant concentrations before FO treatment, which warrants further investigation. PMID- 28342590 TI - A life cycle assessment of distributed energy production from organic waste: Two case studies in Europe. AB - By means of the life cycle assessment methodology, the purpose of this study is to assess the environmental impact when biomethane from organic waste produced at residential level is used to supply energy to a group of dwellings in the distributed generation paradigm. Three different Combined Heat and Power systems, such as fuel cells, Stirling engine and micro gas turbine, installed at household level are assessed in two different settings: one in Northern Europe (UK) and one in Southern Europe (Italy). Different operating strategies are investigated for each technology. Moreover, marginal electricity production technologies are analysed to assess their influence on the results. This study has demonstrated that the type of bio-methane fed micro-CHP technology employed has a significantly different environmental impact: fuel cells are the most environmentally friendly solution in every category analysed; Stirling engines, although can supply heat to the largest number of dwellings are the least environmentally friendly technology. However, key factors investigated in the model presented in this paper influence the decision making on the type of technology adopted and the operating strategy to be implemented. PMID- 28342591 TI - Anaphylaxis During Intracardiac and Endovascular Implantations: A Multifactorial Problem Involving Kounis Syndrome. PMID- 28342592 TI - Polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) in sediments from an urban- and industrial-impacted subtropical estuary (Babitonga Bay, Brazil). AB - Babitonga Bay is a large estuary, which has been under pressure from anthropogenic activities coexisting with a natural area of Atlantic rainforest and mangrove systems. The concentration of persistent organic pollutants (POPs), such as polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) was determined to evaluate the contamination status and the determine possible pollution sources in the estuary. The ?DDT (sum of DDT, DDE and DDD concentrations) was the predominant OCP group, with concentrations ranging from
=105 cfu/g as fed) markedly increased silage fermentation and dry matter recovery in temperate and tropical grasses, alfalfa, and other legumes. However, inoculation did not improve the fermentation of corn, sorghum, or sugarcane silages. Inoculation with LAB reduced clostridia and mold growth, butyric acid production, and ammonia-nitrogen in all silages, but it had no effect on aerobic stability. Silage inoculation (>=105 cfu/g as fed) increased milk yield and the response had low heterogeneity. However, inoculation had no effect on diet digestibility and feed efficiency. Inoculation with LAB improved the fermentation of grass and legume silages and the performance of dairy cows but did not affect the fermentation of corn, sorghum, and sugar cane silages or the aerobic stability of any silage. Further research is needed to elucidate how silage inoculated with homofermentative and facultative heterofermentative LAB improves the performance of dairy cows. PMID- 28342608 TI - Production of reuterin in a fermented milk product by Lactobacillus reuteri: Inhibition of pathogens, spoilage microorganisms, and lactic acid bacteria. AB - We assessed the antimicrobial activity of reuterin produced in vitro in glycerol aqueous solutions in situ by Lactobacillus reuteri ATCC 53608 as part of a fermented milk product against starter (Lactobacillus delbrueckii ssp. bulgaricus and Streptococcus thermophilus), spoilage (Penicillium expansum), pathogenic (Staphylococcus aureus Salmonella enterica ssp. enterica, and Listeria monocytogenes), and pathogen surrogate (Escherichia coli DH5alpha) microorganisms. We also assayed the influence of cold storage (28 d at 4 degrees C) and reuterin on the color and rheology of the fermented milk product. We obtained maximum reuterin concentrations of 107.5 and 33.97 mM in glycerol aqueous solution and fermented milk product, respectively. Reuterin was stable throughout its refrigerated shelf life. Gram-positive microorganisms were more resistant to reuterin than gram-negative microorganisms. Penicillium expansum and Lactobacillus reuteri ATCC 53608 survived at concentrations up to 10 and 8.5 mM, respectively. Escherichia coli DH5alpha was the most sensitive to reuterin (0.9 mM). The presence of reuterin did not cause relevant changes in the quality parameters of the fermented milk product, including pH, acidity, soluble solids, color, and rheological aspects (storage and loss moduli and viscosity). This study demonstrated the viability of using Lactobacillus reuteri ATCC 53608 as a biopreservative in a fermented milk product through reuterin synthesis, without drastically modifying its quality parameters. PMID- 28342609 TI - Randomized, blinded, controlled clinical trial shows no benefit of homeopathic mastitis treatment in dairy cows. AB - Mastitis is one of the most common diseases in dairy production, and homeopathic remedies have been used increasingly in recent years to treat it. Clinical trials evaluating homeopathy have often been criticized for their inadequate scientific approach. The objective of this triple-blind, randomized controlled trial was to assess the efficacy of homeopathic treatment in bovine clinical mastitis. The study was conducted on a conventionally managed dairy farm between June 2013 and May 2014. Dairy cows with acute mastitis were randomly allocated to homeopathy (n = 70) or placebo (n = 92), for a total of 162 animals. The homeopathic treatment was selected based on clinical symptoms but most commonly consisted of a combination of nosodes with Streptococcinum, Staphylococcinum, Pyrogenium, and Escherichia coli at a potency of 200c. Treatment was administered to cows in the homeopathy group at least once per day for an average of 5 d. The cows in the placebo group were treated similarly, using a placebo preparation instead (lactose globules without active ingredients). If necessary, we also used allopathic drugs (e.g., antibiotics, udder creams, and anti-inflammatory drugs) in both groups. We recorded data relating to the clinical signs of mastitis, treatment, time to recovery, milk yield, somatic cell count at first milk recording after mastitis, and culling. We observed cows for up to 200 d after clinical recovery. Base-level data did not differ between the homeopathy and placebo groups. Mastitis lasted for an average of 6 d in both groups. We observed no significant differences in time to recovery, somatic cell count, risk of clinical cure within 14 d after disease occurrence, mastitis recurrence risk, or culling risk. The results indicated no additional effect of homeopathic treatment compared with placebo. The advantages or disadvantages of homeopathy should be carefully assessed for individual farms. PMID- 28342610 TI - Intentionally induced intestinal barrier dysfunction causes inflammation, affects metabolism, and reduces productivity in lactating Holstein cows. AB - Study objectives were to evaluate the effects of intentionally reduced intestinal barrier function on productivity, metabolism, and inflammatory indices in otherwise healthy dairy cows. Fourteen lactating Holstein cows (parity 2.6 +/- 0.3; 117 +/- 18 d in milk) were enrolled in 2 experimental periods. Period 1 (5 d) served as the baseline for period 2 (7 d), during which cows received 1 of 2 i.v. treatments twice per day: sterile saline or a gamma-secretase inhibitor (GSI; 1.5 mg/kg of body weight). Gamma-secretase inhibitors reduce intestinal barrier function by inhibiting crypt cell differentiation into absorptive enterocytes. During period 2, control cows receiving sterile saline were pair-fed (PF) to the GSI-treated cows, and all cows were killed at the end of period 2. Administering GSI increased goblet cell area 218, 70, and 28% in jejunum, ileum, and colon, respectively. In the jejunum, GSI-treated cows had increased crypt depth and reduced villus height, villus height-to-crypt depth ratio, cell proliferation, and mucosal surface area. Plasma lipopolysaccharide binding protein increased with time, and tended to be increased 42% in GSI-treated cows relative to PF controls on d 5 to 7. Circulating haptoglobin and serum amyloid A concentrations increased (585- and 4.4-fold, respectively) similarly in both treatments. Administering GSI progressively reduced dry matter intake (66%) and, by design, the pattern and magnitude of decreased nutrient intake was similar in PF controls. A similar progressive decrease (42%) in milk yield occurred in both treatments, but we observed no treatment effects on milk components. Cows treated with GSI tended to have increased plasma insulin (68%) and decreased circulating nonesterified fatty acids (29%) compared with PF cows. For both treatments, plasma glucose decreased with time while beta-hydroxybutyrate progressively increased. Liver triglycerides increased 221% from period 1 to sacrifice in both treatments. No differences were detected in liver weight, liver moisture, or body weight change. Intentionally compromising intestinal barrier function caused inflammation, altered metabolism, and markedly reduced feed intake and milk yield. Further, we demonstrated that progressive feed reduction appeared to cause leaky gut and inflammation. PMID- 28342611 TI - Short communication: Identification of Corynebacterium bovis by MALDI-mass spectrometry. AB - Corynebacterium bovis is a mastitis-causing microorganism responsible for economic losses related to decrease in milk production. The aim of the study was identify Corynebacterium spp. strains recovered from milk samples of subclinical mastitis by using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). Samples were collected during a 10-mo mastitis-monitoring program in a high-production dairy farm. In this study, 80 strains were analyzed; from these 54 (67.5%) were identified at species level as Corynebacterium bovis, 24 (31.2%) isolates were identified at the genus level as Corynebacterium spp., and only 1 (1.35%) isolated had unreliable identification. Results demonstrated that MALDI MS could be an important technique for the identification of Corynebacterium spp. in milk. PMID- 28342612 TI - Can by-products replace conventional ingredients in concentrate of dairy goat diet? AB - Intensive dairy goat production in the Mediterranean basin is based on imported conventional ingredients to be included in concentrates. Fourteen Murciano Granadina goats in the middle of the third lactation were allocated into 2 groups of 7 animals each fed, respectively, a control diet based on alfalfa hay and concentrate in a 40:60 ratio, and a diet in which the concentrate included tomato fruits, citrus pulp, brewer's grain and brewer's yeast (T100CBY) to study the effect of diet on nutrient utilization, ruminal fermentation, purine derivatives excretion in urine, milk yield and composition, and methane emissions. No effect of the diet on total dry matter intake was observed. Digestibility of neutral detergent fiber and acid detergent fiber were higher for T100CBY compared with the control diet. The N in feces and urine was lower and balance and retained N were higher in animals fed T100CBY than the control diet. Milk protein N and energy were similar for both diets. Metabolizable energy per energy intake and metabolizable energy per digestible energy were higher and energy in methane was lower with diet T100CBY than with the control. Milk yield and composition were not affected by diet, with the exception of protein, casein, and total solids, which were higher for diet T100CBY than the control. Diet T100CBY promoted less saturated fatty acids and higher mono- and polyunsaturated fatty acids in milk than the control diet. Diet T100CBY produced less methane and NH3 concentration in the rumen, higher propionate, and a lower acetate-to-propionate ratio without an effect on the volatile fatty acid concentration. The concentrate with by products did not affect urinary excretion of total purine derivatives, reduced feeding costs, and increased profit margin by 14 and 16% compared with the control. The mixture of tomato fruits, citrus pulp, brewer's grain, and brewer's yeast could replace 47% of conventional ingredients (corn, wheat bran, sunflower meal, and soy flour) in the concentrate of the dairy goat diet, reducing feeding cost and methane production, leading to a healthier fatty acids profile in milk without compromising nutrient utilization or milk yield. PMID- 28342613 TI - Amino acid supplementation of calf milk replacers containing plasma protein. AB - We determined the effects of calf milk replacers containing 0, 5, or 10% bovine plasma protein (PP), either without or with the supplemental amino acids (AA) Ile and Thr, on growth and health of male Holstein calves (n = 104) for 56 d. Milk replacers were formulated to contain 22% crude protein (CP), 20% fat, and 2.0% Lys. Milk replacers (12.5% solids) were fed at a rate of 1.5% of body weight (BW) on a dry matter basis during wk 1 and 1.75% of BW beginning on d 8. Starter was introduced on d 36 so that effects of PP and AA balance in milk replacers could be isolated. Intake, respiratory scores, and fecal scores were measured daily. Body weight and stature were measured weekly and blood serum samples were obtained during wk 4. Treatments had no effects on intakes of dry matter, CP, or metabolizable energy. During wk 6 and 8, BW was less as PP inclusion increased without AA supplementation compared with the other treatments. In wk 7, calves fed the higher level of PP without AA had lower BW than calves fed either the lower level of PP without supplemented AA or the higher inclusion of PP with supplemented AA. Average daily gain and gain:feed were lowest for calves fed the higher inclusion of PP without supplemented AA; heart girth in wk 7 was smallest for those calves. During the first 21 d, occurrence of scours was greater in calves fed the control milk replacer than in calves fed milk replacers containing the higher inclusion of PP either without or with supplemental AA. Occurrence of scours was also greater for the lower inclusion of PP compared with the higher inclusion of PP when AA were supplemented. Throughout the 56-d experiment, the chance of antibiotic treatment was greater for calves fed the control milk replacer than for all other treatments except the higher inclusion of PP without supplemental AA. Additionally, chance of antibiotic treatment was greater for the higher inclusion of PP without supplemental AA than for other milk replacers with PP. Calves fed treatments with the higher inclusion of PP had fewer days of scours than the controls. All milk replacers with PP, except the milk replacer containing higher PP without supplemental AA, had fewer days of treatment with antibiotics compared to the all-milk control. Inclusion of PP provided similar performance and improved health as long as milk replacers were balanced for Ile and Thr. PMID- 28342614 TI - Genetic analysis of groups of mid-infrared predicted fatty acids in milk. AB - The objective of this study was to investigate genetic variability of mid infrared predicted fatty acid groups in Canadian Holstein cattle. Genetic parameters were estimated for 5 groups of fatty acids: short-chain (4 to 10 carbons), medium-chain (11 to 16 carbons), long-chain (17 to 22 carbons), saturated, and unsaturated fatty acids. The data set included 49,127 test-day records from 10,029 first-lactation Holstein cows in 810 herds. The random regression animal test-day model included days in milk, herd-test date, and age season of calving (polynomial regression) as fixed effects, herd-year of calving, animal additive genetic effect, and permanent environment effects as random polynomial regressions, and random residual effect. Legendre polynomials of the third degree were selected for the fixed regression for age-season of calving effect and Legendre polynomials of the fourth degree were selected for the random regression for animal additive genetic, permanent environment, and herd-year effect. The average daily heritability over the lactation for the medium-chain fatty acid group (0.32) was higher than for the short-chain (0.24) and long-chain (0.23) fatty acid groups. The average daily heritability for the saturated fatty acid group (0.33) was greater than for the unsaturated fatty acid group (0.21). Estimated average daily genetic correlations were positive among all fatty acid groups and ranged from moderate to high (0.63-0.96). The genetic correlations illustrated similarities and differences in their origin and the makeup of the groupings based on chain length and saturation. These results provide evidence for the existence of genetic variation in mid-infrared predicted fatty acid groups, and the possibility of improving milk fatty acid profile through genetic selection in Canadian dairy cattle. PMID- 28342615 TI - Effect of increasing body condition on oxidative stress and mitochondrial biogenesis in subcutaneous adipose tissue depot of nonlactating dairy cows. AB - With the onset of lactation, dairy cows with a body condition score >3.5 are sensitive to oxidative stress and metabolic disorders. Adipose tissue (AT) can adapt to varying metabolic demands and energy requirements by the plasticity of its size during lactation. In AT, angiogenesis is necessary to guarantee sufficient oxygen and nutrient supply for adipocytes. Cellular energy metabolism is reflected mainly by mitochondria, which can be quantified by the mitochondrial DNA copy number per cell. In the present study, we aimed to investigate the effect of overconditioning on angiogenesis and mitochondrial biogenesis in AT of nonlactating cows, irrespective of the physiological influences of lactation and pregnancy. Eight nonpregnant, nonlactating cows received a ration of increasing energy density for 15 wk, during which body weight and body condition increased substantially. Subcutaneous AT was biopsied every 8 wk, and blood was sampled monthly. The blood concentrations of indicators of oxidative stress increased continuously throughout the experimental period, possibly damaging mitochondrial DNA. Concomitantly, HIF-1alpha, a major marker for hypoxia, increased until wk 8, indicating insufficient angiogenesis in the rapidly expanding AT. Based on the observation that the number of apoptotic cells decreased with increasing hypoxia, the increasing mitochondrial DNA copy numbers might compensate for the hypoxia, reinforcing the production of oxidative stressors. Key transcription factors of mitochondrial biogenesis were largely unaffected. Thus, increased oxidative stress does not impair mitochondrial DNA. PMID- 28342616 TI - Performance of leading artifact removal algorithms assessed across microwave breast imaging prototype scan configurations. AB - Microwave imaging is a promising imaging modality for the detection of early stage breast cancer. One of the most important signal processing components of microwave radar-based breast imaging is early-stage artifact removal. Several artifact removal algorithms have been reported in the literature. However, the neighbourhood-based skin subtraction and hybrid artifact removal algorithms have shown particularly promising results in different realistic 3D breast phantoms. For the first time in this paper, both algorithms have been evaluated and compared using the scan approaches of the most common microwave breast imaging prototype systems. The tests include 3D numerical as well as experimental breast phantoms scanned with hemispherical, cylindrical and adaptive scanning patterns. The efficacy of both algorithms has been evaluated across a range of appropriate performance metrics. PMID- 28342617 TI - A study of stigma among Iranian family caregivers of patients with multiple sclerosis: A descriptive explorative qualitative study. AB - AIM: This study was done to investigate the experiences of family caregivers of people with multiple sclerosis (MS) about stigmatization in Iranian health care context. BACKGROUND: Stigmatization has been observed obviously among patients with MS but few studies have been conducted on stigma among the family caregivers of these patients. METHODS: This qualitative study with thematic analysis was done to explore this issue. Fourteen family caregivers of patients with MS were selected by purposive sampling. The data were collected through in-depth and unstructured interviews. RESULTS: Four main subthemes emerged from the analysis of the transcripts: "feeling shame", "fear of being ridiculed by others", "ignored by family" and "concealing disease to be secure against the perceptions of disease". CONCLUSIONS: Healthcare professionals should be encouraged to inform caregivers about social engagement strategies and to train them on the management of stigma as an important factor for the reduction of their social problems. PMID- 28342619 TI - Depressive symptoms in 9th graders: Stress and physiological contributors. PMID- 28342618 TI - A realist synthesis of social connectivity interventions during transition to parenthood: The value of relationships. AB - BACKGROUND: Social connections are important during the transition to parenthood. A wide body of literature suggests that these connections enhance health and contribute to wellbeing. In the case of parents and families, social connections can influence child development. Nurses and public health agencies are in a unique position to advocate for resources and approaches to enhance social connectivity for parents during this important life transition. OBJECTIVES: The aim of this review was to identify the universal social connectivity interventions that work, and the conditions that foster social connections for parents and enhance child development. The review was undertaken as part of a larger research project to inform the question: What are the population-level interventions that public health can implement to promote social, emotional and cognitive development from the prenatal period to the end of the first year of life? Social connectivity is one of three domains that were explored in the full study. DESIGN: Realist synthesis. DATA SOURCES: Medline, CINAHL, ERIC, SocAbs, PsychINFO, grey literature. REVIEW METHODS: A literature search was conducted using relevant key words and MeSH headings. Nearly 2000 papers were reviewed by title and sorted based on inclusion and exclusion criteria. Data extraction aided quality appraisal and analysis and informed the development of an explanatory mechanism. RESULTS: Twenty-seven papers were included in the synthesis, with findings described in four theme areas: (a) connections in the community, (b) internet connections, (c) prenatal connections, and (d) connections for fathers. The literature available to answer the research question is scant and of varying quality. Community development, family-systems intervention practices, principles of father inclusive practice and group prenatal care models have been demonstrated to foster social connectivity for parents. Online social networking provides valuable informational support. CONCLUSIONS: Changing social structures and technology have influenced the way in which new parents access support. Social connections fostered in the parenting environment have the potential to enhance wellbeing for parents and thus contribute to children's positive development. Nurses are in a position to advocate for the use of evidence informed approaches when planning programs and services for parents. PMID- 28342620 TI - Parent decision factors, safety strategies, and fears about infant sleep locations. AB - : Infant sleep safety is a primary concern of parents. Infant sleep locations vary around the world. PURPOSE: This pilot study investigated the decision factors, fears, and safety strategies reported by parents internationally. METHODS: participants (n=49) recruited online from 10 countries completed an anonymous Internet survey in English and submitted a picture of the infant's primary nighttime sleep location. Pictures were coded into 'shared' (29%) or 'separate' (71%) sleep surfaces. RESULTS: primary decision factors about infant sleep location were safety, comfort, family sleep quality, and overall ease. Parents maximized safety by providing a clear sleep surface, no blankets, no toys, sleep sack use, and a firm mattress. Different worries and fears emerged depending on the sleep surface. CONCLUSION: differences in the specific worries and strategies used by parents when deciding whether to share or not share a sleep surface with an infant may be used to tailor future interventions. PMID- 28342621 TI - How nurse-led practices perceive implementation of the patient-centered medical home. AB - PURPOSE: The Affordable Care Act (ACA) promotes the Patient-Centered Medical Home (PCMH) model as a way to improve healthcare quality, the patient experience, and has identified nurse-led primary care as a mechanism meeting the increasing demand for quality primary care. The purpose of this study was to investigate the implementation of a PCMH model in nurse-led primary care practices and to identify facilitators and barriers to the implementation of this model. METHODS: Data were collected through in-depth interviews with providers and staff in nurse led practices. RESULTS: These data suggest two categories of processes that facilitate the integration of PCMH in the nurse-led practice setting: patient oriented facilitators and organizational facilitators. In addition, a number of barriers were identified to implementing the PCMH model. Overall, these practices creatively engaged in the transformation process by structuring themselves as a complex adaptive system and building upon the core principles of nurse-led care. CONCLUSION: Since the core principles of nurse-led care map onto many of the same principles of the PCMH model, this study discusses the possibility that nurse-led practices may experience fewer barriers when transitioning into PCMHs. PMID- 28342622 TI - An analysis of the relationship between burnout, socio-demographic and workplace factors and job satisfaction among emergency department health professionals. AB - INTRODUCTION: Burnout among emergency medical practitioners and personnel negatively affects career satisfaction and job performance and can lead to mental health issues, including anxiety, depression, and suicide. PURPOSE: This study investigated the relationship between the perceptions of burnout and job satisfaction of those working in two different hospital's emergency departments assessing the effect of burnout dimensions and additional factors (age, position, marital status, annual income, employment type, gender, patient encounters, and household economic well-being) on job satisfaction. This study addresses a gap in the literature of the relationships between a) burnout and job satisfaction of emergency department's health care personnel (physicians, nurses, technicians) and b) the factors that are associated with emergency department employees' job satisfaction. METHOD: A cross-sectional survey of two hundred and fifty participants was interviewed, using validated instruments (the Maslach Burnout Scale and the Minnesota Satisfaction Questionnaire). Participants include 38 physicians, 89 nurses, and 84 medical technicians, and 39 information technicians. The Maslach Burnout Inventory Scale, which assesses emotional exhaustion (EE), depersonalization (DP) and personal accomplishment (PA), and the Minnesota Satisfaction Questionnaire (MSQ), which assesses intrinsic satisfaction (IS), extrinsic satisfaction (ES) and overall satisfaction (OS), were used for data collection. RESULTS: Study findings indicate that significant relationship exists between burnout and job satisfaction; annual income and household economic well-being had a positive association with job satisfaction, whereas gender, age, education, marital status had no significant effect on any form of satisfaction. Moreover, this study reveals that emotional exhaustion (EE) is a significant predictor of all three dimensions of job satisfaction while depersonalization (DP) had no significant showing. CONCLUSION: Results of this study suggest that it is not yet clear which factors are salient contributors in demonstrating the relationship between burnout and job satisfaction. This study may draw attention to a better understanding of this relationship will help enable health care administrators to design and implement tools to help increase job satisfaction and decrease burnout as a combined goal rather than treat each issue separately. PMID- 28342623 TI - Mother-newborn health indicators in possible victims of gender-based violence during pregnancy. AB - BACKGROUND: Pregnancy increases the risk of gender-based violence, considered an underdiagnosed public health problem. OBJECTIVE: To determine the association between the situation of possible gender-based violence in the pregnant woman and variables related to pregnancy, labor, puerperium, and newborn health. DESIGN: An observational multicenter study. SETTINGS: Three Spanish hospitals during 2015. PARTICIPANTS: 141 pregnant women in which information is collected sociodemographic variables and data related to pregnancy, labor, and puerperium were gathered by interview and from clinical records. Comparisons of means and logistic regression analyses were performed, calculating crude and adjusted odds ratios. RESULTS: The study included 141 women; 44 in a situation of possible abuse required more medication during labor (p=0.018), had less early skin contact with their newborn (p=0.021) and more non-reassuring cardiotocography traces (p=0.012), and reported greater pain during labor (p=0.013). The children of the mothers in this situation had a lower mean Apgar score (p?0.059), less frequently began breastfeeding early (p=0.008), and had higher risk of low birth weight (p?0.001). CONCLUSION: The situation of possible abuse in pregnant women may negatively affect their pregnancy, their pain and need for medication during labor, and other newborn health indicators, among other health parameters. PMID- 28342624 TI - The level of anxiety, depression and quality of life among patients with heart failure in Greece. AB - PURPOSE: The assessment of the level of anxiety, depression and quality of life among patients with heart failure. METHODS: It was an observational study. The populations were 231 patients with heart failure who were hospitalized in cardiology departments of 2 general hospitals in Athens, from September 1, 2010 through January 31, 2012. We used the "Minnesota Living with Heart Failure Questionnaire - MLHFQ" to evaluate patients' quality of life and the " State Trait Anxiety Inventory - STAI" and the "Maastricht Questionnaire - MQ" to evaluate the level of stress and depression, respectively. RESULTS: The mean age of patients was 66.1+/-10.1years. The quality of life was poor, since the average score in MLHFQ was 65.4+/-20.6. Also, patients revealed high levels of both trait and state anxiety (mean score in STAI was 54.5+/-9.4 and 52.8+/-8.5 respectively) and depression (mean score in MQ was 34.3+/-8.4). Factors associated with poor quality of life and high levels of anxiety and depression were older age, low level of education, unemployment, poor economic situation, multiple hospitalizations (> 4 times) and heart failure stages III and IV in NYHA (p<0.001 in all cases). CONCLUSION: Patients with heart failure present severe symptoms of anxiety and depression and poor quality of life. Assessing those patients for these symptoms and providing holistic health care by a multidisciplinary team, will lead to the prevention and early treatment not only of physical but also of the psychosocial manifestations of the disease. PMID- 28342625 TI - Development of a theory-guided storytelling narrative intervention to improve HPV vaccination behavior: Save our daughters from cervical cancer. PMID- 28342626 TI - Understanding the health care utilization of children who require medical technology: A descriptive study of children who require tracheostomies. AB - Children who require medical technology have complex chronic illnesses. This medical technology, including ventilators, oximeters, tracheostomy tubes, and feeding tubes, allows children and their families to live at home; however, the management of the children's care by informal caregivers is complex with the need for intensive, specialized care. The purpose of this study was to examine the sociodemographic and clinical characteristics that affect health care utilization in a population of children who require medical technology. A retrospective electronic health record (EHR) review was completed on the EHR records on 171 children who require medical technology, specifically tracheostomies, at an outpatient technology dependent pulmonary clinic over a three year period (January 2010-December 2012). Descriptive statistics were used to analyze sociodemographic and clinical characteristics, including medical diagnoses, and emergency department (ED) visits and hospitalizations. Of the 171 children requiring medical technology studied, there were numerous medical diagnoses (n=791), 99% had chronic illnesses affecting two or more body systems, and 88% required two or more technologies, including a tracheostomy and a feeding tube. In addition, 91% of the children had at least one ED visit or hospitalization and were treated in the ED approximately three times over the three year period. The findings from this study noted an increased utilization of health care by these children, and identified common symptoms and medical technologies for which caregivers may need interventions, focusing on education in managing symptoms and medical technology prior to presentation to the ED or hospital. PMID- 28342627 TI - Applicability of calf subcutaneous tissue to subcutaneous injection in young adults. AB - AIM: The aim of the study is to provide usage of subcutaneous tissue of lateral calf area (region of M. Gastrocnemius) in addition to the existing injection regions and to compare tissue thicknesses of the lateral upper arm, anterior and lateral thigh, anterior abdomen regions and calf regions. BACKGROUND: Subcutaneous injection (SC) is an application of 0.5cc drug with an injection (No. 25 and 8-15-18mm long) to the connective tissue under the skin. Individuals to which SC injection is frequently applied, should rotate the injection areas. METHODS: This research uses the descriptive method. One hundred and sixty-one students (aged; 20.09+/-2.268) were used as test subjects. Demographic data was obtained from the students who agreed to participate in the research. Body Mass Index (BMI) was calculated. Skin thickness measured using the Holtain Skinfold Caliper. SPSS 20 package software was used for statistical analysis of the data. For comparison of the tissue thicknesses between genders, the t-test was used for independent groups. In order to determine the interactions between anthropometric measurements within each other and other numerical measurements (age, length. BMI, etc.). Pearson Correlation coefficient and related P value was performed. Statistical P value is taken as 0.05. RESULTS: Consideration of subcutaneous injection applicability of the calf region depended on the injector lengths: 8mm, 15mm and 18mm, 86.3%, 59.6% and 47.8% of the population, respectively were found applicable for this region. CONCLUSIONS: The calf region could be recommended as SC injection region with an 8mm injector. According to the findings it can be said that the calf region of female genders is more applicable than male genders for SC injection. Calf region could be proposed as anticoagulation treatment. PMID- 28342628 TI - Poor sleep quality, depression and hope before breast cancer surgery. AB - AIM: This study aims to identify the predictors of poor sleep quality and the associations between depression, hope and sleep in a sample of 156 women with breast cancer prior to surgery. BACKGROUND: The care and treatment of breast cancer is among the most important scientific challenges in public health. Sleep disturbances and depression are the important complaint of cancer patients. However, they are often neglected. Patients diagnosed with breast cancer also experience prejudice, fear of death, suffering, mutilation, fear of lymphedema, as well as feelings of social devaluation leading to hopelessness Several studies point to hope as an effective strategy to help patients cope with difficulties and achieve their goals, especially patients with cancer. METHODS: This is a report of baseline data extracted from a longitudinal study. DATA COLLECTION TOOLS: Pittsburgh Sleep Quality Index, Beck Depression Inventory, and the Herth Hope Index. Data were analyzed with the Spearman's Rank Correlation test and Multiple Logistic Regression analysis. RESULTS: The majority of women had tumors in initial stages (78.7%), reported poor sleep quality (58.9%), and had moderate to severe or severe depression (27.2%). Significant correlations were found between hope and depression (Spearman r=-0.4341), and between sleep quality and depression (Spearman r=0.3938). Significant associations were found between poor sleep quality and pain, symptoms of menopause and depression. Depression and symptoms of menopause were independent predictors of poor sleep quality. CONCLUSION: The evaluation of sleep quality, depression and hope should be implemented in clinical practice. Increased hope lessens depression and may positively affect sleep quality, all of which improves quality of life for women with breast cancer. PMID- 28342629 TI - Nursing Leadership and Research on Patient Outcomes: Moving the Profession Forward toward Better Understanding of Our Nursing Work. PMID- 28342630 TI - Statins attenuate but do not eliminate the reverse epidemiology of total serum cholesterol in patients with non-ischemic chronic heart failure. AB - BACKGROUND: In patients with chronic heart failure (CHF) increasing levels of total serum cholesterol are associated with improved survival - while statin usage is not. The impact of statin treatment on the "reverse epidemiology" of cholesterol is unclear. METHODS: 2992 consecutive patients with non-ischemic CHF due to left ventricular systolic dysfunction from the Norwegian CHF Registry and the CHF Registries of the Universities of Hull, UK, and Heidelberg, Germany, were studied. 1736 patients were individually double-matched on both cholesterol levels and the individual propensity scores for statin treatment. All-cause mortality was analyzed as a function of baseline cholesterol and statin use in both the general and the matched sample. RESULTS: 1209 patients (40.4%) received a statin. During a follow-up of 13,740 patient-years, 360 statin users (29.8%) and 573 (32.1%) statin non-users died. When grouped according to total cholesterol levels as low (<=3.6mmol/L), moderate (3.7-4.9mmol/L), high (4.8 6.2mmol/L), and very high (>6.2mmol/L), we found improved survival with very high as compared with low cholesterol levels. This association was present in statin users and non-users in both the general and matched sample (p<0.05 for each group comparison). The negative association of total cholesterol and mortality persisted when cholesterol was treated as a continuous variable (HR 0.83, 95%CI 0.77-0.90, p<0.001 for matched patients), but it was less pronounced in statin users than in non-users (F-test p<0.001). CONCLUSIONS: Statins attenuate but do not eliminate the reverse epidemiological association between increasing total serum cholesterol and improved survival in patients with non-ischemic CHF. PMID- 28342631 TI - Systematic review: Impact of the new task force criteria in the diagnosis of arrhythmogenic right ventricular cardiomyopathy. AB - BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disorder of cardiac desmosomes associated with ventricular arrhythmias and sudden cardiac death. The clinical diagnosis is problematic and relies on a complex criteria composed of clinical and non-clinical parameters. In 2010, the original 1994 Task Force Criteria (TFC) was revised with particular attention given to the imaging parameters. METHODS: Five retrospective studies compared the diagnostic concordance between the 1994 and 2010 TFC. Three studies used cardiac magnetic resonance (CMR) and compared major and minor CMR criteria and three studies compared definite ARVC cases; one study assessed both. RESULTS: Three studies with 1435 patients compared the 1994 imaging and the 2010 CMR criteria. Using the 1994 criteria, 123 (8.6%) and 419 (29.2%) patients satisfied major and minor criteria compared to only 52 (3.6%) and 28 (1.9%) using the 2010 criteria; 57.7% and 94.3% reduction in major and minor criteria (p value, 0.0001 and 0.0001). Three studies with 611 patients assessed for definite ARVC. Using the 1994 and 2010 criteria, 207 (33.9%) and 243 (39.8%) patients satisfied the parameters respectively. This resulted in a statistically significant 17.4% (p value, 0.0379) increase in ARVC cases driven largely by two sub-groups. CONCLUSIONS: The 2010 revised TFC have resulted in a significant reduction in the number of patients that satisfy CMR criteria particularly those that satisfied minor imaging abnormalities using the 1994 criteria. In addition, in certain groups the revised criteria have significantly increased the number of patients diagnosed with definite ARVC. PMID- 28342632 TI - The pharmacodynamics of low and standard doses of ticagrelor in patients with end stage renal disease on hemodialysis. AB - BACKGROUND: Patients with end-stage renal disease (ESRD) on maintenance hemodialysis (HD) respond poorly to clopidogrel. We assessed the utility of low dose ticagrelor in ESRD patients on maintenance HD. METHODS: In this single center, prospective, randomized pharmacodynamic study, 52 ESRD patients on HD were prescribed clopidogrel (300mg loading dose [LD], then 75mg daily), standard dose ticagrelor (180mg LD, then 90mg twice daily), or low-dose ticagrelor (90mg LD, then 90mg daily) for 14days. Platelet function was evaluated before and after therapy via light transmittance aggregometry and the VerifyNowTM P2Y12 assay. RESULTS: The adenosine diphosphate (ADP)-induced maximal extent of platelet aggregation differed significantly between the low-dose ticagrelor and clopidogrel groups (ANCOVA, p=0.04 after stimulation with 5MUmol/L ADP; p<0.01 after stimulation with 20MUmol/L ADP). Inhibition of platelet aggregation increased significantly in the order of clopidogrel, low-dose ticagrelor, and standard-dose ticagrelor, as revealed by adjusted intergroup comparison analysis (ANCOVA, p=0.04 after stimulation with 5MUmol/L ADP; p=0.005 after stimulation with 20MUmol/L ADP). The rates of onset of the antiplatelet effect curves from 0 to 5h after administration of the LDs were greater in the standard- and low-dose ticagrelor groups than in the clopidogrel group. Significant sequential reductions in P2Y12 reaction units were noted, in the following order: clopidogrel, low-dose ticagrelor, and standard-dose ticagrelor (ANCOVA, p<0.001). No bleeding occurred in the low-dose ticagrelor group. CONCLUSIONS: Low-dose ticagrelor afforded greater platelet inhibition than did clopidogrel in ESRD patients on HD. PMID- 28342633 TI - PCA3 as a second-line biomarker in a prospective controlled randomized opportunistic prostate cancer screening programme. AB - OBJECTIVES: PCA3 performance as a single second line biomarker is compared to the European Randomised Study of Screening for Prostate Cancer risk calculator model 3 (ERSPC RC-3) in an opportunistic screening in prostate cancer (PCa). MATERIAL AND METHODS: 5,199 men, aged 40-75y, underwent prostate-specific antigen (PSA) screening and digital rectal examination (DRE). Men with a normal DRE and PSA >=3ng/ml had a PCA3 test done. All men with PCA3 >=35 underwent an initial biopsy (IBx) -12 cores-. Men with PCA3 <35 were randomized 1:1 to either IBx or observation. We compared them to those obtained with ERSPC RC-3. RESULTS: PCA3 test was performed on 838 men (16.1%). In PCA3(+) and PCA3(-) groups, global PCa detection rates were 40.9% and 14.7% with a median follow-up (FU) of 21.7 months (P<.001). In the PCA3(+) arm (n=301, 35.9%), PCa was identified in 115 men at IBx (38.2%). In the randomized arm, 256 underwent IBx and PCa was found in 46 (18.0%) (P<.001). The biopsy-sparing potential would have been 64.1% as opposed to 76.6% if we had used ERSPC RC-3. However, the estimated false negative cases for HGPCa would have been reduced by 37.1% (89 to 56 patients). Moreover, if we had applied PCA3-35 to avoid IBx, 14.7% PCa and 9.1% of clinical significant PCa patients would not have been diagnosed during this FU. CONCLUSIONS: When PCA3-35 is used as a second-line biomarker when PSA >=3ng/ml and DRE is normal, IBx could be avoided in 12.5% less than if ERSPC RC-3 is used and would reduce the false negative cases by 36.2%. At a FU of 21.7 months, this dual protocol would miss 9.1% of clinically significant PCa, so strict FU is mandatory with established biopsy criteria based on PSA and DRE in cases with PCA3 <35. PMID- 28342634 TI - [Prevalence trends of high risk of mental disorders in the Spanish adult population: 2006-2012]. AB - OBJECTIVE: To evaluate the prevalence of high risk of psychiatric morbidity in the Spanish adult population and its changes between 2006 and 2012. METHODS: Data from 47,905 participants obtained from the National Health Surveys in 2006 and 2012 were used. Mental health status was assessed with the General Health Questionnaire score. Adjusted logistic regression models were fitted. RESULTS: The prevalence of high risk of psychiatric morbidity was 20.5% in 2012 and 21.3% in 2006. Using 2006 as the reference, the odds ratio (OR) for these problems in 2012 was 0.84 (0.79-0.89) in women and 1.10 (1.02-1.18) in men. In women, it decreased for all ages. In men, these ORs were 1.15 (1.04-1.27) in the aged 16-44 group, 1.23 (1.08-1.40) in the aged 45-64 group and 0.81 (0.68-0.96) in the aged >= 65 group. CONCLUSIONS: The prevalence of high risk of psychiatric morbidity decreased except in males <65 years of age, who are more sensitive to the economic crisis. PMID- 28342635 TI - 'Nature Knows No Boundaries': The Role of Nature Conservation in Peacebuilding. AB - Humanity is facing a biodiversity crisis. To solve environmental problems, we bring people from Israel, Jordan, and the Palestinian Authority to the same table. Conservation efforts are beneficial for all communities and facilitate constructive dialog across divides in conflict zones. This pleads for the integration of nature conservation into peacebuilding interventions. PMID- 28342636 TI - Rituximab as first-line treatment of pemphigus. PMID- 28342637 TI - First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel group, open-label randomised trial. AB - BACKGROUND: High doses of corticosteroids are considered the standard treatment for pemphigus. Because long-term corticosteroid treatment can cause severe and even life-threatening side-effects in patients with this disease, we assessed whether first-line use of rituximab as adjuvant therapy could improve the proportion of patients achieving complete remission off-therapy, compared with corticosteroid treatment alone, while decreasing treatment side-effects of corticosteroids. METHODS: We did a prospective, multicentre, parallel-group, open label, randomised trial in 25 dermatology hospital departments in France (Ritux 3). Eligible participants were patients with newly diagnosed pemphigus aged 18-80 years being treated for the first time (not at the time of a relapse). We randomly assigned participants (1:1) to receive either oral prednisone alone, 1.0 or 1.5 mg/kg per day tapered over 12 or 18 months (prednisone alone group), or 1000 mg of intravenous rituximab on days 0 and 14, and 500 mg at months 12 and 18, combined with a short-term prednisone regimen, 0.5 or 1.0 mg/kg per day tapered over 3 or 6 months (rituximab plus short-term prednisone group). Follow up was for 3 years (study visits were scheduled weekly during the first month of the study, then monthly until month 24, then an additional visit at month 36). Treatment was assigned through central computer-generated randomisation, with stratification according to disease-severity (severe or moderate, based on Harman's criteria). The primary endpoint was the proportion of patients who achieved complete remission off-therapy at month 24 (intention-to-treat analysis). This study is registered with ClinicalTrials.gov, number NCT00784589. FINDINGS: Between May 10, 2010, and Dec 7, 2012, we enrolled 91 patients and randomly assigned 90 to treatment (90 were analysed; 1 patient withdrew consent before the random assignment). At month 24, 41 (89%) of 46 patients assigned to rituximab plus short-term prednisone were in complete remission off-therapy versus 15 (34%) of 44 assigned to prednisone alone (absolute difference 55 percentage points, 95% CI 38.4-71.7; p<0.0001. This difference corresponded to a relative risk of success of 2.61 (95% CI 1.71-3.99, p<0.0001), corresponding to 1.82 patients (95% CI 1.39-2.60) who would need to be treated with rituximab plus prednisone (rather than prednisone alone) for one additional success. No patient died during the study. More severe adverse events of grade 3-4 were reported in the prednisone-alone group (53 events in 29 patients; mean 1.20 [SD 1.25]) than in the rituximab plus prednisone group (27 events in 16 patients; mean 0.59 [1.15]; p=0.0021). The most common of these events in both groups were diabetes and endocrine disorder (11 [21%] with prednisone alone vs six [22%] with rituximab plus prednisone), myopathy (ten [19%] vs three [11%]), and bone disorders (five [9%] vs five [19%]). INTERPRETATION: Data from our trial suggest that first-line use of rituximab plus short-term prednisone for patients with pemphigus is more effective than using prednisone alone, with fewer adverse events. FUNDING: French Ministry of Health, French Society of Dermatology, Roche. PMID- 28342638 TI - [Rationale and complications of the anterior-lateral extrapleural retroperitoneal approach for unstable thoracolumbar fractures: Experience in 86 consecutive patients]. AB - OBJECTIVES: To describe the rationale, pros and cons, and complications of the anterior-lateral extrapleural retroperitoneal approach for unstable (TLICS>4) thoracolumbar fractures. PATIENTS AND METHODS: Clinical and radiological data and outcomes from a cohort treated surgically via said approach were retrospectively reviewed. All patients were operated on exclusively by 5 neurosurgeons trained in spine surgery. RESULTS: Between June 1999 and December 2015, 86 patients underwent surgery (median age 42years, most common level: L1). Approximately 32.5% presented with a preoperative neurological defect. After surgery (mean duration: 275minutes), 75.6% presented with no neurological sequelae and only one third required blood transfusion. Median postoperative stay was 7days. Correction of kyphosis was considered adequate and suboptimal but acceptable in 91% and 9% of the patients, respectively. Complications occurred in 36 patients, the majority being transient. We observed failure of the construct in 2 cases (collapse of an expandable cage and extrusion of a locking screw). No infections, vascular or visceral lesions, permanent neurological worsening or mortality occurred during hospitalisation. One patient ultimately needed additional posterior fixation due to persistence of pain. Median follow-up was 252days (27.9% was lost to follow-up). CONCLUSIONS: The extrapleural extraperitoneal approach provides solid anterior reconstruction, allows wide decompression of the spinal canal, and permits adequate and long-lasting correction of kyphosis. The rates of infection, construct failure, need for reoperation and vascular or visceral lesions are minimal. PMID- 28342640 TI - Systematic Review Links the Prevalence of Intraductal Carcinoma of the Prostate to Prostate Cancer Risk Categories. AB - : Intraductal carcinoma of the prostate (IDC-P) is associated with poor prognosis. While it is often regarded as a rare pathology, the prevalence of IDC P remains unclear, with variable reports from small and disparate patient populations. To determine how common IDC-P is across the spectrum of prostate cancer, we conducted a systematic review correlating IDC-P prevalence with prostate cancer risk. Electronic searches of the OVID Medline, PubMed, and Scopus literature databases identified 38 patient cohorts in 24 articles, which were divided between four prostate cancer risk categories (low, moderate, high, and recurrent or metastatic disease). This review, which included radical prostatectomy and prostate biopsy specimens from >7000 patients, revealed an unexpectedly high rate of IDC-P. The IDC-P prevalence increased from 2.1% in low risk patient cohorts to 23.1%, 36.7%, and 56.0% in moderate-risk, high-risk, and metastatic or recurrent disease risk categories, respectively (p<0.0001). IDC-P was also highly prevalent in tumours following androgen deprivation therapy or chemotherapy (60%). Contrary to common perceptions, this study demonstrates a strong association between IDC-P prevalence and aggressive prostate cancer, with a significantly higher frequency in high-risk disease. Greater recognition and systematic reporting of IDC-P may improve patient risk stratification. PATIENT SUMMARY: Prostate cancer can grow within ducts of the prostate, as well as in prostate tissue. By reviewing all reports describing prostate cancer growing within ducts, we found that it occurs more commonly than many scientists and clinicians appreciate, especially in aggressive prostate cancers. We conclude that there should be more awareness of this pattern of prostate cancer. PMID- 28342639 TI - Sendai Virus Mucosal Vaccination Establishes Lung-Resident Memory CD8 T Cell Immunity and Boosts BCG-Primed Protection against TB in Mice. AB - Accumulating evidence has shown the protective role of CD8+ T cells in vaccine induced immunity against Mycobacterium tuberculosis (Mtb) despite controversy over their role in natural immunity. However, the current vaccine BCG is unable to induce sufficient CD8+ T cell responses, especially in the lung. Sendai virus, a respiratory RNA virus, is here engineered firstly as a novel recombinant anti TB vaccine (SeV85AB) that encodes Mtb immuno-dominant antigens, Ag85A and Ag85B. A single mucosal vaccination elicited potent antigen-specific T cell responses and a degree of protection against Mtb challenge similar to the effect of BCG in mice. Depletion of CD8+ T cells abrogated the protective immunity afforded by SeV85AB vaccination. Interestingly, only SeV85AB vaccination induced high levels of lung-resident memory CD8+ T (TRM) cells, and this led to a rapid and strong recall of antigen-specific CD8+ T cell responses against Mtb challenge infection. Furthermore, when used in a BCG prime-SeV85AB boost strategy, SeV85AB vaccine significantly enhanced protection above that seen after BCG vaccination alone. Our findings suggest that CD8+ TRM cells that arise in lungs responding to this mucosal vaccination might help to protect against TB, and SeV85AB holds notable promise to improve BCG's protective efficacy in a prime-boost immunization regimen. PMID- 28342641 TI - Procedure-specific Risks of Thrombosis and Bleeding in Urological Cancer Surgery: Systematic Review and Meta-analysis. AB - CONTEXT: Pharmacological thromboprophylaxis involves balancing a lower risk of venous thromboembolism (VTE) against a higher risk of bleeding, a trade-off that critically depends on the risks of VTE and bleeding in the absence of prophylaxis (baseline risk). OBJECTIVE: To provide estimates of the baseline risk of symptomatic VTE and bleeding requiring reoperation in urological cancer surgery. EVIDENCE ACQUISITION: We identified contemporary observational studies reporting symptomatic VTE or bleeding after urological procedures. We used studies with the lowest risk of bias and accounted for use of thromboprophylaxis and length of follow-up to derive best estimates of the baseline risks within 4 wk of surgery. We used the GRADE approach to assess the quality of the evidence. EVIDENCE SYNTHESIS: We included 71 studies reporting on 14 urological cancer procedures. The quality of the evidence was generally moderate for prostatectomy and cystectomy, and low or very low for other procedures. The duration of thromboprophylaxis was highly variable. The risk of VTE in cystectomies was high (2.6-11.6% across risk groups) whereas the risk of bleeding was low (0.3%). The risk of VTE in prostatectomies varied by procedure, from 0.2-0.9% in robotic prostatectomy without pelvic lymph node dissection (PLND) to 3.9-15.7% in open prostatectomy with extended PLND. The risk of bleeding was 0.1-1.0%. The risk of VTE following renal procedures was 0.7-2.9% for low-risk patients and 2.6-11.6% for high-risk patients; the risk of bleeding was 0.1-2.0%. CONCLUSIONS: Extended thromboprophylaxis is warranted in some procedures (eg, open and robotic cystectomy) but not others (eg, robotic prostatectomy without PLND in low-risk patients). For "close call" procedures, decisions will depend on values and preferences with regard to VTE and bleeding. PATIENT SUMMARY: Clinicians often give blood thinners to patients to prevent blood clots after surgery for urological cancer. Unfortunately, blood thinners also increase bleeding. This study provides information on the risk of clots and bleeding that is crucial in deciding for or against giving blood thinners. PMID- 28342642 TI - Performance comparison of new generation HCV core antigen test versus HCV RNA test in management of hepatitis C virus infection. AB - The study has evaluated the performance of HCV core antigen (Cag) test by comparing HCV RNA PCR assay which is considered the gold standard for management of HCV infection. Totally, 132 samples sent for HCV RNA (real-time PCR) test were included in the study. Anti-HCV antibody test and HCV Cag test were performed by chemiluminescent enzyme immunoassay (CMEI). Anti-HCV test was positive in all samples. HCV RNA was detected in 112/132 (84.8%) samples, and HCV Cag in 105/132 (79.5%). The most common HCV genotype was genotype 1 (86%). Considering the HCV RNA test as gold standard; the sensitivity, specificity, positive predictive value, negative predictive value and accuracy of Cag test were found to be 93.75%, 100%, 100%, 74.07% and 94.69%, respectively, and paired test results were detected as highly concordant. A high level of correlation was seen between HCV RNA and Cag tests, however, the concordance between the two tests appeared to be disrupted at viral loads lower than 103IU/mL. On the contrary, the correlation reached significance for the values higher than 103IU/mL. Viral loads were in the 17-2500IU/mL range for the negative results for Cag test. Pearson's correlation coefficient revealed a considerably high correlation. The concordance between HCV RNA and Cag tests was disrupted under a viral load lower than 103IU/mL. Therefore, it would be appropriate to consider cost effectiveness, advantages and limitations of the HCV RNA and Cag tests during the decision on which method to use for patient management. PMID- 28342643 TI - The Influence of Pre-Left Ventricular Assist Device (LVAD) Implantation Glomerular Filtration Rate on Long-Term LVAD Outcomes. AB - BACKGROUND: Chronic kidney disease (CKD) is a known predictor for adverse outcomes in patients with advanced heart failure requiring left ventricular assist devices (LVADs). The effect of pre-LVAD glomerular filtration rate (GFR) on post-LVAD outcomes in CKD patients is not completely understood. Additionally, a subset of patients improve their GFR after LVAD placement. In this study we sought to determine the effects of pre-LVAD GFR on post-LVAD outcomes. METHODS: Two hundred and seventy consecutive patients with LVADs were enrolled. Patients were stratified based on a GFR cut-off of 60mL/min/1.73m2. Patients with preoperative GFR <60 were further divided into two subgroups based post-LVAD discharge GFR of 60. Post-LVAD major adverse effects were analysed. RESULTS: Patients with pre-implant GFR <60 had higher all cause mortality than patients with pre-implant GFR >=60 (45% vs. 27%, p=0.006). These patients also had higher incidence of early right ventricular failure and congestive heart failure hospitalisations. Kaplan-Meier survival analysis confirmed poor survival in this group. When the subgroup analysis of patients in the GFR <60 cohort was performed, the above findings were heavily weighted towards patients who did not improve their GFR to >=60 post-LVAD. CONCLUSION: Pre-implant GFR is an important prognostic marker in LVAD patients. Patients with pre-implant GFR <60 are at higher risk of cardiovascular morbidity and mortality. Our findings suggest that the patients who do not improve their GFR post-LVAD are at the highest risk. PMID- 28342644 TI - Steeper Slope of Age-Related Changes in White Matter Microstructure and Processing Speed in Bipolar Disorder. AB - OBJECTIVES: Bipolar disorder (BD) is associated with compromised white matter (WM) integrity and deficits in processing speed (PS). Few studies, however, have investigated age relationships with WM structure and cognition to understand possible changes in brain health over the lifespan. This investigation explored whether BD and healthy counterpart (HC) participants exhibited differential age related associations with WM and cognition, which may be suggestive of accelerated brain and cognitive aging. DESIGN: Cross-sectional study. SETTING: University of California San Diego and the Veterans Administration San Diego Healthcare System. PARTICIPANTS: 33 euthymic BD and 38 HC participants. MEASUREMENTS: Diffusion tensor imaging was acquired as a measure of WM integrity, and tract-specific fractional anisotropy (FA) was extracted utilizing the Johns Hopkins University probability atlas. PS was assessed with the Number and Letter Sequencing conditions of the Delis-Kaplan Executive Function System Trail Making Test. RESULTS: BD participants demonstrated slower PS compared with the HC group, but no group differences were found in FA across tracts. Multiple linear regressions revealed a significant group-by-age interaction for the right uncinate fasciculus, the left hippocampal portion of the cingulum, and for PS, such that older age was associated with lower FA values and slower PS in the BD group only. The relationship between age and PS did not significantly change after accounting for uncinate FA, suggesting that the observed age associations occur independently. CONCLUSIONS: Results provide support for future study of the accelerated aging hypothesis by identifying markers of brain health that demonstrate a differential age association in BD. PMID- 28342646 TI - [Postoperative pneumonia after cardiac surgery: Really, can it be under our control?] PMID- 28342645 TI - The expression and activation of the AIM2 inflammasome correlates with inflammation and disease severity in patients with acute pancreatitis. AB - BACKGROUND: Acute pancreatitis is an inflammatory disorder of the pancreas that is responsible for significant morbidity and mortality. The inflammasome pathway has acquired significant relevance in the pathogenesis of many inflammatory disorders, but its role in patients with acute pancreatitis still awaits clarification. METHODS: We performed a prospective study in which 27 patients with acute pancreatitis and 16 healthy controls were included. We isolated peripheral blood mononuclear cells (PBMCs) and we assessed the expression and activation of different inflammasomes as well as their association with the clinical course of the disease. RESULTS: Our results show that PBMCs from patients with acute pancreatitis have elevated expression of several components of the inflammasome complex, including the inflammasome-forming receptor absent in melanoma 2 (AIM2), early during the onset of the disease. Activation of the AIM2 or NLRP3 inflammasomes in PBMCs from patients with acute pancreatitis results in exacerbated IL-1beta and IL-18 production compared with PBMCs from healthy controls. Furthermore, both AIM2 mRNA expression and AIM2-mediated production of IL-1beta by PBMCs correlated with increased systemic inflammation in these patients. Last, AIM2 expression was further increased in those patients that developed transient or persistent organ failure (moderate or severe acute pancreatitis). CONCLUSIONS: Our data demonstrates that AIM2 inflammasome expression and activation is increased early during the course of acute pancreatitis, and suggests that AIM2 activation may affect systemic inflammation and organ failure in these patients. PMID- 28342647 TI - Recurrence patterns after a decreased dose of 40Gy to the elective treated neck in head and neck cancer. AB - PURPOSE: To investigate the patterns of regional recurrences with emphasis on recurrences in the electively irradiated lymph node regions after dose de escalation to 40Gy (EQD2Gy) in head and neck cancer. METHODS AND MATERIALS: Two hundred thirty-three patients treated with radio(chemo)therapy using 40Gy (EQD2Gy) to the elective lymph node regions were included. All regional recurrences were reconstructed and projected on the initial radiotherapy planning Computed Tomography studies to identify the localization of recurrence. Furthermore, patient and treatment characteristics were correlated with the regional recurrences to identify risk factors. RESULTS: The median follow-up in our study was 26months. Overall- and disease-specific survival at 2years were 71.2% (95% CI 65.3-77.1) and 64.2% (95% CI 59.2-69.3), respectively. Local, regional and distant control at 2years was 84.1% (95% CI 79.1-89.2), 89.2% (95% CI 84.3-94.1) and 83.2% (95% CI 76.3-90.1), respectively. Twenty-eight patients experienced a regional recurrence. Fourteen of these patients had a recurrence within the high dose volume (14 of 28). Nine had a recurrence in the electively irradiated lymph node regions (9 of 28) and 5 recurrences occurred outside the target volume. The actuarial rate of recurrence in the electively irradiated lymph node regions was 3.9% (95% CI 1.8-6.0) at 2years. No significant associations could be observed between recurrence in electively irradiated lymph node regions and age, gender, tumor site, stage, or the presence of human papillomavirus in oropharyngeal cancers. CONCLUSIONS: The actuarial rate of recurrence in the electively irradiated lymph node regions was 3.9% (95% CI 1.8 6.0) at 2years. This incidence is comparable to recurrence rates after standard dose of 50Gy, suggesting that lower doses to the elective neck do not result in higher regional recurrences. PMID- 28342648 TI - The first clinical implementation of a real-time six degree of freedom target tracking system during radiation therapy based on Kilovoltage Intrafraction Monitoring (KIM). AB - PURPOSE: We present the first clinical implementation of a real-time six-degree of freedom (6DoF) Kilovoltage Intrafraction Monitoring (KIM) system which tracks the cancer target translational and rotational motions during treatment. The method was applied to measure and correct for target motion during stereotactic body radiotherapy (SBRT) for prostate cancer. METHODS: Patient: A patient with prostate adenocarcinoma undergoing SBRT with 36.25Gy, delivered in 5 fractions was enrolled in the study. 6DoF KIM technology: 2D positions of three implanted gold markers in each of the kV images (125kV, 10mA at 11Hz) were acquired continuously during treatment. The 2D->3D target position estimation was based on a probability distribution function. The 3D->6DoF target rotation was calculated using an iterative closest point algorithm. The accuracy and precision of the KIM method was measured by comparing the real-time results with kV-MV triangulation. RESULTS: Of the five treatment fractions, KIM was utilised successfully in four fractions. The intrafraction prostate motion resulted in three couch shifts in two fractions when the prostate motion exceeded the pre-set action threshold of 2mm for more than 5s. KIM translational accuracy and precision were 0.3+/-0.6mm, 0.2+/-0.3mm and 0.2+/-0.7mm in the Left-Right (LR), Superior-Inferior (SI) and Anterior-Posterior (AP) directions, respectively. The KIM rotational accuracy and precision were 0.8 degrees +/-2.0 degrees , -0.5 degrees +/-3.3 degrees and 0.3 degrees +/-1.6 degrees in the roll, pitch and yaw directions, respectively. CONCLUSION: This treatment represents, to the best of our knowledge, the first time a cancer patient's tumour position and rotation have been monitored in real time during treatment. The 6 DoF KIM system has sub-millimetre accuracy and precision in all three translational axes, and less than 1 degrees accuracy and 4 degrees precision in all three rotational axes. PMID- 28342649 TI - The prognosis of dementia with Lewy bodies. AB - Dementia with Lewy bodies is the second most common form of neurodegenerative dementia, yet scarce evidence is available about its prognosis and natural history, which are crucial to inform clinical practice and research. Patients with dementia with Lewy bodies might have a less favourable prognosis, with accelerated cognitive decline, shorter lifespan, and increased admission to residential care than patients with Alzheimer's disease. Health-care costs and, importantly, caregiver burden, are also reported to be higher in dementia with Lewy bodies than in Alzheimer's disease. It is probable that causative factors for this less favourable prognosis are the increased prevalence and early emergence of neuropsychiatric symptoms in patients with dementia with Lewy bodies, and the challenge of accurate diagnosis. Evidence concerning quality of life and hospital admission rates is limited, despite their clinical and economic relevance. PMID- 28342650 TI - Subtotal cholecystectomy for the hostile gallbladder: failure to control the cystic duct results in significant morbidity. AB - BACKGROUND: Outcomes following the inability to control the cystic duct due to a hostile triangle of Calot during cholecystectomy remain unknown. The purpose of this study was to analyze the safety and efficacy of subtotal cholecystectomy, with attention to the necessity for secondary interventions. METHODS: Sixteen thousand five hundred ninety six cholecystectomies from January 2002 to August 2014 were reviewed, identifying patients managed with subtotal cholecystectomy, defined as the inability to isolate/transect the cystic duct. After propensity matching, we investigated surgical indications, perioperative outcomes, and the necessity for secondary ERCP, percutaneous drainage, and completion cholecystectomy. RESULTS: 65 (0.39%) patients underwent subtotal cholecystectomy; 54 (83.1%) began laparoscopically, of which 30 (55.6%) required conversion to laparotomy. Subtotal cholecystectomy, performed more frequently for acute cholecystitis (70.8% vs 34.6%), was associated with extended hospitalizations (4 d vs 2 d) and frequent surgical site infections (20% vs 4.6%). 25 (38.5%) subtotal cholecystectomy patients required >=1 secondary intervention, and compared to standard cholecystectomy, underwent higher rates postoperative ERCP (30.8% vs 5.4%), percutaneous drainage (9.2% vs 1.5%), and completion cholecystectomy (6.2% vs 0%) [all P < 0.05]. DISCUSSION: Subtotal cholecystectomy fails to control the cystic duct, resulting in significant morbidity. Most do not require completion cholecystectomy; however, patients demand close observation and, frequently, secondary interventions. PMID- 28342651 TI - From classical to nonparametric growth models: Towards comprehensive modelling of mussel growth patterns. AB - Understanding biological processes, such as growth, is crucial to development management and sustainability plans for bivalve populations. Von Bertalanffy and Gompertz models have been commonly used to fit bivalve growth. These models assume that individual growth is only determined by size, overlooking the effects of environmental and intrinsic conditions on growth patterns. The comparison between classical models and nonparametric GAM (generalized additive models) fits conducted in this work shows that the latter provide a more realistic approach of mussel growth measured in terms of shell length, and dry weight of hard and soft tissues. GAM fits detected a reduction in growth during the cold season, under unfavourable nutritional conditions. These fits also captured the decoupling between hard and soft tissue growth, widely addressed in the literature but not incorporated in growth models. In addition a GAM fit of condition index allowed us to explain annual changes in resources allocation, identifying the asymptotic growth of shell and the effects of the reproductive cycle on soft tissue fluctuations. PMID- 28342652 TI - Effective Hospital-Wide Education in Hemorrhage Control. AB - BACKGROUND: Uncontrolled hemorrhage is the leading cause of potentially preventable traumatic death. Bleeding victims must receive immediate medical attention to save lives, and the first opportunity to control bleeding after trauma often comes from bystanders. Educating the general public is important for improving outcomes for hemorrhaging victims, and it is imperative for all people, including those with no clinical training, to have the knowledge to respond until trained medical specialists arrive. STUDY DESIGN: An 8-minute educational module was deployed to all hospital employees and included information on the location and contents of hemorrhage control bags in the hospital and how to use the materials in the bags to respond to uncontrolled hemorrhage. A pre-post questionnaire was administered with the module to evaluate effectiveness. McNemar tests were used to compare the responses and evaluate effectiveness of the education. RESULTS: Eighty-four percent of eligible employees (n = 4,845) completed the module and all items on the questionnaires. Three-quarters of respondents provided direct or ancillary care to patients, and one-quarter worked in nonclinical roles. On average, 57% of questions were answered correctly in the pre-questionnaire and 98% were answered correctly in the post-questionnaire. The module was effective for all employees regardless of clinical training. CONCLUSIONS: There is currently no succinct hemorrhage control education available that can be deployed across a large workplace environment. Results demonstrate that the brief learning module was effective in educating all employees in the basics of hemorrhage control. The module could be deployed in clinical and nonclinical settings. PMID- 28342653 TI - Antibiotic stewardship: Revisiting quinolone antibiotics. PMID- 28342654 TI - The Role of the Signal Intensity Ratio on Fluid-Attenuated Inversion Recovery in Stroke Patients Achieving Successful Recanalization with Endovascular Treatment. AB - BACKGROUND: This study aimed to investigate whether fluid-attenuated inversion recovery (FLAIR) imaging hyperintensity can be used as a surrogate marker for the severity of ischemic insult and predict lesion growth. METHODS: Based on a prospective stroke registry database, we identified patients with ischemic stroke who were treated with endovascular treatment (EVT) within 8 hours of onset and achieved successful recanalization (modified thrombolysis in cerebral infarction >=2B). FLAIR hyperintensity was measured using the signal intensity ratio (SIR), defined as the mean SIR of diffusion-restricted lesions to the corresponding areas in the contralateral hemisphere. Lesion growth was defined as the ratio of final infarct volume on follow-up FLAIR to initial infarct volume on diffusion weighted imaging. RESULTS: For 69 patients meeting the eligibility criteria, the median FLAIR SIR was 1.17 (interquartile range, 1.08-1.23) and the median lesion growth ratio was 1.70 (interquartile range, 1.35-2.79) (Pearson's r = -.146, P = .231). In multiple linear regression models, the FLAIR SIR was not significantly correlated with the lesion growth ratio. Interestingly, the time interval from initial magnetic resonance imaging (MRI) to successful recanalization was independently correlated with the lesion growth ratio (beta = .072, P < .001). With respect to clinical outcomes, the FLAIR SIR was not associated with either discharge modified Rankin scale score <=2 (beta = -3.41, P = .30) or symptomatic hemorrhagic transformation (beta = 2.75; P = .63). CONCLUSIONS: Contrary to our hypothesis, FLAIR hyperintensity on initial MRI before EVT was not associated with lesion growth in patients who were recanalized successfully with EVT. Instead, our results suggest that time interval from MRI acquisition to recanalization is an independent predictor of lesion growth. PMID- 28342656 TI - Nurses Are as Specific and Are Earlier in Calling In-Hospital Stroke Alerts Compared to Physicians. AB - INTRODUCTION: In-hospital stroke alerts are typically activated by nurses or physicians when a patient's neurological status acutely changes from baseline. It is unclear if knowledge of stroke symptoms translates to accurate activation of the acute stroke team. We hypothesized that nurses who activate the stroke alert system would correctly identify as great a proportion of acute strokes as physicians. We also investigated the time to activation of these in-hospital stroke alerts. METHODS: We retrospectively reviewed consecutive inpatient stroke team calls over a 12-month period at a single, tertiary care center. Calls and exact times were identified from the acute stroke pager log. The type of provider who called the stroke alert, patient characteristics, last known well time, and acute stroke symptoms was prospectively collected and retrospectively verified through electronic medical record review. Patients with definite stroke then were retrospectively identified by World Health Organization Monitoring of Trends and Determinants in Cardiovascular Disease (WHO MONICA) criterion. RESULTS: A total of 93 calls were analyzed. Nurses and physicians/midlevel providers activated the in-hospital stroke alert with a similar percentage of correct stroke diagnosis (62.7% versus 58.8%, P = .82). Nurses activated stroke alerts significantly earlier than physicians/midlevel providers (median 2 hours [IQR .5-6 hours] versus 4.9 hours [IQR 1.3-21.3 hours], P = .0096) from last known well time. CONCLUSIONS: Nurses identify in-hospital ischemic events with a similar percentage as physicians, and they activate the stroke alerts significantly earlier. The median nursing activation time fell within a 3-hour window for potential systemic thrombolytic or early endovascular therapy. An intensive, focused, collaborative education of nursing staff may further improve inpatient stroke outcomes. PMID- 28342655 TI - Tacrolimus-Induced Reversible Cerebral Vasoconstriction Syndrome with Delayed Multi-Segmental Vasoconstriction. AB - Reversible cerebral vasoconstriction syndrome (RCVS) is a cerebrovascular syndrome characterized by multi-segmental constrictions of the cerebral arteries that resolves spontaneously within 3 months. Although RCVS is considered to be due to transient dysregulation of vascular tone, the exact pathomechanism remains unclear. We describe the case of a 15-year-old girl with RCVS induced by tacrolimus, who developed generalized seizure during the postoperative course of orthotropic heart transplantation. Magnetic resonance imaging at symptom onset showed a few vasoconstrictions accompanying brain edema and convexity subarachnoid hemorrhage. Although her neurological conditions rapidly improved after discontinuing tacrolimus, a repeat magnetic resonance angiogram demonstrated delayed progression of the multi-segmental vasoconstrictions followed by subsequent resolution. Our case demonstrates that cautious observation of the cerebral arteries using magnetic resonance angiography and careful management of vasoconstrictions with vasodilators are necessary for delayed vasoconstrictions even when the clinical symptoms improve. PMID- 28342657 TI - Targeting BAP1: a new paradigm for mesothelioma. AB - New treatment strategies for malignant pleural mesothelioma (MPM) are important. BAP1 mutations are present in 47-67% of the MPM tumors, making this a good target for treatment. Multiple functions of BAP1 are investigated in the preclinical situation. Due to many functions of BAP1, the phenotypic effect of BAP1 is diverse. Preclinical data on inhibitors reversing these phenotypic effects are promising. However, the mechanism of BAP1 is not fully elucidated yet and further research about the mechanism and possible inhibitors is necessary. PMID- 28342658 TI - Educational needs of adolescents with congenital heart disease: Impact of a transition intervention programme. AB - BACKGROUND: Adolescents and young adults with congenital heart disease (CHD) have complex health needs and require lifelong follow-up. Interventions to facilitate the paediatric-to-adult healthcare transition are recommended, but outcomes remain largely under-investigated. AIMS: To identify the educational needs and the impact of a transition intervention on knowledge and self-management skills in adolescents and young adults with CHD. METHODS: From September 2014 to May 2015, 115 adolescents and young adults with CHD (mean age 17+/-2 years; 47 girls) were consecutively enrolled. Among these, 22 had participated in a structured educational programme in the previous 11+/-4 months (education group) and 93 had not (comparison group). Knowledge about their health status was assessed using a targeted CHD questionnaire. RESULTS: The mean overall health knowledge score (maximum of 20) in the education group was significantly higher than in the comparison group (11.7+/-3.5 vs. 8.6+/-3.2; P<0.001). We observed significant gaps in knowledge in the comparison group: e.g. 61.3% vs. 90.0% knew their condition name (P=0.01), 21.5% vs. 63.6% were aware of recommended follow-up (P=0.004), and 12.8% vs. 75.0% of girls knew to check their heart condition before pregnancy (P<0.01). In multivariable analysis, after adjustment for age, structured CHD education and higher academic attainment were significant determinants of health-related knowledge (P<0.01). CONCLUSION: Education during adolescent-to-adult transition has a significant impact on health knowledge. Structured CHD educational programmes could improve understanding and prevent potential future complications. PMID- 28342659 TI - Urologic Oncologic SurveyRobotic level III inferior vena cava tumor thrombectomy: Initial series. Gill IS, Metcalfe C, Abreu A, Duddalwar V, Chopra S, Cunningham M, Thangathurai D, Ukimura O, Satkunasivam R, Hung A, Papalia R, Aron M, Desai M, Gallucci M. J Urol. 2015 Oct;194(4):929-938. [Epub 2015 Apr 6]. doi: 10.1016/j.juro.2015.03.119. AB - PURPOSE: Level III inferior vena cava tumor thrombectomy for renal cancer is one of the most challenging open urologic surgeries. We present the initial series of completely intracorporeal robotic level III inferior vena cava tumor thrombectomy. MATERIALS AND METHODS: Nine patients underwent robotic level III inferior vena cava thrombectomy and 7 patients underwent level II thrombectomy. The entire operation (high intrahepatic inferior vena cava control, caval exclusion, tumor thrombectomy, inferior vena cava repair, radical nephrectomy, and retroperitoneal lymphadenectomy) was performed exclusively robotically. To minimize the chances of intraoperative inferior vena cava thrombus embolization, an "inferior vena cava-first, kidney-last" robotic technique was developed. Data were accrued prospectively. RESULTS: All 16 robotic procedures were successful, without open conversion or mortality. For level III cases (9), median primary kidney (right 6, left 3) cancer size was 8.5cm (range: 5.3-10.8) and inferior vena cava thrombus length was 5.7cm (range: 4-7). Median operative time was 4.9 hours (range: 4.5-6.3), estimated blood loss was 375ml (range: 200-7,000), and hospital stay was 4.5 days. All surgical margins were negative. There were no intraoperative complications and 1 postoperative complication (Clavien 3b). At a median 7 months of follow-up (range: 1-18) all patients are alive. Compared to level II thrombi the level III cohort trended toward greater inferior vena cava thrombus length (3.3 vs 5.7cm), operative time (4.5 vs 4.9h) and blood loss (290 vs 375ml). CONCLUSIONS: With appropriate patient selection, surgical planning and robotic experience, completely intracorporeal robotic level III inferior vena cava thrombectomy is feasible and can be performed efficiently. Larger experience, longer follow-up and comparison with open surgery are needed to confirm these initial outcomes. PMID- 28342660 TI - Caveolin-1 as prognostic factor of disease recurrence and survival in patients treated with radical cystectomy for bladder cancer. AB - PURPOSE: Overexpression of Caveolin-1 has been associated with cancer growth, migration, and metastases in several malignancies, but only few data are available on its role in bladder cancer (BCa). The aim of this study is to validate Caveolin-1 as a prognosticator of recurrence-free survival (RFS), overall survival (OS) and cancer-specific survival (CSS) in a large cohort of patients treated with radical cystectomy (RC) for BCa. METHODS: Caveolin-1 expression was evaluated by immunochemistry on a tissue microarray from 424 patients treated with RC for UCB at a single institution. Caveolin-1 was considered overexpressed when at least 50% of the tumor cells stained positively. Univariable and multivariable Cox proportional hazards regression models were used to assess the association of Caveolin-1 expression with RFS, OS, and CSS. RESULTS: Overexpression of Caveolin-1 was observed in 116 (27.4%) patients and was associated with lymph node metastasis (P = 0.003). Median follow-up for patients alive at last follow-up was 129 months (interquartile range [IQR]: 82 178). Patients with overexpression of Caveolin-1 had significant worse RFS, OS, and CSS compared to those with normal expression (log-rank test, P = 0.008, P = 0.001, and P = 0.005, respectively). At multivariable analyses that adjusted for the effects of standard clinicopathologic features, Caveolin-1 remained associated with OS (hazard ratio = 1.47, P = 0.002) and CSS (hazard ratio = 1.42, P = 0.03). Conversely, no association with RFS was found (P = 0.1). Addition of Caveolin-1 in a model for prediction of survival did not improve the accuracy of the prognostic model. Actually, C-index did not differ among models with or without Caveolin-1 (0.72 for a model predicting RFS, 0.65 for OS, and 0.71 for CSS). CONCLUSIONS: Caveolin-1 is overexpressed in one-third of patients with BCa treated with RC. Overexpression of Caveolin-1 is significantly associated with OS and CSS, but not with RFS, in patients with BCa treated with RC. However, it is not clinically useful as it does not improve upon the predictive accuracy of survival achieved by pathologic variables alone. PMID- 28342661 TI - Climate change and human infectious diseases: A synthesis of research findings from global and spatio-temporal perspectives. AB - The life cycles and transmission of most infectious agents are inextricably linked with climate. In spite of a growing level of interest and progress in determining climate change effects on infectious disease, the debate on the potential health outcomes remains polarizing, which is partly attributable to the varying effects of climate change, different types of pathogen-host systems, and spatio-temporal scales. We summarize the published evidence and show that over the past few decades, the reported negative or uncertain responses of infectious diseases to climate change has been growing. A feature of the research tendency is the focus on temperature and insect-borne diseases at the local and decadal scale. Geographically, regions experiencing higher temperature anomalies have been given more research attention; unfortunately, the Earth's most vulnerable regions to climate variability and extreme events have been less studied. From local to global scales, agreements on the response of infectious diseases to climate change tend to converge. So far, an abundance of findings have been based on statistical methods, with the number of mechanistic studies slowly growing. Research gaps and trends identified in this study should be addressed in the future. PMID- 28342663 TI - Intramural coronary hematoma, a complex three-dimensional entity: Multimodality assessment. AB - A 62-year-old woman was admitted with chest pain of two hours' duration, ECG changes in the precordial leads and left ventricular ejection fraction of 30% on the echocardiogram. Emergent catheterization demonstrated severe flow disturbance in the left coronary artery. An intra-aortic balloon pump and a drug-eluting stent were implanted. However, the flow disturbance persisted. Optical coherence tomography followed by intravascular ultrasound provided crucial data on the mechanism and helped to optimize treatment in this critical patient. PMID- 28342662 TI - Use of BRCA Mutation Test in the U.S., 2004-2014. AB - INTRODUCTION: BRCA mutation testing has been used for screening women at high risk of breast and ovarian cancer and for selecting the best treatment for those with breast cancer. To optimize the infrastructure and medical resources allocation for genetic testing, it is important to understand the use of BRCA mutation testing in the U.S. health system. METHODS: This retrospective cohort study included 53,254 adult women with insurance claims for BRCA mutation testing between 2004 and 2014 from ClinformaticsTM Data Mart Database. Data analysis was performed in 2016. This study assessed trends in the use of BRCA mutation testing in women with previously diagnosed breast or ovarian cancer and those without (unaffected women). RESULTS: Between 2004 and 2014, of those receiving BRCA testing, the proportion of BRCA tests performed in unaffected women increased significantly (p<0.001), from 24.3% in 2004 to 61.5% in 2014. An increase in the proportion of BRCA tests used in unaffected women was found in each characteristic subgroup. In 2014, most subgroups had a proportion surpassing 50%, except for those aged 51-65 years and those without a family history of breast cancer. There was a much lower proportion of those aged 20-40 years among tested women with previously diagnosed breast or ovarian cancer than in unaffected women (17.6% vs 41.7%, p<0.001). CONCLUSIONS: During the past decade, the role of BRCA testing has gradually shifted from being used primarily in cancer patients to being used in unaffected women in the U.S. PMID- 28342664 TI - A novel live attenuated anthrax spore vaccine based on an acapsular Bacillus anthracis Sterne strain with mutations in the htrA, lef and cya genes. AB - We recently reported the development of a novel, next-generation, live attenuated anthrax spore vaccine based on disruption of the htrA (High Temperature Requirement A) gene in the Bacillus anthracis Sterne veterinary vaccine strain. This vaccine exhibited a highly significant decrease in virulence in murine, guinea pig and rabbit animal models yet preserved the protective value of the parental Sterne strain. Here, we report the evaluation of additional mutations in the lef and cya genes, encoding for the toxin components lethal factor (LF) and edema factor (EF), to further attenuate the SterneDeltahtrA strain and improve its compatibility for human use. Accordingly, we constructed seven B. anthracis Sterne-derived strains exhibiting different combinations of mutations in the htrA, cya and lef genes. The various strains were indistinguishable in growth in vitro and in their ability to synthesise the protective antigen (PA, necessary for the elicitation of protection). In the sensitive murine model, we observed a gradual increase (DeltahtrA107spores) of the most attenuated triple mutant strain SterneDeltahtrAlefMUTDeltacya induced a robust immune response, providing complete protection against a subsequent respiratory lethal challenge. Partial protection was observed in animals vaccinated with a double dose of as few as 105spores. Furthermore, protective immune status was maintained in all vaccinated guinea pigs and rabbits for at least 40 and 30weeks, respectively. PMID- 28342666 TI - Stabilization study of inactivated foot and mouth disease virus vaccine by size exclusion HPLC and differential scanning calorimetry. AB - The inactivated foot and mouth disease virus (FMDV), which has a sedimentation coefficient of 146S, is crucial to the efficacy of vaccine preparations, but extremely unstable in vitro. It is prone to dissociate into smaller particles referred to as 12S with a concomitant decrease in immunogenicity; therefore, it is of great importance to find the best condition for stabilizing the FMDV. In the present work, the effects of solution pH and temperature on the dissociation of 146S was investigated and potential stabilizers were screened, with aid of high-performance size-exclusion chromatography (HPSEC) for rapid and quantitative determination of 146S, together with differential scanning calorimetry (DSC) technology for thermal stability analysis. The most stable pH was found between 7.5 and 8.0. Among excipients tested, sucrose and glycerol provided the best protection, such that the half-life of 146S in solution at 45 degrees C could be prolonged from less than 30min to more than 3days by adding 20% sucrose. The stabilization mechanism was confirmed using DSC analysis, which showed that the transition temperature related to 146S dissociation was increased by 5.4 degrees C in the presence of 20% sucrose. The physical stabilization effects afforded by these stabilizers would allow for the retaining of effective 146S antigens during transportation and storage under relative harsh condition. PMID- 28342665 TI - Recombinant Newcastle disease virus expressing the infectious bronchitis virus S1 gene protects chickens against Newcastle disease virus and infectious bronchitis virus challenge. AB - The recombinant LaSota strain expressing a chimeric IBV S1 gene (rLaSota-S1) was constructed with the S1 gene of the LX4 type IBV ck/CH/LDL/091022. The expression of the S1 protein was detected by an indirect immunofluorescence assay and Western blotting. The rLaSota-S1 strain was slightly attenuated, and its growth dynamics were similar to that of the parental LaSota strain. Vaccination of specific pathogen-free chickens with the rLaSota-S1 strain induced NDV hemagglutination inhibition antibodies, and it protected chickens from challenge with virulent NDV. In addition, vaccination with the rLaSota-S1 strain induced IBV-specific IgG antibodies and cellular immunity; however, a single vaccination provided partial protection with reduced virus shedding. Better protection efficiency was observed after a booster vaccination, which resulted in higher antibody titers, significantly fewer disease symptoms, and reduced virus replication and shedding. Our results suggest that the rLaSota-S1 strain is a bivalent vaccine candidate against both NDV and IBV. PMID- 28342667 TI - A fast and efficient purification platform for cell-based influenza viruses by flow-through chromatography. AB - Since newly emerging influenza viruses with pandemic potentials occurred in recent years, the demand for producing pandemic influenza vaccines for human use is high. For the development of a quick and efficient vaccine production, we proposed an efficient purification platform from the harvest to the purified bulk for the cell-based influenza vaccine production. This platform based on flow through chromatography and filtration steps and the process only involves a few purification steps, including depth filtration, inactivation by formaldehyde, microfiltration, ultrafiltration, anion-exchange and ligand-core chromatography and sterile filtration. In addition, in the proposed chromatography steps, no virus capture steps were employed, and the purification results were not affected by the virus strain variation, host cells and culturing systems. The results from different virus strains which produced by Vero or MDCK cells in different culturing systems also obtained 33-46% HA recovery yields by this platform. The overall removal rates of the protein and DNA concentration in the purified bulk were over 96.1% and 99.7%, respectively. The low residual cellular DNA concentrations were obtained ranged from 30 to 130pg per human dose (15ug/dose). All influenza H5N1 purified bulks met the regulatory requirements for human vaccine use. PMID- 28342668 TI - The herd effects of infant PCV7/PCV13 sequential implementation on adult invasive pneumococcal disease, six years post implementation; a nationwide study in Israel. AB - BACKGROUND: Introduction of pneumococcal conjugate vaccine (PCV) has nearly eliminated vaccine-type (VT) invasive pneumococcal disease (IPD) in children, yet the reported resulting reduction of adult IPD is variable. We present the indirect impact of sequential PCV7/PCV13 implementation in Israel on adult IPD. METHODS: An ongoing nationwide active surveillance was initiated on July 2009 when PCV7 was implemented (with Catch-up). PCV7 was gradually replaced by PCV13 since November 2010. Comorbidity and outcome data were collected from medical files. Incidence rates were calculated for overall and vaccine-type IPD. RESULTS: A total of 2579 IPD cases were diagnosed among a population of 5.0-5.5 million adults >18y (2009-2015). Incidence rates were 9.15/100,000 and 10.16/100,000 in the first and second study years, respectively. However, after PCV13 implementation, the rates decreased to 7.19 within four years, and remained stable in the two following years. Within 6years, PCV7-VT-IPD incidence decreased from 2.52 to 0.52 (79%) and PCV13-VT-IPD from 6.15 to 1.81 (71%). Concurrently, non-VT13 incidence increased from 2.99 to 5.25. Approximately 50% of all patients were adults >=65y, in whom the decrease in PCV13-VT-IPD incidence was smaller and slower (65% vs. >80% decrease in adults <50y). CONCLUSIONS: Despite continued reduction in PCV13-VT-IPD, overall IPD was stable during the last two years due to serotype replacement. Yet, the significant decrease in adult IPD, six years post-PCV7/13 implementation emphasizes the importance of indirect protection in achieving overall population impact and should be considered when discussing the potential additional benefits of direct adult PCV vaccination. PMID- 28342669 TI - Extended protection capabilities of an immature dendritic-cell targeting malaria sporozoite vaccine. AB - Mouse studies evaluating candidate malaria vaccines have typically examined protective efficacy over the relatively short time frames of several weeks after the final of multiple immunizations. The current study examines the protective ability in a mouse model system of a novel protein vaccine construct in which the adjuvant polyinosinic polycytidilic acid (poly(I:C)) is used in combination with a vaccine in which the immature dendritic cell targeting chemokine, macrophage inflammatory protein 3 alpha (MIP3alpha), is fused to the circumsporozoite protein (CSP) of Plasmodium falciparum (P. falciparum). Two vaccinations, three weeks apart, elicited extraordinarily high, MIP3alpha-dependent antibody responses. MIP3alpha was able to target the vaccine to the CCR6 receptor found predominantly on immature dendritic cells and significantly enhanced the cellular influx at the vaccination site. At three and 23 weeks after the final of two immunizations, mice were challenged by intravenous injection of 5*103 transgenic Plasmodium berghei sporozoites expressing P. falciparum CSP, a challenge dose approximately one order of magnitude greater than that which is encountered after mosquito bite in the clinical setting. A ninety-seven percent reduction in liver sporozoite load was observed at both time points, 23 weeks being the last time point tested. PMID- 28342670 TI - Chemical composition and acaricide activity of an essential oil from a rare chemotype of Cinnamomum verum Presl on Rhipicephalus microplus (Acari: Ixodidae). AB - The Essential Oils (EOs) from the leaves of species Cinnamomum verum J. Presl are used in the pharmaceutical industry for their numerous biological activities. Currently, the main compound of C. verum EO is eugenol which has acaricidal activity; however, a rare chemotype with benzyl benzoate as the main component can be found. Benzyl benzoate is recognized as an acaricide; however, studies of the C. verum EOs benzyl benzoate chemotype on Rhipicephalus microplus were not reported. The aim of this study was to evaluate the acaricide activity of an EO from a rare chemotype of C. verum, as well as purified benzyl benzoate, against larvae and engorged females of R. microplus resistant to amidines and pyrethroids. The EO was extracted from C. verum leaves and the compounds present were identified using a gas phase chromatograph coupled to a mass spectrometer. Efficacy against R. microplus was assessed by the larval packet and the engorged female immersion tests. A rare chemotype of C. verum was found to produce EOs with benzyl benzoate (65.4%) as the main compound. The C. verum essential oil was 3.3 times more efficient on the R. microplus larvae than was benzyl benzoate. However, no differences were found on the R. microplus engorged females. This is the first report regarding the acaricidal activity of C. verum with chemotype benzyl benzoate, and this compound showed acaricidal activity on R. microplus larvae. PMID- 28342671 TI - Apoptosis of peritoneal leucocytes during early stages of Fasciola hepatica infections in sheep. AB - Several immunomodulatory properties have been described in Fasciola hepatica infections. Apoptosis has been shown to be an effective mechanism to avoid the immune response in helminth infections. The aim of the present work was to study apoptosis in peritoneal leucocytes of sheep experimentally infected with F. hepatica during the early stages of infection. Five groups (n=5) of sheep were used. Groups 2-5 were orally infected with 200 metacercariae (mc) and sacrificed at 1, 3, 9 and 18days post-infection (dpi), respectively. Group 1 was used as the uninfected control (UC). Apoptosis was detected using three different methods 1) immunocytochemistry (ICC) with a polyclonal antibody anti-active caspase-3; 2) an annexin V flow cytometry assay using the Annexin V-FITC/propidium iodide (PI); and 3) transmission electron microscopy (TEM). The differential leucocyte count revealed that the majority of peritoneal granulocytes were eosinophils, which increased significantly at 9 and 18 dpi with respect to the uninfected controls. The ICC study revealed that the percentage of caspase-3+ apoptotic peritoneal leucocytes increased significantly from 3 dpi onwards with respect to the uninfected controls. The flow cytometry annexin V assay detected a very significant (P<0.001) increase of apoptotic peritoneal macrophages, lymphocytes and granulocytes, which remained higher than in the UC until 18 dpi. Transmission electron microscopy studies also confirmed the presence of apoptosis in peritoneal eosinophils at 18 dpi. This is the first report of apoptosis induced by F. hepatica in the peritoneal leucocytes of sheep in vivo. The results of this work suggest the importance of apoptosis induction for the survival of the juvenile parasites in the peritoneal migratory stages of infection. PMID- 28342672 TI - An in vitro larval migration assay for assessing anthelmintic activity of different drug classes against Ascaris suum. AB - In vitro methods have been developed for the detection of anthelmintic resistance in a range of nematode species. However, the life cycle of Ascaris suum renders the commonly used egg hatch assay and larval development assay unusable. In this study we developed a combined multi-well culture and agar gel larval migration assay to test the effect of benzimidazole and tetrahydropyrimidin/imidazothiazole anthelmintics against nine isolates of A. suum collected from locations in China and Denmark. Drugs tested were thiabendazole, fenbendazole, mebendazole, levamisole, and pyrantel. The percentages of larvae that migrated to the surface of each treated and control well were used to calculate the drug concentration which inhibits 50% of the larvae migration (EC50). The values of EC50 of thiabendazole, fenbendazole, mebendazole, levamisole, and pyrantel against A. suum isolates ranged 74-150, 4.9-13.9, 2.3-4.3, 358-1150 and 1100-4000nM, respectively. This combined multi-well culture and agar gel larval migration assay was a sensitive bioassay for anthelmintic activity and could serve as an in vitro method to detect for lowered drug efficacy against A. suum or possibly to screen for anthelmintic drug candidates. PMID- 28342673 TI - Therapeutic use of Bacillus thuringiensis in the treatment of psoroptic mange in naturally infested New Zealand rabbits. AB - Bacillus thuringiensis is a bacteria known for its bioinsecticidal toxins and it has been proposed as an alternative in the treatment of several parasites that infect domestic animals (helminths, ticks, mites). In this work, we evaluated the clinical efficiency of the Bacillus thuringiensis GP532 strain in the treatment of six rabbits naturally infested with the P. cuniculi mite. GP532 extract (10mg/ml) was applied by aspersion in both pinna, with a second application after seven days, and the therapeutic effect was measured in both qualitative and quantitative manner. GP532 application resulted in a decreased infestation rate, which was observed as early as 3days post-treatment. At day 14, a decrease from 4.66+/-0.61 to 0.50+/-0.10 in the left pinna and from 1.66+/-0.21 to 0.66+/-0.16 (P<0.05) in the right pinna was observed. This response was comparable to the commercial drug Ivermectin, which induced a decreased infestation rate from 4.00+/-0.51 to 0.16+/-0.10 in the left pinna and from 4.66+/-0.80 to 0.25+/-0.11 in the right pinna (P<0.05). At day 30 post-treatment, GP532 decreased the total infested area by 76.80+/-16.06%, whereas Ivermectin resulted in a 97.41+/-0.99% decrease. Neither treatment produced irritation or macroscopic lesions. Our results show that the B. thuringiensis GP532 strain has a therapeutic potential in the treatment of psoroptic mange in rabbits. PMID- 28342674 TI - Mindfulness predicts student nurses' communication self-efficacy: A cross national comparative study. AB - OBJECTIVES: The aim of this study was to compare student nurses' communication self-efficacy, empathy, and mindfulness across two countries, and to analyse the relationship between these qualities. METHODS: The study had a cross-sectional design. Data was collected from final year student nurses in Norway and Sweden. Communication self-efficacy, empathy, and mindfulness were reported by questionnaires; Clear-cut communication with patients, Jefferson Scale of Empathy, and Langer 14 items mindfulness scale. RESULTS: The study included 156 student nurses, 94 (60%) were Swedish. The mean communication self-efficacy score was 119 (95% CI 116-122), empathy score 115 (95% CI 113-117) and mindfulness score 79 (95% CI 78-81). A Mann-Whitney test showed that Swedish students scored significantly higher on communication self-efficacy, empathy, and mindfulness than Norwegian students did. When adjusted for age, gender, and country in a multiple linear regression, mindfulness was the only independent predictor of communication self-efficacy. CONCLUSION: The Swedish student nurses in this study scored higher on communication self-efficacy, empathy, and mindfulness than Norwegian students did. Student nurses scoring high on mindfulness rated their communication self-efficacy higher. PRACTICE IMPLICATIONS: A mindful learning approach may improve communication self-efficacy and possibly the effect of communication skills training. PMID- 28342675 TI - The Digital Heart Manual: A pilot study of an innovative cardiac rehabilitation programme developed for and with users. AB - OBJECTIVE: Patients are seeking greater choice and flexibility in how they engage with self-management programmes. While digital innovations offer opportunities to deliver supportive interventions to patients undergoing cardiac rehabilitation little is known about how accessible, useful and acceptable they are for this group. This project developed a digital version of a leading evidenced cardiac rehabilitation programme, the Heart Manual (HM). The prototype was developed and evaluated iteratively in collaboration with end users. METHODS: Using a mixed methods design 28 participants provided feedback using semi-structured questionnaires and telephone interviews. RESULTS: Rich data revealed the perceived user-friendliness of the HM digital format and its effectiveness at communicating the programme's key messages. It flagged areas requiring development, such as more flexible and intuitive navigation pathways. These suggestions informed the refinement of the resource. CONCLUSION: This evaluation offers support for the new Digital Heart Manual and confirms the value of employing a user-centred approach when developing and improving online interventions. The system is now in use and recommendations from the evaluation are being translated into quality improvements. PRACTICE IMPLICATIONS: The Digital Heart Manual is user friendly and accessible to patients and health professionals, regardless of age, presenting a suitable alternative to the paper version. PMID- 28342676 TI - [Role of nuclear medicine in the differential diagnosis of bone infarction and osteomyelitis in drepanocytosis]. PMID- 28342677 TI - Prevalence of Voice Disorders in Singers: Systematic Review and Meta-Analysis. AB - OBJECTIVE: The study aimed to review the prevalence of self-reported voice disorders in singers. STUDY DESIGN: The study is a systematic review and meta analysis. METHODS: A systematic review of five major scientific databases was conducted. An extensive search strategy was used considering the rules of each database. Original articles were included only if they had data related to self perception of dysphonia in the past. Furthermore, heterogeneity and its relative significance were assessed. RESULTS: There were 2371 articles identified; duplicates were deleted, screenings were conducted, and inclusion and exclusion criteria were applied. The final analysis was conducted on 11 studies. The most implemented instruments for the study were customized questionnaires. The findings about singing styles, voice use, and age were found to be different among subjects. The overall prevalence of self-reported dysphonia in singers was 46.09% (95% confidence interval: 38.16-54.12). The heterogeneity was considerable among the studied samples (I2 = 90.59%). Four groups were then established students, teachers, classical, and nonclassical-and compared regarding overall prevalence (21.76% in students, and significantly higher and nondifferent in the other three groups, 55.15%, 40.53%, and 46.96%, respectively) and heterogeneity (low only for the students' studies). CONCLUSION: Although with low homogeneity, singers present a high prevalence of self-perceived dysphonia over their careers. Singing students were the group with a lower prevalence. On the other hand, traditional and popular music singers, as well as singing teachers, revealed significantly higher prevalence of self-perceived dysphonia. Overall, singers are likely to report voice disorders, no matter their singing style or skills. This highlights the need of a preventive approach to address voice disorders in traditional and untrained singers. PMID- 28342678 TI - Spontaneous coronary artery intramural hematoma in a patient with vascular Ehlers Danlos syndrome: Serial findings in coronary computed tomographic angiography. PMID- 28342679 TI - Pharmacogenomic aspects of bipolar disorder: An update. AB - The hopes for readily implementable precision medicine are high. For many complex disorders, such as bipolar disorder, these hopes critically hinge on tangible successes in pharmacogenetics of treatment response or susceptibility to adverse events. In this article, we review the current state of pharmacogenomics of bipolar disorder including latest results from candidate genes and genome-wide association studies. The majority of studies focus on response to lithium treatment. Although a host of genes has been studied, hardly any replicated findings have emerged so far. Very small samples sizes and heterogeneous phenotype definition may be considered the major impediments to success in this field. Drawing from current experiences and successes in studies on diagnostic psychiatric phenotypes, we suggest several approaches for our way forward. PMID- 28342681 TI - Understanding the usefulness of prognostic models in clinical decision-making. PMID- 28342680 TI - Late gastrobronchial fistula postsleeve gastrectomy. PMID- 28342682 TI - A home program of strength training, movement strategy training and education did not prevent falls in people with Parkinson's disease: a randomised trial. AB - QUESTIONS: For people with idiopathic Parkinson's disease, does a 6-week, comprehensive, home exercise program reduce falls and disability and improve health-related quality of life? Is the program cost-effective? DESIGN: Randomised, controlled trial with concealed allocation and assessor blinding. PARTICIPANTS: One hundred and thirty-three community-dwelling adults with Parkinson's disease. INTERVENTION: The experimental group completed a 6-week home program comprising progressive resistance strength training, movement strategy training and falls education. The control group completed 6 weeks of non-specific life skills training. Participants in both groups received weekly therapist guided sessions for 6 consecutive weeks and a weekly self-directed home program. OUTCOME MEASURES: The primary outcome was the rate of falls, documented for the 12-month period immediately after therapy. Secondary outcomes were disability and health-related quality of life, assessed before and after intervention and at a 12-month follow-up. RESULTS: A total of 2255 falls were reported by the 12-month follow-up. The proportion of fallers in the experimental and control groups was 61 and 72%, respectively, which was not statistically significantly different (RR=0.85, 95% CI 0.66 to 1.09). There was no significant between-group difference in the rate of falls (incidence rate ratio=1.58, 95% CI 0.73 to 3.43). A survival analysis of participant time to first fall did not show a significant between group difference (log-rank test chi2=0.79, p=0.37). No significant between-group differences occurred for mobility, disability or quality of life. The mean cost of delivering the experimental intervention was AUD1596. CONCLUSION: A home program of strength and movement strategy training and falls education does not prevent falls when applied at the dose used in this study. Arguably, the dosage of therapy was insufficient. Future trials need to explore further therapy content, repetitions and duration, in order to optimise outcomes and cost effectiveness. [Morris ME, Taylor NF, Watts JJ, Evans A, Horne M, Kempster P, Danoudis M, McGinley J, Martin C, Menz HB (2017) A home program of strength training, movement strategy training and education did not prevent falls in people with Parkinson's disease: a randomised trial. Journal of Physiotherapy 63: 94-100]. PMID- 28342683 TI - White Grape Juice Elicits a Lower Breath Hydrogen Response Compared with Apple Juice in Healthy Human Subjects: A Randomized Controlled Trial. AB - BACKGROUND: Diets low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPS) are used to manage symptoms in individuals with irritable bowel syndrome. Although effective at reducing symptoms, the diet can be complex and restrictive. In addition, there are still large gaps in the literature and many foods with unclear effects in the gastrointestinal (GI) tract, like fruit juice. Although many fruits are allowable on a low-FODMAP diet, consumption of all fruit juice is generally cautioned due to the large fructose load contained in juice, regardless of the glucose concentration. Very little research exists regarding the importance of limiting fructose load during a low FODMAP diet; therefore, individuals following a low-FODMAP diet may be unnecessarily restricting their diets. OBJECTIVE: To determine whether there is a difference in GI tolerance between juice from a high-FODMAP fruit (apple juice) and juice from a low-FODMAP fruit (white grape juice) in healthy human subjects. The goal is to provide insight into the role of juice in a low-FODMAP diet. METHODS: A double-blind, randomized, controlled crossover study was conducted with 40 healthy adults. Fasted subjects consumed 12 oz of either apple juice or white grape juice. Breath hydrogen measures were taken at baseline, 1, 2, and 3 hours. Subjective GI tolerance surveys were completed at the same time intervals and at 12 and 24 hours. Breath hydrogen and GI symptoms were assessed with area under the curve analysis. Significance was determined with a two-sided t test with a P value <0.05. RESULTS: Consumption of apple juice resulted in a greater mean breath hydrogen area under the curve at 23.3 ppm/hour (95% CI 13.0 to 33.6) compared with white grape juice at 5.8 ppm/hour (95% CI -4.6 to 16.1) (P<0.001). No differences in reported GI symptoms were seen between treatments. CONCLUSIONS: Both juices were well tolerated and neither produced any severe symptoms in healthy adults. White grape juice consumption resulted in only a small rise in breath hydrogen, which may suggest excluding foods only because of the high fructose load could be unnecessarily restrictive. The results of this study suggest that the fructose-to-glucose ratio is likely more important than the total fructose load of the food when considering the acceptability of a food on a low-FODMAP diet. More research is needed in individuals with irritable bowel syndrome to determine whether white grape juice and other juices from low-FODMAP fruits could be additional beverage options for individuals following a low FODMAP diet. PMID- 28342684 TI - Persistent pulmonary hypertension of the newborn. AB - Failure of the normal circulatory adaptation to extrauterine life results in persistent pulmonary hypertension of the newborn (PPHN). Although this condition is most often secondary to parenchymal lung disease or lung hypoplasia, it may also be idiopathic. PPHN is characterized by elevated pulmonary vascular resistance with resultant right-to-left shunting of blood and hypoxemia. Although the preliminary diagnosis of PPHN is often based on differential cyanosis and labile hypoxemia, the diagnosis is confirmed by echocardiography. Management strategies include optimal lung recruitment and use of surfactant in patients with parenchymal lung disease, maintaining optimal oxygenation and stable blood pressures, avoidance of respiratory and metabolic acidosis and alkalosis, and pulmonary vasodilator therapy. Extracorporeal membrane oxygenation is considered when medical management fails. Although mortality associated with PPHN has decreased significantly with improvements in medical care, there remains the potential risk for neurodevelopmental disability which warrants close follow-up of affected infants after discharge. PMID- 28342685 TI - Hiding in Plain Sight. PMID- 28342687 TI - Analysis of the best available techniques for wastewaters from a denim manufacturing textile mill. AB - The present study was undertaken as the first plant scale application and evaluation of Best Available Techniques (BAT) within the context of the Integrated Pollution Prevention and Control/Industrial Emissions Directive to a textile mill in Turkey. A "best practice example" was developed for the textile sector; and within this context, BAT requirements for one of the World's leading denim manufacturing textile mills were determined. In order to achieve a sustainable wastewater management; firstly, a detailed wastewater characterization study was conducted and the possible candidate wastewaters to be reused within the mill were identified. A wastewater management strategy was adopted to investigate the possible reuse opportunities for the dyeing and finishing process wastewaters along with the composite mill effluent. In line with this strategy, production processes were analysed in depth in accordance with the BAT Reference Document not only to treat the generated wastewaters for their possible reuse, but also to reduce the amount of water consumed and wastewater generated. As a result, several applicable BAT options and strategies were determined such as reuse of dyeing wastewaters after treatment, recovery of caustic from alkaline finishing wastewaters, reuse of biologically treated composite mill effluent after membrane processes, minimization of wash water consumption in the water softening plant, reuse of concentrate stream from reverse osmosis plant, reducing water consumption by adoption of counter-current washing in the dyeing and finishing processes. The adoption of the selected in process BAT options for the minimization of water use provided a 30% reduction in the total specific water consumption of the mill. The treatability studies adopted for both segregated and composite wastewaters indicated that nanofiltration is satisfactory in meeting the reuse criteria for all the wastewater streams considered. PMID- 28342686 TI - Taiji (Tai Chi) For Fall Prevention in the Elderly: Training the Trainers Evaluation Project. AB - Falls in the elderly are common and a major, costly health problem. Taiji addresses many issues related to fall risk. We determined whether intensive weekend training can sufficiently train persons who have baseline familiarity with Taiji to model and teach fundamentals of Taiji to the elderly. Prior to training, registrants received a manual, video and online links for review and practice. Assessments were completed pre-/post-training. Training occurred in four cities of one state. 34 adults completed training, two did not complete evaluations (ns = 12, 13, 4, and 5 at the four sites). Each training course consisted of two 9-hour days that educated prospective instructors on issues pertinent to the elderly, evaluation techniques, warm-up and cool-down movements and seated and standing Taiji postures. Assessments included pre-/post-knowledge test, Timed Up, and Go and Functional Reach Assessment. Nearly all participants with pre-/post-assessments (30/32, 94%) demonstrated adequate skills post training. Knowledge of Taiji increased significantly from pre- to post-training (P < .01). Brief, intensive weekend training can increase the available workforce to train the elderly in fundamentals of Taiji for fall prevention. PMID- 28342688 TI - In-hospital mortality, 30-day readmission, and length of hospital stay after surgery for primary colorectal cancer: A national population-based study. AB - INTRODUCTION: The simultaneous assessment of multiple indicators for quality of care is essential for comparisons of performance between hospitals and health care systems. The aim of this study was to assess the rates of in-hospital mortality and 30-day readmission and length of hospital stay (LOS) in patients who underwent surgical procedures for colorectal cancer between 2005 and 2014 in Italy. METHODS: All patients in the National Italian Hospital Discharge Dataset who underwent a surgical procedure for colorectal cancer during the study period were included. The adjusted odd ratios for risk factors for in-hospital mortality, 30-day readmission, and LOS were calculated using multilevel multivariable logistic regression. RESULTS: Among the 353 941 patients, rates of in-hospital mortality and 30-day readmission were 2.5% and 6%, respectively, and the median LOS was 13 days. High comorbidity, emergent/urgent admission, male gender, creation of a stoma, and an open approach increased the risks of all the outcomes at multivariable analysis. Age, hospital volume, hospital geographic location, and discharge to home/non-home produced different effects depending on the outcome considered. The most frequent causes of readmission were infection (19%) and bowel obstruction (14.6%). CONCLUSIONS: We assessed national averages for mortality, LOS and readmission and related trends over a 10-year time. Laparoscopic surgery was the only one that could be modified by improving surgical education. Higher hospital volume was associated with a LOS reduction, but our findings only partially support a policy of centralization for colorectal cancer procedures. Surgical site infection was identified as the most preventable cause of readmission. PMID- 28342689 TI - Induction of out-of-season egg laying by artificial photoperiod in Yangzhou geese and the associated endocrine and molecular regulation mechanisms. AB - This study was carried out to induce out-of-season breeding, in the summer, and to achieve high reproductive performance using artificial photoperiod manipulation in the long-day breeding Yangzhou goose. Young geese were subject to a two-phase short-to-long (group A) or a three-phase (long-short-long; group B) photoperiod program February through October. Egg-laying was induced to start similarly in both groups in May, increased to a peak level in July, and then decreased gradually through to October. The peak and post-peak laying rates were higher with the three-phase than with the two-phase program. Plasma progesterone concentrations changed similarly in the two groups, increasing from low levels during the pre-lay periods until the peak laying stage, then decreasing with decline in the egg-laying rate. Plasma T3 concentrations increased from the beginning of the experiment to form the first peak under a short photoperiod, declined to a trough at peak lay and then progressively increased to high levels towards the end of the experiment. Plasma T4 concentrations increased throughout the experiment, showing little response to changes in photoperiod. GnIH mRNA expression level in the hypothalamus steadily decreased from high levels under the short photoperiod to a nadir at peak of lay, but was abruptly up-regulated by over a thousand-fold thereafter. This mRNA expression pattern was also shared by GnIHR, VIPR, TRHR, TSH, and PRL genes in the pituitary gland, and to lesser extent, by GnRH, VIP, and TRH genes in the hypothalamus. Pituitary GnRHR mRNA expression levels changed in a similar manner to that of reproductive activities of geese in both groups. FSH beta subunits mRNA expression levels increased to high levels after day 11 of the long photoperiod, and were higher in group B than in group A at peak laying. LH beta gene expression level was similarly upregulated by photoperiod and was higher in group B than in group A when used the multivariable and two-way analyses of variance. Taken together, photoperiod, through regulation of expression of an array of genes in the hypothalamus and pituitary gland, synchronized stimulation and refractoriness of the reproductive system in Yangzhou geese. The higher out-of-season egg laying performance following the three-phase photo-program treatment was mediated by higher FSH beta and LH beta subunit mRNA expression levels. PMID- 28342690 TI - Correlation, Causation and Confounding-What Is the True Risk of Lung Cancer following Breast Cancer Radiotherapy? PMID- 28342691 TI - Indenocinnoline derivatives as G-quadruplex binders, topoisomerase IIalpha inhibitors and antiproliferative agents. AB - DNA intercalating agents are a consolidated therapeutic option in the treatment of tumor diseases. Starting from previous findings in the antiproliferative efficacy of a series of indeno[1,2-c]cinnoline-11-one derivatives, we performed a suitable decoration of this scaffold by means of a simple and straightforward chemistry, aiming to a) enlarge the planar core to a pentacyclic benzo[h]indeno[1,2-c]cinnoline-13-one and b) introduce a basic head tethered through a simple polymethylene chain. In fluorescence melting and fluorescence intercalator displacement assays, these new compounds displayed fair to very good intercalating properties on different nucleic acid strands, with preference for G quadruplex sequences. Inhibition of human topoisomerase IIalpha and antiproliferative assays on HeLa and MCF7 tumor cell lines outlined a multitarget antiproliferative profile for tetracyclic 6 and pentacyclic derivative 20, both bearing a N,N-dimethylamine as the protonatable moiety. Particularly, compound 6 displayed a very potent inhibition of tumor cell proliferation, while 20 returned the highest thermal stabilization in melting experiments. In summary, these results outlined a potential of such highly planar scaffolds for nucleic acid binding and antiproliferative effects. PMID- 28342693 TI - The Road to Leadership in SPN. PMID- 28342692 TI - Novel pyrazolo[1,5-a]pyridines as orally active EP1 receptor antagonists: Synthesis, structure-activity relationship studies, and biological evaluation. AB - Novel pyrazolo[1,5-a]pyridine derivatives were designed, synthesized and evaluated as orally active EP1 antagonists for the treatment of overactive bladder. Matched molecular pair analysis (MMPA) allowed the design of a new series of pyrazolo[1,5-a]pyridine derivatives 4-6. Structure-activity relationships (SAR) studies of 4-6 were performed, leading to identification of the nanomolar-level EP1 antagonist 4c, which exhibited good pharmacological effect through intraduodenal (id) administration in a 17-phenyltrinor prostaglandin E2-induced bladder contraction model in rats. PMID- 28342694 TI - Nursing-led Home Visits Post-hospitalization for Children with Medical Complexity. AB - PURPOSE: Hospital discharge for children with medical complexity (CMC) can be challenging for families. Home visits could potentially benefit CMC and their families after leaving the hospital. We assessed the utility of post-discharge home visits to identify and address health problems for recently hospitalized CMC. DESIGN AND METHODS: A prospective study of 36 CMC admitted to a children's hospital from 4/15/2015 to 4/14/2016 identified with a possible high risk of hospital readmission and offered a post-discharge home visit within 72h of discharge. The visit was staffed by a hospital nurse familiar with the child's admission. The home visit goals were to reinforce education of the discharge plan, assess the child's home environment, and identify and address any problems or issues that emerged post-discharge. RESULTS: The children's median age was 6years [interquartile range (IQR) 2-18]. The median distance from hospital to their home was 38miles (IQR 8-78). All (n=36) children had multiple chronic conditions; 89% (n=32) were assisted with medical technology. The nurse identified and helped with a post-discharge problem during every (n=36) visit. Of the 147 problems identified, 26.5% (n=39) pertained to social/family issues (e.g., financial instability), 23.8% (n=35) medications (e.g., wrong dose), 20.4% (n=30) durable medical equipment (e.g., insufficient supply or faulty function), 20.4% (n=30) child's home environment (e.g., unsafe sleeping arrangement), and 8.8% (n=13) child's health (e.g., unresolved health problem). CONCLUSIONS: Home visits helped identify and address post-discharge issues that occurred for discharged CMC. PRACTICAL IMPLICATIONS: Hospitals should consider home visits when optimizing discharge care for CMC. PMID- 28342695 TI - In vivo serum concentration of vancomycin in antibiotic-loaded acrylic cement for the treatment and prevention of periprosthetic hip infection. AB - BACKGROUND: Although antibiotic-loaded acrylic cement (ALAC) is used to prevent and treat periprosthetic hip infection, it is unknown how much antibiotic is deposited in the body in vivo, how high the serum concentration rises, or how long its effects last. The aim of this study was firstly to determine the amount of vancomycin (VCM) deposited as ALAC in the body, and secondly to assess the safety and drug elution profile of VCM in ALAC. METHODS: We administered VCM to prevent infection after total hip arthroplasty (THA) or to treat patients with methicillin-resistant Staphylococcus aureus. Patients were classified into two groups: a low-dose group (21 hips) that received primary THA for high-risk cases, revision THA without infection, or one-staged revision THA for infection; and a high-dose group (6 hips) that received cement beads during a two-staged revision THA. The amount of VCM placed as ALAC into the hip was calculated using the remaining ALAC. The serum concentrations of VCM and creatinine were evaluated at postoperative days 1, 4, 7, 14, and 28, and at 3 and 6 months. RESULTS: The mean amount of VCM placed as ALAC into the hip was 0.9 g and 3.4 g for cemented THA and cement beads, respectively (P < 0.0001). The mean serum concentration of VCM from ALAC in the high-dose group was significantly increased compared with that in the low-dose group on postoperative days 1, 4, 7, 14, and 28 (P < 0.0001), but it remained within a clinically safe range. No significant differences were observed between the preoperative and postoperative serum creatinine levels of either group. CONCLUSION: The average serum concentrations of VCM from ALAC were always less than the effective blood concentration, and were detectable until 6 months after surgery. PMID- 28342696 TI - Measurement of change on medial and lateral joint gaps by navigation system in multi-radius PS TKA. AB - BACKGROUND: The purpose of this study was to evaluate the joint gap kinematics in posterior-stabilized total knee arthroplasty (PS TKA). METHODS: Between January 2010 and April 2011, 44 consecutive patients (55 knees) who underwent primary PS TKA using the navigation system were assessed. There were 37 women and 7 men with a mean age at operation of 63 years (range; 58-73 years). After fixation of all components with cement and insertion of polyethylene trial insert, medial and lateral joint gap measurements were carried out without distraction force and separately using a navigation system on each flexion angles. The joint gaps were measured before and after deflation of tourniquet, first with patella everted and then reduced. RESULTS: Deflation of tourniquet did not effect on gap. In patellofemoral joint reduction situation, the medial gap relatively maintained throughout the range of knee motion, but the lateral gap is gradually decreasing with knee flexion from 30 degrees to 120 degrees flexion. However, in patellar eversion situation, the medial gap showed a significant increase and also statistically significantly increased compared with patellar reduced position over 90 degrees knee flexion status, but the lateral gaps are decreased compared with patellofemoral reduction situation throughout the range of knee motion except full flexion status. In more physiologic status that is patella reduced and tourniquet deflated status, the average medial joint gap change was 2.30 +/- 1.64 mm and the average lateral joint gap change was 2.90 +/- 1.53 mm throughout the range of motion. CONCLUSIONS: Medial and lateral joint gaps showed different patterns with patellar eversion and patellofemoral joint reduction. However, such changes occurred within 3 mm in average throughout whole range of knee motion even with multi-radius femoral component. PMID- 28342697 TI - Recent publications from the Alzheimer's Disease Neuroimaging Initiative: Reviewing progress toward improved AD clinical trials. AB - INTRODUCTION: The Alzheimer's Disease Neuroimaging Initiative (ADNI) has continued development and standardization of methodologies for biomarkers and has provided an increased depth and breadth of data available to qualified researchers. This review summarizes the over 400 publications using ADNI data during 2014 and 2015. METHODS: We used standard searches to find publications using ADNI data. RESULTS: (1) Structural and functional changes, including subtle changes to hippocampal shape and texture, atrophy in areas outside of hippocampus, and disruption to functional networks, are detectable in presymptomatic subjects before hippocampal atrophy; (2) In subjects with abnormal beta-amyloid deposition (Abeta+), biomarkers become abnormal in the order predicted by the amyloid cascade hypothesis; (3) Cognitive decline is more closely linked to tau than Abeta deposition; (4) Cerebrovascular risk factors may interact with Abeta to increase white-matter (WM) abnormalities which may accelerate Alzheimer's disease (AD) progression in conjunction with tau abnormalities; (5) Different patterns of atrophy are associated with impairment of memory and executive function and may underlie psychiatric symptoms; (6) Structural, functional, and metabolic network connectivities are disrupted as AD progresses. Models of prion-like spreading of Abeta pathology along WM tracts predict known patterns of cortical Abeta deposition and declines in glucose metabolism; (7) New AD risk and protective gene loci have been identified using biologically informed approaches; (8) Cognitively normal and mild cognitive impairment (MCI) subjects are heterogeneous and include groups typified not only by "classic" AD pathology but also by normal biomarkers, accelerated decline, and suspected non-Alzheimer's pathology; (9) Selection of subjects at risk of imminent decline on the basis of one or more pathologies improves the power of clinical trials; (10) Sensitivity of cognitive outcome measures to early changes in cognition has been improved and surrogate outcome measures using longitudinal structural magnetic resonance imaging may further reduce clinical trial cost and duration; (11) Advances in machine learning techniques such as neural networks have improved diagnostic and prognostic accuracy especially in challenges involving MCI subjects; and (12) Network connectivity measures and genetic variants show promise in multimodal classification and some classifiers using single modalities are rivaling multimodal classifiers. DISCUSSION: Taken together, these studies fundamentally deepen our understanding of AD progression and its underlying genetic basis, which in turn informs and improves clinical trial design. PMID- 28342699 TI - This Month in AJP. PMID- 28342698 TI - Targeted exome sequencing and chromosomal microarray for the molecular diagnosis of nevoid basal cell carcinoma syndrome. AB - BACKGROUND: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder mainly caused by heterozygous mutations of PTCH1. In addition to characteristic clinical features, detection of a mutation in causative genes is reliable for the diagnosis of NBCCS; however, no mutations have been identified in some patients using conventional methods. OBJECTIVE: To improve the method for the molecular diagnosis of NBCCS. METHODS: We performed targeted exome sequencing (TES) analysis using a multi-gene panel, including PTCH1, PTCH2, SUFU, and other sonic hedgehog signaling pathway-related genes, based on next-generation sequencing (NGS) technology in 8 cases in whom possible causative mutations were not detected by previously performed conventional analysis and 2 recent cases of NBCCS. Subsequent analysis of gross deletion within or around PTCH1 detected by TES was performed using chromosomal microarray (CMA). RESULTS: Through TES analysis, specific single nucleotide variants or small indels of PTCH1 causing inferred amino acid changes were identified in 2 novel cases and 2 undiagnosed cases, whereas gross deletions within or around PTCH1, which are validated by CMA, were found in 3 undiagnosed cases. However, no mutations were detected even by TES in 3 cases. Among 3 cases with gross deletions of PTCH1, deletions containing the entire PTCH1 and additional neighboring genes were detected in 2 cases, one of which exhibited atypical clinical features, such as severe mental retardation, likely associated with genes located within the 4.3Mb deleted region, especially. CONCLUSION: TES-based simultaneous evaluation of sequences and copy number status in all targeted coding exons by NGS is likely to be more useful for the molecular diagnosis of NBCCS than conventional methods. CMA is recommended as a subsequent analysis for validation and detailed mapping of deleted regions, which may explain the atypical clinical features of NBCCS cases. PMID- 28342700 TI - Nicotine replacement therapy in patients with aneurysmal subarachnoid hemorrhage: Systematic review of the literature, and survey of Canadian practice. AB - Tobacco smoke increases the risk of aneurysmal subarachnoid hemorrhage (SAH), as well as complications such as vasospasm. Most patients presenting with aneurysmal SAH smoke, and many survivors continue to smoke after discharge. Neurosurgeons often hesitate to use nicotine replacement therapy (NRT) during hospitalization of patients with SAH due to concerns of inducing vasospasm. We aimed to evaluate the safety and efficacy, and patterns of use of NRT in smokers hospitalized for SAH. We performed a systematic review of MEDLINE, CENTRAL, Embase, and unpublished sources of literature to October 2016 for randomized and observational studies comparing exposure to non-exposure of smoking cessation products in the acute phase of aneurysmal SAH. Additionally, we surveyed 50 Canadian vascular neurosurgeons to evaluate patterns of NRT use in SAH. Four cohort studies (n=1210) met our eligibility criteria. Three studies enrolled patients with aneurysmal SAH, and one study enrolled all neurocritically ill patients. We rated the quality of evidence as very low using the GRADE approach. We could not meta-analyze studies due to methodological heterogeneity. Individual studies reported beneficial or neutral effects of NRT on functional outcome, death, and clinical or radiographic vasospasm. None of the studies assessed long term abstinence from tobacco. Of the 14 vascular neurosurgeons responding to our survey, most never used NRT in patients hospitalized with SAH, often citing training or standard of practice as the reason. Current evidence suggests that NRT does not induce vasospasm, and is associated with improved outcomes in smokers hospitalized for SAH. Protocol registered in PROSPERO, available at: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016037200. PMID- 28342701 TI - Predictive (subtle or overlooked) initial head CT findings in patients who develop delayed chronic subdural hematoma. AB - With the aging population, the incidence of chronic subdural hematoma (CSDH) is expected to rise. Once symptomatic the morbidity from CSDH is not insignificant. We studied patients who had a minor head injury and CT brain scan prior to developing CSDH to determine if there were any predictors on these scans for subsequent development of a CSDH. A retrospective review was performed on all patients operated for CSDH over a 3-year period and a review performed on those who had imaging studies at the time of a preceding minor head injury. Seven of 37 patients had CT scans prior to developing CSDH. All had evidence of small increases in CSF intensity on the side or sides of the subsequent CSDH. In conclusion, in those patients with a history of minor head injury prior to developing a CSDH, CT brain demonstrated small increases in cerebral spinal fluid (CSF) intensity on the side or sides of the subsequent CSDH. Recognizing this finding may be helpful in monitoring these patients or initiating medical therapy. PMID- 28342702 TI - Apigenin attenuates oxidative stress and neuronal apoptosis in early brain injury following subarachnoid hemorrhage. AB - Apigenin (API) is a naturally occurring plant flavone that exhibits powerful antioxidant and antiapoptosis. Oxidative stress plays an important role in the pathogenesis of early brain injury (EBI) following subarachnoid hemorrhage (SAH). The potential anti-oxidative and anti-apoptosis effects of API on EBI following SAH, however, have not been elucidated. The aim of this study was to assess whether API alleviates EBI after SAH via its anti-oxidative and anti-apoptotic effects. The endovascular puncture model was used to induce SAH and all the rats were subsequently sacrificed at 24h after SAH. Our data demonstrated that administration of API could significantly alleviate EBI (including neurological deficiency, brain edema, blood-brain barrier permeability, and cortical cell apoptosis) after SAH in rats. Meanwhile, API treatment reduced the reactive oxygen species (ROS) level and the concentration of malondialdehyde (MDA) and myeloperoxidase (MPO), elevated the ratio of glutathione (GSH) and oxidized glutathione (GSSG), and increased the amount of super-oxide dismutase (SOD) and hydrogen peroxide in brain cortex at 24h following SAH. Moreover, API treatment inhibited SAH-induced the expression of Bax and caspase-3, significantly reduced neuronal apoptosis. Collectively, API exerts its neuroprotective effect likely through the dual activities of anti-oxidation and anti-apoptosis, at least partly. These data provide a basic platform to consider API may be safely used as a potential drug for treatment of SAH. PMID- 28342703 TI - Intracranial white epidermoid cyst with dystrophic calcification - A case report and literature review. AB - White epidermoids are a rare variant of an intracranial epidermoid cyst that do not exhibit typical 'near- cerebrospinal fluid (CSF)' CT density or MRI intensity. Here, the authors present the case of a 58year old man with an acute onset of aphasia and altered consciousness, due to a large heterogeneous cranial mass in the left frontal region with unusual signal intensity. Subsequent histopathological analysis identified the lesion as an epidermoid cyst. PMID- 28342704 TI - Trends in the presentation, surgical treatment, and outcomes of tethered cord syndrome: A nationwide study from 2001 to 2010. AB - OBJECTIVE: This is a nationwide query into surgical management techniques for tethered cord syndrome, focusing on patient demographic, hospital characteristics, and treatment outcomes. Our hypothesis is that detethering vs. fusion for TCS results in different in-hospital complications. MATERIALS AND METHODS: Retrospective review of the Nationwide Inpatient Sample 2001-2010. Inclusion: TCS discharges undergoing detethering or fusion. Sub-analysis compared TCS cases by age (pediatric [<=9years] vs. adolescent [10-18year]). Independent t tests identified differences between fusion and detethering for hospital-related and surgical factors; multivariate analysis investigated procedure as a risk factor for complications/mortality. RESULTS: 6457 TCS discharges: 5844 detetherings, 613 fusions. Fusion TCS had higher baseline Deyo Index (0.16 vs. 0.06), procedure-related complications (21.3% vs. 7.63%), and mortality (0.33% vs. 0.09%) than detethering, all p<0.001. Detethering for TCS was a significant factor for reducing mortality (OR 0.195, p<0.001), cardiac (OR 0.27, p<0.001), respiratory (OR 0.26, p<0.001), digestive system (OR 0.32, p<0.001), puncture nerve/vessel (OR 0.56, p=0.009), wound (OR 0.25, p<0.001), infection (OR 0.29, p<0.001), posthemorrhagic anemia (OR 0.04, p=0.002), ARDS (OR 0.13, p<0.001), and venous thrombotic (OR 0.53, p=0.043) complications. Detethering increased nervous system (OR 1.34, p=0.049) and urinary (OR 2.60, p<0.001) complications. Adolescent TCS had higher Deyo score (0.08 vs. 0.03, p<0.001), LOS (5.77 vs. 4.13days, p<0.001), and charges ($54,592.28 vs. $33,043.83, p<0.001), but similar mortality. Adolescent TCS discharges had increased prevalence of all procedure related complications, and higher overall complication rate (11.10% vs. 5.08%, p<0.001) than pediatric. CONCLUSIONS: With fusion identified as a significant risk factor for mortality and multiple procedure-related complications in TCS surgical patients, this study could aid surgeons in counseling TCS patients to optimize outcomes. PMID- 28342705 TI - Comparison of 20% mannitol and 3% hypertonic saline on intracranial pressure and systemic hemodynamics. AB - Mannitol and hypertonic saline (HS) are most commonly used hyperosmotic agents for intraoperative brain relaxation. We compared the changes in ICP and systemic hemodynamics after infusion of equiosmolar solutions of both agents in patients undergoing craniotomy for supratentorial tumors. Forty enrolled adults underwent a standard anesthetic induction. Apart from routine monitoring parameters, subdural ICP with Codmann catheter and cardiac indices by Vigileo monitor, were recorded. The patients were randomized to receive equiosmolar solutions of either 20% mannitol (5ml/kg) or 3% HS (5.35ml/kg) for brain relaxation. The time of placement of ICP catheter was marked as T0 and baseline ICP and systemic hemodynamic variables were noted; it was followed by recording of the same parameters every 5min till 45min (Study Period). After the completion of study period, brain relaxation score as assessed by the neurosurgeon was recorded. Arterial blood gas (ABG) was analysed every 30min starting from T0 upto one and half hours (T90), and values of various parameters were recorded. Data was analysed using appropriate statistical methods. Both mannitol and HS significantly reduced the ICP; the values were comparable in between the two groups at most of the times. The brain relaxation score was comparable in both the groups. Urine output was significantly higher with mannitol. The perioperative complications, overall hospital stay, and Glasgow outcome score at discharge were comparable in between the two groups. To conclude, both mannitol and hypertonic saline in equiosmolar concentrations produced comparable effects on ICP reduction, brain relaxation, and systemic hemodynamics. PMID- 28342706 TI - Emotional and behavioral influence of headache in Pediatric rheumatic diseases. PMID- 28342707 TI - Clinical characteristics, microbiology and outcomes of external ventricular drainage-associated infections: The importance of active treatment. AB - Data concerning clinical characteristics, microbiology, treatment and outcomes of external ventricular drainage-associated infections (EVDAI) are limited. All hospitalized patients with EVDAI in a University Hospital between January 2009 and December 2015 were retrospective recorded. Only the first episode per patient was included. An antibiotic was considered "active" when its pharmacokinetic properties were appropriate for EVDAI and the implicated microorganism was in vitro susceptible. During the 7-year study period, 36 EVDAI were identified. Median patient age was 53years and 23 (63.9%) were male. Catheter types were intraventricular (70.6%) and lumbar (29.4%). Median catheterization duration before infection was 14days. Gram-negative bacteria (GNB) predominated (57.9%), followed by gram-positives (36.8%) and fungi (5.3%). Administered antibiotics were considered "active" in 69.4% of empirical and in 86.1% of definitive treatment regimens. In 10 infections, intraventricular/intrathecal (IVT) antibiotics were administered. Eleven patients died (30.6%) during hospitalization. Patients who died had higher rates of EVDAI by GNB (p=0.011) and higher rates of treatment with intravenous colistin (p=0.019 for empirical and p=0.006 for definitive colistin). Compared to EVDAI by other pathogens, patients with EVDAI by GNB had longer catheter-days before infection (p<0.001) and higher mortality (p=0.011). In our study, GNB were a frequent cause of EVDAI, and were related with high rates of inactive treatment and mortality. Intravenous colistin alone is not effective and treatment should include IVT antibiotics and intravenous antibiotics that achieve adequate CSF levels. PMID- 28342708 TI - Hemodynamic phenotyping based on exercise catheterization predicts outcome in patients with heart failure and reduced ejection fraction. AB - BACKGROUND: Exercise right heart catheterization (RHC) unmasks different phenotypes based on hemodynamic response to exertion in patients with heart failure. The prognostic relevance of this approach in patients with heart failure and reduced ejection fraction (HFrEF) is uncertain. METHODS: We analyzed 167 patients with HFrEF from the Kerckhoff-Klinik Heart Failure Registry who underwent supine exercise RHC with constant external workload between September 2009 and August 2014. The primary outcome was heart transplant/assist device-free survival. Hemodynamic parameters that significantly predicted outcome were identified by multivariate Cox regression analysis and assessed further by Kaplan Meier analysis after dichotomization using cutoffs derived from receiver operating characteristic analysis. Hemodynamic phenotypes were defined based on a dichotomized flow response (exercise-induced change in cardiac output [?CO]) combined with a dichotomized pressure response (exercise-induced change in systolic [?sPAP] or mean pulmonary arterial pressures). RESULTS: ?CO independently predicted transplant/assist device-free survival (multivariate hazard ratio [HR] 1.67; 95% confidence interval [CI], 1.09-2.58; p = 0.02). Patients with ?CO >=1.15 liter/min had significantly better 5-year transplant/assist device-free survival than patients with lower ?CO (72.9% vs 22.5%; log-rank p < 0.001 [Kaplan-Meier analysis]). The hemodynamic phenotype of ?CO <1.15 liter/min combined with ?sPAP <17.5 mm Hg was associated with worse transplant/assist device-free survival than ?CO >=1.15 liter/min combined with ?sPAP >=17.5 mm Hg (multivariate HR 7.39; 95% CI, 2.27-24.05; p = 0.001). CONCLUSIONS: Exercise RHC parameters are important prognostic indices in HFrEF. Hemodynamic phenotyping using ?CO and ?sPAP allows enhanced risk stratification. PMID- 28342709 TI - Transitioning from pediatric to adult care after thoracic transplantation. AB - With improving outcomes after thoracic transplantation, more children are surviving to adulthood and requiring specialized adult care. A systematic and effective program is essential to transition these patients from a pediatric to adult health care setting. In this review, we discuss the concept of transition and the factors leading to an effective transfer to an adult care provider, including administrative support, patient/provider preparation, and the navigation of potential barriers. Notably, there is a paucity of data for many details of transition, making this a significant opportunity for future research. PMID- 28342711 TI - Epidemiological profile and vaccination coverage in splenectomy patients in a health area of Murcia (1993-2012). AB - OBJECTIVE: Splenectomy patients have a high risk of suffering severe infections, many of them preventable by vaccination. The aim of the study was to analyse the clinical epidemiological characteristics and vaccine coverage of these patients in Health Area III of the Region of Murcia. METHOD: A cross-sectional study was conducted on a population of patients that were splenectomised during the period 1993-2012, according to the Register of the Basic Minimum Data Set. Patients were classified on the basis of splenectomy (neoplasm, haematological diseases, trauma, and others), vaccination, and vital status, using official records of health data. Statistical analysis was performed using SPSS 21.0 statistics program. RESULTS: The sample consisted of 196 patients, of which 68.4% (n=134) were male. The mean age at which they underwent splenectomy was 50.1 years (SD: 22.2). The most common reason for removal of the spleen was neoplasia in 39.1% (n=59). Splenectomy due to trauma reasons was associated with lower patient age (p<.001) and male gender (p=.03). Vaccination coverage for Streptococcus pneumoniae was 23.8%, 5.7% for Neisseria meningitidis C, and 8.6% for Haemophilus influenzae B. Only 2.9% of patients were correctly vaccinated for all three. CONCLUSIONS: Vaccination coverage was insufficient for this fragile patient profile. It should be taken into account in the early detection and counselling in this group so susceptible to disease, with nurses being a decisive part in the process. PMID- 28342712 TI - Therapeutic targets in the selective killing of cancer cells by nanomaterials. AB - Cancer is the result of numerous defects in key regulatory proteins and pathways, and targeting them with anticancer agents is associated with severe systemic toxicity. Increased levels of reactive oxygen species (ROS) and compensatory antioxidant levels in cancer cells have emerged as broad spectrum targets for therapeutic interventions. The biochemical features of cancer provide multiple but overlapping opportunities that could be efficiently exploited by the optimally engineered particulate characteristics of nanomaterials (NMs). Altered potentials in membranes of cancer cells as well as in key organelles favor more stable electrochemical interactions with NMs that have an optimum size and surface charge. This preferential interaction of NMs with cancer cell membranes over normal cell membranes could lead to the greater internalization of NMs in cancer cells. Moreover, the low pH in cytoplasmic fluids and organelles of cancer cells could cause the internalized NMs to dissolve differently than they would in normal cells. In addition to differential dissolution, internalized NMs can induce cell death in cancer cells by activating all possible cell death pathways (apoptosis, necroptosis or autophagy) either alone or in a synergistic manner. With their inherent ability to generate ROS and deplete cellular antioxidants, NMs with optimal physicochemical properties might provide fertile ground in the field of anticancer research. PMID- 28342713 TI - A laboratory score at presentation to rule-out serious cardiac outcomes or death in patients presenting with symptoms suggestive of acute coronary syndrome. AB - BACKGROUND: We evaluated whether a low high-sensitivity cardiac troponin (hs-cTn) cutoff combined with glucose, red cell distribution width (RDW), and the estimated glomerular filtration rate (eGFR) can be used to rule-out a serious cardiac outcome or death in patients presenting with symptoms suggestive of acute coronary syndrome (ACS). METHODS: This was a prospective observational emergency department (ED) study enrolling consecutive patients presenting with symptoms suggestive of ACS (ClinicalTrials.gov: NCT01994577). The primary outcome was a 7 day composite of myocardial infarction, unstable angina, decompensated congestive heart failure, serious ventricular cardiac arrhythmia, or death. A laboratory score combining glucose, RDW, eGFR with hs-cTnT (Roche) or hs-cTnI (Abbott) was compared to hs-cTn alone using the limit of detection (LoD; hs-cTnT<5ng/l/hs cTnI<2ng/l) as the cutoff. A benchmark of >99% sensitivity was used to assess the laboratory panel with hs-cTn versus the LoD alone to identify low-risk patients suitable for discharge. RESULTS: A total of 1095 patients (n=267 composite outcomes) had measurements of glucose, RDW, eGFR, hs-cTnT, and hs-cTnI at presentation. Applying the hs-cTn LoD alone as the cutoff missed 5 composite outcomes (sensitivity=98.1%), however the addition of the laboratory panel to the hs-cTn LoD increased the sensitivity to >99% with approximately 10% of the population identified as low-risk. The percentage of low-risk patients was increased to 15% (1 composite-outcome missed) when employing a low measurable hs cTnI cutoff with the laboratory panel (laboratory score<2 points). CONCLUSION: A laboratory score with hs-cTn may identify low-risk patients suitable for ED discharge at presentation. PMID- 28342714 TI - Higher uric acid serum levels are associated with better muscle function in the oldest old: Results from the Mugello Study. AB - BACKGROUND: Sarcopenia is the progressive loss of muscle mass and strength that occurs with advancing age and plays a pivotal role in the causal pathway leading to frailty, disability and, eventually, to death among older persons. As oxidative damage of muscle proteins has been shown to be a relevant contributory factor, in this study we hypothesized that uric acid (UA), a powerful endogenous antioxidant, might exert a protective effect on muscle function in the oldest old and we tested our hypothesis in a group of nonagenarians who participated in the Mugello Study. METHODS: 239 subjects, 73 men and 166 women, mean age 92.8years+/ SD 3.1, underwent the assessment of UA serum level and isometric handgrip strength, a widely used clinical measure of sarcopenia. RESULTS: Mean UA serum level was 5.69mg/dL+/-SD 1.70 and mean handgrip strength was 15.0kg+/-SD 6.9. After adjusting for relevant confounders, higher UA serum levels remained independent positive predictors of isometric handgrip strength (beta 1.24+/ SE(beta) 0.43, p=0.005). CONCLUSION: Our results show that higher UA serum levels are associated with better muscle function in the oldest old and, accordingly, might slow down the progression of sarcopenia. PMID- 28342710 TI - Emerging role of chemoprotective agents in the dynamic shaping of plasma membrane organization. AB - In the context of an organism, epithelial cells by nature are designed to be the defining barrier between self and the outside world. This is especially true for the epithelial cells that form the lining of the digestive tract, which absorb nutrients and serve as a barrier against harmful substances. These cells are constantly bathed by a complex mixture of endogenous (bile acids, mucus, microbial metabolites) and exogenous (food, nutrients, drugs) bioactive compounds. From a cell biology perspective, this type of exposure would directly impact the plasma membrane, which consists of a myriad of complex lipids and proteins. The plasma membrane not only functions as a barrier but also as the medium in which cellular signaling complexes form and function. This property is mediated by the organization of the plasma membrane, which is exquisitely temporally (nanoseconds to minutes) and spatially (nanometers to micrometers) regulated. Since numerous bioactive compounds found in the intestinal lumen can directly interact with lipid membranes, we hypothesize that the dynamic reshaping of plasma membrane organization underlies the chemoprotective effect of select membrane targeted dietary bioactives (MTDBs). This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escriba. PMID- 28342716 TI - Immediate postpartum intrauterine device and implant program outcomes: a prospective analysis. AB - BACKGROUND: In-hospital placement of intrauterine devices and contraceptive implants following vaginal and cesarean delivery is increasingly popular and responds to maternal motivation for highly effective postpartum contraception. Immediate postpartum intrauterine device insertion is associated with higher expulsion than interval placement, but emerging evidence suggests that the levonorgestrel intrauterine device may have a higher expulsion rate than the copper intrauterine device. OBJECTIVE: This study evaluated in-hospital provision, expulsion, and 6-month continuation of immediate postpartum copper T380 intrauterine devices, levonorgestrel intrauterine devices, and contraceptive implants. STUDY DESIGN: We offered enrollment in this prospective observational trial to women presenting to the University of Utah labor and delivery unit from October 2013 through February 2016 who requested an intrauterine device or implant for postpartum contraception during prenatal care or hospitalization at the time of delivery. Following informed consent, participants completed questionnaires prior to hospital discharge and at 3 and 6 months postpartum. Data on expulsions at 6 months were validated by chart abstraction. RESULTS: During the study period, 639 patients requested a postpartum intrauterine device or implant and 350 patients enrolled in prospective follow-up prior to discharge from the hospital. Among enrollees, 325 (93%) received their preferred contraceptive device prior to hospital discharge: 88 (27%) copper intrauterine device users, 123 (38%) levonorgestrel intrauterine device users, and 114 (35%) implant users. Participants predominantly were Hispanic (90%), were multiparous (87%), reported a household income <$24,000 per year (87%), and underwent a vaginal delivery (77%). At 6 months postpartum, 289 of 325 device recipients (89%) completed follow-up. Among levonorgestrel intrauterine device users 17% reported expulsions relative to 4% of copper intrauterine device users. The adjusted hazard ratio for expulsion was 5.8 (confidence interval, 1.3-26.4). There was no statistically significant difference in expulsions by delivery type or continuation by device type. Among the 21 women who experienced intrauterine device expulsions, 14 (67%) requested a replacement long-acting reversible contraception device for contraception. The 6-month device continuation was >=80% for all device types. CONCLUSION: An immediate postpartum long-acting reversible contraception program effectively provides women who desire highly effective reversible contraceptive devices with their method of choice prior to hospital discharge. Immediate postplacental levonorgestrel intrauterine device users have higher expulsion rates than copper intrauterine device users, but >8 of 10 women initiating an intrauterine device or implant continue use at 6 months postpartum. PMID- 28342718 TI - Noisy Response to Antibiotic Stress Predicts Subsequent Single-Cell Survival in an Acidic Environment. AB - Antibiotics elicit drastic changes in microbial gene expression, including the induction of stress response genes. While certain stress responses are known to "cross-protect" bacteria from other stressors, it is unclear whether cellular responses to antibiotics have a similar protective role. By measuring the genome wide transcriptional response dynamics of Escherichia coli to four antibiotics, we found that trimethoprim induces a rapid acid stress response that protects bacteria from subsequent exposure to acid. Combining microfluidics with time lapse imaging to monitor survival and acid stress response in single cells revealed that the noisy expression of the acid resistance operon gadBC correlates with single-cell survival. Cells with higher gadBC expression following trimethoprim maintain higher intracellular pH and survive the acid stress longer. The seemingly random single-cell survival under acid stress can therefore be predicted from gadBC expression and rationalized in terms of GadB/C molecular function. Overall, we provide a roadmap for identifying the molecular mechanisms of single-cell cross-protection between antibiotics and other stressors. PMID- 28342717 TI - Slow Chromatin Dynamics Allow Polycomb Target Genes to Filter Fluctuations in Transcription Factor Activity. AB - Genes targeted by Polycomb repressive complex 2 (PRC2) are regulated in cis by chromatin modifications and also in trans by diffusible regulators such as transcription factors. Here, we introduce a mathematical model in which transcription directly antagonizes Polycomb silencing, thereby linking these cis- and trans-regulatory inputs to gene expression. The model is parameterized by recent experimental data showing that PRC2-mediated repressive chromatin modifications accumulate extremely slowly. The model generates self-perpetuating, bistable active and repressed chromatin states that persist through DNA replication, thereby ensuring high-fidelity transmission of the current chromatin state. However, sufficiently strong, persistent activation or repression of transcription promotes switching between active and repressed chromatin states. We observe that when chromatin modification dynamics are slow, transient pulses of transcriptional activation or repression are effectively filtered, such that epigenetic memory is retained. Noise filtering thus depends on slow chromatin dynamics and may represent an important function of PRC2-based regulation. PMID- 28342715 TI - Prediction of neonatal respiratory morbidity by quantitative ultrasound lung texture analysis: a multicenter study. AB - BACKGROUND: Prediction of neonatal respiratory morbidity may be useful to plan delivery in complicated pregnancies. The limited predictive performance of the current diagnostic tests together with the risks of an invasive procedure restricts the use of fetal lung maturity assessment. OBJECTIVE: The objective of the study was to evaluate the performance of quantitative ultrasound texture analysis of the fetal lung (quantusFLM) to predict neonatal respiratory morbidity in preterm and early-term (<39.0 weeks) deliveries. STUDY DESIGN: This was a prospective multicenter study conducted in 20 centers worldwide. Fetal lung ultrasound images were obtained at 25.0-38.6 weeks of gestation within 48 hours of delivery, stored in Digital Imaging and Communication in Medicine format, and analyzed with quantusFLM. Physicians were blinded to the analysis. At delivery, perinatal outcomes and the occurrence of neonatal respiratory morbidity, defined as either respiratory distress syndrome or transient tachypnea of the newborn, were registered. The performance of the ultrasound texture analysis test to predict neonatal respiratory morbidity was evaluated. RESULTS: A total of 883 images were collected, but 17.3% were discarded because of poor image quality or exclusion criteria, leaving 730 observations for the final analysis. The prevalence of neonatal respiratory morbidity was 13.8% (101 of 730). The quantusFLM predicted neonatal respiratory morbidity with a sensitivity, specificity, positive and negative predictive values of 74.3% (75 of 101), 88.6% (557 of 629), 51.0% (75 of 147), and 95.5% (557 of 583), respectively. Accuracy was 86.5% (632 of 730) and positive and negative likelihood ratios were 6.5 and 0.3, respectively. CONCLUSION: The quantusFLM predicted neonatal respiratory morbidity with an accuracy similar to that previously reported for other tests with the advantage of being a noninvasive technique. PMID- 28342720 TI - Rebubbling in Descemet Membrane Endothelial Keratoplasty: Influence of Pressure and Duration of the Intracameral Air Tamponade. AB - PURPOSE: To explore the impact of intracameral air tamponade pressure and duration on graft attachment and rebubbling rates. DESIGN: A prospective, interventional, nonrandomized study. METHODS: setting: Department of Ophthalmology, Charite - Universitatsmedizin Berlin. STUDY POPULATION: One hundred seventeen patients who underwent Descemet membrane endothelial keratoplasty (DMEK). OBSERVATION: Intraocular pressure (IOP) at the end of the surgery, immediately after filling the anterior chamber with air, categorized into low (<10 mm Hg), normal (10-20 mm Hg), and high (>20 mm Hg), and the time until partial removal of the air. MAIN OUTCOME MEASURES: Rebubbling rates and endothelial cell density over a 3-month follow-up period analyzed by a multivariable Cox regression model and an analysis of covariance model. RESULTS: Thirty-two patients required a rebubbling (27% [95% CI 19%-35%]). Nine patients required more than 1 rebubbling (7% [95% CI 3%-12%]). Compared with normal IOP, lower (HR 8.98 [95% CI 1.07-75.41]) and higher IOP (HR 10.63 [95% CI 1.44-78.27]) increased the risk of requiring a rebubbling (P = .006). Independent of the IOP, an air tamponade duration beyond 2 hours reduced the risk of rebubbling (HR 0.36 [95% CI 0.18-0.71, P = .003]). One month after surgery, the mean endothelial cell loss was 13% (95% CI 2%-25%) and 23% (95% CI 17%-29%) in the group with air tamponade duration of below and above 2 hours, respectively (P = .126). At 3 months after surgery, it was 31% (95% CI 17%-42%) and 42% (95% CI 32%-52%) in the respective groups (P = .229). CONCLUSIONS: A postsurgical air tamponade of at least 2 hours with an IOP within the physiological range could help to reduce rebubbling rates. PMID- 28342719 TI - Association of Structural and Functional Measures With Contrast Sensitivity in Glaucoma. AB - PURPOSE: To test the hypothesis that structural and functional measures predict contrast sensitivity (CS) outcomes in glaucomatous eyes. DESIGN: Cross-sectional prospective study. METHODS: One hundred five eyes of 65 patients who underwent macular spectral-domain optical coherence tomography imaging, 24-2 standard achromatic visual fields (VF), and CS measurement on the same day were enrolled. Association of CS at 4 spatial frequencies (3, 6, 12, and 18 cycles per degree, cpd) with structural and functional outcomes was explored with correlation and regression analyses. RESULTS: The median (IQR) 24-2 visual field mean deviation was -7.6 (-11.1 to -3.0). Significant correlations were found between CS at 6 cpd and ganglion cell/inner plexiform layer thickness at inferotemporal and inferonasal macular sectors (rho = 0.222, P = .023 and rho = 0.209, P = .032, respectively). CS at 6 cpd demonstrated higher correlations with full macular thickness measurements, the strongest of which was with the central macular thickness in the superior 6 * 3-degree region (rho = 0.311, P = .001). Contrast sensitivity at 6 cpd also had the strongest correlation with mean deviation of the 4 central VF points (rho = -0.420; P < .001). There was a significant correlation between logMAR visual acuity and contrast sensitivity at 6, 12, and 18 cpd (rho = -0.306, rho = -0.348 and rho = -0.241, P < .013, respectively). CONCLUSIONS: Structural and functional measures showed a fair relationship with contrast sensitivity. This association was most prominent between full-thickness macular measures or central VF parameters and CS at 6 cpd. Contrast sensitivity was not a reliable surrogate for glaucoma severity in this cross-sectional study. PMID- 28342721 TI - Four-year Follow-up of the Changes in Anterior Segment After Phakic Collamer Lens Implantation. AB - PURPOSE: To assess the changes and relationship in central vaulting, flare intensity, and crystalline lens thickness during a follow-up period of 4 years after implantable collamer lens (ICL) implantation in eyes with high myopia. DESIGN: Retrospective observational study. METHODS: Ninety-eight eyes of 50 patients were followed up with routine measurements of central vaulting, crystalline lens thickness, endothelial cell density, and aqueous flare postoperatively. Data were analyzed by repeated-measures analysis of variance. The relationship between the annual change in crystal lens thickness after surgery and age was evaluated by Pearson correlation coefficient and linear regression. RESULTS: There was a continuous reduction in central vaulting and endothelial cell density as well as an increase in crystalline lens thickness in ICL eyes from 1 month onward to 5 years postoperatively (P < .001). Although the trend of variation during the individual visit period was accentuated, the variation turned out to be smaller between 12 and 36 months or 60 months postoperatively (P = .42, P = .65). Aqueous flare intensity increased significantly after surgery and returned to normal 1 year later. Additionally, a positive correlation between patient age and crystalline lens thickness (r = 0.617, P < .0001) was observed in eyes with ICL implantation. CONCLUSIONS: The changes in central vaulting, endothelial cell density, and crystalline lens thickness are more prominent during the first year after ICL implantation, tending to be relatively stable afterwards. The anterior inflammation during the early postoperative period synchronizes with the sharp progression of crystalline lens changes within the first year. PMID- 28342722 TI - The effects of graft size and insertion site location during anterior cruciate ligament reconstruction on intercondylar notch impingement. AB - BACKGROUND: Intercondylar notch impingement is detrimental to the anterior cruciate ligament (ACL). Notchplasty is a preventative remodeling procedure performed on the intercondylar notch during ACL reconstruction (ACLR). This study investigates how ACL graft geometry and both tibial and femoral insertion site location may affect ACL-intercondylar notch interactions post ACLR. A range of ACL graft sizes are reported during ACLR, from six millimeters to 11mm in diameter. Variability of three millimeters in ACL insertion site location is reported during ACLR. This study aims to determine the post-operative effects of minor variations in graft size and insertion location on intercondylar notch impingement. METHODS: Several 3D finite element knee joint models were constructed using three ACL graft sizes and polar arrays of tibial and femoral insertion locations. Each model was subjected to flexion, tibial external rotation, and valgus motion. Impingement force and contact area between the ACL and intercondylar notch compared well with experimental cadaver data from literature. RESULTS: A three millimeter anterior-lateral tibial insertion site shift of the maximum size ACL increased impingement force by 242.9%. A three millimeter anterior-proximal femoral insertion site shift of the maximum size ACL increased impingement by 346.2%. Simulated notchplasty of five millimeters eliminated all impingement for the simulation with the greatest impingement. For the kinematics applied, small differences in graft size and insertion site location led to large increases in impingement force and contact area. CONCLUSIONS: Minor surgical variations may increase ACL impingement. The results indicate that notchplasty reduces impingement during ACLR. Notchplasty may help to improve ACLR success rates. PMID- 28342723 TI - Effects of eccentric overload training on patellar tendon and vastus lateralis in three days of consecutive running. AB - BACKGROUND: The analysis of structural changes in patellar tendon and muscle of healthy subjects in response to mechanical loads provides useful insight into the mechanism underlying overuse injuries. METHODS: Changes produced in tendon and muscles structures after eccentric overload training and three consecutive running days were examined. Twenty healthy subjects were recruited and divided into two groups. One group (ECC) performed eccentric overload squat training (six weeks). After such training, the ECC group performed three running sessions on consecutive days, as did the control group (CONT). The structure of their patellar tendons and vastus lateralis muscles was quantified using ultrasound and Doppler imaging. Images were obtained before and after eccentric training for the ECC group and on every day of running performance for both groups. RESULTS: After eccentric training, the ECC group experienced an increase in cross-sectional area (CSA) of patellar tendon (P=0.012). After every day of running, the ECC group experienced a decrease in CSA (P=0.027). In the CONT group, after one day of running a significant increase was observed in anteroposterior width of their patellar tendon (P=0.028), as well as a decrease in pennation angle of vastus lateralis muscle (P=0.028) within three days of running sessions. CONCLUSIONS: Eccentric overload training brought about changes in the patellar tendon consistent with an improvement in the quality of the tissue. The ECC group in our study showed a more normalised pattern than the CONT group in the running performance, in agreement with previous research. LEVEL OF EVIDENCE: Level 3, controlled trial. PMID- 28342724 TI - A Hypergraph and Arithmetic Residue-based Probabilistic Neural Network for classification in Intrusion Detection Systems. AB - Over the past few decades, the design of an intelligent Intrusion Detection System (IDS) remains an open challenge to the research community. Continuous efforts by the researchers have resulted in the development of several learning models based on Artificial Neural Network (ANN) to improve the performance of the IDSs. However, there exists a tradeoff with respect to the stability of ANN architecture and the detection rate for less frequent attacks. This paper presents a novel approach based on Helly property of Hypergraph and Arithmetic Residue-based Probabilistic Neural Network (HG AR-PNN) to address the classification problem in IDS. The Helly property of Hypergraph was exploited for the identification of the optimal feature subset and the arithmetic residue of the optimal feature subset was used to train the PNN. The performance of HG AR PNN was evaluated using KDD CUP 1999 intrusion dataset. Experimental results prove the dominance of HG AR-PNN classifier over the existing classifiers with respect to the stability and improved detection rate for less frequent attacks. PMID- 28342725 TI - Editorial overview: Biofortification of crops: achievements, future challenges, socio-economic, health and ethical aspects. PMID- 28342726 TI - Noninvasive prenatal testing for fetal aneuploidy and single gene disorders. AB - Our concept of nucleic acid biology has advanced dramatically over the past two decades, with a growing appreciation that cell-free DNA (cfDNA) fragments are present in all body fluids including plasma. In no other field has plasma DNA been as rapidly translated into clinical practice as in noninvasive prenatal testing (NIPT) for fetal chromosome abnormalities. NIPT is a screening test that requires confirmation with diagnostic testing, but other applications of cfDNA provide diagnostic information and do not require invasive testing. These applications are referred to as noninvasive prenatal diagnosis (NIPD) and include determination of fetal sex, blood group and some single gene disorders. As technology advances, noninvasive tests based on cell-free nucleic acids will continue to expand. This review will outline the technical and clinical aspects of NIPT and NIPD relevant to the daily practice of maternity carers. PMID- 28342727 TI - Pancreatic hematoma due to ruptured splenic pseudoaneurysm mimicking pancreatic malignancy. PMID- 28342728 TI - Comparative Analysis for Diagnostic Yield of Small Cell Lung Cancer by Cytology and Histology During the Same Bronchoscopic Procedure. AB - BACKGROUND: Biopsy, brushing, and transbronchial needle aspiration (TBNA) are the most common methods used for the diagnosis of small cell lung cancer during the same diagnostic bronchoscopic procedure. However, it is not clear which method provides better results. PATIENTS AND METHODS: A retrospective analysis was performed of 140 patients who had undergone video bronchoscopy for diagnostic purposes. Bronchial brushings were obtained from all subjects. Biopsy specimens were also obtained from all subjects, except for 6 cases that could not be sampled; the TBNA method was used for some special lesions. The results were analyzed separately by histology and cytology. RESULTS: The diagnostic yield of cytology was significantly greater than that of histology (P < .01) and that of conventional smear preparations in cytology was obviously greater than that of hematoxylin and eosin stains in histology (P < .01). The false-negative results were significantly lower with cytology than with histology (P < .01). Also, the cases of sampling site restriction with cytology were distinctly less than those with histology (P < .05). Stretch deformation of the tissue structure and cell morphology was the main reason for the false-negative results in the histologic diagnosis. The use of TBNA resolved all 4 cases of hilar adenopathy and 2 cases of lesions outside the bronchus. Multiple brushings of the tissue adjacent to cancer tissue and liquid-based preparations of cancerous necrotic tissue can significantly reduce the false-negative results from biopsy. CONCLUSIONS: The diagnostic yield of cytologic examination of brushings and TBNA for small cell lung cancer was superior to that of histologic examination of hematoxylin and eosin stains and immunohistochemistry. PMID- 28342729 TI - Repeatability and agreement of Scheimpflug-based and swept-source optical biometry measurements. AB - PURPOSE: To evaluate the repeatability and comparability of biometry parameters between a Scheimpflug-based topography with axial length measurement (Pentacam AXL, Oculus, Wetzlar, Germany) and a swept-source optical biometry (IOLMaster 700, Carl Zeiss Meditec AG, Jena, Germany). METHODS: A total of 50 eyes from 50 adult subjects had biometry measurements in one session three times using the Pentacam AXL and the IOLMaster 700. Keratometry, anterior chamber depth (ACD) and axial length (AL) values were obtained by both devices. Mean keratometry (Kmean) was calculated and the corneal spherocylinder was converted into power vectors (J0, J45). Repeatability was assessed based on intraclass correlation coefficient (ICC). Agreement was evaluated by linear regression analysis and Bland-Altman analysis by calculating the mean difference and 95% limits of agreement (LoA). RESULTS: Assessment of intraoperator repeatability by means of ICC showed excellent reproducibility of measurements for both devices and all parameters examined ranging from 0.994 to 1.0. IOLMaster 700 exhibited significantly higher Kmean (p<0.001) and AL (p<0.001) values than the Pentacam AXL. Pentacam AXL showed significantly higher ACD (p<0.001) measurements than IOLMaster 700. There was no statistically significant difference of J0 (p=0.115) and J45 (p=0.255) values between Pentacam AXL and IOLMaster 700. CONCLUSIONS: Both devices provide high reproducible values for all parameters investigated. J0 and J45 values are statistically and clinically interchangeable between Pentacam AXL and IOLMaster 700. All other parameters are statistically different. In clinical practice, the differences for ACD and AL are to small and the values can be used interchangeable. However, Kmean values are clinically and statistically different and cannot be used interchangeable between the two devices. PMID- 28342730 TI - The association of dietary inflammatory potential with depression and mental well being among U.S. adults. AB - Current treatment for depression is not considered effective among all cases and, thus far, nutritional protocols are minimal within depression treatment guidelines. Recently, there has been increasing interest in a possible protective and modifiable role of diet in common mental disorders, including depression, due to pro- and anti-inflammatory properties of nutrients. This study aims to investigate whether the Dietary Inflammatory Index (DII), designed to estimate the inflammatory potential of diet, is associated with depression and other measures of mental health. In a representative sample of U.S. adults (>=20years of age, N=11,592), the distribution of DII score is assessed. Multivariate logistic regression models determine the association between DII quintile and depression. Associations of DII quintile with frequent distress and frequent anxiety are also evaluated. In fully adjusted models, higher DII score is associated with over a two-fold higher odds of depression (OR (95% CI)=2.26 (1.60, 3.20) for highest vs. lowest quintile, Type III p-value<=0.0001). DII score is also associated with higher odds of frequent distress (OR (95% CI)=1.81 (1.20, 2.71) for highest vs. lowest quintile, Type III p-value=0.0167). This association was not significant for frequent anxiety (Type III p-value=0.12). Results of this study indicate that dietary inflammatory potential is associated with depression. These results are consistent with existing hypotheses that inflammatory pathways play a role in the etiology of depression. Further research examining the underlying biological and cellular mechanisms of depression is warranted. PMID- 28342732 TI - Hydrogen bond strength in membrane proteins probed by time-resolved 1H-detected solid-state NMR and MD simulations. AB - 1H-detected solid-state NMR in combination with 1H/2D exchange steps allows for the direct identification of very strong hydrogen bonds in membrane proteins. On the example of the membrane-embedded potassium channel KcsA, we quantify the longevity of such very strong hydrogen bonds by combining time-resolved 1H detected solid-state NMR experiments and molecular dynamics simulations. In particular, we show that the carboxyl-side chain of the highly conserved residue Glu51 is involved in ultra-strong hydrogen bonds, which are fully-water-exposed and yet stable for weeks. The astonishing stability of these hydrogen bonds is important for the structural integrity of potassium channels, which we further corroborate by computational studies. PMID- 28342731 TI - Preferred Management of Primary Deep Arm Vein Thrombosis. AB - OBJECTIVE: Given its rarity, the management of primary upper extremity deep vein thrombosis is controversial. Although anticoagulation alone is commonly advocated for its treatment, it is unclear if this will reduce the risk of developing post thrombotic syndrome (PTS). The aim of this "Evidence Driven" Clinical Scenario is to evaluate whether more aggressive treatments (including catheter directed thrombolysis or surgery) might help reduce the risk of PTS or recurrent venous thromboembolism in patients with primary upper extremity deep vein thrombosis (DVT). METHODS: An electronic systematic review of Ovid MEDLINE and Embase was conducted. Randomised controlled trials and observational studies were eligible. The primary outcome was PTS. RESULTS: The initial search identified 146 articles, and 36 more were identified during a secondary search. In total, 25 studies, reporting the outcome of 1271 patients, were included. None of the studies included was a randomised controlled trial and the large majority of studies were retrospective cohorts. The use of anticoagulation alone was associated with a significant risk of PTS. In patients treated with surgery with or without thrombolysis the incidence of PTS was significantly reduced. CONCLUSION: Current evidence, albeit with some methodological limitations, suggests that anticoagulation may not be sufficient to prevent PTS in patients with primary upper extremity DVT and that surgery with or without thrombolysis to repair the anatomical defects is needed. PMID- 28342733 TI - Probing intermolecular interactions in a diethylcarbamazine citrate salt by fast MAS 1H solid-state NMR spectroscopy and GIPAW calculations. AB - Fast magic-angle spinning (MAS) NMR is used to probe intermolecular interactions in a diethylcarbamazine salt, that is widely used as a treatment against adult worms of Wuchereria bancrofti which cause a common disease in tropical countries named filariasis. Specifically, a dihydrogen citrate salt that has improved thermal stability and solubility as compared to the free form is studied. One dimensional 1H, 13C and 15N and two-dimensional 1H-13C and 14N-1H heteronuclear correlation NMR experiments under moderate and fast MAS together with GIPAW (CASTEP) calculations enable the assignment of the 1H, 13C and 14N/15N resonances. A two-dimensional 1H-1H double-quantum (DQ) -single-quantum (SQ) MAS spectrum recorded with BaBa recoupling at 60kHz MAS identifies specific proton proton proximities associated with citrate-citrate and citrate-diethylcarbamazine intermolecular interactions. PMID- 28342734 TI - Integration of microbiome and epigenome to decipher the pathogenesis of autoimmune diseases. AB - The interaction between genetic predisposition and environmental factors are of great significance in the pathogenesis and development of autoimmune diseases (AIDs). The human mucosa is the most frequent site that interacts with the exterior environment, and commensal microbiota at the gut and other human mucosal cavities play a crucial role in the regulation of immune system. Growing evidence has shown that the compositional and functional changes of mucosal microbiota are closely related to AIDs. Gut dysbiosis not only influence the expression level of Toll-like receptors (TLRs) of antigen presenting cells, but also contribute to Th17/Treg imbalance. Epigenetic modifications triggered by environmental factors is an important mechanism that leads to altered gene expression. Researches addressing the role of DNA methylation, histone modification and non-coding RNA in AIDs have been increasing in recent years. Furthermore, studies showed that human microbiota and their metabolites can regulate immune cells and cytokines via epigenomic modifications. For example, short-chain fatty acids (SCFAs) produced by gut microbiota promote the differentiation of naive T cell into Treg by suppressing histone deacetylases (HDACs). Therefore, we propose that dysbiosis and resulting metabolites may cause aberrant immune responses via epigenetic modifications, and lead to AIDs. With the development of high-throughput sequencing, metagenome analysis has been applied to investigate the dysbiosis in AIDs patients. We have tested the fecal, dental and salivary samples from treatment-naive rheumatoid arthritis (RA) individuals by metagenomic shotgun sequencing and a metagenome-wide association study. Dysbiosis was detected in the gut and oral microbiomes of RA patients, but it was partially restored after treatment. We also found functional changes of microbiota and molecular mimicry of human antigens in RA individuals. By integrating the analysis of multi-omics of microbiome and epigenome, we could explore the interaction between human immune system and microbiota, and thereby unmasking specific and more sensitive biomarkers as well as potential therapeutic targets. Future studies aiming at the crosstalk between human dysbiosis and epigenetic modifications and their influences on AIDs will facilitate our understanding and better managing of these debilitating AIDs. PMID- 28342736 TI - Amyloidogenicity at a Distance: How Distal Protein Regions Modulate Aggregation in Disease. AB - The misfolding of proteins to form amyloid is a key pathological feature of several progressive, and currently incurable, diseases. A mechanistic understanding of the pathway from soluble, native protein to insoluble amyloid is crucial for therapeutic design, and recent efforts have helped to elucidate the key molecular events that trigger protein misfolding. Generally, either global or local structural perturbations occur early in amyloidogenesis to expose aggregation-prone regions of the protein that can then self-associate to form toxic oligomers. Surprisingly, these initiating structural changes are often caused or influenced by protein regions distal to the classically amyloidogenic sequences. Understanding the importance of these distal regions in the pathogenic process has highlighted many remaining knowledge gaps regarding the precise molecular events that occur in classic aggregation pathways. In this review, we discuss how these distal regions can influence aggregation in disease and the recent technical and conceptual advances that have allowed this insight. PMID- 28342735 TI - Inhibition of effector antigen-specific T cells by intradermal administration of heme oxygenase-1 inducers. AB - Developing protocols aimed at inhibiting effector T cells would be key for the treatment of T cell-dependent autoimmune diseases including type 1 autoimmune diabetes (T1D) and multiple sclerosis (MS). While heme oxygenase-1 (HO-1) inducers are clinically approved drugs for non-immune-related diseases, they do have immunosuppressive properties when administered systemically in rodents. Here we show that HO-1 inducers inhibit antigen-specific effector T cells when injected intradermally together with the T cell cognate antigens in mice. This phenomenon was observed in both a CD8+ T cell-mediated model of T1D and in a CD4+ T cell-dependent MS model. Intradermal injection of HO-1 inducers induced the recruitment of HO-1+ monocyte-derived dendritic cell (MoDCs) exclusively to the lymph nodes (LN) draining the site of intradermal injection. After encountering HO-1+MoDCs, effector T-cells exhibited a lower velocity and a reduced ability to migrate towards chemokine gradients resulting in impaired accumulation to the inflamed organ. Intradermal co-injection of a clinically approved HO-1 inducer and a specific antigen to non-human primates also induced HO-1+ MoDCs to accumulate in dermal draining LN and to suppress delayed-type hypersensitivity. Therefore, in both mice and non-human primates, HO-1 inducers delivered locally inhibited effector T-cells in an antigen-specific manner, paving the way for repositioning these drugs for the treatment of immune-mediated diseases. PMID- 28342737 TI - Are lower urinary tract symptoms in children associated with urinary symptoms in their mothers? AB - BACKGROUND: The association between parents who suffered daytime incontinence as children and children who are incontinence has been reported. However, the association of lower urinary tract (LUT) dysfunction in children and urinary symptoms in mothers has not been studied. OBJECTIVE: To test the hypothesis that the children of mothers with lower urinary tract symptoms (LUTS) are more likely to have urinary symptoms. STUDY DESIGN: A cross-sectional multicenter study was conducted in two cities in Brazil. Children/adolescents of 5-17 years of age and their mothers were interviewed. Children with neurological problems, previously detected urinary tract abnormalities or who refused to sign the informed consent or assent form were excluded. The DVSS questionnaire was used to evaluate the presence of LUTS in the children and the ICIQ-OAB questionnaire was used to evaluate their mothers. Constipation in the children was investigated using the ROME III criteria. RESULTS: A total of 827 mother-child pairs were included, with 414 of the children (50.06%) being male. Mean age was 9.1 +/- 2.9 years for the children and 35.9 +/- 6.5 years for the mothers. Urinary symptoms (occurring at least once or twice a week) were present in 315 children (38.1%), incontinence in 114 (13.8%) and urinary urgency in 141 (17%). Of the mothers, 378 (45.7%) had at least one LUTS, with 103 (12.5%) having incontinence and 153 (18.5%) urgency. According to the DVSS, the overall prevalence of LUT dysfunction was 9.1%. The children's DVSS scores were significantly associated with the mothers' ICIQ-OAB scores (p < 0.0010). Mothers with urinary symptoms were 2.5 times more likely to have a child with LUT dysfunction (95%CI: 1.52-4.17; p < 0.001), while mothers with overactive bladder were 2.8 times more likely to have a child with an overactive bladder (95%CI: 1.63-4.86; p < 0.001). In the multivariate analysis, these same characteristics were confirmed as independent predictive factors of the presence of LUT dysfunction in the child. Children of mothers with incontinence and urinary urgency were also more likely to have incontinence and urgency. CONCLUSION: Mothers with typical symptoms of overactive bladder are more likely to have a child with LUT dysfunction. This correlation is also positive for the isolated symptoms of urinary urgency and incontinence. Independent predictive factors of the presence of LUT dysfunction in children were: being female, enuresis, constipation, and having a mother with LUTS. PMID- 28342739 TI - Supervised physical therapy vs home exercise program for patients with distal radius fracture: A single-blind randomized clinical study. AB - STUDY DESIGN: Randomized clinical study. INTRODUCTION: Supervised physical therapy (PT) and home exercise programs (HEPs) are frequently used in the rehabilitation of patients with distal radius fracture (DRF). However, there is no consensus as to whether unsupervised HEP provides comparable benefits to those achieved by supervised PT. PURPOSE OF THE STUDY: To compare the improvements in pain and functional status between a supervised PT program and unsupervised HEP in DRF patients older than 60 years. METHODS: A total of 74 patients were randomized into 2 groups. One group received 12 sessions of supervised PT (n = 37), and the other group followed an exercise program at home (n = 37). Three evaluations were performed, before the initiation of treatment, at 6-week, and 6 month follow-up. The study conducted a statistical power analysis to detect an intergroup difference score of 15 points on the Patient-Rated Wrist Evaluation (PRWE). The t-test or Mann-Whitney test was used, and it was set with a significance level of .05. RESULTS: The supervised PT group showed clinically significant differences in the total PRWE score at 6 weeks (17.67 points, P = .000) in the PRWE function score (15.2 points, P = .000) and in the PRWE pain score (5.6 points, P = .039). There was also a significant difference in the total PRWE score at 6-month follow-up (17.05 points, P = .000) in the PRWE function score (14.5 points, P = .000) and in the PRWE pain score (2.5 points, P = .35). CONCLUSIONS: A supervised PT program is more effective for improving function in the short- and medium-term when compared with HEP in patients older than 60 years with DRF extraarticular without immediate complications. LEVEL OF EVIDENCE: 1b. PMID- 28342738 TI - American Brachytherapy Society consensus statement for soft tissue sarcoma brachytherapy. AB - PURPOSE: Radiation therapy represents an essential treatment option in the management of soft tissue sarcomas (STS). Brachytherapy represents an important subset of radiation therapy techniques used for STS, with evolving indications and applications. Therefore, the purpose of this guideline was to update clinicians regarding the data surrounding brachytherapy (BT) and provide recommendations for the utilization of BT in patients with STS. METHODS AND MATERIALS: Members of the American Brachytherapy Society with expertise in STS, and STS BT in particular, created an updated guideline for the use of BT in STS based on a literature review and clinical experience. RESULTS: Guidelines are presented with respect to dose and fractionation and technical features to improve outcomes and potentially reduce the risk of toxicity. Brachytherapy as monotherapy can be considered in low-risk cases or in situations where re irradiation is being considered. Brachytherapy boost can be considered in cases at higher risk of recurrence or where BT alone cannot adequately cover the target volume. To limit wound complications, the start of BT delivery should be delayed until final wound closure, or if after immediate reconstruction, started after postoperative Day 5. CONCLUSIONS: The current guidelines have been created to provide clinicians with a review of the data supporting BT in the management of STS as well as providing indications and technique guidelines to ensure optimal patient selection and clinical outcomes. PMID- 28342740 TI - The development of a real-time reverse transcription-polymerase chain reaction (rRT-PCR) assay using TaqMan technology for the pan detection of bluetongue virus (BTV). AB - Bluetongue virus (BTV) is an infectious, non-contagious viral disease of domestic and wild ruminants that is transmitted by adult females of certain Culicoides species. Since 2006, several serotypes including BTV-1, 2, 4, 6, 8, 9 and 16, have spread from the Mediterranean basin into Northern Europe for the first time. BTV-8 in particular, caused a major epidemic in northern Europe. As a result, it is evident that most European countries are at risk of BTV infection. The objective of this study was to develop and validate a real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) assay based on TaqMan technology for the detection of representative strains of all BTV serotypes. Primers and probes were based on genome segment 10 of the virus, the NS3 gene. The assay was tested for sensitivity, and specificity. The analytical sensitivity of the rRT-PCR assay was 200 copies of RNA per reaction. The assay did not amplify the closely related orbivirus epizootic hemorrhagic disease virus (EHDV) but successfully detected all BTV reference strains including clinical samples from animals experimentally infected with BTV-8. This real time RT-PCR assay offers a sensitive, specific and rapid alternative assay for the pan detection of BTV that could be used as part of a panel of diagnostic assays for the detection of all serotypes of BTV. PMID- 28342741 TI - Treatment of Secondary Vestibulodynia with Conjugated Estrogen Cream: A Pilot, Double-Blind, Randomized Placebo-Controlled Trial. AB - OBJECTIVE: To assess the efficacy of conjugated equine estrogen cream in reducing dyspareunia associated with secondary provoked vestibulodynia. METHODS: We conducted a randomized, double-blind, placebo-controlled trial that included women with secondary provoked vestibulodynia. Participants were randomly allocated to daily application of conjugated equine estrogen cream on the vulvar vestibule (estrogen group) or daily application of a similar placebo cream (placebo group). All patients were evaluated before and after eight weeks of treatment, using a visual analogue scale for superficial dyspareunia (primary outcome), the McGill Pain Questionnaire for superficial dyspareunia, the Female Sexual Function Index for sexual satisfaction, and vulvoscopy for vestibular erythema. RESULTS: The targeted recruitment for this study was 44 women, but because of funding shortfalls recruitment was limited to 20 women. These 20 participants were randomly assigned to two groups of 10. Improvement of superficial dyspareunia on the visual analogue scale was not significantly different between the two groups (estrogen group: 27% improvement vs. placebo group: 3% improvement, P = 0.29). However, the use of conjugated equine estrogen cream was associated with a significant post-treatment improvement in superficial dyspareunia and in all three secondary outcomes (P < 0.05), whereas this was not the case with the use of placebo. CONCLUSION: Daily application of conjugated equine estrogen cream to the vulvar vestibule could potentially reduce superficial dyspareunia in women with secondary provoked vestibulodynia, but a randomized trial with adequate statistical power will be required to demonstrate this. PMID- 28342742 TI - Should HPV Vaccination Be Offered to Mid-adult Women? PMID- 28342743 TI - Measurement of ion fluxes across epithelia. AB - Epithelial tissues line all wet surfaces of vertebrate bodies. Their major function is directional transport of ions and water. Cells forming an epithelial layer are bound together by a tight junction that forms a barrier to ion flux. Ions and water are transported via specialized molecules. The presence of a defect in a single ion channel molecule leads to cystic fibrosis - the most common, fatal, human genetic disease. The paper describes ion transport data obtained by means of different experimental techniques. Special attention is given to radiochemical tracers, transepithelial resistance determination, open circuit potential and short circuit current measurements, the nasal potential difference in healthy and cystic fibrosis patients, the use of ion selective electrodes, and electrochemical mapping of the cell membrane surface. The effect of different activators and blockers of ion transport molecules on measured parameters are also discussed. PMID- 28342744 TI - Synthesis and anti-cancer activity of chiral tetrahydropyrazolo[1,5-a]pyridine fused steroids. AB - Regio- and stereoselective synthesis of novel chiral 4,5,6,7 tetrahydropyrazolo[1,5-a]pyridine-fused steroids via [8pi+2pi] cycloaddition of diazafulvenium methides with steroidal scaffolds is reported. The biological evaluation of the new family of hexacyclic steroids as anti-cancer agents was also carried out. Hexacyclic steroids bearing a benzyl group at C-22, derived from 16-dehydropregnenolone and 16-dehydroprogesterone, show considerable cytotoxicity against EL4 (murine T-lymphoma) in contrast with the corresponding C 22-unsubstituted derivatives showing low cytotoxicity. Thus, results indicate that the presence of the benzyl group is important to ensure cytotoxicity. PMID- 28342745 TI - Culture of non-typeable Haemophilus influenzae from the nasopharynx: Not all media are equal. AB - The efficacy of chocolate agar, versus bacitracin, vancomycin, clindamycin, chocolate agar (BVCCA) for the isolation of non-typeable Haemophilus influenzae (NTHi) from nasopharyngeal swabs was determined. BVCCA cultured NTHi from 97.3% of NTHi-positive swabs, compared to 87.1% for chocolate agar. To maximise culture sensitivity, the use of both media is recommended. PMID- 28342746 TI - Diagnosing acute HIV infection: The performance of quantitative HIV-1 RNA testing (viral load) in the 2014 laboratory testing algorithm. AB - New recommendations for laboratory diagnosis of HIV infection in the United States were published in 2014. The updated testing algorithm includes a qualitative HIV-1 RNA assay to resolve discordant immunoassay results and to identify acute HIV-1 infection (AHI). The qualitative HIV-1 RNA assay is not widely available; therefore, we evaluated the performance of a more widely available quantitative HIV-1 RNA assay, viral load, for diagnosing AHI. We determined that quantitative viral loads consistently distinguished AHI from a false-positive immunoassay result. Among 100 study participants with AHI and a viral load result, the estimated geometric mean viral load was 1,377,793copies/mL. PMID- 28342748 TI - RNAi of arcRNA hsromega affects sub-cellular localization of Drosophila FUS to drive neurodiseases. AB - Defective RNA metabolism is common pathogenic mechanisms involved in neurological disorders. Indeed, a conspicuous feature of some neurodegenerative diseases is the loss of nuclear activities of RNA-binding proteins (RBPs) like Fused in sarcoma (FUS) and eventually, their accumulation in cytoplasmic proteinaceous inclusions. Long non-coding RNAs (lncRNAs) are emerging as important regulators of tissue physiology and disease processes, including neurological disorders. A subset of these lncRNAs is the core of nuclear bodies (NBs), which are the sites of RNA processing and sequestration of specific ribonucleoproteins (RNPs) complexes. In Drosophila melanogaster the lncRNA hsromega is the architectural RNA (arcRNA) of the NB omega speckles (omega-speckles). Here, we show that the neuron-specific and motor neuron-specific knockdown of hsromega impairs locomotion in larval and adult flies and induces anatomical defects in presynaptic terminals of motor neurons, suggesting a novel role of arcRNA hsromega in development of neuromuscular junctions. Since RBPs are recognized as important regulators of neuronal activities, to examine the molecular mechanism of such neurodegeneration, we analysed interaction between hsromega and Drosophila orthologue of human FUS (dFUS). Strictly, we found that dFUS genetically and physically interacts with the arcRNA hsromega. Moreover, we revealed that a fine regulation of gene expression occurs between hsromega and dFUS and surprisingly, we uncover that depletion of hsromega affects the sub cellular compartmentalization of dFUS thus, enhancing its cytoplasmic localization and inducing its loss of nuclear function. The model we propose shows the role of arcRNA in diseases affecting the nervous system and in particular it elucidates the molecular mechanism underlying the loss of dFUS nuclear function in the absence of its mutations. Our new findings could provide new insights into the pathogenesis of neurodegenerative disease dependent on mis function or mis-localization of aggregation prone RNA binding proteins like FUS in Amyotrophic Lateral Sclerosis. PMID- 28342747 TI - Subthalamic nucleus beta and gamma activity is modulated depending on the level of imagined grip force. AB - Motor imagery involves cortical networks similar to those activated by real movements, but the extent to which the basal ganglia are recruited is not yet clear. Gamma and beta oscillations in the subthalamic nucleus (STN) vary with the effort of sustained muscle activity. We recorded local field potentials in Parkinson's disease patients and investigated if similar changes can be observed during imagined gripping at three different 'forces'. We found that beta activity decreased significantly only for imagined grips at the two stronger force levels. Additionally, gamma power significantly scaled with increasing imagined force. Thus, in combination, these two spectral features can provide information about the intended force of an imaginary grip even in the absence of sensory feedback. Modulations in the two frequency bands during imaginary movement may explain the rehabilitating benefit of motor imagery to improve motor performance. The results also suggest that STN LFPs may provide useful information for brain-machine interfaces. PMID- 28342749 TI - Characterizing the differential roles of striatal 5-HT1A auto- and hetero receptors in the reduction of l-DOPA-induced dyskinesia. AB - l-DOPA remains the benchmark treatment for Parkinson's disease (PD) motor symptoms, but chronic use leads to l-DOPA-induced dyskinesia (LID). The serotonin (5-HT) system has been established as a key modulator of LID and 5-HT1A receptors (5-HT1AR) stimulation has been shown to convey anti-dyskinetic effects. However, 5-HT1AR agonists often compromise clinical efficacy or display intrinsic side effects and their site(s) of actions remain debatable. Recently, highly selective G-protein biased 5-HT1AR agonists, F13714 and F15599, were shown to potently target 5-HT1A auto- or hetero-receptors, respectively. The current investigation sought to identify the signaling mechanisms and neuroanatomical substrates by which 5-HT1AR produce behavioral effects. In experiment 1, hemi-parkinsonian, l DOPA-primed rats received systemic injections of vehicle, F13714 (0.01 or 0.02mg/kg), or F15599 (0.06 or 0.12mg/kg) 5min prior to l-DOPA (6mg/kg), after which LID, motor performance and 5-HT syndrome were rated. Both compounds significantly reduced LID, without affecting motor performance, however, acute administration of F13714 significantly induced 5-HT syndrome at anti-dyskinetic doses. In experiment 2, we elucidated the role of striatal 5-HT1AR in the effects of F13714 and F15599. Hemi-parkinsonian, l-DOPA-primed rats received bilateral intra-striatal microinjections of either F13714 (0, 2 or 10MUg/side) or F15599 (0, 10 or 30MUg/side) 5min prior to systemic l-DOPA (6mg/kg). Intra-striatal effects mimicked systemic effects, suggesting that striatal 5-HT1AR sub populations play an important role in the anti-LID and pro-5-HT syndrome profiles of F13714 and F15599. Finally, in experiment 3, we examined the effects of F13714 and F15599 on D1 receptor (D1R) agonist-induced dyskinesia by administering either compound 5min prior to SKF 38393 (2mg/kg). While F13714 resulted in a mild delay in D1R-mediated dyskinesia, F15599 had no effect. Collectively these data suggest that the F-series compounds articulate their anti-LID effects through activation of a diverse set of striatal 5-HT1A hetero-receptor populations. PMID- 28342751 TI - Reproducibility of four frequently used local heating protocols to assess cutaneous microvascular function. AB - BACKGROUND: Skin microvascular responses to local heating are frequently used to assess microvascular function. Several local heating protocols have been developed, all varying slightly in execution. The aim of this study was to determine the inter-day reproducibility of the four most commonly used local heating protocols in healthy young subjects. METHODS: Fifteen, healthy males (28+/-5yrs, BMI 25+/-2kg/m2) attended two experimental trials 2-7days apart. During each trial, baseline and maximal thermally stimulated forearm skin responses were examined simultaneously at four sites on the dominant forearm using laser Doppler flowmetry (LDF). The following heating protocols were adopted: 1. Rapid 39 degrees C (0.5 degrees C/5s), 2. Rapid 42 degrees C (0.5 degrees C/5s) 3. Gradual 42 degrees C (0.5 degrees C/2min 30s) and 4. Slow 42 degrees C (0.5 degrees C/5min). The coefficient of variation (CV) was calculated for absolute flux, cutaneous vascular conductance (CVC; flux/mean arterial pressure, MAP) and CVC expressed as a percentage of maximal CVC at 44 degrees C (%CVCmax) at three different time points; baseline (33 degrees C), plateau (39/42 degrees C) and maximal (44 degrees C). RESULTS: Reproducibility of baseline flux, CVC and %CVCmax was 17-29% across all protocols. During the plateau, Rapid, Gradual and Slow 42 degrees C demonstrated a reproducibility of 13-18% for flux and CVC and 5-11% for %CVCmax. However, Rapid 39 degrees C demonstrated a lower reproducibility for flux, CVC and %CVCmax (all 21%). Reproducibility at 44 degrees C was 12-15% for flux and CVC across all protocols. CONCLUSION: This is the first study examining inter-day reproducibility across four local heating protocols. The good-to-moderate reproducibility of the Rapid, Gradual and Slow 42 degrees C protocols support their (simultaneous) use to assess microvascular function. Using Rapid 39 degrees C may require a greater number of subjects to detect differences within subjects. PMID- 28342752 TI - Chitosan-doped-hybrid/TiO2 nanocomposite based sol-gel coating for the corrosion resistance of aluminum metal in 3.5% NaCl medium. AB - The study outlines the role of chitosan, a biopolymer on corrosion behavior of Hy/nano-TiO2 based sol-gel coating over aluminum metal. In this study organic inorganic hybrid sols were synthesized through hydrolysis and condensation of 3 glycidoxypropyltrimethoxy silane (GPTMS), tetraethoxysilane (TEOS) and titanium (IV) isopropoxide (TIP) in acidic solution. Chitosan was doped into sol-gel matrix and self-assembled over aluminum substrate. The resultant chitosan-doped Hy/nano-TiO2 sol-gel coating was characterized by Fourier Transform Infrared (FT IR) spectra, Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), Scanning Electron Microscopy (SEM), Atomic Force Microscopy (AFM) and Energy-Dispersive X ray Spectroscopy (EDX) analyses. The as-tailored aluminum substrate was evaluated for corrosion resistance in neutral medium. The protection ability of these coatings was evaluated by electrochemical impedance studies (EIS) and potentiodynamic polarization (PP) measurements in 3.5% NaCl medium. The EIS and PP results showed that chitosan-doped- Hy/nano-TiO2 sol-gel coating exhibited better protection from corrosion than the undoped Hy/TiO2 nanocomposite coating. PMID- 28342750 TI - Mutation of the caspase-3 cleavage site in the astroglial glutamate transporter EAAT2 delays disease progression and extends lifespan in the SOD1-G93A mouse model of ALS. AB - Downregulation in the astroglial glutamate transporter EAAT2 in amyotrophic lateral sclerosis (ALS) patients and mutant SOD1 mouse models of ALS is believed to contribute to the death of motor neurons by excitotoxicity. We previously reported that caspase-3 cleaves EAAT2 at a unique cleavage consensus site located in its c-terminus domain, a proteolytic cleavage that also occurs in vivo in the mutant SOD1 mouse model of ALS and leads to accumulation of a sumoylated EAAT2 C terminus fragment (CTE-SUMO1) beginning around onset of disease. CTE-SUMO1 accumulates in PML nuclear bodies of astrocytes and causes them to alter their mature phenotypes and secrete factors toxic to motor neurons. Here, we report that mutating the caspase-3 consensus site in the EAAT2 sequence with an aspartate to asparagine mutation (D504N), thereby inhibiting caspase-3 cleavage of EAAT2, confers protection to the SOD1-G93A mouse. EAAT2-D504N knock-in mutant mice were generated and crossed with SOD1-G93A mice to assess the in vivo pathogenic relevance for ALS symptoms of EAAT2 cleavage. The mutation did not affect normal EAAT2 function nor non-ALS mice. In agreement with the timing of CTE-SUMO1 accumulation, while onset of disease was not affected, the mutation caused an extension in progression time, a delay in the development of hindlimb and forelimb muscle weakness, and a significant increase in the lifespan of SOD1 G93A mice. PMID- 28342753 TI - Evaluation of chitosan as a wall material for microencapsulation of squalene by spray drying: Characterization and oxidative stability studies. AB - The present study was aimed at investigating the efficacy of chitosan as a wall material for microencapsulation of squalene by spray drying for functional food applications. Based on different core to wall material ratio (1:1, 0.5:1 and 0.3:1 on w/w basis), emulsions were prepared and evaluated in terms of emulsion stability, particle size, zeta potential, polydispersity Index (PDI), rheology and microstructure. The optimized emulsion combination was spray dried and characterized, physically and chemically. The encapsulation efficiency of the powder was found to be 26+/-0.6% whereas other properties such as particle size, zeta potential, water activity, hygroscopicity, Carr Index, Hausner ratio have shown satisfactory results. SEM analysis showed that the squalene microcapsules were smooth spherical particles free from dents and fissures. FTIR data further confirmed the encapsulation of squalene with chitosan. However, TGA, oxidative stability and accelerated Rancimat results showed that chitosan was not able to protect squalene from oxidation during storage. The results suggest that chitosan is not an appropriate wall material for microencapsulation of squalene and hence a combination of wall materials could be attempted for the encapsulation of squalene. PMID- 28342754 TI - Dietary supplementation of thiamine and pyridoxine-loaded vanillic acid-grafted chitosan microspheres enhances growth performance, metabolic and immune responses in experimental rats. AB - In the present investigation, the effect of dietary supplementation of thiamine and pyridoxine loaded vanillic acid-grafted chitosan microspheres (TPVGC) on growth, metabolic and immune responses in Wistar strain albino rats was studied. Eight experimental groups, namely four groups each for male and female rats were fed with 0, 0.4, 0.8 and 1.6% of TPVGC in the diet. At the end of 45days feeding trials, both male and female rats supplemented with TPVGC had higher weight gain% and specific growth rate than the control groups. Significantly (p<0.05) lower blood glucose level and higher respiratory burst activity were recorded in the treatment groups than the control groups of both male and female rats. Activity of metabolic enzymes (aspartate amino transferase, alanine aminotransferase, alkaline phosphatase and acid phosphatase) and antioxidant enzymes (superoxide dismutase, catalase and glutathione S-transferase) were significantly higher (p<0.05) in the control groups and a decreasing trend in the same was observed with a gradual increase in the inclusion level of TPVGC in the diet of the treatment groups. However, a reverse trend was observed for acetylcholine esterase. It was inferred that dietary supplementation of thiamine and pyridoxine loaded vanillic acid-grafted chitosan enhanced the growth performance, metabolic and immune responses in the animal-model. PMID- 28342755 TI - Mutation analysis of the interactions between Mycobacterium tuberculosis caseinolytic protease C1 (ClpC1) and ecumicin. AB - Ecumicin is a well-known and potent inhibitor of Mycobacterium tuberculosis. Although the target of ecumicin is caseinolytic protease C1 (ClpC1), the exact mechanism by which ecumicin inhibits ClpC1 has not been identified. To analyze ecumicin's action on ClpC1, site-directed mutagenesis was performed on its binding site. The estimated binding residues within ClpC1 to ecumicin were selected via in silico analysis using molecular docking. The selected residues were mutated by site-directed mutagenesis and the effects on ecumicin binding were analyzed. Mutation at the R83 residue, especially the R83A mutation, in ClpC1 resulted in strong resistance to ATPase activation and inhibition of proteolytic activity. In addition, binding of ecumicin to the R83A ClpC1 N terminal domain (residues 1-145) was not observed in native gel analysis. These results reveal that the R83 residue plays an important role in the binding of ecumicin. This result provides a basis for the development of an anti tuberculosis agent based on ecumicin derivatives. PMID- 28342756 TI - Photocatalytic and antimicrobial activities of chitosan-TiO2 nanocomposite. AB - Chitosan, a natural polysaccharide widely used for various biological applications due to their potential benefits. Incorporation of biomaterials with semiconductor has been exploited for waste water treatment and biological applications due to their nanometric sizes and biocompatibility of chitosan. Chitosan-Titanium dioxide (CS-TiO2) nanocomposite was synthesized and their optical, structural, spectral, thermal, morphological and elemental analyses were carried out by several techniques. The particle size of the synthesized CS-TiO2 nanocomposite was around 90nm and has a crystalline structure with anatase phase of TiO2. The prepared nanocomposite acts as a photocatalyst for the removal of rhodamine B (RhB) and congo red (CR) dyes under visible light irradiation. The pseudo first order kinetics was derived according to Langmuir-Hinshelwood (L-H) model. The nanocomposite also proved to be an excellent antimicrobial agent against Gram-positive and Gram-negative bacteria; and also show activity against fungus. The antimicrobial activity of the CS-TiO2 nanocomposites exhibits a zone of inhibition ranged between 10.333+/-0.5773 and 25.667+/-1.5275 (mm). PMID- 28342757 TI - Role of enzymatic free radical scavengers in management of oxidative stress in autoimmune disorders. AB - Autoimmune disorders are distinct with over production and accumulation of free radicals due to its undisclosed genesis. The cause of numerous disorders as cancer, arthritis, psoriasis, diabetes, alzheimer's, cardiovascular disease, Parkinson's, respiratory distress syndrome, colitis, crohn's, pulmonary fibrosis, obesity and ageing have been associated with immune dysfunction and oxidative stress. In an oxidative stress, reactive oxygen species generally provoke the series of oxidation at cellular level. The buildup of free radicals in turn triggers various inflammatory cells causing release of various inflammatory interleukins, cytokines, chemokines, and tumor necrosis factors which mediate signal transduction and transcription pathways as nuclear factor- kappa B (NF kappaB), signal transducer and activator of transcription 3 (STAT3), hypoxia inducible factor-1 (HIF-1alpha) and nuclear factor-erythroid 2-related factor (Nrf2). The imbalance could only be combat by supplementing natural defensive antioxidant enzymes such as superoxide dismutase and catalase. The efficiency of these enzymes is enhanced by use of colloidal carriers which include cellular carriers, vesicular and particulate systems like erythrocytes, leukocytes, platelets, liposomes, transferosomes, solid lipid nanoparticles, microspheres, emulsions. Thus this review provides a platform for understanding importance of antioxidant enzymes and its therapeutic applications in treatment of various autoimmune disorders. PMID- 28342758 TI - Effects of low-frequency ultrasound on heterogenous deacetylation of chitin. AB - The effects of low frequency ultrasound to the heterogeneous deacetylation of chitin from the shell of white shrimp (Penaeus vannamei) were examined. The deacetylation process was carried out in the range of NaOH concentrations from 35% to 65% (w/w) with and without the ultrasound in the frequency of 37kHz, RMS=300W. The chitosan obtained was characterized in the degree of deacetylation, solubility, FT-IR and X-ray diffraction. The results showed that the behaviors of the deacetylation in two cases, with and without ultrasound, were similar but the ultrasound enhanced the deacetylation rate and therefore reduced the time of the reaction to get the same degree of deacetylation. The role of ultrasound in the process showed more clearly in the low concentration of sodium hydroxide, below 45% (w/w). At the higher concentration of sodium hydroxide, the influence of ultrasound on facilitating deacetylation decreased significantly, however, ultrasound was still keeping on its improving effect on the solubility of the chitosan obtained. The data from FT-IR and X-ray diffraction did not show any considerable change in structure of both kinds of chitosan. This study showed the potential of using low frequency ultrasound in enhancing the deacetylation of chitin for reducing the chemical consumption. PMID- 28342760 TI - Correction of Hirschsprung-Associated Mutations in Human Induced Pluripotent Stem Cells Via Clustered Regularly Interspaced Short Palindromic Repeats/Cas9, Restores Neural Crest Cell Function. AB - BACKGROUND & AIMS: Hirschsprung disease is caused by failure of enteric neural crest cells (ENCCs) to fully colonize the bowel, leading to bowel obstruction and megacolon. Heterozygous mutations in the coding region of the RET gene cause a severe form of Hirschsprung disease (total colonic aganglionosis). However, 80% of HSCR patients have short-segment Hirschsprung disease (S-HSCR), which has not been associated with genetic factors. We sought to identify mutations associated with S-HSCR, and used the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing system to determine how mutations affect ENCC function. METHODS: We created induced pluripotent stem cell (iPSC) lines from 1 patient with total colonic aganglionosis (with the G731del mutation in RET) and from 2 patients with S-HSCR (without a RET mutation), as well as RET+/- and RET-/ iPSCs. IMR90-iPSC cells were used as the control cell line. Migration and differentiation capacities of iPSC-derived ENCCs were analyzed in differentiation and migration assays. We searched for mutation(s) associated with S-HSCR by combining genetic and transcriptome data from patient blood- and iPSC-derived ENCCs, respectively. Mutations in the iPSCs were corrected using the CRISPR/Cas9 system. RESULTS: ENCCs derived from all iPSC lines, but not control iPSCs, had defects in migration and neuronal lineage differentiation. RET mutations were associated with differentiation and migration defects of ENCCs in vitro. Genetic and transcriptome analyses associated a mutation in the vinculin gene (VCL M209L) with S-HSCR. CRISPR/Cas9 correction of the RET G731del and VCL M209L mutations in iPSCs restored the differentiation and migration capacities of ENCCs. CONCLUSIONS: We identified mutations in VCL associated with S-HSCR. Correction of this mutation in iPSC using CRISPR/Cas9 editing, as well as the RET G731del mutation that causes Hirschsprung disease with total colonic aganglionosis, restored ENCC function. Our study demonstrates how human iPSCs can be used to identify disease-associated mutations and determine how they affect cell functions and contribute to pathogenesis. PMID- 28342759 TI - Activation of Epithelial Signal Transducer and Activator of Transcription 1 by Interleukin 28 Controls Mucosal Healing in Mice With Colitis and Is Increased in Mucosa of Patients With Inflammatory Bowel Disease. AB - BACKGROUND & AIMS: We investigated the roles of interleukin 28A (also called IL28A or interferon lambda2) in intestinal epithelial cell (IEC) activation, studying its effects in mouse models of inflammatory bowel diseases (IBD) and intestinal mucosal healing. METHODS: Colitis was induced in C57BL/6JCrl mice (controls), mice with IEC-specific disruption of Stat1 (Stat1IEC-KO), mice with disruption of the interferon lambda receptor 1 gene (Il28ra-/-), and mice with disruption of the interferon regulatory factor 3 gene (Irf3-/-), with or without disruption of Irf7 (Irf7-/-). We used high-resolution mini-endoscopy and in vivo imaging methods to assess colitis progression. We used 3-dimensional small intestine and colon organoids, along with RNA-Seq and gene ontology methods, to characterize the effects of IL28 on primary IECs. We studied the effects of IL28 on the human intestinal cancer cell line Caco-2 in a wound-healing assay, and in mice colon wounds. Colonic biopsies and resected tissue from patients with IBD (n = 62) and patients without colon inflammation (controls, n = 23) were analyzed by quantitative polymerase chain rection to measure expression of IL28A, IL28RA, and other related cytokines; biopsy samples were also analyzed by immunofluorescence to identify sources of IL28 production. IECs were isolated from patient tissues and incubated with IL28; signal transducer and activator of transcription 1 (STAT1) phosphorylation was measured by immunoblots and confocal imaging. RESULTS: Lamina propria cells in colon tissues of patients with IBD, and mice with colitis, had increased expression of IL28 compared with controls; levels of IL28R were increased in the colonic epithelium of patients with IBD and mice with colitis. Administration of IL28 induced phosphorylation of STAT1 in primary human and mouse IECs, increasing with dose. Il28ra-/-, Irf3-/-, Irf3-/-Irf7-/-, as well as Stat1IEC-KO mice, developed more severe colitis after administration of dextran sulfate sodium than control mice, with reduced epithelial restitution. Il28ra-/- and Stat1IEC-KO mice also developed more severe colitis in response to oxazolone than control mice. We found IL28 to induce phosphorylation (activation) of STAT1 in epithelial cells, leading to their proliferation in organoid culture. Administration of IL28 to mice with induced colonic wounds promoted mucosal healing. CONCLUSIONS: IL28 controls proliferation of IECs in mice with colitis and accelerates mucosal healing by activating STAT1. IL28 might be developed as a therapeutic agent for patients with IBD. PMID- 28342761 TI - Cardiovascular tolerance of intravenous bupivacaine in broiler chickens (Gallus gallus domesticus) anesthetized with isoflurane. AB - OBJECTIVE: To determine the median effective dose (ED50) of intravenous (IV) bupivacaine associated with a 50% probability of causing clinically relevant cardiovascular effects [defined as 30% change in heart rate (HR) or mean arterial pressure (MAP)] in chickens anesthetized with isoflurane. STUDY DESIGN: Randomized up-and-down study. ANIMALS: A total of 14 Ross-708 broiler chickens (Gallus gallus domesticus) weighing 1.70-2.75 kg. METHODS: Anesthesia was induced and maintained with isoflurane. Monitoring included the electrocardiogram and invasive arterial pressures. Chickens were administered bupivacaine IV over 2 minutes using a dose based on the response of the previous animal. Dose was decreased when HR and/or MAP in the previous animal increased or decreased >=30% after bupivacaine administration, or increased when HR or MAP changed <30%. The ED50 was defined as the dose resulting in >=30% variation in HR or MAP in 50% of the population studied. RESULTS: The IV ED50 of bupivacaine was 1.94 mg kg-1 using Dixon's up-and-down method and 1.96 mg kg-1 by logistic regression. CONCLUSIONS AND CLINICAL RELEVANCE: These results suggest that 1.33 and 1.96 mg kg-1 of IV bupivacaine are associated with a respective 1 or 50% probability of a clinically significant change in MAP in isoflurane-anesthetized chickens. Identification of the cardiovascular changes associated with different doses of bupivacaine can be used as the basis for studies of therapeutic applications in the domestic chicken. Further studies are required to determine interspecies variation. PMID- 28342762 TI - Male accessory gland proteins affect differentially female sexual receptivity and remating in closely related Drosophila species. AB - In sexual species, mating success depends on the male's capacity to find sexual partners and on female receptivity to mating. Mating is under evolutionary constraints to prevent interspecific mating and to maximize the reproductive success of both sexes. In Drosophila melanogaster, female receptivity to mating is mainly controlled by Sex peptide (SP, i.e. Acp70A) produced by the male accessory glands with other proteins (Acps). The transfer of SP during copulation dramatically reduces female receptivity to mating and prevents remating with other males. To date, female postmating responses are well-known in D. melanogaster but have been barely investigated in closely-related species or strains exhibiting different mating systems (monoandrous versus polyandrous). Here, we describe the diversity of mating systems in two strains of D. melanogaster and the three species of the yakuba complex. Remating delay and sexual receptivity were measured in cross-experiments following SP orthologs or Acp injections within females. Interestingly, we discovered strong differences between the two strains of D. melanogaster as well as among the three species of the yakuba complex. These results suggest that reproductive behavior is under the control of complex sexual interactions between the sexes and evolves rapidly, even among closely-related species. PMID- 28342763 TI - Serotonin and neuroplasticity - Links between molecular, functional and structural pathophysiology in depression. AB - Serotonin modulates neuroplasticity, especially during early life, and dysfunctions in both systems likewise contribute to pathophysiology of depression. Recent findings demonstrate that serotonin reuptake inhibitors trigger reactivation of juvenile-like neuroplasticity. How these findings translate to clinical antidepressant treatment in major depressive disorder remains unclear. With this review, we link preclinical with clinical work on serotonin and neuroplasticity to bring two pathophysiologic models in clinical depression closer together. Dysfunctional developmental plasticity impacts on later-life cognitive and emotional functions, changes of synaptic serotonin levels and receptor levels are coupled with altered synaptic plasticity and neurogenesis. Structural magnetic resonance imaging in patients reveals disease state-specific reductions of gray matter, a marker of neuroplasticity, and reversibility upon selective serotonin reuptake inhibitor treatment. Translational evidence from magnetic resonance imaging in animals support that reduced densities and sizes of neurons and reduced hippocampal volumes in depressive patients could be attributable to changes of serotonergic neuroplasticity. Since ketamine, physical exercise or learning enhance neuroplasticity, combinatory paradigms with selective serotonin reuptake inhibitors could enhance clinical treatment of depression. PMID- 28342764 TI - Ketamine as a rapid-acting agent for suicidal ideation: A meta-analysis. AB - The current systematic review and meta-analysis aimed at exploring acute effects of intravenous (IV) ketamine, an antagonist of N-methyl-D-aspartate (NMDA), in subjects with current suicidal ideation. We included clinical trials testing a single IV dose of ketamine and assessing changes in suicidal ideation within 4h after treatment. Meta-analyses based on random-effects models, were carried out generating pooled standardized mean differences (SMDs) between endpoint and baseline scores. Heterogeneity among studies was estimated using the I2 index. We searched main Electronic Databases, identifying five studies that met our inclusion criteria. The trials included 99 subjects treated with IV ketamine bolus or infusion. Data showed a large (SMD=-0.92; 95%CI: -1.40 to -0.44; p<0.001) and consistent (I2=21.6%) decrease of suicidal ideation, with effects comparable between IV bolus and infusion ketamine. Additional analyses confirmed the efficacy of ketamine across different time points. However, relevant, emerging evidence should be considered as 'very low' so far. Randomized, controlled and adequately powered trials are needed. PMID- 28342765 TI - Hippocampal insulin resistance and altered food decision-making as players on obesity risk. AB - There are increasing evidences that hippocampus can modulate the decision of what, when and how much to eat, in addition to its already recognized role in learning and memory processes. Insulin also has been linked to brain functions such as feeding behavior and the imbalance of its mechanism of action on hippocampus is being related to cognitive dysfunction. The discussion here is whether changes in insulin action could contribute to intake dysregulation and obesogenic behavior as a primary consequence of impairing hippocampal functioning, aside from the role of this hormone on obesity development through peripheral metabolic pathways. Excess intake of high-fat and high-sugar diets leads to insulin resistance, which disrupts hippocampal function. Hippocampal physiology is sensitive to signals of hunger and satiety, inhibiting the ability of food cues to evoke appetite and eating, therefore alterations in hippocampal integrity could affect food inhibitory control leading to increased intake and obesity. PMID- 28342766 TI - Antisocial behaviour and psychopathy: Uncovering the externalizing link in the P3 modulation. AB - In 2009, Gao and Raine's meta-analysis analysed P3 modulation over the antisocial spectrum. However, some questions remained open regarding the P3 modulation patterns across impulsive and violent manifestations of antisocial behaviour, phenotypic components of psychopathy, and P3 components. A systematic review of 36 studies was conducted (N=3514) to extend previous results and to address these unresolved questions. A clear link between decreased P3 amplitude and antisocial behaviour was found. In psychopathy, dimensional approaches become more informative than taxonomic models. Distinct etiological pathways of psychopathy were evidenced in cognitive tasks: impulsive-antisocial psychopathic traits mainly predicted blunted P3 amplitude, while interpersonal-affective psychopathic traits explained enhanced P3 amplitude. Supporting the low fear hypothesis, the interpersonal-affective traits were associated with reduced P3 amplitude in emotional-affective learning tasks. From the accumulated knowledge we propose a framework of P3 amplitude modulation that uncovers the externalizing link between psychopathy and antisocial behaviour. However, the main hypotheses are exploratory and call for more data before stablishing robust conclusions. PMID- 28342767 TI - Developing Cognitive Task Analysis-based Educational Videos for Basic Surgical Skills in Plastic Surgery. AB - OBJECTIVE: To describe the development of cognitive task analysis (CTA)-based multimedia educational videos for surgical trainees in plastic surgery. DESIGN: A needs assessment survey was used to identify 5 plastic surgery skills on which to focus the educational videos. Three plastic surgeons were video-recorded performing each skill while describing the procedure, and were interviewed with probing questions. Three medical student reviewers coded transcripts and categorized each step into "action," "decision," or "assessment," and created a cognitive demands table (CDT) for each skill. The CDTs were combined into 1 table that was reviewed by the surgeons performing each skill to ensure accuracy. The final CDTs were compared against each surgeon's original transcripts. The total number of steps identified, percentage of steps shared, and the average percentage of steps omitted were calculated. SETTING: Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada, an urban tertiary care teaching center. PARTICIPANTS: Canadian junior plastic surgery residents (n = 78) were sent a needs assessment survey. Four plastic surgeons and 1 orthopedic surgeon performed the skills. RESULTS: Twenty-eight residents responded to the survey (36%). Subcuticular suturing, horizontal and vertical mattress suturing, hand splinting, digital nerve block, and excisional biopsy had the most number of residents (>80%) rank the skills as being skills that students should be able to perform before entering residency. The number of steps identified through CTA ranged from 12 to 29. Percentage of steps shared by all 3 surgeons for each skill ranged from 30% to 48%, while the average percentage of steps that were omitted by each surgeon ranged from 27% to 40%. CONCLUSIONS: Instructional videos for basic surgical skills may be generated using CTA to help experts provide comprehensive descriptions of a procedure. A CTA-based educational tool may give trainees access to a broader, objective body of knowledge, allowing them to learn decision making processes before entering the operating room. PMID- 28342768 TI - Role of the lateral preoptic area in cardiovascular and neuroendocrine responses to acute restraint stress in rats. AB - The lateral preoptic area (LPO) is connected with limbic structures involved in physiological and behavioral responses to stress. Accordingly, exposure to stressors stimuli activates neurons within the LPO. In spite of these evidence, an involvement of the LPO on cardiovascular and neuroendocrine adjustments during aversive threats has not yet been investigated. Therefore, in the present study we tested the hypothesis that the LPO is involved in the control of cardiovascular and neuroendocrine responses to acute restraint stress in rats. Bilateral microinjection of the nonselective synaptic blocker CoCl2 (0.1nmol/100nl) into the LPO did not affect basal values of either arterial pressure, heart rate, tail skin temperature, or plasma corticosterone concentration. However, LPO treatment with CoCl2 enhanced the tachycardiac response and the increase in plasma corticosterone concentration caused by restraint stress. Conversely, LPO synaptic blockade decreased restraint-evoked pressor response. Sympathetic-mediated cutaneous vasoconstriction during restraint stress was not affected by LPO pharmacological treatment. These findings indicate an inhibitory influence of LPO on tachycardiac and plasma corticosterone responses evoked during aversive threats. Additionally, data suggest that LPO plays a facilitatory influence on stress-evoked pressor response. PMID- 28342769 TI - A laboratory study on attentional bias as an underlying mechanism affecting the link between cortisol and performance, leading to a discussion on the nature of the stressor (artificial vs. psychosocial). AB - Although cortisol is assumed to influence performance by affecting cognition during stressful and competitive situations, to date this assumption has not been tested empirically. Therefore, the aim of this study was to investigate whether the influence of cortisol on performance is mediated by attentional processing of emotional information. Forty-six male golfers were tested in a mixed design. The cold pressor task (CPT) was used to artificially increase cortisol levels in the experimental group relative to the control group, who had to put their forearm in warm water. Before and after water immersion the golfers performed one-armed 1.5 m puts and completed the Sport Emotional Stroop Task. Cortisol was significantly increased in the experimental group (CPT). Further, a significant decrease in attentional bias toward negative sport words was detected in the CPT group. However, no changes in putting performance due to an increase in cortisol were observed in the CPT group. Regarding the cortisol-performance relationship, the nature of the stressor (i.e., artificial vs. psychosocial) seems to play a role, as no connection was found in this study using an artificial stressor, whereas previous research using a psychosocial stressor (e.g., an actual competition) did find a connection. On the basis of these results I cautiously conclude that the subjective appraisal of a stressor, which is arguably higher for a psychosocial stressor, is more relevant for sport performance than just a change in cortisol level. However, as the stress response is psychophysiological in nature, future research should continue to investigate the role of cortisol. PMID- 28342770 TI - High risk no gain-metabolic performance of hatchery reared Atlantic salmon smolts, effects of nest emergence time, hypoxia avoidance behaviour and size. AB - When animals are reared for conservational releases it is paramount to avoid reducing genetic and phenotypic variation over time. This requires an understanding of how diverging behavioural and physiological traits affect performance both in captivity and after release. In Atlantic salmon, emergence time from the spawning gravel has been linked to certain behavioural and physiological characteristics and to the concept of stress coping styles. Early emerging fry has for example been shown to be bolder and more aggressive and to have higher standard metabolic rates compared to late emerging fry. The first aim was therefore to examine if emergence latency affect the behavioural stress coping response also beyond the fry and parr stage. This was done using a hypoxia avoidance test, where an active behavioural avoidance response can be related to higher risk taking. No behavioural differences were found between the two emergence fractions either at the parr or pre-smolt stage, instead smaller individuals were more prone to express an "active" hypoxia avoidance response. Further, an individual expressing a "passive" response as parr were also more prone to express this behaviour at the pre-smolt stage. While there are some previous studies showing that early emerging individuals with a bolder personality may be favored within a hatchery setting it is not known to what extent these early differences persist to affect performance after release. The second aim was therefore to compare the physiological performance at the time of release as smolts using the two subgroups; 1) early emerging fish showing active hypoxia avoidance (Early+Bold) and 2) late emerging fish showing a passive hypoxia response (Late+Shy). The Early+Bold group showed a higher red blood cell swelling, suggesting a higher adrenergic output during stress, whereas there was no difference in post-stress plasma cortisol or physiological smolt status. While there was no difference in standard metabolic rate between the groups, the Early+Bold group exhibited a lower maximum metabolic rate and aerobic scope following strenuous swimming. In captivity this may have no clear negative effects, but in the wild, a more risk prone behavioural profile linked to a lower aerobic capacity to escape from e.g. a predator attack, could clearly be disadvantageous. PMID- 28342771 TI - The area postrema (AP) and the parabrachial nucleus (PBN) are important sites for salmon calcitonin (sCT) to decrease evoked phasic dopamine release in the nucleus accumbens (NAc). AB - The pancreatic hormone amylin and its agonist salmon calcitonin (sCT) act via the area postrema (AP) and the lateral parabrachial nucleus (PBN) to reduce food intake. Investigations of amylin and sCT signaling in the ventral tegmental area (VTA) and nucleus accumbens (NAc) suggest that the eating inhibitory effect of amylin is, in part, mediated through the mesolimbic 'reward' pathway. Indeed, administration of the sCT directly to the VTA decreased phasic dopamine release (DA) in the NAc. However, it is not known if peripheral amylin modulates the mesolimbic system directly or whether this occurs via the AP and PBN. To determine whether and how peripheral amylin or sCT affect mesolimbic reward circuitry we utilized fast scan cyclic voltammetry under anesthesia to measure phasic DA release in the NAc evoked by electrical stimulation of the VTA in intact, AP lesioned and bilaterally PBN lesioned rats. Amylin (50MUg/kg i.p.) did not change phasic DA responses compared to saline control rats. However, sCT (50MUg/kg i.p.) decreased evoked DA release to VTA-stimulation over 1h compared to saline treated control rats. Further investigations determined that AP and bilateral PBN lesions abolished the ability of sCT to suppress evoked phasic DA responses to VTA-stimulation. These findings implicate the AP and the PBN as important sites for peripheral sCT to decrease evoked DA release in the NAc and suggest that these nuclei may influence hedonic and motivational processes to modulate food intake. PMID- 28342772 TI - Elucidating the structural organization of a novel low-density lipoprotein nanoparticle reconstituted with docosahexaenoic acid. AB - Low-density lipoprotein nanoparticles reconstituted with unesterified docosahexaenoic acid (LDL-DHA) is promising nanomedicine with enhanced physicochemical stability and selective anticancer cytotoxic activity. The unique functionality of LDL-DHA ultimately relates to the structure of this nanoparticle. To date, however, little is known about the structural organization of this nanoparticle. In this study chemical, spectroscopic and electron microscopy analyses were undertaken to elucidate the structural and molecular organization of LDL-DHA nanoparticles. Unesterified DHA preferentially incorporates into the outer surface layer of LDL, where in this orientation the anionic carboxyl end of DHA is exposed to the LDL surface and imparts an electronegative charge to the nanoparticles surface. This negative surface charge promotes the monodisperse and homogeneous distribution of LDL-DHA nanoparticles in solution. Further structural analyses with cryo-electron microscopy revealed that the LDL-DHA nanostructure consist of a phospholipid bilayer surrounding an aqueous core, which is distinctly different from the phospholipid monolayer/apolar core organization of plasma LDL. Lastly, apolipoprotein B-100 remains strongly associated with this complex and maintains a discrete size and shape of the LDL-DHA nanoparticles similar to plasma LDL. This preliminary structural assessment of LDL-DHA now affords the opportunity to understand the important structure-function relationships of this novel nanoparticle. PMID- 28342773 TI - Generation of enhanced definitive endoderm from human embryonic stem cells under an albumin/insulin-free and chemically defined condition. AB - AIM: To enhance survival and generation of definitive endoderm cells from human embryonic stem cells in a simple and reproducible system. MAIN METHODS: Definitive endoderm (DE) differentiation from human embryonic stem cells (hESCs) was induced under a chemical-defined condition withdrawn insulin supplement and serum albumin. We dissected influence of "alternative growth factors", WNT3A, BMP4 and bFGF in activin A-driven differentiation by detection of DE-associated genes expression and cell viability. Expression of DE-associated SOX17 and FOXA2 genes was analyzed by real time reverse transcription polymerase chain reaction (RT-PCR) and Western blot assays. Quantitative evaluation of DE efficiency was performed by flow cytometry analysis of CXCR4-expressed cell population. Cell viability during DE differentiation was analyzed by an Annexin V/PI double staining test. KEY FINDINGS: Supplementation with WNT3A, BMP4 or bFGF promoted DE generation in a dose- and time-dependent manner. Cell apoptosis elicited by activin A was significantly ameliorated by a cocktail with WNT3A, BMP4 and bFGF. This allowed for sustained cell viability without insulin-containing supplements, thereby indirectly improving the efficiency of DE generation. Therefore, the cocktail containing is optimal for efficient DE generation in the presence of activin A and an insulin/albumin-free condition. SIGNIFICANCE: This optimal condition facilitates the balance between the productivity and the viability maintenance, and could be valuable for mass production of DE with minimal variation. PMID- 28342774 TI - Hypercapnia-induced brain acidosis: Effects and putative mechanisms on acute kainate induced seizures. AB - AIMS: This study investigated the mechanism of the anticonvulsant effects of carbogen containing 5% CO2 in a kainic acid (KA) rat model. MAIN METHODS: Four week-old Sprague-Dawley rats were divided into four groups: control, carbogen, KA+air, and KA+carbogen. Carbogen containing 5% CO2 was applied immediately after KA injection, and cortical pH was recorded. High-performance liquid chromatography was used to detect the release of gamma-aminobutyric acid (GABA) and glutamate. We used electrophysiology to measure cortical and hippocampal activities. KEY FINDINGS: Carbogen increased the onset latency of seizure (KA+air group, 26.12+/-2.11min; KA+carbogen group 43.65+/-2.78min, P<0.001) and reduced the frequency of seizures (KA+air group, 12.50+/-1.77; KA+carbogen group, 5.63+/ 1.59, P<0.001). Carbogen inhalation could reduce cortical pH (KA+air group, 7.04+/-0.04; KA+carbogen group, 6.82+/-0.03, P<0.001). After carbogen inhalation, the levels of excitatory amino acid glutamate decreased (595.90+/-7.51 in KA+air group vs. 467.95+/-4.82 in KA+carbogen s group, P<0.001), whereas GABA increased significantly (158.30+/-5.05 in KA+air group vs. 216.62+/-5.59 in KA+carbogen, P<0.05). Carbogen reduced both electrohippocampalogram (119.57+/-2.83 in KA+air group vs. 107.48+/-2.95 in KA+carbogen group, P<0.01) and electrocorticogram (130.74+/-2.48 in KA+air group vs. 115.35+/-2.11 in KA+carbogen group, P<0.01). SIGNIFICANCE: Carbogen containing 5% CO2 decreased seizures by reducing cortical pH, by increasing GABA release, and by affecting electrical activity of the brain. PMID- 28342775 TI - The Cash and Counseling model of self-directed long-term care: Effectiveness with young adults with disabilities. AB - BACKGROUND: Young adults with disabilities face numerous barriers to independence and achieving markers of adulthood. Qualitative evidence suggests that flexible, self-directed budgets for purchasing home and community-based services might help fill an identified service gap and help improve the transition to adulthood for this group. OBJECTIVE: Our aim was to evaluate the effectiveness of the Cash and Counseling model of self-directed budgets for young adults with long-term care disabilities by analyzing secondary data from the Cash and Counseling Demonstration and Evaluation randomized control trial. METHODS: We compared nine month community involvement, satisfaction rating, health status rating compared to peers, and unmet needs outcomes using bivariate and multivariate logistic regression. Our sample included 456 participants aged 18 to 30 randomized to treatment groups with the opportunity to receive Cash and Counseling (n = 207) or control groups eligible for agency-based care (n = 249), whether self-reported (n = 128) or by proxy (n = 328). RESULTS: Multivariate logistic regression models showed that compared to controls at nine-month follow-up, treatment group members had significantly greater odds of being very satisfied with life, when care was received, the care arrangement, transportation, help around the house and community, personal care, and getting along with paid attendants, and significantly lower odds of unmet needs with medication and routine health care at home and with transportation. CONCLUSIONS: Cash and Counseling performed better than or comparable with agency-based care for young adults with long-term care disabilities, suggesting its viability as a service option for this population. PMID- 28342776 TI - Effect of Needle Size in Ultrasound-guided Core Needle Breast Biopsy: Comparison of 14-, 16-, and 18-Gauge Needles. AB - INTRODUCTION: The aim of the present study was to assess the diagnostic accuracy of ultrasound-guided core needle biopsy (US-CNB) of breast lesions, comparing smaller needles (16- and 18-gauge) with the 14-gauge needle, and to analyze the lesion characteristics influencing US-CNB diagnostic performance. PATIENTS AND METHODS: All the patients provided informed consent before the biopsy procedure. The data from breast lesions that had undergone US-CNB in our institution from January 2011 to January 2015 were retrospectively reviewed. The inclusion criterion was the surgical histopathologic examination findings of the entire lesion or radiologic follow-up data for >= 24 months. The exclusion criterion was the use of preoperative neoadjuvant therapy. The US-CNB results were compared with the surgical pathologic results or with the follow-up findings in the 3 needle size groups (14-, 16-, and 18-gauge). The needle size- and lesion characteristic-specific diagnostic accuracy parameters were evaluated. Statistical analysis was performed using a dedicated software program, and P <= .01 was considered significant. RESULTS: A total of 1118 US-CNB cases (1042 patients) were included. Of the 1118 cases, 630 (56.3%) were in the 14-gauge group, 136 (12.2%) in the 16-gauge, and 352 (31.5%) in the 18-gauge needle group. Surgery was performed on 800 lesions (71.6%). Of these, 619 were malignant, 77 were high risk, and 104 were benign. The remaining 318 lesions (28.4%) underwent follow-up imaging studies. All the lesions were stable and, therefore, were considered benign. No differences were observed in the diagnostic accuracy parameters among the 3 needle size groups (P > .01). The false-negative rate was greater for lesions < 10 mm (7.2%) (P < .01) but without statistically significant differences among the 3 gauges (P > .01). CONCLUSION: US-CNB performed with small needles (16 and 18 gauge) had the same diagnostic accuracy as that performed with 14-gauge needles, regardless of the lesion characteristics. PMID- 28342777 TI - Teaching and Assessing Professionalism in Radiology Resident Education. AB - Radiologists in teaching hospitals and in practices with residents rotating through are involved in the education of their residents. The Accreditation Council for Graduate Medical Education requires evidence that trainees are taught and demonstrate competency not only in medical knowledge and in patient care-the historic focus of radiology education-but also in the so-called non interpretative core competencies, which include professionalism and interpersonal skills. In addition to accreditation agencies, the prominent assessment practices represented by the American Board of Radiology core and certifying examinations for trainees, as well as Maintenance of Certification for practitioners, are planning to feature more non-interpretative competency assessment, including professionalism to a greater extent. Because professionalism was incorporated as a required competency in medical education as a whole, more clarity about the justification and expected content for teaching about competence in professionalism, as well as greater understanding and evidence about appropriate and effective teaching and assessment methods, have emerged. This article summarizes justifications and expectations for teaching and assessing professionalism in radiology residents and best practices on how to teach and evaluate professionalism that can be used by busy radiology faculty in their everyday practice supervising radiology residents. PMID- 28342778 TI - [The burden of fungal infections in Algeria]. AB - In Algeria, superficial mycoses are very commonly diagnosed. Deep fungal infections are less often observed. Few data from Algeria are found in the literature. We report for the first time the main causes of these diseases in our country and provide burden estimates. We searched for existing data and estimated the incidence and prevalence of fungal diseases based on the population at risk and available epidemiological data. Demographic data were derived from the Service (Office) of the Statistics (ONES), World Health Organization (WHO), The Joint Nations Programme on HIV/AIDS (UNAIDS) and national published reports. When no data existed, risk populations were used to estimate frequencies of fungal infections, using previously described methodology. Algeria has 40.4 million inhabitants and probably at least 568,900 (1.41 %) of Algerians have a serious fungal infection each year. Recurrent vulvovaginal candidiasis (485,000) and fungal asthma (72,000) are probably the commonest problems as there are over 1 million adult asthmatics. Candidaemia is estimated in 2020, invasive aspergillosis in 2865, intra-abdominal candidiasis in 303 people and are the most common life-threatening problems. AIDS is uncommon, but cancer is not (45,000 new cases of cancer among including 1500 in children) and nor is COPD (an estimated 317,762 patients of whom 20.3 % are admitted to hospital each year). A focus on improving the diagnosis and epidemiological data related to fungal infection is necessary in Algeria. PMID- 28342780 TI - A neural basis for the visual sense of number and its development: A steady-state visual evoked potential study in children and adults. AB - While recent studies in adults have demonstrated the existence of a neural mechanism for a visual sense of number, little is known about its development and whether such a mechanism exists at young ages. In the current study, I introduce a novel steady-state visual evoked potential (SSVEP) technique to objectively quantify early visual cortical sensitivity to numerical and non-numerical magnitudes of a dot array. I then examine this neural sensitivity to numerical magnitude in children between three and ten years of age and in college students. Children overall exhibit strong SSVEP sensitivity to numerical magnitude in the right occipital sites with negligible SSVEP sensitivity to non-numerical magnitudes, the pattern similar to what is observed in adults. However, a closer examination of age differences reveals that this selective neural sensitivity to numerical magnitude, which is close to absent in three-year-olds, increases steadily as a function of age, while there is virtually no neural sensitivity to other non-numerical magnitudes across these ages. These results demonstrate the emergence of a neural mechanism underlying direct perception of numerosity across early and middle childhood and provide a potential neural mechanistic explanation for the development of humans' primitive, non-verbal ability to comprehend number. PMID- 28342781 TI - Modulation of neuroinflammation: Role and therapeutic potential of TRPV1 in the neuro-immune axis. AB - Transient receptor potential vanilloid type 1 channel (TRPV1), as a ligand-gated non-selective cation channel, has recently been demonstrated to have wide expression in the neuro-immune axis, where its multiple functions occur through regulation of both neuronal and non-neuronal activities. Growing evidence has suggested that TRPV1 is functionally expressed in glial cells, especially in the microglia and astrocytes. Glial cells perform immunological functions in response to pathophysiological challenges through pro-inflammatory or anti-inflammatory cytokines and chemokines in which TRPV1 is involved. Sustaining inflammation might mediate a positive feedback loop of neuroinflammation and exacerbate neurological disorders. Accumulating evidence has suggested that TRPV1 is closely related to immune responses and might be recognized as a molecular switch in the neuroinflammation of a majority of seizures and neurodegenerative diseases. In this review, we evidenced that inflammation modulates the expression and activity of TRPV1 in the central nervous system (CNS) and TRPV1 exerts reciprocal actions over neuroinflammatory processes. Together, the literature supports the hypothesis that TRPV1 may represent potential therapeutic targets in the neuro immune axis. PMID- 28342779 TI - Suppression of calpain expression by NSAIDs is associated with inhibition of cell migration in rat duodenum. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the alleviation of pain and inflammation, but these drugs are also associated with a suite of negative side effects. Gastrointestinal (GI) toxicity is particularly concerning since it affects an estimated 70% of individuals taking NSAIDs routinely, and evidence suggests the majority of toxicity is occurring in the small intestine. Traditionally, NSAID-induced GI toxicity has been associated with indiscriminate inhibition of cyclooxygenase isoforms, but other mechanisms, including inhibition of cell migration, intestinal restitution, and wound healing, are likely to contribute to toxicity. Previous efforts demonstrated that treatment of cultured intestinal epithelial cells (IEC) with NSAIDs inhibits expression and activity of calpain proteases, but the effects of specific inhibition of calpain expression in vitro or the effects of NSAIDs on intestinal cell migration in vivo remain to be determined. Accordingly, we examined the effect of suppression of calpain protease expression with siRNA on cell migration in cultured IECs and evaluated the effects of NSAID treatment on epithelial cell migration and calpain protease expression in rat duodenum. Our results show that calpain siRNA inhibits protease expression and slows migration in cultured IECs. Additionally, NSAID treatment of rats slowed migration up the villus axis and suppressed calpain expression in duodenal epithelial cells. Our results are supportive of the hypothesis that suppression of calpain expression leading to slowing of cell migration is a potential mechanism through which NSAIDs cause GI toxicity. PMID- 28342782 TI - The modified Glasgow prognostic score in patients undergoing surgery for bone and soft tissue sarcoma. AB - BACKGROUND: The prognostic significance of markers of the systemic inflammatory response in patients with soft tissue and bone sarcomas remains unclear. Therefore, the present study aimed to compare the prognostic value of markers of the systemic inflammatory response in patients undergoing surgery for primary soft tissue and bone sarcoma. METHOD: Patients who underwent resection of primary soft tissue/bone sarcoma between 2008 and 2012 and had pre-operative measurements of the systemic inflammatory response [C-reactive protein, albumin, white cell, neutrophil, lymphocyte and platelet counts, and the combination of C-reactive protein and albumin (mGPS)] were included in the study (n = 111). RESULTS: The majority of the patients were <=50 years old (84%), were female (63%), had soft tissue sarcoma (62%), and had tumours >10 cm (52%), mostly of high grade (85%). The median follow-up of survivors was 50 months (range 34-78); 24 (21%) developed local recurrence, 35 (31%) developed distant metastases and 30 (30%) died of their cancer. On univariate analysis, tumour size (P < 0.001), tumour grade (P < 0.001), C-reactive protein level (P < 0.001), albumin level (P < 0.001) and mGPS (P < 0.001) were significantly associated with distant recurrence-free survival. On a multivariate analysis, only tumour size [hazard ratios (HR) 2.57, 95% confidence intervals (CI) 1.14-5.32, P < 0.05], tumour grade (HR 7.01, 95% CI 0.94-52.17, P < 0.10) and mGPS (HR 1.92, 95% CI 1.31-2.83, P < 0.01) were independently associated with distant recurrence-free survival. On a multivariate analysis, only tumour size (HR 2.85, 95% CI 1.10-7.39, P < 0.05) and the mGPS (HR 2.03, 95% CI 1.31-3.16, P < 0.01) were independently associated with cancer specific survival. CONCLUSION: The systemic inflammatory response, as evidenced by the mGPS, was an important independent predictor of recurrence-free survival and cancer-specific survival in patients undergoing surgery for bone and soft tissue sarcoma. PMID- 28342783 TI - Effect of storage on the physical stability of thin polymethacrylate-perphenazine films. AB - We evaluated the physical stability of thin polymethacrylate-drug films under three different storage conditions by X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy, polarized light microscopy, and Fourier transform infrared spectroscopy. Mechanical properties i.e. elongation, mechanical strength, and in vitro drug release from the thin films were also determined during storage. The films consisted of ammonium methacrylate copolymer (RLPO)/dimethylaminoethyl methacrylate copolymer (EPO), polyvinylpyrroline (PVP)/polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus) and perphenazine (PPZ). PPZ remained fully amorphous in all RLPO- and EPO -films for up to 12months' storage at 4 degrees C in dry conditions. Instead, in EPO+PVP+PPZ 15% -films, higher temperature induced recrystallization of PPZ within three months and higher humidity also at six months. Crystallization was also observed in EPO+Soluplus+PPZ 10% -films at high temperature at 12months. The amount of PPZ released was significantly lower from recrystallized PPZ films than from stable amorphous films. The better stability of RLPO -films was attributed to PPZ being molecularly dispersed and also because of strong drug-polymer interactions in the films, while increasing storage temperatures weakened the hydrogen bonding interactions in the EPO -films. In addition, the presence of hygroscopic PVP facilitated PPZ recrystallization in the EPO -films if they were stored in a highly humid environment. PMID- 28342785 TI - Predatory Publishing: A Growing Threat to HIV Nursing? PMID- 28342784 TI - Inositol phosphate multikinase dependent transcriptional control. AB - Production of lipid-derived inositol phosphates including IP4 and IP5 is an evolutionarily conserved process essential for cellular adaptive responses that is dependent on both phospholipase C and the inositol phosphate multikinase Ipk2 (also known as Arg82 and IPMK). Studies of Ipk2, along with Arg82 prior to demonstrating its IP kinase activity, have provided an important link between control of gene expression and IP metabolism as both kinase dependent and independent functions are required for proper transcriptional complex function that enables cellular adaptation in response to extracellular queues such as nutrient availability. Here we define a promoter sequence cis-element, 5' CCCTAAAAGG-3', that mediates both kinase-dependent and independent functions of Ipk2. Using a synthetic biological strategy, we show that proper gene expression in cells lacking Ipk2 may be restored through add-back of two components: IP4/IP5 production and overproduction of the MADS box DNA binding protein, Mcm1. Our results are consistent with a mechanism by which Ipk2 harbors a dual functionality that stabilizes transcription factor levels and enzymatically produces a small molecule code, which together coordinate control of biological processes and gene expression. PMID- 28342786 TI - Pharmaceutical solvates, hydrates and amorphous forms: A special emphasis on cocrystals. AB - Active pharmaceutical ingredients (APIs) may exist in various solid forms, which can lead to differences in the intermolecular interactions, affecting the internal energy and enthalpy, and the degree of disorder, affecting the entropy. Differences in solid forms often lead to differences in thermodynamic parameters and physicochemical properties for example solubility, dissolution rate, stability and mechanical properties of APIs and excipients. Hence, solid forms of APIs play a vital role in drug discovery and development in the context of optimization of bioavailability, filing intellectual property rights and developing suitable manufacturing methods. In this review, the fundamental characteristics and trends observed for pharmaceutical hydrates, solvates and amorphous forms are presented, with special emphasis, due to their relative abundance, on pharmaceutical hydrates with single and two-component (i.e. cocrystal) host molecules. PMID- 28342787 TI - Forecasting Ebola with a regression transmission model. AB - We describe a relatively simple stochastic model of Ebola transmission that was used to produce forecasts with the lowest mean absolute error among Ebola Forecasting Challenge participants. The model enabled prediction of peak incidence, the timing of this peak, and final size of the outbreak. The underlying discrete-time compartmental model used a time-varying reproductive rate modeled as a multiplicative random walk driven by the number of infectious individuals. This structure generalizes traditional Susceptible-Infected Recovered (SIR) disease modeling approaches and allows for the flexible consideration of outbreaks with complex trajectories of disease dynamics. PMID- 28342788 TI - Analytical ultracentrifugation for analysis of doxorubicin loaded liposomes. AB - Analytical ultracentrifugation (AUC) is a powerful tool for the study of particle size distributions and interactions with high accuracy and resolution. In this work, we show how the analysis of sedimentation velocity data from the AUC can be used to characterize nanocarrier drug delivery systems used in nanomedicine. Nanocarrier size distribution and the ratio of free versus nanoparticle encapsulated drug in a commercially available liposomal doxorubicin formulation are determined using interference and absorbance based AUC measurements and compared with results generated with conventional techniques. Additionally, the potential of AUC in measuring particle density and the detection of nanocarrier sub-populations is discussed as well. The unique capability of AUC in providing reliable data for size and composition in a single measurement and without complex sample preparation makes this characterization technique a promising tool both in nanomedicine product development and quality control. PMID- 28342789 TI - Enhanced gastric stability of esomeprazole by molecular interaction and modulation of microenvironmental pH with alkalizers in solid dispersion. AB - Due to the instability of esomeprazole magnesium dihydrate (EPM), a proton pump inhibitor, in gastric fluid, enteric-coated dosage form is commonly used for therapeutic application. In this study, we prepared new gastric fluid resistant solid dispersions (SDs) containing alkalizers. Then, new mechanistic evidence regarding the effects of pharmaceutical alkalizers on the aqueous stability of EPM in simulated gastric fluid was investigated. The alkalizer-loaded SD were prepared by dissolving or dispersing EPM, hydroxypropyl methylcellulose (HPMC) 6 cps, and an alkalizer, in ethanol 50% (v/v) followed by spray drying. Nine different alkalizers were assessed for in vitro stability in two media, simulated gastric fluid (pH 1.2 buffer) and simulated intestinal fluid (pH 6.8 buffer). The microenvironmental pH (pHM) was measured to evaluate the effect of the alkalizer on the pHM of SDs. Drug crystallinity and morphology of the SDs were also examined by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). The interactions among EPM, the polymer, and the alkalizer were elucidated by Fourier transform infrared (FTIR) spectroscopy. The in vivo absorption studies of the optimized alkalizer containing SD and the enteric-coated reference tablet Nexium(r) were then conducted in beagle dogs. Among alkalizers, MgO loaded in SDs proved to be the best alkalizer to stabilize EPM in simulated gastric fluid. pHM values of the alkalizer-containing SDs were significantly higher than that of the SD without alkalizer. The pHM values decreased in the following order: MgO, Na2CO3, Ca(OH)2, and no alkalizer. DSC and PXRD data exhibited a change in the drug crystallinity of the SDs from crystalline to amorphous form. SEM data showed a relatively spherical shape of the MgO-loaded SD compared to the less-defined shape of pure drug. FTIR indicated a strong molecular interaction among EPM, alkalizer and polymer; in particular, MgO showed the strongest interaction with EPM. It was evident that alkalizer interacts with benzimidazole ring and/or sulfonyl group of EPM for enhancing EPM stability in gastric fluid. Regarding the in vivo absorption studies in beagle dogs, the optimized SD (C16) was bioequivalent to the reference Nexium(r) and had a considerable greater absorption at the early stages. The current alkalizer-containing SD could provide a promising approach for aqueous stabilization of acid-labile drugs without using enteric coating method. PMID- 28342790 TI - Lipocalin-2 and iron trafficking in the tumor microenvironment. AB - Iron is an essential element for virtually all organisms. It facilitates cell proliferation and growth but also contributes to major hallmarks of cancer such as tumor initiation, growth, and metastasis. Often, iron handling of tumor cells is disturbed, with altered iron acquisition, efflux, and storage. Targeting perturbed iron metabolic pathways might open opportunities towards novel approaches in cancer treatment. It is becoming clear that cells of the tumor microenvironment such as macrophages contribute to tumor progression. Since macrophages evolved a multitude of mechanisms to sequester, transport, store, and release iron it can be speculated that tumor cells educate them to supply iron to support tumor growth. Recent evidence supports the existence of transferrin independent iron transport mechanisms in the tumor microenvironment, which points to local iron transport proteins such as lipocalin-2 and/or low molecular weight iron-trafficking substances such as siderophores. We hypothesize that tumor cells educate immune cells, i.e. macrophages in their neighborhood to make them delivering iron for the benefit of cancer progression. In particular, we pay attention to recent developments, pointing to lipocalin-2 and siderophores as alternative iron transport molecules in the tumor microenvironment. PMID- 28342791 TI - Endocardial Pacing in Infants and Young Children Weighing Less Than 10 Kilograms. PMID- 28342792 TI - Relaxin Concentrations in Acute Heart Failure Patients. Response. PMID- 28342793 TI - About the Specialty Treating Patients With Heart Failure. PMID- 28342794 TI - Stented Bovine Jugular Vein Graft (Melody Valve) in Mitral Position. Could Be an Alternative for Mechanical Valve Replacement in the Pediatric Population? PMID- 28342795 TI - Genetic variation of 17 autosomal STR loci in the Zhuang ethnic minority from Guangxi Zhuang Autonomous Region in the south of China. PMID- 28342796 TI - Making progress in education: The EUROFORGEN master degree pilot project in forensic genetics. PMID- 28342797 TI - Forensic evaluation of the 20 STR loci in the population of Croatia. PMID- 28342798 TI - Allele frequencies and other forensic parameters of the HID-Ion AmpliSeqTM Identity Panel markers in Basques using the Ion Torrent PGMTM platform. AB - The HID-Ion AmpliSeqTM Identity Panel amplifies 90 autosomal SNPs and 34 Y- SNPs with massively parallel sequencing (MPS) using the Ion Torrent PGMTM platform. In the present study, 105 Basques were analyzed to assess this panel. All loci were in Hardy-Weinberg equilibrium and no association between them was detected. Forensic parameters were calculated as 5.74*10-36 for combined match probability and 99.99998% for combined power of exclusion. In conclusion, the HID Identity panel and the use of this new MPS technology are very promising tools for paternity testing and human identification in routine casework in the forensic field. PMID- 28342799 TI - Lost in processing? Perceived healthfulness, taste and caloric content of whole and processed organic food. AB - The "organic" claim explicitly informs consumers about the food production method. Yet, based on this claim, people often infer unrelated food attributes. The current research examined whether the perceived advantage of organic over conventional food generalizes across different organic food types. Compared to whole organic foods, processed organic foods are less available, familiar and prototypical of the organic food category. In two studies (combined N = 258) we investigated how both organic foods types were perceived in healthfulness, taste and caloric content when compared to their conventional alternatives. Participants evaluated images of both whole (e.g., lettuce) and processed organic food exemplars (e.g., pizza), and reported general evaluations of these food types. The association of these evaluations with individual difference variables self-reported knowledge and consumption of organic food, and environmental concerns - was also examined. Results showed that organically produced whole foods were perceived as more healthful, tastier and less caloric than those produced conventionally, thus replicating the well-established halo effect of the organic claim in food evaluation. The organic advantage was more pronounced among individuals who reported being more knowledgeable about organic food, consumed it more frequently, and were more environmentally concerned. The advantage of the organic claim for processed foods was less clear. Overall, processed organic (vs. conventional) foods were perceived as tastier, more healthful (Study 1) or equally healthful (Study 2), but also as more caloric. We argue that the features of processed food may modulate the impact of the organic claim, and outline possible research directions to test this assumption. Uncovering the specific conditions in which food claims bias consumer's perceptions and behavior may have important implications for marketing, health and public-policy related fields. PMID- 28342800 TI - Development of an isothermal recombinase polymerase amplification assay for rapid detection of pseudorabies virus. AB - Recombinase polymerase amplification assays using real-time fluorescent detection (real-time RPA assay) and lateral flow dipstick (RPA LFD assay) were developed targeting the gD gene of pseudorabies virus (PRV). Both assays were performed at 39 degrees C within 20 min. The sensitivity of the real-time RPA assay and the RPA LFD assay was 100 copies per reaction and 160 copies per reaction, respectively. Both assays did not detect DNAs from other virus or PRV negative samples. Therefore, the developed RPA assays provide a rapid, simple, sensitive and specific alternative tool for detection of PRV. PMID- 28342801 TI - Geographic disparities in pneumonia-specific under-five mortality rates in Mainland China from 1996 to 2015: a population-based study. AB - OBJECTIVES: This study aimed to investigate the disparities in pneumonia-specific under-five mortality rates (U5MRs) among and within three geographic regions in Mainland China from 1996 to 2015. METHODS: Data were obtained from the national Under-Five Child Mortality Surveillance System and grouped into 2-year periods. The Cochran-Armitage trend test and Cochran-Mantel-Haenszel test were used to assess trends and differences in the pneumonia-specific U5MRs among and within geographic regions. Relative risks (RRs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: The pneumonia-specific U5MR decreased by 90.6%, 89.0%, and 83.5% in East, Middle, and West China, respectively, with a larger decrease in rural areas. The pneumonia-specific U5MR was highest in West China, and was 7.2 (95% CI 5.9-8.7) times higher than that in East China in 2014-2015. In 2014 2015, the RRs were 1.7 (95% CI 1.2-2.5), 1.6 (95% CI 1.1-2.1), and 3.4 (95% CI 2.8-4.0) between rural and urban areas in East, Middle, and West China, respectively. CONCLUSIONS: Pneumonia-specific U5MRs decreased from 1996 to 2015 across China, particularly in rural areas. However, disparities remained among and within geographic regions. Additional strategies and interventions should be introduced in West China, especially the rural areas, to further reduce the pneumonia-specific U5MR. PMID- 28342802 TI - Adjuvant interferon-gamma immunotherapy in a patient with progressive cerebral Nocardia abscesses. AB - Despite advances in medical care, mortality due to cerebral Nocardia abscesses remains unacceptably high. The case of a typical immunocompromised patient, who deteriorated clinically despite optimal antimicrobial treatment, is reported here. Adjuvant immunotherapy with interferon-gamma resulted in partial restoration of the immune response and a corresponding clinical and radiographic recovery. PMID- 28342803 TI - Antigen-specific CTLs: to produce autologous cells product for adoptive cellular therapy. AB - : As antiretroviral therapy provides long term viral suppression but no cure, alternative therapies such as adoptive cellular therapy have thus been investigated in the anti-AIDS field. OBJECTIVE: This study sought to establish a HLA-A02 specific CTL cell culture method with comparison of the effects of different cytokines used in CTL cultivation to decide the best cultivation environment. In order to produce CTLs with targeted HLA-A02 restricted antigen specificity for adoptive cellular therapy, we evaluated autologous PBMC cultivation in different cytokine environment to select a better expansion condition to produce qualified CTL production. METHODS: We co-cultivated PBMC and peptides of these patients with HLA-A02 allele with different cytokines. After cultivation, multiple parameters were tested. RESULTS: 1) Cytokines IL-2 alone can effectively amplify HLA-A02 specific CTL cells, and the count of CTLs was >85% all through the process. 2) The HLA-A02 specific cells at the end of the cultivation were mainly CD3+CD8+ cells. 3) The interferon stimulation test had shown that the expanded CTLs secreted more IFN-gamma than before cultivation (0.9% -11.70%). CONCLUSION: This model of CTL cultivation is successful in redirecting the specificity of antigen recognition and safely for HLA-A02+ patients cell adoptive therapy. PMID- 28342804 TI - Easy-to-use equations for the estimation of urine relative saturation in the assessment of risk of recurrence in urinary stones formers. AB - It is a fact that recurrence of urinary stones is a common medical problem. One of the key factors used in determining the risk of urinary stone-formation is the urine relative saturation in the major constituents of lithiasis. Nomograms were developed in the 1970's to estimate the relative saturation of urine. We present here easy-to-use mathematical equations derived from these nomograms. These equations can be integrated directly in the LIS of any laboratories, and can be used as a tool in the treatment and prevention of recurrent stone-formation. PMID- 28342805 TI - Phosphoethanolamine addition to the Heptose I of the Lipopolysaccharide modifies the inner core structure and has an impact on the binding of Polymyxin B to the Escherichia coli outer membrane. AB - Phosphoethanolamine (pEtN) decoration of E. coli Lipopolysaccharide (LPS) provides resistance to the antimicrobial Polymyxin B (PolB). While EptA and EptB enzymes catalyze the addition of pEtN to the Lipid A and Kdo (pEtN-Kdo-Lipid A), EptC catalyzes the pEtN addition to the Heptose I (pEtN-HeptI). In this study, we investigated the contribution of pEtN-HeptI to PolB resistance using eptA/eptB and eptC deficient E. coli K12 and its wild-type parent strains. These mutations were shown to decrease the antimicrobial activity of PolB on cells grown under pEtN-addition inducing conditions. Furthermore, the 1-N-phenylnapthylamine uptake assay revealed that in vivo PolB has a reduced OM-permeabilizing activity on the DeltaeptA/eptB strain compared with the DeltaeptC strain. In vitro, the changes in size and zeta potential of LPS-vesicles indicate that pEtN-HeptI reduce the PolB binding, but in a minor extent than pEtN-Kdo-Lipid A. Molecular dynamics analysis revealed the structural basis of the PolB resistance promoted by pEtN HeptI, which generate a new hydrogen-bonding networks and a denser inner core region. Altogether, the experimental and theoretical assays shown herein indicate that pEtN-HeptI addition promote an LPS conformational rearrangement, that could act as a shield by hindering the accession of PolB to inner LPS-targets moieties. PMID- 28342806 TI - Molecular regulation of mitochondrial dynamics in cardiac disease. AB - Mitochondrial homeostasis is critical for keeping functional heart in response to metabolic or environmental stresses. Mitochondrial fission and fusion (mitochondrial dynamics) play essential roles in maintaining mitochondrial homeostasis, defects in mitochondrial dynamics lead to cardiac diseases such as ischemia-reperfusion injury (IRI), heart failure and diabetic cardiomyopathy. Mitochondrial dynamics is determined by mitochondrial fission and fusion proteins, including OPA1, mitofusins and Drp1. These proteins are tightly regulated by a series of signaling pathways through different aspects such as transcription, post translation modifications (PTMs) and proteasome-dependent protein degradation. By modulating these mitochondrial fission and fusion proteins, mitochondria fine-tune their metabolic status to meet the energy demands of the heart. Moreover, these mitochondrial fission and fusion proteins are essential for mediating mitochondrial autophagy (mitophagy), leading to clearance of damaged mitochondria to maintain a healthy population of mitochondria in heart under stressed conditions. Mitochondrial dynamics dependent improvement in mitochondrial metabolism and quality could partially reverse the pathological conditions of heart. This review describes an overview of mechanisms on mitochondrial dynamics regulation and provides potential therapeutic targets for treating cardiovascular diseases. PMID- 28342807 TI - Myocardin inhibited the gap protein connexin 43 via promoted miR-206 to regulate vascular smooth muscle cell phenotypic switch. AB - Myocardin is regarded as a key mediator for the change of smooth muscle phenotype. The gap junction protein connexin 43 (Cx43) has been shown to be involved in vascular smooth muscle cells (VSMCs) proliferation and the development of atherosclerosis. However, the role of myocardin on gap junction of cell communication and the relation between myocardin and Cx43 in VSMC phenotypic switch has not been investigated. The goal of the present study is to investigate the molecular mechanism by which myocardin affects Cx43-regulated VSMC proliferation. Data presented in this study demonstrated that inhibition of the Cx43 activation process impaired VSMC proliferation. On the other hand, overexpression miR-206 inhibited VSMC proliferation. In additon, miR-206 silences the expression of Cx43 via targeting Cx43 3' Untranslated Regions. Importantly, myocardin can significantly promote the expression of miR-206. Cx43 regulates VSMCs' proliferation and metastasis through miR-206, which could be promoted by myocardin and used as a marker for diagnosis and a target for therapeutic intervention. Thus myocardin affected the gap junction by inhibited Cx43 and myocardin-miR-206-Cx43 formed a loop to regulate VSMC phenotypic switch. PMID- 28342808 TI - Role of mTORC1-S6K1 signaling pathway in regulation of hematopoietic stem cell and acute myeloid leukemia. AB - Dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1)-p70 ribosomal protein kinase 1 (S6K1) signaling pathway occurs frequently in acute myeloid leukemia (AML) patients. This pathway also plays a critical role in maintaining normal cellular processes. Given the importance of leukemia stem cells (LSCs) in the development of minimal residual disease, it is critical to use therapeutic interventions that target the LSC population to prevent disease relapse. The mTORC1-S6K1 pathway has been identified as an important regulator of hematopoietic stem cell (HSC) and LSC functions. Both HSC and LSC functions require regulation of key cellular processes including proliferation, metabolism, and autophagy, which are regulated by mTORC1 pathway. Despite the mTORC1-S6K1 pathway being a critical regulator of AML initiation and progression, inhibitors of this pathway alone have yielded mixed results in clinical studies. Recent studies have identified strategies to develop new mTORC1-S6K1 inhibitors such as RapaLink-1, which could circumvent the drug resistance observed in AML cells and in LSCs. Here, we review recent advances made in identifying the role of different components of this pathway in the regulation of HSCs and LSCs and discuss possible therapeutic approaches. PMID- 28342811 TI - Myeloid Sarcoma: Presentation, Diagnosis, and Treatment. AB - Myeloid sarcoma is an extramedullary tumor of immature granulocytic cells. It is a rare condition, most often associated with acute myeloid leukemia (AML), although in some rare cases it may present in nonleukemic patients. It should therefore be considered as a differential diagnosis of any atypical cellular infiltrate. It may occur at any site, leading to very varied clinical presentations. Diagnosis is challenging and relies on a high index of suspicion as well as radiology, histology, immunophenotyping, and molecular analyses, which also are essential for risk stratification and treatment planning. Systemic chemotherapy using AML-like regimens should be commenced early, even in nonleukemic disease. Surgery and/or radiotherapy may be indicated for symptomatic lesions or tumors causing local organ dysfunction or obstruction. Allogeneic hematopoietic stem cell transplantation has demonstrated promising results, particularly in patients who achieved complete remission with AML-induction protocols, and recent advances in genetic profiling may enable the development of novel targeted therapies. Prospective multicenter controlled trials are required to further refine management decisions and investigate the role of novel targeted therapies. PMID- 28342810 TI - Expression and putative role of mitochondrial transport proteins in cancer. AB - Cancer cells undergo major changes in energy and biosynthetic metabolism. One of them is the Warburg effect, in which pyruvate is used for fermentation rather for oxidative phosphorylation. Another major one is their increased reliance on glutamine, which helps to replenish the pool of Krebs cycle metabolites used for other purposes, such as amino acid or lipid biosynthesis. Mitochondria are central to these alterations, as the biochemical pathways linking these processes run through these organelles. Two membranes, an outer and inner membrane, surround mitochondria, the latter being impermeable to most organic compounds. Therefore, a large number of transport proteins are needed to link the biochemical pathways of the cytosol and mitochondrial matrix. Since the transport steps are relatively slow, it is expected that many of these transport steps are altered when cells become cancerous. In this review, changes in expression and regulation of these transport proteins are discussed as well as the role of the transported substrates. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux. PMID- 28342812 TI - A Laparoendoscopic Single-site Surgical Approach to Laparoscopic Salpingectomy. AB - STUDY OBJECTIVE: To demonstrate a laparoendoscopic single-site (LESS) surgical approach to salpingectomy. DESIGN: A technical video showing step-by-step a LESS surgical approach to salpingectomy (Canadian Task Force classification level III). Institutional review board approval was not required for this study. SETTING: Of all gynecologic cancer types, ovarian cancer has the highest mortality rate and is the fifth leading cause of cancer deaths among women [1,2]. The leading theory of epithelial ovarian carcinogenesis indicates that serous, endometrioid, and clear cell ovarian carcinomas originated from the fallopian tube and endometrium and not directly from the ovary itself [1-10]. This has led to the use of prophylactic salpingectomy as a theoretical form of ovarian cancer risk reduction at the time of hysterectomy or as a means of tubal sterilization. Prophylactic salpingectomy does not appear to increase the risk of complications and appears to be safe [2]. Ovarian function does not seem to be compromised by salpingectomy based on serum markers or response rates with in vitro fertilization [11-16]. A LESS approach may reduce the morbidity associated with the placement of multiple ports and can improve cosmetic outcomes. Prophylactic LESS bilateral salpingo-oohorectomy was shown to be feasible and safe for high risk patients for ovarian cancer [17]. INTERVENTIONS: Laparoscopic salpingectomy at the time of hysterectomy or as a means of tubal sterilization using the LESS technique. CONCLUSION: This is a simple and reproducible technique for preventing major complications associated with LESS salpingectomy. This approach permits easier specimen retrieval because of the large solitary incision that is made. There is a significant improvement in cosmetic satisfaction when compared with a traditional laparoscopic approach in the setting of prophylactic risk reduction surgery [18]. PMID- 28342809 TI - Identity and function of a cardiac mitochondrial small conductance Ca2+-activated K+ channel splice variant. AB - We provide evidence for location and function of a small conductance, Ca2+ activated K+ (SKCa) channel isoform 3 (SK3) in mitochondria (m) of guinea pig, rat and human ventricular myocytes. SKCa agonists protected isolated hearts and mitochondria against ischemia/reperfusion (IR) injury; SKCa antagonists worsened IR injury. Intravenous infusion of a SKCa channel agonist/antagonist, respectively, in intact rats was effective in reducing/enhancing regional infarct size induced by coronary artery occlusion. Localization of SK3 in mitochondria was evidenced by Western blot of inner mitochondrial membrane, immunocytochemical staining of cardiomyocytes, and immunogold labeling of isolated mitochondria. We identified a SK3 splice variant in guinea pig (SK3.1, aka SK3a) and human ventricular cells (SK3.2) by amplifying mRNA, and show mitochondrial expression in mouse atrial tumor cells (HL-1) by transfection with full length and truncated SK3.1 protein. We found that the N-terminus is not required for mitochondrial trafficking but the C-terminus beyond the Ca2+ calmodulin binding domain is required for Ca2+ sensing to induce mK+ influx and/or promote mitochondrial localization. In isolated guinea pig mitochondria and in SK3 overexpressed HL-1 cells, mK+ influx was driven by adding CaCl2. Moreover, there was a greater fall in membrane potential (DeltaPsim), and enhanced cell death with simulated cell injury after silencing SK3.1 with siRNA. Although SKCa channel opening protects the heart and mitochondria against IR injury, the mechanism for favorable bioenergetics effects resulting from SKCa channel opening remains unclear. SKCa channels could play an essential role in restraining cardiac mitochondria from inducing oxidative stress-induced injury resulting from mCa2+ overload. PMID- 28342813 TI - Anxiety can be reduced by music during colonoscopy examination, but the effect may be varied by musical styles. PMID- 28342814 TI - Tear cytokine profile of glaucoma patients treated with preservative-free or preserved latanoprost. AB - PURPOSE: To determine variations in cytokine levels of glaucoma patients treated either with preservative-free latanoprost or preserved latanoprost, relative to healthy individuals. METHODS: Tear samples were collected from 39 healthy subjects, 20 glaucoma patients treated with preserved latanoprost, and 20 patients treated with preservative-free latanoprost. A set of 27 inflammatory cytokines was analyzed in each group, including interleukin (IL)-1beta, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, eotaxin, fibroblast growth factor (FGF) basic, granulocyte colony stimulating factor (G-CSF), granulocyte monocyte colony stimulating factor (GM-CSF), interferon (IFN)-gamma, interferon gamma-induced protein (IP)-10, monocyte chemo attractant protein (MCP)-1MCAF, macrophage inflammatory protein (MIP)-1alpha, MIP 1beta, platelet-derived growth factor (PDGF)-BB, regulated on activation, normal T cell expressed and secreted (RANTES), tumor necrosis factor (TNF)-alpha and vascular endothelial growth factor (VEGF). Cytokine concentrations were obtained by the Bio-Plex Human Cytokine Immunoassay. Non-invasive tear breakup time (NI TBUT), tear meniscus height, corneal fluorescein staining, conjunctival hyperemia and ocular surface disease index (OSDI) were assessed in patients treated with preservative-free and preserved latanoprost. RESULTS: The levels of IL-2, IL-5, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, FGF basic, PDGF-BB, and TNF-alpha were significantly higher in patients receiving preserved latanoprost, compared to normal controls (p < 0.05). The expression of all the cytokines studied remained statistically invariable in patients receiving preservative-free latanoprost, compared to healthy subjects (p > 0.05). Ocular surface parameters were not significantly different in both glaucoma groups, and no correlation between these clinical parameters and cytokine levels was observed. CONCLUSIONS: Treatment with preserved latanoprost has a direct impact on tear cytokine levels, whereas this effect is not observed upon preservative-free latanoprost instillation. PMID- 28342815 TI - Heart Failure in Women: Risk Across a Woman's Adult Life. PMID- 28342816 TI - Antineutrophil Cytoplasmic Antibody-Associated Rapid Progressive Glomerulonephritis after Pembrolizumab Treatment in Thymic Epithelial Tumor: A Case Report. PMID- 28342817 TI - Complete genome sequence of Streptomyces griseochromogenes ATCC 14511T, a producer of nucleoside compounds and diverse secondary metabolites. AB - ATCC 14511T (=DSM 40499, =NBRC 13413) is a type strain of Streptomyces griseochromogenes. It is known as a producer of nucleoside antibiotic, blasticidin S. In this report we present the complete genome sequence of S. griseochromogenes ATCC 14511T, which consists of 10,764,674bp with a linear chromosome, 9822 protein-coding genes, 6 rRNA operons, 74 tRNA and 3 sRNA. The genomic analysis revealed that 52 putative gene clusters are involved in the biosynthesis of secondary metabolites, including four gene clusters of nucleoside antibiotics. These gene clusters provide a beneficial source for production of bioactive natural compounds. PMID- 28342818 TI - Intraneural microcystic lymphatic malformation of the ulnar nerve at the Guyon canal: Unusual cause of ulnar pain in a child. AB - We present a case of an unusual cause of ulnar pain on a 9-year-old patient. The patient had pain on the ulnar side of the wrist after a fall. MRI showed a poorly defined lesion on the ulnar nerve at Guyon's canal. The initial diagnosis was traumatic neuropathy. Following conservative treatment of symptoms for one year, the pain started again. Therefore, a new MRI was performed where progression of the lesion was observed. Excision of the lesion was performed and the specimen sent for pathologic analysis. The diagnosis was of microcystic lymphatic malformation. The patient had a satisfactory evolution, with complete resolution. This is the first description of a microcystic lymphatic malformation in an intraneuronal location. PMID- 28342819 TI - Ankylosis of the knee after septic arthritis following anterior cruciate ligament reconstruction in a 13-year-old male. AB - We present the case of an adolescent male developing an ankylosis of the knee after septic arthritis following anterior cruciate ligament reconstruction (ACLR). The patient was shifted to our institution with postoperative septic arthritis associated with a systemic septic condition. Before, repeated arthroscopic surgery had been conducted without any improvement. MRI showed a concomitant osteomyelitis. The infection (Gachter IV, Staphylococcus aureus) was controlled by an open surgical approach and graft removal. An increasing joint stiffness was documented. X-rays showed an ankylosis at 30 degrees of flexion and early closure of growth plates. Functional knee scores showed significantly worse results. Early diagnosis and a stage-adapted treatment in septic arthritis following ACLR are mandatory. In advanced stages or concomitant osteomyelitis an open approach and graft removal may be appropriate. The antibiotic treatment should be adapted consistently. PMID- 28342820 TI - Injury of the obturator nerve in the modified Stoppa approach for acetabular fractures. AB - INTRODUCTION: The modified Stoppa approach for acetabular fractures has become popular. However, the possibility of injury to the obturator nerve with this approach has not been sufficiently considered. We have experienced a case of nerve entrapment in severely displaced fractures. Therefore, we performed a retrospective study to: (1) evaluate the incidence of obturator nerve injury in the modified Stoppa approach for acetabular fractures; (2) analyze the relationship between the extent of displacement of the quadrilateral plate and injury to the obturator nerve. HYPOTHESIS: We hypothesized that obturator nerve injury would be related to a marked medial displacement of the quadrilateral plate. PATIENTS AND METHODS: We conducted a retrospective cohort study of 22 patients with acetabular fractures that were surgically treated with the modified Stoppa approach. The medial displacement of the quadrilateral plate was measured on a three-dimensional reconstruction image with the inlet view. Postoperative electrodiagnostic tests were performed based on clinical suspicion of neurological injury. Nerve injuries were divided into initial trauma or postoperative complication, and recovery of nerve function was evaluated. We identified the incidence of obturator nerve injury and analyzed the relationship between obturator nerve injury and medial displacement of the quadrilateral plate. RESULTS: The incidence of obturator nerve injury was 2/22 (9.1%), and all injuries resulted from the initial trauma. The average displacement of the quadrilateral plate was 15.9+/-13.4mm. Patients were divided into two groups, using a displacement of 24mm as a cutoff point, identified using a receiver operating characteristic curve analysis. There were 16 patients in group 1 (<24mm) and 6 patients in group 2 (>=24mm). The incidence of obturator nerve injury from trauma was 0/16 (0%) in group 1 and 2/6 (33.3%) in group 2 (P=0.018). CONCLUSIONS: No cases of postoperative obturator nerve injury were identified. Preoperative obturator nerve injury was more common in patients with a displacement of the quadrilateral plate>=24mm. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 28342821 TI - Correction of axial deformity during lengthening in fibular hypoplasia: Hexapodal versus monorail external fixation. AB - INTRODUCTION: Childhood fibular hypoplasia is a rare pathology which may or may not involve limb-length discrepancy and axial deformity in one or more dimensions. The objective of the present study was to compare the quality of the axial correction achieved in lengthening procedures by hexapodal versus monorail external fixators. The hypothesis was that the hexapodal fixator provides more precise correction. MATERIAL AND METHODS: A retrospective multicenter study included 52 children with fibular hypoplasia. Seventy-two tibias were analyzed, in 2 groups: 52 using a hexapodal fixator, and 20 using a monorail fixator. Mean age was 10.2 years. Mean lengthening was 5.7cm. Deformities were analyzed and measured in 3 dimensions and classified in 4 preoperative types and 4 post lengthening types according to residual deformity. RESULTS: Complete correction was achieved in 26 tibias in the hexapodal group (50%) and 2 tibias in the monorail group (10%). Mean post-correction mechanical axis deviation was smaller in the hexapodal group: 12.83mm, versus 14.29mm in the monorail group. Mean post correction mechanical lateral distal femoral angle was 87.5 degrees in the hexapodal group, versus 84.3 degrees in the monorail group (P=0.002), and mean mechanical medial proximal tibial angle 86.9 degrees versus 89.5 degrees , respectively (P=0.015). DISCUSSION: No previous studies focused on this congenital pathology in lengthening and axial correction programs for childhood lower-limb deformity. The present study found the hexapodal fixator to be more effective in conserving or restoring mechanical axes during progressive bone lengthening for fibular hypoplasia. CONCLUSION: The hexapodal fixator met the requirements of limb-length equalization in childhood congenital lower-limb hypoplasia, providing better axial correction than the monorail fixator. LEVEL OF EVIDENCE: IV. PMID- 28342822 TI - Antiplatelet activity of drugs used in hypertension, dyslipidemia and diabetes: Additional benefit in cardiovascular diseases prevention. AB - Beyond its function in hemostasis, platelets activation has an important role in cardiovascular diseases (CVD) development. There are different clinical conditions that can mediate abnormal platelet activation and favors pathological thrombosis and CVD. These include Hypertension, diabetes and dyslipidemia, all risks factors from CVD development. Different drugs employed in the handled of these conditions have showed decreases platelet activation and related markers. This effect is in part by improved the base condition; however someone of these drugs can modulate platelet targets. We discuss about underlying mechanisms and the possible implications in the treatment of CVD. PMID- 28342823 TI - Evidence that increased Kcnj6 gene dose is necessary for deficits in behavior and dentate gyrus synaptic plasticity in the Ts65Dn mouse model of Down syndrome. AB - Down syndrome (DS), trisomy 21, is caused by increased dose of genes present on human chromosome 21 (HSA21). The gene-dose hypothesis argues that a change in the dose of individual genes or regulatory sequences on HSA21 is necessary for creating DS-related phenotypes, including cognitive impairment. We focused on a possible role for Kcnj6, the gene encoding Kir3.2 (Girk2) subunits of a G-protein coupled inwardly-rectifying potassium channel. This gene resides on a segment of mouse Chromosome 16 that is present in one extra copy in the genome of the Ts65Dn mouse, a well-studied genetic model of DS. Kir3.2 subunit-containing potassium channels serve as effectors for a number of postsynaptic metabotropic receptors including GABAB receptors. Several studies raise the possibility that increased Kcnj6 dose contributes to synaptic and cognitive abnormalities in DS. To assess directly a role for Kcnj6 gene dose in cognitive deficits in DS, we produced Ts65Dn mice that harbor only 2 copies of Kcnj6 (Ts65Dn:Kcnj6++- mice). The reduction in Kcnj6 gene dose restored to normal the hippocampal level of Kir3.2. Long-term memory, examined in the novel object recognition test with the retention period of 24h, was improved to the level observed in the normosomic littermate control mice (2N:Kcnj6++). Significantly, both short-term and long term potentiation (STP and LTP) was improved to control levels in the dentate gyrus (DG) of the Ts65Dn:Kcnj6++- mouse. In view of the ability of fluoxetine to suppress Kir3.2 channels, we asked if fluoxetine-treated DG slices of Ts65Dn:Kcnj6+++ mice would rescue synaptic plasticity. Fluoxetine increased STP and LTP to control levels. These results are evidence that increased Kcnj6 gene dose is necessary for synaptic and cognitive dysfunction in the Ts65Dn mouse model of DS. Strategies aimed at pharmacologically reducing channel function should be explored for enhancing cognition in DS. PMID- 28342825 TI - Association between parasitic infections and tuberculin skin test results in refugees. AB - BACKGROUND: Parasitic infections are known to modulate the immune response necessary for controlling Mycobacterium tuberculosis infection. We sought to investigate species-specific effects of parasite infection on M. tuberculosis infection. METHODS: As part of the Refugee Health Assessment Program, stool examinations and tuberculin skin testing were performed on refugees seen at Boston Medical Center between 1995 and 2012. Tuberculin skin test (TST) and stool examination data were collected for 6669 refugees; 3349 (50.2%) were TST positive (>=10 mm). RESULTS: Among TST-positive subjects, 176 (5.3%) had helminth infections and 1149 (34.3%) protozoa. After adjusting for sex, age, and country of origin, helminth and protozoan infections were not associated with TST positivity. When species-specific effects were examined, subjects infected with Trichuris trichiura and Giardia lamblia had reduced odds of TST-positivity (adjusted OR [aOR] 0.65 [95%CI 0.44-0.96; p = 0.03] and aOR 0.79 [95%CI 0.65 0.95, p = 0.01], respectively). CONCLUSIONS: Our findings suggest that T. trichiura and G. lamblia may provide protection against M. tuberculosis infection. This study adds to a growing body of literature suggesting that immune response modulation and susceptibility to M. tuberculosis infection is parasite species-dependent. PMID- 28342826 TI - New trends of the microcephaly and Zika virus outbreak in Brazil, July 2016 December 2016. PMID- 28342824 TI - Development of CAR T cells designed to improve antitumor efficacy and safety. AB - Chimeric antigen receptor (CAR) T cell therapy has shown promising efficacy against hematologic malignancies. Antitumor activity of CAR T cells, however, needs to be improved to increase therapeutic efficacy in both hematologic and solid cancers. Limitations to overcome are 'on-target, off-tumor' toxicity, antigen escape, short CAR T cell persistence, little expansion, trafficking to the tumor and inhibition of T cell activity by an inhibitory tumor microenvironment. Here we will discuss how optimizing the design of CAR T cells through genetic engineering addresses these limitations and improves the antitumor efficacy of CAR T cell therapy in pre-clinical models. PMID- 28342827 TI - Foreign citizen mortality in Iceland January 2006 - December 2016. AB - BACKGROUND: In recent years, tourism has become the number one account for foreign exchange income in Iceland, overtaking the fisheries industry and aluminium production. The rise of tourism has strongly affected Icelandic society in various sectors. With the increase of tourists visiting Iceland, the number of foreign citizens that died and were autopsied also rose. METHOD: Data were collected from the Department of Forensic Pathology at Landspitali University Hospital in Reykjavik for the period January 2006 - December 2016. RESULT: During this time there were 109 autopsies performed on foreign citizens of which 58 died from natural causes, 49 were injury deaths and in 2 cases no certain cause of death could be determined. Most represented were citizens from North America, United Kingdom and Germany (each 11%). The main causes of death were cardiovascular events (41%) followed by unintentional injuries (34%). CONCLUSION: The research at hand shows the significant influence of tourism on Forensic Medicine and provides an update on deaths of overseas travellers. Furthermore this study points out variable risks of travel-related injuries and deaths in Iceland. PMID- 28342828 TI - Resistance Training for Muscle Weakness in Multiple Sclerosis: Direct Versus Contralateral Approach in Individuals With Ankle Dorsiflexors' Disparity in Strength. AB - OBJECTIVE: To compare effects of contralateral strength training (CST) and direct strength training of the more affected ankle dorsiflexors on muscle performance and clinical functional outcomes in people with multiple sclerosis (MS) exhibiting interlimb strength asymmetry. DESIGN: Randomized controlled trial. SETTING: University hospital. PARTICIPANTS: Individuals with relapsing-remitting MS (N=30) and mild-to-moderate disability (Expanded Disability Status Scale score <=6) presenting with ankle dorsiflexors' strength disparity. INTERVENTIONS: Participants were randomly assigned to a CST (n=15) or direct strength training (n=15) group performing 6 weeks of maximal intensity strength training of the less or more affected dorsiflexors, respectively. MAIN OUTCOME MEASURES: Maximal strength, endurance to fatigue, and mobility outcomes were assessed before, at the intervention end, and at 12-week follow-up. Strength and fatigue parameters were measured after 3 weeks of training (midintervention). RESULTS: In the more affected limb of both groups, pre- to postintervention significant increases in maximal strength (P<=.006) and fatigue endurance (P<=.04) were detected along with consistent retention of these improvements at follow-up (P<=.04). At midintervention, the direct strength training group showed significant improvements (P<=.002), with no further increase at postintervention, despite training continuation. Conversely, the CST group showed nonsignificant strength gains, increasing to significance at postintervention (P<=.003). In both groups, significant pre- to postintervention improvements in mobility outcomes (P<=.03), not retained at follow-up, were observed. CONCLUSIONS: After 6 weeks of training, CST proved as effective as direct strength training in enhancing performance of the more affected limb with a different time course, which may have practical implications in management of severely weakened limbs where direct strength training is not initially possible. PMID- 28342829 TI - Effects of Peer Mentoring on Self-Efficacy and Hospital Readmission After Inpatient Rehabilitation of Individuals With Spinal Cord Injury: A Randomized Controlled Trial. AB - OBJECTIVE: To investigate the effect of intensive peer mentoring on patient reported outcomes of self-efficacy and unplanned hospital readmissions for persons with spinal cord injury/disease (SCI/D) within the first 6 months after discharge from inpatient rehabilitation. DESIGN: Randomized controlled trial. SETTING: Nonprofit inpatient rehabilitation hospital specializing in care of persons with SCI/D and brain injury. PARTICIPANTS: Patients (N=158) admitted to the SCI/D rehabilitation program whose discharge location was a community setting. Participants (51% with paraplegia and 49% with tetraplegia) were 73% white and 77% men, with a mean age of 38 years. INTERVENTIONS: Participants in the experimental group received initial consult/introduction with a peer support program liaison and were assigned a peer mentor, who met with the participant weekly throughout the inpatient stay and made weekly contact by phone, e-mail, or in person for 90 days postdischarge. Participants also were encouraged to participate in regularly scheduled peer support activities. Nonexperimental group participants were introduced to peer support and provided services only on request. MAIN OUTCOME MEASURES: General Self-efficacy Scale (adapted to SCI/D), project-developed community integration self-efficacy scale, and patient-reported unplanned rehospitalizations. RESULTS: Growth rate for self-efficacy in the first 6 months postdischarge was significantly higher for experimental group participants than nonexperimental group participants. Experimental group participants also had significantly fewer unplanned hospital days. CONCLUSIONS: This study provides evidence that individuals receiving intensive peer mentoring during and after rehabilitation for SCI/D demonstrate greater gains in self efficacy over time and have fewer days of unplanned rehospitalization in the first 180 days postdischarge. More research is needed to examine the long-term effects of this intervention on health care utilization and the relation between improved health and patient-reported quality of life outcomes. PMID- 28342830 TI - Patients Taking Amoxicillin-Clavulanic Can Become Simultaneously Sensitized to Both Drugs. AB - BACKGROUND: Patients can react to amoxicillin (AX) and clavulanic acid (CLV) taken in combination because of selective reactions to either drug. However, scant information exists concerning patients who react simultaneously to both compounds. OBJECTIVE: To analyze the mechanisms involved in 4 patients who developed allergic reactions to AX-CLV administration (3 with immediate IgE mediated reaction and 1 with nonimmediate T-cell-mediated reaction) and who responded specifically to both AX and CLV. METHODS: Skin tests with benzylpenicillin (BP), AX, and CLV were done and, if necessary, drug provocation tests with BP/penicillin V, AX, and AX-CLV were carried out. In immediate reactors, serum specific IgE to benzylpenicilloyl and amoxicilloyl was determined by using the CAP-FEIA system (Pharmacia Diagnostics, Uppsala, Sweden), and basophil activation test to BP, AX, CLV, and AX-CLV was done. In nonimmediate reactors, immunohistochemistry of skin biopsy and analysis of dendritic cell maturation and T-cell-specific response to BP, AX, CLV, and AX-CLV at both acute and resolution phases of the reaction were conducted. RESULTS: All patients with immediate reactions (N = 3) had good tolerance to BP and penicillin V. Two cases also had specific IgE to AX and all had a basophil activation test positive to AX, CLV, and AX-CLV. The patient with a nonimmediate reaction exhibited dendritic cell and T-lymphocyte responses specific to both AX and CLV. Finally, the analysis of the cells infiltrating the skin and peripheral blood during the acute phase indicated a TH1 pattern response. CONCLUSIONS: Our study provides evidence that reactions to both AX and CLV can appear in the same patient. PMID- 28342831 TI - Inference of direct and multistep effective connectivities from functional connectivity of the brain and of relationships to cortical geometry. AB - BACKGROUND: The problem of inferring effective brain connectivity from functional connectivity is under active investigation, and connectivity via multistep paths is poorly understood. NEW METHOD: A method is presented to calculate the direct effective connection matrix (deCM), which embodies direct connection strengths between brain regions, from functional CMs (fCMs) by minimizing the difference between an experimental fCM and one calculated via neural field theory from an ansatz deCM based on an experimental anatomical CM. RESULTS: The best match between fCMs occurs close to a critical point, consistent with independent published stability estimates. Residual mismatch between fCMs is identified to be largely due to interhemispheric connections that are poorly estimated in an initial ansatz deCM due to experimental limitations; improved ansatzes substantially reduce the mismatch and enable interhemispheric connections to be estimated. Various levels of significant multistep connections are then imaged via the neural field theory (NFT) result that these correspond to powers of the deCM; these are shown to be predictable from geometric distances between regions. COMPARISON WITH EXISTING METHODS: This method gives insight into direct and multistep effective connectivity from fCMs and relating to physiology and brain geometry. This contrasts with other methods, which progressively adjust connections without an overarching physiologically based framework to deal with multistep or poorly estimated connections. CONCLUSIONS: deCMs can be usefully estimated using this method and the results enable multistep connections to be investigated systematically. PMID- 28342832 TI - Optimized CLARITY technique detects reduced parvalbumin density in a genetic model of schizophrenia. AB - BACKGROUND: Novel tissue clearing technologies have, for the first time, made it possible to study intact tissue samples. This approach provides a tool for further clarifying findings from animal models of schizophrenia by studying parvalbumin-positive (PV+) interneuron density from a 3D perspective. NEW METHOD: This study has developed an optimised CLARITY protocol, including an improved electrophoretic tissue clearing (ETC) chamber, an evaluation of antibody diffusion into cleared tissue slices, and a computational method for detecting PV+ interneurons in 3D. RESULTS: A reduced PV+ interneuron density was found in both prelimbic and motor cortex regions of the Df(h15q13)/+ mice, while no changes were observed in the Df(h22q11)/+ mice. COMPARISON WITH EXISTING METHOD: The developed ETC chamber enables tissue clearing of variable tissue sizes while minimizing the resistance. It was found that a high concentration of primary and secondary antibodies were necessary for sufficient antibody staining of PV+ interneurons. Additionally, the developed computational method showed improved detection rates of interneurons compared to non-processed image stacks. CONCLUSION: Our optimization of the CLARITY technology and automated 3D counting of cells were found to be useful for quantification of PV+ interneuron density. The results may provide insight into understanding the pathophysiology underlying the phenotype observed in Df(h15q13)/+ mice. PMID- 28342833 TI - A high density CHO-S transient transfection system: Comparison of ExpiCHO and Expi293. AB - Chinese Hamster Ovary (CHO) cells are the principal mammalian host used for stable cell line generation and biotherapeutic protein production. Until recently, production of milligrams to grams of protein in CHO transient systems was challenging. As such, Human Embryonic Kidney (HEK293) cells are the most common mammalian cell type used for transient transfection. The post translational modifications (PTMs) of a protein are dictated in part by the cell line used for expression, and changes in PTMs have been shown to affect both the activity and biophysical properties of proteins. Therefore, it is potentially advantageous to keep the host cell type consistent throughout drug discovery and development. To this end, we compared the ExpiCHO system, a high density CHO-S transient transfection system, to the Expi293 and FreeStyle MAX CHO transient systems. Fourteen proteins were expressed in both the Expi293 and ExpiCHO systems. For a majority of proteins tested, the protein titers observed with the ExpiCHO system were higher than those seen with both the FreeStyle MAX CHO and Expi293 systems. Antibodies expressed using the ExpiCHO system had glycosylation patterns more similar to antibodies produced in stable CHO cell lines than Expi293-derived antibodies. However, culture duration and temperature were found to affect protein titer, monodispersity, enzyme activity, and PTMs and should be carefully selected when using the ExpiCHO system. The ExpiCHO transient transfection systems allows for facile production of milligrams to grams of protein in CHO cells and de-risks the transition from transient to stable material during drug development. PMID- 28342834 TI - ACEs and Child Health Policy: The Enduring Case for EPSDT. PMID- 28342835 TI - Lipids in exosomes: Current knowledge and the way forward. AB - Lipids are essential components of exosomal membranes, and it is well-known that specific lipids are enriched in exosomes compared to their parent cells. In this review we discuss current knowledge about the lipid composition of exosomes. We compare published data for different lipid classes in exosomes, and what is known about their lipid species, i.e. lipid molecules with different fatty acyl groups. Moreover, we elaborate on the hypothesis about hand-shaking between the very-long chain sphingolipids in the outer leaflet and PS 18:0/18:1 in the inner leaflet, and we propose this to be an important mechanism in membrane biology, not only for exosomes. The similarity between the lipid composition of exosomes, HIV particles, and detergent resistant membranes, used as lipid rafts models, is also discussed. Furthermore, we summarize knowledge about the role of specific lipids and lipid metabolizing enzymes on the formation and release of exosomes. Finally, the use of exosomal lipids as biomarkers and how the lipid composition of exosomes may be of importance for researchers aiming to use exosomes as drug delivery vehicles is discussed. In conclusion, we have summarized what is presently known about lipids in exosomes and identified issues that should be taken into consideration in future studies. PMID- 28342837 TI - [Malignant cutaneous adnexal neoplasms of the face and scalp: Diagnostic and therapeutic update]. AB - INTRODUCTION: Malignant cutaneous adnexal neoplasms are rare and have been characterized only recently. They can occur at any age but preferentially in elderly. There are 3 of them: trichoblastic carcinoma, trichilemmal carcinoma and malignant pilomatricoma. The aim of our study was to make a diagnostic and therapeutic update about these tumors when located at the face or at the scalp. MATERIALS AND METHODS: A bibliographic research was made on PubMed using following keywords: appendage skin carcinoma AND pathology AND/OR therapeutic. Articles published before 2000 were considered outdated and were excluded. RESULTS: Twenty-five articles met the inclusion criteria. Clinical presentation was non-specific. Histological examination only allowed for diagnosis. Lesions were locally or loco-regionally aggressive. Lymphatic or hematogenous metastasis were reported. No consensus about treatment was found. When surgery was used, it consisted in resection with safety margins ranging from 0.5 to 3cm depending on the teams. In case of metastasis, treatment consisted in chemo- and/or radiotherapy. A quarterly medical monitoring was recommended. DISCUSSION: Malignant cutaneous adnexal tumors are rare. There is nowadays no treatment consensus. An initial staging by mean of a head and neck, chest, abdominal and pelvic CT-scan is mandatory. Treatment has to be decided in a multidisciplinary cancer committee. In the absence of metastasis, the reference treatment is surgical resection, possibly by Mohs micrographic technique, with large safety margins. In case of metastasis or if the loco-regional extension does not allow for a complete excision, chemotherapy and/or radiotherapy may be proposed. A close monitoring is essential. PMID- 28342836 TI - Membrane fatty acid composition as a determinant of Listeria monocytogenes sensitivity to trans-cinnamaldehyde. AB - trans-Cinnamaldehyde, the major compound of cinnamon essential oil, is a potentially interesting natural antimicrobial food preservative. Although a number of studies have addressed its mode of action, the factors that determine bacterial sensitivity or tolerance to trans-cinnamaldehyde are poorly understood. We report the detailed characterization of a Listeria monocytogenes Scott A trans cinnamaldehyde hypersensitive mutant defective in IlvE, which catalyzes the reversible transamination of branched-chain amino acids to the corresponding short-chain alpha-ketoacids. This mutant showed an 8.4 fold extended lag phase during growth in sublethal concentrations (4 mM), and faster inactivation in lethal concentrations of trans-cinnamaldehyde (6 mM). trans-Cinnamaldehyde hypersensitivity could be corrected by genetic complementation with the ilvE gene and supplementation with branched-chain alpha-ketoacids. Whole-cell fatty acid analyses revealed an almost complete loss of anteiso branched-chain fatty acids (BCFAs), which was compensated by elevated levels of unbranched saturated fatty acids and iso-BCFAs. Sub-inhibitory concentrations of trans-cinnamaldehyde induced membrane fatty acid adaptations predicted to reduce membrane fluidity, possibly as a response to counteract the membrane fluidizing effect of trans cinnamaldehyde. These results demonstrate the role of IlvE in BCFA production and the role of membrane composition as an important determinant of trans cinnamaldehyde sensitivity in L. monocytogenes. PMID- 28342838 TI - The effect of the packaging system and storage time on myofibrillar protein degradation and oxidation process in relation to beef tenderness. AB - This study investigated the impact of packaging systems on the degradation and oxidation of beef proteins regarding beef tenderness of longissimus lumborum (LL) and biceps femoris (BF) muscles stored in vacuum skin packaging (VSP), a modified atmosphere with high oxygen concentration (MAP), and combined of these two methods (VSP+MAP). A significant decrease in the Warner-Bratzler shear force (WBSF) in VSP at D14 and D28 for LL was observed compared to BF. A significant effect of packaging system on troponin-T (Tn-T) and desmin degradation was shown (p<=0.001). A high concentration of oxygen in MAP and VSP+MAP affected protein oxidation, which was reflected in myosin oxidative cross-linking. An increase of WBSF values detected in steaks packed in VSP and VSP+MAP systems could be caused by the intensification of protein oxidation. Furthermore, BF was more susceptible to oxidation compared to LL. The VSP+MAP packaging system has resulted in the maintenance of a bright, red color, however has not improved the beef tenderness. PMID- 28342839 TI - A case of severely calcified neoatherosclerosis after paclitaxel eluting stent implantation. AB - A 79-year-old male who had a history of coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) received coronary angiography (CAG), because of angina pectoris. CAG showed in-stent restenosis of the paclitaxel eluting stent (PES). Since the devices could not pass the lesion, we performed rotational atherectomy. Although we could not identify the calcified lesion by the optical frequency domain imaging (OFDI) findings because of strong attenuation, the intravascular ultrasound (IVUS) image showed the superficial calcification. On the other hand, strong attenuation in OFDI suggested the presence of foamy macrophage, which was essential for the diagnosis of neoatherosclerosis. We could obtain a favorable result by deploying another drug eluting stent. While an earlier report showed the calcified neoatherosclerosis following bare-metal stent implantation, we clearly showed the calcified neoatherosclerosis following PES implantation. PMID- 28342840 TI - The ratio of contrast volume to glomerular filtration rate predicts acute kidney injury and mortality after transcatheter aortic valve implantation. AB - OBJECTIVE: The aim of this study was to assess the impact of the ratio of volume of contrast medium to the glomerular filtration rate (V/GFR) on acute kidney injury (AKI) after transcatheter aortic valve implantation (TAVI) and its impact on long-term mortality. METHODS: We retrospectively calculated V/GFR in 397 patients undergoing TAVI. AKI was defined as VARC-modified Risk, Injury, Failure, Loss and End-stage (RIFLE) kidney disease score>=2. RESULTS: The incidence of AKI was 17.9%. The mean V/GFR ratio was 3.0+/-2.7 in patients without AKI and 7.8+/ 8.8 in patients with AKI (p<0.001). The receiver-operator characteristic curve analysis showed fair discrimination between patients with and without AKI (C statistic 0.85) at a V/GFR ratio of 3.2. Multivariable regression analysis indicated that V/GFR>3.2 was an independent predictor of both AKI (OR 3.4, 95% CI 1.0-6.1, p<0.001) and long-term mortality (OR 3.3, 95% CI 2.0-5.2, p<0.001). CONCLUSIONS: A V/GFR > 3.2 was found to be correlated with a higher incidence of AKI and mortality after TAVI. Therefore, this ratio could potentially be used to calculate the maximum volume of contrast medium that can be administered without significantly increasing the risk of AKI and mortality. Further larger studies are needed to validate these findings. PMID- 28342841 TI - Use of a parallel stiff wire to facilitate percutaneous Impella RP ventricular assist device positioning. AB - Despite optimal medical management, some patients with severe right ventricular failure fail to respond and may benefit from additional support with the implantation of a RV assist device. Experience to date with Impella RP is limited. We report a case of percutaneous Impella RP implantation, using a parallel stiff wire to reduce anatomical tortuosity by acting as a buddy-wire to facilitate device implantation and reduce the risk of tricuspid ring damage in a patient recently treated with tricuspid ring annuloplasty. PMID- 28342842 TI - Protectin DX suppresses hepatic gluconeogenesis through AMPK-HO-1-mediated inhibition of ER stress. AB - Several studies have shown that protectins, which are omega-3 fatty acid-derived proresolution mediators, may improve insulin resistance. Recently, protectin DX (PDX) was documented to attenuate insulin resistance by stimulating IL-6 expression in skeletal muscle, thereby regulating hepatic gluconeogenesis. These findings made us investigate the direct effects of PDX on hepatic glucose metabolism in the context of diabetes. In the current study, we show that PDX regulates hepatic gluconeogenesis in a manner distinct from its indirect glucoregulatory activity via IL-6. We found that PDX stimulated AMP-activated protein kinase (AMPK) phosphorylation, thereby inducing heme oxygenase 1 (HO-1) expression. This induction blocked hepatic gluconeogenesis by suppressing endoplasmic reticulum (ER) stress in hepatocytes under hyperlipidemic conditions. These effects were significantly dampened by silencing AMPK or HO-1 expression with small interfering RNA (siRNA). We also demonstrated that administration of PDX to high fat diet (HFD)-fed mice resulted in increased hepatic AMPK phosphorylation and HO-1 expression, whereas hepatic ER stress was substantially attenuated. Furthermore, PDX treatment suppressed the expression of gluconeogenic genes, thereby decreasing blood glucose levels in HFD-fed mice. In conclusion, our findings suggest that PDX inhibits hepatic gluconeogenesis via AMPK-HO-1 dependent suppression of ER stress. Thus, PDX may be an effective therapeutic target for the treatment of insulin resistance and type 2 diabetes through the regulation of hepatic gluconeogenesis. PMID- 28342844 TI - A system dynamics modelling approach to assess the impact of launching a new nicotine product on population health outcomes. AB - In 2012 the US FDA suggested the use of mathematical models to assess the impact of releasing new nicotine or tobacco products on population health outcomes. A model based on system dynamics methodology was developed to project the potential effects of a new nicotine product at a population level. A model representing traditional smoking populations (never, current and former smokers) and calibrated using historical data was extended to a two-product model by including electronic cigarettes use statuses. Smoking mechanisms, such as product initiation, switching, transition to dual use, and cessation, were represented as flows between smoking statuses (stocks) and the potential effect of smoking renormalisation through a feedback system. Mortality over a 50-year period (2000 2050) was the health outcome of interest, and was compared between two scenarios, with and without e-cigarettes being introduced. The results suggest that by 2050, smoking prevalence in adults was 12.4% in the core model and 9.7% (including dual users) in the counterfactual. Smoking-related mortality was 8.4% and 8.1%, respectively. The results suggested an overall beneficial effect from launching e cigarettes and that system dynamics could be a useful approach to assess the potential population health effects of nicotine products when epidemiological data are not available. PMID- 28342843 TI - The stress-response molecule NR4A1 resists ROS-induced pancreatic beta-cells apoptosis via WT1. AB - Pancreatic beta-cells often face endoplasmic reticulum stress and/or ROS associated oxidative stress under adverse conditions. Our previous work has verified that NR4A1 protects pancreatic beta-cells from ER-stress induced apoptosis. However, It remains unknown whether NR4A1 is able to protect pancreatic beta-cells against ROS-associated oxidative stress. In the present study, our data showed that NR4A1 protein expression rapidly increased in MIN6 cells upon H2O2 treatment, and overexpression of NR4A1 in MIN6 cells conferred resistance to cell apoptosis induced by H2O2. These results were further substantiated in isolated islets from mice infected with an adenovirus overexpressing NR4A1. 8-hydroxy-2'-deoxyguanosine (8-OHdG) was used as a biomarker for oxidative stress or a marker for ROS damage. We found that the 8 OHdG level in the islets from NR4A1 knockout mice fed with high-fat diet was much higher than that in the islets from parental control mice; and higher apoptotic rate was observed in the islets from NR4A1 KO mice compared to control mice. Further investigation of underlying mechanisms of NR4A1's protective effects showed that NR4A1 overexpression in MIN6 cells reduced Caspase 3 activation caused by H2O2, and increased expression of WT1 and SOD1. There is a putative NR4A1 binding site (-1118bp to -1111bp) in WT1 promoter; our data demonstrated that NR4A1 protein physically associates with the WT1 promoter, and enhanced WT1 promoter transactivation and knockdown of WT1 in MIN6 cells induced apoptosis. These findings suggest that NR4A1 protects pancreatic beta-cells against H2O2 mediated apoptosis by up-regulating WT1 expression. PMID- 28342845 TI - Genotoxic and cytotoxic evaluation of Jatropha dioica Sesse ex Cerv. by the micronucleus test in mouse peripheral blood. AB - Jatropha dioica Sesse ex Cerv. is a medicinal plant credited with low cytotoxicity in vitro. Thus, the objective of this work was to evaluate the possible genotoxic and cytotoxic effect in vivo of the J. dioica aqueous extract by means of micronucleus assay in mouse peripheral blood. Four different J. dioica aqueous extract dose-units were evaluated (30, 60, 100, and 300 mg/kg). The extract was administered orally to male Balb-C-strain mice every 24 h during 5 days. Blood samples were taken at 0, 24, 48, 72, 96, and 120 h from the mouse's tail and were performed in duplicate extensions. The number of Polychromatic Erythrocytes (PCE), Polychromatic Micronucleus Erythrocytes (PCEMN), and Micronucleus Erythrocytes (MNE) was determined at the different sampling times in the different study groups. Our results showed that the group that received 60 mg/kg of cyclophosphamide (positive control) presented a significant decrease in the PCE (p = 0.044) proportion and a significant increase in MNE (p = 0.032, p = 0.0001). The groups that received the different J. dioica aqueous extract doses did not present either a PCE decrease or an increase in PCEMN and MNE. J. dioica exerts neither a genotoxic nor a cytotoxic effect on mouse peripheral blood at high doses. PMID- 28342846 TI - New studies on the in vitro genotoxicity of sodium molybdate and their impact on the overall assessment of the genotoxicity of molybdenum substances. AB - The potential of molybdenum substances to cause genotoxic effects has been studied previously. However, a review of existing in vitro data, including an assessment of relevance and reliability, has shown that inconsistent results have been observed in the past. To resolve the inconsistencies, new studies were performed with the highly soluble sodium molybdate dihydrate according to OECD test guidelines. In a bacterial reverse mutation assay sodium molybdate dihydrate did not induce reverse mutations in five strains of Salmonella typhimurium. No mutagenic or clastogenic effect was observed at the tk locus of L5178Y mouse lymphoma cells. In a micronucleus test in cultured human peripheral blood lymphocytes no clastogenic or aneugenic effects were seen. These results can be read across to other inorganic molybdenum substances, that all release the molybdate ion [MoO4]2- under physiological conditions as the only toxicologically relevant species. In summary, a weight of evidence assessment of all available in vitro data shows no evidence of genotoxicity of molybdenum substances. PMID- 28342847 TI - Na+/K+-ATPase interaction with methylglyoxal as reactive metabolic side product. AB - Proteins are subject to oxidative modification and the formation of adducts with a broad spectrum of reactive species via enzymatic and non-enzymatic mechanisms. Here we report that in vitro non-enzymatic methylglyoxal (MGO) binding causes the inhibition and formation of MGO advanced glycation end-products (MAGEs) in Na+/K+ ATPase (NKA). Concretely, MGO adducts with NKA amino acid residues (mainly Arg) and Nepsilon-(carboxymethyl)lysine (CML) formation were found. MGO is not only an inhibitor for solubilized NKA (IC50=91+/-16MUM), but also for reconstituted NKA in the lipid bilayer environment, which was clearly demonstrated using a DPPC/DPPE liposome model in the presence or absence of the NKA-selective inhibitor ouabain. High-resolution mass spectrometric analysis of a tryptic digest of NKA isolated from pig (Sus scrofa) kidney indicates that the intracellular alpha-subunit is naturally (post-translationally) modified by MGO in vivo. In contrast to this, the beta-subunit could only be modified by MGO artificially, and the transmembrane part of the protein did not undergo MGO binding under the experimental setup used. As with bovine serum albumin, serving as the water-soluble model, we also demonstrated a high binding capacity of MGO to water-poorly soluble NKA using a multi-spectral methodology based on electroanalytical, immunochemical and fluorimetric tools. In addition, a partial suppression of the MGO-mediated inhibitory effect could be observed in the presence of aminoguanidine (pimagedine), a glycation suppressor and MGO scavenger. All the results here were obtained with the X-ray structure of NKA in the E1 conformation (3WGV) and could be used in the further interpretation of the functionality of this key enzyme in the presence of highly-reactive metabolic side-products, glycation agents and generally under oxidative stress conditions. PMID- 28342848 TI - Ultraviolet A-induced oxidation in cornea: Characterization of the early oxidation-related events. AB - Exposure to sunlight ultraviolet-A (UVA), the main component of solar UV reaching the eyes, is suspected to play an important part in the onset of ocular pathologies. UVA primary biological deleterious effects arise from the photo induction of oxidative stress in cells. However, the molecular bases linking UVA induced oxidation to UVA toxicity in eyes remain poorly understood, especially with regards to the cornea. To shed some light on this issue, we have investigated the susceptibility and response potential of the different corneal cellular layers (epithelium, stroma and endothelium) to UVA-induced oxidation. We have monitored UVA-induced immediate effects on cellular redox balance, on mitochondrial membrane potential, on 8-Hydroxy-2'-deoxyguanosine (8-OHdG) accumulation in cellular DNA and on S-glutathionylated proteins (PSSG) levels along whole rabbit corneas. Higher redox imbalance was observed in the posterior part of the cornea following irradiation. Conversely, UVA-altered mitochondrial membrane potentials were observed only in anterior portions of the cornea. UVA induced 8-OHdG were found in nuclear DNA of epithelia, while they were found in both nuclear and mitochondrial DNA in stromal and endothelial cells. Finally, significantly higher levels of cytosolic PSSG were measured in epithelia and endothelia immediately after UVA exposure, but not in stromas. Taken together, our findings indicate that while corneal epithelial cells are subjected to important modifications in response to UVA exposure, they efficiently limit the early manifestations of UVA-induced toxicity. On the other hand, the corneal endothelium is more susceptible to UVA-induced oxidation-related toxicity. PMID- 28342849 TI - Comparative effects of EtOH consumption and thiamine deficiency on cognitive impairment, oxidative damage, and beta-amyloid peptide overproduction in the brain. AB - The effects of chronic EtOH consumption, associated or not with thiamine deficiency (TD), on cognitive impairment, oxidative damage, and beta-amyloid (Abeta) peptide accumulation in the brain were investigated in male C57BL/6 mice. We established an alcoholic mouse model by feeding an EtOH liquid diet, a TD mouse model by feeding a thiamine-depleted liquid diet, and an EtOH treatment associated with TD mouse model by feeding a thiamine-depleted EtOH liquid diet for 7 weeks. The learning and memory functions of the mice were detected through the Y-maze test. Biochemical parameters were measured using corresponding commercial kits. The Abeta expression in the hippocampus was observed by immunohistochemical staining. Several results were obtained. First, EtOH significantly reduced cognitive function by significantly decreasing the Glu content in the hippocampus; increasing the AChE activity in the cortex; and reducing the thiamine level, and superoxide dismutase (SOD), glutathione peroxidase (GPx), and choline acetyltransferase (ChAT) activities in both the hippocampus and cortex. The treatment also increased the levels of malondialdehyde (MDA), protein carbonyl, 8-hydroxydeoxyguanosine (8-OHdG), and nitric oxide (NO) and the activities of total nitric oxide synthase (tNOS), inducible nitric oxide synthase (iNOS), and monoamine oxidase B (MAO-B). Furthermore, EtOH enhanced the expression levels of Abeta1-42 and Abeta1-40 in the hippocampus. Second, TD induced the same dysfunctions caused by EtOH in the biochemical parameters, except for learning ability, 8-OHdG content, and GPx, tNOS, and AChE activities in the cortex. Third, the modification of MDA, protein carbonyl and NO levels, and GPx, iNOS, ChAT, and MAO-B activities in the brain induced by chronic EtOH treatment associated with TD was greater than that induced by EtOH or TD alone. The synergistic effects of EtOH and TD on Abeta1-40 and Glu release, as well as on SOD activity, depended on their actions on the hippocampus or cortex. These findings suggest that chronic EtOH consumption can induce TD, cognitive impairment, Abeta accumulation, oxidative stress injury, and neurotransmitter metabolic abnormalities. Furthermore, the association of chronic EtOH consumption with TD causes dramatic brain dysfunctions with a severe effect on the brain. PMID- 28342850 TI - Structural basis for differential activities of enantiomeric PPARgamma agonists: Binding of S35 to the alternate site. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily. It functions as a ligand-activated transcription factor and plays important roles in the regulation of adipocyte differentiation, type 2 diabetes mellitus, and inflammation. Many PPARgamma agonists bind to the canonical ligand-binding pocket near the activation function-2 (AF-2) helix (i.e., helix H12) of the ligand-binding domain (LBD). More recently, an alternate ligand-binding site was identified in PPARgamma LBD; it is located beside the Omega loop between the helices H2' and H3. We reported previously that the chirality of two optimized enantiomeric PPARgamma ligands (S35 and R35) differentiates their PPARgamma transcriptional activity, binding affinity, and inhibitory activity toward Cdk5 (cyclin-dependent kinase 5)-mediated phosphorylation of PPARgamma at Ser245 (in PPARgamma1 numbering; Ser273 in PPARgamma2 numbering). S35 is a PPARgamma phosphorylation inhibitor with promising glucose uptake potential, whereas R35 behaves as a potent conventional PPARgamma agonist. To provide a structural basis for understanding the differential activities of these enantiomeric ligands, we have determined crystal structures of the PPARgamma LBD in complex with either S35 or R35. S35 and R35 bind to the PPARgamma LBD in significantly different manners. The partial agonist S35 occupies the alternate site near the Omega loop, whereas the full agonist R35 binds entirely to the canonical LBP. Alternate site binding of S35 affects the PPARgamma transactivation and the inhibitory effect on PPARgamma Ser245 phosphorylation. This study provides a useful platform for the development of a new generation of PPARgamma ligands as anti-diabetic drug candidates. PMID- 28342852 TI - Effects of sub-culturing on genetic and physiological parameters in different Beauveria bassiana isolates. AB - Beauveria bassiana is a fungus which is widely used as a biological insecticide to control a number of economically important insect pests. Knowledge of the genetic diversity of the isolates, understanding the underlying nature of these evolutionary phenomena and finding appropriate and simple screening tools play an important role in developing effective biocontrol agents. Here, we monitored changes of electrophoretic karyotype of small molecules of extrachromosomal DNAs, presumably mitochondrial DNA or plasmids in several individual isolates of B. bassiana during the forced in vitro evolution by continual subculture on artificial media and then we evaluated these changes on the virulence of the isolates. Through agarose gel electrophoresis of the small extrachromosomal DNAs molecules, we found that mutations accumulate quickly and obvious changes take place in extrachromosomal DNAs of some isolates, although this did not always occur. This plasticity in response to culturing pressure suggests that buffering capacity of fungal genome against mutations is isolate dependent. Following the forced evolution by sub-culturing, five discriminable electrophoretic karyotype of extrachromosomal DNAs was observed among isolates. The results showed that some isolates are prone to deep mutations, but during enforced sub-culturing some others have efficiently conserved genome. These differences are influensive in screening appropriate isolates for mass production as a keystone in biocontrol program. To determine the effects of these changes on isolate traits, virulence, germination rate and spore-bound Pr1 activity were assessed parallel to sub culturing. The results clearly revealed that parallel to sub-culturing and in correlation with karyotypic changes, isolates significantly suffered from virulence, germination rate and spore-bound Pr1 activity deficiencies. PMID- 28342851 TI - Site-specific photocoupling of pBpa mutated scFv antibodies for use in affinity proteomics. AB - Recombinant antibody libraries can provide a source of renewable and high performing binders tailored for use in affinity proteomics. In this context, the process of generating site-specific 1:1 tagging/functionalization and/or orientated surface immobilization of antibodies has, however, proved to be challenging. Hence, novel ways of generating such engineered antibodies for use in affinity proteomics could have a major impact on array performance. In this study, we have further tailored the design of human recombinant scFv antibodies for site-specific photocoupling through the use of an unnatural amino acid (UAA) and the Dock'n'Flash technology. In more detail, we have generated the 2nd generation of scFvs carrying the photoreactive UAA p-benzoyl-l-phenylalanine (pBpa). Based on key properties, such as expression levels, activity, and affinity, a preferred choice of site for pBpa, located in the beginning of the C terminal affinity-tag, was for the first time pin-pointed. Further, the results showed that pBpa mutated antibody could be site-specifically photocoupled to free and surface immobilized beta-cyclodextrin (an affinity ligand to pBpa). This paves the way for use of scFv antibodies, engineered for site-specific photochemical-based tagging, functionalization, and orientated surface immobilization, in affinity proteomics. PMID- 28342853 TI - Thyroid hormone promotes differentiation of colon cancer stem cells. AB - Tumor formation and maintenance depend on a small fraction of cancer stem cells (CSCs) that can self-renew and generate a wide variety of differentiated cells. CSCs are resistant to chemotherapy and radiation, and can represent a reservoir of cancer cells that often cause relapse after treatment. Evidence suggests that CSCs also give rise to metastases. Thyroid hormone (TH) controls a variety of biological processes including the development and functioning of most adult tissues. Recent years has seen the emergence of an intimate link between TH and multiple steps of tumorigenesis. Thyroid hormone controls the balance between the proliferation and differentiation of CSCs, and may thus be a druggable anti cancer agent. Here, we review current understanding of the effects of TH on colorectal CSCs, including the cross regulatory loops between TH and regulators of CSC stemness. Targeting TH in the tumor microenvironment may improve treatment strategies. PMID- 28342854 TI - Evolution of ligands, receptors and metabolizing enzymes of thyroid signaling. AB - Thyroid hormones (THs) play important roles in vertebrates such as the control of the metabolism, development and seasonality. Given the pleiotropic effects of thyroid disorders (developmental delay, mood disorder, tachycardia, etc), THs signaling is highly investigated, specially using mammalian models. In addition, the critical role of TH in controlling frog metamorphosis has led to the use of Xenopus as another prominent model to study THs action. Nevertheless, animals regarded as non-model species can also improve our understanding of THs signaling. For instance, studies in amphioxus highlighted the role of Triac as a bona fide thyroid hormone receptor (TR) ligand. In this review, we discuss our current understanding of the THs signaling in the different taxa forming the metazoans (multicellular animals) group. We mainly focus on three actors of the THs signaling: the ligand, the receptor and the deiodinases, enzymes playing a critical role in THs metabolism. By doing so, we also pinpoint many key questions that remain unanswered. How can THs accelerate metamorphosis in tunicates and echinoderms while their TRs have not been yet demonstrated as functional THs receptors in these species? Do THs have a biological effect in insects and cnidarians even though they do not have any TR? What is the basic function of THs in invertebrate protostomia? These questions can appear disconnected from pharmacological issues and human applications, but the investigation of THs signaling at the metazoans scale can greatly improve our understanding of this major endocrinological pathway. PMID- 28342855 TI - Regulation of reproduction via tight control of gonadotropin hormone levels. AB - Mammalian reproduction is controlled by the hypothalamic-pituitary-gonadal axis. GnRH from the hypothalamus regulates synthesis and secretion of gonadotropins, LH and FSH, which then control steroidogenesis and gametogenesis. In females, serum LH and FSH levels exhibit rhythmic changes throughout the menstrual or estrous cycle that are correlated with pulse frequency of GnRH. Lack of gonadotropins leads to infertility or amenorrhea. Dysfunctions in the tightly controlled ratio due to levels slightly outside the normal range occur in a larger number of women and are correlated with polycystic ovaries and premature ovarian failure. Since the etiology of these disorders is largely unknown, studies in cell and mouse models may provide novel candidates for investigations in human population. Hence, understanding the mechanisms whereby GnRH regulates gonadotropin hormone levels will provide insight into the physiology and pathophysiology of the reproductive system. This review discusses recent advances in our understanding of GnRH regulation of gonadotropin synthesis. PMID- 28342856 TI - Reproductive endocrinology of vitamin D. AB - Vitamin D is a versatile hormone with several functions beyond its well established role in maintenance of skeletal health and calcium homeostasis. The effects of vitamin D are mediated by the vitamin D receptor, which is expressed together with the vitamin D metabolizing enzymes in the reproductive tissues. The reproductive organs are therefore responsive to and able to metabolize vitamin D locally. The exact role remains to be clarified but several studies have suggested a link between vitamin D and production/release of reproductive hormones into circulation, which will be the main focus of this review. Current evidence is primarily based on small human association studies and rodent models. This highlights the need for randomized clinical trials, but also functional animal and human in vitro studies, and larger, prospective cohort studies are warranted. Given the high number of men and women suffering from reproductive problems and abnormal endocrinology research addressing the role of vitamin D in reproductive endocrinology may be of clinical importance. PMID- 28342857 TI - Antinociceptive and anti-inflammatory effects of the methanolic stem bark extract of Antrocaryon klaineanum Pierre (Anacardiaceae) in mice and rat. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Antrocaryon klaineanum is used by traditional healers to treat many disorders including pain and inflammatory diseases. This study aimed to evaluate the analgesic and antiinflammatory activities of methanol extract of A. klaineanum in mice and rats. MATERIALS AND METHODS: Reverse phase high-performance liquid chromatography (RP-HPLC) was performed to establish the chromatographic fingerprint and to identify various chemical components of the plant extract. The anti-nociceptive activity of methanol extract of A. klaineanum was assessed using the acetic acid-induced abdominal constriction model, formalin test, capsaicin and cinnamaldehyde induced-neurogenic pain and hot plate test. Anti-inflammatory activity was assessed on carrageenan-induced inflammation. Extract was administrated orally at 200, 400 and 600mg/kg. RESULTS: Phytochemical analysis indicated the presence of proanthocyanidins, phenolic acids and flavonoids. The results of anti-nociceptive and anti-inflammatory activities showed that methanol extract significantly (p<0.01) reduced the pain induced by acetic acid with an inhibition percentage of 45.49% (600mg/kg). In the formalin test, the extract also significantly (p<0.01) reduced linking time in both phase (neurogenic and inflammatory) of the test with inhibition percentage of 56.28% and 60.73% respectively at the dose of 600mg/kg. The methanol extract of A. klaineanum significantly (P<0.001) reduced neurogenic pain linking time induced by capsaicin and cinnamaldehyde by 82.54% and 75.94% at the highest dose (600mg/kg) respectively. More over the extract significantly increase the reaction time in hot plate test. In the inflammatory test, the plant extract significantly reduced the carrageen induced rat paw oedema from 30min to 6h with a maximum percentage inhibition of 89.88% (6h) at the dose of 600mg/kg. CONCLUSION: These results demonstrate that the methanol extract of A. klaineanum may possess analgesic and anti-inflammatory effects and provide support of the traditional use of this plant in the treatment of different pain and inflammatory conditions. Further investigation could reveal metabolites of the extract responsible for the observed effects. PMID- 28342858 TI - Aqueous extract from leaf of Artocarpus altilis provides cardio-protection from isoproterenol induced myocardial damage in rats: Negative chronotropic and inotropic effects. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The leaves of Artocarpus altilis (Parkinson ex F.A.Zorn, Fosberg) (Moraceae) are used in the management of hypertension; this study assessed the cardio-protective effects of the leaf extract on isoproterenol (ISO) induced myocardial damage in rats. MATERIAL AND METHODS: Twenty (20) adult male Sprague-Dawley rats (175-230g) were divided into 5 groups. Group 1 (Control), 2 (AA) received 50mg/Kg Artocarpus altilis (AA) only; 3 (ISO) received 85mg/Kg ISO only; 4 (ISO+AA/50) and 5 (ISO+AA/100) received 50 and 100mg/Kg AA respectively for 6 days, after induced with ISO twice (85mg/Kg) at a 24-h period. Blood pressure readings were taken before and after the administering of ISO using the tail cuff method. ECG was performed on anaesthetized rats. Cardiac contractility was measured in isolated right atrial muscles. Assessment of myocardial infarct (MI) size, heart/body weight ratio, biochemical, hematological and histo-morphological parameters were conducted at the end of seven days. An aqueous extract from leaves of A. altilis was analyzed for organic compounds using UHPLC mass spectrometry. RESULTS: ISO induced myocardial damage through an elevation of the heart rate (HR), infarct size and ECG distortions. Treatment with AA significantly (p?0.05) reduced heart/body weight ratio (49%), MI (96%), HR (27%), sympathovagal imbalance (36%) and serum cardiac biomarkers (AST, LDH, HDL, triglycerides and CCK) caused by ISO. AA decreased the beat frequency of isolated right atrium (11%) cause by ISO, an action similar to propranolol (beta adrenergic antagonist; 20%), but showed no significant changes in the QTc intervals of the ECG (suggesting no cardio-toxic drug-herb interactions), Thirty nine compounds were detected using high resolution LC-MS analysis (HPLC-Orbitrap APCI-MS) in the extract. Pure compounds, as gallic acid and rutin, presented a higher negative chronotropic effect, similar to propranolol. CONCLUSION: Oral administration of aqueous extract of Artocarpus artilis has cardio-protective functions in myocardial injury, in part, by decreasing the HR, reduced contractility and infarct size. These findings may explain the cardio-protective use of A. altilis in traditional medicine. PMID- 28342859 TI - Hydroethanolic extract from Echinodorus scaber Rataj leaves inhibits inflammation in ovalbumin-induced allergic asthma. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Echinodorus scaber, Alismataceae, is popularly known in Brazil as "chapeu-de-couro". The plant leaves are used by the population as decoction, infusion, or maceration in bottled spirits, to treat inflammatory respiratory diseases. AIM OF THE STUDY: To investigate the anti-inflammatory mechanism of the hydroethanolic extract of leaves of Echinodorus scaber (HEEs) in allergic asthma. A phytochemical analysis of the extract was performed as well. MATERIALS AND METHODS: The leaves of Echinodorus scaber were prepared by maceration in 75% ethanol. Preliminary phytochemical analysis was carried out using basic classical methods, and the secondary metabolites detected in HEEs were analyzed and confirmed by high-performance liquid chromatography (HPLC). The in vivo anti-inflammatory activity of HEEs was evaluated in Swiss male albino mice sensitized and challenged by OVA. The HEEs (1, 5 and 30mg/kg, p.o.) was administered to mice twice a day, 1h before the challenge, from days 19 through 24. The mechanism of action of HEEs was studied by evaluating the levels of TH2 cytokines (IL-4, IL-5 and IL-13) in bronchoalveolar lavage fluid (BALF) and IgE production in blood plasma. Histopathological changes triggered by OVA sensitization/challenge in the lung tissue were also investigated. RESULTS: HEEs reduced total leukocyte, eosinophil, neutrophil, and mononuclear cell counts at all doses tested, with maximum effect at 30mg/kg (73.9%, 75.9%, 75.5%, and 65.2% reduction, p<0.001, respectively). Increases in TH2 cytokine secretion (IL-4, IL 5 and IL-13) and in IgE levels were also attenuated by HEEs. Preliminary phytochemical screening seems to indicated the presence of phenolic compounds, flavonoids and alkaloids. HPLC analyses evidenced the presence of phenolic compounds, such as gallic acid, rutin and vitexin. CONCLUSION: Our findings provided pharmacological preclinical evidence for the popular use of the leaves of Echinodorus scaber in allergic inflammation. Its anti-inflammatory effect was dependent on the decrease in migratory inflammatory cells, and both TH2 cytokines and IgE levels. It is suggested that vitexin, gallic acid and rutin, known anti inflammatory compounds, may participate in the anti-asthamtic effect of the HEEs, by acting jointly along with other components present in the extract. PMID- 28342860 TI - Functional characterization of lysophosphatidic acid receptor 1 mutants identified in rat cancer tissues. AB - Lysophosphatidic acid (LPA), an extracellular lipid mediator, exerts various cellular effects through activation of LPA receptors, LPA1-LPA6, in many types of cells including cancer cells. We recently found several missense mutations of Lpar1 in rat cancer tissues. One of these mutations is located at the extracellular tip of the seventh transmembrane domain of LPA1, and another three mutations are found within the NPXXY motif in the seventh transmembrane domain. These mutants are designated F295S LPA1 and P308S, I310T, and Y311H LPA1, respectively. Here, we examined the functions of these LPA1 mutants. Compared with wild-type (WT) LPA1, F295S, P308S, and I310T LPA1 showed decreased maximal responses in inhibition of cAMP formation, Ca2+ mobilization, and cytoskeletal changes. Y311H LPA1 failed to show LPA-induced cellular responses. However, these LPA1 mutants were internalized in response to LPA exposure. Finally, while WT and F295S LPA1 showed a similar, broad distribution throughout the cell, P308S, I310T, and Y311H LPA1 displayed a restricted cellular distribution and co localized with the endoplasmic reticulum. These data suggest that the LPA1 mutants perturb LPA signaling in cancer tissues. PMID- 28342862 TI - miR-29a suppresses growth and migration of hepatocellular carcinoma by regulating CLDN1. AB - CLDN1 (claudin1) is essential for intercellular junctions and has been reported to be involving in cell migration and metastasis, making it as an oncogene in various cancer types. However, the biological function roles and regulatory mechanisms of CLDN1 in hepatocellular carcinoma (HCC) are still not clarified. In this study, we found down-regulation of miR-29a and up-regulation of CLDN1 in HCC tissues and cell lines. Further found an inverse relation between the expressions of miR-29a and CLDN1 in HCC. Dual-luciferase reporter assay indicated that miR 29a regulated the expression of CLDN1 by binding to its 3' untranslated region (3'UTR). Knockdown of CLDN1 led to decrease in tumor cell growth and migration capacities in vitro and in vivo. While overexpression of miR-29a suppressed tumor growth and migration, these effects could be reversed by re-expressing CLDN1. Taken together, out data suggested that miR-29a may regulate tumor growth and migration by targeting CLDN1, providing promising therapeutic targets for HCC. PMID- 28342861 TI - MicroRNA-548j inhibits type I interferon production by targeting ZBTB11 in patients with chronic hepatitis B. AB - Type I IFNs play crucial roles in antiviral immune responses. By inducing cellular resistance to viral infection and apoptosis of virus-infected cells, they impair virus replication and eliminate the invading pathogens. However, in CHB patients, generation of type I IFN was significantly impaired and the underlying mechanisms have not been fully understood. MicroRNA-548 family has been implicated in regulating antiviral response upon various infections. Here we explored the potential role of miR-548j in modulating type I IFN production in CHB. We found that miR-548j expression increased in MoDCs from CHB patients than that from healthy volunteers and transient transfection of miR-548j mimic led to a marked decrease of IFN-alpha/beta production in MoDCs from healthy volunteers while blockade of miR-548j by anti-miR-548j significantly restored IFN-alpha/beta secretion in MoDCs from CHB patients. In addition, Zinc finger and BTB domain containing 11 (ZBTB11) was predicted and finally confirmed to be a target of miR 548j. Forced expression of ZBTB11 also restored IFN-alpha/beta secretion in MoDCs from CHB patients. These results indicate the involvement of miR-548j in aberrant production of type I IFN in CHB patients, and provide a potential target for developing anti-HBV therapies. PMID- 28342863 TI - Disturbed tryptophan metabolism correlating to progression and metastasis of esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most frequent malignancies worldwide. Lymph node metastasis is the leading cause of death in ESCC patients. To identify early diagnostic and prognostic biomarkers of ESCC and elucidate underlying pathogenesis of the disease, a targeted metabolomics strategy based on liquid chromatography combined with tandem mass spectrometry was applied to explore tryptophan metabolism between ESCC patients, metastatic ESCC patients (mESCC), and healthy controls. Statistical analysis on metabolite expression abundance and compound concentration ratio was conducted to discriminate patients from healthy controls. The concentration ratio of kynurenine, 5-hydroxytryptophan, 5-hydroxyindole-3-acetic acid, 5 hydroxytryptamine to their precursor tryptophan were identified as potential biomarkers, presenting high diagnostic capacity for distinguishing ESCC and mESCC patients from healthy controls. Moreover, a prognostic prediction model was also built on these ratios to distinguish metastasis patients from non-metastasis patients successfully. The high performance of ESCC prediction models suggest that concentration ratios of compounds may be used as biomarkers for early diagnosis and prognosis of the disease. In addition, concentration ratios of compounds show a progressively increased trend from non-metastasis to metastasis patients compared with healthy controls, which is in accordance with process of malignant transformation of ESCC. This interested finding suggests that disturbed tryptophan metabolism is correlated to progression and metastasis of ESCC since concentration ratios of compounds reflect activity of enzymes involved in tryptophan metabolism. This study reveals the impact of tryptophan metabolism to tumorigenesis and metastasis of ESCC, which help biologists investigate mechanism of the disease. PMID- 28342864 TI - OsLBD37 and OsLBD38, two class II type LBD proteins, are involved in the regulation of heading date by controlling the expression of Ehd1 in rice. AB - LATERAL ORGAN BOUNDARIES DOMAIN (LBD) proteins are plant-specific transcription factors which are involved in many biological process of plant development, including lateral organ development, photomorphogenesis, pathogen response, pollen development and plant regeneration. Here, we report new functions of LBD proteins that participate in the regulation of heading date and yield in rice. OsLBD37 and OsLBD38 are two class II type LBD proteins, function as transcriptional activators. Overexpression of OsLBD37 and OsLBD38 separately causes delayed heading date and increased yield. Both OsLBD37 and OsLBD38 are expressed in rhythmic pattern, and their proteins are localized in the nucleus. Further analysis revealed that OsLBD37 and OsLBD38 delayed heading date by down regulating the expression of the florigen genes Hd3a and RFT1 through key regulator of heading date Ehd1. These data indicates that OsLBD37 and OsLBD38, may function as novel regulators of heading date and crop yield in rice. PMID- 28342865 TI - KSHV-encoded viral interferon regulatory factor 4 (vIRF4) interacts with IRF7 and inhibits interferon alpha production. AB - Before an infection can be completely established, the host immediately turns on the innate immune system through activating the interferon (IFN)-mediated antiviral pathway. Kaposi's sarcoma-associated herpesvirus (KSHV) utilizes a unique antagonistic mechanism of type I IFN-mediated host antiviral immunity by incorporating four viral interferon regulatory factors (vIRF1-4). Herein, we characterized novel immune evasion strategies of vIRF4 to inhibit the IRF7 mediated IFN-alpha production. KSHV vIRF4 specifically interacts with IRF7, resulting in inhibition of IRF7 dimerization and ultimately suppresses IRF7 mediated activation of type I IFN. These results suggest that each of the KSHV vIRFs, including vIRF4, subvert IFN-mediated anti-viral response via different mechanisms. Therefore, it is indicated that KSHV vIRFs are indeed a crucial immunomodulatory component of their life cycles. PMID- 28342866 TI - The T47D cell line is an ideal experimental model to elucidate the progesterone specific effects of a luminal A subtype of breast cancer. AB - Cell lines are often used as in vitro tools to mimic certain types of in vivo system; several cell lines, including MCF-7 and T47D, have been widely used in breast cancer studies without investigating the cell lines' characteristics. In this study, we compared the genome-wide binding profiles of ERalpha, PR, and P300, and the gene expression changes between MCF-7 and T47D cell lines that represent the luminal A subtype of breast cancer. Surprisingly, several thousand genes were differentially expressed under estrogenic condition. In addition, ERalpha, PR, and P300 binding to regulatory elements showed distinct genomic landscapes between MCF-7 and T47D cell lines in the same hormonal states. In particular, the T47D cell line was markedly susceptible to progesterone, whereas the MCF-7 cell line did not respond to progesterone in the presence of estrogen. Consistently, changes in the expression level of the PR-target gene, STAT5A, were only observed in the T47D cell line, not the MCF-7 cell line, when treated with progesterone. Overall, the results highlight the importance of selecting appropriate cell lines for breast cancer studies and suggest that T47D cell lines can be an ideal experimental model to elucidate the progesterone-specific effects of a luminal A subtype of breast cancer. PMID- 28342867 TI - GSK3beta attenuates TGF-beta1 induced epithelial-mesenchymal transition and metabolic alterations in ARPE-19 cells. AB - While TGF-beta1 is known to induce epithelial-mesenchymal transition (EMT), a major factor in the pathogenesis of proliferative vitreoretinopathy (PVR), in ARPE-19 cells. The molecular pathways involved in EMT formation have not yet to be fully characterized. In this study, we have found that TGF-beta1-mediated induction of EMT in ARPE-19 cells varied in a dose- and time-dependent manner. Specifically, TGF-beta1 inhibited GSK-3beta by accelerating phosphorylation at ser9. GSK-3beta inhibitor or knockdown of GSK-3beta resulted in enhanced TGF beta1-mediated EMT, migration and collagen contraction in ARPE-19 cells, which were then abrogated by GSK-3beta overexpression and PI3K/AKT inhibitor. Importantly, GSK-3beta also mediated metabolic reprogramming in TGF-beta1-treated cells. Our results indicate that GSK-3beta plays a pivotal role in TGF-beta1 mediated EMT in ARPE-19 cells. PMID- 28342868 TI - Increased interleukin-1beta and basic fibroblast growth factor levels in the cerebrospinal fluid during human herpesvirus-6B (HHV-6B) encephalitis. AB - Human herpesvirus 6B (HHV-6B) causes exanthema subitum in infants and is known to be mildly pathogenic. However, HHV-6B infection can induce febrile seizures in a high percentage of patients, and in rare cases, result in encephalitis. We detected higher levels of interleukin (IL)-1beta and basic fibroblast growth factor (bFGF) in the cerebrospinal fluid (CFS) of patients with HHV-6B encephalitis when compared to those in patients with non-HHV-6B-induced febrile seizures. In vitro, IL-1beta and bFGF enhanced HHV-6B gene expression in infected U373 astrocytes during the initial and maintenance phases of infection, respectively. These findings indicated that IL-1beta and bFGF contribute to HHV 6B growth and the onset of encephalitis. PMID- 28342869 TI - MicroRNA-448 promotes multiple sclerosis development through induction of Th17 response through targeting protein tyrosine phosphatase non-receptor type 2 (PTPN2). AB - Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system, and its pathogenesis remains largely unclear. Much attention has been paid to the role of microRNAs (miRs) in regulation of autoimmune disease. Here, we found, for the first time, that miR-448 expression was significantly increased in periphery blood mononuclear cells (PBMC) and cerebrospinal fluid (CSF) of patients with MS, and its expression positively correlated with the disease severity. We further demonstrated that CD4+ T cells, especially the Th17 lineage, were the major source of miR-448 expression. Using gain- and loss-of-function approaches, we further verified that miR-448 could enhance Th17 differentiation, characterized by up-regulated expression levels of IL-17A and RORgammat. Interleukin (IL)-1beta as a potent driver of pathogenic Th17 cells was able to strongly induce miR-448 expression in CD4+ T cells through activating NF-kappaB pathway. Additionally, we identified that miR-448 directly targeted protein tyrosine phosphatase non-receptor type 2 (PTPN2), which has been known as an anti-inflammatory player with capacity to suppress Th17 differentiation. We also observed markedly decreased expression of PTPN2 in PBMC and CSF of MS patients. Our results suggest that miR-448 might promote Th17 differentiation in MS and thus aggravate the disease through inhibiting PTPN2. PMID- 28342870 TI - The RAB GTPase RAB18 modulates macroautophagy and proteostasis. AB - Macroautophagy is a conserved degradative pathway and its deterioration is linked to disturbances in cellular proteostasis and multiple diseases. Here, we show that the RAB GTPase RAB18 modulates autophagy in primary human fibroblasts. The knockdown of RAB18 results in a decreased autophagic activity, while its overexpression enhances the degradative pathway. Importantly, this function of RAB18 is dependent on RAB3GAP1 and RAB3GAP2, which might act as RAB GEFs and stimulate the activity of the RAB GTPase. Moreover, the knockdown of RAB18 deteriorates proteostasis and results in the intracellular accumulation of ubiquitinated degradation-prone proteins. Thus, the RAB GTPase RAB18 is a positive modulator of autophagy and is relevant for the maintenance of cellular proteostasis. PMID- 28342871 TI - Oxidative damage induces apoptosis and promotes calcification in disc cartilage endplate cell through ROS/MAPK/NF-kappaB pathway: Implications for disc degeneration. AB - Cartilage endplate (CEP) cell calcification and apoptosis play a vital role in the intervertebral disc degeneration (IVDD). Oxidative stress is a key factor in inducing programmed cell death and cartilage calcification. However, the cell death and calcification of cartilage endplate cells under oxidative stress have never been described. The present study investigated the apoptosis and calcification in the cartilage endplate cell under oxidative stress induced by H2O2 to understand the underlying mechanism of IVDD. The cartilage endplate cells isolated from human lumbar discs were subjected to different concentrations of H2O2 for various time periods. The cell viability was determined by CCK-8 assay, whereas Western blot, immunofluorescence, and Alcian blue, Alizarin red, and Von Kossa staining evaluated the apoptosis and calcification. The level of mitochondria-specific reactive oxygen species (ROS) was quantified with an oxygen radical-sensitive probe-MitoSOX. The potential signaling pathways were investigated by Western blot after the addition of N-acetyl-l-cysteine (NAC). We found that the oxidative stress induced by H2O2 increased the apoptosis and subsequently the calcification in the cartilage endplate cells through the ROS/p38/ERK/p65 pathway. The apoptosis and the calcification of the cartilage endplate cells induced by H2O2 can be abolished by NAC. These results suggested that regulating the apoptosis and the calcification in the cartilage endplate cells under oxidative stress should be advantageous for the survival of cells and might delay the process of disc degeneration. PMID- 28342872 TI - Covalent conjugation of the equine infectious anemia virus Gag with SUMO. AB - The conjugation of small ubiquitin-like modifier (SUMO) to the target protein, namely, SUMOylation, is involved in the regulation of many important biological events including host-pathogen interaction. Some viruses have evolved to exploit the host SUMOylation machinery to modify their own protein. Retroviral Gag protein plays critical roles in the viral life cycle. The HIV-1 p6 and the Moloney murine leukemia virus CA have been reported to be conjugated with SUMO. In this study, we report for the first time, to our knowledge, the covalent conjugation of equine infectious anemia virus (EIAV) Gag with SUMO. The C terminal p9 domain of Gag is a main target for SUMOylation and SUMO is attached to multiple sites of p9, including K30 whose mutation abolished p9 SUMOylation completely. The SUMOylation of p9, but not the p9-K30 mutant, was also detected in equine fibroblastic cells ATCC(r) CCL-57TM. Ubc9 and its C93 residue are indispensable for the SUMOylation of p9. Using confocal microscopy, it is found that EIAV Gag localizes primarily, if not exclusively, in the cytoplasm of the cell and the co-localization of EIAV Gag with Ubc9 was observed. Our findings that EIAV Gag is SUMOylated at p9-K30, together with previous findings on the defects of p9-K30 mutant in viral DNA translocation from cytoplasm to the nucleus, suggests that SUMOylation of Gag may be involved in such functions. PMID- 28342873 TI - Relationships of BRAF mutation and HMGB1 to papillary thyroid carcinoma. AB - A poor papillary thyroid cancer (PTC) prognosis is strongly associated with the BRAF V600E mutation. During tumor progression, levels of the high mobility group box 1 (HMGB1) protein are often dysregulated. Results herein demonstrate that HMGB1 protein levels differ between tumor and adjacent non-tumor tissue and that HMGB1 mRNA levels were higher in wild-type BRAF PTC tissues than in BRAF V600E PTC tissues (2-?Ct 0.31 +/- 0.25 vs. 0.16 +/- 0.12; P < 0.05). HMGB1 protein levels also differed in the same manner (wild-type BRAF PTC tissues 0.11 +/- 0.04 vs. BRAF V600E PTC tissues 0.03 +/- 0.03; P < 0.001). Although not detected in peripheral blood, low levels of HMGB1 were significantly related to PTC cell lymph node metastasis and extra-glandular infiltration (P = 0.045 and P = 0.002). Experimental results at the cellular level were consistent with tissues and further verified the relationship of BRAF V600E and HMGB1. These findings demonstrate that the BRAF V600E mutation down-regulates levels of HMGB1, likely through activation of the mitogen-activated protein kinase (MAPK) signaling pathways. PMID- 28342875 TI - The nociception genes painless and Piezo are required for the cellular immune response of Drosophila larvae to wasp parasitization. AB - In vertebrates, interaction between the nervous system and immune system is important to protect a challenged host from stress inputs from external sources. In this study, we demonstrate that sensory neurons are involved in the cellular immune response elicited by wasp infestation of Drosophila larvae. Multidendritic class IV neurons sense contacts from external stimuli and induce avoidance behaviors for host defense. Our findings show that inactivation of these sensory neurons impairs the cellular response against wasp parasitization. We also demonstrate that the nociception genes encoding the mechanosensory receptors Painless and Piezo, both expressed in class IV neurons, are essential for the normal cellular immune response to parasite challenge. PMID- 28342874 TI - Activation of PPARgamma inhibits pro-inflammatory cytokines production by upregulation of miR-124 in vitro and in vivo. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) and miR-124 have been reported to play important roles in regulation of inflammation. However, the underlying anti-inflammatory mechanisms remain not well understood. In the present study, we demonstrated that the expression level of PPARgamma is positively correlated with that of miR-124 in patients with sepsis. Activation of PPARgamma upregulates miR-124 and in turn inhibits miR-124 target gene. PPARgamma bound directly to PPRE in the miR-124 promoter region, and enhanced the promoter transcriptional activity. PPARgamma-induced miR-124 is involved in the suppression of pro-inflammatory cytokine in vitro and in vivo. These results suggest that PPARgamma-induced miR-124 inhibits the production of pro inflammatory cytokines is a novel PPARgamma anti-inflammatory mechanism and also indicate that miR-124 may be a potential therapeutic target for the treatment of inflammatory diseases. PMID- 28342876 TI - Increased activity of unlinked Zika virus NS2B/NS3 protease compared to linked Zika virus protease. AB - Zika virus (ZIKV) is a flavivirus spread by daytime-active Aedes spp. mosquitoes such as A. aegypti and A. albopictus. Previously thought to be a mild infection, the latest ZIKV outbreak in the Americas is causally associated with more severe symptoms as well as severe birth defects, such as microcephaly. Currently no vaccine or antiviral exists. However, recent progress has demonstrated the viral NS2B/NS3 protease may be a suitable target for the development of small-molecule antiviral agents. To better understand the ZIKV protease, we expressed, purified, and characterized unlinked and linked NS2B/NS3 protease corresponding to an isolate from the recent outbreak in Puerto Rico. Unlinked ZIKV protease is more active and binds substrate with greater affinity than linked ZIKV protease. Therefore, we propose that unlinked ZIKV protease be used when evaluating or designing ZIKV protease inhibitors. Additionally, potent inhibitors of related viral proteases, like West Nile Virus and Dengue virus, may serve as advanced starting points to identify and develop ZIKV protease inhibitors. PMID- 28342877 TI - Quantitative visualization of synchronized insulin secretion from 3D-cultured cells. AB - Quantitative visualization of synchronized insulin secretion was performed in an isolated rat pancreatic islet and a spheroid of rat pancreatic beta cell line using a method of video-rate bioluminescence imaging. Video-rate images of insulin secretion from 3D-cultured cells were obtained by expressing the fusion protein of insulin and Gaussia luciferase (Insulin-GLase). A subclonal rat INS-1E cell line stably expressing Insulin-GLase, named iGL, was established and a cluster of iGL cells showed oscillatory insulin secretion that was completely synchronized in response to high glucose. Furthermore, we demonstrated the effect of an antidiabetic drug, glibenclamide, on synchronized insulin secretion from 2D and 3D-cultured iGL cells. The amount of secreted Insulin-GLase from iGL cells was also determined by a luminometer. Thus, our bioluminescence imaging method could generally be used for investigating protein secretion from living 3D cultured cells. In addition, iGL cell line would be valuable for evaluating antidiabetic drugs. PMID- 28342878 TI - 3D printing for the design and fabrication of polymer-based gradient scaffolds. AB - : To accurately mimic the native tissue environment, tissue engineered scaffolds often need to have a highly controlled and varied display of three-dimensional (3D) architecture and geometrical cues. Additive manufacturing in tissue engineering has made possible the development of complex scaffolds that mimic the native tissue architectures. As such, architectural details that were previously unattainable or irreproducible can now be incorporated in an ordered and organized approach, further advancing the structural and chemical cues delivered to cells interacting with the scaffold. This control over the environment has given engineers the ability to unlock cellular machinery that is highly dependent upon the intricate heterogeneous environment of native tissue. Recent research into the incorporation of physical and chemical gradients within scaffolds indicates that integrating these features improves the function of a tissue engineered construct. This review covers recent advances on techniques to incorporate gradients into polymer scaffolds through additive manufacturing and evaluate the success of these techniques. As covered here, to best replicate different tissue types, one must be cognizant of the vastly different types of manufacturing techniques available to create these gradient scaffolds. We review the various types of additive manufacturing techniques that can be leveraged to fabricate scaffolds with heterogeneous properties and discuss methods to successfully characterize them. STATEMENT OF SIGNIFICANCE: Additive manufacturing techniques have given tissue engineers the ability to precisely recapitulate the native architecture present within tissue. In addition, these techniques can be leveraged to create scaffolds with both physical and chemical gradients. This work offers insight into several techniques that can be used to generate graded scaffolds, depending on the desired gradient. Furthermore, it outlines methods to determine if the designed gradient was achieved. This review will help to condense the abundance of information that has been published on the creation and characterization of gradient scaffolds and to provide a single review discussing both methods for manufacturing gradient scaffolds and evaluating the establishment of a gradient. PMID- 28342879 TI - Stable subcutaneous cartilage regeneration of bone marrow stromal cells directed by chondrocyte sheet. AB - : In vivo niche plays an important role in regulating differentiation fate of stem cells. Due to lack of proper chondrogenic niche, stable cartilage regeneration of bone marrow stromal cells (BMSCs) in subcutaneous environments is always a great challenge. This study explored the feasibility that chondrocyte sheet created chondrogenic niche retained chondrogenic phenotype of BMSC engineered cartilage (BEC) in subcutaneous environments. Porcine BMSCs were seeded into biodegradable scaffolds followed by 4weeks of chondrogenic induction in vitro to form BEC, which were wrapped with chondrocyte sheets (Sheet group), acellular small intestinal submucosa (SIS, SIS group), or nothing (Blank group) respectively and then implanted subcutaneously into nude mice to trace the maintenance of chondrogenic phenotype. The results showed that all the constructs in Sheet group displayed typical cartilaginous features with abundant lacunae and cartilage specific matrices deposition. These samples became more mature with prolonged in vivo implantation, and few signs of ossification were observed at all time points except for one sample that had not been wrapped completely. Cell labeling results in Sheet group further revealed that the implanted BEC directly participated in cartilage formation. Samples in both SIS and Blank groups mainly showed ossified tissue at all time points with partial fibrogenesis in a few samples. These results suggested that chondrocyte sheet could create a chondrogenic niche for retaining chondrogenic phenotype of BEC in subcutaneous environment and thus provide a novel research model for stable ectopic cartilage regeneration based on stem cells. STATEMENT OF SIGNIFICANCE: In vivo niche plays an important role in directing differentiation fate of stem cells. Due to lack of proper chondrogenic niche, stable cartilage regeneration of bone marrow stromal cells (BMSCs) in subcutaneous environments is always a great challenge. The current study demonstrated that chondrocyte sheet generated by high-density culture of chondrocytes in vitro could cearte a chondrogenic niche in subcutaneous environment and efficiently retain the chondrogenic phenotype of in vitro BMSC engineered cartilage (vitro-BEC). Furthermore, cell tracing results revealed that the regenerated cartilage mainly derived from the implanted vitro BEC. The current study not only proposes a novel research model for microenvironment simulation but also provides a useful strategy for stable ectopic cartilage regeneration of stem cells. PMID- 28342880 TI - [For a targeted use of aspirin]. AB - The use of low-dose aspirin in pregnancy should remain a highly targeted indication since its long-term safety has not been established and should be restricted to women at high risk of vascular complications. Indications for which the benefit of aspirin has been shown are women with a history of preeclampsia responsible for a premature birth before 34 weeks, those having at least two history of preeclampsia, those with an antiphospholipid syndrome and those with lupus associated with positive antiphospholipid antibodies or renal failure. In all other cases, the level of evidence of the benefit of aspirin is insufficient to recommend its routine prescription. PMID- 28342881 TI - Pericardial patch graft repair of severe localized scleral thinning encountered during strabismus surgery. AB - This article presents a surgical technique using a pericardial patch for the permanent repair of severe scleral thinning encountered during strabismus surgery. In the present case scleral thinning resulted from buckle removal. Familiarity with this technique may prove important for the strabismus surgeon treating patients with a history of surface ocular hardware or disease-induced scleral thinning. This video article may be viewed atjaapos.org. PMID- 28342882 TI - Functional neuroimaging findings in healthy middle-aged adults at risk of Alzheimer's disease. AB - It is well established that the neurodegenerative process of Alzheimer's disease (AD) begins many years before symptom onset. This preclinical phase provides a crucial time-window for therapeutic intervention, though this requires biomarkers that could evaluate the efficacy of future disease-modification treatments in asymptomatic individuals. The last decade has witnessed a proliferation of studies characterizing the temporal sequence of the earliest functional and structural brain imaging changes in AD. These efforts have focused on studying individuals who are highly vulnerable to develop AD, such as those with familial genetic mutations, susceptibility genes (i.e. apolipoprotein epsilon-4 allele), and/or a positive family history of AD. In this paper, we review the rapidly growing literature of functional imaging changes in cognitively intact individuals who are middle-aged: positron emission tomography (PET) studies of amyloid deposition, glucose metabolism, as well as arterial spin labeling (ASL), task-dependent, resting-state functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) studies. The prevailing evidence points to early brain functional changes in the relative absence of cognitive impairment and structural atrophy, although there is marked variability in the directionality of the changes, which could, in turn, be related to antagonistic pleiotropy early in life. A common theme across studies relates to the spatial extent of these changes, most of which overlap with brain regions that are implicated in established AD. Notwithstanding several methodological caveats, functional imaging techniques could be preferentially sensitive to the earliest events of AD pathology prior to macroscopic grey matter loss and clinical manifestations of AD. We conclude that while these techniques have great potential to serve as biomarkers to identify at-risk individuals, more longitudinal studies with greater sample size and robust correction for multiple comparisons are still warranted to establish their utility. PMID- 28342883 TI - Kinetic and Mechanistic Study of the pH-Dependent Activation (Epoxidation) of Prodrug Treosulfan Including the Reaction Inhibition in a Borate Buffer. AB - A prodrug treosulfan (T) undergoes a pH-dependent activation to epoxide derivatives. The process seems to involve an intramolecular Williamson reaction (IWR) but clear kinetic evidence is lacking. Moreover, a cis-diol system present in the T structure is expected to promote complexation with boric acid. As a result, the prodrug epoxidation would be inhibited; however, this phenomenon has not been investigated. In this article, the effect of pH on the kinetics of T conversion to its monoepoxide was studied from a mechanistic point of view. Also, the influence of boric acid on the reaction kinetics was examined. The rate constants observed for the activation of T (kobs) in acetate, phosphate, and carbonate buffers satisfied the equation logkobs = -7.48 + 0.96 pH. The reaction was inhibited in the excess of boric acid over T, and the kobs decreased with increasing borate buffer concentration. The experimental results were consistent with the inhibition model that included the formation of a tetrahedral, anionic T boric acid monoester. To conclude, in nonborate buffers, the T activation to (2S,3S)-1,2-epoxybutane-3,4-diol 4-methanesulfonate follows IWR mechanism. A borate buffer changes the reaction kinetics and complicates kinetic analysis. PMID- 28342885 TI - High-throughput identification of miRNAs of Taenia ovis, a cestode threatening sheep industry. AB - Taenia ovis is a tapeworm that is mainly transmitted between dogs and sheep or goats and has an adverse effect on sheep industry. miRNAs are short regulatory non-coding RNAs, involved in parasite development and growth as well as parasite infection. The miRNA profile of T. ovis remains to be established. Herein, 33 known miRNAs belonging to 23 different families were identified in T. ovis metacestodes using deep sequencing approach. Of them, expression of some miRNAs such as tov-miR-10 and -let-7 was absolutely predominant. Moreover, comparative analysis revealed the presence of a miR-71/2b/2c cluster in T. ovis, which was also completely conserved in other 6 cestodes. The study provides rich data for further understandings of T. ovis biology. PMID- 28342884 TI - Oral Cancer Reconstruction Using the Supraclavicular Artery Island Flap: Comparison to Free Radial Forearm Flap. AB - PURPOSE: To evaluate whether the pedicled supraclavicular artery island flap (SCAIF) is a sufficient alternative to the fasciocutaneous radial forearm free flap (RFFF) for oral reconstruction in cancer surgery. PATIENTS AND METHODS: The authors designed and implemented a retrospective cohort study composed of all consecutive patients who underwent head and neck reconstruction after cancer surgery at their tertiary university hospital from 2013 to 2016. Demographics and peri- and postoperative information were recorded and statistically analyzed. RESULTS: Of 83 patients who underwent head and neck reconstruction after cancer, 50 were identified as having stage III or IV squamous cell carcinoma of the oral cavity and oropharynx and underwent surgery and reconstruction with the SCAIF (n = 25) or the RFFF (n = 25). Total surgery time (411.0 vs 576.4 minutes; P < .001), flap elevation time (39.00 vs 93.78 minutes; P < .001), need for intensive care observation (32 vs 96%; P < .05), and rate of tracheotomy (64 vs 88%; P < .05) were significantly lower in the SCAIF group. There was no statistical difference in the postoperative complication rate or postoperative functional swallowing ability between the 2 groups. Total perioperative costs were significantly lower in patients who underwent reconstruction with the SCAIF (2,621.15 vs 4,453.77?; P < .01). CONCLUSION: The results of this study suggest that the SCAIF is a straightforward and reliable flap with shorter operative times and comparable outcomes compared with the RFFF. PMID- 28342886 TI - Using genetic data to improve species distribution models. AB - Tsetse flies (Diptera, Glossinidae) transmit human and animal trypanosomoses in Africa, respectively a neglected human disease (sleeping sickness) and the most important constraint to cattle production in infested countries (nagana). We recently developed a methodology to map landscape friction (i.e. resistance to movement) for tsetse in West Africa. The goal was to identify natural barriers to tsetse dispersal, and potentially isolated tsetse populations for targeting elimination programmes. Most species distribution models neglect landscape functional connectivity whereas environmental factors affecting suitability or abundance are not necessarily the same as those influencing gene flows. Geographic distributions of a given species can be seen as the intersection between biotic (B), abiotic (A) and movement (M) factors (BAM diagram). Here we show that the suitable habitat for Glossina palpalis gambiensis as modelled by Maxent can be corrected by landscape functional connectivity (M) extracted from our friction analysis. This procedure did not degrade the specificity of the distribution model (P=0.751) whereas the predicted distribution area was reduced. The added value of this approach is that it reveals unconnected habitat patches. The approach we developed on tsetse to inform landscape connectivity (M) is reproducible and does not rely on expert knowledge. It can be applied to any species: we call for a generalization of the use of M to improve distribution models. PMID- 28342887 TI - Genetic detection and characterization of goose parvovirus: Implications for epidemiology and pathogenicity in Cherry Valley Pekin ducks. PMID- 28342888 TI - Effect of exogenous TGF-beta1 on the cadmium-induced nephrotoxicity by inhibiting apoptosis of proximal tubular cells through PI3K-AKT-mTOR signaling pathway. AB - Heavy metal polluted soils have been a serious problem for the global ecological balance and people's health. Cadmium (Cd), one of the heavy metals, could induce apoptosis of proximal tubular cells in many experimental models and lead to damage the human kidney. Here, we reported a potent chemokine TGF-beta1 which could ameliorate cadmium-induced nephrotoxicity. Interestingly, western blotting and TUNEL staining assays indicated that PI3K-AKT-mTOR signaling pathway was involved in the protective mechanism of TGF-beta1 in vitro and in vivo. Moreover, TGF-beta1 could alleviate Cd-induced nephrotoxicity by inhibiting apoptosis of proximal tubular cells through detecting the level of caspase 3, 8 and 9. Therefore, up-regulation of exogenous TGF-beta1 may be a potential strategy to reverse cadumium-induced nephrotoxicity. PMID- 28342889 TI - Heteromeric complexes of aldo-keto reductase auxiliary KVbeta subunits (AKR6A) regulate sarcolemmal localization of KV1.5 in coronary arterial myocytes. AB - Redox-sensitive potassium channels consisting of the voltage-gated K+ (KV) channel pore subunit KV1.5 regulate resting membrane potential and thereby contractility of vascular smooth muscle cells. Members of the KV1 family associate with cytosolic auxiliary beta subunits, which are members of the aldo keto reductase (AKR) superfamily (AKR6A subfamily). The Kvbeta subunits have been proposed to regulate Kv1 gating via pyridine nucleotide cofactor binding. However, the molecular identity of KVbeta subunits that associate with native KV1.5 channels in the vasculature is unknown. Here, we examined mRNA and protein expression of KVbeta subunits and tested whether KVbeta isoforms interact with KV1.5 channels in murine coronary arteries. We detected KVbeta1 (AKR6A3), KVbeta2 (AKR6A5) and KVbeta3 (AKR6A9) transcripts and KVbeta1 and KVbeta2 protein in left anterior descending coronary arteries by real time quantitative PCR and Western blot, respectively. In situ proximity ligation assays indicated abundant protein protein interactions between KV1.5/KVbeta1, KV1.5/KVbeta2 and KVbeta1/beta2 in coronary arterial myocytes. Confocal microscopy and membrane fractionation analyses suggest that arterial myocytes from KVbeta2-null mice have reduced abundance of sarcolemmal KV1.5. Together, data suggest that in coronary arterial myocytes, KV1.5 channels predominantly associate with KVbeta1 and KVbeta2 proteins and that KVbeta2 performs a chaperone function for KV1.5 channels in arterial myocytes, thereby facilitating Kv1alpha trafficking and membrane localization. PMID- 28342890 TI - Vasodilatory effect of nitroglycerin in Japanese subjects with different aldehyde dehydrogenase 2 (ALDH2) genotypes. AB - The functional genetic polymorphism of aldehyde dehydrogenase 2 (ALDH2) influences the enzymatic activities of its wild type (Glu504 encoded by ALDH2*1) and mutant type (Lys504 encoded by ALDH2*2) proteins. The enzymatic activities of mutant-type ALDH2 are limited compared with those of the wild type. ALDH2 has been suggested as a critical factor for nitroglycerin-mediated vasodilation by some human studies and in vitro studies. Currently, there is no research on direct observations of the vasodilatory effect of nitroglycerin sublingual tablets, which is the generally used dosage form. In the present study, the contribution of ALDH2 to the vasodilatory effect of nitroglycerin sublingual tablets was investigated among three genotype groups (ALDH2*1/*1, ALDH2*1/*2, and ALDH2*2/*2) in Japanese. The results by direct assessments of in vivo nitroglycerin-mediated dilation showed no apparent difference in vasodilation among all genotypes of ALDH2. Furthermore, to analyze the effect of other factors (age and flow-mediated dilation), multiple regression analysis and Pearson's correlation coefficient analysis were carried out. These analyses also indicated that the genotypes of ALDH2 were not related to the degree of vasodilation. These results suggest the existence of other predominant pathway(s) for nitroglycerin biotransformation, at least with regard to clinical nitroglycerin (e.g., a sublingual tablet) in Japanese subjects. PMID- 28342891 TI - Cost-Utility of Group Acceptance and Commitment Therapy for Fibromyalgia Versus Recommended Drugs: An Economic Analysis Alongside a 6-Month Randomized Controlled Trial Conducted in Spain (EFFIGACT Study). AB - : The aim of this study was to analyze the cost utility of a group-based form of acceptance and commitment therapy (GACT) in patients with fibromyalgia (FM) compared with patients receiving recommended pharmacological treatment (RPT) or on a waiting list (WL). The data were derived from a previously published study, a randomized controlled trial that focused on clinical outcomes. Health economic outcomes included health-related quality of life and health care use at baseline and at 6-month follow-up using the EuroQoL and the Client Service Receipt Inventory, respectively. Analyses included quality-adjusted life years, direct and indirect cost differences, and incremental cost effectiveness ratios. A total of 156 FM patients were randomized (51 GACT, 52 RPT, 53 WL). GACT was related to significantly less direct costs over the 6-month study period compared with both control arms (GACT ?824.2 +/- 1,062.7 vs RPT ?1,730.7 +/- 1,656.8 vs WL ?2,462.7 +/- 2,822.0). Lower direct costs for GACT compared with RPT were due to lower costs from primary care visits and FM-related medications. The incremental cost effectiveness ratios were dominant in the completers' analysis and remained robust in the sensitivity analyses. In conclusion, acceptance and commitment therapy appears to be a cost-effective treatment compared with RPT in patients with FM. PERSPECTIVE: Decision-makers have to prioritize their budget on the treatment option that is the most cost effective for the management of a specific patient group. From government as well as health care perspectives, this study shows that a GACT is more cost effective than pharmacological treatment in management of FM. PMID- 28342893 TI - A rare cause of recurrent acute pancreatitis: duodenum intussusception by a fenestrated duodenal web. PMID- 28342894 TI - Endoscopic treatment of cervical esophageal transluminal bridge. PMID- 28342895 TI - A welcome diagnosis for painless biliary dilatation (with video). PMID- 28342892 TI - Comparison of three cell-based drug screening platforms for HSV-1 infection. AB - Acyclovir (ACV) and its derivatives have been highly effective for treating recurrent, lytic infections with Herpes Simplex Virus, type 1 (HSV-1), but searches for additional antiviral drugs are motivated by recent reports of resistance to ACV, particularly among immunocompromised patients. In addition, the relative neurotoxicity of ACV and its inability to prevent neurological sequelae among HSV-1 encephalitis survivors compel searches for new drugs to treat HSV-1 infections of the central nervous system (CNS). Primary drug screens for neurotropic viruses like HSV-1 typically utilize non-neuronal cell lines, but they may miss drugs that have neuron specific antiviral effects. Therefore, we compared the effects of a panel of conventional and novel anti-herpetic compounds in monkey epithelial (Vero) cells, human induced pluripotent stem cells (hiPSCs) derived neural progenitor cells (NPCs) and hiPSC-derived neurons (N = 73 drugs). While the profiles of activity for the majority of the drugs were similar in all three tissues, Vero cells were less likely than NPCs to identify drugs with substantial inhibitory activity in hiPSC-derived neurons. We discuss the relative merits of each cell type for antiviral drug screens against neuronal infections with HSV-1. PMID- 28342896 TI - Neuroprotective and axonal outgrowth-promoting effects of tetramethylpyrazine nitrone in chronic cerebral hypoperfusion rats and primary hippocampal neurons exposed to hypoxia. AB - Chronic cerebral hypoperfusion is an important risk factor for vascular dementia and other brain dysfunctions, for which there are currently no effective medications available. We investigated the neuroprotective and axonal outgrowth promoting effects of tetramethylpyrazine nitrone (TBN) in a permanent bilateral occlusion of the common carotid arteries (2VO) rat model and in primary hippocampal neurons exposed to oxygen glucose deprivation (OGD). At 6th week after 2VO, TBN increased the time spent in novel arms in the Y-maze test and improved the discrimination ratio in object reorganization task. TBN attenuated axonal damage, and reduced oxidative DNA injury and lipid peroxidation in white matter. TBN also attenuated the neuronal apoptosis and ameliorated accumulation of astrocytes in parietal cortex and CA1 region of hippocampus. Western blot analyses indicated that TBN increased Bcl-2 expression, decreased Bax and Caspase 3 expressions, and upregulated the phosphorylation levels of high-molecular weight neurofilament (p-NFH), Akt (p-Akt) and glycogen synthase kinase-3beta (p GSK3beta) in hippocampus at 6th week after chronic hypoperfusion. In vitro, TBN rescued hippocampal neuronal viability and axonal elongation from OGD damage. The p-Akt and p-GSK3beta upregulation by TBN was abolished by a specific phosphoinositide 3-kinase (PI3K) inhibitor LY294002, resulting in suppression of axonal outgrowth. Collectively, the results showed that TBN alleviated white matter lesion and impairment of cortex and hippocampus, attenuated oxidative damage and enhanced axonal outgrowth through the regulation of PI3K/Akt/GSK3beta signaling pathway, leading to improved cognitive deficit in a rat chronic hypoperfusion model. PMID- 28342897 TI - Dose-response effect of acute phencyclidine on functional connectivity and dopamine levels, and their association with schizophrenia-like symptom classes in rat. AB - Current drug treatments for schizophrenia (SCZ) can alleviate positive symptoms, but have little effect on the negative symptoms and cognitive deficits that are difficult to translate into preclinical models for drug development. Therefore, we aimed to determine the dose-response effects of acute phencyclidine (PCP, 1.0 5.0 mg/kg) on rat brain connectivity and detect markers for different SCZ-like symptoms. Pharmacological functional magnetic resonance imaging (phMRI) and microdialysis were used to investigate PCP-induced effects on functional connectivity (FC) and dopamine levels, respectively. Next, we evaluated the association between PCP-induced changes in imaging parameters and behavior. PCP at doses of 3.0-5.0 mg/kg induced fMRI signal changes in several brain regions associated with SCZ. Additionally, the FC was globally disturbed, dopamine levels increased, and locomotor activity increased, reflecting the manifestation of SCZ like positive symptoms. A distinct pattern in the measures was observed at lower PCP doses (1.0-2.0 mg/kg); PCP induced fMRI signal changes in the fronto-cortical regions, and increased dopamine levels in the medial prefrontal cortex. In addition to the dysconnectivity of these regions, the hippocampal FC was disrupted. These observations are consistent with the induction of SCZ-like cognitive deficits and negative symptoms, which were observed as impaired novel object recognition and decreased social interaction. No indicators for positive symptoms were observed at lower PCP doses. We conclude that acute PCP induces SCZ like symptom classes in a dose-dependent manner; PCP doses of 1.0-2.0 mg/kg are more suitable for modeling SCZ-like negative symptoms and cognitive deficits, while SCZ-like positive symptoms dominate at doses of 3.0-5.0 mg/kg. PMID- 28342898 TI - Temperature induces significant changes in both glycolytic reserve and mitochondrial spare respiratory capacity in colorectal cancer cell lines. AB - Thermotherapy, as a method of treating cancer, has recently attracted considerable attention from basic and clinical investigators. A number of studies and clinical trials have shown that thermotherapy can be successfully used as a therapeutic approach for various cancers. However, the effects of temperature on cancer bioenergetics have not been studied in detail with a real time, microplate based, label-free detection approach. This study investigates how changes in temperature affect the bioenergetics characteristics (mitochondrial function and glycolysis) of three colorectal cancer (CRC) cell lines utilizing the Seahorse XF96 technology. Experiments were performed at 32 degrees C, 37 degrees C and 42 degrees C using assay medium conditions and equipment settings adjusted to produce equal oxygen and pH levels ubiquitously at the beginning of all experiments. The results suggest that temperature significantly changes multiple components of glycolytic and mitochondrial function of all cell lines tested. Under hypothermia conditions (32 degrees C), the extracellular acidification rates (ECAR) of CRC cells were significantly lower compared to the same basal ECAR levels measured at 37 degrees C. Mitochondrial stress test for SW480 cells at 37 degrees C vs 42 degrees C demonstrated increased proton leak while all other OCR components remained unchanged (similar results were detected also for the patient-derived xenograft cells Pt.93). Interestingly, the FCCP dose response at 37 degrees C vs 42 degrees C show significant shifts in profiles, suggesting that single dose FCCP experiments might not be sufficient to characterize the mitochondrial metabolic potential when comparing groups, conditions or treatments. These findings provide valuable insights for the metabolic and bioenergetic changes of CRC cells under hypo- and hyperthermia conditions that could potentially lead to development of better targeted and personalized strategies for patients undergoing combined thermotherapy with chemotherapy. PMID- 28342899 TI - Contributions of intestinal epithelial barriers to health and disease. AB - A core function of epithelia is to form barriers that separate tissue compartments within complex organisms. These barriers also separate the internal milieu from the external environment and are, therefore, an essential component of host defense. However, in many cases, a perfect barrier would be improbable with life itself. Examples include the air spaces within the lungs, the renal tubules, and the intestines. Here, we focus on the mechanisms by which barriers are assembled, maintained, and regulated in the context of health and disease. Because of its unique challenges and extensive study, we focus on the gastrointestinal tract as an organ-specific example of the essential contributions of the paracellular barrier to life. PMID- 28342901 TI - The sympathetic neuro-adipose connection and the control of body weight. AB - In recent decades, obesity has become a global public health crisis irrespective of age or gender [20]. But according to historic records, concerns over appropriate maintenance of body size have been long established. For more than to 2 millennia, the main therapeutic approach to curb excess weight has been to recommend dietary restrictions and regular exercise (Haslam, 2016). Nevertheless, more contemporary studies indicate that the employment of such approaches in the treatment of severely obese patients causes metabolic adaptions which impair their long-term success in weight management [8]. These evidences highlight thus, the urgency in the search for a more comprehensive knowledge of the mechanisms that underlie the control of body weight, which would be essential for the development of effective strategies for the treatment of obesity and its comorbidities. Importantly, the discovery of the hormone leptin [33]and the use of novel techniques in targeted transgenesis [32] have enabled progress in defining some of the key players and the molecular mechanisms that are involved in the processes that control body size homeostasis and energy balance, and how obesity may disrupt leptin's feedback loop and lead to the pathology of metabolic syndrome. On the light of such findings, here we review how the sympathetic nervous system modulates adipose tissue metabolism downstream of leptin's action on the CNS, with particular focus on how this system may be disrupted in the context of excess adiposity, plus highlight the potential clinical implications arising from a better understanding of the physiologic control of the sympathetic neuro-adipose connection. PMID- 28342900 TI - Critical roles of CTP synthase N-terminal in cytoophidium assembly. AB - Several metabolic enzymes assemble into distinct intracellular structures in prokaryotes and eukaryotes suggesting an important functional role in cell physiology. The CTP-generating enzyme CTP synthase forms long filamentous structures termed cytoophidia in bacteria, yeast, fruit flies and human cells independent of its catalytic activity. However, the amino acid determinants for protein-protein interaction necessary for polymerisation remained unknown. In this study, we systematically analysed the role of the conserved N-terminal of Drosophila CTP synthase in cytoophidium assembly. Our mutational analyses identified three key amino acid residues within this region that play an instructive role in organisation of CTP synthase into a filamentous structure. Co transfection assays demonstrated formation of heteromeric CTP synthase filaments which is disrupted by protein carrying a mutated N-terminal alanine residue thus revealing a dominant-negative activity. Interestingly, the dominant-negative activity is supressed by the CTP synthase inhibitor DON. Furthermore, we found that the amino acids at the corresponding position in the human protein exhibit similar properties suggesting conservation of their function through evolution. Our data suggest that cytoophidium assembly is a multi-step process involving N terminal-dependent sequential interactions between correctly folded structural units and provide insights into the assembly of these enigmatic structures. PMID- 28342902 TI - Spearman-Brown prophecy formula and Cronbach's alpha: different faces of reliability and opportunities for new applications. AB - OBJECTIVES: There are similarities between the different forms of reliability, such as internal consistency (internal reliability) and interrater and intrarater reliability. Reliability coefficients that are based on classical test theory can be expressed as intraclass correlation coefficients (ICCs), such as Cronbach's alpha. The Spearman-Brown prophecy formula (SB formula) is used to calculate the reliability when the number of items in a questionnaire is changed. This paper aims to increase insight into reliability studies by pointing to the assumptions of reliability coefficients, similarities between various coefficients, and the subsequent new applications of reliability coefficients. DESIGN, SETTINGS AND RESULTS: The origin and assumptions of Cronbach's alpha and the SB formula are discussed. Cronbach's alpha is written as an ICC formula, using the well-known property that taking the average value of a number of ratings increases the reliability of a measurement. We illustrate with an example that the ICC formulas for average measurements of multiple raters and the SB formula give similar results. This implies that the SB formula can be used to decide on the number of measurements to be averaged and thus on the number of raters required, for obtaining measurements with acceptable reliability, even if the variance components of the ICC formula are not known. Using the same example, we illustrate the principle of "Cronbach's alpha if item deleted" to decide on the poorest performing raters in a set of raters. CONCLUSION: These applications have different assumptions: the principle of "Cronbach's alpha if item deleted" is based on the assumption of a fixed set of items/raters and the SB formula is based on the assumption of random raters. The example also emphasizes the need for more raters in the design of the reliability study to obtain a robust estimation of reliability. PMID- 28342903 TI - Structural equation modeling-based effect-size indices were used to evaluate and interpret the impact of response shift effects. AB - OBJECTIVES: The investigation of response shift in patient-reported outcomes (PROs) is important in both clinical practice and research. Insight into the presence and strength of response shift effects is necessary for a valid interpretation of change. STUDY DESIGN AND SETTING: When response shift is investigated through structural equation modeling (SEM), observed change can be decomposed into change because of recalibration response shift, change because of reprioritization and/or reconceptualization response shift, and change because of change in the construct of interest. Subsequently, calculating effect-size indices of change enables evaluation and interpretation of the clinical significance of these different types of change. RESULTS: Change was investigated in health-related quality of life data from 170 cancer patients, assessed before surgery and 3 months after surgery. Results indicated that patients deteriorated on general physical health and general fitness and improved on general mental health. The decomposition of change showed that the impact of response shift on the assessment of change was small. CONCLUSION: SEM can be used to enable the evaluation and interpretation of the impact of response shift effects on the assessment of change, particularly through calculation of effect-size indices. Insight into the occurrence and clinical significance of possible response shift effects will help to better understand changes in PROs. PMID- 28342904 TI - Sham surgical procedures for pain intervention result in significant improvements in pain: systematic-review and meta-analysis: Clinical heterogeneity and risk of bias on the placebo effect associated with sham surgeries. PMID- 28342905 TI - When is a null finding in register-based epidemiology convincing? PMID- 28342906 TI - Citation analysis did not provide a reliable assessment of core outcome set uptake. AB - OBJECTIVES: The aim of the study was to evaluate citation analysis as an approach to measuring core outcome set (COS) uptake, by assessing whether the number of citations for a COS report could be used as a surrogate measure of uptake of the COS by clinical trialists. STUDY DESIGN AND SETTING: Citation data were obtained for COS reports published before 2010 in five disease areas (systemic sclerosis, rheumatoid arthritis, eczema, sepsis and critical care, and female sexual dysfunction). Those publications identified as a report of a clinical trial were examined to identify whether or not all outcomes in the COS were measured in the trial. RESULTS: Clinical trials measuring the relevant COS made up a small proportion of the total number of citations for COS reports. Not all trials citing a COS report measured all the recommended outcomes. Some trials cited the COS reports for other reasons, including the definition of a condition or other trial design issues addressed by the COS report. CONCLUSION: Although citation data can be readily accessed, it should not be assumed that the citing of a COS report indicates that a trial has measured the recommended COS. Alternative methods for assessing COS uptake are needed. PMID- 28342907 TI - Active placebo control groups of pharmacological interventions were rarely used but merited serious consideration: a methodological overview. AB - OBJECTIVES: Active placebos are control interventions that mimic the side effects of the experimental interventions in randomized trials and are sometimes used to reduce the risk of unblinding. We wanted to assess how often randomized clinical drug trials use active placebo control groups; to provide a catalog, and a characterization, of such trials; and to analyze methodological arguments for and against the use of active placebo. STUDY DESIGN AND SETTING: An overview consisting of three thematically linked substudies. In an observational substudy, we assessed the prevalence of active placebo groups based on a random sample of 200 PubMed indexed placebo-controlled randomized drug trials published in October 2013. In a systematic review, we identified and characterized trials with active placebo control groups irrespective of publication time. In a third substudy, we reviewed publications with substantial methodological comments on active placebo groups (searches in PubMed, The Cochrane Library, Google Scholar, and HighWirePress). RESULTS: The prevalence of trials with active placebo groups published in 2013 was 1 out of 200 (95% confidence interval: 0-2), 0.5% (0-1%). We identified and characterized 89 randomized trials (published 1961-2014) using active placebos, for example, antihistamines, anticholinergic drugs, and sedatives. Such trials typically involved a crossover design, the experimental intervention had noticeable side effects, and the outcomes were patient-reported. The use of active placebos was clustered in specific research settings and did not appear to reflect consistently the side effect profile of the experimental intervention, for example, selective serotonin reuptake inhibitors were compared with active placebos in pain trials but not in depression trials. We identified and analyzed 25 methods publications with substantial comments. The main argument for active placebo was to reduce risk of unblinding; the main argument against was the risk of unintended therapeutic effect. CONCLUSION: Pharmacological active placebo control interventions are rarely used in randomized clinical trials, but they constitute a methodological tool which merits serious consideration. We suggest that active placebos are used more often in trials of drugs with noticeable side effects, especially in situations where the expected therapeutic effects are modest and the risk of bias due to unblinding is high. PMID- 28342908 TI - Intestinal dendritic cell licensing through Toll-like receptor 4 is required for oral tolerance in allergic contact dermatitis. AB - BACKGROUND: Induction of oral tolerance to haptens is an efficient way to prevent allergic contact dermatitis (ACD) in mice. Toll-like receptor (TLR)-mediated sensing of the microbiota contributes to gut homeostasis, yet whether it contributes to induction of oral tolerance has not been documented. OBJECTIVE: We examined whether oral tolerance to the contact sensitizer 2,4-dinitro fluorobenzene (DNFB) depends on microbiota/TLRs and evaluated the role of TLR4 on the tolerogenic function of intestinal dendritic cells (DCs). METHODS: Oral tolerance was induced by DNFB gavage in germ-free and mice deficient in several TLRs. Tolerance was assessed by means of suppression of contact hypersensitivity and hapten-specific IFN-gamma-producing effector T cells. The tolerogenic function of intestinal DCs was tested by adoptive transfer experiments, ex vivo hapten presentation, and forkhead box p3 regulatory T-cell conversion. RESULTS: Oral tolerance induced by DNFB gavage was impaired in germ-free mice and TLR4 deficient mice. Bone marrow chimeras revealed that TLR4 expression on hematopoietic cells was necessary for oral tolerance induction. TLR4 appeared to be essential for the ability of intestinal dendritic cells from DNFB-fed mice to inhibit ACD on adoptive transfer. Indeed, TLR4 conditioned the in vivo mobilization to mesenteric lymph nodes of intestinal migratory CD103+ DCs carrying oral DNFB, especially the CD103+CD11b+ DC subset expressing the vitamin A-converting enzyme retinaldehyde dehydrogenase and specialized in forkhead box p3-positive regulatory T-cell conversion. CONCLUSIONS: Our data demonstrate that TLR4 conditions induction of oral tolerance to DNFB through licensing tolerogenic gut DCs. Oral biotherapy with TLR4 ligands might be useful to potentiate oral tolerance to haptens and alleviate ACD in human subjects. PMID- 28342909 TI - The cellular immune system comes of age. PMID- 28342910 TI - Receptor-interacting protein kinase 3 controls keratinocyte activation in a necroptosis-independent manner and promotes psoriatic dermatitis in mice. PMID- 28342913 TI - Thunderstorm-related asthma attacks. PMID- 28342911 TI - Basophils, high-affinity IgE receptors, and CCL2 in human anaphylaxis. AB - BACKGROUND: The role of basophils in anaphylaxis is unclear. OBJECTIVE: We sought to investigate whether basophils have an important role in human anaphylaxis. METHODS: In an emergency department study we recruited 31 patients with acute anaphylaxis, predominantly to Hymenoptera venom. We measured expression of basophil activation markers (CD63 and CD203c); the absolute number of circulating basophils; whole-blood FCER1A, carboxypeptidase A3 (CPA3), and L-histidine decarboxylase (HDC) gene expression; and serum markers (CCL2, CCL5, CCL11, IL-3, and thymic stromal lymphopoietin) at 3 time points (ie, during the anaphylactic episode and in convalescent samples 7 and 30 days later). We recruited 134 patients with Hymenoptera allergy and 76 healthy control subjects for comparison. We then investigated whether the changes observed during venom-related anaphylaxis also occur during allergic reactions to food in 22 patients with peanut allergy undergoing double-blind, placebo-controlled food challenge to peanut. RESULTS: The number of circulating basophils was significantly lower during anaphylaxis (median, 3.5 cells/MUL) than 7 and 30 days later (17.5 and 24.7 cells/MUL, P < .0001) and compared with those in patients with venom allergy and healthy control subjects (21 and 23.4 cells/MUL, P < .0001). FCER1A expression during anaphylaxis was also significantly lower than in convalescent samples (P <= .002) and control subjects with venom allergy (P < .0001). CCL2 levels (but not those of other serum markers) were significantly higher during anaphylaxis (median, 658 pg/mL) than in convalescent samples (314 and 311 pg/mL at 7 and 30 days, P < .001). Peanut-induced allergic reactions resulted in a significant decrease in circulating basophil counts compared with those in prechallenge samples (P = .016), a decrease in FCER1A expression (P = .007), and an increase in CCL2 levels (P = .003). CONCLUSIONS: Our findings imply an important and specific role for basophils in the pathophysiology of human anaphylaxis. PMID- 28342912 TI - Peanut oleosins associated with severe peanut allergy-importance of lipophilic allergens for comprehensive allergy diagnostics. AB - BACKGROUND: Peanut allergy is one of the most common and most severe food allergies in Western countries and its accurate diagnosis to prevent potential life-threatening allergic reactions is crucial. However, aqueous extracts used for routine diagnostic measurements are devoid of lipophilic allergens such as oleosins. We have recently succeeded in the isolation and purification of these unique proteins, and the present study evaluates their allergenic potential and clinical relevance. OBJECTIVE: We sought to assess allergenicity and sensitization prevalence of oleosins obtained from both raw and in-shell roasted peanuts. In addition, we tested the utilization of natural and recombinant oleosins for allergy diagnostic purposes. METHODS: Oleosin sensitization, prevalence, and impact of thermal processing were analyzed by immunoblot with sera from 52 peanut-allergic individuals displaying different clinical phenotypes. The application of natural and recombinant oleosins for allergy diagnostics was investigated by basophil activation test (BAT). IgE-binding epitopes were identified by oligopeptide microarray. RESULTS: Sensitization to oleosins was observed exclusively in peanut-allergic subjects suffering from severe systemic reactions. IgE-binding capacity of oleosins derived from in-shell roasted peanuts was increased as shown by immunoblot analysis and BAT. Both natural and recombinant molecules can be used to identify oleosin-sensitized patients by BAT. A linear epitope of Ara h 15 was determined that displays high similarity to other seed-derived oleosins. CONCLUSIONS: Oleosins are clinically relevant peanut allergens and most likely associated with severe allergic symptoms. In-shell roasting increases their allergenicity, which is consistent with the observation that most allergic reactions are in connection with roasted peanuts. PMID- 28342914 TI - Blood eosinophils predict therapeutic effects of a GATA3-specific DNAzyme in asthma patients. PMID- 28342916 TI - Granulocyte transfusions in patients with chronic granulomatous disease and refractory infections: The NIH experience. PMID- 28342915 TI - Regulated in development and DNA damage responses 1 (REDD1) links stress with IL 1beta-mediated familial Mediterranean fever attack through autophagy-driven neutrophil extracellular traps. AB - BACKGROUND: Familial Mediterranean fever (FMF) is an IL-1beta-dependent autoinflammatory disease caused by mutations of Mediterranean fever (MEFV) encoding pyrin and characterized by inflammatory attacks induced by physical or psychological stress. OBJECTIVE: We investigated the underlying mechanism that links stress-induced inflammatory attacks with neutrophil activation and release of IL-1beta-bearing neutrophil extracellular traps (NETs) in patients with FMF. METHODS: RNA sequencing was performed in peripheral neutrophils from 3 patients with FMF isolated both during attacks and remission, 8 patients in remission, and 8 healthy subjects. NET formation and proteins were analyzed by using confocal immunofluorescence microscopy, immunoblotting, myeloperoxidase-DNA complex ELISA, and flow cytometry. Samples from patients with Still's disease and bacterial infections were used also. RESULTS: The stress-related protein regulated in development and DNA damage responses 1 (REDD1) is significantly overexpressed during FMF attacks. Neutrophils from patients with FMF during remission are resistant to autophagy-mediated NET release, which can be overcome through REDD1 induction. Stress-related mediators (eg, epinephrine) decrease this threshold, leading to autophagy-driven NET release, whereas the synchronous inflammatory environment of FMF attack leads to intracellular production of IL-1beta and its release through NETs. REDD1 in autolysosomes colocalizes with pyrin and nucleotide-binding domain, leucine-rich repeat/pyrin domain-containing 3. Mutated pyrin prohibits this colocalization, leading to higher IL-1beta levels on NETs. CONCLUSIONS: This study provides a link between stress and initiation of inflammatory attacks in patients with FMF. REDD1 emerges as a regulator of neutrophil function upstream to pyrin, is involved in NET release and regulation of IL-1beta, and might constitute an important piece in the IL-1beta-mediated inflammation puzzle. PMID- 28342917 TI - Science of health care delivery as a first step to advance undergraduate medical education: A multi-institutional collaboration. AB - Physicians must possess knowledge and skills to address the gaps facing the US health care system. Educators advocate for reform in undergraduate medical education (UME) to align competencies with the Triple Aim. In 2014, five medical schools and one state university began collaborating on these curricular gaps. The authors report a framework for the Science of Health Care Delivery (SHCD) using six domains and highlight curricular examples from each school. They describe three challenges and strategies for success in implementing SHCD curricula. This collaboration highlights the importance of multi-institutional partnerships to accelerate innovation and adaptation of curricula. PMID- 28342918 TI - Evidence of the impact of visuo-spatial processing on magnitude representation in 22q11.2 microdeletion syndrome. AB - The influence of visuo-spatial skills on numerical magnitude processing is the subject of a long-standing debate. As most of the numerical and non-numerical magnitude abilities underpinning mathematical development are visual by nature, they are often assessed in the visual modality, thereby confusing visuo-spatial and numerical processing. In order to assess the influence of visuo-spatial processing on numerical magnitude representation, we examined magnitude processing in patients with 22q11.2 deletion syndrome (22q11DS), a genetic condition characterized by a cognitive profile with a relative weakness in visuo spatial abilities but with preserved verbal abilities. Twenty-seven participants with 22q11DS were compared to two control groups (one matched on verbal intelligence and the other on visuo-spatial abilities) on several magnitude comparison tasks each with different visuo-spatial processing requirements. Our results showed that participants with 22q11DS present a consistent pattern of impairment in magnitude comparison tasks requiring the processing of visuo spatial dimensions: comparison of lengths and collections. In contrast, their performance did not differ from the control groups in a visual task with no spatial processing requirement (i.e. numerical comparison of flashed dot sequences) or in auditory tasks (i.e., duration comparison and numerical comparison of sound sequences). Finally, a specific deficit of enumeration processes was observed in the subitizing range. Taken together, these results show that deficits in magnitude can occur as a consequence of a visuo-spatial deficit. This highlights the influence of the nature of the tasks selected to assess magnitude representation. PMID- 28342919 TI - Radiation Exposure to the Surgeon During Ultrasound-Assisted Transforaminal Percutaneous Endoscopic Lumbar Discectomy: A Prospective Study. AB - OBJECTIVE: To determine the radiation dose to the surgeon during ultrasound assisted transforaminal percutaneous endoscopic lumbar discectomy (PELD) for lumbar disc herniation, and to investigate whether the usage of ultrasonography could reduce the radiation exposure to the surgeon. METHODS: The stages of needle insertion and foraminal plasty for transforaminal PELD were performed under ultrasound guidance and confirmed by fluoroscopy according to the standard technique by 2 spinal surgeons separately in 25 transforaminal PELDs (25 levels). The radiation exposure dose of the surgeons' chest above and below the shielding and the fluoroscopy time were recorded. The effective dose and number of possible levels per year within the yearly occupational exposure limit (OEL) were calculated. The radiation dose per level and fluoroscopy time between ultrasound assisted PELD and fluoroscopy-assisted PELD were compared. RESULTS: The mean operation time and fluoroscopy time were 67.6 +/- 14.6 minutes and 2.9 +/- 0.7 seconds, respectively. The mean effective dose to the surgeons per level was 1.3 +/- 0.6 MUSv. One surgeon could perform PELDs at 38,462 levels per year without exceeding the OEL for whole-body radiation wearing a lead apron, and 1938 levels per year without using any shielding devices. Ultrasound-assisted PELD had significantly less radiation dose per level at the chest below and above apron, effective dose per level, and fluoroscopy time, compared with fluoroscopy assisted PELD (all P < 0.05). CONCLUSIONS: The method of ultrasound-assisted needle insertion and foraminal plasty in transforaminal PELD can reduce radiation exposure to the surgeons compared with fluoroscopy-assisted PELD. PMID- 28342920 TI - What Is the More Appropriate Proximal Fusion Level for Adult Lumbar Degenerative Flat Back? AB - OBJECTIVE: To determine the optimal proximal fusion level after long instrumented fusion to the sacrum for lumbar degenerative flat back. METHODS: Data from 70 patients with lumbar degenerative flat back were reviewed retrospectively. Three groups were designated according to the upper instrumented vertebrae (UIV): group 1 (UIV = T10 or above), group 2 (UIV = T11-12), and group 3 (UIV = L1 or below). Pre- and postoperative pelvic parameters, degree of correction, and prevalence of proximal junctional kyphosis (PJK) and its risk factors were evaluated. RESULTS: The prevalence of PJK was 27.1% (average 35.5 months of follow-up). Preoperative pelvic incidence (PI) and sacral slope (SS) in group 1 were higher in the PJK group than in the non-PJK group (P = 0.03 and P = 0.001, respectively). Preoperative thoracolumbar (TL) in group 3 was higher in the PJK group than in the non-PJK group (P = 0.01). Postoperative pelvic tilt (PT) was lower (<20 degrees ) in the non-PJK group than in the PJK group (P = 0.025 in group 3). Postoperative TL in group 3 was lower than in the non-PJK group (P = 0.024). CONCLUSIONS: If the PI is >=50 degrees , TL kyphosis is >=5 degrees , and SS is >=20 degrees , the UIV should be raised above T10 up to the midthoracic level. If the PI is >=50 degrees , SS is <=20 degrees , and thoracic kyphosis (TK) is normal despite TL kyphosis, the UIV should be at T10. Even if the PI is >=50 degrees , TK is normal, and there is no TL kyphosis, the UIV should be set at L1 or below. Regardless of the UIV, the postoperative PT should be <=20 degrees . PMID- 28342921 TI - Intensive Reduction of Systolic Blood Pressure in Acute Intracerebral Hemorrhage: Is There a Benefit? PMID- 28342922 TI - Smartphones and Programmable Shunts: Are These Indispensable Phones Safe and Smart? AB - OBJECTIVE: This study aimed to determine whether smartphones affect programmable shunts. METHODS: iPhone 5S (Apple Inc., Cupertino, CA, USA) and Samsung Galaxy S5 (Samsung Electronics, Gumi, South Korea) smartphones were chosen for this study. For both phones, magnetic field mapping was performed with 3-dimensional magnetic scanning systems constructed with high-precision motorized stages, and a Hall effect sensor was used to measure the flux density on the smartphone surface. The distance (h) between the distal outlet of the reservoir and the rugby ball of the Strata valve (Medtronic Inc., Minneapolis, MN, USA) was measured using highly sensitive microanalysis optical method. During optical microanalysis, while keeping a 3-cm distance between the valve and the magnetic generator, the h value (MUm) was recorded for different magnetic flux densities (MFDs). Then, direct x ray radiography was performed for radiologic assessment after each process under different magnetic fields. For analysis of the Codman Certas valve (Codman Neuro, Raynham, MA, USA), the magnet orientation and the angle between the magnet with the tantalum ball were measured with the same optical analysis. RESULTS: Maximum MFDs found 62 G for iPhone 5S and 61 G for Samsung Galaxy S5. When the magnetic generator formed a current at 0, 30, 60, and 90 G, the h values of the Strata valve adjusted to 100 mm H2O opening pressure were 320, 280, 190, and 175 MUm, respectively. When the magnetic generator was removed from the environment, the h value returned to 320 MUm. In direct graphs taken after each optical analysis at different Gauss values, substitution was not observed at the indicator. The angle in the Codman Certas valve was 123.9 degrees , 112.5 degrees , and 103.6 degrees at the magnetic flux densities of 0, 60, and 90 G, respectively. When the magnetic field was removed (0 G), the angle was still 103.6 degrees , suggesting an irreversible effect in the shunt construct. CONCLUSIONS: Smartphones exert reversible effects on Strata programmable valves without producing remarkable radiologic findings and irreversible effects on Codman Certas valves. PMID- 28342923 TI - Giant Intracranial Aneurysms: Surgical Treatment and Analysis of Risk Factors. AB - OBJECTIVE: To study clinical outcome of giant intracranial aneurysms (diameter >=25 mm) treated with different surgical modalities and to analyze factors affecting prognosis. METHODS: A retrospective analysis was performed of 204 consecutive patients with giant intracranial aneurysms who underwent surgical treatment in our department from 1995 to 2008. Clinical outcome was evaluated with the Glasgow Outcome Scale. RESULTS: Surgical modalities included direct aneurysm neck clipping in 102 patients (50.0%), parent artery reconstruction in 51 patients (25.0%), proximal artery ligation in 23 patients (11.3%; 4 patients combined with revascularization), trapping in 26 patients (12.7%), and wrapping in 2 patients (1.0%). Follow-up data were available for 181 patients (88.7%), with a mean follow-up period of 62 months (range, 12-164 months). A good outcome (Glasgow Outcome Scale score 5) was observed in 114 patients (63.0%), and a poor outcome (Glasgow Outcome Scale score 1-4) was observed in 67 patients (37.0%). Independent factors that affected prognosis were age and location of aneurysm. Older age (>=50 years) and location of aneurysm in posterior circulation were associated with poor outcome. In 85 patients with preoperative subarachnoid hemorrhage, patients with a higher Hunt and Hess grade (>=3) had a worse outcome compared with patients with a low Hunt and Hess grade (1 or 2). Surgical modalities and other factors were not significantly associated with clinical outcome. CONCLUSIONS: Giant intracranial aneurysms are effectively treated with craniotomy and surgical treatment. Older age, aneurysm location in posterior circulation, and higher Hunt and Hess grade are risk factors affecting prognosis. PMID- 28342924 TI - Effect of an Anterior Cingulotomy on Pain, Cognition, and Sensory Pathways. AB - BACKGROUND: Anterior cingulotomy (AC) was originally used to treat patients with a psychiatric disorder, but it is also useful for treating patients with chronic intractable pain. We reviewed 24 patients at our hospital who underwent AC for chronic intractable pain to determine whether surgery influenced patient cognition and the pain circuit. METHODS: A visual analog scale (VAS) was used to evaluate patients' pain scale preoperatively, at 1 month and 3-6 months postoperatively, and at the final follow-up. Mini-Mental State Examination (MMSE) and Cognitive Abilities Screening Instrument (CASI) were used to evaluate postoperative cognitive function. The latencies of peaks P20 and P37 of the somatosensory evoked potential (SSEP) conductive time were used to evaluate the intactness of the thalamocortical tract after AC. RESULTS: The median preoperative VAS score was 8, MMSE score was 27, and CASI score was 86.8. Six patients underwent a reoperation because of recurrent pain. Pain was significantly reduced after AC, and the median VAS score at the last follow-up was 5. There was no significant pain improvement in patients who underwent a reoperation. There were no significant changes in MMSE and CASI scores or SSEP after cingulotomy. There were no operation-related complications in the patients. CONCLUSIONS: A stereotactic AC was safe and effective in resolving chronic refractory pain. It did not affect patient cognition or the sensory conductive pathway. However, patients who had recurrent intractable pain after a cingulotomy did not respond well to the reoperation. PMID- 28342925 TI - Epidemiology and Characteristics of Neurosurgical Conditions at Mbarara Regional Referral Hospital. AB - BACKGROUND: The unmet surgical need, specifically neurosurgical need, in Uganda is significant, yet only 2 public hospitals currently perform neurosurgery in the country. This study examines the epidemiology and outcomes of neurosurgical conditions presenting to 1 of 12 regional referral hospitals in Uganda, in an effort to understand the neurosurgical needs of this population. METHODS: The study was conducted at Mbarara Regional Referral Hospital (MRRH), in southwestern Uganda. Demographics, clinical characteristics, and outcomes were retrospectively collected for all patients who presented to MRRH with a neurosurgical condition between January 2012 and September 2015. RESULTS: During the study period, 1854 patients presented to MRRH with a neurosurgical condition. More than half of the patients were between 19 and 40 years old, and the majority were males (76.1%). The overall median length of stay was 5 days (interquartile range: 2.5-10). The majority of admissions were due to trauma (87%), with almost 60% due to road traffic incidents. The overall mortality rate was 12.8%. A multivariable Cox proportional hazards model revealed that age, closed head injury, and admission Glasgow Coma Scale have a strong positive correlation with mortality while getting a diagnostic image and neurosurgical procedure were negatively correlated with mortality. CONCLUSION: Traumatic brain injury represented the majority of neurosurgical admissions at MRRH, disproportionately affecting young males. Age, closed head injury, admission Glasgow Coma Scale, getting a diagnostic image, and neurosurgical procedure were all independent predictors of mortality. Resource appropriate interventions throughout the health system are needed to meet the demand and improve outcomes. PMID- 28342926 TI - Causes and Clinical Features of Infertile Men With Nonobstructive Azoospermia and Histopathologic Diagnosis of Hypospermatogenesis. AB - OBJECTIVE: To analyze the causes and the clinical features of infertile men with nonobstructive azoospermia and hypospermatogenesis (HS). MATERIALS AND METHODS: This retrospective cohort study included 100 patients with nonobstructive azoospermia and HS and 8 patients with obstructive azoospermia and normal spermatogenesis. The severity of HS was subdivided into 3 groups (mild, moderate, and severe) based on spermatogenic score. Data of history, physical findings, serum hormone profiles, genetic studies, and sperm retrieval rate were collected. Whole genome DNA methylation analysis and microarray mRNA expression analysis were used to identify the candidate genes of methylation dysregulation in HS. RESULTS: Thirty-two (32%) patients had at least 1 prior/current testicular insults and 13 (13%) patients had genetic anomalies. Fifty-five (55%) patients were categorized as idiopathic HS. Patients with mild HS had a higher frequency of testicular insults, and patients with severe HS had a significantly higher frequency of genetic anomalies. Sperm retrieval rate was 100%, 100%, and 88.4% for patients with mild, moderate, and severe HS, respectively. Four sterility related genes, including BOLL, DDX4, HORMAD1, and MAEL, were found to have increased methylation at CpGs of the promoter regions and decreased mRNA expressions in HS testis. CONCLUSION: The causes of HS are complex and multifactorial. The main causes of HS were prior or current testicular insults and chromosomal or genetic anomalies. More than half of the patients were categorized as idiopathic HS. With high throughput analysis, methylation dysregulations of BOLL, DDX4, HORMAD1, and MAEL are believed to be associated with HS. PMID- 28342927 TI - Re: Cai et al.: Is Preoperative Assessment and Treatment of Asymptomatic Bacteriuria Necessary for Reducing the Risk of Postoperative Symptomatic Urinary Tract Infections After Urologic Surgical Procedures? (Urology 2017;99:100-105). PMID- 28342928 TI - Does Implementing an Enhanced Recovery After Surgery Protocol Increase Hospital Charges? Comparisons From a Radical Cystectomy Program at a Specialty Cancer Center. AB - OBJECTIVE: To compare perioperative charges induced at the initial phase of a standardized enhanced recovery after surgery (ERAS) program from a tertiary referral center. METHODS: A multidisciplinary ERAS protocol was implemented in our department on July 2015. During the subsequent year, all patients were treated according to this protocol (ERAS group). The patients were compared in terms of real in-hospital charges per surgical episode with a control group consisting of consecutive patients before the start of ERAS. Individual charges were analyzed per sample population and compared with the Wilcoxon rank-sum test or t test. Additionally, cost variances for each group were evaluated. RESULTS: A total of 257 consecutive patients were evaluated of which the last 112 were ERAS patients. The median length of stay for each group was 6 days (P = .748). ERAS patients incurred higher medication charges ($1939 vs $1729, P = .036). Control patients incurred higher supplies ($861 vs $692), treatment ($90 vs $72), and miscellaneous charges ($537 vs $388) (all, P < .001). The median total charges per patient were $59,539 for the control group and $60,655 for the ERAS group (P = .175). ERAS adoption significantly reduced variance in billed charges (P < .001). CONCLUSION: ERAS implementation did not significantly increase expenditure for cystectomy patients. ERAS showed decreased variance in charges likely due to standardization of care while eliciting savings in supplies, treatment, and miscellaneous costs. PMID- 28342929 TI - Commentary on: Radiation With or Without Antiandrogen Therapy in Recurrent Prostate Cancer. PMID- 28342930 TI - Commentary on: Padeliporfin Vascular-targeted Photodynamic Therapy Versus Active Surveillance in Men With Low-risk Prostate Cancer (CLIN1001 PCM301): An Open label, Phase 3, Randomized Controlled Trial. PMID- 28342931 TI - Clear Cell Renal Cell Carcinoma With Extensive Osseous Metaplasia: Report of a Rare Case. AB - A 48-year-old Chinese woman presenting with continuing dull pain in the right lower back and abdomen was found to have a tumor with extensive osseous metaplasia in the upper-middle pole of the right kidney. The excised neoplasm specimen revealed a 29 * 26 mm hard tumor with dense ossification. Histopathological examination of the tumor showed that it contained lamellar bone forming trabeculae intermingled and spherical or polygonal epithelial cells that contained slightly irregular nuclei with small nucleoli and abundant pink to clear cytoplasm. Clear cell renal cell carcinoma with extensive osseous metaplasia is a very rare occurrence. PMID- 28342933 TI - Regulation of airway inflammation and remodeling in asthmatic mice by TLR3/TRIF signal pathway. AB - This paper aims to investigate the effect of Toll-like receptors 3 (TLR3)/TIR domain-containing adapter-inducing interferon-beta (TRIF) signal pathway on the airway inflammation and remodeling in asthmatic mice. C57BL/6 and TLR3-/- mice were randomly divided into three groups (10 mice per group), including Control group (mice inhaled phosphate buffer saline (PBS)), Asthma group (mice inhaled ovalbumin (OVA)) and polyriboinosinic-ribocytidylic acid (poly (I: C)) group (asthmatic mice were injected intraperitoneally with TLR3 agonist poly (I: C)). Hematoxylin-eosin (HE) staining, Wright-Giemsa staining, Enzyme-linked immunosorbent assay (ELISA), Immunohistochemistry, Hydroxyproline assay, quantitative real time polymerase chain reaction (qRT-PCR) and Western blot were used to assess for the indices of airway inflammation and remodeling. In terms of WT mice, all asthma groups with or without the addition of poly (I: C) showed exaggerated inflammation and remodeling in the airways as compared to Control group, which were more seriously in poly (I: C) group than Asthma group. Furthermore, we observed the significant inhibition of airway inflammation and remodeling in the TLR3-/- mice in both Asthma no matter with or without addition of poly (I: C) than the WT mice. TLR3 knockout could obviously relieve the airway inflammation and remodeling in asthma through inhibiting TLR3/TRIF signaling pathway. PMID- 28342932 TI - Changes in HbA2 and HbF in alpha thalassemia carriers with KLF1 mutation. AB - alpha-thalassemia carriers are common in Mediterranean regions, particularly in the Sardinian population. Their haematological phenotype is characterized by reduced MCV and/or MCH with normal or slightly reduced HbA2 levels and normal HbF. Kruppel-like factor 1 (KLF1) is a pleiotropic erythroid transcription factor that is essential for haematopoiesis. Mutations in the KLF1 gene trigger a series of benign human red blood phenotypes, such as an increase in HbA2 and HBF. Recently, it has been found that KLF1 mutations were a frequent cause of borderline HbA2 levels in a group of Sardinian subjects. Here, we found that KLF1 mutations modulate the phenotype in a cohort of alpha-thalassemia carriers. PMID- 28342934 TI - Mitochondrial transplantation: From animal models to clinical use in humans. AB - Mitochondrial transplantation is a novel therapeutic intervention to treat ischemia/reperfusion related disorders. The method for mitochondrial transplantation is simple and rapid and can be delivered to the end organ either by direct injection or vascular infusion. In this review, we provide mechanistic and histological studies in large animal models and present data to show clinical efficacy in human patients. PMID- 28342935 TI - Interpreting Patient Reported Urinary and Sexual Function Outcomes across Multiple Validated Instruments. AB - PURPOSE: Comparing patient reported outcomes such as urinary and erectile function across institutions is critical for prostate cancer research and quality assurance. Such comparisons are complicated due to the use of different questionnaires. We aimed to develop a method to convert scores among 4 commonly used instruments. MATERIALS AND METHODS: Patient reported data on urinary and sexual function were collected on 1,284 men with localized prostate cancer using the EPIC-26 (Expanded Prostate Index Composite), PCI (UCLA Prostate Cancer Index), SHIM (Sexual Health Inventory for Men) and I-PSS (International Prostate Symptom Scale) questionnaires. We investigated several methods to convert scores among questionnaires. RESULTS: Conversion between EPIC and PCI urinary and sexual function subscales was best achieved using only the subset of questions asked on both questionnaires. For the conversion between EPIC or PCI erectile function scores and SHIM scores, we defined thresholds of poor, intermediate and good function as EPIC/PCI 0 to 40 and SHIM 1 to 7, EPIC/PCI 41 to 59 and SHIM 8 to 16, and EPIC/PCI 60 to 100 and SHIM 17 to 25, respectively. Urinary continence scores highly correlated for PCI and EPIC (r = 0.94). No comparison was possible for I PSS with EPIC and PCI due to differences in the domains addressed by these questionnaires. CONCLUSIONS: We have introduced methods to convert scores among the EPIC, PCI and SHIM questionnaires. While these conversion methods may introduce minor imprecision, to our knowledge they represent the best available tools to combine and compare patient reported outcomes that are assessed using different instruments in men undergoing radical prostatectomy or active surveillance. PMID- 28342937 TI - Molecular epidemiology of Staphylococcus aureus nasal colonization among patients and their parents /guardian in an Iranian referral hospital. AB - INTRODUCTION: Carriage of Staphylococcus aureus in the nose appears to play a key role in the epidemiology and pathogenesis of infection. It is important to investigate the genetic relatedness of S. aureus and MRSA clones in different geographic regions. The aim of this study was to assess the nasal carriage rate of S. aureus, including MRSA strains in both hospitalized children and general adult population (parents/guardian). In addition, antibiotic susceptibility pattern and molecular diversity of S. aureus in both population was evaluated in an Iranian referral pediatrics Hospital. MATERIAL AND METHODS: All samples were obtained through nasal screening of patients and general adult population at admission and discharge day. The prevalence, resistance, and molecular diversity of all S. aureus isolates were examined. RESULTS: In the current study, nasal carriage of S. aureus and Staphylococcus non aureus was identified in 384 (26%) and 1004 (68%) of the study population. The prevalence of MRSA nasal carriage in children and adults was 6.6% (29 out of 438) and 2.8% (29 out of 1046), respectively. Among S. aureus strains isolated obtained from patients and general adult population at admission day, high sensitivity to most of the antibiotics such as vancomycin (100%), rifampin (95%), linezolid (94%), quinupristin/dalfopristin (94%), minocycline (94%), chloramphenicol (89%), gentamycin (87%), amikacin (87%), clindamycin (86%) and moxifloxacin (83%) was seen. The most resistance antibiotics were penicillin (96-98%) and methicillin (44-47%). The susceptibility patterns of nasal S. aureus strains isolated at discharge day was not statistically different from S. aureus isolates obtained at admission day. Admission S. aureus isolated strains of 77 patients (64%) were similar to the isolated S. aureus strains of discharge, while S. aureus isolated strains of 43 patients (36%) was not similar to the strain of discharge (had similarity of less than 70%). CONCLUSION: High prevalence of nasal carriage of S. aureus and MRSA indicates the urgent need to improve strategies for management of S. aureus infections. Our findings are useful for understanding of S. aureus nasal colonization dynamics within the patients and general population. Surveillance for S. aureus in community settings can provide data on circulating strains and might help developing control measures for reducing of infection spread in hospitals. PMID- 28342936 TI - Clinical Outcomes in Patients with Panurothelial Carcinoma Treated with Radical Nephroureterectomy Following Cystectomy for Metachronous Recurrence. AB - PURPOSE: We report pathological, functional and oncologic outcomes in patients treated with radical nephroureterectomy following radical cystectomy. MATERIALS AND METHODS: We identified patients who underwent radical cystectomy and then radical nephroureterectomy for metachronous urothelial recurrence at our institution between January 1995 and December 2014. Univariable Cox regression was used to assess the association between overall survival and age, grade, stage, lymph node metastasis and radiographic findings. RESULTS: Of the 3,173 patients treated with radical cystectomy 64 underwent subsequent radical nephroureterectomy for metachronous urothelial recurrence. Median age at radical cystectomy was 66 years (IQR 61-74). In the 64 patients who underwent radical nephroureterectomy median time from radical cystectomy to radical nephroureterectomy was 2.7 years (IQR 1.4-4.6). Among 37 patients who underwent ureteroscopy prior to radical nephroureterectomy 29 (78%) had a positive biopsy. Radical nephroureterectomy pathology findings revealed locally advanced disease (pT3/pT4) in 39% of cases and positive node status in 11% compared with locally advanced disease in 17% and positive node status in 6% on radical cystectomy pathology findings. The post-radical nephroureterectomy estimated glomerular filtration rate was less than 60 and less than 30 ml/minute/1.73 m2 in 96% and 40% of patients, respectively. Median overall survival after radical nephroureterectomy was 3.1 years (95% CI 2.4-4.3). Only lymph node involvement at radical nephroureterectomy was significantly associated with worse overall mortality (HR 2.73, 95% CI 1.04-7.15, p = 0.041). CONCLUSIONS: The prognosis is poor in patients with panurothelial carcinoma treated with nephroureterectomy following cystectomy with locally advanced disease in a large proportion. Renal function after these procedures diminished and almost all patients were ineligible for cisplatin based chemotherapy. PMID- 28342938 TI - The impact of neoadjuvant therapy on the histopathological features of pancreatic ductal adenocarcinoma - A systematic review and meta-analysis. AB - BACKGROUND: Due to increased rates of curative tumor resections exceeding 60% after FOLFIRINOX-treatment, neoadjuvant therapy/NTx is increasingly recognized as an effective therapy option for downstaging borderline or locally advanced pancreatic ductal adenocarcinoma/PDAC. Yet, the effects of NTx on the common histopathological features of PDAC have not been systematically analysed. Therefore, the aim of the current study was to assess the impact of NTx on relevant histopathological features of PDAC. PATIENTS AND METHODS: Biomedical databases were systematically screened for predefined searching terms related to NTx and PDAC. The Preferred-Reporting-Items-for-Systematic-review-and-Meta Analysis/PRISMA-guidelines were used to perform a systematic review and meta analysis. Articles meeting the predefined criteria were analysed on relevance, and a meta-analysis was performed. RESULTS: A total of 9031 studies could be identified that analysed the effect of NTx on PDAC. Only 35 studies presented comparative data on the histological features of neoadjuvantly treated vs. upfront resected PDAC patients. In meta-analyses, the beneficial effect of NTx was reflected by reduced tumor size (T1/2: RR 2.87, 95%-CI: 1.52-5.42, P=0.001, T3/4: RR 0.78, 95%-CI: 0.69-0.89, P=0.0002), lower N-Stage (N0: RR 2.14, 95%-CI: 1.85-2.46, P<0.00001, N1: RR 0.59, 95%-CI: 0.53-0.65, P<0.00001), higher R0-rates (R0: RR 1.13, 95%-CI: 1.08-1.18, P<0.00001, R1: RR 0.66, 95%-CI: 0.58-0.76, P<0.00001), less perineural invasion (Pn1: RR 0.78, 95%-CI: 0.73-0.83, P<0.00001), less lymphatic vessel invasion (RR: 0.50, 95%-CI: 0.36-0.70, P<0.0001) and fewer G3-tumors (RR 0.82, 95%-CI: 0.71-0.94, P=0.005). CONCLUSIONS: NTx in PDAC seems to exert its beneficial effect in borderline or locally advanced PDAC over genuine tumor downstaging. Thus, although at least 40% of all NTx treated patients remain unresectable even with modern NTx regimes, neoadjuvantly treated PDAC showed not only increasing resectability rates especially after FOLFIRINOX, but even reach a lower tumor stage than primarily resected PDAC. PMID- 28342939 TI - Recent synthetic and medicinal perspectives of dihydropyrimidinones: A review. AB - Dihydropyrimidines are the most important heterocyclic ring systems which play an important role in the synthesis of DNA and RNA. Synthetically they were synthesized using Multi-component reactions like Biginelli reaction and Hantzschdihydropyridine. In the past decades, such Biginelli type dihydropyrimidones have received a considerable amount of attention due to the interesting pharmacological properties associated with this heterocyclic scaffold. In this review, we highlight recent developments in this area, with a focus on the DHPMs, recently developed as anti-inflammatory, anti-HIV, anti tubercular, antifungal anticancer, antibacterial, antifilarial, antihyperglycemic, antihypertensive, analgesic, anti-convulsant, antioxidant, anti-TRPA1, anti-SARS, and anti-cancer activity and alpha1a binding affinity. PMID- 28342940 TI - High test-retest-reliability of pain-related evoked potentials (PREP) in healthy subjects. AB - Pain-related evoked potentials (PREP) is an established electrophysiological method to evaluate the signal transmission of electrically stimulated A-delta fibres. Although prerequisite for its clinical use, test-retest-reliability and side-to-side differences of bilateral stimulation in healthy subjects have not been examined yet. We performed PREP twice within 3-14days in 33 healthy subjects bilaterally by stimulating the dorsal hand. Detection (DT) and pain thresholds (PT) after electrical stimulation, the corresponding pain ratings, latencies of P0, N1, P1 and N2 components and the corresponding amplitudes were assessed. Impact of electrically induced pain intensity, age, sex, and arm length on PREP was analysed. MANOVA, t-Test, interclass correlation coefficient (ICC), standard error of measurement (SEM), smallest real difference (SRD), Bland-Altmann Analysis as well as ANCOVA were used for statistical analysis. Measurement from both sides on both days resulted in mean N1-latencies from 142.39+/-18.12ms to 144.03+/-16.62ms and in mean N1P1-amplitudes from 39.04+/-12.26MUV to 40.53+/ 12.9MUV. Analysis of a side-to-side effect showed for the N1-latency a F-value of 0.038 and for the N1P1-amplitude of 0.004 (p>0.8). We found intraclass correlation coefficients (ICC) from 0.88 to 0.93 and a standard error of measurement (SEM)<10% of mean values for all measurements concerning the N1 Latency and N1P1-amplitude. Intraclass correlation coefficients, standard error of measurement and Bland-Altman-Analyses revealed excellent test-retest reliability for N1-latency and N1P1-amplitude without systematic error and there was no side-to-side effect on PREP. N1-latency (r=0.35, p<0.05) and N1P1 amplitude (r=-0.45, p<0.05) correlated with age and additionally N1-latency correlated with arm length (r=0.45, p<0.001). In contrast, pain intensity during the stimulation had no effect on both N1-latency and N1P1-amplitude. In summary, PREP showed high test-retest-reliability and negligible side-to-side differences concerning the commonly used parameters N1-latency and N1P1-amplitude. PMID- 28342941 TI - Is there any crosstalk between the chemotaxis and virulence induction signaling in Agrobacterium tumefaciens? AB - Agrobacterium tumefaciens, a soil-born phytopathogenic bacterium, is well known as a nature's engineer due to its ability to genetically transform the host by transferring a DNA fragment (called T-DNA) from its Ti plasmid to host-cell genome. To combat the harsh soil environment and seek the appropriate host, A. tumefaciens can sense and be attracted by a large number of chemical compounds released by wounded host. As a member of alpha-proteobacterium, A. tumefaciens has a chemotaxis system different from that found in Escherichia coli, since many chemoattractants for A. tumefaciens chemotaxis are virulence (vir) inducers. However, advances in the study of the chemotaxis paradigm, E. coli chemotaxis system, have provided enough information to analyze the A. tumefaciens chemotaxis. At low concentration, chemoattractants elicit A. tumefaciens chemotaxis and attract the species to the wound sites of the host. At high concentration, chemoattractants induce the expression of virulence genes and trigger T-DNA transfer. Recent studies on the VirA and ChvE of the vir-induction system provide some evidences to support the crosstalk between chemotaxis and vir induction. This review compares the core components of chemotaxis signaling system of A. tumefaciens with those observed in other species, discusses the connection between chemotaxis and vir-induction in A. tumefaciens, and proposes a model depicting the signaling crosstalk between chemotaxis and vir-induction. PMID- 28342942 TI - The nature of early astroglial protection-Fast activation and signaling. AB - Our present review is focusing on the uniqueness of balanced astroglial signaling. The balance of excitatory and inhibitory signaling within the CNS is mainly determined by sharp synaptic transients of excitatory glutamate (Glu) and inhibitory gamma-aminobutyrate (GABA) acting on the sub-second timescale. Astroglia is involved in excitatory chemical transmission by taking up i) Glu through neurotransmitter-sodium transporters, ii) K+ released due to presynaptic action potential generation, and iii) water keeping osmotic pressure. Glu uptake coupled Na+ influx may either ignite long-range astroglial Ca2+ transients or locally counteract over-excitation via astroglial GABA release and increased tonic inhibition. Imbalance of excitatory and inhibitory drives is associated with a number of disease conditions, including prevalent traumatic and ischaemic injuries or the emergence of epilepsy. Therefore, when addressing the potential of early therapeutic intervention, astroglial signaling functions combating progress of Glu excitotoxicity is of critical importance. We suggest, that excitotoxicity is linked primarily to over-excitation induced by the impairment of astroglial Glu uptake and/or GABA release. Within this framework, we discuss the acute alterations of Glu-cycling and metabolism and conjecture the therapeutic promise of regulation. We also confer the role played by key carrier proteins and enzymes as well as their interplay at the molecular, cellular, and organ levels. Moreover, based on our former studies, we offer potential prospect on the emerging theme of astroglial succinate sensing in course of Glu excitotoxicity. PMID- 28342943 TI - Would I take antipsychotics, if I had psychotic symptoms? Examining determinants of the decision to take antipsychotics. AB - Poor adherence to treatment in schizophrenia is mainly associated to patients related factors. However, social negative representations of schizophrenia and its treatment may also contribute to patients' decision to take or not to take antipsychotics. A web-based study on 1,807 participants was conducted during which participants imagined that they had a particular chronic illness based on clinical vignettes (mental illnesses: schizophrenia, depression; somatic illnesses: multiple sclerosis, rheumatoid arthritis). Participants rated their subjective distress and perceived social stigma associated with each illness. They also rated the perceived treatability of the illness, their belief in the effectiveness of treatment, and their treatment preference regarding medication. Results show that schizophrenia was considered more distressful, less treatable and associated with higher social stigma than somatic illnesses. Medication was less preferred for treating schizophrenia compared to somatic illnesses. Perceived treatability of illness and belief in the effectiveness of pharmacological treatment were the factors driving preference for medication in schizophrenia and depression, respectively; these factors had weaker influence on preference for medication in somatic illnesses. Our study points out more severe negative representations of mental illnesses in general, and their treatment, particularly schizophrenia. These attitudes are not confined to patients, and may influence patients' decisions to take psychotropic drugs. PMID- 28342944 TI - The anti-inflammatory mechanism of antidepressants - SSRIs, SNRIs. AB - The cytokine theory of depression no longer brings about any doubts. Experiments and research studies conducted in the last ten years have confirmed that both physical and psychological (emotional) stress increases the likelihood of occurrence of mental disorders (including depressive disorders) owing to the action of a series of hormonal and biochemical mechanisms. Selective serotonin reuptake inhibitors (SSRI) as well as serotonin and norepinephrine reuptake inhibitors (SNRIs) are some of the most commonly applied drugs in the world during pharmacotherapy of recurrent depressive disorder. The underestimated anti inflammatory and anti-oxidative effect may be one of the potential mechanisms of action of the preparations mentioned above. The detailed specificity of action of this mechanism still remains unknown. The aim of our work will be to perform a review of contemporary literature in order to present the latest scientific reports regarding the anti-inflammatory effects of SSRIs and SNRIs. The mechanism of anti-inflammatory action may serve as a possible explanation for the efficacy of antidepressants from the groups of SSRIs and SNRIs. PMID- 28342945 TI - Cognitive impairment in first-episode drug-naive patients with schizophrenia: Relationships with serum concentrations of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. AB - OBJECTIVES: Evidence suggests that brain-derived neurotrophic factor (BDNF) and glial cell line -derived neurotrophic factor (GDNF) are important in the regulation of synaptic plasticity, which plays a key role in the cognitive processes in psychiatric disorders. Our work aimed at exploring the associations between serum BDNF and GDNF levels and cognitive functions in first-episode drug naive (FEDN) patients with schizophrenia. METHODS: The BDNF and GDNF levels of 58 FEDN patients and 55 age- and sex-matched healthy controls were measured and test subjects were examined using several neurocognitive tests including the verbal fluency test (VFT), the trail making test (TMT), the digit span test (DST), and the Stroop test. RESULTS: Patients performed significantly worse than controls in nearly all neurocognitive performances except the forward subscale part of the DST. BDNF levels were inversely correlated to TMT-part B scores and positively correlated to VFT-action in the FEDN group. GDNF levels showed a positive correlation with VFT-action scores and a negative correlation with TMT-part B scores of these patients. CONCLUSION: Current data suggests that cognitive dysfunction widely exists in the early stages of schizophrenia. BDNF and GDNF may be jointly contributed to the pathological mechanisms involved in cognitive impairment in FEDN patients with schizophrenia. PMID- 28342946 TI - NegAIT: A new parser for medical text simplification using morphological, sentential and double negation. AB - Many different text features influence text readability and content comprehension. Negation is commonly suggested as one such feature, but few general-purpose tools exist to discover negation and studies of the impact of negation on text readability are rare. In this paper, we introduce a new negation parser (NegAIT) for detecting morphological, sentential, and double negation. We evaluated the parser using a human annotated gold standard containing 500 Wikipedia sentences and achieved 95%, 89% and 67% precision with 100%, 80%, and 67% recall, respectively. We also investigate two applications of this new negation parser. First, we performed a corpus statistics study to demonstrate different negation usage in easy and difficult text. Negation usage was compared in six corpora: patient blogs (4K sentences), Cochrane reviews (91K sentences), PubMed abstracts (20K sentences), clinical trial texts (48K sentences), and English and Simple English Wikipedia articles for different medical topics (60K and 6K sentences). The most difficult text contained the least negation. However, when comparing negation types, difficult texts (i.e., Cochrane, PubMed, English Wikipedia and clinical trials) contained significantly (p<0.01) more morphological negations. Second, we conducted a predictive analytics study to show the importance of negation in distinguishing between easy and difficulty text. Five binary classifiers (Naive Bayes, SVM, decision tree, logistic regression and linear regression) were trained using only negation information. All classifiers achieved better performance than the majority baseline. The Naive Bayes' classifier achieved the highest accuracy at 77% (9% higher than the majority baseline). PMID- 28342948 TI - Waist/Hip Ratio Better Predicts Development of Severe Liver Disease Within 20 Years Than Body Mass Index: A Population-based Cohort Study. AB - BACKGROUND & AIMS: Obesity, commonly assessed based on body mass index (BMI), is associated with an increased risk for severe liver disease. It is not known if other measures of body composition are better determinants of risk for severe liver disease, and/or if these differ between women and men. We investigated the body composition measures that best predict the development of severe liver disease. METHODS: We collected data from the Malmo Diet and Cancer study in Sweden, comprising 16,784 women and 10,833 (mean age, 58.1 years at baseline), and followed patients for a median 19.8 years. We analyzed data on measures of body composition including BMI, waist/hip ratio, and others. We determined whether subjects were diagnosed with severe liver disease, or died from severe liver disease, until the end of 2014 using Swedish national registers. Associations between body composition measures and severe liver disease were assessed using Cox regression models, stratified by sex and adjusted for age, alcohol consumption, smoking, education, and physical activity. RESULTS: All studied measures of body composition were significantly associated with severe liver disease. Waist/hip ratio was the best predictor of severe liver disease in women (hazard ratio [HR] per standard deviation increment, 1.30; 95% confidence interval [CI], 1.16-1.46) and men (HR, 1.46; 95% CI, 1.31-1.63). BMI had the lowest HR in women (HR, 1.12; 95% CI, 1.00-1.27) and men (HR, 1.26; 95% CI, 1.12 1.42). The association between waist/hip ratio and development of liver disease was independent of BMI. CONCLUSIONS: In a Swedish population-based cohort study, we associated all measures of body composition with risk of severe liver disease. However, measures of abdominal obesity were best at predicting development of severe liver disease. PMID- 28342947 TI - What good are positive emotions for treatment? Trait positive emotionality predicts response to Cognitive Behavioral Therapy for anxiety. AB - OBJECTIVE: Cognitive behavioral therapy (CBT) is empirically supported for the treatment of anxiety disorders; however, not all individuals achieve recovery following CBT. Positive emotions serve a number of functions that theoretically should facilitate response to CBT - they promote flexible patterns of information processing and assimilation of new information, encourage approach-oriented behavior, and speed physiological recovery from negative emotions. We conducted a secondary analysis of an existing clinical trial dataset to test the a priori hypothesis that individual differences in trait positive emotions would predict CBT response for anxiety. METHOD: Participants meeting diagnostic criteria for panic disorder (n = 28) or generalized anxiety disorder (n = 31) completed 10 weekly individual CBT sessions. Trait positive emotionality was assessed at pre treatment, and severity of anxiety symptoms and associated impairment was assessed throughout treatment. RESULTS: Participants who reported a greater propensity to experience positive emotions at pre-treatment displayed the largest reduction in anxiety symptoms as well as fewer symptoms following treatment. Positive emotions remained a robust predictor of change in symptoms when controlling for baseline depression severity. CONCLUSIONS: Initial evidence supports the predictive value of trait positive emotions as a prognostic indicator for CBT outcome in a GAD and PD sample. PMID- 28342949 TI - Use of Thiopurines During Conception and Pregnancy Is Not Associated With Adverse Pregnancy Outcomes or Health of Infants at One Year in a Prospective Study. AB - BACKGROUND & AIMS: Most data on the safety of thiopurine therapy for inflammatory bowel disease (IBD) during pregnancy come from retrospective studies, which makes it difficult to adjust for confounding factors. We performed a prospective cohort study to determine whether thiopurine use affects pregnancy outcomes or health outcomes of children. METHODS: We performed a prospective study of all women who visited the IBD preconception outpatient clinic at our tertiary health center in The Netherlands from December 2008 through May 2016. Patients were counseled before pregnancy and seen bimonthly during pregnancy. We collected and analyzed data on medication use, as well as lifestyle and clinical factors, during conception and pregnancy. Pregnancy outcomes (live birth, spontaneous abortion, elective abortion, and stillbirth), birth outcomes (gestational age, birth weight, and congenital abnormalities), and health outcomes of infants 1 year after birth were compared between women who did and did not use a thiopurine during conception and pregnancy. In addition, health outcomes of infants 1 year after birth were compared with infants born to mothers without IBD from the same geographic region. RESULTS: Our study comprised 309 women with confirmed IBD (216 with Crohn's disease, 85 with ulcerative colitis, and 8 with IBD unclassified). During the study period, 311 pregnancies of 232 women resulted in a live birth; a thiopurine was used during 108 pregnancies (35%). After correction for diagnosis, fertility treatment, and disease activity, there was no association between thiopurine use and spontaneous abortions. Birth outcomes were similar between women who did and did not use a thiopurine. Among infants 1 year of age, there were no differences in median growth, number of infections, allergies, adverse reactions to vaccinations, or chronic diseases between those born to women who did and did not use a thiopurine or between women with and without IBD. CONCLUSIONS: In this prospective cohort study, we found no association between maternal thiopurine use during pregnancy and increased spontaneous abortions, adverse birth outcomes, or adverse health outcomes of infants 1 year after birth. PMID- 28342950 TI - Progression of Unresected Intraductal Papillary Mucinous Neoplasms of the Pancreas to Cancer: A Systematic Review and Meta-analysis. AB - BACKGROUND & AIMS: It is not clear how best to manage patients with low-risk intraductal papillary mucinous neoplasms (IPMNs) of the pancreas because little is known about IPMN progression to cancer. We sought to determine the cumulative incidence of development of pancreatic cancer in persons with unresected IPMNs (particularly low-risk IPMNs). METHODS: We performed a systematic search of the MEDLINE and Embase databases through November 30, 2016 for studies reporting the cumulative incidence of pancreatic cancer in patients with unresected IPMNs or studies that provided data in sufficient detail for us to calculate cumulative incidence values. We categorized patient series as studies on low-risk IPMNs (lesions without main pancreatic duct involvement or mural nodules) or non-low risk IPMNs. We calculated meta-analytic cumulative incidence values for pancreatic cancer at 1, 3, 5, and 10 years of follow-up by using the inverse variance method and random-effects model. RESULTS: Among 1514 articles screened, we identified 10 studies of low-risk IPMNs (n = 2411) and 9 studies of non-low risk IPMNs (n = 825). In studies of low-risk IPMNs, the meta-analytic cumulative incidence values for pancreatic cancer were 0.02% at 1 year (95% confidence interval [CI], 0.0%-0.23%; I2= 0.0%), 1.40% at 3 years (95% CI, 0.58%-2.48%; I2 = 58.5%), 3.12% at 5 years (95% CI, 1.12%-5.90%; I2 = 88.0%), and 7.77% at 10 years (95% CI, 4.09%-12.39%; I2 = 79.8%). These values were much higher in studies of non-low-risk IPMNs; cumulative incidence values for pancreatic cancer were 1.95% at 1 year (95% CI, 0.0%-5.99%; I2 = 84.2%), 5.69% at 3 years (95% CI, 1.10% 12.77%; I2 = 89.9%), 9.77% at 5 years (95% CI, 3.04%-19.27%; I2 = 92.0%), and 24.68% at 10 years (95% CI, 14.87%-35.90%; I2 = 74.3%). The pooled cumulative incidence steadily increased linearly as the follow-up duration increased. CONCLUSIONS: In a systematic review and meta-analysis, we found that low-risk IPMNs have almost 8% chance of progressing to pancreatic cancer within 10 years, and higher-risk IPMNs have almost 25% chance of progressing to cancer in 10 years; incidence values increase linearly with time. Continued long-term surveillance is therefore vital for patients with low-risk IPMNs. PMID- 28342952 TI - An Unusual Flat Anorectal Lesion Mimicking a Laterally Spreading Tumor. PMID- 28342951 TI - A Model To Identify Individuals at High Risk for Esophageal Squamous Cell Carcinoma and Precancerous Lesions in Regions of High Prevalence in China. AB - BACKGROUND & AIMS: We aimed to develop a population-based model to identify individuals at high risk for esophageal squamous cell carcinoma (ESCC) in regions of China with a high prevalence of this cancer. METHODS: We collected findings from 15,073 permanent residents (45-69 years old) of 334 randomly selected villages in Hua County, Henan Province, China who underwent endoscopic screening (with iodine staining) for ESCC from January 2012 through September 2015. The entire esophagus and stomach were examined; biopsies were collected from all focal lesions (or from standard sites in the esophagus if no abnormalities were found) and analyzed histologically. Squamous dysplasia, carcinoma in situ, and ESCC were independently confirmed by 2 pathologists. Before endoscopy, subjects completed a questionnaire on ESCC risk factors. Variables were evaluated with unconditional univariate logistic regression analysis; variables found to be significantly associated with ESCC were then analyzed by multivariate logistic regression modeling. We used the Akaike information criterion to develop our final model structure and the coding form of variables with multiple measures. We developed 2 groups of models, separately defining severe dysplasia and above (SDA) (lesions including severe dysplasia and higher-grade lesions) and moderate dysplasia and above (lesions including moderate dysplasia and higher-grade lesions) as outcome events. Age-stratified and whole-age models were developed; their discriminative ability in the full multivariate model and the simple age model was compared. We performed area under the receiver operating characteristic curve (AUC) and the DeLong test to evaluate model performance. RESULTS: Our age stratified prediction models identified individuals 60 years of age or younger with SDA with an AUC value of 0.795 (95% confidence interval, 0.736-0.854) and individuals older than 60 years with SDA with an AUC value of 0.681 (95% confidence interval, 0.618-0.743). Factors associated with SDA in individuals 60 years or younger included age closer to 60 years, use of coal or wood as a main source of cooking fuel, body mass index of 22 kg/m2 or less, unexplained epigastric pain, and rapid ingestion of meals. In subjects older than 60 years, SDA associated with age, family history of ESCC, cigarette smoking, body mass index of 22 kg/m2 or less, pesticide exposure, irregular eating habits, intake of high temperature foods, rapid ingestion of meals, and ingestion of leftover food in summer months. Use of our model in screening could have allowed 27% of subjects 60 years or younger and 9% of subjects older than 60 years to avoid endoscopy without missing SDAs. This means that approximately 2500 of endoscopies in total (16.6%) could have been avoided. CONCLUSIONS: We developed a low-cost, easy-to-use model to identify individuals at risk for severe dysplasia or cancer of the esophagus living in a region of China with a high risk of ESCC. This model might be used to select individuals and groups of persons who should undergo endoscopy analysis for esophageal cancer. PMID- 28342953 TI - Upper Gastrointestinal Bleeding Caused by Hereditary Hemorrhagic Telangectasia. PMID- 28342954 TI - Colonic Schwannoma Diagnosed by Endoscopic Ultrasound With Fine-Needle Aspiration. PMID- 28342955 TI - White Paper AGA: Drug Development for Eosinophilic Esophagitis. AB - Since first characterized in 2 small case series in the early 1990s, eosinophilic esophagitis (EoE) has emerged as a commonly identified cause of esophageal symptoms in children and adults.1,2 Although several highly effectively dietary, pharmacologic, and endoscopic therapies have been reported, none is currently approved by either the US Food and Drug Administration (FDA) or European regulatory authorities. Evolving diagnostic criteria have challenged drug development, in particular the recognition of complex interactions with the most prevalent esophageal disorder, gastroesophageal reflux disease (GERD). Heterogeneity in the clinical presentations of affected children and adults has created difficulties with uniform inclusion criteria and the development of disease-specific, patient-reported outcome (PRO) instruments. Furthermore, controversies regarding the appropriate therapeutic endpoints of EoE have impeded the design of clinical trials. Despite these obstacles, collaborative efforts by investigators, industry, the FDA, and patient advocacy groups have resulted in substantial progress in drug development in EoE over the past 2 decades.3 The purpose of this article is to summarize discussions on EoE based on the 2016 Drug Development Conference sponsored by the Center for Diagnostics and Therapeutics of the American Gastroenterological Association. PMID- 28342957 TI - Letter by Chen et al. regarding article "Effect of prehospital advanced airway management for pediatric out-of-hospital cardiac arrest". PMID- 28342956 TI - Disparities in telephone CPR access and timing during out-of-hospital cardiac arrest. AB - AIM: Spanish-only speaking residents in the United States face barriers to receiving potentially life-saving 911 interventions such as Telephone cardiopulmonary resuscitation (TCPR) instructions. Since 2015, 911 dispatchers have placed an increased emphasis on rapid identification of potential cardiac arrest. The purpose of this study was to describe the utilization and timing of the 911 system during suspected out-of-hospital cardiac arrest (OHCA) by Spanish speaking callers in Metropolitan Phoenix, Arizona. METHODS: The dataset consisted of suspected OHCA from 911 centers from October 10, 2010 through December 31, 2013. Review of audio TCPR process data included whether the need for CPR was recognized by telecommunicators, whether CPR instructions were provided, and the time elements from call receipt to initiation of compressions. RESULTS: A total of 3398 calls were made to 911 for suspected OHCA where CPR was indicated. A total of 39 (1.2%) were determined to have a Spanish language barrier. This averages to 18 calls per year with a Spanish language barrier during the study period, compared with 286 OHCAs expected per year among this population. The average time until telecommunicators recognized CPR need was 87.4s for the no language barrier group compared to 160.6s for the Spanish-language barrier group (p<0.001).Time to CPR instructions started was significantly different between these groups (144.4s vs 231.3s, respectively) (p<0.001), as was time to first compression, (174.4s vs. 290.9s, respectively) (p<0.001). CONCLUSIONS: Our study suggests that Hispanic callers under-utilize the 911 system, and when they do call 911, there are significant delays in initiating CPR. PMID- 28342958 TI - Where do I take my patient post ROSC in the absence of ST elevation on the ECG? PMID- 28342960 TI - Geophagy during pregnancy: Is there a health risk for infants? AB - Prenatal lead exposure is a public health concern. Geophagy, the practice of soil eating, is documented for pregnant women of sub-Saharan Africa to treat pregnancy related malaise. The soils however can contain substantial amounts of lead. In an exploratory study on 48 mother-child pairs in the Democratic Republic of Congo, we found striking site-specific differences in prenatal lead exposure, i.e., higher lead levels at Kisangani than at Isiro. Kisangani women consumed 1/ more often soil during the first trimester of pregnancy as well as 2/ a different type of soil compared to Isiro women (P<0.05). We conclude geophagy may be a potential source of prenatal lead exposure. PMID- 28342959 TI - Early Lance-Adams syndrome after cardiac arrest: Prevalence, time to return to awareness, and outcome in a large cohort. AB - INTRODUCTION: Early myoclonus after cardiac arrest (CA) is traditionally viewed as a poor prognostic sign (status myoclonus). However, some patients may present early Lance-Adams syndrome (LAS): under appropriate treatment, they can reach a satisfactory functional outcome. Our aim was to describe their profile, focusing on pharmacologic management in the ICU, time to return of awareness, and long term prognosis. METHODS: Adults with early LAS (defined as generalized myoclonus within 96h, with epileptiform EEG within 48h after CA) were retrospectively identified in our CA registry between 2006 and 2016. Functional outcome was assessed through cerebral performance categories (CPC) at 3 months, CPC 1-2 defined good outcome. RESULTS: Among 458 consecutive patients, 7 (1.5%) developed early LAS (4 women, median age 59 years). Within 72h after CA, in normothemia and off sedation, all showed preserved brainstem reflexes and localized pain. All patients were initially treated with valproate, levetiracetam and clonazepam; additional agents, including propofol and midazolam, were prescribed in the majority. First signs of awareness occurred after 3-23 days (median 11.8); 3/7 reached a good outcome at 3 months. CONCLUSION: Early after CA, myoclonus together with a reactive, epileptiform EEG, preserved evoked potentials and brainstem reflexes suggests LAS. This condition was managed with a combination of highly dosed, large spectrum antiepileptic agents including propofol and midazolam. Even if awakening was at times delayed, good outcome occurred in a substantial proportion of patients. PMID- 28342961 TI - Particulate metal bioaccessibility in physiological fluids and cell culture media: Toxicological perspectives. AB - According to the literature, tiny amounts of transition metals in airborne fine particles (PM2.5) may induce proinflammatory cell response through reactive oxygen species production. The solubility of particle-bound metals in physiological fluids, i.e. the metal bioaccessibility is driven by factors such as the solution chemical composition, the contact time with the particles, and the solid-to-liquid phase ratio (S/L). In this work, PM2.5-bound metal bioaccessibility was assessed in various physiological-like solutions including cell culture media in order to evidence the potential impact on normal human bronchial epithelial cells (NHBE) when studying the cytotoxicity and inflammatory responses of PM2.5 towards the target bronchial compartment. Different fluids (H2O, PBS, LHC-9 culture medium, Gamble and human respiratory mucus collected from COPD patients), various S/L conditions (from 1/6000 to 1/100,000) and exposure times (6, 24 and 72h) were tested on urban PM2.5 samples. In addition, metals' total, soluble and insoluble fractions from PM2.5 in LHC-9 were deposited on NHBE cells (BEAS-2B) to measure their cytotoxicity and inflammatory potential (i.e., G6PDH activity, secretion of IL-6 and IL-8). The bioaccessibility is solution-dependent. A higher salinity or organic content may increase or inhibit the bioaccessibiliy according to the element, as observed in the complex mucus matrix. Decreasing the S/L ratio also affect the bioaccessibility depending on the solution tested while the exposure time appears less critical. The LHC-9 culture medium appears to be a good physiological proxy as it induces metal bioaccessibilities close to the mucus values and is little affected by S/L ratios or exposure time. Only the insoluble fraction can be linked to the PM2.5-induced cytotoxicity. By contrast, both soluble and insoluble fractions can be related to the secretion of cytokines. The metal bioaccessibility in LHC-9 of the total, soluble, and insoluble fractions of the PM2.5 under study did not explain alone, the cytotoxicity nor the inflammatory response observed in BEAS-2B cells. These findings confirm the urgent need to perform further toxicological studies to better evaluate the synergistic effect of both bioaccessible particle-bound metals and organic species. PMID- 28342962 TI - Intellectual evaluation of children exposed to phthalate-tainted products after the 2011 Taiwan phthalate episode. AB - INTRODUCTION: Phthalate exposure may reduce intellectual development in young children. In 2011, numerous Taiwanese children had been reported to have consumed phthalate-tainted products. We investigated the effects of phthalate exposure on the intellectual development of these children after the 2011 Taiwan di-2 ethylhexyl phthalate (DEHP) episode. METHODS: We recruited 204 children, aged 3 12 y, from 3 hospitals in Taiwan between 2012 and 2013. First-morning urine samples were collected for analyzing 5 phthalate metabolites. We applied a Bayesian model to estimate the past DEHP exposure (estDEHPADD) of each participant before the 2011 DEHP episode. Demographic information, consumption of phthalate-tainted products, and maternal education, of each participant were obtained using a questionnaire. We used the Wechsler intelligence evaluation tools for assessing the children's and maternal intelligence quotient. RESULTS AND DISCUSSION: The median levels of mono-2-ethylhexyl phthalate, mono(2-ethyl-5 hydroxyhexyl) phthalate, mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-n-butyl phthalate, and mono-iso-butyl phthalate in the children were 9.97, 45.8, 32.2, 46.2, and 24.3MUg/g creatinine, respectively. Using the aforementioned urinary phthalate metabolites, we found that the children's verbal comprehension index (N =98) was significantly negatively associated with urinary log10 MEOHP (beta, 11.92; SE, 5.33; 95%CI, -22.52~ -1.33; P=0.028) and log10 SigmaDBP metabolites (beta, -10.95; SE, 4.93; 95%CI, -20.74~ -1.16; P=0.029) after adjustment for age, gender, maternal IQ and education, passive smoking, estDEHPADD, active and passive smoking during pregnancy. Through a tolerable daily intake-based approach, we only found a significant negative association between past estimate DEHPADD and VIQ>=3-<6 in preschool children whereas no correlation was observed between current DEHP exposure and IQ>=3-<6 score with/ without estimate DEHPADD adjustment. It revealed that the effect of past high-DEHP exposure on verbal related neurodevelopment of younger child are more sensitive. CONCLUSION: Our results are consistent with the hypothesis that exposure to DEHP and DnBP affects intellectual development in preschool and school-aged children, particularly their language learning or expression ability. PMID- 28342963 TI - New insights into cellular cholesterol acquisition: promoter analysis of human HMGCR and SQLE, two key control enzymes in cholesterol synthesis. AB - BACKGROUND: The two control points of cholesterol synthesis, 3-hydroxy-3 methylglutaryl-coenzyme A reductase (HMGCR) and squalene monooxygenase (SQLE) are known targets of the transcription factor sterol-regulatory element binding protein-2 (SREBP-2). Yet the location of the sterol-regulatory elements (SREs) and cofactor binding sites, nuclear factor-Y (NF-Y) and specificity protein 1 (Sp1), have not been satisfactorily mapped in the human SQLE promoter, or at all in the human HMGCR promoter. METHODS: We used luciferase reporter assays to screen the sterol-responsiveness of a library of predicted SRE, Sp1 and NF-Y site mutants and hence identify bone fide binding sites. We confirmed SREs via an electrophoretic mobility shift assay (EMSA) and ChIP-PCR. RESULTS: We identified two SREs in close proximity in both the human HMGCR and SQLE promoters, as well as one NF-Y site in HMGCR and two in SQLE. In addition, we found that HMGCR expression is highly activated only when SREBP-2 levels are very high, in contrast to the low density lipoprotein receptor (LDLR), a result reflected in mouse models used in other studies. CONCLUSIONS: Both HMGCR and SQLE promoters have two SREs that may act as a homing region to attract a single SREBP-2 homodimer, with HMGCR being activated only when there is absolute need for cholesterol synthesis. This ensures preferential uptake of exogenous cholesterol via LDLR, thereby conserving energy. GENERAL SIGNIFICANCE: We provide the first comprehensive investigation of SREs and NF-Ys in the human HMGCR and SQLE promoters, increasing our fundamental understanding of the transcriptional regulation of cholesterol synthesis. PMID- 28342964 TI - Establishing a novel biosynthetic pathway for the production of 3,4 dihydroxybutyric acid from xylose in Escherichia coli. AB - 3-Hydroxy-gamma-butyrolactone (3HBL) is an attractive building block owing to its broad applications in pharmaceutical industry. Currently, 3HBL is commercially produced by chemical routes using petro-derived carbohydrates, which involves hazardous materials and harsh processing conditions. Only one biosynthetic pathway has been reported for synthesis of 3HBL and its hydrolyzed form 3,4 dihydroxybutyric acid (3,4-DHBA) using glucose and glycolic acid as the substrates and coenzyme A as the activator, which involves multiple steps (>10 steps) and suffers from low productivity and yield. Here we established a novel five-step biosynthetic pathway for 3,4-DHBA generation from D-xylose based on the non-phosphorylative D-xylose metabolism, which led to efficient production of 3,4 DHBA in Escherichia coli. Pathway optimization by incorporation of efficient enzymes for each step and host strain engineering by knocking out competing pathways enabled 1.27g/L 3,4-DHBA produced in shake flasks, which is the highest titer reported so far. The novel pathway established in engineered E. coli strain demonstrates a new route for 3,4-DHBA biosynthesis from xylose, and this engineered pathway has great potential for industrial biomanufacturing of 3,4 DHBA and 3HBL. PMID- 28342965 TI - Effects of I2-imidazoline receptor (IR) alkylating BU99006 in the mouse brain: Upregulation of nischarin/I1-IR and MU-opioid receptor proteins and modulation of associated signalling pathways. AB - 5-isothiocyanato-2-benzofuranyl-2-imidazoline (BU99006) was shown to selectively and irreversibly bind to I2-imidazoline receptors (IRs) in vitro and in vivo, but cell signalling consequences of I2-IR alkylation have not been reported previously. This study assessed by Western blot the effects of BU99006 on nischarin (candidate I1-IR), MU-OR (regulated by nischarin) and associated signalling mediators in the mouse brain. Acute treatment with BU99006 (20 mg/kg, i.p., 1-3 h) led to fast (peak at 1 h) and shortlasting (decline up to 3 h) upregulation of nischarin and MU-OR contents in the hippocampus (less or non significant effects in cortex) and altered the expression of cytoskeletal beta actin (reduced contents at 3 h). In the same hippocampal samples of BU99006 treated mice, an inhibition of the MAPK species MEK, ERK and JNK was detected at 1 and/or 2 h after drug administration, which was paralleled by enhanced calpain activity (increased contents of p25 and spectrin breakdown products). Correlation analysis indicated the involvement of cdk5/p25 in MEK/ERK inhibition. These neurochemical effects of I2-alkylating BU99006 show a close relation between I1- and I2-IRs expressed in the mouse brain and between these receptors and the MU OR, accompanied by cytoskeletal alterations and differential effects on multifunctional MAPK and cdk5 signalling pathways. PMID- 28342967 TI - The effects of omega-3 fatty acids and vitamin E co-supplementation on clinical and metabolic status in patients with Parkinson's disease: A randomized, double blind, placebo-controlled trial. AB - The current research was performed to evaluate the effects of omega-3 fatty acids and vitamin E co-supplementation on clinical signs and metabolic status in people with Parkinson's disease (PD). This randomized double-blind placebo-controlled clinical trial was conducted in 60 patients with PD. Participants were randomly assigned into two groups to receive either 1000 mg omega-3 fatty acids from flaxseed oil plus 400 IU vitamin E supplements (n = 30) or placebo (n = 30) for 12 weeks. Unified Parkinson's disease rating stage (UPDRS) were recorded at baseline and the after 3-month intervention. After 12 weeks' intervention, compared with the placebo, omega-3 fatty acids and vitamin E co-supplementation led to a significant improve in UPDRS (-3.3 +/- 10.0 vs. +4.4 +/- 14.9, P = 0.02). Furthermore, co-supplementation decreased high-sensitivity C-reactive protein (hs-CRP) (-0.3 +/- 0.6 vs. +0.3 +/- 0.3 MUg/mL, P < 0.001), and increased total antioxidant capacity (TAC) (+65.2 +/- 68.7 vs. +16 +/- 52.4 MUmol/L, P = 0.003) and glutathione (GSH) concentrations (+41.4 +/- 80.6 vs. -19.6 +/- 55.9 MUmol/L, P = 0.001) compared with the placebo. Additionally, co-supplementation meaningfully decreased insulin (-2.1 +/- 4.9 vs. +1.4 +/- 6.2 MUIU/mL, P = 0.01), homeostasis model of assessment-estimated insulin resistance (-0.7 +/- 1.8 vs.+0.3 +/- 1.6, P = 0.02) and Beta cell function (-5.9 +/- 13.9 vs. +5.7 +/- 25.5, P = 0.03), and increased quantitative insulin sensitivity check index (+0.009 +/- 0.02 vs. -0.006 +/- 0.03, P = 0.03) compared with the placebo. Overall, our study demonstrated that omega-3 fatty acids and vitamin E co supplementation in people with PD had favorable effects on UPDRS, hs-CRP, TAC, GSH and markers of insulin metabolism. PMID- 28342966 TI - Time courses of post-injury mitochondrial oxidative damage and respiratory dysfunction and neuronal cytoskeletal degradation in a rat model of focal traumatic brain injury. AB - Traumatic brain injury (TBI) results in rapid reactive oxygen species (ROS) production and oxidative damage to essential brain cellular components leading to neuronal dysfunction and cell death. It is increasingly appreciated that a major player in TBI-induced oxidative damage is the reactive nitrogen species (RNS) peroxynitrite (PN) which is produced in large part in injured brain mitochondria. Once formed, PN decomposes into highly reactive free radicals that trigger membrane lipid peroxidation (LP) of polyunsaturated fatty acids (e.g. arachidonic acid) and protein nitration (3-nitrotyrosine, 3-NT) in mitochondria and other cellular membranes causing various functional impairments to mitochondrial oxidative phosphorylation and calcium (Ca2+) buffering capacity. The LP also results in the formation of neurotoxic reactive aldehyde byproducts including 4 hydroxynonenal (4-HNE) and propenal (acrolein) which exacerbates ROS/RNS production and oxidative protein damage in the injured brain. Ultimately, this results in intracellular Ca2+ overload that activates proteolytic degradation of alpha-spectrin, a neuronal cytoskeletal protein. Therefore, the aim of this study was to establish the temporal evolution of mitochondrial dysfunction, oxidative damage and cytoskeletal degradation in the brain following a severe controlled cortical impact (CCI) TBI in young male adult rats. In mitochondria isolated from an 8 mm diameter cortical punch including the 5 mm wide impact site and their respiratory function studied ex vivo, we observed an initial decrease in complex I and II mitochondrial bioenergetics within 3 h (h). For complex I bioenergetics, this partially recovered by 12-16 h, whereas for complex II respiration the recovery was complete by 12 h. During the first 24 h, there was no evidence of an injury-induced increase in LP or protein nitration in mitochondrial or cellular homogenates. However, beginning at 24 h, there was a gradual secondary decline in complex I and II respiration that peaked at 72 h. post-TBI that coincided with progressive peroxidation of mitochondrial and cellular lipids, protein nitration and protein modification by 4-HNE and acrolein. The oxidative damage and respiratory failure paralleled an increase in Ca2+-induced proteolytic degradation of the neuronal cytoskeletal protein alpha-spectrin indicating a failure of intracellular Ca2+ homeostasis. These findings of a surprisingly delayed peak in secondary injury, suggest that the therapeutic window and needed treatment duration for certain antioxidant treatment strategies following CCI-TBI in rodents may be longer than previously believed. PMID- 28342968 TI - Heterologous expression, purification and characterization of three novel esterases secreted by the lignocellulolytic fungus Penicillium purpurogenum when grown on sugar beet pulp. AB - The lignocellulolytic fungus, Penicillium purpurogenum, grows on a variety of natural carbon sources, among them sugar beet pulp. Culture supernatants of P. purpurogenum grown on sugar beet pulp were partially purified and the fractions obtained analyzed for esterase activity by zymograms. The bands with activity on methyl umbelliferyl acetate were subjected to mass spectrometry to identify peptides. The peptides obtained were probed against the proteins deduced from the genome sequence of P. purpurogenum. Eight putative esterases thus identified were chosen for future work. Their cDNAs were expressed in Pichia pastoris. The supernatants of the recombinant clones were assayed for esterase activity, and five of the proteins were active against one or more substrates: methyl umbelliferyl acetate, indoxyl acetate, methyl esterified pectin and fluorescein diacetate. Three of those enzymes were purified, further characterized and subjected to a BLAST search. Based on their amino acid sequence and properties, they were identified as follows: RAE1, pectin acetyl esterase (CAZy family CE 12); FAEA, feruloyl esterase (could not be assigned to a CAZy family) and EAN, acetyl esterase (former CAZy family CE 10). PMID- 28342969 TI - Structural and genetic characterization of the O-antigen of Enterobacter cloacae C5529 related to the O-antigen of E. cloacae G3054. AB - On mild acid degradation of the lipopolysaccharide of Enterobacter cloacae C5529, the O-polysaccharide chain was cleaved at the linkages of 5,7-diacetamido-3,5,7,9 tetradeoxy-l-glycero-l-manno-non-2-ulosonic acid (di-N-acetylpseudaminic acid, Psep5Ac7Ac). The resultant oligosaccharide and an alkali-treated lipopolysaccharide were studied by sugar analysis along with 1H and 13C NMR spectroscopy, and the following structure of the tetrasaccharide repeating unit of the O-polysaccharide was established: ->4)-beta-Psep5Ac7Ac-(2 -> 3)-beta-d Galp-(1 -> 6)-beta-d-Galf-(1 -> 3)-alpha-d-Galp-(1-> It differs from a structurally related O-polysaccharide of E. cloacae G3045 studied early (Perepelov, A. V.; Wang, M.; Filatov, A. V.; Guo, X.; Shashkov, A. S.; Wang, L.; Knirel, Y. A. Carbohydr. Res. 2015; 407:59-62) in positions of substitution of beta-Psep5Ac7Ac (O-4 vs. O-8) and beta-Galp (O-3 vs. O-6) and the absence of a side-chain alpha-Galp residue. The O-antigen gene clusters of E. cloacae C5529 and G3045 are organized identically and include genes with the same putative functions in the O-polysaccharide synthesis. Based on these and serological data, it is suggested to combine E. cloacae C5529 and G3054 in one O-serogroup as two subgroups. PMID- 28342970 TI - Not in one metric: Neuroticism modulates different resting state metrics within distinctive brain regions. AB - INTRODUCTION: Neuroticism is a complex personality trait encompassing diverse aspects. Notably, high levels of neuroticism are related to the onset of psychiatric conditions, including anxiety and mood disorders. Personality traits are stable individual features; therefore, they can be expected to be associated with stable neurobiological features, including the Brain Resting State (RS) activity as measured by fMRI. Several metrics have been used to describe RS properties, yielding rather inconsistent results. This inconsistency could be due to the fact that different metrics portray different RS signal properties and that these properties may be differently affected by neuroticism. To explore the distinct effects of neuroticism, we assessed several distinct metrics portraying different RS properties within the same population. METHOD: Neuroticism was measured in 31 healthy subjects using the Zuckerman-Kuhlman Personality Questionnaire; RS was acquired by high-resolution fMRI. Using linear regression, we examined the modulatory effects of neuroticism on RS activity, as quantified by the Amplitude of low frequency fluctuations (ALFF, fALFF), regional homogeneity (REHO), Hurst Exponent (H), global connectivity (GC) and amygdalae functional connectivity. RESULTS: Neuroticism modulated the different metrics across a wide network of brain regions, including emotional regulatory, default mode and visual networks. Except for some similarities in key brain regions for emotional expression and regulation, neuroticism affected different metrics in different ways. DISCUSSION: Metrics more related to the measurement of regional intrinsic brain activity (fALFF, ALFF and REHO), or that provide a parsimonious index of integrated and segregated brain activity (HE), were more broadly modulated in regions related to emotions and their regulation. Metrics related to connectivity were modulated across a wider network of areas. Overall, these results show that neuroticism affects distinct aspects of brain resting state activity. More in general, these findings indicate that a multiparametric approach may be required to obtain a more detailed characterization of the neural underpinnings of a given psychological trait. PMID- 28342971 TI - A novel dual GLP-1/GIP receptor agonist alleviates cognitive decline by re sensitizing insulin signaling in the Alzheimer icv. STZ rat model. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder, accompanied by memory loss and cognitive impairments, and there is no effective treatment for it at present. Since type 2 diabetes (T2DM) has been identified as a risk factor for AD, the incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP), promising antidiabetic agents for the treatment of type 2 diabetes, have been tested in models of neurodegenerative disease including AD and achieved good results. Here we show for the first time the potential neuroprotective effect of a novel dual GLP-1/GIP receptor agonist (DA JC4) in the icv. streptozotocin (STZ)-induced AD rat model. Treatment with DA-JC4 (10nmol/kg ip.) once-daily for 14days after STZ intracerebroventricular (ICV) administration significantly prevented spatial learning deficits in a Y- maze test and Morris water maze tests, and decreased phosphorylated tau levels in the rat cerebral cortex and hippocampus. DA-JC4 also alleviated the chronic inflammation response in the brain (GFAP-positive astrocytes, IBA1-positive microglia). Apoptosis was reduced as shown in the reduced ratio of pro-apoptotic BAX to anti- apoptotic Bcl-2 levels. Importantly, insulin signaling was re sensitized as evidenced by a reduction of phospho-IRS1Ser1101 levels and phospho AktSer473 up-regulation. In conclusion, the novel dual agonist DA-JC4 shows promise as a novel treatment for sporadic AD, and reactivating insulin signaling pathways may be a key mechanism that prevents disease progression in AD. PMID- 28342972 TI - Remodeling the Th1 polarized systemic environment contributes to neurogenesis and cognitive function via the Wnt7a pathway in neonatal mice. AB - Neonatal Bacillus Calmette-Guerin (BCG) vaccination results in a positive effect on hippocampal neurogenesis and cognition. Serum cytokines are considered to be the chief culprit. In this study, serum from BCG-treated mice was identified as Th1 polarized serum. The serum showed an increased ratio of IFN-gamma to IL-4 and decreased levels of TNF-alpha and IL-6. After Th1 polarized serum was injected intraperitoneally into postnatal mice, the levels of cytokines and ratio of IFN gamma to IL-4 in the serum and hippocampus of postnatal mice showed a similar alteration as those in Th1 polarized serum. This result indicated that the immune homeostatic milieu in postnatal mice was broken and the Th1 polarized systemic environment in the BCG-serum group was remodeled. The BCG-serum group displayed more BrdU+/DCX+ cells, BrdU+/NeuN+ cells, Nestin+ cells and better cognitive abilities. In neural stem cells, the Wnt7a/beta-catenin signaling pathway was activated and exposure to the Wnt7a antagonist Dickkopf-1 inhibited BCG-serum induced Wnt7a/beta-catenin signaling, neurogenesis and cognitive function. Additionally, BCG-serum was associated with elevations in hippocampal brain derived neurotrophic factor (BDNF) levels, and BDNF expression in the BCG-serum group was offset by Dickkopf-1 treatment. By rebalancing the Th1 polarized systemic environment in neonatal mice, it is possible that treatment with BCG serum promotes hippocampal neurogenesis and improves cognitive functions, which are associated with Wnt7a/beta-catenin-BDNF signaling. PMID- 28342973 TI - Effects of a sustained release formulation of 1,25-dihydroxyvitamin D3-glycosides for milk fever prevention on serum 1,25-dihydroxyvitamin D3, calcium and phosphorus in dairy cows. AB - Milk fever (MF) is a metabolic disease in dairy cows around parturition. The clinical lead sign is muscular paresis leading in severe cases to paralysis of the affected animal. Multiparturient animals of high performing dairy breeds are most likely to be affected and have a high probability of recurrence. An acute drop in blood calcium levels causes the disease when the demand for calcium at the onset of lactation exceeds the ability to replete blood calcium levels through mobilization from bone and intestinal uptake. With the understanding of the underlying mechanism, calcium supply management and vitamin D supplementation became prime candidates for MF prevention and therapy. Several strategies have been developed for MF prevention. Application of the active form of Vitamin D, 1,25(OH)2D3, was found to prevent MF effectively. In order to prevent a delayed hypocalcemia, which was occasionally seen after stopping the treatment with 1,25(OH)2D3, a new approach was chosen by applying Solanum glaucophyllum extract (SGE), which contains 1,25(OH)2D3-glycosides, as instant-release (irSGE) in combination with slow-release (srSGE) tablets. In a first study, non-lactating cows were treated with a single bolus of either synthetic 1,25(OH)2D3, irSGE, or srSGE and the results were compared to a control group without treatment. Blood serum levels of 1,25(OH)2D3 (1,25D), calcium (Ca), phosphate (P) and magnesium (Mg) were followed for 11days and the area under the curve (AUC) was calculated. Calcium and phosphate excretion in urine were determined during 15days. While serum concentration of 1,25(OH)2D3 was back to pre-treatment level in the irSGE, srSGE and 1,25(OH)2D3 treated group within 3days, calcium and phosphate levels remained elevated for up to 9days. AUC of serum 1,25(OH)2D3 was 2.89 (1,25D), 3.13 (irSGE) and 4.21 (srSGE) times higher than control. Serum calcium levels were 1.07* (for 1.25D); 1.08* (for irSGE) and 1.12* (for srSGE) times higher than control. Serum phosphate levels were 1.20* (for 1,25D); 1.30* (for irSGE) and 1.41* (for srSGE) times higher than control, with * p<0.05. In a second field study calving cows treated with one bolus containing ir- and sr- tablets of SGE were compared to an untreated control group and to a group treated with 4 boli of commercial calcium salts. As a result, calcium serum levels increased (+19% compared to baseline) around calving after treatment with the single bolus of SGE. The single bolus of SGE lead also to an increase of serum phosphate (+31% compared to baseline). These calcium and phosphate increases were statistically significant (p<0.001) 0-24h after calving compared to the control group and to the group treated with calcium salts. The sample size of the study was too small to draw a conclusion on the effect on MF prevention. In conclusion, application of a single bolus of a SGE extract lead to an increase of serum calcium and phosphate for up to 9days and may thus have the potential to prevent a hypocalcemia and -phosphatemia, an important cause for clinical milk fever. PMID- 28342974 TI - After total knee replacement younger patients demonstrate superior balance control compared to older patients when recovering from a forward fall. AB - BACKGROUND: National joint replacement registries have reported a substantial growth in younger knee osteoarthritic patients (<55years old) undergoing total knee replacement, however this younger population is generally understudied. Importantly, studies examining experimentally controlled perturbation have shown age-related differences between younger and older healthy adults, whether similar age-related differences exist among total knee replacement patients is unknown. METHODS: A total of 59 participants, including 29 unilateral total knee replacement patients (six-months post-surgery) made up the four experimental groups: 1) younger patient (54.3 (SD 7.9) years), 2) younger control (55.2 (SD 4.0) years), 3) older patient (76.9 (SD 4.7) years), and 4) older control (77.7 (SD 4.1) years). Using a tether-release method to perturb balance and simulate a forward fall, center of mass and stepping characteristics were analyzed. FINDINGS: Younger patients recovered following the perturbation with a significantly smaller center of mass displacement compared to the older patients (14.85 (SD 0.01) v. 18.13 (SD 0.02) %ht, p=0.02); utilizing a longer (0.43 (SD 0.02) v. 0.39 (SD 0.03) m, p<0.001) and higher velocity (2.01 (SD 0.2) v. 1.59 (SD 0.2) m/s, p=0.001) recovery step. Importantly, younger patients did not differ significantly from the younger controls in center of mass displacement or recovery step characteristics (p>0.05). INTERPRETATION: The younger patients demonstrated superior center of mass control in response to a forward perturbation, suggesting that younger patients would be at a reduced risk of falling when recovering from a forward-directed postural perturbation compared to older patients. PMID- 28342975 TI - Biomechanical testing of a PEEK-based dynamic instrumentation device in a lumbar spine model. AB - BACKGROUND: The purpose of this study was to investigate the range-of-motion after posterior polyetheretherketone-based rod stabilisation combined with a dynamic silicone hinge in order to compare it with titanium rigid stabilisation. METHODS: Five human cadaveric lumbar spines with four vertebra each (L2 to L5) were tested in a temperature adjustable spine-testing set-up in four trials: (1) native measurement; (2) kinematics after rigid monosegmental titanium rod instrumentation with anterior intervertebral bracing of the segment L4/5; (3) kinematics after hybrid posterior polyetheretherketone rod instrumentation combined with a silicone hinge within the adjacent level (L3/4) and (4) kinematics after additional decompression with laminectomy of L4 and bilateral resection of the inferior articular processes (L3). During all steps, the specimens were loaded quasi-statically with 1 degrees /s with pure moment up to 7.5Nm in flexion/extension, lateral bending and axial rotation. FINDINGS: In comparison to the native cadaveric spine, both the titanium device and polyetheretherketone-based device reduce the range-of-motion within the level L4/5 significantly (flexion/extension: reduction of 77%, p<0.001; lateral bending: reduction of 62%, p<0.001; axial rotation: reduction of 71%, p<0.001). There was a clear stabilisation effect after hybrid-instrumentation within the level L3/4, especially in flexion/extension (64%, p<0.001) and lateral bending (62%, p<0.001) but without any effect on the axial rotation. Any temperature dependency has not been observed. INTERPRETATION: Surprisingly, the hybrid device compensates for laminectomy L4 and destabilising procedure within the level L3/4 in comparison to other implants. Further studies must be performed to show its effectiveness regarding the adjacent segment instability. PMID- 28342976 TI - Translating the microRNA signature of microvesicles derived from human coronary artery smooth muscle cells in patients with familial hypercholesterolemia and coronary artery disease. AB - AIMS: To analyze the impact of atherogenic lipoproteins on the miRNA signature of microvesicles derived from human coronary artery smooth muscle cells (CASMC) and to translate these results to familial hypercholesterolemia (FH) and coronary artery disease (CAD) patients. METHODS: Conditioned media was collected after exposure of CASMC to atherogenic lipoproteins. Plasma samples were collected from two independent populations of diagnosed FH patients and matched normocholesterolemic controls (Study population 1, N=50; Study population 2, N=24) and a population of patients with suspected CAD (Study population 3, N=50). Extracellular vesicles were isolated and characterized using standard techniques. A panel of 30 miRNAs related to vascular smooth muscle cell (VSMC) (patho )physiology was analyzed using RT-qPCR. RESULTS: Atherogenic lipoproteins significantly reduced levels of miR-15b-5p, -24-3p, -29b-3p, -130a-3p, -143-3p, 146a-3p, -222-3p, -663a levels (P<0.050) in microvesicles (0.1MUm-1MUm in diameter) released by CASMC. Two of these miRNAs, miR-24-3p and miR-130a-3p, were reduced in circulating microvesicles from FH patients compared with normocholesterolemic controls in a pilot study (Study population 1) and in different validation studies (Study populations 1 and 2) (P<0.050). Supporting these results, plasma levels of miR-24-3p and miR-130a-3p were also downregulated in FH patients compared to controls (P<0.050). In addition, plasma levels of miR 130a-3p were inversely associated with coronary atherosclerosis in a cohort of suspected CAD patients (Study population 3) (P<0.050). CONCLUSIONS: Exposure to atherogenic lipoproteins modifies the miRNA profile of CASMC-derived microvesicles and these alterations are reflected in patients with FH. Circulating miR-130a-3p emerges as a potential biomarker for coronary atherosclerosis. PMID- 28342978 TI - A new benzenediamine derivative modulates Toll-like receptors-induced myeloid dendritic cells activation and ameliorates lupus-like syndrome in MRLlpr/lpr mice. AB - Modulators of the over-activation of myeloid dendritic cells (mDCs) by Toll-like receptors (TLRs) have an advantage in the treatment of systemic lupus erythematosus (SLE). This study was designed to evaluate the effects of FC-99, a novel benzenediamine derivative, on TLR-induced activation of mDCs, and to assess the efficacy of FC-99 in a murine model of SLE. In vitro, FC-99 inhibited the phenotypic (CD40 and MHC-II) and functional activation (IL-12 and CXCL10) of mDCs induced by TLR ligands. In vivo, MRLlpr/lpr mice displayed renal diseases associated with increased levels of proteinuria and immunoglobulin, which were ameliorated by FC-99. Enhanced accumulation and activation of mDCs in lymphoid organs was also impaired by FC-99. Additionally, FC-99 inhibited the activation of IkappaB-alpha and upregulated the expression of TNFalpha-induced protein 3 (TNFAIP3) in vitro and in vivo. These results indicate that FC-99 modulates TLR induced activation of mDCs and ameliorates lupus-like syndrome in MRLlpr/lpr mice. This effect is closely associated with the inhibition of IkappaB-alpha and upregulation of TNFAIP3. PMID- 28342977 TI - The role of miR-2~13~71 cluster in resistance to deltamethrin in Culex pipiens pallens. AB - Excessive and continuous application of deltamethrin has resulted in the development of deltamethrin resistance among mosquitoes, which becomes a major obstacle for mosquito control. In a previous study, differentially expressed miRNAs between deltamethrin-susceptible (DS) strain and deltamethrin-resistant (DR) strain using illumina sequencing in Culex pipiens pallens were identified. In this study, we applied RNAi and the Centers for Disease Control and Prevention (CDC) bottle bioassay to investigate the relationship between miR-2~13~71 cluster (miR-2, miR-13 and miR-71) and deltamethrin resistance. We used quantitative real time PCR (qRT-PCR) to measure expression levels of miR-2~13~71 clusters. MiR 2~13~71 cluster was down regulated in adult female mosquitoes from the DR strain and played important roles in deltamethrin resistance through regulating target genes, CYP9J35 and CYP325BG3. Knocking down CYP9J35 and CYP325BG3 resulted in decreased mortality of DR mosquitoes. This study provides the first evidence that miRNA clusters are associated with deltamethrin resistance in mosquitoes. Moreover, we investigated the regulatory networks formed between miR-2~13~71 cluster and its target genes, which provide a better understanding of the mechanism involved in deltamethrin resistance. PMID- 28342979 TI - Guggulsterone sensitized drug-resistant human hepatocarcinoma cells to doxorubicin through a Cox-2/P-gp dependent pathway. AB - Previous researches indicated that cyclooxygenase-2 (Cox-2) might be involved in P-glycoprotein (P-gp)-mediated multidrug resistance in hepatocellular carcinoma cells. Doxorubicin-resistant hepatocellular carcinoma PLC/PRF/5 cells (PLC/PRF/5R) and HepG2 (HepG2R) cells were developed in the present study. The modulatory effect of guggulsterone on Cox-2 and P-gp in PLC/PRF/5R and HepG2R cells was investigated. Cells proliferation, Cox-2 and P-gp expression, and prostaglandin E2 release were examined using MTT, flow cytometry, western blot and ELISA assays. Small interfering RNA (siRNA) targeted against Cox-2 and multidrug resistance protein (Mdr-1) was used to regulate the expression of Cox-2 and P-gp. The results showed that co-administration of guggulsterone resulted in a significant increase in chemo-sensitivity of PLC/PRF/5R cells to doxorubicin, as compared with doxorubicin treatment alone. When doxorubicin (10uM) was combined with guggulsterone (50uM), the mean apoptotic population of PLC/PRF/5R cells was 20.16%. It was increased by 1.5 times, as compared with doxorubicin (10uM) treatment alone. Furthermore, guggulsterone had significantly inhibitory effect on the levels of Cox-2, P-gp and prostaglandin E2. However, guggulsterone did not show significantly inhibitory effect on the expression of prostaglandin E receptors. In addition, Cox-2 siRNA simultaneously reduced the expression of Cox 2 and P-gp in PLC/PRF/5R cells. Mdr-1 siRNA had no influence on Cox-2, but inhibited P-gp expression. The present study suggested that guggulsterone might enhance the cytotoxic effect of doxorubicin to PLC/PRF/5R cells through a Cox-2/P gp dependent pathway. PMID- 28342980 TI - Muscarinic receptor mediated signaling pathways in hepatocytes from CCL4 - induced liver fibrotic rat. AB - The pathological changes of parasympathetic nerves are considered as an independent prognostic factor of the survival rate for patients with chronic liver disease. The non-selective muscarinic acetylcholine receptors (mAchR) agonists and antagonists can affect the proliferation of hepatocytes, but little is known about the role of mAChR in hepatocytes and hepatic fibrosis and the signaling pathway of this receptor in regulation of hepatocytes remains elusive. Here, 3ml/kg 40% carbon tetrachloride (CCL4) was given to induce hepatic fibrosis in rats and the hepatocytes were isolated to investigate the expression of mAchR and the cell signaling pathways which were involved in. Compared with the normal state, the expression levels of m1, 3, 5 in fibrotic hepatocytes (FHC) and the cells treated with 10MUM pilocarpine (Pi) were obviously increased, while decreased in m2,4. Pi could increase the value of alanine aminotransferase (ALT), hydroxyproline (Hyp), decrease albumin (ALB) and cell viability, while atropine could ameliorate fibrotic hepatocytes fuction. The p-AKT, p-ERK, p- JNK and p-P38 increased in Pi group or FHC group, but the inhibitors of PI3K, MAPK and PKC could reverse the Pi action and improve the FHC fuction. In this study we found that mAchR played an important role in the regulation of hepatic fibrosis process and the PKC, ERK, P38 and PI3K/AKT signaling pathways involved in the parasympathetic excitation mediated by mAchR. PMID- 28342981 TI - Mechanisms of in vivo release of triamcinolone acetonide from PLGA microspheres. AB - Little is known about the underlying effects controlling in vitro-in vivo correlations (IVIVCs) for biodegradable controlled release microspheres. Most reports of IVIVCs that exist are empirical in nature, typically based on a mathematical relationship between in vitro and in vivo drug release, with the latter often estimated by deconvolution of pharmacokinetic data. In order to improve the ability of in vitro release tests to predict microsphere behavior in vivo and develop more meaningful IVIVCs, the in vivo release mechanisms need to be characterized. Here, two poly(lactic-co-glycolic acid) (PLGA) microsphere formulations encapsulating the model steroid triamcinolone acetonide (Tr-A) were implanted subcutaneously in rats by using a validated cage model, allowing for free fluid and cellular exchange and microsphere retrieval during release. Release kinetics, as well as mechanistic indicators of release such as hydrolysis and mass loss, was measured by direct analysis of the recovered microspheres. Release of Tr-A from both formulations was greatly accelerated in vivo compared to in vitro using agitated phosphate buffered saline +0.02% Tween 80 pH7.4, including rate of PLGA hydrolysis, mass loss and water uptake. Both microsphere formulations exhibited erosion-controlled release in vitro, indicated by similar polymer mass loss kinetics, but only one of the formulations (low molecular weight, free acid terminated) exhibited the same mechanism in vivo. The in vivo release of Tr-A from microspheres made of a higher molecular weight, ester end capped PLGA displayed an osmotically induced/pore diffusion mechanism based on confocal micrographs of percolating pores in the polymer, not previously observed in vitro. This research indicates the need to fully understand the in vivo environment and how it causes drug release from biodegradable microspheres. This understanding can then be applied to develop in vitro release tests which better mimic this environment and cause drug release by the relevant mechanistic processes, ultimately leading to the development of mechanism based IVIVCs. PMID- 28342982 TI - Mastocarcinoma therapy synergistically promoted by lysosome dependent apoptosis specifically evoked by 5-Fu@nanogel system with passive targeting and pH activatable dual function. AB - This manuscript describes a synergistic therapy for mastocarcinoma by pH and temperature dual-sensitive nanogel, and effects of microstructure, composition and properties of nanogel on the cellular response mechanism. The extracellular internalization of nanogels was obviously enhanced, due to the passive targeting function at T>VPTT. Interestingly, the increased cytotoxicity was further synergistically enhanced by an unexpected apoptosis as evoked by the 5 fluorouracil loaded nanogel (FLNG). The systemically evaluation of the effectors generated from different sub-cellular organelles including endosome, lysosome, autophagosome confirmed that it was a lysomal dependent apoptosis. Such specific apoptosis was mainly attributed to its activatable protonated PEI at low pH, which caused lysosomal membrane destruction and lysosomal enzyme cathepsin B (Cat B) leakage. This Cat B was then translocated to the mitochondria resulting in mitochondrial membrane permeability increase and mitochondrial membrane potential (MMP) decrease, followed by cytochrome c (Cyt C) release. Cyt C was the main molecule that evoked apoptosis as reflected by overexpression of caspase 9. Additionally, such lysosome dependent, apoptosis was further enhanced by the passive cellular targeting at T>VPTT. Thus, the tumor growth inhibition was synergistically enhanced by the extracellular temperature dependent passive targeting and intracellular pH activatable lysosomal dependent apoptosis. PMID- 28342984 TI - HDAC4 and HDAC6 sustain DNA double strand break repair and stem-like phenotype by promoting radioresistance in glioblastoma cells. AB - The role of histone deacetylase (HDAC) 4 and 6 in glioblastoma (GBM) radioresistance was investigated. We found that tumor samples from 31 GBM patients, who underwent temozolomide and radiotherapy combined treatment, showed HDAC4 and HDAC6 expression in 93.5% and 96.7% of cases, respectively. Retrospective clinical data analysis demonstrated that high-intensity HDAC4 and/or HDAC6 immunostaining was predictive of poor clinical outcome. In vitro experiments revealed that short hairpin RNA-mediated silencing of HDAC4 or HDAC6 radiosensitized U87MG and U251MG GBM cell lines by promoting DNA double-strand break (DSBs) accumulation and by affecting DSBs repair molecular machinery. We found that HDAC6 knock-down predisposes to radiation therapy-induced U251MG apoptosis- and U87MG autophagy-mediated cell death. HDAC4 silencing promoted radiation therapy-induced senescence, independently by the cellular context. Finally, we showed that p53WT expression contributed to the radiotherapy lethal effects and that HDAC4 or HDAC6 sustained GBM stem-like radioresistant phenotype. Altogether, these observations suggest that HDAC4 and HDAC6 are guardians of irradiation-induced DNA damages and stemness, thus promoting radioresistance, and may represent potential prognostic markers and therapeutic targets in GBM. PMID- 28342985 TI - Mast cells are directly activated by contact with cancer cells by a mechanism involving autocrine formation of adenosine and autocrine/paracrine signaling of the adenosine A3 receptor. AB - Mast cells (MCs) constitute an important part of the tumor microenvironment (TME). However, their underlying mechanisms of activation within the TME remain poorly understood. Here we show that recapitulating cell-to-cell contact interactions by exposing MCs to membranes derived from a number of cancer cell types, results in MC activation, evident by the increased phosphorylation of the ERK1/2 MAP kinases and Akt, in a phosphatidylinositol 3-kinase dependent fashion. Activation is unidirectional since MC derived membranes do not activate cancer cells. Stimulated ERK1/2 phosphorylation is strictly dependent on the ecto enzyme CD73 that mediates autocrine formation of adenosine, and is inhibited by knockdown of the A3 adenosine receptor (A3R) as well as by an A3R antagonist or by agonist-stimulated down-regulation of the A3R. We also show that cancer cell mediated triggering upregulates expression and stimulates secretion of interleukin 8 from the activated MCs. These findings provide evidence for a novel mode of unidirectional crosstalk between MCs and cancer cells implicating direct activation by cancer cells in MC reprogramming into a pro tumorigenic profile. PMID- 28342983 TI - Lipid quantification by Raman microspectroscopy as a potential biomarker in prostate cancer. AB - Metastatic castration-resistant prostate cancer (mCRPC) remains incurable and is one of the leading causes of cancer-related death among American men. Therefore, detection of prostate cancer (PCa) at early stages may reduce PCa-related mortality in men. We show that lipid quantification by vibrational Raman Microspectroscopy and Biomolecular Component Analysis may serve as a potential biomarker in PCa. Transcript levels of lipogenic genes including sterol regulatory element-binding protein-1 (SREBP-1) and its downstream effector fatty acid synthase (FASN), and rate-limiting enzyme acetyl CoA carboxylase (ACACA) were upregulated corresponding to both Gleason score and pathologic T stage in the PRAD TCGA cohort. Increased lipid accumulation in late-stage transgenic adenocarcinoma of mouse prostate (TRAMP) tumors compared to early-stage TRAMP and normal prostate tissues were observed. FASN along with other lipogenesis enzymes, and SREBP-1 proteins were upregulated in TRAMP tumors compared to wild-type prostatic tissues. Genetic alterations of key lipogenic genes predicted the overall patient survival using TCGA PRAD cohort. Correlation between lipid accumulation and tumor stage provides quantitative marker for PCa diagnosis. Thus, Raman spectroscopy-based lipid quantification could be a sensitive and reliable tool for PCa diagnosis and staging. PMID- 28342986 TI - Oncogenic roles of DNA hypomethylation through the activation of cancer-germline genes. AB - Global loss of DNA methylation is frequently observed in the genome of human tumors. Although this epigenetic alteration is clearly associated with cancer progression, the way it exerts its pro-tumoral effect remains incompletely understood. A remarkable consequence of DNA hypomethylation in tumors is the aberrant activation of "cancer-germline" genes (also known as "cancer-testis" genes), which comprise a diverse group of germline-specific genes that use DNA methylation as a primary mechanism for repression in normal somatic tissues. Here we review the evidence that such cancer-germline genes contribute to key processes of tumor development. Notably, several cancer-germline genes were found to stimulate oncogenic pathways involved in cell proliferation (SSX, DDX43, MAEL, PIWIL1), angiogenesis (DDX53), immortality (BORIS/CTCFL), and metastasis (CT GABRA3). Others appear to inhibit tumor suppressor pathways, including those controlling growth inhibition signals (MAGEA11, MAGEB2), apoptosis (MAGEA2, MAGEC2), and genome integrity (HORMAD1, NXF2). Cancer-germline genes were also implicated in the regulation of tumor metabolism (MAGEA3/MAGEA6). Together, our survey substantiates the concept that DNA hypomethylation promotes tumorigenesis via transcriptional activation of oncogenes. Importantly, considering their highly restricted pattern of expression, cancer-germline genes may represent valuable targets for the development of anti-cancer therapies with limited side effects. PMID- 28342987 TI - Circular RNAs and cancer. AB - Circular RNAs (circRNAs) are a type of non-coding RNA molecules that lack a 5' terminal cap and 3'-terminal poly A tail. A large number of circRNAs have been identified through biological experiments, computational methods and high throughput sequencing. CircRNA sequence composition determines if a given circRNA is exonic, intronic or retained-intronic. CircRNAs are more abundant and stable than linear mRNAs, and their expression is both step- and location-specific. CircRNAs mediate transcriptional and post-transcriptional regulation of gene and protein expression. CircRNAs regulate cancer development via multiple mechanisms, including miRNA sponges, modulating Wnt signaling pathway and epithelial mesenchymal transition. An in-depth study of circRNA will provide a better understanding of carcinogenesis and assist in developing clinical diagnostic and therapeutic strategies. PMID- 28342988 TI - An anti-inflammatory dietary intervention to reduce breast cancer recurrence risk: Study design and baseline data. AB - U.S. breast cancer survivors (BCSs) are expected to increase to 4 million in the next 5-10years. Cancer recurrence risk is highest among obese survivors. Inflammatory (Pro-I) biomarkers including C-reactive protein (CRP), Interleukins 3, -6, and -8 (IL-3, IL-6, IL-8), and Tumor Necrosis Factor (TNF)-alpha have been associated with cancer recurrence risk. Nutritional interventions aimed at reducing inflammation (INF) may contribute to reduced cancer recurrence risk, but studies have been limited to animal models. The goals of this one-year, culinary based, pilot intervention were to: 1) decrease Pro-I biomarkers and increase anti inflammatory (AI) cytokine, IL-10, by promoting AI food incorporation into BCS diets; and 2) examine intervention effects on cancer risk factors including body mass index (BMI) and circulating adipose stromal cells (ASCs). A total of 153 BCSs were recruited. Overweight and obese women aged 18 or older were randomized into Intervention (IG; n=76) and Control (CG; n=77) groups. CG received monthly nutritional brochures from the American Institute for Cancer Research. IG attended 6 monthly workshops (lectures on AI topics and chef-prepared food demonstrations), and received monthly newsletters and telephone calls incorporating Motivational Interviewing. At baseline, 6- and 12-month assessments, fasting serum was assayed for Pro-I/AI marker and ASC levels. Using R and Stata version 14 (Stata Corp, 2015), no significant differences were found between groups on baseline demographic variables. Correlations between serum cytokine levels, BMI, % body fat, ASCs, and self-reported variables are discussed. PMID- 28342991 TI - Transformation of 17alpha-ethinylestradiol by simultaneous photo-enzymatic process in Humic water. AB - The fate of estrogens in surface water is mainly dependent on two processes, i.e. photodegradation and biotransformation. Each of the separate process is invariably of interest, but research on the combination of the two processes has rarely been explored. In the present work, the transformation of 17alpha ethinylestradiol (EE2) by simultaneous photochemical and enzymatic process in water was systematically investigated. The combined transformation rate of EE2 (0.057 h-1) in the presence of natural organic matter (NOM) and horseradish peroxidase (HRP) under simulated sunlight irradiation was markedly faster than that in the presence of NOM only (0.032 h-1). Similar pattern was also observed in real water matrix sampled from Taihu Lake. Further study revealed that the photodegradation and enzymatic transformation of EE2 were dramatically affected by NOM concentrations ranging from 0 to 20 mgC L-1. NOM was found to invariably accelerate the photodegradation of EE2 with increasing concentration. On the contrary, the transformation rate of EE2 mediated by HRP was decreased along with the increase of NOM concentration. The reason may be that HRP was prone to be inactivated in solution with high NOM concentration. The transformation experiment of EE2 at ambient level under sunlight confirmed the significant contribution of HRP to the degradation of EE2 in the presence of NOM. The results indicated that oxidation mediated by HRP was an essential fate of EE2 and other congener contaminants in aquatic environment. PMID- 28342990 TI - Telephone-adapted Mindfulness-based Stress Reduction (tMBSR) for patients awaiting kidney transplantation. AB - BACKGROUND: Patients with progressive kidney disease experience increasing physiologic and psychosocial stressors and declining health-related quality of life (HRQOL). METHODS: We conducted a randomized, active-controlled, open-label trial to test whether a Mindfulness-based Stress Reduction (MBSR) program delivered in a novel workshop-teleconference format would reduce symptoms and improve HRQOL in patients awaiting kidney transplantation. Sixty-three transplant candidates were randomized to one of two arms: i) telephone-adapted MBSR (tMBSR, an 8-week program of meditation and yoga); or ii) a telephone-based support group (tSupport). Participants completed self-report questionnaires at baseline, post intervention, and after 6-months. Anxiety, measured by the State-Trait Anxiety Inventory (STAI) post-intervention served as the primary outcome. Secondary outcomes included: depression, sleep quality, pain, fatigue, and HRQOL assessed by SF-12 Physical and Mental Component Summaries (PCS, MCS). RESULTS: 55 patients (age 54+/-12yrs) attended their assigned program (tMBSR, n=27; tSupport, n=28). 49% of patients had elevated anxiety at baseline. Changes in anxiety were small and did not differ by treatment group post-intervention or at follow-up. However, tMBSR significantly improved mental HRQOL at follow-up: +6.2 points on the MCS - twice the minimum clinically important difference (95% CI: 1.66 to 10.8, P=0.01). A large percentage of tMBSR participants (>=90%) practiced mindfulness and reported it helpful for stress management. CONCLUSIONS: Neither mindfulness training nor a support group resulted in clinically meaningful reductions in anxiety. In contrast, finding that tMBSR was more effective than tSupport for bolstering mental HRQOL during the wait for a kidney transplant is encouraging and warrants further investigation. ClinicalTrials.govNCT01254214. PMID- 28342992 TI - Estimating removals of contaminants of emerging concern from wastewater treatment plants: The critical role of wastewater hydrodynamics. AB - Accurate data is needed to evaluate the capacity of wastewater treatments plants (WWTPs) to remove contaminants of emerging concern (CECs). The variability of CEC removals reported in the literature has raised questions about the methods used to estimate removals. In this study, we used the recently proposed "fractionated approach" to account for the influence of hydrodynamics in WWTPs and applied this method for estimating the removal of 23 target CECs. Data on the conductivity and temperature of wastewater at two WWTPs were used to determine the hydraulic model that best described the flow regime of treatment units. Composite samples (24-h) were collected at different stages of treatment over successive days. The concentrations of the target compounds in wastewater were determined by liquid chromatography with mass spectrometry. Different hydraulic models were necessary to define the hydrodynamics at the two WWTPs, resulting in different load fractions to be used in the calculation of removals. For WWTP A, that has a primary clarifier, all target CECs, except triclosan, were poorly removed during this step at efficiencies <30%. On the other hand, the activated sludge treatment unit at both WWTPs removed most target CECs at >70%. This study expanded the application of the fractionated approach to compare the hydraulics of two treatment trains of different configurations, including primary and secondary treatment. It demonstrated the sensitivity of the method to account for variations between the different treatment units. Reliable removals of an extended list of CECs in primary and secondary treatment were also provided in this study. PMID- 28342989 TI - Patient engagement and study design of PROP UP: A multi-site patient-centered prospective observational study of patients undergoing hepatitis C treatment. AB - BACKGROUND: New highly efficacious direct-acting antiviral (DAA) therapies are available to treat chronic hepatitis C viral (HCV) infection. Real-world, patient centered data on harms and benefits associated with these therapies are needed. METHODS: PROP UP is a multi-center prospective observational study that plans to enroll 1600 patients starting treatment with recently-approved DAA regimens. Informed by extensive input from a HCV patient engagement group who prioritized outcomes most important to them, patient-reported outcomes will be characterized using surveys at five time points: Baseline (T1), treatment week 4 (T2), end of treatment (T3), 12weeks post-treatment (T4), 12months post-treatment (T5). OUTCOMES: (1) Changes in side effects, functioning, pre-existing conditions, and out-of-pocket costs during therapy (T1 vs T2/T3); (2) Medication adherence in relation to a history of mental health/substance abuse, treatment regimens, pill burden, reasons for missed doses, and cure rates; (3) Short term impact of cure on functioning and amelioration of symptoms (T1 vs T4); (4) Long-term treatment harms or benefits of cure on symptoms, side effects, pre-existing conditions, and functioning (T1 vs T5). Similarities between regimens will be examined where comparisons are appropriate and meaningful. CONCLUSION: PROP UP complements previous clinical trials by focusing on patient-reported outcomes in a representative sample of patients treated in clinical practice, by collaborating with a patient engagement group, by characterizing the experiences of vulnerable subgroups, and by investigating long-term harms and benefits of treatments. PROP UP is designed to provide novel and detailed information to support informed decision-making for patients and providers contemplating HCV treatment (PCORI CER 1408-20,660; NCT02601820). PMID- 28342993 TI - Teratogenic responses of zebrafish embryos to decabromodiphenyl ether (BDE-209) in the presence of nano-SiO2 particles. AB - This study investigated the influence of nano-SiO2 particles (nSiO2) on the teratogenic responses of zebrafish embryos to decabromodiphenyl ether (BDE-209). Zebrafish embryos were exposed to BDE-209 in the absence and presence of nSiO2 for 96 h post fertilization (hpf). Results showed that formation of nSiO2-BDE-209 associates promoted both extracellular and intracellular uptake of BDE-209 by zebrafish embryos, thereby increasing the bioconcentration of BDE-209 on the chorion surface and the embryos. Results also showed embryos delay hatching temporarily when co-exposure to BDE-209 and nSiO2 at 60 hpf. Furthermore, there was heartbeat decline (28.3 beats/10s) and increase in irregular heartbeat (45.8%) in zebrafish larvae at 96 hpf, compared to the sole exposure to BDE-209 (32.7 beats/10s and 0%). Malformation in terms of spinal curvature (SC), pericardial edema (PE) and yolk sac edema (YSE) were observed on zebrafish larvae at 33.9, 23.4, and 18%, respectively. Overall, abnormal development of zebrafish was apparent when co-exposure to BDE-209 and nSiO2. All relevant evidence considered, nSiO2 could facilitate the transport of BDE-209 towards zebrafish embryos and negatively impact the development of zebrafish. PMID- 28342994 TI - Persistent organic pollutants (POPs) in the atmosphere of coastal areas of the Ross Sea, Antarctica: Indications for long-term downward trends. AB - Passive air samplers were used to evaluate long-term trends and spatial distribution of trace organic compounds in Antarctica. Duplicate PUF disk samplers were deployed at six automatic weather stations in the coastal area of the Ross sea (East Antarctica), between December 2010 and January 2011, during the XXVI Italian Scientific Research Expedition. Among the investigated persistent organic compounds, Hexachlorobenzene was the most abundant, with air concentrations ranging from 0.8 to 50 pg m-3. In general, the following decreasing concentration order was found for the air samples analyzed: HCB > PeCB > PCBs > DDTs > HCHs. While HCB concentrations were in the same range as those reported in the atmosphere of other Antarctic sampling areas and did not show a decline, HCHs and DDTs levels were lower or similar to those determined one or two decades ago. In general, the very low concentrations reflected the pristine state of the East Antarctica air. Backward trajectories indicated the prevalence of air masses coming from the Antarctic continent. Local contamination and volatilization from ice were suggested as potential sources for the presence of persistent organic pollutants in the atmosphere. PMID- 28342995 TI - Mechanisms of metal sorption by biochars: Biochar characteristics and modifications. AB - Biochar produced by thermal decomposition of biomass under oxygen-limited conditions has received increasing attention as a cost-effective sorbent to treat metal-contaminated waters. However, there is a lack of information on the roles of different sorption mechanisms for different metals and recent development of biochar modification to enhance metal sorption capacity, which is critical for biochar field application. This review summarizes the characteristics of biochar (e.g., surface area, porosity, pH, surface charge, functional groups, and mineral components) and main mechanisms governing sorption of As, Cr, Cd, Pb, and Hg by biochar. Biochar properties vary considerably with feedstock material and pyrolysis temperature, with high temperature producing biochars with higher surface area, porosity, pH, and mineral contents, but less functional groups. Different mechanisms dominate sorption of As (complexation and electrostatic interactions), Cr (electrostatic interactions, reduction, and complexation), Cd and Pb (complexation, cation exchange, and precipitation), and Hg (complexation and reduction). Besides sorption mechanisms, recent advance in modifying biochar by loading with minerals, reductants, organic functional groups, and nanoparticles, and activation with alkali solution to enhance metal sorption capacity is discussed. Future research needs for field application of biochar include competitive sorption mechanisms of co-existing metals, biochar reuse, and cost reduction of biochar production. PMID- 28342997 TI - The author's reply to N.R. Haddaway. AB - In this reply we respond to the commentary of Dr. Haddaway addressed in searching for pitfalls in our systematic mapping exercise "Collating science-based evidence to inform public opinion on the environmental effects of marine drilling platforms in the Mediterranean Sea" recently published in Journal of Environmental Management (Mangano, M.C. and Sara, G. 2017. Journal of Environmental Management 188: 195-202). We discussed each so called "pitfalls" and, in our opinion, the main cornerstones of systematic map - SM (repeatability, comprehensiveness, transparency, traceability, quality, generalizability) are safe guaranteeing the "gold standard" required by this technique. Where needed we explain our position in doing a "tailoring" of some steps, and we stressed the differences among our approach and a SM protocol. We also stressed the importance of our main message, to select the most rigorous approach (evidence-based), to create a credible, salient and effective knowledge baseline to inform end users and guarantee the creation of a solid science-policy nexus (here specifically we provided a final review product, an easy to follow up graphical evidence). PMID- 28342996 TI - Induction of Neuroendocrine Differentiation in Prostate Cancer Cells by Dovitinib (TKI-258) and its Therapeutic Implications. AB - Prostate cancer (PCa) remains the second-leading cause of cancer-related deaths in American men with an estimated mortality of more than 26,000 in 2016 alone. Aggressive and metastatic tumors are treated with androgen deprivation therapies (ADT); however, the tumors acquire resistance and develop into lethal castration resistant prostate cancer (CRPC). With the advent of better therapeutics, the incidences of a more aggressive neuroendocrine prostate cancer (NEPC) variant continue to emerge. Although de novo occurrences of NEPC are rare, more than 25% of the therapy-resistant patients on highly potent new-generation anti-androgen therapies end up with NEPC. This, along with previous observations of an increase in the number of such NE cells in aggressive tumors, has been suggested as a mechanism of resistance development during prostate cancer progression. Dovitinib (TKI-258/CHIR-258) is a pan receptor tyrosine kinase (RTK) inhibitor that targets VEGFR, FGFR, PDGFR, and KIT. It has shown efficacy in mouse-model of PCa bone metastasis, and is presently in clinical trials for several cancers. We observed that both androgen receptor (AR) positive and AR-negative PCa cells differentiate into a NE phenotype upon treatment with Dovitinib. The NE differentiation was also observed when mice harboring PC3-xenografted tumors were systemically treated with Dovitinib. The mechanistic underpinnings of this differentiation are unclear, but seem to be supported through MAPK-, PI3K-, and Wnt-signaling pathways. Further elucidation of the differentiation process will enable the identification of alternative salvage or combination therapies to overcome the potential resistance development. PMID- 28342998 TI - Field evaluation of Cucurbit yellow stunting disorder virus transmission by Bemisia tabaci. AB - Cucurbit yellow stunting disorder virus (CYSDV) is a whitefly-transmitted Crinivirus (Closteroviridae) that impacts melon production in many parts of the world including the USA. It has been responsible for melon crop loss in the southwestern U.S. since 2006 when it was first identified. Control strategies have revolved mainly around chemical control, but research to identify suitable products and approaches to implementing them have lagged. The current study investigated the performance of four systemic insecticides in the field while concurrently tracking CYSDV disease progression after controlled and natural whitefly inoculation of young melon plants. Assessments of virus incidence were made using two different visual observation methods in concert with ELISA analyses of leaf disks samples collected biweekly. Infection rates were consistently lowest in plots treated with the butenolide insecticide flupyradifurone while dinotefuran was second in efficacy measures. Flupyradifurone also held whitefly densities to their lowest numbers relative to the other treatments. Two other insecticides, imidacloprid and cyantraniliprole, exacerbated virus incidence in multiple trials. Further investigation into the anomalous finding of increased virus incidence due to insecticide application is ongoing. PMID- 28342999 TI - Hippocampal CA3-dentate gyrus volume uniquely linked to improvement in associative memory from childhood to adulthood. AB - Associative memory develops into adulthood and critically depends on the hippocampus. The hippocampus is a complex structure composed of subfields that are functionally-distinct, and anterior-posterior divisions along the length of the hippocampal horizontal axis that may also differ by cognitive correlates. Although each of these aspects has been considered independently, here we evaluate their relative contributions as correlates of age-related improvement in memory. Volumes of hippocampal subfields (subiculum, CA1-2, CA3-dentate gyrus) and anterior-posterior divisions (hippocampal head, body, tail) were manually segmented from high-resolution images in a sample of healthy participants (age 8 25 years). Adults had smaller CA3-dentate gyrus volume as compared to children, which accounted for 67% of the indirect effect of age predicting better associative memory via hippocampal volumes. Whereas hippocampal body volume demonstrated non-linear age differences, larger hippocampal body volume was weakly related to better associative memory only when accounting for the mutual correlation with subfields measured within that region. Thus, typical development of associative memory was largely explained by age-related differences in CA3 dentate gyrus. PMID- 28343000 TI - Evidence for similar patterns of neural activity elicited by picture- and word based representations of natural scenes. AB - A long-standing core question in cognitive science is whether different modalities and representation types (pictures, words, sounds, etc.) access a common store of semantic information. Although different input types have been shown to activate a shared network of brain regions, this does not necessitate that there is a common representation, as the neurons in these regions could still differentially process the different modalities. However, multi-voxel pattern analysis can be used to assess whether, e.g., pictures and words evoke a similar pattern of activity, such that the patterns that separate categories in one modality transfer to the other. Prior work using this method has found support for a common code, but has two limitations: they have either only examined disparate categories (e.g. animals vs. tools) that are known to activate different brain regions, raising the possibility that the pattern separation and inferred similarity reflects only large scale differences between the categories or they have been limited to individual object representations. By using natural scene categories, we not only extend the current literature on cross-modal representations beyond objects, but also, because natural scene categories activate a common set of brain regions, we identify a more fine-grained (i.e. higher spatial resolution) common representation. Specifically, we studied picture- and word-based representations of natural scene stimuli from four different categories: beaches, cities, highways, and mountains. Participants passively viewed blocks of either phrases (e.g. "sandy beach") describing scenes or photographs from those same scene categories. To determine whether the phrases and pictures evoke a common code, we asked whether a classifier trained on one stimulus type (e.g. phrase stimuli) would transfer (i.e. cross-decode) to the other stimulus type (e.g. picture stimuli). The analysis revealed cross-decoding in the occipitotemporal, posterior parietal and frontal cortices. This similarity of neural activity patterns across the two input types, for categories that co activate local brain regions, provides strong evidence of a common semantic code for pictures and words in the brain. PMID- 28343001 TI - Comprehensive functional analysis of large lists of genes and proteins. AB - The interpretation of high dimensional datasets resulting from genomic and proteomic experiments in a timely and efficient manner is challenging. ClueGO software is a Cytoscape App that extracts representative functional biological information for large lists of genes or proteins. The functional enrichment analysis is based on the latest publicly available data from multiple annotation and ontology resources that can be automatically accessed through ClueGO. Predefined settings for the selection of the terms are provided to facilitate the analysis. Results are visualized as networks in which Gene Ontology (GO) terms and pathways are grouped based on their biological role. Many species are now supported by ClueGO and additional organisms are added on demand. ClueGO can be used together with the CluePedia App to enable the visualization of protein protein interactions within or between pathways. PMID- 28343002 TI - Pulmonary metastatic angiosarcoma from scalp with fatal complication: A case report. AB - INTRODUCTION: Angiosarcoma is a rare malignant neoplasm with poor prognosis. Angiosarcoma of the scalp is frequently recurs locally, and metastasizes early despite various treatments. The common sites of metastatic are lung, liver, and lymph nodes. Pulmonary metastasis with hemoptysis and pneumothorax is rare but threatening. PRESENTATION OF CASE: A 77-year-old male had recurrent angiosarcoma of the scalp even with post operation radiotherapy. At the same time, recurrent pneumothorax was noted, thus he underwent wedge resection of the right upper lobe of the lung plus pleural biopsy. The final pathologic report of cystic lesions showed metastatic Angiosarcoma. He received intravenous paclitaxel and the lung lesions dramatically diminished subsequently. DISCUSSION: Pulmonary metastasis from soft tissue sarcoma had fatal complications and poor prognosis. Metastases of AS to the lung have a well-described morphology on CT scan, but appear to be hypometabolic on PET scan and are easily misinterpreted as benign cysts. CONCLUSION: Angiosarcoma is a rare but highly vascular invasive endothelial tumor that generally metastasizes to the lung. It could cause repeated hemoptysis pneumothorax and pleural effusion. Preoperative chest CT may be recommended routinely. Aggressive treatment resulted in not only symptoms control but also good prognosis. PMID- 28343004 TI - Actively controlled release of Dexamethasone from neural microelectrodes in a chronic in vivo study. AB - Stable interconnection to neurons in vivo over long time-periods is critical for the success of future advanced neuroelectronic applications. The inevitable foreign body reaction towards implanted materials challenges the stability and an active intervention strategy would be desirable to treat inflammation locally. Here, we investigate whether controlled release of the anti-inflammatory drug Dexamethasone from flexible neural microelectrodes in the rat hippocampus has an impact on probe-tissue integration over 12 weeks of implantation. The drug was stored in a conducting polymer coating (PEDOT/Dex), selectively deposited on the electrode sites of neural probes, and released on weekly basis by applying a cyclic voltammetry signal in three electrode configuration in fully awake animals. Dex-functionalized probes provided stable recordings and impedance characteristics over the entire chronic study. Histological evaluation after 12 weeks of implantation revealed an overall low degree of inflammation around all flexible probes whereas electrodes exposed to active drug release protocols did have neurons closer to the electrode sites compared to controls. The combination of flexible probe technology with anti-inflammatory coatings accordingly offers a promising approach for enabling long-term stable neural interfaces. PMID- 28343003 TI - Essential design considerations for the resazurin reduction assay to noninvasively quantify cell expansion within perfused extracellular matrix scaffolds. AB - Precise measurement of cellularity within bioartificial tissues and extracellular matrix (ECM) scaffolds is necessary to augment rigorous characterization of cellular behavior, as accurate benchmarking of tissue function to cell number allows for comparison of data across experiments and between laboratories. Resazurin, a soluble dye that is reduced to highly fluorescent resorufin in proportion to the metabolic activity of a cell population, is a valuable, noninvasive tool to measure cell number. We investigated experimental conditions in which resazurin reduction is a reliable indicator of cellularity within three dimensional (3D) ECM scaffolds. Using three renal cell populations, we demonstrate that correlation of viable cell numbers with the rate of resorufin generation may deviate from linearity at higher cell densities, lower resazurin working volumes, or longer incubation times that all contribute to depleting the pool of resazurin. In conclusion, while the resazurin reduction assay provides a powerful, noninvasive readout of metrics enumerating cellularity and growth within ECM scaffolds, assay conditions may strongly influence its applicability for accurate quantification of cell number. The approach and methodological recommendations presented herein may be used as a guide for application-specific optimization of this assay to obtain rigorous and accurate measurement of cellular content in bioengineered tissues. PMID- 28343005 TI - Development of a UV crosslinked biodegradable hydrogel containing adipose derived stem cells to promote vascularization for skin wounds and tissue engineering. AB - The aim of this study was to design a dermal substitute containing adipose derived stem cells (ADSC) that can be used to improve the regeneration of skin on difficult wound beds by stimulating rapid neovascularization. This was achieved by first synthesizing methacrylated gelatin (GelMA) and methacrylated hyaluronic acid (HAMA) precursors which could be stored at -80 oC after lyophilisation. Polymer precursors were then dissolved in media (in 15:1 ratio), ADSCs added together with the photoinitiator and crosslinked with 40 s of UV. Hydrogels degraded by 50% over 3 weeks in an in vitro environment. ADSC loaded hydrogels could be easily handled with forceps (compressive modulus was 6 kPa). Transparency of the gel would allow a full field-of-view of a wound site. The hydrogels provided a suitable microenvironment for ADSC proliferation as shown by the filopodia observed in confocal micrographs. In vivo studies demonstrated that stem cell loaded hydrogels increased vascularization by up to 3 fold compared to their cell free counterparts. In conclusion, GelMA/HAMA hydrogels loaded with ADSC showed the desired proliferative and angiogenic properties essential to promote angiogenesis for wound healing and improving survival of tissue engineered skin. PMID- 28343006 TI - Trouble on takeoff: Crude oil on feathers reduces escape performance of shorebirds. AB - The ability to takeoff quickly and accelerate away from predators is crucial to bird survival. Crude oil can disrupt the fine structure and function of feathers, and here we tested for the first time how small amounts of oil on the trailing edges of the wings and tail of Western sandpipers (Calidris mauri) affected takeoff flight performance. In oiled birds, the distance travelled during the first 0.4s after takeoff was reduced by 29%, and takeoff angle was decreased by 10 degrees compared to unoiled birds. Three-axis accelerometry indicated that oiled sandpipers produced less mechanical power output per wingbeat during the initial phase of flight. Slower and lower takeoff would make oiled birds more likely to be targeted and captured by predators, reducing survival and facilitating the exposure of predators to oil. Whereas the direct mortality of heavily-oiled birds is often obvious and can be quantified, our results show that there are significant sub-lethal effects of small amounts crude oil on feathers, which must be considered in natural resource injury assessments for birds. PMID- 28343007 TI - Bioconcentration and multi-biomarkers of organic UV filters (BM-DBM and OD-PABA) in crucian carp. AB - Organic UV filters (OUV-Fs) are increasingly used in sunscreens and personal care products. In the present work, the bioconcentration and multi-biomarker effects of butyl methoxydibenzoylmethane (BM-DBM) and ethylhexyl dimethyl p-aminobenzoate (OD-PABA) were investigated in crucian carp (Carassius auratus). The fish were exposed to various concentrations of BM-DBM (3.88, 35.61, 181.85 and 337.15MUg/L), OD-PABA (4.66, 53.83, 264.22 and 459.32MUg/L) and their mixture (2.31+2.79, 23.69+26.18, 97.37+134.81 and 193.93+246.08MUg/L) for 28 days. The maximal concentrations of two OUV-Fs were detected in the fish liver, followed by the brain, kidney, gill and muscle in most cases. The maximal BCF values of OD PABA calculated in various exposure concentrations were 0.37 - 101.21 in single exposure groups and 0.11 - 31.09 in mixed exposure groups. Acetylcholinesterase (AChE) activity was significantly inhibited by BM-DBM as well as the mixtures at all of the exposure concentrations and by OD-PABA at higher concentrations (>=264.22MUg/L) during 28 days of exposure. The maximal inhibition rates of AChE activity reached 64.04% for BM-DBM, 41.05% for OD-PABA and 61.50% for the mixtures at the highest concentration, which indicated that these two OUV-Fs might damage the central nervous system. Concerning oxidative stress status, BM DBM and the mixtures significantly increased superoxide dismutase (SOD) and glutathione reductase (GR) activities and inhibited catalase (CAT) activity, while OD-PABA caused a significant increase of GR and CAT activities. AChE and GR activities seemed to be more sensitive biomarkers for BM-DBM and OD-PABA. PMID- 28343008 TI - Electroclinical features of epilepsy in patients with InvDup(15). AB - PURPOSE: InvDup(15) syndrome is one of the most common chromosomal abnormalities associated with epilepsy. Here we review the seizure types described in InvDup(15) patients and the main electroclinical, therapeutic, and prognostic aspects of the syndrome. METHODS: A literature search of PubMed, MEDLINE, and EMBASE was performed to identify papers examining InvDup(15) syndrome and epilepsy. RESULTS: About 65% of the InvDup(15) patients described in the literature had multiple seizure types with a predominance (40.4%) of tonic-clonic seizures. Age at seizure onset was before 10 years in more than half of them. Patients suffered from a variety of EEG abnormalities, generalized spike activity being the most frequent. Brain MRI was unremarkable in the majority of patients. Treatment was with several anticonvulsant drugs used as mono- or polytherapy. Valproic acid was the most common treatment against generalized seizures and was often effective, although drug resistance was a major concern in a large number of cases. Finally, more than 30% of the children suffered from infantile spasms, and status epilepticus was described in nearly 20% of patients, occasionally resulting in death. CONCLUSION: Seizures are very common in InvDup(15) patients, who suffer from a variety of seizure types. Information about EEG and brain MRI findings, seizure treatment, and prognosis is often poor. The overall prognosis is fair. Prospective studies of larger samples are needed, to gain further insights into the natural history of InvDup(15) syndrome. PMID- 28343009 TI - Prognostic analysis for short- and long-term outcomes of newly diagnosed epilepsy. AB - PURPOSE: To explore predictors for short- and long-term prognosis of newly diagnosed epilepsy. METHODS: 549 consecutive patients with newly diagnosed epilepsy were reviewed, 336 were enrolled in the study. Two-year remission in the short term (5 years) and five-year remission in the long term (>5, up to 8 years) were assessed as the outcomes. Logistic regression was used to identify independent predictors for unfavorable outcomes. chi2 test was used to compare the retention rates of old and new antiepileptic drugs (AEDs). RESULTS: 185 patients (55%) attained two-year remission in the short term, 163 (48.5%) attained terminal remission in the long term. The time interval between index seizure and AED start >12 months implied an unfavorable outcome in the short term (OR=1.9, p=0.03). Two or more seizures in the first year after AED start showed the strongest negative prognostic impact in the both short- and long-term outcomes (OR=2.3, p=0.02; OR=1.9, p=0.03). As the seizure frequency rose, the possibility for unfavorable outcome increased. The terminal retention rates of traditional and new AEDs were not significantly different (p=0.07). CONCLUSIONS: For patients with newly diagnosed epilepsy, the time interval between index seizure and AED start only influences the short-term outcome. Number of seizures in the first year after AED start is associated with both short- and long-term outcomes. It's imperative to initiate adequate, tolerated and appropriately chosen AED schedules after the definitive diagnosis of epilepsy. PMID- 28343010 TI - Structural and dynamics studies of the TetR family protein, CprB from Streptomyces coelicolor in complex with its biological operator sequence. AB - In Streptomycetes, tetracycline repressor family of transcription regulators (TetR-FTRs) controls various biological processes including antibiotic biosynthesis, cellular morphology and innate resistance. Here, we focus on understanding the structural basis of transcription regulation by CprB, a member of TetR-FTRs from S. coelicolor. CprB is implicated as a receptor of gamma butyrolactones, a class of quorum sensing molecules, responsible for initiating secondary metabolic pathways. In order to understand the molecular mechanism of DNA recognition, the X-ray structure of CprB in complex with its biological relevant operator sequence was solved to a resolution of 3.95A. Furthermore, to refine and compliment the results, atomistic molecular dynamics simulations were carried out using the X-ray structure as the template. The studies reveal that CprB binds to DNA as dimer of dimers with this mode of interaction results in minimal distortion in the DNA, enabling these proteins to recognize multiple sequences with varying affinity. Another crucial finding from our simulation results was that the positively charged N-terminal arm of CprB brings extra stability to the protein-DNA complex by interacting with the minor-groove of the DNA and anchoring itself to the phosphate backbone. Corroborating electrophoretic mobility shift assay and fluorescence anisotropy experiments showed that the mutant DeltaN6-CprB exhibited about 7-8 fold reduced DNA binding. Comparison with other TetR-FTRs reveals that this strategy is also employed by over 25% of TetR FTRs, where N-terminal anchoring mechanism is used to enhance selectivity for a particular DNA sequence. PMID- 28343011 TI - Ultrasound characterization of ankle involvement in Lofgren syndrome. AB - BACKGROUND: Bilateral ankle arthritis is a classic diagnostic criterion for Lofgren syndrome. The objective of this study was to use ultrasonography to characterize the articular and periarticular involvement of the ankles in patients with Lofgren syndrome. METHODS: Multicenter descriptive cohort study of patients with Lofgren syndrome who underwent ultrasonography of the ankles. We collected clinical data, imaging study findings, blood test results, and joint fluid properties in patients who underwent joint aspiration. RESULTS: Findings from ultrasonography of the ankles in 40 patients were analyzed. The most common B-mode abnormality was subcutaneous edema (26/40), followed by tenosynovitis (22/40), with no differences in frequency across compartments. Joint involvement manifested as synovitis in 7 patients and effusion in 10 patients. Synovitis with increased vascularity by power Doppler was found in 3 patients. No statistically significant associations were found linking synovitis or tenosynovitis to clinical features (age and gender), laboratory tests, or imaging study findings. CONCLUSION: Contrary to the classical view, our results indicate that ankle involvement in Lofgren syndrome is more often abarticular than articular. The inclusion of bilateral ankle arthritis among the diagnostic criteria for Lofgren syndrome deserves reappraisal. PMID- 28343012 TI - Occurrence of rheumatic symptoms in celiac disease: A meta-analysis: Comment on the article "Osteoarticular manifestations of celiac disease and non-celiac gluten hypersensitivity" by Dos Santos and Liote. Joint Bone Spine 2016, doi:10.1016/j.jbspin.2016.09.007. PMID- 28343013 TI - Inflammatory myopathies: A new landscape. AB - Greater accuracy in clinical descriptions combined with advances in muscle histology and immunology have established that inflammatory myopathies (IMs), similarly to inflammatory rheumatic diseases, constitute a highly heterogeneous group of conditions. The topographic distribution, severity, and tempo of onset of the myopathy vary widely, and the histological findings distinguish at least five different profiles, which may reflect different pathophysiological processes. Most IMs are connective tissue diseases that can affect multiple organs, among which the most common targets are the skin, joints, and lungs. The extramuscular manifestations may antedate the muscular involvement and should therefore suggest a diagnosis of IM even in the absence of obvious muscle disease. About 20 different autoantibodies have been identified in patients with IM. Some are mutually exclusive and associated with specific combinations of clinical manifestations. Following the model of antisynthetase syndrome, about 10 syndromes associated with autoantibodies specific of IM have been identified. Thus, polymyositis is now emerging as a rare entity that is often mistaken for more recently described patterns of IM. No consensus exists to date about the classification of IMs. Nevertheless, the clinical manifestations, autoantibody profile, and muscle histology can be used to distinguish patient subgroups with fairly homogeneous patterns of complications, treatment responses, and outcomes. These subgroups are also characterized by specific genetic and environmental factors. The advances made in the nosology of IMs have benefited the diagnosis, personalization of treatment strategies, and understanding of pathophysiological mechanisms. They can be expected to assist in the development of specific treatments. PMID- 28343014 TI - Natural lipids enriched self-nano-emulsifying systems for effective co-delivery of tamoxifen and naringenin: Systematic approach for improved breast cancer therapeutics. AB - The nano-miceller drug delivery carriers of tamoxifen (TMX) having natural ingredients like polyunsaturated fatty acid (PUFA) with self-nano-emulsifying properties was developed with naringenin (NG) in a synergistic manner i.e. TMX-NG SNEDDS. The optimized nano-formulation revealed complete drug release in 30 min and >80% permeation in 45 min. Superior cellular uptake potential (4.6-6.5-fold) of the TMX-NG-SNEDDS using Caco-2 cells while cytotoxicity study on MCF-7 cells indicated significant results (P<0.05) of TMX-NG-SNEDDS. The in vivo pharmacokinetic study also construed remarkable improvement (7.3 and 11.4-fold increase in Cmax and AUC) in rate of drug absorption and 2-fold reduction in Tmax by optimized TMX-NG-SNEDDS. In vivo DMBA model construed superior efficacy of the formulation by reducing tumor size, and improved survival rate of the animals justifies its safety aspect as well. PMID- 28343015 TI - Systemic delivery of the tumor necrosis factor gene to tumors by a novel dual DNA nanocomplex in a nanoparticle system. AB - Many cancers fail to respond to immunotherapy as a result of immune suppression by the tumor microenvironment. The exogenous expression of immune cytokines to reprogram the tumor microenvironment represents an approach to circumvent this suppression. The present studies describe the development of a novel dual nanoparticle (DNP) system for driving DNA expression vectors encoding inflammatory cytokines in tumor cells. The DNP system consists of a DNA expression vector-cationic peptide nanocomplex (NC) surrounded by a diblock polymeric NP. Tumor necrosis factor alpha (TNF) was selected as the prototype cytokine for this system, based on its pleotropic inflammatory and anti-cancer activities. Our results demonstrate that the DNP system is highly effective in driving expression of TNF in tumor cells. We also demonstrate that the DNPs are effective in inducing apoptosis and anti-tumor activity. These findings support a novel immunotherapeutic approach for the intratumoral delivery of DNA vectors that express inflammatory cytokines. PMID- 28343017 TI - beta-Lactoglobulin: An efficient nanocarrier for advanced delivery systems. AB - Thanks to the progress of nanotechnology there are several agent-delivery systems that can be selected to achieve rapid and specific delivery of a wide variety of biologically active agents. Consequently, the manipulation and engineering of biopolymers has become one of the most exciting subjects for those who study delivery systems on the nanoscale. In this regard, both nanoparticle formation and a carrier role have been observed in the case of the globular milk whey protein, beta-lactoglobulin (beta-LG), setting it apart from many other proteins. To date, many efforts adopting different approaches have created beta-LG nanoparticles useful in forming delivery systems for various agents with specific targets. In this review, the potential of beta-LG to play the role of an efficient and diverse carrier protein, as well as its ability to form a well targeted nano-scale delivery system is discussed. PMID- 28343016 TI - Evaluation of antitumor activity and cardiac toxicity of a bone-targeted ph sensitive liposomal formulation in a bone metastasis tumor model in mice. AB - Chemotherapy for bone tumors is a major challenge because of the inability of therapeutics to penetrate dense bone mineral. We hypothesize that a nanostructured formulation with high affinity for bone could deliver drug to the tumor while minimizing off-target toxicity. Here, we evaluated the efficacy and toxicity of a novel bone-targeted, pH-sensitive liposomal formulation containing doxorubicin in an animal model of bone metastasis. Biodistribution studies with the liposome showed good uptake in tumor, but low accumulation of doxorubicin in the heart. Mice treated with the bone-targeted liposome formulation showed a 70% reduction in tumor volume, compared to 35% reduction for free doxorubicin at the same dose. Both cardiac toxicity and overall mortality were significantly lower for animals treated with the bone-targeted liposomes compared to free drug. Bone targeted, pH-sensitive, doxorubicin containing liposomes represent a promising approach to selectively delivering doxorubicin to bone tumors while minimizing cardiac toxicity. PMID- 28343019 TI - A new opportunity for nanomedicines: Micellar cytochrome P450 inhibitors to improve drug efficacy in a cancer therapy model. AB - Nanomedicines are mainly used as drug delivery systems; here we evaluate a new application - to inhibit a drug's metabolism thereby enhancing its effective dose. Micelles containing the natural furanocoumarin 6',7'-dihydroxybergamottin (DHB), a known CYP450 inhibitor, were developed to transiently block hepatic CYP450-mediated drug metabolism and increase the bioavailability of the oncology drug docetaxel. Administered in mice 24h prior to the drug, DHB-micelles enhanced antitumor efficacy in the tumor xenograft models HT-29 and MDA-MB-231, when compared to the drug alone. These DHB-micelles have similar composition to marketed docetaxel-micelles for human use. Despite not being optimized in terms of targeting hepatocytes, they do represent the first injectable example of nanosized metabolism-blocking agents and open the way for further work on such nanomedicines in man. PMID- 28343018 TI - CuS as a gatekeeper of mesoporous upconversion nanoparticles-based drug controlled release system for tumor-targeted multimodal imaging and synergetic chemo-thermotherapy. AB - In this work, a tumor-targeted multifunctional mesoporous upconversion nanoparticle-based drug controlled release system was developed for UCL/MRI/PAT guided synergetic chemo-thermotherapy. Herein, the core-shell mesoporous upconversion nanoparticles served as drug carrier exhibiting higher upconversion luminescence emission intensity, with CuS as a gatekeeper through a cleavable disulfide bond under the influence of glutathione. CuS could not only prevent drug from early release during the delivery but also improve the delivery system function with the ability of photothermal therapy and photoacoustic tomography. Hyaluronic acid grafted on the surface of mesoporous upconversion nanoparticles could interact with CD44 receptors over-expressed in tumor cells, facilitating the drug delivery system to accumulate in tumor tissues. The synergy between chemotherapy and photothermal therapy was studied in vitro and in vivo, showing powerful anti-tumor effect. In cooperation with the multi-mode imaging, the size, site and morphology of tumor were clearly observed throughout the disease's progression. PMID- 28343020 TI - Selenium speciation influences bioaccumulation in Limnodynastes peronii tadpoles. AB - Despite being essential for animal health and fitness, Se has a relatively narrow range between deficiency and toxicity, and excess Se can cause a variety of adverse effects in aquatic organisms. Amphibians are particularly vulnerable to contaminants during larval aquatic life stage, because they can accumulate toxic ions through various routes including skin, gills, lungs and digestive tract. Few attempts have been made to understand the tissue-specific accumulation of trace elements, including the impacts of chemical speciation in developing amphibian larvae. We used radiolabelled 75Se to explore the biokinetics and tissue distributions of the two dominant forms occurring in surface waters, selenite (SeIV) and selenate (SeVI). Tadpoles of the native Australian frog Limnodynastes peronii were exposed to Se in both forms, and live-animal gamma spectroscopy was used to track accumulation and retention over time. Tissue biodistributions were also quantified at the end of the uptake and depuration phases. Results showed the bioconcentration of SeIV to be 3 times greater compared to SeVI, but rates of elimination were similar for both forms. This suggests a change of Se speciation within the organism prior to excretion. Depuration kinetics were best described by a one-phase exponential decay model, and tadpoles retained approximately 19% of the accumulated Se after 12 days of depuration in clean water. Selenium bioaccumulation was greatest in digestive and excretory organs, as well as the eye, which may directly relate to previously reported Se-induced impairments. Results demonstrate how the use of radiotracing techniques can significantly improve our understanding of trace element toxicokinetics and tissue distributions in developing amphibians. From an environmental monitoring perspective, the findings highlight the importance of considering chemical speciation as this could influence the accuracy of risk assessment. PMID- 28343021 TI - Application of mixed-methods design in community-engaged research: Lessons learned from an evidence-based intervention for Latinos with chronic illness and minor depression. AB - The purpose of this paper is to share lessons learned from a collaborative, community-informed mixed-methods approach to adapting an evidence-based intervention to meet the needs of Latinos with chronic disease and minor depression and their family members. Mixed-methods informed by community-based participatory research (CBPR) were employed to triangulate multiple stakeholders' perceptions of facilitators and barriers of implementing the adapted intervention in community settings. Community partners provided an insider perspective to overcome methodological challenges. The study's community informed mixed-methods: research approach offered advantages to a single research methodology by expanding or confirming research findings and engaging multiple stakeholders in data collection. This approach also allowed community partners to collaborate with academic partners in key research decisions. PMID- 28343022 TI - Stakeholder evaluation of an online program to promote physical activity and workplace safety for individuals with disability. AB - Individuals with disabilities face increasing health and employment disparities, including increased risk of morbidity and mortality and decreased earnings, occupational roles, and greater risk of injury at work. Thus, there is a need to improve workplace safety and health promotion efforts for people with disability. The purpose of this study was to obtain stakeholder feedback about an online program, Be Active, Work Safe, which was developed to increase the physical activity and workplace safety practices of individuals with disability. Eight stakeholders (content experts and individuals with disability) evaluated the 8 week online program and provided feedback on accessibility, usability, and content using quantitative and qualitative approaches. Stakeholders suggested changes to the organization, layout and accessibility, and content. This included making a stronger connection between the physical activity and workplace safety components of the program, broadening content to apply to individuals in different vocational fields, and reducing the number of participant assessments. Engaging stakeholders in the development of health promotion programs is critical to ensure the unique issues of the population are addressed and facilitate engagement in the program. Feedback provided by stakeholders improved the program and provided insight on barriers for adoption of the program. PMID- 28343023 TI - Classification of footwear outsole patterns using Fourier transform and local interest points. AB - Successful classification of questioned footwear has tremendous evidentiary value; the result can minimize the potential suspect pool and link a suspect to a victim, a crime scene, or even multiple crime scenes to each other. With this in mind, several different automated and semi-automated classification models have been applied to the forensic footwear recognition problem, with superior performance commonly associated with two different approaches: correlation of image power (magnitude) or phase, and the use of local interest points transformed using the Scale Invariant Feature Transform (SIFT) and compared using Random Sample Consensus (RANSAC). Despite the distinction associated with each of these methods, all three have not been cross-compared using a single dataset, of limited quality (i.e., characteristic of crime scene-like imagery), and created using a wide combination of image inputs. To address this question, the research presented here examines the classification performance of the Fourier-Mellin transform (FMT), phase-only correlation (POC), and local interest points (transformed using SIFT and compared using RANSAC), as a function of inputs that include mixed media (blood and dust), transfer mechanisms (gel lifters), enhancement techniques (digital and chemical) and variations in print substrate (ceramic tiles, vinyl tiles and paper). Results indicate that POC outperforms both FMT and SIFT+RANSAC, regardless of image input (type, quality and totality), and that the difference in stochastic dominance detected for POC is significant across all image comparison scenarios evaluated in this study. PMID- 28343024 TI - Sex estimation with the total area of the proximal femur: A densitometric approach. AB - The estimation of sex is a central step to establish the biological profile of an anonymous skeletal individual. Imaging techniques, including bone densitometry, have been used to evaluate sex in remains incompletely skeletonized. In this paper, we present a technique for sex estimation using the total area (TA) of the proximal femur, a two-dimensional areal measurement determined through densitometry. TA was acquired from a training sample (112 females; 112 males) from the Coimbra Identified Skeletal Collection (University of Coimbra, Portugal). Logistic regression (LR), linear discriminant analysis (LDA), reduce error pruning trees (REPTree), and classification and regression trees (CART) were employed in order to obtain models that could predict sex in unidentified skeletal remains. Under cross-validation, the proposed models correctly estimated sex in 90.2-92.0% of cases (bias ranging from 1.8% to 4.5%). The models were evaluated in an independent test sample (30 females; 30 males) from the 21st Century Identified Skeletal Collection (University of Coimbra, Portugal), with a sex allocation accuracy ranging from 90.0% to 91.7% (bias from 3.3% to 10.0%). Overall, data mining classifiers, especially the REPTree, performed better than the traditional classifiers (LR and LDA), maximizing overall accuracy and minimizing bias. This study emphasizes the significant value of bone densitometry to estimate sex in cadaveric remains in diverse states of preservation and completeness, even human remains with soft tissues. PMID- 28343025 TI - Recording skeletal completeness: A standardised approach. AB - Recording the preservation of human skeletal remains is the foundation of osteological analyses for forensic and archaeological skeletal material. Methods for recording the skeletal completeness, one of the components of skeletal preservation documentation, are however currently non-standardised and subjective. To provide practitioners with a scientific means to accurately quantify skeletal completeness in an adult skeleton, percentage values for each skeletal element have been established. Using computed tomography (CT) volume rendering applications and post-mortem CT skeletal data for one adult individual, the percentage value for each bone relative to the complete skeleton was calculated based on volume. Percentage values for skeletal elements ranged from 0.01% (select hand and foot bones) to 8.43% (femur). Visual and written mediums detailing individual skeletal percentages have been provided as user-friendly reference sources. Calculating the percentage of skeletal remains available for analysis provides practitioners with a means to scientifically and objectively record skeletal completeness. PMID- 28343026 TI - Comparison of unilateral versus bilateral pedicle screw fixation at the level of fracture using posterior short-segment pedicle instrumentation in the treatment of severe thoracolumbar burst fractures. AB - BACKGROUND: Thoracolumbar burst fractures (TBFs) are often followed by bilateral pedicle screw fixation (BPSF) at the level of fracture using posterior short segment pedicle instrumentation (SSPI). There has been increasing support for unilateral pedicle screw fixation (UPSF) in an attempt to reduce complications and costs. The aim of this study was to compare the clinical and radiologic results of UPSF versus BPSF at the level of fracture using SSPI in the treatment of severe TBFs. METHODS: The records of 42 consecutive patients with severe TBFs who underwent SSPI were divided into 2 groups according to the number of screws in the fracture level, including 20 patients (five screws) in UPSF group and 22 patients (six screws) in BPSF. Different clinical and radiological parameters were recorded before surgery, after surgery, and 1.5 years after operation. The patients'clinical outcomes were assessed using visual analog scale (VAS), and Oswestry Disability Index (ODI). For radiological evaluation, changes in local kyphosis angle (LKA), vertebral wedge angle (VWA), and anterior vertebral height (AVH) were investigated using plain radiographs. RESULTS: Mean follow-up was 18.3 months for UPSF group and 19.0 months for BPSF group (P > 0.05). There were no significant differences in the age, gender, fracture type and site in both groups. Radiologically, no statistically difference was observed between the two groups in corrected rate of LKA, VWA, or AVH(all P > 0.05). With respect to clinical variants including VAS and ODI scores, there were also no significant differences. However, the UPSF group seemed to have advantages over BPSF group in operative time, blood loss, postoperative drainage, hospitalization time (P > 0.05). Especially, implant cost for the BPSF group was 22% greater than the UPSF group. No serious complications occurred in our study. In all cases, fusions healed well and no revision surgery was performed for loss of correction or failure of instrumentation during follow-up. CONCLUSIONS: The present study is the first to demonstrate that patients undergoing SSPI with UPSF as compared with BPSF for the treatment of severe TBFs had similar clinical and radiologic outcomes. PMID- 28343027 TI - Outpatient placement of perforated setons prior to treatment of sealants for perianal fistula: A Technical Note. PMID- 28343028 TI - Epidemiology of penetrating injuries in the United Kingdom: A systematic review. AB - INTRODUCTION: Penetrating injuries account for a significant number of deaths in the United Kingdom (UK) annually. Numerous articles have examined the epidemiology of penetrating trauma in various areas of the UK. This article aimed to systematically review the current literature and evaluate the incidence and mortality of penetrating injury according to region in the UK. METHODS: A systematic literature search was performed using MEDLINE(r) (1946 to June 2016), EMBASE(r) (1974 to June 2016), and PsycINFO(r) (1806 to June 2016) databases. The following keywords were used in combination with Boolean operators: "epidemiology", "incidence", "frequency", "pattern", "distribution"; "penetrating"; "injuries", "injury", "trauma"; "United Kingdom", "UK", "England", "Scotland", "Wales", "London". RESULTS: Eleven relevant studies were identified across five regions of the UK. Study periods ranged from 3 months to 16 years and encompassed between 343 and 127,191 patients. Relative incidence within individual studies ranged from 0.3% (Midlands) to 21.0% (London) and mortality ranged from 0.5% (London) to 15.4% (Midlands). The majority of patients were young males. DISCUSSION: An extensive range of incidence and mortality rates were observed between studies in all regions. This was largely dependent on the study population under review. London was found to have the highest incidence of penetrating injuries, however these studies tended to focus on populations of trauma patients. The high proportion of male victims may reflect the risk of becoming involved in gangs and violence. CONCLUSIONS: Our ambiguous results indicate the need for further work directed towards the epidemiology of penetrating injuries within regional trauma networks. PMID- 28343029 TI - Meta-analysis of Transhiatal Esophagectomy in carcinoma of esophagogastric junction, does it have an advantage? AB - PURPOSE: Compare the clinical outcome of Transhiatal Esophagectomy (THE) approach and open Thoracic Esophagectomy (TTE) approach in the carcinoma of esophagogastric junction (CEGJ). METHODS: Relevant literature published until 2016 from PubMed, Cochrane Library, Ovid (Medline) and EMBASE were retrieved. Meta-analysis was achieved by using the Stata12 software. RESULTS: A total of 18 studies and 2202 cases of patients were involved in this meta-analysis. THE showed to decrease the hospital stay, hospital mortality, surgical time, and blood loss in the operation. However, fewer lymph nodes would be yielded by this surgical option. A 5-year survival advantage of THE was only observed in North America subgroup. CONCLUSIONS: Except the above operative related advantages, there was no clear evidence that THE has a further advantage in CEGJ. PMID- 28343030 TI - Diagnostic and therapeutic role of endoscopic retrograde pancreatography in the management of traumatic pancreatic duct injury patients: Single center experience for 34 years. AB - BACKGROUND: Traumatic pancreatic injuries are rare and present diagnostic and therapeutic difficulties. We evaluated the usefulness of endoscopic retrograde pancreatography and transpapillary pancreatic stent in the diagnosis and treatment of pancreatic trauma patients. METHODS: We reviewed medical records of 83 pancreas trauma patients who underwent endoscopic retrograde pancreatography for the suspicion of pancreas duct injury between January 1983 and December 2016. Patient notes, radiologic findings, laboratory investigations, operative records, and endoscopic retrograde pancreatography reports were reviewed. RESULTS: Pre endoscopic retrograde pancreatography abdominal computed tomography was performed in 52 patients. Twenty-seven patients of them were diagnosed with a major pancreatic duct injury by subsequent endoscopic retrograde pancreatography. Eleven major pancreatic duct injuries (40.7%) were missed by the pre-endoscopic retrograde pancreatography abdominal CT. Major pancreatic duct injury was confirmed by endoscopic retrograde pancreatography in 43 patients. These 43 major pancreatic duct injury patients were classified into the Operative (n = 21), Stent (n = 15), and Conservative (n = 7) groups according to the first treatment modality which was chosen by attending surgeon. Age, initial white blood cell count, initial serum amylase, associated injury, and major pancreatic duct injury site were similar among groups, while the rate of parenchymal leakage (Dye leakage confined to pancreatic capsule) on endoscopic retrograde pancreatography findings differed. Parenchymal leakage was most common in the Conservative group. Pancreas related mortality occurred in 1 (4.76%) Operative group, 2 (13.33%) Stent group, and 0 (0%) Conservative group. Pancreas related complication occurred in 16 (76.19%) Operative group, 10 (66.67%), Stent group and 5 (71.43%) Conservative group. There were no statistically significant differences in the occurrence rate of pancreas related complications and mortalities among three groups. CONCLUSION: Endoscopic retrograde pancreatography helps clinicians choose a treatment modality for major pancreatic duct injury since it provides information about the precise condition of the major pancreatic duct injury. Endoscopic retrograde pancreatography with transpapillary pancreatic stenting also shows promise as a substitute for laparotomy or pancreatic resection in selected patients. PMID- 28343031 TI - Assessing the genotoxic effects of two lipid peroxidation products (4-oxo-2 nonenal and 4-hydroxy-hexenal) in haemocytes and midgut cells of Drosophila melanogaster larvae. AB - Lipid peroxidation products can induce tissue damage and are implicated in diverse pathological conditions, including aging, atherosclerosis, brain disorders, cancer, lung and various liver disorders. Since in vivo studies produce relevant information, we have selected Drosophila melanogaster as a suitable in vivo model to characterise the potential risks associated to two lipid peroxidation products namely 4-oxo-2-nonenal (4-ONE) and 4-hydroxy-hexenal (4-HHE). Toxicity, intracellular reactive oxygen species production, and genotoxicity were the end-points evaluated. Haemocytes and midgut cells were the evaluated targets. Results showed that both compounds penetrate the intestine of the larvae, affecting midgut cells, and reaching haemocytes. Significant genotoxic effects, as determined by the comet assay, were observed in both selected cell targets in a concentration/time dependent manner. This study highlights the importance of D. melanogaster as a model organism in the study of the different biological effects caused by lipid peroxidation products entering via ingestion. This is the first study reporting genotoxicity data in haemocytes and midgut cells of D. melanogaster larvae for the two selected compounds. PMID- 28343032 TI - Tissue depletion study of enrofloxacin and its metabolite ciprofloxacin in broiler chickens after oral administration of a new veterinary pharmaceutical formulation containing enrofloxacin. PMID- 28343033 TI - Quinocetone induces mitochondrial apoptosis in HepG2 cells through ROS-dependent promotion of VDAC1 oligomerization and suppression of Wnt1/beta-catenin signaling pathway. AB - Quinocetone (QCT) has been used as an animal feed additive in China since 2003. However, investigations indicate that QCT has potential toxicity due to the fact that it shows cytotoxicity, genotoxicity, hepatotoxicity, nephrotoxicity and immunotoxicity in vitro and animal models. Although QCT-induced mitochondrial apoptosis has been established, the molecular mechanism remains unclear. This study was aimed to investigate the role of voltage-dependent anion channel 1 (VDAC1) oligomerization and Wnt/beta-catenin pathway in QCT-induced mitochondrial apoptosis. The results showed VDAC inhibitor 4, 4-diisothiocyano stilbene-2, 2 disulfonic acid (DIDS) partly compromised QCT-induced cell viability decrease (from 34.1% to 68.5%) and mitochondrial apoptosis accompanied by abating VDAC1 oligomerization, cytochrome c (Cyt c) release and the expression levels of cleaved caspase-9, -3 and poly (ADP-ribose) polymerase (PARP). Meanwhile, overexpression VDAC1 exacerbated QCT-induced VDAC1 oligomerization and Cyt c release. In addition, lithium chloride (LiCl), an activator of Wnt/beta-catenin pathway, markedly attenuated QCT-induced mitochondrial apoptosis by partly restoring the expression levels of Wnt1 and beta-catenin. Finally, reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine (NAC) obviously blocked QCT induced VDAC1 oligomerization and the inhibition of Wnt1/beta-catenin pathway. Taken together, our results reveal that QCT induces mitochondrial apoptosis by ROS-dependent promotion of VDAC1 oligomerization and suppression of Wnt1/beta catenin pathway. PMID- 28343034 TI - Bioactivities of Achillea phrygia and Bupleurum croceum based on the composition of phenolic compounds: In vitro and in silico approaches. AB - This study presents the effects of the Achillea phrygia Boiss. et Bal. and Bupleurum croceum Fenzl. extracts obtained by different solvents (ethyl acetate, methanol and water) on selected enzyme inhibitory effects and antioxidant ability with screening bioactive compounds. Total and individual bioactive compounds were detected by spectrophotometric and HPLC-DAD techniques. Antioxidant abilities were evaluated by different methods including free radical scavenging (ABTS and DPPH), reducing power (CUPRAC and FRAP), phosphomolybdenum and metal chelating. Enzyme inhibitory effects were tested against cholinesterases, tyrosinase, amylase, glucosidase and lipase. Total phenolic contents were ranged from 20.52 mgGAE/g extract (B. croceum methanol extract) to 41.13 mgGAE/g extract (A. phrygia methanol extract). Generally, methanol and water extracts showed the strongest antioxidant abilities, while the ethyl acetate extracts had the most promising enzyme inhibitory effects. HPLC analysis revealed the abundance of some phenolics including rutin, quercetin, sinapic acid and chlorogenic acid, respectively. These components were also assessed using molecular modelling with the aim to study their docking properties on a set of six enzymes used in this study. Overall, these species could be suggested as valuable sources of natural bioactive agents for developing new functional, pharmacological and health promoting ingredients. PMID- 28343035 TI - Evaluation of 4-methylcyclohexanemethanol (MCHM) in a combined irritancy and Local Lymph Node Assay (LLNA) in mice. AB - 4-Methylcyclohexanemethanol (MCHM) is a flotation reagent used in fine coal beneficiation. On January 9, 2014, crude MCHM, a mixture containing predominantly MCHM, was inadvertently released into the Elk River, a municipal water source that serves about 300,000 people in the Charleston, WV area, resulting in temporary contamination of 15 percent of the state's tap water and causing significant dermal exposure. The current studies were undertaken to determine whether crude MCHM or MCHM has the potential to produce dermal irritancy and/or sensitization. BALB/c female mice were treated daily for 3 consecutive days by direct epicutaneous application of 25 MUL of various concentrations of crude MCHM or MCHM to the dorsum of each ear. A mouse ear-swelling test was used to determine irritancy potential and was undertaken in combination with the standardized Local Lymph Node Assay (LLNA) to determine skin sensitizing potential. MCHM was found to produce skin irritation at concentrations above 20% and did not produce sensitization. Crude MCHM also produced irritation, although weaker, and in addition was found to be a weak to moderate skin sensitizer. The results are discussed in terms of potential human health hazard. PMID- 28343036 TI - Behaviour of 137Cs in forest humus detected across the territory of the Czech Republic. AB - The activity concentration of 137Cs in samples of coniferous forest humus collected across the territory of the Czech Republic in 1995 and 2005 was analysed, and it was found significantly correlated with the surface deposition caused by the Chernobyl accident. The effective (12.8 y) and environmental (22.3 y) half-lives of radiocaesium in humus were calculated and compared with those in spruce bark. The impact of important forest stand factors, that is, precipitation, content of organic matter, age of trees and pH, on the behaviour of 137Cs in humus was studied. It was observed that humus samples with a higher proportion of organic matter, higher pH(H2O) and pH(CaCl2) contained higher amounts of 137Cs. Conversely, with the age of trees, the activity concentration of 137Cs in humus is decreasing. Higher precipitation and humus acidity decrease the reduction rate of the 137Cs in humus. These stand factors increase bioavailability of 137Cs in humus. The transfer and retention of available 137Cs in biomass of organisms living in humus for a long time can satisfactorily explain the longer residence time of 137Cs in humus affected by the studied factors. PMID- 28343037 TI - Concentration and sources of atmospheric nitrous acid (HONO) at an urban site in Western China. AB - Highly time-resolved measurements of nitrous acid (HONO) were carried out with a highly sensitive long path absorption photometer (LOPAP) at an urban site of Xi'an in Western China from 24 July to 6 August 2015 to investigate the atmospheric variations, sources, and formation pathways of HONO. The concentrations of HONO vary from 0.02 to 4.3ppbv with an average of 1.12ppbv for the entire measurement period. The variation trends of HONO and NO2 are very similar and positively correlated which, together with the similar diurnal profiles of HONO/NO2 ratio and HONO, suggest the importance of heterogeneous conversion of HONO from NO2. The nocturnal HONO level is governed by heterogeneous formation from NO2, followed by homogeneous formation of NO with OH and then by direct emissions. Further, it is found that the heterogeneous formation of HONO is largely affected by relative humidity and aerosol surface. Daytime HONO budget analysis indicates that an additional unknown source with HONO production rate of 0.75ppbvh-1 is required to explain the observed HONO concentration, which contributes 60.8% of the observed daytime HONO. PMID- 28343038 TI - Physicochemical characterization of ambient PM2.5 in Tehran air and its potential cytotoxicity in human lung epithelial cells (A549). AB - As air pollution is a major problem in Tehran, this study aimed to investigate the physicochemical characterization of the water-soluble and organic contents of ambient PM2.5 in Tehran and determine its in vitro toxicological impact on human lung epithelial cells (A549). A total of 11 sampling stations were selected, including three categories: traffic, urban, and suburban. All sampling was carried out in the spring and summer of 2015. Ion chromatography (IC), inductively coupled plasma atomic emission spectroscopy (ICP-AES), and GC-MS were used to analyze ionic compounds, heavy metals, and polycyclic aromatic hydrocarbons (PAHs), respectively, and an ELISA reader was used for cytotoxicity analysis. The most prevalent ionic species found for all three categories was SO42-. PAH concentrations were 43.45+/-32.71, 50.51+/-37.27, and 29.13+/ 33.29ng/m3 for traffic, urban, and suburban stations, respectively. For all sampling stations, Al and Fe had the highest values among the investigated heavy metals. Cell viability measurements, carried out using the MTT assay, showed that all three categories of samples cause cytotoxicity, although the urban station samples showed higher cytotoxicity than those from the other stations (p?0.05). Based on the results of the present study, organic compounds and insoluble particles could be the main causes of cytotoxicity. PMID- 28343039 TI - Study of trace metal imbalances in the blood, scalp hair and nails of oral cancer patients from Pakistan. AB - Oral cancer is an important cause of cancer morbidity and mortality globally and exposure to trace metals alongside tobacco, alcohol and HPV are the important etiological factors in its development. Selected essential and toxic trace metals (Cd, Cr, Cu, Fe, Mn, Ni, Pb and Zn) were measured in the blood, scalp hair and nails of oral cancer patients and counterpart controls by atomic absorption spectrometry. Mean concentrations of Cd, Ni and Pb were found to be significantly higher (p<0.05) and those of Cu, Fe and Zn were considerably lower in the blood, scalp hair and nails of the patients than the controls. Most of the metal concentrations exhibited higher dispersion and asymmetry in the blood, scalp hair and nails of the patients compared with the controls. The correlation study revealed significantly diverse relationships among the metals in blood, scalp hair and nails of both donor groups. Variations in the metal levels were also noted for various stages (I, II, III & IV) as well as the types (adenocarcinoma and squamous cell carcinoma) of oral cancer. Multivariate cluster analysis of the metal levels in the patients were also significantly dissimilar than the controls. The study evidenced considerably divergent variations in the metal levels in oral cancer patients in comparison with the controls. PMID- 28343040 TI - The influence of lead content in drinking water, household dust, soil, and paint on blood lead levels of children in Flin Flon, Manitoba and Creighton, Saskatchewan. AB - Lead exposure continues to be an important health issue despite the general removal of lead sources in commercial and industrial applications. Low levels of lead exposure have been found to produce adverse neurodevelopmental effects in children with no evidence that a threshold exists for this critical endpoint. Blood lead levels (BLLs) were measured in children (n=118) under the age of 7years in the northern Canadian smelter community of Flin Flon, Manitoba and Creighton, Saskatchewan. An environmental sampling component was included to examine the relationship between lead content in outdoor soil, household dust, tap water, and paint within a given household and the corresponding BLLs in participating children. The geometric mean (GM) BLL for study participants was 1.41MUg/dL. Blood lead levels varied slightly by age category with the lowest levels found among the children under age 2 (GM=1.11MUg/dL) and the highest levels found among children between 2 and 3years of age (GM=1.98MUg/dL). Results from the multivariate modeling indicated that BLLs had a significant positive association with the age of housing (p<0.05), with children living in households constructed prior to 1945 being more likely to have higher levels (p=0.034). Outdoor soil (GM=74.7MUg/g), household dust from kitchen floors (GM=1.34MUg/ft2), and maximum household lead paint were found to be significantly correlated (p<0.05) to BLLs. Although a statistically significant association between concentrations of lead in these household media and the corresponding BLLs exists, the variability in BLLs was poorly explained by these factors alone (r2=0.07, 0.12 and 0.06 for soil, household dust, and paint, respectively). Lead concentrations in flushed (GM=0.89MUg/L) and stagnant (GM=2.07MUg/L and 1.18MUg/L) tap water samples were not significantly correlated (p>0.05) to BLLs. PMID- 28343041 TI - Characterization of regional cold-hydrothermal inflows enriched in arsenic and associated trace-elements in the southern part of the Duero Basin (Spain), by multivariate statistical analysis. AB - Naturally occurring arsenic in groundwater exceeding the limit for potability has been reported along the southern edge of the Cenozoic Duero Basin (CDB) near its contact with the Spanish Central System (SCS). In this area, spatial variability of arsenic is high, peaking at 241MUg/L. Forty-seven percent of samples collected contained arsenic above the maximum allowable concentration for drinking water (10MUg/L). Correlations of As with other hydrochemical variables were investigated using multivariate statistical analysis (Hierarchical Cluster Analysis, HCA and Principal Component Analysis, PCA). It was found that As, V, Cr and pH are closely related and that there were also close correlations with temperature and Na+. The highest concentrations of arsenic and other associated Potentially Toxic Geogenic Trace Elements (PTGTE) are linked to alkaline NaHCO3 waters (pH~9), moderate oxic conditions and temperatures of around 18 degrees C 19 degrees C. The most plausible hypothesis to explain the high arsenic concentrations is the contribution of deeper regional flows with a significant hydrothermal component (cold-hydrothermal waters), flowing through faults in the basement rock. Water mixing and water-rock interactions occur both in the fissured aquifer media (igneous and metasedimentary bedrock) and in the sedimentary environment of the CDB, where agricultural pollution phenomena are also active. A combination of multivariate statistical tools and hydrochemical analysis enabled the distribution pattern of dissolved As and other PTGTE in groundwaters in the study area to be interpreted, and their most likely origin to be established. This methodology could be applied to other sedimentary areas with similar characteristics and problems. PMID- 28343042 TI - In situ determination of trace elements in Fucus spp. by field-portable-XRF. AB - Fresh and freeze-dried sample sections of the coastal macroalgae, Fucus serratus and F. vesiculosus, and the brackish water macroalga, F. ceranoides, have been analysed for trace elements by field-portable-X-ray fluorescence (FP-XRF) spectrometry using a Niton XL3t in a low density mode with thickness correction. When analysed fresh in a laboratory accessory stand for a period of 200 seconds, As, Br, Fe and Zn were registered in the apex, mid-frond and lower stipe of all species, with detection limits of a few MUg g-1 (As) or a few tens of MUg g-1 (Br, Fe, Zn); when analysed dry under the same conditions, concentrations returned were systematically higher and Cu and Pb were detected in a number of F. ceranoides sections. Concentrations arising from both approaches on a dry weight basis were highly correlated, with deviations from unit slope attributed to the absorption of fluorescent X-rays by internal and surficial water when analysed fresh. With algorithms correcting for the effects of water on mass and X-ray absorption, sections of F. vesiculosus and F. ceranoides were analysed in situ with the XRF connected to a mobile stand and laptop. Dry weight concentrations returned for As and Zn were significantly correlated with respective concentrations subsequently determined by ICP-MS following acid digestion and with a slope close to unity; lower concentrations of Fe returned by ICP were attributed to the incomplete acid digestion of silt particles that evaded an initial cleaning step, while Br concentrations could not be verified independently because of loss of volatile forms during digestion. The in situ determination of trace elements in fucoids by FP-XRF provides a rapid and non destructive means of monitoring environmental quality and identifying hot-spots of contamination, and enables a research strategy to be developed iteratively that is informed by immediate results. PMID- 28343043 TI - Clonal integration increases tolerance of a phalanx clonal plant to defoliation. AB - Defoliation by herbivores commonly imposes negative effects on plants, and physiological integration (resource sharing) can enhance the ability of guerilla clonal plants to tolerate stresses. Here we examined whether physiological integration can increase the ability of phalanx clonal plants to withstand defoliation. On a high mountain grassland in southwestern China, we subjected the phalanx clonal plant Iris delavayi within 10cm*10cm plots to three levels of defoliation intensity, i.e., control (no defoliation), moderate (50% shoot removal to simulate moderate herbivory) and heavy defoliation (100% shoot removal to simulate heavy herbivory), and kept rhizomes at the plot edges connected (allowing physiological integration) or disconnected (preventing integration) with intact ramets outside the plots. Defoliation significantly reduced leaf biomass, root biomass and ramet number of I. delavayi. Clonal integration did not affect the growth of I. delavayi under control, but significantly increased total biomass, rhizome and root biomass under heavy defoliation, and leaf biomass and ramet number under moderate defoliation. We conclude that clonal integration associated with resource reallocation plays an important role in maintaining the productivity of the alpine and subalpine grassland ecosystems in SW China where clonal plants are a dominant component of the grasslands and are commonly extensively managed with moderate grazing intensity. Our results also help to better understand the adaption and tolerance of phalanx clonal plants subjected to long-term grazing in the high mountain environment. PMID- 28343044 TI - A system of containment to prevent oil spills from sunken tankers. AB - Worldwide tank spills represent 10% of the average annual input of oil in the sea. When such spills arise from wrecks at depth, neutralisation of environmental impacts is difficult to achieve. Extracting oil from sunken tankers is expensive, and, unfortunately, all of the oil cannot be extracted, as the Prestige case demonstrates. We propose an environmentally appropriate, cost-effective and proactive method to stop the long-term problem of leaks from sunken tankers similar to the Prestige. This method confines the wreck with a "sediment" capping of sepiolite mineral that emulates a natural sediment. A set of experiments and simulations shows that sepiolite has the characteristics necessary to accomplish the confinement of any current or future sunken tanker with minimal environmental perturbation. PMID- 28343045 TI - Cervical disc arthroplasty: do conflicts of interest influence the outcome of clinical studies? AB - BACKGROUND CONTEXT: Cervical disc arthroplasty (CDA) is an emerging technique for the treatment of cervical degenerative disease. Multiple studies have investigated the outcomes of CDA, particularly in comparison with cervical arthrodesis techniques such as anterior cervical discectomy and fusion (ACDF). As many entities have financial interests in CDA implants, it is imperative to consider the influence of conflicts of interest on the results of studies investigating the efficacy of CDA. PURPOSE: This study aimed to determine if there is an association between the presence of conflicts of interest among study authors and the reported outcome of studies involving CDA. STUDY DESIGN: This is a systematic review of clinical CDA publications until October 2016. OUTCOME MEASURE: The outcome measures are presence of conflicts of interest, level of evidence, and outcome for all included studies. METHODS: PubMed and MEDLINE databases were searched for articles presenting clinical, radiographic, and cost outcomes of CDA. Data extracted from each article included title, authors, publication year, level of evidence, prosthesis type, number of operative levels, presence of conflicts of interest, and outcome. Conflicts of interest were determined by the presence of any conflicts for any author within manuscript disclosure sections or through Open Payments reporting. Outcomes of each study were graded as either favorable, unfavorable, or equivocal. The presence of conflicts of interest was tested for an association with the level of evidence and study outcome using Pearson chi-square analysis, Fisher exact test, or logistic regression for categorical variables. The authors report no conflicts of interest directly related to this work, and have not received any funds in support of this work. RESULTS: A total of 98 articles were included in this analysis. In total, 44.9% (44) of articles had the presence of a conflict of interest, whereas 55.1% (54) of articles did not. Conflicted studies were more likely to present level I evidence and less likely to present level IV evidence than non-conflicted studies (p<.001). Furthermore, conflicted studies were more likely to report favorable outcomes after CDA than non-conflicted studies (90.9% vs. 74.1%, p=.040). CONCLUSIONS: The results of this study suggest that the majority of conflicted and non-conflicted studies report favorable results in patients undergoing CDA. However, conflicted studies were also more likely to report favorable outcomes compared with non-conflicted studies. Individual clinicians must critically review published studies for potential conflicts of interest before incorporating CDA into their practice. PMID- 28343046 TI - Perioperative hemoglobin A1c as a predictor of deep infection following single level lumbar decompression in patients with diabetes. AB - BACKGROUND CONTEXT: Although multiple studies have cited that diabetes mellitus as a risk factor decreased functional outcomes, increased infectious complications, and overall increased reoperation rate following degenerative lumbar spinal surgery, few have investigated how perioperative glycemic control influences such complications. PURPOSE: The primary goal of the present study was to use a national database to evaluate the association of perioperative glycemic control as demonstrated by hemoglobin A1c (HbA1c) levels in patients with diabetes undergoing primary, single-level decompression without concomitant fusion with the incidence of deep postoperative infection requiring operative irrigation and debridement. Our secondary objective was to calculate a threshold level of HbA1c above which the risk of postoperative infection after lumbar decompression increases significantly in patients with diabetes. STUDY DESIGN/SETTING: This is a retrospective case control database study, with Level III evidence. PATIENT SAMPLE: This study comprised private-payer patients with diabetes mellitus undergoing single-level lumbar decompression with an HbA1c laboratory value recorded in the database within 3 months of surgery. OUTCOME MEASURES: The outcome examined in this study was deep infection following primary, single-level lumbar decompression requiring surgical intervention. Postoperative infection within 1 year of the index primary, single-level lumbar decompression was assessed using Current Procedural Terminology (CPT) procedure codes and the International Classification of Diseases, 9th Revision (ICD-9) diagnostic codes. METHODS: The Humana private-payer dataset from the PearlDiver database was used for this study. The database was queried for patients with diabetes mellitus undergoing primary, single-level lumbar decompression surgery using CPT codes. Patients with a diagnosis of diabetes mellitus who had an HbA1c level drawn within 3 months before or after their surgical date were then selected to form the study group using the ICD-9 diagnostic codes. Patients were then divided into groups based on their HbA1c level by increments of 0.5 mg/dL. The incidence of deep infection requiring operative intervention within 1 year for each HbA1c group was then identified using CPT and ICD-9 codes. A receiver operating characteristic (ROC) and area under the curve (AUC) analysis was performed to determine an optimal threshold value of the HbA1c above which the risk of postoperativeinfection was significantly increased. The threshold value was tested using a multivariable binomial logistic regression analysis. RESULTS: A total of 5,194 patients who underwent primary, single-level lumbar decompression with diabetes and a perioperative HbA1c recorded within 3 months of surgery were included in the study. The rate of infection ranged from a low of 0.5% up to 3.5% for patients with an HbA1c level >11.0 mg/dL (p=.012). The inflection point of the ROC curve corresponded to an HbA1c level above 7.5 mg/dL (p=.01, AUC=0.71, specificity=70%, sensitivity=53%). After controlling for patient demographics and medical comorbidities, patients with an HbA1c level of 7.5 mg/dL or above had a significantly higher risk for deep infection compared with patients below this threshold (odds ratio: 2.9, 95% confidence interval: 1.8 4.9, p<.0001). CONCLUSIONS: The risk of deep postoperative infection requiring surgical intervention following single-level lumbar decompression in patients with diabetes mellitus increases as the perioperative HbA1c increases. The ROC and multivariable regression analyses determined that a perioperative HbA1c above 7.5 mg/dL could serve as a threshold for a significantly increased risk of deep postoperative infection following lumbar decompression. PMID- 28343047 TI - The odyssey of sagittal pelvic morphology during human evolution: a perspective on different Hominoidae. PMID- 28343048 TI - Protective effect of CDDO-ethyl amide against high-glucose-induced oxidative injury via the Nrf2/HO-1 pathway. AB - BACKGROUND CONTEXT: Intervertebral disc degeneration (IDD) is the main cause of low back pain, and nucleus pulposus (NP) cell apoptosis is an important risk factor of IDD. However, the molecular mechanism of this disease remains unknown. PURPOSE: To assess the potential protective effect of CDDO-ethyl amide (EA) against high-glucose-induced oxidative stress injury in NP cells and to investigate the mechanism of antioxidative effects and apoptotic inhibition. STUDY DESIGN/SETTING: To find new molecule to inhibit intervertebral disc degeneration. METHODS: Viability, reactive oxygen species (ROS) levels, and apoptosis were examined in NP cells. The protein expression levels of HO-1 and Nrf2 were measured through Western blot RESULTS: CDDO-EA elicited cytoprotective effects against NP cell apoptosis and ROS accumulation induced by high glucose. CDDO-EA treatment increased the HO-1 and Nrf2 expression abrogated by HO-1, Nrf2, and mitogen-activated protein kinase inhibitors. CONCLUSIONS: The phosphorylation and nuclear translocation of Nrf2 are crucial for HO-1 overexpression induced by CDDO-EA, which is essential for the cytoprotection against high-glucose-induced oxidative stress in NP cells. PMID- 28343049 TI - Stabilisation of spent mushroom substrate for application as a plant growth promoting organic amendment. AB - Over three million tonnes of spent mushroom substrate (SMS) are produced in Europe every year as a by-product of the cultivation of Agaricus bisporus. The management of SMS has become an increasing challenge for the mushroom production industry, and finding environmentally and economically sustainable solutions for this organic residue is, therefore, highly desirable. Due to its physical properties and nutrient content, SMS has great potential to be employed in agricultural and horticultural sectors, and further contribute to reduce the use of non-renewable resources, such as peat. However, SMS is often regarded as not being stable and/or mature, which hampers its wide use for crop production. Here, we demonstrate the stabilisation of SMS and its subsequent use as organic fertiliser and partial peat replacement in horticulture. The stabilisation was performed in a laboratory-scale composting system, with controlled temperature and aeration. Physical and chemical parameters were monitored during composting and provided information on the progress of the process. Water soluble carbohydrates (WSC) content was found to be the most reliable parameter to predict SMS stability. In situ oxygen consumption indicated the main composting phases, reflecting major changes in microbial activity. The structure of the bacterial community was also found to be a potential predictor of stability, as the compositional changes followed the composting progress. By contrast, the fungal community did not present clear successional process along the experiment. Maturity and quality of the stabilised SMS were assessed in a horticultural growing trial. When used as the sole fertiliser source, SMS was able to support Lolium multiflorum (Italian ryegrass) growth and significantly improved grass yield with a concentration-dependent response, increasing grass biomass up to 300%, when compared to the untreated control. In summary, the results indicated that the method employed was efficient in generating a stable and mature product, which has a great potential to be applied in horticulture. This study represents a step forward in the management of SMS residue, and also provides an alternative to reduce the use of peat in horticulture, alleviating environmental impacts to peatland ecosystems. PMID- 28343050 TI - Photocatalytic efficiency of Fe2O3/TiO2 for the degradation of typical dyes in textile industries: Effects of calcination temperature and UV-assisted thermal synthesis. AB - The inadequate management practices in industrial textile effluents have a considerable negative impact on the environment and human health due to the indiscriminate release of dyes. Photocatalysis is one of the diverse advance oxidation processes (AOPs) and titanium dioxide (TiO2) is recognized for its high oxidation and reduction power. A composite photocatalyst of Fe2O3/TiO2 is synthesized using different mass ratios of Fe:TiO2 to improve its photoactivity. The composite photocatalyst is calcined at 300-900 degrees C. Their photocatalytic activity for the degradation of Congo red (CR) and methyl orange (MO) is investigated by total organic carbon (TOC) analysis. The formation and characterization of the as-prepared composite are studied by scanning electron microscopy (SEM) coupled with energy dispersive X-ray spectroscopy (EDS). The effect of calcination temperature on the composite Fe2O3/TiO2 photocatalyst is investigated using Fourier transform infrared spectroscopy (FTIR). The photocatalytic activity and the phase conversion are studied by X-ray diffraction (XRD). The specific surface area of photocatalysts at different calcination temperatures is investigated based on Brunauer-Emmett-Teller (BET) surface area analysis. Results show that at an optimum calcination temperature of 300 degrees C for the photocatalyst preparation, the specific surface area is maximum and the photocatalyst has the highest photoactivity. Thus, the degradation of organic materials reaches 62.0% for MO and 46.8% for CR in the presence of Fe2O3/TiO2 (0.01 w:w Fe:TiO2) calcined at 300 degrees C with the highest specific surface area (98.73 m2/g). The transformation of TiO2 from anatase to rutile is facilitated by high temperature and high concentration of iron while high crystallization and particle size increase occur. An optimum calcination temperature of 300 degrees C is found at which the degradation of typical dyes in textile industries is maximum. PMID- 28343051 TI - Tolerability of cariprazine in the treatment of acute bipolar I mania: A pooled post hoc analysis of 3 phase II/III studies. AB - BACKGROUND: Atypical antipsychotics have broad-spectrum efficacy against core symptoms of acute mania/mixed states in bipolar disorder; however, they are associated with clinically significant adverse effects (AEs). METHODS: This post hoc analysis evaluated the safety and tolerability of the atypical antipsychotic cariprazine in the treatment of adult patients with acute manic/mixed episodes of bipolar I disorder. Data were taken from three 3-week randomized, double-blind, placebo-controlled, flexible-dose trials of cariprazine 3-12mg/d. Patient subgroups categorized by modal daily dose (3-6mg/d; 9-12mg/d) were used to assess dose response. RESULTS: The pooled safety population comprised 1065 patients (placebo=442; cariprazine 3-6mg/d=263; cariprazine 9-12mg/d=360). More cariprazine- than placebo-treated patients reported double-blind treatment emergent AEs; the overall AE incidence was similar among cariprazine-dose groups. AEs reported in >=5% of cariprazine patients overall with at least twice the incidence of placebo were akathisia, extrapyramidal symptoms, restlessness, and vomiting. The incidence of SAEs was low and similar between the placebo- and cariprazine-treatment groups. Metabolic parameter changes were small and generally similar between cariprazine and placebo groups; mean increases in fasting glucose levels were greater with cariprazine (3-6mg/d=6.6mg/dL; 9 12mg/d=7.2mg/dL) than placebo (1.7mg/dL). Mean weight change was 0.54kg and 0.17kg for cariprazine and placebo, respectively; weight increase >=7% was <3% in all treatment groups. Cariprazine was not associated with clinically meaningful changes in electrocardiogram parameters. LIMITATIONS: Post hoc analysis, flexible dose design, short trial duration. CONCLUSION: Cariprazine was generally safe and well-tolerated in patients with manic/mixed episodes associated with bipolar I disorder. PMID- 28343053 TI - Self-Reported Graphic Personal and Social Performance Scale (SRG-PSP) for measuring functionality in patients with bipolar disorder. AB - OBJECTIVES: The self-reported graphic version of the Personal and Social Performance Scale (SRG-PSP) is the first graphic, self-reported rating scale that assesses functioning, and its reliability and validity have been documented in patients with schizophrenia. This study investigated the validity of SRG-PSP in patients with bipolar disorder (BD). METHODS: Patients with BD were recruited from psychiatric outpatient clinics, and assessed with the Young Mania Rating Scale (YMRS), the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impression Scale (CGI)-Bipolar and CGI-Depression, the Positive and Negative Symptom Scale (PANSS), the Global assessment of function (GAF), and the PSP. All participants completed the self-rating questionnaires: the SRG-PSP, the 36-Item Short-Form Health Survey (SF-36), and the Sheehan disability Scale (SDS). RESULTS: In total, 114 patients with BD were enrolled. The criterion-related validities between the SRG-PSP and the PSP were all significantly correlated with their counterparts. The global score of the SRG-PSP was significantly correlated with the scores of the YMRS, MADRS, PANSS, CGI-Depression, GAF, SF-36, and SDS. Three SRG-PSP domains (socially useful activities, personal and social relationships, and self-care) were negatively correlated with the scores of the MADRS, PANSS, CGI-depression, and SDS; and were positively correlated with the GAF, SF-36 scores. The disturbing and aggressive behavior domain was positively correlated with the scores of the YMRS, MADRS, PANSS, CGI-Bipolar, CGI Depression, and SDS; and was negatively correlated with the GAF, SF-36 scores (all p<0.01). CONCLUSION: The SRG-PSP is a validated self-reported scale for assessing functionality in patients with BD. PMID- 28343052 TI - Season of treatment initiation with antidepressants and suicidal behavior: A population-based cohort study in Sweden. AB - BACKGROUND: Decreased binding capacity of SERT in the prefrontal cortex has been observed in both suicide victims and suicide attempters. Moreover, some studies have shown that SERT has a seasonal variation with lower binding capacity in the spring and summer, which coincides with a seasonal peak of suicides. Our aim was to explore whether the season of treatment initiation with antidepressants is associated with suicide or suicide attempt and compare it with the underlying suicide seasonality in the general population. METHODS: Using Swedish registers, patients who initiated treatment with an antidepressant were followed up to three months for suicidal behavior. Cox regression analyses were used. Results were compared with the underlying seasonal pattern by calculating standardized mortality ratios (SMRs) for suicides and standardized incidence ratios (SIRs) for suicide attempts. RESULTS: Patients aged >=65 years had higher risk for suicide when initiating antidepressant treatment in the summer, and also a higher risk for suicide attempt when initiating treatment in the spring and summer. Young patients (0-24 years) presented a higher risk for suicide attempt when initiating treatment in the autumn. Patients with previous suicide attempt had a seasonal pattern, with a higher risk to carry out a suicide attempt in the summer and autumn. Results from the SMR and SIR calculations numerically support these findings. LIMITATIONS: We used information of filling an antidepressant prescription as a proxy of actual antidepressant treatment. Patients with combination, augmentation therapy or those switching antidepressant during follow up were excluded. Thus, our results refer to less complicated psychopathology. CONCLUSIONS: Our results indicate an interaction between biological and health care-related factors for the observed seasonal pattern of suicidal behavior in the elderly, whereas psychological and societal factors may be more important for the seasonality observed in the younger patients. PMID- 28343054 TI - "Role of cardiovascular magnetic resonance in assessing patients with chest pain, increased troponin levels and normal coronary arteries". PMID- 28343055 TI - Effects of porous carrier size on biofilm development, microbial distribution and nitrogen removal in microaerobic bioreactors. AB - In this study, effects of porous carrier's size (polyurethane-based) on microbial characteristics were systematically investigated in addition to nitrogen removal performance in six microaerobic bioreactors. Among different sized carriers (50, 30, 20, 15,10, 5mm), 15mm carrier showed highest nitrogen removal (98%) due to optimal micro-environments created for aerobic nitrifiers in outer layer (0-7mm), nitrifiers and denitrifiers in middle layer (7-10mm) and anaerobic denitrifiers in inner layer (10-15mm). Candidatus brocadia, a dominant anammox bacteria, was solely concentrated close to centroid (0-70MUm) and strongly co-aggregated with other bacterial communities in the middle layer of the carrier. Contrarily, carriers with a smaller (<15mm) or larger size (>15mm) either destroy the effective zone for anaerobic denitrifiers or damage the microaerobic environments due to poor mass transfer. This study is of particular use for optimal design of carriers in enhancing simultaneous nitrification-denitrification in microaerobic wastewater treatment processes. PMID- 28343056 TI - Preliminary investigation of the microwave pyrolysis mechanism of sludge based on high frequency structure simulator simulation of the electromagnetic field distribution. AB - Under microwave irradiation, raw sludge was pyrolyzed mainly by evaporation of water, with a weight loss ratio of 84.8% and a maximum temperature not exceeding 200 degrees C. High-temperature pyrolysis of SiC sludge could be realized, with a weight loss ratio of 93.4% and a final pyrolysis temperature of 1131.7 degrees C. Variations between the electric field intensity distribution are the main reason for the differences of pyrolysis efficiencies. HFSS simulation showed that the electric field intensity of the raw sludge gradually decreased from 2.94*104V/m to 0.88*104V/m when pyrolysis ends, while that of SiC sludge decreased from 3.73*104V/m at the beginning to 1.28*104V/m, then increased to 4.03*104V/m. The electromagnetic effect is the main factor (r>=0.91) influencing the temperature increase and weight loss of raw sludge. Both the electromagnetic effect and heat conduction effect influenced temperature rise and weight loss of SiC sludge, but the former's influence was comparatively larger. PMID- 28343057 TI - Effects of side-stream ratio on sludge reduction and microbial structures of anaerobic side-stream reactor coupled membrane bioreactors. AB - An anoxic/oxic membrane bioreactor (AO-MBR) and three anaerobic side-stream reactor (ASSR) coupled MBRs (ASSR-MBR) were operated to investigate effects of side-stream ratio (SR) on sludge reduction and microbial community structure of ASSR-MBRs. The ASSR-MBR achieved efficient COD and ammonium nitrogen removal. SR increased from 0.2 to 1.0 favored nitrogen removal, and increased sludge reduction from 6.0% to 49.7%. The total released COD in the ASSR increased with the rising SR and was inversely proportional to sludge yield of ASSR-MBR. Pyrosequencing analysis showed that phyla Chloroflexi and Armatimonadetes surviving in anaerobic conditions were enriched in the ASSR, while Nitrospirae was dominant in the MBR. Comparison at the genus level revealed that higher SR favored the growth of slow growers, while lower SR enriched hydrolytic and predatory bacteria. The results suggested that SR has a profound effect on nitrogen removal, sludge reduction and microbial community structure in the ASSR MBR. PMID- 28343058 TI - Butyric acid production from lignocellulosic biomass hydrolysates by engineered Clostridium tyrobutyricum overexpressing xylose catabolism genes for glucose and xylose co-utilization. AB - Clostridium tyrobutyricum can utilize glucose and xylose as carbon source for butyric acid production. However, xylose catabolism is inhibited by glucose, hampering butyric acid production from lignocellulosic biomass hydrolysates containing both glucose and xylose. In this study, an engineered strain of C. tyrobutyricum Ct-pTBA overexpressing heterologous xylose catabolism genes (xylT, xylA, and xylB) was investigated for co-utilizing glucose and xylose present in hydrolysates of plant biomass, including soybean hull, corn fiber, wheat straw, rice straw, and sugarcane bagasse. Compared to the wild-type strain, Ct-pTBA showed higher xylose utilization without significant glucose catabolite repression, achieving near 100% utilization of glucose and xylose present in lignocellulosic biomass hydrolysates in bioreactor at pH 6. About 42.6g/L butyrate at a productivity of 0.56g/L.h and yield of 0.36g/g was obtained in batch fermentation, demonstrating the potential of C. tyrobutyricum Ct-pTBA for butyric acid production from lignocellulosic biomass hydrolysates. PMID- 28343059 TI - Internal cycling, not external loading, decides the nutrient limitation in eutrophic lake: A dynamic model with temporal Bayesian hierarchical inference. AB - Lake eutrophication is associated with excessive anthropogenic nutrients (mainly nitrogen (N) and phosphorus (P)) and unobserved internal nutrient cycling. Despite the advances in understanding the role of external loadings, the contribution of internal nutrient cycling is still an open question. A dynamic mass-balance model was developed to simulate and measure the contributions of internal cycling and external loading. It was based on the temporal Bayesian Hierarchical Framework (BHM), where we explored the seasonal patterns in the dynamics of nutrient cycling processes and the limitation of N and P on phytoplankton growth in hyper-eutrophic Lake Dianchi, China. The dynamic patterns of the five state variables (Chla, TP, ammonia, nitrate and organic N) were simulated based on the model. Five parameters (algae growth rate, sediment exchange rate of N and P, nitrification rate and denitrification rate) were estimated based on BHM. The model provided a good fit to observations. Our model results highlighted the role of internal cycling of N and P in Lake Dianchi. The internal cycling processes contributed more than external loading to the N and P changes in the water column. Further insights into the nutrient limitation analysis indicated that the sediment exchange of P determined the P limitation. Allowing for the contribution of denitrification to N removal, N was the more limiting nutrient in most of the time, however, P was the more important nutrient for eutrophication management. For Lake Dianchi, it would not be possible to recover solely by reducing the external watershed nutrient load; the mechanisms of internal cycling should also be considered as an approach to inhibit the release of sediments and to enhance denitrification. PMID- 28343060 TI - UV/chlorine treatment of carbamazepine: Transformation products and their formation kinetics. AB - Carbamazepine (CBZ) is one of the pharmaceuticals most frequently detected in the aqueous environment. This study investigated the transformation products when CBZ is degraded by chlorine under ultraviolet (UV) irradiation (the UV/chlorine process). Detailed pathways for the degradation of CBZ were elucidated using ultra-high performance liquid chromatography (UHPLC)-quadrupole time-of-flight mass spectrometry (QTOF-MS). CBZ is readily degraded by hydroxyl radicals (HO) and chlorine radicals (Cl) in the UV/chlorine process, and 24 transformation products were identified. The products indicate that the 10,11-double bond and aromatic ring in CBZ are the sites most susceptible to attack by HO and Cl. Subsequent reaction produces hydroxylated and chlorinated aromatic ring products. Four specific products were quantified and their evolution was related with the chlorine dose, pH, and natural organic matter concentration. Their yields showed an increase followed by a decreasing trend with prolonged reaction time. CBZ 10,11-epoxide (I), the main quantified transformation product from HO oxidation, was observed with a peak transformation yield of 3-32% depending on the conditions. The more toxic acridine (IV) was formed involving both HO and Cl with peak transformation yields of 0.4-1%. All four quantified products together amounted to a peak transformation yield of 34.5%. The potential toxicity of the transformation products was assayed by evaluating their inhibition of the bioluminescence of the bacterium Vibrio Fischeri. The inhibition increased at first and the decreased at longer reaction times, which was in parallel with the evolution of transformation products. PMID- 28343061 TI - Automated diabetic macular edema (DME) grading system using DWT, DCT Features and maculopathy index. AB - The cause of diabetic macular edema (DME) is due to prolonged and uncontrolled diabetes mellitus (DM) which affects the vision of diabetic subjects. DME is graded based on the exudate location from the macula. It is clinically diagnosed using fundus images which is tedious and time-consuming. Regular eye screening and subsequent treatment may prevent the vision loss. Hence, in this work, a hybrid system based on Radon transform (RT), discrete wavelet transform (DWT) and discrete cosine transform (DCT) are proposed for an automated detection of DME. The fundus images are subjected to RT to obtain sinograms and DWT is applied on these sinograms to extract wavelet coefficients (approximate, horizontal, vertical and diagonal). DCT is applied on approximate coefficients to obtain 2D DCT coefficients. Further, these coefficients are converted into 1D vector by arranging the coefficients in zig-zag manner. This 1D signal is subjected to locality sensitive discriminant analysis (LSDA). Finally, various supervised classifiers are used to classify the three classes using significant features. Our proposed technique yielded a classification accuracy of 100% and 97.01% using two and seven significant features for private and public (MESSIDOR) databases respectively. Also, a maculopathy index is formulated with two significant parameters to discriminate the three groups distinctly using a single integer. Hence, our obtained results suggest that this system can be used as an eye screening tool for diabetic subjects for DME. PMID- 28343062 TI - The material, moral, and affective worlds of dealing and crime among young men entrenched in an inner city drug scene. AB - A large body of previous research has elucidated how involvement in drug dealing and crime among marginalized urban youth who use drugs is shaped by the imperatives of addiction and survival in the context of poverty. However, a growing body of research has examined how youth's involvement in these activities is shaped by more expansive desires and moralities. In this paper, we examine the material, moral, and affective worlds of loosely gang affiliated, street level dealing and crime among one group of young men in Vancouver, Canada. Drawing on longitudinal interviews with 44 young men from 2008 to 2016, and ethnographic fieldwork with a group of approximately 15 of those young men over the same time period, we argue that for these youth, dealing and crime were not solely about economic survival, or even the accrual of highly meaningful forms of "street capital" in the margins. Rather, as "regimes of living," dealing and crime also opened up new value systems, moral logics, and affects in relation to the tremendous risks, potential rewards, and crushing boredom of life in the margins. These activities were also understood as a way into deeply desired forms of social spatial belonging in the city, which had previously only been imagined. However, across time dealing and crime "embedded" young men in cycles of incarceration, destitution, addictions, and mental health crises that ultimately reinforced their exclusion-from legal employment, but also within the world of crime. The findings of this study underscore the importance of adopting a life course perspective in order to meaningfully address the harms associated with involvement in dealing and crime among youth in our setting. PMID- 28343063 TI - Motives for illicit prescription drug use among university students: A systematic review and meta-analysis. AB - BACKGROUND: There is a growing body of research on the motives for prescription drug misuse (PDM) among university students. However, the overall findings of this research are hard to decipher. Studies use different methods, they examine different drug types, the motives are phrased in various ways, and the results differ widely. In order to make sense of this body of knowledge, it is necessary to synthesise the results across studies and draw out conclusions. METHODS: The research comprises a systematic review and meta-analysis of studies on the motives of university students for illicit use of four different types of prescription medication (stimulants, analgesics, tranquillisers and sedatives). The search for studies was conducted on six bibliographic databases with stated criteria governing search eligibility and inclusion in the final review. RESULTS: Overall, the most prevalent motives for PDM among university students cover some kind of personal enhancement to the user in terms of performance (in relation to sports, and academic outcomes), mental health (ability sleep, to reduce anxiety), or physical health (manage pre-existing illnesses). Fewer than half of users said that they were involved in PDM for pleasure purposes (to party, to get high, or to experiment). CONCLUSION: PDM among students might be viewed as a means of self improvement when other means of achieving desired objectives are unavailable or restricted. A more thorough understanding of motives for PDM, especially in relation to their influence on behaviour, might help in devising university-based treatment and prevention programmes. PMID- 28343064 TI - A barley homolog of yeast ATG6 is involved in multiple abiotic stress responses and stress resistance regulation. AB - Autophagy is a highly conserved degradation pathway among eukaryote cells, which can recycle damaged or unwanted cell materials upon encountering stress conditions. As a key component of the Class III PI3K kinase complex, ATG6/Beclin 1 is essential for autophagosome formation. In this study, we isolated a putative HvATG6 gene in barley genome. The protein encoded by HvATG6 shares high sequence identity to ATG6 orthologs in rice and wheat, and has a typical autophagy specific domain containing segments of repeated beta-sheet-alpha-helix. The expression of HvATG6 protein restored the appearance of autophagosomes in yeast atg6 mutant, indicating that HvATG6 complements the deficiency of yeast ATG6 protein in autophagy. Punctate florescence signals, considered as the PAS for autophagosome initiation, were observed in the cytoplasm of cells when HvATG6-GFP fusion construct was transformed into barley protoplast. Furthermore, the expression of HvATG6 was upregulated by various abiotic stresses including dark, H2O2 treatment, nitrogen deficiency, high salinity, drought, low temperature and toxic aluminum. Knockdown of HvATG6 in barley leaves through barley strip mosaic virus (BSMV)-induced gene silencing led to accelerated yellowing under dark and H2O2 treatments. Based on the above findings, we propose that barley ATG6 plays the similar role as other plant ATG6 orthologs, and might be involved in stress induced autophagy process. PMID- 28343065 TI - Interaction of a chelating agent, 5-hydroxy-2-(hydroxymethyl)pyridin-4(1H)-one, with Al(III), Cu(II) and Zn(II) ions. AB - 5-Hydroxy-2-(hydroxymethyl)pyridin-4(1H)-one ligand, an iron chelator, was evaluated for its coordination ability toward Al(III), Cu(II) and Zn(II) ions by using potentiometric, NMR, EPR and UV-Vis techniques. The behavior of the ligand with the non-essential Al(III) ion has been examined, as well as its potential influence on the homeostatic equilibria of the essential Cu(II) and Zn(II) ions. Structural information on the complex formation equilibria have been obtained from 1D and 2D NMR study. The donor atoms involved in the coordination of Al(III), Cu(II) and Zn(II) ions are (O, O) the same as for Fe(III) at physiological pH value, even if from the complexation competition study the ligand appears to be more selective toward Fe(III) ions supporting that it can be used as an iron chelating agent. The involvement of N-donor atoms at high pH in Cu(II) coordination has been determined by using EPR and UV-Vis techniques. PMID- 28343067 TI - Reading problems and major mental disorders - co-occurrences and familial overlaps in a Swedish nationwide cohort. AB - Reading problems often co-occur with ADHD and conduct disorder. However, the patterns of co-occurrence and familial overlap between reading problems and other psychiatric disorders have not been systematically explored. We conducted a register-based cohort study including 8719 individuals with reading problems and their siblings, along with matched comparison individuals. Conditional logistic regressions estimated risks for ADHD, autism, obsessive-compulsive disorder, anorexia nervosa, schizophrenia, bipolar disorder, depression, substance use disorder, and violent/non-violent criminality in individuals with reading problems and their siblings. Diagnoses of psychiatric disorders were physician assigned and ascertained from the Swedish National Patient Register, and crime convictions from the Swedish National Crime Register. We found that individuals with reading problems had excess risks for all psychiatric disorders (except anorexia nervosa) and criminality, with risk ratios between 1.34 and 4.91. Siblings of individuals with reading problems showed excess risks for ADHD, autism, schizophrenia, bipolar disorder, depression, substance use disorder, and non-violent criminality, with risk ratios between 1.14 and 1.70. In summary, individuals with reading problems had increased risks of virtually all psychiatric disorders, and criminality. The origin of most of these overlaps was familial, in that siblings of individuals with reading problems also had elevated risks of ADHD, autism, schizophrenia, bipolar disorder, depression, substance use disorder, and non-violent criminality. These findings have implications for gene searching efforts, and suggest that health care practitioners should be alert for signs of psychiatric disorders in families where reading problems exist. PMID- 28343066 TI - Calcium triggers reversal of calmodulin on nested anti-parallel sites in the IQ motif of the neuronal voltage-dependent sodium channel NaV1.2. AB - Several members of the voltage-gated sodium channel family are regulated by calmodulin (CaM) and ionic calcium. The neuronal voltage-gated sodium channel NaV1.2 contains binding sites for both apo (calcium-depleted) and calcium saturated CaM. We have determined equilibrium dissociation constants for rat NaV1.2 IQ motif [IQRAYRRYLLK] binding to apo CaM (~3nM) and (Ca2+)4-CaM (~85nM), showing that apo CaM binding is favored by 30-fold. For both apo and (Ca2+)4-CaM, NMR demonstrated that NaV1.2 IQ motif peptide (NaV1.2IQp) exclusively made contacts with C-domain residues of CaM (CaMC). To understand how calcium triggers conformational change at the CaM-IQ interface, we determined a solution structure (2M5E.pdb) of (Ca2+)2-CaMC bound to NaV1.2IQp. The polarity of (Ca2+)2-CaMC relative to the IQ motif was opposite to that seen in apo CaMC-Nav1.2IQp (2KXW), revealing that CaMC recognizes nested, anti-parallel sites in Nav1.2IQp. Reversal of CaM may require transient release from the IQ motif during calcium binding, and facilitate a re-orientation of CaMN allowing interactions with non-IQ NaV1.2 residues or auxiliary regulatory proteins interacting in the vicinity of the IQ motif. PMID- 28343069 TI - Linc00152 promotes cancer progression in hepatitis B virus-associated hepatocellular carcinoma. AB - BACKGROUND: The X protein (HBx) plays as a key role in hepatocarcinogenesis associated with hepatitis B virus (HBV) infections. The study aimed to figure out the role of Linc00152 in hepatocellular carcinoma (HCC) and the association between the expression levels of Linc00152 and HBx. METHODS: QRT-PCR assays were applied to analyzed the expression levels of Linc00152 and HBx. Kaplan-Meier survival curve was performed to identify the association between LINC00152 and the over survival time (OS) in HCC patients. Cell growth and invasion ability was evaluated by CCK8 cell proliferation and transwell invasion assays. Western-blot analysis was detected the protein expression. RNA immunoprecipitation (RIP), RNA pull down and chromatin Immunoprecipitation (ChIP) assays was also been carried out. RESULTS: We demonstrated that LINC00152 expression in hepatocellular carcinoma (HCC) patients was significantly higher compared with adjacent non tumour tissues and positively correlated with tumor size, HBV infection (HBsAg) and tumor number. Patient with hepatitis B virus (HBV) infection HCC was higher expression than that without HBV. Furthermore, the expression levels of Linc00152 were positively correlated with HBx expression in HCC tissues and higher Linc00152 expression levels were correlated with poor prognosis of HCC patients. In vitro, Linc00152 was up-regulated in Huh-7 and SM7721 cells after overexpression of HBx and down-regulated after silencing HBx. Furthermore, silencing Linc00152 suppressed the cell proliferation and invasion. Moreover, we found that Linc00152 inhibited the E-cadherin expression via interacting with EZH2 and promoted the Epithelial-mesenchymal transition (EMT) phenomenon in HCC cells. CONCLUSIONS: These results suggested that HBx enhanced LINC00152 expression and inhibition of LINC00152 could provide a therapeutic target for HCC. PMID- 28343068 TI - The role of TRAIL in fatigue induced by repeated stress from radiotherapy. AB - Fatigue is one of the most common and debilitating side effects of cancer and cancer treatment, and yet its etiology remains elusive. The goal of this study is to understand the role of chronic inflammation in fatigue following repeated stress from radiotherapy. Fatigue and non-fatigue categories were assessed using >= 3-point change in Functional Assessment of Cancer Therapy-Fatigue questionnaire (FACT-F) administered to participants at baseline/before radiotherapy and one year post-radiotherapy. Whole genome microarray and cytokine multiplex panel were used to examine fatigue-related transcriptome and serum cytokine changes, respectively. The study included 86 subjects (discovery phase n = 40, validation phase n = 46). The sample in the discovery phase included men with prostate cancer scheduled to receive external-beam radiotherapy. A panel of 48 cytokines were measured and the significantly changed cytokine found in the discovery phase was validated using sera from a separate cohort of men two years after completing radiotherapy for prostate cancer at a different institution. Effects of the significantly changed cytokine on cell viability was quantified using the MTT assay. During the discovery phase, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and TRAIL decoy receptor, TNFRSF10C (TRAIL-R3), were significantly upregulated in fatigued (>=3-point decrease from baseline to 1yr-post radiotherapy) subjects (n = 15). In the validation phase, TRAIL correlated with fatigue scores 2yrs post-radiotherapy. TRAIL caused selective cytotoxicity in neuronal cells, but not in microglial and muscle cells, in vitro. Late-onset inflammation directed by TRAIL may play a role in fatigue pathogenesis post-repeated stress from irradiation. PMID- 28343070 TI - The activation of Akt/mTOR pathway by bleomycin in Epithelial-to-mesenchymal transition of human submandibular gland cells: A treatment mechanism of bleomycin for mucoceles of the salivary glands. AB - OBJECTIVE: Bleomycin (BLM) has been found safe and highly effective in the treatment of the mucoceles by intralesional injection in our previous study. The present research was designed to investigate whether epithelial-to-mesenchymal transition (EMT) contributes to the therapeutic effects of BLM for mucoceles of the salivary glands. MATERIAL AND METHODS: The cell proliferation and apoptosis of human submandibular gland cells (HSG cells) were examined by Cell Counting Kit 8 assay and Annexin V binding assay respectively. Epithelial and mesenchymal markers of HSG cells were measured by real-time quantitative PCR and Western blot analysis. Acinar differentiation and cell migration assays were performed to evaluate HSG cells function. RESULTS: High-dose BLM (>=0.5MUg/mL) significantly inhibited the cell proliferation and induced the cell apoptosis, while the treatment with low-dose BLM (0.05 and 0.1MUg/mL) for 48h induced EMT in HSG cells. Furthermore, Akt/mTOR pathway, rather than MAPK pathway, was activated through treated with 0.05 and 0.1MUg/mL BLM, as well as activation of the transcription factor Slug and Zeb 1. The migration of HSG cells was also enhanced through 0.05 and 0.1MUg/mL BLM, but the ability of acinar differentiation was diminished. CONCLUSION: Our results indicated that an EMT process was involved in the BLM-induced therapeutic effects on the HSG cells through the Akt/mTOR pathway. Importantly, the results indicated the potential role of this process in the BLM sclerotherapy of mucoceles of the salivary glands. PMID- 28343071 TI - Analgesia effect of baicalein against NTG-induced migraine in rats. AB - BACKGROUND: Migraine is a complex nervous system disease characterized by typical throbbing and unilateral headache, which causes severe healthy and social issues worldwide. The purpose of this study was to investigate the effect of baicalein (BAI) on the treatment of migraine. MATERIAL AND METHODS: Twenty-four rats were randomly divided equally into four groups, including a blank group, model group, positive group (ibuprofen tablets 82mg/kg), and BAI group (60mg/kg). All rats were intragastrically treated with the corresponding treatment for 10 consecutive days, and they were subcutaneously injected with NTG (10mg/kg) 1h after the last treatment, except in the blank group. After model establishment, the behaviors of all rats, including scratching head and shaking body were observed continuously for 100min. Four hours after NTG treatment, all rats were anaesthetized and the blood was collected. Thereafter, nitric oxide (NO) in plasma was determined by colorimetric method, the level of calcitonin gene-related peptide (CGRP) and endothelin (ET) were detected by radioimmunoassay method. In addition, immunohistochemistry was applied to detect c-Fos neuronal activity in trigeminal nucleus caudalis (TNC). RESULTS: Behavioral research showed that BAI administration alleviated the hyperalgesia in migraine rats. Compared with the model group, the levels of NO and CGRP in BAI administration groups were markedly decreased (p<0.01), and the levels of ET was significantly increased (p<0.01). Meanwhile, immunohistochemistry results showed that NTG treatment significantly activated c-Fos neurons while BAI treatment inhibited the expression of c-Fos. CONCLUSIONS: BAI could alleviate the migraine-like headache induced by NTG, which is related to the regulation of vasoactive substances. These findings may contribute to the further study of BAI as a potential drug for migraine pharmacotherapy. PMID- 28343073 TI - Breviscapine confers a neuroprotective efficacy against transient focal cerebral ischemia by attenuating neuronal and astrocytic autophagy in the penumbra. AB - Breviscapine is a flavonoid derived from a traditional Chinese herb Erigerin breviscapus (Vant.) Hand-Mazz, and has been extensively used in clinical treatment for cerebral stroke in China, but the underlying pharmacological mechanisms are still unclear. In present study, we investigated whether breviscapine could confer a neuroprotection against cerebral ischemia injury by targeting autophagy mechanisms. A cerebral stroke model in Sprague-Dawley rats was prepared by middle cerebral artery occlusion (MCAO), rats were then randomly divided into 5 groups: MCAO+Bre group, rats were treated with breviscapine; MCAO+Tat-Beclin-1 group, animals were administrated with specific autophagy inducer Tat-Beclin-1; MCAO+Bre+Tat-Beclin-1 group, rats were treated with both breviscapine and Tat-Beclin-1, MCAO+saline group, rats received the same volume of physiological saline, and Sham surgery group. The autophagy levels in infarct penumbra were evaluated by western blotting, real-time PCR and immunofluorescence 7days after the insult. Meanwhile, infarct volume, brain water content and neurological deficit score were assessed. The results illustrated that the infarct volume, brain water content and neurofunctional deficiency were significantly reduced by 7days of breviscapine treatment in MCAO+Bre group, compared with those in MCAO+saline group. Meanwhile, the western blotting, quantitative PCR and immunofluorescence showed that the autophagy in both neurons and astrocytes at the penumbra were markedly attenuated by breviscapine admininstration. Moreover, these pharmacological effects of breviscapine could be counteracted by autophagy inducer Tat-Beclin-1. Our study suggests that breviscapine can provide a neuroprotection against transient focal cerebral ischemia, and this biological function is associated with attenuating autophagy in both neurons and astrocytes. PMID- 28343072 TI - Ribonuclease attenuates hepatic ischemia reperfusion induced cognitive impairment through the inhibition of inflammatory cytokines in aged mice. AB - BACKGROUND: Elderly patients undergoing major surgery often develop cognitive dysfunction, and no optimum treatment exists for this postoperative complication. Ribonuclease, the counterpart of ribonucleic acid, has mostly been reported in terms of its use as a potential modality in anticancer therapy, and recent studies have demonstrated that ribonuclease can exert organ-protective effects in several pathological conditions. Our study also demonstrated that ribonuclease protects the liver against ischemia reperfusion injury. Nevertheless, it is unknown whether ribonuclease can attenuate the cognitive dysfunction that is induced by liver ischemia reperfusion. In this study, we aimed to evaluate the effect of ribonuclease on cognitive function after liver ischemia reperfusion. METHODS: Aged mice underwent sham surgery or 60min of hepatic ischemia reperfusion, vehicle or ribonuclease, which were administered subcutaneously. The primary observation endpoint was the Morris water maze; following 24h, 3days, and 7days of reperfusion, the levels of serum and hippocampus proinflammatory cytokines were measured to reveal the underlying mechanism. RESULTS: A probe test was conducted on day 3 and a reversal probe test was conducted on day 7 after surgery; the results demonstrated a reduction in cognitive function after liver ischemia reperfusion and that ribonuclease treatment attenuated cognitive impairment. The levels of serum and hippocampus proinflammatory cytokines (interleukin-6 and interleukin-1beta) and extracellular ribonucleic acid were significantly increased at 24h after reperfusion, but ribonuclease treatment markedly reduced the proinflammatory cytokine increase. CONCLUSION: The results of the study suggested that hepatic ischemia reperfusion leads to cognitive impairment in aged mice and an increase in inflammatory cytokine expression in both serum and the hippocampus; more importantly, ribonuclease showed protective effects against cognitive impairment through inhibiting the release of inflammatory cytokines. PMID- 28343074 TI - Cratoxy formosum leaf extract inhibits proliferation and migration of human breast cancer MCF-7 cells. AB - In this study we investigated how Cratoxy formosum (CF) leaf extract affects the viability and migration of human breast cancer cells including the mechanism(s) responsible. Our results showed that CF leaf extract strongly induced MCF-7 cell death in a concentration- and time-dependent manner, with IC50 values of 85.70+/ 4.52MUg/mL and 53.74+/-3.02MUg/mL at 24h and 48h, respectively. Additionally, CF leaf extract potentiated the activity of 4 anticancer drugs with the greatest synergy occurring between CF and 5-FU. CF leaf extract also caused a dose dependent decrease in colony forming ability with IC50 values of 36.37+1.80 MUg/mL and cell migration, with IC50 values of 43.68+/-0.86MUg/mL. Moreover, CF significantly induced ROS formation, increased caspase 3 activities, and reduced the mitochondrial membrane potential, leading to cancer cell apoptosis and cell death. In addition, the extract inhibited cancer cell migration at 25MUg/mL by reducing MMP 2 and MMP 9 protein expression. Moreover, CF leaf extracts strongly decreased expression of the cell cycle regulatory protein Rac1 and downstream protein, cdk6. CF leaf extract significantly stimulated p21 and this correlated with a reduction in cyclin D1 protein levels. In summary, CF leaf extract can inhibit cell proliferation, induce cell apoptosis, and reduce cell migration in the MCF-7 cell line. It could also be beneficial for enhancing the activity of anticancer drugs used to treat breast cancer. PMID- 28343075 TI - An update on application of nanotechnology and stem cells in spinal cord injury regeneration. AB - Spinal cord injury (SCI) is damage to the spinal cord that leads to sudden loss of motor and autonomic function and sensory under the level of the injury. The pathophysiological advancement of SCI is divided into two categories: primary injury and secondary injury. Due to the loss of motor, sensory, or cognitive function, a patient's quality of life is likely reduced and places a great burden on society in order to supply health care costs. Therefore, it is important to develop suitable therapeutic strategies for SCI therapy. Nano biomedical systems and stem cell based therapy have the potential to provide new therapeutic availability and efficacy over conventional medicine. Due to their unique properties, nanomaterials and mesenchymal stem cells can be used to offer efficient treatments. Nanoparticles have a potential to deliver therapeutic molecules to the target tissue of interest, reducing side effects of untargeted therapies in unwanted areas. Mesenchymal stem cells (MSCs) can reduce activating inflammation responses that lead to cell death and promote functional recovery and cell growth. We review recent uses of nanomaterials and stem cells in regeneration of SCI. PMID- 28343076 TI - Repression of DOK7 mediated by DNMT3A promotes the proliferation and invasion of KYSE410 and TE-12 ESCC cells. AB - Increasing evidence shows that aberrant epigenetic regulation of tumor suppressor genes is a contributing factor to their altered expression in esophageal squamous cell carcinoma (ESCC). In the current study, we investigate the role of DOK7 in ESCC cells. We found that enforced expression of DOK7 inhibited the proliferation and invasion of ESCC cells. We also found that treatment of ESCC cells with the DNA methylation inhibitor, 5-aza-2-deoxycytidine (5-azadC), induced the demethylation of DOK7 in promoter and DOK7 expression. Moreover, silencing DNMT3A decreased methylation of DOK7 and increased DOK7 expression, followed by repressing the proliferation and invasion of ESCC cells. Collectively, our data indicated that silencing DNMT3A inhibits proliferation and invasion in ESCC cells by inducing demethylation of DOK7. PMID- 28343077 TI - Separation and characterization of unknown impurities and isomers in flomoxef sodium by LC-IT-TOF MS and study of their negative-ion fragmentation regularities. AB - Thirteen unknown impurities in flomoxef sodium were separated and characterized by liquid chromatography coupled with high resolution ion trap/time-of-flight mass spectrometry (LC-IT-TOF MS)with positive and negative modes of electrospray ionization method for further improvement of official monographs in pharmacopoeias. The fragmentation patterns of impurities in flomoxef in the negative ion mode were studied in detail, and new negative-ion fragmentation regularities were discovered. Chromatographic separation was performed on a Kromasil C18 column (250mm*4.6mm, 5MUm). The mobile phase consisted of (A) ammonium formate aqueous solution (10mM)-methanol (84:16, v/v) and (B) ammonium formate aqueous solution (10mM)-methanol (47:53, v/v). In order to determine the m/z values of the molecular ions and formulas of all detected impurities, full scan LC-MS in both positive and negative ion modes was firstly executed to obtain the m/z value of the molecules. Then LC-MS2 and LC-MS3 were carried out on target compounds to obtain as much structural information as possible. Complete fragmentation patterns of impurities were studied and used to obtain information about the structures of these impurities. Structures of thirteen unknown degradation products in flomoxef sodium were deduced based on the high resolution MSn data with both positive and negative modes. The forming mechanisms of degradation products in flomoxef sodium were also studied. PMID- 28343078 TI - Development and validation of liquid chromatography tandem mass spectrometry method quantitative determination of polymyxin B1, polymyxin B2, polymyxin B3 and isoleucine-polymyxin B1 in human plasma and its application in clinical studies. AB - Polymyxin B (PB) is an antibiotic consisting of a cyclic heptapeptide and a tripeptide side chain used in treatment of infections caused by Gram-negative bacteria. Commercial formulations of PB contain multiple structurally related components with major constituents of PB1, PB2, PB3 and ile-PB1. To understand the pharmacokinetics of these major components, we have developed and validated a LC-MS/MS method to quantify PB1, PB2, PB3 and ile-PB1 in human plasma. PB was extracted from plasma by protein precipitation using trichloroacetic acid followed by chromatographic separation on Zorbax Bonus-RP column (100mm*2.1mm, 1.8MUm) using stepwise gradient elution of water containing 0.1% of formic acid and 0.1% of trichloroacetic acid (mobile phase A) and 90% acetonitrile with 0.1% formic acid (mobile phase B). Despite of structural similarities, these PBs were completely resolved in the analytical run time of 6.5min. Detection and quantification of PBs were performed by selected reaction monitoring (SRM) under positive ionization mode in the mass spectrometer. Separation of PB1 and ile-PB1, as well as PB2 and PB3, before quantification is crucial because they are structural isomers detected based the same SRM. Excellent linearity was achieved (r2>0.99) in the calibration curves of PB. The developed method was accurate (95.3-111.7%) and precise (CV<5.1%). Recovery of PB from the plasma extraction was between 53 and 76% and reproducible (CV<4.5%). Matrix effect was not observed by post-column infusion of PB in the mass spectrometer. This methodology has been successfully applied to clinical study of patients dosed with intravenous infusions of PB. PMID- 28343079 TI - Population model of bladder motion and deformation based on dominant eigenmodes and mixed-effects models in prostate cancer radiotherapy. AB - In radiotherapy for prostate cancer irradiation of neighboring organs at risk may lead to undesirable side-effects. Given this setting, the bladder presents the largest inter-fraction shape variations hampering the computation of the actual delivered dose vs. planned dose. This paper proposes a population model, based on longitudinal data, able to estimate the probability of bladder presence during treatment, using only the planning computed tomography (CT) scan as input information. As in previously-proposed principal component analysis (PCA) population-based models, we have used the data to obtain the dominant eigenmodes that describe bladder geometric variations between fractions. However, we have used a longitudinal analysis along each mode in order to properly characterize patient's variance from the total population variance. We have proposed is a mixed-effects (ME) model in order to separate intra- and inter-patient variability, in an effort to control confounding cohort effects. Other than using PCA, bladder shapes are represented by using spherical harmonics (SPHARM) that additionally enables data compression without information lost. Based on training data from repeated CT scans, the ME model was thus implemented following dimensionality reduction by means of SPHARM and PCA. We have evaluated the model in a leave-one-out cross validation framework on the training data but also using independent data. Probability maps (PMs) were thus generated with several draws from the learnt model as predicted regions where the bladder will likely move and deform. These PMs were compared with the actual regions using metrics based on mutual information distance and misestimated voxels. The prediction was also compared with two previous population PCA-based models. The proposed model was able to reduce the uncertainties in the estimation of the probable region of bladder motion and deformation. This model can thus be used for tailoring radiotherapy treatments. PMID- 28343080 TI - Ring artifact correction in gamma-ray process tomography imaging. AB - Ring artifacts have been studied for X-ray based Computed Tomography (CT) systems but not on gamma-ray based in-situ applications. This paper discusses application of recently proposed automatic ring artifact reduction method (Yoon et al., 2016) on previously obtained experimental projection data from a gamma-ray based Industrial Process Tomography (IPT) system for a prototype catalytic column. Studies include qualitative and quantitative evaluation of the method. It is observed that ring artifacts are suppressed without loss of significant information in gamma-ray PT images. PMID- 28343081 TI - Simultaneous determination of 226Ra, 228Ra and 210Pb in drinking water using 3M EmporeTM RAD disk by LSC-PLS. AB - A procedure for the rapid and simultaneous determination of 226Ra, 228Ra and 210Pb in drinking water by means of extraction with a 3M EmporeTM Radium RAD disk and liquid scintillation spectrometry is described. The selective elution of 210Pb from the RAD disk and a multivariate calibration using partial least squares regression (PLS) are tested as methods to avoid overlap in the spectra between 228Ra and 210Pb. The validated procedure was tested with mixtures of radionuclides and interlaboratory materials; finally, it was applied to natural waters. PMID- 28343082 TI - Lateralizing language function with pre-operative functional magnetic resonance imaging in early proficient bilingual patients. AB - Research on bilinguals with brain lesions is complicated by high patient variability, making it difficult to find well-matched controls. We benefitted from a database of over 700 patients and conducted an analysis of pre-operative functional magnetic resonance imaging data to assess language dominance in 25 early, highly proficient Spanish-English bilinguals, and 25 carefully matched monolingual controls. Our results showed that early bilingualism is associated with greater bilateral hemispheric involvement, and monolingualism is associated with stronger left hemisphere lateralization (p=0.009). The bilinguals showed more pronounced right hemisphere activation (p=0.008). Although language dominance values were concordant in the bilingual group, there were a few (12%) atypical cases with different lateralization patterns in L1 and L2. Finally, we found distinct areas of activity in first and second language within the language network, in addition to regions of convergence. These data underscore the need to map all languages proficiently spoken by surgical candidates. PMID- 28343083 TI - Life satisfaction and perceived stress among young offenders in a residential therapeutic community: Latent change score analysis. AB - Recent rehabilitation frameworks underscore the importance of strength-based interventions for young offenders who may lack internal and external resources to manage their stress and plan for their life. This multi-wave longitudinal study investigated the dynamic relationship between perceived stress and life satisfaction among a group of young ex-offenders in a residential therapeutic community. Four waves of data were collected from 117 Hong Kong youths (24.0% female, mean age = 17.7) over one year. Latent change score analysis was employed to examine the univairate and bivariate changes of their perceived stress and life satisfaction. Results suggest a positive growth trajectory in life satisfaction over time. The results of perceived stress were less conclusive. Bivariate models indicated that the previous level of life satisfaction was negatively linked to the subsequent perceived stress level but not vice versa. The findings suggest that improvement in life satisfaction may reduce perceived stress in young ex-offenders. PMID- 28343084 TI - Role of pterostilbene in attenuating immune mediated devastation of pancreatic beta cells via Nrf2 signaling cascade. AB - Nrf2 (nuclear factor erythroid 2-related factor-2) is a transcription factor that regulates oxidative/xenobiotic stress response and also suppress inflammation. Nrf2 signaling is associated with an increased susceptibility to various kinds of stress. Nrf2 has been shown as a promising therapeutic target in various human diseases including diabetes. Our earlier studies showed Pterostilbene (PTS) as a potent Nrf2 activator, and it protects the pancreatic beta-cells against oxidative stress. In this study, we investigated PTS confer protection against cytokine-induced beta-cell apoptosis and its role on insulin secretion in streptozotocin (STZ)-induced diabetic mice. The Nrf2 activation potential of PTS was assessed by dissociation of the Nrf2-Keap1 complex and by expression of ARE driven downstream target genes in MIN6 cells. Further, the nuclear Nrf2 translocation and blockage of apoptotic signaling as demonstrated by the reduction of BAX/Bcl-2 ratio, Annexin-V positive cells and caspase-3 activity conferred the cyto-protection of PTS against cytokine-induced cellular damage. In addition, PTS treatment markedly improved glucose homeostasis and abated inflammatory response evidenced by the reduction of proinflammatory cytokines in diabetic mice. The inhibition of beta-cell apoptosis by PTS as assessed by BAX/Bcl-2 ratio and caspase-3 activity in the pancreas was associated with the activation of Nrf2 and the expression of its downstream target genes. PTS also inhibited the activation of iNOS and decreased nitric oxide (NO) formation in the pancreas of diabetic animals. The results obtained from both in vitro and in vivo experiments showed that PTS improves beta-cell function and survival against cytokine stress and also prevents STZ-induced diabetes. PMID- 28343086 TI - Modeling the influence of acute changes in bladder elasticity on pressure and wall tension during filling. AB - Tension-sensitive nerves in the bladder wall are responsible for providing bladder sensation. Bladder wall tension, and therefore nerve output, is a function of bladder pressure, volume, geometry and material properties. The elastic modulus of the bladder is acutely adjustable, and this material property is responsible for adjustable preload tension exhibited in human and rabbit detrusor muscle strips and dynamic elasticity revealed during comparative-fill urodynamics in humans. A finite deformation model of the bladder was previously used to predict filling pressure and wall tension using uniaxial tension test data and the results showed that wall tension can increase significantly during filling with relatively little pressure change. In the present study, published uniaxial rabbit detrusor data were used to quantify regulated changes in the elastic modulus, and the finite deformation model was expanded to illustrate the potential effects of elasticity changes on pressure and wall tension during filling. The model demonstrates a shift between relatively flat pressure-volume filling curves, which is consistent with a recent human urodynamics study, and also predicts that dynamic elasticity would produce significant changes in wall tension during filling. The model results support the conclusion that acute regulation of bladder elasticity could contribute to significant changes in wall tension for a given volume that could lead to urgency, and that a single urodynamic fill may be insufficient to characterize bladder biomechanics. The model illustrates the potential value of quantifying wall tension in addition to pressure during urodynamics. PMID- 28343087 TI - CAD/CAM machining Vs pre-sintering in-lab fabrication techniques of Y-TZP ceramic specimens: Effects on their mechanical fatigue behavior. AB - This study evaluated the effects of different pre-sintering fabrication processing techniques of Y-TZP ceramic (CAD/CAM Vs. in-lab), considering surface characteristics and mechanical performance outcomes. Pre-sintered discs of Y-TZP ceramic (IPS e.max ZirCAD, Ivoclar Vivadent) were produced using different pre sintering fabrication processing techniques: Machined- milling with a CAD/CAM system; Polished- fabrication using a cutting device followed by polishing (600 and 1200 SiC papers); Xfine- fabrication using a cutting machine followed by grinding with extra-fine diamond bur (grit size 30 MUm); Fine- fabrication using a cutting machine followed by grinding with fine diamond bur (grit size 46 MUm); SiC- fabrication using a cutting machine followed by grinding with 220 SiC paper. Afterwards, the discs were sintered and submitted to roughness (n=35), surface topography (n=2), phase transformation (n=2), biaxial flexural strength (n=20), and biaxial flexural fatigue strength (fatigue limit) (n=15) analyses. No monoclinic-phase content was observed in all processing techniques. It can be observed that obtaining a surface with similar characteristics to CAD/CAM milling is essential for the observation of similar mechanical performance. On this sense, grinding with fine diamond bur before sintering (Fine group) was the best mimic protocol in comparison to the CAD/CAM milling. PMID- 28343085 TI - Guava fruit extract and its triterpene constituents have osteoanabolic effect: Stimulation of osteoblast differentiation by activation of mitochondrial respiration via the Wnt/beta-catenin signaling. AB - The aim of this study was to evaluate the skeletal effect of guava triterpene enriched extract (GE) in rats and identify osteogenic compounds thereof, and determine their modes of action. In growing female rats, GE at 250 mg/kg dose increased parameters of peak bone mass including femur length, bone mineral density (BMD) and biomechanical strength, suggesting that GE promoted modeling directed bone growth. GE also stimulated bone regeneration at the site of bone injury. In adult osteopenic rats (osteopenia induced by ovariectomy, OVX) GE completely restored the lost bones at both axial and appendicular sites, suggesting a strong osteoanabolic effect. Serum metabolomics studies showed changes in several metabolites (some of which are related to bone metabolism) in OVX compared with ovary-intact control and GE treatment to OVX rats reversed those. Out of six abundantly present triterpenes in GE, ursolic acid (UA) and 2alpha-hydroxy ursolic acid (2alpha-UA) induced osteogenic differentiation in vitro as did GE by activating Wnt/beta-catenin pathway assessed by phosphorylation of GSK-3beta. Over-expressing of constitutively active GSK-3beta (caGSK-3beta) in osteoblasts abolished the differentiation-promoting effect of GE, UA and 2alpha-UA. All three increased both glycolysis and mitochondrial respiration but only rotenone (inhibitor of mitochondrial electron transfer) and not 2-deoxyglucose (to block glycolysis) inhibited osteoblast differentiation. In addition, caGSK-3beta over-expression attenuated the enhanced mitochondrial respiration caused by GE, UA and 2alpha-UA. We conclude that GE has osteoanabolic effect which is contributed by UA and 2alpha-UA, and involve activation of canonical Wnt signaling which in turn modulates cellular energy metabolism leading to osteoblast differentiation. PMID- 28343088 TI - Pathway of protection: Ethnic identity, self-esteem, and substance use among multiracial youth. AB - Fifty percent of adolescents have tried an illicit drug and 70% have tried alcohol by the end of high school, with even higher rates among multiracial youth. Ethnic identity is a protective factor against substance use for minority groups. However, little is known about the mechanisms that facilitate its protective effects, and even less is known about this relationship for multiracial youth. The purpose of the present study was to examine the protective effect of ethnic identity on substance use and to determine whether this relationship operated indirectly through self-esteem, a strong predictor of substance use for among adolescent populations. Participants included 468 multiracial youth in grades six through 12 (53% female). The results found that ethnic identity was indeed related to substance use, partially through changes in self-esteem. Findings from this study contribute to our understanding and development of models of risk and protection for an understudied population. PMID- 28343089 TI - Cortisol and physical performance in older populations: Findings from the international mobility in aging study (IMIAS). AB - OBJECTIVE: To compare diurnal cortisol profiles across samples of older adults from diverse populations and to examine if differences in circadian cortisol secretion are associated with poor physical performance (SPPB<9). METHODS: Data were collected during the baseline survey of the International Mobility in Aging Study conducted in 2012 in Kingston (Canada), Saint-Hyacinthe (Canada), Tirana (Albania) and Manizales (Colombia). Salivary cortisol was collected from a subsample of 309 participants instructed to collect saliva on two consecutive days, and 5 different intervals each day: upon awakening (M1), 30min (M2) and 60min after awakening, at 15:00h and before bedtime (E). Cortisol was analyzed using enzyme immunoassay kits. Physical performance was measured by the Short Physical Performance Battery (SPPB). Mixed linear models were fit to assess the associations between cortisol diurnal output and physical performance, adjusting for potential confounders. RESULTS: Kingston, Saint-Hyacinthe and Tirana residents had significantly higher cortisol values than their Manizales counterparts, with the population from Tirana showing the highest levels. Attenuated morning cortisol peak (M2) (p=0.025), higher cortisol bed time (E) (p=0.005), and lower M2/E ratio (p<0.001) were found among those with SPPB<9 compared with those with good physical performance (SPPB>=9). These results were not altered after adjustment by potential confounders. CONCLUSION: Cortisol profiles varied across four diverse populations of older adults. Circadian cortisol secretion is associated with physical performance as an attenuated morning response and higher bed time values were observed in older adults with SPPB<9. PMID- 28343090 TI - Developmental systems of plasticity and trans-generational epigenetic inheritance in nematodes. AB - Several decades of research provided detailed insight into how genes control development and evolution, whereas recent studies have expanded this purely genetic perspective by presenting strong evidence for environmental and epigenetic influences. We summarize examples of phenotypic plasticity and trans generational epigenetic inheritance in the nematode model organisms Pristionchus pacificus and Caenorhabditis elegans, which indicate that the response of developmental systems to environmental influences is hardwired into the organisms genome. We argue that genetic programs regulating these organismal-environmental interactions are themselves subject to natural selection. Indeed, macro evolutionary studies of nematode feeding structures indicate evolutionary trajectories in which plasticity followed by genetic assimilation results in extreme diversity highlighting the role of plasticity as major facilitator of phenotypic diversification. PMID- 28343091 TI - Rapid detection and ruling out of neonatal sepsis by PCR coupled with Electrospray Ionization Mass Spectrometry (PCR/ESI-MS). AB - BACKGROUND: Sepsis is an important cause of morbidity and mortality in neonates and clinicians are typically required to administer empiric antibiotics while waiting for blood culture results. However, prolonged and inappropriate use of antibiotics is associated with various complications and adverse events. Better tools to rapidly rule out bacterial infections are therefore needed. AIMS: We aimed to assess the negative predictive value of PCR coupled with Electrospray Ionization Mass Spectrometry (PCR/ESI-MS) compared to conventional blood cultures in neonatal sepsis. STUDY DESIGN: Prospective observational study. SUBJECTS: All consecutive neonates (<28days old) with clinical suspicion of sepsis. Samples for PCR/ESI-MS analysis were collected at the same time as samples for the blood culture, before the initiation of antibiotics. OUTCOME MEASURES: Our primary objective was to evaluate the negative predictive value of PCR/ESI-MS for the detection of bacteria in the bloodstream of newborns with suspected sepsis. Our secondary objective was the evaluation of the sensitivity, specificity and positive predictive value of the PCR/ESI-MS in such a neonatal population. RESULTS: We analysed 114 samples over 14months. The median age and weight were 32weeks+3days and 1840g, respectively. Two patients had negative PCR/ESI-MS results, but positive blood cultures. Overall, the negative predictive value was 98% (95%CI: 92% to 100%). CONCLUSIONS: Based on these results, PCR/ESI-MS analysis of blood samples of neonates with suspected sepsis appears to have a very good negative predictive value when compared to blood cultures as gold standard. This novel test might allow for early reassessment of the need for antibiotics. PMID- 28343092 TI - The impact of cumulative pain/stress on neurobehavioral development of preterm infants in the NICU. AB - BACKGROUND: Vulnerable preterm infants experience repeated and prolonged pain/stress stimulation during a critical period in their development while in the neonatal intensive care unit (NICU). The contribution of cumulative pain/stressors to altered neurodevelopment remains unclear. The study purpose was to investigate the impact of early life painful/stressful experiences on neurobehavioral outcomes of preterm infants in the NICU. METHODS: A prospective exploratory study was conducted with fifty preterm infants (28 0/7-32 6/7weeks gestational age) recruited at birth and followed for four weeks. Cumulative pain/stressors (NICU Infant Stressor Scale) were measured daily and neurodevelopmental outcomes (NICU Network Neurobehavioral Scale) were examined at 36-37weeks post-menstrual age. Data analyses were conducted on the distribution of pain/stressors experienced over time and the linkages among pain/stressors and neurobehavioral outcomes. RESULTS: Preterm infants experienced a high degree of pain/stressors in the NICU, both in numbers of daily acute events (22.97+/-2.30 procedures) and cumulative times of chronic/stressful exposure (42.59+/-15.02h). Both acute and chronic pain/stress experienced during early life significantly contributed to the neurobehavioral outcomes, particularly in stress/abstinence (p<0.05) and habituation responses (p<0.01), meanwhile, direct breastfeeding and skin-to-skin holding were also significantly associated with habituation (p<0.01 0.05). CONCLUSION: Understanding mechanisms by which early life experience alters neurodevelopment will assist clinicians in developing targeted neuroprotective strategies and individualized interventions to improve infant developmental outcomes. PMID- 28343093 TI - Influence of genetic variants of CYP2D6, CYP2C9, CYP2C19 and CYP3A4 on antiepileptic drug metabolism in pediatric patients with refractory epilepsy. AB - BACKGROUND: Identified the polymorphisms of CYP2D6, CYP2C9, CYP2C19 and CYP3A4, within a rigorously selected population of pediatric patients with drug-resistant epilepsy. METHOD: The genomic DNA of 23 drug-resistant epilepsy patients and 7 patients with good responses were analyzed. Ten exons in these four genes were genotyped, and the drug concentrations in saliva and plasma were determined. RESULTS: The relevant SNPs with pharmacogenomics relations were CYP2D6*2 (rs16947) decreased your activity and CYP2D6*4 (rs1065852), CYP2C19*2 (rs4244285) and CYP3A4*1B (rs2740574) by association with poor metabolizer. The strongest risk factors were found in the AA genotype and allele of SNP rs3892097 from the CYP2D6 gene, followed by the alleles A and T of SNPs rs2740574 and rs2687116, respectively from CYP3A4. The most important concomitance was between homozygous genotype AA of rs3892097 and genotype AA of rs2740574 with 78.3% in drug resistant epilepsy patients as compared to 14.3% in control patients. CONCLUSION: The results demonstrated the important role of the CYP 3A4*1B allelic variant as risk factor for developing drug resistance and CYP2D6, CYP2C19 SNPs and haplotypes may affect the response to antiepileptic drugs. PMID- 28343094 TI - Effects of posted point-of-sale warnings on alcohol consumption during pregnancy and on birth outcomes. AB - In 23 states and Washington D.C., alcohol retailers are required by law to post alcohol warning signs (AWS) that warn against the risks of drinking during pregnancy. Using the variation in the adoption of these laws across states and within states over time, I find a statistically significant reduction in prenatal alcohol use associated with AWS. I then use this plausibly exogenous change in drinking behavior to establish a causal link between prenatal alcohol exposure and birth outcomes. I find that AWS laws are associated with decreases in the odds of very low birth weight and very pre-term birth. PMID- 28343095 TI - Ion mobility-mass spectrometry and orthogonal gas-phase techniques to study amyloid formation and inhibition. AB - Amyloidogenic peptide oligomers are responsible for a variety of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Due to their dynamic, polydisperse, and polymorphic nature, these oligomers are very challenging to characterize using traditional condensed-phase methods. In the last decade, ion mobility-mass spectrometry (IM-MS) and related gas-phase techniques have emerged as a powerful alternative to disentangle the structure and assembly characteristics of amyloid forming systems. This review highlights recent advances in which IM-MS was used to characterize amyloid oligomers and their underlying assembly pathway. In addition, we summarize recent studies in which IM-MS was used to size- and mass-select species for a further spectroscopic investigation and outline the potential of IM-MS as a tool for the screening of amyloid inhibitors. PMID- 28343096 TI - SD-SEM: sparse-dense correspondence for 3D reconstruction of microscopic samples. AB - Scanning electron microscopy (SEM) imaging has been a principal component of many studies in biomedical, mechanical, and materials sciences since its emergence. Despite the high resolution of captured images, they remain two-dimensional (2D). In this work, a novel framework using sparse-dense correspondence is introduced and investigated for 3D reconstruction of stereo SEM images. SEM micrographs from microscopic samples are captured by tilting the specimen stage by a known angle. The pair of SEM micrographs is then rectified using sparse scale invariant feature transform (SIFT) features/descriptors and a contrario RANSAC for matching outlier removal to ensure a gross horizontal displacement between corresponding points. This is followed by dense correspondence estimation using dense SIFT descriptors and employing a factor graph representation of the energy minimization functional and loopy belief propagation (LBP) as means of optimization. Given the pixel-by-pixel correspondence and the tilt angle of the specimen stage during the acquisition of micrographs, depth can be recovered. Extensive tests reveal the strength of the proposed method for high-quality reconstruction of microscopic samples. PMID- 28343097 TI - STRait Razor v2s: Advancing sequence-based STR allele reporting and beyond to other marker systems. AB - STRait Razor has provided the forensic community a free-to-use, open-source tool for short tandem repeat (STR) analysis of massively parallel sequencing (MPS) data. STRait Razor v2s (SRv2s) allows users to capture physically phased haplotypes within the full amplicon of both commercial (ForenSeq) and "early access" panels (PowerSeq, Mixture ID). STRait Razor v2s may be run in batch mode to facilitate population-level analysis and is supported by all Unix distributions (including MAC OS). Data are reported in tables in string (haplotype), length-based (e.g., vWA allele 14), and International Society of Forensic Genetics (ISFG)-recommended (vWA [CE 14]-GRCh38-chr12:5983950-5984049 (TAGA)10 (CAGA)3 TAGA) formats. STRait Razor v2s currently contains a database of ~2500 unique sequences. This database is used by SRv2s to match strings to the appropriate allele in ISFG-recommended format. In addition to STRs, SRv2s has configuration files necessary to capture and report haplotypes from all marker types included in these multiplexes (e.g., SNPs, InDels, and microhaplotypes). To facilitate mixture interpretation, data may be displayed from all markers in a format similar to that of electropherograms displayed by traditional forensic software. The download package for SRv2s may be found at https://www.unthsc.edu/graduate-school-of-biomedical-sciences/molecular-and medical-genetics/laboratory-faculty-and-staff/strait-razor. PMID- 28343098 TI - Developmental validation of QIAGEN Investigator(r) 24plex QS Kit and Investigator(r) 24plex GO! Kit: Two 6-dye multiplex assays for the extended CODIS core loci. AB - The original CODIS database based on 13 core STR loci has been overwhelmingly successful for matching suspects with evidence. In order to increase the power of discrimination, reduce the possibility of adventitious matches, and expand global data sharing, the CODIS Core Loci Working Group determined the expansion of the CODIS core loci to 20 STR plus three additional "highly recommended" loci (SE33, DY391, Amelogenin) Hares, 2015, 2012 [1,2]. The QIAGEN Investigator 24plex QS and Investigator 24plex GO! Kits are 6-dye multiplex assays that contain all markers of the expanded 23 CODIS core loci along with a unique internal performance control that is co-amplified with the STR markers. The "Quality Sensor" generates additional information for quality control and performance checks. Investigator 24plex QS is designed for purified DNA from casework and reference samples, whereas 24plex GO! is dedicated to direct amplification of reference samples, like blood or buccal cells on FTA or swabs. A developmental validation study was performed on both assays. Here, we report the results of this study which followed the recommendations of the European Network of Forensic Science Institutes (ENFSI) [3] and the Revised Validation Guidelines of the Scientific Working Group on DNA Analysis Methods (SWGDAM) [4]. Data included are for PCR based procedures e.g. reaction conditions, effects of PCR annealing temperature variations, amplification cycles or cyclers, sensitivity (also in the context of the Quality Sensor), performance with simulated inhibition, stability and efficiency, precision, reproducibility, mixture study, concordance, stutter, species specificity, and case-type samples. The validation results demonstrate that the Investigator 24plex QS and Investigator 24plex GO! Kits are robust and reliable identification assays as required for forensic DNA typing in forensic casework analysis and databasing. PMID- 28343099 TI - Source apportionments of ambient fine particulate matter in Israeli, Jordanian, and Palestinian cities. AB - This manuscript evaluates spatial and temporal variations of source contributions to ambient fine particulate matter (PM2.5) in Israeli, Jordanian, and Palestinian cities. Twenty-four hour integrated PM2.5 samples were collected every six days over a 1-year period (January to December 2007) in four cities in Israel (West Jerusalem, Eilat, Tel Aviv, and Haifa), four cities in Jordan (Amman, Aqaba, Rahma, and Zarka), and three cities in Palestine (Nablus, East Jerusalem, and Hebron). The PM2.5 samples were analyzed for major chemical components, including organic carbon and elemental carbon, ions, and metals, and the results were used in a positive matrix factorization (PMF) model to estimate source contributions to PM2.5 mass. Nine sources, including secondary sulfate, secondary nitrate, mobile, industrial lead sources, dust, construction dust, biomass burning, fuel oil combustion and sea salt, were identified across the sampling sites. Secondary sulfate was the dominant source, contributing 35% of the total PM2.5 mass, and it showed relatively homogeneous temporal trends of daily source contribution in the study area. Mobile sources were found to be the second greatest contributor to PM2.5 mass in the large metropolitan cities, such as Tel Aviv, Hebron, and West and East Jerusalem. Other sources (i.e. industrial lead sources, construction dust, and fuel oil combustion) were closely related to local emissions within individual cities. This study demonstrates how international cooperation can facilitate air pollution studies that address regional air pollution issues and the incremental differences across cities in a common airshed. It also provides a model to study air pollution in regions with limited air quality monitoring capacity that have persistent and emerging air quality problems, such as Africa, South Asia and Central America. PMID- 28343100 TI - The potential of L. scoparium, K. robusta and P. radiata to mitigate N-losses in silvopastural systems. AB - Silvopastoral systems aim to enhance economic, cultural and social principles by sustainably combining forest management with agriculture. In these typically high nitrogen (N) environments, plant species selection can profoundly influence N fluxes. For grazed pastures, plants may be exposed to urine patches that have received the equivalent of up to 1000 kg N ha-1. We aimed to determine the growth and N fluxes in three potential trees that may be used in silvopastoral systems: L. scoparium, K. robusta and P. radiata. Plants were grown in a greenhouse lysimeter experiment, with controlled irrigation and temperature and exposed to N at rates of 200 kg ha-1 equiv. for 15 weeks, followed by the addition of 800 kg ha-1 N equiv, to simulate a urine patch. Urea produced a positive growth response of all plant species. Treatments containing L. scoparium and K. robusta leached lower amounts of nitrate (NO3-) (2 kg ha-1 NO3-) compared to P. radiata (53 kg ha 1). Measurements of N2O over 20 days after the application of 800 kg N ha-1 indicated an inhibitory effect of L. scoparium and K. robusta on denitrification, hence loss of N via N2O. Both L. scoparium and K. robusta demonstrated that they have potential to reduce N-losses in silvopastural systems, while producing valuable biomass. PMID- 28343101 TI - The influence of odd-even car trial on fine and coarse particles in Delhi. AB - The odd-even car trial scheme, which reduced car traffic between 08.00 and 20.00 h daily, was applied from 1 to 15 January 2016 (winter scheme, WS) and 15-30 April 2016 (summer scheme, SS). The daily average PM2.5 and PM10 exceeded national standards, with highest concentrations (313 MUg m-3 and 639 MUg m-3, respectively) during winter and lowest (53 MUg m-3 and 130 MUg m-3) during the monsoon (June-August). PM concentrations during the trials can be interpreted either as reduced or increased, depending on the periods used for comparison purposes. For example, hourly average net PM2.5 and PM10 (after subtracting the baseline concentrations) reduced by up to 74% during the majority (after 1100 h) of trial hours compared with the corresponding hours during the previous year. Conversely, daily average PM2.5 and PM10 were higher by up to 3-times during the trial periods when compared with the pre-trial days. A careful analysis of the data shows that the trials generated cleaner air for certain hours of the day but the persistence of overnight emissions from heavy goods vehicles into the morning odd-even hours (0800-1100 h) made them probably ineffective at this time. Any further trial will need to be planned very carefully if an effect due to traffic alone is to be differentiated from the larger effect caused by changes in meteorology and especially wind direction. PMID- 28343102 TI - Acoustic and hybrid 3D-printed electrochemical biosensors for the real-time immunodetection of liver cancer cells (HepG2). AB - This study presents an efficient acoustic and hybrid three-dimensional (3D) printed electrochemical biosensors for the detection of liver cancer cells. The biosensors function by recognizing the highly expressed tumor marker CD133, which is located on the surface of liver cancer cells. Detection was achieved by recrystallizing a recombinant S-layer fusion protein (rSbpA/ZZ) on the surface of the sensors. The fused ZZ-domain enables immobilization of the anti-CD133 antibody in a defined manner. These highly accessible anti-CD133 antibodies were employed as a sensing layer, thereby enabling the efficient detection of liver cancer cells (HepG2). The recognition of HepG2 cells was investigated in situ using a quartz crystal microbalance with dissipation monitoring (QCM-D), which enabled the label-free, real-time detection of living cells on the modified sensor surface under controlled conditions. Furthermore, the hybrid 3D additive printing strategy for biosensors facilitates both rapid development and small scale manufacturing. The hybrid strategy of combining 3D-printed parts and more traditionally fabricated parts enables the use of optimal materials: a ceramic substrate with noble metals for the sensing element and 3D-printed capillary channels to guide and constrain the clinical sample. Cyclic voltammetry (CV) measurements confirmed the efficiency of the fabricated sensors. Most importantly, these sensors offer low-cost and disposable detection platforms for real-world applications. Thus, as demonstrated in this study, both fabricated acoustic and electrochemical sensing platforms can detect cancer cells and therefore may have further potential in other clinical applications and drug screening studies. PMID- 28343103 TI - Pd-Au@carbon dots nanocomposite: Facile synthesis and application as an ultrasensitive electrochemical biosensor for determination of colitoxin DNA in human serum. AB - In this study, a green and fast method was developed to synthesize high-yield carbon dots (CDs) via one-pot microwave treatment of banana peels without using any other surface passivation agents. Then the as-prepared CDs was used as the reducing agent and stabilizer to synthesize a Pd-Au@CDs nanocomposite by a simple sequential reduction strategy. Finally, Pd-Au@CDs nanocomposite modified glassy carbon electrode (Pd-Au@CDs/GCE) was obtained as a biosensor for target DNA after being immobilized a single-stranded probe DNA by a carboxyl ammonia condensation reaction. Under the optimal conditions, the sensor could detect target DNA concentrations in the range from 5.0*10-16 to 1.0*10-1 degrees molL-1. The detection limit (LD) was estimated to be 1.82*10-17molL-1, which showed higher sensitivity than other electrochemical biosensors reported. In addition, the DNA sensor was also successfully applied to detect colitoxin DNA in human serum. PMID- 28343104 TI - Localized surface plasmon resonance-mediated fluorescence signals in plasmonic nanoparticle-quantum dot hybrids for ultrasensitive Zika virus RNA detection via hairpin hybridization assays. AB - The current epidemic caused by the Zika virus (ZIKV) and the devastating effects of this virus on fetal development, which result in an increased incidence of congenital microcephaly symptoms, have prompted the World Health Organization (WHO) to declare the ZIKV a public health issue of global concern. Efficient probes that offer high detection sensitivity and specificity are urgently required to aid in the point-of-care treatment of the virus. In this study, we show that localized surface plasmon resonance (LSPR) signals from plasmonic nanoparticles (NPs) can be used to mediate the fluorescence signal from semiconductor quantum dot (Qdot) nanocrystals in a molecular beacon (MB) biosensor probe for ZIKV RNA detection. Four different plasmonic NPs functionalized with 3-mercaptopropionic acid (MPA), namely MPA-AgNPs, MPA-AuNPs, core/shell (CS) Au/AgNPs, and alloyed AuAgNPs, were synthesized and conjugated to L-glutathione-capped CdSeS alloyed Qdots to form the respective LSPR-mediated fluorescence nanohybrid. The concept of the plasmonic NP-Qdot-MB biosensor involves using LSPR from the plasmonic NPs to mediate a fluorescence signal to the Qdots, triggered by the hybridization of the target ZIKV RNA with the DNA loop sequence of the MB. The extent of the fluorescence enhancement based on ZIKV RNA detection was proportional to the LSPR-mediated fluorescence signal. The limits of detection (LODs) of the nanohybrids were as follows: alloyed AuAgNP Qdot646-MB (1.7 copies/mL)) > CS Au/AgNP-Qdot646-MB (LOD =2.4 copies/mL) > AuNP Qdot646-MB (LOD =2.9 copies/mL) > AgNP-Qdot646-MB (LOD =7.6 copies/mL). The LSPR mediated fluorescence signal was stronger for the bimetallic plasmonic NP-Qdots than the single metallic plasmonic NP-Qdots. The plasmonic NP-Qdot-MB biosensor probes exhibited excellent selectivity toward ZIKV RNA and could serve as potential diagnostic probes for the point-of care detection of the virus. PMID- 28343105 TI - Photoluminescence light-up detection of zinc ion and imaging in living cells based on the aggregation induced emission enhancement of glutathione-capped copper nanoclusters. AB - In this work, we prepared glutathione (GSH)-capped copper nanoclusters (Cu NCs) with red emission by simply adjusting the pH of GSH/Cu2+ mixture at room temperature. A photoluminescence light-up method for detecting Zn2+ was then developed based on the aggregation induced emission enhancement of GSH-capped Cu NCs. Zn2+ could trigger the aggregation of Cu NCs, inducing the enhancement of luminescence and the increase of absolute quantum yield from 1.3% to 6.2%. GSH capped Cu NCs and the formed aggregates were characterized, and the possible mechanism was also discussed. The prepared GSH-capped Cu NCs exhibited a fast response towards Zn2+ and a wider detection range from 4.68 to 2240MUM. The detection limit (1.17MUM) is much lower than that of the World Health Organization permitted in drinking water. Furthermore, taking advantages of the low cytotoxicity, large Stokes shift, red emission and light-up detection mode, we explored the use of the prepared GSH-capped Cu NCs in the imaging of Zn2+ in living cells. The developed luminescence light-up nanoprobe may hold the potentials for Zn2+-related drinking water safety and biological applications. PMID- 28343106 TI - A structure based plasma protein pre-fractionation using conjoint immobilized metal/chelate affinity (IMA) system. AB - The potential of immobilized metal/chelate affinity (IMA) in a continuous fashion, referred as conjoint approach, to pre-fractionate plasma proteins (in their native state) prior to LC-MS analysis was investigated in this study. Four transition metal-ions (Co (II), Zn (II), Ni (II) and Cu (II)) were individually chelated with IDA (iminodiacetic acid) coated CIM (Convective Interaction Media) disks and placed in a single housing in the following sequential order: IDA-Co (II)->IDA-Zn (II)->IDA-Ni (II)->IDA-Cu (II). The rationale behind this order is to retain proteins based on their specific requirement for surface exposed histidine topography. This structural pre-fractionation hypothesis was successfully proven using four human plasma proteins (fibrinogen, IgG, transferrin, and albumin) with varying histidine topographies. This conjoint IMA pre-fractionation strategy not only fractionated proteins (from plasma) based on their native surface histidine topography, but also identified 157 proteins from human plasma. The advantage of our conjoint IMA is its ability to fractionate proteins in their native state and reduce plasma complexity in a single step by employing single buffer system. PMID- 28343107 TI - Phosphorylated-tyrosine based pseudobioaffinity adsorbent for the purification of immunoglobulin G. AB - The present study evaluated the phosphorylated-tyrosine (P-Tyr) based pseudobioaffinity adsorbent for the purification of human immunoglobulin G (IgG). P-Tyr was selected as a ligand to mimic the natural interactions that occur between the immunoreceptor tyrosine-based activation motif and the IgG. The ligand was coupled to bisoxirane-activated agarose gel and the effect of buffer system, pH, and conductivity was performed to elucidate the nature of IgG-P-Tyr interactions. P-Tyr-agarose was able to purify IgG from human plasma solution in HEPES buffer at pH 7.0 exhibiting a purification factor of 9.1 with IgG purity of 91% (based on ELISA analysis of albumin, transferrin, and immunoglobulins A, G, and M). The evaluation of different functional groups of P-Tyr on the adsorption of human IgG indicated the predominance of electrostatic interactions with phosphate groups, although the contributions of aromatic and carboxylic groups also play a role. The thermodynamic parameters (DeltaH degrees , DeltaS degrees , DeltaG degrees ) for IgG adsorption onto P-Tyr-agarose were determined from the temperature dependence. The maximum IgG binding capacity at 20 degrees C was 273.51+/-12.63mgg-1 and the dissociation constant value of the complex IgG-P-Tyr was in the order of 10-5molL-1 indicating low-affinity. PMID- 28343108 TI - The effects of modified versus unmodified wheat gluten administration in patients with celiac disease. AB - Celiac disease (CD) treatment requires a gluten-free diet (GFD), although alternative approaches have been proposed. Modification of gliadin peptides using microbial transglutaminase (mTG) inhibits their ability to induce immune response in vitro. Our aim was to evaluate the safety of mTG-modified wheat flour ingestion in CD patients. Twenty-one CD patients in remission were randomized to receive mTG-modified (n=11) or unmodified (n=10) wheat flour rusks, in double blind fashion. Monthly, patients completed a symptom questionnaire. Serum anti tTG, EMA and creatinine levels were monitored. At baseline and after 90days, serum anti-actin antibodies (AAA) were measured and upper endoscopy was performed. Data were analyzed by non-parametric tests. 7/11 patients eating modified rusks and 7/10 patients receiving unmodified rusks completed the study. At baseline, all patients showed negative serum anti-tTG and EMA results. At the end, 2/7 (28.6%) patients ingesting modified and 4/7 (57.1%) patients taking unmodified rusks presented positive serum anti-tTG and EMA results. Creatinine results were unmodified. Moreover, 1/7 (14.3%) patients ingesting modified and 4/7 (57.1%) patients taking unmodified rusks presented villous atrophy. In patients who received unmodified rusks, the AAA levels increased significantly and duodenal anti-tTG levels appeared higher than those measured in patients who ate modified rusks. Abdominal swelling, bloating and nausea were more severe in patients ingesting unmodified rusks than those taking modified rusks. Our results may support larger clinical trials to confirm the enzymatic treatment of wheat flour as an alternative to GFD. Clinicaltrials.gov registration no: NCT02472119. PMID- 28343109 TI - A visual analysis of gender bias in contemporary anatomy textbooks. AB - Empirical research has linked gender bias in medical education with negative attitudes and behaviors in healthcare providers. Yet it has been more than 20 years since research has considered the degree to which women and men are equally represented in anatomy textbooks. Furthermore, previous research has not explored beyond quantity of representation to also examine visual gender stereotypes and, in light of theoretical advancements in the area of intersectional research, the relationship between representations of gender and representations of ethnicity, body type, health, and age. This study aimed to determine the existence and representation of gender bias in the major anatomy textbooks used at Australian Medical Schools. A systematic visual content analysis was conducted on 6044 images in which sex/gender could be identified, sourced from 17 major anatomy textbooks published from 2008 to 2013. Further content analysis was performed on the 521 narrative images, which represent an unfolding story, found within the same textbooks. Results indicate that the representation of gender in images from anatomy textbooks remain predominantly male except within sex-specific sections. Further, other forms of bias were found to exist in: the visualization of stereotypical gendered emotions, roles and settings; the lack of ethnic, age, and body type diversity; and in the almost complete adherence to a sex/gender binary. Despite increased attention to gender issues in medicine, the visual representation of gender in medical curricula continues to be biased. The biased construction of gender in anatomy textbooks designed for medical education provides future healthcare providers with inadequate and unrealistic information about patients. PMID- 28343110 TI - The harder they fall? Sex and race/ethnic specific suicide rates in the U.S. foreclosure crisis. AB - Previous work shows suicide rates increase during economic recessions, but little research has examined the extent to which the foreclosure crisis-a unique aspect of the Great Recession-has contributed to disparities in rising suicide rates by race and sex. We develop and test two competing hypotheses regarding the association between foreclosures and race by sex specific suicide rates. We link foreclosure data (RealtyTrac) and suicide data (CDC) from 174 metropolitan areas from 2005 to 2010 (1044 MSA-year observations) and find that-net of time invariant unobserved between-metro area differences, national time trends, and time-varying confounders-a rise in the foreclosure rate is associated with a marginal increase in suicide, but this main effect masks considerable heterogeneity across groups. The association is particularly strong for white males, and weaker or non-existent for other race by sex groups. PMID- 28343111 TI - The intimate relationship as a site of social protection: Partnerships between people who inject drugs. AB - Public health research treats intimate partnerships as sites of risk management, including in the management of HIV and hepatitis C transmission. This risk infused biomedical approach tends to undermine appreciation of the emotional and socially situated meanings of care in intimate partnerships. In this article we explore qualitative interview accounts of the care enacted in partnerships between people who inject drugs, drawing on a 2014 study of 34 couples and 12 individuals living in two locations of Australia. A thematic analysis highlights 'best friend relationships', 'doing everything together', 'co-dependency', and 'doing normalcy' as core to narratives of care. As we will argue, the accounts position the care undertaken by couples as at once shaped by day-to-day practices of drug use and by social situation, with the partnership enacting care as a form of social protection, including protection from stigma and other environmental hostilities. The intimacy of doing everything together offers insulation against stigma, yet also reproduces its isolating effects. While the care produced in drug-using partnerships is presented as double-edged, we note how interview accounts are used to deflect the charge that these relationships represent harmful co-dependency. Taken together, the interview accounts negotiate a 'counter-care' in relation to normalcy, presenting the intimate partnership between people who use drugs as a legitimate embodiment of care. PMID- 28343112 TI - The impact of Australian legislative changes on synthetic cannabinoid exposures reported to the New South Wales Poisons Information Centre. AB - BACKGROUND: The emergence of new psychoactive substances (NPS), including synthetic cannabinoid receptor agonists (SCRAs) poses novel challenges for drug regulation and public health. Misconceptions of safety and legality, coupled with the fact that NPS are undetectable on routine drugs screens contributes to their popularity. Concerns over the unpredictable toxicity and abuse potential of NPS has led to a variety of legislative responses worldwide. We wish to describe Australian trends in SCRA use, examining the effects of legislative changes on calls to Australia's largest poisons centre. METHODS: A retrospective review of calls to the New South Wales Poisons Information Centre (NSWPIC). Cases occurring between 1 January 2010 and 30 June 2015 with documented use of SCRAs were included. RESULTS: There were 146 exposures to SCRAs recorded in the NSWPIC database. Federal bans of specific SCRA compounds in 2011/2012 had little impact on call volumes. State-based legislation introduced in 2013 banning specific brand names of SCRA products was followed by a dramatic, sustained decrease in exposures. The most common symptoms reported with SCRA use were tachycardia, vomiting, drowsiness, anxiety/panic, decreased level of consciousness, chest pain, agitation, hallucinations, confusion, seizures and hypertension. CONCLUSION: Banning of specific brand names of SCRA (timed with raids and social media campaigns) appears effective at reducing SCRA exposures. We postulate that this raised awareness within the community of the illegality of these substances while also reducing supply through bricks-and-mortar shops. These results could help inform future legislative responses. PMID- 28343113 TI - How four U.S. states are regulating recreational marijuana edibles. AB - BACKGROUND: Sales of edible marijuana products have been strong in Colorado and Washington State since the legalization of recreational marijuana. Initially, these states did not have comprehensive labelling or packaging requirements in place. In response to increases in marijuana-related emergency room visits and poison control centre calls, additional regulations were implemented. Currently, Alaska, Colorado, Oregon, and Washington each have passed into law various labelling and packaging requirements for edibles. METHODS: This article presents the primary legal research findings of relevant statutes and regulations for edibles in Alaska, Colorado, Oregon, and Washington. These laws were identified by using Boolean terms and connectors searches in these states' legal databases in LexisNexis. RESULTS: Alaska, Colorado, Oregon, and Washington vary greatly in how they regulate labelling and packaging. Colorado, Oregon and Washington require a Universal Symbol to be affixed to edibles, but only Oregon and Washington require that the use of pesticides be disclosed on the label. Only Colorado and Oregon require that the packaging for edibles bear a Nutrition Facts Panel on the label. Delta9-Tetrahydracannabinol (THC) in a single serving or single edible product as Alaska and Oregon. All four states prohibit the manufacture or packaging of edibles that appeal to youth. CONCLUSION: State laws governing recreational marijuana edibles have evolved since the first recreational edible products were available for sale. Alaska, Colorado, Oregon, and Washington now require edible product labels to disclose a variety of product information, including risk factors associated with consumption. However, there still remain concerns about the regulatory gaps that exist in each of these states, inherent difficulties in enforcing laws around the labelling, packaging, and manufacturing of edibles, and the outstanding question of whether these edible laws are actually informing consumers and keeping the public safe. PMID- 28343114 TI - Seeing through the public health smoke-screen in drug policy. AB - In deliberations on drug policy in United Nations fora, a consensus has emerged that drug use and drug dependence should be treated primarily as public health concerns rather than as crimes. But what some member states mean by "public health approach" merits scrutiny. Some governments that espouse treating people who use drugs as "patients, not criminals" still subject them to prison-like detention in the name of drug-dependence treatment or otherwise do not take measures to provide scientifically sound treatment and humane social support to those who need them. Even drug treatment courts, which the U.S. and other countries hold up as examples of a public health approach to drug dependence, can serve rather to tighten the hold of the criminal justice sector on concerns that should be addressed in the health sector. The political popularity of demonisation of drugs and visibly repressive approaches is an obvious challenge to leadership for truly health-oriented drug control. This commentary offers some thoughts for judging whether a public health approach is worthy of the name and cautions drug policy reformers not to rely on facile commitments to health approaches that are largely rhetorical or that mask policies and activities not in keeping with good public health practise. PMID- 28343115 TI - Patterns of drinking and driving offenses among nightclub patrons in Brazil. AB - BACKGROUND: Brazil has a strict drinking and driving law known as the Brazilian "Dry Law". The aim of the present study was to investigate characteristics associated with the breaking of the Brazilian traffic law, on drinking and driving, at nightclub exit among a representative sample of nightclub patrons in the city of Sao Paulo, Brazil. METHODS: Portal survey realized with a two-stage cluster sampling survey design to collect data from 2422 patrons at the entrance and 1822 patrons at the exit of 31 nightclubs in the city of Sao Paulo, Brazil. Patrons' breath alcohol concentrations (BrACs) at the entrance and exit of the nightclubs were categorized according to the law as either a "traffic offense" or a "traffic offense and crime". Weighted multinomial logistic regression was used to analyze factors associated with different patterns of drinking and driving offenses. RESULTS: Of the subjects, 16.5% (n=369) were identified as driving patrons at the entrance and exit of the nightclubs. At entry, 80.1% of the patrons had a zero BrAC, 14.9% had a BrAC meeting the traffic offense criteria and 5.0% had a BrAC meeting the traffic offense and crime criteria. Women were less likely to have BrACs meeting the traffic offense criteria. At nightclub exit, 63.4% of patrons had maintained a zero BrAC, 24.7% had a BrAC that had increased and now met the traffic offense and crime criteria, and 11.9% had a decreased or stable BrAC. An increased BrAC was more frequently identified in patrons who were men, were single, and had used illicit drugs inside the nightclub. CONCLUSION: Despite the existence of a strict law regarding drinking and driving, a significant proportion of nightclub patrons in the city of Sao Paulo had violated this law, suggesting a perception of impunity and need for law enforcement. PMID- 28343116 TI - Health and weight - gender-specific linkages under heterogeneity, interdependence and resilience factors. AB - Many studies have shown that obesity is a serious health problem for our society. Empirical analyses often neglect a number of methodological issues and relevant influences on health. This paper investigates empirically whether neglecting these items leads to systematically different estimates. Based on data from the German Socio-Economic Panel, this study derives the following results. (1) Many combinations of weight and height lead to the same health status. (2) The relationship between health and body mass index is nonlinear. (3) Underweight strengthens individual health and severe obesity has a clear negative impact on health status. Underweight women are more affected than men but obese men are hit harder than women. (4) The hypothesis has to be rejected that weight has an exogenous influence on health. (5) A worse health status is linked with weight fluctuations and deviations between desired and actual working hours. (6) A healthy diet and long but not too long sleeping contribute to a good health status. Moreover, a good parental education and a high parental social status act favorably on health as does personal high income. (7) Four of the big five components of personality, namely openness, extraversion, conscientiousness and agreeableness, contribute to resilience against health problems. PMID- 28343117 TI - Power assertion in everyday mother-infant interactions. AB - Mothers' power assertion was assessed following everyday infant transgressions. Power assertiveness showed limited stability, increased with age, and was higher when infants were harming others and when the physical danger was more severe. Naturalistic research is key to understanding how power assertion influences social development. PMID- 28343118 TI - Real-time formation of salivary films onto polymeric materials for dental applications: Differences between unstimulated and stimulated saliva. AB - The formation of salivary films onto oral prostheses materials is of central importance for understanding their performance and interaction with oral tissue and flora. The aim of this work was to study and compare the salivary films formed from unstimulated and stimulated whole saliva on two common polymeric materials, polycarbonate and poly(methyl methacrylate). Irradiating these materials with UV light is a simple way to modify their wettability, roughness and zeta-potential. Therefore, the effect of UV exposure of polycarbonate and poly(methyl methacrylate) on saliva adsorption was also investigated. For this purpose a quartz crystal microbalance with dissipation and SDS-PAGE have been combined in order to associate the thicknesses and viscoelastic properties of the salivary films with their protein composition. SDS-PAGE results suggest that a larger diversity of proteins is involved in the formation of stimulated saliva pellicles. Furthermore, according to QCM-D, pellicles formed from stimulated saliva are thinner and stiffer than the ones formed from unstimulated saliva if the polymeric materials have not been exposed to UV light although both types of saliva form a biphasic layer. For UV-treated materials, the same is applied to polycarbonate but not to poly(methyl methacrylate) where stimulated saliva yields thicker and softer films than unstimulated saliva being the adsorption process of a multiphasic nature. These results highlight the importance of choosing the appropriate sample depending on the type of study to be performed. PMID- 28343119 TI - Synergistically enhanced stability of laccase immobilized on synthesized silver nanoparticles with water-soluble polymers. AB - Silver nanoparticles (AgNPs) were synthesized by citrate reduction method in the presence of polymers, poly(ethylene glycol) (PEG), poly(vinyl alcohol) (PVA) and chitosan, used as stabilizing agents, and an oxidoreductase enzyme, laccase (Lac), with the goal of expanding the NPs antimicrobial action. AgNPs were characterized by UV-vis spectrometry, dynamic light scattering and transmission electron microscopy. As protecting agents, PEG and PVA promoted the formation of spherical uniformly-shaped, small-sized, monodispersed AgNPs (~20nm). High Mw polymers were established as most effective in producing small-sized NPs. Chitosan's viscosity led to the formation of aggregates. Despite the decrease in Lac activity registered for the hybrid formulation, AgNPs-polymer-Lac, a significant augment in stability over time (up to 13days, at 50 degrees C) was observed. This novel formulation displays improved synergistic performance over AgNPs-Lac or polymer-Lac conjugates, since in the former the Lac activity becomes residual at the end of 3days. By enabling many ionic interactions, chitosan restricted the mass transfer between Lac and substrate and, thus, inhibited the enzymatic activity. These hybrid nanocomposites made up of inorganic NPs, organic polymers and immobilized antimicrobial oxidoreductive enzymes represent a new class of materials with improved synergistic performance. Moreover, the Lac and the AgNPs different antimicrobial action, both in time and mechanism, may also constitute a new alternative to reduce the probability of developing resistance associated mutations. PMID- 28343120 TI - Nanoemulgel using a bicephalous heterolipid as a novel approach to enhance transdermal permeation of tenofovir. AB - Improvements in permeation enhancement strategies, such as nanoemulsions (NEs) and nanoemulgels (NEGs), have led to a renewed interest in transdermal drug delivery (TDD). This study aimed to investigate the potential of LLA1E, a novel dendritic permeation enhancer, as an oily phase in the development of a NEG for the TDD of tenofovir (TNF). TNF loaded NEs (TNEs) were prepared and analysed for mean globule diameter (MGD), polydispersity index (PDI), zeta potential (ZP) and morphology. NEGs of the TNEs (TNEGs) were prepared and evaluated for ex vivo transdermal permeation efficacy. The skin integrity before and after the experiments was assessed using histology and transepithelial electrical resistance (TEER). TNEs had a MGD of 129.06+/-3.35nm, a PDI of 0.192+/-0.038 and a ZP of 20.9+/-2.02mV, with an incorporation efficiency of 91.94+/-0.84%. There was no significant change is these properties after incorporating the TNEs into the hydrogel, as MGD, PDI and ZP of TNEGs were found to be 136.13+/-5.21nm, 0.182+/-0.020 and -20.9+/-2.08mV respectively. Ex vivo permeation studies showed that the TNEG significantly enhanced the TNF permeation by 39.65-fold, with a cumulative amount of 1866.54+/-108.62MUgcm-2. Histological and TEER assessments showed no permanent effects on the skin by TNEG, indicating that this novel TNEG nanosystem has the potential to translate into clinical trials as treatment alternatives for HIV/AIDs patients. PMID- 28343121 TI - Phylogeny and Systematics of Leptomyxid Amoebae (Amoebozoa, Tubulinea, Leptomyxida). AB - We describe four new species of Flabellula, Leptomyxa and Rhizamoeba and publish new SSU rRNA gene and actin gene sequences of leptomyxids. Using these data we provide the most comprehensive SSU phylogeny of leptomyxids to date. Based on the analyses of morphological data and results of the SSU rRNA gene phylogeny we suggest changes in the systematics of the order Leptomyxida (Amoebozoa: Lobosa: Tubulinea). We propose to merge the genera Flabellula and Paraflabellula (the genus Flabellula remains valid by priority rule). The genus Rhizamoeba is evidently polyphyletic in all phylogenetic trees; we suggest retaining the generic name Rhizamoeba for the group unifying R. saxonica, R.matisi n. sp. and R. polyura, the latter remains the type species of the genus Rhizamoeba. Based on molecular and morphological evidence we move all remaining Rhizamoeba species to the genus Leptomyxa. New family Rhizamoebidae is established here in order to avoid paraphyly of the family Leptomyxidae. With the suggested changes both molecular and morphological systems of the order Leptomyxida are now fully congruent to each other. PMID- 28343123 TI - Estimation of red-light running frequency using high-resolution traffic and signal data. AB - Red-light-running (RLR) emerges as a major cause that may lead to intersection related crashes and endanger intersection safety. To reduce RLR violations, it's critical to identify the influential factors associated with RLR and estimate RLR frequency. Without resorting to video camera recordings, this study investigates this important issue by utilizing high-resolution traffic and signal event data collected from loop detectors at five intersections on Trunk Highway 55, Minneapolis, MN. First, a simple method is proposed to identify RLR by fully utilizing the information obtained from stop bar detectors, downstream entrance detectors and advance detectors. Using 12 months of event data, a total of 6550 RLR cases were identified. According to a definition of RLR frequency as the conditional probability of RLR on a certain traffic or signal condition (veh/1000veh), the relationships between RLR frequency and some influential factors including arriving time at advance detector, approaching speed, headway, gap to the preceding vehicle on adjacent lane, cycle length, geometric characteristics and even snowing weather were empirically investigated. Statistical analysis shows good agreement with the traffic engineering practice, e.g., RLR is most likely to occur on weekdays during peak periods under large traffic demands and longer signal cycles, and a total of 95.24% RLR events occurred within the first 1.5s after the onset of red phase. The findings confirmed that vehicles tend to run the red light when they are close to intersection during phase transition, and the vehicles following the leading vehicle with short headways also likely run the red light. Last, a simplified nonlinear regression model is proposed to estimate RLR frequency based on the data from advance detector. The study is expected to helpbetter understand RLR occurrence and further contribute to the future improvement of intersection safety. PMID- 28343122 TI - Genetic and epigenetic variation of transposable elements in Arabidopsis. AB - Transposable elements are mobile genetic elements that are prevalent in plant genomes and are silenced by epigenetic modification. Different epigenetic modification pathways play distinct roles in the control of transposable element transcription, replication and recombination. The Arabidopsis genome contains families of all of the major transposable element classes, which are differentially enriched in particular genomic regions. Whole genome sequencing and DNA methylation profiling of hundreds of natural Arabidopsis accessions has revealed that transposable elements exhibit significant intraspecific genetic and epigenetic variation, and that genetic variation often underlies epigenetic variation. Together, epigenetic modification and the forces of selection define the scope within which transposable elements can contribute to, and control, genome evolution. PMID- 28343124 TI - Effects of acute alcohol consumption on measures of simulated driving: A systematic review and meta-analysis. AB - Driving simulators are used in a wide range of research settings to help develop an understanding of driver behavior in complex environments. Acute alcohol impairment is an important research topic for traffic safety and a large number of studies have indicated levels of simulated driving impairment imposed by alcohol across a range of performance outcome variables. The aim of the present study was to examine the impact of acute alcohol consumption on simulated driving performance by conducting a systematic review and meta-analysis of the available evidence. The online databases PubMed (MEDLINE), Web of Science (via Thomas Reuters) and Scopus were searched to identify studies that measured simulated car driving performance under control ('no alcohol' or 'placebo alcohol' ingestion) and intervention (acute alcohol ingestion) conditions, using repeated-measures experimental designs. Primary research outcomes were standard deviation of lane position (SDLP) and standard deviation of speed (SDSP); (total number of lane crossings (LC) and average speed (Speed) were secondary research outcomes). Meta analytic procedures were used to quantify the effect of acute alcohol consumption on vehicle control, and to determine the influence of methodological variables (i.e. the duration of the simulated driving task, the limb of the BAC curve (ascending vs. descending) and the type of driving simulator employed (i.e. car vs. PC-based)) on the magnitude of the performance change due to alcohol consumption. 423 records were screened, and 50 repeated-measures trials (n=962 participants, 62% male) derived from 17 original publications were reviewed. 37 trials (n=721 participants) used a 'placebo alcohol' comparator to determine the effect of alcohol consumption on SDLP (32/37) and SDSP (22/37). Alcohol consumption significantly increased SDLP by 4.0+/-0.5cm (95% CI: 3.0, 5.1) and SDSP by 0.38+/-0.10km?h-1 (95% CI: 0.19, 0.57). Regression analyses indicate BAC (p=0.004) and driving simulator platform (p<0.001) influence the magnitude of the SDLP change, such that higher BAC levels and the use of PC-based driving simulators were associated with larger performance decrements (R2=0.80). The limb of the BAC curve and the duration of the driving task did not significantly alter the magnitude of the performance change. Eleven trials (n=205 participants) used a 'no alcohol' comparator to measure the effect of alcohol consumption on SDLP (10/11); few trials assessed SDSP (3/11). Alcohol consumption resulted in a small significant increase in SDLP under these conditions (standardized difference in means=0.23, 95% CI: 0.06, 0.39). These results demonstrate that lateral (SDLP and LC) and longitudinal (SDSP) vehicle control measures in a driving simulator are impaired with acute alcohol consumption. However, SDLP appears to be a more sensitive indicator of driving impairment than other driving performance variables and the results of the present study support its use as a performance outcome when examining alcohol-induced simulated driving impairment. PMID- 28343125 TI - Structural modeling of human organic cation transporters. AB - Human organic cation transporters (hOCTs) belong to solute carriers (SLC) 22 family of membrane proteins that play a central role in transportation of chemotherapeutic drugs for several clinical and pathological conditions, including cancer and diabetes. These transporters mediate drug transport; however, the precise mechanism of drug-binding and transport by them is not fully uncovered yet, partly due to unavailability of any crystal structure record. In this work, we performed a multi-phasic approach to compute the 3D structural models of seven human organic cation transporters (hOCTs) starting from primary protein sequence. Our structure modeling approach included 1) I-TASSER based comparative sequence alignment, threading and ab-initio protein modeling; 2) models comparison with PSIPRED secondary structure prediction; 3) loop modeling for incongruent secondary structure in Chimera 1.10.1; 4) high resolution structure simulation, refinement, energy minimization using ModRefiner, and 5) validation of the structure models using PROCHECK at SAVEs. From structural point, the computed 3D structures of hOCTs consist of a typical major facilitator superfamily (MFS) fold of twelve alpha-transmembrane helix domains arranged in a manner rendering hOCTs a barrel shaped structure with a large cleft that opens in cytoplasm. The modeled 3D structure of all hOCTs closely resemble to human SLC2A3 (GLUT3) transporter (PDB ID: 5c65) and displayed an outward-open confirmation and putative cyclic C1 protein symmetry. In addition, hOCTs has a large (>100 amino acids) unique extracellular loop between TMH1 and TMH2 having potential glycosylation sites (Asn-Xaa-Ser/Thr) and cysteine residues, both features indicative of putative role in drug binding and uptake. There is an intracellular three/four-helix loop between TMH6 and TMH7 containing putative phosphorylation sites for precise regulation of hOCTs function as drug transporters. There are nine loops of 4 to 11 amino acids length that protrude from membrane, both intracellularly and extracellularly, and connect adjacent TMHs. The 2D structure prediction showed Nin-Cin topology of all hOCTs. In the unavailability of the crystal structures of hOCTs, the 3D structural models computed in-silico and presented herein can be used for studying the mechanism of drug binding and transport by hOCTs. PMID- 28343127 TI - Direct immobilization of manganese chelates on silica nanospheres for MRI applications. AB - The development of tissue specific magnetic resonance imaging (MRI) contrast agents (CAs) is very desirable to achieve high contrast ratio combined with excellent anatomical details. To this end, we introduce a highly effective manganese(II) containing silica material, with the aim to shorten the longitudinal (T1) relaxation time. The microporous silica nanospheres (MSNSs) with enlarged porosity and specific surface area were prepared by a surfactant assisted aqueous method. Subsequently, the surface silanol groups were amino functionalized, reacted with diethylenetriaminepentaacetic (DTPA) dianhydride and finally deposited with Mn2+. After comprehensive characterization, the MRI properties of functionalized MSNSs were investigated. The resulting nanospheres demonstrated substantial contrast enhancement during the in vitro MRI investigations, which was also evidenced by significant contrast enhancement on T1-weighted MR images in vivo. Moreover, in vitro cytotoxicity assay of functionalized MSNSs on hepatocyte mono- and hepatocyte-Kuppfer cell co-cultures showed no significant decrease in cell viability. Our findings confirmed our hypothesis, that Mn2+-chelating MSNSs are appropriate candidates for liver specific T1-weighted MRI CAs with high relaxivities (r1=7.18mM-1s-1). PMID- 28343128 TI - Peroxy-Titanium Complex-based inks for low temperature compliant anatase thin films. AB - Stable highly crystalline titanium dioxide colloids are of paramount importance for the establishment of a solution-processable library of materials that could help in bringing the advantages of digital printing to the world of photocatalysis and solar energy conversion. Nano-sized titanium dioxide in the anatase phase was synthesized by means of hydrothermal methods and treated with hydrogen peroxide to form Peroxy-Titanium Complexes (PTCs). The influence of hydrogen peroxide on the structural, optical and rheological properties of titanium dioxide and its colloidal solutions were assessed and a practical demonstration of a low temperature compliant digitally printed anatase thin film given. PMID- 28343129 TI - Nano-sized molecularly imprinted polymer for selective ultrasound-assisted microextraction of pesticide Carbaryl from water samples: Spectrophotometric determination. AB - Ultrasound-assisted dispersive solid phase microextraction followed by UV-Vis spectrophotometry (UA-DSPME UV-Vis) was designed for the extraction and preconcentration of Carbaryl using nano-sized molecularly-imprinted polymer (MIP NP). Nano-sized Carbaryl-imprinted polymer was characterized by scanning electron microscopy. A preliminary Plackett-Burman design was applied for screening. Subsequently, central composite design under response surface methodology was used to investigate and model the Carbaryl adsorption as response as well as to optimize this response versus variables such as Carbaryl MIP-NP mass, sonication time, temperature, eluent volume, pH and vortex time. At optimum experimental conditions, UAMSPE-UV-Vis exhibited a linear range of 0.1-1.2mgL-1. The enhancement and preconcentration factors were obtained to be 30.6 and 25.0, respectively, for the extraction of Carbaryl by MIP-NP. In addition, the values of 0.033 and 0.11mgL-1 were obtained for limit of detection and limit of quantification, respectively. The value of 4.3% determined for relative standard deviation for the separation and preconcentration of Carbaryl after 5 repetitions shows the acceptable repeatability of the process. Finally, the developed method was successfully applied for the determination of Carbaryl in water samples. PMID- 28343130 TI - Computational study of ibuprofen removal from water by adsorption in realistic activated carbons. AB - Molecular simulations using the Grand Canonical Monte Carlo (GCMC) method have been performed in order to obtain physical insights on how the interaction between ibuprofen (IBP) and activated carbons (ACs) in aqueous mixtures affects IBP removal from water by ACs. A nanoporous carbon model based on units of polyaromatic molecules with different number of rings, defects and polar oxygenated sites is described. Individual effects of factors such as porous features and chemical heterogeneities in the adsorbents are investigated and quantified. Results are in good agreement with experimental adsorption data, highlightening the ability of GCMC simulation to describe the macroscopic adsorption performance in drug removal applications, while also providing additional insights into the IBP/water adsorption mechanism. The simulation results allow finding the optimal type of activated carbon material for separating this pollutant in water treatment. PMID- 28343126 TI - PI3K signaling in cancer: beyond AKT. AB - The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most frequently altered pathways in human cancer and has a critical role in driving tumor initiation and progression. Although PI3K and its lipid product phosphatidylinositol-3,4,5-trisphosphate (PIP3) have been shown to activate multiple downstream signaling proteins, the vast majority of studies have focused on the protein kinase AKT as the dominant effector of PI3K signaling. However, recent studies have demonstrated many contexts under which other PIP3-dependent signaling proteins critically contribute to cancer progression, illustrating the importance of understanding AKT-independent signaling downstream of PI3K. Here, we highlight three PI3K-dependent, but AKT-independent, signaling branches that have recently been shown to have important roles in promoting phenotypes associated with malignancy. First, the PDK1-mTORC2-SGK axis can substitute for AKT in survival, migration, and growth signaling and has emerged as a major mechanism of resistance to PI3K and AKT inhibitors. Second, Rac signaling mediates the reorganization of the actin cytoskeleton to regulate cancer cell migration, invasion, and metabolism. Finally, the TEC family kinase BTK has a critical role in B cell function and malignancy and represents a recent example of an effective therapeutic target in cancer. These mechanisms highlight how understanding PI3K-dependent, but AKT-independent, signaling mechanisms that drive cancer progression will be crucial for the development of novel and more effective approaches for targeting the PI3K pathway for therapeutic benefit in cancer. PMID- 28343131 TI - Synthesis of mesoporous poly(melamine-formaldehyde) particles by inverse emulsion polymerization. AB - Mesoporous poly(melamine-formaldehyde) (MF) particles with surface areas of up to 200m2g-1 were synthesized by an inverse emulsion polymerization using dodecane and Span80(r) as continuous phase. The finer details of the shape control (using emulsion techniques) and the porosity control (using silica nanoparticles as hard template) are discussed. The impact of phase-separation processes on the observable porosity of the 20-200um sized spherical particles is analysed by gas sorption methods and electron microscopy. The high density of amine and triazine functional groups in the porous MF particles make the material a promising adsorber for heavy metal ions and methylene blue. In a preliminary column experiment, the synthesized material exhibited a total capacity of 2.54mmol/g (? 812.4mg/g) for the adsorption of methylene blue. PMID- 28343132 TI - Probing polarity of flame retardants and correlating with interaction between flame retardants and PET fiber. AB - The empirical polarity parameter ET(30) was determined for polyethylene terephthalate (PET) fiber and five phosphorus flame retardants by UV-Vis absorption spectrum of solvatochromic probe. To investigate the interaction between flame retardant and PET fiber during the finishing process, the partition coefficients K of these flame retardants between water and PET fiber were determined and an interesting linear relationship between lnK and ET(30) of the flame retardants was obtained, suggesting ET(30) is definitely an excellent estimation of the interaction of flame retardants with PET. Additionally, the thermodynamic criterion of this finishing process, standard Gibbs free energy of transfer of the flame retardants from water to PET fiber, DeltaGt0(FR,H2O->PET), was found to linearly correlate with ET(30) of the flame retardants as well, DeltaGt0(FR,H2O->PET)=0.3664*ET(30)(FR) -18.60 (R2=0.9168), demonstrating polarity of flame retardant is an important and determining factor for its fixation on PET fiber. This work may provide theoretical guidance for choosing flame retardant finishing agent more compatible with PET fabric. PMID- 28343133 TI - Single-crystal Cr2O3 nanoplates with differing crystalinities, derived from trinuclear complexes and embedded in a carbon matrix, as an electrode material for supercapacitors. AB - As one kind of important p-type semiconductors, Cr2O3 has been widely used for optical and electronic devices due to its high electrical conductivity and special optoelectronic characteristics, as well as high chemical and thermal stability. In this paper, single-crystalline Cr2O3 nanoplates embedded in carbon matrix were successfully synthesized through direct thermal decomposition of a trinuclear cluster complex of [Cr3O(CH3CO2)6(H2O)3]NO3.CH3COOH ([Cr3O]) in Ar atmosphere. The synergetic effect of the plate-like structure and embedding in carbon matrix contributes to the enhanced electrochemical performance of the Cr2O3-C nanoplates. Owing to different crystallinity and composition, the obtained products at 400, 500, 600, and 700 degrees C with different carbon content of 12.52, 8.26, 5.35 and 3.27% exhibited enhanced battery-type electrode materials in three-electrode system with high specific capacitance (823.11, 781.65, 720.72, and 696.73Fg-1 at 1Ag-1) and remarkable cycling stability (about 0.3, 2.7, 4.5 and 5.6% loss of its initial capacitance after 5000 charge discharge cycles at a current density of 5Ag-1). Furthermore, an assembled asymmetric device (Cr2O3-C nanoplates (positive electrode)//activated carbon (AC, negative one)) with an extended operating voltage window of 1.8V achieves a specific capacitance of 58.06Fg-1 at the current density of 1Ag-1 and an energy density of 26.125Whkg-1 at power density of 0.9kWkg-1, as well as superior cycling stability with 91.4% capacitance retention after 10,000 cycles. The results indicate that the Cr2O3 nanoplates embedded in carbon matrix show promising potential to construct high-performance energy storage devices. PMID- 28343134 TI - Exfoliated graphene nanosheets: pH-sensitive drug carrier and anti-cancer activity. AB - A straightforward and facile method for the exfoliation of graphene sheets using poly(vinylpyrrolidone) nanoparticles of an average size of 42nm was developed and their dual role as pH-sensitive drug carrier and anti-cancer agent was evaluated. The cytotoxic impact of the exfoliated nanosheets (GRP-PVP-NP) was examined on various cells (HCT-116, HeLa, SCC-9, NIH-3T3 and HEK-293cells) by a series of assays. Their cytotoxic nature was attributed to affecting the mitochondrial enzyme activity, proliferation capability, and the formation of tight junctions in cancer cells. The endocytosis was found to be internalization mechanism for the cellular uptake of nanosheets. The generation of reactive oxygen species and elicitation of caspase-3 activity which was undoubtedly associated with triggering of oxidative stress speculated to be the dominant cause of the cytotoxic pattern of nanosheets against cancer cells. Additionally, the results also showed the role of the nanosheets as a pH-sensitive drug carrier through drug loading by supramolecular interaction. The efficient release of doxorubicin was seen at low pH and in an environment with a low oxygen concentration, thus under conditions mimicking the typical tumor microenvironment. Therefore, these findings provide the first evidence for a dual function of exfoliated graphene sheets and also elucidate the cytotoxic mechanism responsible for the cancer cell death. PMID- 28343135 TI - Monodisperse Ag/Pd core/shell nanoparticles assembled on reduced graphene oxide as highly efficient catalysts for the transfer hydrogenation of nitroarenes. AB - Addressed herein is a facile seed-mediated synthesis of Ag/Pd core/shell nanoparticles (NPs) and their assembly on reduced graphene oxide (rGO) to catalyze the transfer hydrogenation of nitroarenes to anilines using ammonia borane (AB) as a hydrogen donor under ambient conditions. Monodisperse Ag/Pd core/shell NPs with controllable Pd shell-thickness were synthesized by the means of thermal decomposition of palladium(II) bromide over as-prepared Ag NPs in the mixture of oleylamine and oleic acid at 220 degrees C. As-synthesized Ag/Pd core/shell NPs were characterized by TEM, HR-TEM, XRD, XPS, UV-Vis spectroscopy and ICP-MS and then they were assembled on reduced graphene oxide (rGO). Next, rGO@Ag/Pd catalysts were tested in the transfer hydrogenation of nitroarenes in which ammonia borane (AB) was used as a hydrogen donor at room temperature. It was demonstrated that the thickness of the Pd shell has a significant effect on the catalytic activity of rGO@Ag/Pd catalysts and the 1.75nm Pd shell provided the highest performance in the transfer hydrogenation reactions. The rGO@Ag/Pd catalyzed transfer hydrogenation reactions were tested over a variety of nitroarenes (total 16 examples) and they were all converted to the corresponding aniline derivatives with high yields in 5-15min under ambient conditions. PMID- 28343136 TI - Facile microfluidic production of composite polymer core-shell microcapsules and crescent-shaped microparticles. AB - HYPOTHESIS: Core-shell microcapsules and crescent-shaped microparticles can be used as picolitre bioreactors for cell culture and microwells for cell trapping/immobilisation, respectively. RESULTS: Monodisperse polylactic acid (PLA) core-shell microcapsules with a diameter above 200MUm, a shell thickness of 10MUm, and 96% water entrapment efficiency were produced by solvent evaporation from microfluidically generated W/O/W emulsion drops with core-shell structure, and used to encapsulate Saccharomyces cerevisiae yeast cells in their aqueous cores. The morphological changes of the capsules stained with Nile red were studied over 14days under different osmotic pressure and pH gradients. FINDINGS: The shell retained its integrity under isotonic conditions, but buckling and particle crumbling occurred in a hypertonic solution. When the capsules containing 5wt% aqueous Eudragit(r) S 100 solution in the core were incubated in 10-4M HCl solution, H+ diffused through the PLA film into the core causing an ionic gelation of the inner phase and its phase separation into polymer-rich and water-rich regions, due to the transition of Eudragit from a hydrophilic to hydrophobic state. Crescent-shaped composite microparticles with Eudragit cores and PLA shells were fabricated by drying core-shell microcapsules with gelled cores, due to the collapse of PLA shells encompassing water-rich crescent regions. PMID- 28343137 TI - Synthesis of novel muramic acid derivatives and their interaction with lysozyme: Action of lysozyme revisited. AB - HYPOTHESIS: The interaction of lysozyme with the N-acetylmuramic acid (NAM) and N acetylglucosamine (NAG) unit of peptidoglycan (PGN) polymer of the bacterial cell wall is of immense importance to understand the mechanism of lysozyme on PGN. EXPERIMENTS: The synthesis of three novel NAM derivatives containing fused oxazinone ring to the NAM moiety has been achieved. The synthesized compounds were evaluated for their potential as a glycomimetic acceptor of lysozyme using different biophysical and computational methods such as 1H NMR, STD NMR, DOSY and Molecular docking. FINDINGS: Novel modified muramic acid derivatives have been synthesized in excellent yield containing fused cyclooxazine ring embedded on the muramic acid moiety using a newly developed hydrazinolysis reaction condition. From various biophysical studies, it has been established that the compound containing endo modified muramic acid moiety (compound 1) shows significant binding property for the lysozyme while the other isomer (compound 2) did not bind to the lysozyme. The catalytic residues Glu35 and Asp52 were found to be in the close proximity for the active molecule which justifies the selectivity of this molecule in conjunction to lysozyme enzymatic activity. PMID- 28343138 TI - Revisiting the impact of OXTR rs53576 on empathy: A population-based study and a meta-analysis. AB - Oxytocin in the brain is related to empathy, which refers to the ability to understand and share others' internal states or responses. Previous studies have investigated the impact of OXTR rs53576, the most intensively examined polymorphism in the oxytocin receptor (OXTR) gene, on individual differences in empathy. However, these studies produced inconsistent results. In the current study, we reexamined the association of OXTR rs53576 with empathy in a relatively large population (N=1830) and also evaluated the association by a comprehensive meta-analysis (N=6631, 13 independent samples). The replication study indicated that OXTR rs53576 was indeed associated with individual differences in empathy. Individuals with a greater number of G alleles showed better empathic ability, particularly in fantasizing other's feelings and actions. The meta-analysis not only confirmed this association, but also indicated that the impact of this polymorphism was significant in both Europeans and Asians. These findings provide convincing evidence for the impact of OXTR rs53576 on empathy, highlighting the importance of OXTR gene in individuals' social cognition. PMID- 28343140 TI - Sequence-encoded material properties dictate the structure and function of nuclear bodies. AB - Concomitant with packaging the genome, the cell nucleus must also spatially organize the nucleoplasm. This complex mixture of proteins and nucleic acids partitions into a variety of phase-separated, membraneless organelles called nuclear bodies. Significant progress has been made in understanding the relationship between the material properties of nuclear bodies and their structural and functional consequences. Furthermore, the molecular basis of these condensed phases is beginning to emerge. Here, I review the latest work in this exciting field, highlighting recent advances and new challenges. PMID- 28343139 TI - Oxytocin in corticosterone-induced chronic stress model: Focus on adrenal gland function. AB - Chronic stress conditions can lead to considerable and extensible changes in physiological and psychological performances, and in emergence of risk for various somatic diseases. On the other hand, the neuropeptide oxytocin is reported to increase the resistance of the organism to stress and modulate activity of autonomic nervous system. Chronic corticosterone administration is used as a rat model for a state observed in terms of chronic stress exposure, when negative feedback mechanism of hypothalamus-pituitary-adrenal axis activity is disrupted. In our study, we aimed to investigate whether chronic administration of oxytocin (10 IU/400MUL/day for 14days, s.c.) influenced adrenal gland morphology and activity in adult male Wistar rats during long-term corticosterone administration via drinking water (100mg/L for 21days). We examined the influence of treatments on the levels of adrenal gland hormones, corticosterone, adrenaline and noradrenaline, as well as their response to an acute stress challenge evoked by 15-min forced swimming. In addition, the expression of two main monoamine transporters, the noradrenaline transporter (NAT) and vesicular monoamine transporter 2 (VMAT2) in adrenal medulla was measured in the rats exposed to acute stress. Our results showed that oxytocin treatment prevented corticosterone-induced decrease in body weight gain, attenuated adrenal gland atrophy by increasing glandular weight, and the area of the zona fasciculate and reticularis. Chronic corticosterone intake blunted the response of all measured hormones to acute stress, whereas concomitant oxytocin treatment reversed adrenaline and noradrenaline response to acute stress. Furthermore, in adrenal medulla, oxytocin produced significant vasodilatation and stimulated expression of both catecholamine transporters detected both on mRNA and protein level. Our data suggest that oxytocin, by reducing atrophy of adrenal gland, and by increasing catecholamine storage capacity, may be beneficial in conditions accompanied with high glucocorticoid levels, such as chronic stress exposure. PMID- 28343141 TI - Survival outcomes in iron chelated and non-chelated patients with lower-risk myelodysplastic syndromes: Review and pooled analysis of observational studies. PMID- 28343142 TI - Circuit mechanisms of sleepiness and cataplexy in narcolepsy. AB - Narcolepsy is a debilitating sleep disorder caused by loss of orexin neurons in the lateral hypothalamus. Excessive daytime sleepiness and cataplexy are the major complaints in narcolepsy, and are associated with impaired quality of life. Although it is unclear how orexin loss causes sleepiness and cataplexy, animal models have been instrumental in identifying the neurobiological underpinnings of narcolepsy because they reliably recapitulate disease symptoms. Current evidence indicates that orexin cell loss causes sleepiness and cataplexy by destabilizing the ability of the circuits that initiate and sustain normal levels of arousal and motor activity. This review highlights the latest research concerning the normal function of the orexin system and how its dysfunction causes narcolepsy symptoms. PMID- 28343143 TI - Impact of rivaroxaban on point-of-care assays. AB - BACKGROUND: Point-of-care testing (POCT) is regularly used to assess haemostasis in various clinical settings. The impact of rivaroxaban on those POCT is still elusive. We aimed to study the effects of rivaroxaban on most commonly used POCT assays. METHODS: Blood samples were taken before, 3h, and 24h after administration of 20mg rivaroxaban to 20 healthy volunteers as part of a prospective, multicenter validation study (clinicaltrials.govNCT01710267). Blood samples were analysed with thromboelastometry (ROTEM(r)), two platelet function assays (INNOVANCE(r) PFA-200 and Multiplate(r)), and the CoaguChek(r) XS. Rivaroxaban plasma levels were determined using liquid chromatography-mass spectrometry. RESULTS: Rivaroxaban significantly modified some thromboelastometry parameters (CT INTEM: mean difference 56.1s, 95% CI: 41.8, 70.3; CT EXTEM: 47.5s, 95% CI: 37.8, 57.1; CT HEPTEM: 50.1s, 95% CI: 34.7, 65.6), and CoaguChek(r) XS parameters (prothrombin time: mean difference 3.8s, 95% CI: 3.3, 4.2; INR: 0.32, 95% CI: 0.27, 0.38; prothrombin ratio: -36.1%, 95% CI: -32.3, -39.9). CT EXTEM and INR showed a moderate correlation with rivaroxaban plasma levels (r=0.83; 95% CI 0.69, 0.9 and r=0.83; 95% CI 0.70, 0.91, respectively) and a high sensitivity to detect rivaroxaban treatment at peak levels (0.95; 95% CI: 0.76, 1.0 and 0.90, 95% CI 0.70, 0.99, respectively). CONCLUSIONS: Rivaroxaban 20mg treatment significantly alters ROTEM(r) and CoaguChek(r) XS parameters. Even though POCT do not allow precise quantification of rivaroxaban plasma concentration, CT EXTEM and CoaguChek XS detect the presence of rivaroxaban at peak level with a high sensitivity. PMID- 28343145 TI - Effects of tiletamine on the adenosine monophosphate-activated protein kinase signaling pathway in the rat central nervous system. AB - OBJECTIVE: The dissociative anesthetic tiletamine, which acts on the central nervous system (CNS), is widely used in veterinary medicine and animal experiments. Recent studies indicate that adenosine 5'-monophosphate activated protein kinase (AMPK) plays a key role in the analgesic action of tiletamine. In the present study, the effects of tiletamine on the AMPK signaling pathway in rats were investigated. METHODS: Sprague-Dawley rats were injected intraperitoneally with tiletamine and executed at 10, 20, 40 and 60min post injection. The cerebral cortex, hippocampus, thalamus, cerebellum and brainstem were immediately taken out to evaluate the mRNA and protein phosphorylation levels of liver kinase B1 (LKB1), AMPKalpha and eIF4E-binding protein 1 (4EBP1) using quantitative real-time polymerase chain reaction and western blot analysis. RESULTS: Tiletamine increased AMPK mRNA expression in the rat brain (P<0.01). Increased mRNA expression of AMPK was accompanied by an increase in phosphorylation of LKB1, resulting in significant decreases in the phosphorylation levels of 4EBP1 in the corresponding brain regions (P<0.01). CONCLUSION: In summary, the findings indicate that tiletamine regulates the mRNA expression and protein phosphorylation levels of LKB1, AMPK and 4EBP1 in the CNS, suggesting that the analgesic effect of the anesthetic is mediated, at least in part, by the AMPK signaling pathway. PMID- 28343144 TI - Gene and protein expressions and metabolomics exhibit activated redox signaling and wnt/beta-catenin pathway are associated with metabolite dysfunction in patients with chronic kidney disease. AB - Changes in plasma concentration of small organic metabolites could be due to their altered production or urinary excretion and changes in their urine concentration may be due to the changes in their filtered load, tubular reabsorption, and/or altered urine volume. Therefore, these factors should be considered in interpretation of the changes observed in plasma or urine of the target metabolite(s). Fasting plasma and urine samples from 180 CKD patients and 120 age-matched healthy controls were determined by UPLC-HDMS-metabolomics and quantitative real-time RT-PCR techniques. Compared with healthy controls, patients with CKD showed activation of NF-kappaB and up-regulation of pro inflammatory and pro-oxidant mRNA and protein expression as well as down regulation of Nrf2-associated anti-oxidant gene mRNA and protein expression, accompanied by activated canonical Wnt/beta-catenin signaling. 124 plasma and 128 urine metabolites were identified and 40 metabolites were significantly altered in both plasma and urine. Plasma concentration and urine excretion of 25 metabolites were distinctly different between CKD and controls. They were related to amino acid, methylamine, purine and lipid metabolisms. Logistic regression identified four plasma and five urine metabolites. Parts of them were good correlated with eGFR or serum creatinine. 5-Methoxytryptophan and homocystine and citrulline were good correlated with both eGFR and creatinine. Clinical factors were incorporated to establish predictive models. The enhanced metabolite model showed 5-methoxytryptophan, homocystine and citrulline have satisfactory accuracy, sensitivity and specificity for predictive CKD. The dysregulation of CKD was related to amino acid, methylamine, purine and lipid metabolisms. 5 methoxytryptophan, homocystine and citrulline could be considered as additional GFR-associated biomarker candidates and for indicating advanced renal injury. CKD caused dysregulation of the plasma and urine metabolome, activation of inflammatory/oxidative pathway and Wnt/beta-catenin signaling and suppression of antioxidant pathway. PMID- 28343146 TI - Antimicrobial effect of the Biotronic(r) Top3 supplement and efficacy in protecting rainbow trout (Oncorhynchus mykiss) from infection by Aeromonas salmonicida subsp. salmonicida. AB - Demand for more environmentally friendly practices have led to the adoption of several feed supplements by the fish farming industry. In the present study, we investigated a commercially available formula that includes a mixture of three compounds: organic acids, a phytochemical and Biomin(r) Permeabilizing Complex. This mixture demonstrated antimicrobial properties in vitro and was able to inhibit growth of multiple species of aquatic bacterial pathogens, including Aeromonas salmonicida. Bacterial challenge was performed using A. salmonicida and three exposure routes: intra-peritoneal injection, immersion, and cohabitation. Mortality rates following infection by injection were significantly decreased in the fish that had received the supplemented feed. Fish infected through the other routes did not show a significant difference in mortality. In term of farming performance, while the fish that had received the feed supplement showed an improvement in weight gain and final weight, these changes were not found to be statistically significant. Similarly, no significant difference was observed in the feed conversion ratio. The results of this study suggest that this feed supplement may be effective at protecting rainbow trout from fish furunculosis. PMID- 28343147 TI - Ethical perspectives and ramifications of the Paolo Macchiarini case. AB - The Paolo Macchiarini case has several ethical ramifications. Professor Macchiarini, formerly of the Karolinska Institutet (KI), became famous for the tracheal surgeries he conducted between 2008 and 2014. His rapid rise to fame was followed by an almost equally rapid fall from grace as official reports, articles in newspapers and television programmes revealed several aspects related to misconduct in his curriculum vitae, professional practices and publishing-related activity. Formal misconduct reports issued by four KI co-workers in late 2014, then again in 2016, coupled with social scandals, including the tricking of a famous US television newscaster into a false marriage, a previous arrest in Italy for apparent bribery, and acute narcissism, all tainted Macchiarini's legend. In the short space of just two years, Macchiarini was no longer remembered for the revolutionary changes he had claimed to have brought about in stem cell research and regenerative medicine. Instead, at least seven dead patients later, Macchiarini faces potential aggravated manslaughter charges and an uphill battle to save his published research, now shrouded in scandal and scientific doubt, from being retracted and scratched out from the list of verified medical science. This paper examines some of the possible ethical ramifications of the Macchiarini case. PMID- 28343148 TI - De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy. AB - BACKGROUND: Moyamoya angiopathy (MMA) is characterised by a progressive stenosis of the terminal part of the internal carotid arteries and the development of abnormal collateral deep vessels. Its pathophysiology is unknown. MMA can be the sole manifestation of the disease (moyamoya disease) or be associated with various conditions (moyamoya syndrome) including some Mendelian diseases. We aimed to investigate the genetic basis of moyamoya using a whole exome sequencing (WES) approach conducted in sporadic cases without any overt symptom suggestive of a known Mendelian moyamoya syndrome. METHODS: A WES was performed in four unrelated early-onset moyamoya sporadic cases and their parents (trios). Exome data were analysed under dominant de novo, autosomal recessive and X-linked hypotheses. A panel of 17 additional sporadic cases with early-onset moyamoya was available for mutation recurrence analysis. RESULTS: We identified two germline de novo mutations in CBL in two out of the four trio probands, two girls presenting with an infancy-onset severe MMA. Both mutations were predicted to alter the ubiquitin ligase activity of the CBL protein that acts as a negative regulator of the RAS pathway. These two germline CBL mutations have previously been described in association with a developmental Noonan-like syndrome and susceptibility to juvenile myelomonocytic leukaemia (JMML). Notably, the two mutated girls never developed JMML and presented only subtle signs of RASopathy that did not lead to evoke this diagnosis during follow-up. CONCLUSIONS: These data suggest that CBL gene screening should be considered in early-onset moyamoya, even in the absence of obvious signs of RASopathy. PMID- 28343150 TI - Combined intramedullary and intradural extramedullary spinal metastases in malignant melanoma. PMID- 28343149 TI - beta-Adrenergic Stimulation Induces Histone Deacetylase 5 (HDAC5) Nuclear Accumulation in Cardiomyocytes by B55alpha-PP2A-Mediated Dephosphorylation. AB - BACKGROUND: Class IIa histone deacetylase (HDAC) isoforms such as HDAC5 are critical signal-responsive repressors of maladaptive cardiomyocyte hypertrophy, through nuclear interactions with transcription factors including myocyte enhancer factor-2. beta-Adrenoceptor (beta-AR) stimulation, a signal of fundamental importance in regulating cardiac function, has been proposed to induce both phosphorylation-independent nuclear export and phosphorylation dependent nuclear accumulation of cardiomyocyte HDAC5. The relative importance of phosphorylation at Ser259/Ser498 versus Ser279 in HDAC5 regulation is also controversial. We aimed to determine the impact of beta-AR stimulation on the phosphorylation, localization, and function of cardiomyocyte HDAC5 and delineate underlying molecular mechanisms. METHODS AND RESULTS: A novel 3-dimensional confocal microscopy method that objectively quantifies the whole-cell nuclear/cytoplasmic distribution of green fluorescent protein tagged HDAC5 revealed the beta-AR agonist isoproterenol to induce beta1-AR-mediated and protein kinase A-dependent HDAC5 nuclear accumulation in adult rat cardiomyocytes, which was accompanied by dephosphorylation at Ser259/279/498. Mutation of Ser259/Ser498 to Ala promoted HDAC5 nuclear accumulation and myocyte enhancer factor-2 inhibition, whereas Ser279 ablation had no such effect and did not block isoproterenol-induced nuclear accumulation. Inhibition of the Ser/Thr phosphatase PP2A blocked isoproterenol-induced HDAC5 dephosphorylation. Co immunoprecipitation revealed a specific interaction of HDAC5 with the PP2A targeting subunit B55alpha, as well as catalytic and scaffolding subunits, which increased >3-fold with isoproterenol. Knockdown of B55alpha in neonatal cardiomyocytes attenuated isoproterenol-induced HDAC5 dephosphorylation. CONCLUSIONS: beta-AR stimulation induces HDAC5 nuclear accumulation in cardiomyocytes by a mechanism that is protein kinase A-dependent but requires B55alpha-PP2A-mediated dephosphorylation of Ser259/Ser498 rather than protein kinase A-mediated phosphorylation of Ser279. PMID- 28343151 TI - Gastric outlet obstruction: an unusual case of primary duodenal tuberculosis. AB - BACKGROUND: Tuberculosis is a major health problem worldwide. Gastrointestinal tuberculosis presenting as isolated involvement of the duodenum is a rare case. CASE PRESENTATION: A 13 year male, presented with features of gastric outlet obstruction. CT enterography scan showed circumferential mural thickening in first and second part of duodenal junction causing luminal narrowing. Upper GI endoscopy confirmed the narrowing of D1-D2 junction. Duodenal biopsy showed duodenitis with negative result for AFB stain, Helicobacter Pylori. Patient underwent roux-en-y gastro-jejunostomy. Histo-pathological findings were consistent with tuberculosis. Patient was started on AKT and discharged. At 3 months follow up; patient asymptomatic. CONCLUSION: The unusual location of gastrointestinal tuberculosis, lack of specific signs and symptoms, radiological studies and endoscopy findings makes diagnosis a challenge. The treatment of duodenal tuberculosis is still medical and surgery should be reserved for emergency like gastric outlet obstruction causing nutritional compromise. PMID- 28343152 TI - The answer is blowing in the wind: an uncommon cause for severe ARDS accompanied by circulatory insufficiency requiring extracorporeal membrane oxygenation. AB - We report a rare complication in an immunosuppressed patient with IgA nephropathy who suffered from severe acute respiratory distress syndrome, severe capillary leakage and shock after placement of a double lumen central venous catheter. He could be successfully treated by extracorporeal membrane oxygenation (ECMO) and therapeutic plasma exchange. This report highlights the severity of late-onset complications of catheter placements and shows the potential of ECMO treatment for the management of acute illnesses with bridge to recovery. PMID- 28343153 TI - De Garengeot's hernia: an unusual case on call. AB - De Garengeot's hernia is defined as a femoral hernia that contains the appendix. Owing to the extreme rarity of de Garengeot's hernia, it could represent a diagnostic challenge; however, it should remain in the differential diagnosis, particularly in this patient demographic. A female patient aged 96 years, who presented as an emergency with acute right iliac fossa pain, was found to have de Garengeot's hernia. The diagnosis was made intraoperatively, where she was treated with an appendicectomy and repair of the hernia defect. The incidence of de Garengeot's hernia is 0.5-5% and the incidence of appendicitis within a femoral hernia is extremely rare. Preoperative diagnosis is challenging to the treating surgeon, which requires a high index of suspicion and is usually made intraoperatively. There is no standard treatment; however, simple appendicectomy and hernia repair seems to be an accepted management. PMID- 28343154 TI - Silent uterine rupture in scarred uterus. AB - : Uterine rupture in pregnancy is a rare and catastrophic complication with a high incidence of fetal and maternal morbidity. Very few cases have been reported in the literature. CASE PRESENTATION: A 28-year-old fifth gravid woman with a history of one caesarean section presented to our department at 39 weeks and 6 days gestation with complaints of headache, epigastric pain and nausea. Her blood pressure was elevated and there was proteinuria. Emergency caesarean section was performed in view of symptoms. Uterine rupture was found during the surgery. A live male infant was delivered in good condition. Postnatal recovery was unremarkable and the woman discharged on postoperative day 5. CONCLUSION: Rupture of the uterus can present in third trimester even before labour with minimal or no symptoms. PMID- 28343155 TI - More than just muscle spasms: a rare presentation of aortic dissection. AB - Acute aortic dissection is associated with significant morbidity and mortality, often from complications including aortic regurgitation, cardiac tamponade and myocardial infarction. Typical clinical presentation includes a sudden onset of severe chest pain, although this is not always consistent. Clinical signs and symptoms are diverse with an estimated 38% of cases being missed on initial evaluation. Primary neurological symptoms at presentation are rare but have been reported often to coexist with chest pain. We present a case of acute aortic dissection in which the initial presenting symptoms were predominantly neurological. Stanford type A dissection is a surgical emergency with a high burden of cardiovascular death; thus, aggressive identification and management is paramount. Our case re-emphasises the importance of having a higher index of suspicion and a keen clinical eye for atypical presentations of acute aortic dissection. PMID- 28343156 TI - Ectopic ACTH-producing large cell neuroendocrine Pancoast tumour presenting as Horner syndrome. AB - We present an interesting case where a patient is presented with a droopy left eyelid (as part of Horner syndrome) and Cushingoid features which were a result of a Pancoast tumour (apical lung tumour in superior pulmonary sulcus) involving the left lung. This tumour was secreting ectopic adrenocorticotropic hormone (ACTH), a paraneoplastic endocrine phenomenon, which resulted in Cushing syndrome symptomatology. Though most ectopic ACTH-producing lung cancers are either small cell or carcinoid tumours, this was in fact a large cell neuroendocrine cancer (LCNEC). Patient underwent surgical resection and adjuvant/neoadjuvant chemotherapy with radiation; however, he succumbed to LCNEC given aggressive nature of the disease. PMID- 28343157 TI - Isolated unilateral upper alveolar numbness in silent sinus syndrome. AB - We present a case of a 59-year-old man with left upper alveolar numbness of 2 years' duration in the absence of sinonasal symptoms. On physical examination, he demonstrated mild left facial asymmetry and diminished sensation of his left upper alveolus from the left second upper incisor to first canine. CT imaging revealed chronic sinusitis changes of the left maxillary sinus, with reduced volume and depressed anterior wall. The patient underwent functional endoscopic sinus surgery to re-establish maxillary sinus ventilation. He was noted to have some improvement of his upper alveolar paraesthesia postoperatively. Silent sinus syndrome is part of the spectrum of chronic maxillary atelectasis. In the presented case, chronic osteitic bony sclerosis, as opposed to osteopenic change of the maxillary sinus, was seen. We postulate that bony encasement of the anterior superior alveolar nerve resulted in chronic nerve compression and the patient's unusual symptom of upper alveolar paraesthesia. PMID- 28343158 TI - Ethmoiditis with subperiosteal and retro-ocular abscesses due to Aeromonas sobria in a 16-year-old boy exposed to the Ardeche river. PMID- 28343159 TI - Half-and-half nails in a patient on antituberculosis treatment. PMID- 28343160 TI - An injury prevention pyramid for elite sports teams. PMID- 28343161 TI - Fulminant invasive meningococcal disease due to serogroup Y infection: a highly unusual case reflecting worrying increases in carriage and incidence. AB - A young man presented to accident and emergency with a short history of diarrhoea and vomiting, with no medical history. He deteriorated rapidly during triage and never regained consciousness. He was pronounced dead after hours of attempted resuscitation. He was found to have organisms suggestive of diplococci on his blood film and subsequently had MenY found via PCR testing. This case illustrates a highly unusual presentation of invasive meningococcal disease caused by MenY which is quietly and dangerously increasing in incidence in the UK, particularly in young healthy patients. All clinicians are reminded to be vigilant in order to diagnose and treat this often fatal disease as well as to promote uptake of the quadrivalent MenACWY vaccine. PMID- 28343163 TI - S100A6 - focus on recent developments. AB - The Ca2+-binding protein, S100A6, belongs to the S100 family. Binding of Ca2+ induces a conformational change, which causes an increase in the overall S100A6 hydrophobicity and allows it to interact with many targets. S100A6 is expressed in different normal tissues and in many tumors. Up to now it has been shown that S100A6 is involved in cell proliferation, cytoskeletal dynamics and tumorigenesis, and that it might have some extracellular functions. In this review, we summarize novel discoveries concerning S100A6 targets, its involvement in cellular signaling pathways, and presence in stem/progenitor cells, extracellular matrix and body fluids of diseased patients. PMID- 28343162 TI - Mesothelin promoter variants are associated with increased soluble mesothelin related peptide levels in asbestos-exposed individuals. AB - BACKGROUND: Soluble mesothelin-related peptide (SMRP) is a promising diagnostic biomarker for malignant pleural mesothelioma (MPM), but various confounders hinder its usefulness in surveillance programmes. We previously showed that a single nucleotide polymorphism (SNP) within the 3'untranslated region (3'UTR) of the mesothelin (MSLN) gene could affect the levels of SMRP. OBJECTIVES: To focus on SNPs located within MSLN promoter as possible critical genetic variables in determining SMRP levels. METHODS: The association between SMRP and SNPs was tested in 689 non-MPM subjects and 70 patients with MPM. Reporter plasmids carrying the four most common haplotypes were compared in a dual luciferase assay, and in silico analyses were performed to investigate the putative biological role of the SNPs. RESULTS: We found a strong association between serum SMRP and variant alleles of rs3764247, rs3764246 (in strong linkage disequilibrium with rs2235504) and rs2235503 in non-MPM subjects. Inclusion of the genotype information led to an increase in SMRP specificity from 79.9% to 85.5%. Although not statistically significant, the group with MPM showed the same trend of association. According to the in vitro luciferase study, rs3764247 itself had a functional role. In silico approaches showed that the binding sites for transcription factors such as Staf and ZNF143 could be affected by this SNP. The other SNPs were shown to interact with each other in a more complex way. CONCLUSIONS: These data support the suggestion that SMRP performance is affected by individual (ie, genetic) variables and that MSLN expression is influenced by SNPs located within the promoter regulatory region. PMID- 28343164 TI - A Quantitative Concordance Measure for Comparing and Combining Treatment Selection Markers. AB - Motivated by an HIV example, we consider how to compare and combine treatment selection markers, which are essential to the notion of precision medicine. The current literature on precision medicine is focused on evaluating and optimizing treatment regimes, which can be obtained by dichotomizing treatment selection markers. In practice, treatment decisions are based not only on efficacy but also on safety, cost and individual preference, making it difficult to choose a single cutoff value for all patients in all settings. It is therefore desirable to have a statistical framework for comparing and combining treatment selection markers without dichotomization. We provide such a framework based on a quantitative concordance measure, which quantifies the extent to which higher marker values are predictive of larger treatment effects. For a given marker, the proposed concordance measure can be estimated from clinical trial data using a U statistic, which can incorporate auxiliary covariate information through an augmentation term. For combining multiple markers, we propose to maximize the estimated concordance measure among a specified family of combination markers. A cross-validation procedure can be used to remove any re-substitution bias in assessing the quality of an optimized combination marker. The proposed methodology is applied to the HIV example and evaluated in simulation studies. PMID- 28343165 TI - Student-Directed Video Validation of Psychomotor Skills Performance: A Strategy to Facilitate Deliberate Practice, Peer Review, and Team Skill Sets. AB - Background Essential nursing skills for safe practice are not limited to technical skills, but include abilities for determining salience among clinical data within dynamic practice environments, demonstrating clinical judgment and reasoning, problem-solving abilities, and teamwork competence. Effective instructional methods are needed to prepare new nurses for entry-to-practice in contemporary healthcare settings. Method This mixed-methods descriptive study explored self-reported perceptions of a process to self-record videos for psychomotor skill performance evaluation in a convenience sample of 102 pre licensure students. Results Students reported gains in confidence and skill acquisition using team skills to record individual videos of skill performance, and described the importance of teamwork, peer support, and deliberate practice. Conclusion Although time consuming, the production of student-directed video validations of psychomotor skill performance is an authentic task with meaningful accountabilities that is well-received by students as an effective, satisfying learner experience to increase confidence and competence in performing psychomotor skills. PMID- 28343166 TI - Development and validation of a yoga module for Parkinson disease. AB - Background Parkinson's disease (PD), a progressive neurodegenerative disease, affects motor and nonmotor functions, leading to severe debility and poor quality of life. Studies have reported the beneficial role of yoga in alleviating the symptoms of PD; however, a validated yoga module for PD is unavailable. This study developed and validated an integrated yoga module(IYM) for PD. Methods The IYM was prepared after a thorough review of classical yoga texts and previous findings. Twenty experienced yoga experts, who fulfilled the inclusion criteria, were selected validating the content of the IYM. A total of 28 practices were included in the IYM, and each practice was discussed and rated as (i) not essential, (ii) useful but not essential, and (iii) essential; the content validity ratio (CVR) was calculated using Lawshe's formula. Results Data analysis revealed that of the 28 IYM practices, 21 exhibited significant content validity (cut-off value: 0.42, as calculated by applying Lawshe's formula for the CVR). Conclusions The IYM is valid for PD, with good content validity. However, future studies must determine the feasibility and efficacy of the developed module. PMID- 28343167 TI - The unappreciated roles of the cholecystokinin receptor CCK(1) in brain functioning. AB - The CCK(1) receptor is a G-protein-coupled receptor activated by the sulfated forms of cholecystokinin (CCK), a gastrin-like peptide released in the gastrointestinal tract and mammal brain. A substantial body of research supports the hypothesis that CCK(1)r stimulates gallbladder contraction and pancreatic secretion in the gut, as well as satiety in brain. However, this receptor may also fulfill relevant roles in behavior, thanks to its widespread distribution in the brain. The strategic location of CCK(1)r in mesolimbic structures and specific hypothalamic and brainstem nuclei lead to complex interactions with neurotransmitters like dopamine, serotonin, and glutamate, as well as hypothalamic hormones and neuropeptides. The activity of CCK(1)r maintains adequate levels of dopamine and regulates the activity of serotonin neurons of raphe nuclei, which makes CCK(1)r an interesting therapeutic target for the development of adjuvant treatments for schizophrenia, drug addiction, and mood disorders. Unexplored functions of CCK(1)r, like the transmission of interoceptive sensitivity in addition to the regulation of hypothalamic hormones and neurotransmitters affecting emotional states, well-being, and attachment behaviors, may open exciting roads of research. The absence of specific ligands for the CCK(1) receptor has complicated the study of its distribution in brain so that research about its impact on behavior has been published sporadically over the last 30 years. The present review reunites all this body of evidence in a comprehensive way to summarize our knowledge about the actual role of CCK in the neurobiology of mental illness. PMID- 28343168 TI - Potential skin involvement in ALS: revisiting Charcot's observation - a review of skin abnormalities in ALS. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons of the brain and spinal cord, leading to progressive paralysis and death. Interestingly, many skin changes have been reported in ALS patients, but never as yet fully explained. These observations could be due to the common embryonic origin of the skin and neural tissue known as the ectodermal germ layer. Following the first observation in ALS patients' skin by Dr Charcot in the 19th century, in the absence of bedsores unlike other bedridden patients, other morphological and molecular changes have been observed. Thus, the skin could be of interest in the study of ALS and other neurodegenerative diseases. This review summarizes skin changes reported in the literature over the years and discusses about a novel in vitro ALS tissue-engineered skin model, derived from patients, for the study of ALS. PMID- 28343169 TI - A Bayesian semiparametric factor analysis model for subtype identification. AB - Disease subtype identification (clustering) is an important problem in biomedical research. Gene expression profiles are commonly utilized to infer disease subtypes, which often lead to biologically meaningful insights into disease. Despite many successes, existing clustering methods may not perform well when genes are highly correlated and many uninformative genes are included for clustering due to the high dimensionality. In this article, we introduce a novel subtype identification method in the Bayesian setting based on gene expression profiles. This method, called BCSub, adopts an innovative semiparametric Bayesian factor analysis model to reduce the dimension of the data to a few factor scores for clustering. Specifically, the factor scores are assumed to follow the Dirichlet process mixture model in order to induce clustering. Through extensive simulation studies, we show that BCSub has improved performance over commonly used clustering methods. When applied to two gene expression datasets, our model is able to identify subtypes that are clinically more relevant than those identified from the existing methods. PMID- 28343170 TI - miRNAs, single nucleotide polymorphisms (SNPs) and age-related macular degeneration (AMD). AB - Advanced age-related macular degeneration (AAMD) is a complex sight-threating disease of public health significance. Micro RNAs (miRNAs) have been proposed as biomarkers for AAMD. The presence of certain single nucleotide polymorphisms (SNPs) may influence the explanatory value of these biomarkers. Here we present findings from an integrated approach used to determine whether AAMD-associated SNPs have the capacity to influence miRNA-mRNA pairing and, if so, to what extent such pairing may be manifested in a discrete AAMD transcriptome. Using a panel of 8854 SNPs associated with AAMD at p-values <=5.0E-7 from a cohort of >30,000 elderly people, we identified SNPs in miRNA target-encoding constituents of: (1) regulator of complement activation (RCA) genes (rs390679, CFHR1, p<=2.14E-214 | rs12140421, CFHR3, p<=4.63E-29); (2) genes of major histocompatibility complex (MHC) loci (rs4151672, CFB, p<=8.91E-41 | rs115404146, HLA-C, p<=6.32E-12 | rs1055821, HLA-B, p<=1.93E-9 | rs1063355, HLA-DQB1, p<=6.82E-14); and (3) genes of the 10q26 AAMD locus (rs1045216, PLEKHA1, p<=4.17E-142 | rs2672603, ARMS2, p<=7.14E-46). We used these findings with existing data on AAMD-related retinal miRNA and transcript profiles for the purpose of making inferences on SNP-mRNA miRNA-AAMD relationships. Four of 12 miRNAs significantly elevated in AAMD retina (hsa-miR-155-5p, hsa-let-7a-5p, hsa-let-7b-5p hsa-let-7d-5p) also showed strong pairing capacity (TarBase 7.1 context++ score <-0.2, miRanda 3.3 pairing score >150) with miRNA target transcripts encoded by AAMD-associated SNPs resident in HLA-DQB1 (rs1063355, hsa-miR-155-5p) and TGFBR1 (rs868, hsa-let-7). Three of the 12 miRNAs overexpressed in AAMD retina are inducible by NFkB and have high affinity targets in the complement factor H (CFH) mRNA 3' UTR. We used ENSEMBL to identify polymorphic regions in the CFH mRNA 3' UTR with the capacity to disrupt miRNA-mRNA pairing. Two variants (rs766666504 and rs459598) existed in DNA sequence encoding the seed region of hsa-miR-146a-5p in the CFH mRNA 3' UTR - as this miRNA is also elevated in both vitreous and serum of people with AAMD, it shows great value as a biomarker. Our findings suggest that knowledge on the nature of DNA sequence variation may increase the explanatory power of miRNA biomarkers in genetically diverse populations, while yielding information with which to develop: (1) mechanistic tests on processes implicated in AMD pathogenesis; and, (2) site-specific small molecules (synthetic mimetics or anti miRNAs) with preventive or therapeutic efficacy for AAMD. PMID- 28343171 TI - Circulating free light chain measurement in the diagnosis, prognostic assessment and evaluation of response of AL amyloidosis: comparison of Freelite and N latex FLC assays. AB - BACKGROUND: The measurement of circulating free light chain (FLC) is essential in the diagnosis, prognostic stratification and evaluation of response to therapy in light chain (AL) amyloidosis. For more than 10 years, this has been done with an immunonephelometric assay based on polyclonal antibodies (Freelite), and cutoffs for staging and response assessment have been validated with this method. Recently, a new assay based on monoclonal antibodies (N latex FLC) has been marketed in Europe. METHODS: We evaluated and compared the clinical performance of the two assays in 426 patients with newly diagnosed AL amyloidosis. RESULTS: We found suboptimal agreement between the two methods, with differences between values obtained with the Freelite and N latex FLC assays increasing with the concentration of clonal FLC. The diagnostic sensitivity of the Freelite (82%) and N latex FLC (84%) assays was similar, and both improved to 98% in combination with serum and urine immunofixation. The concentration of FLC measured with both methods had prognostic significance. Less pronounced decreases in FLC best predicted improved survival with the N latex FLC assay (33% vs. 50%), and there was poor concordance (84%) in discrimination of responders. CONCLUSIONS: The two assays have similar diagnostic and prognostic performance. However, they are not interchangeable, and follow-up should be done with either one. New response criteria are needed for the N latex FLC assay. PMID- 28343172 TI - Novel immunoassays for detection of CUZD1 autoantibodies in serum of patients with inflammatory bowel diseases. AB - BACKGROUND: Pancreatic autoantibodies (PABs) are detected in patients with inflammatory bowel disease (IBD). Their prevalence is higher in Crohn's disease (CrD) than in ulcerative colitis (UC). Glycoprotein 2 (GP2) and, more recently, CUB and zona pellucida-like domain-containing protein 1 (CUZD1) have been identified as target autoantigens of PAB. The clinical utility of CUZD1 autoantibodies has only recently been assessed by indirect immunofluorescence (IIF) assays. In this study, we developed and validated novel immunoassays for the detection of CUZD1 autoantibodies. METHODS: Recombinant CUZD1 protein was utilized as a solid-phase antigen for the development of two immunoassays for the detection of IgG and IgA CUZD1 autoantibodies. Serum samples from 100 patients with CrD, 100 patients with UC, 129 patients assessed for various autoimmune diseases (vADs) and 50 control individuals were analyzed. RESULTS: Two immunofluorometric assays for the detection of IgG and IgA CUZD1-specific antibodies were developed. CUZD1 autoantibodies were detected in 12.5% (25/200) IBD patients, including 16% of patients with CrD and in 9% of patients with UC (CrD vs. UC, p<0.05), compared with 3.1% (4/129) patients suspected of having vADs (CrD vs. ADs, p<0.05; UC vs. ADs, p=0.08). CUZD1 autoantibody positivity was not found to be related to disease location, age of disease onset or disease phenotype. CONCLUSIONS: This is the first study to describe novel IgA and IgG CUZD1 autoantibody enzyme-linked immunosorbent assay. These immunoassays agree well with standard IIF techniques and can be utilized in multicenter studies to investigate the diagnostic and clinical utility of CUZD1 autoantibodies. PMID- 28343173 TI - Fast track protocols using highly sensitive troponin assays for ruling out and ruling in non-ST elevation acute coronary syndrome. AB - The introduction of "highly sensitive" cardiac troponin assays (hsTn) has reinforced the evidence that only serial testing incorporated in running algorithms allows a more accurate diagnosis of acute myocardial infarction. In this report, we consider the available evidence supporting the use of fast track protocols for ruling out and ruling in non-ST elevation myocardial infarction (NSTEMI) and compare it with the content of recently released guideline by the European Society of Cardiology, noting some uncomfortable aspects that need urgent clarification and/or revision. Firstly, the guideline drafters have to reconsider the available evidence that does not permit to assign the same class and level of evidence to the very well-validated 0-3 h algorithm and to the 0-1 h algorithm. In agreement with the validity of available data, the limitations of fast track protocols, in particular of the 0-1 h algorithm for NSTEMI rule-in, calls for caution. Secondly, as the current diagnostics guidance by the UK National Institute for Health and Care Excellence recommends, rapid diagnostic protocols should be performed only using well-validated hsTn; recommending the use of an assay before being commercially available is not fair and scientifically sound. PMID- 28343174 TI - miRNA analysis in pancreatic cancer: the Dartmouth experience. AB - Pancreatic cancer is considered one of the most lethal cancers being the fourth leading cause of cancer deaths in adults in the United States because of the lack of early signs and symptoms and the lack of early detection. Pancreatic ductal adenocarcinoma (PDAC) is the most common histological type among pancreatic cancers, representing 80%-90% of all solid tumors of the pancreas. The majority of PDAC develops from three precursor lesions: pancreatic intraepithelial neoplasia, intraductual papillary mucinous neoplasm and mucinous cystic neoplasm. Although histologic tissue evaluation remains the gold standard for diagnosis, endoscopic ultrasound-guided fine needle aspiration has become the preferred modality for obtaining pathologic confirmation. At Dartmouth-Hitchcock Medical Center (DHMC),we have developed and validated a microRNA (miRNA) panel for patients with pancreatic diseases that can be used in association with the gold standard method for diagnosis. miRNAs have an important role in biological processes, such as apoptosis, metabolism, cell growth and differentiation. In cancer, miRNAs can be classified as either oncogenic or tumor suppressor according to their function in the carcinogenic process. In this study, we describe the expression of many miRNA in benign and malignant pancreatic tissues as well as their clinical significance. For this reason, miRNAs have been considered potential biomarkers of pancreatic diseases that could potentially contribute to an early diagnosis, predict disease progression, accurately monitor disease, contribute to better treatment strategies and reduce mortality by improving disease management. PMID- 28343175 TI - Not all good things come in big packages. PMID- 28343176 TI - Proactive approach at the limits of viability improves the short-term outcome of neonates born after 23 weeks' gestation. AB - OBJECTIVE: The aim of this single-center study was to identify factors that affect the short-term outcome of newborns delivered around the limits of viability. METHODS: A group of 137 pregnant women who gave birth between 22+0/7 and 25+6/7 weeks of gestation was retrospectively studied. The center supports a proactive approach to infants around the limits of viability. Perinatal and neonatal characteristics were obtained and statistically evaluated. RESULTS: A total of 166 live-born infants were enrolled during a 6-year period; 162 (97.6%) of them were admitted to the neonatal intensive care unit (ICU) and 119 (73.5%) survived until discharge. The decrease in neonatal mortality was associated with an advanced gestational age (P<0.001) and a completed course of corticosteroids (P=0.002). Neonatal morbidities were common among infants of all gestational ages. The incidence of severe intraventricular hemorrhage significantly depended on gestational age (P<0.001) and a completed course of corticosteroids (P=0.002). Survival without severe neonatal morbidities was 39.5% and occurred mostly after 24+0/7 weeks of gestation. CONCLUSION: The short-term outcome of newborns delivered around the limits of viability is mostly affected by gestational age and antenatal corticosteroid treatment. A consistently proactive approach improves the survival of infants at the limits of viability. This is most pronounced in cases where the delivery is delayed beyond 24 completed gestational weeks. PMID- 28343177 TI - Gaps in obstetric care processes - we can only improve what is being measured. AB - A multifaceted intervention at all six obstetric units in the Stockholm Health Region was performed in 2008-2011 in order to increase safety for the newborn infants. Case-controlled criterion-based reviews of care processes during labor and delivery have been used to assess factors associated with suboptimal care during labor and delivery. Categories of increased risk of adverse outcome during labor and delivery were defined. Cases with low Apgar scores and healthy controls were scrutinized and compared to data from a study with an identical design performed before the intervention. The risk of suboptimal care increased twice among controls and three times among cases when reviewing specific criteria after a multifaceted intervention. There are still gaps in care processes that need attention. Improving guidelines is important but not enough alone, and the management of fetal surveillance needs further improvement. The complexity of reviewing care processes using criterion-based research methodology is highlighted. PMID- 28343178 TI - Fetal cardiac tumors: clinical features, management and prognosis. AB - Fetal cardiac tumors are rare and usually benign. While echocardiography is a reliable technique for diagnosing fetal cardiac tumors, their definitive diagnosis relies on pathological examination. The strategies used to manage fetal cardiac tumors are challenging. A good clinical result is their complete regression during pregnancy or shortly after birth, as often occurs with cardiac rhabdomyomas. Moreover, the fetal prognosis depends on the nature of the tumors, namely, their location, size, number and associated complications. The active treatment options for symptomatic fetuses depend on the fetal status and may include fetal open surgery, postnatal tumor resection with or without the bridge of intrauterine pericardiocentesis, and thoracoamniotic shunting. The ex utero intrapartum treatment procedure provides an alternative technique for performing fetal open surgery and has shown promising preliminary results in selected cases, but is invasive for both the mother and fetus. PMID- 28343179 TI - Nulliparous teenagers and preterm birth in California. AB - BACKGROUND: Young maternal age is one of the numerous risk factors for delivery before 37 weeks of gestation, yet the mechanisms are unclear. The purpose of the current study was to investigate the association between teenagers and the risk of preterm birth (PTB) in a large and recent cohort study. METHODS: We conducted a population-based retrospective cohort study using 2007-2011 California birth certificate records linked with hospital discharge indices and United States census data for nulliparous 13-20 year olds who gave birth to singletons. Maternal age was examined categorically at 1 year intervals. PTB was defined as delivery at <37 weeks of gestation with further distinction between <32 and 32-36 weeks, and between spontaneous and medically indicated deliveries. Adjusted multivariable logistic regression was used to estimate odds ratios (OR) for PTB. RESULTS: The prevalence of PTB was highest among the youngest (13 year olds, 14.5%) and lowest among the oldest (20 year olds, 6.7%). After adjusting for maternal and paternal race/ethnicity, paternal age, initiation of prenatal care, source of payment, pre-pregnancy body-mass-index (BMI), height, smoking, and poverty; young mothers of ages 13, 14, 15, and 16 years had increased odds for spontaneous PTB at <32 weeks [OR (CI): 3.76 (1.83-7.75), 1.65 (1.10-2.48), 1.55 (1.24-1.93), 1.19 (1.00-1.42), respectively] compared to 20 year olds. All teenagers, excluding 19 year olds, had elevated odds of spontaneous PTB at 32-36 weeks. CONCLUSIONS: Nulliparous teenagers were at increased risk for spontaneous PTB, especially those 16 years or younger. Medically indicated PTB was not associated with young age. PMID- 28343180 TI - Oxygen saturation trends in normal healthy term newborns: normal vaginal delivery vs. elective cesarean section. AB - OBJECTIVES: To study the normal oxygen saturation trends and fetomaternal correlates in healthy term newborns within 30 min of life born by normal vaginal delivery (NVD) and elective cesarean section (CS). MATERIALS AND METHODS: A cross sectional study was conducted on 200 healthy term newborns born by NVD and elective CS at a tertiary care centre. Routine care as per the Neonatal Resuscitation Program (NRP) 2015 (Wyckoff MH, Aziz K, Escobedo MB, Kapadia VS, Kattwinkel J, Perlman JM, et al. Part 13: neonatal resuscitation: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2015;132:S543-60) protocol was given and pre-ductal arterial oxygen saturation was assessed by pulse oximetry at different intervals after birth. RESULTS: The mean peripheral oxygen saturation (SpO2) was 85.4%, 90.8%, 94.1%, 95.7%, 96.7% and 97.4% at 5, 10, 15, 20, 25 and 30 min, respectively, after birth. Higher mean SpO2 was observed in NVD compared to elective CS (P<0.005). The mean time for SpO2 to reach >90% was 9.13 min in NVD and 12.31 min in elective CS (P<0.001). Maternal hemoglobin (Hb) (r=-0.15; P<0.01), birth weight (r=-0.125; P<0.05) and Apgar at 10 min (r=0.33; P<0.001) were significantly correlated with SpO2 of newborns at 10 min of life. CONCLUSION: Our study defines normal SpO2 levels in healthy term newborns in the first 30 min of life born by NVD and elective CS. Babies born by NVD had significantly higher SpO2 levels and attained SpO2 >90% faster than those born by elective CS. Maternal Hb, birth weight and Apgar at 10 min were significant factors affecting SpO2 levels of newborns at 10 min of life. PMID- 28343181 TI - A non-invasive method to rule out transient tachypnea of the newborn (TTN): fetal pulmonary artery acceleration to ejection time ratio. AB - OBJECTIVE: To investigate whether fetal pulmonary artery acceleration to ejection time (PATET) ratio can predict or rule out subsequent diagnosis of transient tachypnea of the newborn (TTN). METHODS: This prospective cohort study included 105 pregnant women in labor, who met the inclusion criteria. Eighteen of these women were removed from the study cohort, because of an inability to acquire sufficient Doppler waveforms and a longer duration of deliveries. According to subsequent diagnosis of TTN in the neonate, the two groups were constituted, TTN+ and TTN-. RESULTS: There were no statistically significant differences between the groups regarding maternal obstetric and demographic features. The neonatal intensive care unit (NICU) submission rate was significantly higher in the TTN+ group (100%, 17%, P<0.0001, respectively). Regarding the fetal pulmonary artery Doppler findings, PATET ratio in the TTN+ group was significantly lower than the TTN- group (0.307 vs. 0.389, P<0.0001, respectively). The PATET ratio and diagnosis of TTN were inversely correlated (r=-0.41, P<0.001), even if adjusted for birth weight, gestational age and fetal gender (r=0.42, P=0.0021). The cut off value of 0.319 provided 82.7% specificity, 83.3% sensitivity, 96% negative predictive value and 41.6% positive predictive value. Additionally intraobserver ICC for PATET was found to be 0.86. CONCLUSION: The fetal PATET ratio seems to serve as a promising tool to rule out subsequent diagnosis of TTN. PMID- 28343182 TI - 3D/4D Sonography. PMID- 28343183 TI - Intrapartum care. PMID- 28343184 TI - Regulatory role of NGFs in neurocognitive functions. AB - Nerve growth factors (NGFs), especially the prototype NGF and brain-derived neurotrophic factor (BDNF), have a diverse array of functions in the central nervous system through their peculiar set of receptors and intricate signaling. They are implicated not only in the development of the nervous system but also in regulation of neurocognitive functions like learning, memory, synaptic transmission, and plasticity. Evidence even suggests their role in continued neurogenesis and experience-dependent neural network remodeling in adult brain. They have also been associated extensively with brain disorders characterized by neurocognitive dysfunction. In the present article, we aimed to make an exhaustive review of literature to get a comprehensive view on the role of NGFs in neurocognitive functions in health and disease. Starting with historical perspective, distribution in adult brain, implied molecular mechanisms, and developmental basis, this article further provides a detailed account of NGFs' role in specified neurocognitive functions. Furthermore, it discusses plausible NGF-based homeostatic and adaptation mechanisms operating in the pathogenesis of neurocognitive disorders and has presents a survey of such disorders. Finally, it elaborates on current evidence and future possibilities in therapeutic applications of NGFs with an emphasis on recent research updates in drug delivery mechanisms. Conclusive remarks of the article make a strong case for plausible role of NGFs in comprehensive regulation of the neurocognitive functions and pathogenesis of related disorders and advocate that future research should be directed to explore use of NGF-based mechanisms in the prevention of implicated diseases as well as to target these molecules pharmacologically. PMID- 28343185 TI - Frameworking memory and serotonergic markers. AB - The evidence for neural markers and memory is continuously being revised, and as evidence continues to accumulate, herein, we frame earlier and new evidence. Hence, in this work, the aim is to provide an appropriate conceptual framework of serotonergic markers associated with neural activity and memory. Serotonin (5 hydroxytryptamine [5-HT]) has multiple pharmacological tools, well-characterized downstream signaling in mammals' species, and established 5-HT neural markers showing new insights about memory functions and dysfunctions, including receptors (5-HT1A/1B/1D, 5-HT2A/2B/2C, and 5-HT3-7), transporter (serotonin transporter [SERT]) and volume transmission present in brain areas involved in memory. Bidirectional influence occurs between 5-HT markers and memory/amnesia. A growing number of researchers report that memory, amnesia, or forgetting modifies neural markers. Diverse approaches support the translatability of using neural markers and cerebral functions/dysfunctions, including memory formation and amnesia. At least, 5-HT1A, 5-HT4, 5-HT6, and 5-HT7 receptors and SERT seem to be useful neural markers and therapeutic targets. Hence, several mechanisms cooperate to achieve synaptic plasticity or memory, including changes in the expression of neurotransmitter receptors and transporters. PMID- 28343186 TI - [Profile of adults suffering from COPD in Poland]. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is one of the most common chronic diseases in adults. It is estimated, that in Poland around two million people suffer from COPD. THE AIM: The aim of this study, was to characterize population of patients with COPD in Poland. MATERIAL AND METHODS: The study, established and coordinated by the Polish Respiratory Society, included a representative sample of 500 GPs where were asked to fill questionnaires on diagnosis and treatment of their COPD patients. The questions dealt with disease history and clinical presentation, COPD severity stage, diagnostic and therapeutic procedures. RESULTS: Altogether 298 physicians (59.6% of invited) provided information about 2756 COPD patients aged 61.6 +/- 11.1 years (36.3% were women). According to GOLD recommendations 16.6% of patients had mild, 57.0% moderate, 18.6% severe and 2.1% very severe COPD. Smoking history was declared by 97.8% of respondents. 51.4% of COPD patients had continued smoking. Over the last year Ambulance Service intervened in 19.7% of patients and 29.1% of respondents required hospital treatment of COPD. Among more than 80% of patients, doctor diagnosed limitation in exercise tolerance, and shortness of breath at rest, and in approximately 60% of the respondents were presented productive cough, weakened vesicular murmur and prolonged phase of exhalation. CONCLUSIONS: Despite the diagnosis, more than half of men and women had continued smoking. The number of hospitalizations and emergency intervention positively correlated with the severity of the disease. The survey results emphasize the urgent need for health education in patients with COPD. PMID- 28343187 TI - [Hormonal contraception use in social and psychological context]. AB - INTRODUCTION: The purpose of this article is to consider, form psychological point of view, hormonal contraception and its effects on women's body and health. Beliefs and decisions of young women in this area are the main plane of these analyzes. This study reflects on their motivations to use or not to use hormonal contraception and rate its influence on their body. It was also verified, if there is any difference in self-esteem between women who use and who do not use hormonal contraception. MATERIAL AND METHODS: The study was conducted amongst 95 women aged form 18 to 35. Two instruments were used in this study: Body Esteem Scale (BES) and questionnaire on hormonal contraception. RESULTS: The results show, that hormonal contraception is used only by 1/3 of the women. The main reason, why women use this method is contraception. Women regard, this method is inoffensive for them. Women do not use hormonal contraception mainly, because of their ideological views, religious beliefs and fears for their own health. Women, who use hormonal contraception acquire higher self-esteem in this aspects of their body, which can be control with diet or physical exercises. CONCLUSIONS: Women choose hormonal contraception because of its: high efficiency, extra health benefits and no difficulties in use. This contrasts with low popularity of this method amongst young women in the study. Verification, why women are anxious about their health and fertility, is believed to be an important issue. Moreover, it seems valuable to check, how important for women is a partner's role in terms of contraception. PMID- 28343188 TI - Multimodal evoked potentials in patients with multiple sclerosis in assessment of the course of the disease. AB - INTRODUCTION: Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system with a multifocal damage. THE AIM: The assessment of the MS course by multimodal evoked potentials (EP). MATERIAL AND METHODS: We evaluated 95 patients (63 female, 32 male) with relapsing-remitting MS in the average age of 36.4+/-10.4. The average disease duration was 4.6+/-7.4 year. Among them, 48 patients (50.5%) were treated with immunomodulatory drugs. All patients underwent neurological examination and EP testing: VEP (visual evoked potentials), SEP (somatosensory evoked potentials), endogenous potential P300. The latencies of following waves were evaluated: P100 (VEP), N4 , N9 , N13, N20, P22 (SEP) and P300, with the reference values of the Neurophysiological Research Laboratory of the Department of Neurology in Zabrze. RESULTS: Abnormal VEP(I) was found in 80 patients (84.2%), SEP(I) in 9 patients (9.5%), P300(I) in 15 patients (15.8%). Abnormal result of the control research VEP (II) was found in 23 patients (82.1%), SEP(II) in 1 patient (3.6%), P300(II) in 4 patients (14.3%). The average values of the waves latencies in the control study were higher, however the statistical significance was not found. The correlation was observed between EDSS, and N20 and P22. No relationship was found between EP and age, disease duration, number of relapses and treatment. CONCLUSIONS: In the era of neuroimaging, usage of EP in the diagnosis and assessment of MS is limited. Electrophysiological studies may be used in addition to the clinical examination to confirm the multifocal damage. PMID- 28343189 TI - Study of motivational factors in doctors in respect of healthcare quality improvement. AB - INTRODUCTION: The article presents the results of a survey among doctors with different certification categories and experience who work at inpatient and outpatient departments of Sumy healthcare institutions, in respect of the main factors that motivate them to provide quality healthcare. The aim of the study is to identify the factors that may be used as motivators to improve healthcare quality in terms of medical staff in order to ensure system construction of motivational component of healthcare quality management ("incentive picture"). MATERIALS AND METHODS: We conducted a survey among physicians working at inpatient and outpatient departments. A total of 167 respondents were interviewed. The obtained results were processed using OCA-program. CONCLUSIONS: We have found an association between the salary level and certification category of a physician. Despite heavy workload, most doctors were willing to work harder and better for some additional payment. Even though financial satisfaction was low, most doctors did not agree to change their profession for a more payable one. The study revealed that, in doctors' opinion, the introduction of incentive system in healthcare institutions was necessary to provide quality healthcare. Regardless of length of service and workplace, two of the main motivational factors for doctors were moral satisfaction from work and respect of people. PMID- 28343190 TI - [Analysis of the cellular composition and of the inflammatory response activity in the lymph nodes of patients with sarcoidosis at different stages of the clinical course and treatment with systemic glucocorticosteroids]. AB - Vstup: Vivchennyu dinamiki zeapal?nix zemin v limfatichnix vuzelax xvorix sarkoidozeom na foni likuvannya glyukokoritkosteroidami (GKS) ta beze nix pridilyaet?sya nedostatnya uvaga, shcho i obumovlyue aktual?nist? naukovix poshukiv u danomu napryamku. Meta: Dosliditi osoblivosti klitinnogo skladu ta aktivnosti zeapal?noi reaktsii u limfatichnix vuzelax xvorix sarkoidozeom na rizenix etapax perebigu ta likuvannya GKS ze uraxuvannyam chasu vstanovlennya diagnozeu i stupenya aktivnosti patologii. Materiali ta metodi: Do analizeu bulo zealucheno rezeul?tati morfologichnogo doslidzhennya biopsiinogo materialu, otrimanogo ize urazhenix limfatichnix vuzeliv xvorix na sarkoidoze. ZE metoyu vstanovlennya klitinnogo skladu ta otsinki aktivnosti zeapal?noi reaktsii nami buli dodatkovo zeastosovani spetsifichni imunogistoximichni (IGX) markeri CD68, CD20, CD3 ta Collagen IV. Rezeul?tati: Prizenachennya terapii sistemnimi GKS u xvorix ze aktivnim sarkoidozeom spriyae zemenshennyu intensivnosti ekspresii IGX markeriv CD68, CD20, CD3, Collagen IV v oseredkax produktivnogo zeapalennya. ZEa vidsutnosti likuvannya GKS v oseredkax produktivnogo zeapalennya u xvorix na sarkoidoze zerostae kil?kist? sudin, shcho ekspresuyut? Collagen IV ze pidtrimkoyu imunnogo zeapalennya v tsentral?nii ta periferichnii chastini granul?omi, shcho skladaet?sya perevazhno ze aktivnix form makrofagiv (CD68) ta T limfotsitiv (CD 3). Visnovki: ZEastosuvannya GKS dlya likuvannya aktivnogo sarkoidozeu dozevolyae zenizeiti intensivnist? zeapal?noi reaktsii ta poperediti poshirennya protsesiv fibrozeuvannya v ushkodzhenix limfatichnix vuzelax patsientiv. PMID- 28343191 TI - The impact of cigarette smoking, alcohol drinking and physical inactivity on the risk of urolithiasis occurrence and recurrence. AB - INTRODUCTION: Prevention of urolithiasis occurrence and recurrence is important issue, due to one affects mainly people of the working age and often leads to disability. AIM: To study the impact of harmful habits like smoking, alcohol drinking, and hypodynamics on the risk of urolithiasis occurrence and recurrence. MATERIALS AND METHODS: It was conducted a retrospective epidemiological study of a representative sample of 443 patients with urolithiasis (basic group, 403 - of them without recurrences and 40 - with recurrences) and 203 patients without urolithiasis - control group, at discharge them from urologic in-patient departments of health care facilities of Ivano-Frankivsk region. RESULTS: It was established widespread of smoking and alcohol consumption among male respondents (31.8% smoke and 42.1% smoked, 43.4% used alcohol weekly or more) and generally low physical activity (53.6% among both sexes). The Odds Ratio was at: smoking - 0.90 (95% CI = 0.64-1.26; p>0.05) for occurrence and 1.43 (0.74-2.74; p>0.05) for recurrence; alcohol drinking - 0.81 (0.56-1.16; p>0.05) and 0.92 (0.43-1.94; p>0.05) respectively; low physical activity - 1.44 (0.81-2.56; p>0.05) and 3.52 (0.47-26.44; p>0.05). CONCLUSION: It was received no credible evidence that cigarette smoking, alcohol drinking and hypodynamics influence the occurrence and recurrence of urolithiasis. The research in this approach should continue. PMID- 28343192 TI - Post-stroke fatigue and its dimensions within first 3 months after stroke. AB - INTRODUCTION: Post-stroke fatigue (PSF) is a common stroke complication with long term negative consequences. AIM: Assess the qualitative and quantitative PSF characteristics during 3 month post-stroke period. MATERIALS AND METHODS: There were examined 141 patients with acute ischemic or hemorrhagic strokes at hospital stay, in 1, 2 and 3 months after stroke. PSF was measured by fatigue assessment scale (FAS), multidimensional fatigue inventory-20 (MFI-20) and fatigue severity scale (FSS). RESULTS: 116 (82.3%) patients had ischemic strokes, 25 (17.7%) had hemorrhagic strokes. According to FAS and MFI-20 "global fatigue" sub-scale, PSF was present, respectively, in 22.0% and 25.5% cases at hospital stay, in 38.3% and 35.5% cases in 3 month after stroke. The growing prevalence of PSF was based on significantly increasing the rates of PSD physical domain (from 28.4% to 41.1%) and the rates of PSF mental domain (from 19.1% to 31.9%). On the other hand, the rates of PSF activity-related component had been significantly reduced from 36.2% to 17.0% within observation period. Moreover, according to MFI-20, it had been revealed significant increasing of PSF intensities in global, physical and mental domains during first 3 post-stroke months. According to FSS value ranks, proportions of patients with "no PSF" had been decreased in 1.5 times due to simultaneously rising rates of "moderate" as well as "severe" PSF impacts on daily life. CONCLUSION: The PSF spreading is significantly increased during the first 3 post-stroke months due to increasing of rates and intensities of physical and mental PSF domains. PMID- 28343193 TI - Role of genetic mutations in development of immunological and clinical disorders in children with chronic pyelonephritis. AB - INTRODUCTION: At the present time, the study of mechanisms of recognition of foreign agents, which is realized by means of Toll-like receptors (TLR) of the innate immune system, has become one of the main tasks of clinical immunology. The aim of our study was to investigate the prevalence of polymorphism of Toll like receptor 4 (Asp299Gly, Gly299Gly) among children with chronic pyelonephritis (CP) and determine the association of this TLR4 polymorphism with phenotypic features of chronic pyelonephritis and level of interleukin-6 (IL-6). MATERIALS AND METHODS: The clinical and laboratory examination of 60 children with chronic pyelonephritis during the stage of exacerbation, who were under inpatient treatment at the pediatric department of Children's Regional Clinical Hospital in Poltava, was performed. The group of healthy patients included 95 people, living in the Poltava region. RESULTS: Significantly higher frequency of the mutant allele 299Gly among children with CP was revealed. Significant correlation between the presence of 299Gly TLR4, association of U. urealyticum and M. hominis in lower sections of urinary tract and highest levels of IL-6 concentration was reflected. Sick children with polymorphous locus of TLR4 gene had higher risk of CP early manifestation and formation of its recurrent course with protracted urinary syndrome and unstable remission in comparison with the carriers of "wild" genotype. CONCLUSIONS: Obtained results prove the important role of TLR4 in the realization of innate immune response in children with CP and allow considering the TLR4 polymorphism as an additional prognostic indicator in this category of patients. PMID- 28343194 TI - Lipid metabolism and feeding habits of indigenous peoples of the sakha republic (yakutia) in today's socio-economic development. AB - INTRODUCTION: By results of a single-step epidemiological research indicators of a lipid range at 355 Evenks of the Olenyoksky District of the Republic of Sakha (Yakutia) are estimated. The aim of this research was assessment of lipid exchange and character of a delivery of Evenks of the item of Zhilinda. MATERIAL AND METHODS: 355 evenks aged over 20 years (170 men, women-185). Total cholesterol (OCHS), cholesterol (low-density lipoproteins (LDL-CHOLESTEROL), highdensity lipoprotein cholesterol ((XC-LVNP), triglycerides (TG), the calculated coefficient of haemoglobin (Ka). The measurement is taken at biochemical autoanalyzer Architest 80000 model Systems, firm Abbot (United States) generally accepted method. Food has been studied using questionnaire CYNDI. Results of the Lipid profile compared to the Evenks of Yakut and Russian population of the Republic's population has a high concentration of CS LPHD, low content of TG and haemoglobin index. Food Evenks is characterized by significant disbalance-1/4 surveyed every day consume meat and fish every day consumes but 1/5 surveyed. the shortage of basic products is replaced with bread, pasta and sweets. CONCLUSION: The identified indicators of lipid range Evenks have more healthy than the Yakut. Nutrition Evenks departs from the traditional protein lipid in carbohydrate-protein. PMID- 28343195 TI - Research of the protection actions of derived 2-oxoindole in acute stress. AB - INTRODUCTION: Correction of pathological anxiety and stress level of frustration leads to the development of new anxiolytics, notably including derivatives of 2 oksoyndolyn- 3-hlyoksylic acid. The aim of work - to study the effect of 2 oksyindolin-3-hlyoksylic acid on emotional and behavioral reactions of rats subjected to behavioral stress tests of different averiability. MATERIALS AND METHODS: In experiments on 150 white mature male rats Wistar investigated the effects of 2-oksoindolin (2-hydroxy-N-naphthalene-1-yl-2-(2-hydroxy-1,2- dihydro indole-3-ylidene)-acetamide) with laboratory codes 18 when intraperitoneally administered to acute immobilization stress on Sel'ye on emotional and behavioral responses of animals to test "open field", "a raised cross maze" and test "conflict behavior" (option Vogel). RESULTS: Established that the prophylactic use of the compound 18 in a test of "open field" warned the stress changes in the latent period of the first movement, likely increased the number of exits to the center installation, warned breach vertical and horizontal motor activity and significantly increased the number of acts of grooming and reduced the number of boluses compared with stress without correction. Revealed changes suggest that the substance 18 prevents anxiety disorders conduct stress genesis. In the test "a raised cross maze" of 2-oksoindolin significantly increased the number of outputs rats in open arms maze and reduced the number of fecal balls compared with those in the control disorders. In the study antyconflict action found that the compound increased the number of approaches to the drinkers, but the activity in this test yielded diazepam. CONCLUSION: Installed conservation action anksyolityc 2-hydroxy-N-naphthalene-1-yl-2-(2-hydroxy-1,2-dihydro-indole-3 ylidene)-atsetamidu acute stress may be associated with indirect stimulation of GABA - benzdiazepin receptor complex, by strengthening endogenous GABA affinity to the receptors and/or indirect stimulation of GABA receptors by other neurotransmitter systems, including serotonergic, which makes compounds for further study the possibility of post stress with anxiety disorders. PMID- 28343196 TI - [Hope as psychological resource for nurturant professionals (medicine case study)]. AB - INTRODUCTION: In the article, the issues concerning hope, which is one of the most important resources for specialists of many nurturant professions, are observed. The theoretical analysis of hope and its categorization from the perspective of subjective and resource-based view is given. The special scientific and practical interest to human subjective and personal resources is determined by their unique role not only in human life support, but also in overcoming hard situations and extreme obstacles, including crisis situations in professional activity, with the example of the profession of a doctor. The aim of the empirical research is studying the correlation between hope and such manifestations of subjective regulations medical practice as inner subjective control and failure avoidance motivation. MATERIALS AND METHODS: 120 doctors (60 men and 60 women) working in St. Petersburg hospitals took part in the research. Several research methods were used, such as 'Resource map' application form, R. Snyder's hope scale adapted by K. Muzdybayev, 'Subjective control level' method by E. Bazhin, E. Golynkina and L. Etkind, 'Failure avoidance motivation' method by T. Ehlers. RESULTS: Doctors think that Hope and Optimism are among important components of their professional practice, together with willing features helping them to reach their goals (such as persistence, patience, eagerness, insistence and endurance) and such personal qualities as self-assuredness, motion control in different situations, ability to solve hard problems. According the data of correlation and regression analyses, the anticipation that hope is determined by high level of inner control locus and low failure avoidance motivation (responsibility for patients' lives) within medical practice. CONCLUSIONS: Most doctors have average or high level of hope, which lets determine this personal disposition quality as one of the important ones for this profession. Being the positive result of professional practice and not depending on the doctors' sex and specialization, hope is linked to achievement drive and most rates of inner locus control. Obtained results can be used for psychodiagnostics and development of such psychological results as faith, hope and optimism, helping to keep nurturant professionals' mental health. PMID- 28343197 TI - [Skin cancers in kidney transplant recipients]. AB - Kidney transplantation is the best treatment for end-stage renal failure. It prolongs the patient's life, improves quality of life and reduces costs associated with renal replacement therapy. Increasingly, newer immunosuppressive regimens allow for the proper functioning of the transplanted organ for many years. The progress in transplantation, qualification patients in older age for the procedure and longer survival of kidney graft lead to an increase in the number of patients receiving immunosuppressive drugs. They are exposed to various side effects associated with long-term suppression of the immune system, including an increased risk of cancer development. The most common malignancies (40- 50%) diagnosed in renal transplant recipients are skin cancers. Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are the most common types of tumors occurring in this population. The use of immunosuppression resulted in the increase of the incidence of tumors that in the general population are relatively rare such as melanoma, Merkel cell cancer, Kaposi's sarcoma, anogenital cancer as well as sebaceous carcinoma. PMID- 28343198 TI - [Why ovarian cancer cells escape from immune surveillance?] AB - Ovarian cancer is a malignancy of high mortality rates. In respect of the number of deaths caused by cancers it occupies the fourth place among women in Poland. Recent studies are focusing on the role of immune system in ovarian cancer pathogenesis. It has been reported that immune response against ovarian cancer cells may be inhibited by a number of immunosuppressive mechanisms active in cancer microenvironment. It causes difficulties in recognizing and destroying cancer cells by immune system which leads to the development of immune tolerance and is associated with a low efficacy of standard therapeutic strategies. In the presented paper we have described selected, new immunosuppressive mechanisms in ovarian cancer patients. They may be a novel, additional and relevant criterion that should be considered whilst developing new therapeutic strategies. Possibly, modulation of immunosuppressive mechanisms could contribute to modifying standard therapies and in consequence improve treatment outcome in ovarian cancer patients. PMID- 28343199 TI - [Hypogonadism in patients with testicular tumors and prostate cancer]. AB - Hypogonadism is defined as an array of symptoms arising from a deficiency of androgens. It is caused by a hormonal and spermatogenic dysfunction of the testes. It results in impaired fertility and has a negative impact on the functions of multiple organs and systems, physical well-being, sexual functions and also mental state. Particularly patients with a history of cancer have a high risk of developing hypogonadism as a result of not only the nature of the disease, but mainly its treatment. While leaving the patient with cancer without treatment does not fall within the concept of the art of medicine and the ethical canon of a physician, the symptoms of hypogonadism are often ignored and left untreated. Among urological patients special attention should be given to those with testicular tumors and prostate cancer. PMID- 28343200 TI - Sentinel lymph node (sln) in breast cancer. Review of current identification methods. AB - The subject of the paper is the review of the current methods for identifying the sentinel lymph node in breast cancer treatment, taking into account the latest techniques and based on the up-to-date analyses of many years of experience in using this method. PMID- 28343202 TI - European experience of regulating distance selling of medicines for Ukraine. AB - INTRODUCTION: Some countries have already tried and tested mechanisms of regulating distance sales as form of distribution of medicines that have been used more or less effectively for a fairly long time. Herewith, so far, the approach of the competent authorities of some countries including Ukraine can be called prevailing in quantitative terms under which the official prohibition on distance sales of medicines is set. AIM: The aim of this study is a detailed examination of the nature of the prohibition of the medicines distance selling in Ukraine, namely the an analysis of advantages and disadvantages of this form of distribution of medicines and identification of appropriate ways for gradual repeal of the prohibition in terms of regulatory reform in Ukraine in the sphere of circulation of medicines due to the process of adaptation of statutory regulation in this area to the EU legislation. MATERIAL AND METHODS: This study is based on Ukrainian regulation acts, Council Directives 97/7/EC, 2000/31/EC, 2001/83/EC, scientific works and opinions of progressiveminded people in this sphere. Such methods as dialectical, comparative, analytic, synthetic and comprehensive have been used in the article. CONCLUSION: Reception of the described experience of regulation in EU will allow a further review of the principles of regulation in Ukraine in the sphere of medicines with a shift in the main emphasis in the direction of ensuring adequate consumer rights in this area and preventing the risks of patients' and public health. PMID- 28343201 TI - [Ibrutinib - new tool in hematologist hand, new challenges for internist]. AB - Chronic lymphocytic leukemia is the most common cancer of the lymphatic tissue in adults. The peak incidence falls on the 65-70 year old. Therefore, the majority of patients with chronic lymphocytic leukemia (CLL) has at least one coexisting disease. Successful oncological and supportive treatment, that is common in recent years, significantly prolongs the survival. This paper presents ibrutinib a new drug used to treat CLL. The aim of this paper is, to show an example of this drug, meaning and benefits of modern methods of pharmacotherapy in the treatment of oncology. PMID- 28343203 TI - Developing the professional competence of future doctors in the instructional setting of higher medical educational institutions. AB - INTRODUCTION: The main objectives of higher medical education is the continuous professional improvement of physicians to meet the needs dictated by the modern world both at undergraduate and postgraduate levels. In this respect, the system of higher medical education has undergone certain changes - from determining the range of professional competences to the adoption of new standards of education in medicine. AIM: The article aims to analyze the parameters of doctor's professionalism in the context of competence-based approach and to develop practical recommendations for the improvement of instruction techniques. MATERIALS AND METHODS: The authors reviewed the psycho-pedagogical materials and summarized the acquired experience of teachers at higher medical institutions as to the development of instruction techniques in the modern educational process. The study is based on the results of testing via the technique developed by T.I. Ilyina. Analytical and biblio-semantic methods were used in the paper. RESULTS: It has been found that the training process at medical educational institution should be focused on the learning outcomes. The authors defined the quality parameters of doctors' training and suggested the model for developing the professional competence of medical students. This model explains the cause-and effect relationships between the forms of instruction, teaching techniques and specific components of professional competence in future doctors. CONCLUSIONS: The paper provides practical recommendations on developing the core competencies which a qualified doctor should master. The analysis of existing interactive media in Ukraine and abroad has been performed. It has been found that teaching the core disciplines with the use of latest technologies and interactive means keeps abreast of the times, while teaching social studies and humanities to medical students still involves certain difficulties. PMID- 28343204 TI - [Risk management of hospital infections as a supporting tool for the improvement of hospital quality - some European examples]. AB - Prevention and control of nosocomial infections is one of the main pillars of security in each medical facility. This affects the quality of services and helps to minimize the economic losses incurred as a result of such infections. (Prolonged hospitalization, expensive antibiotic therapies, court costs of damages). Nosocomial infections occur in every medical facility in the hospitals in terms of risk of infection compared to other medicinal entities are at greater risk of environmental (number of hospitalizations for one bed, the amount of disinfectants, etc.). The number and diverse category of employment of medical and auxiliary, which should meet certain standards for the prevention of hospital infections, has an impact on the incidence of infection. It is impossible to eliminate hospital-acquired infections, but can be limited by appropriate measures, ranging from monitoring through the use of risk management methods, which are one of the elements supporting the improvement of the quality of medical entities. Hospital infection is a threat not only for patients but also for workers exposed to the risk of so-called occupational exposure. A comprehensive approach including elements of active surveillance and effective monitoring can help to minimize the risk of nosocomial infections. PMID- 28343205 TI - [Biliary atresia - signs and symptoms, diagnosis, clinical management]. AB - Biliary atresia is a chronic cholangiopathy leading to progressive fibrosis of both intra- and extrahepatic bile ducts. The cause of the condition is unknown. Fundamental management of biliary atresia is surgical intervention and the outcomes of the treatment depend on the child's age with best results when performed within the first 2 months of life. Thus, the main role of pediatric healthcare is an urgent differential diagnosis and prompt qualification for the surgery, optimal postoperative management and early qualification for the liver transplantation in patients with persistent cholestasis. The authors discuss the clinical presentation, diagnosis and management of biliary atresia. PMID- 28343206 TI - [Euthanasia - an attempt to organize issue]. AB - This article is an attempt to complete and holistically discuss problem of euthanasia, especially its ethical and legal aspects, comparing to Polish law. The subject of euthanasia arouse interest of the society because it touches one of the most important aspects of life, which is the death. Even bigger emotions are aroused amongst physicians. They are forced to put on the line the life as biggest value on the one side and autonomy of human being on the other. It also touches the empathy for suffering. The euthanasia was divided into three forms: active euthanasia, passive euthanasia and assisted suicide. Any form of euthanasia is illegal in Poland according to both the Penal Code and Code of Medical Ethics. Range of possible penal consequences perpetrator is very wide from waiver of punishment to life imprisonment and it comes from different penal qualification of the euthanasia. Qualification of the euthanasia is based on terms of intent of perpetrator's act, request of patient, strong empathy for suffering if the patient and decision based on up-to-date medical knowledge. It is valuable to mention "do-not-resuscitate" DNR procedure, which in case of medical futility is legally accepted in Poland, but in other form may be qualified as passive euthanasia. PMID- 28343207 TI - [Liability for damages resulting from hospital falls]. AB - The aim of the work is to analyze the conditions for liability of medical institutions for damages resulting from hospital fails. The study identifies achievements of polish jurisprudence. The authors also pointed to factors specific for claims of this type. The paper discusses: legal consequences of failure to provide security of patient stay and the responsibilities of hospitals in relation to patients especially vulnerable to falls. It also analyzes the problems faced by patients claiming compensation for damages resulting from such events: constraints of the evidence in establishing the conditions for liability, the argument unpredictability of event and the detrimental impact of the actions taken in the hospital to reduce the risk of falling. PMID- 28343208 TI - Legal features of the drug advertising. AB - INTRODUCTION: In the article discribed current trends of advertising in the pharmaceutical market and foreign experience of legal regulation of these relations. As for the advertising of medicines identified it's symptoms, types, basic rules and prohibitions. Modern pharmaceutical companies can not successfully carry out economic activities without advertising. Besides we can mention some fundamental changes in society (information overload, universal access to internet, social media, freedom of movement of goods, labor and finance), also self-medication becomes more popular. At the same time, the number of deaths after improper and uncontrolled use of drugs ranks fifth in the world among the causes of death. AIM: Investigate current trends of advertising on the pharmaceutical market, find advertising signs, basic restrictions and prohibitions on advertising of medicines, as well as foreign experience of legal regulation of these relations. MATERIAL AND METHODS: Despite the fact that pharmaceutical advertising were studied by such scholars as M. Abraham, L. Bradley, C. Dunn, J. Donoh'yu, D. Castro, M. Lipski, K. Taylor and others, number of issues related features of drug advertising, remained without proper theoretical studies. RESULTS: Based on the analysis can come to the conclusion that advertising of medicinal products are the subject of special attention from the state. Drugs, unlike other products, are a group of specialized consumer products. Risks increase when patients under the influence of "aggressive" advertising resort to self-medication. If a complete ban on advertising of medicines is inappropriate, you should set stricter requirements for the content of advertising and product placement rules. That is, in the national legislation to implement regulatory requirements of Directive 2001/83 / EC. CONCLUSIONS: Legal regulation of drug advertising can be improved by such legal means: - should provide for a mechanism of public control over the observance of ethical standards in the advertising of medicinal products; - Prohibit the advertising of medicines for children, as well as drugs for the treatment of infectious, parasitic diseases and pathogens of these diseases, chronic insomnia, cardiovascular diseases, and those costs are reimbursed by government programs or trade names may lead to mix with prescription drugs; - Adopt ethical standards (codes) promotion of drugs for pharmaceutical companies; - Advertising to the public shall not contain any reference to cost or pricing features for medicines. PMID- 28343209 TI - Terminological collocations in medical latin and english: a comparative study. AB - INTRODUCTION: The present paper examines the linguistic status of terminological collocations in medical Latin and English, discusses the most productive term formation models and ways of Latin-English translation. AIM: The authors aim to provide the comparative analysis of Latin and English terminological collocations and suggest their classification in terms of the idiomaticity level and semantic valency. MATERIALS AND METHODS: The research is based on the corpus of terminological collocations in Latin and English medical discourse using structural, etymological, typological, comparative methods, as well as the method of semantic analysis and conceptual metaphor theory. RESULTS: The research has resulted in the delineation of the following groups of terminological collocations in medical Latin and English: (1) terminological collocations with lower degree of idiomaticity - analytical units whose semantics correlates with the amount of free meanings of the components; (2) terminological collocations with semantic cohesion of the components due to metaphorical nature of the terminological element with active / passive valency; (3) clinical idioms - terminological collocations with higher degree of idiomaticity. Within the latter group, we suggest to discern eponymic, toponymic, zoomorphic, botanic and mythonimic subtypes of terminological collocations. CONCLUSIONS: A promising area of future research is the development of bilingual explanatory dictionaries with Latin and English equivalents of terminological collocations, as well as the information about the semantics of their components. PMID- 28343210 TI - Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (pfapa) syndrome in children. AB - INTRODUCTION: Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome refers to a group of primary immunodeficiencies, namely autoinflammatory diseases. Most pediatricians and otolaryngologists do not suspect PFAPA syndrome when treating recurrent pharyngitis (according to Ukrainian classification - tonsillitis) and stomatitis. Therefore, patients with a given syndrome receive unnecessary treatment (antibiotic therapy or antiviral drugs) and the diagnosis is made late. The aim of the research was to provide pediatricians, family physicians and otolaryngologists with information on the importance of early diagnosis of PFAPA syndrome. MATERIALS AND METHODS: The analysis of the prevalence and diagnosis of PFAPA syndrome in Ukraine and worldwide has been made as well as a late diagnosis of PFAPA syndrome in a child living in Ivano-Frankivsk, Ukraine has been described (case report). RESULTS: The Sase report 7-year-old boy, who grows and develops normally. The symptoms of pharyngitis including high body temperature (>40 o S), sore throat and white spots on the tonsils appeared for the first time at the age of two years. The boy received antibacterial drugs about 10 times a year. During a four-year period of recurrent episodes of the disease antimicrobial susceptibility testing to determine susceptibility of the oropharyngeal flora to the antibiotics were continuously performed, different blood tests for herpes viruses, Epstein-Barr virus infection and cytomegalovirus in particular were made using the enzyme immunoassay (EIA) and polymerase chain reaction (PCR) in addition to long-term treatment. CONCLUSIONS: An example of late diagnosing PFAPA syndrome (four years after the onset of first symptoms) resulting in regular examinations, medical manoeuvres, outpatient and inpatient treatment, use of antibiotic therapy including intravenous injections on a monthly basis has been studied. PMID- 28343211 TI - [Rare case of slowly progressing lung cancer with colon metastases]. AB - Lung cancer is one of the most frequent cancers in the world and the fist cause of death of neoplastic origin. In half of patients at the time of diagnosis distant metastases are determined. Most frequent localizations are bones, liver, brain and adrenal glands. In described case there was documented slow, long-term development of lung adenocarcinoma. After initial diagnosis the patient remained without treatment for three years. Aside from slow progression of the disease the fact of asymptomatic metastases to the colon as a very rare localization should draw attention. Due to a fast diagnosis of metastases and introduction of a proper treatment 3 year patient survival was achieved. PMID- 28343212 TI - Suicide case with multiple injuries with sharp objects. AB - The work of forensic - medical expert examination of the corpse at the place of its discovery and further research in the morgue often there are certain difficulties associated with the solution of a number of issues, including the establishment of a kind of death. Bringing the case demonstrates that, during the initial examination of the corpse to the place of its discovery the presence of multiple injuries on the body of a different nature, as a rule, initially suggest investigators to suspect that the murder occurred. But further questioning around him lately those studying survey data and scene study results allowed the corpse to make objective conclusions. PMID- 28343213 TI - Gross Hematuria Is More Common in Male and Older Patients with Renal Tuberculosis in China: A Single-Center 15-Year Clinical Experience. AB - OBJECTIVES: This study aimed to investigate the clinical features of renal tuberculosis and identify the age- and gender-related differences. METHODS: A total of 419 patients at the Peking University First Hospital from January 2000 to July 2015 were retrospectively reviewed. Data on demographic characteristics, clinical presentation, complications, laboratory results, radiologic imaging, surgical procedures, and pathology features were collected and compared between genders and 3 different age groups (under 40 years, 41-60, years and over 60 years). RESULTS: The most common local presentations were lower urinary tract symptoms (65.2%), flank pain (37.9%), and gross hematuria (26.3%). Constitutional symptoms were also observed in 38.9% of the patients. Gross hematuria was more common in male patients (32.2%) and older patients (45.5%). Flank pain was more common in female patients (43.6%). Patients younger than 40 years of age had lower frequencies of calcification of the urinary tract (22.2%) and kidney atrophy (4.2%) in CT. In the postoperative pathological reports, atrophy (35.9%) and fibrosis (38.5%) were found to be significantly more common in older patients. CONCLUSIONS: While gross hematuria is more prevalent in older patients and male patients, flank pain is more common in female patients. Radiological and pathological features including calcification of the urinary tract, fibrosis, and kidney atrophy are more common in older patients. PMID- 28343214 TI - Moderate-Grade Germinal Matrix Haemorrhage Activates Cell Division in the Neonatal Mouse Subventricular Zone. AB - Precise temporal and spatial control of the neural stem/progenitor cells within the subventricular zone (SVZ) germinal matrix of the brain is important for normal development in the third trimester and the early postnatal period. The high metabolic demands of proliferating germinal matrix precursors, coupled with the flimsy structure of the germinal matrix cerebral vasculature, are thought to account for the high rates of haemorrhage in extremely- and very-low-birth-weight preterm infants. Germinal matrix haemorrhage can commonly extend to intraventricular haemorrhage (IVH). Because neural stem/progenitor cells are sensitive to microenvironmental cues from the ventricular, intermediate, and basal domains within the germinal matrix, haemorrhage has been postulated to impact neurological outcomes through aberration of normal neural stem/progenitor cell behaviour. We developed an animal model of neonatal germinal matrix haemorrhage using stereotactic injection of autologous blood into the mouse neonatal germinal matrix. Pathological analysis at 4 days postinjury showed high rates of intraventricular extension and ventricular dilatation but low rates of parenchymal disruption outside the germinal zone, recapitulating key features of human "Papile grade III" IVH. At 4 days postinjury we observed proliferation in the wall of the lateral ventricle with significantly increased numbers of transient amplifying cells within the SVZ and the corpus callosum. Analysis at 21 days postinjury revealed that cortical development was also affected, with increased neuronal and concomitant reduced oligodendroglial differentiation. At the molecular level, we showed downregulation of the expression of the transmembrane receptor Notch2 in CD133+ve cells of the SVZ, raising the possibility that the burst of precocious proliferation seen in our experimental mouse model and the skewed differentiation could be mediated by downregulation of the Notch pathway within the proximal/ventricular domain. These findings raise the possibility that Notch regulation plays a critical role in mediating the response of the neonatal SVZ to ischaemic and haemorrhagic insults. PMID- 28343215 TI - A Study of Biological Rhythm Disturbances in Polish Remitted Bipolar Patients using the BRIAN, CSM, and SWPAQ Scales. AB - BACKGROUND/AIMS: The Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) is a novel tool allowing for a complex assessment of biological rhythms. We compared patients with bipolar disorder (BD) and healthy control subjects (HC) using the Polish version of the BRIAN scale. METHOD: Fifty four remitted BD patients (17 males and 37 females aged 52 +/- 13 years) and 54 healthy control subjects (25 males and 29 females aged 42 +/- 14 years) were studied. In addition to the BRIAN scale, the Composite Scale of Morningness (CSM) and the Sleep-Wake Pattern Assessment Questionnaire (SWPAQ) were employed. RESULTS: The Polish version of the BRIAN scale displayed high feasibility and consistency, showing that the patients had greater biological rhythm disturbances than the controls. After regression analysis, significant differences were obtained for the BRIAN subscales activity and predominant chronotype, and for the SWPAQ items quality of night-time sleep and ability to stay awake. We obtained positive correlations between higher BRIAN scores and morningness and eveningness, but the correlations with vigilance and the ability to stay awake (on the SWPAQ) were negative. CONCLUSIONS: Using the BRIAN scale, we confirmed the greater disturbances of biological rhythm in Polish remitted bipolar patients, compared with healthy controls. The differences between these 2 groups in sleep-awake patterns were also demonstrated by the SWPAQ scores. In contrast to other studies, we were unable to confirm an evening chronotype as a discriminating factor between remitted bipolar patients and healthy subjects. This can be explained by the older age and the use of lithium by a significant proportion of the patients. PMID- 28343217 TI - Contribution of Hyoid and Tonsillar Procedures to Outcome in Multilevel Surgery for Obstructive Sleep Apnea Syndrome. AB - BACKGROUND/OBJECTIVE: In multilevel surgery for obstructive sleep apnea (OSA), the contribution of distinct operative steps is still unclear. The aim of the present study is to retrospectively compare different combinations of multilevel surgeries in order to estimate the contribution of hyoid and tonsillar procedures to the outcome. METHODS: A total of 45 patients were selected in a retrospectively matched case-control study from a database of patients who underwent surgery for OSA at our institution: group A (n = 15) had hyoid suspension, tonsillectomy, and radiofrequency-assisted uvulopalatoplasty (RAUP); group B (n = 15) had hyoid pharyngoplasty with resection of the hyoid body and preepiglottic fat tissue, tonsillectomy, and RAUP; and group C (n = 15) had hyoid suspension and RAUP but no tonsillectomy, because the tonsils had already been removed. The apnea-hypopnea index (AHI) was defined as the primary outcome measure. RESULTS: The postoperative AHI significantly improved in groups A and B, in which all patients had a tonsillectomy. However, the improvement in the patients of group C, who had no tonsillectomy, was not significant (p = 0.08). CONCLUSION: The patients having undergone multilevel surgery without tonsillectomy showed significantly poorer postoperative results, suggesting that the effectiveness of hyoid procedures at the level of the hypopharynx may be limited. However, removal of the tonsils is a major predictive factor for postoperative success. PMID- 28343216 TI - Susceptibility-Weighted Imaging Identifies Iron-Oxide-Labeled Human Neural Stem Cells: Automated Computational Detection. AB - Neonatal hypoxic-ischemic brain injury (HII) can lead to devastating neurological outcomes such as cerebral palsy, epilepsy, and mental retardation. Human neural stem cell (hNSC) therapy provides new hope for the treatment of neonatal HII. These multipotent cells can aid in HII recovery by activating multiple reparative mechanisms including secretion of neurotrophic factors that enhance brain repair and plasticity. For clinical use of implanted hNSCs, methods are required to identify, quantify, track, and visualize migration and replication in an automated and reproducible fashion. In the current study, we used a model of unilateral HII in 10-day-old rat pups that were implanted with 250,000 Feridex labeled hNSCs into the contralateral ventricle 3 days after HII. In addition to standard noninvasively acquired serial magnetic resonance imaging (MRI) sequences (11.7 and 4.7 T) that included diffusion-weighted imaging and T2-weighted imaging, we also acquired susceptibility-weighted imaging (SWI) 1-90 days after hNSC implantation. SWI is an advanced MRI method that enhances the visualization of iron-oxide-labeled hNSCs within affected regions of the injured neonatal brain. hNSC contrast was further enhanced by creating minimal intensity projections from the raw SWI magnitude images combined with phase information. Automated computational analysis using hierarchical region splitting (HRS) was applied for semiautomatic detection of hNSCs from SWI images. We found hNSCs in the ipsilateral HII lesion within the striatum and cortex adjacent to the lesion that corresponded to histological staining for iron. Quantitative phase values (radians) obtained from SWI revealed temporally evolving increased phase which reflects a decreased iron oxide content that is possibly related to cell division and the replicative capacity of the implanted hNSCs. SWI images also revealed hNSC migration from the contralateral injection site towards the ipsilateral HII lesion. Our results demonstrate that MRI-based SWI can monitor iron-labeled hNSCs in a clinically relevant manner and that automated computational methods such as HRS can rapidly identify iron-oxide-labeled hNSCs. PMID- 28343218 TI - Effect of L-Carnitine Supplementation on Reverse Remodeling in Patients with Ischemic Heart Disease Undergoing Coronary Artery Bypass Grafting: A Randomized, Placebo-Controlled Trial. AB - During cardiac failure, cardiomyocytes have difficulty in using the substrates to produce energy. L-carnitine is a necessary nutrient for the transport of fatty acids that are required for generating energy. Coronary artery graft surgery reduces the plasma levels of L-carnitine and increases the oxidative stress. This study demonstrates the effect of L-carnitine supplementation on the reverse remodeling of patients undergoing coronary artery bypass graft. Patients with ischemic heart failure who underwent coronary graft surgery were randomized to group A - supplemented with L-carnitine or group B controls. Left ventricular ejection fraction, left ventricular systolic and diastolic diameters were assessed preoperatively, 60 and 180 days after surgery. Our study included 28 patients (26 [93.0%] males) with a mean age +/- SD of 58.1 +/- 10.5 years. The parameters for the evaluation of reverse remodeling did not improve after 60 and 180 days of coronary artery bypass grafting in comparison between groups (p > 0.05). Evaluation within the L-carnitine group showed a 37.1% increase in left ventricle ejection fraction (p = 0.002) and 14.3% (p = 0.006) and 3.3% (p > 0.05) reduction in systolic and diastolic diameters, respectively. L-carnitine supplementation at a dose of 50 mg/kg combined with artery bypass surgery did not demonstrate any additional benefit in reverse remodeling. However, evaluation within the L-carnitine group may indicate a clinical benefit of L-carnitine supplementation. PMID- 28343219 TI - Simulation-Based Training in Flexible Bronchoscopy and Endobronchial Ultrasound Guided Transbronchial Needle Aspiration (EBUS-TBNA): A Systematic Review. AB - BACKGROUND: The use of simulators in a training programme for technically challenging procedures has the advantages of lowering the risk of patient complications while helping the trainees with the initial part of their learning curve. OBJECTIVES: The aim of this study was to perform a systematic review of simulation-based training in flexible bronchoscopy and endobronchial ultrasound (EBUS). METHODS: We identified 1,006 publications in the PubMed database and included publications on flexible bronchoscopy below the carina and EBUS involving hands-on simulation-based training. Publications were excluded if they were written in languages other than English, if paediatric airways were involved or if they were not journal articles. The screening process was performed by 2 individuals, and a third reviewer made the final decision in case of disagreement. RESULTS: We included 30 publications. The studies included participants of varying experience and most commonly used a virtual reality simulator as a training modality. Assessment of the participants' skills was based on simulator metrics or on an assessment tool. Some studies included performance on patients for assessment of the operator after training on a simulator. CONCLUSIONS: Simulation-based training was demonstrated to be more efficient than the traditional apprenticeship model. Physical models and virtual reality simulators complement each other. Simulation-based education should be based on a mastery learning approach and structured as directed self-regulated learning in a distributed training programme. PMID- 28343220 TI - Hemorrhagic Transformations after Thrombectomy: Risk Factors and Clinical Relevance. AB - BACKGROUND: Hemorrhagic transformation (HT) is a major complication of acute ischemic stroke, potentially associated with clinical deterioration. We attempted to identify risk factors and evaluated clinical relevance of minor and major HTs following endovascular thrombectomy (ET) in isolated middle cerebral artery (MCA) occlusions. METHODS: This is a retrospective single-center analysis of 409 patients with isolated MCA occlusion treated with ET. Patients' and procedural characteristics, severity of HT according to the European Cooperative Acute Stroke Study criteria, and clinical outcomes were analyzed. Multivariate logistic regression models with standard retention criteria (p < 0.1) were used to determine risk factors and clinical relevance of HT. Results are shown as adjusted OR (aOR) and respective 95% CIs. Good neurologic short-term outcome was defined as National Institutes of Health Stroke Scale (NIHSS) score <5 at the day of discharge. RESULTS: Of 299 patients included, hemorrhagic infarction (HI) was detected in 87 patients, while 13 patients developed parenchymal hematoma (PH). Higher age (aOR 0.970, 95% CI 0.947-0.993, p = 0.012), eligibility for intravenous recombinant tissue plasminogen activator (IV rtPA; aOR 0.512, 95% CI 0.267-0.982, p = 0.044), and complete recanalization (TICI 3, aOR 0.408, 95% CI 0.210-0.789, p = 0.008) were associated with a lower risk of HI. Risk factors for HI included higher admission NIHSS score (aOR 1.080, 95% CI 1.010-1.153, p = 0.024) and higher admission glucose levels (aOR 1.493, 95% CI 1.170-1.904, p = 0.001). Further, female sex tended to be associated with a lower risk of HI (aOR 0.601, 95% CI 0.316-1.143, p = 0.121), while a statistical trend was observable for proximal MCA occlusion (aOR 1.856, 95% CI 0.945-3.646, p = 0.073) and a history of hypertension (aOR 2.176, 95% CI 0.932-5.080, p = 0.072) to increase risk of HI. Longer intervals from symptom onset to first digital subtraction angiography runs (aOR 1.013, 95% CI 1.003-1.022, p = 0.009), lower preinterventional Alberta Stroke Program Early CT score (aOR 0.536, 95% CI 0.307 0.936, p = 0.028) and wake-up stroke (aOR 18.540, 95% CI 1.352-254.276, p = 0.029) were associated with PH. Both, PH and HI were independently associated with lower rates of good neurologic outcome (aOR 0.086, 95% CI 0.008-0.902, p = 0.041 and aOR 0.282, 95% CI 0.131-0.606, p = 0.001). CONCLUSION: Risk of HI following MCA occlusion and subsequent ET is mainly determined by factors influencing infarct severity. Good recanalization results seem to be protective against subsequent HI. Our results support the notion that occurrence of PH after ET is time dependent and risk increases with more extensive early ischemic damage. Both, HI and PH do not seem to be facilitated by bridging therapy with IV rtPA or the use of oral anticoagulants, but were independently associated with more severe neurologic disability. These results support the notion that HI is not a "benign" imaging sign. PMID- 28343222 TI - Oral Health Education in the Medical Curriculum. PMID- 28343221 TI - Abandoning Prophylactic Abdominal Drainage after Hepatic Surgery: 10 Years of No Drain Policy in an Enhanced Recovery after Surgery Environment. AB - BACKGROUND: Routine prophylactic abdominal drainage after hepatic surgery is still being debated, as it may be unnecessary, possibly harmful, and uncomfortable for patients. This study evaluated the safety of a no-drain policy after liver resection within an Enhanced Recovery after Surgery (ERAS) programme. METHODS: All hepatectomies performed without prophylactic drainage during 2005 2014 were included. Primary end points were resection-surface-related (RSR) morbidity, defined as the presence of postoperative biloma, hemorrhage or abscess, and reinterventions. Secondary end points were length of stay, total postoperative morbidity, the composite end point of liver surgery-specific complications, readmissions, and 90-day mortality. Uni- and multivariate analyses were performed to identify independent risk factors for RSR morbidity. A systematic search was performed to compare the results of this study to literature. RESULTS: A total of 538 resections were included in the study. The RSR complication and reintervention rate was 15 and 12%, respectively. Major liver resection (>=3 segments) was an independent risk factor for the development of RSR morbidity (OR 3.01, 95% CI 1.61-5.62; p = 0.001) and need for RSR reintervention (OR 3.02, 95% CI 1.59-5.73; p = 0.001). CONCLUSION: RSR morbidity, mortality, and reintervention rates after liver surgery without prophylactic drainage in patients, treated within an ERAS programme, were comparable to previously published data. A no-drain policy after partial hepatectomy seems safe and feasible. PMID- 28343223 TI - Sildenafil Enhances Quantity of Immature Neurons and Promotes Functional Recovery in the Developing Ischemic Mouse Brain. AB - BACKGROUND: Hypoxic-ischemic (HI) injury to the developing brain occurs in 1 out of 1,000 live births and remains a major cause of significant morbidity and mortality. A large number of survivors suffer from long-term sequelae including seizures and neurological deficits. However, the pathophysiological mechanisms of recovery after HI insult are not clearly understood, and preventive measures or clinical treatments are nonexistent or not sufficiently effective in the clinical setting. Sildenafil as a specific phosphodiesterase 5 inhibitor leads to increased levels of the second messenger cyclic guanosine monophosphate (cGMP) and promotes functional recovery and neurogenesis after ischemic injury to the adult brain. OBJECTIVE: Here, we investigated the effect of sildenafil treatment on activation of intracellular signaling pathways, histological and neurogenic response including functional recovery after an ischemic insult to the developing brain. DESIGN/METHODS: Nine-day-old C57BL/6 mice were subjected either to sham operation or underwent ligation of the right common carotid artery followed by hypoxia (8%) for 60 min. Animals were either administered sildenafil (10 mg/kg, i.p.) or vehicle 2 h after hypoxia. A subgroup of animals received multiple injections of 10 mg/kg daily on 5 consecutive days. Pups were either perfusion fixed at postnatal days 14 or 47 for immunohistochemical analysis, or brains were dissected 2, 6, 12, and 24 h after the end of hypoxia and analyzed for cGMP, pAkt, pGSK-3beta, and beta-catenin by means of ELISA or immunoblotting. In addition, behavioral studies using the wire hang test and elevated plus maze were conducted 21 and 38 days after HI injury. RESULTS: Based on cresyl violet staining, single or multiple sildenafil injections did not reveal any differences in injury scoring compared to sham animals. However, cerebral levels of cGMP were altered after sildenafil therapy. Treatment significantly increased numbers of immature neurons, as indicated by doublecortin immunoreactivity in the ipsilateral subventricular zone and striatum. In addition, animals treated with sildenafil after HI insult demonstrated improved functional recovery. pAkt, pGSK 3beta, and beta-catenin levels vary after HI injury but additional sildenafil treatment had no impact on protein expression compared to the level of sham controls. CONCLUSIONS: Here, we report that treatment with sildenafil after HI insult did not improve histological brain injury scores. Nevertheless, our results suggest involvement of the cGMP and PI3K/Akt/GSK-3beta signaling pathway with promotion of a neurogenic response and reduction of neurological deficits. In summary, sildenafil may have a role in promoting recovery from HI injury in the developing brain. PMID- 28343224 TI - The Evidence of Acute Kidney Injury in the Community and for Primary Care Interventions. AB - BACKGROUND: Almost two-thirds of patients with acute kidney injury (AKI) damage their kidneys whilst in the community. This paper aims to review existing data on incidence, mortality, and morbidity of AKI within the community and explore the evidence base for primary care strategies aimed at reducing incidence and improving early detection and management of AKI. METHODS: A literature search was carried out using PubMed; key words including AKI, primary care, community acquired, and electronic alerts (e-alerts) were used to capture relevant data. RESULTS: Incidence of AKI developing in the community is variable between studies due to differences in AKI definition. Community-acquired AKI (CA-AKI) but identified in hospital (CAH-AKI) is more prevalent than hospital-acquired AKI and increases short- and long-term mortality and length of stay in hospital. CA-AKI identified in primary care is less severe than CAH-AKI but is associated with increased mortality. The use of e-alerts has good diagnostic accuracy for detecting AKI but their impact on outcomes in secondary care remains uncertain; it is likely that they should be complemented with other interventions to improve management. Evidence has not yet emerged regarding the effects of e-alerts on outcomes in primary care. CONCLUSION: Given the significance of developing AKI in the community, strategies to aid early detection and promote prevention are warranted. A multifaceted approach combining e-alerts, educational programs, and care bundles across the interface between primary and secondary care has the potential to improve outcomes in the future. PMID- 28343225 TI - Clinical Trial of Vadadustat in Patients with Anemia Secondary to Stage 3 or 4 Chronic Kidney Disease. AB - BACKGROUND: Therapeutic options for the treatment of anemia secondary to chronic kidney disease (CKD) remain limited. Vadadustat (AKB-6548) is an oral hypoxia inducible factor prolyl-hydroxylase domain (HIF-PHD) inhibitor that is being investigated for the treatment of anemia secondary to CKD. METHODS: A phase 2a, multicenter, randomized, double-blind, placebo-controlled, dose-ranging trial (NCT01381094) was undertaken in adults with anemia secondary to CKD stage 3 or 4. Eligible subjects were evenly randomized to 5 groups: 240, 370, 500, or 630 mg of once-daily oral vadadustat or placebo for 6 weeks. All subjects received low-dose supplemental oral iron (50 mg daily). The primary endpoint was the mean absolute change in hemoglobin (Hb) from baseline to the end of treatment. Secondary endpoints included iron indices, safety, and tolerability. RESULTS: Ninety-three subjects were randomized. Compared with placebo, vadadustat significantly increased Hb after 6 weeks in a dose-dependent manner (analysis of variance; p < 0.0001). Vadadustat increased the total iron-binding capacity and decreased concentrations of ferritin and hepcidin. The proportion of subjects with at least 1 treatment-emergent adverse event was similar between vadadustat- and placebo treated groups. No significant changes in blood pressure, vascular endothelial growth factor, C-reactive protein, or total cholesterol were observed. Limitations of this study included its small sample size and short treatment duration. CONCLUSIONS: Vadadustat increased Hb levels and improved biomarkers of iron mobilization and utilization in patients with anemia secondary to stage 3 or 4 CKD. Global multicenter, randomized phase 3 trials are ongoing in non-dialysis dependent and dialysis-dependent patients. PMID- 28343226 TI - The Effect of Ineffective Esophageal Motility on Gastroesophageal Reflux Disease. AB - BACKGROUND/AIMS: Ineffective esophageal motility (IEM) is the most common gastrointestinal motility disorder. Studies have reported that IEM is related to gastroesophageal reflux disease (GERD). However, the relationship between IEM and GERD remains uncertain. This study aims to clarify this relationship retrospectively. METHODS: We analyzed 195 subjects who underwent high-resolution manometry between January 2011 and September 2016. Of these subjects, 72 had normal esophageal motility (NEM) and 26 had IEM. We investigated differences in the clinical characteristics, severity and duration of GERD symptoms, and comorbid extra-esophageal symptoms of the subjects. Comorbid extra-esophageal symptoms were assessed with the Gastrointestinal Symptom Rating Scale questionnaire. Investigation-defined GERD was diagnosed when erosive esophagitis or abnormal multichannel intraluminal impedance was present. RESULTS: We found no significant difference in the prevalence of IEM between patients with and without GERD (37.5 and 21.1%, respectively; p = 0.174). There were no differences in age, gender, body mass index, presence of hiatal hernia, or duration of GERD between the groups. Compared to patients with NEM, those with IEM were significantly less likely to have comorbid extra-esophageal symptoms (p < 0.05). CONCLUSION: There is no association between IEM and GERD. PMID- 28343227 TI - What Is the Key to Improving Renal Transplant Recipients' Awareness of Skin Cancer Risk? AB - BACKGROUND: Previous studies have shown poor compliance rates regarding sun protection among organ transplant recipients. OBJECTIVE: The main objective of the present study was to assess the awareness among renal transplant recipients (RTRs) of their risk of non-melanoma skin cancer (NMSC) development and their sunscreen use. The influence of several potentially relevant variables was also assessed in order to identify possible weak points on which to concentrate efforts in this respect. METHODS: A total of 132 RTRs (92 males and 40 females) were included. The following information was collected and elaborated: (a) demographics; (b) skin phototype; (c) educational level; (d) time elapsed since transplantation; (e) immunosuppressive treatments; (f) previous dermatological visits; (g) patients' awareness of their NMSC risk; (h) use of sunscreen; and (i) previous documented NMSCs or NMSCs found during the study visit. RESULTS: Overall, 65 patients (49.2%) expressed awareness of their susceptibility to skin cancers. A high educational level was the main factor associated with patients' awareness. Thirty-six RTRs (27.3%) reported using sunscreen regularly. High educational level and awareness of personal susceptibility to NMSC development were the most relevant factors associated with sun protection habits. CONCLUSION: The present study showed the low level of sunscreen use among RTRs and their scanty awareness of personal skin cancer risk. Since educational level has been found to be highly related to both awareness of cancer risk and adequate use of sunscreen among RTRs, it is necessary to improve the way education is delivered by dermatologists and nephrologists, especially to subjects with a low educational level. PMID- 28343230 TI - Idiopathic Pulmonary Fibrosis in Switzerland: Diagnosis and Treatment. AB - Idiopathic pulmonary fibrosis (IPF) is a severe progressive and irreversible lung disease. Novel antifibrotic drugs that slow disease progression are now available. However, many issues regarding patient management remain unanswered, such as the choice between available drugs, their use in particular subgroups and clinical situations, time of treatment onset, termination, combination or switch, or nonpharmacologic management. To guide Swiss respiratory physicians in this evolving field still characterized by numerous areas of uncertainty, the Swiss Working Group for interstitial and rare lung diseases of the Swiss Respiratory Society provides a position paper on the diagnosis and treatment of IPF. PMID- 28343229 TI - Cytological Findings of Ascitic Fluid with a Malignant Ovarian Steroid Cell Tumor: A Case Report and Literature Review. AB - BACKGROUND: Ovarian steroid cell tumors (SCTs) are rare and usually benign, although 25-43% are reportedly malignant. The cytologic findings of these rare ovarian tumors have almost never been reported. CASE: We report a rare case of a malignant ovarian SCT with peritoneal dissemination and malignant ascites in a 40 year-old woman. Her tumor was classified as stage IIB (pT2bNoM0) according to the FIGO (International Federation of Gynecology and Obstetrics) classification system, and she was treated with adjuvant chemotherapy following staging laparotomy. Cytology of the ascitic fluid revealed large, polygonal-to-round cells and multinucleated cells with atypia, appearing in clusters with slight overlapping or as isolated tumor cells. Numerous tumor cells had small central round or eccentric nuclei with conspicuous nucleoli, and a moderate-to-abundant amount of cytoplasm, varying from granular and eosinophilic to pale and multivacuolated (foamy), with cannibalism formations. The nuclear chromatin was fine and granular, with irregular distribution and nuclear-membrane thickening. CONCLUSION: These may be the first reported cytology results for ascites with a malignant SCT. Our patient's cytological ascitic findings, rather than the histopathologic features of the original and disseminated tumors, represent the malignant features of the tumor. PMID- 28343231 TI - Segmental Testicular Infarction: Case Series and Literature Review of a Rare Diagnosis in Men with Acute Testicular Pain. AB - The incidence of segmental testicular infarction (STI) is very low. Such a disorder most often affects young men. The most common symptom is sudden testicular pain. We report 6 cases of men diagnosed with STI. Clinical examination, blood test, urine analysis, and ultrasound examination with colour Doppler were performed. Furthermore, tissue sonoelastography or MRI was performed in selected patients. All men underwent surgical exploration. In all but one man, the affected testis was preserved. Although STI is a rare condition, it should be taken into account if testicular pain prior to suspicious ultrasound imaging occurs. To be aware of this benign testicular pathology and its clinical and imaging features is important to avoid unnecessary orchiectomies in young patients. PMID- 28343228 TI - Focal Brain Injury Associated with a Model of Severe Hypoxic-Ischemic Encephalopathy in Nonhuman Primates. AB - Worldwide, hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal mortality and morbidity. To better understand the mechanisms contributing to brain injury and improve outcomes in neonates with HIE, better preclinical animal models that mimic the clinical situation following birth asphyxia in term newborns are needed. In an effort to achieve this goal, we modified our nonhuman primate model of HIE induced by in utero umbilical cord occlusion (UCO) to include postnatal hypoxic episodes, in order to simulate apneic events in human neonates with HIE. We describe a cohort of 4 near-term fetal Macaca nemestrina that underwent 18 min of in utero UCO, followed by cesarean section delivery, resuscitation, and subsequent postnatal mechanical ventilation, with exposure to intermittent daily hypoxia (3 min, 8% O2 3-8 times daily for 3 days). After delivery, all animals demonstrated severe metabolic acidosis (pH 7 +/- 0.12; mean +/- SD) and low APGAR scores (<5 at 10 min of age). Three of 4 animals had both electrographic and clinical seizures. Serial blood samples were collected and plasma metabolites were determined by 2-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GC * GC-TOFMS). The 4 UCO animals and a single nonasphyxiated animal (delivered by cesarean section but without exposure to UCO or prolonged sedation) underwent brain magnetic resonance imaging (MRI) on day 8 of life. Thalamic injury was present on MRI in 3 UCO animals, but not in the control animal. Following necropsy on day 8, brain histopathology revealed neuronal injury/loss and gliosis in portions of the ventrolateral thalamus in all 4 UCO, with 2 animals also demonstrating putamen/globus pallidus involvement. In addition, all 4 UCO animals demonstrated brain stem gliosis, with neuronal loss present in the midbrain, pons, and lateral medulla in 3 of 4 animals. Transmission electron microscopy imaging of the brain tissues was performed, which demonstrated ultrastructural white matter abnormalities, characterized by perinuclear vacuolation and axonal dilation, in 3 of 4 animals. Immunolabeling of Nogo-A, a negative regulator of neuronal growth, was not increased in the injured brains compared to 2 control animals. Using GC * GC-TOFMS, we identified metabolites previously recognized as potential biomarkers of perinatal asphyxia. The basal ganglia-thalamus-brain stem injury produced by UCO is consistent with the deep nuclear/brainstem injury pattern seen in human neonates after severe, abrupt hypoxic-ischemic insults. The UCO model permits timely detection of biomarkers associated with specific patterns of neonatal brain injury, and it may ultimately be useful for validating therapeutic strategies to treat neonatal HIE. PMID- 28343232 TI - Genetic Polymorphisms in DEFB1 and miRNA202 Are Involved in Salivary Human beta Defensin 1 Levels and Caries Experience in Children. AB - The antimicrobial peptides human beta-defensins (hBDs) are encoded by beta defensin genes (DEFBs) and are possibly involved in caries susceptibility. In this study we aimed (1) to investigate the relationship between salivary hBDs and caries and (2) to evaluate the association of genetic polymorphisms in DEFB1 and microRNA202 (miRNA202) with salivary levels of hBDs and caries experience. Two data sets were available for this study, totalizing 678 Brazilian children. Dental examination and saliva collection were performed in all included children. The salivary level for hDB1, hBD2, and hBD4 was assessed by ELISA sandwich technique in 168 children. The DNA was extracted from saliva, and polymorphisms in DEFB1 and miRNA202 were analyzed by real-time PCR. Statistical analysis was performed to investigate the associations between caries experience, hBD salivary level, genotype, and allele distribution, with an alpha of 0.05. The hBD1 level was significantly higher in caries-free children (p < 0.0001). The miRNA202 was associated with a lower level of salivary hBD1 (p < 0.05). Also, the polymorphic distribution of miRNA202 was associated with caries (p = 0.006). The polymorphisms in DEFB1 were not associated with hBD salivary level and caries experience (p > 0.05). In conclusion, our results indicate that genetic polymorphism in miRNA202 is involved in hBD1 salivary level as well as caries experience in children. PMID- 28343233 TI - Incidence of and Factors Influencing Femoral Neck Shortening in Elderly Patients After Fracture Fixation with Multiple Cancellous Screws. AB - BACKGROUND To study the incidence of and factors influencing "neck shortening" in elderly patients treated for femoral neck fractures using multiple cancellous screws. MATERIAL AND METHODS Of the 197 femoral neck fracture cases treated via closed reduction and cancellous screws fixation from January 2006 to February 2010, 110 were followed up. Patient age, gender, operative time, implantation method, reduction quality, fracture type, bone mineral density, loading time, length of hospital stay, and Harris hip score 12 months after operation were recorded. The patients were divided into two groups (shortening and non shortening) based on their X-ray performance during follow-up. The healing rates and Harris hip scores of the two groups were compared, and the influencing factors of femoral neck shortening were analyzed. RESULTS Of the 110 cases followed up, 94.5% (104/110) were healed and neck shortening occurred in 41.8% (46/110) within 12.5 months (mean) after treatment. The Harris hip score of the shortening group was lower than that of the non-shortening group (78+/-17 vs. 86+/-23, p=0.048). The fracture healing rates of the two groups were not significantly different (p=0.068). The factors influencing neck shortening were significantly correlated with bone mineral density, patient age, gender, and type of fracture. CONCLUSIONS The incidence of neck shortening in elderly patients treated for femoral neck fracture using cancellous screws was high. Bone mineral density, patient age, gender, and type of fracture were the influencing factors of neck shortening. PMID- 28343234 TI - Serum Endocan as a Predictive Marker for Decreased Urine Volume in Peritoneal Dialysis Patients. AB - BACKGROUND Endocan is expressed in vascular endothelial cells, and its expression is enhanced following endothelial injury via inflammatory cytokines. Subsequently, endocan is secreted into the circulation. Thus, serum endocan levels are considered a marker of endothelial injury. However, to the best of our knowledge, no data on the serum endocan levels in peritoneal dialysis (PD) patients are available. MATERIAL AND METHODS This study included 21 PD patients who underwent peritoneal equilibration test (PET) more than once between 2011 and 2015. Serum samples were collected from each patient, and the 24-h urine volume was measured at the time of PET. Serum endocan levels were measured using enzyme linked immunosorbent assay (ELISA) at the time of the first PET, and their relationship with clinical data or the extent of urine volume decline (mL/year) was analyzed retrospectively. RESULTS Serum endocan levels were positively correlated with proteinuria level, serum creatinine level, serum tumor necrosis factor (TNF)-alpha level, beta2-microglobulin level, and PD drainage volume, but not with urine volume at baseline. The extent of decline in urine volume was significantly associated with serum endocan level, proteinuria level, serum creatinine level, and serum TNF-alpha level at baseline in a simple linear regression analysis. Moreover, multiple linear regression analysis showed that the serum endocan level and proteinuria level at baseline were independent predictors for the extent of decline in urine volume. CONCLUSIONS The results of this study indicate that serum endocan level and proteinuria level may be useful predictive markers for decreased urine volume in PD patients. PMID- 28343235 TI - Transcription-dependent radial distribution of TCF7L2 regulated genes in chromosome territories. AB - Human chromosomes occupy distinct territories in the interphase nucleus. Such chromosome territories (CTs) are positioned according to gene density. Gene-rich CTs are generally located in the center of the nucleus, while gene-poor CTs are positioned more towards the nuclear periphery. However, the association between gene expression levels and the radial positioning of genes within the CT is still under debate. In the present study, we performed three-dimensional fluorescence in situ hybridization experiments in the colorectal cancer cell lines DLD-1 and LoVo using whole chromosome painting probes for chromosomes 8 and 11 and BAC clones targeting four genes with different expression levels assessed by gene expression arrays and RT-PCR. Our results confirmed that the two over-expressed genes, MYC on chromosome 8 and CCND1 on chromosome 11, are located significantly further away from the center of the CT compared to under-expressed genes on the same chromosomes, i.e., DLC1 and SCN3B. When CCND1 expression was reduced after silencing the major transcription factor of the WNT/beta-catenin signaling pathway, TCF7L2, the gene was repositioned and mostly detected in the interior of the CT. Thus, we suggest a non-random distribution in which over-expressed genes are located more towards the periphery of the respective CTs. PMID- 28343236 TI - Effects of restricting perioperative use of intravenous chloride on kidney injury in patients undergoing cardiac surgery: the LICRA pragmatic controlled clinical trial. AB - PURPOSE: The administration of chloride-rich intravenous (IV) fluid and hyperchloraemia have been associated with perioperative renal injury. The aim of this study was to determine whether a comprehensive perioperative protocol for the administration of chloride-limited IV fluid would reduce perioperative renal injury in adults undergoing cardiac surgery. METHODS: From February 2014 through to December 2015, all adult patients undergoing cardiac surgery within a single academic medical center received IV fluid according to the study protocol. The perioperative protocol governed all fluid administration from commencement of anesthesia through to discharge from the intensive care unit and varied over four sequential periods, each lasting 5 months. In periods 1 and 4 a chloride-rich strategy, consisting of 0.9% saline and 4% albumin, was adopted; in periods 2 and 3, a chloride-limited strategy, consisting of a buffered salt solution and 20% albumin, was used. Co-primary outcomes were peak delta serum creatinine (?SCr) within 5 days after the operation and KDIGO-defined stage 2 or stage 3 acute kidney injury (AKI) within 5 days after the operation. RESULTS: We enrolled and analysed data from 1136 patients, with 569 patients assigned to a chloride-rich fluid strategy and 567 to a chloride-limited one. Compared with a chloride limited strategy and adjusted for prespecified covariates, there was no association between a chloride-rich perioperative fluid strategy and either peak ?S Cr, transformed to satisfy the assumptions of multivariable linear regression [regression coefficient 0.03, 95% confidence interval (CI) -0.03 to 0.08); p = 0.39], or stage 2 or 3 AKI (adjusted odds ratio 0.97, 95% CI 0.65-1.47; p = 0.90]. CONCLUSIONS: A perioperative fluid strategy to restrict IV chloride administration was not associated with an altered incidence of AKI or other metrics of renal injury in adult patients undergoing cardiac surgery. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02020538. PMID- 28343237 TI - Actogram analysis of free-flying migratory birds: new perspectives based on acceleration logging. AB - The use of accelerometers has become an important part of biologging techniques for large-sized birds with accelerometer data providing information about flight mode, wing-beat pattern, behaviour and energy expenditure. Such data show that birds using much energy-saving soaring/gliding flight like frigatebirds and swifts can stay airborne without landing for several months. Successful accelerometer studies have recently been conducted also for free-flying small songbirds during their entire annual cycle. Here we review the principles and possibilities for accelerometer studies in bird migration. We use the first annual actograms (for red-backed shrike Lanius collurio) to explore new analyses and insights that become possible with accelerometer data. Actogram data allow precise estimates of numbers of flights, flight durations as well as departure/landing times during the annual cycle. Annual and diurnal rhythms of migratory flights, as well as prolonged nocturnal flights across desert barriers are illustrated. The shifting balance between flight, rest and different intensities of activity throughout the year as revealed by actogram data can be used to analyse exertion levels during different phases of the life cycle. Accelerometer recording of the annual activity patterns of individual birds will open up a new dimension in bird migration research. PMID- 28343238 TI - Visualization of endothelial barrier damage prior to formation of atherosclerotic plaques. AB - En-face fat staining is frequently used to visualize atherosclerotic lesions. This method, however, is not suitable to visualize endothelial barrier damage prior to microscopically detectable morphological alterations of the arterial wall such as sub-endothelial lipid deposition. To enable the investigation of early endothelial barrier damage and in particular the initial steps of atherosclerosis, a new method has to fulfill three requirements: (i) easy and fast to perform, (ii) low cost of applicability without requirement for highly sophisticated technical equipment, and (iii) reliable reproducibility of valid results. To this end, we used intracardial Evans blue dye injection after washout of blood and measured dye deposition within the aortic wall as a parameter of endothelial barrier leakiness, which is recognized as one of the earliest signs of atherosclerotic plaque formation. These analyses were performed in ApoE -/-, LDL receptor -/- and Cc1 -/- mouse models which have been reported to develop aortic plaques with or without high cholesterol diet. Our data show that sub endothelial dye deposition is a reliable and reproducible readout parameter to assess endothelial barrier damage. Along these lines, measurements of aortic intima areas with Evans blue deposition in relation to total intima circumference enabled quantitative assessments of the results. Our technique enables the imaging of endothelial barrier damage prior to detectable aortic lipid deposition and plaque development. Thus, it will facilitate the detection of the initial vascular pathogenetic processes that lead to cardiovascular diseases. It will also enable the testing of new drugs and therapeutic procedures to prevent these disorders. PMID- 28343240 TI - Childhood angular kyphosis: a plea for involvement of the pediatric neurosurgeon. AB - INTRODUCTION: Childhood angular kyphosis is rare, as most children are affected by a mixed kyphotic and scoliotic deformity. Published series involving a mix of kyphosis and kyphoscoliosis, pediatric and adult, congenital and acquired cases are almost exclusively authored by orthopedic surgeons, suggesting that (pediatric) neurosurgeons are not involved. CASE SERIES: We present five cases that illustrate the spectrum of angular kyphosis, and these were treated by a multidisciplinary team including child neurologist, orthopedic surgeon, and pediatric neurosurgeon as complementary partners. DISCUSSION: Angular kyphosis is a cosmetic problem but above all a serious threat to the spinal cord and as such to the child's ambulatory, sphincter, and genito-urinary functions. Spinal cord stretch over the internal kyphosis may cause pain and/or neurological deficit, often accompanied by myelomalacia or even segmental cord atrophy. Spinal cord function may be additionally affected by associated disorders such as syringomyelia or tethered cord, an orthopedic surgeon may be less familiar with. The decision when and how to proceed surgically should be made by a multidisciplinary team, including a pediatric neurosurgeon who actively participates in the operation and helps to safely achieve adequate spinal cord decompression and stabilization. CONCLUSION: Childhood angular kyphosis is a complex, heterogeneous disorder that should be managed by a multidisciplinary team in specialized pediatric spine centers. While every case is truly unique, the spinal cord is always at risk, especially during decompression, stabilization, and eventual correction of deformity. Pediatric neurosurgeons have an important role to play in preoperative work-up, actual operation, and follow up. PMID- 28343241 TI - In vitro activity of alpha-mangostin in killing and eradicating Staphylococcus epidermidis RP62A biofilms. AB - Alpha-mangostin (alpha-MG) has been reported to be an effective antibacterial agent against planktonic cells of many Gram-positive bacteria. However, the antibiofilm potency of alpha-MG remains unexplored till date. In this study, the antibiofilm and mature biofilm eradication ability of alpha-MG against Staphylococcus epidermidis RP62A (ATCC 35984) biofilms were evaluated. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of alpha-MG against S. epidermidis RP62A were found to be 1.25 and 5 MUg/mL, respectively. alpha-MG exhibited a phenomenal concentration dependent rapid bactericidal activity (>4-log reduction within 5 min). In a multi-passage resistance analysis using S. epidermidis, no development of resistance to alpha MG as well as antibiotics was observed in its habituation. alpha-MG at its 1/2 MIC effectively inhibited the initial biofilm formation of S. epidermidis, which was further confirmed through scanning electron microscopic (SEM) analysis that portrayed a lucid reduction in the aggregation and the spread of biofilm. The crystal violet staining and viable cell quantification results confirmed the eradication of preformed immature and mature biofilms of S. epidermidis by alpha MG in a concentration dependent manner. Besides, the biofilm eradication ability was also confirmed through SEM and live/dead BacLight staining using confocal laser scanning microscopy (CLSM). Thus, the present study exemplifies that alpha MG could plausibly assist to eliminate biofilm infections associated with multidrug-resistance staphylococci. PMID- 28343239 TI - Improved full-length killer cell immunoglobulin-like receptor transcript discovery in Mauritian cynomolgus macaques. AB - Killer cell immunoglobulin-like receptors (KIRs) modulate disease progression of pathogens including HIV, malaria, and hepatitis C. Cynomolgus and rhesus macaques are widely used as nonhuman primate models to study human pathogens, and so, considerable effort has been put into characterizing their KIR genetics. However, previous studies have relied on cDNA cloning and Sanger sequencing that lack the throughput of current sequencing platforms. In this study, we present a high throughput, full-length allele discovery method utilizing Pacific Biosciences circular consensus sequencing (CCS). We also describe a new approach to Macaque Exome Sequencing (MES) and the development of the Rhexome1.0, an adapted target capture reagent that includes macaque-specific capture probe sets. By using sequence reads generated by whole genome sequencing (WGS) and MES to inform primer design, we were able to increase the sensitivity of KIR allele discovery. We demonstrate this increased sensitivity by defining nine novel alleles within a cohort of Mauritian cynomolgus macaques (MCM), a geographically isolated population with restricted KIR genetics that was thought to be completely characterized. Finally, we describe an approach to genotyping KIRs directly from sequence reads generated using WGS/MES reads. The findings presented here expand our understanding of KIR genetics in MCM by associating new genes with all eight KIR haplotypes and demonstrating the existence of at least one KIR3DS gene associated with every haplotype. PMID- 28343242 TI - Identification of a polysaccharide produced by the pyruvate overproducer Candida glabrata CCTCC M202019. AB - Candida glabrata has great potential for the accumulation of pyruvate as a preferred strain in pyruvate production by fermentation. However, its substrate conversion rate is relatively low. In this study, a novel polysaccharide containing alpha-1,4-glucosidic bonds was observed accidentally in screening a high-titer pyruvate strain by atmospheric and room temperature plasma mutagenesis of C. glabrata. Chemical analysis of the partially purified polysaccharide S4-C10 showed the main components were 1.2% (w/w) protein and 94.2% (w/w) total sugar. Fourier transform infrared and molecular mass distribution analysis indicated that the main component (PSG-2) of S4-C10 was a small molecular homogeneous protein-bound polysaccharide. Monosaccharide analysis of PSG-2 showed it consisted of glucose, mannose, and fructose. By optimizing the vitamin mix content, 77.6 g L-1 S4-C10 polysaccharide could be obtained after 72 h fermentation at 30 degrees C in 500-mL flasks. RT-qPCR analysis showed that transcriptional level of some key genes related to polysaccharide biosynthesis was upregulated compared to that of wild-type strain. By knocking out two most significantly upregulated genes, CAGL0H02695g and CAGL0K10626g, in the wild-type strain, the pyruvate consumption rate was significantly reduced in late pyruvate fermentation phase, while the titer of polysaccharides was reduced by 18.0%. Besides the potential applications of the novel identified polysaccharide, this study provided clues for increasing the conversion ratio of glucose to pyruvate in C. glabrata by further decreasing the accumulation of polysaccharides. PMID- 28343243 TI - Fusarium species-a promising tool box for industrial biotechnology. AB - Global demand for biotechnological products has increased steadily over the years. Thus, need for optimized processes and reduced costs appear as a key factor in the success of this market. A process tool of high importance is the direct or indirect use of enzymes to catalyze the generation of various substances. Also, obtaining aromas and pigments from natural sources has becoming priority in cosmetic and food industries in order to supply the demand from consumers to substitute synthetic compounds, especially when by-products can be used as starting material for this purpose. Species from Fusarium genera are recognized as promising sources of several enzymes for industrial application as well as biocatalysts in the production of aromas, pigments and second generation biofuels, among others. In addition, secondary metabolites from these strains can present important biological activities for medical field. In this approach, this review brings focus on the use of Fusarium sp. strains in biotechnological production of compounds of industrial interest, showing the most recent researches in this area, results obtained and the best process conditions for each case. PMID- 28343244 TI - A New Reactive 1,8-Naphthalimide Derivative for Highly Selective and Sensitive Detection of Hg2. AB - A 1,8-naphthalimide derivative with a reactive aliphatic hydroxyl was designed and synthesized as a fluorescent probe. Its structure was characterized by IR, 1H NMR, 13C NMR, LC-MS and HPLC. The probe showed high selectivity and sensitivity to Hg2+ over other metal ions such as Pb2+, Na+, K+, Cd2+, Cr3+, Zn2+, Cu2+, Ni2+, Ca2+, Fe3+, Fe2+, Co2+, Mn2+ and Mg2+ in MeCN/H2O (15/85, v/v). The increase in fluorescence intensity was linearly proportional to the concentration of Hg2+ in the range of 18-40 MUM with a detection limit of 1.38 * 10-7 mol/L. The probe could work in a pH span of 4.3-9.0 and respond to Hg2+ quickly with strong anti-interference ability. Job's plot suggested a 1:2 complex of the probe and Hg2+. PMID- 28343245 TI - An Acid-Inert Fluorescent Probe for the Detection of Nitrite. AB - The fluorescent detection of nitrite ions has been challenging owing to the poor acid-stability of typical fluorescent probes. Herein, an acid-inert rhodamine based fluorescent probe has been developed for the fast detection of trace amount of nitrite ions with turn-on mode. The detection limit of nitrite ions was determined to be 9.4 nM (S/N = 3) and the linear range with high linear correlation was observed between 0.025 to 2.5 MUM. A test paper method was developed for rapid visual detection of nitrite ions. Quantitative analysis of two real water samples also confirmed the reliability and sensitivity of the developed fluorescent method. PMID- 28343246 TI - Sex Differences and Predictors of Changes in Body Weight and Noncommunicable Diseases in a Random, Newly-Arrived Group of Refugees Followed for Two Years. AB - We have reported that none of the psychological/mental variables examined predicted the increase in BMI and non-communicable diseases (NCDs) in Iraqi refugees after 1 year resettlement in Michigan. We continuously followed the same cohort of refugees for 2 years (Y2 FU) to further determine the gender difference in predicting of increased BMI and NCDs. Only 20% of the BMI variability could be accounted for by the factors examined. Number of dependent children and depression were positively and stress negatively associated with BMI in male refugees but not in females. Number of dependent children was negatively associated with changes in BMI and in males only. Two-third of the NCD variability was accounted for by gender, BMI, employment status, depression, posttraumatic stress disorders and coping skills. Unmarried, unemployed and with high PTSD scores at Y2 in males were positively and number of dependent children was negatively associated with NCD changes in females. Factors such as dietary patterns and lifestyle may have contributed to the increased BMI and NCDs in these refugees at 2 years post-settlement. PMID- 28343247 TI - Development of a QTL-environment-based predictive model for node addition rate in common bean. AB - KEY MESSAGE: This work reports the effects of the genetic makeup, the environment and the genotype by environment interactions for node addition rate in an RIL population of common bean. This information was used to build a predictive model for node addition rate. To select a plant genotype that will thrive in targeted environments it is critical to understand the genotype by environment interaction (GEI). In this study, multi-environment QTL analysis was used to characterize node addition rate (NAR, node day- 1) on the main stem of the common bean (Phaseolus vulgaris L). This analysis was carried out with field data of 171 recombinant inbred lines that were grown at five sites (Florida, Puerto Rico, 2 sites in Colombia, and North Dakota). Four QTLs (Nar1, Nar2, Nar3 and Nar4) were identified, one of which had significant QTL by environment interactions (QEI), that is, Nar2 with temperature. Temperature was identified as the main environmental factor affecting NAR while day length and solar radiation played a minor role. Integration of sites as covariates into a QTL mixed site-effect model, and further replacing the site component with explanatory environmental covariates (i.e., temperature, day length and solar radiation) yielded a model that explained 73% of the phenotypic variation for NAR with root mean square error of 16.25% of the mean. The QTL consistency and stability was examined through a tenfold cross validation with different sets of genotypes and these four QTLs were always detected with 50-90% probability. The final model was evaluated using leave-one-site-out method to assess the influence of site on node addition rate. These analyses provided a quantitative measure of the effects on NAR of common beans exerted by the genetic makeup, the environment and their interactions. PMID- 28343248 TI - Uncovering specific changes in network wiring underlying the primate cerebrotype. AB - Regular scaling of brain networks during evolution has been proposed to be the major process leading to enlarged brains. Alternative views, however, suggest that deviations from regular scaling were crucial to the evolution of the primate brain and the emergence of different cerebrotypes. Here, we examined the scaling within the major link between the cerebellum and the cerebral cortex by studying the deep cerebellar nuclei (DCN). We compared the major axonal and dendritic wiring in the DCN of rodents and monkeys in search of regular scaling. We were able to confirm regular scaling within the density of neurons, the general dendritic length per neuron and the Purkinje cell axon length. However, we also observed specific modification of the scaling rules within the primates' largest and phylogenetically newest DCN, the dentate nucleus (LN/dentate). Our analysis shows a deviation from regular scaling in the predicted dendritic length per neuron in the LN/dentate. This reduction in the dendritic length is also associated with a smaller dendritic region-of-influence of these neurons. We also detected specific changes in the dendritic diameter distribution, supporting the theory that there is a shift in the neuronal population of the LN/dentate towards neurons that exhibit spatially restricted, clustered branching trees. The smaller dendritic fields would enable a larger number of network modules to be accommodated in the primate LN/dentate and would provide an explanation for the unique folded structure of the primate LN/dentate. Our results show that, in some brain regions, connectivity maximization (i.e., an increase of dendritic fields) is not the sole optimum and that increases in the number of network modules may be important for the emergence of a divergent primate cerebrotype. PMID- 28343249 TI - Intraobserver and interobserver variability in CT angiography and MR angiography measurements of the size of cerebral aneurysms. AB - PURPOSE: Accurate and reliable measurement of aneurysm size is important for treatment planning. The purpose of this study was to determine intraobserver and interobserver variability of CTA and MRA for measurement of the size of cerebral aneurysms. METHODS: Thirty patients with 33 unruptured cerebral aneurysms (saccular, >3 mm in their maximal dimension, with no daughter sacs or lobulations) who underwent 256-row multislice CTA, 3-D TOF MRA at 3.0T, and 3D rotational angiography (3DRA) were retrospectively analyzed. Three independent observers measured the neck, height, and width of the aneurysms using the CTA and MRA images. Intraobserver and interobserver variability of CTA and MRA measurements was evaluated using the standardized difference and intraclass correlation coefficient, with 3DRA measurements as the reference standard. In addition, the mean values of the measurements using CTA and MRA were compared with those using 3DRA. RESULTS: The overall intraobserver and interobserver standardized differences in CTA/MRA were 12.83-15.92%/13.48-17.45% and 14.08 17.00%/12.08-17.67%, respectively. The overall intraobserver and interobserver intraclass correlation coefficients of CTA/MRA were 0.88-0.98/0.84-0.96 and 0.86 0.98/0.85-0.95, respectively. Compared to the height and width measurements, measurements of the neck dimensions showed higher intraobserver and interobserver variability. The sizes of the cerebral aneurysms measured by CTA and MRA were 1.13-9.26 and 5.20-9.67% larger than those measured by 3DRA, respectively; however, these differences were not statistically significant. CONCLUSION: There were no noticeable differences between intraobserver and interobserver variability for both CTA- and MRA-based measurements of the size of cerebral aneurysms. PMID- 28343250 TI - Apparent diffusion coefficient changes predict survival after intra-arterial bevacizumab treatment in recurrent glioblastoma. AB - PURPOSE: Superselective intra-arterial cerebral infusion (SIACI) of bevacizumab (BV) has emerged as a novel therapy in the treatment of recurrent glioblastoma (GB). This study assessed the use of apparent diffusion coefficient (ADC) in predicting length of survival after SIACI BV and overall survival in patients with recurrent GB. METHODS: Sixty-five patients from a cohort enrolled in a phase I/II trial of SIACI BV for treatment of recurrent GB were retrospectively included in this analysis. MR imaging with a diffusion-weighted (DWI) sequence was performed before and after treatment. ROIs were manually delineated on ADC maps corresponding to the enhancing and non-enhancing portions of the tumor. Cox and logistic regression analyses were performed to determine which ADC values best predicted survival. RESULTS: The change in minimum ADC in the enhancing portion of the tumor after SIACI BV therapy was associated with an increased risk of death (hazard ratio = 2.0, 95% confidence interval(CI) [1.04-3.79], p = 0.038), adjusting for age, tumor size, BV dose, and prior IV BV treatments. Similarly, the change in ADC after SIACI BV therapy was associated with greater likelihood of surviving less than 1 year after therapy (odds ratio = 7.0, 95% CI [1.08-45.7], p = 0.04). Having previously received IV BV was associated with increased risk of death (OR 18, 95% CI [1.8-180.0], p = 0.014). CONCLUSION: In patients with recurrent GB treated with SIACI BV, the change in ADC value after treatment is predictive of overall survival. PMID- 28343251 TI - Neurological aspects of chemical and biological terrorism: guidelines for neurologists. AB - This statement paper deals with the key role an neurologist plays in the management of victims of chemical warfare/terrorist attacks. Because terrorist factions have expanded the war zone creating a worldwide risk of terrorist attacks, not only limited to some conflict zones in the Middle East, neurologists in all countries/regions have to be prepared for disaster response. The scope of this paper is to provide guidelines for the neurological management of victims of chemical and biological terrorist attacks. PMID- 28343252 TI - Erratum to: Managing Cardiovascular Risk in Lysosomal Acid Lipase Deficiency. PMID- 28343253 TI - A pulsatile pharyngeal wall: case report and clinical relevance. PMID- 28343255 TI - Giving voice to African thought in medical research ethics. AB - In this article, I consider the virtual absence of an African voice and perspective in global discourses of medical research ethics against the backdrop of the high burden of diseases and epidemics on the continent and the fact that the continent is actually the scene of numerous and sundry medical research studies. I consider some reasons for this state of affairs as well as how the situation might be redressed. Using examples from the HIV/AIDS and Ebola epidemics, I attempt to show that the marginalization of Africa in medical research and medical research ethics is deliberate rather than accidental. It is causally related, in general terms, to a Eurocentric hegemony derived from colonialism and colonial indoctrination cum proselytization. I end by proposing seven theses for the critical reflection and appraisal of the reader. PMID- 28343254 TI - Dynamic measurements of cervical neural foramina during neck movements in asymptomatic young volunteers. AB - PURPOSE: Neural foraminal dimensions are considered important in nerve root compression and development of cervical radiculopathy, but baseline data regarding their range during normal motion are not available. An in vivo study of cervical foraminal motion was conducted to characterize normal 3D dynamic foraminal dimensions during physiological neck motion and compare between different tasks and intervertebral segments. METHODS: Biplane X-ray imaging and computed tomography-based markerless tracking were used to measure foraminal height (FH) and width (FW) from five asymptomatic subjects during neck axial rotation and extension. FH and FW were quantified as the minimum (SI.Min and AP.Min), range (SI.Range and AP.Range), and median (SI.Med and AP.Med) of superoinferior (SI) and anteroposterior (AP) dimensions for each trial and as the coefficient of variation of these variables from three trials (SI.Med.CV and AP.Med.CV, SI.Range.CV and AP.Range.CV) at C3-4 through C6-7 levels for each subject. Differences were analyzed using mixed model ANOVA. RESULTS: AP.Range and AP.Med.CV were greater (P < 0.0001) while AP.Min and AP.Range.CV were smaller (P < 0.0006 and P < 0.0005) during neck extension than rotation. SI.Range and SI.Med.CV were greater for extension than rotation at C5-6 (P < 0.002 and P < 0.03), whereas SI.Med.CV was greater for rotation than extension at C3-4 (P < 0.03). AP.Range (P < 0.02), AP.Med.CV (P < 0.05), SI.Range (P < 0.0004), and SI.Med.CV (P < 0.02) were different between cervical levels, the latter two being during extension only. CONCLUSIONS: Patterns of FH and FW during normal motion are different between tasks and cervical levels. These findings are expected to provide a basis for future studies of spinal degeneration and surgical efficacy. PMID- 28343256 TI - Spatiotemporal deep imaging of syncytium induced by the soybean cyst nematode Heterodera glycines. AB - Parasite infections cause dramatic anatomical and ultrastructural changes in host plants. Cyst nematodes are parasites that invade host roots and induce a specific feeding structure called a syncytium. A syncytium is a large multinucleate cell formed by cell wall dissolution-mediated cell fusion. The soybean cyst nematode (SCN), Heterodera glycines, is a major soybean pathogen. To investigate SCN infection and the syncytium structure, we established an in planta deep imaging system using a clearing solution ClearSee and two-photon excitation microscopy (2PEM). Using this system, we found that several cells were incorporated into the syncytium; the nuclei increased in size and the cell wall openings began to be visible at 2 days after inoculation (DAI). Moreover, at 14 DAI, in the syncytium developed in the cortex, there were thickened concave cell wall pillars that resembled "Parthenon pillars." In contrast, there were many thick board-like cell walls and rarely Parthenon pillars in the syncytium developed in the stele. We revealed that the syncytia were classified into two types based on the pattern of the cell wall structures, which appeared to be determined by the position of the syncytium inside roots. Our results provide new insights into the developmental process of syncytium induced by cyst nematode and a better understanding of the three-dimensional structure of the syncytium in host roots. PMID- 28343257 TI - Leaf ontogeny of Schinus molle L. plants under cadmium contamination: the meristematic origin of leaf structural changes. AB - Previous works show the development of thicker leaves on tolerant plants growing under cadmium (Cd2+) contamination. The aim of this study was to evaluate the Cd2+ effects on the leaf meristems of the tolerant species Schinus molle. Plants were grown in nutrient solution containing 0, 10, and 50 MUM of Cd2+. Anatomical analysis was performed on leaf primordia sampled at regular time intervals. Under the lowest Cd2+ level (10 MUM), increased ground meristem thickness, diameter of the cells, cell elongation rate, and leaf dry mass were found. However, 50 MUM of Cd2+ reduced all these variables. In addition, the ground meristem cells became larger when exposed to any Cd2+ level. The epidermis, palisade parenchyma, and vascular tissues developed earlier in Cd2+-exposed leaves. The modifications found on the ground meristem may be related to the development of thicker leaves on S. molle plants exposed to low Cd2+ levels. Furthermore, older leaves showed higher Cd2+ content when compared to the younger ones, preventing the Cd2+ toxicity to these leaves. Thus, low Cd2+ concentrations change the ground meristem structure and function reflecting on the development of thicker and enhanced leaves. PMID- 28343258 TI - Variation of antibiotic consumption and its correlated factors in Turkey. AB - BACKGROUND: Presentation of antibiotic utilization data by reliable and comparable analyses constitutes an important way of ensuring rational use of antibiotics. This study aimed to evaluate antibiotic consumption (AC) of Turkey by each city/region and to investigate any association of such consumption with socio-economic factors. METHOD: For 81 provinces and 12 regions in Turkey, AC data from IMS (Intercontinental Medical Statistics) in 2011 was analyzed in accordance with "ATC/DDD, DID" (Anatomical Therapeutic Chemical/Defined Daily Doses, DID = DDD/1000 inhabitants/day) methodology supported by World Health Organization. Association between provincial AC rates and socio-economic development index (SEDI)-2011 and between regional AC rates and some health indicators were analyzed. RESULTS: While provincial AC data of Turkey was detected to vary between 17.2 and 55.2 DID (Hakkari and Usak, respectively), regional AC ranged from 28.4 to 48.9 DID (Middle Eastern Anatolia and Western Anatolia, respectively). Mostly consumed antibiotic group among all regions were beta-lactamase inhibitor/penicillin combinations (range: 9.9-17.6 DID). SEDI and AC of each city showed positive correlation (rho = 0.683, p < 0.001). While regional AC was positively associated with percentage of 14-year-old population (p = 0.002) and pharmacist density (p < 0.001), it was negatively associated with physician density (p = 0.038). CONCLUSION: It is remarkable that Turkey, at both provincial and regional levels, exhibits important variations in AC, which is proportional to socio-economic status. Besides, the consumption is found to be closely associated with recognized critical factors of access to healthcare. These findings are expected to provide important insights to the activities promoting rational use of antibiotics. PMID- 28343259 TI - Numerical and experimental analysis of the transitional flow across a real stenosis. AB - In this paper, we present a numerical study of the pulsatile transitional flow crossing a severe real stenosis located right in front of the bifurcation between the right subclavian and right common carotid arteries. The simulation allows one to determine relevant features of this subject-specific flow, such as the pressure waves in the right subclavian and right common carotid arteries. We explain the subclavian steal syndrome suffered by the patient in terms of the drastic pressure drop in the right subclavian artery. This pressure drop is caused by both the diverging part of the analyzed stenosis and the reverse flow in the bifurcation induced by another stenosis in the right internal carotid artery. PMID- 28343260 TI - Urethral lumen occlusion by artificial sphincteric devices: a computational biomechanics approach. AB - The action induced by artificial sphincteric devices to provide urinary continence is related to the problem of evaluating the interaction between the occlusive cuff and the urethral duct. The intensity and distribution of the force induced within the region of application determine a different occlusion process and potential degradation of the urethral tissue, mostly at the borders of the cuff. This problem is generally considered in the light of clinical and surgical operational experience, while a valid cooperation is established with biomechanical competences by means of experimental and numerical investigation. A three-dimensional model of the urethra is proposed aiming at a representation of the phases of the urethral occlusion through artificial sphincters. Different conformations of the cuff are considered, mimicking different loading conditions in terms of force intensity and distribution and consequent deformation caused in soft tissues. The action induced in the healthy urethra is investigated, as basis for an evaluation of the efficacy and reliability of the sphincteric devices. The problem is characterized by coupled nonlinear geometric and material problem and entails a complex constitutive formulation. A heavy computational procedure is developed by means of analyses that operate within an explicit finite element formulation. Results reported outline the overall response of the urethral duct during lumen occlusion, leading to an accurate description of the phenomenon in the different phases. PMID- 28343261 TI - Stress Processes Linking Parent-Child Disconnection to Disease Risk in Young Adulthood: Amplification by Genotype. AB - Previous studies have documented that early stressful family relationships influence subsequent stressful life circumstances and health outcomes over the life course. Less is known, however, about whether stressful parent-child relationships increase the influence of proximal stressors on youth health operating as a stress-sensitizing life context, and individual genetic variations have effects on these developmental processes. Informed by life course stress process theory, which focuses on the proliferation, accumulation, and interactions of stressors over the life course as health risks, we examined whether (a) parent-child disconnection influences the occurrence of stressful life events in young adulthood, (b) parent-child disconnection potentiates the impact of stressful life events on young adults' health, or (c) potential health impact is intensified further by individual genotype. Using longitudinal data from a nationally representative sample of 11,290 adolescents (Mean age 15.5 years, 53% female) over a period of 13 years, we found parent-child disconnection influenced young adults' stressful life events and amplified the impact of stressful life events on cardio-metabolic disease risk. We also found the association between stressful life events and cardio-metabolic disease risk was further intensified by the 5-HTTLPR polymorphism. Our findings demonstrate that stressful family relationships not only initiate stress processes over the early life course, but also sensitize youth to stressors, and that 5-HTTLPR polymorphism interacts with stressful life experiences to predict heightened disease risk. PMID- 28343262 TI - Cavin-1 deficiency modifies myocardial and coronary function, stretch responses and ischaemic tolerance: roles of NOS over-activity. AB - Caveolae and associated cavin and caveolins may govern myocardial function, together with responses to mechanical and ischaemic stresses. Abnormalities in these proteins are also implicated in different cardiovascular disorders. However, specific roles of the cavin-1 protein in cardiac and coronary responses to mechanical/metabolic perturbation remain unclear. We characterised cardiovascular impacts of cavin-1 deficiency, comparing myocardial and coronary phenotypes and responses to stretch and ischaemia-reperfusion in hearts from cavin-1 +/+ and cavin-1 -/- mice. Caveolae and caveolins 1 and 3 were depleted in cavin-1 -/- hearts. Cardiac ejection properties in situ were modestly reduced in cavin-1 -/- mice. While peak contractile performance in ex vivo myocardium from cavin-1 -/- and cavin-1 +/+ mice was comparable, intrinsic beating rate, diastolic stiffness and Frank-Starling behaviour (stretch-dependent diastolic and systolic forces) were exaggerated in cavin-1 -/- hearts. Increases in stretch dependent forces were countered by NOS inhibition (100 uM L-NAME), which exposed negative inotropy in cavin-1 -/- hearts, and were mimicked by 100 uM nitroprusside. In contrast, chronotropic differences appeared largely NOS independent. Cavin-1 deletion also induced NOS-dependent coronary dilatation, >=3 fold prolongation of reactive hyperaemic responses, and exaggerated pressure dependence of coronary flow. Stretch-dependent efflux of lactate dehydrogenase and cardiac troponin I was increased and induction of brain natriuretic peptide and c-Fos inhibited in cavin-1 -/- hearts, while ERK1/2 phospho-activation was preserved. Post-ischaemic dysfunction and damage was also exaggerated in cavin-1 /- hearts. Diverse effects of cavin-1 deletion reveal important roles in both NOS dependent and -independent control of cardiac and coronary functions, together with governing sarcolemmal fragility and myocardial responses to stretch and ischaemia. PMID- 28343263 TI - Genotypic and pathogenic characterization of genotype VII Newcastle disease viruses isolated from commercial farms in Egypt and evaluation of heterologous antibody responses. AB - Newcastle disease viruses (NDV) represent a major threat to poultry production worldwide. Recently in Egypt NDV circulated extensively, even in vaccinated farms. In the present study samples were collected from sixteen vaccinated broiler farms in animals exhibiting the typical gross lesions of NDV. Virus isolation and pathogenicity studies for positive samples were carried out in accordance to reference procedures and phylogenetic analysis was carried out based on partial sequences of the Fusion gene. Furthermore, in vivo investigation of the ability of heterologous antibody, induced by commercially available lentogenic strain-based vaccines, to efficiently reduce viral shedding was examined. Results revealed that all the sixteen farms were positive for the presence of NDV. Out of these fifteen were confirmed to due to velogenic viruses, based on a main death time (MDT) <= 48 hours and partial sequencing of the F gene that showed the presence of a polybasic amino acid motif. However, three patterns in the cleavage site of these velogenic viruses were identified in the present study. Phylogenetic analysis revealed that all fifteen isolates were clustered with class II genotype VIIb while the remaining isolate (B81) was class II genotype II. Results of the in vivo study revealed that adequate heterologous antibody levels, induced by the proposed vaccination program, sufficiently protected birds from morbidity and mortality. However, virus shedding was quantitatively affected in relation to the time of challenge after vaccination. Altogether, with an absence of vaccines able to induce homologous antibody to the presently circulating viruses, higher antibody levels, which depend on efficient and timely implementation of the vaccination program, are considered as highly important in relation to the reduction of virus shedding. PMID- 28343264 TI - Modulating the pH Activity Profiles of Phenylalanine Ammonia Lyase from Anabaena variabilis by Modification of Center-Near Surface Residues. AB - Phenylalanine ammonia lyase from Anabaena variabilis (Av-PAL) is a candidate for the treatment of phenylketonuria (PKU). However, Av-PAL shows its optimal pH at 8.5 and maintains only 70% of its highest activity when pH decreases to 7.3-7.4 (the condition of human plasma). The objective of the study was to shift its optimal pH by mutating surface amino acid residues which interact with the general base Tyr78. Based on the crystal structure and the online program GETAREA, we selected five sites: Asn69, Glu72, Glu75, Asn89, and Val90. Removing negative charges or introducing positive charges near the general base Tyr78 by mutation, the pH optima were successfully shifted to more acidic range. Especially, the pH optima of E75A, E75L, and E75Q were shifted to 7.5 with 35, 30, and 24% higher specific activities than that of the wild, respectively. Half lives of E75L and E75Q at 70 degrees C prolonged to 190 and 180 min from 130 min of the wild, respectively. In addition, the higher resistance to a low pH of 3.5 and protease made E75L a candidate for oral medicine of PKU. This work would improve the therapeutic prospect of Av-PAL and provide guidance in modulating optimal pH of enzymes. PMID- 28343265 TI - Effect of 10% cerium chloride on artificial caries lesions of human enamel evaluated using quantitative light-induced fluorescence: an in vitro study. AB - AIM: To evaluate the effect of 10% cerium chloride intervention on pre demineralised human enamel subjected to cycles of de- and remineralisation. METHODS: This was an in vitro, comparative type study of 60 human enamel samples that were randomly divided into control and test groups. The samples were then subjected to a cycle of demineralisation followed by intervention with respective treatment solutions (control group: placebo solution; test: 10% cerium chloride) for 30 s under constant agitation and then to a 2nd cycle of demineralisation followed by remineralisation using artificial saliva. After the first and second cycles of demineralisation (4th and 8th day) and a cycle of remineralisation (22nd day), the samples were evaluated for fluorescence values using a quantitative light-induced fluorescence camera. The data was analysed using paired t test and ANOVA. RESULTS: Comparing the fluorescence values and mean difference of lesion area between the first cycle of demineralisation to the cycle of remineralisation and the second cycle of demineralisation to the cycle of remineralisation, the test group showed a statistically significant reduction in loss of fluorescence values and lesion area compared to the control group (p < 0.001). Mean fluorescence values and lesion area comparison between cycles of de- and remineralisation for control and test groups (inter-group comparison) showed a statistically significant difference (p < 0.001). CONCLUSIONS: Cerium chloride alone reduced demineralisation and improved remineralisation of artificial caries lesions in human enamel when subjected to pH cycling in vitro. PMID- 28343266 TI - The influence of general health on the need for dental general anaesthesia in children. AB - AIM: To analyse the occurrence and causes of dental general anaesthesia (DGA) in healthy and medically compromised children, and to investigate if there are differences between those groups considering factors associated with DGA and DGA procedures. METHODS: The data was collected from medical records of children under 7 years of age treated under DGA in the years 2009 and 2010 at the Oulu University Hospital, Finland. The children were divided into two groups: 0-35 month-olds and >=36-month olds. Background information (year, age, gender, dental diagnosis, health) and the procedures performed were registered. The procedures were analysed considering the child's age and tooth types. RESULTS: The number of children treated under DGA increased between 2009 (58) and 2010 (82), particularly in the group of healthy children. The two main diagnoses leading to DGA were dental caries and dental fear. Dental caries as the first dental diagnosis leading to DGA was more common among the medically compromised children (61.5%) compared to the healthy children (38.6%). The procedures performed were similar among the two groups. However, they varied between the age groups and tooth types and even between upper and lower teeth. The medically compromised children had been treated more frequently under DGA in the past. CONCLUSIONS: The threshold for treating medically compromised children under DGA seems to be lower than for healthy children. However, the occurrence of DGA among healthy children has increased recently. To avoid unnecessary DGA, the control of caries should be carried out according to individual needs and independent of whether the child is healthy or has a chronic disease. PMID- 28343267 TI - Tumor-Associated Macrophages and Regulatory T Cells Infiltration and the Clinical Outcome in Colorectal Cancer. AB - The aim of the study is the assessment of the intensity of the infiltration of tumor-associated macrophages (TAMs) CD68+/iNOS- and Tregs CD8+/FoxP3+ in colorectal cancer (CRC) patients as prognostic factors with respect to disease free survival (DFS) and overall survival (OS). In this retrospective study, tissue samples were obtained from 89 patients undergoing resection for CRC (stage IIA, pT3N0M0 and stages IIIB and IIIC, pT3N1-2M0). Recurrence was observed in 45 patients at the time of the follow-up (10 local recurrences, 35 distant metastases). In patients with recurrence the following were present: a tendency to an older average age at the time of diagnosis (p = 0.07), higher nodal involvement (p = 0.002) and more advanced clinical disease (p = 0.01). The analysis of the clinical data and immunohistochemical studies were performed with the methodology of identification of TAM and Treg subsets in histological sections, with the aim to use it in routine clinical management. Both DSF and OS were the clinical parameters assessed in the study. The presence of intense infiltration of TAMs in the tumor stroma was related to shorter DFS (p = 0.005) and OS (p = 0.006). The opposite tendency was observed in the tumor front (p = 0.061). The relative risks of recurrence and cancer-related death were more than twice higher in the group of patients with intense infiltration of TAMs in the tumor stroma (RR 2.05, 95% CI 1.33-3.14; p = 0.001 and RR 2.08, 95% CI 1.28-3.39; p = 0.003, respectively). Intense infiltration of Tregs in the tumor stroma was related to shorter DFS and OS (p < 0.0001). The relative risks of recurrence and death in a group of patients with intense infiltration of Tregs in the tumor stroma were more than 12 times higher than in patients with less intense infiltration (RR 12.3, 95% CI 5.44-27.9; p < 0.0001 and RR 12.5, 95% CI 4.9-32.4; p < 0.0001, respectively). Infiltration of TAMs CD68+/iNOS- and Tregs CD8+/FoxP3+ in the tumor stroma are negative prognostic factors with a positive correlation between them. Tregs may constitute an independent prognostic factor in patients with CRC. PMID- 28343269 TI - Neophobia is negatively related to reversal learning ability in females of a generalist bird of prey, the Chimango Caracara, Milvago chimango. AB - In an ever-changing environment, the ability to adapt choices to new conditions is essential for daily living and ultimately, for survival. Behavioural flexibility allows animals to maximise survival and reproduction in novel settings by adjusting their behaviour based on specific information and feedback acquired in their current environments. However, a growing body of evidence indicates that an individual's personality type can limit the extent to which the individual might behave flexibly, by influencing the way an individual pays attention to novelty and how much information it collects and stores, which in turn affects the individual's decision-making and learning process. In this study, the behavioural flexibility of a generalist predator, the Chimango Caracara, Milvago chimango, was analysed using the reversal learning paradigm, focusing on the comparison between age classes, and the relation of learning flexibility with a personality trait, the level of neophobia. Due to the low number of male individuals captured, this study was carried out only with female birds. The results showed that age had no significant effect either on the acquisition of a stimulus-reward association, or on the capacity of reversing this previously learned association. Reversal of the response was a harder task for these birds in comparison with the initial acquisition process. The individual's performances in the learning tasks seemed to be uncorrelated with each other, suggesting that they involve different neural mechanisms. Contrary to the general pattern observed in the majority of previous work on personality and cognition in non-human animals, the level of neophobia did not correlate with the initial associative learning performance in both adults and juveniles, yet it showed a significant negative relationship with reversal learning ability, mainly in the regressive phase of this task, for the two age classes. Our results suggest that the predatory and generalist lifestyle of female individuals of M. chimango along with the selective pressures of the environment of the individuals studied might play a critical role in the degree and direction of the linkage between novelty response and learning flexibility observed in this study. PMID- 28343270 TI - Magnetic field discrimination, learning, and memory in the yellow stingray (Urobatis jamaicensis). AB - Elasmobranch fishes (sharks, skates, and rays) have been hypothesized to use the geomagnetic field as a cue for orienting and navigating across a wide range of spatial scales. Magnetoreception has been demonstrated in many invertebrate and vertebrate taxa, including elasmobranchs, but this sensory modality and the cognitive abilities of cartilaginous fishes are poorly studied. Wild caught yellow stingrays, Urobatis jamaicensis (N = 8), underwent conditioning to associate a magnetic stimulus with a food reward in order to elicit foraging behaviors. Behavioral conditioning consisted of burying magnets and non-magnetic controls at random locations within a test arena and feeding stingrays as they passed over the hidden magnets. The location of the magnets and controls was changed for each trial, and all confounding sensory cues were eliminated. The stingrays learned to discriminate the magnetic stimuli within a mean of 12.6 +/- 0.7 SE training sessions of four trials per session. Memory probes were conducted at intervals between 90 and 180 days post-learning criterion, and six of eight stingrays completed the probes with a >=75% success rate and minimum latency to complete the task. These results show the fastest rate of learning and longest memory window for any batoid (skate or ray) to date. This study demonstrates that yellow stingrays, and possibly other elasmobranchs, can use a magnetic stimulus as a geographic marker for the location of resources and is an important step toward understanding whether these fishes use geomagnetic cues during spatial navigation tasks in the natural environment. PMID- 28343268 TI - Cytogenetic comparison of heteromorphic and homomorphic sex chromosomes in Coccinia (Cucurbitaceae) points to sex chromosome turnover. AB - Our understanding of the evolution of plant sex chromosomes is increasing rapidly due to high-throughput sequencing data and phylogenetic and molecular-cytogenetic approaches that make it possible to infer the evolutionary direction and steps leading from homomorphic to heteromorphic sex chromosomes. Here, we focus on four species of Coccinia, a genus of 25 dioecious species, including Coccinia grandis, the species with the largest known plant Y chromosome. Based on a phylogeny for the genus, we selected three species close to C. grandis to test the distribution of eight repetitive elements including two satellites, and several plastid and mitochondrial probes, that we had previously found to have distinct accumulation patterns in the C. grandis genome. Additionally, we determined C-values and performed immunostaining experiments with (peri-)centromere-specific antibodies on two species (for comparison with C. grandis). In spite of no microscopic chromosomal heteromorphism, single pairs of chromosomes in male cells of all three species accumulate some of the very same repeats that are enriched on the C. grandis Y chromosome, pointing to either old (previous) sex chromosomes or incipient (newly arising) ones, that is, to sex chromosome turnover. A 144-bp centromeric satellite repeat (CgCent) that characterizes all C. grandis chromosomes except the Y is highly abundant in all centromeric regions of the other species, indicating that the centromeric sequence of the Y chromosome diverged very recently. PMID- 28343271 TI - Protein degradation systems in the skeletal muscles of parr and smolt Atlantic salmon Salmo salar L. and brown trout Salmo trutta L. AB - Although protein degradation limits the rate of muscle growth in fish, the role of proteolytic systems responsible for degrading myofibrillar proteins in skeletal muscle is not well defined. The study herein aims to evaluate the role of calpains (calcium-activated proteases) and proteasomes (ATP-dependent proteases) in mediating muscle protein turnover at different life stages in wild salmonids. Protease activities were estimated in Atlantic salmon (Salmo salar L.) and brown trout (Salmo trutta L.) parr and smolts from the Indera River (Kola Peninsula, Russia). Calpain and proteasome activities in Atlantic salmon skeletal muscles were lower in smolts as compared with parr. Reduced muscle protein degradation accompanying Atlantic salmon parr-smolt transformation appeared to provide intense muscle growth essential for a minimum threshold size achievement that is required for smoltification. Calpain and proteasome activities in brown trout parr and smolts at age 3+ did not significantly differ. However, calpain activity was higher in smolts brown trout 4+ as compared with parr, while proteasome activity was lower. Results suggest that brown trout smoltification does not correspond with intense muscle growth and is more facultative and plastic in comparison with Atlantic salmon smoltification. Obtained data on muscle protein degradation capacity as well as length-weight parameters of fish reflect differences between salmon and trout in growth and smoltification strategies. PMID- 28343273 TI - Pharmacokinetic comparison of cyclosporin A and tacrolimus in graft-versus-host disease prophylaxis. AB - A number of studies were published with contradictory results comparing tacrolimus (Tac) and cyclosporine A (CsA) for graft-versus-host disease (GVHD) prophylaxis, but there are only few that accounted for pharmacokinetic (PK) parameters. In this study, we created a model based on median concentrations, variability of concentrations, and failures to maintain target levels that distinguished patients with low, intermediate, and high risks of acute GVHD (hazard ratios (HR) 1.77, 95%CI 1.36-2.32, p < 0.0001). This model was used to compare 95 patients with CsA and 239 with Tac GVHD prophylaxis. In the multivariate analysis, incorporating PK risk, no differences were observed for grade II-IV acute GVHD (HR 0.73, 95%CI 0.48-1.10, p = 0.13), but grade III-IV acute GVHD was lower in the Tac group (HR 0.47, 95%CI 0.28-0.78, p = 0.004). The observed difference was due to patients with high PK risk (HR 0.377, 95%CI 0.19 0.75, p = 0.005), but not with low and intermediate PK risk (p > 0.05). Patients in the Tac group had better GVHD relapse-free survival (HR = 0.659, p = 0.01) and comparable overall survival (p > 0.05). In conclusion, PK risk should be accounted for in comparisons of GVHD prophylaxis regimens with calcineurin inhibitors, and Tac was superior to CsA in patients with high, but not intermediate and low PK risk. PMID- 28343272 TI - Effect of ATRA and ATO on the expression of tissue factor in NB4 acute promyelocytic leukemia cells and regulatory function of the inflammatory cytokines TNF and IL-1beta. AB - The characteristic hemorrhages of acute promyelocytic leukemia (APL) are caused in part by the high expression of tissue factor (TF) on leukemic cells, which also produce TNF and IL-1beta, proinflammatory cytokines known to increase TF in various cell types. Exposure of NB4 cells, an APL cell line, to all-trans retinoic acid (ATRA) or arsenic trioxide (ATO) rapidly and strongly reduced TF mRNA. Both drugs also reduced TNF mRNA, but later, and moreover increased IL 1beta mRNA. The effect on procoagulant activity of cells and microparticles, as measured with calibrated automated thrombography, was delayed and only partial at 24 h. TNF and IL-1beta inhibition reduced TF mRNA and activity only partially. Inhibition of the inflammatory signaling intermediate p38 reduced TF mRNA by one third but increased TNF and IL-1beta mRNA. NF-kappaB inhibition reduced, within 1 h, TF and TNF mRNA but did not change IL-1beta mRNA, and rapidly and markedly reduced cell survival, with procoagulant properties still being present. In conclusion, although we provide evidence that TNF, IL-1beta, and their signaling intermediates have a regulatory function on TF expression by NB4 APL cells, the effect of ATRA and ATO on TF can only partially be accounted for by their impact on these cytokines. PMID- 28343274 TI - Predictive score of haematological toxicity in patients treated with linezolid. AB - OBJECTIVE: The aims of our study were to determine the factors associated with developing haematological toxicity (HT) in patients taking linezolid (LZD), to develop a predictive model of HT in these patients, and to evaluate factors associated with 30-day mortality. METHODS: This was an observational retrospective cohort study of patients treated for at least 5 days with LDZ in 2015. Demographic, clinical and analytical data were collected. Development of HT was defined as a 25% platelet count decrease between the basal count and the 1 week lab test. RESULTS: Five hundred forty-nine patients were finally included, mean age was 73.3 (SD 15.4) years, and 303 (55.2%) were men. One hundred seventy five (30.1%) patients achieved HT criteria during treatment with LZD and 41 (7.5%) died. The final model included the presence of cerebrovascular disease (2 points), moderate or severe liver disease (2 points), renal failure (2 points) and basal platelet count less than 90,000/mm3 (8 points). This new model showed an AUC of 0.711 (IC 95% 0.664-0.757; p < 0.001) to predict the development of HT. The probability of HT based on this classification was 6.2, 29.9 and 76.5% for low (0-4 points), intermediate (5-10 points) and high risk (>10 points), respectively. The independent variables associated with 30-day mortality were metastatic solid tumor, lymphoma, age >75 years and HT. CONCLUSION: This score could help in the identification of patients with high risk for HT and assess the use of an antibiotic other than LZD, an important issue considering its relation with 30-day mortality observed in our study. PMID- 28343275 TI - Potential toxic elements in stream sediments, soils and waters in an abandoned radium mine (central Portugal). AB - The Alto da Varzea radium mine (AV) exploited ore and U-bearing minerals, such as autunite and torbernite. The mine was exploited underground from 1911 to 1922, closed in 1946 without restoration, and actually a commercial area is deployed. Stream sediments, soils and water samples were collected between 2008 and 2009. Stream sediments are mainly contaminated in As, Th, U and W, which is related to the AV radium mine. The PTEs, As, Co, Cr, Sr, Th, U, W, Zn, and electrical conductivity reached the highest values in soils collected inside the mine influence. Soils are contaminated with As and U and must not be used for any purpose. Most waters have pH values ranging from 4.3 to 6.8 and are poorly mineralized (EC = 41-186 uS/cm; TDS = 33-172 mg/L). Groundwater contains the highest Cu, Cr and Pb contents. Arsenic occurs predominantly as H2(AsO4)- and H(AsO4)2-. Waters are saturated in goethite, haematite and some of them also in lepidocrocite and ferrihydrite, which adsorbs As (V). Lead is divalent in waters collected during the warm season, being mobile in these waters. Thorium occurs mainly as Th(OH)3(CO3)-, Th(OH)2(CO3) and Th(OH)2(CO3) 22- , which increase water Th contents. Uranium occurs predominantly as UO2CO3, but CaUO2(CO3) 32- and CaUO2(CO3)3 also occur, decreasing its mobility in water. The waters are contaminated in NO2-, Mn, Cu, As, Pb and U and must not be used for human consumption and in agricultural activities. The water contamination is mainly associated with the old radium mine and human activities. A restoration of the mining area with PTE monitoring is necessary to avoid a public hazard. PMID- 28343276 TI - An updated review of cardiac devices in heart failure. AB - BACKGROUND: Heart failure has the highest rates of adult hospitalisations, the highest mortality rates and significant costs associated with its care. The cost of heart failure is expected continue to grow on a global scale, with $108 billion spent on heart failure in 2012. Mortality rates are high, with incident cases of heart failure resulting in 30% 1-year mortality, and in hospital mortality of acute heart failure, 28%. METHODS AND RESULTS: This article reviews the devices currently in use for the treatment of heart failure, as well as those that are under investigation. A review of the mechanism of action of devices, the literature supporting their application as therapy, and the cost effectiveness associated with their use are discussed. Conventional techniques discussed herein include the guideline-supported therapies of mechanical circulatory support (MCS) and cardiac resynchronisation therapy (CRT). Novel devices that are discussed include invasive physiological monitoring, neuromodulation, percutaneous ventricular assist devices (VADs) and cardiac contractility modulation (CCM). There has been advancement in mechanical circulatory support devices for the treatment of both acute and chronic heart failure. In addition to MCS, only CRT has resulted in reduced mortality. CONCLUSION: Due to the clinical and economic arguments, treatment of heart failure is said to be the biggest unmet need in cardiology today. The data reviewed herein support this statement. PMID- 28343278 TI - The Berlin Declaration: building upon St Vincent. PMID- 28343277 TI - Pancreatic alpha cell-selective deletion of Tcf7l2 impairs glucagon secretion and counter-regulatory responses to hypoglycaemia in mice. AB - AIMS/HYPOTHESIS: Transcription factor 7-like 2 (TCF7L2) is a high mobility group (HMG) box-containing transcription factor and downstream effector of the Wnt signalling pathway. SNPs in the TCF7L2 gene have previously been associated with an increased risk of type 2 diabetes in genome-wide association studies. In animal studies, loss of Tcf7l2 function is associated with defective islet beta cell function and survival. Here, we explore the role of TCF7L2 in the control of the counter-regulatory response to hypoglycaemia by generating mice with selective deletion of the Tcf7l2 gene in pancreatic alpha cells. METHODS: Alpha cell-selective deletion of Tcf7l2 was achieved by crossing mice with floxed Tcf7l2 alleles to mice bearing a Cre recombinase transgene driven by the preproglucagon promoter (PPGCre), resulting in Tcf7l2AKO mice. Glucose homeostasis and hormone secretion in vivo and in vitro, and islet cell mass were measured using standard techniques. RESULTS: While glucose tolerance was unaffected in Tcf7l2AKO mice, glucose infusion rates were increased (AUC for glucose during the first 60 min period of hyperinsulinaemic-hypoglycaemic clamp test was increased by 1.98 +/- 0.26-fold [p < 0.05; n = 6] in Tcf7l2AKO mice vs wild-type mice) and glucagon secretion tended to be lower (plasma glucagon: 0.40 +/- 0.03-fold vs wild-type littermate controls [p < 0.01; n = 6]). Tcf7l2AKO mice displayed reduced fasted plasma glucose concentration. Glucagon release at low glucose was impaired in islets isolated from Tcf7l2AKO mice (0.37 +/- 0.02-fold vs islets from wild-type littermate control mice [p < 0.01; n = 6). Alpha cell mass was also reduced (72.3 +/- 20.3% [p < 0.05; n = 7) in Tcf7l2AKO mice compared with wild-type mice. CONCLUSIONS/INTERPRETATION: The present findings demonstrate an alpha cell-autonomous role for Tcf7l2 in the control of pancreatic glucagon secretion and the maintenance of alpha cell mass and function. PMID- 28343279 TI - The independent influences of heat strain and dehydration upon cognition. AB - PURPOSE: Many researchers have addressed the potential effects of hyperthermia and dehydration on cognition, often revealing contradictory outcomes. A possible reason for this inconsistency is that experiments may have been inadequately designed for such effects. In this study, the impact of hyperthermia, dehydration and their combination on cognition were evaluated in eight young males, after accounting for a range of experimental limitations. METHODS: Passive heating and thermal clamping at two mean body temperatures (36.5, 38.5 degrees C) were performed under three hydration states (euhydrated, 3 and 5% dehydrated) to assess their effects on difficulty-matched working memory and visual perception tasks, and on a difficulty manipulated perceptual task. Data were analysed according to signal detection theory to isolate changes in response sensitivity, bias and speed. RESULTS: Neither moderate hyperthermia (P = 0.141) nor dehydration (P > 0.604) modified response sensitivity, nor did they significantly interact (P > 0.698). Therefore, the ability to distinguish correct from incorrect responses was unaffected. Nevertheless, hyperthermia, but not dehydration (P = 0.301), reduced the response bias (-0.08 versus 2.2 [normothermia]; P = 0.010) and reaction time (mean reduction 49 ms; P < 0.001), eliciting more liberal and faster responses (P = 0.010). Response bias was reduced for the memory relative to the perceptual task (P = 0.037), and this effect was enhanced during hyperthermia (P = 0.031). CONCLUSIONS: These observations imply that, once potentially confounding influences were controlled, moderate hyperthermia, significant dehydration and their combined effects had insufficient impact to impair cognition within the memory and perceptual domains tested. Nonetheless, moderate hyperthermia elicited more liberal and rapid responses. PMID- 28343280 TI - Relationships between work-related factors and musculoskeletal health with current and future work ability among male workers. AB - PURPOSE: The purpose was to increase job-specific knowledge about individual and work-related factors and their relationship with current and future work ability (WA). We studied cross-sectional relationships between mental demands, physical exertion during work, grip strength, musculoskeletal pain in the upper extremities and WA and the relationships between these variables and WA 11 years later. METHODS: We used a dataset of a prospective cohort study (1997-2008) among employees of an engineering plant (n = 157). The cohort was surveyed by means of tests and written questions on work demands, musculoskeletal health, WA score (WAS; 0-10), and mental and physical WA. Spearman correlation coefficients and logistic regression analysis were used. RESULTS: Among manual workers, we found weak correlations between grip strength and current and future physical WA. We did not find predictors for future poor WA among the manual workers. Among the office workers, we found that musculoskeletal pain was moderately and negatively related to current WAS and physical WA. More handgrip strength related to better future WAS and physical WA. Musculoskeletal pain (OR 1.67 p < 0.01) and lower handgrip strength (OR 0.91 p < 0.05) predicted future poor WA among office workers. CONCLUSIONS: Our results showed cross-sectional and longitudinal relationships between musculoskeletal health and work ability depending on occupation. However, the present implies that predicting work ability in the far future based on health surveillance data is rather difficult. Testing the musculoskeletal system (grip strength) and asking workers' about their musculoskeletal health seems relevant when monitoring work ability. PMID- 28343282 TI - Effective chemotherapy of heterogeneous and drug-resistant early colon cancers by intermittent dose schedules: a computer simulation study. AB - PURPOSE: The effectiveness of cancer chemotherapy is limited by intra-tumor heterogeneity, the emergence of spontaneous and induced drug-resistant mutant subclones, and the maximum dose to which normal tissues can be exposed without adverse side effects. The goal of this project was to determine if intermittent schedules of the maximum dose that allows colon crypt maintenance could overcome these limitations, specifically by eliminating mixtures of drug-resistant mutants from heterogeneous early colon adenomas while maintaining colon crypt function. METHODS: A computer model of cell dynamics in human colon crypts was calibrated with measurements of human biopsy specimens. The model allowed simulation of continuous and intermittent dose schedules of a cytotoxic chemotherapeutic drug, as well as the drug's effect on the elimination of mutant cells and the maintenance of crypt function. RESULTS: Colon crypts can tolerate a tenfold greater intermittent dose than constant dose. This allows elimination of a mixture of relatively drug-sensitive and drug-resistant mutant subclones from heterogeneous colon crypts. Mutants can be eliminated whether they arise spontaneously or are induced by the cytotoxic drug. CONCLUSIONS: An intermittent dose, at the maximum that allows colon crypt maintenance, can be effective in eliminating a heterogeneous mixture of mutant subclones before they fill the crypt and form an adenoma. PMID- 28343281 TI - Using Patterns of Genetic Association to Elucidate Shared Genetic Etiologies Across Psychiatric Disorders. AB - Twin studies indicate that latent genetic factors overlap across comorbid psychiatric disorders. In this study, we used a novel approach to elucidate shared genetic factors across psychiatric outcomes by clustering single nucleotide polymorphisms based on their genome-wide association patterns. We applied latent profile analysis (LPA) to p-values resulting from genome-wide association studies across three phenotypes: symptom counts of alcohol dependence (AD), antisocial personality disorder (ASP), and major depression (MD), using the European-American case-control genome-wide association study subsample of the collaborative study on the genetics of alcoholism (N = 1399). In the 3-class model, classes were characterized by overall low associations (85.6% of SNPs), relatively stronger association only with MD (6.8%), and stronger associations with AD and ASP but not with MD (7.6%), respectively. These results parallel the genetic factor structure identified in twin studies. The findings suggest that applying LPA to association results across multiple disorders may be a promising approach to identify the specific genetic etiologies underlying shared genetic variance. PMID- 28343283 TI - The Types of Trust Involved in American Muslim Healthcare Decisions: An Exploratory Qualitative Study. AB - Trust in physicians and the healthcare system underlies some disparities noted among minority populations, yet a descriptive typology of different types of trust informing healthcare decisions among minority populations is limited. Using data from 13 focus groups with 102 American Muslims, we identified the types and influence of trust in healthcare decision-making. Participants conveyed four types of trust implicating their health-seeking behaviors-(I) trust in allopathic medicine, (II) trust in God, (III) trust in personal relationships, and (IV) trust in self. Healthcare disparity research can benefit from assessing how these types of trust are associated with health outcomes among minority populations so as to inform intervention programs that seek to enhance trust as a means to improve community health. PMID- 28343284 TI - The Relationship of Religious Comfort and Struggle with Anxiety and Satisfaction with Life in Roman Catholic Polish Men: The Moderating Effect of Sexual Orientation. AB - The aim of the research was to analyze the relationships of religious comfort and struggle with state anxiety and satisfaction with life in homosexual and heterosexual samples of men. A hundred and eight men aged between 18 and 43 participated in the research in total, 54 declared themselves as homosexual and 54 as heterosexual. The Religious Comfort and Strain Scale, the State-Trait Anxiety Inventory and the Satisfaction with Life Scale were applied to the research. The results of hierarchical multiple regression analyses revealed that sexual orientation moderated the relationships of religious comfort and struggle with state anxiety and satisfaction with life. The highest state anxiety was observed in homosexual participants with high negative social interactions surrounding religion scores. Negative religious social interactions with fellow congregants and religious leaders, including disapproval and criticism, create anxiety among homosexual people. It seems that homosexual participants are engaged in a trade-off between valued and necessary religious engagement and the harassment and persecution they may be forced to endure in order to access that engagement. PMID- 28343285 TI - The Prevalence and Antecedents of Religious Beliefs About Health Control in the US Population: Variations by Race and Religious Background. AB - The ways in which religious beliefs influence beliefs about health have important implications for motivation to engage in positive health behaviors and comply with medical treatment. This study examines the prevalence of two health-related religious beliefs: belief in healing miracles and deferral of responsibility for health outcomes to God. Data came from a representative nationwide US survey of religion and health (N = 3010). Full-factorial ANOVA indicated that there were significant differences in both dimensions of belief by race, by religious background, and by the interaction between the two. Black people believed religion played the largest role in health regardless of religious background. Among White and Hispanic groups, Evangelical Protestants placed more responsibility for their health on God in comparison with other religious groups. ANCOVA controlling for background factors socioeconomic status, health, and religious involvement partially explained these group differences. PMID- 28343286 TI - A mimic of sexually-motivated homicide: insect stings and heat exhaustion in a forest. AB - We report the case a woman who was found dead in a forest. The body was nude and the position of the body suggested a sexually motivated homicide. We concluded that death was not related to homicide, but was related to the conjunction of environmental factors, including insect stings, and acute psychosis. A medicolegal death investigation with postmortem examination was undertaken to determine cause of death. At the scene, the body was supine with legs spread apart and the knees flexed, exposing the external genitalia. There were multiple apparent bruises on the body and neck. At autopsy, based on macroscopic and microscopic examination, the apparent bruises were found to be hemorrhagic insect bites. No significant injuries were present and no semen was found. Death appeared to be related to heat exhaustion and innumerable insect stings. Investigation of the medical history revealed longstanding schizoaffective disorder with episodic psychotic decompensations. In the past, during an acute psychotic episode the decedent removed her clothing and ran wildly in a forest, until she was rescued in a state of exhaustion and marked agitation, and taken to hospital for treatment. We concluded that the same circumstances had been repeated but with a fatal outcome. This case is an example of a mimic of sexually motivated homicide and is a reminder to forensic pathologists to avoid tunnel vision. We need to be skeptical of the allure of common sense based on first impressions of the scene and the body. Forensic pathologists must be unafraid to scientifically explore improbable, but true, alternate explanations. PMID- 28343287 TI - Catabolic effects of FGF-1 on chondrocytes and its possible role in osteoarthritis. AB - Fibroblast growth factor 1 (FGF-1) is a classical member of the FGF family and is produced by chondrocytes cultured from osteoarthritic patients. Also, this growth factor was shown to bind to CCN family protein 2 (CCN2), which regenerates damaged articular cartilage and counteracts osteoarthritis (OA) in an animal model. However, the pathophysiological role of FGF-1 in cartilage has not been well investigated. In this study, we evaluated the effects of FGF-1 in vitro and its production in vivo by use of an OA model. Treatment of human chondrocytic cells with FGF-1 resulted in marked repression of genes for cartilaginous extracellular matrix components, whereas it strongly induced matrix metalloproteinase 13 (MMP-13), representing its catabolic effects on cartilage. Interestingly, expression of the CCN2 gene was dramatically repressed by FGF-1, which repression eventually caused the reduced production of CCN2 protein from the chondrocytic cells. The results of a reporter gene assay revealed that this repression could be ascribed, at least in part, to transcriptional regulation. In contrast, the gene expression of FGF-1 was enhanced by exogenous FGF-1, indicating a positive feedback system in these cells. Of note, induction of FGF-1 was observed in the articular cartilage of a rat OA model. These results collectively indicate a pathological role of FGF-1 in OA development, which includes an insufficient cartilage regeneration response caused by CCN2 down regulation. PMID- 28343289 TI - The effect of mucin, fibrinogen and IgG on the corrosion behaviour of Ni-Ti alloy and stainless steel. AB - In this study, Ni-Ti alloy and stainless steal were exposed to artificial saliva containing fibrinogen, IgG or mucin, and the resultant corrosion behavior was studied. The purpose was to determine the mechanisms by which different types of protein contribute to corrosion. The effect of different proteins on the electrochemical resistance of Ni-Ti and SS was tested by potentiodynamic polarization, and the repair capacity of passivation film was tested by cyclic polarization measurements. The dissolved corrosion products were determined by ICP-OES, and the surface was analyzed by SEM and AFM. The results showed fibrinogen, IgG or mucin could have different influences on the susceptibility to corrosion of the same alloy. Adding protein lead to the decrease of corrosion resistance of SS, whereas protein could slow down the corrosion process of Ni-Ti. For Ni-Ti, adding mucin could enhance the corrosion stability and repair capacity of passivation film. The susceptibility to pitting corrosion of Ni-Ti and stainless steal in fibrinogen AS is not as high as mucin and IgG AS. There are different patterns of deposition formation on the metal surface by different types of protein, which is associated with their effects on the corrosion process of the alloys. PMID- 28343288 TI - Associations Between Household Secondhand Smoke Exposure and Health Problems Among Non-Smoking Adolescents in the Republic of Korea. AB - This study examined the association between household secondhand smoke exposure (HSHSE) and health status among non-smoking adolescents in Korea using two subsamples obtained from nationally representative cross-sectional secondary data: males (n = 25,653) and females (n = 31,187). Two self-reported HSHSE measures included exposure to household secondhand smoke during the week before the survey (yes or no) and number of days of HSHSE (1-7 days); and five self reported health problems included asthma, perceived stress, depression, suicidal ideation, and self-rated health. For each subsample, this study performed (1) multivariate logistic regressions to examine HSHSE effects on asthma, depression, and suicidal ideation; and (2) multiple linear regressions to examine HSHSE effects on perceived stress and self-rated health. The rate and number of days of HSHSE were significantly higher among females (30.1% and 3.4 days) than among males (25.9% and 3.1 days). In both subsamples, HSHSE was associated with all five health problems (ORs 1.15-1.32; betas: 0.04-0.14). An increase in the number of days of HSHSE was positively associated with (1) greater perceived stress and poorer self-rated health in both subsamples (betas: 0.01-0.04), and (2) greater odds of asthma, depression, and suicidal ideation in the female subsample (ORs 1.03-1.12). Given the findings related to the strong associations (1) between HSHSE and physical, mental, and general health problems; and (2) between days of HSHSE and a greater number of health problems in females, health professionals should actively implement interventions that encourage adult smokers to stop smoking in their homes. PMID- 28343290 TI - Muscle Injury After Intramuscular Administration of Diclofenac: A Case Report Supported by Magnetic Resonance Imaging. AB - Intramuscular injection of diclofenac is still frequently practiced, although there is ample evidence that the risk of local tissue intolerability is highly underestimated. The aim of this study was to evaluate local toxicity in a patient using magnetic resonance imaging. A patient who gave written informed consent received a medically indicated intramuscular administration of diclofenac 75 mg/2 mL. Simultaneously with magnetic resonance imaging of the depot, a clinical chemical evaluation and quantification of diclofenac in plasma was performed. A manifold enhancement of the T2-weighted magnetic resonance signal was observed in a muscle area of approximately 60 mL volume, with maximum signal intensity 30 min after injection, the time of maximum diclofenac plasma exposure. Plasma creatine kinase activity was elevated approximately sixfold within 8 h and normalized within 1 week, whereas the magnetic resonance enhancement disappeared within 5 weeks. Interestingly, the patient did not complain about any clinical symptoms at the injection site. Asymptomatic tissue injury after intramuscular injection of diclofenac, caused by intramuscular dosing, can be reliably evaluated by magnetic resonance imaging and should be applied early during the development of parenteral dosage forms. Clinical Trials Registration Number: BB130/16 (Ethics Committee of the University Medicine Greifswald). PMID- 28343291 TI - Intercalary frozen autograft for reconstruction of malignant bone and soft tissue tumours. AB - PURPOSE: In 1999, we developed a technique using frozen autografts-tumour containing bone treated with liquid nitrogen-for the reconstruction of malignant bone tumours. The purpose of this study was to evaluate the functional and oncological outcomes of frozen autografts for intercalary reconstruction of malignant bones and soft tissue tumours. METHODS: This retrospective study was designed to assess 34 patients of mean age 35 (range, 6-79) years. The mean follow-up period was 62 (24-214) months. The median length of the frozen autografts was 138.4 +/- 60.39 (50-290) mm. RESULTS: Postsurgically, 20 patients remained disease-free, seven patients survived with no evidence of disease, five patients were alive with disease, and two patients died of disease. The five- and ten-year survival rates of the frozen autografts were 91.2% and the mean International Society of Limb Salvage score was 90%. Complete bony union was achieved in 97% of the patients. There were five cases of nonunion, six cases of fracture, two cases of deep infection and four cases of local recurrence. CONCLUSION: Utilizing intercalary frozen autografts for patients with a nonosteolytic primary or secondary bone tumour without involvement of the subchondral bone is a good alternative treatment, because it is a straightforward biological technique and can provide excellent limb function. PMID- 28343292 TI - Psychometric Validation of the Heart Failure Caregiver Questionnaire (HF-CQ(r)). AB - BACKGROUND: The Heart Failure Caregiver Questionnaire (HF-CQ(r)) was developed to assess subjective outcomes of heart failure caregivers. The HF-CQ(r) comprises 21 questions on three domains, namely physical, emotional/psychological and lifestyle. The objective of this study was to evaluate the psychometric properties of the HF-CQ(r). METHODS: Patients (n = 150) with heart failure and their primary caregivers (n = 150) were recruited from 11 sites in USA. Caregivers completed the HF-CQ(r) and additional questionnaires, namely Caregiver Reaction Assessment, Work Productivity and Activity Impairment questionnaire, EuroQol-5 domain, and the Hospital Anxiety and Depression Scale. Patient completed Global Impression of Severity, construct validity, concurrent validity, reliability and responsiveness of the HF-CQ(r) were also assessed. RESULTS: In the physical and lifestyle domains, all items showed acceptable validity. No high correlations between HF-CQ(r) scores and other caregiver-completed instruments, including the Hospital Anxiety and Depression Scale, Work Productivity and Activity Impairment questionnaire, EuroQol-5 domain or Caregiver Reaction Assessment, were reported. The intra-class correlation coefficient exceeded the threshold for reliability (>0.7) across the physical well-being (0.785), emotional/psychological (0.797), lifestyle (0.787) and total scores (0.850), indicating acceptable reliability. Internal consistency results using Cronbach's alpha showed the total aggregate score of 0.942 to be reliable. In the responsiveness analyses, each of the three scales and the total score showed responsiveness to changes defined by the Caregiver Global Impression of Severity. The overall caregiver burden score increased with increased severity of illness in the cared-for patients. CONCLUSIONS: The study provides initial evidence for the acceptable validity of the HF-CQ(r) as an instrument to measure heart failure caregiver burden. PMID- 28343293 TI - Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Chronic Lymphocytic Leukemia: Ibrutinib, Idelalisib, and Venetoclax. AB - Management of chronic lymphocytic leukemia has changed markedly over the last several years with the emergence of several novel oral agents targeting B-cell receptor and Bcl-2 signaling pathways. For patients requiring treatment, ibrutinib, idelalisib, and venetoclax offer unique clinical benefits with a different set of therapeutic considerations compared with traditional parenteral therapy. Despite the conveniences afforded by oral therapy, these agents also carry unique logistical obstacles. Drug interactions with agents that are metabolized via the cytochrome P450 3A4 pathway are possible with all three agents. Unique treatment-related adverse events including bleeding and atrial fibrillation with ibrutinib, hepatotoxicity with idelalisib, and tumor lysis syndrome with venetoclax can be severe and dose limiting. Furthermore, dose adjustments for organ dysfunction may also be warranted. Here, we review the available literature on the pharmacokinetic and pharmacodynamic properties of these novel agents to guide the reader in the appropriate use of ibrutinib, idelalisib, and venetoclax. PMID- 28343294 TI - Neuroprotective Role of Exogenous Brain-Derived Neurotrophic Factor in Hypoxia Hypoglycemia-Induced Hippocampal Neuron Injury via Regulating Trkb/MiR134 Signaling. AB - Hypoxic-ischemic brain injury is an important cause of neonatal mortality and morbidity. Brain-derived neurotrophic factor (BDNF) has been reported to play a neuroprotective role in hypoxic-ischemic brain injury; however, the specific effects and mechanism of BDNF on hypoxic-hypoglycemic hippocampal neuron injury remains unknown. The current study investigated the action of BDNF in regulating cerebral hypoxic-ischemic injury by simulating hippocampal neuron ischemia and hypoxia. We found that BDNF, p-Trkb, and miR-134 expression levels decreased, and that exogenous BDNF increased survival and reduced apoptosis in hypoxic hypoglycemic hippocampal neurons. The results also show that BDNF inhibits MiR 134 expression by activating the TrkB pathway. Transfection with TrkB siRNA and pre-miR-134 abrogated the neuroprotective role of BDNF in hypoxic-hypoglycemic hippocampal neurons. Our results suggest that exogenous BDNF alleviates hypoxic ischemic brain injury through the Trkb/MiR-134 pathway. These findings may help to identify a potential therapeutic agent for the treatment of hypoxic-ischemic brain injury. PMID- 28343295 TI - Identification of Sphingosine 1-Phosphate Receptor Subtype 1 (S1P1) as a Pathogenic Factor in Transient Focal Cerebral Ischemia. AB - Medically relevant roles of receptor-mediated sphingosine 1-phosphate (S1P) signaling have become a successful or promising target for multiple sclerosis or cerebral ischemia. Animal-based proof-of-concept validation for the latter is particularly through the neuroprotective efficacy of FTY720, a non-selective S1P receptor modulator, presumably via activation of S1P1. In spite of a clear link between S1P signaling and cerebral ischemia, it remains unknown whether the role of S1P1 is pathogenic or neuroprotective. Here, we investigated the involvement of S1P1 along with its role in cerebral ischemia using a transient middle cerebral artery occlusion ("tMCAO") model. Brain damage following tMCAO, as assessed by brain infarction, neurological deficit score, and neural cell death, was reduced by oral administration of AUY954, a selective S1P1 modulator as a functional antagonist, in a therapeutic paradigm, indicating that S1P1 is a pathogenic mediator rather than a neuroprotective mediator. This pathogenic role of S1P1 in cerebral ischemia was reaffirmed because tMCAO-induced brain damage was reduced by genetic knockdown with an intracerebroventricular microinjection of S1P1 shRNA lentivirus into the brain. Genetic knockdown of S1P1 or AUY954 exposure reduced microglial activation, as assessed by reduction in the number of activated microglia and reversed morphology from amoeboid to ramified, and microglial proliferation in ischemic brain. Its role in microglial activation was recapitulated in lipopolysaccharide-stimulated primary mouse microglia, in which the mRNA expression level of TNF-alpha and IL-1beta, well-known markers for microglial activation, was reduced in microglia transfected with S1P1 siRNA. These data suggest that the pathogenic role of S1P1 is associated with microglial activation in ischemic brain. Additionally, the pathogenic role of S1P1 in cerebral ischemia appears to be associated with the blood-brain barrier disruption and brain-derived neurotrophic factor (BDNF) downregulation. Overall, findings from the current study clearly identify S1P1 signaling as a pathogenic factor in transient focal cerebral ischemia, further implicating S1P1 antagonists including functional antagonists as plausible therapeutic agents for human stroke. PMID- 28343296 TI - Ibuprofen Protects from Cypermethrin-Induced Changes in the Striatal Dendritic Length and Spine Density. AB - Microgliosis and inflammation are major wrongdoers in cypermethrin-induced Parkinsonism along with oxidative stress, mitochondrial dysfunction and alpha synuclein aggregation. Dopamine depletion could alter dendritic morphology, length and spine number in the striatum. Present study investigated the effect of ibuprofen on the dendritic morphology, length and spine density in cypermethrin PD model. Male pups were treated intraperitoneally with cypermethrin during postnatal days followed by adulthood to induce Parkinsonism using standard procedure along with controls. Subsets of animals were pre-treated with ibuprofen 2 h prior to cypermethrin treatment during adulthood. Standard methods were used to confirm Parkinsonism/neuroprotection. Striatal dendritic morphology, length, spine number and expression of synaptophysin and postsynaptic density protein-95 (PSD-95) along with the nigrostriatal pro-inflammatory and apoptotic proteins were measured. Cypermethrin induced Parkinsonian traits and attenuated the dendritic length, spine number and expression of synaptophysin and PSD-95. While cypermethrin increased the expression of interleukin-1beta, interleukin-4, interferon-gamma, inducible nitric oxide synthase, caspase-3, caspase-9 and B cell lymphoma (Bcl)-xl proteins, it attenuated Bcl-2 expression. Ibuprofen normalized the changes in dendritic morphology, length, spine number and expression of synaptophysin, PSD-95, and pro-inflammatory and apoptotic proteins. Results demonstrate that cypermethrin induces inflammation and alters dendritic morphology, length and spine number, which are encountered by ibuprofen. PMID- 28343297 TI - Association of the CX3CR1-V249I Variant with Neurofibrillary Pathology Progression in Late-Onset Alzheimer's Disease. AB - Neuroinflammation and microglial dysfunction have a prominent role in the pathogenesis of late-onset Alzheimer's disease (LOAD). CX3CR1 is a microglia specific gene involved in microglia-neuron crosstalk and neuroinflammation. Numerous evidence show the involvement of CX3CR1 in AD. The aim of this study was to investigate if some functional genetic variants of this gene could influence on LOAD's outcome, in a neuropathologically confirmed Spanish cohort. We designed an open, pragmatic, case-control retrospective study including a total of 475 subjects (205 pathologically confirmed AD cases and 270 controls). We analyzed the association of the two CX3CR1 functional variants (V249I, rs3732379; and T280M, rs3732378) with neurofibrillary pathology progression rate according to Braak's staging system, age at onset (AAO), survival time, and risk of suffering LOAD. We found that individuals heterozygous for CX3CR1-V249I presented a lower neurofibrillary pathology stage at death (OR = 0.42, 95%CI [0.23, 0.74], p = 0.003, adj-p = 0.013) than the other genotypes. Eighty percent of the subjects homozygous for 249I had higher neurofibrillary pathology progression (Braak's stage VI). Moreover, homozygosis for 280M and 249I could be associated with a higher AAO in the subgroups of AD with Lewy bodies and without Lewy bodies. These CX3CR1 genetic variants could represent new modifying factors of pathology progression and age at onset in LOAD. These results provide further evidence of the involvement of CX3CR1 pathway and microglia/macrophages in the pathogenesis of LOAD. PMID- 28343298 TI - Thiazide increases serum calcium in anuric patients: the role of parathyroid hormone. AB - : We evaluated the effect of hydrochlorothiazide in a sample of anuric patients on hemodialysis and found an increase in serum calcium, which occurred only in those with parathyroid hormone >300 pg/ml. This finding highlights the extra renal effect of this diuretic and a possible role of parathyroid hormone in the mechanism. PURPOSE: Thiazide diuretics are commonly used in patients with chronic kidney disease to treat hypertension. Their effects on calcium and bone metabolism are not well established, once calciuria may not fully explain levels of calcium and parathyroid hormone (PTH) in this population. A previous study has suggested that thiazides require the presence of PTH as a permissive condition for its renal action. In anuric patients, however, the role of PTH, if any, in the thiazide effect is unknown. METHODS: To assess thiazide extra renal effect on serum calcium and whether such an effect is reliant on PTH, hydrochlorothiazide (HCTZ) 100 mg was given orally once a day to a sample of 19 anuric patients on hemodialysis for 2 weeks. Laboratories' analyses were obtained in three phases: baseline, after diuretic use, and after a 2-week washout phase. RESULTS: We demonstrated that serum calcium (Ca) increased in ten patients (52.6%) after HCTZ use, returning to previous levels after the washout period. Out of the 19 patients, ten presented PTH >= 300 pg/ml, and Ca has increased in eight of them, whereas in the other nine patients with PTH < 300 pg/ml, serum Ca has increased only in two individuals (RR risk of increase Ca 3.9; p = 0.012). CONCLUSIONS: HCTZ was capable of increasing serum Ca in a sample of anuric patients on hemodialysis and seems this effect is highly dependent on PTH levels. Caution is required while interpreting this result, as the small sample size might implicate in a finding caused by chance. PMID- 28343300 TI - Conversion rates of abstracts presented at the Canadian Rheumatology Association Annual Meetings into full-text journal articles. AB - Dissemination of research studies is important for research ideas to be transformed from initial abstracts to full publications. Analyses of the scientific impact and publication record of the Canadian Rheumatology Association (CRA) Annual meeting have not been previously described. This study determines the publication rate of abstracts presented at the CRA Annual Meetings 2005-2013 to full-text journal articles and the factors associated with publication. Program records of previous CRA meetings from 2005 to 2013 were obtained. Abstracts were searched for corresponding full-text publication in Google Scholar and PubMed using a search algorithm. Abstracts and subsequent published articles were evaluated for type of abstract, time to publication, study type, publishing journal, and journal impact factor. A total of 1401 abstracts were included in the study, 567 of which were converted to full publications. The average time to publication was 19.7 months, with 89% of abstracts published within 3 years of being presented. Eighty-three percent of abstracts were clinical in nature, and 58% of published studies were observational in design. Articles were published in a wide range of journals, with the top publisher being the Journal of Rheumatology (31%). Average time to publication was 19.7 months. Eighty-six percent of articles had a Journal Impact Factor > 2. Overall, 40.5% of abstracts presented at the CRA Annual Meetings 2005-2013 were published. Further research is needed to determine barriers and reasons for abstracts not being published as full-text articles. PMID- 28343299 TI - The role of LINE-1 methylation in predicting survival among colorectal cancer patients: a meta-analysis. AB - BACKGROUND: The prognostic value of long interspersed nucleotide element-1 (LINE 1) methylation in patients with colorectal cancer (CRC) remains uncertain. We have therefore performed a meta-analysis to elucidate this issue. METHODS: The PubMed and Web of Science databases were searched for studies published up to 30 June 2016 which reported on an association between LINE-1 methylation and overall survival (OS), disease-free survival (DFS), or cancer-specific survival (CSS) among CRC patients. The reference lists of the identified studies were also analyzed to identify additional eligible studies. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using the fixed-effects or the random effects model. Stratification analysis and meta-regression analysis were performed to detect the source of heterogeneity. Analyses of sensitivity and publication bias were also carried out. RESULTS: Thirteen independent studies involving 3620 CRC patients were recruited to the meta-analysis. LINE-1 hypomethylation was found to be significantly associated with shorter OS (HR 2.92, 95% CI 2.20-3.88, p < 0.001) and DFS (HR 2.18, 95% CI 1.46-3.27, p < 0.001), as well as unfavorable CSS (HR 1.96, 95% CI 1.35-2.85, p < 0.001). No heterogeneity was found among the studies evaluating the associations between LINE-1 hypomethylation and OS or DFS, with the exception being CSS. Moreover, meta-regression analysis suggested that one of the contributors to between-study heterogeneity on the association between LINE-1 methylation and CSS was statistical methodology. The subgroup analysis suggested that the association in studies using the Cox model statistical method (HR 2.76, 95% CI 1.90-4.01, p < 0.001) was stronger than that in studies using the Log-rank test (HR 1.41, 95% CI 1.07-1.87, p = 0.015). CONCLUSIONS: The results of this meta-analysis suggest that LINE-1 methylation is significantly associated with the survival of CRC patients and that it could be a predictive factor for CRC prognosis. PMID- 28343301 TI - Comparison of optical see-through head-mounted displays for surgical interventions with object-anchored 2D-display. AB - PURPOSE: Optical see-through head-mounted displays (OST-HMD) feature an unhindered and instantaneous view of the surgery site and can enable a mixed reality experience for surgeons during procedures. In this paper, we present a systematic approach to identify the criteria for evaluation of OST-HMD technologies for specific clinical scenarios, which benefit from using an object anchored 2D-display visualizing medical information. METHODS: Criteria for evaluating the performance of OST-HMDs for visualization of medical information and its usage are identified and proposed. These include text readability, contrast perception, task load, frame rate, and system lag. We choose to compare three commercially available OST-HMDs, which are representatives of currently available head-mounted display technologies. A multi-user study and an offline experiment are conducted to evaluate their performance. RESULTS: Statistical analysis demonstrates that Microsoft HoloLens performs best among the three tested OST-HMDs, in terms of contrast perception, task load, and frame rate, while ODG R-7 offers similar text readability. The integration of indoor localization and fiducial tracking on the HoloLens provides significantly less system lag in a relatively motionless scenario. CONCLUSIONS: With ever more OST HMDs appearing on the market, the proposed criteria could be used in the evaluation of their suitability for mixed reality surgical intervention. Currently, Microsoft HoloLens may be more suitable than ODG R-7 and Epson Moverio BT-200 for clinical usability in terms of the evaluated criteria. To the best of our knowledge, this is the first paper that presents a methodology and conducts experiments to evaluate and compare OST-HMDs for their use as object-anchored 2D display during interventions. PMID- 28343302 TI - Force-assisted ultrasound imaging system through dual force sensing and admittance robot control. AB - PURPOSE: Ultrasound imaging has been a gold standard for clinical diagnoses due to its unique advantages compared to other imaging modalities including: low cost, noninvasiveness, and safeness to the human body. However, the ultrasound scanning process requires applying a large force over extended periods of time, often in uncomfortable postures in order to maintain the desired orientation. This physical requirement over sonographers' careers often leads to musculoskeletal pain and strain injuries. METHODS: To address this problem, we propose a cooperatively controlled robotic ultrasound system to reduce the force sonographers apply. The proposed system consists of two key components: a six axis robotic arm that holds and actuates the ultrasound probe, and a dual force sensor setup that enables cooperative control and adaptive force assistance. With the admittance force control, the robotic arm complies with the motion of the operator, while assisting with force during the scanning. RESULTS: We validated the system through a user study involving expert sonographers and lay people and demonstrated 32-73% reduction in human applied force and 8- 18% improvement in image stability. CONCLUSION: These results indicate that the system has the potential to not only reduce the burden on the sonographer, but also provide more stable ultrasound scanning. PMID- 28343303 TI - Can real-time RGBD enhance intraoperative Cone-Beam CT? AB - PURPOSE: Cone-Beam Computed Tomography (CBCT) is an important 3D imaging technology for orthopedic, trauma, radiotherapy guidance, angiography, and dental applications. The major limitation of CBCT is the poor image quality due to scattered radiation, truncation, and patient movement. In this work, we propose to incorporate information from a co-registered Red-Green-Blue-Depth (RGBD) sensor attached near the detector plane of the C-arm to improve the reconstruction quality, as well as correcting for undesired rigid patient movement. METHODS: Calibration of the RGBD and C-arm imaging devices is performed in two steps: (i) calibration of the RGBD sensor and the X-ray source using a multimodal checkerboard pattern, and (ii) calibration of the RGBD surface reconstruction to the CBCT volume. The patient surface is acquired during the CBCT scan and then used as prior information for the reconstruction using Maximum Likelihood Expectation-Maximization. An RGBD-based simultaneous localization and mapping method is utilized to estimate the rigid patient movement during scanning. RESULTS: Performance is quantified and demonstrated using artificial data and bone phantoms with and without metal implants. Finally, we present movement-corrected CBCT reconstructions based on RGBD data on an animal specimen, where the average voxel intensity difference reduces from 0.157 without correction to 0.022 with correction. CONCLUSION: This work investigated the advantages of a C-arm X-ray imaging system used with an attached RGBD sensor. The experiments show the benefits of the opto/X-ray imaging system in: (i) improving the quality of reconstruction by incorporating the surface information of the patient, reducing the streak artifacts as well as the number of required projections, and (ii) recovering the scanning trajectory for the reconstruction in the presence of undesired patient rigid movement. PMID- 28343304 TI - Geometry calibration between X-ray source and detector for tomosynthesis with a portable X-ray system. AB - PURPOSE: Tomosynthesis is attracting attention as a low-dose tomography technology compared with X-ray CT. However, conventional tomosynthesis imaging devices are large and stationary. Furthermore, there is a limitation in the working range of the X-ray source during image acquisition. We have previously proposed the use of a portable X-ray device for tomosynthesis that can be used for ward rounds and emergency medicine. The weight of this device can be reduced by using a flat panel detector (FPD), and flexibility is realized by the free placement of the X-ray source and FPD. Tomosynthesis using a portable X-ray device requires calibration of the geometry between the X-ray source and detector at each image acquisition. We propose a method for geometry calibration and demonstrate tomosynthesis image reconstruction by this method. METHODS: An image processing-based calibration method using an asymmetric and multilayered calibration object (AMCO) is presented. Since the AMCO is always attached to the X-ray source housing for geometry calibration, the additional setting of a calibration object or marker around or on the patients is not required. The AMCO's multilayer structure improves the calibration accuracy, especially in the out-of-plane direction. RESULTS: Two experiments were conducted. The first was performed to evaluate the calibration accuracy using an XY positioning stage and a gonio stage. As a result, an accuracy of approximately 1 mm was achieved both in the in-plane and out-of-plane directions. An angular accuracy of approximately [Formula: see text] was confirmed. The second experiment was conducted to evaluate the reconstructed image using a foot model phantom. Only the sagittal plane could be clearly observed with the proposed method. CONCLUSION: We proposed a tomosynthesis imaging system using a portable X-ray device. From the experimental results, the proposed method could provide sufficient calibration accuracy and a clear sagittal plane of the reconstructed tomosynthesis image. PMID- 28343305 TI - Clinicopathologic and genetic features of primary bronchopulmonary mucoepidermoid carcinoma: the MD Anderson Cancer Center experience and comprehensive review of the literature. AB - Primary bronchopulmonary mucoepidermoid carcinoma (BPMEC) is a rare tumor. The fusion protein MECT1-MAML2 has been implicated as a causative genetic event in salivary and BPMECs. Several studies have shown the impact of MECT1-MAML2 on the diagnosis and prognosis of salivary gland mucoepidermoid carcinoma; however, few studies have been published regarding MECT1-MAML2 in the context of primary BPMEC. We describe the clinicopathologic, genetic, and outcome data of 16 patients with BPMEC. Clinicopathologic features were recorded from the electronic medical records. All tumors were reviewed by two expert pulmonary pathologists and graded according to previously established criteria. The presence of MECT1 MAML2 was evaluated with reverse transcription polymerase chain reaction using RNA extracted from formalin-fixed paraffin-embedded tumor tissue. Patients included 9 women and 7 men with a median age of 50 years (range, 7 to 82 years). Tumors exhibited low (n = 14, 88%), and high (n = 2, 12%) grade histologic features. Eight of nine tested tumors (89%) were positive for MECT1-MAML2. The median follow-up time was 40.8 months (range, 1.8-120). Median overall survival for patients with high-grade tumors was 12 months, which was significantly (p = 0.002) shorter than that for patients with low-grade tumors (survival undefined). We also provide a comprehensive review of literature of cases of primary bronchopulmonary mucoepidermoid carcinoma and summarize our findings in this context. MECT1-MAML2 fusion transcript is a driver genetic event in the pathogenesis of primary BPMEC. Histologic grade continues to play a pivotal role in the survival of patients with primary bronchopulmonary mucoepidermoid carcinoma. PMID- 28343306 TI - The ins and outs of molecular pathology reporting. AB - The raid evolution in molecular pathology resulting in an increasing complexity requires careful reporting. The need for standardisation is clearer than ever. While synoptic reporting was first used for reporting hereditary genetic diseases, it is becoming more frequent in pathology, especially molecular pathology reports too. The narrative approach is no longer feasible with the growing amount of essential data present on the report, although narrative components are still necessary for interpretation in molecular pathology. On the way towards standardisation of reports, guidelines can be a helpful tool. There are several guidelines that focus on reporting in the field of hereditary diseases, but it is not always feasible to extrapolate these to the reporting of somatic variants in molecular pathology. The rise of multi-gene testing causes challenges for the laboratories. In order to provide a continuous optimisation of the laboratory testing process, including reporting, external quality assessment is essential and has already proven to improve the quality of reports. In general, a clear and concise report for molecular pathology can be created by including elements deemed important by different guidelines, adapting the report to the process flows of the laboratory and integrating the report with the laboratory information management system and the patient record. PMID- 28343307 TI - Modular organization of muscle activity patterns in the leading and trailing limbs during obstacle clearance in healthy adults. AB - Human locomotor patterns require precise adjustments to successfully navigate complex environments. Studies suggest that the central nervous system may control such adjustments through supraspinal signals modifying a basic locomotor pattern at the spinal level. To explore this proposed control mechanism in the leading and trailing limbs during obstructed walking, healthy young adults stepped over obstacles measuring 0.1 and 0.2 m in height. Unobstructed walking with no obstacle present was also performed as a baseline. Full body three-dimensional kinematic data were recorded and electromyography (EMG) was collected from 14 lower limb muscles on each side of the body. EMG data were analyzed using two techniques: by mapping the EMG data to the approximate location of the motor neuron pools on the lumbosacral enlargement of the spinal cord and by applying a nonnegative matrix factorization algorithm to unilateral and bilateral muscle activations separately. Results showed that obstacle clearance may be achieved not only with the addition of a new activation pattern in the leading limb, but with a temporal shift of a pattern present during unobstructed walking in both the leading and trailing limbs. An investigation of the inter-limb coordination of these patterns suggested a strong bilateral linkage between lower limbs. These results highlight the modular organization of muscle activation in the leading and trailing limbs, as well as provide a mechanism of control when implementing a locomotor adjustment when stepping over an obstacle. PMID- 28343308 TI - The nociceptive withdrawal response of the foot in the spinalized rat exhibits limited dependence on stimulus location. AB - The nociceptive withdrawal response (NWR) of the limb is a protective, multi joint movement in response to noxious stimulation of the homonymous limb. Previous studies in animal models differed as to the dependence of the response direction and magnitude on stimulus location. The specific aim of our research was to use three-dimensional high-speed video to determine whether movement of the foot in response to heat stimuli delivered to the foot and lower leg depended on the location of the stimulus. In particular, we sought to determine whether the movement strategy was categorical or continuous. In spinalized rats, localized, presumably nociceptive heat stimuli were delivered along three dimensions-circumferentially around the lower leg, circumferentially around the foot and along the plantar surface of the foot. Our results demonstrate that in spite of a wide range of stimulus locations over the hind foot and leg, response directions were restricted to two-rostral/medial/dorsal and caudal/medial/dorsal directions, consistent with a categorical strategy. Further, the preference for these two directions was also reflected in the distance of the movement, which was greatest for stimuli directly opposite the preferred response directions. However, significant but weak dependencies of response direction and distance on stimulus location were found for all three dimensions of stimulus application, supporting a continuous strategy. Together, our results demonstrate, based on movement analysis, that the NWR employs a hybrid categorical-continuous strategy that may minimize the harmful consequences of noxious stimuli. PMID- 28343309 TI - Breast cancer detection and tumor characteristics in BRCA1 and BRCA2 mutation carriers. AB - PURPOSE: To describe imaging findings, detection rates, and tumor characteristics of breast cancers in a large series of patients with BRCA1 and BRCA2 mutations to potentially streamline screening strategies. METHODS: An IRB-approved, HIPAA compliant retrospective analysis of 496 BRCA mutation carriers diagnosed with breast carcinoma from 1999 to 2013 was performed. Institutional database and electronic medical records were reviewed for mammography and MRI imaging. Patient and tumor characteristics including age at diagnosis, tumor histology, grade, receptor, and nodal status were recorded. RESULTS: Tumors in BRCA1 mutation carriers were associated exhibited significantly higher nuclear and histological grade compared to BRCA2 (p < 0.001). Triple-negative tumors were more frequent in BRCA1 mutation carriers, whereas hormone receptor-positive tumors were more frequent in BRCA2 mutation carriers (p < 0.001). BRCA2 mutation carriers more frequently presented with ductal carcinoma in situ (DCIS) alone 14% (35/246) and cancers more frequently exhibiting calcifications (p < 0.001). Mammography detected fewer cancers in BRCA1 mutation carriers compared to BRCA2 (p = 0.04): 81% (186/231) BRCA1 versus 89% (212/237) BRCA2. MRI detected 99% cancers in each group. Mammography detected cancer in two patients with false-negative MRI (1 invasive cancer, 1 DCIS). Detection rates on both mammography and MRI did not significantly differ for women over 40 years and women below 40 years. CONCLUSIONS: Breast cancers in BRCA1 mutation carriers are associated with more aggressive tumor characteristics compared to BRCA2 and are less well seen on mammography. Mammography rarely identified cancers not visible on MRI. Thus, the omission of mammography in BRCA1 mutation carriers screened with MRI can be considered. PMID- 28343310 TI - Steroidogenic genes expressions are repressed by high levels of leptin and the JAK/STAT signaling pathway in MA-10 Leydig cells. AB - The adipose tissue is an important endocrine organ secreting numerous peptide hormones, including leptin. Increased circulating levels of leptin, as a result of hormonal resistance in obese individuals, may contribute to lower androgen production in obese males. However, the molecular mechanisms involved need to be better defined. Androgens are mainly produced by Leydig cells within the testis. In male rodents, activation of the leptin receptor modulates a cascade of intracellular signal transduction pathways which may lead to regulation of transcription factors having influences on steroidogenesis in Leydig cells. Thus, as a result of high leptin levels interacting with its receptor and modulating the activity of the JAK/STAT signaling pathway, the activity of transcription factors important for steroidogenic genes expressions may be inhibited in Leydig cells. Here we show that Lepr is increasingly expressed within Leydig cells according to postnatal development. Although high levels of leptin (corresponding to obesity condition) alone had no effect on Leydig cells' steroidogenic genes expression, it downregulated cAMP-dependent activations of the cholesterol transporter Star and of the rate-limiting steroidogenic enzyme Cyp11a1. Our results suggest that STAT transcriptional activity is downregulated by high levels of leptin, leading to reduced cAMP-dependent steroidogenic genes (Star and Cyp11a1) expressions in MA-10 Leydig cells. However, other transcription factors such as members of the SMAD and NFAT families may be involved and need further investigation to better define how leptin regulates their activities and their relevance for Leydig cells function. PMID- 28343311 TI - Mechanistic insight of platelet apoptosis leading to non-surgical bleeding among heart failure patients supported by continuous-flow left ventricular assist devices. AB - Non-surgical bleeding (NSB) is the most common clinical complication in heart failure (HF) patients supported by continuous-flow left ventricular assist devices (CF-LVADs). In this study, oxidative stress and alteration of signal pathways leading to platelet apoptosis were investigated. Thirty-one HF patients supported by CF-LVADs were divided into bleeder (n = 12) and non-bleeder (n = 19) groups. Multiple blood samples were collected at pre-implant (baseline) and weekly up to 1-month post-implant. A single blood sample was collected from healthy subjects (reference). Production of reactive oxygen species (ROS) in platelets, total antioxidant capacity (TAC), oxidized low-density lipoproteins (oxLDL), expression of Bcl-2 and Bcl-xL, Bax and release of cytochrome c (Cyt.c), platelet mitochondrial membrane potential (Deltapsi m), activation of caspases, gelsolin cleavage and platelet apoptosis were examined. Significantly elevated ROS, oxLDL and depleted TAC were evident in the bleeder group compared to non bleeder group (p < 0.05). Platelet pro-survival proteins (Bcl-2, Bcl-xL) were significantly reduced in the bleeder group in comparison to the non-bleeder group (p < 0.05). Translocation of Bax into platelet mitochondria membrane and subsequent release of Cyt.c were more prevalent in the bleeder group. Platelet mitochondrial damage, activation of caspases, gelsolin cleavage, and ultimate platelet apoptosis in the bleeder group were observed. Oxidative stress and activation of both intrinsic and extrinsic pathways of platelet apoptosis may be linked to NSB in CF-LVAD patients. Additionally, biomarkers of oxidative stress, examination of pro-survivals and pro-apoptotic proteins in platelets, mitochondrial damage, caspase activation, and platelet apoptosis may be used to help identify HF patients at high risk of NSB post-implant. PMID- 28343312 TI - Role of Acid-Base Homeostasis in Diabetic Kidney Disease. AB - PURPOSE OF REVIEW: Acid-base homeostasis is impaired in chronic kidney disease (CKD) and may contribute to disease progression. Diabetes, a major cause of CKD worldwide, may exacerbate acidosis further due to differences in acid production and excretion. Here, we review the role of abnormal acid-base homeostasis in the pathogenesis and progression of diabetes and diabetic kidney disease. RECENT FINDINGS: Acidosis and dietary acid loading may contribute to the development and worsening of insulin resistance and hypertension, thereby promoting diabetes and diabetic CKD. However, although metabolic acidosis associates with progression of CKD generally, the results in diabetic CKD are mixed. Data suggests that metabolic acid production in diabetes may be higher than would be predicted based on dietary intake alone, and new observational data suggests that this higher diet-independent acid production could potentially be protective. The role of acid-base homeostasis in diabetic CKD progression is complex and must consider differences in endogenous acid production and excretion in diabetes. Ongoing observational and interventional studies in this field should consider the unique physiology of diabetes. PMID- 28343313 TI - Spontaneous cervical intradural disc herniation presenting with Brown-Sequard and Horner's syndrome: lesson learned from a very unique case. AB - PURPOSE: Cervical spontaneous intradural disc herniation (IDH) is an extremely rare condition. We describe a unique case of a patient presenting with a Brown Sequard syndrome (BSS) and Horner's syndrome (HS). This study aimed to report an unusual case of spontaneous cervical intradural disc herniation that presented with Horner's and Brown-Sequard syndrome (BSS) and discuss difficulties in preoperative diagnosis and treatment difficulties of intradural cervical disc. METHODS: Notes and images review, and analysis of the relevant literature. RESULTS: A 45-year old female presented with acute Horner's syndrome and Brown Sequard syndrome. The magnetic resonance imaging of cervical spine revealed C4-5 disc extrusion with cord compression. The patient underwent urgent decompression through an anterior cervical corpectomy and fusion. Patient fully recovered 6 months after disease onset. CONCLUSION: We would like to emphasize that prompt and anterior cervical decompression is the treatment of choice, as it directly address the problem and allows dura repair in spontaneous cervical disc herniation. PMID- 28343315 TI - Expanding the 'Digital Protologue' database (DPD) to 'Archives of Microbiology': an offer to scientists and science. PMID- 28343314 TI - Rectus abdominis atrophy after ventral abdominal incisions: midline versus chevron. AB - PURPOSE: Although many outcomes have been compared between a midline and chevron incision, this is the first study to examine rectus abdominis atrophy after these two types of incisions. METHODS: Patients undergoing open pancreaticobiliary surgery between 2007 and 2011 at our single institution were included in this study. Rectus abdominis muscle thickness was measured on both preoperative and follow-up computed tomography (CT) scans to calculate percent atrophy of the muscle after surgery. RESULTS: At average follow-up of 24.5 and 19.0 months, respectively, rectus abdominis atrophy was 18.9% greater in the chevron (n = 30) than in the midline (n = 180) group (21.8 vs. 2.9%, p < 0.0001). Half the patients with a chevron incision had >20% atrophy at follow-up compared with 10% with a midline incision [odds ratio (OR) 9.0, p < 0.0001]. No significant difference was observed in incisional hernia rates or wound infections between groups. CONCLUSION: In this study, chevron incisions resulted in seven times more atrophy of the rectus abdominis compared with midline incisions. The long-term effects of transecting the rectus abdominis and disrupting its innervation creates challenging abdominal wall pathology. Atrophy of the abdominal wall can not be readily fixed with an operation, and this significant side effect of a transverse incision should be factored into the surgeon's decision-making process when choosing a transverse over a midline incision. PMID- 28343316 TI - Translation and validation of ICIQ-FLUTS for Tamil-speaking women. AB - AIMS: Research in to lower urinary tract symptoms (LUTS) in women in South Asia is hampered by lack of validated tools. Our aim was to validate the International Consultation on Incontinence Modular Questionnaire on Female Lower Urinary Tract Symptoms (ICIQ-FLUTS) from English to Tamil. METHOD: After translation to Tamil, a validation study was carried out among women attending the gynecology clinic at District General Hospital-Mannar. RESULTS: Content validity assessed by the level of missing data was <2%. Construct validity was assessed by the ability of the questionnaire to identify patients with incontinence (n = 45) from controls (n = 93) using the incontinence score [patients = 7.7 standard deviation (SD) = 4.7, controls = 1.4 SD = 2.2, p < 0.001] and those with symptomatic anterior wall prolapse (n = 16) from controls (n = 93) using voiding symptoms score (patients = 4.8 SD = 2.3, controls = 0.3 SD = 0.8, p < 0.001). Internal consistency was assessed using Cronbach's coefficient alpha score [0.80 (0.77-0.81)]. Test-retest reliability assessed by weighted kappa (kappa) ranged from 0.73 to 0.87. Patients with incontinence (n = 30, pretreatment incontinence score = 7.9, SD = 4.9 versus posttreatment incontinence score = 3.3, SD = 3.1) and symptomatic anterior wall prolapse (n = 14, preoperative voiding symptoms score = 4.9 SD = 2.5 versus postoperative voiding symptoms score = 0.9 SD = 1.5) showed an improvement with treatment (Wilcoxon matched--pairs signed-rank test p < 0.001 and p < 0.01, respectively). An incontinence score >= 3 (sensitivity = 86.7%, specificity = 78.4%) and a voiding symptoms score >= 3 (sensitivity = 87.5%, specificity = 96.2%) detected any form of incontinence and symptomatic anterior wall prolapse, respectively. CONCLUSION: Tamil translation of ICIQ-FLUTS retained the psychometric properties of the original English questionnaire and will be an invaluable tool to detect LUTS among Tamil-speaking women. PMID- 28343317 TI - Do glucocorticoids induce addiction in humans? PMID- 28343318 TI - Prevalence of thyroid dysfunction and its impact on cognition in older mexican adults: (SADEM study). AB - INTRODUCTION: Subclinical thyroid dysfunction is a possible risk factor for cognitive impairment in old age, but results are inconsistent. Aim of the present study was to evaluate the prevalence of thyroid dysfunction among older community dwelling adults and to see whether thyroid function impacts the cognitive status of the elderly. METHODS: We included 1750 participants from the Study on Aging and Dementia in Mexico (SADEM). All subjects were evaluated clinically via specific interviews. TSH levels were analyzed by chemiluminescent immunometry assay. We classified participants into five thyroid state groups: (1) normal TSH levels (0.40-4.0 IU/L) were considered euthyroid; (2) Overt hyperthyroidism: TSH <0.3 IU/l and FT4 >23 pmol/l; (3) Overt hypothyroidism: TSH >4.8 IU/l, FT4 <13 pmol/l; (4) Subclinical hyperthyroidism: TSH <0.3 IU/l, FT4: 13-23 pmol/l; (5) Subclinical hypothyroidism: TSH >4.8 IU/l, FT4: 13-23 pmol/l. RESULTS: The overall estimated prevalence of thyroid dysfunction in Mexican population was 23.7% (95% CI, 22.66-26.77). Of these, 15.4% older adults were classified as subclinical hypothyroidism, 7.2% overt hypothyroidism, 0.5% subclinical hyperthyroidism, and 0.6% overt hyperthyroidism. The association of thyroid dysfunction with cognitive impairment was most evident in overt hypothyroidism OR = 1.261 (1.185-1.343). CONCLUSIONS: The present study demonstrated a high prevalence of thyroid dysfunction in Mexican elderly people living in the community. A relationship between cognitive impairment and the presence of hypothyroidism was also shown, and to a lesser degree in hyperthyroidism. PMID- 28343319 TI - Robotic resection of an obturator schwannoma with preservation of normal nerve fascicles and function. AB - An asymptomatic pelvic tumor was incidentally found in a 27-year-old man. A CT guided needle biopsy with a pathologic examination confirmed the diagnosis of a benign schwannoma. We describe the complete robotic resection with the conservation of normal fascicles. The postoperative course was uneventful. No neurological deficit occurred, and the electromyogram was normal 6 weeks and 7 months later. PMID- 28343320 TI - Allergic airway inflammation induces migration of mast cell populations into the mouse airway. AB - Mast cells (MCs) and airway nerves play an important role in allergic asthma. However, little is known about the MCs and their interaction with airway nerves during allergic airway inflammation. This study aims to investigate the distribution and proliferation of MC populations in different lung compartments, along with the association of mast cells with nerve endings, using a house dust mite (HDM) model for allergic airway inflammation. BALB/c mice were exposed to HDM extract intranasally (25 MUg/50 MUl) for 5 consecutive days a week over 7 weeks. Immunofluorescence and Edu stains were used to examine the colocalisation of MCs and nerves and the proliferation of MCs, respectively. HDM treatment caused an increased migration of MCs into bronchi, alveolar parenchyma and airway vessels. The proportions of tryptase-chymase expressing MC (MCTC) increased significantly in the bronchi and the alveolar parenchyma but not in the vascular tissues, by allergic airway inflammation. The association of MCs with nerves was found only in the bronchi and there were no changes in comparison of controls to HDM-treated animals. The present study shows a strong migration of tryptase expressing MC (MCT) and MCTC into the bronchi and the alveolar parenchyma, as well as of MCT in the vascular compartment under HDM treatment. This supports the hypothesis that these mast cell populations may contribute to allergic airway inflammation. PMID- 28343321 TI - A risk score based on admission characteristics to predict progressive hemorrhagic injury from traumatic brain injury in children. AB - : Traumatic brain injury (TBI) is one of the leading causes of death and disability in children, and progressive hemorrhagic injury (PHI) post TBI is associated with poor outcomes. Therefore, the objective of this study was to develop and validate a prognostic model that uses the information available at admission to determine the likelihood of PHI occurrence after TBI in children. The identified demographic data, cause of injury, clinical predictors on admission, computed tomography scan characteristics, and routine laboratory parameters were collected and used to develop a PHI prognostic model with logistic regression analysis, and the prediction model was validated in 68 children. Eight independent prognostic factors were identified: lower Glasgow coma scale score (3 ~ 8) (6 points), intra-axial bleeding/brain contusion (4 points), midline shift >=5 mm (9 points), platelets <100 * 109/L (11 points), prothrombin time >14 s (6 points), international normalized ratio >1.25 (7 points), D-dimer >=5 mg/L (14 points), and glucose ?10 mmol/L (11 points). We calculated risk scores for each child and defined three risk groups: low risk (0 16 points), intermediate risk (17-36 points), and high risk (37-68 points). In the development cohort, the PHI rates after TBI for the low-, intermediate-, and high-risk groups were 10.1, 47.9, and 84.2%, respectively. In the validation cohort, the corresponding PHI rates were 10.9, 47.5, and 85.4%, respectively. The C-statistic for the point system was 0.873 (p = 0.586 by the Hosmer-Lemeshow test) in the development cohort and 0.877 (p = 0.524 by the Hosmer-Lemeshow test) in the validation cohort. CONCLUSION: Using admission predictors, we developed a relatively simple risk score that accurately predicted the risk of PHI after TBI in children. What is Known: * TBI is one of the leading causes of death and disability in children, and PHI post TBI is associated with poor outcomes. *Prediction of patients at low risk of PHI could help reduce treatment costs, whereas identification of patients at high risk of PHI could direct early medical intervention to improve outcomes. What is New: * This study firstly developed a risk score system by assessing the admission information that could provide an earlier prediction of the occurrence of PHI after acute TBI in children. PMID- 28343322 TI - Coulrophobia: how irrational is fear of clowns? PMID- 28343324 TI - A new species of Neocosmocercella Baker & Vaucher, 1983 (Nematoda: Cosmocercidae), a parasite of Phyllomedusa vaillantii Boulenger (Anura: Phyllomedusidae) in the Caxiuana National Forest, eastern Amazon, Brazil. AB - Neocosmocercella bakeri n. sp. is described from the large intestine of Phyllomedusa vaillantii Boulenger collected in the Caxiuana National Forest in the Eastern Brazilian Amazon. The new species is easily distinguished from the type-species of the genus, Neocosmocercella paraguayensis Baker & Vaucher, 1983 in possessing a triangular mouth opening with three simple lips (vs three bi lobed lips and hexagonal mouth opening) and somatic papillae, which are absent in N. paraguayensis. The males of the new species are distinguished by the distribution of the sessile cloacal papillae and the dimensions of the gubernaculum, whereas the females are distinguished by their smaller size and opisthodelphic uterus. This study expands the diagnostic characters of Neocosmocercella Baker & Vaucher, 1983, reports the first species parasitising anurans of the Brazilian Amazon, a new host record for the genus, and the description of the second species of the genus. PMID- 28343323 TI - Post-Traumatic Sleep-Wake Disorders. AB - All living organisms that face a traumatic life event are susceptible to sleep wake disturbances. Stress, which can result in trauma, evokes a high level of physiological arousal associated with sympathetic nervous system activation, during both sleep and wakefulness. Heredity, sex hormones, early losses, developmental factors and intra- and interpersonal conflicts, contribute to the level of baseline physiological arousal, producing either subclinical, clinical or complex clinical traits, acutely and at any time after exposure to a traumatic event. The risk of acute sleep-wake disturbances becoming disorders and syndromes depends on the type of traumatic event and all of the aforementioned factors. Taken together, with consideration for behavioural and environmental heterogeneity, in research, will aid identification and understanding of susceptibility factors in long-term sleep and wakefulness pathology after exposure to traumatic events. PMID- 28343325 TI - MRI can accurately detect meniscal ramp lesions of the knee. AB - PURPOSE: Posterior horn meniscal tears are commonly found in conjunction with anterior cruciate ligament (ACL) injury. Some believe tears in the posterior meniscocapsular zone, coined ramp lesions, are important to knee stability. The purpose of this study was to determine whether pre-operative MRI evaluation was able to accurately and reproducibly identify ramp lesions. METHODS: Three blinded reviewers assessed MRIs twice for the presence of ramp lesions in patients undergoing ACL reconstruction. Sensitivity, specificity, negative predictive value, and positive predictive value for MRI were calculated based on arthroscopic diagnosis of a ramp lesion. Intra-class correlation coefficient was calculated to assess intra- and interobserver reliability of the MRI assessment between the three examiners. Significance was set at p < 0.05. RESULTS: Ninety patients met inclusion criteria (45 males, 45 females, mean age 28.0 years). Thirteen of these patients had arthroscopy-confirmed ramp lesions, while the other 77 had other meniscal pathology. Sensitivity of detecting a ramp lesion on MRI ranged from 53.9 to 84.6%, while specificity was 92.3-98.7%. Negative predictive value was 91.1-97.4%, while positive predictive value was 50.0-90.0%. Inter-rater reliability between three reviewers was moderate at 0.56. The observers had excellent intra-rater reliability ranging from 0.75 to 0.81. CONCLUSIONS: This study demonstrates high sensitivity and excellent specificity in detecting meniscal ramp lesions on MRI. Ramp lesions are likely more common and may have greater clinical implications than previously appreciated; the outcomes of untreated lesions must be investigated. Pre-operative identification of ramp lesions may aid clinicians in surgical planning and patient education to improve outcomes by addressing pathology which may have otherwise been missed. LEVEL OF EVIDENCE: III. PMID- 28343326 TI - Segmental ureterectomy is not inferior to radical nephroureterectomy for either middle or distal ureter urothelial cell carcinomas within 3.5 cm. AB - OBJECTIVE: To evaluate oncologic outcomes of segmental ureterectomy (SU) compared with radical nephroureterectomy (RNU) for urothelial carcinoma of ureter. To evaluate whether tumor position is a factor to influence outcomes of different surgical procedures. METHODS: From November 2003 to June 2016, 131 patients with urothelial carcinoma of ureter underwent SU or RNU at our department. We used survival analysis and Cox regression models to compare oncologic outcomes after SU and RNU. Covariates included surgical type, tumor stage, cancer grade, lesion position, presence of preoperative hydronephrosis and histories of bladder cancer. Patients were divided according to lesion sites for further comparison. RESULTS: The mean length of follow-up was 55.3 and 50.9 months for the RNU and SU group, respectively. The bladder recurrences, local recurrences, distant metastasis, cancer-specific survival and overall survival rates showed no significant differences between RNU and SU (p = 0.596, p = 0.636, p = 0.740, p = 0.809, p = 0.553, respectively). For mid-ureter or distal ureter lesions, no significant difference of oncologic outcomes between SU and RUN was observed. CONCLUSIONS: Our study suggested SU is not inferior to RNU for either middle or distal ureter urothelial cell carcinomas. PMID- 28343327 TI - Osteolytic-variant POEMS syndrome: an uncommon presentation of "osteosclerotic" myeloma. AB - Polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome, a form of osteosclerotic myeloma, is a multisystem disease related to a monoclonal plasma cell proliferative disorder. Osseous lesions are most commonly sclerotic on radiographs and computed tomography (CT), demonstrate low T1 and T2 signal intensity on magnetic resonance imaging (MRI), and have variable degrees of avidity on positon emission tomography (PET) imaging using 18 fluorodeoxyglucose (18F-FDG). We present three cases of POEMS syndrome manifesting as osteolytic lesions with indolent features, including well-defined thin sclerotic rims, no cortical disruption or periosteal reaction, no associated soft-tissue mass, and a periarticular location, all features that could lead to misinterpretation as benign bone lesions. We also report increased T1 signal and diffuse solid enhancement of these lesions on MRI, features previously unreported. POEMS syndrome should not be discounted as a diagnostic consideration in the setting of osteolytic lesions with non-aggressive imaging characteristics on radiographs or CT, especially in the presence of other supportive clinical features. PMID- 28343328 TI - Skeletal development of the hand and wrist: digital bone age companion-a suitable alternative to the Greulich and Pyle atlas for bone age assessment? AB - PURPOSE: To assess reader performance and subjective workflow experience when reporting bone age studies with a digital bone age reference as compared to the Greulich and Pyle atlas (G&P). We hypothesized that pediatric radiologists would achieve equivalent results with each method while digital workflow would improve speed, experience, and reporting quality. MATERIALS AND METHODS: IRB approval was obtained for this HIPAA-compliant study. Two pediatric radiologists performed research interpretations of bone age studies randomized to either the digital (Digital Bone Age Companion, Oxford University Press) or G&P method, generating reports to mimic clinical workflow. Bone age standard selection, interpretation reporting time, and user preferences were recorded. Reports were reviewed for typographical or speech recognition errors. Comparisons of agreement were conducted by way of Fisher's exact tests. Interpretation-reporting times were analyzed on the natural logarithmic scale via a linear mixed model and transformed to the geometric mean. Subjective workflow experience was compared with an exact binomial test. Report errors were compared via a paired random permutation test. RESULTS: There was no difference in bone age determination between atlases (p = 0.495). The interpretation-reporting time (p < 0.001) was significantly faster with the digital method. The faculty indicated preference for the digital atlas (p < 0.001). Signed reports had fewer errors with the digital atlas (p < 0.001). CONCLUSIONS: Bone age study interpretations performed with the digital method were similar to those performed with the Greulich and Pyle atlas. The digital atlas saved time, improved workflow experience, and reduced reporting errors relative to the Greulich and Pyle atlas when integrated into electronic workflow. PMID- 28343329 TI - Stress fractures of the foot and ankle, part 2: site-specific etiology, imaging, and treatment, and differential diagnosis. AB - Stress fractures of the foot and ankle are a commonly encountered problem among athletes and individuals participating in a wide range of activities. This illustrated review, the second of two parts, discusses site-specific etiological factors, imaging appearances, treatment options, and differential considerations of stress fractures of the foot and ankle. The imaging and clinical management of stress fractures of the foot and ankle are highly dependent on the specific location of the fracture, mechanical forces acting upon the injured site, vascular supply of the injured bone, and the proportion of trabecular to cortical bone at the site of injury. The most common stress fractures of the foot and ankle are low risk and include the posteromedial tibia, the calcaneus, and the second and third metatarsals. The distal fibula is a less common location, and stress fractures of the cuboid and cuneiforms are very rare, but are also considered low risk. In contrast, high-risk stress fractures are more prone to delayed union or nonunion and include the anterior tibial cortex, medial malleolus, navicular, base of the second metatarsal, proximal fifth metatarsal, hallux sesamoids, and the talus. Of these high-risk types, stress fractures of the anterior tibial cortex, the navicular, and the proximal tibial cortex may be predisposed to poor healing because of the watershed blood supply in these locations. The radiographic differential diagnosis of stress fracture includes osteoid osteoma, malignancy, and chronic osteomyelitis. PMID- 28343330 TI - Human papilloma virus (HPV) infection leads to the development of head and neck lesions but offers better prognosis in malignant Indian patients. AB - Head and neck cancers constitute a multifactorial global disease burden and are associated with human papilloma virus (HPV) as a possible risk factor. The aim of the study is to understand the relationship between HPV and the development of head and neck lesions in Indian patients. To this end, frequency of HPV was assessed in relation to different demographic and etiological features and correlated with patient survival. The prevalence of HPV significantly increased from mild dysplastic lesions (43.6%) to head and neck squamous cell carcinoma (HNSCC) stage IV (68.5%) with HPV 16 being pre-dominant in both dysplasia (43.8%) and HNSCC (61.5%). Similar trend was observed in increasing grades of the tumour. In invasive lesions, patients aged below the median age of onset showed significantly higher occurrence of HPV than those above it. Patients harbouring HPV showed a significantly better survival irrespective of age of onset. Likewise, better survival was observed in tobacco habit negative/HPV-positive patients, and as reflected in both univariate and multivariate analysis. Majority of the HPV 16-positive samples showed moderate/high nuclear expression of HPV E6 and E7 proteins in tumours and respective basal layer of adjacent normal tissues. Thus, our data indicate that frequent HPV infection, along with tobacco habit, is a pre-requisite factor for the development of HNSCC of Indian patients but offers a better survival even during tobacco usage, implicating its diagnostic and prognostic importance. PMID- 28343331 TI - Economic and public health consequences of delayed access to medical care for migrants living with HIV in France. AB - In 2013, migrants accounted for 46% of newly diagnosed cases of HIV (human immunodeficiency virus) infection in France. These populations meet with specific obstacles leading to late diagnosis and access to medical care. Delayed access to care (ATC) for HIV-infected migrants reduces their life expectancy and quality of life. Given the reduction of infectivity under antiretroviral (ARV) treatment, delayed ATC for HIV-infected migrants may also hinder the control of the HIV epidemic. The objective of this study is to measure the public health and economic consequences of delayed ATC for migrants living with HIV in France. Using a healthcare payer perspective, our model compares the lifetime averted infections and costs of early vs. late ATC for migrants living with HIV in France. Early and late ATC are defined by an entry into care with a CD4 cell count of 350 and 100/mm3, respectively. Our results show that an early ATC is dominant, even in the worst-case scenario. In the most favorable scenario, early ATC generates an average net saving of ?198,000 per patient, and prevents 0.542 secondary infection. In the worst-case scenario, early ATC generates an average net saving of ?32,000 per patient, and prevents 0.299 secondary infection. These results are robust to various adverse changes in key parameters and to a definition of late ATC as an access to care at a CD4 level of 200/mm3. In addition to individual health benefits, improving ATC for migrants living with HIV proves efficient in terms of public health and economics. These results stress the benefit of ensuring early ATC for all individuals living with HIV in France. PMID- 28343332 TI - Posterior elements disruption with hybrid constructs in AIS patients: is there an impact on proximal junctional kyphosis? AB - PURPOSE: Proximal junctional kyphosis (PJK) is a frequent proximal adjacent segment disease following spinal fusion in adolescent idiopathic scoliosis (AIS) and its rate has been estimated to 28% in the literature. The etiology is multifactorial, and risk factors associated with PJK are controversial. The aim of this study was to demonstrate that the disruption of muscular and bony tissue above the upper instrumented vertebra (UIV) during surgery does not increase the rate of PJK in patients undergoing posterior fusion for adolescent idiopathic scoliosis. MATERIAL AND METHOD: 50 patients with AIS operated between June 2014 and January 2016 were included. Every patient underwent a long posterior spine arthrodesis with a hybrid construct (proximal lamino-laminar claw, thoracic sublaminar bands and lumbar screws). The dissection of posterior elements above the UIV was necessary for the placement of proximal anchors. Radiographic analysis including proximal junctional angle, spino-pelvic parameters (cervical lordosis, thoracic kyphosis TK, lumbar lordosis, pelvic incidence, pelvic tilt, sacral slope) and sagittal vertical axis were collected preoperatively and postoperatively at the last control. The numbers of fused levels, locations of upper instrumented vertebra, locations of lower instrumented vertebra, length of fusion segments were also recorded. Multiple odd ratios and other statistical analysis were performed to evaluate the relation between PJK and the potential risk factors. RESULTS: There were 43 females and 7 males with a mean age of 14.8 years at surgery. PJK occurred in 5 out of 50 cases with an incidence of 10%. The mean follow-up was 18 months. There was no significant difference in gender (OR 1.36, p = 0.8), decrease of TK (OR 1.63, p = 0 0.69), location of UIV (OR 2.25, p = 0.4), LIV (OR 2, p = 0.55), and SVA change (OR 1.63, p = 0.46). CONCLUSIONS: The disruption of ligamentous and bony tissue proximal to the UIV during the surgery does not increase the rate of PJK. Level of evidence IV. PMID- 28343333 TI - Use of phase-locking value in sensorimotor rhythm-based brain-computer interface: zero-phase coupling and effects of spatial filters. AB - Phase-locking value (PLV) is a potentially useful feature in sensorimotor rhythm based brain-computer interface (BCI). However, volume conduction may cause spurious zero-phase coupling between two EEG signals and it is not clear whether PLV effects are independent of spectral amplitude. Volume conduction might be reduced by spatial filtering, but it is uncertain what impact this might have on PLV. Therefore, the goal of this study was to explore whether zero-phase PLV is meaningful and how it is affected by spatial filtering. Both amplitude and PLV feature were extracted in the frequency band of 10-15 Hz by classical methods using archival EEG data of 18 subjects trained on a two-target BCI task. The results show that with right ear-referenced data, there is meaningful long-range zero-phase synchronization likely involving the primary motor area and the supplementary motor area that cannot be explained by volume conduction. Another novel finding is that the large Laplacian spatial filter enhances the amplitude feature but eliminates most of the phase information seen in ear-referenced data. A bipolar channel using phase-coupled areas also includes both phase and amplitude information and has a significant practical advantage since fewer channels required. PMID- 28343334 TI - Design and test of a Microsoft Kinect-based system for delivering adaptive visual feedback to stroke patients during training of upper limb movement. AB - The present paper describes the design and test of a low-cost Microsoft Kinect based system for delivering adaptive visual feedback to stroke patients during the execution of an upper limb exercise. Eleven sub-acute stroke patients with varying degrees of upper limb function were recruited. Each subject participated in a control session (repeated twice) and a feedback session (repeated twice). In each session, the subjects were presented with a rectangular pattern displayed on a vertical mounted monitor embedded in the table in front of the patient. The subjects were asked to move a marker inside the rectangular pattern by using their most affected hand. During the feedback session, the thickness of the rectangular pattern was changed according to the performance of the subject, and the color of the marker changed according to its position, thereby guiding the subject's movements. In the control session, the thickness of the rectangular pattern and the color of the marker did not change. The results showed that the movement similarity and smoothness was higher in the feedback session than in the control session while the duration of the movement was longer. The present study showed that adaptive visual feedback delivered by use of the Kinect sensor can increase the similarity and smoothness of upper limb movement in stroke patients. PMID- 28343335 TI - A new infant hybrid respiratory simulator: preliminary evaluation based on clinical data. AB - A new hybrid (numerical-physical) simulator of the respiratory system, designed to simulate spontaneous and artificial/assisted ventilation of preterm and full term infants underwent preliminary evaluation. A numerical, seven-compartmental model of the respiratory system mechanics allows the operator to simulate global and peripheral obstruction and restriction of the lungs. The physical part of the simulator is a piston-based construction of impedance transformer. LabVIEW real time software coordinates the work of both parts of the simulator and its interaction with a ventilator. Using clinical data, five groups of "artificial infants" were examined: healthy full-term infants, very low-birth-weight preterm infants successfully (VLBW) and unsuccessfully extubated (VLBWun) and extremely low-birth-weight preterm infants without (ELBW) and with bronchopulmonary dysplasia (ELBW_BPD). Pressure-controlled ventilation was simulated to measure peak inspiratory pressure, mean airway pressure, total (patient + endotracheal tube) airway resistance (R), total dynamic compliance of the respiratory system (C), and total work of breathing by the ventilator (WOB). The differences between simulation and clinical parameters were not significant. High correlation coefficients between both types of data were obtained for R, C, and WOB (gamma R = 0.99, P < 0.0005; gamma C = 0.85, P < 0.005; gammaWOB = 0.96, P < 0.05, respectively). Thus, the simulator accurately reproduces infant respiratory system mechanics. PMID- 28343336 TI - Sunitinib-induced hypothyroidism predicts progression-free survival in metastatic renal cell carcinoma patients. AB - Sunitinib is a tyrosine kinase inhibitor (TKI) used in treatment of metastatic renal cell carcinoma (mRCC), gastrointestinal stromal tumors and pancreatic neuroendocrine tumors. One of the most common side effects related to sunitinib is hypothyroidism. Recent trials suggest correlation between the incidence of hypothyroidism and treatment outcome in patients treated with TKI. This study evaluates whether development of hypothyroidism is a predictive marker of progression-free survival (PFS) in patients with mRCC treated with sunitinib. Twenty-seven patients diagnosed with clear cell mRCC, after nephrectomy and in 'good' or 'intermediate' MSKCC risk prognostic group, were included in the study. All patients received sunitinib as a first-line treatment on a standard schedule (initial dose 50 mg/day, 4 weeks on, 2 weeks off). The thyroid-stimulating hormone serum levels were obtained at the baseline and every 12 weeks of treatment. In statistic analyses, we used Kaplan-Meier method for assessment of progression-free survival; for comparison of survival, we used log-rank test. In our study, the incidence of hypothyroidism was 44%. The patients who had developed hypothyroidism had better median PFS to patients with normal thyroid function 28,3 months [95% (CI) 20.4-36.2 months] versus 9.8 months (6.4-13.1 months). In survival analysis, we perceive that thyroid dysfunction is a predictive factor of a progression-free survival (PFS). In the unified group of patients, the development of hypothyroidism during treatment with sunitinib is a positive marker for PFS. During that treatment, thyroid function should be evaluated regularly. PMID- 28343337 TI - Trismus following different treatment modalities for head and neck cancer: a systematic review of subjective measures. AB - The aim of this review was to compare systematically the subjective measure of trismus between different interventions to treat head and neck cancer, particularly those of the oropharynx. Using The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) Guidelines, Six databases were searched for the text using various terms which include "oropharyngeal/head and neck cancer", "trismus/mouth opening" and the various treatment modalities. Included in the review were clinical studies (> or =10 patients). Three observers independently assessed the papers identified. Among the six studies reviewed, five showed a significantly worst outcome with regard to the quality-of-life questionnaire scores for a radiotherapy or surgery and radiotherapy (RT) +/- chemotherapy or chemoradiotherapy when compared to surgery alone. Only one study showed no significant difference between surgery alone and other treatment modalities. Subjective quality-of-life measures are a concurrent part of modern surgical practice. Although subjective measures were utilised to measure post operative trismus successfully, there was no consensus as to which treatment modality had overall better outcomes, with conflicting studies in keeping with the current debate in this field. Larger and higher quality studies are needed to compare all three treatment modalities. PMID- 28343339 TI - Bound PAHs in Sediment and Related Environmental Significance. AB - Extractable polycyclic aromatic hydrocarbons (EPAHs) and bound PAHs (BPAHs) were measured in a sediment core using conventional Soxhlet extraction and a more astringent extraction method, with the objectives of determining the influence of BPAHs on the historical reconstruction of PAHs and exploring the formation of BPAHs and long-term behaviors of PAHs in sediment. The results indicated that the formation of BPAHs was clearly sediment-depth and molecular-size dependent. BPAHs represents an important portion of PAHs in sediment and cannot be extracted by conventional Soxhlet extraction. This suggests that the previously developed vertical profile of PAHs is not the real chronology of PAHs and the plausible interpretation derived from the sedimentary records of PAHs needs reexamination. Based on the previous findings, a biphase model was proposed and the formation of BPAHs was predicted. Due to the different nature of geosorbents in sediment, redistribution of PAHs among these geosorbents logically leads to the formation of BPAHs and is kinetically favorable for smaller molecular PAHs. This is consistent with the obtained results. Many factors may influence the formation of BPAHs, such as the physicochemical structure of sediment and environmental conditions. There is still a long way to reveal the thermodynamical characteristics in action during the formation of BPAHs. PMID- 28343338 TI - Expression of typical osteoclast markers by PBMCs after PEG-induced fusion as a model for studying osteoclast differentiation. AB - Bone is a metabolically active organ subjected to continuous remodeling process that involves resorption by osteoclast and subsequent formation by osteoblasts. Osteoclast involvement in this physiological event is regulated by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappaB ligand (RANKL). Fusion of mono-nuclear pre-osteoclasts is a critical event for osteoclast differentiation and for bone resorption. Here we show that PBMCs can be successfully fused with polyethylenglicol (PEG) in order to generated viable osteoclast-like cells that exhibit tartrate-resistant acid phosphatase (TRAP) and bone resorptive activities. PEG-fused PBMCs expressed additional markers compatible with osteoclastogenic differentiation such as carbonic anhydrase II (CAII), calcitonin receptor (CR), cathepsin K (Cat K), vacuolar ATPase (V-ATPase) subunit C1 (V-ATPase), integrin beta3, RANK and cell surface aminopeptidase N/CD13. Actin redistribution in PEG-fused cells was found to be affected by cell cycle synchronization at G0/G1 or G2/M phases. PEG-induced fusion also led to expression of tyrosine kinases c-Src and Syk in their phosphorylated state. Scanning electron microscopy images showed morphological features typical of osteoclast-like cells. The results here shown allow concluding that PEG-induced fusion of PBMCs provides a suitable model system for understanding the mechanisms involved in osteoclastogenesis and for assaying new therapeutic strategies. PMID- 28343340 TI - A lake-centric geospatial database to guide research and inform management decisions in an Arctic watershed in northern Alaska experiencing climate and land use changes. AB - Lakes are dominant and diverse landscape features in the Arctic, but conventional land cover classification schemes typically map them as a single uniform class. Here, we present a detailed lake-centric geospatial database for an Arctic watershed in northern Alaska. We developed a GIS dataset consisting of 4362 lakes that provides information on lake morphometry, hydrologic connectivity, surface area dynamics, surrounding terrestrial ecotypes, and other important conditions describing Arctic lakes. Analyzing the geospatial database relative to fish and bird survey data shows relations to lake depth and hydrologic connectivity, which are being used to guide research and aid in the management of aquatic resources in the National Petroleum Reserve in Alaska. Further development of similar geospatial databases is needed to better understand and plan for the impacts of ongoing climate and land-use changes occurring across lake-rich landscapes in the Arctic. PMID- 28343341 TI - Public availability of research data in dentistry journals indexed in Journal Citation Reports. AB - OBJECTIVES: Dentistry is a medical discipline with an increasing scientific production in the last years. Due to the importance of data sharing in science, this study aims at analyzing the availability of raw data in articles from scientific journals indexed in the Dentistry category of the 2014 edition of the Journal Citation Reports. MATERIAL AND METHODS: A review of the 88 websites of journals from the Dentistry category was conducted to determine the data-sharing editorial policies. Furthermore, a search in the PubMed Central repository to collect information about the characteristics of the supplementary material of articles from those journals was carried out. RESULTS: The possibility of publishing a supplementary material was higher in the first quartile journals. A percentage of 7.6% of the articles registered in PubMed Central contained a supplementary material, especially text documents, but the presence of spreadsheets was scarce. CONCLUSIONS: There is a relationship between openness policies and the impact of the journals according to their quartile or position ranking by the impact factor in the JCR, but the willingness of sharing raw data in spreadsheets format is still limited. CLINICAL RELEVANCE: This study will reveal the resources of raw data which will improve quality of research and clinical practice. PMID- 28343342 TI - Caregiver-Teacher Concordance of Challenging Behaviors in Children with Autism Spectrum Disorder Served in Community Mental Health Settings. AB - Children with autism spectrum disorder (ASD) exhibit high rates of challenging behaviors that impair functioning and represent the primary presenting problem in mental health (MH) services. Obtaining symptom reports from multiple informants is critical for treatment planning. This study evaluated caregiver-teacher concordance of ratings of the intensity of challenging behaviors in children with ASD receiving MH services, and identified child clinical factors associated with concordance. This sample included 141 children (M = 9.07 years), their caregivers, and teachers. Caregiver-teacher concordance of challenging behaviors was low and impacted by the degree and type of child psychiatric comorbidity. Findings support need for increased attention to the range of psychiatric problems children with ASD present to tailor treatment recommendations and service delivery. PMID- 28343343 TI - Child and Adult Factors Related to Quality of Life in Adults with Autism. AB - The WHO Quality of Life-Brief questionnaire was used to assess quality of life (QoL) among 52 adults with autism (mean age 49 years) followed-up since childhood. Overall, assessments of QOL were more positive than measures of objective social outcome (jobs, independence, relationships etc.) but correlations between caregiver and self-reports were low. Informant ratings indicated few correlations between current QoL and any child or adult factors. On self-report ratings, QoL was significantly negatively correlated with severity of repetitive behaviours in childhood; higher QoL was positively associated with better adult social outcomes. However, only a minority of adults (n = 22) could provide self-report data and findings highlight the need to develop valid measures for assessing the well-being of adults with autism. PMID- 28343344 TI - Simultaneous detection of chlorinated polycyclic aromatic hydrocarbons with polycyclic aromatic hydrocarbons by gas chromatography-mass spectrometry. AB - Chlorinated polycyclic aromatic hydrocarbons (ClPAHs), including polychlorinated naphthalenes (PCNs), are hazardous and widespread in the environment, but studies of these substances in the wastewater environment are lacking. In this study, five typical PCNs and five typical ClPAHs (other than PCNs) were simultaneously detected along with their parent polycyclic aromatic hydrocarbons in wastewater samples. All these compounds could be analyzed by gas chromatography- electron ionization mass spectrometry in selected ion monitoring mode and separated on a DB-17ms column. Calibration curves were created both in pure solvent and in wastewater matrix samples. The coefficients of determination for most compounds were greater than 0.99, indicating a satisfactory degree of linearity in the complex matrix samples. The influence of the matrix on the true concentrations of the environmental samples was corrected by use of the matrix calibration curve. The recoveries of all compounds were between 58% and 127%, with standard deviations lower than 20%. The method detection and quantification limits were less than 27.6 ng/L and less than 91.9 ng/L respectively in the aqueous phase, and less than 0.18 ng/L and less than 0.61 ng/L respectively in the solid phase of 4-L wastewater samples. This analytical method was successfully used to detect PCNs and ClPAHs in the water from a river receiving effluent from a wastewater treatment plant. The concentrations of each compound ranged from 3.1 to 29.6 ng/L. This method could also be used for detection of other polycyclic aromatic hydrocarbon derivatives with similar physical and chemical properties in different matrix samples. Graphical Abstract ?. PMID- 28343345 TI - Assessment of nucleosides as putative tumor biomarkers in prostate cancer screening by CE-UV. AB - Cancer is responsible for millions of deaths worldwide, but most base diseases may be cured if detected early. Screening tests may be used to identify early stage malignant neoplasms. However, the major screening tool for prostate cancer, the prostate-specific antigen test, has unsuitable sensitivity. Since cancer cells may affect the pattern of consumption and excretion of nucleosides, such biomolecules are putative biomarkers that can be used for diagnosis and treatment evaluation. Using a previously validated method for the analysis of nucleosides in blood serum by capillary electrophoresis with UV-vis spectroscopy detection, we investigated 60 samples from healthy individuals and 42 samples from prostate cancer patients. The concentrations of nucleosides in both groups were compared and a multivariate partial least squares-discriminant analysis classification model was optimized for prediction of prostate cancer. The validation of the model with an independent sample set resulted in the correct classification of 82.4% of the samples, with sensitivity of 90.5% and specificity of 76.7%. A significant downregulation of 5-methyluridine and inosine was observed, which can be indicative of the carcinogenic process. Therefore, such analytes are potential candidates for prostate cancer screening. Graphical Abstract Separation of the studied nucleosides and the internal standard 8-Bromoguanosine by CE-UV (a); classification of the external validation samples (30 from healthy volunteers and 21 from prostate cancer patients) by the developed Partial Least Square - Discriminant Analysis (PLS-DA) model with accuracy of 82.4% (b); Receiver Operating Characteristics (ROC) curve (c); and Variable Importance in the Projection (VIP) values for the studied nucleosides (d). A significant down regulation of 5- methyluridine (5mU) and inosine (I) was observed, which can be indicative of the presence of prostate tumors. PMID- 28343346 TI - Molecularly imprinted polymer prepared with polyhedral oligomeric silsesquioxane through reversible addition-fragmentation chain transfer polymerization. AB - Polyhedral oligomeric silsesquioxane (POSS) was utilized to prepare imprinted polymer through reversible addition-fragmentation chain transfer polymerization (RAFT) successfully. The imprinted polymer was made with a mixture of RAFT agent, 4-vinylpyridine (4-VP), POSS monomer [PSS-(1-propylmethacrylate)-heptaisobutyl substituted, MA 0702], and ethylene glycol dimethacrylate (EDMA), with ketoprofen (KET) as template. The influence of polymerization variables, the amount of RAFT agent and POSS monomer, the ratio of KET to 4-VP, and the ratio of 4-VP to EDMA, were investigated on the retention factor and imprinting effect. The greatest imprinting factor of the RAFT agent-based POSS MIP was 15.2, about 1.5 times higher than the RAFT agent-free agent POSS MIP. The permeability, surface morphology, as well as pore size distribution of POSS MIP monoliths made with RAFT agent and without RAFT agent were also studied. The optimal MIP was applied to solid phase extraction for KET from commercial tablets. The mean recoveries of KET for RAFT-based POSS MIP was 85.2% with a relative standard deviation of 2.6%. PMID- 28343347 TI - Bioanalysis of farnesyl pyrophosphate in human plasma by high-performance liquid chromatography coupled to triple quadrupole tandem mass spectrometry and hybrid quadrupole Orbitrap high-resolution mass spectrometry. AB - The isoprenoids farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are pivotal intermediates for cholesterol homeostasis and cell signaling in the mevalonate pathway. We developed a sensitive and selective high performance liquid chromatography tandem triple quadrupole mass spectrometry (LC QQQ-MS) method for FPP in human plasma without the need for a derivatization process. We optimized the sample preparation procedure to extract FPP and 13C5 FPP (as internal standard) from sample fluids using methanol. Phosphate-buffered saline was used as the surrogate matrix for the preparation of calibration curves and quality control samples. Using an XBridge C18 column (3.5 MUm, 2.1 * 100-mm ID) with gradient elution composed of 10 mmol/L ammonium carbonate/ammonium hydroxide (1000:5, v/v) and acetonitrile/ammonium hydroxide (1000:5, v/v) provided the sharp peaks of FPP and 13C5-FPP in human plasma. The calibration curve ranged from 0.2 to 20 ng/mL in human plasma with acceptable intra-day and inter-day precision and accuracy. The sensitivity of this bioanalytical method was sufficient for clinical analysis. The endogenous FPP plasma concentrations in 40 human healthy volunteers ascertained by LC-QQQ-MS and high-performance liquid chromatography tandem hybrid quadrupole Orbitrap high-resolution mass spectrometry (LC-Q-Orbi-MS) were comparable. Furthermore, the endogenous GGPP in human plasma was selectively detected for the first time by LC-Q-Orbi-MS. In conclusion, a sensitive bioanalytical method for FPP in human plasma by means of LC-QQQ-MS and LC-Q-Orbi-MS was developed in this study. Taking into account the versatility of LC-Q-Orbi-MS, the simultaneous detection of FPP and GGPP may be feasible in clinical practice. PMID- 28343348 TI - Process analytical techniques for hot-melt extrusion and their application to amorphous solid dispersions. AB - Newly developed active pharmaceutical ingredients (APIs) are often poorly soluble in water. As a result the bioavailability of the API in the human body is reduced. One approach to overcome this restriction is the formulation of amorphous solid dispersions (ASDs), e.g., by hot-melt extrusion (HME). Thus, the poorly soluble crystalline form of the API is transferred into a more soluble amorphous form. To reach this aim in HME, the APIs are embedded in a polymer matrix. The resulting amorphous solid dispersions may contain small amounts of residual crystallinity and have the tendency to recrystallize. For the controlled release of the API in the final drug product the amount of crystallinity has to be known. This review assesses the available analytical methods that have been recently used for the characterization of ASDs and the quantification of crystalline API content. Well-established techniques like near- and mid-infrared spectroscopy (NIR and MIR, respectively), Raman spectroscopy, and emerging ones like UV/VIS, terahertz, and ultrasonic spectroscopy are considered in detail. Furthermore, their advantages and limitations are discussed with regard to general practical applicability as process analytical technology (PAT) tools in industrial manufacturing. The review focuses on spectroscopic methods which have been proven as most suitable for in-line and on-line process analytics. Further aspects are spectroscopic techniques that have been or could be integrated into an extruder. PMID- 28343350 TI - An exploration of differences between Japan and two European countries in the self-reporting and valuation of pain and discomfort on the EQ-5D. AB - PURPOSE: To investigate the systematic differences in the self-reporting and valuation of overall health and, in particular, pain/discomfort between three countries (England/UK, Japan, and Spain) on the EQ-5D. METHODS: Existing datasets were used to explore differences in responses on the EQ-5D descriptive system between Japan (3L and 5L), the UK (3L), England (5L), and Spain (5L), particularly on the dimension of pain/discomfort. The role of different EQ dimensions in determining self-reported overall health scores for the EuroQol visual analog scale (EQ-VAS) was investigated using ordinary least squares regression. Time trade-off (TTO) results from Japanese and UK respondents for the EQ-5D-3L as well as Japanese and English respondents for the EQ-5D-5L were compared using t tests. RESULTS: For the EQ-5D-3L, a higher percentage of respondents in Japan than in the UK reported 'no pain/discomfort' (81.6 vs 67.0%, respectively); for the EQ-5D-5L, the proportions were 79.2% in Spain, 73.2% in Japan, and 63-64% in England, after adjusting for age differences in samples. The 'pain/discomfort' dimension had the largest impact on respondents' self-reported EQ-VAS only for EQ-5D-3L in Japan. Using the EQ-5D-3L, Japanese respondents were considerably less willing to trade off time to avoid pain/discomfort than the UK respondents; for example, moving from health state, 11121 (some problems with pain/discomfort) to 11131 (extreme pain/discomfort) represented a decrement of 0.65 on the observed TTO value in the UK compared with 0.15 in Japan. Using the EQ-5D-5L, Japanese respondents were also less willing to trade off time to avoid pain/discomfort than respondents in England; however, the difference in values was much smaller than that observed using EQ-5D-3L data. CONCLUSIONS: This study provides evidence of between-country differences in the self-reporting and valuation of health, including pain/discomfort, when using EQ-5D in general population samples. The results suggest a need for caution when comparing or aggregating EQ-5D self-reported data in multi-country studies. PMID- 28343349 TI - Modernizing quality of life assessment: development of a multidimensional computerized adaptive questionnaire for patients with schizophrenia. AB - OBJECTIVE: Quality of life (QoL) is still assessed using paper-based and fixed length questionnaires, which is one reason why QoL measurements have not been routinely implemented in clinical practice. Providing new QoL measures that combine computer technology with modern measurement theory may enhance their clinical use. The aim of this study was to develop a QoL multidimensional computerized adaptive test (MCAT), the SQoL-MCAT, from the fixed-length SQoL questionnaire for patients with schizophrenia. METHODS: In this multicentre cross sectional study, we collected sociodemographic information, clinical characteristics (i.e., duration of illness, the PANSS, and the Calgary Depression Scale), and quality of life (i.e., SQoL). The development of the SQoL-CAT was divided into three stages: (1) multidimensional item response theory (MIRT) analysis, (2) multidimensional computerized adaptive test (MCAT) simulations with analyses of accuracy and precision, and (3) external validity. RESULTS: Five hundred and seventeen patients participated in this study. The MIRT analysis found that all items displayed good fit with the multidimensional graded response model, with satisfactory reliability for each dimension. The SQoL-MCAT was 39% shorter than the fixed-length SQoL questionnaire and had satisfactory accuracy (levels of correlation >0.9) and precision (standard error of measurement <0.55 and root mean square error <0.3). External validity was confirmed via correlations between the SQoL-MCAT dimension scores and symptomatology scores. CONCLUSION: The SQoL-MCAT is the first computerized adaptive QoL questionnaire for patients with schizophrenia. Tailored for patient characteristics and significantly shorter than the paper-based version, the SQoL-MCAT may improve the feasibility of assessing QoL in clinical practice. PMID- 28343351 TI - Health-related quality of life (HRQoL) and its correlates among community recruited children living with HIV and uninfected children born to HIV-infected parents in West Bengal, India. AB - PURPOSE: Helping children living with HIV (CLH) to attain an optimum quality of life is an important goal for HIV programs around the world. Our principal objectives were to determine the association of HIV infection with different domains of health-related quality of life (HRQoL) among 8- to 15-year-old CLH in India and to compare the HRQoL parameters between CLH and HIV-negative children born to HIV-infected parents ("HIV-affected"). We also assessed whether antiretroviral therapy (ART) and CD4 lymphocyte counts were associated with HRQoL among CLH. METHODS: Using the "Quality of Life (health-related) of Children Living with HIV/AIDS in India" instrument, we interviewed 199 CLH and 194 HIV affected children from three districts of West Bengal, India. Participants were asked to quantify the difficulties faced by them in six HRQoL domains: physical, emotional, social, school functioning, symptoms, and discrimination. RESULTS: The mean age of the participants was 11.6 (SD +/- 2.5) years. CLH, compared to HIV affected children, had poorer scores on all HRQoL domains except 'discrimination.' Among CLH, there were no significant differences in HRQoL domain scores (except in the 'discrimination' domain) between ART-treated and untreated groups. CD4 lymphocyte count was found to be a significant positive predictor of the 'symptom' scale score. CONCLUSIONS: In India, interventions for CLH mostly focus on biological disease. However, the current study revealed that HRQoL among CLH was much poorer than that of a socio-demographically comparable group. Culturally and developmentally appropriate psychosocial support measures for Indian CLH are urgently needed. PMID- 28343352 TI - The Role of Hypofractionated Radiotherapy in Prostate Cancer. AB - PURPOSE OF REVIEW: It is now accepted that prostate cancer has a low alpha/beta ratio, establishing a strong basis for hypofractionation of prostate radiotherapy. This review focuses on the rationale for hypofractionation and presents the evidence base for establishing moderate hypofractionation for localised disease as the new standard of care. The emerging evidence for extreme hypofractionation in managing localized and oligometastatic prostate cancer is reviewed. RECENT FINDINGS: The 5-year efficacy and toxicity outcomes from four phase III studies have been published within the last 12 months. These studies randomizing over 6000 patients to conventional fractionation (1.8-2.0 Gy per fraction) or moderate hypofractionation (3.0-3.4 Gy per fraction). They demonstrate hypofractionation to be non-inferior to conventional fractionation. Moderate hypofractionation for localized prostate cancer is safe and effective. There is a growing body of evidence in support of extreme hypofractionation for localized prostate cancer. Extreme hypofractionation may have a role in managing prostate oligometastases, but further studies are needed. PMID- 28343353 TI - Development, Reproduction, Survival, and Demographic Patterns of Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) on Different Commercial Tomato Cultivars. AB - The increase in the production of tomato, Solanum lycopersicon Mill. (Solanaceae), has favored the proliferation of pests, especially Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae). In this study, the development, reproduction, survival, and demographic parameters of T. absoluta reared on six commercial tomato cultivars (Cherry, Cordilheira, Giuliana, Nemoneta, Paron, and Santa Clara) were evaluated. Tuta absoluta completed its development in all tomato cultivars. Development from newly hatched caterpillar to newly emerged adult varied between 24.8 and 28.2 days. Female fecundity ranged from 126.3 to 166.9 eggs, with fertility from 54.2 to 84.1%. Mortality during egg-adult development varied between 21.4 and 46.4% for insects reared on cultivars Cherry and Giuliana, respectively. The cultivars Cordilheira, Giuliana, and Santa Clara are promising options to tomato producers in order to decrease the attack and proliferation of T. absoluta. However, the development and population growth of T. absoluta is faster on the tomato cultivar Cherry. PMID- 28343354 TI - Unusual severe case of hemolytic uremic syndrome due to Shiga toxin 2d-producing E. coli O80:H2. AB - BACKGROUND: Hemolytic uremic syndrome (HUS) is one of the most common causes of acute renal failure in children, with the majority of cases caused by an infection with Shiga toxin-producing Escherichia coli (STEC). Whereas O157 is still the predominant STEC serotype, non-O157 serotypes are increasingly associated with STEC-HUS. However, little is known about this emerging and highly diverse group of non-O157 serotypes. With supportive therapy, STEC-HUS is often self-limiting, with occurrence of chronic sequelae in just a small proportion of patients. CASE DIAGNOSIS/TREATMENT: In this case report, we describe a 16-month old boy with a highly severe and atypical presentation of STEC-HUS. Despite the presentation with multi-organ failure and extensive involvement of central nervous system due to extensive thrombotic microangiopathy (suggestive of atypical HUS), fecal diagnostics revealed an infection with the rare serotype: shiga toxin 2d-producing STEC O80:H2. CONCLUSIONS: This report underlines the importance of STEC diagnostic tests in all children with HUS, including those with an atypical presentation, and emphasizes the importance of molecular and serotyping assays to estimate the virulence of an STEC strain. PMID- 28343355 TI - Anti-C1q autoantibodies as markers of renal involvement in childhood-onset systemic lupus erythematosus. AB - BACKGROUND: Childhood-onset systemic lupus erythematosus (cSLE) is rare, and considered more severe than its adult-onset counterpart. Lupus nephritis (LN) occurs more frequently in children, accounting for higher long-term morbidity and mortality compared with adults. Thus, reliable biological markers are needed to predict disease course. This study aimed to investigate the capacity of anti-C1q autoantibodies (Abs) to predict renal flare and global disease activity in cSLE patients, and association with disease activity and kidney involvement. METHODS: Twenty-eight patients with cSLE including 19 patients (68%) with a history of LN were included retrospectively. Anti-C1q Abs were analysed by ELISA at renal flare up or in the quiescent phase of disease and compared with Farr dsDNA assay. RESULTS: Thirty-one flares occurred during follow-up: anti-C1q Abs were positive in 26 (84%), strongly associated with active disease status (p < 0.0001), and correlated with global disease activity score (p < 0.0001) and anti-dsDNA Abs presence (p < 0.0001). The specificity of anti-C1q Abs was higher than anti-dsDNA (73% vs 19%) in discriminating LN patients, whereas the receiver operating characteristic curves were not statistically different (0.83 +/- 0.06 vs 0.78 +/- 0.08 respectively), similar to C3 dosage. The presence of anti-C1q Abs at diagnosis was not predictive for global or renal flare. Introduction of a modified SLEDAI score excluding dsDNA Abs, demonstrated a stronger correlation of anti-C1q Abs titres with SLEDAI score in comparison with the Farr test. CONCLUSION: Anti-C1q Abs seem very specific to flares, including LN in children, and their role in daily practice compared with the Farr dsDNA assay needs to be defined. PMID- 28343356 TI - Development of a novel strategy to target CD39 antithrombotic activity to the endothelial-platelet microenvironment in kidney ischemia-reperfusion injury. AB - Kidney ischemia-reperfusion injury (IRI) is common during transplantation. IRI is characterised by inflammation and thrombosis and associated with acute and chronic graft dysfunction. P-selectin and its ligand PSGL-1 are cell adhesion molecules that control leukocyte-endothelial and leukocyte-platelet interactions under inflammatory conditions. CD39 is the dominant vascular nucleotidase that facilitates adenosine generation via extracellular ATP/ADP-phosphohydrolysis. Adenosine signalling is protective in renal IRI, but CD39 catalytic activity is lost with exposure to oxidant stress. We designed a P-selectin targeted CD39 molecule (rsol.CD39-PSGL-1) consisting of recombinant soluble CD39 that incorporates 20 residues of PSGL-1 that bind P-selectin. We hypothesised that rsol.CD39-PSGL-1 would maintain endothelial integrity by focusing the ectonucleotidase platelet-inhibitory activity and reducing leukocyte adhesion at the injury site. The rsol.CD39-PSGL-1 displayed ADPase activity and inhibited platelet aggregation ex vivo, as well as bound with high specificity to soluble P selectin and platelet surface P-selectin. Importantly, mice injected with rsol.CD39-PSGL-1 and subjected to renal IRI showed significantly less kidney damage both biochemically and histologically, compared to those injected with solCD39. Furthermore, the equivalent dose of rsol.CD39-PSGL-1 had no effect on tail template bleeding times. Hence, targeting recombinant CD39 to the injured vessel wall via PSGL-1 binding resulted in substantial preservation of renal function and morphology after IRI without toxicity. These studies indicate potential translational importance to clinical transplantation and nephrology. PMID- 28343357 TI - Gut Microbiome in Chronic Kidney Disease. AB - With over 100 trillion microbial cells, the gut microbiome plays important roles in both the maintenance of health and the pathogenesis of disease. Gut microbiome dysbiosis, resulted from alteration of composition and function of the gut microbiome and disruption of gut barrier function, is commonly seen in patients with chronic kidney disease (CKD). The dysbiotic gut microbiome generates excessive amounts of uremic toxins, and the impaired intestinal barrier permits translocation of these toxins into the systemic circulation. Many of these uremic toxins have been implicated in the progression of CKD and increased cardiovascular risk. Various therapeutic interventions have been proposed that aim to restore gut microbiome symbiosis. If proven effective, these interventions will have a significant impact on the management of CKD patients. In this review, we discuss the consequences of gut microbiome dysbiosis in the context of CKD, discuss the consequences of gut dysbiosis, and highlight some of the recent interventions targeting the gut microbiome for therapeutic purposes. PMID- 28343358 TI - Expression of the cyanobacterial enzyme cyanase increases cyanate metabolism and cyanate tolerance in Arabidopsis. AB - Cyanate and its derivatives are considered as environmental hazardous materials. Cyanate is released to the environment through many chemical industries and mining wastewater. Cyanase enzyme converts cyanate into CO2 and NH3 in a bicarbonate-dependent reaction. At low cyanate concentrations, the endogenous plant cyanases play a vital role in cyanate detoxification. However, such cyanate biodegradation system is probably insufficient due to the excess cyanate concentrations at contaminated sites. In this study, we have transferred the activity of the cyanobacterial cyanase into Arabidopsis thaliana plants in order to enhance plant resistance against cyanate toxicity. The enzyme was shown to be active in planta. Transgenic plants exposed to cyanate, either applied by foliar spray or supplemented in growth medium, showed less reduction in pigment contents, antioxidant enzymes, carbohydrate contents, and reduced levels of plant growth retardation. Plant growth assays under cyanate stress showed enhanced growth and biomass accumulation in cyanase overexpressors compared to control plants. Results of this study provide evidence for developing novel eco-friendly phytoremediation systems for cyanate detoxification. PMID- 28343359 TI - Characterization of PM2.5 chemical composition at the Demokritos suburban station, in Athens Greece. The influence of Saharan dust. AB - The aim of this work is to study the atmospheric concentrations of selected major and trace elements and ions found in PM2.5, at a suburban site in Athens, Greece, and discuss on the impact of the different sources. Special focus is given to the influence of Saharan dust episodes. The seasonal variability in the metal and ion concentrations is also examined. The results show that PM2.5 mass concentrations are significantly influenced by Saharan dust events; it is observed that when the PM2.5 concentration is higher than 25 MUg/m3, five out of six times, the air mass crossed North Africa at an altitude within the boundary layer. Fe is found to be the element with the more significant seasonal variability, displaying much higher concentrations during cold period. The frequent Saharan dust intrusions in the cold period of this dataset may explain this result. Mineral dust and secondary aerosol are the main PM2.5 components (29 and 34%, respectively). During Saharan dust events, the concentration of mineral dust is increased by 35% compared to the days without dust intrusions, while an increase of 68% of the sea salt is also observed. During event days, PM2.5 concentrations are also increased by 14%. Anthropogenic components do not decrease during those days, while sulfate displays even a slight increase, suggesting enrichment of mineral dust with secondary sulfates. The results indicate that African dust intrusions add a rather significant PM pollution load even in the PM2.5 fraction, with implication to population exposure and human health. PMID- 28343360 TI - Tsunami run-up and inundation along the coast of Sabah and Sarawak, Malaysia due to a potential Brunei submarine mass failure. AB - Submarine landslides, also known as submarine mass failures (SMFs), are major natural marine disasters that could critically damage coastal facilities such as nuclear power plants and oil and gas platforms. It is therefore essential to investigate submarine landslides for potential tsunami hazard assessment. Three dimensional seismic data from offshore Brunei have revealed a giant seabed mass deposited by a previous SMF. The submarine mass extends over 120 km from the continental slope of the Baram Canyon at 200 m water depth to the deep basin floor of the Northwest Borneo Trough. A suite of in-house two-dimensional depth averaged tsunami simulation model TUNA (Tsunami-tracking Utilities and Application) is developed to assess the vulnerability of coastal communities in Sabah and Sarawak subject to potential SMF tsunami. The submarine slide is modeled as a rigid body moving along a planar slope with the center of mass motion parallel to the planar slope and subject to external forces due to added mass, gravity, and dissipation. The nonlinear shallow water equations are utilized to simulate tsunami propagation from deepwater up to the shallow offshore areas. A wetting-drying algorithm is used when a tsunami wave reaches the shoreline to compute run up of tsunami along the shoreline. Run-up wave height and inundation maps are provided for seven densely populated locations in Sabah and Sarawak to highlight potential risks at each location, subject to two scenarios of slide slopes: 2 degrees and 4 degrees . The first wave may arrive at Kudat as early as 0.4 h after the SMF, giving local communities little time to evacuate. Over a small area, maximum inundated depths reaching 20.3 m at Kudat, 26.1 m at Kota Kinabalu, and 15.5 m at Miri are projected, while the maximum inundation distance of 4.86 km is expected at Miri due to its low-lying coast. In view of the vulnerability of some locations to the SMF tsunami, it is important to develop and implement community resilience program to reduce the potential damage that could be inflicted by SMF tsunamis. PMID- 28343361 TI - Genetic dissociation of morphine analgesia from hyperalgesia in mice. AB - RATIONALE: Morphine is the prototypic mu opioid, producing its analgesic actions through traditional 7 transmembrane domain (7TM) G-protein-coupled receptors generated by the mu opioid receptor gene (Oprm1). However, the Oprm1 gene undergoes extensive alternative splicing to yield three structurally distinct sets of splice variants. In addition to the full-length 7TM receptors, it produces a set of truncated variants comprised of only 6 transmembrane domains (6TM). OBJECTIVES: This study explored the relative contributions of 7TM and 6TM variants in a range of morphine actions. METHODS: Groups of male and mixed-gender wild-type and exon 11 Oprm1 knockout mice were examined in a series of behavioral assays measuring analgesia, hyperalgesia, respiration, and reward in conditioned place preference assays. RESULTS: Loss of the 6TM variants in an exon 11 knockout (E11 KO) mouse did not affect morphine analgesia, reward, or respiratory depression. However, E11 KO mice lacking 6TM variants failed to show morphine induced hyperalgesia, developed tolerance more slowly than wild-type mice, and did not display hyperlocomotion. CONCLUSIONS: Together, our findings confirm the established role of 7TM mu receptor variants in morphine analgesia, reward, and respiratory depression, but reveal an unexpected obligatory role for 6TM variants in morphine-induced hyperalgesia and a modulatory role in morphine tolerance and dependence. PMID- 28343362 TI - Climate controls over ecosystem metabolism: insights from a fifteen-year inductive artificial neural network synthesis for a subalpine forest. AB - Eddy covariance (EC) datasets have provided insight into climate determinants of net ecosystem productivity (NEP) and evapotranspiration (ET) in natural ecosystems for decades, but most EC studies were published in serial fashion such that one study's result became the following study's hypothesis. This approach reflects the hypothetico-deductive process by focusing on previously derived hypotheses. A synthesis of this type of sequential inference reiterates subjective biases and may amplify past assumptions about the role, and relative importance, of controls over ecosystem metabolism. Long-term EC datasets facilitate an alternative approach to synthesis: the use of inductive data-based analyses to re-examine past deductive studies of the same ecosystem. Here we examined the seasonal climate determinants of NEP and ET by analyzing a 15-year EC time-series from a subalpine forest using an ensemble of Artificial Neural Networks (ANNs) at the half-day (daytime/nighttime) time-step. We extracted relative rankings of climate drivers and driver-response relationships directly from the dataset with minimal a priori assumptions. The ANN analysis revealed temperature variables as primary climate drivers of NEP and daytime ET, when all seasons are considered, consistent with the assembly of past studies. New relations uncovered by the ANN approach include the role of soil moisture in driving daytime NEP during the snowmelt period, the nonlinear response of NEP to temperature across seasons, and the low relevance of summer rainfall for NEP or ET at the same daytime/nighttime time step. These new results offer a more complete perspective of climate-ecosystem interactions at this site than traditional deductive analyses alone. PMID- 28343363 TI - Sample pooling for real-time PCR detection and virulence determination of the footrot pathogen Dichelobacter nodosus. AB - Dichelobacter nodosus is the principal cause of ovine footrot and strain virulence is an important factor in disease severity. Therefore, detection and virulence determination of D. nodosus is important for proper diagnosis of the disease. Today this is possible by real-time PCR analysis. Analysis of large numbers of samples is costly and laborious; therefore, pooling of individual samples is common in surveillance programs. However, pooling can reduce the sensitivity of the method. The aim of this study was to develop a pooling method for real-time PCR analysis that would allow sensitive detection and simultaneous virulence determination of D. nodosus. A total of 225 sheep from 17 flocks were sampled using ESwabs within the Swedish Footrot Control Program in 2014. Samples were first analysed individually and then in pools of five by real-time PCR assays targeting the 16S rRNA and aprV2/B2 genes of D. nodosus. Each pool consisted of four negative and one positive D. nodosus samples with varying amounts of the bacterium. In the individual analysis, 61 (27.1%) samples were positive in the 16S rRNA and the aprV2/B2 PCR assays and 164 (72.9%) samples were negative. All samples positive in the aprV2/B2 PCR-assay were of aprB2 variant. The pooled analysis showed that all 41 pools were also positive for D. nodosus 16S rRNA and the aprB2 variant. The diagnostic sensitivity for pooled and individual samples was therefore similar. Our method includes concentration of the bacteria before DNA-extraction. This may account for the maintenance of diagnostic sensitivity. Diagnostic sensitivity in the real-time PCR assays of the pooled samples were comparable to the sensitivity obtained for individually analysed samples. Even sub-clinical infections were able to be detected in the pooled PCR samples which is important for control of the disease. This method may therefore be implemented in footrot control programs where it can replace analysis of individual samples. PMID- 28343364 TI - Comparison between the effect of 6 weeks of morning or evening aerobic exercise on appetite and anthropometric indices: a randomized controlled trial. AB - Several studies have shown that exercise is directly related to creating negative energy balance and changes in appetite. However, few studies have examined the effect of exercise time during the day on these factors. The aim of the present study was to demonstrate the effect of 6 weeks of morning and evening aerobic exercise on appetite and anthropometric indices. A total of 48 overweight females were recruited to this clinical trial. By the time of exercise, they were divided into two groups (morning or evening) and performed 6 weeks of exercise with a target heart rate on the ventilatory threshold. Appetite change, calorie intake and anthropometric indices were assessed. Consistent changes in appetite scores were not found during the 6 weeks (P > 0.05). Calorie consumption of the morning group decreased significantly more than that of the evening group (P = 0.02) during the 6 weeks. In addition, significant changes in body weight, body mass index, abdominal skin fold thickness and abdominal circumference were seen in the morning group. It appears that moderate- to high-intensity aerobic exercise in the morning could be considered a more effective programme than evening exercise on appetite control, calorie intake and weight loss in inactive overweight women. However, the limitations of the study, such as short-term duration, should be noticed. PMID- 28343365 TI - SOX10 immunohistochemistry in sweat ductal/glandular neoplasms. AB - BACKGROUND: SOX10 is a newer Schwannian and melanocytic marker that has generated great interest for its relative sensitivity and specificity in the diagnosis of neural crest-derived tumors. Previous studies with SOX10 have shown positive immunohistochemical expression in cutaneous eccrine glands and negative expression in eccrine ducts, apocrine glands and hair follicles. Thus, we hypothesized that some sweat gland tumors of presumed eccrine origin would be positive for SOX10, whereas apocrine-derived sweat gland tumors would not. METHODS: A mouse monoclonal anti-SOX10 (clone BC34: Biocare Medical; Concord, California) immunohistochemical antibody was performed on various sweat gland tumors and basal cell carcinoma. RESULTS: SOX10 showed positivity in spiradenomas (13/13), cylindromas (9/10), hidradenoma papilliferum (10/10), syringocystadenoma papilliferum (8/10), apocrine adenomas (8/10), and negativity in poromas (0/12), syringomas (0/10), and basal cell carcinomas (0/13). There was mixed staining of hidradenomas (6/15). CONCLUSIONS: SOX10 immunohistochemistry may be of utility in distinguishing some of the varying adnexal tumors from each other, and from basal cell carcinoma (BCC), but given the staining of both apocrine and eccrine tumors, does not seem to provide information as to their origins as either eccrine or apocrine tumors. PMID- 28343367 TI - Magnetic resonance imaging features of leukoaraiosis in elderly dogs. AB - Leukoaraiosis is a descriptive term used to designate bilateral, symmetrical, white matter lesions identified in brains of elderly human patients. These lesions are isointense to normal in magnetic resonance imaging (MRI) T1-weighted pulse sequences, non-contrast enhancing, and hyperintense in T2-weighted and FLAIR pulse sequences. Pathophysiologic mechanisms for leukoaraiosis remain incompletely understood; however, an ischemic origin is currently being favored. Age-related changes, such as brain atrophy, ventricular enlargement, and well demarcated sulci, have also been previously described in dogs over 9 years of age. Objectives of this retrospective case series study were to describe MRI features of leukoaraiosis and brain atrophy in a group of elderly dogs. The Dick White Referrals MRI database between October 2009 and April 2016 was reviewed. Dogs with bilaterally symmetrical periventricular areas of T2 and FLAIR hyperintensity compatible with leukoaraiosis, and older than 9 years, were included. Fourteen dogs met the inclusion criteria, with a total of 18 MRI studies available for review. Median age for sampled dogs was 13 years. Ten dogs had MRI signs of concurrent brain atrophy; one of them had signs of brain atrophy before leukoaraiotic changes could be identified. In those cases where serial MRIs were available, progressive reduction of interthalamic adhesion thickness was observed. The current study introduces leukoaraiosis as a descriptive term for the MRI sign of bilaterally symmetrical, periventricular T2, and FLAIR hyperintensities in brains of elderly dogs. Future studies are needed to determine pathophysiologic mechanisms for this MRI sign. PMID- 28343368 TI - A focus on Rome III criteria for the assessment of constipation in Parkinson's disease. PMID- 28343369 TI - Heavier birth weight associated with taller height but not age at menarche in US women born 1991-1998. AB - OBJECTIVES: Heavier birth weight predicts taller adult height, but it remains unknown the extent to which this additional height increment results from a faster average growth rate versus an extension of the growth period. Aiming to distinguish these effects, this study examined associations between birth weight (BW), age at menarche (an established proxy for growth duration), and near-adult height in a cohort of US young women born in the 1990s. METHODS: Multiple regression evaluated age-adjusted height as an outcome of BW, age at menarche, indicators of family socioeconomic status, and other potential confounders in a sample of US teens who participated in the National Health and Nutrition Examination Survey between 2007 and 2012 (N = 342). Relevant interactions were also evaluated. RESULTS: Mean +/- SD was 11.9 +/- 1.2 years and 3262 +/- 592 g for age at menarche and BW, respectively. BW did not predict age at menarche (beta = -.01, p = .838). Girls were 1.3 cm taller per year delay in menarche (p < .001) and 2.9 cm taller per 1 kg increase in BW (p < .001). Additionally, the greatest gain in height associated with delayed menarche was observed among the heaviest BW quartile. CONCLUSIONS: Girls born heavier were taller but experienced menarche at similar ages to girls born lighter. To the extent that age at menarche reflected growth duration, these results demonstrate faster average growth among heavier-born girls. Consistent with fetal programming of average growth rate, these results held after adjustment for confounders of postnatal growth like family socioeconomic status. PMID- 28343370 TI - The Esthetic and Psychologic Benefits of an Intraoperative Provisional Restoration. AB - OBJECTIVE: When multiple visible teeth are prepared, the prolonged treatment time may lead to patients needing a break that requires them to leave the operatory. Such a situation allows the patient to view their prepared teeth, a process that can be disconcerting to some patients. CLINICAL CONSIDERATIONS: An intraoperative provisional restoration can be made by using a thermoplastic vacuum-formed matrix of the patient's teeth that is filled with white-colored impression material and then placed over the prepared teeth to form a provisional restoration. CONCLUSIONS: The use of an intraoperative provisional restoration can be effectively used to cover prepared teeth while providing normal tooth morphology and facial appearance after preparation of visible teeth. CLINICAL SIGNIFICANCE: When visible teeth are prepared, an intraoperative provisional restoration can be used to cover the prepared teeth and prevent concerned patients from viewing their prepared teeth. (J Esthet Restor Dent 29:189-192, 2017). PMID- 28343366 TI - Motor learning in animal models of Parkinson's disease: Aberrant synaptic plasticity in the motor cortex. AB - In Parkinson's disease (PD), dopamine depletion causes major changes in the brain, resulting in the typical cardinal motor features of the disease. PD neuropathology has been restricted to postmortem examinations, which are limited to only a single time of PD progression. Models of PD in which dopamine tone in the brain is chemically or physically disrupted are valuable tools in understanding the mechanisms of the disease. The basal ganglia have been well studied in the context of PD, and circuit changes in response to dopamine loss have been linked to the motor dysfunctions in PD. However, the etiology of the cognitive dysfunctions that are comorbid in PD patients has remained unclear until now. In this article, we review recent studies exploring how dopamine depletion affects the motor cortex at the synaptic level. In particular, we highlight our recent findings on abnormal spine dynamics in the motor cortex of PD mouse models through in vivo time-lapse imaging and motor skill behavior assays. In combination with previous studies, a role of the motor cortex in skill learning and the impairment of this ability with the loss of dopamine are becoming more apparent. Taken together, we conclude with a discussion on the potential role for the motor cortex in PD, with the possibility of targeting the motor cortex for future PD therapeutics. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28343371 TI - Response to Expression of Programmed Cell Death-1 and Its Ligand B7 Homolog 1 in Peripheral Blood Lymphocytes From Patients With Peripartum Cardiomyopathy. PMID- 28343372 TI - East of the Andes: The genetic profile of the Peruvian Amazon populations. AB - OBJECTIVES: Assuming that the differences between the Andes and the Amazon rainforest at environmental and historical levels have influenced the distribution patterns of genes, languages, and cultures, the maternal and paternal genetic reconstruction of the Peruvian Amazon populations was used to test the relationships within and between these two extreme environments. MATERIALS AND METHODS: We analyzed four Peruvian Amazon communities (Ashaninka, Huambisa, Cashibo, and Shipibo) for both Y chromosome (17 STRs and 8 SNPs) and mtDNA data (control region sequences, two diagnostic sites of the coding region, and one INDEL), and we studied their variability against the rest of South America. RESULTS: We detected a high degree of genetic diversity in the Peruvian Amazon people, both for mtDNA than for Y chromosome, excepting for Cashibo people, who seem to have had no exchanges with their neighbors, in contrast with the others communities. The genetic structure follows the divide between the Andes and the Amazon, but we found a certain degree of gene flow between these two environments, as particularly emerged with the Y chromosome descent cluster's (DCs) analysis. DISCUSSION: The Peruvian Amazon is home to an array of populations with differential rates of genetic exchanges with their neighbors and with the Andean people, depending on their peculiar demographic histories. We highlighted some successful Y chromosome lineages expansions originated in Peru during the pre-Columbian history which involved both Andeans and Amazon Arawak people, showing that at least a part of the Amazon rainforest did not remain isolated from those exchanges. PMID- 28343374 TI - Article update. PMID- 28343373 TI - Weighted win loss approach for analyzing prioritized outcomes. AB - To analyze prioritized outcomes, Buyse (2010) and Pocock et al. (2012) proposed the win loss approach. In this paper, we first study the relationship between the win loss approach and the traditional survival analysis on the time to the first event. We then propose the weighted win loss statistics to improve the efficiency of the unweighted methods. A closed-form variance estimator of the weighted win loss statistics is derived to facilitate hypothesis testing and study design. We also calculated the contribution index to better interpret the results of the weighted win loss approach. Simulation studies and real data analysis demonstrated the characteristics of the proposed statistics. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28343375 TI - FOXO1 Suppression is a Determinant of Acquired Lapatinib-Resistance in HER2 Positive Gastric Cancer Cells Through MET Upregulation. AB - PURPOSE: Lapatinib is a candidate drug for treatment of trastuzumab-resistant, human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). Unfortunately, lapatinib resistance renders this drug ineffective. The present study investigated the implication of forkhead box O1 (FOXO1) signaling in the acquired lapatinib resistance in HER2-positive GC cells. MATERIALS AND METHODS: Lapatinib-resistant GC cell lines (SNU-216 LR2-8) were generated in vitro by chronic exposure of lapatinib-sensitive, HER2-positive SNU-216 cells to lapatinib. SNU-216 LR cells with FOXO1 overexpression were generated by stable transfection of a constitutively active FOXO1 mutant (FOXO1A3). HER2 and MET in SNU-216 LR cells were downregulated using RNA interference. The sensitivity of GC cells to lapatinib and/or cisplatin was determined by crystal violet assay. In addition, Western blot analysis, luciferase reporter assay and reverse transcription-polymerase chain reaction were performed. RESULTS: SNU-216 LR cells showed upregulations of HER2 and MET, but downregulation of FOXO1 compared to parental SNU-216 cells. FOXO1 overexpression in SNU-216 LR cells significantly suppressed resistance to lapatinib and/or cisplatin. In addition, FOXO1 negatively controlled HER2 and MET at the transcriptional level and was negatively controlled by these molecules at the post-transcriptional level. A positive crosstalk was shown between HER2 and MET, each of which increased resistance to lapatinib and/or cisplatin. CONCLUSION: FOXO1 serves as an important linker between HER2 and MET signaling pathways through negative crosstalks and is a key regulator of the acquired lapatinib resistance in HER2 positive GC cells. These findings provide a rationale for establishing a novel treatment strategy to overcome lapatinib resistance in a subtype of GC patients. PMID- 28343376 TI - Ruthenium-106 Brachytherapy with or without Additional Local Therapy Shows Favorable Outcome for Variable-Sized Choroidal Melanomas in Korean Patients. AB - PURPOSE: The purpose of this study was to report clinical outcomes of ruthenium 106 (106Ru) brachytherapy with or without additional local therapy for choroidal melanomas in Korean patients. MATERIALS AND METHODS: A total of 88 patients diagnosed with choroidal melanomas were treated with 106Ru brachytherapy between 2006 and 2012. Patients were divided into two groups according to their tumor height: a large group (>= 6 mm, n=50) and a small group (< 6 mm, n=38). Most patients in the large group received combined therapy with local excision and/or transpupillary thermotherapy. In general, 85-95 Gy was administered to the apex of the tumor, while 100 Gy was administered to the point 2-6 mm from the outer surface of the sclera for patients undergoing combined therapy. RESULTS: The median follow-up duration was 30 months. The 3-year local control rate was significantly higher in the small group than in the large group (94% vs. 70%, p=0.047). The free from distant metastasis (FFDM) rate and the overall survival (OS) rate were also higher in patients in the small group (3-year FFDM, 97% vs. 76%; p=0.031 and 3-year OS, 97% vs. 72%; p=0.036). A total of 13 patients underwent enucleation. The eye-preservation rate was also higher in the small group (3-year eye-preservation rate, 94% vs. 70%; p=0.050), and tumor height was a significant prognostic factor for eye-preservation. CONCLUSION: 106Ru brachytherapy showed favorable outcomes in small choroidal melanomas in Korean patients. Although additional local treatment could improve eye-preservation rate for large tumors, other strategies should be considered for disease control. PMID- 28343377 TI - Protein Kinase C Mediates the Corticosterone-induced Sensitization of Dorsal Root Ganglion Neurons Innervating the Rat Stomach. AB - Background/Aims: Gastric hypersensitivity contributes to abdominal pain in patients with functional dyspepsia. Recent studies showed that hormones induced by stress are correlated with visceral hypersensitivity. However, the precise mechanisms underlying gastric hypersensitivity remain largely unknown. The aim of the present study was designed to investigate the roles of corticosterone (CORT) on excitability of dorsal root ganglion (DRG) neurons innervating the stomach. Methods: DRG neurons innervating the stomach were labeled by DiI injection into the stomach wall. Patch clamp recordings were employed to examine neural excitability and voltage-gated sodium channel currents. Electromyograph technique was used to determine the responses of neck muscles to gastric distension. Results: Incubation of acutely isolated DRG neurons with CORT significantly depolarized action potential threshold and enhanced the number of action potentials induced by current stimulation of the neuron. Under voltage-clamp mode, incubation of CORT enhanced voltage-gated sodium current density of the recorded neurons. Pre-incubation of GF109203X, an inhibitor of protein kinase C, blocked the CORT-induced hyperexcitability and potentiation of sodium currents. However, pre-incubation of H-89, an inhibitor of protein kinase A, did not alter the sodium current density. More importantly, intraperitoneal injection of CORT produced gastric hypersensitivity of healthy rats, which was blocked by pre administration of GF109203X but not H-89. Conclusions: Our data strongly suggest that CORT rapidly enhanced neuronal excitability and sodium channel functions, which is most likely mediated by protein kinase C but not protein kinase A signaling pathway in DRG neurons innervating the stomach, thus underlying the gastric hypersensitivity induced by CORT injection. PMID- 28343378 TI - Adipose-Derived Stem Cells Suppress Inflammation Induced by IL-1beta through Down Regulation of P2X7R Mediated by miR-373 in Chondrocytes of Osteoarthritis. AB - Adipose-derived stem cells (ADSCs) were previously considered to have an anti inflammatory effect, and Interleukin-1beta (IL-1beta) was found to be a pro inflammatory factor in chondrocytes, but the mechanism underlying ADSCs and IL 1beta is unclear. In this study, we investigate whether P2X7 receptor (P2X7R) signalling, regulated by microRNA 373 (miR-373), was involved in the ADSCs and IL 1beta mediated inflammation in osteoarthritis (OA). Chondrocytes were collected from 20 OA patients and 20 control participants, and ADSCs were collected from patients who had undergone abdominal surgery. The typical surface molecules of ASDCs were detected by flow cytometry. The level of nitric oxide (NO) was determined by Griess reagent. Concentrations of prostaglandin E2 (PGE2), interleukin 6 (IL-6), matrix metallopeptidase 3 (MMP-3) were detected by enzyme linked immunosorbent assay (ELISA). The expressions of IL-6, MMP-3, miR-373 and P2X7R were determined by real-time polymerase chain reaction (PCR), and Western blot was used to detect the protein expression of P2X7R. The typical potential characters of ADSCs were verified. In chondrocytes or OA tissues, the miR-373 expression level was decreased, but the P2X7R expression was increased. IL-1beta stimulation increased the level of inflammatory factors in OA chondrocytes, and ADSCs co-cultured with IL-1beta-stimulated chondrocytes decreased the inflammation. OA chondrocytes transfected with the miR-373 inhibitor increased the inflammation level. The miR-373 mimic suppressed the inflammation by targeting P2X7R and regulated its expression, while its effect was reversed by overexpression of P2X7R. IL-1beta induced inflammation in OA chondrocytes, while ADSCs seemed to inhibit the expression of P2X7R that was regulated by miR-373 and involved in the anti-inflammatory process in OA. PMID- 28343380 TI - Ratiometric Visualization of NO/H2S Cross-Talk in Living Cells and Tissues Using a Nitroxyl-Responsive Two-Photon Fluorescence Probe. AB - It is of scientific significance to explore the intricate relationship between two crucial gasotransmitters nitric oxide (NO) and hydrogen sulfide (H2S) because they exert similar and interdependent biological actions within the living organisms. Nevertheless, visualization of the NO/H2S crosstalk using effective molecular imaging tools remains challenging. To address this issue, and given that nitroxyl (HNO) has been implicated as the interdependent production of NO and H2S via a network of cascading chemical reactions, we herein design a ratiometric two-photon fluorescent probe for HNO, termed TP-Rho-HNO, which consists of benzo[h]chromene-rhodol scaffold as two-photon energy transfer cassette with phosphine moiety as specific HNO recognition unit. The newly proposed probe has been successfully applied in ratiometric two-photon bioimaging of endogenous HNO derived from NO and H2S interaction in the human umbilical vein cells (HUVECs) and as well as in rat brain tissues. Intriguingly, the imaging results consistently demonstrate that the mutually dependent upgeneration of H2S and NO are present in living biosystems, indicating that this molecular probe would provide a powerful approach to elucidate the chemical foundation for the anfractuous cross-talk between the NO and H2S signaling pathways in biology. PMID- 28343379 TI - Hepatitis C Virus Nonstructural 5A Protein (HCV-NS5A) Inhibits Hepatocyte Apoptosis through the NF-kappab/miR-503/bcl-2 Pathway. AB - The nonstructural protein 5A (NS5A) encoded by the human hepatitis C virus (HCV) RNA genome is a multifunctional phosphoprotein. To analyse the influence of NS5A on apoptosis, we established an Hep-NS5A cell line (HepG2 cells that stably express NS5A) and induced apoptosis using tumour necrosis factor (TNF)-alpha. We utilised the MTT assay to detect cell viability, real-time quantitative polymerase chain reaction and Western blot to analyse gene and protein expression, and a luciferase reporter gene experiment to investigate the targeted regulatory relationship. Chromatin immunoprecipitation was used to identify the combination of NF-kappaB and miR-503. We found that overexpression of NS5A inhibited TNF-alphainduced hepatocellular apoptosis via regulating miR-503 expression. The cell viability of the TNF-alpha induced Hep-mock cells was significantly less than the viability of the TNF-alpha induced Hep-NS5A cells, which demonstrates that NS5A inhibited TNF-alpha-induced HepG2 cell apoptosis. Under TNF-alpha treatment, miR-503 expression was decreased and cell viability and B-cell lymphoma 2 (bcl-2) expression were increased in the Hep-NS5A cells. Moreover, the luciferase reporter gene experiment verified that bcl-2 was a direct target of miR-503, NS5A inhibited TNF-alpha-induced NF-kappaB activation and NF-kappaB regulated miR-503 transcription by combining with the miR-503 promoter. After the Hep-NS5A cells were transfected with miR-503 mimics, the data indicated that the mimics could reverse TNF-alpha-induced cell apoptosis and blc 2 expression. Collectively, our findings suggest a possible molecular mechanism that may contribute to HCV treatment in which NS5A inhibits NF-kappaB activation to decrease miR-503 expression and increase bcl-2 expression, which leads to a decrease in hepatocellular apoptosis. PMID- 28343382 TI - Associations among Protein Biomarkers and pH and Color Traits in Longissimus thoracis and Rectus abdominis Muscles in Protected Designation of Origin Maine Anjou Cull Cows. AB - This study investigated the relationships among a list of 23 protein biomarkers with CIE-L*a*b* meat color traits and ultimate pH on Longissimus thoracis (LT) and Rectus abdominis (RA) muscles of 48 protected designation of origin Maine Anjou cows. The technological parameters were correlated with several biomarkers and were in some cases muscle-dependent. More biomarkers were related to pHu in LT than in RA muscle. Some consistencies were found, by the common correlation of pHu with MyHC-IIa and MyHC-IIx. The pHu of the LT muscle was also correlated with other cytoskeletal entities and proteins belonging to metabolism and cellular stress. In contrast to the relationships found between biomarkers and LT pHu, more proteins were related to the instrumental color coordinates in RA than in LT muscle. The regression equations were parameter- and muscle-dependent. Certain of the retained proteins explained more than one color coordinate. Hsp70-Grp75 was positive in the models of L*, a*, b*, and C* of LT and of b* in the RA muscle. Further heat shock proteins were strongly related with the meat color coordinates in both muscles. The involvement of metabolic enzymes and myofibrillar proteins in the meat color development was also verified in this experiment. This study confirmed once again the importance of numerous biological pathways in beef color. PMID- 28343381 TI - Rerouting the Pathway for the Biosynthesis of the Side Ring System of Nosiheptide: The Roles of NosI, NosJ, and NosK. AB - Nosiheptide (NOS) is a highly modified thiopeptide antibiotic that displays formidable in vitro activity against a variety of Gram-positive bacteria. In addition to a central hydroxypyridine ring, NOS contains several other modifications, including multiple thiazole rings, dehydro-amino acids, and a 3,4 dimethylindolic acid (DMIA) moiety. The DMIA moiety is required for NOS efficacy and is synthesized from l-tryptophan in a series of reactions that have not been fully elucidated. Herein, we describe the role of NosJ, the product of an unannotated gene in the biosynthetic operon for NOS, as an acyl carrier protein that delivers 3-methylindolic acid (MIA) to NosK. We also reassign the role of NosI as the enzyme responsible for catalyzing the ATP-dependent activation of MIA and MIA's attachment to the phosphopantetheine moiety of NosJ. Lastly, NosK catalyzes the transfer of the MIA group from NosJ-MIA to a conserved serine residue (Ser102) on NosK. The X-ray crystal structure of NosK, solved to 2.3 A resolution, reveals that the protein is an alpha/beta-fold hydrolase. Ser102 interacts with Glu210 and His234 to form a catalytic triad located at the bottom of an open cleft that is large enough to accommodate the thiopeptide framework. PMID- 28343383 TI - New Nematotoxic Indoloditerpenoid Produced by Gymnoascus reessii za-130. AB - Chemical investigation of the fungal strain Gymnoascus reessii za-130, which was previously isolated from the rhizosphere of tomato plants infected by the root knot nematode Meloidogyne incognita, led to the isolation and identification of a new indoloditerpenoid metabolite designated gymnoascole acetate. Its structure was established by spectroscopic methods including 1D- and 2D-NMR and MS analyses. Gymnoascole acetate demonstrated strong adverse effects on M. incognita second-stage juvenile (J2) viability; exposure to 36 MUg/mL for 24 h induced 100% paralysis of J2 (EC50 = 47.5 MUg/mL). Gymnoascole acetate suppressed M. incognita egg hatch relative to controls by >90% at 133 MUg/mL after 7 days of exposure. The numbers of root galls and J2 in both soil and roots were significantly reduced (p = 0.05) by treatment with 2-200 MUg/mL gymnoascole acetate/kg soil, compared to untreated control plants; nematode suppression increased with gymnoascole acetate concentration. This study demonstrated the nematotoxicity of gymnoascole acetate and indicates that it might be a potential biobased component in integrated management of M. incognita. PMID- 28343385 TI - Development of a Rapid LC-MS/MS Method for the Quantification of Cannabidiol, Cannabidivarin, Delta9-Tetrahydrocannabivarin, and Cannabigerol in Mouse Peripheral Tissues. AB - Cannabis has been known as a medicine for several thousand years across many cultures and its beneficial effects are mostly due to the presence of cannabinoids, unique natural products, whose pharmacology is going to gain increasing interest in the scientific community. The discovery of the main psychoactive constituent of Cannabis sativa L., Delta9-tetrahydrocannabinol (Delta9-THC), led to the identification of at least 100 additional phytocannabinoids, including cannabidiol (CBD), cannabidivarin (CBDV), Delta9 tetrahydrocannabivarin (Delta9-THCV), and cannabigerol (CBG). These molecules are gaining growing interest for their medical properties; however, further research is needed to assess the differences in their pharmacokinetic and pharmacodymanic profiles. The aim of this study was to set up a rapid and accurate method, by using the LC-MS-IT-TOF technology, to detect and quantify CBD, CBDV, Delta9-THCV, and CBG in biological matrices. Data show that the method developed here is linear in the calibration range; recoveries from mouse tissues were in the 50-60% range and sensitivity was 2 ng/mL for CBDV, 4 ng/mL for CBG and THCV, and 7 ng/mL for CBD. The method is rapid, precise and accurate, and it will represent a fundamental tool to evaluate the pharmacokinetic and pharmacodynamic properties of selected phytocannabinoids in tissues from different animal models, and develop new cannabinoid-based medicine. PMID- 28343386 TI - Characterization of the Potent Odorants Contributing to the Characteristic Aroma of Matcha by Gas Chromatography-Olfactometry Techniques. AB - The odorants contributing to the characteristic aroma of matcha were investigated by analysis of the headspace samples and the volatile fractions prepared by a combination of solvent extraction and the SAFE techniques using three matcha powders of different grades (high, medium, and low). Gas chromatography olfactometry of the headspace samples (GCO-H) and aroma extract dilution analysis (AEDA) applied to the volatile fractions revealed 16 (FD factor >=1) and 39 (FD factor >=43) odor-active peaks, respectively. Among them, 14 and 37 of the odorants, most of which were newly detected in matcha, were identified or tentatively identified by GC-MS and GC-O, respectively. By comparing the perceived odorants of three matcha powders, it was revealed that eight compounds with sweet, green, metallic, and floral notes showed high flavor dilution (FD) factors irrespective of the grades. In addition, some odorants were suggested to influence the characteristic aroma of each grade. Furthermore, trans-4,5-epoxy (E)-2-decenal, one of the potent odorants of matcha, was revealed to exist as a racemic mixture in matcha. This result suggested that trans-4,5-epoxy-(E)-2 decenal is formed by a nonenzymatic reaction in matcha, different from that in black tea, and that the unique manufacturing process of matcha has a close connection with its formation. PMID- 28343384 TI - N6', N6''', and O4' Modifications to Neomycin Affect Ribosomal Selectivity without Compromising Antibacterial Activity. AB - The synthesis of a series of neomycin derivatives carrying the 2-hydroxyethyl substituent on N6' and/or N6''' both alone and in combination with a 4'-O-ethyl group is described. By means of cell-free translation assays with wild-type bacterial ribosomes and their hybrids with eukaryotic decoding A sites, we investigate how individual substituents and their combinations affect activity and selectivity at the target level. In principle, and as shown by cell-free translation assays, modifications of the N6' and N6''' positions allow enhancement of target selectivity without compromising antibacterial activity. As with the 6'OH aminoglycoside paromomycin, the 4'-O-ethyl modification affects the ribosomal activity, selectivity, and antibacterial profile of neomycin and its 6' N-(2-hydroxyethyl) derivatives. The modified aminoglycosides show good antibacterial activity against model Gram-positive and Gram-negative microbes including the ESKAPE pathogens Staphylococcus aureus, Klebsiella pneumoniae, Enterobacter cloacae, and Acinetobacter baumannii. PMID- 28343387 TI - Hydroxyl and Methoxyl Derivatives of Benzylglucosinolate in Lepidium densiflorum with Hydrolysis to Isothiocyanates and non-Isothiocyanate Products: Substitution Governs Product Type and Mass Spectral Fragmentation. AB - A system of benzylic glucosinolates was found and characterized in common pepperweed, Lepidium densiflorum Schrad. The major glucosinolate was the novel 4 hydroxy-3,5-dimethoxybenzylglucosinolate (3,5-dimethoxysinalbin), present at high levels in seeds, leaves, and roots. Medium-level glucosinolates were 3,4 dimethoxybenzylglucosinolate and 3,4,5-trimethoxybenzylglucosinolate. Minor glucosinolates included benzylglucosinolate, 3-hydroxy- and 3 methoxybenzylglucosinolate, 4-hydroxybenzylglucosinolate (sinalbin), the novel 4 hydroxy-3-methoxybenzylglucosinolate (3-methoxysinalbin), and indole-type glucosinolates. A biosynthetic connection is suggested. NMR, UV, and ion trap MS/MS spectral data are reported, showing contrasting MS fragmentation of p hydroxyls and p-methoxyls. Additional investigations by GC-MS focused on glucosinolate hydrolysis products. Whereas glucosinolates generally yielded isothiocyanates, the dominating 3,5-dimethoxysinalbin with a free p-hydroxyl group produced the corresponding alcohol and syringaldehyde (4-hydroxy-3,5 dimethoxybenzaldehyde). After thermal deactivation of the endogenous myrosinase enzyme, massive accumulation of the corresponding nitrile was detected. This case study points out how non-isothiocyanate glucosinolate hydrolysis products are prevalent in nature and of interest in both plant-pathogen interactions and human health. PMID- 28343388 TI - Development and Validation of an Enzymatic Method To Determine Stevioside Content from Stevia rebaudiana. AB - An enzymatic method for specific determination of stevioside content was established. Recombinant beta-glucosidase BT_3567 (rBT_3567) from Bacteroides thetaiotaomicron HB-13 exhibited selective hydrolysis of stevioside at beta-1,2 glycosidic bond to yield rubusoside and glucose. Coupling of this enzyme with glucose oxidase and peroxidase allowed for quantitation of stevioside content in Stevia samples by using a colorimetric-based approach. The series of reactions for stevioside determination can be completed within 1 h at 37 degrees C. Stevioside determination using the enzymatic assay strongly correlated with results obtained from HPLC quantitation (r2 = 0.9629, n = 16). The percentages of coefficient variation (CV) of within day (n = 12) and between days (n = 12) assays were lower than 5%, and accuracy ranges were 95-105%. This analysis demonstrates that the enzymatic method developed in this study is specific, easy to perform, accurate, and yields reproducible results. PMID- 28343389 TI - Mechanical Properties of Organic Semiconductors for Stretchable, Highly Flexible, and Mechanically Robust Electronics. AB - Mechanical deformability underpins many of the advantages of organic semiconductors. The mechanical properties of these materials are, however, diverse, and the molecular characteristics that permit charge transport can render the materials stiff and brittle. This review is a comprehensive description of the molecular and morphological parameters that govern the mechanical properties of organic semiconductors. Particular attention is paid to ways in which mechanical deformability and electronic performance can coexist. The review begins with a discussion of flexible and stretchable devices of all types, and in particular the unique characteristics of organic semiconductors. It then discusses the mechanical properties most relevant to deformable devices. In particular, it describes how low modulus, good adhesion, and absolute extensibility prior to fracture enable robust performance, along with mechanical "imperceptibility" if worn on the skin. A description of techniques of metrology precedes a discussion of the mechanical properties of three classes of organic semiconductors: pi-conjugated polymers, small molecules, and composites. The discussion of each class of materials focuses on molecular structure and how this structure (and postdeposition processing) influences the solid-state packing structure and thus the mechanical properties. The review concludes with applications of organic semiconductor devices in which every component is intrinsically stretchable or highly flexible. PMID- 28343390 TI - High-Performance Rh2P Electrocatalyst for Efficient Water Splitting. AB - The search for active, stable, and cost-efficient electrocatalysts for hydrogen production via water splitting could make a substantial impact on energy technologies that do not rely on fossil fuels. Here we report the synthesis of rhodium phosphide electrocatalyst with low metal loading in the form of nanocubes (NCs) dispersed in high-surface-area carbon (Rh2P/C) by a facile solvo-thermal approach. The Rh2P/C NCs exhibit remarkable performance for hydrogen evolution reaction and oxygen evolution reaction compared to Rh/C and Pt/C catalysts. The atomic structure of the Rh2P NCs was directly observed by annular dark-field scanning transmission electron microscopy, which revealed a phosphorus-rich outermost atomic layer. Combined experimental and computational studies suggest that surface phosphorus plays a crucial role in determining the robust catalyst properties. PMID- 28343391 TI - Single-Molecule Peptide-Lipid Affinity Assay Reveals Interplay between Solution Structure and Partitioning. AB - Interactions between short protein segments and phospholipid bilayers dictate fundamental aspects of cellular activity and have important applications in biotechnology. Yet, the lack of a suitable methodology for directly probing these interactions has hindered the mechanistic understanding. We developed a precision atomic force microscopy-based single-molecule force spectroscopy assay and probed partitioning into lipid bilayers by measuring the mechanical force experienced by a peptide. Protein segments were constructed from the peripheral membrane protein SecA, a key ATPase in bacterial secretion. We focused on the first 10 amino terminal residues of SecA (SecA2-11) that are lipophilic. In addition to the core SecA2-11 sequence, constructs with nearly identical chemical composition but with differing geometry were used: two copies of SecA2-11 linked in series and two copies SecA2-11 linked in parallel. Lipid bilayer partitioning interactions of peptides with differing structures were distinguished. To model the energetic landscape, a theory of diffusive barrier crossing was extended to incorporate a superposition of potential barriers with variable weights. Analysis revealed two dissociation pathways for the core SecA2-11 sequence with well-separated intrinsic dissociation rates. Molecular dynamics simulations showed that the three peptides had significant conformational differences in solution that correlated well with the measured variations in the propensity to partition into the bilayer. The methodology is generalizable and can be applied to other peptide and lipid species. PMID- 28343393 TI - Selenium Bioaccessibility and Speciation in Selenium-Enriched Lettuce: Investigation of the Selenocompounds Liberated after in Vitro Simulated Human Digestion Using Two-Dimensional HPLC-ICP-MS. AB - The evaluation of selenium-enriched vegetables as potential dietary sources of selenium, an essential element for humans, requires an assessment of the plant's accumulation ability as well as of the bioaccessibility and speciation of the accumulated selenium, which influence its biological effects in humans. Lettuce hydroponically grown at three selenite (SeVI)/selenate (SeIV) amendment levels was characterized accordingly. Selenium accumulation in lettuce leaves was greatest with Se(VI) amendment, whereas bioaccessibility was 70% on average in both cases. Selenium speciation in gastrointestinal hydrolysates, characterized by anion and cation exchange HPLC-ICP-MS, showed that Se(IV) was largely biotransformed into organoselenium metabolites, with selenomethionine accounting for 1/3 of the total detected species, whereas Se(VI) was incorporated as such in the edible portion of the plant, with only a small fraction (~20%) converted into organic species. Taking into account both nutritional quality and safety, the Se(IV)-enriched lettuce appeared more favorable as a potential selenium source for human consumption. PMID- 28343392 TI - Pharmacokinetic and Biodistribution Studies of HPMA Copolymer Conjugates in an Aseptic Implant Loosening Mouse Model. AB - N-(2-Hydroxypropyl) methacrylamide (HPMA) copolymers were previously found to represent a versatile delivery platform for the early detection and intervention of orthopedic implant loosening. In this article, we evaluated the impact of different structural parameters of the HPMA copolymeric system (e.g., molecular weight (MW), drug content) to its pharmacokinetics and biodistribution (PK/BD) profile. Using 125I, Alexa Fluor 488, and IRDye 800 CW-labeled HPMA copolymer dexamethasone (P-Dex) conjugates with different MW and dexamethasone (Dex) contents, we found the MW to be the predominant impact factor on the PK/BD profiles of P-Dex, with Dex content as a secondary impact factor. In gamma counter-based PK/BD studies, increased MW of P-Dex reduced elimination, leading to lower clearance, longer half-life, and higher systemic exposure (AUC and MRT). In the semiquantitative live animal optical imaging evaluation, the distribution of P-Dex to the peri-implant inflammatory lesion increased when MW was increased. This result was further confirmed by FACS analyses of cells isolated from peri implant regions after systemic administration of Alexa Fluor 488-labeled P-Dex. Since the in vitro cell culture study suggested that the internalization of P-Dex by macrophages is generally independent of P-Dex's MW and Dex content, the impact of the MW and Dex content on its PK/BD profile was most likely exerted at physiological and pathophysiological levels rather than at the cellular level. In both gamma counter-based PK/BD analyses and semiquantitative optical imaging analyses, P-Dex with 6 wt % Dex content showed fast clearance. Dynamic light scattering analyses unexpectedly revealed significant molecular aggregation of P Dex at this Dex content level. The underlining mechanisms of the aggregation and fast in vivo clearance of the P-Dex warrant further investigation. PMID- 28343395 TI - Investigation of the Spectroscopic Information on Functional Groups Related to Carbohydrates in Different Morphological Fractions of Corn Stover and Their Relationship to Nutrient Supply and Biodegradation Characteristics. AB - The objectives of this study were to investigate (1) nutritive values and biodegradation characteristics and (2) mid-IR spectroscopic features within the regions associated with carbohydrate functional groups (including cellulosic component (CELC), structural carbohydrate (STCHO), and total carbohydrate (CHO)) in different morphological fractions of corn stover. Furthermore, correlation and regression analyses were also applied to determine the relationship between nutritional values and spectroscopic parameters. The results showed that different morphological sections of corn stover had different nutrient supplies, in situ biodegradation characteristics, and spectral structural features within carbohydrate regions. The stem rind and ear husk were both high in fibrous content, which led to the lowest effective degradabilities (ED) among these stalk fractions. The ED values of NDF were ranked ear husk > stem pith > leaf blade > leaf sheath > whole plant > stem rind. Intensities of peak height and area within carbohydrate regions were relatively more stable compared with spectral ratio profiles. Significant difference was found only in peak area intensity of CELC, which was at the highest level for stem rind, followed by stem pith, leaf sheath, whole plant, leaf blade, and ear husk. Correlation results showed that changes in some carbohydrate spectral ratios were highly associated with carbohydrate chemical profiles and in situ rumen degradation kinetics. Among the various carbohydrate molecular spectral parameters that were tested in multiple regression analysis, CHO height ratios, and area ratios of CELC:CHO and CELC:STCHO as well as CELC area were mostly sensitive to nutrient supply and biodegradation characteristics in different morphological fractions of corn stover. PMID- 28343394 TI - Metal-Organic Nanosheets Formed via Defect-Mediated Transformation of a Hafnium Metal-Organic Framework. AB - We report a hafnium-containing MOF, hcp UiO-67(Hf), which is a ligand-deficient layered analogue of the face-centered cubic fcu UiO-67(Hf). hcp UiO-67 accommodates its lower ligand:metal ratio compared to fcu UiO-67 through a new structural mechanism: the formation of a condensed "double cluster" (Hf12O8(OH)14), analogous to the condensation of coordination polyhedra in oxide frameworks. In oxide frameworks, variable stoichiometry can lead to more complex defect structures, e.g., crystallographic shear planes or modules with differing compositions, which can be the source of further chemical reactivity; likewise, the layered hcp UiO-67 can react further to reversibly form a two-dimensional metal-organic framework, hxl UiO-67. Both three-dimensional hcp UiO-67 and two dimensional hxl UiO-67 can be delaminated to form metal-organic nanosheets. Delamination of hcp UiO-67 occurs through the cleavage of strong hafnium carboxylate bonds and is effected under mild conditions, suggesting that defect ordered MOFs could be a productive route to porous two-dimensional materials. PMID- 28343396 TI - Insight into the Mechanism of Reversible Ring-Opening of 1,3-Benzoxazine with Thiols. AB - The reversible ring-opening addition and fragmentation reaction of p-cresol-based N-phenylbenzoxazine with aliphatic and aromatic thiols was investigated in solvent-mediated and solvent-free reactions. Independently of the used thiol, N phenylbenzoxazine and the thiols reacted to equilibrium with comparable amounts of reactants and products in aprotic solvent, whereas in protic solvent almost full conversions were reached. In contrast, thiol reactivity was a crucial factor in solvent-free reactions yielding fast and complete conversions for a more acidic thiol and balanced equilibrium concentrations in case of thiols with high pKa values. The strong influence of thiols with low pKa values emphasizes the relevance of the protonation step in the ring-opening reactions of 1,3 benzoxazines with thiols in absence of solvents where acidity predominates nucleophilicity. The reverse reactions, namely adduct dissociation and benzoxazine recovery, were successfully conducted at elevated temperatures and reduced pressure facilitated by the removal of the formed thiols yielding up to 95% recovered 1,3-benzoxazine. These results provide deeper understanding of the reversible ring-opening reaction mechanism of 1,3-benzoxazine with thiols. PMID- 28343397 TI - Interfacial Activity of Starch-Based Nanoparticles at the Oil-Water Interface. AB - Understanding the interfacial activity of polysaccharide nanoparticles adsorbed at oil-water interfaces is essential and important for the application of these nanoparticles as Pickering stabilizers. The interfacial properties of starch based nanospheres (SNPs) at the interface of an n-hexane-water system were investigated by monitoring the interfacial tension at different bulk concentrations. The three-phase contact angle (theta) and the adsorption energy (DeltaE) increased with increasing size and degree of substitution with octenyl succinic groups (OSA) in the particles. Compared with the OSA-modified starch (OSA-S) macromolecule, the SNPs effectively reduced the interfacial tension of the n-hexane-water system at a relatively higher concentration. These results and the method reported herein are useful for selecting and preparing polysaccharide nanoparticles as Pickering stabilizers for oil-water emulsions. PMID- 28343398 TI - An Anti-Programmed Death-1 Antibody (alphaPD-1) Fusion Protein That Self Assembles into a Multivalent and Functional alphaPD-1 Nanoparticle. AB - Cancer immune checkpoint therapy has achieved remarkable clinical successes in various cancers. However, current immune checkpoint inhibitors block the checkpoint of not only the immune cells that are important to cancer therapy but also the immune cells that are irrelevant to the therapy. Such an indiscriminate blockade limits the efficacy and causes the autoimmune toxicity of the therapy. It might be beneficial to use a carrier to target immune checkpoint inhibitors to cancer-reactive immune cells. Here, we explore a method to load the inhibitors into carriers. We used the anti-programmed death-1 antibody (alphaPD-1) as a model immune checkpoint inhibitor. First, we generated a recombinant single-chain variable fragment (scFv) of alphaPD-1. Then, we designed and generated a fusion protein consisting of the scFv and an amphiphilic immune-tolerant elastin-like polypeptide (iTEP). Because of the amphiphilic iTEP, the fusion was able to self assemble into a nanoparticle (NP). The NP was proved to block the PD-1 immune checkpoint in vitro and in vivo. Particularly, the NP exacerbated diabetes development in nonobese diabetic mice as effectively as natural, intact alphaPD 1. In summary, we successfully expressed alphaPD-1 as a recombinant protein and linked alphaPD-1 to a NP, which lays a foundation to develop a delivery system to target alphaPD-1 to a subpopulation of immune cells. PMID- 28343399 TI - Analysis of postoperative ultrasonography surveillance after total thyroidectomy in patients with papillary thyroid carcinoma: a multicenter study. AB - Background In papillary thyroid carcinoma (PTC) patients, postoperative ultrasonography (US) surveillance is recommended at intervals of six or 12 months even though evidence is weak. Purpose To determine the optimal interval of postoperative US surveillance in patients after total thyroidectomy for the treatment of PTC using multicenter data. Material and Methods A total of 1400 patients from seven tertiary hospitals who underwent total thyroidectomy for treatment of PTC were included. Based on a retrospective review of clinical and pathologic results, multiple factors were analyzed according to recurrence/persistence or no recurrence/persistence. In recurrence/persistence group, the interval and number of follow-up US sessions in the initial detection of recurrence/persistence were investigated. Results Of the 1400 patients, 115 (8.2%) showed tumor recurrence/persistence on follow-up US. Of 115 recurrence/persistence cases, 89 (77.4%) were initially detected on US: nodal recurrence/persistence (n = 92), non-nodal recurrence/persistence (n = 22), and both (n = 1). Among the clinical and pathologic factors, only tumor size and N stage were significant predictors for recurrence/persistence. In the recurrence/persistence group, the mean interval and number of follow-up US sessions in the initial detection of recurrence/persistence was 22.3 +/- 16.8 months and 2.2 +/- 1.9, respectively. Approximately two-thirds of recurrence/persistence cases (76/115, 66.1%) were detected in follow-up US within two years after total thyroidectomy. Conclusion In PTC patients after total thyroidectomy, the optimal interval of the first US follow-up may be one to two years after thyroid surgery, and the appropriate number of postoperative US surveillance sessions within the first five years may be only one or two. PMID- 28343400 TI - Lifestyles and Mortality in Taiwan: An 11-Year Follow-up Study. AB - The associations of modifiable lifestyle-related factors with cardiovascular and all-cause mortality were examined in a population-based sample of older Taiwanese people. A total of 4176 individuals aged 50 years and older, with 11 years of follow-up, were analyzed. Current and former smokers had a higher risk of all cause mortality compared with never smokers ([HR = 1.33; 95% CI = 1.12, 1.58], [HR = 1.39; 95% CI = 1.16, 1.68]). Low intake of vegetables and fruits was associated with a significantly higher risk of 1.43 (95% CI = 1.13, 1.81) for cardiovascular mortality and 1.22 (95% CI = 1.09, 1.38) for all-cause mortality. The low physical activity group at baseline who became part of the low, moderate, and high physical activity groups during follow-up had the following risks of cardiovascular mortality: ([HR = 2.89; 95% CI = 1.91, 4.36], [HR = 2.17; 95% CI = 1.29, 3.63], [HR = 1.59; 95% CI = 0.90, 2.82]). Similarly, the moderate physical activity group at baseline who became part of the low, moderate, and high physical activity groups during follow-up had the following risks of cardiovascular mortality: ([HR = 3.52; 95% CI = 2.14, 5.80], [HR = 2.25; 95% CI = 1.34, 3.80], [HR = 1.44; 95% CI = 0.78, 2.66]). The same tendencies were found in all-cause mortality. Smoking, diet, and physical activity were significantly modifiable lifestyle-related factors for mortality.Besides, individuals who decreased their physical activity had a significantly higher risk, whereas those who increased their physical activity had a significantly lower risk. PMID- 28343401 TI - Effect of probiotic on innate inflammatory response and viral shedding in experimental rhinovirus infection - a randomised controlled trial. AB - Ingestion of probiotics appears to have modest effects on the incidence of viral respiratory infection. The mechanism of these effects is not clear; however, there is evidence from animal models that the probiotic may have an effect on innate immune responses to pathogens. The purpose of this randomised, placebo controlled study was to determine the effect of administration of Bifidobacterium animalis subspecies lactis Bl-04 on innate and adaptive host responses to experimental rhinovirus challenge. The effect on the response of chemokine (C-X-C motif) ligand 8 (CXCL8) to rhinovirus infection was defined as the primary endpoint for the study. 152 seronegative volunteers who had been supplemented for 28 days, 73 with probiotic and 79 with placebo, were challenged with RV-A39. Supplement or placebo administration was then continued for five days during collection of specimens for assessment of host response, infection, and symptoms. 58 probiotic and 57 placebo-supplemented volunteers met protocol-defined criteria for analysis. Probiotic resulted in higher nasal lavage CXCL8 on day 0 prior to virus challenge (90 vs 58 pg/ml, respectively, P=0.04, ANCOVA). The CXCL8 response to rhinovirus infection in nasal lavage was significantly reduced in the probiotic treated group (P=0.03, ANCOVA). Probiotic was also associated with a reduction in nasal lavage virus titre and the proportion of subjects shedding virus in nasal secretions (76% in the probiotic group, 91% in the placebo group, P=0.04, Fisher Exact test). The administration of probiotic did not influence lower respiratory inflammation (assessed by exhaled nitric oxide), subjective symptom scores, or infection rate. This study demonstrates that ingestion of Bl 04 may have an effect on the baseline state of innate immunity in the nose and on the subsequent response of the human host to rhinovirus infection. Clinicaltrials.gov registry number: NCT01669603. PMID- 28343402 TI - Probiotic administration improves sperm quality in asthenozoospermic human donors. AB - The objective of this study is to analyse the effect of the ingestion of two selected antioxidant probiotics strains (Lactobacillus rhamnosus CECT8361 and Bifidobacterium longum CECT7347) on sperm quality parameters in asthenozoospermic males after three and six weeks of administration. Nine asthenozoospermic men without any medical treatment under similar diet conditions participated in the study. The quality of individual sperm samples was evaluated before (previous to ingestion), during (after 3 and 6 weeks of ingestion) and after probiotic administration (3 and 6 weeks after finishing the treatment). Sperm motility was evaluated by computer-assisted sperm analysis system, DNA fragmentation by sperm chromatin structure assay, cell viability by flow cytometry and measurement of intracellular H2O2 (reactive oxygen species; ROS) by flow cytometry using dichloro-dihydrofluorescein diacetate. Sperm motility was drastically improved after the treatment (approximately 6 fold change), DNA fragmentation was statistically reduced after probiotic administration from (approximately 1.2 fold change) and intracellular H2O2 level was decreased (approximately 3.5 fold change). Cell viability was not affected by the treatment. The significant improvement in sperm motility and the decrease in DNA fragmentation reported in this study provide preliminary evidence that probiotics could be administrated to improve motility and decrease DNA fragmentation and ROS levels in asthenozoospermic human males. PMID- 28343403 TI - Meaning in life, resilience, and psychological well-being among children affected by parental HIV. AB - Meaning in life has been posited to improve psychological well-being. People facing adversities can reduce psychological distress through pursuing a sense of purpose in life. However, the effectiveness of meaning in life in promoting psychological well-being has been found varied, and what factors may affect the function of meaning in life remain unclear. In this paper, the authors suggest that resilience, the positive adaptation during or following significant adversity, can strengthen the protective effects of meaning in life on psychological well-being. To test this hypothesis, we analyzed data from a sample of 518 vulnerable children of parents living with HIV about their meaning in life, resilience, depression, and loneliness. Results showed that resilience moderated the relationship between meaning in life and depression, and between meaning in life and loneliness. Meaning in life was associated with lower levels of depression and loneliness among children high in resilience, in comparison to children low in resilience. Future interventions targeting meaning in life and well-being should consider children's resilience, which can allow for better individualization of the treatment. PMID- 28343404 TI - Emerging from the database shadows: characterizing undocumented immigrants in a large cohort of HIV-infected persons. AB - Little is known about how HIV affects undocumented immigrants despite social and structural factors that may place them at risk of poor HIV outcomes. Our understanding of the clinical epidemiology of HIV-infected undocumented immigrants is limited by the challenges of determining undocumented immigration status in large data sets. We developed an algorithm to predict undocumented status using social security number (SSN) and insurance data. We retrospectively applied this algorithm to a cohort of HIV-infected adults receiving care at a large urban healthcare system who attended at least one HIV-related outpatient visit from 1997 to 2013, classifying patients as "screened undocumented" or "documented". We then reviewed the medical records of screened undocumented patients, classifying those whose records contained evidence of undocumented status as "undocumented per medical chart" (charted undocumented). Bivariate measures of association were used to identify demographic and clinical characteristics associated with undocumented immigrant status. Of 7593 patients, 205 (2.7%) were classified as undocumented by the algorithm. Compared to documented patients, undocumented patients were younger at entry to care (mean 38.5 years vs. 40.6 years, p < 0.05), less likely to be female (33.2% vs. 43.1%, p < 0.01), less likely to report injection drug use as their primary HIV risk factor (3.4% vs. 18.0%, p < 0.001), and had lower median CD4 count at entry to care (288 vs. 339 cells/mm3, p < 0.01). After medical record review, we re classified 104 patients (50.7%) as charted undocumented. Demographic and clinical characteristics of charted undocumented did not differ substantially from screened undocumented. Our algorithm allowed us to identify and clinically characterize undocumented immigrants within an HIV-infected population, though it overestimated the prevalence of patients who were undocumented. PMID- 28343406 TI - Corrigendum. PMID- 28343405 TI - Human T-Lymphotropic Virus Type-1-Associated Myelopathy/Tropical Spastic Paraparesis: The First Case Report in Southeast Asia. AB - Human T-lymphotropic virus type-1 (HTLV-1) infection was diagnosed in a Thai patient with chronic progressive myelopathy. The phylogenetic tree of the ltr sequencing of HTLV-1 indicated that the virus belongs to the transcontinental genotype of the cosmopolitan subtype A. This is the first case report of HTLV-1 associated myelopathy in Southeast Asia. Awareness of HTLV-1 and related condition should be encouraged in this region and routine screening should be applied to blood donors. PMID- 28343407 TI - What are the complications and emerging strategies for preventing depression following traumatic brain injury? AB - INTRODUCTION: Depression is a common and disabling complication of traumatic brain injury (TBI). The high rates of post-TBI depression (PTBID) make this condition an important candidate for selective preventive interventions. Areas covered: The authors recently reported on the efficacy of sertraline, a selective serotonin reuptake inhibitor (SSRI), for the prevention of new cases of depression in the first six months after TBI. The authors review this and other studies on preventive strategies in PTBID as ascertained from a PubMed and citation search. The potential complications and barriers to the implementation of pharmacological prevention in patients with TBI are also discussed. Expert commentary: The prevention of depression in patients with TBI has received little attention relative to other medical conditions. Future studies are needed to confirm the benefit of SSRIs and investigate other pharmacological and non pharmacological interventions, including in special groups of patients at greater risk of developing PTBID. PMID- 28343408 TI - Safety of oral direct acting antiviral regimens for chronic hepatitis C in real life conditions. AB - OBJECTIVES: Direct acting antivirals (DAA) are extremely effective to treat chronic hepatitis C. The aim of this study was to evaluate, by using objective variables, the safety of DAA combinations under clinical practice conditions. METHODS: A retrospective study was carried out in mono-infected patients with chronic hepatitis C treated with DAA between January and December 2015 in our centre. Discontinuations, treatment modifications, deaths and laboratory parameters were studied (liver function tests, hemoglobin, creatinine and lipid profile at baseline, weeks 4, 8 and post 12). Temporal variation of laboratory parameters was analyzed by t-test for paired data, and comparison between groups was made by t-test for independent samples and ANOVA. RESULTS: 227 patients were included (40.5% cirrhotic). Sustained virological response (SVR) was achieved in 97.3% of patients. In only one case was the antiviral medication suspended due to toxicity, and there were no voluntary treatment discontinuations. The use of ribavirin (RBV) was associated with mild transient hyperbilirubinemia (41.2%) and anemia (32.6%, with RBV dose reduction in 7.9% of cases). There was an elevation in total cholesterol and LDL-cholesterol (LDL-C) during and after treatment: mean increase of 23 mg/dL (0.59 mmol/L) and 22 mg/dL (0.57 mmol/L), respectively in post 12 (p < .0001). An increment of 20% of patients with cholesterol levels over optimal figures was observed after DAA completion. CONCLUSION: DAA have an optimum safety profile in real life conditions, with infrequent discontinuation and minor laboratory alterations. PMID- 28343409 TI - Development of a Prediction Model for Post-Concussive Symptoms following Mild Traumatic Brain Injury: A TRACK-TBI Pilot Study. AB - Post-concussive symptoms occur frequently after mild traumatic brain injury (mTBI) and may be categorized as cognitive, somatic, or emotional. We aimed to: 1) assess whether patient demographics and clinical variables predict development of each of these three symptom categories, and 2) develop a prediction model for six-month post-concussive symptoms. MTBI patients (Glasgow Coma Scale score 13 15) from the prospective multicenter Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Pilot study (2010-2012) who completed the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) at six-months post-injury were included. Linear regression was utilized to determine the predictive value of candidate predictors for cognitive, somatic, and emotional subscales individually as well as the overall RPQ. The final prediction model was developed using Lasso shrinkage and bootstrap validation. We included 277 mTBI patients (70% male, median age 42y). No major differences in the predictive value of our set of predictors existed for the cognitive, somatic, and emotional subscales, and therefore one prediction model for the RPQ total scale was developed. Years of education, pre-injury psychiatric disorders and prior TBI were the strongest predictors of six-month post-concussive symptoms. The total set of predictors explained 21% of the variance, which decreased to 14% after bootstrap validation. Demographic and clinical variables at baseline are predictive of six-month post concussive symptoms following mTBI, however these variables explain less than one fifth of the total variance in outcome. Model refinement with larger datasets, more granular variables, and objective biomarkers are needed before implementation in clinical practice. PMID- 28343410 TI - Change in subjective social status following HIV diagnosis and associated effects on mental and physical health among HIV-positive gay men in Australia. AB - OBJECTIVE: This study investigates the impact of HIV diagnosis on subjective social status and if changes are linked to health outcomes. DESIGN: Two measures of subjective social status, socio-economic and standing in the community were examined in 342 Australian HIV-positive gay men in 2014. Participants recalled ratings at diagnosis were compared with current ratings. MAIN OUTCOME MEASURES: Self-reported mental (psychological distress, self-esteem, positive mental health and satisfaction with life) and physical health (self-rated health, CD4 count, viral load). RESULTS: Half of the participants reported improvements in subjective socio-economic status (59%) or standing in the community (52%) since diagnosis, yet one quarter reported socio-economic status (25%) or standing in the community had decreased (23%). Increases in either measure of subjective social status were linked to higher self-esteem, positive mental health, satisfaction with life and better self-rated health. Decreases in subjective social status, however, were strongly linked to poorer outcomes on all mental health measures. Decreases in standing in the community were also associated with poorer physical self-rated health. CONCLUSION: Most participants reported their subjective social status were the same or better since diagnosis. Changes in subjective social status following diagnosis were strongly linked to mental health outcomes. Those who reported a decrease in subjective social status were particularly vulnerable to mental health problems. PMID- 28343411 TI - Three-Dimensional Liver Surgery Simulation: Computer-Assisted Surgical Planning with Three-Dimensional Simulation Software and Three-Dimensional Printing. AB - To perform accurate hepatectomy without injury, it is necessary to understand the anatomical relationship among the branches of Glisson's sheath, hepatic veins, and tumor. In Japan, three-dimensional (3D) preoperative simulation for liver surgery is becoming increasingly common, and liver 3D modeling and 3D hepatectomy simulation by 3D analysis software for liver surgery have been covered by universal healthcare insurance since 2012. Herein, we review the history of virtual hepatectomy using computer-assisted surgery (CAS) and our research to date, and we discuss the future prospects of CAS. We have used the SYNAPSE VINCENT medical imaging system (Fujifilm Medical, Tokyo, Japan) for 3D visualization and virtual resection of the liver since 2010. We developed a novel fusion imaging technique combining 3D computed tomography (CT) with magnetic resonance imaging (MRI). The fusion image enables us to easily visualize anatomic relationships among the hepatic arteries, portal veins, bile duct, and tumor in the hepatic hilum. In 2013, we developed an original software, called Liversim, which enables real-time deformation of the liver using physical simulation, and a randomized control trial has recently been conducted to evaluate the use of Liversim and SYNAPSE VINCENT for preoperative simulation and planning. Furthermore, we developed a novel hollow 3D-printed liver model whose surface is covered with frames. This model is useful for safe liver resection, has better visibility, and the production cost is reduced to one-third of a previous model. Preoperative simulation and navigation with CAS in liver resection are expected to help planning and conducting a surgery and surgical education. Thus, a novel CAS system will contribute to not only the performance of reliable hepatectomy but also to surgical education. PMID- 28343412 TI - Yttrium-90 microsphere radioembolization in unresectable intrahepatic cholangiocarcinoma. AB - Intrahepatic cholangiocarcinoma is increasing in frequency worldwide, but radical surgical treatment is practicable in 30-40% of cases. The median survival without therapy is about 8 months, increased to 12 months in combination with systemic chemotherapy. Therefore, locoregional therapies, such as, radiofrequency ablation or transarterial chemoembolization have been employed. Radioembolization with yttrium-90 microspheres (90Y-TARE) is a novel intrarterial treatment which could be included in the armamentarium of treatment options, having shown higher median survival (up to 22 months) and low complication rates. Evidence-based algorithms for staging and allocation to treatment should be defined in the future, after robust results obtained through randomized controlled trials, thus establishing the exact role and timing of 90Y-TARE in the treatment protocol of unresectable intrahepatic cholangiocarcinoma. PMID- 28343414 TI - Zika virus and pregnant women: A psychological approach. AB - Zika virus presents risk of physical harm to pregnant women, but the fear of infection is also affecting women around the world. There is a gap in the research on Zika virus in the areas involving the impact on the psychosocial well being of pregnant women. Therefore, this study is aimed at the investigation of the psychosocial adjustment of pregnant women to the risks of Zika virus infection during pregnancy. We investigated 14 pregnant women who were classified in three different groups: six in the first trimester, five in the second trimester and three in the third trimester, aged from 28 to 40 years (33.43 +/- 3.76 years). Content analysis was used to interpret data. Our results show that the psychosocial adjustment of participants was significantly negative and included five aspects: (1) negative feelings, (2) changes in family planning, (3) adopting new customs (avoiding places of risk, use of specific clothes and use of repellent), (4) changed attitudes regarding body image and (5) feeling of external demand regarding prevention. The fear of Zika virus infection and all its associated risks have a negative biopsychosocial impact on the pregnant women in this study. PMID- 28343413 TI - Development and Implementation: B'More Healthy Communities for Kid's Store and Wholesaler Intervention. AB - Higher rates of obesity and obesity-related chronic disease are prevalent in communities where there is limited access to affordable, healthy food. The B'More Healthy Communities for Kids (BHCK) trial worked at multiple levels of the food environment including food wholesalers and corner stores to improve the surrounding community's access to healthy food. The objective of this article is to describe the development and implementation of BHCK's corner store and wholesaler interventions through formal process evaluation. Researchers evaluated each level of the intervention to assess reach, dose delivered, and fidelity. Corner store and wholesaler reach, dose delivered, and fidelity were measured by number of interactions, promotional materials distributed, and maintenance of study materials, respectively. Overall, the corner store implementation showed moderate reach, dose delivered, and high fidelity. The wholesaler intervention was implemented with high reach, dose, and fidelity. The program held 355 corner store interactive sessions and had 9,347 community member interactions, 21% of which were with children between the ages of 10 and 14 years. There was a 15% increase in corner store promoted food stocking during Wave 1 and a 17% increase during Wave 2. These findings demonstrate a successfully implemented food retailer intervention in a low-income urban setting. PMID- 28343415 TI - Is Therapeutic Hypothermia for Acute Respiratory Distress Syndrome the Future? AB - INTRODUCTION: Severe acute respiratory distress syndrome (ARDS) has a high mortality, and there is limited knowledge about management of severe ARDS refractory to standard therapy. Early evidence suggests that therapeutic hypothermia (TH) could be a viable treatment for acute respiratory failure. We present 2 cases where TH was successfully used to manage refractory ARDS on extracorporeal membrane oxygenation (ECMO) and a review of the literature around TH and acute respiratory failure. RESULTS: We present 2 cases of ARDS secondary to H1N1 influenza and human metapneumovirus. Both patients were treated with the current evidence-based therapy for ARDS. Venovenous ECMO was used in both patients for refractory hypoxemia. Therapeutic hypothermia was applied for 24 hours with improved oxygenation. We did a review of the literature summarizing 38 patients in 10 publications where TH was successfully utilized in the treatment of acute respiratory failure. CONCLUSION: Therapeutic hypothermia may be a viable salvage therapy for ARDS refractory to the current evidence-based therapy but needs further evaluation. PMID- 28343417 TI - Erratum. PMID- 28343416 TI - Cuff Leak Test for the Diagnosis of Post-Extubation Stridor. AB - BACKGROUND: Cuff leak test was developed to predict the occurrence of post extubation stridor (PES). This study evaluated the diagnostic performance of this test in unselected critically ill patients. METHODS: Multicenter prospective study including unselected ventilated patients at the time of their first planned extubation. The diagnostic performance of 4 different cuff leak tests was assessed. RESULTS: Post-extubation stridor occurred in 34 (9.4%) of 362 included patients. Compared to patients without PES, patients with PES required more frequently reintubation (6 [17.6%] vs 26 [7.9%], P = .041), prolonged duration of ventilation (6 [3-13] vs 5 [2-9] days, P = .029), and longer intensive care unit (ICU) stay (12 [6-17.5] vs 7.5 [4-13] days, P = .018). However, ICU mortality was similar in both groups (1 [2.9%] vs 23 [7.0%], P = .61). The 4 cuff leak tests display poor diagnostic accuracy: sensitivities ranging from 27% to 46%, specificities from 70% to 88%, positive predictive values from 14% to 19%, and negative predictive values from 92% to 93%. CONCLUSION: Post-extubation stridor occurs in less than 10% of unselected critically ill patients. The several cuff leak tests display limited diagnostic performance for the detection of PES. Given the high rate of false positives, routine cuff leak test may expose to undue prolonged mechanical ventilation. PMID- 28343418 TI - Epigenetic factors as drivers of fibrosis in systemic sclerosis. AB - Prolonged activation of fibroblasts is a central hallmark of fibrosing disorders such as systemic sclerosis (SSc). Fibroblasts are the key effector cells. They differentiate into an activated myofibroblast phenotype. In contrast to normal wound healing with transient activation, myofibroblasts persist in fibrosing disorders. Current hypothesis suggests that profibrotic cytokines might trigger epigenetic changes which contribute to the persistently activated fibroblast phenotype. In the last years, several epigenetic alterations have been described in SSc and have been linked to different pathogenic aspects of the disease, in particular to aberrant fibroblast activation and tissue fibrosis, but also to vascular manifestations and inflammation. The focus of this review is the current knowledge on epigenetic changes in fibroblast activation in SSc. PMID- 28343420 TI - Portable devices and mobile instruments for infectious diseases point-of-care testing. AB - INTRODUCTION: Rapidity, simplicity, and portability are highly desirable characteristics of tests and devices designed for performing diagnostics at the point of care (POC), either near patients managed in healthcare facilities or to offer bioanalytical alternatives in external settings. By reducing the turnaround time of the diagnostic cycle, POC diagnostics can reduce the dissemination, morbidity, and mortality of infectious diseases and provide tools to control the global threat of antimicrobial resistance. Areas covered: A literature search of PubMed and Google Scholar, and extensive mining of specialized publications, Internet resources, and manufacturers' websites have been used to organize and write this overview of the challenges and requirements associated with the development of portable sample-to-answer diagnostics, and showcase relevant examples of handheld devices, portable instruments, and less mobile systems which may or could be operated at POC. Expert commentary: Rapid (<1 h) diagnostics can contribute to control infectious diseases and antimicrobial resistant pathogens. Portable devices or instruments enabling sample-to-answer bioanalysis can provide rapid, robust, and reproducible testing at the POC or close from it. Beyond testing, to realize some promises of personalized/precision medicine, it will be critical to connect instruments to healthcare data management systems, to efficiently link decentralized testing results to the electronic medical record of patients. PMID- 28343419 TI - Clinical features, long-term clinical outcomes, and prognostic factors of tuberculous meningitis in West China: a multivariate analysis of 154 adults. AB - BACKGROUND: Tuberculosis is prevalent in China, which is the second greatest contributor to the global tuberculosis burden. Tuberculosis meningitis (TBM) is the most severe disease form but few reports describe long-term clinical outcomes and prognostic factors. Thus, we studied these features in Chinese TBM patients. METHODS: A retrospective follow-up study was used to collect clinical features and outcomes of adult TB meningitis at the First Affiliated Hospital of Chongqing Medical University from June 2012 to August 2015. Univariate analysis and multivariate analysis were used to identify predictive factors associated with outcomes at discharge and follow-up. RESULTS: TBM patients (N = 154) were a median age of 41 years (range: 16-82 years). Median time to follow-up was 26.4 months (range: 9.3-46.5 months) and 31% had poor outcomes at follow-up and limb weakness (p = 0.016), lower GCS scores (p < 0.001), cranial-nerve palsy (p = 0.024), and hydrocephalus (p = 0.009) were closely associated with these poor outcomes. Furthermore, a high neutrophil to lymphocytes ratio, high D-dimer, a low albumin to globulin ratio and slow background of EEG associated with poor outcomes as well. CONCLUSIONS: Mortality and disability associated with TBM are high in China. Limb weakness, GCS scores, cranial-nerve palsy and hydrocephalus were independent predictors of poor outcomes, and AGR, NLR, D-dimer, and EEG abnormalities may be prognostic factors of TBM. PMID- 28343422 TI - Challenges for epigenetic research in inflammatory bowel diseases. AB - The human epigenome may link environmental exposures and commensal microbiota changes to host pathology in respect to the developmental origins of inflammatory bowel diseases (ulcerative colitis [UC] and Crohn's disease [more appropriately Crohn disease, CD]). Genetic predisposition - prenatal, perinatal and pediatric environmental influences - microbiome aberration (dysbiosis) and immune dysregulation appear to be important elements in disease development, progression and maintenance. The prevalence of combined genetic and epigenetic susceptibility toward UC and CD is calculated herein to be as high as 2%, and approximately 1% for UC and CD in highly developed countries, respectively. This review emphasizes the significant challenges for epigenetic research in inflammatory bowel diseases. Overcoming these challenges, however, could reveal unique opportunities for disease prevention, treatment and possible cure. PMID- 28343421 TI - In vitro and in vivo fitness costs associated with Mycobacterium tuberculosis RpoB mutation H526D. AB - AIM: There is controversy regarding the potential fitness costs of rifampicin (RIF) resistance-conferring mutations in the Mycobacterium tuberculosis (Mtb) rpoB gene. We characterized the pathogenicity of an Mtb RpoB H526D mutant. MATERIALS & METHODS: A mutant containing the RpoB H526D mutation was isolated from wild-type Mtb grown on RIF-containing plates and complemented for determination of in vitro and in vivo fitness costs. RESULTS: The RpoB H526D mutant showed reduced survival relative to control strains during progressive hypoxia and delayed growth following resuscitation from nutrient starvation (p < 0.05), which was associated with reduced expression of the resuscitation promoting factor genes rpfB, rpfC and rpfE. Relative to the isogenic wild-type strain, the mutant showed significantly attenuated growth and long-term survival as well as reduced inflammation in mouse lungs. Conclusion & future perspective: Our data suggest that RpoB H526D mutation confers a fitness cost during growth limiting conditions in vitro and in mouse lungs. PMID- 28343423 TI - Management of precipitated opiate withdrawal syndrome induced by nalmefene mistakenly prescribed in opiate-dependent patients: a review for clinicians. AB - INTRODUCTION: Nalmefene, a long-acting u-opioid antagonist approved to treat alcohol use disorder, is occasionally mistakenly prescribed to opiate-dependent or opioid-treated patients. We review recent literature on drug-drug interactions between nalmefene and opioids that lead to precipitated opioid withdrawal, and focus on its management and planning for care at discharge. Areas covered: This article provides a brief and comprehensive review of management of precipitated opioid withdrawal syndrome when nalmefene is associated with an opioid, whether misused or legally prescribed. Expert opinion: When treating an opiate-dependent patient with co-occurring alcohol use disorder, both conditions need to be a focus of clinical attention. New drugs for alcohol use disorder have been approved, but must be given cautiously and with a full understanding of their potential drug-drug interactions with opioid medications. Opiate-dependent patients should be intensively monitored for risk factors of alcohol use disorder and should be continuously motivated for treatment maintenance. When nalmefene is administered to opiate-dependent patients, acute opioid withdrawal syndrome may occur. Management of precipitated acute opioid withdrawal may include short or long-acting u-opioid agonists during hospitalization, in addition to supportive treatment. The best management of polydrug abusers is based on a multidisciplinary approach, which should be pursued and improved through continuing medical education. PMID- 28343424 TI - Biosimilar biologic drugs: a new frontier in medical care. AB - Physicians in training are expected to be aware of the newest developments in patient care. Biologic therapies have changed treatment of many diseases by specifically targeting key disease mediators, but patient access to these therapies can be limited. As patents for the first biologic therapies are expiring, the development and approval of products known as biosimilars is rapidly gaining momentum. A biosimilar is a biologic product that is highly similar to a reference product (a licensed biologic product), notwithstanding minor differences in clinically inactive components. Biosimilars undergo a thorough evaluation compared with the licensed biologic and need to demonstrate comparable clinical pharmacokinetics, efficacy, and safety including immunogenicity. Understanding the processes for new drug approvals, the rigorous evaluation of biosimilars, and considerations about their selection and use can help recently trained physicians to make informed treatment decisions and improve patient outcomes. PMID- 28343425 TI - PPAR-alpha agonists are still on the rise: an update on clinical and experimental findings. AB - INTRODUCTION: Non-fasting plasma triglyceride (TG) and remnant cholesterol levels, cholesterol content of triglyceride-rich lipoproteins, have been suggested to be an additional cause of cardiovascular diseases; thus, pharmacological TG-lowering with fibrates, activators of PPAR-alpha system, has been linked to risk reduction. Areas covered: This manuscript reviews available evidence on clinical trials involving highly selective PPAR-alpha agonists (i.e., pemafibrate) and drugs used in the pre-clinical and experimental setting (e.g., WY14,643). Original publications in English were selected, as well as Abstracts of international meetings' presentations. Clinical trials were identified using the clinicaltrial.gov database and the EU Clinical Trials Register (clinicaltrialsregister.eu). Expert opinion: In addition to the aim of improving lipid profile with fibrates, the interest in new PPAR-alpha activators stems from the need to overcome some of the clinical problems encountered with dose dependent adverse events; a rise of plasma creatinine, gallstone formation, drug drug interactions (i.e. gemfibrozil), and myopathy. New PPAR-alpha agonists improved TG and HDL-C levels as well as other parameters related to TG metabolism (remnant cholesterol and apoB), without raising liver enzymes. Although the use of fibrates is rated 'second choice' by many clinicians, new PPAR-alpha agonists may offer a more accessible route to the management of hypertriglyceridemia, a frequent clinical condition. PMID- 28343426 TI - Suicide hurts people. PMID- 28343427 TI - Optimisation of adherence and discontinuation practices for maintenance antidepressant therapy. PMID- 28343428 TI - Poor physical health in mental health: Finding a way forward. PMID- 28343429 TI - An Erudite Encounter with: Patrick McGorry, AO. PMID- 28343430 TI - Does training of cognitive functions help affective remediation? PMID- 28343431 TI - Contributions to dementia research by Australian Psychiatry. PMID- 28343432 TI - Cognitive and affective remediation training for mood disorders. PMID- 28343434 TI - Putting the CART before the horse? PMID- 28343433 TI - Interactions between police and people with mental illness. PMID- 28343435 TI - Royal Australian and New Zealand College of Psychiatrists expert consensus statement for the treatment, management and monitoring of the physical health of people with an enduring psychotic illness. AB - OBJECTIVE: To use expert consensus to inform the development of policy and guidelines for the treatment, management and monitoring of the physical health of people with an enduring psychotic illness. METHOD: The Delphi method was used. A systematic search of websites, books and journal articles was conducted to develop a 416-item survey containing strategies that health professionals should use to treat, manage and monitor the physical health of people with an enduring psychotic illness. Three panels of Australian experts (55 clinicians, 21 carers and 20 consumers) were recruited and independently rated the items over three rounds, with strategies reaching consensus on a priori-defined levels of importance written into the expert consensus statement. RESULTS: The participation rate for the clinicians across all three rounds was 65%, with consumers and carers only completing one round due to high endorsement rates. Finally, 386 strategies were endorsed as essential or important by one or all panels. The endorsed strategies provided information on engagement and collaborative partnerships; clinical governance; risk factors, morbidity and mortality in people with enduring psychotic illness; assessment, including initial and follow-up assessments; barriers to care; strategies to improve care of people with enduring psychotic illness; education and training; treatment recommendations; medication side effects; and the role of health professionals. CONCLUSION: The consensus statement is intended to be used by health professionals, people with an enduring psychotic illness and their families and carers. The next step needed is an implementation strategy by the Royal Australian and New Zealand College of Psychiatrists and other stakeholders. PMID- 28343436 TI - Ethos. AB - BACKGROUND: Ethics in nursing care are traditionally discussed in terms of moral norms or principles. When taking an ontological approach to ethics, ethics is about ethos. Ethos involves both an internal and an external side of ethics. Considering ethics and health from an ontological perspective can provide a different understanding of ethics and health in caring and nursing. Aim and research question: The aim of this study is to deepen the ontological understanding of ethics and health in caring and nursing. The research question is as follows: What is the ontology of health and ethics in caring and nursing? RESEARCH DESIGN: The study follows a hermeneutical design inspired by Gadamer. Participants and research context: essays about ethics and health were gathered from PhD students in nursing and caring sciences. Ethical considerations: The research follows Responsible conduct of research guidelines provided by the Finnish Advisory Board on Research Integrity. FINDINGS: An ethos with the values of freedom and responsibility seem to ontologically be important for ethics and health. These values allow a movement between the internal and the external sides of ethics that is important for health. DISCUSSION: The ethos of freedom and responsibility that is essential for ethics and health can provide the current ethical debate a new starting point that previous research asks for. CONCLUSION: Ontologically, an ethos of freedom and responsibility is essential for ethics and health in nursing and caring. PMID- 28343437 TI - Organs-on-chips: Progress, challenges, and future directions. AB - The National Institutes of Health Microphysiological Systems (MPS) program, led by the National Center for Advancing Translational Sciences, is part of a joint effort on MPS development with the Defense Advanced Research Projects Agency and with regulatory guidance from FDA, is now in its final year of funding. The program has produced many tangible outcomes in tissue chip development in terms of stem cell differentiation, microfluidic engineering, platform development, and single and multi-organ systems-and continues to help facilitate the acceptance and use of tissue chips by the wider community. As the first iteration of the program draws to a close, this Commentary will highlight some of the goals met, and lay out some of the challenges uncovered that will remain to be addressed as the field progresses. The future of the program will also be outlined. Impact statement This work is important to the field as it outlines the progress and challenges faced by the NIH Microphysiological Systems program to date, and the future of the program. This is useful information for the field to be aware of, both for current program stakeholders and future awardees and partners. PMID- 28343438 TI - Hsa-miR-27b is up-regulated in cytomegalovirus-infected human glioma cells, targets engrailed-2 and inhibits its expression. AB - Human cytomegalovirus (HCMV) dormant infection can alter the expression of the hosts' microRNAs (miRNAs) and impact on the regulation of target genes. To investigate the differentially expressed miRNAs induced by HCMV in human glioma U251 cells, a comprehensive miRNA screen was performed. As a result, 19 up regulated and 14 down-regulated miRNAs were determined. Of these, hsa-miR-27b (miR-27b) attracted our attention. MiR-27b levels in U251 cells increased 7.70 fold, 8.64-fold, and 4.78-fold, respectively, post 24 h, 48 h, and 72 h HCMV infection, compared to those in the mimic-infected cells, and this up-regulation was further confirmed by quantitative RT-PCR. The bioinformatic analyses show that miR-27b targets engrailed-2 (EN2) gene; however, the effect of miR-27b on EN2 is rarely encountered. In this study, we initially conducted dual luciferase assay to validate the target function of miR-27b on EN2. The results manifested that EN2 is a novel target of miR-27b, which could directly target the 3' untranslated region (3'-UTR) of the gene. We further found that the miR-27b transfected glioma U251 cells exhibited longer cell bodies with more synapses and multiple-angle shapes; moreover, Western blot detection revealed that the EN2 protein levels in these cells were significantly low. In conclusion, our study originally reports the up-regulation of miR-27b in HCMV-infected glioma cells. Our study also provides the first experimental evidence that miR-27b could affect glioma cells' growth, target EN2 and inhibit its expression in glioma cells. Our data indicate that miR-27b may be related to the development of neurological disorders with HCMV infection. The newly identified miR-27b/EN2 signal pathway may provide new insights into the glioma pathogenesis and a novel target for glioma therapy. Impact statement Our study is the first to demonstrate that the HCMV infection could alter the expression of cellular microRNAs of the host glioma cells, which may develop an understanding of the pathogenesis of the HCMV infection in the microRNA level. Recently, HCMV infection and engrailed-2 have been reported to be related to the autism spectrum disorder (ASD). In this study, we confirmed that engrailed-2 is the target of hsa-miR-27b. As far as we know, our findings of the hsa-miR-27b up-regulation in the HCMV-infected glioma cells, targeting engrailed-2 and inhibiting its expression have never been reported or documented. Our data indicate that miR-27b may be related to the development of neurological disorders with the HCMV infection. The newly identified miR-27b/EN2 signal pathway may provide new insights into the glioma pathogenesis and a novel target for glioma therapy. PMID- 28343440 TI - Early interventions to promote work participation in people with regional musculoskeletal pain: a systematic review and meta-analysis. AB - OBJECTIVES: To determine the effectiveness of early multidisciplinary interventions in promoting work participation and reducing work absence in adults with regional musculoskeletal pain. DATA SOURCES: Seven databases (CENTRAL, CINAHL, EMBASE, MEDLINE, Scopus, OT Seeker, PEDro; 1990 to December 2016) were searched for eligible studies. REVIEW METHODS: Trials were included if they reported on work-based outcomes for participants experiencing difficulties at work or <= three months' sick leave. Interventions had to include two or more elements of the biopsychosocial model delivered as a coordinated programme. Quality was assessed using the GRADE criteria. Results were analysed by hazard ratios for return to work data; continuous outcomes were analysed as standardised mean difference with 95% confidence intervals. RESULTS: A total of 20 randomized controlled trials, with 16,319 participants were included; the interventions were grouped according to their main components for meta-analyses. At 12-months follow up, moderate quality evidence suggests that programmes involving a stepped care approach (four studies) were more effective than the comparisons in promoting return to work (hazard ratio (HR) 1.29 (95% confidence interval (CI) 1.03 to 1.61), p = 0.03), whereas case management (two studies) was not (HR 0.92 (95% CI 0.69 to 1.24), p = 0.59). Analyses suggested limited effectiveness in reducing sickness absences, in pain reduction or functional improvement across the intervention categories. CONCLUSION: There is uncertainty as to the effectiveness of early multicomponent interventions owing to the clinical heterogeneity and varying health and social insurance systems across the trials. PMID- 28343441 TI - An investigation of the psychometric properties of the Chinese (Cantonese) version of Subjective Index of Physical and Social Outcome (SIPSO). AB - OBJECTIVE: The objectives of this study were 1) to translate and make cultural adaptations to the English version of the SIPSO questionnaire to create a Chinese (Cantonese) version, 2) evaluate the internal consistency, test-retest reliability the C-SIPSO questionnaire, and 3) compare the SIPSO-C scores of stroke survivors with different demographic characteristics to establish the discriminant validity of the questionnaire Design: Translation of questionnaire, cross sectional study. SETTING: University-based clinical research laboratory. Subjects Community-dwelling chronic stroke survivors. INTERVENTIONS: Not applicable. MAIN MEASURES: Subjective Index of Physical and Social Outcome, Geriatric Depression Scale, 10-metre Walk test. RESULTS: Two bilingual professional translators translated the SIPSO questionnaire independently. An expert panel comprising five registered physiotherapists verified the content validity of the final version (C-SIPSO). C-SIPSO demonstrated good internal consistency (Cronbach's alpha = 0.83) and excellent test-retest reliability (ICC3,1 = 0.866) in ninety-two community dwelling chronic stroke survivors. Stroke survivors scored higher than 10 in the Geriatric Depression Scale ( U = 555.0, P < 0.001) and with the comfortable walking speed lower than 0.8ms-1 ( U = 726.5; P = 0.012) scored significantly lower on SIPSO-C. CONCLUSION: SIPSO-C is a reliable instrument that can be used to measure the level of community integration in community-dwelling stroke survivors in Hong Kong and southern China. Stroke survivors who were at high risk of minor depression and with limited community ambulation ability demonstrated a lower level of community integration as measured with SIPSO-C. PMID- 28343442 TI - Effectiveness of neuromuscular electrical stimulation for management of shoulder subluxation post-stroke: a systematic review with meta-analysis. AB - OBJECTIVES: To examine the effectiveness of neuromuscular electrical stimulation (NMES) for the management of shoulder subluxation after stroke including assessment of short (1 hour or less) and long (more than one hour) daily treatment duration. DATA SOURCES: MEDLINE, CENTRAL, CINAHL, WOS, KoreaMed, RISS and reference lists from inception to January 2017 Review methods: We considered randomized controlled trials that reported neuromuscular electrical stimulation for the treatment of shoulder subluxation post-stroke. Two reviewers independently selected trials for inclusion, assessed trial quality, and extracted data. RESULTS: Eleven studies were included (432 participants); seven studies were good quality, four were fair. There was a significant treatment effect of neuromuscular electrical stimulation for reduction of subluxation for persons with acute and subacute stroke (SMD:-1.11; 95% CI:-1.53, -0.68) with either short (SMD:-0.91; 95% CI:-1.43, -0.40) or long (SMD:-1.49; 95% CI:-2.31, 0.67) daily treatment duration. The effect for patients with chronic stroke was not significant (SMD:-1.25; 95% CI:-2.60, 0.11). There was no significant effect of neuromuscular electrical stimulation on arm function or shoulder pain. CONCLUSION: This meta-analysis suggests a beneficial effect of neuromuscular electrical stimulation, with either short or long daily treatment duration, for reducing shoulder subluxation in persons with acute and subacute stroke. No significant benefits were observed for persons with chronic stroke or for improving arm function or reducing shoulder pain. PMID- 28343439 TI - Toward improved myocardial maturity in an organ-on-chip platform with immature cardiac myocytes. AB - In vitro studies of cardiac physiology and drug response have traditionally been performed on individual isolated cardiomyocytes or isotropic monolayers of cells that may not mimic desired physiological traits of the laminar adult myocardium. Recent studies have reported a number of advances to Heart-on-a-Chip platforms for the fabrication of more sophisticated engineered myocardium, but cardiomyocyte immaturity remains a challenge. In the anisotropic musculature of the heart, interactions between cardiac myocytes, the extracellular matrix (ECM), and neighboring cells give rise to changes in cell shape and tissue architecture that have been implicated in both development and disease. We hypothesized that engineered myocardium fabricated from cardiac myocytes cultured in vitro could mimic the physiological characteristics and gene expression profile of adult heart muscle. To test this hypothesis, we fabricated engineered myocardium comprised of neonatal rat ventricular myocytes with laminar architectures reminiscent of that observed in the mature heart and compared their sarcomere organization, contractile performance characteristics, and cardiac gene expression profile to that of isolated adult rat ventricular muscle strips. We found that anisotropic engineered myocardium demonstrated a similar degree of global sarcomere alignment, contractile stress output, and inotropic concentration-response to the beta-adrenergic agonist isoproterenol. Moreover, the anisotropic engineered myocardium exhibited comparable myofibril related gene expression to muscle strips isolated from adult rat ventricular tissue. These results suggest that tissue architecture serves an important developmental cue for building in vitro model systems of the myocardium that could potentially recapitulate the physiological characteristics of the adult heart. Impact statement With the recent focus on developing in vitro Organ-on-Chip platforms that recapitulate tissue and organ-level physiology using immature cells derived from stem cell sources, there is a strong need to assess the ability of these engineered tissues to adopt a mature phenotype. In the present study, we compared and contrasted engineered tissues fabricated from neonatal rat ventricular myocytes in a Heart-on-a-Chip platform to ventricular muscle strips isolated from adult rats. The results of this study support the notion that engineered tissues fabricated from immature cells have the potential to mimic mature tissues in an Organ-on-Chip platform. PMID- 28343443 TI - Lacosamide-Induced Recurrent Ventricular Tachycardia in the Acute Care Setting. AB - Lacosamide is a new-generation antiepileptic drug (AED) most commonly used adjunctively in the setting of partial-onset seizures refractory to traditional therapy. We describe the first case report, to our knowledge, of a patient who developed recurrent, sustained ventricular tachycardia with multiple administrations of lacosamide in an acute setting. A 70-year-old woman with a history significant for valvular heart disease was admitted to the inpatient cardiology service for worsening heart failure. On hospital day 7, she received a bioprosthetic aortic valve. Prior to surgery and immediately after, the patient's electrocardiogram (ECG) was normal. After developing multiple generalized tonic clonic seizures refractory to levetiracetam, fosphenytoin, and valproic acid, the decision was made to initiate lacosamide. Two hours following the second lacosamide dose, the patient developed a wide complex QRS that transitioned into sustained ventricular tachycardia requiring electrical cardioversion. Sustained ventricular tachycardia occurred again, just hours after the third dose of lacosamide was given. Following cessation of lacosamide, the patient's QRS interval normalized and has since had no documented episodes of ventricular tachycardia. Clinicians should be aware of the potential for life-threatening rhythmic disturbances in patients initiated on lacosamide and the need for vigilant ECG, electrolyte, and drug-drug monitoring. PMID- 28343445 TI - A Case of Anagrelide-Induced Nonischemic Cardiomyopathy in a Patient With Essential Thrombocythemia. AB - BACKGROUND: Anagrelide is an established treatment option for essential thrombocythemia (ET). Cardiovascular adverse events can occur with its use including heart failure and cardiomyopathy. CASE REPORT: A 52-year-old African American male with ET presented with chest pain, shortness of breath, and dyspnea on exertion. His ET was managed with hydroxyurea 1500 mg by mouth twice a day and anagrelide 1 mg by mouth 3 times a day. The patient was receiving anagrelide for approximately 2 years prior to presentation. The patient's platelet count was 2.07 * 105 cells/mm3. Transthoracic echocardiography revealed decreased left systolic dysfunction. Also, cardiac magnetic resonance imaging showed an increased left ventricle cavity size with severely depressed systolic dysfunction and an ejection fraction (EF) of 18%. Anagrelide therapy was discontinued and the patient was maintained on hydroxyurea for ET. Three months later, following treatment by a heart failure clinic, the patient's EF was 55%. Five months after discontinuation, the patient improved from New York Heart Association (NYHA) class II to NYHA class I. CONCLUSION: A 52-year-old man with ET presented with an EF of 18% after 2 years of anagrelide therapy. His EF increased from 18% to 55% 3 months after discontinuation of anagrelide. PMID- 28343444 TI - A Pilot Study for Antimicrobial Stewardship Post-Discharge: Avoiding Pitfalls at the Transitions of Care. AB - PURPOSE: Lack of patient follow-up is a major concern during care transitions, and the role of an antimicrobial stewardship program (ASP) in assessing antimicrobial regimens after hospital discharge is not well described. We implemented an expanded ASP to include patients recently discharged from the hospital and measured its impact on inappropriate antimicrobial therapy 72 hours after inpatient culture data were finalized. METHODS: A prospective cohort study was conducted at a 583-bed tertiary care center in the Upper Midwest of America. All patients discharged from our facility on antimicrobial therapy with pending culture results between February 3, 2016, and March 2, 2016, were included for review. If a pathogen nonsusceptible to all prescribed antimicrobials was identified post-discharge, a recommendation for therapy modification was communicated to the prescriber. RESULTS: Thirty-eight patients discharged from our hospital on antimicrobial therapy with pending culture results were evaluated for intervention. When final culture susceptibilities were considered, 5 of 38 patients had been prescribed an inappropriate antimicrobial agent. An ASP pharmacist intervened on 4 of 5 patients, resulting in 3 of 5 patients transitioning to appropriate antimicrobial therapy. When compared to a historical cohort, our transitions-of-care ASP yielded a 3.6-fold increase in antimicrobial related interventions among discharged patients while reducing inappropriate outpatient antimicrobial therapy by 39%. CONCLUSION: We believe this is the first pharmacist-driven ASP represented in the medical literature which evaluated all available inpatient culture data to serve patients discharged from the hospital. Antimicrobial stewardship for patients in care transitions may provide an opportunity to increase ASP interventions and reduce inappropriate antimicrobial therapy. PMID- 28343446 TI - Responding to aggression and reactive behaviours in the home. AB - Behaviours such as hitting, spitting, swearing and kicking can be a common response to personal, social and environmental challenges experienced by people with dementia. Little attention, however, has been given to how partners in care experience and respond to these behaviours in the home. This paper examines the emerging theme of 'aggression,' in seven interviews with nine former partners in care of people with dementia in Ontario, Canada. We explore how partners in care talk about, interpret and respond to these behaviours drawing on recent conceptualizations of structural and interpersonal violence in health and social geography and contributing to the growing body of research on relational care. We discuss the responses to, and implications of, these behaviours at a range of spatial scales and identify important considerations for future research. PMID- 28343447 TI - The undifferentiated carcinoma that became a melanoma: Re-biopsy of a cancer of an unknown primary site: a case report. AB - BACKGROUND: Cancer of unknown primary site is still a demanding condition as it is per definition metastatic, with heterogeneous biological behavior, and it is often resistant to therapy. Cancer of unknown primary site accounts for approximately 1 to 5 % of all cancers, but is currently among the top six causes of cancer deaths in Western countries. To correctly identify the biological origin of the tumor, a large spectrum of differential diagnoses must be considered and scrutinized. At progression, re-biopsy might be necessary to reveal the true origin of the tumor or actionable targets. CASE PRESENTATION: A 62-year-old Norwegian woman, with a fast growing lump in her left groin, was primarily diagnosed as having undifferentiated carcinoma that was BRAF V600 positive. There was complete response with paclitaxel-carboplatin and she was recurrence-free for 18 months. She had recurrence in both lungs and subcutaneously in her left groin and thigh; a re-biopsy revealed transformation to a malignant melanoma. She was resistant to BRAF inhibitors, then treated with ipilimumab and is currently a long-term survivor of 4 years and 4 months since the first diagnosis, with no clinical or radiological evidence of recurrence. CONCLUSIONS: A biopsy from patients with metastasis of unknown primary should be analyzed thoroughly to identify organ of origin, molecular make-up, and possible molecular targets. Re-biopsy of cancer of unknown primary site at progression can reveal the true cellular origin of the tumor as well as provide novel therapeutic opportunities, including immunotherapy. PMID- 28343448 TI - Hemoadsorption by CytoSorb in septic patients: a case series. AB - BACKGROUND: Septic shock, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, is a highly lethal condition that causes substantial morbidity and mortality among critically ill patients. One of the hallmarks of sepsis is the excessive release of cytokines and other inflammatory mediators causing refractory hypotension, tissue damage, metabolic acidosis and ultimately multiple organ failure. In this context, cytokine reduction by hemoadsorption represents a new concept for blood purification, developed to attenuate the overwhelming systemic levels of pro-inflammatory and anti-inflammatory mediators released in the early phase of sepsis. METHODS: In the present case series, we evaluated the impact of a new hemoadsorption device (CytoSorb) used as adjunctive therapy, on hemodynamics and clinically relevant outcome parameters in 26 critically ill patients with septic shock and in need of renal replacement therapy. RESULTS: We found that treatment of these patients with septic shock was associated with hemodynamic stabilization and a reduction in blood lactate levels. Actual mortality in the overall patient population was lower than mortality predicted by acute physiology and chronic health evaluation II (APACHE II). These effects seem to be more pronounced in patients in whom therapy started within 24 h of sepsis diagnosis, whereas a delay in the start of therapy was associated with a poor response to therapy in terms of reduction of catecholamine demand and survival. Moreover, from our patient population, medical patients seemed to benefit more than post-surgical patients in terms of survival. Treatment using the CytoSorb device was safe and well-tolerated with no device related adverse events during or after the treatment sessions. CONCLUSION: Hemoadsorption using CytoSorb resulted in rapid hemodynamic stabilization and increased survival, particularly in patients in whom therapy was started early. Given the positive clinical experience of this case series, randomized controlled trials are urgently needed to define the potential benefits of this new treatment option. PMID- 28343450 TI - Spinal pain in Danish school children - how often and how long? The CHAMPS Study DK. AB - BACKGROUND: Spinal pain in children and adolescents is a common condition, usually transitory, but the picture of spinal pain still needs elucidation, mainly due to variation in measurement methods. The aim of this study was to describe the occurrence of spinal pain in 8-15 year-old Danish school children, over a 3-year period. Specifically determining the characteristics of spinal pain in terms of frequency and duration. METHODS: The study was a 3-year prospective longitudinal cohort study including 1400 school children. The outcomes were based on weekly text messages (SMS) to the parents inquiring about the child's musculoskeletal pain, and on clinical data from examinations of the children. RESULTS: The 3-year prevalence was 55%. The prevalence was 29%, 33% and 31% for each of the three study years respectively, and increased statistically significantly with age, especially for lumbopelvic pain. Most children had few and short-lasting episodes with spinal pain, but more than one out of five children had three or more episodes during a study year and 17% of all episodes lasted for more than 4 weeks. CONCLUSION: This study demonstrates that spinal pain is a substantial problem. Most episodes are brief, but there are a vast number of children with frequent and long-lasting episodes of spinal pain indicating a need for action regarding evidence-based prevention and management. PMID- 28343449 TI - Post-mortem study of the association between cardiac iron and fibrosis in transfusion dependent anaemia. AB - BACKGROUND: Heart failure related to cardiac siderosis remains a major cause of death in transfusion dependent anaemias. Replacement fibrosis has been reported as causative of heart failure in siderotic cardiomyopathy in historical reports, but these findings do not accord with the reversible nature of siderotic heart failure achievable with intensive iron chelation. METHODS: Ten whole human hearts (9 beta-thalassemia major, 1 sideroblastic anaemia) were examined for iron loading and fibrosis (replacement and interstitial). Five had died from heart failure, 4 had cardiac transplantation for heart failure, and 1 had no heart failure (death from a stroke). Heart samples iron content was measured using atomic emission spectroscopy. Interstitial fibrosis was quantified by computer using picrosirius red (PSR) staining and expressed as collagen volume fraction (CVF) with normal value for left ventricle <3%. RESULTS: The 9 hearts affected by heart failure had severe iron loading with very low T2* of 5.0 +/- 2.0 ms (iron concentration 8.5 +/- 7.0 mg/g dw) and diffuse granular myocardial iron deposition. In none of the 10 hearts was significant macroscopic replacement fibrosis present. In only 2 hearts was interstitial fibrosis present, but with low CVF: in one patient with no cardiac siderosis (death by stroke, CVF 5.9%) and in a heart failure patient (CVF 2%). In the remaining 8 patients, no interstitial fibrosis was seen despite all having severe cardiac siderosis and heart failure (CVF 1.86% +/-0.87%). CONCLUSION: Replacement cardiac fibrosis was not seen in the 9 post-mortem hearts from patients with severe cardiac siderosis and heart failure leading to death or transplantation, which contrasts markedly to historical reports. Minor interstitial fibrosis was also unusual and very limited in extent. These findings accord with the potential for reversibility of heart failure seen in iron overload cardiomyopathy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00520559. PMID- 28343452 TI - SYSTEMATIC REVIEWS OF ECONOMIC EVALUATIONS: HOW EXTENSIVE ARE THEIR SEARCHES? AB - OBJECTIVES: Economic evaluation (EE) is an accepted element of decision making and priority setting in healthcare. As the number of published EEs grows, so does the number of systematic reviews (SRs) of EEs. Although search methodology makes an important contribution to SR quality, search methods in reviews of EEs have not been evaluated in detail. We investigated the resources used to identify studies in recent, published SRs of EEs, and assessed whether the resources reflected recommendations. METHODS: We searched MEDLINE for SRs of EEs published since January 2013 and extracted the following from eligible reviews: databases searched, health technology assessment (HTA) sources searched, supplementary search techniques used. Results were compared against the minimum search resources recommended by National Institute for Health and Care Excellence (NICE) (MEDLINE, Embase, NHS EED, EconLit) for economic evidence for single technology appraisals, and resource types suggested in the summary of current best evidence from SuRe Info (economic databases, general databases, HTA databases, HTA agency Web pages, gray literature). RESULTS: Sixty-five SRs met the inclusion criteria; data were extracted from forty-two. Five reviews (12 percent) met or exceeded the NICE recommended resources. Nine reviews (21 percent) searched at least four of the five types of resource recommended by SuRe Info. Five reviews (12 percent) searched all five. Twenty-three reviews (55 percent) did not meet the NICE recommendations or four of five of the SuRe Info recommended resource types. Search reporting was frequently unclear or incorrect. CONCLUSIONS: Searches conducted for the majority of recently published SRs of EEs do not meet two published approaches. PMID- 28343451 TI - The association between the day of the week of milestones in the care pathway of patients with hip fracture and 30-day mortality: findings from a prospective national registry - The National Hip Fracture Database of England and Wales. AB - BACKGROUND: Recent publications indicate increased mortality in patients admitted to hospital at the weekend, but these findings may be subject to inadequate adjustment for case-mix and the complexities of resource provision. Hip fractures generally occur in a frail comorbid population with a consistent diagnosis precipitating admission as an emergency. We therefore aimed to examine the association between the day of the week of milestones in the care pathway and 30 day mortality in this population. METHODS: Using data from a prospective national database of hip fractures, we investigated the association between day of the week of admission, surgery, inpatient stay, and discharge (care pathway milestones) and 30-day mortality using generalised linear models. Data was collected between January 1, 2011, and December 31, 2014, on 241,446 patients. An incremental case-mix adjustment strategy was performed using patient characteristics, non-surgical interventions, surgical interventions and discharge characteristics. RESULTS: The day of admission was not associated with 30-day mortality. Sunday surgery (OR, 1.094; 95% CI, 1.043-1.148; P < 0.0001) and a delay to surgery of more than 24-hours (OR, 1.094; 95% CI, 1.059, 1.130; P < 0.0001) were both associated with a 9.4% increase in 30-day mortality. Discharge from the hospital on a Sunday (OR, 1.515; 95% CI, 1.224, 1.844; P < 0.0001) or out-of-hours discharge (OR, 1.174; 95% CI, 1.081, 1.276; P < 0.0001) were associated with a 51.5% and 17.4% increase in 30-day mortality, respectively. Mortality during the inpatient stay was 5.6% lower (IRR, 0.944; 95% CI, 0.909, 0.980; P = 0.003) at the weekend compared to weekdays. CONCLUSIONS: There is limited evidence of a generalised weekend effect in patients admitted to hospital for hip fracture. Optimising resource utilisation is an essential element of planning and delivering healthcare services. Interventions that lead to surgery within 24-hours of admission are justified. Factors such as Sunday operations, discharge and out-of-hours discharge require further investigation. PMID- 28343454 TI - ADHD patients fail to maintain task goals in face of subliminally and consciously induced cognitive conflicts. AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) patients have been reported to display deficits in action control processes. While it is known that subliminally and consciously induced conflicts interact and conjointly modulate action control in healthy subjects, this has never been investigated for ADHD. METHOD: We investigated the (potential) interaction of subliminally and consciously triggered response conflicts in children with ADHD and matched healthy controls using neuropsychological methods (event-related potentials; ERPs) to identify the involved cognitive sub-processes. RESULTS: Unlike healthy controls, ADHD patients showed no interaction of subliminally and consciously triggered response conflicts. Instead, they only showed additive effects as their behavioural performance (accuracy) was equally impaired by each conflict and they showed no signs of task-goal shielding even in cases of low conflict load. Of note, this difference between ADHD and controls was not rooted in early bottom-up attentional stimulus processing as reflected by the P1 and N1 ERPs. Instead, ADHD showed either no or reversed modulations of conflict-related processes and response selection as reflected by the N2 and P3 ERPs. CONCLUSION: There are fundamental differences in the architecture of cognitive control which might be of use for future diagnostic procedures. Unlike healthy controls, ADHD patients do not seem to be endowed with a threshold which allows them to maintain high behavioural performance in the face of low conflict load. ADHD patients seem to lack sufficient top-down attentional resources to maintain correct response selection in the face of conflicts by shielding the response selection process from response tendencies evoked by any kind of distractor. PMID- 28343456 TI - Implementation of Neurocritical Care Is Associated With Improved Outcomes in Traumatic Brain Injury. AB - : Background Traditionally, the delivery of dedicated neurocritical care (NCC) occurs in distinct NCC units and is associated with improved outcomes. Institution-specific logistical challenges pose barriers to the development of distinct NCC units; therefore, we developed a consultancy NCC service coupled with the implementation of invasive multimodal neuromonitoring, within a medical surgical intensive care unit. Our objective was to evaluate the effect of a consultancy NCC program on neurologic outcomes in severe traumatic brain injury patients. METHODS: We conducted a single-center quasi-experimental uncontrolled pre- and post-NCC study in severe traumatic brain injury patients (Glasgow Coma Scale <=8). The NCC program includes consultation with a neurointensivist and neurosurgeon and multimodal neuromonitoring. Demographic, injury severity metrics, neurophysiologic data, and therapeutic interventions were collected. Glasgow Outcome Scale (GOS) at 6 months was the primary outcome. Multivariable ordinal logistic regression was used to model the association between NCC implementation and GOS at 6 months. RESULTS: A total of 113 patients were identified: 76 pre-NCC and 37 post-NCC. Mean age was 39 years (standard deviation [SD], 2) and 87 of 113 (77%) patients were male. Median admission motor score was 3 (interquartile ratio, 1-4). Daily mean arterial pressure was higher (95 mmHg [SD, 10]) versus (88 mmHg [SD, 10], p<0.001) and daily mean core body temperature was lower (36.6 degrees C [SD, 0.90]) versus (37.2 degrees C [SD, 1.0], p=0.001) post-NCC compared with pre-NCC, respectively. Multivariable regression modelling revealed the NCC program was associated with a 2.5 increased odds (odds ratios, 2.5; 95% confidence interval, 1.1-5.3; p=0.022) of improved 6-month GOS. CONCLUSIONS: Implementation of a NCC program is associated with improved 6 month GOS in severe TBI patients. PMID- 28343455 TI - Reducing Clostridium difficile in the Inpatient Setting: A Systematic Review of the Adherence to and Effectiveness of C. difficile Prevention Bundles. AB - BACKGROUND Clostridium difficile infection (CDI) is the most common infectious cause of nosocomial diarrhea, and its prevention is an urgent public health priority. However, reduction of CDI is challenging because of its complex pathogenesis, large reservoirs of colonized patients, and the persistence of infectious spores. The literature lacks high-quality evidence for evaluating interventions, and many hospitals have implemented bundled interventions to reduce CDI with variable results. Thus, we conducted a systematic review to examine the components of CDI bundles, their implementation processes, and their impact on CDI rates. METHODS We conducted a comprehensive literature search of multiple computerized databases from their date of inception through April 30, 2016. The protocol was registered in PROSPERO, an international prospective register of systematic reviews. Bundle effectiveness, adherence, and study quality were assessed for each study meeting our criteria for inclusion. RESULTS In the 26 studies that met the inclusion criteria for this review, implementation and adherence factors to interventions were variably and incompletely reported, making study reproducibility and replicability challenging. Despite contextual differences and the variety of bundle components utilized, all 26 studies reported an improvement in CDI rates. However, given the lack of randomized controlled trials in the literature, assessing a causal relationship between bundled interventions and CDI rates is currently impossible. CONCLUSION Cluster randomized trials that include a rigorous assessment of the implementation of bundled interventions are urgently needed to causally test the effect of intervention bundles on CDI rates. Infect Control Hosp Epidemiol 2017;38:639-650. PMID- 28343457 TI - Development of a model to quantify the accessibility of a Canadian trauma system. AB - OBJECTIVES: Trauma systems have been widely implemented across Canada, but access to trauma care remains a challenge for much of the population. This study aims to develop and validate a model to quantify the accessibility of definitive care within one provincial trauma system and identify populations with poor access to trauma care. METHODS: A geographic information system (GIS) was used to generate models of pre-scene and post-scene intervals, respectively. Models were validated using a population-based trauma registry containing data on prehospital time intervals and injury locations for Nova Scotia (NS). Validated models were then applied to describe the population-level accessibility of trauma care for the NS population as well as a cohort of patients injured in motor vehicle collisions (MVCs). RESULTS: Predicted post-scene intervals were found to be highly correlated with documented post-scene intervals (beta 1.05, p<0.001). Using the model, it was found that 88.1% and 42.7% of the population had access to Level III and Level I trauma care within 60 minutes of prehospital time from their residence, respectively. Access for victims of MVCs was lower, with 84.3% and 29.7% of the cohort having access to Level III and Level I trauma care within 60 minutes of the location of injury, respectively. CONCLUSION: GIS models can be used to identify populations with poor access to care and inform service planning in Canada. Although only 43% of the provincial population has access to Level I care within 60 minutes, the majority of the population of NS has access to Level III trauma care. PMID- 28343453 TI - A trans-diagnostic perspective on obsessive-compulsive disorder. AB - Progress in understanding the underlying neurobiology of obsessive-compulsive disorder (OCD) has stalled in part because of the considerable problem of heterogeneity within this diagnostic category, and homogeneity across other putatively discrete, diagnostic categories. As psychiatry begins to recognize the shortcomings of a purely symptom-based psychiatric nosology, new data-driven approaches have begun to be utilized with the goal of solving these problems: specifically, identifying trans-diagnostic aspects of clinical phenomenology based on their association with neurobiological processes. In this review, we describe key methodological approaches to understanding OCD from this perspective and highlight the candidate traits that have already been identified as a result of these early endeavours. We discuss how important inferences can be made from pre-existing case-control studies as well as showcasing newer methods that rely on large general population datasets to refine and validate psychiatric phenotypes. As exemplars, we take 'compulsivity' and 'anxiety', putatively trans diagnostic symptom dimensions that are linked to well-defined neurobiological mechanisms, goal-directed learning and error-related negativity, respectively. We argue that the identification of biologically valid, more homogeneous, dimensions such as these provides renewed optimism for identifying reliable genetic contributions to OCD and other disorders, improving animal models and critically, provides a path towards a future of more targeted psychiatric treatments. PMID- 28343458 TI - Association between urinary metabolic profile and the intestinal effects of cocoa in rats. AB - The aim of this study was to elucidate the relationship between the urinary metabolic fingerprint and the effects of cocoa and cocoa fibre on body weight, hormone metabolism, intestinal immunity and microbiota composition. To this effect, Wistar rats were fed, for 3 weeks, a diet containing 10 % cocoa (C10) or two other diets with same the proportion of fibres: one based on cocoa fibre (CF) and another containing inulin as a reference (REF) diet. The rats' 24 h urine samples were analysed by an untargeted 1H NMR spectroscopy-based metabonomic approach. Concentrations of faecal IgA and plasma metabolic hormones were also quantified. The C10 diet decreased the intestinal IgA, plasma glucagon-like peptide-1 and glucagon concentrations and increased ghrelin levels compared with those in the REF group. Clear differences were observed between the metabolic profiles from the C10 group and those from the CF group. Urine metabolites derived from cocoa correlated with the cocoa effects on body weight, immunity and the gut microbiota. Overall, cocoa intake alters the host and bacterial metabolism concerning energy and amino acid pathways, leading to a metabolic signature that can be used as a marker for consumption. This metabolic profile correlates with body weight, metabolic hormones, intestinal immunity and microbiota composition. PMID- 28343459 TI - A retrospective analysis of a societal experiment among the Danish population suggests that exposure to extra doses of vitamin A during fetal development may lower type 2 diabetes mellitus (T2DM) risk later in life. AB - Vitamin A deficiency has been associated with impaired fetal pancreatic development and increased risk of developing type 2 diabetes mellitus (T2DM). In 1962, mandatory margarine fortification with vitamin A was increased by 25 % in Denmark. We aimed to determine whether offspring of mothers who had been exposed to the extra vitamin A from fortification during pregnancy had a lower risk of developing T2DM in adult life, compared with offspring of mothers exposed to less vitamin A. Individuals from birth cohorts with the higher prenatal vitamin A exposure (born 1 December 1962-31 March 1964) and those with lower prenatal exposure (born 1 September 1959-31 December 1960) were followed up with regard to development of T2DM before 31 December 2012 in the Danish National Diabetes Registry and National Patient Register. Logistic and Cox regression analyses were performed to determine the risk of T2DM by vitamin A exposure level. A total of 193 803 individuals were followed up until midlife. Our results showed that individuals exposed prenatally to extra vitamin A from fortified margarine had a lower risk of developing T2DM than those exposed to lower levels: OR 0.88; 95 % CI 0.81, 0.95, P=0.001, after adjustment for sex. Fetal exposure to small, extra amounts of vitamin A from food fortification may reduce the risk of T2DM. These results may have public health relevance, as they demonstrate that one of the most costly chronic diseases may be prevented by food fortification - a simple and affordable public health nutrition intervention. PMID- 28343460 TI - New Methods of Morphometric Analyses on Scyphozoan Jellyfish Statoliths Including the first Direct Evidence for Statolith Growth Using Calcein as a Fluorescent Marker. AB - Statoliths are the only hard structures in the gelatinous bell of most scyphozoan medusae and investigations on these structures could promote investigations of the understudied population dynamics and phylogeny of jellyfish. We examined the statoliths of Aurelia aurita jellyfish of different ages by light microscopic and microtomographic measurements supplemented by scanning electron microscopy. The morphometric analyses confirmed that statolith numbers and sizes increase during jellyfish development and revealed that newly-formed statoliths had similar shapes that may change during statolith growth. Nevertheless, most statoliths had a typical compact rod shape with an aspect ratio of 1-2.5 at all ages and we suggest that the composition of statolith shapes may be taxa specific. We developed a new approach allowing exact measurements of statolith growth for the first time. The application of calcein as a fluorescent marker resulted in clear fluorescent lines within the statoliths, allowing calculations of the statolith side face growth increments (0.1 um/day; n=252). A single-crystal analysis revealed that the calcein incubation did not affect the statolith crystal structure. In conclusion, calcein labeling is an excellent method to follow the growth of bassanite statoliths. PMID- 28343461 TI - The impact of maternal obesity on inflammatory processes and consequences for later offspring health outcomes. AB - Obesity is a global epidemic, affecting both developed and developing countries. The related metabolic consequences that arise from being overweight or obese are a paramount global health concern, and represent a significant burden on healthcare systems. Furthermore, being overweight or obese during pregnancy increases the risk of offspring developing obesity and other related metabolic complications in later life, which can therefore perpetuate a transgenerational cycle of obesity. Obesity is associated with a chronic state of low-grade metabolic inflammation. However, the role of maternal obesity-mediated alterations in inflammatory processes as a mechanism underpinning developmental programming in offspring is less understood. Further, the use of anti inflammatory agents as an intervention strategy to ameliorate or reverse the impact of adverse developmental programming in the setting of maternal obesity has not been well studied. This review will discuss the impact of maternal obesity on key inflammatory pathways, impact on pregnancy and offspring outcomes, potential mechanisms and avenues for intervention. PMID- 28343462 TI - Exploring the neuroanatomical bases of psychotic features in bipolar disorder. AB - Although bipolar disorder (BD) is traditionally conceptualised as one diagnostic entity, the heterogeneity of pathophysiological manifestations in BD suggests the need to classify the subtypes of the illness based on neural markers. Specifically, the presence of psychotic symptoms seems to be relevant for the clinical outcome and may have specific neuroanatomical bases. The main objective of the present review was to assess whether the distinction between psychotic BD (PBD) and non-psychotic BD (NPBD) can improve the identification of the neurobiological markers of this complex illness. To this end, we summarised the findings from the magnetic resonance imaging studies that explored the cerebral correlates of psychosis in BD in terms of grey matter volume (GMV). Overall, the results suggest the presence of peculiar GMV differences between PBD and NPBD. Specifically, psychosis in BD seems to be associated with cortical GMV deficits compared with both healthy controls and NPBD, mainly in the frontal region. Conversely, NPBD patients showed GMV deficits in selective regions of the basal ganglia when compared with the other groups. Taken together, this evidence confirms the importance to classify BD based on the psychotic dimension, which may have a specific neurobiological architecture that partially overlaps across multiple psychotic disorders. PMID- 28343463 TI - Prospective, Head-to-Head Study of Three Computerized Neurocognitive Assessment Tools Part 2: Utility for Assessment of Mild Traumatic Brain Injury in Emergency Department Patients. AB - OBJECTIVES: The aim of this study was to evaluate the reliability and validity of three computerized neurocognitive assessment tools (CNTs; i.e., ANAM, DANA, and ImPACT) for assessing mild traumatic brain injury (mTBI) in patients recruited through a level I trauma center emergency department (ED). METHODS: mTBI (n=94) and matched trauma control (n=80) subjects recruited from a level I trauma center emergency department completed symptom and neurocognitive assessments within 72 hr of injury and at 15 and 45 days post-injury. Concussion symptoms were also assessed via phone at 8 days post-injury. RESULTS: CNTs did not differentiate between groups at any time point (e.g., M 72-hr Cohen's d=-.16, .02, and .00 for ANAM, DANA, and ImPACT, respectively; negative values reflect greater impairment in the mTBI group). Roughly a quarter of stability coefficients were over .70 across measures and test-retest intervals in controls. In contrast, concussion symptom score differentiated mTBI vs. control groups acutely), with this effect size diminished over time (72-hr and day 8, 15, and 45 Cohen's d=-.78, -.60, .49, and -.35, respectively). CONCLUSIONS: The CNTs evaluated, developed and widely used to assess sport-related concussion, did not yield significant differences between patients with mTBI versus other injuries. Symptom scores better differentiated groups than CNTs, with effect sizes weaker than those reported in sport-related concussion studies. Nonspecific injury factors, and other characteristics common in ED settings, likely affect CNT performance across trauma patients as a whole and thereby diminish the validity of CNTs for assessing mTBI in this patient population. (JINS, 2017, 23, 293-303). PMID- 28343464 TI - Life, lifestyle and location: examining the complexities of psychological distress in young adult Indigenous and non-Indigenous Australians. AB - Mental health is fundamental to an individual's health and well-being. Mental health disorders affect a substantial portion of the Australian population, with the most vulnerable time in adolescence and young adulthood. Indigenous Australians fare worse than other Australians on almost every measure of physical and mental health. Cross-sectional data from young adults (21-27 years) participating in the Life Course Program, Northern Territory, Australia, is presented. Rates of psychological distress were high in remote and urban residing Indigenous and urban non-Indigenous young adults. This rate was more pronounced in young women, particularly in Indigenous remote and urban residing women. Young adults with high psychological distress also had lower levels of positive well being, higher perceived stress levels, experienced a higher number of major life events and were at an increased risk of suicidal ideation and/or self-harm. This study supports the need for a continued focus on early screening and treatment at this vulnerable age. The significant association seen between psychological distress and other markers of emotional well-being, particularly risk of suicidal ideation and/or self-harm, highlights the need for a holistic approach to mental health assessment and treatment. A concerted focus on improving the environs of young adults by lowering levels of stress, improving access to adequate housing, educational and employment opportunity, will assist in improving the emotional health of young adults. PMID- 28343465 TI - Academic Outcomes in Individuals With Childhood-Onset Epilepsy: Mediating Effects of Working Memory. AB - OBJECTIVES: Academic difficulties are common in children with epilepsy, although little is known about the effect of various seizure-related and cognitive variables. Given that persistent seizures may negatively impact academics, and that working memory is predictive of academic abilities, we examined the effects of recent seizures and working memory on word reading, spelling, and arithmetic in pediatric epilepsy. We hypothesized that persistent seizures would be associated with lower working memory ability, which would in turn result in poorer academic performance. METHODS: Our sample consisted of 91 children with epilepsy being treated at the Hospital for Sick Children in Toronto, Canada, who underwent neuropsychological testing between 2002 and 2009 to help determine surgical candidacy. Four to 11 years later, follow-up testing was conducted on both surgical (n=61) and non-surgical (n=30) patients. Seizure status was defined by the presence or absence of seizures within the preceding 12 months. RESULTS: 5000 bias-corrected bootstrap resamples with replacement were used to calculate the 95% confidence intervals (CIs) for the indirect effect of seizure status on academics through working memory, controlling for baseline academic functioning. Persistent seizures were associated with reduced working memory, which was in turn associated with lower reading (B=-4.64, 95% CI [-10.21, -1.30]), spelling (B=-7.09, 95% CI [-13.97, -2.56], and arithmetic scores (B=-8.04, 95% CI [-13.66, -3.58] at follow-up. CONCLUSIONS: For children with intractable epilepsy, working memory deficits present a significant barrier to the development of academic skills. Working memory interventions may be a helpful adjunct to academic remediation in this population to facilitate academic progress. (JINS, 2017, 23, 594-604). PMID- 28343466 TI - Treatment of gambling disorder patients with comorbid depression. AB - OBJECTIVE: This study was conducted to investigate and clinically assess comorbid depression and its relevance in individuals suffering from gambling disorders. The DSM-V defines the condition of gambling disorder as a persistent and recurrent problematic gambling behaviour leading to clinically significant impairment or distress. METHOD: A total of 61 subjects with gambling disorders were assessed using the Structured Clinical Interview for the DSM-IV (SCID-I), the South Oaks Gambling Screen (SOGS) and the Major Depression inventory (MDI). RESULTS: Two-way analysis of variance showed highly significant treatment outcomes associated with reductions in SOGS, F(1,60)=84.79, p<0.0001, MDI, F(1,60)=38.13, p<0.0001, craving, F(1,60)=29.59, p<0.0001, and gambling control, 47.65, p<0.0001. There was also a highly significant outcome associated with comorbidity in MDI, F(1,60)=9.17, p<0.0001. Finally, there was a significant interaction effect between treatment outcome and comorbidity, F(1,60)=3.90, p<0.005, suggesting that both treatment and comorbidity contributed to reductions in depressive symptoms. CONCLUSION: These results suggest and highlights the importance and benefits of integrated treatment of gambling disorders and its comorbidity, but also stresses the importance of adequate screening and detection of these two variables. PMID- 28343467 TI - Successful chimera production in the Hungarian goose (Anser anser domestica) by intracardiac injection of blastodermal cells in 3-day-old embryos. AB - The conservation of genetic resources of avian species has become increasingly important over the past decade. The aim of the present study was to develop a genome preservation technique for the Hungarian goose Anser anser domestica. To this end, we developed a novel approach combining the simplicity of isolating a blastodermal cell suspension, which includes forming primordial germ cells (PGCs), with the efficiency of targeting future gonads by injecting these cells into the cardiac vein of the developing host embryo. First, we determined that the migratory period of PGCs in goose embryos was between 69 and 84h of development. Then, we injected the blastodermal cell suspension into the bloodstream of recipient embryos at this stage of development and monitored donor cell transmission into the genital tract. In all, 249 embryos were injected; three were found to be chimeras in gonadal tissues, whereas only one was a chimera in other tissues. Based on these results, it is concluded that this method is suitable for producing chimeras in the domestic goose. The optimal time of cell injection was found to be between 74 and 76h. The present study is the first report of the generation of chimeras in the domestic goose using intracardiac transplantation of embryonic cells. PMID- 28343469 TI - Introduction to "Extra-Renal Complications of Cystinosis". PMID- 28343468 TI - Glutamine protects rabbit spermatozoa against oxidative stress via glutathione synthesis during cryopreservation. AB - Mammalian spermatozoa are extremely susceptible to high doses of reactive oxygen species (ROS). The aim of the present study was to investigate the potential role of glutamine in protecting rabbit spermatozoa against ROS stress during cryopreservation and post-thaw incubation. Freshly ejaculated semen was diluted with Tris-citrate-glucose extender supplemented with glutamine. The addition of 20mM glutamine significantly improved sperm motility, acrosome integrity, membrane integrity and mitochondrial activity. Meanwhile, 20mM glutamine addition decreased lipid peroxidation and DNA damage in frozen-thawed spermatozoa. Interestingly, supplementation with 20mM glutamine led to increases in glutathione content and gamma-glutamyl cysteine synthetase and glutathione peroxidase activity, with concomitant decreases in ROS levels during cryopreservation and post-thaw incubation. In conclusion, the addition of glutamine to extender solutions protects rabbit spermatozoa from ROS attack by enhancing glutathione synthesis. PMID- 28343470 TI - Neurocognitive Complications of Cystinosis. PMID- 28343471 TI - Ocular Complications of Infantile Nephropathic Cystinosis. PMID- 28343472 TI - Bone Complications of Cystinosis. PMID- 28343473 TI - Myopathy and Less Frequent Complications of Cystinosis. PMID- 28343474 TI - Conclusions to the Supplement, "Extra-Renal Complications of Cystinosis". PMID- 28343475 TI - Endocrine Complications of Cystinosis. PMID- 28343476 TI - Pulmonary Complications of Cystinosis. PMID- 28343478 TI - Correction. PMID- 28343477 TI - Rehabilitation Research at the National Institutes of Health: Moving the Field Forward (Executive Summary). PMID- 28343480 TI - Past, Present, Future. PMID- 28343479 TI - National Institutes of Health Research Plan on Rehabilitation. AB - One in five Americans experiences disability that affects their daily function because of impairments in mobility, cognitive function, sensory impairment, or communication impairment. The need for rehabilitation strategies to optimize function and reduce disability is a clear priority for research to address this public health challenge. The National Institutes of Health (NIH) recently published a Research Plan on Rehabilitation that provides a set of priorities to guide the field over the next 5 years. The plan was developed with input from multiple Institutes and Centers within the NIH, the National Advisory Board for Medical Rehabilitation Research, and the public. This article provides an overview of the need for this research plan, an outline of its development, and a listing of six priority areas for research. The NIH is committed to working with all stakeholder communities engaged in rehabilitation research to track progress made on these priorities and to work to advance the science of medical rehabilitation. PMID- 28343481 TI - ISSWSH Special Report on the US Food and Drug Administration Draft Guidance on Low Sexual Desire and Arousal: A New Hope or Old Habits Die Hard? PMID- 28343482 TI - Presentation of the Special Issue: Quality and Clinica Safety. The nurse as the cornerstone for improving the quality and safety of healthcare services. PMID- 28343483 TI - Nursing guaranteeing healthcare quality for people and families in public health services: A view from Latin America. PMID- 28343484 TI - Culture of healthcare safety and quality: challenges for nursing Practice. PMID- 28343485 TI - Discussion. PMID- 28343486 TI - Discussion. PMID- 28343487 TI - Discussion. PMID- 28343488 TI - Discussion. PMID- 28343489 TI - Discussion. PMID- 28343490 TI - Discussion. PMID- 28343492 TI - Discussion. PMID- 28343491 TI - Discussion. PMID- 28343493 TI - Discussion. PMID- 28343494 TI - Discussion. PMID- 28343495 TI - Discussion. PMID- 28343496 TI - Discussion. PMID- 28343497 TI - Discussion. PMID- 28343498 TI - Discussion. PMID- 28343499 TI - Discussion. PMID- 28343500 TI - Discussion. PMID- 28343501 TI - Discussion. PMID- 28343502 TI - Discussion. PMID- 28343503 TI - Discussion. PMID- 28343504 TI - Discussion. PMID- 28343505 TI - Discussion. PMID- 28343506 TI - Discussion. PMID- 28343507 TI - Discussion. PMID- 28343508 TI - Discussion. PMID- 28343509 TI - Discussion. PMID- 28343510 TI - Discussion. PMID- 28343511 TI - Discussion. PMID- 28343512 TI - Discussion. PMID- 28343513 TI - Discussion. PMID- 28343514 TI - Discussion. PMID- 28343515 TI - Discussion. PMID- 28343516 TI - Discussion. PMID- 28343517 TI - Discussion. PMID- 28343518 TI - Discussion. PMID- 28343520 TI - RDNs of the Future: Building Bridges with Technology. PMID- 28343521 TI - 2017 Academy Member Benefits Update. PMID- 28343522 TI - Healthy Eating Index-Beyond the Score. PMID- 28343523 TI - Promoting Food Pantry Environments that Encourage Nutritious Eating Behaviors. PMID- 28343524 TI - Clearing Up Copyright Confusion and Social Media Use: What Nutrition and Dietetics Practitioners Need to Know. PMID- 28343525 TI - Report on the Academy/Commission on Dietetic Registration 2016 Needs Satisfaction Survey. PMID- 28343526 TI - What Is the International Dysphagia Diet Standardisation Initiative? PMID- 28343527 TI - Should infants be screened for the risk for future obesity? PMID- 28343528 TI - Nutrition and brain development: it's complicated. PMID- 28343529 TI - 50 Years Ago in The Journal of Pediatrics: Systemic Infection with Haemophilus Influenzae in Very Young Infants. PMID- 28343530 TI - 50 Years Ago in The Journal of Pediatrics: The Relationship of Erythrocyte Glucose-6-Phosphate Dehydrogenase Deficiency to Hyperbilirubinemia in Negro Premature Infants. PMID- 28343531 TI - 50 Years Ago in The Journal of Pediatrics: Sequential Therapy of Acute Leukemia in Childhood. PMID- 28343533 TI - Is preventing BPD the target, or should we strive for something else? PMID- 28343532 TI - How to identify children with familial hypercholesterolemia. PMID- 28343534 TI - Neonatal jaundice: more than a number. PMID- 28343535 TI - 50 Years Ago in The Journal of Pediatrics: Bacterial Interference in the Treatment of Recurrent Staphylococcal Infections in a Family. PMID- 28343536 TI - Underimmunization drives community outbreaks of pertussis. PMID- 28343537 TI - 50 Years Ago in The Journal of Pediatrics: Pneumomediastinum, a Silent Lesion in the Newborn. PMID- 28343538 TI - Accelerated hypofractionated adjuvant whole breast radiation with simultaneous integrated boost using volumetric modulated arc therapy for early breast cancer: A phase I/II dosimetric and clinical feasibility study from a tertiary cancer care centre of India. AB - BACKGROUND: Hypofractionation has become standard of care after Breast Conserving Therapy (BCT) in many European and few others western countries. Though still debatable, tumor cavity boost is routinely practised in our centre. Hypofractionation is not yet the current standard of practice in Asian countries. Employing hypofractionation and simultaneous integrated boost to lumpectomy cavity with conformal technique is not the current practice in this region. Hence the study was performed to see whether accelerated hypofractionation and simultaneous boost can be combined using volumetric modulated arc therapy (VMAT) in treating early breast cancer (EBC) patients. PATIENTS AND METHODS: Female patients with EBC treated by whole breast radiation and boost were treated simultaneously to a dose of 40.5Gy and 48Gy in fifteen fractions over three weeks to entire breast and tumor cavity respectively with VMAT. Dosimetry including target coverage, OAR (organ at risk) sparing and acute radiation toxicity were evaluated. RESULTS: Ten consecutive patients were treated. Planning target volume (PTV) coverage and OAR sparing were mostly satisfactory. Mean volume of PTVWB and PTVBoost were 786.18cm3 and 228.9cm3 respectively. Mean Dmean to PTVWB and PTVBOOST were 41.9Gy and 49.1Gy respectively. Dmax to PTVWB and PTVBOOST were 127.56% and 110.67% respectively. Ipsilateral lung mean dose and V20 were 13.92Gy and 21.53% respectively. V40 and V25 of heart were 0.17% and 2.25% respectively. All patients are disease free after a median follow up of two years. Most acute toxicities were Grade1. Only two patients out of ten developed Grade 2 skin reaction during radiation. Early cosmesis using Harvard cosmesis scale is good to excellent. CONCLUSIONS: Accelerated hypofractionated RT using SIB-VMAT is a clinically feasible technique with acceptable initial result. Initial results are encouraging. MINI ABSTRACT: Simultaneous integrated boost with accelerated hypofractionated whole breast radiotherapy using Volumetric Modulated Arc Therapy is a novel approach. Patient selection and technical considerations are of paramount importance. The present study describes successful implementation of this approach. PMID- 28343539 TI - Charles M. LeMaistre (1924-2017): Former M. D. Anderson President Dr. Charles A. LeMaistre Passes Away at 92. PMID- 28343540 TI - Histone Code Aberrancies in Small Cell Lung Cancer. PMID- 28343541 TI - Predicting Clinical Outcomes Using Proteomics in Non-Small Cell Lung Cancer-The Past, Present, and Future. PMID- 28343542 TI - Is Mesothelioma in China Rare or Misdiagnosed? PMID- 28343543 TI - Single-Fraction Carbon Ion Radiotherapy for Early-Stage NSCLC-The Future Is Now. PMID- 28343544 TI - Sequential Immunologic Reactions after Suspension of Nivolumab Treatment in Lung Adenocarcinoma Patient. PMID- 28343545 TI - Compound Uncommon EGFR Mutations in a Patient with Advanced NSCLC and Durable Response to Sequential EGFR Targeted Therapies. PMID- 28343546 TI - Laparoscopy for Differential Diagnosis and Treatment of a Rarely Remembered Cause of Acute Inflammatory Abdomen in Women: Urachal Cyst Abscess. PMID- 28343547 TI - Le recours a la laparoscopie dans l'etablissement d'un diagnostic differentiel et dans le traitement d'une cause souvent oubliee de l'abdomen aigu chez la femme : l'infection d'un kyste de l'ouraque. PMID- 28343548 TI - All about Connection: A Message from JOGC's New Managing Editor. PMID- 28343549 TI - Une question de communication : message de la nouvelle directrice de la redaction du JOCG. PMID- 28343551 TI - Extraits de la litterature medicale mondiale. PMID- 28343550 TI - Excerpts from the World Medical Literature. PMID- 28343552 TI - Testosterone in Women: Measurement and Therapeutic Use. AB - Androgens, both in excessive and depleted states, have been implicated in female reproductive health disorders. As such, serum testosterone measurements are frequently ordered by physicians in cases of sexual dysfunction and in women presenting with hirsutism. Commercially available androgen assays have significant limitations in the female population. Furthermore, the measurements themselves are not always informative in patient diagnosis, treatment, or prognosis. This article reviews the limitations of serum androgen measurements in women suspected to have elevated or reduced androgen action. Finally, we consider when therapeutic use of androgen replacement may be appropriate for women with sexual interest/arousal disorders. PMID- 28343553 TI - Alpha Lipoic Acid Plus Omega-3 Fatty Acids for Vestibulodynia Associated With Painful Bladder Syndrome. AB - OBJECTIVE: This study assessed the effectiveness of alpha lipoic acid (ALA) plus omega-3 polyunsaturated fatty acids (n-3 PUFAs) in combination with amitriptyline therapy in patients with vestibulodynia/painful bladder syndrome (VBD/PBS). METHODS: Women with VBD/PBS were randomly assigned to receive amitriptyline or amitriptyline plus a commercially available preparation (ALAnerv Age; Alfa Wassermann, Bologna, Italy) containing, in 2 capsules, ALA 600 mg plus docosahexaenoic acid 250 mg and eicosapentaenoic acid 16.67 mg. Symptoms of burning and pain were assessed using a 10-cm visual analog scale and the short form of the McGill-Melzack Pain Questionnaire. RESULTS: Among 84 women who were randomized, the mean +/- standard deviation dose of amitriptyline was 21.7 +/- 6.6 mg/day, without statistical difference between the two groups. Pain, as assessed using both the pain rating index of the visual analog scale and the short-form McGill Pain Questionnaire, decreased significantly in both trial groups, with a greater effect seen with the addition of ALA and n-3 PUFAs. The addition of ALA/n-3 PUFAs to amitriptyline treatment was also associated with improvements in dyspareunia and pelvic floor muscle tone. The overall incidence of adverse events was low, and none led to treatment discontinuation. CONCLUSIONS: The addition of ALA/n-3 PUFAs to amitriptyline treatment in patients with VBD/PBS appears to improve outcomes and may allow for a lower dosage of amitriptyline, which may lead to fewer adverse effects. PMID- 28343554 TI - Prioritization of Patients for Publicly Funded IVF in Ontario: A Survey of Fertility Centres. AB - OBJECTIVE: On December 21, 2015, Ontario began funding one cycle of IVF for any Ontarian under age 43, with a program cap of 5000 cycles per year, which is below expected demand. Our objective was to determine how fertility clinics are prioritizing patients for limited-funded IVF cycles. METHODS: An electronic survey was emailed to medical directors of all 25 fertility clinics providing funded IVF in Ontario. RESULTS: From January to March 2016, 22 (88%) of the clinics responded. All reported providing access to funded IVF, and 100% already had a wait list. Eight clinics prioritized patients on a first-come, first-served basis; two used a lottery; 11 reported using multiple patient factors to determine priority for funding; and one declined to answer. Of the clinics reporting multiple factors, the five most common factors were first-come, first served (90.9%); older aged patients (81.8%); patients about to lose their funding eligibility (63.6%); duration of infertility (36.3%); and duration at current clinic (36.3%). CONCLUSIONS: There is variation in how patients are prioritized for publicly funded IVF in Ontario. Some clinics have chosen to prioritize patients in a first-come, first-served manner, whereas others have chosen to prioritize patients based on multiple factors that would favour older patients. This is the first study providing the public and government insight on how the new fertility program has been implemented by individual clinics. This information is important for patients to understand their own chances of receiving a funded IVF cycle because this may vary depending on individual clinics. PMID- 28343555 TI - Provoked Vestibulodynia: Diagnosis, Self-Reported Pain, and Presentation During Gynaecological Examinations. AB - OBJECTIVE: To explore factors associated with the diagnosis of provoked vestibulodynia (PVD) through (1) self-reported pain characteristics and (2) Friedrich's criteria (vestibular pain during sexual activity/gynaecological examination). We also identified cases in which incorrect diagnoses were assigned and explored group differences in gynaecological examination presentation and associations with self-reported pain. METHODS: Data were extracted from nine studies conducted in our research laboratory. Information obtained during a telephone interview and a standardized gynaecological examination was compiled for 106 participants with vulvar pain and 106 pain-free control participants, matched for age, hormonal contraceptive use, and parity. RESULTS: Cohen's kappa (0.78) indicated substantial agreement (87.3%) between the telephone interview group categorization and diagnosis after the gynaecological examination. A discriminant function analysis yielded one significant function: Friedrich's first two criteria correctly classified 84.2% of cases, accounting for 76.0% of group membership variance. Of note, those in the other genital pain group were most likely to have received an incorrect diagnosis following the telephone interview (P < 0.001). Paired-samples t tests showed that those with pain reported lower pain intensity during the gynaecological examination than during intercourse (P < 0.001) and that intercourse pain was not necessarily related to pain during the examination. However, many participants (72.8%) indicated that the pain elicited during the cotton swab test was similar to the pain they felt with intercourse. CONCLUSION: These results support the use of a targeted clinical interview and the evaluation of vestibular pain during sexual activity and the gynaecological examination for diagnosing PVD. Caution should be exercised when a patient presents with genital pain symptoms other than those typically observed in PVD. Furthermore, the cotton swab test may underestimate the degree of pain regularly experienced. PMID- 28343556 TI - Reporting Caesarean Delivery in Quebec Using the Robson Classification System. AB - OBJECTIVE: The increasing rates of Caesarean sections throughout the world is preoccupant, and a good understanding of which groups of women contribute the most to the CS rate represents an important question in public health. Therefore, we sought to report the CS rate according to the Robson's classification system in the Quebec population. METHOD: We performed a secondary analysis of the QUARISMA database, including all deliveries after 24 weeks' gestation from 32 maternity wards in the province of Quebec between 2008 and 2011 (n = 184 952 deliveries). CS rates were reported according to the modified Robson criteria from The Society of Obstetricians and Gynaecologists of Canada with the relative contribution to the total number of CSs. RESULTS: We observed a global CS rate of 22.9%. Women with previous CS and a fetus in cephalic presentation at term accounted for 35% of all Caesarean deliveries. Nulliparous women with cephalic presentation at term accounted for 30% of all CSs. Among nulliparous women with cephalic presentation, women with spontaneous labour contributed to 12% of all CSs, whereas women with an induction of labour contributed to 16% of all CSs. Non cephalic fetal presentation accounted for 19% of all CSs. Other indications accounted for the remaining 16% of CSs. CONCLUSION: Most CSs are performed for multiparous women with previous CS; nulliparous women with a cephalic presentation at term, especially those undergoing labour induction; and non cephalic fetal presentation. PMID- 28343557 TI - Infants Born to Opioid-Dependent Women in Ontario, 2002-2014. AB - BACKGROUND: There is a paucity of data characterizing mother-infant pairs with prenatal opioid dependence in Canada. We therefore conducted a study of relevant births in Ontario from 2002 to 2014. METHODS: We used data from the Institute for Clinical Evaluative Sciences, the linked databases of coded population-based Ontario health services records. Differences in characteristics of opioid dependent mother-neonate pairs and infant hospital costs by year were assessed using linear regression, and we calculated rates of preterm birth, low birth weight, birth defects, mortality, and neonatal abstinence syndrome. RESULTS: The number of infants born to opioid-dependent women in Ontario rose from 46 in 2002 to almost 800 in 2014. Methadone was most frequently used for prenatal opioid dependence; there was little buprenorphine or buprenorphine + naloxone use. Rates of preterm birth and low birth weight were high. The proportion of neonates with neonatal abstinence syndrome (58%) was stable over the study period. The mean length of neonatal hospital stay was 13.96 days. Infant hospital costs increased from $724 774 in 2003 to $10 539 988 in 2013, and the mean cost per infant grew from $9928 to $12 917. Birth defect prevalence was 75.84/1000 live births (95% CI 68.12/1000 to 84.10/1000). The stillbirth rate was 11.39/1000 births (95% CI 8.47/1000 to 14.99/1000), and the infant mortality rate was 12.21/1000 live births (95% CI 9.16/1000 to 15.95/1000). CONCLUSION: We observed a 16-fold increase in the number of mother-infant pairs affected by opioid dependence in Ontario over the past decade. Adverse birth outcome rates were high. Expanded services for opioid-dependent women and their children are needed. PMID- 28343558 TI - Simulator Based Obstetric Ultrasound Training: A Prospective, Randomized Single Blinded Study. AB - OBJECTIVE: To compare the use of simulator-based and patient-based obstetric ultrasound training. METHODS: This was a prospective, randomized, single-blinded trial. Eighteen consenting obstetric trainees with minimal previous ultrasound exposure were recruited. Enrolled patients were also fully consenting. Mid trimester fetal brain anatomy in the standard planes (i.e., biparietal diameter and head circumference, cavum septum pellucidum, posterior fossa, and lateral ventricle) was chosen as a surrogate for all fetal anatomy ultrasound training. Trainees were randomized into two groups according to training method: simulator group (n = 9) or patient group (n = 9). All participating trainees went through the following sequence: a didactic session regarding the required planes; a "real" patient 15-minute pretest; a 45-minute training session with a dedicated ultrasound educator, using either a simulator or a "real" patient (according to the randomized group assignment); and a 15-minute post-test to obtain and label the standard four planes on a "real" patient. All images were stored and then scored by two blinded Maternal Fetal Medicine staff, according to 3 set criteria: image quality, landmarks, and measurements. Each criterion was scored 0 to 15 for a total score of 0 to 60. RESULTS: Pretest competence was similar between the two groups. For each of the two groups there was a significant score improvement following training: real patient (mean score pretest 13.3 vs. post-test 24.6; P < 0.04) and simulator group (mean score pretest 15.9 vs. post-test 28.9; P < 0.05). All trainees demonstrated significant overall score improvements (mean score pretest 14.6 vs. post-test 26.6; P < 0.04) regardless of training method. Trainees were further divided by their initial level of confidence (pretest score <=5: very unconfident; pretest >5: unconfident). The improvement was similar for both groups, but "very unconfident" trainees' performance improved more in the simulator group (mean pretest vs. post-test score 3.5 to 35) compared with the patient group (mean pretest vs. post-test score 2.3 to 25.6) CONCLUSION: Simulator-based obstetric ultrasound training performed as well as real patient training and was found to be especially beneficial for beginner trainees. Simulator-based ultrasound training has a high rate of acceptance by trainees, does not require investment of patient or clinic resources, and warrants consideration as an educational tool for the safe and effective teaching of obstetric ultrasound. PMID- 28343559 TI - Hospital-associated Costs of Chronic Pelvic Pain in Canada: A Population-based Descriptive Study. AB - OBJECTIVE: To determine the hospital-related costs incurred by women requiring surgery or inpatient admission for chronic pelvic pain in Canada. METHODS: We conducted a population-based, cross-sectional study, focusing on women ages 15-59 with a most responsible International Classification of Diseases diagnosis of pelvic and perineal pain, dysmenorrhea, or dyspareunia who had surgery or inpatient admission with a discharge date between April 1, 2008 and March 31, 2012. This study was based on the Canadian Institute for Health Information Discharge Abstract database and the National Ambulatory Care Reporting System. Clinical diagnoses and interventions and resource intensity weights (RIW) were extracted. Hospital costs were estimated by multiplying cost per weighted case (CPWC) calculated at the national level with respective RIWs. RESULTS: Over four years, there were 34 346 cases of surgery or inpatient admission for chronic pelvic pain amounting to $100.5 million with an average cost of $25 million per year. Pelvic and perineal pain accounted for 61.5% (n = 21 127) of the cases, while dysmenorrhea accounted for 31.8% (n = 10 936), and dyspareunia accounted for 6.6% (n = 2283). The vast majority of the cases (92.9%, n = 31 923) were associated with surgical interventions, with the most common surgeries being hysterectomy (47.1%, n = 16 189), followed by laparoscopy (25.8%, n = 8850), adnexal surgery (6.8%, n = 2349), and other procedures (11.6%, n = 3968). CONCLUSION: While these estimates do not take into account non-hospital related costs, such as outpatient treatment, loss of productivity, and impact on quality of life, this study demonstrates that chronic pelvic pain represents a considerable economic burden to Canada's health care system. PMID- 28343560 TI - Acoustic levitation of liquid drops: Dynamics, manipulation and phase transitions. AB - The technique of acoustic levitation normally produces a standing wave and the potential well of the sound field can be used to trap small objects. Since no solid surface is involved it has been widely applied for the study of fluid physics, nucleation, bio/chemical processes, and various forms of soft matter. In this article, we survey the works on drop dynamics in acoustic levitation, focus on how the dynamic behavior is related to the rheological properties and discuss the possibility to develop a novel rheometer based on this technique. We review the methods and applications of acoustic levitation for the manipulation of both liquid and solid samples and emphasize the important progress made in the study of phase transitions and bio-chemical analysis. We also highlight the possible open areas for future research. PMID- 28343561 TI - Locomotor and energetic consequences of behavioral thermoregulation in the sanguivorous leech Hirudo verbana. AB - Medicinal leeches (Hirudo verbana) thermoregulate with respect to their sanguivorous feeding behavior. Immediate postprandial preferences are for warmer than their initial acclimation temperature (Ta, 21 degrees C, Petersen et al. 2011), while unfed leeches have a lower preferred temperature (Tpref, 12.5 degrees C). This may reduce energy expenditure and defer starvation if feeding opportunities are limited. Energetic benefits may have an associated cost if low temperatures reduce mobility and the ability to locate further hosts. These costs could be limited if mobility is unimpaired at low temperatures, or if acclimation can restore locomotor performance to the levels at Ta. The transition from Ta to the unfed Tpref significantly reduced speed and propulsive cycle frequency during swimming, and extension and retraction rates during crawling. Aerobic metabolic rate was also reduced from 0.20+/-0.03Wkg-1 at Ta to 0.10+/-0.03Wkg-1 at Tpref. The Q10 values of 1.7-2.9 for energetic and swimming parameters indicate a substantial temperature effect, although part of the decline in swimming performance can be attributed to temperature-related changes in water viscosity. 6 weeks at Ta resulted in no detectable acclimation in locomotor performance or aerobic metabolism. The energetic savings associated with a lower Tpref in unfed leeches effectively doubled the estimated time until depletion of energy reserves. Given that some mobility is still retained at Tpref, and that acclimation is in itself costly, the energetic benefits of selecting cooler temperatures between feedings may outweigh the costs associated with reduced locomotor performance. PMID- 28343562 TI - Prenatal exposure to diurnal temperature variation and early childhood pneumonia. AB - BACKGROUND: Childhood pneumonia is one of the leading single causes of mortality and morbidity in children worldwide, but its etiology still remains unclear. OBJECTIVE: We investigate the association between childhood pneumonia and exposure to diurnal temperature variation (DTV) in different timing windows. METHODS: We conducted a prospective cohort study of 2,598 children aged 3-6 years in Changsha, China. The lifetime prevalence of pneumonia was assessed by a questionnaire administered by the parents. Individual exposure to DTV during both prenatal and postnatal periods was estimated. Logic regression models was used to examine the association between childhood pneumonia and DTV exposure in terms of odds ratios (OR) and 95% confidence interval (CI). RESULTS: Lifetime prevalence of childhood pneumonia in preschool children in Changsha was high up to 38.6%. We found that childhood pneumonia was significantly associated with prenatal DTV exposure, with adjusted OR (95%CI) =1.19 (1.02-1.38), particularly during the second trimester. However, childhood pneumonia not associated with postnatal DTV exposure. Sensitivity analysis indicated that boys are more susceptible to the pneumonia risk of diurnal temperature variation than girls. We further observed that the prevalence of childhood pneumonia was decreased in recent years as DTV shrinked. CONCLUSIONS: Early childhood pneumonia was associated with prenatal exposure to the diurnal temperature variation (DTV) during pregnancy, particularly in the second trimester, which suggests fetal origin of childhood pneumonia. PMID- 28343563 TI - Effect of thermal exposure on physiological adaptability and seminal attributes of rams under semi-arid environment. AB - Thermal stress in hot semi-arid environment is a major limitation of sheep production in tropical and sub-tropical climatic condition. The animals tend to maintain homeostasis through physiological adjustments in a hot environment (maximum temperature reaches up to 47.5 degrees C). Therefore, the present study was carried out to assess the effect of thermal exposure on physiological adaptability and seminal attributes of rams under semi-arid environment. The experiment was conducted for eight weeks involving sixteen Malpura crossbred rams (GMM: Garole X Malpura X Malpura). The rams were divided equally into two groups, designated as G1 and G2, respectively. The rams in G1 (Control) group were kept in a sheep shed under naturally prevailing environment without artificial manipulation of ambient temperature (Temperature 30.48+/-0.38 degrees C; Relative Humidity 28.59+/-1.15%). The rams of G2 group were exposed to different temperature at different hours of the day (38 degrees C at 1000-1100h; 40 degrees C at 1100-1200h; 42 degrees C at 12:00-1300h; 43 degrees C at 1300-1400h; 44 degrees C at 1400-1500h and 42 degrees C at 1500-1600h) in a climatic chamber for thermal exposure. Physiological responses, blood biochemical profile, blood endocrine profile, sexual behavior and seminal attributes were measured for both the groups. Thermal exposure significantly (P<0.05) increased the water intake; respiration rate, rectal temperature and skin temperature at afternoon in rams. Exposure of rams to thermal stress (G2) significantly (P<0.05) increased cortisol level and decreased tri-ido-thyronine level. The latency period after the first ejaculation, decreased significantly (P<0.05) in G2. The percentage of rapid motile sperm, linearity and average path velocity of sperm were also altered significantly (P<0.05) in thermal exposed rams as compared to control. However, comparable feed intake, body weight, and major blood biochemical parameters, as well as acceptable semen quality attributes of all the rams indicated that the Fec B gene introgressed Malpura cross rams adapted to the thermal exposure under semi-arid tropical climate. PMID- 28343564 TI - Embryos of non-native anoles are robust to urban thermal environments. AB - The transformation of natural habitats into urban landscapes dramatically alters thermal environments, which in turn, can impact local biota. Ectothermic organisms that are oviparous are particularly sensitive to these altered environments because their embryos cannot behaviorally thermoregulate and the surrounding environment determines the temperature experienced during development. We studied the effects of urban and forested thermal environments on embryo development and hatchling phenotypes in two non-native lizards (Anolis sagrei and A. cristatellus) in metropolitan Miami, Florida. To determine if embryos from urban and forested sites are adapted to their respective thermal environments, we incubated eggs from each site using temperatures that simulate likely nest conditions in both urban and forested environments. For both species, urban thermal environments accelerated embryonic development, but had no impact on egg survival or any of the phenotypic traits that were measured (e.g., body size, running performance, and locomotor behavior). Our results provide no evidence that embryos from urban and forested sites are adapted to their respective thermal environments. Instead, the lack of any major effects suggest that embryos of both species are physiologically robust with respect to novel environments, which could have facilitated their success in establishing in non native ranges and in human-modified landscapes. PMID- 28343565 TI - Thermal tolerance and preferred temperature range of juvenile meagre acclimated to four temperatures. AB - The present study reports the temperature tolerance, estimated using dynamic and static methodologies, and preferred temperature range, based on oxygen consumption rate (OCR), of juvenile meagre (Argyrosomus regius) (Asso, 1801) (3.4+/-0.9g) after 30 days of acclimation at 18, 22, 26 and 30 degrees C. Meagre has dynamic and static thermal tolerance zones of 551 degrees C2 and 460 degrees C2, respectively and is a low resistance fish species, with a resistance zone area of 87 degrees C2. The OCR of juvenile meagre at the above acclimation temperatures was 370, 410, 618 and 642mgh-1kg-1, respectively, and is significantly different (P<0.0001, n=20). The fact that OCR increases by rising temperatures and gradually decreases after 26 degrees C indicates that the preferred temperature range of juvenile meagre is between 26 and 30 degrees C. Our study suggests that meagre is unable to respond to low and high temperature variation in aquaculture facilities or its natural habitats. PMID- 28343566 TI - Living in sympatry: The effect of habitat partitioning on the thermoregulation of three Mediterranean lizards. AB - The ability for effective, accurate and precise thermoregulation is of paramount importance for ectotherms. Sympatric lizards often partition their niche and select different microhabitats. These microhabitats, however, usually differ in their thermal conditions and lizards have to adapt their thermoregulation behavior accordingly. Here, we evaluated the impact of habitat partitioning on the thermal biology of three syntopic, congeneric lacertids (Podarcis peloponnesiacus, P. tauricus and P. muralis) from central Peloponnese, Greece. We assessed thermoregulation effectiveness (E) using the three standard thermal parameters: body (Tb), operative (Te) and preferred (Tpref) temperatures. We hypothesized that the microhabitats used by each species would differ in thermal quality. We also predicted that all species would effectively thermoregulate, as they inhabit a thermally challenging mountain habitat. As expected, the partition of the habitat had an effect on the thermoregulation of lizards since microhabitats had different thermal qualities. All three species were effective and accurate thermoregulators but one of them achieved smaller E values as a result of the lower Tb in the field. This discrepancy could be attributed to the cooler (but more benign) thermal microhabitats that this species occupies. PMID- 28343567 TI - Validation of a new whole-body cryotherapy chamber based on forced convection. AB - Whole-body cryotherapy (WBC) and partial-body cryotherapy (PBC) are two methods of cold exposure (from -110 to -195 degrees C according to the manufacturers). However, temperature measurement in the cold chamber during a PBC exposure revealed temperatures ranging from -25 to -50 degrees C next to the skin of the subjects (using isolating layer placed between the sensor and the skin). This discrepancy is due to the human body heat transfer. Moreover, on the surface of the body, an air layer called the boundary layer is created during the exposure and limits heat transfer from the body to the cabin air. Incorporating forced convection in a chamber with a participant inside could reduce this boundary layer. The aim of this study was to explore the use of a new WBC technology based on forced convection (frontal unilateral wind) through the measurement of skin temperature. Fifteen individuals performed a 3-min WBC exposure at -40 degrees C with an average wind speed of 2.3ms-1. The subjects wore a headband, a surgical mask, underwear, gloves and slippers. The skin temperature of the participants was measured with a thermal camera just before exposure, just after exposure and at 1, 3, 5, 10, 15 and 20min after exposure. Mean skin temperature significantly dropped by 11 degrees C just after exposure (p<0.001) and then significantly increased during the 20-min post exposure period (p<0.001). No critically low skin temperature was observed at the end of the cold exposure. This decrease was greater than the mean decreases in all the cryosauna devices with reported exposures between -140 degrees C and -160 degrees C and those in two other WBC devices with reported exposures between -60 degrees C and -110 degrees C. The use of this new technology provides the ability to reach decreases in skin temperature similar to other technologies. The new chamber is suitable and relevant for use as a WBC device. PMID- 28343568 TI - Thermogenic and psychogenic recruitment of human eccrine sweat glands: Variations between glabrous and non-glabrous skin surfaces. AB - Human eccrine sweat-gland recruitment and secretion rates were investigated from the glabrous (volar) and non-glabrous hand surfaces during psychogenic (mental arithmetic) and thermogenic stimuli (mild hyperthermia). It was hypothesised that these treatments would activate glands from both skin surfaces, with the non thermal stimulus increasing secretion rates primarily by recruiting more sweat glands. Ten healthy men participated in two seated, resting trials in temperate conditions (25-26 degrees C). Trials commenced under normothermic conditions during which the first psychogenic stress was applied. That was followed by passive heating (0.5 degrees C mean body temperature elevation) and thermal clamping, with a second cognitive challenge then applied. Sudomotor activity was evaluated from both hands, with colourimetry used to identify activated sweat glands, skin conductance to determine the onset of precursor sweating and ventilated sweat capsules to measure rates of discharged sweating. From glandular activation and sweat rate data, sweat-gland outputs were derived. These psychogenic and thermogenic stimuli activated sweat glands from both the glabrous and non-glabrous skin surfaces, with the former dominating at the glabrous skin and the latter at the non-glabrous surface. Indeed, those stimuli individually accounted for ~90% of the site-specific maximal number of activated sweat glands observed when both stimuli were simultaneously applied. During the normothermic psychological stimulation, sweating from the glabrous surface was elevated via a 185% increase in the number of activated glands within the first 60s. The hypothetical mechanism for this response may involve the serial activation of additional eccrine sweat glands during the progressive evolution of psychogenic sweating. PMID- 28343569 TI - A 3D thermal model to analyze the temperature changes of digits during cold stress and predict the danger of frostbite in human fingers. AB - The existing computational models of frostbite injury are limited to one and two dimensional schemes. In this study, a coupled thermo-fluid model is applied to simulate a finger exposed to cold weather. The spatial variability of finger-tip temperature is compared to experimental ones to validate the model. A semi realistic 3D model for tissue and blood vessels is used to analyze the transient heat transfer through the finger. The effect of heat conduction, metabolic heat generation, heat transport by blood perfusion, heat exchange between tissues and large vessels are considered in energy balance equations. The current model was then tested in different temperatures and air speeds to predict the danger of frostbite in humans for different gloves. Two prevalent gloves which are commonly used in cold climate are considered for investigation. The endurance time and the fraction of necrotic tissues are two main factors suggested for obtaining the response of digit tissues to different environmental conditions. PMID- 28343570 TI - Supplemental intermittent-day heat training and the lactate threshold. AB - Heat acclimation over consecutive days has been shown to improve aerobic-based performance. Recently, it has been suggested that heat training can improve performance in a temperate environment. However, due to the multifactorial training demands of athletes, consecutive-day heat training may not be suitable. The current study aimed to investigate the effect of brief (8*30min) intermittent (every 3-4 days) supplemental heat training on the second lactate threshold point (LT2) in temperate and hot conditions. 21 participants undertook eight intermittent-day mixed-intensity treadmill exercise training sessions in hot (30 degrees C; 50% relative humidity [RH]) or temperate (18 degrees C; 30% RH) conditions. A pre- and post-incremental exercise test occurred in temperate (18 degrees C; 30% RH) and hot conditions (30 degrees C; 50% RH) to determine the change in LT2. The heat training protocol did not improve LT2 in temperate (Effect Size [ES]+/-90 confidence interval=0.10+/-0.16) or hot (ES=0.26+/-0.26) conditions. The primary finding was that although the intervention group had a change greater than the SWC, no statistically significant improvements were observed following an intermittent eight day supplemental heat training protocol comparable to a control group training only in temperate conditions. This is likely due to the brief length of each heat training session and/or the long duration between each heat exposure. PMID- 28343571 TI - A method to transform a variable thermal regime to a physiologically equivalent effective temperature. AB - We present a method to characterize variable thermal regimes in terms of an equivalent or effective temperature. Our method is based on a first order exponential transformation of a time series of temperatures to yield an exponentially-weighted mean temperature characteristic of the regime and independent of any particular species or end point. The resulting effective temperature or exponential mean, Te-, offers an improved method for summarizing mean temperature where biological response scales exponentially to temperature. The exponential mean allows growth under varying thermal regimes to be predicted using constant temperature models and offers a compact descriptor communicating the growth capacity of variable thermal regimes. The method combines mathematical simplicity with translatability to different Q10 values without recourse to the underlining time series data. It also provides a quantitative baseline that improves on mean temperature by incorporating the effect of Jensen's inequality and it remains applicable at near zero temperatures where thermal sums lack accuracy. PMID- 28343572 TI - Effect of the timing of ice slurry ingestion for precooling on endurance exercise capacity in a warm environment. AB - It has been demonstrated that precooling with ice slurry ingestion enhances endurance exercise capacity in the heat. However, no studies have yet evaluated the optimal timing of ice slurry ingestion for precooling. This study aimed to investigate the effects of varying the timing of ice slurry ingestion for precooling on endurance exercise capacity in a warm environment. Ten active male participants completed 3 experimental cycling trials to exhaustion at 55% peak power output (PPO) after 15min of warm-up at 30% PPO at 30 degrees C and 80% relative humidity. Three experimental conditions were set: no ice slurry ingestion (CON), pre-warm-up ice slurry ingestion (-1 degrees C; 7.5gkg-1) (PRE), and post-warm-up ice slurry ingestion (POST). Rectal and mean skin temperatures at the beginning of exercise in the POST condition (37.1+/-0.2 degrees C, 33.8+/ 0.9 degrees C, respectively) were lower than those in the CON (37.5+/-0.3 degrees C; P<0.001, 34.8+/-0.8 degrees C; P<0.01, respectively) and PRE (37.4+/-0.2 degrees C; P<0.01, 34.6+/-0.7 degrees C; P<0.01, respectively) conditions. These reductions increased heat storage capacity and resulted in improved exercise capacity in the POST condition (60.2+/-8.7min) compared to that in the CON (52.0+/-11.9min; effect size [ES]=0.78) and PRE (56.9+/-10.4min; ES=0.34) conditions. Ice slurry ingestion after warm-up effectively reduced both rectal and skin temperatures and increased cycling time to exhaustion in a warm environment. Timing ice slurry ingestion to occur after warm-up may be effective for precooling in a warm environment. PMID- 28343573 TI - Metabolic and cellular stress responses of catfish, Horabagrus brachysoma (Gunther) acclimated to increasing temperatures. AB - We investigated the metabolic and cellular stress responses in an endemic catfish Horabagrus brachysoma acclimated to ambient (26 degrees C), 31, 33 and 36 degrees C for 30 days. After acclimation, fish were sampled to investigate changes in the levels of blood glucose, tissue glycogen and ascorbic acid, activities of enzymes involved in glycolysis (LDH), citric acid cycle (MDH), gluconeogenesis (FBPase and G6Pase), pentose phosphate pathway (G6PDH), protein metabolism (AST and ALT), phosphate metabolism (ACP and ALP) and energy metabolism (ATPase), and HSP70 levels in various tissues. Acclimation to higher temperatures (33 and 36 degrees C) significantly increased activities of LDH, MDH, ALP, ACP, AST, ALT and ATPase and blood glucose levels, whereas decreased the G6PDH enzyme activity and, tissue glycogen and ascorbic acid. Results indicated an overall increase in the carbohydrate, protein and lipid metabolism implying increased metabolic demands for maintaining homeostasis in fish acclimated to higher temperatures (33 and 36 degrees C). We observed tissue specific response of HSP70 in H. brachysoma, with significant increase in gill and liver at 33 and 36 degrees C, and in brain and muscle at 36 degrees C, enabling cellular protection at higher acclimation temperatures. In conclusion, H. brachysoma adjusted metabolic and cellular responses to withstand increased temperatures, however, these responses suggest that the fish was under stress at 33 degrees C or higher temperature. PMID- 28343574 TI - Individualising the exposure of -110 degrees C whole body cryotherapy: The effects of sex and body composition. AB - The purpose of this study was to investigate the effects of whole body cryotherapy (WBC) on a range of thermoregulatory measures. We also sought to examine the influence of sex and body composition. A convenience sample of 18 healthy participants (10 males and 8 females) (27+/-6yr) volunteered for this study. Temperature (core, tympanic, skin and mean body), heart rate, blood pressure, and thermal comfort and sensation were recorded pre- and post- (immediately and every 5min until 35min post) exposure to a single bout of WBC (30s at -60 degrees C, 150s at 110 degrees C). Anthropometric data (height, weight, body surface area, body mass index, fat mass and fat free mass) were also recorded. No significant differences in temperature (core, tympanic, skin and mean body), heart rate, blood pressure, or thermal comfort / sensation were observed between male and females at baseline. Immediately post WBC mean body (male:31.9+/-0.8 degrees C; female:31.0+/-0.9 degrees C; ? mean body temperature:0.9+/-0.1 degrees C; P<=0.05, d=0.64) and mean skin (male:22.1+/-2.2 degrees C; female:19.6+/-2.8 degrees C; ? mean skin temperature:-2.5+/-0.6 degrees C; d=0.99, P<=0.05) temperature was significantly different between sexes. Sex differences were also observed in regional skin temperature (male thigh, 20.8+/-1.1 degrees C; female thigh, 16.7+/-1.1 degrees C, ? mean thigh skin temperature:-4.1 degrees C; d=3.72; male calf, 20.5+/-1.1 degrees C; female calf, 18.2+/-1 degrees C, ? mean calf skin temperature:-2.3+/-0.1 degrees C; d=3.61; male arm, 21.7+/-1 degrees C; female arm, 19+/-0.4 degrees C, ? mean arm skin temperature: -2.7+/-0.3 degrees C; d=3.54; P<=0.05). Mean arterial pressure was significantly different over time (P<=0.001) and between sexes (male 0mins:94+/-10mmHg; female 0mins:85+/-7mmHg; male 35mins:88+/-7mmHg; female 35mins:80+/-6mmHg; P<=0.05). Combined data set indicated a strong negative relationship between skin temperature and body fat percentage 35min' post WBC (r= 0.749, P<=0.001) and for core temperature and body mass index in males only (r=0.726, P<=0.05) immediately after WBC. There were no significant differences between sexes in any other variables (heart rate, tympanic and perceptual variables). We observed sex differences in mean skin and mean body temperature following exposure to whole body cryotherapy. In an attempt to optimise treatment, these differences should be taken into account if whole body cryotherapy is prescribed. PMID- 28343575 TI - Expression analysis of Toll like receptors and interleukins in Tharparkar cattle during acclimation to heat stress exposure. AB - Six male Tharparkar cattle of 2-3 years old were selected for the study. After 15 days acclimation at thermo neutral zone (TNZ) in psychrometric chamber, animals were exposed at 42 degrees C for 6h up to 23 days followed by 12 days of recovery period. Blood samples were collected during control period at TNZ (day 1, 5 and 12), after heat stress exposure (day 1-10, Short Term Heat Stress Acclimation - STHSA; day 15-23, Long Term Heat Stress Acclimation - LTHSA) and recovery period (day 7 and 12) and peripheral blood mononuclear cells (PBMCs) were isolated for RNA and protein extraction. Serum cortisol concentration was assessed by RIA. The mRNA and protein expression in PBMCs were determined by qPCR and western blot respectively. Samples at TNZ were taken as control. Serum cortisol concentration was increased (P<0.05) during STHSA and gradually declined during LTHSA. Toll like receptor 2 (TLR 2) expression was up regulated (P<0.05) during STHSA and declined to basal level during LTHSA and recovery phase. However, toll like receptor 4 (TLR 4) expression was up regulated (P<0.05) during STHSA and LTHSA while declined in recovery phase. Interleukin 2 (IL2) and interleukin 6 (IL 6) were up regulated (P<0.05) during STHSA and reduced to basal level during LTHSA. PBMCs culture study was conducted to study transcriptional abundance of TLR2/4 and IL2/6 at different temperature-time combinations. The present findings indicate that TLR 2/4 and IL 2/6 could possibly play a vital role in thermo tolerance in Tharparkar cattle during short term and long term heat stress exposure. PMID- 28343576 TI - The metabolic response in fish to mildly elevated water temperature relates to species-dependent muscular concentrations of imidazole compounds and free amino acids. AB - Fish species show distinct differences in their muscular concentrations of imidazoles and free amino acids (FAA). This study was conducted to investigate whether metabolic response to mildly elevated water temperature (MEWT) relates to species-dependent muscular concentrations of imidazoles and FAA. Thirteen carp and 17 Nile tilapia, housed one per aquarium, were randomly assigned to either acclimation (25 degrees C) or MEWT (30 degrees C) for 14 days. Main muscular concentrations were histidine (HIS; P<0.001) in carp versus N-alpha acetylhistidine (NAH; P<0.001) and taurine (TAU; P=0.001) in tilapia. Although the sum of imidazole (HIS+NAH) and TAU in muscle remained constant over species and temperatures (P>0.05), (NAH+HIS)/TAU ratio was markedly higher in carp versus tilapia, and decreased with MEWT only in carp (P<0.05). Many of the muscular FAA concentrations were higher in carp than in tilapia (P<0.05). Plasma acylcarnitine profile suggested a higher use of AA and fatty acids in carp metabolism (P<0.05). On the contrary, the concentration of 3-hydroxyisovalerylcarnitine, a sink of leucine catabolism, (P=0.009) pointed to avoidance of leucine use in tilapia metabolism. Despite a further increase of plasma longer-chain acylcarnitines in tilapia at MEWT (P=0.009), their corresponding beta-oxidation products (3-hydroxy longer-chain acylcarnitines) remained constant. Together with higher plasma non esterified fatty acids (NEFA) in carp (P=0.001), the latter shows that carp, being a fatter fish, more readily mobilises fat than tilapia at MEWT, which coincides with more intensive muscular mobilization of imidazoles. This study demonstrates that fish species differ in their metabolic response to MEWT, which is associated with species-dependent changes in muscle imidazole to taurine ratio. PMID- 28343577 TI - Effects of pregnancy on body temperature and locomotor performance of velvet geckos. AB - Pregnancy is a challenging period for egg laying squamates. Carrying eggs can encumber females and decrease their locomotor performance, potentially increasing their risk of predation. Pregnant females can potentially reduce this handicap by selecting higher temperatures to increase their sprint speed and ability to escape from predators, or to speed up embryonic development and reduce the period during which they are burdened with eggs ('selfish mother' hypothesis). Alternatively, females might select more stable body temperatures during pregnancy to enhance offspring fitness ('maternal manipulation hypothesis'), even if the maintenance of such temperatures compromises a female's locomotor performance. We investigated whether pregnancy affects the preferred body temperatures and locomotor performance of female velvet geckos Amalosia lesueurii. We measured running speed of females during late pregnancy, and one week after they laid eggs at four temperatures (20 degrees , 25 degrees , 30 degrees and 35 degrees C). Preferred body temperatures of females were measured in a cost-free thermal gradient during late pregnancy and one week after egg laying. Females selected higher and more stable set-point temperatures when they were pregnant (mean =29.0 degrees C, Tset =27.8-30.5 degrees C) than when they were non-pregnant (mean =26.2 degrees C, Tset =23.7-28.7 degrees C). Pregnancy was also associated with impaired performance; females sprinted more slowly at all four test temperatures when burdened with eggs. Although females selected higher body temperatures during late pregnancy, this increase in temperature did not compensate for their impaired running performance. Hence, our results suggest that females select higher temperatures during pregnancy to speed up embryogenesis and reduce the period during which they have reduced performance. This strategy may decrease a female's probability of encountering predatory snakes that use the same microhabitats for thermoregulation. Selection of stable temperatures by pregnant females may also benefit embryos, but manipulative experiments are necessary to test this hypothesis. PMID- 28343578 TI - Untranslated regions (UTRs) orchestrate translation reprogramming in cellular stress responses. AB - Stress is the result of an organism's interaction with environmental challenges. Regulations of gene expression including translation modulations are critical for adaptation and survival under stress. Untranslated regions (UTRs) of the transcripts play significant roles in translation regulation and continue to raise many intriguing questions in our understanding of cellular stress physiology. IRES (Internal ribosome entry site) and uORF (upstream open reading frame) mediated alternative translation initiations are emerging as unique mechanisms. Recent studies have revealed novel means of mRNAs stabilization in stress granules and their reversible modifications. Differential regulation of select transcripts is possible by the interplay between the adenine/uridine-rich elements (AREs) in 3'UTR with their binding proteins (AUBP) and by microRNA mediated effects. Coordination of these various mechanisms control translation and thereby enables appropriate responses to environmental stress. In this review, we focus on the role of sequence signatures both at 5' and 3'UTRs in translation reprogramming during cellular stress responses. PMID- 28343579 TI - Combined effects of temperature and interspecific competition on the mortality of the invasive garden ant, Lasius neglectus: A laboratory study. AB - The invasive garden ant, Lasius neglectus, is a dominant species due to its capacity to form large supercolonies. This species was assumed to possess a wide thermal niche since it is able to adapt to cold climates, which is a factor that boosted its rapid expansion from south to many central-northern European Countries. However, the effect of variations in environmental temperatures on its competitive ability against other species has still not been investigated. In this paper, we analyzed the change in survival ability of Lasius neglectus during encounters with two Mediterranean dominant ants (Crematogaster scutellaris and Tapinoma nigerrimum) at four different temperatures (15, 20, 25 and 30 degrees C). Firstly, control tests were performed to provide the baseline survival ability of the three species at different temperatures. Secondly, competition tests were carried out at the same temperatures. Lasius neglectus survival was negatively affected by high temperature (30 degrees C) in control tests, and this impairment was much more pronounced in competition tests. On the contrary, the two opponent species were only marginally affected by temperatures in control tests. Crematogaster scutellaris was a better competitor than L. neglectus, particularly at high temperatures. Tapinoma nigerrimum was a weaker competitor and was always outcompeted by L. neglectus, particularly at low temperatures. This result could suggest that L. neglectus is at a disadvantage during interspecific encounters when temperatures are high and that the predicted future increase in environmental temperatures may potentially enhance this handicap. PMID- 28343580 TI - Behavioral thermal tolerances of free-ranging rattlesnakes (Crotalus oreganus) during the summer foraging season. AB - Increasing temperature due to climate change is one of the greatest challenges for wildlife worldwide. Behavioral data on free-ranging individuals is necessary to determine at what temperatures animals modify activity as this would determine their capacity to continue to move, forage, and mate under altered thermal regimes. In particular, high temperatures could limit available surface activity time and time spent on fitness-related activities. Conversely, performance, such as feeding rate, can increase with temperature potentially having positive fitness effects. Here, we examine how the hunting behaviors of free-ranging Northern Pacific Rattlesnakes (Crotalus oreganus) associate with air temperature and body temperature. We continuously recorded snakes in the field using videography, capturing behaviors rarely considered in past studies such as movements in and out of refuge and strikes on prey. We found that as mean daily air temperature increased, hunting activity and the likelihood of hunting at night decreased, while the number of movements and distance moved per day increased. Snakes typically retreated to refuge before body temperatures reached 31 degrees C. Body temperatures of snakes hunting on the surface were lower compared to temperatures of non-hunting snakes in refuge in the morning, while this relationship was inverted in the afternoon. Snake body size influenced the disparity of these temperatures. Finally, strike initiation and success occurred across a wide range of body temperatures, indicating hunting performance may not be strongly constrained by temperature. These results on the temperatures at which free-ranging rattlesnakes exhibit fitness-related behaviors could be valuable for understanding their vulnerabilities to future climates. PMID- 28343581 TI - Proteomic analysis of physiological function response to hot summer in liver from lactating dairy cows. AB - Lactation performance of dairy cattle is susceptible to heat stress. The liver is one of the most crucial organs affected by high temperature in dairy cows. However, the physiological adaption by the liver to hot summer conditions has not been well elucidated in lactating dairy cows. In the present study, proteomic analysis of the liver in dairy cows in spring and hot summer was performed using a label-free method. In total, 127 differentially expressed proteins were identified; most of the upregulated proteins were involved in protein metabolic processes and responses to stimuli, whereas most of the downregulated proteins were related to oxidation-reduction. Pathway analysis indicated that 3 upregulated heat stress proteins (HSP90alpha, HSP90beta, and endoplasmin) were enriched in the NOD-like receptor signaling pathway, whereas several downregulated NADH dehydrogenase proteins were involved in the oxidative phosphorylation pathway. The protein-protein interaction network indicated that several upregulated HSPs (HSP90alpha, HSP90beta, and GRP78) were involved in more interactions than other proteins and were thus considered as central hub nodes. Our findings provide novel insights into the physiological adaption of liver function in lactating dairy cows to natural high temperature. PMID- 28343582 TI - The effect of local skin cooling before a sustained, submaximal isometric contraction on fatigue and isometric quadriceps femoris performance: A randomized controlled trial. AB - The central- and peripheral mechanisms by which heat strain limits physical performance are not fully elucidated. Nevertheless, pre-cooling is often used in an attempt to improve subsequent performance. This study compared the effects of pre-cooling vs. a pre-thermoneutral application on central- and peripheral fatigue during 60% of isometric maximum voluntary contraction (MVC) of the right quadriceps femoris muscle. Furthermore, the effects between a pre-cooling and a pre-thermoneutral application on isometric MVC of the right quadriceps femoris muscle and subjective ratings of perceived exertion (RPE) were investigated. In this randomized controlled trial, 18 healthy adults voluntarily participated. The participants received either a cold (experimental) application (+8 degrees C) or a thermoneutral (control) application (+32 degrees C) for 20min on their right thigh (one cuff). After the application, central (fractal dimension - FD) and peripheral (muscle fiber conduction velocity - CV) fatigue was estimated using sEMG parameters during 60% of isometric MVC. Surface EMG signals were detected from the vastus medialis and lateralis using bidimensional arrays. Immediately after the submaximal contraction, isometric MVC and RPE were assessed. Participants receiving the cold application were able to maintain a 60% isometric MVC significantly longer when compared to the thermoneutral group (mean time: 78 vs. 46s; p=0.04). The thermoneutral application had no significant impact on central fatigue (p>0.05) compared to the cold application (p=0.03). However, signs of peripheral fatigue were significantly higher in the cold group compared to the thermoneutral group (p=0.008). Pre-cooling had no effect on isometric MVC of the right quadriceps muscle and ratings of perceived exertion. Pre-cooling attenuated central fatigue and led to significantly longer submaximal contraction times compared to the pre-thermoneutral application. These findings support the use of pre-cooling procedures prior to submaximal exercises of the quadriceps muscle compared to pre-thermoneutral applications. PMID- 28343583 TI - Indirect hand and forearm vasomotion: Regional variations in cutaneous thermosensitivity during normothermia and mild hyperthermia. AB - In this experiment, hand and forearm vasomotor activity was investigated during localised, but stable heating and cooling of the face, hand and thigh, under open loop (clamped) conditions. It was hypothesised that facial stimulation would provoke the most potent vascular changes. Nine individuals participated in two normothermic trials (mean body temperature clamp: 36.6 degrees C; water-perfused suit and climate chamber) and two mildly hyperthermic trials (37.9 degrees C). Localised heating (+5 degrees C) and cooling (-5 degrees C) stimuli were applied to equal surface areas of the face, hand and thigh (perfusion patches: 15min), while contralateral forearm or hand blood flows (venous-occlusion plethysmography) were measured (separate trials). Thermal sensation and discomfort votes were recorded before and during each thermal stimulation. When hyperthermic, local heating induced more sensitive vascular responses, with the combined thermosensitivity of both limb segments averaging 0.011mL.100mL-1.min 1.mmHg-1. degrees C-1, and 0.005mL.100mL-1.min-1.mmHg-1. degrees C-1 during localised cooling (P<0.05). Inter-site comparisons among the stimulated sites yielded minimal evidence of variations in local thermal sensation, and no differences were observed for vascular conductance (P>0.05). Therefore, regional differences in vasomotor and sensory sensitivity appeared not to exist. When combined with previous observations of sudomotor sensitivity, it seems that, during mild heating and cooling, regional representations within the somatosensory cortex may not translate into meaningful differences in thermal sensation or the central integration of thermoafferent signals. It was concluded that inter-site variations in the cutaneous thermosensitivity of these thermolytic effectors have minimal physiological significance over the ranges investigated thus far. PMID- 28343584 TI - Percutaneous Cryoablation of the Horseshoe Kidney: An Initial Experience. AB - Between June 2006 and January 2016, 6 renal cryoablation procedures were performed in 5 patients with horseshoe kidneys. Renal cell carcinoma (RCC) accounted for 5 of the tumors, and the sixth was a carcinoid tumor. All 6 procedures were technically successful. The patient with the carcinoid tumor developed local tumor progression 38 months after ablation. Technique effectiveness was achieved in all 5 patients with RCC. Two complications occurred: obstructive hematuria and transient inguinal neuralgia after ablation. In this small initial experience, percutaneous cryoablation appears feasible in treatment of primary tumors in horseshoe kidneys. PMID- 28343585 TI - Embolization of Three Bronchial Artery Aneurysms. PMID- 28343586 TI - Addressing Confounders in Retrospective Studies. PMID- 28343587 TI - Hybrid Snorkel Endovascular Repair of a Ruptured Abdominal Aortic Aneurysm Related to a Type IA Endoleak Utilizing an Axillary Conduit. PMID- 28343588 TI - Preoperative Biliary Drainage in Patients with Resectable Perihilar Cholangiocarcinoma: Is Percutaneous Transhepatic Biliary Drainage Safer and More Effective than Endoscopic Biliary Drainage? A Meta-Analysis. AB - PURPOSE: To determine the best initial procedure for performing preoperative biliary drainage in patients with resectable perihilar cholangiocarcinoma (PHCC). MATERIALS AND METHODS: MEDLINE/PubMed and the Cochrane database were searched for all studies published until June 2016 comparing endoscopic biliary drainage (EBD) and percutaneous transhepatic biliary drainage (PTBD) for preoperative biliary drainage. Meta-analysis was performed by using Review Manager 5.3 software. RESULTS: Four retrospective studies were identified that met the criteria. The analysis was performed on 433 patients who underwent preoperative biliary drainage for resectable PHCC. Of those, 275 (63.5%) had EBD and 158 (36.5%) had PTBD as the initial procedure. The overall procedure-related morbidity rate was significantly lower in the PTBD group than in the EBD group (39 of 147 [26.5%] vs 82 of 185 [44.3%]; odds ratio [OR], 2.23; 95% confidence interval [CI], 1.39 3.57; P = .0009). The rate of conversion from one procedure to the other was significantly lower in the PTBD group than in the EBD group (8 of 158 [5.0%] vs 73 of 275 [26.5%]; odds ratio, 4.76; 95% CI, 2.71-8.36; P < .00001). Pancreatitis occurred only in the EBD group (25 of 275 [9.0%] vs 0 of 158; OR, 7.46; 95% CI, 3.02-18.44; P < .0001). The cholangitis rate was significantly lower in the PTBD group than in the EBD group (12 of 158 [7.6%] vs 93 of 275 [33.8%]; OR, 5.41; 95% CI, 2.75-10.63; P < .00001). CONCLUSIONS: This meta-analysis shows that PTBD has a lower rate of complications than EBD as the initial procedure to perform preoperative biliary drainage in resectable PHCC. PTBD is associated with less conversion and lower rates of pancreatitis and cholangitis. PMID- 28343589 TI - CT-Guided Cryoablation of a Substernal Mediastinal Ectopic Parathyroid Adenoma. PMID- 28343590 TI - Balloon-Occluded Retrograde Abdominal Lymphangiography and Embolization for Opacification and Treatment of Abdominal Chylous Leakage. PMID- 28343591 TI - Iatrogenic Common Iliac Artery Rupture from Resuscitative Endovascular Balloon Occlusion of the Aorta. PMID- 28343592 TI - Percutaneous Pulmonary Embolectomy Using the FlowTriever Retrieval/Aspiration System. PMID- 28343593 TI - Venous Neovascularization in a Recipient of a Pediatric Kidney Transplant. PMID- 28343594 TI - Do Radiopaque Polyvinyl Alcohol Beads Cause Artifact on Postcontrast MR Imaging? PMID- 28343595 TI - Re: Hashimoto M, Ohuchi Y, Ogawa T, Iwamoto A, Noguchi N. Percutaneous Transhepatic Holmium:YAG Laser Choledochojejunostomy for the Recanalization of Obstructed Surgical Anastomosis. (J Vasc Interv Radiol 2017; 28:310-312). PMID- 28343596 TI - No additional benefit of using a calcium hydroxide liner during stepwise caries removal: A randomized clinical trial. AB - BACKGROUND: Clinicians often use calcium hydroxide liners during stepwise treatment of advanced caries. In this randomized clinical trial, the authors compared the short-term outcome of stepwise caries removal with and without use of a calcium hydroxide liner in conjunction with provisional resin-modified glass ionomer (RMGI) restorations. METHODS: The authors included in the trial 98 patients aged 15 to 30 years who had a deep carious lesion in a posterior tooth. The authors measured the dentin thickness radiographically and recorded its color, consistency, and moisture, as well as the bacterial count of the lesions. After partial caries removal, the authors assigned patients randomly to have their caries provisionally restored using RMGI with (control group) or without (test group) a calcium hydroxide liner. The primary outcome measure was tooth vitality after 90 days. Secondary outcomes included changes in dentinal, radiographic, and microbiological characteristics of the lesions. RESULTS: The authors found no statistically significant difference between the test and control groups in tooth vitality after 90 days. Irrespective of calcium hydroxide liner use, the authors observed darker, harder, drier, and less contaminated dentin after the provisional restorations, but dentin thickness remained unchanged. CONCLUSIONS: On the basis of this 3-month clinical trial's results, the use of a calcium hydroxide liner during stepwise caries excavation and provisional restoration did not provide any additional benefit. PRACTICAL IMPLICATIONS: After 3 months, using a calcium hydroxide liner does not appear to offer any additional benefit when clinicians use RMGI provisional restorations during stepwise caries removal. Longer studies are needed to confirm these results. PMID- 28343597 TI - National Trends and In-Hospital Outcomes in Pregnant Women With Heart Disease in the United States. AB - Investigation of trends and outcomes in heart disease (HD) and pregnancy has been limited. We chose to identify the prevalence, trends, and outcomes of pregnant women with different forms of HD in the United States. Healthcare Cost and Utilization Project's National Inpatient Sample was screened for hospital admissions for delivery in pregnant women with HD from 2003 to 2012. Maternal clinical characteristics and outcomes were identified in women with and without HD, and in HD subtypes: congenital (CHD), valvular HD, cardiomyopathy, and pulmonary hypertension (PH). Primary outcomes of interest were prevalence, trends, and major adverse cardiac events (MACEs), a composite of in-hospital death, acute myocardial infarction, heart failure, arrhythmia, cerebrovascular event, embolic events, or cardiac complications of anesthesia. We studied 81,295 patients with HD and 39,894,032 without. CHD was the most frequent type (41.8%, 33,982 of 81,295 patients), followed by valvular HD (30.9%, 25,138 of 81,295 patients), cardiomyopathy (20.8%, 16,926 of 81,295 patients), and PH (6.5%, 5,250 of 81,295 patients). MACE was highest among women with cardiomyopathy and lowest among women with CHD (44.0%, 7,449 of 16,926 vs 6.2%, 2,102 of 33,982; p <0.0001). PH patients had the highest in-hospital death, followed by cardiomyopathy patients (1.0%, 51 of 5,250 and 0.7%, 124 of 16,926, respectively). Pregnant women with HD significantly increased by 24.7%, related to increases in cardiomyopathy, CHD, and PH from 2003 to 2012. MACE significantly increased by 18.8%. In conclusion, pregnancy in women with HD is increasing, particularly for high risk conditions such as cardiomyopathy and PH. There is a significant and gradual increase in MACE for women with HD. PMID- 28343598 TI - Incremental Prognostic Value of Global Longitudinal Strain and 18F Fludeoxyglucose Positron Emission Tomography in Patients With Systemic Sarcoidosis. AB - In independent studies, abnormal global longitudinal strain (GLS) and myocardial inflammation or scar detected by 18F-fludeoxyglucose positron emission tomography (FDG-PET) are associated with poor prognosis among patients with high likelihood for cardiac sarcoidosis. However, commonly used imaging modalities have not been evaluated in the same population. Our goals were to examine the relation between GLS and FDG-PET, and to evaluate the incremental prognostic value of these imaging techniques for predicting major adverse cardiac events (MACE) in patients suspected to have cardiac sarcoidosis. We identified patients with systemic sarcoidosis who underwent an echocardiogram and FDG-PET within 60 days. Regional strain (average of base, mid, and apical segmental strains from each of 6 wall regions) was calculated and compared with regional FDG-PET findings. The associations among GLS, FDG-PET findings, and MACE (defined as death, ventricular tachycardia, heart failure hospitalization, or transplantation) were evaluated using a Cox model. Of 84 patients, 51 had abnormal FDG-PET. GLS was impaired in patients with abnormal versus normal FDG-PET (-14.2 +/- 4.7% vs -17.9 +/- 3.5%, p <0.01). After adjusting for clinical risk factors, both GLS and the number of segments with abnormal perfusion and metabolism on FDG-PET were associated with adverse cardiac events (p <0.01 for both). In conclusion, GLS and regional LS are impaired in patients with abnormal perfusion and metabolism detected using FDG PET. Additionally, both GLS and abnormal FDG-PET have incremental prognostic value for predicting MACE in patients with systemic sarcoidosis. PMID- 28343599 TI - Presence, Characteristics, and Volumes of Coronary Plaque Determined by Computed Tomography Angiography in Young Type 2 Diabetes Mellitus. AB - Prevention and management of coronary artery disease (CAD) is of great concern in patients with diabetes mellitus. Although the impact of coronary atherosclerosis is described well for subjects older than 40 years, the prevalence and types of coronary atherosclerosis in young patients are not well known. The aim of this study was to evaluate the prevalence, extent, severity, and volumes of coronary plaque in type 2 diabetes mellitus (T2DM) population younger than of 40 years. This prospective study enrolled 181 subjects (25-40 year old) undergoing coronary computed tomography angiography, with 86 T2DM and 95 nondiabetic age/gender matched subjects. Coronary artery calcium (CAC), plaque assessment including total segment stenosis (sum of individual segmental stenosis), total plaque scores (sum of semiquantitative segmental plaque burden), segment involvement scores (number of segments with plaque) were evaluated. In addition, we quantitatively measured plaque volumes in total, fibrous, fibrous fatty, dense calcified, and low-attenuation plaque using novel plaque software. Compared with nondiabetic patients, the prevalence of CAD, calcified, and noncalcified plaques was higher in patients with T2DM (19% vs 58%; p <0.001). In patients with a zero CAC, T2DM had a higher prevalence (46%) of noncalcified plaque (p <0.0001). In multivariate linear regression models after adjusting for traditional cardiovascular risk factors, increased total segmental stenosis, total plaque scores, and segment involvement scores were associated with T2DM. Regarding quantitative plaque assessment, all volumes in noncalcified plaque type were approximately threefold higher in patients with T2DM. In conclusion, young patients with T2DM are susceptible to premature CAD with more calcified and noncalcified plaques. Early prevention program using computed tomography angiography might be helpful in identifying young diabetic patients with subclinical atherosclerosis. PMID- 28343600 TI - Comparison of Late Mortality Among Twins Versus Singletons With Congenital Heart Defects. AB - In 2014, in the United States, nearly 7% of newborns were twins. Congenital heart defects (CHDs) are more frequent in both monozygotic and dizygotic twins than in singletons. Still, the longer-term prognosis for CHD twins is unknown. Here we assess the mortality pattern for CHD twins up to age 36 years and compare it with that for non-CHD twins, non-CHD co-twins, and CHD singletons. We identified all twins and a 5% random sample of all singletons born in Denmark from 1977 to 2009 by linking Danish national population and health registers. CHD cases were defined as subjects having a primary inpatient diagnosis of CHD (excluding preterm ductus) within the first year of life, and mortality was assessed through 2013. Among 63,362 live-born twin individuals, a total of 373 twins (0.59%) had a CHD diagnosis, whereas the corresponding numbers for singletons were 383 of 98,647 (0.39%). During the follow-up, 82 (22.0%) CHD twins died compared with 91 (23.8%) CHD singletons (p = 0.56). Despite a 5 times higher proportion of prematurity, CHD twins had a tendency toward only a moderately increased neonatal mortality compared with CHD singletons (hazard ratio 1.5, 95% confidence interval 0.94 to 2.5), and after the neonatal period up to age 36 the tendency was reversed (hazard ratio 0.8, 95% confidence interval 0.5 to 1.2). A potential underlying mechanism for this mortality pattern is selective intrauterine and neonatal mortality of twins with the most severe CHD. In conclusion, the study indicates that the overall survival prognosis for CHD twins is similar to that of CHD singletons. PMID- 28343601 TI - Effects of RG7652, a Monoclonal Antibody Against PCSK9, on LDL-C, LDL-C Subfractions, and Inflammatory Biomarkers in Patients at High Risk of or With Established Coronary Heart Disease (from the Phase 2 EQUATOR Study). AB - RG7652 (MPSK3169A), a fully human immunoglobulin G1 (IgG1) monoclonal antibody directed against proprotein convertase subtilisin/kexin type 9 (PCSK9), blocks the interaction between PCSK9 and low-density lipoprotein (LDL) receptor. EQUATOR (ClinicalTrials.govNCT01609140), a randomized, double-blind, and dose-ranging phase 2 study, evaluated RG7652 in patients (1) at high risk for or (2) with coronary heart disease (CHD). The primary end point was change in LDL cholesterol (LDL-C) from baseline to day 169. Patients (n = 248; median age, 64 years; 57% men; 52% with established CHD; 82% on statins) with baseline LDL-C levels of 90 to 250 mg/dl (mean, 126 mg/dl) continuing on standard-of-care therapy were randomized to receive 1 of 5 RG7652 doses or placebo, subcutaneously every 4, 8, or 12 weeks for 24 weeks. Significant dose-dependent reductions in LDL-C levels from baseline to nadir (56 to 74 mg/dl [48% to 60%]) were observed in all RG7652 dosed patients; effects persisted to day 169 with the highest doses (reduction vs placebo up to 62 mg/dl [51%]) with no unexpected safety signals. RG7652 reduced apolipoprotein B and lipoprotein(a) levels. LDL-C subfraction analysis by nuclear magnetic resonance spectroscopy revealed a prominent decrease in large LDL-C and some decrease in small LDL particles. There was significant reduction in mean particle size of LDL-C on day 169 but no significant reductions in systemic markers of inflammation (high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-alpha). RG7652 reduced LDL-C levels and was well tolerated in patients at high risk for or with CHD on standard-of-care therapy. In conclusion, RG7562 treatment affected large LDL-C and, to a lesser extent, small LDL-C particles; RG7562 did not affect systemic circulating pro-inflammatory cytokines or high-sensitivity C-reactive protein. PMID- 28343602 TI - Intracellular enzymes of the retinal pigment epithelial cells for controlled drug delivery. PMID- 28343603 TI - Cardioversion for Atrial Fibrillation Improves Quality of Life: It's Obvious (or Isn't It?). PMID- 28343604 TI - Tracking Syncope in Canada Using Administrative Data: What Lessons Can We Learn? Where Do We Need to Be? PMID- 28343605 TI - Treatment for Patients With Chronic Thromboembolic Pulmonary Hypertension: Where Does Balloon Pulmonary Angioplasty Sit in the Treatment Algorithm? PMID- 28343606 TI - Respiratory Muscles and Chemoreflex Sensitivity in Heart Failure: A Breath of Fresh Air. PMID- 28343607 TI - Bioresorbable Vascular Scaffold During ST-Elevation Myocardial Infarction: A Systematic Review. AB - BACKGROUND: The bioresorbable vascular scaffold (BVS) represents a novel technology designed to overcome the long-term limitations of metallic coronary stent implantation in percutaneous coronary intervention. In this context, primary percutaneous coronary intervention in ST-elevation myocardial infarction (STEMI) could be a preferred scenario for BVS implantation. Nevertheless, data on efficacy and safety are lacking in this specific subset of patients. METHODS: We conducted a systematic review to examine the safety and efficacy of BVS use in STEMI patients. We searched PubMed, EMBASE, and the Cochrane Library through June 2016 for studies that included outcome data for BVS implantation in STEMI patients. Outcomes of interest included cardiac death, myocardial infarction, scaffold thrombosis, target lesion revascularization, restenosis, and composite end points. RESULTS: We identified 9 eligible articles, which included 1 randomized controlled trial and 8 cohort studies (5 controlled), for a total of 846 patients. These studies varied in size (11-290) and follow-up duration (1-24 months). The incidence of major cardiac events ranged from 1.1% to 13%, with no statistically significant difference between BVS and control groups in studies that included a comparison group. Although there was a trend toward an increase in scaffold thrombosis in the largest controlled registries, no statistically significant increase was found. CONCLUSIONS: Current clinical data are scarce, but suggest that BVS might represent a reasonable alternative to drug-eluting stents in STEMI patients. The lack of large randomized controlled trials with extended follow-up periods and the scaffold thrombosis signal are limiting factors for widespread use before additional large-scale trials are available. PMID- 28343608 TI - Management of Bilateral Axillary Aneurysms, Threatened Limb, and Diffuse Vasculopathy in a Patient With ACTA2 Mutation. AB - We describe the case of a 36-year-old man with bilateral axillary artery aneurysms and a threatened upper limb. We postulate that his aneurysms and diffuse vasculopathy resulted from a missense mutation identified in his ACTA2 gene known to be highly pathogenic. The risk factors and sequelae of axillary aneurysms are reviewed, with a focus on their surgical management and the effect of ACTA2 mutations on the cardiorespiratory system. PMID- 28343609 TI - Very Late-Onset Dabigatran-Induced Esophageal Injury. AB - An 87-year-old man with persistent atrial fibrillation experienced heartburn and dysphagia at 2 years 9 months after initiation of dabigatran. An esophagogastroduodenoscopy demonstrated multiple longitudinal white plaques with ulcers in the narrowed midesophagus compressed between the left atrium and the tortuous aorta. We speculate that the esophageal stenosis contributed to stasis of dabigatran within the esophagus, resulting in prolonged mucosal contact with the caustic contents of the drug. Progressive enlargement of the left atrium may have led to the late onset of the potentially serious complication. PMID- 28343610 TI - What's New in GOLD 2017? PMID- 28343611 TI - Hospital esophagectomy volume and postoperative length of stay: A systematic review and meta-analysis. AB - BACKGROUND: Much attention in the volume-outcomes literature has focused on the empirical impact of surgical caseload on outcomes. However, relevant studies on the association between surgical volume and variables that potentially contribute to healthcare costs are limited. The objective of this study was to systematically elucidate a contemporary analysis of the empirical relationship between hospital esophagectomy volume and postoperative length of stay, a cost related outcome. DATA SOURCES: OvidSP, PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ISI Web of Science and OpenGrey were searched for relevant articles published from 2000 to 2016. RESULTS: High hospital esophagectomy volume was associated with reduced postoperative length of stay (mean: 3 days; 95%CI: 2.8, 3.2) and risk of prolonged length of stay (RR: 0.80, 95%CI: 0.74, 0.87) in a dose-response fashion. CONCLUSIONS: Complex surgeries performed at high surgical volume centers may be associated with overall decrease in postoperative length of stay, a cost-related outcome. PMID- 28343612 TI - Single-incision laparoscopy versus standard laparoscopy for colorectal surgery: A systematic review and meta-analysis. AB - The aim of this meta-analysis was to evaluate if the advantages of single incision laparoscopic surgery (SILS) to perform a colorectal resection justify a broad application of this approach. A total of 32 studies including 3863 patients, comparing colorectal procedures performed with SILS or multi-port laparoscopy (LCS) were analyzed after a systematic review. Colorectal SILS had comparable outcomes to multi-port LCS in terms of operating time (P = 0.44), conversion rate (2.0% vs 3.0%; P = 0.52), reoperations (1.1% vs 1.7%; P = 0.26), postoperative complications (14.4% vs 13.6%; P = 0.10) and mortality (0.24% vs 0.68%; P = 0.46). Mean hospital stay was significantly shorter in CSILS group, (MD = -0.88 [-1.33, -0,42], 95% CI, P = 0.0001), but heterogeneity was found (I2 = 65%; P < 0.0001). The oncological results of SILS for colorectal cancer were satisfactory, as demonstrated by similar average lymph node retrieval (P = 0.72) and adequate resection margins (negative in all cases) compared to those obtained with LCS. Nevertheless, there are currently no available long-term follow-up data comparing the survival rates and local recurrence between both approaches. Insufficient data were available for evaluating long-term incisional hernia rates, and other potential benefits associated with colorectal SILS (cosmesis, postoperative pain) remain to be objectively proved. To date there is insufficient evidence to recommend widespread use of SILS instead of LCS for colorectal surgery. PMID- 28343613 TI - Effects of the use of growth hormone in children and adolescents with juvenile idiopathic arthritis: a systematic review. AB - INTRODUCTION: Children with juvenile idiopathic arthritis (JIA) often have impaired growth and short stature. There is evidence that the therapeutic use of growth hormone (GH) is useful and safe in these patients. OBJECTIVE: To analyze the effects of GH use in patients with JIA. METHOD: A systematic review of the literature over the last 18 years in Medline and Embase databases. The criteria were analyzed independently by the researchers. We used the following keywords: "growth hormone", "arthritis, juvenile", "arthritis, rheumatoid", "child" and "adolescent". RESULTS: Among the 192 identified articles, 20 corresponded to the inclusion criteria. Seventeen longitudinal studies and 3 case reports were found. Most studies analyzed observed increased growth, muscle mass and bone mass using GH. Adverse effects observed were glucose intolerance, diabetes, bone deformities, osteonecrosis, reactivation of the disease and low final height. CONCLUSION: The majority of studies reported positive effects after the therapeutic use of GH, but some variability in response to treatment was observed. The combination of growth hormone with other drugs seems to be a good option. PMID- 28343614 TI - Incidence and prevalence of systemic sclerosis in Campo Grande, State of Mato Grosso do Sul, Brazil. AB - INTRODUCTION: Systemic sclerosis is an autoimmune disease which shows extreme heterogeneity in its clinical presentation and that follows a variable and unpredictable course. Although some discrepancies in the incidence and prevalence rates between geographical regions may reflect methodological differences in the definition and verification of cases, they may also reflect true local differences. OBJECTIVES: To determine the prevalence and incidence of systemic sclerosis in the city of Campo Grande, state capital of Mato Grosso do Sul (MS), Brazil, during the period from January to December 2014. METHODS: All health care services of the city of Campo Grande - MS with attending in the specialty of Rheumatology were invited to participate in the study through a standardized form of clinical and socio-demographic assessment. Physicians of any specialty could report a suspected case of systemic sclerosis, but necessarily the definitive diagnosis should be established by a rheumatologist, in order to warrant the standardization of diagnostic criteria and exclusion of other diseases resembling systemic sclerosis. At the end of the study, 15 rheumatologists reported that they attended patients with systemic sclerosis and sent the completed forms containing epidemiological data of patients. RESULTS: The incidence rate of systemic sclerosis in Campo Grande for the year 2014 was 11.9 per million inhabitants and the prevalence rate was 105.6 per million inhabitants. Systemic sclerosis patients were mostly women, white, with a mean age of 50.58 years, showing the limited form of the disease with a mean duration of the disease of 8.19 years. Regarding laboratory tests, 94.4% were positive for antinuclear antibody, 41.6% for anti-centromere antibody and 19.1% for anti-Scl70; anti-RNA Polymerase III was performed in 37 patients, with 16.2% positive. CONCLUSIONS: The city of Campo Grande, the state capital of MS, presented a lower incidence/prevalence of systemic sclerosis in comparison with those numbers found in US studies and close to European studies' data. PMID- 28343615 TI - Intra-articular injection with triamcinolone hexacetonide in patients with rheumatoid arthritis: prospective assessment of goniometry and joint inflammation parameters. AB - OBJECTIVES: To evaluate local joint variables after intra-articular injection with triamcinolone hexacetonide in rheumatoid arthritis patients. METHODS: We blindly and prospectively (baseline, 1, 4, 12 and 24 weeks) evaluated metacarpophalangeal, wrist, elbow, shoulder, knee and ankle joints after triamcinolone hexacetonide intra-articular injection by the following outcome measures: visual analogue scale 0-10cm (VAS) for rest pain (VASR); VAS for movement pain (VASM); VAS for joint swelling (VASSw); flexion (FlexG) and extension (ExtG). RESULTS: 289 patients (635 joints) were studied. VASSw (p<0.001) and VASR (0.0010.05). CONCLUSION: This study shows that Kinesio Taping leads to improvements on pain, pressure pain threshold and cervical range of motion, but not disability in short time. Therefore, Kinesio Taping can be used as an alternative therapy method in the treatment of patients with MPS. PMID- 28343626 TI - The rat-a-gorical imperative: Moral intuition and the limits of affective learning. AB - Decades of psychological research have demonstrated that intuitive judgments are often unreliable, thanks to their inflexible reliance on limited information (Kahneman, 2003, 2011). Research on the computational underpinnings of learning, however, indicates that intuitions may be acquired by sophisticated learning mechanisms that are highly sensitive and integrative. With this in mind, Railton (2014) urges a more optimistic view of moral intuition. Is such optimism warranted? Elsewhere (Greene, 2013) I've argued that moral intuitions offer reasonably good advice concerning the give-and-take of everyday social life, addressing the basic problem of cooperation within a "tribe" ("Me vs. Us"), but that moral intuitions offer unreliable advice concerning disagreements between tribes with competing interests and values ("Us vs. Them"). Here I argue that a computational perspective on moral learning underscores these conclusions. The acquisition of good moral intuitions requires both good (representative) data and good (value-aligned) training. In the case of inter-tribal disagreement (public moral controversy), the problem of bad training looms large, as training processes may simply reinforce tribal differences. With respect to moral philosophy and the paradoxical problems it addresses, the problem of bad data looms large, as theorists seek principles that minimize counter-intuitive implications, not only in typical real-world cases, but in unusual, often hypothetical, cases such as some trolley dilemmas. In such cases the prevailing real-world relationships between actions and consequences are severed or reversed, yielding intuitions that give the right answers to the wrong questions. Such intuitions-which we may experience as the voice of duty or virtue-may simply reflect the computational limitations inherent in affective learning. I conclude, in optimistic agreement with Railton, that progress in moral philosophy depends on our having a better understanding of the mechanisms behind our moral intuitions. PMID- 28343627 TI - Invited review: Milk phospholipid vesicles, their colloidal properties, and potential as delivery vehicles for bioactive molecules. AB - The milk fat globule membrane (MFGM) is a unique colloidal assembly of phospholipids and proteins, with numerous potential applications as functional ingredient. The phospholipid components of the MFGM are gaining interest as they are a useful matrix for use as a constituent of delivery systems such as liposomes. Liposomes formulated with milk phospholipids are becoming an alternative to other sources of phospholipids such as soybean or egg yolk. However, incorporation of phospholipids fractionated from the milk fat globule membrane in dairy products requires an in-depth understanding of the functional properties of phospholipids. In particular, it is critical to understand which factors play a role in their stability and bioefficacy as delivery systems. Moreover, chemical and physical modifications of phospholipid liposomes occurring during digestion and the fate of the encapsulated compounds are very important to understand. This review discusses recent findings on the structure and functionality of MFGM, the bioactivity of the phospholipids fraction, their utilization as delivery systems, and their stability through gastrointestinal transit. PMID- 28343628 TI - Functional Architectures of Local and Distal Regulation of Gene Expression in Multiple Human Tissues. AB - Genetic variants that modulate gene expression levels play an important role in the etiology of human diseases and complex traits. Although large-scale eQTL mapping studies routinely identify many local eQTLs, the molecular mechanisms by which genetic variants regulate expression remain unclear, particularly for distal eQTLs, which these studies are not well powered to detect. Here, we leveraged all variants (not just those that pass stringent significance thresholds) to analyze the functional architecture of local and distal regulation of gene expression in 15 human tissues by employing an extension of stratified LD score regression that produces robust results in simulations. The top enriched functional categories in local regulation of peripheral-blood gene expression included coding regions (11.41*), conserved regions (4.67*), and four histone marks (p < 5 * 10-5 for all enrichments); local enrichments were similar across the 15 tissues. We also observed substantial enrichments for distal regulation of peripheral-blood gene expression: coding regions (4.47*), conserved regions (4.51*), and two histone marks (p < 3 * 10-7 for all enrichments). Analyses of the genetic correlation of gene expression across tissues confirmed that local regulation of gene expression is largely shared across tissues but that distal regulation is highly tissue specific. Our results elucidate the functional components of the genetic architecture of local and distal regulation of gene expression. PMID- 28343631 TI - A baseline record of trace elements concentration along the beach placer mining areas of Kanyakumari coast, South India. AB - Trace element concentration in the beach placer mining areas of Kanyakumari coast, South India was assessed. Sewage and contaminated sediments from mining sites has contaminated the surface sediments. Enrichment factor indicates moderately severe enrichment for Pb, minor enrichment for Mn, Zn, Ni, Fe and no enrichment for Cr and Cu. The Igeo values show higher concentration of Pb ranging in the scale of 3-4, which shows strong contamination due to high anthropogenic activity such as mining and terrestrial influences into the coastal regions. Correlation coefficient shows that most of the elements are associated with each other except Ni and Pb. Factor analysis reveals that Mn, Zn, Fe, Cr, Pb and Cu are having a significant loading and it indicates that these elements are mainly derived from similar origin. The cluster analysis clearly indicated that the mining areas are grouped under cluster 2 and non-mining areas are clustered under group 1. PMID- 28343632 TI - Metal pollution in Al-Khobar seawater, Arabian Gulf, Saudi Arabia. AB - In order to assess heavy metals pollution along the Al-Khobar coastline, 30 seawater samples and 15 sediment ones were collected for Al, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Sr, Mo, Cd, Hg and Pb analysis by Inductively Coupled Plasma Mass Spectrometer (ICP-MS). The analysis indicated a southward decreasing pattern in most heavy metal concentrations and the average values of Zn, Fe, Mn, Cu, As and Cr were higher than the ones reported from some worldwide seas and gulfs. Most of the highest levels were recorded within the bays and were related with in situ under sediments especially that composed of clays and very fine sands, and in localities characterized with anthropogenic activities like landfilling, desalination plants, fishing boats, oil spills and solid rubbish. The results of the present study provide useful background for further marine investigation and management in the Arabian Gulf region. PMID- 28343630 TI - De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome. AB - Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in ~35%-40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis. We identified 14 individuals with mild to severe ID and/or developmental delay and de novo truncating PPM1D mutations. Additionally, deep phenotyping revealed overlapping behavioral problems (ASD, ADHD, and anxiety disorders), hypotonia, broad-based gait, facial dysmorphisms, and periods of fever and vomiting. PPM1D is expressed during fetal brain development and in the adult brain. All mutations were located in the last or penultimate exon, suggesting escape from nonsense mediated mRNA decay. Both PPM1D expression analysis and cDNA sequencing in EBV LCLs of individuals support the presence of a stable truncated transcript, consistent with this hypothesis. Exposure of cells derived from individuals with PPM1D truncating mutations to ionizing radiation resulted in normal p53 activation, suggesting that p53 signaling is unaffected. However, a cell-growth disadvantage was observed, suggesting a possible effect on the stress-response pathway. Thus, we show that de novo truncating PPM1D mutations in the last and penultimate exons cause syndromic ID, which provides additional insight into the role of cell-cycle checkpoint genes in neurodevelopmental disorders. PMID- 28343629 TI - Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features. AB - Ubiquitination is a posttranslational modification that regulates many cellular processes including protein degradation, intracellular trafficking, cell signaling, and protein-protein interactions. Deubiquitinating enzymes (DUBs), which reverse the process of ubiquitination, are important regulators of the ubiquitin system. OTUD6B encodes a member of the ovarian tumor domain (OTU) containing subfamily of deubiquitinating enzymes. Herein, we report biallelic pathogenic variants in OTUD6B in 12 individuals from 6 independent families with an intellectual disability syndrome associated with seizures and dysmorphic features. In subjects with predicted loss-of-function alleles, additional features include global developmental delay, microcephaly, absent speech, hypotonia, growth retardation with prenatal onset, feeding difficulties, structural brain abnormalities, congenital malformations including congenital heart disease, and musculoskeletal features. Homozygous Otud6b knockout mice were subviable, smaller in size, and had congenital heart defects, consistent with the severity of loss-of-function variants in humans. Analysis of peripheral blood mononuclear cells from an affected subject showed reduced incorporation of 19S subunits into 26S proteasomes, decreased chymotrypsin-like activity, and accumulation of ubiquitin-protein conjugates. Our findings suggest a role for OTUD6B in proteasome function, establish that defective OTUD6B function underlies a multisystemic human disorder, and provide additional evidence for the emerging relationship between the ubiquitin system and human disease. PMID- 28343633 TI - Seasonal dynamics of marine litter along the Bulgarian Black Sea coast. AB - In this study marine litter (ML) surveys were conducted in 8 beaches along the Bulgarian Black Sea coastline within 4 seasons for 2015-2016. The monitoring applied OSPAR guideline, classifying ML in eight categories and 167 types. The results exhibited predominance of artificial polymer materials - 84.3%. ML densities ranged from 0.0587+/-0.005 to 0.1343+/-0.008 n/m2, highest on the urban beaches. The seasonal dynamics of most top 10 ML showed highest quantities in summer than the other seasons, as the differences are of high statistical significance (0.001<=P<=0.05). Top 1 ML item for most of the beaches was cigarette butts and filters reaching 1008+/-10.58 nos. in summer and from 19+/ 3.41 to 89+/-7.81 nos. during the rest of the seasons (P<0.001). For the pronounced seasonality contributed the recreational activities, increased tourist flow and the wild camping. The investigation will enrich data scarcity for Descriptor 10 "Marine litter". PMID- 28343634 TI - Identification of heavy metal pollutant tolerance-associated genes in Avicennia marina (Forsk.) by suppression subtractive hybridization. AB - The halophytic Avicennia marina (Forsk.) is one of the pioneer mangroves along the south coast of China. It is an appropriate material for understanding molecular mechanisms of heavy metal tolerance in mangrove plants. A forward and a reverse cDNA library was constructed by PCR-based suppressive subtractive hybridization (SSH) to isolate these tolerance-associated genes from A. marina leaves. A total of 99 ESTs obtained from the forward and reverse libraries showed significant differential expressions. Twenty-nine genes selected by SSH were studied by real-time PCR in order to analyze their expression level. Most of these genes' expression increased in leaves under Cd stress, which suggests that these genes contribute to the heavy metal tolerance in A. marina. The diversity of these genes indicated that heavy metal stress resulted in a complex response in mangrove plants. This could prove a useful approach for further exploring the molecular mechanisms behind such heavy metal tolerance. PMID- 28343635 TI - Swedish-Registered Nurse Anesthetists' Evaluation of Their Professional Self. AB - PURPOSE: This study aimed to explore how the nurse anesthetist values their professional self, compared with their peers, and also to explore whether professional self is affected by age, work experience, and/or gender. DESIGN: An explorative and prospective cross-sectional design. METHODS: During April 2011, a total of 108 registered nurse anesthetists from three different hospitals were surveyed using the Professional Self-Description Form with questions covering 21 items. FINDINGS: A total of 87 (80%) responded: 21 men and 66 women with a mean age of 45 years (range, 28 to 64 years) and mean professional experience of 12 years (range, 1 to 41 years). Four factors were found: professionalism, trait of character, scientific knowledge, and empathy, with Cronbach alpha of 0.96 overall. Analysis showed that perceived professional self depends on age and amount of work experience, but not on gender. CONCLUSIONS: The Professional Self Description Form exhibits satisfactory internal consistency. Work experience and age influenced the development of professional self of nurse anesthetists. PMID- 28343636 TI - Interruptions in Preanesthesia Nursing Workflow: A Pilot Study of Pediatric Patient Safety. AB - PURPOSE: Preanesthesia care is a high-risk system where interruptions during the preanesthesia assessment may jeopardize the quality of information obtained. The objective of this study was to (1) identify the number and nature of interruptions occurring during the nursing preanesthesia assessment, (2) evaluate effectiveness of a no interruption zone (NIZ) on the number and nature of interruptions experienced, and (3) determine the frequency with which nurses returned to their original task after interruption. DESIGN: A pre-post, quasi experimental pilot study design was used. METHODS: Study included observational methodology to compare the number and nature of interruptions which occurred during the preanesthesia assessment before and after implementation of a NIZ. FINDINGS: There was a statistically significant decrease in interruptions per observation after implementation of a NIZ with physical and verbal interruptions being the most common. Nurses returned to the original task more often after the implementation of the NIZ. CONCLUSION: Findings suggest use of a NIZ decreased interruptions experienced by nurses and thereby decreases the potential for workflow fragmentation. PMID- 28343637 TI - Investigation of Preoperative Fasting Times in Children. AB - PURPOSE: The aim of this study was to investigate preoperative fasting times of children. DESIGN: A prospective and descriptive design was used. METHODS: The study was carried out in the pediatric surgery departments of a University Faculty of Medicine Hospital, between January 1 and May 31, 2012. The sample included 332 pediatric patients having surgery with general anesthesia and their family. Data were collected via patient and family interview using a 28-item questionnaire developed by the researchers. FINDINGS: 29.2% of the sample was between the age of 1 and 3 years, of which 68.1% were male. 82.5% had day surgery. 94.9% of families were informed about the operation and 97.6% about nutrition before the operation. The children were fed an average of 10.51 hours before the operation (n = 203) with clear liquids, 6.27 hours (n = 52) with breast milk, 9.9 hours (n = 107) with baby food or cow's milk, 11.22 hours (n = 100) with toast and other, and 12.25 hours (n = 106) with daily food. About 65.6% of children between the years 0 and 3 (n = 151) declared being hungry when they were going to surgery, and 58.9% said that they were thirsty. Of the children older than 3 years (n = 181), 55.2% were hungry and 58.0% were thirsty. CONCLUSIONS: Results indicate that patients' preoperative fasting times were longer than recommended by current guidelines. PMID- 28343638 TI - Patient Care Handoff in the Postanesthesia Care Unit: A Quality Improvement Project. AB - PURPOSE: The goal of this project was to improve the process of transferring patient information between certified registered nurse anesthetists and postanesthesia care unit registered nurses using an evidence-based handoff checklist and evaluate completeness and accuracy of transferred information. DESIGN: A convenience sample of 14 certified registered nurse anesthetists and 7 registered nurses working at a single regional health system was recruited. METHODS: The Handoff Accuracy Scoring Tool was developed to include a pre /postinterventional design to compare scores of verbal handoffs conducted in the preintervention phase without checklist (n = 20) and postintervention phase with checklist (n = 20). FINDING: An unpaired sample t test revealed that differences in scores between the preintervention phase (mean = 9.50, standard deviation = 3.36) and postintervention phase (mean = 20.9, standard deviation = 1.74) were statistically significant (t[19] = 13.21; P = .0001; 95% confidence interval = [9.59, 13.21]). CONCLUSIONS: A department-specific handoff checklist can reduce the number of omission errors that may occur during patient handoff. PMID- 28343640 TI - Alcohol Withdrawal Syndrome. PMID- 28343639 TI - The Benefits of a Preoperative MRSA Swabbing Protocol. AB - Infection control practices pose a challenge to nursing care in general, but can have a huge negative impact on the perioperative process. Prior to July of 2012, our institution did not perform routine methacillin resistant staphylococcus aureus (MRSA) screening on preoperative patients with a prior history of MRSA. This resulted in patients remaining in isolation throughout their entire perioperative course. Screening for MRSA was delayed until the patient arrived in the medical surgical unit. Many of these patients were later found to have negative nasal swabs. The delay in screening often resulted in the unnecessary use of supplies (increased cost), delayed post anesthesia care unit (PACU) bay turnover and decreased staff satisfaction. Meetings with Hospital Infection Control, lab personnel and PACU staff resulted in the development of a preoperative MRSA swabbing protocol. In July of 2012 a preoperative MRSA swabbing protocol was implemented. Since implementation, the PACU has experienced a cost savings between $7,200- $11,800, a minimum of 40 minutes on PACU bay turnover and an increase in staff satisfaction. PMID- 28343641 TI - Does Your Leadership Team Work? PMID- 28343642 TI - New Evidence on Drug Interactions: Improving Patient Safety. PMID- 28343643 TI - Intravenous Acetaminophen. PMID- 28343644 TI - 2017-2018 Perianesthesia Standards. PMID- 28343645 TI - Protecting Children From Perioperative Infection: Understanding the Risks. PMID- 28343646 TI - Joy in the Morning. PMID- 28343647 TI - JoPAN and The Publishing Process. PMID- 28343648 TI - Women's Experiences of Undergoing Total Knee Joint Replacement Surgery. AB - PURPOSE: The purpose of the study was to describe women's experiences of undergoing total knee joint replacement surgery. DESIGN: A qualitative approach was used. METHOD: A content analysis of the text from interviews with five women was conducted. FINDINGS: The time before surgery was marked by the experience of constant pain, which affected the women negatively in their everyday lives. During surgery, the information provided by the staff gave each woman a sense of security; the women handed over responsibility to the staff and experienced a sensation of relief. The postoperative period was characterized by a feeling of joy when the surgery was over, although a rough and tedious rehabilitation phase then began. Challenges in everyday life were a factor for motivation and confidence, although postoperative pain was experienced as discouraging. CONCLUSION: Support from health care staff is an important factor for coping with everyday life during the preoperative, perioperative and postoperative phases of undergoing knee joint replacement. PMID- 28343649 TI - Increasing Access to Auricular Acupuncture for Postoperative Nausea and Vomiting. AB - PURPOSE: Postoperative nausea and vomiting (PONV) affects more than 30% of surgical patients. Auricular acupuncture (AA) has been shown to decrease the incidence of PONV in select populations. DESIGN: An evidence-based quality improvement project made AA available to all adult surgical patients, and the results were recorded in a database. A retrospective between-groups analysis of 210 database entries was conducted, of those 25 receiving AA. FINDINGS: More risk factors for PONV were present in the AA group (P < .001). Both groups experienced a less-than-expected rate of PONV. Similar rates were shown between groups for PONV, postanesthesia care unit length of stay, and opioid consumption. Patient satisfaction was 96% with AA. The AA group was treated with less antiemetic medication (P < .001), yet PONV rates remained similar. CONCLUSIONS: A multimodal approach treating patients at risk for PONV is recommended. Administration of multiple antiemetics may result in unnecessary cost or unfavorable side effects when effective and less costly alternatives exist. AA is a viable treatment for PONV, considering cost and patient satisfaction. PMID- 28343650 TI - [Surveillance system on drug abuse: Interest of the French national OPPIDUM program of French addictovigilance network]. AB - It is important to assess drug abuse liability in 'real life' using different surveillance systems. OPPIDUM ('Observation of illegal drugs and misuse of psychotropic medications') surveillance system anonymously collects information on drug abuse and dependence observed in patients recruited in specialized care centers dedicated to drug dependence. The aim of this article is to demonstrate the utility of OPPIDUM system using 2015 data. OPPIDUM is a cross-sectional survey repeated each year since 1995. In 2015, 5003 patients described the modality of use of 10,159 psychoactive drugs. Among them, 77% received an opiate maintenance treatment: 68% methadone (half of them consumed capsule form) and 27% buprenorphine (39% consumed generic form). Brand-name buprenorphine is more often injected than generic buprenorphine (10% vs. 2%) and among methadone consumers 7% of methadone capsule consumers have illegally obtained methadone (vs. 9% for syrup form). The proportion of medications among psychoactive drugs injected is important (42%), with morphine representing 21% of the total psychoactive drugs injected and buprenorphine, 16%. OPPIDUM highlighted emergent behaviors of abuse with some analgesic opioids (like tramadol, oxycodone or fentanyl), pregabalin, or quetiapine. OPPIDUM highlighted variations of drugs use regarding geographic approaches or by drug dependence care centers (like in harm reduction centers). OPPIDUM clearly demonstrated that collection of valid and useful data on drug abuse is possible, these data have an interest at regional, national and international levels. PMID- 28343651 TI - Reconstruction of large cranial defects with poly-methyl-methacrylate (PMMA) using a rapid prototyping model and a new technique for intraoperative implant modeling. AB - BACKGROUND: Reconstruction of large cranial defects after craniectomy can be accomplished by free-hand poly-methyl-methacrylate (PMMA) or industrially manufactured implants. The free-hand technique often does not achieve satisfactory cosmetic results but is inexpensive. In an attempt to combine the accuracy of specifically manufactured implants with low cost of PMMA. METHODS: Forty-six consecutive patients with large skull defects after trauma or infection were retrospectively analyzed. The defects were reconstructed using computer aided design/computer-aided manufacturing (CAD/CAM) techniques. The computer file was imported into a rapid prototyping (RP) machine to produce an acrylonitrile butadiene-styrene model (ABS) of the patient's bony head. The gas-sterilized model was used as a template for the intraoperative modeling of the PMMA cranioplasty. Thus, not the PMMA implant was generated by CAD/CAM technique but the model of the patients head to easily form a well-fitting implant. Cosmetic outcome was rated on a six-tiered scale by the patients after a minimum follow-up of three months. RESULTS: The mean size of the defect was 74.36cm2. The implants fitted well in all patients. Seven patients had a postoperative complication and underwent reoperation. Mean follow-up period was 41 months (range 2-91 months). Results were excellent in 42, good in three and not satisfactory in one patient. Costs per implant were approximately 550 Euros. CONCLUSION: PMMA implants fabricated in-house by direct molding using a bio-model of the patients bony head are easily produced, fit properly and are inexpensive compared to cranial implants fabricated with other RP or milling techniques. PMID- 28343652 TI - Predictors of non-return to work 2 years post-injury in road traffic crash survivors: Results from the UQ SuPPORT study. AB - PURPOSE: Individuals who have sustained an injury from a road traffic crash (RTC) are at increased risk for long lasting health problems and non-return to work (NRTW). Determining the predictors of NRTW is necessary to develop screening tools to identify at-risk individuals and to provide early targeted intervention for successful return to work (RTW). The aim of this study was to identify factors that can predict which individuals will not RTW following minor or moderate injuries sustained from a RTC. METHOD: Participants were 194 claimants (63.4% female) within a common-law "fault-based" system from the UQ SuPPORT cohort who were working prior to their RTC. Participants were assessed at 6 months on a variety of physical and mental health measures and RTW status was determined at 2 years post-RTC. RTW rate was 78.4%. RESULTS: Univariate predictors of NRTW included being the driver or passenger, having a prior psychiatric diagnosis, high disability level, low mental or physical quality of life, predicted non-recovery, high pain, low function, high expectations of pain persistency, low expectations about RTW, having a psychiatric diagnosis, elevated depression or anxiety. The final multivariable logistic regression model included only two variables: disability level and expectations about RTW. Seventy-five percent of individuals who will not RTW by 2 years can be identified accurately at an early stage, using only these two predictors. CONCLUSION: The results are promising, because they suggest that having information about two factors, which are easily obtainable, can predict with accuracy those who will require additional support to facilitate RTW. PMID- 28343653 TI - Swallow-induced syncope and carotid sinus hypersensitivity: Coincident or associated conditions? AB - Swallow induced syncope is a rare clinical condition which is thought to result from an abnormal vagal reflex leading to bradycardia and cerebral hypoperfusion. It mostly occurs in patients with organic or functional disorders of the esophagus, and often requires permanent pacemaker implantation, along with treatment of the underlying esophageal pathology. In the following case, we report of a 71-year-old male with achalasia post per oral endoscopic myectomy, who presented with syncope and documented AV-block while eating solid food. In addition, long sinus pauses were noted during carotid sinus massage, suggesting that the two distinct entities may be associated, and further supporting the mechanism of neurally mediated syncope in the pathophysiology of swallow-induced syncope. PMID- 28343654 TI - Negative concordant T waves during paced ventricular rhythm: An honest enemy is better than a false friend. AB - The ECG diagnosis of myocardial infarction and ischemia in pacemaker patients is often challenging. The three criteria, proposed by Sgarbossa et al. in 1996, useful to suspect myocardial ischaemia in patient with left bundle branch block were demonstrated to be valid also in pacemaker patients. In the last years, concordant negative T waves in patients with ventricular paced rhythm were linked to various expressions of acute myocardial injury. If available, comparison with previous ECG is crucial. Partial persistence of cardiac memory during fusion beats created an anomalous concordance between negative T waves and QRS axis and could induce erroneous suspicions. AV delay modification could help to unmask this situation. PMID- 28343656 TI - Reply. PMID- 28343655 TI - Who to Refer for Speech Therapy at 4 Years of Age Versus Who to "Watch and Wait"? AB - OBJECTIVE: To examine predictors of speech disorder resolution versus persistence at age 7 years in children with speech errors at age 4 years. STUDY DESIGN: Participants were drawn from a longitudinal, community cohort. Assessment at age 4 years (N?=?1494) identified children with speech errors. Reassessment at age 7 years allowed categorization into resolved or persistent categories. Logistic regression examined predictors of speech outcome, including family history, sex, socioeconomic status, nonverbal intelligence, and speech error type (delay vs disorder). RESULTS: At age 7 years, persistent errors were seen in over 40% of children who had errors at age 4 years. Speech symptomatology was the only significant predictor of outcome (P?=?.02). Children with disordered errors at age 4 years were twice as likely to have poor speech outcomes at age 7 years compared with those with delayed errors. CONCLUSIONS: Children with speech delay at age 4 years seem more likely to resolve, and this might justify a "watch and wait" approach. In contrast, those with speech disorder at age 4 years appear to be at greater risk for persistent difficulties, and could be prioritized for therapy to offset long-term impacts. PMID- 28343657 TI - Bradycardia Associated with Prednisolone in Children with Severe Kawasaki Disease. AB - OBJECTIVE: To identify the prevalence of bradycardia associated with use of prednisolone in patients with Kawasaki disease and analyze the association between bradycardia and responsiveness to intravenous immunoglobulin (IVIG). STUDY DESIGN: We performed a retrospective cohort study of 176 patients with severe Kawasaki disease admitted to the Tokyo Metropolitan Children's Medical Center between March 2010 and December 2015. The group treated with IVIG plus prednisolone therapy from February 2012 was compared with the control group who received IVIG monotherapy before this date. The primary outcome was the prevalence of bradycardia, defined as heart rate less than the first percentile for normal children. Next, we determined whether bradycardia was associated with the clinical course in the patient subgroup treated with IVIG plus prednisolone therapy. RESULTS: The prevalence of bradycardia was significantly higher in the IVIG plus prednisolone subgroup than in the IVIG group (79.1% vs 7.1%; P?.05). CONCLUSIONS: This study suggests the presence of more remodeling and/or inflammatory phenomena around titanium implant abutments than around zirconia abutments of a different design during the early stages but not at 1 year. PMID- 28343677 TI - Influence of adhesive cementation systems on the bond strength of relined fiber posts to root dentin. AB - STATEMENT OF PROBLEM: Glass fiber post cementation procedures have undergone significant development. Relining the post with composite resin is a technique that aims to reduce resin cement thickness and consequently problems inherent to polymerization. Evidence is sparse regarding the efficacy of bonding procedures at increasing depths (from cervical to apical) using different adhesive cementation techniques. PURPOSE: The purpose of this in vitro study was to evaluate the push-out bond strength (PBS) of composite resin relined glass fiber posts cemented to bovine root dentin using different adhesive cementation protocols. MATERIAL AND METHODS: Eighteen bovine teeth (n=6) were embedded in polystyrene resin blocks, and the crowns were sectioned leaving a root portion of 20 mm in length. Root canals were prepared using rotary instruments provided by the post manufacturer (Whitepost DC #1), resulting in a uniform root canal preparation. The root canals were lubricated with a water-soluble glycerin gel. Silane (Prosil) was applied and the posts relined with a microhybrid composite resin (Filtek Z100) to conform to the root canal anatomy. Three adhesive cementation protocols were evaluated: a 3-step etch-and-rinse adhesive system (Adper Scotchbond Multi Purpose) in combination with a dual polymerizing resin cement (RelyX ARC); a universal adhesive system (Scotchbond Universal) associated with a dual polymerizing resin cement (RelyX Ultimate); and a self-adhesive dual polymerizing resin cement (RelyX Unicem 2). The roots were sectioned, resulting in four 2-mm segments at 4 different depths (cervical to apical) and evaluated by the PBS test, using a universal testing machine (Instron 4411) at 0.5 mm/min, until failure. Interfaces were evaluated by scanning electron microscopy, and failures were classified as cohesive failure in composite resin, cohesive failure in cement, cohesive failure in root dentin, adhesive failure, or mixed. Data were analyzed by 2-way split-plot ANOVA and the Tukey post hoc test (alpha=.05). RESULTS: No statistical differences were found for PBS when different cementation systems were compared (P=.253). Increased depths resulted in reduced PBS values for all cementation protocols evaluated (P<.001). CONCLUSIONS: Regardless the cementation system used, the lowest PBS values were at the apical region of resin relined glass fiber posts bonded to root dentin. Furthermore, the highest PBS is observed at the cervical portion of root dentin. PMID- 28343678 TI - Maxillofacial prosthetics training and practice profiles in the United States. AB - STATEMENT OF PROBLEM: The motivation of maxillofacial prosthodontists to go into fellowship training and specific procedures in maxillofacial prosthetics practice once they have completed training has not been previously evaluated. PURPOSE: The purpose of this study was to survey maxillofacial prosthodontists in the United States to investigate their reasons for pursuing maxillofacial prosthetic training and their practice profiles. MATERIAL AND METHODS: In June 2015, a survey was sent to all US maxillofacial prosthodontists asking for descriptive demographics, their reasoning as to what prompted entrance into a maxillofacial prosthetic program, and their practice pattern. Frequencies, percentages, means, and standard deviations were calculated and reported. RESULTS: The survey response rate was 60.4%. The main reason for pursuing maxillofacial training was primarily personal satisfaction, prosthodontic residency exposure, and mentorship rather than media exposure and compensation. The time spent in prosthodontic practice varied among practitioners, with the majority of practice time spent accomplishing standard prosthodontic procedures (65.59%) versus maxillofacial (25.53%) or surgical procedures (9.67%). Of 12 clinical maxillofacial procedures inquired about, the most prevalent were obturators, dental oncology, and mandibular resections. CONCLUSIONS: This study reveals that personal satisfaction, mentorship, and prosthodontic residency exposure were the reasons most prosthodontists pursued an additional year of maxillofacial prosthetic fellowship. Most were very satisfied with their training and chosen career path and would recommend an additional year of training. The majority of maxillofacial prosthodontists provided maxillofacial prosthetic treatment for approximately one fourth of their practice time. The most common procedures performed were obturators, dental oncology, and mandibular resections. PMID- 28343679 TI - Postoperative agitation on emergence of general anesthesia revealing former post traumatic stress disorder. PMID- 28343680 TI - The medical itineraries of Blaise Cendrars. Neuropsychiatry marks life and literature. AB - Neuropsychiatry had a profound impact on the life and work of one of the most influential French writers of the 20th century, Frederic Sauser, better known by his pen name Blaise Cendrars (1887-1961). Cendrars, whose right writing hand was amputated after a battlefield wound in 1915, described with acuity his stump pain and phantom limb syndrome. He became a left-handed writer. Between 1956 and his death in 1961, he also suffered two strokes that progressively paralyzed his left side and greatly diminished his ability to speak. Cendrars had started medical school in his youth and found that his ideas about the genesis of mental disorders conflicted with the generally accepted psychiatric conceptions of hysteria or psychoanalysis. His theories were greatly enriched by his observations of fellow World War I soldiers, victims of neuropsychiatric disorders. In his novels, many of his characters had borderline conditions, including two spectacularly mad serial killers, Moravagine and Febronio. The case of Moravagine, fashioned after a patient with a brain tumor, allowed Cendrars to examine the nebulous frontier between neurological and psychiatric diseases. PMID- 28343681 TI - Ultrasound evaluation of diaphragm function and its application in critical patients, mechanical ventilation and brachial plexus block. AB - Before diaphragm ultrasonography, assessment of diaphragm function was very difficult due to the complex nature of its exploration. The use of this new technique has shed light on diagnostic problems and treatment with an improvement in final outcomes for critically ill patients, in whom the incidence of diaphragm weakness or dysfunction has been underestimated. Better knowledge of diaphragm function enables us earlier diagnosis by quantification of diaphragm contractile activity or evaluation of functional status after delivery of plexus block anaesthesia, facilitating therapeutic decisions. It is also being used as a guide in the process of weaning from mechanical ventilation or as the safest approach for braquial plexus block. In this review we present how to perform a systematic exploration of diaphragm function and its clinical implications. PMID- 28343683 TI - Preliminary results of polymyxin B hemoperfusion in abdominal septic shock. PMID- 28343682 TI - Fluid therapy recommendations for major abdominal surgery. Via RICA recommendations revisited. Part III: Goal directed hemodynamic therapy. Rationale for maintaining vascular tone and contractility. PMID- 28343684 TI - Fluid therapy recommendations for major abdominal surgery. Via RICA recommendations revisited. Part II: Goal directed hemodynamic therapy. Rationale for optimising intravascular volume. PMID- 28343685 TI - Evaluation of sources of irreproducibility of retention indices under programmed temperature gas chromatography conditions. AB - Retention index under the programmed temperature gas chromatography (PTGC) conditions (IT) is widely accepted despite of its unsatisfactory reproducibility. Effects of heating rate (rT), stationary liquid film thickness (df), inlet pressure (pi), initial temperature (To) and polarity of stationary phase (sp) on IT reproducibility were studied in the present work. We found that excellent reproducibility and regularity of IT values are obtainable at conditions of relatively low To and relatively high rT and pi, as well as use of quality thick film column under an operation in a single-retention behavior region (i.e., cubic equation model region). Most solutes were eluted in the dual-retention behavior region under the commonly used conditions described in the literature (i.e., relatively high To and relatively low rT for thin-film columns). The IT reproducibility under the optimum condition was approximately 37 times better than that under the commonly used conditions. The present work further validated the concept about dual- and single-retention behaviors of solutes in PTGC and proposed a principle to improve IT reproducibility. PMID- 28343686 TI - Analysis of essential oils and fragrances with a new generation of highly inert gas chromatographic columns coated with ionic liquids. AB - In the fields of essential oils and fragrances, samples often consist of mixtures of compounds with similar structural and physical characteristics (e.g. mono- and sesquiterpenoids), whose correct identification closely depends on the synergic combination of chromatographic and mass spectral data. This sample complexity means that new GC stationary phases with different selectivities are continually being investigated. Ionic liquids (ILs) are of great interest as GC stationary phases in this field because of their selectivity (significantly different than that of currently phases) and their high temperature stability. A first generation of IL GC columns was found to be competitive when applied to these field, in terms of selectivity and efficiency, compared to conventional columns (polydimethylsiloxane, (e.g. OV-1), methyl-polysiloxane 5%-phenyl (e.g. SE-52), 7%-cyanopropyl, 7%-phenyl polysiloxane (e.g. OV-1701), and polyethylen glycol (e.g. PEG-20M). However, these columns showed significant activity towards polar or active analytes, which primarily affected their quantitative performance. A new generation of highly-inactive columns coated with three of the most widely used ionic liquid GC stationary phases has recently been introduced; these phases are SLB-IL60i (1,12-di(tripropylphosphonium) dodecane bis(trifluoromethylsulfonyl) imide [NTf2], SLB-IL76i (tri-(tripropylphosphonium hexanamido)-triethylamine [NTf2]), and SLB-IL111i (1,5-di (2,3 dimethyllimidazolium) pentane [NTf2]). This study carefully tested the new inert IL columns, in view of their routine application in the fragrance and essential oil fields. They were found to have unusually high selectivity, comparable to that of first-generation IL columns, while their inertness and efficiency were competitive with those of currently-used conventional columns. The IL column performance of first and second generations was compared, through the quali quantitative analysis of components in a group of different complexity samples; these included the Grob test, a standard mixture of "suspected" skin allergens, and the essential oils of chamomile and sandalwood. PMID- 28343687 TI - Multiple, simultaneous, independent gradients for a versatile multidimensional liquid chromatography. Part II: Application 2: Computer controlled pH gradients in the presence of urea provide improved separation of proteins: Stability influenced anion and cation exchange chromatography. AB - This paper details the use of a method of creating controlled pH gradients (pISep) to improve the separation of protein isoforms on ion exchange (IEX) stationary phases in the presence of various isocratic levels of urea. The pISep technology enables the development of computer controlled pH gradients on both cationic (CEX) and anionic (AEX) IEX stationary phases over the very wide pH range from 2 to 12. In pISep, titration curves generated by proportional mixing of the acidic and basic pISep working buffers alone, or in the presence of non buffering solutes such as the neutral salt NaCl (0-1M), polar organics such as urea (0-8M) or acetonitrile (0-80 Vol%), can be fitted with high fidelity using high order polynomials which, in turn allows construction of a mathematical manifold %A (% acidic pISep buffer) vs. pH vs. [non-buffering solute], permitting precise computer control of pH and the non-buffering solute concentration allowing formation of dual uncoupled liquid chromatographic (LC) gradients of arbitrary shape (Hirsh and Tsonev, 2012 [1]). The separation of protein isoforms examined in this paper by use of such pH gradients in the presence of urea demonstrates the fractionation power of a true single step two dimensional liquid chromatography which we denote as Stability-Influenced Ion Exchange Chromatography (SIIEX). We present evidence that SIIEX is capable of increasing the resolution of protein isoforms difficult to separate by ordinary pH gradient IEX, and potentially simplifying the development of laboratory and production purification strategies involving on-column simultaneous pH and urea unfolding or refolding of targeted proteins. We model some of the physics implied by the dynamics of the observed protein fractionations as a function of both urea concentration and pH assuming that urea-induced native state unfolding competes with native state electrostatic interaction binding to an IEX stationary phase. Implications for in vivo protein-membrane interactions are discussed. PMID- 28343688 TI - Who's afraid of the big bad wolf? PMID- 28343689 TI - Localizing small nodules: Is it time for a randomized trial? PMID- 28343690 TI - A Toddler With Severe Anemia, Pica, and Extremity Swelling. PMID- 28343691 TI - Improving the Quality of Nasal Specimen Collection for Influenza A and B Screening. AB - CONTRIBUTION TO EMERGENCY NURSING PRACTICE: PROBLEM: Rapid diagnosis of seasonal influenza leads to optimized clinical care and reduces the spread of infection. The collection of adequate cellular material can be facilitated by the presence of moisture in the nares. The specific aim of this project was to determine if the installation of sterile saline into the nares prior to specimen collection would improve the quality of the specimen. METHODS: This quasi-experimental single group design tested an initial "dry swab" specimen against a second swab after instillation of sterile saline solution using a nasal atomizer, a "wet swab." RESULTS: A total of 80 paired specimens were collected and analyzed between December 7, 2015, and April 21, 2016, with an 11.25% infection rate in those tested. Of 9 positive tests, 6 subjects tested positive for influenza A or B for both the dry swab and the wet swab. Three subjects tested positive for influenza A or B for only the wet swab, and these subjects had experienced their symptoms longer than did subjects who tested positive for both methods (mean symptom onset of 72 hours vs 66 hours). We found an important inconsistency between manufacturers' recommendations and typical hospital practice. IMPLICATIONS FOR PRACTICE: The results appear somewhat equivocal. Because viral shedding declines after the first 48 to 72 hours in adults, the wet swab method may be clinically superior for detecting influenza in adults presenting later in the course of their illness. Hospital policy was revised for consistency in using the gel medium before sampling in accordance with manufacturer recommendations. PMID- 28343692 TI - Quality survey of natural mineral water and spring water sold in France: Monitoring of hormones, pharmaceuticals, pesticides, perfluoroalkyl substances, phthalates, and alkylphenols at the ultra-trace level. AB - The aim of the present study, one of the most complete ever performed in France, was to carry out an extensive survey on the potential presence of a large amount of emerging contaminants in 40 French bottled waters, including parent compounds and metabolites. The studied samples represented 70% of the French bottled water market in volume. Six classes of compounds were investigated, most of them being unregulated in bottled waters: pesticides and their transformation products (118), pharmaceutical substances (172), hormones (11), alkylphenols (APs) (8), phthalates (11) and perfluoroalkyl substances (PFAS) (10). One of the objectives of this work was to achieve low and reliable limits of quantification (LOQs) (87% of the LOQs were below 10ng/L) using advanced analytical technologies and reliable sample preparation methodologies, including stringent quality controls. Among the 14,000 analyses performed, 99.7% of the results were below the LOQs. None of the hormones, pharmaceutical substances and phthalates were quantified. Nineteen compounds out of the 330 investigated were quantified in 11 samples. Eleven were pesticides including 7 metabolites, 6 were PFAS and 2 were APs. As regards pesticides, their sum was at least twice lower than the quality standards applicable for bottled waters in France. The presence of a majority of pesticide metabolites suggested a former use in the recharge areas of the exploited aquifers. The quantification of a few unregulated emerging compounds at the nano trace level, such as PFAS, raised the issue of their potential sources, including long-range atmospheric transport and deposition. This study confirmed that the groundwater aquifers exploited for bottling were well-preserved from chemicals, as compared to less geologically protected groundwaters, and also underlined the need to pursue the protection policies implemented in recharge areas in order to limit the anthropogenic pressure. PMID- 28343693 TI - Utility of radiation therapy for early-stage uterine papillary serous carcinoma. AB - OBJECTIVE: Early-stage uterine papillary serous carcinoma (UPSC) has a poor prognosis and high recurrence rate. While adjuvant chemotherapy is generally recommended, the role of radiation is uncertain. We examined the association between vaginal brachytherapy and whole pelvic radiation and survival in women treated with and without adjuvant chemotherapy. METHODS: The National Cancer Data Base was used to identify women with stage I-II UPSC treated between 1998 and 2012. Trends in use of chemotherapy, brachytherapy, and external beam radiation over time were examined. The association between these treatments and mortality were examined using multivariable Cox proportional hazards models. RESULTS: A total of 7325 patients were identified. Overall, 2779 (37.9%) received chemotherapy. The use of vaginal brachytherapy increased from 7.2% in 1998 to 29.1% in 2012 (P<0.0001), while use of external beam radiation decreased from 18.2% to 11.7% over the same period (P<0.0001). Use of chemotherapy was associated with a 22% reduction in mortality (HR=0.78; 95% CI, 0.69-0.88). While brachytherapy was associated with decreased mortality (HR=0.67; 95% CI, 0.57 0.78), use of external beam radiation was not associated with survival (HR=1.03; 95% CI, 0.92-1.17). Stratified by stage, use of chemotherapy was associated with decreased mortality for women with stage IB and II tumors, but not for stage IA neoplasms. Vaginal brachytherapy was associated with reduced mortality for stage IA and II neoplasms. CONCLUSION: For women with early-stage UPSC, chemotherapy is associated with improved survival. Vaginal brachytherapy was also associated with improved survival, however, there was little benefit to use of external beam radiation. PMID- 28343694 TI - Open versus endovascular abdominal aortic aneurysm repair in Medicare beneficiaries. AB - Abdominal aortic aneurysms are relatively common and often life-threatening, with especially high mortality after aneurysm rupture. The introduction of endovascular aneurysm repair, a minimally invasive alternative to traditional open repair, led to decreased mortality and morbidity in randomized controlled trials, but these trials were conducted in highly selected patients and providers and were underpowered to detect differences in rare adverse events throughout follow-up. With observational studies of Medicare beneficiaries, we demonstrate that the randomized trial results are generalizable to the majority of patients undergoing abdominal aortic aneurysm repair in the United States. Additionally, with a larger cohort, comparative analyses evaluating rare, previously unstudied late outcomes such as laparotomy-related complications, late reinterventions, mortality with reinterventions, and late rupture could be conducted. Furthermore, trends in management over time and relationships between surgeon and hospital volume and outcomes can be studied. The goal of this review was to summarize the existing literature regarding abdominal aortic aneurysms among Medicare beneficiaries and to evaluate the benefits and limitations of administrative claims data in comparative effectiveness research. PMID- 28343695 TI - Treatment with milk fat globule epidermal growth factor-factor 8 (MFG-E8) reduces inflammation and lung injury in neonatal sepsis. AB - BACKGROUND: Sepsis remains one of the leading causes of infant death worldwide. It is characterized by uncontrolled inflammatory responses due to proven bacterial infection. Despite improvement in supportive care and the availability of effective antibiotics, no specific therapy targeting the dysregulated inflammatory response is available for neonatal sepsis. Milk fat globule epidermal growth factor-factor 8 (MFG-E8) is a secretory glycoprotein abundantly present in human milk. MFG-E8 suppresses the systemic inflammatory responses in adult murine injury models by improving the clearance of dying cells. We hypothesized that exogenous administration of recombinant mouse MFG-E8 could inhibit the exaggerated inflammatory response and lung injury in a murine model of neonatal sepsis. METHODS: Neonatal sepsis was induced in 5- to 7-day-old male and female C57BL6 mice using an intraperitoneal injection of cecal slurry. At 1 hour after sepsis induction, a single dose of 40 MUg/kg recombinant mouse MFG-E8 or vehicle was administered via retro-orbital injection. All neonates were returned to their mothers as a group. At 10 hours after cecal slurry injection, pups were killed and blood and lung tissues were collected. Control mice underwent a similar procedure with the exception of cecal slurry intraperitoneal injection. RESULTS: Serum lactate dehydrogenase, IL-1beta, and IL-6 were significantly increased 10 hours after cecal slurry injection. Treatment with recombinant mouse MFG-E8 decreased these levels by 30%, 56%, and 37%, respectively. Lung morphology was significantly compromised in the vehicle group after cecal slurry injection, whereas the recombinant mouse MFG-E8-treated groups demonstrated a 48% improvement in the lung injury score. Lung IL-6 and MIP-2 protein levels were significantly reduced with recombinant mouse MFG-E8 treatment. Lung neutrophil infiltration as observed by Gr-1 staining and, TUNEL positive cells were also significantly reduced with recombinant mouse MFG-E8 treatment. CONCLUSION: Treatment with recombinant mouse MFG-E8 attenuated inflammation and lung injury in murine neonatal sepsis. Thus, MFG-E8 could be developed as a possible therapy for neonatal sepsis. PMID- 28343696 TI - Hypothermic perfusion with retrograde outflow during right hepatectomy is safe and feasible. AB - BACKGROUND: In situ hypothermic perfusion during liver resection performed under vascular inflow occlusion decreases hepatic ischemia-reperfusion injury, but technical limitations have restricted its widespread use. In situ hypothermic perfusion with retrograde outflow circumvents these impediments and thus could extend the applicability of in situ hypothermic perfusion. The safety and feasibility of in situ hypothermic perfusion with retrograde outflow were analyzed in selected patients undergoing right (extended) hepatectomy and compared to intermittent vascular inflow occlusion, the gold standard method, in this randomized pilot study. METHODS: Patients were first screened for parenchymal liver disease (exclusion criteria: steatosis >=30%, cirrhosis, or cholestasis). Study participants were randomized intraoperatively to undergo in situ hypothermic perfusion with retrograde outflow (n = 9) or intermittent vascular inflow occlusion (n = 9). The target liver core temperature during in situ hypothermic perfusion with retrograde outflow was 28 degrees C. The primary end point was ischemia-reperfusion injury (expressed by peak postoperative transaminase levels). Secondary outcomes included functional liver regeneration (assessed by hepatobiliary scintigraphy) and clinical outcomes. RESULTS: Peak transaminase levels, total bilirubin, and the international normalized ratio were similar between both groups, although a trend toward more rapid normalization of bilirubin levels was noted for the in situ hypothermic perfusion with retrograde outflow group. Functional liver regeneration as evaluated by hepatobiliary scintigraphy was improved on postoperative day 3 fafter in situ hypothermic perfusion with retrograde outflow but not after intermittent vascular inflow occlusion. Furthermore, in situ hypothermic perfusion with retrograde outflow (requiring continuous ischemia) was comparable to intermittent vascular inflow occlusion for all clinical outcomes, including postoperative complications and hospital stay. CONCLUSION: The use of in situ hypothermic perfusion with retrograde outflow appears to be safe and feasible in selected patients with healthy liver parenchyma and may benefit early functional liver regeneration. Future applications of in situ hypothermic perfusion with retrograde outflow include patients with damaged liver parenchyma who would require major hepatic resection with a prolonged vascular inflow occlusion duration. PMID- 28343698 TI - My most valuable learning experience: Starting a business. AB - Alexander is a preliminary medicine resident at State University of New York Upstate Medical University and a recent graduate of Harvard Medical School. While in medical school, he cofounded Wizdy Games, a company developing mobile games that teach children to manage various health conditions, and PreMed Insiders, an advisory service for those considering or applying to medical school. PMID- 28343697 TI - Modeling Avoidance in Mood and Anxiety Disorders Using Reinforcement Learning. AB - BACKGROUND: Serious and debilitating symptoms of anxiety are the most common mental health problem worldwide, accounting for around 5% of all adult years lived with disability in the developed world. Avoidance behavior-avoiding social situations for fear of embarrassment, for instance-is a core feature of such anxiety. However, as for many other psychiatric symptoms the biological mechanisms underlying avoidance remain unclear. METHODS: Reinforcement learning models provide formal and testable characterizations of the mechanisms of decision making; here, we examine avoidance in these terms. A total of 101 healthy participants and individuals with mood and anxiety disorders completed an approach-avoidance go/no-go task under stress induced by threat of unpredictable shock. RESULTS: We show an increased reliance in the mood and anxiety group on a parameter of our reinforcement learning model that characterizes a prepotent (pavlovian) bias to withhold responding in the face of negative outcomes. This was particularly the case when the mood and anxiety group was under stress. CONCLUSIONS: This formal description of avoidance within the reinforcement learning framework provides a new means of linking clinical symptoms with biophysically plausible models of neural circuitry and, as such, takes us closer to a mechanistic understanding of mood and anxiety disorders. PMID- 28343699 TI - Operative innovation and device development: A trainee's perspective. AB - Farokh R. Demehri, MD, is a chief resident in general surgery and Pediatric Innovation Fellow at the University of Michigan. As a trainee, he has worked on device development in pediatric enteral access with James D. Geiger, MD, and device solutions for short bowel syndrome under the mentorship of Daniel H. Teitelbaum, MD. PMID- 28343700 TI - Fostering a culture of innovation in academic surgery. AB - Dr McCarthy is a fellow in cardiothoracic surgery at the University of Washington. During his general surgery training at Northwestern University, he completed a research fellowship in surgical innovation and obtained masters' degrees with a focus on health enterprise management, entrepreneurship, and innovation. PMID- 28343702 TI - Yellow fever outbreaks and Twitter: Rumors and misinformation. PMID- 28343703 TI - Knowledge, attitudes, and practices regarding environmental cleaning among environmental service workers in Chinese hospitals. AB - We conducted a study using a face-to-face survey to assess knowledge, attitudes, and practices of environmental service workers (ESWs) concerning routine cleaning and disinfection at 3 tertiary hospitals in China. There were 115 (89.1%) respondents who agreed that environmental cleaning can contribute to keep patients safe, whereas 63 (48.8%) reported they were very willing to make cleaning practices better. Only 15 (11.6%) ESWs agreed they were in risk of nosocomial infections during daily cleaning. Our findings suggest that the level of ESWs' knowledge regarding cleaning practices was passable, but the awareness of occupational safety and health was weak. There is a need to introduce sustained education and training aimed at ESWs. PMID- 28343704 TI - Correlation between the function of regenerating liver parenchyma and the small for size syndrome. PMID- 28343701 TI - Toll-like receptor 8 agonist nanoparticles mimic immunomodulating effects of the live BCG vaccine and enhance neonatal innate and adaptive immune responses. AB - BACKGROUND: Newborns display distinct immune responses, leaving them vulnerable to infections and impairing immunization. Targeting newborn dendritic cells (DCs), which integrate vaccine signals into adaptive immune responses, might enable development of age-specific vaccine formulations to overcome suboptimal immunization. OBJECTIVE: Small-molecule imidazoquinoline Toll-like receptor (TLR) 8 agonists robustly activate newborn DCs but can result in reactogenicity when delivered in soluble form. We used rational engineering and age- and species specific modeling to construct and characterize polymer nanocarriers encapsulating a TLR8 agonist, allowing direct intracellular release after selective uptake by DCs. METHODS: Chemically similar but morphologically distinct nanocarriers comprised of amphiphilic block copolymers were engineered for targeted uptake by murine DCs in vivo, and a range of TLR8 agonist-encapsulating polymersome formulations were then synthesized. Novel 96-well in vitro assays using neonatal human monocyte-derived DCs and humanized TLR8 mouse bone marrow derived DCs enabled benchmarking of the TLR8 agonist-encapsulating polymersome formulations against conventional adjuvants and licensed vaccines, including live attenuated BCG vaccine. Immunogenicity of the TLR8 agonist adjuvanted antigen 85B (Ag85B)/peptide 25-loaded BCG-mimicking nanoparticle formulation was evaluated in vivo by using humanized TLR8 neonatal mice. RESULTS: Although alum-adjuvanted vaccines induced modest costimulatory molecule expression, limited TH-polarizing cytokine production, and significant cell death, BCG induced a robust adult-like maturation profile of neonatal DCs. Remarkably, TLR8 agonist polymersomes induced not only newborn DC maturation profiles similar to those induced by BCG but also stronger IL-12p70 production. On subcutaneous injection to neonatal mice, the TLR8 agonist-adjuvanted Ag85B peptide 25 formulation was comparable with BCG in inducing Ag85B-specific CD4+ T-cell numbers. CONCLUSION: TLR8 agonist encapsulating polymersomes hold substantial potential for early-life immunization against intracellular pathogens. Overall, our study represents a novel approach for rational design of early-life vaccines. PMID- 28343705 TI - Relevance of the porcine model of hepatectomy for studying portal inflow modulation by splenectomy. PMID- 28343706 TI - The crucial role of portal flow after major liver resection: the "small-for-flow" syndrome may solve the mystery. PMID- 28343708 TI - A new case of Pitt-Hopkins-like syndrome 2? PMID- 28343707 TI - Fibrin scaffold enhances function of insulin producing cells differentiated from human umbilical cord matrix-derived stem cells. AB - Tissue engineering is a new strategy which proposed to treat numerous human diseases nowadays. Three dimensional (3D) scaffolds fill the gap between two dimensional cell culture (2D) and animal tissues through mimicking the environmental behaviors surrounding the cells. In this study, hUCMs into insulin producing cells in fibrin scaffold were differentiated compare to conventional culture condition. Differentiation rate was estimated by real time PCR, immunocytochemistry (ICC) and the chemiluminesence (CLIA) and enzyme immunoassay (EIA). Real time PCR's results showed an increasing expression in NKX2.2, PDX1 and INS (producing the hormone insulin) genes in fibrin scaffold. Furthermore ICC analysis exhibited that insulin and pro-insulin proteins were more in fibrin scaffolds. CLIA and EIA on insulin and C peptide secretion indicated that both of groups were sensitive to the glucose challenge test but significant higher response was observed in fibrin scaffold (6.5 fold in 3D, 1.8 fold in 2D culture). It could be concluded that differentiation of hUCM cells into insulin producing cells in fibrin scaffold 3D culture system is much more efficient than 2D conventional culture system. PMID- 28343709 TI - A distributed model predictive control based load frequency control scheme for multi-area interconnected power system using discrete-time Laguerre functions. AB - This paper proposes a distributed model predictive control based load frequency control (MPC-LFC) scheme to improve control performances in the frequency regulation of power system. In order to reduce the computational burden in the rolling optimization with a sufficiently large prediction horizon, the orthonormal Laguerre functions are utilized to approximate the predicted control trajectory. The closed-loop stability of the proposed MPC scheme is achieved by adding a terminal equality constraint to the online quadratic optimization and taking the cost function as the Lyapunov function. Furthermore, the treatments of some typical constraints in load frequency control have been studied based on the specific Laguerre-based formulations. Simulations have been conducted in two different interconnected power systems to validate the effectiveness of the proposed distributed MPC-LFC as well as its superiority over the comparative methods. PMID- 28343710 TI - A new computing approach for power signal modeling using fractional adaptive algorithms. AB - Estimating the harmonic parameters is fundamental requirement for signal modelling in a power supply system. In this study, exploration and exploitation in fractional adaptive signal processing (FrASP) is carried out for identification of parameters in power signals. We design FrASP algorithms based on recently introduced variants of generalized least mean square (LMS) adaptive strategies for parameter estimation of the model. The performance of the proposed fractional adaptive schemes is evaluated for number of scenarios based on step size and noise variations. Results of the simulated system for sufficient large number of independent runs validated the reliability and effectiveness of the given methods through different performance measures in terms of mean square error, variance account for, and Nash Sutcliffe efficiency. PMID- 28343712 TI - Nurses on health care governing boards: An integrative review. AB - BACKGROUND: Nurses are key change agents in health care; yet, nurses have not been sufficiently engaged on boards to shape decision making. Without an equal voice in the boardroom, nurses cannot fulfill their professional obligation to society. PURPOSE: The purpose of this study was to understand the progression in research focus and recommendations over time about nurses on boards (NOB), identify research gaps, and make research/practice recommendations. METHODS: An integrative review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines (2009) for data evaluation and analysis. Eleven studies (six quantitative, three qualitative, and two quasi-mixed methods) were included in the review. FINDINGS: The focus/recommendations of research about NOB have changed from passive observation to action-oriented inquiry that considers nurse expertise and value but lacks a coordinated approach to advance board appointments for nurses. CONCLUSION: A systematic approach to the research is needed to advance NOB as key agents in health care transformation and social justice. PMID- 28343711 TI - Overview of the Robert Wood Johnson Foundation Nurse Faculty Scholars program. AB - BACKGROUND: The Robert Wood Johnson Foundation Nurse Faculty Scholars program was created to address the nursing faculty shortage and thereby decrease the nursing shortage. PURPOSE: The purpose of the study was to describe the program development, implementation, and ongoing outcome evaluation. METHODS: Data on scholarly productivity, impact of research, research funding, and leadership positions were compiled, including an h-index (impact of publications) comparison with a comparison group of other interdisciplinary faculty at the same institutions of the 90 current and alumni scholars. DISCUSSION: There is evidence of the achievements of the individual scholars; however, the effect of the synergy of the multiple components of the program is difficult to capture in traditional evaluation strategies. CONCLUSIONS: The sense of possibility and responsibility (to the profession, to improving the health of all Americans, and to one's school of nursing and university) was a significant outcome of the program. Lessons learned from the program are important for the leadership development and retention of nursing faculty. PMID- 28343713 TI - Workplace violence against women nurses working in two public sector hospitals of Lahore, Pakistan. AB - BACKGROUND: Cultural and structural forces help sustain workplace violence (WPV) against feminized professions like nursing in Pakistan. PURPOSE: The purpose of this study was to identify the prevalence and patterns of workplace violence (WPV) against women nurses (more than 95% of entire nursing population) in two hospitals of Pakistan. METHODS: A standardized international survey developed by the World Health Organization was used to collect cross-sectional data. Descriptive statistics, chi-square tests, and multivariate regression were used for data analysis. A total of 309 nurse respondents were sampled from two public sector tertiary care hospitals of Lahore. RESULTS: Findings show that 73.1% of nurses reported experiencing some sort of violence in the last 12 months; with 53.4% suffering from physical violence, 57.3% from verbal violence, and 26.9% from sexual violence. The main perpetrators were reported to be male coworkers, patients, and attendants. Higher risk for WPV includes single status, non-Punjabi provincial belonging, Islamic faith, staff and student nurse designations, temporary government contract, and working additional hours in the evening and night. The primary response to violence included not doing anything and remaining silent. It was also reported that nurse victims experienced moderate levels of emotional grievances after facing violence. CONCLUSION: The results of this study suggest that public sector hospitals in the region need to improve their policy for the protection and monitoring of WPV against female nurses. Reporting and counseling bodies need to be installed to encourage both complaints and the seeking of medical attention after victimization. PMID- 28343714 TI - Sensitivity of eastern oyster (Crassostrea virginica) spermatozoa and oocytes to dispersed oil: Cellular responses and impacts on fertilization and embryogenesis. AB - The 2010 Deepwater Horizon (DWH) oil spill released millions of barrels of oil and dispersant into the Gulf of Mexico. The timing of the spill coincided with the spawning season of Crassostrea virginica. Consequently, gametes released in the water were likely exposed to oil and dispersant. This study aimed to (i) evaluate the cellular effects of acute exposure of spermatozoa and oocytes to surface slick oil, dispersed mechanically (HEWAF) and chemically (CEWAF), using flow-cytometric (FCM) analyses, and (ii) determine whether the observed cellular effects relate to impairments of fertilization and embryogenesis of gametes exposed to the same concentrations of CEWAF and HEWAF. Following a 30-min exposure, the number of spermatozoa and their viability were reduced due to a physical action of oil droplets (HEWAF) and a toxic action of CEWAF respectively. Additionally, reactive oxygen species (ROS) production in exposed oocytes tended to increase with increasing oil concentrations suggesting that exposure to dispersed oil resulted in an oxidative stress. The decrease in fertilization success (1-h), larval survival (24-h) and increase in abnormalities (6-h and 24 h) may be partly related to altered cellular characteristics. FCM assays are a good predictor of sublethal effects especially on fertilization success. These data suggest that oil/dispersant are cytotoxic to gametes, which may affect negatively the reproduction success and early development of oysters. PMID- 28343715 TI - Occurrence, profiles, and toxic equivalents of chlorinated and brominated polycyclic aromatic hydrocarbons in E-waste open burning soils. AB - We conducted this study to assess the occurrence, profiles, and toxicity of chlorinated polycyclic aromatic hydrocarbons (Cl-PAHs) and brominated polycyclic aromatic hydrocarbons (Br-PAHs) in e-waste open burning soils (EOBS). In this study, concentrations of 15 PAHs, 26 Cl-PAHs and 14 Br-PAHs were analyzed in EOBS samples. We found that e-waste open burning is an important emission source of Cl PAHs and Br-PAHs as well as PAHs. Concentrations of total Cl-PAHs and Br-PAHs in e-waste open burning soil samples ranged from 21 to 2800 ng/g and from 5.8 to 520 ng/g, respectively. Compared with previous studies, the mean of total Cl-PAH concentrations of the EOBS samples in this study was higher than that of electronic shredder waste, that of bottom ash, and comparable to fly ash from waste incinerators in Korea and Japan. The mean of total Br-PAH concentrations of the EOBS samples was generally three to four orders of magnitude higher than those in incinerator bottom ash and comparable to incinerator fly ash, although the number of Br-PAH congeners measured differed among studies. We also found that the Cl-PAH and Br-PAH profiles were similar among all e-waste open burning soil samples but differed from those in waste incinerator fly ash. The profiles and principal component analysis results suggested a unique mechanism of Cl-PAH and Br-PAH formation in EOBS. In addition, the Cl-PAHs and Br-PAHs showed high toxicities equivalent to PCDD/Fs measured in same EOBS samples when calculated based on their relative potencies to benzo[a]pyrene. Along with chlorinated and brominated dioxins and PAHs, Cl-PAHs and Br-PAHs are important environmental pollutants to investigate in EOBS. PMID- 28343716 TI - Transformation of zinc-concentrate in surface and subsurface environments: Implications for assessing zinc mobility/toxicity and choosing an optimal remediation strategy. AB - Zinc contamination in near- and sub-surface environments is a serious threat to many ecosystems and to public health. Sufficient understanding of Zn speciation and transport mechanisms is therefore critical to evaluating its risk to the environment and to developing remediation strategies. The geochemical and mineralogical characteristics of contaminated soils in the vicinity of a Zn ore transportation route were thoroughly investigated using a variety of analytical techniques (sequential extraction, XRF, XRD, SEM, and XAFS). Imported Zn concentrate (ZnS) was deposited in a receiving facility and dispersed over time to the surrounding roadside areas and rice-paddy soils. Subsequent physical and chemical weathering resulted in dispersal into the subsurface. The species identified in the contaminated areas included Zn-sulfide, Zn-carbonate, other O coordinated Zn-minerals, and Zn species bound to Fe/Mn oxides or clays, as confirmed by XAFS spectroscopy and sequential extraction. The observed transformation from S-coordinated Zn to O-coordinated Zn associated with minerals suggests that this contaminant can change into more soluble and labile forms as a result of weathering. For the purpose of developing a soil washing remediation process, the contaminated samples were extracted with dilute acids. The extraction efficiency increased with the increase of O-coordinated Zn relative to S-coordinated Zn in the sediment. This study demonstrates that improved understanding of Zn speciation in contaminated soils is essential for well informed decision making regarding metal mobility and toxicity, as well as for choosing an appropriate remediation strategy using soil washing. PMID- 28343717 TI - [Associated tripe palms and clubbed fingers revealing pulmonary adenocarcinoma]. PMID- 28343718 TI - [Comparative evaluation of dermoscopy and capillaroscopy in Raynaud's phenomenon]. AB - OBJECTIVE: Raynaud's phenomenon (RP) is a common cause for consultation. Capillaroscopy is a well-established technique to detect capillary abnormalities suggestive of a connective tissue disease, but it is sometimes unavailable. The aim of this study was to compare dermoscopy and capillaroscopy in the assessment of RP. METHODS: This was a prospective single-centre observational study in adult patients consulting for RP at the Hopital Nord Franche-Comte between January 2014 and June 2015. Dermoscopy was performed at dermatological consultations and capillaroscopy was prescribed. For each capillaroscopy and dermoscopy, the following parameters were examined: normal appearance, giant capillaries, avascular areas, dystrophic capillaries or tortuosity and haemorrhages. Kappa coefficients were calculated. RESULTS: Twenty-six patients participated in this study. The kappa coefficient was 0.76 for "normal" status, 0.78 for tortuosity, 0.70 for giant capillaries, 0.48 for haemorrhage and 0.62 for avascular areas. The global kappa coefficient was 0.33. Detection of these abnormalities with capillaroscopy was significantly associated with abnormal dermoscopic status (P<0.05). The sensitivity of dermoscopy for the detection of "abnormal" capillaroscopic status was 0.87. CONCLUSION: The correlation coefficients were good. Despite poor global concordance, 80% of patients had the same status, normal or abnormal, for both capillaroscopy and dermoscopy, which resulted in the same clinical management. Dermoscopy is thus a valuable tool screening for periungual anomalies and provides support for clinical examination by the dermatologist, although the reference method continues to be capillaroscopy. PMID- 28343719 TI - Thromboprophylaxis after Knee Arthroscopy: Out of the Maze? AB - The use of thromboprophylaxis after knee arthroplasty is heterogeneous among orthopedic surgeons. Two recent studies showed that low molecular weight heparin is not effective for preventing venous thromboembolism, whereas thrombotic episodes may be significantly reduced using direct oral anticoagulants, thus opening an interesting perspective for periprocedural management of knee arthroscopy. PMID- 28343721 TI - Is Robotic Kidney Transplant the Near Future? PMID- 28343720 TI - Hydroxy-fipronil is a new urinary biomarker of exposure to fipronil. AB - Occupational medical surveillance is highly desirable in manufacturing facilities where exposure to chemicals is significant. The insecticide fipronil is generally considered safe for humans but with increasing use, exposure to fipronil is of concern. Identification of urinary metabolites of fipronil may allow development of affordable, cheap and rapid procedures for human exposure evaluation. In this study we developed a fast and easy approach for synthesis of hydroxy-fipronil, a potential urinary metabolite of fipronil. This standard was used to develop a sensitive analytical LC-MS/MS method with a limit of quantification (LOQ) of 0.4ng/mL. Fipronil sulfone, a known metabolite, and hydroxy-fipronil were quantified in urine samples from rats treated with a fipronil containing diet. Fipronil sulfone concentration centered around 20ng/mL, while the concentration of hydroxy-fipronil was dose-dependent ranging in 10-10,000ng/mL and thus being a more sensitive marker of fipronil exposure. A fipronil immunoassay with cross reactivity to hydroxy-fipronil showed a good correlation in signal intensity with LC-MS data. It was also used to demonstrate the applicability of the method for sample screening in the evaluation of exposure levels. PMID- 28343722 TI - A newborn saved by embolisation and surgery of a giant teratoma of the orbit. PMID- 28343723 TI - [The search for electrophysiological predictors of visual comfort after presbyopia correction with contact lenses]. AB - Starting at 40 years of age, prespyopia affects a quarter of the world population. Many techniques of presbyopia surgery have emerged in recent years. The purpose of this study was to compare monovision and multifocality and to identify clinical and electrophysiological predictive markers of visual comfort for each correction available in clinical practice. Ten presbyopic patients participated in this study. Patients received monovision and multifocal correction using contact lenses for three weeks each in a random order. A clinical evaluation (visual acuity, TNO test, binocular contrast sensitivity and quality of vision questionnaires) and an electrophysiological evaluation (monocular and binocular pattern VEP with multiple spatial frequencies: 60, 30 and 15') were performed before and after each correction modality. The P100 was significantly wider and slightly earlier after binocular compared to monocular stimulation at T0. The TNO stereopsis score decreased significantly after correction. No other significant differences, either on clinical or electrophysiological criteria, were found between the two modes of correction. Several significant correlations were found between the stereoacuity difference depending upon correction and evoked potentials by binocular pattern at T0. The larger the stereoacuity difference (better stereoacuity with multifocal compensation), the longer the latency of the P100 using 60' checks (R=0.82; P=0.004) and the greater the amplitude of the N75 using 30' (R=0.652; P=0.04). Our study found no differences between the 2 types of correction, but it highlights a benefit of VEP used in current practice and measurement of the P100 wave, the best indicator of stereopsis and the most consistent, to predict visual comfort after compensation presbyopia. PMID- 28343724 TI - Expulsive total iridodialysis through microincision phacoemulsification wound. PMID- 28343725 TI - Newly developed method for mouse olfactory behavior tests using an automatic video tracking system. AB - OBJECTIVE: The mouse is the most popular animal model in olfactory research. Behavior tests with odorants are essential for determining olfactory phenotype. To the best of our knowledge, the mouse olfactory behavior test has not been standardized, making the results vulnerable to inter-observer variation. We sought to develop a new mouse olfactory behavior test assessed by an automatic video tracking system with minimal inter-observer variation. METHODS: A video tracking system was used to automatically track mouse behavior in standard breeding cages with C57BL/6N mice. We tested two odorants (peanut butter for the preference test, 2MB acid for the avoidance test) and distilled water (for a control). Mouse behavior was recorded for 3min and analyzed. For the preference test, investigation time was measured. For the avoidance test, time spent in sectors away from the odorant zone was measured. To confirm our experimental settings, we also evaluated an anosmia mouse model prepared with intranasal administration of ZnSO4. RESULTS: All strains of mice showed reproducible behavior patterns of preference or avoidance for the odorants. The anosmia mouse model, as expected, failed to show an olfactory ability for preference or avoidance, and this was well-matched by histologic changes caused by the ZnSO4 treatment. The automatic video tracking system successfully tracked and automatically calculated mouse behavior with good reproducibility. CONCLUSION: Our olfactory behavior test offers a simple and accurate method to evaluate olfactory function in mice. This test can be utilized as a possible standard method to search for features of olfactory phenotypes in mice. PMID- 28343726 TI - Rapid measurement of low-order aberrations using Fourier transforms of crystalline Ronchigrams. AB - The aberrations of the objective lens should be measured and adjusted to realize high spatial resolution in scanning transmission electron microscopy (STEM). Here we report a method of measuring low-order aberrations using the Fourier transforms of Ronchigrams of an arbitrary crystal such as a specimen of interest. We have applied this technique to measure first- and second-order geometrical aberrations using typical standard specimens. Focus and twofold astigmatism are measured using two Ronchigrams obtained under different foci. Axial coma and threefold astigmatism are evaluated using the Fourier transforms of small subareas of a Ronchigram. The time dependences of focus and twofold astigmatism are examined using this technique for an aberration-corrected microscope. PMID- 28343727 TI - Carbapenemase-producing Acinetobacter baumannii: An outbreak report with special highlights on economic burden. AB - OBJECTIVE: We aimed to describe the management of a carbapenemase-producing Acinetobacter baumannii (CP-AB) outbreak using the Outbreak Reports and Intervention Studies of Nosocomial Infection (ORION) statement. We also aimed to evaluate the cost of the outbreak and simulate costs if a dedicated unit to manage such outbreak had been set-up. METHODS: We performed a prospective epidemiological study. Multiple interventions were implemented including cohorting measures and limitation of admissions. Cost estimation was performed using administrative local data. RESULTS: Five patients were colonized with CP-AB and hospitalized in the neurosurgery ward. The index case was a patient who had been previously hospitalized in Portugal. Four secondary colonized patients were further observed within the unit. The strains of A. baumannii were shown to belong to the same clone and all of them produced an OXA-23 carbapenemase. The closure of the ward associated with the discharge of the five patients in a cohorting area of the Infectious Diseases Unit with dedicated staff put a stop to the outbreak. The estimated cost of this 17-week outbreak was $474,474. If patients had been managed in a dedicated unit - including specific area for cohorting of patients and dedicated staff - at the beginning of the outbreak, the estimated cost would have been $189,046. CONCLUSION: Controlling hospital outbreaks involving multidrug-resistant bacteria requires a rapid cohorting of patients. Using simulation, we highlighted cost gain when using a dedicated cohorting unit strategy for such an outbreak. PMID- 28343728 TI - Can Apparent Diffusion Coefficient Predict the Clinical Outcome in Drowned Children? AB - INTRODUCTION: Pediatric cerebral hypoxic-ischemic injury frequently results in severe neurological outcome. Imaging with diffusion-weighted magnetic resonance imaging (DWi) demonstrates that the acute cerebral injury and apparent diffusion coefficient (ADC) allow the assessment of the severity of brain damage. The main objective was to examine if spatial distribution of reductions in ADC values is associated with clinical outcome in drowned children. METHODS: This is a retrospective study of 7 children (7 examinations) suffering from a hypoxic ischemic event who underwent DWi. Seven subjects with normal DWi served as controls. The mean patient age was 4.88 +/- 2.93 years and the male-to-female ratio was 5:2. The neurological outcome was divided into 2 categories: 4 children with Apallic syndrome and 3 deaths. We analysed the differences between the drowned children and the control group regarding clinical data, DWi abnormalities, and ADC values. RESULTS: The ADC values in the occipital and parietal grey matter were significantly different between the drowned children (765.14 +/- 65.47 vs 920.95 +/- 69.62; P = .003) and the control group (670.82 +/ 233.99 vs 900.66 +/- 92.72; P = .005). The ADC showed low values in the precentral area also (P = .044). CONCLUSION: The ADC reduction may be useful to predict the poor outcome in drowned children and can be a valuable tool for clinical assessment. PMID- 28343729 TI - The ambiguities of performance-based governance reforms in Italy: Reviving the fortunes of evaluation and performance measurement. AB - Over the past two decades, Italy's administrative reforms have institutionalized evaluation to improve program effectiveness, staff productivity, and results driven accountability against waste and corruption. Across ministries, regional governments, universities, schools and environmental protection agencies, seemingly unexpected consequences have emerged out of the implementation of performance measurement and evaluation regimes within public organizations. Formal compliance to legally binding evaluation procedures, judicially-sanctioned managerial accountability and lack of cross-agency coordination coupled with long standing cultural separations among evaluators are some of the ambiguities associated with a performance-based governance system within Italian public administration. Building upon the 'new governane theory,' and qualitative fieldwork, I explore the political consequences of evaluation and performance measurement for possible improvements. From a normative perspective, greater integration between program evaluation and performance measurement can support organizational learning and democratic accountability both at the central and local level. PMID- 28343730 TI - Targeted therapy in small cell lung cancer: A new era? PMID- 28343731 TI - Endoplasmic Reticulum Aminopeptidase 2, a common immunological link to adverse pregnancy outcomes and cancer clearance? AB - Endoplasmic Reticulum Aminopeptidase 2 (ERAP2) trims HLA class I-binding peptides, determining the peptide repertoire presented for immune recognition. Variation in the ERAP2 amino acid sequence could affect the ability of some fetuses and tumors to achieve immune evasion. For example, homozygosity for an ERAP2 variant that has increased trimming efficiency for hydrophobic molecules has never been detected in mothers and fetuses. Thus, it is possible that this single nucleotide polymorphism (SNP) in the ERAP2 gene has been selected against in order to prevent alteration of the immune privileged uterine environment, and to allow tumors to escape immune recognition. Currently, there are no immunological treatments or prophylactic approaches to ensure a healthy pregnancy outcome, and the success of cancer immunotherapies is variable. Understanding the role of ERAP2 in immune evasion mechanisms in pregnancy and cancer may improve fetal survival and tumor clearance. This review summarizes current knowledge about ERAP2 and its N392 variant, and their relationship to pregnancy outcomes and cancer immune evasion/recognition. PMID- 28343732 TI - Ethical issues in non-intervention trials for thyroid cancer. AB - In recent years, the increasing numbers of small, apparently indolent thyroid cancers diagnosed in the world have encouraged investigators to consider non intervention as an alternative to surgical management. In the following pages, the prospect of a non-intervention trial for thyroid cancer is considered with attention to the ethical issues that such a trial might raise. Such a non intervention trial is analyzed relative to 7 ethical considerations: the social or scientific value of the research, the scientific validity of the trial, the necessity of fair selection of participants, a favorable risk-benefit ratio for trial participants, independent review of the trial, informed consent, and allowing the study participants to withdraw from the trial. A non-intervention trial for thyroid cancer is also considered relative to the central concept of equipoise. PMID- 28343733 TI - Low-risk papillary microcarcinoma of the thyroid: A review of active surveillance trials. AB - Papillary microcarcinoma (PMC) of the thyroid is defined as papillary thyroid carcinoma (PTC) measuring <=1 cm. Many autopsy studies on subjects who died of non-thyroidal diseases reported latent small thyroid carcinoma in up to 5.2% of the subjects. A mass screening study for thyroid cancer in Japanese adult women detected small thyroid cancer in 3.5% of the examinees. This incidence was close to the incidence of latent thyroid cancer and more than 1000 times the prevalence of clinical thyroid cancer in Japanese women reported at that time. The question of whether it was correct to treat such PMCs surgically then arose. In 1993, according to Dr. Miyauchi's proposal, Kuma Hospital initiated an active surveillance trial for low-risk PMC as defined in the text. In 1995, Cancer Institute Hospital in Tokyo, Japan, started a similar observation trial. The accumulated data from the trials at these two institutions strongly suggest that active surveillance (i.e., observation without immediate surgery) can be the first-line management for low-risk PMC. Although our data showed that young age and pregnancy might be risk factors of disease progression, we think that these patients can also be candidates for active surveillance, because all of the patients who showed progression signs were treated successfully with a rescue surgery, and none of them died of PTC. In this review, we summarize the data regarding the active surveillance of low-risk PMC as support for physicians and institutions that are considering adopting this strategy. PMID- 28343734 TI - Challenging hierarchy in healthcare teams - ways to flatten gradients to improve teamwork and patient care. AB - In healthcare, mistakes that are potentially harmful or fatal to patients are often the result of poor communication between members of a team. This is particularly important in high-risk areas such as operating theatres or during any intervention, and the ability to challenge colleagues who are in authority when something does not seem right or is clearly wrong, is crucial. Colleagues in oral and maxillofacial surgery recognised the importance of this as early as 2004, and it is now well known that failure or reluctance to challenge others who might be wrong can severely compromise a patient's safety. The Royal College of Surgeons of Edinburgh runs popular regular courses (Non-technical Skills for Surgeons, NOTSS) that teach how to ensure safety through good communication and teamwork. In this paper we introduce the concept of hierarchical challenge, and discuss models and approaches to address situations when problems arise within a team. PMID- 28343735 TI - Safer alternative for extraction of impacted supernumerary teeth of a patient in the mixed dentition stage with the aid of an image-guided operating system. PMID- 28343736 TI - Three-dimensional facial changes correlated with sagittal jaw movements in patients with class III skeletal deformities. AB - The aim of this prospective study was to correlate the postoperative 3 dimensional facial changes in skeletal class III deformity with sagittal jaw movements in 84 patients who had been treated by one piece Le Fort I maxillary advancement only (n=18), mandibular setback only (n=38), or both procedures (n=28). At the times of evaluation before and six months after operation all patients had fixed orthodontic appliances. Soft tissue changes were evaluated on optical 3-dimensional scans, while lateral cephalograms were superimposed to assess sagittal jaw movements. Three-dimensional surface facial scans were divided into 11 regions. We modelled soft tissue changes in each region by linear regression with maxillary (point A) and mandibular (point B) sagittal movements as predictors, and adjusted for sex, age, body mass index, type of operation, and interincisal angle. We found the highest values of regression coefficients (around 0.5) for the sagittal movements of the variables points A and B within the regions of the upper and lower lips. This meant that for each mm of maxillary advancement and mandibular setback, the soft tissue moved 0.5mm. In the sides of the face the regression coefficients were between 0.1 and 0.3, as were those within regions indirectly affected by the operations. PMID- 28343737 TI - Recurrent Mixed Cryoglobulinemia Despite Sustained Virologic Response to Treatment: A Case Report. AB - Cryoglobulinemia is a manifestation of hepatitis C virus (HCV) infection. Treatment of HCV is the mainstay of therapy for mixed cryoglobulinemia syndrome, and newer HCV therapies with direct-acting antiviral agents have achieved great success in treating HCV infection compared with pegylated interferon alfa and ribavirin. Recurrence of mixed cryoglobulinemia syndrome following successful treatment with direct-acting antiviral agents is uncommon, and when it occurs, it is most often due to relapse of HCV viremia. We report a case of recurrent mixed cryoglobulinemia syndrome following HCV treatment with a new direct-acting antiviral agent (sofosbuvir) and ribavirin, in which HCV RNA was undetectable in serum, but detectable in the cryoprecipitate. PMID- 28343738 TI - Short-term association between road traffic noise and healthcare demand generated by Parkinson's disease in Madrid, Spain. AB - OBJECTIVE: To analyse whether there is a short-term association between road traffic noise in the city of Madrid and Parkinson's disease (PD)-related demand for healthcare. METHODS: Time-series analysis (2008-2009) using variables of analysis linked to emergency and daily PD-related demand for healthcare (ICD-10: G20-G21), namely, PD-hospital admissions (HAs), PD-outpatient visits (OVs) and PD emergency medical calls in Madrid. The noise pollution measurements used were Leqd, equivalent sound level for the daytime hours (from 8 a.m. to 10 p.m.), and Leqn, equivalent sound level for night time hours (from 10 p.m. to 8 a.m.) in dB(A). We controlled for temperature, pollution, trends and seasons, and used the Poisson regression model to calculate relative risk (RR). RESULTS: The association between Leqd and HAs was found to be linear. Leqd and Leqn at lag 0.1 and temperature at lags 1 and 5 were the only environmental variables associated with increased PD-related healthcare demand. The RR (lag 0) for Leqd and HA was 1.07 (1.04-1.09), the RR (lag 0) for Leqd and OV was 1.28 (1.12-1.45), and the RR (lags 0.1) for Leqn and emergency medical calls was 1.46 (1.06-2.01). CONCLUSION: The above results indicate that road traffic noise is a risk factor for PD exacerbation. Measures to reduce noise-exposure levels could result in a lower PD related healthcare demand. PMID- 28343739 TI - [Applicability and perceived utility of the European Quality Instrument for Health Promotion (EQUIHP) in a health promotion programme]. AB - OBJECTIVE: To describe the results of applying the European Quality Instrument for Health Promotion (EQUIHP) tool in the MIHsalud programme and to discuss its perceived utility by the programme's team members. METHOD: Evaluation study applying EQUIHP to a health promotion programme. A total of ten MIHsalud staff (eight women and two men) completed the EQUIHP and participated in two group interviews to discuss its perceived utility. RESULTS: The programme obtained a total score of 6.5 points out of 10 in quality. The use of EQUIHP enabled the programme's weaknesses to be identified, such as lack of a communication plan, evaluability and sustainability; as well as its strengths, such as the inclusion of health promotion principles. The MIHsalud team believes that the EQUIHP is a useful tool which can facilitate a comprehensive evaluation of the programme in terms of a health promotion initiative. CONCLUSION: The use of the EQUIHP has made it possible to evaluate the quality of the programme and to make recommendations for its improvement, and it could be applied to other programmes and activities. PMID- 28343740 TI - Pediatric oncology enters an era of precision medicine. AB - With the use of high-throughput molecular profiling technologies, precision medicine trials are ongoing for adults with cancer. Similarly, there is an interest in how these techniques can be applied to tumors in children and adolescents to expand our understanding of the biology of pediatric cancers and evaluate the clinical implications of genomic testing for these patients. This article reviews the early studies in pediatric oncology showing the feasibility of this approach, describe the future plans to evaluate the clinical implications in a multicenter clinical trial and identify the challenges of applying genomics in this patient population. PMID- 28343741 TI - Time as context: The influence of hierarchical patterning on sensory inference. AB - Time, or more specifically temporal structure, is a critical variable in understanding how the auditory system uses acoustic patterns to predict input, and to filter events based on their relevance. A key index of this filtering process is the auditory evoked potential component known as mismatch negativity or MMN. In this paper we review findings of smaller MMN in schizophrenia through the lens of time as an influential contextual variable. More specifically, we review studies that show how MMN to a locally rare pattern-deviation is modulated by the longer-term context in which it occurs. Empirical data is presented from a non-clinical sample confirming that the absence of a stable higher-order structure to sound sequences alters the way MMN amplitude changes over time. This result is discussed in relation to how hierarchical pattern learning might enrich our understanding of how and why MMN amplitude modulation is disrupted in schizophrenia. PMID- 28343742 TI - Automatic matching of surgeries to predict surgeons' next actions. AB - OBJECTIVE: More than half a million surgeries are performed every day worldwide, which makes surgery one of the most important component of global health care. In this context, the objective of this paper is to introduce a new method for the prediction of the possible next task that a surgeon is going to perform during surgery. MATERIAL AND METHOD: We formulate the problem as finding the optimal registration of a partial sequence to a complete reference sequence of surgical activities. We propose an efficient algorithm to find the optimal partial alignment and a prediction system using maximum a posteriori probability estimation and filtering. We also introduce a weighting scheme allowing to improve the predictions by taking into account the relative similarity between the current surgery and a set of pre-recorded surgeries. RESULTS: Our method is evaluated on two types of neurosurgical procedures: lumbar disc herniation removal and anterior cervical discectomy. Results show that our method outperformed the state of the art by predicting the next task that the surgeon will perform with 95% accuracy. CONCLUSIONS: This work shows that, even from the low-level description of surgeries and without other sources of information, it is often possible to predict the next surgical task when the conditions are consistent with the previously recorded surgeries. We also showed that our method is able to assess when there is actually a large divergence between the predictions and decide that it is not reasonable to make a prediction. PMID- 28343743 TI - Controversies in Fibrosis and Emphysema. PMID- 28343744 TI - New technology for recovering residual metals from nonmetallic fractions of waste printed circuit boards. AB - Recycling of waste printed circuit boards is important for environmental protection and sustainable resource utilization. Corona electrostatic separation has been widely used to recycle metals from waste printed circuit boards, but it has poor separation efficiency for finer sized fractions. In this study, a new process of vibrated gas-solid fluidized bed was used to recycle residual metals from nonmetallic fractions, which were treated using the corona electrostatic separation technology. The effects of three main parameters, i.e., vibration frequency, superficial air flow velocity, and fluidizing time on gravity segregation, were investigated using a vibrating gas-solid fluidized bed. Each size fraction had its own optimum parameters. Corresponding to their optimal segregation performance, the products from each experiment were analyzed using an X-ray fluorescence (XRF) and a scanning electron microscope (SEM) equipped with an energy dispersive spectrometer (EDS). From the results, it can be seen that the metal recoveries of -1+0.5mm, -0.5+0.25mm, and -0.25mm size fractions were 86.39%, 82.22% and 76.63%, respectively. After separation, each metal content in the -1+0.5 or -0.5+0.25mm size fraction reduced to 1% or less, while the Fe and Cu contents are up to 2.57% and 1.50%, respectively, in the -0.25mm size fraction. Images of the nonmetallic fractions with a size of -0.25mm indicated that a considerable amount of clavate glass fibers existed in these nonmetallic fractions, which may explain why fine particles had the poorest segregation performance. PMID- 28343745 TI - Feasibility of sulfate-calcined eggshells for removing pathogenic bacteria and antibiotic resistance genes from landfill leachates. AB - High abundance of human pathogen and antibiotic resistance genes (ARGs) in landfill leachate has become an emerging threat against human health. Therefore, sulfate- and calcination-modified eggshells as green agricultural bioresource were applied to test the feasibility of removing pathogenic bacteria and ARGs from leachate. The highest removal of Escherichia coli (E. coil) and gentamycin resistant gene (gmrA) from artificial contaminated landfill leachate was achieved by the application of eggshell with combined treatment of sulfate and calcination. The 16S and gmrA gene copies of E. coil declined significantly from 1.78E8+/-8.7E6 and 4.12E8+/-5.9E6 copies mL-1 to 1.32E7+/-2.6E6 and 2.69E7+/ 7.2E6 copies mL-1, respectively, within 24h dynamic adsorption equilibrium process (p<0.05). Moreover, according to the Langmuir kinetic model, the greatest adsorption amount (1.56*109 CFU E. coil per gram of modified eggshells) could be obtained at neutral pH of 7.5. The optimal adsorption eggshells were then screened to the further application in three typical landfill leachates in Nanjing, eastern China. Significant decrease in species and abundance of pathogenic bacteria and ARGs (tet, sul, erm, qnr, and ampC) indicated its great efficiency to purify landfill leachates. This study demonstrated that sulfate calcined eggshells can be an environmentally-friendly and highly efficient bioadsorbent to the management of reducing dissemination risk of pathogen and ARGs in landfill leachate. PMID- 28343746 TI - Preliminary development of an advanced modular pressure relief cushion: Testing and user evaluation. AB - STUDY AIM: Effective pressure relief cushions are identified as a core assistive technology need by the World Health Organization Global Cooperation on Assistive Technology. High quality affordable wheelchair cushions could provide effective pressure relief for many individuals with limited access to advanced assistive technology. MATERIALS: Value driven engineering (VdE) principles were employed to develop a prototype modular cushion. Low cost dynamically responsive gel balls were arranged in a close packed array and seated in bilayer foam for containment and support. Two modular cushions, one with high compliance balls and one with moderate compliance balls were compared with High Profile and Low Profile Roho(r) and Jay(r) Medical 2 cushions. METHODS: ISO 16480-2 biomechanical standardized tests were applied to assess cushion performance. A preliminary materials cost analysis was carried out. A prototype modular cushion was evaluated by 12 participants who reported satisfaction using a questionnaire based on the Quebec User Evaluation of Satisfaction with Assistive Technology (QUEST 2.0) instrument. RESULTS: Overall the modular cushions performed better than, or on par with, the most widely prescribed commercially available cushions under ISO 16480-2 testing. Users rated the modular cushion highly for overall appearance, size and dimensions, comfort, safety, stability, ease of adjustment and general ease of use. Cost-analysis indicated that every modular cushion component a could be replaced several times and still maintain cost-efficacy over the complete cushion lifecycle. CONCLUSION: A VdE modular cushion has the potential provide effective pressure relief for many users at a low lifetime cost. PMID- 28343747 TI - Unilateral uveitis associated with IgA nephropathy. AB - CASE REPORT: The case is presented of a 42 year-old man with episodes of unilateral uveitis in his right eye. Ophthalmic examination showed a granulomatous anterior uveitis with vitritis. Systemic investigations revealed non-nephrotic proteinuria and microhaematuria. A renal biopsy showed IgA nephropathy. DISCUSSION: Uveitis and glomerulonephritis may have common immunological pathogenesis. IgA nephropathy should be a differential diagnosis in patients with uveitis and nephropathy. PMID- 28343749 TI - Manual calf massage and passive ankle motion reduce the incidence of deep vein thromboembolism after total hip arthroplasty. AB - BACKGROUND: Venous thromboembolism is one of the general complications following total hip arthroplasty, wherein various preventive treatments have been recommended. Several studies reported that venous thromboembolism incidence after total hip arthroplasty was similar in patients who were administered prophylaxis with a conventional mechanical procedure alone, and those who were administered pharmacological anticoagulation therapy. Therefore, the optimum methods of prophylaxis are still controversial. The purpose of this study was to investigate whether manual calf massage and passive ankle motion could lower the risk for venous thromboembolism after total hip arthroplasty. METHODS: We retrospectively reviewed the data of 126 consecutive patients undergoing elective primary unilateral total hip arthroplasty wherein manual calf massage and passive ankle motion were performed after the surgery at our hospitals between January and October 2014. The 138 patients of the control group underwent total hip arthroplasty using the same surgical approach and pre- and postoperative protocols without this mechanical prophylaxis between January and December 2013. This mechanical prophylaxis was performed simultaneously 30 times during approximately 10 s; these procedures were repeated thrice immediately after total hip arthroplasty. Duplex ultrasonography was performed to observe the veins of both legs in all the patients on postoperative day 7. RESULTS: The incidence of deep vein thrombosis was 6.52% and 0.79% in the control and manual calf massage and passive ankle motion groups, respectively. The odds ratio for the manual calf massage and passive ankle motion groups was 8.72. Performing this mechanical prophylaxis reduced the incidence of venous thromboembolism after total hip arthroplasty. This mechanical prophylaxis is not only simple and easy, but is also safe and inexpensive. CONCLUSIONS: We therefore recommend that manual calf massage and passive ankle motion be performed in patients who will undergo total hip arthroplasty, if deep vein thrombosis does not exist before the surgery. PMID- 28343750 TI - Academic Remediation: Why Early Identification and Intervention Matters. AB - At our institution, we have developed a remediation team of strong, focused experts who help us with struggling learners in making the diagnosis and then coaching on their milestone deficits. It is key for all program directors to recognize struggling residents because early recognition and intervention gives the resident the best chance of success. PMID- 28343748 TI - B cells expressing the IgA receptor FcRL4 participate in the autoimmune response in patients with rheumatoid arthritis. AB - The clinical efficacy of B cell targeting therapies highlights the pathogenic potential of B cells in inflammatory diseases. Expression of Fc Receptor like 4 (FcRL4) identifies a memory B cell subset, which is enriched in the joints of patients with rheumatoid arthritis (RA) and in mucosa-associated lymphoid tissue. The high level of RANKL production by this B cell subset indicates a unique pathogenic role. In addition, recent work has identified a role for FcRL4 as an IgA receptor, suggesting a potential function in mucosal immunity. Here, the contribution of FcRL4+ B cells to the specific autoimmune response in the joints of patients with RA was investigated. Single FcRL4+ and FcRL4- B cells were sorted from synovial fluid and tissue from RA patients and their immunoglobulin genes characterized. Levels of hypermutation in the variable regions in both populations were largely consistent with memory B cells selected by an antigen- and T cell-dependent process. Recombinant antibodies were generated based on the IgH and IgL variable region sequences and investigated for antigen specificity. A significantly larger proportion of the recombinant antibodies generated from individual synovial FcRL4+ B cells showed reactivity towards citrullinated autoantigens. Furthermore, both in analyses based on heavy chain sequences and flow cytometric detection, FcRL4+ B cells have significantly increased usage of the IgA isotype. Their low level of expression of immunoglobulin and plasma cell differentiation genes does not suggest current antibody secretion. We conclude that these activated B cells are a component of the local autoimmune response, and through their RANKL expression, can contribute to joint destruction. Furthermore, their expression of FcRL4 and their enrichment in the IgA isotype points towards a potential role for these cells in the link between mucosal and joint inflammation. PMID- 28343751 TI - Presbyopic and non-presbyopic contact lens opinions and vision correction preferences. AB - PURPOSE: To compare vision correction preferences, refractive error, and gender of non-presbyopes and presbyopes. METHODS: Adults who wear spectacles or contact lenses completed a survey about refractive correction opinions and refractive error was measured. RESULTS: Of the 304 subjects, 38.2% were presbyopic (>=40 years) and 59.2% were female. Spectacles were the primary vision correction for 78.0% of subjects. Compared to contact lens wearers, the proportion of presbyopes was higher (p=0.006) in spectacle wearers. There was no difference in the proportion of presbyopes and non-presbyopes who have tried contact lenses (p=0.2) or who would prefer to wear contact lenses (p=0.2). In contact lens wearers, there was no difference in the proportion of presbyopes and non-presbyopes with a history of temporary discontinuation (p=0.9). Within the contact lens wearing group, there was no refractive error difference between presbyopes and non presbyopes (spherical equivalent p=0.6; power vector J0 p=0.5; power vector J45 p=0.4; anisometropia p=0.2). Overall, contact lens wearers were more likely to be female (p=0.004). There was no difference in gender in presbyopic and non presbyopic contact lens wearers (p=0.5). CONCLUSIONS: Presbyopes and non presbyopes have similar opinions about spectacles and contact lenses. Presbyopes of all refractive errors prefer contact lens correction when good vision and comfort can be achieved. Eye care providers should not assume that presbyopia, refractive error, or gender are factors that preclude a patient from being interested in contact lens wear. PMID- 28343752 TI - Efficacy of tedizolid against methicillin-resistant Staphylococcus aureus and Peptostreptococcus anaerobius in thigh mixed-infection mouse model. AB - OBJECTIVE: The purpose of this study is to compare the antimicrobial activity of human simulated exposures of tedizolid 200 mg daily, and linezolid 600 mg every 12 h for the treatment of complicated skin and skin structure infection (cSSSI) caused by MRSA and Peptostreptococcus anaerobius in both the neutropenic mice thigh mixed-infection models. MATERIAL AND METHOD: Tedizolid phosphate and linezolid were used for all in vivo testing. A total of one MRSA and two P. anaerobius isolates were utilized. Antimicrobial efficacy was calculated for each isolate as the change in bacterial numbers (Deltalog10 CFU/ml) obtained in the treated mice after 24 h compared with the numbers in the starting control animals (0 h). RESULTS: The tedizolid and linezolid MICs for MRSA was 0.25 and 2 MUg/ml. Tedizolid MIC for P. anaerobius was 0.12 MUg/ml, and linezolid MICs for two P. anaerobius isolates were 0.5 and 1 MUg/ml. In mixed infection model, tedizolid therapy showed similar antimicrobial activities for one MRSA and two P. anaerobius isolates evaluated, compared with linezolid therapy. Additionally, when comparing the activity of tedizolid and linezolid monotherapy between single infection and mixed infection model, antimicrobial activities of both antimicrobials were attenuated when mixed infection model was used. CONCLUSION: In the neutropenic murine thigh infection model, human simulated exposures of tedizolid and linezolid resulted in similar efficacies against MRSA, even though single and mixed infection models were used. These data support the clinical utility of tedizolid for use against MRSA and P. anaerobius in the treatment of cSSSI. PMID- 28343754 TI - Feeding a cancer patient: Much more than supportive care. PMID- 28343753 TI - Limnothrix sp. KO05: A newly characterized cyanobacterial biosorbent for cadmium removal: the enzymatic and non-enzymatic antioxidant reactions to cadmium toxicity. AB - In this study, we isolated five indigenous cyanobacterial strains from different aqueous environments, with heavy metals contamination, in East Azerbaijan Province (northwest portion of Iran). A strain was identified by morphological and 16S rRNA sequence analysis as Limnothrix sp. KO05 and selected for further studies as having the greatest potential for cadmium uptake. Scanning electron microscopy (SEM) demonstrated cyanobacterium Limnothrix sp. KO05 forms filamentous structures and is straight or curved to some extent. The utmost biosorption capacity was found to be 82.18+/-1.22mgg-1 at a Cd (II) concentration level of 150mgL-1. Langmuir adsorption isotherm indicated a better fit to the experimental data. Response surface methodology (RSM) on the basis of four independent variables and the predicted maximum biosorption efficiency was 98.7% under the optimum condition. FT-IR spectroscopy profile of the Cd treated sample as demonstrated in confirmation of the benefits of various functional groups of proteins and polysaccharides of cyanobacterial biomass, involved in surface binding of Cd. The determination of catalase (CAT) activity in strain KO05 exposed to Cd (II) concentrations of 2, 5 and 10mgL-1 showed an increase in enzyme activity after 24h exposure compared to unexposed cells. Correspondingly, CAT activity showed a significant decrease after 48h of treatment with Cd (II) concentrations of 5 and 10mgL-1. CAT activity was decreased significantly at all concentrations within 72h after exposure to Cd. On the contrary, while ascorbate peroxidase (APX) gave the expected lower activity compared to the CAT within 24h after Cd treatment, its activity lasted up to 72h. Limnothrix sp. KO05 cells treated with 5 and 10mgL-1 Cd (II) over 72h exposure showed a reduction in chlorophyll a contents compared to the controls. However, following exposure to Cd, chlorophyll a and carotenoid contents is reduced and after overcoming stress and deployment of an adaptation mechanism, the amounts of these pigments is gradually increased in the cells. The reduction was slower for chlorophyll a pigment compared to carotenoids that may be an indication of the physiological importance of chlorophyll pigment for the phtosynthetic cells. Results related to lipid peroxidation in Limnothrix sp. KO05 represent a significant increase of MDA in the first 24h after exposure to the different concentrations of Cd (2, 5 and 10mgL-1). However, the MDA levels were decreased over time and no significant difference attained after 72h exposure to Cd concentrations of 2 and 10mgL-1 compared to control. PMID- 28343756 TI - Inhibition of Malassezia globosa carbonic anhydrase with phenols. AB - A panel of 22 phenols was investigated as inhibitors of the beta-class carbonic anhydrase (CAs, EC 4.2.1.1) from the fungal parasite Malassezia globosa (MgCA), a validated anti-dandruff drug target. The displayed inhibitory activities were compared to the ones previously reported against the off-target widely distributed human (h) isoforms hCA I and II. All tested phenols possessed a better efficacy in inhibiting MgCA than the clinically used sulfonamide acetazolamide, with KIs in the range of 2.5 and 65.0MUM. A homology-built model of MgCA was also used for understanding the binding mode of phenols to the fungal enzyme. Indeed, a wide network of hydrogen bonds and hydrophobic interactions between the phenol and active site residues were evidenced. The OH moiety of the inhibitor was observed anchored to the zinc-coordinated water, also making hydrogen bonds with Ser48 and Asp49. The diverse substituents at the phenolic scaffold were observed to interact with different portions of the hydrophobic pocket according to their nature and position. Considering the effective MgCA inhibitory properties of phenols, beside to the rather low inhibition against the off-target hCA I and II, this class of compounds might be of considerable interest in the cosmetics field as potential anti-dandruff drugs. PMID- 28343755 TI - Covalently linked kanamycin - Ciprofloxacin hybrid antibiotics as a tool to fight bacterial resistance. AB - To address the growing problem of antibiotic resistance, a set of 12 hybrid compounds that covalently link fluoroquinolone (ciprofloxacin) and aminoglycoside (kanamycin A) antibiotics were synthesized, and their activity was determined against both Gram-negative and Gram-positive bacteria, including resistant strains. The hybrids were antagonistic relative to the ciprofloxacin, but were substantially more potent than the parent kanamycin against Gram-negative bacteria, and overcame most dominant resistance mechanisms to aminoglycosides. Selected hybrids were 42-640 fold poorer inhibitors of bacterial protein synthesis than the parent kanamycin, while they displayed similar inhibitory activity to that of ciprofloxacin against DNA gyrase and topoisomerase IV enzymes. The hybrids showed significant delay of resistance development in both E. coli and B. subtilis in comparison to that of component drugs alone or their 1:1 mixture. More generally, the data suggest that an antagonistic combination of aminoglycoside-fluoroquinolone hybrids can lead to new compounds that slowdown/prevent the emergence of resistance. PMID- 28343757 TI - Clinical utility of newly developed highly purified human menopausal gonadotrophins: a randomized controlled trial. AB - The aim of this study was to evaluate the safety and efficacy of IVF-M HP, a newly developed highly purified human menopausal gonadotrophin preparation, for ovarian stimulation in women with infertility undergoing IVF, intracytoplasmic sperm injection (IVF-ICSI) and embryo transfer using a GnRH antagonist protocol. This was a multicentre, randomized, active-controlled, parallel design, open label, non-inferiority clinical study. Of the 112 patients randomized for treatment using the GnRH antagonist protocol, 111 were treated. No significant difference was found in the number of oocytes retrieved from the IVF-M HP and Menopur groups (13.1 +/- 7.6 versus 10.3 +/- 6.7, respectively). The lower limit of the one-sided 97.5% confidence interval for the difference between the groups was -0.25, i.e., greater than the pre-defined non-inferiority margin (-5). Therefore, the IVF-M HP treatment was considered non-inferior to Menopur. Furthermore, no significant difference was observed between the groups in the number of good-quality oocytes, leading follicles, good-quality embryos, or in fertilization, implantation, positive beta-HCG and clinical pregnancy rates. The safety analysis revealed that 40.4% and 35.2% in the IVF-M HP and Menopur groups, respectively, reported adverse events. In conclusion, IVF-M HP had comparable clinical efficacy and safety profiles to Menopur. PMID- 28343758 TI - Synergistic Expression of Histone Deacetylase 9 and Matrix Metalloproteinase 12 in M4 Macrophages in Advanced Carotid Plaques. AB - OBJECTIVE/BACKGROUND: Expression patterns and association with cell specific gene expression signatures of the epigenetic regulator histone deacetylase 9 (HDAC9) and matrix metalloproteinase 12 (MMP12) in human plaque are not known. METHODS: This was a prospective cohort study. Genome wide expression analysis was performed in carotid, femoral, aortic plaques (n = 68) and left internal thoracic (LITA) controls (n = 28) and plaque histological severity assessed. Correlation and hierarchical cluster analysis was utilised. RESULTS: HDAC9 was associated with MMP12 expression in carotid plaques (r = .46, p = .012) and controls (r = .44, p = .034). HDAC9 and MMP12 clustered with inflammatory macrophage markers but not with smooth muscle cell (SMC) rich markers. In plaques from all arterial sites, MMP12 but not HDAC9 showed positive correlation (p < .05) with M2 and M4 polarized macrophage markers, and negative correlation with SMC rich signatures. In the carotid plaques, all M4 macrophage markers associated with MMP12 and HDAC9. The negative association of MMP12 with SMC rich signatures was pronounced in the carotid plaques. Neither HDAC9 nor MMP12 associated consistently with plaque stabilisation or thrombosis related genes. Immunohistochemistry further supported the association between HDAC9 and MMP12 in atherosclerotic plaques. CONCLUSION: M4 macrophages are a possible source for HDAC9 and MMP12 expression in advanced human plaques. PMID- 28343760 TI - Perceptual Decision-Making: Picking the Low-Hanging Fruit? AB - How do we decide what we perceive? Obviously, we base our decisions on sensory evidence. However, a new and surprising study by Hagura et al. shows that our perceptual decisions are also biased by the action costs that are associated with our decisions. PMID- 28343759 TI - Incidence of Postsuppression Virologic Rebound in Perinatally HIV-Infected Asian Adolescents on Stable Combination Antiretroviral Therapy. AB - PURPOSE: To assess the incidence and predictors of postsuppression virologic rebound (VR) among adolescents on stable combination antiretroviral therapy in Asia. METHODS: Perinatally HIV-infected Asian adolescents (10-19 years) with documented virologic suppression (two consecutive viral loads [VLs] <400 copies/mL >=6 months apart) were included. Baseline was the date of the first VL <400 copies/mL at age >=10 years or the 10th birthday for those with prior suppression. Cox proportional hazards models were used to identify predictors of postsuppression VR (VL >1,000 copies/mL). RESULTS: Of 1,379 eligible adolescents, 47% were males. At baseline, 22% were receiving protease inhibitor-containing regimens; median CD4 cell count (interquartile range [IQR]) was 685 (448-937) cells/mm3; 2% had preadolescent virologic failure (VF) before subsequent suppression. During adolescence, 180 individuals (13%) experienced postsuppression VR at a rate of 3.4 (95% confidence interval: 2.9-3.9) per 100 person-years, which was consistent over time. Median time to VR during adolescence (IQR) was 3.3 (2.1-4.8) years. Wasting (weight-for-age z-score < 2.5), being raised by grandparents, receiving second-line protease inhibitor based regimens, starting combination antiretroviral therapy after 2005, and having preadolescent VF were independent predictors of adolescent VR. At VR, median age, CD4 cell count, and VL (IQR) were 14.8 (13.2-16.4) years, 507 (325 723) cells/mm3, and 4.1 (3.5-4.7) log10 copies/mL, respectively. CONCLUSIONS: A modest and consistent incidence of postsuppression VR was documented during adolescence in our cohort. Having poor weight, receiving second-line regimens, and prior VF were associated with an increased VR rate. Adolescents at higher risk of VR may benefit from more intensive VL monitoring to enhance adherence management. PMID- 28343761 TI - Isolated diastolic hypertension and incident heart failure in community-dwelling older adults: Insights from the Cardiovascular Health Study. AB - BACKGROUND: Isolated systolic hypertension and isolated diastolic hypotension are common in older adults and associated with a higher risk of incident heart failure (HF). However, little is known about the prevalence and impact of isolated diastolic hypertension in this population. METHODS: In the Cardiovascular Health Study (CHS), of the 5776 community-dwelling older adults >=65years who had data on baseline systolic and diastolic blood pressure (SBP and DBP), 28 had isolated diastolic hypertension (DBP >=90mmHg and SBP <140mmHg). From the 5748 without isolated diastolic hypertension, we excluded those with SBP >=120mmHg (n=4451), DBP 80-89mmHg (n=20), DBP <60mmHg (n=425), normal BP taking anti-hypertensive medications (n=311), normal BP taking no anti-hypertensive medications but with history of hypertension (n=38), and baseline HF (n=5). The final cohort of 524 participants included 27 with isolated diastolic hypertension. RESULTS: Patients (n=524) had a mean (+/-SD) age of 71 (+/-5) years, 58% were women and 9% African American. There were no significant between group age or sex differences; 37% of those with isolated diastolic hypertension (versus 7% without) were African American. Incident HF occurred in 19% and 7% of participants with and without isolated diastolic hypertension, respectively (multivariable-adjusted hazard ratio {HR}, 4.65; 95% confidence interval {CI}, 1.09-19.90; p=0.038). There was a trend toward higher cardiovascular mortality (HR, 4.59; 95% CI, 0.92-23.88; p=0.063). CONCLUSION: Among community-dwelling older adults, isolated diastolic hypertension is rare and is associated with higher risk for incident HF and cardiovascular mortality. PMID- 28343762 TI - Clozapine and incidence of myocarditis and sudden death - Long term Australian experience. AB - BACKGROUND: Clozapine is the cornerstone of therapy for refractory schizophrenia; however, the potential for cardiotoxicity is an important limitation in its use. In the current analysis we sought to evaluate the long term cardiac outcomes of clozapine therapy. METHODS: All-cause mortality, incidence of sudden death and time to myocarditis were assessed in a cohort of patients maintained on clozapine between January 2009 and December 2015. All patients had regular electrocardiograms, complete blood count, clozapine levels and echocardiography as part of a formal protocol. RESULTS: A total of 503 patients with treatment resistant schizophrenia were maintained on clozapine during the study period of which 93 patients (18%) discontinued therapy with 29 (6%) deaths. The incidence of sudden death and myocarditis were 2% (n=10) and 3% (n=14) respectively. Amongst patients with sudden death, 7 out of 10 (70%) were documented to have used illicit drugs prior to death, with a tendency to weight gain also noted. The mean time to myocarditis post clozapine commencement was 15+/-7days. The reduction in left ventricular ejection fraction in those with myocarditis was 11+/-2%. CONCLUSION: Myocarditis and sudden cardiac death are uncommon but clinically important complications in a cohort of patients followed while maintained on clozapine undergoing regular cardiac assessment. Further studies are required to document the role of preventive measures for left ventricular dysfunction and sudden cardiac death in this population. PMID- 28343763 TI - Identifying high-risk post-infarction patients by autonomic testing - Below the tip of the iceberg. AB - Despite major advances in medical therapies late mortality after myocardial infarction (MI) is still high. A substantial proportion of post-MI patients die from sudden cardiac death. Prophylactic implantable-cardioverter defibrillator (ICD) therapy has been established for post-MI patients with reduced left ventricular ejection fraction (LVEF <=35%). However, most patients who die after MI have an LVEF >35%. For this large group of patients, no specific prophylactic strategies exist. There is strong evidence that measures of cardiac autonomic dysfunction after MI provide important prognostic information in post-MI patients with preserved LVEF. Combinations of autonomic markers can identify high-risk patients after MI with LVEF >35% whose prognosis is equally worse than that of patients with LVEF <=35%. The ongoing REFINE-ICD (NCT00673842) and SMART-MI trials (NCT02594488) test different preventive strategies in high-risk post-MI patients with cardiac autonomic dysfunction and LVEF 36-50%. While REFINE-ICD follows the traditional concept of ICD-implantation, SMART-MI uses implantable cardiac monitors with remote monitoring capabilities to sensitively detect asymptomatic, but prognostically relevant arrhythmias that could trigger specific diagnostic and therapeutic interventions. PMID- 28343764 TI - Channelopathies, genetic testing and risk stratification. AB - The cardiac channelopathies are a group of diseases with (disease-) specific electrocardiographic (ECG) characteristics and a disease-specific risk of sudden cardiac death (SCD). This group includes the Long QT Syndromes (LQTS), Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), Brugada Syndrome (BrS), Short QT Syndromes (SQTS), and Early Repolarization Syndrome (ERS). In the past 2 decades the genetic basis for these disease entities has largely been unraveled and that, together with the identification of the genetic basis of the cardiomyopathies, has paved the way for the complete new field of Cardiogenetics. By virtue of the identification of the genetic underpinning of a given disease, presymptomatic carriers of the genetic aberrancy can be identified and timely treatment can be installed. In addition, it has become clear that the pathophysiological substrate of some diseases previously considered to be one disease is not identical, and this has led to gene-specific treatment in some and complete new treatment, based on the newly developed insight, in others. Finally, the genetic information proved to be important in the prediction of risk on lethal ventricular arrhythmias of affected individuals and that is the topic of this brief review. PMID- 28343765 TI - Human cardiac progenitor cells with regenerative potential can be isolated and characterized from 3D-electro-anatomic guided endomyocardial biopsies. AB - AIMS: In the present study, we aimed to develop a percutaneous approach and a reproducible methodology for the isolation and expansion of Cardiac Progenitor Cells (CPCs) from EndoMyocardial Biopsies (EMB) in vivo. Moreover, in an animal model of non-ischemic heart failure (HF), we would like to test whether CPCs obtained by this methodology may engraft the myocardium and differentiate. METHODS AND RESULTS: EMB were obtained using a preformed sheath and a disposable bioptome, advanced via right femoral vein in 12 healthy mini pigs, to the right ventricle. EMB were enzymatically dissociated, cells were expanded and sorted for c-kit. We used 3D-Electro-Anatomic Mapping (3D-EAM) to obtain CPCs from 32 patients affected by non-ischemic cardiomyopathy. The in vivo regenerative potential of CPCs was tested in a rodent model of drug-induced non-ischemic cardiomyopathy. c-kit positive CPCs replicative capacity was assessed in 30 patients. Telomere length averaged 7.4+/-0.4kbp and telomerase activity was present in all preparations (1.7*105 copies). The in situ hybridization experiments showed that injected human CPCs may acquire a neonatal myocyte phenotype given the expression of the alpha-sarcomeric actin together with the presence of the Alu probe, suggesting a beneficial impact on LV performance. CONCLUSIONS: The success in obtaining CPCs characterized by high regenerative potential, in vitro and in vivo, from EMB indicates that harvesting without thoracotomy in patients affected by either ischemic or non-ischemic cardiomyopathy is feasible. These initial results may potentially expand the future application of CPCs to all patients affected by HF not undergoing surgical procedures. PMID- 28343766 TI - Prediction of high on-treatment platelet reactivity in clopidogrel-treated patients with acute coronary syndromes. AB - BACKGROUND: About 40% of clopidogrel-treated patients display high platelet reactivity (HPR). Alternative treatments of HPR patients, identified by platelet function tests, failed to improve their clinical outcomes in large randomized clinical trials. A more appealing alternative would be to identify HPR patients a priori, based on the presence/absence of demographic, clinical and genetic factors that affect PR. Due to the complexity and multiplicity of these factors, traditional statistical methods (TSMs) fail to identify a priori HPR patients accurately. The objective was to test whether Artificial Neural Networks (ANNs) or other Machine Learning Systems (MLSs), which use algorithms to extract model like 'structure' information from a given set of data, accurately predict platelet reactivity (PR) in clopidogrel-treated patients. METHODS: A complete set of fifty-nine demographic, clinical, genetic data was available of 603 patients with acute coronary syndromes enrolled in the prospective GEPRESS study, which showed that HPR after 1month of clopidogrel treatment independently predicted adverse cardiovascular events in patients with Syntax Score >14. Data were analysed by MLSs and TSMs. ANNs identified more variables associated PR at 1month, compared to TSMs. RESULTS: ANNs overall accuracy in predicting PR, although superior to other MLSs was 63% (95% CI 59-66). PR phenotype changed in both directions in 35% of patients across the 3 time points tested (before PCI, at hospital discharge and at 1month). CONCLUSIONS: Despite their ability to analyse very complex non-linear phenomena, ANNs or MLS were unable to predict PR accurately, likely because PR is a highly unstable phenotype. PMID- 28343767 TI - Neural cell adhesion molecule expression in dilated cardiomyopathy is associated with intramyocardial inflammation and hypertrophy. AB - Chronic intramyocardial inflammation (inflammatory cardiomyopathy/DCMi) is linked to the pathogenesis of dilated cardiomyopathy (DCM). Neural cell adhesion molecule (NCAM) is involved in orchestrating cardiac muscle morphogenesis, but is down-regulated after embryogenesis. We investigated NCAM expression in adult DCM hearts, its possible association with DCMi-parameters, and with cardiomyocyte hypertrophy (CMH). Endomyocardial biopsies (EMBs) from DCM patients (n=85; n=37 females; age: 48+/-19years; LVEF <40%) and controls from non-cardiac deaths were immunostained for DCMi markers and for NCAM expression, and quantified by digital image analysis (DIA). NCAM expression on the intercalated discs and the sarcolemma was confirmed in n=46 (54%) of the DCM-EMBs. In the 17 controls, NCAM expression was confined to scattered intramyocardial nerves, but was absent on cardiomyocytes. DIA-quantified area fraction (AF) of NCAM was significantly (p=0.0001) higher in the DCM hearts (0.0044+/-0.017) compared with the controls (0.0006+/-0.0004). Multivariate analysis of DIA-quantified NCAM-AF revealed significant associations with infiltrates (CD18+, CD11a/LFA-1+, CD11b/Mac-1+, TNFalpha+, CD3+) and with endothelial cell adhesion molecules (CAM; CD54/ICAM-1 and CD29; p<0.05). The mean cardiomyocyte diameter (MCD) correlated highly significantly (p<0.01) with NCAM-AF, ICAM-1-AF, CD29-AF, CD18+ and TNFa+ infiltrates, and was associated less significantly (p<0.05) with CD3+, CD11a/LFA 1+, and CD11b/Mac-1+ infiltrates. In conclusion, NCAM-expression in ca. 50% of adult DCM hearts is associated with CMH, and may be induced by inflammatory pathways. PMID- 28343768 TI - Successful Spontaneous Conception and Live Birth in a Woman with an Extremely Low Level of Anti-Mullerian Hormone Who Received Korean Herbal Medicine (Bogungsamul tang): A Case Report. AB - Conventional treatments do not appreciably improve fecundity in women with extremely low-serum levels of anti-Mullerian hormone (AMH). In Korea, herbal medicine is widely used to treat female infertility. We report a case in which an infertile woman with a very low AMH level naturally conceived after two months of herbal treatment (Bogungsamul-tang), ultimately giving birth to a full-term baby. Although AMH levels were not measured immediately before and after treatment, our study suggests that Korean herbal remedies are a viable option for infertile women with negligible AMH levels. Further studies should be performed to fully assess the clinical effects of Bogungsamul-tang in such women. PMID- 28343769 TI - Response to "Collating science-based evidence to inform public opinion on the environmental effects of marine drilling platforms in the Mediterranean Sea". AB - In their recent review article, Mangano and Sera (Journal of Environmental Management, 188:195-202) collate and describe the evidence base relating to the impacts of marine drilling platforms in the Mediterranean. The authors claim to have undertaken a systematic map using the Guidelines for Systematic Review in Environmental Management produced by the Collaboration for Environmental Evidence (CEE) as a basis for their methods. Here, I highlight major problems with their methods and the reporting of their activities. I demonstrate that a higher level of rigour and transparency is necessary for a true systematic map. Whilst their work is not without merit and may prove useful for decision-makers, their review could have been conducted and reported to a greater level of reliability. I stress the importance of transparency, comprehensiveness, and repeatability in ensuring that reviews are reliable and fit-for-purpose. I highlight the pitfalls of the authors' approach in terms of: question framing; searching for evidence; the definition of grey literature; key outputs from systematic maps; and the dangers of vote-counting. PMID- 28343770 TI - Epidemiology of varicella in Haidian district, Beijing, China-2007-2015. AB - BACKGROUND: 1-Dose varicella vaccination was recommended for children in Beijing before November 2012. To further control school-based outbreaks and decrease incidence, a 2-dose vaccination was implemented in 2013. We described the varicella epidemiology and assessed impact of the 2-dose vaccination in Haidian district, Beijing, 2007-2015. METHODS: We examined the estimated incidence and disease characteristics of varicella during 2007-2015 and obtained the 1-dose vaccination coverage for children born during 2005-2013. Number of vaccine doses given was used to indirectly reflect the second-dose vaccination coverage. Overall and age-specific estimated incidences were compared between 2007-2012 and 2013-2015. RESULTS: A total of 23,497 cases were reported during 2007-2015. Of the 23,497 cases, 13,440 (57.20%) were male, and 68.40% were <20years of age and 70.02% were students and children in kindergarten. The estimated incidence increased from 82 cases per 100,000 population in 2007 to 104 in 2011, before substantially decreasing from 86 in 2012 to 56 in 2015. The median age increased from 14years in 2007 to 18years in 2015. The 1-dose varicella coverage for children at >=2years of age gradually increased from 74.21% in 2007 to 90.06% in 2015. Compared with 2007-2012, two-fold average vaccine doses were given during 2013-2015, and the overall estimated incidence declined by 34.4%, particularly in children aged 5-9years, with a significantly declined trend in children aged 1 9years and older adolescents aged 15-19years and non-significantly declined trend in adults aged >=20years, but a significant increasing trend in infants. CONCLUSIONS: The overall incidence of varicella has decreased substantially in Haidian district since 2013, with largest decline in children aged 5-9years. The 2-dose varicella vaccination might not lead to increase in incidence in adults. Long-term surveillance is needed to fully evaluate the long-term impact of the 2 dose varicella vaccination. PMID- 28343771 TI - Characterization of human monoclonal antibodies that neutralize multiple poliovirus serotypes. AB - Following the eradication of wild poliovirus (PV), achieving and maintaining a polio-free status will require eliminating potentially pathogenic PV strains derived from the oral attenuated vaccine. For this purpose, a combination of non cross-resistant drugs, such as small molecules and neutralizing monoclonal antibodies (mAbs), may be ideal. We previously isolated chimpanzee and human mAbs capable of neutralizing multiple PV types (cross-neutralization). Here, we describe three additional human mAbs that neutralize types 1 and 2 PV and one mAb that neutralizes all three types. Most bind conformational epitopes and have unusually long heavy chain complementarity determining 3 domains (HC CDR3). We assessed the ability of the mAbs to neutralize A12 escape mutant PV strains, and found that the neutralizing activities of the mAbs were disrupted by different amino acid substitutions. Competitive binding studies further suggested that the specific mAb:PV interactions that enable cross-neutralization differ among mAbs and serotypes. All of the cloned mAbs bind PV in the vicinity of the "canyon", a circular depression around the 5-fold axis of symmetry through which PV recognizes its cellular receptor. We were unable to generate escape mutants to two of the mAbs, suggesting that their epitopes are important for the PV life cycle. These data indicate that PV cross-neutralization involves binding to highly conserved structures within the canyon that binds to the cellular receptor. These may be facilitated by the long HC CDR3 domains, which may adopt alternative binding configurations. We propose that the human and chimpanzee mAbs described here could have potential as anti-PV therapeutics. PMID- 28343772 TI - Report of the WHO technical consultation on the effect of maternal influenza and influenza vaccination on the developing fetus: Montreal, Canada, September 30 October 1, 2015. AB - In 2012, the World Health Organization (WHO) released a position paper on influenza vaccination recommending that pregnant women have the highest priority for seasonal vaccination in countries where the initiation or expansion of influenza immunization programs is under consideration. Although the primary goal of the WHO recommendation is to prevent influenza illness in pregnant women, the potential benefits of maternal immunization in protecting young infants are also recognized. The extent to which maternal influenza vaccination may prevent adverse birth outcomes such as preterm birth or small-for-gestational-age birth, however, is unclear as available studies are in disagreement. To inform WHO about the empirical evidence relating to possible benefits of influenza vaccination on birth outcomes, a consultation of experts was held in Montreal, Canada, September 30-October 1, 2015. Presentations and discussions covered a broad range of issues, including influenza virus infection during pregnancy and its effect on the health of the mother and the fetus, possible biological mechanisms for adverse birth outcomes following maternal influenza illness, evidence on birth outcomes following influenza illness during pregnancy, evidence from both observational studies and randomized controlled trials on birth outcomes following influenza vaccination of pregnant women, and methodological issues. This report provides an overview of the presentations, discussions and conclusions. PMID- 28343773 TI - Enhancing heterologous protection in pigs vaccinated with chimeric porcine reproductive and respiratory syndrome virus containing the full-length sequences of shuffled structural genes of multiple heterologous strains. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is the causative agent of arguably the most economically important global swine disease. The extensive genetic variation of PRRSV strains is a major obstacle for heterologous protection of current vaccines. Previously, we constructed a panel of chimeric viruses containing only the ectodomain sequences of DNA-shuffled structural genes of different PRRSV strains in the backbone of a commercial vaccine, and found that one chimeric virus had an improved cross-protection efficacy. In this present study, to further enhance the cross-protective efficacy against heterologous strains, we constructed a novel chimeric virus VR2385-S3456 containing the full-length sequences of shuffled structural genes (ORFs 3-6) from 6 heterologous PRRSV strains in the backbone of PRRSV strain VR2385. We showed that the chimeric virus VR2385-S3456 induced a high level of neutralizing antibodies in pigs against two heterologous strains. A subsequent vaccination and challenge study in 48 pigs revealed that the chimeric virus VR2385-S3456 conferred an enhanced cross-protection when challenged with heterologous virus strain NADC20 or a contemporary heterologous strain RFLP 1-7-4. The results suggest that the chimera VR2385-S3456 may be a good PRRSV vaccine candidate for further development to confer heterologous protection. PMID- 28343774 TI - Immunogenicity and safety of a high-dose hepatitis B vaccine among patients receiving methadone maintenance treatment: A randomized, double-blinded, parallel controlled trial. AB - BACKGROUND AND AIMS: To explore whether the immunization with high-dose (60MUg) hepatitis B vaccines in patients receiving methadone maintenance treatment (MMT) could yield a superior protection against hepatitis B infection than did the standard dose (20MUg). METHODS: We conducted a randomized, double-blinded, parallel-controlled trial in MMT patients. Patients with serologically negative hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) were randomized in a ratio of 1:1 to receive three intramuscular injections of 20MUg or 60MUg recombinant hepatitis B vaccine at months 0, 1, and 6. Serum HBsAg and anti-HBs were measured at months 7 and 12 post-vaccination to assess the immunogenicity. RESULTS: A total of 196 MMT patients were randomized and 195 received at least one injection (98 and 97 in 20 and 60MUg vaccine groups, respectively). The 60MUg vaccine group showed a seroconversion of anti-HBs of 87.3%, high-level response rate of 56.3%, and GMC of 742.9mIU/mL at month 7. While these results were numerically higher than the 20MUg group, a statistical difference was not found. HIV infection and concomitant drug abuse were negatively associated with the robust immune responses. 7.7% of MMT patients receiving at least one dose of vaccine reported solicited adverse reactions within 7days after vaccination, 2.6% reported unsolicited adverse reactions within 28days after vaccination. None of the MMT patients reported serious adverse events or became HBsAg positive during the follow-up. CONCLUSIONS: The three-dose regimen of 60MUg recombinant hepatitis B vaccine at months 0, 1, and 6 can yield a similar immunogenicity among MMT patients as compared to the 20MUg vaccine. ClinicalTrials.gov identifier: NCT02991599. PMID- 28343775 TI - Lower vaccine uptake amongst older individuals living alone: A systematic review and meta-analysis of social determinants of vaccine uptake. AB - INTRODUCTION: Vaccination is a key intervention to reduce infectious disease mortality and morbidity amongst older individuals. Identifying social factors for vaccine uptake enables targeted interventions to reduce health inequalities. OBJECTIVE: To systematically appraise and quantify social factors associated with vaccine uptake amongst individuals aged >=60years from Europe. METHODS: We searched Medline and Embase from inception to 24/02/2016. The association of vaccine uptake was examined for social factors relevant at an individual level, to provide insight into individuals' environment and enable development of targeted interventions by healthcare providers to deliver equitable healthcare. Factors included: living alone, marital status, education, income, vaccination costs, area-level deprivation, social class, urban versus rural residence, immigration status and religion. Between-study heterogeneity for each factor was identified using I2-statistics and Q-statistics, and investigated by stratification and meta-regression analysis. Meta-analysis was conducted, when appropriate, using fixed- or random-effects models. RESULTS: From 11,754 titles, 35 eligible studies were identified (uptake of: seasonal influenza vaccine (SIV) only (n=27) or including pneumococcal vaccine (PV) (n=5); herpes zoster vaccine (n=1); pandemic influenza vaccine (n=1); PV only (n=1)). Higher SIV uptake was reported for individuals not living alone (summary odds ratios (OR)=1.39 (95% confidence interval (CI): 1.16-1.68). Lower SIV uptake was observed in immigrants and in more deprived areas: summary OR=0.57 (95%CI: 0.47-0.68) and risk ratio=0.93 (95%CI: 0.92-0.94) respectively. Higher SIV uptake was associated with higher income (OR=1.26 (95%CI: 1.08-1.47)) and higher education (OR=1.05 (95%CI: 1-1.11)) in adequately adjusted studies. Between-study heterogeneity did not appear to result from variation in categorisation of social factors, but for education was partly explained by varying vaccination costs (meta-regression analysis p=<0.0001); individuals with higher education had higher vaccine uptake in countries without free vaccination. CONCLUSIONS: Quantification of associations between social factors and lower vaccine uptake, and notably living alone (an overlooked factor in vaccination programmes), should enable health professionals target specific social groups to tackle vaccine-related inequalities. PMID- 28343776 TI - A effective DNA vaccine against diverse genotype J infectious hematopoietic necrosis virus strains prevalent in China. AB - Infectious hematopoietic necrosis virus (IHNV) is the most important pathogen threatening the aquaculture of salmonid fish in China. In this study, a DNA vaccine, designated pIHNch-G, was constructed with the glycoprotein (G) gene of a Chinese IHNV isolate SD-12 (also called Sn1203) of genotype J. The minimal dose of vaccine required, the expression of the Mx-1 gene in the muscle (vaccine delivery site) and anterior kidney, and the titers of the neutralizing antibodies produced were used to evaluate the vaccine efficacy. To assess the potential utility of the vaccine in controlling IHNV throughout China, the cross protective efficacy of the vaccine was determined by challenging fish with a broad range of IHNV strains from different geographic locations in China. A single 100ng dose of the vaccine conferred almost full protection to rainbow trout fry (3g) against waterborne or intraperitoneal injection challenge with IHNV strain SD-12 as early as 4days post-vaccination (d.p.v.), and significant protection was still observed at 180d.p.v. Intragenogroup challenges showed that the DNA vaccine provided similar protection to the fish against all the Chinese IHNV isolates tested, suggesting that the vaccine can be widely used in China. Mx-1 gene expression was significantly upregulated in the muscle tissue (vaccine delivery site) and anterior kidney in the vaccinated rainbow trout at both 4 and 7d.p.v. Similar levels of neutralizing antibodies were determined with each of the Chinese IHNV strains at 60 and 180d.p.v. This DNA vaccine should play an important role in the control of IHN in China. PMID- 28343777 TI - Neisseria meningitidis nasopharyngeal carriage during the Hajj: A cohort study evaluating the need for ciprofloxacin prophylaxis. AB - BACKGROUND: The annual Muslim pilgrimage has the potential of increase risk for acquisition of Neisseria meningitidis. Here, we evaluate the Hajj impact on the prevalence of N. meningitidis carriage in a paired and non-paired cohort of pilgrims. Secondary objectives were to calculate the compliance with recommended vaccination. METHODS: This is a prospective paired (arriving and departing), non paired arriving and non-paired departing cohort study with the collection of nasopharyngeal samples at the start and the end of the Hajj. RESULTS: The study included unpaired arriving pilgrims at King Abdul Aziz International Airport (N=1055), unpaired departing cohort (N=373), and a paired cohort (N=628) who were tested on arrival and departure. Meningococcal vaccination was received by all pilgrims, 98.2% received quadrivalent polysaccharide vaccine (ACWY), and 1.8% received meningococcal quadrivalent conjugate vaccine (MCV4). Only 1.61% and 23.03% received pneumococcal and influenza vaccines, respectively. Of the 1055 arriving unpaired pilgrim, 36 (3.4%) tested positive for nasopharyngeal carriage of N. meningitidis, and 24 (66.7%) of these were serogroup B, the remainder were non-groupable. Haemophilus influenza was detected among 45 (4.3%), and 11 (1%) carriers were positive for both N. meningitidis and H. influenzae. Out of 373 in the unpaired departing cohort, 6 (1.61%) tested positive for N. meningitidis, and 34 (9.1%) were positive for H. influenzae. Of the 628 paired cohort pilgrims, 36 (5.7%) pilgrims were positive for N. meningitidis at arrival and 16 (2.5%) pilgrims were positive after the hajj. CONCLUSION: This the largest study of the epidemiology of N. meningitidis among pilgrims. The study showed a significant difference in the carriage between pilgrims from high endemicity and other pilgrims with a predominance of serogroup B. The continued use of ciprofloxacin as prophylactic antibiotics should be reconsidered as well as the consideration to add serogroup B as a required vaccination. PMID- 28343778 TI - Rabies: Still a silent killer targeting the poor. PMID- 28343779 TI - Antigenic and immunogenic spectrum of foot-and-mouth disease vaccine strain O1 Campos against representative viruses of topotypes that circulated in Asia over the past decade. AB - Identifying vaccine strains to control outbreaks of foot-and-mouth disease virus that could spread to new regions is essential for contingency plans. This is the first report on the antigenic/immunogenic relationships of the South American O1/Campos vaccine strain with representative isolates of the three currently active Asian type O topotypes. Virus neutralization tests using O1/Campos post vaccination sera derived from cattle and pigs predicted for both species acceptable cross-protection, even after single vaccination, established by r1 values and by expectancy of protection using monovalent or polyvalent vaccines. The results indicate that effective oil vaccines containing the O1/Campos strain can be used against Asian isolates, expanding the scope of O1/Campos strain included in vaccine banks to control emergencies caused by Asian viruses, even on single-dose vaccination, and to cover the need of effective vaccines in Asia during systematic vaccination. PMID- 28343780 TI - Propagation of Brazilian Zika virus strains in static and suspension cultures using Vero and BHK cells. AB - The recent spread of Zika virus (ZIKV) in the Americas and the Pacific has reached alarming levels in more than 60 countries. However, relatively little is known about the disease on a virological and epidemiological level and its consequences for humans. Accordingly, a large demand for in vitro derived Brazilian ZIKV material to support in vitro and in vivo studies has arisen. However, a prompt supply of ZIKV and ZIKV antigens cannot be guaranteed as the production of this virus typically using Vero or C6/36 cell lines remains challenging. Here we present a production platform based on BHK-21 suspension (BHK-21SUS) cells to propagate Brazilian ZIKV at larger quantities in perfusion bioreactors. Scouting experiments performed in tissue culture flasks using adherent BHK-21 and Vero cells have demonstrated similar permissivity and virus yields for four different Brazilian ZIKV isolates. The cell-specific yield of infectious virus particles varied between respective virus strains (1 48PFU/cell), and the ZIKV isolate from the Brazilian state Pernambuco (ZIKVPE) showed to be a best performing isolate for both cell lines. However, infection studies of BHK-21SUS cells with ZIKVPE in shake flasks resulted in poor virus replication, with a maximum titer of 8.9*103PFU/mL. Additional RT-qPCR measurements of intracellular and extracellular viral RNA levels revealed high viral copy numbers within the cell, but poor virus release. Subsequent cultivation in a perfusion bioreactor using an alternating tangential flow filtration system (ATF) under controlled process conditions enabled cell concentrations of about 1.2*107cells/mL, and virus titers of 3.9*107PFU/mL. However, while the total number of infectious virus particles was increased, the cell-specific yield (3.3PFU/cell) remained lower than determined in adherent cell lines. Nevertheless, the established perfusion process allows to provide large amounts of ZIKV material for research and is a first step towards process development for manufacturing inactivated or live-attenuated ZIKV vaccines. PMID- 28343782 TI - Lifestyle, socioeconomic characteristics, and medical history of elderly persons who receive seasonal influenza vaccination in a tax-supported healthcare system. AB - BACKGROUND: Observational studies on effectiveness of influenza vaccination in the elderly are thought to be biased by healthier lifestyles and higher socioeconomic status among vaccinated vs. unvaccinated persons. We examined this hypothesis in a uniform tax-supported health care system with free-of-charge influenza vaccination to the elderly. METHODS: We conducted a cross-sectional study among Danes aged 65-79years participating in a survey. We compared elderly persons with and without a recent (within six months) influenza vaccination in terms of (i) lifestyle and socioeconomic characteristics obtained from the survey and (ii) health factors including medical history provided by Danish registries. We compared the prevalence of study variables among vaccinated and unvaccinated persons using age- and sex-adjusted prevalence ratios (aPRs) with 95% confidence intervals (CIs). RESULTS: Among the 4237 elderly persons completing the survey, 1718 (41%) had received an influenza vaccination. Vaccinated persons had more comorbidity than unvaccinated persons (aPR for high comorbidity level: 1.51 95% CI 1.24-1.84), were less likely to never have smoked (aPR: 0.88, 95% CI 0.80 0.97), and had a higher prevalence of physical inactivity (aPR: 1.08, 95% CI 1.03 1.13). Levels of education and income were similar in the two groups. Vaccinated persons had a higher prevalence of major physical limitations (aPR: 1.40, 95% CI 1.17-1.66) and need for assistance with activities of daily living (aPR: 1.29, 95% CI 1.13-1.47). CONCLUSION: Elderly influenza vaccinated persons were not healthier in terms of lifestyle and burden of disease, did not have a higher socioeconomic status, and were more frail than unvaccinated persons. PMID- 28343781 TI - Sublingual targeting of STING with 3'3'-cGAMP promotes systemic and mucosal immunity against anthrax toxins. AB - Anthrax is caused by Bacillus anthracis, a zoonotic bacterial pathogen affecting humans and livestock worldwide. The current human anthrax vaccine, anthrax vaccine adsorbed (AVA), is an injected vaccine with a cumbersome administration schedule and fails to promote mucosal immunity. Bacterial enterotoxins, which stimulate production of the cyclic nucleotide cAMP are effective experimental mucosal vaccine adjuvants, but their inherent toxicity has precluded their use in humans. We investigated whether cyclic dinucleotides that target Stimulator of Interferon Gamma Genes (STING) in mammalian cells could represent an alternative to bacterial enterotoxins as adjuvant for sublingual immunization and promotion of mucosal immunity and secretory IgA responses in addition to systemic immunity. We found that sublingual immunization of mice with Bacillus anthracis protective antigen (PA) and the STING ligand 3'3'-cGAMP promotes PA-specific serum IgG Ab responses of the same magnitude as those induced after immunization with PA and the experimental adjuvant cholera toxin (CT). Interestingly, this STING ligand also promoted serum anti-PA IgA and IgA-producing cells in the bone marrow. Furthermore, the saliva of mice immunized with the STING ligand exhibited similar levels of PA-specific IgA Abs as groups immunized with CT as adjuvant. The adjuvant activity of 3'3'-cGAMP was associated with mixed Th1, Th2, and Th17 responses. This STING ligand also induced rapid IFN-beta and IL-10 responses in sublingual tissues and cervical lymph nodes, and TGF-beta responses in the cervical lymph nodes, which could contribute to promoting IgA responses after sublingual immunization. PMID- 28343783 TI - How reliable is the vomer flap in early hard palate repair? AB - Hard palate closure with a vomer flap at the time of lip repair has been widely adopted. A recent study by Deshpande et al. showed a high rate of failure of the vomer flap and led the authors to abandon the technique. We conducted a retrospective study of vomer flap healing in a consecutive series of cases performed by the senior author (D.O.). The case records of 71 patients who underwent repair of unilateral cleft lip and palate with a vomer flap at the time of lip repair were studied. Vomer flap healing was assessed and documented by the senior author at the time of definitive palate closure, and this was recorded. Adequate records were available for 66 cases. Twelve patients (18%) had associated syndromes and were included in the analysis. The median age at the time of lip and vomer flap repair was 3.5 months, and that at the time of palate repair was 8 months. At definitive palatoplasty, the vomer flap was intact in 62 patients (94%). Four patients (6%) had partial or complete failure of the vomer flap. All failures occurred in cases where the vomer flap was sutured directly to the nasal mucosa, a technique since abandoned in favour of double-breasting the flap to the raw surface of the oral mucosa. Five patients had incomplete healing of the palate following definitive palatoplasty, two of whom had a previous vomer flap failure. Contrary to Deshpande et al., we found the vomer flap to be highly reliable in closing the hard palate at the time of primary lip repair. PMID- 28343784 TI - A modified intraoral and extraoral approach osteotomy for the prominent mandibular angle. AB - BACKGROUND: A prominent mandibular angle (PMA) is a relatively common condition in Asians, and surgeons typically use the intraoral approach to treat it. However, the approach can have many drawbacks due to the limited operative field and view. The procedures of osteotomy are not easily manipulated, and an exact resection is difficult. In addition, some major complications can easily occur. This article presents a modified osteotomy method for the PMA that avoids these disadvantages and makes the procedure easier to execute. METHODS: Four modifications of the procedures have been made: 1. The addition of a small extraoral incision in the auriculocephalic sulcus behind the earlobe; 2. A modest reduction in both the intraoral incision length and excessive mouth traction; 3. The use of a reciprocating saw through the extraoral incision tunnel to simplify the operative procedure; and 4. Extraction of sustained-suction drains from the extraoral incision. Postoperatively, all patients were followed up and administered the validated satisfaction questionnaire and the Patient Scar Assessment Questionnaire. RESULTS: From June 2010 to June 2015, 46 patients with a PMA underwent surgery using this method. All patients were satisfied with the esthetic results. The majority of patients could not feel an objectionable jaw line or bony step (86.9%), visible deformity (97.8%) or bony regrowth (95.6%). All patients noted a positive psychosocial influence. All patients perceived the overall appearance of their extraoral scar to be "good" or "excellent." Forty five (97.8%) were "not at all" self-conscious of their scar. The overall complication rate was 6.5%, and no major complication was seen. CONCLUSION: The described method for the surgical treatment of PMA is a simple and safe procedure with fewer complications. The procedure is easy to perform, consumes less time, and can help resect the PMA accurately and easily. PMID- 28343785 TI - Pericardial mesothelioma presenting as a suspected ST-elevation myocardial infarction. AB - Primary cardiac and pericardial tumors are rare entities with an autopsy frequency of 0.001-0.03%. Metastases to the heart and pericardium are much more common than primary tumors. Malignant pericardial mesotheliomas account for up to 50% of primary pericardial tumors. We report the case of a 75-year-old woman with hypertension, dyslipidemia and atrial fibrillation who went to the emergency department due to nonspecific thoracic discomfort of over six hours duration associated with syncope. Physical examination revealed a low-amplitude arrhythmic pulse, no heart murmurs and no signs of pulmonary congestion. The ECG revealed atrial fibrillation with ST-segment elevation in V2-V6, I and aVL. The patient was transferred for emergent coronary angiography, which revealed a long stenosis in the mid-distal portion of the left anterior descending artery. The echocardiogram showed a large pericardial effusion with diffuse thickening of the myocardium. Due to worsening hemodynamics, cardiac rupture was suspected and the patient underwent urgent sternotomy and pericardiotomy with drainage of a large quantity of hematic fluid. The surgeons then identified a large, unresectable tumor occupying the distal half of the anterior portion of the heart. This is, to our knowledge, the first case report of primary pericardial mesothelioma presenting with suspected ST-elevation myocardial infarction. In this case, direct observation of the tumor led to biopsy and the final diagnosis. These are highly malignant tumors and when diagnosed are usually already at an advanced stage. PMID- 28343786 TI - Cardiac resynchronization therapy: Femoral approach. AB - We describe the case of a 62-year-old female patient with bilateral subclavian vein occlusion, in whom a cardiac resynchronization system was implanted via a femoral vein. PMID- 28343787 TI - Relationship between rotors and complex fractionated electrograms in atrial fibrillation using a novel computational analysis. AB - INTRODUCTION: Rotors and complex fractionated atrial electrograms (CFAEs) have been suggested as possible therapeutic targets in ablation of atrial fibrillation (AF). The aim of this study was to assess the relationship between rotors and CFAEs in patients with AF. METHODS: We studied 18 patients with AF (mean age 69+/ 8 years, 33% female) who underwent rotor ablation and pulmonary vein isolation. Endocardial mapping was performed with a basket catheter to identify the presence, number and location of rotors and CFAEs. The FIRMTM (Abbott) and CARTOTM (Biosense) systems were used with overlapping of frames from continuous 30-s recordings. CFAEs were classified as stable if present in >15 frames, moderately stable if present in 10-15 frames and unstable if present in 5-9 frames. RESULTS: A total of 44 rotors and 60 CFAEs (39 of them stable) were identified. The mean number of rotors and stable CFAEs per patient was 2.6+/-1.4 and 2.2+/-1.5, respectively. In 27 of the 44 identified rotors, CFAEs were found in the same location. Conversely, in 20 of the 39 stable CFAEs identified, a focal rotor was found in the same location. The majority of CFAEs found at the same location as a focal rotor were stable (63% vs. 37%, p=0.001). CONCLUSION: Rotors and CFAEs are frequently found in the same location within the atria, particularly when only stable CFAEs are considered. This relationship may have implications in the selection of substrate targets for ablation. PMID- 28343788 TI - Reply to the Letter to the Editor "Methodology, as well as physiological and pathological conditions, can affect analysis of the lymphocyte-to-monocyte ratio". PMID- 28343789 TI - Methodology, as well as physiological and pathological conditions, can affect analysis of the lymphocyte-to-monocyte ratio. PMID- 28343790 TI - Ablation of stable complex fractionated atrial electrogram defined by dynamic overlaid mapping in persistent atrial fibrillation. PMID- 28343791 TI - Androgen receptor-deficient islet beta-cells exhibit alteration in genetic markers of insulin secretion and inflammation. A transcriptome analysis in the male mouse. AB - AIMS: Testosterone action is mediated via the androgen receptor (AR). We have reported that male mice lacking AR selectively in beta-cells (betaARKO-/y) develop decreased glucose-stimulated insulin secretion (GSIS), producing glucose intolerance. We showed that testosterone action on AR in beta-cells amplifies the insulinotropic action of GLP-1 on its receptor via a cAMP-dependent protein kinase-A pathway. METHODS: To investigate AR-dependent gene networks in beta cells, we performed a high throughput whole transcriptome sequencing (RNA-Seq) in islets from male betaARKO-/y and control mice. RESULTS: We identified 214 differentially expressed genes (DEGs) (158 up- and 56 down-regulated) with a false discovery rate (FDR) < 0.05 and a fold change (FC) > 2. Our analysis of individual transcripts revealed alterations in beta-cell genes involved in cellular inflammation/stress and insulin secretion. Based on 312 DEGs with an FDR < 0.05, the pathway analysis revealed 23 significantly enriched pathways, including cytokine-cytokine receptor interaction, Jak-STAT signaling, insulin signaling, MAPK signaling, type 2 diabetes (T2D) and pancreatic secretion. The gene ontology analysis confirmed the results of the individual DEGs and the pathway analysis in showing enriched biological processes encompassing inflammation, ion transport, exocytosis and insulin secretion. CONCLUSIONS: AR deficient islets exhibit altered expression of genes involved in inflammation and insulin secretion demonstrating the importance of androgen action in beta-cell health in the male with implications for T2D development in men. PMID- 28343792 TI - Liberating A1C goals in older adults may not protect against the risk of hypoglycemia. AB - AIMS: Hemoglobin A1C is universally used as a marker for glycemic control and to establish glycemic goals in patients with diabetes. In the older population, experts recommend liberating A1C goals to decrease the risk of hypoglycemia. However, it's not clear which A1C level is optimal for this purpose. This study's aim was to understand the relationship between A1C levels and risk of hypoglycemia. METHODS: In a prospective study, we performed continuous glucose monitoring (CGM) on older adults on insulin. Hypoglycemia duration and A1C were measured at baseline while patients were on multiple insulin injections, and again after de-intensification to once-a-day basal insulin with non-insulin agents. RESULTS: We assessed 65 patients; mean age76+/-6years with on average 3.7+/-1.3 insulin injections/day. At baseline, 26% of the patients had A1C<7% (53mmol/mol), 42% between 7.1% and 8% (54-64mmol/mol), 21% between 8.1% and 9% (65-75mmol/mol), and 11% >9% (76mmol/mol). The duration of hypoglycemia (<70mg/dl, <60mg/dl, <50mg/dl) was not different between the A1c groups, regardless of treatment intensity (multiple insulin injections or once-a-day basal insulin with non-insulin agents). CONCLUSIONS: A1C levels are not associated with hypoglycemia risk in older population with type-2 diabetes on insulin therapy. Higher A1C goals do not protect against hypoglycemia. PMID- 28343793 TI - Critical analysis and review of the literature on healthcare privatization and its association with access to medical care in Saudi Arabia. AB - This paper is a review of the literature on hospitals privatization to assess the influence of privatization on access to medical care. The results are used to complete further analysis on the situation in Saudi Arabia. Over 979 references were initially identified through a database search, and an additional 237 were included from other sources. From these sources, only 11 articles were considered for review after excluding the ineligible articles, such as those that did not meet the hospitals privatization's definition or other exclusion criteria. There is weak evidence and low scientific validity supporting the argument that privatization could increase access to medical care. Prior to privatization, Saudi Arabia has to consider reforming its healthcare financing, including auditing and efficiency. After privatization, a policy has to be developed to ensure that the most vulnerable groups have access to good-quality healthcare while controlling costs for care providers. PMID- 28343794 TI - Sickness presenteeism among health care providers in an academic tertiary care center in Riyadh. AB - The term sickness presenteeism (SP) has been described as the act of going to work despite having a state of health that may be regarded as poor enough to justify sick leave. SP has been observed to be prevalent among three-quarters of health care providers (HCPs). Working while sick not only puts patients at risk but also decreases productivity and increases the probability of medical errors. Moreover, SP has been identified as a risk factor for many negative health outcomes among the HCPs themselves, such as depression, burnout, and serious cardiac events. The aim of this study was to identify the reasons for and prevalence of SP and perceptions of the impact of this practice on patient safety among HCPs. A cross-sectional study was conducted, including 279 purposively selected healthcare professionals (doctors, nurses, dentists, pharmacists and other health care professionals) working at the Ministry of National Guard Health Affairs-King Abdulaziz Medical City (MNGHA-KAMC). While nearly all of the participants (91%) believed that working while sick exposed patients to risk, the rate of SP during the past year was reported as 74%, and one fourth of respondents reported working while sick 3-4 times during the past year. More than half of the participants were not aware of the existence of a departmental policy regarding sick leave. The most common reasons reported for working while sick were not wanting to burden co-workers (71%), feelings of duty toward patients (67%), and avoiding an increased future workload caused by absence (59%). A lack of awareness regarding the existing rules and polices related to sick leave was reported by more than half of the participants. Several predisposing and enabling factors were reported as determinants influencing SP, e.g., observation of the practice of SP by peers and feelings of sympathy towards coworkers, including not wanting to overburden them, were reported to be determinants informing the decision of whether to work while sick. PMID- 28343795 TI - Use of magnetic resonance imaging in low-dose-rate and high-dose-rate prostate brachytherapy from diagnosis to treatment assessment: Defining the knowledge gaps, technical challenges, and barriers to implementation. AB - MRI is rapidly evolving as an imaging tool in both low-dose-rate and high-dose rate brachytherapy for prostate cancer. The ability of MRI to identify intraprostatic tumors and reduce uncertainties in the workflow process should enable a more accurate and precise radiation delivery approach while simultaneously improving the quality assurance process. The ability to identify functional anatomic structures adjacent to the prostate cancer could reduce or eliminate some of the more common side effects of the treatment. However, MRI is complex, and collaborative efforts and future research are required to address the current knowledge gaps, technical challenges, and barriers to widespread the implementation of MRI-assisted and MRI-guided prostate brachytherapy. PMID- 28343796 TI - Dabigatran: Important Considerations in the Elderly. PMID- 28343797 TI - Early Brain Edema is a Predictor of In-Hospital Mortality in Traumatic Brain Injury. AB - BACKGROUND: Identifying patients who may progress to a poor clinical outcome will encourage earlier appropriate therapeutic interventions. Brain edema may contribute to secondary injury in traumatic brain injury (TBI) and thus, may be a useful prognostic indicator. OBJECTIVE: We determined whether the presence of brain edema on the initial computed tomography (CT) scan of TBI patients would predict poor in-hospital outcome. METHODS: We performed a retrospective review of all trauma patients with nonpenetrating head trauma at a Level I Trauma Center. International Classification of Diseases, Ninth Revision codes indicated the presence of brain edema and we evaluated the validity of this pragmatic assessment quantitatively in a random subset of patients. In-hospital mortality was the primary outcome variable. Univariate analysis and logistic regression identified predictors of mortality in all TBI patients and those with mild TBI. RESULTS: Over 7200 patients were included in the study, including 6225 with mild TBI. Measurements of gray and white matter CT density verified radiological assessments of brain edema. Patients with documented brain edema had a mortality rate over 10 times that of the entire study population. With logistic regression accounting for Injury Severity Score, Glasgow Coma Scale score, other CT findings, and clinical variables, brain edema predicted an eightfold greater mortality rate in all patients (odds ratio 8.0, 95% confidence interval 4.6-14.0) and fivefold greater mortality rate for mild TBI patients (odds ratio 4.9, 95% confidence interval 2.0-11.7). CONCLUSIONS: Brain edema is an independent prognostic variable across all categories of TBI severity. By alerting emergency physicians to patients with poor predicted clinical outcomes, this finding will drive better resource allocation, earlier intervention, and reduced patient mortality. PMID- 28343798 TI - Assessment of a novel transdermal selective beta1-blocker, the bisoprolol patch, for treating frequent premature ventricular contractions in patients without structural heart disease. AB - BACKGROUND: The autonomic nervous system involves the genesis of premature ventricular contractions (PVCs). Previous studies demonstrated that heart rate (HR) dependency of idiopathic PVCs has different autonomic mechanisms. Recently, the bisoprolol patch, a novel transdermal beta1-blocker formulation containing bisoprolol, became clinically available. We examined the efficacy of the bisoprolol patch for treating frequent PVCs in patients without structural heart disease (SHD) regarding the HR dependency of PVCs. METHODS: This prospective study included 44 consecutive patients without SHD (25 men, mean age, 63.6+/-12.3 years) with PVC counts>=3000 beats as measured by 24-hour Holter electrocardiograms (ECGs). PVCs were divided into positive HR-dependent PVCs (P PVCs) and non-positive HR-dependent PVCs (NP-PVCs) based on the relationship between the hourly PVC density and hourly mean HR. A bisoprolol patch was administered once daily at a dose of 4mg. The 24-hour Holter ECGs were performed before and 1 month after the initiation of the therapy. RESULTS: In 44 patients, there were 24 P-PVCs and 20 NP-PVCs. The bisoprolol patch reduced the PVC count significantly (from 16,563+/-10,056 to 7892+/-8817 beats/24hours, p<0.001) in the P-PVC group, while the PVC count did not change significantly (from 16,409+/-9571 to 13,476+/-12,191beats/24hours, p=0.34) in the NP-PVC group. Moreover, in the P PVC group, the patients with mean HRs >=80 beats/minute had a significantly higher percent improvement in the PVC count than those with mean HRs <80 beats/minute (p=0.0080). The bisoprolol patch resulted in a significant reduction in the PVC count from baseline during each time period for the changes within a 24-hour period in the P-PVC group. CONCLUSIONS: The transdermal bisoprolol patch was effective for a PVC reduction in patients with P-PVCs, particularly in those with faster mean HRs. Furthermore, it demonstrated a stable PVC-reducing effect during the 24-hour period in the P-PVC group. PMID- 28343799 TI - Characterization of deficits across the spectrum of motor abilities in dialysis patients and the impact of sarcopenic overweight and obesity. AB - BACKGROUND & AIMS: Physical performance deficits in kidney failure predict mortality and quality of life. We aimed to quantify deficits in multiple motor abilities, investigate associations of lean and fat tissue content with test results and analyzed performance of sarcopenic individuals with adipose tissue excess. METHODS: Ninety hemodialysis patients and 140 healthy controls performed 6-minute walk test, gait speed measurement, sit-to-stand and time up and go tests, upper extremity handgrip and tapping tests, Stork balance and forward bend flexibility tests. Human Activity Profile questionnaire was used to assess habitual activity. Body composition was measured by bioimpedance analysis. RESULTS: Relative performance deficit of dialysis patients in age, sex, height and comorbidity adjusted estimated marginal means was largest for balance and flexibility (-52 and -33%), followed by lower extremity deficits in sit-to-stand, time up and go and 6-minute walk tests (-29, -19 and -15%, respectively), p < 0.05 for all comparisons. Upper extremity performance was less affected. Lean tissue index associated significantly positively with five and fat tissue index associated significantly negatively with two out of nine tests. Sarcopenic overweight and obese individuals exhibited significant deficits mainly in lower extremity tests with worse composite lower extremity score when compared to other categories of body composition. CONCLUSIONS: Patients with hemodialysis treated kidney failure have largest functional deficits in balance, flexibility and lower extremity functions. Lean and fat mass associate oppositely with physical performance measures and individuals at unfavorable extremes of these indices express significantly impaired lower extremity functions. PMID- 28343800 TI - Understanding mitochondrial diseases. PMID- 28343801 TI - Impact of therapeutic food compared to oral nutritional supplements on nutritional outcomes in mildly underweight healthy children in a low-medium income society. AB - BACKGROUND & AIMS: Therapeutic foods (RUTF) are used to treat severe acute malnutrition in children 5 years and under in low and middle income countries (LMI), while liquid nutritional supplements (ONS) are used in affluent societies. With globalisation and economic growth in LMI, there will be an inclination to move towards practices applied in affluent countries. This study compared the effect of supplementation with a RUTF and an ONS, on nutritional outcomes in mildly underweight children. METHODS: 68 Pakistani (5-10 y), mildly underweight (weight Z-score: -2 to -1) children randomly received either RUTF or ONS (500 kcal/day), in addition to their habitual diet for four weeks. Weight, height, skinfolds and their changes during intervention, were compared between the two groups and at follow up, post-supplementation. RESULTS: All nutritional outcomes and height improved with both supplements, but net weight gain (kg) and changes from baseline for weight, height, triceps and sub-scapular thickness Z-scores did not differ between the two supplements [mean (SD), RUTF vs ONS; weight gain (kg), 0.59 (0.30) vs 0.65 (0.42), p = 0.483; weight Z-score, 0.12 (0.09) vs 0.15 (0.13), p = 0.347; height Z-score, 0.04 (0.08) vs 0.04 (0.08), p = 0.908; triceps Z-score, 0.29 (0.24) vs 0.31 (0.23), p = 0.796; subscapular Z-score, 0.37 (0.29) vs 0.31 (0.25), p = 0.385]. Weight gain (0.6 kg) for both groups was lower than anticipated (2 kg). Post-supplementation, there was a tendency for weight and height Z-score to return to baseline. CONCLUSIONS: RUTF and ONS are equivalently effective in improving nutritional outcomes in children 5 to 10 y at risk of malnutrition but the observed benefit is less than expected and not sustainable. TRIAL REGISTRATION: This trial was registered at www.controlled-trials.com reference: ISRCTN51555749. RCT REGISTRATION: This trial was registered at www.controlled-trials.com reference: ISRCTN51555749. PMID- 28343802 TI - [The effect of methylphenidate on appetite and weight]. AB - OBJECTIVES: To better delineate in the medical literature the effect of methylphenidate on weight and appetite. METHODS: A search on PubMed was carried out for articles published with no restrictions on language or year of publication using the terms: "methylphenidate"; "weight"; "appetite". RESULTS: Methylphenidate increases dopamine and noradrenaline in synapses because of its blockage of the transporters of these monoamines in the frontal cortex and insular lobe. The intracerebral activity of methylphenidate is incriminated in the dysregulation of appetite due to its probable effect stimulating the disgust sensation generated after the activation of the insular lobe by the drug. The anorexigenic effect of methylphenidate has been demonstrated in preclinical studies although the dosage and the administration routes differ in animals from those used for human beings. In clinical studies, methylphenidate decreases the weight of children and adolescents during the first 3 to 6 months after its initiation due to the appetite reduction effect that it generates with a tendency of weight curves to rejoin the curves of subjects who did not receive the treatment a few years after its initiation. CONCLUSION: The anorexigenic effect of methylphenidate does not persist over the long-term in children and adolescents who receive it. PMID- 28343803 TI - [Man, woman? Make your choice]. PMID- 28343804 TI - Evaluation of the Grafted Fascia in the Vocal Fold of Dogs: A Histologic Study. AB - INTRODUCTION: There is no consensus on the ideal graft for medialization surgery of the vocal folds in the literature. One of the most favorable proposals is the use of autologous fascia, which seems limited by the lack of information regarding the integration of grafted tissue. Our study aims to evaluate the degree of fully engrafted fascia integration in the vocal fold lamina propria of dogs. MATERIALS AND METHODS: Fourteen adult mongrel dogs that underwent intravenous general anesthesia were selected and kept under spontaneous ventilation. A fascia lata fragment of 4 cm2 was obtained from the right leg of each dog. The dogs underwent laryngoscopy; a 3 mm incision was made in the vocal process, next to the vestibular process, and the fascia was grafted into the right vocal fold. The left vocal fold was used as a control. The animals were divided into two groups: group A, evaluated after 2 months of the procedure, and group B, evaluated after 6 months of the procedure. Histologic analysis was made semiquantitatively regarding the presence of inflammatory reaction, fibrosis, and neovascularization. RESULTS: Our final studied group comprised 12 dogs. Microscopic examination of the larynx revealed the absence of any detectable inflammation in the incision site. The lamina propria of the grafted vocal fold showed identifiable compact, thick, and eosinophilic collagen bands. The surrounding tissue showed thin collagen bands with some organization, similar to the contralateral vocal fold. CONCLUSION: The grafted fascia integrates into the vocal fold lamina propria and seems not to cause inflammatory reaction response. PMID- 28343805 TI - The Reported Incidence and Nature of Voice Disorders in the Private Healthcare Context of Gauteng. AB - OBJECTIVES: The study aimed to determine the incidence and nature of voice disorders, as reported by ear, nose, and throat specialists (ENTs), in the Gauteng private healthcare context. STUDY DESIGN: This is a cross-sectional survey design. METHODS: The respondents had to be certified ENTs working in the private healthcare context in Gauteng. The survey was sent out electronically to all 94 ENTs, registered with the ENT Society, working in the private healthcare context; thus, no additional requirements had to be met. The survey inquired about the total number of referrals from January 2015 to January 2016, the total number of referrals who were diagnosed with a voice disorder, as well as information regarding the patients such as the nature of the voice disorders. RESULTS: Of the 94 surveys sent out, 24 of them were completed (25.5%). The incidence of voice disorders reported was 5.2%. The most commonly diagnosed voice disorder is acute laryngitis (32%). The majority of ENTs (75%) received referrals from general practitioners and referred to speech-language pathologists if the patient presented with a voice disorder. CONCLUSIONS: The results from this study may enable healthcare professionals to adequately plan service delivery resource allocations to provide appropriate services. Additional studies are required to examine the incidence of voice disorders in the public healthcare context as well as the prevalence of voice disorders in Gauteng. PMID- 28343806 TI - Ultrasonographic Evaluation of Anterolateral Ligament Injuries: Correlation With Magnetic Resonance Imaging and Pivot-Shift Testing. AB - PURPOSE: (1) To compare the diagnostic ability of ultrasonography (US) and magnetic resonance imaging (MRI) to detect anterolateral ligament (ALL) injuries in anterior cruciate ligament (ACL)-deficient patients, and (2) to evaluate the correlation between ALL injury status (as determined by US and MRI) and the knee's rotational stability. METHODS: Thirty patients with an isolated ACL injury were included prospectively over a 3-month period. The condition of the ALL was evaluated by 2 experienced radiologists using both US and MRI. Rotational stability was evaluated by 2 surgeons with the pivot-shift test with patients under general anesthesia. It was classified as either negative (grades 0 and I) or positive (grades II and III). The radiologists were blinded to the knee's rotational stability, and the surgeons were blinded to the ALL's status based on the US images. The correlation between the ALL's injury status (US and MRI) and the pivot shift was determined with the Pearson chi2 test. To evaluate the reproducibility of the results, the agreement between observers was determined with the Cohen kappa coefficient. RESULTS: On US, the ALL was identified and visible over its entire length in 100% of patients (30 of 30, kappa = 1). The ALL was injured in 63% of patients (19 of 30, kappa = 0.93). On MRI, the ALL was identified in 96% of patients (29 of 30, kappa = 0.91). The ALL appeared injured in 53% of cases (16 of 30, kappa = 0.93). An ALL that appeared injured on US was more often associated with a positive pivot shift than was an uninjured ALL (75% vs 39%, chi2 = 13.7, P < .05). The interobserver agreement was high for both US (kappa = 0.91-1) and MRI (kappa = 0.76-1). CONCLUSIONS: US is a reproducible examination for the diagnosis of ALL injury. An ALL injury is most often associated with a high pivot-shift grade. LEVEL OF EVIDENCE: Level II, prospective comparative study. PMID- 28343807 TI - Dial Test: Unrecognized Predictor of Anterior Cruciate Ligament Deficiency. AB - PURPOSE: To evaluate the effect of isolated anterior cruciate ligament (ACL) injury on tibial external rotation as measured by the dial test. METHODS: Twenty seven consecutive patients scheduled to undergo a primary ACL reconstruction were prospectively evaluated. Physical examination and magnetic resonance imaging findings were analyzed to exclude multiligamentous injury. The dial test was performed with the patient under anesthesia with a goniometer on both the affected and unaffected knees at 30 degrees and 90 degrees . Intraoperatively, the arthroscopic posterolateral corner gaps before reconstruction and after reconstruction were documented. Postoperatively, the dial test was again performed on both knees at 30 degrees and 90 degrees . RESULTS: At 30 degrees , there was a significantly larger dial test result in the affected knee before ACL reconstruction compared with after ACL reconstruction (27.6 degrees vs 21.0 degrees , P < .0001) and compared with the unaffected knee (27.6 degrees vs 20.5 degrees , P < .0001), but this difference was eliminated after reconstruction (21.0 degrees vs 20.5 degrees , P = .5089). At 90 degrees , there was a significantly larger dial test result in the affected knee before ACL reconstruction compared with after ACL reconstruction (27.6 degrees vs 21.1 degrees , P < .0001) and compared with the unaffected knee (27.6 degrees vs 20.9 degrees , P < .0001), with this difference was eliminated after reconstruction (21.1 degrees vs 20.9 degrees , P = .7831). CONCLUSIONS: Incompetence of the ACL accounts for nearly 7 degrees of tibial external rotation found by the dial test. During examination of an injured knee, if the dial test is positive, an isolated ACL injury should not be excluded. Findings of the dial test should thus be interpreted with caution in the setting of ACL injury. LEVEL OF EVIDENCE: Level II, prospective comparative study. PMID- 28343808 TI - An Anatomic Evaluation of Arthroscopic Access to the Radial Head. AB - PURPOSE: To determine the area of the radial head accessible for visualization and screw placement from the standard anteromedial and anterolateral portals used in elbow arthroscopy. METHODS: Five cadaveric elbows were arthroscopically evaluated using standard anteromedial and anterolateral portals. Markers (pins) were placed into the accessible portions of the radial head at maximal pronation and supination. Specimens were then evaluated by computed tomography, and the arc of the radial head accessible from each portal was determined. RESULTS: A continuous 220.04 degrees +/- 37.58 degrees arc of the radial head was accessible from the combination of the anterolateral and anteromedial portals. From the anteromedial portal, the arc obtained measured 147.96 degrees +/- 21.81 degrees , and from the anterolateral portal, the arc obtained measured 156.02 degrees +/- 33.32 degrees . Using the radial styloid as a marker for 0 degrees , the mean total arc ranged from 92.3 degrees +/- 34.06 degrees dorsal to 127.74 degrees +/- 23.65 degrees volar relative to the radial styloid. CONCLUSIONS: Standard anteromedial and anterolateral portals used for elbow arthroscopy allow access to an average 220 degrees area of the radial head. CLINICAL RELEVANCE: This study defines the area of the radial head that can be contacted using commonly used, safe, and simple portals. PMID- 28343810 TI - Policy objective of generic medicines from the investment perspective: The case of clopidogrel. AB - The objective of generic drug policies in most countries is defined from a disinvestment perspective: reduction in expenditures without compromising health outcomes. However, in countries with restricted access of patients to original patented drugs, the objective of generic drug policies can also be defined from an investment perspective: health gain by improved patient access without need for additional health budget. This study examines the investment aspect of generic medicines by analyzing clopidogrel utilization in European countries between 2004 and 2014 using multilevel panel data models. We find that clopidogrel consumption was strongly affected by affordability constraints before the generic entry around 2009, but this effect decayed by 2014. After controlling for other variables, utilization had a substantially larger trend increase in lower-income European countries than in the higher-income ones. Generic entry increased clopidogrel consumption only in lower- and average-income countries but not in the highest-income ones. An earlier generic entry was associated with a larger effect. The case of clopidogrel indicates that the entrance of generics may increase patient access to effective medicines, most notably in lower-income countries, thereby reducing inequalities between European patients. Policymakers should also consider this investment aspect of generic medicines when designing pharmaceutical policies. PMID- 28343809 TI - In Vivo Analysis of Dynamic Graft Bending Angle in Anterior Cruciate Ligament Reconstructed Knees During Downward Running and Level Walking: Comparison of Flexible and Rigid Drills for Transportal Technique. AB - PURPOSE: To determine the in vivo dynamic graft bending angle (GBA) in anterior cruciate ligament (ACL)-reconstructed knees, correlate the angle to tunnel positions and tunnel widening, and evaluate the effects of 2 femoral tunnel drilling techniques on GBA. METHODS: Patients with an isolated ACL injury undergoing reconstruction from 2011 to 2012 were included. Transportal techniques were used to create femoral tunnels. Tunnel locations were determined by 3 dimensional computed tomography. Tibiofemoral kinematics during treadmill walking and running were assessed by dynamic stereo x-ray analysis 6 months and 2 years postoperatively. The GBA was calculated from the 3-dimensional angle between the graft and femoral tunnel vectors on each motion frame. The cross-sectional areas of femoral tunnels were measured at 6 months and compared with the initial size to assess tunnel widening. RESULTS: A total of 54 patients were included. Use of flexible drills resulted in significantly higher GBAs during walking (80.6 degrees +/- 7.8 degrees , P < .001) and running (80.5 degrees +/- 9.0 degrees , P = .025) than rigid drills (walking, 67.5 degrees +/- 9.3 degrees ; running, 74.1 degrees +/- 9.6 degrees ). Their use led to greater tunnel widening of 113.9% +/- 17.6%, as compared with 97.7% +/- 17.5% for rigid drills (P = .003). The femoral and tibial apertures were located in similar anatomic positions in both groups, but the femoral tunnel exits were located more anteriorly (P < .001) in the flexible drill group. A higher GBA was highly correlated with anterior location of femoral exits (r = 0.63, P < .001) and moderately correlated with greater tunnel widening (r = 0.48, P < .001). CONCLUSIONS: High GBAs were identified during dynamic activities after anatomic ACL reconstruction with a transportal femoral tunnel drilling technique. The GBA was greater when flexible drills were used. The high bending angle resulted from the more anterior location of the femoral tunnel exits, and it correlated with early bone tunnel widening at 6 months. These results suggest that a high GBA may increase stress at the bone graft interface and contribute to greater tunnel widening after anatomic ACL reconstruction, although the clinical impact should be further investigated. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 28343811 TI - Brexit and the NHS: Challenges, uncertainties and opportunities. PMID- 28343812 TI - Stature estimation in a contemporary Japanese population based on clavicular measurements using multidetector computed tomography. AB - The aims of this study was to assess the correlation between stature and clavicular measurements in a contemporary Japanese population using three dimensional (3D) computed tomographic (CT) images, and to establish regression equations for predicting stature. A total of 249 cadavers (131 males, 118 females) underwent postmortem CT scanning and subsequent forensic autopsy between October 2011 and May 2016 in our department. Four clavicular variables (linear distances between the superior margins of the left and right sternal facets to the anterior points of the left and right acromial ends and between the superior margins of the left and right sternal facets to the left and right conoid tubercles) were measured using 3D CT reconstructed images that extracted only bone data. The correlations between stature and each of the clavicular measurements were assessed with Pearson product-moment correlation coefficients. These clavicular measurements correlated significantly with stature in both sexes. The lowest standard error of estimation value in all, male, and female subjects was 3.62cm (r2=0.836), 3.55cm (r2=0.566), and 3.43cm (r2=0.663), respectively. In conclusion, clavicular measurements obtained from 3D CT images may be useful for stature estimation of Japanese individuals, particularly in cases where better predictors, such as long bones, are not available. PMID- 28343813 TI - Radiological assessment of the compression depth: A hospital based trauma database quantitative analysis from China. PMID- 28343814 TI - Authors respond to Both qSOFA score and bedside plasma lactate are the predictors of mortality for patients with infections in ED. PMID- 28343816 TI - The risk of unintentional out-of-network encounters with hospital-based physicians at in-network hospitals. AB - OBJECTIVE: When hospital-based specialists including emergency physicians, anesthesiologists, pathologists and radiologists are not included in the same insurance networks as their parent hospitals, it creates confusion and leads to unexpected costs for patients. This study explored the frequency with which hospital-based physicians at academic medical centers are not included in the network directories for the same insurance networks as their parent teaching hospitals. METHODS: We studied teaching hospitals with residency programs in all four hospital-based specialties. Using insurance plan provider directories, we determined whether each teaching hospital was in-network for randomly selected locally available insurance plans offered through the federal and state marketplace exchanges. For each established hospital-network relationship, we then determined whether hospital-based specialists were included in the provider network directory by searching for the name of each specialty's residency program director and the name of the physician practice group. RESULTS: We identified 79 teaching hospitals participating in 144 locally available insurance plan networks. Hospital-based specialist inclusion in these hospital-network relationships was: emergency physicians: 50.0% (CI: 40%-59%); anesthesiologists: 50.0% (CI: 42%-58%); pathologists: 45.4% (CI: 37%-54%); and radiologists: 55.1% (46%-64%). Inclusion of all four hospital-based specialties occurred in only 45.0% (CI: 36%-54%) of the hospital-network relationships. CONCLUSION: For insurance plans offered through the federal and state marketplace exchanges, hospital-based specialists frequently are not included in the directories for the insurance networks in which their parent teaching hospitals participate. Further research is needed to explore this issue at non-academic hospitals and for off exchange insurance products, and to determine effective policy solutions. PMID- 28343815 TI - Soft tissue oxygen saturation to predict admission from the emergency department: A prospective observational study. AB - OBJECTIVE: We evaluated a soft tissue oxygen saturation (Sto2) measurement at triage for predicting admission to the hospital in adults presenting to the emergency department (ED) in addition to data routinely gathered at triage. METHODS: This was a prospective, observational, single center study of adults presenting to the ED for evaluation. Research assistants obtained thenar eminence Sto2 measurements on subjects in ED triage. ED providers not involved in the study then made all management and disposition decisions. We prospectively collected data on each subject's final ED disposition (admission versus discharge). We identified the optimal Sto2 cutoff value for predicting admission. We then used logistic regression modeling to describe the added predictive value of Sto2 beyond routinely collected triage data including Emergency Severity Index level, age, and vital signs. RESULTS: We analyzed 2588 adult (>17years) subjects with 743 subjects (28.7%) admitted to the hospital. Sto2<76% was the optimal diagnostic cutoff for predicting admission. Of subjects with Sto2<76%, 158 of 384 (41.1%) underwent admission versus 585 of 2204 (26.5%) subjects with Sto2>=76. After controlling for age, vital signs, and ESI level in the logistic regression analysis, Sto2<76% had an odds ratio of 1.54 (95% confidence interval (CI), 1.19 to 1.98) for predicting admission. CONCLUSIONS: Sto2 may provide additional prognostic data to routine triage assessment regarding the disposition for undifferentiated adult patients presenting to the ED. PMID- 28343817 TI - Conventional vs invert-grayscale X-ray for diagnosis of pneumothorax in the emergency setting. AB - INTRODUCTION: Pneumothorax is a pathologic condition in which air is accumulated between the visceral and parietal pleura. After clinical suspicion, in order to diagnose the severity of the condition, imaging is necessary. By using the help of Picture Archiving and Communication Systems (PACS) direct conventional X-rays are converted to gray-scale and this has become a preferred method among many physicians. METHODS: Our study design was a case-control study with cross-over design study. Posterior-anterior chest X-rays of patients were evaluated for pneumothorax by 10 expert physicians with at least 3years of experience and who have used inverted gray-scale posterior anterior chest X-ray for diagnosing pneumothorax. RESULTS: The study included posterior anterior chest X-ray images of 268 patients of which 106 were diagnosed with spontaneous pneumothorax and 162 patients used as a control group. The sensitivity of Digital-conventional X-rays was found to be higher than that of inverted gray-scale images (95% CI (2,08 5,04), p<0,01). There was no statistically significant difference between the gold standard and digital-conventional images (95% CI (0,45-2,17), p=0,20), while the evaluations of the gray-scale images were found to be less sensitive for diagnosis (95% CI (3,16-5,67) p<0,01). CONCLUSION: Inverted gray-scale imaging is not a superior imaging modality over digital-conventional X-ray for the diagnosis of pneumothorax. Prospective studies should be performed where diagnostic potency of inverted gray-scale radiograms is tested against gold standard chest CT. Further research should compare inverted grayscale to lung ultrasound to assess them as alternatives prior to CT. PMID- 28343818 TI - Comparative performances of serologic and molecular assays for detecting human T lymphotropic virus type 1 and type 2 (HTLV-1 and HTLV-2) in patients infected with human immunodeficiency virus type 1 (HIV-1). AB - The present study evaluated several techniques currently available (commercial kits and in-house assays) for diagnosing human T lymphotropic viruses types 1 and 2 in two groups of patients enrolled at HIV/AIDS specialized care services in Sao Paulo: Group 1 (G1), n=1608, 1237 male/371 female, median age 44.3 years old, majority using highly active antiretroviral therapy (HAART); G2, n=1383, 930 male/453 female, median age of 35.6 years old, majority HAART naive. Enzyme immunoassays [(EIA) Murex and Gold ELISA] were employed for human T lymphotropic viruses types 1 and 2 screening; Western blotting (WB), INNO-LIA (LIA), real-time PCR pol (qPCR), and nested-PCR-RFLP (tax) were used to confirm infection. Samples were considered human T lymphotropic viruses types 1 and 2 positive when there was reactivity using at least one of the four confirmatory assays. By serological screening, 127/2991 samples were positive or borderline, and human T lymphotropic virus infection was confirmed in 108 samples (three EIA-borderline): 56 human T lymphotropic virus type 1 [G1 (27)+G2 (29)]; 45 human T lymphotropic virus type 2 [G1 (21)+G2 (24)]; one human T lymphotropic virus type 1+human T lymphotropic virus type 2 (G2); six human T lymphotropic virus [G1 (2)+G2 (4)]. Although there were differences in group characteristics, human T lymphotropic viruses types 1 and 2 prevalence was similar [3.1% (G1) and 4.2% (G2), p=0.113]. The overall sensitivities of LIA, WB, qPCR, and PCR-RFLP were 97.2%, 82.4%, 68.9%, and 68.4%, respectively, with some differences among groups, likely due to the stage of human T lymphotropic virus infection and/or HAART duration. Indeterminate immunoblotting results were detected in G2, possibly due to the seroconversion period. Negative results in molecular assays could be explained by the use of HAART, the occurrence of defective provirus and/or the low circulating proviral load. In conclusion, when determining the human T lymphotropic virus infection, the findings highlight that there is a need to consider the blood samples with borderline results in screening assays. Of all the tested assays, LIA was the assay of choice for detecting human T lymphotropic virus type 1 and human T lymphotropic virus type 2 in human immunodeficiency virus type 1-infected patients. PMID- 28343819 TI - Meropenem-induced low valproate levels in a cerebral palsy child. PMID- 28343821 TI - Use of Chronic Methadone Before Total Knee Arthroplasty. AB - BACKGROUND: A subset of patients who undergo total knee arthroplasty (TKA) are on methadone maintenance. They require more and often unpredictable quantities of opioids to function as effective painkillers. This study aims to compare the opioid requirements and the immediate postoperative course for patients on methadone maintenance with those who are not, after a TKA. METHODS: A retrospective, case-control study was performed. From 2005 to 2010, 36 patients, who underwent a unilateral TKA, on chronic methadone maintenance were identified. A control group matched for age, gender, and body mass index comprised patients from the same period, who did not self-report taking methadone. Chart review and analysis of patient demographics, type of anesthesia used, preoperative methadone use, inpatient opioid use (converted to oral morphine equivalent doses), need for in-house pain management consult, length of hospital stay, and need for reoperation were performed. RESULTS: Patients on chronic methadone maintenance used significantly more opioids than patients not on methadone during their entire inpatient stay (P < .001). This was demonstrated by a higher median daily usage of opioids and higher patient-controlled analgesia usage. Patients on methadone maintenance had a significantly longer postoperative inpatient hospitalization (P < .001). Finally, these patients required significantly more inpatient pain management referrals (P = .025). CONCLUSION: There is a significantly higher opioid requirement, length of stay, and pain management consults in patients on methadone maintenance compared with those who are not after a TKA. These patients may benefit from a nonroutine approach to perioperative care in TKA. PMID- 28343822 TI - The New Surgical Technique for Improving Total Knee and Hip Arthroplasty Outcomes: Patient Selection. AB - BACKGROUND: Inclusion of patient satisfaction scores in setting reimbursements has been suggested by health care policy makers to contain cost and improve outcomes. The Short Form 36 Health Survey (SF-36) score provides a health-related quality of life (HRQoL) measure of arthroplasty outcome. Although previous work identified factors that influence this score for hip and knee arthroplasty patients, they did not focus on how a surgeon might use this information in a clinical setting. The present study examined whether relatively simple criteria might identify patients more likely to experience minimal HRQoL improvement. METHODS: "Improvements" in SF-36 composite physical scores and subscales were calculated from the difference between initial (preoperative) and SF-36 scores at 1 year. The rates of achieving a clinically significant improvement were compared between patient groups. RESULTS: After knee arthroplasty, women and younger patients achieved a clinically significant improvement in physical function more frequently than men and older patients (P = .04 and .02, respectively). The largest differences in improvement occurred between the diabetic and nondiabetic groups (P = .001), where the diabetic patients with >=2 additional comorbidities demonstrated the lowest rate of achieving a clinically significant improvement in physical function and bodily pain. In comparison, in hip patients only age had significant influence on gains in physical function, but this did not alter the rate at which patients achieved a clinically significant improvement. CONCLUSION: These data indicate simple screening criteria can identify patients where arthroplasty might provide marginal HRQoL improvement. They suggest HRQoL-based reimbursement incentives will favor practices with younger, healthier patient populations. PMID- 28343820 TI - Commensal Microbes and Hair Follicle Morphogenesis Coordinately Drive Treg Migration into Neonatal Skin. AB - Regulatory T cells (Tregs) are required to establish immune tolerance to commensal microbes. Tregs accumulate abruptly in the skin during a defined window of postnatal tissue development. However, the mechanisms mediating Treg migration to neonatal skin are unknown. Here we show that hair follicle (HF) development facilitates the accumulation of Tregs in neonatal skin and that upon skin entry these cells localize to HFs, a primary reservoir for skin commensals. Further, germ-free neonates had reduced skin Tregs indicating that commensal microbes augment Treg accumulation. We identified Ccl20 as a HF-derived, microbiota dependent chemokine and found its receptor, Ccr6, to be preferentially expressed by Tregs in neonatal skin. The Ccl20-Ccr6 pathway mediated Treg migration in vitro and in vivo. Thus, HF morphogenesis, commensal microbe colonization, and local chemokine production work in concert to recruit Tregs into neonatal skin, thereby establishing this tissue Treg niche early in life. PMID- 28343823 TI - Process Improvement Project Using Tranexamic Acid Is Cost-Effective in Reducing Blood Loss and Transfusions After Total Hip and Total Knee Arthroplasty. AB - BACKGROUND: Tranexamic acid (TXA) has been associated with decreased blood loss and transfusion after total hip arthroplasty (THA) and total knee arthroplasty (TKA). The purpose of this study was to examine both transfusion utilization and the economic impact of a Process Improvement Project implementing TXA for THA and TKA. METHODS: After standardization of TXA administration in THA and TKA patients, retrospective data were compared from 12 consecutive months before (group A, n = 336 procedures) and after (group B, n = 436 procedures) project initiation. RESULTS: TXA administration increased with project implementation (group A = 3.57%, group B = 86.01%) and was associated with reductions in perioperative hemoglobin decrement (20.2%), patients transfused (45%), and number of units transfused per patient (61.9%). Cost savings were notable per patient ($128) and annually program wide ($55,884) with the primary THA subgroup contributing the most to the savings. No increase in adverse effects was observed. CONCLUSION: Standardized administration of TXA is an effective and economically favorable blood-reduction strategy for patients undergoing elective THA or TKA. Although reduction in transfusions with TXA may be greater after TKA, the economic and clinical impact of transfusion reduction is more substantial in THA patients. PMID- 28343824 TI - Assessment of Corrosion, Fretting, and Material Loss of Retrieved Modular Total Knee Arthroplasties. AB - BACKGROUND: Modular junctions in total hip arthroplasties have been associated with fretting, corrosion, and debris release. The purpose of this study is to analyze damage severity in total knee arthroplasties of a single design by qualitative visual assessment and quantitative material loss measurements to evaluate implant performance and patient impact via material loss. METHODS: Twenty-two modular knee retrievals of the same manufacturer were identified from an institutional review board-approved database. Junction designs included tapers with an axial screw and tapers with a radial screw. Constructs consisted of 2 metal alloys: CoCr and Ti6Al4V. Components were qualitatively scored and quantitatively measured for corrosion and fretting. Negative values represent adhered material. Statistical differences were analyzed using sign tests. Correlations were tested with a Spearman rank order test (P < .05). RESULTS: The median volumetric material loss and the maximum linear depth for the total population were -0.23 mm3 and 5.84 MUm, respectively. CoCr components in mixed metal junctions had higher maximum linear depth (P = .007) than corresponding Ti components. Fretting scores of Ti6Al4V alloy components in mixed metal junctions were statistically higher than the remaining groups. Taper angle did not correlate with material loss. CONCLUSION: Results suggest that CoCr components in mixed metal junctions are more vulnerable to corrosion than other components, suggesting preferential corrosion when interfacing with Ti6Al4V. Overall, although corrosion was noted in this series, material loss was low, and none were revised for clinical metal-related reaction. This suggests the clinical impact from corrosion in total knee arthroplasty is low. PMID- 28343825 TI - Silver-Coated Megaprosthesis of the Proximal Tibia in Patients With Sarcoma. AB - BACKGROUND: Proximal tibia arthroplasty is associated with high rates of infection. This study is the largest one that has compared the infection rates with titanium vs silver-coated megaprostheses in patients treated for sarcomas. METHODS: The infection rate in 98 patients with sarcoma or giant-cell tumor in the proximal tibia who underwent placement of a titanium (n = 42) or silver coated (n = 56) megaprosthesis (MUTARS) was assessed, along with the treatments administered for any infection. RESULTS: As the primary end point of the study, the rates of infection were 16.7% in the titanium group and 8.9% in the silver group, resulting in 5-year prosthesis survival rates of 90% in the silver and 84% in the titanium group. Whereas in the titanium group 37.5% of patients ultimately had to undergo amputation in the present study, these mutilating surgical procedures were only necessary in the silver group in one patient (14.3%). CONCLUSION: The use of silver-coated prosthesis reduced the infection rate in a relatively large and homogeneous group of patients. In addition, less-aggressive treatment of infection was possible in the group with silver-coated prosthesis. PMID- 28343826 TI - Diagnosis of Periprosthetic Joint Infection-An Algorithm-Based Approach. AB - BACKGROUND: Periprosthetic joint infection (PJI) remains one of the most challenging and devastating modes of failure after total hip and knee arthroplasties. Despite the profound urgency and impact of PJI on an individual and societal basis, historically, there have not been standardized definitions of and diagnostic algorithms for infection after total joint arthroplasty. METHODS: In a recent symposium, the American Academy of Hip and Knee Surgeons put forth a standardized approach to the prevention, diagnosis, and management of the patient with a suspected PJI. RESULTS: This review article summarizes these findings, and reviews the algorithmic approach to the diagnosis of PJI. CONCLUSION: The diagnosis of PJI is easily made in our experience in 90% of patients by getting an erythrocyte sedimentation rate and C-reactive protein followed by selective aspiration of the joint if these values are elevated or if the clinical suspicion is high. Synovial fluid obtained should be sent for a synovial fluid white blood cell count, differential, and cultures. PMID- 28343827 TI - Diabetes Mellitus and Hyperglycemia and the Risk of Aseptic Loosening in Total Joint Arthroplasty. AB - BACKGROUND: It is unknown to what extent diabetes mellitus modifies the long-term risk of aseptic loosening in total hip arthroplasty (THA) and total knee arthroplasty (TKA). We examined the association between diabetes mellitus, perioperative hyperglycemia, and the likelihood of revisions for aseptic loosening. METHODS: We studied 16,085 primary THA and TKA procedures performed at a large tertiary care hospital between 2002 and 2009. All blood glucose values around the time of surgery (within 1 week) were retrieved. Subsequent revision surgeries and the reasons for revision were ascertained through the institutional joint registry. Multivariate Cox models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for aseptic loosening associated with diabetes mellitus and hyperglycemia adjusting for age, gender, body mass index, and surgery type. RESULTS: A total of 2911 (18%) surgeries had a diagnosis of diabetes mellitus at the time of surgery. Glucose testing was performed at least once in 7055 (44%) procedures within +/-1 week of surgery. Although diabetic patients did not experience a higher risk of revision for aseptic loosening (HR, 0.87; 95% CI, 0.55-1.38), higher preoperative glucose values on the day before surgery were significantly associated with both the overall risk of revisions (HR, 2.80; 95% CI, 1.00-7.85) and revisions for aseptic loosening (HR, 4.95; 95% CI, 1.26-19.54). CONCLUSION: High preoperative hyperglycemia is a potential risk factor for aseptic loosening in THA and TKA. PMID- 28343829 TI - Corrigendum to "Metal on Metal or Ceramic on Ceramic for Cementless Total Hip Arthroplasty: A Meta-Analysis" [The Journal of Arthroplasty 31 (2016) 2637-2645]. PMID- 28343828 TI - The Morscher Press-Fit Acetabular Component: An Independent Long-Term Review at 18-22 Years. AB - BACKGROUND: There are relatively few 20-year results of uncemented acetabular components, and most of these are modular designs. This study reports the 20-year results of a monoblock press-fit acetabular component. METHODS: A total of 122 total hip arthroplasties (111 patients) using the Morscher cup were reviewed at a mean of 19.7 years. The average age at implantation was 57.3 years (range, 36-74 years), and 81 (66%) were men. RESULTS: Twenty-two patients (25 hips) had died. Seven hips were revised, including 5 acetabular revisions. Six patients (6 hips) declined to participate but were known not to have been revised. The mean Oxford hip score was 41.1 (range, 22-48), and the mean reduced Western Ontario and McMaster Universities Osteoarthritis Index score was 5.7/48 (range, 0-24). Eccentric wear was seen in 13 (15.7%) and major osteolysis in 14 (17%) of 82 surviving hips with radiographs. The all-cause revision rate was 0.32 per 100 observed component years (95% confidence interval [CI], 0.13-0.66). The 20-year Kaplan-Meier survival was 93.4% (CI, 86.6-96.8) for all-cause revisions, 95.5% (CI, 89.4-98.1) for any acetabular revision, and 97.1% (CI, 91.2-99.1) for acetabular aseptic loosening, wear, or osteolysis. CONCLUSION: The Morscher acetabular component has continued to perform well at 20 years despite using conventional polyethylene with results that match or surpass other cementless acetabulae. PMID- 28343830 TI - Fall Risk Score at the Time of Discharge Predicts Readmission Following Total Joint Arthroplasty. AB - BACKGROUND: Readmission among Medicare recipients is a leading driver of healthcare expenditure. To date, most predictive tools are too coarse for direct clinical application. Our objective in this study is to determine if a pre existing tool to identify patients at increased risk for inpatient falls, the Hendrich Fall Risk Score, could be used to accurately identify Medicare patients at increased risk for readmission following arthroplasty, regardless of whether the readmission was due to a fall. METHODS: This study is a retrospective cohort study. We identified 2437 Medicare patients who underwent a primary elective total joint arthroplasty (TJA) of the hip or knee for osteoarthritis between 2011 and 2014. The Hendrich Fall Risk score was recorded for each patient preoperatively and postoperatively. Our main outcome measure was hospital readmission within 30 days of discharge. RESULTS: Of 2437 eligible TJA recipients, there were 226 (9.3%) patients who had a score >=6. These patients were more likely to have an unplanned readmission (unadjusted odds ratio 2.84, 95% confidence interval 1.70-4.76, P < .0001), were more likely to have a length of stay >3 days (49.6% vs 36.6%, P = .0001), and were less likely to be sent home after discharge (20.8% vs 35.8%, P < .0001). The effect of a score >=6 on readmission remained significant (adjusted odds ratio 2.44, 95% confidence interval 1.44-4.13, P = .0009) after controlling for age, paralysis, and the presence of a major psychiatric disorder. CONCLUSION: Increased Hendrich fall risk score after TJA is strongly associated with unplanned readmission. Application of this tool will allow hospitals to identify these patients and plan their discharge. PMID- 28343831 TI - Stepping Toward Objective Outcomes: A Prospective Analysis of Step Count After Total Joint Arthroplasty. AB - BACKGROUND: Functional recovery monitoring after total hip arthroplasty (THA) and total knee arthroplasty (TKA) is often limited to surgeon-based assessment and patient self-reporting rather than objective measures. However, traditional outcomes may not reliably gauge return of function. The goal of this study was to evaluate and compare an objective measure of postoperative recovery, daily step count, with patient self-reported outcomes. METHODS: Prospectively, 589 patients used a mobile step-tracking application to record daily steps. Steps were recorded for 4 weeks before surgery and 12 weeks, thereafter. Patient-reported lower extremity functional scale (LEFS) scores were recorded at 1, 6, and 12 weeks, postoperatively. LEFS scores were correlated to weekly median daily steps using the Spearman rank correlation coefficient. RESULTS: Preoperative median daily steps were 2682 and 1988 for patients undergoing THA and TKA, respectively. Steps for weeks 1, 6, and 12 were 214, 3,170, and 3884 after THA and 153, 1772, and 2311 after TKA, respectively. Step-count demonstrated a weakly positive correlation with LEFS scores. For week 1, the correlation was 0.27 and 0.29 for THA and TKA patients, respectively. For week 6, the correlation was 0.18 and 0.29 for THA and TKA patients, respectively. CONCLUSION: Physical function improved over the first 12 weeks as measured by both steps and patient-reported assessments. Postoperative steps weakly correlated with LEFS scores, suggesting patient-reported outcomes may provide only part of the story. Incorporating objective measures may be a valuable addition to the surgeon's armamentarium for monitoring patient recovery. PMID- 28343832 TI - Transpalatal wiring for the management of sagittal fracture of the maxilla/palate. PMID- 28343833 TI - [Consequences of impacted wisdom teeth extraction on the periodontal environment of second molars. A pilot study]. AB - INTRODUCTION: Wisdom teeth extraction is a common procedure, generally considered as safe by patients. However, complications are possible, especially periodontal ones. The aim of this study was to evaluate the frequency and the consequences of periodontal complications at the level the 2nd molars after extraction of the wisdom teeth. MATERIAL AND METHODS: A single-center retrospective observational multi-operator study was conducted at the university hospital of Besancon - France. The files of all the adult patients who underwent extraction of four impacted wisdom teeth by mean of a standardized surgical technique between November 2012 and November 2014 and who could be followed 1 year postoperatively at least and that precisely mentioned the periodontal status of the surgical sites were included. Postoperative complications, gingival and plaque indexes according to Loe and Silness, periodontal attachment level and periodontal second molar probing were recorded. The main judgment criterion was the occurrence of a periodontal complication in the second molar areas. RESULTS: The files of 20 patients (15 women - 5 men), operated on by five different surgeons, met the inclusion criteria. Two patients suffered from dry socket at one of the avulsion sites. No patient had a gingival or plaque index greater than 2. No gingival recession or periodontal pocket over 4mm was found. DISCUSSION: Extraction of impacted third molars in young healthy adults didn't have any impact on the second molars periodontal environment in our study. Literature suggests that surgical technique greatly influences the occurrence and the extent of periodontal sequelae. PMID- 28343834 TI - Evaluating the impact of obesity on safety and efficacy of weight-based norepinephrine dosing in septic shock: A single-center, retrospective study. AB - OBJECTIVE: Norepinephrine is the first-line vasopressor recommended for patients in septic shock. Weight-based dosing may increase drug exposure and the risk of adverse effects in obese patients. The objective was to evaluate the safety and efficacy of weight-based norepinephrine dosing using actual body weight in the morbidly obese compared with normal weight patients. METHODS: This was a single centre, retrospective study of adult patients admitted with septic shock requiring norepinephrine for at least 12hours. The primary endpoint was the incidence of tachycardia within 48hours after norepinephrine initiation. Secondary endpoints included timing and dosing of norepinephrine when adjunctive agents were added. RESULTS: The incidence of tachycardia was similar between groups. Total norepinephrine exposure was significantly greater in obese patients on day 1 (p=0.02). Obese patients were more likely to be started on vasopressin (p<0.001) and steroids at a lower weight-based norepinephrine dose (p=0.016). CONCLUSIONS: Weight-based norepinephrine dosing using actual body weight did not result in more tachycardia in the morbidly obese compared to normal weight patients, despite greater total exposure. These results were limited by the low doses used and a small cohort. However, use of actual body weight in morbidly obese patients appears to be safe. PMID- 28343836 TI - Cervical Cancer: Prevention and Early Detection. AB - OBJECTIVE: To review effective methods of prevention that can be used to control the incidence of cervical cancer and detection strategies that can identify the precancerous lesions before they become true cancer. DATA SOURCES: Current medical, scientific and nursing literature, and national and international guidelines of cervical cancer. CONCLUSION: Nearly all cervical cancers are caused by specific types of human papillomavirus (HPV). Prophylactic vaccination for HPV provides the most effective method of primary prevention against HPV-related diseases. The use of the Pap test and HPV test, according to published guidelines, provides the most effective means of screening for cervical cancer. IMPLICATIONS FOR NURSING PRACTICE: Nurses are in a key position to provide health education with the goal of supporting vaccine uptake and screening guidelines. PMID- 28343835 TI - Cancer Screening and Early Detection in the 21st Century. AB - OBJECTIVE: To review the trends in and principles of cancer screening and early detection. DATA SOURCES: Journal articles, United States Preventive Services Task Force (USPSTF) publications, professional organization position statements, and evidence-based summaries. CONCLUSION: Cancer screening has contributed to decreasing the morbidity and mortality of cancer. Efforts to improve the selection of candidates for cancer screening, to understand the biological basis of carcinogenesis, and the development of new technologies for cancer screening will allow for improvements in cancer screening over time. IMPLICATIONS FOR NURSING PRACTICE: Nurses are well-positioned to lead the implementation of cancer screening recommendations in the 21st century through their practice, research, educational efforts, and advocacy. PMID- 28343837 TI - Gastrointestinal Cancers: Screening and Early Detection. AB - OBJECTIVE: To present an overview of current practices in the screening and early detection of gastrointestinal cancers. DATA SOURCES: Literature reviews. CONCLUSION: Screening for gastrointestinal cancers is less than desirable, particularly in underserved populations. There are inadequate methods of screening for early detection of esophageal and gastric cancers. IMPLICATIONS FOR NURSING PRACTICE: Education of patients is needed to reinforce the importance of screening for gastrointestinal cancers. PMID- 28343838 TI - Cancer Screening and Early Detection in Older People: Considerations for Nursing Practice. AB - OBJECTIVE: To synthesize relevant issues in cancer screening for older people for nursing practice. DATA SOURCES: Published scientific literature, clinical literature, and published cancer screening guidelines from the United States and Canada. CONCLUSION: Nurses are caring for increasing numbers of older patients and, with this demographic shift, face increasing demands to address cancer screening and detection in both primary and specialty practice. IMPLICATIONS FOR NURSING PRACTICE: Ageism, self-stereotyping, cancer fear and fatalism, and cancer survivorship experiences influence cancer screening and generate the need for improved awareness of these issues to advance nursing practice. PMID- 28343839 TI - Introduction. PMID- 28343840 TI - Prostate Cancer Screening. AB - OBJECTIVE: To review the current state of prostate cancer screening and future directions. DATA SOURCES: Nursing, medical and scientific literature related to prostate cancer screening, and national and international professional recommendations. CONCLUSION: Prostate cancer screening has been a topic of robust discussion for a number of years. Research continues to examine novel options for prostate cancer screening to either replace or compliment the prostate specific antigen test, but require additional validation before they will be widely accepted into clinical practice. IMPLICATIONS FOR NURSING PRACTICE: As new data emerges and professional organizations update their recommendations, it is important for oncology nurses to keep abreast of the latest developments to educate patients. PMID- 28343841 TI - Baroflex Activation Therapy for Refractory Congestive Heart Failure: Anesthetic Implications. PMID- 28343842 TI - Cranial nerve palsy following central neuraxial block in obstetrics - a review of the literature and analysis of 43 case reports. AB - BACKGROUND: Cranial nerve palsy is a rarely reported complication of central neuraxial block in obstetrics. The aetiology is diverse and includes both decreased and increased intracranial pressure. METHODS: Medline, CINAHL, and EMBASE databases were searched to identify cases of cranial nerve palsy following obstetric central neuraxial block. Possible aetiology, clinical symptoms and signs, treatment, and time to resolution were assessed. RESULTS: Forty-one articles containing 43 case reports of cranial nerve palsy following obstetric central neuraxial block were identified. Four cranial nerve palsies were bilateral; the remainder being unilateral. The cranial nerves most commonly affected were the abducens (17 case reports) and facial (12 case reports) nerves. Epidural block was implicated in 25 cases. Classical post-dural puncture headache preceded cranial nerve palsy in 27 cases. Subdural haematomas were reported in six cases and cortical venous or transverse sinus thrombosis in one case. Epidural blood patch was administered for treatment of cranial nerve palsy in 17 cases. Thirty-five patients had complete resolution of symptoms but in eight the cranial nerve palsy was permanent. No case reports of olfactory, oculomotor, glossopharyngeal, accessory or hypoglossal nerve palsy were identified. CONCLUSION: Intracranial hypotension is the most common aetiology of cranial nerve palsy after central neuraxial block in obstetrics. Neuroimaging is recommended in every case, to exclude other neurological causes. Epidural blood patch was the most utilised treatment for post-dural puncture cranial nerve palsy, but outcomes were variable. The majority of cranial nerve palsies resolved over the subsequent weeks and months. PMID- 28343843 TI - alphaS1-Casein elucidate major T-cell responses in cow's milk allergy. PMID- 28343844 TI - Inflammatory and autoimmune manifestations in X-linked carriers of chronic granulomatous disease in the United Kingdom. PMID- 28343845 TI - Curcumin inhibits Zika and chikungunya virus infection by inhibiting cell binding. AB - Several compounds extracted from spices and herbs exhibit antiviral effects in vitro, suggesting potential pharmacological uses. Curcumin, a component of turmeric, has been used as a food additive and herbal supplement due to its potential medicinal properties. Previously, curcumin exhibited antiviral properties against several viruses, including dengue virus and hepatitis C virus, among others. Here, we describe the antiviral effect of curcumin on Zika and chikungunya viruses, two mosquito-borne outbreak viruses. Both viruses responded to treatment of cells with up to 5 MUM curumin without impacting cellular viability. We observed that direct treatment of virus with curcumin reduced infectivity of virus in a dose- and time-dependent manner for these enveloped viruses, as well as vesicular stomatitis virus. In contrast, we found no change in infectivity for Coxsackievirus B3, a non-enveloped virus. Derivatives of curcumin also exhibited antiviral activity against enveloped viruses. Further examination revealed that curcumin interfered with the binding of the enveloped viruses to cells in a dose-dependent manner, though the integrity of the viral RNA was maintained. Together, these results expand the family of viruses sensitive to curcumin and provide a mechanism of action for curcumin's effect on these enveloped viruses. PMID- 28343847 TI - Global developmental delay and intellectual disability associated with a de novo TOP2B mutation. AB - BACKGROUND: More than 100 genes had been identified for autism spectrum disorder (ASD). With the advancement of whole-exome/genome sequencing (WES/WGS), disease causing gene in ASD can be identified in a holistic and unbiased approach. The identification of new ASD genes can further explore the molecular basis of ASD. METHODS: We report a 15yo girl with developmental delay, intellectual disability, hypotonia, microcephaly and autistic feature. She first presented at 6months old with primitive response to noise. Physical examination showed the patient was hypotonic despite normal muscle power and reflexes. She also had progressive microcephaly. Developmental assessment at 6y showed the patient had a corresponding functional age of 1y. The patient also had autistic feature. RESULTS: The patient had no abnormal biochemical or radiological findings. To investigate the molecular basis of the clinical presentation, we applied clinical whole-exome sequencing (WES) for the proband and the family, and we identified a novel de novo heterozygous missense pathogenic variant, TOP2B: NM_001068.2:c.172C>T; NP_001059.2:p.His58Tyr. TOP2B encodes for the enzyme, topoisomerase II isoenzyme beta which is abundant in both developing and adult brain. Defect of topoisomerase is also known to cause ASD. CONCLUSIONS: Using clinical WES, we were able to identify the disease-causing gene for this patient in a holistic approach and end the diagnostic odyssey with a therapeutic impact. PMID- 28343846 TI - Higher levels of IL-6, CD4 turnover and Treg frequency are already present before cART in HIV-infected subjects with later low CD4 recovery. AB - Immunological characterization of HIV-infected subjects with low CD4-recovery (LR subjects) has been extensively performed after a variable period of combined antiretroviral therapy (cART). We now explore immunological alterations present before the cART onset. In a case-control study, we selected pre-cART samples of HIV-subjects with and without low CD4-recovery after cART (n = 21 per group). CD4 T-cell activation, senescence and exhaustion related markers were not found specifically altered before cART initiation. On the other hand, we found that LR subjects before cART already showed increased levels of IL6 (p = 0.009) and increased frequencies of Ki67+CD4+ T-cells (p = 0.026), CD45RA-CD27+CD4+ T-cells (p = 0.008) and Treg (p = 0.001), as well as increased expression of CD95 and CD127 on CD4 T-cells (p = 0.016; p = 0.032, respectively). These parameters characterize the immunological damage in LR-subjects before the cART onset and could be associated to the mechanisms hindering the subsequent CD4 recovery. PMID- 28343848 TI - Capillary dysfunction is associated with symptom severity and neurodegeneration in Alzheimer's disease. AB - INTRODUCTION: We examined whether cortical microvascular blood volume and hemodynamics in Alzheimer's disease (AD) are consistent with tissue hypoxia and whether they correlate with cognitive performance and the degree of cortical thinning. METHODS: Thirty-two AD patients underwent cognitive testing, structural magnetic resonance imaging (MRI), and perfusion MRI at baseline and after 6 months. We measured cortical thickness, microvascular cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), and capillary transit time heterogeneity (CTH) and estimated tissue oxygen tension (PtO2). RESULTS: At baseline, poor cognitive performance and regional cortical thinning correlated with lower CBF and CBV, with higher MTT and CTH and with low PtO2 across the cortex. Cognitive decline over time was associated with increasing whole brain relative transit time heterogeneity (RTH = CTH/MTT). DISCUSSION: Our results confirm the importance of microvascular pathology in AD. Deteriorating microvascular hemodynamics may cause hypoxia, which is known to precipitate amyloid retention. PMID- 28343849 TI - Oral anticoagulant therapy for older patients with atrial fibrillation: a review of current evidence. AB - Atrial fibrillation is more frequent in older patients, who have a higher risk of cardioembolic stroke and thromboembolism. Oral anticoagulant therapy is the standard of treatment for stroke prevention; however, under-prescription is still very common in older patients. The reasons underlying this phenomenon have not been systematically investigated, and true contraindications only partially account for it. An intimate skepticism on the real benefit-risk balance of oral anticoagulant therapy in the oldest patients seems to derive from the fact that most studies supporting it were conducted decades ago and included younger patients, with overall better functional and clinical status. In this review we will focus on the main barriers to anticoagulant therapy prescription in older patients and summarize the available evidences on the efficacy and safety of vitamin K antagonists and direct oral anticoagulants in this population. The encouraging evidence of a higher net clinical benefit of direct oral anticoagulants compared with warfarin should hopefully widen the treatment options also for frail individuals, thereby allowing a greater number of patients to be treated according to current international guidelines. PMID- 28343850 TI - Homeopathy provided by a national health service: Only in Italy? PMID- 28343851 TI - Somatosensory rehabilitation for allodynia in complex regional pain syndrome of the upper limb: A retrospective cohort study. AB - STUDY DESIGN: Retrospective cohort study. INTRODUCTION: Somatosensory rehabilitation is a standardized method of evaluation and conservative treatment of painful disorders of vibrotactile sensation, including the mechanical allodynia and burning pain of complex regional pain syndrome (CRPS). PURPOSE OF THE STUDY: The purpose of this study was to examine the effectiveness of somatosensory rehabilitation for reducing allodynia in persons with CRPS of 1 upper limb in a retrospective consecutive cohort of patients. METHODS: An independent chart review of all client records (May 2004-August 2015) in the Somatosensory Rehabilitation Centre (Fribourg, Switzerland) identified 48 persons meeting the Budapest criteria for CRPS of 1 limb who had undergone assessment and treatment. Outcomes of interest were the French version of the McGill Pain Questionnaire (Questionnaire de la Douleur St-Antoine [QDSA]), total area of allodynia as recorded by mapping the area of skin where a 15-g monofilament was perceived as painful, and the allodynia threshold (minimum pressure required to elicit pain within the allodynic territory). RESULTS: This cohort was primarily women (70%), with a mean age of 45 years (range: 18-74). Mean duration of burning pain was 31 months (range: 1 week-27.5 years), and baseline QDSA core was 48. The average primary area of allodynia was 66 cm2 (range: 2.6-320), and the most common allodynia threshold was 4.0 g. The average duration of treatment was 81 days. At cessation of treatment, the average QDSA score was 20 (effect size Cohen's d = 1.64). Allodynia completely resolved in 27 persons (56% of the total sample where only 58% completed treatment). DISCUSSION: This uncontrolled retrospective study suggests that somatosensory rehabilitation may be an effective treatment with a large effect size for reducing the allodynia and painful sensations associated with CRPS of the upper limb. More work is in progress to provide estimates of reliability and validity for the measurement tools for allodynia employed by this method. LEVEL OF EVIDENCE: 2c. PMID- 28343852 TI - Hand grip strength and dexterity function in children aged 6-12 years: A cross sectional study. AB - STUDY DESIGN: Cross-sectional and clinical measurement. INTRODUCTION: Assessment of hand function considers an essential part in clinical practice. PURPOSE OF THE STUDY: To develop normative values of hand grip strength and dexterity function for 6-12-year-old children in Saudi Arabia. METHODS: Grip strength and dexterity function was measured in 525 children using Grip Track hand dynamometer (JTECH Medical, Midvale, UT, USA) and 9-hole pegboard test respectively. RESULTS: The grip strength and dexterity function was improved as age progressed regardless of gender. Across all age groups, the hand grip strength of boys was significantly higher than girls for dominant hand (31.75 +/- 10.33 vs 28.24 +/- 9.35; P < .001) and nondominant hand (31.01 +/- 10.27 vs 27.27 +/- 9.30; P < .001). The girls performed slightly faster than boys for dominant hand (19.70 vs 20.68; P < .05) and nondominant hand (21.79 vs 23.46; P < .05). In general, girls completed a 9 HPT faster than boys in the 2 of 7 age groups: 11 years (9-HPT scores = 2.10 seconds; P < .01) and 12 years (9-HPT scores = 1.93 seconds; P < .01). DISCUSSION: The overall patterns of hand grip strength and dexterity function observed in the present study are similar to the previous studies that established acceleration of grip strength with advanced age, and faster performance scores in older children than younger children in both genders. CONCLUSIONS: Norms of hand grip strength and dexterity enable therapists to identify some developmental characteristics of hand function among Saudi children, determine the presence of impairment, and compare scores from children in different clinical settings. LEVEL OF EVIDENCE: Not applicable. PMID- 28343853 TI - Factors influencing functional outcome of proximal interphalangeal joint collateral ligament injury when treated with buddy strapping and exercise. AB - STUDY DESIGN: Prospective cohort. INTRODUCTION AND PURPOSE: This study evaluates the factors influencing treatment outcomes of proximal interphalangeal (PIP) joint collateral ligament injuries when treated with buddy strapping. METHODS: Sixty-seven patients treated with buddy strapping for a PIP joint injury were enrolled. The finger range of motion (ROM), grip strength, and a Quick Disability of the Arm, Shoulder, and Hand (QuickDASH) score were assessed at 3 and 6 months after the initial injury. The factors that were assessed for their influence on the functional outcomes included age, sex, hand dominance, affected finger, type of injury, injury severity, time to treatment, the duration of buddy strapping, and exercise training. RESULTS: Buddy strapping for PIP joint injuries led to satisfactory results with 77% recovery of grip strength, 84% recovery in ROM, and mean QuickDASH scores of 14 at 6 months. A decrease in grip strength was associated with an increase in age and injury severity at 6 months, and these 2 factors accounted for 22% of the variance in the grip strength. A decrease in ROM was associated with the delayed treatment, which accounted for 18% of the variance in ROM at 6 months. An increased disability was associated with delayed treatment, female gender, and radial digit injury at 3 months, and these 3 factors accounted for 37% of the variance in disability. At 6 months, only the delayed treatment remained an associated factor, which accounted for 20% variance in disability. DISCUSSION AND CONCLUSIONS: PIP collateral ligament injuries had very good outcomes with buddy strapping. However, delayed treatment was significantly associated with poor functional outcomes in terms of the ROM and disability. An increase in age and injury severity were associated with lower grip strength up to 6 months, whereas a female gender and radial digit injury were associated with an increased disability up to 3 months. LEVEL OF EVIDENCE: 2. PMID- 28343855 TI - Outbreak of group A streptococcal pharyngitis at a national sports competition in Montevideo, Uruguay. PMID- 28343854 TI - Effect of Maryland's 2011 Alcohol Sales Tax Increase on Alcohol-Positive Driving. AB - INTRODUCTION: The 2011 Maryland alcohol sales tax increase from 6% to 9% provided an opportunity to evaluate the impact on rates of alcohol-positive drivers involved in injury crashes. METHODS: Maryland police crash reports from 2001 to 2013 were analyzed using an interrupted time series design and a multivariable analysis employing generalized estimating equations models with a negative binomial distribution. Data were analyzed in 2014-2015. RESULTS: There was a significant gradual annual reduction of 6% in the population-based rate of all alcohol-positive drivers (p<0.03), and a 12% reduction for drivers aged 15-20 years (p<0.007), and 21-34 years (p<0.001) following the alcohol sales tax increase. There were no significant changes in rates of alcohol-positive drivers aged 35-54 years (rate ratio, 0.98; 95% CI=0.89, 1.09). Drivers aged >=55 years had a significant immediate 10% increase in the rate of alcohol-positive drivers (rate ratio, 1.10; 95% CI=1.04, 1.16) and a gradual increase of 4.8% per year after the intervention. Models using different denominators and controlling for multiple factors including a proxy for unmeasured factors found similar results overall. CONCLUSIONS: The 2011 Maryland alcohol sales tax increase led to a significant reduction in the rate of all alcohol-positive drivers involved in injury crashes especially among drivers aged 15-34 years. This is the first study to examine the impact of alcohol sales taxes on crashes; previous research focused on excise tax. Increasing alcohol taxes is an important but often neglected intervention to reduce alcohol-impaired driving. PMID- 28343856 TI - Contribution to the knowledge of pathogenic fungi of spiders in Argentina. Southernmost record in the world. AB - The aim of this study was to identify entomopathogenic fungi infecting spiders (Araneae) in a protected area of Buenos Aires province, Argentina. The Araneae species identified was Stenoterommata platensis. The pathogens identified were Lecanicillium aphanocladii Zare & W. Gams, Purpureocillium lilacinum (Thom) Luangsa-ard, Houbraken, Hywel Jones & Samson and Ophiocordyceps caloceroides (Berk & M.A. Curtis). This study constitutes the southernmost records in the world and contributes to expanding the knowledge of the biodiversity of pathogenic fungi of spiders in Argentina. PMID- 28343857 TI - Staphylococcus aureus nasal carriage in health care workers: First report from a major public hospital in Argentina. AB - Staphylococcus aureus causes numerous mild to severe infections in humans, both in health facilities and in the community. Patients and health care workers (HCWs) may disseminate strains during regular medical examinations or hospitalization. The aim of this study was to determine the nasal carriage rate of methicillin-susceptible and methicillin-resistant S. aureus among health care workers at Hospital Provincial del Centenario, a public general hospital in Rosario, Argentina. A transversal study was conducted on 320 health care workers. Nasal swabs were taken and presumptive S. aureus colonies were isolated. Bacterial identity and methicillin resistance status were confirmed by amplification of the nuc and mec genes. Chi square test and Fisher exact test were used for statistical analysis. Of 320 HCWs, 96 (30%) were nasal carriers of S. aureus, 20 of whom (6.3%) carried methicillin-resistant S. aureus (MRSA) and 76 (23.7%) methicillin-susceptible S. aureus (MSSA). Carriage was within thepublished values for physicians (30%) and higher for technicians (57%). Accompanying resistance (62/96, 64.6%) was detected, including resistance to fluoroquinolones (23/96, 24%), aminoglucosides (13/96, 13.5%) or to macrolides (33/96, 34.4%). All the strains were susceptible to vancomycin whereas only 3.1% (3/96), all of them on MSSA strains, were resistant to mupirocin. This study is the first one of its kind in Argentina and one of the few performed in South America, to highlight the relevance of nasal carriage of MRSA and MSSA in health care personnel and brings to light the need for consensus recommendations for regular S. aureus carriage screening as well as for decolonization strategies. PMID- 28343858 TI - [Inhibitory capacity of Lactobacillus spp. against pathogens involved in foodborne diseases]. AB - The genus Lactobacillus daily generates a growing interest among microbiologists and technologists, who try to discover new biotechnological applications and probiotic properties. The main goal of this study was to evaluate the inhibitory capacity of Lactobacillus spp. against pathogens (Escherichia coli O157:H7, Salmonella spp., Staphylococcus aureus) involved in foodborne diseases. For this purpose, samples were collected at different stages of the pork production chain. Seventy eight bacterial strains were isolated. Twenty seven (27) of these strains (37.18%) had genotypic and phenotypic characteristics corresponding to Lactobacillus spp. whereas 85.18% of them showed inhibitory capacity. These data showed that the studied strains represent a potential alternative to inactivate foodborne pathogens and thus provide safe food to consumers. PMID- 28343859 TI - [Azospirillum brasilense Az39 labeled with GFP in Arabidopsis thaliana roots]. PMID- 28343860 TI - Mesophilic continuous fermentative hydrogen production from acid pretreated de oiled jatropha waste hydrolysate using immobilized microorganisms. AB - Mesophilic hydrogen production from acid pretreated hydrolysate (biomass concentration of 100g/L and 2% hydrochloric acid) of de-oiled jatropha waste was carried out in continuous system using immobilized microorganisms at various hydraulic retention times (HRTs) ranging from 48 to 12h. The experimental results of the reusability of immobilized microorganisms showed their stability up to 10 cycles with an average cumulative hydrogen production of 770mL/L. The peak hydrogen production rate and hydrogen yield were 0.9L/L*d and 86mL/greducing sugars added, respectively at 16h HRT, with butyrate as the predominant volatile fatty acid. The microbial community analysis revealed that majority of the PCR DGGE bands were assigned to genus Clostridium and were perhaps the key drivers of the higher hydrogen production. PMID- 28343861 TI - Oxidative biodegradation of 4-chlorophenol by using recombinant monooxygenase cloned and overexpressed from Arthrobacter chlorophenolicus A6. AB - In this study, cphC-I and cphB, encoding a putative two-component flavin diffusible monooxygenase (TC-FDM) complex, were cloned from Arthrobacter chlorophenolicus A6. The corresponding enzymes were overexpressed to assess the feasibility of their utilization for the oxidative decomposition of 4 chlorophenol (4-CP). Soluble CphC-I was produced at a high level (~50%), and subsequently purified. Since CphB was expressed in an insoluble form, a flavin reductase, Fre, cloned from Escherichia coli was used as an alternative reductase. CphC-I utilized cofactor FADH2, which was reduced by Fre for the hydroxylation of 4-CP. This recombinant enzyme complex exhibited a higher specific activity for the oxidation of 4-CP (45.34U/mg-protein) than that exhibited by CphC-I contained in cells (0.18U/mg-protein). The Michaelis-Menten kinetic parameters were determined as: vmax=223.3MUM.min-1, KM=249.4MUM, and kcat/KM=0.052min-1.MUM-1. These results could be useful for the development of a new biochemical remediation technique based on enzymatic agents catalyzing the degradation of phenolic contaminants. PMID- 28343862 TI - Phosphorus and short-chain fatty acids recovery from waste activated sludge by anaerobic fermentation: Effect of acid or alkali pretreatment. AB - Waste activated sludge (WAS) was pretreated by acid or alkali to enhance the anaerobic fermentation (AF) for phosphorus (P) and short-chain fatty acids (SCFAs) release into the liquid simultaneously. With acid pretreatment, the released total P concentration achieved 120mg/L, which was 71.4% higher than that with alkali pretreatment. In addition, alkali pretreatment enhanced organic P release with about 35.3% of organic P in the solid being converted to inorganic P, while little had changed with acid pretreatment. The results also showed that acid and alkali pretreatment enhanced SCFAs production by 15.3 and 12.5times, respectively. Acid pretreatment could be preferred for simultaneous recovery of P and SCFAs by AF. PMID- 28343863 TI - Emerging role of Geographical Information System (GIS), Life Cycle Assessment (LCA) and spatial LCA (GIS-LCA) in sustainable bioenergy planning. AB - Sustainability of a bioenergy project depends on precise assessment of biomass resource, planning of cost-effective logistics and evaluation of possible environmental implications. In this context, this paper reviews the role and applications of geo-spatial tool such as Geographical Information System (GIS) for precise agro-residue resource assessment, biomass logistic and power plant design. Further, application of Life Cycle Assessment (LCA) in understanding the potential impact of agro-residue bioenergy generation on different ecosystem services has also been reviewed and limitations associated with LCA variability and uncertainty were discussed. Usefulness of integration of GIS into LCA (i.e. spatial LCA) to overcome the limitations of conventional LCA and to produce a holistic evaluation of the environmental benefits and concerns of bioenergy is also reviewed. Application of GIS, LCA and spatial LCA can help alleviate the challenges faced by ambitious bioenergy projects by addressing both economics and environmental goals. PMID- 28343864 TI - Diazepam Binding Inhibitor Promotes Stem Cell Expansion Controlling Environment Dependent Neurogenesis. AB - Plasticity of adult neurogenesis supports adaptation to environmental changes. The identification of molecular mediators that signal these changes to neural progenitors in the niche has remained elusive. Here we report that diazepam binding inhibitor (DBI) is crucial in supporting an adaptive mechanism in response to changes in the environment. We provide evidence that DBI is expressed in stem cells in all neurogenic niches of the postnatal brain. Focusing on the hippocampal subgranular zone (SGZ) and employing multiple genetic manipulations in vivo, we demonstrate that DBI regulates the balance between preserving the stem cell pool and neurogenesis. Specifically, DBI dampens GABA activity in stem cells, thereby sustaining the proproliferative effect of physical exercise and enriched environment. Our data lend credence to the notion that the modulatory effect of DBI constitutes a general mechanism that regulates postnatal neurogenesis. PMID- 28343866 TI - Selective Entrainment of Theta Oscillations in the Dorsal Stream Causally Enhances Auditory Working Memory Performance. AB - The implication of the dorsal stream in manipulating auditory information in working memory has been recently established. However, the oscillatory dynamics within this network and its causal relationship with behavior remain undefined. Using simultaneous MEG/EEG, we show that theta oscillations in the dorsal stream predict participants' manipulation abilities during memory retention in a task requiring the comparison of two patterns differing in temporal order. We investigated the causal relationship between brain oscillations and behavior by applying theta-rhythmic TMS combined with EEG over the MEG-identified target (left intraparietal sulcus) during the silent interval between the two stimuli. Rhythmic TMS entrained theta oscillation and boosted participants' accuracy. TMS induced oscillatory entrainment scaled with behavioral enhancement, and both gains varied with participants' baseline abilities. These effects were not seen for a melody-comparison control task and were not observed for arrhythmic TMS. These data establish theta activity in the dorsal stream as causally related to memory manipulation. VIDEO ABSTRACT. PMID- 28343865 TI - Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31. AB - Microsatellite expansion disorders are pathologically characterized by RNA foci formation and repeat-associated non-AUG (RAN) translation. However, their underlying pathomechanisms and regulation of RAN translation remain unknown. We report that expression of expanded UGGAA (UGGAAexp) repeats, responsible for spinocerebellar ataxia type 31 (SCA31) in Drosophila, causes neurodegeneration accompanied by accumulation of UGGAAexp RNA foci and translation of repeat associated pentapeptide repeat (PPR) proteins, consistent with observations in SCA31 patient brains. We revealed that motor-neuron disease (MND)-linked RNA binding proteins (RBPs), TDP-43, FUS, and hnRNPA2B1, bind to and induce structural alteration of UGGAAexp. These RBPs suppress UGGAAexp-mediated toxicity in Drosophila by functioning as RNA chaperones for proper UGGAAexp folding and regulation of PPR translation. Furthermore, nontoxic short UGGAA repeat RNA suppressed mutated RBP aggregation and toxicity in MND Drosophila models. Thus, functional crosstalk of the RNA/RBP network regulates their own quality and balance, suggesting convergence of pathomechanisms in microsatellite expansion disorders and RBP proteinopathies. PMID- 28343867 TI - Grid and Nongrid Cells in Medial Entorhinal Cortex Represent Spatial Location and Environmental Features with Complementary Coding Schemes. AB - The medial entorhinal cortex (mEC) has been identified as a hub for spatial information processing by the discovery of grid, border, and head-direction cells. Here we find that in addition to these well-characterized classes, nearly all of the remaining two-thirds of mEC cells can be categorized as spatially selective. We refer to these cells as nongrid spatial cells and confirmed that their spatial firing patterns were unrelated to running speed and highly reproducible within the same environment. However, in response to manipulations of environmental features, such as box shape or box color, nongrid spatial cells completely reorganized their spatial firing patterns. At the same time, grid cells retained their spatial alignment and predominantly responded with redistributed firing rates across their grid fields. Thus, mEC contains a joint representation of both spatial and environmental feature content, with specialized cell types showing different types of integrated coding of multimodal information. PMID- 28343868 TI - Medial Prefrontal Cortex Reduces Memory Interference by Modifying Hippocampal Encoding. AB - The prefrontal cortex (PFC) is crucial for accurate memory performance when prior knowledge interferes with new learning, but the mechanisms that minimize proactive interference are unknown. To investigate these, we assessed the influence of medial PFC (mPFC) activity on spatial learning and hippocampal coding in a plus maze task that requires both structures. mPFC inactivation did not impair spatial learning or retrieval per se, but impaired the ability to follow changing spatial rules. mPFC and CA1 ensembles recorded simultaneously predicted goal choices and tracked changing rules; inactivating mPFC attenuated CA1 prospective coding. mPFC activity modified CA1 codes during learning, which in turn predicted how quickly rats adapted to subsequent rule changes. The results suggest that task rules signaled by the mPFC become incorporated into hippocampal representations and support prospective coding. By this mechanism, mPFC activity prevents interference by "teaching" the hippocampus to retrieve distinct representations of similar circumstances. PMID- 28343869 TI - Spatiotemporal Regulation of Synaptic Vesicle Fusion Sites in Central Synapses. AB - The number and availability of vesicle release sites at the synaptic active zone (AZ) are critical factors governing neurotransmitter release; yet, these fundamental synaptic parameters have remained undetermined. Moreover, how neural activity regulates the spatiotemporal properties of the release sites within individual central synapses is unknown. Here, we combined a nanoscale imaging approach with advanced image analysis to detect individual vesicle fusion events with ~27 nm localization precision at single hippocampal synapses under physiological conditions. Our results revealed the presence of multiple distinct release sites within individual hippocampal synapses. Release sites were distributed throughout the AZ and underwent repeated reuse. Furthermore, the spatiotemporal properties of the release sites were activity dependent with a reduction in reuse frequency and a shift in location toward the AZ periphery during high-frequency stimulation. These findings have revealed fundamental spatiotemporal properties of individual release sites in small central synapses and their activity-dependent modulation. PMID- 28343870 TI - CD15 focus score: Infection diagnosis and stratification into low-virulence and high-virulence microbial pathogens in periprosthetic joint infection. AB - INTRODUCTION: The aim of the work was to validate the CD15 focus score for the infection pathology of periprosthetic joint infection in a large group and to clarify whether a stratification into low-virulence and high-virulence microbial pathogens is possible by means of the CD15 focus score (quantification of CD15 positive granulocytes). METHODS: The histopathology of 275 synovial tissue samples taken intraoperatively during revision operations (n=127 hip, n=141 knee, n=2 shoulder, n=5 ankle) was evaluated according to the SLIM consensus classification (SLIM=synovial-like interface membrane). Neutrophilic granulocytes (NG) were quantified by the CD15 focus score on the basis of the principle of focal maximum infiltration (focus) with evaluation of one field of vision (about 0.3mm2). The quantification values were compared with the microbiological diagnoses taking into consideration the virulence groups of low-virulence and high-virulence microbial pathogens and mixed infection. RESULTS: The patients with positive microbiological findings (n=160) had significantly (p<0.001, Mann Whitney U test) higher CD15 focus score values than patients with negative microbiological findings (n=115), the cut-off value being 39 cells per high power field (HPF). The CD15 focus score values of low-virulence microbial pathogens (n=94) were significantly lower (p<0.001, Mann-Whitney U test) than the values of high-virulence microbial pathogens (n=55), the cut-off value being 106 cells per HPF. Based on the microbiological diagnosis the sensitivity with respect to a microbial infection is 0.91, the specificity 0.92 (PPV=0.94; NPV=0.88; accuracy: 0.92; AUC=0.95). Based on the differentiation of the CD15 focus score values between low-virulence and high-virulence microbes the sensitivity is 0.70 and the specificity 0.77 (PPV=0.63; NPV=0.81; accuracy=0.74; AUC=0.74). CONCLUSION: As a result of the high sensitivity and specificity, the easy to use CD15 focus score is a diagnostically valid score for microbial periprosthetic infection. A differentiation between low-virulence and high-virulence microorganism of sufficiently high diagnostic quality is additionally possible as a result of the defined quantification of CD15 positive granulocytes (the CD15 focus score) histopathological diagnosis of microbial infections is possible, which on the one hand supports the microbiological diagnosis and on the other hand by the stratification into low-virulence and high-virulence microbial pathogens could represent an additional basis for a pathogen-specific antibiotic treatment in the event of unclear constellations of findings. PMID- 28343871 TI - Over-expression of CircRNA_100876 in non-small cell lung cancer and its prognostic value. AB - Circular RNAs (circRNAs) are a novel type of endogenous RNAs featuring stable structure and high tissue-specific expression. Recently, accumulating evidence has revealed that aberrant circRNAs expression plays important roles in carcinogenesis and tumor progression. However, the expression pattern and biological function of circRNAs in non small cell lung cancer (NSCLC) remain largely unknown. Therefore, the purpose of this study was to clarify the possible role of one of typical circRNAs, circRNA_100876 in NSCLC and to define its prognostic value in NSCLC. Quantitative real-time polymerase chain reaction (qRT PCR) was used to detect the expression of circRNA_100876 in tumor tissues and their adjacent nontumorous tissues in 101 patients with NSCLC. We found that the expression level of circRNA_100876 was significantly elevated in NSCLC tissues when compared with their adjacent nontumorous tissues (P=0.000). Moreover, there was a close correlation between the circRNA_100876 up-regulation expression and lymph node metastasis (P=0.001) and tumor staging (P=0.001) in NSCLC. In addition, Kaplan-Meier survival analysis demonstrated that the overall survival time of NSCLC patients with high circRNA_100876 expression was significantly shorter than those patients with low circRNA_100876 expression (P=0.000). In conclusion, our findings indicate that circRNA_100876 is closely related to the carcinogenesis of NSCLC and it might be served as a potential prognostic biomarker and therapeutic target for NSCLC. PMID- 28343872 TI - Orbital decompression for thyroid eye disease. AB - The literature regarding orbital decompression for thyroid eye disease is vast, spanning multiple specialty areas including neurosurgery, head and neck, maxillofacial, and ophthalmic plastic surgery. Although techniques have advanced considerably over the more than 100 years during which this procedure has been performed, the 4 major approaches remain: transorbital, transcranial, transantral, and transnasal. The explosion in literature related to orbital decompression has mostly involved minor technical variations on broader surgical themes. The purpose of this review is to organize the major approaches in terms of bony anatomy and to contextualize variation in transdisciplinary techniques within a common conceptualization. PMID- 28343873 TI - Transport of bacteria in porous media and its enhancement by surfactants for bioaugmentation: A review. AB - The success of bioaugmentation processes for groundwater bioremediation requires efficient transport of bacteria in the subsurface environment. In this paper, the factors that influence transport of bacterial cells in porous media are reviewed and the effects of surfactants on the transport are discussed. Movement of bacterial cells in porous media is a process driven by advection and hydrodynamic dispersion forces of fluids. Immobilization of bacterial cells takes place due to processes such as adsorption and straining. Blocking and ripening along with bacterial migration process decrease and increase the retention of cells in porous media, respectively. Physicochemical properties of the porous media, groundwater chemistry, and properties of the bacterial cells affect the transport behavior. Surfactants have the potential to modify bacterial surface properties for both bacterial cells and medium solids, and thus enhance bacterial transport. PMID- 28343874 TI - Synthesis and in vitro investigation of potential antiproliferative monosaccharide-d-secoestrone bioconjugates. AB - The syntheses of monosaccharide-d-secoestrone conjugates are reported. They were prepared from 3-(prop-2-inyloxy)-d-secoestrone alcohol or oxime and monosaccharide azides via Cu(I)-catalyzed azide-alkyne cycloaddition reactions (CuAAC). The antiproliferative activities of the conjugates were investigated in vitro against a panel of human adherent cancer cell lines (HeLa, A2780 and MCF-7) by means of MTT assays. The protected d-glucose-containing d-secoestrone oxime bioconjugate (24b) proved to be the most effective with an IC50 value in the low micromolar range against A2780 cell line. PMID- 28343875 TI - Discovery and structure-activity relationship studies of N-substituted indole derivatives as novel Mcl-1 inhibitors. AB - Myeloid cell leukemia-1 (Mcl-1) is an important antiapoptotic protein functioning through protein-protein interactions. We discovered LSL-A6 (2-((2-carbamoyl-1-(3 (4-methoxyphenoxy)propyl)-1H-indol-6-yl)oxy)acetic acid) with a novel N substituted indole scaffold to interfere Mcl-1 binding as a novel Mcl-1 inhibitor. Molecular modeling indicated that this compound binds with Mcl-1 by interaction with P2 and R263 hot-spots. Structure modification focused on several moieties including indole core, hydrophobic tail and acidic chain were conducted and structure-activity relationship was analyzed. The most potent compound 24d which exhibited Ki value of 110nM for interfering Mcl-1 binding was obtained after hit-to-lead modification. PMID- 28343876 TI - Constituents with potent alpha-glucosidase inhibitory activity from Pueraria lobata (Willd.) ohwi. AB - One new flavone hydrate named lobatflavate (1), one new chromone named lobatchrosin (2), and one new isoflavone named 3S,4R-tuberosin (3), along with four known isoflavone analogues (4-7), were isolated from the traditional Chinese medicinal plant of Pueraria lobata (Willd.) ohwi. Their structures were elucidated by extensive spectroscopic methods of IR, UV, HR-ESI-MS, 1D and 2D NMR. The absolute configuration of 3 was determined by CD spectrum associated with TD-DFT calculation analysis. All compounds except for 2 were assayed the inhibitory activity against alpha-glucosidase. Every tested compound was proved to be more active than positive control of acarbose. Of which 1 and 4 showed significant activity with IC50 value of 1.79MUM and 23.01MUM (IC50 of acarbose was 1998.79MUM). Enzyme kinetic experiments revealed that 1 was irreversible whereas 4 was reversible and non-competitive alpha-glucosidase inhibitors. Moreover, structure-activity relationship was discussed and the docking studies of 1, 3 and 4 were also carried out. PMID- 28343877 TI - What Are Nursing Facilities Doing to Reduce Potentially Avoidable Hospitalizations? AB - OBJECTIVES: Hospitalizations among nursing facility residents are frequent and often potentially avoidable. A number of initiatives and interventions have been developed to reduce excessive hospitalizations; however, little is known about the specific approaches nursing facilities use to address this issue. The objective of this study is to better understand which types of interventions nursing facilities have introduced to reduce potentially avoidable hospitalizations of long-stay nursing facility residents. DESIGN: Cross-sectional survey. SETTING: 236 nursing facilities from 7 states. PARTICIPANTS: Nursing facility administrators. MEASUREMENTS: Web-based survey to measure whether facilities introduced any policies or procedures designed specifically to reduce potentially avoidable hospitalizations of long-stay nursing facility residents between 2011 and 2015. We surveyed facilities about seven types of interventions and quality improvement activities related to reducing avoidable hospitalizations, including use of Interventions to Reduce Acute Care Transfers (INTERACT) and American Medical Directors Association tools. RESULTS: Ninety-five percent of responding nursing facilities reported having introduced at least one new policy or procedure to reduce nursing facility resident hospitalizations since January 2011. The most common practice reported was hospitalization rate tracking or review, followed by standardized communication tools, such as Situation, Background, Assessment, Recommendation (SBAR). We found some variation in the extent and types of these reported interventions. CONCLUSIONS: Nearly all facilities surveyed reported having introduced a variety of initiatives to reduce potentially avoidable hospitalizations, likely driven by federal, state, and corporate initiatives to decrease hospital admissions and readmissions. PMID- 28343878 TI - Ingested Intra-Abdominal Christmas Foreign Body in an Elderly Patient. PMID- 28343879 TI - Anorexia of Aging and Avoidant/Restrictive Food Intake Disorder. PMID- 28343880 TI - [Acute respiratory distress syndrome in childhood: Changing definition and news from the Pediatric Consensus Conference]. AB - Acute respiratory distress syndrome (ARDS) is a rapidly progressive hypoxemic respiratory insufficiency induced by alveolar filling mainly caused by alveolocapillary wall disruption, following direct or indirect pulmonary injury. Much less frequent in children than in adults, pediatric intensivists had long applied adult guidelines to their daily practice. In 2015, experts from the Pediatric Acute Lung Injury Consensus Conference (PALICC) published the first international guidelines specifically dedicated to pediatric ARDS. After a short summary of the history of the ARDS definition since its first report in 1967, we describe the main diagnostic and therapeutic guidelines for PALICC. PMID- 28343881 TI - Musculoskeletal pain in children, when hypermobility is the problem. PMID- 28343882 TI - A contemporary description of French newborns' growth using the Efemeris cohort. AB - BACKGROUND: Overweight and obesity in childhood are a major concern in developed countries. Reference growth curves are used in current practice to identify children at risk, especially at risk of overweight or obesity. National reference growth curves were published 35 years ago from children born in the 1950s to study growth from birth to adulthood. Additionally, more recent national curves exist to study birth weight and height according to gestational age. The primary objective was to describe anthropometric measurements of French children born in the 2000s and to compare them with the French references. The secondary objective was to describe overweight indicators during infancy. METHODS: A total of 77,315 singletons live-born from 1 July 2004 to 31 December 2013 recorded in the Efemeris (a French cohort of women and their children) were included. The z-score means based on the French references for weight, height, and body mass index (BMI) at birth, 9 months, and 24 months were calculated. RESULTS: At birth, the weight and height of the cohort did not deviate from the recent French references taking into account gestational age. At 9 and 24 months, the cohort was between 0.12 and 0.39 standard deviations (SD) heavier and between 0.70 and 0.97 SD taller than the old French reference population. Between 0 and 2 years, 28.6% of the children underwent a rapid weight gain (change in SD scores>0.67). The prevalence of overweight at 2 years was between 5 and 6% using the International obesity task force (IOTF) references. CONCLUSION: The distributions of the height, weight, and BMI during early childhood differ from those of children in the national growth references. Contemporary children at 2 years are taller and heavier than children born in the 1950s. Approximately one in 20 children is overweight at 2 years. PMID- 28343883 TI - [Disseminated actinomycosis treated with clindamycin]. AB - Actinomycosis is a rare bacterial disease caused by Actinomyces spp., an anaerobic bacteria from the oropharynx, digestive, and female genital tracts. Initial clinical presentation often mimics malignancy, which can lead to a delay in diagnosis. Cervico-facial, genitourinary, digestive, and respiratory features are the most frequent. Few cases are reported in children and risk factors are not well known in this population. We report on the case of an 8-year-old boy with disseminated actinomycosis with cervico-facial, pulmonary, and bone involvement caused by Actinomyces israelii. The infiltrative appearance initially suggested malignancy and the patient was started on chemotherapy for presumed histiocytosis. Evaluation of subsequent tissue samples demonstrated the presence of filamentous structures consistent with fungal or filamentous bacterial infection. Prolonged culture yielded the correct diagnosis. The patient had a severe allergic reaction to piperacillin/tazobactam and was therefore transitioned to clindamycin to complete a 9-month course. This treatment, which has not been reported in children, led to a favorable clinical, biological, and radiological response, with a good clinical tolerance. PMID- 28343884 TI - Short-term desensitization of fast escape behavior associated with suppression of Mauthner cell activity in larval zebrafish. AB - Escape is among the simplest animal behaviors employed to study the neural mechanisms underlying learning. Teleost fishes exhibit behavioral learning of fast escape initiated with a C-shaped body bend (C-start). C-starts are subdivided into short-latency (SLC) and long-latency (LLC) types in larval zebrafish. Whether these two can be separately modified, and the neural correlates of this modification, however, remains undetermined. We thus performed Ca2+ imaging of Mauthner (M-) cells, a pair of giant hindbrain neurons constituting a core element of SLC circuit, during behavioral learning in larval zebrafish. The Ca2+ response corresponding to a single spiking of the M-cells was coupled with SLCs but not LLCs. Conditioning with a repeated weak sound at subthreshold intensity to elicit C-starts selectively suppressed SLC occurrence for 10min without affecting LLC responsiveness. The short-term desensitization of SLC was associated with the suppression of M-cell activity, suggesting that changes in single neuron responsiveness mediate behavioral learning. The conditioning did not affect the acoustically evoked mechanotransduction of inner ear hair cells, further suggesting plastic change in transmission efficacy within the auditory input circuit between the hair cells and the M-cell. PMID- 28343886 TI - Cyclic seizures - A clue to seizure termination? PMID- 28343887 TI - Corrigendum to "Magnetoencephalography signals are influenced by skull defects" [Clin. Neurophysiol. 125 (2014) 1653-1662]. PMID- 28343885 TI - Carpal tunnel syndrome impairs index finger responses to unpredictable perturbations. AB - The fine-tuning of digit forces to object properties can be disrupted by carpal tunnel syndrome (CTS). CTS' effects on hand function have mainly been investigated using predictable manipulation tasks; however, unpredictable perturbations are commonly encountered during manual tasks, presenting situations which may be more challenging to CTS patients given their hand impairments. The purpose of this study was to investigate muscle and force responses of the index finger to unpredictable perturbations in patients with CTS. Nine CTS patients and nine asymptomatic controls were instructed to stop the movement of a sliding plate by increasing index finger force following an unexpected perturbation. The electrical activity of the first dorsal interosseous muscle and forces exerted by the index finger were recorded. CTS patients demonstrated 20.9% greater muscle response latency and 12.0% greater force response latency compared to controls (p<0.05). The duration of plate sliding was significantly different between groups (p<0.05); the CTS group's duration was 142.2+/-5.8ms compared to the control group's duration of 133.1+/-8.4ms. Although CTS patients had increased muscle and force response durations comparatively, these differences were not statistically significant. Findings from this study suggest CTS-induced sensorimotor deficits interfere with accurate detection, processing and response to unpredictable perturbations. These deficits could be accounted for at multiple levels of the peripheral and central nervous systems. Delayed and decreased responses may indicate inefficient object manipulation by CTS patients and may help to explain why CTS patients tend to drop objects. PMID- 28343888 TI - A muscle ultrasound score in the diagnosis of amyotrophic lateral sclerosis. AB - OBJECTIVE: The aims of this study are to elucidate the frequencies and distribution of fasciculations using muscle ultrasound in patients with amyotrophic lateral sclerosis (ALS) and those with other conditions mimicking ALS, and subsequently to develop a novel fasciculation score for the diagnosis of ALS. METHODS: Ultrasound of 21 muscles was performed to detect fasciculations in 36 consecutive patients suspected of having ALS. We developed a fasciculation ultrasound score that indicated the number of muscles with fasciculations in statistically selected muscles. RESULTS: A total of 525 muscles in 25 ALS patients and 231 in 11 non-ALS patients were analysed. Using relative operating characteristic and multivariate logistic regression analysis, we selected the trapezius, deltoid, biceps brachii, abductor pollicis brevis, abdominal, vastus lateralis, vastus medialis, biceps femoris, and gastrocnemius muscles for the fasciculation ultrasound score. The mean scores were higher in the ALS group than those in the non-ALS group (5.3+/-0.5vs. 0.3+/-0.7) (mean+/-SD); p<0.001. CONCLUSIONS: Two or more of the fasciculation ultrasound scores showed high sensitivity and specificity in differentiating ALS patients from non-ALS patients. SIGNIFICANCE: The fasciculation ultrasound score can be a simple and useful diagnostic marker of ALS. PMID- 28343889 TI - Feasibility, safety and efficacy of two-stage hepatectomy for bilobar liver metastases of colorectal cancer: a LiverMetSurvey analysis. AB - BACKGROUND: The combination of liver resection and chemotherapy has become the standard of care for colorectal liver metastases (LM). The objective of the present study was to evaluate the impact of two-stage hepatectomy (TSH) on the long-term survival of patients with bilobar LM. METHODS: We included adult (over 18) patients from the LiverMetSurvey registry with confirmed multiple colorectal LM and having undergone either one-stage hepatectomy or TSH with curative intent. The "TSH (2/2)" group (n = 625) comprised patients having completed both stages of TSH; the "TSH (1/2)" group (n = 244) comprised patients having undergone only the first stage of TSH; the "hepatectomy" group. The primary outcome criterion was the overall survival (OS). The secondary outcomes were the morbidity and mortality rates. RESULTS: The 30- and 90-day mortality rates were respectively 3.8% and 9.3% in the TSH (2/2) group, 9.4% and 16.4% in the TSH (1/2) group, and 5.4% and 9.1% in the "hepatectomy" group. The three-year OS rate was 45% in the TSH (2/2) group, 30% in the TSH (1/2) group and 50.7% in the hepatectomy group. CONCLUSION: The LiverMetSurvey registry's data indicate that TSH is associated with rather good long-term survival and acceptable morbidity and mortality rates. PMID- 28343890 TI - Glycine receptor subunits expression in the developing rat retina. AB - BACKGROUND AND METHODS: Glycine receptor (GlyR) consists of two alpha (1-4) and three beta subunits. Considerable evidence indicates that the adult retina expresses the four types of alpha subunits; however, the proportion of these subunits in adult and immature retina is almost unknown. In this report we have studied mRNA and the protein expression of GlyR subunits in the retina during postnatal rat development by Real-Time qRT-PCR and western blot. RESULTS: mRNA and protein expression indicated a gradual increase of the alpha1, alpha3, alpha4 and beta GlyR subunits during postnatal ages tested. The mRNA beta subunit showed higher expression levels (~3 fold) than those observed for the alpha1 and alpha3 subunits. Very interestingly, the alpha2 GlyR subunit had the highest expression in the retina, even in the adult. CONCLUSIONS: These results revealed the expression of GlyR at early postnatal ages, supporting its role in retina development. In addition, our results indicated that the adult retina expressed a high proportion of the alpha2 subunit, suggesting the expression of monomeric and/or heteromeric receptors. A variety of studies are needed to further characterize the role of the specific subunits in both adult and immature retina. PMID- 28343891 TI - An investigation on the effects of the angles between the mitral and aortic orifice during diastolic period using FSI. AB - BACKGROUND: It was well documented that the changes in the physiological structure of the heart can alter the hemodynamic behaviour of the human left ventricle. Although there were various imaging tools that can stipulate the blood flow characteristics inside the ventricle, but the effect of the variation in the angles between the mitral and aortic orifices were yet to be determined. Hence the primary focus of this paper was to use Fluid-Structure Interaction scheme throughout the diastolic phase to examine and determine the hemodynamic behaviour inside the cavity under various angles between the mitral and aortic orifices (50 degrees , 55 degrees and 60 degrees ). METHODS: The incompressible Newtonian liquid (time dependent), linear viscous liquid and stress tensor equations were combined together with the Navier-Stoke's equations and Arbitrary Lagrangian Eulerian and for the elasticity of the structure. RESULTS: During diastasis, the position of the vortex was seen to be slightly upwards (55 degrees ) compared to 50 degrees and 60 degrees . Also, the influence of the wall shear stress was primarily observed to be much higher with the rise in the inlet velocity but the effect was seen reduced when the inlet velocity was minimal. Moreover, at the end of the filling phase maximum intraventricular pressure was obtained to be at the tip of LV for 50 degrees compared to 55 degrees and 60 degrees . CONCLUSION: These findings provide significant insights on hemodynamic conditions and structural displacement, which from a clinical point of view would be useful in determining different conditions of cardiac diseases. PMID- 28343892 TI - How to Succeed in Academic Radiology: A Primer for Young Faculty Members. PMID- 28343893 TI - Local hemostatic matrix for endoscope-assisted removal of intracerebral hemorrhage is safe and effective. AB - BACKGROUND/PURPOSE: Minimally invasive endoscope-assisted (MIE) evacuation of spontaneous intracerebral hemorrhage (ICH) is simple and effective, but the limited working space may hinder meticulous hemostasis and might lead to rebleeding. Management of intraoperative hemorrhage is therefore a critical issue of this study. This study presents experience in the treatment of patients with various types of ICH by MIE evacuation followed by direct local injection of FloSeal Hemostatic Matrix (Baxter Healthcare Corp, Fremont, CA, USA) for hemostasis. METHODS: The retrospective nonrandomized clinical and radiology-based analysis enrolled 42 patients treated with MIE evacuation of ICH followed by direct local injection of FloSeal Hemostatic Matrix. Rebleeding, morbidity, and mortality were the primary endpoints. The percentage of hematoma evacuated was calculated from the pre- and postoperative brain computed tomography (CT) scans. Extended Glasgow Outcome Scale (GOSE) was evaluated at 6 months postoperatively. RESULTS: Forty-two ICH patients were included in this study, among these, 23 patients were putaminal hemorrhage, 16 were thalamic ICH, and the other three were subcortical type. Surgery-related mortality was 2.4%. The average percentage of hematoma evacuated was 80.8%, and the rebleeding rate was 4.8%. The mean operative time was 102.7 minutes and the average blood loss was 84.9 mL. The mean postoperative GOSE score was 4.55 at 6-months' follow-up. CONCLUSION: This study shows that local application of FloSeal Hemostatic Matrix is safe and effective for hemostasis during MIE evacuation of ICH. In our experience, this shortens the operation time, especially in cases with intraoperative bleeding. A large, prospective, randomized trial is needed to confirm the findings. PMID- 28343894 TI - [1-9-NalphaC]-crourorb A1 isolated from Croton urucurana latex induces G2/M cell cycle arrest and apoptosis in human hepatocarcinoma cells. AB - [1-9-NalphaC]-crourorb A1 is a cyclic peptide isolated from Croton urucurana Baillon latex, found in midwestern Brazil, that has been shown to exert cytotoxic effects against a panel of cancer cell lines. However, the underlying mechanisms responsible for the crourorb A1-induced cytotoxicity in cancer cells remain unknown. In this study, the effects of crourorb A1 on the viability, apoptosis, cell cycle and migration of Huh-7 (human hepatocarcinoma) cells were investigated. We evaluated the viability of Huh-7 cells treated with crourorb A1 in 2D and 3D collagen cultures and found that cells in 3D culture exhibited increased resistance to crourorb A1 compared to cells in 2D culture (IC50: 62MUg/ml versus 35.75MUg/ml). Crourorb A1 treatment decreases the viability of Huh-7 cells in a dose- and time-dependent manner and is associated with the induction of apoptosis, in the absence of necrotic cells, through the activation of caspase-3/7 and increased expression of the pro-apoptotic proteins Bak, Bid, Bax, Puma, Bim, and Bad. The effects of crourorb A1 are also associated with G2/M phase cell cycle arrest and increases in cyclin-dependent kinase (CDK1) and cyclin B1 expression. A significant reduction in Huh-7 cell migration induced by crourorb A1 was also observed in the presence of mitomycin C. Finally, we showed that the JNK/MAP pathway, but not ERK signaling, is involved in crourorb A1 induced hepatocarcinoma cell mortality. PMID- 28343895 TI - Pharmacokinetic profile of promising acetylcholinesterase reactivators K027 and K203 in experimental pigs. AB - Standard treatment of organophosphorus compounds (OPs) poisoning includes administration of an anti-muscarinic (atropine), anticonvulsive (diazepam) and acetylcholinesterase reactivator (oxime). From a wide group of newly synthesized oximes, oxime K027 and oxime K203 seem to be perspective compounds in some specific OPs intoxication. The available in vitro and in vivo preclinical data indicate that both oximes may be considered for potential human use. The main aim of this study was to establish plasmatic concentration curves of both oximes after intramuscular (i.m.) and intragastric (i.g.) application with subsequent pharmacokinetic analysis and study distribution after (i.m.) application on a non rodent animal model (experimental pigs; 1500mg/animal). According to the results, both oximes had similar Cmax (K027: 106+/-19MUg/mL and K203: 111+/-8MUg/mL) in Tmax 19+/-5min, respectively, in 22+/-3min. Bioavailability of oxime K027 calculated as AUCtotal (8389+/-1024minMUg/mL) was halved compared to oxime K203 (16938+/-795minMUg/mL). The highest concentration from peripheral tissues was found in the kidney and lung, but the brain concentrations stay very low, the plasma/brain ratio being approximately 1%. The applied doses were derived from the recommendation where it is possible to use three autoinjectors to save human life. The results provide us with knowledge about the pharmacokinetics and distribution of these new oximes and may help us to better estimate the human pharmacokinetic profile. PMID- 28343896 TI - Assessment of hepatic function decline after stereotactic body radiation therapy for primary liver cancer. AB - PURPOSE: This study aims to determine how the albumin-bilirubin (ALBI) score compares with the Child-Pugh (CP) score for assessing liver function following stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: In total, 60 patients, 40 with hepatocellular carcinoma (HCC) and 20 with cholangiocarcinoma (CCA), were treated with SBRT. Liver function panels were obtained before and at 1, 3, 6, and 12 months after SBRT. Laboratory values were censored after locoregional recurrence, further liver-directed therapies, or liver transplant. RESULTS: A significant decline in hepatic function occurred after SBRT for HCC patients only (P = .001 by ALBI score; P < .0001 by CP score). By converting radiation doses to biologically equivalent doses by using a standard linear quadratic model using alpha/beta of 10, the strongest dosimetric predictor of liver function decline for HCC was the volume of normal liver irradiated by a dose of 40 Gy when assessing liver function by the ALBI score (P = .07), and the volume of normal liver irradiated by a dose of 20 Gy by using the CP score (P= .0009). For CCA patients, the volume of normal liver irradiated by a dose of 40 Gy remained the strongest dosimetric predictor when using the ALBI score (P = .002), but no dosimetric predictor was significant using the CP score. Hepatic function decline correlated with worse overall survival for HCC (by ALBI, P = .0005; by CP, P < .0001) and for CCA (by ALBI, P = NS; by CP, P = .008). CONCLUSIONS: ALBI score was similarly able to predict hepatic function decline compared with CP score, and both systems correlated with survival. PMID- 28343897 TI - PepperHub, an Informatics Hub for the Chili Pepper Research Community. PMID- 28343898 TI - Comparison of human mesenchymal stromal cells from four neonatal tissues: Amniotic membrane, chorionic membrane, placental decidua and umbilical cord. AB - BACKGROUND: Mesenchymal stromal cells (MSCs) are being investigated as a potential alternative for cellular therapy. This study was designed to compare the biological characteristics of MSCs isolated from amniotic membrane (A-MSCs), chorionic membrane (C-MSCs), placental decidua (D-MSCs) and umbilical cord (UC MSCs) to ascertain whether any one of these sources is superior to the others for cellular therapy purposes. METHODS: MSCs were isolated from amniotic membrane, chorionic membrane, umbilical cord and placental decidua. Immunophenotype, differentiation ability, cell size, cell complexity, polarity index and growth kinetics of MSCs isolated from these four sources were analyzed. RESULTS: MSCs were successfully isolated from all four sources. Surface marker profile and differentiation ability were consistent with human MSCs. C-MSCs in suspension were the smallest cells, whereas UC-MSCs presented the greatest length and least width. A-MSCs had the lowest polarity index and UC-MSCs, as more elongated cells, the highest. C-MSCs, D-MSCs and UC-MSCs exhibited similar growth capacity until passage 8 (P8); C-MSCs presented better lifespan, whereas insignificant proliferation was observed in A-MSCs. DISCUSSION: Neonatal and maternal tissues can serve as sources of multipotent stem cells. Some characteristics of MSCs obtained from four neonatal tissues were compared and differences were observed. Amniotic membrane was the least useful source of MSCs, whereas chorionic membrane and umbilical cord were considered good options for future use in cell therapy because of the known advantages of immature cells. PMID- 28343899 TI - Predictive Value of the SYNTAX Score in Culprit and Nonculprit Vessel Disease. Response. PMID- 28343900 TI - [Choroidal metastasis from a lung adenocarcinoma treated by intravitreal injection of anti-VEGF and external beam radiotherapy: A case report]. AB - Choroidal metastases of lung cancer are very uncommon. This localization should be suspected on blurred vision and confirmed with an ophthalmological examination. Its treatment is not entirely codified. We report a case of blurred vision secondary to bilateral choroidal metastasis in a patient with choroidal metastases from a lung adenocarcinoma, treated by intravitreal anti-vascular endothelial growth factor (VEGF) injection and external beam radiotherapy. According to a literature review, we analyzed the place of the targeted treatments used alone or combined with the radiotherapy. PMID- 28343901 TI - GPER blockers as Nox downregulators: A new drug class to target chronic non communicable diseases. AB - Oxidative stress is a hallmark of chronic non-communicable diseases such as arterial hypertension, coronary artery disease, diabetes, and chronic renal disease. Cardiovascular diseases are characterized by increased production of reactive oxygen species (ROS) by NAPDH oxidase 1 (Nox1) and additional Nox isoforms among other sources. Activation of the G protein-coupled estrogen receptor (GPER) can mediate multiple salutary effects on the cardiovascular system. However, GPER also has constitutive activity, e.g. in the absence of specific agonists, that was recently shown to promote hypertension and aging induced tissue damage by promoting Nox1-derived production of ROS. Furthermore, the small molecule GPER blocker (GRB) G36 reduces blood pressure and vascular ROS production by selectively down-regulating Nox1 expression. These unexpected findings revealed GRBs as first in class Nox downregulators capable to selectively reduce the increased expression and activity of Nox1 in disease conditions. Here, we will discuss the paradigm shift from selective GPER activation to ligand-independent, constitutive GPER signaling as a key regulator of Nox-derived oxidative stress, and the surprising identification of GRBs as the first Nox downregulators for the treatment of chronic non-communicable diseases. PMID- 28343902 TI - Stepwise strategies to successfully recruit diabetes patients in a large research study in Mexican population. AB - AIMS: Describe stepwise strategies (electronic chart review, patient preselection, call-center, personnel dedicated to recruitment) for the successful recruitment of >5000 type 2 diabetes patients in four months. METHODS: Twenty five family medicine clinics from Mexico City and the State of Mexico participated: 13 usual care, 6 specialized diabetes care and 6 chronic disease care. Appointments were scheduled from 11/3/2015 to 3/31/2016. Phone calls were generated automatically from an electronic database. A telephone questionnaire verified inclusion criteria, and scheduled an appointment, with a daily report of appointments, patient attendance, acceptance rate, and questionnaire completeness. Another recruitment log reviewed samples collected. Absolute number (percentage) of patients are reported. Means and standard deviations were estimated for continuous variables, chi2 test and independent "t" tests were used. OR and 95% CI were estimated. RESULTS: 14,358 appointments were scheduled, 9146 (63.7%) attended their appointment: 5710 (62.4%) fulfilled inclusion criteria and 5244 agreed to participate (91.8% acceptance). Those accepting participation were more likely women, younger and with longer disease duration (p<0.05). The cost of the call-center service was $3,010,000.00 Mexican pesos (~$31.70 USD per recruited patient). CONCLUSIONS: Stepwise strategies recruit a high number of patients in a short time. Call centers offer a low cost per patient. PMID- 28343903 TI - [Spinal cord injuries resulting from diving accidents in the Canary Islands]. AB - OBJECTIVE: Diving accidents is one of the leading causes of spinal cord injury after falls and car accidents. The objective of this study was to determine the epidemiological and clinical characteristics of these patients in our setting to better prevent these injuries. MATERIAL AND METHODS: We performed a retrospective, descriptive study of patients who have suffered from a traumatic spinal cord injury after a diving accident in the Canary Islands, Spain from 2000 to 2014. These patients were admitted to the Spinal Cord Unit of Hospital Universitario Insular de Gran Canaria. RESULTS: Of the 264 patients admitted to our unit for acute traumatic spinal cord injury, 23 (8.7%) cases were due to diving. Grouping the patients into 5years periods, 56% of the injuries occurred in 2000-2005, 17% in 2006-2010 and 26% in 2011-2014. All patients were male, with a mean age of 29years. Approximately 65% were under 30years. A total of 22/23 patients had a fracture and injury most commonly occurred to the C5 vertebra. Burst fractures were the most common. A total of 86% of cases underwent surgery. All the spinal cord injuries were cervical, with C6 being the neurological level most often affected. A total of 65% of spinal cord injuries were complete injuries. CONCLUSIONS: Spinal cord injury secondary to diving accidents is the third leading cause of traumatic spinal cord injury in our setting. It affects young males and the most common clinical presentation is a complete cervical spinal cord injury. Given the irreversible nature of the injury, prevention, aimed mainly at young people, is of great importance. PMID- 28343905 TI - The Dana Farber Consortium Protocol for the Treatment of Adolescents and Young Adults With Acute Lymphoblastic Leukemia: A Single Institution Experience in Saudi Arabia. AB - BACKGROUND: Recent retrospective analyses and phase II trials have shown differential outcomes in adolescents and young adults when treated with pediatric compared with adult protocols. The aim of this study was to evaluate the efficacy and toxicity of the Dana Farber Consortium Protocol (DFCP) in Saudi young adults diagnosed with de novo acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: In this retrospective study we included 38 patients with de novo ALL who presented to King Abdulla Medical City in the period from June 2010 to March 2015 and received the DFCP (Princess Margret modified version). RESULTS: A total of 38 patients were included with a median age of 19 years. Two patients died during induction treatment, and 35 of 38 patients achieved complete remission (92.1%). With a median follow-up period of 22 months, at 1 and 3 years, leukemia-free survival was 80% and 68%, respectively, and overall survival was 88% and 72%, respectively. Age younger than 21 years showed a significant association with longer survival. Toxicities included febrile neutropenia in all patients during induction, typhilitis in 8/38 (21%), pneumonia in 10/38 (26%), and pancreatitis in 5/38 patients (13%), 3/38 (7.8%) during induction and 2/38 (5.2%) during intensification. Osteonecrosis affected 3/38 patients (7.8%), and was detected during screening in 2/38 (5.2%) of these patients. There were no fractures or surgical interventions, and no venous thromboembolism was recorded. CONCLUSION: Although it might be feasible to use pediatric-inspired protocols in this age group, toxicity cannot be overlooked, and the application of these protocols might require modification of drug doses or schedules relative to those used for younger children. Moreover, additional surveillance and supportive measures should be implemented to maximize benefits while minimizing toxicity. PMID- 28343904 TI - Clinical and Serologic Responses After a Two-dose Series of High-dose Influenza Vaccine in Plasma Cell Disorders: A Prospective, Single-arm Trial. AB - BACKGROUND: Patients with multiple myeloma (MM) and other plasma cell disorders are highly susceptible to influenza infections, which are major causes of morbidity in this population, despite the routine administration of a seasonal influenza vaccination. Existing data are limited by small and retrospective studies, which suggest poor seroprotection rates of < 20% after standard influenza vaccination in patients with MM. PATIENTS AND METHODS: Patients with plasma cell dyscrasia (n = 51) were treated with a 2-dose series of high-dose inactivated trivalent influenza vaccine during the 2014 to 2015 influenza season. Laboratory-confirmed influenza infections were identified through seasonal surveillance, sera were collected for influenza hemagglutination antibody inhibition (HAI) titer assays, and logistic regression models were used to identify the clinical correlates to the HAI serologic responses. RESULTS: Influenza vaccine was well tolerated, without any vaccine-related grade >= 2 adverse events. Only 3 patients (6%) experienced laboratory-confirmed influenza. The rates of HAI seroprotection against all 3 vaccine strains (A/California/7/2009 [H1N1] pdm09-like virus; A/Texas/50/2012 [H3N2]-like virus; and a B/Massachusetts/2/2012-like virus) increased from 4% at baseline to 49% and 65% after 1 and 2 doses, respectively. The risk factors associated with a lower likelihood of HAI serologic response included plasma cell disorder requiring therapy, less than a partial response found on disease response assessment, and active conventional chemotherapy. Alternatively, active therapy with an immunomodulatory drug alone or with a proteasome inhibitor was associated with a greater likelihood of an HAI serologic response. CONCLUSION: These data have demonstrated that, in contrast to the historically poor results with standard influenza vaccination, this novel high-dose booster vaccination strategy leads to high rates of seroprotection. Randomized controlled studies are needed to compare this novel strategy to the standard vaccination strategy. PMID- 28343906 TI - Comparative analysis of iterative reconstruction algorithms with resolution recovery and new solid state cameras dedicated to myocardial perfusion imaging. AB - New technologies are available in myocardial perfusion imaging. They include new software that recovers image resolution and limits image noise, multifocal collimators and dedicated cardiac cameras in which solid-state detectors are used and all available detectors are constrained to imaging just the cardiac field of view. These innovations resulted in shortened study times or reduced administered activity to patients, while preserving image quality. Many single center and some multicenter studies have been published during the introduction of these innovations in the clinical practice. Most of these studies were lead in the framework of "agreement studies" between different methods of clinical measurement. They aimed to demonstrate that these new software/hardware solutions allow the acquisition of images with reduced acquisition time or administered activity with comparable results (as for image quality, image interpretation, perfusion defect quantification, left ventricular volumes and ejection fraction) to the standard-time or standard-dose SPECT acquired with a conventional gamma camera and reconstructed with the traditional FBP method, considered as the gold standard. The purpose of this review is to provide the reader with a comprehensive understanding of the pro and cons of the different approaches summarizing the achievements reached so far and the issues that need further investigations. PMID- 28343908 TI - [Fetal MRI practices in a university prenatal center]. AB - OBJECTIVES: Fetal MRI is a third intention examination to prenatal diagnosis. If its diagnostic value is well known in many pathologies, its place in the management of pregnancies remains unclear. METHODS: We collected retrospectively demographical, radiological (fetal MRI indications, fetal anatomical region and diagnostic information provided by fetal MRI) and obstetrical data of pregnant patients in university prenatal center during a 5 years' period. RESULTS: Among 2439 patients of the prenatal center, 196 (8%) patients with fetal MRI were included. The main anatomical regions studied were the brain (n=132, 67%), the thorax (n=31, 16%) and the abdomen (n=25, 13%). No cardiac fetal MRI was performed. Ninety-five percent of fetal MRI was consecutively of an ultrasound sign. Fetal brain MRI was abnormal in 65% of cases, the thoracic and abdominopelvic MRI in 81.5%. The ultrasound diagnosis was unchanged in 42%, completed in 50% and redirected in 8% of cases. A termination of pregnancy was deemed admissible in 31% of patients with MRI versus 21% in patients without MRI (P=0.001). CONCLUSION: Fetal MRI requires selective indications and provides additional diagnostic information with important implications for the future of the pregnancy, particularly in case of severe and incurable pathologies. Our results could be useful as a reference basis for the comparison with others prenatal center practices. PMID- 28343907 TI - [Intra-uterine insemination at either 24 or 48hours after ovulation induction: Pregnancy and birth rates]. AB - OBJECTIVE: Comparing rates of pregnancy and childbirth between IUI at either 24 or 48hours after injection of HCG. METHODS: This is a single-center retrospective study of couples who underwent intrauterine insemination between January 2013 and December 2014 at Medical-Surgical Obstetrical Centre of Schiltigheim. Stimulation of ovulation was done by FSH or HMG, and ovulation induction by 250MUg of recombinant HCG. The insemination was performed after 2 days (group D2) or the day after (group D1). RESULTS: Among the 1092 intrauterine insemination cycles included in our study, 62 were done the day after ovulation induction by HCG (D1), and 1030 the day after (D2). Our study showed no significant difference in the rate of biological pregnancy, defined by a rate of BHCG>15IU/L, between the group D1 (19.35%) and the group D2 (18.12%), P=0.94, and no difference in live birth rate: respectively 14,50% and 11.75%, P=0.18. CONCLUSION: Our study reported similar rates of pregnancy and childbirth in the group who underwent IUI at D1 and D2 of ovulation induction, suggesting the possibility of IUI on day 1 when the organization of the service needs it, without loss of opportunity for pregnancy. PMID- 28343909 TI - Pneumonia. AB - Neonatal pneumonia may occur in isolation or as one component of a larger infectious process. Bacteria, viruses, fungi, and parasites are all potential causes of neonatal pneumonia, and may be transmitted vertically from the mother or acquired from the postnatal environment. The patient's age at the time of disease onset may help narrow the differential diagnosis, as different pathogens are associated with congenital, early-onset, and late-onset pneumonia. Supportive care and rationally selected antimicrobial therapy are the mainstays of treatment for neonatal pneumonia. The challenges involved in microbiological testing of the lower airways may prevent definitive identification of a causative organism. In this case, secondary data must guide selection of empiric therapy, and the response to treatment must be closely monitored. PMID- 28343910 TI - Anti-skin-aging effect of epigallocatechin gallate by regulating epidermal growth factor receptor pathway on aging mouse model induced by d-Galactose. AB - Epigallocatechin gallate(EGCG) is a monomer separated from tea catechins, as an well-known antioxidant, which helps fight wrinkles and rejuvenate skin cells. In this study, we investigated the anti-aging effect of EGCG, and to clarify underlying mechanism of skin aging in a d-galactose-induced aging mouse model. Forty-five male mice were divided into 5 groups and treated with different dose of EGCG, Vitamin C (VitC) to mice as a positive control. All groups except vehicle were established aging model induced by d-galactose (200mg/kg/day) that was subcutaneously injected to mice for 8 weeks. Two weeks after injection of d galactose, EGCG and Vit C groups were simultaneously administered once a day by subcutaneously inject after 5h for injecting d-galactose. The results show that EGCG can be absorbed by the skin. Overall, the conditions of the skin of EGCG treatment groups were improved, the whole structure of skin were better than control groups, and the levels of oxidative stress and the expression of relate with EGFR proteins were significantly higher than control group after EGCG treatment. All these findings suggest that EGCG can resist skin senility effectively. And the EGFR with relate of downstream proteins are implicated in the skin aging. PMID- 28343911 TI - Cardiac implantable electronic device infections: From recognizing risk to prevention. PMID- 28343912 TI - The right timing for the left lead: Now or later? PMID- 28343913 TI - SUMOylation Inhibition Mediated by Disruption of SUMO E1-E2 Interactions Confers Plant Susceptibility to Necrotrophic Fungal Pathogens. AB - Protein modification by SUMO modulates essential biological processes in eukaryotes. SUMOylation is facilitated by sequential action of the E1-activating, E2-conjugating, and E3-ligase enzymes. In plants, SUMO regulates plant development and stress responses, which are key determinants in agricultural productivity. To generate additional tools for advancing our knowledge about the SUMO biology, we have developed a strategy for inhibiting in vivo SUMO conjugation based on disruption of SUMO E1-E2 interactions through expression of E1 SAE2UFDCt domain. Targeted mutagenesis and phylogenetic analyses revealed that this inhibition involves a short motif in SAE2UFDCt highly divergent across kingdoms. Transgenic plants expressing the SAE2UFDCt domain displayed dose dependent inhibition of SUMO conjugation, and have revealed the existence of a post-transcriptional mechanism that regulates SUMO E2 conjugating enzyme levels. Interestingly, these transgenic plants displayed increased susceptibility to necrotrophic fungal infections by Botrytis cinerea and Plectosphaerella cucumerina. Early after fungal inoculation, host SUMO conjugation was post transcriptionally downregulated, suggesting that targeting SUMOylation machinery could constitute a novel mechanism for fungal pathogenicity. These findings support the role of SUMOylation as a mechanism involved in plant protection from environmental stresses. In addition, the strategy for inhibiting SUMO conjugation in vivo described in this study might be applicable in important crop plants and other non-plant organisms regardless of their genetic complexity. PMID- 28343914 TI - Falls and fear of falling predict future falls and related injuries in ambulatory individuals with spinal cord injury: a longitudinal observational study. AB - QUESTIONS: What is the 1-year incidence of falls and injurious falls in a representative cohort of community-dwelling ambulatory individuals with chronic spinal cord injury? What are the predictors of recurrent falls (more than two/year) and injurious falls in this population? DESIGN: One-year longitudinal observational multi-centre study. PARTICIPANTS: A representative sample of 68 (of 73 included) community-dwelling ambulatory individuals with traumatic SCI attending regular follow-up programs at rehabilitation centres. OUTCOME MEASURES: Primary outcome measures were incidence and predictors of recurrent falls (more than two/year) and injurious falls reported every 2 weeks for 1year. RESULTS: A total of 48% of participants reported recurrent falls. Of the 272 reported falls, 41% were injurious. Serious injuries were experienced by 4% of participants, all of whom were women. Multivariate logistic regression analysis showed that recurrent falls in the previous year (OR=111, 95% CI=8.6 to 1425), fear of falling (OR=6.1, 95% CI=1.43 to 26) and longer time taken to walk 10m (OR=1.3, 95% CI=1.0 to 1.7) were predictors of recurrent falls. Fear of falling (OR=4.3, 95% CI=1.3 to 14) and recurrent falls in the previous year (OR=4.2, 95% CI=1.2 to 14) were predictors of injurious falls. CONCLUSION: Ambulatory individuals have a high risk of falling and of fall-related injuries. Fall history, fear of falling and walking speed could predict recurrent falls and injurious falls. Further studies with larger samples are needed to validate these findings. [Jorgensen V, Butler Forslund E, Opheim A, Franzen E, Wahman K, Hultling C, Seiger A, Stahle A, Stanghelle JK, Roaldsen KS (2017) Falls and fear of falling predict future falls and related injuries in ambulatory individuals with spinal cord injury: a longitudinal observational study. Journal of Physiotherapy 63: 108-113]. PMID- 28343915 TI - Nerve ultrasound in carpal tunnel syndrome. Usefulness of an evaluation along a long tract. PMID- 28343916 TI - Epidemiologic trend of adult bacterial meningitis in southern Taiwan (2006-2015). AB - The purpose of this study is to analyze recent epidemiologic trend of adult bacterial meningitis (ABM) in Taiwan. The clinical features, laboratory data and therapeutic outcomes of 157 patients with ABM from 2006-2015 were analyzed. The results were compared with those of our previous two epidemiologic studies of ABM (1st study: 202 cases, January 1986-June 1999; 2nd study: 181 cases, July 1999 December 2005). Of the 157 patients with ABM, 96 were men and 61 women, and 68.2% (107/157) of them had a postneurosurgical state as the underlying condition. Monomicrobial infections and mixed infections were found in 92.4% (145/157) and 7.6% (12/145) of the cases, respectively. Of the implicated pathogens of monomicrobial infections, staphylococcal species were the most common, accounting for 27.6% (40/145) of them and Klebsiella species were the second common accounting for 13.8% (20/145) of them. The other common Gram-negative pathogens were Pseudomonas species and Acinetobacter species, accounting for 10.3% (15/145) and 7.6% (11/145), respectively. The overall mortality rate was 25.5% (40/157), and septic shock and liver cirrhosis were significant prognostic factors. This study revealed a change in the epidemiologic trend of ABM and the study results may offer important information for clinicians managing patients with ABM. PMID- 28343917 TI - A curious case of neuromyelitis optica spectrum disorder co-existing with idiopathic intracranial hypertension. PMID- 28343918 TI - Primary lung metastasis of glioblastoma multiforme with epidural spinal metastasis: Case report. AB - Extracranial metastasis of glioblastoma multiforme (GBM) is rare, but has recently been reported with increasing frequency. GBM metastases typically present after a biopsy or resection of the primary tumor. An otherwise healthy 54year-old woman presented with recurring pleural effusions originally believed to be from a primary lung malignancy. The patient subsequently experienced a generalized tonic clonic seizure and a right temporal brain mass was discovered. The patient later developed weakness and radiculopathy, and an extramedullary extradural mass spreading from C7 to T6 was discovered. She underwent resection of both central nervous system lesions as well as a lung biopsy, and all pathologic specimens were consistent with GBM. The case presented is unique in that the patient's initial symptoms were related to her metastasis. Furthermore, a purely epidural spread of GBM that respects the leptomeninges and intramedullary parenchyma is highly unusual. PMID- 28343919 TI - Medulloblastoma with tri-vergent melanocytic, myogenic and cartiligious elements. PMID- 28343920 TI - Impact of insurance status and race on receipt of treatment for acoustic neuroma: A national cancer database analysis. AB - Acoustic neuroma (AN) management involves surgery, radiation, or observation. Previous studies have demonstrated that patient race and insurance status impact in-hospital morbidity/mortality following surgery; however the nationwide impact of these demographics on the receipt of each treatment modality has not been examined. The National Cancer Data Base (NCDB) from 2004 to 2013 identified AN patients. Multivariate analysis adjusted for several variables within each treatment modality, including patient age, race, sex, income, primary payer for care, tumor size, and medical comorbidities. Patients who were African-American (OR=0.7; 95%CI=0.5-0.9; p=0.01), elderly (minimum age 65) (OR=0.4; 95%CI=0.4-0.6; p<0.0001), on Medicare (OR=0.6; 95% CI=0.4-0.7; p=0.0005), or treated at a community hospital (OR=0.4; 95%CI=0.2-0.7; p=0.007) were less likely to receive surgery. Patients on Medicaid (OR=1.2; 95%CI=0.8-1.8; p=0.04) or treated at an integrated network (OR=1.2; 95%CI=0.9-1.6; p=0.0004) were more likely to receive surgery. Patients who were elderly (OR=2.2; 95%CI=1.7-2.9; p<0.0001) or treated in a comprehensive cancer center (OR=1.5; 95%CI=1.3-1.9; p=0.02) were more likely and Medicaid patients (OR=0.8; 95%CI=0.5-1.2; p=0.04) were less likely to receive radiation. Patients who were elderly (OR=2.2; 95%CI=1.7-2.7; p<0.0001), African American (OR=1.5; 95%CI=1.1-2.0; p=0.01), on Medicare (OR=1.8; 95%CI=1.4-2.3; p=0.0003), or treated in a community hospital (OR=3.0; 95%CI=1.6-5.6; p=0.0007) were more likely to receive observation. Patients on Medicaid (OR=0.8; 95%CI=0.5 1.2; p=0.04) or treated in an integrated network (OR=0.8; 95%CI=0.6-1.0; p=0.0001) were less likely to receive observation. African-American race, elderly age, and community hospital treatment triaged towards observation/away from surgery; age also triaged towards radiation. Conversely, integrated networks triaged towards surgery/away from observation; comprehensive cancer centers triaged towards radiation. Medicaid insurance triaged towards surgery/away from radiation/observation; this may be detrimental since lack of private insurance is a known risk factor for increased in-hospital postoperative morbidity. PMID- 28343921 TI - Cell growth of immortalized arachnoid cells in the presence of fibroblasts and blood products. AB - OBJECT: The pathophysiology of non-obstructive hydrocephalus involves alteration in cerebrospinal fluid (CSF) pathways. The exact mechanism is unknown, but as arachnoid CSF egress is a major route of CSF removal, damage or alteration to the growth of arachnoid cells may influence the rate of CSF absorption. We investigated the effect of soluble factors secreted by fibroblasts and the presence of blood products on arachnoid cell growth. METHODS: An immortalized arachnoid cell line was developed and cells were grown on semipermeable membranes in a culture chamber. Arachnoid cells were plated in Transwells(r), with fibroblasts separated from the arachnoid cells. Cell phenotype was analyzed and cell growth rates were determined by manual counts. Similar experiments were conducted with biliverdin, bilirubin, as well as fibroblast challenge. DNA content in the cell cultures was then determined as corroborative data. Cell counts for the additional arachnoid cell lines were calculated at each day and represented the controls. RESULTS: Cell counts increased with each time point. Arachnoid cells in the three experimental conditions showed a statistically significant decrease in cell counts for each day when compared to the control group. Post hoc analysis showed differences between the control and experimental conditions but no significant difference between groups. The DNA content for each experimental condition was reduced at all time points when compared to the control arachnoid cells, but only became statistically significant at day 7. CONCLUSION: Inflammation and hemorrhage are two common conditions associated with the development of hydrocephalus. The arachnoid membrane is exposed to fibroblasts and blood products (bilirubin, biliverdin) in these conditions, and their effect on arachnoid cell growth was studied. We have shown that arachnoid cell growth decreases in the presence of fibroblasts, bilirubin, and biliverdin. Given its intimate relationship with CSF, it is possible that the decreased growth of arachnoid cells may affect absorption and thus contribute to the development of hydrocephalus. PMID- 28343922 TI - Correlation of matrix metalloproteinase (MMP)-1, -2, -3, and -9 expressions with demographic and radiological features in primary lumbar intervertebral disc disease. AB - Degeneration of IVD is a progressive and irreversible process and can be evaluated with immunohistochemical examination or radiological grading. MMPs are a family of proteolytic enzymes and involved in the degradation of the matrix components of the IVD. We aimed to compare MMP-1, -2, -3, and -9 expressions with demographic features, visual analogue scale (VAS), Oswestry Disability Index (ODI) and radiological (MRI) grades. The study involved 60 participants. We recorded data about age, complaint, radiological imaging, expression levels of MMP-1, -2, -3, and -9, ODI and VAS for back pain retrospectively. Intervertebral disc degeneration was graded on a 0-5 scale according to the Pfirrmann classification. As a result of the study, the median age was 52.09+/-12.74years. There were statistical significances between age and MMP-1, and MMP-2. There was a close correlation between grade and MMP-9. We found correlation between the VAS and the MMP-9 expression. In addition, there was relationship between expression of MMP-2 and MMP-1, MMP-3, MMP-9. In conclusion, the expressions of MMP-1 and -2 are increased with aging. There was no relationship between radiological evaluation of IVDD and aging. Increased expression of MMPs affected IVDD positively. The relationship with MMPs is not explained. This study adds to our understanding of the interaction between MMPs and IVDD. PMID- 28343923 TI - First characterization of an archaeal amino acid racemase with broad substrate specificity from the hyperthermophile Pyrococcus horikoshii OT-3. AB - A novel amino acid racemase with broad substrate specificity (BAR) was recently isolated from the hyperthermophilic archaeon Pyrococcus horikoshii OT-3. Characterization of this enzyme has been difficult, however, because the recombinant enzyme is produced mainly as an inclusion body in Escherichia coli. In this study, expression of the recombinant protein into the soluble fraction was markedly improved by co-expression with chaperone molecules. The purified enzyme retained its full activity after incubation at 80 degrees C for at least 2 h in buffer (pH 7-10), making this enzyme the most thermostable amino acid racemase so far known. Besides the nine amino acids containing hydrophobic and aromatic amino acids previously reported (Kawakami et al., Amino Acids, 47, 1579 1587, 2015), the enzyme exhibited substantial activity toward Thr (about 42% of relative activity toward Phe) and showed no activity toward Arg, His, Gln, and Asn. The substrate specificity of this enzyme thus differs markedly from those of other known amino acid racemases. In particular, the high reaction rate with Trp and Tyr, in addition to Leu, Met and Phe as substrates is a noteworthy feature of this enzyme. The high reactivity toward Trp and Tyr, as well as extremely high thermostability, is likely a major advantage of using BAR for biochemical conversion of these aromatic amino acids. PMID- 28343924 TI - Properties of discontinuous S2-glass fiber-particulate-reinforced resin composites with two different fiber length distributions. AB - PURPOSE: To investigate the reinforcing efficiency and light curing properties of discontinuous S2-glass fiber-particulate reinforced resin composite and to examine length distribution of discontinuous S2-glass fibers after a mixing process into resin composite. METHODS: Experimental S2-glass fiber-particulate reinforced resin composites were prepared by mixing 10wt% of discontinuous S2 glass fibers, which had been manually cut into two different lengths (1.5 and 3.0mm), with various weight ratios of dimethacrylate based resin matrix and silaned BaAlSiO2 filler particulates. The resin composite made with 25wt% of UDMA/SR833s resin system and 75wt% of silaned BaAlSiO2 filler particulates was used as control composite which had similar composition as the commonly used resin composites. Flexural strength (FS), flexural modulus (FM) and work of fracture (WOF) were measured. Fractured specimens were observed by scanning electron microscopy. Double bond conversion (DC) and fiber length distribution were also studied. RESULTS: Reinforcement of resin composites with discontinuous S2-glass fibers can significantly increase the FS, FM and WOF of resin composites over the control. The fibers from the mixed resin composites showed great variation in final fiber length. The mean aspect ratio of experimental composites containing 62.5wt% of particulate fillers and 10wt% of 1.5 or 3.0mm cutting S2 glass fibers was 70 and 132, respectively. No difference was found in DC between resin composites containing S2-glass fibers with two different cutting lengths. CONCLUSION: Discontinuous S2-glass fibers can effectively reinforce the particulate-filled resin composite and thus may be potential to manufacture resin composites for high-stress bearing application. PMID- 28343925 TI - Influence of Alveolar Bone Loss and Cement Layer Thickness on the Biomechanical Behavior of Endodontically Treated Maxillary Incisors: A 3-dimensional Finite Element Analysis. AB - INTRODUCTION: In order to understand the mechanical behavior of a weakened incisor, this study aimed to evaluate the stress distribution caused by different alveolar bone heights and cement layer thickness. METHODS: A finite element analysis was conducted for this investigation. An intact maxillary central incisor was initially modeled, and the bone of the models was modified in order to simulate 4 levels of bone height: BL0 (no bone loss), BL1 (1/3 bone loss), BL2 (1/2 bone loss), and BL3 (2/3 bone loss). These teeth models were remodeled with a fiber post at 2 different cement thicknesses and restored with a ceramic crown; "A" refers to the well-adapted fiber post (0.3 mm) and "B" to the nonadapted fiber post (1 mm), resulting in 12 models. RelyX ARC (3M ESPE, St Paul, MN) cement was simulated for the cementation of the crowns and fiber posts for all groups. Numeric models received a load of 100 N on the lingual surface. All materials and structures were considered linear elastic, homogeneous, and isotropic. Numeric models were plotted and meshed with isoparametric elements, and results were expressed in maximum principal stress. RESULTS: For fiberglass posts, cement, and dentin, the highest stress concentration occurred in the groups with increased bone loss. For cortical bone, the highest values were for the groups with 1/3 bone loss. A greater thickness of cement layer concentrates more stress. CONCLUSIONS: More bone loss and greater CLT were the influential factors in concentrating the stress. PMID- 28343926 TI - Cobalt Chloride Enhances the Stemness of Human Dental Pulp Cells. AB - INTRODUCTION: Hypoxia is a factor in controlling stem cell stemness. We investigated if cobalt chloride (CoCl2), a chemical agent that mimics hypoxia in vitro, affected human dental pulp cell (hDPC) stemness by examining cell proliferation, stem cell marker expression, and osteogenic differentiation. METHODS: hDPCs were cultured with or without 25 or 50 MUmol/L CoCl2. The 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to determine cell proliferation. The number of STRO-1+ cells was determined by flow cytometry. The messenger RNA expression of the stem cell markers REX1, OCT4, SOX2, and NANOG and the osteogenic-associated genes ALP, COLI, and RUNX2 were evaluated using reverse transcription polymerase chain reaction or real-time polymerase chain reaction. Osteogenic differentiation was assessed by alkaline phosphatase (ALP) activity and mineralization assays. RESULTS: Although 25 and 50 MUmol/L CoCl2 suppressed hDPC proliferation, 50 MUmol/L CoCl2 increased the number of STRO-1+ cells. Moreover, CoCl2 dose dependently induced stem cell marker expression. Additionally, CoCl2 treatment suppressed osteogenic-associated gene expression, ALP activity, and calcium deposition. The addition of apigenin, a hypoxia inducible factor 1-alpha inhibitor, reversed the inhibitory effect of CoCl2 on ALP activity. CONCLUSIONS: This study indicated that CoCl2 may enhance hDPC stemness. PMID- 28343927 TI - Palatal Radicular Groove Morphology of the Maxillary Incisors: A Case Series Report. AB - INTRODUCTION: Teeth with a palatal radicular groove are challenging to diagnose, treat, and save. We classified this condition using cone-beam computed tomographic (CBCT) cross-sectional configurations combined with radiographic and morphologic observations during an intentional replantation procedure to identify and analyze the characteristics of palatal radicular grooves comprehensively as a reference for diagnosis, treatment planning, and prognosis evaluation of this condition. METHODS: Eight cases with palatal radicular grooves present in permanent maxillary incisors were investigated by radiography and CBCT imaging before intentional replantation. RESULTS: The palatal radicular grooves were classified into 3 types based on groove depth and cross-sectional shape on CBCT images: type I, with a shallow groove depth, corresponding to a normal, simple, and single root canal; type II, with a medium groove depth, corresponding to a C shaped canal system; and type III, with a deep groove depth, almost bisecting the root of the tooth, simultaneously present with 2 independent root canals and an apex with normal shape, corresponding to a labial groove connecting with a palatal groove. The extracted teeth and their radiographic images showed corresponding characteristics. CONCLUSIONS: The CBCT cross-sectional images allowed the best visualization of the depth of the grooves and highlighted the difficulties entailed in treating such teeth. Intentional replantation is an effective therapeutic decision for this type of deformity and can provide better prognosis estimation, especially in teeth with type II and III grooves. PMID- 28343928 TI - Endodontics, Endodontic Retreatment, and Apical Surgery Versus Tooth Extraction and Implant Placement: A Systematic Review. AB - INTRODUCTION: The aim of this systematic review was to answer the following clinical question: Which is the best treatment option for a pulpally involved tooth? METHODS: An electronic search was conducted in the Cochrane, PubMed (MEDLINE), and ScienceDirect databases between December 2015 and February 2016. A manual search was also performed. The inclusion criteria were randomized clinical trials, prospective or retrospective cohort studies, and cross-sectional studies performed on humans with at least 1 year of follow-up and published within the last 10 years. Two researchers independently screened the title and abstract of every article identified in the search in order to establish its eligibility. The selected articles were classified into different levels of evidence by means of the Strength of Recommendation Taxonomy criteria. RESULTS: Sixty articles met the inclusion criteria for this systematic review. The survival rate of single-tooth implants was greater than the success rate of the distinct conservative treatments. However, among comparative studies, no important differences between both treatments were observed until at least 8 years later. CONCLUSIONS: The endodontic treatment and the implant placement are both valid and complementary options for planning oral rehabilitation. Although a level B recommendation can be stated, these results come from retrospective comparative studies because there is a lack of randomized clinical studies comparing both types of therapeutic options. PMID- 28343929 TI - Cytotoxicity of GuttaFlow Bioseal, GuttaFlow2, MTA Fillapex, and AH Plus on Human Periodontal Ligament Stem Cells. AB - INTRODUCTION: The aim of the present study was to evaluate the in vitro cytotoxicity of endodontic sealers (GuttaFlow Bioseal, GuttaFlow2, and MTA Fillapex) on human periodontal ligament stem cells (hPDLSCs). As a reference, AH Plus was compared with the more recent endodontic sealers regarding cell viability and cell attachment. METHODS: Biological testing was carried out in vitro on hPDLSCs. Cell viability assay was performed by using eluates from each endodontic sealer. To assess cell morphology and attachment to the different sealers, the hPDLSCs were directly seeded onto the material surfaces and analyzed by scanning electron microscopy. Chemical composition of the sealers was determined by energy-dispersive x-ray, and eluates were analyzed by inductively coupled plasma mass spectrometry. Statistical differences were assessed by analysis of variance and Tukey test (P < .05). RESULTS: Cell viability was evident after 24 hours in the presence of GuttaFlow Bioseal and GuttaFlow 2 but not in the case of AH Plus or MTA Fillapex. At 168 hours, GuttaFlow Bioseal and GuttaFlow 2 exhibited high and moderate cell viability, respectively, whereas AH Plus and MTA Fillapex revealed low rates of cell cell viability (P < .001). Finally, scanning electron microscopy studies revealed a high degree of proliferation, cell spreading, and attachment, especially when using GuttaFlow Bioseal disks. CONCLUSIONS: GuttaFlow Bioseal and GuttaFlow2 showed lower cytotoxicity than MTA Fillapex and AH plus. Further in vitro and in vivo investigations are required to confirm the suitability of GuttaFlow Bioseal for clinical application. PMID- 28343930 TI - Cost-effectiveness of Different Post-retained Restorations. AB - OBJECTIVES: Dentists can choose between metal and fiber post systems to provide post-retained restorations. The risk of tooth loss and other complications differs between different post systems, as do the initial treatment costs. We aimed to assess the cost-effectiveness of (1) cast metal (MC), (2) preformed metal (MP), (3) glass fiber (GF), and (4) carbon fiber (CF) post-retained restorations. METHODS: A mixed public-private payer's perspective within German healthcare was taken. Risks of complications were extracted from systematic reviews. Costs were estimated by using fee items and 2016 material costs. A Markov model was constructed to follow up an endodontically treated molar receiving a post-retained crown in an initially 50-year-old patient during his lifetime. Monte Carlo microsimulations were performed to assess lifetime costs and tooth retention time. RESULTS: MPs were least costly (?692?), retaining teeth for 26.7 years. GFs were more costly (?745?), retaining teeth for 27.6 years. MCs were minimally more effective but also more costly than GFs (?774?). CFs were less effective and most expensive (?825?, 26.7 years). For payers willing to invest more than ?60? per tooth retention year, GF was cost-effective. Payers willing to invest an additional ?670? found MC to be cost-effective. These findings were found robust in sensitivity analyses. CONCLUSIONS: For payers not willing to invest additional money for longer tooth retention, MP seemed most suitable to retain restorations. For payers with additional willingness to pay, GF seemed suitable, retaining teeth for longer. MC was only cost-effective under very high willingness to pay. CF is not recommendable on the basis of their cost effectiveness. PMID- 28343931 TI - Coronal and Intraradicular Appearances Affect Radiographic Perception of the Periapical Region. AB - INTRODUCTION: The influence of the radiographic appearances of the coronal and intraradicular areas on periapical radiographic interpretation has been minimally evaluated in dentistry and endodontics. The purpose of this study was to evaluate the effects that the coronal and intraradicular radiographic appearance has on endodontists' radiographic interpretations of periapical areas. METHODS: In a split-group study design using an online survey format, 2 pairs of digital periapical radiographic images were evaluated by 2 groups (A and B) of endodontist readers for the presence of a periapical finding. The images in each pair were identical except that 1 image of each image pairs had coronal restorations and/or root canal fillings altered using Adobe Photoshop software (Adobe Systems, San Jose, CA). The periapical areas were not altered. Using a 5 point Likert scale, the endodontist readers were asked to "Please evaluate the periapical area(s)." A Mann-Whitney U test was used to statistically evaluate the difference between the groups. Significance was set at P < .01. RESULTS: There were 417 readers in group A and 442 readers in group B. The Mann-Whitney U test showed a significant difference in the responses between the groups for both image pairs (P < .01). CONCLUSIONS: Because the periapical areas of the image pairs were unaltered, the differing coronal and intraradicular areas of the radiographs appear to have influenced endodontists' interpretations of the periapical areas. This finding has implications for all radiographic outcome assessments. PMID- 28343932 TI - Fracture Incidence of WaveOne and Reciproc Files during Root Canal Preparation of up to 3 Posterior Teeth: A Prospective Clinical Study. AB - INTRODUCTION: Reciprocating instruments were developed to improve and simplify the preparation of the root canal system by allowing greater centralization of the canal and requiring a shorter learning curve. Despite the risk of instrument separation, using a reciprocating instrument in more than 1 case is a relatively common clinical practice. The aim of this study was to evaluate the fracture resistance of Reciproc (R25; VDW, Munich, Germany) and WaveOne (Primary; Dentsply Maillefer, Ballaigues, Switzerland) instruments according to the number of uses during the preparation of root canals in up to 3 posterior teeth. METHODS: A prospective clinical study was conducted by 3 experienced specialists who performed treatment of 358 posterior teeth (1130 canals) over a period of 12 months using 120 reciprocating instruments, 60 of which were Reciproc R25 and 60 were WaveOne Primary. The motion used during instrumentation followed the recommendations of the respective manufacturers. After each use, the instruments were observed under a dental operating microscope at 8* magnification. In the case of fracture or deformation, the instrument was discarded. RESULTS: None of the instruments showed any signs of deformation, but 3 instruments fractured (0.26% of the number of canals and 0.84% of the number of teeth). All fractures occurred in mandibular molars (1 WaveOne Primary file during the third use and 2 Reciproc R25 files, 1 during the first use and the other during the third use). CONCLUSIONS: There was a low incidence of fracture when reciprocating files were used in up to 3 cases of endodontic treatment in posterior teeth. PMID- 28343933 TI - Testing the immunocompetence handicap hypothesis: Testosterone manipulation does not affect wound healing in male salamanders. AB - In vertebrates, a bidirectional relationship exists between the immune system and the hypothalamic-pituitary-gonadal axis. In addition, sexual dimorphism in immunity has been documented in many vertebrates as well as some invertebrates, and males are generally less immunocompetent than their female counterparts. A possible explanation for this is described by the immunocompetence handicap hypothesis (ICHH), which proposes that elevated testosterone (T) levels direct resources towards the promotion of secondary sexual characteristics at a cost to immune function. To further test the ICHH, we examined the effects of T on cutaneous wound healing, an integrative measure of immunity, using male Allegheny Mountain dusky salamanders; a species that has sexually dimorphic courtship glands and testosterone-dependent mating behavior. We did this via two methods: surgical manipulation and transdermal delivery of T. In both experiments, elevated plasma T did not delay wound healing. Interestingly, intact animals healed more slowly than animals that had undergone prior invasive surgery, suggesting that the prior surgery had an immune-priming effect that enhanced healing of a second wound. PMID- 28343934 TI - Hitchhiker's guide to the red cell storage galaxy: Omics technologies and the quality issue. AB - Red blood cell storage in the blood bank makes millions of units of available for transfusion to civilian and military recipients every year. From glass bottles to plastic bags, from anticoagulants to complex additives, from whole blood to leukocyte filtered packed red blood cells: huge strides have been made in the field of blood component processing and storage in the blood bank during the last century. Still, refrigerated preservation of packed red blood cells under blood bank conditions results in the progressive accumulation of a wide series of biochemical and morphological changes to the stored erythrocytes, collectively referred to as the storage lesion(s). Approximately ten years ago, retrospective clinical evidence had suggested that such lesion(s) may be clinically relevant and mediate some of the untoward transfusion-related effects observed especially in some categories of recipients at risk (e.g. massively or chronically transfused recipients). Since then, randomized clinical trials have failed to prospectively detect any signal related to red cell storage duration and increased morbidity and mortality in several categories of recipients, at the limits of the statistical power of these studies. While a good part of the transfusion community has immediately adopted the take-home message "if it isn't broken, don't fix it" (i.e. no change to the standard of practice should be pursued), decision makers have been further questioning whether there may be room for further improvements in this field. Provocatively, we argue that consensus has yet to be unanimously reached on what makes a good quality marker of the red cell storage lesion and transfusion safety/efficacy. In other words, if it is true that "you can't manage what you can't measure", then future advancements in the field of transfusion medicine will necessarily rely on state of the art analytical omics technologies of well-defined quality parameters. Heavily borrowing from Douglas Adam's imaginary repertoire from the world famous "Hitchhiker's guide to the galaxy", we briefly summarize how some of the principles for intergalactic hitchhikers may indeed apply to inform navigation through the complex universe of red cell storage quality, safety and efficacy. PMID- 28343935 TI - Blood derived products in pediatrics: New laboratory tools for optimizing potency assignment and reducing side effects. AB - Neonates and children can develop rare bleeding disorders due to congenital/acquired coagulation Factor deficiencies, or allo-immune/autoimmune complications, or can undergo surgeries at high haemorrhagic risk. They then need specialized transfusion of blood components/products, or purified blood extracted products or recombinant proteins. Blood-derived therapies conventionally used for management of affected infants with genetic/acquired deficiencies, bleeding problems (coagulation Factor reduced or missing) or thrombotic disorders (reduced or missing anticoagulant proteins) pose some additional risks. These remedial therapies can cause tolerance when used very early in life and, sometimes needed, repeatedly. The introduction of recombinant proteins has allowed manufacturers to produce large amounts of the proteins usually present at very low concentration in blood. This has also changed the risk pattern of plasma-extracted products, especially in terms of continual reduction of viral transmission. Many efforts have been made over these past decades to reduce the risks associated with the use of all these products in terms of viral and bacterial safety, as well as immune disorders but they are not the objective of this article. Other associated side effects are the presence of undesired activities in blood products, which can produce thrombotic events or adverse reactions. The progressive introduction of blood derived products has greatly improved the prognosis and quality of life of affected patients. This concerns whole blood, but also blood cell concentrates, mainly platelets and red blood cells, plasma, while the blood extracted products are increasingly replaced by recombinant proteins. All these therapeutic products, i.e. blood extracted drugs, improve health and quality of life for hemophiliac's A or B, or patients with auto/allo-immune thrombocytopenias or with rare bleeding disorders, and those with thrombotic events occurring in childhood, which are mainly due to Protein C or Protein S deficiencies (congenital or acquired). Progress in analytical methods and biotechnology allow better control of the manufacturing processes for all blood derived or plasma extracted products and recombinant proteins, and contribute to improved manufacturing processes to minimize the occurrence of side effects. These adverse events can be due to the aging of the blood cell concentrate with release of their granule content, and generation of EVs, which can produce anaphylactic reactions and risk of thrombosis, but also to the presence of activated coagulation Factors in purified products, such as Factor Xia as recently identified in immunoglobulin concentrates. Characterization and measurement of contaminant products is of special usefulness during product preparation and for optimization of manufacturing processes for purified extracted products, but also for recombinant proteins. The pharmaceutical industry introduces these new methods for validating manufacturing processes, or for quality control assessments. The objective is first to warrant the full quality and safety of the lots produced, and assure the highest efficacy with the lowest risks when used in patients. For cell concentrates and fresh blood, storage conditions are critical and measurement of analytes such as EVs or Annexin V allows evaluation of quality of each individual transfused pouch. In addition to all the rules around viral and bacterial transmission risk, and immune tolerance, our available laboratory methods contribute to reducing the side effects of blood cell concentrates and derived plasma products, as well as those of the therapeutic recombinant proteins. PMID- 28343936 TI - Hemolysis in six week-old autologous red blood cell components questioned: Worth addressing the issue of homologous components as well? PMID- 28343937 TI - Co-infection of blood borne viruses in blood donors: A cross-sectional study from North India. AB - BACKGROUND: There are several studies on prevalence of individual infectious disease markers (mono-infection) in donors but none on prevalence of coinfection. Co-infection is significant as it leads to accelerated disease progression. We, therefore, evaluated the prevalence of co-infection among blood donors. MATERIALS AND METHODS: The cross-sectional analysis was conducted in blood donors. All donors were tested for anti-HIV I and II, HBsAg, anti-HBC IgM, anti-HCV, Malaria and syphilis by chemiluminescence and ID-NAT assay. All reactive donor samples were confirmed by using confirmatory assays. Donors were grouped as mono-infected and co-infected. The student t-test was used for comparison. RESULTS: During the study period, a total of 106,238 blood donors were tested. Mean age of donors was 34.2 years and 94.2% of blood donors were males. 1776 (1.67%) donor samples were confirmed serologically reactive. 1714 (1.61%) samples were reactive for single marker (mono-infected) while 62 (0.05%) donors' samples exhibited co-infection. 18 donors were positive for HBV+HCV followed by HIV +syphilis (14). CONCLUSION: We report for the first time the prevalence of different co-infection patterns in blood donors. Co-infection influence the disease progression; it would be important to investigate the co-infection prevalence in larger sample size. PMID- 28343938 TI - Testosterone influences volitional, but not reflexive orienting of attention in human males. AB - The impact of testosterone (T) on the exogenous (Experiment 1) and endogenous (Experiment 2) orienting of visual attention in males was examined. Sixteen male participants completed both an exogenous and an endogenous cuing task on two separate days. About 2-3h prior to testing, either a placebo or a dose of T was administered. The inhibition of return (IOR) phenomenon was observed during the exogenous cuing task, but IOR was not influenced by T. During the endogenous task, participants demonstrated the expected cuing effects on both days. However, longer reaction time to invalid target locations was observed following T administration. The manipulation of T-levels in males provides converging evidence of dissociation between reflexive and volitional orienting of attention. PMID- 28343939 TI - A tale of gastric layering and sieving: Gastric emptying of a liquid meal with water blended in or consumed separately. AB - BACKGROUND: The process of gastric emptying determines how fast gastric content is delivered to the small intestine. It has been shown that solids empty slower than liquids and that a blended soup empties slower than the same soup as broth and chunks, due to the liquid fraction emptying more quickly. This process of 'gastric sieving' has not been investigated for liquid foods. OBJECTIVE: To determine whether gastric sieving of water can also occur for liquid foods. METHOD: Two groups of men participated in a parallel design (n=15, age 22.6+/ 2.4y, BMI 22.6+/-1.8kg/m2, and n=19, age 22.2+/-2.5y, BMI 21.8+/-1.5kg/m2) and consumed an isocaloric shake (2093kJ, CARBOHYDRATES: 71g, FAT: 18g, PROTEIN: 34g), either in a 500-mL version (MIXED) or as a 150-mL shake followed by 350mL water (SEPARATE). Participants provided appetite ratings and were scanned using MRI to determine gastric emptying rate and volume at three time-points within 35min post ingestion. RESULTS: Gastric emptying the percentage emptied in 35min was significantly smaller for MIXED (29+/-19%) than for SEPARATE (57+/-11%, p<0.001). CONCLUSION: In the present study we show that gastric sieving can occur for liquid foods; water is able to drain from the stomach while a layer of nutrient rich liquid is retained. In indirect gastric emptying measurements, the behavior of labelling agents may be affected by the layering and confound emptying measurements. PMID- 28343941 TI - Characterization of culturable bacteria isolated from hot springs for plant growth promoting traits and effect on tomato (Lycopersicon esculentum) seedling. AB - To elucidate the functional diversity of hot spring bacteria, 123 bacteria were isolated and screened for evaluating their multifunctional plant growth promoting (PGP) properties. The antagonistic activity against different phytopathogens showed the presence of a high amount of biocontrol bacteria in the hot springs. During screening for PGP properties, 61.0% isolates showed production of indole acetic acid and 23.6% showed inorganic phosphate solubilization qualitatively. For production of extracellular enzymes, it was found that 61.0% isolates produced lipase, 56.9% produced protease, and 43.9% produced cellulase. In extreme properties, half of the isolates showed tolerance to 5% NaCl (w/v) and 48.8% isolates survived heat shock at 70 degrees C. The identification of 12 multipotential bacteria based on 16S rRNA gene sequencing revealed that the bacteria belonged to Aneurinibacillus aneurinilyticus and Bacillus spp. Bacterization of tomato seeds showed that the hot spring bacteria promoted shoot height, fresh shoot weight, root length, and fresh root weight of tomato seedlings, with values ranging from 3.12% to 74.37%, 33.33% to 350.0%, 16.06% to 130.41%, and 36.36% to 318.18%, respectively, over the control. This research shows that multifunctional bacteria could be isolated from the hot springs. The outcome of this research may have a potential effect on crop production methodologies used in saline and arid environments. PMID- 28343942 TI - Current Resources for Evidence-Based Practice, May/June 2017. PMID- 28343940 TI - Lithocholic Acid Hydroxyamide Destabilizes Cyclin D1 and Induces G0/G1 Arrest by Inhibiting Deubiquitinase USP2a. AB - USP2a is a deubiquitinase responsible for stabilization of cyclin D1, a crucial regulator of cell-cycle progression and a proto-oncoprotein overexpressed in numerous cancer types. Here we report that lithocholic acid (LCA) derivatives are inhibitors of USP proteins, including USP2a. The most potent LCA derivative, LCA hydroxyamide (LCAHA), inhibits USP2a, leading to a significant Akt/GSK3beta independent destabilization of cyclin D1, but does not change the expression of p27. This leads to the defects in cell-cycle progression. As a result, LCAHA inhibits the growth of cyclin D1-expressing, but not cyclin D1-negative cells, independently of the p53 status. We show that LCA derivatives may be considered as future therapeutics for the treatment of cyclin D1-addicted p53-expressing and p53-defective cancer types. PMID- 28343943 TI - Insomnia Treatment Preferences During Pregnancy. AB - OBJECTIVE: To determine pregnant women's preferences for the treatment of insomnia: cognitive behavioral therapy (CBT-I), pharmacotherapy, or acupuncture. DESIGN: A cross-sectional survey of pregnant women. SETTING: We recruited participants in person at a low-risk maternity clinic and a pregnancy and infant trade show and invited them to complete an online questionnaire. PARTICIPANTS: The sample (N = 187) was primarily White (70%), married or common-law married (96%), and on average 31 years of age; the mean gestational age was 28 weeks. METHODS: Participants read expert-validated descriptions of CBT-I, pharmacotherapy, and acupuncture and then indicated their preferences and perceptions of each approach. RESULTS: Participants indicated that if they experienced insomnia, they preferred CBT-I to other approaches, chi2(2) = 38.10, p < .001. They rated CBT-I as the most credible treatment (eta2partial = .22, p < .001) and had stronger positive reactions to it than to the other two approaches (eta2partial = .37, p < .001). CONCLUSION: Participants preferred CBT-I for insomnia during pregnancy. This preference is similar to previously reported preferences for psychotherapy for treatment of depression and anxiety during pregnancy. It is important for clinicians to consider women's preferences when discussing possible treatment for insomnia. PMID- 28343945 TI - As human lung microvascular endothelia achieve confluence, src family kinases are activated, and tyrosine-phosphorylated p120 catenin physically couples NEU1 sialidase to CD31. AB - In postconfluent human pulmonary microvascular endothelial cell (HPMEC)s, NEU1 sialidase associates with and desialylates the src family kinase (SFK) substrate, CD31, and disrupts angiogenesis. We asked whether the NEU1-CD31 interaction might be SFK-driven. We found that normalized phospho-SFK (PY416) signal is increased in postconfluent HPMECs compared to subconfluent cells and prior SFK inhibition with PP2 or SU6656 completely blocked NEU1 association with and desialylation of CD31. Prior silencing of each of the four SFKs expressed in HPMECs, as well as CD31, dramatically reduced confluence-induced SFK activation. No increases in tyrosine phosphorylation of NEU1 or CD31 were detected. However, in postconfluent cells, we found increased tyrosine phosphorylation of a 120 kDa protein that was identified as p120 catenin (p120ctn). Prior silencing of c-src, fyn, or yes each reduced p120ctn phosphorylation. Prior knockdown of p120ctn prevented NEU1-CD31 association in both co-immunoprecipitation and pull-down assays. In these same assays, p120ctn associated with each of the four HPMEC-expressed SFKs as well as CD31 and NEU1. The CD31-p120ctn interaction was SFK-dependent whereas the NEU1 p120ctn interaction was not. Using purified recombinant binding partners in a cell-free system, direct protein-protein interactions between NEU1, CD31, and p120ctn were detected. Our combined data indicate that as HPMECs achieve confluence and CD31 ectodomains become homophilically engaged, multiple SFKs are activated to increase tyrosine phosphorylation of p120ctn, which in turn, functions as a cross-bridging adaptor molecule that physically couples NEU1 to CD31, permitting NEU1-mediated desialylation of CD31. These findings establish a SFK-driven, p120ctn-dependent mechanism for NEU1 recruitment to CD31. PMID- 28343944 TI - RACK1 cooperates with NRASQ61K to promote melanoma in vivo. AB - Melanoma is the deadliest skin cancer. RACK1 (Receptor for activated protein kinase C) protein was proposed as a biological marker of melanoma in human and domestic animal species harboring spontaneous melanomas. As a scaffold protein, RACK1 is able to coordinate the interaction of key signaling molecules implicated in both physiological cellular functions and tumorigenesis. A role for RACK1 in rewiring ERK and JNK signaling pathways in melanoma cell lines had been proposed. Here, we used a genetic approach to test this hypothesis in vivo in the mouse. We show that Rack1 knock-down in the mouse melanoma cell line B16 reduces invasiveness and induces cell differentiation. We have developed the first mouse model for RACK1 gain of function, Tyr::Rack1-HA transgenic mice, targeting RACK1 to melanocytes in vivo. RACK1 overexpression was not sufficient to initiate melanomas despite activated ERK and AKT. However, in a context of melanoma predisposition, RACK1 overexpression reduced latency and increased incidence and metastatic rate. In primary melanoma cells from Tyr::Rack1-HA, Tyr::NRasQ61K mice, activated JNK (c-Jun N-terminal kinase) and activated STAT3 (signal transducer and activator of transcription 3) acted as RACK1 oncogenic partners in tumoral progression. A sequential and coordinated activation of ERK, JNK and STAT3 with RACK1 is shown to accelerate aggressive melanoma development in vivo. PMID- 28343946 TI - Double-stranded RNA induces cathelicidin expression in the intestinal epithelial cells through phosphatidylinositol 3-kinase-protein kinase Czeta-Sp1 pathway and ameliorates shigellosis in mice. AB - Cathelicidin antimicrobial peptide is a key component of the host innate immune system. It is constitutively expressed by the intestinal epithelial cells, but induced at further higher levels by different host-derived and microbial stimuli, including the ligands for Toll-like receptors (TLRs). While the underlying mechanisms of cathelicidin expression remain incompletely understood, altered expression may be associated with gastro-intestinal infections and inflammatory diseases. We demonstrate here that viral double-stranded RNA and its synthetic analog poly(I:C) are potent and tissue-specific inducers of cathelicidin mRNA and protein expression in the mouse as well as human intestinal epithelial cells. Reporter assays showed that poly(I:C) transcriptionally regulates murine cathelicidin-related antimicrobial peptide (mCRAMP) by recruiting Sp1 transcription factor to the GC-box cis-regulatory element at -71bp of the mCRAMP putative promoter. Sp1 recruitment to the endogenous mCRAMP promoter was confirmed by chromatin immunoprecipitation (ChIP) assays. Immunoblotting, qPCR, ChIP and siRNA-mediated gene knockdown studies revealed that the activation of phosphatidylinositol 3-kinase/protein kinase Czeta pathways in poly(I:C) stimulated cells underlies Sp1 phosphorylation and recruitment to the mCRAMP promoter, leading to enhanced transcription. We further showed that intra-rectal poly(I:C) administration in mice reduces intestinal bacterial load and mucosal inflammation following Shigella flexneri 2a infection by inducing mCRAMP expression in the colonic epithelial cells. This study reports novel regulatory mechanisms of cathelicidin expression that may be targeted to treat gastro intestinal infections. PMID- 28343947 TI - TAVI or Not TAVI-in Low Risk Patients? That Is the Question. PMID- 28343948 TI - Left Ventricular Non-Compaction: A Cardiomyopathy With Acceptable Prognosis in Children. AB - BACKGROUND: Data on children with left ventricular non-compaction (LVNC) is sparse. The purpose of this study was to evaluate its clinical profiles in a population of Chinese children. METHODS: From January 2010 to March 2016, consecutive Chinese children (aged <18 years) with LVNC diagnosed by cardiovascular magnetic resonance (CMR) were prospectively recruited at Fuwai Hospital. RESULTS: A total of 41 Chinese children (male: 28%; mean age: 14+/ 4years) were included in this study. Left ventricular non-compaction was not detected in 13 (32%) patients at initial echocardiographic evaluation. Congenital heart disease (CHD) was found in 11 (27%) patients. Four (10%) patients had Wolff Parkinson-White (WPW) syndrome. Mean left ventricular ejection fraction (LVEF) was 41+/-15%. Late gadolinium enhancement (LGE) was detected in eight (20%) subjects. During a mean follow-up of 2.9 years, four (9%) patients died or received heart transplantation. These patients had lower systolic blood pressure (91+/-10 vs. 108+/-14mmHg; p=0.02), diastolic blood pressure (57+/-7 vs. 68+/ 8mmHg; p=0.007) and LVEF (19+/-7 vs. 44+/-12%; p=0.002) than the survivors. In addition, advanced heart failure (100% vs. 16%; p=0.002) and LGE (50% vs. 5%; p=0.04) were detected more in these subjects. CONCLUSIONS: Left ventricular non compaction is easily overlooked at echocardiographic assessment. Congenital heart disease and WPW syndrome were relatively common in LVNC children. The prognosis of children with LVNC seemed to be better than previous studies reported, and its long-term prognosis needs to be further investigated. PMID- 28343949 TI - Lactate and Echocardiography Before Veno-Venous Extracorporeal Membrane Oxygenation Support. AB - BACKGROUND: Lactate has been recognised as a prognostic factor in several critical conditions. Veno-Venous Extracorporeal Membrane Oxygenation (VV-ECMO) is a well-established therapy in patients with Acute Respiratory Disease Syndrome (ARDS) unresponsive to conventional therapy and echocardiography pre ECMO initiation has been recently reported to help in risk stratifying these patients. METHODS: We assessed whether the detection of hyperlactataemia could be associated with the presence of left ventricle (LV) or right ventricle (RV) dysfunction in 121 consecutive patients with refractory ARDS. RESULTS: The mortality rate was 42.9% (52/121). Higher dosages of norepinephrine and dobutamine were administered to non survivors (p=0.023 and p=0.047, respectively) who showed significantly higher levels of lactate (p=0.002). At echocardiography, non survivors showed higher values of systolic pulmonary artery pressure (sPAP) (p=0.05) and a higher incidence of RV dysfunction (as indicated by lower Tricuspid Annular Plane Excursion (TAPSE)) and RV dilatation (p=0.001). At multivariate logistic regression analysis, the following variables were independent predictors of death: body mass index (BMI) (OR: 0.914, 95%CI 0.857 0.975, p=0.006), RV dilatation (OR: 0.239, 95%CI 0.101-0.561, p=0.001) and lactate (OR: 1.292, 95%CI 1.015-1.645, p=0.038). Lactate values were directly correlated with the simplified acute physiology score (SAPS) II (r=0.38, p<0.001), while they showed an indirect correlation with left ventricular ejection fraction (LVEF) (r=-0.24, p=0.009) and TAPSE (r=-0.21, p=0.024). CONCLUSIONS: In refractory ARDS, hyperlactataemia before VVV-ECMO identified a subset of patients at higher risk of death, being an independent predictor of in Intensive Care Unit (ICU) mortality. Lactate values are mainly related to disease severity (as indicated by SAPS II) and haemodynamic impairment (as inferred by LVEF) and RV failure, as (indicated by TAPSE). PMID- 28343950 TI - Spontaneous Haemothorax Secondary to Rib Exostosis. PMID- 28343951 TI - Orthopedic In-Training Examination: A Performance Review Based on Program- and Resident-Specific Characteristics. AB - OBJECTIVES: The orthopedic in-training examination (OITE) is the most common and objective method used to assess resident knowledge in the United States. As such, residents and programs use a number of strategies to maximize OITE performance. The purpose of this work was to better understand what strategies were being implemented and to determine which program-specific and resident-specific characteristics best correlate with improved scores. DESIGN: A national survey of orthopedic residents and program directors (PDs) was performed to better understand OITE performance and correlate scores with various test preparation strategies. SETTING: Mayo Clinic, Rochester, MN. PARTICIPANTS: The survey was completed by 33 of 48 (68.8%) PDs and 341 of 878 (38.8%) eligible residents. RESULTS: The most commonly used program-wide strategies were as follows: negative consequences for poor performance (72.7%), formal OITE prep program (54.5%), and purchase of OITE test prep material for residents (51.5%). The program-specific characteristics that had the strongest correlation with increased scores were negative consequences for poor performance (p < 0.001), high value placed on the OITE by PD and residents (p < 0.001), excusing residents from clinical duties the evening prior (p < 0.001), having residents take the examination on different days (p = 0.012), and allowing residents to lead a review course (p = 0.047). The resident-specific characteristics that correlated most with score were increased study time leading up to the test (p = 0.031) and attendance at their program's OITE prep program (p = 0.062). CONCLUSIONS: Although programs and residents looking to improve knowledge acquisition and OITE scores use a number of techniques, a few distinct strategies correlate with the greatest increases in OITE performance. These may be appropriate methods to consider for those looking to improve their performance in coming years. PMID- 28343952 TI - Program Director Perceptions of the General Surgery Milestones Project. AB - OBJECTIVE: As a result of the Milestones Project, all Accreditation Council for Graduate Medical Education accredited training programs now use an evaluation framework based on outcomes in 6 core competencies. Despite their widespread use, the Milestones have not been broadly evaluated. This study sought to examine program director (PD) perceptions of the Milestones Project. DESIGN, SETTING, AND PARTICIPANTS: A national survey of general surgery PDs distributed between January and March of 2016. RESULTS: A total of 132 surgical PDs responded to the survey (60% response rate). Positive perceptions included value for education (55%) and evaluation of resident performance (58%), as well as ability of Milestones to provide unbiased feedback (55%) and to identify areas of resident deficiency (58%). Meanwhile, time input and the ability of Milestones to discriminate underperforming programs were less likely to be rated positively (25% and 21%, respectively). Half of PDs felt that the Milestones were an improvement over their previous evaluation system (55%). CONCLUSIONS: Using the Milestones as competency-based, developmental outcomes measures, surgical PDs reported perceived benefits for education and objectivity in the evaluation of resident performance. The overall response to the Milestones was generally favorable, and most PDs would not return to their previous evaluation systems. To improve future iterations of the Milestones, many PDs expressed a desire for customization of the Milestones' content and structure to allow for programmatic differences. PMID- 28343953 TI - Development and Validation of a Novel and Cost-Effective Animal Tissue Model for Training Transurethral Resection of the Prostate. AB - OBJECTIVES: To develop and validate a new and cost-effective animal tissue training model for practicing resection skills of transurethral resection of the prostate (TURP). METHODS AND MATERIALS: A porcine kidney was prepared and restructured to simulate the relevant anatomy of the human prostate. The restructured prostate was connected to an artificial urethra and bladder. Face, content, and construct validity of the model was carried out using a 5-point Likert scale questionnaire, and comparison in task performance between participants and experts was made using observational clinical human reliability analysis. RESULTS: A total of 24 participants and 11 experts who practiced TURP skills on this model from October 2014 to December 2015 were recruited. The mean score on specific feature of the anatomy and color, sensation of texture and feeling of resection, conductibility of current, and efficacy and safety of the model were 4.34 +/- 0.37, 4.51 +/- 0.63, 4.13 +/- 0.53, and 4.35 +/- 0.71, respectively, by participants whereas they were 4.22 +/- 0.23, 4.30 +/- 0.48, 4.11 +/- 0.62, and 4.56 +/- 0.77, respectively, by the experts on a scale of 1 (unrealistic) to 5 (very realistic). Participants committed more technical errors than the experts (11 vs 7, p < 0.001), produced more movements of the instruments (51 vs 33, p < 0.001), and required longer operating time (11.4 vs 6.2min, p < 0.001). CONCLUSIONS: A newly developed restructured animal tissue model for training TURP was reported. Validation study on the model demonstrates that this is a very realistic and effective model for skills training of TURP. Trainees committed more technical errors, more unproductive movements, and required longer operating time. PMID- 28343954 TI - A new whole mitochondrial genome qPCR (WMG-qPCR) with SYBR Green(r) to identify phlebotomine sand fly blood meals. AB - Phlebotomine sand flies are blood-feeding insects of marked medical and veterinary significance. Investigations on the biology of these insects hold great importance for both ecological and epidemiological purposes. The present work describes a new approach for real-time PCR (qPCR) with SYBR Green(r), named WMG-qPCR, to identify phlebotomine blood meals. The novelty of the assay was to design primers based on the Whole Mitochondrial Genome (WMG) of the potential hosts (human, dog, cat, brown rat and chicken) aiming to amplify through qPCR the regions of mitochondrial DNA (mtDNA) which are less conserved among all species. Initially, the best method for mtDNA extraction to be applied in WMG-qPCR was determined. Afterwards, amplification specificities were accessed by cross reaction assays with mtDNA samples from all animal species, besides phlebotomine DNA. Finally, the selected primers were also tested for their limit of DNA detection through standard curves constructed by serial dilution of blood DNA obtained for each target animal species. The WMG-qPCR was able to detect as low as 10pL of blood, equivalent to 26, 84, 130, and 320fg DNA of cat, human, dog and rat, respectively. The assay was also capable to amplify as low as 5pL of chicken blood (5pg DNA). In conclusion, WMG-qPCR seems to be a promising tool to identify phlebotomine blood meals, with high species-specificity and sensitivity. Furthermore, as no supplementary techniques are required, this new approach presents minimized costs and simplified technical-training requirements for execution. PMID- 28343955 TI - Comparison of commercial ELISA tests for the detection of Toxoplasma antibodies in the meat juice of naturally infected pigs. AB - Toxoplasmosis is a globally distributed protozoal zoonosis. Pigs are considered an important reservoir of Toxoplasma gondii and pork a major infection source of human toxoplasmosis. ELISA methods are commonly used diagnostic tools for detecting Toxoplasma infections. They are also used for slaughterhouse-based serological monitoring of toxoplasmosis in pigs to identify positive farms. The methods used are non-standardised with varying sensitivity and specificity. In our study, four commercial ELISA tests for the detection of Toxoplasma antibodies in the meat juice of slaughter pigs were compared with a modified agglutination test (MAT) as a reference. The cut-off values of the ELISA tests provided by the manufacturer varied between 0.20 and 0.50, and clearly influenced prevalence. The sensitivity of tests I, II and III varied between 96.4 and 78.6. Sensitivity was unacceptably low (3.6) for test IV (cut-off=0.30). Tests I, II and III had the highest accuracy and the best agreement with the reference test when a cut-off of 0.30 was used. Test II and III showed very good agreement (K=0.92 and 0.84, respectively) with the MAT. A very strong correlation (Pearson correlation >0.89) was observed between the S/P values of tests I, II and III. Our results demonstrate that the test and cut-off value used influence the results of the apparent seroprevalence studies. PMID- 28343956 TI - Effect of Cd2+ and Cd2+/auxin mixtures on lipid monolayers - Model membrane studies on the role of auxins in phytoremediation of metal ions from contaminated environment. AB - In this work Langmuir monolayer experiments were performed to analyze the effect of Cd2+ ions and their mixtures with synthetic auxin (1-naphthaleneacetic acid - NAA) on lipid films. These investigations were motivated by the fact that auxins act effectively as the agents improving the removal of metal ions from contaminated water and soil by plants (phytoextraction), and although their mechanism of action in this area is still unclear, it was suggested that it can be membrane-related. The experiments were done for one component (1,2-dipalmitoyl sn-glycero-3-phosphocholine - DPPC; 1,2-dioleoyl-sn-glycero-3-phosphocholine - DOPC; 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (sodium salt) - DPPG) monolayers and mixed (DPPG/DOPC and DPPG/DPPC) films treated as model of plant leaves membranes. The monolayer properties were analyzed based on the surface pressure-area isotherms obtained during film compression, stability measurements and Brewster angle microcopy studies. The collected results together with the data presented in literature evidenced that both metal ions and auxins modify lipid system properties and by using them in a combination it is possible to weaken the influence of sole metal ions on membrane organization. This seems to be in agreement with the hypothesis that the role of plant growth regulators in increasing phytoextraction effectiveness may be membrane-related. However, further experiments are required to find possible correlations between the type and concentration of metal ion, composition of membrane or structural elements in auxin molecule and observed alterations in membrane properties. PMID- 28343957 TI - Adult out-of-hospital cardiac arrest in philadelphia from 2008-2012: An epidemiological study. AB - BACKGROUND: Wide variation in out-of-hospital cardiac arrest (OHCA) survival has been reported, with low survival in urban settings. We sought to describe the epidemiology of OHCA in Philadelphia, Pennsylvania, the fifth largest U.S. city, and identify potential areas for targeted interventions to improve survival. METHODS AND RESULTS: Retrospective chart review of adult, non-traumatic, OHCA occurring in Philadelphia between 2008 and 2012. We determined incidence and epidemiological factors including: demographics, initial cardiac rhythm, bystander cardiopulmonary resuscitation, automated external defibrillator use, return of spontaneous circulation and 30-day survival. 5198 cases of adult, non traumatic OHCA were identified. The incidence was 81.5/100,000. The majority of cases occurred in a residence (76.2%); 30.4% were witnessed events; the initial cardiac rhythm was pulseless ventricular tachycardia or ventricular fibrillation in 6.2% of cases, pulseless electrical activity in 21.0%, asystole in 38.3% and was unknown or undocumented in the remaining 34.5%. Multivariate logistic regression analysis demonstrated increased 30-day survival with younger age, shockable cardiac rhythms, and daytime arrest. 30-day survival was 8.1% for EMS assessed patients and 8.6% for EMS-transported patients. CONCLUSIONS: Philadelphia's reported incidence is consistent with urban settings although the survival rate is higher than other urban centers. PMID- 28343958 TI - Simultanagnosia does not affect processes of auditory Gestalt perception. AB - Simultanagnosia is a neuropsychological deficit of higher visual processes caused by temporo-parietal brain damage. It is characterized by a specific failure of recognition of a global visual Gestalt, like a visual scene or complex objects, consisting of local elements. In this study we investigated to what extend this deficit should be understood as a deficit related to specifically the visual domain or whether it should be seen as defective Gestalt processing per se. To examine if simultanagnosia occurs across sensory domains, we designed several auditory experiments sharing typical characteristics of visual tasks that are known to be particularly demanding for patients suffering from simultanagnosia. We also included control tasks for auditory working memory deficits and for auditory extinction. We tested four simultanagnosia patients who suffered from severe symptoms in the visual domain. Two of them indeed showed significant impairments in recognition of simultaneously presented sounds. However, the same two patients also suffered from severe auditory working memory deficits and from symptoms comparable to auditory extinction, both sufficiently explaining the impairments in simultaneous auditory perception. We thus conclude that deficits in auditory Gestalt perception do not appear to be characteristic for simultanagnosia and that the human brain obviously uses independent mechanisms for visual and for auditory Gestalt perception. PMID- 28343959 TI - The neural basis of language learning: Brief introduction to the special issue. PMID- 28343960 TI - Reduced specificity in emotion judgment in people with autism spectrum disorder. AB - There is a conflicting literature on facial emotion processing in autism spectrum disorder (ASD): both typical and atypical performance have been reported, and inconsistencies in the literature may stem from different processes examined (emotion judgment, face perception, fixations) as well as differences in participant populations. Here we conducted a detailed investigation of the ability to discriminate graded emotions shown in morphs of fear-happy faces, in a well-characterized high-functioning sample of participants with ASD and matched controls. Signal detection approaches were used in the analyses, and concurrent high-resolution eye-tracking was collected. Although people with ASD had typical thresholds for categorical fear and confidence judgments, their psychometric specificity to detect emotions across the entire range of intensities was reduced. However, fixation patterns onto the stimuli were typical and could not account for the reduced specificity of emotion judgment. Together, our results argue for a subtle and specific deficit in emotion perception in ASD that, from a signal detection perspective, is best understood as a reduced specificity due to increased noise in central processing of the face stimuli. PMID- 28343961 TI - Protein depletion using the arabinose promoter in Xanthomonas citri subsp. citri. AB - Xanthomonas citri subsp. citri (X. citri) is a plant pathogen and the etiological agent of citrus canker, a severe disease that affects all the commercially important citrus varieties, and has worldwide distribution. Citrus canker cannot be healed, and the best method known to control the spread of X. citri in the orchards is the eradication of symptomatic and asymptomatic plants in the field. However, in the state of Sao Paulo, Brazil, the main orange producing area in the world, control is evolving to an integrated management system (IMS) in which growers have to use less susceptible plants, windshields to prevent bacterial spread out and sprays of cupric bactericidal formulations. Our group has recently proposed alternative methods to control citrus canker, which are based on the use of chemical compounds able to disrupt vital cellular processes of X. citri. An important step in this approach is the genetic and biochemical characterization of genes/proteins that are the possible targets to be perturbed, a task not always simple when the gene/protein under investigation is essential for the organism. Here, we describe vectors carrying the arabinose promoter that enable controllable protein expression in X. citri. These vectors were used as complementation tools for the clean deletion of parB in X. citri, a widespread and conserved gene involved in the essential process of bacterial chromosome segregation. Overexpression or depletion of ParB led to increased cell size, which is probably a resultant of delayed chromosome segregation with subsequent retard of cell division. However, ParB is not essential in X. citri, and in its absence the bacterium was fully competent to colonize the host citrus and cause disease. The arabinose expression vectors described here are valuable tools for protein expression, and especially, to assist in the deletion of essential genes in X. citri. PMID- 28343963 TI - Maternally Inherited Stable Intronic Sequence RNA Triggers a Self-Reinforcing Feedback Loop during Development. AB - Maternally inherited noncoding RNAs (ncRNAs) can regulate zygotic gene expression across generations [1-4]. Recently, many stable intronic sequence RNAs (sisRNAs), which are byproducts of pre-mRNA splicing, were found to be maternally deposited and persist till zygotic transcription in Xenopus and Drosophila [5-7]. In various organisms, sisRNAs can be in linear or circular conformations, and they have been suggested to regulate host gene expression [5-10]. It is unknown whether maternally deposited sisRNAs can regulate zygotic gene expression in the embryos. Here, we show that a maternally inherited sisRNA (sisR-4) from the deadpan locus is important for embryonic development in Drosophila. Mothers, but not fathers, mutant for sisR-4 produce embryos that fail to hatch. During embryogenesis, sisR-4 promotes transcription of its host gene (deadpan), which is essential for development. Interestingly, sisR-4 functions by activating an enhancer present in the intron where sisR-4 is encoded. We propose that a maternal sisRNA triggers expression of its host gene via a positive feedback loop during embryogenesis. PMID- 28343962 TI - Contextually Mediated Spontaneous Retrieval Is Specific to the Hippocampus. AB - Although it is now well established that the hippocampus supports memory encoding [1, 2], little is known about hippocampal activity during spontaneous memory retrieval. Recent intracranial electroencephalographic (iEEG) work has shown that hippocampal activity during encoding predicts subsequent temporal organization of memories [3], supporting a role in contextual binding. It is an open question, however, whether the hippocampus similarly supports contextually mediated processes during retrieval. Here, we analyzed iEEG recordings obtained from 215 epilepsy patients as they performed a free recall task. To identify neural activity specifically associated with contextual retrieval, we compared correct recalls, intrusions (incorrect recall of either items from prior lists or items not previously studied), and deliberations (matched periods during recall when no items came to mind). Neural signals that differentiate correct recalls from both other retrieval classes reflect contextual retrieval, as correct recalls alone arise from the correct context. We found that in the hippocampus, high-frequency activity (HFA, 44-100 Hz), a proxy for neural activation [4], was greater prior to correct recalls relative to the other retrieval classes, with no differentiation between intrusions and deliberations. This pattern was not observed in other memory-related cortical regions, including DLPFC, thus supporting a specific hippocampal contribution to contextually mediated memory retrieval. PMID- 28343964 TI - The Temporal Tuning of the Drosophila Motion Detectors Is Determined by the Dynamics of Their Input Elements. AB - Detecting the direction of motion contained in the visual scene is crucial for many behaviors. However, because single photoreceptors only signal local luminance changes, motion detection requires a comparison of signals from neighboring photoreceptors across time in downstream neuronal circuits. For signals to coincide on readout neurons that thus become motion and direction selective, different input lines need to be delayed with respect to each other. Classical models of motion detection rely on non-linear interactions between two inputs after different temporal filtering. However, recent studies have suggested the requirement for at least three, not only two, input signals. Here, we comprehensively characterize the spatiotemporal response properties of all columnar input elements to the elementary motion detectors in the fruit fly, T4 and T5 cells, via two-photon calcium imaging. Between these input neurons, we find large differences in temporal dynamics. Based on this, computer simulations show that only a small subset of possible arrangements of these input elements maps onto a recently proposed algorithmic three-input model in a way that generates a highly direction-selective motion detector, suggesting plausible network architectures. Moreover, modulating the motion detection system by octopamine-receptor activation, we find the temporal tuning of T4 and T5 cells to be shifted toward higher frequencies, and this shift can be fully explained by the concomitant speeding of the input elements. PMID- 28343965 TI - The N-Terminal Non-Kinase-Domain-Mediated Binding of Haspin to Pds5B Protects Centromeric Cohesion in Mitosis. AB - Sister-chromatid cohesion, mediated by the multi-subunit cohesin complex, must be precisely regulated to prevent chromosome mis-segregation. In prophase and prometaphase, whereas the bulk of cohesin on chromosome arms is removed by its antagonist Wapl, cohesin at centromeres is retained to ensure chromosome biorientation until anaphase onset. It remains incompletely understood how centromeric cohesin is protected against Wapl in mitosis. Here we show that the mitotic histone kinase Haspin binds to the cohesin regulatory subunit Pds5B through a conserved YGA/R motif in its non-catalytic N terminus, which is similar to the recently reported YSR-motif-dependent binding of Wapl to Pds5B. Knockout of Haspin or disruption of Haspin-Pds5B interaction causes weakened centromeric cohesion and premature chromatid separation, which can be reverted by centromeric targeting of a N-terminal short fragment of Haspin containing the Pds5B-binding motif or by prevention of Wapl-dependent cohesin removal. Conversely, excessive Haspin capable of binding Pds5B displaces Wapl from Pds5B and suppresses Wapl activity, and it largely bypasses the Wapl antagonist Sgo1 for cohesion protection. Taken together, these data indicate that the Haspin-Pds5B interaction is required to ensure proper sister-chromatid cohesion, most likely through antagonizing Wapl-mediated cohesin release from mitotic centromeres. PMID- 28343966 TI - Astrocytes Regulate Daily Rhythms in the Suprachiasmatic Nucleus and Behavior. AB - Astrocytes are active partners in neural information processing [1, 2]. However, the roles of astrocytes in regulating behavior remain unclear [3, 4]. Because astrocytes have persistent circadian clock gene expression and ATP release in vitro [5-8], we hypothesized that they regulate daily rhythms in neurons and behavior. Here, we demonstrated that daily rhythms in astrocytes within the mammalian master circadian pacemaker, the suprachiasmatic nucleus (SCN), determine the period of wheel-running activity. Ablating the essential clock gene Bmal1 specifically in SCN astrocytes lengthened the circadian period of clock gene expression in the SCN and in locomotor behavior. Similarly, excision of the short-period CK1epsilon tau mutation specifically from SCN astrocytes resulted in lengthened rhythms in the SCN and behavior. These results indicate that astrocytes within the SCN communicate to neurons to determine circadian rhythms in physiology and in rest activity. PMID- 28343967 TI - Evolutionary History of the Hymenoptera. AB - Hymenoptera (sawflies, wasps, ants, and bees) are one of four mega-diverse insect orders, comprising more than 153,000 described and possibly up to one million undescribed extant species [1, 2]. As parasitoids, predators, and pollinators, Hymenoptera play a fundamental role in virtually all terrestrial ecosystems and are of substantial economic importance [1, 3]. To understand the diversification and key evolutionary transitions of Hymenoptera, most notably from phytophagy to parasitoidism and predation (and vice versa) and from solitary to eusocial life, we inferred the phylogeny and divergence times of all major lineages of Hymenoptera by analyzing 3,256 protein-coding genes in 173 insect species. Our analyses suggest that extant Hymenoptera started to diversify around 281 million years ago (mya). The primarily ectophytophagous sawflies are found to be monophyletic. The species-rich lineages of parasitoid wasps constitute a monophyletic group as well. The little-known, species-poor Trigonaloidea are identified as the sister group of the stinging wasps (Aculeata). Finally, we located the evolutionary root of bees within the apoid wasp family "Crabronidae." Our results reveal that the extant sawfly diversity is largely the result of a previously unrecognized major radiation of phytophagous Hymenoptera that did not lead to wood-dwelling and parasitoidism. They also confirm that all primarily parasitoid wasps are descendants of a single endophytic parasitoid ancestor that lived around 247 mya. Our findings provide the basis for a natural classification of Hymenoptera and allow for future comparative analyses of Hymenoptera, including their genomes, morphology, venoms, and parasitoid and eusocial life styles. PMID- 28343969 TI - Pds5 Regulates Sister-Chromatid Cohesion and Chromosome Bi-orientation through a Conserved Protein Interaction Module. AB - Sister-chromatid cohesion is established by the cohesin complex in S phase and persists until metaphase, when sister chromatids are captured by microtubules emanating from opposite poles [1]. The Aurora-B-containing chromosome passenger complex (CPC) plays a crucial role in achieving chromosome bi-orientation by correcting erroneous microtubule attachment [2]. The centromeric localization of the CPC relies largely on histone H3-T3 phosphorylation (H3-pT3), which is mediated by the mitotic histone kinase Haspin/Hrk1 [3-5]. Hrk1 localization to centromeres depends largely on the cohesin subunit Pds5 in fission yeast [5]; however, it is unknown how Pds5 regulates Hrk1 localization. Here we identify a conserved Hrk1-interacting motif (HIM) in Pds5 and a Pds5-interacting motif (PIM) in Hrk1 in fission yeast. Mutations in either motif result in the displacement of Hrk1 from centromeres. We also show that the mechanism of Pds5-dependent Hrk1 recruitment is conserved in human cells. Notably, the PIM in Haspin/Hrk1 is reminiscent of the YSR motif found in the mammalian cohesin destabilizer Wapl and stabilizer Sororin, both of which bind PDS5 [6-12]. Similarly, and through the same motifs, fission yeast Pds5 binds to Wpl1/Wapl and acetyltransferase Eso1/Eco1, in addition to Hrk1. Thus, we have identified a protein-protein interaction module in Pds5 that serves as a chromatin platform for regulating sister-chromatid cohesion and chromosome bi-orientation. PMID- 28343968 TI - MET-2-Dependent H3K9 Methylation Suppresses Transgenerational Small RNA Inheritance. AB - In C. elegans, alterations to chromatin produce transgenerational effects, such as inherited increase in lifespan and gradual loss of fertility. Inheritance of histone modifications can be induced by double-stranded RNA-derived heritable small RNAs. Here, we show that the mortal germline phenotype, which is typical of met-2 mutants, defective in H3K9 methylation, depends on HRDE-1, an argonaute that carries small RNAs across generations, and is accompanied by accumulated transgenerational misexpression of heritable small RNAs. We discovered that MET-2 inhibits small RNA inheritance, and, as a consequence, induction of RNAi in met-2 mutants leads to permanent RNAi responses that do not terminate even after more than 30 generations. We found that potentiation of heritable RNAi in met-2 animals results from global hyperactivation of the small RNA inheritance machinery. Thus, changes in histone modifications can give rise to drastic transgenerational epigenetic effects, by controlling the overall potency of small RNA inheritance. PMID- 28343971 TI - Clarithromycin resistance in Helicobacter pylori and its molecular determinants in Northern Spain, 2013-2015. AB - OBJECTIVES: Clarithromycin resistance (CLR-R) is the main reason for failure of Helicobacter pylori infection treatment, which is frequently empirically prescribed due to the erroneous belief that culture for susceptibility testing is difficult. The aim of this study was to determine CLR-R in a region of southern Europe and to evaluate the utility of a PCR sequencing assay applied on gastroduodenal biopsies in detecting H. pylori and clarithromycin (CLR) susceptibility. METHODS: The susceptibility of all H. pylori isolates obtained by culture during 2013-2015 was determined by Etest. During 2014-2015, H. pylori detection and CLR susceptibility were also studied by PCR followed by sequencing performed on gastroduodenal biopsies. Point mutations in the 23S rRNA gene were studied in all CLR-resistant isolates in 2014. RESULTS: Of 1986 H. pylori isolates obtained by culture (63 from children and 1923 from adults), 349 (17.6%) were CLR-resistant [21/63 (33.3%) in children and 328/1923 (17.1%) in adults; P<0.001], of which 31.5% were also resistant to levofloxacin. The main mutations detected were A2147G (79.8%), A2146G (17.2%) and A2146C (2%). Concordance between the PCR sequencing assay on biopsies and CLR susceptibility by Etest after culture was 89.8%. CONCLUSIONS: CLR-R was high in Gipuzkoa, northern Spain. The molecular PCR method performed directly on biopsies was a good alternative to the traditional Etest susceptibility method and was an aid when culture was non viable. PMID- 28343970 TI - Phenylmethimazole and a thiazole derivative of phenylmethimazole inhibit IL-6 expression by triple negative breast cancer cells. AB - Inhibition of interleukin-6 (IL-6) holds significant promise as a therapeutic approach for triple negative breast cancer (TNBC). We previously reported that phenylmethimazole (C10) reduces IL-6 expression in several cancer cell lines. We have identified a more potent derivative of C10 termed COB-141. In the present work, we tested the hypothesis that C10 and COB-141 inhibit TNBC cell expressed IL-6 and investigated the potential for classical IL-6 pathway induced signaling within TNBC cells. A panel of TNBC cell lines (MDA-MB-231, Hs578T, MDA-MB-468) was used. Enzyme linked immunosorbent assays (ELISA) revealed that C10 and COB 141 inhibit MDA-MB-231 cell IL-6 secretion, with COB-141 being ~6.5 times more potent than C10. Therefore, the remainder of the study focused on COB-141 which inhibited IL-6 secretion, and was found, via quantitative real time polymerase chain reaction (QRT-PCR), to inhibit IL-6 mRNA in the TNBC panel. COB-141 had little, if any, effect on metabolic activity indicating that the IL-6 inhibition is not via a toxic effect. Flow cytometric analysis and QRT-PCR revealed that the TNBC cell lines do not express the IL-6 receptor (IL-6Ralpha). Trans-AM assays suggested that COB-141 exerts its inhibitory effect, at least in part, by reducing NF-kappaB (p65/p50) DNA binding. In summary, COB-141 is a potent inhibitor of TNBC cell expressed IL-6 and the inhibition does not appear to be due to non-specific toxicity. The TNBC cell lines do not have an intact classical IL-6 signaling pathway. COB-141's inhibitory effect may be due, at least in part, to reducing NF-kappaB (p65/p50) DNA binding. PMID- 28343972 TI - Time to reconsider prophylactic cranial irradiation in extensive-stage small-cell lung cancer? PMID- 28343973 TI - New NICE criteria for drug access. PMID- 28343974 TI - Monoclonal antibody YS110 for refractory solid tumours. PMID- 28343975 TI - Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. AB - BACKGROUND: Although trastuzumab plus chemotherapy is the standard of care for first-line treatment of HER2-positive advanced gastric cancer, there is no established therapy in the second-line setting. In GATSBY, we examined the efficacy and tolerability of trastuzumab emtansine in patients previously treated for HER2-positive advanced gastric cancer (unresectable, locally advanced, or metastatic gastric cancer, including adenocarcinoma of the gastro-oesophageal junction). METHODS: This is the final analysis from GATSBY, a randomised, open label, adaptive, phase 2/3 study, done at 107 centres (28 countries worldwide). Eligible patients had HER2-positive advanced gastric cancer and progressed during or after first-line therapy. In stage one of the trial, patients were randomly assigned to treatment groups (2:2:1) to receive intravenous trastuzumab emtansine (3.6 mg/kg every 3 weeks or 2.4 mg/kg weekly) or physician's choice of a taxane (intravenous docetaxel 75 mg/m2 every 3 weeks or intravenous paclitaxel 80 mg/m2 weekly). In stage two, patients were randomly assigned to treatment groups (2:1) to receive the independent data monitoring committee (IDMC)-selected dose of trastuzumab emtansine (2.4 mg/kg weekly) or a taxane (same regimen as above). We used permuted block randomisation, stratified by world region, previous HER2 targeted therapy, and previous gastrectomy. The primary endpoint (overall survival) was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01641939. FINDINGS: Between Sept 3, 2012, and Oct 14, 2013, 70 patients were assigned to receive trastuzumab emtansine 3.6 mg/kg every 3 weeks, 75 to receive trastuzumab emtansine 2.4 mg/kg weekly, and 37 to receive a taxane in the stage 1 part of the trial. At the pre planned interim analysis (Oct 14, 2013), the IDMC selected trastuzumab emtansine 2.4 mg/kg weekly as the dose to proceed to stage 2. By Feb 9, 2015, a further 153 patients had been randomly assigned to receive trastuzumab emtansine 2.4 mg/kg weekly and a further 80 to receive a taxane. At data cutoff, median follow-up was 17.5 months (IQR 12.1-23.0) for the trastuzumab emtansine 2.4 mg/kg weekly group and 15.4 months (9.2-18.1) in the taxane group. Median overall survival was 7.9 months (95% CI 6.7-9.5) with trastuzumab emtansine 2.4 mg/kg weekly and 8.6 months (7.1-11.2) with taxane treatment (hazard ratio 1.15, 95% CI 0.87-1.51, one sided p=0.86). The trastuzumab emtansine 2.4 mg/kg group had lower incidences of grade 3 or more adverse events (134 [60%] of 224 patients treated with trastuzumab emtansine vs 78 [70%] of 111 patients treated with a taxane), and similar incidences of adverse events leading to death (eight [4%] vs four [4%]), serious adverse events (65 [29%] vs 31 [28%]), and adverse events leading to treatment discontinuation (31 [14%] vs 15 [14%]) than did taxane treatment. The most common grade 3 or more adverse events in the trastuzumab emtansine 2.4 mg/kg weekly group were anaemia (59 [26%]) and thrombocytopenia (25 [11%]) compared with neutropenia (43 [39%]), and anaemia (20 [18%]), in the taxane group. The most common serious adverse events were anaemia (eight [4%]), upper gastrointestinal haemorrhage (eight [4%]), pneumonia (seven [3%]), gastric haemorrhage (six [3%]), and gastrointestinal haemorrhage (five [2%]) in the trastuzumab emtansine 2.4 mg/kg weekly group compared with pneumonia (four [4%]), febrile neutropenia (four [4%]), anaemia (three [3%]), and neutropenia (three [3%]) in the taxane group. INTERPRETATION: Trastuzumab emtansine was not superior to taxane in patients with previously treated, HER2-positive advanced gastric cancer. There is still an unmet need in this patient group and therapeutic options remain limited. FUNDING: F Hoffmann-La Roche. PMID- 28343977 TI - Sacituzumab govitecan activity in advanced breast cancer. PMID- 28343978 TI - Targeting HER2 beyond progression in gastroesophageal cancer. PMID- 28343976 TI - Prophylactic cranial irradiation versus observation in patients with extensive disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial. AB - BACKGROUND: Results from a previous phase 3 study suggested that prophylactic cranial irradiation reduces the incidence of symptomatic brain metastases and prolongs overall survival compared with no prophylactic cranial irradiation in patients with extensive-disease small-cell lung cancer. However, because of the absence of brain imaging before enrolment and variations in chemotherapeutic regimens and irradiation doses, concerns have been raised about these findings. We did a phase 3 trial to reassess the efficacy of prophylactic cranial irradiation in the treatment of extensive-disease small-cell lung cancer. METHODS: We did this randomised, open-label, phase 3 study at 47 institutions in Japan. Patients with extensive-disease small-cell lung cancer who had any response to platinum-based doublet chemotherapy and no brain metastases on MRI were randomly assigned (1:1) to receive prophylactic cranial irradiation (25 Gy in ten daily fractions of 2.5 Gy) or observation. All patients were required to have brain MRI at 3-month intervals up to 12 months and at 18 and 24 months after enrolment. Randomisation was done by computer-generated allocation sequence, with age as a stratification factor and minimisation by institution, Eastern Cooperative Oncology Group performance status, and response to initial chemotherapy. The primary endpoint was overall survival, analysed in the intention-to-treat population. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000001755, and is closed to new participants. FINDINGS: Between April 3, 2009, and July 17, 2013, 224 patients were enrolled and randomly assigned (113 to prophylactic cranial irradiation and 111 to observation). In the planned interim analysis on June 18, 2013, of the first 163 enrolled patients, Bayesian predictive probability of prophylactic cranial irradiation being superior to observation was 0.011%, resulting in early termination of the study because of futility. In the final analysis, median overall survival was 11.6 months (95% CI 9.5-13.3) in the prophylactic cranial irradiation group and 13.7 months (10.2-16.4) in the observation group (hazard ratio 1.27, 95% CI 0.96-1.68; p=0.094). The most frequent grade 3 or worse adverse events at 3 months were anorexia (six [6%] of 106 in the prophylactic cranial irradiation group vs two [2%] of 111 in the observation group), malaise (three [3%] vs one [<1%]), and muscle weakness in a lower limb (one [<1%] vs six [5%]). No treatment-related deaths occurred in either group. INTERPRETATION: In this Japanese trial, prophylactic cranial irradiation did not result in longer overall survival compared with observation in patients with extensive-disease small-cell lung cancer. Prophylactic cranial irradiation is therefore not essential for patients with extensive-disease small-cell lung cancer with any response to initial chemotherapy and a confirmed absence of brain metastases when patients receive periodic MRI examination during follow-up. FUNDING: The Ministry of Health, Labour and Welfare of Japan. PMID- 28343979 TI - Proposed US Government budget cuts would 'devastate' cancer research. PMID- 28343980 TI - Nerve Damage From Bone Allografts and Xenografts-A Case Series. AB - The concept of socket preservation by placing a particulate bone allograft or xenograft into a tooth socket or on the alveolar ridge after tooth removal remains a somewhat controversial topic. The concept is that it will preserve the ridge from resorption and such that subsequent implant insertion will be easier, with fewer complications. However, one particular issue is that these materials, although not directly neurotoxic, appear to be an irritant to the nerves if they come in contact with them. We present a case series demonstrating this complication. PMID- 28343981 TI - Global epidemiology of HCV subtypes and resistance-associated substitutions evaluated by sequencing-based subtype analyses. AB - BACKGROUND & AIMS: HCV genotype, subtype, and presence of resistance-associated substitutions (RASs) are key determinants for the selection of direct-acting antiviral (DAA) treatment regimens. However, current HCV genotyping assays have limitations in differentiating between HCV subtypes, and RAS prevalence is largely undefined. The aim of this study was to investigate HCV epidemiology in 12,615 patient samples from 28 different countries across five geographic regions. METHODS: We compared HCV genotype and subtypes using INNO-LiPA 2.0 vs. amplicon sequencing among 8,945 patients from phase II/III clinical trials of DAAs. Global HCV molecular epidemiology in 12,615 patients was investigated. Subtype RAS prevalence was determined by population or deep sequencing, and phylogenetic analyses investigating subtype diversity were performed. RESULTS: Although there was high concordance between INNO-LiPA and sequencing for genotype determination, INNO-LiPA was insufficient for subtype determination for genotype 2, 3, 4, and 6. Sequencing provided subtype refinement for 42%, 10%, 81%, and 78% of genotype 2, 3, 4, and six patients, respectively. Genotype discordance (genotype 2-genotype 1) was observed in 28 of 950 (3%) genotype 2 patients, consistent with inter-genotype recombinants. Sequencing-based analyses demonstrated variations in regional subtype prevalence, notably within genotype 2, 4 and 6. RAS prevalence varied by subtype, with the clinically relevant NS3 RAS Q80K found in genotype 1a, 5a and 6a and the NS5A RAS Y93H in genotype 1b, 3a, 4b, 4r and 7. CONCLUSIONS: Together, these analyses provide an understanding of subtyping accuracy and RAS distribution that are crucial for the implementation of global HCV treatment strategies. LAY SUMMARY: Hepatitis C virus (HCV) is highly variable, with seven genotypes and 67 subtypes characterized to date. The aim of this study was to i) compare two different methods of discriminating between genotypes; ii) investigate the prevalence of HCV subtypes for each genotype around the world; iii) find the prevalence of resistance associated substitutions (RASs) in different subtypes. We found that both methods showed high concordance in genotype discrimination, but specific subtypes were not always identified accurately. Sequencing-based analyses demonstrated variations in regional subtype prevalence for some genotypes, notably within GT2, 4 and 6. RAS prevalence also varied by subtype. These variations could determine how successful different drugs are for treating HCV. PMID- 28343982 TI - Single-Cell 5-Formylcytosine Landscapes of Mammalian Early Embryos and ESCs at Single-Base Resolution. AB - Active DNA demethylation in mammals involves ten-eleven translocation (TET) family protein-mediated oxidation of 5-methylcytosine (5mC). However, base resolution landscapes of 5-formylcytosine (5fC) (an oxidized derivative of 5mC) at the single-cell level remain unexplored. Here, we present "CLEVER-seq" (chemical-labeling-enabled C-to-T conversion sequencing), which is a single-cell, single-base resolution 5fC-sequencing technology, based on biocompatible, selective chemical labeling of 5fC and subsequent C-to-T conversion during amplification and sequencing. CLEVER-seq shows intrinsic 5fC heterogeneity in mouse early embryos, Epi stem cells (EpiSCs), and embryonic stem cells (ESCs). CLEVER-seq of mouse early embryos also reveals the highly patterned genomic distribution and parental-specific dynamics of 5fC during mouse early pre implantation development. Integrated analysis demonstrates that promoter 5fC production precedes the expression upregulation of a clear set of developmentally and metabolically critical genes. Collectively, our work reveals the dynamics of active DNA demethylation during mouse pre-implantation development and provides an important resource for further functional studies of epigenetic reprogramming in single cells. PMID- 28343983 TI - Comprehensive Cell Surface Protein Profiling Identifies Specific Markers of Human Naive and Primed Pluripotent States. AB - Human pluripotent stem cells (PSCs) exist in naive and primed states and provide important models to investigate the earliest stages of human development. Naive cells can be obtained through primed-to-naive resetting, but there are no reliable methods to prospectively isolate unmodified naive cells during this process. Here we report comprehensive profiling of cell surface proteins by flow cytometry in naive and primed human PSCs. Several naive-specific, but not primed specific, proteins were also expressed by pluripotent cells in the human preimplantation embryo. The upregulation of naive-specific cell surface proteins during primed-to-naive resetting enabled the isolation and characterization of live naive cells and intermediate cell populations. This analysis revealed distinct transcriptional and X chromosome inactivation changes associated with the early and late stages of naive cell formation. Thus, identification of state specific proteins provides a robust set of molecular markers to define the human PSC state and allows new insights into the molecular events leading to naive cell resetting. PMID- 28343985 TI - Functional connectivity dynamically evolves on multiple time-scales over a static structural connectome: Models and mechanisms. AB - Over the last decade, we have observed a revolution in brain structural and functional Connectomics. On one hand, we have an ever-more detailed characterization of the brain's white matter structural connectome. On the other, we have a repertoire of consistent functional networks that form and dissipate over time during rest. Despite the evident spatial similarities between structural and functional connectivity, understanding how different time-evolving functional networks spontaneously emerge from a single structural network requires analyzing the problem from the perspective of complex network dynamics and dynamical system's theory. In that direction, bottom-up computational models are useful tools to test theoretical scenarios and depict the mechanisms at the genesis of resting-state activity. Here, we provide an overview of the different mechanistic scenarios proposed over the last decade via computational models. Importantly, we highlight the need of incorporating additional model constraints considering the properties observed at finer temporal scales with MEG and the dynamical properties of FC in order to refresh the list of candidate scenarios. PMID- 28343986 TI - The hemodynamic signal as a first-order low-pass temporal filter: Evidence and implications for neuroimaging studies. AB - Neuronal activation triggers local changes in blood flow and hemoglobin oxygenation. These hemodynamic signals can be recorded through functional magnetic resonance imaging or intrinsic optical imaging, and allows inferring neural activity in response to stimuli. These techniques are widely used to uncover functional brain architectures. However, their accuracy suffers from distortions inherent to hemodynamic responses and noise. The analysis of these signals currently relies on models of impulse hemodynamic responses to brief stimuli. Here, in order to infer precise functional architectures, we focused on integrated signals associated to the dynamic response of functional maps. To this end, we recorded orientation and direction maps in cat primary visual cortex and compared two protocols: the conventional episodic stimulation technique and a continuous, periodic stimulation paradigm. Conventional methods show that the dynamics of activation and deactivation of the functional maps follows a linear first-order differential equation representing a low-pass filter. Comparison with the periodic stimulation methods confirmed this observation: the phase shifts and magnitude attenuations extracted at various frequencies were consistent with a low-pass filter with a 5s time constant. This dynamics presumably reflects the variations in deoxyhemoglobin mediated by arterial dilations. This dynamics open new avenues in the analysis of neuroimaging data that differs from common methods based on the hemodynamic response function. In particular, we demonstrate that inverting this first-order low-pass filter minimized the distortions of the signal and enabled a much faster and accurate reconstruction of functional maps. PMID- 28343987 TI - Age-related reduction of hemispheric lateralisation for spatial attention: An EEG study. AB - A group-level visuospatial attention bias towards the left side of space (pseudoneglect) is consistently observed in young adults, which is likely to be a consequence of right parieto-occipital dominance for spatial attention. Conversely, healthy older adults demonstrate a rightward shift of this behavioural bias, hinting that an age-related reduction of lateralised neural activity may occur within visuospatial attention networks. We compared young (aged 18-25) and older (aged 60-80) adults on a computerised line bisection (landmark) task whilst recording event-related potentials (ERPs). Full-scalp cluster mass permutation tests identified a larger right parieto-occipital response for long lines compared to short in young adults (confirming Benwell et al., 2014a) which was not present in the older group. To specifically investigate age-related differences in hemispheric lateralisation, cluster mass permutation tests were then performed on a lateralised EEG dataset (RH-LH electrodes). A period of right lateralisation was identified in response to long lines in young adults, which was not present for short lines. No lateralised clusters were present for either long or short lines in older adults. Additionally, a reduced P300 component amplitude was observed for older adults relative to young. We therefore report here, for the first time, an age-related and stimulus-driven reduction of right hemispheric control of spatial attention in older adults. Future studies will need to determine whether this is representative of the normal aging process or an early indicator of neurodegeneration. PMID- 28343984 TI - Amitosis of Polyploid Cells Regenerates Functional Stem Cells in the Drosophila Intestine. AB - Organ fitness depends on appropriate maintenance of stem cell populations, and aberrations in functional stem cell numbers are associated with malignancies and aging. Symmetrical division is the best characterized mechanism of stem cell replacement, but other mechanisms could also be deployed, particularly in situations of high stress. Here, we show that after severe depletion, intestinal stem cells (ISCs) in the Drosophila midgut are replaced by spindle-independent ploidy reduction of cells in the enterocyte lineage through a process known as amitosis. Amitosis is also induced by the functional loss of ISCs coupled with tissue demand and in aging flies, underscoring the generality of this mechanism. However, we also found that random homologous chromosome segregation during ploidy reduction can expose deleterious mutations through loss of heterozygosity. Together, our results highlight amitosis as an unappreciated mechanism for restoring stem cell homeostasis, but one with some associated risk in animals carrying mutations. PMID- 28343988 TI - Sampling maternal care behaviour in domestic dogs: What's the best approach? AB - Our understanding of the frequency and duration of maternal care behaviours in the domestic dog during the first two postnatal weeks is limited, largely due to the inconsistencies in the sampling methodologies that have been employed. In order to develop a more concise picture of maternal care behaviour during this period, and to help establish the sampling method that represents these behaviours best, we compared a variety of time sampling methods Six litters were continuously observed for a total of 96h over postnatal days 3, 6, 9 and 12 (24h per day). Frequent (dam presence, nursing duration, contact duration) and infrequent maternal behaviours (anogenital licking duration and frequency) were coded using five different time sampling methods that included: 12-h night (1800 0600h), 12-h day (0600-1800h), one hour period during the night (1800-0600h), one hour period during the day (0600-1800h) and a one hour period anytime. Each of the one hour time sampling method consisted of four randomly chosen 15-min periods. Two random sets of four 15-min period were also analysed to ensure reliability. We then determined which of the time sampling methods averaged over the three 24-h periods best represented the frequency and duration of behaviours. As might be expected, frequently occurring behaviours were adequately represented by short (oneh) sampling periods, however this was not the case with the infrequent behaviour. Thus, we argue that the time sampling methodology employed must match the behaviour of interest. This caution applies to maternal behaviour in altricial species, such as canids, as well as all systematic behavioural observations utilising time sampling methodology. PMID- 28343989 TI - Social interaction, food, scent or toys? A formal assessment of domestic pet and shelter cat (Felis silvestris catus) preferences. AB - Domestic cats (Felis silvestris catus) engage in a variety of relationships with humans and can be conditioned to engage in numerous behaviors using Pavlovian and operant methods Increasingly cat cognition research is providing evidence of their complex socio-cognitive and problem solving abilities. Nonetheless, it is still common belief that cats are not especially sociable or trainable. This disconnect may be due, in part, to a lack of knowledge of what stimuli cats prefer, and thus may be most motivated to work for. The current study investigated domestic cat preferences at the individual and population level using a free operant preference assessment. Adult cats from two populations (pet and shelter) were presented with three stimuli within each of the following four categories: human social interaction, food, toy, and scent. Proportion of time interacting with each stimulus was recorded. The single most-preferred stimulus from each of the four categories were simultaneously presented in a final session to determine each cat's most-preferred stimulus overall. Although there was clear individual variability in cat preference, social interaction with humans was the most-preferred stimulus category for the majority of cats, followed by food. This was true for cats in both the pet and shelter population. Future research can examine the use of preferred stimuli as enrichment in applied settings and assess individual cats' motivation to work for their most-preferred stimulus as a measure of reinforcer efficacy. PMID- 28343990 TI - Impact of Freeze/Thaw Process on Drug Substance Storage of Therapeutics. AB - The storage of drug substance at subzero temperatures mitigates potential risks associated with liquid storage, such as degradation and shipping stress, making it the best solution for long-term storage. However, slower (generally uncontrolled) rates of freezing and thawing of drug substance in conventional large storage containers (>2L) can lead to greater cryoconcentration (exclusion of solute molecules) resulting in zones of higher protein and excipient concentrations and changes to the desired formulation pH and excipient concentration. These conditions can negatively impact product quality, thus changing the target product profile. Freeze/thaw studies can provide valuable knowledge on the molecule even when performed from an early formulation image. This study attempts to provide guidance and strategy for planning of drug substance freeze and thaw studies in early development using a scale-down model, evaluating the impact of the (1) freeze/thaw rate, (2) mode of freezing, (3) drug substance container, (4) drug substance concentration, and (5) formulation on the drug substance product quality. Data presented in this study showed no impact on drug substance product quality after undergoing the typical one freeze/thaw cycle process for the variables evaluated. These findings suggest that a qualified scale-down model is not required for early phases of process development and that existing small-scale models can be used for drug substance storage development studies. Based on our experience, a workflow is suggested with minimal experimental design to reduce the material requirement by >70% at early stages of product development to reduce constraints. PMID- 28343991 TI - Transdermal Iontophoretic Delivery of Lysine-Proline-Valine (KPV) Peptide Across Microporated Human Skin. AB - Lysine-proline-valine (KPV) is a C-terminal peptide fragment of alpha-melanocyte stimulating hormone with potent anti-inflammatory properties. Present study investigates various transdermal enhancement strategies such as iontophoresis (ITP), microneedles (MN), and their combination (ITP + MN) on KPV delivery across dermatomed human skin. KPV attains a positive charge at pH less than 7.0, thus anodal ITP was used. The influence of current strength, KPV concentration, and duration of current application on the KPV delivery was investigated. At defined ITP parameters, the influence of MN on KPV delivery (ITP + MN) across skin was also determined. KPV permeation was less than detectable levels (limit of detection, 0.01 MUg/mL) by simple passive diffusion. However, KPV permeation was increased to 4.4 MUg/cm2/h by MN treatment. Furthermore, ITP and ITP + MN increased the permeation rate by 8 and 35 fold, respectively, as compared to MN alone. The skin retention levels of KPV by MN, ITP, and ITP + MN were increased by 5, 10, and 10 fold, respectively, as compared to passive diffusion. Confocal studies indicate that fluorescein isothiocyanate-labeled KPV migrated through the stratum corneum, along the microchannels and into the lower epidermal tissue because the fluorescence was observed beyond the depth of 100 MUm. PMID- 28343992 TI - Letter to the editor: A late response from a female scientist to Hoy, 'gender imbalance at brain stimulation conferences: We have a problem and it is Everyone's problem'. PMID- 28343993 TI - Discovering key residues of dengue virus NS2b-NS3-protease: New binding sites for antiviral inhibitors design. AB - The NS2B-NS3 protease is essential for the Dengue Virus (DENV) replication process. This complex constitutes a target for efficient antiviral discovery because a drug could inhibit the viral polyprotein processing. Furthermore, since the protease is highly conserved between the four Dengue virus serotypes, it is probable that a drug would be equally effective against all of them. In this article, a strategy is reported that allowed us to identify influential residues on the function of the Dengue NS2b-NS3 Protease. Moreover, this is a strategy that could be applied to virtually any protein for the search of alternative influential residues, and for non-competitive inhibitor development. First, we incorporated several features derived from computational alanine scanning mutagenesis, sequence, structure conservation, and other structure-based characteristics. Second, these features were used as variables to obtain a multilayer perceptron model to identify defined groups (clusters) of key residues as possible candidate pockets for binding sites of new leads on the DENV protease. The identified residues included: i) amino acids close to the beta sheet-loop-beta sheet known to be important in its closed conformation for NS2b ii) residues close to the active site, iii) several residues evenly spread on the NS2b-NS3 contact surface, and iv) some inner residues most likely related to the overall stability of the protease. In addition, we found concordance on our list of residues with previously identified amino acids part of a highly conserved peptide studied for vaccine development. PMID- 28343994 TI - Revelation of the dynamic progression of hypoxia-reoxygenation injury by visualization of the lysosomal hydrogen peroxide. AB - Hydrogen peroxide (H2O2) plays an important role in pathological conditions, such as cerebral ischemia-reperfusion (I-R) injury. Fluorescent probes may serve as valuable tools to detect the amount, temporal and spatial distribution of H2O2 in living cells. To investigate the role of lysosomal H2O2 involved in cerebral I-R injury, we designed and synthesized a lysosome-targetable two-photon fluorescent probe ztl-4, through expansion and substitution of the original pyridazinone scaffold, conjugation of electronic-donating aromatic ring and precise terminal modification of the alkyl linker. The probe ztl-4 exhibited fast, sensitive and highly selective response toward H2O2. ztl-4 could image exogenous H2O2 in SH SY5Y cells and brain slices. In addition, ztl-4 was located in lysosomes with high colocalization coefficient compared with LysoTracker. ztl-4 was further applied for detecting the endogenous generation of H2O2 in SH-SY5Y cells subjected to oxygen and glucose deprivation (OGD) or OGD/reoxygenation (OGD/R) injury. Both OGD- and OGD/R-induced cell injury caused a time-dependent increase of H2O2 production within lysosomes. Moreover, OGD/R-treated cells showed much more amount of H2O2 than OGD-treated cells, indicating that reoxygenation will promote H2O2 accumulation in lysosomes of post-hypoxia cells. Therefore, the probe is suitable for monitoring the dynamic changes of lysosomal H2O2 in cells. PMID- 28343995 TI - Urolithin A alleviates myocardial ischemia/reperfusion injury via PI3K/Akt pathway. AB - Ischemia/reperfusion (I/R) induces additional damage to the restoration of blood flow to ischemic myocardium. This study examined the effects of urolithin A (UA) on myocardial injury of ischemia/reperfusion in vivo and vitro and explored its underlying mechanisms. Mice were subjected to myocardial ischemia followed by reperfusion. Cells were subjected to hypoxia followed by reoxygenation. UA alleviated hypoxia/reoxygenation (H/R) injury in myocardial cells, reduced myocardial infarct size and cell death in mice after ischemia/reperfusion. Meanwhile, UA enhanced antioxidant capacity in cardiomyocytes following hypoxia/reoxygenation. UA reduced myocardial apoptosis following ischemia/reperfusion. The protection of UA was abolished by LY294002, a PI3K/Akt inhibitor. These results demonstrated that UA alleviates myocardial ischemia/reperfusion injury probably through PI3K/Akt pathway. PMID- 28343997 TI - DNA double-strand breaks and Aurora B mislocalization induced by exposure of early mitotic cells to H2O2 appear to increase chromatin bridges and resultant cytokinesis failure. AB - Aneuploidy, an abnormal number of chromosomes that is a hallmark of cancer cells, can arise from tetraploid/binucleated cells through a failure of cytokinesis. Reactive oxygen species (ROS) have been implicated in various diseases, including cancer. However, the nature and role of ROS in cytokinesis progression and related mechanisms has not been clearly elucidated. Here, using time-lapse analysis of asynchronously growing cells and immunocytochemical analyses of synchronized cells, we found that hydrogen peroxide (H2O2) treatment at early mitosis (primarily prometaphase) significantly induced cytokinesis failure. Cytokinesis failure and the resultant formation of binucleated cells containing nucleoplasmic bridges (NPBs) seemed to be caused by increases in DNA double strand breaks (DSBs) and subsequent unresolved chromatin bridges. We further found that H2O2 induced mislocalization of Aurora B during mitosis. All of these effects were attenuated by pretreatment with N-acetyl-L-cysteine (NAC) or overexpression of Catalase. Surprisingly, the PARP inhibitor PJ34 also reduced H2O2-induced Aurora B mislocalization and binucleated cell formation. Results of parallel experiments with etoposide, a topoisomerase IIalpha inhibitor that triggers DNA DSBs, suggested that both DNA DSBs and Aurora B mislocalization contribute to chromatin bridge formation. Aurora B mislocalization also appeared to weaken the "abscission checkpoint". Finally, we showed that KRAS-induced binucleated cell formation appeared to be also H2O2-dependent. In conclusion, we propose that a ROS, mainly H2O2 increases binucleation through unresolved chromatin bridges caused by DNA damage and mislocalization of Aurora B, the latter of which appears to augment the effect of DNA damage on chromatin bridge formation. PMID- 28343996 TI - Optimization of overexpression of a chaperone protein of steroid C25 dehydrogenase for biochemical and biophysical characterization. AB - Molybdenum is an essential nutrient for metabolism in plant, bacteria, and animals. Molybdoenzymes are involved in nitrogen assimilation and oxidoreductive detoxification, and bioconversion reactions of environmental, industrial, and pharmaceutical interest. Molybdoenzymes contain a molybdenum cofactor (Moco), which is a pyranopterin heterocyclic compound that binds a molybdenum atom via a dithiolene group. Because Moco is a large and complex compound deeply buried within the protein, molybdoenzymes are accompanied by private chaperone proteins responsible for the cofactor's insertion into the enzyme and the enzyme's maturation. An efficient recombinant expression and purification of both Moco free and Moco-containing molybdoenzymes and their chaperones is of paramount importance for fundamental and applied research related to molybdoenzymes. In this work, we focused on a D1 protein annotated as a chaperone of steroid C25 dehydrogenase (S25DH) from Sterolibacterium denitrificans Chol-1S. The D1 protein is presumably involved in the maturation of S25DH engaged in oxygen-independent oxidation of sterols. As this chaperone is thought to be a crucial element that ensures the insertion of Moco into the enzyme and consequently, proper folding of S25DH optimization of the chaperon's expression is the first step toward the development of recombinant expression and purification methods for S25DH. We have identified common E. coli strains and conditions for both expression and purification that allow us to selectively produce Moco-containing and Moco-free chaperones. We have also characterized the Moco-containing chaperone by EXAFS and HPLC analysis and identified conditions that stabilize both forms of the protein. The protocols presented here are efficient and result in protein quantities sufficient for biochemical studies. PMID- 28343998 TI - Carnosic acid (CA) attenuates collagen-induced arthritis in db/db mice via inflammation suppression by regulating ROS-dependent p38 pathway. AB - Rheumatoid arthritis (RA) is a multifactorial autoimmune disease, characterized by inflammation of synovial joints. Carnosic acid (CA) is a phenolic diterpene isolated from Rosmarinus officinailis, playing a central role in cytoprotective responses to oxidative stress and inflammation response. Our study aimed to investigate the effects of CA on RA progression in diabetic animals. Carnosic acid (CA) was used to treat collagen-induced arthritis (CIA)-induced db/db mice. Blood glucose, oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were investigated to explore insulin resistance. CA significantly down regulated fasting blood glucose, glucose level in OGTT and ITT, ameliorated CIA induced bone loss, and reduced pro-inflammatory cytokines and reactive oxygen species (ROS) in db/db mice with arthritis induced by CIA. In vitro, CA suppressed Receptor Activator for Nuclear Factor-kappa B Ligand (RANKL)- and Macrophage colony-stimulating factor (M-CSF)-induced osteoclastogenesis. The osteoclastic specific markers were inhibited by CA. Signal transduction studies showed that CA significantly decreased the expression of molecules contributing to ROS and increased anti-oxidants. Additionally, CA inactivated the RANKL- and M CSF-induced p38 mitogen activated protein kinases (MAPK), inhibited NF-kappaB phosphorylation, causing pro-inflammatory cytokines down-regulation. Together, CA ameliorated osteoclast formation and CIA-induced bone loss in db/db mice through inflammation suppression by regulating ROS-dependent p38 pathway. PMID- 28343999 TI - A Genome-wide Analysis of Human Pluripotent Stem Cell-Derived Endothelial Cells in 2D or 3D Culture. AB - A defined protocol for efficiently deriving endothelial cells from human pluripotent stem cells was established and vascular morphogenesis was used as a model system to understand how synthetic hydrogels influence global biological function compared with common 2D and 3D culture platforms. RNA sequencing demonstrated that gene expression profiles were similar for endothelial cells and pericytes cocultured in polyethylene glycol (PEG) hydrogels or Matrigel, while monoculture comparisons identified distinct vascular signatures for each cell type. Endothelial cells cultured on tissue-culture polystyrene adopted a proliferative phenotype compared with cells cultured on or encapsulated in PEG hydrogels. The proliferative phenotype correlated to increased FAK-ERK activity, and knockdown or inhibition of ERK signaling reduced proliferation and expression for cell-cycle genes while increasing expression for "3D-like" vasculature development genes. Our results provide insight into the influence of 2D and 3D culture formats on global biological processes that regulate cell function. PMID- 28344000 TI - Long-Term Adult Feline Liver Organoid Cultures for Disease Modeling of Hepatic Steatosis. AB - Hepatic steatosis is a highly prevalent liver disease, yet research is hampered by the lack of tractable cellular and animal models. Steatosis also occurs in cats, where it can cause severe hepatic failure. Previous studies demonstrate the potential of liver organoids for modeling genetic diseases. To examine the possibility of using organoids to model steatosis, we established a long-term feline liver organoid culture with adult liver stem cell characteristics and differentiation potential toward hepatocyte-like cells. Next, organoids from mouse, human, dog, and cat liver were provided with fatty acids. Lipid accumulation was observed in all organoids and interestingly, feline liver organoids accumulated more lipid droplets than human organoids. Finally, we demonstrate effects of interference with beta-oxidation on lipid accumulation in feline liver organoids. In conclusion, feline liver organoids can be successfully cultured and display a predisposition for lipid accumulation, making them an interesting model in hepatic steatosis research. PMID- 28344001 TI - Inducible and Deterministic Forward Programming of Human Pluripotent Stem Cells into Neurons, Skeletal Myocytes, and Oligodendrocytes. AB - The isolation or in vitro derivation of many human cell types remains challenging and inefficient. Direct conversion of human pluripotent stem cells (hPSCs) by forced expression of transcription factors provides a potential alternative. However, deficient inducible gene expression in hPSCs has compromised efficiencies of forward programming approaches. We have systematically optimized inducible gene expression in hPSCs using a dual genomic safe harbor gene targeting strategy. This approach provides a powerful platform for the generation of human cell types by forward programming. We report robust and deterministic reprogramming of hPSCs into neurons and functional skeletal myocytes. Finally, we present a forward programming strategy for rapid and highly efficient generation of human oligodendrocytes. PMID- 28344002 TI - Establishment of a Human Blood-Brain Barrier Co-culture Model Mimicking the Neurovascular Unit Using Induced Pluri- and Multipotent Stem Cells. AB - In vitro models of the human blood-brain barrier (BBB) are highly desirable for drug development. This study aims to analyze a set of ten different BBB culture models based on primary cells, human induced pluripotent stem cells (hiPSCs), and multipotent fetal neural stem cells (fNSCs). We systematically investigated the impact of astrocytes, pericytes, and NSCs on hiPSC-derived BBB endothelial cell function and gene expression. The quadruple culture models, based on these four cell types, achieved BBB characteristics including transendothelial electrical resistance (TEER) up to 2,500 Omega cm2 and distinct upregulation of typical BBB genes. A complex in vivo-like tight junction (TJ) network was detected by freeze fracture and transmission electron microscopy. Treatment with claudin-specific TJ modulators caused TEER decrease, confirming the relevant role of claudin subtypes for paracellular tightness. Drug permeability tests with reference substances were performed and confirmed the suitability of the models for drug transport studies. PMID- 28344003 TI - Abnormal Neural Progenitor Cells Differentiated from Induced Pluripotent Stem Cells Partially Mimicked Development of TSC2 Neurological Abnormalities. AB - Tuberous sclerosis complex (TSC) is a disease featuring devastating and therapeutically challenging neurological abnormalities. However, there is a lack of specific neural progenitor cell models for TSC. Here, the pathology of TSC was studied using primitive neural stem cells (pNSCs) from a patient presenting a c.1444-2A>C mutation in TSC2. We found that TSC2 pNSCs had higher proliferative activity and increased PAX6 expression compared with those of control pNSCs. Neurons differentiated from TSC2 pNSCs showed enlargement of the soma, perturbed neurite outgrowth, and abnormal connections among cells. TSC2 astrocytes had increased saturation density and higher proliferative activity. Moreover, the activity of the mTOR pathway was enhanced in pNSCs and induced in neurons and astrocytes. Thus, our results suggested that TSC2 heterozygosity caused neurological malformations in pNSCs, indicating that its heterozygosity might be sufficient for the development of neurological abnormalities in patients. PMID- 28344004 TI - Identification of Three Early Phases of Cell-Fate Determination during Osteogenic and Adipogenic Differentiation by Transcription Factor Dynamics. AB - Age-related skeletal degeneration in patients with osteoporosis is characterized by decreased bone mass and occurs concomitant with an increase in bone marrow adipocytes. Using microarray expression profiling with high temporal resolution, we identified gene regulatory events in early stages of osteogenic and adipogenic lineage commitment of human mesenchymal stromal cells (hMSCs). Data analysis revealed three distinct phases when cells adopt a committed expression phenotype: initiation of differentiation (0-3 hr, phase I), lineage acquisition (6-24 hr, phase II), and early lineage progression (48-96 hr, phase III). Upstream regulator analysis identified 34 transcription factors (TFs) in phase I with a role in hMSC differentiation. Interestingly, expression levels of identified TFs did not always change and indicate additional post-transcriptional regulatory mechanisms. Functional analysis revealed that forced expression of IRF2 enhances osteogenic differentiation. Thus, IRF2 and other early-responder TFs may control osteogenic cell fate of MSCs and should be considered in mechanistic models that clarify bone-anabolic changes during clinical progression of osteoporosis. PMID- 28344006 TI - Drug-resistant tuberculosis in 2017: at a crossroads. PMID- 28344005 TI - miR-342-5p Regulates Neural Stem Cell Proliferation and Differentiation Downstream to Notch Signaling in Mice. AB - Notch signaling is critically involved in neural development, but the downstream effectors remain incompletely understood. In this study, we cultured neurospheres from Nestin-Cre-mediated conditional Rbp-j knockout (Rbp-j cKO) and control embryos and compared their miRNA expression profiles using microarray. Among differentially expressed miRNAs, miR-342-5p showed upregulated expression as Notch signaling was genetically or pharmaceutically interrupted. Consistently, the promoter of the miR-342-5p host gene, the Ena-vasodilator stimulated phosphoprotein-like (Evl), was negatively regulated by Notch signaling, probably through HES5. Transfection of miR-342-5p promoted the differentiation of neural stem cells (NSCs) into intermediate neural progenitors (INPs) in vitro and reduced the stemness of NSCs in vivo. Furthermore, miR-342-5p inhibited the differentiation of neural stem/intermediate progenitor cells into astrocytes, likely mediated by targeting GFAP directly. Our results indicated that miR-342-5p could function as a downstream effector of Notch signaling to regulate the differentiation of NSCs into INPs and astrocytes commitment. PMID- 28344007 TI - The war on tuberculosis must continue. PMID- 28344008 TI - The time has come: sparing injectables in paediatric MDR-TB. PMID- 28344009 TI - The uphill battle to find new TB treatments. PMID- 28344010 TI - Will we ever eliminate tuberculosis, the voiceless disease? PMID- 28344012 TI - Signaling pathways involved in metal-based nanomaterial toxicity towards aquatic organisms. AB - Environmental risk assessment of engineered nanomaterials (ENMs) is an emergent field since nanotechnology industry is rapidly growing due to the interesting physicochemical properties of nanomaterials. Metal-based nanomaterials are among the most rapidly commercialized materials and their toxicity towards aquatic animals has been investigated at different levels of the biological organization. The objective of this synthesis review is to give an overview of the signaling molecules that have a key role in metal-based NM mediated cytotoxicity in both marine and freshwater organisms. Since toxicity of metal-based NMs could be (partly) due to metal dissolution, this review only highlights studies that showed a specific nano-effect. From this bibliographic study, three mechanisms (detoxification, immunomodulation and genotoxicity) have been selected as they represent the major cell defense mechanisms and the most studied ones following ENM exposure. This better understanding of NM-mediated cytotoxicity may provide a sound basis for designing environmentally safer nanomaterials. PMID- 28344013 TI - A self-adherent, bullet-shaped microneedle patch for controlled transdermal delivery of insulin. AB - Proteins are important biologic therapeutics used for the treatment of various diseases. However, owing to low bioavailability and poor skin permeability, transdermal delivery of protein therapeutics poses a significant challenge. Here, we present a new approach for transdermal protein delivery using bullet-shaped double-layered microneedle (MN) arrays with water-swellable tips. This design enabled the MNs to mechanically interlock with soft tissues by selective distal swelling after skin insertion. Additionally, prolonged release of loaded proteins by passive diffusion through the swollen tips was obtained. The bullet-shaped MNs provided an optimal geometry for mechanical interlocking, thereby achieving significant adhesion strength (~1.6Ncm-2) with rat skin. By harnessing the MN's reversible swelling/deswelling property, insulin, a model protein drug, was loaded in the swellable tips using a mild drop/dry procedure. The insulin-loaded MN patch released 60% of insulin when immersed in saline over the course of 12h and approximately 70% of the released insulin appeared to have preserved structural integrity. An in vivo pilot study showed a prolonged release of insulin from swellable MN patches, leading to a gradual decrease in blood glucose levels. This self-adherent transdermal MN platform can be applied to a variety of protein drugs requiring sustained release kinetics. PMID- 28344011 TI - The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis. AB - Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms-including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions-are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues. PMID- 28344014 TI - Fabrication of coated polymer microneedles for transdermal drug delivery. AB - As an alternative to hypodermic needles, coated polymer microneedles (MNs) are able to deliver drugs to subcutaneous tissues after being inserted into the skin. The dip-coating process is a versatile, rapid fabricating method that can form coated MNs in a short time. However, it is still a challenge to fabricate coated MNs with homogeneous and precise drug doses in the dip-coating process. In this study, to fabricate coated polymer microneedles with controlled drug loading, an adjustable apparatus that can be lifted and lowered was designed to immerse a polylactic acid (PLA) MN patch in the coating solutions. Using the coating solution containing 0.5% (w/w) sulforhodamine B, the drug loadings were up to 12ng, 14ng, and 18ng per needle for the MNs with heights of 550MUm, 650MUm, and 750MUm, respectively. Moreover, for the MNs with a 650-MUm height, when increasing the viscosity of the coating solutions from 150mPa.s to 1360mPa.s, 2850mPa.s, and 8200mPa.s, the drug loading increased from 2.5ng to 5ng, 14ng, and 22ng per needle, respectively. Meanwhile, the drug delivery efficiencies of these MNs were approximately 90%. In the insertion experiments, the MNs could successfully penetrate the skin and deliver the coated drug with approximately 90% efficiency when the MN tips were exposed to the outer environment. In vivo studies in mice indicated that the coated polymer MNs continuously delivered drugs, and the skin recovered without any injuries. These results demonstrated that the coated polymer MN was a safe and effective method for transdermal drug delivery. PMID- 28344015 TI - Transdermal delivery of atorvastatin calcium from novel nanovesicular systems using polyethylene glycol fatty acid esters: Ameliorated effect without liver toxicity in poloxamer 407-induced hyperlipidemic rats. AB - CONTEXT: Atorvastatin calcium (ATV), a cholesterol-lowering agent, suffers from poor systemic availability (14%) after oral administration in addition to other side effects on the gastrointestinal tract, liver and muscle. OBJECTIVE: The goal of the present investigation was to improve ATV bioavailability and overcome complications attendant with peroral administration by developing a new nanovesicular system encapsulating ATV for its delivery via the transdermal route. METHODS: The vesicular systems were prepared by incorporating different polyethylene glycol fatty acid esters such as Labrasol, Cremophor EL, Gelucire 44/14 and Tween 80 as edge activators (EAs) in the lipid bilayer. The effect of the phosphatidylcholine (PC):EA molar ratio on the physicochemical properties of the vesicles was investigated. The pharmacokinetic studies of the optimized formulation were evaluated in rats. The optimized formulation was tested in poloxamer 407-induced hyperlipidemic rats. The plasma lipid profile, activity of liver enzymes, and oxidative stress parameters were measured using commercially available kits. RESULTS: The results revealed high ATV entrapment efficiency (EE%) ranging from 55.62 to 83.91%. The formulations that contained Labrasol showed the highest EE%. The mean diameter of the vesicles was in the range of 186 583nm. T8 containing Gelucire 44/14 as an EA in the molar ratio of 15:1 (PC:EA) gave the smallest size and exhibited the best permeation parameters across the skin. The pharmacokinetic studies revealed that about three times statistically significant (p<0.05) improvement in bioavailability, after transdermal administration of nanotransfersomal ATV gel compared to oral ATV suspension. The transdermal vesicular system exhibited a significant decrease in plasma total cholesterol, triglycerides and LDL cholesterol comparable to oral ATV. Additionally, it lowered the malondialdehyde levels in plasma and abolished the increase in liver enzyme activity. CONCLUSION: The results obtained suggest that the proposed transdermal vesicular system can serve as a promising alternative means for delivery of ATV. PMID- 28344016 TI - GRP78 enabled micelle-based glioma targeted drug delivery. AB - GRP78, a specific cancer cell-surface marker, is implicated in cancer cells proliferation, apoptosis resistance, metastasis and drug resistance. l-VAP (SNTRVAP) is a tumor homing peptide exhibiting high binding affinity in vitro to GRP78 protein overexpressed on glioma, glioma stem cells, vasculogenic mimicry and neovasculature. Even though short peptides are often non-immunogenic and demonstrate high affinity to tumor cells, their targeting efficacy is always undermined by rapid blood clearance and enzymatic degradation. In the present study, two d peptides RI-VAP (retro inverso isomer of l-VAP) and d-VAP (retro isomer of l-VAP) were developed by structure-guided peptide design and retro inverso isomerization technique for glioma targeting. RI-VAP and d-VAP were predicted to bind their receptor GRP78 protein with similar binding affinity, which was experimentally confirmed. The results of in vivo imaging demonstrated that RI-VAP and d-VAP had remarkably advantage over l-VAP for tumor accumulation. In addition, RI-VAP and d-VAP modified paclitaxel-loaded polymeric micelle had better anti-tumor efficacy in comparison to taxol, paclitaxel-loaded plain micelles and l-VAP modified micelles. Overall, the VAP modified micelles suggested in the present study could effectively achieve glioma-targeted drug delivery, validating the potential of the stable VAP peptides in improving the therapeutic efficacy of paclitaxel for glioma. PMID- 28344018 TI - Enhanced topical penetration, system exposure and anti-psoriasis activity of two particle-sized, curcumin-loaded PLGA nanoparticles in hydrogel. AB - Psoriasis is an immune-mediated skin disorder, which is triggered by the aberrant activation of dendritic cells in skin. This activation is followed by the complex interaction between the immune cells in the skin and keratinocyte in the epidermis. To improve the conditions of poor aqueous solubility and chemical stability, overcome skin barriers, and enhance in vivo anti-psoriatic activity, curcumin (Cur) loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were fabricated and administered by topical route to treat imiquimod (IMQ) induced psoriasis-like mouse model. Spherical Cur-NPs with the mean particle sizes of 50nm and 150nm, respectively, were fabricated using a multi-inlet vortex mixer system, with both exhibiting significantly stronger anti-proliferation effect than Cur solution on HaCaT cells in vitro. Psoriatic skin was utilized in the in vitro skin penetration studies, and the results demonstrated that more drugs penetrated through or accumulated in the skin when administered as the Cur NPs-loaded hydrogel compared to the drug suspension loaded hydrogel. To compare the nanosizing effect of these Cur-NPs, the mice with IMQ-induced psoriasis-like skin disease were treated with blank gel, Cur gel, 50nm sized NPs gel, 150nm sized NPs gel or tracrolimus cream (positive control), respectively. The results indicated that Cur-NPs hydrogel has a superior performance to Cur hydrogel on the IMQ-induced psoriasis-like mouse model in terms of morphological evaluation, biomarkers at mRNA, and protein levels. In conclusion, encapsulation of Cur into PLGA NPs, particularly for NPs of 50nm, could facilitate lipophilic Cur's dispersion, sustained-release, accumulation, and penetration across the skin and into the blood circulation, which significantly improves anti-psoriasis activity in mice. PMID- 28344017 TI - Intranasal delivery of N-terminal modified leptin-pluronic conjugate for treatment of obesity. AB - Leptin is an adipocyte-secreted hormone that is delivered via a specific transport system across the blood-brain barrier (BBB) to the brain where it acts on the hypothalamus receptors to control appetite and thermogenesis. Peripheral resistance to leptin due to its impaired brain delivery prevents therapeutic use of leptin in overweight and moderately obese patients. To address this problem, we modified the N-terminal amine of leptin with Pluronic P85 (LepNP85) and administered this conjugate intranasally using the nose-to-brain (INB) route to bypass the BBB. We compared this conjugate with the native leptin, the N-terminal leptin conjugate with poly(ethylene glycol) (LepNPEG5K), and two conjugates of leptin with Pluronic P85 attached randomly to the lysine amino groups of the hormone. Compared to the random conjugates of leptin with P85, LepNP85 has shown higher affinity upon binding with the leptin receptor, and similarly to native hormone activated hypothalamus receptors after direct injection into brain. After INB delivery, LepNP85 conjugate was transported to the brain and accumulated in the hypothalamus and hippocampus to a greater extent than the native leptin and LepNPEG5K and activated leptin receptors in hypothalamus at lower dose than native leptin. Our work suggests that LepNP85 can access the brain directly after INB delivery and confirms our hypothesis that the improvement in brain accumulation of this conjugate is due to its enhanced brain absorption. In conclusion, the LepNP85 with optimized conjugation chemistry is a promising candidate for treatment of obesity. PMID- 28344019 TI - Open versus minimally invasive surgical approaches in pediatric urology: Trends in utilization and complications. AB - OBJECTIVE: Minimally invasive surgery (MIS) techniques are anecdotally reported to be increasingly used, but little objective data supports this. Our objective was to assess trends in MIS utilization across various procedures in pediatric urology and to compare postoperative complication rates between MIS and open procedures. METHODS: We analyzed the 1998-2012 Nationwide Inpatient Sample. We identified children (<18 years old) undergoing open and MIS inpatient procedures and any in-hospital post-operative complications that occurred during that postoperative hospitalization. We utilized propensity score matching and multivariable logistic regression to adjust for confounding factors. RESULTS: We identified 163,838 weighted encounters in the "overall cohort," 70,273 of which were at centers performing more than five MIS procedures over the years studied. Use of MIS techniques increased significantly over time for several procedures, most prominently for nephrectomy (Fig.). The overall rate of complications was lower in patients undergoing MIS compared with open surgery (6% vs. 11%, p < 0.001). Specialized centers had a significantly lower overall rate of complications than unspecialized centers (9% vs. 12%, p < 0.001). Within specialized centers, MIS had lower complication rates than open procedures (7% vs. 9%, p < 0.001); this finding was consistent even after adjusting for other factors (OR 0.71, p = 0.02). DISCUSSION: Limitations include that these data may not be generalizable to encounters not in the sample pool. As a large, retrospective, administrative database, NIS may be affected by miscoding bias - rendering our analysis sensitive to the accuracy of procedure coding in NIS. Although the accuracy level of NIS is high for an administrative database, it is possible at least some portion of our cohort may be incorrectly coded. Further, the NSQIP complications we identified may represent associated comorbidities and not true postoperative complications, as NIS does not provide temporal relationships between different diagnosis codes. Despite these limitations, we note that the NIS database is rigorously monitored and audited for coding accuracy and, therefore, represents a reasonably reliable panorama of the characteristics of an inpatient surgical cohort. However, it is important to note that the choice of operative modality is, undoubtedly, multifactorial and patient/setting-specific. CONCLUSIONS: There is increasing use of MIS for pediatric urology procedures, although utilization rates vary among procedures. MIS was associated with a lower postoperative complication rate than for open procedures. Higher-volume MIS centers have a lower complication rate than lower volume centers. PMID- 28344020 TI - The incidence of isolated penile torsion in North India: A study of 5,018 male neonates. AB - OBJECTIVE: Congenital penile torsion is a three-dimensional deformity with helical rotation of the distal corporal bodies with the penile crurae remaining fixed to the pubic rami. The first case of congenital penile torsion (hypospadias) was described in 1857. Isolated penile torsion is an under-reported anomaly. The reported incidence of isolated penile torsion is 1.7-27% and severe torsion is 0.7%. There are no studies available from Indian subcontinent on the incidence of isolated penile torque. The objective of this study was to determine the overall incidence of isolated penile torque in a north Indian population. MATERIALS AND METHODS: A prospective study of deliveries of male children was conducted at our institute between April 2014 and June 2015. Penile torsion was measured using a small protractor either by the deviation of the median raphae or the direction of the meatus. Data were collected on the incidence of congenital isolated penile torsion, including the degree and direction (left or right) of torsion. Torsion was classified as mild (<450), moderate (450-900), and severe (>900). Statistical analysis was done using the chi-square test with variables of age and parity of the mother and weight of the child. RESULTS: There were 99 cases of isolated penile torque among 5018 male neonates assessed for penile torque. The incidence of isolated penile torque was 19.7 per 1000 births. The degree of torsion varied from 30 to 110 degrees (average 51.46 degrees ). Seventy-nine percent (79%) of them had left side and 21% had right side torque (4:1). The degree of torsion was mild in 30%, with 20% having left side torque and 10% having right side torque (2:1). A moderate degree of torsion was seen in 69%: 84% of them had left torque and only 16% had right sided torque (5:1). Only one patient had severe left torque. The incidence of isolated congenital penile torsion was highest in the maternal age group of >30 years followed by the 26-30 year age group, and was lowest in 21-25 year age group. In multiparous women, the incidence of isolated congenital penile torsion was highest (2.54%), and it was lowest in primiparous women (1.36%). CONCLUSION: The incidence of isolated penile torsion was 1.97% and the left-to-right ratio was 3:1, but for moderate torque it was 5:1. There was a strong association between incidence of penile torque with the age of the mother (p = 0.012) and parity (p = 0.008) but not with the weight of the baby (p = 0.415). PMID- 28344021 TI - Pharmaceutical cocrystals, salts and multicomponent systems; intermolecular interactions and property based design. AB - As small molecule drugs become harder to develop and less cost effective for patient use, efficient strategies for their property improvement become increasingly important to global health initiatives. Improvements in the physical properties of Active Pharmaceutical Ingredients (APIs), without changes in the covalent chemistry, have long been possible through the application of binary component solids. This was first achieved through the use of pharmaceutical salts, within the last 10-15years with cocrystals and more recently coamorphous systems have also been consciously applied to this problem. In order to rationally discover the best multicomponent phase for drug development, intermolecular interactions need to be considered at all stages of the process. This review highlights the current thinking in this area and the state of the art in: pharmaceutical multicomponent phase design, the intermolecular interactions in these phases, the implications of these interactions on the material properties and the pharmacokinetics in a patient. PMID- 28344022 TI - American Gastroenterological Association Institute Clinical Practice Update Expert Review: Care of Patients Who Have Achieved a Sustained Virologic Response After Antiviral Therapy for Chronic Hepatitis C Infection. AB - Chronic hepatitis C virus infection is well-recognized as a common blood-borne infection with global public health impact affecting 3 to 5 million persons in the United States and more than 170 million persons worldwide. Chronic hepatitis C virus infection is associated with significant morbidity and mortality due to complications of liver cirrhosis and hepatocellular carcinoma. Current therapies with all-oral direct-acting antiviral agents are associated with high rates of sustained virologic response (SVR), generally exceeding 90%. SVR is associated with a reduced risk of liver cirrhosis, hepatic decompensation, need for liver transplantation, and both liver-related and all-cause mortality. However, a subset of patients who achieve SVR will remain at long-term risk for progression to cirrhosis, liver failure, hepatocellular carcinoma, and liver-related mortality. Limited evidence is available to guide clinicians on which post-SVR patients should be monitored vs discharged, how to monitor and with which tests, how frequently should monitoring occur, and for how long. In this clinical practice update, available evidence and expert opinion are used to generate best practice recommendations on the care of patients with chronic hepatitis C virus who have achieved SVR. PMID- 28344023 TI - Cardiac vagal control in a knock-in mouse model of dilated cardiomyopathy with a troponin mutation. AB - The aim of this study was to evaluate cardiac vagal nerve activity and identify the abnormality of cardiac vagal control in heart failure caused by dilated cardiomyopathy (DCM) using a knock-in mouse model with a DeltaK210 mutation in the cardiac troponin T gene. The effects of electrical stimulation of the cervical vagal nerve at 5 and 10Hz (peripheral vagal control) and alpha2 adrennoceptor stimulation by intravenous medetomidine at 0.1mg/kg (central vagal control) were examined in wild-type (WT) mice and DCM mice. Microdialysis technique was applied to the left ventricular myocardium of anesthetized mice and myocardial interstitial acetylcholine (ACh) levels were measured by HPLC as an index of ACh release from cardiac vagal nerve endings. Electrical vagal nerve stimulation increased cardiac interval and myocardial interstitial ACh level in both WT and DCM mice, and these responses did not differ between WT and DCM mice. In contrast, intravenous medetomidine increased cardiac interval and myocardial interstitial ACh level in both WT and DCM mice, but the responses of cardiac interval and myocardial interstitial ACh level were significantly suppressed in DCM mice compared to WT mice. Medetomidine did not affect the myocardial interstitial ACh response induced by vagal nerve stimulation in WT mice. In this mouse model of DCM, peripheral vagal control including ACh release from vagal nerve endings and the postsynaptic response of pacemaker cells was preserved, but central vagal control through alpha2-adrenoceptors was impaired. PMID- 28344024 TI - Putative model based on iTRAQ proteomics for Spirulina morphogenesis mechanisms. AB - The morphology of Spirulina during cultivation is susceptible to external interferences, but the morphogenesis mechanism is still unclear. Here the proteomic changes of linear Spirulina and spiral Spirulina were comparatively investigated via isobaric tag for relative and absolute quantitation (iTRAQ). Totally 165 and 167 differences in proteins expression were screened out from the TJSD2/TJSD3 and TJBC4-1/TJBC4-2 groups, respectively. Gene ontology and metabolic pathway analysis of differences in proteins expression uncovered the metabolic pathways (photosynthesis, carbon fixation, sugar metabolism) that were significantly enriched with the proteins correlated with Spirulina morphogenesis. The results of differences in proteins expression in metabolic pathway were verified by quantitative real-time PCR. We also built a putative model of Spirulina morphogenesis mechanism and thought multiple metabolic pathways interact and take part in Spirulina morphogenesis. PMID- 28344025 TI - Any action? Reflections on the Australian Midwifery Action Project. AB - BACKGROUND: In 1997 a group of midwifery academics, researchers and practitioners met to discuss issues of concern related to the midwifery profession in Australia. It became clear from this discussion that midwifery in Australia was lagging behind similarly developed countries and that urgent action was required. From this meeting, a plan was developed to seek funding for a major national study into midwifery education and practice standards and as such, the Australian Midwifery Action Project (AMAP) was born. DISCUSSION: This discussion paper presents an overview of a number of midwifery education and regulation changes within the framework of the recommendations from the Australian Midwifery Action Project. A key question arising from this discussion is whether our current midwifery education and regulation standards provide a fit-for-purpose workforce that ensures all women and their families receive best practice midwifery care. Over the past 20 years the Midwifery profession in Australia has undergone significant changes and developments and these changes have had, and continue to have, significant impact on midwifery education and therefore on the quality of midwifery practice in Australia. CONCLUSION: Many changes have been implemented in the nearly 20 years since AMAP was first conceived. However, many of the issues that provided the impetus for a project such as AMAP remain and are still to be resolved. The midwifery profession continues to be subsumed with nursing, it is not possible to gain accurate midwifery workforce data and, despite the development of national standards for midwifery education, wide variations in courses still exist across Australia. PMID- 28344026 TI - The impact of various scaffold components on vascularized bone constructs. AB - Bone tissue engineering is gaining more interest in the field of craniofacial surgery where continuous efforts are being made to improve the outcomes via modulation of the scaffold components. In an in vitro three dimensional (3D) culture, the effect of bone morphogenic protein 2 (BMP2, 60 MUg/ml) and the effect of different cell seeding densities (0.25, 0.5, and 1 * 104) of rat mesenchymal stem cells seeded on nanocrystalline hydroxyapatite in silica gel matrix (Nanobone(r)) on the cell viability and differentiation were studied. Alkaline phosphatase and viability assays were performed at day 7, day 14, and day 21 to assess the differentiation and the relative fraction of viable cells in the 3D cell cultures. In a subsequent in vivo study, we examined the effect of axial vascularization, the scaffold's particle size and the nature of the matrix (collagen type I vs. diluted fibrin) on vascularization and tissue generation in vascularized bone construct in rats. Regarding vascularization, we compared constructs vascularized randomly by extrinsic vascularization from the periphery of the implanted construct with others vascularized axially via an implanted arteriovenous loop (AVL). Regarding the particle size, we compared constructs having a scaffold particle size of 0.2 mm (powder) with other constructs having a particle size of 2 * 0.6 mm (granules). Regarding the matrix we compared constructs having a collagen matrix with others having a fibrin matrix. Various groups were compared regarding the amount of tissue generation, vascularization, and cellular proliferation. The initial seeding density had a temporary and minimal effect on the overall osteogenic differentiation of the cells. On the contrary, adding BMP2 in a concentration of 60 MUg/ml over one week led to an overall enhanced osteogenic differentiation despite depressed cell viability. Axial vascularization was mandatory for efficient tissue formation and vascularization of the bone construct. Collagen matrix and a smaller particle size provided more favorable results in terms of vascularization and tissue formation than diluted fibrin and larger Nanobone particles. PMID- 28344027 TI - Differences in interpalpebral fissure measurement in patients with unilateral enophthalmos resulting from orbital wall fractures. AB - PURPOSE: To determine the correlation between the degree of enophthalmos and interpalpebral fissure (IPF) measurements in a group of patients with unilateral orbital wall fractures. MATERIALS AND METHODS: The medical charts of 45 patients diagnosed with unilateral enophthalmos resulting from an orbital wall fracture were reviewed. Demographic characteristics were investigated, including patient age, sex, medical history, and type of orbital wall fracture. The correlation between the degree of enophthalmos and IPF was determined, adjusting for confounding demographic factors. RESULTS: In the group with orbital wall fractures, the correlation between the degree of enophthalmos and the IPF measurements was positive and significant (R = 0.299, p = 0.046, Pearson's correlation). The correlation coefficient increased after adjusting for age, sex, medical history, and type of orbital wall fracture (R = 0.316, p = 0.044). CONCLUSION: The patient group with more severe enophthalmos tended to have lower IPF values. PMID- 28344028 TI - Fracture patterns after bilateral sagittal split osteotomy of the mandibular ramus according to the Obwegeser/Dal Pont and Hunsuck/Epker modifications. AB - The aim of this study was to compare the fracture patterns after sagittal split osteotomy according to Obwegeser/Dal Pont (ODP) and Hunsuck/Epker (HE), as well as to investigate the relationship between lateral bone cut ending or angle and the incidence of unfavorable/bad splits. Postoperative cone-beam computed tomograms of 124 splits according to ODP and 60 according to HE were analyzed. ODP led to 75.8% and HE led to 60% lingual fractures with mandibular foramen contact. Horizontal fractures were found in 9.7% and 6.7%, respectively, and unfavorable/bad splits were found in 11.3% and 10%, respectively. The lateral osteotomy angle was 106.22 degrees (SD 12.03) degrees for bad splits and 106.6 degrees (SD 13.12) degrees for favorable splits. Correlations were found between favorable fracture patterns and split modifications and between buccal ending of the lateral bone cut and bad splits (p < 0.001). No relationship was observed between split modifications (p = 0.792) or the osteotomy angle (p = 0.937) and the incidence of unfavorable/bad splits. Split modifications had no influence on the incidence of unfavorable/bad splits, but the buccal ending of the lateral bone cut did have an influence. More lingual fractures with mandibular foramen contact are expected with the ODP modification. The osteotomy angle did not differ between favorable and bad splits. PMID- 28344029 TI - Herbal remedies for urinary stones used in India and China: A review. AB - ETHANOPHARMACOLOGICAL RELEVANCE: The process of formation or appearance of a urinary stone anywhere in the renal tract is known as urolithiasis. It is a longstanding health problem, known to exist since early age of civilization. Records about symptoms, signs and treatment strategies of urinary stones diseases are found in the several ancient texts of traditional medicines such as Ayurveda, Traditional Chinese Medicine (TCM), Siddha and Unani. In Ayurveda, urolithiasis has been considered as one of the eight most troublesome diseases. Ayurvedic management and cure of urinary stone involves herbal formulas, alkaline liquids and surgical procedures. Whereas, TCM recommends polyherbal drugs, acupuncture and mexibustion for treatment of the urinary stones. Among these therapies, herbal remedies are in practice till today for the treatment and cure urinary stone diseases. MATERIALS AND METHODS: A comprehensive review of the scientific literature about pathophysiology of urinary stones and antiurolithiatic plants was undertaken using the following bibliographic databases: MEDLINE/PubMed, Scopus, Web of Knowledge and Google Scholar. The search was conducted from publications from all years until Dec., 2015 by combination of the search terms and Boolean operators; 'urinary stone' OR 'kidney stone' AND 'plant' OR 'medicine' OR 'antiurolithiatic plants'. Outputs were restricted to those completed studies only published in English. In this review, literatures about plants which are used as diuretic and/or in treatment urinary tract infections have not also been considered. The Plant List and Royal Botanical Garden, Kew databases were used to authenticate botanical names of plants. Books and monographs published in English were used to collect information about historical records of antiurolithiatic plants. RESULTS: Recent pharmacological interventions accredited ancient antiurolithiatic claims to several plants and their formulations. The majority of antiurolithiatic plants were found to either dissolve the stones or inhibit the process of urinary stone formation. Plants such as Phyllanthus niruri L. and Elymus repens (L.) Gould, as well as herbal products including 'Wu-Ling-San' formula, 'Cystone' and 'Herbmed' have been proved their utility as promising antiurolithiatic medicines in the different phases of clinical trials. In addition, some of the isolated phytochemicals such as berberine, lupeol, khelin, visnagin, 7-hydroxy-2',4',5'-trimethoxyisoflavone and 7-hydroxy-4'-methoxyisoflavone were reported to have potent antiurolithiatic activity. CONCLUSION: In ancient medicinal texts, antiurolithiatic potential has been ascribed to several plants and their formulations. Present scientific studies provide scientific evidences for few of these claims however, they are insufficient to establish many of these plants and herbal formulations as therapeutic remedies for the treatment and management of urinary stones. Conversely, findings of pre-clinical and clinical studies about some plants and herbal formulations are promising, which underlines the utility of herbal remedies as alternative medicines for the treatment and management of urinary stones in the future. PMID- 28344030 TI - Antibacterial activity of medicinal plants from The Physicians of Myddvai, a 14th century Welsh medical manuscript. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Antimicrobial drug resistance is a growing threat to global public health. Historical records and herbal texts relating to traditional Celtic medicine indicate an extensive pharmacopeia of plants for treating infections likely caused by microbes. However, a major barrier for successful integration of these remedies into mainstream practice is the current lack of accurate interpretation and scientific validation. MATERIALS AND METHODS: We investigated the flora of the Isle of Arran, Scotland, via in situ targeted screening of 83 out of 138 plants identified in Meddygion Myddvai (a 14th century Welsh manuscript) to treat conditions related to microbial infections, and an additional 18 plants from modern ethnobotanical knowledge on the island (Scottish School of Herbal Medicine). In a follow-up proof-of-concept study, bioassay guided fractionation was performed to identify bioactive constituents from two high scoring hits that inhibited Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative) bacterial growth. RESULTS: 67 historical plants (80.7%) and 14 modern plants (77.8%) were found to have detectable levels of antimicrobial activity when tested using Mobile Discovery kits, with human saliva as a source of bacteria for screening. Sabinene, a natural bicyclic monoterpene from juniper "berries" (Juniperus communis L.) and alliin, a natural sulfoxide from garlic cloves (Allium sativum L.), were isolated and confirmed as primary antibacterial leads. CONCLUSION: Using historical medical sources such as those associated with traditional Celtic medicine to guide rigorous, evidence-based scientific investigation, provides additional leads for new and alternative bioactive molecules for combating bacterial diseases. PMID- 28344031 TI - Culture-Bound Syndromes of a Brazilian Amazon Riverine population: Tentative correspondence between traditional and conventional medicine terms and possible ethnopharmacological implications. AB - ETHNOPHARMACOLOGICAL RELEVANCE: It is not always possible to correlate the "emic" terms to the "etic" ones during ethnopharmacological surveys, especially regarding those related to Culture-Bound Syndromes (CBS). Nevertheless, it is the role of ethnopharmacology to address these correlations, since they are the basis for the understanding of potential bioactives. AIM AND OBJECTIVES: This study reports the clinical manifestations and therapeutic resources used for the treatment of CBS among some riverine inhabitants of Brazilian Amazonia. An effort was made to establish a correspondence between the local "emic" terms of traditional medicine and the symptoms or diseases known by conventional medicine ("etic" terms). The ultimate goal was to gain insights to suggest further pharmacological studies with the local resources. MATERIAL AND METHODS: Fieldwork was guided by methods of anthropology, botany and zoology-with the assistance of a doctor-among the traditional healing experts in Jau National Park (during 199 days in 1995) and Unini River Extractive Reserve (210 days from 2008 to 2012). RESULTS: Fifty-nine healers of different kinds were interviewed: a prayer-maker, medium, natural resource expert, massage therapist, midwife and snakebite healer. The clinical manifestations and healing resources of the following CBS were collected: "mau olhado" (evil eye), "quebrante" (chipping); "espante" (fright or susto); "doenca do ar" (air diseases); "vento caido" (fallen wind); "derrame" (leakage); "mae do corpo" (mother of the body) and "panema" (unlucky). The first three seem to be local variations of other CBSs already described in Latin America. "doenca do ar", "vento caido", "derrame" and "mae do corpo" seem to be folk terms for known conventional medical disorders, while "panema" is a yet undescribed Brazilian CBS that is possibly related to dysthymic disorder or depression and deserves further investigation. Treatments included prayer rituals, fumigation, baths and oral remedies using 25 plants and 10 animals. CONCLUSION: It was possible to establish hypothetical correlations between CBS as described by the riverine population studied and some "etic" terms. The main importance of this is to help the proposition of target-oriented pharmacological studies of the natural resources used by these communities. Accordingly, the following plants are suggested to be submitted to further studies for antidepressant and anxiolytic activities: Siparuna guianensis, Mansoa alliacea, Leucas martinicensis, Petiveria alliacea, Annona montana and Alpinia nutans; for anti-seizure activity: Protium amazonicum, Protium aracouchini and Protium heptaphyllum; finally for antispasmodic activity: Leucas martinicensis. PMID- 28344032 TI - Editorial Comment. PMID- 28344033 TI - Editorial Comment. PMID- 28344034 TI - Editorial Comment. PMID- 28344035 TI - Larvae of Ixodiphagus wasps (Hymenoptera: Encyrtidae) in Rhipicephalus sanguineus sensu lato ticks (Acari: Ixodidae) from Brazil. AB - The biological control of ticks represents an alternative method to the chemical control, given its ecological-friendly approach. Amongst the alternatives, the use of parasitoids of the genus Ixodiphagus (Hymenoptera: Encyrtidae) has been largely investigated. The aim of this study was to document and molecularly characterize Ixodiphagus wasps in ticks from a tropical region of Brazil. From October 2015 to March 2016, Rhipicephalus sanguineus sensu lato ticks (n=1814) were collected from naturally infested dogs and Ixodiphagus larvae were detected by microscopic examination. In addition, adult wasps were obtained in the laboratory. Larvae and adults were molecularly identified as Ixodiphagus hookeri. These findings suggest that this type of parasitism deserves to be studied in local tick populations, in order to elucidate the role of these wasps as a potential alternative to chemical tick control. PMID- 28344036 TI - Focus: The interface between data collection and data processing in cryo-EM. AB - We present a new software package called Focus that interfaces cryo-transmission electron microscopy (cryo-EM) data collection with computer image processing. Focus creates a user-friendly environment to import and manage data recorded by direct electron detectors and perform elemental image processing tasks in a high throughput manner while new data is being acquired at the microscope. It provides the functionality required to remotely monitor the progress of data collection and data processing, which is essential now that automation in cryo-EM allows a steady flow of images of single particles, two-dimensional crystals, or electron tomography data to be recorded in overnight sessions. The rapid detection of any errors that may occur greatly increases the productivity of recording sessions at the electron microscope. PMID- 28344037 TI - Methods for decoding Cas9 protospacer adjacent motif (PAM) sequences: A brief overview. AB - Recently the Cas9, an RNA guided DNA endonuclease, emerged as a powerful tool for targeted genome manipulations. Cas9 protein can be reprogrammed to cleave, bind or nick any DNA target by simply changing crRNA sequence, however a short nucleotide sequence, termed PAM, is required to initiate crRNA hybridization to the DNA target. PAM sequence is recognized by Cas9 protein and must be determined experimentally for each Cas9 variant. Exploration of Cas9 orthologs could offer a diversity of PAM sequences and novel biochemical properties that may be beneficial for genome editing applications. Here we briefly review and compare Cas9 PAM identification assays that can be adopted for other PAM-dependent CRISPR Cas systems. PMID- 28344038 TI - Structural insights into the substrate recognition and reaction specificity of the PLP-dependent fold-type I isoleucine 2-epimerase from Lactobacillus buchneri. AB - The isoleucine 2-epimerase from Lactobacillus buchneri has been previously identified and characterized to catalyze the pyridoxal 5'-phosphate (PLP) dependent racemization and epimerization of a broad spectrum of nonpolar amino acids from L- to D-form and vice versa, in particular isoleucine. In this study, crystal structures of both native and PLP-complex forms of this racemase are presented at 2.6 and 2.15 A resolution, respectively. Both structures show that the protein belongs to the fold-type I subgroup of PLP-dependent enzymes and is very close to aminobutyrate aminotransferases family, as it has been suspected because of their sequence homology. The extensive structural comparison with fold type I enzymes with known amino acid racemization activities, including the alpha amino-epsilon-caprolactam racemase from Achromobacter obae and the cystathionine beta-lyase from Escherichia coli, allows us to identify the active site residues responsible for its nonpolar amino acid recognition and reactivity specificity. Our observations also suggest that the racemization reaction by the fold-type I racemases may generally occur thanks to a revised two-base mechanism. Lastly, both structures reveal details on the conformational changes provoked by PLP binding that suggest an induced fit of the active site "entrance door", necessary to accommodate PLP and substrate molecules. PMID- 28344041 TI - STAT5 signaling in kisspeptin cells regulates the timing of puberty. AB - Previous studies have shown that kisspeptin neurons are important mediators of prolactin's effects on reproduction. However, the cellular mechanisms recruited by prolactin to affect kisspeptin neurons remain unknown. Using whole-cell patch clamp recordings of brain slices from kisspeptin reporter mice, we observed that 20% of kisspeptin neurons in the anteroventral periventricular nucleus was indirectly depolarized by prolactin via an unknown population of prolactin responsive neurons. This effect required the phosphatidylinositol 3-kinase signaling pathway. No effects on the activity of arcuate kisspeptin neurons were observed, despite a high percentage (70%) of arcuate neurons expressing prolactin induced STAT5 phosphorylation. To determine whether STAT5 expression in kisspeptin cells regulates reproduction, mice carrying Stat5a/b inactivation specifically in kisspeptin cells were generated. These mutants exhibited an early onset of estrous cyclicity, indicating that STAT5 transcription factors exert an inhibitory effect on the timing of puberty. PMID- 28344043 TI - Renewed awareness of motor symptoms in psychiatric assessment. PMID- 28344040 TI - m6A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program. AB - The dynamic and reversible N6-methyladenosine (m6A) RNA modification installed and erased by N6-methyltransferases and demethylases regulates gene expression and cell fate. We show that the m6A demethylase ALKBH5 is highly expressed in glioblastoma stem-like cells (GSCs). Silencing ALKBH5 suppresses the proliferation of patient-derived GSCs. Integrated transcriptome and m6A-seq analyses revealed altered expression of certain ALKBH5 target genes, including the transcription factor FOXM1. ALKBH5 demethylates FOXM1 nascent transcripts, leading to enhanced FOXM1 expression. Furthermore, a long non-coding RNA antisense to FOXM1 (FOXM1-AS) promotes the interaction of ALKBH5 with FOXM1 nascent transcripts. Depleting ALKBH5 and FOXM1-AS disrupted GSC tumorigenesis through the FOXM1 axis. Our work uncovers a critical function for ALKBH5 and provides insight into critical roles of m6A methylation in glioblastoma. PMID- 28344044 TI - Impairments of motor function among children with a familial risk of schizophrenia or bipolar disorder at 7 years old in Denmark: an observational cohort study. AB - BACKGROUND: Owing to the genetic overlap between schizophrenia and bipolar disorder, we aimed to assess domain-specific motor aberrations and disorder specificity among 7-year-old children with a familial risk of schizophrenia or bipolar disorder by comparing children in familial risk groups with each other and with children not in these risk groups. METHODS: In the Danish High Risk and Resilience Study, we established a cohort of 7-year-old children with no, one, or two parents with schizophrenia or bipolar disorder in Denmark between Jan 1, 2013, and Jan 31, 2016. We matched children of parents diagnosed with schizophrenia to children of parents without schizophrenia on the basis of their home address, age, and sex. Even though we did not match children of parents with bipolar disorder directly to controls because of resource constraints, we only recruited children into the three groups who did not differ in terms of age, sex, and urbanicity. We investigated motor function in children using the Movement Assessment Battery for Children-Second Edition. Motor function raters were masked to participants' clinical risk status during assessments. We assessed the effects of familial risk group in a mixed-model analysis with repeated measures with an unstructured variance component matrix. FINDINGS: We studied 514 children (198 [39%] children of parents with schizophrenia, 119 [23%] of parents with bipolar disorder, and 197 [38%] of parents without schizophrenia or bipolar disorder). Children of parents with schizophrenia showed impaired motor performance compared with those of parents without in the subdomains of manual dexterity (mean difference -1.42 [95% CI -2.08 to -0.77]; p<0.0001) and balance (-1.38 [-2.03 to 0.72]; p<0.0001), but not of aiming and catching (-0.39 [-0.97 to 0.19]; p=0.18). Children of parents with bipolar disorder did not show any significant difference in motor performance to children of parents without in the subdomains of manual dexterity (-0.69 [-1.44 to 0.07]; p=0.08), balance (-0.68 [-1.44 to 0.08]; p=0.08), and aiming and catching (-0.36 [-1.03 to 0.31]; p=0.29). Comparison of familial risk groups of mental disorders revealed no significant differences in the subdomains of manual dexterity (-0.74 [-1.49 to 0.02]; p=0.06), balance ( 0.70 [-1.46 to 0.06]; p=0.07), or aiming and catching (-0.03 [-0.70 to 0.63]; p=0.92). INTERPRETATION: Motor abnormalities in children with a familial risk of schizophrenia are specific at 7 years of age with respect to fine motor function and balance, but non-specific with respect to familial risk of bipolar disorder. Clinicians should be aware of motor symptoms and refer children with definite motor problems (below the fifth percentile) to a child physiotherapist. FUNDING: Mental Health Services of the Capital Region of Denmark, Aarhus University, and the Lundbeck Foundation Initiative for Integrative Psychiatric Research. PMID- 28344042 TI - Exercise differentially affects metabolic functions and white adipose tissue in female letrozole- and dihydrotestosterone-induced mouse models of polycystic ovary syndrome. AB - Here we hypothesized that exercise in dihydrotestosterone (DHT) or letrozole (LET)-induced polycystic ovary syndrome mouse models improves impaired insulin and glucose metabolism, adipose tissue morphology, and expression of genes related to adipogenesis, lipid metabolism, Notch pathway and browning in inguinal and mesenteric fat. DHT-exposed mice had increased body weight, increased number of large mesenteric adipocytes. LET-exposed mice displayed increased body weight and fat mass, decreased insulin sensitivity, increased frequency of small adipocytes and increased expression of genes related to lipolysis in mesenteric fat. In both models, exercise decreased fat mass and inguinal and mesenteric adipose tissue expression of Notch pathway genes, and restored altered mesenteric adipocytes morphology. In conclusion, exercise restored mesenteric adipocytes morphology in DHT- and LET-exposed mice, and insulin sensitivity and mesenteric expression of lipolysis-related genes in LET-exposed mice. Benefits could be explained by downregulation of Notch, and modulation of browning and lipolysis pathways in the adipose tissue. PMID- 28344039 TI - Development of Peptidomimetic Inhibitors of the ERG Gene Fusion Product in Prostate Cancer. AB - Transcription factors play a key role in the development of diverse cancers, and therapeutically targeting them has remained a challenge. In prostate cancer, the gene encoding the transcription factor ERG is recurrently rearranged and plays a critical role in prostate oncogenesis. Here, we identified a series of peptides that interact specifically with the DNA binding domain of ERG. ERG inhibitory peptides (EIPs) and derived peptidomimetics bound ERG with high affinity and specificity, leading to proteolytic degradation of the ERG protein. The EIPs attenuated ERG-mediated transcription, chromatin recruitment, protein-protein interactions, cell invasion and proliferation, and tumor growth. Thus, peptidomimetic targeting of transcription factor fusion products may provide a promising therapeutic strategy for prostate cancer as well as other malignancies. PMID- 28344045 TI - EZH2-mediated alpha-actin methylation needs lncRNA TUG1, and promotes the cortex cytoskeleton formation in VSMCs. AB - Recent studies have revealed that long non-coding RNAs (lncRNAs) participate in vascular homeostasis and pathophysiological conditions development. But still very few literatures elucidate the regulatory mechanism of non-coding RNAs in this biological process. Here we identified lncRNA taurine up-regulated gene 1 (TUG1) in rat vascular smooth muscle cells (VSMCs), and got 4612bp nucleotide sequence. The expression level of TUG1 RNA was increased in synthetic VSMCs by real-time PCR analysis. Meanwhile, the expression of enhancer of zeste homolog 2 (EZH2) (TUG1 binding protein) increased in cytoplasm of VSMCs under the same conditions. Immunofluoresce analysis displayed the colocalization of EZH2 with alpha-actin in cytoplasm and F-actin in cell edge ruffles. This leads us to hypothesize the existence of cytoplasmic TUG1/EZH2/alpha-actin complex. Using RNA pull down assay, we found that TUG1 interacted with both EZH2 and alpha-actin. Disruption of TUG1 abolished the interaction of EZH2 with alpha-actin, and accelerated depolymerization of F-actin in VSMCs. Based on EZH2 methyltransferase activity and the potential methylation sites in alpha-actin structure, we revealed that alpha-actin was lysine-methylated. Furthermore, the methylation of alpha-actin was inhibited by knockdown of TUG1. In conclusion, these findings partly suggested that EZH2-mediated methylation of alpha-actin may be dependent on TUG1, and thereby promotes cortex F-actin polymerization in synthetic VSMCs. PMID- 28344046 TI - Long-term Outcomes of Induction Carboplatin and Gemcitabine Followed by Concurrent Radiotherapy With Low-dose Paclitaxel and Gemcitabine for Stage III Non-small-cell Lung Cancer. AB - BACKGROUND: Standard treatment for unresectable stage III non-small-cell lung cancer (NSCLC) is concurrent chemo-radiation (CRT). A regimen of induction carboplatin and gemcitabine followed by CRT was developed at the McGill University Health Centre to prevent delays in treatment initiation. We report the long-term outcomes with this regimen based on a pooled analysis of both protocol patients from a phase II study and nonprotocol patients. METHODS AND MATERIALS: Outcomes and toxicity data were retrieved for 142 patients with stage III NSCLC: 43 patients treated on protocol between January 2003 and November 2004, and 101 patients treated off-protocol between December 2004 and August 2013. Patients received 2 cycles of carboplatin with an area under the curve of 5 intravenously (IV) on day 1 and gemcitabine 1000 mg/m2 IV on days 1 and 8 every 3 weeks, followed on day 50 by CRT, 60 Gy/30 over 6 weeks, concomitantly with 2 cycles of paclitaxel 50 mg/m2 IV and gemcitabine 100 mg/m2 IV on days 1 and 8 every 3 weeks. RESULTS: The median overall survival was 23.2 months. With a median follow up of 23.8 months, the 3-, 4-, and 5-year overall survival was 38%, 30%, and 26%, respectively. The median and 5-year progression-free survival rates were 12.5 months and 25%, respectively. Rates of grade >= 3 hematologic, esophageal, and respiratory toxicity were 20%, 10%, and 10%, respectively. Forty-eight patients received further lines of chemotherapy. CONCLUSION: The present analysis affirms the favorable toxicity profile of this novel induction chemotherapy, without apparent compromise in clinical outcomes, when compared with regimens using immediate concurrent CRT. PMID- 28344047 TI - Sub-additive effects of photodynamic therapy combined with erlotinib for the treatment of epidermoid carcinoma: An in vitro study. AB - BACKGROUND: Photodynamic therapy (PDT) is an antitumour treatment that employs the combination of a photosensitive compound, oxygen and visible light. To improve the antitumour activity of PDT, the present study used the strategy of combining PDT with erlotinib (ERL), a drug frequently used in the treatment of epidermoid carcinoma. METHODS: An MTT cell viability assay was used to evaluate the cytotoxicity of PDT combined with ERL on A431 epidermoid carcinoma cells in vitro. This study evaluated the cytotoxicity of the following treatments: red laser irradiation (660nm) at different power densities (1.25-180J/cm2), the photosensitizer methylene blue (MB) at concentrations of 0.39-100MUM, PDT (12.5MUM MB and laser power densities from 1.25 to 180J/cm2), and PDT (12.5MUM MB and a laser density of 120J/cm2) plus ERL (1MUM). RESULTS: The laser power densities that were tested showed no cytotoxicity in A431 cells. MB showed a dose dependent cytotoxicity. In PDT, an increase in the dose of light resulted in an increase in the cytotoxicity of MB. In addition, there was a sub-additive effect between PDT and ERL compared to the effect of each therapy alone. CONCLUSIONS: The sub-additive effect between PDT and ERL suggests that their combination may be an important strategy in the treatment of epidermoid carcinoma. PMID- 28344049 TI - [Serum potassium levels and long-term mortality in the elderly with hypertension]. AB - : There is increasing evidence that small variations within the normal range (3.5 5mEq/L) of potassium are associated with mortality. OBJECTIVE: To determine whether there is an association between serum potassium level (sK) and mortality in a cohort of elderly hypertensive patients. PATIENTS AND METHODS: A retrospective, observational study was conducted on patients who had sK levels available in a period of clinical stability during their recruitment between January and April 2006 and followed-up for 10 years. The study obtained a total of 62 stable patients, with a mean age of 82.19+/-6 years (range 69-97), with 74.2% women, 33.9% diabetics, 20.3% with a history of heart failure, Ischaemic heart disease was observed in 19.4% and 44.3% received Angiotensin Converting Enzyme (ACE) inhibitors. An analysis was performed on the mortality rate during the 10 year period. The statistics were performed using the SPSS15.0 package. RESULTS: There were 49 deaths. The sK had a normal distribution. Baseline mean sK levels and median were 4.45+/-0.5mEq/L (range 3.1-5.5 mEq/L). Baseline sK levels were significantly higher in diabetic patients and patients on ACE inhibitors. The patients that died had higher sK levels (4.53+/-0.49mEq/L versus 4.14+/ 0.40mEq/L, P=.011). Survival estimated using Kaplan Meier showed that patients with sK levels higher than the median and P75 had higher mortality. CONCLUSIONS: In our study, sK levels greater than 4.45mEq/L were associated with mortality. When selecting antihypertensive treatment in hypertensive elderly patients,, the use of ACE inhibitors should be assessed individually, with close monitoring at sK levels and try to keep them in the lower limit of the normal range (<4.45 mEq/L). PMID- 28344048 TI - CD24+ tumor-initiating cells from oral squamous cell carcinoma induce initial angiogenesis in vivo. AB - BACKGROUND: In oral squamous cell carcinoma (OSCC), a minor subset of cancer stem cells has been identified using the surface marker CD24. The CD24+ cell population is involved in initiating, maintaining, and expanding tumor growth, but has not been reported to be involved in angiogenesis to date. METHODS: NOD/SCID mice were equipped with dorsal skinfold chambers and gelatin sponges seeded with CD24+, CD24-, and unsorted cancer cells suspended in Matrigel(r) were implanted. Following intravital fluorescence microscopy, specimens were examined by immunohistology. RESULTS: Sponges seeded with CD24+ cells showed a significantly higher functional capillary density than those seeded with CD24- cells. The presence of endothelial cells was confirmed by immunohistochemistry for CD31. CONCLUSION: For the first time, CD24+ tumorigenic cells with angiogenic potential, which were isolated from OSCC, were characterized. Our findings provide a promising in vivo model to facilitate the development of therapeutic agents against cancer stem cells and their angiogenic pathways. PMID- 28344050 TI - Liver Double-Tightened Maneuver: Optimal Outflow Control During Liver Parenchymal Transection of the Right and Left Hepatectomies. PMID- 28344051 TI - Massive Biliary Dilation after Roux-en-Y Gastric Bypass: Is it Ampullary Achalasia? AB - BACKGROUND: This series of patients with a history of Roux-en-Y gastric bypass (RYGB) and cholecystectomy presented with symptoms consistent with obstructive biliary disease and massive biliary dilation of >=15 mm, suggesting a structural cause. Findings from laparoscopic-assisted transgastric (TG) ERCP were a normal appearing ampulla without structural lesions or stones, suggesting a functional cause instead. STUDY DESIGN: Patients who underwent TGERCP from January 2008 to October 2016 and had a surgical history of RYGB and cholecystectomy were identified from an institutional database. Inclusion criteria was biliary dilation >=15 mm, age 18 years or older, and no explanatory obstructive pathology. RESULTS: Nine female patients met the inclusion criteria. At time of TGERCP, their mean age was 53.9 years, mean BMI was 32.5 kg/m2, mean bile duct diameter was 18.1 mm, and all patients experienced abdominal pain. Six patients (66.7%) presented with abnormal liver enzymes, 5 (55.6%) with nausea and/or vomiting, and 4 (44.4%) with earlier episode(s) of acute pancreatitis. Each patient had a normal-appearing papilla of Vater without stones or strictures at the time of TGERCP, with 8 (88.9%) patients experiencing cessation of abdominal pain after biliary sphincterotomy. CONCLUSIONS: This cohort of patients with a history of RYGB and cholecystectomy presented with massively dilated biliary trees lacking an obstructive disease process and experienced immediate symptom improvement after sphincterotomy. Their surgical history predisposed them to vagal nerve injury, leading to denervation of the sphincter of Oddi, and resulting in tonic contraction of the ampulla, that is, ampullary achalasia. PMID- 28344052 TI - Keeping fat on time: Circadian control of adipose tissue. AB - Circadian clocks harmonize processes ranging from intracellular biochemistry to whole-body physiology in accordance with the Earth's 24h rotation. These intrinsic oscillators are based on an interlocked transcriptional-translational feedback loop comprised from a set of core clock factors. In addition to maintaining rhythmicity in nearly every cell of the body, these clock factors also mediate tissue specific metabolic functions. In this review, we will explore how the molecular clock shapes the unique features of different adipose depots. PMID- 28344054 TI - The role of cardiac energy metabolism in cardiac hypertrophy and failure. AB - In mammalian heart, incessant production of cellular energy is vital for maintaining continuous mechanical pumping function providing the body for oxygen and nutrients. To ensure this essential function, cardiac muscle adapt to increased energy demand or compromised energy supply by reprogramming the network of genes whose products are necessary to match the production of energy to consumption. Failure in this regulation leads to severe cardiac dysfunction and has been associated with cardiac pathogenesis including cardiac hypertrophy, failure and diabetes. Metabolic adaptations are induced by network of transcriptional pathways that are activated by a variety of factors such as hormones, nutrients, second messengers and oxygen. The metabolic phenotype of the heart is maintained by pathways controlling transcriptional regulators, which include peroxisome proliferator-activated receptors, estrogen-related receptors and nuclear respiratory factors, as well as their common coactivator protein peroxisome proliferator-activated receptor gamma coactivator 1. These central regulators of gene expression are complemented with factors such as hypoxia inducible factor 1, which is activated in insufficient oxygenation of the tissue. Here, we discuss how these pathways relate to the cardiac metabolism and how they interact with pathways controlling the contractile phenotype of the heart. PMID- 28344053 TI - Reduced cancer mortality at high altitude: The role of glucose, lipids, iron and physical activity. AB - Residency at high altitude (HA) demands adaptation to challenging environmental conditions with hypobaric hypoxia being the most important one. Epidemiological and experimental data suggest that chronic exposure to HA reduces cancer mortality and lowers prevalence of metabolic disorders like diabetes and obesity implying that adaption to HA modifies a broad spectrum of physiological, metabolic and cellular programs with a generally beneficial outcome for humans. However, the complexity of multiple, potentially tumor-suppressive pathways at HA impedes the understanding of mechanisms leading to reduced cancer mortality. Many adaptive processes at HA are tightly interconnected and thus it cannot be ruled out that the entirety or at least some of the HA-related alterations act in concert to reduce cancer mortality. In this review we discuss tumor formation as a concept of competition between healthy and cancer cells with improved fitness - and therefore higher competitiveness - of healthy cells at high altitude. We discuss HA-related changes in glucose, lipid and iron metabolism that may have an impact on tumorigenesis. Additionally, we discuss two parameters with a strong impact on tumorigenesis, namely drug metabolism and physical activity, to underpin their potential contribution to HA-dependent reduced cancer mortality. Future studies are needed to unravel why cancer mortality is reduced at HA and how this knowledge might be used to prevent and to treat cancer patients. PMID- 28344055 TI - Role of skeletal muscle glucocorticoid receptor in systemic energy homeostasis. AB - Glucocorticoids (GCs) affect nearly every organ and tissue in the body, regulating diverse physiologic processes including energy homeostasis. The metabolic mission of GCs is to supply enough glucose into the circulation to fuel the brain and ensure survival of the organism under conditions of acute stress or starvation. Recent studies have revealed that GCs, via orchestration between multiple organs, physiologically elicit fine tuning of systemic energy metabolism. PMID- 28344056 TI - Chronic cutaneous mycobacterial ulcers due to Mycobacterium ulcerans (Buruli ulcer): the first indigenous case report from Jordan and a literature review. AB - BACKGROUND: Buruli ulcer is the third most common mycobacterial infection worldwide. It is endemic in tropical, subtropical, and temperate climates. It causes devastating disease with morbidity and mortality. The treatment duration is long and the regimens considered are limited. Chronic cutaneous ulcers of mycobacterial etiology have been reported previously in Amman, but these were not associated with Mycobacterium ulcerans infection. METHODS: The case patient's initial diagnosis was based on chronological and morphological features, combined with appropriate diagnostic tests. The skin features were assessed histopathologically. Skin testing was positive for acid-fast bacilli (AFB), and M. ulcerans was identified by DNA strip test (GenoType Mycobacterium CM/AS, Hain Lifescience), which is based on a PCR technique targeting a 23S rRNA gene region, followed by reverse hybridization and a line probe technology. RESULTS: The skin mycobacterial infection was evaluated and verified as having a Mycobacterium marinum-M. ulcerans pattern in the GenoType CM assay. It was then counted as a pattern representing individual species and was resolved with the GenoType AS assay as having an M. ulcerans pattern. M. ulcerans DNA was isolated and amplified by PCR, and then detected against reverse hybridization probes in the strip assay. CONCLUSIONS: An indigenous case of M. ulcerans (Buruli ulcer) is reported for the first time from Jordan and the surrounding region. PMID- 28344057 TI - Ruxolitinib as Salvage Therapy in Steroid-Refractory Acute Graft-versus-Host Disease in Pediatric Hematopoietic Stem Cell Transplant Patients. AB - We describe our retrospective clinical experience with ruxolitinib for steroid refractory acute graft-versus-host disease (GVHD) in pediatric allogeneic hematopoietic stem cell transplant (HSCT) patients. Ruxolitinib was administered orally at 5 mg twice daily for children >= 25 kg or 2.5 mg twice daily if <25 kg. We excluded patients who received new immune suppressive agents within 2 weeks before initiation of ruxolitinib from response analysis. Patients were called a treatment failure if ruxolitinib was stopped before completion of 4 weeks of therapy because of adverse effects and not because of progression of acute GVHD. Thirteen patients received ruxolitinib, and 11 patients were assessable for response. One patient achieved a complete response, 4 had a partial response, and 2 had no response at 4 weeks after the first ruxolitinib dose. Four patients were treatment failures. Overall response rate was 45%. Adverse effects (n = 13) included grades 3 to 4 elevated alanine transaminase (n = 7), grades 3 to 4 neutropenia (n = 5), and grade 4 thrombocytopenia (n = 3). Infectious complications in patients included for response analysis (n = 11) were Epstein Barr viremia (n = 2), adenovirus (n = 2), BK (n = 3), bacterial infections (n = 6), and fungal infections (n = 1). Seven of 13 patients were alive at a median follow-up of 401 days (range, 219 to 969) after HSCT. We observed a high rate of reversible adverse effects in children with steroid-refractory acute GVHD and a fair overall response of ruxolitinib as a salvage therapeutic agent. Further pharmacokinetic studies are needed to determine the best-tolerated dose of ruxolitinib that will achieve efficacy without significant adverse effects. PMID- 28344058 TI - Possible Impact of Cytomegalovirus-Specific CD8+ T Cells on Immune Reconstitution and Conversion to Complete Donor Chimerism after Allogeneic Stem Cell Transplantation. AB - Complete donor chimerism is strongly associated with complete remission after allogeneic stem cell transplantation (allo-SCT) in patients with hematologic malignancies. Donor-derived allo-immune responses eliminate the residual host hematopoiesis and thereby mediate the conversion to complete donor chimerism. Recently, cytomegalovirus (CMV) reactivation was described to enhance overall T cell reconstitution, to increase graft-versus-host disease incidence, and to reduce the leukemia relapse risk. However, the link between CMV and allo-immune responses is still unclear. Here, we studied the relationship between CMV specific immunity, overall T cell reconstitution, and residual host chimerism in 106 CMV-seropositive patients transplanted after reduced-intensity conditioning including antithymocyte globulin. In accordance with previous reports, the recovery of CMV-specific cytotoxic T cells (CMV-CTLs) was more frequent in CMV seropositive recipients (R) transplanted from CMV-seropositive than from seronegative donors (D). However, once CMV-CTLs were detectable, the reconstitution of CMV-specific CTLs was comparable in CMV R+/D- and R+/D+ patients. CD3+ and CD8+ T cell reconstitution was significantly faster in patients with CMV-CTLs than in patients without CMV-CTLs both in the CMV R+/D- and R+/D+ setting. Moreover, CMV-CTL numbers correlated with CD3+ and CD8+ T cell numbers in both settings. Finally, presence of CMV-CTLs was associated with low host chimerism levels 3 months after allo-SCT. In conclusion, our data provide a first indication that CMV-CTLs in CMV-seropositive patients might trigger the reconstitution of T cells and allo-immune responses reflected by the conversion to complete donor chimerism. PMID- 28344059 TI - Gastrointestinal Toxicity, Systemic Inflammation, and Liver Biochemistry in Allogeneic Hematopoietic Stem Cell Transplantation. AB - Liver toxicity is frequently seen in relation to allogeneic hematopoietic stem cell transplantation (HSCT), but pathogenesis and the risk factors are poorly understood. The purpose of this study was to investigate associations between liver toxicity, gastrointestinal toxicity, and levels of immune-regulating cytokines during the early post-transplantation period. We prospectively included 81 children and adults undergoing HSCT after myeloablative conditioning. Alanine aminotransferase (ALT), total bilirubin levels, and international normalized ratio were measured longitudinally until 3 months after the transplantation and related to levels of inflammatory markers (C-reactive protein [CRP], IL-6, and IL 10) and to plasma citrulline as a marker of intestinal toxicity during the first 3 weeks after HSCT. The majority of patients experienced ALT levels above the normal range (45 U/L) with significant increases at 3 months after HSCT. Increased levels of total bilirubin were observed in 26% during the 3-month period. Citrulline levels decreased significantly to a nadir at day 7 (B = .23; 95% confidence interval [CI], .12 to .35; P < .0001), but citrulline levels at nadir were not associated with parameters of liver toxicity. However, a faster reconstitution of mucosa with higher citrulline levels at day +21 correlated with lower bilirubin levels 3 months after HSCT (r = -.26, P = .034) and increased overall survival (hazard ratio, .88; 95% CI, .79 to .97; P = .008) . Increased levels of CRP and IL-6 at day 7 after HSCT correlated positively with ALT and bilirubin, and in the multivariate analysis, IL-6 at day 7 appeared to be the only predicting risk factor for increased mean bilirubin during the early post transplantation phase (B = .01; 95% CI, .01 to .02; P = .001) as well as maximum levels of bilirubin (B = .3; 95% CI, .12 to .48; P= .001) and occurrence of sinusoidal obstruction syndrome during the first 3 months after HSCT (odds ratio, 1.003; 95% CI, 1.001 to 1.005; P = .002). The results of this study indicate that liver toxicity after HSCT is associated with an increased inflammatory response mounted during the phase of maximal gastrointestinal toxicity in the early phase after transplantation. PMID- 28344060 TI - Basal CD34+ Cell Count Predicts Peripheral Blood Stem Cell Mobilization in Healthy Donors after Administration of Granulocyte Colony-Stimulating Factor: A Longitudinal, Prospective, Observational, Single-Center, Cohort Study. AB - A longitudinal, prospective, observational, single-center, cohort study on healthy donors (HDs) was designed to identify predictors of CD34+ cells on day 5 with emphasis on the predictive value of the basal CD34+ cell count. As potential predictors of mobilization, age, sex, body weight, height, blood volume as well as white blood cell count, peripheral blood (PB) mononuclear cells, platelet count, hematocrit, and hemoglobin levels were considered. Two different evaluations of CD34+ cell counts were determined for each donor: baseline (before granulocyte colony-stimulating factor [G-CSF] administration) and in PB after G CSF administration on the morning of the fifth day (day 5). A total of 128 consecutive HDs (66 males) with a median age of 43 years were enrolled. CD34+ levels on day 5 displayed a non-normal distribution, with a median value of 75.5 cells/uL. To account for the non-normal distribution of the dependent variable, a quantile regression analysis to predict CD34+ on day 5 using the baseline value of CD34+ as the key predictor was performed. On crude analysis, a baseline value of CD34+ ranging from .5 cells/uL to 1 cells/uL predicts a median value of 50 cells/uL on day 5; a value of 2 cells/uL predicts a median value of 70.7 cells/uL; a value of 3 cells/uL to 4 cells/uL predicts a median value of 91.3 cells/uL, and a value >= 5 predicts a median value of 112 cells/uL. In conclusion, the baseline PB CD34+ cell count correlates with the effectiveness of allogeneic PB stem cell mobilization and could be useful to plan the collection. PMID- 28344062 TI - IL-21 May Promote Granzyme B-Dependent NK/Plasmacytoid Dendritic Cell Functional Interaction in Cutaneous Lupus Erythematosus. AB - Autoimmune skin lesions are characterized by a complex cytokine milieu and by the accumulation of plasmacytoid dendritic cells (pDCs). Granzyme B (GrB) transcript is abundant in activated pDCs, though its mechanisms of regulation and biological role are largely unknown. Here we report that IL-21 was the only T helper 1/T helper 17 cytokine able to induce the expression and secretion of GrB by pDCs and that this action was counteracted by the autocrine production of type I IFNs. In lupus erythematosus skin lesions, the percentage of GrB+ pDCs directly correlated with the IL-21/MxA ratio, indicating that the interplay between these two cytokines finely tunes the levels of pDC-dependent GrB also in vivo. In lupus erythematosus, pDCs colocalized with professional cytotoxic cells at sites of epithelial damage, suggesting a role in keratinocyte killing. Accordingly, we demonstrate that supernatants of IL-21-activated pDCs promoted autologous keratinocyte killing by natural killer cells and this action was dependent on GrB. These results propose a GrB-dependent functional interaction between pDCs and natural killer cells and highlight a negative feedback regulation by type I IFNs in vitro and in vivo that may function to limit excessive tissue damage. PMID- 28344061 TI - Compartmentation of Mitochondrial and Oxidative Metabolism in Growing Hair Follicles: A Ring of Fire. AB - Little is known about the energetics of growing hair follicles, particularly in the mitochondrially abundant bulb. Here, mitochondrial and oxidative metabolism was visualized by multiphoton and light sheet microscopy in cultured bovine hair follicles and plucked human hairs. Mitochondrial membrane potential (DeltaPsi), cell viability, reactive oxygen species (ROS), and secretory granules were assessed with parameter-indicating fluorophores. In growing follicles, lower bulb epithelial cells had high viability, and mitochondria were polarized. Most epithelially generated ROS co-localized with polarized mitochondria. As the imaging plane captured more central and distal cells, DeltaPsi disappeared abruptly at a transition to a nonfluorescent core continuous with the hair shaft. Approaching the transition, DeltaPsi and ROS increased, and secretory granules disappeared. ROS and DeltaPsi were strongest in a circumferential paraxial ring at putative sites for formation of the outer cortex/cuticle of the hair shaft. By contrast, polarized mitochondria in dermal papillar fibroblasts produced minimal ROS. Plucked hairs showed a similar abrupt transition of degranulation/depolarization near sites of keratin deposition, as well as an ROS generating paraxial ring of fire. Hair movement out of the follicle appeared to occur independently of follicular bulb bioenergetics by a tractor mechanism involving the inner and outer root sheaths. PMID- 28344064 TI - White Paper AGA: Optimal Strategies to Define and Diagnose Gastroesophageal Reflux Disease. PMID- 28344063 TI - Asthma Is Associated With Subsequent Development of Inflammatory Bowel Disease: A Population-based Case-Control Study. AB - BACKGROUND & AIMS: Asthma and the inflammatory bowel diseases (IBD) each arise through complex interactions between genetic and environmental factors, and share many environmental risk factors. We examined the association between asthma and Crohn's disease or ulcerative colitis. METHODS: We performed a population-based case-control study using health administrative data from the province of Alberta, Canada. The odds of a diagnosis of asthma preceding the diagnosis of either Crohn's disease (N = 3087) or ulcerative colitis (N = 2377) were compared with the odds of diagnosis of asthma among persons without IBD (N = 402,800) using logistic regression. Effect measure modification by age at diagnosis of IBD (16 years or less, 17-40 years, or older than 40 years) was tested using a likelihood ratio test. RESULTS: A diagnosis of asthma was associated with increased odds of incident Crohn's disease (adjusted odds ratio [OR], 1.45; 95% confidence interval [CI], 1.31-1.60). No effect measure modification was observed for age at diagnosis for Crohn's disease (P = .42). However, we observed effect measure modification by age at diagnosis for ulcerative colitis (P = .0103), with an adjusted OR of 1.49 (95% CI, 1.08-2.07) among individuals diagnosed at an age of 16 years or less (OR) and an adjusted OR of 1.57 (95% CI, 1.31-1.89) among individuals diagnosed at an age older than 40 years. However, there was no association between asthma and ulcerative colitis among individuals diagnosed between ages 17 and 40 (adjusted OR, 1.05; 95% CI, 0.86-1.26). CONCLUSIONS: In a population-based case-control study, we associated asthma with Crohn's disease, and with early and late-onset ulcerative colitis. PMID- 28344065 TI - Lifestyle and Clinical Correlates of Hepatocellular Carcinoma in South Texas: A Matched Case-control Study. PMID- 28344066 TI - Old Farts - Fact or Fiction? Results From a Population-Based Survey of 16,000 Americans Examining the Association Between Age and Flatus. PMID- 28344067 TI - Upregulation of orexin/hypocretin expression in aged rats: Effects on feeding latency and neurotransmission in the insular cortex. AB - Aging is associated with changes in numerous homeostatic functions, such as food intake, that are thought to be mediated by the hypothalamus. Orexin/hypocretin neurons of the hypothalamus regulate several physiological functions, including feeding, sleep and wakefulness. Evidence from both clinical and animal studies supports the notion that aging is associated with loss or dysregulation of the orexin system. Here, we used virus-mediated gene transfer to manipulate expression of orexin peptides in young and aged rats and examined behavioral and neurochemical correlates of food intake in these animals. Aged rats showed slower feeding latencies when presented with palatable food compared to young control rats, and these deficits were ameliorated by upregulation of orexin expression. Similarly, young animals treated with a virus designed to decrease preproorexin expression showed longer feeding latencies reminiscent of aged control rats. Feeding was also associated with increased acetylcholine, glutamate and GABA efflux in insular cortex of young control animals. Orexin upregulation did not restore deficits in feeding-elicited release of these neurotransmitters in aged rats, but did enhance basal neurotransmitter levels which may have contributed to the behavioral correlates of these genetic manipulations. These studies demonstrate that age-related deficits in behavioral and neurochemical measures of feeding are likely to be mediated, in part, by the orexin system. Because these same neurotransmitter systems have been shown to underlie orexin effects on cognition, treatments which increase orexin function may have potential for improving both physiological and cognitive manifestations of certain age-related disorders. PMID- 28344068 TI - Interlimb differences in coordination of unsupported reaching movements. AB - Previous research suggests that interlimb differences in coordination associated with handedness might result from specialized control mechanisms that are subserved by different cerebral hemispheres. Based largely on the results of horizontal plane reaching studies, we have proposed that the hemisphere contralateral to the dominant arm is specialized for predictive control of limb dynamics, while the non-dominant hemisphere is specialized for controlling limb impedance. The current study explores interlimb differences in control of 3-D unsupported reaching movements. While the task was presented in the horizontal plane, participant's arms were unsupported and free to move within a range of the vertical axis, which was redundant to the task plane. Results indicated significant dominant arm advantages for both initial direction accuracy and final position accuracy. The dominant arm showed greater excursion along a redundant axis that was perpendicular to the task, and parallel to gravitational forces. In contrast, the non-dominant arm better impeded motion out of the task-plane. Nevertheless, non-dominant arm task errors varied substantially more with shoulder rotation excursion than did dominant arm task errors. These findings suggest that the dominant arm controller was able to take advantage of the redundant degrees of freedom of the task, while non-dominant task errors appeared enslaved to motion along the redundant axis. These findings are consistent with a dominant controller that is specialized for intersegmental coordination, and a non-dominant controller that is specialized for impedance control. However, the findings are inconsistent with previously documented conclusions from planar tasks, in which non-dominant control leads to greater final position accuracy. PMID- 28344069 TI - Selective post-training time window for memory consolidation interference of cannabidiol into the prefrontal cortex: Reduced dopaminergic modulation and immediate gene expression in limbic circuits. AB - The prefrontal cortex (PFC), amygdala and hippocampus display a coordinated activity during acquisition of associative fear memories. Evidence indicates that PFC engagement in aversive memory formation does not progress linearly as previously thought. Instead, it seems to be recruited at specific time windows after memory acquisition, which has implications for the treatment of post traumatic stress disorders. Cannabidiol (CBD), the major non-psychotomimetic phytocannabinoid of the Cannabis sativa plant, is known to modulate contextual fear memory acquisition in rodents. However, it is still not clear how CBD interferes with PFC-dependent processes during post-training memory consolidation. Here, we tested whether intra-PFC infusions of CBD immediately after or 5h following contextual fear conditioning was able to interfere with memory consolidation. Neurochemical and cellular correlates of the CBD treatment were evaluated by the quantification of extracellular levels of dopamine (DA), serotonin, and their metabolites in the PFC and by measuring the cellular expression of activity-dependent transcription factors in cortical and limbic regions. Our results indicate that bilateral intra-PFC CBD infusion impaired contextual fear memory consolidation when applied 5h after conditioning, but had no effect when applied immediately after it. This effect was associated with a reduction in DA turnover in the PFC following retrieval 5days after training. We also observed that post-conditioning infusion of CBD reduced c-fos and zif-268 protein expression in the hippocampus, PFC, and thalamus. Our findings support that CBD interferes with contextual fear memory consolidation by reducing PFC influence on cortico-limbic circuits. PMID- 28344070 TI - Unintentional force changes in cyclical tasks performed by an abundant system: Empirical observations and a dynamical model. AB - The study explored unintentional force changes elicited by removing visual feedback during cyclical, two-finger isometric force production tasks. Subjects performed two types of tasks at 1Hz, paced by an auditory metronome. One - Force task - required cyclical changes in total force while maintaining the sharing, defined as relative contribution of a finger to total force. The other task - Share task - required cyclical changes in sharing while keeping total force unchanged. Each trial started under full visual feedback on both force and sharing; subsequently, feedback on the variable that was instructed to stay constant was frozen, and finally feedback on the other variable was also removed. In both tasks, turning off visual feedback on total force elicited a drop in the mid-point of the force cycle and an increase in the peak-to-peak force amplitude. Turning off visual feedback on sharing led to a drift of mean share toward 50:50 across both tasks. Without visual feedback there was consistent deviation of the two force time series from the in-phase pattern (typical of the Force task) and from the out-of-phase pattern (typical of the Share task). This finding is in contrast to most earlier studies that demonstrated only two stable patterns, in phase and out-of-phase. We interpret the results as consequences of drifts of parameters in a dynamical system leading in particular to drifts in the referent finger coordinates toward their actual coordinates. The relative phase desynchronization is caused by the right-left differences in the hypothesized drift processes, consistent with the dynamic dominance hypothesis. PMID- 28344071 TI - Exposure to diphtheria toxin during the juvenile period impairs both inner and outer hair cells in C57BL/6 mice. AB - Diphtheria toxin (DT) administration into transgenic mice that express the DT receptor (DTR) under control of specific promoters is often used for cell ablation studies in vivo. Because DTR is not expressed in mice, DT injection has been assumed to be nontoxic to cells in vivo. In this study, we demonstrated that DT application during the juvenile stage leads to hearing loss in wild-type mice. Auditory brainstem response measurement showed severe hearing loss in C57BL/6 mice administered DT during the juvenile period, and the hearing loss persisted into adulthood. However, ototoxicity did not occur when DT was applied on postnatal day 28 or later. Histological studies demonstrated that hearing loss was accompanied by significant degeneration of inner and outer hair cells (HCs), as well as spiral ganglion neurons. Scanning electron microscopy showed quick degeneration of inner HCs within 3days and gradual degeneration of outer HCs within 1week. These results demonstrated that DT has ototoxic action on C57BL/6 mice during the juvenile period, but not thereafter, and the hearing loss was due to degeneration of inner and outer HCs by unknown DT-related mechanisms. PMID- 28344072 TI - Osteopontin-metallothionein I/II interactions in experimental autoimmune encephalomyelitis. AB - Osteopontin (OPN), an extracellular matrix (ECM) glyco-phosphoprotein, plays an important role in autoimmune-mediated demyelinating diseases, including multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). As an integrin and CD44 binding protein it participates in bidirectional communication between the ECM and target cells and affects transduction pathways that maintain neuronal and immune cell homeostasis. Its biological activity is also heavily influenced by microenvironment, which stimulates the cleavage of OPN and changes its functions. In this study we estimated the expression profile of OPN in neural tissues of DA rats during the first relapse of chronic relapsing EAE and investigated the relationship of OPN to metallothionein I+II (MTs), which play pivotal role in zinc-related cell homeostasis and in protection of CNS against cytokine-induced injury. The data showed that in EAE rats OPN mRNA and protein levels increased concurrently with the transcription of MTs and that within the spinal cord (SC) lysates EAE-afflicted rats had a higher content of OPN fragments of low molecular weight than untreated and CFA-treated rats. The expression of OPN and MTs was upregulated on ependymal, lymphoid and astroglial cells and on multiple alphavbeta3+ neurons in SC and in the brain (cortex, white matter, hippocampus, and cerebellum). Besides, multiple cells co-expressed OPN and MTs. Granular OPN signals were detected in secretory vesicles of Golgy (alphavbeta3 neurons) and in patches adjacent to the plasma membrane (subventricular zone). The findings imply that in demyelinating lesions are generated proteolytic OPN fragments and that OPN/MT interactions contribute to tissue remodeling during an autoimmune attack. PMID- 28344073 TI - Role of thrombin-PAR1-PKCtheta/delta axis in brain pericytes in thrombin-induced MMP-9 production and blood-brain barrier dysfunction in vitro. AB - Thrombin, an essential component in the coagulation cascade, participates in the pathogenesis of brain diseases, such as ischemic stroke, intracerebral hemorrhage, Alzheimer's disease and Parkinson's disease through blood-brain barrier (BBB) dysfunction. It is thought that the thrombin-matrix metalloproteinase (MMP)-9 axis is an important process in the pathogenesis of neurovascular disease, such as BBB dysfunction. We recently reported that brain pericytes are the most MMP-9-releasing cells in response to thrombin stimulation among the BBB-constituting cells. This thrombin-induced MMP-9 release is partially due to protease-activated receptor (PAR1), one of the specific thrombin receptors. Then, we evaluated the intracellular signaling pathways involved in MMP-9 release and the contribution of thrombin-reactive brain pericytes to BBB dysfunction. PKC activator evoked MMP-9 release from brain pericytes. The thrombin-induced MMP-9 release was inhibited by U0126, LY294002, Go6976, and Go6983. However, Go6976 decreased phosphorylation levels of PKCtheta and Akt, and Go6983 decreased phosphorylation levels of PKCdelta and extracellular signal regulated kinase (ERK). Additionally, treatment of pericytes with thrombin or PAR1-activating peptide stimulated PKCdelta/theta signaling. These substances impaired brain endothelial barrier function in the presence of brain pericytes. Brain pericytes function through two independent downstream signaling pathways via PAR1 activation to release MMP-9 in response to thrombin - the PKCtheta-Akt pathway and the PKCdelta-ERK1/2 pathway. These pathways participate in PAR1 mediated MMP-9 release from pericytes, which leads to BBB dysfunction. Brain pericytes and their specific signaling pathways could provide novel therapeutic targets for thrombin-induced neurovascular diseases. PMID- 28344074 TI - Aberrant distributions of nuclear pore complex proteins in ALS mice and ALS patients. AB - Nuclear pore complexes (NPCs) play important roles in traffic of molecules between the nucleus and cytoplasm, aberrant distributions of components of NPCs were demonstrated in C9orf72 amyotrophic lateral sclerosis (C9-ALS) patients, but it is elusive whether such abnormities are also the case with other cause of ALS disease. In the present study, we investigated the spatiotemporal distributions of RanGAP1 and 4 representative nucleoporins (GP210, NUP205, NUP107 and NUP50) of NPCs in human Cu/Zn superoxide dismutase-1 mutation transgenic (SOD1-Tg) mice and sporadic ALS patients. Compared with wild type (WT), these proteins displayed age dependent and progressive nuclear precipitations, and cytoplasmic aberrant expressions in motor neurons of lumbar cord in SOD1-Tg mice from 10 to 18weeks (W). Double immunofluorescent analysis showed abnormal nuclear retention and apparent co-localizations of RanGAPl with NUP205 and NUP205 with NUPl07, meanwhile, GP210 with NUP205 mainly co-localized in the nuclear envelope (NE) of motor neurons. Furthermore, RanGAP1, GP210 and NUP50 showed similarly abnormal nuclear precipitations and cytoplasmic upregulations in SOD1-Tg mice and ALS patients, moreover, aberrant co-localizations of RanGAP1 with TDP-43 and NUP205 with TDP-43 were also observed in motor neurons. The present study indicated that the mislocalization of these proteins of NPCs may underlie the pathogenesis of ALS both in SOD1-Tg mice and human sporadic ALS patients, and these dysfunctions may be a fundamental pathway for ALS that is not specific only in C9-ALS but also in SOD1-ALS, which may be amenable to pharmacotherapeutic intervention. PMID- 28344076 TI - Inhibition of human CYP3A4 and CYP3A5 enzymes by gomisin C and gomisin G, two lignan analogs derived from Schisandra chinensis. AB - Gomisin C (GC) and gomisin G (GG) are two lignan analogs isolated from the Traditional Chinese Medicine Schisandra chinensis which possesses multiple pharmacological activities. However, the potential herb-drug interactions (HDI) between these lignans and other drugs through inhibiting human cytochrome P450 3A4 (CYP3A4) and CYP3A5 remains unclear. In the present study, the inhibitory action of GC and GG on CYP3A4 and CYP3A5 were investigated. The results demonstrated that both GC and GG strongly inhibited CYP3A-mediated midazolam 1' hydroxylation, nifedipine oxidation and testosterone 6beta-hydroxylation. Notably, the inhibitory intensity of GC towards CYP3A4 was stronger than CYP3A5 when using midazolam and nifedipine as substrates. While inhibition of GC towards CYP3A5 was weaker than CYP3A4 when using testosterone as substrate. In contrast, GG showed a stronger inhibitory activity on CYP3A5 than CYP3A4 without substrate dependent behavior. In addition, docking simulations indicated that the pi-pi interaction between CYP3A4 and GC, and hydrogen-bond interaction between CYP3A5 and GG might result in their different inhibitory actions. Furthermore, the AUC of drugs metabolized by CYP3A was estimated to increase by 8%-321% and 2%-3190% in the presence of GC and GG, respectively. These findings strongly suggested that GC and GG showed high HDI potentials, and the position of methylenedioxy group determined their different inhibitory effect towards CYP3A4 and CYP3A5, which are of significance for the application of Schisandra chinensis-containing herbs. PMID- 28344077 TI - Erythematous plaques on the auditory canal. PMID- 28344075 TI - Functional reorganization in obstructive sleep apnoea and insomnia: A systematic review of the resting-state fMRI. AB - Functional neuroimaging techniques have accelerated progress in the study of sleep disorders. Considering the striking prevalence of these disorders in the general population, however, as well as their strong bidirectional relationship with major neuropsychiatric disorders, including major depressive disorder, their numbers are still surprisingly low. This review examines the contribution of resting state functional MRI to current understanding of two major sleep disorders, insomnia disorder and obstructive sleep apnoea. An attempt is made to learn from parallels of previous resting state functional neuroimaging findings in major depressive disorder. Moreover, shared connectivity biomarkers are suggested for each of the sleep disorders. Taken together, despite some inconsistencies, the synthesis of findings to date highlights the importance of the salience network in hyperarousal and affective symptoms in insomnia. Conversely, dysfunctional connectivity of the posterior default mode network appears to underlie cognitive and depressive symptoms of obstructive sleep apnoea. PMID- 28344078 TI - Laryngeal leishmaniasis, a rare manifestation of an emerging disease. PMID- 28344079 TI - Nasal foreign bodies in children in a pediatric hospital in Senegal: A three-year assessment. AB - OBJECTIVES: Nasal foreign bodies (NFB) constitute a common domestic accident in children. The objectives of the present study were to report the particularities of NFBs in children presenting at a pediatric hospital in Senegal, and to describe our therapeutic attitude. MATERIAL AND METHODS: A retrospective descriptive study included all under-15 year-olds presenting with NFB in the ENT department of the National Children's Hospital Center of Diamniadio, Senegal, between January 1, 2013 and December 31, 2015. Study variables comprised: age, gender, provenance, presenting symptoms, time to consultation, type of NFB, extraction method, and complications. RESULTS: 58 NFB cases were retrieved. Mean age was 3years 4months; 93% of patients were under 5 years old. There was female predominance of 53.45%: i.e., sex-ratio, 0.87. Location was in the right cavity in 43 patients (74.1%). The presenting symptom was purulent rhinorrhea in 51.7% of cases. Time to consultation was within 24hours in 17.24% of cases. NFB type was firstly foam rubber (29.3%), followed by grain (20.7%). Extraction was performed in consultation in 84.5% of cases and in the operating room in 15.5%. Morbidity was 22.41%: 17.24% epistaxis and 5.17% nasal infection. CONCLUSION: NFBs constitute a common domestic accident in under-5 year-olds. The rural Senegalese context shows delay in consultation. PMID- 28344080 TI - Translation of CircRNAs. AB - Circular RNAs (circRNAs) are abundant and evolutionarily conserved RNAs of largely unknown function. Here, we show that a subset of circRNAs is translated in vivo. By performing ribosome footprinting from fly heads, we demonstrate that a group of circRNAs is associated with translating ribosomes. Many of these ribo circRNAs use the start codon of the hosting mRNA, are bound by membrane associated ribosomes, and have evolutionarily conserved termination codons. In addition, we found that a circRNA generated from the muscleblind locus encodes a protein, which we detected in fly head extracts by mass spectrometry. Next, by performing in vivo and in vitro translation assays, we show that UTRs of ribo circRNAs (cUTRs) allow cap-independent translation. Moreover, we found that starvation and FOXO likely regulate the translation of a circMbl isoform. Altogether, our study provides strong evidence for translation of circRNAs, revealing the existence of an unexplored layer of gene activity. PMID- 28344081 TI - Plasma Membrane CRPK1-Mediated Phosphorylation of 14-3-3 Proteins Induces Their Nuclear Import to Fine-Tune CBF Signaling during Cold Response. AB - In plant cells, changes in fluidity of the plasma membrane may serve as the primary sensor of cold stress; however, the precise mechanism and how the cell transduces and fine-tunes cold signals remain elusive. Here we show that the cold activated plasma membrane protein cold-responsive protein kinase 1 (CRPK1) phosphorylates 14-3-3 proteins. The phosphorylated 14-3-3 proteins shuttle from the cytosol to the nucleus, where they interact with and destabilize the key cold responsive C-repeat-binding factor (CBF) proteins. Consistent with this, the crpk1 and 14-3-3kappalambda mutants show enhanced freezing tolerance, and transgenic plants overexpressing 14-3-3lambda show reduced freezing tolerance. Further study shows that CRPK1 is essential for the nuclear translocation of 14-3 3 proteins and for 14-3-3 function in freezing tolerance. Thus, our study reveals that the CRPK1-14-3-3 module transduces the cold signal from the plasma membrane to the nucleus to modulate CBF stability, which ensures a faithfully adjusted response to cold stress of plants. PMID- 28344082 TI - Circ-ZNF609 Is a Circular RNA that Can Be Translated and Functions in Myogenesis. AB - Circular RNAs (circRNAs) constitute a family of transcripts with unique structures and still largely unknown functions. Their biogenesis, which proceeds via a back-splicing reaction, is fairly well characterized, whereas their role in the modulation of physiologically relevant processes is still unclear. Here we performed expression profiling of circRNAs during in vitro differentiation of murine and human myoblasts, and we identified conserved species regulated in myogenesis and altered in Duchenne muscular dystrophy. A high-content functional genomic screen allowed the study of their functional role in muscle differentiation. One of them, circ-ZNF609, resulted in specifically controlling myoblast proliferation. Circ-ZNF609 contains an open reading frame spanning from the start codon, in common with the linear transcript, and terminating at an in frame STOP codon, created upon circularization. Circ-ZNF609 is associated with heavy polysomes, and it is translated into a protein in a splicing-dependent and cap-independent manner, providing an example of a protein-coding circRNA in eukaryotes. PMID- 28344084 TI - A rapid procedure for the in situ assay of periplasmic, PQQ-dependent methanol dehydrogenase in intact single bacterial colonies. AB - Mechanistic details of methanol oxidation catalyzed by the periplasmically located pyrroloquinoline quinone-dependent methanol dehydrogenase of methylotrophs can be elucidated using site-directed mutants. Here, we present an in situ colony assay of methanol dehydrogenase, which allows robotic screening of large populations of intact small colonies, and regrowth of colonies for subsequent analysis. PMID- 28344083 TI - Cholesterol Modification of Smoothened Is Required for Hedgehog Signaling. AB - Hedgehog (Hh) has been known as the only cholesterol-modified morphogen playing pivotal roles in development and tumorigenesis. A major unsolved question is how Hh signaling regulates the activity of Smoothened (SMO). Here, we performed an unbiased biochemical screen and identified that SMO was covalently modified by cholesterol on the Asp95 (D95) residue through an ester bond. This modification was inhibited by Patched-1 (Ptch1) but enhanced by Hh. The SMO(D95N) mutation, which could not be cholesterol modified, was refractory to Hh-stimulated ciliary localization and failed to activate downstream signaling. Furthermore, homozygous SmoD99N/D99N (the equivalent residue in mouse) knockin mice were embryonic lethal with severe cardiac defects, phenocopying the Smo-/- mice. Together, the results of our study suggest that Hh signaling transduces to SMO through modulating its cholesterylation and provides a therapeutic opportunity to treat Hh-pathway related cancers by targeting SMO cholesterylation. PMID- 28344085 TI - Protection of polyphenols in blueberry juice by vacuum-assisted block freeze concentration. AB - Block freeze concentration allows produces high-quality cryoconcentrates with important protection of valuable components from fresh fruit juices. The aim of this study was to investigate the use of vacuum-assisted block freeze concentration under different experimental conditions to protect polyphenols in the elaboration of concentrated blueberry juice. Fresh blueberry juice was radial or unidirectional frozen at -20 and -80 degrees C for 12 h and vacuum process was performed at 80 kPa during 120 min. Results showed a significant solute increased in the concentrated fraction in all treatments, and the best treatment was - 20 degrees C/unidirectional with a value of ~63 degrees Brix, equivalent to an increase of 3.8 times in the total polyphenol content (76% of retention). The color of concentrated samples was darker than the initial sample, with DeltaE* values of >25 CIELab units in all treatments. The vacuum-assisted block freeze concentrations was an effective technology for protecting polyphenols and obtain a concentrated with a higher concentration of solids from blueberry juice, as well as interesting values of process parameters. PMID- 28344086 TI - RIFM fragrance ingredient safety assessment, isoamyl hexanoate, CAS Registry Number 2198-61-0. PMID- 28344087 TI - Subacute alcohol and/or disulfiram intake affects bioelements and redox status in rat testes. AB - The aim of the study was to investigate if alcohol and disulfiram (DSF) individually and in combination affect bioelements' and red-ox homeostasis in testes of the exposed rats. The animals were divided into groups according to the duration of treatments (21 and/or 42 days): C21/C42 groups (controls); OL21 and OL22-42 groups (0.5 mL olive oil intake); A1-21 groups (3 mL 20% ethanol intake); DSF1-21 groups (178.5 mg DSF/kg/day intake); and A21+DSF22-42 groups (the DSF ingestion followed previous 21 days' treatment with alcohol). The measured parameters in testes included metals: zinc (Zn), copper (Cu), iron (Fe), magnesium (Mg) and selenium (Se); as well as oxidative stress (OS) parameters: superoxide anion radical (O2*-), glutathione reduced (GSH) and oxidized (GSSG), malondialdehyde (MDA), hydrogen peroxide (H2O2) decomposition and activities of total superoxide dismutase (tSOD), glutathione-S-transferase (GST) and glutathione reductase (GR). Metal status was changed in all experimental groups (Fe rose, Zn fell, while Cu increased in A21+DSF24-32 groups). Development of OS was demonstrated in A1-21 groups, but not in DSF1-21 groups. In A21+DSF22-42 groups, OS was partially reduced compared to A groups (A1-21>MDA>C; A1-2160% v/v ethanol), with little loss of secondary structure, but with significant tertiary structure changes. The thermodynamic data (Tm and DeltaH) suggest a loosening of intramolecular weak interactions, which reflects in a flexibility increase such that the catalytic capacity can be increased or decreased according to the ethanol concentration into the system. Overall results we suggest that in range of 0-60% v/v ethanol/buffer, alpha-trypsin undergoes reversible multimerization phenomena with catalytic activity. However from 60% v/v ethanol/buffer, population of folded partially states with less catalytic activity are predominant. PMID- 28344092 TI - The over expression of long non-coding RNA ANRIL promotes epithelial-mesenchymal transition by activating the ATM-E2F1 signaling pathway in pancreatic cancer: An in vivo and in vitro study. AB - This study aims to investigate the roles of lncRNA ANRIL in epithelial mesenchymal transition (EMT) by regulating the ATM-E2F1 signaling pathway in pancreatic cancer (PC). PC rat models were established and ANRIL overexpression and interference plasmids were transfected. The expression of ANRIL, EMT markers (E-cadherin, N-cadherin and Vimentin) and ATM-E2F1 signaling pathway-related proteins (ATM, E2F1, INK4A, INK4B and ARF) were detected. Small molecule drugs were applied to activate and inhibit the ATM-E2F1 signaling pathway. Transwell assay and the scratch test were adopted to detect cell invasion and migration abilities. ANRIL expression in the PC cells was higher than in normal pancreatic duct epithelial cells. In the PC rat models and PC cells, ANRIL interference promoted the expressions of INK4B, INK4A, ARF and E-cadherin, while reduced N cadherin and Vimentin expression. Over-expressed ANRIL decreased the expression of INK4B, INK4A, ARF and E-cadherin, but raised N-cadherin and Vimentin expressions. By inhibiting the ATM-E2F1 signaling pathway in PC cells, E-cadherin expression increased but N-cadherin and Vimentin expressions decreased. After ANRIL was silenced or the ATM-E2F1 signaling pathway inhibited, PC cell migration and invasion abilities were decreased. In conclusion, over-expression of lncRNA ANRIL can promote EMT of PC cells by activating the ATM-E2F1 signaling pathway. PMID- 28344093 TI - Synthesis and characterization of a novel cationic hydrogel base on salecan-g PMAPTAC. AB - Salecan is a biological macromolecular and biocompatible polysaccharide that has been investigated for recent years. Herein, we report a novel cationic hydrogel fabricated by graft-polymerizing 3-(methacryloylamino)propyl-trimethylammonium chloride (MAPTAC) onto salecan chains. The obtained hydrogels were transparent, solid-elastic, macro-porous, ion-sensitive, and non-cytotoxic. The swelling ratios increased with salecan content, while mechanical strength does the opposite. Moreover, drug delivery test was studied as a potential application. Diclofenac sodium (DS) and insulin were selected as model drugs. Interestingly, in drug loading process, DS molecules exhibited highly affinity to these cationic hydrogels. Almost all the DS molecules in loading solution were absorbed and spread into the hydrogel. For drug release profiles, insulin-loaded hydrogel showed an initial rapid release and a sustained release. As a comparison, DS loaded hydrogel exhibited a more sustained release profile. Results suggested salecan-g-PMAPTAC hydrogel could be a good candidate for anionic drug loading and delivery. PMID- 28344094 TI - Controlled release of antibiotic amoxicillin drug using carboxymethyl cellulose cl-poly(lactic acid-co-itaconic acid) hydrogel. AB - In this paper, microwave assisted preparation of carboxymethyl cellulose-cl poly(lactic acid-co-itaconic acid) (CMC-cl-P(LA-co-IA)) hydrogel was reported via facile graft copolymerization using N,N1-methylene-bis-acrylamide (MBA) and potassium persulphate as cross linker and initiator. Different reaction parameters were optimized to achieve good yield. The formation of hydrogel was confirmed by characterization techniques such as Fourier transform infrared spectroscopy, field emission scanning electron microscopy, X-ray diffraction, thermo gravimetric analysis, transmission electron microscopy etc. The antimicrobial activities of the hydrogel were studied against Staphylococcus aureus and Escherichia coli. About 95% killing of bacteria was recorded after 24h. The controlled release of amoxicillin drug from hydrogel was evaluated as a function of pH and time. Maximum drug release of 98% was recorded at 2.2 pH after 7h. The kinetic studies showed non-Fickian diffusion of the drug. PMID- 28344095 TI - Early detection, clinical diagnosis, and management of lung disease from exposure to diacetyl. AB - Inhalation of diacetyl-containing products is associated with risk for occupational bronchiolitis obliterans (BO) and fixed airways obstruction, particularly in workers exposed to heated liquids and powdered formulations. This review describes the occupational settings in which diacetyl-related lung disease has been reported and the clinical presentation of disease, along with an approach to diagnosis and management. The importance of early disease recognition, appropriate removal from exposure, and medical monitoring to optimize prognosis is reviewed. The roles of public health follow-up and medical surveillance for primary and secondary prevention are discussed. PMID- 28344096 TI - Dissociable effects of systemic and orbitofrontal administration of adrenoceptor antagonists on yohimbine-induced motor impulsivity. AB - The alpha2-adrenoceptor antagonist, yohimbine, is commonly used as a pharmacological stressor. Its behavioural effects are typically attributed to elevated noradrenaline release via blockade of central, inhibitory autoreceptors. We have previously reported that yohimbine increases motor impulsivity in rats on the five-choice serial reaction time task (5CSRTT), a cognitive behavioural assessment which measures motor impulsivity and visuospatial attention. Furthermore, this effect depended on cyclic adenomonophosphate (cAMP) signalling via cAMP response element binding (CREB) protein in the orbitofrontal cortex (OFC). However, the role of specific adrenoceptors in this effect is not well characterised. We therefore investigated whether the pro-impulsive effects of systemic yohimbine could be reproduced by direct administration into the OFC, or attenuated by intra-OFC or systemic administration of prazosin and propranolol antagonists at the alpha1- and beta-adrenoceptor, respectively. Male Long-Evans rats were trained on the 5CSRTT and implanted with guide cannulae aimed at the OFC. Systemically administered alpha1- or beta-adrenoceptor antagonists attenuated yohimbine-induced increases in premature responding. In contrast, local infusion of yohimbine into the OFC reduced such impulsive responding, while blockade of alpha1- or beta-adrenoceptors within the OFC had no effect on either basal or yohimbine-stimulated motor impulsivity. Direct administration of selective antagonists at the alpha1-, alpha2- or beta-adrenoceptor into the OFC therefore produce clearly dissociable effects from systemic administration. Collectively, these data suggest that the pro-impulsivity effect of yohimbine can be modulated by adrenergic signalling in brain areas outside of the OFC, in addition to non-adrenergic signalling pathways within the OFC. PMID- 28344097 TI - Whence river blindness? The domestication of mammals and host-parasite co evolution in the nematode genus Onchocerca. AB - The genus Onchocerca includes 34 described species and represents one of the largest genera of the filarial nematodes within the family Onchocercidae. Representative members of this genus are mainly parasites of ungulates, with some exceptions such as Onchocerca lupi and Onchocerca volvulus, infecting carnivores and/or humans. For a long time, the evolutionary relationships amongst onchocercids remained poorly studied, as the systematics of this genus was impaired by the high morphological variability of species included in the taxon. Although some molecular phylogenies were developed, these studies were mainly focused on bovine Onchocerca spp. and O. volvulus, including assessments of Wolbachia endosymbionts. In the present study, we analysed 13 Onchocerca spp. from a larger host spectrum using a panel of seven different genes. Analysis of the coxI marker supports its usefulness for the identification of species within the genus. The evolutionary history of the genus has been herein revised by multi gene phylogenies, presenting three strongly supported clades of Onchocerca spp. Analyses of co-evolutionary scenarios between Onchocerca and their vertebrate hosts underline the effect of domestication on Onchocerca speciation. Our study indicates that a host switch event occurred between Bovidae, Canidae and humans. Cophylogenetic analyses between Onchocerca and the endosymbiotic bacterium Wolbachia indicate the strongest co-evolutionary pattern ever registered within the filarial nematodes. Finally, this dataset indicates that the clade composed by O. lupi, Onchocerca gutturosa, Onchocerca lienalis, Onchocerca ochengi and O. volvulus derived from recent speciation. PMID- 28344098 TI - Human leukocyte antigen class I deficiencies. PMID- 28344099 TI - Mechanisms of resistance to selective estrogen receptor down-regulator in metastatic breast cancer. AB - Based on the prominent role estrogen receptor (ER) plays in breast cancer, endocrine therapy has been developed to block the ER pathway and has shown great effectiveness. Fulvestrant, the first selective ER down-regulator (SERD), was demonstrated to completely suppress ERalpha and notably efficient. However, resistance to fulvestrant occurs, either intrinsic or acquired during the treatment. Several potential mechanisms inducing fulvestrant resistance have been proposed, composed of activated ERalpha-independent compensatory growth factor signaling, stimulated downstream kinases, altered cell cycle mediators, etcetera. Experimentally, combinations of fulvestrant with targeted treatments were reported to eliminate the resistance and improve the effect of fulvestrant. Meanwhile, some clinical trials associated with the targeted combination therapies are in progress. This review focuses on the underlying mechanisms that contribute to fulvestrant resistance in ER-positive breast cancer and provides an overview of combined fulvestrant with targeted agents to shed light on optimal therapies for patients with ER-positive breast cancer. PMID- 28344100 TI - Facilitated Pronociceptive Pain Mechanisms in Radiating Back Pain Compared With Localized Back Pain. AB - : Facilitated pain mechanisms and impaired pain inhibition are often found in chronic pain patients. This study compared clinical pain profiles, pain sensitivity, as well as pronociceptive and antinociceptive mechanisms in patients with localized low back pain (n = 18), localized neck pain (n = 17), low back and radiating leg pain (n = 18), or neck and radiating arm pain (n = 17). It was hypothesized that patients with radiating pain had facilitated pain mechanisms and impaired pain inhibition compared with localized pain patients. Cuff algometry was performed on the nonpainful lower leg to assess pressure pain threshold, tolerance, temporal summation of pain (increase in pain scores to 10 repeated stimulations at pressure pain tolerance intensity), and conditioning pain modulation (increase in pressure pain threshold during pain conditioning on the contralateral leg). Heat detection and heat pain threshold at the nonpainful hand were also assessed. Clinical pain intensity, psychological distress, and disability were assessed with questionnaires. Temporal summation of pain was increased in patients with radiating back pain compared with localized back pain (P < .03). Patients with radiating arm pain or localized low back pain demonstrated hyperalgesia to heat and pressure in nonpainful body areas (P < .05), as well as well as a facilitated clinical pain profile compared with patients with localized neck pain (P = .03). Patients with radiating pain patterns demonstrated facilitated temporal summation suggesting differences in the underlying pain mechanisms between patients with localized back pain and radiating pain. PERSPECTIVE: These findings have clinical implications because the underlying mechanisms in different back pain conditions may require different treatment strategies. PMID- 28344101 TI - Predictors of Acute Postsurgical Pain After Inguinal Hernioplasty. AB - : Acute postsurgical pain (APSP) is a common and anticipated problem after surgery with detrimental consequences if not appropriately managed. This study examined the independent and joint contribution of presurgical demographic, clinical, and psychological variables as predictors of APSP intensity, evaluated using an 11-point numeric rating scale, after inguinal hernioplasty, one of the most performed surgeries worldwide. In a prospective observational cohort study, a consecutive sample of 135 men undergoing hernioplasty was assessed before and 48 hours after surgery. When adjusted for depression, helplessness, and magnification scores, a multiple hierarchical regression analysis revealed that younger age (beta = -.247, P < .005), previous chronic pain (beta = .175, P < .05), presurgical anxiety (beta = .235, P < .05), and the rumination component of pain catastrophizing (beta = .222, P < .05) were significant predictors of APSP intensity. The integrative predictive model found in this study revealed the simultaneous influence that demographic, clinical, and psychological factors have on APSP after inguinal hernioplasty. Therefore, these results improve knowledge on APSP predictors after inguinal hernioplasty and highlight potential modifiable intervention targets, such as anxiety and pain catastrophizing (rumination), for the design of interventions focused on APSP prevention and management. Hence, taken together, these findings lend support for the inclusion of presurgical screening and psychological interventions among surgical patients at risk for higher APSP intensity. PERSPECTIVE: This study found that, when adjusted for depression, helplessness, and magnification scores, the variables younger age, previous chronic pain, presurgical anxiety, and the rumination component of pain catastrophizing are significant predictors of APSP intensity after inguinal hernioplasty. These findings improve knowledge on APSP and highlight potential modifiable intervention targets for the design of interventions focused on APSP prevention and management. PMID- 28344103 TI - Evaluation of geranylgeranylacetone against cisplatin-induced ototoxicity by auditory brainstem response, heat shock proteins and oxidative levels in guinea pigs. AB - This study aims to assess whether geranylgeranylacetone (GGA) could reduce ototoxicity induced by cisplatin through upregulation of not only heat shock protein(HSP)-70, but also HSP-27 and HSP-40, and to study if GGA would reduce cisplatin-induced increase in oxidative stress. 48 guinea pigs were used in this study and treated with the following regimen: 0.5% CMC (sodium carboxymethyl cellulose) control for 7days, GGA (600mg/kg/d) for 7days, a combination of GGA (600mg/kg) for 7days and then one dose of 10mg/kg cisplatin (GGA+Cis), and a combination of CMC for 7days and then 10mg/kg cisplatin (cisplatin group). Auditory brainstem response (ABR) measurement was performed in each animal at time before treatment and 7days after the last dose. Additionally, HSPs, nitric oxide (NO), and lipid peroxidation (LPO) levels in cochlear membranous tissues were assessed. The mean ABR thresholds in the cisplatin group were significantly (p<0.05) increased when compared to the other three groups. In guinea pigs receiving both GGA and cisplatin, the mean threshold shift (TS) were smaller (p<0.05) than those of the cisplatin group, but larger (p<0.05) than those of the CMC control or GGA only group with statistical significance. Compared to the GGA only group or the group treated with GGA+Cis, the cisplatin group had the highest (p<0.05) oxidative stress (NO and LPO levels), and the lowest (p<0.05) mean HSPs expression levels. It can be concluded that GGA attenuate ototoxicity induced by cisplatin through upregulation of HSP-27, -40, and -70. Moreover, increased oxidative stress induced by cisplatin in the cochlea membranous tissue could be reduced by pre-treatment of GGA. PMID- 28344102 TI - Effect of Visceral Disease Site on Outcomes in Patients With Metastatic Castration-resistant Prostate Cancer Treated With Enzalutamide in the PREVAIL Trial. AB - BACKGROUND: The Multinational Phase 3, Randomized, Double-Blind, Placebo Controlled Efficacy and Safety Study of Oral MDV3100 in Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer Who Have Failed Androgen Deprivation Therapy (PREVAIL) trial was unique as it included patients with visceral disease. This analysis was designed to describe outcomes for the subgroup of men from PREVAIL with specific sites of visceral disease to help clinicians understand how these patients responded to enzalutamide prior to chemotherapy. PATIENTS AND METHODS: Prespecified analyses examined the coprimary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS) only. All other efficacy analyses were post hoc. The visceral subgroup was divided into liver or lung subsets. Patients with both liver and lung metastases were included in the liver subset. RESULTS: Of the 1717 patients in PREVAIL, 204 (12%) had visceral metastases at screening (liver only or liver/lung metastases, n = 74; lung only metastases, n = 130). In patients with liver metastases, enzalutamide was associated with an improvement in rPFS (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.22-0.90) but not OS (HR, 1.04; 95% CI, 0.57 1.87). In patients with lung metastases only, the HR for rPFS (0.14; 95% CI, 0.06 0.36) and the HR for OS (0.59; 95% CI, 0.33-1.06) favored enzalutamide over placebo. Patients with liver metastases had worse outcomes than those with lung metastases, regardless of treatment. Enzalutamide was well tolerated in patients with visceral disease. CONCLUSIONS: Enzalutamide is an active first-line treatment option for men with asymptomatic or mildly symptomatic chemotherapy naive metastatic castration-resistant prostate cancer and visceral disease. Patients with lung-only disease fared better than patients with liver disease, regardless of treatment. PMID- 28344104 TI - Antimicrobial medium- and long-chain free fatty acids prevent PrfA-dependent activation of virulence genes in Listeria monocytogenes. AB - The foodborne pathogen Listeria monocytogenes is the causative agent of the invasive disease listeriosis. Infection by L. monocytogenes involves bacterial crossing of the intestinal barrier and intracellular replication in a variety of host cells. The PrfA protein is the master regulator of virulence factors required for bacterial entry, intracellular replication and cell-to-cell spread. PrfA-dependent activation of virulence genes occurs primarily in the blood and during intracellular infection. In contrast, PrfA does not play a significant role in regulation of virulence gene expression in the intestinal environment. In the gastrointestinal phase of infection, the bacterium encounters a variety of antimicrobial agents, including medium- and long-chain free fatty acids that are commonly found in our diet and as active components of bile. Here we show that subinhibitory concentrations of specific antimicrobial free fatty acids act to downregulate transcription of PrfA-activated virulence genes. Interestingly, the inhibitory effect is also evident in cells encoding a constitutively active variant of PrfA. Collectively, our data suggest that antimicrobial medium- and long-chain free fatty acids may act as signals to prevent PrfA-mediated activation of virulence genes in environments where PrfA activation is not required, such as in food and the gastrointestinal tract. PMID- 28344105 TI - A new reconstructed human epidermis for in vitro skin irritation testing. AB - Different models of reconstructed human epidermis (RHE) are currently validated to assess skin irritation in vitro and ultimately to the animal replacement of the Draize test. The development of a new RHE model is a challenge for many laboratories, representing a potential gain of autonomy and improvement of technological knowledge. The Organization for Economic Co-operation and Development (OECD) encourages the development of new models and, for this purpose, offers a thorough guideline on quality control parameters (OECD TG 439 performance standards). This work aimed to develop an RHE model (i.e. USP-RHE) for in vitro skin irritation assays, following the OECD TG 439. The developed model presents a well-differentiated epidermis similar to the Validated Reference Methods (VRM) and to native human epidermis. Quality parameters, i.e. optical density of negative control, tissue integrity and barrier function, were similar to VRM and in accordance with OECD TG 439. Moreover, the USP-RHE model was shown to have 85,7% of specificity (6/7), 100% of sensitivity (6/6) and 92,3% of accuracy (12/13) when compared to in vivo UN GHS classification. The within laboratory reproducibility was 92.3% (12/13). Thus, we demonstrated that USP-RHE model attends to all OECD TG 439 performance standards and is ready to be used by private and public laboratories and companies for future validation studies. PMID- 28344106 TI - Molecular phylogenetic relationships reveal contrasting evolutionary patterns in Gorgoniidae (Octocorallia) in the Eastern Pacific. AB - The description and delimitation of species in an evolutionary framework is essential for understanding patterns of biodiversity and distribution, and in the assessment of conservation strategies for natural resources. This study seeks to clarify the evolutionary history and genetic variation within and between closely related octocoral species that are fundamental to benthic marine ecosystems for harbouring a high diversity of associated fauna. For our study system, we focused on members of the Gorgoniidae family in the Eastern Pacific, particularly of the Ecuadorian littoral, a less studied marine ecosystem. According to our results, the diagnosis of the genus Pacifigorgia is here amended to include species previously considered in the genus Leptogorgia. The genera Leptogorgia and Eugorgia are included within a single clade, and neither are recovered as monophyletic. In this case, according to the priority rule of the International Code of Zoological Nomenclature (ICZN), our proposal is to include the species considered in these two genera in Leptogorgia. In addition, we found evidence of interesting speciation patterns: morphological differentiation with no apparent genetic differentiation (in Pacifigorgia), and inconsistencies between mitochondrial and nuclear data that suggest a hybridisation phenomenon (in Leptogorgia). In the first case, recent radiation, ancient hybridisation, sympatric speciation, and in the second, reticulate evolution may have contributed to the evolutionary history of the studied taxa. Therefore, incongruences observed between morphological and molecular evidences in these octocorals, and in corals in general, may reveal the types of events/patterns that have influenced their evolution. PMID- 28344108 TI - The Inescapable Heterogeneity of Heart Failure. PMID- 28344107 TI - Molecular phylogenetics and historical biogeography of Sorbus sensu stricto (Rosaceae). AB - Explaining how plants from eastern Asia migrated to other Northern Hemisphere regions is still challenging. The genus Sorbus sensu stricto (including c. 88 species) is considered as a good example to illuminate this scenario, due to the wide distribution in the temperate zone and high diversity in the Himalayas and Hengduan Mountains. Based on four nuclear markers (LEAFY-2, GBSSI-1, SBEI and WD) and one chloroplast marker (rps16-trnK), we reconstructed the phylogenetic relationship of Sorbus using 54 taxa (60% of the genus representing all subgenera, sections, or series and geographical areas in the previous classifications), and estimated divergence time and historical biogeography of the genus. Phylogenetic analyses supported that the subgenera Sorbus and Albo carmesinae, as defined by traditional morphological characters (such as fruit color), are suitable. However, five clades defined by phylogenetic analysis of the genus are not consistent with traditionally defined sections or series. Molecular dating and biogeographic reconstruction showed that the age of the most recent common ancestor was estimated at 41mya (95% HPD: 49-35mya) in eastern Asia. Four dispersal events are assumed to explain the wide distribution of Sorbus in the temperate zone and diversification in the edges of Qinghai-Tibet Plateau (QTP). Species dispersed from eastern Asia to the Tianshan Mountains, North America and Europe during the Oligocene and Miocene period. We found that polyploidization occurred multiple times in the subgenus Albo-carmesinae, in the Tianshan Mountains, Himalayas, and H-D Mountains. Finally, we suggest that apomixis, polyploidization, and hybridization may have combined with the multistage uplifting of Himalayas and H-D Mountains (and the subsequent increases in geologic, ecological and climatic heterogeneity) to drive the striking species diversity of Sorbus in this region. PMID- 28344109 TI - Phylogenomic proximity and metabolic discrepancy of Methanosarcina mazei Go1 across methanosarcinal genomes. AB - Methanosarcina mazei Go1 is a heterotrophic methanogenic archaean contributing a significant role in global methane cycling and biomethanation process. Phylogenomic relatedness and metabolic discrepancy of this genome were described herein by comparing its whole genome sequence, intergenomic distance, genome function, synteny homologs and origin of replication, and marker genes with very closely related genomes, Methanosarcina acetivorans and Methanosarcina barkeri. Phylogenomic analysis of this study revealed that genome functional feature and metabolic core of M. mazei and M. barkeri could be originated from M. acetivorans. The metabolic core of these genomes shares a common evolutionary origin to perform the metabolic activity at different environmental niches. Genome expansion, dynamics and gene collinearity were constrained and restrained the conservation of the metabolic core genes by duplication events occurring across methanosarcinal genomes. The Darwinian positive selection was an evolutionary constraint to purify the function of core metabolic genes. Using genome-wide metabolic survey, we found the existence of four novel putative metabolic pathways such as complete methanogenesis from acetate, indole-3-acetate biosynthesis V, 4-aminobutyrate degradation III, galactosamine biosynthesis I and siroheme biosynthesis. Overall, the present study would provide a stand point to revisit its phylogenomic status in order to understand the origin and evolution history of this organism. PMID- 28344111 TI - No sight, no smell? - Brain anatomy of two amphipod crustaceans with different lifestyles. AB - The brain anatomy of Niphargus puteanus and Orchestia cavimana, two amphipod species with different lifestyles, has been studied using a variety of recent techniques. The general aspects of the brain anatomy of both species correspond to those of other malacostracans. However, both species lack hemiellipsoid bodies. Furthermore, related to their lifestyle certain differences have been observed. The aquatic subterranean species N. puteanus lacks eye structures, the optic nerve, and the two outer optic neuropils lamina and medulla. Only partial remains of the lobula have been detected. In contrast to this, the central complex in the protocerebrum and the olfactory glomeruli in the deutocerebrum are well differentiated. The terrestrial species Orchestia cavimana shows a reduced first antenna, the absence of olfactory neuropils in the deutocerebrum, and a reduction of the olfactory globular tract. The characteristics in defining the hemiellipsoid bodies are critically discussed. Contradictions about presence or absence of this neuropil are due to different conceptualizations. A comparison with other crustaceans that live in dark environments reveal similar patterns of optic system reduction, but to different degrees following a centripetal pattern. Retaining the olfactory system seems a general problem of terrestrialization in crustaceans with the notable exception of terrestrial hermit crabs. PMID- 28344110 TI - Toward a systematic exploration of nano-bio interactions. AB - Many studies of nanomaterials make non-systematic alterations of nanoparticle physicochemical properties. Given the immense size of the property space for nanomaterials, such approaches are not very useful in elucidating fundamental relationships between inherent physicochemical properties of these materials and their interactions with, and effects on, biological systems. Data driven artificial intelligence methods such as machine learning algorithms have proven highly effective in generating models with good predictivity and some degree of interpretability. They can provide a viable method of reducing or eliminating animal testing. However, careful experimental design with the modelling of the results in mind is a proven and efficient way of exploring large materials spaces. This approach, coupled with high speed automated experimental synthesis and characterization technologies now appearing, is the fastest route to developing models that regulatory bodies may find useful. We advocate greatly increased focus on systematic modification of physicochemical properties of nanoparticles combined with comprehensive biological evaluation and computational analysis. This is essential to obtain better mechanistic understanding of nano bio interactions, and to derive quantitatively predictive and robust models for the properties of nanomaterials that have useful domains of applicability. PMID- 28344112 TI - Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial. AB - BACKGROUND: Several pharmacological treatment options are available for type 2 diabetes; however, many patients do not achieve optimum glycaemic control and therefore new therapies are necessary. We assessed the efficacy and safety of semaglutide, a glucagon-like peptide-1 (GLP-1) analogue in clinical development, compared with insulin glargine in patients with type 2 diabetes who were inadequately controlled with metformin (with or without sulfonylureas). METHODS: We did a randomised, open-label, non-inferiority, parallel-group, multicentre, multinational, phase 3a trial (SUSTAIN 4) at 196 sites in 14 countries. Eligible participants were insulin-naive patients with type 2 diabetes, aged 18 years and older, who had insufficient glycaemic control with metformin either alone or in combination with a sulfonylurea. We randomly assigned participants (1:1:1) to either subcutaneous once-weekly 0.5 mg or 1.0 mg semaglutide (doses reached after following a fixed dose-escalation regimen) or once-daily insulin glargine (starting dose 10 IU per day, then titrated weekly to a pre-breakfast self measured plasma glucose target of 4.0-5.5 mmol/L [72-99 mg/dL]) for 30 weeks. In all treatment groups, previous background metformin and sulfonylurea treatment was continued throughout the trial. We did the randomisation using an interactive voice or web response system. The primary endpoint was change in mean HbA1c from baseline to week 30 and the confirmatory secondary endpoint was the change in mean bodyweight from baseline to week 30. We assessed efficacy and safety in the modified intention-to-treat population (mITT; all randomly assigned participants who were exposed to at least one dose of study drug) and used a margin of 0.3% to establish non-inferiority in HbA1c reduction. This trial is registered with ClinicalTrials.gov, number NCT02128932. FINDINGS: Between Aug 4, 2014, and Sept 3, 2015, we randomly assigned 1089 participants to treatment; the mITT population consisted of 362 participants assigned to 0.5 mg semaglutide, 360 to 1.0 mg semaglutide, and 360 to insulin glargine. 49 (14%) participants assigned to 0.5 mg semaglutide discontinued treatment prematurely, compared with 55 (15%) assigned to 1.0 mg semaglutide, and 26 (7%) assigned to insulin glargine. Most discontinuations were due to adverse events-mostly gastrointestinal with semaglutide, and others such as skin and subcutaneous tissue disorders (eg, rash, pruritus, and urticaria) with insulin glargine. From a mean baseline HbA1c of 8.17% (SD 0.89), at week 30, 0.5 and 1.0 mg semaglutide achieved reductions of 1.21% (95% CI 1.10-1.31) and 1.64% (1.54-1.74), respectively, versus 0.83% (0.73 0.93) with insulin glargine; estimated treatment difference versus insulin glargine -0.38% (95% CI -0.52 to -0.24) with 0.5 mg semaglutide and -0.81% (-0.96 to -0.67) with 1.0 mg semaglutide (both p<0.0001). Mean bodyweight at baseline was 93.45 kg (SD 21.79); at week 30, 0.5 and 1.0 mg semaglutide achieved weight losses of 3.47 kg (95% CI 3.00-3.93) and 5.17 kg (4.71-5.66), respectively, versus a weight gain of 1.15 kg (0.70-1.61) with insulin glargine; estimated treatment difference versus insulin glargine -4.62 kg (95% CI -5.27 to -3.96) with 0.5 mg semaglutide and -6.33 kg (-6.99 to -5.67) with 1.0 mg semaglutide (both p<0.0001). Severe or blood glucose-confirmed hypoglycaemia was reported by 16 (4%) participants with 0.5 mg semaglutide and 20 (6%) with 1.0 mg semaglutide versus 38 (11%) with insulin glargine (p=0.0021 and p=0.0202 for 0.5 mg and 1.0 mg semaglutide vs insulin glargine, respectively). Severe hypoglycaemia was reported by two (<1%) participants with 0.5 mg semaglutide, five (1%) with 1.0 mg semaglutide, and five (1%) with insulin glargine. Six deaths were reported: four (1%) in the 0.5 mg semaglutide group (three cardiovascular deaths, one pancreatic carcinoma, which was assessed as being possibly related to study medication) and two (<1%) in the insulin glargine group (both cardiovascular death). The most frequently reported adverse events were nausea with semaglutide, reported in 77 (21%) patients with 0.5 mg and in 80 (22%) with 1.0 mg, and nasopharyngitis reported in 44 (12%) patients with insulin glargine. INTERPRETATION: Compared with insulin glargine, semaglutide resulted in greater reductions in HbA1c and weight, with fewer hypoglycaemic episodes, and was well tolerated, with a safety profile similar to that of other GLP-1 receptor agonists. FUNDING: Novo Nordisk A/S. PMID- 28344113 TI - Clinical features of patients with Zika and dengue virus co-infection in Singapore. PMID- 28344114 TI - Avian influenza A in poultry stalls of Lahore District, Pakistan in 2009-2010. PMID- 28344115 TI - A series of Zika virus cases imported into the UK 2016: Comparative epidemiological and clinical features. PMID- 28344117 TI - Learning the skills needed to perform shoulder arthroscopy by simulation. AB - INTRODUCTION: Simulation for arthroscopy helps surgical trainees develop their surgery skills in a safe environment. This teaching technique has become more widespread in recent years because of the need to provide surgeons in training with an alternative to the current methods. We hypothesized that a resident in surgery could acquire the skills needed to perform arthroscopic shoulder surgery by working on a simulator. MATERIAL AND METHODS: The study was conducted over a 4 month period from June to September 2016. All the surgeons and residents in our department participated in the study. We recorded each participant's age, sex, dominant hand, and video gaming experience. We used the Arthro MentorTM simulator from Simbionix (now 3D Systems). Testing was carried out at the start and end of training to evaluate the participant's skills and their progression. The changes were evaluated statistically. RESULTS: Fourteen surgeons were included in the study. They were split into two groups: controls and residents. There was a statistically significant improvement in the intern group between the overall pre test score and the overall post-test score. There was no significant improvement in the overall score of the control group between the pre-test and post-test. DISCUSSION: For surgeons in training, shoulder arthroscopy simulation helps them acquire the skills needed to perform arthroscopy such as hand-eye coordination, triangulation and the ability to work in three-dimensions based on two dimensional visual information. We believe that the benefit of simulation resides in learning the skills needed to perform a surgical procedure, not in learning the procedure itself. LEVEL OF EVIDENCE: III-case-control study. PMID- 28344116 TI - Asymptomatic group A Streptococcal throat carriage in Royal Marines recruits and Young Officers. AB - AIMS: A prospective observational study was conducted in Royal Marines (RM) recruits to investigate throat carriage of group A Streptococcus (GAS) and incidence of soft tissue infections. METHODS: 1012 RM recruits were followed through a 32-week training programme, with throat swabs being obtained in weeks 1, 6, 15, and 32. Alongside a separate cohort of 46 RM Young Officers (YO) undergoing training were sampled in parallel. RESULTS: Carriage of group A Streptococcus was detected in only 5/1012 (0.49%) recruits at the beginning of training and remained low throughout training. There was no association between GAS carriage and development of soft tissue infection. There was no carriage of GAS in the smaller YO cohort at the start of training, (0/46). At week 6, a surge in GAS carriage was detected in 8/46 (17%) YO, that could be ascribed to a cluster of GAS genotype emm83. CONCLUSIONS: Asymptomatic GAS carriage is very infrequent among young adults in England and this should be borne in mind when considering the relevance of a positive throat swab result in symptomatic patients or outbreaks. Despite low prevalence, there is however potential for GAS to rapidly and transiently disseminate among adults during outbreaks. PMID- 28344118 TI - Geographic variation in the relationship between body mass index and the built environment. AB - Studies examining associations between weight status and neighborhood built environment (BE) have shown inconsistent results and have generally focused on urban settings. However, many Americans do not live in metropolitan areas and BE impacts may be different outside of metropolitan areas. We sought to examine whether the relationship between body mass index (BMI) and neighborhood BE exists and varies by geographic region across small towns in the United States. We conducted telephone surveys with 2156 adults and geographic information systems data in nine towns located within three geographic regions (Northeast, Texas, Washington) in 2011 and 2012. Multiple regression models examined the relationship between individual BMI and BE measures. Most physical activity variables were significantly associated with lower BMI in all geographic regions. We saw variation across geographic region in the relationship between characteristics of the BE variables and BMI. Some perceived and objectively measured characteristics of the BE were significantly associated with adult BMI, but significant relationships varied by geographic region. For example, in the Northeast, perceived attractiveness of the neighborhood as a reason for why they chose to live there was associated with lower BMI; in Texas, the perceived presence of a fast food restaurant was negatively associated with BMI; in Washington, perceived presence of trees along the streets was associated with lower BMI. Our findings suggest that regional variation plays a role in the relationship between adult BMI and BE characteristics in small towns. Regardless of geographic location, interventions should encourage utilitarian walking and other forms of physical activity. PMID- 28344119 TI - Acculturation and weight change in Asian-American children: Evidence from the ECLS-K:2011. AB - Despite relatively low rates of overweight and obesity among Asian-American children, disparities exist based on acculturation, socioeconomic status, and Asian ethnicity. The purpose of this study was to examine the association between acculturation and weight change in Asian-American children. Secondary aims were to compare changes by Asian ethnic group and acculturation x socioeconomic status. Participants included 1200 Asian-American children from the Early Childhood Longitudinal Study, Kindergarten Class of 2010-11, a longitudinal study of U.S. children attending kindergarten in 2010-2011. Multinomial logistic regressions were conducted to predict weight change based on body mass indices in kindergarten (spring 2011) and second grade (spring 2013): consistently healthy weight, consistently overweight/obese, healthy weight change, and unhealthy weight change. Models included demographic, household, socioeconomic status, and acculturation measures, specifically mother's English proficiency and percentage of life spent in the U.S. Overall, 72.3% of children were at healthy weights in kindergarten and second grade. Of all Asian ethnic groups, Filipino children had the highest rate of being consistently overweight/obese (24.8%) and the lowest rate of being consistently healthy weight (62.9%). In addition, mother's English proficiency predicted unhealthy weight change (OR: 0.83; 95% CI: 0.75-0.92) and healthy weight change (OR: 0.75; 95% CI: 0.65-0.86), relative to "consistently healthy weight." English proficiency also predicted being consistently overweight/obese for children with less educated mothers. Findings enhance our understanding of obesity disparities within Asian Americans and highlight the need to disaggregate the population. Obesity interventions are needed for Filipino children and families with low socioeconomic status but high English proficiency. PMID- 28344121 TI - Brevibacillus laterosporus pathogenesis and local immune response regulation in the house fly midgut. AB - The insect midgut represents the primary site of action of the entompathogenic bacterium Brevibacillus laterosporus. While most studies on this microorganism focus on the identification and characterization of possible virulence factors and toxins, little is known about the insect immune defense mechanisms that are activated against this pathogen. In this study we have investigated the local immune response of different house fly stages to B. laterosporus at the transcriptional level, and we tested the hypothesis that an improvement in entomopathogenicity can be achieved by impairing host innate immunity. Gene expression analyses showed that immediately after spore ingestion (6-12h) both larvae and adults increased the transcription rate of immune related genes in the midgut tissues, with special regard to those encoding for the main house fly antimicrobial peptides (AMPs) (i.e., attacin, cecropin, defensin, diptericin, domesticin, muscin) and for prophenoloxydase that is normally involved in the cascade of events leading to the generation of reactive oxygen species (ROS) and other factors with antibacterial properties. In experiments evaluating the use of an immunosuppressive agent to enhance the virulence of B. laterosporus against adult house flies, a significant downregulation of the same genes was observed 12 24h after the administration of sub-lethal doses of the botanical compound azadirachtin. Consequently, a significant increase in B. laterosporus entomopathogenic action was observed when flies were preliminarily or simultaneously exposed to a sub-lethal dose of azadirachtin. These results provide an important contribution to the prospect of employing immune-impairing tools to implement pest management strategies. PMID- 28344120 TI - A systematic review of lifestyle counseling for diverse patients in primary care. AB - Prior research and systematic reviews have examined strategies related to weight management, less is known about lifestyle and behavioral counseling interventions optimally suited for implementation in primary care practices generally, and among racial and ethnic patient populations. Primary care practitioners may find it difficult to access and use available research findings on effective behavioral and lifestyle counseling strategies and to assess their effects on health behaviors among their patients. This systematic review compiled existing evidence from randomized trials to inform primary care providers about which lifestyle and behavioral change interventions are shown to be effective for changing patients' diet, physical activity and weight outcomes. Searches identified 444 abstracts from all sources (01/01/2004-05/15/2014). Duplicate abstracts were removed, selection criteria applied and dual abstractions conducted for 106 full text articles. As of June 12, 2015, 29 articles were retained for inclusion in the body of evidence. Randomized trials tested heterogeneous multi-component behavioral interventions for an equally wide array of outcomes in three population groups: diverse patient populations (23 studies), African American patients only (4 studies), and Hispanic/Mexican American/Latino patients only (2 studies). Significant and consistent findings among diverse populations showed that weight and physical activity related outcomes were more amenable to change via lifestyle and behavioral counseling interventions than those associated with diet modification. Evidence to support specific interventions for racial and ethnic minorities was promising, but insufficient based on the small number of studies. PMID- 28344122 TI - Three-dimensional evidence network plot system: covariate imbalances and effects in network meta-analysis explored using a new software tool. AB - OBJECTIVES: The aim of the study was to develop the three-dimensional (3D) evidence network plot system-a novel web-based interactive 3D tool to facilitate the visualization and exploration of covariate distributions and imbalances across evidence networks for network meta-analysis (NMA). STUDY DESIGN AND SETTING: We developed the 3D evidence network plot system within an AngularJS environment using a third party JavaScript library (Three.js) to create the 3D element of the application. Data used to enable the creation of the 3D element for a particular topic are inputted via a Microsoft Excel template spreadsheet that has been specifically formatted to hold these data. We display and discuss the findings of applying the tool to two NMA examples considering multiple covariates. These two examples have been previously identified as having potentially important covariate effects and allow us to document the various features of the tool while illustrating how it can be used. RESULTS: The 3D evidence network plot system provides an immediate, intuitive, and accessible way to assess the similarity and differences between the values of covariates for individual studies within and between each treatment contrast in an evidence network. In this way, differences between the studies, which may invalidate the usual assumptions of an NMA, can be identified for further scrutiny. Hence, the tool facilitates NMA feasibility/validity assessments and aids in the interpretation of NMA results. CONCLUSION: The 3D evidence network plot system is the first tool designed specifically to visualize covariate distributions and imbalances across evidence networks in 3D. This will be of primary interest to systematic review and meta-analysis researchers and, more generally, those assessing the validity and robustness of an NMA to inform reimbursement decisions. PMID- 28344123 TI - Effects of Campylobacter jejuni lipopolysaccharide on axonal injury in the spinal cord in rats. AB - To explore the effects of Campylobacter jejuni lipopolysaccharide (Cj-LPS) on axonal injury in the spinal cord. Wistar rats were divided into the control (NC) group, model group (Cj-LPS), and LPS antibody group (Anti-LPS). Rats in the NC group were injected with a mixture of normal saline and complete Freund's adjuvant (CFA) while those in Cj-LPS group were injected with Cj-LPS, composed of LPS, CFA, and saline. Rats were sacrificed at 4th week and 6th week after injection, and hematoxylin and eosin (HE) staining was performed on the spinal cord sections. Real time-reverse transcription(RT-PCR) was used to detect mRNA expression of the axonal nutrition factor neurotrophin-3 (NT-3) with its receptor tropomyosin receptor kinase C (TrkC) and axon inhibitory factor of NogoA/NgR (Nogo receptor). The results indicated that Cj-LPS induce axonal injury in the rat spinal cord, decreased the mRNA expression of the axonal nutrition factor NT 3/TrkC, and increased the mRNA expression of the inhibitory factor NogoA/NgR. However, anti-LPS ameliorated axonal injury in the rat spinal cord induced by Cj LPS. PMID- 28344124 TI - Comparative genomics of transport proteins in probiotic and pathogenic Escherichia coli and Salmonella enterica strains. AB - Escherichia coli is a genetically diverse species that can be pathogenic, probiotic, commensal, or a harmless laboratory strain. Pathogenic strains of E. coli cause urinary tract infections, diarrhea, hemorrhagic colitis, and pyelonephritis, while the two known probiotic E. coli strains combat inflammatory bowel disease and play a role in immunomodulation. Salmonella enterica, a close relative of E. coli, includes two important pathogenic serovars, Typhi and Typhimurium, causing typhoid fever and enterocolitis in humans, respectively, with the latter strain also causing a lethal typhoid fever-like disease in mice. In this study, we identify the transport systems and their substrates within seven E. coli strains: two probiotic strains, two extracellular pathogens, two intracellular pathogens, and K-12, as well as the two intracellular pathogenic S. enterica strains noted above. Transport systems characteristic of each probiotic or pathogenic species were thus identified, and the tabulated results obtained with all of these strains were compared. We found that the probiotic and pathogenic strains generally contain more iron-siderophore and sugar transporters than E. coli K-12. Pathogens have increased numbers of pore-forming toxins, protein secretion systems, decarboxylation-driven Na+ exporters, electron flow driven monovalent cation exporters, and putative transporters of unknown function compared to the probiotic strains. Both pathogens and probiotic strains encode metabolite transporters that reflect their intracellular versus extracellular environments. The results indicate that the probiotic strains live extracellularly. It seems that relatively few virulence factors can convert a beneficial or commensal microorganism into a pathogen. Taken together, the results reveal the distinguishing features of these strains and provide a starting point for future engineering of beneficial enteric bacteria. PMID- 28344125 TI - Capadenoson, a clinically trialed partial adenosine A1 receptor agonist, can stimulate adenosine A2B receptor biased agonism. AB - The adenosine A2B receptor (A2BAR) has been identified as an important therapeutic target in cardiovascular disease, however in vitro and in vivo targeting has been limited by the paucity of pharmacological tools, particularly potent agonists. Interestingly, 2-((6-amino-3,5-dicyano-4-(4 (cyclopropylmethoxy)phenyl)-2-pyridinyl)thio)acetamide (BAY60-6583), a potent and subtype-selective A2BAR agonist, has the same core structure as 2-amino-6-[[2-(4 chlorophenyl)-1,3-thiazol-4-yl]methylsulfanyl]-4-[4-(2 hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitril (capadenoson). Capadenoson, currently classified as an adenosine A1 receptor (A1AR) partial agonist, has undergone two Phase IIa clinical trials, initially in patients with atrial fibrillation and subsequently in patients with stable angina. Capadenoson has also been shown to decrease cardiac remodeling in an animal model of advanced heart failure and a capadenoson derivative, neladenoson bialanate, recently entered clinical development for the treatment of chronic heart failure. The therapeutic effects of capadenoson are currently thought to be mediated through the A1AR. However, the ability of capadenoson to stimulate additional adenosine receptor subtypes, in particular the A2BAR, has not been rigorously assessed. In this study, we demonstrate that capadenoson does indeed have significant A2BAR activity in physiologically relevant cells, cardiac fibroblasts and cardiomyocytes, which endogenously express the A2BAR. Relative to the non selective adenosine receptor agonist NECA, capadenoson was a biased A2BAR agonist with a preference for cAMP signal transduction over other downstream mediators in cells with recombinant and endogenous A2BAR expression. These findings suggest the reclassification of capadenoson as a dual A1AR/A2BAR agonist. Furthermore, a potential A2BAR contribution should be an important consideration for the future clinical development of capadenoson-like therapeutics, as the A2BAR can promote cardioprotection and modulate cardiac fibrosis in heart disease. PMID- 28344126 TI - Regulation of the nitric oxide oxidase activity of myeloperoxidase by pharmacological agents. AB - The leukocyte-derived heme enzyme myeloperoxidase (MPO) is released extracellularly during inflammation and impairs nitric oxide (NO) bioavailability by directly oxidizing NO or producing NO-consuming substrate radicals. Here, structurally diverse pharmacological agents with activities as MPO substrates/inhibitors or antioxidants were screened for their effects on MPO NO oxidase activity in human plasma and physiological model systems containing endogenous MPO substrates/antioxidants (tyrosine, urate, ascorbate). Hydrazide based irreversible/reversible MPO inhibitors (4-ABAH, isoniazid) or the sickle cell anaemia drug, hydroxyurea, all promoted MPO NO oxidase activity. This involved the capacity of NO to antagonize MPO inhibition by hydrazide-derived radicals and/or the ability of drug-derived radicals to stimulate MPO turnover thereby increasing NO consumption by MPO redox intermediates or NO-consuming radicals. In contrast, the mechanism-based irreversible MPO inhibitor 2 thioxanthine, potently inhibited MPO turnover and NO consumption. Although the phenolics acetaminophen and resveratrol initially increased MPO turnover and NO consumption, they limited the overall extent of NO loss by rapidly depleting H2O2 and promoting the formation of ascorbyl radicals, which inefficiently consume NO. The vitamin E analogue trolox inhibited MPO NO oxidase activity in ascorbate depleted fluids by scavenging NO-consuming tyrosyl and urate radicals. Tempol and related nitroxides decreased NO consumption in ascorbate-replete fluids by scavenging MPO-derived ascorbyl radicals. Indoles or apocynin yielded marginal effects. Kinetic analyses rationalized differences in drug activities and identified criteria for the improved inhibition of MPO NO oxidase activity. This study reveals that widely used agents have important implications for MPO NO oxidase activity under physiological conditions, highlighting new pharmacological strategies for preserving NO bioavailability during inflammation. PMID- 28344127 TI - Replicated association between the European GWAS locus rs10503253 at CSMD1 and schizophrenia in Asian population. AB - Schizophrenia is one of the most severe mental disorders with significant heritability. Recent genetic association studies including genome-wide association studies (GWAS) have identified multiple common variants conferring risk of schizophrenia. An intronic SNP within CSMD1, rs10503253, is one of the top risk SNPs for schizophrenia in Europeans discovered through large GWAS. However, whether rs10503253 is also a risk SNP for schizophrenia in other populations, such as Asians, is still unknown. To answer this question, we examined the association of rs10503253 with schizophrenia in a total of 7514 schizophrenia patients, 9058 healthy controls and 1115 nuclear families originated from Asia using a meta-analytic approach. In the meta-analysis of all the samples, we confirmed the association of rs10503253 A-allele with schizophrenia in Asian population (P-value=0.0093, odds ratio=1.062, 95% confidence interval=1.015-1.111), and no genetic heterogeneity between individual samples (P=0.810) was observed. Using the "Leave-one-out" sensitivity analysis, we further confirmed the association between rs10503253 and schizophrenia. These data show that rs10503253 is likely a common schizophrenia risk variant in multiple ethnic groups, and further studies regarding the underlying molecular mechanisms are needed. PMID- 28344128 TI - High-sucrose-induced maternal obesity disrupts ovarian function and decreases fertility in Drosophila melanogaster. AB - As the obesity epidemic worsens, the prevalence of maternal obesity is expected to rise. Both high-fat and high-sucrose diets are known to promote maternal obesity and several studies have elucidated the molecular influence of high-fat feeding on female reproduction. However, to date, the molecular impact of a high sucrose diet on maternal obesity remains to be investigated. Using our previously reported Drosophila high-sucrose maternal obesity model, we sought to determine how excess dietary sucrose impacted the ovary. High-sucrose diet (HSD) fed adult females developed systemic insulin resistance and exhibited an ovarian phenotype characterized by excess accumulation of lipids and cholesterol in the ovary, decreased ovary size, and impaired egg maturation. We also observed decreased expression of antioxidant genes and increased protein carbonylation in the ovaries of HSD females. HSD females laid fewer eggs; however, the overall survival of offspring was unchanged relative to lean control females. Ovaries of HSD females had increased mitochondrial DNA copy number and decreased expression of key mitochondrial regulators, suggestive of an ineffective compensatory response to mitochondrial dysfunction. Mitochondrial alterations were also observed in male offspring of obese females. This study demonstrates that high sucrose-induced maternal obesity promotes insulin resistance, while disrupting ovarian metabolism and function. PMID- 28344130 TI - Aquaporin-3 deletion in mice results in renal collecting duct abnormalities and worsens ischemia-reperfusion injury. AB - Aquaporin-3 (AQP3), a transporter of water, glycerol and H2O2, is expressed in basolateral membranes of principal cells in kidney collecting duct. Here, we report that AQP3 deletion in mice affects renal function and modulates renal injury. We found collecting duct hyperplasia and cell swelling in kidneys of adult AQP3 null mice. After mild renal ischemia-reperfusion (IR), AQP3 null mice had significantly greater blood urea nitrogen (57mg/dl) and creatinine (136MUM) than wild-type mice (35mg/dl and 48MUM, respectively), and showed renal morphological changes, including tubular dilatation, erythrocyte diapedesis and collecting duct incompletion. MPO, MDA and SOD following IR in AQP3 null mice were significantly different from that in wild-type mice (1.7U/g vs 0.8U/g, 3.9MUM/g vs 2.4MUM/g, 6.4U/mg vs 11U/mg, respectively). Following IR, AQP3 deletion inhibited activation of mitogen-activated protein kinase (MAPK) signaling and produced an increase in the ratios of Bax/Bcl-2, cleaved caspase 3/caspase-3 and p-p53/p53. Studies in transfected MDCK cells showed that AQP3 expression attenuated reduced cell viability following hypoxia-reoxygenation, with reduced apoptosis and increased MAPK signaling. Our results support a novel role for AQP3 in modulating renal injury and suggest the mechanisms involved in protection against hypoxic injury. PMID- 28344131 TI - Specific patterns of spinal metabolites underlying alpha-Me-5-HT-evoked pruritus compared with histamine and capsaicin assessed by proton nuclear magnetic resonance spectroscopy. AB - The mechanism behind itching is not well understood. Proton nuclear magnetic resonance (1H-NMR) spectroscopic analysis of spinal cord extracts provides a quick modality for evaluating the specific metabolic activity of alpha-Me-5-HT evoked pruritus mice. In the current study, four groups of young adult male C57Bl/6 mice were investigated; one group treated with saline, while the other groups intradermally injected with alpha-Me-5-HT (histamine independent pruritogen), histamine (histamine dependent pruritogen) and capsaicin (algogenic substance), respectively. The intradermal microinjection of alpha-Me-5-HT and histamine resulted in a dramatic increase in the itch behavior. Furthermore, the results of NMR studies of the spinal cord extracts revealed that the metabolites show very different patterns for these different drugs, especially when comparing alpha-Me-5-HT and capsaicin. All the animals in the groups of alpha-Me-5-HT and capsaicin were completely separated using the metabolite parameters and principal component analysis. For alpha-Me-5-HT, the concentrations of glutamate, GABA, glycine and aspartate increased significantly, especially for GABA (increased 17.2%, p=0.008). Furthermore, the concentration of NAA increased, but there was no significant difference (increased 11.3%, p=0.191) compared to capsaicin (decreased 29.1%, p=0.002). Thus the application of magnetic resonance spectroscopy technique, coupled with statistical analysis, could further explain the mechanism behind itching evoked by alpha-Me-5-HT or other drugs. It can thus improve our understanding of itch pathophysiology and pharmacological therapies which may contribute to itch relief. PMID- 28344129 TI - Role of microRNA in diabetic cardiomyopathy: From mechanism to intervention. AB - Diabetic cardiomyopathy is a chronic and irreversible heart complication in diabetic patients, and is characterized by complex pathophysiologic events including early diastolic dysfunction, cardiac hypertrophy, ventricular dilation and systolic dysfunction, eventually resulting in heart failure. Despite these characteristics, the underlying mechanisms leading to diabetic cardiomyopathy are still elusive. Recent studies have implicated microRNA, a small and highly conserved non-coding RNA molecule, in the etiology of diabetes and its complications, suggesting a potentially novel approach for the diagnosis and treatment of diabetic cardiomyopathy. This brief review aims at capturing recent studies related to the role of microRNA in diabetic cardiomyopathy. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure - edited by Jun Ren & Megan Yingmei Zhang. PMID- 28344132 TI - Management of Anticoagulants and Antiplatelet Agents During Colonoscopy. AB - Colonoscopy frequently is performed for patients who are taking aspirin, nonsteroidal anti-inflammatory drugs, antiplatelet agents, and other anticoagulants. These colonoscopies often involve polypectomy, which can be complicated by bleeding. The risks of precipitating thromboembolic complications if anticoagulants are stopped must be weighed against the risk of postpolypectomy bleeding if these agents are continued. This article systematically reviews the management of anticoagulation during elective and emergency colonoscopy. For patients undergoing colonoscopic polypectomy, the overall risk of postpolypectomy bleeding is <0.5%. Risk factors for postpolypectomy bleeding include large polyp size and anticoagulant use, especially warfarin and thienopyridines. For patients who do not stop aspirin or other nonsteroidal anti-inflammatory drugs prior to colonoscopy, the rate of postpolypectomy bleeding is not significantly different from that for patients who do not take those medications. For patients who continue thienopyridines and undergo polypectomy, the risk of delayed postpolypectomy bleeding is approximately 2.4%. Even for patients who interrupt warfarin, the risk of postpolypectomy bleeding is increased. The direct oral anticoagulants (direct thrombin inhibitors and factor Xa inhibitors) have a rapid onset and offset of action, and periprocedural bridging generally is not necessary. For the thienopyridines, warfarin, and the direct oral anticoagulants, the decision to interrupt or continue these agents for endoscopy will involve considerable exercise of clinical judgment. PMID- 28344133 TI - Associated Risk of Malignancy in Patients with Cardiovascular Disease: Evidence and Possible Mechanism. AB - Cardiovascular disease and malignancy are leading causes of morbidity and mortality. Increased risk of malignancy was identified in patients with cardiovascular disease, including patients with heart failure, heart failure after myocardial infarction, patients undergoing cardiac intervention, and patients after a thrombotic event. Common risk factors and biological pathways can explain this association and are explored in this review. Further research is needed to establish the causes of malignancy in this population and direct possible intervention. PMID- 28344134 TI - Cytomegalovirus-Associated Hemophagocytic Syndrome in a 59-Year-Old Woman with Ulcerative Colitis. PMID- 28344135 TI - Not Just Skin Deep: Distant Metastases from Cutaneous Squamous Cell Carcinoma. PMID- 28344137 TI - Non-Classic Cystic Fibrosis: The Value in Family History. PMID- 28344136 TI - Prognostic Value of Soluble ST2 After Myocardial Infarction: A Community Perspective. AB - BACKGROUND: Soluble ST2 (sST2) is a marker of cardiac mechanical strain hypothesized to adversely impact short-term prognosis after myocardial infarction. We examined the association of sST2 with longer-term outcomes after myocardial infarction in a geographically defined community. METHODS: Olmsted County, Minnesota residents who experienced an incident (first-ever) myocardial infarction between November 1, 2002 and December 31, 2012 were prospectively enrolled; sST2 levels were measured. Patients were followed for heart failure and death. RESULTS: We studied 1401 patients with incident myocardial infarction (mean age 67 years; 61% men; 79% non-ST-elevation myocardial infarction). Median sST2 (ng/mL) was 48.7 (25th-75th percentile 32.5-103.3). Soluble ST2 was elevated in 51% of patients. Higher values of sST2 were associated with increased age, female sex, and comorbidities. During 5 years of follow-up, 388 persons died and 360 developed heart failure. After adjustment for age, sex, comorbidities, Killip class, and troponin T, the hazard ratios for death were 1.73 (95% confidence interval [CI], 1.22-2.45) and 3.57 (95% CI, 2.57-4.96) for sST2 tertiles 2 and 3, respectively (Ptrend <.001). For heart failure, the hazard ratios were 1.67 (95% CI, 1.18-2.37) and 2.88 (95% CI, 2.05-4.05), respectively (Ptrend <.001). Results were similar among 30-day survivors. CONCLUSIONS: In the community, sST2 elevation is present in half of myocardial infarctions. Higher values of sST2 are associated with a large excess risk of death and heart failure independently of other prognostic indicators. Measurement of sST2 should be considered for risk stratification after myocardial infarction. PMID- 28344138 TI - Black Pump Independence. PMID- 28344139 TI - Post-Discharge Worsening Renal Function in Patients with Type 2 Diabetes and Recent Acute Coronary Syndrome. AB - BACKGROUND: Worsening renal function during hospitalization for an acute coronary syndrome is strongly predictive of in-hospital and long-term outcome. However, the role of post-discharge worsening renal function has never been investigated in this setting. METHODS: We considered the placebo cohort of the AleCardio trial comparing aleglitazar with standard medical therapy among patients with type 2 diabetes mellitus and a recent acute coronary syndrome. Patients who had died or had been admitted to hospital for heart failure before the 6-month follow-up, as well as patients without complete renal function data, were excluded, leaving 2776 patients for the analysis. Worsening renal function was defined as a >20% reduction in estimated glomerular filtration rate from discharge to 6 months, or progression to macroalbuminuria. The Cox regression analysis was used to determine the prognostic impact of 6-month renal deterioration on the composite of all-cause death and hospitalization for heart failure. RESULTS: Worsening renal function occurred in 204 patients (7.34%). At a median follow-up of 2 years the estimated rates of death and hospitalization for heart failure per 100 person years were 3.45 (95% confidence interval [CI], 2.46-6.36) for those with worsening renal function, versus 1.43 (95% CI, 1.14-1.79) for patients with stable renal function. At the adjusted analysis worsening renal function was associated with the composite endpoint (hazard ratio 2.65; 95% CI, 1.57-4.49; P <.001). CONCLUSIONS: Post-discharge worsening renal function is not infrequent among patients with type 2 diabetes and acute coronary syndromes with normal or mildly depressed renal function, and is a strong predictor of adverse cardiovascular events. PMID- 28344140 TI - High-Value, Cost-Conscious Care: Iterative Systems-Based Interventions to Reduce Unnecessary Laboratory Testing. AB - BACKGROUND: Inappropriate testing contributes to soaring healthcare costs within the United States, and teaching hospitals are vulnerable to providing care largely for academic development. Via its "Choosing Wisely" campaign, the American Board of Internal Medicine recommends avoiding repetitive testing for stable inpatients. We designed systems-based interventions to reduce laboratory orders for patients admitted to the wards at an academic facility. METHODS: We identified the computer-based order entry system as an appropriate target for sustainable intervention. The admission order set had allowed multiple routine tests to be ordered repetitively each day. Our iterative study included interventions on the automated order set and cost displays at order entry. The primary outcome was number of routine tests controlled for inpatient days compared with the preceding year. Secondary outcomes included cost savings, delays in care, and adverse events. RESULTS: Data were collected over a 2-month period following interventions in sequential years and compared with the year prior. The first intervention led to 0.97 fewer laboratory tests per inpatient day (19.4%). The second intervention led to sustained reduction, although by less of a margin than order set modifications alone (15.3%). When extrapolating the results utilizing fees from the Centers for Medicare and Medicaid Services, there was a cost savings of $290,000 over 2 years. Qualitative survey data did not suggest an increase in care delays or near-miss events. CONCLUSIONS: This series of interventions targeting unnecessary testing demonstrated a sustained reduction in the number of routine tests ordered, without adverse effects on clinical care. PMID- 28344141 TI - Single High-Sensitivity Cardiac Troponin I to Rule Out Acute Myocardial Infarction. AB - BACKGROUND: This study examined the performance of single high-sensitivity cardiac troponin I (hs-cTnI) measurement strategies to rule out acute myocardial infarction. METHODS: This was a prospective, observational study of consecutive patients presenting to the emergency department (n = 1631) in whom cTnI measurements were obtained using an investigational hs-cTnI assay. The goals of the study were to determine 1) negative predictive value (NPV) and sensitivity for the diagnosis of acute myocardial infarction, type 1 myocardial infarction, and type 2 myocardial infarction; and 2) safety outcome of acute myocardial infarction or cardiac death at 30 days using hs-cTnI less than the limit of detection (LoD) (<1.9 ng/L) or the High-STEACS threshold (<5 ng/L) alone and in combination with normal electrocardiogram (ECG). RESULTS: Acute myocardial infarction occurred in 170 patients (10.4%), including 68 (4.2%) type 1 myocardial infarction and 102 (6.3%) type 2 myocardial infarction. For hs cTnI=60%, considered therapeutic, was substantially higher in the interventional group: 79% versus 25% (P <.0001). The INR variability (standard deviation of each patient's INR measurements) decreased significantly in the interventional group, from 0.53 to 0.32 (P <.0001) after intervention but not in the control group. CONCLUSIONS: Patient-specific tailored intervention significantly improves anticoagulation therapy in patients with heart failure. PMID- 28344145 TI - How the USPSTF's Mammographic Screening Guidelines Should Be Interpreted. PMID- 28344146 TI - Arterial Thromboses Heralding Cholangiocarcinoma. PMID- 28344147 TI - Evaluation of Deprescribing Amiodarone After New-Onset Atrial Fibrillation in Critical Illness. AB - BACKGROUND: Recent studies have shed light on the continued prescription of inpatient medications upon hospital discharge, despite the original intent of short-term inpatient therapy. Amiodarone, an antiarrhythmic associated with significant adverse effects with long-term use, is commonly used for new-onset atrial fibrillation in critical illness (NAFCI). Although it is often preferred in this setting of hemodynamic instability, a prescription for long-term use should be carefully considered, preferably by a cardiologist. This study was conducted to evaluate the incidence of patients discharged on amiodarone without a cardiology consult or referral after being initiated on amiodarone for NAFCI. METHODS: We conducted a retrospective review of all patients newly prescribed amiodarone for NAFCI over a 2-year period. The primary outcome was the percentage of patients who were continued on amiodarone upon hospital discharge without review by or outpatient referral to a cardiologist. RESULTS: Of the 100 patients who met inclusion criteria, 59 patients were prescribed amiodarone upon hospital discharge. Of these, 48 patients (81.4%) had converted to normal sinus rhythm with the resolution of critical illness. Of 100 patients, 23 received prescriptions for amiodarone upon discharge without a cardiology consult or referral. CONCLUSION: Amiodarone was frequently continued upon discharge without referral to a cardiologist in patients initiated on this therapy for NAFCI. This may contribute to unnecessary long-term therapy, thereby increasing the risk for significant side effects, drug interactions, and increased healthcare costs. This study suggests that careful medication reconciliation through all transitions of care, including discharge, is essential. PMID- 28344148 TI - Hemidiaphragmatic Hernia and Volvulus in a 94-Year-Old Woman. PMID- 28344149 TI - Life with One Kidney: Primary Care and the Living Kidney Donor. PMID- 28344150 TI - Cardiorespiratory Fitness Change and Mortality Risk Among Black and White Patients: Henry Ford Exercise Testing (FIT) Project. AB - BACKGROUND: Little is known about the relationship of change in cardiorespiratory fitness and mortality risk in Black patients. This study assessed change in cardiorespiratory fitness and its association with all-cause mortality risk in Black and White patients. METHODS: This is a retrospective, longitudinal, observational cohort study of 13,345 patients (age = 55 +/- 11 years; 39% women; 26% black) who completed 2 exercise tests, at least 12 months apart at Henry Ford Hospital, Detroit, Mich. All-cause mortality was identified through April 2013. Data were analyzed in 2015-2016 using Cox regression to calculate hazard ratios (HR) for risk of mortality associated with change in sex-specific cardiorespiratory fitness. RESULTS: Mean time between the tests was 3.4 years (interquartile range 1.9-5.6 years). During 9.1 years (interquartile range 6.3 11.6 years) of follow-up, there were 1931 (14%) deaths (16.5% black, 13.7% white). For both races, change in fitness from Low to the Intermediate/High category resulted in a significant reduction of death risk (HR 0.65 [95% confidence interval (CI), 0.49-0.87] for Black; HR 0.41 [95% CI, 0.34-0.51] for White). Each 1-metabolic-equivalent-of-task increase was associated with a reduced mortality risk in black (HR 0.84 [95% CI, 0.81-0.89]) and white (HR 0.87 [95% CI, 0.82-0.86]) patients. There was no interaction by race. CONCLUSIONS: Among black and white patients, change in cardiorespiratory fitness from Low to Intermediate/High fitness was associated with a 35% and 59% lower risk of all cause mortality, respectively. PMID- 28344152 TI - Trait-based food-cravings are encoded by regional homogeneity in the parahippocampal gyrus. AB - Food cravings can reflect an intense trait-like emotional-motivational desire to eat palatable food, often resulting in the failure of weight loss efforts. Studies have linked trait-based food-cravings to increased risk of overeating. However, little is known about resting-state neural mechanisms that underlie food cravings. We investigated this issue using resting-state functional magnetic resonance imaging (fMRI) to test the extent to which spontaneous neural activity occurs in regions implicated in emotional memory and reward motivation associated with food cravings. Spontaneous regional activity patterns correlating to food cravings were assessed among 65 young healthy women using regional homogeneity analysis to assess temporal synchronization of spontaneous activity. Analyses indicated that women with higher scores on the Food Cravings Questionnaire displayed increased local functional homogeneity in brain regions involved in emotional memory and visual attention processing (i.e., parahippocampal gyrus and fusiform gyrus) but not reward. In view of parahippocampal gyrus involvement in hedonic learning and incentive memory encoding, this study suggests that trait based food cravings are encoded by emotional memory circuits. PMID- 28344151 TI - Enhancing oligodendrocyte differentiation by transient transcription activation via DNA nanoparticle-mediated transfection. AB - : Current approaches to derive oligodendrocytes from human pluripotent stem cells (hPSCs) need extended exposure of hPSCs to growth factors and small molecules, which limits their clinical application because of the lengthy culture time required and low generation efficiency of myelinating oligodendrocytes. Compared to extrinsic growth factors and molecules, oligodendrocyte differentiation and maturation can be more effectively modulated by regulation of the cell transcription network. In the developing central nervous system (CNS), two basic helix-loop-helix transcription factors, Olig1 and Olig2, are decisive in oligodendrocyte differentiation and maturation. Olig2 plays a critical role in the specification of oligodendrocytes and Olig1 is crucial in promoting oligodendrocyte maturation. Recently viral vectors have been used to overexpress Olig2 and Olig1 in neural stem/progenitor cells (NSCs) to induce the maturation of oligodendrocytes and enhance the remyelination activity in vivo. Because of the safety issues with viral vectors, including the insertional mutagenesis and potential tumor formation, non-viral transfection methods are preferred for clinical translation. Here we report a poly(beta-amino ester) (PBAE)-based nanoparticle transfection method to deliver Olig1 and Olig2 into human fetal tissue-derived NSCs and demonstrate efficient oligodendrocyte differentiation following transgene expression of Olig1 and Olig2. This approach is potentially translatable for engineering stem cells to treat injured or diseased CNS tissues. STATEMENT OF SIGNIFICANCE: Current protocols to derive oligodendrocytes from human pluripotent stem cells (hPSCs) require lengthy culture time with low generation efficiencies of mature oligodendrocytes. We described a new approach to enhance oligodendrocyte differentiation through nanoparticle-mediated transcription modulation. We tested an effective transfection method using cell compatible poly (beta-amino ester) (PBAE)/DNA nanoparticles as gene carrier to deliver transcription factor Olig1 and Olig2 into human fetal tissue-derived neural stem/progenitor cells, and showed efficient oligodendrocyte differentiation following transgene expression of Olig1 and Olig2. We believe that this translatable approach can be applied to many other cell-based regenerative therapies as well. PMID- 28344153 TI - Plant hormone cytokinins control cell cycle progression and plastid replication in apicomplexan parasites. AB - Cytokinins are plant hormones that are involved in regulation of cell proliferation, cell cycle progression, and cell and plastid development. Here, we show that the apicomplexan parasites Toxoplasma gondii and Plasmodium berghei, an opportunistic human pathogen and a rodent malaria agent, respectively, produce cytokinins via a biosynthetic pathway similar to that in plants. Cytokinins regulate the growth and cell cycle progression of T. gondii by mediating expression of the cyclin gene TgCYC4. A natural form of cytokinin, trans-zeatin (t-zeatin), upregulated expression of this cyclin, while a synthetic cytokinin, thidiazuron, downregulated its expression. Immunofluorescence microscopy and quantitative PCR analysis showed that t-zeatin increased the genome-copy number of apicoplast, which are non-photosynthetic plastid, in the parasite, while thidiazuron led to their disappearance. Thidiazuron inhibited growth of T. gondii and Plasmodium falciparum, a human malaria parasite, suggesting that thidiazuron has therapeutic potential as an inhibitor of apicomplexan parasites. PMID- 28344154 TI - Characterization of Toxoplasma gondii isolates from herds of sheep in southern Brazil reveals the archetypal type II genotype and new non-archetypal genotypes. AB - Recent studies have demonstrated that, in Brazil and South America, strains of Toxoplasma gondii are often genotypically and biologically different from those found in countries on other continents. The objective of this study was to genotypically characterize T. gondii isolates from naturally infected sheep in herds in the southern region of the state of Rio Grande do Sul, Brazil, by means of the polymerase chain reaction with restriction fragment length polymorphism (PCR-RFLP). Five T. gondii isolates obtained from sheep in five municipalities in the state of Rio Grande do Sul were used. Application of multilocus PCR-RFLP multilocus using 12 genetic markers (SAG1, 5'3' SAG2, alt. SAG2, SAG3, BTUB, c22 8, c29-2, GRA6, L358, PK1, APICO and CS3) revealed four different genotypes in the five isolates studied: clonal type II (TgOvBrRS4), type BrIV (TgOvBrRS2 and TgOvBrRS3) and two new non-archetypal genotypes, ToxoDB-RFLP#270 and #271 (TgOvBrRS1 and TgOvBrRS5, respectively). The genotype structure found in the T. gondii isolates from naturally infected sheep in the southern region of Brazil was revealed to have high diversity. This study confirms the presence of rare circulation of the clonal type II genotype in Brazil. PMID- 28344155 TI - Enzymatic incorporation of caffeoyl into castor oil to prepare the novel castor oil-based caffeoyl structured lipids. AB - In this work, a novel castor oil-based caffeoyl structured lipids was successfully prepared by the enzymatic transesterification using castor oil (CO) as caffeoyl acceptor. During the structured lipids preparation, two competitive reactions, the hydrolysis of CO to form hydrophilic caffeoyl glycerols (CG)+dicaffeoyl glycerols (DCG) and the transesterification of CO with ethyl caffeate (EC) to form lipophilic caffeoyl mono- and di-acylglycerols (CMAG and CDAG), were found. Reaction progress was monitored using HPLC-ESI-MS and HPLC-UV. The effects of by-product ethanol removal and reaction variables on the transesterification and reaction selectivity were evaluated. Results showed that, the activation energies for the transesterification and for the selective formations of CMAG+CDAG and CG+DCG were 57.60kJ/mol, 58.86kJ/mol, and 60.53kJ/mol, respectively. Under the optimal reaction conditions (enzyme load 23%, 90 degrees C, 1:3 molar ratio of EC to CO, and 46.5h), EC conversion and the yield of CMAG+CDAG were 93.68+/-2.52% and 78.11+/-1.35%, respectively. PMID- 28344156 TI - Enhancing fructooligosaccharides production by genetic improvement of the industrial fungus Aspergillus niger ATCC 20611. AB - Aspergillus niger ATCC20611 is one of the most potent filamentous fungi used commercially for production of fructooligosaccharides (FOS), which are prospective components of functional food by stimulating probiotic bacteria in the human gut. However, current strategies for improving FOS yield still rely on production process development. The genetic engineering approach hasn't been applied in industrial strains to increase FOS production level. Here, an optimized polyethylene glycol (PEG)-mediated protoplast transformation system was established in A. niger ATCC 20611 and used for further strain improvement. The pyrithiamine resistance gene (ptrA) was selected as a dominant marker and protoplasts were prepared with high concentration (up to 108g-1 wet weight mycelium) by using mixed cell wall-lysing enzymes. The transformation frequency with ptrA can reach 30-50 transformants per MUg of DNA. In addition, the efficiency of co-transformation with the EGFP reporter gene (egfp) was high (approx. 82%). Furthermore, an activity-improved variant of beta fructofuranosidase, FopA(A178P), was successfully overexpressed in A. niger ATCC 20611 by using the transformation system. The transformant, CM6, exhibited a 58% increase in specific beta-fructofuranosidase activity (up to 507U/g), compared to the parental strain (320U/g), and effectively reduced the time needed for completion of FOS synthesis. These results illustrate the feasibility of strain improvement through genetic engineering for further enhancement of FOS production level. PMID- 28344157 TI - Surgical procedures in liver transplant patients: A monocentric retrospective cohort study. AB - BACKGROUND: Pre-existing chronic liver diseases and the complexity of the transplant surgery procedures lead to a greater risk of further surgery in transplanted patients compared to the general population. The aim of this monocentric retrospective cohort study was to assess the epidemiology of surgical complications in liver transplanted patients who require further surgical procedures and to characterize their post-operative risk of complications to enhance their medical care. PATIENTS AND METHODS: From January 1997 to December 2011, 1211 patients underwent orthotropic liver transplantation in our center. A retrospective analysis of prospectively collected data was performed considering patients who underwent surgical procedures more than three months after transplantation. We recorded liver transplantation technique, type of surgery, post-operative complications, time since the liver transplant and immunosuppressive regimens. RESULTS: Among these, 161 patients (15%) underwent a further 183 surgical procedures for conditions both related and unrelated to the transplant. The most common surgical procedure was for an incisional hernia repair (n = 101), followed by bilioenteric anastomosis (n = 44), intestinal surgery (n = 23), liver surgery (n = 8) and other surgical procedures (n = 7). Emergency surgery was required in 19 procedures (10%), while 162 procedures (90%) were performed electively. Post-operative mortality and morbidity were 1% and 30%, respectively. According to the Dindo-Clavien classification, the most common grade of morbidity was grade III (46%), followed by grade II (40%). CONCLUSION: Surgical procedures on liver transplanted patients are associated with a significantly high risk of complications, irrespective of the time elapsed since transplantation. PMID- 28344158 TI - Laparoscopic vs open approach for transverse colon cancer. A systematic review and meta-analysis of short and long term outcomes. AB - BACKGROUND: Transverse colon malignancies have been excluded from all randomized controlled trials comparing laparoscopic against open colectomies, potentially due to the advanced laparoscopic skills required for dissecting around the middle colic vessels and the associated morbidity. Concerns have been expressed that the laparoscopic approach may compromise the oncological clearance in transverse colon cancer. This study aimed to comprehensively compare the laparoscopic (LPA) to the open (OPA) approach by performing a meta-analysis of long and short term outcomes. METHODS: Medline, Embase, Cochrane library, Scopus and Web of Knowledge databases were interrogated. Selected studies were critically appraised and the short-term morbidity and long term oncological outcomes were meta-analyzed. Sensitivity analysis according to the quality of the study, type of procedure (laparoscopic vs laparoscopically assisted) and level of lymphadenectomy was performed. Statistical heterogeneity and publication bias were also investigated. RESULTS: Eleven case control trials (1415 patients) were included in the study. There was no difference between the LPA and the OPA in overall survival [Hazard Ratio (HR) = 0.83 (0.56, 1.22); P = 0.34], disease free survival (p = 0.20), local recurrence (p = 0.81) or distant metastases (p = 0.24). LPA was found to have longer operative time [Weighted mean difference (WMD) = 45.00 (29.48, 60.52); P < 0.00001] with earlier establishment of oral intake [WMD = -1.68 ( 1.84, -1.53); P < 0.00001] and shorter hospital stay [WMD = -2.94 (-4.27, -1.62); P = 0.0001]. No difference was found in relation to anastomotic leakage (p = 0.39), intra-abdominal abscess (p = 0.25), lymph nodes harvested (p = 0.17). CONCLUSIONS: LPA seems to be safe with equivalent oncological outcomes to OPA and better short term outcomes in selected patient populations. High quality Randomized control trials are required to further investigate the role of laparoscopy in transverse colon cancer. PMID- 28344159 TI - Significance of preoperative planning software for puncture and channel establishment in percutaneous endoscopic lumbar DISCECTOMY: A study of 40 cases. AB - BACKGROUND: Preoperative planning software has been widely used in many other minimally invasive surgeries, but there is a lack of information describing the clinical benefits of existing software applied in percutaneous endoscopic lumbar discectomy (PELD). This study aimed to compare the clinical efficacy of preoperative planning software in puncture and channel establishment of PELD with routine methods in treating lumbar disc herniation (LDH). MATERIAL AND METHODS: From June 2016 to October 2016, 40 patients who had single L4/5 or L5/S1 disc herniation were divided into two groups. Group A adopted planning software for preoperative puncture simulation while Group B took routine cases discussion for making puncture plans. The channel establishment time, operative time, fluoroscopic times and complications were compared between the two groups. The surgical efficacy was evaluated according to the Visual Analogue Scale (VAS), Oswestry Disability Index (ODI) and modified Macnab's criteria. RESULTS: The mean channel establishment time was 25.1 +/- 4.2 min and 34.6 +/- 5.4 min in Group A and B, respectively (P < 0.05). The mean operative time was 80.8 +/- 8.4 min and 92.1 +/- 7.3 min in Group A and B, respectively (P < 0.05). The fluoroscopic times were 21.5 +/- 5.2 in Group A and 29.3 +/- 5.5 in Group B (P < 0.05). There were no significant differences in VAS and ODI scorings between the two groups either preoperatively or postoperatively (P > 0.05). The findings of modified Macnab's criteria at each follow-up also showed no significant differences (P > 0.05). CONCLUSION: The application of preoperative planning software in puncture and cannula insertion planning in PELD was easy and reliable, and could reduce the channel establishment time, operative time and fluoroscopic times of PELD significantly. PMID- 28344160 TI - Pre-operative predictors of poor outcomes in patients undergoing surgical lower extremity revascularisation - Retrospective cohort study. AB - BACKGROUND: Surgical lower extremity revascularisation (LER) can lead to poor outcomes that include delayed hospital discharge, in-hospital mortality, major amputations and readmissions. The aim of this study was to identify pre-operative predictors associated with these poor clinical outcomes. MATERIALS AND METHODS: All patients (n = 635; mean age 69; male 67.4%) who underwent surgical LER over a 5 year period in a single tertiary vascular institution were identified. Patients considered to have suffered a poor outcome (Group A) included all in-hospital mortality and major amputations, delayed discharges with a length of stay (LOS) over one standard deviation above the mean or any readmission under any specialty within 12 months. Group A included 247 patients (38.9%) and the good outcome group included the remaining 388 patients (61.1%) from which a sample of 99 patients were selected as controls (Group B). RESULTS: Mean LOS for the entire study group was 14.4 +/- 17.5 days, 12 month readmission rate was 29.1% and in hospital mortality and major amputation rate was 2.7% and 1.4%, respectively. Pre admission residence other than own home (OR 9.0; 95% CI 1.2-70.1; P = 0.036), atherosclerotic disease burden (OR 2.2; 95% CI 1.3-3.8; P = 0.003) and tissue loss (OR 3.0; 95% CI 1.6-5.3; P < 0.001) were identified as independent, statistically significant pre-operative predictors of poor outcome. Following discharge, group B patients had a significantly higher rate of amputation free survival and graft infection free survival (P < 0.001) compared to group A. CONCLUSION: Recognition of pre-operative predictors of poor outcome should inform case selection and identify high risk patients requiring intensive perioperative optimisation and post discharge follow up. PMID- 28344161 TI - Cross-resistance to human cationic antimicrobial peptides and to polymyxins mediated by the plasmid-encoded MCR-1? AB - OBJECTIVES: To evaluate whether acquired resistance to cationic antimicrobial peptide (CAMP) group molecules, being normal components of the human immune system, may select co-resistance to antibiotic peptides such as polymyxins, considering they share the same mechanism of action. We aimed to evaluate strains producing the recently identified plasmid-encoded polymyxin resistance determinant MCR-1, which is a phosphoethanolamine transferase that modifies the lipopolysaccharide structure of Gram-negative bacteria. METHODS: In vitro susceptibility studies were performed using human CAMPs, namely cathelicidin LL 37, alpha-defensin 5 (HD5), and beta-defensin 3 (HDB3), towards MCR-1-producing and colistin-resistant Escherichia coli or Klebsiella pneumoniae. RESULTS: Cross resistance to CAMPs and colistin mediated by MCR-1 or chromosomal mechanisms was neither observed in E. coli nor in K. pneumoniae. CONCLUSION: Future therapeutic development of human CAMPs is not likely to be impeded by the spread of MCR-1 plasmid-mediated resistance to polymyxins, at least in E. coli. PMID- 28344162 TI - Identification of genetic markers of resistance to echinocandins, azoles and 5 fluorocytosine in Candida glabrata by next-generation sequencing: a feasibility study. AB - OBJECTIVES: Multi-antifungal drug resistance in Candida glabrata is increasing. We examined the feasibility of next-generation sequencing (NGS) to investigate the presence of antifungal drug resistance markers in C. glabrata. METHODS: The antifungal susceptibility of 12 clinical isolates and one ATCC strain of C. glabrata was determined using the Sensititre YeastOne(r) YO10 assay. These included three isolate pairs where the second isolate of each pair had developed a rise in drug MICs. Single nucleotide polymorphisms (SNPs) in genes known to be linked to echinocandin, azole and 5-fluorocytosine resistance were analysed in all isolates through NGS. RESULTS: High-quality non-synonymous SNPs in antifungal resistance genes such as FKS1, FKS2, CgCDR1, CgPDR1 and FCY2 were identified. For two of three isolate pairs, there was a >60-fold rise in MICs to all echinocandins in the second isolate from each pair; one echinocandin-resistant isolate harboured a mutation in FKS1 (S629P) and the other in FKS2 (S663P). Of the third pair, both the 5-fluorocytosine-susceptible, and resistant isolates had a mutation in FCY2 (A237T). SNPs in CgPDR1 were found in pan-azole-resistant isolates. SNPs in other genes linked to azole resistance (CgCDR1, ERG9 and CgFLR1) were present in both azole-susceptible and azole-resistant isolates. SNPs were also identified in Candida adhesin genes EPA1, EPA6, PWP2 and PWP5 but their presence was not associated with higher drug MICs. CONCLUSIONS: Genome-wide analysis of antifungal resistance markers was feasible and simultaneously revealed mutation patterns of genes implicated in resistance to different antifungal drug classes. PMID- 28344163 TI - Characterization of antibody response in neuroinvasive infection caused by Toscana virus. AB - OBJECTIVES: Among sandfly-borne pathogens, Toscana virus (TOSV) is a prominent cause of summer meningitis in Mediterranean Europe. Here, we assessed the kinetics of anti-TOSV antibodies over time in 41 patients diagnosed with TOSV meningitis or meningoencephalitis in northeastern Italy. METHODS: Acute and follow-up serum samples were collected up to 20 months after diagnosis of TOSV infection and tested for the presence of specific antibody using immunoenzymatic and indirect immunofluorescence assays. In addition, maturation of anti-TOSV IgG over time was evaluated as well as production of neutralizing antibodies. RESULTS: Specific IgM and IgG response was present at diagnosis in 100% of patients; TOSV-specific IgM and IgG were detected in patients' sera up to 6 and 20 months after diagnosis, respectively. The avidity index (AI) increased over the first month after infection in 100% of patients and most cases exceeded 60% by Day 30 post infection. The AI subsequently plateaued then declined at 20 months after diagnosis. Finally, neutralization assay to TOSV was performed in 217 sera collected from 41 patients; 69.6% of tested samples resulted in reactive and moderate levels of neutralizing antibodies observed during all phases of infection despite high titres of total anti-TOSV IgG. CONCLUSIONS: Specific antibody response develops rapidly and is long-lasting for neuroinvasive TOSV infection. Serodiagnosis of neuroinvasive TOSV requires simultaneous detection of specific IgM and IgG. Moderate levels of neutralizing antibodies were maintained over the study period, while the protective role of antibodies lacking neutralizing activity is unclear and requires further evaluation. PMID- 28344164 TI - Outbreak of brainstem encephalitis associated with enterovirus-A71 in Catalonia, Spain (2016): a clinical observational study in a children's reference centre in Catalonia. AB - OBJECTIVES: To describe the characteristics of an outbreak of brainstem encephalitis and encephalomyelitis related to enterovirus (EV) infection in Catalonia (Spain), a setting in which these manifestations were uncommon. METHODS: Clinical and microbiological data were analysed from patients with neurological symptoms associated with EV detection admitted to a reference paediatric hospital between April and June 2016. RESULTS: Fifty-seven patients were included. Median age was 27.7 months (p25-p75 17.1-37.6). Forty-one (72%) were diagnosed with brainstem encephalitis, seven (12%) with aseptic meningitis, six (11%) with encephalitis, and three (5%) with encephalomyelitis (two out of three with cardiopulmonary failure). Fever, lethargy, and myoclonic jerks were the most common symptoms. Age younger than 12 months, higher white-blood-cell count, and higher procalcitonin levels were associated with cardiopulmonary failure. Using a PAN-EV real-time PCR, EV was detected in faeces and/or nasopharyngeal aspirate in all the patients, but it was found in cerebrospinal fluid only in patients with aseptic meningitis. EV was genotyped in 47 out of 57 and EV-A71 was identified in 40 out of 47, being the only EV type found in patients with brainstem symptoms. Most of the detected EV-A71 strains were subgenogroup C1. Intravenous immunoglobulins were used in 34 patients. Eight cases (14%) were admitted to the intensive care unit. All the patients but three, those with encephalomyelitis, showed a good clinical course and had no significant sequelae. No deaths occurred. CONCLUSIONS: The 2016 outbreak of brainstem encephalitis in Catalonia was associated with EV-A71 subgenogroup C1. Despite the clinical manifestations of serious disease, a favourable outcome was observed in the majority of patients. PMID- 28344165 TI - Mechanisms governing metastatic dormancy in breast cancer. AB - Breast cancer is a systemic disease characterized by early dissemination of tumor cells to distant organs. In this foreign environment, tumor cells may stay in a dormant state as single cells or as micrometastases for many years before growing out into a macrometastatic lesion. As metastasis is the primary cause for breast cancer-related death, it is important to understand the mechanisms underlying the maintenance of dormancy and dormancy escape to find druggable targets to eradicate metastatic tumor cells. Metastatic dormancy is regulated by complex interactions between tumor cells and the local microenvironment. In addition, cancer-directed immunity and systemic instigation play a crucial role. PMID- 28344166 TI - microRNAs as players and signals in the metastatic cascade: Implications for the development of novel anti-metastatic therapies. AB - microRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. Increasing evidence emerging from human tumor preclinical models clearly indicates that specific miRNAs, collectively termed "metastamirs," play a functional role in different steps of the metastatic cascade, by exerting either pro- or anti-metastatic functions, and behave as signaling mediators to enable tumor cell to colonize a specific organ. miRNAs also actively participate in the proficient interaction of cancer cells with tumor microenvironment, either at the primary or at the metastatic site. Circulating miRNAs, released by multiple cell types, following binding to proteins or encapsulation in extracellular vesicles, play a main role in this cross-talk by acting as transferrable messages. The documented involvement of specific miRNAs in the dissemination process has aroused interest in the development of miRNA-based strategies for the treatment of metastasis. Preclinical research carried out in tumor experimental models, using both miRNA replacement and miRNA inhibitory approaches, is encouraging towards translating miRNA-based strategies into human cancer therapy, based on the observed therapeutic activity in the absence of main toxicity. However, to accelerate their adoption in the clinic, further improvements in terms of efficacy and targeted delivery to the tumor are still necessary. PMID- 28344167 TI - Protection and antibody reactivity following vaccination of lumpfish (Cyclopterus lumpus L.) against atypical Aeromonas salmonicida. AB - Atypical Aeromonas salmonicida is frequently associated with disease and mortality in farmed lumpfish (Cyclopterus lumpus L). Challenge experiments using different modes of exposure identified both high and low pathogenic isolates. Intraperitoneal vaccination induced production of high levels of specific antibodies particularly in fish given multiple injections. The immune sera contained antibodies cross reactive with both high and low pathogenic isolates. SDS-PAGE and LC/MSMS analyses showed that the highly virulent isolate expressed the virulence array protein (A-layer) while the less virulent isolate did not. Vaccines, containing the highly virulent isolate, formulated as a monovalent or as a trivalent vaccine, provided 73 and 60 relative percent survival (RPS) respectively, following intraperitoneal challenge. The detection of high levels of specific antibodies in immune sera and the protection provided by the test vaccines strongly indicate that it is possible to vaccinate lumpfish against atypical A. salmonicida and most probably also against other infectious bacterial diseases. PMID- 28344168 TI - Molecular characterization, expression and antimicrobial activities of two c-type lysozymes from manila clam Venerupis philippinarum. AB - Lysozymes play an important role in the innate immune responses with which mollusks respond to bacterial invasion through its lytic activity. In the present study, two c-type lysozymes (designed as VpCLYZ-1 and VpCLYZ-2, respectively) were identified and characterized from the manila clam Venerupis philippinarum. The full-length cDNA of VpCLYZ-1 and VpCLYZ-2 was of 629 and 736 bp, encoding a polypeptide of 156 and153 amino acid residues, respectively. The deduced amino acid sequences of VpCLYZs showed high similarity to other known invertebrate c type lysozymes. Multiple alignments and phylogenetic relationship strongly suggested that VpCLYZ-1 and VpCLYZ-2 belonged to the c-type lysozyme family. Both VpCLYZ-1 and VpCLYZ-2 transcripts were constitutively expressed in a wide range of tissues with different levels. The VpCLYZ-1 transcript was dominantly expressed in hepatopancreas and hemocytes, while VpCLYZ-2 transcript was mainly expressed in the tissues of hepatopancreas and gills. Both the mRNA expression of VpCLYZ-1 and VpCLYZ-2 was significantly up-regulated at 12 h post Vibrio anguillarum challenge. The recombinant VpCLYZ-1 and VpCLYZ-2 (designed as rVpCLYZ 1 and rVpCLYZ-2) exhibited lytic activity against all tested bacteria, and rVpCLYZ-1 showed higher activities than rVpCLYZ-2 in killing Micrococcus luteus and V. anguillarum. Overall, our results suggested that VpCLYZ-1 and VpCLYZ-2 belonged to the c-type lysozyme family, and played important roles in the immune responses of manila clam, especially in the elimination of pathogens. PMID- 28344169 TI - The identification, characterization, and function of two TREMs genes in Chinese Yangzhou goose (Anas cygnoides). AB - Triggering receptor expressed on myeloid cells (TREM) is a cell-surface receptor primarily expressed on macrophages. Here, two novel TREM genes, AcTREM1 and AcTREM2, were identified from Anas cygnoides. AcTREM1 cDNA contained a putative signal peptide, two IG domains, and a transmembrane domain. The deduced AcTREM2 sequence also contained a signal peptide, an IG domain, and a transmembrane domain. qRT-PCR, fluorescence in situ hybridization, and immunofluorescence experiments showed that AcTREM1 and AcTREM2 were mainly expressed in the liver and spleen, and both genes and proteins were mainly distributed in cytoplasm. AcTREM1 expression in the liver and spleen was significantly upregulated following lipopolysaccharide (LPS) challenge at an early stage of infection and then decreased at a later stage. Changes in AcTREM2 expression were reciprocal to those of AcTREM1 in the liver and spleen after LPS challenge. Our results indicate that AcTREM1 and AcTREM2 participate in the antibacterial immunity of A. cygnoides. PMID- 28344170 TI - Chronic hyperosmotic stress inhibits renal Toll-Like Receptors expression in striped catfish (Pangasianodon hypophthalmus, Sauvage) exposed or not to bacterial infection. AB - Toll-like Receptors (TLRs) are the first innate receptors in recognizing pathogen associated molecular patterns. In fish, upregulation of toll-like receptors during infection has been largely demonstrated while the effects of abiotic stressors on their expression remain poorly investigated. In this study, striped catfish were submitted during 20 days to three salinity profiles (freshwater, low saline water, saline water), followed by injection of a bacterial strain of Edwardsiella ictaluri. The expression of TLRs 1, 3, 4, 5, 7, 9, 19, 21, and 22 was measured in kidney at different time points in non infected and infected striped catfish. Infection induced overexpression of TLRs 1, 3, 4, 5, 7, 21 and 22. With elevated salinity, the expression of all TLRs, except TLR5, was severely decreased, particularly after bacterial infection. The TLRs responsiveness of striped catfish facing bacterial disease and salinity stress and possible consequences on striped catfish immune response's efficiency are discussed. PMID- 28344172 TI - Physicochemical attributes and dissolution testing of ophthalmic ointments. AB - The investigation of semisolid ophthalmic ointments is challenging due to their complex physicochemical properties and the unique anatomy of the human eye. Using Lotemax(r) as a model ophthalmic ointment, three different manufacturing processes and two excipient sources (Fisher(r) (OWP) and Fougera(r) (NWP)) were used to prepare loteprednol etabonate ointments that were qualitatively and quantitatively the same across the manufactured formulations. Physicochemical properties including drug content and uniformity, particle size and distribution, as well as rheological parameters (onset point, crossover modulus, storage modulus and Power law consistency index) were investigated. In addition, USP apparatus 2 with enhancer cells was utilized to study the in vitro drug release characteristics of the ophthalmic ointments. Both manufacturing processes and excipient sources had a significant influence on the physicochemical attributes and the in vitro drug release profiles of the prepared ointments. Ointments prepared via the hot melt processes exhibited higher rheological parameters and lower drug release rates compared to ointments prepared without hot melting. Ointments prepared with OWP demonstrated higher rheological parameters and lower in vitro drug release rates compared to ointments prepared with NWP. A strong correlation between the rheological parameters and in vitro drug release rate was shown using logarithmic linear regression. This correlation may be useful in predicting in vitro drug release from measured physicochemical properties, and identifying the critical quality attributes during the development of ointment formulations. PMID- 28344171 TI - Lipopolysaccharide induced Interleukin-6 production is mediated through activation of ERK 1/2, p38 MAPK, MEK, and NFkappaB in chicken thrombocytes. AB - Thrombocytes express Toll-like receptor 4 and apparently use both mitogen activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFKB) pathways for nuclear signaling. However, it is not well known if the same enzyme systems found in mammalian cells are fully functional in chickens. Therefore, kinase inhibitors were used with thrombocytes to block kinases in lipopolysaccharide (LPS) stimulated cells to determine if interleukin (IL)-6 expression and production would be diminished. Results demonstrated that extracellular-signal-regulated kinase (ERK)1/2 and p38 MAPK pathways influence gene expression of IL-6 through treatment with either ERK or p38 MAPK inhibitor. In addition, thrombocyte lysates from cells treated with ERK, p38, mitogen activated protein kinase kinase (MEK)1/2 and inhibitor of nuclear factor kappa-B kinase (IKK) inhibitor showed different levels of the phosphorylated form of ERK1/2, p38 and NFkappaB. Furthermore, IL-6 gene expression and production were significantly upregulated in LPS stimulated thrombocytes relative to all inhibitor-treated cells. PMID- 28344173 TI - Exploring the structure-permeation relationship of topical tricyclic antidepressants used for skin analgesia. AB - The purpose of this study was to evaluate the skin permeation of tricyclic antidepressants (TCAs) with propamine moiety to select candidates for the development of topical analgesics to treat cutaneous pain. We sought to establish the structure-permeation relationship (SPR) of topical TCAs. The lipophilicity, melting point, and aqueous solubility were determined to develop the physicochemical characterization. The TCA permeation into pig and nude mouse skins was estimated using Franz diffusion cell. TCAs and lidocaine were comparatively examined for cutaneous analgesia by pinprick assay. Cutaneous tolerance to TCAs was assessed using nude mouse skin. The skin deposition increased following the increase of lipophilicity after excluding the effect of solubility, with clomipramine exhibiting the highest skin retention. A contrary result was observed for TCA penetration into the receptor. Of the permeants tested, clomipramine demonstrated the best skin-targeting ability. Nortriptyline and clomipramine demonstrated selective uptake into the hair follicles, exhibiting a 2.5-fold higher follicular accumulation than desipramine. Replacement of nitrogen with carbon in the seven-member ring increased skin absorption. The tertiary amine TCAs demonstrated higher absorption than the secondary amine TCAs. The position of the double bond also affected skin transport. Topical clomipramine had a longer duration of analgesic action than lidocaine (240min versus 60min). Exploring the SPR revealed that clomipramine could be an analgesic candidate drug for future development. PMID- 28344174 TI - Core/shell poly(ethylene oxide)/Eudragit fibers for site-specific release. AB - Electrospinning was used to prepare core/shell fibers containing the active pharmaceutical ingredients indomethacin (IMC) or mebeverine hydrochloride (MB HCl). The shell of the fibers was fabricated from the pH sensitive Eudragit S100 polymer, while the drug-loaded core was based on the mucoadhesive poly(ethylene oxide) (PEO). Three different drug loadings (from 9 to 23% (w/w) of the core mass) were prepared, and for MB-HCl two different molecular weights of PEO were explored. The resultant fibers generally comprise smooth cylinders, although in some cases defects such as surface particles or flattened or merged fibers were visible. Transmission electron microscopy showed all the systems to have clear core and shell compartments. The drugs are present in the amorphous physical form in the fibers. Dissolution tests found that the fibers can effectively prevent release in acidic conditions representative of the stomach, particularly for the acidic indomethacin. After transfer to a pH 7.4 medium, sustained release over between 6 and 22h is observed. Given the mucoadhesive nature of the PEO core, after dissolution of the shell the fibers will be able to adhere to the walls of the intestinal tract and give sustained local drug release. This renders them promising for the treatment of conditions such as irritable bowel disease and colon cancer. PMID- 28344175 TI - Transforming Growth Factor Beta Family in the Pathogenesis of Meningiomas. AB - BACKGROUND: Meningiomas account for 36% of primary brain tumors. The pathogenesis of these tumors is not completely established, hindering development of effective chemotherapy. Numerous studies have identified alterations in several growth factors and receptor kinases that regulate meningioma growth. These may be targets for new therapies. One of these, sometimes overlooked, is the transforming growth factor beta (TGF-beta) family of proteins. Its receptors and signaling pathways play a critical role in development or progression of many forms of neoplasia. METHODS: Evidence suggesting a potential role for TGF-beta, bone morphogenetic protein, and their mediators is reviewed. RESULTS: TGF-beta inhibition of growth in normal leptomeninges may be lost in neoplasia. Moreover, loss of TGF-beta and bone morphogenetic protein signaling components and TGF-beta type III receptor likely contribute to the development and/or progression of higher grade meningiomas. CONCLUSIONS: Accumulating evidence suggests that derangement of TGF-beta family signaling contributes to development and progression of meningiomas. The TGF-beta family may represent new targets for chemotherapy and could include inhibitors of kinases activated by TGF-beta. PMID- 28344176 TI - Stereotactic Radiosurgery for ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations)-Eligible Spetzler-Martin Grade I and II Arteriovenous Malformations: A Multicenter Study. AB - OBJECTIVE: ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations) found better short-term outcomes after conservative management compared with intervention for unruptured arteriovenous malformations (AVMs). However, because Spetzler-Martin (SM) grade I-II AVMs have the lowest treatment morbidity, sufficient follow-up of these lesions may show a long-term benefit from intervention. The aim of this multicenter, retrospective cohort study is to assess the outcomes after stereotactic radiosurgery (SRS) for ARUBA-eligible SM grade I-II AVMs. METHODS: We pooled SRS data for patients with AVM from 7 institutions and selected ARUBA-eligible SM grade I-II AVMs with >=12 months follow-up for analysis. Favorable outcome was defined as AVM obliteration, no post-SRS hemorrhage, and no permanently symptomatic radiation-induced changes. RESULTS: The ARUBA-eligible SM grade I-II AVM cohort comprised 232 patients (mean age, 42 years). The mean nidus volume, SRS margin dose, and follow-up duration were 2.1 cm3, 22.5 Gy, and 90.5 months, respectively. The actuarial obliteration rates at 5 and 10 years were 72% and 87%, respectively; annual post-SRS hemorrhage rate was 1.0%; symptomatic and permanent radiation-induced changes occurred in 8% and 1%, respectively; and favorable outcome was achieved in 76%. Favorable outcome was significantly more likely in patients treated with a margin dose >20 Gy (83%) versus <=20 Gy (62%; P < 0.001). Stroke or death occurred in 10% after SRS. CONCLUSIONS: For ARUBA-eligible SM grade I-II AVMs, long-term SRS outcomes compare favorably with the natural history. SRS should be considered for adult patients harboring unruptured, previously untreated low-grade AVMs with a minimum life expectancy of a decade. PMID- 28344177 TI - Multimodality, Multidirectional Resection of Craniopharyngioma: Versatility in Alternating the Principal and Auxiliary Surgical Corridors and Visualization Modalities. AB - BACKGROUND: Large tumors of the skull base may require multiple approaches for safe removal, as unidirectional approaches may require excessive brain retraction. METHODS: Two patients underwent simultaneous, endoscopic and microscopic resection of tumors using 2 anatomic corridors. The corridor used for most of the tumor dissection was designated as "principal," whereas the secondary corridor used for assisting the main operation was designated "auxiliary." The endoscope and microscope were used interchangeably in the 2 corridors. RESULTS: For the first patient, the principal corridor was transventricular, and the auxiliary corridor was orbitofrontal. The endoscope was used exclusively in the latter and yielded visual information of the undersurface of the tumor, used for protection of the optic chiasm. For the second case, the corridors were reversed. Tumor resection was performed using the microscope and endoscope in alternating fashion. The endoscope, when used in the auxiliary ventricular corridor, was useful in delivering tumor components into the principal operative field. CONCLUSIONS: Multidirectional approaches to large tumors can be considered less invasive if the surgical corridors are combined in a way to minimize traction forces on both brain and tumor and maximize visualization and protection of critical structures. These combination approaches can be made simpler with the seamless integration of the endoscope and microscope. The choice between the principal and auxiliary corridors should alternate just as smoothly as the visual modality and must be dictated by the anatomy and minute-to-minute tactical situation during the operation. PMID- 28344178 TI - Systemic and Cerebral Concentration of Nimodipine During Established and Experimental Vasospasm Treatment. AB - BACKGROUND: Oral nimodipine is an established prophylactic agent for cerebral vasospasm after subarachnoid hemorrhage (SAH). In highly selected cases, intra arterial (IA) or intravenous (IV) application of nimodipine may be considered; however, the optimum dosage and modality of application remain a matter of debate. The purpose of this investigation is analysis of nimodipine concentration in serum, cerebrospinal fluid, and cerebral microdialysate in the context of currently effective dose and route of application (oral, IA, IV). METHODS: We prospectively collected 156 samples from 37 patients treated for aneurysmal SAH from May 2014 to July 2015. Treatment groups were stratified according to modality of application and low-dose or high-dose treatment. At time of sampling, current dose and modality of application effectively sustained cerebral perfusion as documented by common diagnostics. Samples were analyzed for nimodipine concentration via high-performance liquid chromatography and tandem mass spectrometry. RESULTS: In most cases (94.3%), nimodipine remained below the limit of quantification (0.5 ng/mL) within the brain (microdialysis, cerebrospinal fluid), even during targeted, local application (IA nimodipine). The median serum concentration for all treatment groups was 17.3 ng/mL. Modality of application (oral, IA, IV) was not associated with significant differences in serum concentrations (P = 0.712), even after stratification for dosage (P = 0.371), implying a comparable systemic distribution, if not efficacy. CONCLUSIONS: Nimodipine does not accumulate sufficiently within the target organ for treatment monitoring. Comparable systemic concentrations can be observed irrespective of application modality and dosing. Future studies will clarify the role of efficacy driven treatment algorithms, in which lowest dose and least invasive mode of application still effective should be identified. PMID- 28344179 TI - First Gross Anatomic Findings of an Os Odontoideum. AB - BACKGROUND: Os odontoideum is an uncommon abnormality of the craniovertebral junction where the tip of the odontoid process lacks continuity with the body of C2. The clinical presentation is variable, but severe neurologic impairment can result. CASE DESCRIPTION: We report the gross and radiologic findings of a cadaver found to harbor an os odontoideum. CONCLUSIONS: To our knowledge, there are no cadaveric reports in the literature regarding an os odontoideum. Such a case allows a rare window into the anatomy and relationships of this pathologic structure. PMID- 28344180 TI - Benefit and Complications of Frame-Based Stereotactic Biopsy in Old and Very Old Patients. AB - OBJECTIVE: Stereotactic biopsy is an everyday procedure implemented in numerous neurosurgical departments. The procedure is performed to obtain tumor tissue of unclear diagnosis. Going in hand with low complication rates and high diagnostic yield, stereotactic biopsies can be performed in adults and children likewise for histopathologic evaluation of lesions in eloquent localizations. However, little is known about whether aged patients do benefit from stereotactic biopsy or rather the therapy that is derived from histopathologic results. In this study, we therefore focused on old (80-84 years) and very old patients (85 years and older) to evaluate whether stereotactic biopsy should be performed leading to further therapy. We also assessed the complication rates of the procedure in this aged population. METHODS: We performed a retrospective analysis of our database and included all patients older than 80 years who underwent stereotactic biopsy at our department from October 2005 until May 2016. Forty-seven patients were included in this study. These patients were divided into 2 subgroups: group 1 consisted of patients from 80 to 84 years old and group 2 of patients aged 85 years and older. All patients underwent stereotactic biopsy to establish histopathologic diagnosis. We excluded patients who underwent cyst puncture or puncture of a hemorrhage because the procedure was not performed for diagnostic purposes. We assessed gender, neuroradiologic diagnosis, Karnofsky Performance Score (KPS), number of tissue samples taken, histopathologic diagnosis, localization, postoperative hemorrhage, modality of anesthesia anticoagulation, and further therapy. RESULTS: Group 1 consisted of 34 patients and group 2 of 13 patients. KPS was 80 and 70, respectively. A histopathologic diagnosis was possible in all but 1 patient. In group 1, 61.8% of the patients agreed to further postoperative therapy (radiation, 35.3%; chemotherapy, 11.8%; combined radiochemotherapy, 11.8%; complication that prevented therapy, 2.9%), as did 53.8% of the patients in group 2 (resection, 7.7%; radiation, 15.4%; combined radiochemotherapy, 30.7%). In group 1, 38.2% declined further therapy, as did 64.1% in group 2. CONCLUSIONS: Also in old and very old patients, a final histopathologic diagnosis should be established to provide adequate therapy. Our data show that most of these aged patients want to be treated. PMID- 28344181 TI - Stereotactic Radiosurgery for Pediatric High-Grade Brain Arteriovenous Malformations: Our Experience and Review of Literature. AB - INTRODUCTION: Although high-grade AVMs pose a particularly high lifetime hemorrhage risk to pediatric patients (age <18 years), little is known about the treatment outcomes. Therefore, the aim of this retrospective cohort study was to evaluate the outcomes after single-session stereotactic radiosurgery (SRS) for pediatric high-grade AVMs. METHODS: We reviewed baseline and treatment outcomes data from pediatric patients aged less than 18 years with Spetzler-Martin grade IV AVMs treated with SRS in a single session at our institution. The study cohort comprised 28 pediatric patients with Spetzler-Martin grade IV AVMs, with a mean age of 12.1 years. Statistical analyses were performed to determine predictors of obliteration and compare the outcomes of patients with versus without previous AVM hemorrhage. RESULTS: The mean nidus volume, radiosurgical margin dose, and follow-up duration were 5.9 cm3, 19.4 Gy, and 116 months, respectively. The actuarial obliteration rates at 3, 5, 7, and 10 years were 11%, 19%, 29%, and 35%, respectively. Older age was significantly associated with obliteration in the univariate Cox proportional regression analysis (P = 0.01). During the latency period before obliteration, the annual post-SRS hemorrhage rate was 3.2%. Symptomatic and permanent radiation-induced changes were detected in 7.1% and 3.5%, respectively. A favorable outcome was achieved in 35.7%, and it was more frequently achieved for those with ruptured AVMs (P = 0.0484). CONCLUSIONS: The efficacy of single-session SRS for the treatment of high-grade AVMs in the pediatric population is limited, particularly for those with unruptured nidi. Multimodal therapies should be considered in the management of selected pediatric high-grade AVMs. However, further prospective analyses are warranted to define the optimal management strategy for these challenging vascular malformations. PMID- 28344182 TI - Repair of Frontoethmoidal Encephalocele in the Philippines: An Account of 30 Cases Between 2008-2013. AB - BACKGROUND: Frontoethmoidal encephalocele is a congenital abnormality of the anterior skull base involving herniation of cranial contents through a midline skull defect. Patency of the foramen cecum, along with other multifactorial variables, contributes to the development of frontoethmoidal encephaloceles. Because of limited resources, financial constraints, and lack of surgical expertise, repair of frontoethmoidal encephaloceles is limited in developing countries. METHODS: Between 2008 and 2013 an interdisciplinary team composed of neurosurgeons, craniofacial surgeons, otolaryngologists, plastic surgeons, and nursing personnel, conducted surgical mission trips to Davao City in Mindanao, Philippines. All patients underwent a combined extracranial/intracranial surgical approach, performed in tandem by a neurosurgeon and a craniofacial surgeon, to detach and remove the encephalocele. This procedure was followed by reconstruction of the craniofacial defects. RESULTS: A total of 30 cases of frontoethmoidal encephalocele were repaired between 2008 and 2013 (20 male; 10 female). The average age at operation was 8.7 years, with 7 patients older than 17 years. Of the 3 subtypes, the following breakdown was observed in patients: 18 nasoethmoidal; 9 nasofrontal; and 3 naso-orbital. Several patients showed concurrent including enlarged ventricles, arachnoid cysts (both unilateral and bilateral), and gliotic changes, as well as orbit and bulbus oculi (globe) deformities. There were no operative-associated mortalities or neurologic deficits, infections, or hydrocephalus on follow-up during subsequent trips. CONCLUSIONS: Despite the limitations of performing advanced surgery in a developing country, the combined interdisciplinary surgical approach has offered effective treatment to improve physical appearance and psychological well-being in afflicted patients. PMID- 28344183 TI - TEEN HEED: Design of a clinical-community youth diabetes prevention intervention. PMID- 28344184 TI - Arteriovenous Hybrid Graft with Outflow in the Proximal Axillary Vein. AB - BACKGROUND: The patency of long-term hemodialysis access in end-stage renal disease patients remains a significant challenge. Often these patients are affected with limited venous outflow options, requiring limb abandonment, and creation of new access in the contralateral arm. Vascular surgeons are familiar with the exposure of the proximal axillary artery via an infraclavicular incision. The axillary vein is easily exposed through this technique. The use of the hybrid Gore graft can make the venous anastomosis easier. A hybrid graft with its venous outflow placed in the proximal axillary vein can extend the options of upper extremity access procedures. We reviewed our early experience with this technique. METHODS: A review of dialysis procedures at the Loma Linda VA was performed. All patients undergoing placement of arteriovenous grafts utilizing the Gore hybrid placed into the proximal axillary vein for outflow were identified. Outcomes in terms of primary and secondary patency rates were determined. RESULTS: Eight patients had placement of an arteriovenous hybrid graft in the proximal axillary vein via an infraclavicular incision. All patients had exhausted other options for hemodialysis access in the ipsilateral upper extremity. All grafts were used successfully for dialysis. The mean primary and secondary patency rates at 6 months were 37.5% and 62.5%, respectively. One patient developed steal syndrome, requiring proximalization of the graft. Seven out of the 8 patients required secondary procedures including thrombectomy (n = 16) and angioplasty (n = 17). CONCLUSIONS: Placement of a hybrid graft in the proximal axillary vein is an effective and suitable option for patients who have exhausted arteriovenous access sites in the arm. This procedure can easily be performed in an outpatient setting with a low complication rate and allowing for preservation of the contralateral upper extremity for future use. PMID- 28344185 TI - Arthrogryposis as neonatal presentation of Loeys-Dietz syndrome due to a novel TGFBR2 mutation. AB - Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized mainly by cardiovascular, craniofacial and skeletal features. We report on a patient with LDS, whose prenatal examination was compatible with the diagnosis of arthrogryposis multiplex congenita. Neonatal assessment showed craniofacial and cardiovascular findings suggestive of LDS whose diagnosis was confirmed by the detection of a novel mutation (HGVN: NM_003242.5 (TGFBR2): c.1381T > C (p.(Cys461Arg))) in the TGFBR2 gene. Few prenatal and neonatal cases of LDS have been reported in the literature. We reviewed all cases reported to date with perinatal onset to delineate the clinical manifestations that allow us to prompt diagnosis of this syndrome at an early stage to prevent fatal cardiovascular complications. Furthermore we discuss the multidisciplinary follow up required in these patients. PMID- 28344186 TI - Omission of predilation in balloon-expandable transcatheter aortic valve implantation: retrospective analysis in a large-volume centre. AB - AIMS: We aimed to evaluate the effect of omitting predilation on feasibility, procedural results and safety in balloon-expandable TAVI. METHODS AND RESULTS: We performed an analysis of all 680 patients scheduled for a balloon-expandable TAVI prosthesis between January 2011 and August 2016. Patients treated with or without predilation were compared. Procedure times decreased from 85.6+/-42.9 to 56.7+/ 26.1 minutes (p<0.001), fluoroscopy times from 9.5+/-5.7 to 6.2+/-3.9 minutes (p<0.001) and contrast volume from 131.9+/-60.8 to 85.4+/-37.4 ml (p<0.001) without predilation. Intraprocedural CPR was significantly more frequent in the predilation group (5.3% vs. 1.4%, p=0.01). Stroke rate was low at 1.5% and with no detectable difference. Applying VARC-2 definitions, the combined endpoints device success (88.3% vs. 92.4%, p=0.07) and clinical efficacy (88.7% vs. 92.4%, p=0.11) were comparable with or without prior valvuloplasty, while early safety was less frequent with predilation (85.2% vs. 90.2%, p=0.04). At 30 days, all cause mortality and cardiovascular mortality were 6.8% with predilation vs. 2.9% without predilation (p=0.03) and 5.3% vs. 1.4% (p=0.01). CONCLUSIONS: TAVI without prior valvuloplasty is feasible without apparent adverse impact in patients receiving a balloon-expandable TAVI prosthesis. The omission of predilation is associated with shorter procedure time, less radiation exposure and lower rates of intraprocedural resuscitation. PMID- 28344187 TI - Iatrogenic coronary artery dissection induced during invasive absolute coronary blood flow measurement: optical coherence tomography findings. PMID- 28344188 TI - Acute myocardial infarction in a young endurance athlete caused by probable plaque erosion. PMID- 28344189 TI - Diffusivity of the double negatively charged mono-vacancy in silicon. AB - Lightly-doped silicon (Si) samples of n-type conductivity have been irradiated with 2.0 MeV [Formula: see text] ions at a temperature of 30 K and characterized in situ by deep level transient spectroscopy (DLTS) measurements using an on-line setup. Migration of the Si mono-vacancy in its double negative charge state (V 2 ) starts to occur at temperatures above ~70 K and is monitored via trapping of V 2- by interstitial oxygen impurity atoms ([Formula: see text]), leading to the growth of the prominent vacancy-oxygen ([Formula: see text]) center. The [Formula: see text] center gives rise to an acceptor level located at ~0.17 eV below the conduction band edge (E c ) and is readily detected by DLTS measurements. Post-irradiation isothermal anneals at temperatures in the range of 70 to 90 K reveal first-order kinetics for the reaction [Formula: see text] in both Czochralski-grown and Float-zone samples subjected to low fluences of [Formula: see text] ions, i.e. the irradiation-induced V concentration is dilute ([Formula: see text]1013 cm-3). On the basis of these kinetics data and the content of [Formula: see text], the diffusivity of V 2- can be determined quantitatively and is found to exhibit an activation energy for migration of ~0.18 eV with a pre-exponential factor of ~[Formula: see text] cm2 s-1. The latter value evidences a simple jump process without any entropy effects for the motion of V 2-. No deep level in the bandgap to be associated with V 2- is observed but the results suggest that the level is situated deeper than ~0.19 eV below E c , corroborating results reported previously in the literature. PMID- 28344190 TI - An artificial intelligence approach fit for tRNA gene studies in the era of big sequence data. AB - Unsupervised data mining capable of extracting a wide range of knowledge from big data without prior knowledge or particular models is a timely application in the era of big sequence data accumulation in genome research. By handling oligonucleotide compositions as high-dimensional data, we have previously modified the conventional self-organizing map (SOM) for genome informatics and established BLSOM, which can analyze more than ten million sequences simultaneously. Here, we develop BLSOM specialized for tRNA genes (tDNAs) that can cluster (self-organize) more than one million microbial tDNAs according to their cognate amino acid solely depending on tetra- and pentanucleotide compositions. This unsupervised clustering can reveal combinatorial oligonucleotide motifs that are responsible for the amino acid-dependent clustering, as well as other functionally and structurally important consensus motifs, which have been evolutionarily conserved. BLSOM is also useful for identifying tDNAs as phylogenetic markers for special phylotypes. When we constructed BLSOM with 'species-unknown' tDNAs from metagenomic sequences plus 'species-known' microbial tDNAs, a large portion of metagenomic tDNAs self organized with species-known tDNAs, yielding information on microbial communities in environmental samples. BLSOM can also enhance accuracy in the tDNA database obtained from big sequence data. This unsupervised data mining should become important for studying numerous functionally unclear RNAs obtained from a wide range of organisms. PMID- 28344191 TI - Transposition of insertion sequence IS256Bsu1 in Bacillus subtilis 168 is strictly dependent on recA. AB - We developed an insertion sequence transposition detection system called the "jumping cat assay" and applied it to the Bacillus subtilis chromosome using IS256Bsu1 derived from B. subtilis natto. The high frequency of transposition enabled us to explore host factors; combining the assay and genetic analyses revealed that recA is essential for the transposition of IS256Bsu1. Detailed analyses using various domain mutants of recA demonstrated that this essentiality is not related to the function of recA in homologous recombination. Instead, the ATP binding and hydrolysis function seemed to be crucial for IS transposition. To elucidate the role of recA, we focused on the muB gene of the enterobacteriophage Mu. Based on information from the NCBI Conserved Domain Database, both MuB and RecA belong to the P-loop dNTPase superfamily. Further experiments revealed that muB complements the transposition-defective phenotype of a recA deletant, although it could not rescue UV sensitivity. These results suggest that recA shares a common function with muB that helps the transposition of IS256Bsu1 in B. subtilis. PMID- 28344192 TI - Effect of investigational kisspeptin/metastin analog, TAK-683, on luteinizing hormone secretion at different stages of the luteal phase in goats. AB - This study aimed to examine the response of luteinizing hormone (LH) secretion and ovarian steroid profile to TAK-683, an investigational metastin/kisspeptin analog, through treatment during different stages of the luteal phase in goats. Nine cycling Shiba goats (4.4 +/- 2.3 years old) were assigned to early luteal phase (ELP, n = 4), mid-luteal phase (MLP, n = 4), and control (n = 5) groups. The ELP and MLP groups were administered 50 ug of TAK-683 intravenously on either day 5 or between days 7-14 after ovulation, respectively. The control group received vehicle between days 7-14 after ovulation. Blood samples were collected at 10-min (2-6 h), 2-h (6-24 h), and 24-h (24-96 h) intervals after treatment. Significant increases in plasma LH concentration were detected during the periods of 3 to 5 h and 2 to 5 h in the ELP and MLP groups, respectively. Estradiol concentrations continuously increased with the rise of basal LH secretion after TAK-683 treatment in two goats of the ELP group with a surge-like release of LH, but not in the goats without LH surge, i.e. the MLP and control group ones. Plasma progesterone concentration and the lengths of estrous cycle in all groups did not change significantly from the time before and after treatment. Present findings indicate that the responses of LH and ovarian steroids to treatment with TAK-683 depend on the stage of the luteal phase of the estrous cycle. We suggest that the stimulatory effects of TAK-683 on LH secretion are reduced in the process leading to the mid-luteal phase in cycling goats. PMID- 28344193 TI - Polyphasic insights into the microbiomes of the Takamatsuzuka Tumulus and Kitora Tumulus. AB - Microbial outbreaks and related biodeterioration problems have affected the 1300 year-old multicolor (polychrome) mural paintings of the special historic sites Takamatsuzuka Tumulus (TT) and Kitora Tumulus (KT). Those of TT are designated as a national treasure. The microbiomes of these tumuli, both located in Asuka village, Nara, Japan, are critically reviewed as the central subject of this report. Using culture-dependent methods (conventional isolation and cultivation), we conducted polyphasic studies of the these microbial communities and identified the major microbial colonizers (Fusarium spp., Trichoderma spp., Penicillium spp., dark Acremonium spp., novel Candida yeast spp., Bacillus spp., Ochrobactrum spp., Stenotrophomonas tumulicola, and a few actinobacterial genera) and noteworthy microbial members (Kendrickiella phycomyces, Cephalotrichum verrucisporum (=Doratomyces verrucisporus), Sagenomella striatispora, Sagenomella griseoviridis, two novel Cladophialophora spp., Burgoa anomala, one novel species Prototheca tumulicola, five novel Gluconacetobacter spp., three novel Bordetella spp., and one novel genus and species Krasilnikoviella muralis) involved in the biodeterioration of mural paintings, plaster walls, and stone chamber interiors. In addition, we generated microbial community data from TT and KT samples using culture-independent methods (molecular biological methods, including PCR-DGGE, clone libraries, and pyrosequence analysis). These data are comprehensively presented, in contrast to those derived from culture-dependent methods. Furthermore, the microbial communities detected using both methods are analytically compared, and, as a result, the complementary roles of these methods and approaches are highlighted. In related contexts, knowledge of similar biodeterioration problems affecting other prehistoric cave paintings, mainly at Lascaux in France and Altamira in Spain, are referred to and commented upon. Based on substrate preferences (or ecological grouping) and mapping (plotting detection sites of isolates), we speculate on the possible origins and invasion routes whereby the major microbial colonizers invaded the TT stone chamber interior. Finally, concluding remarks, lessons, and future perspectives based on our microbiological surveys of these ancient tumuli, and similar treasures outside of Japan, are briefly presented. A list of the microbial taxa that have been identified and fully or briefly described by us as known and novel taxa for TT and KT isolates since 2008 is presented in Supplementary Materials. PMID- 28344194 TI - An administration of TAK-683 at a minimally effective dose for luteinizing hormone stimulation under the absence of the ovary induces luteinizing hormone surge in ovary-intact goats. AB - The present study aimed to evaluate hormonal responses and their association with the TAK-683 blood concentrations in goats administered TAK-683 at a low dose, which had been previously determined as the minimally effective dose for luteinizing hormone (LH) stimulation in ovariectomized goats. In Experiment 1, 5 ug of TAK-683 treatment had no significant stimulatory effect on LH secretion in ovariectomized Shiba goats (n = 4). In Experiment 2, cycling goats received the treatment of prostaglandin F2alpha and progesterone-releasing controlled internal drug releasing (CIDR) to induce the follicular phase, then they were treated with 5 ug of TAK-683 (hour 0) intravenously (n = 4, IV) or subcutaneously (n = 3, SC) or with vehicle intravenously (n = 4, control) at 12 h after CIDR removal. Blood samples were collected at 10-min (-2-6 h), 2-h (6-24 h), or 6-h (24-48 h) intervals. Ovarian ultrasonographic images were assessed daily to confirm ovulation after the treatment. A surge-like release of LH was immediately observed after injection in all animals in the IV (peak time: 4.2 +/- 0.6 h, peak concentration: 73.3 +/- 27.5 ng/ml) and SC (peak time: 4.6 +/- 0.4 h, peak concentration: 62.6 +/- 23.2 ng/ml) groups, but not in the control group. Ovulation was detected within 3 days after TAK-683 injection in all animals in the IV and SC groups, and the interval period from TAK-683 administration to ovulation in the IV group was significantly (P < 0.05) shorter than that of the control group. No significant changes were observed between the IV and SC groups in terms of luteal diameter and blood progesterone levels after ovulation. The present findings suggest that the involvement of one or more ovarian factor(s) is indispensable for a TAK-683-induced LH surge leading to ovulation in goats. PMID- 28344195 TI - Significance of Serum Polyunsaturated Fatty Acid Level Imbalance in Patients with Acute Venous Thromboembolism. AB - AIM: Polyunsaturated fatty acids (PUFAs) take part in various biological events linked to the pathogenesis of venous thromboembolism (VTE), including inflammation, endothelial dysfunction, and hypercoagulability. Several studies have demonstrated the association between PUFAs and the occurrence of VTE. However, the role of PUFAs in the pathogenesis of VTE remains unclear. METHODS: We enrolled 45 patients with acute VTE and 37 age-, gender-, and body mass index matched healthy volunteers to examine their PUFA levels. Serum omega 3 (eicosapentaenoic acid: EPA and docosahexaenoic acid: DHA) and omega 6 (dihomogammalinolenic acid: DGLA and arachidonic acid: AA) fatty acids levels were measured within 24 h of admission. RESULTS: Patients with VTE showed significantly higher AA and lower EPA levels, and lower EPA/AA ratios than the controls. Multivariate analysis revealed that AA was an independent marker for VTE. In addition, we divided the patients based on their median age (58 years old). The younger patients with VTE showed significantly lower EPA/AA levels than their age-matched controls, whereas older patients with VTE showed a significantly higher AA/DGLA levels than the older controls. CONCLUSIONS: High serum AA levels and low EPA levels are associated with the development of acute VTE, suggesting that the imbalance of PUFAs may be a potential therapeutic target for preventing acute VTE. PMID- 28344196 TI - Design of the Familial Hypercholesterolaemia Australasia Network Registry: Creating Opportunities for Greater International Collaboration. AB - Familial Hypercholesterolemia (FH) is the most common and serious monogenic disorder of lipoprotein metabolism that leads to premature coronary heart disease. There are over 65,000 people estimated to have FH in Australia, but many remain undiagnosed. Patients with FH are often under-treated, but with early detection, cascade family testing and adequate treatment, patient outcomes can improve. Patient registries are key tools for providing new information on FH and enhancing care worldwide. The development and design of the FH Australasia Network Registry is a crucial component in the comprehensive model of care for FH, which aims to provide a standardized, high-quality and cost-effective system of care that is likely to have the highest impact on patient outcomes. Informed by stakeholder engagement, the FH Australasia Network Registry was collaboratively developed by government, patient and clinical networks and research groups. The open-source, web-based Rare Disease Registry Framework was the architecture chosen for this registry owing to its open-source standards, modular design, interoperability, scalability and security features; all these are key components required to meet the ever changing clinical demands across regions. This paper provides a high level blueprint for other countries and jurisdictions to help inform and map out the critical features of an FH registry to meet their particular health system needs. PMID- 28344197 TI - Effects of Food on the Pharmacokinetics of Omega-3-Carboxylic Acids in Healthy Japanese Male Subjects: A Phase I, Randomized, Open-label, Three-period, Crossover Trial. AB - AIMS: Omega-3-carboxylic acids (OM3-CA) contain omega-3 free fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as carboxylic acids. Food intake is known to affect the bioavailability of ethyl ester fatty acid formulations. We conducted a phase I study to investigate the effects of the timing of OM3-CA administration relative to food intake on the pharmacokinetics of EPA and DHA. METHODS: In this randomized, open-label, three-period crossover study, Japanese healthy male subjects were administered 4*1 g OM3-CA capsules with continued fasting, before a meal, or after a meal. All subjects fasted for >=10 h prior to drug/meal administration. The primary objective was to examine the effect of meal timing on the pharmacokinetics of EPA and DHA after OM3-CA administration. The secondary objectives were to examine the safety and tolerability of OM3-CA. RESULTS: A total of 42 Japanese subjects was enrolled in the study. The baseline-adjusted maximum concentration and area under the concentration-time curve from 0 to 72 h for EPA, DHA, and EPA +DHA were lower in the fasting and before meal conditions than in the after meal condition. The maximum total EPA, total DHA, and total EPA+DHA concentrations were reached later when administered in fasting conditions than in fed conditions, indicating slower absorption in fasting conditions. Diarrhea was reported by five, six, and no subjects in the fasting, before meal, and after meal conditions, respectively. CONCLUSIONS: The timing of OM3-CA administration relative to food intake influences the systemic bioavailability of EPA and DHA in healthy Japanese male subjects. TRIAL REGISTRATION: NCT02372344. PMID- 28344198 TI - Radiosensitizing Effect of P2X7 Receptor Antagonist on Melanoma in Vitro and in Vivo. AB - Melanoma is highly malignant, and generally exhibits radioresistance, responding poorly to radiation therapy. We previously reported that activation of P2X7, P2Y6, and P2Y12 receptors is involved in the DNA damage response after gamma irradiation of human lung adenocarcinoma A549 cells. However, it is not clear whether these receptors are also involved in the case of melanoma cells, although P2X7 receptor is highly expressed in various cancers, including melanoma. Here, we show that P2X7 receptor antagonist enhances radiation-induced cytotoxicity in B16 melanoma cells in vitro and in vivo. We confirmed that these cells express P2X7 receptor mRNA and exhibit P2X7 receptor-mediated activities, such as ATP induced pore formation and cytotoxicity. We further examined the radiosensitizing effect of P2X7 receptor antagonist Brilliant Blue G (BBG) in vitro by colony formation assay of B16 cells. gamma-Irradiation dose-dependently reduced cell survival, and pretreatment with BBG enhanced the radiation-induced cytotoxicity. BBG pretreatment also decreased the number of DNA repair foci in nuclei, supporting involvement of P2X7 receptor in the DNA damage response. Finally, we investigated the radiosensitizing effect of BBG on B16 melanoma cells inoculated into the hind footpad of C57BL/6 mice. Neither 1 Gy gamma-irradiation alone nor BBG alone suppressed the increase of tumor volume, but the combination of irradiation and BBG significantly suppressed tumor growth. Our results suggest that P2X7 receptor antagonist BBG has a radiosensitizing effect in melanoma in vitro and in vivo. BBG, which is used as a food coloring agent, appears to be a promising candidate as a radiosensitizer. PMID- 28344200 TI - New-Onset Diabetes Mellitus After Heart Transplantation - Incidence, Risk Factors and Impact on Clinical Outcome. AB - BACKGROUND: New-onset diabetes mellitus (DM) can occur as a serious complication after heart transplantation, but the comparative data on its clinical impact on survival and on transplant-related adverse events are limited.Methods and Results:We reviewed a total of consecutive 391 patients aged >=17 years undergoing isolated orthotopic heart transplantation at the present institution from 1992 to 2013. The entire cohort was divided into 3 groups: (1) no diabetes (n=257); (2) pre-existing DM (n=46); and (3) new-onset DM (n=88). Early and long term clinical outcomes were compared across the 3 groups. Early death occurred in 8 patients (2.0%). Of the 345 non-diabetic patients before transplantation, 88 (25.5%) developed new-onset DM postoperatively. During follow-up, 83 (21.2%) died. On time-varying Cox analysis, new-onset DM was associated with increased risk for overall death (HR, 2.11; 95% CI: 1.26-3.55) and tended to have a greater risk for severe chronic kidney disease (HR, 1.77; 95% CI: 0.94-3.44). Compared with the no-diabetes group, the new-onset DM group had a worse survival rate (P=0.035), but a similar survival rate to that of the pre-existing DM group (P=0.364). CONCLUSIONS: New-onset DM has a negative effect on long-term survival and kidney function after heart transplantation. Further studies are warranted to evaluate the relevance of early diagnosis and timely control of new-onset DM to improve long-term survival. PMID- 28344199 TI - Association of Toll-Like Receptor 4 on Human Monocyte Subsets and Vulnerability Characteristics of Coronary Plaque as Assessed by 64-Slice Multidetector Computed Tomography. AB - BACKGROUND: Although Toll-like receptor 4 (TLR-4) is involved in monocyte activation in patients with accelerated forms of atherosclerosis, the relationship between the expression of TLR-4 on circulating monocytes and coronary plaque vulnerability has not previously been evaluated. We investigated this relationship using 64-slice multidetector computed tomography (MDCT) in patients with stable angina pectoris (SAP).Methods and Results:We enrolled 65 patients with SAP who underwent MDCT. Three monocyte subsets (CD14++CD16-, CD14++CD16+, and CD14+CD16+) and expression of TLR-4 were measured by flow cytometry. Intracoronary plaques were assessed by 64-slice MDCT. We defined vulnerability of intracoronary plaques according to the presence of positive remodeling (remodeling index >1.05) and/or low CT attenuation (<35 HU). The circulating CD14++CD16+monocytes more frequently expressed TLR-4 than CD14++CD16 and CD14+CD16+monocytes (P<0.001). The relative proportion of the expression of TLR-4 on CD14++CD16+monocytes was significantly greater in patients with vulnerable plaque compared with those without (10.4 [4.1-14.5] % vs. 4.5 [2.8 7.8] %, P=0.012). In addition, the relative proportion of TLR-4 expression on CD14++CD16+monocytes positively correlated with the remodeling index (r=0.28, P=0.025) and negatively correlated with CT attenuation value (r=-0.31, P=0.013). CONCLUSIONS: Upregulation of TLR-4 on CD14++CD16+monocytes might be associated with coronary plaque vulnerability in patients with SAP. PMID- 28344201 TI - Stenotic Bicuspid and Tricuspid Aortic Valves - Micro-Computed Tomography and Biological Indices of Calcification. AB - BACKGROUND: Valve calcification is well estimated by ex-vivo micro-computed tomography (micro-CT). The objective of this study was to investigate the associations between micro-CT findings and biological indices of calcification in aortic stenosis (AS), as well as differences between bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV).Methods and Results:Aortic valves and plasma were obtained from patients undergoing valve surgery. Valves were dissected and underwent micro-CT, genetic analyses, and calcium content assessment. Plasma levels of calcification markers were measured. Forty-two patients with isolated severe AS, including 22 with BAV, were studied. BAV patients had a lower median CT value (140.0 [130.0-152.0] vs. 157.0 [147.0-176.0], P=0.002) and high-density calcification (HDC) fraction (9.3 [5.7-23.3] % vs. 21.3 [14.3-31.2] %, P=0.01), as compared with TAV. Calcification fraction (CF) correlated with AS severity (measured as maximal transvalvular pressure gradient [r=0.34, P=0.03], maximal flow velocity [r=0.38, P=0.02], and indexed aortic valve area [r=-0.37, P=0.02]). For TAV patients only, mRNA expression of integrin-binding sialoprotein correlated with CF (r=0.45, P=0.048), and the receptor activator of the nuclear factor kappa-B ligand transcript correlated with HDC corrugation (r=0.54, P=0.01). CONCLUSIONS: TAV patients with AS present more mineralized calcifications in micro-CT than BAV subjects. The relative volume of calcifications increases with the AS severity. In TAV patients, upregulated expression of genes involved in osteoblastogenesis in AS correlates with leaflet mineralization in micro-CT. PMID- 28344202 TI - Three-Year Clinical Outcome After 2nd-Generation Cryoballoon-Based Pulmonary Vein Isolation for the Treatment of Paroxysmal and Persistent Atrial Fibrillation - A 2-Center Experience. AB - BACKGROUND: Pulmonary vein isolation (PVI) using the 2nd-generation cryoballoon (CB2) for the treatment of atrial fibrillation (AF) has demonstrated encouraging acute and mid-term results. However, follow-up data on outcomes beyond 1 year are sparse. We investigated the 3-year outcome after PVI using the CB2.Methods and Results:100 patients with paroxysmal (PAF, 70/100 [70%] patients) or persistent AF (pAF, 30/100 [30%] patients) underwent CB2-based PVI in 2 experienced centers in Germany. Freeze-cycle duration was 240 s. After successful PVI a bonus freeze cycle of the same duration was applied in the first 71 patients but was omitted in the following 29 patients. Phrenic nerve palsy occurred in 3 patients (3%); 2 patients were lost to follow-up. After a median follow-up of 38 (29-50) months, 59/98 (60.2%) patients remained in stable sinus rhythm (PAF: 48/70 (69%), pAF: 11/28 (39%) P=0.0084). In 32/39 (77%) patients with arrhythmia recurrence, a second ablation procedure using radiofrequency energy was conducted. Persistent PVI was noted in 76/125 (61%) PVs. After a mean of 1.37+/-0.6 procedures and a median follow-up of 35 (25-39) months, 77/98 (78.6%) patients remained in stable sinus rhythm (PAF: 56/70 (80%), pAF: 20/28 (71%), P=0.0276). CONCLUSIONS: CB2 based PVI resulted in a 60.2% single-procedure and a 78.6% multiple-procedure success rate after 3 years. Repeat procedures demonstrated a high rate of durable PVI. PMID- 28344203 TI - Myocardial Edema in Takotsubo Syndrome - Serial Cardiovascular Magnetic Resonance Imaging of the Natural Course. PMID- 28344204 TI - Atrial Septum Hematoma - Another Way to Die in Acute Aortic Dissection. PMID- 28344206 TI - Infective Endocarditis of a Completely Endothelialized CardioSEAL Patent Foramen Ovale Closure Device - Extremely Rare Entity. PMID- 28344205 TI - Decreased Serum Albumin Predicts Bleeding Events in Patients on Antiplatelet Therapy After Percutaneous Coronary Intervention. AB - BACKGROUND: Antiplatelet therapy (APT) after percutaneous coronary intervention (PCI) prevents ischemic events with increased risk of bleeding. Little is known about the relationship between hypoalbuminemia and bleeding risk in patients receiving APT after PCI. This study investigated the association between serum albumin level and bleeding events in this population.Methods and Results:We enrolled 438 consecutive patients who were prescribed dual APT (DAPT; aspirin and thienopyridine) beyond 1 month after successful PCI without adverse events. The patients were divided into 3 groups according to serum albumin tertile: tertile 1, <=3.7 g/dL; tertile 2, 3.8-4.1 g/dL; and tertile 3, >=4.2 g/dL. Adverse bleeding events were defined as Bleeding Academic Research Consortium criteria types 2, 3, and 5. During the median follow-up of 29.5 months, a total of 30 adverse bleeding events were observed. Median duration of DAPT was 14 months. The tertile 1 group had the highest risk of adverse bleeding events (event-free rate, 83.1%, 94.3% and 95.8%, respectively; P<0.001). On Cox proportional hazards modeling, serum albumin independently predicted adverse bleeding events (HR, 0.10, 95% CI: 0.027-0.39, P=0.001, for tertile 3 vs. tertile 1). CONCLUSIONS: Decreased serum albumin predicted bleeding events in patients with APT after PCI. PMID- 28344207 TI - Dipeptidyl Peptidase-IV Inhibition for the Treatment of Cardiovascular Disease - Recent Insights Focusing on Angiogenesis and Neovascularization. AB - Dipeptidyl peptidase IV (DPP-IV) is a complex enzyme that acts as a membrane anchored cell surface exopeptidase and transmits intracellular signals through a small intracellular tail. DPP-IV exists in human blood in a soluble form, and truncates a large number of peptide hormones, chemokines, cytokines, and growth factors in vitro and in vivo. DPP-IV has gained considerable interest as a therapeutic target, and a variety of DPP-IV inhibitors that prolong the insulinotropic effects of glucagon-like peptide-1 (GLP-1) are widely used in clinical settings as antidiabetic drugs. Indeed, DPP-IV is upregulated in proinflammatory states, including obesity and cardiovascular disease with and without diabetes mellitus. Consistent with this maladaptive role, DPP-IV inhibitors seem to exert a protective role in cardiovascular disease. In addition to their GLP-1-dependent vascular protective actions, DPP-IV inhibitors exhibit GLP-1-independent beneficial effects on angiogenesis/neovascularization via several signaling pathways (e.g., stromal cell-derived factor-1alpha/C-X-C chemokine receptor type-4, vascular endothelial growth factor-A/endothelial nitric oxide synthase, etc.). This review focuses on recent findings in this field, highlighting the role of DPP-IV in therapeutic angiogenesis/neovascularization in ischemic heart disease and peripheral artery disease. PMID- 28344208 TI - Clinical Outcomes of Repetition of Drug-Coated Balloon for Femoropopliteal Restenosis After Drug-Coated Balloon Treatment. AB - BACKGROUND: To compare the clinical outcomes of patients undergoing repeated drug coated balloon (DCB) treatment for femoropopliteal (FP) DCB restenosis with those of patients without repetition-DCB.Methods and Results:From March 2013 to September 2014, 102 patients (118 affected legs) underwent DCB for symptomatic FP disease; 47 patients had restenosis, and 37 underwent reintervention over a 45 month follow-up. We compared the outcomes of repetition-DCB for DCB restenosis with those of patients without repetition. The baseline patient and lesion characteristics were similar between groups. The mean lesion length was 200.8+/ 113.1 and 195.2+/-134.6 mm, P=0.894, respectively. In addition, the procedural and follow-up outcomes were not different. The rates of freedom from binary restenosis (70% vs. 14%, P=0.001) and clinically driven target lesion revascularization (CD-TLR) (78% vs. 38%, P=0.026) at 1 year were statistically different between groups. Cox regression analysis showed that repetition of DCB was the only predictor for freedom from binary restenosis (hazard ratio [HR]: 6.15, 95% confidence interval (CI) 1.60 to 23.6, P=0.008) and CD-TLR (HR: 5.37, 95% CI 1.32-22.0, P=0.019). CONCLUSIONS: For FP DCB restenosis, repetition of DCB can potentially improve vessel patency and significantly reduce the need for reintervention compared with conventional treatment. However, these observations require further confirmation in larger scale studies. PMID- 28344209 TI - CORRIGENDUM: Circulating miR-122-5p/miR-133b Ratio Is a Specific Early Prognostic Biomarker in Acute Myocardial Infarction. PMID- 28344212 TI - Age-Dependent Effects of Prenatal Dexamethasone Exposure on Immune Responses in Male Rats. AB - Prenatal glucocorticoid therapy is indicated in preterm delivery to prevent respiratory distress. This study was designed to evaluate the age-dependent effects of prenatal dexamethasone (DEX) therapy on the immune system using a rat model. Pregnant Sprague-Dawley rats received an intraperitoneal injection of DEX (0.1 mg/kg/day) or saline (VEH) over gestational days 14-20. Male offspring were sacrificed at postnatal day 7 (D7; infant stage), D120 (young adult stage), and D180 (adult stage) for evaluation of leukocyte subsets and isolation of splenocytes. The production of innate and adaptive immune cytokines was assessed from the culture supernatants of splenocytes, stimulated with lipopolysaccharide and concanavalin A, respectively. For innate cytokines, the levels of interferon gamma inducible protein 10 were significantly higher, but those of tumor necrosis factor-alpha were significantly lower, in the culture medium of splenocytes prepared from the DEX group at D120 than those in the VEH group. For adaptive cytokines, the levels of interleukin-4 (IL-4) were significantly higher at D7 and those of IL-10 were significantly higher at D120 after prenatal exposure to DEX. We also showed that the expression level of IL-4 mRNA was significantly higher in splenocytes prepared from the DEX group at D7, compared with the VEH group. Importantly, the mRNA expression level of T-bet, a key transcription factor for immune cells, was greatly decreased in the spleen of the DEX group at D7, compared with the VEH group. In conclusion, prenatal dexamethasone exposure shows the greater impact on immune responses of their male offspring in early life. PMID- 28344213 TI - Over-Expression of TBL1XR1 Indicates Poor Prognosis of Serous Epithelial Ovarian Cancer. AB - Transducin (beta)-like 1 X-linked receptor 1 (TBL1XR1) is a core component of the NCoR/SMRT transcription co-repressor complex, and its role in regulating cancer progression has been reported. Serous epithelial ovarian cancer (EOC) is the most common histological type of EOC. Here we explored the significance of TBL1XR1 expression in predicting outcomes of patients with serous EOC. Real-time quantitative PCR analysis showed that the expression level of TBL1XR1 mRNA was significantly higher in EOC tissues compared with adjacent non-tumorous tissues. The protein levels of TBL1XR1 in EOC tissues were assessed by immunohistochemistry, and the patients were classified into low-expression group (n = 62) and high-expression group (n = 54) according to the immunoreactivity. Prognostic significance of TBL1XR1 was evaluated by univariate and multivariate analyses, showing that over-expression of TBL1XR1 was correlated with poor prognosis. In addition, TBL1XR1 was positively associated with the lymph node metastasis of EOC. Because vascular endothelial growth factor (VEGF)-C is known as a critical mediator of lymph node metastasis, we measured the expression level of VEGF-C mRNA in EOC tissues and thus identified a positive correlation between TBL1XR1 and VEGF-C mRNA levels. Subsequently, using human EOC cell lines, we showed that silencing of TBL1XR1 decreased VEGF-C expression, suggesting that TBL1XR1 may function as an upstream regulator of VEGF-C in EOC. Furthermore, the proliferation and invasion of EOC cells were inhibited by TBL1XR1 silencing. In conclusion, TBL1XR1 overexpression may be an unfavorable prognostic factor for EOC. We also suggest that the TBL1XR1-VEGF-C axis may determine the EOC progression. PMID- 28344214 TI - The outcomes of intravascular ultrasound-guided drug-eluting stent implantation among patients with complex coronary lesions: a comprehensive meta-analysis of 15 clinical trials and 8,084 patients. AB - OBJECTIVE: The effects of intravascular ultrasound (IVUS)-guided drug-eluting stent (DES) implantation in patients with complex coronary artery lesions remains to be controversial. This study sought to evaluate the outcomes of IVUS guidance in these patients. METHODS: The EMBASE, Medline, and other internet sources were searched for relevant articles. The primary endpoint was major adverse cardiac events (MACE), including all-cause mortality, myocardial infarction (MI), and target-vessel revascularization (TVR). The incidence of definite/probable stent thrombosis (ST) was analyzed as the safety endpoint. RESULTS: Fifteen clinical trials involving 8.084 patients were analyzed. MACE risk was significantly decreased following IVUS-guided DES implantation compared with coronary angiography (CAG) guidance (odds ratio [OR] 0.63, 95% confidence intervals [CI]: 0.53-0.73, p<0.001), which might mainly result from the lower all-cause mortality risk (OR 0.52, 95% CI: 0.40-0.67, p<0.001), MI (OR 0.70, 95% CI: 0.56-0.86, p=0.001), and TVR (OR 0.53, 95% CI: 0.40-0.70, p<0.001). The subgroup analyses indicated better outcomes of IVUS guidance in DES implantation for these patients with left main disease or bifurcation lesions. CONCLUSION: IVUS guidance in DES implantation is associated with a significant reduction in MACE risk in patients with complex lesions, particularly those with left main disease or bifurcation lesions. More large and powerful randomized trials are still warranted to guide stenting decision making. PMID- 28344215 TI - Ethyl acetate fraction of Allium hirtifolium improves functional parameters of isolated hearts of diabetic rats. AB - OBJECTIVE: Allium hirtifolium (Persian shallot) has a hypoglycemic effect on diabetic animals. The aim of this study was to assess the effect of the ethyl acetate fraction of Allium hirtifolium on the function of isolated hearts of diabetic rats. METHODS: The control and diabetic animals were randomly divided into four groups: saline- or extract-treated controls (n=10 and n=6, respectively) and saline- or extract-treated diabetic rats (n=8 and n=9, respectively), which received normal saline or extract for four weeks by daily gavage. The hearts were perfused according to the Langendorff method. Cardiac function parameters, including left ventricular developed pressure (LVDP), heart rate (HR), rate pressure product (RPP; LVDP*HR), and dp/dt were measured. RESULTS: The findings of this study showed that in the extract-treated diabetic rats, LVDP (94.5+/-9.1 mm Hg, mean+/-SEM), HR (249+/-15 beats/min), RPP (22732+/ 1246) and +dp/dt (2598+/-230) at the baseline were significantly higher than those in the saline-treated diabetic animals, (71.5+/-4.0), (189+/-6), (13923+/ 984), and (1701+/-124), respectively. Furthermore, RPP and HR were also significantly higher than the corresponding values obtained in the saline-treated diabetic rats after ischemia. CONCLUSION: Besides blood glucose lowering action, oral administration of the ethyl acetate fraction of Allium hirtifolium significantly improved the baseline and post-ischemic cardiac function parameters in streptozotocin-induced diabetic rats. PMID- 28344216 TI - Major bleeding events in Jordanian patients undergoing percutaneous coronary intervention (PCI): Incidence, associated factors, impact on prognosis, and predictability of the CRUSADE bleeding risk score. Results from the First Jordanian PCR (PCR1). AB - OBJECTIVE: Determine the incidence of major bleeding events, their risk factors, and their impact on prognosis in Jordanian patients undergoing percutaneous coronary intervention (PCI). Evaluate the ability of the CRUSADE bleeding risk score (BRS) to predict major bleeding. METHODS: Major bleeding events were defined according to the CRUSADE classification and their incidence was evaluated from hospital admission to one year of follow up. The CRUSADE bleeding risk score was calculated for each patient during the index admission. Incidence of major bleeding events was evaluated in each of the bleeding score quintiles. JoPCR1 is a prospective, observational, multicenter registry of consecutive patients who underwent PCI at 12 tertiary care centers in Jordan. A case report form was used to record data prospectively at hospital admission, at discharge, and at 1 and 12 months of follow-up. RESULTS: The study included 2426 consecutive patients who underwent PCI. During the index hospitalization, major and minor bleeding events occurred in 0.95% and 2.6% of patients, respectively. Multivariate analysis showed that only two variables were significantly associated with major bleeding: female gender (OR=3.7; 95% CI 1.6, 8.5; p=0.002) and past history of cardiovascular disease (OR=2.6; 95% CI 1.1, 5.9; p=0.026). Patients who had in hospital major bleeding events had higher cardiac mortality during index hospitalization (13.0% vs. 0.7%, p<0.005) and at one year of follow up (13.0% vs. 1.8%, p<0.005) compared to those who had no such events. Receiver operating characteristic curve analysis showed that the CRUSADE BRS has a high ability to predict major bleeding. CONCLUSION: Major bleeding events were uncommon in this ME registry of a contemporary cohort of patients undergoing PCI but were associated with a higher mortality rate compared with those who did not have major bleeding events. CRUSADE BRS was highly predictive of the incidence of major bleeding events. PMID- 28344217 TI - Left ventricular twist was decreased in isolated left bundle branch block with preserved ejection fraction. AB - OBJECTIVE: Left ventricular (LV) rotation and twist play an important role in LV contraction and relaxation. Left bundle branch block (LBBB) deteriorates both diastolic and systolic functions. We evaluated the LV twist in patients with LBBB and preserved ejection fraction (EF) (>50%) to determine twist as a potential marker for subtle myocardial dysfunction. METHODS: This observational cross sectional study included 34 LBBB patients with preserved EF who were free from ischemic and valvular disease (Group 1) and 36 healthy controls (Group 2). All patients underwent 2-D Doppler and 2-D speckle tracking echocardiography. LV apical, basal rotation, and twist were evaluated in both groups and compared accordingly. In addition, subjects were dichotomized considering the median twist value of the study population. Binary logistic regression analysis was performed to determine the independent variables associated with inframedian twist. RESULTS: Baseline clinical characteristics were similar in LBBB patients and controls. Mean apical rotation (2.5 degrees +/-1.9 degrees vs. 4.4 degrees +/ 2.9 degrees ; p=0.002), basal rotation (-2.9 degrees +/-2.3 degrees vs. -4.1 degrees +/-2.7 degrees ; p=0.05), and twist (5.4 degrees +/-3 degrees vs. 8.6 degrees +/-3.3 degrees ; p<0.001) were decreased in group 1. Parameters related to intra- and interventricular mechanical dyssynchrony, such as longitudinal left ventricular dyssynchrony index (LVdys) and preejection interval of LV, interventricular mechanical delay (IVMD), and left posterior wall contractions (SPMWD) were significantly higher in the LBBB group. The median twist value of the studied population was 6.65 degrees . Binary logistic regression analysis showed that only presence of LBBB was independently associated with inframedian twist (OR=6.250; 95% CI: 2.215-17.632; p<0.001). CONCLUSION: The LBBB might have induced the reduction of LV twist by diminishing the LV rotation before inducing a prominent effect on the left ventricular ejection fraction (LVEF). Therefore, twist may be considered as a marker for subtle LV dysfunction in LBBB with substantially normal EF. PMID- 28344218 TI - Electrochemical Synthesis of Mesoporous CoPt Nanowires for Methanol Oxidation. AB - A new electrochemical method to synthesize mesoporous nanowires of alloys has been developed. Electrochemical deposition in ionic liquid-in-water (IL/W) microemulsion has been successful to grow mesoporous CoPt nanowires in the interior of polycarbonate membranes. The viscosity of the medium was high, but it did not avoid the entrance of the microemulsion in the interior of the membrane's channels. The structure of the IL/W microemulsions, with droplets of ionic liquid (4 nm average diameter) dispersed in CoPt aqueous solution, defined the structure of the nanowires, with pores of a few nanometers, because CoPt alloy deposited only from the aqueous component of the microemulsion. The electrodeposition in IL/W microemulsion allows obtaining mesoporous structures in which the small pores must correspond to the size of the droplets of the electrolytic aqueous component of the microemulsion. The IL main phase is like a template for the confined electrodeposition. The comparison of the electrocatalytic behaviours towards methanol oxidation of mesoporous and compact CoPt nanowires of the same composition, demonstrated the porosity of the material. For the same material mass, the CoPt mesoporous nanowires present a surface area 16 times greater than compact ones, and comparable to that observed for commercial carbon-supported platinum nanoparticles. PMID- 28344219 TI - Potential Impact of Multi-Walled Carbon Nanotubes Exposure to the Seedling Stage of Selected Plant Species. AB - Phytotoxicity is a significant consideration in understanding the potential environmental impact of nanoparticles. Abundant experimental data have shown that multi-walled carbon nanotubes (MWNTs) are toxic to plants, but the potential impacts of exposure remain unclear. The objective of the present study was to evaluate possible phytotoxicity of MWNTs at 0, 20, 200, 1000, and 2000 mg/L with red spinach, lettuce, rice, cucumber, chili, lady's finger, and soybean, based on root and shoot growth, cell death, and electrolyte leakage at the seedling stage. After 15 days of hydroponic culture, the root and shoot lengths of red spinach, lettuce, and cucumber were significantly reduced following exposure to 1000 mg/L and 2000 mg/L MWNTs. Similar toxic effects occurred regarding cell death and electrolyte leakage. Red spinach and lettuce were most sensitive to MWNTs, followed by rice and cucumber. Very little or no toxic effects were observed for chili, lady's finger, and soybean. PMID- 28344220 TI - Recent Advances in the Application of Magnetic Nanoparticles as a Support for Homogeneous Catalysts. AB - Magnetic nanoparticles are a highly valuable substrate for the attachment of homogeneous inorganic and organic containing catalysts. This review deals with the very recent main advances in the development of various nanocatalytic systems by the immobilisation of homogeneous catalysts onto magnetic nanoparticles. We discuss magnetic core shell nanostructures (e.g., silica or polymer coated magnetic nanoparticles) as substrates for catalyst immobilisation. Then we consider magnetic nanoparticles bound to inorganic catalytic mesoporous structures as well as metal organic frameworks. Binding of catalytically active small organic molecules and polymers are also reviewed. After that we briefly deliberate on the binding of enzymes to magnetic nanocomposites and the corresponding enzymatic catalysis. Finally, we draw conclusions and present a future outlook for the further development of new catalytic systems which are immobilised onto magnetic nanoparticles. PMID- 28344221 TI - Evaluation of Superparamagnetic Silica Nanoparticles for Extraction of Triazines in Magnetic in-Tube Solid Phase Microextraction Coupled to Capillary Liquid Chromatography. AB - The use of magnetic nanomaterials for analytical applications has increased in the recent years. In particular, magnetic nanomaterials have shown great potential as adsorbent phase in several extraction procedures due to the significant advantages over the conventional methods. In the present work, the influence of magnetic forces over the extraction efficiency of triazines using superparamagnetic silica nanoparticles (NPs) in magnetic in tube solid phase microextraction (Magnetic-IT-SPME) coupled to CapLC has been evaluated. Atrazine, terbutylazine and simazine has been selected as target analytes. The superparamagnetic silica nanomaterial (SiO2-Fe3O4) deposited onto the surface of a capillary column gave rise to a magnetic extraction phase for IT-SPME that provided a enhancemment of the extraction efficiency for triazines. This improvement is based on two phenomena, the superparamegnetic behavior of Fe3O4 NPs and the diamagnetic repulsions that take place in a microfluidic device such a capillary column. A systematic study of analytes adsorption and desorption was conducted as function of the magnetic field and the relationship with triazines magnetic susceptibility. The positive influence of magnetism on the extraction procedure was demonstrated. The analytical characteristics of the optimized procedure were established and the method was applied to the determination of the target analytes in water samples with satisfactory results. When coupling Magnetic-IT-SPME with CapLC, improved adsorption efficiencies (60%-63%) were achieved compared with conventional adsorption materials (0.8%-3%). PMID- 28344222 TI - NiO Nanofibers as a Candidate for a Nanophotocathode. AB - p-type NiO nanofibers have been synthesized from a simple electrospinning and sintering procedure. For the first time, p-type nanofibers have been electrospun onto a conductive fluorine doped tin oxide (FTO) surface. The properties of the NiO nanofibers have been directly compared to that of bulk NiO nanopowder. We have observed a p-type photocurrent for a NiO photocathode fabricated on an FTO substrate. PMID- 28344223 TI - Work Function Engineering of Graphene. AB - Graphene is a two dimensional one atom thick allotrope of carbon that displays unusual crystal structure, electronic characteristics, charge transport behavior, optical clarity, physical & mechanical properties, thermal conductivity and much more that is yet to be discovered. Consequently, it has generated unprecedented excitement in the scientific community; and is of great interest to wide ranging industries including semiconductor, optoelectronics and printed electronics. Graphene is considered to be a next-generation conducting material with a remarkable band-gap structure, and has the potential to replace traditional electrode materials in optoelectronic devices. It has also been identified as one of the most promising materials for post-silicon electronics. For many such applications, modulation of the electrical and optical properties, together with tuning the band gap and the resulting work function of zero band gap graphene are critical in achieving the desired properties and outcome. In understanding the importance, a number of strategies including various functionalization, doping and hybridization have recently been identified and explored to successfully alter the work function of graphene. In this review we primarily highlight the different ways of surface modification, which have been used to specifically modify the band gap of graphene and its work function. This article focuses on the most recent perspectives, current trends and gives some indication of future challenges and possibilities. PMID- 28344224 TI - Reproductive Toxicity and Life History Study of Silver Nanoparticle Effect, Uptake and Transport in Arabidopsis thaliana. AB - Concerns about nanotechnology have prompted studies on how the release of these engineered nanoparticles impact our environment. Herein, the impact of 20 nm silver nanoparticles (AgNPs) on the life history traits of Arabidopsis thaliana was studied in both above- and below-ground parts, at macroscopic and microscopic scales. Both gross phenotypes (in contrast to microscopic phenotypes) and routes of transport and accumulation were investigated from roots to shoots. Wild type Arabidopsis growing in soil, regularly irrigated with 75 MUg/L of AgNPs, did not show any obvious morphological change. However, their vegetative development was prolonged by two to three days and their reproductive growth shortened by three to four days. In addition, the germination rates of offspring decreased drastically over three generations. These findings confirmed that AgNPs induce abiotic stress and cause reproductive toxicity in Arabidopsis. To trace transport of AgNPs, this study also included an Arabidopsis reporter line genetically transformed with a green fluorescent protein and grown in an optical transparent medium with 75 MUg/L AgNPs. AgNPs followed three routes: (1) At seven days after planting (DAP) at S1.0 (stages defined by Boyes et al. 2001 [41]), AgNPs attached to the surface of primary roots and then entered their root tips; (2) At 14 DAP at S1.04, as primary roots grew longer, AgNPs gradually moved into roots and entered new lateral root primordia and root hairs; (3) At 17 DAP at S1.06 when the Arabidopsis root system had developed multiple lateral roots, AgNPs were present in vascular tissue and throughout the whole plant from root to shoot. In some cases, if cotyledons of the Arabidopsis seedlings were immersed in melted transparent medium, then AgNPs were taken up by and accumulated in stomatal guard cells. These findings in Arabidopsis are the first to document specific routes and rates of AgNP uptake in vivo and in situ. PMID- 28344226 TI - Synthesis Characterization and Photocatalytic Studies of Cobalt Ferrite-Silica Titania Nanocomposites. AB - In this work, CoFe2O4@SiO2@TiO2 core-shell magnetic nanostructures have been prepared by coating of cobalt ferrite nanoparticles with the double SiO2/TiO2 layer using metallorganic precursors. The Transmission Electron Microscopy (TEM), Energy Dispersive X-Ray Analysis (EDX), Vibrational Sample Magnetometer (VSM) measurements and Raman spectroscopy results confirm the presence both of the silica and very thin TiO2 layers. The core-shell nanoparticles have been sintered at 600 degrees C and used as a catalyst in photo-oxidation reactions of methylene blue under UV light. Despite the additional non-magnetic coatings result in a lower value of the magnetic moment, the particles can still easily be retrieved from reaction mixtures by magnetic separation. This retention of magnetism was of particular importance allowing magnetic recovery and re-use of the catalyst. PMID- 28344225 TI - Hyperthermia Using Antibody-Conjugated Magnetic Nanoparticles and Its Enhanced Effect with Cryptotanshinone. AB - Heat dissipation by magnetic nanoparticles (MNPs) under an alternating magnetic field can be used to selectively treat cancer tissues. Antibodies conjugated to MNPs can enhance the therapeutic effects of hyperthermia by altering antibody antigen interactions. Fe3O4 nanoparticles (primary diameter, 20-30 nm) coated with polyethylenimine (PEI) were prepared and conjugated with CH11, an anti-Fas monoclonal antibody. HeLa cell growth was then evaluated as a function of antibody and MNP/antibody complex doses. HeLa cell growth decreased with increased doses of the antibody and complexes. However, MNPs alone did not affect cell growth; thus, only the antibody affected cell growth. In hyperthermia experiments conducted using an alternating magnetic field frequency of 210 kHz, cell viability varied with the intensity of the applied alternating magnetic field, because the temperature increase of the culture medium with added complexes was dependent on magnetic field intensity. The HeLa cell death rate with added complexes was significantly greater as compared with that with MNPs alone. Cryptotanshinone, an anti-apoptotic factor blocker, was also added to cell cultures, which provided an additional anti-cancer cell effect. Thus, an anti cancer cell effect using a combination of magnetic hyperthermia, an anti-Fas antibody and cryptotanshinone was established. PMID- 28344227 TI - Directed Kinetic Self-Assembly of Mounds on Patterned GaAs (001): Tunable Arrangement, Pattern Amplification and Self-Limiting Growth. AB - We present results demonstrating directed self-assembly of nanometer-scale mounds during molecular beam epitaxial growth on patterned GaAs (001) surfaces. The mound arrangement is tunable via the growth temperature, with an inverse spacing or spatial frequency which can exceed that of the features of the template. We find that the range of film thickness over which particular mound arrangements persist is finite, due to an evolution of the shape of the mounds which causes their growth to self-limit. A difference in the film thickness at which mounds at different sites self-limit provides a means by which different arrangements can be produced. PMID- 28344231 TI - Assessment of the Aerosol Generation and Toxicity of Carbon Nanotubes. AB - Current interest in the pulmonary toxicity of carbon nanotubes (CNTs) has resulted in a need for an aerosol generation system that is capable of consistently producing a CNT aerosol at a desired concentration level. This two part study was designed to: (1) assess the properties of a commercially-available aerosol generator when producing an aerosol from a purchased powder supply of double-walled carbon nanotubes (DWCNTs); and (2) assess the pulmonary sub-acute toxicity of DWCNTs in a murine model during a 5-day (4 h/day) whole-body exposure. The aerosol generator, consisting of a novel dustfeed mechanism and venturi ejector was determined to be capable of producing a DWCNT consistently over a 4 h exposure period at an average level of 10.8 mg/m3. The count median diameter was 121 nm with a geometric standard deviation of 2.04. The estimated deposited dose was 32 ug/mouse. The total number of cells in bronchoalveolar lavage (BAL) fluid was significantly (p < 0.01) increased in exposed mice compared to controls. Similarly, macrophages in BAL fluid were significantly elevated in exposed mice, but not neutrophils. All animals exposed to CNT and euthanized immediately after exposure had changes in the lung tissues showing acute inflammation and injury; however these pathological changes resolved two weeks after the exposure. PMID- 28344229 TI - Emergent Properties and Toxicological Considerations for Nanohybrid Materials in Aquatic Systems. AB - Conjugation of multiple nanomaterials has become the focus of recent materials development. This new material class is commonly known as nanohybrids or "horizon nanomaterials". Conjugation of metal/metal oxides with carbonaceous nanomaterials and overcoating or doping of one metal with another have been pursued to enhance material performance and/or incorporate multifunctionality into nano-enabled devices and processes. Nanohybrids are already at use in commercialized energy, electronics and medical products, which warrant immediate attention for their safety evaluation. These conjugated ensembles likely present a new set of physicochemical properties that are unique to their individual component attributes, hence increasing uncertainty in their risk evaluation. Established toxicological testing strategies and enumerated underlying mechanisms will thus need to be re-evaluated for the assessment of these horizon materials. This review will present a critical discussion on the altered physicochemical properties of nanohybrids and analyze the validity of existing nanotoxicology data against these unique properties. The article will also propose strategies to evaluate the conjugate materials' safety to help undertake future toxicological research on the nanohybrid material class. PMID- 28344230 TI - Superparamagnetic Nanoparticles for Atherosclerosis Imaging. AB - The production of magnetic nanoparticles of utmost quality for biomedical imaging requires several steps, from the synthesis of highly crystalline magnetic cores to the attachment of the different molecules on the surface. This last step probably plays the key role in the production of clinically useful nanomaterials. The attachment of the different biomolecules should be performed in a defined and controlled fashion, avoiding the random adsorption of the components that could lead to undesirable byproducts and ill-characterized surface composition. In this work, we review the process of creating new magnetic nanomaterials for imaging, particularly for the detection of atherosclerotic plaque, in vivo. Our focus will be in the different biofunctionalization techniques that we and several other groups have recently developed. Magnetic nanomaterial functionalization should be performed by chemoselective techniques. This approach will facilitate the application of these nanomaterials in the clinic, not as an exception, but as any other pharmacological compound. PMID- 28344234 TI - Magnetic Nanomaterials and Their Applications. AB - This Special Issue of Nanomaterials is dedicated to the development of new magnetic nanomaterials and their applications in biomedicine, catalysis, spintronics and other areas. The publications in this Issue demonstrate that the interest in magnetic nanomaterials is continuously growing and their realm is expanding rapidly. Some highlights of the publications in this issue are discussed below. [...]. PMID- 28344233 TI - Biological Effects of Clinically Relevant CoCr Nanoparticles in the Dura Mater: An Organ Culture Study. AB - Medical interventions for the treatment of spinal disc degeneration include total disc replacement and fusion devices. There are, however, concerns regarding the generation of wear particles by these devices, the majority of which are in the nanometre sized range with the potential to cause adverse biological effects in the surrounding tissues. The aims of this study were to develop an organ culture model of the porcine dura mater and to investigate the biological effects of CoCr nanoparticles in this model. A range of histological techniques were used to analyse the structure of the tissue in the organ culture. The biological effects of the CoCr wear particles and the subsequent structural changes were assessed using tissue viability assays, cytokine assays, histology, immunohistochemistry, and TEM imaging. The physiological structure of the dura mater remained unchanged during the seven days of in vitro culture. There was no significant loss of cell viability. After exposure of the organ culture to CoCr nanoparticles, there was significant loosening of the epithelial layer, as well as the underlying collagen matrix. TEM imaging confirmed these structural alterations. These structural alterations were attributed to the production of MMP-1, -3, -9, -13, and TIMP-1. ELISA analysis revealed that there was significant release of cytokines including IL-8, IL-6, TNF-alpha, ECP and also the matrix protein, tenascin-C. This study suggested that CoCr nanoparticles did not cause cytotoxicity in the dura mater but they caused significant alterations to its structural integrity that could lead to significant secondary effects due to nanoparticle penetration, such as inflammation to the local neural tissue. PMID- 28344232 TI - Mechanisms Underlying Cytotoxicity Induced by Engineered Nanomaterials: A Review of In Vitro Studies. AB - Engineered nanomaterials are emerging functional materials with technologically interesting properties and a wide range of promising applications, such as drug delivery devices, medical imaging and diagnostics, and various other industrial products. However, concerns have been expressed about the risks of such materials and whether they can cause adverse effects. Studies of the potential hazards of nanomaterials have been widely performed using cell models and a range of in vitro approaches. In the present review, we provide a comprehensive and critical literature overview on current in vitro toxicity test methods that have been applied to determine the mechanisms underlying the cytotoxic effects induced by the nanostructures. The small size, surface charge, hydrophobicity and high adsorption capacity of nanomaterial allow for specific interactions within cell membrane and subcellular organelles, which in turn could lead to cytotoxicity through a range of different mechanisms. Finally, aggregating the given information on the relationships of nanomaterial cytotoxic responses with an understanding of its structure and physicochemical properties may promote the design of biologically safe nanostructures. PMID- 28344235 TI - Accumulation and Toxicity of Copper Oxide Engineered Nanoparticles in a Marine Mussel. AB - Cu is an essential trace element but can be highly toxic to aquatic organisms at elevated concentrations. Greater use of CuO engineered nanoparticles (ENPs) may lead to increased concentrations of CuO ENPs in aquatic environments causing potential ecological injury. We examined the toxicity of CuO ENPs to marine mussels and the influence of mussels on the fate and transport of CuO ENPs. We exposed marine mussels to 1, 2, or 3 mg L-1 CuO ENPs for four weeks, and measured clearance rate, rejection, excretion and accumulation of Cu, and mussel shell growth. Mussel clearance rate was 48% less, and growth was 68% less, in mussels exposed to 3 mg L-1 than in control animals. Previous studies show 100% mortality at 1 mg Cu L-1, suggesting that CuO ENPs are much less toxic than ionic Cu, probably due to the slow dissolution rate of the ENPs. Mussels rejected and excreted CuO ENPs in biodeposits containing as much as 110 mg Cu g-1, suggesting the potential for magnification in sediments. Mussels exposed to 3 mg L-1 CuO ENPs accumulated 79.14 +/- 12.46 ug Cu g-1 dry weight, which was 60 times more Cu than in control animals. Our results suggest that mussels have the potential to influence the fate and transport of CuO ENPs and potentially cause magnification of CuO ENPs in mussel bed communities, creating a significant source of Cu to marine benthos. PMID- 28344237 TI - Mesoporous Titania Powders: The Role of Precursors, Ligand Addition and Calcination Rate on Their Morphology, Crystalline Structure and Photocatalytic Activity. AB - We evaluate the influence of the use of different titania precursors, calcination rate, and ligand addition on the morphology, texture and phase content of synthesized mesoporous titania samples, parameters which, in turn, can play a key role in titania photocatalytic performances. The powders, obtained through the evaporation-induced self-assembly method, are characterized by means of ex situ X Ray Powder Diffraction (XRPD) measurements, N2 physisorption isotherms and transmission electron microscopy. The precursors are selected basing on two different approaches: the acid-base pair, using TiCl4 and Ti(OBu)4, and a more classic route with Ti(OiPr)4 and HCl. For both precursors, different specimens were prepared by resorting to different calcination rates and with and without the addition of acetylacetone, that creates coordinated species with lower hydrolysis rates, and with different calcination rates. Each sample was employed as photoanode and tested in the water splitting reaction by recording I-V curves and comparing the results with commercial P25 powders. The complex data framework suggests that a narrow pore size distribution, due to the use of acetylacetone, plays a major role in the photoactivity, leading to a current density value higher than that of P25. PMID- 28344238 TI - Electrochemical Properties of Poly(Anthraquinonyl Sulfide)/Graphene Sheets Composites as Electrode Materials for Electrochemical Capacitors. AB - Poly(anthraquinonyl sulfide) (PAQS)/graphene sheets (GSs) composite was synthesized through in situ polymerization to evaluate its performance as an electrode material for electrochemical capacitors. PAQS was successfully synthesized in the presence of GSs with uniform distribution. PAQS/GSs showed a pair of reversible redox peaks at around 0 V (vs. Ag/AgCl). The specific capacitance of PAQS/GSs was 349 F.g-1 (86 mAh.g-1) at a current density of 500 mA.g-1, and a capacitance of 305 F.g-1 was maintained even at a high current density of 5000 mA.g-1. The in situ polymerization of PAQS with GSs facilitated their interaction and enabled faster charge transfer and redox reaction, resulting in enhanced electrode properties. PMID- 28344239 TI - Design of Magnetic Gelatine/Silica Nanocomposites by Nanoemulsification: Encapsulation versus in Situ Growth of Iron Oxide Colloids. AB - The design of magnetic nanoparticles by incorporation of iron oxide colloids within gelatine/silica hybrid nanoparticles has been performed for the first time through a nanoemulsion route using the encapsulation of pre-formed magnetite nanocrystals and the in situ precipitation of ferrous/ferric ions. The first method leads to bi-continuous hybrid nanocomposites containing a limited amount of well-dispersed magnetite colloids. In contrast, the second approach allows the formation of gelatine-silica core-shell nanostructures incorporating larger amounts of agglomerated iron oxide colloids. Both magnetic nanocomposites exhibit similar superparamagnetic behaviors. Whereas nanocomposites obtained via an in situ approach show a strong tendency to aggregate in solution, the encapsulation route allows further surface modification of the magnetic nanocomposites, leading to quaternary gold/iron oxide/silica/gelatine nanoparticles. Hence, such a first time rational combination of nano-emulsion, nanocrystallization and sol-gel chemistry allows the elaboration of multi-component functional nanomaterials. This constitutes a step forward in the design of more complex bio-nanoplatforms. PMID- 28344240 TI - Templated Synthesis of Magnetic Nanoparticles through the Self-Assembly of Polymers and Surfactants. AB - The synthesis of superparamagnetic nanoparticles (NPs) for various technological applications continues to be an interesting research topic. The successful application of superparamagnetic NPs to each specific area typically depends on the achievement of high magnetization for the nanocrystals obtained, which is determined by their average size and size distribution. The size dispersity of magnetic NPs (MNPs) is markedly improved when, during the synthesis, the nucleation and growth steps of the reaction are well-separated. Tuning the nucleation process with the assistance of a hosting medium that encapsulates the precursors (such as self-assembled micelles), dispersing them in discrete compartments, improves control over particle formation. These inorganic-organic hybrids inherit properties from both the organic and the inorganic materials, while the organic component can also bring a specific functionality to the particles or prevent their aggregation in water. The general concept of interest in this review is that the shape and size of the synthesized MNPs can be controlled to some extent by the geometry and the size of the organic templates used, which thus can be considered as molds at the nanometer scale, for both porous continuous matrices and suspensions. PMID- 28344236 TI - Autophagy as a Possible Underlying Mechanism of Nanomaterial Toxicity. AB - The rapid development of nanotechnologies is raising safety concerns because of the potential effects of engineered nanomaterials on human health, particularly at the respiratory level. Since the last decades, many in vivo studies have been interested in the pulmonary effects of different classes of nanomaterials. It has been shown that some of them can induce toxic effects, essentially depending on their physico-chemical characteristics, but other studies did not identify such effects. Inflammation and oxidative stress are currently the two main mechanisms described to explain the observed toxicity. However, the exact underlying mechanism(s) still remain(s) unknown and autophagy could represent an interesting candidate. Autophagy is a physiological process in which cytoplasmic components are digested via a lysosomal pathway. It has been shown that autophagy is involved in the pathogenesis and the progression of human diseases, and is able to modulate the oxidative stress and pro-inflammatory responses. A growing amount of literature suggests that a link between nanomaterial toxicity and autophagy impairment could exist. In this review, we will first summarize what is known about the respiratory effects of nanomaterials and we will then discuss the possible involvement of autophagy in this toxicity. This review should help understand why autophagy impairment could be taken as a promising candidate to fully understand nanomaterials toxicity. PMID- 28344241 TI - Fabrication of Meso-Porous Sintered Metal Thin Films by Selective Etching of Silica Based Sacrificial Template. AB - Meso-porous metal materials have enhanced surface energies offering unique surface properties with potential applications in chemical catalysis, molecular sensing and selective separation. In this paper, commercial 20 nm diameter metal nano-particles, including silver and copper were blended with 7 nm silica nano particles by shear mixing. The resulted powders were cold-sintered to form dense, hybrid thin films. The sacrificial silica template was then removed by selective etching in 12 wt% hydrofluoric acid solutions for 15 min to reveal a purely metallic meso-porous thin film material. The impact of the initial silica nano particle diameter (7-20 nm) as well as the sintering pressure (5-20 ton.m-2) and etching conditions on the morphology and properties of the final nano-porous thin films were investigated by porometry, pyknometery, gas and liquid permeation and electron microscopy. Furthermore, the morphology of the pores and particle aggregation during shear mixing were assessed through cross-sectioning by focus ion beam milling. It is demonstrated that meso-pores ranging between 50 and 320 nm in average diameter and porosities up to 47% can be successfully formed for the range of materials tested. PMID- 28344242 TI - Effect of Porosity and Concentration Polarization on Electrolyte Diffusive Transport Parameters through Ceramic Membranes with Similar Nanopore Size. AB - Diffusive transport through nanoporous alumina membranes (NPAMs) produced by the two-step anodization method, with similar pore size but different porosity, is studied by analyzing membrane potential measured with NaCl solutions at different concentrations. Donnan exclusion of co-ions at the solution/membrane interface seem to exert a certain control on the diffusive transport of ions through NPAMs with low porosity, which might be reduced by coating the membrane surface with appropriated materials, as it is the case of SiO2. Our results also show the effect of concentration polarization at the membrane surface on ionic transport numbers (or diffusion coefficients) for low-porosity and high electrolyte affinity membranes, which could mask values of those characteristic electrochemical parameters. PMID- 28344243 TI - High-Temperature Synthesis of Ordered Mesoporous Aluminosilicates from ZSM-5 Nanoseeds with Improved Acidic Properties. AB - Ordered mesoporous SBA-15 analogs with different Si/Al ratios were successfully prepared in a two-step process from self-assembly of ZSM-5 nanoseeds at high temperature in mildly acidic media (473 K, pH 3.5). The obtained products were characterized as SAXS, XRD, N2 sorption, FTIR, TEM, NH3-TPD, AAS and ICP. The results show that the initial Si/Al molar ratio of ZSM-5 precursors strongly affects the final materials' properties. A highly condensed, well-ordered mesoporous SBA-15 analog with improved hydrothermal stability and acidic properties can be prepared from low aluminum containing ZSM-5 precursors (Si/Al >= 20). Reducing the initial Si/Al molar ratio to 10, however, leads to the formation of a disordered mesoporous SBA-15 type material accompanied by degraded textural and acidic properties. The gas phase cracking of cumene, carried out as probe reaction to evaluate Bronsted acidity, reveals that an increased density of Bronsted acid sites has been achieved over the SBA-15 analogs compared to conventional Al-SBA-15 due to the preservation of zeolite building units in the mesopore walls of the SBA-15 analogs. PMID- 28344246 TI - Challenges and Advances in Nanotoxicology. AB - This Special Issue of Nanomaterials examines the potential for engineered nanomaterials to negatively impact biological systems and highlights some advances in evaluating key areas of their hazard potential. Nanomaterial science is evolving rapidly with the generation of more complex nanostructures with exciting potential applications. Keeping modern toxicology abreast of this innovation to the point that it guides a safer nanotechnology presents an equally exciting and eminently worthwhile challenge. [...]. PMID- 28344244 TI - The Use of the Calcitonin Minimal Recognition Module for the Design of DOPA Containing Fibrillar Assemblies. AB - Amyloid deposits are insoluble fibrous protein aggregates, identified in numerous diseases, which self-assemble through molecular recognition. This process is facilitated by short amino acid sequences, identified as minimal modules. Peptides corresponding to these motifs can be used for the formation of amyloid like fibrillar assemblies in vitro. Such assemblies hold broad appeal in nanobiotechnology due to their ordered structure and to their ability to be functionalized. The catechol functional group, present in the non-coded L-3,4 dihydroxyphenylalanine (DOPA) amino acid, can take part in diverse chemical interactions. Moreover, DOPA-incorporated polymers have demonstrated adhesive properties and redox activity. In this work, amyloid-like fibrillar assemblies were formed through the self-assembly of a pentapeptide containing DOPA residues, Asp-DOPA-Asn-Lys-DOPA. The design of this peptide was based on the minimal amyloidogenic recognition motif of the human calcitonin hormone, Asp-Phe-Asn-Lys Phe, the first amyloidogenic pentapeptide identified. By substituting phenylalanine with DOPA, we obtained DOPA-functionalized amyloid-like assemblies in water. Electron microscopy revealed elongated, linear fibril-like nanometric assemblies. Secondary structure analysis indicated the presence of amyloid characteristic beta-sheet structures as well as random coil structures. Deposition of silver on the DOPA-incorporated assemblies suggested redox activity and demonstrated the applicative potential of this novel nanobiomaterial. PMID- 28344245 TI - Nano-Assemblies of Modified Cyclodextrins and Their Complexes with Guest Molecules: Incorporation in Nanostructured Membranes and Amphiphile Nanoarchitectonics Design. AB - A variety of cyclodextrin-based molecular structures, with substitutions of either primary or secondary faces of the natural oligosaccharide macrocycles of alpha-, beta-, or gamma-cyclodextrins, have been designed towards innovative applications of self-assembled cyclodextrin nanomaterials. Amphiphilic cyclodextrins have been obtained by chemical or enzymatic modifications of their macrocycles using phospholipidyl, peptidolipidyl, cholesteryl, and oligo(ethylene oxide) anchors as well as variable numbers of grafted hydrophobic hydrocarbon or fluorinated chains. These novel compounds may self-assemble in an aqueous medium into different types of supramolecular nanoassemblies (vesicles, micelles, nanorods, nanospheres, and other kinds of nanoparticles and liquid crystalline structures). This review discusses the supramolecular nanoarchitectures, which can be formed by amphiphilic cyclodextrin derivatives in mixtures with other molecules (phospholipids, surfactants, and olygonucleotides). Biomedical applications are foreseen for nanoencapsulation of drug molecules in the hydrophobic interchain volumes and nanocavities of the amphiphilic cyclodextrins (serving as drug carriers or pharmaceutical excipients), anticancer phototherapy, gene delivery, as well as for protection of instable active ingredients through inclusion complexation in nanostructured media. PMID- 28344247 TI - Self-Assembling Organic Micro-/Nano-Pillars on Gold and Glass Surfaces. AB - In this work, we report the formation of a family of organic micro-/nano-pillars prepared from surface-assisted self-assembly processes and factors controlling the growth of the pillars. These acids include cyanuric acid (CA), 1,3,5 benzenetricarboxylic acid (TMA), 1,2,4,5-benzenetetracarboxylic acid (TA) and 3,4,9,10-perylenetetracarboxylic acid (PTA). Aqueous solutions mixed with acids and melamine (M) can be fine-tuned to prepare ordered micro-/nano-pillars on substrates, which can be further optimized for their applications. PMID- 28344248 TI - Inclusion of Zinc Oxide Nanoparticles into Virus-Like Peptide Nanocapsules Self Assembled from Viral beta-Annulus Peptide. AB - A viral beta-annulus peptide connected with a zinc oxide (ZnO)-binding sequence (HCVAHR) at its N-terminal was synthesized, and the inclusion behavior of quantum sized ZnO nanoparticles into the peptide nanocapsules formed by self-assembly of the peptide in water was investigated. Dynamic light scattering (DLS) measurements showed that ZnO nanoparticles (approximately 10 nm) in the presence of the peptide (0.1 mM) formed assemblies with an average size of 48 +/- 24 nm, whereas ZnO nanoparticles in the absence of the peptide formed large aggregates. Transmission electron microscopy (TEM) observations of the ZnO nanoparticles in the presence of the peptide revealed that ZnO nanoparticles were encapsulated into the peptide nanocapsules with a size of approximately 50 nm. Fluorescence spectra of a mixture of the peptide and ZnO nanoparticles suggested that the ZnO surface and the peptide interact. Template synthesis of ZnO nanoparticles with the peptide nanocapsules afforded larger nanoparticles (approximately 40 nm), which are not quantum-sized ZnO. PMID- 28344249 TI - Self-Assembly in Biosilicification and Biotemplated Silica Materials. AB - During evolution, living organisms have learned to design biomolecules exhibiting self-assembly properties to build-up materials with complex organizations. This is particularly evidenced by the delicate siliceous structures of diatoms and sponges. These structures have been considered as inspiration sources for the preparation of nanoscale and nanostructured silica-based materials templated by the self-assembled natural or biomimetic molecules. These templates range from short peptides to large viruses, leading to biohybrid objects with a wide variety of dimensions, shapes and organization. A more recent strategy based on the integration of biological self-assembly as the driving force of silica nanoparticles organization offers new perspectives to elaborate highly-tunable, biofunctional nanocomposites. PMID- 28344250 TI - Encapsulation of Anti-Tuberculosis Drugs within Mesoporous Silica and Intracellular Antibacterial Activities. AB - Tuberculosis is a major problem in public health. While new effective treatments to combat the disease are currently under development, they tend suffer from poor solubility often resulting in low and/or inconsistent oral bioavailability. Mesoporous materials are here investigated in an in vitro intracellular assay, for the effective delivery of compound PA-824; a poorly soluble bactericidal agent being developed against Tuberculosis (TB). Mesoporous materials enhance the solubility of PA-824; however, this is not translated into a higher antibacterial activity in TB-infected macrophages after 5 days of incubation, where similar values are obtained. The lack of improved activity may be due to insufficient release of the drug from the mesopores in the context of the cellular environment. However, these results show promising data for the use of mesoporous particles in the context of oral delivery with expected improvements in bioavailability. PMID- 28344251 TI - Fungal Hydrophobin Proteins Produce Self-Assembling Protein Films with Diverse Structure and Chemical Stability. AB - Hydrophobins are small proteins secreted by fungi and which spontaneously assemble into amphipathic layers at hydrophilic-hydrophobic interfaces. We have examined the self-assembly of the Class I hydrophobins EAS?15 and DewA, the Class II hydrophobin NC2 and an engineered chimeric hydrophobin. These Class I hydrophobins form layers composed of laterally associated fibrils with an underlying amyloid structure. These two Class I hydrophobins, despite showing significant conformational differences in solution, self-assemble to form fibrillar layers with very similar structures and require a hydrophilic hydrophobic interface to trigger self-assembly. Addition of additives that influence surface tension can be used to manipulate the fine structure of the protein films. The Class II hydrophobin NC2 forms a mesh-like protein network and the engineered chimeric hydrophobin displays two multimeric forms, depending on assembly conditions. When formed on a graphite surface, the fibrillar EAS?15 layers are resistant to alcohol, acid and basic washes. In contrast, the NC2 Class II monolayers are dissociated by alcohol treatment but are relatively stable towards acid and base washes. The engineered chimeric Class I/II hydrophobin shows increased stability towards alcohol and acid and base washes. Self-assembled hydrophobin films may have extensive applications in biotechnology where biocompatible; amphipathic coatings facilitate the functionalization of nanomaterials. PMID- 28344252 TI - A Novel Method to Determine the Thermal Conductivity of Interfacial Layers Surrounding the Nanoparticles of a Nanofluid. AB - Nanofluids are becoming increasingly popular as heat transfer fluids in a variety of industrial applications, due to their enhanced heat transfer characteristics. The thermal conductivity of nanofluids is usually found to be much larger than that predicted from the classical models, such as the Maxwell model. The key mechanism of enhancement of thermal conductivity of dilute nanofluids is the solvation of nanoparticles with a layer of matrix liquid. As of now, little is known quantitatively about the thermal conductivity of the interfacial layers surrounding the nanoparticles. In this article, a novel method is presented to determine the thermal conductivity of the interfacial layers of the nanoparticles. The proposed method allows the estimation of the thermal conductivity of interfacial layers based on the combined measurements of the intrinsic viscosity and intrinsic thermal conductivity of a bulk nanofluid. From the measured intrinsic viscosity of the nanofluid, the thickness of the interfacial layer is estimated. Using the known interfacial layer thickness along with the measured intrinsic thermal conductivity of the nanofluid, the thermal conductivity of the interfacial layer is estimated. The proposed method is validated by simulation and experimental results. PMID- 28344253 TI - Impact of the De-Alloying Kinetics and Alloy Microstructure on the Final Morphology of De-Alloyed Meso-Porous Metal Films. AB - Nano-textured porous metal materials present unique surface properties due to their enhanced surface energy with potential applications in sensing, molecular separation and catalysis. In this paper, commercial alloy foils, including brass (Cu85Zn15 and Cu70Zn30) and white gold (Au50Ag50) foils have been chemically de alloyed to form nano-porous thin films. The impact of the initial alloy micro structure and number of phases, as well as chemical de-alloying (DA) parameters, including etchant concentration, time and solution temperature on the final nano porous thin film morphology and properties were investigated by electron microscopy (EM). Furthermore, the penetration depth of the pores across the alloys were evaluated through the preparation of cross sections by focus ion beam (FIB) milling. It is demonstrated that ordered pores ranging between 100 nm and 600 nm in diameter and 2-5 MUm in depth can be successfully formed for the range of materials tested. The microstructure of the foils were obtained by electron back-scattered diffraction (EBSD) and linked to development of pits across the material thickness and surface during DA. The role of selective etching of both noble and sacrificial metal phases of the alloy were discussed in light of the competitive surface etching across the range of microstructures and materials tested. PMID- 28344254 TI - Polymer Coating of Carbon Nanotube Fibers for Electric Microcables. AB - Carbon nanotubes (CNTs) are considered the most promising candidates to replace Cu and Al in a large number of electrical, mechanical and thermal applications. Although most CNT industrial applications require macro and micro size CNT fiber assemblies, several techniques to make conducting CNT fibers, threads, yarns and ropes have been reported to this day, and improvement of their electrical and mechanical conductivity continues. Some electrical applications of these CNT conducting fibers require an insulating layer for electrical insulation and protection against mechanical tearing. Ideally, a flexible insulator such as hydrogenated nitrile butadiene rubber (HNBR) on the CNT fiber can allow fabrication of CNT coils that can be assembled into lightweight, corrosion resistant electrical motors and transformers. HNBR is a largely used commercial polymer that unlike other cable-coating polymers such as polyvinyl chloride (PVC), it provides unique continuous and uniform coating on the CNT fibers. The polymer coated/insulated CNT fibers have a 26.54 MUm average diameter-which is approximately four times the diameter of a red blood cell-is produced by a simple dip-coating process. Our results confirm that HNBR in solution creates a few microns uniform insulation and mechanical protection over a CNT fiber that is used as the electrically conducting core. PMID- 28344255 TI - Removal of Radioactive Cesium Using Prussian Blue Magnetic Nanoparticles. AB - Radioactive cesium (137Cs) has inevitably become a human concern due to exposure from nuclear power plants and nuclear accident releases. Many efforts have been focused on removing cesium and the remediation of the contaminated environment. In this study, we elucidated the ability of Prussian blue-coated magnetic nanoparticles to eliminate cesium from radioactive contaminated waste. Thus, the obtained Prussian blue-coated magnetic nanoparticles were then characterized and examined for their physical and radioactive cesium adsorption properties. This Prussian blue-coated magnetic nanoparticle-based cesium magnetic sorbent can offer great potential for use in in situ remediation. PMID- 28344256 TI - Ordered Mesoporous Nanomaterials. AB - The Special Issue of Nanomaterials "Ordered Mesoporous Nanomaterials" covers novel synthetic aspects of mesoporous materials and explores their use in diverse areas like drug delivery, photocatalysis, filtration or electrocatalysis. The range of materials tackled includes metals and alloys, aluminosilicates, silica, alumina and transition metal oxides. The variety of materials, synthetic approaches and applications examined is vivid proof of the interest that mesoporous materials spark among researchers world-wide.[...]. PMID- 28344257 TI - Properties of An Oral Nanoformulation of A Molecularly Dispersed Amphotericin B Comprising A Composite Matrix of Theobroma Oil and Bee'S Wax. AB - An amphotericin B-containing (AmB) solid lipid nanoparticulate drug delivery system intended for oral administration, comprised of bee's wax and theobroma oil as lipid components was formulated with the aim to ascertain the location of AmB within the lipid matrix: (a) a homogenous matrix; (b) a drug-enriched shell; or (c) a drug enriched core. Both the drug-loaded and drug-free nanoparticles were spherical with AmB contributing to an increase in both the z-average diameter (169 +/- 1 to 222 +/- 2 nm) and zeta potential (40.8 +/- 0.9 to 50.3 +/- 1.0 mV) of the nanoparticles. A maximum encapsulation efficiency of 21.4% +/- 3.0%, corresponding to 10.7 +/- 0.4 mg encapsulated AmB within the lipid matrix was observed. Surface analysis and electron microscopic imaging indicated that AmB was dispersed uniformly within the lipid matrix (option (a) above) and, therefore, this is the most suitable of the three models with regard to modeling the propensity for uptake by epithelia and release of AmB in lymph. PMID- 28344258 TI - Synthesis and Application of Amine Functionalized Iron Oxide Nanoparticles on Menaquinone-7 Fermentation: A Step towards Process Intensification. AB - Industrial production of menaquione-7 by Bacillus subtilis natto is associated with major drawbacks. To address the current challenges in menaquione-7 fermentation, studying the effect of magnetic nanoparticles on the bacterial cells can open up a new domain for intensified menqainone-7 process. This article introduces the new concept of production and application of l-lysine coated iron oxide nanoparticles (l-Lys@IONs) as a novel tool for menaquinone-7 biosynthesis. l-Lys@IONs with the average size of 7 nm were successfully fabricated and were examined in a fermentation process of l-Lys@IONs decorated Bacillus subtilis natto. Based on the results, higher menaquinone-7 specific yield was observed for l-Lys@IONs decorated bacterial cells as compared to untreated bacteria. In addition, more than 92% removal efficacy was achieved by using integrated magnetic separation process. The present study demonstrates that l-Lys@IONs can be successfully applied during a fermentation of menaquinone-7 without any negative consequences on the culture conditions. This study provides a novel biotechnological application for IONs and their future role in bioprocess intensification. PMID- 28344259 TI - Effects of Particle Hydrophobicity, Surface Charge, Media pH Value and Complexation with Human Serum Albumin on Drug Release Behavior of Mitoxantrone Loaded Pullulan Nanoparticles. AB - We prepared two types of cholesterol hydrophobically modified pullulan nanoparticles (CHP) and carboxyethyl hydrophobically modified pullulan nanoparticles (CHCP) substituted with various degrees of cholesterol, including 3.11, 6.03, 6.91 and 3.46 per polymer, and named CHP-3.11, CHP-6.03, CHP-6.91 and CHCP-3.46. Dynamic laser light scattering (DLS) showed that the pullulan nanoparticles were 80-120 nm depending on the degree of cholesterol substitution. The mean size of CHCP nanoparticles was about 160 nm, with zeta potential -19.9 mV, larger than CHP because of the carboxyethyl group. A greater degree of cholesterol substitution conferred greater nanoparticle hydrophobicity. Drug loading efficiency depended on nanoparticle hydrophobicity, that is, nanoparticles with the greatest degree of cholesterol substitution (6.91) showed the most drug encapsulation efficiency (90.2%). The amount of drug loading increased and that of drug release decreased with enhanced nanoparticle hydrophobicity. Nanoparticle surface-negative charge disturbed the amount of drug loading and drug release, for an opposite effect relative to nanoparticle hydrophobicity. The drug release in pullulan nanoparticles was higher pH 4.0 than pH 6.8 media. However, the changed drug release amount was not larger for negative-surface nanoparticles than CHP nanoparticles in the acid release media. Drug release of pullulan nanoparticles was further slowed with human serum albumin complexation and was little affected by nanoparticle hydrophobicity and surface negative charge. PMID- 28344261 TI - Dense Plasma Focus-Based Nanofabrication of III-V Semiconductors: Unique Features and Recent Advances. AB - The hot and dense plasma formed in modified dense plasma focus (DPF) device has been used worldwide for the nanofabrication of several materials. In this paper, we summarize the fabrication of III-V semiconductor nanostructures using the high fluence material ions produced by hot, dense and extremely non-equilibrium plasma generated in a modified DPF device. In addition, we present the recent results on the fabrication of porous nano-gallium arsenide (GaAs). The details of morphological, structural and optical properties of the fabricated nano-GaAs are provided. The effect of rapid thermal annealing on the above properties of porous nano-GaAs is studied. The study reveals that it is possible to tailor the size of pores with annealing temperature. The optical properties of these porous nano GaAs also confirm the possibility to tailor the pore sizes upon annealing. Possible applications of the fabricated and subsequently annealed porous nano GaAs in transmission-type photo-cathodes and visible optoelectronic devices are discussed. These results suggest that the modified DPF is an effective tool for nanofabrication of continuous and porous III-V semiconductor nanomaterials. Further opportunities for using the modified DPF device for the fabrication of novel nanostructures are discussed as well. PMID- 28344260 TI - Receptor-Mediated Drug Delivery Systems Targeting to Glioma. AB - Glioma has been considered to be the most frequent primary tumor within the central nervous system (CNS). The complexity of glioma, especially the existence of the blood-brain barrier (BBB), makes the survival and prognosis of glioma remain poor even after a standard treatment based on surgery, radiotherapy, and chemotherapy. This provides a rationale for the development of some novel therapeutic strategies. Among them, receptor-mediated drug delivery is a specific pattern taking advantage of differential expression of receptors between tumors and normal tissues. The strategy can actively transport drugs, such as small molecular drugs, gene medicines, and therapeutic proteins to glioma while minimizing adverse reactions. This review will summarize recent progress on receptor-mediated drug delivery systems targeting to glioma, and conclude the challenges and prospects of receptor-mediated glioma-targeted therapy for future applications. PMID- 28344263 TI - Effects of Thickness and Amount of Carbon Nanofiber Coated Carbon Fiber on Improving the Mechanical Properties of Nanocomposites. AB - In the current study, carbon nanofibers (CNFs) were grown on a carbon fiber (CF) surface by using the chemical vapor deposition method (CVD) and the influences of some parameters of the CVD method on improving the mechanical properties of a polypropylene (PP) composite were investigated. To obtain an optimum surface area, thickness, and yield of the CNFs, the parameters of the chemical vapor deposition (CVD) method, such as catalyst concentration, reaction temperature, reaction time, and hydrocarbon flow rate, were optimized. It was observed that the optimal surface area, thickness, and yield of the CNFs caused more adhesion of the fibers with the PP matrix, which enhanced the composite properties. Besides this, the effectiveness of reinforcement of fillers was fitted with a mathematical model obtaining good agreement between the experimental result and the theoretical prediction. By applying scanning electronic microscope (SEM), transmission electron microscope (TEM), and Raman spectroscopy, the surface morphology and structural information of the resultant CF-CNF were analyzed. Additionally, SEM images and a mechanical test of the composite with a proper layer of CNFs on the CF revealed not only a compactness effect but also the thickness and surface area roles of the CNF layers in improving the mechanical properties of the composites. PMID- 28344264 TI - Determination of Cd2+ and Pb2+ Based on Mesoporous Carbon Nitride/Self-Doped Polyaniline Nanofibers and Square Wave Anodic Stripping Voltammetry. AB - The fabrication and evaluation of a glassy carbon electrode (GCE) modified with self-doped polyaniline nanofibers (SPAN)/mesoporous carbon nitride (MCN) and bismuth for simultaneous determination of trace Cd2+ and Pb2+ by square wave anodic stripping voltammetry (SWASV) are presented here. The morphology properties of SPAN and MCN were characterized by transmission electron microscopy (TEM), and the electrochemical properties of the fabricated electrode were characterized by cyclic voltammetry (CV). Experimental parameters, such as deposition time, pulse potential, step potential, bismuth concentration and NaCl concentration, were optimized. Under the optimum conditions, the fabricated electrode exhibited linear calibration curves ranging from 5 to 80 nM for Cd2+ and Pb2+. The limits of detection (LOD) were 0.7 nM for Cd2+ and 0.2 nM for Pb2+ (S/N = 3). Additionally, the repeatability, reproducibility, anti-interference ability and application were also investigated, and the proposed electrode exhibited excellent performance. The proposed method could be extended for other heavy metal determination. PMID- 28344262 TI - Biosensors Incorporating Bimetallic Nanoparticles. AB - This article presents a review of electrochemical bio-sensing for target analytes based on the use of electrocatalytic bimetallic nanoparticles (NPs), which can improve both the sensitivity and selectivity of biosensors. The review moves quickly from an introduction to the field of bio-sensing, to the importance of biosensors in today's society, the nature of the electrochemical methods employed and the attendant problems encountered. The role of electrocatalysts is introduced with reference to the three generations of biosensors. The contributions made by previous workers using bimetallic constructs, grouped by target analyte, are then examined in detail; following which, the synthesis and characterization of the catalytic particles is examined prior to a summary of the current state of endeavor. Finally, some perspectives for the future of bimetallic NPs in biosensors are given. PMID- 28344265 TI - Aqueous Dispersions of Silica Stabilized with Oleic Acid Obtained by Green Chemistry. AB - The present study describes for the first time the synthesis of silica nanoparticles starting from sodium silicate and oleic acid (OLA). The interactions between OLA and sodium silicate require an optimal OLA/OLANa molar ratio able to generate vesicles that can stabilize silica particles obtained by the sol-gel process of sodium silicate. The optimal molar ratio of OLA/OLANa can be ensured by a proper selection of OLA and respectively of sodium silicate concentration. The titration of sodium silicate with OLA revealed a stabilization phenomenon of silica/OLA vesicles and the dependence between their average size and reagent's molar ratio. Dynamic light scattering (DLS) and scanning electron microscopy (SEM) measurements emphasized the successful synthesis of silica nanoparticles starting from renewable materials, in mild condition of green chemistry. By grafting octadecyltrimethoxysilane on the initial silica particles, an increased interaction between silica particles and the OLA/OLANa complex was achieved. This interaction between the oleyl and octadecyl chains resulted in the formation of stable gel-like aqueous systems. Subsequently, olive oil and an oleophylic red dye were solubilized in these stable aqueous systems. This great dispersing capacity of oleosoluble compounds opens new perspectives for future green chemistry applications. After the removal of water and of the organic chains by thermal treatment, mesoporous silica was obtained. PMID- 28344266 TI - Targeted Sterically Stabilized Phospholipid siRNA Nanomedicine for Hepatic and Renal Fibrosis. AB - Since its discovery, small interfering RNA (siRNA) has been considered a potent tool for modulating gene expression. It has the ability to specifically target proteins via selective degradation of messenger RNA (mRNA) not easily accessed by conventional drugs. Hence, RNA interference (RNAi) therapeutics have great potential in the treatment of many diseases caused by faulty protein expression such as fibrosis and cancer. However, for clinical application siRNA faces a number of obstacles, such as poor in vivo stability, and off-target effects. Here we developed a unique targeted nanomedicine to tackle current siRNA delivery issues by formulating a biocompatible, biodegradable and relatively inexpensive nanocarrier of sterically stabilized phospholipid nanoparticles (SSLNPs). This nanocarrier is capable of incorporating siRNA in its core through self association with a novel cationic lipid composed of naturally occuring phospholipids and amino acids. This overall assembly protects and delivers sufficient amounts of siRNA to knockdown over-expressed protein in target cells. The siRNA used in this study, targets connective tissue growth factor (CTGF), an important regulator of fibrosis in both hepatic and renal cells. Furthermore, asialoglycoprotein receptors are targeted by attaching the galactosamine ligand to the nanocarries which enhances the uptake of nanoparticles by hepatocytes and renal tubular epithelial cells, the major producers of CTGF in fibrosis. On animals this innovative nanoconstruct, small interfering RNA in sterically stabilized phospholipid nanoparticles (siRNA-SSLNP), showed favorable pharmacokinetic properties and accumulated mostly in hepatic and renal tissues making siRNA-SSLNP a suitable system for targeting liver and kidney fibrotic diseases. PMID- 28344268 TI - Repair of the Orbital Wall Fractures in Rabbit Animal Model Using Nanostructured Hydroxyapatite-Based Implant. AB - Cellular uptake and cytotoxicity of nanostructured hydroxyapatite (nanoHAp) are dependent on its physical parameters. Therefore, an understanding of both surface chemistry and morphology of nanoHAp is needed in order to be able to anticipate its in vivo behavior. The aim of this paper is to characterize an engineered nanoHAp in terms of physico-chemical properties, biocompatibility, and its capability to reconstitute the orbital wall fractures in rabbits. NanoHAp was synthesized using a high pressure hydrothermal method and characterized by physico-chemical, structural, morphological, and optical techniques. X-ray diffraction revealed HAp crystallites of 21 nm, while Scanning Electron Microscopy (SEM) images showed spherical shapes of HAp powder. Mean particle size of HAp measured by DLS technique was 146.3 nm. Biocompatibility was estimated by the effect of HAp powder on the adhesion and proliferation of mesenchymal stem cells (MSC) in culture. The results showed that cell proliferation on powder coated slides was between 73.4% and 98.3% of control cells (cells grown in normal culture conditions). Computed tomography analysis of the preformed nanoHAp implanted in orbital wall fractures, performed at one and two months postoperative, demonstrated the integration of the implants in the bones. In conclusion, our engineered nanoHAp is stable, biocompatible, and may be safely considered for reconstruction of orbital wall fractures. PMID- 28344267 TI - The Influence of Carbonaceous Matrices and Electrocatalytic MnO2 Nanopowders on Lithium-Air Battery Performances. AB - Here, we report new gas diffusion electrodes (GDEs) prepared by mixing two different pore size carbonaceous matrices and pure and silver-doped manganese dioxide nanopowders, used as electrode supports and electrocatalytic materials, respectively. MnO2 nanoparticles are finely characterized in terms of structural (X-ray powder diffraction (XRPD), energy dispersive X-ray (EDX)), morphological (SEM, high-angle annular dark field (HAADF)-scanning transmission electron microscopy (STEM)/TEM), surface (Brunauer Emmet Teller (BET)-Barrett Joyner Halenda (BJH) method) and electrochemical properties. Two mesoporous carbons, showing diverse surface areas and pore volume distributions, have been employed. The GDE performances are evaluated by chronopotentiometric measurements to highlight the effects induced by the adopted materials. The best combination, hollow core mesoporous shell carbon (HCMSC) with 1.0% Ag-doped hydrothermal MnO2 (M_hydro_1.0%Ag) allows reaching very high specific capacity close to 1400 mAh.g 1. Considerably high charge retention through cycles is also observed, due to the presence of silver as a dopant for the electrocatalytic MnO2 nanoparticles. PMID- 28344269 TI - The Coupled Photothermal Reaction and Transport in a Laser Additive Metal Nanolayer Simultaneous Synthesis and Pattering for Flexible Electronics. AB - The Laser Direct Synthesis and Patterning (LDSP) technology has advantages in terms of processing time and cost compared to nanomaterials-based laser additive microfabrication processes. In LDSP, a scanning laser on the substrate surface induces chemical reactions in the reactive liquid solution and selectively deposits target material in a preselected pattern on the substrate. In this study, we experimentally investigated the effect of the processing parameters and type and concentration of the additive solvent on the properties and growth rate of the resulting metal film fabricated by this LDSP technology. It was shown that reactive metal ion solutions with substantial viscosity yield metal films with superior physical properties. A numerical analysis was also carried out the first time to investigate the coupled opto-thermo-fluidic transport phenomena and the effects on the metal film growth rate. To complete the simulation, the optical properties of the LDSP deposited metal film with a variety of thicknesses were measured. The characteristics of the temperature field and the thermally induced flow associated with the moving heat source are discussed. It was shown that the processing temperature range of the LDSP is from 330 to 390 K. A semi-empirical model for estimating the metal film growth rate using this process was developed based on these results. From the experimental and numerical results, it is seen that, owing to the increased reflectivity of the silver film as its thickness increases, the growth rate decreases gradually from about 40 nm at initial to 10 nm per laser scan after ten scans. This self-controlling effect of LDSP process controls the thickness and improves the uniformity of the fabricated metal film. The growth rate and resulting thickness of the metal film can also be regulated by adjustment of the processing parameters, and thus can be utilized for controllable additive nano/microfabrication. PMID- 28344270 TI - White Light-Emitting Diodes Based on AgInS2/ZnS Quantum Dots with Improved Bandwidth in Visible Light Communication. AB - Quantum dot white light-emitting diodes (QD-WLEDs) were fabricated from green- and red-emitting AgInS2/ZnS core/shell QDs coated on GaN LEDs. Their electroluminescence (EL) spectra were measured at different currents, ranging from 50 mA to 400 mA, and showed good color stability. The modulation bandwidth of previously prepared QD-WLEDs was confirmed to be much wider than that of YAG:Ce phosphor-based WLEDs. These results indicate that the AgInS2/ZnS core/shell QDs are good color-converting materials for WLEDs and they are capable in visible light communication (VLC). PMID- 28344272 TI - Frontiers in Mesoporous Nanomaterials. AB - The Special Issue of Nanomaterials "Frontiers in Mesoporous Nanomaterials" gathers four reviews, one communication and eight regular papers. PMID- 28344271 TI - X-ray Absorption Spectroscopy Characterization of a Li/S Cell. AB - The X-ray absorption spectroscopy technique has been applied to study different stages of the lithium/sulfur (Li/S) cell life cycle. We have investigated how speciation of S in Li/S cathodes changes upon the introduction of CTAB (cetyltrimethylammonium bromide, CH3(CH2)15N+(CH3)3Br-) and with charge/discharge cycling. The introduction of CTAB changes the synthesis reaction pathway dramatically due to the interaction of CTAB with the terminal S atoms of the polysulfide ions in the Na2Sx solution. For the cycled Li/S cell, the loss of electrochemically active sulfur and the accumulation of a compact blocking insulating layer of unexpected sulfur reaction products on the cathode surface during the charge/discharge processes make the capacity decay. A modified coin cell and a vacuum-compatible three-electrode electro-chemical cell have been introduced for further in-situ/in-operando studies. PMID- 28344273 TI - Resistive Switching of Plasma-Treated Zinc Oxide Nanowires for Resistive Random Access Memory. AB - ZnO nanowires (NWs) were grown on Si(100) substrates at 975 degrees C by a vapor liquid-solid method with ~2 nm and ~4 nm gold thin films as catalysts, followed by an argon plasma treatment for the as-grown ZnO NWs. A single ZnO NW-based memory cell with a Ti/ZnO/Ti structure was then fabricated to investigate the effects of plasma treatment on the resistive switching. The plasma treatment improves the homogeneity and reproducibility of the resistive switching of the ZnO NWs, and it also reduces the switching (set and reset) voltages with less fluctuations, which would be associated with the increased density of oxygen vacancies to facilitate the resistive switching as well as to average out the stochastic movement of individual oxygen vacancies. Additionally, a single ZnO NW based memory cell with self-rectification could also be obtained, if the inhomogeneous plasma treatment is applied to the two Ti/ZnO contacts. The plasma induced oxygen vacancy disabling the rectification capability at one of the Ti/ZnO contacts is believed to be responsible for the self-rectification in the memory cell. PMID- 28344274 TI - Excipient Nanoemulsions for Improving Oral Bioavailability of Bioactives. AB - The oral bioavailability of many hydrophobic bioactive compounds found in natural food products (such as vitamins and nutraceuticals in fruits and vegetables) is relatively low due to their low bioaccessibility, chemical instability, or poor absorption. Most previous research has therefore focused on the design of delivery systems to incorporate isolated bioactive compounds into food products. However, a more sustainable and cost-effect approach to enhancing the functionality of bioactive compounds is to leave them within their natural environment, but specifically design excipient foods that enhance their bioavailability. Excipient foods typically do not have functionality themselves but they have the capacity to enhance the functionality of nutrients present in natural foods by altering their bioaccessibility, absorption, and/or chemical transformation. In this review article we present the use of excipient nanoemulsions for increasing the bioavailability of bioactive components from fruits and vegetables. Nanoemulsions present several advantages over other food systems for this application, such as the ability to incorporate hydrophilic, amphiphilic, and lipophilic excipient ingredients, high physical stability, and rapid gastrointestinal digestibility. The design, fabrication, and application of nanoemulsions as excipient foods will therefore be described in this article. PMID- 28344276 TI - Synthesis of Nickel Nanowires with Tunable Characteristics. AB - A one-step synthesis of magnetic nickel nanowires (NiNWs) with tunable characteristics is reported. The method is simple and easy to be conducted, leading to high compatibility with scaling-up. It is discovered that the size and morphology of NiNWs can be adjusted by tuning the reaction temperature, time length, as well as surfactant concentration. It is found that the products have shown high purity which remained after being stored for several months. A remarkable enhanced saturation magnetization of the product was also observed, compared to that of bulk nickel. By providing both practical experimental details and in-depth mechanism, the work introduced in this paper may advance the mass production and further applications of NiNWs. PMID- 28344275 TI - Nitrogen-Doped Banana Peel-Derived Porous Carbon Foam as Binder-Free Electrode for Supercapacitors. AB - Nitrogen-doped banana peel-derived porous carbon foam (N-BPPCF) successfully prepared from banana peels is used as a binder-free electrode for supercapacitors. The N-BPPCF exhibits superior performance including high specific surface areas of 1357.6 m2/g, large pore volume of 0.77 cm3/g, suitable mesopore size distributions around 3.9 nm, and super hydrophilicity with nitrogen containing functional groups. It can easily be brought into contact with an electrolyte to facilitate electron and ion diffusion. A comparative analysis on the electrochemical properties of BPPCF electrodes is also conducted under similar conditions. The N-BPPCF electrode offers high specific capacitance of 185.8 F/g at 5 mV/s and 210.6 F/g at 0.5 A/g in 6 M KOH aqueous electrolyte versus 125.5 F/g at 5 mV/s and 173.1 F/g at 0.5 A/g for the BPPCF electrode. The results indicate that the N-BPPCF is a binder-free electrode that can be used for high performance supercapacitors. PMID- 28344277 TI - A Graphene Oxide-Based Fluorescent Platform for Probing of Phosphatase Activity. AB - We presented a strategy for fabricating graphene oxide (GO)-based fluorescent biosensors to monitor the change of phosphorylation state and detect phosphatase activity. By regulating the interaction between the negatively charged phosphate group and the positively charged amino residue, we found that GO showed different quenching efficiency toward the phosphorylated and dephosphorylated dye-labeled peptides. To demonstrate the application of our method, alkaline phosphatase (ALP) was tested as a model enzyme with phosphorylated fluorescein isothiocyanate (FITC)-labeled short peptide FITC-Gly-Gly-Gly-Tyr(PO32-)-Arg as the probe. When the negatively charged phosphate group in the Tyr residue was removed from the peptide substrate by enzymatic hydrolysis, the resulting FITC-Gly-Gly-Gly-Tyr-Arg was readily adsorbed onto the GO surface through electrostatic interaction. As a result, fluorescence quenching was observed. Furthermore, the method was applied for the screening of phosphatase inhibitors. PMID- 28344278 TI - Investigation of MnO2 and Ordered Mesoporous Carbon Composites as Electrocatalysts for Li-O2 Battery Applications. AB - The electrocatalytic activities of the MnO2/C composites are examined in Li-O2 cells as the cathode catalysts. Hierarchically mesoporous carbon-supported manganese oxide (MnO2/C) composites are prepared using a combination of soft template and hydrothermal methods. The composites are characterized by X-ray powder diffraction, scanning electron microscopy, transmission electron microscopy, small angle X-ray scattering, The Brunauer-Emmett-Teller (BET) measurements, galvanostatic charge-discharge methods, and rotating ring-disk electrode (RRDE) measurements. The electrochemical tests indicate that the MnO2/C composites have excellent catalytic activity towards oxygen reduction reactions (ORRs) due to the larger surface area of ordered mesoporous carbon and higher catalytic activity of MnO2. The O2 solubility, diffusion rates of O2 and O2*- coefficients (DO2 and DO-2), the rate constant (kf) for producing O2*-, and the propylene carbonate (PC)-electrolyte decomposition rate constant (k) of the MnO2/C material were measured by RRDE experiments in the 0.1 M TBAPF6/PC electrolyte. The values of kf and k for MnO2/C are 4.29 * 10-2 cm.s-1 and 2.6 s 1, respectively. The results indicate that the MnO2/C cathode catalyst has higher electrocatalytic activity for the first step of ORR to produce O2*- and achieves a faster PC-electrolyte decomposition rate. PMID- 28344279 TI - Coupling of Nanocrystalline Anatase TiO2 to Porous Nanosized LaFeO3 for Efficient Visible-Light Photocatalytic Degradation of Pollutants. AB - In this work we have successfully fabricated nanocrystalline anatase TiO2/perovskite-type porous nanosized LaFeO3 (T/P-LFO) nanocomposites using a simple wet chemical method. It is clearly demonstrated by means of atmosphere controlled steady-state surface photovoltage spectroscopy (SPS) responses, photoluminescence spectra, and fluorescence spectra related to the formed OH- radical amount that the photogenerated charge carriers in the resultant T/P-LFO nanocomposites with a proper mole ratio percentage of TiO2 display much higher separation in comparison to the P-LFO alone. This is highly responsible for the improved visible-light activities of T/P-LFO nanocomposites for photocatalytic degradation of gas-phase acetaldehyde and liquid-phase phenol. This work will provide a feasible route to synthesize visible-light responsive nano photocatalysts for efficient solar energy utilization. PMID- 28344282 TI - Composites of Quasi-Colloidal Layered Double Hydroxide Nanoparticles and Agarose Hydrogels for Chromate Removal. AB - Composite hydrogels were prepared that consisted of quasi-colloidal layered double hydroxide (LDH) nanoparticles and agarose via the electrophoretic method, starting from three different agarose concentrations of 0.5, 1, and 2 wt/v%. The composite hydrogel was identified to have a uniform distribution of LDH nanoparticles in agarose matrix. Microscopic studies revealed that the composite hydrogel had a homogeneous quasi-colloidal state of LDHs, while the simple mixture of LDH powder and agarose hydrogels did not. It was determined that agarose concentration of the starting hydrogel did not significantly influence the amount of LDH that developed in the composite. The chromate scavenging efficiency of the composite hydrogel and corresponding agarose or mixture hydrogel was evaluated with respect to time, and chromate concentration. In general, the composite hydrogels exhibited much higher chromate removal efficacy compared with agarose or mixture hydrogels. Through estimating chromate adsorption by LDH moiety in the composite or mixture hydrogel, it was suggested that the agarose component facilitated the stability and dispersibility of the quasi-colloidal state of LDH nanoparticles in the composite resulting in high adsorption efficacy. From Freundlich isotherm adsorption fitting, composites were determined to possess beneficial cooperative adsorption behavior with a high adsorption coefficient. PMID- 28344281 TI - A Nanostructured SERS Switch Based on Molecular Beacon-Controlled Assembly of Gold Nanoparticles. AB - In this paper, highly purified and stable gold nanoparticle (AuNP) dimers connected at the two ends of DNA linkage were prepared by a versatile method. A nanostructured, surface-enhanced Raman scattering (SERS) switching sensor system was fabricated based on the controlled organization of gold nanoparticles (AuNPs) by a DNA nanomachine through the controlled formation/deformation of SERS "hotspots". This strategy not only opens opportunities in the precise engineering of gap distances in gold-gold nanostructures in a highly controllable and reproducible fashion, but also provides a unique ability to research the origin of SERS and sequence-specific DNA detection. PMID- 28344284 TI - Extended Superspheres for Shape Approximation of Near Polyhedral Nanoparticles and a Measure of the Degree of Polyhedrality. AB - Crystalline nanoparticles or nanoprecipitates with a cubic structure often have near polyhedral shapes composed of low-index planes with {100}, {111} and {110}. To consider such near polyhedral shapes, algebraic formulas of extended superspheres that can express intermediate shapes between spheres and various polyhedra have been presented. Four extended superspheres, (i) {100} regular hexahedral; (ii) {111} regular-octahedral (iii) {110} rhombic-dodecahedral and (iv) {100}-{111}-{110} rhombicuboctahedral superspheres are treated in this study. A measure ? to indicate the degree of polyhedrality is presented to discuss shape transitions of the extended superspheres. As an application of ? superspherical coherent precipitate is shown. PMID- 28344283 TI - Manufacturing Techniques and Surface Engineering of Polymer Based Nanoparticles for Targeted Drug Delivery to Cancer. AB - The evolution of polymer based nanoparticles as a drug delivery carrier via pharmaceutical nano/microencapsulation has greatly promoted the development of nano- and micro-medicine in the past few decades. Poly(lactide-co-glycolide) (PLGA) and chitosan, which are biodegradable and biocompatible polymers, have been approved by both the Food & Drug Administration (FDA) and European Medicine Agency (EMA), making them ideal biomaterials that can be advanced from laboratory development to clinical oral and parental administrations. PLGA and chitosan encapsulated nanoparticles (NPs) have successfully been developed as new oral drug delivery systems with demonstrated high efficacy. This review aims to provide a comprehensive overview of the fabrication of PLGA and chitosan particulate systems using nano/microencapsulation methods, the current progress and the future outlooks of the nanoparticulate drug delivery systems. Especially, we focus on the formulations and nano/micro-encapsulation techniques using top down techniques. It also addresses how the different phases including the organic and aqueous ones in the emulsion system interact with each other and subsequently influence the properties of the drug delivery system. Besides, surface modification strategies which can effectively engineer intrinsic physicochemical properties are summarised. Finally, future perspectives and potential directions of PLGA and chitosan nano/microencapsulated drug systems are outlined. PMID- 28344285 TI - Spectroscopic and Electrochemical Studies of Imogolite and Fe-Modified Imogolite Nanotubes. AB - Carbon nanotubes and other forms of carbon nanoparticles, as well as metal nanoparticles have been widely used in film electrochemistry because they allow for the immobilization of larger amounts of catalyst (either biological or inorganic) on the top of the modified electrodes. Nevertheless, those nanoparticles present high costs of synthesis and of separation and purification that hamper their employment. On the other hand, imogolites (Im), with the general formula (OH)3Al2O3SiOH, are naturally-occurring nanomaterials, which can be obtained from glassy volcanic ash soils and can also be synthesized at mild conditions. In this research paper, we characterize through spectroscopic techniques (i.e., fourier transform infrared spectroscopy (FTIR) spectroscopy, powder X-ray diffraction (XRD) and transmission electron microscopy (TEM)) synthetized Im and Fe-modified imogolite (Im(Fe)). Moreover, the Im and Im(Fe) were physically adsorbed on the top of a graphite electrode (GE) and were characterized electrochemically in the potential region ranging from -0.8 to 0.8 V vs. the saturated calomel electrode (SCE). When the film of the Im or of the Im(Fe) was present on the top of the electrode, the intensity of the charging/discharging current increased two-fold, but no redox activity in the absence of O2 could be appreciated. To show that Im and Im(Fe) could be used as support for catalysts, iron phthalocyanine (FePc) was adsorbed on the top of the Im or Im(Fe) film, and the electrocatalytic activity towards the O2 reduction was measured. In the presence of the Im, the measured electrocatalytic current for O2 reduction increased 30%, and the overpotential drastically decreased by almost 100 mV, proving that the Im can act as a good support for the electrocatalysts. PMID- 28344286 TI - Simultaneous Reduction and Functionalization of Graphene Oxide by 4 Hydrazinobenzenesulfonic Acid for Polymer Nanocomposites. AB - Graphene oxide (GO) was functionalized and reduced simultaneously by a new reductant, 4-hydrazinobenzenesulfonic acid (HBS), with a one-step and environmentally friendly process. The hydrophilic sulfonic acid group in HBS was grafted onto the surface of GO through a covalent bond. The successful preparation of HBS reduced GO (HBS-rGO) was testified by scanning electron microscope (SEM), X-ray diffraction (XRD), Raman spectroscopy, Fourier transform infrared spectra (FTIR), X-ray photoelectron spectroscopic (XPS) and thermogravimetric analysis (TGA). The interlayer space of HBS-rGO was increased to 1.478 nm from 0.751 nm for GO, resulting in a subdued Van der Waals' force between layers and less possibility to form aggregations. The aqueous dispersibility of graphene was improved to 13.49 mg/mL from 0.58 mg/mL after the functionalization. The viscosity of the epoxy resin based HBS-rGO composite could be regulated by an adjustment of the content of HBS-rGO. This study provides a new and applicable approach for the preparation of hydrophilic functionalized graphene, and makes it possible for the application of graphene in some functional polymer nanocomposites, such as specialty water-based coatings. PMID- 28344287 TI - Characterization of Nanoparticle Dispersion in Red Blood Cell Suspension by the Lattice Boltzmann-Immersed Boundary Method. AB - Nanodrug-carrier delivery in the blood stream is strongly influenced by nanoparticle (NP) dispersion. This paper presents a numerical study on NP transport and dispersion in red blood cell (RBC) suspensions under shear and channel flow conditions, utilizing an immersed boundary fluid-structure interaction model with a lattice Boltzmann fluid solver, an elastic cell membrane model and a particle motion model driven by both hydrodynamic loading and Brownian dynamics. The model can capture the multiphase features of the blood flow. Simulations were performed to obtain an empirical formula to predict NP dispersion rate for a range of shear rates and cell concentrations. NP dispersion rate predictions from the formula were then compared to observations from previous experimental and numerical studies. The proposed formula is shown to accurately predict the NP dispersion rate. The simulation results also confirm previous findings that the NP dispersion rate is strongly influenced by local disturbances in the flow due to RBC motion and deformation. The proposed formula provides an efficient method for estimating the NP dispersion rate in modeling NP transport in large-scale vascular networks without explicit RBC and NP models. PMID- 28344288 TI - Effect of NaCl on the Lifetime of Micro- and Nanobubbles. AB - Micro- and nanobubbles (MNBs) are potentially useful for industrial applications such as the purification of wastewater and the promotion of physiological activities of living organisms. To develop such applications, we should understand their properties and behavior, such as their lifetime and their number density in solution. In the present study, we observed oxygen MNBs distributed in an electrolyte (NaCl) solution using a transmission electron microscope to analyze samples made with the freeze-fracture replica method. We found that MNBs in a 100 mM NaCl solution remain for at least 1 week, but at higher concentrations decay more quickly. To better understand their lifetimes, we compared measurements of the solution's dissolved oxygen concentration and the zeta-potential of the MNBs. Our detailed observations of transmission electron microscopy (TEM) images allows us to conclude that low concentrations of NaCl stabilize MNBs due to the ion shielding effect. However, higher concentrations accelerate their disappearance by reducing the repulsive force between MNBs. PMID- 28344289 TI - Energy Transfer between Conjugated Colloidal Ga2O3 and CdSe/CdS Core/Shell Nanocrystals for White Light Emitting Applications. AB - Developing solid state materials capable of generating homogeneous white light in an energy efficient and resource-sustainable way is central to the design of new and improved devices for various lighting applications. Most currently-used phosphors depend on strategically important rare earth elements, and rely on a multicomponent approach, which produces sub-optimal quality white light. Here, we report the design and preparation of a colloidal white-light emitting nanocrystal conjugate. This conjugate is obtained by linking colloidal Ga2O3 and II-VI nanocrystals in the solution phase with a short bifunctional organic molecule (thioglycolic acid). The two types of nanocrystals are electronically coupled by Forster resonance energy transfer owing to the short separation between Ga2O3 (energy donor) and core/shell CdSe/CdS (energy acceptor) nanocrystals, and the spectral overlap between the photoluminescence of the donor and the absorption of the acceptor. Using steady state and time-resolved photoluminescence spectroscopies, we quantified the contribution of the energy transfer to the photoluminescence spectral power distribution and the corresponding chromaticity of this nanocrystal conjugate. Quantitative understanding of this new system allows for tuning of the emission color and the design of quasi-single white light emitting inorganic phosphors without the use of rare-earth elements. PMID- 28344290 TI - EU Regulation of Nanobiocides: Challenges in Implementing the Biocidal Product Regulation (BPR). AB - The Biocidal Products Regulation (BPR) contains several provisions for nanomaterials (NMs) and is the first regulation in the European Union to require specific testing and risk assessment for the NM form of a biocidal substance as a part of the information requirements. Ecotoxicological data are one of the pillars of the information requirements in the BPR, but there are currently no standard test guidelines for the ecotoxicity testing of NMs. The overall objective of this work was to investigate the implications of the introduction of nano-specific testing requirements in the BPR and to explore how these might be fulfilled in the case of copper oxide nanoparticles. While there is information and data available in the open literature that could be used to fulfill the BPR information requirements, most of the studies do not take the Organisation for Economic Co-operation and Development's nanospecific test guidelines into consideration. This makes it difficult for companies as well as regulators to fulfill the BPR information requirements for nanomaterials. In order to enable a nanospecific risk assessment, best practices need to be developed regarding stock suspension preparation and characterization, exposure suspensions preparation, and for conducting ecotoxicological test. PMID- 28344291 TI - Degradable Dextran Nanopolymer as a Carrier for Choline Kinase (ChoK) siRNA Cancer Therapy. AB - Although small interfering RNA (siRNA) therapy has proven to be a specific and effective treatment in cells, the delivery of siRNA is a challenge for the applications of siRNA therapy. We present a degradable dextran with amine groups as an siRNA nano-carrier. In our nano-carrier, the amine groups are conjugated to the dextran platform through the acetal bonds, which are acid sensitive. Therefore this siRNA carrier is stable in neutral and basic conditions, while the amine groups can be cleaved and released from dextran platform under weak acid conditions (such as in endosomes). The cleavage and release of amine groups can reduce the toxicity of cationic polymer and enhance the transfection efficiency. We successfully applied this nano-carrier to deliver choline kinase (ChoK) siRNA for ChoK inhibition in cells. PMID- 28344292 TI - Influence of Nitrogen Doping on Device Operation for TiO2-Based Solid-State Dye Sensitized Solar Cells: Photo-Physics from Materials to Devices. AB - Solid-state dye-sensitized solar cells (ssDSSC) constitute a major approach to photovoltaic energy conversion with efficiencies over 8% reported thanks to the rational design of efficient porous metal oxide electrodes, organic chromophores, and hole transporters. Among the various strategies used to push the performance ahead, doping of the nanocrystalline titanium dioxide (TiO2) electrode is regularly proposed to extend the photo-activity of the materials into the visible range. However, although various beneficial effects for device performance have been observed in the literature, they remain strongly dependent on the method used for the production of the metal oxide, and the influence of nitrogen atoms on charge kinetics remains unclear. To shed light on this open question, we synthesized a set of N-doped TiO2 nanopowders with various nitrogen contents, and exploited them for the fabrication of ssDSSC. Particularly, we carefully analyzed the localization of the dopants using X-ray photo-electron spectroscopy (XPS) and monitored their influence on the photo-induced charge kinetics probed both at the material and device levels. We demonstrate a strong correlation between the kinetics of photo-induced charge carriers probed both at the level of the nanopowders and at the level of working solar cells, illustrating a direct transposition of the photo-physic properties from materials to devices. PMID- 28344293 TI - Nano-Welding of Multi-Walled Carbon Nanotubes on Silicon and Silica Surface by Laser Irradiation. AB - In this study, a continuous fiber laser (1064 nm wavelength, 30 W/cm2) is used to irradiate multi-walled carbon nanotubes (MWCNTs) on different substrate surfaces. Effects of substrates on nano-welding of MWCNTs are investigated by scanning electron microscope (SEM). For MWCNTs on silica, after 3 s irradiation, nanoscale welding with good quality can be achieved due to breaking C-C bonds and formation of new graphene layers. While welding junctions can be formed until 10 s for the MWCNTs on silicon, the difference of irradiation time to achieve welding is attributed to the difference of thermal conductivity for silica and silicon. As the irradiation time is prolonged up to 12.5 s, most of the MWCNTs are welded to a silicon substrate, which leads to their frameworks of tube walls on the silicon surface. This is because the accumulation of absorbed energy makes the temperature rise. Then chemical reactions among silicon, carbon and nitrogen occur. New chemical bonds of Si-N and Si-C achieve the welding between the MWCNTs and silicon. Vibration modes of Si3N4 appear at peaks of 363 cm-1 and 663 cm-1. There are vibration modes of SiC at peaks of 618 cm-1, 779 cm-1 and 973 cm-1. The experimental observation proves chemical reactions and the formation of Si3N4 and SiC by laser irradiation. PMID- 28344294 TI - Supramolecular Assembly of Gold Nanoparticles on Carbon Nanotubes: Application to the Catalytic Oxidation of Hydroxylamines. AB - A supramolecular heterogeneous catalyst was developed by assembly and stabilization of gold nanoparticles on the surface of carbon nanotubes. A layer by-layer assembly strategy was used and the resulting nanohybrid was involved in the catalytic oxidation of hydroxylamines under mild conditions. The nanohybrid demonstrated high efficiency and selectivity on hydroxylamine substrates. PMID- 28344295 TI - Thermal Plasma Synthesis of Crystalline Gallium Nitride Nanopowder from Gallium Nitrate Hydrate and Melamine. AB - Gallium nitride (GaN) nanopowder used as a blue fluorescent material was synthesized by using a direct current (DC) non-transferred arc plasma. Gallium nitrate hydrate (Ga(NO3)3?xH2O) was used as a raw material and NH3 gas was used as a nitridation source. Additionally, melamine (C3H6N6) powder was injected into the plasma flame to prevent the oxidation of gallium to gallium oxide (Ga2O3). Argon thermal plasma was applied to synthesize GaN nanopowder. The synthesized GaN nanopowder by thermal plasma has low crystallinity and purity. It was improved to relatively high crystallinity and purity by annealing. The crystallinity is enhanced by the thermal treatment and the purity was increased by the elimination of residual C3H6N6. The combined process of thermal plasma and annealing was appropriate for synthesizing crystalline GaN nanopowder. The annealing process after the plasma synthesis of GaN nanopowder eliminated residual contamination and enhanced the crystallinity of GaN nanopowder. As a result, crystalline GaN nanopowder which has an average particle size of 30 nm was synthesized by the combination of thermal plasma treatment and annealing. PMID- 28344296 TI - Developments of the Physical and Electrical Properties of NiCr and NiCrSi Single Layer and Bi-Layer Nano-Scale Thin-Film Resistors. AB - In this study, commercial-grade NiCr (80 wt % Ni, 20 wt % Cr) and NiCrSi (55 wt % Ni, 40 wt % Cr, 5 wt % Si) were used as targets and the sputtering method was used to deposit NiCr and NiCrSi thin films on Al2O3 and Si substrates at room temperature under different deposition time. X-ray diffraction patterns showed that the NiCr and NiCrSi thin films were amorphous phase, and the field-effect scanning electronic microscope observations showed that only nano-crystalline grains were revealed on the surfaces of the NiCr and NiCrSi thin films. The log (resistivity) values of the NiCr and NiCrSi thin-film resistors decreased approximately linearly as their thicknesses increased. We found that the value of temperature coefficient of resistance (TCR value) of the NiCr thin-film resistors was positive and that of the NiCrSi thin-film resistors was negative. To investigate these thin-film resistors with a low TCR value, we designed a novel bi-layer structure to fabricate the thin-film resistors via two different stacking methods. The bi-layer structures were created by depositing NiCr for 10 min as the upper (or lower) layer and depositing NiCrSi for 10, 30, or 60 min as the lower (or upper) layer. We aim to show that the stacking method had no apparent effect on the resistivity of the NiCr-NiCrSi bi-layer thin-film resistors but had large effect on the TCR value. PMID- 28344297 TI - N-doped TiO2 Nanotubes as an Effective Additive to Improve the Catalytic Capability of Methanol Oxidation for Pt/Graphene Nanocomposites. AB - N-doped TiO2 nanotubes have been prepared as additives to improve the catalytic capability of Pt/graphene composites in methanol oxidation reactions. Electrochemical experiments show that the catalytic performance of Pt/graphene composites has been greatly improved by the introduction of N-doped TiO2 nanotubes. PMID- 28344299 TI - Dielectric Barrier Discharge (DBD) Plasma Assisted Synthesis of Ag2O Nanomaterials and Ag2O/RuO2 Nanocomposites. AB - Silver oxide, ruthenium oxide nanomaterials and its composites are widely used in a variety of applications. Plasma-mediated synthesis is one of the emerging technologies to prepare nanomaterials with desired physicochemical properties. In this study, dielectric barrier discharge (DBD) plasma was used to synthesize Ag2O and Ag2O/RuO2 nanocomposite materials. The prepared materials showed good crystallinity. The surface morphology of the Ag2O exhibited "garland-like" features, and it changed to "flower-like" and "leaf-like" at different NaOH concentrations. The Ag2O/RuO2 composite showed mixed structures of aggregated Ag2O and sheet-like RuO2. Mechanisms governing the material's growth under atmospheric pressure plasma were proposed. Chemical analysis was performed using Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). Thermogravimetric analysis (TGA) showed the thermal decomposition behavior and the oxygen release pattern. PMID- 28344300 TI - Effect of Saturation Pressure Difference on Metal-Silicide Nanopowder Formation in Thermal Plasma Fabrication. AB - A computational investigation using a unique model and a solution algorithm was conducted, changing only the saturation pressure of one material artificially during nanopowder formation in thermal plasma fabrication, to highlight the effects of the saturation pressure difference between a metal and silicon. The model can not only express any profile of particle size-composition distribution for a metal-silicide nanopowder even with widely ranging sizes from sub nanometers to a few hundred nanometers, but it can also simulate the entire growth process involving binary homogeneous nucleation, binary heterogeneous co condensation, and coagulation among nanoparticles with different compositions. Greater differences in saturation pressures cause a greater time lag for co condensation of two material vapors during the collective growth of the metal silicide nanopowder. The greater time lag for co-condensation results in a wider range of composition of the mature nanopowder. PMID- 28344298 TI - A Brief Review on Multivalent Intercalation Batteries with Aqueous Electrolytes. AB - Rapidly growing global demand for high energy density rechargeable batteries has driven the research toward developing new chemistries and battery systems beyond Li-ion batteries. Due to the advantages of delivering more than one electron and giving more charge capacity, the multivalent systems have gained considerable attention. At the same time, affordability, ease of fabrication and safety aspects have also directed researchers to focus on aqueous electrolyte based multivalent intercalation batteries. There have been a decent number of publications disclosing capabilities and challenges of several multivalent battery systems in aqueous electrolytes, and while considering an increasing interest in this area, here, we present a brief overview of their recent progress, including electrode chemistries, functionalities and challenges. PMID- 28344302 TI - Formation and Controlled Drug Release Using a Three-Component Supramolecular Hydrogel for Anti-Schistosoma Japonicum Cercariae. AB - A novel three-component supramolecular hydrogel based on riboflavin, melamine and amino acid derivatives were constructed for controlled release of pesticides, Niclosamide derivatives. The formation of hydrogel may be attributed to self assemble via hydrogen bonding and pi-pi interaction, which have been researched via scanning electron microscopy (SEM) and Fourier transform infrared (FT-IR) spectra. The rheological experiments showed that the hydrogel materials and drug loaded hydrogel all demonstrated good mechanical strength and high stability. Further experimental results indicated that the drug-loaded hydrogels show large drug loadings, long-term release time and relatively higher efficiency to anti cercariae in the water environment. PMID- 28344303 TI - High Refractive Organic-Inorganic Hybrid Films Prepared by Low Water Sol-Gel and UV-Irradiation Processes. AB - Organic-inorganic hybrid sols (Ti-O-Si precursor) were first synthesized by the sol-gel method at low addition of water, and were then employed to prepare a highly refractive hybrid optical film. This film was obtained by blending the Ti O-Si precursor with 2-phenylphenoxyethyl acrylate (OPPEA) to perform photo polymerization by ultraviolet (UV) irradiation. Results show that the film transparency of poly(Ti-O-Si precursor-co-OPPEA) film is higher than that of a pure poly(Ti-O-Si precursor) film, and that this poly(Ti-O-Si precursor-co-OPPEA) hybrid film exhibits a high transparency of ~93.7% coupled with a high refractive index (n) of 1.83 corresponding to a thickness of 2.59 MUm. PMID- 28344301 TI - Atomic Layer Deposition of Pt Nanoparticles within the Cages of MIL-101: A Mild and Recyclable Hydrogenation Catalyst. AB - We present the in situ synthesis of Pt nanoparticles within MIL-101-Cr (MIL = Materials Institute Lavoisier) by means of atomic layer deposition (ALD). The obtained Pt@MIL-101 materials were characterized by means of N2 adsorption and X ray powder diffraction (XRPD) measurements, showing that the structure of the metal organic framework was well preserved during the ALD deposition. X-ray fluorescence (XRF) and transmission electron microscopy (TEM) analysis confirmed the deposition of highly dispersed Pt nanoparticles with sizes determined by the MIL-101-Cr pore sizes and with an increased Pt loading for an increasing number of ALD cycles. The Pt@MIL-101 material was examined as catalyst in the hydrogenation of different linear and cyclic olefins at room temperature, showing full conversion for each substrate. Moreover, even under solvent free conditions, full conversion of the substrate was observed. A high concentration test has been performed showing that the Pt@MIL-101 is stable for a long reaction time without loss of activity, crystallinity and with very low Pt leaching. PMID- 28344304 TI - Copper Nanowires and Their Applications for Flexible, Transparent Conducting Films: A Review. AB - Cu nanowires (NWs) are attracting considerable attention as alternatives to Ag NWs for next-generation transparent conductors, replacing indium tin oxide (ITO) and micro metal grids. Cu NWs hold great promise for low-cost fabrication via a solution-processed route and show preponderant optical, electrical, and mechanical properties. In this study, we report a summary of recent advances in research on Cu NWs, covering the optoelectronic properties, synthesis routes, deposition methods to fabricate flexible transparent conducting films, and their potential applications. This review also examines the approaches on protecting Cu NWs from oxidation in air environments. PMID- 28344305 TI - Colloidal Gold-Mediated Delivery of Bleomycin for Improved Outcome in Chemotherapy. AB - Nanoparticles (NPs) can be used to overcome the side effects of poor distribution of anticancer drugs. Among other NPs, colloidal gold nanoparticles (GNPs) offer the possibility of transporting major quantities of drugs due to their large surface-to-volume ratio. This is while confining these anticancer drugs as closely as possible to their biological targets through passive and active targeting, thus ensuring limited harmful systemic distribution. In this study, we chose to use bleomycin (BLM) as the anticancer drug due to its limited therapeutic efficiency (harmful side effects). BLM was conjugated onto GNPs through a thiol bond. The effectiveness of the chemotherapeutic drug, BLM, is observed by visualizing DNA double strand breaks and by calculating the survival fraction. The action of the drug (where the drug takes effect) is known to be in the nucleus, and our experiments have shown that some of the GNPs carrying BLM were present in the nucleus. The use of GNPs to deliver BLM increased the delivery and therapeutic efficacy of the drug. Having a better control over delivery of anticancer drugs using GNPs will establish a more successful NP-based platform for a combined therapeutic approach. This is due to the fact that GNPs can also be used as radiation dose enhancers in cancer research. PMID- 28344307 TI - Nanoparticles Composed of Zn and ZnO Inhibit Peronospora tabacina Spore Germination in vitro and P. tabacina Infectivity on Tobacco Leaves. AB - Manufactured nanoparticles (NPs) are increasingly being used for commercial purposes and certain NP types have been shown to have broad spectrum antibacterial activity. In contrast, their activities against fungi and fungi like oomycetes are less studied. Here, we examined the potential of two types of commercially available Zn NPs (Zn NPs and ZnO NPs) to inhibit spore germination and infectivity on tobacco leaves resulting from exposure to the fungi-like oomycete pathogen Peronospora tabacina (P. tabacina). Both types of NPs, as well as ZnCl2 and bulk ZnO control treatments, inhibited spore germination compared to a blank control. ZnO ENMs were shown to be a much more powerful suppressor of spore germination and infectivity than bulk ZnO. ZnO and Zn NPs significantly inhibited leaf infection at 8 and 10 mg.L-1, respectively. Both types of NPs were found to provide substantially higher concentration dependent inhibition of spore germination and infectivity than could be readily explained by the presence of dissolved Zn. These results suggest that both NP types have potential for use as economic, low-dose, potentially non-persistent anti-microbial agents against the oomycete P. tabacina. PMID- 28344306 TI - Toxicity Testing of Pristine and Aged Silver Nanoparticles in Real Wastewaters Using Bioluminescent Pseudomonas putida. AB - Impact of aging on nanoparticle toxicity in real matrices is scarcely investigated due to a lack of suitable methodologies. Herein, the toxicity of pristine and aged silver nanoparticles (Ag NPs) to a bioluminescent Pseudomonas putida bioreporter was measured in spiked crude and final wastewater samples (CWs and FWs, respectively) collected from four wastewater treatment plants (WWTPs). Results showed lower toxicity of pristine Ag NPs in CWs than in FWs. The effect of the matrix on the eventual Ag NP toxicity was related to multiple physico chemical parameters (biological oxygen demand (BOD), chemical oxygen demand (COD), total suspended solids (TSS) pH, ammonia, sulfide and chloride) based on a multivariate analysis. However, no collection site effect was concluded. Aged Ag NPs (up to eight weeks) were found less toxic than pristine Ag NPs in CWs; evident increased aggregation and decreased dissolution were associated with aging. However, Ag NPs exhibited consistent toxicity in FWs despite aging; comparable results were obtained in artificial wastewater (AW) simulating effluent. The study demonstrates the potency of performing nanoparticle acute toxicity testing in real and complex matrices such as wastewaters using relevant bacterial bioreporters. PMID- 28344309 TI - Investigating the Effect of Carbon Nanotube Diameter and Wall Number in Carbon Nanotube/Silicon Heterojunction Solar Cells. AB - Suspensions of single-walled, double-walled and multi-walled carbon nanotubes (CNTs) were generated in the same solvent at similar concentrations. Films were fabricated from these suspensions and used in carbon nanotube/silicon heterojunction solar cells and their properties were compared with reference to the number of walls in the nanotube samples. It was found that single-walled nanotubes generally produced more favorable results; however, the double and multi-walled nanotube films used in this study yielded cells with higher open circuit voltages. It was also determined that post fabrication treatments applied to the nanotube films have a lesser effect on multi-walled nanotubes than on the other two types. PMID- 28344308 TI - Porphyrin-Based Nanostructures for Photocatalytic Applications. AB - Well-defined organic nanostructures with controllable size and morphology are increasingly exploited in optoelectronic devices. As promising building blocks, porphyrins have demonstrated great potentials in visible-light photocatalytic applications, because of their electrical, optical and catalytic properties. From this perspective, we have summarized the recent significant advances on the design and photocatalytic applications of porphyrin-based nanostructures. The rational strategies, such as texture or crystal modification and interfacial heterostructuring, are described. The applications of the porphyrin-based nanostructures in photocatalytic pollutant degradation and hydrogen evolution are presented. Finally, the ongoing challenges and opportunities for the future development of porphyrin nanostructures in high-quality nanodevices are also proposed. PMID- 28344310 TI - Reduction of Nitroarenes into Aryl Amines and N-Aryl hydroxylamines via Activation of NaBH4 and Ammonia-Borane Complexes by Ag/TiO2 Catalyst. AB - In this study, we report the fabrication of mesoporous assemblies of silver and TiO2 nanoparticles (Ag/MTA) and demonstrate their catalytic efficiency for the selective reduction of nitroarenes. The Ag/TiO2 assemblies, which show large surface areas (119-128 m2.g-1) and narrow-sized mesopores (ca. 7.1-7.4 nm), perform as highly active catalysts for the reduction of nitroarenes, giving the corresponding aryl amines and N-aryl hydroxylamines with NaBH4 and ammonia-borane (NH3BH3), respectively, in moderate to high yields, even in large scale reactions (up to 5 mmol). Kinetic studies indicate that nitroarenes substituted with electron-withdrawing groups reduced faster than those with electron-donating groups. The measured positive rho values from the formal Hammett-type kinetic analysis of X-substituted nitroarenes are consistent with the proposed mechanism that include the formation of possible [Ag]-H hybrid species, which are responsible for the reduction process. Because of the high observed chemo selectivities and the clean reaction processes, the present catalytic systems, i.e., Ag/MTA-NaBH4 and Ag/MTA-NH3BH3, show promise for the efficient synthesis of aryl amines and N-aryl hydroxylamines at industrial levels. PMID- 28344311 TI - Polyelectrolyte Complex Based Interfacial Drug Delivery System with Controlled Loading and Improved Release Performance for Bone Therapeutics. AB - An improved interfacial drug delivery system (DDS) based on polyelectrolyte complex (PEC) coatings with controlled drug loading and improved release performance was elaborated. The cationic homopolypeptide poly(l-lysine) (PLL) was complexed with a mixture of two cellulose sulfates (CS) of low and high degree of substitution, so that the CS and PLL solution have around equal molar charged units. As drugs the antibiotic rifampicin (RIF) and the bisphosphonate risedronate (RIS) were integrated. As an important advantage over previous PEC systems this one can be centrifuged, the supernatant discarded, the dense pellet phase (coacervate) separated, and again redispersed in fresh water phase. This behavior has three benefits: (i) Access to the loading capacity of the drug, since the concentration of the free drug can be measured by spectroscopy; (ii) lower initial burst and higher residual amount of drug due to removal of unbound drug and (iii) complete adhesive stability due to the removal of polyelectrolytes (PEL) excess component. It was found that the pH value and ionic strength strongly affected drug content and release of RIS and RIF. At the clinically relevant implant material (Ti40Nb) similar PEC adhesive and drug release properties compared to the model substrate were found. Unloaded PEC coatings at Ti40Nb showed a similar number and morphology of above cultivated human mesenchymal stem cells (hMSC) compared to uncoated Ti40Nb and resulted in considerable production of bone mineral. RIS loaded PEC coatings showed similar effects after 24 h but resulted in reduced number and unhealthy appearance of hMSC after 48 h due to cell toxicity of RIS. PMID- 28344312 TI - A Case of Anti-Glomerular Basement Membrane Glomerulonephritis Complicated by Type 1 Diabetes Mellitus, Mimicking Urinary Tract Infection. AB - BACKGROUND Type 1 diabetes mellitus (DM) tends to complicate other autoimmune diseases. When considering renal dysfunction in patients with DM, diabetic nephropathy is a likely diagnosis. By contrast, anti-glomerular basement membrane (GBM) glomerulonephritis, an autoimmune disease, is one cause of rapidly progressive glomerulonephritis. CASE REPORT We report the case of a 44-year-old woman diagnosed with anti-glomerular basement membrane (GBM) glomerulonephritis. The diagnosis was made on the basis of serological test results and pathological findings of a renal biopsy. Five years before admission, she was diagnosed with type 1 DM. At admission, she presented with a fever, chills, nausea, low back pain, and malaise, which were followed by progressive renal dysfunction. The initial presentation mimicked a urinary tract infection, which delayed the correct diagnosis. CONCLUSIONS Our patient's course strongly suggests that rapidly progressive glomerulonephritis should be considered as an early differential diagnosis in cases of progressive renal dysfunction, especially when accompanied by fever, regardless of the underlying disease. PMID- 28344313 TI - Liver Injury and Tumor-Inhibiting Effect of Sequential Transcatheter Arterial Chemoembolization and Portal Venous Embolization on Rabbit VX2 Liver Carcinoma. AB - BACKGROUND The concepts of sequential transcatheter arterial chemoembolization (TACE) and portal venous embolization (PVE) were proposed to prevent the detrimental tumor growth-inducing effect of PVE and to facilitate growth of further future liver remnant (FLR). This study aimed to investigate the effect of sequential TACE and PVE on liver damage and the therapeutic effect in a rabbit VX2 liver tumor model. MATERIAL AND METHODS Rabbits bearing VX2 liver tumors were randomly divided into TACE+PVE, TACE, PVE, and Sham groups. Plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBIL), and alkaline phosphatase (ALP) at 6 h, 24 h, 3 days, and 7 days were measured by ELISA assay. Tumor diameter on day 7 was measured and the tumor sections with cleaved caspase-3 was stained and observed. RESULTS Plasma ALT, AST, and ALP levels were significantly increased at the first hours after the interventions. The TACE group had higher increases than the TACE+PVE and PVE alone groups. ALT, AST, and ALP levels decreased on day 7 and presented a trend to return to the baseline level. The TACE+PVE group showed stronger tumor inhibiting effect than the TACE and PVE alone groups and also induced the highest level of tumor cell apoptosis. CONCLUSIONS The liver damage caused by TACE+PVE is mild and recoverable. TACE+PVE showed stronger tumor-inhibiting effect than in the TACE and PVE group and also induced the highest level of tumor cell apoptosis. PMID- 28344314 TI - Low Dimensional String-like Relaxation Underpins Superionic Conduction in Fluorites and Related Structures. AB - Among the superionic conductors that show a Faraday transition - the continuous increase in the ionic conductivity over a range of temperatures - the fluorite structures have enjoyed incisive examinations over the past four decades; yet the fundamental nature of superionicity has remained largely inconclusive. Departing from the traditional quasi-static defect framework, we provide weighty evidence for string-like dynamical structures that govern the fast ion conduction process in fluorites. We show that lower temperatures encourage the growth of longer but slowly relaxing strings and vice-versa - a direct manifestation of heterogeneous dynamics. Remarkably, the ionic conductivity is inversely correlated to the lifetime of the ions that participate in the strings and not explicitly to the ion population. Our analysis methodology, which resolves a long-standing disagreement on defect structures and the mechanism of ionic transport in fcc fluorite structures, is well-positioned to describe the dynamics of low dimensional conduction in a larger class of superionic conductors. PMID- 28344315 TI - Proteomic characterization of human multiple myeloma bone marrow extracellular matrix. AB - The extracellular matrix (ECM) is a major component of the tumor microenvironment, contributing to the regulation of cell survival, proliferation, differentiation and metastasis. In multiple myeloma (MM), interactions between MM cells and the bone marrow (BM) microenvironment, including the BM ECM, are critical to the pathogenesis of the disease and the development of drug resistance. Nevertheless, composition of the ECM in MM and its role in supporting MM pathogenesis has not been reported. We have applied a novel proteomic-based strategy and defined the BM ECM composition in patients with monoclonal gammopathy of undetermined significance (MGUS), newly diagnosed and relapsed MM compared with healthy donor-derived BM ECM. In this study, we show that the tumor ECM is remodeled at the mRNA and protein levels in MGUS and MM to allow development of a permissive microenvironment. We further demonstrate that two ECM affiliated proteins, ANXA2 and LGALS1, are more abundant in MM and high expression is associated with a decreased overall survival. This study points to the importance of ECM remodeling in MM and provides a novel proteomic pipeline for interrogating the role of the ECM in cancers with BM tropism. PMID- 28344316 TI - Gain in the short arm of chromosome 2 (2p+) induces gene overexpression and drug resistance in chronic lymphocytic leukemia: analysis of the central role of XPO1. PMID- 28344317 TI - Epigenetic loss of the RNA decapping enzyme NUDT16 mediates C-MYC activation in T cell acute lymphoblastic leukemia. PMID- 28344318 TI - Recurrent MYB rearrangement in blastic plasmacytoid dendritic cell neoplasm. PMID- 28344319 TI - PD-L1 is commonly expressed and transcriptionally regulated by STAT3 and MYC in ALK-negative anaplastic large-cell lymphoma. PMID- 28344320 TI - DPP4 truncated GM-CSF and IL-3 manifest distinct receptor-binding and regulatory functions compared with their full-length forms. AB - Dipeptidylpeptidase 4 (DPP4/CD26) enzymatically cleaves select penultimate amino acids of proteins, including colony-stimulating factors (CSFs), and has been implicated in cellular regulation. To better understand the role of DPP4 regulation of hematopoiesis, we analyzed the activity of DPP4 on the surface of immature blood cells and then comparatively assessed the interactions and functional effects of full-length (FL) and DPP4 truncated (T) factors (T granulocyte-macrophage-CSF (T-GM-CSF)) and T-interleukin-3 (T-IL-3)) on both in vitro and in vivo models of normal and leukemic cells. T-GM-CSF and -IL-3 had enhanced receptor binding, but decreased CSF activity, compared with their FL forms. Importantly, T-GM-CSF and -IL-3 significantly, and reciprocally, blunted receptor binding and myeloid progenitor cell proliferation activity of both FL-GM CSF and -IL-3 in vitro and in vivo. Similar effects were apparent in vitro using cluster-forming cells from patients with acute myeloid leukemia regardless of cytogenetic or molecular alterations and in vivo using animal models of leukemia. This suggests that DPP4 T-molecules have modified binding and functions compared with their FL counterparts and may serve regulatory roles in normal and malignant hematopoiesis. PMID- 28344321 TI - Broad spectrum antiviral activity for paramyxoviruses is modulated by biophysical properties of fusion inhibitory peptides. AB - Human paramyxoviruses include global causes of lower respiratory disease like the parainfluenza viruses, as well as agents of lethal encephalitis like Nipah virus. Infection is initiated by viral glycoprotein-mediated fusion between viral and host cell membranes. Paramyxovirus viral fusion proteins (F) insert into the target cell membrane, and form a transient intermediate that pulls the viral and cell membranes together as two heptad-repeat regions refold to form a six-helix bundle structure that can be specifically targeted by fusion-inhibitory peptides. Antiviral potency can be improved by sequence modification and lipid conjugation, and by adding linkers between the protein and lipid components. We exploit the uniquely broad spectrum antiviral activity of a parainfluenza F-derived peptide sequence that inhibits both parainfluenza and Nipah viruses, to investigate the influence of peptide orientation and intervening linker length on the peptides' interaction with transitional states of F, solubility, membrane insertion kinetics, and protease sensitivity. We assessed the impact of these features on biodistribution and antiviral efficacy in vitro and in vivo. The engineering approach based on biophysical parameters resulted in a peptide that is a highly effective inhibitor of both paramyxoviruses and a set of criteria to be used for engineering broad spectrum antivirals for emerging paramyxoviruses. PMID- 28344322 TI - Astragaloside IV attenuates free fatty acid-induced ER stress and lipid accumulation in hepatocytes via AMPK activation. AB - Although the pathogenesis of non-alcoholic fatty liver disease (NAFLD) is not completely understood, the increased influx of free fatty acids (FFAs) into the liver and the FFA-induced hepatic endoplasmic reticulum (ER) stress are two crucial pathogenic processes in the initiation and development of NAFLD. In this study we investigated the effects of astragaloside IV (AS-IV), a bioactive compound purified from Astragali Radix, on FFA-induced lipid accumulation in hepatocytes and elucidated the underlying mechanisms. Human HepG2 cells and primary murine hepatocytes were exposed to FFAs (1 mmol/L, oleate/palmitate, 2:1 ratio) with or without AS-IV for 24 h. Exposure to FFAs induced marked lipid accumulation in hepatocytes, whereas co-treatment with AS-IV (100 MUg/mL) significantly attenuated this phenomenon. Notably, AS-IV (50-200 MUg/mL) concentration-dependently enhanced the phosphorylation of AMPK, acetyl-CoA carboxylase (ACC) and SREBP-1c, inhibited the accumulation and nuclear translocation of mature SREBP-1 and subsequently decreased the mRNA levels of lipogenic genes including acc1, fas and scd1. AS-IV treatment also concentration dependently attenuated FFA-induced hepatic ER stress evidenced by the reduction of the key markers, GRP78, CHOP and p-PERK. Pretreated the cells with the AMPK inhibitor compound C (20 MUmol/L) greatly diminished these beneficial effects of AS-IV. Our results demonstrate that AS-IV attenuates FFA-induced ER stress and lipid accumulation in an AMPK-dependent manner in hepatocytes, which supports its use as promising therapeutics for hepatic steatosis. PMID- 28344323 TI - New knowledge of the mechanisms of sorafenib resistance in liver cancer. AB - Sorafenib is an oral multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis and promotes tumor cell apoptosis. It was approved by the FDA for the treatment of advanced renal cell carcinoma in 2006, and as a unique target drug for advanced hepatocellular carcinoma (HCC) in 2007. Sorafenib can significantly extend the median survival time of patients but only by 3-5 months. Moreover, it is associated with serious adverse side effects, and drug resistance often develops. Therefore, it is of great importance to explore the mechanisms underlying sorafenib resistance and to develop individualized therapeutic strategies for coping with these problems. Recent studies have revealed that in addition to the primary resistance, several mechanisms are underlying the acquired resistance to sorafenib, such as crosstalk involving PI3K/Akt and JAK-STAT pathways, the activation of hypoxia-inducible pathways, and epithelial-mesenchymal transition. Here, we briefly describe the function of sorafenib, its clinical application, and the molecular mechanisms for drug resistance, especially for HCC patients. PMID- 28344325 TI - The giant deep-sea octopus Haliphron atlanticus forages on gelatinous fauna. AB - Feeding strategies and predator-prey interactions of many deep-sea pelagic organisms are still unknown. This is also true for pelagic cephalopods, some of which are very abundant in oceanic ecosystems and which are known for their elaborate behaviors and central role in many foodwebs. We report on the first observations of the giant deep-sea octopus Haliphron atlanticus with prey. Using remotely operated vehicles, we saw these giant octopods holding medusae in their arms. One of the medusae could be identified as Phacellophora camtschatica (the egg-yolk jelly). Stomach content analysis confirmed predation on cnidarians and gelatinous organisms. The relationship between medusae and H. atlanticus is discussed, also in comparison with other species of the Argonautoidea, all of which have close relationships with gelatinous zooplankton. PMID- 28344326 TI - Mutual information model for link prediction in heterogeneous complex networks. AB - Recently, a number of meta-path based similarity indices like PathSim, HeteSim, and random walk have been proposed for link prediction in heterogeneous complex networks. However, these indices suffer from two major drawbacks. Firstly, they are primarily dependent on the connectivity degrees of node pairs without considering the further information provided by the given meta-path. Secondly, most of them are required to use a single and usually symmetric meta-path in advance. Hence, employing a set of different meta-paths is not straightforward. To tackle with these problems, we propose a mutual information model for link prediction in heterogeneous complex networks. The proposed model, called as Meta path based Mutual Information Index (MMI), introduces meta-path based link entropy to estimate the link likelihood and could be carried on a set of available meta-paths. This estimation measures the amount of information through the paths instead of measuring the amount of connectivity between the node pairs. The experimental results on a Bibliography network show that the MMI obtains high prediction accuracy compared with other popular similarity indices. PMID- 28344324 TI - Diallyl trisulfide suppresses tumor growth through the attenuation of Nrf2/Akt and activation of p38/JNK and potentiates cisplatin efficacy in gastric cancer treatment. AB - Diallyl trisulfide (DATS), a garlic organosulfide, has shown excellent chemopreventive potential. Cisplatin (DDP) is widely used to treat solid malignant tumors, but causing serious side effects. In the current study, we attempted to elucidate the chemopreventive mechanisms of DATS in human gastric cancer BGC-823 cells in vitro, and to investigate whether DATS could enhance the anti-tumor efficacy of DDP and improve quality of life in BGC-823 xenograft mice in vivo. Treatment with DATS (25-400 MUmol/L) dose-dependently inhibited the viability of BGC-823 cells in vitro with an IC50 of 115.2+/-4.3 MUmol/L after 24 h drug exposure. DATS (50-200 MUmol/L) induced cell cycle arrest at G2/M phase in BGC-823 cells, which correlated with significant accumulation of cyclin A2 and B1. DATS also induced BGC-823 cell apoptosis, which was accompanied by the modulation of Bcl-2 family members and caspase cascade activation. In BGC-823 xenograft mice, administration of DATS (20-40 mg.kg-1.d-1, ip) dose-dependently inhibited tumor growth and markedly reduced the number of Ki-67 positive cells in tumors. Interestingly, combined administration of DATS (30 mg.kg-1.d-1, ip) with DDP (5 mg/kg, every 5 d, ip) exhibited enhanced anti-tumor activity with fewer side effects. We showed that treatment of BGC-823 cells with DATS in vitro and in vivo significantly activated kinases such as p38 and JNK/MAPK and attenuated the Nrf2/Akt pathway. This study provides evidence that DATS exerts anticancer effects and enhances the antitumor efficacy of DDP, making it a novel candidate for adjuvant therapy for gastric cancer. PMID- 28344328 TI - Renal physiology: HCO3- reclamation in the renal proximal tubule. PMID- 28344329 TI - Glomerular disease: mTOR in FSGS. PMID- 28344330 TI - Acute kidney injury: Intravenous hydration for the prevention of CIAKI. PMID- 28344327 TI - Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells. AB - The mevalonate (MEV) cascade is responsible for cholesterol biosynthesis and the formation of the intermediate metabolites geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate (FPP) used in the prenylation of proteins. Here we show that the MEV cascade inhibitor simvastatin induced significant cell death in a wide range of human tumor cell lines, including glioblastoma, astrocytoma, neuroblastoma, lung adenocarcinoma, and breast cancer. Simvastatin induced apoptotic cell death via the intrinsic apoptotic pathway. In all cancer cell types tested, simvastatin-induced cell death was not rescued by cholesterol, but was dependent on GGPP- and FPP-depletion. We confirmed that simvastatin caused the translocation of the small Rho GTPases RhoA, Cdc42, and Rac1/2/3 from cell membranes to the cytosol in U251 (glioblastoma), A549 (lung adenocarcinoma) and MDA-MB-231(breast cancer). Simvastatin-induced Rho-GTP loading significantly increased in U251 cells which were reversed with MEV, FPP, GGPP. In contrast, simvastatin did not change Rho-GTP loading in A549 and MDA-MB-231. Inhibition of geranylgeranyltransferase I by GGTi-298, but not farnesyltransferase by FTi-277, induced significant cell death in U251, A549, and MDA-MB-231. These results indicate that MEV cascade inhibition by simvastatin induced the intrinsic apoptosis pathway via inhibition of Rho family prenylation and depletion of GGPP, in a variety of different human cancer cell lines. PMID- 28344331 TI - Basis-neutral Hilbert-space analyzers. AB - Interferometry is one of the central organizing principles of optics. Key to interferometry is the concept of optical delay, which facilitates spectral analysis in terms of time-harmonics. In contrast, when analyzing a beam in a Hilbert space spanned by spatial modes - a critical task for spatial-mode multiplexing and quantum communication - basis-specific principles are invoked that are altogether distinct from that of 'delay'. Here, we extend the traditional concept of temporal delay to the spatial domain, thereby enabling the analysis of a beam in an arbitrary spatial-mode basis - exemplified using Hermite Gaussian and radial Laguerre-Gaussian modes. Such generalized delays correspond to optical implementations of fractional transforms; for example, the fractional Hankel transform is the generalized delay associated with the space of Laguerre Gaussian modes, and an interferometer incorporating such a 'delay' obtains modal weights in the associated Hilbert space. By implementing an inherently stable, reconfigurable spatial-light-modulator-based polarization-interferometer, we have constructed a 'Hilbert-space analyzer' capable of projecting optical beams onto any modal basis. PMID- 28344333 TI - Stressor exposure has prolonged effects on colonic microbial community structure in Citrobacter rodentium-challenged mice. AB - Stressor exposure significantly affects the colonic mucosa-associated microbiota, and exacerbates Citrobacter rodentium-induced inflammation, effects that can be attenuated with probiotic Lactobacillus reuteri. This study assessed the structure of the colonic mucosa-associated microbiota in mice exposed to a social stressor (called social disruption), as well as non-stressed control mice, during challenge with the colonic pathogen C. rodentium. Mice were exposed to the social stressor or home cage control conditions for six consecutive days and all mice were challenged with C. rodentium immediately following the first exposure to the stressor. In addition, mice received probiotic L. reuteri, or vehicle as a control, via oral gavage following each stressor exposure. The stressor-exposed mice had significant differences in microbial community composition compared to non-stressed control mice. This difference was first evident following the six cycle exposure to the stressor, on Day 6 post-C. rodentium challenge, and persisted for up to 19 days after stressor termination. Mice exposed to the stressor had different microbial community composition regardless of whether they were treated with L. reuteri or treated with vehicle as a control. These data indicate that stressor exposure affects the colonic microbiota during challenge with C. rodentium, and that these effects are long-lasting and not attenuated by probiotic L. reuteri. PMID- 28344332 TI - Molecular and functional heterogeneity of early postnatal porcine satellite cell populations is associated with bioenergetic profile. AB - During postnatal development, hyperplastic and hypertrophic processes of skeletal muscle growth depend on the activation, proliferation, differentiation, and fusion of satellite cells (SC). Therefore, molecular and functional SC heterogeneity is an important component of muscle plasticity and will greatly affect long-term growth performance and muscle health. However, its regulation by cell intrinsic and extrinsic factors is far from clear. In particular, there is only minor information on the early postnatal period which is critical for muscle maturation and the establishment of adult SC pools. Here, we separated two SC subpopulations (P40/50, P50/70) from muscle of 4-day-old piglets. Our results characterize P40/50 as homogeneous population of committed (high expression of Myf5), fast-proliferating muscle progenitors. P50/70 constituted a slow proliferating phenotype and contains high numbers of differentiated SC progeny. During culture, P50/70 is transformed to a population with lower differentiation potential that contains 40% Pax7-positive cells. A reversible state of low mitochondrial activity that results from active down-regulation of ATP-synthase is associated with the transition of some of the P50/70 cells to this more primitive fate typical for a reserve cell population. We assume that P40/50 and P50/70 subpopulations contribute unequally in the processes of myofiber growth and maintenance of the SC pool. PMID- 28344334 TI - The KIF1A homolog Unc-104 is important for spontaneous release, postsynaptic density maturation and perisynaptic scaffold organization. AB - The kinesin-3 family member KIF1A has been shown to be important for experience dependent neuroplasticity. In Drosophila, amorphic mutations in the KIF1A homolog unc-104 disrupt the formation of mature boutons. Disease associated KIF1A mutations have been associated with motor and sensory dysfunctions as well as non syndromic intellectual disability in humans. A hypomorphic mutation in the forkhead-associated domain of Unc-104, unc-104bris, impairs active zone maturation resulting in an increased fraction of post-synaptic glutamate receptor fields that lack the active zone scaffolding protein Bruchpilot. Here, we show that the unc-104brismutation causes defects in synaptic transmission as manifested by reduced amplitude of both evoked and miniature excitatory junctional potentials. Structural defects observed in the postsynaptic compartment of mutant NMJs include reduced glutamate receptor field size, and altered glutamate receptor composition. In addition, we observed marked loss of postsynaptic scaffolding proteins and reduced complexity of the sub-synaptic reticulum, which could be rescued by pre- but not postsynaptic expression of unc 104. Our results highlight the importance of kinesin-3 based axonal transport in synaptic transmission and provide novel insights into the role of Unc-104 in synapse maturation. PMID- 28344336 TI - Experimental demonstration of a fully inseparable quantum state with nonlocalizable entanglement. AB - Localizability of entanglement in fully inseparable states is a key ingredient of assisted quantum information protocols as well as measurement-based models of quantum computing. We investigate the existence of fully inseparable states with nonlocalizable entanglement, that is, with entanglement which cannot be localized between any pair of subsystems by any measurement on the remaining part of the system. It is shown, that the nonlocalizable entanglement occurs already in suitable mixtures of a three-qubit GHZ state and white noise. Further, we generalize this set of states to a two-parametric family of fully inseparable three-qubit states with nonlocalizable entanglement. Finally, we demonstrate experimentally the existence of nonlocalizable entanglement by preparing and characterizing one state from the family using correlated single photons and linear optical circuit. PMID- 28344335 TI - Influenza A virus hemagglutinin and neuraminidase act as novel motile machinery. AB - Influenza A virus (IAV) membrane proteins hemagglutinin (HA) and neuraminidase (NA) are determinants of virus infectivity, transmissibility, pathogenicity, host specificity, and major antigenicity. HA binds to a virus receptor, a sialoglycoprotein or sialoglycolipid, on the host cell and mediates virus attachment to the cell surface. The hydrolytic enzyme NA cleaves sialic acid from viral receptors and accelerates the release of progeny virus from host cells. In this study, we identified a novel function of HA and NA as machinery for viral motility. HAs exchanged binding partner receptors iteratively, generating virus movement on a receptor-coated glass surface instead of a cell surface. The virus movement was also dependent on NA. Virus movement mediated by HA and NA resulted in a three to four-fold increase in virus internalisation by cultured cells. We concluded that cooperation of HA and NA moves IAV particles on a cell surface and enhances virus infection of host cells. PMID- 28344337 TI - Role of oxygen functional groups in reduced graphene oxide for lubrication. AB - Functionalized and fully characterized graphene-based lubricant additives are potential 2D materials for energy-efficient tribological applications in machine elements, especially at macroscopic contacts. Two different reduced graphene oxide (rGO) derivatives, terminated by hydroxyl and epoxy-hydroxyl groups, were prepared and blended with two different molecular weights of polyethylene glycol (PEG) for tribological investigation. Epoxy-hydroxyl-terminated rGO dispersed in PEG showed significantly smaller values of the friction coefficient. In this condition, PEG chains intercalate between the functionalized graphene sheets, and shear can take place between the PEG and rGO sheets. However, the friction coefficient was unaffected when hydroxyl-terminated rGO was coupled with PEG. This can be explained by the strong coupling between graphene sheets through hydroxyl units, causing the interaction of PEG with the rGO to be non- effective for lubrication. On the other hand, antiwear properties of hydroxyl-terminated rGO were significantly enhanced compared to epoxy-hydroxyl functionalized rGO due to the integrity of graphene sheet clusters. PMID- 28344338 TI - Monitoring of dynamic changes in Keyhole Limpet Hemocyanin (KLH)-specific B cells in KLH-vaccinated cancer patients. AB - Keyhole limpet hemocyanin (KLH) is used as an immunogenic neo-antigen for various clinical applications and during vaccine development. For advanced monitoring of KLH-based interventions, we developed a flow cytometry-based assay for the ex vivo detection, phenotyping and isolation of KLH-specific B cells. As proof-of principle, we analyzed 10 melanoma patients exposed to KLH during anti-cancer dendritic cell vaccination. Our assay demonstrated sensitive and specific detection of KLH-specific B cells in peripheral blood and KLH-specific B cell frequencies strongly correlated with anti-KLH serum antibody titers. Profiling of B cell subsets over the vaccination course revealed that KLH-specific B cells matured from naive to class-switched memory B cells, confirming the prototypic B cell response to a neo-antigen. We conclude that flow-cytometric detection and in depth phenotyping of KLH-specific B cells is specific, sensitive, and scalable. Our findings provide novel opportunities to monitor KLH-specific immune responses and serve as a blueprint for the development of new flow-cytometric protocols. PMID- 28344339 TI - The Evolution and Expression Pattern of Human Overlapping lncRNA and Protein coding Gene Pairs. AB - Long non-coding RNA overlapping with protein-coding gene (lncRNA-coding pair) is a special type of overlapping genes. Protein-coding overlapping genes have been well studied and increasing attention has been paid to lncRNAs. By studying lncRNA-coding pairs in human genome, we showed that lncRNA-coding pairs were more likely to be generated by overprinting and retaining genes in lncRNA-coding pairs were given higher priority than non-overlapping genes. Besides, the preference of overlapping configurations preserved during evolution was based on the origin of lncRNA-coding pairs. Further investigations showed that lncRNAs promoting the splicing of their embedded protein-coding partners was a unilateral interaction, but the existence of overlapping partners improving the gene expression was bidirectional and the effect was decreased with the increased evolutionary age of genes. Additionally, the expression of lncRNA-coding pairs showed an overall positive correlation and the expression correlation was associated with their overlapping configurations, local genomic environment and evolutionary age of genes. Comparison of the expression correlation of lncRNA-coding pairs between normal and cancer samples found that the lineage-specific pairs including old protein-coding genes may play an important role in tumorigenesis. This work presents a systematically comprehensive understanding of the evolution and the expression pattern of human lncRNA-coding pairs. PMID- 28344340 TI - Regulatory elements: A boost to RNA processing. PMID- 28344342 TI - Disease genomics: Transitioning from association to causation with eQTLs. PMID- 28344343 TI - Genome organization: Zooming in on nuclear organization. PMID- 28344344 TI - Detecting truly clonal alterations from multi-region profiling of tumours. AB - Modern cancer therapies aim at targeting tumour-specific alterations, such as mutations or neo-antigens, and maximal treatment efficacy requires that targeted alterations are present in all tumour cells. Currently, treatment decisions are based on one or a few samples per tumour, creating uncertainty on whether alterations found in those samples are actually present in all tumour cells. The probability of classifying clonal versus sub-clonal alterations from multi-region profiling of tumours depends on the earliest phylogenetic branching event during tumour growth. By analysing 181 samples from 10 renal carcinoma and 11 colorectal cancers we demonstrate that the information gain from additional sampling falls onto a simple universal curve. We found that in colorectal cancers, 30% of alterations identified as clonal with one biopsy proved sub-clonal when 8 samples were considered. The probability to overestimate clonal alterations fell below 1% in 7/11 patients with 8 samples per tumour. In renal cell carcinoma, 8 samples reduced the list of clonal alterations by 40% with respect to a single biopsy. The probability to overestimate clonal alterations remained as high as 92% in 7/10 renal cancer patients. Furthermore, treatment was associated with more unbalanced tumour phylogenetic trees, suggesting the need of denser sampling of tumours at relapse. PMID- 28344346 TI - Choroid plexus aquaporin 1 and intracranial pressure are increased in obese rats: towards an idiopathic intracranial hypertension model? AB - BACKGROUND/OBJECTIVES: Idiopathic intracranial hypertension (IIH) is a condition of increased intracranial pressure (ICP) without identifiable cause. The majority of IIH patients are obese, which suggests a connection between ICP and obesity. The aim of the study was to compare ICP in lean and obese rats. We also aimed to clarify if any ICP difference could be attributed to changes in some well-known ICP modulators; retinol and arterial partial pressure of CO2 (pCO2). Another potential explanation could be differences in water transport across the choroid plexus (CP) epithelia, and thus we furthermore investigated expression profiles of aquaporin 1 (AQP1) and Na/K ATPase. METHODS: ICP was measured in obese and lean Zucker rats over a period of 28 days. Arterial pCO2 and serum retinol were measured in serum samples. The CPs were isolated, and target messenger RNA (mRNA) and protein were analyzed by quantitative PCR and western blot, respectively. RESULTS: Obese rats had elevated ICP compared to lean controls on all recording days except day 0 (P<0.001). Serum retinol (P=0.35) and arterial pCO2 (P=0.16) did not differ between the two groups. Both AQP1 mRNA and protein levels were increased in the CP of the obese rats compared to lean rats (P=0.0422 and P=0.0281). There was no difference in Na/K ATPase mRNA or protein levels (P=0.2688 and P=0.1304). CONCLUSION: Obese Zucker rats display intracranial hypertension and increased AQP1 expression in CP compared to lean controls. The mechanisms behind these changes are still unknown, but appear to be unrelated to altered pCO2 levels or retinol metabolism. This indicates that the increase in ICP might be related to increased AQP1 levels in CP. Although further studies are warranted, obese Zucker rats could potentially model some aspects of the IIH pathophysiology. PMID- 28344341 TI - Functional variomics and network perturbation: connecting genotype to phenotype in cancer. AB - Proteins interact with other macromolecules in complex cellular networks for signal transduction and biological function. In cancer, genetic aberrations have been traditionally thought to disrupt the entire gene function. It has been increasingly appreciated that each mutation of a gene could have a subtle but unique effect on protein function or network rewiring, contributing to diverse phenotypic consequences across cancer patient populations. In this Review, we discuss the current understanding of cancer genetic variants, including the broad spectrum of mutation classes and the wide range of mechanistic effects on gene function in the context of signalling networks. We highlight recent advances in computational and experimental strategies to study the diverse functional and phenotypic consequences of mutations at the base-pair resolution. Such information is crucial to understanding the complex pleiotropic effect of cancer genes and provides a possible link between genotype and phenotype in cancer. PMID- 28344345 TI - Gastric bypass surgery with exercise alters plasma microRNAs that predict improvements in cardiometabolic risk. AB - BACKGROUND/OBJECTIVES: Roux-en-Y gastric bypass (RYGB) surgery improves insulin sensitivity (SI) and beta-cell function in obese non-diabetic subjects. Exercise also improves SI and may be an effective adjunct therapy to RYGB surgery. However, the mechanisms by which exercise or weight loss improve peripheral SI after RYGB surgery are unclear. We hypothesized that microRNAs (miRNAs) mediate at least some of the regulatory processes driving such mechanisms. Consequently, this work aimed at profiling plasma miRNAs in participants of the Physical Activity Following Surgery Induced Weight Loss study (clinicaltrials.gov identifier: NCT00692367), to assess whether miRNA levels track with improvements in SI and cardiometabolic risk factors. SUBJECTS/METHODS: Ninety-four miRNAs implicated in metabolism were profiled in plasma samples from 22 severely obese subjects who were recruited 1-3 months after RYGB surgery and followed for 6 months of RYGB surgery-induced weight loss, with (exercise program (EX), N=11) or without (CON, N=11) an exercise training intervention. The subjects were selected, considering a priori sample size calculations, among the participants in the parent study. Mixed-effect modeling for repeated measures and partial correlation analysis was implemented in the R environment for statistical analysis. RESULTS: Mirroring results in the parent trial, both groups experienced significant weight loss and improvements in cardiometabolic risk. In the CON group, weight loss significantly altered the pattern of circulating miR-7, miR 15a, miR-34a, miR-106a, miR-122 and miR-221. In the EX group, a distinct miRNA signature was altered: miR-15a, miR-34a, miR-122, miR-135b, miR-144, miR-149 and miR-206. Several miRNAs were significantly associated with improvements in acute insulin response, SI, and other cardiometabolic risk factors. CONCLUSIONS: These findings present novel insights into the RYGB surgery-induced molecular changes and the effects of mild exercise to facilitate and/or maintain the benefits of a 'comprehensive' weight-loss intervention with concomitant improvements in cardiometabolic functions. Notably, we show a predictive value for miR-7, miR 15a, miR-106b and miR-135b. PMID- 28344347 TI - Evolve and survive. PMID- 28344350 TI - Structural biology: In situ architecture of the type III secretion system. PMID- 28344351 TI - Viral evolution: On the origin of capsids. PMID- 28344349 TI - Microorganisms maintain crowding homeostasis. AB - Macromolecular crowding affects the mobility of biomolecules, protein folding and stability, and the association of macromolecules with each other. Local differences in crowding that arise as a result of subcellular components and supramolecular assemblies contribute to the structural organization of the cytoplasm. In this Opinion article we discuss how macromolecular crowding affects the physicochemistry of the cytoplasm and how this, in turn, affects microbial physiology. We propose that cells maintain the overall concentration of macromolecules within a narrow range and discuss possible mechanisms for achieving crowding homeostasis. In addition, we propose that the term 'homeocrowding' is used to describe the process by which cells maintain relatively constant levels of macromolecules. PMID- 28344352 TI - Bacterial physiology: When things turn sour for Helicobacter. PMID- 28344353 TI - Environmental microbiology: Is evidence for ancient microbial life set in stone? PMID- 28344348 TI - Metal homeostasis and resistance in bacteria. AB - Metal ions are essential for many reactions, but excess metals can be toxic. In bacteria, metal limitation activates pathways that are involved in the import and mobilization of metals, whereas excess metals induce efflux and storage. In this Review, we highlight recent insights into metal homeostasis, including protein based and RNA-based sensors that interact directly with metals or metal containing cofactors. The resulting transcriptional response to metal stress takes place in a stepwise manner and is reinforced by post-transcriptional regulatory systems. Metal limitation and intoxication by the host are evolutionarily ancient strategies for limiting bacterial growth. The details of the resulting growth restriction are beginning to be understood and seem to be organism-specific. PMID- 28344355 TI - Increased soil nutrition and decreased light intensity drive species loss after eight years grassland enclosures. AB - Enclosures (fenced, grazing or clipping) within a certain period of years are the most common tools for restoration of degraded grasslands in temperate regions. Short-term enclosures can improve biodiversity and productivity by effectively relieving grazing pressure, while long-term enclosures can reduce species diversity. We therefore carried out a field experiment to investigate the specific causes of the reduced species diversity in Hulunbeier grassland of northern China. After eight years of enclosure, the significantly increased soil available nitrogen (AN) and available phosphorus (AvP) in enclosure community reduced nitrogen (N) limitation but most vegetation was still N limited. Many environmental factors led to decreased species richness, but increased soil AN and decreased light intensity at the community bottom were the most significant ones. Community density decreased independently of soil nutrition but significantly related to decreased species richness. Density of dominant canopy species increased, while dominant understory species decreased during assemblage level thinning; therefore, the random-loss hypothesis was not supported. The dominant understory species responded to lower light availability by increasing their height, leaf area, and chlorophyll content. Moreover, our results were expected to provide some specific guidance for the restoration mode selection of degraded grasslands in northern China. PMID- 28344354 TI - HDAC1-3 inhibitor MS-275 enhances IL10 expression in RAW264.7 macrophages and reduces cigarette smoke-induced airway inflammation in mice. AB - Chronic obstructive pulmonary disease (COPD) constitutes a major health burden. Studying underlying molecular mechanisms could lead to new therapeutic targets. Macrophages are orchestrators of COPD, by releasing pro-inflammatory cytokines. This process relies on transcription factors such as NF-kappaB, among others. NF kappaB is regulated by lysine acetylation; a post-translational modification installed by histone acetyltransferases and removed by histone deacetylases (HDACs). We hypothesized that small molecule HDAC inhibitors (HDACi) targeting class I HDACs members that can regulate NF-kappaB could attenuate inflammatory responses in COPD via modulation of the NF-kappaB signaling output. MS-275 is an isoform-selective inhibitor of HDAC1-3. In precision-cut lung slices and RAW264.7 macrophages, MS-275 upregulated the expression of both pro- and anti-inflammatory genes, implying mixed effects. Interestingly, anti-inflammatory IL10 expression was upregulated in these model systems. In the macrophages, this was associated with increased NF-kappaB activity, acetylation, nuclear translocation, and binding to the IL10 promoter. Importantly, in an in vivo model of cigarette smoke exposed C57Bl/6 mice, MS-275 robustly attenuated inflammatory expression of KC and neutrophil influx in the lungs. This study highlights for the first time the potential of isoform-selective HDACi for the treatment of inflammatory lung diseases like COPD. PMID- 28344356 TI - Methylation status as a predictor of intravesical Bacillus Calmette-Guerin (BCG) immunotherapy response of high grade non-muscle invasive bladder tumor. AB - BACKGROUND AND AIMS: Genetic and epigenetic alterations play an important role in urothelial cancer pathogenesis. Deeper understanding of these processes could help us achieve better diagnosis and management of this life-threatening disease. The aim of this research was to evaluate the methylation status of selected tumor suppressor genes for predicting BCG response in patients with high grade non muscle-invasive bladder tumor (NMIBC). MATERIALS AND METHODS: We retrospectively evaluated 82 patients with high grade non-muscle-invasive bladder tumor (stage Ta, T1, CIS) who had undergone BCG instillation therapy. We compared epigenetic methylation status in BCG-responsive and BCG-failure groups. We used the MS-MLPA (Methylation-Specific Multiplex Ligation-Dependent Probe Amplification probe sets ME001 and ME004. The control group was 13 specimens of normal urotel (bladder tissue)). RESULTS: Newly identified methylations in high grade NMIBC were found in MUS81a, NTRK1 and PCCA. The methylation status of CDKN2B (P=0.00312**) and MUS81a (P=0.0191*) is associated with clinical outcomes of BCG instillation therapy response. CDKN2B and MUS81a unmethylation was found in BCG failure patients. CONCLUSION: The results show that the methylation status of selected tumor suppressor genes (TSGs) has the potential for predicting BCG response in patients with NMIBC high grade tumors. Tumor suppressor genes such as CDKN2b, MUS81a, PFM-1, MSH6 and THBS1 are very promising for future research. PMID- 28344358 TI - How Social Preferences Shape Incentives in (Experimental) Markets for Credence Goods. AB - Credence goods markets suffer from inefficiencies caused by superior information of sellers about the surplus-maximising quality. While standard theory predicts that equal mark-up prices solve the credence goods problem if customers can verify the quality received, experimental evidence indicates the opposite. We identify a lack of robustness with respect to heterogeneity in social preferences as a possible cause of this and conduct new experiments that allow for parsimonious identification of sellers' social preference types. Our results confirm the assumed heterogeneity in social preferences and provide strong support for our explanation of the failure of verifiability to increase efficiency. PMID- 28344359 TI - Privacy and Security in Mobile Health: A Research Agenda. AB - Mobile health technology has great potential to increase healthcare quality, expand access to services, reduce costs, and improve personal wellness and public health. However, mHealth also raises significant privacy and security challenges. PMID- 28344360 TI - Smoking Trajectories Among Monoracial and Biracial Black Adolescents and Young Adults. AB - INTRODUCTION: Cigarette smoking trajectories were assessed among monorace Blacks, Black-American Indians, Black-Asians, Black-Hispanics, and Black-Whites. METHOD: We used a subsample of nationally representative data obtained from the National Longitudinal Study of Adolescent Health (Add Health). The sample consisted of adolescents who were in Grades 7 - 12 in 1994, and followed across four waves of data collection into adulthood. Wave 4 data were collected in 2007-2008 when most respondents were between 24 and 32 years old. Respondents could report more than one race/ethnicity. Poisson regression was used to analyze the data. RESULTS: We found distinct smoking trajectories among monorace and biracial/ethnic Blacks, with all groups eventually equaling or surpassing trajectories of Whites. The age of cross-over varied by gender for some subgroups, with Black-American Indian males catching up earlier than Black-American Indian females. Black-White females smoked on more days than monorace Black females until age 26 and also smoked more than Black-White males between ages 11 and 29 years. Black-Hispanic males smoked on more days than Black-Hispanic females from ages 11 to 14. The results of the interaction tests also indicated different smoking trajectories across SES levels among White, Black, and Black-White respondents. CONCLUSION: Significant heterogeneity was observed regarding smoking trajectories between monoracel and biracial/ethnic Blacks. Knowledge of cigarette smoking patterns among monorace and biracial/ethnic Black youth and young adults extends our understanding of the etiology of tobacco use and may inform interventions. PMID- 28344357 TI - Quantum Dot Surface Engineering: Toward Inert Fluorophores with Compact Size and Bright, Stable Emission. AB - The surfaces of colloidal nanocrystals are complex interfaces between solid crystals, coordinating ligands, and liquid solutions. For fluorescent quantum dots, the properties of the surface vastly influence the efficiency of light emission, stability, and physical interactions, and thus determine their sensitivity and specificity when they are used to detect and image biological molecules. But after more than 30 years of study, the surfaces of quantum dots remain poorly understood and continue to be an important subject of both experimental and theoretical research. In this article, we review the physics and chemistry of quantum dot surfaces and describe approaches to engineer optimal fluorescent probes for applications in biomolecular imaging and sensing. We describe the structure and electronic properties of crystalline facets, the chemistry of ligand coordination, and the impact of ligands on optical properties. We further describe recent advances in compact coatings that have significantly improved their properties by providing small hydrodynamic size, high stability and fluorescence efficiency, and minimal nonspecific interactions with cells and biological molecules. While major progress has been made in both basic and applied research, many questions remain in the chemistry and physics of quantum dot surfaces that have hindered key breakthroughs to fully optimize their properties. PMID- 28344361 TI - The interaction of fluorescent nanodiamond probes with cellular media. AB - Fluorescent nanodiamonds (FNDs) are promising tools to image cells, bioanalytes and physical quantities such as temperature, pressure, and electric or magnetic fields with nanometer resolution. To exploit their potential for intracellular applications, the FNDs have to be brought into contact with cell culture media. The interactions between the medium and the diamonds crucially influence sensitivity as well as the ability to enter cells. The authors demonstrate that certain proteins and salts spontaneously adhere to the FNDs and may cause aggregation. This is a first investigation on the fundamental questions on how (a) FNDs interact with the medium, and (b) which proteins and salts are being attracted. A differentiation between strongly binding and weakly binding proteins is made. Not all proteins participate in the formation of FND aggregates. Surprisingly, some main components in the medium seem to play no role in aggregation. Simple strategies to prevent aggregation are discussed. These include adding the proteins, which are naturally present in the cell culture to the diamonds first and then inserting them in the full medium. Graphical abstractSchematic of the interaction of nanodiamonds with cell culture medium. Certain proteins and salts adhere to the diamond surface and lead to aggregation or to formation of a protein corona. PMID- 28344362 TI - Positive serum ethanol concentration on admission to hospital as the factor predictive of treatment outcome in acute methanol poisoning. AB - ABSTRACT: Mass methanol poisonings present a serious problem for health systems worldwide, with poor outcome associated with delayed treatment. Positive pre hospital serum ethanol concentration may have predictive value as the prognostic factor of the treatment outcome. We studied the effect of positive serum ethanol level on admission to hospital on survival in patients treated during the Czech methanol outbreak during 2012-2014. Cross-sectional cohort study was performed in 100 hospitalized patients with confirmed methanol poisoning. Pre-hospital ethanol was administered in 42 patients (by paramedic/medical staff to 30 patients and self-administered by 12 patients before admission); 58 patients did not receive pre-hospital ethanol. Forty-two patients had detectable serum ethanol concentration on admission to hospital [median 18.3 (IQR 6.6-32.2) mmol dm-3]. Pre-hospital ethanol administration by paramedic/medical staff had a significant effect on survival without visual and CNS sequelae when adjusted for arterial blood pH on admission (OR 8.73; 95 % CI 3.57-21.34; p < 0.001). No patients receiving pre-hospital ethanol died compared with 21 not receiving (p < 0.001). Positive serum ethanol concentration on admission to hospital was a predictor for survival without health sequelae when adjusted for arterial blood pH (OR 8.10; 95 % CI 2.85-23.02; p < 0.001). The probability of visual and CNS sequelae in survivors reduced with increasing serum ethanol concentration on admission. GRAPHICAL ABSTRACT: PMID- 28344363 TI - Electrochemical determination of closantel in the commercial formulation by square-wave adsorptive stripping voltammetry. AB - ABSTRACT: In this paper, the square-wave adsorptive stripping voltammetric (SWAdSV) determination of the veterinary drug closantel using a renewable silver amalgam film electrode (Hg(Ag)FE) is presented. As observed in SWAdSV, closantel provided one well-shaped reduction peak suitable for analytical purposes at potential ca. -1.4 V in the Britton-Robinson (B-R) buffer at pH 7.0. At optimal conditions, the SWAdSV response of Hg(Ag)FE for determining closantel was linear over two concentration ranges of 5.0 * 10-8 to 2.0 * 10-7 mol dm-3 and 2.0 * 10-7 to 1.2 * 10-6 mol dm-3 with a detection limit of 1.1 * 10-8 mol dm-3. In addition, a relevance of the developed SWAdSV method was successfully verified by the quantitative analysis of closantel in the commercial formulation Closamectin Pour-On with satisfactory results (RSD = 5.8%, recovery = 101.8%). The results showed that the developed procedure can be adequate for screening purposes. Also, the electrochemical behavior of closantel was characterized by cyclic voltammetry, and it was found that closantel exhibited a quasi-reversible behavior with cathodic peak on the forward scan at ca. -1.4 V and anodic peak on the reverse scan at ca. -1.35 V vs. Ag/AgCl in B-R buffer, pH 7.0. As the obtained results showed that the electrode mechanism of closantel is controlled by the adsorption, the effect of adsorption was studied using the electrochemical impedance spectroscopy technique. GRAPHICAL ABSTRACT: PMID- 28344364 TI - Improved electroanalytical characteristics for flumetralin determination in the presence of surface active compound. AB - ABSTRACT: The use of square wave voltammetry (SWV) and square wave adsorptive stripping voltammetry (SWAdSV) in conjunction with a cyclic renewable silver amalgam film electrode for the determination of flumetralin is presented. Poor separation of two overlapped reduction peaks is significantly improved when hexadecyltrimethylammonium bromide is used as a component of the supporting electrolyte solution (together with BR buffer pH 9.5). The SW technique parameters were investigated and found optimal as follows: frequency 50 Hz, amplitude 40 mV, and step potential 5 mV. Accumulation time and potential were studied to select the optimal conditions in adsorptive voltammetry. The analytical curve was linear for the flumetralin concentration range from 1.0 * 10 6 to 1.0 * 10-5 mol dm-3 and from 5.0 * 10-9 to 1.0 * 10-7 mol dm-3 for SWV and SWAdSV, respectively. Detection limit of 6.5 * 10-10 mol dm-3 was calculated for accumulation time 60 s at -0.2 V. The repeatability of the method was determined at a flumetralin concentration level equal to 5.0 * 10-9 mol dm-3 and expressed as %RSD = 5.0% (n = 6). The proposed method was applied and validated successfully by studying the recovery of herbicide content in spiked environmental samples. GRAPHICAL ABSTRACT: PMID- 28344365 TI - Synthesizing Results From Empirical Research on Computer-Based Scaffolding in STEM Education: A Meta-Analysis. AB - Computer-based scaffolding assists students as they generate solutions to complex problems, goals, or tasks, helping increase and integrate their higher order skills in the process. However, despite decades of research on scaffolding in STEM (science, technology, engineering, and mathematics) education, no existing comprehensive meta-analysis has synthesized the results of these studies. This review addresses that need by synthesizing the results of 144 experimental studies (333 outcomes) on the effects of computer-based scaffolding designed to assist the full range of STEM learners (primary through adult education) as they navigated ill-structured, problem-centered curricula. Results of our random effect meta-analysis (a) indicate that computer-based scaffolding showed a consistently positive (g = 0.46) effect on cognitive outcomes across various contexts of use, scaffolding characteristics, and levels of assessment and (b) shed light on many scaffolding debates, including the roles of customization (i.e., fading and adding) and context-specific support. Specifically, scaffolding's influence on cognitive outcomes did not vary on the basis of context-specificity, presence or absence of scaffolding change, and logic by which scaffolding change is implemented. Scaffolding's influence was greatest when measured at the principles level and among adult learners. Still scaffolding's effect was substantial and significantly greater than zero across all age groups and assessment levels. These results suggest that scaffolding is a highly effective intervention across levels of different characteristics and can largely be designed in many different ways while still being highly effective. PMID- 28344366 TI - Mercury in Feathers and Blood of Gulls from the Southern Baltic Coast, Poland. AB - Gulls were assessed as sentinels of contamination in the coastal zone of the Southern Baltic, research material being obtained from dead birds collected on Polish beaches and near fishing ports in 2009-2012. In feathers and blood of four gull species: herring gull (Larus argentatus), common gull (Larus canus), black headed gull (Chroicocephalus ridibundus), and great black-backed gull (Larus marinus), concentration of total mercury (HgT) was assayed, taking into account the type of feathers, sex, and age. Stable isotopes (delta15N, delta13C) were used as tracers of trophic position in the food web. In the study, feathers and blood were compared as non-invasive indicators of alimentary exposure introducing mercury into the system. In order to do that, the correlations between mercury concentrations in the blood, feathers, and the birds' internal tissues were examined. The strongest relations were observed in the liver for each species R2Common Gull = 0.94, p = 0.001; R2Black-headed Gull = 0.89, p = 0.001; R2Great Black-backed Gull = 0.53, p = 0.001; R2Herring Gull = 0.78, p = 0.001. While no correlation was found with feathers, only developing feathers of juvenile herring gulls were found to be a good indicator immediate of exposure through food (R2muscle = 0.71, p = 0.001; R2kidneys = 0.73, p = 0.001; R2heart = 0.89, p = 0.001; R2lungs = 0.86, p = 0.001; R2brain = 0.83, p = 0.001). Additionally, based on studies of herring gull primary feathers, decrease of mercury concentration in the diet of birds over the last two decades is also discussed. PMID- 28344367 TI - Cross-Saharan transport of water vapor via recycled cold pool outflows from moist convection. AB - Very sparse data have previously limited observational studies of meteorological processes in the Sahara. We present an observed case of convectively driven water vapor transport crossing the Sahara over 2.5 days in June 2012, from the Sahel in the south to the Atlas in the north. A daily cycle is observed, with deep convection in the evening generating moist cold pools that fed the next day's convection; the convection then generated new cold pools, providing a vertical recycling of moisture. Trajectories driven by analyses were able to capture the direction of the transport but not its full extent, particularly at night when cold pools are most active, and analyses missed much of the water content of cold pools. The results highlight the importance of cold pools for moisture transport, dust and clouds, and demonstrate the need to include these processes in models in order to improve the representation of Saharan atmosphere. PMID- 28344368 TI - The Decline of Arranged Marriage? Marital Change and Continuity in India. AB - This article evaluates whether arranged marriage declined in India from 1970 to 2012. Specifically, the authors examine trends in spouse choice, the length of time spouses knew each other prior to marriage, intercaste marriage, and consanguineous marriage at the national level, as well as by region, urban residence, and religion/caste. During this period, women were increasingly active in choosing their own husbands, spouses meeting on their wedding day decreased, intercaste marriage rose, and consanguineous marriage fell. However, many of these changes were modest in size and substantial majorities of recent marriages still show the hallmarks of arranged marriage. Further, instead of displacing parents, young women increasingly worked with parents to choose husbands collectively. Rather than unilateral movement towards Western marriage practices, as suggested by theories of family change and found in other Asian contexts, these trends point to a hybridization of customary Western and Indian practices. PMID- 28344369 TI - Approach-avoidance of facial affect is moderated by the presence of an observer irrelevant trigger. AB - This study examined whether approach-avoidance related behaviour elicited by facial affect is moderated by the presence of an observer-irrelevant trigger that may influence the observer's attributions of the actor's emotion. Participants were shown happy, disgusted, and neutral facial expressions. Half of these were presented with a plausible trigger of the expression (a drink). Approach avoidance related behaviour was indexed explicitly through a questionnaire (measuring intentions) and implicitly through a manikin version of the affective Simon task (measuring automatic behavioural tendencies). In the absence of an observer-irrelevant trigger, participants expressed the intention to avoid disgusted and approach happy facial expressions. Participants also showed a stronger approach tendency towards happy than towards disgusted facial expressions. The presence of the observer-irrelevant trigger had a moderating effect, decreasing the intention to approach happy and to avoid disgusted expressions. The trigger had no moderating effect on the approach-avoidance tendencies. Thus the influence of an observer-irrelevant trigger appears to reflect more of a controlled than automatic process. PMID- 28344371 TI - DeepDive: Declarative Knowledge Base Construction. AB - The dark data extraction or knowledge base construction (KBC) problem is to populate a SQL database with information from unstructured data sources including emails, webpages, and pdf reports. KBC is a long-standing problem in industry and research that encompasses problems of data extraction, cleaning, and integration. We describe DeepDive, a system that combines database and machine learning ideas to help develop KBC systems. The key idea in DeepDive is that statistical inference and machine learning are key tools to attack classical data problems in extraction, cleaning, and integration in a unified and more effective manner. DeepDive programs are declarative in that one cannot write probabilistic inference algorithms; instead, one interacts by defining features or rules about the domain. A key reason for this design choice is to enable domain experts to build their own KBC systems. We present the applications, abstractions, and techniques of DeepDive employed to accelerate construction of KBC systems. PMID- 28344370 TI - Effectiveness of an Intervention for Children with Externalizing Behavior and Mild to Borderline Intellectual Disabilities: A Randomized Trial. AB - This study evaluated the effectiveness of Standing Strong Together (SST), a combined group based parent and child intervention for externalizing behavior in 9-16 year-old children with mild to borderline intellectual disabilities (MBID). Children with externalizing behavior and MBID (IQ from 55 to 85) (N = 169) were cluster randomly assigned to SST combined with care as usual or to care as usual only. SST led to a significant benefit on teacher reported but not on parent reported externalizing behavior. SST had significant effects on parent rated positive parenting and the parent-child relationship. The present study shows that a multicomponent group based intervention for children with MBID is feasible and has the potential to reduce children's externalizing behavior and improve both parenting behavior and the parent-child relationship. PMID- 28344372 TI - Radicals and molecular products from the gas-phase pyrolysis of lignin model compounds. Cinnamyl alcohol. AB - The experimental results on detection and identification of intermediate radicals and molecular products from gas-phase pyrolysis of cinnamyl alcohol (CnA), the simplest non-phenolic lignin model compound, over the temperature range of 400 800 degrees C are reported. The low temperature matrix isolation - electron paramagnetic resonance (LTMI-EPR) experiments along with the theoretical calculations, provided evidences on the generation of the intermediate carbon and oxygen centered as well as oxygen-linked, conjugated radicals. A mechanistic analysis is performed based on density functional theory to explain formation of the major products from CnA pyrolysis; cinnamaldehyde, indene, styrene, benzaldehyde, 1-propynyl benzene, and 2-propenyl benzene. The evaluated bond dissociation patterns and unimolecular decomposition pathways involve dehydrogenation, dehydration, 1,3-sigmatropic H-migration, 1,2-hydrogen shift, C O and C-C bond cleavage processes. PMID- 28344373 TI - Fertility Decline, Gender Composition of Families, and Expectations of Old Age Support. AB - Recent fertility declines in non-Western countries may have the potential to transform gender systems. One pathway for such transformations is the creation of substantial proportions of families with children of only one gender. Such families, particularly those with only daughters, may facilitate greater symmetry between sons and daughters. This article explores whether such shifts may influence gendered expectations of old age support. In keeping with patriarchal family systems, old age support is customarily provided by sons, but not daughters, in India. Using data from the 2005 Indian Human Development Survey, I find that women with sons overwhelmingly expect old age support from a son. By contrast, women with only daughters largely expect support from a daughter or a source besides a child. These findings suggest that fertility decline may place demographic pressure on gendered patterns of old age support and the gender system more broadly. PMID- 28344374 TI - Visibility Equalizer Cutaway Visualization of Mesoscopic Biological Models. AB - In scientific illustrations and visualization, cutaway views are often employed as an effective technique for occlusion management in densely packed scenes. We propose a novel method for authoring cutaway illustrations of mesoscopic biological models. In contrast to the existing cutaway algorithms, we take advantage of the specific nature of the biological models. These models consist of thousands of instances with a comparably smaller number of different types. Our method constitutes a two stage process. In the first step, clipping objects are placed in the scene, creating a cutaway visualization of the model. During this process, a hierarchical list of stacked bars inform the user about the instance visibility distribution of each individual molecular type in the scene. In the second step, the visibility of each molecular type is fine-tuned through these bars, which at this point act as interactive visibility equalizers. An evaluation of our technique with domain experts confirmed that our equalizer based approach for visibility specification was valuable and effective for both, scientific and educational purposes. PMID- 28344375 TI - Political liberalism and religious claims: Four blind spots. AB - This article gives an overview of 4 important lacunae in political liberalism and identifies, in a preliminary fashion, some trends in the literature that can come in for support in filling these blind spots, which prevent political liberalism from a correct assessment of the diverse nature of religious claims. Political liberalism operates with implicit assumptions about religious actors being either 'liberal' or 'fundamentalist' and ignores a third, in-between group, namely traditionalist religious actors and their claims. After having explained what makes traditionalist religious actors different from liberal and fundamentalist religious actors, the author develops 4 areas in which political liberalism should be pushed further theoretically in order to correctly theorize the challenge which traditional religious actors pose to liberal democracy. These 4 areas (blind spots) are: (1) the context of translation; (2) the politics of exemptions; (3) the multivocality of theology; and (4) the transnational nature of norm-contestation. PMID- 28344376 TI - Verification measurements of the IRMM-1027 and the IAEA large-sized dried (LSD) spikes. AB - In the frame of the accountancy measurements of the fissile materials, reliable determinations of the plutonium and uranium content in spent nuclear fuel are required to comply with international safeguards agreements. Large-sized dried (LSD) spikes of enriched 235U and 239Pu for isotope dilution mass spectrometry (IDMS) analysis are routinely applied in reprocessing plants for this purpose. A correct characterisation of these elements is a pre-requirement for achieving high accuracy in IDMS analyses. This paper will present the results of external verification measurements of such LSD spikes performed by the European Commission and the International Atomic Energy Agency. PMID- 28344377 TI - Effect of nitrogen compounds on transport of ruthenium through the RCS. AB - Ruthenium is a fission product that can be released from the fuel in case of a severe nuclear accident. In this work the impact of the atmosphere composition, including air radiolysis products, on the transport of ruthenium through a primary circuit was examined. Experiments were performed at temperatures 1300, 1500 and 1700 K in a slightly humid air. In the experiments significant effect of nitrogen oxides (N2O, NO2) and nitric acid on the ruthenium chemistry in the model primary circuit was observed. The obtained results indicate a strong effect of air radiolysis products on the quantity partitioning of transported ruthenium to gaseous and aerosol compounds. PMID- 28344379 TI - "Would You Do That in Your Home?" Making Nursing Homes Home-like in Culture Change Implementation. AB - Qualitative interviews with nursing home administrators reveal innovative and cost-conscious ways to physically modify facilities that help institute culture change practices. Telephone interviews were conducted following a national survey of nursing home nursing directors and administrators. In this cross-sectional snapshot of administrator experiences, motivations for making facilities more home-like and less institutional and creative responses to challenges are described. State and corporate support and regulator encouragement are noted that help their reform efforts. Administrators note that small steps to create a more home-like environment can result in a positive impact that minimizes disruption to existing care processes. They describe how they respond to challenges, such as the physical plant and high costs, and note how comparative shopping, cost conscious physical improvements, and continuous involvement of staff and residents contribute to successful efforts. Their examples illustrate novel ways to humanize long-term care facilities that other nursing homes can emulate. PMID- 28344378 TI - The long and the short of it: a global analysis of hawkmoth pollination niches and interaction networks. AB - 1. Proboscis length has been proposed as a key dimension of plant pollination niches, but this niche space has not previously been explored at regional and global scales for any pollination system. Hawkmoths are ideal organisms for exploring pollinator niches as they are important pollinators in most of the biodiverse regions of the earth and vary greatly in proboscis length, with some species having the longest proboscides of all insects. 2. Using datasets for nine biogeographical regions spanning the Old and New World, we ask whether it is possible to identify distinct hawkmoth pollination niches based on the frequency distribution of proboscis length, and whether these niches are reflected in the depths of flowers that are pollinated by hawkmoths. We also investigate the levels of specialization in hawkmoth pollination systems at the regional and community level using data from interaction network studies. 3. We found that most regional hawkmoth assemblages have bimodal or multimodal distributions of proboscis length, and that these are matched by similar distributions of floral tube lengths. Hawkmoths, particularly those with longer proboscides, are polyphagous and at the network level show foraging specialization equivalent to or less than that of bees and hummingbirds. In the case of plants, shorter-tubed flowers are usually visited by numerous hawkmoth species, while those that are longer-tubed tend to exclude shorter-proboscid hawkmoths and thus become ecologically specialized on longer-proboscid hawkmoth species. Longer-tubed flowers tend to have greater nectar rewards and this promotes short-term constancy by long-proboscid hawkmoths. 4. Our results show that pollinator proboscis length is a key niche axis for plants and can account for patterns of evolution in functional traits such as floral tube length and nectar volume. We also highlight a paradoxical trend for nectar resource niche breadth to increase according to proboscis length of pollinators, while pollinator niche breadth decreases according to the tube length of flowers. PMID- 28344380 TI - Time is money: Rational life cycle inertia and the delegation of investment management. AB - Many households display inertia in investment management over their life cycles. Our calibrated dynamic life cycle portfolio choice model can account for such an apparently 'irrational' outcome, by incorporating the fact that investors must forgo acquiring job-specific skills when they spend time managing their money, and their efficiency in financial decision making varies with age. Resulting inertia patterns mesh well with findings from prior studies and our own empirical results from Panel Study of Income Dynamics (PSID) data. We also analyze how people optimally choose between actively managing their assets versus delegating the task to financial advisors. Delegation proves valuable to both the young and the old. Our calibrated model quantifies welfare gains from including investment time and money costs as well as delegation in a life cycle setting. PMID- 28344381 TI - Shame and Guilt-Proneness as Mediators of Associations Between General Causality Orientations and Depressive Symptoms. AB - The present study examined the roles of shame- and guilt-proneness as mediators of associations between general causality orientations and depressive symptoms. We expected autonomy would be associated with less depressive symptoms based on higher guilt-proneness and lower shame-proneness, whereas control would be associated with more depressive symptoms based on lower guilt-proneness and higher shame-proneness. Undergraduates (N = 354) completed assessments of general causality orientations, shame- and guilt-proneness, and depressive symptoms in exchange for extra credit. Results of mediation analyses were generally supportive of the framework indicating that shame- and guilt-proneness mediate associations between self-determination and depressive symptoms. Autonomy was indirectly associated with less depressive symptoms through positive associations with guilt-proneness, in spite of unexpected positive associations with shame proneness. Control and impersonal orientation were indirectly associated with more depressive symptoms through positive associations with shame-proneness. Results extend previous research relating self-determination to mental health in providing preliminary support suggesting that individual differences in self determination facilitate differential tendencies in experiencing guilt and shame. PMID- 28344382 TI - An Extended Kalman Filter to Estimate Human Gait Parameters and Walking Distance. AB - In this work, we present a novel method to estimate joint angles and distance traveled by a human while walking. We model the human leg as a two-link revolute robot. Inertial measurement sensors placed on the thigh and shin provide the required measurement inputs. The model and inputs are then used to estimate the desired state parameters associated with forward motion using an extended Kalman filter (EKF). Experimental results with subjects walking in a straight line show that distance walked can be measured with accuracy comparable to a state of the art motion tracking systems. The EKF had an average RMSE of 7 cm over the trials with an average accuracy of greater than 97% for linear displacement. PMID- 28344383 TI - Spectroscopic properties of poly(9,9-dioctylfluorene) thin films possessing varied fractions of beta-phase chain segments: enhanced photoluminescence efficiency via conformation structuring. AB - Poly(9,9-dioctylfluorene) (PFO) is a widely studied blue-emitting conjugated polymer, the optoelectronic properties of which are strongly affected by the presence of a well-defined chain-extended "beta-phase" conformational isomer. In this study, optical and Raman spectroscopy are used to systematically investigate the properties of PFO thin films featuring a varied fraction of beta-phase chain segments. Results show that the photoluminescence quantum efficiency (PLQE) of PFO films is highly sensitive to both the beta-phase fraction and the method by which it was induced. Notably, a PLQE of ~69% is measured for PFO films possessing a ~6% beta-phase fraction induced by immersion in solvent/nonsolvent mixtures; this value is substantially higher than the average PLQE of ~55% recorded for other beta-phase films. Furthermore, a linear relationship is observed between the intensity ratios of selected Raman peaks and the beta-phase fraction determined by commonly used absorption calibrations, suggesting that Raman spectroscopy can be used as an alternative means to quantify the beta-phase fraction. As a specific example, spatial Raman mapping is used to image a mm scale beta-phase stripe patterned in a glassy PFO film, with the extracted beta phase fraction showing excellent agreement with the results of optical spectroscopy. (c) 2016 The Authors. Journal of Polymer Science Part B: Polymer Physics Published by Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2016, 54, 1995-2006. PMID- 28344384 TI - Ferroelectric switching and electrochemistry of pyrrole substituted trialkylbenzene-1,3,5-tricarboxamides. AB - We explore a new approach to organic ferroelectric diodes using a benzene tricarboxamide (BTA) core connected with C10 alkyl chains to pyrrole groups, which can be polymerized to provide a semiconducting ferroelectric material. The compound possesses a columnar hexagonal liquid crystalline (LC) phase and exhibits ferroelectric switching. At low switching frequencies, an additional process occurs, which leads to a high hysteretic charge density of up to ~1000 mC/m2. Based on its slow rate, the formation of gas bubbles, and the emergence of characteristic polypyrrole absorption bands in the UV-Vis-NIR, the additional process is identified as the oxidative polymerization of pyrrole groups, enabled by the presence of amide groups. Polymerization of the pyrrole groups, which is essential to obtain semiconductivity, is limited to thin layers at the electrodes, amounting to ~17 nm after cycling for 21 h. (c) 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2017, 55, 673-683. PMID- 28344385 TI - A Dynamical Modeling Approach for Analysis of Longitudinal Clinical Trials in the Presence of Missing Endpoints. AB - Randomized longitudinal clinical trials are the gold standard to evaluate the effectiveness of interventions among different patient treatment groups. However, analysis of such clinical trials becomes difficult in the presence of missing data, especially in the case where the study endpoints become difficult to measure because of subject dropout rates or/and the time to discontinue the assigned interventions are different among the patient groups. Here we report on using a validated mathematical model combined with an inverse problem approach to predict the values for the missing endpoints. A small randomized HIV clinical trial where endpoints for most of patients are missing is used to demonstrate this approach. PMID- 28344386 TI - The sound of cooperation: Musical influences on cooperative behavior. AB - Music as an environmental aspect of professional workplaces has been closely studied with respect to consumer behavior while sparse attention has been given to its relevance for employee behavior. In this article, we focus on the influence of music upon cooperative behavior within decision-making groups. Based on results from two extended 20-round public goods experiments, we find that happy music significantly and positively influences cooperative behavior. We also find a significant positive association between mood and cooperative behavior. Consequently, while our studies provide partial support for the relevance of affect in relation to cooperation within groups, we also show an independently important function of happy music that fits with a theory of synchronous and rhythmic activity as a social lubricant. More generally, our findings indicate that music and perhaps other atmospheric variables that are designed to prime consumer behavior might have comparably important effects for employees and consequently warrant closer investigation. PMID- 28344388 TI - Isolation and purification of all-trans diadinoxanthin and all-trans diatoxanthin from diatom Phaeodactylum tricornutum. AB - Two diatom-specific carotenoids are engaged in the diadinoxanthin cycle, an important mechanism which protects these organisms against photoinhibition caused by absorption of excessive light energy. A high-performance and economical procedure of isolation and purification of diadinoxanthin and diatoxanthin from the marine diatom Phaeodactylum tricornutum using a four-step procedure has been developed. It is based on the use of commonly available materials and does not require advanced technology. Extraction of pigments, saponification, separation by partition and then open column chromatography, which comprise the complete experimental procedure, can be performed within 2 days. This method allows HPLC grade diadinoxanthin and diatoxanthin of a purity of 99 % or more to be obtained, and the efficiency was estimated to be 63 % for diadinoxanthin and 73 % for diatoxanthin. Carefully selected diatom culture conditions as well as analytical ones ensure highly reproducible performance. A protocol can be used to isolate and purify the diadinoxanthin cycle pigments both on analytical and preparative scale. PMID- 28344387 TI - Coordination chemistry insights into the role of alkali metal promoters in dinitrogen reduction. AB - The Haber-Bosch process is a major contributor to fixed nitrogen that supports the world's nutritional needs and is one of the largest-scale industrial processes known. It has also served as a testing ground for chemists' understanding of surface chemistry. Thus, it is significant that the most thoroughly developed catalysts for N2 reduction use potassium as an electronic promoter. In this review, we discuss the literature on alkali metal cations as promoters for N2 reduction, in the context of the growing knowledge about cooperative interactions between N2, transition metals, and alkali metals in coordination compounds. Because the structures and properties are easier to characterize in these compounds, they give useful information on alkali metal interactions with N2. Here, we review a variety of interactions, with emphasis on recent work on iron complexes by the authors. Finally, we draw conclusions about the nature of these interactions and areas for future research. PMID- 28344389 TI - Reductive activity of free and immobilized cells of cyanobacteria toward oxophosphonates-comparative study. AB - This report, based on the previous studies, compares the reductive activity of different modes of following photobiocatalysts (on laboratory and preparative scale): Arthrospira maxima, Nostoc cf. muscorum and Nodularia sphaerocarpa, toward diethyl esters of 2-oxopropylphosphonate (1), 2-oxo-2 phenylethylphosphonate (2), and 2-oxobutylphosphonate (3). It was confirmed that immobilization in alginate matrix do not affect the activity and viability of the biocatalysts. Corresponding (S)-hydroxyphosphonates (1a-3a) were obtained with similar efficiency compared to the free-cell mode with the yield and of the optical purity e.e respectively (e.g., N. sphaerocarpa experiments): (1) yield: 21 %, e.e. 84 %; (2) yield 97 %, e.e. 97; (3) yield 21 %, e.e. 89 %. Scaling up the processes for the best biocatalyst, N. sphaerocarpa, indicated that the use of free-living cells of cyanobacteria is more effective (640 mg of substrate 2, 44 % of yield, 91 % of e.e.), compared to the column bioreactor packed with immobilized cells of this photobiocatalyst (384 mg of substrate 2, 38 % of yield, 86 % of e.e). In the case of free and immobilized cells of N. cf. muscorum, agitation of the medium was the crucial activity mediator. Shaking culture of free cells of N. cf. muscorum converted the diethyl 2-oxo-2 phenylethylphosphonate (2) with the yield of 43 % (99 % of e.e.) compared to 18 % (99 % of e.e., stationary culture). Immobilized cells of this cyanobacterium were also more active toward (2) under shaking conditions (28 % of yield, 99 % of e.e.) than free ones without agitation. PMID- 28344390 TI - Algal cultivation in urban wastewater: an efficient way to reduce pharmaceutical pollutants. AB - The purpose of this study was to investigate whether pharmaceutical pollutants in urban wastewater can be reduced during algal cultivation. A mixed population of wild freshwater green algal species was grown on urban wastewater influent in a 650 L photobioreactor under natural light and with the addition of flue gases. Removal efficiencies were very high (>90 %), moderate (50-90 %), low (10-50 %), and very low or non-quantifiable (<10 %) for 9, 14, 11, and 18 pharmaceuticals, respectively, over a 7-day period. High reduction was found in the following pharmaceuticals: the beta-blockers atenolol, bispropol, and metoprolol; the antibiotic clarithromycine; the antidepressant bupropion; the muscle relaxant atracurium; hypertension drugs diltiazem and terbutaline used to relive the symptoms of asthma. Regression analysis did not detect any relationship between the reduction in pharmaceutical contents and light intensity reaching the water surface of the algal culture. However, the reduction was positively correlated with light intensity inside the culture and stronger when data collected during the night were excluded. Algae cultivation can remove partially or totally pharmaceutical pollutants from urban wastewater, and this opens up new possibilities for treating urban wastewater. PMID- 28344391 TI - pH-driven solubilization and isoelectric precipitation of proteins from the brown seaweed Saccharina latissima-effects of osmotic shock, water volume and temperature. AB - In the light of the global search for novel and sustainable protein sources, macroalgal proteins are becoming an attractive target. To date, mainly red and green macroalgae have been investigated in this respect, whereas the brown species are less studied, possibly because of the lower content of protein. In a biorefinery context, however, the protein content of brown macroalgae can still be economically interesting due to fast growth and the possibility to co-extract other compounds, such as alginates. The aim of this study was to develop a simple, scalable pH shift-based protein isolation technique applicable on wet Saccharina latissima biomass. Factors investigated were extraction volume, temperature, protein solubilization pH, osmoshock pretreatment and protein precipitation pH. Maximum protein solubility was obtained at pH 12, where 34 % of the total protein content could be extracted with 5.56 volumes of extraction solution (20 volumes on dry weight (dw) basis). Osmoshocking significantly increased the yield, and 20, 40 and 60 volumes of water (dw basis) gave 45.1, 46.8 and 59.5 % yield, respectively. The temperature during osmoshocking did not significantly affect the extraction yield, and extended time (16 vs. 1 or 2 h) reduced protein yield. Precipitation of solubilized proteins was possible below pH 4; the highest precipitation yield, 34.5 %, was obtained at pH 2. After combined alkaline extraction and acid precipitation, 16.01 % of the Saccharina proteins were recovered, which can be considered acceptable in comparison to other studies on algae but leaves some room for improvement when compared to protein extraction from, for instance, soy. PMID- 28344392 TI - Seasonal population dynamics of Sargassum fusiforme (Fucales, Phaeophyta), Suo Oshima Is., Seto Inland Sea, Japan-development processes of a stand characterized by high density and productivity. AB - Seasonal population dynamics of Sargassum fusiforme, one of the most important edible macroalgae in Japan, were studied. Recruits were mainly generated by vegetative reproduction at the margins of filamentous holdfasts. They first appeared in late spring and peaked in summer as upright thalli of the previous generation withered. After producing recruits, holdfasts withered indicating that holdfasts were also annual, the same as upright thalli. All recruits produced main branches and became new upright thalli in early autumn. During this transitional period, the thallus density decreased due to the crowded conditions induced by simultaneous growth initiation. After this early mortality, however, thallus density remained almost constant over much of the growth season. Thallus growth continued during winter and the stand biomass peaked in spring. During this biomass accumulation, development of a thallus size hierarchy was moderate and no size-dependent mortality was observed. Main branch number per thallus was also constant until spring, indicating the main branches also persisted after being produced in early autumn. This lack of severe intraspecific competition both at a thallus and main branch level is supported by the ambient wave condition of the habitat which gives moderate undulation and enables light and nutrients to be supplied to each thallus, and allowed the S. fusiforme stand to maintain its densely-packed feature with a high productivity. PMID- 28344393 TI - Influence of dispatching rules on average production lead time for multi-stage production systems. AB - In this paper the influence of different dispatching rules on the average production lead time is investigated. Two theorems based on covariance between processing time and production lead time are formulated and proved theoretically. Theorem 1 links the average production lead time to the "processing time weighted production lead time" for the multi-stage production systems analytically. The influence of different dispatching rules on average lead time, which is well known from simulation and empirical studies, can be proved theoretically in Theorem 2 for a single stage production system. A simulation study is conducted to gain more insight into the influence of dispatching rules on average production lead time in a multi-stage production system. We find that the "processing time weighted average production lead time" for a multi-stage production system is not invariant of the applied dispatching rule and can be used as a dispatching rule independent indicator for single-stage production systems. PMID- 28344394 TI - Seroprevalence of bovine herpesvirus-1 antibodies in bovines in five districts of Uttarakhand. AB - AIM: This study was conducted to know the status of bovine herpesvirus-1 (BHV-1) antibodies in the bovines of the selected area of Uttarakhand. MATERIALS AND METHODS: A total of 489 serum samples, 392 of cattle and 97 of buffaloes were randomly collected from the unvaccinated bovine population of five districts viz., Dehradun, Haridwar, Nainital, Pithoragarh, and Udham Singh Nagar and were tested by avidin biotin enzyme-linked immunosorbent assay for BHV-1 antibodies. RESULTS: The overall prevalence was observed to be 29.03%. At district level, the highest prevalence was recorded in Pithoragarh district (40.00%) while it was lowest in district Udham Singh Nagar (16.00%). The prevalence of BHV-1 antibodies was found to be higher in unorganized dairy units (31.02%) compared to organized farms (26.51%) in Uttarakhand. Buffaloes were found to have greater prevalence (38.14%) than cattle (26.78%) while on sex-wise basis; it was found that more females (30.08%) were harboring antibodies to the virus than males (16.21%). CONCLUSION: The study revealed that the population in the area under study has been exposed to BHV-1 and hence prevention and control strategies must be implemented. PMID- 28344395 TI - Characterization of Salmonella Gallinarum from an outbreak in Raigarh, Chhattisgarh. AB - AIM: The present investigation was conducted to isolate and characterize Salmonella Gallinarum from an outbreak of fowl typhoid in layer birds. MATERIALS AND METHODS: Clinically ill and dead layer birds from an outbreak were investigated. History, clinical signs, and postmortem lesions were suggestive of fowl typhoid. Postmortem samples including heart blood, intestinal contents, pieces of ovary, and liver were collected and processed immediately for bacterial culture, serotyping and antibiotic sensitivity tests. Isolates were further screened for the presence of extended spectrum beta lactamase (ESBL) (blaTEM) gene by polymerase chain reaction. RESULTS: On the basis of cultural, staining and biochemical characteristics; three bacterial isolates were confirmed as S. Gallinarum. On serotyping, somatic antigen O: 9 and 12 with nonflagellated antigen were detected in all three isolates. Isolates were intermediate sensitive to amoxycillin, amoxyclav, gentamicin and ciprofloxacin and resistant to most of the antibiotics including chloramphenicol, ampicillin, ceftazidime, cefexime, cefepime, azithromycin, nalidixin, tetracycline, oxytetracycline, and streptomycin. Two isolates were found to harbor ESBL (blaTEM) gene. CONCLUSION: Beta lactamase producer S. Gallinarum was confirmed as cause of increased mortality in layer birds during present investigation. Existence of multi drug resistant Salmonella poses serious threat to poultry industry in Chhattisgarh. PMID- 28344396 TI - Effect of supplementation of lecithin and carnitine on growth performance and nutrient digestibility in pigs fed high-fat diet. AB - AIM: To study the effect of dietary supplementation of lecithin and carnitine on growth performance and nutrient digestibility in pigs fed high-fat diet. MATERIALS AND METHODS: A total of 30 weaned female large white Yorkshire piglets of 2 months of age were selected and randomly divided into three groups allotted to three dietary treatments, T1 - Control ration as per the National Research Council nutrient requirement, T2 - Control ration plus 5% fat, and T3 - T2 plus 0.5% lecithin plus 150 mg/kg carnitine. The total dry matter (DM) intake, fortnightly body weight of each individual animal was recorded. Digestibility trial was conducted toward the end of the experiment to determine the digestibility coefficient of various nutrients. RESULTS: There was a significant improvement (p<0.01) observed for pigs under supplementary groups T2 and T3 than that of control group (T1) with regards to growth parameters studied such as total DM intake, average final body weight and total weight gain whereas among supplementary groups, pigs reared on T3 group had better intake (p<0.01) when compared to T2 group. Statistical analysis of data revealed that no differences were observed (p>0.05) among the three treatments on average daily gain, feed conversion efficiency, and nutrient digestibility during the overall period. CONCLUSION: It was concluded that the dietary inclusion of animal fat at 5% level or animal fat along with lecithin (0.5%) and carnitine (150 mg/kg) improved the growth performance in pigs than non-supplemented group and from the economic point of view, dietary incorporation of animal fat at 5% would be beneficial for improving growth in pigs without dietary modifiers. PMID- 28344397 TI - Comparative study of obstructive urolithiasis and its sequelae in buffalo calves. AB - AIM: The present work was designed to study the incidence of obstructive urolithiasis and to apply comparative diagnosis to urine retention cases. MATERIALS AND METHODS: A total of 78 non-castrated buffalo calves aging 3-11 months were included in this study, 68 calves were admitted to the Veterinary Teaching Hospital, Zagazig University, Egypt, during the study period with a history of anuria, and they were classified into three groups; intact bladder group (19 calves), uroperitoneum group (45 calves), and ruptured urethra group (4 calves). 10 apparently healthy calves were used for comparison. On the basis of history, clinical, laboratory, and ultrasonographic findings diagnosis was achieved. RESULTS: There was a marked increase in the incidence of obstructive urolithiasis in winter season, especially in winter months of 2016. Calves within the age of 3-4 months and 6-8 months were mostly affected. Inappetence to anorexia, restlessness or depression, and abdominal distension were the most observed signs in the diseased calves. Laboratory findings revealed hemoconcentration and a significant increase in blood urea nitrogen and serum creatinine levels in all diseased groups. Hyperproteinemia, hypocalcemia, and hyperphosphatemia with electrolytes imbalance were recorded in the uroperitoneum group. Ultrasonographically, distended urinary bladder with distal acoustic enhancement revealed obstructive urolithiasis with intact bladder while anechoic fluid in abdominal cavity indicates uroperitoneum. CONCLUSION: On the basis of all findings, calves with intact bladder were in superior condition than those with a ruptured urethra and both were better than those with uroperitoneum. PMID- 28344398 TI - Evaluation of tissue-engineered bone constructs using rabbit fetal osteoblasts on acellular bovine cancellous bone matrix. AB - AIM: The aim of this study was to generate composite bone graft and investigate the rabbit fetal osteoblasts adhesion, proliferation and penetration on acellular matrices of cancellous bone. MATERIALS AND METHODS: Acellular cancellous bone was prepared and developed as in the previous study with little modification. These matrices were decellularized by rapid freeze and thaw cycle. To remove the cell debris, they were then treated with hydrogen peroxide (3%) and ethanol to remove antigenic cellular and nuclear materials from the scaffold. Primary osteoblast cells were harvested from 20 to 22 days old rabbit fetal long and calvarial bone. These cells were cultured and characterized using a specific marker. The third passaged fetal osteoblast cells were then seeded on the scaffold and incubated for 14 days. The growth pattern of the cells was observed. Scanning electron microscope and hematoxylin and eosin staining were used to investigate cells proliferation. RESULTS: The cells were found to be growing well on the surface of the scaffold and were also present in good numbers with the matrix filopodial extensions upto inside of the core of the tissue. CONCLUSION: Thus, a viable composite scaffold of bone could be developed which has a great potential in the field of bone tissue engineering. PMID- 28344399 TI - Extraction of chitosan and its oligomers from shrimp shell waste, their characterization and antimicrobial effect. AB - AIM: The present study was performed to utilize the shrimp shell waste for chitin and chitosan production, characterization by Fourier transform infrared (FT-IR) technique and to evaluate the antimicrobial effects of chitosan oligomers produced by depolymerization of chitosan by nitrous acid. MATERIALS AND METHODS: Chitosan was extracted from the shrimp shell waste by the chemical method and characterized by FT-IR. Chitooligomers were produced by depolymerising chitosan using nitrous acid, and the chitooligomers were tested for antimicrobial effect against four gut pathogenic organisms, i.e., Enterobacter aerogen (National Collection of Dairy Culture [NCDC] 106), Enterococcus faecalis (NCDC 119), Escherichia coli (NCDC 134), and Staphylococcus aureus (NCDC 109) by well diffusion method using Muller-Hinton agar. A pure culture of pathogenic organisms was collected from NCDC, ICAR-National Dairy Research Institute, Karnal. RESULTS: Extracted chitosan characterized by FT-IR and chitooligomers demonstrated antimicrobial effect against four gut pathogenic organisms used in this study. Zone of inhibitions (mm) were observed in E. faecalis (13+/-0.20), E. coli (11.5+/-0.4), S. aureus (10.7+/-0.2), and E. aerogen (10.7+/-0.3). E. faecalis showed larger inhibition zone as compared to all other organisms and inhibitions zones of E. aerogen and S. aureus were comparable to each other. CONCLUSION: Shrimp waste can be utilized for chitosan production, and the chitooligomers can be used as feed additive for gut health enhancement and have potential to replace antibiotics from the feed. Along with value addition pollutant load could be reduced by waste utilization. PMID- 28344400 TI - Sex-related differences in hemato-biochemical indices of adult Vanaraja chickens during summer and winter seasons. AB - AIM: The objective of this study was to evaluate the changes in hemato biochemical indices in male and female Vanaraja chickens under tropical environment during summer and winter season. MATERIALS AND METHODS: A total of 120 day-old sexed Vanaraja chicks were selected as experimental chickens and distributed equally in two groups having 60 female and 60 male chickens in each group, respectively. The experiment was continued for 8 weeks (56 days) and both male and female chickens were slaughtered by cervical dislocation method. All parameters were estimated at the end of the experiment in both seasons. RESULTS: Male had higher blood glucose, Ca and P level. Blood glucose level significantly (p<0.05) reduced in summer. Female had higher total protein, albumin, globulin, and albumin/globulin ratio. Alanine aminotransferase and aspartate aminotransferase enzyme concentration were significantly (p<0.05) higher in summer. Total erythrocyte count, total leukocyte count, hemoglobin (Hb), Hb/lymphocyte ratio, and packed cell volume were significantly (p<0.05) higher in males. Mean corpuscular volume and mean corpuscular Hb were significantly (p<0.05) higher in females. CONCLUSION: Sex of chickens had a significant (p<0.05) effect on different parameters whereas season had nonsignificant (p>0.05) effect in most of the observed parameters. Hence, Vanaraja chickens are adaptable to local tropical climate and can be reared efficiently as backyard poultry. PMID- 28344401 TI - Profile and artificial insemination practices of technicians and the artificial insemination success rates in Leyte, Samar, and Biliran, Philippines (2011-2015). AB - BACKGROUND: Artificial insemination (AI) is a reproductive biotechnology that may be influenced by several factors, including the profile of the technicians and the practices used. Assessing technician's profile and their AI practices can be significant in improving AI success rate. AIM: This study aimed to know the profile and current practices used by AI technicians (AITs), to determine the success rates of AI in water buffaloes in Leyte, Samar, and Biliran from 2011 to 2015, and to evaluate the possible association between the parameters investigated. MATERIALS AND METHODS: A total of 50 AITs from Leyte, Samar and Biliran, Philippines, were interviewed using a fixed questionnaire about their profile and employed AI practices, and 20,455 AI-related records of the Philippine Carabao Center (PCC) at Visayas State University (VSU), Baybay City, Leyte, were screened and analyzed. AI success rates were determined by retrospective analysis of the gathered data. Statistical analysis was performed between the technician profile and practices and the AI success rates. RESULTS: Results revealed that most of the technicians were male, around 31-40 years old, married, college graduates, working under local government units, had other sources of income, and with 1-5 years of continuous AI practice averaging 51-100 inseminations per year. Most of them attended only one basic training seminar, which was conducted more than 3 years ago in PCC in VSU. AI success rates were recorded highest in 2011 and lowest in 2015. Statistical analyses showed that some technician profile parameters (civil status, average AI per year, and the training center) and several practices (checking of soft cervix, rectal palpation, thawing temperature method, straw cutting method, and semen deposition) might have an influence on the success of AI. CONCLUSION: This study documents the first report on AIT's profile and their employed AI practices and the AI success rates in Leyte, Samar, and Biliran, Philippines. Selected profile parameters and AI practices may influence AI success rates. AITs should perform more AI services and revisit the employed practices. PMID- 28344402 TI - Preparation of mucosal nanoparticles and polymer-based inactivated vaccine for Newcastle disease and H9N2 AI viruses. AB - AIM: To develop a mucosal inactivated vaccines for Newcastle disease (ND) and H9N2 viruses to protect against these viruses at sites of infections through mucosal immunity. MATERIALS AND METHODS: In this study, we prepared two new formulations for mucosal bivalent inactivated vaccine formulations for Newcastle and Avian Influenza (H9N2) based on the use of nanoparticles and polymer adjuvants. The prepared vaccines were delivered via intranasal and spray routes of administration in specific pathogen-free chickens. Cell-mediated and humoral immune response was measured as well as challenge trial was carried out. In addition, ISA71 water in oil was also evaluated. RESULTS: Our results showed that the use of spray route as vaccination delivery method of polymer and nanoparticles MontanideTM adjuvants revealed that it enhanced the cell mediated immune response as indicated by phagocytic activity, gamma interferon and interleukin 6 responses and induced protection against challenge with Newcastle and Avian Influenza (H9N2) viruses. CONCLUSION: The results of this study demonstrate the potentiality of polymer compared to nanoparticles adjuvantes when used via spray route. Mass application of such vaccines will add value to improve the vaccination strategies against ND virus and Avian influenza viruses. PMID- 28344404 TI - A combinatorial model for effective estrus detection in Murrah buffalo. AB - BACKGROUND: Buffaloes are silent heat animals and lacunae in their estrus detection results a substantial economic loss in developing countries. Many advanced tools to aid heat detection have been developed but are neither affordable nor easily interpretable by marginal farmers. AIM: The present investigation was made to develop a cost-effective estrus detection model by combining several known estrus predicting parameters. MATERIALS AND METHODS: Various signs of estrus were classified under major parameters such as visual, cow behavioral, bull behavioral, biochemical, and gyneco-clinical. Expression of those parameters was observed in buffaloes, and the percentage of positive estrus detection was calculated for each combination of estrus prediction parameters. RESULTS: The present result concludes that the model comprises of five parameters group with several signals with twenty-six different combinations. It was observed that the expression of individual combinations and their corresponding estrus detection efficiency varies significantly, i.e., detection efficiency rises as the number of combination increases. CONCLUSION: Combination of three parameters would provide an estrus detection efficiency >70% and suggested for an easy estrus detection. This would be a cost-effective model for farmers and benefits in enhancing buffalo population/reproduction. PMID- 28344403 TI - Toxoplasma gondii infection in meat animals from Africa: Systematic review and meta-analysis of sero-epidemiological studies. AB - AIM: Toxoplasma gondii is an ubiquitous apicomplexan parasite which causes toxoplasmosis in humans and animals. Felids especially cats are definitive hosts and almost all warm-blooded mammals, including livestock and human can serve as intermediate hosts. Food animals can be reservoirs for T. gondii and act as one of the sources for parasite transmission to humans. The objective of this study is to collect serological data on the prevalence of anti-T. gondii antibody, and risk factors for certain food animals from Africa to provide a quantitative estimate of T. gondii infection among these species from different African countries. MATERIALS AND METHODS: Four databases were used to search seroepidemiological data on the prevalence of anti-T. gondii antibody in food animals between 1969 and 2016 from African countries. The search focused on data obtained by serologic test in food animals and meta-analyses were performed per species. RESULTS: A total of 30,742 individual samples from 24 countries, described in 68 articles were studied. The overall estimated prevalence for toxoplasmosis in chicken, camel, cattle, sheep, goat, pig were 37.4% (29.2 46.0%), 36% (18-56%), 12% (8-17%), 26.1% (17.0-37.0%), 22.9% (12.3-36.0%), and 26.0% (20-32.0%), respectively. Moreover, major risk factor of infection was age, farming system, and farm location. CONCLUSIONS: A significant variation in the seroepidemiological data was observed within each species and country. The results can aid in an updated epidemiological analysis but also can be used as an important input in quantitative microbial risk assessment models. Further studies are required for a better and continual evaluation of the occurrence of this zoonotic infection. PMID- 28344405 TI - Biochemical components of seminal plasma and their correlation to the fresh seminal characteristics in Marwari stallions and Poitou jacks. AB - AIM: To investigate various biochemical components of seminal plasma in Marwari stallions and Poitou Jacks and to find out their correlation with that of the seminal characteristics. MATERIALS AND METHODS: In this study, semen was collected from six Marwari stallions and six Poitou jacks aged from 4 to 6 years and with known fertility status. The semen collection from the stallions were collected during the breeding season, i.e., between the months of April and June. From the collected semen ejaculates, we estimated the values of some biochemical components, viz., total protein content, total lipid content, and enzymes such as glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), alkaline phosphatase (ALP), acid phosphatase (ACP), and lactate dehydrogenase (LDH) as well as concentrations of glucose, cholesterol, total calcium (Ca), and phosphorus (P) and correlations among different seminal parameters were statistically examined using the Pearson correlation coefficient. RESULTS: In this study, we found positive correlations between semen volume as well as sperm concentration and GOT, GPT, ALP and ACP for both the group stallions. Significant correlation between motility and glucose, GOT and GPT could be an indication for their role metabolism and protection against free radicals to the spermatozoa. CONCLUSION: Based on the results, it is concluded that there is a positive correlation between some biochemical values such as glucose, Ca, ALP, and LDH and seminal parameters which play a key role in capacitation and onward movement of the spermatozoa. PMID- 28344406 TI - Attribution of antibacterial and antioxidant activity of Cassia tora extract toward its growth promoting effect in broiler birds. AB - AIM: The study was conducted to evaluate the attribution of antibacterial and antioxidant activity of methanolic extract of Cassia tora toward its growth promoting effect in broiler birds. MATERIALS AND METHODS: A limit test was conducted for C. tora extract in Wistar albino rats. Phytochemical screening of methanolic extract of leaves of C. tora was carried out. In-vitro antibacterial activity was measured by disc diffusion method. 1-day-old Ven Cobb broiler birds (n=90) were randomly allocated into three groups consisting of three replicates with 10 birds in each group. The birds of group T1 (Control) received basal diet, whereas birds of group T2 (Standard) received an antibiotic (Lincomycin at 0.05% in feed). The birds of group T3 (Test) received Cassia tora extract (CSE) at 0.4 g/L in drinking water in addition to basal diet. The treatment was given to birds of all the groups for 6 weeks. Antioxidant activity of C. tora was determined in blood of broiler birds. Cumulative body weight gain, feed intake, feed conversion ratio (FCR), dressing percent, and organ weight factor were evaluated to determine growth performance in broiler birds. RESULTS: Phytochemicals in C. tora were screened. Sensitivity to Escherichia coli and resistant to Staphylococcus aureus and Pseudomonas aeruginosa was observed in in-vitro antibacterial activity test. At the end of 6th week, antioxidant activity reflected significantly (p<=0.05) lower level of erythrocyte malondialdehyde and higher levels of reduced glutathione (GSH) and GSH peroxidase in broiler birds of group T2 and T3 as compared to broiler of group T1. Mean cumulative body weight gain of birds of T2 and T3 were significantly (p<=0.05) higher as compared to T1. Mean FCR of birds of group T3 decreased significantly than group T1. CONCLUSION: Supplementation of C. tora leaves extract at 0.4 g/L in drinking water improved growth performance in broiler birds due to its antimicrobial and antioxidant activity. Therefore, it could be used as an alternative to antibiotic growth promoter in poultry ration. PMID- 28344407 TI - Effect of various levels of date palm kernel on growth performance of broilers. AB - AIM: The aim of this study was the assessment of various levels of date palm kernel (DPK) on the growth performance of broilers. MATERIALS AND METHODS: A 250 day-old broiler chicks were randomly selected and categorized into five groups (50 chicks/group) contained A (control), B, C, D and E fed with 0%, 1%, 2%, 3% and 4% levels of DPK in balanced ration, respectively, for 6 weeks. Feed and water intake were recorded daily in the morning and evening. The data for feed intake, water intake, live body weight, and feed conversion ratio (FCR) were recorded from all birds regularly. The carcass weight and percentage obtained via six slaughtered birds were randomly selected from each group. Finally, economic aspects of the rations evaluated. RESULTS: The most feed intakes of broilers were recorded in Group A (3915.1 g) that was significantly higher than Groups D and E. The highest water intake was in Group E (9067.78 ml) that was significantly higher than Group A and control group. Live body weight was highest in Group E (979.85 g) than Groups B, C, and control group. The best growth weights were determined significantly in Groups D (1921.96 g) and E (1935.95 g). The lowest FCRs were indicated significantly in Groups D (1.97 g/g) and E (1.92 g/g) than Groups B and A. The highest carcass weights were recorded in Groups D (1214.01 g) and E (1230.88 g) that were significantly more than other groups. Dressing percentages in Groups D (61.76%) and E (62.17%) were higher than other groups (p<0.05). The net profits (Rs.) in Groups A, B, C, D and E were indicated 27.01, 32.77, 36.78, 43.47 and 44.51 per broiler, respectively. CONCLUSION: It was concluded that the high levels of DPK (3-4%) significantly decreased broiler feed intake and increased water intake, live body weight, growth weight, carcass weight, dressing percentage, net profit per bird and also had positive effects on growth of broilers. PMID- 28344408 TI - Potential antibacterial activity of some Saudi Arabia honey. AB - AIM: The aim of this study was to investigate the potential antibacterial activity of some Saudi Arabia honey against selected bacterial strains of medical importance. MATERIALS AND METHODS: A total of 10 Saudi Arabia honey used to evaluate their antimicrobial activity against some antibiotic-resistant pathogenic bacterial strains. The bacterial strains were Staphylococcus aureus, Streptococcus pyogenes, Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa. RESULTS: The antibacterial activity of Saudi honey against five bacterial strains showed different levels of inhibition according to the type of honey. The overall results showed that the potential activity was differing according to the pathogen and honey type. CONCLUSION: It could be concluded that the Saudi honey inhibit the growth of bacterial strains and that honey can be used as complementary antimicrobial agent against selected pathogenic bacteria. PMID- 28344409 TI - Outbreak of foot and mouth disease and peste des petits ruminants in sheep flock imported for immediate slaughter in Riyadh. AB - AIM: To detect and identify the causative agent or agents of the following clinical symptoms which were fever, lack of appetite, salivation, vesiculation, erosions of the buccal mucosa, nose, and feet. The signs vary from mild to severe. The mortality rate of the disease is high. The morbidity rate reaches up to 100%. Sheep also show bloody diarrhea and rapid respiration. Sheep flock resident in El-Kharje Governorate. MATERIALS AND METHODS: A total of 50 serum samples and 50 buffy coat samples were collected from Marino sheep flock suffered from high mortalities, fever, lameness, diarrhea, stomatitis, and respiratory distress. PrioCHECK(r) foot and mouth disease virus (FMDV) nonstructural (NS) (marketable enzyme-linked immunosorbent assay [ELISA] kit) was used for revealing of the NS antibodies and liquid phase blocking enzyme immunoassay (LPBE) for identifying the FMD serotype and examined by competitive ELISA (cELISA) for detection of peste des petits ruminants (PPR) antibodies. The buffy coat samples were examined by immunocapture ELISA (Ic ELISA) for detection of PPR antigen. RESULTS: Using PrioCHECK(r) FMDV NS: Commercial ELISA kit: 38/50 (76%) of the serum samples were positive for the presence of FMD NS viral proteins. In addition, using LPBE the positive samples were identified as FMD serotype O. Examination of the serum sample by cELISA for detection of PPR antibodies gave positive results in 32/50 (64%). While the Ic ELISA identified 32 (64%) positive reactors for PPR antigen. CONCLUSION: This study reflected high susceptibility of the imported sheep flocks to the infection with FMD and PPR viruses, which are endemic in the Kingdom of Saudi Arabia (KSA). Hence, the imported flocks that prepared for slaughter must be vaccinated with the used vaccine in KSA in the quarantine for the control of FMD especially when importation occurs from counters that are free from these diseases. PMID- 28344410 TI - Identification of single nucleotide polymorphism in protein phosphatase 1 regulatory subunit 11 gene in Murrah bulls. AB - AIM: This study was conducted with the objective to identify single nucleotide polymorphism (SNP) in protein phosphatase 1 regulatory subunit 11 (PPP1R11) gene in Murrah bulls. MATERIALS AND METHODS: Genomic DNA was isolated by phenol chloroform extraction method from the frozen semen samples of 65 Murrah bulls maintained at Artificial Breeding Research Centre, ICAR-National Dairy Research Institute, Karnal. The quality and concentration of DNA was checked by spectrophotometer reading and agarose gel electrophoresis. The target region of PPP1R11 gene was amplified using four sets of primer designed based on Bos taurus reference sequence. The amplified products were sequenced and aligned using Clustal Omega for identification of SNPs. Animals were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using EcoNI restriction enzyme. RESULTS: The sequences in the NCBI accession number NW_005785016.1 for Bubalus bubalis were compared and aligned with the edited sequences of Murrah bulls with Clustal Omega software. A total of 10 SNPs were found, out of which 1 at 5'UTR, 3 at intron 1, and 6 at intron 2 region. PCR-RFLP using restriction enzyme EcoNI revealed only AA genotype indicating monomorphism in PPP1R11 gene of all Murrah animals included in the study. CONCLUSION: A total of 10 SNPs were found. PCR-RFLP revealed only AA genotype indicating monomorphism in PPP1R11 gene of all Murrah animals included in the study, due to which association analysis with conception rate was not feasible. PMID- 28344411 TI - Effect of ethanolic extract of propolis as an alternative to antibiotics as a growth promoter on broiler performance, serum biochemistry, and immune responses. AB - AIM: An in vivo experiment was conducted to investigate the effect of different levels of ethanolic extract of propolis, on growth performance, carcass traits, serum biochemistry, and humoral immune responses of chickens, as compared with the antibiotic flavophospholipol. MATERIALS AND METHODS: 312 1-day-old as-hatched broiler chicks (Ross 308) were randomly allotted to 6 treatments with 4 replicate pens per treatment. The 6 dietary treatments fed for 42 days consisted of a corn soybean meal basal diet (control); control plus 4.5 mg/kg flavophospholipol, and control plus 50, 100, 200, and 300 mg/kg ethanol extracts of propolis, respectively. RESULTS: Neither propolis nor antibiotic affected the performance criteria; however, dietary treatments tended to enhance to enhance body weight and daily feed intake of broiler chickens compared with control group (p>0.05). None of the dietary treatments significantly altered feed: Gain though; broilers fed diet supplemented with 200 mg/kg propolis had better feed: gain values compared with other groups in starter, and grower phases as well as the whole experimental period (p>0.05). Carcass yield and internal organ relative weights were not affected by treatments on day 42, except for abdominal fat pad weight that decreased in broilers supplemented with antibiotic. None of the treatments significantly affected humoral immune function. Dietary treatments failed to induce any significant effect on serum biochemistry (p>0.05); though broilers receiving 100 mg/kg propolis had greater high-density lipoprotein-cholesterol and lower triglyceride concentrations compared with other groups. CONCLUSION: In conclusion, the results indicated that addition of ethanolic extract of propolis to routine dietary components of broilers, such as corn and soybean, seems not to have a positive influence on performance criteria. PMID- 28344412 TI - Clinical and hematobiochemical response in canine monocytic ehrlichiosis seropositive dogs of Punjab. AB - AIM: As in India especially, the Punjab state sero-prevalence and distribution of ehrlichiosis in relation to clinico-hematobiochemical response remains largely unexplored. Thus, this study was designed to determine the prevalence of vector (tick)-borne tropical canine pancytopenia caused by Ehrlichia canis through enzyme labeled ImmunoComb(r) (IC) assay in dogs from in and around Ludhiana, Punjab. Correlation of prevalence was made with various clinico-hematobiochemical parameters. MATERIALS AND METHODS: Seroprevalence study was carried out using IC(r) test kit (Biogal, Galed Labs). The study was conducted in 84 dogs presented to the Small Animal Clinics, Teaching Veterinary Clinical Complex, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana, Punjab. RESULTS: Out of 84 suspected dogs for ehrlichiosis, based on peripheral thin blood smear examination 12 (14.28%) cases were positive for the morulae of E. canis and 73 (86.90%) dogs were found positive to E. canis antibodies through IC(r) canine Ehrlichia antibody test kit, respectively. Among the different age groups 1-3 years of aged group showed highest prevalence (41.09%), followed by the 3-6 years age group (32.87%), infection levels were lower in the <1 year of age group dogs (13.69%) and more than 6 years age group dogs (12.32%). The highest prevalence was seen in Labrador retriever. This study indicates that season plays a very important role in the prevalence of ehrlichiosis. The most common findings observed were anemia, leukocytosis, neutropenia, lymphopenia, thrombocytopenia, eosinophilia followed by hyperbilirubinemia, increased levels of aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase, hypoalbuminemia, hyperglobulinaemia, decrease in albumin and globulin ratio, increase in blood urea nitrogen and creatinine. CONCLUSIONS: Serological techniques like IC(r) are more useful for detecting chronic and subclinical infections and are ideally suited to epidemiological investigations. PMID- 28344413 TI - Evaluation of some heavy metals residues in batteries and deep litter rearing systems in Japanese quail meat and offal in Egypt. AB - AIM: The main objectives of this study were for comparing the effect of batteries and deep litter rearing systems of domesticated Japanese quail, Coturnix coturnix japonica, on the concentration levels of cadmium, copper, lead, and zinc from the quail meat and offal in Ismailia, Egypt. MATERIALS AND METHODS: A total of 40 quail meat and their offal samples were randomly collected from two main quail rearing systems: Battery (Group I) and deep litter system (Group II) for determination of concentration levels of cadmium, copper, lead, and zinc. In addition, 80 water and feed samples were randomly collected from water and feeders of both systems in the Food Hygiene Laboratory, Faculty of Veterinary Medicine, Suez Canal University for heavy metals determination. RESULTS: The mean concentration levels of cadmium, copper, lead, and zinc in Group I were 0.010, 0.027, 1.137, and 0.516 ppm and for Group II were 0.093, 0.832, 0.601, and 1.651 ppm, respectively. The mean concentration levels of cadmium, copper, lead, and zinc in quail feed in Group I were 1.114, 1.606, 5.822, and 35.11 ppm and for Group II were 3.010, 2.576, 5.852, and 23.616 ppm, respectively. The mean concentration levels of cadmium, copper, lead, and zinc in quail meat for Group I were 0.058, 5.902, 10.244, and 290 ppm and for Group II were 0.086, 6.092, 0.136, and 1.280 ppm, respectively. The mean concentration levels of cadmium, copper, lead, and zinc for liver samples in Group I were 0.15, 8.32, 1.05, and 3.41 ppm and for Group II were 0.13, 8.88, 0.95, and 4.21 ppm, respectively. The mean concentration levels of cadmium, copper, lead, and zinc in kidney samples for the Group I were 0.24, 4.21, 1.96, and 4.03 ppm and for Group II were 0.20, 5.00, 1.56, and 3.78 ppm, respectively. Kidney had the highest concentration levels of heavy metals followed by liver then muscles. The highest concentration levels of copper were observed in liver samples. The order of the levels of these trace elements obtained from the four different quail organs is Ca > Pb > Zn > Cu. Lead and cadmium concentration levels in quail meat samples were exceeded the Egyptian standardization limits and suggesting a health threat from lead and cadmium to the quail consumers. CONCLUSION: Battery rearing system is more hygienic than deep litter system from the point of heavy metals pollution of water and feeds of quail. Feed samples from battery system had means concentration levels of lead not significantly higher (p>0.05) than those samples from deep litter system. Meanwhile, water samples from battery system had means concentration levels of cadmium, copper, and zinc significantly higher (p>0.05) than those samples from deep litter system. Quail may carry health risks to consumers. PMID- 28344414 TI - Three-Dimensional Echocardiography: Current Status and Real-Life Applications. AB - The use of cardiac ultrasound is fundamental to the understanding of normal heart function and crucial to pathophysiological diagnosis. The growing availability of 3D echocardiography (3DE) over the last decade has allowed its applications to expand from establishing reference values for chamber size and elucidating ventricular mechanics, to assessing valvular disease severity and playing pivotal roles in interventional procedures. Several important advantages of 3DE include eliminating geometric assumptions, quantifying complex geometric shape volumes, viewing structures from any perspective, assessing lesion in simultaneous multiplanes or multislice mode, all of which are not possible with traditional 2D echocardiography (2DE). Real-time 3DE has been shown to be simple, accurate, reproducible, and versatile, and generally has superior outcome prognosis compared to the 2DE. PMID- 28344415 TI - Percutaneous Coronary Intervention versus Coronary Artery Bypass Grafting in Patients with Diabetic Nephropathy and Left Main Coronary Artery Disease. AB - BACKGROUND: Patients with diabetic nephropathy and unprotected left main (LM) coronary artery disease suffer from high cardiovascular morbidity and mortality. Although surgical revascularization is currently recommended in this special patient population, the optimal revascularization method for this distinct patient group has remained unclear. METHODS: We collected 99 consecutive patients with unprotected LM disease and diabetic nephropathy, including 46 patients who had undergone percutaneous coronary intervention (PCI), and 53 who had coronary artery bypass grafting (CABG), with a mean age of 72 +/- 10; with 80.8% male. Diabetic nephropathy was defined as overt proteinuria (proteinuria > 500 mg/day) and estimated glomerular filtration rate (eGFR) by the modified Modification of Diet in Renal Disease (MDRD) equation of less than 60 mL/min/1.73 m2. The baseline characteristics, angiographic results and long-term clinical outcomes were retrospectively analyzed. RESULTS: The baseline characteristic of all patients were similar except for smokers, low density lipoprotein (LDL) level and extension of coronary artery disease involvement. The median follow-up period was 3.8 years. There were 73 patients (74%) considered as high risk with additive European System for Cardiac Operative Risk Evaluation (EuroSCORE) >= 6. During follow-up period, the long term rate of all-cause death (PCI vs. CABG: 45.7% vs. 58.5%, p = 0.20) and all-cause death/myocardial infarction (MI)/stroke (PCI vs. CABG: 52.2% vs. 60.4%, p = 0.41) were comparable between the PCI and CABG group, whereas the repeat revascularization rate was significantly higher in the PCI group (PCI vs. CABG: 32.6% vs. 9.4%, p < 0.01). eGFR remained an independent predictor for all-cause death [hazard ratio: 0.97, 95% confidence interval: 0.96 to 0.99; p = 0.002] in multivariate logistic regression. CONCLUSIONS: In the real world practice of high-risk patients with unprotected LM disease and diabetic nephropathy, we found that PCI was a comparable alternative to CABG in terms of long-term risks of all-cause death/MI/stroke, with significantly higher repeat revascularization rate. Given the small patient number and retrospective nature, our findings should be validated by larger-scale randomized studies. PMID- 28344417 TI - Circulating Adiponectin Levels Following Treatment Can Predict Late Clinical Outcomes in Chronic Heart Failure. AB - BACKGROUND: Circulating adiponectin concentration increases in patients with chronic heart failure (HF). We sought to explore the prognostic value of temporal changes in adiponectin concentration following treatment for chronic HF. METHODS: Serum adiponectin levels were measured at baseline and after a 3-month anti failure treatment in 124 patients with symptomatic chronic systolic HF. Major adverse cardiac events (MACE) including death, heart transplantation, or hospitalization with worsening HF during a median follow-up period of 752 days were determined. RESULTS: Univariate and multivariate analysis showed that high levels of adiponectin after a 3-month treatment were associated with a 3.8-fold increased risk of MACE (p = 0.03), independent of amino-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. Moreover, the combining of circulating levels of adiponectin with NT-proBNP provided independent and additional prognostic value in identifying high risk patients with MACE during follow-up. CONCLUSIONS: Changes in adiponectin and NT-proBNP over time provide prognostic information. When adiponectin is used in conjunction with NT-proBNP in chronic HF, the prognostic value may be better than if each biomarker is used separately. PMID- 28344416 TI - One-Year Outcomes of Acute Decompensated Systolic Heart Failure in Taiwan: Lessons from TSOC-HFrEF Registry. AB - BACKGROUND: Heart failure (HF) is a global health problem. The Taiwan Society of Cardiology-Heart Failure with reduced Ejection Fraction (TSOC-HFrEF) registry was a multicenter, observational survey of patients admitted with HFrEF in Taiwan. The aim of this study was to report the one-year outcome in this large-cohort of hospitalized patients presenting with acute decompensated HFrEF. METHODS: Patients hospitalized for acute HFrEF were recruited in 21 hospitals in Taiwan. A total of 1509 patients were enrolled into the registry by the end of October 2014. Clinical status, readmission rates and dispensed medications were collected and analyzed 1 year after patient index hospitalization. RESULTS: Our study indicated that re-hospitalization rates after HFrEF were 31.9% and 38.5% at 6 and 12 months after index hospitalization, respectively. Of these patients, 9.7% of them were readmitted more than once. At 6 and 12 months after hospital discharge, all-cause mortality rates were 9.5% and 15.9%, respectively, and cardiovascular mortality rates were 6.8% and 10.5%, respectively. Twenty-three patients (1.5%) underwent heart transplantation. During a follow-up period of 1 year, 46.4% of patients were free from mortality, HF re-hospitalization, left ventricular assist device use and heart transplantation. At the conclusion of follow-up, 57.5% of patients were prescribed either with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers; also, 66.3% were prescribed with beta-blockers and 40.8% were prescribed with mineralocorticoid receptor antagonists. CONCLUSIONS: The TSOC-HFrEF registry showed evidence of suboptimal practice of guideline directed medical therapy and high HF re-hospitalization rate in Taiwan. The one year mortality rate of the TSOC-HFrEF registry remained high. Ultimately, our data indicated a need for further improvement in HF care. PMID- 28344418 TI - Hyperbaric Oxygen Preconditioning Provides Preliminary Protection Against Doxorubicin Cardiotoxicity. AB - BACKGROUND: Doxorubicin (DOX) is generally recognized to have important cardiotoxic side effects. Studies are contradictory about the interaction between hyperbaric oxygen (HBO2) therapy and doxorubicin-induced cardiomyotoxicity. Recent data suggests that HBO2 therapy can lead to preconditioning of myocardium while generating oxidative stress. Herein we have investigated the effect of HBO2 therapy in a DOX-induced cardiomyocyte injury animal model. METHODS: Twenty-one rats were divided into three equal groups as follows: 1) Group 1 is a control group (without any intervention), used for evaluating the basal cardiac structures and determining the normal value of cardiacs and serum oxidative markers; 2) Group 2 is the doxorubicin group (single dose i.p. 20 mg/kg doxorubicin) for detecting the cardiotoxic and systemic effects of doxorubicin; 3) Group 3 is the doxorubicin and HBO2 group (100% oxygen at 2.5 atmospheric for 90 minutes, daily), for evaluating the effect of HBO2 in doxorubicin induced cardiotoxicity. At the end of the protocols, the hearts were harvested and blood samples (2 ml) were obtained. RESULTS: The doxorubicin treated animals (Group 2) had increased oxidative stress markers (both cardiac and serum) and severe cardiac injury as compared to the basal findings in the control group. Nevertheless, the highest cardiac oxidative stress index was detected in Group 3 (control vs. Group 3, p = 0.01). However, histological examination revealed that cardiac structures were well preserved in Group 3 when compared with Group 2. CONCLUSIONS: Our results suggest that HBO2 preconditioning appears to be protective in the doxorubicin-induced cardiotoxicity model. Future studies are required to better elucidate the basis of this preconditioning effect of HBO2. PMID- 28344419 TI - Determinants of Treatment Modification in Hypercholesterolemic Patients. AB - BACKGROUND: There is a lack of knowledge of those contemporary factors associated with modifying subtherapeutic treatments in hypercholesterolemic patients. The aim of this study was to assess determinants of treatment modification in patients not attaining their low-density lipoprotein cholesterol goals. METHODS: The CEntralized Pan-Asian survey on tHE Under-treatment of hypercholeSterolemia enrolled patients taking stable lipid-lowering medications. The study physicians then determined existing patient treatments, which were to be continued or modified when treatments failed. The patient questionnaire surveying patient attitudes and perceptions toward their hypercholesterolemia management was prospectively collected. The odds ratios (ORs) (95% confidence intervals) were calculated. RESULTS: Among the 420 patients included for analysis, 35.7% were designated for planned treatment modification. Those patients assigned to treatment modification were more likely to have a family history of premature coronary heart disease (40% vs. 19%), an indication for secondary prevention (76% vs. 61%), elevated triglyceride (60% vs. 48%) and fasting sugar (84% vs. 67%), and were less adherent to their medications (29% vs. 12%) than patients assigned to treatment continuation. Patient recognition of treatment failure [OR, 1.82 (1.13-2.94)], the lower frequency of cholesterol checkup [OR, 2.40 (1.41-4.08)], patient satisfaction with provided cholesterol information [OR, 2.30 (1.21 4.39)], and their feelings toward cholesterol management [OR, 0.25 (0.10-0.62) and 3.80 (2.28-6.32)] for confusion and no strong feeling, respectively were determinants of the treatment modification assignment. CONCLUSIONS: There was a large gap between evidence-based goals and modification of subtherapeutic treatments, particularly among patients with lower treatment satisfaction and better compliance. Our findings have emphasized the need to further reduce inertia in implementing hypercholesterolemia management. PMID- 28344420 TI - Insomnia and the Risk of Atrial Fibrillation: A Population-Based Cohort Study. AB - BACKGROUND: Although advancements in the treatment of atrial fibrillation have improved patient prognosis for this persistent condition, interest in atrial fibrillation development is growing. Of note is the fact that additional attention is being focused on the accompanying effect of insomnia. The aim of the study was to investigate the effects of insomnia on the risk of atrial fibrillation development. METHODS: This was a nationwide population-based retrospective cohort study using data from the Taiwan National health Insurance Research Database. We analyzed 64,421 insomnia cases and 128,842 matched controls without insomnia from January 1, 2000, to December 31, 2010. A Cox regression model was used to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for atrial fibrillation development. RESULTS: During the follow-up period, the incidence of atrial fibrillation development was significantly higher in the insomnia cases than in the comparison cohort (2.6% vs. 2.3%, p < 0.001). Insomnia was associated with an increased risk of atrial fibrillation (HR = 1.08, 95% CI: 1.01-1.14). Males, those > 65 years of age, and patients with peripheral artery disease who have insomnia had a higher rate of atrial fibrillation development. CONCLUSIONS: The findings of this nationwide analysis support the hypothesis that insomnia is associated with a significant risk of atrial fibrillation development. PMID- 28344421 TI - Impact of Physician-Coordinated Intensive Follow-Up on Long-Term Medical Costs in Patients with Unstable Angina Undergoing Percutaneous Coronary Intervention. AB - BACKGROUND: To investigate the impact of professional physician-coordinated intensive follow-up on long-term expenditures after percutaneous coronary intervention (PCI) in unstable angina (UA) patients. METHODS: In this study, there were 669 UA patients who underwent successful PCI and followed up for 3 years, then divided into the intensive follow-up group (N = 337), and the usual follow-up group (N = 332). Patients were provided with detailed discharge information and individualized follow-up schedules. The intensive group received the extra follow-up times and medical consultations, and all patients were followed up for approximately 3 years. RESULTS: At the 3-year mark after PCI, the cumulative major adverse cardiac events (MACE), recurrence of myocardial ischemia, cardiac death, all-cause death and revascularization in the intensive group were lower than in the usual group. Additionally, the proportion of good medication adherence was significantly higher than in the usual group (56.4% vs. 46.1%, p < 0.001). The hospitalization daytime, total hospitalization cost and total medical cost in the intensive group were lower. Multiple linear regression showed that diabetes, hypertension, intensive follow-up and good medication adherence were associated with emergency and regular clinical cost (p < 0.05), the re-hospitalization cost (p < 0.05) and the total medical cost (p < 0.05) of patient care. Intensive follow-up and good adherence were negatively correlated with the cost of re-hospitalization (standardized coefficients = -0.132, -0.128, p < 0.05) and total medical costs (standardized coefficients = -0.072, -0.086, p < 0.05). CONCLUSIONS: Intensive follow-up can reduce MACE, improve medication adherence and save long-term total medical costs, just by increasing the emergency and regular clinical visits cost in UA patients after PCI. PMID- 28344422 TI - Impaired Left Ventricular Diastolic Functions and Thickened Epicardial Adipose Tissue in Rheumatoid Arthritis Patients is Correlated with DAS-28 Score. AB - BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease that is known to be associated with high cardiovascular (CV) morbidity and mortality. In this study, we aimed to demonstrate whether RA disease activity reflected with disease activity score-28 (DAS-28) had an impact on left ventricular diastolic functions and epicardial adipose tissue (EAT) thickness in RA patients with no traditional CV risk factors. METHODS: In this retrospective study, 41 patients newly diagnosed with RA were included. In addition to medical history, detailed physical examination findings and laboratory tests, left ventricular systolic and diastolic functions, chamber dimensions, and EAT thickness were evaluated with transthoracic echocardiography in the study population. RESULTS: This study included 41 subjects with a median age of 45 years (38.00-55.50), of which 29.27% were male. In the binomial logistic regression analysis, DAS-28 score was found to be an independent associate of diastolic dysfunction, Additionally, DAS-28 was found to be independently associated with EAT thickness. CONCLUSIONS: Patients with high DAS-28 score should be evaluated thoroughly for CV disease, and patients should undergo advanced diagnostic studies as required and receive appropriate treatment. PMID- 28344423 TI - Anti-Platelet Factor 4/Heparin Antibody Plays a Significant Role in Progression of Arterial Stiffness among Hemodialysis Patients. AB - BACKGROUND: Arterial stiffness is a determinant of cardiovascular disease in end stage renal disease. Hemodialysis patients may develop anti-platelet factor 4/heparin antibody (PF4-H Ab) because of heparin treatment in dialysis. We tested whether PF4-H Ab was associated with progression of arterial stiffness in a 3 year follow-up. METHODS: We enrolled 74 hemodialysis patients and studied their clinical, biochemical and arterial stiffness measurement with brachial-ankle pulse wave velocity (baPWV) over 3 years. Baseline and changes in baPWV after 3 years (DeltabaPWV) were collected and compared with related clinical and biochemical parameters. PF4-H Ab was evaluated by the enzyme-linked immunosorbent assay and titer >= 0.4 was defined to have PF4-H Ab. RESULTS: We found a positive PF4-H Ab status in 25 of 74 patients. Mean baPWV was 16.1 +/- 3.8 (m/s) at baseline and 17.6 +/- 4.0 (m/s) after 3 years. Mean DeltabaPWV was 3.4 +/- 2.2 (m/s) in the PF4-H Ab positive group, and 0.6 +/- 1.2 (m/s) in the PF4-H Ab negative group. Baseline baPWV was only significantly associated with age (beta = 0.49, p < 0.01). DeltabaPWV was significantly different between the PF4-H Ab positive and negative groups (p < 0.01). In multivariate regression analysis, only PF4-H Ab was positively associated with DeltabaPWV (beta = 0.71, p < 0.01). CONCLUSIONS: Our study concluded that PF4-H Ab was associated with progression of arterial stiffness in hemodialysis patients. PMID- 28344424 TI - Is Left Atrial Size a Predictor of Mortality after Coronary Artery Bypass Surgery? A Single Center Study. AB - BACKGROUND: To investigate the left atrial (LA) size as an independent predictor of mortality following coronary artery bypass surgery (CABG). METHODS: This single center study evaluated determinants of mortality in 1070 patients who underwent isolated CABG from 2005-2014. Clinical, laboratory and demographic data were obtained from medical records. Collinearity between enlarged LA size (diameter >= 4 cm) and covariates was identified. The adjusted effects of enlarged LA size on 30-day mortality post CABG were tested using multiple logistic regression models. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were reported. RESULTS: The mean age was 59 +/- 9.8 years, and 238 patients were female. Two multivariate logistic regression models were evaluated. In Model A, mitral regurgitation (MR), ejection fraction, intensive care unit length-of-stay and variables found to be collinear with LA size as predictors of mortality were excluded. In model B, the collinear variables were included. By multivariate analysis (Model A), the statistically significant independent predictors of 30-day mortality after CABG were: enlarged LA size (OR 4.82, 95% CI 2.16-10.79), emergency CABG (OR 3.54, 95% CI 1.75-7.18), prolonged inotropic support (OR 2.79, 95% CI 1.38-5.6), diuretic use >= 1 month (OR 1.29, 95% CI 1.3 8.42), and use of clopidogrel within a week before surgery (OR 3.27, 95% CI 1.28 8.36. In Model B, enlarged LA and moderate MR were identified as independent predictors of 30-day mortality. CONCLUSIONS: Increased LA size is a strong independent predictor of mortality after isolated CABG. PMID- 28344425 TI - Surgical Treatment of an Invasive Thymoma with Intracaval and Intracardiac Extension. AB - A 53-year-old male with an invasive thymoma extending to the superior vena and right atrium, presenting as superior vena cava syndrome is herein reported. However invasive thymoma with this growth pattern is extremely rare. In this case, the tumor was successfully resected via median sternotomy with cardiopulmonary bypass. After 17 months of follow-up, the patient was still free from any signs and symptoms indicative of superior vena cava syndrome, but recurrent tumor in the right pleura was observed on the follow-up chest computed tomography. PMID- 28344427 TI - Partial reciprocal sums of the Mathieu series. AB - It is well known that the Mathieu series has a wide application in mathematics science. In this paper, we use the elementary method and construct some new inequalities to study the computational problem of the partial reciprocal sums related to the Mathieu series and obtain an interesting inequality and a related identity. PMID- 28344426 TI - Competitive sports participation in high school and subsequent substance use in young adulthood: Assessing differences based on level of contact. AB - The objective of this analysis is to examine how participation in different types of competitive sports (based on level of contact) during high school is associated with substance use 1 to 4 years after the 12th grade. The analysis uses nationally representative samples of 12th graders from the Monitoring the Future Study who were followed 1 to 4 years after the 12th grade. The longitudinal sample consisted of 970 12th graders from six recent cohorts (2006 2011). The analyses found that respondents who participated in at least one competitive sport during the 12th grade had greater odds of binge drinking during the past two weeks (AOR = 2.04; 95% CI = 1.43, 2.90) 1 to 4 years after the 12th grade, when compared to their peers who did not participate in sports during their 12th grade year. Moreover, respondents who participated in high-contact sports (i.e., football, ice hockey, lacrosse, and wrestling) had greater odds of binge drinking (AOR = 1.80; 95% CI = 1.18, 2.72) and engaging in marijuana use during the past 30 days (AOR = 1.81; 95% CI = 1.12, 2.93) 1 to 4 years after the 12th grade when compared to their peers who did not participate in these types of sports during their 12th grade year. Accordingly, the findings indicate important distinctions in sport participation experiences on long-term substance use risk that can help inform potential interventions among young athletes. PMID- 28344428 TI - Material girls and Material love: Consuming femininity and the contradictions of post-girl power among Kenyan schoolgirls. AB - In this paper, I use qualitative data to explore the practices engaged in by Kenyan schoolgirls to participate in modern consuming womanhood, as well as the contradictory implications of these practices for thinking about globalized mediated femininities and their enactment in resource-poor settings. The paper examines the centrality of consumption to valued modern femininity among young women around the world, as well as the structural reality of gendered access to income. I show how the cooptation of the materiality of romantic love and normative expectations of male provision in romantic relationships bridge the gap between consumption desires and economic realities among Kenyan schoolgirls in both powerful and problematic ways. The paper ends with a reflection of the implications of these findings for post-girl power, the post-feminist age and the re-inscription of patriarchy. PMID- 28344429 TI - Scan Order in Gibbs Sampling: Models in Which it Matters and Bounds on How Much. AB - Gibbs sampling is a Markov Chain Monte Carlo sampling technique that iteratively samples variables from their conditional distributions. There are two common scan orders for the variables: random scan and systematic scan. Due to the benefits of locality in hardware, systematic scan is commonly used, even though most statistical guarantees are only for random scan. While it has been conjectured that the mixing times of random scan and systematic scan do not differ by more than a logarithmic factor, we show by counterexample that this is not the case, and we prove that that the mixing times do not differ by more than a polynomial factor under mild conditions. To prove these relative bounds, we introduce a method of augmenting the state space to study systematic scan using conductance. PMID- 28344430 TI - Don't Assume Deaf Students are Visual Learners. AB - In the education of deaf learners, from primary school to postsecondary settings, it frequently is suggested that deaf students are visual learners. That assumption appears to be based on the visual nature of signed languages-used by some but not all deaf individuals-and the fact that with greater hearing losses, deaf students will rely relatively more on vision than audition. However, the questions of whether individuals with hearing loss are more likely to be visual learners than verbal learners or more likely than hearing peers to be visual learners have not been empirically explored. Several recent studies, in fact, have indicated that hearing learners typically perform as well or better than deaf learners on a variety of visual-spatial tasks. The present study used two standardized instruments to examine learning styles among college deaf students who primarily rely on sign language or spoken language and their hearing peers. The visual-verbal dimension was of particular interest. Consistent with recent indirect findings, results indicated that deaf students are no more likely than hearing students to be visual learners and are no stronger in their visual skills and habits than their verbal skills and habits, nor are deaf students' visual orientations associated with sign language skills. The results clearly have specific implications for the educating of deaf learners. PMID- 28344431 TI - Control Engineering Methods for the Design of Robust Behavioral Treatments. AB - In this paper, a robust control approach is used to address the problem of adaptive behavioral treatment design. Human behavior (e.g., smoking and exercise) and reactions to treatment are complex and depend on many unmeasurable external stimuli, some of which are unknown. Thus, it is crucial to model human behavior over many subject responses. We propose a simple (low order) uncertain affine model subject to uncertainties whose response covers the most probable behavioral responses. The proposed model contains two different types of uncertainties: uncertainty of the dynamics and external perturbations that patients face in their daily life. Once the uncertain model is defined, we demonstrate how least absolute shrinkage and selection operator (lasso) can be used as an identification tool. The lasso algorithm provides a way to directly estimate a model subject to sparse perturbations. With this estimated model, a robust control algorithm is developed, where one relies on the special structure of the uncertainty to develop efficient optimization algorithms. This paper concludes by using the proposed algorithm in a numerical experiment that simulates treatment for the urge to smoke. PMID- 28344432 TI - Quantification of mixing in vesicle suspensions using numerical simulations in two dimensions. AB - We study mixing in Stokesian vesicle suspensions in two dimensions on a cylindrical Couette apparatus using numerical simulations. The vesicle flow simulation is done using a boundary integral method, and the advection-diffusion equation for the mixing of the solute is solved using a pseudo-spectral scheme. We study the effect of the area fraction, the viscosity contrast between the inside (the vesicles) and the outside (the bulk) fluid, the initial condition of the solute, and the mixing metric. We compare mixing in the suspension with mixing in the Couette apparatus without vesicles. On the one hand, the presence of vesicles in most cases slightly suppresses mixing. This is because the solute can be only diffused across the vesicle interface and not advected. On the other hand, there exist spatial distributions of the solute for which the unperturbed Couette flow completely fails to mix whereas the presence of vesicles enables mixing. We derive a simple condition that relates the velocity and solute and can be used to characterize the cases in which the presence of vesicles promotes mixing. PMID- 28344433 TI - A novel investigation of a micropolar fluid characterized by nonlinear constitutive diffusion model in boundary layer flow and heat transfer. AB - The rheological and heat-conduction constitutive models of micropolar fluids (MFs), which are important non-Newtonian fluids, have been, until now, characterized by simple linear expressions, and as a consequence, the non Newtonian performance of such fluids could not be effectively captured. Here, we establish the novel nonlinear constitutive models of a micropolar fluid and apply them to boundary layer flow and heat transfer problems. The nonlinear power law function of angular velocity is represented in the new models by employing generalized "n-diffusion theory," which has successfully described the characteristics of non-Newtonian fluids, such as shear-thinning and shear thickening fluids. These novel models may offer a new approach to the theoretical understanding of shear-thinning behavior and anomalous heat transfer caused by the collective micro-rotation effects in a MF with shear flow according to recent experiments. The nonlinear similarity equations with a power law form are derived and the approximate analytical solutions are obtained by the homotopy analysis method, which is in good agreement with the numerical solutions. The results indicate that non-Newtonian behaviors involving a MF depend substantially on the power exponent n and the modified material parameter [Formula: see text] introduced by us. Furthermore, the relations of the engineering interest parameters, including local boundary layer thickness, local skin friction, and Nusselt number are found to be fitted by a quadratic polynomial to n with high precision, which enables the extraction of the rapid predictions from a complex nonlinear boundary-layer transport system. PMID- 28344434 TI - Compact Graph based Semi-Supervised Learning for Medical Diagnosis in Alzheimer's Disease. AB - Dementia is one of the most common neurological disorders among the elderly. Identifying those who are of high risk suffering dementia is important for early diagnosis in order to slow down the disease progression and help preserve some cognitive functions of the brain. To achieve accurate classification, significant amount of subject feature information are involved. Hence identification of demented subjects can be transformed into a pattern classification problem. In this letter, we introduce a graph based semi-supervised learning algorithm for Medical Diagnosis by using partly labeled samples and large amount of unlabeled samples. The new method is derived by a compact graph that can well grasp the manifold structure of medical data. Simulation results show that the proposed method can achieve better sensitivities and specificities compared with other state-of-art graph based semi-supervised learning methods. PMID- 28344435 TI - EXPOSURE TO DOMESTIC VIOLENCE AND CHILDHOOD EMOTIONAL ABUSE: Childhood Domestic Violence Exposure among a Community Sample of Adult Perpetrators: What Mediates the Connection? AB - The association between childhood exposure to domestic violence and later intimate partner violence (IPV) perpetration in adulthood has been well established in the literature. However, the literature examining the factors of exposure that contribute to perpetration in adulthood is fraught with mixed findings, with some studies finding a direct link between childhood domestic violence exposure and later IPV perpetration and others ruling out a link after controlling for other contextual barriers such as community violence and socioeconomic status. This study examined 124 non-treatment-seeking and unadjudicated adult male IPV perpetrators and found exposure to domestic violence in childhood contributes to the normalization of violence, which could predict future adult IPV perpetration. Practice implications are discussed, namely primary and secondary prevention of intimate partner violence. PMID- 28344436 TI - New Insights into the Fractional Order Diffusion Equation Using Entropy and Kurtosis. AB - Fractional order derivative operators offer a concise description to model multi scale, heterogeneous and non-local systems. Specifically, in magnetic resonance imaging, there has been recent work to apply fractional order derivatives to model the non-Gaussian diffusion signal, which is ubiquitous in the movement of water protons within biological tissue. To provide a new perspective for establishing the utility of fractional order models, we apply entropy for the case of anomalous diffusion governed by a fractional order diffusion equation generalized in space and in time. This fractional order representation, in the form of the Mittag-Leffler function, gives an entropy minimum for the integer case of Gaussian diffusion and greater values of spectral entropy for non-integer values of the space and time derivatives. Furthermore, we consider kurtosis, defined as the normalized fourth moment, as another probabilistic description of the fractional time derivative. Finally, we demonstrate the implementation of anomalous diffusion, entropy and kurtosis measurements in diffusion weighted magnetic resonance imaging in the brain of a chronic ischemic stroke patient. PMID- 28344437 TI - Eplerenone repolarizes muscle membrane through Na,K-ATPase activation by Tyr10 dephosphorylation. AB - Eplerenone, an aldosterone antagonist, repolarizes muscle membrane in-vitro and increases strength in-vivo in channelopathies. In Duchenne dystrophy, it is administered for cardiomyopathy. We studied its mechanism of action on skeletal muscle to test its suitability for increasing strength in Duchenne dystrophy. Using membrane potential measurements, quantitative PCR, ELISA, and Western blots, we examined the effects of eplerenone on skeletal muscle Na,K-ATPase. The repolarizing effect of eplerenone in muscle fibres was counteracted by oubain, an ATPase blocker. In our experiment, ATPA1A mRNA and total ATPase protein were not elevated. Instead, Tyr10 of the alpha1 subunit was dephosphorylated which would agree with ATPase activation. Dephosporylation of the coupled Akt kinase corroborated our findings. We conclude that eplerenone repolarizes muscle membrane by Na,K-ATPase activation by dephosphorylation at Tyr10. Since ATPase protein is known to be compensatorily increased in Duchenne patients without activity change, eplerenone treatment may be beneficial. PMID- 28344438 TI - Learning disabilities in neuromuscular disorders: a springboard for adult life. AB - Although the presence of cognitive deficits in Duchenne muscular dystrophy or myotonic dystrophy DM1 is well established in view of brain-specific expression of affected muscle proteins, in other neuromuscular disorders, such as congenital myopathies and limb-girdle muscular dystrophies, cognitive profiles are poorly defined. Also, there are limited characterization of the cognitive profile of children with congenital muscular dystrophies, notwithstanding the presence of cerebral abnormality in some forms, and in spinal muscular atrophies, with the exception of distal spinal muscular atrophy (such as the DYN1CH1- associated form). Starting from the Duchenne muscular dystrophy, which may be considered a kind of paradigm for the co-occurrence of learning disabilities in the contest of a progressive muscular involvement, the findings of neuropsychological (or cognitive) dysfunctions in several forms of neuromuscular diseases will be examined and reviewed. PMID- 28344439 TI - Family context in muscular dystrophies: psychosocial aspects and social integration. AB - Muscular dystrophies (MDs) are degenerative diseases which may led to marked functional impairment and reduced life expectancy. Being caregivers of a loved one with MD may be both a rewarding and a demanding experience that may have relevant impact on the quality of life of the whole family. In this short review we summarize the main findings of the first survey on family context in MD in Italy. The study was carried out on 502 key-relatives of patients suffering from Duchenne, Becker, or Limb-Girdle MD, aged between 4 and 25 years, and attending one of 8 participating Centers, all over 2012. The results revealed that practical difficulties were mainly related to relatives' involvement in helping the patient in moving and in relative's constraints of leisure activities. Furthermore, feelings of loss and perception of patient's condition as having negative effects on the family life were the psychological consequences more frequently complained. However, despite the difficulties, 88% of the key relatives acknowledged the caregiving as a positive experience. In fact 94% of the respondents stated they could rely on friends in case of own physical illness, and 88% in case of psychological stress. Burden was found higher among relatives of patients with lower functional autonomy and longer duration of illness, and among relatives with lower professional and social support. Conversely, the positive aspects of the caregiving were more frequently acknowledged by those who received higher level of professional help and psychological social support. These results reveal that the caregiving experience has a positive impact on key-relatives quality of life despite the practical demands, and that the support of professionals is essential to help families in identifying the benefits of this experience without denying its difficulties. PMID- 28344441 TI - Successful treatment of periodic paralysis with coenzyme Q10: two case reports. AB - Primary periodic paralyses (PPs) are autosomal dominant ion channel disorders characterized by episodic flaccid weakness associated with variations in serum potassium level. The main prophylactic therapy of choice for PPsis carbonic anhydrase inhibitors that are not always effective. In this report, we described two PP patients who were successfully treated with coenzyme Q10. They remained asymptomatic since initiation of treatment, which may be associated with promotion of energy synthesis, anti-oxidant activity, influence of the fiber type composition and regulation of the expression of gene. To our knowledge, this is the first report of primary periodic paralyses which have been successfully treated with CoQ10. More observations need to substantiate this clinical finding in PPs. PMID- 28344440 TI - Increased heterogeneity of ventricular repolarization in myotonic dystrophy type 1 population. AB - Sudden cardiac death in myotonic dystrophy type I (DM1) patients can be attributed to atrioventricular blocks as far as to the development of life threatening arrhythmias which occur even in hearts with normal left ventricular systolic and diastolic function. Heterogeneity of ventricular repolarization is considered to provide an electrophysiological substrate for malignant arrhythmias. QTc dispersion (QTc-D), JTc dispersion (JTc-D) and transmural dispersion of repolarization (TDR) could reflect the physiological variability of regional and transmural ventricular repolarization. Aim of the present study was to investigate the heterogeneity of ventricular repolarization in patients with DM1 and preserved diastolic and systolic cardiac function. The study enrolled 50 DM1 patients (mean age 44 +/- 5 years; M:F: 29:21) with preserved systolic and diastolic function of left ventricle among 247 DM1 patients followed at Cardiomyology and Medical Genetics of Second University of Naples, and 50 sexand age-matched healthy controls. The electrocardiographic parameters investigated were the following: Heart Rate, QRS duration, maximum and minimum QT and JT intervals, QTc- D, JTc-D and TDR. Compared to the controls, the DM1 group presented increased values of QTc-D (86.7 +/- 40.1 vs 52.3 +/- 11.9 ms; p = 0.03), JTc-D (78.6 +/- 31.3 vs 61.3 +/- 10.2 ms; p = 0.001) and TDR (101.6 +/- 18.06 vs 90.1 +/- 14.3 ms; p = 0.004) suggesting a significant increase in regional and transmural heterogeneity of the ventricular repolarization in these patients, despite a preserved systolic and diastolic cardiac function. PMID- 28344443 TI - Flow-directed PCA for monitoring networks. AB - Measurements recorded over monitoring networks often possess spatial and temporal correlation inducing redundancies in the information provided. For river water quality monitoring in particular, flow-connected sites may likely provide similar information. This paper proposes a novel approach to principal components analysis to investigate reducing dimensionality for spatiotemporal flow-connected network data in order to identify common spatiotemporal patterns. The method is illustrated using monthly observations of total oxidized nitrogen for the Trent catchment area in England. Common patterns are revealed that are hidden when the river network structure and temporal correlation are not accounted for. Such patterns provide valuable information for the design of future sampling strategies. PMID- 28344442 TI - Voltage-directed cavo-tricuspid isthmus ablation using a novel ablation catheter mapping technology in a myotonic dystrophy type I patient. AB - A successful case of maximum voltage-directed cavo-tricuspid isthmus (CTI) ablation using a novel ablation catheter mapping technology in a myotonic dystrophy type I (DM1) patient is reported. The patient complained recurrent episodes of atrial flutter, revealed by the atrio-ventricular electrograms analysis during the routine pacemaker controls. PMID- 28344444 TI - Distribution of Platelet-rich Plasma after Ultrasound-Guided Injection for Chronic Elbow Tendinopathies. AB - Characteristics of the spreads of platelet-rich plasma (PRP) are not widely known despite commonly use. This study aims to evaluate whether PRP stays within the injected area by using ultrasonography, to improve understanding of the spreads of intratendinous injected PRP. Thirty-nine patients (15 males, 24 females; mean age, 49.3 years), who had symptoms on their elbows (> 6 months) and diagnosed as lateral (25 elbows) or medial (14 elbows) tendinopathies of elbow, were included. The severity of tendon pathology was assessed by ultrasonography as tear or no tear. Immediately after ultrasound-guided PRP injection, ultrasound images were evaluated to assess the area of PRP distribution, which was defined as the presence of fluid or microbubbles. Ultrasound revealed that 13 elbows had tendon tear and 26 had no tear, respectively. Post-injection ultrasound confirmed the injected PRP was within the tendon in all cases. The mean distance of distribution from the injection site was 12.6 mm (5.0-26.0 mm). There was no difference in the distance of PRP distribution between tendon tear and no tear. Injected PRP spread to soft tissue outside the tendon in 20 of 39 cases. Intra articular extension of PRP was observed in 5 cases. Although PRP remained intratendinous after the injection in all cases, some portion tended to spread outside from the injection site in a short space of time. Postinjection ultrasonographic imaging has a value for observing the spreading patterns of intratendinous PRP injection. PMID- 28344445 TI - Effects of Static and Dynamic Stretching on the Isokinetic Peak Torques and Electromyographic Activities of the Antagonist Muscles. AB - The aim of this study was to investigate if static and dynamic stretching exercises of the knee muscles (quadriceps and hamstring muscles) have any effects on concentric and eccentric isokinetic peak torques and electromyographic amplitudes (EMG) of the antagonist muscles. Twenty healthy male athletes (age between 18-30 years) voluntarily participated in this study. All of the subjects visited the laboratory to complete the following intervention in a randomized order on 5 separate days; (a) non-stretching (control), (b) static stretching of the quadriceps muscles, (c) static stretching of the hamstring muscles, (d) dynamic stretching of the quadriceps muscles, and (e) dynamic stretching of the hamstring muscles. Static stretching exercises either for the quadriceps or the hamstring muscles were carried out at the standing and sitting positions. Subjects performed four successive repetitions of each stretching exercises for 30 seconds in both stretching positions. Similar to static stretching exercises two different stretching modes were designed for dynamic stretching exercises. Concentric and eccentric isokinetic peak torque for the non-stretched antagonist quadriceps or hamstring muscles at angular velocities of 60 degrees /sec and 240 degrees /sec and their concurrent electromyographic (EMG) activities were measured before and immediately after the intervention. Isokinetic peak torques of the non-stretched agonist hamstring and quadriceps muscles did not represent any significant (p > 0.05) differences following static and dynamic stretching of the antagonist quadriceps and hamstring muscles, respectively. Similarly, the EMG activities of the agonist muscles exhibited no significant alterations (p > 0.05) following both stretching exercises of the antagonist muscles. According to the results of the present study it is possible to state that antagonist stretching exercises either in the static or dynamic modes do not affect the isokinetic peak torques and the EMG activities of the non-stretched agonist quadriceps or hamstring muscles. PMID- 28344446 TI - Prediction of Tennis Performance in Junior Elite Tennis Players. AB - Predicting current and future tennis performance can lead to improving the development of junior tennis players. The aim of this study is to investigate whether age, maturation, or physical fitness in junior elite tennis players in U13 can explain current and future tennis performance. The value of current tennis performance for future tennis performance is also investigated. A total of 86 junior elite tennis players (boys, n = 44; girls, n = 42) U13 (aged: 12.5 +/- 0.3 years), and followed to U16, took part in this study. All players were top-30 ranked on the Dutch national ranking list at U13, and top-50 at U16. Age, maturation, and physical fitness, were measured at U13. A principal component analysis was used to extract four physical components from eight tests (medicine ball throwing overhead and reverse, ball throwing, SJ, CMJas, Sprint 5 and 10 meter, and the spider test). The possible relationship of age, maturation, and the physical components; "upper body power", "lower body power", "speed", and "agility" with tennis performance at U13 and U16 was analyzed. Tennis performance was measured by using the ranking position on the Dutch national ranking list at U13 and U16. Regression analyses were conducted based on correlations between variables and tennis performance for boys and girls, separately. In boys U13, positive correlations were found between upper body power and tennis performance (R2 is 25%). In girls, positive correlations between maturation and lower body power with tennis performance were found at U13. Early maturing players were associated with a better tennis performance (R2 is 15%). In girls U16, only maturation correlated with tennis performance (R2 is 13%); later-maturing girls at U13 had better tennis performances at U16. Measuring junior elite tennis players at U13 is important for monitoring their development. These measurements did not predict future tennis performance of junior elite tennis players three years later. Future research should focus on other aspects in order to predict tennis performance better. PMID- 28344447 TI - Movement Demands and Running Intensities of Semi-Professional Rugby League Players during A 9's Tournament: A Case Study. AB - The objective of the study was to describe the movement demands and running intensities of semi-professional rugby league players during a rugby league 9's (RL9's) tournament. Six semi-professional rugby league players competed in a RL9's tournament over a two-day period comprising of six games. Movement demands and running intensities were recorded using Global Positioning System (GPS) devices providing data on distance and speeds. Data is presented as mean (95% Confidence Intervals) with changes (>= 75%) likely to exceed the smallest worthwhile change (0.2) considered practically important. Outside backs performed significantly (p < 0.05) more relative VHSR (3.9 m [3.5-4.3] vs 2.4 m [2.1-2.8]) absolute (97.7 m [81.3-114.1] vs 22.6m [15.8-29.3]) and relative (5.0 m.min-1 [4.2-5.9] vs 1.2 m.min-1 [0.8-1.6]) sprint distance than the forwards. Outside backs also performed significantly (p < 0.05) more absolute (97.7 m [81.3-114.1] vs 43.9 m [27.2-60.7]) and relative (5.0 m.min-1 [4.2-5.9] vs 2.3 m.min-1 [1.4 3.2]) sprint distance than the adjustables. Moderate (0.6 - 1.2) to very large (> 2.0) decreases in performance variables were observed over the two days. The biggest magnitude of change over the two days was seen with very large decreases in relative HSR (- 2.10) and sprint (- 2.14) distance. Between playing groups, the outside backs had the biggest decrease in running intensity with a very large (- 2.32) significant (p < 0.05) decrease in VHSR on day 2 (3.3 m.min-1 [2.5 - 4.1]) compared to day 1 (4.9 m.min-1 [4.4 - 5.4]). Running intensities are decreased during an intensified RL9's tournament in semi-professional rugby league players. The observed decreases in running performances between playing groups are in agreement with previous research and may support the use of individualized player monitoring and recovery management during a RL9's tournament-style competition. PMID- 28344448 TI - Is Empirical Research on Periodization Trustworthy? A Comprehensive Review of Conceptual and Methodological Issues. AB - Periodization is a core concept in training. Recently, systematic reviews and meta-analyses have attempted to provide a comprehensive overview of the topic, but theoretical criticisms have arisen with regard to how such research has been conducted. The purpose of the study was to review comprehensively the conceptual and methodological issues surrounding empirical research on periodization in training with human subjects. A search was conducted late in February 2016 on Academic Search Complete, CINAHL Plus, MedicLatina, MEDLINE, PsycINFO, PubMed, Scielo, Scopus, SPORTDiscus and Web of Science. Forty-two randomized or randomized controlled trials were retrieved. Problems emerged in three domains: (a) Conceptually, periodization and variation were applied differently in research, while no empirical research tested predictions concerning direction, timing or magnitude of the adaptations; (b) Study design: More than 95% of papers investigated the 'physical' factor (mainly strength). Research on long-term effects was absent (no study lasted more than nine months). Controlling for confounding factors such as nutrition, supplementation and medication was largely ignored; (c) Data analysis was biased as dispersion in responsiveness was ignored when discussing the findings. Overall, research on periodization fails to analyze the conceptual premises proposed by these approaches. PMID- 28344449 TI - The Effects of 3 Weeks of Uphill and Downhill Walking on Blood Lipids and Glucose Metabolism in Pre-Diabetic Men: A Pilot Study. AB - The prevention of type 2 diabetes in persons at risk for diabetes is of utmost importance. Physical activity in general and even exercises at moderate intensities such as walking significantly reduce the risk of the development of type 2 diabetes. However, it is still a matter of debate whether lipids and glucose metabolism are differently affected by regular concentric (e.g., uphill walking) and eccentric (e.g., downhill walking) endurance exercise. The aim of this study was to investigate the effects of short-term (3 weeks) uphill and downhill walking on glucose metabolism and blood lipids in pre-diabetic middle aged men in a real world setting. The study was designed as an investigator initiated 2 group random selection pre-test post-test trial. Sixteen pre-diabetic men (age: 56.9 +/- 5.1 years; BMI: 28.1 +/- 2.3 kg.m-2) performed 9 uphill (n = 8) or 9 downhill (n = 8) walking sessions within 3 weeks. The primary outcomes were the markers of glucose metabolism and blood lipids measured before and after the training period. After uphill walking glucose tolerance (area under the curve of the oral glucose tolerance test: -43.25 +/- 53.12 mg.dl-1; p = 0.05; effect size: 0.81), triglycerides (-48.75 +/- 54.49 mg.dl-1; p = 0.036; effect size: 0.89), HDL-C (+7.86 +/- 9.54 mg.dl-1; p = 0.05; effect size: 0.82) and total cholesterol/HDL-C ratio (-0.58 +/- 0.41; p = 0.012; effect size: 1.39) had significantly improved. No significant metabolic adaptations were found after downhill walking. However, when adjusted for estimated energy expenditure, uphill and downhill walking had equal effects on almost all metabolic parameters. Moreover, the magnitude of the baseline impairments of glucose tolerance was significantly related to the extent of change in both groups. Depending on the fitness level and individual preferences both types of exercise may be useful for the prevention of type 2 diabetes and disorders in lipid metabolism. PMID- 28344450 TI - Test Re-Test Reliability of Four Versions of the 3-Cone Test in Non-Athletic Men. AB - Until recently, measurement and evaluation in sport science, especially agility testing, has not always included key elements of proper test construction. Often tests are published without reporting reliability and validity analysis for a specific population. The purpose of the present study was to examine the test re test reliability of four versions of the 3-Cone Test (3CT), and provide guidance on proper test construction for testing agility in athletic populations. Forty male students enrolled in classes in the Department of Physical Education at a mid-Atlantic university participated. On each of test day participants performed 10 trials. In random order, they performed three trials to the right (3CTR, standard test), three to the left (3CTL), and two modified trials (3CTAR and 3CTAL), which included a reactive component in which a visual cue was given to indicate direction. Intra-class correlation coefficients (ICC) indicated a moderate to high reliability for the four tests, 3CTR 0.79 (0.64-0.88, 95%CI), 3CTL 0.73 (0.55-0.85), 3CTAR 0.85(0.74-0.92), and 3CTAL 0.79 (0.64-0.88). Small standard error of the measurement (SEM) was found; range 0.09 to 0.10. Pearson correlations between tests were high (0.82-0.92) on day one as well as day two (0.72-0.85). These results indicate each version of the 3-Cone Test is reliable; however, further tests are needed with specific athletic populations. Only the 3CTAR and 3CTAL are tests of agility due to the inclusion of a reactive component. Future studies examining agility testing and training should incorporate technological elements, including automated timing systems and motion capture analysis. Such instrumentation will allow for optimal design of tests that simulate sport-specific game conditions. PMID- 28344451 TI - Retrospective Injury Epidemiology and Risk Factors for Injury in CrossFit. AB - The objective of the study is to examine injury epidemiology and risk factors for injury in CrossFit athletes. A survey was administered to athletes at four owner operated facilities in South Florida. Respondents reported number, location of injury, and training exposure from the preceding six months and answered questions regarding potential risk factors for injury. Fifty out of 191 athletes sustained 62 injuries during CrossFit participation in the preceding six months. The most frequently injured locations were the shoulder, knee, and lower back. Injury incidence was 2.3/1000 athlete training hours. Competitors were more likely to be injured (40% v 19%, p = 0.002) and had greater weekly athlete training hours (7.3 +/- 7.0 v 4.9 +/- 2.9, p < 0.001) than non-competitors. Athletes who reported injury also reported significantly higher values for the following risk factors: years of participation (2.7 +/- 1.8 v 1.8 +/- 1.5, p = 0.001), weekly athlete training hours (7.3 +/- 3.8 v 4.9 +/- 2.1, p = 0.020), weekly athlete-exposures (6.4 +/- 3.8 v 4.7 +/- 2.1, p = 0.003), height (1.72 +/- 0.09 m v 1.68 +/- 0.01 m, p = 0.011), and body mass (78.24 +/- 16.86 kg v 72.91 +/- 14.77 kg, p = 0.037). Injury rates during CrossFit and location of injuries were similar to those previously reported. Injury incidence was similar to related sports, including gymnastics and powerlifting. While being a competitor was related to injury, increased exposure and length of participation in CrossFit likely underlied this association. Specifically, increased exposure to training in the form of greater weekly athlete training hours and weekly participations may contribute to injury. Increased height and body mass were also related to injury which is likely reflective of increased load utilized during training. Further research is warranted to determine if biomechanical factors associated with greater height and ability to lift greater loads are modifiable factors that can be adapted to reduce the increase risk of injury during CrossFit. PMID- 28344452 TI - The Effects of a Sports Nutrition Education Intervention on Nutritional Status, Sport Nutrition Knowledge, Body Composition, and Performance during Off Season Training in NCAA Division I Baseball Players. AB - This study investigated the effects of a sport nutrition education intervention (SNEI) on dietary intake, knowledge, body composition, and performance in NCAA Division I baseball players. Resistance trained NCAA Division I baseball players (82.4 +/- 8.2 kg; 1.83 +/- 0.06 m; 13.7 +/- 5 % body fat) participated in the study during 12 weeks of off-season training. Fifteen players volunteered for SNEI while 15 players matched for position served as controls (C) for body composition and performance. The nutrition intervention group (NI) received a 90 min SNEI encompassing energy intake (Kcal), carbohydrate (CHO), protein (PRO), fat, food sources, and hydration. Sport nutrition knowledge questionnaires were administered to NI pre and post. Nutritional status was determined by three-day dietary logs administered to NI pre and post. Body composition and performance (5 10-5 shuttle test, vertical jump, broad jump, 1 RM squat) were measured pre and post for C and NI. Knowledge increased in NI. Pro and fat, but not CHO intake increased in NI. FM decreased pre to post in NI (11.5 +/- 4.8 vs. 10.5 +/- 5.4 kg) but not C (11.3 +/- 4.7 vs. 11.9 +/- 4.5 kg). FFM increased pre to post with no differences between groups. The 5-10-5 shuttle times decreased significantly more in NI (4.58 +/- 0.15 vs. 4.43 +/- 0.13 sec) compared to C (4.56 +/- 0.18 vs. 4.50 +/- 0.16 sec). Jump and squat performance increased pre to post with no differences between groups. Our findings indicate that an off season SNEI is effective at improving sport nutrition knowledge and some, but not all, nutrient intakes and performance measures in Division I baseball players. PMID- 28344453 TI - High-Intensity Exercise and Carbohydrate Supplementation do not Alter Plasma Visfatin. AB - The purpose of the study was to examine the effect of high-intensity exercise and carbohydrate supplementation (CHO) on plasma visfatin. On 2 separate days, 10 sprint-trained males (age = 26.4 +/- 5.3 yr; Ht = 1.77 +/- 0.03 m; Wt = 78.78 +/- 9.10 kg; BF% = 13.96 +/- 7.28%) completed 4, 3-min bouts of cycling at 50% mean anaerobic power, with 6 min of rest between bouts. On CHO day, subjects ingested 50g of CHO 30 min before exercise. On control day, subjects ingested a sugar-free drink (CON) 30 min before exercise. Blood was drawn before supplementation, 15 min before exercise, before and after each exercise bout, and 15 and 30 min post exercise. Visfatin, glucose, and insulin were determined. Truncal fat was assessed by dual energy x-ray. Visfatin was not significantly different between treatments (CHO vs CON) at any time point (p = 0.163), and was not significantly altered by exercise (p = 0.692). Insulin [25.65 vs 8.35 mU/l, CHO vs CON, respectively] and glucose [138.57 vs 98.10 mg/dl, CHO vs CON, respectively] were significantly elevated after CHO ingestion and remained elevated throughout the first half of exercise. Baseline visfatin was significantly correlated with truncal fat (r2 = 0.7782, p < 0.05). Visfatin was correlated to truncal fat in sprint-trained males, but was not altered by exercise or CHO supplementation. PMID- 28344454 TI - The Effect of Intermittent Head Cooling on Aerobic Performance in the Heat. AB - Thermoregulation is critical for athletes, particularly those for those who must perform in the heat. Most strategies aimed at reducing heat stress have cooled participants before or during activity. The objective of this study is to investigate whether seven minutes of head cooling applied between bouts of aerobic exercise in hot (35 +/- 1.0 degrees C) and dry (14.68 +/-4.29% rh) environmental conditions could positively effect participants peak power output (PP) on a maximal effort graded exercise test (GXT). Twenty-two recreational active men ages 18 to 23 (19.8 +/- 1.6 yrs.) completed three performance trials over a 21 day period. During the first trial, participants were familiarized with procedures and completed a maximal effort GXT on a cycle ergometer to establish maximal baseline performances. The second and third trials, which were counterbalanced, consisted of a cooling and placebo condition. During both of these trials, participants cycled 40 minutes at 65% of their maximum VO2, in hot (35 +/- 1.0 degrees C) and dry (17-20% rh) environmental conditions. Immediately after this initial bout of activity, participants were given seven minutes of recovery in which head cooling was applied during the cooling condition and withheld during the placebo condition. Participants then completed a maximal effort GXT. Significant differences (p < 0.001) in participants peak power output (W) were measured when cooling was applied compared to the placebo condition (304.23(W) +/- 26.19(W) cooling, 291.68(W) +/- 26.04(W) placebo). These results suggest that a relatively brief period of intermittent cooling may enhance subsequent aerobic performance. PMID- 28344455 TI - Running and Metabolic Demands of Elite Rugby Union Assessed Using Traditional, Metabolic Power, and Heart Rate Monitoring Methods. AB - The aims of this study were (1) to analyze elite rugby union game demands using 3 different approaches: traditional, metabolic and heart rate-based methods (2) to explore the relationship between these methods and (3) to explore positional differences between the backs and forwards players. Time motion analysis and game demands of fourteen professional players (24.1 +/- 3.4 y), over 5 European challenge cup games, were analyzed. Thresholds of 14.4 km.h-1, 20 W.kg-1 and 85% of maximal heart rate (HRmax) were set for high-intensity efforts across the three methods. The mean % of HRmax was 80.6 +/- 4.3 % while 42.2 +/- 16.5% of game time was spent above 85% of HRmax with no significant differences between the forwards and the backs. Our findings also show that the backs cover greater distances at high-speed than forwards (% difference: +35.2 +/- 6.6%; p<0.01) while the forwards cover more distance than the backs (+26.8 +/- 5.7%; p<0.05) in moderate-speed zone (10-14.4 km.h-1). However, no significant difference in high metabolic power distance was found between the backs and forwards. Indeed, the high-metabolic power distances were greater than high-speed running distances of 24.8 +/- 17.1% for the backs, and 53.4 +/- 16.0% for the forwards with a significant difference (+29.6 +/- 6.0% for the forwards; p<0.001) between the two groups. Nevertheless, nearly perfect correlations were found between the total distance assessed using the traditional approach and the metabolic power approach (r = 0.98). Furthermore, there is a strong association (r = 0.93) between the high-speed running distance (assessed using the traditional approach) and the high-metabolic power distance. The HR monitoring methods demonstrate clearly the high physiological demands of professional rugby games. The traditional and the metabolic-power approaches shows a close correlation concerning their relative values, nevertheless the difference in absolute values especially for the high intensity thresholds demonstrates that the metabolic power approach may represent an interesting alternative to the traditional approaches used in evaluating the high-intensity running efforts required in rugby union games. PMID- 28344456 TI - Caffeine Ingestion Improves Repeated Freestyle Sprints in Elite Male Swimmers. AB - The purpose of this investigation was to determine the efficacy of a moderate dose of caffeine to improve repeat-sprint performance in elite freestyle sprinters. Nine highly trained male swimmers performed 6 x 75 m freestyle sprints on two occasions 1-h after consuming either 3 mg.kg-1 caffeine (CAF), or placebo, in a cross-over manner. Capillary blood samples for the analysis of blood lactate concentration and pH were collected after the 1st, 3rd, and 5th sprint, while heart rate and perceived exertion (RPE) were collected after every sprint. There was a moderate effect for improved mean sprint time in the CAF condition (0.52 s; 1.3%; d = 0.50). When assessed individually, there was a large effect for improved performance in sprints 3 (1.00 s; 2.5%; d = 1.02) and 4 (0.84 s; 2.1%; d = 0.84) in CAF compared to placebo, with worthwhile performance improvement found for each of the first 5 sprints. There was a significant treatment effect for higher blood lactate concentration for CAF (p = 0.029), and a significant treatment*time effect for reduced pH in the CAF condition (p = 0.004). Mean heart rate (167 +/- 9 bpm vs 169 +/- 7 bpm) and RPE (17 +/- 1 vs 17 +/- 1) were not different between placebo and CAF trials, respectively. This investigation is the first to demonstrate enhanced repeat-sprint ability in swimmers following acute caffeine ingestion. It appears likely that the combination of a moderate dose of caffeine (3-6 mg.kg-1) with trained athletes is most likely to enhance repeat sprint ability in various athletic populations; however, the exact mechanism(s) for an improved repeat-sprint ability following acute caffeine ingestion remain unknown. PMID- 28344457 TI - Bone Mineralization in Rhythmic Gymnasts Entering Puberty: Associations with Jumping Performance and Body Composition Variables. AB - This study examined bone mineral density (BMD) accrual in prepubertal rhythmic gymnasts entering puberty and their age-matched untrained control girls, and associations with baseline jumping performance and body composition over the 3 year period. Whole body (WB) and femoral neck (FN) BMD, WB fat mass (FM) and fat free mass (FFM), countermovement jump (CMJ) and rebound jumps for 15 s (RJ15s) were assessed in 25 rhythmic gymnasts and 25 untrained controls at baseline and after 3-year period. The changes over this period were calculated (Delta scores). Pubertal maturation over the 3-year period was slower in rhythmic gymnasts compared to untrained controls, while no difference in bone age development was seen. WB BMD increased similarly in both groups, while the increase in FN BMD was higher in rhythmic gymnasts compared with untrained controls. In rhythmic gymnasts, baseline FFM was the most significant predictor of DeltaWB BMD explaining 19.2% of the variability, while baseline RJ15s was the most significant predictor of DeltaFN BMD explaining 18.5% of the variability. In untrained controls, baseline FM explained 51.8 and 18.9% of the variability in DeltaWB BMD and DeltaFN BMD, respectively. In conclusion, mechanical loading of high-intensity athletic activity had beneficial effect on BMD accrual in rhythmic gymnasts and may have counterbalanced such negative factors on bone development as slower pubertal maturation and lower body FM. Baseline FFM and repeated jumps test performance were related to BMD accrual in rhythmic gymnasts, while baseline FM was related to BMD accrual in untrained controls. PMID- 28344458 TI - The Effects of Non-Contingent Feedback on the Incidence of Plateau at VO2max. AB - : The purpose of this study was to examine the effects of non-contingent feedback in the form of heart rate (HR) on the incidence of plateau at VO2max. Ten physically active males (age 24.8 yrs +/- 4.2; mass 81.4 +/- 9.0 kg; stature 1.80 +/- 0.11 m, VO2max 53.2 +/- 5.8 ml.kg-1.min-1) who were VO2max testing naive but were cognisant as to the heart rate responses to exercise completed four incremental tests to volitional exhaustion, separated by ~72 h for the determination of VO2max and gas exchange threshold. The first trial served as a familiarisation with the remaining three being experimental conditions where HR was presented in a screen projection as either the actual response (HR-A) or 10 b.min-1 higher than recorded (HR-H) or 10 b.min-1 lower (HR-L). Throughout all trials VO2 was recorded on a breath-by-breath basis with plateau criteria of <= 50 ml.min-1. RESULTS: A significant difference was observed for Delta VO2 over the final two consecutive 30s sampling periods between HR-A, both HR-L and HR-H (p = 0.049) and for the incidence of plateau response between condition (p = 0.021). An additional significant difference was observed for sub-maximal Delta VO2 responses between HR-A and HR-H (p = 0.049) and HR-A and HR-L (p = 0.006). Non-significant differences were observed for all other criteria. These data indicate that when presented with non-contingent feedback in the form of HR, that the perceptually orientated pacing schema becomes disrupted promoting a sparing of the finite anaerobic capacity to compensate for the imbalance between the afferent signal and perception of effort. PMID- 28344459 TI - Applied Sports Nutrition Support, Dietary Intake and Body Composition Changes of a Female Athlete Completing 26 Marathons in 26 Days: A Case Study. AB - The aim of this case study is to describe the nutrition practices of a female recreational runner (VO2max 48.9 ml.kg-1.min-1) who completed 26 marathons (42.195 km) in 26 consecutive days. Information relating to the nutritional intake of female runners during multi-day endurance events is extremely limited, yet the number of people participating year-on-year continues to increase. This case study reports the nutrition intervention, dietary intake, body composition changes and performance in the lead-up and during the 26 days. Prior to undertaking the 26 marathon challenge, three consultations were held between the athlete and a sports nutrition advisor; planning and tailoring the general diet and race-specific strategies to the endurance challenge. During the marathons, the mean energy and fluid intake was 1039.7 +/- 207.9 kcal (607.1 - 1453.2) and 2.39 +/- 0.35 L (1.98 - 3.19). Mean hourly carbohydrate intake was 38.9 g.hr-1. 11 days following the completion of the 26 marathons, body mass had reduced by 4.6 kg and lean body mass increasing by 0.53 kg when compared with 20 days prior. This case study highlights the importance of providing general and event-specific nutrition education when training for such an event. This is particularly prudent for multi-day endurance running events. PMID- 28344460 TI - Intra- and Inter-Rater Reliability of the Modified Tuck Jump Assessment. AB - The Tuck Jump Assessment (TJA) is a clinician-friendly screening tool that was designed to support practitioners with identification of neuromuscular deficits associated with anterior cruciate ligament injury. This study aimed to evaluate the inter- and intra-rater reliability of the modified scoring (0 to 2) TJA to add an additional range of objectivity for each criterion. A total of 24 elite youth volleyball athletes (12 males and 12 females) were included in this study. Each participant's recorded performance of the TJA was scored independently by two raters across ten criteria using the modified scale. The two raters then scored the same videos one week later. Another investigator who was blind to the identity of the raters analyzed the scores from both raters for each participant. Kappa coefficient (k) and percentage of exact agreement (PEA) for both intra- and inter-rater reliability were analyzed for each item. Intraclass correlation coefficients (ICC) were calculated to determine intra- and inter-rater reliability of the modified TJA total score. Intra- and inter-rater k was good to excellent for most items (0.65-0.91). Average PEA between the two raters and two sessions ranged from 83.3 to 100% in all scored items. The ICC for the total score was excellent in both inter- and inter-rater correlations (0.94-0.96). This research demonstrated that the modified version of the TJA predominantly shows good to excellent intra- and inter-rater reliability in all analyzed criteria. PMID- 28344461 TI - Within Session Sequence of Balance and Plyometric Exercises Does Not Affect Training Adaptations with Youth Soccer Athletes. AB - The integration of balance and plyometric training has been shown to provide significant improvements in sprint, jump, agility, and other performance measures in young athletes. It is not known if a specific within session balance and plyometric exercise sequence provides more effective training adaptations. The objective of the present study was to investigate the effects of using a sequence of alternating pairs of exercises versus a block (series) of all balance exercises followed by a block of plyometric exercises on components of physical fitness such as muscle strength, power, speed, agility, and balance. Twenty-six male adolescent soccer players (13.9 +/- 0.3 years) participated in an 8-week training program that either alternated individual balance (e.g., exercises on unstable surfaces) and plyometric (e.g., jumps, hops, rebounds) exercises or performed a block of balance exercises prior to a block of plyometric exercises within each training session. Pre- and post-training measures included proxies of strength, power, agility, sprint, and balance such as countermovement jumps, isometric back and knee extension strength, standing long jump, 10 and 30-m sprints, agility, standing stork, and Y-balance tests. Both groups exhibited significant, generally large magnitude (effect sizes) training improvements for all measures with mean performance increases of approximately >30%. There were no significant differences between the training groups over time. The results demonstrate the effectiveness of combining balance and plyometric exercises within a training session on components of physical fitness with young adolescents. The improved performance outcomes were not significantly influenced by the within session exercise sequence. PMID- 28344462 TI - Effects of Neuromuscular Training on the Rear-foot Angle Kinematics in Elite Women Field Hockey Players with Chronic Ankle Instability. AB - The aims of this study were to investigate the ankle position, the changes and persistence of ankle kinematics after neuromuscular training in athletes with chronic ankle instability (CAI). A total of 21 national women's field hockey players participated (CAI = 12, control = 9). Ankle position at heel strike (HS), midstance (MS), and toe touch (TT) in the frontal plane during walking, running and landing were measured using 3D motion analysis. A 6-week neuromuscular training program was undertaken by the CAI group. Measurements of kinematic data for both groups were measured at baseline and the changes in kinematic data for CAI group were measured at 6 and 24 weeks. The kinematic data at HS during walking and running demonstrated that the magnitude of the eversion in the CAI group (-5.00 degrees and -4.21 degrees ) was less than in the control group ( 13.45 degrees and -9.62 degrees ). The kinematic data at MS also exhibited less ankle eversion in the CAI group (-9.36 degrees and -8.18 degrees ) than in the control group (-18.52 degrees and -15.88 degrees ). Ankle positions at TT during landing were comparable between groups. Following the 6-week training, the CAI participants demonstrated a less everted ankle at HS during walking and running ( 1.77 degrees and -1.76 degrees ) compared to the previous positions. They also showed less ankle eversion at MS (-5.14 degrees and -4.19 degrees ). Ankle orientation at TT changed significantly to an inverted ankle position (from -0.26 degrees to 4.11 degrees ). The ankle kinematics were restored back to the previous positions at 24 weeks except for landing. It appeared that athletes with unstable ankle had a relatively inverted ankle position, and that 6-week neuromuscular training had an immediate effect on changing ankle orientation toward a less everted direction. The changed ankle kinematics seemed to persist during landing but not during walking and running. PMID- 28344463 TI - Curcumin and Piperine Supplementation and Recovery Following Exercise Induced Muscle Damage: A Randomized Controlled Trial. AB - The aim of this study was to analyze the effects of oral consumption of curcumin and piperine in combination on the recovery kinetics after exercise-induced muscle damage. Forty-eight hours before and following exercise-induced muscle damage, ten elite rugby players consumed curcumin and piperine (experimental condition) or placebo. A randomized cross-over design was performed. Concentric and isometric peak torque for the knee extensors, one leg 6 seconds sprint performance on a non-motorized treadmill, counter movement jump performance, blood creatine kinase concentration and muscle soreness were assessed immediately after exercise, then at 24h, 48h and 72h post-exercise. There were moderate to large effects of the exercise on the concentric peak torque for the knee extensors (Effect size (ES) = -1.12; Confidence interval at 90% (CI90%): -2.17 to -0.06), the one leg 6 seconds sprint performance (ES=-1.65; CI90% = -2.51to 0.80) and the counter movement jump performance (ES = -0.56; CI90% = -0.81 to 0.32) in the 48h following the exercise. There was also a large effect of the exercise on the creatine kinase level 72h after the exercise in the control group (ES = 3.61; CI90%: 0.24 to 6.98). This decrease in muscle function and this elevation in creatine kinase indicate that the exercise implemented was efficient to induce muscle damage. Twenty four hours post-exercise, the reduction (from baseline) in sprint mean power output was moderately lower in the experimental condition (-1.77 +/- 7.25%; 1277 +/- 153W) in comparison with the placebo condition (-13.6 +/- 13.0%; 1130 +/- 241W) (Effect Size = -1.12; Confidence Interval 90%=-1.86 to -0.86). However, no other effect was found between the two conditions. Curcumin and piperine supplementation before and after exercise can attenuate some, but not all, aspects of muscle damage. PMID- 28344464 TI - The Biomechanics of Standing Start and Initial Acceleration: Reliability of the Key Determining Kinematics. AB - The reliability of the key determining kinematic variables associated with short sprint performance provide insight into how and why movement may vary between individual trials. Currently, literature surrounding these determinants is scarce when investigating the first three strides of a sprint. The purpose of this study was to investigate the reliability of sprint acceleration and the key kinematic determinants involved during the first three steps of the movement. The aim was to use a practical method of kinematic analysis to help explain why changes may occur in sprint performance via the use of correlative statistics and to provide reference values for intervention research to make conclusions about their change scores. Ten male volunteers from various team sports attended two separate testing sessions, a minimum of 48 hours apart. They performed three maximal sprint trials over a 10m distance from a standing start, where researchers captured 5m and 10m sprint times alongside high speed camera footage, from which the key kinematic variables were measured. Results demonstrated that although 5m and 10m sprint times depicted moderate to large levels of similarity between sessions, neither of these variables met the criteria to be classified as adequately, or highly reliable. Kinematic measures typically produced ICC values > 0.70 and CV% < 10%, demonstrating all relevant statistical traits to be categorised as reliable measures. Step frequency and flight time during the third step showed the largest correlation with performance, exhibiting 'r' values of 0.386 and 0.396, respectively. These findings demonstrate that kinematic variables may not have an influential role with sprint times; therefore suggesting kinetic concepts may in fact be the key determinants of speed. Future research is required investigating the interaction of kinetic and kinematic variables associated with sprinting and how the variability in these concepts effects the reliability of performance. PMID- 28344466 TI - An overview of pharmacodynamic modelling, ligand-binding approach and its application in clinical practice. AB - The study of the magnitude and variation of drug response is defined as pharmacodynamics (PDs). PD models examine plasma concentration and effect relationship. It can predict the archetypal effect ([Formula: see text]) of a drug as a function of the drug concentration ([Formula: see text]) and estimate an unknown PD parameter ([Formula: see text]). The PD models have been described as fixed, linear, log-linear, [Formula: see text], sigmoid [Formula: see text], and indirect PD response. Ligand binding model is an example of a PD model that works on the underpinning PD principle of a drug, eliciting its pharmacological effect at the receptor site. The pharmacological effect is produced by the drug binding to the receptor to either activate or antagonise the receptor. Ligand binding models describe a system of interacting components, i.e. the interaction of one or more ligands with one or more binding sites. The [Formula: see text] model is the central method that provides an empirical justification for the concentration/dose-effect relationship. However, for ligand binding models justification is provided by theory of receptor occupancy. In essence, for ligand binding models, the term [Formula: see text] is best used to describe the fraction of receptors occupied at a particular ligand concentration. It is stated that the [Formula: see text], which means the effect of a drug should depend on the fraction of receptors that are occupied. In the future, network-based systems pharmacology models using ligand binding principles could be an effective way of understanding drug-related adverse effects. This will facilitate and strengthen the development of rational drug therapy in clinical practice. PMID- 28344467 TI - Temperature excursion management: A novel approach of quality system in pharmaceutical industry. AB - Quality of pharmaceutical product largely depends upon the environment controls during its storage and handling. Each pharmaceutical product should be handled and stored under specified storage condition labelled on product information data sheet or product pack. Hence the temperature excursions during receipt of raw materials, manufacturing of pharmaceutical products and distribution should be managed during entire product life cycle with holistic approach. The research is based on primary data and exploratory study through literature review. The temperature excursion may be observed during transportation of raw materials manufacturing as well as distribution of pharmaceutical products, which have potential to deteriorate the product quality. Temperature excursion in pharmaceutical industry should be recorded and reported to the manufacturer for further investigation and risk analysis. The concept of temperature excursions, its reasons, consequences and handling mechanism should be well understood to ensure the concerted efforts under the aegis of Quality Management System. Based on the reasons and consequences of temperature excursions during pharmaceutical operations, a system based quality management has been envisaged through this study. The concept and procedure to handle temperature excursion have evolved after this study which shall be useful to pharmaceutical industry as well as to medicine distributors and consumers. PMID- 28344468 TI - High-performance thin layer chromatography based assay and stress study of a rare steroidal alkaloid solanopubamine in six species of Solanum grown in Saudi Arabia. AB - The present study describes a method developed for quantification and stability study of a rare steroidal alkaloid solanopubamine (SPN) in aerial parts of six different species of genus Solanum extracted with two different solvents. The Solanum species selected for investigation include S. schimperianum (SS), S. villosum (SV), S. coagulans (SC), S. glabratum (SG), S. incanum (SI) and S. nigrum (SN). The estimation of SPN was done by a validated high-performance thin layer chromatography method. The developed chromatographic system was found to give a sharp spot for solanopubamine at Rf = 0.39 +/- 0.01. The steroidal alkaloid SPN was observed to be present only in extracts of aerial parts of S. schimperianum. The sensitivity of developed method produced 40 ng and 115 ng band 1, respectively as LOD and LOQ values. The percentage yield of SPN in aerial parts of S. schimperianum extracted by ethanol (95%) only and a mixture of ethanol and ammonium hydroxide (6:4) was found to be 1.03 w/w and 2.09 w/w, respectively. Stability studies of SPN exhibited the maximum (100%) degradation in an alkaline environment and H2O2 treated samples and 61.4% in acidic conditions. The SPN was found to be significantly stable against UV exposure, photo-oxidation and at room temperature while 13.83% and 57.88% destruction has been observed when exposed to dry heat at 40 degrees C and 60 degrees C, respectively. PMID- 28344465 TI - The Pharmacological Potential of Rutin. AB - The contemporary scientific community has presently recognized flavonoids to be a unique class of therapeutic molecules due to their diverse therapeutic properties. Of these, rutin, also known as vitamin P or rutoside, has been explored for a number of pharmacological effects. Tea leaves, apples, and many more possess rutin as one of the active constituents. Today, rutin has been observed for its nutraceutical effect. The present review highlights current information and health-promoting effects of rutin. Along with this, safety pharmacology issues and SAR of the same have also been discussed. PMID- 28344469 TI - Acute toxicity profiling of the ethyl acetate fraction of Swietenia macrophylla seeds and in-vitro neuroprotection studies. AB - Swietenia macrophylla (SM) is a medicinally important plant found in tropical and subtropical regions of the world. The ethyl acetate fraction of the seeds of S. macrophylla (SMEAF) is reported to exhibit potent anticancer, antitumor, anti inflammatory and antifeedant activities. Till date, there have been no studies reported on the acute oral toxicity profile of the ethyl acetate fraction of the seeds of SM. The objective of the present study was to determine the acute toxicity of SMEAF and evaluate the in-vitro neuroprotective activity of SMEAF using primary neuronal cell cultures. In acute oral toxicity study, the SMEAF did not produce any lethal signs of morbidity and mortality. Histo-pathological findings, support the safety of SMEAF, as there were no significant changes observed in any of the parameters studied. Based on the results obtained in MTT assay, we infer that SMEAF has a significant neuroprotective effect, as it increased the cell viability and exhibited protection to the neuronal cells against TBHP induced oxidative stress. Thus, SMEAF can be suggested for use in the development of herbal drug formulations with neuroprotective potential. PMID- 28344470 TI - Prolonged exposure of colon cancer cells to 5-fluorouracil nanoparticles improves its anticancer activity. AB - In this study, we aimed to improve the anticancer effect of 5-FU on human colon cancer cell lines by incorporating in poly(d,l lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). The 5-FU-PLGA NPs were prepared by nanoprecipitation technique. Prepared NPs were moderately dispersed with an average diameter of 133 +/- 25.19 nm. Scanning Electron Microscope (SEM) images revealed spherical structures with subtle surface irregularity. Free 5-FU dose-response curves were constructed (12.5-2000 MUM) using MTT assay on HCT 116 and HT-29 cell lines for 1, 3, and 5 days. The calculated IC50 on HCT 116 were 185 MUM after 1 day, 11.3 MUM after 3 days, and 1.48 MUM after 5 days. On HT-29, IC50 was only reached after 5 days of 5-FU treatment (11.25 MUM). The HCT 116 viability following treatment with 100 MUM 5-FU in free or NPs forms for 3 days was 38.8% and 18.6%, respectively. Similarly, when 250 MUM was applied, HCT 116 viability was 17.03% and 14.6% after treatment with free and NPs forms of 5-FU, respectively. Moreover, HT-29 cell viability after 250 MUM 5-FU treatment in free or NPs forms was 55.45% and 34.01%, respectively. We also noticed that HCT 116 cells were more sensitive to 5-FU-PLGA NPs as compared to HT-29 cells. Overall, our data indicate that 5-FU activity is time dependent and the prolonged effects created by PLGA NPs may contribute, at least in part, to the noticed enhancement of the anticancer activity of 5-FU drug. PMID- 28344471 TI - Synthesis and evaluation of anticancer activity of 6-pyrazolinylcoumarin derivatives. AB - A series of novel 6-pyrazolinylcoumarins has been synthesized via multi-step protocol. The synthetic procedure was based on the acetylation of hydroxycoumarins; Fries rearrangement and Claisen-Schmidt condensation; the target 6-[5-aryl-4,5-dihydropyrazol-3-yl]-5-hydroxy-7-methylcoumarins (33-49) were obtained under reactions of hydrazine and 2-aryl-5-methyl-2,3 dihydropyrano[2,3-f]chromen-4,8-diones as the last phase of the protocol. Anticancer activity screening in NCI60-cell lines assay allowed identification of compound 47 with the highest level of antimitotic activity with mean GI50 value of 10.20 MUM and certain sensitivity profile toward the Leukemia cell lines CCRF CEM and MOLT-4 (GI50/TGI values 1.88/5.06 MUM and 1.92/4.04 MUM respectively). PMID- 28344473 TI - d-alpha-tocopherol nanoemulsions: Size properties, rheological behavior, surface tension, osmolarity and cytotoxicity. AB - The aim of this study was the assessment of the physicochemical stability of d alpha-tocopherol formulated in medium chain triglyceride nanoemulsions, stabilized with Tween(r)80 and Lipoid(r)S75 as surfactant and co-surfactant, respectively. d-alpha-tocopherol was selected as active ingredient because of its well-recognized interesting anti-oxidant properties (such as radical scavenger) for food and pharmaceutical industries. A series of nanoemulsions of mean droplet size below 90 nm (polydispersity index < 0.15) have been produced by high pressure homogenization, and their surface electrical charge (zeta potential), pH, surface tension, osmolarity, and rheological behavior, were characterized as a function of the d-alpha-tocopherol loading. In vitro studies in Caco-2 cell lines confirmed the safety profile of the developed nanoemulsions with percentage of cell viability above 90% for all formulations. PMID- 28344472 TI - Prevalence of UDP-glucuronosyltransferase polymorphisms (UGT1A6*2, 1A7*12, 1A8*3, 1A9*3, 2B7*2, and 2B15*2) in a Saudi population. AB - Glucuronidation is an important phase II pathway responsible for many endogenous substances and drug metabolism. The present work evaluated allele frequencies of certain UDP-glucuronosyl-transferases (UGT 1A6*2, A7*12, A8*3, A9*3, 2B7*2, and 2B15*2) in Saudi Arabians that could provide essential ethnic information. Blood samples from 192 healthy unrelated Saudi males of various geographic regions were collected. Genomic DNA was isolated and genotyping of various UGTs was carried out using polymerase chain reaction (PCR) followed by direct sequencing. For UGT1A6*2 A/G genotype, the most common variant was the homozygous repeat (AA) and the most common allele was (A) with a frequency of 46.5% and 67.3%, respectively. Similarly, the most common variant for UGT1A7*12 T/C genotype was the heterozygous repeat (TC) with a frequency of 78.7% while the mutant allele (C) was present in 60.6% of the study population. Both UGT1A8*3 (G/A) and UGT1A9*3 (T/C) showed only a wild homozygous pattern in all screened subjects. For UGT2B7*2, the heterozygous repeat (TC) was found with a frequency of 57.3% and the alleles (A) showed a frequency of 50.8%. In contrast, for UGT2B15*2 (G253T), the heterozygous repeat (TG) presented 62.3% of the subjects where the most common allele (G) was with a frequency of 66.2%. In conclusion, our data indicate that Saudis harbor some important UGT mutations known to affect enzyme activity. Additional studies are therefore, warranted to assess the clinical implications of these gene polymorphisms in this ethnic group. PMID- 28344474 TI - Biologically-guided isolation of leishmanicidal secondary metabolites from Euphorbia peplus L. AB - Leishmaniasis is a worldwide health problem, highly endemic in developing countries. Moreover, the severe side effects and the reported drug resistance make it an urgent need to search for effective drugs that can replace or supplement those currently used. In a research program designed to investigate the antileishmanial activity of plants collected from the Egyptian flora, twenty extracts from fifteen plants growing in Egypt have been investigated for in vitro leishmanicidal activity against Leishmania donovani promastigotes. Among the tested extracts, the methanol extract of Euphorbia peplus aerial parts exhibited a significant antileishmanial activity as it produced 100% inhibition of growth with activity similar to amphotericin B. The total extract was subjected to liquid-liquid fractionation using solvents of different polarities, followed by testing the antileishmanial activity of the successive fractions. Phytochemical exploration of the active n-hexane fraction (which produced 75% inhibition of growth) led to isolation of four compounds: simiarenol (1), 1-hexacosanol (2), beta-sitosterol (3), and beta-sitosterol-3-O-glucoside (4) from the biologically active sub-fractions. Structure elucidation was aided by 1D and 2D NMR techniques. In conclusion, E. peplus plant has many non-polar secondary metabolites that can be used as drug leads for treatment of leishmaniasis. PMID- 28344475 TI - Antiproliferative and apoptotic effect of Morus nigra extract on human prostate cancer cells. AB - Background: Morus nigra L. belongs to the family Moraceae and is frequently used in traditional medicine. Numerous studies have investigated the antiproliferative effects of various extracts of different Morus species, but studies involving the in vitro cytotoxic effect of M. nigra extract are very limited. The purpose of this study was to evaluate the phenolic composition and antioxidant activity of dimethyl sulfoxide extract of M. nigra (DEM) and to investigate, for the first time, the probable cytotoxic effect in human prostate adenocarcinoma (PC-3) cells together with the mechanism involved. Methods: Total polyphenolic contents (TPC), ferric reducing antioxidant power (FRAP) and phenolic compounds of DEM were evaluated using spectrophotometric procedures and HPLC. The cytotoxic effect of DEM on PC-3 cells was revealed using the MTT assay. Mechanisms involved in the cytotoxic effect of DEM on PC-3 cells were then investigated in terms of apoptosis, mitochondrial membrane potential and cell cycle using flow cytometry, while caspase activity was investigated using luminometric analysis. Results: TPC and FRAP values were 20.7 +/- 0.3 mg gallic acid equivalents and 48.8 +/- 1.6 mg trolox equivalents per g sample, respectively. Ascorbic acid and chlorogenic acid were the major phenolic compounds detected at HPLC analysis. DEM arrested the cell cycle of PC-3 cells at the G1 phase, induced apoptosis via increased caspase activity and reduced mitochondrial membrane potential. Conclusions: Our results indicate that M. nigra may be a novel candidate for the development of new natural product based therapeutic agents against prostate cancer. PMID- 28344476 TI - Effect of Pelargonidin isolated from Ficus benghalensis L. on phenotypic changes in zebrafish (Danio rerio) embryos. AB - In the present study, the extraction and isolation of Pelargonidin, an anthocyanin compound from stem bark of Ficus benghalensis are described. The study also involves evaluation of the effect of Pelargonidin on phenotypic variations in zebra fish embryos. Extraction and isolation of Pelargonidin were carried out by employing liquid-liquid extraction technique, phytochemical tests, column chromatography, UV and FT-IR. In the zebra fish embryo model, Paclitaxel was employed as a negative control. A series of phenotypic changes in different stages of embryonic development were studied with treatment concentrations of Pelargonidin between 3.0 and 20 ppm at 0-72-hour post-fertilization (hpf). The results of our studies indicate that, after exposure of zebra fish embryos to 3.3 20 ppm concentration of Pelargonidin for 72 h, a significant reduction in aortic development occurs. At the dose level of 0.5 ppm Paclitaxel and Pelargonidin in the dose range between 3.3 and 20 ppm, the zebra fish embryos were found to have bent tail, malformed eyes and developmental delays in vasculature. Based on the results obtained, we infer that Pelargonidin can exhibit phenotypic anti angiogenic variations in embryonic stage of fish embryos and it can be applied in future for exploration of its anti-angiogenic potential. Furthermore, Pelargonidin could serve as a candidate drug for in vivo inhibition of angiogenesis and can be applied for the treatment of neovascular diseases and tumor. PMID- 28344477 TI - Development and characterization of methoxy poly(ethylene oxide)-block poly(epsilon-caprolactone) (PEO-b-PCL) micelles as vehicles for the solubilization and delivery of tacrolimus. AB - Tacrolimus is a potent immunosuppressant; however, it suffers from several problems such as poor water solubility (4-12 MUg/mL), low and variable oral bioavailability in patients, and narrow therapeutic window that could not be solved by the currently available i.v. formulation (Prograf(r)). Moreover, Prograf(r) contains HCO-60 (PEGylated castor oil) as a surfactant, which is reported to cause several side effects including hypersensitivity reactions. Therefore, the aim of the present study was to investigate the potential of PEO-b PCL polymeric micelles as alternative vehicles for the solubilization and delivery of tacrolimus. Four PEO-b-PCL block copolymers, with different molecular weights of PCL, were synthesized by ring opening polymerization of epsilon caprolactone using methoxy polyethylene oxide (5,000 g mol-1) as initiator and stannous octoate as catalyst. Synthesized copolymers were characterized for their average molecular weights and polydispersity index by 1H NMR and gel permeation chromatography (GPC), respectively. Drug-free micelles of PEO-b-PCL were prepared through a co-solvent evaporation method using acetone as the organic co-solvent. Tacrolimus-loaded micelles were prepared using the same method with different initial amounts of drug. Prepared micelles were characterized for their mean diameter size and polydispersity of the micellar population by dynamic light scattering, and an HPLC assay was used to determine the encapsulation efficiency of tacrolimus. The average molecular weights of the synthesized copolymers were in the range of 8,400-28,000 with narrow distributions (PDI = 1.06-1.11). The copolymers were designated according to the degree of polymerization of epsilon caprolactone, namely PEO114-b-PCL30, PEO114-b-PCL60, PEO114-b-PCL120, and PEO114 b-PCL200. All the prepared micelles were having diameters sizes less than 100 nm with narrow distributions. The highest drug solubilization was achieved with PEO114-b-PCL120, where the aqueous solubility of tacrolimus exceeded 300 MUg/mL. Our results show a potential for PEO-b-PCL micelles as solubilizing vehicles for the delivery of tacrolimus. PMID- 28344478 TI - Synthesis and antimicrobial properties of 4-acylaminobenzenethiosulfoacid S esters. AB - A series of esters of 4-acetyl, 4-trifluoroacetyl- and 4-(3 chloropropionyl)aminobenzenethiosulfoacids (twenty-four compounds) were synthesized and characterized by elemental analysis, 1H NMR and IR spectroscopy. The antibacterial activity of the novel candidates has been screened using the agar diffusion or serial dilution methods against representative Gram-positive (Staphylococcus aureus, Bacillus subtilis, Bacillus mesentericus, Mycobacterium sp., Mycobacterium luteum), Gram-negative (Aeromonas sp., Burkholderia cepacia, Alcaligenes faecalis, Pseudomonas aeruginosa, Escherichia coli, Proteus vulgaris) bacteria and fungi (Candida albicans, Candida tenuis, Candida glabrata, Verticillium dahliae, Trichophyton gypseum, Aspergillus niger, Aspergillus fumigatus, Penicillium chrysogenum). Particular potency has been discovered against all tested pathogenic bacteria and fungi by compounds 1l and 3l at nanomolar concentrations. Some appropriate effect of thiosulfoesters structure upon their antimicrobial activity was determined. PMID- 28344479 TI - Synthesis of chalcone incorporated quinazoline derivatives as anticancer agents. AB - A series of ten novel chalcone incorporated quinazoline derivatives (11a-11j) were designed and synthesized. All the synthesized compounds were evaluated for their anticancer activities against four human cancer cell lines (A549, HT-29, MCF-7 and A375). Among them, four compounds, 11f, 11g, 11i and 11j showed more potent anticancer activity than the control drug, Combretastatin - A4. PMID- 28344480 TI - Changing paradigms in bioequivalence trials submitted to the EMA for evaluation - A clinical and regulatory perspective. AB - BACKGROUND: The selection of a robust bioequivalence (BE) study designs for registering a generic product remains still a hard task. This task is still challenging despite the fact that generic products are much needed by health care providers in economical terms. Thus, BE study designs could be a means to allow companies to reduce costs and reach the market earlier. We therefore investigated whether different approaches in various products assessed by the European Medicines Agency during the approval phase resulted in a reduction in resources required to show bioequivalence for different medicinal products. METHODS: European Public Assessment Reports (EPARs) for off-patent medicinal products authorised within the European Union (EU) through the centralised procedure during the period 2007-2015 were retrieved and reviewed to identify the clinical studies that resulted in fewer number of subjects, the number of centres or trial duration versus the two-period crossover design. RESULTS: 7 studies out of 108 were considered as having benefitted from having a different design. Differences noted included having a different dose allocation scheme, having a different number of dosing periods, having a different number of treatment arms, and having one study evaluating different strengths. Benefits noted included a decrease in the number of subjects and centres required, decreases in study duration and a reduced number of studies required to demonstrate bioequivalence. CONCLUSION: Bioequivalence studies can be designed in a specific manner to require fewer resources to carry out. Fewer resources required to register a medicinal product, could impart an advantage to companies (such as to be first on the market) or could even translate to making medicines more accessible (such as cheaper) to patients. PMID- 28344481 TI - Stability of erythropoietin repackaging in polypropylene syringes for clinical use. AB - Introduction: Epoetin alfa (Eprex(r)) is a subcutaneous, injectable formulation of short half-life recombinant human erythropoietin (rHuEPO). To current knowledge there are no published studies regarding the stability of rHuEPO once repackaging occurs (r-EPO) for clinical trial purposes. Materials and methods: We assessed EPO concentration in Eprex(r) and r-EPO syringes at 0, 60, 90, and 120 days after repackaging in polypropylene syringes. R-EPO was administered to 56 patients taking part in a clinical trial in Friedreich Ataxia. Serum EPO levels were measured at baseline and 48 h after r-EPO administration. Results: No differences were found between r-EPO and Eprex(r) syringes, but both globally decreased in total EPO content during storage at 4 degrees C. Patients receiving r-EPO had similar levels in EPO content as expected from previous trials in Friedreich Ataxia and from pharmacokinetics studies in healthy volunteers. Discussion: We demonstrate that repackaging of EPO does not alter its concentration if compared to the original product (Eprex(r)). This is true both for repackaging procedures and for the stability in polypropylene tubes. The expiration date of r-EPO can be extended from 1 to 4 months after repackaging, in accordance with pharmacopeia rules. PMID- 28344482 TI - The genetic profiles of CYP1A1, CYP1A2 and CYP2E1 enzymes as susceptibility factor in xenobiotic toxicity in Turkish population. AB - Evaluation and sequencing of heritable alterations in the human genome and the large-scale identification of gene polymorphism for understanding the genetic background of individuals in response to potential toxicants are provided by toxicogenetics. Cytochrome P450 (CYP) enzymes play role not only phase I dependent metabolism of xenobiotics but also metabolism of endogenous compounds. CYP1A1, CYP1A2 and CYP2E1 enzymes, which are in phase I enzymes, are responsible for metabolic activation and detoxification of several chemical compounds. In the present study, it was determined the genotype and allele frequency of CYP1A1*2A, CYP1A2*1C, CYP1A2*1F, CYP2E1 and CYP2E1*6, very common and functional single nucleotide polymorphisms (SNPs), in Turkish healthy volunteers. It is believed that the determination of polymorphisms in the enzymes may be beneficial to prevent and reduce and adverse effects and death in response to drugs. The allele frequencies of these genes were 24%, 9%, 33%, 42%, and 12%, respectively. In the present study, the genotype profile of Turkish population was determined about critical enzymes for xenobiotic metabolism. It is suggested that the obtained results might be beneficial in order to dose adjustment of drugs and prevention of adverse reactions, and further investigation about mentioned enzymes and their polymorphisms. PMID- 28344483 TI - Pharmacovigilance system in Saudi Arabia. AB - Pharmacovigilance plays an important role in ensuring that patients are receiving safe drugs. In Saudi Arabia, Saudi Food and Drug Authority, health institutions, marketing authorization holders and healthcare professional are involved in pharmacovigilance activities regardless of the level of the involvement. Although pharmacovigilance is well established in developed nations and it is considered a new concept in Saudi Arabia. It is a collective effort from various stakeholders to make pharmacovigilance successful toward promoting safe and effective use of medicines among the population. However, the practice of pharmacovigilance still needs more attention especially from marketing authorization holders and healthcare professionals. The aim of this review was to describe the current situation of pharmacovigilance in Saudi Arabia and the activities that have been conducted by the stakeholders. PMID- 28344484 TI - The prevalence extent of Complementary and Alternative Medicine (CAM) use among Saudis. AB - Introduction: There is worldwide interest in the use of CAM. Studying CAM in Saudi population is important as it will reflect the influence of psychosocial, cultural and religious factors on health beliefs and behaviors. The objective of this study was to present an updated review on the use of CAM practices in Saudi Arabia including commonly used types, common conditions for which it has been used and who uses CAM. Methods: This review used data from national surveys conducted in Saudi Arabia and published between 2000 and 2015. The literature search was performed considering standards adopted such as Moose guidelines for observational studies. Two authors independently reviewed each article. The search yielded 73 articles, and a total of 36 articles were included. Further careful data extraction was carried out by two independents reviewers. Results: Most of the reviewed studies were cross-sectional in design and were published between 2014 and 2015, and mostly in Riyadh region. Substantial difference in the findings for the patterns of CAM use was revealed. The most commonly employed practice was of spiritual type such as prayer and reciting Quran alone or on water. Other types include herbs (8-76%), honey (14-73%) and dietary products (6 82%). Cupping (Alhijamah) was least used (4-45%). Acupuncture was more practiced among professionals. Conclusion: The utilization of CAM is widely practiced in Saudi Arabia. There is need for efforts to promote research in the field of CAM to address each practice individually. Population surveys should be encouraged supported by mass media to raise knowledge and awareness about the practice of different CAM modalities. The national center of CAM should play a major role in these efforts. PMID- 28344486 TI - Antibiotic prophylaxis in organophosphorus poisoning: A study of health and economic outcomes. AB - Objective: Organophosphorus poisoning (OPP) is a major concern for developing countries. There are no guidelines for the prophylactic use of antibiotics in the management of OPP which in such critical cases might add to the economic burden of the patients as well as antibiotic resistance. We compared the health and economic outcomes in patients prescribed with prophylactic antibiotics with respect to the patients not prescribed with any antibiotics. Methods: A retrospective observational study was carried out for two years for patients admitted to ICU with OPP. Patients were graded for severity of OPP, and divided into two groups based on prophylactic prescription and no prescription of antibiotics. The length of stay (LOS), hospitalization cost and outcomes were measured and compared between the two groups using statistical tests. Results: Out of the 254 patients observed, 108 were prescribed with prophylactic antibiotics and 94 were not prescribed with any antibiotic. There was a significant difference between LOS, cost of treatment and outcomes in the two groups (p < 0.001). When antibiotics were not prescribed, the odds of improvement was 1.854 times higher compared to those who received prophylactic antibiotics although after adjusting for severity of poisoning, significance was lost. On an average, 2-3 antibiotics were prescribed to every patient in the first group. Conclusion: OPP is an important health concern where issues of antibiotic misuse and overuse are practiced. Our study suggested that systemic antibiotic prophylaxis did not offer any advantage over non-use of any antibiotics in patients with OPP. PMID- 28344487 TI - Synthesis, characterization and biological evaluation of novel 2,5 substituted 1,3,4 oxadiazole derivatives. AB - In the present study, a series of 3-(5-cyclohexyl-1,3,4-oxadiazol-2-yl)-N substituted aniline have been synthesized by multistep reaction scheme. Benzohydrazide was used as the starting material. The structures of all synthesized compounds are characterized and confirmed by FT-IR, 1H and C13 NMR and mass spectral studies with the intention of developing the novel biologically active compounds. All title synthetic compounds were screened for their antidiabetic, anti-inflammatory and anticancer activities. PMID- 28344488 TI - Direct and enhanced delivery of nanoliposomes of anti schizophrenic agent to the brain through nasal route. AB - The problem of inadequate oral bioavailability of Quetiapine Fumarate, a lipophilic drug used for schizophrenia, due to hepatic metabolism and repulsion by brain barrier was attempted in this study. Combination of two approaches, viz. Quetiapine inclusion into the liposomal carrier for better diffusion and administration through nasal route to avoid hepatic metabolism and barrier elimination was applied. Thin film hydration followed by sonication method was employed in liposome preparation and the formulation was optimized using 32 full factorial design. The number of sonication cycles (X1) of 2 min and 80% amplitude and molar ratio of constructional components such as cholesterol to egg phosphatidylcholine (X2) as independent variables and a % of entrapment efficiency (Y1) and cumulative in vitro drug release (Y2) at 6 h as dependent variables was selected. Batch F7 prepared by 2 cycles of sonication and 1:3 M ratio of cholesterol:egg phosphatidylcholine was optimized as a consequence of substantial entrapment efficiency of 75.63 +/- 3.77%, and 99.92 +/- 1.88% drug release and 32.33 +/- 1.53% drug diffusion, which was optimum among all other batches at 6 h. Diffusion study was done for all the batches of liposomal formulation by using sheep nasal mucosa and good amount with better diffusion rate was measured which proved liposomal dispersion a virtuous delivery system for brain drug delivery through nasal route. Results of in vivo, ciliotoxicity and gamma scintigraphy studies on mice supported the above inference. PMID- 28344489 TI - Utilization of gel electrophoreses for the quantitative estimation of digestive enzyme papain. AB - SDS-PAGE densitometric method for analysis of papain in pharmaceutical formulations was developed and validated for the first time. Standard and samples were mixed with SDS sample buffer and denatured at 95 degrees C for 5 min and the gel was run at 20 mA and 200 V for 30-40 min in SDS-PAGE buffer. Gels were stained in Coomassie blue solution and distained by 5% methanol and 10% acetic acid. Destained gels were imaged and analyzed using the ChemiDocTM XRS+ System. Bands of papain appeared at Rf value 0.78 +/- 0.03 corresponding to molecular weight 23406 Da between proteins with molecular weight 31,000 and 21,500 Da of the broad range protein standard. The generated calibration curve was used for quantitative estimation of papain in pharmaceutical formulations. The developed method was validated for precision, accuracy, specificity and robustness as described by the ICH guidelines. The proposed method gives an alternative approach for enzymes and protein analysis. PMID- 28344485 TI - Biochemical and molecular modulation of CCl4-induced peripheral and central damage by Tilia americana var. mexicanaextracts. AB - Around the world, species from the genus Tilia are commonly used because of their peripheral and central medicinal effects; they are prepared as teas and used as tranquilizing, anticonvulsant, and analgesic agents. In this study, we provide evidence of the protective effects of organic and aqueous extracts (100 mg/kg, i.p.) obtained from the leaves of Tilia americana var. mexicana on CCl4-induced liver and brain damage in the rat. Protection was observed in the liver and brain (cerebellum, cortex and cerebral hemispheres) by measuring the activity of antioxidant enzymes and levels of malondialdehyde (MDA) using spectrophotometric methods. Biochemical parameters were also assessed in serum samples from the CCl4 treated rats. The T. americana var. mexicana leaf extracts provided significant protection against CCl4-induced peripheral and central damage by increasing the activity of antioxidant enzymes, diminishing lipid peroxidation, and preventing alterations in biochemical serum parameters, such as the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-globulin (gamma-GLOB), serum albumin (ALB), total bilirubin (BB), creatinine (CREA) and creatine kinase (CK), relative to the control group. Additionally, we correlated gene expression with antioxidant activity in the experimental groups treated with the organic and aqueous Tilia extracts and observed a non-statistically significant positive correlation. Our results provide evidence of the underlying biomedical properties of T. americana var. mexicana that confer its neuro- and hepatoprotective effects. PMID- 28344490 TI - Comparison of physicochemical properties of suppositories containing starch hydrolysates. AB - The purpose of this work was to determine the effect of starch hydrolysates (SH) on the physicochemical properties of suppositories. The study was conducted with suppositories with acetaminophen (AAP) a typical antipyretic analgesic, as model drug on lipophilic (cocoa butter) and hydrophilic base (polyethylene glycol 1500 + 400). The suppositories with and without the addition of SH were examined for physicochemical tests according to European Pharmacopoeia 8th edition (Ph. Eur.): the uniformity of mass of single-dose preparation test, the softening time determination of lipophilic suppositories test, the disintegration of suppositories test, and dissolution test with flow-through apparatus. The results confirm the possibility of using starch hydrolysates as a cheap and safe addition to modify physicochemical properties of suppositories. PMID- 28344491 TI - Effect of Aster tataricus on production of inflammatory mediators in LPS stimulated rat astrocytoma cell line (C6) and THP-1 cells. AB - Neuroinflammation is the commonest cause of neurodegenerative diseases such as Alzheimer's disease. Present investigation evaluates the inhibitory effect of ethanolic root extract of Aster tataricus (AS) on inflammatory mediators production in lipopolysaccharide (LPS) stimulated C6 cells. C6 cells were treated with AS (20 and 40 mg/kg) and nimesulide (NSL, 1.5 MUg/ml) for 1 day. Thereafter various parameters such as production of ROS, release of nitrite, MDA, glutathione level and NF-kappaB translocation were estimated in C6 cell lines. Effect of AS was estimated on the expressions of tumor necrosis factor alpha (TNF alpha) of human monocytic leukemia cell line (THP-1). It was observed that AS (20 and 40 mg/ml) treated group shows significant (p < 0.01) decrease in production of ROS, Nitrite release and MDA level in LPS activated C6 cell lines compared to negative control group. Moreover, treatment with it decreases glutathione level and inhibits the translocation of NF-kappaB in LPS activated C6 cell lines compared to negative control group. There were significant (p < 0.01) decreases in expression of TNF-alpha in AS treated group compared to negative control group in THP-1 cell lines. Present investigation concludes the anti neuroinflammatory effect of ethanolic extract of AS root by decreasing oxidative stress and attenuates the cytokine. PMID- 28344492 TI - CYP2C9, CYPC19 and CYP2D6 gene profiles and gene susceptibility to drug response and toxicity in Turkish population. AB - Pharmacogenetics is a vast field covering drug discovery research, the genetic basis of pharmacokinetics and dynamics, genetic testing and clinical management in diseases. Pharmacogenetic approach usually focuses on variations of drug transporters, drug targets, drug metabolizing enzymes and other biomarker genes. Cytochrome P450 (CYP) enzymes, an essential source of variability in drug response, play role in not only phase I-dependent metabolism of xenobiotics but also metabolism of endogenous compounds such as steroids, vitamins and fatty acids. CYP2C9, CYP2C19 and CYP2D6 enzymes being highly polymorphic are responsible for metabolism of a variety of drug groups. In the study, it was determined the genotype and allele frequency of CYP2C9*2, CYP2C19*3, CYP2C19*2, CYP2C19*3, CYP2C19*17, CYP2D6*9 and CYP2D6*41, very common and functional single nucleotide polymorphisms (SNPs), in healthy volunteers. The genotype distributions were consistent with the Hardy-Weinberg equilibrium in the population (p > 0.05). It is believed that the determination of polymorphisms in the enzymes may be beneficial in order to prevention or reduction in adverse effects and death. The recessive allele frequencies of CYP2C9*2, CYP2C19*3, CYP2C19*2, CYP2C19*3, CYP2C19*17, CYP2D6*9 and CYP2D6*41 were 11, 13, 12, 13, 25, 4 and 15%, respectively. According to the obtained results, the carriers of CYP2D6*9 variant allele should be received higher doses of the drugs metabolizing with this enzyme in Turkish population, while the carriers of other variant alleles do not generally have any requirement of dose regimen. PMID- 28344493 TI - Volatile constituents and biological activities of the leaf and root of Echinacea species from South Africa. AB - Echinacea is used ethnomedicinally for the treatment of various diseases such as cough, respiratory infections, and bronchitis among other uses in Eastern Cape region of South Africa. This study evaluated the volatile components of the essential oil of the plant, its toxicity, anti-inflammatory and analgesic activities in rodents. Dried leaf and root of the plant were separately processed by hydrodistillation for 4 h and their essential oils (EOs) were collected. Extracted oils were subjected to GC/GC-MS analysis. The essential oil was further evaluated for acute toxicity, anti-inflammatory and analgesic activities. The toxicity profile of the essential oil was evaluated in mice through the oral route (p.o.), and anti-inflammatory activity was evaluated on the carrageenan induced edema model in rats at the doses of 100-200 mg/kg, while its analgesic effect was evaluated on the acetic acid-induced writhings model in mice at doses of 100-200 mg/kg. GC/GC-MS analysis of EOs showed that a number of compounds identified in the leaf and root oils were 25 and 31 respectively. The chemical compositions of the oils varied and the major compounds identified in the oils include germacrene D, naphthalene, caryophyllene oxide, alpha-phellandrene and alpha-cadinol. The essential root oil did not cause mortality at the highest dose of 5000 mg/kg; hence, its LD50 was estimated to be ?5000 mg/kg, p.o. The anti inflammatory test results showed that the essential root oil caused significant (p < 0.05-0.01) reduction in edema size compared to the negative control group on the carrageenan-induced edema and the results for the analgesic test showed that the essential root oil caused significant (p < 0.05) reduction in number of writhings at 1000 mg/kg compared to the negative control group. It is concluded that root and leaf of this Echinacea species contain volatile oils which varied in their yield and chemical compositions. The essential root oil is non-toxic orally and it demonstrated significant anti-inflammatory and analgesic activities in laboratory animals. PMID- 28344494 TI - Prophylactic and curative anti-ulcerogenic activity and the possible mechanisms of action of some desert plants. AB - The present study aimed to evaluate the anti-ulcerogenic activities and the possible mechanisms of action of seven desert plants from different families. Conyza dioscoridis (L.) Desf. (Asteraceae), Euphorbia hirta L. (Euphorpiaceae), Origanum syriacum L., Salvia lanigera L. (Lamiaceae), Sisymbrium irio L., Solanum nigrum Linn. (Solanaceae) and Solenostemma arghel (Del.) Hayne. (Asclepiadaceae), were tested using prophylactic and curative models of absolute ethanol-induced ulcer, at three doses (125, 250 & 500 mg/kg) of each extract. The investigated extracts possessed dose dependent anti-ulcerogenic activities in both models, with LD50 higher than 5 g/kg. The most effective extracts were C. dioscoridis and S. irio with percent protection of control ulcer; 91.1% and 85.4% respectively. The antisecretory activity of both C. dioscoridis and S. irio appears to be mainly related to the suppression of gastrin release. The in vitro potential radical (DPPH) scavenging activities of the investigated extracts were well supported with the reduction in gastric MDA (50.6% and 43.3%) and enhancing the level of reduced GSH (2.84, 2.59 mg/g tissue) for C. dioscoridis and S. irio respectively. In addition, suppression of the inflammatory mediator TNF-alpha may be one of the possible mechanisms of action. The alcohol extracts of C. dioscoridis and S. irio showed no alteration on liver and kidney functions. Phytochemical screening of the investigated extracts revealed the presence of flavonoids, tannins and sterols which could be related to the activities. PMID- 28344495 TI - Enantioselective analysis of fluoxetine in pharmaceutical formulations by capillary zone electrophoresis. AB - Fluoxetine is an antidepressant, a selective serotonin reuptake inhibitor (SSRI) used primarily in the treatment of major depression, panic disorder and obsessive compulsive disorder. Chiral separation of racemic fluoxetine is necessary due to its enantioselective metabolism. In order to develop a suitable method for chiral separation of fluoxetine, cyclodextrin (CD) modified capillary electrophoresis (CE) was employed. A large number of native and derivatized, neutral and ionized CD derivatives were screened to find the optimal chiral selector. As a result of this process, heptakis(2,3,6-tri-O-methyl)-beta-CD (TRIMEB) was selected for enantiomeric discrimination. A factorial analysis study was performed by orthogonal experimental design in which several factors are varied at the same time to optimize the separation method. The optimized method (50 mM phosphate buffer, pH = 5.0, 10 mM TRIMEB, 15 degrees C, + 20 kV, 50 mbar/1 s, detection at 230 nm) was successful for baseline separation of fluoxetine enantiomers within 5 min. Our method was validated according to ICH guidelines and proved to be sensitive, linear, accurate and precise for the chiral separation of fluoxetine. PMID- 28344496 TI - The impact of formulation attributes and process parameters on black seed oil loaded liposomes and their performance in animal models of analgesia. AB - This study aimed to formulate black seed oil (Nigella sativa) loaded liposomes using the ethanol injection method to enhance oral bioavailability and improve therapeutic activity in small animal studies of analgesia. The impact of formulation attributes and process parameters on the liposomal system was evaluated with key quality attributes being particle size, morphology, and entrapment efficiency. The particle size and entrapment efficiency of the liposome preparation were found to be between the range of 50-900 nm and 34-87% respectively. Particle size distribution data suggested that increasing the percentage of oil, up to a certain concentration, reduced the size of the liposomes significantly from 520 +/- 81.2 nm to 51.48 +/- 1.31 nm. Stirring and injection rate were shown to have marked impact on the average particle size of liposome. It was observed that entrapment efficiency of liposomes was greatly influenced by the amount of cholesterol and type of cryoprotectant used during formulation. The stability study indicated that the liposomal preparation was stable at ambient conditions for one month. In vivo studies showed that the liposomal preparation demonstrated significant analgesic activity in mice. PMID- 28344497 TI - Effect of nitazoxanide on albendazole pharmacokinetics in cerebrospinal fluid and plasma in rats. AB - Background: Although albendazole is the drug-of-choice for the treatment of neurocysticercosis, its efficacy is limited due to its low bioavailability. An alternative for optimizing pharmacological treatment is through drug combinations. In vitro studies have shown that nitazoxanide and tizoxanide (the active metabolite of nitazoxanide) exhibit cysticidal activity and that the combination of tizoxanide with albendazole sulfoxide (the active metabolite of albendazole) produced an additive effect. Objectives: (1) To assess the concentration profile of tizoxanide in plasma and in cerebrospinal fluid; and (2) to evaluate the influence of nitazoxanide on the pharmacokinetics of albendazole in plasma and in cerebrospinal fluid. Methods: Two different studies were conducted. In study 1, 10 male Sprague-Dawley rats received a single oral dose of 7.5 mg/kg of nitazoxanide and serial blood and cerebrospinal fluid samples were collected over a period of 4 h. In study 2, 38 healthy male Sprague-Dawley rats were randomly divided into two groups: one of these received a single dose of albendazole (15 mg/kg) and, in the other group, albendazole (15 mg/kg) was co administered with nitazoxanide (7.5 mg/kg). Plasma and cerebrospinal fluid samples were collected from 0 to 16 h after administration. Albendazole sulfoxide and tizoxanide levels were assayed by using HPLC or LC/MS techniques. Results: In study 1, tizoxanide reached a maximum plasma concentration of 244.42 +/- 31.98 ng/mL at 0.25 h; however, in cerebrospinal fluid, this could be detected only at 0.5 h, and levels were below the quantification limit (10 ng/mL). These data indicate low permeation of tizoxanide into the blood brain barrier. In study 2, Cmax, the area under the curve, and the mean residence time of albendazole sulfoxide in plasma and cerebrospinal fluid were not affected by co administration with nitazoxanide. Conclusion: The results of the present study indicate that in rats at the applied doses, tizoxanide does not permeate into the cerebrospinal fluid. Furthermore, nitazoxanide does not appear to alter significantly the pharmacokinetics of albendazole in plasma or in cerebrospinal fluid. PMID- 28344499 TI - New microbial source of the antifungal allylamine "Terbinafine". AB - The isolated active compound "F12" from the culture media of the Streptomyces sp. KH-F12 was identified using different spectroscopic techniques. Both 1D- and 2D NMR as well as HRESIMS were utilized to characterize the structure of the isolated compound. 'F12" was found to be the known systemic antifungal drug terbinafine marketed under the name "Lamisil". Full analysis of the COSY, HSQC and HMBC enables the full assignment of proton and carbon atoms. Terbinafine is a synthetic allylamine and is reported here for the first time from natural source. PMID- 28344498 TI - Investigation of the in vitro performance difference of drug-Soluplus(r) and drug PEG 6000 dispersions when prepared using spray drying or lyophilization. AB - PURPOSE: To evaluate the physicochemical and in vitro characteristics of solid dispersions using BCS II model drugs with Soluplus(r) and one of its component homopolymers, PEG 6000. METHODS: Nifedipine (NIF) and sulfamethoxazole (SMX) of 99.3% and 99.5% purity, respectively, were selected as BCS II model drugs, such that an improved dissolution rate and concentration in the gastrointestinal tract should increase oral bioavailability. Soluplus(r) is an amorphous, tri-block, graft co-polymer with polyvinyl caprolactam, polyvinyl acetate, and polyethylene glycol (PCL:PVAc:PEG6000) in the ratio 57:30:13. PEG 6000 (BASF) is a waxy material with melting point of about 60 degrees C. Solid dispersions were prepared using lyophilization or spray drying techniques. Dissolution study, crystallinity content, and analysis for new chemical bond formation have been used to evaluate the dispersed materials. RESULTS: Although each polymer improved the drug dissolution rate, dissolution from Soluplus(r) was slower. Enhanced dissolution rates were observed with NIF solid dispersions, but the dissolution profiles were quite different due to the selected technique, polymer, and dissolution medium. For SMX, there was similarity across the dissolution profiles despite the medium, polymer, or applied technique. Each polymer was able to maintain an elevated drug concentration over the three hour duration of the dissolution profile, i.e., supersaturation was supported by the polymer. DSC thermograms revealed no melting endotherm, suggesting that the drug is amorphous or molecularly dispersed. CONCLUSION: NIF and SMX solid dispersions were successfully prepared by spray drying and lyophilization using Soluplus(r) or PEG 6000. Each polymer enhanced the drug dissolution rate; NIF dissolution rate was improved to a greater extent. Dispersions with PEG 6000 had a faster dissolution rate due to its hydrophilic nature. DSC analysis showed that no crystalline material exists in the dispersions. PMID- 28344500 TI - Plant growth and diosgenin enhancement effect of silver nanoparticles in Fenugreek (Trigonella foenum-graecum L.). AB - Various methods have been used to enhance production of chemically diverse phytochemicals especially medicinal natural products. With the advancement in nanotechnology, nanoparticles have been reported to have varying impact in plant growth and inducibility of phytochemical composition. Major objective of the study was to study the secondary metabolite modulatory effect of silver nanoparticles. In the current study, treatment of fenugreek seedlings with biosynthesized silver nanoparticles (Ag-NPs) was found to have significant impact on its growth parameters such as leaf number, root length, shoot length and wet weight. On HPLC based analysis, Ag-NPs treated seedlings showed an enhancement in the production of major phytochemical diosgenin to a level of 214.06 +/- 17.07 MUg/mL. An untreated control gave an yield of only 164.44 +/- 7.67 MUg/mL of diosgenin, and the observed phytochemical enhancement effect induced by Ag-NP was very significant. Most remarkably, the Ag-NP used in the study was found to play dual role of enhancement of both plant growth and diosgenin synthesis. Hence the study is of immense application as it opens up development of new methods based on nanoelicitors to enhance the biosynthesis of medicinal natural products in plants. PMID- 28344501 TI - Effects of Peripheral Eccentricity and Head Orientation on Gaze Discrimination. AB - Visual search tasks support a special role for direct gaze in human cognition, while classic gaze judgment tasks suggest the congruency between head orientation and gaze direction plays a central role in gaze perception. Moreover, whether gaze direction can be accurately discriminated in the periphery using covert attention is unknown. In the present study, individual faces in frontal and in deviated head orientations with a direct or an averted gaze were flashed for 150 ms across the visual field; participants focused on a centred fixation while judging the gaze direction. Gaze discrimination speed and accuracy varied with head orientation and eccentricity. The limit of accurate gaze discrimination was less than +/-6 degrees eccentricity. Response times suggested a processing facilitation for direct gaze in fovea, irrespective of head orientation, however, by +/-3 degrees eccentricity, head orientation started biasing gaze judgments, and this bias increased with eccentricity. Results also suggested a special processing of frontal heads with direct gaze in central vision, rather than a general congruency effect between eye and head cues. Thus, while both head and eye cues contribute to gaze discrimination, their role differs with eccentricity. PMID- 28344502 TI - EMOTIONAL MODULATION OF ATTENTION ORIENTING BY GAZE VARIES WITH DYNAMIC CUE SEQUENCE. AB - Recent gaze cueing studies using dynamic cue sequences have reported increased attention orienting by gaze with faces expressing fear, surprise or anger. Here, we investigated whether the type of dynamic cue sequence used impacted the magnitude of this effect. When the emotion was expressed before or concurrently with gaze shift, no modulation of gaze-oriented attention by emotion was seen. In contrast, when the face cue averted gaze before expressing an emotion (as if reacting to the object after first localizing it), the gaze orienting effect was clearly increased for fearful, surprised and angry faces compared to neutral faces. Thus, the type of dynamic sequence used, and in particular the order in which the gaze shift and the facial expression are presented, modulate gaze oriented attention, with maximal modulation seen when the expression of emotion follows gaze shift. PMID- 28344504 TI - Stereoselective Synthesis of Functionalized Bicyclic Scaffolds by Passerini 3 Center-2-Component Reactions of Cyclic Ketoacids. AB - We report the use of bifunctional starting materials (ketoacids) in a diastereoselective Passerini three-center-two-component reaction. Study of the reaction scope revealed the required structural features for stereoselectivity in the isocyanide addition. In this system, an interesting isomerization of the primary Passerini product - the alpha-carboxamido lactone - into an atypical product, an alpha-hydroxy imide, was found to occur under acidic conditions. Furthermore, enantioenriched Passerini products can be generated from an enantioenriched ketoacid obtained by chemoenzymatic synthesis. PMID- 28344503 TI - Metal-Catalysed Azidation of Organic Molecules. AB - The azide moiety is a desirable functionality in organic molecules, useful in a variety of transformations such as olefin aziridination, C-H bond amination, isocyanate synthesis, the Staudinger reaction and the formation of azo compounds. To harness the versatility of the azide functionality fully it is important that these compounds be easy to prepare, in a clean and cost-effective manner. Conventional (non-catalysed) methods to synthesise azides generally require quite harsh reaction conditions that are often not tolerant of functional groups. In the last decade, several metal-catalysed azidations have been developed in attempts to circumvent this problem. These methods are generally faster, cleaner and more functional-group-tolerant than conventional methods to prepare azides, and can sometimes even be conveniently combined with one-pot follow-up transformations of the installed azide moiety. This review highlights metal catalysed approaches to azide synthesis, with a focus on the substrate scopes and mechanisms, as well as on advantages and disadvantages of the methods. Overall, metal-catalysed azidation reactions provide shorter routes to a variety of potentially useful organic molecules containing the azide moiety. PMID- 28344505 TI - Neutron-skin effect in direct-photon and charged-hadron production in Pb+Pb collisions at the LHC. AB - A well-established observation in nuclear physics is that in neutron-rich spherical nuclei the distribution of neutrons extends farther than the distribution of protons. In this work, we scrutinize the influence of this so called neutron-skin effect on the centrality dependence of high-[Formula: see text] direct-photon and charged-hadron production. We find that due to the estimated spatial dependence of the nuclear parton distribution functions, it will be demanding to unambiguously expose the neutron-skin effect with direct photons. However, when taking a ratio between the cross sections for negatively and positively charged high-[Formula: see text] hadrons, even centrality dependent nuclear-PDF effects cancel, making this observable a better handle on the neutron skin. Up to 10% effects can be expected for the most peripheral collisions in the measurable region. PMID- 28344506 TI - Characteristics of the new phase in CDT. AB - The approach of Causal Dynamical Triangulations (CDT), a candidate theory of nonperturbative quantum gravity in 4D, turns out to have a rich phase structure. We investigate the recently discovered bifurcation phase [Formula: see text] and relate some of its characteristics to the presence of singular vertices of very high order. The transition lines separating this phase from the "time-collapsed" B-phase and the de Sitter phase [Formula: see text] are of great interest when searching for physical scaling limits. The work presented here sheds light on the mechanisms behind these transitions. First, we study how the B-[Formula: see text] transition signal depends on the volume fixing implemented in the simulations, and find results compatible with the previously determined second order character of the transition. The transition persists in a transfer matrix formulation, where the system's time extension is taken to be minimal. Second, we relate the new [Formula: see text]-[Formula: see text] transition to the appearance of singular vertices, which leads to a direct physical interpretation in terms of a breaking of the homogeneity and isotropy observed in the de Sitter phase when crossing from [Formula: see text] to the bifurcation phase [Formula: see text]. PMID- 28344507 TI - Patients' experience of using primary care services in the context of Indonesian universal health coverage reforms. AB - BACKGROUND: The World Health Organization (WHO) recommendation on universal coverage has been implemented in Indonesia as Jaminan Kesehatan Nasional (JKN). It was designed to provide people with equitable and high-quality health care by strengthening primary care as the gate-keeper to hospitals. However, during its first year of implementation, recruitment of JKN members was slow, and the referral rates from primary to secondary care remained high. Little is known about how the public views the introduction of JKN or the factors that influence their decision to enroll in JKN. AIM: This research aimed to explore patients' views on the implementation of JKN and factors that influence a person's decision to enroll in the JKN scheme. METHODS: This study was informed by interpretative phenomenological analysis (IPA) methodology to understand patients' views. The interview participants were purposively recruited using maximum variation criteria. The data were gathered using in-depth interviews and was conducted in Yogyakarta from October to December 2014. The interviews were transcribed, translated and analyzed using IPA analysis. RESULT: Twenty three participants were interviewed from eight primary care clinics. Three superordinate themes: access, trust, and separation anxiety were identified which impacted on the uptake of JKN. Participants acknowledged that whilst primary care clinics were conveniently located, access was often complicated by long waiting times and short opening hours. Participants also expressed lower levels of trust with primary care doctors compared to hospital and specialist care. They also reported a sense of anxiety that the current JKN regulation might limit their ability to access the hospital service guaranteed in the past. DISCUSSION: This study identified patients' views that could challenge the implementation of the gate keeper role of primary care in Indonesia. While the patients valued the availability of medical care close to home, their lack of trust in primary care doctors and fear that they might lost the hospital care in the future appears to have impacted on the uptake of JKN. Unless targeted efforts are made to address these views through sustained public education and further capacity building in primary care, it is unlikely that the full potential of the JKN scheme in primary care will be realized. PMID- 28344508 TI - Quantifying spatial distribution of spurious mixing in ocean models. AB - Numerical mixing is inevitable for ocean models due to tracer advection schemes. Until now, there is no robust way to identify the regions of spurious mixing in ocean models. We propose a new method to compute the spatial distribution of the spurious diapycnic mixing in an ocean model. This new method is an extension of available potential energy density method proposed by Winters and Barkan (2013). We test the new method in lock-exchange and baroclinic eddies test cases. We can quantify the amount and the location of numerical mixing. We find high-shear areas are the main regions which are susceptible to numerical truncation errors. We also test the new method to quantify the numerical mixing in different horizontal momentum closures. We conclude that Smagorinsky viscosity has less numerical mixing than the Leith viscosity using the same non-dimensional constant. PMID- 28344510 TI - Interventions for preventing silent cerebral infarcts in people with sickle cell disease. AB - This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effectiveness of red blood transfusions and hydroxyurea alone or in combination and HSCT to reduce or prevent SCI in people with SCD. PMID- 28344512 TI - Computerised decision support systems to promote appropriate use of blood products. AB - This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effect of computerised decision support systems (DSSs) on transfusion practice. PMID- 28344511 TI - Interventions for chronic kidney disease in people with sickle cell disease. AB - This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effectiveness of any intervention in preventing or reducing kidney complications or CKD in people with SCD (including red blood cell transfusions, hydroxyurea and ACEI (either alone or in combination with each other)). PMID- 28344514 TI - Australia's first transition to professional practice in primary care program for graduate registered nurses: a pilot study. AB - BACKGROUND: Increases in ageing, chronic illness and complex co-morbidities in the Australian population are adding pressure to the primary care nursing workforce. Initiatives to attract and retain nurses are needed to establish a sustainable and skilled future primary care nursing workforce. We implemented a transition to professional practice program in general practice settings for graduate nurses and evaluated graduate nurse competency, the graduate nurse experience and program satisfaction. This study aimed to determine whether a transition to professional practice program implemented in the general practice setting led to competent practice nurses in their first year post-graduation. METHODS: A longitudinal, exploratory mixed-methods design was used to assess the pilot study. Data were collected at three times points (3, 6, 12 months) with complete data sets from graduate nurses (n = 4) and preceptors (n = 7). We assessed perceptions of the graduates' nursing competency and confidence, satisfaction with the preceptor/graduate relationship, and experiences and satisfaction with the program. Graduate nurse competency was assessed using the National Competency Standards for Nurses in General Practice. Semi-structured interviews with participants at Time 3 sought information about barriers, enablers, and the perceived impact of the program. RESULTS: Graduate nurses were found to be competent within their first year of clinical practice. Program perceptions from graduate nurses and preceptors were positive and the relationship between the graduate nurse and preceptor was key to this development. CONCLUSIONS: With appropriate support registered nurses can transition directly into primary care and are competent in their first year post graduation. While wider implementation and research is needed, findings from this study demonstrate the potential value of transition to professional practice programs within primary care as a nursing workforce development strategy. PMID- 28344513 TI - A final-year nursing student survey: rural attitudes, perceived competencies and intention to work across five Asian countries. AB - BACKGROUND: Shortages and maldistribution of nurses remain significant problems in many countries. Having appropriate intervention strategies to retain nurses in underserved areas, where they are most needed, are crucial for health system strengthening. This study aimed to quantify attitudes to working in rural areas, perceived competencies, and intention to work among final-year nursing students, and to analyze the associations between those factors and their background characteristics across five countries in the Asia-Pacific Network for Health Professional Education Reforms (ANHER), namely Bangladesh, China, India, Thailand, and Vietnam. METHODS: A descriptive comparative cross-sectional survey was conducted between July 2012 and July 2013, using a self-administered questionnaire to assess students' attitudes towards working in rural areas, their perceived competencies, and their intended job choices. A total of 10,169 final year nursing students in five countries were selected. Bivariate models were constructed to compare students' characteristics. Statistically significant variables were further analyzed using multivariate models. RESULTS: Most nursing students in five countries had rural backgrounds. Students in India (67.1%) and Thailand (65.1%) held more positive attitudes towards working in rural areas. Students in Bangladesh (78.8%) and India (62.6%) believed that their schools prepared them well, and inspired them, to work in rural areas. The 'Lifelong learning' competency was ranked highest by students in all five countries, ranging from 76.2 to 91.7%. Their perceived competencies were significantly related to their background of having graduated from rural high schools and being admitted to study through rural recruitment. Rural upbringing and rural recruitment were significantly associated with more positive attitudes towards rural areas (p-value < 0.5). A majority of students in China (83.8%), Thailand (67.7%) and Vietnam (86.5%) intended to work in the public sector immediately after graduation. CONCLUSIONS: These findings from five Asian countries confirm that nursing students with rural upbringing and recruitment had more positive attitudes toward rural areas and were more likely to choose working in rural areas after graduation. This study provides additional evidence from country implementation to support the value of WHO recommendations of effective strategies to address issues of rural retention by focusing on the recruitment of students with a rural background. PMID- 28344515 TI - Burnout among nurses working in social welfare centers for the disabled. AB - BACKGROUND: In the healthcare sector, we often come across the burnout syndrome. It is an occupational syndrome which causes, physical and emotional exhaustion. More information is needed on the dangers of burnout and how often it occurs in healthcare. The purpose of this study was to investigate burnout and factors associated with the syndrome among nurses working with people that are mentally challenged. METHODS: A cross-sectional survey was conducted, among 180 nurses working in public health centers for the disabled in multiple regions of Greece. A self-administered questionnaire with questions about socio-demographic and work related characteristics was used, as well as the Maslach Burnout Inventory (MBI) for burnout assessment. Univariate and multivariate analyzes were performed. RESULTS: The burnout dimensions of emotional exhaustion (Mean = 31.36) and depersonalization (Mean = 11.27) were at high levels while personal accomplishment was at low levels (Mean = 44.02). Female nurses had a higher personal accomplishment score (Mean = 44.82, p = 0.047) than men (Mean = 42.10, p = 0.047). Marital status, daily routine and relationships with supervisors were significantly related with emotional exhaustion and personal accomplishment and professional experience with higher levels of emotional exhaustion and depersonalization. Reason for professional selection was an independent predictor for depersonalization and personal accomplishment, with those that have selected the nursing profession randomly or because of the fear of unemployment having higher scores. Moderate relationships with colleagues was an independent predictor for all burnout dimensions. CONCLUSIONS: Nurses working in services for people with intellectual disabilities in Greece show increased burnout levels. Burnout can be prevented by offering more opportunities for professional advancement and education, new ways to provide supervisor support, provide incentives for nurses to initiate or participate in innovative programs. Specific training on conflict resolution, collaboration, reinforcement and stress coping techniques must be implemented. PMID- 28344516 TI - Ulinastatin ameliorates tissue damage of severe acute pancreatitis through modulating regulatory T cells. AB - BACKGROUND: Ulinastatin or urinary trypsin inhibitor (UTI) has been shown to ameliorate the inflammatory response induced by experimental severe acute pancreatitis (SAP) and hence reduce the mortality, however the mechanism of its action remains incompletely understood. We have investigated the effect of ulinastatin on regulatory T-cells (Tregs) in an established rat model of SAP. METHODS: We established a rat SAP model by injecting 5% Na-taurocholate into the pancreatic duct and treated the SAP rats with ulinastatin with different dose level (5000, 10000, 30000 U/kg) through intraperitoneal injection at 0, 6 and 12 h. RESULTS: We showed that the tissue damage of pancreas and the mortality of the SAP rats were significantly reduced by ulinastatin. We also showed that in the SAP rats the frequencies of CD4+ T cells and Tregs, as well as the expressions of TGF-beta1, CTLA-4, and Foxp3 were decreased in the SAP animals while IL-1beta, IL 10 and TNF-alpha were significantly increased. Treatment with ulinastatin up regulated the proportion of Tregs in CD4+ T cells and the expression of IL-10, Foxp3 and CTLA-4 in the SAP rats in a dose dependence fashion, while down regulating the levels of L-1beta and TNF-alpha, myeloperoxidase (MPO) activity. CONCLUSIONS: Our findings suggest that ulinastatin alleviates inflammatory response and tissue damage in SAP rats by increasing the proportion of Tregs. Our study provides a new mechanism for the beneficial effect of ulinastatin in SAP rat model. PMID- 28344517 TI - Economic evaluation of participatory learning and action with women's groups facilitated by Accredited Social Health Activists to improve birth outcomes in rural eastern India. AB - BACKGROUND: Neonatal mortality remains unacceptably high in many low and middle income countries, including India. A community mobilisation intervention using participatory learning and action with women's groups facilitated by Accredited Social Health Activists (ASHAs) was conducted to improve maternal and newborn health. The intervention was evaluated through a cluster-randomised controlled trial conducted in Jharkhand and Odisha, eastern India. This aims to assess the cost-effectiveness this intervention. METHODS: Costs were estimated from the provider's perspective and calculated separately for the women's group intervention and for activities to strengthen Village Health Sanitation and Nutrition Committees (VHNSC) conducted in all trial areas. Costs were estimated at 2017 prices and converted to US dollar (USD). The incremental cost effectiveness ratio (ICER) was calculated with respect to a do-nothing alternative and compared with the WHO thresholds for cost-effective interventions. ICERs were calculated for cases of neonatal mortality and disability-adjusted life years (DALYs) averted. RESULTS: The incremental cost of the intervention was USD 83 per averted DALY (USD 99 inclusive of VHSNC strengthening costs), and the incremental cost per newborn death averted was USD 2545 (USD 3046 inclusive of VHSNC strengthening costs). The intervention was highly cost-effective according to WHO threshold, as the cost per life year saved or DALY averted was less than India's Gross Domestic Product (GDP) per capita. The robustness of the findings to assumptions was tested using a series of one way sensitivity analyses. The sensitivity analysis does not change the conclusion that the intervention is highly cost-effective. CONCLUSION: Participatory learning and action with women's groups facilitated by ASHAs was highly cost effective to reduce neonatal mortality in rural settings with low literacy levels and high neonatal mortality rates. This approach could effectively complement facility-based care in India and can be scaled up in comparable high mortality settings. PMID- 28344518 TI - Hypogonadism in the HIV-Infected Man. AB - Low testosterone levels are frequently observed among men with treated and untreated HIV infection. However, the interpretations of biochemical measurements of testicular function are challenging and need to be considered in the context of the clinical presentation and scenario. The distinction between primary and secondary hypogonadism and determination of the underlying clinical pathophysiology are not always straightforward. Early recognition of clinical hypogonadism and appropriate treatment may improve clinical outcomes and quality of life for affected individuals. A principal aim of testosterone replacement is to maintain serum testosterone concentrations in the normal physiological range and should be considered in clinically symptomatic patients. PMID- 28344519 TI - Assessment of REPLI-g Multiple Displacement Whole Genome Amplification (WGA) Techniques for Metagenomic Applications. AB - Amplification of minute quantities of DNA is a fundamental challenge in low biomass metagenomic and microbiome studies because of potential biases in coverage, guanine-cytosine (GC) content, and altered species abundances. Whole genome amplification (WGA), although widely used, is notorious for introducing artifact sequences, either by amplifying laboratory contaminants or by nonrandom amplification of a sample's DNA. In this study, we investigate the effect of REPLI-g multiple displacement amplification (MDA; Qiagen, Valencia, CA, USA) on sequencing data quality and species abundance detection in 8 paired metagenomic samples and 1 titrated, mixed control sample. We extracted and sequenced genomic DNA (gDNA) from 8 environmental samples and compared the quality of the sequencing data for the MDA and their corresponding non-MDA samples. The degree of REPLI-g MDA bias was evaluated by sequence metrics, species composition, and cross-validating observed species abundance and species diversity estimates using the One Codex and MetaPhlAn taxonomic classification tools. Here, we provide evidence of the overall efficacy of REPLI-g MDA on retaining sequencing data quality and species abundance measurements while providing increased yields of high-fidelity DNA. We find that species abundance estimates are largely consistent across samples, even with REPLI-g amplification, as demonstrated by the Spearman's rank order coefficient (R2 > 0.8). However, REPLI-g MDA often produced fewer classified reads at the species, genera, and family level, resulting in decreased species diversity. We also observed some areas with the PCR "jackpot effect," with varying input DNA values for the Metagenomics Research Group (MGRG) controls at specific genomic loci. We visualize this effect in whole genome coverage plots and with sequence composition analyses and note these caveats of the MDA method. Despite overall concordance of species abundance between the amplified and unamplified samples, these results demonstrate that amplification of DNA using the REPLI-g method has some limitations. These concerns could be addressed by future improvements in the enzymes or methods for REPLI-g to be considered a >99% robust method for increasing the amount of high fidelity DNA from low-biomass samples or at the very least, accounted for during computational analysis of MDA samples. PMID- 28344521 TI - Timing of Debridement and Infection Rates in Open Fractures of the Hand: A Systematic Review. AB - Background: Literature on open fracture infections has focused primarily on long bones, with limited guidelines available for open hand fractures. In this study, we systematically review the available hand surgery literature to determine infection rates and the effect of debridement timing and antibiotic administration. Methods: Searches of the MEDLINE, EMBASE, and Cochrane computerized literature databases and manual bibliography searches were performed. Descriptive/quantitative data were extracted, and a meta-analysis of different patient cohorts and treatment modalities was performed to compare infection rates. Results: The initial search yielded 61 references. Twelve articles (4 prospective, 8 retrospective) on open hand fractures were included (1669 open fractures). There were 77 total infections (4.6%): 61 (4.4%) of 1391 patients received preoperative antibiotics and 16 (9.4%) of 171 patients did not receive antibiotics. In 7 studies (1106 open fractures), superficial infections (requiring oral antibiotics only) accounted for 86%, whereas deep infections (requiring operative debridement) accounted for 14%. Debridement within 6 hours of injury (2 studies, 188 fractures) resulted in a 4.2% infection rate, whereas debridement within 12 hours of injury (1 study, 193 fractures) resulted in a 3.6% infection rate. Two studies found no correlation of infection and timing to debridement. Conclusions: Overall, the infection rate after open hand fracture remains relatively low. Correlation does exist between the administration of antibiotics and infection, but the majority of infections can be treated with antibiotics alone. Timing of debridement, has not been shown to alter infection rates. PMID- 28344520 TI - Does the approximate number system serve as a foundation for symbolic mathematics? PMID- 28344523 TI - Scaphoid Nonunion With Poor Prognostic Factors: The Role of the Free Medial Femoral Condyle Vascularized Bone Graft. AB - Background: To report on the results of free medial femoral condyle (MFC) vascularized bone graft for scaphoid nonunions with 1 or more poor prognostic factors. Methods: We have used the free MFC vascularized bone graft for scaphoid nonunions that have 1 or more factors associated with a poor prognosis. These were, a delay in presentation of over 5 years, a proximal pole nonunion, the presence of avascular necrosis (AVN), or previous nonunion surgery. We used this technique on 20 patients over a 4.5-year period. Results: Our overall union rate was 88.5% (17 of 19 patients), with 1 patient failing to attend for follow-up. Our mean union time was 7 months (2-18). All patients had at least 1 poor prognostic factor and over half had 2 or more. Of those with AVN with or without other factors, the union rate was 85% (11 of 13). There were 2 donor site complications that required a further procedure and 2 patients with residual wrist pain that required a scapho-trapezio-trapezoid joint fusion and a radial styloidectomy, respectively. Both nonunions were offered further surgery, and 1 elected to undergo successful revision surgery. Conclusions: Overall, this technique showed good results, in a subgroup of patients that typically have poorer outcomes, with a low incidence of donor site morbidity. Our union rate compares favorably with other techniques for this difficult subset of patients with 1 or more poor prognostic factors, although results are clearly not as good as those of studies using the MFC graft for all scaphoid nonunions. We continue to reserve this technique for nonunions with 1 or more poor prognostic factors, and we believe that this technique should at least be considered in these patients. PMID- 28344522 TI - Vascularized Bone Grafting in Scaphoid Nonunion: A Review of Patient-Centered Outcomes. AB - Background: The radiographic and clinical outcomes following vascularized bone grafting (VBG) for scaphoid nonunion have previously been reported in the literature; however, few studies report on patient-derived outcomes. The purpose of this study was to determine the effect of VBG for scaphoid nonunion on patient derived outcomes. Methods: The MEDLINE and PubMed databases were queried for the use of VBG in scaphoid nonunion. We included studies that reported on patient derived outcomes. We excluded studies with less than 10 patients or less than 6 months of follow-up. The primary outcomes assessed included functionality, percent and time to return to preinjury activity, postoperative pain, and patient satisfaction. Results: Twenty-six articles described the outcomes of 520 patients with an average of 19.3 patients per study. Functionality was most commonly assessed by the Mayo Modified Wrist Score and Disabilities of the Arm, Shoulder and Hand scores, which improved by 53.1% and 81.7% postoperatively, respectively. Within 16 weeks, 90.3% of patients returned to their previous occupation or sporting activity. Pain was most commonly reported using a 0 to 10 visual analog scale and improved 4-fold postoperatively. Complete satisfaction was reported by 92% of patients. The most common complications were superficial infections (1.56%), neuropathic pain (1.56%), and complex regional pain syndrome (1.25%). Conclusions: VBG for scaphoid nonunion results in the improvement of patient derived outcomes, and high rates of return to preinjury activity levels and patient satisfaction. Multiple metrics of patient-derived outcomes were utilized by the studies in our review without a clear consensus as to which metric is most responsive and accurate. PMID- 28344524 TI - Complications and Outcomes of One-Bone Forearm Reconstruction. AB - Background: The objective of this study was to review the outcomes of patients who underwent one-bone forearm (OBF) reconstruction. Methods: A retrospective review of patients who underwent OBF surgery between 1994 and 2014 was undertaken. Patient demographics, etiology, associated injuries, number of surgeries prior to OBF surgery, surgical details, and postoperative information were collected. A telephone interview was conducted at final follow-up, including a Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) questionnaire, a 10-point scoring system used by Peterson et al, and a series of questions concerning pain and patient satisfaction. Results: There were 6 males and 2 females with a mean age of 44 years (range, 20-66 years). All patients had traumatic etiology, with 6 having open wounds and 2 having closed wounds. All patients had union with a mean follow-up of 83.6 months (range, 16-218 months). The mean pain score was 3 (range, 0-8), of which 3 were painless (score 0). The mean QuickDASH score was 39 (range, 7-75), and 4 patients had good or excellent results according to the 10-point score system used by Peterson et al. All patients were satisfied with the result. Five of 8 had complications related to soft tissues that were residual from their prior injuries and surgeries. One patient had post healing fracture requiring revision fixation and 1 had a postoperative infection requiring parenteral antibiotics. Conclusions: OBF surgery is an effective salvage procedure for complicated forearm instability, particularly after trauma. While union rates are high, complications are typically related to pain and soft tissue secondary to the previous injury and reconstructive procedures. PMID- 28344525 TI - MRI Correlation of Radial Head Fractures and Forearm Injuries. AB - Background: Radial head fractures can be associated with soft tissue injuries of the forearm and wrist. The Essex-Lopresti injury can lead to significant morbidity, especially if the diagnosis is not made acutely. Better identification of such injuries is needed to allow optimal surgical treatment and prevent long term sequelae. We used magnetic resonance imaging (MRI) to correlate the degree of soft tissue injuries with radial head fractures. Methods: Sixteen pairs of forearms with an associated radial head fracture in 15 patients prospectively underwent an MRI within 2 weeks of their injury. MRI findings were correlated with fracture type, associated soft tissue injury, and presence of symptomatic wrist pain. Results: According to the modified Mason classification, there were 8 type I, 5 type II, and 3 type III radial head fractures. Wrist pain was reported in 8 of 16 extremities, and 2 had associated wrist pathology, including an acute scaphoid fracture in 1 patient and a preexisting stage II scapholunate advanced collapse (SLAC) wrist in another patient. The MRI findings included an elbow effusion in all 16 patients, edema in the proximal third of the radius in 15 extremities, which extended to the middle third in 3 extremities, edema of the interosseous membrane (IOM) in 5 extremities, and edema of the soft tissues including the supinator and/or pronator quadratus in 13 extremities. Conclusions: Eighty percent of patients with edema of the IOM had associated wrist pain. Soft tissue injuries of the forearm did not correlate with the severity of the radial head fracture. PMID- 28344526 TI - Delayed Repair of Ulnar Artery at the Distal Forearm. AB - Background:The purpose of this study was to evaluate the rate of patency after delayed repair of the ulnar artery following primary ligation. Methods: Adult patients with primary ligation of the injured ulnar artery at the forearm who had a delayed repair of the artery were included. Postoperative arterial patency was determined by either physical examination or color Doppler ultrasonographic imaging. Postoperative complications and Disabilities of the Arm, Shoulder and Hand score were recorded. Results: Eight consecutive patients during a 3-year period were included. The mean age was 35 years. Four cases were women. The surgery was performed at a mean of 5 days after the injury and ligation. At a mean follow-up of 22 months, 7 patients had a patent artery. One patient suffered a hematoma. Conclusions: A high rate of patency can be obtained after delayed repair of the ulnar artery at the forearm. PMID- 28344527 TI - Reverse Radial Forearm Flap to Provide Arterial Inflow to a Toe Transfer. AB - Background: Toe-to-thumb transfer has become the gold standard for thumb reconstruction, but in badly mutilated hands, additional soft tissue coverage may be required or a suitable recipient artery may not be available. There are only 3 case reports describing the successful use of a reverse radial forearm flap for coverage of a soft tissue defect around the thumb as well as providing arterial inflow for a toe transfer, performed either simultaneously or secondarily. Methods: A single surgeon's experience of all toe-to-hand transfers performed in conjunction with a reverse radial forearm flap between 1995 and 2014 was reviewed, including patient demographics, type of toe transfer and vascular pedicle, whether immediate or secondary, follow-up, and complications. Results: Eight toe-to-hand transfers were performed in 7 patients-3 children (age range, 3 15 years) and 4 adults (age range, 19-39 years). Three patients underwent primary toe-to-thumb transfer simultaneously with a reverse radial forearm flap, and 5 patients underwent secondary toe-to-hand transfer between 4 months and 21/2 years after an initial reverse radial forearm flap. All toe transfers survived completely. Average follow-up was 5.1 years. All patients were satisfied with the function and appearance of their reconstructed thumb. Conclusion: The reverse radial forearm flap is a very reliable procedure as a "Sister" or "Siamese" flap to provide immediate arterial inflow to a simultaneous toe-to-thumb transfer, or to provide primary soft tissue coverage on the radial aspect of the hand and subsequently provide a recipient arterial inflow for a secondary toe transfer. PMID- 28344528 TI - Surgical Approach and Anesthetic Modality for Carpal Tunnel Release: A Nationwide Database Study With Health Care Cost Implications. AB - Background: Carpal tunnel release (CTR) is commonly performed for carpal tunnel syndrome once conservative treatment has failed. Operative technique and anesthetic modality vary by surgeon preference and patient factors. However, CTR practices and anesthetic trends have, to date, not been described on a nationwide scale in the United States. Methods: The PearlDiver Patient Records Database was used to search Current Procedural Terminology codes for elective CTR from 2007 to 2011. Anesthetic modality (eg, general and regional anesthesia vs local anesthesia) and surgical approach (eg, endoscopic vs open) were recorded for this patient population. Cost analysis, patient demographics, regional variation, and annual changes in CTR surgery were evaluated. Results: We identified 86 687 patients who underwent carpal tunnel surgery during this 5-year time period. In this patient sample, 80.5% of CTR procedures were performed using general or regional anesthesia, compared with 19.5% of procedures performed using local anesthesia; 83.9% of all CTR were performed in an open fashion, and 16.1% were performed using an endoscopic technique. Endoscopic surgery was on average $794 more expensive than open surgery, and general or regional anesthesia was $654 more costly than local anesthesia. Conclusions: In the United States, open CTR under local anesthesia is the most cost-effective way to perform a CTR. However, only a small fraction of elective CTR procedures are performed with this technique, representing a potential area for significant health care cost savings. In addition, regional and age variations exist in procedure and anesthetic type utilized. PMID- 28344529 TI - Clinical Evaluation After Peripheral Nerve Repair With Caprolactone Neurotube. AB - Background: Peripheral nerve injuries with substance loss are challenges to surgeons because direct suture repair may result in malfunction due to nerve suture tension. Autologous nerve grafts are alternatives for treating those lesions; however, harvesting grafts adds morbidity at donor sites. Synthetic substitutes are options to bridge the gaps in these situations. The caprolactone neurotubes are used to assist nerve regeneration, but the literature lacks studies that evaluate their results. Methods: This research was designed to clinically evaluate patients undergoing repair of peripheral nerves with that conduit. We described results of 12 case series consisting of operations with Neurolac(r). All nerves severed were sensory and had small gaps (ie, less than 25 mm). Subjective and objective clinical evaluations were performed and registered. Results: Physical examination by monofilament testing and 2-point discrimination showed results rated as good or excellent. However, the patients had complaints regarding sensory changes. Conclusions: Synthetic bioabsorbable guides for nerve repair are promising. The caprolactone conduits were demonstrated to be a safe option treatment and with a simple technique. Although in our study there were some operative complications, they were in line with previous descriptions in the literature. This case series added information about the treatment prognosis, but a higher evidence level study is necessary for decision making. PMID- 28344530 TI - Patient Comprehension of Carpal Tunnel Surgery: An Investigation of Health Literacy. AB - Background: Health literacy is the ability of a patient to understand their medical condition. The purpose of this investigation is to determine whether patients are able to obtain an elementary understanding of the fundamental principles of carpal tunnel release and the postoperative instructions after going through the process of informed consent and being provided an additional standardized postoperative instruction document. Our hypothesis is that patients will lack an understanding of these principles and, therefore, will be at risk for being noncompliant in their postoperative care. Methods: Fifty patients with a diagnosis of carpal tunnel surgery who elected to undergo carpal tunnel release alone were enrolled. A standardized education process was performed. Patients completed the questionnaire at their postoperative visit. Results: The average percentage of correct answers was 75.8% (8.34 out of 11 correct). Fisher exact test analysis demonstrated that patients with a lower education level were less likely to know how long it takes for their preoperative symptoms to resolve (P = .0071), and they were less likely to correctly choose all of the important elements of postoperative care during the first week after surgery (P = .022). Conclusions: Although we made efforts to help patients achieve health literacy in carpal tunnel surgery, we found that patients continued to lack comprehension of pertinent components of carpal tunnel surgery, particularly understanding the involved anatomy. PMID- 28344531 TI - Hand and Wrist Injuries in Elite Boxing: A Longitudinal Prospective Study (2005 2012) of the Great Britain Olympic Boxing Squad. AB - Background: The purpose of this investigation was to explore prospectively the nature and duration of hand and wrist injuries in training and competition in the Great Britain (GB) amateur boxing squad between 2005 and 2012. Methods: Longitudinal prospective injury surveillance of the GB boxing squad was performed from 2005 to 2012. The location, region affected, description, and the duration of each injury were recorded by the team doctor and team physiotherapist. We recorded whether the injury occurred during competition or training and also whether it was a new or a recurrent injury. The injury rate during competition was calculated as the number of injuries per 1000 hours. Results: Finger carpometacarpal instability and finger metacarpophalangeal joint extensor hood and capsule sprain also known as "boxer's knuckle" injuries were significantly more common than other injury diagnoses. The number of injuries during training or competition was similar, which is remarkable given the far greater number of training hours than competition hours performed. Injury rate for hand and wrist injuries in competition was 347 injuries per 1000 hours, while the estimated injury rate in training was <0.5 injuries per 1000 hours. Conclusion: Carpometacarpal instability and boxer's knuckle were more common than any other kind of hand and wrist injury in this cohort of elite amateur boxers. The rate of hand and wrist injuries was higher in competition than in training. Our study highlights the importance of hand and wrist injury prevention in the competition environment. PMID- 28344532 TI - Atypical Mycobacterial Infections of the Upper Extremity: Becoming More Atypical? AB - Background: Atypical mycobacterial infections are uncommon and characterized by a chronic, indolent course before diagnosis. Historically, these infections are associated with marine-related injury and/or immune dysfunction. Our institution has successfully diagnosed and treated an increasing number of these infections. The objective of this study is to review our experience with these rare infections and verify the developing trends encountered. Methods: A retrospective review was performed for patients with positive nontuberculous mycobacterial cultures of the upper extremity from 2000 to 2013. Patient demographics, source of transmission, symptom duration, mycobacterial species, operative and antibiotic treatments, and outcomes were recorded. Results: Thirty-four patients were identified. The mean symptomatic period before diagnosis was 9 months (range, 1-60 months). Fourteen patients had identifiable causes of immune dysfunction while the rest appeared immune competent. Patients were infected by Mycobacterium marinum (n = 14), Mycobacterium abscessus (n = 8), Mycobacterium fortuitum (n = 7), and other less common species (n = 5). Although most patients had unidentifiable causes of infection (n = 15), some could correlate infection to marine injury, lacerations, insect bites, animal bites, and tattoos. All patients received operative intervention including debridement. Antibiotics were given for a mean duration of 5 months. Ninety-seven percent had complete resolution of disease. Conclusions: Although M. marinum infections make up the majority of infections at our institution, we report a higher total incidence of nonmarinum infections. These infections are occurring in seemingly healthy individuals with no history of exposure with marine water. Successful treatment relies on having a heightened clinical awareness and adequate diagnosis. PMID- 28344533 TI - Diagnostic Wrist Arthroscopy for Nonspecific Wrist Pain. AB - Background: This study addresses the prevalence of discrete pathophysiology accounting for patients' symptoms during diagnostic wrist arthroscopy in individuals with wrist pain without a specific preoperative diagnosis. Secondarily, we determined the number and type of surgeries subsequent to diagnostic wrist arthroscopy. Methods: Between January 2000 and January 2015, 135 diagnostic wrist arthroscopies were performed by 12 surgeons in 3 urban academic hospitals. We recorded the diagnostic findings of diagnostic wrist arthroscopy and any subsequent surgeries. Results: One hundred and five patients had synovitis or a normal wrist (78%), 17 had likely age-appropriate changes (eg, central triangular fibrocartilage complex defects scapholunate changes) (13%), 8 (6%) were given uncommon diagnoses, and 5 (4%) had osteochondral defects. Sixteen patients (12%) had subsequent wrist surgery: 2 were for adverse events, 2 were carpal tunnel releases, and 12 were other surgeries. Conclusion: Diagnostic arthroscopy performed in the setting of an unclear preoperative diagnosis yielded limited diagnostic benefit. PMID- 28344534 TI - The Influence of Psychological Factors on the Michigan Hand Questionnaire. AB - Background: Psychosocial factors help account for the gap between impairment and disability. This study examines the relationship between the Michigan Hand Questionnaire (MHQ) and commonly used psychological measures in patients with upper extremity illness. Methods: A cohort of 135 new or follow-up patients presenting to an urban academic hospital-based hand surgeon were invited to complete a web-based version of the MHQ, Abbreviated Pain Catastrophizing Scale (PCS), and two Patient-Reported Outcomes Measurement Information System (PROMIS) based questionnaires: Pain Interference and Depression. Bivariate and multivariable analyses measured the correlation of these psychological measures with MHQ. Results: Accounting for potential confounding factors in multivariable regression, upper extremity disability as rated by the MHQ was independently associated with PROMIS Depression, PROMIS Pain Interference, visit type, and working status. The model accounted for 37% of the variability in MHQ scores, with PROMIS Pain Interference having the most influence. Conclusion: Among the non-pathophysiological factors that contribute to patient-to-patient variation in MHQ scores, the measure of less effective coping strategies and symptoms of depression were most influential. Our data add to the evidence of the pivotal role of emotional health in upper extremity symptoms and limitations and the importance of psychosocial considerations in the care of hand illness. PMID- 28344535 TI - The Correlation Between a Numerical Rating Scale of Patient Satisfaction With Current Management of an Upper Extremity Disorder and a General Measure of Satisfaction With the Medical Visit. AB - Background: Patient satisfaction is used as an indicator of quality of care, but the measures currently available are lengthy and cumbersome and may not be feasible in orthopedic surgical practices. We set out to assess the relationship between the Medical Interview Satisfaction Scale (MISS-21) and a numerical rating scale (NRS) of patient satisfaction with current management of an orthopedic upper extremity condition. Methods: In this cross-sectional study, 86 patients from the practices of 2 hand surgeons were included during an initial or follow up visit. Questionnaires assessing demographics, upper extremity specific disability, pain during rest and activity, satisfaction with the medical visits (MISS-21), and satisfaction with current management of an orthopedic upper extremity condition (NRS satisfaction) were completed. Results: Eighty-six patients completed all questionnaires. A small correlation of .21 (P = .050) was found between the MISS-21 and the NRS satisfaction. In bivariate analysis, NRS pain at rest and during activity had small correlations with the MISS-21 (-.29, P = .05 and -.23, P = .034) and with NRS satisfaction (-.27, P = .011 and -0.27, P = 0.012). Quick Disability of Arm, Shoulder and Hand (QuickDASH) had a small correlation with NRS satisfaction (-0.023, P <= 0.001), but did not correlate with MISS-21. Conclusions: Although there is small overlap about the 2 satisfaction measures, a complex patient satisfaction questionnaire consisting of multiple facets of patient satisfaction like MISS-21 is not replaceable by 1 simple NRS patient satisfaction question. PMID- 28344536 TI - Capitate Chondroblastoma: A Case Report and Review of the Literature. AB - Background: Chondroblastomas are benign tumors that typically occur in the epiphysis of long bones. Carpal bone chondroblastomas are very rare and are known to have less aggressive behavior with no evidence of recurrence reported. Methods: We present a case of a recurrent chondroblastoma in the capitate that was treated with repeat curettage, application of phenol, and bone grafting. Results: At 3 years post surgery, the patient is disease free with excellent functional return. Conclusion: Chondroblastomas are rare within the carpus. We present a review of the literature detailing their occurrence and treatment. PMID- 28344537 TI - Intravenous Glomus Tumor Masquerading as Lateral Antebrachial Cutaneous Neuroma. AB - Background: Intravenous glomus tumors are extremely rare. Methods: We report a patient with an intravenous glomus tumor within a venous aneurysm misdiagnosed as a neuroma of the lateral antebrachial cutaneous nerve, based on clinical exam, electrodiagnostic studies, and findings on a magnetic resonance imaging neurogram. Results: After surgical resection, the patient's symptoms, including pain and localized hypersensitivity, totally resolved. Conclusions: This case illustrates 2 important points. First, unlike extradigital glomus tumors, magnetic resonance imaging is not reliable in diagnosing intravenous glomus tumors. Second, in the presence of chronic localized neuroma type pain and sensitivity in the upper limb without a clear cause, an extradigital cutaneous or intravenous glomus tumor must be considered in the differential diagnosis. PMID- 28344538 TI - Surgical Excision of Mycosis Fungoides Using Thumb-Sparing Reconstruction. AB - Background: The differential for soft tissue tumors of the hand and upper limb is broad. Hematologic malignancy remains quite low on the differential for soft tissue tumors involving the hand, and there is little in the literature describing surgical management of such cutaneous manifestations. When the tumor is large or involves the thumb, careful consideration of reconstructive options is required. Methods: We present a rare case of an aggressively enlarging mycosis fungoides, a cutaneous T-cell lymphoma tumor, involving the thumb. This tumor had a history of multiple failed treatment attempts, including radiation and chemotherapy. Results: Our surgical plan was a reverse radial forearm osteocutaneous flap. Conclusion: A reverse radial osteocutaneous forearm flap was successfully used to avoid thumb amputation and preserve thumb function. PMID- 28344539 TI - Scaphocapitate Syndrome With Associated Trans-Scaphoid, Trans-Hamate Perilunate Dislocation: A Case Report and Description of Surgical Fixation. AB - Background: Perilunate fracture dislocations are often associated with fractures of the distal pole of the scaphoid or the proximal pole of the capitate. However, the combination of perilunate dislocation with multiple carpal fractures and associated scaphocapitate syndrome is very rare. Methods: We report a unique case of scaphocapitate fracture syndrome with perilunate dislocation and fracture of the hamate resulting from a high-energy injury to the wrist during a dirt-bike competition. Results: Open reduction and internal fixation of the scaphoid fracture with a 3.0-mm headless screw, the head of the capitate with a 1.5-mm lag screw, and the hamate fracture with a 1.3-mm lag screw was performed. The lunotriquetral dissociation was reduced, with the ligament repaired and the joint stabilized using a Kirschner wire. All screw heads are carefully buried under the articulate cartilage. Conclusions: Prompt anatomic reduction and stable osteosynthesis of all fractures in this patient resulted in successful healing and return to activity. PMID- 28344540 TI - Tubulointerstitial nephritis antigen-like 1 protein is downregulated in the placenta of pre-eclamptic women. AB - BACKGROUND: Tubulointerstitial nephritis antigen-like 1 protein (TINAGL1), is a matricellular protein, known to play role in cell adhesion and cell receptor interaction. Research related to TINAGL1 is limited to cell culture and animal models. Demonstration of TINAGL1 as a positive regulator of angiogenesis and its expression in the decidua of postimplantation mouse uterus, prompted us to validate its expression in human placenta during impaired angiogenesis in pre eclamptic condition. METHODS: Placental tissue from normotensive (n = 25) and pre eclamptic (n = 25) pregnancies were used to study the differentially expressed proteins by two-dimensional gel electrophoresis and TINAGL1 protein was validated with Western blotting. RESULTS: A total of 55 protein spots were differentially expressed (fold change >1.5, p < 0.05), of which 27 were upregulated and 28 were downregulated in the pre-eclamptic placenta. TINAGL1 was found to be downregulated in pre-eclamptic compared to normotensive pregnant women. CONCLUSION: This is the first study reporting TINAGL1 to be present in human placenta and differentially expressed in pre-eclamptic condition. The functional role of TINAGL1 in association to human pregnancy needs to be explored further. PMID- 28344542 TI - The training of New Jersey emergency service first responders in autism awareness. AB - This study investigated the extent and adequacy of training among New Jersey first responders (e.g., police, firefighters, emergency medical technicians) specifically as relates to a 2008 state law mandating that autism and hidden disability recognition and response training be conducted. The results show that a significant percentage of emergency service personnel have not completed the state mandated training. Recommendations for improving the training, such as by involving parents, advocates, and field and training personnel as a part of the training process, are discussed. PMID- 28344541 TI - OLFM4, KNG1 and Sec24C identified by proteomics and immunohistochemistry as potential markers of early colorectal cancer stages. AB - BACKGROUND: Despite recent advances in colorectal cancer (CRC) diagnosis and population screening programs, the identification of patients with preneoplastic lesions or with early CRC stages remains challenging and is important for reducing CRC incidence and increasing patient's survival. METHODS: We analysed 76 colorectal tissue samples originated from early CRC stages, normal or inflamed mucosa by label-free proteomics. The characterisation of three selected biomarker candidates was performed by immunohistochemistry on an independent set of precancerous and cancerous lesions harbouring increasing CRC stages. RESULTS: Out of 5258 proteins identified, we obtained 561 proteins with a significant differential distribution among groups of patients and controls. KNG1, OLFM4 and Sec24C distributions were validated in tissues and showed different expression levels especially in the two early CRC stages compared to normal and preneoplastic tissues. CONCLUSION: We highlighted three proteins that require further investigations to better characterise their role in early CRC carcinogenesis and their potential as early CRC markers. PMID- 28344543 TI - Chinese immigrant men smokers' sources of cigarettes in Canada: A qualitative study. AB - BACKGROUND: Immigrants often experience economic hardship in their host country and tend to belong to economically disadvantaged groups. Individuals of lower socioeconomic status tend to be more sensitive to cigarette price changes. This study explores the cigarette purchasing patterns among Chinese Canadian male immigrants. METHODS: Semi-structured in-depth interviews were conducted with 22 Chinese Canadian immigrants who were smoking or had quit smoking in the last five years. RESULTS: Because of financial pressures experienced by participants, the high price of Canadian cigarettes posed a significant challenge to their continued smoking. While some immigrants bought fully-taxed cigarettes from licensed retailers, more often they sought low-cost cigarettes from a variety of sources. The two most important sources were cigarettes imported during travels to China and online purchases of Chinese cigarettes. The cigarettes obtained through online transactions were imported by smoking or non-smoking Chinese immigrants and visitors, suggesting the Chinese community were involved or complicit in sustaining this form of purchasing behavior. Other less common sources included Canada-USA cross border purchasing, roll your-own pouch tobacco, and buying cigarettes available on First Nations reserves. CONCLUSIONS: Chinese Canadian immigrant men used various means to obtain cheap cigarettes. Future research studies could explore more detailed features of access to expose gaps in policy and improve tobacco regulatory frameworks. PMID- 28344544 TI - The association between occupational secondhand smoke exposure and life satisfaction among adults in the European Union. AB - BACKGROUND: Despite existing legislation, a large proportion of the European Union (EU) population is exposed to occupational secondhand smoke (SHS). The aim of this study was to explore associations between occupational exposure to SHS and self-reported life satisfaction. METHODS: We analysed data collected through the Eurobarometer survey (wave 82.4) from n = 11,788 individuals working in indoor spaces. The sample was representative of the population of the 28 EU member states. We fitted a multilevel logistic regression model adjusting for smoking, age, gender, occupation, area of residence, education, difficulty paying bills, marital status and social class. RESULTS: 27.5% of those working indoors reported at least some occupational exposure to SHS. People exposed to occupational SHS were less likely to report that they were satisfied with the life they lead (adjusted Odds Ratio = 0.72, 95% Confidence Interval: 0.60-0.87). The effect of occupational exposure on life satisfaction did not differ by smoking status, with all interaction terms between smoking status and occupational exposure to SHS not statistically significant. CONCLUSION: Exposure to SHS at the workplace does not only have negative consequences on physical health, but it can also impact life satisfaction of smokers and non-smokers. Our findings highlight the need for stricter enforcement of smokefree environments at the workplace in the EU. PMID- 28344545 TI - Music Improves Subjective Feelings Leading to Cardiac Autonomic Nervous Modulation: A Pilot Study. AB - It is widely accepted that listening to music improves subjective feelings and reduces fatigue sensations, and different kinds of music lead to different activations of these feelings. Recently, cardiac autonomic nervous modulation has been proposed as a useful objective indicator of fatigue. However, scientific considerations of the relation between feelings of fatigue and cardiac autonomic nervous modulation while listening to music are still lacking. In this study, we examined which subjective feelings of fatigue are related to participants' cardiac autonomic nervous function while they listen to music. We used an album of comfortable and relaxing environmental music, with blended sounds from a piano and violin as well as natural sound sources. We performed a crossover trial of environmental music and silent sessions for 20 healthy subjects, 12 females, and 8 males, after their daily work shift. We measured changes in eight types of subjective feelings, including healing, fatigue, sleepiness, relaxation, and refreshment, using the KOKORO scale, a subjective mood measurement system for self-reported feelings. Further, we obtained measures of cardiac autonomic nervous function on the basis of heart rate variability before and after the sessions. During the music session, subjective feelings significantly shifted toward healing and a secure/relaxed feeling and these changes were greater than those in the silent session. Heart rates (DeltaHR) in the music session significantly decreased compared with those in the silent session. Other cardiac autonomic parameters such as high-frequency (HF) component and the ratio of low frequency (LF) and HF components (LF/HF) were similar in the two sessions. In the linear regression analysis of the feelings with DeltaHR and changes in LF/HF (DeltaLF/HF), increases and decreases in DeltaHR were correlated to the feeling axes of Fatigue-Healing and Anxiety/Tension-Security/Relaxation, whereas those in DeltaLF/HF were related to the feeling axes of Sleepiness-Wakefulness and Gloomy Refreshed. This indicated that listening to music improved the participants' feelings of fatigue and decreased their heart rates. However, it did not reduce the cardiac LF/HF, suggesting that cardiac LF/HF might show a delayed response to fatigue. Thus, we demonstrated changes in cardiac autonomic nervous functions based on feelings of fatigue. PMID- 28344546 TI - Choosing MUSE: Validation of a Low-Cost, Portable EEG System for ERP Research. AB - In recent years there has been an increase in the number of portable low-cost electroencephalographic (EEG) systems available to researchers. However, to date the validation of the use of low-cost EEG systems has focused on continuous recording of EEG data and/or the replication of large system EEG setups reliant on event-markers to afford examination of event-related brain potentials (ERP). Here, we demonstrate that it is possible to conduct ERP research without being reliant on event markers using a portable MUSE EEG system and a single computer. Specifically, we report the results of two experiments using data collected with the MUSE EEG system-one using the well-known visual oddball paradigm and the other using a standard reward-learning task. Our results demonstrate that we could observe and quantify the N200 and P300 ERP components in the visual oddball task and the reward positivity (the mirror opposite component to the feedback related negativity) in the reward-learning task. Specifically, single sample t tests of component existence (all p's < 0.05), computation of Bayesian credible intervals, and 95% confidence intervals all statistically verified the existence of the N200, P300, and reward positivity in all analyses. We provide with this research paper an open source website with all the instructions, methods, and software to replicate our findings and to provide researchers with an easy way to use the MUSE EEG system for ERP research. Importantly, our work highlights that with a single computer and a portable EEG system such as the MUSE one can conduct ERP research with ease thus greatly extending the possible use of the ERP methodology to a variety of novel contexts. PMID- 28344548 TI - GSK-3beta Overexpression Alters the Dendritic Spines of Developmentally Generated Granule Neurons in the Mouse Hippocampal Dentate Gyrus. AB - The dentate gyrus (DG) plays a crucial role in hippocampal-related memory. The most abundant cellular type in the DG, namely granule neurons, are developmentally generated around postnatal day P6 in mice. Moreover, a unique feature of the DG is the occurrence of adult hippocampal neurogenesis, a process that gives rise to newborn granule neurons throughout life. Adult-born and developmentally generated granule neurons share some maturational aspects but differ in others, such as in their positioning within the granule cell layer. Adult hippocampal neurogenesis encompasses a series of plastic changes that modify the function of the hippocampal trisynaptic network. In this regard, it is known that glycogen synthase kinase 3beta (GSK-3beta) regulates both synaptic plasticity and memory. By using a transgenic mouse overexpressing GSK-3beta in hippocampal neurons, we previously demonstrated that the overexpression of this kinase has deleterious effects on the maturation of newborn granule neurons. In the present study, we addressed the effects of GSK-3beta overexpression on the morphology and number of dendritic spines of developmentally generated granule neurons. To this end, we performed intracellular injections of Lucifer Yellow in developmentally generated granule neurons of wild-type and GSK-3beta overexpressing mice and analyzed the number and morphologies of dendritic spines (namely, stubby, thin and mushroom). GSK-3beta overexpression led to a general reduction in the number of dendritic spines. In addition, it caused a slight reduction in the percentage, head diameter and length of thin spines, whereas the head diameter of mushroom spines was increased. PMID- 28344549 TI - Functional Brain Activation in Response to a Clinical Vestibular Test Correlates with Balance. AB - The current study characterizes brain fMRI activation in response to two modes of vestibular stimulation: Skull tap and auditory tone burst. The auditory tone burst has been used in previous studies to elicit either a vestibulo-spinal reflex [saccular-mediated colic Vestibular Evoked Myogenic Potentials (cVEMP)], or an ocular muscle response [utricle-mediated ocular VEMP (oVEMP)]. Research suggests that the skull tap elicits both saccular and utricle-mediated VEMPs, while being faster and less irritating for subjects than the high decibel tones required to elicit VEMPs. However, it is not clear whether the skull tap and auditory tone burst elicit the same pattern of brain activity. Previous imaging studies have documented activity in the anterior and posterior insula, superior temporal gyrus, inferior parietal lobule, inferior frontal gyrus, and the anterior cingulate cortex in response to different modes of vestibular stimulation. Here we hypothesized that pneumatically powered skull taps would elicit a similar pattern of brain activity as shown in previous studies. Our results provide the first evidence of using pneumatically powered skull taps to elicit vestibular activity inside the MRI scanner. A conjunction analysis revealed that skull taps elicit overlapping activation with auditory tone bursts in the canonical vestibular cortical regions. Further, our postural control assessments revealed that greater amplitude of brain activation in response to vestibular stimulation was associated with better balance control for both techniques. Additionally, we found that skull taps elicit more robust vestibular activity compared to auditory tone bursts, with less reported aversive effects, highlighting the utility of this approach for future clinical and basic science research. PMID- 28344550 TI - Hyperpolarization-Activated Current Induces Period-Doubling Cascades and Chaos in a Cold Thermoreceptor Model. AB - In this article, we describe and analyze the chaotic behavior of a conductance based neuronal bursting model. This is a model with a reduced number of variables, yet it retains biophysical plausibility. Inspired by the activity of cold thermoreceptors, the model contains a persistent Sodium current, a Calcium activated Potassium current and a hyperpolarization-activated current (Ih) that drive a slow subthreshold oscillation. Driven by this oscillation, a fast subsystem (fast Sodium and Potassium currents) fires action potentials in a periodic fashion. Depending on the parameters, this model can generate a variety of firing patterns that includes bursting, regular tonic and polymodal firing. Here we show that the transitions between different firing patterns are often accompanied by a range of chaotic firing, as suggested by an irregular, non periodic firing pattern. To confirm this, we measure the maximum Lyapunov exponent of the voltage trajectories, and the Lyapunov exponent and Lempel-Ziv's complexity of the ISI time series. The four-variable slow system (without spiking) also generates chaotic behavior, and bifurcation analysis shows that this is often originated by period doubling cascades. Either with or without spikes, chaos is no longer generated when the Ih is removed from the system. As the model is biologically plausible with biophysically meaningful parameters, we propose it as a useful tool to understand chaotic dynamics in neurons. PMID- 28344547 TI - APP Function and Lipids: A Bidirectional Link. AB - Extracellular neuritic plaques, composed of aggregated amyloid-beta (Abeta) peptides, are one of the major histopathological hallmarks of Alzheimer's disease (AD), a progressive, irreversible neurodegenerative disorder and the most common cause of dementia in the elderly. One of the most prominent risk factor for sporadic AD, carrying one or two aberrant copies of the apolipoprotein E (ApoE) epsilon4 alleles, closely links AD to lipids. Further, several lipid classes and fatty acids have been reported to be changed in the brain of AD-affected individuals. Interestingly, the observed lipid changes in the brain seem not only to be a consequence of the disease but also modulate Abeta generation. In line with these observations, protective lipids being able to decrease Abeta generation and also potential negative lipids in respect to AD were identified. Mechanistically, Abeta peptides are generated by sequential proteolytic processing of the amyloid precursor protein (APP) by beta- and gamma-secretase. The alpha-secretase appears to compete with beta-secretase for the initial cleavage of APP, preventing Abeta production. All APP-cleaving secretases as well as APP are transmembrane proteins, further illustrating the impact of lipids on Abeta generation. Beside the pathological impact of Abeta, accumulating evidence suggests that Abeta and the APP intracellular domain (AICD) play an important role in regulating lipid homeostasis, either by direct effects or by affecting gene expression or protein stability of enzymes involved in the de novo synthesis of different lipid classes. This review summarizes the current literature addressing the complex bidirectional link between lipids and AD and APP processing including lipid alterations found in AD post mortem brains, lipids that alter APP processing and the physiological functions of Abeta and AICD in the regulation of several lipid metabolism pathways. PMID- 28344554 TI - Cannabis in Chinese Medicine: Are Some Traditional Indications Referenced in Ancient Literature Related to Cannabinoids? AB - Cannabis sativa L. (Cannabaceae) has a long history of utilization as a fiber and seed crop in China, and its achenes ("seeds") as well as other plant parts have been recorded in Chinese medical texts for nearly 2000 years. While the primary applications of cannabis in Chinese medicine center around the use of the achenes, ancient indications for the female inflorescence, and other plant parts include conditions such as pain and mental illness that are the subject of current research into cannabinoids such as cannabidiol (CBD) and Delta9 tetrahydrocannabinol (THC). However, little previous research has been conducted to analyze the Chinese medical literature in light of recent advances in the pharmacology and taxonomy of cannabis, and most of the relevant Chinese historical records have not yet been translated into Western languages to facilitate textual research. Furthermore, many key questions remain unresolved in the Chinese literature, including how various traditional drug names precisely correspond to different plant parts, as well as the implications of long-term selection for fiber-rich cultivars on the medical applications of cannabis in Chinese medicine. In this article, prominent historical applications of cannabis in Chinese medicine are chronologically reviewed, and indications found in ancient Chinese literature that may relate to cannabinoids such as CBD and Delta9 THC are investigated. PMID- 28344553 TI - Youthful Processing Speed in Older Adults: Genetic, Biological, and Behavioral Predictors of Cognitive Processing Speed Trajectories in Aging. AB - Objective: To examine the impact of genetic, inflammatory, cardiovascular, lifestyle, and neuroanatomical factors on cognitive processing speed (CPS) change over time in functionally intact older adults. Methods: This observational study conducted over two time points, included 120 community dwelling cognitively normal older adults between the ages of 60 and 80 from the University of California San Francisco Memory and Aging Center. Participants were followed with composite measures of CPS, calculated based on norms for 20-30 year-olds. Variables of interest were AD risk genes (APOE, CR1), markers of inflammation (interleukin 6) and cardiovascular health (BMI, LDL, HDL, mean arterial pressure, fasting insulin), self-reported physical activity, and corpus callosum (CC) volumes. The sample was divided into three groups: 17 "resilient-agers" with fast and stable processing speed; 56 "average-agers" with average and stable processing speed; and 47 "sub-agers" with average baseline speed who were slower at follow-up. Results: Resilient-agers had larger baseline CC volumes than sub agers (p < 0.05). Resilient-agers displayed lower levels of interleukin-6 (IL-6) and insulin (ps < 0.05) than sub-agers, and reported more physical activity than both average- and sub-agers (ps < 0.01). In a multinomial logistic regression, physical activity and IL-6 predicted average- and sub-ager groups. Resilient agers displayed a higher frequency of APOE e4 and CR1 AA/AG alleles. Conclusion: Robust and stable CPS is associated with larger baseline CC volumes, lower levels of inflammation and insulin, and greater self-reported physical activity. These findings highlight the relevance of neuroanatomical, biological, and lifestyle factors in the identification and prediction of heterogeneous cognitive aging change over time. PMID- 28344555 TI - Drug Repurposing of the Anthelmintic Niclosamide to Treat Multidrug-Resistant Leukemia. AB - Multidrug resistance, a major problem that leads to failure of anticancer chemotherapy, requires the development of new drugs. Repurposing of established drugs is a promising approach for overcoming this problem. An example of such drugs is niclosamide, a known anthelmintic that is now known to be cytotoxic and cytostatic against cancer cells. In this study, niclosamide showed varying activity against different cancer cell lines. It revealed better activity against hematological cancer cell lines CCRF-CEM, CEM/ADR5000, and RPMI-8226 compared to the solid tumor cell lines MDA-MB-231, A549, and HT-29. The multidrug resistant CEM/ADR5000 cells were similar sensitive as their sensitive counterpart CCRF-CEM (resistance ration: 1.24). Furthermore, niclosamide caused elevations in reactive oxygen species and glutathione (GSH) levels in leukemia cells. GSH synthetase (GS) was predicted as a target of niclosamide. Molecular docking showed that niclosamide probably binds to the ATP-binding site of GS with a binding energy of -9.40 kcal/mol. Using microscale thermophoresis, the binding affinity between niclosamide and recombinant human GS was measured (binding constant: 5.64 MUM). COMPARE analyses of the NCI microarray database for 60 cell lines showed that several genes, including those involved in lipid metabolism, correlated with cellular responsiveness to niclosamide. Hierarchical cluster analysis showed five major branches with significant differences between sensitive and resistant cell lines (p = 8.66 * 105). Niclosamide significantly decreased nuclear factor of activated T-cells (NFAT) activity as predicted by promoter binding motif analysis. In conclusion, niclosamide was more active against hematological malignancies compared to solid tumors. The drug was particularly active against the multidrug-resistant CEM/ADR5000 leukemia cells. Inhibition of GSH synthesis and NFAT signaling were identified as relevant mechanisms for the anticancer activity of niclosamide. Gene expression profiling predicted the sensitivity or resistance of cancer cells to niclosamide. PMID- 28344557 TI - Dissecting Target Toxic Tissue and Tissue Specific Responses of Irinotecan in Rats Using Metabolomics Approach. AB - As an anticancer agent, irinotecan (CPT-11) has been widely applied in clinical, especially in the treatment of colorectal cancer. However, its clinical use has long been limited by the side effects and potential tissue toxicity. To discriminate the target toxic tissues and dissect the specific response of target tissues after CPT-11 administration in rats, untargeted metabolomic study was conducted. First, differential metabolites between CPT-11 treated group and control group in each tissue were screened out. Then, based on fold changes of these differential metabolites, principal component analysis and hierarchical cluster analysis were performed to visualize the degree and specificity of the influences of CPT-11 on the metabolic profiles of nine tissues. Using this step wise method, ileum, jejunum, and liver were finally recognized as target toxic tissues. Furthermore, tissue specific responses of liver, ileum, and jejunum to CPT-11 were dissected and specific differential metabolites were screened out. Perturbations in Krebs cycle, amino acid, purine and bile acid metabolism were observed in target toxic tissues. In conclusion, our study put forward a new approach to dissect target toxic tissues and tissue specific responses of CPT-11 using metabolomics. PMID- 28344556 TI - The Immunomodulatory Effects of Plant Extracts and Plant Secondary Metabolites on Chronic Neuroinflammation and Cognitive Aging: A Mechanistic and Empirical Review. AB - Advances in healthcare have considerably improved the life expectancy of the human population over the last century and this has brought about new challenges. As we live longer the capacity for cognitive aging increases. Consequently, it has been noted that decline in cognitive performance in the elderly in domains of reasoning, problem solving skills, attention, processing speed, working memory and episodic memory is a significant societal problem. Despite the enormity of this issue there are relatively few interventions for cognitive aging. This may be due to our current state of knowledge on biological factors that underpin cognitive aging. One of the biological contributors to cognitive aging is chronic neuroinflammation. This review will provide an overview of the peripheral and central mechanisms involved in chronic neuroinflammation and how neuroinflammation may be related to age-associated cognitive decline. Plant based extracts including herbal and nutritional supplements with anti-inflammatory properties will be examined in relation to their utility in treating age-related cognitive decline. Plant based extracts in particular offer interesting pharmacological properties that may be quickly utilized to prevent cognitive aging. PMID- 28344559 TI - Cyclooxygenase-2 Inhibition Limits Angiotensin II-Induced DNA Oxidation and Protein Nitration in Humans. AB - Compared to other cyclooxygenase-2 inhibitors, celecoxib is associated with a lower cardiovascular risk, though the mechanism remains unclear. Angiotensin II is an important mediator of oxidative stress in the pathophysiology of vascular disease. Cyclooxygenase-2 may modify the effects of angiotensin II though this has never been studied in humans. The purpose of the study was to test the effects of selective cyclooxygenase-2 inhibition on plasma measures of oxidative stress, the vasoconstrictor endothelin-1, and nitric oxide metabolites, both at baseline and in respose to Angiotensin II challenge in healthy humans. Measures of 8-hydroxydeoxyguanosine, advanced oxidation protein products, nitrotyrosine, endothelin-1, and nitric oxide metabolites were assessed from plasma samples drawn at baseline and in response to graded angiotensin II infusion (3 ng/kg/min * 30 min, 6 ng/kg/min * 30 min) before and after 14 days of cyclooxygenase-2 inhibition in 14 healthy subjects (eight male, six female) in high salt balance, a state of maximal renin angiotensin system suppression. Angiotensin II infusion significantly increased plasma oxidative stress compared to baseline (8 hydroxydeoxyguanosine; +17%; advanced oxidation protein products; +16%), nitrotyrosine (+76%). Furthermore, levels of endothelin-1 levels were significantly increased (+115%) and nitric oxide metabolites were significantly decreased (-20%). Cycloxygenase-2 inhibition significantly limited the increase in 8-hydroxydeoxyguanosine, nitrotyrosine and the decrease in nitric oxide metabolites induced by angiotensin II infusion, though no changes in advanced oxidation protein products and endothelin-1 concentrations were observed. Cyclooxygenase-2 inhibition with celecoxib partially limited the angiotensin II mediated increases in markers of oxidative stress in humans, offering a potential physiological pathway for the improved cardiovascular risk profile of this drug. PMID- 28344558 TI - Role of Autonomic Nervous System and Orexinergic System on Adipose Tissue. AB - Adipose tissue, defined as white adipose tissue (WAT) and brown adipose tissue (BAT), is a biological caloric reservoir; in response to over-nutrition it expands and, in response to energy deficit, it releases lipids. The WAT primarily stores energy as triglycerides, whereas BAT dissipates chemical energy as heat. In mammals, the BAT is a key site for heat production and an attractive target to promote weight loss. The autonomic nervous system (ANS) exerts a direct control at the cellular and molecular levels in adiposity. The sympathetic nervous system (SNS) provides a complex homeostatic control to specifically coordinate function and crosstalk of both fat pads, as indicated by the increase of the sympathetic outflow to BAT, in response to cold and high-fat diet, but also by the increase or decrease of the sympathetic outflow to selected WAT depots, in response to different lipolytic requirements of these two conditions. More recently, a role has been attributed to the parasympathetic nervous system (PNS) in modulating both adipose tissue insulin-mediated glucose uptake and fatty free acid (FFA) metabolism in an anabolic way and its endocrine function. The regulation of adipose tissue is unlikely to be limited to the autonomic control, since a number of signaling cytokines and neuropeptides play an important role, as well. In this review, we report some experimental evidences about the role played by both the ANS and orexins into different fat pads, related to food intake and energy expenditure, with a special emphasis on body weight status and fat mass (FM) content. PMID- 28344560 TI - Nitric Oxide Has a Concentration-Dependent Effect on the Cell Cycle Acting via EIN2 in Arabidopsis thaliana Cultured Cells. AB - Ethylene is known to influence the cell cycle (CC) via poorly characterized roles whilst nitric oxide (NO) has well-established roles in the animal CC but analogous role(s) have not been reported for plants. As NO and ethylene signaling events often interact we examined their role in CC in cultured cells derived from Arabidopsis thaliana wild-type (Col-0) plants and from ethylene-insensitive mutant ein2-1 plants. Both NO and ethylene were produced mainly during the first 5 days of the sub-cultivation period corresponding to the period of active cell division. However, in ein2-1 cells, ethylene generation was significantly reduced while NO levels were increased. With application of a range of concentrations of the NO donor, sodium nitroprusside (SNP) (between 20 and 500 MUM) ethylene production was significantly diminished in Col-0 but unchanged in ein2-1 cells. Flow cytometry assays showed that in Col-0 cells treatments with 5 and 10 MUM SNP concentrations led to an increase in S-phase cell number indicating the stimulation of G1/S transition. However, at >=20 MUM SNP CC progression was restrained at G1/S transition. In the mutant ein2-1 strain, the index of S-phase cells was not altered at 5-10 MUM SNP but decreased dramatically at higher SNP concentrations. Concomitantly, 5 MUM SNP induced transcription of genes encoding CDKA;1 and CYCD3;1 in Col-0 cells whereas transcription of CDKs and CYCs were not significantly altered in ein2-1 cells at any SNP concentrations examined. Hence, it is appears that EIN2 is required for full responses at each SNP concentration. In ein2-1 cells, greater amounts of NO, reactive oxygen species, and the tyrosine nitrating peroxynitrite radical were detected, possibly indicating NO-dependent post-translational protein modifications which could stop CC. Thus, we suggest that in Arabidopsis cultured cells NO affects CC progression as a concentration dependent modulator with a dependency on EIN2 for both ethylene production and a NO/ethylene regulatory function. PMID- 28344561 TI - Fetal Growth Restriction Induces Heterogeneous Effects on Vascular Biomechanical and Functional Properties in Guinea Pigs (Cavia porcellus). AB - Aim: Fetal growth restriction (FGR) is associated with a variety of cardiometabolic diseases in adulthood which could involve remodeling processes of the vascular walls that could start in the fetal period. However, there is no consensus whether this remodeling affects in a similar way the whole vascular system. We aimed to determine the effects of FGR on the vasoactive and biomechanical properties of umbilical and systemic vessels in fetal guinea pigs. Methods: FGR was induced by implanting ameroid occluders at mid-gestation in uterine arteries of pregnant guinea pigs, whilst the control group was exposed to simulated surgery. At the term of gestation, systemic arteries (aorta, carotid and femoral) and umbilical vessels were isolated to determine ex vivo contractile and biomechanical responses (stretch-stress until rupture) on a wire myograph, as well as opening angle and residual stresses. Histological characteristics in tissue samples were measured by van Gieson staining. Results: Aorta and femoral arteries from FGR showed an increased in biomechanical markers of stiffness (p < 0.01), contractile capacity (p < 0.05) and relative media thickness (p < 0.01), but a reduced internal diameter (p < 0.001), compared with controls. There were no differences in the biomechanical properties of carotid and umbilical from control and FGR fetuses, but FGR umbilical arteries had a decreased contractile response to KCl (p < 0.05) along with a reduced relative media thickness (p < 0.05). Conclusion: Altogether, these changes in functional, mechanical and morphological properties suggest that FGR is associated with a heterogeneous pro constrictive vascular remodeling affecting mainly the lower body fetal arteries. These effects would be set during a pathologic pregnancy in order to sustain the fetal blood redistribution in the FGR and may persist up to adulthood increasing the risk of a cardiovascular disease. PMID- 28344562 TI - Attachment Styles and Suicide-Related Behaviors in Adolescence: The Mediating Role of Self-Criticism and Dependency. AB - Insecure attachment and the personality dimensions of self-criticism and dependency have been proposed as risk factors for suicide in adolescents. The present study examines whether self-criticism and dependency mediate the relationship between insecure attachment styles and suicidality. A sample of 340 high-school students (73.2% females), ranging in age from 13 to 20 years (M = 16.47, SD = 1.52), completed the Depressive Experiences Questionnaire for Adolescents, the Depressive Experiences Questionnaire for Adolescents, the Attachment Style Questionnaire, and the Suicidal Behaviors Questionnaire-Revised. The results partially support the expected mediation effects. Self-criticism, but not dependency, mediates the link between insecure attachment (anxiety and avoidance) and suicide-related behaviors. Implications for suicide risk assessment and management are discussed. PMID- 28344551 TI - Construction and Analysis of Weighted Brain Networks from SICE for the Study of Alzheimer's Disease. AB - Alzheimer's Disease (AD) is the most common neurodegenerative disease in elderly people, and current drugs, unfortunately, do not represent yet a cure but only slow down its progression. This is explained, at least in part, because the understanding of the neurodegenerative process is still incomplete, being sometimes mistaken, particularly at the first steps of the illness, with the natural aging process. A better identification of how the functional activity deteriorates is thus crucial to develop new and more effective treatments. Sparse inverse covariance estimates (SICE) have been recently employed for deriving functional connectivity patterns from Positron Emission Tomography (PET) of brains affected by Alzheimer's Disease. SICE, unlike the traditional covariance methods, allows to analyze the interdependencies between brain regions factoring out the influence of others. To analyze the effects of the illness, connectivity patterns of brains affected by AD are compared with those obtained for control groups. These comparisons are, however, carried out for binary (undirected and unweighted) adjacency matrices with the same number of arcs. Additionally, the effect of the number of subjects employed or the validity of the regularization parameter used to compute the SICE have been not hitherto analyzed. In this paper, we delve into the construction of connectivity patterns from PET using SICE. In particular, we describe the effect that the number of subjects employed has on the results and identify, based on the reconstruction error of linear regression systems, a range of valid values for the regularization parameter. The amount of arcs is also proved as a discriminant value, and we show that it is possible to pass from unweighted (binary) to weighted adjacency matrices, where the weight of a connection corresponding to the existence of a relationship between two brain areas can be correlated to the persistence of this relationship when computed for different values of the regularization parameter and sets of subjects. Finally, network measures are computed for the connectivity patterns confirming that SICE may be particularly apt for assessing the efficiency of drugs, since it produces reliable brain connectivity models with small sample sizes, and that connectivity patterns affected by AD seem much less segregated, reducing the small-worldness. PMID- 28344563 TI - A Review of Demographic, Medical, and Treatment Variables Associated with Health Related Quality of Life (HRQOL) in Survivors of Hematopoietic Stem Cell (HSCT) and Bone Marrow Transplantation (BMT) during Childhood. AB - Hematopoietic stem cell transplantation (HSCT) is a standard treatment after disease relapse and failure of conventional treatments for cancer in childhood or as a first line treatment for some high-risk cancers. Since hematopoietic stem cells can be found in the marrow (previously called a bone marrow transplantation) or periphery, we refer to HSCT as inclusive of HSCT regardless of the origin of the stem cells. HSCT is associated with adverse side effects, prolonged hospitalization, and isolation. Previous studies have shown that survivors of HSCT are at particularly high risk for developing late effects and medical complications, and thus, in addition to survival, quality of life in survivors of HSCT is an important outcome. This review summarizes and distills findings on the health-related quality of life (HRQOL) of long-term childhood cancer survivors of HSCT and examines significant sociodemographic, medical, disease and treatment correlates of HRQOL, as well as the methodology of the studies (instruments, type of studies, timing of assessment, type of transplantation). Because previous reviews covered the studies published before 2006, this review searched three databases published between January, 2006, and August, 2016. The search identified nine studies, including 2 prospective cohort studies and 7 cross-sectional studies. All studies reported a follow-up time of >5 years. The review found that HRQOL is significantly impacted over time following childhood HSCT, with salient correlates of HRQOL found to be presence of a severe chronic health or major medical condition, graft vs. host disease (GVHD), or pain. Continual evaluation of HRQOL must be integrated into long-term follow-up after childhood HSCT, and intervention should be offered for those survivors with poor HRQOL. Longitudinal studies should be emphasized in future research to allow for predictor models of resilience and poor HRQOL. PMID- 28344552 TI - Adding Recognition Discriminability Index to the Delayed Recall Is Useful to Predict Conversion from Mild Cognitive Impairment to Alzheimer's Disease in the Alzheimer's Disease Neuroimaging Initiative. AB - Background: Ongoing research is focusing on the identification of those individuals with mild cognitive impairment (MCI) who are most likely to convert to Alzheimer's disease (AD). We investigated whether recognition memory tasks in combination with delayed recall measure of episodic memory and CSF biomarkers can predict MCI to AD conversion at 24-month follow-up. Methods: A total of 397 amnestic-MCI subjects from Alzheimer's disease Neuroimaging Initiative were included. Logistic regression modeling was done to assess the predictive value of all RAVLT measures, risk factors such as age, sex, education, APOE genotype, and CSF biomarkers for progression to AD. Estimating adjusted odds ratios was used to determine which variables would produce an optimal predictive model, and whether adding tests of interaction between the RAVLT Delayed Recall and recognition measures (traditional score and d-prime) would improve prediction of the conversion from a-MCI to AD. Results: 112 (28.2%) subjects developed dementia and 285 (71.8%) subjects did not. Of the all included variables, CSF Abeta1-42 levels, RAVLT Delayed Recall, and the combination of RAVLT Delayed Recall and d prime were predictive of progression to AD (chi2 = 38.23, df = 14, p < 0.001). Conclusions: The combination of RAVLT Delayed Recall and d-prime measures may be predictor of conversion from MCI to AD in the ADNI cohort, especially in combination with amyloid biomarkers. A predictive model to help identify individuals at-risk for dementia should include not only traditional episodic memory measures (delayed recall or recognition), but also additional variables (d prime) that allow the homogenization of the assessment procedures in the diagnosis of MCI. PMID- 28344564 TI - Investigating the Grammatical and Pragmatic Origins of Wh-Questions in Children with Autism Spectrum Disorders. AB - Compared to typically developing children, children with autism (ASD) show delayed production of wh-questions. It is currently controversial the degree to which such deficits derive from social-pragmatic requirements and/or because these are complex grammatical structures. The current study employed the intermodal preferential looking (IPL) paradigm, which reduces social-pragmatic demands. The IPL paradigm can help distinguish these proposals, as successful comprehension promotes the "pragmatics-origins" argument whereas comprehension difficulties would implicate a "grammatical-origins" argument. Additionally, we tested both the linguistic and social explanations by assessing the contributions of children's early grammatical knowledge (i.e., SVO word order) and their social pragmatic scores on the Vineland to their later wh-question comprehension. Fourteen children with ASD and 17 TD children, matched on language level, were visited in their homes at 4-month intervals. Comprehension of wh-questions and SVO word order were tested via IPL: the wh-question video showed a costumed horse and bird serving as agents or patients of familiar transitive actions. During the test trials, they were displayed side by side with directing audios (e.g., "What did the horse tickle?", "What hugged the bird?", "Where is the horse/bird?"). Children's eye movements were coded offline; the DV was their percent looking to the named item during test. To show comprehension, children should look longer at the named item during a where-question than during a subject-wh or object-wh question. Results indicated that TD children comprehended both subject and object wh-questions at 32 months of age. Comprehension of object-wh questions emerged chronologically later in children with ASD compared to their TD peers, but at similar levels of language. Moreover, performance on word order and social pragmatic scores independently predicted both groups' later performance on wh question comprehension. Our findings indicate that both grammar and social pragmatics are implicated in the comprehension of wh-questions. The "grammatical origins" argument is supported because the ASD group did not reveal earlier and stable comprehension of wh-questions; furthermore, their performance on SVO word order predicted their later success in linguistic processing of wh-questions. The "pragmatic-origins" argument is also supported because children's earlier socialization and communication scores strongly predicted their successful performance on wh-question comprehension. PMID- 28344565 TI - From Attire to Assault: Clothing, Objectification, and De-humanization - A Possible Prelude to Sexual Violence? AB - In the context of objectification and violence, little attention has been paid to the perception neuroscience of how the human brain perceives bodies and objectifies them. Various studies point to how external cues such as appearance and attire could play a key role in encouraging objectification, dehumanization and the denial of agency. Reviewing new experimental findings across several areas of research, it seems that common threads run through issues of clothing, sexual objectification, body perception, dehumanization, and assault. Collating findings from several different lines of research, this article reviews additional evidence from cognitive and neural dynamics of person perception (body and face perception processes) that predict downstream social behavior. Specifically, new findings demonstrate cognitive processing of sexualized female bodies as object-like, a crucial aspect of dehumanized percept devoid of agency and personhood. Sexual violence is a consequence of a dehumanized perception of female bodies that aggressors acquire through their exposure and interpretation of objectified body images. Integrating these findings and identifying triggers for sexual violence may help develop remedial measures and inform law enforcement processes and policy makers alike. PMID- 28344566 TI - The Onset Time of the Ownership Sensation in the Moving Rubber Hand Illusion. AB - The rubber hand illusion (RHI) is a perceptual illusion whereby a model hand is perceived as part of one's own body. This illusion has been extensively studied, but little is known about the temporal evolution of this perceptual phenomenon, i.e., how long it takes until participants start to experience ownership over the model hand. In the present study, we investigated a version of the rubber hand experiment based on finger movements and measured the average onset time in active and passive movement conditions. This comparison enabled us to further explore the possible role of intentions and motor control processes that are only present in the active movement condition. The results from a large group of healthy participants (n = 117) showed that the illusion of ownership took approximately 23 s to emerge (active: 22.8; passive: 23.2). The 90th percentile occurs in both conditions within approximately 50 s (active: 50; passive: 50.6); therefore, most participants experience the illusion within the first minute. We found indirect evidence of a facilitatory effect of active movements compared to passive movements, and we discuss these results in the context of our current understanding of the processes underlying the moving RHI. PMID- 28344568 TI - Time Is Money: The Decision Making of Smartphone High Users in Gain and Loss Intertemporal Choice. AB - Nowadays the smartphone plays an important role in our lives. While it brings us convenience and efficiency, its overuse can cause problems. Although a great number of studies have demonstrated that people affected by substance abuse, pathological gambling, and internet addiction disorder have lower self-control than average, scarcely any study has investigated the decision making of smartphone high users by using a behavioral paradigm. The present study employed an intertemporal task, the Smartphone Addiction Inventory (SPAI) and the Barratt Impulsiveness Scale 11th version (BIS-11) to explore the decision control of smartphone high users in a sample of 125 college students. Participants were divided into three groups according to their SPAI scores. The upper third (69 or higher), middle third (from 61 to 68) and lower third (60 or lower) of scores were defined as high smartphone users, medium users and low users, respectively. We compared the percentage of small immediate reward/penalty choices in different conditions between the three groups. Relative to the low users group, high users and medium users were more inclined to request an immediate monetary reward. Moreover, for the two dimensions of time and money in intertemporal choice, high users and medium users showed a bias in intertemporal choice task among most of the time points and value magnitude compared to low users. These findings demonstrated that smartphone overuse was associated with problematic decision making, a pattern similar to that seen in persons affected by a variety of addictions. PMID- 28344569 TI - Eye Contact Judgment Is Influenced by Perceivers' Social Anxiety But Not by Their Affective State. AB - Fast and accurate judgment of whether another person is making eye contact or not is crucial for our social interaction. As affective states have been shown to influence social perceptions and judgments, we investigated the influence of observers' own affective states and trait anxiety on their eye contact judgments. In two experiments, participants were required to judge whether animated faces (Experiment 1) and real faces (Experiment 2) with varying gaze angles were looking at them or not. Participants performed the task in pleasant, neutral, and unpleasant odor conditions. The results from two experiments showed that eye contact judgments were not modulated by observers' affective state, yet participants with higher levels of social anxiety accepted a wider range of gaze deviations from the direct gaze as eye contact. We conclude that gaze direction judgments depend on individual differences in affective predispositions, yet they are not amenable to situational affective influences. PMID- 28344567 TI - Does Hunger Contribute to Socioeconomic Gradients in Behavior? AB - Recent research has uncovered many examples of socioeconomic gradients in behavior and psychological states. As yet there is no theoretical consensus on the nature of the causal processes that produce these gradients. Here, I present the hunger hypothesis, namely the claim that part of the reason that people of lower socioeconomic position behave and feel as they do is that they are relatively often hungry. The hunger hypothesis applies in particular to impulsivity-hyperactivity, irritability-aggression, anxiety, and persistent narcotic use, all of which have been found to show socioeconomic gradients. I review multiple lines of evidence showing that hunger produces strong increases in these outcomes. I also review the literatures on food insufficiency and food insecurity to show that, within affluent societies, the poor experience a substantial burden of hunger, despite obtaining sufficient or excess calories on average. This leads to the distinctive prediction that hunger is an important mediator of the relationships between socioeconomic variables and the behavioral/psychological outcomes. This approach has a number of far-reaching implications, not least that some behavioral and psychological differences between social groups, though persistent under current economic arrangements, are potentially highly reversible with changes to the distribution of financial resources and food. PMID- 28344570 TI - Tanycytes As Regulators of Seasonal Cycles in Neuroendocrine Function. AB - Annual cycles of physiology and behavior are highly prevalent in organisms inhabiting temperate and polar regions. Examples in mammals include changes in appetite and body fat composition, hibernation and torpor, growth of antlers, pelage and horns, and seasonal reproduction. The timing of these seasonal cycles reflects an interaction of changing environmental signals, such as daylength, and intrinsic rhythmic processes: circannual clocks. As neuroendocrine signals underlie these rhythmic processes, the focus of most mechanistic studies has been on neuronal systems in the hypothalamus. Recent studies also implicate the pituitary stalk (pars tuberalis) and hypothalamic tanycytes as key pathways in seasonal timing. The pars tuberalis expresses a high density of melatonin receptors, so is highly responsive to changes in the nocturnal secretion of melatonin from the pineal gland as photoperiod changes across the year. The pars tuberalis in turn regulates tanycyte function in the adjacent hypothalamus via paracrine signals. Tanycytes are radial glial cells that persist into adulthood and function as a stem cell niche. Their cell soma are embedded in the ependymal lining of the third ventricle, and they also send elaborate projections through the arcuate nucleus, many of which terminate on capillaries in the median eminence. This anatomy underlies their function as sensors of nutrients in the circulation, and as regulators of transport of hormones and metabolites into the hypothalamus. In situ hybridization studies reveal robust seasonal changes in gene expression in tanycytes, for example, those controlling transport and metabolism of thyroid hormone and retinoic acid. These hormonal signals play a key role in the initial development of the brain, and experimental manipulation of thyroid hormone availability in the adult hypothalamus can accelerate or block seasonal cyclicity in sheep and Siberian hamsters. We hypothesize that seasonal rhythms depends upon reuse of developmental mechanisms in the adult hypothalamus and that tanycytes are key orchestrators of these processes. PMID- 28344571 TI - Translation Initiation Factor eIF4E and eIFiso4E Are Both Required for Peanut stripe virus Infection in Peanut (Arachis hypogaea L.). AB - Peanut stripe virus (PStV) belongs to the genus Potyvirus and is the most important viral pathogen of cultivated peanut (Arachis hypogaea L.). The eukaryotic translation initiation factor, eIF4E, and its isoform, eIF(iso)4E, play key roles during virus infection in plants, particularly Potyvirus. In the present study, we cloned the eIF4E and eIF(iso)4E homologs in peanut and named these as PeaeIF4E and PeaeIF(iso)4E, respectively. Quantitative real-time PCR (qRT-PCR) analysis showed that these two genes were expressed during all growth periods and in all peanut organs, but were especially abundant in young leaves and roots. These also had similar expression levels. Yeast two-hybrid analysis showed that PStV multifunctional helper component proteinase (HC-Pro) and viral protein genome-linked (VPg) both interacted with PeaeIF4E and PeaeIF(iso)4E. Bimolecular fluorescence complementation assay showed that there was an interaction between HC-Pro and PeaeIF4E/PeaeIF(iso)4E in the cytoplasm and between VPg and PeaeIF4E/PeaeIF(iso)4E in the nucleus. Silencing either PeaeIF4E or PeaeIF(iso)4E using a virus-induced gene silencing system did not significantly affect PStV accumulation. However, silencing both PeaeIF4E and PeaeIF(iso)4E genes significantly weakened PStV accumulation. The findings of the present study suggest that PeaeIF4E and PeaeIF(iso)4E play important roles in the PStV infection cycle and may potentially contribute to PStV resistance. PMID- 28344572 TI - Gut Colonization by Methanogenic Archaea Is Associated with Organic Dairy Consumption in Children. AB - The gut microbiota represents a complex and diverse ecosystem with a profound impact on human health, promoting immune maturation, and host metabolism as well as colonization resistance. Important members that have often been disregarded are the methanogenic archaea. Methanogenic archaea reduce hydrogen levels via the production of methane, thereby stimulating food fermentation by saccharolytic bacteria. On the other hand, colonization by archaea has been suggested to promote a number of gastrointestinal and metabolic diseases such as colorectal cancer, inflammatory bowel disease, and obesity. Archaea have been shown to be absent during infancy while omnipresent in school-aged children, suggesting that colonization may result from environmental exposure during childhood. The factors that determine the acquisition of methanogenic archaea, however, have remained undefined. Therefore, we aimed to explore determinants associated with the acquisition of the two main gastrointestinal archaeal species, Methanobrevibacter smithii and Methanosphaera stadtmanae, in children. Within the context of the KOALA Birth Cohort Study, fecal samples from 472 children aged 6-10 years were analyzed for the abundance of M. smithii and M. stadtmanae using qPCR. Environmental factors such as diet, lifestyle, hygiene, child rearing, and medication were recorded by repeated questionnaires. The relationship between these determinants and the presence and abundance of archaea was analyzed by logistic and linear regression respectively. Three hundred and sixty-nine out of the 472 children (78.2%) were colonized by M. smithii, and 39 out of the 472 children (8.3%) by M. stadtmanae. The consumption of organic yogurt (odds ratio: 4.25, CI95: 1.51; 11.95) and the consumption of organic milk (odds ratio: 5.58, CI95: 1.83; 17.01) were positively associated with the presence of M. smithii. We subsequently screened raw milk, processed milk, and yogurt samples for methanogens. We identified milk products as possible source for M. smithii, but not M. stadtmanae. In conclusion, M. smithii seems present in milk products and their consumption may determine archaeal gut colonization in children. For the first time, a large variety of determinants have been explored in association with gut colonization by methanogenic archaea. Although more information is needed to confirm and unravel the mechanisms in detail, it provides new insights on microbial colonization processes in early life. PMID- 28344573 TI - Submarine Basaltic Glass Colonization by the Heterotrophic Fe(II)-Oxidizing and Siderophore-Producing Deep-Sea Bacterium Pseudomonas stutzeri VS-10: The Potential Role of Basalt in Enhancing Growth. AB - Phylogenetically and metabolically diverse bacterial communities have been found in association with submarine basaltic glass surfaces. The driving forces behind basalt colonization are for the most part unknown. It remains ambiguous if basalt provides ecological advantages beyond representing a substrate for surface colonization, such as supplying nutrients and/or energy. Pseudomonas stutzeri VS 10, a metabolically versatile bacterium isolated from Vailulu'u Seamount, was used as a model organism to investigate the physiological responses observed when biofilms are established on basaltic glasses. In Fe-limited heterotrophic media, P. stutzeri VS-10 exhibited elevated growth in the presence of basaltic glass. Diffusion chamber experiments demonstrated that physical attachment or contact of soluble metabolites such as siderophores with the basaltic glass plays a pivotal role in this process. Electrochemical data indicated that P. stutzeri VS-10 is able to use solid substrates (electrodes) as terminal electron donors and acceptors. Siderophore production and heterotrophic Fe(II) oxidation are discussed as potential mechanisms enhancing growth of P. stutzeri VS-10 on glass surfaces. In correlation with that we discuss the possibility that metabolic versatility could represent a common and beneficial physiological trait in marine microbial communities being subject to oligotrophic and rapidly changing deep-sea conditions. PMID- 28344574 TI - Health-Associated Niche Inhabitants as Oral Probiotics: The Case of Streptococcus dentisani. AB - Oral diseases, including dental caries and periodontitis, are among the most prevalent diseases worldwide and develop as a consequence of a microbial dysbiosis. Several bacterial strains are being tested as potential oral health promoting organisms, but usually they are species isolated from niches other than the site where they must exert its probiotic action, typically from fecal samples. We hypothesize that oral inhabitants associated to health conditions will be more effective than traditional, gut-associated probiotic species in key aspects such as colonization of the oral site where disease takes place or the possession of oral health promoting functions, as well as more practical issues like safety and toxicity, and establishing proper doses for administration. As an example of these active colonizers, we describe the case of Streptococcus dentisani, a new streptococcal species isolated from dental plaque of caries-free individuals. We have detected it in 98% of dental plaque samples from healthy individuals and, as expected, it does not produce any toxic secondary metabolite and does not survive a simulated stomach digestion, preventing potential secondary effects. Besides, this species has a double probiotic action, as it inhibits the growth of major oral pathogens through the production of bacteriocins, and also buffers acidic pH (the primary cause of dental caries) through an arginolytic pathway. We propose the use of S. dentisani as a promising probiotic against tooth decay. PMID- 28344575 TI - Identification of Capsid/Coat Related Protein Folds and Their Utility for Virus Classification. AB - The viral supergroup includes the entire collection of known and unknown viruses that roam our planet and infect life forms. The supergroup is remarkably diverse both in its genetics and morphology and has historically remained difficult to study and classify. The accumulation of protein structure data in the past few years now provides an excellent opportunity to re-examine the classification and evolution of viruses. Here we scan completely sequenced viral proteomes from all genome types and identify protein folds involved in the formation of viral capsids and virion architectures. Viruses encoding similar capsid/coat related folds were pooled into lineages, after benchmarking against published literature. Remarkably, the in silico exercise reproduced all previously described members of known structure-based viral lineages, along with several proposals for new additions, suggesting it could be a useful supplement to experimental approaches and to aid qualitative assessment of viral diversity in metagenome samples. PMID- 28344576 TI - Genomic Characterization of Recent Chicken Anemia Virus Isolates in China. AB - Chicken anemia virus (CAV) causes diseases in young chickens, which include increased pathogenicity of secondary infectious agents, generalized lymphoid depletion, and immunodepression. In the present study, we have identified 22 CAV strains isolated from several commercial chicken farms in Northern China during 2014-2015. In addition, two CAVs were also isolated from stray mouse and dog feces, respectively. To our knowledge, this is the first report of identification of CAV from mouse and dog feces. Phylogenetic analysis of 121 full-length CAV genome sequences showed that all available CAV could be classified into eight lineages, supported by phylogenetic trees estimated using different methods. Furthermore, the 24 novel CAV sequences scattered across different branches, lack of clear spatio-temporal distribution characterization. Analysis of the 450 amino acids of VP1 protein identified 33 amino acid substitutions that were specific for CAVs from northern China. Putative gene recombination events were also detected in the genomes of newly isolated CAVs. In particular, a putative recombinant event was detected in the CAV-Dog genome with high statistical support. In summary, we established a robust classification system for CAV, revealed additional genomic diversity of CAV, and therefore, warranted additional efforts to explore CAV genomics and epidemiology. PMID- 28344577 TI - Linear Epitopes of Paracoccidioides brasiliensis and Other Fungal Agents of Human Systemic Mycoses As Vaccine Candidates. AB - Dimorphic fungi are agents of systemic mycoses associated with significant morbidity and frequent lethality in the Americas. Among the pathogenic species are Paracoccidioides brasiliensis and Paracoccidioides lutzii, which predominate in South America; Histoplasma capsulatum, Coccidioides posadasii, and Coccidioides immitis, and the Sporothrix spp. complex are other important pathogens. Associated with dimorphic fungi other important infections are caused by yeast such as Candida spp. and Cryptococcus spp. or mold such as Aspergillus spp., which are also fungal agents of deadly infections. Nowadays, the actual tendency of therapy is the development of a pan-fungal vaccine. This is, however, not easy because of the complexity of eukaryotic cells and the particularities of different species and isolates. Albeit there are several experimental vaccines being studied, we will focus mainly on peptide vaccines or epitopes of T-cell receptors inducing protective fungal responses. These peptides can be carried by antibody inducing beta-(1,3)-glucan oligo or polysaccharides, or be mixed with them for administration. The present review discusses the efficacy of linear peptide epitopes in the context of antifungal immunization and vaccine proposition. PMID- 28344578 TI - On How Fas Apoptosis-Independent Pathways Drive T Cell Hyperproliferation and Lymphadenopathy in lpr Mice. AB - Fas induces massive apoptosis in T cells after repeated in vitro T cell receptor (TCR) stimulation and is critical for lymphocyte homeostasis in Fas-deficient (lpr) mice. Although the in vitro Fas apoptotic mechanism has been defined, there is a large conceptual gap between this in vitro phenomenon and the pathway that leads to in vivo development of lymphadenopathy and autoimmunity. A striking abnormality in lpr mice is the excessive proliferation of CD4+ and CD8+ T cells, and more so of the double-negative TCR+CD4-CD8-B220+ T cells. The basis of lpr T cell hyperproliferation remains elusive, as it cannot be explained by Fas deficient apoptosis. T cell-directed p21 overexpression reduces hyperactivation/hyperproliferation of all lpr T cell subtypes and lymphadenopathy in lpr mice. p21 controls expansion of repeatedly stimulated T cells without affecting apoptosis. These results confirm a direct link between hyperactivation/hyperproliferation, autoreactivity, and lymphadenopathy in lpr mice and, with earlier studies, suggest that Fas apoptosis-independent pathways control lpr T cell hyperproliferation. lpr T cell hyperproliferation could be an indirect result of the defective apoptosis of repeatedly stimulated lpr T cells. Nonetheless, in this perspective, we argue for an alternative setting, in which lack of Fas would directly cause lpr T cell hyperactivation/hyperproliferation in vivo. We propose that Fas/Fas ligand (FasL) acts as an activation inhibitor of recurrently stimulated T cells, and that its disruption causes overexpansion of T cells in lpr mice. Research to define the underlying mechanism of this Fas/FasL effect could resolve the phenotype of lpr mice and lead to therapeutics for related human syndromes. PMID- 28344579 TI - Reslizumab and Eosinophilic Asthma: One Step Closer to Precision Medicine? AB - Human eosinophils represent approximately 1% of peripheral blood leukocytes. However, these cells have the propensity to leave the blood stream and migrate into inflamed tissues. Eosinophilic inflammation is present in a significant proportion of patients with severe asthma. Asthma is a chronic inflammatory disorder that affects more than 315 million people worldwide, with 10% having severe uncontrolled disease. Although the majority of patients can be efficiently treated, severe asthmatics continue to be uncontrolled and are at risk of exacerbations and even death. Interleukin-5 (IL-5) plays a fundamental role in eosinophil differentiation, maturation, activation and inhibition of apoptosis. Therefore, targeting IL-5 is an appealing approach to the treatment of patients with severe eosinophilic asthma. Reslizumab, a humanized anti-IL-5 monoclonal antibody, binds with high affinity to amino acids 89-92 of IL-5 that are critical for binding to IL-5 receptor alpha. Two phase III studies have demonstrated that reslizumab administration in adult patients with severe asthma and eosinophilia (>=400 cells/MUL) improved lung function, asthma control, and symptoms. Thus, the use of blood eosinophils as a baseline biomarker could help to select patients with severe uncontrolled asthma who are likely to achieve benefits in asthma control with reslizumab. In conclusion, targeted therapy with reslizumab represents one step closer to precision medicine in patients with severe eosinophilic asthma. PMID- 28344580 TI - A Perspective on the Development of Plant-Made Vaccines in the Fight against Ebola Virus. AB - The Ebola virus (EBOV) epidemic indicated a great need for prophylactic and therapeutic strategies. The use of plants for the production of biopharmaceuticals is a concept being adopted by the pharmaceutical industry, with an enzyme for human use currently commercialized since 2012 and some plant based vaccines close to being commercialized. Although plant-based antibodies against EBOV are under clinical evaluation, the development of plant-based vaccines against EBOV essentially remains an unexplored area. The current technologies for the production of plant-based vaccines include stable nuclear expression, transient expression mediated by viral vectors, and chloroplast expression. Specific perspectives on how these technologies can be applied for developing anti-EBOV vaccines are provided, including possibilities for the design of immunogens as well as the potential of the distinct expression modalities to produce the most relevant EBOV antigens in plants considering yields, posttranslational modifications, production time, and downstream processing. PMID- 28344583 TI - RBM25 Mediates Abiotic Responses in Plants. AB - Alternative splicing (AS) of pre-mRNAs is one of the most important post transcriptional regulations that enable a single gene to code for multiple proteins resulting in the biodiversity of proteins in eukaryotes. Recently, we have shown that an Arabidopsis thaliana RNA recognition motif-containing protein RBM25 is a novel splicing factor to modulate plant response to ABA during seed germination and post-germination through regulating HAB1 pre-mRNA AS. Here, we show that RBM25 is preferentially expressed in stomata and vascular tissues in Arabidopsis and is induced by ABA and abiotic stresses. Loss-of-function mutant is highly tolerant to drought and sensitive to salt stress. Bioinformatic analysis and expression assays reveal that Arabidopsis RBM25 is induced by multiple abiotic stresses, suggesting a crucial role of RBM25 in Arabidopsis responses to adverse environmental conditions. Furthermore, we provide a comprehensive characterization of the homologous genes of Arabidopsis RBM25 based on the latest plant genome sequences and public microarray databases. Fourteen homologous genes are identified in different plant species which show similar structure in gene and protein. Notably, the promoter analysis reveals that RBM25 homologs are likely controlled by the regulators involved in multiple plant growth and abiotic stresses, such as drought and unfavorable temperature. The comparative analysis of general and unique cis regulatory elements of the RBM25 homologs highlights the conserved and unique molecular processes that modulate plant response to abiotic stresses through RBM25-mediated alternative splicing. PMID- 28344581 TI - Type I Interferons as Regulators of Lung Inflammation. AB - Immune responses to lung infections must be tightly regulated in order to permit pathogen eradication while maintaining organ function. Exuberant or dysregulated inflammation can impair gas exchange and underlies many instances of lung disease. An important driver of inflammation in the lung is the interferon (IFN) response. Type I IFNs are antiviral cytokines that induce a large range of proteins that impair viral replication in infected cells. This cell-intrinsic action plays a crucial role in protecting the lungs from spread of respiratory viruses. However, type I IFNs have also recently been found to be central to the initiation of lung inflammatory responses, by inducing recruitment and activation of immune cells. This helps control virus burden but can cause detrimental immunopathology and contribute to disease severity. Furthermore, there is now increasing evidence that type I IFNs are not only induced after viral infections but also after infection with bacteria and fungi. The pro-inflammatory function of type I IFNs in the lung opens up the possibility of immune modulation directed against this antiviral cytokine family. In this review, the initiation and signaling of type I IFNs as well as their role in driving and maintaining lung inflammation will be discussed. PMID- 28344582 TI - Involvement of Small RNAs in Phosphorus and Sulfur Sensing, Signaling and Stress: Current Update. AB - Plants require several essential mineral nutrients for their growth and development. These nutrients are required to maintain physiological processes and structural integrity in plants. The root architecture has evolved to absorb nutrients from soil and transport them to other parts of the plant. Nutrient deficiency affects several physiological and biological processes in plants and leads to reduction in crop productivity and yield. To compensate this adversity, plants have developed adaptive mechanisms to enhance the acquisition, conservation, and mobilization of these nutrients under deficient or adverse conditions. In addition, plants have evolved an intricate nexus of complex signaling cascades, which help in nutrient sensing and uptake as well as to maintain nutrient homeostasis. In recent years, small non-coding RNAs such as micro RNAs (miRNAs) and endogenous small interfering RNAs have emerged as important component in regulating plant stress responses. A set of these small RNAs (sRNAs) have been implicated in regulating various processes involved in nutrient uptake, assimilation, and deficiency. In response to phosphorus (P) and sulphur (S) deficiencies, role of sRNAs, miR395 and miR399, have been identified to be instrumental; however, many more miRNAs might be involved in regulating the plant response to these nutrient stresses. These sRNAs modulate expression of target genes in response to P and S deficiencies and regulate their uptake and utilization for proper growth and development of the plant. This review summarizes the current understanding of uptake, sensing, and signaling of P and S and highlights the regulatory role of sRNAs in adaptive responses to these nutrient stresses in plants. PMID- 28344584 TI - Lanthanum Affects Bell Pepper Seedling Quality Depending on the Genotype and Time of Exposure by Differentially Modifying Plant Height, Stem Diameter and Concentrations of Chlorophylls, Sugars, Amino Acids, and Proteins. AB - Lanthanum (La) is considered a beneficial element, capable of inducing hormesis. Hormesis is a dose-response relationship phenomenon characterized by low-dose stimulation and high-dose inhibition. Herein we tested the effect of 0 and 10 MUM La on growth and biomolecule concentrations of seedlings of four sweet bell pepper (Capsicum annuum L.) varieties, namely Sven, Sympathy, Yolo Wonder, and Zidenka. Seedling evaluations were performed 15 and 30 days after treatment applications (dat) under hydroponic greenhouse conditions. Seedling height was significantly increased by La, growing 20% taller in Yolo Wonder plants, in comparison to the control. Similarly, La significantly enhanced shoot diameter, with increases of 9 and 9.8% in measurements performed 15 and 30 dat, respectively, as compared to the control. Likewise, La-treated seedlings had a higher number of flower buds than the control. An increase in the number of leaves because of La application was observed in Yolo Wonder seedlings, both 15 and 30 dat, while leaf area was augmented in this variety only 30 dat. Nevertheless, La did not affect dry biomass accumulation. La effects on biomolecule concentration were differential over time. In all varieties, La stimulated the biosynthesis of chlorophyll a, b and total 15 dat, though 30 dat only the varieties Sympathy and Yolo Wonder showed enhanced concentrations of these molecules because of La. Total soluble sugars increased in La-treated seedlings 30 dat. Interestingly, while most varieties exposed to La showed a reduction in amino acid concentration 15 dat, the opposite trend was observed 30 dat. Importantly, in all varieties evaluated, La stimulated soluble protein concentration 30 dat. It is important to note that while chlorophyll concentrations increased in all varieties exposed to La, both 15 and 30 dat, those of soluble sugars and proteins consistently increased only 30 dat, but not 15 dat. Our results confirm that La may improve seedling quality by enhancing some growth parameters and biomolecule concentrations, depending on the genotype, and time of exposure. PMID- 28344586 TI - Comparative Transcriptome Reveals Benzenoid Biosynthesis Regulation as Inducer of Floral Scent in the Woody Plant Prunus mume. AB - Mei (Prunus mume) is a peculiar woody ornamental plant famous for its inviting fragrance in winter. However, in this valuable plant, the mechanism behind floral volatile development remains poorly defined. Therefore, to explore the floral scent formation, a comparative transcriptome was conducted in order to identify the global transcripts specifying flower buds and blooming flowers of P. mume. Differentially expressed genes were identified between the two different stages showing great discrepancy in floral volatile production. Moreover, according to the expression specificity among the organs (stem, root, fruit, leaf), we summarized one gene cluster regulating the benzenoid floral scent. Significant gene changes were observed in accordance with the formation of benzenoid, thus pointing the pivotal roles of genes as well as cytochrome-P450s and short chain dehydrogenases in the benzenoid biosynthetic process. Further, transcription factors like EMISSION OF BENZENOID I and ODORANT I performed the same expression pattern suggesting key roles in the management of the downstream genes. Taken together, these data provide potential novel anchors for the benzenoid pathway, and the insight for the floral scent induction and regulation mechanism in woody plants. PMID- 28344585 TI - Ectopic Expression of OsSta2 Enhances Salt Stress Tolerance in Rice. AB - Salt stress can severely reduce crop yields. To understand how rice (Oryza sativa) plants respond to this environmental challenge, we investigated the genes involved in conferring salt tolerance by screening T-DNA tagging lines and identified OsSta2-D (Oryza sativa Salt tolerance activation 2-Dominant). In that line, expression of OsSta2 was enhanced by approximately eightfold when compared with the non-transformed wild type (WT). This gene was highly expressed in the callus, roots, and panicles. To confirm its role in stress tolerance, we generated transgenic rice that over-expresses OsSta2 under a maize ubiquitin promoter. The OsSta2-Ox plants were salt-tolerant at the vegetative stage, based on our calculations of chlorophyll fluorescence (Fv/Fm), fresh and dry weights, chlorophyll concentrations, and survival rates. Under normal paddy field conditions, the Ox plants were somewhat shorter than the WT control but had improved agronomic traits such as higher total grain yield. They were also more tolerant to osmotic stress and hypersensitive to abscisic acid. Based on all of these results, we suggest that OsSta2 has important roles in determining yields as well as in conferring tolerance to salt stresses. PMID- 28344588 TI - AtLSG1-2 Regulates Leaf Growth by Affecting Cell Proliferation and the Onset of Endoreduplication and Synergistically Interacts with AtNMD3 during Cell Proliferation Process. AB - AtLSG1-2 is a circularly permuted GTPase required for ribosome biogenesis and recently shown to be involved in early leaf development, although it was unclear how AtLSG1-2 affects leaf growth. Here, we found that atlsg1-2 mutants had reduced leaf size as a result of decreased cell size and cell number. Leaf kinematic analysis and CYCB1;1::GUS expression pattern in atlsg1-2 mutant indicated that loss of function of AtLSG1-2 delays the transition from cell division to cell expansion. Decreases in ploidy levels and trichome branch number suggest that AtLSG1-2 deficiency suppresses endoreduplication. Real-time PCR analysis showed that genes specifically expressed in the proliferation stage were highly expressed and those involved in endoreduplication were differentially regulated. LSG1 is known to mediate the recruitment of nucleocytoplasmic shuttling protein NMD3 back to the nucleus in yeast, yet their relationship was unclear in plants. Our genetic analysis revealed that the atlsg1 atnmd3 double mutant displayed enhanced phenotypes as compared with the respective single mutant and that AtLSG1-2 and AtNMD3 synergistically affect the cell proliferation process. PMID- 28344587 TI - The Chloroplast Genome of Passiflora edulis (Passifloraceae) Assembled from Long Sequence Reads: Structural Organization and Phylogenomic Studies in Malpighiales. AB - The family Passifloraceae consists of some 700 species classified in around 16 genera. Almost all its members belong to the genus Passiflora. In Brazil, the yellow passion fruit (Passiflora edulis) is of considerable economic importance, both for juice production and consumption as fresh fruit. The availability of chloroplast genomes (cp genomes) and their sequence comparisons has led to a better understanding of the evolutionary relationships within plant taxa. In this study, we obtained the complete nucleotide sequence of the P. edulis chloroplast genome, the first entirely sequenced in the Passifloraceae family. We determined its structure and organization, and also performed phylogenomic studies on the order Malpighiales and the Fabids clade. The P. edulis chloroplast genome is characterized by the presence of two copies of an inverted repeat sequence (IRA and IRB) of 26,154 bp, each separating a small single copy region of 13,378 bp and a large single copy (LSC) region of 85,720 bp. The annotation resulted in the identification of 105 unique genes, including 30 tRNAs, 4 rRNAs, and 71 protein coding genes. Also, 36 repetitive elements and 85 SSRs (microsatellites) were identified. The structure of the complete cp genome of P. edulis differs from that of other species because of rearrangement events detected by means of a comparison based on 22 members of the Malpighiales. The rearrangements were three inversions of 46,151, 3,765 and 1,631 bp, located in the LSC region. Phylogenomic analysis resulted in strongly supported trees, but this could also be a consequence of the limited taxonomic sampling used. Our results have provided a better understanding of the evolutionary relationships in the Malpighiales and the Fabids, confirming the potential of complete chloroplast genome sequences in inferring evolutionary relationships and the utility of long sequence reads for generating very accurate biological information. PMID- 28344589 TI - Characterization of Genes Encoding Key Enzymes Involved in Anthocyanin Metabolism of Kiwifruit during Storage Period. AB - 'Hongyang' is a red fleshed kiwifruit with high anthocyanin content. In this study, we mainly investigated effects of different temperatures (25 and 0 degrees C) on anthocyanin biosynthesis in harvested kiwifruit, and characterized the genes encoding key enzymes involved in anthocyanin metabolism, as well as evaluated the mode of the action, by which low temperature regulates anthocyanin accumulation in 'Hongyang' kiwifruit during storage period. The results showed that low temperature could effectively enhance the anthocyanin accumulation of kiwifruit in the end of storage period (90 days), which related to the increase in mRNA levels of ANS1, ANS2, DRF1, DRF2, and UGFT2. Moreover, the transcript abundance of MYBA1-1 and MYB5-1, the genes encoding an important component of MYB bHLH-WD40 (MBW) complex, was up-regulated, possibly contributing to the induction of specific anthocyanin biosynthesis genes under the low temperature. To further investigate the roles of AcMYB5-1/5-2/A1-1 in regulation of anthocyanin biosynthesis, genes encoding the three transcription factors were transiently transformed in Nicotiana benthamiana leaves. Overexpression of AcMYB5-1/5-2/A1-1 activated the gene expression of NtANS and NtDFR in tobacco. Our results suggested that low temperature storage could stimulate the anthocyanin accumulation in harvested kiwifruit via regulating several structural and regulatory genes involved in anthocyanin biosynthesis. PMID- 28344590 TI - Proteome Profiling of Paulownia Seedlings Infected with Phytoplasma. AB - Phytoplasma is an insect-transmitted pathogen that causes witches' broom disease in many plants. Paulownia witches' broom is one of the most destructive diseases threatening Paulownia production. The molecular mechanisms associated with this disease have been investigated by transcriptome sequencing, but changes in protein abundance have not been investigated with isobaric tags for relative and absolute quantitation. Previous results have shown that methyl methane sulfonate (MMS) can help Paulownia seedlings recover from the symptoms of witches' broom and reinstate a healthy morphology. In this study, a transcriptomic-assisted proteomic technique was used to analyze the protein changes in phytoplasma infected Paulownia tomentosa seedlings, phytoplasma-infected seedlings treated with 20 and 60 mg.L-1 MMS, and healthy seedlings. A total of 2,051 proteins were obtained, 879 of which were found to be differentially abundant in pairwise comparisons between the sample groups. Among the differentially abundant proteins, 43 were related to Paulownia witches' broom disease and many of them were annotated to be involved in photosynthesis, expression of dwarf symptom, energy production, and cell signal pathways. PMID- 28344591 TI - Studying the Genetics of Resistance to CyHV-3 Disease Using Introgression from Feral to Cultured Common Carp Strains. AB - Sustainability and further development of aquaculture production are constantly challenged by outbreaks of fish diseases, which are difficult to prevent or control. Developing fish strains that are genetically resistant to a disease is a cost-effective and a sustainable solution to address this challenge. To do so, heritable genetic variation in disease resistance should be identified and combined together with other desirable production traits. Aquaculture of common carp has suffered substantial losses from the infectious disease caused by the cyprinid herpes virus type 3 (CyHV-3) virus and the global spread of outbreaks indicates that many cultured strains are susceptible. In this research, CyHV-3 resistance from the feral strain "Amur Sassan" was successfully introgressed into two susceptible cultured strains up to the first backcross (BC1) generation. Variation in resistance of families from F1 and BC1 generations was significantly greater compared to that among families of any of the susceptible parental lines, a good starting point for a family selection program. Considerable additive genetic variation was found for CyHV-3 resistance. This phenotype was transferable between generations with contributions to resistance from both the resistant feral and the susceptible cultured strains. Reduced scale coverage (mirror phenotype) is desirable and common in cultured strains, but so far, cultured mirror carp strains were found to be susceptible. Here, using BC1 families ranging from susceptible to resistant, no differences in resistance levels between fully scaled and mirror full-sib groups were found, indicating that CyHV-3 resistance was successfully combined with the desirable mirror phenotype. In addition, the CyHV-3 viral load in tissues throughout the infection of susceptible and resistant fish was followed. Although resistant fish get infected, viral loads in tissues of these fish are significantly lesser than in those of susceptible fish, allowing them to survive the disease. Taken together, in this study we have laid the foundation for breeding CyHV-3-resistant strains and started to address the mechanisms underlying the phenotypic differences in resistance to this disease. PMID- 28344592 TI - Dysbindin Deficiency Modifies the Expression of GABA Neuron and Ion Permeation Transcripts in the Developing Hippocampus. AB - The neurodevelopmental factor dysbindin is required for synapse function and GABA interneuron development. Dysbindin protein levels are reduced in the hippocampus of schizophrenia patients. Mouse dysbindin genetic defects and other mouse models of neurodevelopmental disorders share defective GABAergic neurotransmission and, in several instances, a loss of parvalbumin-positive interneuron phenotypes. This suggests that mechanisms downstream of dysbindin deficiency, such as those affecting GABA interneurons, could inform pathways contributing to or ameliorating diverse neurodevelopmental disorders. Here we define the transcriptome of developing wild type and dysbindin null Bloc1s8sdy/sdy mouse hippocampus in order to identify mechanisms downstream dysbindin defects. The dysbindin mutant transcriptome revealed previously reported GABA parvalbumin interneuron defects. However, the Bloc1s8sdy/sdy transcriptome additionally uncovered changes in the expression of molecules controlling cellular excitability such as the cation-chloride cotransporters NKCC1, KCC2, and NCKX2 as well as the potassium channel subunits Kcne2 and Kcnj13. Our results suggest that dysbindin deficiency phenotypes, such as GABAergic defects, are modulated by the expression of molecules controlling the magnitude and cadence of neuronal excitability. PMID- 28344593 TI - Agaricus brasiliensis polysaccharides stimulate human monocytes to capture Candida albicans, express toll-like receptors 2 and 4, and produce pro inflammatory cytokines. AB - BACKGROUND: Agaricus brasiliensis is a medicinal mushroom with immunomodulatory and antitumor activities attributed to the beta-glucans presented in the polysaccharide fraction of its fruiting body. Since beta-glucans enhance cellular immunoresponsiveness, in this study we aimed to evaluate the effect of an acid treated polysaccharide-rich fraction (ATF) of A. brasiliensis on the ability of human monocytes to adhere/phagocyte C. albicans yeast cells, their expression of pattern recognition receptors and their ability to produce cytokines. METHODS: Adhesion/phagocytosis of FITC-labeled C. albicans was evaluated by flow cytometry. Cells were incubated with specific fluorochrome-labeled antibodies for TLR2 and 4, betaGR and MR and also evaluated by flow cytometry. Monocytes were cultured with ATF, and culture supernatants were collected for analysis of in vitro cytokine production by ELISA (TNF-alpha, IL-1beta, IL-12 and IL-10). RESULTS: ATF significantly increased the adherence/phagocytosis of C. albicans by monocytes and this was associated with enhanced expression of TLR2 and TLR4, while no effect was observed on betaGR or MR. Moreover, expression of TLR4 and TLR2 was associated with higher levels of in vitro production of TNF-alpha and IL 1, respectively. Production of IL-10 was also increased by ATF treatment, but we found no association between its production and the expression of Toll-like receptors. CONCLUSION: Our results provided us with evidence that A. brasiliensis polysaccharides affect human monocytes probably through the modulation of Toll like receptors. PMID- 28344594 TI - Articular inflammation induced by an enzymatically-inactive Lys49 phospholipase A2: activation of endogenous phospholipases contributes to the pronociceptive effect. AB - BACKGROUND: Arthritis is a set of inflammatory conditions that induce aching, stiffness, swelling, pain and may cause functional disability with severe consequences to the patient's lives. These are multi-mediated pathologies that cannot be effectively protected and/or treated. Therefore, the aim of this study was to establish a new model of acute arthritis, using a Lys49-PLA2 (Bothrops asper myotoxin II; MT-II) to induce articular inflammation. METHODS: The articular inflammation was induced by MT-II (10 MUg/joint) injection into the left tibio-tarsal or femoral-tibial-patellar joints. Cellular influx was evaluated counting total and differential cells that migrated to the joint. The plasma extravasation was determined using Evans blue dye. The edematogenic response was evaluated measuring the joint thickness using a caliper. The articular hypernociception was determined by a dorsal flexion of the tibio-tarsal joint using an electronic pressure-meter test. The mediators involved in the articular hypernociception were evaluated using receptor antagonists and enzymatic inhibitors. RESULTS: Plasma extravasation in the knee joints was observed 5 and 15 min after MT-II (10 MUg/joint) injection. MT-II also induced a polymorphonuclear cell influx into the femoral-tibial-patellar joints observed 8 h after its injection, a period that coincided with the peak of the hyperalgesic effect. Hyperalgesia was inhibited by the pretreatment of the animals with cyclooxygenase inhibitor indomethacin, with type-2 cyclooxygenase inhibitor celecoxib, with AACOCF3 and PACOCF3, inhibitors of cytosolic and Ca2+-independent PLA2s, respectively, with bradykinin B2 receptor antagonist HOE 140, with antibodies against TNFalpha, IL-1beta, IL-6 and CINC-1 and with selective ET-A (BQ-123) and ET-B (BQ-788) endothelin receptors antagonists. The MT-II-induced hyperalgesia was not altered by the lipoxygenase inhibitor zileuton, by the bradykinin B1 receptor antagonist Lys-(Des-Arg9,Leu8)-bradykinin, by the histamine and serotonin antagonists promethazine and methysergide, respectively, by the nitric oxide inhibitor LNMMA and by the inhibitor of matrix 1-, 2-, 3-, 8- and 9- metalloproteinases GM6001 (Ilomastat). CONCLUSION: These results demonstrated the multi-mediated characteristic of the articular inflammation induced by MT-II, which demonstrates its relevance as a model for arthritis mechanisms and treatment evaluation. PMID- 28344596 TI - Deinagkistrodon acutus envenomation: a report of three cases. AB - BACKGROUND: Deinagkistrodon acutus envenomation is associated with severe hematological and wound complications but is rarely described. CASE PRESENTATION: Herein, we report three cases of victims bitten by D. acutus and indicate that rapid-onset severe coagulopathy and thrombocytopenia are distinct features of D. acutus snakebite, which are not observed in other crotaline snakebites (i.e., Trimeresurus stejnegeri and Protobothrops mucrosquamatus) in Taiwan. The toxic effects could occur as early as 2 to 3 h following D. acutus envenomation and persist if the administration of specific antivenom is delayed or even not commenced. Based on our findings, 2 to 4 vials of specific antivenom as the first dose should be administered to victims and repeated at 6 to 8 h intervals if coagulopathy or thrombocytopenia persists. Fresh frozen plasma or platelet replacement is probably safe as an adjunct therapy for D. acutus bite in the presence of venom-induced consumptive coagulopathy. CONCLUSION: Severe coagulopathy and thrombocytopenia could occur as early as 2 to 3 h after D. acutus envenomation. The current recommendation for antivenom is 2 to 4 vials as the first dose and repeated every 6- to 8 h if coagulopathy or thrombocytopenia persists. These cases studied may be helpful to first-line medical personnel in the early diagnosis and management of D. acutus envenomation among other crotaline snakebites in Taiwan. PMID- 28344595 TI - Alpha-type phospholipase A2 inhibitors from snake blood. AB - It is of popular and scientific knowledge that toxins from snake venom (among them the PLA2 and myotoxins) are neutralized by various compounds, such as antibodies and proteins purified from animal blood. Venomous and nonvenomous snakes have PLA2 inhibitory proteins, called PLIs, in their blood serum. One hypothesis that could explain the presence of these PLIs in the serum of venomous snakes would be self-protection against the enzymes of their own venom, which eventually could reach the circulatory system. However, the presence of PLIs in non-venomous snakes suggests that their physiological role might not be restricted to protection against PLA2 toxins, but could be extended to other functions, as in the innate immune system and local regulation of PLA2s. The present study aimed to review the currently available literature on PLA2 and myotoxin alpha inhibitors present in snake plasma, thus helping to improve the research on these molecules. Furthermore, this review includes current information regarding the mechanism of action of these inhibitors in an attempt to better understand their application, and proposes the use of these molecules as new models in snakebite therapy. These molecules may help in the neutralization of different types of phospholipases A2 and myotoxins, complementing the conventional serum therapy. PMID- 28344597 TI - High biologically effective dose radiation therapy using brachytherapy in combination with external beam radiotherapy for high-risk prostate cancer. AB - PURPOSE: To evaluate the outcomes of high-risk prostate cancer patients treated with biologically effective dose (BED) >= 220 Gy of high-dose radiotherapy, using low-dose-rate (LDR) brachytherapy in combination with external beam radiotherapy (EBRT) and short-term androgen deprivation therapy (ADT). MATERIAL AND METHODS: From 2005 to 2013, a total of 143 patients with high-risk prostate cancer were treated by radiotherapy of BED >= 220 Gy with a combination of LDR brachytherapy, EBRT, and androgen deprivation therapy (ADT). The high-risk patients in the present study included both high-risk and very high-risk prostate cancer. The number of high-risk features were: 60 patients with 1 high-risk factor (42%), 61 patients with 2 high-risk factors (43%), and 22 patients with 3 high-risk factors (15%) including five N1 disease. External beam radiotherapy fields included prostate and seminal vesicles only or whole pelvis depending on the extension of the disease. Biochemical failure was defined by the Phoenix definition. RESULTS: Six patients developed biochemical failure, thus providing a 5-year actual biochemical failure-free survival (BFFS) rate of 95.2%. Biochemical failure was observed exclusively in cases with distant metastasis in the present study. All six patients with biochemical relapse had clinical failure due to bone metastasis, thus yielding a 5-year freedom from clinical failure (FFCF) rate of 93.0%. None of the cases with N1 disease experienced biochemical failure. We observed four deaths, including one death from prostate cancer, therefore yielding a cause-specific survival (CSS) rate of 97.2%, and an overall survival (OS) rate of 95.5%. CONCLUSIONS: High-dose (BED >= 220 Gy) radiotherapy by LDR in combination with EBRT has shown an excellent outcome on BFFS in high-risk and very high-risk cancer, although causal relationship between BED and BFFS remain to be explained further. PMID- 28344598 TI - Radiation dose to the left anterior descending coronary artery during interstitial pulsed-dose-rate brachytherapy used as a boost in breast cancer patients undergoing organ-sparing treatment. AB - PURPOSE: To assess dose received by the left anterior descending (LAD) coronary artery during interstitial pulsed-dose-rate brachytherapy (PDR-BT) boost for left sided breast cancer patients undergoing organ-sparing treatment. MATERIAL AND METHODS: Thirty consecutive pT1-3N0-1M0 breast cancer patients boosted between 2014 and 2015 with 10 Gy/10 pulses/hour PDR-BT following a computed tomography (CT) simulation with the multi-catheter implant were included. The most common localization of primary tumor were upper quadrants. Patients were implanted with rigid tubes following breast conserving surgery and whole breast external beam irradiation (40 Gy/15 or 50 Gy/25 fractions). Computed tomography scans were retrospectively reviewed and LADs were contoured without and with margin of 5 mm (LAD5mm). Standard treatment plan encompassed tumor bed determined by the surgical clips with margin of 2 cm. Dosimetric parameters were extracted from the dose-volume histograms. RESULTS: The mean D90 and V100 were 10.3 Gy (range: 6.6 13.3), and 42.0 cc (range: 15.3-109.3), respectively. The median dose non uniformity ratio (DNR) was 0.50 (range: 0.27-0.82). The mean doses to LAD and LAD5mm were 1.0 Gy and 0.96 Gy, and maximal doses were 1.57 Gy and 1.99 Gy, respectively. Dose to the 0.1 cc of the LAD and LAD5mm were 1.42 Gy and 1.85 Gy (range: 0.01-4.98 Gy and 0.1-6.89 Gy), respectively. CONCLUSIONS: Interstitial multi-catheter PDR-BT used as a boost for left-sided breast cancer is generally associated with low dose to the LAD. However, higher dose in individual cases may require alternative approaches. PMID- 28344599 TI - Does ultrasound measurement improve the accuracy of electronic brachytherapy in the treatment of superficial non-melanomatous skin cancer? AB - PURPOSE: Electronic brachytherapy (eBT) is a form of contact radiation therapy used for thin superficial non-melanomatous skin cancers (NMSCs). An accurate measurement of diameter and depth is important for eBT treatment planning. Therefore, we compared clinical measurements by an experienced physician to measurements obtained using ultrasound (US), an objective imaging modality, in order to determine if clinical measurements were accurate enough for adequate NMSC treatment. MATERIAL AND METHODS: Eighteen patients with 20 biopsy-proven NMSCs first had a clinical examination and then an US evaluation prior to starting eBT. One physician provided a clinical measurement for diameter and depth based on physical examination during radiation oncology consultation. The patients then had an US evaluation with a 14 or 18 MHz US unit, to determine both the diameter and depth measurements; eBT dose prescription was done using the US derived measurements. The clinical measurements and US measurements were compared using a t-test. RESULTS: Seventeen lesions were basal cell carcinoma and 3 lesions were squamous cell carcinoma. The most common location was the nose (10 lesions). The difference between the clinical and the US derived measurements for the second largest diameter was found to be statistically significant (p = 0.03), while the difference for the largest diameter of the lesions was not (p = 0.24). More importantly, the depth measurements obtained with US were also found to be significantly different from the clinical estimates (p = 0.02). All patients have had a complete response to therapy with a median follow-up of 24 months. CONCLUSIONS: Statistically different measurements were obtained in 2 of 3 parameters used in choosing applicator size and prescription depth using an US assessment. The data presented suggests that US is a more objective modality than clinical judgment for determining superficial NMSC diameter and prescription depth for personalized eBT planning. PMID- 28344600 TI - Staged reconstruction brachytherapy has lower overall cost in recurrent soft tissue sarcoma. AB - PURPOSE: Adjuvant brachytherapy (AB) with immediate (IR) and staged reconstruction (SR) are distinct treatment modalities available for patients with recurrent soft tissue sarcoma (STS). Although SR may offer local control and toxicity benefit, it requires additional upfront procedures, and there is no evidence that it improves overall survival. With the importance of value-based care, our goal is to identify which technique is more cost effective. MATERIAL AND METHODS: A retrospective review of 22 patients with recurrent extremity STS treated with resection followed by AB alone. Hospital charges were used to compare the cost between SR and IR at the time of initial treatment, at 6-month intervals following surgery, and cumulative cost comparisons at 18 months. RESULTS: Median follow-up was 31 months. Staged reconstruction (n = 12) was associated with an 18-month local control benefit (85% vs. 42%, p = 0.034), compared to IR (n = 10). Staged reconstruction had a longer hospital stay during initial treatment (10 vs. 3 days, p = 0.002), but at 18 months, the total hospital stay was no longer different (11 vs. 11 days). Initially, there was no difference in the cost of SR and IR. With longer follow-up, cost eventually favored SR, which was attributed primarily to the costs associated with local failure (LF). On multivariate analysis, cost of initial treatment was associated with length of hospital stay (~$4.5K per hospital day, p < 0.001), and at 18 months, the cumulative cost was ~175K lower with SR (p = 0.005) and $58K higher with LF (p = 0.02). CONCLUSIONS: In recurrent STS, SR has a longer initial hospital stay when compared to IR. At 18 months, SR had lower rates of LF, translating to lower total costs for the patient. SR is the more cost-effective brachytherapy approach in the treatment of STS, and should be considered as healthcare transitions into value-based medicine. PMID- 28344601 TI - High-dose-rate intraluminal brachytherapy prior to external radiochemotherapy in locally advanced esophageal cancer: preliminary results. AB - PURPOSE: Dysphagia is a common initial presentation in locally advanced esophageal cancer and negatively impacts patient quality of life and treatment compliance. To induce fast relief of dysphagia in patients with potentially operable esophageal cancer high-dose-rate (HDR) brachytherapy was applied prior to definitive radiochemotherapy. MATERIAL AND METHODS: In this single arm phase II clinical trial between 2013 to 2014 twenty patients with locally advanced esophageal cancer (17 squamous cell and 3 adenocarcinoma) were treated with upfront 10 Gy HDR brachytherapy, followed by 50.4 Gy external beam radiotherapy (EBRT) and concurrent chemotherapy with cisplatin/5-fluorouracil. RESULTS: Tumor response, as measured by endoscopy and/or computed tomography scan, revealed complete remission in 16 and partial response in 4 patients (overall response rate 100%). Improvement of dysphagia was induced by brachytherapy within a few days and maintained up to the end of treatment in 80% of patients. No differences in either response rate or dysphagia resolution were found between squamous cell and adenocarcinoma histology. The grade 2 and 3 acute pancytopenia or bicytopenia reported in 4 patients, while sub-acute adverse effects with painful ulceration was seen in five patients, occurring after a median of 2 months. A perforation developed in one patient during the procedure of brachytherapy that resolved successfully with immediate surgery. CONCLUSIONS: Brachytherapy before EBRT was a safe and effective procedure to induce rapid and durable relief from dysphagia, especially when combined with EBRT. PMID- 28344602 TI - Safety and outcome of external beam radiation and neutron brachytherapy in elderly patients with esophageal squamous cell cancer. AB - PURPOSE: The aim of this study was to retrospectively observe and analyze the long-term treatment outcomes of 191 elderly patients with esophageal squamous cell cancer (ESCC) who were treated with californium-252 (252Cf) neutron brachytherapy (NBT) in combination with external beam radiotherapy (EBRT). MATERIAL AND METHODS: From January 2002 to November 2012, 191 patients with ESCC underwent NBT in combination with EBRT. The total radiation dose to the reference point via NBT was 8-25 Gy-eq in two to five fractions with one fraction per week. The total dose via EBRT was 50-60 Gy, which was delivered over a period of 5 to 6 weeks with normal fractionation. RESULTS: The median survival time for the 191 patients was 23.6 months, and the 5-year rates for overall survival (OS) and local-regional control (LRC) were 28.7% and 54.2%, respectively. The patients' age was a factor that was significantly associated with OS (p = 0.010), according to univariate analysis. The 5-year OS (LRC) was 37.3% (58.6%) for patients aged 70-74 years and 14.5% (47.9%) for patients aged > 74 years (p = 0.010 and p = 0.038). In multivariate analysis, age and clinical N stage were associated with OS and LRC (p = 0.011 [0.041] and p = 0.005 [0.005]). From the time of treatment completion to the development of local-regional recurrence or death, 5 (2.6%) patients experienced fistula and 15 (7.9%) experienced massive bleeding. The incidence of severe late complications was related to older age (p = 0.027), higher NBT dose/fraction (20-25 Gy/5 fractions), and higher total dose (> 66 Gy). CONCLUSIONS: The clinical data indicated that NBT in combination with EBRT produced favorable local control and long-term survival rates for elderly patients with ESCC, and that the side effects were tolerable. Patient's age, clinical stage N status, and radiation dose could be used to select the appropriate treatment for elderly patients. PMID- 28344603 TI - Isobio software: biological dose distribution and biological dose volume histogram from physical dose conversion using linear-quadratic-linear model. AB - PURPOSE: To develop an in-house software program that is able to calculate and generate the biological dose distribution and biological dose volume histogram by physical dose conversion using the linear-quadratic-linear (LQL) model. MATERIAL AND METHODS: The Isobio software was developed using MATLAB version 2014b to calculate and generate the biological dose distribution and biological dose volume histograms. The physical dose from each voxel in treatment planning was extracted through Computational Environment for Radiotherapy Research (CERR), and the accuracy was verified by the differentiation between the dose volume histogram from CERR and the treatment planning system. An equivalent dose in 2 Gy fraction (EQD2) was calculated using biological effective dose (BED) based on the LQL model. The software calculation and the manual calculation were compared for EQD2 verification with pair t-test statistical analysis using IBM SPSS Statistics version 22 (64-bit). RESULTS: Two and three-dimensional biological dose distribution and biological dose volume histogram were displayed correctly by the Isobio software. Different physical doses were found between CERR and treatment planning system (TPS) in Oncentra, with 3.33% in high-risk clinical target volume (HR-CTV) determined by D90%, 0.56% in the bladder, 1.74% in the rectum when determined by D2cc, and less than 1% in Pinnacle. The difference in the EQD2 between the software calculation and the manual calculation was not significantly different with 0.00% at p-values 0.820, 0.095, and 0.593 for external beam radiation therapy (EBRT) and 0.240, 0.320, and 0.849 for brachytherapy (BT) in HR CTV, bladder, and rectum, respectively. CONCLUSIONS: The Isobio software is a feasible tool to generate the biological dose distribution and biological dose volume histogram for treatment plan evaluation in both EBRT and BT. PMID- 28344604 TI - 3D image-based adapted high-dose-rate brachytherapy in cervical cancer with and without interstitial needles: measurement of applicator shift between imaging and dose delivery. AB - PURPOSE: Using 3D image-guided adaptive brachytherapy for cervical cancer treatment, it often means that patients are transported and moved during the treatment procedure. The purpose of this study was to determine the intra fractional longitudinal applicator shift in relation to the high risk clinical target volume (HR-CTV) by comparing geometries at imaging and dose delivery for patients with and without needles. MATERIAL AND METHODS: Measurements were performed in 33 patients (71 fractions), where 25 fractions were without and 46 were with interstitial needles. Gold markers were placed in the lower part of the cervix as a surrogate for HR-CTV, enabling distance measurements between HR-CTV and the ring applicator. Shifts of the applicator relative to the markers were determined using planning computed tomography (CT) images used for planning, and the radiographs obtained at dose delivery. Differences in the physical D90 for HR CTV due to applicator shifts were simulated individually in the treatment planning system to provide the relative dose variation. RESULTS: The maximum distances of the applicator shifts, in relation to the markers, were 3.6 mm (caudal), and -2.5 mm (cranial). There was a significant displacement of -0.7 mm (SD = 0.9 mm) without needles, while with needles there was no significant shift. The relative dose variation showed a significant increase in D90 HR-CTV of 1.6% (SD = 2.6%) when not using needles, and no significant dose variation was found when using needles. CONCLUSIONS: The results from this study showed that there was a small longitudinal displacement of the ring applicator and a significant difference in displacement between using interstitial needles or not. PMID- 28344605 TI - A method to incorporate interstitial components into the TPS gynecologic rigid applicator library. AB - PURPOSE: T2 magnetic resonance imaging (MRI) is recommended as the imaging modality for image-guided brachytherapy. In locally advanced cervical carcinoma, combined endocavitary and interstitial applicators are appropriate (Vienna or Utrecht). To cover extensive disease, Template Benidorm (TB) was developed. Treatment planning system applicator libraries are currently unavailable for the Utrecht applicator or the TB. The purpose of this work is to develop an applicator library for both applicators. MATERIAL AND METHODS: The library developed in this work has been used in the Oncentra Brachytherapy TPS, version 4.3.0, which has a brachytherapy module that includes a library of rigid applicators. To add the needles of the Utrecht applicator and to model the TB, we used FreeCAD and MeshLab. The reconstruction process was based on the points that the rigid section and the interstitial part have in common. This, together with the free length, allowed us to ascertain the position of the tip. RESULTS: In case of the Utrecht applicator, one of the sources of uncertainty in the reconstruction was determining the distance of the tip of needle from the ovoid. In case of the TB, the large number of needles involved made their identification time consuming. The developed library resolved both issues. CONCLUSIONS: The developed library for the Utrecht and TB is feasible and efficient improving accuracy. It allows all the required treatment planning to proceed using just a T2 MRI sequence. The additional use of specific free available software applications makes it possible to add this information to the already existing library of the Oncentra Brachytherapy TPS. Specific details not included on this manuscript will be available under request. This library is also currently being implemented also into the Sagiplan v 2.0 TPS. PMID- 28344606 TI - Edema worsens target coverage in high-dose-rate interstitial brachytherapy of mobile tongue cancer: a report of two cases. AB - PURPOSE: We report our study on two patients to highlight the risk of underdosage of the clinical target volume (CTV) due to edema during high-dose-rate interstitial brachytherapy (HDR-ISBT) of mobile tongue cancer. MATERIAL AND METHODS: To treat the lateral side of the CTV, flexible applicator tubes were implanted on the mouth floor. Two-dimensional planning was performed using X-ray images for Case 1, and three-dimensional (3D) planning was performed using computed tomography (CT) for Case 2. Prescribed doses for both cases were 54 Gy in nine fractions. CASE REPORTS: Case 1 was treated for cancer of the right lateral border of the tongue in 2005. Tongue edema occurred after implantation, and part of the lateral border of the tongue protruded between the applicator tubes. Acute mucosal reaction abated in the protruded area earlier than in the other parts of the CTV. In this case, the tumor recurred in this area 5 months after the treatment. Case 2 was treated for cancer of the left lateral border of the tongue. Because tongue edema occurred in this case also, plastic splints were inserted between the applicator tubes to push the edematous region into the irradiated area. The mucosal surface of the CTV was covered by the 70% isodose, and 100% isodose line for before and after splint insertion. Local control of the tumor was achieved 4 years after treatment. DISCUSSION AND CONCLUSIONS: To ensure sufficient target coverage, 3D image-based planning using CT should be performed, followed by re-planning using repeated CT as needed. Also, the development of devices to prevent protrusion of the edematous tissue outside the target area will help to ensure the full dosing of CTV. PMID- 28344607 TI - Locally advanced adenocarcinoma of the cervix on uterus didelphys: a case report. AB - In November 2013, a woman with Herlyn-Werner-Wunderlich (HWW) syndrome was diagnosed with a locally advanced left cervical adenocarcinoma. The patient's malformation consisted of two uteri with two cervixes, a obstructed vagina, and a left renal agenesis. Classification FIGO: stage IIIa because of infiltration of the inferior third of the vagina wall. Locoregional management comprised an infrarenal lateral aortic lymphadenectomy followed by concomitant radio chemotherapy to the pelvic (inguinal, pelvic, and infrarenal para aortic nodes) volumes. A total of 50.4 Gy were delivered (1.8 Gy/fraction/day) to the node (inguinal, pelvic, and aortic infrarenal) and pelvic volume; a concomitant boost to the primary cervical tumor and macroscopic nodes to 59.92 Gy (2.14 Gy/fraction/day) was performed. 20 Gy were delivered with intracavitary brachytherapy boost with mold technique and a pulsed-dose-rate technique due to the rarity of this uterine malformation. After 30 months of follow-up, there was no evidence of locoregional or distant recurrence. PMID- 28344608 TI - A brief look at model-based dose calculation principles, practicalities, and promise. AB - Model-based dose calculation algorithms (MBDCAs) have recently emerged as potential successors to the highly practical, but sometimes inaccurate TG-43 formalism for brachytherapy treatment planning. So named for their capacity to more accurately calculate dose deposition in a patient using information from medical images, these approaches to solve the linear Boltzmann radiation transport equation include point kernel superposition, the discrete ordinates method, and Monte Carlo simulation. In this overview, we describe three MBDCAs that are commercially available at the present time, and identify guidance from professional societies and the broader peer-reviewed literature intended to facilitate their safe and appropriate use. We also highlight several important considerations to keep in mind when introducing an MBDCA into clinical practice, and look briefly at early applications reported in the literature and selected from our own ongoing work. The enhanced dose calculation accuracy offered by a MBDCA comes at the additional cost of modelling the geometry and material composition of the patient in treatment position (as determined from imaging), and the treatment applicator (as characterized by the vendor). The adequacy of these inputs and of the radiation source model, which needs to be assessed for each treatment site, treatment technique, and radiation source type, determines the accuracy of the resultant dose calculations. Although new challenges associated with their familiarization, commissioning, clinical implementation, and quality assurance exist, MBDCAs clearly afford an opportunity to improve brachytherapy practice, particularly for low-energy sources. PMID- 28344609 TI - Treatment planning for multicatheter interstitial brachytherapy of breast cancer from Paris system to anatomy-based inverse planning. AB - In the last decades, treatment planning for multicatheter interstitial breast brachytherapy has evolved considerably from fluoroscopy-based 2D to anatomy-based 3D planning. To plan the right positions of the catheters, ultrasound or computed tomography (CT) imaging can be used, but the treatment plan is always based on postimplant CT images. With CT imaging, the 3D target volume can be defined more precisely and delineation of the organs at risk volumes is also possible. Consequently, parameters calculated from dose-volume histogram can be used for quantitative plan evaluation. The catheter reconstruction is also easier and faster on CT images compared to X-ray films. In high dose rate brachytherapy, using a stepping source, a number of forward dose optimization methods (manual, geometrical, on dose points, graphical) are available to shape the dose distribution to the target volume, and these influence dose homogeneities to different extent. Currently, inverse optimization algorithms offer new possibilities to improve dose distributions further considering the requirements for dose coverage, dose homogeneity, and dose to organs at risk simultaneously and automatically. In this article, the evolvement of treatment planning for interstitial breast implants is reviewed, different forward optimization methods are discussed, and dose-volume parameters used for quantitative plan evaluation are described. Finally, some questions of the inverse optimization method are investigated and initial experiences of the authors are presented. PMID- 28344610 TI - Left heart decompression in patients supported with extracorporeal membrane oxygenation for cardiac disease. PMID- 28344611 TI - Percutaneous pulmonary valve implantation - state of the art and Polish experience. AB - Percutaneous pulmonary valve implantation (PPVI) is a relatively new method of treating patients with right ventricular outflow tract (RVOT) dysfunction after surgical repair of congenital heart disease. Since its introduction in 2000 by Bonhoeffer, more than ten thousand PPVI procedures have been performed worldwide. Indications for PPVI have been adapted from those accepted for surgical intervention. Two types of valves are being used: Melody Medtronic available in diameters 16 mm and 18 mm and the family of Edwards SAPIEN valves 23, 26 and 29. The procedure has been shown to be feasible and safe when performed in patients with full pulmonary conduit dysfunction and in selected cases of patched RVOT. The low complication rate and the reduced number of open-chest re-interventions over a patient's lifetime are among the main advantages of the procedure. The most important problem responsible for late mortality and reinterventions is infective endocarditis. Size restrictions of the currently available valves limit deployment in the majority of patients with a wide RVOT. Newer devices are being developed to make these patients suitable for PPVI. A literature review, Polish experience and results of PPVI performed in 66 patients in the Institute of Cardiology in Warsaw are briefly reported. PMID- 28344612 TI - The Polish Interventional Cardiology TAVI Survey (PICTS): adoption and practice of transcatheter aortic valve implantation in Poland. AB - INTRODUCTION: Few studies have assessed the development of transcatheter aortic valve implantation (TAVI) in Poland since its introduction in 2008, and data on current TAVI activity or practice are missing. AIM: To assess the dynamics of TAVI adoption in Poland and to detect differences among Polish centres in TAVI practice and decision-making. MATERIAL AND METHODS: The Polish Interventional Cardiology TAVI Survey (PICTS) was approved by the Polish Association of Cardiovascular Interventions and presented to all 21 national TAVI centres. Between 2008 and 2015 the cumulative number of TAVI performed in Poland was 2189. The annual number of TAVI rose from 8 in 2008 to 670 in 2015 (0.21 to 17.4 implants per million inhabitants, respectively). RESULTS: The median TAVI experience per centre was 80 procedures (95% CI: 38.1-154.6). In 2015 the TAVI penetration rate reached 5.12% of the estimated eligible Polish population. Inoperable and high-risk patients are treated with TAVI in all centres, with 52% of Heart Teams also qualifying medium-risk patients. The rate of transfemoral implantations increased to 83.2% of all procedures in 2015, while transapical implantations decreased to 12%. The frequency of subclavian, direct aortic or transcarotid routes in 2015 was below 3% each. CONCLUSIONS: The PICTS survey observed a positive but slow rate of adoption of TAVI in Poland. When compared to Western European countries, our findings highlight a significant treatment gap in high or prohibitive surgical risk patients with severe aortic stenosis. Remarkable variations in TAVI practices among Polish TAVI centres warrant publication of joint national guidelines and recommendations. PMID- 28344613 TI - ANP and BNP plasma levels in patients with rheumatic mitral stenosis after percutaneous balloon mitral valvuloplasty. AB - INTRODUCTION: Atrial (ANP) and B-type (BNP) natriuretic peptides are hormones secreted by the heart as a response to volume expansion and pressure overload. AIM: To assess the changes of ANP and BNP after percutaneous balloon mitral valvuloplasty (PBMV) and to investigate factors associated with endpoints. MATERIAL AND METHODS: The study included 96 patients (90.7% females, age 51.6 +/ 12.2 years) with rheumatic mitral valve stenosis (mitral valve area (MVA) 1.18 (1.01-1.33) cm2, mean mitral gradient (MMG) 8.2 (7.1-9.2) mm Hg, NYHA 2.09 (1.9 2.5)). Patients were followed up for 29.1 months for the search of endpoints. RESULTS: The PBMV was successful in all cases. After the procedure MVA increased (1.18-1.78 cm2, p < 0.01) and pulmonary capillary wedge pressure (PCWP) decreased (29.8-21.8 mm Hg, p < 0.01). Concentration of ANP significantly rose 30 min after the PBMV (79.2 vs. 134.2 pg/ml, p = 0.012) and dropped significantly after 24 h (134.2 vs. 70.4 pg/ml, p = 0.01). Furthermore, after 36 months concentration of ANP did not differ from the baseline value (p = NS). BNP concentration at day 1 was lower than at baseline (94.5 vs. 80.2 pg/ml, p = 0.032). Moreover, during the follow-up period BNP continued to fall at all time points. In univariate analysis parameters associated with endpoint occurrence were baseline PAP (p = 0.023), baseline PCWP (p = 0.022), baseline NYHA (p = 0.041) and increase in 6-minute walk test (6MWT) (p = 0.043). In multivariate analysis the only factor associated with endpoint occurrence was baseline NYHA (HR = 1.52, 95% CI: -1.3-1.91, p = 0.022). CONCLUSIONS: Patients with MS had increased levels of both BNP and ANP. Baseline NYHA class was found to be associated with outcomes after the procedure. PMID- 28344614 TI - Do we need invasive confirmation of cardiac magnetic resonance results? AB - INTRODUCTION: Coronary artery revascularization is indicated in patients with documented significant obstruction of coronary blood flow associated with a large area of myocardial ischemia and/or untreatable symptoms. There are a few invasive or noninvasive methods that can provide information about the functional results of coronary artery narrowing. The application of more than one method of ischemia detection in one patient to reevaluate the indications for revascularization is used in case of atypical or no symptoms and/or borderline stenosis. AIM: To evaluate whether the results of cardiac magnetic resonance need to be reconfirmed by the invasive functional method. MATERIAL AND METHODS: The hospital database revealed 25 consecutive patients with 29 stenoses who underwent cardiac magnetic resonance (CMR) and fractional flow reserve (FFR) between the end of 2010 and the end of 2014. The maximal time interval between CMR and FFR was 6 months. None of the patients experienced any clinical events or underwent procedures on coronary arteries between the studies. RESULTS: According to the analysis, the agreement of CMR perfusion with the FFR method was at the level of 89.7%. Assuming that FFR is the gold standard in assessing the severity of stenoses, the sensitivity of CMR perfusion was 90.9%. The percentage of non-severe lesions which were correctly identified in CMR was 88.9%. CONCLUSIONS: The study shows that CMR perfusion is a highly sensitive method to detect hemodynamically significant CAD and exclude nonsevere lesions. With FFR as the reference standard, the diagnostic accuracy of MR perfusion to detect ischemic CAD is high. PMID- 28344615 TI - Usefulness of the platelet-to-lymphocyte ratio in predicting long-term cardiovascular mortality in patients with peripheral arterial occlusive disease. AB - INTRODUCTION: Inflammation and increased platelet activation play a crucial role in the initiation and progression of atherosclerosis. Platelet-to-lymphocyte ratio (PLR) has recently been reported as a new independent predictor for major adverse cardiovascular events in cardiovascular diseases. AIM: To investigate the relation between PLR and cardiovascular mortality in patients with intermittent claudication or critical limb ischemia (CLI) or both. MATERIAL AND METHODS: In our retrospective study, 602 consecutive patients who were admitted to a large tertiary hospital with the diagnosis of symptomatic peripheral arterial occlusive disease (PAOD) were included. Patients were divided into two groups according to their PLR as follows: high PLR (PLR > 142) and low PLR (PLR <= 142) groups. RESULTS: During the follow-up period (median: 33.8 months (interquartile range: 21-45)), 131 deaths occurred out of 602 (21.8%) patients. Cardiovascular mortality was found to be significantly higher in the high PLR group compared to the low PLR group (31.6% vs. 17.2 %; p < 0.001). Even after adjustment for various risk factors, PLR > 142 and age were found to be independent predictors of long-term cardiovascular mortality in Cox regression analysis (hazard ratios (95% confidence interval): 1.03 (1.01-1.04) and 1.04 (1.02-1.06), p < 0.001 and p < 0.001, respectively). CONCLUSIONS: Platelet-to-lymphocyte ratio, which is one of the parameters of routine complete blood count, reflects increased inflammatory status, platelet activation and aggregation. PLR is a cheap and readily available marker that has the ability to improve risk stratification provided by conventional risk scores in predicting long-term cardiovascular mortality in PAOD. PMID- 28344616 TI - The impact of a single episode of remote ischemic preconditioning on myocardial injury after elective percutaneous coronary intervention. AB - INTRODUCTION: Myocardial injury after percutaneous coronary intervention (PCI) occurs in approximately 30% of procedures, and is related to worse prognosis. Effects of remote ischemic preconditioning (RIPC) on reperfusion injury have been investigated before, yielding conflicting results. AIM: To assess the impact of a single episode of RIPC on myocardial injury after elective PCI. MATERIAL AND METHODS: One hundred and four patients undergoing elective PCI, with normal baseline cardiac troponin-I (cTn-I) values, were randomized to two groups. Two patients were excluded due to data loss, and 102 patients were analyzed. Five minutes of ischemic preconditioning was delivered just before the intervention to the preconditioning group, by inflating the blood pressure cuff up to 200 mm Hg on the non-dominant arm. Postprocedural 16th hour cTn-I, DeltacTn-I (difference between the 16th h and baseline cTn-I values) and the prevalence of type 4a myocardial infarction were compared between the two groups. RESULTS: Median cTn-I values after the procedure were compared. 16th hour cTn-I was insignificantly lower in the preconditioning arm (0.026 MUg/l vs. 0.045 MUg/l, p = 0.186). The incidence of cTn-I elevation 5-fold above the upper reference limit (URL) (> 0.115 MUg/l) was lower in the preconditioning group, but it was also not significant (21.6% vs. 11.8%, p = 0.184). CONCLUSIONS: A single episode of RIPC before elective PCI demonstrated less troponin elevation but failed to show a significant effect. PMID- 28344617 TI - Twelve months follow-up after retrograde recanalization of superficial femoral artery chronic total occlusion. AB - INTRODUCTION: Fifty percent of cases of peripheral artery disease are caused by chronic total occlusion (CTO) of the superficial femoral artery (SFA). Ten fifteen percent of percutaneous SFA recanalization procedures are unsuccessful. In those cases the retrograde technique can increase the success rate of the procedure, but the long-term follow-up of such procedures is still unknown. AIM: To assess the efficacy and clinical outcomes during long-term follow-up after retrograde recanalization of the SFA. MATERIAL AND METHODS: We included patients after at least one unsuccessful percutaneous antegrade recanalization of the SFA. Patients were evaluated for the procedural and clinical follow-up of mean time 13.9 months. RESULTS: The study included 17 patients (7 females, 10 males) who underwent percutaneous retrograde recanalization of the SFA from June 2011 to June 2015. The mean age of patients was 63 +/-7 years. Retrograde puncture of the distal SFA was successful in all cases. A retrograde procedure was performed immediately after antegrade failure in 4 (23.5%) patients and after a previously failed attempt in 13 (76.5%) patients. The procedure was successful in 15 (88.2%) patients, and unsuccessful in 2 (11.8%) patients. Periprocedural complications included 1 peripheral distal embolization (successfully treated with aspiration thrombectomy), 1 bleeding event from the puncture site and 7 puncture site hematomas. During follow-up the all-cause mortality rate was 5.8% (1 patient, non cardiac death). The primary patency rate at 12 months was 88.2% and secondary patency 100%. CONCLUSIONS: The retrograde SFA puncture seems to be a safe and successful technique for CTO recanalization and is associated with a low rate of perioperative and long-term follow-up complications. PMID- 28344618 TI - Patient- and lesion-tailored algorithm of endovascular treatment for arterial occlusive disease of extracranial arteries supplying the brain: safety of the treatment at 30-day follow-up. AB - INTRODUCTION: Although surgical endarterectomy remains the treatment of choice for carotid artery stenosis, stenting plays an important role as an alternative treatment modality, especially in high-risk patients. The actual safety profile associated with stenting procedures is probably better than that reported by randomized controlled trials. AIM: To assess the safety of stent implantations in extracranial arteries supplying the brain, and also to identify risk factors associated with this procedure. MATERIAL AND METHODS: This was a post hoc analysis, with 30-day follow-up. We analyzed the results of treatment of 372 patients who underwent 408 procedures, 197 such procedures in asymptomatic, and 211 in symptomatic individuals. Stenting procedures were performed using a technique and armamentarium which were tailored to the type and anatomy of lesions. RESULTS: There were 6 (1.5%) strokes, including 2 (0.5%) major strokes, 1 ipsi- and 1 contralateral, and 4 (1.0%) minor strokes. In asymptomatic patients there was 1 (0.3%) minor stroke. Transient ischemic attacks occurred in 5 (1.2%) patients. There were 2 (0.5%) non-STEMI myocardial infarctions and 2 (0.5%) non stroke related fatalities. Risk factors of these adverse events were diabetes mellitus, lesions localized in a tortuous segment of the artery, embolic material in the filter and bilateral stenoses of carotid arteries. Additional risk factors in asymptomatic patients were renal impairment and advanced coronary artery disease; and in symptomatic patients, grade 3 arterial hypertension, dislipidemia, cigarette smoking and lesions requiring predilatation. CONCLUSIONS: Stenting procedures of extracranial arteries supplying the brain, which are tailored to the type and anatomy of lesions, seem to be relatively safe. PMID- 28344619 TI - The Watchman FLX - a new device for left atrial appendage occlusion - design, potential benefits and first clinical experience. PMID- 28344620 TI - High-risk percutaneous coronary intervention with Impella CP hemodynamic support. A case series and method presentation. PMID- 28344621 TI - Transseptal balloon atrial septostomy for decompression of the left atrium during extracorporeal membrane oxygenation support as a "bridge to transplantation" in dilated cardiomyopathy. PMID- 28344622 TI - Transcatheter closure of multi-hole perimembranous ventricular septal defect with aneurysm using two occluders. PMID- 28344623 TI - Should we implant a permanent pacemaker in patients with left bundle branch block and PQ prolongation following transcatheter aortic valve implantation? PMID- 28344624 TI - Retrograde recanalization of chronic total occlusion. A novel maneuver of the old technique. PMID- 28344625 TI - Congenital aortocaval fistula mimicking atrial septal defect on transthoracic echocardiography. PMID- 28344626 TI - Super-dominant right coronary artery, absent left circumflex artery and left anterior descending artery arising from right coronary sinus. PMID- 28344627 TI - Intravascular ultrasonography guided 60-mm long drug-eluting tapered stent implantation in a long calcified lesion in a patient with stable coronary artery disease. PMID- 28344628 TI - Neointima development in externally stented saphenous vein grafts. Progress in medicine is good for the patient: why not use total arterial revascularization?: Response to the Letter to the Editor: Neointima development in externally stented saphenous vein grafts. External stents are bad for the patient: why not use an undamaged saphenous vein for coronary artery bypass graft? PMID- 28344629 TI - Comparison of response patterns in different survey designs: a longitudinal panel with mixed-mode and online-only design. AB - BACKGROUND: Increasing availability of the Internet allows using only online data collection for more epidemiological studies. We compare response patterns in a population-based health survey using two survey designs: mixed-mode (choice between paper-and-pencil and online questionnaires) and online-only design (without choice). METHODS: We used data from a longitudinal panel, the Hygiene and Behaviour Infectious Diseases Study (HaBIDS), conducted in 2014/2015 in four regions in Lower Saxony, Germany. Individuals were recruited using address-based probability sampling. In two regions, individuals could choose between paper-and pencil and online questionnaires. In the other two regions, individuals were offered online-only participation. We compared sociodemographic characteristics of respondents who filled in all panel questionnaires between the mixed-mode group (n = 1110) and the online-only group (n = 482). Using 134 items, we performed multinomial logistic regression to compare responses between survey designs in terms of type (missing, "do not know" or valid response) and ordinal regression to compare responses in terms of content. We applied the false discovery rates (FDR) to control for multiple testing and investigated effects of adjusting for sociodemographic characteristic. For validation of the differential response patterns between mixed-mode and online-only, we compared the response patterns between paper and online mode among the respondents in the mixed-mode group in one region (n = 786). RESULTS: Respondents in the online-only group were older than those in the mixed-mode group, but both groups did not differ regarding sex or education. Type of response did not differ between the online only and the mixed-mode group. Survey design was associated with different content of response in 18 of the 134 investigated items; which decreased to 11 after adjusting for sociodemographic variables. In the validation within the mixed-mode, only two of those were among the 11 significantly different items. The probability of observing by chance the same two or more significant differences in this setting was 22%. CONCLUSIONS: We found similar response patterns in both survey designs with only few items being answered differently, likely attributable to chance. Our study supports the equivalence of the compared survey designs and suggests that, in the studied setting, using online-only design does not cause strong distortion of the results. PMID- 28344631 TI - A behavioural syndrome, but less evidence for a relationship with cognitive traits in a spatial orientation context. AB - BACKGROUND: Animals show consistent individual behavioural differences in many species. Further, behavioural traits (personality traits) form behavioural syndromes, characterised by correlations between different behaviours. Mechanisms maintaining these correlations could be constrained due to underlying relationships with cognitive traits. There is growing evidence for the non independence of animal personality and general cognitive abilities in animals, but so far, studies on the direction of the relationship between them revealed contradictory results. Still, it is hypothesised that individuals may exhibit consistent learning and decision styles. Fast behavioural types (consistently bolder and more active individuals) are expected to show faster learning styles. Slow behavioural types in contrast are assumed to learn slower but more accurately. This can be caused by a speed-accuracy trade-off that individuals face during decision making. We measured the repeatability of three personality and four spatial cognitive traits in adult Eurasian harvest mice (Micromys minutus). We analysed correlations among personality traits (behavioural syndrome). We further investigated the relationships between personality and spatial cognitive traits as a first step exploring the potential connection between personality and cognition in this species. RESULTS: Our results showed that exploration, activity and boldness were repeatable in adult mice. Spatial recognition measured in a Y Maze was also significantly repeatable, as well as spatial learning performance and decision speed. We found no repeatability of decision accuracy. Harvest mice showed a behavioural syndrome as we observed strong positive correlations between personality traits. The speed-accuracy trade off was not apparent within, nor between individuals. Nevertheless, we found weak evidence for a relationship between personality and spatial cognitive traits as fast behavioural types learned a spatial orientation task faster than slow types, and shyer harvest mice made decisions quicker than bolder mice. CONCLUSIONS: Given these correlations, our data provided some first insights into the relationship between personality and spatial cognitive traits in harvest mice and will hopefully stimulate more studies in this field. PMID- 28344630 TI - Flexible reaction norms to environmental variables along the migration route and the significance of stopover duration for total speed of migration in a songbird migrant. AB - BACKGROUND: Predicting the consequences of continuing anthropogenic changes in the environment for migratory behaviours such as phenology remains a major challenge. Predictions remain particularly difficult, because our knowledge is based on studies from single-snapshot observations at specific stopover sites along birds' migration routes. However, a general understanding on how birds react to prevailing environmental conditions, e.g. their 'phenotypic reaction norm', throughout the annual cycle and along their entire migration routes is required to fully understand how migratory birds respond to rapid environmental change. RESULTS: Here, we provide direct evidence that northern wheatears (Oenanthe oenanthe) from a breeding population in Alaska adjusted their probability to resume migration as well as the distance covered per night, i.e. travel speed, to large-scale environmental conditions experienced along their 15,000 km migratory route on both northwards and southwards migrations. These adjustments were found to be flexible in space and time. At the beginning of autumn migration, northern wheatears showed high departure probabilities and high travel speeds at low surface air temperatures, while far away from Alaska both traits decreased with increasing air temperatures. In spring, northern wheatears increasingly exploited flow assistance with season, which is likely a behavioural adjustment to speed up migration by increasing the distance travelled per night. Furthermore, the variation in total stopover duration but not in travel speed had a significant effect on the total speed of migration, indicating the prime importance of total stopover duration in the overall phenology of bird migration. CONCLUSION: Northern wheatears from Alaska provide evidence that the phenotypic reaction norm to a set of environmental conditions cannot be generalized to universal and persistent behavioural reaction pattern across entire migratory pathways. This highlights the importance of full annual-cycle studies on migratory birds to better understand their response to the environment. Understanding the mechanisms behind phenotypic plasticity during migration is particularly important in the assessment of whether birds can keep pace with the potentially increasing phenological mismatches observed on the breeding grounds. PMID- 28344632 TI - Dynamic and temporal assessment of human dried blood spot MS/MSALL shotgun lipidomics analysis. AB - BACKGROUND: Real-time and dynamic assessment of an individual's lipid homeostatic state in blood is complicated due to the need to collect samples in a clinical environment. In the context of precision medicine and population health, tools that facilitate sample collection and empower the individual to participate in the process are necessary to complement advanced bioanalytical analysis. The dried blood spot (DBS) methodology via finger prick or heel prick is a minimally invasive sample collection method that allows the relative ease and low cost of sample collection as well as transport. However, it has yet to be integrated into broad scale personalized lipidomic analysis. Therefore, in this study we report the development of a novel DBS high resolution MS/MSALL lipidomics workflow. METHODS: In this report we compared lipidomic analysis of four types of blood sample collection methods (DBS, venous whole blood, serum, and plasma) across several parameters, which include lipidomics coverage of each matrix and the effects of temperature and time on the coverage and stability of different lipid classes and molecular species. The novel DBS-MS/MSALL lipidomics platform developed in this report was then applied to examine postprandial effects on the blood lipidome and further to explore the temporal fluctuation of the lipidome across hours and days. RESULTS: More than 1,200 lipid molecular species from a single DBS sample were identified and quantified. The lipidomics profile of the DBS samples is comparable to whole blood matrix. DBS-MS/MSALL lipidomic analysis in postprandial experiments revealed significant alterations in triacylglyceride species. Temporal analysis of the lipidome at various times in the day and across days identified several lipid species that fluctuate as a function of time, and a subset of lipid species were identified to be significantly altered across hours within a day and within successive days of the week. CONCLUSIONS: A novel DBS MS/MSALL lipidomics method has been established for human blood. The feasibility and application of this method demonstrate the potential utility for lipidomics analysis in both healthy and diverse diseases states. This DBS MS-based lipidomics analysis represents a formidable approach for empowering patients and individuals in the era of precision medicine to uncover novel biomarkers and to monitor lipid homeostasis. PMID- 28344634 TI - An image analysis pipeline for automated classification of imaging light conditions and for quantification of wheat canopy cover time series in field phenotyping. AB - BACKGROUND: Robust segmentation of canopy cover (CC) from large amounts of images taken under different illumination/light conditions in the field is essential for high throughput field phenotyping (HTFP). We attempted to address this challenge by evaluating different vegetation indices and segmentation methods for analyzing images taken at varying illuminations throughout the early growth phase of wheat in the field. 40,000 images taken on 350 wheat genotypes in two consecutive years were assessed for this purpose. RESULTS: We proposed an image analysis pipeline that allowed for image segmentation using automated thresholding and machine learning based classification methods and for global quality control of the resulting CC time series. This pipeline enabled accurate classification of imaging light conditions into two illumination scenarios, i.e. high light contrast (HLC) and low light-contrast (LLC), in a series of continuously collected images by employing a support vector machine (SVM) model. Accordingly, the scenario-specific pixel-based classification models employing decision tree and SVM algorithms were able to outperform the automated thresholding methods, as well as improved the segmentation accuracy compared to general models that did not discriminate illumination differences. CONCLUSIONS: The three-band vegetation difference index (NDI3) was enhanced for segmentation by incorporating the HSV-V and the CIE Lab-a color components, i.e. the product images NDI3*V and NDI3*a. Field illumination scenarios can be successfully identified by the proposed image analysis pipeline, and the illumination-specific image segmentation can improve the quantification of CC development. The integrated image analysis pipeline proposed in this study provides great potential for automatically delivering robust data in HTFP. PMID- 28344633 TI - The function of myostatin in the regulation of fat mass in mammals. AB - Myostatin (MSTN), also referred to as growth and differentiation factor-8, is a protein secreted in muscle tissues. Researchers believe that its primary function is in negatively regulating muscle because a mutation in its coding region can lead to the famous double muscle trait in cattle. Muscle and adipose tissue develop from the same mesenchymal stem cells, and researchers have found that MSTN is expressed in fat tissues and plays a key role in adipogenesis. Interestingly, MSTN can exert a dual function, either inhibiting or promoting adipogenesis, according to the situation. Due to its potential function in controlling body fat mass, MSTN has attracted the interest of researchers. In this review, we explore its function in regulating adipogenesis in mammals, including preadipocytes, multipotent stem cells and fat mass. PMID- 28344636 TI - Development of an efficient glucosinolate extraction method. AB - BACKGROUND: Glucosinolates, anionic sulfur rich secondary metabolites, have been extensively studied because of their occurrence in the agriculturally important brassicaceae and their impact on human and animal health. There is also increasing interest in the biofumigant properties of toxic glucosinolate hydrolysis products as a method to control agricultural pests. Evaluating biofumigation potential requires rapid and accurate quantification of glucosinolates, but current commonly used methods of extraction prior to analysis involve a number of time consuming and hazardous steps; this study aimed to develop an improved method for glucosinolate extraction. RESULTS: Three methods previously used to extract glucosinolates from brassicaceae tissues, namely extraction in cold methanol, extraction in boiling methanol, and extraction in boiling water were compared across tissue type (root, stem leaf) and four brassicaceae species (B. juncea, S. alba, R. sativus, and E. sativa). Cold methanol extraction was shown to perform as well or better than all other tested methods for extraction of glucosinolates with the exception of glucoraphasatin in R. sativus shoots. It was also demonstrated that lyophilisation methods, routinely used during extraction to allow tissue disruption, can reduce final glucosinolate concentrations and that extracting from frozen wet tissue samples in cold 80% methanol is more effective. CONCLUSIONS: We present a simplified method for extracting glucosinolates from plant tissues which does not require the use of a freeze drier or boiling methanol, and is therefore less hazardous, and more time and cost effective. The presented method has been shown to have comparable or improved glucosinolate extraction efficiency relative to the commonly used ISO method for major glucosinolates in the Brassicaceae species studied: sinigrin and gluconasturtiin in B. juncea; sinalbin, glucotropaeolin, and gluconasturtiin in S. alba; glucoraphenin and glucoraphasatin in R. sativus; and glucosatavin, glucoerucin and glucoraphanin in E. sativa. PMID- 28344635 TI - The combination of gas-phase fluorophore technology and automation to enable high throughput analysis of plant respiration. AB - BACKGROUND: Mitochondrial respiration in the dark (Rdark) is a critical plant physiological process, and hence a reliable, efficient and high-throughput method of measuring variation in rates of Rdark is essential for agronomic and ecological studies. However, currently methods used to measure Rdark in plant tissues are typically low throughput. We assessed a high-throughput automated fluorophore system of detecting multiple O2 consumption rates. The fluorophore technique was compared with O2-electrodes, infrared gas analysers (IRGA), and membrane inlet mass spectrometry, to determine accuracy and speed of detecting respiratory fluxes. RESULTS: The high-throughput fluorophore system provided stable measurements of Rdark in detached leaf and root tissues over many hours. High-throughput potential was evident in that the fluorophore system was 10 to 26 fold faster per sample measurement than other conventional methods. The versatility of the technique was evident in its enabling: (1) rapid screening of Rdark in 138 genotypes of wheat; and, (2) quantification of rarely-assessed whole plant Rdark through dissection and simultaneous measurements of above- and below ground organs. DISCUSSION: Variation in absolute Rdark was observed between techniques, likely due to variation in sample conditions (i.e. liquid vs. gas phase, open vs. closed systems), indicating that comparisons between studies using different measuring apparatus may not be feasible. However, the high throughput protocol we present provided similar values of Rdark to the most commonly used IRGA instrument currently employed by plant scientists. Together with the greater than tenfold increase in sample processing speed, we conclude that the high-throughput protocol enables reliable, stable and reproducible measurements of Rdark on multiple samples simultaneously, irrespective of plant or tissue type. PMID- 28344637 TI - Growth curve registration for evaluating salinity tolerance in barley. AB - BACKGROUND: Smarthouses capable of non-destructive, high-throughput plant phenotyping collect large amounts of data that can be used to understand plant growth and productivity in extreme environments. The challenge is to apply the statistical tool that best analyzes the data to study plant traits, such as salinity tolerance, or plant-growth-related traits. RESULTS: We derive family wise salinity sensitivity (FSS) growth curves and use registration techniques to summarize growth patterns of HEB-25 barley families and the commercial variety, Navigator. We account for the spatial variation in smarthouse microclimates and in temporal variation across phenotyping runs using a functional ANOVA model to derive corrected FSS curves. From FSS, we derive corrected values for family-wise salinity tolerance, which are strongly negatively correlated with Na but not significantly with K, indicating that Na content is an important factor affecting salinity tolerance in these families, at least for plants of this age and grown in these conditions. CONCLUSIONS: Our family-wise methodology is suitable for analyzing the growth curves of a large number of plants from multiple families. The corrected curves accurately account for the spatial and temporal variations among plants that are inherent to high-throughput experiments. PMID- 28344638 TI - The feasibility of genome-scale biological network inference using Graphics Processing Units. AB - Systems research spanning fields from biology to finance involves the identification of models to represent the underpinnings of complex systems. Formal approaches for data-driven identification of network interactions include statistical inference-based approaches and methods to identify dynamical systems models that are capable of fitting multivariate data. Availability of large data sets and so-called 'big data' applications in biology present great opportunities as well as major challenges for systems identification/reverse engineering applications. For example, both inverse identification and forward simulations of genome-scale gene regulatory network models pose compute-intensive problems. This issue is addressed here by combining the processing power of Graphics Processing Units (GPUs) and a parallel reverse engineering algorithm for inference of regulatory networks. It is shown that, given an appropriate data set, information on genome-scale networks (systems of 1000 or more state variables) can be inferred using a reverse-engineering algorithm in a matter of days on a small scale modern GPU cluster. PMID- 28344639 TI - Aflatoxin B1 inhibits the type 1 interferon response pathway via STAT1 suggesting another mechanism of hepatocellular carcinoma. AB - BACKGROUND: Aflatoxin B1 (AFB1) contamination of food is very high in most sub Saharan African countries. AFB1 is known to cause hepatocellular carcinoma (HCC) by inducing mutation in the tumour suppressor gene TP53. The number of new HCC cases is high in West Africa with an accompanying high mortality. The type I interferon (IFN) pathway of the innate immune system limits viral infections and exerts its anti-cancer property by up-regulating tumour suppressor activities and pro-apoptotic pathways. Indeed, IFN-alpha is reported to show significant protective effects against hepatic fibrogenesis and carcinogenesis. However, the mechanism behind AFB1 deregulation of the type I interferon (IFN) signalling pathway, with consequent HCC is largely unknown. This current study seeks to test the hypothesis that AFB1 inhibits the type I IFN response by directly interfering with key signalling proteins and thus increase the risk of HCC in humans. METHODS: We evaluated the effects of AFB1 on the type I IFN signalling pathway using IFN stimulated response element (ISRE)-based luciferase reporter gene assay. In addition, the effects of AFB1 on the transcript levels of JAK1, STAT1 and OAS3 were assessed by real-time quantitative polymerase chain reaction (RT qPCR) and confirmed by immunoblot assay. RESULTS: Our results indicated that AFB1 inhibited the type I IFN signalling pathway in human hepatoma cell line HepG2 cells by suppressing the transcript levels of JAK1, STAT1 and OAS3. AFB1 also decreased the accumulation of STAT1 protein. CONCLUSION: The inhibition of the type I IFN anti-cancer response pathway by AFB1 suggest a novel mechanism by which AFB1 may induce hepatocellular carcinoma in humans. PMID- 28344640 TI - The effects of antiviral treatment on breast cancer cell line. AB - BACKGROUND: Recent studies have revealed the positive antiproliferative and cytotoxic effects of antiviral agents in cancer treatment. The real effect of adjuvant antiviral therapy is still controversial due to the lack of studies in biochemical mechanisms. Here, we studied the effect of the antiviral agent acyclovir on morphometric and migratory features of the MCF7 breast cancer cell line. Molecular levels of various proteins have also been examined. METHODS: To evaluate and assess the effect of antiviral treatment on morphometric, migratory and other cellular characteristics of MCF7 breast cancer cells, the following experiments were performed: (i) MTT assay to measure the viability of MCF7 cells; (ii) Colony formation ability by soft agar assay; (iii) Morphometric characterization by immunofluorescent analysis using confocal microscopy; (iv) wound healing and transwell membrane assays to evaluate migration and invasion capacity of the cells; (v) ELISA colorimetric assays to assess expression levels of caspase-3, E-cadherin and enzymatic activity of aldehyde dehydrogenase (ALDH). RESULTS: We demonstrate the suppressive effect of acyclovir on breast cancer cells. Acyclovir treatment decreases the growth and the proliferation rate of cells and correlates with the upregulated levels of apoptosis associated cytokine Caspase-3. Moreover, acyclovir inhibits colony formation ability and cell invasion capacity of the cancer cells while enhancing the expression of E cadherin protein in MCF7 cells. Breast cancer cells are characterized by high ALDH activity and associated with upregulated proliferation and invasion. According to this study, acyclovir downregulates ALDH activity in MCF7 cells. CONCLUSIONS: These results are encouraging and demonstrate the possibility of partial suppression of cancer cell proliferation using an antiviral agent. Acyclovir antiviral agents have a great potential as an adjuvant therapy in the cancer treatment. However, more research is necessary to identify relevant biochemical mechanisms by which acyclovir induces a potent anti-cancer effect. PMID- 28344642 TI - Rescue medical activities in the mediterranean migrant crisis. PMID- 28344641 TI - LitDB - Keeping Track of Research Papers From Your Institute Made Simple. AB - BACKGROUND: In science peer-reviewed publications serve as an important indicator of scientific excellence and productivity. Therefore, every scientist and institution must carefully maintain and update records of their scientific publications. However, in most institutions and universities articles are often managed in a redundant file-based and non-central way. Whereas excellent reference management software packages such as Zotero, Endnote or Mendeley exist to manage bibliographies and references when writing scientific articles, we are not aware of any open source database solution keeping track of publication records from large scientific groups, entire institutions and/or universities. RESULTS: We here describe LitDB, a novel open source literature database solution for easy maintenance of publication lists assigned to various topics. In the last 2 years more than 50 users have been using LitDB at our research institute. The LitDB system is accessed via a web browser. Publications can be uploaded through direct exports from reference manager libraries or by entering PubMed IDs. Single users or user groups can track their citation counts, h-index and impact factor statistics and gain insights into the publication records of other users. It offers various visualization functions like coauthor networks and provides ways to organize publications from dedicated projects and user groups. The latter is in particular beneficial to manage publication lists of large research groups and research initiatives through a "crowd-sourcing" effort. CONCLUSIONS: Keeping track of papers authored and published by a research group, institute or university is an important and non-trivial task. By using a centralized web-based platform for publication management such as LitDB the compilation of project- and group-related publication lists becomes easily manageable and it is less likely that papers are forgotten along the way. PMID- 28344643 TI - GOLIAH (Gaming Open Library for Intervention in Autism at Home): a 6-month single blind matched controlled exploratory study. AB - BACKGROUND: To meet the required hours of intensive intervention for treating children with autism spectrum disorder (ASD), we developed an automated serious gaming platform (11 games) to deliver intervention at home (GOLIAH) by mapping the imitation and joint attention (JA) subset of age-adapted stimuli from the Early Start Denver Model (ESDM) intervention. Here, we report the results of a 6 month matched controlled exploratory study. METHODS: From two specialized clinics, we included 14 children (age range 5-8 years) with ASD and 10 controls matched for gender, age, sites, and treatment as usual (TAU). Participants from the experimental group received in addition to TAU four 30-min sessions with GOLIAH per week at home and one at hospital for 6 months. Statistics were performed using Linear Mixed Models. RESULTS: Children and parents participated in 40% of the planned sessions. They were able to use the 11 games, and participants trained with GOLIAH improved time to perform the task in most JA games and imitation scores in most imitation games. GOLIAH intervention did not affect Parental Stress Index scores. At end-point, we found in both groups a significant improvement for Autism Diagnostic Observation Schedule scores, Vineland socialization score, Parental Stress Index total score, and Child Behavior Checklist internalizing, externalizing and total problems. However, we found no significant change for by time * group interaction. CONCLUSIONS: Despite the lack of superiority of TAU + GOLIAH versus TAU, the results are interesting both in terms of changes by using the gaming platform and lack of parental stress increase. A large randomized controlled trial with younger participants (who are the core target of ESDM model) is now discussed. This should be facilitated by computing GOLIAH for a web platform. Trial registration Clinicaltrials.gov NCT02560415. PMID- 28344644 TI - Strategies for using nanoprobes to perceive and treat cancer activity: a review. AB - Nanomedicine has seen a significant increase in research on stimuli-responsive activatable nanoprobes for tumor-specific delivery and diagnosis. The tumor microenvironment has particular characteristics that can be exploited to implement therapeutic strategies based on disparities between normal tissues and tumor tissues, including differences in pH, oxygenation, enzymatic expression, gene activation/inactivation, and vasculature. The nanocarriers of activatable nanoparticles maintain their structure while circulating in the body and, upon reaching the tumor site, are altered by unique tumoral stimuli, leading to the release of a drug or other agent. This review demonstrates the latest achievements in the use of internal stimuli-responsive, activatable nanoparticles with respect to unique design strategies and applications. PMID- 28344645 TI - Mimicking lichens: incorporation of yeast strains together with sucrose-secreting cyanobacteria improves survival, growth, ROS removal, and lipid production in a stable mutualistic co-culture production platform. AB - BACKGROUND: The feasibility of heterotrophic-phototrophic symbioses was tested via pairing of yeast strains Cryptococcus curvatus, Rhodotorula glutinis, or Saccharomyces cerevisiae with a sucrose-secreting cyanobacterium Synechococcus elongatus. RESULTS: The phototroph S. elongatus showed no growth in standard BG 11 medium with yeast extract, but grew well in BG-11 medium alone or supplemented with yeast nitrogen base without amino acids (YNB w/o aa). Among three yeast species, C. curvatus and R. glutinis adapted well to the BG-11 medium supplemented with YNB w/o aa, sucrose, and various concentrations of NaCl needed to maintain sucrose secretion from S. elongatus, while growth of S. cerevisiae was highly dependent on sucrose levels. R. glutinis and C. curvatus grew efficiently and utilized sucrose produced by the partner in co-culture. Co cultures of S. elongatus and R. glutinis were sustained over 1 month in both batch and in semi-continuous culture, with the final biomass and overall lipid yields in the batch co-culture 40 to 60% higher compared to batch mono-cultures of S. elongatus. The co-cultures showed enhanced levels of palmitoleic and linoleic acids. Furthermore, cyanobacterial growth in co-culture with R. glutinis was significantly superior to axenic growth, as S. elongatus was unable to grow in the absence of the yeast partner when cultivated at lower densities in liquid medium. Accumulated reactive oxygen species was observed to severely inhibit axenic growth of cyanobacteria, which was efficiently alleviated through catalase supply and even more effectively with co-cultures of R. glutinis. CONCLUSIONS: The pairing of a cyanobacterium and eukaryotic heterotroph in the artificial lichen of this study demonstrates the importance of mutual interactions between phototrophs and heterotrophs, e.g., phototrophs provide a carbon source to heterotrophs, and heterotrophs assist phototrophic growth and survival by removing/eliminating oxidative stress. Our results establish a potential stable production platform that combines the metabolic capability of photoautotrophs to capture inorganic carbon with the channeling of the resulting organic carbon directly to a robust heterotroph partner for producing biofuel and other chemical precursors. PMID- 28344646 TI - Comparative insights into the saccharification potentials of a relatively unexplored but robust Penicillium funiculosum glycoside hydrolase 7 cellobiohydrolase. AB - BACKGROUND: GH7 cellobiohydrolases (CBH1) are vital for the breakdown of cellulose. We had previously observed the enzyme as the most dominant protein in the active cellulose-hydrolyzing secretome of the hypercellulolytic ascomycete Penicillium funiculosum (NCIM1228). To understand its contributions to cellulosic biomass saccharification in comparison with GH7 cellobiohydrolase from the industrial workhorse-Trichoderma reesei, we natively purified and functionally characterized the only GH7 cellobiohydrolase identified and present in the genome of the fungus. RESULTS: There were marginal differences observed in the stability of both enzymes, with P. funiculosum (PfCBH1) showing an optimal thermal midpoint (Tm) of 68 degrees C at pH 4.4 as against an optimal Tm of 65 degrees C at pH 4.7 for T. reesei (TrCBH1). Nevertheless, PfCBH1 had an approximate threefold lower binding affinity (Km), an 18-fold higher turnover rate (kcat), a sixfold higher catalytic efficiency as well as a 26-fold higher enzyme-inhibitor complex equilibrium dissociation constant (Ki) than TrCBH1 on p-nitrophenyl-beta-d lactopyranoside (pNPL). Although both enzymes hydrolyzed cellooligomers (G2-G6) and microcrystalline cellulose, releasing cellobiose and glucose as the major products, the propensity was more with PfCBH1. We equally observed this trend during the hydrolysis of pretreated wheat straws in tandem with other core cellulases under the same conditions. Molecular dynamic simulations conducted on a homology model built using the TrCBH1 structure (PDB ID: 8CEL) as a template enabled us to directly examine the effects of substrate and products on the protein dynamics. While the catalytic triads-EXDXXE motifs-were conserved between the two enzymes, subtle variations in regions enclosing the catalytic path were observed, and relations to functionality highlighted. CONCLUSION: To the best of our knowledge, this is the first report about a comprehensive and comparative description of CBH1 from hypercellulolytic ascomycete-P. funiculosum NCIM1228, against the backdrop of the same enzyme from the industrial workhorse-T. reesei. Our study reveals PfCBH1 as a viable alternative for CBH1 from T. reesei in industrial cellulase cocktails. PMID- 28344647 TI - Ternary ionic liquid-water pretreatment systems of an agave bagasse and municipal solid waste blend. AB - BACKGROUND: Pretreatment is necessary to reduce biomass recalcitrance and enhance the efficiency of enzymatic saccharification for biofuel production. Ionic liquid (IL) pretreatment has gained a significant interest as a pretreatment process that can reduce cellulose crystallinity and remove lignin, key factors that govern enzyme accessibility. There are several challenges that need to be addressed for IL pretreatment to become viable for commercialization, including IL cost and recyclability. In addition, it is unclear whether ILs can maintain process performance when utilizing low-cost, low-quality biomass feedstocks such as the paper fraction of municipal solid waste (MSW), which are readily available in high quantities. One approach to potentially reduce IL cost is to use a blend of ILs at different concentrations in aqueous mixtures. Herein, we describe 14 IL water systems with mixtures of 1-ethyl-3-ethylimidazolium acetate ([C2C1Im][OAc]), 1-butyl-3-ethylimidazolium acetate ([C4C1Im][OAc]), and water that were used to pretreat MSW blended with agave bagasse (AGB). The detailed analysis of IL recycling in terms of sugar yields of pretreated biomass and IL stability was examined. RESULTS: Both biomass types (AGB and MSW) were efficiently disrupted by IL pretreatment. The pretreatment efficiency of [C2C1Im][OAc] and [C4C1Im][OAc] decreased when mixed with water above 40%. The AGB/MSW (1:1) blend demonstrated a glucan conversion of 94.1 and 83.0% using IL systems with ~10 and ~40% water content, respectively. Chemical structures of fresh ILs and recycle ILs presented strong similarities observed by FTIR and 1H NMR spectroscopy. The glucan and xylan hydrolysis yields obtained from recycled IL exhibited a slight decrease in pretreatment efficiency (less than 10% in terms of hydrolysis yields compared to that of fresh IL), and a decrease in cellulose crystallinity was observed. CONCLUSIONS: Our results demonstrated that mixing ILs such as [C2C1Im][OAc] and [C4C1Im][OAc] and blending the paper fraction of MSW with agricultural residues, such as AGB, may contribute to lower the production costs while maintaining high sugar yields. Recycled IL-water mixtures provided comparable results to that of fresh ILs. Both of these results offer the potential of reducing the production costs of sugars and biofuels at biorefineries as compared to more conventional IL conversion technologies.Graphical abstractSchematic of ionic liquid (IL) pretreatment of agave bagasse (AB) and paper-rich fraction of municipal solid waste (MSW). PMID- 28344648 TI - Cellulosic ethanol production via consolidated bioprocessing by a novel thermophilic anaerobic bacterium isolated from a Himalayan hot spring. AB - BACKGROUND: Cellulose-degrading thermophilic anaerobic bacterium as a suitable host for consolidated bioprocessing (CBP) has been proposed as an economically suited platform for the production of second-generation biofuels. To recognize the overall objective of CBP, fermentation using co-culture of different cellulolytic and sugar-fermenting thermophilic anaerobic bacteria has been widely studied as an approach to achieving improved ethanol production. We assessed monoculture and co-culture fermentation of novel thermophilic anaerobic bacterium for ethanol production from real substrates under controlled conditions. RESULTS: In this study, Clostridium sp. DBT-IOC-C19, a cellulose-degrading thermophilic anaerobic bacterium, was isolated from the cellulolytic enrichment cultures obtained from a Himalayan hot spring. Strain DBT-IOC-C19 exhibited a broad substrate spectrum and presented single-step conversion of various cellulosic and hemicellulosic substrates to ethanol, acetate, and lactate with ethanol being the major fermentation product. Additionally, the effect of varying cellulose concentrations on the fermentation performance of the strain was studied, indicating a maximum cellulose utilization ability of 10 g L-1 cellulose. Avicel degradation kinetics of the strain DBT-IOC-C19 displayed 94.6% degradation at 5 g L-1 and 82.74% degradation at 10 g L-1 avicel concentration within 96 h of fermentation. In a comparative study with Clostridium thermocellum DSM 1313, the ethanol and total product concentrations were higher by the newly isolated strain on pretreated rice straw at an equivalent substrate loading. Three different co culture combinations were used on various substrates that presented two-fold yield improvement than the monoculture during batch fermentation. CONCLUSIONS: This study demonstrated the direct fermentation ability of the novel thermophilic anaerobic bacteria on various cellulosic and hemicellulosic substrates into ethanol without the aid of any exogenous enzymes, representing CBP-based fermentation approach. Here, the broad substrate utilization spectrum of isolated cellulolytic thermophilic anaerobic bacterium was shown to be of potential utility. We demonstrated that the co-culture strategy involving novel strains is efficient in improving ethanol production from real substrate. PMID- 28344649 TI - Overexpression of a Domain of Unknown Function 266-containing protein results in high cellulose content, reduced recalcitrance, and enhanced plant growth in the bioenergy crop Populus. AB - BACKGROUND: Domain of Unknown Function 266 (DUF266) is a plant-specific domain. DUF266-containing proteins (DUF266 proteins) have been categorized as 'not classified glycosyltransferases (GTnc)' due to amino acid similarity with GTs. However, little is known about the function of DUF266 proteins. RESULTS: Phylogenetic analysis revealed that DUF266 proteins are only present in the land plants including moss and lycophyte. We report the functional characterization of one member of DUF266 proteins in Populus, PdDUF266A. PdDUF266A was ubiquitously expressed with high abundance in the xylem. In Populus transgenic plants overexpressing PdDUF266A (OXPdDUF266A), the glucose and cellulose contents were significantly higher, while the lignin content was lower than that in the wild type. Degree of polymerization of cellulose in OXPdDUF266A transgenic plants was also higher, whereas cellulose crystallinity index remained unchanged. Gene expression analysis indicated that cellulose biosynthesis-related genes such as CESA and SUSY were upregulated in mature leaf and xylem of OXPdDUF266A transgenic plants. Moreover, PdDUF266A overexpression resulted in an increase of biomass production. Their glucose contents and biomass phenotypes were further validated via heterologous expression of PdDUF266A in Arabidopsis. Results from saccharification treatment demonstrated that the rate of sugar release was increased by approximately 38% in the OXPdDUF266A transgenic plants. CONCLUSIONS: These results suggest that the overexpression of PdDUF266A can increase cellulose content, reduce recalcitrance, and enhance biomass production, and that PdDUF266A is a promising target for genetic manipulation for biofuel production. PMID- 28344650 TI - Improving carbohydrate and starch accumulation in Chlorella sp. AE10 by a novel two-stage process with cell dilution. AB - BACKGROUND: Microalgae are highly efficient cellular factories that capture CO2 and are also alternative feedstock for biofuel production. Carbohydrates, proteins, and lipids are major biochemical components in microalgae. Carbohydrates or starch in microalgae are possible substrates in yeast fermentation for biofuel production. The carbon partitioning in microalgae could be regulated through environmental stresses, such as high concentration of CO2, high light intensity, and nitrogen starvation conditions. It is essential to obtain carbohydrate-rich microalgae via an optimal bioprocess strategy. RESULTS: The carbohydrate accumulation in a CO2 tolerance strain, Chlorella sp. AE10, was investigated with a two-stage process. The CO2 concentration, light intensity, and initial nitrogen concentration were changed drastically in both stages. During the first stage, it was cultivated over 3 days under 1% CO2, a photon flux of 100 MUmol m-2 s-1, and 1.5 g L-1 NaNO3. It was cultivated under 10% CO2, 1000 MUmol m-2 s-1, and 0.375 g L-1 NaNO3 during the second stage. In addition, two operation modes were compared. At the beginning of the second stage of mode 2, cells were diluted to 0.1 g L-1 and there was no cell dilution in mode 1. The total carbohydrate productivity of mode 2 was increased about 42% compared with that of mode 1. The highest total carbohydrate content and the highest starch content of mode 2 were 77.6% (DW) and 60.3% (DW) at day 5, respectively. The starch productivity was 0.311 g L-1 day-1 and the total carbohydrate productivity was 0.421 g L-1 day-1 in 6 days. CONCLUSIONS: In this study, a novel two-stage process was proposed for improving carbohydrate and starch accumulation in Chlorella sp. AE10. Despite cell dilution at the beginning of the second stage, environmental stress conditions of high concentration of CO2, high light intensity, and limited nitrogen concentration at the second stage were critical for carbohydrate and starch accumulation. Although the cells were diluted, the growths were not inhibited and the carbohydrate productivity was improved. These results were helpful to establish an integrated approach from CO2 capture to biofuel production by microalgae. PMID- 28344651 TI - Identification of a novel DMD duplication identified by a combination of MLPA and targeted exome sequencing. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked recessive muscle wasting disease caused by a mutation in the DMD gene. The aim of this study was to identify a de novo mutation of the DMD gene in the family of a 9-month-old Chinese male patient, as well as to describe the phenotypic characteristics of this patient. RESULTS: The patient was suspected to suffer from DMD according to physical examination, biochemical analyses, and electromyogram. We identified a duplication of exons 4-42 in DMD gene with targeted exome sequencing and multiplex ligation-dependent probe amplification (MLPA). In addition, the patient's mother was a carrier of the same mutation. CONCLUSIONS: We identified a de novo duplication of exons 4-42 in a patient with early stage DMD. The discovery of this mutation may provide insights into future investigations. PMID- 28344652 TI - Molecular cytogenetic characterisation of a novel de novo ring chromosome 6 involving a terminal 6p deletion and terminal 6q duplication in the different arms of the same chromosome. AB - BACKGROUND: Ring chromosome 6 is a rare sporadic chromosomal abnormality, associated with extreme variability in clinical phenotypes. Most ring chromosomes are known to have deletions on one or both chromosomal arms. Here, we report an atypical and unique ring chromosome 6 involving both a distal deletion and a distal duplication on the different arms of the same chromosome. CASE PRESENTATION: In a patient with intellectual disability, short stature, microcephaly, facial dysmorphology, congenital heart defects and renovascular disease, a ring chromosome 6 was characterised using array-CGH and dual-colour FISH. The de-novo ring chromosome 6 involved a 1.8 Mb terminal deletion in the distal short arm and a 2.5 Mb duplication in the distal long arm of the same chromosome 6. This results in monosomy for the region 6pter to 6p25.3 and trisomy for the region 6q27 to 6qter. Analysis of genes in these chromosomal regions suggests that haploinsufficiency for FOXC1 and GMDS genes accounts for the cardiac and neurodevelopmental phenotypes in the proband. The ring chromosome 6 reported here is atypical as it involves a unique duplication of the distal long arm. Furthermore, the presence of renovascular disease is also a unique feature identified in this patient. CONCLUSION: To the best of our knowledge, a comparable ring chromosome 6 involving both a distal deletion and duplication on different arms has not been previously reported. The renovascular disease identified in this patient may be a direct consequence of the described chromosome rearrangement or a late clinical presentation in r(6) cases. This clinical finding may further support the implicated role of FOXC1 gene in renal pathology. PMID- 28344653 TI - Characterization of a de novo sSMC 17 detected in a girl with developmental delay and dysmorphic features. AB - BACKGROUND: The majority of small supernumerary marker chromosome cases arise de novo and their frequency in newborns is 0.04%. We report on a girl with developmental delay and dysmorphic features with a non-mosaic de novo sSMC that originated from the pericentric region of q arm in chromosome 17. CASE PRESENTATION: The girl presented with developmental delay, speech delay, myopia, mild muscle hypotonia, hypoplasia of orbicular muscle, poor concentration, and hyperactivity. Main dysmorphic features included: round face, microstomia, small chin, down-slanting palpebral fissures and small lobules of both ears. At present, her developmental abilities are still delayed for her chronological age but she is making evident progress with speech. A postnatal array comparative genomic hybridization showed a 2.31 Mb genomic gain indicating microduplication derived from pericentric regions q11.1 and q11.2 of chromosome 17. Additional conventional cytogenetic analysis from peripheral blood characterized the karyotype as 47,XX,+mar in a non-mosaic form. The location of microduplication was confirmed with fluorescence in situ hybridization. CONCLUSION: The proband's microduplication encompassed approximately 40 annotated genes, several of which have been associated with phenotypic characteristics of the proband. This is the first report of sSMC 17 including this particular chromosomal region in non mosaic form. PMID- 28344654 TI - Endovascular thrombectomy with or without systemic thrombolysis? AB - OBJECTIVES: Current recommendations advocate that pretreatment with intravenous thrombolysis (IVT) should first be offered to all eligible patients with emergent large vessel occlusion (ELVO) before an endovascular thrombectomy (ET) procedure. However, there are observational data that question the safety and efficacy of IVT pretreatment in patients with ELVO. METHODS: We performed a meta-analysis of the included subgroups from ET randomized controlled trials (RCTs) to evaluate the comparative efficacy between direct ET without IVT pretreatment and bridging therapy (IVT and ET) in patients with ELVO. RESULTS: We included a total of seven RCTs, including 1764 patients with ELVO (52.8% men). Patients receiving bridging therapy (IVT followed by ET) had lower rates (p = 0.041) of 90-day death/severe dependency (modified Rankin Scale-score of 5-6; 19.0%, 95% CI: 14.1-25.1%) compared with patients receiving only ET (31.0%, 95% CI: 21.2-42.9%). Moreover, patients receiving IVT and ET had a nonsignificant (p = 0.389) trend towards higher 90-day functional independence rates (51.4%, 95% CI: 42.5-60.1%) compared with patients undergoing only ET (41.7%, 95% CI: 24.1-61.7%). Finally, shift analysis uncovered a nonsignificant trend towards functional improvement at 90 days for bridging therapy over ET (cOR = 1.28, 95% CI: 0.91-1.89; p = 0.155). It should be noted that patients included in the present meta-analysis were not randomized to receive IVT, and thus the two groups (bridging therapy versus ET monotherapy) may differ in terms of baseline characteristics and, in particular, in terms of onset to groin puncture time and thus the risk of confounding bias cannot be ruled out. CONCLUSION: Despite the limitations and the risk of confounding bias, our findings contradict the recent notion regarding potential equality between ET and bridging therapy in ELVO patients and suggest that IVT and ET are complementary therapies that should be pursued in a parallel and noncompeting fashion. PMID- 28344655 TI - Interactions among COX-2, GPIIIa and P2Y1 variants are associated with aspirin responsiveness and adverse events in patients with ischemic stroke. AB - BACKGROUND: The effect of gene variants and their interactions on response to aspirin and clinical adverse outcomes after an acute ischemic stroke (IS) is not fully understood. The aim of this study was to investigate the association of aspirin-relevant gene variants and their interactions with clinical adverse outcomes in IS patients taking aspirin. METHODS: A total of 14 variants from six genes encoding COX enzymes (COX-1, COX-2), platelet membrane receptors (TXAS1, P2Y1, P2Y12) and glycoprotein receptor (GPIIIa) were examined in 850 acute IS patients. Gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) analysis. All patients were followed up for 1 year after admission. Primary outcome was a composite of recurrent ischemic stroke (RIS), myocardial infarction (MI) and death. RESULTS: The primary outcome occurred in 112 (13.5%) patients (81 RIS, 16 MI and 15 deaths). There were no significant differences in the frequencies of the genotypes of the 14 variants between the patients with and without primary outcome using single-locus analytical approach. However, there was significant gene-gene interaction among rs20417, rs1371097 and rs2317676. The high-risk interactive genotypes of rs20417, rs1371097 and rs2317676 were independently associated with primary adverse outcome of RIS, MI, and death after acute IS. CONCLUSION: The three-loci interactions are associated with sensitivity of IS patients to aspirin and aspirin-induced adverse clinical events. The combinatorial analysis used in this study may be helpful to elucidate complex genetic risk of aspirin resistance (AR). CLINICAL TRIAL REGISTRATION: The study described here is registered at http://www.chictr.org/ (unique identifier: ChiCTR-OCH-14004724). PMID- 28344656 TI - Levodopa-carbidopa enteral suspension in advanced Parkinson's disease: clinical evidence and experience. AB - The duration of action of oral levodopa becomes shorter as Parkinson's disease (PD) progresses. Patients with advanced PD may develop potentially disabling motor fluctuations and abnormal involuntary movement (dyskinesia), which cannot be managed with optimized oral or transdermal PD medications. The progressively worsening symptoms can have a substantial impact on the patient quality of life (QoL). Levodopa-carbidopa intestinal gel (LCIG) is delivered continuously via a percutaneous endoscopic gastrostomy with a jejunal extension (PEG-J). LCIG is licensed for the treatment of levodopa-responsive advanced PD in individuals experiencing severe motor fluctuations and dyskinesia when available combinations of antiparkinsonian medications have not given satisfactory results. Initial evidence for the efficacy and tolerability of LCIG came from a number of small scale studies, but recently, three prospective studies have provided higher quality evidence. A 12-week double-blind comparison of LCIG with standard levodopa therapy, a 52-week open-label study extension of the double-blind study, and a 54-week open-label safety study, demonstrated significant improvements in 'off' time and 'on' time without troublesome dyskinesia, and QoL measures that were maintained in the longer term. There are also observations that LCIG may be effective treatment for nonmotor symptoms (NMS) although the evidence is limited. There is a need for further research on the efficacy of LCIG in reducing NMS, dyskinesia and improving QoL. This review surveys the clinical evidence for the effectiveness and tolerability of LCIG in the management of advanced PD and highlights some practical considerations to help optimize treatment. PMID- 28344659 TI - Comparison of in-hospital glycemic variability and admission blood glucose in predicting short-term outcomes in non-diabetes patients with ST elevation myocardial infarction underwent percutaneous coronary intervention. AB - AIMS: Admission hyperglycemia is associated with increased mortality and major adverse cardiac events (MACE) in patients with or without diabetes mellitus after acute myocardial infarction (AMI). However, effects of glycemic variability (GV) on outcomes of non-diabetes patients with AMI still remains unclear. The aim of this study is to compare the prognostic value of in-hospital GV with admission blood glucose (ABG) for 3-month MACE in non-diabetes patients with ST elevation myocardial infarction (STEMI) who underwent percutaneous coronary intervention (PCI). METHODS: We analyzed 256 non-diabetes patients with STEMI in study. The GV accessed by mean amplitude of glycemic excursions (MAGE) was calculated from blood glucose profiles of continuous glucose monitoring system (CGMS) during hospitalization. ABG was measured on admission. Main endpoints were 3-month MACE; secondary endpoints were GRACE scores and enzymatic infarct size. Predictive effects of MAGE and ABG on the MACE in patients were analyzed. RESULTS: In all participants, MAGE level was associated with ABG level (r = 0.242, p < 0.001). Both elevated MAGE levels (p = 0.001) and elevated ABG (p = 0.046) were associated with incidences of short-term MACE. Patients with a higher MAGE level had a significantly higher cardiac mortality (5.8 vs. 0.6%, p = 0.017) and incidence of acute heart failure (12.8 vs. 2.4%, p = 0.001) during 3 months follow-up. In multivariable analysis, high MAGE level (HR 2.165, p = 0.023) was significantly associated with incidence of short-term MACE, but ABG (HR 1.632, p = 0.184) was not. The area under the receiver-operating characteristic curve for MAGE (0.690, p < 0.001) was superior to that for ABG (0.581, p = 0.076). CONCLUSIONS: To compare with ABG, in-hospital GV may be a more important predictor of short-term MACE and mortality in non-diabetes patients with STEMI treated with PCI. PMID- 28344658 TI - Flightless-I governs cell fate by recruiting the SUMO isopeptidase SENP3 to distinct HOX genes. AB - BACKGROUND: Despite recent studies on the role of ubiquitin-related SUMO modifier in cell fate decisions, our understanding on precise molecular mechanisms of these processes is limited. Previously, we established that the SUMO isopeptidase SENP3 regulates chromatin assembly of the MLL1/2 histone methyltransferase complex at distinct HOX genes, including the osteogenic master regulator DLX3. A comprehensive mechanism that regulates SENP3 transcriptional function was not understood. RESULTS: Here, we identified flightless-I homolog (FLII), a member of the gelsolin family of actin-remodeling proteins, as a novel regulator of SENP3. We demonstrate that FLII is associated with SENP3 and the MLL1/2 complex. We further show that FLII determines SENP3 recruitment and MLL1/2 complex assembly on the DLX3 gene. Consequently, FLII is indispensible for H3K4 methylation and proper loading of active RNA polymerase II at this gene locus. Most importantly, FLII-mediated SENP3 regulation governs osteogenic differentiation of human mesenchymal stem cells. CONCLUSION: Altogether, these data reveal a crucial functional interconnection of FLII with the sumoylation machinery that converges on epigenetic regulation and cell fate determination. PMID- 28344657 TI - Well-positioned nucleosomes punctuate polycistronic pol II transcription units and flank silent VSG gene arrays in Trypanosoma brucei. AB - BACKGROUND: The compaction of DNA in chromatin in eukaryotes allowed the expansion of genome size and coincided with significant evolutionary diversification. However, chromatin generally represses DNA function, and mechanisms coevolved to regulate chromatin structure and its impact on DNA. This included the selection of specific nucleosome positions to modulate accessibility to the DNA molecule. Trypanosoma brucei, a member of the Excavates supergroup, falls in an ancient evolutionary branch of eukaryotes and provides valuable insight into the organization of chromatin in early genomes. RESULTS: We have mapped nucleosome positions in T. brucei and identified important differences compared to other eukaryotes: The RNA polymerase II initiation regions in T. brucei do not exhibit pronounced nucleosome depletion, and show little evidence for defined -1 and +1 nucleosomes. In contrast, a well-positioned nucleosome is present directly on the splice acceptor sites within the polycistronic transcription units. The RNA polyadenylation sites were depleted of nucleosomes, with a single well-positioned nucleosome present immediately downstream of the predicted sites. The regions flanking the silent variant surface glycoprotein (VSG) gene cassettes showed extensive arrays of well-positioned nucleosomes, which may repress cryptic transcription initiation. The silent VSG genes themselves exhibited a less regular nucleosomal pattern in both bloodstream and procyclic form trypanosomes. The DNA replication origins, when present within silent VSG gene cassettes, displayed a defined nucleosomal organization compared with replication origins in other chromosomal core regions. CONCLUSIONS: Our results indicate that some organizational features of chromatin are evolutionarily ancient, and may already have been present in the last eukaryotic common ancestor. PMID- 28344660 TI - Predictive biomarkers and effectiveness of MUC1-targeted dendritic-cell-based vaccine in patients with refractory non-small cell lung cancer. AB - BACKGROUND: The dendritic cell (DC)-based vaccine targeting the highly immunogenic tumor antigen, MUC1, has been promising for a cancer immunotherapy; however, predictive biomarkers for beneficial clinical responses of the vaccine remain to be determined. METHODS: DCs loaded with MUC1-derived peptide were subcutaneously administered to patients with MUC1-positive non-small cell lung cancer (NSCLC) that was refractory to standard anticancer therapies, every 2 weeks. The effectiveness and tolerability of the vaccine were evaluated, and predictive biomarkers of clinical responses were explored. RESULTS: Between August 2005 and May 2015, 40 patients received the vaccines. The median survival time (MST) after the initial vaccination was 7.4 months, and the 1-year survival rate was 25.0%. The MST for patients who received more than six vaccinations was 9.5 months, and the 1-year survival rate was 39.3%. In this cohort, patients who experienced immune-related adverse events, including skin reactions at the vaccination site and fever, had significantly longer survival times compared with patients without those immune-related adverse events (12.6 versus 6.7 months, p = 0.042). Longer survival times were also observed in patients whose peripheral white blood cells contained >20.0% lymphocytes (12.6 versus 4.5 months; p = 0.014). MUC1-specific cytotoxic immune responses were achieved in all of seven patients analyzed who received six vaccinations. CONCLUSION: The MUC1-targeted DC based vaccine induced an antitumor immune response that promoted prolonged survival of patients with refractory NSCLC. The occurrence of immune-related adverse events and having a higher percentage of peripheral lymphocytes were predictive biomarkers of a beneficial clinical response during cancer immunotherapy for NSCLC. PMID- 28344661 TI - Liposomal irinotecan in gemcitabine-refractory metastatic pancreatic cancer: efficacy, safety and place in therapy. AB - Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. The majority of patients are diagnosed with locally advanced or metastatic disease with a prognosis of short months. Therapeutic options are limited and until recently, there was no standard second-line chemotherapy option. Liposomal constructs have been engineered to encapsulate chemotherapy thereby preventing premature metabolism, improving distribution and minimizing toxicity. Favourable preclinical data on liposomal irinotecan and early phase trials, led to a recently published phase III trial of liposomal irinotecan in combination with fluorouracil and folinic acid in patients with metastatic PDAC, who progressed after gemcitabine-based chemotherapy. As a direct result, the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved the use of liposomal irinotecan in this setting. However, first-line treatment options for this disease now include the combination regimen, FOLFIRINOX, in patients with good performance status, and the role of second-line combination treatment with liposomal irinotecan in this setting is unclear. Recent advances have changed the therapeutic landscape, as clinicians are now able to choose a sequential approach to treatment tailored to the individual patient characteristics. This article reviews current treatment options for metastatic PDAC and focuses on the efficacy, safety and place in therapy of liposomal irinotecan. PMID- 28344663 TI - Everolimus treatment for neuroendocrine tumors: latest results and clinical potential. AB - Neuroendocrine tumors (NETs) are a heterogeneous class of diseases characterized by challenging management. Preclinical evidence shows that the PI3K/AKT/mTOR signaling pathway plays a central role in the pathogenesis and progression of NETs. Everolimus is a direct inhibitor of this pathway, and therefore this molecule appears to be a well-grounded strategy for the treatment of NETs, capable of changing clinical practice. The efficacy and safety of everolimus was demonstrated in the RADIANT trials. In this work, we comment on the results of the RADIANT trials, and other recent key evidence from fully published clinical trials on everolimus, and we discuss the current role of everolimus in the treatment of NETs. PMID- 28344662 TI - Nivolumab in renal cell carcinoma: latest evidence and clinical potential. AB - Similar to melanoma, renal cell carcinoma (RCC) has been historically considered as an immunogenic tumor, with interleukin 2 (IL-2) and interferon alpha (IFN alpha) being the first approved treatments in the 1990s. However, these therapies were effective in only 10-20% of cases and were not well tolerated. Recently, new insights on the interaction between the immune system and tumor have identified the programmed death-1/programmed death-ligand-1 (PD-1/PD-L1) pathway to be a key player in evading host immune responses. The strategy of immune checkpoint blockade is to reduce inhibitory signaling and restore the patient's natural tumor-specific T-cell-mediated immune responses. Nivolumab is the first PD-1 inhibitor to have gained approval for the treatment of patients with metastatic melanoma, squamous and nonsquamous non-small cell lung cancer (NSCLC), Hodgkin disease and recently RCC. In this review, we discuss results from studies of nivolumab in RCC, clinical experience with this agent, and its future development. PMID- 28344664 TI - Current understanding and approach to well differentiated lung neuroendocrine tumors: an update on classification and management. AB - Neuroendocrine tumors (NETs) are rare neoplasms that can arise from any tissue. They are classified based on embryonic gut derivative (i.e. foregut, midgut and hindgut) with midgut tumors being the most common (e.g. gastrointestinal NET). The second most common category of NETs is that which arises from the lung. In fact, 25% of primary lung cancers are NETs, including small cell lung cancer (SCLC), which comprises 20% of all lung cancers. The remaining 5% are large cell neuroendocrine cancer (LCNEC, 3%), typical carcinoids (TCs, 1.8%), and atypical carcinoids (ACs, 0.2%). The less common TCs/ACs are well differentiated lung NETs. Their incidence has been increasing in more recent years and although these tumors are slow growing, advanced disease is associated with poor survival. There have been advances in classification of lung NETs that have allowed for more appropriate management upfront. They are cured by surgical resection when disease is limited. However, advanced and metastatic disease requires medical therapy that is ever changing and expanding. In this review, the aim is to summarize the current understanding and classification of well differentiated lung NETs (i.e. TCs and ACs), and focus on recent updates in medical management of advanced disease, along with a brief discussion on potential future discoveries. PMID- 28344666 TI - Erratum. AB - [This corrects the article DOI: 10.1177/1758834016659825.]. PMID- 28344665 TI - Treatment choice in epidermal growth factor receptor mutation-positive non-small cell lung carcinoma: latest evidence and clinical implications. AB - Discovery of sensitizing mutations in epidermal growth factor receptor (EGFR) and the subsequent development of EGFR tyrosine kinase inhibitors (TKIs) have substantially changed the treatment of lung cancer. First-line treatment with EGFR TKIs (gefitinib, erlotinib and afatinib) has demonstrated a superior response rate and progression-free survival (PFS) compared with chemotherapy in EGFR-mutation positive patients. However, a number of open questions remain, such as choice between the three EGFR TKIs licensed, treatment of patients unsuitable for chemotherapy due to morbidity or advanced age, management of acquired resistance and optimal biological sample to determine EGFR status. Recently the first head-to-head trial comparing gefitinib and afatinib (LUX-Lung 7) has been reported. Moreover, third-generation EGFR TKIs such as osimertinib, rociletinib, olmutinib and ASP8273, with preferential activity against T790M mutant tumours, the commonest resistance mechanism to EGFR TKIs, have shown promising results in early clinical trials, with osimertinib now licensed. In this review, we summarize latest advances in the treatment of EGFR-mutation positive patients focusing on controversial areas and emerging challenges to optimally treat these patients in the future. PMID- 28344667 TI - Muller cells and retinal axons can be primary targets in experimental neuromyelitis optica spectrum disorder. AB - Recent work from our laboratory, using different models of experimental neuromyelitis optica spectrum disorder (NMOSD), has led to a number of observations that might be highly relevant for NMOSD patients. For example: (i) in the presence of neuromyelitis optica immunoglobulin G, astrocyte-destructive lesions can be initiated by CD4+ T cells when these cells recognize aquaporin 4 (AQP4), but also when they recognize other antigens of the central nervous system. The only important prerequisite is that the T cells have to be activated within the central nervous system by "their" specific antigen. Recently activated CD4+ T cells with yet unknown antigen specificity are also found in human NMOSD lesions. (ii) The normal immune repertoire might contain AQP4-specific T cells, which are highly encephalitogenic on activation. (iii) The retina might be a primary target of AQP4-specific T cells and neuromyelitis optica immunoglobulin G: AQP4-specific T cells alone are sufficient to cause retinitis with low-grade axonal pathology in the retinal nerve fiber/ganglionic cell layer. A thinning of these layers is also observed in NMOSD patients, where it is thought to be a consequence of optic neuritis. Neuromyelitis optica immunoglobulin G might target cellular processes of Muller cells and cause their loss of AQP4 reactivity, when AQP4-specific T cells open the blood-retina barrier in the outer plexiform layer. Patchy loss of AQP4 reactivity on Muller cells of NMOSD patients has been recently described. Cumulatively, our findings in experimental NMOSD suggest that both CD4+ T cell and antibody responses directed against AQP4 might play an important role in the pathogenesis of tissue destruction seen in NMOSD. PMID- 28344668 TI - Diabetes and bone health: latest evidence and clinical implications. AB - As the prevalence of diabetes is increasing worldwide, research on some of the lesser-known effects, including impaired bone health, are gaining a lot of attention. The two most common forms of diabetes are type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). These two differ in their physiology, with T1DM stemming from an inability to produce insulin, and T2DM involving an insufficient response to the insulin that is produced. This review aims to highlight the most current information regarding diabetes as it relates to bone health. It looks at biochemical changes that characterize diabetic bone; notably increased adiposity, altered bone metabolism, and variations in bone mineral density (BMD). Then several hypotheses are analyzed, concerning how these changes may be detrimental to the highly orchestrated processes that are involved in bone formation and turnover, and ultimately result in the distinguishing features of diabetic bone. The review proceeds by explaining the effects of antidiabetes medications on bone health, then highlighting several ways that diabetes can play a part in other clinical treatment outcomes. With diabetes negatively affecting bone health and creating other clinical problems, and its treatment options potentiating these effects, physicians should consider the use of anti osteoporotic drugs to supplement standard anti-diabetes medications in patients suffering with diabetic bone loss. PMID- 28344669 TI - Belimumab in systemic lupus erythematosus (SLE): evidence-to-date and clinical usefulness. AB - Systemic lupus erythematosus (SLE) is a complex autoimmune rheumatic disease with multiple presentations, whose management presents many challenges. Many disease modifying or immunosuppressive drugs have been used with limited success, especially in patients with more severe disease activity. Belimumab is the first drug to be approved specifically for the treatment of SLE in more than 50 years. By blocking the B-cell activating factor, it interferes in B-cell differentiation and survival. Here we consider the results of the clinical trials that led to its approval, as well as the post-hoc analyses, follow-up studies and the current trials. PMID- 28344670 TI - Tobacco intervention research in low- and middle-income countries: lessons learned and future directions. PMID- 28344671 TI - Narrating Refuge. PMID- 28344672 TI - The Perceived Benefits of an Arts Project for Health and Wellbeing of Older Offenders. AB - The increasing ageing prison population is becoming a pressing issue throughout the criminal justice system. Alongside the rising population, are a host of health and wellbeing issues that contribute to older offenders needs whilst in prison. It has been recommended that meaningful activities can have positive effects on this population and therefore this paper uniquely reviews older offenders accounts of taking part in an arts based project, Good Vibrations, whilst imprisoned. The Good Vibrations project engages individuals in Gamelan music making with an end of project performance. This study used independent in depth interviews to capture the voices of older offenders who took part in an art based prison project. The interview data was analysed using thematic analysis, which highlighted themes that were consistent with other populations who have taken part in a Good Vibrations project, along with specific age relating issues of mobility, motivation, identity and wellbeing. PMID- 28344673 TI - Is Rumination a Risk and a Protective Factor? AB - High trait positive affect (PA) protects against depressive symptoms through cognitive responses such as rumination. However, how rumination in response to positive emotions (positive rumination) protects against depressive symptoms while rumination in response to negative emotions (brooding) predicts depressive symptoms is poorly understood. We hypothesized that (a) positive rumination and brooding represent a shared cognitive process of affect amplification on distinct affective content and (b) less brooding and greater positive rumination would distinctly mediate greater trait PA in predicting fewer depressive symptoms. Our prospective design among 321 adults first compared three confirmatory factor analysis models of the relationship between brooding and positive rumination. We then utilized structural equation modeling to examine whether brooding and positive rumination mediated the relationship between trait PA and depressive symptoms, controlling for baseline depressive symptoms, trait negative affect (NA), and the distinct effects of each mediator. Results supported a conceptualization of brooding and positive rumination as distinct but related constructs, represented as a common process of affect amplification to explain how rumination may amplify resilience or risk in predicting depressive symptoms (chi = 195.07, Deltachi = 8.78, p < .001, CFI = .91, RMSEA = .07). Furthermore, positive rumination and brooding were distinctly predicted by trait PA, suggesting that trait PA exerts distinct effects on protective and risk forms of rumination. Less brooding mediated the relationship between greater trait PA and fewer depressive symptoms (beta = -.04, p = .012), but positive rumination did not (beta = .02, p = .517). Rumination may represent a protective and a risk factor, which may better enable individuals who brood to redirect their rumination on positive content and thereby reduce their risk of depressive symptoms. PMID- 28344674 TI - Relationships Between Individual Endorsement of Aggressive Behaviors and Thoughts With Prejudice Relevant Correlates Among Adolescents. AB - The current study explored how individual differences in endorsement of aggressive behaviors and thoughts relate to individual levels of tolerance and prejudice toward immigrants and established prejudice correlates such as social dominance orientation (SDO) and ethnic out-groups ratings among adolescents. Participants (N = 141; Age M = 16.08, 68% girls) completed the Readiness for Interpersonal Aggression Inventory, the Tolerance and Prejudice Questionnaire, and measures of SDO and ethnic out-groups ratings. Results indicated that higher individual endorsement of aggression was related to higher prejudice and SDO and lower tolerance and ethnic out-groups ratings. Patterns of endorsement of aggression related to habitual and socially determined aggressive acts or stable needs to hurt others as a source of satisfaction were significantly correlated with prejudice. Conversely, the relationship between prejudice and endorsement of impulsive actions lacking of emotional control resulted was less marked. The results highlight how in the cognitive spectrum of prejudice, individual levels of endorsement of aggression may play a significant triggering role during adolescence. These findings may have implications for future studies and interventions aimed at reducing prejudice already in young ages. PMID- 28344675 TI - Believing Is Doing: Emotion Regulation Beliefs Are Associated With Emotion Regulation Behavioral Choices and Subjective Well-Being. AB - Research in emotion regulation has begun to examine various predictors of emotion regulation choices, including individual differences and contextual variables. However, scant attention has been paid to the extent to which people's beliefs about the specific consequences of emotion regulation strategies for the components of an emotional response and long-term well-being predict their behavioral regulatory choices and, in turn, their subjective well-being. Participants completed measures to assess their beliefs about the consequences of functional and dysfunctional strategies, behavioral choices of emotion regulation strategies in negative scenarios, and subjective well-being. The model that fit the data indicated partial mediation whereby beliefs were associated with approximately 9% of the variance in choices. Emotion regulation choices were related to subjective well-being, with an additional direct effect between beliefs and well-being. This suggests beliefs play a role in people's regulatory choices. Future research should explore how beliefs interact with individual differences and contextual variables to better understand why people regulate their emotions in different ways and, ultimately, to help individuals make healthy emotion regulation choices. PMID- 28344676 TI - Transmitting Sport Values: The Importance of Parental Involvement in Children's Sport Activity. AB - The transmission of positive values between parents and children is generally considered to be the hallmark of successful socialization. As this issue has been widely discussed but surprisingly little researched - especially with reference to core sport values - in this study we aimed to: 1) analyze adolescent athletes' acceptance of the sport values their parents want to transmit to them (i.e., parental socialization values) and 2) examine the relationship between parental involvement in children's sportive activity and adolescents' acceptance of their parents' socialization values. One hundred and seventy-two Italian adolescents (48.3% male, 51.7% female) who regularly practice team sports were asked to fill out a questionnaire which included the Youth Sport Values Questionnaire - 2 and the Parental Involvement in Sport Questionnaire. The dyadic correlations revealed that young athletes are in general willing to accept their parents' socialization values in regards to sport. Moreover, from the relative weight analysis (a relatively new data analysis strategy), it emerged that parental involvement characterized by praise and understanding is the most important predictor of adolescents' willingness to accept their parents' sport values. Implications of these results and further expansion of the study are discussed. PMID- 28344677 TI - The Mental Health Continuum-Short Form (MHC-SF) in the Argentinean Context: Confirmatory Factor Analysis and Measurement Invariance. AB - The present research aimed at studying the psychometric properties of the Mental Health Continuum-Short Form (MHC-SF; Keyes, 2005) in a sample of 1,300 Argentinean adults (50% males; 50% females). Their mean age was 40.28 years old (SD = 13.59). The MHC-SF is a 14 item test that assesses three components (i.e., emotional, social, and psychological) of well-being. Convergent and divergent evidence of construct validity was assessed by conducting confirmatory factor analysis, cross-validation, factorial invariance, and correlations with external criteria. Internal consistency was studied using Cronbach's alphas. Results indicated an adequate fit of a three-dimensional model. This structure was also confirmed, and was invariant throughout sex and age. The emotional well-being scores converged with life satisfaction and positive affect measures; the psychological well-being scale had a positive association with the presence of meaning in life; and the social well-being scores showed a positive and strong correlation with an external measure of well-being. Also, all scores were negatively associated with negative affect, search of meaning in life, and presence of depression symptoms. Internal consistency was .89 for the MHC-SF. Furthermore, the findings supported the two - continua model of mental health. PMID- 28344678 TI - Sentimentality and Nostalgia in Elderly People in Bulgaria and Greece - Cross Validity of the Questionnaire SNEP and Cross-Cultural Comparison. AB - Sentimentality and nostalgia are two similar psychological constructs, which play an important role in the emotional lives of elderly people who are usually focused on the past. There are two objectives of this study - making cross cultural comparison of sentimentality and nostalgia among Bulgarian and Greek elderly people using a questionnaire, and establishing the psychometric properties of this questionnaire among Greek elderly people. Sentimentality and nostalgia in elderly people in Bulgaria and Greece were studied by means of Sentimentality and Nostalgia in Elderly People questionnaire (SNEP), created by Gergov and Stoyanova (2013). For the Greek version, one factor structure without sub-scales is proposed, while for the Bulgarian version of SNEP the factor structure had four sub-scales, besides the total score. Together with some similarities (medium level of nostalgia and sentimentality being widespread), the elderly people in Bulgaria and Greece differed cross-culturally in their sentimentality and nostalgia related to the past in direction of more increased sentimentality and nostalgia in the Bulgarian sample. Some gender and age differences revealed that the oldest male Bulgarians were the most sentimental. The psychometric properties of this questionnaire were examined for the first time in a Greek sample of elders and a trend was found for stability of sentimentality and nostalgia in elderly people that could be studied further in longitudinal studies. PMID- 28344679 TI - The Effects of Test Trial and Processing Level on Immediate and Delayed Retention. AB - The purpose of the present study was to investigate the effects of test trial and processing level on immediate and delayed retention. A 2 * 2 * 2 mixed ANOVAs was used with two between-subject factors of test trial (single test, repeated test) and processing level (shallow, deep), and one within-subject factor of final recall (immediate, delayed). Seventy-six college students were randomly assigned first to the single test (studied the stimulus words three times and took one free-recall test) and the repeated test trials (studied the stimulus words once and took three consecutive free-recall tests), and then to the shallow processing level (asked whether each stimulus word was presented in capital letter or in small letter) and the deep processing level (whether each stimulus word belonged to a particular category) to study forty stimulus words. The immediate test was administered five minutes after the trials, whereas the delayed test was administered one week later. Results showed that single test trial recalled more words than repeated test trial in immediate final free-recall test, participants in deep processing performed better than those in shallow processing in both immediate and delayed retention. However, the dominance of single test trial and deep processing did not happen in delayed retention. Additional study trials did not further enhance the delayed retention of words encoded in deep processing, but did enhance the delayed retention of words encoded in shallow processing. PMID- 28344680 TI - Adolescents' and Young Adults' Naive Understandings of the Economic Crisis. AB - Over the last decade, Financial Literacy (FL) and interventions aimed at improving it, that is Financial Education (FE), have been the focus of increased attention from economists, governments, and international organizations such as the world Bank and OECD, but much less by scholars in the fields of Learning and Instruction. We examined open-ended written answers on the causes of the economic crisis that started in 2007-2008, as given by 381 Italian secondary school and university students, and 268 Swiss Italian-speaking secondary school students. Most Italian students mentioned internal political causes (i.e., corrupt politicians or inefficiency of the government), whereas Swiss students mentioned banks more often. International factors were rarely mentioned by either group, and explanations were generally very poor, listing a few causes without making connections between them. These findings indicate the need for economics education aimed at making people more knowledgeable of the workings of the economic system and the effects of financial systems on the real economy. PMID- 28344681 TI - Exploring the Relationship Between Callous-Unemotional Traits, Empathy Processing and Affective Valence in a General Population. AB - Callous-Unemotional (CU) traits are personality attributes, which are associated with a deficit of affective valence and reduced empathetic responding in high CU trait clinical populations. The aim of the research was to explore whether a similar pattern of empathy and emotional responding correlated with CU trait manifestation in the general population. A total of 124 participants completed the Inventory of Callous-Unemotional Traits, the Interpersonal Reactivity Index, the Empathy Quotient, an expression recognition task, and a measure of affective response. Negative correlations with CU trait score were observed for both cognitive empathy and emotional empathy. Accuracy in the identification of fearful expressions presented a negative association with CU trait score. Self rating of affective valence, when viewing both positive and negative images, indicated a universal reduction in emotional response associated with increased CU trait manifestation. PMID- 28344682 TI - Dispositional Mindfulness and Memory Problems: The Role of Perceived Stress and Sleep Quality. AB - There is a growing body of evidence exploring the beneficial effects of mindfulness on stress, sleep quality, and memory, though the mechanisms involved are less certain. The present study explored the roles of perceived stress and sleep quality as potential mediators between dispositional mindfulness and subjective memory problems. Data were from a Boston area subsample of the Midlife in the United States study (MIDUS-II) assessed in 2004-2006, and again approximately one year later (N=299). As expected, higher dispositional mindfulness was associated with lower perceived stress and better sleep quality. There was no direct association found between mindfulness and subjective memory problems, however, there was a significant indirect effect through perceived stress, although not with sleep quality. The present findings suggest that perceived stress may play a mediating role between dispositional mindfulness and subjective memory problems, in that those with higher mindfulness generally report experiencing less stress than those with lower mindfulness, which may be protective of memory problems in everyday life. PMID- 28344683 TI - Dispositional Mindfulness Predicts Adaptive Affective Responses to Health Messages and Increased Exercise Motivation. AB - Feelings can shape how people respond to persuasive messages. In health communication, adaptive affective responses to potentially threating messages constitute one key to intervention success. The current study tested dispositional mindfulness, characterized by awareness of the present moment, as a predictor of adaptive affective responses to potentially threatening health messages and desirable subsequent health outcomes. Both general and discrete negative affective states (i.e., shame) were examined in relation to mindfulness and intervention success. Individuals (n=67) who reported less than 195 weekly minutes of exercise were recruited. At baseline, participants' dispositional mindfulness and exercise outcomes were assessed, including self-reported exercise motivation and physical activity. A week later, all participants were presented with potentially threatening and self-relevant health messages encouraging physical activity and discouraging sedentary lifestyle, and their subsequent affective response and exercise motivation were assessed. Approximately one month later, changes in exercise motivation and physical activity were assessed again. In addition, participants' level of daily physical activity was monitored by a wrist worn accelerometer throughout the entire duration of the study. Higher dispositional mindfulness predicted greater increases in exercise motivation one month after the intervention. Importantly, this effect was fully mediated by lower negative affect and shame specifically, in response to potentially threatening health messages among highly mindful individuals. Baseline mindfulness was also associated with increased self-reported vigorous activity, but not with daily physical activity as assessed by accelerometers. These findings suggest potential benefits of considering mindfulness as an active individual difference variable in theories of affective processing and health communication. PMID- 28344684 TI - Splenic Vein Thrombosis as a Rare Complication of Disseminated Tuberculosis - Imaging Diagnosis and Case Report. AB - BACKGROUND: Venous thromboembolism is a known but rare complication associated with Mycobacterium tuberculosis infection. The reported incidence of venous thromboembolism is 1.5-3.4% of infected patients, and it occurs due to a hypercoagulable state induced by the associated inflammation. CASE REPORT: A young woman with pulmonary tuberculosis was found to have disseminated tuberculosis and a clinically unsuspected partial thrombus in the splenic vein on imaging. Ultrasound demonstrated hepato-splenomegaly with multiple granulomas as well as ascites and a left-sided pleural effusion. An increased calibre of the splenic vein with a hyperechogenicity within it raised the suspicion of a thrombus, which was confirmed on a contrast-enhanced CT examination. CECT of the abdomen also showed a small peripheral splenic infarct, while CECT of the chest revealed bilateral miliary lesions in the lungs along with necrotic mediastinal lymphadenopathy. The final imaging diagnosis was disseminated tuberculosis complicated by splenic vein thrombosis. A timely institution of anti-coagulant and anti-tubercular treatment led to a complete resolution of the splenic vein thrombosis. CONCLUSIONS: Contrast-enhanced CT serves as a useful imaging tool for the detection of venous thrombosis and for the estimation of a complete burden of the disease. This condition should be kept in mind by both clinicians and radiologists and looked for in order to prevent life-threatening complications. PMID- 28344685 TI - Focal Biliary System Obstruction and Atypical Liver Mass: Intrabiliary Ruptured Cyst Hydatid Case Report. AB - BACKGROUND: Hydatid disease can involve any part of the body, but the liver is the most frequently affected organ. Intrabiliary rupture is one of the most serious complications of a hepatic hydatid cyst. Radiological findings, especially magnetic resonance imaging and magnetic resonance cholangiopancreatography (MRI/MRCP), are helpful in the diagnosis of hydatid disease. CASE REPORT: We present a 48-year-old female patient with complaints of abdominal pain and jaundice. Radiological examination showed a heterogeneous lesion that contained cystic-solid components and millimetric calcifications in the liver. Adjacent intrahepatic bile ducts were dilated. CONCLUSIONS: In geographical areas endemic for hydatid disease, cyst rapture into the bile ducts should be included in the differential diagnosis even in seronegative cases, although it is not typical for hydatid cyst to be found as a mass lesion in the liver on US in patients with right upper quadrant pain and jaundice.Detailed imaging by MRI/MRCP should be done. PMID- 28344686 TI - Comparison of Image Quality, Diagnostic Accuracy and Radiation Dose Between Flash Model and Retrospective ECG-Triggered Protocols in Dual Source Computed Tomography (DSCT) in Congenital Heart Diseases. AB - BACKGROUND: Dual source computed tomography (DSCT) plays an important role in the diagnosis of congenital heart diseases (CHD). However, the issue of radiation related side effects constitutes a wide public concern. The aim of the study was to explore the differences in diagnostic accuracy, radiation dose and image quality between a prospectively ECG - triggered high - pitch spiral acquisition (flash model) and a retrospective ECG-gated protocol of DSCT used for the detection of CHD. MATERIAL/METHODS: The study included 58 patients with CHD who underwent a DSCT examination, including two groups of 29 patients in each protocol. Then, both subjective and objective image quality, diagnostic accuracy and radiation dose were compared between the two protocols. RESULTS: The image quality and the total as well as partial diagnostic accuracy did not differ significantly between the protocols. The radiation dose in the flash model was obviously lower than that in the retrospective model (P<0.05). CONCLUSIONS: Compared to the retrospective protocol, the flash model can significantly reduce the dose of radiation, while maintaining both diagnostic accuracy and image quality. PMID- 28344688 TI - No one is talking about the elephant in the room. PMID- 28344687 TI - Disseminated Pancreatic Neuroendocrine Neoplasm (NEN) with an Uncommon Localisation in the Central Nervous System. A Case Report. AB - BACKGROUND: Neuroendocrine neoplasms (NEN) are rare neoplasms that originate from neuroendocrine cells and are characterized by the potential of hormonal activity. Approximately 70% of these tumours are located in the gastrointestinal system (GI), followed by the bronchi, endocrine glands-like C cells of the thyroid (medullary carcinoma), the parasympathetic and sympathetic system (paragangliomas, pheochromocytoma) and other very rare locations. The prevalence of cerebral metastases in neuroendocrine tumours is estimated by various authors to be approximately 1.5-5%. When the primary tumour is located in the pancreas, it is associated with a risk of cerebral metastases lower than 2%. CASE REPORT: We describe a patient with a disseminated pancreatic NEN that presented with an isolated lesion in the brain. We gathered the important data via medical history,, observation, analysis of medical records, imaging and others diagnostic tests. Despite the fairly rare prevalence of cerebral metastases in NENs, a neurological work-up should be performed. This should include neuroimaging of the brain, preferably with MR, together with the somatostatin receptor scintigraphy (SRS), in each clinically suspicious case. A histopathological examination of the CNS tumour can confirm a dedifferentiation of NEN in the direction of a neuroendocrine carcinoma (NEC - neuroednocrine carcinoma) with a poor prognosis. CONCLUSIONS: Cerebral metastases are diagnosed in 1.5-5% of patients with a neuroendocrine neoplasm. In each case suggestive of a dissemination into the central nervous system, MRI of the brain should be performed. PMID- 28344689 TI - Exploring social media and admissions decision-making - friends or foes? AB - BACKGROUND: Despite the ever-increasing use of social media (e.g., Facebook, Twitter) little is known about its use in medical school admissions. This qualitative study explores whether and how social media (SM) is used in undergraduate admissions in Canada, and the attitudes of admissions personnel towards such use. METHODS: Phone interviews were conducted with admissions deans and nominated admissions personnel. A qualitative descriptive analysis was performed using iterative coding and comparing, and grouping data into themes. RESULTS: Personnel from 15 of 17 Canadian medical schools participated. A sizeable proportion had, at some point, examined social media (SM) profiles to acquire information on applicants. Participants did not report using it explicitly to screen all applicants (primary use); however, several did admit to looking at SM to follow up on preliminary indications of misbehaviour (secondary use). Participants articulated concerns, such as validity and equity, about using SM in admissions. Despite no schools having existing policy, participants expressed openness to future use. CONCLUSIONS: While some of the 15 schools had used SM to acquire information on applicants, criteria for formulating judgments were obscure, and participants expressed significant apprehension, based on concerns for fairness and validity. Findings suggest participant ambivalence and ongoing risks associated with "hidden" selection practices. PMID- 28344690 TI - Attitudes of Canadian psychiatry residents if mentally ill: awareness, barriers to disclosure, and help-seeking preferences. AB - BACKGROUND: The medical culture is defined by mental illness stigma, non disclosure, and avoidance of professional treatment. Little research has explored attitudes and help-seeking behaviors of psychiatry trainees if they were to become mentally ill. METHOD: Psychiatry residents (n = 106) from training centres across Ontario, Canada completed a postal survey on their attitudes, barriers to disclosure, and help-seeking preferences in the context of hypothetically becoming mentally ill. RESULTS: Thirty-three percent of respondents reported personal history of mental illness and the frequency of mental illness by year of training did not significantly differ. The most popular first contact for disclosure of mental illness was family and friends (n = 61, 57.5%). Frequent barriers to disclosure included career implications (n = 39, 36.8%), stigma (n = 11, 10.4%), and professional standing (n = 15, 14.2%). Personal history of mental illness was the only factor associated with in-patient treatment choice, with those with history opting for more formal advice versus informal advice. CONCLUSIONS: At the level of residency training, psychiatrists are reporting barriers to disclosure and help-seeking if they were to experience mental illness. A majority of psychiatry residents would only disclose to informal supports. Those with a history of mental illness would prefer formal treatment services over informal services. PMID- 28344691 TI - Physician recruitment and retention in New Brunswick: a medical student perspective. AB - BACKGROUND: Physician recruitment and retention is a priority for many Canadian provinces. Each province is unique in terms of recruitment strategies and packages offered; however, little is known about how medical students evaluate these programs. The purpose of the current study was to determine which factors matter most to New Brunswick (NB) medical students when considering their location of future practice. METHOD: A survey of NB medical students was conducted. Descriptive statistics were produced and a linear regression model was developed to study factors predictive of a student's expressed willingness to practice in NB. RESULTS: 158 medical students completed the online survey, which is a response rate of 55%. Job availability and spouse's ability to work in the province were ranked as the top factors in deciding where to practice. In the final regression model, factors predictive of an expressed desire to practice in NB include being female, living in NB prior to medical school, attending medical school at Universite de Sherbrooke, participation in the NB Preceptorship program, and a desire to practice family medicine. CONCLUSIONS: This study provides insight into what medical students consider when deciding where to practice. This research may be used to inform physician recruitment efforts and guide future research into medical education and policy. PMID- 28344692 TI - A landscape analysis of leadership training in postgraduate medical education training programs at the University of Ottawa. AB - BACKGROUND: There is growing recognition of the importance of physician leadership in healthcare. At the same time, becoming an effective leader requires significant training. While educational opportunities for practicing physicians exist to develop their leadership skills, there is a paucity of leadership opportunities for post graduate trainees. In response to this gap, both the Royal College of Physicians and Surgeons of Canada and the Association of Faculties of Medicine of Canada have recommended that leadership training be considered a focus in Post Graduate Medical Education (PGME). However, post-graduate leadership curricula and opportunities in PGME training programs in Canada are not well described. The goal of this study was to determine the motivation for PGME leadership training, the opportunities available, and educational barriers experienced by PGME programs at the University of Ottawa. METHODS: An electronic survey was distributed to all 70 PGME Program Directors (PDs) at the University of Ottawa. Two PDs were selected, based on strong leadership programs, for individual interviews. RESULTS: The survey response rate was 55.7%. Seventy-seven percent of responding PDs reported resident participation in leadership training as being "important," while only 37.8% of programs incorporated assessment of resident leadership knowledge and/or skills into their PGME program. Similarly, only 29.7% of responding residency programs offered chief resident leadership training. CONCLUSIONS: While there is strong recognition of the importance of training future physician leaders, the nature and design of PGME leadership training is highly variable. These data can be used to potentially inform future PGME leadership training curricula. PMID- 28344693 TI - Point-of-care ultrasound as a competency for general internists: a survey of internal medicine training programs in Canada. AB - BACKGROUND: Point-of-care ultrasound (POCUS) is increasingly used on General Internal Medicine (GIM) inpatient services, creating a need for defined competencies and formalized training. We evaluated the extent of training in POCUS and the clinical use of POCUS among Canadian GIM residency programs. METHOD: Internal Medicine trainees and GIM Faculty at the University of Toronto were surveyed on their clinical use of POCUS and the extent of their training. We separately surveyed Canadian IM Program Directors and Division Directors on the extent of POCUS training in their programs, barriers in the implementation of POCUS curricula, and recommendations for POCUS competencies in IM. RESULTS: A majority of IM trainees (90/118, 76%) and GIM Faculty (15/29, 52%) used POCUS clinically. However, the vast majority of resident (111/117, 95%) and GIM Faculty (18/28, 64%) had received limited training. Of the Program Leaders surveyed, half (9/17, 53%) reported POCUS clinical use by their trainees; however only one quarter (4/16, 25%) reported offering formal curricula. Most respondents agreed that POCUS training should be incorporated into IM residency curricula, specifically for procedural guidance. CONCLUSIONS: A considerable discrepancy exists between the clinical use of POCUS and the extent of formal training among Canadian IM residents and GIM Faculty. We propose that formalized POCUS training should be incorporated into IM residency programs, GIM fellowships, and Faculty development sessions, and identify POCUS skills that could be incorporated into future IM curricula. PMID- 28344694 TI - Addressing gaps in physician knowledge regarding transgender health and healthcare through medical education. AB - BACKGROUND: Transgender people (those people whose sex at birth does not "match" their felt gender identity) are a priority group for healthcare as they experience high rates of discrimination and related illnesses. Despite this, there is a trend of poor healthcare access for trans people due, in large part, to the denial of care on the part of physicians. A small body of literature is beginning to suggest that this denial of care may be due to a lack of physician knowledge as well as, in some cases, to transphobia. There is a dearth of research in Canada, however, exploring whether and/or how knowledge gaps create barriers to quality care, and whether medical education can attend to these gaps while and through addressing gender normativity. METHODS: To fill these gaps in the literature, we undertook a qualitative study with 30 trans identified people and 11 physicians (N=41) in Winnipeg, Manitoba. Methods included semi-structured individual interviews and focus groups. Data were transcribed and analyzed with NVivo qualitative data software using iterative methods. RESULTS: An overwhelming finding of this study was a lack of physician knowledge, as reported both by trans people and by physicians, that resulted in a denial of trans-specific care and also impacted general care. Transphobia was also identified as a barrier to quality care by both trans people and physicians. Physicians were open to learning more about trans health and healthcare. CONCLUSIONS: The findings suggest a pressing need for better medical education that exposes students to basic skills in trans health so that they can become competent in providing care to trans people. This learning must take place alongside anti-transphobia education. Based on these findings, we suggest key recommendations at the close of the paper for providing quality trans health curriculum in medical education. PMID- 28344696 TI - Systems 1 and 2 thinking processes and cognitive reflection testing in medical students. AB - BACKGROUND: Diagnostic decision-making is made through a combination of Systems 1 (intuition or pattern-recognition) and Systems 2 (analytic) thinking. The purpose of this study was to use the Cognitive Reflection Test (CRT) to evaluate and compare the level of Systems 1 and 2 thinking among medical students in pre clinical and clinical programs. METHODS: The CRT is a three-question test designed to measure the ability of respondents to activate metacognitive processes and switch to System 2 (analytic) thinking where System 1 (intuitive) thinking would lead them astray. Each CRT question has a correct analytical (System 2) answer and an incorrect intuitive (System 1) answer. A group of medical students in Years 2 & 3 (pre-clinical) and Years 4 (in clinical practice) of a 5-year medical degree were studied. RESULTS: Ten percent (13/128) of students had the intuitive answers to the three questions (suggesting they generally relied on System 1 thinking) while almost half (44%) answered all three correctly (indicating full analytical, System 2 thinking). Only 3-13% had incorrect answers (i.e. that were neither the analytical nor the intuitive responses). Non-native English speaking students (n = 11) had a lower mean number of correct answers compared to native English speakers (n = 117: 1.0 s 2.12 respectfully: p < 0.01). As students progressed through questions 1 to 3, the percentage of correct System 2 answers increased and the percentage of intuitive answers decreased in both the pre-clinical and clinical students. CONCLUSIONS: Up to half of the medical students demonstrated full or partial reliance on System 1 (intuitive) thinking in response to these analytical questions. While their CRT performance has no claims to make as to their future expertise as clinicians, the test may be used in helping students to understand the importance of awareness and regulation of their thinking processes in clinical practice. PMID- 28344695 TI - Are we adequately preparing the next generation of physicians to prescribe exercise as prevention and treatment? Residents express the desire for more training in exercise prescription. AB - BACKGROUND: Physical activity (PA) is a key intervention for chronic disease, yet few physicians provide exercise prescription (EP). EP is an important component in larger strategies of reducing non-communicable disease (NCD). Our objective was to assess Family Medicine Residents (FMR) knowledge, competence, and perspectives of EP to help inform future curriculum development. METHODS: A 49 item cross-sectional survey was administered to 396 University of British Columbia FMR. Residents' EP knowledge, competence, attitudes/beliefs, current practices, personal physical activity levels, and perspectives of training were assessed using, primarily, a 7-point Likert scale. RESULTS: The response rate was 80.6% (319/396). After eliminating 25 that failed to meet the inclusion criteria, 294 were included in the final analysis. The majority 95.6% of FMR reported EP as important in their future practice, despite having low knowledge of the Canadian PA Guidelines (mean score 1.77/4), low self-reported competence prescribing exercise as prevention (mean score 13.35/21), and rating themselves "somewhat incompetent" prescribing exercise to patients with chronic disease (mean score 11.26/21). FMR believe PA is integral to their patients' health (98.0%), sedentary behaviour is harmful (97.9%), and feel a responsibility to discuss PA with patients (99.7%). Few FMR (14.9%) perceived their training in EP as adequate and 91.0% desire more. CONCLUSIONS: FMR report EP is important, yet do not perceive they are sufficiently prepared to provide EP. In future curricular development, medical educators should consider residents' low knowledge, competence, perceived program support, and their expressed desire for more training in exercise prescription. PMID- 28344697 TI - Learning-by-Concordance (LbC): introducing undergraduate students to the complexity and uncertainty of clinical practice. AB - BACKGROUND: A current challenge in medical education is the steep exposure to the complexity and uncertainty of clinical practice in early clerkship. The gap between pre-clinical courses and the reality of clinical decision-making can be overwhelming for undergraduate students. The Learning-by-Concordance (LbC) approach aims to bridge this gap by embedding complexity and uncertainty by relying on real-life situations and exposure to expert reasoning processes to support learning. LbC provides three forms of support: 1) expert responses that students compare with their own, 2) expert explanations and 3) recognized scholars' key-messages. METHOD: Three different LbC inspired learning tools were used by 900 undergraduate medical students in three courses: Concordance-of Reasoning in a 1st-year hematology course; Concordance-of-Perception in a 2nd year pulmonary physio-pathology course, and; Concordance-of-Professional-Judgment with 3rd-year clerkship students. Thematic analysis was conducted on freely volunteered qualitative comments provided by 404 students. RESULTS: Absence of a right answer was challenging for 1st year concordance-of-reasoning group; the 2nd year visual concordance group found radiology images initially difficult and unnerving and the 3rd year concordance-of-judgment group recognized the importance of divergent expert opinion. CONCLUSIONS: Expert panel answers and explanations constitute an example of "cognitive apprenticeship" that could contribute to the development of appropriate professional reasoning processes. PMID- 28344698 TI - Supporting clinician educators to achieve "work-work balance". AB - Clinician Educators (CE) have numerous responsibilities in different professional domains, including clinical, education, research, and administration. Many CEs face tensions trying to manage these often competing professional responsibilities and achieve "work-work balance." Rich discussions of techniques for work-work balance amongst CEs at a medical education conference inspired the authors to gather, analyze, and summarize these techniques to share with others. In this paper we present the CE's "Four Ps"; these are practice points that support both the aspiring and established CE to help improve their performance and productivity as CEs, and allow them to approach work-work balance. PMID- 28344700 TI - Entitlement and me: problems in Canadian medical education. PMID- 28344701 TI - Entitlement in medical education: an ongoing discourse. PMID- 28344699 TI - Curricular initiatives that enhance student knowledge and perceptions of sexual and gender minority groups: a critical interpretive synthesis. AB - BACKGROUND: There is no accepted best practice for optimizing tertiary student knowledge, perceptions, and skills to care for sexual and gender diverse groups. The objective of this research was to synthesize the relevant literature regarding effective curricular initiatives designed to enhance tertiary level student knowledge, perceptions, and skills to care for sexual and gender diverse populations. METHODS: A modified Critical Interpretive Synthesis using a systematic search strategy was conducted in 2015. This method was chosen to synthesize the relevant qualitative and quantitative literature as it allows for the depth and breadth of information to be captured and new constructs to be illuminated. Databases searched include AMED, CINAHL EBM Reviews, ERIC, Ovid MEDLINE, Ovid Nursing Database, PsychInfo, and Google Scholar. RESULTS: Thirty one articles were included in this review. Curricular initiatives ranging from discrete to multimodal approaches have been implemented. Successful initiatives included discrete sessions with time for processing, and multi-modal strategies. Multi-modal approaches that encouraged awareness of one's lens and privilege in conjunction with facilitated communication seemed the most effective. CONCLUSIONS: The literature is limited to the evaluation of explicit curricula. The wider cultural competence literature offers further insight by highlighting the importance of broad and embedded forces including social influences, the institutional climate, and the implicit, or hidden, curriculum. A combined interpretation of the complementary cultural competence and sexual and gender diversity literature provides a novel understanding of the optimal content and context for the delivery of a successful curricular initiative. PMID- 28344702 TI - Health professions education and globalization: a call for reflexivity. PMID- 28344703 TI - Key challenges for implementing a Canadian-based objective structured clinical examination (OSCE) in a Middle Eastern context. AB - Globalization of medical education is occurring at a rapid pace and many regions of the world are adapting curricula, teaching methods, and assessment tools from established programs. In the Middle East, the use of Objective Structured Clinical Examinations (OSCEs) is rare. The College of Pharmacy at Qatar University recently partnered with the University of Toronto and the Supreme Council of Health in Qatar to adapt policies and procedures of a Canadian-based OSCE as an exit-from-degree assessment for pharmacy students in Qatar. Despite many cultural and contextual barriers, the OSCE was implemented successfully and is now an integrated component of the pharmacy curriculum. This paper aims to provide insight into the adoption and implementation process by identifying four major cultural and contextual challenges associated with OSCEs: assessment tools, standardized actors, assessor calibration, and standard setting. Proposed solutions to the challenges are also given. Findings are relevant to international programs attempting to adapt OSCEs into their contexts, as well as Canadian programs facing increasing rates of cultural diversity within student and assessor populations. PMID- 28344704 TI - Decolonization in health professions education: reflections on teaching through a transgressive pedagogy. AB - BACKGROUND: Canadian health educators travel to the global south to provide expertise in health education. Considering the history of relations between the north and south, educators and healthcare providers from Canada should critically examine their practices and consider non-colonizing ways to relate to their Southern colleagues. METHODS: Using her experience as a teacher with the Toronto Addis Ababa Academic Collaboration in Nursing, the author explored issues of identity and representation as a registered nurse and PhD candidate teaching in Ethiopia. Transgressive pedagogy was used to question how her personal, professional, and institutional identities impacted her role as a teacher. RESULTS: Thinking and acting transgressively can decrease colonizing relations by acknowledging boundaries and limitations within present ideas of teaching and global health work and help moving beyond them. The act of being transgressive begins with a deeper understanding and consciousness of who we are as people and as educators. CONCLUSION: Working responsibly in the global south means being critical about historical relations and transparent about one's own history and desires for teaching abroad. PMID- 28344705 TI - The influence of globalization on medical regulation: a descriptive analysis of international medical graduates registered through alternative licensure routes in Ontario. AB - The increasing globalization of the medical profession has influenced health policy, health human resource planning, and medical regulation in Canada. Since the early 2000s, numerous policy initiatives have been created to facilitate the entry of international medical graduates (IMGs) into the Canadian workforce. In Ontario, the College of Physicians and Surgeons of Ontario (CPSO) developed alternative licensure routes to increase the ability of qualified IMGs to obtain licenses to practice. The current study provides demographic and descriptive information about the IMGs registered through the CPSO's alternative licensure routes between 2000 and 2012. An analysis of the characteristics and career trajectories of all IMGs practicing in the province sheds light on broader globalization trends and raises questions about the future of health human resource planning in Canada. As the medical profession becomes increasingly globalized, health policy and regulation will continue to be influenced by trends in international migration, concerns about global health equity, and the shifting demographics of the Canadian physician workforce. Implications for future policy development in the complex landscape of medical education and practice are discussed. PMID- 28344706 TI - The Voluntariat: A Frieirean framework to understand the nature of undergraduate international (medical) experiences. AB - Despite literature documenting limited and asymmetrical benefits along with ethical issues, short-term international volunteering is increasingly popular among North American university students as a perceived advantage when applying to professional healthcare schools or the job market. Academic institutions are also encouraging students to pursue international experiences in order to cultivate values as global citizens. These experiences are most typically limited to economically privileged students. Furthermore, international activities in developing countries often lack a pedagogy of social justice and may confirm a simplistic understanding of development. Brazilian educator Paulo Freire's "liberation pedagogy" provides a framework for understanding the limitations of international volunteering, whereby the presence of privileged volunteers implementing Western models of development may hinder aspects of local movements. Regardless, university students face intense competition in accessing opportunities, such as medical school, and pay large sums to participate in volunteering to strengthen their academic credentials. We propose that these students form "the voluntariat." They simultaneously play two roles by, first, contributing to the conditions that oppress the very communities in which they volunteer and, second, by playing a role as objects of oppression by the liberal institutions of learning and employment to which they are attempting to gain access. PMID- 28344707 TI - Changing perspectives: attempting to de-colonize the gaze of a Canadian medical student. PMID- 28344708 TI - Support infrastructure available to Canadian residents completing post-graduate global health electives: current state and future directions. AB - BACKGROUND: Global health electives offer medical trainees the opportunity to broaden their clinical horizons. Canadian universities have been encouraged by regulatory bodies to offer institutional support to medical students going abroad; however, the extent to which such support is available to residents has not been extensively studied. METHODS: We conducted a survey study of Canadian universities examining the institutional support available to post-graduate medical trainees before, during, and after global health electives. RESULTS: Responses were received from 8 of 17 (47%) Canadian institutions. Results show that trainees are being sent to diverse locations around the world with more support than recommended by post-graduate regulatory bodies. However, we found that the content of the support infrastructure varies amongst universities and that certain components-pre-departure training, best practices, risk management, and post-return debriefing-could be more thoroughly addressed. CONCLUSION: Canadian universities are encouraged to continue to send their trainees on global health electives. To address the gaps in infrastructure reported in this study, the authors suggest the development of comprehensive standardized guidelines by post-graduate regulatory/advocacy bodies to better ensure patient and participant safety. We also encourage the centralization of infrastructure management to the universities' global health departments to aid in resource management. PMID- 28344709 TI - Capacity building in Nepal. PMID- 28344710 TI - Global health education produces healers. PMID- 28344711 TI - Systems thinking and structural competence in and for medical education. PMID- 28344712 TI - Canadian Medical Education Journal Survey evaluations of University of British Columbia residents' education and attitudes regarding palliative care and physician assisted death. AB - BACKGROUND: Little prior research has been conducted regarding resident physicians' opinions on the subject of Physician Assisted Death (PAD), despite past surveys ascertaining the attitudes of practicing physicians towards PAD in Canada. We solicited British Columbia residents' opinions on the amount of education they receive about palliative care and physician assisted death, and their attitudes towards the implementation of PAD. METHODS: We conducted a cross sectional, anonymous online survey with the resident physicians of British Columbia, Canada. Questions included: close-ended questions, graded Likert scale questions, and comments. RESULTS: Among the respondents (n=299, response rate 24%), 44% received >=5 hours of education in palliative care, 40% received between zero and four hours of education, and 16% reported zero hours. Of all respondents, 75% had received no education about PAD and the majority agreed that there should be more education about palliative care (74%) and PAD (85%). Only 35% of residents felt their program provided them with enough education to make an informed decision about PAD, yet 59% would provide a consenting patient with PAD. Half of the respondents believed PAD would ultimately be provided by palliative care physicians. INTERPRETATION: Residents desire further education about palliative care and PAD. Training programs should consider conducting a thorough needs assessment and implementing structured education to meet this need. PMID- 28344713 TI - Exploring the experience of residents during the first six months of family medicine residency training. AB - BACKGROUND: The shift from undergraduate to postgraduate education signals a new phase in a doctor's training. This study explored the resident's perspective of how the transition from undergraduate to postgraduate (PGME) training is experienced in a Family Medicine program as they first meet the reality of feeling and having the responsibility as a doctor. METHODS: Qualitative methods explored resident experiences using interpretative inquiry through monthly, individual in-depth interviews with five incoming residents during the first six months of training. Focus groups were also held with residents at various stages of training to gather their reflection about their experience of the first six months. Residents were asked to describe their initial concerns, changes that occurred and the influences they attributed to those changes. RESULTS: Residents do not begin a Family Medicine PGME program knowing what it means to be a Family Physician, but learn what it means to fulfill this role. This process involves adjusting to significant shifts in responsibility in the areas of Knowledge, Practice Management, and Relationships as they become more responsible for care outcomes. CONCLUSION: This study illuminated the resident perspective of how the transition is experienced. This will assist medical educators to better understand the early training experiences of residents, how these experiences contribute to consolidating their new professional identity, and how to better align teaching strategies with resident learning needs. PMID- 28344714 TI - Moral distress and burnout in internal medicine residents. AB - BACKGROUND: Residents frequently encounter situations in their workplace that may induce moral distress or burnout. The objective of this study was to measure overall and rotation-specific moral distress and burnout in medical residents, and the relationship between demographics and moral distress and burnout. METHODS: The revised Moral Distress Scale and the Maslach Burnout Inventory (Human Service version) were administered to Internal Medicine residents in the 2013-2014 academic year at the University of British Columbia. RESULTS: Of the 88 residents, 45 completed the surveys. Participants (mean age 30+/-3; 46% male) reported a median moral distress score (interquartile range) of 77 (50-96). Twenty-six percent of residents had considered quitting because of moral distress, 21% had a high level of burnout, and only 5% had a low level of burnout. Moral distress scores were highest during Intensive Care Unit (ICU) and Clinical Teaching Unit (CTU) rotations, and lowest during elective rotations (p<0.0001). Women reported higher emotional exhaustion. Moral distress was associated with depersonalization (p=0.01), and both moral distress and burnout were associated with intention to leave the job. CONCLUSION: Internal Medicine residents report moral distress that is greatest during ICU and CTU rotations, and is associated with burnout and intention to leave the job. PMID- 28344715 TI - The emotional intelligence of pediatric residents - a descriptive cross-sectional study. AB - BACKGROUND: Emotional Intelligence (EI) is a type of social intelligence. Excellent scores are achieved by displaying high levels of empathy in interpersonal relationships, strong skills in managing stressful situations as well as other personal competencies. Many of the social competencies that EI describes may have a direct impact on patient care. The objective of this study was to describe EI of pediatric residents and to identify if there are EI skills that should be selected for targeted intervention. METHODS: This was a cross sectional study administering the EQ-i 2.0(c) psychometric instrument to pediatric residents at the University of Alberta. RESULTS: Thirty-five residents completed the EQ-i 2.0(c) (100% response rate). Their overall EI score was not significantly different than a normative group of college-educated professionals. Residents had relative strengths in the subcategories of Emotional expression, Interpersonal Relationships, Empathy, and Impulse Control (all p<0.05). Areas of relative weakness were in the subcategories of Stress Tolerance, Assertiveness, Independence, and Problem Solving (all p<0.05). CONCLUSION: The EI of pediatric residents is consistent with that of other professionals. Educational interventions may be useful in the areas of weakness to enhance the physician patient relationship. PMID- 28344716 TI - An examination of entrance criteria for international medical graduates (IMGs) into Canadian psychiatry residency programs. AB - BACKGROUND: Although international medical graduates (IMGs) are essential in health care service delivery, a gap exists in the literature about how IMGs are selected into psychiatry residency programs in Canada. The purpose of this study was to identify the relative weight or importance that Canadian program directors (PDs) of psychiatry place on certain selection criteria when matching IMGs into residency programs. METHODS: We electronically distributed a web-based questionnaire to 16 university residency program directors of psychiatry in Canada. Program Directors were asked to rate the importance of 43 selection criteria using 5-point Likert Scales. Criteria were grouped into six domains: academic criteria, extracurricular activities, supporting information, behavioural issues of concern, medical school country, and other education. Mean total values for each set of criteria were calculated and used to create rank orders within each domain. RESULTS: Eight out of 16 program directors responded. Our analysis indicated that academics and behavioral issues of concern were the most important selection criteria. CONCLUSION: Our findings provide valuable insight about the perspectives of Program Directors toward IMGs who apply for psychiatry residency programs in Canada. Further studies are needed to better understand which criteria contribute to IMGs' performances as psychiatric residents. PMID- 28344717 TI - A digital peer-to-peer learning platform for clinical skills development. AB - BACKGROUND: Due to constraints in time and resources, medical curricula may not provide adequate opportunities for pre-clerkship students to practice clinical skills. To address this, medical students at the University of Alberta developed a digital peer-to-peer learning initiative. The initiative assessed if students can learn clinical skills from their peers in co-curricular practice objective structured clinical exams (OSCEs). METHODS: A total of 144 first-year medical students participated. Students wrote case scenarios that were reviewed by physicians. Students enacted the cases in practice OSCEs, acting as the patient, physician, and evaluator. Verbal and electronic evaluations were completed. A digital platform was used to automate the process. Surveys were disseminated to assess student perceptions of their experience. RESULTS: Seventy-five percent of participants said they needed opportunities to practice patient histories and physical exams in addition to those provided in the medical school curriculum. All participants agreed that the co-curricular practice OSCEs met this need. The majority of participants also agreed that the digital platform was efficient and easy to use. CONCLUSION: Students found the practice OSCEs and digital platform effective for learning clinical skills. Thus, peer-to-peer learning and computer automation can be useful adjuncts to traditional medical curricula. PMID- 28344718 TI - IMAGINE-ing interprofessional education: program evaluation of a novel inner city health educational experience. AB - BACKGROUND: Poverty is a key determinant of health that leads to poor health outcomes. Although most healthcare providers will work with patients experiencing poverty, surveys among healthcare students have reported a curriculum gap in this area. This study aims to introduce and evaluate a novel, student-run interprofessional inner city health educational program that combines both practical and didactic educational components. METHODS: Students participating in the program answered pre- and post-program surveys. Wilcoxon signed-rank tests and descriptive thematic analysis were used for quantitative and qualitative data, respectively. RESULTS: A total of 28 out of 35 participants responded (response rate: 80%). Student knowledge about issues facing underserved populations and resources for underserved populations significantly increased after program participation. Student comfort working with underserved populations also significantly increased after program participation. Valued program elements included workshops, shadowing, and a focus on marginalized populations. CONCLUSION: Interprofessional inner city health educational programs are beneficial for students to learn about poverty intervention and resources, and may represent a strategy to address a gap in the healthcare professional curriculum. PMID- 28344719 TI - Residents' perceptions of simulation as a clinical learning approach. AB - BACKGROUND: Simulation is increasingly being integrated into medical education; however, there is little research into trainees' perceptions of this learning modality. We elicited trainees' perceptions of simulation-based learning, to inform how simulation is developed and applied to support training. METHODS: We conducted an instrumental qualitative case study entailing 36 semi-structured one hour interviews with 12 residents enrolled in an introductory simulation-based course. Trainees were interviewed at three time points: pre-course, post-course, and 4-6 weeks later. Interview transcripts were analyzed using a qualitative descriptive analytic approach. RESULTS: Residents' perceptions of simulation included: 1) simulation serves pragmatic purposes; 2) simulation provides a safe space; 3) simulation presents perils and pitfalls; and 4) optimal design for simulation: integration and tension. Key findings included residents' markedly narrow perception of simulation's capacity to support non-technical skills development or its use beyond introductory learning. CONCLUSION: Trainees' learning expectations of simulation were restricted. Educators should critically attend to the way they present simulation to learners as, based on theories of problem-framing, trainees' a priori perceptions may delimit the focus of their learning experiences. If they view simulation as merely a replica of real cases for the purpose of practicing basic skills, they may fail to benefit from the full scope of learning opportunities afforded by simulation. PMID- 28344720 TI - Resetting the compass: exploring the implicit messages of orientation to a community-engaged medical school. AB - BACKGROUND: Although students' transition into medical school is a critical step in their professional journey, orientation has been relatively under-researched, particularly with regard to its intersections with schools' social missions. This paper reports on a study looking at the implicit messages of orientation to the Northern Ontario School of Medicine's undergraduate program. METHODS: An extended mixed methods study was conducted to look at different aspects of the School's Orientation Week. The term "hidden curriculum" was used to shape inquiry, both in its broad sense of implicit educational experiences and messages and in its more specific sense of the educational messages sent by a medical school's culture and activities. Data were collected using participant surveys, focus groups, and interviews. Transcripts and free-text survey responses were analyzed to identify underlying themes. RESULTS: Orientation Week was generally well received and was generally perceived by different stakeholders (such as students, school leaders, and community members) as a positive and necessary undertaking. However, there were points of contention and confusion that created a hidden curriculum with respect to participants' identities, both as students and as future health professionals. CONCLUSION: Orientation to undergraduate medical training can be successfully linked to a school's social mission, but in doing so it can send complex and unintended messages to the participants that may be perceived quite differently based on their circumstances and expectations. PMID- 28344721 TI - Examining the impact of early longitudinal patient exposure on medical students' career choices. AB - BACKGROUND: Medical schools include career direction experiences to help students make informed career decisions. Most experiences are short, precluding students from attaining adequate exposure to long-term encounters within medicine. We investigated the impact of the First Patient Program (FPP), which fosters longitudinal patient exposure by pairing junior medical students with chronically ill patients through their healthcare journey, in instilling career direction. METHODS: Medical students who completed at least 6-months in the FPP participated in a cross-sectional survey. Students' answers were analyzed with respect to the number of FPP appointments attended. Thematic analysis was conducted to explore qualitative responses. RESULTS: One hundred and forty-eight students participated in the survey. Only 28 (19%) students stated that the FPP informed their career decisions. Thirty-nine percent of students who attended four or more appointments indicated that the FPP informed their career decisions, compared to 16% of students who attended less (p=0.021). Thematic analysis revealed two themes: 1) Students focused mainly on patient encounters within FPP; and 2) Students sought career directions from other experiences. CONCLUSION: The majority of students did not attain career guidance from the FPP, but rather used the program to understand the impact of chronic illness from the patient's perspective. PMID- 28344722 TI - Assessment of emergency medicine residents: a systematic review. AB - BACKGROUND: Competency-based medical education is becoming the new standard for residency programs, including Emergency Medicine (EM). To inform programmatic restructuring, guide resources and identify gaps in publication, we reviewed the published literature on types and frequency of resident assessment. METHODS: We searched MEDLINE, EMBASE, PsycInfo and ERIC from Jan 2005 - June 2014. MeSH terms included "assessment," "residency," and "emergency medicine." We included studies on EM residents reporting either of two primary outcomes: 1) assessment type and 2) assessment frequency per resident. Two reviewers screened abstracts, reviewed full text studies, and abstracted data. Reporting of assessment-related costs was a secondary outcome. RESULTS: The search returned 879 articles; 137 articles were full-text reviewed; 73 met inclusion criteria. Half of the studies (54.8%) were pilot projects and one-quarter (26.0%) described fully implemented assessment tools/programs. Assessment tools (n=111) comprised 12 categories, most commonly: simulation-based assessments (28.8%), written exams (28.8%), and direct observation (26.0%). Median assessment frequency (n=39 studies) was twice per month/rotation (range: daily to once in residency). No studies thoroughly reported costs. CONCLUSION: EM resident assessment commonly uses simulation or direct observation, done once-per-rotation. Implemented assessment systems and assessment-associated costs are poorly reported. Moving forward, routine publication will facilitate transitioning to competency-based medical education. PMID- 28344723 TI - On the value of debate in medical school. PMID- 28344724 TI - Functional Fixedness in Creative Thinking Tasks Depends on Stimulus Modality. AB - Pictorial examples during creative thinking tasks can lead participants to fixate on these examples and reproduce their elements even when yielding suboptimal creative products. Semantic memory research may illuminate the cognitive processes underlying this effect. Here, we examined whether pictures and words differentially influence access to semantic knowledge for object concepts depending on whether the task is close- or open-ended. Participants viewed either names or pictures of everyday objects, or a combination of the two, and generated common, secondary, or ad hoc uses for them. Stimulus modality effects were assessed quantitatively through reaction times and qualitatively through a novel coding system, which classifies creative output on a continuum from top-down driven to bottom-up-driven responses. Both analyses revealed differences across tasks. Importantly, for ad hoc uses, participants exposed to pictures generated more top-down-driven responses than those exposed to object names. These findings have implications for accounts of functional fixedness in creative thinking, as well as theories of semantic memory for object concepts. PMID- 28344725 TI - Sensitive and predictable separation of microfluidic droplets by size using in line passive filter. AB - Active manipulation of droplets is crucial in droplet microfluidics. However, droplet polydispersity decreases the accuracy of active manipulation. We develop a microfluidic "droplet filter" that accurately separates droplets by size. The droplet filter has a sharp size cutoff and is capable of distinguishing droplets differing in volume by 20%. A simple model explains the behavior of the droplets as they pass through the filter. We show application of the filter in improving dielectric sorting efficiency. PMID- 28344726 TI - Evaluation of disposable microfluidic chip design for automated and fast Immunoassays. AB - We report here, the design and development of a disposable immunoassay chip for protein biomarker detection within ~1 h. The unique design allows for real-time dynamic calibration of immunoassay for multiple biomarker detections on the chip. The limit of detection achieved for this test chip is 10 pg/ml for IL6, and 50 pg/ml for GFAP with a detection time of 1 h. The prototype instrument used for flowing the reagents through the chip can be easily assembled from off-the-shelf components with the final chemiluminescent detection carried out in a commercial plate reader. Optimization of different aspects of chip design, fabrication, and assay development is discussed in detail. PMID- 28344728 TI - Transgender Youth and Suicidal Behaviors: Applying the Interpersonal Psychological Theory of Suicide. AB - The interpersonal psychological theory of suicide (IPTS) was used to examine suicidal thoughts and behaviors among 129 transgender and gender nonconforming (TGNC) youth. Youth were categorized according to their gender identities: female to-male (FTM), male-to-female (MTF), female-to-different-gender (FTDG), and male to-different gender (MTDG). Higher percentages of suicidal ideation were reported by FTDG and FTM youth; and higher percentages of suicide attempts by FTDG and MTDG youth. Perceived burdensomeness and thwarted belongingness were significantly related to suicidal ideation and/or suicide attempts. Experiences of painful, provocative and harmful events and acquired capability significantly predicted suicide attempts. The findings support IPTS in explaining suicidal behaviors among TGNC youth. Implications for prevention and intervention efforts are discussed. PMID- 28344727 TI - Characterization of vascular permeability using a biomimetic microfluidic blood vessel model. AB - The inflammatory response in endothelial cells (ECs) leads to an increase in vascular permeability through the formation of gaps. However, the dynamic nature of vascular permeability and external factors involved is still elusive. In this work, we use a biomimetic blood vessel (BBV) microfluidic model to measure in real-time the change in permeability of the EC layer under culture in physiologically relevant flow conditions. This platform studies the dynamics and characterizes vascular permeability when the EC layer is triggered with an inflammatory agent using tracer molecules of three different sizes, and the results are compared to a transwell insert study. We also apply an analytical model to compare the permeability data from the different tracer molecules to understand the physiological and bio-transport significance of endothelial permeability based on the molecule of interest. A computational model of the BBV model is also built to understand the factors influencing transport of molecules of different sizes under flow. The endothelial monolayer cultured under flow in the BBV model was treated with thrombin, a serine protease that induces a rapid and reversible increase in endothelium permeability. On analysis of permeability data, it is found that the transport characteristics for fluorescein isothiocyanate (FITC) dye and FITC Dextran 4k Da molecules are similar in both BBV and transwell models, but FITC Dextran 70k Da molecules show increased permeability in the BBV model as convection flow (Peclet number > 1) influences the molecule transport in the BBV model. We also calculated from permeability data the relative increase in intercellular gap area during thrombin treatment for ECs in the BBV and transwell insert models to be between 12% and 15%. This relative increase was found to be within range of what we quantified from F-actin stained EC layer images. The work highlights the importance of incorporating flow in in vitro vascular models, especially in studies involving transport of large size objects such as antibodies, proteins, nano/micro particles, and cells. PMID- 28344729 TI - Heterotopic Ossification in a Newborn: A Case Report. AB - Introduction: Heterotopic ossification is defined as the formation of trabecular bone that forms outside the normal sites of the skeletal structure, materializing in soft tissue where it does not usually exist. Methods/Case Report: This is a case report of a 27-day-old baby with a diagnosis of DiGeorge syndrome who developed heterotopic ossification on the dorsum of his right hand. Discussion: Heterotopic ossification in the pediatric population is a rare finding. Very few cases were published in the literature, and we find it important to increase the knowledge on such cases and discuss possible causes with the treatment used with our patient. Results: General treatments of heterotopic ossification include ruling out superimposed infection, physiotherapy to prevent joint involvement, warm compressors during the active phase of development of heterotopic ossification. If the swelling persists to the point that it interferes significantly with the functional capacity of the patient or becomes a cosmetic concern, the only treatment option remaining would be surgery. PMID- 28344730 TI - Ensuring Rapid Mixing and Low Bias for Asynchronous Gibbs Sampling. AB - Gibbs sampling is a Markov chain Monte Carlo technique commonly used for estimating marginal distributions. To speed up Gibbs sampling, there has recently been interest in parallelizing it by executing asynchronously. While empirical results suggest that many models can be efficiently sampled asynchronously, traditional Markov chain analysis does not apply to the asynchronous case, and thus asynchronous Gibbs sampling is poorly understood. In this paper, we derive a better understanding of the two main challenges of asynchronous Gibbs: bias and mixing time. We show experimentally that our theoretical results match practical outcomes. PMID- 28344731 TI - Review of Physical Activity Benefits and Potential Considerations for Individuals with Surgical Fusion of Spine for Scoliosis. AB - Evidence-based recommendations for physical activity following spinal fusion surgeries for idiopathic scoliosis are limited, specifically in the adolescent population. Individuals with scoliosis treated operatively or non-operatively have been reported to participate in less than 1-3 days/week of even mildly strenuous physical exercises. Over 40% of individuals with scoliosis returned to sports at a level lower than pre-operative participation levels or did not return at all post spinal fusion. It is particularly important for human movement specialists, such as physical therapists, occupational therapists, athletic trainers and kinesiologists to assist these individuals effectively transition to and maintain engagement in physical activity. This review provides a snapshot of common considerations and potential factors influencing individuals with spinal fusion for scoliosis to participate in safe physical activity. PMID- 28344732 TI - Autonomic Modulation in Older Women: Using Resistance Exercise as a Countermeasure. AB - It is unclear if resistance training (RT) can be used to alter declines in autonomic modulation associated with aging. Young women (YW; range 18-25 yrs) and older women (OW; range 50-72 yrs) were compared at baseline. Only OW underwent supervised RT 2 days a week for 12-weeks. Baseline and post-training measurements included heart rate variability (HRV) and complexity (Sample Entropy) to assess autonomic modulation. The 12-weeks of RT consisted of 9 exercises performing 3 sets of 8-12 repetitions. At baseline, group differences in maximal strength, and autonomic modulation were evaluated with a one-way ANOVA with BMI as a covariate. In the OW, the effects of RT were evaluated with repeated-measures ANOVA in order to compare baseline to after RT. The YW had significantly (p<=0.05) lower diastolic, but not systolic blood pressure. The YW also had significantly (p<=0.05) greater absolute Ln (natural logarithm) high-frequency (HF) power and normalized HF power compared to the OW. In addition, there were significantly (p<=0.05) greater levels of normalized low-frequency power (LF) (and the LF/HF ratio) in the OW compared to the YW before RT. However, no difference was found for Sample Entropy. After RT, OW significantly (p<=0.05) increased the chest press (28%) and leg extension (33%). RT had no significant effect on any autonomic parameter suggesting that it may not be a sufficient stimulus to alter the effects of aging. PMID- 28344733 TI - An Acute Bout of a Controlled Breathing Frequency Lowers Sympathetic Neural Outflow but not Blood Pressure in Healthy Normotensive Subjects. AB - Controlled or paced breathing is often used as a stress reduction technique but the impact on blood pressure (BP) and sympathetic outflow have not been consistently reported. The purpose of this study was to determine whether a controlled breathing (12 breaths/min, CB) rate would be similar to an individual's spontaneous breathing (SB) rate. Secondly, would a CB rate of 12 breaths/min alter heart rate (HR), BP, and indices of muscle sympathetic nerve activity (MSNA). Twenty-one subjects (10 women, 11 men) performed two trials: SB, where the subject chose a comfortable breathing rate; and CB, where the subject breathed at a pace of 12 breaths/min. Each trial was 6 min during which respiratory waveforms, HR, BP (systolic, SBP; diastolic, DBP), and MSNA were recorded. During CB, the 6 min average breathing frequency (14+/-4 vs 12+/-1 breaths/min, P<0.05 for SB and CB, respectively), MSNA burst frequency (18+/-12 vs 14+/-10 bursts/min, P<0.01) and MSNA burst incidence (28+/-19 vs 21+/- 6 bursts/100 heart beats, P<0.01) were significantly lower than during SB. HR (66+/ 9 vs 67+/-9 beats/min, P<0.05) was higher during CB. SBP (120+/-13 vs 121+/-15 mmHg, P=0.741), DBP (56+/-8 vs 57+/-9 mmHg, P=0.768), and MSNA total activity (166+/-94 vs 145+/-102 a.u./min, P=0.145) were not different between the breathing conditions. In conclusion, an acute reduction in breathing frequency such as that observed during CB elicited a decrease in indices of MSNA (burst frequency and incidence) with no change in BP. PMID- 28344734 TI - Aerobic Capacity is Related to Repeated Sprint Ability with Sprint Distances Less Than 40 Meters. AB - Research is inconclusive regarding the association between aerobic fitness (objectively measured VO2max) and repeated sprint performance when the sprints are less than 40 meters. Soccer athletes must be able to repeat sprints without significant decreases in speed and strength and conditioning coaches need to better understand if aerobic fitness is related to repeated sprint ability (RSA). Twenty (10 male, 10 female) Division I soccer athletes first completed a graded maximal treadmill test to measure VO2max. Then on a separate day, athletes completed the RSA test. The RSA test consisted of 10, 30-meter sprints which athletes repeated every 30 seconds. There were significant negative correlations (r <= -0.69, P < 0.001) between VO2max and all 10-sprint times and average sprint time. More aerobically fit Division I soccer athletes were faster at all time points during the RSA test. Aerobic fitness is associated with faster sprint times during a more anaerobic RSA test when sprint distances are less than 40 meters. PMID- 28344735 TI - Parental Influences and the Relationship to their Children's Physical Activity Levels. AB - Engaging in a physically active lifestyle relates positively to current health and reduces chances of chronic diseases in the future. Given escalating health care costs, it is paramount to reduce illnesses associated with a lack of physical activity and thus critical to identify factors that influence physical activity - especially in children, with the opportunity for a lifetime impact. One of these influencing factors may be parents/guardians. The intent of this study was to examine the relationship between children's physical activity levels and parental factors including parental physical activity, support/encouragement, restrictiveness, and self-reported participation. Data was collected from 15 child-parent pairs with children ranging in age from 7 to 10 years. Daily physical activity levels were determined from pedometer data using a Piezo SC Step Pedometer. Number of steps and moderate and vigorous physical activity were extracted from the pedometers and levels of support/encouragement, restrictiveness, and participation were quantified from parents' self-reported responses to a questionnaire created for this study. Pearson Product correlation analyses were carried out between: the children's and parent steps (r = -0.069; p = 0.597); children's steps and parent's self-reported encouragement/support (r = 0.045, p = 0.563); children's steps and parents' self-reported restrictiveness (r = -.0254, p = 0.820); and children's steps and parents' self-reported participation (r = -0.002, p = 0.503). The lack of significant relationships among these variables implies that more complex interactions occur between children and their parents regarding physical activity with children's participation influenced by other factors. PMID- 28344736 TI - Recovery of Hip and Back Muscle Fatigue Following a Back Extension Endurance Test. AB - Literature has not shown the minimum time required to recover from muscle fatigue after a prolonged trunk isometric contraction. The purpose of this study was to determine if the lumbar multifidus (LM) and gluteus maximus (GM) muscles would recover from fatigue after three different rest periods following performance of a back extension endurance test. Endurance time and electromyographic (EMG) activity of bilateral LM and GM muscles were collected from 12 healthy adults during a modified Biering-Sorensen test. On three separate visits, each participant performed two modified Biering-Sorensen tests, one before and one after a rest period (3, 6 or 9 min). For each endurance test, endurance time was measured and both mean and median EMG frequency fatigue rates were calculated. The results showed a significantly reduced endurance time and normalized mean frequency fatigue rates on the second modified Biering-Sorensen endurance test regardless of the rest periods (3, 6, and 9 min). This suggests that adequate rest should be considered for fatigue recovery when designing a back and hip endurance exercise program, and that future studies should investigate a rest time longer than 9 minutes for fatigue recovery following a modified Biering Sorensen endurance test. PMID- 28344737 TI - Non-invasive Measures of Core Temperature versus Ingestible Thermistor during Exercise in the Heat. AB - The accuracy of core temperature (Tc) thermometry from temporal, tympanic, and oral thermometry devices has been variable during exercise in a hot, humid environment. The purpose of the present study was to cross-validate temporal, two tympanic devices, and oral devices compared to an ingestible thermistor during exercise in a hot, humid environment. Fourteen young, active adults (6 women) completed a graded exercise test until voluntary exhaustion in an environmental chamber (35.5 +/- 0.6 degrees C, 53.9 +/- 5.8 % RH). There was no statistical difference in mean temperature between tympanic device 1 and pill-based core temperature (PBTc) measurements across all time points and were positively correlated (0.357; P<0.001). Temperatures of tympanic device 2 were statistically higher than PBTc (37.8 +/- 0.7 oC vs. 37.6 +/- 1.0 oC; respectfully) (P=0.008). At all time points, temperatures for the second tympanic device and PBTc were positively correlated (0.192; P=0.043). Temporal and PBTc values did not differ across time points and were positively correlated (0.262; P=0.005) across all time points. Mean oral temperature was significantly less than mean PBTc across all time points. (37.0 +/- 0.4 oC vs. 37.6 +/- 1.0 oC, respectively) (P<0.001). Across all time points, oral and PBTc were positively correlated (0.262; P=0.010). Tympanic and temporal devices can reflect Tc while exercising in a hot, humid environment. However, care should be taken when selecting the tympanic or temporal measurement device and validation is advised prior to heat illness mitigation in the field. PMID- 28344738 TI - Adherence to Exercise Prescription and Improvements in the Clinical and Vascular Health of African Americans. AB - Improvements in indices of vascular health and endothelial function have been inversely associated with hypertension, a risk factor for cardiovascular disease (e.g., myocardial infarction, stroke, and heart failure), renal failure, and mortality. Aerobic exercise training (AEXT) has been positively associated with improvements in clinical health values, as well as vascular health biomarkers, and endothelial function. The purpose of this study was to evaluate whether measures of exercise adherence were related to clinical outcome measures and indices of vascular health subsequent to a 6-month AEXT intervention in a middle to-older aged African American cohort. Following dietary stabilization, sedentary, apparently healthy, African American adults (40 - 71 y/o) underwent baseline testing including blood pressure, flow-mediated dilation (FMD) studies, fasting blood sampling, and graded exercise testing. Upon completion of a supervised 6-month AEXT intervention, participants repeated all baseline tests. Exercise adherence was measured three ways: exercise percentage, exercise volume, and exercise score. There were no significant correlations between the changes in the vascular health biomarkers of the participants and any of the adherence measures. In addition, there were no significant correlations between any of the adherence measures and the clinical values of the participants that had been significantly changed pre-post-AEXT. Participants improved their clinical and vascular health and decreased risk factors for hypertension and cardiovascular disease regardless of their level of adherence to AEXT. Future studies should continue to accurately quantify adherence in order to assess the exercise dose for improvements in vascular and clinical health. PMID- 28344739 TI - Effect of Caffeine on near Maximal Blood Pressure and Blood Pressure Recovery in Physically-Active, College-Aged Females. AB - The purpose of this study is to determine how caffeine affects exercise blood pressure (BP) and active and passive recovery BP after vigorous intensity exercise in physically active college-aged females. Fifteen physically active, ACSM stratified low-risk females (age (y): 23.53 +/- 4.07, weight (kg): 60.34 +/- 3.67, height (cm): 165.14 +/- 7.20, BMI (kg/m2): 22.18 +/- 1.55) participated in two Bruce protocol exercise tests. Before each test participants consumed 1) a placebo or 2) 3.3 mg.kg-1 of caffeine at least one hour before exercise in a counterbalanced double-blinded fashion. After reaching 85% of their age-predicted maximum heart rate, BP was taken and participants began an active (i.e. walking) recovery phase for 6 minutes followed by a passive (i.e. sitting) recovery phase. BP was assessed every two minutes in each phase. Recovery times were assessed until active and passive BP equaled 20 mmHg and 10 mmHg above resting, respectively. Participants completed each test 1-2 weeks a part. Maximal systolic and diastolic blood pressures were not significantly different between the two trials. Active recovery, passive recovery, and total recovery times were all significantly longer during the caffeine trial than the placebo trial. Furthermore, the time to reach age-predicted maximum heart rate was significantly shorter in the placebo trial than the caffeine trial. While caffeine consumption did not significantly affect maximal blood pressure, it did affect active and passive recovery time following vigorous intensity exercise in physically active females. Exercise endurance also improved after consuming caffeine in this population. PMID- 28344741 TI - Comparison of Whole-Body Cooling Techniques for Athletes and Military Personnel. AB - The purpose of this study was to evaluate cooling rates of The Polar Life Pod(r), a military protocol and cold water immersion. A randomized, repeated measures design was used to compare three treatment options. Participants exercised in an environmental chamber, where they followed a military march protocol on a treadmill, followed by the application of one of three treatments: Cold water immersion tub (5 - 10 degrees C), Polar Life Pod(r) (5 - 10 degrees C), Ice sheets at onset (5 - 10 degrees C). Mean cooling rate for CWI was 0.072 oC/min, 0.046oC/min for ice sheets, and 0.040oC/min for The Polar Life Pod(r). There was a significant difference between conditions (F2,26=13.564, p=0.001, ES=0.511, 1 beta=0.969). There was a significant difference in cooling rate among The Polar Life Pod(r) and CWI (p = 0.006), and no significant difference among The Polar Life Pod(r) and Ice Sheets (p = 0.103). There was a significant difference of time to cool among the three conditions F2,26 = 13.564, p = 0.001, ES = 0.401, 1 beta = 0.950. Our results support multiple organizations that deem CWI as the only acceptable treatment, when compared to the cooling rates of The Polar Life Pod(r) and ice sheets. PMID- 28344740 TI - Orchard Sports Injury Classification System 10.1 Plus: An End-User Study. AB - The purpose of this study was to establish the level of ease of use and effectiveness of the Orchard Sport Injury Classification System (OSICS) 10.1 Plus for recording injuries and interventions. Three hundred and forty-two (males=148, females=192, no response=2; age=30.9+/-9.5y; experience=9.1+/-10.5y) athletic trainers (ATs) in the United States completed the survey. Participants were primarily employed in the secondary school (n=135) or collegiate setting (n=171). Participants entered system includes the OSICS 10.1 to catalog injuries and Current Procedural Terminology (CPT) codes to document interventions. Participants completed an 18-item end-user evaluation to assess the ease of use and effectiveness of the OSICS 10.1 Plus (5-point Likert scale). Participants indicated that the OSICS 10.1 Plus is overall easy to use (4.1+/-0.7pts), easy to enter an injury (4.1+/-0.8pts), and easy to enter the associated interventions (3.9+/-0.8pts). Respondents were neutral about whether the OSICS 10.1 Plus matched their current injury (3.5+/-1.0pts) or intervention (3.5+/-0.9pts) records. A majority of participants indicated that they could find the injury (281/342, 82.2%) and interventions (225/342, 65.8%) of interest. A majority of respondents (205/342, 60.0%) indicated they would consider using OSICS 10.1 Plus for injury surveillance in clinical practice. The OSICS 10.1 Plus could serve as an effective and useful mechanism for injury surveillance with minor modifications; however, we, as professionals in sports healthcare, need to improve regular medical documentation first so that we are better able to conduct injury surveillance among our patients. PMID- 28344742 TI - Psychophysiological Tracking of a Female Physique Competitor through Competition Preparation. AB - : Natural physique competitions are based on subjective judgments of how a competitor appears on show day. Prior to competition, there is a prolonged dieting phase referred to as contest preparation. The primary goal is to reduce body fat levels while maintaining skeletal muscle mass. The study tracked the physiological and psychological changes for a 24 year old female preparing for a physique competition. PURPOSE: The study was conducted to describe the physiological and psychological changes of a female physique competitor who engages in long-term contest preparation. METHODS: Diet, body composition, blood work, energy expenditure, mood, and performance were evaluated through contest preparation. RESULTS: The participant lost 10.1kg throughout contest preparation in a strong weekly linear pattern (R2=0.97). Body fat was reduced from 30.45% to 15.85% while fat free mass was maintained. Mood for the participant remained stable until month five, when an observed variation occurred, with performance maintaining. CONCLUSIONS: Contest preparation was successful in reducing the body fat in the participant while having a minimum effect on both performance and fat free mass. For athletes looking to lose large amounts of body fat with minimal performance decrements a prolonged diet period with moderate exercise and food restriction can be an effective solution. PMID- 28344743 TI - The Abscopal Effect of Radiation Therapy: What Is It and How Can We Use It in Breast Cancer? AB - The abscopal effect refers to the ability of localized radiation to trigger systemic antitumor effects. Over the past 50 years, reports on the abscopal effect arising from conventional radiation have been relatively rare. However, with the continued development and use of immunotherapy strategies incorporating radiotherapy with targeted immunomodulators and immune checkpoint blockade, the abscopal effect is becoming increasingly relevant in less immunogenic tumors such as breast cancer. Here, we review the mechanism of the abscopal effect, the current preclinical and clinical data, and the application of the abscopal effect in designing clinical trials of immunotherapy combined with radiotherapy in breast cancer. PMID- 28344744 TI - Automation of PacBio SMRTbell NGS library preparation for bacterial genome sequencing. AB - BACKGROUND: The PacBio RS II provides for single molecule, real-time DNA technology to sequence genomes and detect DNA modifications. The starting point for high-quality sequence production is high molecular weight genomic DNA. To automate the library preparation process, there must be high-throughput methods in place to assess the genomic DNA, to ensure the size and amounts of the sheared DNA fragments and final library. FINDINGS: The library construction automation was accomplished using the Agilent NGS workstation with Bravo accessories for heating, shaking, cooling, and magnetic bead manipulations for template purification. The quality control methods from gDNA input to final library using the Agilent Bioanalyzer System and Agilent TapeStation System were evaluated. CONCLUSIONS: Automated protocols of PacBio 10 kb library preparation produced libraries with similar technical performance to those generated manually. The TapeStation System proved to be a reliable method that could be used in a 96-well plate format to QC the DNA equivalent to the standard Bioanalyzer System results. The DNA Integrity Number that is calculated in the TapeStation System software upon analysis of genomic DNA is quite helpful to assure that the starting genomic DNA is not degraded. In this respect, the gDNA assay on the TapeStation System is preferable to the DNA 12000 assay on the Bioanalyzer System, which cannot run genomic DNA, nor can the Bioanalyzer work directly from the 96-well plates. PMID- 28344745 TI - Can molecular biomarkers replace a clinical risk score for resectable colorectal liver metastasis? AB - In resectable colorectal liver metastasis (CRLM) the role and use of molecular biomarkers is still controversial. Several biomarkers have been linked to clinical outcomes in CRLM, but none have so far become routine for clinical decision making. For several reasons, the clinical risk score appears to no longer hold the same predictive value. Some of the reasons include the ever expanding indications for liver resection, which now increasingly tend to involve extrahepatic disease, such as lung metastases (both resectable and non resectable) and the shift in indication from "what is taken out" (e.g., how much liver has to be resected) to "what is left behind" (that is, how much functional liver tissue the patient has after resection). The latter is amenable to modifications by using adjunct techniques of portal vein embolization and the associating liver partition and portal vein ligation for staged hepatectomy techniques to expand indications for liver resection. Added to this complexity is the increasing number of molecular markers, which appear to hold important prognostic and predictive information, for which some will be discussed here. Beyond characteristics of tissue-based genomic profiles will be liquid biopsies derived from circulating tumor cells and cell-free circulating tumor DNA in the blood. These markers are present in the peripheral circulation in the majority of patients with metastatic cancer disease. Circulating biomarkers may represent more readily available methods to monitor, characterize and predict cancer biology with future implications for cancer care. PMID- 28344747 TI - Gastric peritoneal carcinomatosis - a retrospective review. AB - AIM: To characterize patients with gastric peritoneal carcinomatosis (PC) and their typical clinical and treatment course with palliative systemic chemotherapy as the current standard of care. METHODS: We performed a retrospective electronic chart review of all patients with gastric adenocarcinoma with PC diagnosed at initial metastatic presentation between January 2010 and December 2014 in a single tertiary referral centre. RESULTS: We studied a total of 271 patients with a median age of 63.8 years and median follow-up duration of 5.1 mo. The majority (n = 217, 80.1%) had the peritoneum as the only site of metastasis at initial presentation. Palliative systemic chemotherapy was eventually planned for 175 (64.6%) of our patients at initial presentation, of which 171 were initiated on it. Choice of first-line regime was in accordance with the National Comprehensive Cancer Network Guidelines for Gastric Cancer Treatment. These patients underwent a median of one line of chemotherapy, completing a median of six cycles in total. Chemotherapy disruption due to unplanned hospitalizations occurred in 114 (66.7%), while cessation of chemotherapy occurred in 157 (91.8%), with 42 cessations primarily attributable to PC-related complications. Patients who had initiation of systemic chemotherapy had a significantly better median overall survival than those who did not (10.9 mo vs 1.6 mo, P < 0.001). Of patients who had initiation of systemic chemotherapy, those who experienced any disruptions to chemotherapy due to unplanned hospitalizations had a significantly worse median overall survival compared to those who did not (8.7 mo vs 14.6 mo, P < 0.001). CONCLUSION: Gastric PC carries a grim prognosis with a clinical course fraught with disease-related complications which may attenuate any survival benefit which palliative systemic chemotherapy may have to offer. As such, investigational use of regional therapies is warranted and required validation in patients with isolated PC to maximize their survival outcomes in the long run. PMID- 28344746 TI - CpG island methylator phenotype in adenocarcinomas from the digestive tract: Methods, conclusions, and controversies. AB - Over the last two decades, cancer-related alterations in DNA methylation that regulate transcription have been reported for a variety of tumors of the gastrointestinal tract. Due to its relevance for translational research, great emphasis has been placed on the analysis and molecular characterization of the CpG island methylator phenotype (CIMP), defined as widespread hypermethylation of CpG islands in clinically distinct subsets of cancer patients. Here, we present an overview of previous work in this field and also explore some open questions using cross-platform data for esophageal, gastric, and colorectal adenocarcinomas from The Cancer Genome Atlas. We provide a data-driven, pan-gastrointestinal stratification of individual samples based on CIMP status and we investigate correlations with oncogenic alterations, including somatic mutations and epigenetic silencing of tumor suppressor genes. Besides known events in CIMP such as BRAF V600E mutation, CDKN2A silencing or MLH1 inactivation, we discuss the potential role of emerging actors such as Wnt pathway deregulation through truncating mutations in RNF43 and epigenetic silencing of WIF1. Our results highlight the existence of molecular similarities that are superimposed over a larger backbone of tissue-specific features and can be exploited to reduce heterogeneity of response in clinical trials. PMID- 28344748 TI - Lung cancer metastasis to the gastrointestinal system: An enigmatic occurrence. AB - Adenocarcinoma of the lung infrequently metastasizes to the gastrointestinal tract. We report a rare case of a 65-year-old male with no respiratory symptoms diagnosed with adenocarcinoma of the lung by histopathological examination of metastatic sites which included an ulcer in the gastric body and a mass in the rectum. Metastatic disease also involved the liver as well. Patient was treated with systemic chemotherapy but unfortunately expired five months after the diagnosis was made. PMID- 28344749 TI - Heavily calcified gastrointestinal stromal tumors: Pathophysiology and implications of a rare clinicopathologic entity. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, and are characterized by a broad spectrum of clinical, histological and molecular features at presentation. Although focal and scattered calcifications are not uncommon within the primary tumor mass, heavy calcification within a GIST is rarely described in the literature and the clinical-biological meaning of this feature remains unclear. Cases with such an atypical presentation are challenging and may be associated with diagnostic pitfalls. Herein, we report a gastric GIST with the unusual presentation of prominent calcifications that was identified incidentally on imaging during a post-trauma diagnostic work-up. The patient underwent laparoscopic surgery with a radical resection of the mass, which was subsequently characterized by histological analysis as spindle-shaped tumor cells, positive for CD117/c-KIT, CD34 and DOG1, and with calcified areas. Given the intermediate risk of recurrence, no adjuvant therapy was recommended and the patient underwent regular follow-up for 22 mo, with no evidence of relapse. Our case can be considered of interest because of the rarity of clinical presentation and the uniquely large size of the GIST at diagnosis (longest diameter exceeding 9 cm). In closing, we discuss the pathophysiology and clinical implications of calcifications in GISTs by reviewing the most up-to-date relevant literature. PMID- 28344750 TI - The Effectiveness of Policy Interventions for School Bullying: A Systematic Review. AB - OBJECTIVE: Bullying threatens the mental and educational well-being of students. Although anti-bullying policies are prevalent, little is known about their effectiveness. This systematic review evaluates the methodological characteristics and summarizes substantive findings of studies examining the effectiveness of school bullying policies. METHOD: Searches of 11 bibliographic databases yielded 489 studies completed since January 1, 1995. Following duplicate removal and double-independent screening based on a priori inclusion criteria, 21 studies were included for review. RESULTS: Substantially more educators perceive anti-bullying policies to be effective rather than ineffective. Whereas several studies show that the presence or quality of policies is associated with lower rates of bullying among students, other studies found no such associations between policy presence or quality and reductions in bullying. Consistent across studies, this review found that schools with anti bullying policies that enumerated protections based on sexual orientation and gender identity were associated with better protection of lesbian, gay, bisexual, transgender, and queer (LGBTQ) students. Specifically, LGBTQ students in schools with such policies reported less harassment and more frequent and effective intervention by school personnel. Findings are mixed regarding the relationship between having an anti-bullying policy and educators' responsiveness to general bullying. CONCLUSIONS: Anti-bullying policies might be effective at reducing bullying if their content is based on evidence and sound theory and if they are implemented with a high level of fidelity. More research is needed to improve on limitations among extant studies. PMID- 28344751 TI - Management of critically ill patients with diabetes. AB - Disorders of glucose homeostasis, such as stress-induced hypoglycemia and hyperglycemia, are common complications in patients in the intensive care unit. Patients with preexisting diabetes mellitus (DM) are more susceptible to hyperglycemia, as well as a higher risk from glucose overcorrection, that may results in severe hypoglycemia. In critically ill patients with DM, it is recommended to maintain a blood glucose range between 140-180 mg/dL. In neurological patients and surgical patients, tighter glycemic control (i.e., 110 140 mg/d) is recommended if hypoglycemia can be properly avoided. There is limited evidence that shows that critically ill diabetic patients with a glycosylated hemoglobin levels above 7% may benefit from looser glycemic control, in order to reduce the risk of hypoglycemia and significant glycemic variability. PMID- 28344752 TI - Involvement of Cbl-b-mediated macrophage inactivation in insulin resistance. AB - Aging and overnutrition cause obesity in rodents and humans. It is well-known that obesity causes various diseases by producing insulin resistance (IR). Macrophages infiltrate the adipose tissue (AT) of obese individuals and cause chronic low-level inflammation associated with IR. Macrophage infiltration is regulated by the chemokines that are released from hypertrophied adipocytes and the immune cells in AT. Saturated fatty acids are recognized by toll-like receptor 4 (TLR4) and induce inflammatory responses in AT macrophages (ATMs). The inflammatory cytokines that are released from activated ATMs promote IR in peripheral organs, such as the liver, skeletal muscle and AT. Therefore, ATM activation is a therapeutic target for IR in obesity. The ubiquitin ligase Casitas b-lineage lymphoma-b (Cbl-b) appears to potently suppress macrophage migration and activation. Cbl-b is highly expressed in leukocytes and negatively regulates signals associated with migration and activation. Cbl-b deficiency enhances ATM accumulation and IR in aging- and diet-induced obese mice. Cbl-b inhibits migration-related signals and SFA-induced TLR4 signaling in ATMs. Thus, targeting Cbl-b may be a potential therapeutic strategy to reduce the IR induced by ATM activation. In this review, we summarize the regulatory functions of Cbl-b in ATMs. PMID- 28344753 TI - Statin, testosterone and phosphodiesterase 5-inhibitor treatments and age related mortality in diabetes. AB - AIM: To determine how statins, testosterone (T) replacement therapy (TRT) and phosphodiesterase 5-inhibitors (PDE5I) influence age related mortality in diabetic men. METHODS: We studied 857 diabetic men screened for the BLAST study, stratifying them (mean follow-up = 3.8 years) into: (1) Normal T levels/untreated (total T > 12 nmol/L and free T > 0.25 nmol/L), Low T/untreated and Low T/treated; (2) PDE5I/untreated and PDE5I/treated; and (3) statin/untreated and statin/treated groups. The relationship between age and mortality, alone and with T/TRT, statin and PDE5I treatment was studied using logistic regression. Mortality probability and 95%CI were calculated from the above models for each individual. RESULTS: Age was associated with mortality (logistic regression, OR = 1.10, 95%CI: 1.08-1.13, P < 0.001). With all factors included, age (OR = 1.08, 95%CI: 1.06-1.11, P < 0.001), Low T/treated (OR = 0.38, 95%CI: 0.15-0.92, P = 0.033), PDE5I/treated (OR = 0.17, 95%CI: 0.053-0.56, P = 0.004) and statin/treated (OR = 0.59, 95%CI: 0.36-0.97, P = 0.038) were associated with lower mortality. Age related mortality was as described by Gompertz, r2 = 0.881 when Ln (mortality) was plotted against age. The probability of mortality and 95%CI (from logistic regression) of individuals, treated/untreated with the drugs, alone and in combination was plotted against age. Overlap of 95%CI lines was evident with statins and TRT. No overlap was evident with PDE5I alone and with statins and TRT, this suggesting a change in the relationship between age and mortality. CONCLUSION: We show that statins, PDE5I and TRT reduce mortality in diabetes. PDE5I, alone and with the other treatments significantly alter age related mortality in diabetic men. PMID- 28344754 TI - Role of angiotensin converting enzyme and angiotensinogen gene polymorphisms in angiotensin converting enzyme inhibitor-mediated antiproteinuric action in type 2 diabetic nephropathy patients. AB - AIM: To investigate the role of genetic variants of angiotensin converting enzyme (ACE) and angiotensinogen (AGT) genes in the antiproteinuric efficacy of ACE inhibitor therapy in diabetic nephropathy (DN) patients. METHODS: In the present study, 270 type 2 diabetes mellitus patients with nephropathy were enrolled and treated with ACE inhibitor (ramipril) and followed at 6 mo for renal function and albumin excretion by estimating serum creatinine, end stage renal disease, and albumin/creatinine ratio (ACR) in urine. Genotyping of ACE I/D and AGT M235T polymorphisms were performed by using primer specific polymerase chain reaction (PCR) and PCR-RFLP techniques, respectively. RESULTS: Forty-eight percent of DN patients (responders) benefited with respect to proteinuria from ACE inhibitor therapy at 6 mo follow-up. A significant reduction in ACR was observed after 6 mo treatment with ACE inhibitor irrespective of whether DN patients were micro albuminuric (>= 30 and < 300 mg/g creatinine) or macro-albuminuric (>= 300 mg/g creatinine) at the time of enrollment. However, macro-albuminuric patients (55%) showed better response to therapy. A reduction in urinary ACR was found independent of genotypes of ACE I/D and AGT M235T polymorphisms although macro albuminuric patients having TT genotype showed statistically insignificant increased response (72%). CONCLUSION: ACE inhibitor therapy reduced urinary ACR by >= 30% in 50% of DN patients and the response is independent of ACE I/D and AGT M235T polymorphisms. PMID- 28344755 TI - Effect of Topical Application of Nigella Sativa Oil and Oral Acetaminophen on Pain in Elderly with Knee Osteoarthritis: A Crossover Clinical Trial. AB - BACKGROUND: Limited evidence supports Nigella sativa's role as an effective complementary and alternative medicine and the anti-inflammatory effects of Nigella sativa on patients with allergic rhinitis. OBJECTIVE: The aim of this study was to investigate the effect of topical application of Nigella sativa oil and oral acetaminophen on pain in the elderly with knee osteoarthritis residing in a parents' home in Sabzevar. METHODS: This study is done as a crossover clinical trial. After obtaining written consent of elderly patients with osteoarthritis of the knee, they were randomly divided into two groups. In step 1, in group 1, 1 cc of Nigella sativa oil was applied on the knee joint every 8 hours for 3 weeks; for the second group, every 8 hours for 3 weeks, patients were given 1 tablet of 325 mg acetaminophen. After a period of 1 month without medication to wash out each group, in step 2, each treatment group received the drug interaction in the same way as above. Pain was determined using a visual scale (VAS) before and after the first and second stages. Treatment response was defined as a decrease in pain scores over 1.5. Data analysis was performed with an R software mixed model. RESULTS: This study was done on 40 elderly patients: 18 (45%) men and 22 (55%) women. Their mean year and weight were 75.66+/-8.9 years and 69.67+/-14.33 kg, respectively. Study results showed that topical application of Nigella sativa oil and oral acetaminophen reduced pain in elderly with knee osteoarthritis; after using Nigella sativa oil, the reduction of pain was higher (p=0.01). CONCLUSION: The results of this study showed that topical application of Nigella sativa oil was effective in reducing pain in patients with knee osteoarthritis; therefore, it is recommended as a safe supplement for these elderly. TRIAL REGISTRATION: The trial was registered at TCTR (http://www.clinicaltrials.in.th/) with the ID: TCTR20160125003. FUNDING: This study was approved and supported by the Sabzevar University of Medical Sciences. PMID- 28344756 TI - Measuring Efficiency of Knowledge Production in Health Research Centers Using Data Envelopment Analysis (DEA): A Case Study in Iran. AB - INTRODUCTION: Efficiency analysis is necessary in order to avoid waste of materials, energy, effort, money, and time during scientific research. Therefore, analyzing efficiency of knowledge production in health areas is necessary, especially for developing and in-transition countries. As the first step in this field, the aim of this study was the analysis of selected health research center efficiency using data envelopment analysis (DEA). METHODS: This retrospective and applied study was conducted in 2015 using input and output data of 16 health research centers affiliated with a health sciences university in Iran during 2010 2014. The technical efficiency of health research centers was evaluated based on three basic data envelopment analysis (DEA) models: input-oriented, output oriented, and hyperbolic-oriented. The input and output data of each health research center for years 2010-2014 were collected from the Iran Ministry of Health and Medical Education (MOHE) profile and analyzed by R software. RESULTS: The mean efficiency score in input-oriented, output-oriented, and hyperbolic oriented models was 0.781, 0.671, and 0.798, respectively. Based on results of the study, half of the health research centers are operating below full efficiency, and about one-third of them are operating under the average efficiency level. There is also a large gap between health research center efficiency relative to each other. CONCLUSION: It is necessary for health research centers to improve their efficiency in knowledge production through better management of available resources. The higher level of efficiency in a significant number of health research centers is achievable through more efficient management of human resources and capital. Further research is needed to measure and follow the efficiency of knowledge production by health research centers around the world and over a period of time. PMID- 28344758 TI - No evidence of early head circumference enlargements in children later diagnosed with autism in Israel. AB - BACKGROUND: Large controversy exists regarding the potential existence and clinical significance of larger brain volumes in toddlers who later develop autism. Assessing this relationship is important for determining the clinical utility of early head circumference (HC) measures and for assessing the validity of the early overgrowth hypothesis of autism, which suggests that early accelerated brain development may be a hallmark of the disorder. METHODS: We performed a retrospective comparison of HC, height, and weight measurements between 66 toddlers who were later diagnosed with autism and 66 matched controls. These toddlers represent an unbiased regional sample from a single health service provider in the southern district of Israel. On average, participating toddlers had >8 measurements between birth and the age of two, which enabled us to characterize individual HC, height, and weight development with high precision and fit a negative exponential growth model to the data of each toddler with exceptional accuracy. RESULTS: The analyses revealed that HC sizes and growth rates were not significantly larger in toddlers with autism even when stratifying the autism group based on verbal capabilities at the time of diagnosis. In addition, there were no significant correlations between ADOS scores at the time of diagnosis and HC at any time-point during the first 2 years of life. CONCLUSIONS: These negative results add to accumulating evidence, which suggest that brain volume is not necessarily larger in toddlers who develop autism. We believe that conflicting results reported in other studies are due to small sample sizes, use of misleading population norms, changes in the clinical definition of autism over time, and/or inclusion of individuals with syndromic autism. While abnormally large brains may be evident in some individuals with autism and more clearly visible in MRI scans, converging evidence from this and other studies suggests that enlarged HC is not a common etiology of the entire autism population. Early HC measures, therefore, offer very limited clinical utility for assessment of autism risk in the general population. PMID- 28344757 TI - Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism. AB - BACKGROUND: Autism spectrum disorder (ASD) is one of the most highly heritable neuropsychiatric disorders, but underlying molecular mechanisms are still unresolved due to extreme locus heterogeneity. Leveraging meaningful endophenotypes or biomarkers may be an effective strategy to reduce heterogeneity to identify novel ASD genes. Numerous lines of evidence suggest a link between hyperserotonemia, i.e., elevated serotonin (5-hydroxytryptamine or 5-HT) in whole blood, and ASD. However, the genetic determinants of blood 5-HT level and their relationship to ASD are largely unknown. METHODS: In this study, pursuing the hypothesis that de novo variants (DNVs) and rare risk alleles acting in a recessive mode may play an important role in predisposition of hyperserotonemia in people with ASD, we carried out whole exome sequencing (WES) in 116 ASD parent proband trios with most (107) probands having 5-HT measurements. RESULTS: Combined with published ASD DNVs, we identified USP15 as having recurrent de novo loss of function mutations and discovered evidence supporting two other known genes with recurrent DNVs (FOXP1 and KDM5B). Genes harboring functional DNVs significantly overlap with functional/disease gene sets known to be involved in ASD etiology, including FMRP targets and synaptic formation and transcriptional regulation genes. We grouped the probands into High-5HT and Normal-5HT groups based on normalized serotonin levels, and used network-based gene set enrichment analysis (NGSEA) to identify novel hyperserotonemia-related ASD genes based on LoF and missense DNVs. We found enrichment in the High-5HT group for a gene network module (DAWN-1) previously implicated in ASD, and this points to the TGF beta pathway and cell junction processes. Through analysis of rare recessively acting variants (RAVs), we also found that rare compound heterozygotes (CHs) in the High-5HT group were enriched for loci in an ASD-associated gene set. Finally, we carried out rare variant group-wise transmission disequilibrium tests (gTDT) and observed significant association of rare variants in genes encoding a subset of the serotonin pathway with ASD. CONCLUSIONS: Our study identified USP15 as a novel gene implicated in ASD based on recurrent DNVs. It also demonstrates the potential value of 5-HT as an effective endophenotype for gene discovery in ASD, and the effectiveness of this strategy needs to be further explored in studies of larger sample sizes. PMID- 28344759 TI - Susceptibility to Ebbinghaus and Muller-Lyer illusions in autistic children: a comparison of three different methods. AB - BACKGROUND: Studies reporting altered susceptibility to visual illusions in autistic individuals compared to that typically developing individuals have been taken to reflect differences in perception (e.g. reduced global processing), but could instead reflect differences in higher-level decision-making strategies. METHODS: We measured susceptibility to two contextual illusions (Ebbinghaus, Muller-Lyer) in autistic children aged 6-14 years and typically developing children matched in age and non-verbal ability using three methods. In experiment 1, we used a new two-alternative-forced-choice method with a roving pedestal designed to minimise cognitive biases. Here, children judged which of two comparison stimuli was most similar in size to a reference stimulus. In experiments 2 and 3, we used methods previously used with autistic populations. In experiment 2, children judged whether stimuli were the 'same' or 'different', and in experiment 3, we used a method-of-adjustment task. RESULTS: Across all tasks, autistic children were equally susceptible to the Ebbinghaus illusion as typically developing children. Autistic children showed a heightened susceptibility to the Muller-Lyer illusion, but only in the method-of-adjustment task. This result may reflect differences in decisional criteria. CONCLUSIONS: Our results are inconsistent with theories proposing reduced contextual integration in autism and suggest that previous reports of altered susceptibility to illusions may arise from differences in decision-making, rather than differences in perception per se. Our findings help to elucidate the underlying reasons for atypical responses to perceptual illusions in autism and call for the use of methods that reduce cognitive bias when measuring illusion susceptibility. PMID- 28344761 TI - Acute rectal ischaemia following emergency abdominal aortic aneurysm surgery. AB - We present a case of isolated rectal ischaemia, a rare complication after emergency surgery for a ruptured abdominal aneurysm. We discuss the possible aetiology of this condition and how this rare condition may be missed unless care is taken at the time of reoperation. PMID- 28344762 TI - Protracted refractory pain post-TEVAR: post-implantation syndrome? AB - Aortic dissection is a life-threatening condition and has one of the highest mortality rates of cardiovascular diseases. It remains a devastating disease; with multiple unanswered questions concerning treatment modalities. The role of thoracic endovascular aortic repair (TEVAR) in these patients; especially those with uncomplicated acute aortic Type B dissections (AAD-B) is especially controversial although it has been shown to have better long-term outcomes compared to medical therapy alone. For those who have TEVAR, up to 60% may develop an acute, transient systemic inflammatory response syndrome that remains vaguely defined. The role of local inflammation in this post-implantation syndrome (PIS) has not been highlighted. We present a case of a 57-year-old male patient with an uncomplicated AAD-B who developed an 'atypical' PIS post-TEVAR with severe refractory abdominal pains; leukocytosis and raised C-reactive protein. The role of local inflammation in PIS is highlighted. PMID- 28344760 TI - Severe pulmonary hypertension in aging female apolipoprotein E-deficient mice is rescued by estrogen replacement therapy. AB - BACKGROUND: Apolipoprotein E (ApoE) is a multifunctional protein, and its deficiency leads to the development of atherosclerosis in mice. Patients with pulmonary hypertension (PH) have reduced expression of ApoE in lung tissue. ApoE is known to inhibit endothelial and smooth muscle cell proliferation and has anti inflammatory and anti-platelet aggregation properties. Young ApoE-deficient mice have been shown to develop PH on high fat diet. The combined role of female sex and aging in the development of PH has not been investigated before. Here, we investigated the development of PH in young and middle-aged (MA) female ApoE deficient mice and explored the role of exogenous estrogen (E2) replacement therapy for the aging females. METHODS: Wild type (WT) and ApoE-deficient female mice (Young and MA) were injected with a single intraperitoneal dose of monocrotaline (MCT, 60 mg/kg). Some ApoE-deficient MA female mice that received MCT were also treated with subcutaneous E2 pellets (0.03 mg/kg/day) from day 21 to 30 after MCT injection. Direct cardiac catheterization was performed terminally to record right ventricular systolic pressure (RVSP). Right ventricular (RV), left ventricular (LV), and interventricular septum (IVS) were dissected and weighed. Lung sections were examined using trichrome and immunofluorescence staining. Western blot analyses of lung and RV lysates were performed. RESULTS: In WT female mice, the severity of PH was similar between young and MA mice as RVSP was not significantly different (RVSP = 38.2 +/- 1.2 in young vs. 40.5 +/- 8.3 mmHg in MA, p < 0.05). In ApoE-deficient mice, MA females developed significantly severe PH (RVSP = 63 +/- 10 mmHg) compared to young females (RVSP; 36 +/- 3 mmHg, p < 0.05 vs. MA female). ApoE-deficient MA females also developed more severe RV hypertrophy compared to young females (RV hypertrophy index (RV/[LV + IVS]) = 0.53 +/- 0.06 vs. 0.33 +/- 0.01, p < 0.05). ApoE-deficient MA female mice manifested increased peripheral pulmonary artery muscularization and pulmonary fibrosis. E2 treatment of MA female ApoE-deficient mice resulted in a significant decrease in RVSP, reversal of pulmonary vascular remodeling, and RV hypertrophy. In MA female ApoE-deficient mice with PH, only the expression of ERbeta in the lungs, but not in RV, was significantly downregulated, and it was restored by E2 treatment. The expression of ERalpha was not affected in either lungs or RV by PH. GPR30 was only detected in the RV, and it was not affected by PH in MA female ApoE-deficient mice. CONCLUSIONS: Our results suggest that only aging female ApoE-deficient but not WT mice develop severe PH compared to younger females. Exogenous estrogen therapy rescued PH and RV hypertrophy in aging female ApoE-deficient mice possibly through restoration of lung ERbeta. PMID- 28344763 TI - Utility of human amniotic membrane allograft in re-epithelialization of the nasal tip. AB - Variations in skin thickness and contours pose significant challenges to reconstruction of the lower third of the nose. Human amniotic membrane allograft offers a potential alternative to tissue transfer in reconstruction of the lower third of the nose. We reviewed the procedure and photographs of a healthy 56-year old male with a 22 * 18 mm lower third nasal defect involving full thickness skin and subcutaneous tissue. Following preparation for grafting, dehydrated human amniotic membrane was fashioned to the dimensions of the defect and applied. No further surgical intervention was provided for 3 months. Complete re epithelialization of the nasal and adjacent defects was achieved with minimal scar formation. Human amniotic membrane allograft provides an efficacious and cosmetically acceptable alternative to local and regional tissue transfer. PMID- 28344764 TI - Atypical antipsychotics: recent research findings and applications to clinical practice: Proceedings of a symposium presented at the 29th Annual European College of Neuropsychopharmacology Congress, 19 September 2016, Vienna, Austria. AB - Available evidence suggests that second-generation atypical antipsychotics are broadly similar to first-generation agents in terms of their efficacy, but may have a more favourable tolerability profile, primarily by being less likely to cause extrapyramidal symptoms. However, atypical antipsychotics are variably associated with disturbances in the cardiometabolic arena, including increased body weight and the development of metabolic syndrome, which may reflect differences in their receptor binding profiles. Effective management of schizophrenia must ensure that the physical health of patients is addressed together with their mental health. This should therefore involve consideration of the specific tolerability profiles of available agents and individualization of treatment to minimize the likelihood of adverse metabolic sequelae, thereby improving long-term adherence and optimizing overall treatment outcomes. Alongside this, modifiable risk factors (such as exercise, diet, obesity/body weight and smoking status) must be addressed, in order to optimize patients' overall health and quality of life (QoL). In addition to antipsychotic-induced side effects, the clinical management of early nonresponders and psychopharmacological approaches for patients with treatment-resistant schizophrenia remain important unmet needs. Evidence suggests that antipsychotic response starts early in the course of treatment and that early nonresponse accurately predicts nonresponse over the longer term. Early nonresponse therefore represents an important modifiable risk factor for poor efficacy and effectiveness outcomes, since switching or augmenting antipsychotic treatment in patients showing early nonresponse has been shown to improve the likelihood of subsequent treatment outcomes. Recent evidence has also demonstrated that patients showing early nonresponse to treatment with lurasidone at 2 weeks may benefit from an increase in dose at this timepoint without compromising tolerability/safety. However, further research is required to determine whether these findings are generalizable to other antipsychotic agents. PMID- 28344765 TI - New insights on thyroid hormone mediated regulation of herpesvirus infections. AB - Thyroid hormone (T3) has been suggested to participate in the regulation of herpesvirus replication during reactivation. Clinical observations and in vivo experiments suggest that T3 are involved in the suppression of herpes virus replication. In vitro, differentiated LNCaP cells, a human neuron-like cells, further resisted HSV-1 replication upon addition of T3. Previous studies indicate that T3 controlled the expression of several key viral genes via its nuclear receptors in differentiated LNCaP cells. Additional observation showed that differentiated LNCaP cells have active PI3K signaling and inhibitor LY294002 can reverse T3-mediated repression of viral replication. Active PI3K signaling has been linked to HSV-1 latency in neurons. The hypothesis is that, in addition to repressing viral gene transcription at the nuclear level, T3 may influence PI3K signaling to control HSV-1 replication in human neuron-like cells. We review the genomic and non-genomic regulatory roles of T3 by examining the phosphoinositide 3-kinase (PI3K) pathway gene expression profile changes in differentiated LNCaP cells under the influence of hormone. The results indicated that 15 genes were down-regulated and 22 genes were up-regulated in T3-treated differentiated LNCaP cells in comparison to undifferentiated state. Of all these genes, casein kinase 2 (CK2), a key component to enhance PI3K signaling pathway, was significantly increased upon T3 treatment only while the cells were differentiated. Further studies revealed that CK2 inhibitors tetrabrominated cinnamic acid (TBCA) and 4, 5, 6, 7-tetrabromo-2H-benzotriazole (TBB) both reversed the T3-mediated repression of viral replication. Together these observations suggested a new approach to understanding the roles of T3 in the complicated regulation of HSV-1 replication during latency and reactivation. PMID- 28344766 TI - Phosphorylation of LSD1 by PLK1 promotes its chromatin release during mitosis. AB - BACKGROUND: Lysine-specific histone demethylase 1 (LSD1) modulates chromatin status through demethylation of H3K4 and H3K9. It has been demonstrated that LSD1 is hyperphosphorylated and dissociates from chromatin during mitosis. However, the molecular mechanism of LSD1 detachment is unknown. RESULTS: In this report, we found that polo-like kinase 1 (PLK1) directly interacted with LSD1 and phosphorylated LSD1 at Ser-126 . Nocodazole-induced metaphase arrest promoted release of LSD1 from chromatin, and the phosphorylation-defective mutant LSD1 (S126A) failed to dissociate from chromatin upon nocodazole treatment. CONCLUSIONS: Taken together, our findings demonstrate that phosphorylation of LSD1 at Ser-126 by PLK1 promotes its release from chromatin during mitosis. PMID- 28344767 TI - Finding "truth" across different data sources. AB - The proliferation of new technology platforms and tools is dramatically advancing our ability to capture, integrate and use clinical and other health related data for research and care. Another critical and increasingly common source of data comes directly from patients - often in the form of Patient Reported Outcomes (PRO). As more providers and payers recognize that patient experiences reflect a critical dimension of the value proposition, these data are informing broader strategies to achieve performance improvement and accountability in health systems. Combined with other traditional (e.g., claims) and more recent (e.g., Electronic Health Record) data assets, PROs can help to examine experiences and outcomes that convey a more complete picture of both individual and population health. One of the areas of research where this is most evident is cancer survivorship, including long-term adverse effects, as the population of survivors is increasing given advances in detection and treatment. Key questions remain as to how and under what conditions these new data resources can be used for research, and which are the best "sources of truth" for specific types of information. A recent IJHPR validation study by Hamood et al. reflects important progress in this regard, and establishes the necessary groundwork for a larger planned study. There are some important limitations worth noting, such as a small sample size (which does not support adequate subgroup analysis); a relatively narrow focus on women with only early stage or regionally advanced breast cancer; and a limited focus on outcomes that are primarily clinical and relatively severe in nature (e.g., cardiovascular disease). Finally, as use of EHRs becomes ubiquitous, as patient perspectives and outcome measures are considered, and as more types of data are systematically collected via electronic systems, further comparison and validation of non-clinical data elements captured via such tools will become increasingly possible and important. This will further enhance the capacity of cancer survivorship researchers to address a broader range of important questions to many more types of patients. PMID- 28344768 TI - An end to lifetime blood donation ban in Israel for MSM would be a major step toward a science-based policy that reduces stigma. AB - In recent years, countries around the world have revised their blood donation policies regarding gay and bisexual men, and other men who have sex with men (MSM). The United States lifted the lifetime ban on MSM from donating blood in 2015, replacing it with a 1 year deferral policy allowing MSM to donate if they abstain from sex for 12 months. Other countries followed suit, while Italy and Spain have implemented deferral policies based on individual risk assessments regardless of sexual orientation. If Israel were to adopt a one year deferral policy for MSM, as recommended by Drs. Ginsberg et al. in this issue, the increase in risk to the blood supply would be minimal. Moving to a 1 year deferral policy would be an important step forward, but it could still be seen as stigmatizing to gay and bisexual men. We recommend that Israel consider a deferral policy based on individual risk assessment rather than a blanket deferral for all MSM. MSM can engage in low- and high-risk sexual behaviors. Those who consistently engage in low-risk behaviors, such as using condoms and pre-exposure prophylaxis consistently, pose little risk to the blood supply. An individual risk assessment policy would screen potential donors of all sexual orientations for low-, medium-, and high-risk behaviors. Potential donors identified as high-risk, such as injection drug users, would justifiably be subject to lengthy or permanent bans. MSM who engage in low-risk sexual behaviors would be allowed to donate without deferral. Medium-risk donors, such as men who have recently had unprotected anal sex with another man, would be subject to a deferral period of 1 month, which is in line with the window period of current HIV screening technology. Most fourth generation HIV tests can detect HIV within a month, and the nucleic acid test used to screen blood can detect HIV in just 9 11 days. Various studies have developed questions for ascertaining HIV risk among MSM which could be used in blood donor questionnaires. Using tablets or other technology that enhances privacy to conduct the blood donor questionnaire could improve collection of this sensitive information. PMID- 28344770 TI - Aspiration in injections: should we continue or abandon the practice? AB - Aspiration during any kind of injection is meant to ensure that the needle tip is at the desired location during this blind procedure. While aspiration appears to be a simple procedure, it has generated a lot of controversy concerning the perceived benefits and indications. Advocates and opponents of aspiration both make logically sound claims. However, due to scarcity of available data, there is no evidence that this procedure is truly beneficial or unwarranted. Keeping in view the huge number of injections given worldwide, it is important that we draw attention to key questions regarding aspiration that, up till now, remain unanswered. In this review, we have attempted to gather and present literature on aspiration both from published and non-published sources in order to provide not only an exhaustive review of the subject, but also a starting point for further studies on more specific areas requiring clarification. A literature review was conducted using the US National Institute of Health's PubMed service (including Medline), Google Scholar and Scopus. Guidelines provided by the World Health Organization, Safe Injection Global Network, International Council of Nursing, Center for Disease Control, US Federal Drug Agency, UK National Health Services, British Medical Association, Europe Nursing and Midwifery Council, Public Health Agency Canada, Pakistan Medical Association and International Organization of Standardization recommendations 7886 parts 1-4 for sterile hypodermics were reviewed for relevant information. In addition, curricula of several medical/ nursing schools from India, Nigeria and Pakistan, the US pharmacopeia Data from the WHO Program for International Drug Monitoring network in regard to adverse events as a result of not aspirating prior to injection delivery were reviewed. Curricula of selected major medical/nursing schools in India, Nigeria and Pakistan, national therapeutic formularies, product inserts of most commonly used drugs and other possible sources of information regarding aspiration and injections were consulted as well. PMID- 28344769 TI - Application of antibodies to recombinant heat shock protein 70 in immunohistochemical diagnosis of mycobacterium avium subspecies paratuberculosis in tissues of naturally infected cattle. AB - BACKGROUND: Detection of Mycobacterium avium subspecies paratuberculosis (MAP) infection is key to the control of Johne's disease. Immunohistochemistry is one of the methods of detection of MAP infection in tissues. However, unavailability of commercial antibodies that can detect the organism is a limiting factor for the use of immunohistochemistry. This study was aimed at developing an immunohistochemistry method to diagnose MAP in infected tissues using antibodies against MAP recombinant heat shock protein 70kd. RESULTS: MAP Heat shock protein 70 gene was amplified and cloned into an expression vector, Champion pET-SUMO, then expressed in E coli, purified and used to produce polyclonal rabbit antibodies against the Heat shock protein. Immunohistochemistry was performed in 35 MAP infected tissues with anti-HSP70 polyclonal antibodies. All 35 MAP infected tissues were positive for MAP within macrophages, epithelioid cells and giant cells either in clumps or singly as individual bacilli. No positive staining was seen in the three uninfected normal tissues and in MAP infected tissues where primary antibodies were substituted with PBS or pre-immune serum from the same rabbit. CONCLUSION: Anti-HSP70 produced in this study offers an opportunity for improved diagnosis, screening of MAP in animal tissues and in studies on the pathogenesis of MAP. PMID- 28344771 TI - Synthesis, characterization and toxicity studies of pyridinecarboxaldehydes and L tryptophan derived Schiff bases and corresponding copper (II) complexes. AB - Schiff bases and their metal-complexes are versatile compounds exhibiting a broad range of biological activities and thus actively used in the drug development process. The aim of the present study was the synthesis and characterization of new Schiff bases and their copper (II) complexes, derived from L-tryptophan and isomeric (2-; 3-; 4-) pyridinecarboxaldehydes, as well as the assessment of their toxicity in vitro. The optimal conditions of the Schiff base synthesis resulting in up to 75-85% yield of target products were identified. The structure-activity relationship analysis indicated that the location of the carboxaldehyde group at 2-, 3- or 4-position with regard to nitrogen of the pyridine ring in aldehyde component of the L-tryptophan derivative Schiff bases and corresponding copper complexes essentially change the biological activity of the compounds. The carboxaldehyde group at 2- and 4-positions leads to the higher cytotoxic activity, than that of at 3-position, and the presence of the copper in the complexes increases the cytotoxicity. Based on toxicity classification data, the compounds with non-toxic profile were identified, which can be used as new entities in the drug development process using Schiff base scaffold. PMID- 28344772 TI - Using complex networks for refining survival prognosis in prostate cancer patient. AB - Complex network theory has been used, during the last decade, to understand the structures behind complex biological problems, yielding new knowledge in a large number of situations. Nevertheless, such knowledge has remained mostly qualitative. In this contribution, I show how information extracted from a network representation can be used in a quantitative way, to improve the score of a classification task. As a test bed, I consider a dataset corresponding to patients suffering from prostate cancer, and the task of successfully prognosing their survival. When information from a complex network representation is added on top of a simple classification model, the error is reduced from 27.9% to 23.8%. This confirms that network theory can be used to synthesize information that may not readily be accessible by standard data mining algorithms. PMID- 28344773 TI - Escherichia coli ST131: a multidrug-resistant clone primed for global domination. AB - A single extra-intestinal pathogenic Escherichia coli (ExPEC) clone, named sequence type (ST) 131, is responsible for millions of global antimicrobial resistant (AMR) infections annually. Population genetics indicate that ST131 consists of different clades (i.e. A, B, and C); however, clade C is the most dominant globally. A ST131 subclade, named C1-M27, is emerging in Japan and has been responsible for the recent increase in AMR ExPEC in that country. The sequential acquisition of several virulence and AMR genes associated with mobile genetic elements during the 1960s to 1980s primed clade C (and its subclades C1 and C2) for success in the 1990s to 2000s. IncF plasmids with F1:A2:B20 and F2:A1:B replicons have shaped the evolution of the C1 and C2 subclades. It is possible that ST131 is a host generalist with different accessory gene profiles. Compensatory mutations within the core genome of this clone have counterbalanced the fitness cost associated with IncF plasmids. ST131 clade C had dramatically changed the population structure of ExPEC, but it still remains unclear which features of this clade resulted in one of the most unprecedented AMR successes of the 2000s. PMID- 28344774 TI - The Dockstore: enabling modular, community-focused sharing of Docker-based genomics tools and workflows. AB - As genomic datasets continue to grow, the feasibility of downloading data to a local organization and running analysis on a traditional compute environment is becoming increasingly problematic. Current large-scale projects, such as the ICGC PanCancer Analysis of Whole Genomes (PCAWG), the Data Platform for the U.S. Precision Medicine Initiative, and the NIH Big Data to Knowledge Center for Translational Genomics, are using cloud-based infrastructure to both host and perform analysis across large data sets. In PCAWG, over 5,800 whole human genomes were aligned and variant called across 14 cloud and HPC environments; the processed data was then made available on the cloud for further analysis and sharing. If run locally, an operation at this scale would have monopolized a typical academic data centre for many months, and would have presented major challenges for data storage and distribution. However, this scale is increasingly typical for genomics projects and necessitates a rethink of how analytical tools are packaged and moved to the data. For PCAWG, we embraced the use of highly portable Docker images for encapsulating and sharing complex alignment and variant calling workflows across highly variable environments. While successful, this endeavor revealed a limitation in Docker containers, namely the lack of a standardized way to describe and execute the tools encapsulated inside the container. As a result, we created the Dockstore ( https://dockstore.org), a project that brings together Docker images with standardized, machine-readable ways of describing and running the tools contained within. This service greatly improves the sharing and reuse of genomics tools and promotes interoperability with similar projects through emerging web service standards developed by the Global Alliance for Genomics and Health (GA4GH). PMID- 28344775 TI - Tertiary lymphoid organs in systemic autoimmune diseases: pathogenic or protective? AB - Tertiary lymphoid organs are found at sites of chronic inflammation in autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. These organized accumulations of T and B cells resemble secondary lymphoid organs and generate autoreactive effector cells. However, whether they contribute to disease pathogenesis or have protective functions is unclear. Here, we discuss how tertiary lymphoid organs can generate potentially pathogenic cells but may also limit the extent of the response and damage in autoimmune disease. PMID- 28344776 TI - The mechanism of translation. AB - Translation of the genetic code on the ribosome into protein is a process of extraordinary complexity, and understanding its mechanism has remained one of the major challenges even though x-ray structures have been available since 2000. In the past two decades, single-particle cryo-electron microscopy has contributed a major share of information on structure, binding modes, and conformational changes of the ribosome during its work cycle, but the contributions of this technique in the translation field have recently skyrocketed after the introduction of a new recording medium capable of detecting individual electrons. As many examples in the recent literature over the past three years show, the impact of this development on the advancement of knowledge in this field has been transformative and promises to be lasting. PMID- 28344777 TI - Recent advances in the link between physical activity, sedentary behavior, physical fitness, and colorectal cancer. AB - Physical inactivity is a well-established risk factor for colorectal cancer (CRC). Recent studies have characterized physical activity (PA), sedentary behavior, and cardiorespiratory fitness as distinct, interrelated constructs that influence the risk of CRC and related outcomes. PA levels required to confer protection against CRC may be higher than previously thought. Sedentary behavior, defined as time spent sitting, increases CRC risk independent of PA and may require novel interventions distinct from those targeting PA. Finally, cardiorespiratory fitness is inversely associated with CRC risk and mortality and may provide a potential tool for risk stratification and intervention. PMID- 28344779 TI - Accuracy of the detection of binding events using 3D single particle tracking. AB - BACKGROUND: Nanoparticles can be used as markers to track the position of biomolecules, such as single proteins, inside living cells. The activity of a protein can sometimes be inferred from changes in the mobility of the attached particle. Mean Square Displacement analysis is the most common method to obtain mobility information from trajectories of tracked particles, such as the diffusion coefficient D. However, the precision of D sets a limit to discriminate changes in mobility caused by biological events from changes that reflect the stochasticity inherent to diffusion. This issue is of particular importance in an experiment aiming to quantify dynamic processes. RESULTS: Here, we present simulations and 3D tracking experiments with Gold Nanorods freely diffusing in glycerol solution to establish the best analysis parameters to extract the diffusion coefficient. We applied this knowledge to the detection of a temporary change in diffusion, as it can occur due to the transient binding of a particle to an immobile structure within the cell, and tested its dependence on the magnitude of the change in diffusion and duration of this event. CONCLUSIONS: The simulations show that the spatial accuracy of particle tracking generally does not limit the detection of short binding events. Careful analysis of the magnitude of the change in diffusion and the number of frames per binding event is required for accurate quantification of such events. PMID- 28344778 TI - Methodological advances in imaging intravital axonal transport. AB - Axonal transport is the active process whereby neurons transport cargoes such as organelles and proteins anterogradely from the cell body to the axon terminal and retrogradely in the opposite direction. Bi-directional transport in axons is absolutely essential for the functioning and survival of neurons and appears to be negatively impacted by both aging and diseases of the nervous system, such as Alzheimer's disease and amyotrophic lateral sclerosis. The movement of individual cargoes along axons has been studied in vitro in live neurons and tissue explants for a number of years; however, it is currently unclear as to whether these systems faithfully and consistently replicate the in vivo situation. A number of intravital techniques originally developed for studying diverse biological events have recently been adapted to monitor axonal transport in real-time in a range of live organisms and are providing novel insight into this dynamic process. Here, we highlight these methodological advances in intravital imaging of axonal transport, outlining key strengths and limitations while discussing findings, possible improvements, and outstanding questions. PMID- 28344781 TI - Patient-specific three-dimensional explant spheroids derived from human nasal airway epithelium: a simple methodological approach for ex vivo studies of primary ciliary dyskinesia. AB - BACKGROUND: Three-dimensional explant spheroid formation is an ex vivo technique previously used in studies of airway epithelial ion and water transport. Explanted cells and sheets of nasal epithelium form fully differentiated spheroids enclosing a partly fluid-filled lumen with the ciliated apical surface facing the outside and accessible for analysis of ciliary function. METHODS: We performed a two-group comparison study of ciliary beat pattern and ciliary beat frequency in spheroids derived from nasal airway epithelium in patients with primary ciliary dyskinesia (PCD) and in healthy controls. Nasal ciliary cells and sheets were removed on day 1 by nasal brush biopsy and analyzed with regard to ciliary beat pattern-and frequency using high-speed video imaging for standard reference values. Three-dimensional explant spheroid formation was initiated in the same individual on the same day by incubation of cells and sheets from a separate brush biopsy. Harvested spheroids were analyzed earliest possible and values of spheroid ciliary beat pattern and frequency were compared to the corresponding reference values from day 1. RESULTS: Spheroids formed fast in serum-free culture medium. Formation was successful in 15 out of 18 (82%) sampled individuals. Thus, formation was successful in seven healthy controls and eight PCD patients, while unsuccessful in 3 with PCD due to infection. Median (range) number of days in culture before harvesting of spheroids was 4 (1-5) in healthy versus 2 (1-5) in PCD. Spheroid ciliary beat pattern and frequency were unchanged compared to their corresponding day 1 standard reference values. Spheroid ciliary beat frequency discriminated highly significant between healthy controls (9.3 Hz) and PCD patients (2.4 Hz) (P < 0.0001). Survival of spheroids was 16 days in a single healthy person. CONCLUSION: Patient-specific three-dimensional explant spheroid formation from a minimal invasive nasal brush biopsy is a feasible, fast and valid ex vivo method to assess ciliary function with potential of aiding the diagnosis of PCD. In addition, it may be a useful model in the investigation of pathophysiological aspects and drug effects in human nasal airway epithelium. PMID- 28344780 TI - Abnormal glycosylation in Joubert syndrome type 10. AB - BACKGROUND: The discovery of disease pathogenesis requires systematic agnostic screening of multiple homeostatic processes that may become deregulated. We illustrate this principle in the evaluation and diagnosis of a 5-year-old boy with Joubert syndrome type 10 (JBTS10). He carried the OFD1 mutation p.Gln886Lysfs*2 (NM_003611.2: c.2656del) and manifested features of Joubert syndrome. METHODS: We integrated exome sequencing, MALDI-TOF mass spectrometry analyses of plasma and cultured dermal fibroblasts glycomes, and full clinical evaluation of the proband. Analyses of cilia formation and lectin staining were performed by immunofluorescence. Measurement of cellular nucleotide sugar levels was performed with high-performance anion-exchange chromatography with pulsed amperometric detection. Statistical analyses utilized the Student's and Fisher's exact t tests. RESULTS: Glycome analyses of plasma and cultured dermal fibroblasts identified abnormal N- and O-linked glycosylation profiles. These findings replicated in two unrelated males with OFD1 mutations. Cultured fibroblasts from affected individuals had a defect in ciliogenesis. The proband's fibroblasts also had an abnormally elevated nuclear sialylation signature and increased total cellular levels of CMP-sialic acid. Ciliogenesis and each glycosylation anomaly were rescued by expression of wild-type OFD1. CONCLUSIONS: The rescue of ciliogenesis and glycosylation upon reintroduction of WT OFD1 suggests that both contribute to the pathogenesis of JBTS10. PMID- 28344782 TI - La-related protein 6 controls ciliated cell differentiation. AB - BACKGROUND: La-related protein 6 (LARP6) is an evolutionally conserved RNA binding protein. Vertebrate LARP6 binds the 5' stem-loop found in mRNAs encoding type I collagen to regulate their translation, but other target mRNAs and additional functions for LARP6 are unknown. The aim of this study was to elucidate an additional function of LARP6 and to evaluate the importance of its function during development. METHODS: To uncover the role of LARP6 in development, we utilized Morpholino Oligos to deplete LARP6 protein in Xenopus embryos. Then, embryonic phenotypes and ciliary structures of LAPR6 morphants were examined. To identify the molecular mechanism underlying ciliogenesis regulated by LARP6, we tested the expression level of cilia-related genes, which play important roles in ciliogenesis, by RT-PCR or whole mount in situ hybridization (WISH). RESULTS: We knocked down LARP6 in Xenopus embryos and found neural tube closure defects. LARP6 mutant, which compromises the collagen synthesis, could rescue these defects. Neural tube closure defects are coincident with lack of cilia, antenna-like cellular organelles with motility- or sensory related functions, in the neural tube. The absence of cilia at the epidermis was also observed in LARP6 morphants, and this defect was due to the absence of basal bodies which are formed from centrioles and required for ciliary assembly. In the process of multi-ciliated cell (MCC) differentiation, mcidas, which activates the transcription of genes required for centriole formation during ciliogenesis, could partially restore MCCs in LARP6 morphants. In addition, LARP6 likely controls the expression of mcidas in a Notch-independent manner. CONCLUSIONS: La related protein 6 is involved in ciliated cell differentiation during development by controlling the expression of cilia-related genes including mcidas. This LARP6 function involves a mechanism that is distinct from its established role in binding to collagen mRNAs and regulating their translation. PMID- 28344783 TI - Retrospective report of antimicrobial susceptibility observed in bacterial pathogens isolated from ocular samples at Mount Sinai Hospital, 2010 to 2015. AB - BACKGROUND: Antimicrobial resistance has emerged as a major threat to global public health. Thus, the surveillance of changes in antimicrobial resistance in local and global settings is a paramount necessity. While many studies have tracked antimicrobial resistance, only a small percentage surveyed ocular isolates. The purpose of this study was to report the in vitro susceptibility of bacterial pathogens isolated from ocular samples in New York, NY from 2010 to 2015. METHODS: A retrospective review of ocular isolates was conducted. All organisms were collected by 25 separate inpatient wards and outpatient clinics, and were analyzed by the clinical microbiology laboratory at Mount Sinai Hospital. Clinical Laboratory and Standards Institute (CLSI) guidelines were followed for susceptibility testing and breakpoint interpretations. RESULTS: A total of 549 bacterial organisms were isolated from 1664 cultures (33%) during the 6-year study period. Of these, 358 isolates (65.2%) underwent susceptibility testing. 182 (50.8%) isolates were Gram-positive. The most common Gram-positive bacterium was Staphylococcus aureus (62.1%). Methicillin-resistance decreased in S. aureus isolates (31.3% in 2010, 14.1% in 2015) but was without significant change (p = 0.25). When analyzing all S. aureus isolates recovered during the study period, there were significantly more methicillin-resistant S. aureus (MRSA) isolates resistant to fluoroquinolones (p <0.0001), erythromycin (p <0.0001), and trimethoprim/sulfamethoxazole (TMP/SMZ; p <0.05). Overall, Streptococcus pneumoniae isolates showed reduced susceptibility to erythromycin, but were otherwise susceptible to the other antimicrobials tested. Haemophilus influenzae (26.1%) and Pseudomonas aeruginosa (23.9%) were the most common Gram negative bacteria isolated. Resistance to ampicillin and TMP/SMZ was observed in several of the H. influenzae isolates. P. aeruginosa isolates did not show high resistance overall, however, it was noted that isolates resistant to meropenem were also resistant to other antimicrobials (p < 0.01). CONCLUSION: Overall, antimicrobial resistance was infrequent for the Gram-negative and Gram-positive bacteria analyzed. While the MRSA isolates demonstrated increased resistance to multiple antimicrobial classes, this is expected for this pathogen. Due to the continued use of broad-spectrum oral and systemic antimicrobials to treat ocular infections, findings of this study and other surveillance studies specific to ocular isolates should be used as resources in effective decision making in the treatment of ocular disease. PMID- 28344784 TI - Effects of Tamsulosin and Tolterodine on double J stent-related symptoms: A double-blind, randomized, placebo-controlled trial. AB - BACKGROUND: Ureteral double J stent are routinely applied for urologic patients although stent-related symptoms are common. Several attempts have been reported to minimize these symptoms. OBJECTIVE: To compare Tolterodine, Tamsulosin, and placebo effects on double J stent-related symptoms. MATERIAL AND METHOD: In all, 125 patients (82 males and 43 females) with double J stent were randomly divided into three groups (group 1, n: 42, group2, n: 40 and group 3, n: 43). Each patient randomly received one pack of drug in different colors by a nurse unaware of the content to take Tamsulosin 0.4 mg before sleep (MODALUSINE), Tolterodine 2 mg twice a day or placebo once daily (capsules filled with starch): group 1 received placebo, group 2 Tamsulosin and group 3 Tolterodine for 1 month in a double-blind manner. Ureteral stent-related morbidity indices which analyzed include urinary symptom, pain, general health, quality of work and sex scores. All of indices measured by Ureteral Symptom Score Questionnaire for first and fourth weeks after drug consumption and the first week after double J stent removal (labeled as w1, w4, and w5, respectively). RESULT: The mean age was 44.8 years (range: 15-83 years). There was no statistically significant difference in background characteristics between groups (p value > 0.05). The most important and statistically significant results were Tolterodine-reduced urinary symptom score (p value = 0.001) and improved general health score (p value = 0.007) of the fourth week. The pain score in groups of Tamsulosin and Tolterodine significantly reduced between weeks 4 and 1 and 5 and 1 (both with the p value < 0.05), but in other indices, there was no significant difference between them. CONCLUSION: According to our results, we suggest Tolterodine to minimize stent related urinary symptom and improve general health in patients with double J stent. PMID- 28344785 TI - FITting ADR to colonoscopy indication. PMID- 28344787 TI - Allele-specific transcriptional activity of the variable number of tandem repeats of the inducible nitric oxide synthase gene is associated with idiopathic achalasia. AB - BACKGROUND: Polymorphisms of genes involved in the regulation of the immune response are risk factors for achalasia, but their contribution to disease pathogenesis is unknown. Nitric oxide is involved both in immune function and inhibitory neurotransmission. OBJECTIVE: The objective of this article is to assess the association and the functional relevance of the CCTTT-inducible nitric oxide synthase (NOS2) gene promoter polymorphism in achalasia. METHODS: Genomic DNA was isolated from 181 achalasia patients and 220 controls. Genotyping of the (CCTTT)n repeats was performed by PCR and capillary electrophoresis, and data analyzed by considering the frequency of the different alleles. HT29 cells were transfected with iNOS luciferase promoter-reporter plasmids containing different (CCTTT)n. RESULTS: The alleles' distribution ranged from 7 to 18, with a peak frequency at 12 repeats. Analysis of the allele frequencies revealed that individuals carrying 10 and 13 CCTTT repeats were respectively less and more frequent in achalasia (OR 0.5, 95% CI 0.3-0.5 and OR 1.6, 95% CI 1-2.4, all p < 0.05). Long repeats were also significantly associated with an earlier onset of the disease (OR 1.69, 95% CI 1.13-2.53, p = 0.01). Transfection experiments revealed a similar allele-specific iNOS transcriptional activity. CONCLUSION: The functional polymorphism (CCTTT) of NOS2 promoter is associated with achalasia, likely by an allele-specific modulation of nitric oxide production. PMID- 28344788 TI - Lymphoma development and survival in refractory coeliac disease type II: Histological response as prognostic factor. AB - BACKGROUND: Refractory coeliac disease type II (RCDII) frequently transforms into an enteropathy-associated T-cell lymphoma (EATL) and therefore requires intensive treatment. Current evaluated treatment strategies for RCDII include cladribine (2 CdA) and autologous stem cell transplantation (auSCT). OBJECTIVE: The purpose of this study was to evaluate long-term survival and define clear prognostic criteria for EATL development comparing two treatment strategies. METHODS: A total of 45 patients were retrospectively analysed. All patients received 2-CdA, after which they were either closely monitored (monotherapy, n = 30) or a step-up approach was used including auSCT (step-up therapy, n = 15). RESULTS: Ten patients (22%) ultimately developed EATL; nine of these had received monotherapy. Absence of histological remission after monotherapy was associated with EATL development (p = 0.010). Overall, 20 patients (44%) died with a median survival of 84 months. Overall survival (OS) within the monotherapy group was significantly worse in those without histological remission compared to those with complete histological remission(p = 0.030). The monotherapy group who achieved complete histological remission showed comparable EATL occurrence and OS as compared to the step-up therapy group (p = 0.80 and p = 0.14 respectively). CONCLUSION: Histological response is an accurate parameter to evaluate the effect of 2-CdA therapy and this parameter should be leading in the decisions whether or not to perform a step-up treatment approach in RCDII. PMID- 28344786 TI - United European Gastroenterology evidence-based guidelines for the diagnosis and therapy of chronic pancreatitis (HaPanEU). AB - BACKGROUND: There have been substantial improvements in the management of chronic pancreatitis, leading to the publication of several national guidelines during recent years. In collaboration with United European Gastroenterology, the working group on 'Harmonizing diagnosis and treatment of chronic pancreatitis across Europe' (HaPanEU) developed these European guidelines using an evidence-based approach. METHODS: Twelve multidisciplinary review groups performed systematic literature reviews to answer 101 predefined clinical questions. Recommendations were graded using the Grading of Recommendations Assessment, Development and Evaluation system and the answers were assessed by the entire group in a Delphi process online. The review groups presented their recommendations during the 2015 annual meeting of United European Gastroenterology. At this one-day, interactive conference, relevant remarks were voiced and overall agreement on each recommendation was quantified using plenary voting (Test and Evaluation Directorate). After a final round of adjustments based on these comments, a draft version was sent out to external reviewers. RESULTS: The 101 recommendations covered 12 topics related to the clinical management of chronic pancreatitis: aetiology (working party (WP)1), diagnosis of chronic pancreatitis with imaging (WP2 and WP3), diagnosis of pancreatic exocrine insufficiency (WP4), surgery in chronic pancreatitis (WP5), medical therapy (WP6), endoscopic therapy (WP7), treatment of pancreatic pseudocysts (WP8), pancreatic pain (WP9), nutrition and malnutrition (WP10), diabetes mellitus (WP11) and the natural course of the disease and quality of life (WP12). Using the Grading of Recommendations Assessment, Development and Evaluation system, 70 of the 101 (70%) recommendations were rated as 'strong' and plenary voting revealed 'strong agreement' for 99 (98%) recommendations. CONCLUSIONS: The 2016 HaPanEU/United European Gastroenterology guidelines provide evidence-based recommendations concerning key aspects of the medical and surgical management of chronic pancreatitis based on current available evidence. These recommendations should serve as a reference standard for existing management of the disease and as a guide for future clinical research. PMID- 28344789 TI - A PPAR-gamma agonist protects from radiation-induced intestinal toxicity. AB - OBJECTIVE: Because of its anti-inflammatory, anti-fibrotic, anti-apoptotic and anti-neoplastic properties, the PPAR-gamma agonist rosiglitazone is an interesting drug for investigating for use in the prevention and treatment of radiation-induced intestinal damage. We aimed to evaluate the radioprotective effect of rosiglitazone in a murine model of acute intestinal damage, assessing whether radioprotection is selective for normal tissues or also occurs in tumour cells. METHODS: Mice were total-body irradiated (12 Gy), with or without rosiglitazone (5 mg/kg/day). After 24 and 72 hours, mice were sacrificed and the jejunum was collected. HT-29 human colon cancer cells were irradiated with a single dose of 2 (1000 cells), 4 (1500 cells) or 6 (2000 cells) Gy, with or without adding rosiglitazone (20 uM) 1 hour before irradiation. HT-29-xenografted CD1 mice were irradiated (16 Gy) with or without rosiglitazone; tumour volumes were measured for 33 days. RESULTS: Rosiglitazone markedly reduced histological signs of altered bowel structures, that is, villi shortening, submucosal thickening, necrotic changes in crypts, oedema, apoptosis, and inflammatory infiltrate induced by irradiation. Rosiglitazone significantly decreased p-NF-kB p65 phosphorylation and TGFbeta protein expression at 24 and 72 hours post irradiation and significantly decreased gene expression of Collagen1, Mmp13, Tnfalpha and Bax at 24 hours and p53 at 72 hours post-irradiation. Rosiglitazone reduced HT-29 clonogenic survival, but only produced a slight reduction of xenograft tumour growth. CONCLUSION: Rosiglitazone exerts a protective effect on normal tissues and reduces alterations in bowel structures and inflammation in a radiation-induced bowel toxicity model, without interfering with the radiation effect on HT-29 cancer cells. PPAR-gamma agonists should be further investigated for their application in abdominal and pelvic irradiation. PMID- 28344790 TI - Prognostic factors of hepatocellular carcinoma survival after radiofrequency ablation: A US population-based study. AB - OBJECTIVE: To determine the survival outcome and prognostic factors of hepatocellular carcinoma (HCC) survival in patients who underwent radiofrequency ablation (RFA). METHODS: The Surveillance, Epidemiology and End Results (SEER) database was queried: There were 2588 HCC patients from 2004 to 2012 who underwent RFA. The Kaplan-Meier curves and the multivariate Cox regression analysis were used to assess the prognostic factors. RESULTS: With a median follow-up of 20 months, the 1-, 3- and 5-year overall survival (OS) rates were: 83%, 51% and 33%. Patients with a tumor size <=5 cm in diameter had a better 5 year OS, as compared to patients with a tumor size >5 cm. The 5-year OS was significantly higher among patients with a normal level of alpha-fetoprotein (AFP), compared with those having elevated AFP. In an adjusted multivariate Cox regression analysis, those with >=60 years of age (HR: 1.19; 95% CI 1.05-1.36), non-Asian race (HR: 1.53; 95% CI 1.30-1.81), tumor size >5 cm (HR: 1.43; 95% CI 1.24-1.65), elevated AFP (HR: 1.42; 95% CI 1.22-1.64), American Joint Committee on Cancer (AJCC) stages II-III (HR: 1.30; 95% CI 1.14-1.48) and the year of diagnosis from 2004-2007 (HR: 1.22; 95% CI 1.07-1.40) were significantly associated with a poor prognosis. CONCLUSIONS: Age, race, tumor size, AFP level, AJCC stage and year of diagnosis were prognostic factors for OS in HCC patients who underwent RFA. PMID- 28344791 TI - Differential diagnosis of solid pancreatic masses: contrast-enhanced harmonic (CEH-EUS), quantitative-elastography (QE-EUS), or both? AB - BACKGROUND: Contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) and quantitative-elastography endoscopic ultrasound (QE-EUS) are considered useful tools for the evaluation of solid pancreatic tumors (SPT). The aim of our study was to evaluate the diagnostic accuracy of CEH-EUS, QE-EUS, and the combination of both for the differential diagnosis of SPT. METHODS: Sixty-two consecutive patients (mean age 64.3 years, range 32-89 years, 44 male) who underwent EUS for the evaluation of SPT were prospectively included. EUS was performed with a linear Pentax-EUS and a Hitachi-Preirus processor. The mass (area A) and a reference area B were selected during QE-EUS, and results expressed as B/A (strain ratio). A strain histogram of the mass was also evaluated. Microvascularization of the tumor was evaluated over 2 min during CEH-EUS after intravenous injection of 4.8 mL SonoVue. Final diagnosis was based on histopathology of surgical specimens or EUS-guided tissue acquisition and clinical follow-up in non-operated cases. Diagnostic accuracy of CEH-EUS, QE-EUS, and their combination was calculated. RESULTS: Median size of the masses was 32 mm (range 12-111). Final diagnosis was pancreatic adenocarcinoma (n = 45), neuroendocrine tumor (n = 3), inflammatory mass (n = 10), pancreatic metastasis (n = 2), autoimmune pancreatitis (n = 1), and a mucinous cystadenocarcinoma (n = 1). Overall accuracies for determination of malignancy using QE-EUS, CEH-EUS, their combination, and EUS-guided tissue acquisition were 98.4% (95% confidence interval (CI): 91.4-99.7), 85.5% (95% CI: 74.7-92.2), 91.9% (95% CI: 82.5-96.5), and 91.5% (95% CI: 83.6-99.5), respectively. CONCLUSION: The combination of QE EUS and CEH-EUS is a useful tool for the differential diagnosis of SPT, giving complementary information. However, this combination does not significantly increase the diagnostic accuracy of either of the techniques performed alone. PMID- 28344792 TI - Establishment of Over-The-Scope-Clips (OTSC(r)) in daily endoscopic routine. AB - BACKGROUND: Alongside the evolution of interventional endoscopy, the need for a more sophisticated closure tool tailored to the treatment of new challenging indications has been increasing rapidly. METHODS: We here present our collected data on 262 Over-The-Scope-Clip (OTSC(r)) placements in a total of 233 interventions at our institution. Follow-up was focused on clinically lasting success with regards to different indications. RESULTS: Immediate success of OTSC(r) treatment was observed in 87.1% of all sessions (203/233). The success rates per indication were as follows: spontaneous bleeding 84.8% (28/33); iatrogenic bleeding 100% (20/20); acute perforation 90.3% (65/72); prophylaxis for perforation 100% (24/24); anastomotic leakage 61.1% (11/18); fistulae 80.7% (46/57); diameter reduction of the gastrojejunal anastomosis 100% (6/6); and stent fixation 100% (3/3). At 30-day follow-up, the overall success rate was 67.4% (157/233). The success rates per indication were as follows: spontaneous bleeding 69.7% (23/33); iatrogenic bleeding 90% (18/20); acute perforation 86.1% (62/72); prophylaxis for perforation 100% (24/24); anastomotic leakage 33.3% (6/18); fistulae 29.8% (17/57), diameter reduction of the gastrojejunal anastomosis 83.3% (5/6); and stent fixation 66% (2/3). CONCLUSIONS: Our cohort confirms previous data on the clinical usefulness of the OTSC(r) in daily routine practice. PMID- 28344793 TI - Correlation between adenoma detection rate in colonoscopy- and fecal immunochemical testing-based colorectal cancer screening programs. AB - BACKGROUND: The adenoma detection rate (ADR) is the main quality indicator of colonoscopy. The ADR recommended in fecal immunochemical testing (FIT)-based colorectal cancer screening programs is unknown. METHODS: Using the COLONPREV (NCT00906997) study dataset, we performed a post-hoc analysis to determine if there was a correlation between the ADR in primary and work-up colonoscopy, and the equivalent figure to the minimal 20% ADR recommended. Colonoscopy was performed in 5722 individuals: 5059 as primary strategy and 663 after a positive FIT result (OC-SensorTM; cut-off level 15 ug/g of feces). We developed a predictive model based on a multivariable lineal regression analysis including confounding variables. RESULTS: The median ADR was 31% (range, 14%-51%) in the colonoscopy group and 55% (range, 21%-83%) in the FIT group. There was a positive correlation in the ADR between primary and work-up colonoscopy (Pearson's coefficient 0.716; p < 0.001). ADR in the FIT group was independently related to ADR in the colonoscopy group: regression coefficient for colonoscopy ADR, 0.71 (p = 0.009); sex, 0.09 (p = 0.09); age, 0.3 (p = 0.5); and region 0.00 (p = 0.9). The equivalent figure to the 20% ADR was 45% (95% confidence interval, 35%-56%). CONCLUSIONS: ADR in primary and work-up colonoscopy of a FIT-positive result are positively and significantly correlated. PMID- 28344794 TI - Does calprotectin level identify a subgroup among patients suffering from irritable bowel syndrome? Results of a prospective study. AB - BACKGROUND: Irritable bowel syndrome is a multifactorial disease. Although faecal calprotectin has been shown to be a reliable marker of intestinal inflammation, its role in irritable bowel syndrome remains debated. OBJECTIVE: The aims of this prospective study were to select a subgroup of irritable bowel syndrome patients and to characterise those patients with high faecal calprotectin by systematic work-up. METHODS: Calprotectin levels were determined by enzyme-linked immunosorbent assay test in consecutive irritable bowel syndrome patients fulfilling Rome III criteria in whom normal colonoscopy and appropriate tests had excluded organic disease. Calprotectin levels were compared in irritable bowel syndrome patients, healthy controls and patients with active and quiescent Crohn's disease. When the calprotectin level was higher than 50 ug/g, the absence of ANCA/ASCA antibodies and a normal small bowel examination were required to confirm irritable bowel syndrome diagnosis. Additional explorations included assessment of irritable bowel syndrome severity, anxiety and depression, impact on quality of life, glucose and fructose breath tests, rectal distension test by barostat and quantitative and qualitative assessment of inflammation on colonic biopsies. RESULTS: Among the 93 irritable bowel syndrome patients (73% women; 66.7% with diarrhoea) recruited, 34 (36.6%) had reproducibly elevated calprotectin. Although they tended to be older than those with normal calprotectin (P = 0.06), there were no other differences between the two groups. When elevated, calprotectin was correlated with age (P = 0.03, r = 0.22). CONCLUSIONS: Elevated faecal calprotectin was observed in one third of patients in this series, without any significant association with a specific clinical phenotype (except age) or specific abnormalities. PMID- 28344795 TI - Validation of a tool predicting important findings on computed tomography among Crohn's disease patients. AB - BACKGROUND: Patients with Crohn's disease (CD) are frequently subjected to computed tomography (CT) in the emergency department (ED). This young population is at higher risk of malignancy from radiation exposure. OBJECTIVES: We aimed to validate a decision tool predicting complications (perforation, abscess or other serious finding) on imaging at two sites. METHODS: We conducted a retrospective review of CT outcomes among patients with CD with ED visits at two tertiary care centers. Inclusion criteria were a CT of the abdomen/pelvis with contrast and complete lab data (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) within 24 hours of arrival at the University of Michigan (UM) (2012-2013) and the University of Pittsburgh (UPMC) (2009-2012). Sensitivity, negative predictive value (NPV), miss rate and CT avoidance rate were calculated. RESULTS: At UPMC (n = 210), the tool had a sensitivity of 88.9% and NPV of 98.0%, potentially saving 47.1% from CT with a miss rate of 1.0%. At UM (n = 248), the tool had a sensitivity of 90.9% and NPV of 96.0%, saving 40.3% from CT with a miss rate of 1.6%. CONCLUSION: A decision tool using CRP and ESR predicting CT outcomes among CD patients performed well in an external validation, allowing providers to forgo CT use with a low miss rate. PMID- 28344796 TI - Quality of colonoscopy in an emerging country: A prospective, multicentre study in Russia. AB - BACKGROUND: The quality of colonoscopy has been related to a higher risk of interval cancer, and this issue has been addressed extensively in developed countries. The aim of our study was to explore the main quality indicators of colonoscopy in a large emerging country. METHODS: Consecutive patients referred for colonoscopy in 14 centres were prospectively included between July and October 2014. Before colonoscopy, several clinical and demographic variables were collected. Main quality indicators (i.e. caecal intubation rate, (advanced) adenoma detection rate, rate of adequate cleansing and sedation) were collected. Data were analysed at per patient and per centre level (only for those with at least 100 cases). Factors associated with caecal intubation rate and adenoma detection rate were explored at multivariate analysis. RESULTS: A total of 8829 (males: 35%; mean age: 57 + 14 years) patients were included, with 11 centres enrolling at least 100 patients. Screening (including non-alarm symptoms) accounted for 59% (5188/8829) of the indications. Sedation and split preparation were used in 26% (2294/8829) and 25% (2187/8829) of the patients. Caecal intubation was achieved in 7616 patients (86%), and it was >=85% in 8/11 (73%) centres. Adenoma detection rate was 18% (1550/8829), and it was higher than 20% in five (45%) centres, whilst it was lower than 10% in four (33%) centres. At multivariate analysis, age (OR: 1.020, 95% CI: 1.015-1.024), male sex (OR: 1.2, 95% CI: 1.1-1.3), alarm symptoms (OR: 1.8, 95% CI: 1.7-2), split preparation (OR: 1.4, 95% CI: 1.2-1.6), caecal intubation rate (OR: 1.6, 95% CI: 1.3-1.9) and withdrawal time measurement (OR: 1.2, 95% CI: 1.6-2.1) were predictors of a higher adenoma detection rate, while adequate preparation (OR: 3.4: 95% CI: 2.9 3.9) and sedation (OR: 1.3; 95% CI: 1.1-1.6) were the strongest predictors of caecal intubation rate. CONCLUSIONS: According to our study, there is a substantial intercentre variability in the main quality indicators. Overall, the caecal intubation rate appears to be acceptable in most centres, whilst the overall level of adenoma detection appears low, with less than half of the centres being higher than 20%. Educational and quality assurance programs, including higher rates of sedation and split regimen of preparation, may be necessary to increase the key quality indicators. PMID- 28344797 TI - Poor reproducibility of breath hydrogen testing: Implications for its application in functional bowel disorders. AB - BACKGROUND: Limited data are available regarding the reproducibility of lactulose and fructose breath testing for clinical application in functional bowel disorders. OBJECTIVES: The purpose of this study was to investigate the reproducibility of lactulose and fructose breath hydrogen testing and assess symptom response to fructose testing. METHODS: Results were analysed from 21 patients with functional bowel disorder with lactulose breath tests and 30 with fructose breath tests who completed another test >2 weeks later. Oro-caecal transit time, hydrogen responses, both qualitatively (positive/negative) and quantitatively (area under the curve (AUC) for hydrogen), were compared between tests. In another 36 patients, data scores for overall abdominal symptoms, abdominal pain, bloating, wind, nausea and fatigue were collected during the fructose test and compared to hydrogen responses. RESULTS: No correlations were found for lactulose AUC (linear regression, p = 0.58) or transit time (Spearman's p = 0.54) between tests. A significant proportion (30%) lost the presence of fructose malabsorption (p < 0.01). Hydrogen AUC for fructose did not correlate between tests, (r = 0.28, p = 0.17) independent of time between testing (p = 0.82). Whilst patients with fructose malabsorption were more likely to report symptoms than those without (56% vs 17%; p = 0.04), changes in symptom severity were not different (p > 0.05). CONCLUSIONS: Routine use of lactulose and fructose breath tests in functional bowel disorder patients is not supported due to its poor reproducibility and low predictive value for symptom responses. PMID- 28344799 TI - Young researchers at UEG Week. PMID- 28344798 TI - Long-term outcomes of Botulinum toxin in the treatment of chronic anal fissure: 5 years of follow-up. AB - BACKGROUND: Chronic anal fissure is a frequent and disabling disease, often affecting young adults. Botulinum toxin and lateral internal sphincterotomy are the main therapeutic options for refractory cases. Botulinum toxin is minimally invasive and safer compared with surgery, which carries a difficult post operative recovery and fecal incontinence risk. The long-term efficacy of Botulinum toxin is not well known. OBJECTIVE: The aim of this study was to evaluate the long-term efficacy and safety of Botulinum toxin in the treatment of chronic anal fissure. METHODS: This was a retrospective study at a single center, including patients treated with Botulinum toxin from 2005 to 2010, followed over at least a period of 5 years. All patients were treated with injection of 25U of Botulinum toxin in the intersphincteric groove. The response was registered as complete, partial, refractory and relapse. RESULTS: Botulinum toxin was administered to 126 patients, 69.8% (n = 88) were followed over a period of 5 years. After 3 months, 46.6% (n = 41) had complete response, 23.9% (n = 21) had partial response and 29.5% (n = 26) were refractory. Relapse was observed in 1.2% (n = 1) at 6 months, 11.4% (n = 10) at 1 year, 2.3% (n = 2) at 3 years; no relapse at 5 years. The overall success rate was 64.8% at 5 years of follow-up. Botulinum toxin was well tolerated by all patients and there were no complications. CONCLUSION: The use of Botulinum toxin to treat patients with chronic anal fissure was safe and effective in long-term follow-up. PMID- 28344800 TI - How to get your work published: Tricks and pearls. PMID- 28344802 TI - Erratum. AB - [This corrects the article DOI: 10.1177/2050640615602571.]. PMID- 28344804 TI - Multicomponent meningococcal B vaccination (4CMenB) of adolescents and college students in the United States. AB - Meningococcal disease is rare, easily misdiagnosed, and potentially deadly. Diagnosis in the early stages is difficult and the disease often progresses extremely rapidly. In North America, the incidence of invasive meningococcal disease (IMD) is highest in infants and young children, with a secondary peak in adolescents, a population predominantly responsible for the carriage of disease. Neisseria meningitidis serogroup B (MenB) accounts for a large proportion of meningococcal disease in North America, with documented outbreaks in three universities in the United States (US) during 2008-2013. Vaccination is the most effective way to protect against this aggressive disease that has a narrow timeframe for diagnosis and treatment. 4CMenB is a multi-component vaccine against MenB which contains four antigenic components. We describe in detail the immunogenicity and safety profile of 4CMenB based on results from four clinical trials; the use of 4CMenB to control MenB outbreaks involving vaccination at two US colleges during outbreaks in 2013-2014; and the use of 4CMenB in a Canadian mass vaccination campaign to control the spread of MenB disease. We discuss the reasons why adolescents should be vaccinated against MenB, by examining both the peak in disease incidence and carriage. We consider whether herd protection may be attained for MenB, by discussing published models and comparing with meningitis C (MenC) vaccines. In conclusion, MenB vaccines are now available in the US for people aged 10-25 years, representing an important opportunity to reduce the incidence of IMD in the country across the whole population, and more locally to combat MenB outbreaks. PMID- 28344803 TI - Length of hospitalization is associated with selected biomarkers (albumin and lymphocytes) and with co-morbidities: study on 4000 patients. AB - BACKGROUND: Low albumin levels and low lymphocyte counts are intra hospital conditions that exert a negative influence on prognosis, healing and length of hospitalization. The study aimed to analyze the correlation between low blood levels of albumin, low lymphocytes, and length of stay. The secondary aim was to identify other co-morbidities associated with prolonged hospital stay. METHODS: Retrospective pilot study was conducted by analyzing anamnestic and biochemical data, related to 4038 patients admitted to ten wards of Hospital San Paolo (Milan), collected from July 1st 2012 to December 31st 2012. A statistical analysis was carried out using the Correlation method, Multivariate Analysis and Regression. Lymphocyte count and co-morbidities were evaluated in the whole cohort, albumin levels in 1437 patients. RESULTS: In the whole sample, low albumin levels and low lymphocyte counts were directly correlated to longer hospitalizations. The stratification of the results by department and diagnosis suggests that there is a higher correlation in certain subpopulations, and albumin shows a greater correlation with length of stay than lymphocytes. Also advanced age, high platelets, type of diagnosis, male gender and emergency admission led to longer hospitalizations. CONCLUSIONS: A routine check of albumin, lymphocytes and a spectrum of significant variables can provide precious information which can eventually lead to a shorter hospital stay. Knowledge of the general health status of a patient and the possibility to estimate his/her length of hospital stay are essential information for Clinical Governance, and for the improvement of internal services of hospitals on a large scale. PMID- 28344805 TI - Utilization of cholera toxin B as a mucosal adjuvant elicits antibody-mediated protection against S. pneumoniae infection in mice. AB - BACKGOUND: The introduction of the pneumococcal conjugate and polysaccharide vaccines have been valuable tools for combating invasive pneumococcal infection in children and healthy adults. Despite the available vaccination strategies, pneumococcal pneumonia and associated diseases continue to cause substantial morbidity and mortality, particularly in individuals with chronic disease and ageing populations. Next-generation pneumococcal vaccines will need to be highly immunogenic across patient populations providing both mucosal and systemic protective immunity. Mucosal immunization is an effective strategy for stimulating the immune response at the site of pathogen entry while increasing systemic immunity. In this study we utilized intranasal immunization with pneumococcal surface protein A (PspA), in combination with the mucosal adjuvant cholera toxin B (CTB), to characterize the immune components providing protection against S. pneumoniae challenge. METHODS: Mice were immunized intranasally with CTB and PspA individually, and in combination, followed by lethal bacterial challenge with S. pneumoniae, strain A66.1. Animals were monitored for survival and tested for lung bacterial burden, cytokine production as well as S. pneumoniae-specific antibody titer in mouse sera. The primary immunological contributor to the observed protection was confirmed by cytokine neutralization and serum passive transfer. RESULTS: The combination of CTB and PspA provided complete protection against bacterial challenge, which coincided with a significant decrease in lung bacterial burden. Increases in the T-helper (Th) 1 cytokines, interferon (IFN)-gamma and interleukin (IL)-2 were observed in the lung 24 h post-challenge while decreases in proinflammatory mediators IL-6 and tumor necrosis factor (TNF)-alpha were also recorded at the same time point. The adjuvanted PspA immunization induced significant titers of S. pneumoniae-specific antibody in the serum of mice prior to infection. Serum adoptive transfer passively protected animals against subsequent challenge while IFN-gamma neutralization had no impact on the outcome of immunization, suggesting a primary role for antibody-mediated protection in the context of this immunization strategy. CONCLUSION: Mucosal immunization with CTB and PspA induced a local cellular immune response and systemic humoral immunity which resulted in effective reduction of pulmonary bacterial burden and complete protection against S. pneumoniae challenge. While induction of the pleiotropic cytokine IFN-gamma likely contributes to control of infection through activation of effector pathways, it was not required for protection. Instead, immunization with PspA and CTB-induced S. pneumoniae-specific antibodies in the serum prior to infection that were sufficient to protect against mucosal challenge. PMID- 28344806 TI - Auditory and visual hallucinations after influenza vaccine: a case report. PMID- 28344807 TI - Ipilimumab-induced thrombotic thrombocytopenic purpura (TTP). AB - BACKGROUND: CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4) was the first immune checkpoint receptor clinically targeted for use in cancer treatment. It is expressed exclusively on T-cells where its primary role is to regulate the amplitude of the early stages of T-cell activation.1 Ipilimumab, a CTLA-4 blocking antibody, has been widely used for the treatment of patients with high risk and metastatic melanoma. Given its mechanism of action and consequent immune activation, the side effect profile of this drug greatly differs from that of standard cytotoxic chemotherapy. Adverse events are from the most part immune mediated, ranging from the more common, such as rash and fatigue, to the less common, such as immune endocrinopathy and colitis. CASE PRESENTATION: We describe a case of immune-mediated thrombotic thrombocytopenic purpura (TTP) in a 68 year old woman with high risk, stage III melanoma occurring after 3 cycles of adjuvant treatment with ipilimumab as part of a clinical trial. CONCLUSION: The range of immune-mediated adverse events during treatment with ipilimumab is wide and varied and clinicians should have a high degree of suspicion when managing these patients. PMID- 28344808 TI - Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer. AB - BACKGROUND: T cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s. METHODS: Patients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-alpha) was given with each CART72 infusion to upregulate expression of TAG-72. RESULTS: Fourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (<=14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed. CONCLUSION: These findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity. PMID- 28344809 TI - Basal cell carcinoma: PD-L1/PD-1 checkpoint expression and tumor regression after PD-1 blockade. AB - Monoclonal antibodies that block immune regulatory proteins such as programmed death-1 (PD-1) have demonstrated remarkable efficacy in controlling the growth of multiple tumor types. Unresectable or metastatic basal cell carcinoma, however, has largely gone untested. Because PD-Ligand-1 (PD-L1) expression in other tumor types has been associated with response to anti-PD-1, we investigated the expression of PD-L1 and its association with PD-1 expression in the basal cell carcinoma tumor microenvironment. Among 40 basal cell carcinoma specimens, 9/40 (22%) demonstrated PD-L1 expression on tumor cells, and 33/40 (82%) demonstrated PD-L1 expression on tumor-infiltrating lymphocytes and associated macrophages. PD L1 was observed in close geographic association to PD-1+ tumor infiltrating lymphocytes. Additionally, we present, here, the first report of an objective anti-tumor response to pembrolizumab (anti-PD-1) in a patient with metastatic PD L1 (+) basal cell carcinoma, whose disease had previously progressed through hedgehog pathway-directed therapy. The patient remains in a partial response 14 months after initiation of therapy. Taken together, our findings provide a rationale for testing anti-PD-1 therapy in patients with advanced basal cell carcinoma, either as initial treatment or after acquired resistance to hedgehog pathway inhibition. PMID- 28344811 TI - The role of imaging in the diagnosis of primary prostate cancer. AB - Ultrasound and magnetic resonance imaging (MRI) are key imaging modalities in prostate cancer diagnosis. MRI offers a range of intrinsic contrast mechanisms (T2, diffusion-weighted imaging (DWI), MR spectroscopy (MRS)) and extrinsic contrast-generating options based on tumour vascular state following injection of weakly paramagnetic agents such as gadolinium. Together these parameters are referred to as multiparametric (mp)MRI and are used for detecting and guiding biopsy and staging prostate cancer. Although sensitivity of mpMRI is <75% for disease detection, specificity is >90% and a standardised reporting system together with MR-guided targeted biopsy is the optimal diagnostic pathway. Shear wave ultrasound elastography is a new technique which also holds promise for future studies. This article describes the developments in imaging the primary site of prostate cancer and reviews their current and future utility for screening, diagnosis and T-staging the disease. PMID- 28344810 TI - Novel biomarkers for the detection of prostate cancer. AB - Prostate-specific antigen (PSA) is widely used as a biomarker in the detection of prostate cancer and for decision making regarding treatment options, response to therapy, and clinical follow-up. Despite its widespread use, it is well recognised that PSA has suboptimal performance as a screening tool due to poor specificity, resulting in high negative biopsy rates and potential 'over diagnosis' and 'over-treatment' of clinically insignificant cancers. In particular, PSA does not reliably distinguish either cancer from benign prostatic conditions, or 'clinically significant' from 'indolent cancers', and it is inaccurate in predicting disease burden and response to treatment. There is an urgent demand for novel biomarkers to address these clinical needs. This article provides an update on the novel candidate biomarkers in development, which have shown potential for improving the detection of clinically significant cases of this malignancy. PMID- 28344812 TI - Novel concepts for risk stratification in prostate cancer. AB - Since Partin introduced the analysis of prostate-specific antigen, clinical T stage and Gleason scores to estimate the risk of progression in men with localised prostate cancer, our understanding of factors that modify this risk has changed drastically. There are now multiple risk stratification tools available, including look-up tables, risk stratification/classification analyses, regression tree analyses, nomograms and artificial neural networks. Concurrently, descriptions of novel biopsy strategies, imaging modalities and biomarkers are frequently published with the aim of improving risk stratification. With an abundance of new information available, incorporating advances into clinical practice can be confusing. This article aims to outline the major novel concepts in prostate cancer risk stratification for men with biopsy confirmed prostate cancer. We will detail which of these novel techniques and tools are likely to be adopted to aid treatment decisions and enable more accurate post-diagnosis, pretreatment risk stratification. PMID- 28344813 TI - The modern role of androgen deprivation therapy in the management of localised and locally advanced prostate cancer. AB - INTRODUCTION: Approximately 50% of men diagnosed with prostate cancer will be exposed to androgen deprivation therapy (ADT) at some stage. The role of ADT in the management of metastatic disease has long been recognised, and its place in the management of localised and locally advanced disease has become clearer in the past few years. Nevertheless, concerns remain that some men might not benefit from ADT in earlier-stage disease. The purpose of the current article is to provide a brief narrative review of the role of ADT as part of a strategy of treatment with curative intent, concentrating mainly on key recent developments in the area. METHODS: Narrative literature review of key publications in the English language relating to ADT in the management of localised and locally advanced prostate cancer. RESULTS: In locally advanced and high-risk localised prostate cancer, the use of ADT in combination with radiotherapy improves disease specific and overall survival. There is no evidence to support the use of ADT in the treatment of low-risk localised prostate cancer. There appears to be an increased risk of cardiovascular morbidity and mortality associated with luteinizing hormone-releasing hormone agonists, particularly in men with pre existing cardiovascular disease, but the relevance of this in the adjuvant/neoadjuvant setting is currently unclear. CONCLUSIONS: Future studies should focus on identification of men who are at risk from cardiovascular complications associated with ADT and on the comparison of radiotherapy with ADT versus surgery in the management of localised and locally advanced prostate cancer, particularly with regards to men with pre-existing comorbidities. PMID- 28344814 TI - The role of chemotherapy and new targeted agents in the management of primary prostate cancer. AB - While early treatment of primary prostate cancer is very effective, the incidence of primary prostate cancer continues to rise and therefore the detection of men with high-risk non-metastatic prostate cancer and their subsequent management is becoming increasingly important. There continues to be no molecularly-targeted or chemotherapeutic options with proven, statistically significant survival benefit in this setting. However, there are indications that further risk stratification using molecular features could potentially help distinguish indolent from aggressive prostate cancer, ultimately providing biological markers that could guide a more personalised approach to therapy selection. PMID- 28344815 TI - Occupational exposure to sharps injury among healthcare providers in Ethiopia regional hospitals. AB - BACKGROUND: Sharps injury is a penetrating stab wound from a needle, scalpel, or another sharp object that may result in exposure to blood or other body fluids. According to World Health Organization pooled estimate, the annual incidence of sharps injury in Africa was ranged from 2.10 to 4.68 per person per year, but research data in Ethiopia is limited. The aim of the study was to investigate sharps injury prevalence and associated risk factors. METHODS: Institution based cross-sectional study was conducted with 200 healthcare providers (HCP) in Northeast Ethiopia. Proportionate stratified sampling was used to select HCP. Sharps injury during the last 12 months was an outcome variable whereas demographic characteristics, behavioral attributes, and job environment characteristics were independent variables. Data was collected from April to May 2016 using self-administered questionnaire; which was adapted from World Health Organization best practices for injections and related procedures toolkit. Bivariate and multivariate logistic regression analysis was carried out to identify sharps injury associated risk factors. Epi Info version 3.5.1 software package was used for data coding and entry whereas Statistical Package for Social Sciences (SPSS) version 20 software package was used for analysis. RESULTS: In total, 195 HCP participated with a response rate of 97.5%. The prevalence of sharps injury was 32.8%. Following adjustment for covariates, lack of in-service job training and previous exposure to sharps injury were statistically significant risk factors for sharps injury. HCP who had no in-service job training were 4.7 times more likely sustained sharps injury compared with those who had in-service job training (p < 0.001, OR = 4.7, 95% CI = 2.05-10.56). HCP who had previous exposure to sharps injury were 3.7 times more likely sustained sharps injury compared with those who were not exposed (p-value = 0.002, OR = 3.7, 95% CI = 1.62-8.27). CONCLUSIONS: This study revealed 32.8% or at least three out of ten HCP exposed to sharps injury. This was found statistically significant among HCP who had no in-service job training and who had previous exposure to sharps injury. Thus, training HCP perhaps increase their skill and curiosity to reduce exposure to sharps injury. PMID- 28344816 TI - Vibration upshot of operating mechanical sewing machine: an insight into common peroneal nerve conduction study. AB - BACKGROUND: Most of the people associated with tailoring occupation in Nepal are still using mechanical sewing machine as an alternative of new technology for tailoring. Common peroneal nerves of both right and left legs are exposed to strenuous and chronic stress exerted by vibration and paddling of mechanical sewing machine. METHODS: The study included 30 healthy male tailors and 30 healthy male individuals. Anthropometric variables as well as cardio respiratory variables were determined for each subject. Standard Nerve Conduction Techniques using constant measured distances were applied to evaluate common peroneal nerve (motor) in both legs of each individual. Data were analyzed and compared between study and control groups using Man Whitney U test setting the significance level p <= 0.05. RESULTS: Anthropometric and cardio respiratory variables were not significantly altered between the study and control groups. The Compound muscle action potential (CMAP) latency of common peroneal nerves of both right [(11.29 +/- 1.25 vs. 10.03 +/- 1.37), P < 0.001] and left [(11.28 +/- 1.38 vs. 10.05 +/- 1.37), P < 0.01] legs was found to be significantly prolonged in study group as compared to control group. The Amp-CMAP of common peroneal nerves of both right [(4.57 +/- 1.21 vs. 6.22 +/- 1.72), P < 0.001] and left [(4.31 +/- 1.55 vs. 6.25 +/- 1.70), P < 0.001] legs was found significantly reduced in study group as compared to control group. Similarly, the motor nerve conduction velocity (MNCV) of common peroneal nerves of both right [(43.72 +/- 3.25 vs. 47.49 +/- 4.17), P < 0.001] and left [(42.51 +/- 3.82 vs. 46.76 +/- 4.51), P < 0.001] legs was also found to be significantly reduced in study group in comparison to control group. CONCLUSION: Operating mechanical sewing machine by paddling chronically and arduously could have attributed to abnormal nerve conduction study parameters due to vibration effect of the machine on right and left common peroneal nerves. The results of present study follow the trend towards presymptomatic or asymptomatic neuropathy similar to subclinical neuropathy. PMID- 28344817 TI - Urinary biomarkers as indicator of chronic inflammation and endothelial dysfunction in obese adolescents. AB - BACKGROUND: Obesity is a pro-inflammatory state that may predispose patients to acute coronary syndrome characterized by chronic low grade inflammation resulting in endothelial dysfunction (ED). The aim of the study was to evaluate urinary biomarkers of inflammation and ED in adolescents with obesity. METHODS: Sixty three subjects were recruited for the study. Twenty healthy adolescents with normal body mass (NW), 14 overweight (OW), 29 obese (OA) subjects were selected. An EndoPat 2000 device was used to measure the reactive hyperemia index (RHI). First morning fasting urine samples were tested for interleukin 6 (IL-6), endothelin 1 (ET-1), alpha-1-acid glycoprotein (AGP), tumor necrosis factor- alpha (TNF-alpha) and corrected to urinary creatinine. RESULTS: Urinary TNF-alpha was significantly higher in OA group (52.4 +/- 15.3 pg/mg) compared to adolescents with NW (14.1 +/- 1.2 pg/mg, P = 0.04). ET-1 levels were found to be higher in OW (5.18 +/- 1.6 pg/mg) compared with NW (3 . 47 +/- 0.3 pg/mg, P = 0.24); and higher in OA (8.48 +/- 3.1 pg/mg) compared to both NW (P = 0.19) and OW (P = 0.40). Similarly a higher AGP level was observed in OW (864.8 +/- 156 ng/mg) and OA (808.3 +/- 186 ng/mg) compared to NW (653 +/- 69 ng/mg) (P = 0.16 & 0.49 respectively). Inflammatory markers namely, TNF-alpha, IL-6 and AGP significantly and positively correlated with each other and with ET-1, a marker for endothelial dysfunction. This significant correlation was also observed when tested separately in the subgroups (NW, OW and OA). There were no differences in RHI levels among the study groups. CONCLUSION: Urinary TNF-alpha is significantly elevated in obese adolescents and correlates with urinary ET-1, which is recognized as a biomarker for endothelial dysfunction. Since obesity is a chronic inflammatory state, elevated urinary TNF-alpha might be used as a non invasive tool to monitor the level of that inflammation. PMID- 28344818 TI - Will bevacizumab biosimilars impact the value of systemic therapy in gynecologic cancers? AB - OBJECTIVE: Bevacizumab is an important component in the treatment of various cancers, and despite guidelines recommending its use in both ovarian and cervical cancer, patient access to bevacizumab and other angiogenesis inhibitors is limited. Biosimilars are large, structurally complex molecules that are intended to be highly similar to, and treat the same condition(s) as, an existing licensed or approved (reference) biologic, with no clinically meaningful differences in purity, potency and safety. This article summarizes the role of bevacizumab in the treatment paradigm of ovarian and cervical cancer. We also discuss the potential role of biosimilars to bevacizumab, which may offer more affordable options in the future treatment of gynecologic cancers. METHODS: Literature searches of PubMed and ClinicalTrials.gov databases were conducted. Regulatory and individual pharmaceutical company web pages were also reviewed. Search terms included "biosimilar" and "bevacizumab," and these were used to identify information regarding biosimilar development, reporting results of biosimilar studies or biosimilars in development. RESULTS: At present, four bevacizumab biosimilar candidates are undergoing comparative clinical assessment, with the potential to increase access and offer efficiencies across healthcare systems. CONCLUSIONS: It is anticipated that biologics such as bevacizumab will continue to play a key role in the treatment of an array of gynecologic cancers. Biosimilars to bevacizumab are currently in development and have the potential to increase access to medicines in a variety of settings, including gynecologic cancers. PMID- 28344821 TI - Welcome to volume 3 of Future Science OA. AB - Happy New Year to all of our readers! Welcome to volume 3 of Future Science OA. 2016 was another excellent year, with us receiving some superb content for publication, and our becoming indexed on both Chemical Abstracts and the Emerging Sources Citation Index, meaning our content now appears on Web of Science. We thank our readers, reviewers, authors and Editorial Board members for their continued support, and look forward to working with everyone in 2017. PMID- 28344820 TI - The chordate ancestor possessed a single copy of the Brachyury gene for notochord acquisition. AB - BACKGROUND: The T-box family transcription-factor gene, Brachyury, has two expression domains with discrete functions during animal embryogenesis. The primary domain, associated with the blastopore, is shared by most metazoans, while the secondary domain, involved in the notochord, is specific to chordates. In most animals, Brachyury is present in a single copy, but in cephalochordates, the most basal of the chordates, the gene is present in two copies, suggesting allotment of the two domains to each of the duplicates. RESULTS: In order to clarify whether Brachyury duplication occurred in the common ancestor of chordates after which one of duplicates was lost in the urochordate and vertebrate lineages, we estimated phylogenetic relationships of Brachyury genes and examined the synteny of a Brachyury-containing genomic region of deuterostomes with decoded genomes. The monophyletic origin of tandemly arranged Brachyury genes of cephalochordates indicates that the tandem duplication occurred in the cephalochordate lineage, but not in the chordate ancestor. CONCLUSIONS: Our results thus suggest that, in the common ancestor of chordates, a single copy of Brachyury acquired two expression domains and that the duplication was not involved in the acquisition of the notochord. However, in relation to regulatory mechanisms, both possibilities-namely a single copy with two domains and two copies with different domains-should be considered in future studies of Brachyury. PMID- 28344819 TI - Olfaction as a soldier-- a review of the physiology and its present and future use in the military. AB - Olfaction is one of our 5 main qualitative sensory abilities. In this review, we have examined the physiology of olfaction from the olfactory receptor to the brain. Through analyzing the physiology of olfaction, we have found that the biochemistry of olfactory nerve stimulation is unique from that of other similar pathways. Upon receiving large amounts of input from the olfactory nerve, the olfactory bulb, followed by several layers of centrifugal and centripetal processing in the brain, has to sort the information from the input as well as integrate it with other inputs from the brain to develop a coherent understanding of the input. We then examined the implications of olfaction in the military, the practical applications of electronic noses and problems associated with injury to olfaction that could affect compensation and combat worthiness of a soldier following injury. In the military, olfaction can allow the army to perform at its best through 4 main methods, namely ensuring olfaction is consistent with other dimensions of perception (ensuring optimal olfaction ability in all soldiers in combat), understanding the impact of different common combat environments on the sense of smell, utilizing odor as a defense mechanism and using olfactory aids when necessary. Electronic noses are olfactory aids that have a large potential in the military ranging from saving lives through the detection of explosives to potential methods for improving combustion efficiency. There are several problems associated with injury to olfaction that should be considered when deciding on compensation and combat worthiness of the soldier following an injury. PMID- 28344822 TI - Quantitative analysis of lipids: a higher-throughput LC-MS/MS-based method and its comparison to ELISA. AB - AIM: Lipids such as prostaglandins, leukotrienes and thromboxanes are released as a result of an inflammatory episode in pain (central and peripheral). METHODOLOGY & RESULTS: To measure these lipids as potential mechanistic biomarkers in neuropathic pain models, we developed a higher-throughput LC-MS/MS-based method with simultaneous detection of PGE2, PGD2, PGF2alpha, LTB4, TXB2 and 2 arachidonoyl glycerol in brain and spinal cord tissues. We also demonstrate that the LC-MS/MS method was more sensitive and specific in differentiating PGE2 levels in CNS tissues compared with ELISA. CONCLUSION: The ability to modify the LC-MS/MS method to accommodate numerous other lipids in one analysis, demonstrates that the presented method offers a cost-effective and more sensitive alternative to ELISA method useful in drug discovery settings. PMID- 28344823 TI - Forty-nine years in Biomaterials Science: an interview with Buddy Ratner. AB - Buddy Ratner talks to Francesca Lake, Managing Editor. After receiving his PhD in polymer chemistry from the Polytechnic Institute of Brooklyn (USA) in 1972, Ratner moved to the University of Washington (USA), where he has since become joint professor of bioengineering and chemical engineering and Michael L & Myrna Darland Endowed Chair in Technology Commercialization. Since 1996, he has led the UWEB Research Center for Biomaterials at the University of Washington, originally funded by the National Science Foundation. A pioneer of the biomaterials field, Ratner's research interests include biomaterials, tissue engineering, polymers, biocompatibility and surface analysis of organic materials. A leader in the field, he has received numerous awards, has launched several companies and holds over 20 patents. PMID- 28344824 TI - Horizontal alignment of 5' -> 3' intergene distance segment tropy with respect to the gene as the conserved basis for DNA transcription. AB - AIM: To study the conserved basis for gene expression in comparative cell types at opposite ends of the cell pressuromodulation spectrum, the lymphatic endothelial cell and the blood microvascular capillary endothelial cell. METHODS: The mechanism for gene expression is studied in terms of the 5' -> 3' direction paired point tropy quotients (prpTQs) and the final 5' -> 3' direction episodic sub-episode block sums split-integrated weighted average-averaged gene overexpression tropy quotient (esebssiwaagoTQ). RESULTS: The final 5' -> 3' esebssiwaagoTQ classifies an lymphatic endothelial cell overexpressed gene as a supra-pressuromodulated gene (esebssiwaagoTQ >= 0.25 < 0.75) every time and classifies a blood microvascular capillary endothelial cell overexpressed gene every time as an infra-pressuromodulated gene (esebssiwaagoTQ < 0.25) (100% sensitivity; 100% specificity). CONCLUSION: Horizontal alignment of 5' -> 3' intergene distance segment tropy wrt the gene is the basis for DNA transcription in the pressuromodulated state. PMID- 28344825 TI - Identification of Filamin-A and -B as potential biomarkers for prostate cancer. AB - AIM: A novel strategy for prostate cancer (PrCa) biomarker discovery is described. MATERIALS & METHODS: In vitro perturbation biology, proteomics and Bayesian causal analysis identified biomarkers that were validated in in vitro models and clinical specimens. RESULTS: Filamin-B (FLNB) and Keratin-19 were identified as biomarkers. Filamin-A (FLNA) was found to be causally linked to FLNB. Characterization of the biomarkers in a panel of cells revealed differential mRNA expression and regulation. Moreover, FLNA and FLNB were detected in the conditioned media of cells. Last, in patients without PrCa, FLNA and FLNB blood levels were positively correlated, while in patients with adenocarcinoma the relationship is dysregulated. CONCLUSION: These data support the strategy and the potential use of the biomarkers for PrCa. PMID- 28344826 TI - Impact of bone marrow-derived mesenchymal stem cells on remodeling the lung injury induced by lipopolysaccharides in mice. AB - AIM: This study evaluated the potential of bone marrow derived mesenchymal stem cells (MSCs) to regulate cytokines and remodel the lung induced by lipopolysaccharide (LPS; O-antigen). MATERIALS & METHODS: A group of mice (n = 21) was inoculated intraperitoneally with one dose 0.1 ml containing 0.025 mg LPS/mouse, and another treated intravenously with one dose of labeling bone marrow derived MSCs at 7.5 * 105 cell/mouse 4 h after LPS injection. All animals were sacrificed on the 1st, 7th and 14th days post-injection. RESULTS: MSCs increased the level of IL-10 with suppression of TNF-alpha, decrease of collagen fibers and renewal of alveolar type I cells, together with lung tissue remodeling. CONCLUSION: MSCs were shown to modulate inflammatory cytokines (TNF alpha and IL-10) and to differentiate into alveolar type I cells, which prevented fibrosis in lung tissue from LPS-treated mice. PMID- 28344827 TI - Perinatal high methyl donor alters gene expression in IGF system in male offspring without altering DNA methylation. AB - AIM: To investigate the effect of a protein restriction and a supplementation with methyl donor nutrients during fetal and early postnatal life on the expression and epigenetic state of imprinted genes from the IGF system. MATERIALS & METHODS: Pregnant female rats were fed a protein-restricted diet supplemented or not with methyl donor. RESULTS: Gene expression of the Igf2, H19, Igf1, Igf2r and Plagl1 genes in the liver of male offspring at birth and weaning was strongly influenced by maternal diet. Whereas the methylation profiles of the Igf2, H19 and Igf2r genes were remarkably stable, DNA methylation of Plagl1 promoter was slightly modified. CONCLUSION: DNA methylation of most, but not all, imprinted gene regulatory regions was resistant to methyl group nutritional supply. PMID- 28344828 TI - LC-MS/MS assay for quantitation of enalapril and enalaprilat in plasma for bioequivalence study in Indian subjects. AB - BACKGROUND: Enalapril (EPL) is an angiotensin-converting enzyme inhibitor for the treatment of hypertension and chronic heart failure. Enalaprilat (EPLT) is an active metabolite that contributes to the overall activity of EPL. AIM: To quantitate EPL along with its metabolite EPLT using LC-MS/MS, a bioanalytical method was developed and validated with tolbutamide in human plasma using a protein precipitation technique. RESULTS: The sensitive and selective method has an LLOQ of 1 ng/ml with a linearity range of 1-500 ng/ml for both EPL and EPLT using 300 ul of plasma without any matrix effect. CONCLUSION: Linearity, specificity, accuracy, precision and stability, as well as its application to the analysis of plasma samples after oral administration of 20 mg of EPL maleate in healthy volunteers demonstrate applicability to bioavailability/bioequivalence studies. PMID- 28344829 TI - Systemic angiopoietin-1/2 dysregulation following cardiopulmonary bypass in adults. AB - AIM: Vascular leakage following cardiopulmonary bypass contributes to morbidity. Angiopoietin-1 and -2 are biomarkers of endothelial dysfunction. Our aim was to characterize Ang-1 and -2 association with clinical characteristics and outcomes. METHODS: Observational cohort study measuring Ang-1/-2 with a panel of cytokines in adults undergoing cardiopulmonary bypass. RESULTS: Ang-2 levels increased immediately postop whereas Ang-1 levels decreased over time. No significant correlation was found with other inflammatory mediators. High correlation was found between the hospital length of stay and Ang-2 increase at 24 h (rho = 0.590; p < 0.0001). The predictors of Ang-2 increase were female gender, cross clamp time, transfusion of blood and absence of angiotensin-converting enzyme inhibitor as a pre-op medication. CONCLUSION: Angiopoietins can detect vascular leakage early and could impact patient's management to decrease length of stay after cardiac surgery. PMID- 28344830 TI - Exploring and validating physicochemical properties of mangiferin through GastroPlus(r) software. AB - AIM: Mangiferin (Mgf), a promising therapeutic polyphenol, exhibits poor oral bioavailability. Hence, apt delivery systems are required to facilitate its gastrointestinal absorption. The requisite details on its physicochemical properties have not yet been well documented in literature. Accordingly, in order to have explicit insight into its physicochemical characteristics, the present work was undertaken using GastroPlusTM software. RESULTS: Aqueous solubility (0.38 mg/ml), log P (-0.65), Peff (0.16 * 10-4 cm/s) and ability to act as P-gp substrate were defined. Potency to act as a P-gp substrate was verified through Caco-2 cells, while Peff was estimated through single pass intestinal perfusion studies. Characterization of Mgf through transmission electron microscopy, differential scanning calorimetry, infrared spectroscopy and powder x-ray diffraction has also been reported. CONCLUSION: The values of physicochemical properties for Mgf reported in the current manuscript would certainly enable the researchers to develop newer delivery systems for Mgf. PMID- 28344831 TI - Indole-fused benzooxazepines: a new structural class of anticancer agents. AB - AIM: A new series of compounds (1a-16a) bearing indole-fused benzooxazepine was synthesized, characterized and evaluated for anticancer activity. MATERIALS & METHODS: In this study, all the synthesized compounds were screened via in vitro anticancer testing on Hep-G2 cancer cell line. A computational study was carried out on cancer-related targets including IL-2, IL-6, COX-2 Caspase-3 and Caspase 8. RESULTS: Some of the synthesized compounds effectively controlled the growth of cancerous cells. CONCLUSION: The most active compounds - 6a, 10a, 13a, 14a and 15a - exemplify notable anticancer profile with GI50 <10 MUg/ml. Preliminary structure-activity relationship among the tested compounds can produce an assumption that the electronegative groups at phenyl ring attached with indole fused benzooxazepine are instrumental for the activity. Molecular docking study showed crucial hydrogen bond and pi-pi stacking interactions, with good ADMET profiling and molecular dynamic simulation. PMID- 28344833 TI - Body mass and cancer: genetics, endocrinology... and more. PMID- 28344832 TI - In silico functional elucidation of uncharacterized proteins of Chlamydia abortus strain LLG. AB - AIM: This study reports structural modeling, molecular dynamics profiling of hypothetical proteins in Chlamydia abortus genome database. METHODOLOGY: The hypothetical protein sequences were extracted from C. abortus LLG Genome Database for functional elucidation using in silico methods. RESULTS: Fifty-one proteins with their roles in defense, binding and transporting other biomolecules were unraveled. Forty-five proteins were found to be nonhomologous to proteins present in hosts infected by C. abortus. Of these, 31 proteins were related to virulence. The structural modeling of two proteins, first, WP_006344020.1 (phosphorylase) and second, WP_006344325.1 (chlamydial protease/proteasome-like activity factor) were accomplished. The conserved active sites necessary for the catalytic function were analyzed. CONCLUSION: The finally concluded proteins are envisioned as possible targets for developing drugs to curtail chlamydial infections, however, and should be validated by molecular biological methods. PMID- 28344834 TI - Ligature-associated bacterial profiles are linked to type 2 diabetes mellitus in a rat model and influenced by antibody treatment against TNF-alpha or RAGE. AB - There is a bidirectional relationship between periodontal disease (PD) and type 2 diabetes mellitus (T2D). T2D may lead to ecological perturbations in the oral environment, which may facilitate an altered microbiota. However, previous studies have been inconclusive in determining the effect of T2D on oral bacterial profiles. Therefore, we aimed to evaluate the influence of T2D on the ligature associated bacterial profile in a diabetic rat model with PD and investigated the impact of blocking inflammatory pathways with antibodies targeting either Tumor Necrosis Factor alpha (TNF-alpha) or the receptor of advanced glycation end products (RAGE). A total of 62 Zucker obese rats (45 T2D) and 17 lean (non-T2D) were divided into 4 treatment groups; lean with PD, obese with PD, obese with PD and anti-TNF-alpha treatment, and obese with PD with anti-RAGE treatment. Periodontal disease was ligature induced. Ligature-associated bacterial profiles were analyzed using Human Oral Microbe Identification Microarray (HOMIM). Ligature-associated bacterial profiles differed between lean and obese rats. Furthermore, treatment with antibodies against TNF-alpha or RAGE had an impact on subgingival bacterial profiles. T2D phenotypes are associated with different ligature-associated bacterial profiles and influenced by treatment with antibodies against TNF-alpha or RAGE. PMID- 28344835 TI - A Review of Mercury Exposure and Health of Dental Personnel. AB - Considerable effort has been made to address the issue of occupational health and environmental exposure to mercury. This review reports on the current literature of mercury exposure and health impacts on dental personnel. Citations were searched using four comprehensive electronic databases for articles published between 2002 and 2015. All original articles that evaluated an association between the use of dental amalgam and occupational mercury exposure in dental personnel were included. Fifteen publications from nine different countries met the selection criteria. The design and quality of the studies showed significant variation, particularly in the choice of biomarkers as an indicator of mercury exposure. In several countries, dental personnel had higher mercury levels in biological fluids and tissues than in control groups; some work practices increased mercury exposure but the exposure levels remained below recommended guidelines. Dental personnel reported more health conditions, often involving the central nervous system, than the control groups. Clinical symptoms reported by dental professionals may be associated with low-level, long-term exposure to occupational mercury, but may also be due to the effects of aging, occupational overuse, and stress. It is important that dental personnel, researchers, and educators continue to encourage and monitor good work practices by dental professionals. PMID- 28344836 TI - Human Body Mechanics of Pushing and Pulling: Analyzing the Factors of Task related Strain on the Musculoskeletal System. AB - The purpose of this review is to name and describe the important factors of musculoskeletal strain originating from pushing and pulling tasks such as cart handling that are commonly found in industrial contexts. A literature database search was performed using the research platform Web of Science. For a study to be included in this review differences in measured or calculated strain had to be investigated with regard to: (1) cart weight/ load; (2) handle position and design; (3) exerted forces; (4) handling task (push and pull); or (5) task experience. Thirteen studies met the inclusion criteria and proved to be of adequate methodological quality by the standards of the Alberta Heritage Foundation for Medical Research. External load or cart weight proved to be the most influential factor of strain. The ideal handle positions ranged from hip to shoulder height and were dependent on the strain factor that was focused on as well as the handling task. Furthermore, task experience and subsequently handling technique were also key to reducing strain. Workplace settings that regularly involve pushing and pulling should be checked for potential improvements with regards to lower weight of the loaded handling device, handle design, and good practice guidelines to further reduce musculoskeletal disease prevalence. PMID- 28344837 TI - Exploring Supervisor-Related Job Resources as Mediators between Supervisor Conflict and Job Attitudes in Hospital Employees. AB - BACKGROUND: Conservation of resources theory assumes loss of resources as a cause of job strain. In hospital work, conflicts with supervisors are tested to predict lower resources, that is, supervisory social support, participation possibilities, and appreciation. All three resources are expected to predict, in turn, experienced stress (job strain) and lower job satisfaction, lower affective commitment, and a higher resigned attitude towards the job (job attitudes). METHODS: The sample included 1,073 employees from 14 Swiss hospitals (n = 604 nurses, n = 81 physicians, n = 135 medical therapists, and n = 253 technical and administrative staff). Of the total sample, 83.1% were female and 38.9% worked full-time. The median tenure was between 7 years and 10 years. Constructs were assessed by online questionnaires. Structural equation modeling was used to test mediation. RESULTS: Structural equation modeling confirmed the negative association of conflict with supervisors and job resources. Tests of indirect paths to resources as a link between conflicts with supervisors and job attitudes were significant. For nurses, social support, participation and appreciation showed a significant indirect path, while among medical technicians the indirect paths included social support and appreciation, and among physicians only appreciation showed a significant indirect path. In medical therapists no indirect path was significant. Job resources did not mediate the link between conflict with supervisors and stress in any occupational group. CONCLUSION: Conflicts with supervisors are likely to reduce job resources and in turn to lower job attitudes. Work design in hospitals should, therefore, address interpersonal working conditions and conflict management in leadership development. PMID- 28344838 TI - Establishing a Policy Framework for the Primary Prevention of Occupational Cancer: A Proposal Based on a Prospective Health Policy Analysis. AB - BACKGROUND: Despite our knowledge of the causes of cancer, millions of workers are involuntarily exposed to a wide range of known and suspected carcinogens in the workplace. To address this issue from a policy perspective, we developed a policy framework based on a prospective health policy analysis. Use of the framework was demonstrated for developing policies to prevent cancers associated with diesel engine exhaust (DEE), asbestos, and shift work, three occupational carcinogens with global reach and large cancer impact. METHODS: An environmental scan of existing prospective health policy analyses was conducted to select and describe our framework parameters. These parameters were augmented by considerations unique to occupational cancer. Policy-related resources, predominantly from Canada, were used to demonstrate how the framework can be applied to cancers associated with DEE, asbestos, and shift work. RESULTS: The parameters of the framework were: problem statement, context, jurisdictional evidence, primary prevention policy options, and key policy players and their attributes. Applying the framework to the three selected carcinogens illustrated multiple avenues for primary prevention, including establishing an occupational exposure limit for DEE, banning asbestos, and improving shift schedules. The framework emphasized the need for leadership by employers and government. CONCLUSION: To our knowledge, this is the first proposal for a comprehensive policy framework dedicated to the primary prevention of occupational cancer. The framework can be adapted and applied by key policy players in Canada and other countries as a guide of what parameters to consider when developing policies to protect workers' health. PMID- 28344839 TI - Associations Between Body Fat Percentage and Fitness among Police Officers: A Statewide Study. AB - BACKGROUND: Police work is generally sedentary although there may be situations that require physical endurance and strength, such as foot chases and arresting suspects. Factors such as excessive body fat can impede an officer's physical ability to deal with such occurrences. Our objective was to examine associations between officers' body fat percentage (BF%) and performance on a standardized fitness protocol. METHODS: Data were obtained from fitness screening among 1,826 male and 115 female officers in a large US police agency. The screening consisted of a 2.4-km run, push-ups, sit-ups, and sit-and-reach test. Sex-specific body fat percentages were estimated from skinfold thickness measured using calipers. Linear regression models were used to examine unadjusted and adjusted mean scores of fitness tests across BF% tertiles. RESULTS: The prevalence of overall fitness was 4.3 times greater in male officers and 3.6 times greater in female officers having the lowest BF% tertile compared with the highest tertile (30.3% vs 7.1% and 46.0% vs 12.8%, respectively). BF% was linearly and positively associated with the time of 2.4-km run (p < 0.001), and linearly and inversely associated with the number of push-ups (p < 0.001), sit-ups (p < 0.001), and the distance of sit-and-reach (p < 0.001) in men. Similar associations were observed in women with the exception of sit-and-reach (p = 0.122). Associations were independent of age, race/ethnicity, rank, and duty station. CONCLUSION: Overall, BF% was inversely associated with fitness levels in male and female officers. Future longitudinal studies should be initiated to explore the potentially causal relationship between BF% and fitness in law enforcement officers. PMID- 28344840 TI - Simulation and Damage Analysis of an Accidental Jet Fire in a High-Pressure Compressed Pump Shelter. AB - BACKGROUND: As one of the most frequently occurring accidents in a chemical plant, a fire accident may occur at any place where transfer or handling of combustible materials is routinely performed. METHODS: In particular, a jet fire incident in a chemical plant operated under high pressure may bring severe damage. To review this event numerically, Computational Fluid Dynamics methodology was used to simulate a jet fire at a pipe of a compressor under high pressure. RESULTS: For jet fire simulation, the Kemeleon FireEx Code was used, and results of this simulation showed that a structure and installations located within the shelter of a compressor received serious damage. CONCLUSION: The results confirmed that a jet fire may create a domino effect that could cause an accident aside from the secondary chemical accident. PMID- 28344842 TI - Effectiveness of Direct Safety Regulations on Manufacturers and Users of Industrial Machines: Its Implications on Industrial Safety Policies in Republic of Korea. AB - BACKGROUND: Despite considerable efforts made in recent years, the industrial accident rate and the fatality rate in the Republic of Korea are much higher than those in most developed countries in Europe and North America. Industrial safety policies and safety regulations are also known to be ineffective and inefficient in some cases. METHODS: This study focuses on the quantitative evaluation of the effectiveness of direct safety regulations such as safety certification, self declaration of conformity, and safety inspection of industrial machines in the Republic of Korea. Implications on safety policies to restructure the industrial safety system associated with industrial machines are also explored. RESULTS: Analysis of causes in industrial accidents associated with industrial machines confirms that technical causes need to be resolved to reduce both the frequency and the severity of such industrial accidents. Statistical analysis also confirms that the indirect effects of safety device regulation on users are limited for a variety of reasons. Safety device regulation needs to be shifted to complement safety certification and self-declaration of conformity for more balanced direct regulations on manufacturers and users. An example of cost-benefit analysis on conveyor justifies such a transition. CONCLUSION: Industrial safety policies and regulations associated with industrial machines must be directed towards eliminating the sources of danger at the stage of danger creation, thereby securing the safe industrial machines. Safety inspection further secures the safety of workers at the stage of danger use. The overall balance between such safety regulations is achieved by proper distribution of industrial machines subject to such regulations and the intensity of each regulation. Rearrangement of industrial machines subject to safety certification and self-declaration of conformity to include more movable industrial machines and other industrial machines with a high level of danger is also suggested. PMID- 28344841 TI - Status of Laboratory Biosafety and Biosecurity in Veterinary Research Facilities in Nigeria. AB - BACKGROUND: This study determined current status of laboratory biosafety in Nigerian veterinary research facilities. METHODS: A questionnaire was developed to obtain information from researchers across Nigeria from July 2014 to July 2015. Information regarding demographics, knowledge of laboratory biosafety, availability and proper use of personal protective equipment (PPE), any priority pathogens researched, attitude on and use of standard laboratory practices, and biosafety awareness was obtained using a numeric scoring system. Data were analyzed with descriptive statistics, and univariate and multivariate logistic regression. RESULTS: A total of 74 participants from 19 facilities completed the questionnaire. General knowledge scores ranged from 3 to 28 (out of 28 possible points), with 94.6% of respondents receiving low scores (scores < mean + 1 standard deviation). Very few (17.6%) reported availability or use PPE. Many participants (63.5%) reported no access to biosafety level (BSL)-1-3 facilities. None reported availability of a BSL-4 facility. Knowledge scores pertaining to biosafety management practices ranged from 0 to 14 (out of 14 possible points) with 47.3% of respondents receiving good scores (scores > mean + 1 standard deviation). Only 16.2% of respondents (from four facilities) reported having biosafety officers. Rabies virus was the most researched pathogen (31.1% of respondents). The majority (71.6%) were unaware of laws guiding biosafety. Researchers [odds ratio (OR) = 18.0; 95% confidence interval (CI): 1.63, 198.5; p = 0.023], especially in BSL-2 (OR = 258.5; 95% CI: 12.71, 5256; p < 0.001) facility of research institute (OR = 25.0; 95% CI: 5.18, 120.6; p < 0.001), are more likely to have adequate access to and properly utilize biosafety devices and PPE. CONCLUSIONS: Current knowledge of laboratory biosafety is limited except among a few researchers. PMID- 28344843 TI - The Impact of Job Stress and Job Satisfaction on Workforce Productivity in an Iranian Petrochemical Industry. AB - BACKGROUND: Job stress and job satisfaction are important factors affecting workforce productivity. This study was carried out to investigate the job stress, job satisfaction, and workforce productivity levels, to examine the effects of job stress and job satisfaction on workforce productivity, and to identify factors associated with productivity decrement among employees of an Iranian petrochemical industry. METHODS: In this study, 125 randomly selected employees of an Iranian petrochemical company participated. The data were collected using the demographic questionnaire, Osipow occupational stress questionnaire to investigate the level of job stress, Job Descriptive Index to examine job satisfaction, and Hersey and Goldsmith questionnaire to investigate productivity in the study population. RESULTS: The levels of employees' perceived job stress and job satisfaction were moderate-high and moderate, respectively. Also, their productivity was evaluated as moderate. Although the relationship between job stress and productivity indices was not statistically significant, the positive correlation between job satisfaction and productivity indices was statistically significant. The regression modeling demonstrated that productivity was significantly associated with shift schedule, the second and the third dimensions of job stress (role insufficiency and role ambiguity), and the second dimension of job satisfaction (supervision). CONCLUSION: Corrective measures are necessary to improve the shift work system. "Role insufficiency" and "role ambiguity" should be improved and supervisor support must be increased to reduce job stress and increase job satisfaction and productivity. PMID- 28344845 TI - Respiratory Disorders Among Workers in Slaughterhouses. AB - BACKGROUND: Workers in slaughterhouses are exposed to a wide range of biological contaminants, such as bacteria and fungi, due to their working environment. This study aimed to assess the prevalence of respiratory disorders among workers in slaughterhouses. METHODS: This study was conducted on 81 workers in slaughterhouses and 81 healthy office workers as a reference group. The American Thoracic Society standard respiratory symptoms questionnaire was used to determine the prevalence of respiratory disorders. Besides, lung function tests were conducted using a calibrated spirometer at the beginning (preshift) and at the end (postshift) of the 1st working day. Single-stage Anderson sampler was used to measure the concentration of bioaerosols in different parts of slaughterhouses. RESULTS: The prevalence of respiratory disorders, such as cough, productive cough, breathlessness, phlegm, and wheezing, was 3.17, 4.02, 3.07, 4.66, and 3.94 times, respectively, higher among workers in slaughterhouses compared with the reference group. CONCLUSION: The prevalence of respiratory disorders was significantly higher among workers in slaughterhouses. Thus, the significant reduction in the percentage predicted lung function among workers in slaughterhouses might be associated with exposure to bioaerosols in their work environment. PMID- 28344846 TI - Beating Obesity: Factors Associated with Interest in Workplace Weight Management Assistance in the Mining Industry. AB - BACKGROUND: Rates of overweight and obese Australians are high and continue to rise, putting a large proportion of the population at risk of chronic illness. Examining characteristics associated with preference for a work-based weight-loss program will enable employers to better target programs to increase enrolment and benefit employees' health and fitness for work. METHODS: A cross-sectional survey was undertaken at two Australian mining sites. The survey collected information on employee demographics, health characteristics, work characteristics, stages of behavior change, and preference for workplace assistance with reaching a healthy weight. RESULTS: A total of 897 employees participated; 73.7% were male, and 68% had a body mass index in the overweight or obese range. Employees at risk of developing obesity-related chronic illnesses (based on high body mass index) were more likely to report preference for weight management assistance than lower risk employees. This indicates that, even in the absence of workplace promotion for weight management, some at risk employees want workplace assistance. Employees who were not aware of a need to change their current nutrition or physical activity behaviors were less likely to seek assistance. This indicates that practitioners need to communicate the negative effects of excess weight and promote the benefits of a healthy lifestyle to increase the likelihood of weight management. CONCLUSION: Weight management programs should provide information, motivation. and trouble-shooting assistance to meet the needs of at-risk mining employees, including those who are attempting to change and maintain behaviors to achieve a healthy weight and be suitably fit for work. PMID- 28344844 TI - Effort-reward Imbalance at Work, Parental Support, and Suicidal Ideation in Adolescents: A Cross-sectional Study from Chinese Dual-earner Families. AB - BACKGROUND: In contemporary China, most parents are dual-earner couples and there is only one child in the family. We aimed to examine the associations of parents' work stress with suicidal ideation among the corresponding adolescent. We further hypothesized that low parental support experienced by adolescents may mediate the associations. METHODS: Cross-sectional data from school students and their working parents were used, with 907 families from Kunming City, China. Stress at work was measured by the effort-reward imbalance questionnaire. Perceived parental support was assessed by an item on parental empathy and their willingness to communicate with the adolescent. Suicidal ideation was considered positive if students reported thoughts about suicide every month or more frequently during the previous 6 months. Logistic regression was used to examine the associations. RESULTS: We observed that parents' work stress was positively associated with low parental support, which was in turn associated with adolescent suicidal ideation. The odds ratio for parents' work stress and adolescent suicidal ideation was 2.91 (95% confidence interval: 1.53-5.53), and this association was markedly attenuated to 2.24 (95% confidence interval: 1.15 4.36) after additional adjustment for parental support. Notably, mothers' work stress levels exerted stronger effects on children's suicidal ideation than those of fathers. CONCLUSION: Parents' work stress (particularly mother's work stress) was strongly associated with adolescent's suicidal ideation, and the association was partially mediated by low parental support. These results need to be replicated and extended in prospective investigations within and beyond China, in order to explore potential causal pathways as a basis of preventive action. PMID- 28344847 TI - Exercise Self-Efficacy as a Mediator between Goal-Setting and Physical Activity: Developing the Workplace as a Setting for Promoting Physical Activity. AB - BACKGROUND: Physical activity (PA) is ranked as a leading health indicator and the workplace is a key setting to promote PA. The purpose of this study was to examine how goal-setting and exercise self-efficacy (SE) during a health promotion program influenced PA level among Japanese workers. METHODS: Using a cross-sectional study design, we surveyed 281 employees. The short version of the International Physical Activity Questionnaire was used to assess PA level. Exercise SE was assessed using a partially modified version of Oka's exercise SE scale. Personal goals were assessed as the total numbers of "yes" responses to five items regarding "details of personal goals to perform PA". A mediational model was used to examine whether exercise SE mediates between the number of personal goals and PA level. RESULTS: The mean age of the participants was 46.3 years, 76.2% were men, and the most common occupational category was software engineer (30.6%). The average PA level per week exceeded the recommended level in 127 participants (45.2%). One hundred and eighty-four participants (65.5%) set some form of concrete personal goal to perform PA. The relationship between the number of personal goals and PA level was mediated by exercise SE. CONCLUSION: Our study showed that exercise SE mediates goal-setting and increases PA. The results suggest that the components of PA promotion programs should be tailored to enhance participants' confidence in performing PA. PMID- 28344848 TI - Occupational Heat Stress Impacts on Health and Productivity in a Steel Industry in Southern India. AB - BACKGROUND: Workers laboring in steel industries in tropical settings with high ambient temperatures are subjected to thermally stressful environments that can create well-known risks of heat-related illnesses and limit workers' productivity. METHODS: A cross-sectional study undertaken in a steel industry in a city nicknamed "Steel City" in Southern India assessed thermal stress by wet bulb globe temperature (WBGT) and level of dehydration from urine color and urine specific gravity. A structured questionnaire captured self-reported heat-related health symptoms of workers. RESULTS: Some 90% WBGT measurements were higher than recommended threshold limit values (27.2-41.7 degrees C) for heavy and moderate workloads and radiational heat from processes were very high in blooming mill/coke-oven (67.6 degrees C globe temperature). Widespread heat-related health concerns were prevalent among workers, including excessive sweating, fatigue, and tiredness reported by 50% workers. Productivity loss was significantly reported high in workers with direct heat exposures compared to those with indirect heat exposures (chi2 = 26.1258, degrees of freedom = 1, p < 0.001). Change in urine color was 7.4 times higher among workers exposed to WBGTs above threshold limit values (TLVs). CONCLUSION: Preliminary evidence shows that high heat exposures and heavy workload adversely affect the workers' health and reduce their work capacities. Health and productivity risks in developing tropical country work settings can be further aggravated by the predicted temperature rise due to climate change, without appropriate interventions. Apart from industries enhancing welfare facilities and designing control interventions, further physiological studies with a seasonal approach and interventional studies are needed to strengthen evidence for developing comprehensive policies to protect workers employed in high heat industries. PMID- 28344849 TI - Developing Asbestos Job Exposure Matrix Using Occupation and Industry Specific Exposure Data (1984-2008) in Republic of Korea. AB - BACKGROUND: The goal of this study is to develop a general population job exposure matrix (GPJEM) on asbestos to estimate occupational asbestos exposure levels in the Republic of Korea. METHODS: Three Korean domestic quantitative exposure datasets collected from 1984 to 2008 were used to build the GPJEM. Exposure groups in collected data were reclassified based on the current Korean Standard Industrial Classification (9th edition) and the Korean Standard Classification of Occupations code (6th edition) that is in accordance to international standards. All of the exposure levels were expressed by weighted arithmetic mean (WAM) and minimum and maximum concentrations. RESULTS: Based on the established GPJEM, the 112 exposure groups could be reclassified into 86 industries and 74 occupations. In the 1980s, the highest exposure levels were estimated in "knitting and weaving machine operators" with a WAM concentration of 7.48 fibers/mL (f/mL); in the 1990s, "plastic products production machine operators" with 5.12 f/mL, and in the 2000s "detergents production machine operators" handling talc containing asbestos with 2.45 f/mL. Of the 112 exposure groups, 44 groups had higher WAM concentrations than the Korean occupational exposure limit of 0.1 f/mL. CONCLUSION: The newly constructed GPJEM which is generated from actual domestic quantitative exposure data could be useful in evaluating historical exposure levels to asbestos and could contribute to improved prediction of asbestos-related diseases among Koreans. PMID- 28344850 TI - Adverse neurodevelopmental effects and hearing loss in children associated with manganese in well water, North Carolina, USA. AB - AIM: Heavy metals such as manganese, arsenic and lead can act as neurotoxins. There have been few human studies of neurobehavioral/neurodevelopmental effects of arsenic and manganese on children in the United States. Since 1998, North Carolina has tested all new private wells for manganese, arsenic and lead. This study was conducted to evaluate adverse neurodevelopmental effects (delayed milestones, speech/language disorders and hearing loss) in children and metal concentrations in well water. METHODS: A quasi-regression model of the number of children (0-35 months of age) with adverse neurodevelopmental effects as outcome measures and aggregate mean metal concentration (arsenic, lead, and manganese) in private well water in each county as exposures. RESULTS: Over 70,000 private well water samples from 1998 to 2011 were analyzed for metal content. From 2008 to 2011, an average of 17,000 children was enrolled in the Infant Toddler Program. On average, 1.7% of children in this age range in each county had a speech/language disorder, 0.24% had a diagnosis of delayed milestones, and 0.026% had a diagnosis of hearing loss. The county mean manganese concentration was significantly and positively associated with the prevalence of delayed milestones and hearing loss in the children. No association was found for metal concentrations and speech/language disorders. CONCLUSION: This ecological study indicates that further investigation of manganese in well water and associated neurodevelopmental health outcomes in children is needed. PMID- 28344851 TI - Manipulating Human Memory Through Reconsolidation: Stones Left Unturned. PMID- 28344853 TI - SNAP: A General Purpose Network Analysis and Graph Mining Library. AB - Large networks are becoming a widely used abstraction for studying complex systems in a broad set of disciplines, ranging from social network analysis to molecular biology and neuroscience. Despite an increasing need to analyze and manipulate large networks, only a limited number of tools are available for this task. Here, we describe Stanford Network Analysis Platform (SNAP), a general purpose, high-performance system that provides easy to use, high-level operations for analysis and manipulation of large networks. We present SNAP functionality, describe its implementational details, and give performance benchmarks. SNAP has been developed for single big-memory machines and it balances the trade-off between maximum performance, compact in-memory graph representation, and the ability to handle dynamic graphs where nodes and edges are being added or removed over time. SNAP can process massive networks with hundreds of millions of nodes and billions of edges. SNAP offers over 140 different graph algorithms that can efficiently manipulate large graphs, calculate structural properties, generate regular and random graphs, and handle attributes and meta-data on nodes and edges. Besides being able to handle large graphs, an additional strength of SNAP is that networks and their attributes are fully dynamic, they can be modified during the computation at low cost. SNAP is provided as an open source library in C++ as well as a module in Python. We also describe the Stanford Large Network Dataset, a set of social and information real-world networks and datasets, which we make publicly available. The collection is a complementary resource to our SNAP software and is widely used for development and benchmarking of graph analytics algorithms. PMID- 28344852 TI - Programming T cell Killers for an HIV Cure: Teach the New Dogs New Tricks and Let the Sleeping Dogs Lie. AB - Despite the success of combination antiretroviral therapy (cART), a latent viral reservoir persists in HIV-1-infected persons. Unfortunately, endogenous cytotoxic T lymphocytes (CTLs) are unable to control viral rebound when patients are removed from cART. A "kick and kill" strategy has been proposed to eradicate this reservoir, whereby infected T cells are induced to express viral proteins via latency-inducing drugs followed by their elimination by CTLs. It has yet to be determined if stimulation of existing HIV-1-specific CTL will be sufficient, or if new CTLs should be primed from naive T cells. In this review, we propose that dendritic cells (DCs), the most potent antigen presenting cells, act as dog trainers and can induce T cells (the dogs) to do magnificent tricks. We propose the hypothesis that an HIV-1 cure will require targeting of naive T cells and will necessitate "teaching new dogs new tricks" while avoiding activation of potentially dysfunctional endogenous memory CTLs (letting the sleeping dogs lie). PMID- 28344854 TI - Design and validation of magnetic particle spectrometer for characterization of magnetic nanoparticle relaxation dynamics. AB - The design and validation of a magnetic particle spectrometer (MPS) system used to study the linear and nonlinear behavior of magnetic nanoparticle suspensions is presented. The MPS characterizes the suspension dynamic response, both due to relaxation and saturation effects, which depends on the magnetic particles and their environment. The system applies sinusoidal excitation magnetic fields varying in amplitude and frequency and can be configured for linear measurements (1 mT at up to 120 kHz) and nonlinear measurements (50 mT at up to 24 kHz). Time resolved data acquisition at up to 4 MS/s combined with hardware and software based signal processing allows for wide-band measurements up to 50 harmonics in nonlinear mode. By cross-calibrating the instrument with a known sample, the instantaneous sample magnetization can be quantitatively reconstructed. Validation of the two MPS modes are performed for iron oxide and cobalt ferrite suspensions, exhibiting Neel and Brownian relaxation, respectively. PMID- 28344855 TI - Changes in Colorectal Cancer Screening Knowledge, Behavior, Beliefs, Self Efficacy, and Barriers among Community Health Clinic Patients after a Health Literacy Intervention. AB - OBJECTIVE: The objective in this pre- and post-survey assessment was to compare the effectiveness of a health literacy-directed intervention designed to increase knowledge, beliefs, barriers, self-efficacy and behavior associated with CRC screening with FOBT among patients cared for in predominantly rural community clinics and the change in these characteristics over the first 15 months after enrolling in a study designed to assess screening strategies. METHODS: Between 2008 and 2011, a quasi-experimental intervention was conducted in 8 predominantly rural Federally Qualified Health Centers. Patients were orally administered a 15 minute survey at enrollment by a clinic research assistant (RA) and at 15 months by phone by a central RA. Participants included 428 community clinic patients aged 50-85 (mean 58.5); the majority (79%) were female, 69% were African American, and 54% had limited health literacy. RESULTS: There was significant improvement across all groups with the number of patients reporting they had been given information /education on CRC testing (p<.0001), been given an FOBT kit (p<.0001), and completed an FOBT (p<.0001) with significant improvement in having a doctor recommendation in all groups except usual care. Confidence in an FOBT's potential to decrease chances of dying from CRC improved across all groups as well (p<0.002). In addition, patients 'belief that they would get CRC in their lifetime' decreased across all groups post-intervention (p<0.03) as did their worry that they may find out they have CRC (p<0.04). CONCLUSION: Overall these low income FQHC patients who were not up-to-date with screening had heard of CRC screening, had positive attitudes toward screening and wanted to know if they had cancer. Results demonstrate the value of giving patients a recommendation and a kit; patients in all groups reported significant increases at 15 months in completing CRC screening (>83%) as confirmed by study records. PMID- 28344856 TI - Effects of a Novel Dental Gel on Enamel Surface Recovery from Acid Challenge. AB - BACKGROUND: Objective was to evaluate the in vivo effects of a novel dental gel (Livionex gelR) vs. a comparison dental gel on the surfaces of pre-eroded enamel chips. METHODS: On days 1-5, after toothbrushing with dentifrice, nine subjects each wore 8 enamel chips mounted on a palatal appliance for 4 h. Enamel blocks were pre-demineralized daily. After 2 day washout, subjects repeated the protocol using fresh chips and the second toothpaste on days 8-12. Samples were evaluated using electron microscopy. RESULTS: Ten standardized enamel surface photomicrographs/sample (total 1440 images) were evaluated for signs of erosion visually and on a scale of 0-3 by 1 evaluator. No significant differences were found between the 2 groups (p>0.32, 95% C.I.). Minimal surface erosion on approx. 15% of sample area was visible in both groups. CONCLUSION: The enamel surface appeared similar after usage of a test or control dentifrice. Based on this study, the test formulation did not affect enamel surface recovery from an erosive challenge. PRACTICAL IMPLICATIONS: Dentifrices can contribute to maintaining a healthy enamel surface. An all-natural dental gel formulation with novel anti-plaque mechanism achieved similar recovery from acid challenge to enamel as a control gel. PMID- 28344857 TI - Metastatic BRAF K601E-mutated melanoma reaches complete response to MEK inhibitor trametinib administered for over 36 months. AB - BACKGROUND: The BRAF K601E mutation occurs in 5% of patients with melanoma, and is the third most common type of BRAF mutation. However, treatment with BRAF and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors is only approved in patients with BRAF V600-positive melanoma, and patients with K601E mutated melanoma do not have access to such drugs. CASE PRESENTATION: A female patient was diagnosed with high tumor burden metastatic melanoma harboring the BRAF K601E mutation. After chemotherapy failure, she underwent compassionate treatment with trametinib. Trametinib showed good activity and efficacy, with 48% shrinkage of a metastatic lymphadenopathy after 4 months' treatment. However, the patient reported treatment-related skin toxicity that required dosage reduction and a personalized intermittent trametinib dosing schedule. After over 36 months from the first trametinib administration, and resection of a metastatic lymphadenopathy, the patient experienced complete response. CONCLUSIONS: This case report shows that trametinib could be a valid therapeutic option in patients with metastatic melanoma harboring the rare BRAF K601E mutation. PMID- 28344858 TI - nab-Paclitaxel for the treatment of breast cancer: an update across treatment settings. AB - PURPOSE: The purpose of this systematic review is to discuss recent studies and ongoing trials of nab-paclitaxel in breast cancer and to examine the potential role of nab-paclitaxel as a backbone for immuno-oncology therapies. METHODS: PubMed and selected congress proceedings were searched for studies of nab paclitaxel in breast cancer published between 2013 and 2015. All phase II and III clinical trials, retrospective analyses, and institutional studies were included. Active, ongoing, phase II or III trials on nab-paclitaxel that were listed on ClinicalTrials.gov were also included. RESULTS: Sixty-three studies, including 23 in early-stage and 30 in metastatic breast cancer (some studies not classifiable by setting), were included in this analysis. Trials of neoadjuvant nab-paclitaxel containing regimens have reported pathological complete response rates ranging from 5.7 to 53%. Median overall survival in metastatic breast cancer studies ranged from 10.8 to 23.5 months, depending on dose and regimen. Adverse event profiles of nab-paclitaxel were generally similar to those reported from previous studies. Several ongoing trials are evaluating nab-paclitaxel in the early-stage and metastatic settings, including in combination with immuno-oncology agents. CONCLUSIONS: nab-Paclitaxel continues to demonstrate promising efficacy in breast cancer. Recent studies demonstrate high pathological complete response rates in early-stage breast cancer, particularly in triple-negative breast cancer, an area of high unmet need, and encouraging overall survival in metastatic breast cancer across doses and schedules. Ongoing trials will provide further insights into the role of nab-paclitaxel in breast cancer including use as a potential backbone chemotherapy agent for immuno-oncology therapies such as checkpoint inhibitors. PMID- 28344859 TI - HLA class II antigen-processing pathway in tumors: Molecular defects and clinical relevance. AB - The human leukocyte antigen (HLA) class II antigen-processing machinery (APM) presents to cognate CD4+ T-cells antigenic peptides mainly generated from exogeneous proteins in the endocytic compartment. These CD4+ T cells exert helper function, but may also act as effector cells, thereby recognizing HLA class II antigen-expressing tumor cells. Thus, HLA class II antigen expression by tumor cells influences the tumor antigen (TA)-specific immune responses and, depending on the cancer type, the clinical course of the disease. Many types of human cancers express HLA class II antigens, although with marked differences in their frequency. Some types of cancer lack HLA class II antigen expression, which could be due to structural defects or deregulation affecting different components of the complex HLA class II APM and/or from lack of cytokine(s) in the tumor microenvironment. In this review, we have summarized the information about HLA class II antigen distribution in normal tissues, the structural organization of the HLA class II APM, their expression and regulation in malignant cells, the defects, which have been identified in malignant cells, and their functional and clinical relevance. PMID- 28344860 TI - IL-32 induces indoleamine 2,3-dioxygenase+CD1c+ dendritic cells and indoleamine 2,3-dioxygenase+CD163+ macrophages: Relevance to mycosis fungoides progression. AB - Mycosis fungoides (MF) progresses from patch to tumor stage by expansion of malignant T-cells that fail to be controlled by protective immune mechanisms. In this study, we focused on IL-32, a cytokine, highly expressed in MF lesions. Depending on the other cytokines (IL-4, GM-CSF) present during in vitro culture of healthy volunteers' monocytes, IL-32 increased the maturation of CD11c+ myeloid dendritic cells (mDC) and/or CD163+ macrophages, but IL-32 alone showed a clear ability to promote dendritic cell (DC) differentiation from monocytes. DCs matured by IL-32 had the phenotype of skin-resident DCs (CD1c+), but more importantly, also had high expression of indoleamine 2,3-dioxygenase. The presence of DCs with these markers was demonstrated in MF skin lesions. At a molecular level, indoleamine 2,3-dioxygenase messenger RNA (mRNA) levels in MF lesions were higher than those in healthy volunteers, and there was a high correlation between indoleamine 2,3-dioxygenase and IL-32 expression. In contrast, Foxp3 mRNA levels decreased from patch to tumor stage. Increasing expression of IL-10 across MF lesions was highly correlated with IL-32 and indoleamine 2,3-dioxygenase, but not with Foxp3 expression. Thus, IL-32 could contribute to progressive immune dysregulation in MF by directly fostering development of immunosuppressive mDC or macrophages, possibly in association with IL-10. PMID- 28344861 TI - Zoledronic acid boosts gammadelta T-cell activity in children receiving alphabeta+ T and CD19+ cell-depleted grafts from an HLA-haplo-identical donor. AB - We demonstrated that gammadelta T cells of patients given HLA-haploidentical HSCT after removal of alphabeta+ T cells and CD19+ B cells are endowed with the capacity of killing leukemia cells after ex vivo treatment with zoledronic acid (ZOL). Thus, we tested the hypothesis that infusion of ZOL in patients receiving this type of graft may enhance gammadelta T-cell cytotoxic activity against leukemia cells. ZOL was infused every 28 d in 43 patients; most were treated at least twice. gammadelta T cells before and after ZOL treatments were studied in 33 of these 43 patients, till at least 7 mo after HSCT by high-resolution mass spectrometry, flow-cytometry, and degranulation assay. An induction of Vdelta2 cell differentiation, paralleled by increased cytotoxicity of both Vdelta1 and Vdelta2 cells against primary leukemia blasts was associated with ZOL treatment. Cytotoxic activity was further increased in Vdelta2 cells, but not in Vdelta1 lymphocytes in those patients given more than one treatment. Proteomic analysis of gammadelta T cells purified from patients showed upregulation of proteins involved in activation processes and immune response, paralleled by downregulation of proteins involved in proliferation. Moreover, a proteomic signature was identified for each ZOL treatment. Patients given three or more ZOL infusions had a better probability of survival in comparison to those given one or two treatments (86% vs. 54%, respectively, p = 0.008). Our data indicate that ZOL infusion in pediatric recipients of alphabeta T- and B-cell-depleted HLA haploidentical HSCT promotes gammadelta T-cell differentiation and cytotoxicity and may influence the outcome of patients. PMID- 28344862 TI - Expression profiles of immune-related genes are associated with neoadjuvant ipilimumab clinical benefit. AB - Purpose: Patients with regionally advanced melanoma were treated with neoadjuvant ipilimumab in a previously reported study (PLOS One 2014). Gene expression profiles of tumors of treated patients were investigated for their association with immunotherapeutic benefit. Methods: Patients were treated with ipilimumab (10 mg/kg intravenously every 3 weeks * 2 doses) before and after surgery. Tumor specimens were obtained at baseline and at definitive surgery (weeks 6-8). Gene expression profiling was performed on the tumor biopsies of 27 patients. The primary endpoint was mRNA expression profiling using U133A 2.0 Affymetrix gene chips. Significance analysis of microarrays was performed to test the association of each gene with outcome. Pathway analysis was performed using Ingenuity Pathway Analysis software. The Benjamini and Hochberg method was used to adjust for multiple testing in the pathway analysis. Results: Pathway analysis identified biologically relevant pathways enriched with genes that are significantly associated with clinical outcome at baseline in relation to relapse-free survival (RFS) and disease non-progression (as assessed preoperatively at week 6) as well as early on-treatment (RFS and overall survival). The molecules and pathways that achieved differential expression of highest statistical significance were notably immune related. Association of the gene signature with clinical outcome overlapped between baseline and on-treatment specimens and across clinical endpoints tested. Conclusion: Gene expression profiling identified a signature reflecting an immune active and proinflammatory tumor microenvironment that derived clinical benefit from neoadjuvant ipilimumab at baseline and early on treatment. These findings warrant further investigation in relation to ipilimumab and other immunotherapeutics. PMID- 28344863 TI - Tumor-infiltrating lymphocytes (TILs) from patients with glioma. AB - Tumor-infiltrating lymphocytes (TILs) may represent a viable source of T cells for the biological treatment of patients with gliomas. Glioma tissue was obtained from 16 patients, tumor cell lines were established, and TILs were expanded in 16/16 cases using a combination of IL-2/IL-15/IL-21. Intracellular cytokine staining (ICS, IL-2, IL-17, TNFalpha and IFNgamma production) as well as a cytotoxicity assay was used to detect TIL reactivity against autologous tumor cells or shared tumor-associated antigens (TAAs; i.e., NY-ESO-1, Survivin or EGFRvIII). TILs were analyzed by flow cytometry, including T-cell receptor (TCR) Vbeta family composition, exhaustion/activation and T-cell differentiation markers (CD45RA/CCR7). IL-2/IL-15/IL-21 expanded TILs exhibited a mixture of CD4+, CD8+, as well as CD3+ CD4-CD8- T cells with a predominant central memory CD45RA-CCR7+ phenotype. TIL showed low frequencies of T cells testing positive for PD-1, TIM-3 and CTLA-4. LAG3 tested positive in up to 30% of CD8+ TIL, with low (1.25%) frequencies in CD4+ T cells. TIL cultures exhibited preferential usage of Vbeta families and recognition of autologous tumor cells defined by cytokine production and cytotoxicity. IL-2/IL-15/IL-21 expanded TILs represent a viable source for the cellular therapy of patients with gliomas. PMID- 28344864 TI - An immunogenic WT1-derived peptide that induces T cell response in the context of HLA-A*02:01 and HLA-A*24:02 molecules. AB - The Wilms' tumor oncogene protein (WT1) is a highly validated tumor antigen for immunotherapy. WT1-targeted immunotherapy has been extensively explored in multiple human trials in various cancers. However, clinical investigations using WT1 epitopes have generally focused on two peptides, HLA-restricted to HLA A*02:01 or HLA-A*24:02. The goal of this study was to identify new epitopes derived from WT1, to expand the potential use of WT1 as a target of immunotherapy. Using computer-based MHC-binding algorithms and in vitro validation of the T cell responses specific for the identified peptides, we found that a recently identified HLA-A*24:02-binding epitope (239-247), NQMNLGATL (NQM), was also a strong CD8+ T cell epitope for HLA-A*02:01 molecule. A peptide second position Q240L substitution (NLM) or Q240Y substitution (NYM), further enhanced the T cell responses in both HLA-A*02:01 positive and HLA-A*24:02 positive healthy donors. Importantly, T cells stimulated with the new analog peptides displayed heteroclitic cross-reactivity with the native NQM sequence and were able to kill HLA-matched WT1-positive tumor cell lines and primary leukemia blasts. In addition, longer native and heteroclitic HLA-DR.B1-binding peptides, comprising the nine amino acid NQM or NLM sequences, could induce T cell response that recognized the CD8+ epitope NQM, suggesting the processing and the presentation by HLA-A*02:01 molecules of the CD8+ T cell epitope embedded within it. Our studies suggest that the analog peptides NLM and NYM could be potential candidates for future immunotherapy targeting WT1 positive cancers in the context of HLA-A*02:01 and A*24:02 positive populations. PMID- 28344866 TI - CD13hi Neutrophil-like myeloid-derived suppressor cells exert immune suppression through Arginase 1 expression in pancreatic ductal adenocarcinoma. AB - Perineural invasion and immunosuppressive tumor microenvironment are the distinct features of pancreatic ductal adenocarcinoma (PDAC). Heterogeneous myeloid derived suppressor cells (MDSCs) are potent suppressors of antitumor immunity, posing obstacles for cancer immunotherapy. Increasing evidences have demonstrated the accumulation of MDSCs in PDAC patients. However, the role of MDSCs in perineural invasion of PDAC and the existence of novel MDSC subsets during PDAC remain unclear. This study found that lymphocytic perineural cuffs were frequently present in chronic pancreatitis (CP) tissues and adjacent non neoplastic pancreatic tissues (ANPTs), but not in PDAC with perineural invasion. Meanwhile, we found that neutrophil-like MDSCs (nMDSCs), but not monocyte-like MDSCs (mMDSCs), were significantly increased in PBMCs and tumor tissues of PDAC patients. Further observation identified two distinct subsets of nMDSCs, CD13hi and CD13low nMDSCs in PDAC patients, which have not been reported previously. Despite a similar morphology, CD13hi nMDSCs expressed higher levels of CD11b, CD33, CD16 and arginase 1 but lower levels of CD66b than CD13low nMDSCs. Importantly, CD13hi MDSCs, compared with CD13low nMDSCs, more effectively suppressed alloreactive T cell responses via an arginase-1-related mechanism. After tumor resection, the circulating CD13hi nMDSCs were decreased markedly. PDAC patients with more CD13hi nMDSCs had a shorter overall survival than those with less CD13hi nMDSCs. To conclude, we identified two novel MDSC subsets with different characteristics and functions in PDAC, demonstrated the association of the two MDSC subsets with cancer progression, and explored their roles in perineural invasion and immune escape of PDAC. PMID- 28344867 TI - CD4+ and CD8+ T cells are both needed to induce paraneoplastic neurological disease in a mouse model. AB - Paraneoplastic neurological disorders (PNDs) are rare human autoimmune diseases that mostly affect the central nervous system (CNS). They are triggered by an efficient immune response against a neural self-antigen that is ectopically expressed in neoplastic tumors. Due to this shared antigenic expression, the immune system reacts not only to tumor cells but also to neural cells resulting in neurological damage. Growing data point to a major role of cell-mediated immunity in PNDs associated to autoantibodies against intracellular proteins. However, its precise contribution in the pathogenesis remains unclear. In this context, our study aimed at investigating the impact of anti-tumor cellular immune responses in the development of PND. To this end, we developed an animal model mimicking PND. We used a tumor cell line expressing the hemagglutinin (HA) of influenza virus to induce an anti-tumor response in CamK-HA mice, which express HA in CNS neurons. To promote and track the T cell response against the HA antigen, naive HA-specific CD8+ and/or CD4+ T cells, originating from TCR transgenic animals, were transferred into these mice. We demonstrate that HA expressing tumors, but not control tumors, induce in vivo activation, proliferation and differentiation of naive HA-specific CD4+ and CD8+ T cells into effector cells. Moreover, both T cell subsets were needed to control tumor growth and induce CNS inflammation in CamK-HA mice. Thus, this new mouse model provides further insight into the cellular mechanisms whereby a potent anti-tumor immunity triggers a cancer-associated autoimmune disease, and may therefore help to develop new therapeutic strategies against PND. PMID- 28344865 TI - Identification of genetic determinants of breast cancer immune phenotypes by integrative genome-scale analysis. AB - Cancer immunotherapy is revolutionizing the clinical management of several tumors, but has demonstrated limited activity in breast cancer. The development of more effective treatments is hindered by incomplete knowledge of the genetic determinant of immune responsiveness. To fill this gap, we mined copy number alteration, somatic mutation, and expression data from The Cancer Genome Atlas (TCGA). By using RNA-sequencing data from 1,004 breast cancers, we defined distinct immune phenotypes characterized by progressive expression of transcripts previously associated with immune-mediated rejection. The T helper 1 (Th-1) phenotype (ICR4), which also displays upregulation of immune-regulatory transcripts such as PDL1, PD1, FOXP3, IDO1, and CTLA4, was associated with prolonged patients' survival. We validated these findings in an independent meta cohort of 1,954 breast cancer gene expression data. Chromosome segment 4q21, which includes genes encoding for the Th-1 chemokines CXCL9-11, was significantly amplified only in the immune favorable phenotype (ICR4). The mutation and neoantigen load progressively decreased from ICR4 to ICR1 but could not fully explain immune phenotypic differences. Mutations of TP53 were enriched in the immune favorable phenotype (ICR4). Conversely, the presence of MAP3K1 and MAP2K4 mutations were tightly associated with an immune-unfavorable phenotype (ICR1). Using both the TCGA and the validation dataset, the degree of MAPK deregulation segregates breast tumors according to their immune disposition. These findings suggest that mutation-driven perturbations of MAPK pathways are linked to the negative regulation of intratumoral immune response in breast cancer. Modulations of MAPK pathways could be experimentally tested to enhance breast cancer immune sensitivity. PMID- 28344868 TI - Langerhans cells and NK cells cooperate in the inhibition of chemical skin carcinogenesis. AB - Tissue immunosurveillance is an important mechanism to prevent cancer. Skin treatment with the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA), followed by the tumor promoter 12-O-tetra-decanoyl-phorbol-13-acetate (TPA), is an established murine model for squamous cell carcinoma (SCC). However, the innate immunological events occurring during the initiation of chemical carcinogenesis with DMBA remain elusive. Here, we discovered that natural killer (NK) cells and Langerhans cells (LC) cooperate to impair this oncogenic process in murine skin. The depletion of NK cells or LC caused an accumulation of DNA-damaged, natural killer group 2D-ligand (NKG2D-L) expressing keratinocytes and accelerated tumor growth. Notably, the secretion of TNFalpha mainly by LC promoted the recruitment of NK cells into the epidermis. Indeed, the TNFalpha-induced chemokines CCL2 and CXCL10 directed NK cells to DMBA-treated epidermis. Our findings reveal a novel mechanism how innate immune cells cooperate in the inhibition of cutaneous chemical carcinogenesis. PMID- 28344869 TI - IL-15, TIM-3 and NK cells subsets predict responsiveness to anti-CTLA-4 treatment in melanoma patients. AB - Despite the success of immune checkpoint blockade in melanoma, the majority of patients do not respond. We hypothesized that the T and NK cell subset frequencies and expression levels of their receptors may predict responses and clinical outcome of anti-CTLA-4 treatment. We thus characterized the NK and T cell phenotype, as well as serum levels of several cytokines in 67 melanoma patients recruited in Italy and Sweden, using samples drawn prior to and during treatment. Survival correlated with low expression of the inhibitory receptor TIM 3 on circulating T and NK cells prior to and during treatment and with the increased frequency of mature circulating NK cells (defined as CD3-CD56dim CD16+) during treatment. Survival also correlated with low levels of IL-15 in the serum. Functional experiments in vitro demonstrated that sustained exposure to IL-15 enhanced the expression of PD-1 and TIM-3 on both T and NK cells, indicating a causative link between high IL-15 levels and enhanced expression of TIM-3 on these cells. Receptor blockade of TIM-3 improved NK cell-mediated elimination of melanoma metastasis cell lines in vitro. These observations may lead to the development of novel biomarkers to predict patient response to checkpoint blockade treatment. They also suggest that induction of additional checkpoints is a possibility that needs to be considered when treating melanoma patients with IL 15. PMID- 28344870 TI - Immunological profiling of molecularly classified high-risk endometrial cancers identifies POLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition. AB - High-risk endometrial cancer (EC) is an aggressive disease for which new therapeutic options are needed. Aims of this study were to validate the enhanced immune response in highly mutated ECs and to explore immune profiles in other EC subgroups. We evaluated immune infiltration in 116 high-risk ECs from the TransPORTEC consortium, previously classified into four molecular subtypes: (i) ultramutated POLE exonuclease domain-mutant ECs (POLE-mutant); (ii) hypermutated microsatellite unstable (MSI); (iii) p53-mutant; and (iv) no specific molecular profile (NSMP). Within The Cancer Genome Atlas (TCGA) EC cohort, significantly higher numbers of predicted neoantigens were demonstrated in POLE-mutant and MSI tumors compared with NSMP and p53-mutants. This was reflected by enhanced immune expression and infiltration in POLE-mutant and MSI tumors in both the TCGA cohort (mRNA expression) and the TransPORTEC cohort (immunohistochemistry) with high infiltration of CD8+ (90% and 69%), PD-1+ (73% and 69%) and PD-L1+ immune cells (100% and 71%). Notably, a subset of p53-mutant and NSMP cancers was characterized by signs of an antitumor immune response (43% and 31% of tumors with high infiltration of CD8+ cells, respectively), despite a low number of predicted neoantigens. In conclusion, the presence of enhanced immune infiltration, particularly high numbers of PD-1 and PD-L1 positive cells, in highly mutated, neoantigen-rich POLE-mutant and MSI endometrial tumors suggests sensitivity to immune checkpoint inhibitors. PMID- 28344871 TI - Description of the immune microenvironment of chondrosarcoma and contribution to progression. AB - Chondrosarcoma (CHS) is a rare bone malignancy characterized by its resistance to conventional systemic and radiation therapies. Whether immunotherapy targeting immune checkpoints may be active in these tumors remains unknown. To explore the role of the immune system in this tumor, we analyzed the immune environment of chondrosarcomas both in human sample, and in a syngeneic rat model, and tested the contribution of T lymphocytes and macrophages in chondrosarcoma progression. Immunohistochemical stainings were performed on human chondrosarcoma samples and on Swarm rat chondrosarcoma (SRC) model. Selective immunodepletion assays were performed in SRC to evaluate immune population's involvement in tumor progression. In human and rat chondrosarcoma, immune infiltrates composed of lymphocytes and macrophages were identified in the peritumoral area. Immune infiltrates composition was found correlated with tumors characteristics and evolution (grade, invasiveness and size). In SRC, selective depletion of T lymphocytes resulted in an accelerated growth rates, whereas depletion of CD163+ macrophages slowed down tumor progression. Splenocytes isolated from CHS-bearing SRC showed a specific cytotoxicity directed against chondrosarcoma cells (27%), which significantly decreased in CD3-depleted SRC (11%). The immune environment contributes to CHS progression in both human and animal models, suggesting that immunomodulatory approaches could be tested in bone chondrosarcoma. PMID- 28344872 TI - Intravenously usable fully serotype 3 oncolytic adenovirus coding for CD40L as an enabler of dendritic cell therapy. AB - Vaccination with dendritic cells (DCs), the most potent professional antigen presenting cells in the body, is a promising approach in cancer immunotherapy. However, tumors induce immunosuppression in their microenvironment that suppresses and impairs the function of DCs. Therefore, human clinical trials with DC therapy have often been disappointing. To improve the therapeutic efficacy and to overcome the major obstacles of DC therapy, we generated a novel adenovirus, Ad3-hTERT-CMV-hCD40L, which is fully serotype 3 and expresses hCD40L for induction of antitumor immune response. The specific aim is to enhance DCs function. Data from a human cancer patient indicated that this capsid allows effective transduction of distant tumors through the intravenous route. Moreover, patient data suggested that virally produced hCD40L can activate DCs in situ. The virus was efficient in vitro and had potent antitumor activity in vivo. In a syngeneic model, tumors treated with Ad5/3-CMV-mCD40L virus plus DCs elicited greater antitumor effect as compared with either treatment alone. Moreover, virally coded CD40L induced activation of DCs, which in turn, lead to the induction of a Th1 immune response and increased tumor-specific T cells. In conclusion, Ad3-hTERT-CMV-hCD40L is promising for translation into human trials. In particular, this virus could enable successful dendritic cell therapy in cancer patients. PMID- 28344873 TI - A specific immune and lymphatic profile characterizes the pre-metastatic state of the sentinel lymph node in patients with early cervical cancer. AB - The lymph node (LN) pre-metastatic niche is faintly characterized in lymphophilic human neoplasia, although LN metastasis is considered as the strongest prognostic marker of patient survival. Due to its specific dissemination through a complex bilateral pelvic lymphatic system, early cervical cancer is a relevant candidate for investigating the early nodal metastatic process. In the present study, we analyzed in-depth both the lymphatic vasculature and the immune climate of pre metastatic sentinel LN (SLN), in 48 cases of FIGO stage IB1 cervical neoplasms. An original digital image analysis methodology was used to objectively determine whole slide densities and spatial distributions of immunostained structures. We observed a marked increase in lymphatic vessel density (LVD) and a specific capsular and subcapsular distribution in pre-metastatic SLN when compared with non-sentinel counterparts. Such features persisted in the presence of nodal metastatic colonization. The inflammatory profile attested by CD8+, Foxp3, CD20 and PD-1expression was also significantly increased in pre-metastatic SLN. Remarkably, the densities of CD20+ B cells and PD-1 expressing germinal centers were positively correlated with LVD. All together, these data strongly support the existence of a pre-metastatic dialog between the primary tumor and the first nodal relay. Both lymphatic and immune responses contribute to the elaboration of a specific pre-metastatic microenvironment in human SLN. Moreover, this work provides evidence that, in the context of early cervical cancer, a pre-metastatic lymphangiogenesis occurs within the SLN (pre-metastatic niche) and is associated with a specific humoral immune response. PMID- 28344874 TI - High baseline levels of interleukin-8 in leukocytes and urine predict tumor recurrence in non-muscle invasive bladder cancer patients receiving bacillus Calmette-Guerin therapy: A long-term survival analysis. AB - Bacillus Calmette-Guerin (BCG) therapy for non-muscle invasive bladder cancer (NMIBC) can significantly reduce the risk of recurrence and progression. However, BCG therapy may fail in up to a half of treated patients and may also cause toxicities. Biomarkers to predict the effectiveness of BCG therapy are desired to pre-select patients for BCG therapy to maximize efficacy while avoid unnecessary toxicity. Twelve cytokines were measured in 100 blood and 112 urine samples using cytokine antibody array and correlated with recurrence-free survival in overall and BCG-treated NMIBC patients. Of the 12 cytokines, interleukin (IL) -2, IL-8, IL-10, tumor necrosis factor (TNF)-alpha, granulocyte-macrophage colony stimulating factor (GM-CSF) and interferon (IFN)-gamma were measurable in more than 30% of peripheral blood leukocyte (PBL) samples. Only IL-8 in PBL was found to be significantly associated with tumor recurrence, especially in those who receiving BCG therapy (hazard ratio [HR] = 4.24; 95% confidence interval [95%CI] = 1.65-10.88; p = 0.003). The median recurrence-free survival time for BCG treated patients with high baseline IL-8 levels were much shorter than those with low IL-8 levels (7.9 vs. >78.4 mo, p = 0.004). Furthermore, consistent associations between urinary IL-8 levels and tumor recurrence in patients receiving BCG therapy were observed in 58 pre-BCG and 54 long-term post-BCG treated urine samples (both p <= 0.005). High urinary baseline IL-8 level also predicted shorter time to tumor recurrence in NMIBC patients (both p <= 0.004). By using antibody array-based technology in two separate cohorts of NMIBC patients, we found that PBL and urinary baseline IL-8 levels were significantly associated with tumor recurrence after BCG therapy. PMID- 28344875 TI - Targeting of IL-2 to cytotoxic lymphocytes as an improved method of cytokine driven immunotherapy. AB - The use of high-dose interleukin-2 (IL-2) has fallen out of favor due to severe life-threatening side effects. We have recently described a unique way of directly targeting IL-2 to cytotoxic lymphocytes using a virally encoded immune evasion protein and an IL-2 mutant that avoids off-target side effects such as activation of regulatory T cells and vascular endothelium. PMID- 28344876 TI - 2B4-SAP signaling is required for the priming of naive CD8+ T cells by antigen expressing B cells and B lymphoma cells. AB - Mutations in SH2D1A gene that encodes SAP (SLAM-associated protein) result in X linked lymphoproliferative disease (XLP), a rare primary immunodeficiency disease defined by exquisite sensitivity to the B-lymphotropic Epstein-Barr virus (EBV) and B cell lymphomas. However, the precise mechanism of how the loss of SAP function contributes to extreme vulnerability to EBV and the development of B cell lymphomas remains unclear. Here, we investigate the hypothesis that SAP is critical for CD8+ T cell immune surveillance of antigen (Ag)-expressing B cells or B lymphoma cells under conditions of defined T cell receptor (TCR) signaling. Sh2d1a-/- CD8+ T cells exhibited greatly diminished proliferation relative to wild type when Ag-presenting-B cells or -B lymphoma cells served as the primary Ag-presenting cell (APC). By contrast, Sh2d1a-/- CD8+ T cells responded equivalently to wild-type CD8+ T cells when B cell-depleted splenocytes, melanoma cells or breast carcinoma cells performed Ag presentation. Through application of signaling lymphocyte activation molecule (SLAM) family receptor blocking antibodies or SLAM family receptor-deficient CD8+ T cells and APCs, we found that CD48 engagement on the B cell surface by 2B4 is crucial for initiating SAP dependent signaling required for the Ag-driven CD8+ T cell proliferation and differentiation. Altogether, a pivotal role for SAP in promoting the expansion and differentiation of B cell-primed viral-specific naive CD8+ T cells may explain the selective immune deficiency of XLP patients to EBV and B cell lymphomas. PMID- 28344878 TI - Targeting cytokine signaling checkpoint CIS activates NK cells to protect from tumor initiation and metastasis. AB - The cytokine-induced SH2-containing protein CIS belongs to the suppressor of cytokine signaling (SOCS) protein family. Here, we show the critical role of CIS in suppressing natural killer (NK) cell control of tumor initiation and metastasis. Cish-deficient mice were highly resistant to methylcholanthrene induced sarcoma formation and protected from lung metastasis of B16F10 melanoma and RM-1 prostate carcinoma cells. In contrast, the growth of primary subcutaneous tumors, including those expressing the foreign antigen OVA, was unchanged in Cish-deficient mice. The combination of Cish deficiency and relevant targeted and immuno-therapies such as combined BRAF and MEK inhibitors, immune checkpoint blockade antibodies, IL-2 and type I interferon revealed further improved control of metastasis. The data clearly indicate that targeting CIS promotes NK cell antitumor functions and CIS holds great promise as a novel target in NK cell immunotherapy. PMID- 28344877 TI - Impact of (chemo)radiotherapy on immune cell composition and function in cervical cancer patients. AB - New treatments based on combinations of standard therapeutic modalities and immunotherapy are of potential use, but require a profound understanding of immune modulatory properties of standard therapies. Here, the impact of standard (chemo)radiotherapy on the immune system of cervical cancer patients was evaluated. Thirty patients with cervical cancer were treated with external beam radiation therapy (EBRT), using conventional three-dimensional or intensity modulated radiation therapy without constraints for bone marrow sparing. Serial blood sampling for immunomonitoring was performed before, midway and at 3, 6 and 9 weeks after EBRT to analyze the composition of lymphocyte and myeloid-cell populations, the expression of co-stimulatory molecules, T-cell reactivity and antigen presenting cell (APC) function. Therapy significantly decreased the absolute numbers of circulating leukocytes and lymphocytes. Furthermore, the capacity of the remaining T cells to respond to antigenic or mitogenic stimulation was impaired. During treatment the frequency of both CD4+ and CD8+ T cells dropped and CD4+ T cells displayed an increased expression of programmed cell death-1 (PD-1). In vitro blocking of PD-1 successfully increased T-cell reactivity in all five samples isolated before radiotherapy but was less successful in restoring reactivity in samples isolated at later time points. Moreover, (chemo)radiotherapy was associated with an increase in both circulating monocytes and myeloid-derived suppressor cells (MDSCs) and an impaired capacity of APCs to stimulate allogeneic T cells. T-cell reactivity was slowly restored at 6-9 weeks after cessation of therapy. We conclude that conventional (chemo)radiotherapy profoundly suppresses the immune system in cervical cancer patients, and may restrict its combination with immunotherapy. PMID- 28344879 TI - Prostaglandin E2-mediated adenosinergic effects on CD14+ cells: Self-amplifying immunosuppression in cancer. AB - CD39 and CD73 are surface-expressed ectonucleotidases that hydrolyze ATP in a highly regulated, serial manner into ADP, AMP and adenosine. The end product, adenosine, has both tumor-promoting and immunosuppressive effects. The aim of this study was to determine CD73 expression on immune cells in pleural effusion (PE) in order to have a better understanding of the immune environment in mesothelioma. PE- or blood-derived CD14+ cells of mesothelioma patients and healthy donors were analyzed by flow cytometry for the expression of CD39 and CD73. CD73-induction was studied by exposure of CD14+ cells to the soluble fraction of PE (sPE), while the signaling mechanism, responsible for CD73 induction, by phosphoflow cytometry and receptor-inhibition studies. We observed CD73 expression on CD14+ cells in PE but not peripheral blood of mesothelioma patients or healthy donors. CD73 expression was inducible on CD14+ cells with sPE, cyclic-AMP (cAMP)-inducers (forskolin and prostaglandin-E2 (PGE2)) and adenosine. Inhibition of PGE2 receptors or adenosine A2 receptors blocked CD73 induction by sPE. sPE treatment triggered protein kinase A and p38 activation. However, signal-transducer and activator of transcription 3 (STAT3)-blocking led to enhanced CD73 expression, demonstrating a hitherto unknown negative control of purinergic signaling by STAT3 in CD14+ cells. TNFalpha production by CD73+ CD14+ cells was significantly impaired in the presence of AMP, confirming immunosuppressive function. Taken together, CD73 expression can be induced by PGE2, cAMP or adenosine on human CD14+ cells. We suggest that targeting this autocrine loop is a valid therapeutic approach in mesothelioma that may also enhance immunotherapy. PMID- 28344880 TI - Protective function of interleukin 27 in colitis-associated cancer via suppression of inflammatory cytokines in intestinal epithelial cells. AB - Numerous studies have demonstrated that inflammation contributes to a variety of cancer formation, among them, colitis-associated cancer (CAC) represents a typical inflammation-related cancer. Interleukin 27 (IL-27) has been demonstrated to play an important role in inflammation-related disease. The effect of IL-27 in intestinal inflammation is controversial and its role in CAC is not elucidated yet. In our present study, we found that IL-27 has protective function in murine model of CAC through suppression of inflammatory cytokines in intestinal epithelial cells (IECs). IL-27Ralpha (WSX-1) deficiency promotes the CAC development in mice, which is driven by enhanced tumor cell proliferation, more intensive myeloid-derived suppressor cells (MDSC) accumulation in colon lamina propria and higher level of inflammatory cytokines and chemokines in IECs. The levels of IL-6, TNF-alpha, GM-CSF and CXCL1 triggered in vitro by toll-like receptor ligands are significantly upregulated in IECs from WSX-1 KO mice. Removal of commensal microorganism through antibiotic treatment in mice to eliminate TLR ligands deprives the protective function of IL-27 on CAC tumor growth. Thus, IL-27 suppresses CAC formation through an anti-inflammation mechanism targeting IECs and in turn resists the tumorigenesis. Hence, our study explained how IL-27 exerts its anti-inflammatory function on epithelial cells to fight against chronic-inflammation-associated cancer, which might provide new insights on the potential therapeutic strategies for cancer. PMID- 28344881 TI - Immunosurveillance and immunoediting in MMTV-PyMT-induced mammary oncogenesis. AB - Evidence of cancer immunosurveillance and immunoediting processes has been primarily demonstrated in mouse models of chemically induced oncogenesis. Although these models are very tractable, they are characterized by high mutational loads that represent a minority of human cancers. In this study, we sought to determine whether cancer immunosurveillance and immunoediting could be demonstrated in a more clinically relevant oncogene-induced model of carcinogenesis, the MMTV-PyMT (PyMT) mammary carcinoma model. This model system in the FVB/NJ strain background was previously used to demonstrate that adaptive immunity had no role in limiting primary cancer formation and in fact promoted metastasis, thus calling into question whether cancer immunosurveillance operated in preventing the development of breast cancer. Our current study in the C57BL/6 strain backgrounds provides a different conclusion, as we report here the existence of an adaptive immunosurveillance of PyMT mammary carcinomas using two independent models of immune deficiency. PyMT mice bred onto a Rag1-/- background or immune suppressed by chronic tacrolimus therapy both demonstrated accelerated development of mammary carcinomas. By generating a bank of cell lines from these animals, we further show that a subset of PyMT cell lines had delayed growth after transplantation into wild-type (WT) syngeneic, but not immune-deficient hosts. This reduced growth rate in immunocompetent animals was characterized by an increase in immune cell infiltration and tissue differentiation. Furthermore, loss of the immune cell infiltration that characterized immunoediting of slow growing cell lines, changed them into fast growing variants capable of progressing in the immunocompetent model. In conclusion, our study provides evidence that immunosurveillance and immunoediting of PyMT-derived cell lines modulate tumor progression in this oncogene-induced model of cancer. PMID- 28344882 TI - Tumor PD-L1 expression is correlated with increased TILs and poor prognosis in penile squamous cell carcinoma. AB - Despite its rare incidence worldwide, penile squamous cell carcinoma (PeSCC) still presents with significant morbidity and mortality due to the limited treatment options for advanced patients, especially those in developing countries. The program death-1 (PD-1)/PD-1 ligand (PD-L1) axis has been demonstrated to play an important role in tumor immune escape, and immunotherapies targeting this pathway have shown great success in certain cancer types. Here, we analyzed the expression pattern of PD-L1 in tumor cells and tumor infiltrating lymphocytes (TILs) in PeSCC with a multi-center cohort. We found that the majority of PeSCCs (53.4%) were PD-L1-positive and that high PD-L1 expression in tumor cells was associated with a poor prognosis. Notably, PD-L1 expression in tumor cells was significantly associated with the extent of TILs and CD8+ TILs. Quantitative reverse transcriptase polymerase chain reaction (qRT PCR) showed that PD-L1 was positively correlated with interferon-gamma (IFNgamma) and CD8+ gene expression. Moreover, we defined the constitutive and inducible surface expression of PD-L1 in newly established primary PeSCC cell lines. Interestingly, two PeSCC cell lines had high intrinsic PD-L1 expression. Another cell line showed low PD-L1 expression, but the PD-L1 expression could be induced by IFNgamma stimulation. Overall, our data showed that high PD-L1 expression in penile tumor cells indicated a poor prognosis. The upregulation of PD-L1 in PeSCC included both extrinsic and intrinsic mechanisms. These findings indicated that the PD-1/PD-L1 axis might be a potential therapeutic target for patients with penile squamous cell carcinoma. PMID- 28344883 TI - Acquisition of tumor cell phenotypic diversity along the EMT spectrum under hypoxic pressure: Consequences on susceptibility to cell-mediated cytotoxicity. AB - Tumor escape to immunosurveillance and resistance to immune attacks present a major hurdle in cancer therapy, especially in the current era of new cancer immunotherapies. We report here that hypoxia, a hallmark of most solid tumors, orchestrates carcinoma cell heterogeneity through the induction of phenotypic diversity and the acquisition of distinct epithelial-mesenchymal transition (EMT) states. Using lung adenocarcinoma cells derived from a non-metastatic patient, we demonstrated that hypoxic stress induced phenotypic diversity along the EMT spectrum, with induction of EMT transcription factors (EMT-TFs) SNAI1, SNAI2, TWIST1, and ZEB2 in a hypoxia-inducible factor-1alpha (HIF1A)-dependent or independent manner. Analysis of hypoxia-exposed tumor subclones, with pronounced epithelial or mesenchymal phenotypes, revealed that mesenchymal subclones exhibited an increased propensity to resist cytotoxic T lymphocytes (CTL), and natural killer (NK) cell-mediated lysis by a mechanism involving defective immune synapse signaling. Additionally, targeting EMT-TFs, or inhibition of TGF-beta signaling, attenuated mesenchymal subclone susceptibility to immune attack. Together, these findings uncover hypoxia-induced EMT and heterogeneity as a novel driving escape mechanism to lymphocyte-mediated cytotoxicity, with the potential to provide new therapeutic opportunities for cancer patients. PMID- 28344884 TI - The differentiation and plasticity of Tc17 cells are regulated by CTLA-4-mediated effects on STATs. AB - As the blockade of inhibitory surface-molecules such as CTLA-4 on T cells has led to recent advances in antitumor immune therapy, there is great interest in identifying novel mechanisms of action of CD8+ T cells to evoke effective cytotoxic antitumor responses. Using in vitro and in vivo models, we investigated the molecular pathways underlying the CTLA-4-mediated differentiation of IL-17 producing CD8+ T cells (Tc17 cells) that strongly impairs cytotoxicity. Our studies demonstrate that Tc17 cells lacking CTLA-4 signaling have limited production of STAT3-target gene products such as IL-17, IL-21, IL-23R and RORgammat. Upon re-stimulation with IL-12, these cells display fast downregulation of Tc17 hallmarks and acquire Tc1 characteristics such as IFNgamma and TNF-alpha co-expression, which is known to correlate with tumor control. Indeed, upon adoptive transfer, these cells were highly efficient in the antigen specific rejection of established OVA-expressing B16 melanoma in vivo. Mechanistically, in primary and re-stimulated Tc17 cells, STAT3 binding to the IL 17 promoter was strongly augmented by CTLA-4, associated with less binding of STAT5 and reduced relative activation of STAT1 which is known to block STAT3 activity. Inhibiting CTLA-4-induced STAT3 activity reverses enhancement of signature Tc17 gene products, rendering Tc17 cells susceptible to conversion to Tc1-like cells with enhanced cytotoxic potential. Thus, CTLA-4 critically shapes the characteristics of Tc17 cells by regulating relative STAT3 activation, which provides new perspectives to enhance cytotoxicity of antitumor responses. PMID- 28344886 TI - CAR T-cell intrinsic PD-1 checkpoint blockade: A two-in-one approach for solid tumor immunotherapy. AB - PD-L1/2 expression in solid tumors inhibits chimeric antigen receptor (CAR) T cell efficacy. A PD-1 dominant negative receptor expressed in CAR T cells provides cell-intrinsic checkpoint blockade and augments antitumor efficacy. A combinatorial immunotherapeutic strategy of combining CAR T cells with checkpoint blockade is a promising treatment approach for solid tumors. PMID- 28344885 TI - Pappalysin-1 T cell receptor transgenic allo-restricted T cells kill Ewing sarcoma in vitro and in vivo. AB - Pregnancy-associated plasma protein-A (PAPPA), also known as pappalysin, is a member of the insulin-like growth factor (IGF) family. PAPPA acts as a protease, cleaving IGF inhibitors, i.e., IGF binding proteins (IGFBPs), thereby setting free IGFs. The insulin/IGF-axis is involved in cancer in general and in Ewing sarcoma (ES) in particular. ES is a highly malignant bone tumor characterized by early metastatic spread. PAPPA is associated with various cancers. It is overexpressed and required for proliferation in ES. PAPPA also stimulates normal bone growth. We isolated HLA-A*02:01+/peptide-restricted T cells from A*02:01- healthy donors directed against PAPPA, generated by priming with A*02:01+ PAPPA peptide loaded dendritic cells. After TCR identification, retrovirally TCR transduced CD8+ T cells were assessed for their in vitro specificity and in vivo efficacy in human ES bearing Rag2-/-gammac-/- mice. Engraftment in mice and tumor infiltration of TCR transgenic T cells in the mice was evaluated. The TCR transgenic T cell clone PAPPA-2G6 demonstrated specific reactivity toward HLA A*02:01+/PAPPA+ ES cell lines. We furthermore detected circulating TCR transgenic T cells in the blood in Rag2-/-gammac-/- mice and in vivo engraftment in bone marrow. Tumor growth in mice with xenografted ES was significantly reduced after treatment with PAPPA-2G6 TCR transgenic T cells in contrast to controls. Tumors of treated mice revealed tumor-infiltrating PAPPA-2G6 TCR transgenic T cells. In summary, we demonstrate that PAPPA is a first-rate target for TCR-based immunotherapy of ES. PMID- 28344887 TI - PD-L1, Galectin-9 and CD8+ tumor-infiltrating lymphocytes are associated with survival in hepatocellular carcinoma. AB - Novel systemic treatments for hepatocellular carcinoma (HCC) are strongly needed. Immunotherapy is a promising strategy that can induce specific antitumor immune responses. Understanding the mechanisms of immune resistance by HCC is crucial for development of suitable immunotherapeutics. We used immunohistochemistry on tissue-microarrays to examine the co-expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM and IDO, as well as tumor CD8+ lymphocyte infiltration in HCC, in two independent cohorts of patients. We found that at least some expression in tumor cells was seen in 97% of cases for HVEM, 83% for PD-L1, 79% for Gal-9 and 66% for IDO. In the discovery cohort (n = 94), we found that lack of, or low, tumor expression of PD-L1 (p < 0.001), Galectin-9 (p < 0.001) and HVEM (p < 0.001), and low CD8+TIL count (p = 0.016), were associated with poor HCC-specific survival. PD-L1, Galectin-9 and CD8+TIL count were predictive of HCC-specific survival independent of baseline clinicopathologic characteristics and the combination of these markers was a powerful predictor of HCC-specific survival (HR 0.29; p <0.001). These results were confirmed in the validation cohort (n = 60). We show that low expression levels of PD-L1 and Gal-9 in combination with low CD8+TIL count predict extremely poor HCC-specific survival and it requires a change in two of these parameters to significantly improve prognosis. In conclusion, intra-tumoral expression of these immune inhibiting molecules was observed in the majority of HCC patients. Low expression of PD-L1 and Galectin-9 and low CD8+TIL count are associated with poor HCC specific survival. Combining immune biomarkers leads to superior predictors of HCC mortality. PMID- 28344888 TI - Pre-emptive and therapeutic adoptive immunotherapy for nasopharyngeal carcinoma: Phenotype and effector function of T cells impact on clinical response. AB - Adoptive T cell therapy has emerged as a powerful strategy to treat human cancers especially haematological malignancies. Extension of these therapies to solid cancers remains a significant challenge especially in the context of defining immunological correlates of clinical responses. Here we describe results from a clinical study investigating autologous Epstein-Barr virus (EBV)-specific T cells generated using a novel AdE1-LMPpoly vector to treat patients with nasopharyngeal carcinoma (NPC) either pre-emptively in at-risk patients with no or minimal residual disease (N/MRD) or therapeutically in patients with active recurrent/metastatic disease (ARMD). Tolerability, safety and efficacy, including progression-free survival (PFS) and overall survival (OS), were evaluated following adoptive T-cell immunotherapy. Twenty-nine patients, including 20 with ARMD and nine with N/MRD, successfully completed T-cell therapy. After a median follow-up of 18.5 months, the median PFS was 5.5 months (95% CI 2.1 to 9.0 months) and the median OS was 38.1 months (95% CI 17.2 months to not reached). Post-immunotherapy analyses revealed that disease stabilization in ARMD patients was significantly associated with the functional and phenotypic composition of in vitro-expanded T cell immunotherapy. These included a higher proportion of effector CD8+ T-cells and an increased number of EBV-specific T-cells with broader antigen specificity. These observations indicate that adoptive immunotherapy with AdE1-LMPpoly-expanded T cells stabilizes relapsed, refractory NPC without significant toxicity. Promising clinical outcomes in N/MRD patients further suggest a potential role for this approach as a consolidation treatment following first-line chemotherapy. PMID- 28344889 TI - Loss of tapasin in human lung and colon cancer cells and escape from tumor associated antigen-specific CTL recognition. AB - Cytotoxic T-lymphocytes (CTLs) lyse target cells after recognizing the complexes of peptides and MHC class I molecules (pMHC I) on cell surfaces. Tapasin is an essential component of the peptide-loading complex (PLC) and its absence influences the surface repertoire of MHC class I peptides. In the present study, we assessed tapasin expression in 85 primary tumor lesions of non-small cell lung cancer (NSCLC) patients, demonstrating that tapasin expression positively correlated with patient survival. CD8+ T-cell infiltration of tumor lesions was synergistically observed with tapasin expression and correlated positively with survival. To establish a direct link between loss of tapasin and CTL recognition in human cancer models, we targeted the tapasin gene by CRISPR/Cas9 system and generated tapasin-deficient variants of human lung as well as colon cancer cells. We induced the CTLs recognizing endogenous tumor-associated antigens (TAA), survivin or cep55, and they responded to each tapasin-proficient wild type. In contrast, both CTL lines ignored the tapasin-deficient variants despite their antigen expression. Moreover, the adoptive transfer of the cep55-specific CTL line failed to prevent tumor growth in mice bearing the tapasin-deficient variant. Loss of tapasin most likely limited antigen processing of TAAs and led to escape from TAA-specific CTL recognition. Tapasin expression is thus a key for CTL surveillance against human cancers. PMID- 28344890 TI - Suppression of indoleamine-2,3-dioxygenase 1 expression by promoter hypermethylation in ER-positive breast cancer. AB - Kynurenine formation by tryptophan-catabolic indoleamine-2,3-dioxygenase 1 (IDO1) plays a key role in tumor immune evasion and inhibition of IDO1 is efficacious in preclinical models of breast cancer. As the response of breast cancer to immune checkpoint inhibitors may be limited, a better understanding of the expression of additional targetable immunomodulatory pathways is of importance. We therefore investigated the regulation of IDO1 expression in different breast cancer subtypes. We identified estrogen receptor alpha (ER) as a negative regulator of IDO1 expression. Serum kynurenine levels as well as tumoral IDO1 expression were lower in patients with ER-positive than ER-negative tumors and an inverse relationship between IDO1 and estrogen receptor mRNA was observed across 14 breast cancer data sets. Analysis of whole genome bisulfite sequencing, 450k, MassARRAY and pyrosequencing data revealed that the IDO1 promoter is hypermethylated in ER-positive compared with ER-negative breast cancer. Reduced induction of IDO1 was also observed in human ER-positive breast cancer cell lines. IDO1 induction was enhanced upon DNA demethylation in ER-positive but not in ER-negative cells and methylation of an IDO1 promoter construct reduced IDO1 expression, suggesting that enhanced methylation of the IDO1 promoter suppresses IDO1 in ER-positive breast cancer. The association of ER overexpression with epigenetic downregulation of IDO1 appears to be a particular feature of breast cancer as IDO1 was not suppressed by IDO1 promoter hypermethylation in the presence of high ER expression in cervical or endometrial cancer. PMID- 28344892 TI - Clear cell ovarian cancers with microsatellite instability: A unique subset of ovarian cancers with increased tumor-infiltrating lymphocytes and PD-1/PD-L1 expression. AB - Clear cell ovarian carcinoma (CCOC) represents a distinct histologic subtype of ovarian cancer associated with significantly worse prognosis across all stages and no effective therapeutic options. Here, we report a rare but clinically important cohort of CCOCs with microsatellite instability (MSI) (MSI-CCOCs), which are highly immunogenic and may thus be very responsive to immune checkpoint blockade. CCOCs with MSI exhibit a significantly higher number of CD8+ TILs, higher CD8+/CD4+ ratio, and higher PD-1+ TILs compared with microsatellite stable (MSS) CCOCs and compared with high grade serous ovarian cancers, which are the most common histologic subtype of ovarian cancer. Of note, PD-L1 expression in tumor cells or immune cells was noted in all cases of CCOCs with MSI. These observations open an alternative therapeutic avenue for a fraction of patients with CCOC and argue for the routine testing of CCOCs for MSI, a test that is not currently routinely performed. PMID- 28344891 TI - Tumor-infiltrating CD39+gammadeltaTregs are novel immunosuppressive T cells in human colorectal cancer. AB - Tumor microenvironment (TME) promotes immune suppression through recruiting and expanding suppressive immune cells such as regulatory T cells (Tregs) to facilitate cancer progression. In this study, we identify a novel CD39+ gammadeltaTreg in human colorectal cancer (CRC). CD39+ gammadeltaTregs are the predominant regulatory T cells and have more potent immunosuppressive activity than CD4+ or CD8+ Tregs via the adenosine-mediated pathway but independent of TGF beta or IL-10. They also secrete cytokines including IL-17A and GM-CSF, which may chemoattract myeloid-derived suppressive cells (MDSCs), thus establishing an immunosuppressive network. We further demonstrate that tumor-derived TGF-beta1 induces CD39+ gammadeltaT cells from paired normal colon tissues to produce more adenosine and become potent immunosuppressive T cells. Moreover, CD39+ gammadeltaTreg infiltration is positively correlated with TNM stage and other unfavorable clinicopathological features, implicating that CD39+ gammadeltaTregs are one of the key players in establishment of immunosuppressive TME in human CRC that may be critical for tumor immunotherapy. PMID- 28344893 TI - Integrated analysis of somatic mutations and immune microenvironment in malignant pleural mesothelioma. AB - To investigate the link between the genomic landscape of cancer cells and immune microenvironment in tumor tissues, we characterized somatic mutations and tumor infiltrating lymphocytes (TILs) in malignant pleural mesothelioma (MPM), including mutation/neoantigen load, spatial heterogeneity of somatic mutations of cancer cells and TILs (T-cell receptor beta (TCRbeta) repertoire), and expression profiles of immune-related genes using specimens of three different tumor sites (anterior, posterior, and diaphragm) obtained from six MPM patients. Integrated analysis identified the distinct patterns of somatic mutations and the immune microenvironment signatures both intratumorally and interindividually. MPM cases showed intratumoral heterogeneity in somatic mutations with unique TCRbeta clonotypes of TILs that were restricted to each tumor site, suggesting the presence of a neoantigen-related immune response. Correlation analyses showed that higher neoantigen load was significantly correlated with stronger clonal expansion of TILs (p = 0.048) and a higher expression level of an immune associated cytolytic factor (PRF1 (p = 0.0041) in tumor tissues), suggesting that high neoantigen loads in tumor cells might promote expansion of functional tumor specific T cells in the tumor bed. Our results collectively indicate that MPM tumors constitute a diverse heterogeneity in both the genomic landscape and immune microenvironment, and that mutation/neoantigen load may affect the immune microenvironment in MPM tissues. PMID- 28344894 TI - Postoperative Functional Outcomes in Older Adults. AB - As the world's aging population grows, the surgical population is increasingly made up of older adults. Due to changes in physiologic function and increasing comorbidity burden, older adults are at increased risk of morbidity, mortality, and functional decline after surgery. In addition, decision to undergo surgery for the older adult may be based on the postoperative functional outcome rather than survival. Although few studies have evaluated an older adult's function as a postoperative outcome, surgeons are becoming increasingly aware of the importance of maintaining or regaining function in an older patient. Interventions to improve postoperative functional outcomes are being developed and show promising results. This review discusses existing literature on postoperative functional outcomes in older adults and recently developed interventions. PMID- 28344895 TI - The relationship between mobile phone location sensor data and depressive symptom severity. AB - BACKGROUND: Smartphones offer the hope that depression can be detected using passively collected data from the phone sensors. The aim of this study was to replicate and extend previous work using geographic location (GPS) sensors to identify depressive symptom severity. METHODS: We used a dataset collected from 48 college students over a 10-week period, which included GPS phone sensor data and the Patient Health Questionnaire 9-item (PHQ-9) to evaluate depressive symptom severity at baseline and end-of-study. GPS features were calculated over the entire study, for weekdays and weekends, and in 2-week blocks. RESULTS: The results of this study replicated our previous findings that a number of GPS features, including location variance, entropy, and circadian movement, were significantly correlated with PHQ-9 scores (r's ranging from -0.43 to -0.46, p values < .05). We also found that these relationships were stronger when GPS features were calculated from weekend, compared to weekday, data. Although the correlation between baseline PHQ-9 scores with 2-week GPS features diminished as we moved further from baseline, correlations with the end-of-study scores remained significant regardless of the time point used to calculate the features. DISCUSSION: Our findings were consistent with past research demonstrating that GPS features may be an important and reliable predictor of depressive symptom severity. The varying strength of these relationships on weekends and weekdays suggests the role of weekend/weekday as a moderating variable. The finding that GPS features predict depressive symptom severity up to 10 weeks prior to assessment suggests that GPS features may have the potential as early warning signals of depression. PMID- 28344896 TI - Attenuation of antigen-specific T helper 1 immunity by Neolitsea hiiranensis and its derived terpenoids. AB - BACKGROUND: T cells play a pivotal role in the adaptive immunity that participates in a wide range of immune responses through a complicated cytokine network. Imbalance of T-cell responses is involved in several immune disorders. Neolitsea species, one of the biggest genera in the family Lauraceae, have been employed widely as folk medicines for a long time in Asia. Previous phytochemical investigations revealed the abundance of terpenes in the leaves of N. hiiranensis, an endemic Neolitsea in Taiwan, and demonstrated anti-inflammatory activities. However, the effect of N. hiiranensis on the functionality of immune cells, especially T cells, is still unclear. In this study, we utilize in vitro and in vivo approaches to characterize the effects of leaves of N. hiiranensis and its terpenoids on adaptive immune responses. METHODS: Dried leaves of N. hiiranensis were extracted three times with cold methanol to prepare crude extracts and to isolate its secondary metabolites. The ovalbumin (OVA)-sensitized BALB/c mice were administrated with N. hiiranensis extracts (5-20 mg/kg). The serum and splenocytes of treated mice were collected to evaluate the immunomodulatory effects of N. hiiranensis on the production of OVA-specific antibodies and cytokines. To further identify the N. hiiranensis-derived compounds with immunomodulatory potentials, OVA-primed splenocytes were treated with compounds isolated from N. hiiranensis by determining the cell viability, cytokine productions, and mRNA expression in the presence of OVA in vitro. RESULTS: Crude extracts of leaves of N. hiiranensis significantly inhibited IL 12, IFN-gamma, and IL-2 cytokine productions as well as the serum levels of antigen-specific IgM and IgG2ain vivo. Two of fourteen selected terpenoids and one diterpenoid derived from the leaves of N. hiiranensis suppressed IFN-gamma in vitro. In addition, beta-caryophyllene oxide attenuated the expression of IFN gamma, T-bet, and IL-12Rbeta2 in a dose-dependent manner. N. hiiranensis-derived beta-caryophyllene oxide inhibited several aspects of adaptive immune responses, including T-cell differentiation, IFN-gamma production, and Th1-assocaited genes. CONCLUSION: As IFN-gamma is the key cytokine secreted by T helper-1 cells and plays a pivotal role in Th1 immune responses, our results suggested that the N. hiiranensis and its terpenoids may possess potential therapeutic effects on Th1 mediated immune disorders. PMID- 28344897 TI - Testing of microsatellite multiplexes for individual identification of Cape Parrots (Poicephalus robustus): paternity testing and monitoring trade. AB - BACKGROUND: Illegal trade in rare wildlife species is a major threat to many parrot species around the world. Wildlife forensics plays an important role in the preservation of endangered or threatened wildlife species. Identification of illegally harvested or traded animals through DNA techniques is one of the many methods used during forensic investigations. Natural populations of the South African endemic Cape Parrot (Poicephalus robustus) are negatively affected by the removal of eggs and chicks for the pet trade. METHODS: In this study, 16 microsatellite markers specifically designed for the South African endemic Cape Parrot (P. robustus) are assessed for their utility in forensic casework. Using these 16 loci, the genetic diversity of a subset of the captive Cape Parrot population was also assessed and compared to three wild Cape Parrot populations. RESULTS: It was determined that the full 16 locus panel has sufficient discriminatory power to be used in parentage analyses and can be used to determine if a bird has been bred in captivity and so can be legally traded or if it has been illegally removed from the wild. In cases where birds have been removed from the wild, this study suggests that a reduced 12 locus microsatellite panel has sufficient power to assign confiscated birds to geographic population of origin. DISCUSSION: The level of genetic diversity observed within the captive Cape Parrot population was similar to that observed in the wild populations, which suggests that the captive population is not suffering from decreased levels of genetic diversity. The captive Cape Parrots did however have double the number of private alleles compared to that observed in the most genetically diverse wild population. This is probably due to the presence of rare alleles present in the founder population, which has not been lost due to genetic drift, as many of the individuals tested in this study are F1-F3 wild descendants. The results from this study provide a suit of markers that can be used to aid conservation and law enforcement authorities to better control legal and illegal trade of this South African endemic. PMID- 28344899 TI - A multidisciplinary approach to digital mapping of dinosaurian tracksites in the Lower Cretaceous (Valanginian-Barremian) Broome Sandstone of the Dampier Peninsula, Western Australia. AB - The abundant dinosaurian tracksites of the Lower Cretaceous (Valanginian Barremian) Broome Sandstone of the Dampier Peninsula, Western Australia, form an important part of the West Kimberley National Heritage Place. Previous attempts to document these tracksites using traditional mapping techniques (e.g., surface overlays, transects and gridlines combined with conventional photography) have been hindered by the non-trivial challenges associated with working in this area, including, but not limited to: (1) the remoteness of many of the tracksites; (2) the occurrence of the majority of the tracksites in the intertidal zone; (3) the size and complexity of many of the tracksites, with some extending over several square kilometres. Using the historically significant and well-known dinosaurian tracksites at Minyirr (Gantheaume Point), we show how these issues can be overcome through the use of an integrated array of remote sensing tools. A combination of high-resolution aerial photography with both manned and unmanned aircraft, airborne and handheld high-resolution lidar imaging and handheld photography enabled the collection of large amounts of digital data from which 3D models of the tracksites at varying resolutions were constructed. The acquired data encompasses a very broad scale, from the sub-millimetre level that details individual tracks, to the multiple-kilometre level, which encompasses discontinuous tracksite exposures and large swathes of coastline. The former are useful for detailed ichnological work, while the latter are being employed to better understand the stratigraphic and temporal relationship between tracksites in a broader geological and palaeoecological context. These approaches and the data they can generate now provide a means through which digital conservation and temporal monitoring of the Dampier Peninsula's dinosaurian tracksites can occur. As plans for the on-going management of the tracks in this area progress, analysis of the 3D data and 3D visualization will also likely provide an important means through which the broader public can experience these spectacular National Heritage listed landscapes. PMID- 28344898 TI - The Non-Recurrent Laryngeal Nerve: a meta-analysis and clinical considerations. AB - BACKGROUND: The Non-Recurrent Laryngeal Nerve (NRLN) is a rare embryologically derived variant of the Recurrent Laryngeal Nerve (RLN). The presence of an NRLN significantly increases the risk of iatrogenic injury and operative complications. Our aim was to provide a comprehensive meta-analysis of the overall prevalence of the NRLN, its origin, and its association with an aberrant subclavian artery. METHODS: Through March 2016, a database search was performed of PubMed, CNKI, ScienceDirect, EMBASE, BIOSIS, SciELO, and Web of Science. The references in the included articles were also extensively searched. At least two reviewers judged eligibility and assessed and extracted articles. MetaXL was used for analysis, with all pooled prevalence rates calculated using a random effects model. Heterogeneity among the included studies was assessed using the Chi2 test and the I2 statistic. RESULTS: Fifty-three studies (33,571 right RLNs) reported data on the prevalence of a right NRLN. The pooled prevalence estimate was 0.7% (95% CI [0.6-0.9]). The NRLN was found to originate from the vagus nerve at or above the laryngotracheal junction in 58.3% and below it in 41.7%. A right NRLN was associated with an aberrant subclavian artery in 86.7% of cases. CONCLUSION: The NRLN is a rare yet very clinically relevant structure for surgeons and is associated with increased risk of iatrogenic injury, most often leading to temporary or permanent vocal cord paralysis. A thorough understanding of the prevalence, origin, and associated pathologies is vital for preventing injuries and complications. PMID- 28344900 TI - Temporal patterns and geographic heterogeneity of Zika virus (ZIKV) outbreaks in French Polynesia and Central America. AB - BACKGROUND: Zika virus (ZIKV) transmission has been reported in 67 countries/territories in the Oceania region and the Americas since 2015, prompting the World Health Organization (WHO) to declare ZIKV as a Public Health Emergency of International Concern in February 2016, due to its strong association with medical complications such as microcephaly and Guillain-Barre Syndrome (GBS). However, a substantial gap in knowledge still exists regarding differing temporal pattern and potential of transmission of ZIKV in different regions of the world. METHODS: We use a phenomenological model to ascertain the temporal patterns and transmission potential of ZIKV in various countries/territories, by fitting the model to Zika case data from Yap Island and French Polynesia in the Oceania region and 11 countries/territories with confirmed case data, namely, Colombia, Ecuador, French Guiana, Guadeloupe, Guatemala, Mexico, Nicaragua, Panama, Puerto Rico, Saint Martin, and Suriname, to pinpoint the waves of infections in each country/territory and to estimate the respective basic reproduction number R0. RESULTS: Six of these time series datasets resulted in statistically significant model fit of at least one wave of reported cases, namely that of French Polynesia, Colombia, Puerto Rico, Guatemala, Suriname and Saint Martin. However, only Colombia and Guatemala exhibited two waves of cases while the others had only one wave. Temporal patterns of the second wave in Colombia and the single wave in Suriname are very similar, with the respective turning points separated by merely a week. Moreover, the mean estimates of R0 for Colombia, Guatemala and Suriname, all land-based populations, range between 1.05 and 1.75, while the corresponding mean estimates for R0 of island populations in French Polynesia, Puerto Rico and Saint Martin are significantly lower with a range of 5.70-6.89. We also fit the Richards model to Zika case data from six main archipelagos in French Polynesia, suggesting the outbreak in all six island populations occurred during the same time, albeit with different peak time, with mean R0 range of 3.09-5.05. DISCUSSION: Using the same modeling methodology, in this study we found a significant difference between transmissibility (as quantified by R0) in island populations as opposed to land based countries/territories, possibly suggesting an important role of geographic heterogeneity in the spread of vector-borne diseases and its future course, which requires further monitoring. Our result has potential implications for planning respective intervention and control policies targeted for island and land-based populations. PMID- 28344901 TI - Can video playback provide social information for foraging blue tits? AB - Video playback is becoming a common method for manipulating social stimuli in experiments. Parid tits are one of the most commonly studied groups of wild birds. However, it is not yet clear if tits respond to video playback or how their behavioural responses should be measured. Behaviours may also differ depending on what they observe demonstrators encountering. Here we present blue tits (Cyanistes caeruleus) videos of demonstrators discovering palatable or aversive prey (injected with bitter-tasting Bitrex) from coloured feeding cups. First we quantify variation in demonstrators' responses to the prey items: aversive prey provoked high rates of beak wiping and head shaking. We then show that focal blue tits respond differently to the presence of a demonstrator on a video screen, depending on whether demonstrators discover palatable or aversive prey. Focal birds faced the video screen more during aversive prey presentations, and made more head turns. Regardless of prey type, focal birds also hopped more frequently during the presence of a demonstrator (compared to a control video of a different coloured feeding cup in an empty cage). Finally, we tested if demonstrators' behaviour affected focal birds' food preferences by giving individuals a choice to forage from the same cup as a demonstrator, or from the cup in the control video. We found that only half of the individuals made their choice in accordance to social information in the videos, i.e., their foraging choices were not different from random. Individuals that chose in accordance with a demonstrator, however, made their choice faster than individuals that chose an alternative cup. Together, our results suggest that video playback can provide social cues to blue tits, but individuals vary greatly in how they use this information in their foraging decisions. PMID- 28344902 TI - Isolation and characterization of human articular chondrocytes from surgical waste after total knee arthroplasty (TKA). AB - BACKGROUND: Cartilage tissue engineering is a fast-evolving field of biomedical engineering, in which the chondrocytes represent the most commonly used cell type. Since research in tissue engineering always consumes a lot of cells, simple and cheap isolation methods could form a powerful basis to boost such studies and enable their faster progress to the clinics. Isolated chondrocytes can be used for autologous chondrocyte implantation in cartilage repair, and are the base for valuable models to investigate cartilage phenotype preservation, as well as enable studies of molecular features, nature and scales of cellular responses to alterations in the cartilage tissue. METHODS: Isolation and consequent cultivation of primary human adult articular chondrocytes from the surgical waste obtained during total knee arthroplasty (TKA) was performed. To evaluate the chondrogenic potential of the isolated cells, gene expression of collagen type 2 (COL2), collagen 1 (COL1) and aggrecan (ACAN) was evaluated. Immunocytochemical staining of all mentioned proteins was performed to evaluate chondrocyte specific production. RESULTS: Cartilage specific gene expression of COL2 and ACAN has been shown that the proposed protocol leads to isolation of cells with a high chondrogenic potential, possibly even specific phenotype preservation up to the second passage. COL1 expression has confirmed the tendency of the isolated cells dedifferentiation into a fibroblast-like phenotype already in the second passage, which confirms previous findings that higher passages should be used with care in cartilage tissue engineering. To evaluate the effectiveness of our approach, immunocytochemical staining of the evaluated chondrocyte specific products was performed as well. DISCUSSION: In this study, we developed a protocol for isolation and consequent cultivation of primary human adult articular chondrocytes with the desired phenotype from the surgical waste obtained during TKA. TKA is a common and very frequently performed orthopaedic surgery during which both femoral condyles are removed. The latter present the ideal source for a simple and relatively cheap isolation of chondrocytes as was confirmed in our study. PMID- 28344903 TI - Comparison of consumption behavior and appetite sensations among patients with type 2 diabetes mellitus after bariatric surgery. AB - BACKGROUND: The promising postsurgical weight loss and remission of type 2 diabetes (T2D) from bariatric surgery can be attributed to modified eating physiology after surgical procedures. We sought to investigate the changes in the parameters of consumption behaviors and appetite sensations induced by a mixed meal tolerance test, and to correlate these alterations with age, body mass index, C-peptide levels, and duration of T2D 1 year after bariatric surgery. METHODS: A total of 16 obese patients with T2D who underwent mini-gastric bypass (GB) and 16 patients who underwent sleeve gastrectomy (SG) were enrolled in this study and evaluated using a mixed meal tolerance test one year after surgery. A visual analogue scale was used for scoring appetite sensation at different time points. The area under the curve (AUC) and the incremental or decremental AUC (DeltaAUC) were compared between the two groups. RESULTS: One year after surgery, a decreasing trend in the consumption time was observed in the GB group compared to the SG group, while the duration of T2D before surgery was negatively correlated with the post-operative consumed time in those after GB. Patients who underwent GB had significantly higher fasting scores for fullness and desire to eat, higher AUC0'-180' of scores for desire to eat, as well as more effective post-meal suppression of hunger and desire to eat compared with those undergoing SG one year after surgery. Post-operative C-peptide levels were negatively correlated with DeltaAUC0'-180' for hunger and DeltaAUC0'-180' for desire to eat in the GB group, while negatively correlated with DeltaAUC0'-180' for fullness in the SG group. DISCUSSION: Patients with T2D after either GB or SG exhibit distinct nutrient-induced consumption behaviors and appetite sensations post operatively, which may account for the differential effects on weight loss and glycemic control after different surgery. PMID- 28344904 TI - Insect herbivores increase mortality and reduce tree seedling growth of some species in temperate forest canopy gaps. AB - Insect herbivores help maintain forest diversity through selective predation on seedlings of vulnerable tree species. Although the role of natural enemies has been well-studied in tropical systems, relatively few studies have experimentally manipulated insect abundance in temperate forests and tracked impacts over multiple years. We conducted a three-year experiment (2012-2014) deterring insect herbivores from seedlings in new treefall gaps in deciduous hardwood forests in Maryland. During this study, we tracked recruitment of all tree seedlings, as well as survivorship and growth of 889 individual seedlings from five tree species: Acer rubrum, Fagus grandifolia, Fraxinus spp., Liriodendron tulipifera, and Liquidambar styraciflua. Insect herbivores had little effect on recruitment of any tree species, although there was a weak indication that recruitment of A. rubrum was higher in the presence of herbivores. Insect herbivores reduced survivorship of L. tulipifera, but had no significant effects on A. rubrum, Fraxinus spp., F. grandifolia, or L. styraciflua. Additionally, insects reduced growth rates of early pioneer species A. rubrum, L. tulipifera, and L. styraciflua, but had little effect on more shade-tolerant species F. grandifolia and Fraxinus spp. Overall, by negatively impacting growth and survivorship of early pioneer species, forest insects may play an important but relatively cryptic role in forest gap dynamics, with potentially interesting impacts on the overall maintenance of diversity. PMID- 28344906 TI - Exploring differential health effects of work stress: a latent class cluster approach. AB - BACKGROUND: While evidence highlights the detrimental health consequences of adverse working conditions, effect sizes vary by the stressor examined. In this study, we aimed to explore the differential effects various constellations of job demands have on prevalent symptom clusters. METHODS: We analysed self-reported data from a nationwide Austrian survey (N = 16,466), based on a cross-sectional design. By means of latent class analysis, a set of items was used to assess the burden from several job demands as well as the frequency of occurrence of mental and physical symptoms in order to identify stress profiles and symptom clusters, respectively. RESULTS: Analysis revealed four subgroups that each demonstrated a typological response pattern regarding job demands and health symptoms, respectively. The revealed stress profiles were found to be strongly related to the symptom clusters, while the effects differed considerably depending on the types of demands experienced. CONCLUSION: The current study presents an alternative method of examining the stress-health link by using a combined person and variable-centred approach. The findings suggest a hierarchy in stress exposure with the most pronounced health consequences found for a synchronous burden from physical, psychosocial and organizational demands. PMID- 28344905 TI - Evolution of the patellar sesamoid bone in mammals. AB - The patella is a sesamoid bone located in the major extensor tendon of the knee joint, in the hindlimb of many tetrapods. Although numerous aspects of knee morphology are ancient and conserved among most tetrapods, the evolutionary occurrence of an ossified patella is highly variable. Among extant (crown clade) groups it is found in most birds, most lizards, the monotreme mammals and almost all placental mammals, but it is absent in most marsupial mammals as well as many reptiles. Here, we integrate data from the literature and first-hand studies of fossil and recent skeletal remains to reconstruct the evolution of the mammalian patella. We infer that bony patellae most likely evolved between four and six times in crown group Mammalia: in monotremes, in the extinct multituberculates, in one or more stem-mammal genera outside of therian or eutherian mammals and up to three times in therian mammals. Furthermore, an ossified patella was lost several times in mammals, not including those with absent hindlimbs: once or more in marsupials (with some re-acquisition) and at least once in bats. Our inferences about patellar evolution in mammals are reciprocally informed by the existence of several human genetic conditions in which the patella is either absent or severely reduced. Clearly, development of the patella is under close genomic control, although its responsiveness to its mechanical environment is also important (and perhaps variable among taxa). Where a bony patella is present it plays an important role in hindlimb function, especially in resisting gravity by providing an enhanced lever system for the knee joint. Yet the evolutionary origins, persistence and modifications of a patella in diverse groups with widely varying habits and habitats-from digging to running to aquatic, small or large body sizes, bipeds or quadrupeds-remain complex and perplexing, impeding a conclusive synthesis of form, function, development and genetics across mammalian evolution. This meta-analysis takes an initial step toward such a synthesis by collating available data and elucidating areas of promising future inquiry. PMID- 28344907 TI - Grape seed proanthocyanidin extract protects lymphocytes against histone-induced apoptosis. AB - Apoptosis of lymphocytes is associated with immunosuppression and poor prognosis in sepsis. Our previous report showed that histones, nuclear proteins released from damaged or dying cells in sepsis, can mediate lymphocyte apoptosis via mitochondria damage. Grape seed proanthocyanidin extract (GSPE), a natural substance with protective properties against oxidative stress, plays a vital role in cell and mitochondria protection. We thus hypothesized that GSPE may play a protective role in histone-induced lymphocyte apoptosis through its anti oxidative properties. In this study, we investigated the protective efficacy of GSPE on lymphocyte apoptosis induced by extracellular histones, a main contributor of death in sepsis. Human blood lymphocytes were treated with 50 MUg/ml histones, 2 MUg/ml GSPE, or a combination of both. A total of 100 MUM N acetylcysteine (NAC), a reactive oxygen species (ROS) inhibitor, was used as a positive control for GSPE. Apoptosis, intracellular ROS levels, mitochondrial membrane potential, Bcl-2 expression, and caspase-3 cleavage were measured. Our data clearly indicate that GSPE significantly inhibited lymphocyte apoptosis, generation of ROS, the loss of mitochondrial membrane potential, the decrease in Bcl-2 expression, and caspase-3 activation induced by extracellular histones. In conclusion, we show that GSPE has a protective effect on lymphocyte apoptosis induced by extracellular histones. This study suggests GSPE as a potential therapeutic agent that could help reduce lymphocyte apoptosis, and thus the state of immunosuppression was observed in septic patients. PMID- 28344908 TI - A cross sectional survey on health-related quality of life of elementary school students using the Korean version of the EQ-5D-Y. AB - BACKGROUND AND OBJECTIVE: The Korean version of the EQ-5D-Y was launched in 2015 by the EuroQol group. Currently, there is no HRQOL data obtained by using the EQ 5D-Y in Korea. This study aimed to measure health-related quality of life of Korean elementary school students using the EQ-5D-Y. METHODS: Elementary school students were recruited from 11 primary schools in Gyungbuk, South Korea. The EQ 5D-Y was self-administered in the sample population. Demographic characteristics were collected from the subjects' parents or guardians. The percentage of respondents reporting problems and VAS scores were calculated. Feasibility of the EQ-5D-Y was assessed by analysing the proportion of missing responses. The percentage of reported problems on the dimensions and VAS score between groups were compared by demographic factors. RESULTS: A total of 2,494 questionnaires were collected. There were 24 (0.96%) missing responses on the EQ-5D-Y and 187 (7.5%) missing VAS score responses. The proportion of reported problems ranged from 2.3% on the mobility dimension to 9.8% on the "having pain or discomfort" dimension. There was no significant difference in the proportion of problems by age group in male participants. However, in females, the older group reported significantly more problems on the "having pain or discomfort" and "feeling worried, sad, or unhappy" dimensions compared to the younger group. Students living with parents with the lowest educational level reported significantly more problems on the "looking after myself" and "doing usual activities" dimensions than did those living with parents with higher levels of education. DISCUSSION: This study showed the distribution of health-related quality of life and explored the feasibility of the EQ-5D-Y for measuring health-related quality of life in Korean elementary school students. Further studies are required to examine other psychometric properties of the Korean EQ-5D-Y. PMID- 28344909 TI - Understanding Participation in a Web-Based Measurement Burst Design: Response Metrics and Predictors of Participation. PMID- 28344910 TI - Gravity Stress Radiograph Revealing Instability at the First Metatarso-Cuneiform Joint in Lisfranc Injury. AB - Lisfranc injuries are commonly missed in the acute setting, largely due to subtle findings that often require weightbearing radiographs or more complex imaging for diagnosis. The long-term consequences of missed injuries are debilitating osteoarthritis of the midfoot, but this may be prevented with appropriate diagnosis and treatment. This case study presents a Lisfranc injury initially diagnosed by gravity stress radiograph. While used for other injuries, there is no literature on the use of gravity stress radiographs for diagnosis of Lisfranc injuries. The use of this simple technique to accurately diagnose Lisfranc injuries may improve detection and patient outcomes. PMID- 28344911 TI - Spontaneous Tumor Lysis Syndrome in Small Cell Lung Cancer. AB - Tumor lysis syndrome (TLS) is a life-threatening oncologic complication caused by the lysis of a vast number of malignant cells resulting in metabolic derangements and organ dysfunction. TLS can occur spontaneously before initiation of any therapies often referred to as spontaneous tumor lysis syndrome (STLS), or shortly after the induction of chemotherapy, radiotherapy, or cytolytic antibody therapy. TLS is vastly seen in patients with hematological malignancies with high rapid cell turnover rates such as Burkitt lymphoma, acute myelogenous leukemia, and acute lymphocytic leukemia, and is rarely observed in solid tumors. However, TLS can occur in solid tumors, and there are multiple reports in the literature on the occurrence of TLS in various solid tumors. In this article, we report a case of STLS in small cell lung cancer followed by a brief review of the occurrence of TLS and STLS in small cell lung cancer. PMID- 28344912 TI - The topography of a continental indenter: The interplay between crustal deformation, erosion, and base level changes in the eastern Southern Alps. AB - The topography of the eastern Southern Alps (ESA) reflects indenter tectonics causing crustal shortening, surface uplift, and erosional response. Fluvial drainages were perturbed by Pleistocene glaciations that locally excavated alpine valleys. The Late Miocene desiccation of the Mediterranean Sea and the uplift of the northern Molasse Basin led to significant base level changes in the far field of the ESA and the Eastern Alps (EA), respectively. Among this multitude of mechanisms, the processes that dominate the current topographic evolution of the ESA and the ESA-EA drainage divide have not been identified. We demonstrate the expected topographic effects of each mechanism in a one-dimensional model and compare them with observed channel metrics. We find that the normalized steepness index increases with uplift rate and declines from the indenter tip in the northwest to the foreland basin in the southeast. The number and amplitude of knickpoints and the distortion in longitudinal channel profiles similarly decrease toward the east. Changes in slope of chi-transformed channel profiles coincide spatially with the Valsugana-Fella fault linking crustal stacking and uplift induced by indenter tectonics with topographic evolution. Gradients in chi across the ESA-EA drainage divide imply an ongoing, north directed shift of the Danube-ESA watershed that is most likely driven by a base level rise in the northern Molasse basin. We conclude that the regional uplift pattern controls the geometry of ESA-EA channels, while base level changes in the far field control the overall architecture of the orogen by drainage divide migration. PMID- 28344914 TI - Automatic classification of histopathological diagnoses for building a large scale tissue catalogue. AB - In this paper an automatic classification system for pathological findings is presented. The starting point in our undertaking was a pathologic tissue collection with about 1.4 million tissue samples described by free text records over 23 years. Exploring knowledge out of this "big data" pool is a challenging task, especially when dealing with unstructured data spanning over many years. The classification is based on an ontology-based term extraction and decision tree build with a manually curated classification system. The information extracting system is based on regular expressions and a text substitution system. We describe the generation of the decision trees by medical experts using a visual editor. Also the evaluation of the classification process with a reference data set is described. We achieved an F-Score of 89,7% for ICD-10 and an F-Score of 94,7% for ICD-O classification. For the information extraction of the tumor staging and receptors we achieved am F-Score ranging from 81,8 to 96,8%. PMID- 28344913 TI - Indoor localisation through object detection within multiple environments utilising a single wearable camera. AB - The recent growth in the wearable sensor market has stimulated new opportunities within the domain of Ambient Assisted Living, providing unique methods of collecting occupant information. This approach leverages contemporary wearable technology, Google Glass, to facilitate a unique first-person view of the occupants immediate environment. Machine vision techniques are employed to determine an occupant's location via environmental object detection. This method provides additional secondary benefits such as first person tracking within the environment and lack of required sensor interaction to determine occupant location. Object recognition is performed using the Oriented Features from Accelerated Segment Test and Rotated Binary Robust Independent Elementary Features algorithm with a K-Nearest Neighbour matcher to match the saved key points of the objects to the scene. To validate the approach, an experimental set up consisting of three ADL routines, each containing at least ten activities, ranging from drinking water to making a meal were considered. Ground truth was obtained from manually annotated video data and the approach was previously benchmarked against a common method of indoor localisation that employs dense sensor placement in order to validate the approach resulting in a recall, precision, and F-measure of 0.82, 0.96, and 0.88 respectively. This paper will go on to assess to the viability of applying the solution to differing environments, both in terms of performance and along with a qualitative analysis on the practical aspects of installing such a system within differing environments. PMID- 28344915 TI - From the evaluation of existing solutions to an all-inclusive package for biobanks. AB - The domain of biobanking has gone through many stages and as a result there are a wide range of commercial and open source software solutions available. The utilization of these software tools requires different levels of domain and technical skills for installation, configuration and ultimate us of these biobank software tools. To compound this complexity the biobanking community are required to work together in order to share knowledge and jointly build solutions to underpin the research infrastructure. We have evaluated the available tools, described them in a catalogue (BiobankApps) and made a selection of tools available to biobanks in a reference toolbox (BIBBOX) that are use-case driven. In the BiobankApps tool catalogue, both commercial and open source software solutions related to the biobanking domain are included, classified and evaluated. The evaluation covers: 1) "user review" by an authenticated user 2) domain expert: quick analysis by BBMRI members and 3) domain expert: detailed analysis and test installation with real world data. The evaluation is paired with a survey across the more "advanced" (from a technology perspective) biobanks to investigate what tools are currently used and summarises known benefits/drawbacks of the respective packages. In the second step we recommend tools for specific use cases, and install, configure and connect these in the BIBBOX framework. This service also builds on the existing work in the United Kingdom in seeking to establish the motivations for different stakeholders to become involved and therefore assisting in prioritising the use-cases based on the level of need and support within the research community. All tools associated to a use-case are available as BIBBOX applications (technically this is achieved by docker containers), which are integrated in the BIBBOX framework with central identification and user management. In future work we plan to share the acquired knowledge with other networks, develop an Application Programmable Interface (API) for the exchange of metadata with other tool catalogues and work on an ontology for the evaluation of biobank software. PMID- 28344916 TI - Pentalogy of Cantrell: Is Echocardiography Sufficient in the Neonatal Period? AB - Pentalogy of Cantrell is a rare syndrome that is characterized by varying degrees of midline wall defects and congenital cardiac anomalies. A left ventricular diverticulum (LVD) is defined as partial ectopia cordis, can be part of the pentalogy of Cantrell, and can put the patient at risk of severe complications. Early diagnosis and ligation/resection of the LVD is important to prevent complications. We report on a case of pentalogy of Cantrell, in which a LVD was diagnosed only at 2 months of age despite preceding pre- and postnatal echocardiography. We conclude that in the suspicion of pentalogy of Cantrell, either complete or incomplete, cardiac magnetic resonance imaging should be performed, when possible, to avoid the potential complication of a herniating ventricular diverticulum. PMID- 28344917 TI - Fatal Complications after Pediatric Surgical Interventions: Lessons Learned. AB - Placement of catheters, drains, shunts, and tubes in children can lead to serious or even fatal complications at the moment of placement, such as hemorrhage at insertion, or in the longterm, such as infections and migration into adjacent organs. The clinician should always be aware of these potential complications, especially if the child is unwell. For postmortem diagnostic evaluation, either with a computed tomography scan or an invasive autopsy, all tubes, drains, shunts, and/or catheters should be left in situ. We present three cases with fatal complications after the placement of a chest drain, ventriculoperitoneal shunt, and gastrostomy tube. PMID- 28344918 TI - Missed diagnosis of stroke in the emergency department: a cross-sectional analysis of a large population-based sample. AB - BACKGROUND: Some cerebrovascular events are not diagnosed promptly, potentially resulting in death or disability from missed treatments. We sought to estimate the frequency of missed stroke and examine associations with patient, emergency department (ED), and hospital characteristics. METHODS: Cross-sectional analysis using linked inpatient discharge and ED visit records from the 2009 Healthcare Cost and Utilization Project State Inpatient Databases and 2008-2009 State ED Databases across nine US states. We identified adult patients admitted for stroke with a treat-and-release ED visit in the prior 30 days, considering those given a non-cerebrovascular diagnosis as probable (benign headache or dizziness diagnosis) or potential (any other diagnosis) missed strokes. RESULTS: There were 23,809 potential and 2243 probable missed strokes representing 12.7% and 1.2% of stroke admissions, respectively. Missed hemorrhages (n = 406) were linked to headache while missed ischemic strokes (n = 1435) and transient ischemic attacks (n = 402) were linked to headache or dizziness. Odds of a probable misdiagnosis were lower among men (OR 0.75), older individuals (18-44 years [base]; 45-64:OR 0.43; 65-74:OR 0.28; >= 75:OR 0.19), and Medicare (OR 0.66) or Medicaid (OR 0.70) recipients compared to privately insured patients. Odds were higher among Blacks (OR 1.18), Asian/Pacific Islanders (OR 1.29), and Hispanics (OR 1.30). Odds were higher in non-teaching hospitals (OR 1.45) and low-volume hospitals (OR 1.57). CONCLUSIONS: We estimate 15,000-165,000 misdiagnosed cerebrovascular events annually in US EDs, disproportionately presenting with headache or dizziness. Physicians evaluating these symptoms should be particularly attuned to the possibility of stroke in younger, female, and non-White patients. PMID- 28344920 TI - Six years of INSTAND e. V. sIgE proficiency testing: An evaluation of in vitro allergy diagnostics. AB - BACKGROUND: Even though allergies are an important health issue, wide manufacturer-dependent differences in the detected amounts of allergen-specific IgE (sIgE) have repeatedly been found. These discrepancies hinder diagnostics and research into clinically significant cutoff points for life-threatening symptoms. METHODS: To evaluate whether the reported differences have led to changes in diagnostic testing, we analyzed data from six years of round robin testing (RRT, also known as proficiency testing) at the Gesellschaft zur Forderung der Qualitatssicherung in medizinischen Laboratorien e.V. (Society for Promoting Quality Assurance in medical Laboratories) for the important allergen sources bee venom, wasp venom, and birch pollen. The results of the four main suppliers of in vitro diagnostic sIgE testing were compared in a pseudo-anonymized form using overlay images of box plot graphs for the semiquantitative data and allergen class results. Coefficients of variation (CV) were obtained to study the development of interlaboratory comparability. RESULTS: We found that the large differences between the manufacturer collectives remained constant between January 2010 and April 2015 without any real improvement. The CVs were good for two of the four analyzed suppliers, one was marginal and one above the quality level of 20%. CONCLUSION: The numerous publications that have found discrepancies in the sIgE results of the different suppliers did not change the status quo within the last six years. Unfortunately, this is unlikely to change until there is a characterized standard material with known values of sIgE. PMID- 28344919 TI - Antibodies to HLA Molecules Mimic Agonistic Stimulation to Trigger Vascular Cell Changes and Induce Allograft Injury. AB - Human leukocyte antigen (HLA)-induced signaling in endothelial and smooth muscle cells causes dramatic cytoskeletal rearrangement, increased survival, motility, proliferation, adhesion molecule and chemokine expression, and adhesion of leukocytes. These mechanisms are directly related to endothelial activation, neointimal proliferation, and intragraft accumulation of leukocytes during antibody-mediated rejection (AMR) and chronic rejection. Clustering of HLA by ligands in trans, such as in antigen-presenting cells at the immune synapse, triggers physiological functions analogous to HLA antibody-induced signaling in vascular cells. Emerging evidence has revealed previously unknown functions for HLA beyond antigen presentation, including association with coreceptors in cis to permit signal transduction, and modulation of intracellular signaling downstream of other receptors that may be relevant to HLA signaling in the graft vasculature. We discuss the literature regarding HLA-induced signaling in vascular endothelial and smooth muscle cells, as well as under endogenous biological conditions, and how such signaling relates to functional changes and pathological mechanisms during graft injury. PMID- 28344922 TI - Mobile Devices and Insomnia: Understanding Risks and Benefits. AB - Mobile devices (smartphones and tablet computers) have become widely prevalent due to rapid improvements in function and decreasing costs. As of 2014, 90 % of US adults have a mobile phone, with 58 % having a smartphone, 32 % owning some type of e-reader, and 42 % of US adults owning a tablet computer. Mobile devices are particularly well-suited for the study of common conditions such as sleep difficulties because of their ubiquity. Around 35 to 49 % of the US adult population have problems falling asleep or have daytime sleepiness. These sleep disorders are often under-recognized because of patient-physician communication difficulties, low rates of medical awareness resulting in underreporting of insomnia symptoms, and limited primary care physician (PCP) training in insomnia recognition. Mobile devices have the potential to bridge some of these gaps, but they can also lead to sleep difficulties when used inappropriately. PMID- 28344921 TI - German guideline for the management of adverse reactions to ingested histamine: Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the German Society for Pediatric Allergology and Environmental Medicine (GPA), the German Association of Allergologists (AeDA), and the Swiss Society for Allergology and Immunology (SGAI). AB - Adverse food reactions are far more often perceived than objectively verified. In our scientific knowledge on non-allergic adverse reactions including the so called histamine intolerance, there are large deficits. Due to the fact that this disorder is increasingly discussed in the media and the internet, more and more people suspect it to be the trigger of their symptoms. The scientific evidence to support the postulated link between ingestion of histamine and adverse reactions is limited, and a reliable laboratory test for objective diagnosis is lacking. This position paper by the "Food Allergy" Working Group of the German Society for Allergology and Clinical Immunology (DGAKI) in collaboration with the German Association of Allergologists (AeDA), the Society for Pediatric Allergology and Environmental Medicine (GPA), and the Swiss Society for Allergology and Immunology (SGAI) reviews the data on the clinical picture of adverse reactions to ingested histamine, summarizes important aspects and their consequences, and proposes a practical diagnostic and therapeutic approach. PMID- 28344924 TI - Idiopathic Pleuroparenchymal Fibroelastosis. AB - PURPOSE OF THE REVIEW: Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a rare fibrosing lung disease, affecting the visceral pleura and the subpleural parenchyma with an upper lobe predilection, included as a distinct clinicopathologic entity in the latest international multidisciplinary classification of the idiopathic interstitial pneumonias (IIP). We aim to summarize the current evidence on IPPFE, in terms of clinical features and potential treatments. RECENT FINDINGS: Overall, there is increasing awareness of PPFE in association with a separate ILD pattern. Although an agreed consensus on diagnosis has yet to be defined, a list of radiological and histopathological criteria has been proposed. Due to the unfavorable risk-benefit profile of surgical lung biopsy in a significant proportion of patients, a potential role for transbronchial lung cryobiopsy has been suggested. At present, lung transplantation remains the only curative option. SUMMARY: The increasing awareness of this condition among specialists has led to more frequent identification of IPPFE. Large international studies are needed to better characterize pathogenesis and pheno/endotypes of disease, a key step towards the development of effective treatments. PMID- 28344923 TI - Impact of Drug Treatment at Neonatal Ages on Variability of Drug Metabolism and Drug-drug Interactions in Adult Life. AB - PURPOSE OF REVIEW: As the number of patients taking more than one medication concurrently continues to increase, predicting and preventing drug-drug interactions (DDIs) is now more important than ever. Administration of one drug can cause changes in the expression and activity of drug metabolizing enzymes (DMEs) and alter the efficacy or toxicity of other medications that are substrates for these enzymes, resulting in a DDI. In today's medical practice, potential DDIs are evaluated based on the current medications a patient is taking with little regard to drugs the patient has been exposed to in the past. The purpose of this review is to discuss potential impacts of drug treatment at neonatal ages on the variability of drug metabolism and DDIs in adult life. RECENT FINDINGS: Existing evidence from the last thirty years has shown that exposure to certain xenobiotics during neonatal life has the potential to persistently alter DME expression through adult life. With recent advancements in the understanding of epigenetic regulation on gene expression, this phenomenon is resurfacing in the scientific community in hopes of defining possible mechanisms. Exposure to compounds that have the ability to bind nuclear receptors and trigger epigenetic modifications at neonatal and pediatric ages may have long-term, if not permanent, consequences on gene expression and DME activity. SUMMARY: The information summarized in this review should challenge the way current healthcare providers assess DDI potential and may offer an explanation to the significant interindividual variability in drug metabolism that is observed among patients. PMID- 28344925 TI - Chest Drain Size: the Debate Continues. AB - PURPOSE OF REVIEW: Small-bore chest tubes are widely used in the management of common pleural disease. Guidelines suggest that patients with malignant pleural effusions, pneumothorax and pleural infection may be successfully managed with small-bore drains. However, good quality data is often lacking. This article reviews the evidence for the treatment efficacy and potential adverse effects of different chest tube sizes. RECENT FINDINGS: In a large randomised study, the small difference in pain scores between large and small drains was not clinically significant. However, small-bore chest tubes commonly suffer from blockage or inadvertent removal, and may not be as effective in providing successful pleurodesis for malignant pleural effusions. SUMMARY: Although they may be effective in managing pleural infection, and less painful than large drains, small bore drains may be less effective for pleurodesis. PMID- 28344928 TI - Physical and monetary ecosystem service accounts for Europe: A case study for in stream nitrogen retention. AB - In this paper we present a case study of integrated ecosystem and economic accounting based on the System of Environmental Economic Accounting - Experimental Ecosystem Accounts (SEEA-EEA). We develop accounts, in physical and monetary terms, for the water purification ecosystem service in Europe over a 20 year time period (1985-2005). The estimation of nitrogen retention is based on the GREEN biophysical model, within which we impose a sustainability threshold to obtain the physical indicators of capacity - the ability of an ecosystem to sustainably supply ecosystem services. Key messages of our paper pertain the notion of capacity, operationalized in accounting terms with reference to individual ecosystem services rather than to the ecosystem as a whole, and intended as the stock that provides the sustainable flow of the service. The study clarifies the difference between sustainable flow and actual flow of the service, which should be calculated jointly so as to enable an assessment of the sustainability of current use of ecosystem services. Finally, by distinguishing the notion of 'process' (referred to the ecosystem) from that of 'capacity' (pertaining specific services) and proposing a methodology to calculate capacity and flow, we suggest an implementable way to operationalize the SEEA-EEA accounts. PMID- 28344927 TI - The implementation of the South African Triage Score (SATS) in an urban teaching hospital, Ghana. AB - INTRODUCTION: Triage is the process of sorting patients based on the level of acuity to ensure the most severely injured and ill patients receive timely care before their condition worsens. The South African Triage Scale (SATS) was developed out of a need for an accurate and objective measure of urgency based on physiological parameters and clinical discriminators that is easily implemented in low resource settings. SATS was introduced in the emergency center (EC) of Komfo Anokye Teaching Hospital (KATH) in January 2010. This study seeks to evaluate the accurate use of the SATS by nurses at KATH. METHODS: This cross sectional study was conducted in the EC at KATH in Kumasi, Ghana. Patients 12 years and over with complete triage information were included in this study. Each component of SATS was calculated (i.e. for heart rate of 41-50, a score of 1 was given) and summed. This score was compared to the original triage score. When scores did not equate, the entire triage record was reviewed by an emergency physician and an advanced practice emergency nurse separately to determine if the triage was appropriate. These reviews were compared and consensus reached. RESULTS: 52 of 903 adult patients (5.8%) were judged to have been mis-triaged by expert review; 49 under-triaged (sent to a zone that corresponded to a lower acuity level than they should have been, based on their vital signs) and 3 over triaged. Of the 49 patients who were under-triaged, 34 were under-triaged by one category and 7 by two categories. CONCLUSION: Under-triage is a concern to patient care and safety, and while the under-triage rate of 5.7% in this sample falls within the 5-10% range considered unavoidable by the American College of Surgeons Committee on Trauma, concentrated efforts to regularly train triage nurses to ensure no patients are under-triaged have been undertaken. Overall though, SATS has been implemented successfully in the EC at KATH by triage nurses. PMID- 28344929 TI - Comparing regional precipitation and temperature extremes in climate model and reanalysis products. AB - A growing field of research aims to characterise the contribution of anthropogenic emissions to the likelihood of extreme weather and climate events. These analyses can be sensitive to the shapes of the tails of simulated distributions. If tails are found to be unrealistically short or long, the anthropogenic signal emerges more or less clearly, respectively, from the noise of possible weather. Here we compare the chance of daily land-surface precipitation and near-surface temperature extremes generated by three Atmospheric Global Climate Models typically used for event attribution, with distributions from six reanalysis products. The likelihoods of extremes are compared for area-averages over grid cell and regional sized spatial domains. Results suggest a bias favouring overly strong attribution estimates for hot and cold events over many regions of Africa and Australia, and a bias favouring overly weak attribution estimates over regions of North America and Asia. For rainfall, results are more sensitive to geographic location. Although the three models show similar results over many regions, they do disagree over others. Equally, results highlight the discrepancy amongst reanalyses products. This emphasises the importance of using multiple reanalysis and/or observation products, as well as multiple models in event attribution studies. PMID- 28344926 TI - Mechanotransduction in cancer. AB - Tissue stiffness is tightly controlled under normal conditions, but changes with disease. In cancer, tumors often tend to be stiffer than the surrounding uninvolved tissue, yet the cells themselves soften. Within the past decade, and particularly in the last few years, there is increasing evidence that the stiffness of the extracellular matrix modulates cancer and stromal cell mechanics and function, influencing such disease hallmarks as angiogenesis, migration, and metastasis. This review briefly summarizes recent studies that investigate how cancer cells and fibrosis-relevant stromal cells respond to ECM stiffness, the possible sensing appendages and signaling mechanisms involved, and the emergence of novel substrates - including substrates with scar-like fractal heterogeneity - that mimic the in vivo mechanical environment of the cancer cell. PMID- 28344930 TI - Revisiting the 'disaster and development' debate - Toward a broader understanding of macroeconomic risk and resilience. AB - Debate regarding the relationship between socioeconomic development and natural disasters remains at the fore of global discussions, as the potential risk from climate extremes and uncertainty pose an increasing threat to developmental prospects. This study reviews statistical investigations of disaster and development linkages, across topics of macroeconomic growth, public governance and others to identify key challenges to the current approach to macro-level statistical investigation. Both theoretically and qualitatively, disaster is known to affect development through a number of channels: haphazard development, weak institutions, lack of social safety nets and short-termism of our decision making practices are some of the factors that drive natural disaster risk. Developmental potentials, including the prospects for sustainable and equitable growth, are in turn threatened by such accumulation of disaster risks. However, quantitative evidence regarding these complex causality chains remains contested due to several reasons. A number of theoretical and methodological limitations have been identified, including the use of GDP as a proxy measurement of welfare, issues with natural disaster damage reporting and the adoption of ad hoc model specifications and variables, which render interpretation and cross-comparison of statistical analysis difficult. Additionally, while greater attention is paid to economic and institutional parameters such as GDP, remittance, corruption and public expenditure as opposed to hard-to-quantify yet critical factors such as environmental conditions and social vulnerabilities. These are gaps in our approach that hamper our comprehensive understanding of the disaster-development nexus. Important areas for further research are identified, including recognizing and addressing the data constraints, incorporating sustainability and equity concerns through alternatives to GDP, and finding novel approaches to examining the complex and dynamic relationships between risk, vulnerability, resilience, adaptive capacity and development. PMID- 28344931 TI - Proarrhythmogenic effects of lamotrigine during ajmaline testing for Brugada syndrome. PMID- 28344932 TI - Mutation in TNXB gene causes moderate to severe Ehlers-Danlos syndrome. AB - We report a 28-year-old female who presented with severe joint pain, chronic muscle weakness, Raynaud's phenomenon, and hypermobility. She was found to have a 6074A > T nucleotide transition in the TNXB gene causing an amino acid protein change at Asp2025Val classified as likely pathogenic. We add this clinical report to the literature and classical human disease gene catalogs to identify this specific mutation as disease-causing. This gene variant was reported previously in a different 36-year-old patient who shared our patient's symptoms of joint hypermobility, skeletal and joint pain, skin elasticity and musculoskeletal problems, thereby causing a more severe presentation than seen in the hypermobility type of Ehlers-Danlos syndrome (EDS). At the time of writing, a few mutations in the TNXB gene have been recognized as pathogenic causing EDS due to tenascin-X deficiency, but the variant identified in our patient has not been recognized as pathogenic in online genetic databases. Our case study in combination with peer-reviewed literature suggests that the 6074A > T nucleotide transition in the TNXB gene may be classified as disease-causing for EDS due to tenascin-X deficiency. PMID- 28344935 TI - OUTCOMES OF POSTERIOR SAGITTAL ANORECTOPLASTY FOR HIGH ANORECTAL MALFORMATION IN BENIN CITY, NIGERIA. AB - BACKGROUND: Surgical treatment for high anorectal malformations has evolved over the years with introduction of posterior sagittal anorectoplasty in the early 80s. Posterior sagittal anorectoplasty is being perfomed in many centres which necessitates a review of its outcomes in Benin City, Nigeria. AIM: To report a 10 year outcome and experience gained with posterior saggital anorectoplasty for children diagnosed with high anorectal malformation. METHODS: A retrospective analyses of the records of all children with high anorectal malformation and managed with posterior sagittal anorectoplasty between April 2006 and March 2016 at the University of Benin Teaching Hospital. RESULTS: A total of 96 children were managed for anorectal malformation during the period. High anorectal malformation accounted for 33 (34.4%) cases, the intermediate 15 (15.6%) and the low types were 48 (50%). The 33 radiologically confirmed high type were19 males and 14 females with a male/female ratio of 1.3: 1. They were aged between 2 days and 4 years with a mean of 6.8 +/- 3 months. A child each had additional prune belly syndrome, multiple limbs anomalies and unilateral undescended testis. Recto bladder neck/recto-prostatic and recto-vaginal fistulae were recorded in 31 (94%) children. Five (15%) clinically stable neonates had primary posterior sagittal anorectoplasty without colostomy which was well tolerated. The majority, 28 (85%), had conventional posterior sagittal anorectoplasty that involves initial colostomy. Minor postoperative morbidities recorded in 10 (30.3%) children included superficial wound infection in 3 (9%), anal stenosis in 3 (9%) and fecal incontinence in 2 (6%) children which resolved on conservative treatment while 2 (6%) with rectal mucosal prolapse required refashioning. The functional clinical anal outcomes of posterior sagittal anorectoplasty recorded showed that the majority 18 (54.5%) of children were continent while 4 (12.1%) had voluntary bowel controls corresponding with their ages. Anal stenosis in the 3 and incontinence in the 2 children were the common anal dysfunctions recorded. The child with prune belly syndrome had breakdown of colostomy closure which resulted in the one (3%) death recorded. CONCLUSION: Anorectal malformation was common in this setting during this study with a large proportion of the children diagnosed with the high type and were managed with good outcome using posterior sagittal anorectoplasty. PMID- 28344934 TI - EFFICACY AND SAFETY OF ORAL KETAMINE PREMEDICATION IN CHILDREN UNDERGOING DAY CASE SURGERY. AB - BACKGROUND: Oral premedication for paediatric age group is an uncommon practice amongst anaesthetists in Nigeria. Both parents and the child suffer some form of emotional or psychological distress. AIM: To determine the efficacy and safety of oral formulated ketamine for premedication in children scheduled for ambulatory surgeries. METHODS: Seventy three children aged 1 - 6 years with American Society of Anesthesiologists (ASA) physical status I-II were prospectively studied. They were assigned randomly to receive either 5 mg/kg (Group A), 10 mg/kg (Group B), or no ketamine (Group C).The children were observed for acceptance of premedication, sedation and anxiolysis at 10, 20 and 30 minutes after drug administration. Behavior/response of each child at the time of separation from parents, intravenous access, and acceptance of facemask for induction, postanaesthetic arousal state and complications were also recorded. RESULTS: There were 73 children in this study with a mean age of 37.4+/-18.0 months. The groups were comparable in age. The studied agent was tolerated by both groups that received premedication with no significant difference (P 0.73). Adequate sedation and anxiolysis were observed in groups A and B, (52%, 84%) and (68%, 88%) respectively. However, more children in group B (82.6%) had satisfactory behaviour at separation from parents and a better acceptance of anaesthetic face mask (64%) at induction than those in groups A and C (33.3%, 21.7%, respectively). No side effect was recorded in either of the premedication groups or the control group. CONCLUSION: Oral ketamine is acceptable and safe premedication for children. It provided good sedation, relieved anxiety and had no side effect in the children at the studied doses. PMID- 28344936 TI - EXPERIENCE WITH MANAGING RETROSTERNAL GOITRES IN IBADAN, NIGERIA. AB - BACKGROUND: There is no general consensus on the definition of retrosternal goitre (RSG) however thyroidectomy remains the gold standard of treatment with or without a sternotomy. AIM: To review the outcome of surgical management of retrosternal goitres. METHODOLOGY: Retrospective review of records of patients who had thyroidectomy for RSG over a 15-year period. RESULTS: Out of a total of 45 patients, 34(76%) were females and 11(24%) were males with a male/female ratio of 3:1; while their age ranged between 28 and 72years with a mean of 57+15SD. All the patients were euthyroid and a quarter did not have symptoms apart from a neck mass. In all, 15% of the patients had recurrent goitre. CT scan of neck and chest was done in 31 (72%) patients; while 44 (98%) patients had cervical retrosternal goitres, 1(2%) patient had ectopic retrosternal goitre. A cervical incision was sufficient in 28 (62%) patients while 17 (38%) patients required additional sternotomy. Total thyroidectomy was done in all the patients. There were post operative complications in 19 (42%) patients. Histopathology showed that 3(6.6%) patients had papillary thyroid carcinoma while 42(93.4%) had benign pathology findings. CONCLUSION: Surgical removal is the treatment of choice. Most retrosternal goitres can be resected through a collar stud incision; however the possibility of a need for a sternotomy should always be planned. The simultaneous occurrence of cervical and ectopic retrosternal goitre should always be ruled out with a CT scan. PMID- 28344933 TI - PRECISION MEDICINE - The Golden Gate for Detection, Treatment and Prevention of Alzheimer's Disease. AB - During this decade, breakthrough conceptual shifts have commenced to emerge in the field of Alzheimer's disease (AD) recognizing risk factors and the non-linear dynamic continuum of complex pathophysiologies amongst a wide dimensional spectrum of multi-factorial brain proteinopathies/neurodegenerative diseases. As is the case in most fields of medicine, substantial advancements in detecting, treating and preventing AD will likely evolve from the generation and implementation of a systematic precision medicine strategy. This approach will likely be based on the success found from more advanced research fields, such as oncology. Precision medicine will require integration and transfertilization across fragmented specialities of medicine and direct reintegration of Neuroscience, Neurology and Psychiatry into a continuum of medical sciences away from the silo approach. Precision medicine is biomarker-guided medicine on systems-levels that takes into account methodological advancements and discoveries of the comprehensive pathophysiological profiles of complex multi factorial neurodegenerative diseases, such as late-onset sporadic AD. This will allow identifying and characterizing the disease processes at the asymptomatic preclinical stage, where pathophysiological and topographical abnormalities precede overt clinical symptoms by many years to decades. In this respect, the uncharted territory of the AD preclinical stage has become a major research challenge as the field postulates that early biomarker guided customized interventions may offer the best chance of therapeutic success. Clarification and practical operationalization is needed for comprehensive dissection and classification of interacting and converging disease mechanisms, description of genomic and epigenetic drivers, natural history trajectories through space and time, surrogate biomarkers and indicators of risk and progression, as well as considerations about the regulatory, ethical, political and societal consequences of early detection at asymptomatic stages. In this scenario, the integrated roles of genome sequencing, investigations of comprehensive fluid-based biomarkers and multimodal neuroimaging will be of key importance for the identification of distinct molecular mechanisms and signaling pathways in subsets of asymptomatic people at greatest risk for progression to clinical milestones due to those specific pathways. The precision medicine strategy facilitates a paradigm shift in Neuroscience and AD research and development away from the classical "one-size fits-all" approach in drug discovery towards biomarker guided "molecularly" tailored therapy for truly effective treatment and prevention options. After the long and winding decade of failed therapy trials progress towards the holistic systems-based strategy of precision medicine may finally turn into the new age of scientific and medical success curbing the global AD epidemic. PMID- 28344937 TI - EFFICACY OF INTRAVENOUS ESMOLOL VERSUS LIDOCAINE FOR ATTENUATION OF THE PRESSOR RESPONSE IN NIGERIANS. AB - BACKGROUND: Laryngoscopy and tracheal intubation are an integral component of airway management and general anaesthesia. Direct stimulation of the pharynx and larynx by the laryngoscope blade and the insertion of an endotracheal tube elicit a sympathetic nervous system response with a reflex consisting of a transient increase in blood pressure, heart rate, and the occurrence of cardiac dysrhythmias referred to as the 'pressor' response. This may be of major clinical significance in patients with pre-existing systemic hypertension, hypertensive heart disease, coronary artery disease, eclampsia, aneurysmal vascular disease and head injury in whom such a change may culminate in perioperative myocardial ischaemia or infarction, cardiac failure, dysrhythmias, cerebrovascular accidents or secondary brain injury. AIM: To evaluate and compare the effects of intravenous lidocaine and esmolol on the pressor response as well as determine the occurrence of complications with the use of either agent in a Nigerian population. METHODOLOGY: Ninety adult ASA I and II patients undergoing elective non-cardiac surgery under general anaesthesia were randomly allocated to one of 3 groups; group E: 2mg.kg -1 esmolol, group L: 1.5mg.kg -1 lidocaine and group C: 20mls normal saline 3 minutes before laryngoscopy. Induction of anaesthesia was standardized for all patients. Heart Rate, Systolic Blood Pressure, Diastolic Blood Pressure, Mean Arterial Pressure and Rate Pressure Product were recorded at baseline, immediate post, 1, 3, 5 and 10 minutes after intubation. RESULTS: Mean heart rate increased by 19.1%, 25.7%, and 41.4%, SBP increased 13.3%, 21.6% and 26.9%, MAP by 12.2%, 19.1% and 30.2%, RPP by 28.1%, 45.8% and 78.7% in groups E, L and C respectively post intubation. There were no complications attributable to the use of either agent. CONCLUSION: Intravenous esmolol 2mg.kg-1 given prior to laryngoscopy is more effective than intravenous lidocaine 1.5mg.kg-1 in significantly attenuating the haemodynamic changes associated with pressure response to laryngoscopy and endotracheal intubation in normotensive patients from a Nigerian population. PMID- 28344938 TI - TEMPOROMANDIBULAR PAIN DYSFUNCTION SYNDROME IN PATIENTS ATTENDING LAGOS UNIVERSITY TEACHING HOSPITAL, LAGOS, NIGERIA. AB - BACKGROUND: Temporomandibular joint pain dysfunction syndrome (TMJPDS) is the most common temporomandibular disorder. This condition presents with symptoms of pain, restricted jaw movement and joint noise. Other symptoms include otalgia, headache, neck pain and trismus. AIM: To determine the pattern of Temporomandibular joint pain dysfunction syndrome patients managed at the Lagos University Teaching Hospital, Lagos, Nigeria. METHODOLOGY: A descriptive study of patients with signs and symptoms of Temporomandibular joint pain dysfunction syndrome attending the Oral Medicine Clinic of Lagos University Teaching Hospital. RESULTS: Twenty-one patients with Temporomandibular joint pain dysfunction syndrome were enrolled into the study, out of which 10(48%) were females and 11(52%) were males. The age range was 23-81years with a mean of 45.2 +/- 18.9 years. Majority of the patients 20(95.2%) complained of pain around the joint, in the pre-auricular region, in the muscles of mastication and the ear. While 7(35%) complained of clicking sounds, 10(47.6%) complained of pain on mouth opening and during mastication only. In all 5(23.8%) had impaired movement of the jaws, mouth opening was normal in 18(85.7%) but reduced in 3(14.3%) patients. Over half of patients 12(57%) experienced clicking sounds, there was tenderness around the temporomandibular joint in 16(76.2%) cases, pain in the ear of 7(33.3%) patients and 13(61.9%) people presented with tenderness of the muscles of mastication. Conservative management of all the cases resulted in resolution of the symptoms. CONCLUSION: Temporomandibular joint pain dysfunction syndrome has diverse clinical presentation and though distressing, it responds to prompt and effective conservative management. PMID- 28344939 TI - HEPATITIS B VACCINATION STATUS AND NEEDLE STICK INJURY EXPOSURE AMONG OPERATING ROOM STAFF IN LAGOS, NIGERIA. AB - BACKGROUND: Hepatitis B virus (HBV) is an infective blood-borne pathogen that is a constant threat to operating room staff. The prevalence of Hepatitis B has been reported to range from 4.3% - 68% in Nigeria. The inadequate funding of health care in low income countries impacts negatively on the implementation of effective vaccination programs to protect health care workers including surgical theatre personnel. AIM: To determine the Hepatitis B vaccination status and the needle stick injury exposure among operating room staff in Lagos, Nigeria. METHODOLOGY: The multicentre prospective survey was conducted in three public tertiary hospitals and two private hospitals in Lagos utilising a self administered structured questionnaire that was distributed to operating room staff. RESULTS: We found that 96.7% (265) of respondents agreed that their job had exposed them to the risk of HBV infection. Over half (55.8%) correctly identified three doses of HBV as adequate to confer immunity against infection. It was observed that 58% (159) of the respondents were fully vaccinated, most of whom were doctors (69.8%, p=0.001) while a total of 173 (63.1%) reported exposure to needle-stick injury with blood in the preceding year. CONCLUSION: The operating room personnel were knowledgeable about the risk of HBV as an occupational hazard but a large number were not fully vaccinated against HBV infection. There was therefore the need to improve the vaccination coverage and educate identified high-risk operating room staff on appropriate post exposure prophylaxis practices. PMID- 28344940 TI - VISUAL OUTCOME WITH A MULTIMODALITY APPROACH IN A CASE OF RHINOORBITO- CEREBRAL MUCORMYCOSIS. AB - BACKGROUND: Rhinoorbito-cerebral mucormycosis is an uncommon and acute fungal infection which runs a fulminant course. Uncontrolled diabetes mellitus is the most common predisposing factor. AIM: To assess the outcome of a poorly controlled diabetic with Rhinoorbito-cerebral mucormycosis using a multi-modality management. METHODOLOGY: We report a case of a 57-year old male who presented to us with proptosis and total external ophthalmoplegia diagnosed with rhino-orbito cerebral mucormycosis. Patient was started on conventional intravenous amphotericin B to which he developed systemic toxicity. As an alternative, a combination therapy of oral posacanazole along with peribulbar amphotericin B injections for a more localised effect was initiated. RESULTS: He had a favourable outcome with dramatic improvement in vision and marginal recovery of extra ocular movements within 20 days of initiation of combination therapy. CONCLUSION: Rhinoorbito-cerebral mucormycosis is a major diagnostic dilemma with quick progression and a high mortality. Prompt medical management with a multi modality approach can save the patient from orbital exenteration. PMID- 28344942 TI - Peer-Reviewed Abstracts of Scientific Paper Presentation at The 56th Annual Conference of The West African College of Surgeons at Yaounde, Cameroun 15th - 19th February 2016. PMID- 28344941 TI - Accidental Decannulation OF TRACHEOSTOMY TUBES - Case Series. AB - : Tracheostomy tube (TT) is usually removed in a planned manner once the patient ceases to have the condition that necessitated the procedure. Accidental decannulation or extubation refers to inadvertent removal of tracheostomy tube out of the stoma. It could prove fatal in an otherwise stable patient. We review a variety of unexpected and often-overlooked causes of accidental decannulation with suggestions on preventive measures. We therefore present three cases of accidental decannulation of tracheostomy tubes in order to report our experiences in the management of the condition. CONCLUSION: Accidental decannulation occurs both in hospitalized and patient on home care of their tracheostomy tubes. Reduction in neck circumference due to weight loss predisposes to accidental decannulation, which could be prevented by suturing the flange to the skin. PMID- 28344943 TI - ORAL KETAMINE PREMEDICATION IN CHILDREN. PMID- 28344944 TI - HUMAN BITE INJURIES ON THE JOS PLATEAU. AB - BACKGROUND: Human bite injuries with the associated morbidity are not uncommon in this environment. OBJECTIVE: To determine the pattern, management modalities and treatment outcome of human bites in Jos, Plateau State, Nigeria. DESIGN: A prospective study of all human bite injuries managed at the Jos University Teaching Hospital, Jos, Nigeria between January 2012 and December 2014. SETTING: Jos University Teaching Hospital, Jos, Nigeria. MAIN OUTCOME MEASURES: The pattern and management outcome. RESULTS: A total of 63 patients with human bite injuries were studied during the three-year period. There were 43 males and 20 females with a male:female ratio of 2:1. The age ranged from 8 - 65 years with a mean age of 30.2+/-17 years; in all about 75% of the patients fell into the 20 - 40 years bracket. Though all the social strata were affected, the bites were more common (50%) among the lower social classes and 70% of the patients presented late after 24 hours of sustaining bite injuries. Pain, bleeding, infected wounds, bite and scratch marks were the main presenting features. About 70% of the patients sustained major bites involving the underlying muscles and deeper structures while 89% of the patients sustained their bites during a fight, 8% while raping their victims, and in 3% of patients as they were being mugged. The bites were between spouses in 39% of cases, and between women in polygamous settings in 16%. The sites commonly affected were the upper limbs in 46%, chest in 21%, ears in 13%, abdomen in 10% and the penis in 6%. The associated injuries were scratch marks in 89%, blunt abdominal injuries in 29%, skin lacerations in 16% and urinary bladder/urethral injuries in 3%. There was no mortality but morbidity was 57% which included infections in 29%, disfigurement in 29%, penile injuries in 6% and minor urethral injuries in 3% of cases. CONCLUSION: Human bite injuries in this tropical environment commonly affected the young male, the lower social class and the upper limbs; they were commonly sustained in assaults and domestic conflicts. PMID- 28344945 TI - an evaluation of the possible relationship between chronic periodontitis and hypertension. AB - BACKGROUND: Periodontal diseases have been reported to have a form of reciprocal relationship with the general systemic health, in which case those with some systemic diseases such as hypertension have poorer periodontal health and vice versa. The issue of causal or casual relationship is however yet to be finally resolved. AIM: The aim of this study was to determine any possible relationship between chronic periodontitis and cardiovascular risk factors. METHODOLOGY: A cross-sectional assessment of cardiovascular risk factors such as blood pressure, body mass index, waist circumference and the carotid artery intima media thickness (CIMT) was done among 100 consecutive subjects in the echocardiogram unit of the University College Hospital, Ibadan, Nigeria over a period of six months. These cardiovascular risk factors were compared with periodontal parameters such as Simplified Oral Hygiene index (OHI-S), Gingival index (GI) and Community Periodontal Index (CPI). RESULTS: The systolic blood pressure (SBP) of the respondents ranged from 98 - 210 mm Hg with a mean of 133.1 +/- 15 mm Hg, diastolic blood pressure (DBP) 60 - 136 mm Hg with a mean of 84.6 +/- 6.4 mm Hg. There was a statistically significant relationship between the systolic blood pressure and oral hygiene index (P< 0.000), diastolic blood pressure and oral hygiene index (P < 0.010) and mean carotid artery intima media thickness and oral hygiene index (P< 0.012) among the respondents. CONCLUSION: In view of the significant relationship between the blood pressure and the mean carotid artery intima media thickness, when compared with the oral hygiene status of respondents in this study, more emphasis should be laid on regular preventive dental visit as a way of decreasing cardiovascular health risk. PMID- 28344946 TI - Incidental maxillary sinus findings on cranial computerized tomographic scan in a tropical setting. AB - BACKGROUND: Abnormalities in the maxillary sinuses are occasional findings on routine CT scans of the head. AIM: To study the incidental findings in the CT scans of the maxillary sinuses in patients with indications other than sinuses related diseases. SETTING: Jos University Teaching Hospital, Jos, Nigeria. MATERIALS AND METHODS: Images of patients who underwent CT scan of the head over a 5-month period (January 2015- May 2015) were retrospectively reviewed with the exclusion of those whose indication for the scan was trauma or sinus related disease. RESULTS: A total of 121 CT scan images were reviewed comprising 72 males and 49 females with a male to female ratio of 1.5 to 1.0. Their age range was between 5 and 90 years with a mean of 47.5 +/- 20.4 years. The mean age of males was 48.7+/- 21.2 years while that of females is 45.7+/- 19.1years. The weight of the patients ranged between 12kg and 109kg with a mean weight of 64.7 +/- 16.6kg. The most frequent indications for cranial CT scan were cerebrovascular accident (57; 47.1%), suspected space occupying lesion (23; 19.0%) and persistent headache (5; 4.1%). In all, 93(76.8%) patients had normal scan while 28 (23.2%) patients were observed with sinus pathology. Maxillary mucosal thickening with associated fluid level constituted 11 (9.1%) of the pathologic findings, and this was found bilaterally in 4(3.3%) patients. Seven (5.8%) patients had maxillary mucosal thickening only, with this occurring bilaterally in 4(3.3%) patients and 10 (8.3%) patients had polypoid masses, with bilateral polyps in 1(1.2%) individual. There was no statistical significance with the patient's weight in relation to the sinus findings. CONCLUSION: Incidental maxillary sinus pathologies on cranial CT scan are not infrequent. Vigilance is necessary during routine review and reporting of CT scans of the head for appropriate inclusion and interpretation of these findings towards optimal patient's care. PMID- 28344947 TI - FACTORS ASSOCIATED WITH ODONTOGENIC BACTERAEMIA IN ORTHODONTIC PATIENTS. AB - BACKGROUND: Various researches have investigated factors associated with the prevalence and intensity of bacteraemia following oral procedures including orthodontic procedures. AIM: The aim of this study was to determine the effect of age, gender, plaque and gingival indices on the occurrence of odontogenic bacteraemia following orthodontic treatment procedures. SETTING: Orthodontic Clinic, Lagos University Teaching Hospital (LUTH), Lagos, Nigeria. METHODOLOGY: Using the consecutive, convenience sampling method, a total of 100 subjects who met the inclusion criteria were recruited for the study and peripheral blood was collected before and again within 2 minutes of completion of orthodontic procedures for microbiologic analysis using the BACTEC automated blood culture system and the lysis filtration methods of blood culturing. The subjects were randomly placed in one of four orthodontic procedures investigated: alginate impression making (Group I), separator placement (Group II), band cementation (Group III) and arch wire change (Group IV). Plaque and gingival indices were assessed using the plaque component of the Simplified Oral Hygiene Index (OHI-S) (Greene & Vermillion) and Modified gingival index (Lobene) respectively before blood collection. Spearman Point bi-serial correlations and logistic regression statistics were used for statistical evaluations at p < 0.05 level. RESULTS: An overall baseline prevalence of bacteraemia of 3% and 17% were observed using the BACCTEC and lysis filtration methods respectively. Similarly, overall prevalence of bacteraemia following orthodontic treatment procedures of 16% and 28% were observed respectively using the BACTEC and lysis filtration methods. A statistically significant increase in the prevalence of bateraemia was observed following separator placement (p=0.016). An increase in age, plaque index scores and modified gingival index scores of the subjects were found to be associated with an increase in the prevalence of bacteraemia following orthodontic treatment procedures, with plaque index score showing the strongest correlation. CONCLUSION: Separator placement was found to induce significantly highest level of bacteraemia. Meticulous oral hygiene practice and the use of 0.2% chlorhexidine mouth rinse prior to separator placement may be considered an effective measure in reducing oral bacteria load and consequent reduction of the occurrence of bacteraemia following orthodontic treatment procedures. PMID- 28344948 TI - THE EFFECT OF COMBINING AXILLARY BRACHIAL PLEXUS BLOCK WITH INTERSCALENE OR SUPRACLAVICULAR BLOCK FOR UPPER LIMB SURGERIES USING NEUROSTIMULATION TECHNIQUE. AB - BACKGROUND: The different approaches to the brachial plexus have clinical implications and all these approaches have clinical limitations. Combining different approaches helps to reduce these limitations. Can a combination of two different methods of brachial plexus block give a better anaesthetic outcome? AIM: To compare the effect of combining axillary plexus block with interscalene as opposed to axillary plexus block with supraclavicular blocks. DESIGN OF STUDY: Prospective observational study. SETTING: University of Benin Teaching Hospital, Benin city. Edo state. Nigeria. MATERIALS AND METHODS: A total of 182 patients who met the inclusion criteria were observed and were divided into 5 groups. Group I (interscalene) n=33, Group S (supraclavicular) n=39, Group A (axillary) n=35. Group IA (interscalene and axillary) n=34, Group SA (supraclavicular and axillary) n=41. The brachial plexus was identified using a nerve stimulator and 40ml of 2% lidocaine with 1:200,000 adrenaline and 0.5% bupivacaine, were deposited in each single approach or divided into two equal portions in the combined approach .The time of onset, duration of analgesia, level of satisfaction and complications were compared. RESULTS: There were no differences with regard to the time of onset (p= 0.74), duration of analgesia (p= 0.82), patients' satisfaction between the groups. Horner's syndrome was a commonest complication in the interscalene group consisting (15.15%) cases. CONCLUSION: There was no difference in terms of time of onset, duration of sensory block and level of patients' satisfaction between the combined brachial plexus approaches and single approach. PMID- 28344949 TI - The effect of anesthesia on the ventilatory functions of patients with Maxillo mandibular fixation. AB - BACKGROUND: Maxillo-mandibular fixation (MMF) is a procedure still routinely practiced in developing countries. AIM: To determine the variations in pulmonary functions readings between cases treated under general anesthesia (GA) and those treated under local anesthesia (LA). METHODOLOGY: A descriptive hospital-based study of 106 patients was carried out from January 2011- December 2012. Information was obtained using a questionnaire and all study subjects had their baseline lung functions and their post-operative daily lung function parameters measured for the first week and then weekly for the next five weeks. The data obtained were analyzed using SPSS version 16 and a P-value of <=0.05 was considered significant. RESULTS: A total of 85 males and 21 females participated in the study. The means for age was 30.62+/-8.06, weight 63.92+/- 9.96 and BMI 23.21+/- 3.14 while the means for the pre-operative FVC, FEV1, and PEFR were 3.71 +/- 0.70, 3.14+/- 0.51 and 8.18+/- 1.61 respectively. There was a statistically significant drop (p< 0.05) in the FVC, FEV1 and PEFR in the first post operative week. The drop in the lung function parameters were similar between the GA group and the LA group. CONCLUSION: Maxillo-mandibular fixation causes a significant fall in pulmonary function parameters especially in the first 48 hours post operatively irrespective of whether general or local anaesthesia was used at surgery. The pulmonary functions should be further monitored for more than 48 hours after surgery. PMID- 28344950 TI - IMPALEMENT HEAD INJURY WITH A SPEAR. AB - Impalement injuries to the craniofacial region are uncommon due to the fact that the face is a smaller target in relation to the rest of the body. We report a case of a 26-year old man who was attacked on the face with a spear. He was promptly evaluated and resuscitated; the blade of the spear was successfully extracted under general anaesthesia. He was discharged home after 2 weeks hospitalization; he has been followed up for three months with good outcome. PMID- 28344951 TI - A CASE OF LITTRE'S HERNIA AT ZINDER NATIONAL HOSPITAL, ZINDER, NIGER. AB - : The presence of a Meckel's diverticulum in a hernia sac is known as Littre's hernia. We report a case of Littre's hernia in an 18-year old young man because of the uncommon condition. An 18-year old young patient was admitted to the Emergency Surgical Department of Zinder National Hospital, Zinder, Niger with a painful inguinoscrotal swelling of three days duration. The diagnosis of strangulated right inguinoscrotal hernia was made. At surgery, a Meckel's diverticulum was found at the antimesenteric border of the ileum in the hernia sac, the bowel loop was not viable. Resection of the non-viable ileal loop with the Meckel's diverticulum attached to it was performed with an end-to-end ileal anastomosis. The hernia defect in the groin was repaired according to Bassini procedure. The postoperative recovery was uneventful and the patient was followed up for 5 months without symptoms. CONCLUSION: Littre hernia is uncommon and difficult to diagnose; it is often an incidental finding at surgery which should ensure complete resection of the Meckel's diverticulum in order to prevent future complications. PMID- 28344952 TI - Peer-Reviewed Abstracts of Scientific Paper Presentation at The 56th Annual Conference of The West African College of the Surgeons at Yaounde, Cameroun 15th 19th February 2016 Contd. PMID- 28344953 TI - Editorial HUMAN BITE INJURIES. PMID- 28344954 TI - No fault compensation in perinatal medicine in Japan-from results for 8 years. AB - No fault compensation in perinatal medicine has been established to provide aid to patients in the event of disability due to a medical accident during delivery and to strive to resolve disputes quickly that contributes to reduce medical malpractice suit in the field of perinatal medicine. Furthermore, this system is aimed to establish a mechanism that achieves higher quality of obstetric care by analyzing the causes of accidents. This system is operated by Japan Council for Quality Health Care and 99.9% of childbirth facilities in Japan registered with this compensation system. Compensation system has two major functions including compensation and cause analysis and recurrence prevention based on cases. Compensation eligibility is reviewed in the Review Committee at the organization in Japan Council for Quality Health Care and currently 1,717 cases are judged as eligible cases out of 2,250 since 2009. The cause of each eligible case is analyzed in the Cause Analysis Committee one by one. The Cause Analysis Committee has 7 independent subcommittee and each subcommittee members are consistent of obstetricians, neonatologists, pediatricians, midwives and lawyers. Original cause analysis report is sent to childbirth facility and patient's family. Questionnaire survey demonstrated that 73% of childbirth facilities and 65% of patient family were satisfied with the cause analysis report. The number of medical lawsuit in obstetrics and gynecology is significantly decreased compared to those in all medical departments since the compensation system was introduced suggesting that these cause analysis reports may contribute the decrease in medical lawsuits. The major purpose of the Recurrence Prevention Committee is striving to prevent future cases of cerebral palsy and to improve the quality of obstetric care. To accomplish the purpose, the committee routinely collect information from individual cases and analyze quantitatively and epidemiologically. Furthermore the committee choose subject from cases to discuss for future prevention and provide wide public disclosure of the information with recommendation. The committee issued 6 reports until now and these reports have been distributed to childbirth facilities, perinatal medicine-related scientific society and administrative agencies. PMID- 28344955 TI - Association of citalopram with congenital anomalies: A meta-analysis. AB - OBJECTIVE: The antenatal use of citalopram, a widely prescribed selective serotonin reuptake inhibitor, has been suspected to be associated with congenital, particularly cardiac, anomalies. This study aimed to prove the association between citalopram use and congenital anomalies. METHODS: We searched the English literature from July 1998 to July 2015, by using the search terms ' citalopram', ' pregnancy', ' birth defects', ' congenital anomalies', and ' malformations' in PubMed, Embase, Web of Science, and the Cochrane Library. RESULTS: Eight eligible articles were analyzed including a total of 1,507,896 participants. The odds ratio (OR) of major malformations associated with citalopram use during pregnancy was 1.07 (95% confidence interval [CI], 0.98 to 1.17). Concerning cardiac malformations, the OR for all included studies was 1.31 (95% CI, 0.88 to 1.93). The analysis of cardiac malformations was repeated to reduce heterogeneity after excluding one outlier study (OR, 1.03; 95% CI, 0.84 to 1.26). CONCLUSION: From our data, it can be concluded that citalopram use is not associated with major birth defects. However, physicians should carefully weigh the benefits against the potential risks of citalopram use, and counsel patients accordingly. PMID- 28344956 TI - Maternal serum placental growth factor and pregnancy-associated plasma protein A measured in the first trimester as parameters of subsequent pre-eclampsia and small-for-gestational-age infants: A prospective observational study. AB - OBJECTIVE: To examine the first-trimester maternal serum placental growth factor (PlGF) and pregnancy-associated plasma protein A (PAPP-A) levels in pregnancies associated with pre-eclampsia (PE) or small-for-gestational-age (SGA) infants, and determine the predictive accuracy of PlGF and of PAPP-A for either PE or SGA infants. METHODS: This prospective, observational study included 175 pregnant women, and of these women, due to participant withdrawal or loss to follow-up, delivery data were collected from the medical records of 155 women, including 4 who had twin pregnancies. The women's maternal history was recorded, and the PlGF and PAPP-A levels at 11 to 13 gestational weeks were measured. During the second trimester, the maternal uterine artery's systolic/diastolic ratio was measured. Multiples of the median (MoM) of PlGF and PAPP-A were determined, and the associations of these values with the risk factors of SGA and PE were evaluated. Logistic regression analysis was used to determine whether PlGF and PAPP-A are useful markers for predicting SGA infants. RESULTS: The PAPP-A MoM level was significantly lower in women with advanced maternal age, multipara women, and women with gestational diabetes than in their counterparts. The PlGF and PAPP-A MoM levels were higher in women with a twin pregnancy than in those with a singleton pregnancy. There was a significant relationship between the maternal serum PAPP-A MoM level in the first trimester and the uterine artery systolic/diastolic ratio in the second trimester. Results of logistic regression analysis showed that low PlGF and PAPP-A MoM levels were predictors of SGA infants (odds ratio, 0.143; 95% confidence interval, 0.025 to 0.806; odds ratio, 0.191; 95% confidence interval, 0.051 to 0.718, respectively). CONCLUSION: PlGF and PAPP-A are potentially useful as first-trimester markers for SGA infants and some hypertensive disorders of pregnancy. PMID- 28344957 TI - Predicting factors for success of vaginal delivery in preterm induction with prostaglandin E2. AB - OBJECTIVE: To evaluate the efficacy and safety of prostaglandin (PG) E2 for preterm labor induction and to investigate the predictive factors for the success of vaginal delivery. METHODS: A retrospective cohort study was performed in women (n=155) at 24+0 to 36+6 weeks of gestation who underwent induction of labor using a PGE2 vaginal pessary (10 mg, Propess) from January 2009 to December 2015. Success rates of vaginal delivery according to gestational age at induction and incidence of intrapartum complications such as tachysystole and nonreassuring fetal heart rate were investigated. Multivariable logistic regression analysis was performed to evaluate the predictive factors for success of labor induction. RESULTS: The vaginal delivery rate was 57% (n=89) and the rate of cesarean delivery after induction was 43% (n=66). According to gestational age, labor induction was successful in 16.7%, 50.0%, and 62.8% of patients at 24 to 31, 32 to 33, and 34 to 36 weeks, showing a stepwise increase (P=0.006). There were 18 cases (11%) of fetal distress, 9 cases (5.8%) of tachysystole, and 6 cases (3.8%) of massive postpartum bleeding (>1,000 mL). After adjusting for confounding factors, multiparity (odds ratio [OR], 8.47; 95% confidence interval [CI], 3.10 to 23.14), younger maternal age (OR, 0.84; 95% CI, 0.75 to 0.94), advanced gestational age at induction (OR, 1.06; 95% CI, 1.02 to 1.09), rupture of membranes (OR, 11.83; 95% CI, 3.55 to 39.40), and the Bishop score change after removal of PGE2 (OR, 2.19; 95% CI, 1.0 to 4.8) were significant predictors of successful preterm vaginal delivery. CONCLUSION: An understanding of the principal predictive factors of successful preterm labor induction, as well as the safety of PGE2, will provide useful information when clinicians consult with preterm pregnant women requiring premature delivery. PMID- 28344958 TI - Perioperative administration of propranolol to women undergoing ovarian cancer surgery: A pilot study. AB - OBJECTIVE: This study was done to evaluate whether perioperative propranolol (beta-blocker) in ovarian cancer patients undergoing debulking surgery reduced perioperative tumor growth induced by surgical stress. METHODS: This was a prospective randomized single institution analysis. The primary objective was to compare the changes in CA 125 level (changes between preoperation day 2 and postoperative day 7). As a study arm, patients received a low dose of propranolol 40 mg/day (4*10 mg) starting two days before surgery and 40 mg twice daily for three days following surgery. RESULTS: Twenty-two patients were enrolled and 16 were evaluable for efficacy. The drug was well tolerated. The mean decrease of CA 125 during the seven perioperative days was 83.1+/-8.9% in the propranolol group and 72.4+/-14.7% in the placebo group. The difference was statistically significant (P=0.044). The change of C-reactive protein, cortisol, and anxiety score (State-Trait Anxiety Inventory-X1) were not different between the two groups. CONCLUSION: This preliminary result is the first to directly test the role of perioperative propranolol on tumor growth. Even with the small sample size and short term use of the drug, perioperative propranolol was effective in reducing tumor burden (as measured by CA 125) suggesting its potential benefits in decreasing perioperative tumor growth. PMID- 28344959 TI - Surgical technique for single-port laparoscopy in huge ovarian tumors: SW Kim's technique and comparison to laparotomy. AB - OBJECTIVE: This study aimed to introduce a method to remove huge ovarian tumors (>=15 cm) intact with single-port laparoscopic surgery (SPLS) using SW Kim's technique and to compare the surgical outcomes with those of laparotomy. METHODS: Medical records were retrospectively reviewed for patients who underwent either SPLS (n=21) with SW Kim's technique using a specially designed 30*30-cm2-sized 3XL LapBag or laparotomy (n=22) for a huge ovarian tumor from December 2008 to May 2016. Perioperative surgical outcomes were compared. RESULTS: In 19/21 (90.5%) patients, SPLS was successfully performed without any tumor spillage or conversion to multi-port laparoscopy or laparotomy. There was no significant difference in patient characteristics, including tumor diameter and total operation time, between both groups. The postoperative hospital stay was significantly shorter for the SPLS group than for the laparotomy group (median, 2 [1 to 5] vs. 4 [3 to 17] days; P<0.001). The number of postoperative general diet build-up days was also significantly shorter for the SPLS group (median, 1 [1 to 4] vs. 3 [2 to 16] days; P<0.001). Immediate post-operative pain score was lower in the SPLS group (median, 2.0 [0 to 8] vs. 4.0 [0 to 8]; P=0.045). Patient controlled anesthesia was used less in the SPLS group (61.9% vs. 100%). CONCLUSION: SPLS was successful in removing most large ovarian tumors without rupture and showed quicker recovery and less immediate post-operative pain in comparison to laparotomy. SPLS using SW Kim's technique could be a feasible solution to removing huge ovarian tumors. PMID- 28344960 TI - Thyroid function/antibodies in sudanese women with polycystic ovarian disease. AB - OBJECTIVE: To evaluate thyroid function and hormonal profile in women with polycystic ovary syndrome (PCOS). METHODS: A case-control study was conducted at Saad Abualila Center, Khartoum, Sudan. The cases were women with confirmed PCOS based on Rotterdam criteria. The controls were infertile women with no evidence of PCOS. The socio-demographic characteristics and medical history were gathered using a questionnaire. Thyroid hormones (thyroid-stimulating hormone, free tri iodothyronine, and free thyroxine), anti-thyroid peroxidase, and anti thyroglobulin antibodies were measured. RESULTS: While there were no significant differences in the age and haemoglobin levels of the two studied groups (55 women in each arm), body mass index was significantly higher in women with PCOS. There were no significant differences in the levels of thyroid-stimulating hormone, luteinizing hormone, follicle stimulating hormone, luteinizing hormone/follicle stimulating hormone, anti-thyroid peroxidase, anti-thyroglobulin antibodies, cholesterol, triglycerides and low-density lipoprotein cholesterol between the cases and the controls. The mean+/-standard deviation of free tri-iodothyronine (3.50+/-0.2 vs. 3.38+/-0.3 pg/mL, P=0.040) and median (interquartile) high density lipoprotein cholesterol (37.0 [34.0 to 42.0] vs. 35.80 [29.0 to 41.0] mg/dL, P=0.015) were significantly higher in PCOS patients compared with the control group. In linear regression, PCOS (0.151 pg/mL, P=0.023) and anti-thyroid peroxidase levels (-0.078 pg/mL, P=0.031) were significantly associated with free tri-iodothyronine. CONCLUSION: Free tri-iodothyronine was a significantly higher among PCOS patients compared with the control group. PMID- 28344961 TI - Recurrence factors and reproductive outcomes of laparoscopic myomectomy and minilaparotomic myomectomy for uterine leiomyomas. AB - OBJECTIVE: The aim of this study was to determine recurrence factors and reproductive outcomes of laparoscopic myomectomy (LM) and minilaparotomic myomectomy (MM) for treating uterine leiomyomas. METHODS: Between 2007 and 2013, 160 patients underwent myomectomy, including 122 who underwent LM and 38 who underwent MM. Patients were followed up for recurrence based on pelvic ultrasound exams. Only patients who were followed up for a minimum of two years were selected for this retrospective study. Pregnancy rate, delivery, and delivery methods were compared between the two groups to evaluate reproductive outcomes. Furthermore, mean age, body mass index, preoperative administration of gonadotropin-releasing hormone agonist (GnRHa), and characteristics of leiomyomas were investigated to determine recurrence factors. RESULTS: The mean body mass index in the MM group was significantly (P=0.048) higher than that in the LM group. The number and the largest diameter of removed leiomyoma were also significantly higher in the MM group (both P=0.001). Logistic regression after adjusting significantly different characteristics showed that the LM group had shorter (P=0.020) postoperative hospitalization days compared to the MM group. Other outcome variables including recurrence rate were not significantly different between the two groups. Reproductive outcomes such as pregnancy rate, delivery, and delivery methods were not significantly different between the two groups. Preoperative GnRHa therapy was the only significant (P=0.039) recurrence factor after myomectomy. CONCLUSION: This study showed that LM and MM had similar recurrence rates and reproductive outcomes. The only recurrence factor of significance was preoperative administration of GnRHa. PMID- 28344962 TI - Efficacy of loop electrosurgical excision procedure with cold coagulation for treating cervical intraepithelial neoplasia: A two center cohort study. AB - OBJECTIVE: To evaluate the efficacy of loop electrosurgical excision procedure (LEEP) combined with cold coagulation for treating cervical intraepithelial neoplasia (CIN). METHODS: We reviewed clinic-pathologic data of 498 patients treated with LEEP alone (n=354), and LEEP combined with cold coagulation (n=144) between January 2000 and December 2011. After LEEP, we followed up all patients by using Papanicolaou smear and human papillomavirus (HPV) test, and evaluated abnormal cervical cytology-free interval and high-risk HPV infection-free interval. Moreover, we investigated independent factors affecting abnormal cervical cytology or high-risk HPV infection after LEEP. RESULTS: Abnormal cervical cytology-free interval was longer in patients treated with LEEP combined with cold coagulation than in those treated with LEEP alone (mean, 92.4 vs. 84.4 months; P=0.01), and patients treated with LEEP combined with cold coagulation also showed longer high-risk HPV infection-free interval than those treated with LEEP alone (mean, 87.6 vs. 59.1 months; P=0.01). Moreover, CIN 3 and cold coagulation were factors affecting abnormal cervical cytology after LEEP (adjusted hazard ratios, 1.90 and 0.61; 95% confidence intervals, 1.27 to 2.84 and 0.39 to 0.96), and CIN 3, positive deep cervical margin and cold coagulation were also factors affecting high-risk HPV infection after LEEP (adjusted hazard ratios, 2.07, 4.11, and 0.64; 95% confidence intervals, 1.38 to 3.08, 1.63 to 10.39, and 0.43 to 0.96). When we performed subgroup analyses for patients with CIN 2 or CIN 3, the result were similar. CONCLUSION: LEEP combined with cold coagulation may be more effective for treating CIN than LEEP alone. Moreover, cold coagulation may decrease the risk of potential of recurrence after LEEP. PMID- 28344963 TI - Comparison of sexual function between sacrocolpopexy and sacrocervicopexy. AB - OBJECTIVE: To compare sexual function before and 12 months after between sacrocolpopexy and sacrocervicopexy. METHODS: This retrospective study examined a cohort of 55 sexually active women who underwent either supracervical hysterectomy with sacrocervicopexy (n=28) or total abdominal hysterectomy with sacrocolpopexy (n=27) for stage II to IV pelvic organ prolapse. Pelvic floor support was measured with Pelvic Organ Prolapse-Quantification examination. Pelvic floor function was measured with the Pelvic Floor Distress Inventory-Short Form 20 and sexual function was measured with Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire-Short Form 12 (PISQ-12). RESULTS: Baseline pelvic floor symptoms, demographics and PISQ-12 questionnaire scores were similar between the two groups. Overall improvements in sexual function were seen based on PISQ-12 scores in both groups, but were not statistically significant. No differences were seen in PISQ-12 scores regardless of sparing the cervix or surgical route. Responses to the PISQ-12 question of avoiding sexual intercourse because of vaginal bulging showed significant improvement in both group. No recurrences of prolapse occurred. CONCLUSION: In women with pelvic organ prolapse, sexual function after either sacrocolpopexy or sacrocervicopexy was not different. Sexual dysfunction in terms of avoidance of sexual activity because of vaginal bulging was greatly improved in both groups with statistical significance. PMID- 28344964 TI - Efficacy and safety of drospirenone 2 mg/17beta-estradiol 1 mg hormone therapy in Korean postmenopausal women. AB - This regulatory post-marketing surveillance study aimed to evaluate the therapeutic efficacy and safety of drospirenone (DRSP) 2 mg/estradiol (E2) 1 mg tablet in Korean postmenopausal women. A total of 4,149 patients were enrolled and the study was conducted at 207 clinical research centers. The patients' source data was collected between November 2006 and November 2012. More than 85% of patients experienced improvement of menopausal symptoms. The most frequently reported adverse events were vaginal bleeding and breast pain; most of the women suffering from these symptoms fully recovered. The incidence of adverse event was higher in patients of younger age (20 to 39 years), in patients with concomitant diseases, previous hormone replacement therapy in medical history, those treated with DRSP 2 mg/E2 1 mg for shorter duration (3 years or less) and in patients using concomitant medication. In conclusion, the results from this large post marketing surveillance study confirm the efficacy and safety of DRSP 2 mg/E2 1 mg tablet in Korean postmenopausal women. PMID- 28344965 TI - Tuberculous peritonitis in the first trimester of pregnancy. AB - Tuberculous peritonitis in pregnancy is a rare form of extrapulmonary tuberculosis that is not easily diagnosed. The clinical presentations of tuberculous peritonitis are usually non-specific and mimic those of other diseases, such as ovarian malignancy or chronic liver disease, and this non specificity can cause diagnostic delays and complications. The authors report the case of a 31-year-old primigravida woman who presented with uncontrolled fever, dyspnea, elevated liver enzymes, and mild abdominal distension at 13+2 weeks of gestation. At 14+2 weeks, a therapeutic abortion was conducted and tuberculous peritonitis was confirmed by laparoscopic excisional biopsy of peritoneal nodules and histopathologic examination. The patient recovered on antituberculosis therapy and abdomen and chest follow up radiographic findings have confirmed improvement. PMID- 28344966 TI - Lower limb compartment syndrome by reperfusion injury after treatment of arterial thrombosis post-laparoscopic radical hysterectomy and pelvic lymph node dissection for cervical cancer. AB - Compartment syndrome is a clinical condition associated with decreased blood circulation that can lead to swelling of tissue in limited space. Several factors including lithotomy position, prolonged surgery, intermittent pneumatic compressor, and reperfusion after treatment of arterial thrombosis may contribute to compartment syndrome. However, compartment syndrome rarely occurs after gynecologic surgery. In this case, the patient was diagnosed as compartment syndrome due to reperfusion injury after treatment of arterial thrombosis, which occurred after laparoscopic radical hysterectomy and pelvic lymph node dissection for cervical cancer. Despite its rarity, prevention and identifying the risk factors of complication should be performed perioperatively; furthermore, gynecologist should be aware of the possibility of complications. PMID- 28344967 TI - Mucinous cystadenocarcinoma of ovary with metastasis in 14-year-old girl. AB - Ovarian mucinous tumors in <15 years old are rare with <50 cases reported till date in the literature. Majority of them are benign or borderline epithelial ovarian tumors with only 12 cases of cystadenocarcinomas reported at a young age. We report a case of mucinous cystadenocarcinoma in 14-year-old girl with metastasis to omentum at the time of presentation. Management of such cases is tricky as conservative approach sparing fertility of the patient is adopted. This case is presented for its rarity and unique presentation. To the best of our knowledge, this is the thirteenth case of ovarian cystadenocarcinoma being reported at a very young age and the first case being reported from Indian subcontinent. Extensive review of the previously published cases in the literature has been done in this study. PMID- 28344968 TI - Pulmonary embolism in a healthy woman using the oral contraceptives containing desogestrel. AB - Venous thromboembolism is well known as one of the rare but serious adverse effects of combined oral contraceptives (COCs). The COCs with third and fourth generation progestogens were found to have higher risk of venous thrombosis than those with second generation progestogens. We present a case of pulmonary embolism in a 23-year-old nulligravid woman who was using COCs containing the third generation progestogen (desogestrel). At the time of presentation of the adverse effect, she had been using the COCs for 4 months. She had no additional risk factors for thrombosis such as smoking, surgery, tumor as well as genetic factors. This case demonstrates even young women in otherwise good health may be at risk of venous thromboembolism from low-dose formulations of COCs as an over the-counter drug. We describe this case with a brief review of literatures. PMID- 28344969 TI - Catamenial hemoptysis accompanied by subcutaneous endometriosis treated with combination therapy. AB - Extra pelvic endometriosis is considered to be rare. This paper reports a case of catamenial hemoptysis accompanied by subcutaneous endometriosis in 26-year-old woman. A computed tomography scan of the chest revealed a focal ground-glass opacity lesion in the posterior segment of the right upper lobe. Histopathology confirmed the diagnosis of endometriosis of right lung and concurrent subcutaneous endometriosis. She was treated with surgical resection of the endometriosis lesions on two different sites and perioperative gonadotropin releasing hormone agonist therapy. The 6-month follow-up after combination treatment showed no recurrence. Though long-term follow-up result is needed, aggressive treatment using combination treatment (surgery and perioperative medication) should be considered for symptomatic extra pelvic endometriosis. PMID- 28344970 TI - An Urgent Call for the Renaissance of the World Health Organization: Needed Now More than Ever Before. PMID- 28344972 TI - Parsimonious continuous time random walk models and kurtosis for diffusion in magnetic resonance of biological tissue. AB - In this paper, we provide a context for the modeling approaches that have been developed to describe non-Gaussian diffusion behavior, which is ubiquitous in diffusion weighted magnetic resonance imaging of water in biological tissue. Subsequently, we focus on the formalism of the continuous time random walk theory to extract properties of subdiffusion and superdiffusion through novel simplifications of the Mittag-Leffler function. For the case of time-fractional subdiffusion, we compute the kurtosis for the Mittag-Leffler function, which provides both a connection and physical context to the much-used approach of diffusional kurtosis imaging. We provide Monte Carlo simulations to illustrate the concepts of anomalous diffusion as stochastic processes of the random walk. Finally, we demonstrate the clinical utility of the Mittag-Leffler function as a model to describe tissue microstructure through estimations of subdiffusion and kurtosis with diffusion MRI measurements in the brain of a chronic ischemic stroke patient. PMID- 28344973 TI - Coarse-Grained Conformational Sampling of Protein Structure Improves the Fit to Experimental Hydrogen-Exchange Data. AB - Monitoring hydrogen/deuterium exchange (HDX) undergone by a protein in solution produces experimental data that translates into valuable information about the protein's structure. Data produced by HDX experiments is often interpreted using a crystal structure of the protein, when available. However, it has been shown that the correspondence between experimental HDX data and crystal structures is often not satisfactory. This creates difficulties when trying to perform a structural analysis of the HDX data. In this paper, we evaluate several strategies to obtain a conformation providing a good fit to the experimental HDX data, which is a premise of an accurate structural analysis. We show that performing molecular dynamics simulations can be inadequate to obtain such conformations, and we propose a novel methodology involving a coarse-grained conformational sampling approach instead. By extensively exploring the intrinsic flexibility of a protein with this approach, we produce a conformational ensemble from which we extract a single conformation providing a good fit to the experimental HDX data. We successfully demonstrate the applicability of our method to four small and medium-sized proteins. PMID- 28344974 TI - Assessing Preferences for Animals in Children with Autism: A New Use for Video Based Preference Assessment. AB - The inclusion of animals into interventions for children with autism spectrum disorder (ASD) is a growing practice known as animal-assisted intervention (AAI). The choice of the animal to include in an intervention is often solely up to the interventionist and depends on their experience, subjective judgment, and ease of access to different animals. For individuals with ASD who are non-verbal and unable to indicate preferred stimuli or activities, incorporating preference into interventions has been linked to increases in positive behaviors and enhanced quality of life. We propose that animal choice based on a participant's preference may enhance the experience of AAI and maximize its outcomes. A common technique used to reliably determine preferred interactions and activities in interventions for children with ASD is a stimulus preference assessment. The video-based multiple-stimulus without replacement (MSWO) procedure, in particular, allows for discrimination of complex stimuli that could not feasibly be presented all at once, which is the case when choosing an animal. Based on the well-documented reliability of this technique in the field of applied behavior analysis, we propose that a future direction in AAI is utilizing video-based MSWO to guide animal selection. PMID- 28344971 TI - How to Train a Cell-Cutting-Edge Molecular Tools. AB - In biological systems, the formation of molecular complexes is the currency for all cellular processes. Traditionally, functional experimentation was targeted to single molecular players in order to understand its effects in a cell or animal phenotype. In the last few years, we have been experiencing rapid progress in the development of ground-breaking molecular biology tools that affect the metabolic, structural, morphological, and (epi)genetic instructions of cells by chemical, optical (optogenetic) and mechanical inputs. Such precise dissection of cellular processes is not only essential for a better understanding of biological systems, but will also allow us to better diagnose and fix common dysfunctions. Here, we present several of these emerging and innovative techniques by providing the reader with elegant examples on how these tools have been implemented in cells, and, in some cases, organisms, to unravel molecular processes in minute detail. We also discuss their advantages and disadvantages with particular focus on their translation to multicellular organisms for in vivo spatiotemporal regulation. We envision that further developments of these tools will not only help solve the processes of life, but will give rise to novel clinical and industrial applications. PMID- 28344975 TI - Equine Dental Pulp Connective Tissue Particles Reduced Lameness in Horses in a Controlled Clinical Trial. AB - OBJECTIVE: To assess if injection of allogeneic dental pulp tissue particles would improve lameness in horses with naturally occurring osteoarthritis (OA) or soft tissue (ST) injury. DESIGN: Prospective, randomized, blinded, and controlled clinical trial and client survey assessment. ANIMALS: Forty lame client-owned horses. PROCEDURES: Sterile dental pulp, recovered from otherwise healthy foals that perish during dystocia, was processed under good manufacturing processing to produce mechanically manipulated, unexpanded pulp tissue particles containing viable cells surrounded in extracellular matrix. Forty lame client-owned horses with confirmed OA (n = 20), or ST injury (desmitis or tendonitis) received a 2 mL intra-articular (n = 20 OA) or intra-lesional (n = 20) injection of control transport vehicle (n = 20) or 10 * 106 dental pulp tissue particles (n = 20). Acclimatized horses had baseline measurements performed and were then injected on day 0. Horses were treadmill exercised for 2 weeks, evaluated by clinical parameters, lameness score, edema (score and circumference), pain on flexion (OA) or pressure (ST), and clients' scores for pain and discomfort before and through 45 days after pulp injection. Twenty horses were available for >2.5-year follow up. RESULTS: Pulp-treated horses showed decrease in lameness compared to baseline (P < 0.009) or placebo controls (P < 0.013) for at least 2 weeks. Client assessments of comfort were improved between before and 45 days after pulp injection (P < 0.001). Clinical improvement with ST injury was significantly greater than OA (P < 0.001). At >2.5-year follow-up, at least 10 horses were in work. CONCLUSION AND CLINICAL RELEVANCE: Dental pulp tissue particles can be considered as a treatment option for equine lameness due to OA, desmitis, or tendonitis. PMID- 28344976 TI - A Metataxonomic Approach Could Be Considered for Cattle Clinical Mastitis Diagnostics. AB - Mastitis is one of the most costly diseases affecting the dairy industry, and identification of the causative microorganism(s) is essential. Here, we report the use of next-generation sequencing of bacterial 16S rRNA genes for clinical mastitis diagnosis. We used 65 paired milk samples, collected from the mastitic and a contralateral healthy quarter of mastitic dairy cattle to evaluate the technique as a potential alternative to bacterial culture or targeted PCR. One large commercial dairy farm was used, with one trained veterinarian collecting the milk samples. The 16S rRNA genes were individually amplified and sequenced using the MiSeq platform. The MiSeq Reporter was used in order to analyze the obtained sequences. Cattle were categorized according to whether or not 1 of the 10 most abundant bacterial genera in the mastitic quarter exhibited an increase in relative abundance between the healthy and mastitic quarters equal to, or exceeding, twofold. We suggest that this increase in relative abundance is indicative of the genus being a causative mastitis pathogen. Well-known mastitis causing pathogens such as Streptococcus uberis and Staphylococcus spp. were identified in most cattle. We were able to diagnose 53 out of the 65 studied cases and identify potential new mastitis pathogens such as Sneathia sanguinegens and Listeria innocua, which are difficult to identify by bacterial culture because of their fastidious nature. PMID- 28344978 TI - Large-scale Analysis of Counseling Conversations: An Application of Natural Language Processing to Mental Health. AB - Mental illness is one of the most pressing public health issues of our time. While counseling and psychotherapy can be effective treatments, our knowledge about how to conduct successful counseling conversations has been limited due to lack of large-scale data with labeled outcomes of the conversations. In this paper, we present a large-scale, quantitative study on the discourse of text message-based counseling conversations. We develop a set of novel computational discourse analysis methods to measure how various linguistic aspects of conversations are correlated with conversation outcomes. Applying techniques such as sequence-based conversation models, language model comparisons, message clustering, and psycholinguistics-inspired word frequency analyses, we discover actionable conversation strategies that are associated with better conversation outcomes. PMID- 28344979 TI - Psychological profile of individuals presenting with chronic cough. AB - Chronic refractory cough (CRC) is a common problem in respiratory clinics. Adverse effects on quality of life are documented in the literature, but relatively little is known about the underlying psychological factors in this patient population. We aimed to investigate the association of psychological factors with chronic cough, comparing CRC to explained cough and non-cough groups. 67 patients attending a specialist cough clinic (CRC, n=25; explained cough, n=42) and 22 non-cough individuals participated. All participants completed the Hospital Anxiety & Depression Scale, Big Five Inventory (Personality), Chalder Fatigue Scale and Patient Health Questionnaire-15. Cough patients also completed the Illness Perception Questionnaire-Revised. Appropriate statistical analyses were used to compare participant groups. Chronic refractory coughers displayed significantly higher levels of anxiety, depression, fatigue and somatic physical symptoms than non-cough participants. Compared to explained coughers, there were higher depression and fatigue scores and significantly more negative illness representations (specifically, strong beliefs regarding negative consequences, lower illness coherence and higher emotional representations). "Explained" coughers reported significantly increased fatigue and somatic symptoms in comparison to non-coughers. The prevalence of fatigue, low mood, negative illness beliefs and increased physical symptom reporting should be considered in consultations and in developing novel interventions for CRC patients. PMID- 28344980 TI - Discordance in investigator-reported and adjudicated sudden death in TIOSPIR. AB - Accurate and consistent determination of cause of death is challenging in chronic obstructive pulmonary disease (COPD) patients. TIOSPIR (N=17 135) compared the safety and efficacy of tiotropium Respimat 5/2.5 ug with HandiHaler 18 ug in COPD patients. All-cause mortality was a primary end-point. A mortality adjudication committee (MAC) assessed all deaths. We aimed to investigate causes of discordance in investigator-reported and MAC-adjudicated causes of death and their impact on results, especially cardiac and sudden death. The MAC provided independent, blinded assessment of investigator-reported deaths (n=1302) and assigned underlying cause of death. Discordance between causes of death was assessed descriptively (shift tables). There was agreement between investigator reported and MAC-adjudicated deaths in 69.4% of cases at the system organ class level. Differences were mainly observed for cardiac deaths (16.4% investigator, 5.1% MAC) and deaths assigned to general disorders including sudden death (17.4% investigator, 24.6% MAC). Reasons for discrepancies included investigator attribution to the immediate (e.g. myocardial infarction (MI)) over the underlying cause of death (e.g. COPD) and insufficient information for a definitive cause. Cause-specific mortality varies in COPD, depending on the method of assignment. Sudden death, witnessed and unwitnessed, is common in COPD and often attributed to MI without supporting evidence. PMID- 28344977 TI - Chromatographic Studies of Protein-Based Chiral Separations. AB - The development of separation methods for the analysis and resolution of chiral drugs and solutes has been an area of ongoing interest in pharmaceutical research. The use of proteins as chiral binding agents in high-performance liquid chromatography (HPLC) has been an approach that has received particular attention in such work. This report provides an overview of proteins that have been used as binding agents to create chiral stationary phases (CSPs) and in the use of chromatographic methods to study these materials and protein-based chiral separations. The supports and methods that have been employed to prepare protein based CSPs will also be discussed and compared. Specific types of CSPs that are considered include those that employ serum transport proteins (e.g., human serum albumin, bovine serum albumin, and alpha1-acid glycoprotein), enzymes (e.g., penicillin G acylase, cellobiohydrolases, and alpha-chymotrypsin) or other types of proteins (e.g., ovomucoid, antibodies, and avidin or streptavidin). The properties and applications for each type of protein and CSP will also be discussed in terms of their use in chromatography and chiral separations. PMID- 28344981 TI - The effects of exogenous lipid on THP-1 cells: an in vitro model of airway aspiration? AB - Chronic inflammatory diseases of the airways are associated with gastro oesophageal reflux (GOR) and aspiration events. The observation of lipid-laden macrophages (LLMs) within the airway may indicate aspiration secondary to GOR. The proposed mechanism, that lipid droplets from undigested or partially digested food are aspirated leading to accumulation in scavenging macrophages, led us to hypothesise that an activated population of LLMs could interact with other immune cells to induce bronchial inflammation. To test this, we generated an in vitro model using differentiated THP-1 cells, which were treated with a high-fat liquid feed. Here, we show that THP-1 cells can take up lipid from the high-fat feed independent of actin polymerisation or CD36-dependent phagocytosis. These cells did not exhibit M1 or M2 polarisation. Gene array analysis confirmed over 8000 genes were upregulated by at least twofold following high fat exposure, and IL-8 was the most upregulated gene. Pathway analysis revealed upregulation of genes known to be involved in chronic obstructive pulmonary disease (COPD) pathophysiology. We suggest that aspiration and macrophage phagocytosis may be important mechanisms in the aetiology of diseases such as COPD and cystic fibrosis that are characterised by high levels of IL-8 within the airways. PMID- 28344982 TI - Transbronchial cryobiopsy in interstitial lung disease: experience in 106 cases - how to do it. AB - Transbronchial biopsy using forceps (TBB) is the first diagnostic technique performed on patients with interstitial lung disease (ILD). However, the small size of the samples and the presence of artefacts in the tissue obtained make the yield variable. Our objectives were 1) to attempt to reproduce transbronchial cryobiopsy under the same conditions with which we performed conventional TBB, that is, in the bronchoscopy unit without intubating the patient and without fluoroscopy or general anaesthesia; 2) to describe the method used for its execution; and 3) to analyse the diagnostic yield and its complications. We carried out a prospective study that included 106 patients with clinical and radiological features suggestive of ILD who underwent cryo-transbronchial lung biopsy (cryo-TBB) under moderate sedation without endotracheal intubation, general anaesthesia or use of fluoroscopy. We performed the procedure using two flexible bronchoscopes connected to two video processors, which we alternated until obtaining the number of desired samples. A definitive diagnosis was obtained in 91 patients (86%). As for complications, there were five pneumothoraces (4.7%) and in no case was there severe haemorrhage or exacerbation of the underlying interstitial disease. Cryo-TBB following our method is a minimally invasive, rapid, safe and economic technique that can be performed in a bronchoscopy suite under moderate sedation without the need for intubating the patient or using fluoroscopy and without requiring general anaesthesia. PMID- 28344983 TI - Effects of bile acids on human airway epithelial cells: implications for aerodigestive diseases. AB - Gastro-oesophageal reflux and aspiration have been associated with chronic and end-stage lung disease and with allograft injury following lung transplantation. This raises the possibility that bile acids may cause lung injury by damaging airway epithelium. The aim of this study was to investigate the effect of bile acid challenge using the immortalised human bronchial epithelial cell line (BEAS 2B). The immortalised human bronchial epithelial cell line (BEAS-2B) was cultured. A 48-h challenge evaluated the effect of individual primary and secondary bile acids. Post-challenge concentrations of interleukin (IL)-8, IL-6 and granulocyte-macrophage colony-stimulating factor were measured using commercial ELISA kits. The viability of the BEAS-2B cells was measured using CellTiter-Blue and MTT assays. Lithocholic acid, deoxycholic acid, chenodeoxycholic acid and cholic acid were successfully used to stimulate cultured BEAS-2B cells at different concentrations. A concentration of lithocholic acid above 10 MUmol.L-1 causes cell death, whereas deoxycholic acid, chenodeoxycholic acid and cholic acid above 30 MUmol.L-1 was required for cell death. Challenge with bile acids at physiological levels also led to a significant increase in the release of IL-8 and IL6 from BEAS-2B. Aspiration of bile acids could potentially cause cell damage, cell death and inflammation in vivo. This is relevant to an integrated gastrointestinal and lung physiological paradigm of chronic lung disease, where reflux and aspiration are described in both chronic lung diseases and allograft injury. PMID- 28344984 TI - Advance Directive in End of Life Decision-Making among the Yoruba of South Western Nigeria. AB - End-of-life decision making is value-laden within the context of culture and bioethics. Also, ethics committee role is difficult to understand on this, thus need for ethnomethodological perspective in an expanding bioethical age. Anthropological approach was utilized to document Yoruba definition and perspective of death, cultural beliefs about end-of-life decision making, factors influencing it and ethics committee role. Interviews were conducted among selected Yoruba resident in Akinyele LGA, Oyo State, Nigeria. Content analytical approach was used for data analysis. Yoruba culture, death is socially constructed having spiritual, physical and social significance. Relationship between the dying and significant others influences decision making. Hierarchy of authority informs implementing traditional advance directive. Socialization, gender, patriarchy, religious belief and tradition are major considerations in end-of-life decision making. Awareness, resource allocation and advocacy are important ethics committees' roles. Further research into cultural diversity of end-of-life decision making will strengthen ethical practice in health care delivery. PMID- 28344985 TI - Decolonizing Bioethics in Africa. AB - The global spread of bioethics from its North-American and European provenance to non-Western societies is currently raising some concerns. Part of the concern has to do with whether or not the exportation of bioethics in its full Western sense to developing non-Western states is an instance of ethical imperialism or bioethical neocolonialism. This paper attempts an exploration of this debate in the context of bioethics in sub-Saharan Africa. Rather than conceding that bioethics has a colonial agenda in Africa, this paper defends the position that the current bioethics trend in sub-Saharan Africa is an unintended imperialistic project. It argues that its colonizing character is not entirely a product of the Western programmed goals of training and institution building; rather, it is a structural consequence of many receptive African minds and institutions. Though bioethics in Africa is turning out as a colonizing project, one serious implication of such trend, if unchecked urgently, is that bioethics' invaluable relevance to Africa is being incapacitated. This paper, therefore, attempts a decolonizing trajectory of bioethics in Africa. Contrary to the pretense of 'African bioethics,' which some African scholars are now defending, this paper through the logic of decolonization makes case for 'bioethics in Africa'. In such logic, the principle of existential needs is prioritized over the principle of identity and authenticity that define African voice in bioethics. PMID- 28344986 TI - Erratum to: Pharmacological treatments of presbyopia: a review of modern perspectives. AB - [This corrects the article DOI: 10.1186/s40662-017-0068-8.]. PMID- 28344988 TI - INSPIIRED: Quantification and Visualization Tools for Analyzing Integration Site Distributions. AB - Analysis of sites of newly integrated DNA in cellular genomes is important to several fields, but methods for analyzing and visualizing these datasets are still under development. Here, we describe tools for data analysis and visualization that take as input integration site data from our INSPIIRED pipeline. Paired-end sequencing allows inference of the numbers of transduced cells as well as the distributions of integration sites in target genomes. We present interactive heatmaps that allow comparison of distributions of integration sites to genomic features and that support numerous user-defined statistical tests. To summarize integration site data from human gene therapy samples, we developed a reproducible report format that catalogs sample population structure, longitudinal dynamics, and integration frequency near cancer-associated genes. We also introduce a novel summary statistic, the UC50 (unique cell progenitors contributing the most expanded 50% of progeny cell clones), which provides a single number summarizing possible clonal expansion. Using these tools, we characterize ongoing longitudinal characterization of a patient from the first trial to treat severe combined immunodeficiency-X1 (SCID X1), showing successful reconstitution for 15 years accompanied by persistence of a cell clone with an integration site near the cancer-associated gene CCND2. Software is available at https://github.com/BushmanLab/INSPIIRED. PMID- 28344989 TI - Efficient Presentation of Multiple Endogenous Epitopes to Both CD4+ and CD8+ Diabetogenic T Cells for Tolerance. AB - Antigen-specific immunotherapy of type 1 diabetes, typically via delivery of a single native beta cell antigen, has had little clinical benefit to date. With increasing evidence that diabetogenic T cells react against multiple beta cell antigens, including previously unappreciated neo-antigens that can be emulated by mimotopes, a shift from protein- to epitope-based therapy is warranted. To this end, we aimed to achieve efficient co-presentation of multiple major epitopes targeting both CD4+ and CD8+ diabetogenic T cells. We have compared native epitopes versus mimotopes as well as various targeting signals in an effort to optimize recognition by both types of T cells in vitro. Optimal engagement of all T cells was achieved with segregation of CD8 and CD4 epitopes, the latter containing mimotopes and driven by endosome-targeting signals, after delivery into either dendritic or stromal cells. The CD4+ T cell responses elicited by the endogenously delivered epitopes were comparable with high concentrations of soluble peptide and included functional regulatory T cells. This work has important implications for the improvement of antigen-specific therapies using an epitope-based approach to restore tolerance in type 1 diabetes and in a variety of other diseases requiring concomitant targeting of CD4+ and CD8+ T cells. PMID- 28344987 TI - Safe and Effective Gene Therapy for Murine Wiskott-Aldrich Syndrome Using an Insulated Lentiviral Vector. AB - Wiskott-Aldrich syndrome (WAS) is a life-threatening immunodeficiency caused by mutations within the WAS gene. Viral gene therapy to restore WAS protein (WASp) expression in hematopoietic cells of patients with WAS has the potential to improve outcomes relative to the current standard of care, allogeneic bone marrow transplantation. However, the development of viral vectors that are both safe and effective has been problematic. While use of viral transcriptional promoters may increase the risk of insertional mutagenesis, cellular promoters may not achieve WASp expression levels necessary for optimal therapeutic effect. Here we evaluate a self-inactivating (SIN) lentiviral vector combining a chromatin insulator upstream of a viral MND (MPSV LTR, NCR deleted, dl587 PBS) promoter driving WASp expression. Used as a gene therapeutic in Was-/- mice, this vector resulted in stable WASp+ cells in all hematopoietic lineages and rescue of T and B cell defects with a low number of viral integrations per cell, without evidence of insertional mutagenesis in serial bone marrow transplants. In a gene transfer experiment in non-human primates, the insulated MND promoter (driving GFP expression) demonstrated long-term polyclonal engraftment of GFP+ cells. These observations demonstrate that the insulated MND promoter safely and efficiently reconstitutes clinically effective WASp expression and should be considered for future WAS therapy. PMID- 28344990 TI - INSPIIRED: A Pipeline for Quantitative Analysis of Sites of New DNA Integration in Cellular Genomes. AB - Integration of new DNA into cellular genomes mediates replication of retroviruses and transposons; integration reactions have also been adapted for use in human gene therapy. Tracking the distributions of integration sites is important to characterize populations of transduced cells and to monitor potential outgrow of pathogenic cell clones. Here, we describe a pipeline for quantitative analysis of integration site distributions named INSPIIRED (integration site pipeline for paired-end reads). We describe optimized biochemical steps for site isolation using Illumina paired-end sequencing, including new technology for suppressing recovery of unwanted contaminants, then software for alignment, quality control, and management of integration site sequences. During library preparation, DNAs are broken by sonication, so that after ligation-mediated PCR the number of ligation junction sites can be used to infer abundance of gene-modified cells. We generated integration sites of known positions in silico, and we describe optimization of sample processing parameters refined by comparison to truth. We also present a novel graph-theory-based method for quantifying integration sites in repeated sequences, and we characterize the consequences using synthetic and experimental data. In an accompanying paper, we describe an additional set of statistical tools for data analysis and visualization. Software is available at https://github.com/BushmanLab/INSPIIRED. PMID- 28344991 TI - Antibody-Directed Glucocorticoid Targeting to CD163 in M2-type Macrophages Attenuates Fructose-Induced Liver Inflammatory Changes. AB - Increased consumption of high-caloric carbohydrates contributes substantially to endemic non-alcoholic fatty liver disease in humans, covering a histological spectrum from fatty liver to steatohepatitis. Hypercaloric intake and lipogenetic effects of fructose and endotoxin-driven activation of liver macrophages are suggested to be essential to disease progression. In the present study, we show that a low dose of an anti-CD163-IgG-dexamethasone conjugate targeting the hemoglobin scavenger receptor CD163 in Kupffer cells and other M2-type macrophages has a profound effect on liver inflammatory changes in rats on a high fructose diet. The diet induced severe non-alcoholic steatohepatitis (NASH)-like changes within a few weeks but the antibody-drug conjugate strongly reduced inflammation, hepatocyte ballooning, fibrosis, and glycogen deposition. Non conjugated dexamethasone or dexamethasone conjugated to a control IgG did not have this effect but instead exacerbated liver lipid accumulation. The low-dose anti-CD163-IgG-dexamethasone conjugate displayed no apparent systemic side effects. In conclusion, macrophage targeting by antibody-directed anti inflammatory low-dose glucocorticoid therapy seems to be a promising approach for safe treatment of fructose-induced liver inflammation. PMID- 28344992 TI - Mechanism of Deletion Removing All Dystrophin Exons in a Canine Model for DMD Implicates Concerted Evolution of X Chromosome Pseudogenes. AB - Duchenne muscular dystrophy (DMD) is a lethal, X-linked, muscle-wasting disorder caused by mutations in the large, 2.4-Mb dystrophin gene. The majority of DMD causing mutations are sporadic, multi-exon, frameshifting deletions, with the potential for variable immunological tolerance to the dystrophin protein from patient to patient. While systemic gene therapy holds promise in the treatment of DMD, immune responses to vectors and transgenes must first be rigorously evaluated in informative preclinical models to ensure patient safety. A widely used canine model for DMD, golden retriever muscular dystrophy, expresses detectable amounts of near full-length dystrophin due to alternative splicing around an intronic point mutation, thereby confounding the interpretation of immune responses to dystrophin-derived gene therapies. Here we characterize a naturally occurring deletion in a dystrophin-null canine, the German shorthaired pointer. The deletion spans 5.6 Mb of the X chromosome and encompasses all coding exons of the DMD and TMEM47 genes. The sequences surrounding the deletion breakpoints are virtually identical, suggesting that the deletion occurred through a homologous recombination event. Interestingly, the deletion breakpoints are within loci that are syntenically conserved among mammals, yet the high homology among this subset of ferritin-like loci is unique to the canine genome, suggesting lineage-specific concerted evolution of these atypical sequence elements. PMID- 28344993 TI - Bringing Neural Cell Therapies to the Clinic: Past and Future Strategies. AB - Cell replacement therapy in the nervous system has a rich history, with ~40 years of research and ~30 years of clinical experience. There is compelling evidence that appropriate cells can integrate and function in the dysfunctioning human nervous system, but the clinical results are mixed in practice. A number of factors conspire to vary patient outcome: the indication, cell source, patient selection, and team performing transplantation are all variables that can affect efficacy. Most early clinical trials have used fetal cells, a limited cell source that resists scale and standardization. Direct fetal cell transplantation creates significant challenges to commercialization that is the ultimate goal of an effective cell therapy. One approach to help scale and standardize fetal cell preparations is the expansion of neural cells in vitro. Expansion is achieved by transformation or through the application of mitogens before cryopreservation. Recently, neural cells derived from pluripotent stem cells have provided a scalable alternative. Pluripotent stem cells are desirable for manufacturing but present alternative concerns and manufacturing obstacles. All cell sources require robust and reproducible manufacturing to make nervous system cell replacement therapy an option for patients. Here, we discuss the challenges and opportunities for cell replacement in the nervous system. In this review, we give an overview of completed and ongoing neural cell transplantation clinical trials, and we discuss the challenges and opportunities for future cell replacement trials with a particular focus on pluripotent stem cell-derived therapies. PMID- 28344994 TI - A New Broad Range Plasmid for DNA Delivery in Eukaryotic Cells Using Lactic Acid Bacteria: In Vitro and In Vivo Assays. AB - Lactococcus lactis is well documented as a promising candidate for development of novel oral live vaccines. It has been broadly engineered for heterologous expression, as well as for plasmid expression vector delivery, directly inside eukaryotic cells, for DNA vaccine, or as therapeutic vehicle. This work describes the characteristics of a new plasmid, pExu (extra chromosomal unit), for DNA delivery using L. lactis and evaluates its functionality both by in vitro and in vivo assays. This plasmid exhibits the following features: (1) a theta origin of replication and (2) an expression cassette containing a multiple cloning site and a eukaryotic promoter, the cytomegalovirus (pCMV). The functionality of pExu:egfp was evaluated by fluorescence microscopy. The L. lactis MG1363 (pExu:egfp) strains were administered by gavage to Balb/C mice and the eGFP expression was monitored by fluorescence microscopy. The pExu vector has demonstrated an excellent stability either in L. lactis or in Escherichia coli. The eGFP expression at different times in in vitro assay showed that 15.8% of CHO cells were able to express the protein after transfection. The enterocytes of mice showed the expression of eGFP protein. Thus, L. lactis carrying the pExu is a good candidate to deliver genes into eukaryotic cells. PMID- 28344995 TI - Global Manufacturing of CAR T Cell Therapy. AB - Immunotherapy using chimeric antigen receptor-modified T cells has demonstrated high response rates in patients with B cell malignancies, and chimeric antigen receptor T cell therapy is now being investigated in several hematologic and solid tumor types. Chimeric antigen receptor T cells are generated by removing T cells from a patient's blood and engineering the cells to express the chimeric antigen receptor, which reprograms the T cells to target tumor cells. As chimeric antigen receptor T cell therapy moves into later-phase clinical trials and becomes an option for more patients, compliance of the chimeric antigen receptor T cell manufacturing process with global regulatory requirements becomes a topic for extensive discussion. Additionally, the challenges of taking a chimeric antigen receptor T cell manufacturing process from a single institution to a large-scale multi-site manufacturing center must be addressed. We have anticipated such concerns in our experience with the CD19 chimeric antigen receptor T cell therapy CTL019. In this review, we discuss steps involved in the cell processing of the technology, including the use of an optimal vector for consistent cell processing, along with addressing the challenges of expanding chimeric antigen receptor T cell therapy to a global patient population. PMID- 28344996 TI - Codon Optimization Leads to Functional Impairment of RD114-TR Envelope Glycoprotein. AB - Lentiviral vectors (LVs) are a highly valuable tool for gene transfer currently exploited in basic, applied, and clinical studies. Their optimization is therefore very important for the field of vectorology and gene therapy. A key molecule for LV function is the envelope because it guides cell entry. The most commonly used in transiently produced LVs is the vesicular stomatitis virus glycoprotein (VSV-G) envelope, whose continuous expression is, however, toxic for stable LV producer cells. In contrast, the feline endogenous retroviral RD114-TR envelope is suitable for stable LV manufacturing, being well tolerated by producer cells under constitutive expression. We have previously reported successful, transient and stable production of LVs pseudotyped with RD114-TR for good transduction of T lymphocytes and CD34+ cells. To further improve RD114-TR pseudotyped LV cell entry by increasing envelope expression, we codon-optimized the RD114-TR open reading frame (ORF). Here we show that, despite the RD114-TRco precursor being produced at a higher level than the wild-type counterpart, it is unexpectedly not duly glycosylated, exported to the cytosol, and processed. Correct cleavage of the precursor in the functional surface and transmembrane subunits is prevented in vivo, and, consequently, the unprocessed precursor is incorporated into LVs, making them inactive. PMID- 28344998 TI - Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction. AB - Pompe disease results from acid alpha-glucosidase (GAA) deficiency, and enzyme replacement therapy (ERT) with recombinant human (rh) GAA has clinical benefits, although its limitations include the short half-life of GAA and the formation of antibody responses. The present study compared the efficacy of ERT against gene transfer with an adeno-associated viral (AAV) vector containing a liver-specific promoter. GAA knockout (KO) mice were administered either a weekly injection of rhGAA (20 mg/kg) or a single injection of AAV2/8-LSPhGAA (8 * 1011 vector genomes [vg]/kg). Both treatments significantly reduced glycogen content of the heart and diaphragm. Although ERT triggered anti-GAA antibody formation, there was no detectable antibody response following AAV vector administration. The efficacy of three lower dosages of AAV2/8-LSPhGAA was evaluated in GAA-KO mice, either alone or in combination with ERT. The minimum effective dose (MED) identified was 8 * 1010 vg/kg to reduce glycogen content in the heart and diaphragm of GAA-KO mice. A 3-fold higher dose was required to suppress antibody responses to ERT. Efficacy from liver gene therapy was slightly greater in male mice than in female mice. Vector dose correlated inversely with anti-GAA antibody formation, whereas higher vector doses suppressed previously formed anti-GAA antibodies as late as 25 weeks after the start of ERT and achieved biochemical correction of glycogen accumulation. In conclusion, we identified the MED for effective AAV2/8-LSPhGAA mediated tolerogenic gene therapy in Pompe disease mice. PMID- 28344997 TI - Simple Derivation of Spinal Motor Neurons from ESCs/iPSCs Using Sendai Virus Vectors. AB - Amyotrophic lateral sclerosis (ALS) is a progressive and fatal degenerative disorder of motor neurons (MNs). Embryonic stem cells (ESCs)/induced pluripotent stem cells (iPSCs) now help us to understand the pathomechanisms of ALS via disease modeling. Various methods to differentiate ESCs/iPSCs into MNs by the addition of signaling molecules have been reported. However, classical methods require multiple steps, and newer simple methods using the transduction of transcription factors run the risk of genomic integration of the vector genes. Heterogeneity of the expression levels of the transcription factors also remains an issue. Here we describe a novel approach for differentiating human and mouse ESCs/iPSCs into MNs using a single Sendai virus vector encoding three transcription factors, LIM/homeobox protein 3, neurogenin 2, and islet-1, which are integration free. This single-vector method, generating HB9-positive cells on day 2 from human iPSCs, increases the ratio of MNs to neurons compared to the use of three separate Sendai virus vectors. In addition, the MNs derived via this method from iPSCs of ALS patients and model mice display disease phenotypes. This simple approach significantly reduces the efforts required to generate MNs, and it provides a useful tool for disease modeling. PMID- 28344999 TI - Long-Term Engraftment and Fetal Globin Induction upon BCL11A Gene Editing in Bone Marrow-Derived CD34+ Hematopoietic Stem and Progenitor Cells. AB - To develop an effective and sustainable cell therapy for sickle cell disease (SCD), we investigated the feasibility of targeted disruption of the BCL11A gene, either within exon 2 or at the GATAA motif in the intronic erythroid-specific enhancer, using zinc finger nucleases in human bone marrow (BM) CD34+ hematopoietic stem and progenitor cells (HSPCs). Both targeting strategies upregulated fetal globin expression in erythroid cells to levels predicted to inhibit hemoglobin S polymerization. However, complete inactivation of BCL11A resulting from bi-allelic frameshift mutations in BCL11A exon 2 adversely affected erythroid enucleation. In contrast, bi-allelic disruption of the GATAA motif in the erythroid enhancer of BCL11A did not negatively impact enucleation. Furthermore, BCL11A exon 2-edited BM-CD34+ cells demonstrated a significantly reduced engraftment potential in immunodeficient mice. Such an adverse effect on HSPC function was not observed upon BCL11A erythroid-enhancer GATAA motif editing, because enhancer-edited CD34+ cells achieved robust long-term engraftment and gave rise to erythroid cells with elevated levels of fetal globin expression when chimeric BM was cultured ex vivo. Altogether, our results support further clinical development of the BCL11A erythroid-specific enhancer editing in BM-CD34+ HSPCs as an autologous stem cell therapy in SCD patients. PMID- 28345000 TI - Syngeneic AAV Pseudo-particles Potentiate Gene Transduction of AAV Vectors. AB - Adeno-associated virus (AAV) vectors have emerged as a safe and efficient gene therapy platform. One complication is that a significant amount of empty particles have always been generated as impurities during AAV vector production. However, the effects of such particles on AAV vector performance remain unclear. Here we systemically evaluated the biological properties of three types of "empty" AAV particles: syngeneic pseudo-vectors with partial AAV genomes derived from DNA of the corresponding full particles, allogeneic pseudo-vectors with partial genomes different from the corresponding full particles, and null pseudo vectors with no DNA inside the capsids. The syngeneic particles in excess increased the corresponding full AAV vector transgene expression both in vivo and in vitro. However, such effects were not observed with null or allogeneic particles. The observed differences among these pseudo-AAV particles may be ascribed to the syngeneic pseudo-vector DNA facilitating the complementary DNA synthesis of the corresponding full AAV particles. Our study suggests that the DNA content in the pseudo-vectors plays a key role in dictating their effects on AAV transduction. The effects of residual "empty" particles should be adequately assessed when comparing AAV vector performance. The syngeneic AAV pseudo-vectors may be used to enhance the efficacy of gene therapy. PMID- 28345001 TI - Effective Depletion of Pre-existing Anti-AAV Antibodies Requires Broad Immune Targeting. AB - Pre-existing antibodies (Abs) to AAV pose a critical challenge for the translation of gene therapies. No effective approach is available to overcome pre existing Abs. Given the complexity of Ab production, overcoming pre-existing Abs will require broad immune targeting. We generated a mouse model of pre-existing AAV9 Abs to test multiple immunosuppressants, including bortezomib, rapamycin, and prednisolone, individually or in combination. We identified an effective approach combining rapamycin and prednisolone, reducing serum AAV9 Abs by 70%-80% at 4 weeks and 85%-93% at 8 weeks of treatment. The rapamycin plus prednisolone treatment resulted in significant decreases in the frequency of B cells, plasma cells, and IgG-secreting and AAV9-specific Ab-producing plasma cells in bone marrow. The rapamycin plus prednisolone treatment also significantly reduced frequencies of IgD-IgG+ class-switched/FAS+CL7+ germinal center B cells, and of activated CD4+ T cells expressing PD1 and GL7, in spleen. These data suggest that rapamycin plus prednisolone has selective inhibitory effects on both T helper type 2 support of B cell activation in spleen and on bone marrow plasma cell survival, leading to effective AAV9 Abs depletion. This promising immunomodulation approach is highly translatable, and it poses minimal risk in the context of therapeutic benefits promised by gene therapy for severe monogenetic diseases, with a single or possibly a few treatments over a lifetime. PMID- 28345002 TI - CXCL12 Promotes Stem Cell Recruitment and Uterine Repair after Injury in Asherman's Syndrome. AB - Asherman's syndrome is an acquired condition of uterine fibrosis and adhesions in response to injury that adversely affects fertility and pregnancy. We have previously demonstrated that bone marrow-derived mesenchymal stem cells (BMDSCs) contribute to uterine repair after injury and that stem cells supplementation improves fertility. Here, we demonstrate that CXCL12 is the chemokine that mediates stem cell engraftment and functional improvement using a murine model of Asherman's syndrome. After uterine injury, we demonstrate that CXCL12 augmentation increased BMDSC engraftment and that the CXCL12 receptor (CXCR4) antagonist, ADM3100, blocked stem cell recruitment. CXCL12 reduced, whereas ADM3100 increased fibrosis. CXCL12 treatment led to improved fertility and litter size, whereas ADM3100 treatment reduced fertility and litter size. ADM3100 prevented optimal spontaneous uterine repair mediated by endogenous CXCL12 production, reducing pregnancies after injury in the absence of supplemental CXCL12 administration; however, ADM3100 treatment could be partially rescued by CXCL12 augmentation. CXCL12 or other CXCR4 receptor agonists may be useful in the treatment of infertility or adverse pregnancy outcomes in Asherman's syndrome and other related uterine disorders. PMID- 28345003 TI - Expansion of Human Tregs from Cryopreserved Umbilical Cord Blood for GMP Compliant Autologous Adoptive Cell Transfer Therapy. AB - Umbilical cord blood is a traditional and convenient source of cells for hematopoietic stem cell transplantation. Thymic regulatory T cells (Tregs) are also present in cord blood, and there is growing interest in the use of autologous Tregs to provide a low-risk, fully human leukocyte antigen (HLA) matched cell product for treating autoimmune diseases, such as type 1 diabetes. Here, we describe a good manufacturing practice (GMP)-compatible Treg expansion protocol using fluorescence-activated cell sorting, resulting in a mean 2,092 fold expansion of Tregs over a 16-day culture for a median yield of 1.26 * 109 Tregs from single-donor cryopreserved units. The resulting Tregs passed prior clinical trial release criteria for Treg purity and sterility, including additional rigorous assessments of FOXP3 and Helios expression and epigenetic analysis of the FOXP3 Treg-specific demethylated region (TSDR). Compared with expanded adult peripheral blood Tregs, expanded cord blood Tregs remained more naive, as assessed by continued expression of CD45RA, produced reduced IFN-gamma following activation, and effectively inhibited responder T cell proliferation. Immunosequencing of the T cell receptor revealed a remarkably diverse receptor repertoire within cord blood Tregs that was maintained following in vitro expansion. These data support the feasibility of generating GMP-compliant Tregs from cord blood for adoptive cell transfer therapies and highlight potential advantages in terms of safety, phenotypic stability, autoantigen specificity, and tissue distribution. PMID- 28345004 TI - Homology-Directed Recombination for Enhanced Engineering of Chimeric Antigen Receptor T Cells. AB - Gene editing by homology-directed recombination (HDR) can be used to couple delivery of a therapeutic gene cassette with targeted genomic modifications to generate engineered human T cells with clinically useful profiles. Here, we explore the functionality of therapeutic cassettes delivered by these means and test the flexibility of this approach to clinically relevant alleles. Because CCR5-negative T cells are resistant to HIV-1 infection, CCR5-negative anti-CD19 chimeric antigen receptor (CAR) T cells could be used to treat patients with HIV associated B cell malignancies. We show that targeted delivery of an anti-CD19 CAR cassette to the CCR5 locus using a recombinant AAV homology template and an engineered megaTAL nuclease results in T cells that are functionally equivalent, in both in vitro and in vivo tumor models, to CAR T cells generated by random integration using lentiviral delivery. With the goal of developing off-the-shelf CAR T cell therapies, we next targeted CARs to the T cell receptor alpha constant (TRAC) locus by HDR, producing TCR-negative anti-CD19 CAR and anti-B cell maturation antigen (BCMA) CAR T cells. These novel cell products exhibited in vitro cytolytic activity against both tumor cell lines and primary cell targets. Our combined results indicate that high-efficiency HDR delivery of therapeutic genes may provide a flexible and robust method that can extend the clinical utility of cell therapeutics. PMID- 28345005 TI - Chronic Enzyme Replacement to the Brain of a Late Infantile Neuronal Ceroid Lipofuscinosis Mouse Has Differential Effects on Phenotypes of Disease. AB - Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal inherited neurodegenerative disease caused by loss of lysosomal protease tripeptidyl peptidase 1 (TPP1). We have investigated the effects of chronic intrathecal (IT) administration using enzyme replacement therapy (ERT) to the brain of an LINCL mouse model, in which locomotor function declines dramatically prior to early death. Median lifespan was significantly extended from 126 days to >259 days when chronic IT treatment was initiated before the onset of disease. While treated animals lived longer and showed little sign of locomotor dysfunction as measured by stride length, some or all (depending on regimen) still died prematurely. One explanation is that cerebrospinal fluid (CSF)-mediated delivery may not deliver TPP1 to all brain regions. Morphological studies support this, showing delivery of TPP1 to ventral, but not deeper and dorsal regions. When IT treatment is initiated in severely affected LINCL mice, lifespan was extended modestly in most but dramatically extended in approximately one-third of the cohort. Treatment improved locomotor function in these severely compromised animals after it had declined to the point at which animals normally die. This indicates that some pathology in LINCL is reversible and does not simply reflect neuronal death. PMID- 28345006 TI - Genome-wide Specificity of Highly Efficient TALENs and CRISPR/Cas9 for T Cell Receptor Modification. AB - In T cells with transgenic high-avidity T cell receptors (TCRs), endogenous and transferred TCR chains compete for surface expression and may pair inappropriately, potentially causing autoimmunity. To knock out endogenous TCR expression, we assembled 12 transcription activator-like effector nucleases (TALENs) and five guide RNAs (gRNAs) from the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas9) system. Using TALEN mRNA, TCR knockout was successful in up to 81% of T cells. Additionally, we were able to verify targeted gene addition of a GFP gene by homology-directed repair at the TALEN target site, using a donor suitable for replacement of the reporter transgene with therapeutic TCR chains. Remarkably, analysis of TALEN and CRISPR/Cas9 specificity using integrase-defective lentiviral vector capture revealed only one off-target site for one of the gRNAs and three off-target sites for both of the TALENs, indicating a high level of specificity. Collectively, our work shows highly efficient and specific nucleases for T cell engineering. PMID- 28345007 TI - Partial-occupancy binders identified by the Pan-Dataset Density Analysis method offer new chemical opportunities and reveal cryptic binding sites. AB - Crystallographic fragment screening uses low molecular weight compounds to probe the protein surface and although individual protein-fragment interactions are high quality, fragments commonly bind at low occupancy, historically making identification difficult. However, our new Pan-Dataset Density Analysis method readily identifies binders missed by conventional analysis: for fragment screening data of lysine-specific demethylase 4D (KDM4D), the hit rate increased from 0.9% to 10.6%. Previously unidentified fragments reveal multiple binding sites and demonstrate: the versatility of crystallographic fragment screening; that surprisingly large conformational changes are possible in crystals; and that low crystallographic occupancy does not by itself reflect a protein-ligand complex's significance. PMID- 28345008 TI - Insights into the mechanism of membrane pyrophosphatases by combining experiment and computer simulation. AB - Membrane-integral pyrophosphatases (mPPases) couple the hydrolysis of pyrophosphate (PPi) to the pumping of Na+, H+, or both these ions across a membrane. Recently solved structures of the Na+-pumping Thermotoga maritima mPPase (TmPPase) and H+-pumping Vigna radiata mPPase revealed the basis of ion selectivity between these enzymes and provided evidence for the mechanisms of substrate hydrolysis and ion-pumping. Our atomistic molecular dynamics (MD) simulations of TmPPase demonstrate that loop 5-6 is mobile in the absence of the substrate or substrate-analogue bound to the active site, explaining the lack of electron density for this loop in resting state structures. Furthermore, creating an apo model of TmPPase by removing ligands from the TmPPase:IDP:Na structure in MD simulations resulted in increased dynamics in loop 5-6, which results in this loop moving to uncover the active site, suggesting that interactions between loop 5-6 and the imidodiphosphate and its associated Mg2+ are important for holding a loop-closed conformation. We also provide further evidence for the transport before-hydrolysis mechanism by showing that the non-hydrolyzable substrate analogue, methylene diphosphonate, induces low levels of proton pumping by VrPPase. PMID- 28345009 TI - Optically induced lattice deformations, electronic structure changes, and enhanced superconductivity in YBa2Cu3O6.48. AB - Resonant optical excitation of apical oxygen vibrational modes in the normal state of underdoped YBa2Cu3O6+x induces a transient state with optical properties similar to those of the equilibrium superconducting state. Amongst these, a divergent imaginary conductivity and a plasma edge are transiently observed in the photo-stimulated state. Femtosecond hard x-ray diffraction experiments have been used in the past to identify the transient crystal structure in this non equilibrium state. Here, we start from these crystallographic features and theoretically predict the corresponding electronic rearrangements that accompany these structural deformations. Using density functional theory, we predict enhanced hole-doping of the CuO2 planes. The empty chain Cu dy2-z2 orbital is calculated to strongly reduce in energy, which would increase c-axis transport and potentially enhance the interlayer Josephson coupling as observed in the THz frequency response. From these results, we calculate changes in the soft x-ray absorption spectra at the Cu L-edge. Femtosecond x-ray pulses from a free electron laser are used to probe changes in absorption at two photon energies along this spectrum and provide data consistent with these predictions. PMID- 28345010 TI - Distortion dependent intersystem crossing: A femtosecond time-resolved photoelectron spectroscopy study of benzene, toluene, and p-xylene. AB - The competition between ultrafast intersystem crossing and internal conversion in benzene, toluene, and p-xylene is investigated with time-resolved photoelectron spectroscopy and quantum chemical calculations. By exciting to S2 out-of-plane symmetry breaking, distortions are activated at early times whereupon spin forbidden intersystem crossing becomes (partly) allowed. Natural bond orbital analysis suggests that the pinnacle carbon atoms distorting from the aromatic plane change hybridization between the planar Franck-Condon geometry and the deformed (boat-shaped) S2 equilibrium geometry. The effect is observed to increase in the presence of methyl-groups on the pinnacle carbon-atoms, where largest extents of sigma and pi orbital-mixing are observed. This is fully consistent with the time-resolved spectroscopy data: Toluene and p-xylene show evidence for ultrafast triplet formation competing with internal conversion, while benzene appears to only decay via internal conversion within the singlet manifold. For toluene and p-xylene, internal conversion to S1 and intersystem crossing to T3 occur within the time-resolution of our instrument. The receiver triplet state (T3) is found to undergo internal conversion in the triplet manifold within ~100-150 fs (toluene) or ~180-200 fs (p-xylene) as demonstrated by matching rise and decay components of upper and lower triplet states. Overall, the effect of methylation is found to both increase the intersystem crossing probability and direct the molecular axis of the excited state dynamics. PMID- 28345011 TI - Cross-Cultural Differences of the Non-Motor Symptoms Studied by the Traditional Chinese Version of the International Parkinson and Movement Disorder Society- Unified Parkinson's Disease Rating Scale. AB - BACKGROUND: Given the importance of ethnic differences in the evaluation of various aspects of symptoms in patients with Parkinson's disease (PD), we present the formal procedure for completing the traditional Chinese translation of the International and Parkinson and Movement Disorder Society/UPDRS (MDS-UPDRS) and highlight the discrepancy in nonmotor symptoms (NMS) between patients in Eastern and Western countries. METHODS: A total of 350 native Chinese-speaking PD patients were recruited from multiple hospitals in Eastern countries; they completed the MDS-UPDRS. The translation process was executed and factor analysis was performed to determine the structure of the scale. Chi-squared and t tests were used to compare frequency and severity of PD symptoms between the Chinese speaking and English-speaking groups (n = 876). RESULTS: NMS and motor symptoms were more severe in the Western population (Part I: t(1205) = 5.36, P < 0.0001; and Part III: t(1205) = 7.64, P < 0.0001); however, the prevalence of cognitive dysfunction and impairments in activities of daily living were more frequent in the Eastern patients. The comparative fit index was 0.93 or greater, and the exploratory factor analysis revealed compatible results between the translated scale and the original version. CONCLUSION: The traditional Chinese version of the MDS-UPDRS can be designated as an official translation of the original scale, and it is now available for use. Moreover, NMS in PD constitute a major issue worldwide, and the pattern of NMS among the Chinese population is more marked in terms of cognition-based symptoms and activities of daily living. PMID- 28345012 TI - Enhanced Telecom Emission from Single Group-IV Quantum Dots by Precise CMOS Compatible Positioning in Photonic Crystal Cavities. AB - Efficient coupling to integrated high-quality-factor cavities is crucial for the employment of germanium quantum dot (QD) emitters in future monolithic silicon based optoelectronic platforms. We report on strongly enhanced emission from single Ge QDs into L3 photonic crystal resonator (PCR) modes based on precise positioning of these dots at the maximum of the respective mode field energy density. Perfect site control of Ge QDs grown on prepatterned silicon-on insulator substrates was exploited to fabricate in one processing run almost 300 PCRs containing single QDs in systematically varying positions within the cavities. Extensive photoluminescence studies on this cavity chip enable a direct evaluation of the position-dependent coupling efficiency between single dots and selected cavity modes. The experimental results demonstrate the great potential of the approach allowing CMOS-compatible parallel fabrication of arrays of spatially matched dot/cavity systems for group-IV-based data transfer or quantum optical systems in the telecom regime. PMID- 28345013 TI - A Pilot Randomized Controlled Clinical Trial to Assess Tolerance and Efficacy of Navy Bean and Rice Bran Supplementation for Lowering Cholesterol in Children. AB - : Background: Navy beans and rice bran demonstrate efficacy to regulate serum cholesterol in hypercholesterolemic adults; however, the cardiovascular disease (CVD) protective properties of these foods in children are unknown and merit investigation. Objective: The objectives were to determine whether cooked navy bean powder (NBP) and/or heat-stabilized rice bran (RB) supplementation is tolerable, improves dietary fiber intake in children, and modulates lipid profiles. Methods: Children aged 8 to 13 years at risk for CVD due to abnormal lipids were recruited. Elevated cholesterol levels were defined as total cholesterol >=180 mg/dL and high-density lipoprotein (HDL) <60 mg/dL; low-density lipoprotein (LDL) >=100 mg/dL and HDL <60 mg/dL; or non-HDL >100 mg/dL and HDL <60 mg/dL. Participants completed a pilot 4-week, randomized controlled, 4-arm dietary intervention. They consumed study-provided muffins or a smoothie daily that included 0 g NBP or RB (control), 17.5 g NBP, 15 g RB, or a combination 9 g NBP + 8 g RB. Fasting blood was collected at baseline and week 4. Participants also completed 3-day food logs and gastrointestinal health questionnaires. RESULTS: Thirty-eight children completed the trial (n = 9 control, n = 10 NBP, n = 9 RB, and n = 10 NBP + RB groups). Only 3 participants withdrew due to noncompliance of required food consumption. Participants in the intervention groups significantly increased intake of NBP and RB at week 4 (p<=.01). The NBP and NBP + RB groups increased total fiber intake from baseline to week 4 (p=.02 and p=<.01, respectively). HDL-cholesterol was higher in NBP-group participants compared to control at week 4 (P = .02). Conclusion: Increasing NBP and/or RB intake is tolerable for children, and our findings suggest higher daily intakes are needed for a longer duration to induce favorable changes across multiple serum lipid parameters. PMID- 28345014 TI - The Cigarette and Smokeless Tobacco Markets in Texas Relative to the United States. AB - OBJECTIVE: This study compares the cigarette and smokeless tobacco (SLT) markets in Texas and the United States (US) as a whole. METHODS: Nielsen convenience store sales data from 2014 were obtained for Dallas, Houston, San Antonio/Austin, and the total US. Descriptive statistics highlighted market share differences in Texas compared to the US overall. RESULTS: Marlboro and Copenhagen dominated the cigarette (58.9%) and SLT markets (44.8%) in Texas and had substantially higher relative market shares in Texas than nationally (46.7% and 29.8%, respectively). Camel, with sales driven largely by its Camel Crush variety, held second place in Texas (9.8%), outselling Newport (6.6%), despite Newport's status as second best selling brand in the US (11.5%). Copenhagen led the SLT market in Texas, outselling Grizzly 2 to 1, yet the brands hold roughly equivalent shares nationally. Whereas flavored SLT products made up nearly 60% of the US SLT market, unflavored SLT (58.6%) dominated in Texas markets. Finally, sales of fine cut SLT in Texas were more than triple their national market share. CONCLUSIONS: Regional tobacco market share differences are likely influenced by multiple factors such as marketing, population demographics, culture, and neighboring communities. Policymakers are encouraged to develop local tobacco control policies and programs within the context of this knowledge. PMID- 28345017 TI - Proof of concept demonstration of optimal composite MRI endpoints for clinical trials. AB - BACKGROUND: Atrophy measures derived from structural MRI are promising outcome measures for early phase clinical trials, especially for rare diseases such as primary progressive aphasia (PPA), where the small available subject pool limits our ability to perform meaningfully powered trials with traditional cognitive and functional outcome measures. METHODS: We investigated a composite atrophy index in 26 PPA participants with longitudinal MRIs separated by two years. Rogalski et al. [Neurology 2014;83:1184-1191] previously demonstrated that atrophy of the left perisylvian temporal cortex (PSTC) is a highly sensitive measure of disease progression in this population and a promising endpoint for clinical trials. Using methods described by Ard et al. [Pharmaceutical Statistics 2015;14:418 426], we constructed a composite atrophy index composed of a weighted sum of volumetric measures of 10 regions of interest within the left perisylvian cortex using weights that maximize signal-to-noise and minimize sample size required of trials using the resulting score. Sample size required to detect a fixed percentage slowing in atrophy in a two-year clinical trial with equal allocation of subjects across arms and 90% power was calculated for the PSTC and optimal composite surrogate biomarker endpoints. RESULTS: The optimal composite endpoint required 38% fewer subjects to detect the same percent slowing in atrophy than required by the left PSTC endpoint. CONCLUSIONS: Optimal composites can increase the power of clinical trials and increase the probability that smaller trials are informative, an observation especially relevant for PPA, but also for related neurodegenerative disorders including Alzheimer's disease. PMID- 28345018 TI - The patient portal and abnormal test results: An exploratory study of patient experiences. AB - Many health care institutions are implementing patient portals that allow patients to track and maintain their personal health information, mostly in response to the Health Information Technology for Economic and Clinical Health Act requirements. Test results review is an area of high interest to patients and provides an opportunity to foster their involvement in preventing abnormal test results from being overlooked, a common patient safety concern. However, little is known about how patients engage with portals to review abnormal results and which strategies could facilitate that interaction in order to ensure safe follow up on abnormalities. The objective of this qualitative study was to explore patients' experiences related to abnormal test result notifications through patient portals. The authors conducted semi-structured telephone interviews with 13 participants, patients and primary caregivers, between February 2014 and October 2014. Using content analysis, the authors explored patient experiences accessing abnormal test results through their portals. Respondents strongly favored access to all types of abnormal test results, but they raised several concerns including need for more timely notification and not being able to interpret the exact relevance of the result. Respondents' personal experiences with physicians, test result notification, and the portal heavily influenced respondents' notification preferences. Patient experiences with portals could be improved by development of strategies to help patients understand and manage the information received. These findings suggest important considerations for health professionals and institutions aiming to better engage patients in follow-up of their test results. PMID- 28345016 TI - "By slapping their laps, the patient will know that you truly care for her": A qualitative study on social norms and acceptability of the mistreatment of women during childbirth in Abuja, Nigeria. AB - BACKGROUND: Many women experience mistreatment during childbirth in health facilities across the world. However, limited evidence exists on how social norms and attitudes of both women and providers influence mistreatment during childbirth. Contextually-specific evidence is needed to understand how normative factors affect how women are treated. This paper explores the acceptability of four scenarios of mistreatment during childbirth. METHODS: Two facilities were identified in Abuja, Nigeria. Qualitative methods (in-depth interviews (IDIs) and focus group discussions (FGDs)) were used with a purposive sample of women, midwives, doctors and administrators. Participants were presented with four scenarios of mistreatment during childbirth: slapping, verbal abuse, refusing to help the woman and physical restraint. Thematic analysis was used to synthesize findings, which were interpreted within the study context and an existing typology of mistreatment during childbirth. RESULTS: Eighty-four IDIs and 4 FGDs are included in this analysis. Participants reported witnessing and experiencing mistreatment during childbirth, including slapping, physical restraint to a delivery bed, shouting, intimidation, and threats of physical abuse or poor health outcomes. Some women and providers considered each of the four scenarios as mistreatment. Others viewed these scenarios as appropriate and acceptable measures to gain compliance from the woman and ensure a good outcome for the baby. Women and providers blamed a woman's "disobedience" and "uncooperativeness" during labor for her experience of mistreatment. CONCLUSIONS: Blaming women for mistreatment parallels the intimate partner violence literature, demonstrating how traditional practices and low status of women potentiate gender inequality. These findings can be used to facilitate dialogue in Nigeria by engaging stakeholders to discuss how to challenge these norms and hold providers accountable for their actions. Until women and their families are able to freely condemn poor quality care in facilities and providers are held accountable for their actions, there will be little incentive to foster change. PMID- 28345015 TI - Platelets and platelet alloantigens: Lessons from human patients and animal models of fetal and neonatal alloimmune thrombocytopenia. AB - Platelets play critical roles in hemostasis and thrombosis. Emerging evidence indicates that they are versatile cells and also involved in many other physiological processes and disease states. Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a life threatening bleeding disorder caused by fetal platelet destruction by maternal alloantibodies developed during pregnancy. Gene polymorphisms cause platelet surface protein incompatibilities between mother and fetus, and ultimately lead to maternal alloimmunization. FNAIT is the most common cause of intracranial hemorrhage in full-term infants and can also lead to intrauterine growth retardation and miscarriage. Proper diagnosis, prevention and treatment of FNAIT is challenging due to insufficient knowledge of the disease and a lack of routine screening as well as its frequent occurrence in first pregnancies. Given the ethical difficulties in performing basic research on human fetuses and neonates, animal models are essential to improve our understanding of the pathogenesis and treatment of FNAIT. The aim of this review is to provide an overview on platelets, hemostasis and thrombocytopenia with a focus on the advancements made in FNAIT by utilizing animal models. PMID- 28345019 TI - A vision for using online portals for surveillance of patient-centered communication in cancer care. AB - The Veterans Health Administration (VHA) is charged with providing high-quality health care, not only in terms of technical competence but also with regard to patient-centered care experiences. Patient-centered coordination of care and communication are especially important in cancer care, as deficiencies in these areas have been implicated in many cases of delayed cancer diagnosis and treatment. Additionally, because cancer care facilities are concentrated within the VHA system, geographical and system-level barriers may present prominent obstacles to quality care. Systematic assessment of patient-centered communication (PCC) may help identify both individual veterans who are at risk of suboptimal care and opportunities for quality improvement initiatives at the service, facility, or system-wide level. In this manuscript, we describe our vision to implement an assessment of PCC through patient self-report to improve the quality of cancer care and other health services in the VHA. We outline a possible strategy to assess PCC that leverages the VHA's existing initiative to promote use of an online personal health record for veterans (MyHealtheVet). Questionnaires administered periodically or following specific episodes of care can be targeted to assess PCC in cancer care. Assessment of PCC can also be tied to clinical and administrative data for more robust analysis of patient outcomes. Ultimately, the goal of any assessment of PCC is to gather valid, actionable data that can assist VHA clinicians and staff with providing the best possible care for veterans with cancer. PMID- 28345021 TI - Oncolytic Group B Adenovirus Enadenotucirev Mediates Non-apoptotic Cell Death with Membrane Disruption and Release of Inflammatory Mediators. AB - Enadenotucirev (EnAd) is a chimeric group B adenovirus isolated by bioselection from a library of adenovirus serotypes. It replicates selectively in and kills a diverse range of carcinoma cells, shows effective anticancer activity in preclinical systems, and is currently undergoing phase I/II clinical trials. EnAd kills cells more quickly than type 5 adenovirus, and speed of cytotoxicity is dose dependent. The EnAd death pathway does not involve p53, is predominantly caspase independent, and appears to involve a rapid fall in cellular ATP. Infected cells show early loss of membrane integrity; increased exposure of calreticulin; extracellular release of ATP, HSP70, and HMGB1; and influx of calcium. The virus also causes an obvious single membrane blister reminiscent of ischemic cell death by oncosis. In human tumor biopsies maintained in ex vivo culture, EnAd mediated release of pro-inflammatory mediators such as TNF-alpha, IL-6, and HMGB1. In accordance with this, EnAd-infected tumor cells showed potent stimulation of dendritic cells and CD4+ T cells in a mixed tumor-leukocyte reaction in vitro. Whereas many viruses have evolved for efficient propagation with minimal inflammation, bioselection of EnAd for rapid killing has yielded a virus with a short life cycle that combines potent cytotoxicity with a proinflammatory mechanism of cell death. PMID- 28345020 TI - Bacterial Carriers for Glioblastoma Therapy. AB - Treatment of aggressive glioblastoma brain tumors is challenging, largely due to diffusion barriers preventing efficient drug dosing to tumors. To overcome these barriers, bacterial carriers that are actively motile and programmed to migrate and localize to tumor zones were designed. These carriers can induce apoptosis via hypoxia-controlled expression of a tumor suppressor protein p53 and a pro apoptotic drug, Azurin. In a xenograft model of human glioblastoma in rats, bacterial carrier therapy conferred a significant survival benefit with 19% overall long-term survival of >100 days in treated animals relative to a median survival of 26 days in control untreated animals. Histological and proteomic analyses were performed to elucidate the safety and efficacy of these carriers, showing an absence of systemic toxicity and a restored neural environment in treated responders. In the treated non-responders, proteomic analysis revealed competing mechanisms of pro-apoptotic and drug-resistant activity. This bacterial carrier opens a versatile avenue to overcome diffusion barriers in glioblastoma by virtue of its active motility in extracellular space and can lead to tailored therapies via tumor-specific expression of tumoricidal proteins. PMID- 28345022 TI - Ex Vivo Oncolytic Virotherapy with Myxoma Virus Arms Multiple Allogeneic Bone Marrow Transplant Leukocytes to Enhance Graft versus Tumor. AB - Allogeneic stem cell transplant-derived T cells have the potential to seek and eliminate sites of residual cancer that escaped primary therapy. Oncolytic myxoma virus (MYXV) exhibits potent anti-cancer efficacy against human cancers like multiple myeloma (MM) and can arm transplant-derived T cells to become more effective cancer killers in vitro and in an immunodeficient xenotransplant murine model. Here, we tested ex vivo MYXV virotherapy against residual murine MM in immunocompetent mice using an allogeneic mouse-mouse model. In contrast to all human MM cell lines previously tested, the murine MM cell line tested here was highly resistant to direct MYXV infection and oncolysis in vitro. Despite this in vitro resistance, we found that ex vivo MYXV-armed allogeneic bone marrow (BM) transplantation dramatically ablated pre-seeded residual MM in vivo. Unexpectedly, we show that both neutrophils and activated T cells from the donor function as virus-armed carrier cells, and MYXV-preloaded cells enhanced MM killing. Our results demonstrate a novel therapeutic paradigm for residual cancer, in which multiple classes of allotransplant leukocytes can be armed by MYXV ex vivo to enhance the graft-versus-tumor effects. PMID- 28345023 TI - Enhancement of PSMA-Directed CAR Adoptive Immunotherapy by PD-1/PD-L1 Blockade. AB - Chimeric antigen receptor (CAR) T cell therapy in hematologic malignancies has shown remarkable responses, but the same level of success has not been observed in solid tumors. A new prostate cancer model (Myc-CaP:PSMA(+)) and a second generation anti-hPSMA human CAR T cells expressing a Click Beetle Red luciferase reporter) were used to study hPSMA targeting and assess CAR T cell trafficking and persistence by bioluminescence imaging (BLI). We investigated the antitumor efficacy of human CAR T cells targeting human prostate-specific membrane antigen (hPSMA), in the presence and absence of the target antigen; first alone and then combined with a monoclonal antibody targeting the human programmed death receptor 1 (anti-hPD1 mAb). PDL-1 expression was detected in Myc-CaP murine prostate tumors growing in immune competent FVB/N and immune-deficient SCID mice. Endogenous CD3+ T cells were restricted from the centers of Myc-CaP tumor nodules growing in FVB/N mice. Following anti-programmed cell death protein 1 (PD-1) treatment, the restriction of CD3+ T cells was reversed, and a tumor-treatment response was observed. Adoptive hPSMA-CAR T cell immunotherapy was enhanced when combined with PD-1 blockade, but the treatment response was of comparatively short duration, suggesting other immune modulation mechanisms exist and restrict CAR T cell targeting, function, and persistence in hPSMA expressing Myc-CaP tumors. Interestingly, an "inverse pattern" of CAR T cell BLI intensity was observed in control and test tumors, which suggests CAR T cells undergo changes leading to a loss of signal and/or number following hPSMA-specific activation. The lower BLI signal intensity in the hPSMA test tumors (compared with controls) is due in part to a decrease in T cell mitochondrial function following T cell activation, which may limit the intensity of the ATP-dependent Luciferin luciferase bioluminescence signal. PMID- 28345024 TI - OvAd1, a Novel, Potent, and Selective Chimeric Oncolytic Virus Developed for Ovarian Cancer by 3D-Directed Evolution. AB - Effective therapeutics for ovarian cancer continue to be urgently needed, particularly for chemotherapy-resistant cases. Here we present both a 3D-Matrigel culture-based expansion of our directed evolution method for generation of oncolytic virotherapies and two promising ovarian-cancer targeted oncolytic viruses, OvAd1 and OvAd2. OvAd1 was developed using Matrigel cell cultures, whereas OvAd2 was developed in parallel using traditional monolayer tissue culture methods. Both viruses are potent against a panel of platinum-resistant ovarian cancer cell lines and are attenuated on normal cells in vitro, resulting in therapeutic windows of ~200-fold. We observed two benefits of the use of Matrigel-based cultures for directed evolution of these oncolytics: (1) use of Matrigel generated a bioselected pool that was more strongly attenuated on normal cells while retaining its potency against ovarian cancer cells, and (2) in an ovarian carcinomatosis model, the Matrigel-derived virus OvAd1 suppressed all tumor growth while the non-Matrigel-derived virus was 50% effective. Neither virus stimulated formation of peritoneal adhesions as seen for Ad5-based therapies. Consequently, these viruses are novel candidates for development as new effective treatments for aggressive ovarian cancer. PMID- 28345025 TI - Optimization of a Neural Stem-Cell-Mediated Carboxylesterase/Irinotecan Gene Therapy for Metastatic Neuroblastoma. AB - Despite improved survival for children with newly diagnosed neuroblastoma (NB), recurrent disease is a significant problem, with treatment options limited by anti-tumor efficacy, patient drug tolerance, and cumulative toxicity. We previously demonstrated that neural stem cells (NSCs) expressing a modified rabbit carboxylesterase (rCE) can distribute to metastatic NB tumor foci in multiple organs in mice and convert the prodrug irinotecan (CPT-11) to the 1,000 fold more toxic topoisomerase-1 inhibitor SN-38, resulting in significant therapeutic efficacy. We sought to extend these studies by using a clinically relevant NSC line expressing a modified human CE (hCE1m6-NSCs) to establish proof of concept and identify an intravenous dose and treatment schedule that gave maximal efficacy. Human-derived NB cell lines were significantly more sensitive to treatment with hCE1m6-NSCs and irinotecan as compared with drug alone. This was supported by pharmacokinetic studies in subcutaneous NB mouse models demonstrating tumor-specific conversion of irinotecan to SN-38. Furthermore, NB bearing mice that received repeat treatment with intravenous hCE1m6-NSCs and irinotecan showed significantly lower tumor burden (1.4-fold, p = 0.0093) and increased long-term survival compared with mice treated with drug alone. These studies support the continued development of NSC-mediated gene therapy for improved clinical outcome in NB patients. PMID- 28345026 TI - Oncolytic Adenoviruses Armed with Tumor Necrosis Factor Alpha and Interleukin-2 Enable Successful Adoptive Cell Therapy. AB - Adoptive cell therapy holds much promise in the treatment of cancer but results in solid tumors have been modest. The notable exception is tumor-infiltrating lymphocyte (TIL) therapy of melanoma, but this approach only works with high-dose preconditioning chemotherapy and systemic interleukin (IL)-2 postconditioning, both of which are associated with toxicities. To improve and broaden the applicability of adoptive cell transfer, we constructed oncolytic adenoviruses coding for human IL-2 (hIL2), tumor necrosis factor alpha (TNF-alpha), or both. The viruses showed potent antitumor efficacy against human tumors in immunocompromised severe combined immunodeficiency (SCID) mice. In immunocompetent Syrian hamsters, we combined the viruses with TIL transfer and were able to cure 100% of the animals. Cured animals were protected against tumor re-challenge, indicating a memory response. Arming with IL-2 and TNF-alpha increased the frequency of both CD4+ and CD8+ TILs in vivo and augmented splenocyte proliferation ex vivo, suggesting that the cytokines were important for T cell persistence and proliferation. Cytokine expression was limited to tumors and treatment-related signs of systemic toxicity were absent, suggesting safety. To conclude, cytokine-armed oncolytic adenoviruses enhanced adoptive cell therapy by favorable alteration of the tumor microenvironment. A clinical trial is in progress to study the utility of Ad5/3-E2F-d24-hTNFa-IRES-hIL2 (TILT-123) in human patients with cancer. PMID- 28345027 TI - Pre-clinical Assessment of C134, a Chimeric Oncolytic Herpes Simplex Virus, in Mice and Non-human Primates. AB - Oncolytic herpes simplex virus (oHSV) type I constructs are investigational anti neoplastic agents for a variety of malignancies, including malignant glioma. Clinical trials to date have supported the safety of these agents even when directly administered in the CNS. Traditional pre-clinical US Food and Drug Administration (FDA) toxicity studies for these agents have included the use of two species, generally including murine and primate studies. Recently, the FDA has decreased its requirement of non-human primates as an animal model for ethical reasons, especially for established viral systems where there are good alternative model systems. Here we present data demonstrating the safety of C134, a chimeric oHSV construct, in CBA mice as well as in a limited number of the HSV sensitive non-human primate Aotus nancymaae as a proposed agent for clinical trials. These data, along with the previously conducted clinical trials of oHSV constructs, support the use of the CBA mouse model as sufficient for the pre clinical toxicity studies of this agent. We summarize our experience with different HSV recombinants and differences between them using multiple assays to assess neurovirulence, as well as our experience with C134 in a limited number of A. nancymaae. PMID- 28345028 TI - Self-powered integrated microfluidic point-of-care low-cost enabling (SIMPLE) chip. AB - Portable, low-cost, and quantitative nucleic acid detection is desirable for point-of-care diagnostics; however, current polymerase chain reaction testing often requires time-consuming multiple steps and costly equipment. We report an integrated microfluidic diagnostic device capable of on-site quantitative nucleic acid detection directly from the blood without separate sample preparation steps. First, we prepatterned the amplification initiator [magnesium acetate (MgOAc)] on the chip to enable digital nucleic acid amplification. Second, a simplified sample preparation step is demonstrated, where the plasma is separated autonomously into 224 microwells (100 nl per well) without any hemolysis. Furthermore, self-powered microfluidic pumping without any external pumps, controllers, or power sources is accomplished by an integrated vacuum battery on the chip. This simple chip allows rapid quantitative digital nucleic acid detection directly from human blood samples (10 to 105 copies of methicillin resistant Staphylococcus aureus DNA per microliter, ~30 min, via isothermal recombinase polymerase amplification). These autonomous, portable, lab-on-chip technologies provide promising foundations for future low-cost molecular diagnostic assays. PMID- 28345029 TI - Tidal heat pulses on a reef trigger a fine-tuned transcriptional response in corals to maintain homeostasis. AB - For reef-building corals, extreme stress exposure can result in loss of endosymbionts, leaving colonies bleached. However, corals in some habitats are commonly exposed to natural cycles of sub-bleaching stress, often leading to higher stress tolerance. We monitored transcription in the tabletop coral Acropora hyacinthus daily for 17 days over a strong tidal cycle that included extreme temperature spikes, and show that increases in temperature above 30.5 degrees C triggered a strong transcriptional response. The transcriptomic time series data allowed us to identify a set of genes with coordinated expression that were activated only on days with strong tides, high temperature, and large diel pH and oxygen changes. The responsive genes are enriched for gene products essential to the unfolded protein response, an ancient cellular response to endoplasmic reticulum stress. After the temporary heat pulses passed, expression of these genes immediately decreased, suggesting that homeostasis was restored to the endoplasmic reticulum. In a laboratory temperature stress experiment, we found that the expression of these environmentally responsive genes increased as corals bleached, showing that the unfolded protein response becomes more intense during more severe stress. Our results point to the unfolded protein response as a first line of defense that acroporid corals use when coping with environmental stress on the reef, thus enhancing our understanding of coral stress physiology during a time of major concern for reefs. PMID- 28345030 TI - Wearable/disposable sweat-based glucose monitoring device with multistage transdermal drug delivery module. AB - Electrochemical analysis of sweat using soft bioelectronics on human skin provides a new route for noninvasive glucose monitoring without painful blood collection. However, sweat-based glucose sensing still faces many challenges, such as difficulty in sweat collection, activity variation of glucose oxidase due to lactic acid secretion and ambient temperature changes, and delamination of the enzyme when exposed to mechanical friction and skin deformation. Precise point-of care therapy in response to the measured glucose levels is still very challenging. We present a wearable/disposable sweat-based glucose monitoring device integrated with a feedback transdermal drug delivery module. Careful multilayer patch design and miniaturization of sensors increase the efficiency of the sweat collection and sensing process. Multimodal glucose sensing, as well as its real-time correction based on pH, temperature, and humidity measurements, maximizes the accuracy of the sensing. The minimal layout design of the same sensors also enables a strip-type disposable device. Drugs for the feedback transdermal therapy are loaded on two different temperature-responsive phase change nanoparticles. These nanoparticles are embedded in hyaluronic acid hydrogel microneedles, which are additionally coated with phase change materials. This enables multistage, spatially patterned, and precisely controlled drug release in response to the patient's glucose level. The system provides a novel closed-loop solution for the noninvasive sweat-based management of diabetes mellitus. PMID- 28345031 TI - Repetitive mammalian dwarfing during ancient greenhouse warming events. AB - Abrupt perturbations of the global carbon cycle during the early Eocene are associated with rapid global warming events, which are analogous in many ways to present greenhouse warming. Mammal dwarfing has been observed, along with other changes in community structure, during the largest of these ancient global warming events, known as the Paleocene-Eocene Thermal Maximum [PETM; ~56 million years ago (Ma)]. We show that mammalian dwarfing accompanied the subsequent, smaller-magnitude warming event known as Eocene Thermal Maximum 2 [ETM2 (~53 Ma)]. Statistically significant decrease in body size during ETM2 is observed in two of four taxonomic groups analyzed in this study and is most clearly observed in early equids (horses). During ETM2, the best-sampled lineage of equids decreased in size by ~14%, as opposed to ~30% during the PETM. Thus, dwarfing appears to be a common evolutionary response of some mammals during past global warming events, and the extent of dwarfing seems related to the magnitude of the event. PMID- 28345032 TI - Agrobacterium delivers VirE2 protein into host cells via clathrin-mediated endocytosis. AB - Agrobacterium tumefaciens can cause crown gall tumors on a wide range of host plants. As a natural genetic engineer, the bacterium can transfer both single stranded DNA (ssDNA) [transferred DNA (T-DNA)] molecules and bacterial virulence proteins into various recipient cells. Among Agrobacterium-delivered proteins, VirE2 is an ssDNA binding protein that is involved in various steps of the transformation process. However, it is not clear how plant cells receive the T DNA or protein molecules. Using a split-green fluorescent protein approach, we monitored the VirE2 delivery process inside plant cells in real time. We observed that A. tumefaciens delivered VirE2 from the bacterial lateral sides that were in close contact with plant membranes. VirE2 initially accumulated on plant cytoplasmic membranes at the entry points. VirE2-containing membranes were internalized through clathrin-mediated endocytosis to form endomembrane compartments. VirE2 colocalized with the early endosome marker SYP61 but not with the late endosome marker ARA6, suggesting that VirE2 escaped from early endosomes for subsequent trafficking inside the cells. Dual endocytic motifs at the carboxyl-terminal tail of VirE2 were involved in VirE2 internalization and could interact with the MU subunit of the plant clathrin-associated adaptor AP2 complex (AP2M). Both the VirE2 cargo motifs and AP2M were important for the transformation process. Because AP2-mediated endocytosis is well conserved, our data suggest that the A. tumefaciens pathogen hijacks conserved endocytic pathways to facilitate the delivery of virulence factors. This might be important for Agrobacterium to achieve both a wide host range and a high transformation efficiency. PMID- 28345033 TI - Improved estimates of ocean heat content from 1960 to 2015. AB - Earth's energy imbalance (EEI) drives the ongoing global warming and can best be assessed across the historical record (that is, since 1960) from ocean heat content (OHC) changes. An accurate assessment of OHC is a challenge, mainly because of insufficient and irregular data coverage. We provide updated OHC estimates with the goal of minimizing associated sampling error. We performed a subsample test, in which subsets of data during the data-rich Argo era are colocated with locations of earlier ocean observations, to quantify this error. Our results provide a new OHC estimate with an unbiased mean sampling error and with variability on decadal and multidecadal time scales (signal) that can be reliably distinguished from sampling error (noise) with signal-to-noise ratios higher than 3. The inferred integrated EEI is greater than that reported in previous assessments and is consistent with a reconstruction of the radiative imbalance at the top of atmosphere starting in 1985. We found that changes in OHC are relatively small before about 1980; since then, OHC has increased fairly steadily and, since 1990, has increasingly involved deeper layers of the ocean. In addition, OHC changes in six major oceans are reliable on decadal time scales. All ocean basins examined have experienced significant warming since 1998, with the greatest warming in the southern oceans, the tropical/subtropical Pacific Ocean, and the tropical/subtropical Atlantic Ocean. This new look at OHC and EEI changes over time provides greater confidence than previously possible, and the data sets produced are a valuable resource for further study. PMID- 28345034 TI - From time-resolved atomic-scale imaging of individual donors to their cooperative dynamics. AB - The key elements in the steady miniaturization process of cutting-edge semiconductor devices are the understanding and controlling of charge dynamics on the atomic scale. In detail, we address the study of charging processes of individual doping atoms and, especially, the interaction of those atoms with their surroundings. We use pulsed optical excitation in combination with scanning tunneling microscopy at the n-doped gallium arsenide [GaAs(110)] surface to investigate single donor dynamics within a nanoscaled, localized space charge region. Tuning the tunnel rate can drive the system into nonequilibrium conditions, allowing distinction between the decay of optically induced free charge carriers and the decay of donor charge states. The latter process is atomically resolved and discussed with respect to donor-level binding energies and local donor configurations. PMID- 28345036 TI - Abundant off-fault seismicity and orthogonal structures in the San Jacinto fault zone. AB - The trifurcation area of the San Jacinto fault zone has produced more than 10% of all earthquakes in southern California since 2000, including the June 2016 Mw (moment magnitude) 5.2 Borrego Springs earthquake. In this area, the fault splits into three subparallel strands and is associated with broad VP /VS anomalies. We synthesize spatiotemporal properties of historical background seismicity and aftershocks of the June 2016 event. A template matching technique is used to detect and locate more than 23,000 aftershocks, which illuminate highly complex active fault structures in conjunction with a high-resolution regional catalog. The hypocenters form dipping seismicity lineations both along strike and nearly orthogonal to the main fault, and are composed of interlaced strike-slip and normal faults. The primary faults change dip with depth and become listric by transitioning to a dip of ~70 degrees near a depth of 10 km. The Mw 5.2 Borrego Springs earthquake and past events with M > 4.0 occurred on the main faults, whereas most of the low-magnitude events are located in a damage zone (several kilometers wide) at seismogenic depths. The lack of significant low-magnitude seismicity on the main fault traces suggests that they do not creep. The very high rate of aftershocks likely reflects the large geometrical fault complexity and perhaps a relatively high stress due to a significant length of time elapsed since the last major event. The results provide important insights into the physics of faulting near the brittle-ductile transition. PMID- 28345035 TI - Terrestrial support of lake food webs: Synthesis reveals controls over cross ecosystem resource use. AB - Widespread evidence that organic matter exported from terrestrial into aquatic ecosystems supports recipient food webs remains controversial. A pressing question is not only whether high terrestrial support is possible but also what the general conditions are under which it arises. We assemble the largest data set, to date, of the isotopic composition (delta2H, delta13C, and delta15N) of lake zooplankton and the resources at the base of their associated food webs. In total, our data set spans 559 observations across 147 lakes from the boreal to subtropics. By predicting terrestrial resource support from within-lake and catchment-level characteristics, we found that half of all consumer observations that is, the median were composed of at least 42% terrestrially derived material. In general, terrestrial support of zooplankton was greatest in lakes with large physical and hydrological connections to catchments that were rich in aboveground and belowground organic matter. However, some consumers responded less strongly to terrestrial resources where within-lake production was elevated. Our study shows that multiple mechanisms drive widespread cross-ecosystem support of aquatic consumers across Northern Hemisphere lakes and suggests that changes in terrestrial landscapes will influence ecosystem processes well beyond their boundaries. PMID- 28345037 TI - Pure climb creep mechanism drives flow in Earth's lower mantle. AB - At high pressure prevailing in the lower mantle, lattice friction opposed to dislocation glide becomes very high, as reported in recent experimental and theoretical studies. We examine the consequences of this high resistance to plastic shear exhibited by ringwoodite and bridgmanite on creep mechanisms under mantle conditions. To evaluate the consequences of this effect, we model dislocation creep by dislocation dynamics. The calculation yields to an original dominant creep behavior for lower mantle silicates where strain is produced by dislocation climb, which is very different from what can be activated under high stresses under laboratory conditions. This mechanism, named pure climb creep, is grain-size-insensitive and produces no crystal preferred orientation. In comparison to the previous considered diffusion creep mechanism, it is also a more efficient strain-producing mechanism for grain sizes larger than ca. 0.1 mm. The specificities of pure climb creep well match the seismic anisotropy observed of Earth's lower mantle. PMID- 28345038 TI - Ultra-robust high-field magnetization plateau and supersolidity in bond frustrated MnCr2S4. AB - Frustrated magnets provide a promising avenue for realizing exotic quantum states of matter, such as spin liquids and spin ice or complex spin molecules. Under an external magnetic field, frustrated magnets can exhibit fractional magnetization plateaus related to definite spin patterns stabilized by field-induced lattice distortions. Magnetization and ultrasound experiments in MnCr2S4 up to 60 T reveal two fascinating features: (i) an extremely robust magnetization plateau with an unusual spin structure and (ii) two intermediate phases, indicating possible realizations of supersolid phases. The magnetization plateau characterizes fully polarized chromium moments, without any contributions from manganese spins. At 40 T, the middle of the plateau, a regime evolves, where sound waves propagate almost without dissipation. The external magnetic field exactly compensates the Cr-Mn exchange field and decouples Mn and Cr sublattices. In analogy to predictions of quantum lattice-gas models, the changes of the spin order of the manganese ions at the phase boundaries of the magnetization plateau are interpreted as transitions to supersolid phases. PMID- 28345039 TI - Female brain size affects the assessment of male attractiveness during mate choice. AB - Mate choice decisions are central in sexual selection theory aimed to understand how sexual traits evolve and their role in evolutionary diversification. We test the hypothesis that brain size and cognitive ability are important for accurate assessment of partner quality and that variation in brain size and cognitive ability underlies variation in mate choice. We compared sexual preference in guppy female lines selected for divergence in relative brain size, which we have previously shown to have substantial differences in cognitive ability. In a dichotomous choice test, large-brained and wild-type females showed strong preference for males with color traits that predict attractiveness in this species. In contrast, small-brained females showed no preference for males with these traits. In-depth analysis of optomotor response to color cues and gene expression of key opsins in the eye revealed that the observed differences were not due to differences in visual perception of color, indicating that differences in the ability to process indicators of attractiveness are responsible. We thus provide the first experimental support that individual variation in brain size affects mate choice decisions and conclude that differences in cognitive ability may be an important underlying mechanism behind variation in female mate choice. PMID- 28345040 TI - A highly stretchable, transparent, and conductive polymer. AB - Previous breakthroughs in stretchable electronics stem from strain engineering and nanocomposite approaches. Routes toward intrinsically stretchable molecular materials remain scarce but, if successful, will enable simpler fabrication processes, such as direct printing and coating, mechanically robust devices, and more intimate contact with objects. We report a highly stretchable conducting polymer, realized with a range of enhancers that serve a dual function: (i) they change morphology and (ii) they act as conductivity-enhancing dopants in poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS). The polymer films exhibit conductivities comparable to the best reported values for PEDOT:PSS, with over 3100 S/cm under 0% strain and over 4100 S/cm under 100% strain-among the highest for reported stretchable conductors. It is highly durable under cyclic loading, with the conductivity maintained at 3600 S/cm even after 1000 cycles to 100% strain. The conductivity remained above 100 S/cm under 600% strain, with a fracture strain of 800%, which is superior to even the best silver nanowire- or carbon nanotube-based stretchable conductor films. The combination of excellent electrical and mechanical properties allowed it to serve as interconnects for field-effect transistor arrays with a device density that is five times higher than typical lithographically patterned wavy interconnects. PMID- 28345041 TI - One-pot synthesis of amino acid precursors with insoluble organic matter in planetesimals with aqueous activity. AB - The exogenous delivery of organic molecules could have played an important role in the emergence of life on the early Earth. Carbonaceous chondrites are known to contain indigenous amino acids as well as various organic compounds and complex macromolecular materials, such as the so-called insoluble organic matter (IOM), but the origins of the organic matter are still subject to debate. We report that the water-soluble amino acid precursors are synthesized from formaldehyde, glycolaldehyde, and ammonia with the presence of liquid water, simultaneously with macromolecular organic solids similar to the chondritic IOM. Amino acid products from hydrothermal experiments after acid hydrolysis include alpha-, beta , and gamma-amino acids up to five carbons, for which relative abundances are similar to those extracted from carbonaceous chondrites. One-pot aqueous processing from simple ubiquitous molecules can thus produce a wide variety of meteoritic organic matter from amino acid precursors to macromolecular IOM in chondrite parent bodies. PMID- 28345043 TI - Anomalous photovoltaic effect in organic-inorganic hybrid perovskite solar cells. AB - Organic-inorganic hybrid perovskites (OIHPs) have been demonstrated to be highly successful photovoltaic materials yielding very-high-efficiency solar cells. We report the room temperature observation of an anomalous photovoltaic (APV) effect in lateral structure OIHP devices manifested by the device's open-circuit voltage (VOC) that is much larger than the bandgap of OIHPs. The persistent VOC is proportional to the electrode spacing, resembling that of ferroelectric photovoltaic devices. However, the APV effect in OIHP devices is not caused by ferroelectricity. The APV effect can be explained by the formation of tunneling junctions randomly dispersed in the polycrystalline films, which allows the accumulation of photovoltage at a macroscopic level. The formation of internal tunneling junctions as a result of ion migration is visualized with Kelvin probe force microscopy scanning. This observation points out a new avenue for the formation of large and continuously tunable VOC without being limited by the materials' bandgap. PMID- 28345044 TI - Continental igneous rock composition: A major control of past global chemical weathering. AB - The composition of igneous rocks in the continental crust has changed throughout Earth's history. However, the impact of these compositional variations on chemical weathering, and by extension on seawater and atmosphere evolution, is largely unknown. We use the strontium isotope ratio in seawater [(87Sr/86Sr)seawater] as a proxy for chemical weathering, and we test the sensitivity of (87Sr/86Sr)seawater variations to the strontium isotopic composition (87Sr/86Sr) in igneous rocks generated through time. We demonstrate that the 87Sr/86Sr ratio in igneous rocks is correlated to the epsilon hafnium (epsilonHf) of their hosted zircon grains, and we use the detrital zircon record to reconstruct the evolution of the 87Sr/86Sr ratio in zircon-bearing igneous rocks. The reconstructed 87Sr/86Sr variations in igneous rocks are strongly correlated with the (87Sr/86Sr)seawater variations over the last 1000 million years, suggesting a direct control of the isotopic composition of silicic magmatism on (87Sr/86Sr)seawater variations. The correlation decreases during several time periods, likely reflecting changes in the chemical weathering rate associated with paleogeographic, climatic, or tectonic events. We argue that for most of the last 1000 million years, the (87Sr/86Sr)seawater variations are responding to changes in the isotopic composition of silicic magmatism rather than to changes in the global chemical weathering rate. We conclude that the (87Sr/86Sr)seawater variations are of limited utility to reconstruct changes in the global chemical weathering rate in deep times. PMID- 28345042 TI - Human genetic and metabolite variation reveals that methylthioadenosine is a prognostic biomarker and an inflammatory regulator in sepsis. AB - Sepsis is a deleterious inflammatory response to infection with high mortality. Reliable sepsis biomarkers could improve diagnosis, prognosis, and treatment. Integration of human genetics, patient metabolite and cytokine measurements, and testing in a mouse model demonstrate that the methionine salvage pathway is a regulator of sepsis that can accurately predict prognosis in patients. Pathway based genome-wide association analysis of nontyphoidal Salmonella bacteremia showed a strong enrichment for single-nucleotide polymorphisms near the components of the methionine salvage pathway. Measurement of the pathway's substrate, methylthioadenosine (MTA), in two cohorts of sepsis patients demonstrated increased plasma MTA in nonsurvivors. Plasma MTA was correlated with levels of inflammatory cytokines, indicating that elevated MTA marks a subset of patients with excessive inflammation. A machine-learning model combining MTA and other variables yielded approximately 80% accuracy (area under the curve) in predicting death. Furthermore, mice infected with Salmonella had prolonged survival when MTA was administered before infection, suggesting that manipulating MTA levels could regulate the severity of the inflammatory response. Our results demonstrate how combining genetic data, biomolecule measurements, and animal models can shape our understanding of disease and lead to new biomarkers for patient stratification and potential therapeutic targeting. PMID- 28345045 TI - Bend, stretch, and touch: Locating a finger on an actively deformed transparent sensor array. AB - The development of bendable, stretchable, and transparent touch sensors is an emerging technological goal in a variety of fields, including electronic skin, wearables, and flexible handheld devices. Although transparent tactile sensors based on metal mesh, carbon nanotubes, and silver nanowires demonstrate operation in bent configurations, we present a technology that extends the operation modes to the sensing of finger proximity including light touch during active bending and even stretching. This is accomplished using stretchable and ionically conductive hydrogel electrodes, which project electric field above the sensor to couple with and sense a finger. The polyacrylamide electrodes are embedded in silicone. These two widely available, low-cost, transparent materials are combined in a three-step manufacturing technique that is amenable to large-area fabrication. The approach is demonstrated using a proof-of-concept 4 * 4 cross grid sensor array with a 5-mm pitch. The approach of a finger hovering a few centimeters above the array is readily detectable. Light touch produces a localized decrease in capacitance of 15%. The movement of a finger can be followed across the array, and the location of multiple fingers can be detected. Touch is detectable during bending and stretch, an important feature of any wearable device. The capacitive sensor design can be made more or less sensitive to bending by shifting it relative to the neutral axis. Ultimately, the approach is adaptable to the detection of proximity, touch, pressure, and even the conformation of the sensor surface. PMID- 28345046 TI - Canopy near-infrared reflectance and terrestrial photosynthesis. AB - Global estimates of terrestrial gross primary production (GPP) remain highly uncertain, despite decades of satellite measurements and intensive in situ monitoring. We report a new approach for quantifying the near-infrared reflectance of terrestrial vegetation (NIRV). NIRV provides a foundation for a new approach to estimate GPP that consistently untangles the confounding effects of background brightness, leaf area, and the distribution of photosynthetic capacity with depth in canopies using existing moderate spatial and spectral resolution satellite sensors. NIRV is strongly correlated with solar-induced chlorophyll fluorescence, a direct index of photons intercepted by chlorophyll, and with site-level and globally gridded estimates of GPP. NIRV makes it possible to use existing and future reflectance data as a starting point for accurately estimating GPP. PMID- 28345047 TI - Molecular beam brightening by shock-wave suppression. AB - Supersonic beams are a prevalent source of cold molecules used in the study of chemical reactions, atom interferometry, gas-surface interactions, precision spectroscopy, molecular cooling, and more. The triumph of this method emanates from the high densities produced in relation to other methods; however, beam density remains fundamentally limited by interference with shock waves reflected from collimating surfaces. We show experimentally that this shock interaction can be reduced or even eliminated by cryocooling the interacting surface. An increase of nearly an order of magnitude in beam density was measured at the lowest surface temperature, with no further fundamental limitation reached. Visualization of the shock waves by plasma discharge and reproduction with direct simulation Monte Carlo calculations both indicate that the suppression of the shock structure is partially caused by lowering the momentum flux of reflected particles and significantly enhanced by the adsorption of particles to the surface. We observe that the scaling of beam density with source pressure is recovered, paving the way to order-of-magnitude brighter, cold molecular beams. PMID- 28345048 TI - Kin selection promotes female productivity and cooperation between the sexes. AB - Hamilton's theory of kin selection explains the evolution of costly traits that benefit other individuals by highlighting the fact that passing genes to offspring is not the only way of increasing the representation of those genes in subsequent generations: Genes are also shared with other classes of relatives. Consequently, any heritable trait that affects fitness of relatives should respond to kin selection. We tested this core prediction of kin selection theory by letting bulb mites (Rhizoglyphus robini) evolve in populations structured into groups of relatives or nonrelatives during the reproductive phase of the life cycle. In accordance with predictions derived from kin selection theory, we found that evolution in groups of relatives resulted in increased female reproductive output. This increase at least partly results from the evolution of male traits that elevate their partners' fecundity. Our results highlight the power and universality of kin selection. PMID- 28345049 TI - Biomimetic mineral self-organization from silica-rich spring waters. AB - Purely inorganic reactions of silica, metal carbonates, and metal hydroxides can produce self-organized complex structures that mimic the texture of biominerals, the morphology of primitive organisms, and that catalyze prebiotic reactions. To date, these fascinating structures have only been synthesized using model solutions. We report that mineral self-assembly can be also obtained from natural alkaline silica-rich water deriving from serpentinization. Specifically, we demonstrate three main types of mineral self-assembly: (i) nanocrystalline biomorphs of barium carbonate and silica, (ii) mesocrystals and crystal aggregates of calcium carbonate with complex biomimetic textures, and (iii) osmosis-driven metal silicate hydrate membranes that form compartmentalized, hollow structures. Our results suggest that silica-induced mineral self-assembly could have been a common phenomenon in alkaline environments of early Earth and Earth-like planets. PMID- 28345050 TI - Observation of inverse Edelstein effect in Rashba-split 2DEG between SrTiO3 and LaAlO3 at room temperature. AB - The Rashba physics has been intensively studied in the field of spin orbitronics for the purpose of searching novel physical properties and the ferromagnetic (FM) magnetization switching for technological applications. We report our observation of the inverse Edelstein effect up to room temperature in the Rashba-split two dimensional electron gas (2DEG) between two insulating oxides, SrTiO3 and LaAlO3, with the LaAlO3 layer thickness from 3 to 40 unit cells (UC). We further demonstrate that the spin voltage could be markedly manipulated by electric field effect for the 2DEG between SrTiO3 and 3-UC LaAlO3. These results demonstrate that the Rashba-split 2DEG at the complex oxide interface can be used for efficient charge-and-spin conversion at room temperature for the generation and detection of spin current. PMID- 28345051 TI - Aflatoxin-free transgenic maize using host-induced gene silencing. AB - Aflatoxins, toxic secondary metabolites produced by some Aspergillus species, are a universal agricultural economic problem and a critical health issue. Despite decades of control efforts, aflatoxin contamination is responsible for a global loss of millions of tons of crops each year. We show that host-induced gene silencing is an effective method for eliminating this toxin in transgenic maize. We transformed maize plants with a kernel-specific RNA interference (RNAi) gene cassette targeting the aflC gene, which encodes an enzyme in the Aspergillus aflatoxin biosynthetic pathway. After pathogen infection, aflatoxin could not be detected in kernels from these RNAi transgenic maize plants, while toxin loads reached thousands of parts per billion in nontransgenic control kernels. A comparison of transcripts in developing aflatoxin-free transgenic kernels with those from nontransgenic kernels showed no significant differences between these two groups. These results demonstrate that small interfering RNA molecules can be used to silence aflatoxin biosynthesis in maize, providing an attractive and precise engineering strategy that could also be extended to other crops to improve food security. PMID- 28345052 TI - Cardiac myosin binding protein-C Ser302 phosphorylation regulates cardiac beta adrenergic reserve. AB - Phosphorylation of cardiac myosin binding protein-C (MyBP-C) modulates cardiac contractile function; however, the specific roles of individual serines (Ser) within the M-domain that are targets for beta-adrenergic signaling are not known. Recently, we demonstrated that significant accelerations in in vivo pressure development following beta-agonist infusion can occur in transgenic (TG) mouse hearts expressing phospho-ablated Ser282 (that is, TGS282A) but not in hearts expressing phospho-ablation of all three serines [that is, Ser273, Ser282, and Ser302 (TG3SA)], suggesting an important modulatory role for other Ser residues. In this regard, there is evidence that Ser302 phosphorylation may be a key contributor to the beta-agonist-induced positive inotropic responses in the myocardium, but its precise functional role has not been established. Thus, to determine the in vivo and in vitro functional roles of Ser302 phosphorylation, we generated TG mice expressing nonphosphorylatable Ser302 (that is, TGS302A). Left ventricular pressure-volume measurements revealed that TGS302A mice displayed no accelerations in the rate of systolic pressure rise and an inability to maintain systolic pressure following dobutamine infusion similar to TG3SA mice, implicating Ser302 phosphorylation as a critical regulator of enhanced systolic performance during beta-adrenergic stress. Dynamic strain-induced cross-bridge (XB) measurements in skinned myocardium isolated from TGS302A hearts showed that the molecular basis for impaired beta-adrenergic-mediated enhancements in systolic function is due to the absence of protein kinase A-mediated accelerations in the rate of cooperative XB recruitment. These results demonstrate that Ser302 phosphorylation regulates cardiac contractile reserve by enhancing contractile responses during beta-adrenergic stress. PMID- 28345053 TI - A Rh(II)-catalyzed multicomponent reaction by trapping an alpha-amino enol intermediate in a traditional two-component reaction pathway. AB - Multicomponent reactions (MCRs) represent an ideal organic synthesis tool for the rapid construction of complex molecules due to their step and atom economy. Compared to two-component reactions, the development of new MCRs has been greatly limited during the 170 years since the first MCR was reported. Theoretically, the trapping of an active intermediate generated from two components by a third component could change the traditional two-component reaction pathway, leading to the discovery of MCRs. We report an example of the trapping of alpha-imino enols generated in situ from 1-sulfonyl-1,2,3-triazoles via alpha-imino metal carbene species by vinylimine ions using C(2)-substituted indoles and paraformaldehyde as precursors in the presence of a rhodium(II) catalyst. The traditional enol-ketone transformation pathway was suspended by the trapping procedure and efficiently switched to an MCR pathway to produce alpha-amino-beta-indole ketones in moderate to good yields. Unexpectedly, the resulting products and the theoretical density functional theory (DFT) calculation results indicated that the enolic carbon had a stronger nucleophilicity than the well-known traditional enamic carbon in the trapping process. The reaction mechanism was investigated using control experiments and detailed DFT calculations, and the synthetic application of the products was also illustrated. The developed strategy provides a mild and rapid access to alpha-amino-beta-indole ketones and suggests a rationale for the discovery of MCRs by trapping an active intermediate with a third component in a traditional two-component reaction pathway. PMID- 28345054 TI - Many shades of gray-The context-dependent performance of organic agriculture. AB - Organic agriculture is often proposed as a more sustainable alternative to current conventional agriculture. We assess the current understanding of the costs and benefits of organic agriculture across multiple production, environmental, producer, and consumer dimensions. Organic agriculture shows many potential benefits (including higher biodiversity and improved soil and water quality per unit area, enhanced profitability, and higher nutritional value) as well as many potential costs including lower yields and higher consumer prices. However, numerous important dimensions have high uncertainty, particularly the environmental performance when controlling for lower organic yields, but also yield stability, soil erosion, water use, and labor conditions. We identify conditions that influence the relative performance of organic systems, highlighting areas for increased research and policy support. PMID- 28345055 TI - Earthquake rupture below the brittle-ductile transition in continental lithospheric mantle. AB - Earthquakes deep in the continental lithosphere are rare and hard to interpret in our current understanding of temperature control on brittle failure. The recent lithospheric mantle earthquake with a moment magnitude of 4.8 at a depth of ~75 km in the Wyoming Craton was exceptionally well recorded and thus enabled us to probe the cause of these unusual earthquakes. On the basis of complete earthquake energy balance estimates using broadband waveforms and temperature estimates using surface heat flow and shear wave velocities, we argue that this earthquake occurred in response to ductile deformation at temperatures above 750 degrees C. The high stress drop, low rupture velocity, and low radiation efficiency are all consistent with a dissipative mechanism. Our results imply that earthquake nucleation in the lithospheric mantle is not exclusively limited to the brittle regime; weakening mechanisms in the ductile regime can allow earthquakes to initiate and propagate. This finding has significant implications for understanding deep earthquake rupture mechanics and rheology of the continental lithosphere. PMID- 28345056 TI - Arctic sea ice, Eurasia snow, and extreme winter haze in China. AB - The East China Plains (ECP) region experienced the worst haze pollution on record for January in 2013. We show that the unprecedented haze event is due to the extremely poor ventilation conditions, which had not been seen in the preceding three decades. Statistical analysis suggests that the extremely poor ventilation conditions are linked to Arctic sea ice loss in the preceding autumn and extensive boreal snowfall in the earlier winter. We identify the regional circulation mode that leads to extremely poor ventilation over the ECP region. Climate model simulations indicate that boreal cryospheric forcing enhances the regional circulation mode of poor ventilation in the ECP region and provides conducive conditions for extreme haze such as that of 2013. Consequently, extreme haze events in winter will likely occur at a higher frequency in China as a result of the changing boreal cryosphere, posing difficult challenges for winter haze mitigation but providing a strong incentive for greenhouse gas emission reduction. PMID- 28345057 TI - Chemical imaging of Fischer-Tropsch catalysts under operating conditions. AB - Although we often understand empirically what constitutes an active catalyst, there is still much to be understood fundamentally about how catalytic performance is influenced by formulation. Catalysts are often designed to have a microstructure and nanostructure that can influence performance but that is rarely considered when correlating structure with function. Fischer-Tropsch synthesis (FTS) is a well-known and potentially sustainable technology for converting synthetic natural gas ("syngas": CO + H2) into functional hydrocarbons, such as sulfur- and aromatic-free fuel and high-value wax products. FTS catalysts typically contain Co or Fe nanoparticles, which are often optimized in terms of size/composition for a particular catalytic performance. We use a novel, "multimodal" tomographic approach to studying active Co-based catalysts under operando conditions, revealing how a simple parameter, such as the order of addition of metal precursors and promoters, affects the spatial distribution of the elements as well as their physicochemical properties, that is, crystalline phase and crystallite size during catalyst activation and operation. We show in particular how the order of addition affects the crystallinity of the TiO2 anatase phase, which in turn leads to the formation of highly intergrown cubic close-packed/hexagonal close-packed Co nanoparticles that are very reactive, exhibiting high CO conversion. This work highlights the importance of operando microtomography to understand the evolution of chemical species and their spatial distribution before any concrete understanding of impact on catalytic performance can be realized. PMID- 28345058 TI - Nonrainfall water origins and formation mechanisms. AB - Dryland ecosystems cover 40% of the total land surface on Earth and are defined broadly as zones where precipitation is considerably less than the potential evapotranspiration. Nonrainfall waters (for example, fog and dew) are the least studied and least-characterized components of the hydrological cycle, although they supply critical amounts of water for dryland ecosystems. The sources of nonrainfall waters are largely unknown for most systems. In addition, most field and modeling studies tend to consider all nonrainfall inputs as a single category because of technical constraints, which hinders prediction of dryland responses to future warming conditions. This study uses multiple stable isotopes (2H, 18O, and 17O) to show that fog and dew have multiple origins and that groundwater in drylands can be recycled via evapotranspiration and redistributed to the upper soil profile as nonrainfall water. Surprisingly, the non-ocean-derived (locally generated) fog accounts for more than half of the total fog events, suggesting a potential shift from advection-dominated fog to radiation-dominated fog in the fog zone of the Namib Desert. This shift will have implications on the flora and fauna distribution in this fog-dependent system. We also demonstrate that fog and dew can be differentiated on the basis of the dominant fractionation (equilibrium and kinetic) processes during their formation using the 17O-18O relationship. Our results are of great significance in an era of global climate change where the importance of nonrainfall water increases because rainfall is predicted to decline in many dryland ecosystems. PMID- 28345059 TI - Health and Disease Imprinted in the Time Variability of the Human Microbiome. AB - The animal microbiota (including the human microbiota) plays an important role in keeping the physiological status of the host healthy. Research seeks greater insight into whether changes in the composition and function of the microbiota are associated with disease. We analyzed published 16S rRNA and shotgun metagenomic sequencing (SMS) data pertaining to the gut microbiotas of 99 subjects monitored over time. Temporal fluctuations in the microbial composition revealed significant differences due to factors such as dietary changes, antibiotic intake, age, and disease. This article shows that a fluctuation scaling law can describe the temporal changes in the gut microbiota. This law estimates the temporal variability of the microbial population and quantitatively characterizes the path toward disease via a noise-induced phase transition. Estimation of the systemic parameters may be of clinical utility in follow-up studies and have more general applications in fields where it is important to know whether a given community is stable or not. IMPORTANCE The human microbiota correlates closely with the health status of its host. This article analyzes the microbial composition of several subjects under different conditions over time spans that ranged from days to months. Using the Langevin equation as the basis of our mathematical framework to evaluate microbial temporal stability, we proved that stable microbiotas can be distinguished from unstable microbiotas. This initial step will help us to determine how temporal microbiota stability is related to a subject's health status and to develop a more comprehensive framework that will provide greater insight into this complex system. PMID- 28345060 TI - Genome Reduction and Microbe-Host Interactions Drive Adaptation of a Sulfur Oxidizing Bacterium Associated with a Cold Seep Sponge. AB - As the most ancient metazoan, sponges have established close relationships with particular microbial symbionts. However, the characteristics and physiology of thioautotrophic symbionts in deep-sea sponges are largely unknown. Using a tailored "differential coverage binning" method on 22-Gb metagenomic sequences, we recovered the nearly complete genome of a sulfur-oxidizing bacterium (SOB) that dominates the microbiota of the cold seep sponge Suberites sp. Phylogenetic analyses suggested that this bacterium (an unclassified gammaproteobacterium termed "Gsub") may represent a new deep-sea SOB group. Microscopic observations suggest that Gsub is probably an extracellular symbiont. Gsub has complete sulfide oxidation and carbon fixation pathways, suggesting a chemoautotrophic lifestyle. Comparative genomics with other sponge-associated SOB and free-living SOB revealed significant genome reduction in Gsub, characterized by the loss of genes for carbohydrate metabolism, motility, DNA repair, and osmotic stress response. Intriguingly, this scenario of genome reduction is highly similar to those of the endosymbionts in deep-sea clams. However, Gsub has retained genes for phage defense and protein secretion, with the latter potentially playing a role in interactions with the sponge host. In addition, we recovered the genome of an ammonia-oxidizing archaeon (AOA), which may carry out ammonia oxidation and carbon fixation within the sponge body. IMPORTANCE Sponges and their symbionts are important players in the biogeochemical cycles of marine environments. As a unique habitat within marine ecosystems, cold seeps have received considerable interest in recent years. This study explores the lifestyle of a new symbiotic SOB in a cold seep sponge. The results demonstrate that both this sponge symbiont and endosymbionts in deep-sea clams employ similar strategies of genome reduction. However, this bacterium has retained unique functions for immunity and defense. Thus, the functional features are determined by both the symbiotic relationship and host type. Moreover, analyses of the genome of an AOA suggest that microbes play different roles in biochemical cycles in the sponge body. Our findings provide new insights into invertebrate-associated bacteria in cold seep environments. PMID- 28345061 TI - Inverse Association between Vitamin D Status and Diabetes in a Clinic Based Sample of Hispanic Adults in Puerto Rico. AB - BACKGROUND: Vitamin D deficiency is a public health problem around the world. Diabetes has been associated with vitamin D deficiency. We aimed to examine the association between the vitamin D status and diabetes in a clinic based sample of Hispanic adults in Puerto Rico. METHODS: Demographics and laboratory test results for serum 25(OH)D, Fasting Blood Glucose (FBG), and Haemoglobin A1C (HbAlc) were extracted from medical records. Vitamin D status was classified as deficient (<12 ng/ml); inadequate (12-20 ng/ml); insufficient (21-29 ng/ml) and optimal (>=30 ng/ml) using serum 25(OH)D levels. RESULTS: A total of 716 records were included in the analyses. Most were females (63.3%), with mean age of 54.1+/-14.9 y, mean BMI 30.1+/-6.3 kg/m2 and mean serum 25(OH)D levels of 24.3+/-8.6 ng/ml. Most were classified as diabetics (41.1%). Those with diabetes had lower 25(OH)D levels compared to pre-diabetic and normal glucose status (p<0.05). Serum 25(OH) D levels were inversely correlated to FBG and HbA1c in the total sample and in men (p<0.05). After adjusting for age, gender, BMI and seasonality, there was a greater risk of diabetes, but not prediabetes, in those with serum 25(OH)D levels <30 ng/ml. This risk increased from 1.8 times in those with vitamin D insufficiency to 4.2 times in those with vitamin D deficiency (<12 ng/ml). CONCLUSION: Diabetes risk significantly increased as serum 25(OH)D levels decreased in this group of Hispanic adults, underscoring the importance of routinely screening high risk individuals for vitamin D deficiency and offer supplementation to normalize serum levels. PMID- 28345063 TI - Production and use of regional climate model projections - A Swedish perspective on building climate services. AB - We describe the process of building a climate service centred on regional climate model results from the Rossby Centre regional climate model RCA4. The climate service has as its central facility a web service provided by the Swedish Meteorological and Hydrological Institute where users can get an idea of various aspects of climate change from a suite of maps, diagrams, explaining texts and user guides. Here we present the contents of the web service and how this has been designed and developed in collaboration with users of the service in a dialogue reaching over more than a decade. We also present the ensemble of climate projections with RCA4 that provides the fundamental climate information presented at the web service. In this context, RCA4 has been used to downscale nine different coupled atmosphere-ocean general circulation models (AOGCMs) from the 5th Coupled Model Intercomparison Project (CMIP5) to 0.44 degrees (c. 50 km) horizontal resolution over Europe. Further, we investigate how this ensemble relates to the CMIP5 ensemble. We find that the iterative approach involving the users of the climate service has been successful as the service is widely used and is an important source of information for work on climate adaptation in Sweden. The RCA4 ensemble samples a large degree of the spread in the CMIP5 ensemble implying that it can be used to illustrate uncertainties and robustness in future climate change in Sweden. The results also show that RCA4 changes results compared to the underlying AOGCMs, sometimes in a systematic way. PMID- 28345062 TI - Secondary structure propensity and chirality of the amyloidophilic peptide p5 and its analogues impacts ligand binding - In vitro characterization. AB - BACKGROUND: Polybasic helical peptides, such as peptide p5, bind human amyloid extracts and synthetic amyloid fibrils. When radiolabeled, peptide p5 has been shown to specifically bind amyloid in vivo thereby allowing imaging of the disease. Structural requirements for heparin and amyloid binding have been studied using analogs of p5 that modify helicity and chirality. METHODS: Peptide ligand interactions were studied using CD spectroscopy and solution-phase binding assays with radiolabeled p5 analogs. The interaction of a subset of peptides was further studied by using molecular dynamics simulations. RESULTS: Disruption of the peptide helical structure reduced peptide binding to heparin and human amyloid extracts. The all-D enantiomer and the beta-sheet-structured peptide bound all substrates as well as, or better than, p5. The interaction of helical and beta-sheet structured peptides with Abeta fibrils was modeled and shown to involve both ionic and non-ionic interactions. CONCLUSIONS: The alpha-helical secondary structure of peptide p5 is important for heparin and amyloid binding; however, helicity is not an absolute requirement as evidenced by the superior reactivity of a beta-sheet peptide. The differential binding of the peptides with heparin and amyloid fibrils suggests that these molecular interactions are different. The all-D enantiomer of p5 and the beta-sheet peptide are candidates for amyloid targeting reagents in vivo. GENERAL SIGNIFICANCE: Efficient binding of polybasic peptides with amyloid is dependent on the linearity of charge spacing in the context of an alpha-helical secondary structure. Peptides with an alpha-helix or beta-sheet propensity and with similar alignment of basic residues is optimal. PMID- 28345064 TI - Pneumocephalus in a patient with multiple stab wounds. AB - Pneumocephalus is a complication of trauma to the chest and many iatrogenic interventions. It may arise due to systemic air embolism or retrograde cerebral venous air embolism which is an extremely rare complication. We report a 26-years old female patient who presented to the Emergency Department suffering of multiple stab wounds. She was in a state of shock and after first aid and evaluation she was operated successfully. In the early postoperative period generalized tonic clonic convulsions were observed following cardiopulmonary resuscitation due to sudden cardiovascular collapse. Brain computerized tomography demonstrated free air in intracranial and extracranial venous structures. Pneumocephalus was diagnosed which may be due to a wide spectrum of etiologies including thorax or spinal stab wounds, tube thoracostomy, cardiopulmonary resuscitation or even central venous catheterization. Unfortunately, the patient ended up with brain death despite all effort. In conclusion, we recommend physicians to be aware of this catastrophic complication while taking care of patients with stab wounds. PMID- 28345065 TI - Diabetic ketoacidosis as the presenting manifestation of pancreatic adenocarcinoma with cystic features. AB - The common presenting symptoms of pancreatic cancer are abdominal pain, weight loss, and jaundice. Pancreatic adenocarcinoma presenting with diabetic ketoacidosis is a very rare emergent clinical condition. However, pancreatic ductal cystadenocarcinoma presenting with diabetic ketoacidosis was not reported. We describe a 60-year-old man with pancreatic cystadenocarcinoma presenting with diabetic ketoacidosis as the initial manifestation. It must be kept in mind that in diabetic ketoacidosis cases, the precipitating factor may be pancreatic ductal cystadenocarcinoma. PMID- 28345066 TI - Correlation of central venous pressure with venous blood gas analysis parameters; a diagnostic study. AB - OBJECTIVE: This study was conducted to assess the correlation between central venous pressure (CVP) and venous blood gas (VBG) analysis parameters, to facilitate management of severe sepsis and septic shock in emergency department. MATERIAL AND METHODS: This diagnostic study was conducted from January 2014 until June 2015 in three major educational medical centers, Tehran, Iran. For patients selected with diagnosis of septic shock, peripheral blood sample was taken for testing the VBG parameters and the anion gap (AG) was calculated. All the mentioned parameters were measured again after infusion of 500 cc of normal saline 0.9% in about 1 h. RESULTS: Totally, 93 patients with septic shock were enrolled, 63 male and 30 female. The mean age was 72.53 +/- 13.03 and the mean Shock Index (SI) before fluid therapy was 0.79 +/- 0.30. AG and pH showed significant negative correlations with CVP, While HCO3 showed a significant positive correlation with CVP. These relations can be affected by the treatment modalities used in shock management such as fluid therapy, mechanical ventilation and vasopressor treatment. CONCLUSION: It is likely that there is a significant statistical correlation between VBG parameters and AG with CVP, but further research is needed before implementation of the results of this study. PMID- 28345068 TI - How much risk are emergency department patients willing to accept to avoid diagnostic testing. AB - OBJECTIVES: There is a paucity of research evaluating the risk tolerance of Emergency Department (ED) patients. We hypothesized that a significant percentage of ED patients surveyed would be comfortable with >=5% risk of adverse outcome if they avoided testing in several hypothetical scenarios. MATERIALS AND METHODS: This was a cross-sectional study of a convenience sample of stable inner-city ED patients. Patients completed a written survey and were asked four closed-answer questions regarding risk tolerance/willingness to refuse a test/procedure, including the following scenarios: #1: LP following CT head; #2 overnight serial troponins for rule out myocardial infarction; #3 CT for possible appendicitis, #4 parent deciding whether child should undergo head CT for low risk head injury. Risk preferences were stratified to >=5% (high) and <5% (low). Multivariate logistic regressions performed for each scenario to control for confounding factors. RESULTS: There were 217 patients in the study group; mean age 42 +/- 15 years, 48% female, 66% Hispanic, 87% income < $40,000 income group. A substantial percentage of patients rated high risk tolerance for each scenario, including 31% for #1 (avoid LP), 25% for #2 (avoid cardiac rule-out admission), 27% for #3 (avoid CT for appendicitis), and 19% for #4 (avoid head CT for child). DISCUSSION: For 3 of 4 scenarios, 25% or more of our patients would accept a high risk tolerance of adverse outcome to avoid further testing. CONCLUSION: Our findings contribute further evidence to the growing body of literature supporting patient interest in shared decision making in the ED. PMID- 28345067 TI - Utility of 360-degree assessment of residents in a Turkish academic emergency medicine residency program. AB - OBJECTIVES: This study was designed to test a 360-degree assessment tool for four of the emergency medicine resident competencies as outlined by the Council of Residency Directors in Emergency Medicine on patient care, communication skills, professionalism and system based practice in an academic Emergency Department. MATERIAL AND METHODS: Using the competency framework of the American Accreditation Council for Graduate Medical Education, a 57 item-containing assessment tool was created. Based on the different exposure aspects of the involved evaluator groups, the items were integrated into seven different evaluation forms. All sixteen of 16 residents and members from each evaluator group voluntarily participated in the study. Internal consistency scores, multilayer and multilevel Kappa values were measured. Evaluator group scores and resident ranks in competency areas were compared. All evaluators were asked to comment on the applicability and usefulness of the assessment tool in emergency medicine. RESULTS: Seven groups completed a total of 1088 forms to evaluate 16 residents. The reliability coefficient for the faculty members was 0.99 while it was 0.60 for the ancillary staff. The interrater Kappa values for faculty members, nurses and peer assessment were relevant with a value of greater than 70%. DISCUSSION AND CONCLUSION: Our results showed that the 360-degree assessment did meet expectations by the evaluator group and residents, and that this method was readily accepted in the setting of a Akdeniz University Emergency Medicine residency training program. However, only evaluations by faculty, nurses, self and peers were reliable to have any value. Doing a 360 degrees evaluation is time and effort consuming and thus may not be an ideal tool for larger programs. PMID- 28345069 TI - An uncommon case mimicking cervical trauma: Os odontoideum. AB - Os odontoideum is a separate odontoid process from the body of the axis. It is the most common anomaly of the odontoid process. Patients with this condition can be asymptomatic or present with a wide range of neurological dysfunctions. It may cause cervical instability, atlantoaxial dislocation and myelopathy. This anomaly can mimic Type I and II odontoid fractures. There is a role for conservative treatment of an asymptomatic incidentally found, radiologically stable and non compressive os odontoideum. However, surgical treatment has a definitive role in symptomatic cases. In this study, the case is presented of a 31 year-old male patient with neck pain who was diagnosed with incidental os odontoideum. The diagnosis of acute odontoid fracture was discarded in this case as the radiological findings were of a characteristic cortex with smooth contours, and there was no history of recent trauma, sclerosis or hypertrophy of the anterior tubercle of the atlas. PMID- 28345070 TI - Are scoring systems sufficient for predicting mortality due to sepsis in the emergency department? AB - OBJECTIVES: Scoring systems have been used to risk stratify in intensive care units (ICU), but not routinely used in emergency departments. The aim of this study was to determine accuracy for predicting mortality in emergency medicine with Sequential Organ Failure Assessment (SOFA), Mortality in ED Sepsis (MEDS) score and Simplified Acute Physiology Score (SAPSII). METHODS: This is a prospective observational study. Patients presenting with evidence of sepsis were all included. SAPSII, MEDS, and SOFA scores were calculated. Analysis compared areas under the receiver operator characteristic (ROC) curves for 28-day mortality. RESULTS: Two hundred patients were included; consisting of 31 (14.3%) septic shock. 138 (69%) severe sepsis and 31 (15.5%) infection without organ dysfunction. 53 (26.5%) patients died within 28 days. Area under the ROC curve for mortality was 0.76 for MEDS (0.69-0.82), 0.70 for SAPSII (0.62-0.78); and 1.68 for SOFA (0.60-0.76) scores. Pair wise comparison of AUC between MEDS, SAPSII, SOFA and Lactate were not significant. CONCLUSION: According to our results; SOFA, SAPSII and MEDS were not sufficient to predict mortality. Also this result, MEDS was better than other scoring system. PMID- 28345071 TI - Jolt accentuation and its value as a sign in diagnosis of meningitis in patients with fever and headache. AB - OBJECTIVES: Meningitis is an important disease among the patients being visited in Emergency Departments (EDs). There are many signs to diagnose it with different sensitivity and specificity reported in previously done studies. Current study tries to evaluate diagnostic accuracy of "Jolt accentuation" in the diagnosis (Dx.) of meningitis in patients with fever and headache. MATERIALS AND METHODS: 48 adult patients, who were referred to two teaching EDs for fever and headache and were diagnosed as suspected meningitis, were included in this prospective observational study. Demographic characteristics of patients were recorded in data sheets, as well as the results of exams including nuchal rigidity, Kernig and Brudzinski signs, and Jolt accentuation. Then, lumbar puncture (LP) was done and cerebrospinal fluid (CSF) was analyzed for each patient; pleocytosis (more than five white blood cells in high power field) were considered as meningitis. Sensitivity, specificity, positive and negative predictive values (PPV and NPV), and positive and negative likelihood ratios (LR+ and LR-) of the above mentioned signs were compared to each other. RESULTS: Meningitis was proved in 33 patients (68.8% of them), according to CSF analysis. Jolt accentuation had sensitivity, specificity, PPV, NPV, LR+, and LR- of 69.6%, 33.3%, 69.6%, 33.3%, 1.02, and 0.91, respectively. Jolt accentuation had the highest sensitivity rate all of the signs mentioned above; although, it was not significant. CONCLUSION: Jolt accentuation alone cannot rule in or out the Dx. of meningitis in patients with fever and headache; LP is still recommended for these patients. PMID- 28345072 TI - Pseudoelectrical alternans during supraventricular tachycardia. AB - We present a case of pseudoelectrical alternans occurring during supraventricular tachycardia. PMID- 28345073 TI - Chondrotoxic effects of intra-articular anesthetics in shoulders. PMID- 28345075 TI - Ultrasonographic Detection of Airway Obstruction in a Model of Obstructive Sleep Apnea. AB - Purpose Obstructive sleep apnea (OSA) is a common clinical disorder characterized by repetitive airway obstruction during sleep. The gold standard for diagnosis of OSA, polysomnogram (PSG), cannot anatomically localize obstruction. Precise identification of obstruction has potential to improve outcomes following surgery. Current diagnostic modalities that provide this information require anesthesia, involve ionizing radiation or disrupt sleep. To mitigate these problems, we conceived that ultrasound (US) technology may be adapted (i) to detect, quantify and localize airway obstruction and (ii) for translational application to home-based testing for OSA. Materials and Methods Segmental airway collapse was induced in 4 fresh cadavers by application of negative pressure. Following visualization of airway obstruction, a rotary US probe was used to acquire transcervical images of the airway before and after induction of obstruction. These images (n=800) were analyzed offline using image processing algorithms. Results Our results show that the non-obstructed airway consistently demonstrated the presence of a US air-tissue interface. Importantly, automated detection of the air-tissue interface strongly correlated with manual measurements. The algorithm correctly detected an air-tissue interface in 90% of the US images while incorrectly detecting it in 20% (area under the curve=0.91). Conclusion The non-invasive detection of airway obstruction using US represents a major step in expanding OSA diagnostics beyond PSG. The preliminary data obtained from our model could spur further research in non-invasive localization of obstruction. US offers the benefit of precise localization of the site of obstruction, with potential for improving outcomes in surgical management. PMID- 28345074 TI - Single-cell RNA-seq and computational analysis using temporal mixture modelling resolves Th1/Tfh fate bifurcation in malaria. AB - Differentiation of naive CD4+ T cells into functionally distinct T helper subsets is crucial for the orchestration of immune responses. Due to extensive heterogeneity and multiple overlapping transcriptional programs in differentiating T cell populations, this process has remained a challenge for systematic dissection in vivo. By using single-cell transcriptomics and computational analysis using a temporal mixtures of Gaussian processes model, termed GPfates, we reconstructed the developmental trajectories of Th1 and Tfh cells during blood-stage Plasmodium infection in mice. By tracking clonality using endogenous TCR sequences, we first demonstrated that Th1/Tfh bifurcation had occurred at both population and single-clone levels. Next, we identified genes whose expression was associated with Th1 or Tfh fates, and demonstrated a T cell intrinsic role for Galectin-1 in supporting a Th1 differentiation. We also revealed the close molecular relationship between Th1 and IL-10-producing Tr1 cells in this infection. Th1 and Tfh fates emerged from a highly proliferative precursor that upregulated aerobic glycolysis and accelerated cell cycling as cytokine expression began. Dynamic gene expression of chemokine receptors around bifurcation predicted roles for cell-cell in driving Th1/Tfh fates. In particular, we found that precursor Th cells were coached towards a Th1 but not a Tfh fate by inflammatory monocytes. Thus, by integrating genomic and computational approaches, our study has provided two unique resources, a database www.PlasmoTH.org, which facilitates discovery of novel factors controlling Th1/Tfh fate commitment, and more generally, GPfates, a modelling framework for characterizing cell differentiation towards multiple fates. PMID- 28345076 TI - Dyadic Behavior Analysis in Depression Severity Assessment Interviews. AB - Previous literature suggests that depression impacts vocal timing of both participants and clinical interviewers but is mixed with respect to acoustic features. To investigate further, 57 middle-aged adults (men and women) with Major Depression Disorder and their clinical interviewers (all women) were studied. Participants were interviewed for depression severity on up to four occasions over a 21 week period using the Hamilton Rating Scale for Depression (HRSD), which is a criterion measure for depression severity in clinical trials. Acoustic features were extracted for both participants and interviewers using COVAREP Toolbox. Missing data occurred due to missed appointments, technical problems, or insufficient vocal samples. Data from 36 participants and their interviewers met criteria and were included for analysis to compare between high and low depression severity. Acoustic features for participants varied between men and women as expected, and failed to vary with depression severity for participants. For interviewers, acoustic characteristics strongly varied with severity of the interviewee's depression. Accommodation - the tendency of interactants to adapt their communicative behavior to each other - between interviewers and interviewees was inversely related to depression severity. These findings suggest that interviewers modify their acoustic features in response to depression severity, and depression severity strongly impacts interpersonal accommodation. PMID- 28345077 TI - Improving Website Hyperlink Structure Using Server Logs. AB - Good websites should be easy to navigate via hyperlinks, yet maintaining a high quality link structure is difficult. Identifying pairs of pages that should be linked may be hard for human editors, especially if the site is large and changes frequently. Further, given a set of useful link candidates, the task of incorporating them into the site can be expensive, since it typically involves humans editing pages. In the light of these challenges, it is desirable to develop data-driven methods for automating the link placement task. Here we develop an approach for automatically finding useful hyperlinks to add to a website. We show that passively collected server logs, beyond telling us which existing links are useful, also contain implicit signals indicating which nonexistent links would be useful if they were to be introduced. We leverage these signals to model the future usefulness of yet nonexistent links. Based on our model, we define the problem of link placement under budget constraints and propose an efficient algorithm for solving it. We demonstrate the effectiveness of our approach by evaluating it on Wikipedia, a large website for which we have access to both server logs (used for finding useful new links) and the complete revision history (containing a ground truth of new links). As our method is based exclusively on standard server logs, it may also be applied to any other website, as we show with the example of the biomedical research site Simtk. PMID- 28345078 TI - Online Actions with Offline Impact: How Online Social Networks Influence Online and Offline User Behavior. AB - Many of today's most widely used computing applications utilize social networking features and allow users to connect, follow each other, share content, and comment on others' posts. However, despite the widespread adoption of these features, there is little understanding of the consequences that social networking has on user retention, engagement, and online as well as offline behavior. Here, we study how social networks influence user behavior in a physical activity tracking application. We analyze 791 million online and offline actions of 6 million users over the course of 5 years, and show that social networking leads to a significant increase in users' online as well as offline activities. Specifically, we establish a causal effect of how social networks influence user behavior. We show that the creation of new social connections increases user online in-application activity by 30%, user retention by 17%, and user offline real-world physical activity by 7% (about 400 steps per day). By exploiting a natural experiment we distinguish the effect of social influence of new social connections from the simultaneous increase in user's motivation to use the app and take more steps. We show that social influence accounts for 55% of the observed changes in user behavior, while the remaining 45% can be explained by the user's increased motivation to use the app. Further, we show that subsequent, individual edge formations in the social network lead to significant increases in daily steps. These effects diminish with each additional edge and vary based on edge attributes and user demographics. Finally, we utilize these insights to develop a model that accurately predicts which users will be most influenced by the creation of new social network connections. PMID- 28345079 TI - "Not Just a Receiver": Understanding Patient Behavior in the Hospital Environment. AB - Patient engagement leads to better health outcomes and experiences of health care. However, existing patient engagement systems in the hospital environment focus on the passive receipt of information by patients rather than the active contribution of the patient or caregiver as a partner in their care. Through interviews with hospitalized patients and their caregivers, we identify ways that patients and caregivers actively participate in their care. We describe the different roles patients and caregivers assume in interacting with their hospital care team. We then discuss how systems designed to support patient engagement in the hospital setting can promote active participation and help patients achieve better outcomes. PMID- 28345080 TI - Impact of Sensor Misplacement on Dynamic Time Warping Based Human Activity Recognition using Wearable Computers. AB - Daily living activity monitoring is important for early detection of the onset of many diseases and for improving quality of life especially in elderly. A wireless wearable network of inertial sensor nodes can be used to observe daily motions. Continuous stream of data generated by these sensor networks can be used to recognize the movements of interest. Dynamic Time Warping (DTW) is a widely used signal processing method for time-series pattern matching because of its robustness to variations in time and speed as opposed to other template matching methods. Despite this flexibility, for the application of activity recognition, DTW can only find the similarity between the template of a movement and the incoming samples, when the location and orientation of the sensor remains unchanged. Due to this restriction, small sensor misplacements can lead to a decrease in the classification accuracy. In this work, we adopt DTW distance as a feature for real-time detection of human daily activities like sit to stand in the presence of sensor misplacement. To measure this performance of DTW, we need to create a large number of sensor configurations while the sensors are rotated or misplaced. Creating a large number of closely spaced sensors is impractical. To address this problem, we use the marker based optical motion capture system and generate simulated inertial sensor data for different locations and orientations on the body. We study the performance of the DTW under these conditions to determine the worst-case sensor location variations that the algorithm can accommodate. PMID- 28345081 TI - Discovery of temperature-dependent, autoinductive reversal of enantioselectivity: palladium-mediated [3+3]-annulation of 4-hydroxycoumarins. AB - An unusual temperature-dependent autoinductive reversal of enantioselectivity (TARE) was discovered in an asymmetric palladium-mediated [3+3]-annulation of 4 hydroxycoumarin with Morita-Baylis-Hillman acetate. The absolute stereochemistry of the reaction product can be readily inversed by solely modifying the reaction temperature (from 10 degrees C to 60 degrees C), affording multicyclic adducts with the opposite configurations respectively in moderate to excellent enantiopurities. Furthermore, the first reported example of palladium-mediated bidirectional asymmetric autoinduction was identified to mainly contribute to the reversal of enantioselectivity, in which the corresponding adduct actively participated in the stereocontrol during the reaction. The correlation between reaction temperature and autoinduction was established, which might broaden the horizon of stereocontrol in asymmetric catalysis. PMID- 28345082 TI - Construction of the septahydroxylated ABC-ring system of dihydro-beta agarofurans: application of 6-exo-dig radical cyclization. AB - A synthetic route to the septahydroxylated ABC-ring system of dihydro-beta agarofurans was established. The B-ring was formed by a base-promoted diastereoselective Diels-Alder reaction between 3-hydroxy-2-pyrone and a d glyceraldehyde-derived dienophile, while the C-ring was cyclized by PhSeCl mediated etherification. The remaining A-ring was constructed via a 6-exo-dig radical reaction. Selective transformations gave rise to the ABC-ring system 1 with nine contiguous stereocenters. The thus obtained 1 corresponded to the enantiomer of the densely oxygenated core structure of dihydro-beta-agarofurans. PMID- 28345083 TI - CAL-B catalyzed regioselective bulk polymerization of l-aspartic acid diethyl ester to alpha-linked polypeptides. AB - This paper reports that the bulk polymerization of l-aspartic acid diethyl ester catalyzed by immobilized CAL-B at 80 degrees C for 24 h gives primarily (~95%) alpha-linked poly(l-aspartate) in 70% yield with DPavg = 50 and regioselectivity (alpha/beta) = 94 : 6. Plots of log{[M]0/[M]t} vs. time and DPavgvs. conversion indicate that this polymerization proceeds in a controlled manner by a chain growth mechanism up to 90% conversion. Thereafter, competition occurs between chain growth and step mechanisms. PMID- 28345084 TI - The importance of solvent quality on the modification of conjugated polymer conformation and thermodynamics with illumination. AB - Device efficiency in key organic electronic devices such as organic photovoltaics, field transistors, and light emitting diodes has long been known to be closely tied to the conformation of the conjugated polymer chains which make up the active layers. Our previous results show that light exposure can have a profound effect on the structure and assembly of these optoelectronic materials in solution. In order to advance our understanding of the role which solvent quality plays in this phenomenon, we have further studied the modulation of these illumination dependent structural changes on the key benchmark conjugated polymers P3HT and MEH-PPV as a function of solvent quality over a wide range of polymer solubilities. Analysis of this data indicates that use of poorer conjugated polymer solvents ultimately results in larger absolute alterations to polymer conformation, denoting the crucial role which solution thermodynamics plays in this generic effect. This discovery opens the door to controlling final device morphology through careful manipulation of solvent composition during solution based device casting techniques, moving our efforts closer to the development of a powerful, non-destructive, and tunable method for light-driven control of polymer conformation in novel light-responsive organic materials. PMID- 28345085 TI - Formation of surface nanodroplets facing a structured microchannel wall. AB - Surface nanodroplets are important units for lab-on-a-chip devices, compartmentalised catalytic reactions, high-resolution near-field imaging, and many others. Solvent exchange is a simple solution-based bottom-up approach for producing surface nanodroplets by displacing a good solvent of the droplet liquid by a poor one in a narrow channel in the laminar regime. The droplet size is controlled by the solution composition and the flow conditions during the solvent exchange. In this paper, we investigated the effects of local microfluidic structures on the formation of surface nanodroplets. The microstructures consist of a microgap with a well-defined geometry, embedded on the opposite microchannel wall, facing the substrate where nucleation takes place. For a given channel height, the dimensionless control parameters were the Peclet number of the flow, the ratio between the gap height and the channel height, and the aspect ratio between the gap length and the channel height. We found and explained three prominent features in the surface nanodroplet distribution at the surface opposite to the microgap: (i) enhanced volume of the droplets; (ii) asymmetry as compared to the location of the gap in the spatial droplet distribution with increasing Pe; (iii) reduced exponent of the effective scaling law of the droplet size with Pe. The droplet size also varied with the aspect and height ratios of the microgap at a given Pe value. Our simulations of the profile of oversaturation in the channel reveal that the droplet size distribution may be attributed to the local flow patterns induced by the gap. Finally, in a tapered microchannel, a gradient of surface nanodroplet size was obtained. Our work shows the potential for controlling nanodroplet size and spatial organization on a homogeneous surface in a bottom-up approach by simple microfluidic structures. PMID- 28345086 TI - Selective C-C coupling at a Pt(iv) centre: 100% preference for sp2-sp3 over sp3 sp3. AB - The oxidative addition of three different organic halides RX to the non-symmetric platinum(ii) mer coordinated dicyclometallated C^N^C complex 1 yielded short lived six-coordinate platinum(iv) complexes 2(R) (R = Me, allyl, Bn), with the incoming groups trans across the platinum centre. A spontaneous reductive coupling reaction then occurred with, in each case, a completely chemoselective sp2-sp3 coupling, and exclusively gave R-3, with the newly introduced R group bonded to the previously cyclometallated aryl ring. Following a recyclometallation reaction, the oxidative addition/reductive elimination cycle was repeated and gave the same selectivity. A one-pot route to doubly alkylating the aryl ring was developed. The observed selectivity might have been predicted on the normal basis of a steric barrier associated with non-flat sp3 hybridised groups, but we suggest that it arises from the stereochemistry at the metal, and the orientation of the ligands. PMID- 28345087 TI - Comment on "Conformational analysis of triphenylphosphine ligands in stereogenic monometallic complexes: tools for predicting the preferred configuration of the triphenylphosphine rotor" by J. F. Costello, S. G. Davies, E. T. F. Gould and J. E. Thomson, Dalton Trans., 2015, 44, 5451. AB - In half-sandwich compounds of the type [Cp*ML1L2PPh3] the PPh3 propeller is stabilized by attractive CH/pi interactions in which Co-H bonds specifically interact with the Ci and Co atoms of neighbouring phenyl rings, as in the T shaped benzene dimer (i/o = ipso/ortho). This stabilization was not taken into account in a recent conformational analysis based on van der Waals energy calculations and minimization of steric compression (Dalton Trans., 2015, 44, 5451-5466). It is shown that in all 116 structures discussed in this analysis the CoH-Ci/o distances fall below the sum of the van der Waals radii, establishing attractive CH/pi interactions, although the short contacts could easily be avoided by phenyl rotation to relieve steric strain. In 53 of the described structures there are acyl substituents which form conformation-determining Co HO(acyl) hydrogen bonds that are not taken into account in the recent analysis. The steric-only model is not an adequate description of M-PPh3 complexes. PMID- 28345089 TI - Dancing disclinations in confined active nematics. AB - The spontaneous emergence of collective flows is a generic property of active fluids and often leads to chaotic flow patterns characterised by swirls, jets, and topological disclinations in their orientation field. However, the ability to achieve structured flows and ordered disclinations is of particular importance in the design and control of active systems. By confining an active nematic fluid within a channel, we find a regular motion of disclinations, in conjunction with a well defined and dynamic vortex lattice. As pairs of moving disclinations travel through the channel, they continually exchange partners producing a dynamic ordered state, reminiscent of Ceilidh dancing. We anticipate that this biomimetic ability to self-assemble organised topological disclinations and dynamically structured flow fields in engineered geometries will pave the road towards establishing new active topological microfluidic devices. PMID- 28345088 TI - Near-infrared emitting iridium(iii) complexes for mitochondrial imaging in living cells. AB - Biocompatible transition metal complexes dyes emitting in the near-infrared (NIR) region, are highly desirable in fluorescence imaging techniques. However, a high performance mitochondria-specific labeling NIR probe with high photostability is still lacking. Herein we reported two NIR-emitting cationic iridium(iii) complexes [Ir(pbq-g)2(N^N)]+Cl- (pbq-g = phenylbenzo[g]-quinoline; N^N = 2-(1 benzyl-1H-pyrazol-3-yl) pyridine (Ir1) and 2-(1-(naphthalen-1-ylmethyl)-1H pyrazol-3-yl) pyridine (Ir2)). These two novel Ir(iii) complexes with different N^N ligands exhibited similar NIR emission with lambdamax at 751 nm for Ir1 and 750 nm for Ir2 in PBS solution, with luminescence quantum yields of around 0.62 for Ir1 and 0.85 for Ir2. These two complexes showed high mitochondrial specificity, superior photostability, high resistance to the loss of the mitochondrial membrane potential and appreciable tolerance to environmental changes, allowing NIR imaging of mitochondrial morphological changes over long periods of time. These excellent photophysical and imaging properties made them promising NIR luminescent tags for applications in bioimaging. PMID- 28345090 TI - Exhaustive Suzuki-Miyaura reactions of polyhalogenated heteroarenes with alkyl boronic pinacol esters. AB - A novel Suzuki-Miyaura protocol is described that enables the exhaustive alkylation of polychlorinated pyridines. This method facilitates a formal synthesis of normuscopyridine and the rapid assembly of a dumbbell shaped portion of a [2]rotaxane. PMID- 28345091 TI - Solutal and thermal buoyancy effects in self-powered phosphatase micropumps. AB - Immobilized enzymes generate net fluid flow when exposed to specific reagents in solution. Thus, they function as self-powered platforms that combine sensing and on-demand fluid pumping. To uncover the mechanism of pumping, we examine the effects of solutal and thermal buoyancy on the behavior of phosphatase-based micropumps, using a series of reactants with known thermodynamic and kinetic parameters. By combining modeling and experiments, we perform the first quantitative comparison of thermal and solutal effects in an enzyme micropump system. Despite the significant exothermicity of the catalyzed reactions, we find that thermal effects play a minimal role in the observed fluid flow. Instead, fluid transport in phosphatase micropumps is governed by the density difference between the reactants and the products of the reaction. This surprising conclusion suggests new design principles for catalytic pumps. PMID- 28345092 TI - Integrating optical tweezers with up-converting luminescence: a non-amplification analytical platform for quantitative detection of microRNA-21 sequences. AB - We report a single-microsphere based imaging assay method by integrating up converting luminescence with optical tweezers for detecting microRNA-21 sequences. This method achieves a competitive detection limit of 12 fM with good selectivity and no dedicated signal amplification designs. PMID- 28345093 TI - Diffusion of active dimers in a Couette flow. AB - We study the 3D dynamics of an elastic dimer consisting of an active swimmer bound to a passive cargo, both suspended in a Couette flow. Using numerical simulations, we determine the diffusivity of such an active dimer in the presence of long-range hydrodynamic interactions for different values of its self propulsion speed and the Couette flow. We observe that the effect of hydrodynamic interactions is greatly enhanced under the condition that self-propulsion is strong enough to contrast the shear flow. The magnitude of the effect grows with the size of the dimer's constituents relative to their distance, which makes it appreciable under experimental conditions. PMID- 28345094 TI - A metal-organic framework devised Co-N doped carbon microsphere/nanofiber hybrid as a free-standing 3D oxygen catalyst. AB - A Co-N doped 3D carbon microsphere/nanofiber hybrid was produced by electrospinning. We can effectively control the morphology transformation from a pearl necklace-like nanofiber to a microsphere/nanofiber hybrid. The hybrid shows Pt-like oxygen reduction reaction activity both in acidic and basic solutions, making it one of the best non-noble metal oxygen catalysts. PMID- 28345095 TI - A simple functional carbon nanotube fiber for in vivo monitoring of NO in a rat brain following cerebral ischemia. AB - Nitric oxide (NO) is key free-radical messenger and neuronal signal which is closely related to many brain diseases. It is a challenge to develop a sensitive and reliable biosensor for in vivo monitoring of NO in the brain. In this research, a simple ratiometric electrochemical biosensor for NO monitoring in rat brain following cerebral ischemia was developed using a carbon nanotube fiber (CNF) modified with hemin, in which the CNF not only served as a platform to assemble the hemin molecule, but greatly facilitated the electron transfer of hemin on to the electrode surface. Additionally, the hemin molecule was found to play dual roles: as a stable catalyst for the reduction of NO for selective detection of NO at -0.67 V versus silver/silver chloride, as well as an inner reference element to provide a built-in correction, to avoid the interference from the complicated brain environment. The developed ratiometric biosensor can detect NO with a linear range from 25 to 1000 nM, with a low limit of detection down to 10 nM, which fulfills the requirements for in vivo measurement of NO. The remarkable analytical performance of the present biosensor, as well as the long term stability and good reproducibility established this as a reliable approach for in vivo monitoring of NO in the hippocampus of rat brains following cerebral ischemia. This is the first report that the average level of NO increased from 61 +/- 23 nM to 141 +/- 18 nM after cerebral ischemia for 15 min. PMID- 28345096 TI - Outstanding Reviewers for Soft Matter in 2016. PMID- 28345097 TI - Tailoring single chain polymer nanoparticle thermo-mechanical behavior by cross link density. AB - Single chain polymer nanoparticles (SCPNs) are formed from intrachain cross linking of a single polymer chain, making SCPN distinct from other polymer nanoparticles for which the shape is predefined before polymerization. The degree of cross-linking in large part determines the internal architecture of the SCPNs and therefore their mechanical and thermomechanical properties. Here, we use molecular dynamics (MD) simulations to study thermomechanical behavior of individual SCPNs with different underlying structures by varying the ratio of cross-linking and the degree of polymerization. We characterize the particles in terms of shape, structure, glass transition temperature, mobility, and stress response to compressive loading. The results indicate that the constituent monomers of SCPNs become less mobile as the degree of cross-linking is increased corresponding to lower diffusivity and higher stress at a given temperature. PMID- 28345098 TI - A chiral cobalt(ii) complex catalyzed asymmetric formal [3+2] cycloaddition for the synthesis of 1,2,4-triazolines. AB - A highly efficient catalytic asymmetric formal [3+2] cycloaddition reaction of 5 alkoxyoxazoles with azodicarboxylate compounds has been realized by a chiral N,N' dioxide/Co(BF4)2.6H2O complex. A series of poly-substituted 1,2,4-triazolines compounds were obtained in moderate to excellent yields (70-99%) with excellent enantioselectivities (82-98% ee). PMID- 28345099 TI - Ultrasensitive nanoparticle enhanced laser-induced breakdown spectroscopy using a super-hydrophobic substrate coupled with magnetic confinement. AB - In this study, we developed a substrate to enhance the sensitivity of LIBS by 5 orders of magnitude. Using a combination of field enhancement due to the metal nanoparticles in the substrate, the aggregate effect of super-hydrophobic interfaces and magnetic confinement, we performed a quantitative measurement of copper in solution with concentrations on the ppt level. We also demonstrated that the substrate improves quantitative measurements by providing an opportunity for internal standardization. PMID- 28345100 TI - Visible light-induced heterogeneous Meerwein-Ponndorf-Verley-type reduction of an aldehyde group over an organically modified titanium dioxide photocatalyst. AB - An organically modified titanium dioxide photocatalyst prepared by a simple impregnation method chemoselectively and almost quantitatively converted benzaldehydes having other reducible functional groups to the corresponding benzyl alcohols under visible light irradiation. PMID- 28345101 TI - Nontoxic organic solvents identified using an a priori approach with Hansen solubility parameters. AB - Nontoxicities of organic solvents were predicted using Hansen solubility parameters and various truly nontoxic solvents were identified according to the prediction. The nontoxicity of solvents originates from their exhibition of poor solubility or low diffusivity toward cell constituents and good stability against hydrolytic degradation. PMID- 28345102 TI - A highly stable sodium solid-state electrolyte based on a dodeca/deca-borate equimolar mixture. AB - Na2(B12H12)0.5(B10H10)0.5, a new solid-state sodium electrolyte is shown to offer high Na+ conductivity of 0.9 mS cm-1 at 20 degrees C, excellent thermal stability up to 300 degrees C, and a large electrochemical stability window of 3 V including stability towards sodium metal anodes, all essential prerequisites for a stable room-temperature 3 V all-solid-state sodium-ion battery. PMID- 28345104 TI - Biology and toxicology of tellurium explored by speciation analysis. AB - Tellurium (Te) is widely used in industry because it has unique physicochemical properties. Although Te is a non-essential element in animals and plants, it is expected to be metabolized to organometallic compounds having a carbon-Te bond in living organisms exposed to inorganic Te compounds. Thus, the speciation and identification of tellurometabolites are expected to contribute to the depiction of the metabolic chart of Te. Speciation by elemental mass spectrometry and identification by molecular mass spectrometry coupled with separation techniques have significantly contributed to the discovery of tellurometabolites in animals and plants. The aim of this mini review is to present recent advances in the biology and toxicology of tellurium as revealed by speciation and identification by molecular mass spectrometry. PMID- 28345103 TI - 1,2-Difunctionalization-type (hetero)arylation of unactivated alkenes triggered by radical addition/remote (hetero)aryl migration. AB - A novel difunctionalization-type (hetero)arylation of unactivated alkenes has been developed via remote 1,4(5)-(hetero)aryl migration triggered by radical alkene azidation, trifluoromethylation, or phosphonylation. The overall process serves as an unusual and reliable approach for straightforward access to diversely substituted ketones with broad functional group compatibility from readily available substrates and reagents. PMID- 28345105 TI - Phase behavior of colloid-polymer depletion mixtures with unary or binary depletants. AB - Adding depletants to a colloidal suspension induces an attractive interparticle interaction that can be tuned to obtain desired structures or to probe phase behavior. When the depletant is not uniform in size, however, both the range and strength of the attraction become difficult to predict and hence control. We investigated the effects of depletant bidispersity on the non-equilibrium phase behavior of colloid-polymer mixtures. We added unary or binary mixtures of polystyrene as the depletant to suspensions of charged poly(methyl methacrylate) particles. The structure and dynamics of the particles were compared over three sets of samples with various mixtures of two different polystyrenes whose size varied by an order of magnitude. The structure and dynamics were nearly independent of depletant dispersity if the polymer concentration was represented as a sum of normalized concentrations of each species. Near the transition region between a fluid of clusters and an interconnected gel at intermediate volume fractions, partitioning of polymers in a binary mixture into colloid-rich and polymer-rich phase leads to a slightly different gelation pathway. PMID- 28345106 TI - Phenylamine-functionalized mesoporous silica supported PdAg nanoparticles: a dual heterogeneous catalyst for formic acid/CO2-mediated chemical hydrogen delivery/storage. AB - A PdAg-based nanoparticle catalyst supported on the mesoporous silica material, SBA-15, modified with a weakly basic phenylamine functional group has been developed as a dual heterogeneous catalyst for the H2 delivery and H2 storage reactions mediated by formic acid and carbon dioxide. PMID- 28345107 TI - The smallest cucurbituril analogue with high affinity for Ag. AB - A new host, Me8TD[4], was prepared for the first time from propanediurea formaldehyde condensation in the presence of CaCl2 as the template and it is the smallest cucurbituril analogue reported so far. Measurements of the thermodynamic quantities (log K, DeltaH, and DeltaS values) of the interactions of Me8TD[4] with a series of cations by isothermal titration calorimetry indicated that Me8TD[4] binds selectively towards Ag+ with a high binding constant, K ~ 1.3 * 106 M-1. PMID- 28345108 TI - Specific Contributions of Age of Onset, Callous-Unemotional Traits and Impulsivity to Reactive and Proactive Aggression in Youths with Conduct Disorders. AB - Youths with conduct disorders (CD) are particularly studied for their violent and aggressive behaviors. Many researchers considered aggressive behaviors as being either reactive or proactive. Moreover, factors such as age of CD onset, impulsivity, and callous-unemotional traits, separately, have been related to these different types of aggressive behaviors. However, very few studies addressed the combined contribution of these three factors on proactive and reactive aggression. This question was tested in a sample composed of 43 male adolescents with CD. A single regression analysis including all predictors and outcomes, using Bayesian statistics, was computed. Results indicated that impulsivity was related to reactive aggression, while CU traits were related to proactive aggression. These results suggest first, an important heterogeneity among youth with CD, probably leading to different trajectories and, second, that youths with callous-unemotional traits should receive special attention and care as they are more at risk for proactive aggression. PMID- 28345110 TI - Prediction of fetal loss by first-trimester crown-rump length in IVF pregnancies: prediction rules to avoid misinterpretation. PMID- 28345109 TI - Description of Four New Species of Genus Acanthaegilips Ashmead, 1897 (Hymenoptera: Figitidae: Anacharitinae) from Colombia. AB - There are four new species of the Neotropical Anacharitinae genus Acanthaegilips Ashmead, 1897: A. boyacensis sp. n., A. curvis sp. n., A. timidus sp. n., and A. truncatus sp. n. The diagnostic characters of this new species and data about their morphological variability and similarities with other Acantahegilips species are discussed. An updated key of genus Acanthaegilips is included. PMID- 28345111 TI - Prenatal ultrasonic diagnosis and differential diagnosis of isolated right aortic arch with mirror-image branching. AB - PURPOSE: This study sought to evaluate the fetal echocardiography features of isolated right aortic arch (RAA) with mirror-image branching and to improve the rate and accuracy of prenatal diagnosis of this condition. METHODS: We reviewed fetal echocardiograms from all cases of isolated RAA with mirror-image branching diagnosed at our institution between August 2012 and December 2015 and classified these cases into normal and abnormal types of ductus arteriosus based on the course of the arterial duct arch. We confirmed the diagnoses by postnatal echocardiography. RESULTS: A total of 11 cases of isolated RAA with mirror-image branching, with the left ductus and the descending aorta located on the left side of the spine, were diagnosed using fetal echocardiography. Ten cases involved normal ductus arteriosus, with the left ductus connecting the left pulmonary artery to the descending aorta, five of which were referred to our institution for suspicions of double aortic aorta. 1 case involved abnormal ductus arteriosus, with the left ductus connecting the left pulmonary artery to the left innominate artery. CONCLUSIONS: RAA with mirror-image branching can be detected via fetal echocardiography, which can reveal the relationship between of the aortic arch and the trachea and can enable the identification of the course of brachiocephalic branching. The identification of isolated RAA with mirror-image branching is crucial for distinguishing this condition from other types of aortic arch anomalies, particularly double aortic aorta, which can have a rather different prognosis. PMID- 28345112 TI - Experience with direct acting anti-viral agents for treating hepatitis C virus infection in renal transplant recipients. AB - In recent past, direct-acting anti-viral drugs (DAAs) have become the standard of care for the treatment of hepatitis C virus (HCV) infection. However, the experience with the use of these drugs in Indian renal transplant recipients is limited. We retrospectively reviewed our experience with DAA-based treatment for HCV infection in such patients. Between April 2015 and December 2016, six adults (median age 41 [range 34-52] years, male 5; GT1 2, GT3 3, and GT4 1; including three with prior failed interferon-based treatment) had received genotype-guided, DAA-based anti-HCV treatment 1 to 158 (median 15) months after renal transplantation. Of them, four completed the planned 24-week treatment without any significant adverse event. One of them had increase in serum creatinine after 16 weeks of treatment with sofosbuvir and daclatasvir, with acute interstitial nephritis on kidney biopsy; his renal function improved on stopping the drugs. The other patient had preexisting mild renal dysfunction, which worsened after 8 weeks of sofosbuvir-ledipasvir treatment; this did not reverse on stopping treatment. All the six patients achieved undetectable HCV RNA after 4 weeks of treatment and also achieved sustained virologic response, i.e. lack of detectable HCV RNA in serum 12 weeks after stopping treatment. Overall, DAA-based treatment was effective in treating HCV infection in our renal transplant recipients; however, caution and monitoring of renal function during such treatment is advisable in patients who have additional factors that predispose to renal injury. PMID- 28345114 TI - Peripheral Endothelial Function After Arterial Switch Operation for D-looped Transposition of the Great Arteries. AB - Coronary artery re-implantation during arterial switch operation in patients with D-looped transposition of the great arteries (D-TGA) can alter coronary arterial flow and increase shear stress, leading to local endothelial dysfunction, although prior studies have conflicting results. Endothelial pulse amplitude testing can predict coronary endothelial dysfunction by peripheral arterial testing. This study tested if, compared to healthy controls, patients with D-TGA after arterial switch operation had peripheral endothelial dysfunction. Patient inclusion criteria were (1) D-TGA after neonatal arterial switch operation; (2) age 9-29 years; (3) absence of known cardiovascular risk factors such as hypertension, diabetes, hypercholesterolemia, vascular disease, recurrent vasovagal syncope, and coronary artery disease; and (4) ability to comply with overnight fasting. Exclusion criteria included (1) body mass index >=85th percentile, (2) use of medications affecting vascular tone, or (3) acute illness. We assessed endothelial function by endothelial pulse amplitude testing and compared the results to our previously published data in healthy controls (n = 57). We tested 20 D-TGA patients (16.4 +/- 4.8 years old) who have undergone arterial switch operation at a median age of 5 days (0-61 days). Endothelial pulse amplitude testing indices were similar between patients with D-TGA and controls (1.78 +/- 0.61 vs. 1.73 +/- 0.54, p = 0.73).In our study population of children and young adults, there was no evidence of peripheral endothelial dysfunction in patients with D-TGA who have undergone arterial switch operation. Our results support the theory that coronary arterial wall thickening and abnormal vasodilation reported in these patients is a localized phenomenon and not reflective of overall atherosclerotic burden. PMID- 28345115 TI - Counseling Practices for Fetal Hypoplastic Left Heart Syndrome. AB - While counseling parents of a fetus diagnosed with hypoplastic left heart syndrome (HLHS), pediatric cardiologists play a critical role in shaping a family's expectations for the months and years to come. However, techniques for the most effective counseling practices have not been studied, and significant variation among physicians is likely present. Web-based survey of pediatric cardiologists that perform fetal echocardiography using snowball sampling. 201 physicians responded (61% male, 81% from academic centers, and 95% from the U.S.), with an average experience of 12 years. The majority of respondents (73%) typically received initial referrals for HLHS between 20 and 24 weeks of gestation. Most physicians counsel families alone (54%), while others counsel with a nurse (35%), social worker (12%), and/or maternal-fetal medicine colleague (15%). Termination of pregnancy was discussed by 79% of respondents, although 15% did not know their state's legal limit for termination. While initial counseling sessions routinely described the typical earlier ramifications of HLHS, many long term sequelae of the disease were not commonly discussed. Content of counseling was affected by region of the country, but not by practice setting, experience, or fetal volume. Respondents identified multiple barriers that limited their counseling practices. Our data suggest that current counseling practices often fail to cover important information. Perceived barriers to a full discourse on long-term sequelae of HLHS are common and may lead to a disconnect between reality and a family's understanding of the natural history of palliated HLHS. Opportunities to improve counseling practices exist, and there may be benefits to gain from more formal training. PMID- 28345116 TI - Oligomeric State and Thermal Stability of Apo- and Holo- Human Ornithine delta Aminotransferase. AB - Human ornithine delta-aminotransferase (hOAT) (EC 2.6.1.13) is a mitochondrial pyridoxal 5'-phosphate (PLP)-dependent aminotransferase whose deficit is associated with gyrate atrophy, a rare autosomal recessive disorder causing progressive blindness and chorioretinal degeneration. Here, both the apo- and holo-form of recombinant hOAT were characterized by means of spectroscopic, kinetic, chromatographic and computational techniques. The results indicate that apo and holo-hOAT (a) show a similar tertiary structure, even if apo displays a more pronounced exposure of hydrophobic patches, (b) exhibit a tetrameric structure with a tetramer-dimer equilibrium dissociation constant about fivefold higher for the apoform with respect to the holoform, and (c) have apparent Tm values of 46 and 67 degrees C, respectively. Moreover, unlike holo-hOAT, apo hOAT is prone to unfolding and aggregation under physiological conditions. We also identified Arg217 as an important hot-spot at the dimer-dimer interface of hOAT and demonstrated that the artificial dimeric variant R217A exhibits spectroscopic properties, Tm values and catalytic features similar to those of the tetrameric species. This finding indicates that the catalytic unit of hOAT is the dimer. However, under physiological conditions the apo-tetramer is slightly less prone to unfolding and aggregation than the apo-dimer. The possible implications of the data for the intracellular stability and regulation of hOAT are discussed. PMID- 28345117 TI - Inwardly Rectifying K+ Currents in Cultured Oligodendrocytes from Rat Optic Nerve are Insensitive to pH. AB - Inwardly rectifying K+ (Kir) channel expression signals at an advanced stage of maturation during oligodendroglial differentiation. Knocking down their expression halts the generation of myelin and produces severe abnormalities in the central nervous system. Kir4.1 is the main subunit involved in the tetrameric structure of Kir channels in glial cells; however, the precise composition of Kir channels expressed in oligodendrocytes (OLs) remains partially unknown, as participation of other subunits has been proposed. Kir channels are sensitive to H+; thus, intracellular acidification produces Kir current inhibition. Since Kir subunits have differential sensitivity to H+, we studied the effect of intracellular acidification on Kir currents expressed in cultured OLs derived from optic nerves of 12-day-old rats. Unexpectedly, Kir currents in OLs (2-4 DIV) did not change within the pH range of 8.0-5.0, as observed when using standard whole-cell voltage-clamp recording or when preserving cytoplasmic components with the perforated patch-clamp technique. In contrast, low pH inhibited astrocyte Kir currents, which was consistent with the involvement of the Kir4.1 subunit. The H+ insensitivity expressed in OL Kir channels was not intrinsic because Kir cloning showed no difference in the sequence reported for the Kir4.1, Kir2.1, or Kir5.1 subunits. Moreover, when Kir channels were heterologously expressed in Xenopus oocytes they behaved as expected in their general properties and sensitivity to H+. It is therefore concluded that Kir channel H+-sensitivity in OLs is modulated through an extrinsic mechanism, probably by association with a modulatory component or by posttranslational modifications. PMID- 28345119 TI - Metabolism of Mannose in Cultured Primary Rat Neurons. AB - Glucose is the main peripheral substrate for energy production in the brain. However, as other hexoses are present in blood and cerebrospinal fluid, we have investigated whether neurons have the potential to metabolize, in addition to glucose, also the hexoses mannose, fructose or galactose. Incubation of primary cerebellar granule neurons in the absence of glucose caused severe cell toxicity within 24 h, which could not be prevented by application of galactose or fructose, while the cells remained viable during incubation in the presence of either mannose or glucose. In addition, cultured neurons produced substantial and almost identical amounts of lactate after exposure to either glucose or mannose, while lactate production was low in the presence of fructose and hardly detectable during incubations without hexoses or with galactose as carbon source. Determination of the KM values of hexokinase in lysates of cultured neurons for the hexoses revealed values in the micromolar range for mannose (32 +/- 2 uM) and glucose (59 +/- 10 uM) and in the millimolar range for fructose (4.4 +/- 2.3 mM), demonstrating that mannose is efficiently phosphorylated by neuronal hexokinase. Finally, cultured neurons contained reasonable specific activity of the enzyme phosphomannose isomerase, which is required for isomerization of the hexokinase product mannose-6-phosphate into the glycolysis intermediate fructose-6 phosphate. These data demonstrate that cultured cerebellar granule neurons have the potential and express the required enzymes to efficiently metabolize mannose, while galactose and fructose serve at best poorly as extracellular carbon sources for neurons. PMID- 28345120 TI - Fission Yeast srm1 is Involved in Stress Response and Cell Cycle. AB - Polyamines are well-conserved, multifunctional polycations that contribute to a number of processes in the cells such as cell cycle, apoptosis, stress response, and gene expression. Therefore, polyamine levels should be kept under strict regulation by specific polyamine transporters and polyamine synthases. In this study, the aim is to experimentally characterize a predicted spermidine synthase gene srm1, which was identified upon sequence similarity, in fission yeast Schizosaccharomyces pombe. In an attempt to understand the role of this gene in cell cycle and stress response, deletion mutant of srm1 was generated and analyzed in terms of cell cycle regulation and environmental stress response. The results showed that srm1Delta cells had elongated cell size and were sensitive to osmotic stress, while they showed no sensitivity to DNA-damaging agents. To the best of our knowledge, this is the first experimental characterization of srm1 gene and its role in cell cycle progression and stress response. PMID- 28345118 TI - Effect of Paullinia cupana Mart. Commercial Extract During the Aging of Middle Age Wistar Rats: Differential Effects on the Hippocampus and Striatum. AB - During aging, there is a marked decline in the antioxidant capacity of brain tissue, leading to a gradual loss of the antioxidant/oxidant balance, which causes oxidative damage. The effects of Paullinia cupana Mart. extract, which is described as being rich in caffeine and many polyphenol compounds, on the central nervous system have not been extensively investigated. The aim of this study was to therefore investigate the effect of a commercial guarana extract (CGE) on cognitive function, oxidative stress, and brain homeostasis proteins related to cognitive injury and senescence in middle age, male Wistar rats. Animals were randomly assigned to a group according to their treatment (saline, CGE, or caffeine). Solutions were administered daily by oral gavage for 6 months. Open field and novel object recognition tasks were performed before and after treatment. Biochemical analyses were carried out on the hippocampus and striatum. Our open field data showed an increase in exploratory activity and a decrease in anxiety-like behavior with caffeine but not with the CGE treatment. In the CGE treated group, catalase activity decreased in the hippocampus and increased in the striatum. Analyses of the hippocampus and striatum indicate that CGE and/or caffeine altered some of the analyzed parameters in a tissue-specific manner. Our data suggest that CGE intake does not improve cognitive development, but modifies the oxidative stress machinery and neurodegenerative-signaling pathway, inhibiting pro-survival pathway molecules in the hippocampus and striatum. This may contribute to the development of unfavorable microenvironments in the brain and neurodegenerative disorders. PMID- 28345123 TI - Traumatic Pseudoaneurysms of the Head in War Time: Report of Two Unusual Cases. AB - Either intracranial or extracranial pseudoaneurysms due to penetrating head injuries with gunshot are very rare entities. As the pseudoaneurysms of the superficial temporal artery are represented commonly with a pulsating mass lesion beneath scalp, the intracranial pseudoaneurysms are represented with symptoms including decreased conscious level, seizure, or focal neurological deficits. Here, two patients with combat related pseudoaneurysms are reported; one was in distal cortical branch of anterior cerebral artery and one was in superficial temporal artery. Both of the cases were victims of Libyan war. One was admitted with a swelling in his scalp and a pseudoaneurysms on parietal branch of superficial temporary artery diagnosed with computed tomography; and the other was incidentally diagnosed on distal cortical branch of anterior cerebral artery during operation for removal of an intracranial bullet. Both of the aneurysms treated with surgical excision without any complication. PMID- 28345121 TI - Outcomes of a Randomized Controlled Trial of Genomic Counseling for Patients Receiving Personalized and Actionable Complex Disease Reports. AB - There has been very limited study of patients with chronic disease receiving potentially actionable genomic based results or the utilization of genetic counselors in the online result delivery process. We conducted a randomized controlled trial on 199 patients with chronic disease each receiving eight personalized and actionable complex disease reports online. Primary study aims were to assess the impact of in-person genomic counseling on 1) causal attribution of disease risk, 2) personal awareness of disease risk, and 3) perceived risk of developing a particular disease. Of 98 intervention arm participants (mean age = 57.8; 39% female) randomized for in-person genomic counseling, 76 (78%) were seen. In contrast, control arm participants (n = 101; mean age = 58.5; 54% female) were initially not offered genomic counseling as part of the study protocol but were able to access in-person genomic counseling, if they requested it, 3-months post viewing of at least one test report and post completion of the study-specific follow-up survey. A total of 64 intervention arm and 59 control arm participants completed follow-up survey measures. We found that participants receiving in-person genomic counseling had enhanced objective understanding of the genetic variant risk contribution for multiple complex diseases. Genomic counseling was associated with lowered participant causal beliefs in genetic influence across all eight diseases, compared to control participants. Our findings also illustrate that for the majority of diseases under study, intervention arm participants believed they knew their genetic risk status better than control arm subjects. Disease risk was modified for the majority during genomic counseling, due to the assessment of more comprehensive family history. In conclusion, for patients receiving personalized and actionable genomic results through a web portal, genomic counseling enhanced their objective understanding of the genetic variant risk contribution to multiple common diseases. These results support the development of additional genomic counseling interventions to ensure a high level of patient comprehension and improve patient centered health outcomes. PMID- 28345122 TI - Effect of laser on pain relief and wound healing of recurrent aphthous stomatitis: a systematic review. AB - The aim of this systematic review was to assess a potential benefit of laser use in the treatment of recurrent aphthous stomatitis (RAS). The primary outcome variables were pain relief, duration of wound healing and reduction in episode frequency. A PICO approach was used as a search strategy in Medline, Embase and Cochrane databases. After scanning and excluding titles, abstracts and full texts, 11 studies (ten RCTs and one non-randomised controlled trial) were included. Study selection and data extraction was done by two observers. Study participants varied between 7-90 for the laser and 5-90 for the control groups. Laser treatment included Nd:YAG laser ablation, CO2 laser applied through a transparent gel (non-ablative) and diode laser in a low-level laser treatment (LLLT) mode. Control groups had placebo, no therapy or topical corticosteroid treatment. Significant pain relief immediately after treatment was found in five out of six studies. Pain relief in the days following treatment was recorded in seven studies. The duration of RAS wound healing was also reduced in five studies. However, criteria of evaluation differed between the studies. The episode frequency was not evaluated as only one study addressed this outcome parameter, but did not discriminate between the study (LLLT) and control (corticosteroid) groups. Jadad scores (ranging from 0 to 5) for quality assessment of the included studies range between 0 and 2 (mean = 1.0) for studies analysing pain relief and between 0 and 3 (mean = 1.1) for studies evaluating wound healing. The use of lasers (CO2 laser, Nd:YAG laser and diode laser) to relieve symptoms and promote healing of RAS is a therapeutic option. More studies for laser applications are necessary to demonstrate superiority over topical pharmaceutical treatment and to recommend a specific laser type, wavelength, power output and applied energy (ablative versus photobiomodulation). PMID- 28345124 TI - Evaluation of Cortical Brain Parenchyma by Diffusion and Perfusion MRI Before and After Chronic Subdural Hematoma Surgery. AB - AIM: To evaluate microcirculatory changes in neighboring parenchyma as a result of pressure due to chronic subdural hematoma (CSDH) in early and late periods after hematoma drainage. MATERIAL AND METHODS: The subject group consisted of 25 patients who underwent CSDH drainage. Brain diffusion and perfusion magnetic resonance images (MRIs) were obtained preoperatively, and at 48 hours (early period) and 2 months (late period) postoperatively. Measurements were performed on 1 cm2 regions of interest (ROI) in the neighboring parenchymal tissue. RESULTS: The early postoperative diffusion values showed improvement compared to the preoperative values. The late postoperative values showed improvement compared to the preoperative and early postoperative values. The early postoperative perfusion values showed slight decline compared to the preoperative values. However, the late postoperative values showed improvement compared to the preoperative and early postoperative values. CONCLUSION: The fact that there was an increase in diffusion values from early to late postoperative periods, compared with the preoperative period, indicates that the beneficial effects of surgery increase over time. Brain perfusion was found to be slightly decreased in early postoperative period. Following CSDH drainage, neurological deteriorations are observed in some patients in the early postoperative periods; a slight impairment in perfusion may account for this. However, during the late postoperative period, perfusion was seen to recover prominently. PMID- 28345125 TI - New Clues in the Malignant Progression of Glioblastoma: Can the Thioredoxin System Play a Role? AB - AIM: To evaluate and compare the expression of thioredoxin reductase 1 (TrxR1) in primary and secondary glioblastoma samples. MATERIAL AND METHODS: Surgically resected human glioblastoma samples from 40 patients who underwent surgery at our institution were extracted from their histopathological specimens and divided into three groups. Ten histopathologically regular cerebral tissue samples, acquired from the non-neoplastic portion of the specimens, were assigned as the control group. Twenty specimens that included tumoral tissue from each type of glioblastoma (WHO grade IV, primary and secondary) were assigned as the primary and secondary glioblastoma groups. TrxR1 expression was analyzed by using both quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry. Isocitrate dehydrogenase 1 (IDH1) mutation was analyzed by immunohistochemistry. Ki-67 proliferative index and apoptosis were also analyzed by immunohistochemistry. The differences between the groups were statistically compared and the correlation between these parameters was analyzed. RESULTS: The expressions of TrxR1 and Ki-67 values were significantly higher in primary glioblastoma. IDH1 mutation was significantly higher in secondary glioblastoma. TrxR1 expression was found to be highly correlated with the Ki-67 index. The apoptotic index was similar between primary and secondary glioblastoma. CONCLUSION: This study showed a high TrxR1 expression in primary glioblastoma which could indicate a role of the Trx system in promoting the malignant progression by some complex processes. PMID- 28345126 TI - Open-door Laminoplasty with Preservation of Muscle Attachments of C2 and C7 for Cervical Spondylotic Myelopathy: Retrospective Study. AB - AIM: Some restriction and complications, such as progression of kyphosis, incidence of axial neck pain and decrease of postoperative cervical range of motion are concern. We designed this retrospective clinical study to evaluate the effect of laminoplasty by preserving the muscle attachments of C2 and C7 spinous processes on range of motion (ROM), axial neck pain and cervical lordosis. MATERIAL AND METHODS: Twenty-seven cases with cervical spondylotic myelopathy underwent open-door laminoplasty with the protection of muscle attachments to the C2 and C7 spinous process and laminae between 2007 and 2013. At the end of the followup, cases were evaluated with preoperative and postoperative modified Japanese Orthopedic Association (mJOA) scores, recovery rate, ROM, lordosis angle and visual analogue scale (VAS). Also, patients were divided into two groups and evaluated according to the magnetic resonance imaging (MRI) findings, with or without T2 signal change. RESULTS: The mean age of the patients was 66 years. The mean follow-up duration was 25 months. The postoperative mJOA scores were significantly higher than the preoperative mJOA scores (p < 0.001). The recovery rate was 57.4%. Although the postoperative VAS score was higher than the preoperative VAS score and the mean postoperative ROM was lower than the preoperative ROM there was no significant difference between preoperative and postoperative VAS score and ROM (p > 0.05). The postoperative lordosis angle was significantly lower than the preoperative lordosis angle (p < 0.05). There were no significant differences regarding the postoperative lordosis angle, ROM and mJOA scores with or without T2 signal change on MRI. CONCLUSION: Protection of the anatomic structures around the cervical spine such as the muscles and ligaments provides us better results regarding ROM and cervical axial pain. PMID- 28345127 TI - Zoledronate promotes bone formation by blocking osteocyte-osteoblast communication during bone defect healing. AB - Nitrogen-containing bisphosphonates (N-BPs) are potent antiresorptive drugs and their actions on osteoclasts have been studied extensively. Recent studies have suggested that N-BPs also target bone-forming cells. However, the precise mechanism of N-BPs in osteoblasts is paradoxical, and the specific role of osteocytes is worthy of in-depth study. Here, we investigated the cellular mechanisms of N-BPs regulating bone defect healing by zoledronate (ZA). Bone histomorphometry confirmed an increase in new bone formation by systemic ZA administration. ZA induced more alkaline phosphatase-positive osteoblasts and tartrate-resistant acid phosphatase-positive osteoclasts residing on the bone surface. Inexplicably, ZA increased SOST expression in osteocytes embedded in the bone matrix, which was not compatible with the intense osteoblast activity on the bone surface. ZA induced heterogeneous osteocytes and disturbed the distribution of the osteocytic-canalicular system (OLCS). Furthermore, according to the degree of OLCS regularity, dentin matrix protein 1 reactivity had accumulated around osteocytes in the ZA group, but it was distributed evenly in the OLCS of the control group. The control group showed a dense array of the gap junction protein connexin 43. However, connexin 43 was extremely sparse after ZA administration. In summary, ZA treatment reduces gap junction connections and blocks cellular communication between osteocytes and osteoblasts. Retaining SOST expression in osteocytes leads to activation of the Wnt signaling pathway and subsequent bone formation. PMID- 28345128 TI - RS9, a novel Nrf2 activator, attenuates light-induced death of cells of photoreceptor cells and Muller glia cells. AB - The retina is highly sensitive to oxidative stress because of its high consumption of oxygen associated with the phototransductional processes. Recent findings have suggested that oxidative stress is involved in the pathology of age related macular degeneration, a progressive degeneration of the central retina. A well-known environmental risk factor is light exposure, as excessive and continuous light exposure can damage photoreceptors. Nuclear factor-erythroid 2 related factor 2 (Nrf2) is a transcriptional factor that controls antioxidative responses and phase 2 enzymes. Thus, we hypothesized that RS9, a specific activator of Nrf2, decreases light-induced retinal cell death in vivo and in vitro. Nrf2 was detected in the nucleus of the 661W cells exposed to RS9 and also after light exposure, and the Nrf2-antioxidant response element binding was increased in 661W cells after exposure to RS9. Consequentially, the expression of the phase 2 enzyme's mRNAs of Ho-1, Nqo-1, and Gclm genes was increased in 661W cells after exposure to RS9. Furthermore, RS9 decreased the light-induced death of 661W cells (2500 lux, 24 h), and also reduced the functional damages and the histological degeneration of the nuclei in the outer nuclear layer or the retina in the in vivo studies (8000 lux, 3 h). Heme oxygenase-1 was increased after light exposure, and Nrf2 was translocated into the nucleus after light exposure in vivo. Silencing of Ho-1 reduced the protective effects of RS9 against light induced death of 661W cells. These findings indicate that RS9 has therapeutic potential for retinal diseases that are aggravated by light exposure. PMID- 28345129 TI - The effect of microwave on the interaction of flavour compounds with G-actin from grass carp (Catenopharyngodon idella). AB - BACKGROUND: In order to investigate the influence of non-thermal effects of microwaves on the flavour of fish and meat products, the G-actin of grass carp in ice baths was exposed to different microwave powers (0, 100, 300 or 500 W); the surface hydrophobicity, sulfhydryl contents, secondary structures and adsorption capacity of G-actin to ketones were determined. RESULTS: As microwave power increased from 0 to 300 W, the surface hydrophobicity, total and reactive sulfhydryls increased; alpha-helix, beta-sheet and random coil fractions turned into beta-turn fractions. As microwave power increased from 300 to 500 W, however, hydrophobicity and sulfhydryl contents decreased; beta-turn and random coil fractions turned into alpha-helix and beta-sheet fractions. The tendencies of adsorbed capacity of ketones were similar to hydrophobicity and sulfhydryl contents. CONCLUSION: The increased adsorbing of ketones could be attributed to the unfolding of secondary structures by revealing new binding sites, including thiol groups and hydrophobic binding sites. The decreased binding capacity was related to the refolding and aggregation of protein. The results suggested that microwave powers had obvious effects on the flavour retention and proteins structures in muscle foods. (c) 2017 Society of Chemical Industry. PMID- 28345130 TI - Antiallodynic Activity of Ceftriaxone and Clavulanic Acid in Acute Administration is Associated with Serum TNF-alpha Modulation and Activation of Dopaminergic and Opioidergic Systems. AB - Preclinical Research The aim of this study was to determine the antiallodynic effect of acute administration of the beta-lactam antimicrobials, ceftriaxone (CFX) and clavulanic acid (CLAV), for the control of established pain on a model of neuropathic pain (NP). We also investigated the involvement of dopaminergic and opioidergic pathways as well as alterations in serum concentrations of TNF alpha in the antiallodynic actions of these drugs. CFX, CLAV, or gabapentin (GAP), a reference drug, were administered i.p. twelve days after constriction of the sciatic nerve in rats. Mechanic and cold allodynia were evaluated for 3 h and alterations in serum concentration of TNF-alpha determined. Both CFX and CLAV had antiallodynic effects in response to mechanical and cold stimulation, similar to GAP. The antiallodynic effects of CFX and CLAV were blocked by haloperidol (HAL), a D2 receptor antagonist, and by naloxone (NLX), an opioid receptor antagonist. Additionally, serum TNF-alpha levels were attenuated following CFX and CLAV administration. These results suggest that acute administration of CFX and CLAV may represent a promising approach for treating the acute allodynia of NP, and that the mechanisms involved in these effects involve activation of dopaminergic and opioidergic pathways as well as modulation of TNF-alpha production. Drug Dev Res 78 : 105-115, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28345132 TI - Phenotypic and genotypic features in pediatric and adult mitochondrial disorders. PMID- 28345131 TI - Effect of botulinum toxin on inducibility and maintenance of atrial fibrillation in ovine myocardial tissue. AB - BACKGROUND: Aberrant vagal stimulation may promote the generation and propagation of atrial fibrillation (AF). Researchers have suggested that botulinum toxin (BTX), a neurotoxin that decreases neural vagal stimulation, may decrease the incidence of postoperative AF. The exact electrophysiologic mechanism underlying the observations and histopathologic alterations associated with BTX are unclear. OBJECTIVE: To investigate the electrophysiologic, functional, and histopathologic effects of BTX on fibrillation induction in ovine atria. METHODS: Eight sheep underwent BTX injections into their pulmonary veins, atrial fat pads, and ventricular walls. Electrophysiology with pacing was performed at baseline and 7 days after injection to evaluate the atrial effective refractory period (ERP) and vulnerability to AF with and without vagal stimulation. Echocardiography was performed at baseline and day 7. After euthanasia, histopathologic analysis was performed. RESULTS: Seven sheep completed the study. For both atria, there was significant shortening in the ERP with vagal stimulation versus no stimulation on day 0 but not on day 7. More aggressive pacing was required to induce AF in the left atrium on day 7 than on day 0. Echocardiography on day 7 showed no significant changes in ejection fraction or new wall-motion abnormalities of the left and right ventricle. Histopathologic analysis showed no significant adverse effects. CONCLUSION: The subacute BTX effect reduced the vulnerability of atrial tissue to AF induction and reduced the vagal influence on atrial ERP shortening compared to baseline levels. Direct BTX injection did not cause myocardial dysfunction or histologic adverse effects. PMID- 28345133 TI - Second primary melanoma on a patient undergoing vemurafenib therapy. A case report. AB - BACKGROUND: Several side effects have been reported during treatment with vemurafenib, including multiple benign lesions and, less frequently, atypical melanocytic proliferations and second primary melanomas. METHODS: A 46-year-old man undergoing vemurafenib therapy for metastatic malignant melanoma was clinically and dermoscopically monitored using total-body mapping. RESULTS: During BRAF inhibitor (BRAFi) treatment, the patient developed atypical melanocytic lesions and particularly secondary primary melanoma. CONCLUSIONS: Secondary melanomas are usually diagnosed during the early disease stage, and no case of advanced melanomas is reported in the literature, mostly due to careful surveillance in BRAFi-treated patients. PMID- 28345134 TI - The Association Between Political Violence and the Connection Between Bullying and Suicidality Among Palestinian Youth. AB - We examined the association between protracted political violence and the connection between bullying and suicidality among Palestinian adolescents. Data were collected from a representative sample of Palestinian students (N = 5,713) from 100 schools in the West Bank and East Jerusalem who completed an in-class survey. Students who were victims of bullying or bully victims who were exposed to political violence were at higher risk for suicide attempts compared to students who were victims of bullying or bully victims but not exposed to political violence. Political violence moderated the association between bullying and suicide attempts after controlling for socio demographic and other mental health variables. PMID- 28345135 TI - Eliminating cows' milk, but not wheat, barley or rye, increases the risk of growth deceleration and nutritional inadequacies. AB - AIM: Our study examined the growth and nutritional intake of children on milk and/or wheat, barley or rye elimination diets. METHODS: This was a nested case control study within the Finnish Type 1 Diabetes Prediction and Prevention Study. It investigated 295 children born in the Tampere University Hospital area between 1997 and 2004 on a diet without cows' milk and/or wheat, barley or rye due to food allergies and 265 matched controls. Nutritional intake was recorded with three-day food records at the ages of one, two and three years. Serial growth measurements were recorded annually up to the age of five years. RESULTS: Despite consuming a balanced diet with sufficient energy and protein, the children on milk elimination diets grew slower than the control children (p = 0.009). Wheat, barley or rye elimination was not associated with growth. The intakes of protein and calcium were lower in children in the milk elimination group than the controls, at p < 0.05 for all. However, children on elimination diets consumed less saturated fats and sugar and more vitamin C and iron than the control children. CONCLUSION: Children on elimination diets faced an increased risk of growth deceleration and suboptimal intake of several micronutrients. PMID- 28345136 TI - Twice-Weekly Hemodialysis in China: Can It Be A Better Option for Initiation or Maintenance Dialysis Therapy? AB - Cumulative evidence indicates it may be worthwhile revisiting the twice-weekly hemodialysis (HD) regimen as a valid option for individualized or incremental treatments for selected patients with end-stage renal disease. In this article, we will review the current evidences on the potential pros and cons of twice weekly HD compared to thrice-weekly HD including China's experience in the practice of twice-weekly HD. A prudent patient selection and close dialysis adequacy monitoring might be necessary for this medical treatment choice. More randomized prospective controlled studies for the critical evaluation of twice weekly dialysis are encouraged. PMID- 28345138 TI - U.S. Political Parties and Support for Suicide Prevention. AB - As a public health problem, suicidal behavior demands a community-level response, including government action. We aimed to test whether support for suicide prevention in the United States has been independent from political party affiliation (Democrat and Republican). Actions from both political parties have supported suicide prevention efforts. The only differences in support based on party affiliation showed greater support from the Democrat Party in one instance, and the Republican Party in the other. The results were consistent with the hypothesis that degree of support for suicide prevention cannot be predicted solely by political party. PMID- 28345137 TI - A comparative analysis of phosphoproteome in ovine muscle at early postmortem in relationship to tenderness. AB - BACKGROUND: Tenderness is considered to be the most important quality characteristic of meat as it is the main cause of unacceptability of meat. Post translational modification regulates protein functions that involve in postmortem changes in muscle and meat quality formation. Specifically, phosphorylation was proved to regulate postmortem glycolytic rates and meat tenderisation. However, the relationship between protein phosphorylation and meat tenderness remains unclear. This study examined the phosphoproteomes found in ovine muscle with different degrees of tenderness over time (at 0.5 h, 4 h, and 24 h postmortem). RESULTS: This study detected five, eight and nine phosphoprotein spots (>two-fold change, P < 0.05) at each respective time point. The different phosphoproteins found included glyceraldehyde-3-phosphate dehydrogenase, tropomyosin alpha-1 chain, pyruvate kinase, myosin binding protein H, glycogen phosphorylase, alpha actinin-3, and an uncharacterised protein (GN, myosin-binding protein C2, MYBPC2). Most of the different phosphoproteins maintained sarcomeric functions, or were involved in glycometabolism. CONCLUSION: Phosphorylation levels of multiple proteins that are involved in glycolysis, muscle contraction or sarcomeric structure integrity were identified in ovine muscles with different tenderness. The differential phosphorylation of these proteins explains in part the difference in meat tenderness. (c) 2017 Society of Chemical Industry. PMID- 28345139 TI - Utility of betahCG monitoring in the follow-up of medical management of miscarriage. AB - OBJECTIVE: To evaluate the percentage change in total betaeta-unit human chorionic gonadotropin (betahCG) levels (%DeltabetahCG) in the prediction of treatment outcomes following intravaginal misoprostol for missed miscarriage before 13 weeks. METHODS: A secondary analysis of a randomised controlled study of medical management of miscarriage was performed. Total betahCG levels were collected before misoprostol (baseline) and after a planned seven day interval (follow-up), when a transvaginal ultrasound (TVUS) reported a gestational sac as present or not. If no sac at TVUS, surgery was indicated on clinical criteria. %DeltabetahCG ((baseline betahCG - follow-up betahCG)/baseline betahCG * 100) was evaluated in the prediction of a sac at TVUS and surgery on clinical criteria. RESULTS: %DeltabetahCG was calculated for cases with betahCG levels within two days of misoprostol and TVUS; calculation interval determined case number. The median %DeltabetahCG for 24 cases with a persistent sac (6-9 day interval) was significantly lower than for 145 with no sac (58.75% (interquartile range (IQR): 37.59-76.69; maximum 86.54) vs 97.65% (IQR: 95.44-98.43); P < 0.0001). The median %DeltabetahCG for eight cases needing surgery on clinical criteria (5-9 day interval) was significantly lower than for 140 cases with no sac not needing surgery (79.68% (IQR: 64.63-91.15; maximum 94.06) vs 97.68% (IQR: 95.61-98.50); P < 0.0001). The area under the receiver-operator curve was 0.975 for prediction of a persistent sac and 0.944 for prediction of surgery on clinical criteria, respectively. %DeltabetahCG > 87% predicted no sac at TVUS. %DeltabetahCG > 94.5% predicted no surgery on clinical criteria. CONCLUSION: %DeltabetahCG calculation over one week reliably predicted treatment outcomes after medical management of missed miscarriage. PMID- 28345140 TI - Global trends in the burden of liver cancer. AB - BACKGROUND: The aim of this study is to describe the influence of geography, socio-economic development, and demographic shift on the trends in global incidence, mortality, and prevalence of liver cancer (LC). METHODS: Data (2012 2030) relating to LC and demographic shifts based on WHO regions and HDI areas were extracted from GLOBOCAN 2012 and analyzed to evaluate trends in incidence, mortality, and prevalence. RESULTS: The results of our study document a rising global burden of LC with the maximum impact in the WPRO region. We did not observe a definite association between LC and higher socio-economic status with the highest burden in the MHD region. For the MHD region, we noticed age reversal in burden from the younger age group currently to the older age group in the future (2030). Another finding is the high burden and early onset of disease in some low-income countries such as Mongolia, Lao PDR, and Vietnam. CONCLUSION: The results of our study demonstrate a rising global burden of LC with some significant but uneven trends based on geography, age, and socio-economic status. This information can be used to shape policy and aid strategic targeting of resources to areas with the highest burden. PMID- 28345141 TI - Prevalence of psoriasis in Brazil - a geographical survey. PMID- 28345142 TI - Application of DNA metabarcoding on faeces to identify European catfish Silurus glanis diet. AB - In this study, the results of conventional stomach-content analysis are compared with the recent DNA metabarcoding approach on faeces to identify fish species consumed by non-native European catfish Silurus glanis in the Garonne River (south-western France), with a special emphasis on anadromous prey. Fourteen prey species were identified in the stomach contents or faeces, including four anadromous fish species. Despite higher intestine than stomach emptiness, more species were identified through faecal analysis (11 of 14) than through stomach content analysis (five of 14) suggesting that DNA metabarcoding on faeces is an efficient, non-intrusive technique to study the diet of predatory fishes. PMID- 28345143 TI - Direct C-H Phosphonylation of Electron-Rich Arenes and Heteroarenes by Visible Light Photoredox Catalysis. AB - The direct transformation of ubiquitous, but chemically inert C-H bonds into diverse functional groups is an important strategy in organic synthesis that improves the atom economy and faclitates the preparation and modification of complex molecules. In contrast to the wide applications of aryl phosphonates, their synthesis via direct C-H bond phosphonylation is a less explored area. We report here a general, mild, and broadly applicable visible-light photoredox C-H bond phosphonylation method for electron-rich arenes and heteroarenes. The photoredox catalytic protocol utilizes electron-rich arenes and biologically important heteroarenes as substrates, [Ru(bpz)3 ][PF6 ]2 as photocatalyst, ammonium persulfate as oxidant, and trialkyl phosphites as the phosphorus source to provide a wide range of aryl phosphonates at ambient temperature under very mild reaction conditions. PMID- 28345144 TI - Adapting Evaluations of Alternative Payment Models to a Changing Environment. AB - OBJECTIVE: To identify the most robust methods for evaluating alternative payment models (APMs) in the emerging health care delivery system environment. STUDY DESIGN (APPROACH): We assess the impact of widespread testing of alternative payment models on the ability to find credible comparison groups. We consider the applicability of factorial research designs for assessing the effects of these models. PRINCIPAL FINDINGS: The widespread adoption of alternative payment models could effectively eliminate the possibility of comparing APM results with a "pure" control or comparison group unaffected by other interventions. In this new environment, factorial experiments have distinct advantages over the single-model experimental or quasi-experimental designs that have been the mainstay of recent tests of Medicare payment and delivery models. CONCLUSIONS: The best prospects for producing definitive evidence of the effects of payment incentives for APMs include fractional factorial experiments that systematically vary requirements and payment provisions within a payment model. PMID- 28345146 TI - Evidence for the generation of myristylated FMN by bacterial luciferase. AB - The genes responsible for the light production in bioluminescent bacteria are present as an operon, luxCDABEG. Many strains of Photobacteria carry an additional gene, termed luxF. X-ray crystallographic analysis of LuxF revealed the presence of four molecules of a flavin derivative, i.e. 6-(3'-(R)-myristyl) flavin adenine mononucleotide (myrFMN) non-covalently bound to the homodimer. In the present study, we exploited the binding of myrFMN to recombinant apo-LuxF to explore the occurrence of myrFMN in various bioluminescent bacteria. MyrFMN was detected in all bacterial strains tested including Vibrio and Aliivibrio indicating that it is more widely occurring in bioluminescent bacteria than previously assumed. We also show that apo-LuxF captures myrFMN and thereby relieves the inhibitory effect on luciferase activity. Thus our results provide support for the hypothesis that LuxF acts as a scavenger of myrFMN in bioluminescent bacteria. However, the source of myrFMN remained obscure. To address this issue, we established a cofactor regeneration enzyme-catalyzed cascade reaction that supports luciferase activity in vitro for up to 3 days. This approach enabled us to unambiguously demonstrate that myrFMN is generated in the bacterial bioluminescent reaction. Based on this finding we postulate a reaction mechanism for myrFMN generation that is based on the luciferase reaction. PMID- 28345145 TI - Air pollution and short-term clinical outcomes of patients with acute myocardial infarction. AB - Ambient air pollution is well-known to be a serious risk factor for cardiovascular diseases, stroke, and death. However, the association between air pollutants (AP) exposure and short-term clinical outcomes in acute myocardial infarction (AMI) patients (pts) has not been elucidated well. In the present study, 37 880 AMI pts were enrolled from October 2005 to December 2013 in a nationwide large-scale, prospective, multicentre Korea AMI registry (KAMIR registry; http://www.kamir.or.kr). We obtained data on AP (e.g., NO2 , SO2 , CO, O3 and PM10 ) from the Korean National Institute of Environmental Research (NIER; http://www.nier.go.kr). Clinical endpoints included death, recurrent myocardial infarction (Re-MI), any revascularization and composite of all-cause death and Re MI. Exposure to AP is defined as the average exposure to AP within 24 hours before AMI admission. We observed that a 0.01 part per million (ppm) increase in NO2 concentration, 0.001 ppm increase in SO2 concentration, and 0.1 ppm increase in CO concentration each increased the risk of total death by 9.7% (95% CI, 6.2% 13.4%), 1.9% (95% CI, 0.3%-3.6%), and 2.1% (95% CI, 0.5%-3.9%), respectively. Exceptionally, O3 decreased the risk of total death by 0.6% (95% CI -0.2% to 1.0%) per 0.01 ppm increase. PM10 was not related to any cardiovascular events. AP were each stratified into five quintiles according to ranges of AP levels. After adjusting analysis for risk variables, only high quintiles (Q4, Q5) of NO2 were positively associated with total death, cardiac death and MI, while SO2 , CO, O3 and PM10 were shown to be not related to any cardiovascular events at all levels. In AMI patients, each AP and its concentration has shown a different effect to short-term mortality and cardiovascular events. PMID- 28345147 TI - Nerve conduction velocity and cross-sectional area in ulnar neuropathy at the elbow. AB - INTRODUCTION: In the precise localization of ulnar neuropathy at the elbow (UNE) we have noted discrepancies between electrodiagnostic (EDx) and ultrasonographic (US) findings. We aimed to explore the relationship between the 2 techniques. METHODS: Four study-blind examiners took a history and performed neurologic, EDx, and US examinations of a group of prospectively recruited patients with UNE. They assessed the relationship between ulnar nerve cross-sectional area (CSA) and motor nerve conduction velocity (MNCV). RESULTS: In 106 patients with UNE at the retrocondylar (RTC) groove, the highest CSA and lowest MNCV were noted in the same short segment. In 54 patients with UNE at the humeroulnar aponeurosis (HUA), the highest CSA and lowest MNCV were noted proximal to the HUA. DISCUSSION: MNCV and CSA were highly correlated in UNE. Ulnar nerve slowing proximal to the entrapment at the HUA was surprising, but consistent with previous studies done on carpal tunnel syndrome. Muscle Nerve 56: E65-E72, 2017. PMID- 28345148 TI - Fast Self-Healing of Polyelectrolyte Multilayer Nanocoating and Restoration of Super Oxygen Barrier. AB - A self-healable gas barrier nanocoating, which is fabricated by alternate deposition of polyethyleneimine (PEI) and polyacrylic acid (PAA) polyelectrolytes, is demonstrated in this study. This multilayer film, with high elastic modulus, high glass transition temperature, and small free volume, has been shown to be a super oxygen gas barrier. An 8-bilayer PEI/PAA multilayer assembly (~700 nm thick) exhibits an oxygen transmission rate (OTR) undetectable to commercial instrumentation (<0.005 cc (m-2 d-1 atm-1 )). The barrier property of PEI/PAA nanocoating is lost after a moderate amount of stretching due to its rigidity, which is then completely restored after high humidity exposure, therefore achieving a healing efficiency of 100%. The OTR of the multilayer nanocoating remains below the detection limit after ten stretching-healing cycles, which proves this healing process to be highly robust. The high oxygen barrier and self-healing behavior of this polymer multilayer nanocoating makes it ideal for packaging (food, electronics, and pharmaceutical) and gas separation applications. PMID- 28345149 TI - Trichomonas vaginalis exosome-like vesicles modify the cytokine profile and reduce inflammation in parasite-infected mice. AB - Trichomonas vaginalis (Tv) is a flagellated parasite commonly spread through sexual transmission. This protozoan initiates a severe inflammatory process, inducing nitric oxide, interleukin-6 (IL-6), IL-8, IL-10, IL-17 and IL-22 production by host immune cells. The parasites elicit these responses by releasing surface lipophosphoglycan, small extracellular vesicles (exosomes) and other factors. Tv exosomes are similar to mammalian exosomes and have been implicated in the modulation of IL-8 secretion by epithelial cells. Here, we report that exosome-like vesicles from T. vaginalis (Tv-ELVs) induced a more than 15-fold increase in IL-10 expression in RAW264.7 macrophages but only a two fold increase in IL-6 and TNF-alpha expression levels measured by RT-PCR. Because Tv ELVs modulated the macrophage response, we also explored the effect of Tv-ELVs in a murine model of infection. Pretreatment with Tv-ELVs significantly increased IL 10 production as measured in vaginal washes by days 8 and 16 post-infection. Remarkably, Tv-ELVs-pretreated mice exhibited a decrease in IL-17 production and a significant decrease in vulvar inflammation. In addition, IL-6 and IL-13 were decreased during infection. Our results suggest that Tv-ELVs have an immunomodulatory role on the cytokine profile induced by the parasite and promote a decrease in the inflammatory process in mice infected with T. vaginalis. PMID- 28345150 TI - Decoding facial expressions based on face-selective and motion-sensitive areas. AB - Humans can easily recognize others' facial expressions. Among the brain substrates that enable this ability, considerable attention has been paid to face selective areas; in contrast, whether motion-sensitive areas, which clearly exhibit sensitivity to facial movements, are involved in facial expression recognition remained unclear. The present functional magnetic resonance imaging (fMRI) study used multi-voxel pattern analysis (MVPA) to explore facial expression decoding in both face-selective and motion-sensitive areas. In a block design experiment, participants viewed facial expressions of six basic emotions (anger, disgust, fear, joy, sadness, and surprise) in images, videos, and eyes obscured videos. Due to the use of multiple stimulus types, the impacts of facial motion and eye-related information on facial expression decoding were also examined. It was found that motion-sensitive areas showed significant responses to emotional expressions and that dynamic expressions could be successfully decoded in both face-selective and motion-sensitive areas. Compared with static stimuli, dynamic expressions elicited consistently higher neural responses and decoding performance in all regions. A significant decrease in both activation and decoding accuracy due to the absence of eye-related information was also observed. Overall, the findings showed that emotional expressions are represented in motion-sensitive areas in addition to conventional face-selective areas, suggesting that motion-sensitive regions may also effectively contribute to facial expression recognition. The results also suggested that facial motion and eye-related information played important roles by carrying considerable expression information that could facilitate facial expression recognition. Hum Brain Mapp 38:3113-3125, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28345151 TI - Registries in European post-marketing surveillance: a retrospective analysis of centrally approved products, 2005-2013. AB - PURPOSE: Regulatory agencies and other stakeholders increasingly rely on data collected through registries to support their decision-making. Data from registries are a cornerstone of post-marketing surveillance for monitoring the use of medicines in clinical practice. This study was aimed at gaining further insight into the European Medicines Agency's (EMA) requests for new registries and registry studies using existing registries and to review the experience gained in their conduct. METHODS: European Public Assessment Reports were consulted to identify products for which a request for a registry was made as a condition of the marketing authorisation. All centrally authorised products that received a positive opinion of the EMA Committee for Medicinal Products for Human Use between 1 January 2005 and 31 December 2013 were included. Data regarding registry design and experiences were collected from EMA electronic record keeping systems. RESULTS: Of 392 products that received a positive Committee for Medicinal Products for Human Use opinion during 2005-2013, 31 registries were requested for 30 products in total. Sixty-five percent were product registries whereas 35% were disease registries and 71% of the registries had a primary safety objective. Most commonly reported issues with registries were delayed time to start and low patient accrual rates. CONCLUSIONS: The delays found in getting new registries up and running support the need to improve the timeliness of data collection in the post-marketing setting. Methodological challenges met in conducting this study highlighted the need for a clarification of definitions and epidemiological concepts around patient registries. The results will inform the EMA Patient Registry initiative to support use of existing patient registries for the post-authorisation benefit-risk monitoring of medicinal products. (c) 2017 Commonwealth of Australia. Pharmacoepidemiology & Drug Safety (c) 2017 John Wiley & Sons, Ltd. PMID- 28345152 TI - The impact of seizures on epilepsy outcomes: A national, community-based survey. AB - OBJECTIVE: The aim of this study was to examine the impact of seizures on persons living with epilepsy in a national, community-based setting. METHODS: The data source was the Survey of Living with Neurological Conditions in Canada (SLNCC), a cohort derived from a national population-based survey of noninstitutionalized persons aged 15 or more years. Participants had to be on a seizure drug or to have had a seizure in the past 5 years to meet the definition of active epilepsy. The respondents were further stratified by seizure status: the seizure group experienced >=1 seizure in the past 5 years versus the no seizure group who were seizure-free in the past >=5 years regardless of medication status. Weighted overall and stratified prevalence estimates and odds ratios were used to estimate associations. RESULTS: The SLNCC included 713 persons with epilepsy with a mean age of 45.4 (standard deviation 18.0) years. Fewer people in the seizure group (42.7%) reported being much better than a year ago versus those in the no seizure group (70.1%). Of those with seizures, 32.1% (95% confidence interval [95% CI] 18.8-45.3) had symptoms suggestive of major depression (as per the Patient Health Questionnaire-9) compared to 7.7% (95% CI 3.4-11.9) of those without seizures. Driving, educational, and work opportunities were also significantly limited, whereas stigma was significantly greater in those with seizures. SIGNIFICANCE: This community-based study emphasizes the need for seizure freedom to improve clinical and psychosocial outcomes in persons with epilepsy. Seizure freedom has an important influence on overall health, as those with at least one seizure over the prior 5 years had an increased risk of mood disorders, worse quality of life, and faced significantly more stigma. PMID- 28345153 TI - The functional architectures of addition and subtraction: Network discovery using fMRI and DCM. AB - The neuronal mechanisms underlying arithmetic calculations are not well understood but the differences between mental addition and subtraction could be particularly revealing. Using fMRI and dynamic causal modeling (DCM), this study aimed to identify the distinct neuronal architectures engaged by the cognitive processes of simple addition and subtraction. Our results revealed significantly greater activation during subtraction in regions along the dorsal pathway, including the left inferior frontal gyrus (IFG), middle portion of dorsolateral prefrontal cortex (mDLPFC), and supplementary motor area (SMA), compared with addition. Subsequent analysis of the underlying changes in connectivity - with DCM - revealed a common circuit processing basic (numeric) attributes and the retrieval of arithmetic facts. However, DCM showed that addition was more likely to engage (numeric) retrieval-based circuits in the left hemisphere, while subtraction tended to draw on (magnitude) processing in bilateral parietal cortex, especially the right intraparietal sulcus (IPS). Our findings endorse previous hypotheses about the differences in strategic implementation, dominant hemisphere, and the neuronal circuits underlying addition and subtraction. Moreover, for simple arithmetic, our connectivity results suggest that subtraction calls on more complex processing than addition: auxiliary phonological, visual, and motor processes, for representing numbers, were engaged by subtraction, relative to addition. Hum Brain Mapp 38:3210-3225, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28345154 TI - Outcomes in patients after myocardial infarction similar to those of the PEGASUS TIMI 54 trial: A cohort study in the French national claims database. AB - AIMS: The present study aims to describe real-life outcomes in stable patients after-myocardial infarction (MI) similar to those in the PEGASUS-TIMI 54 trial (PEGASUS), which found long-term benefits of ticagrelor in patients with a history of MI. METHODS: One-year event-free post-MI patients were identified in the French claims database representative 1/97 sample (2005-2010) and followed for up to 3 years. A PEGASUS-like (PL) population included patients with age >= 65 years, or age >= 50 and diabetes, renal dysfunction or prior MI, without stroke, end-stage renal failure or oral anticoagulation. Outcomes were: a composite of all-cause death or hospital admission for MI or stroke; individual events; major bleeding. RESULTS: There were 1585 post-MI patients totalling 3926 person-years including 865 PL patients (2114 PY); 68% were male; mean age was 66 (standard deviation 15) in post-MI, 74 (10) in PL. Outcomes per 100 person-years [95% confidence interval] were, respectively, in post-MI and PL 6.3 [5.6-7.1] and 7.8 [6.7-8.9] for the composite outcome; 5.1 [4.4-5.8] and 6.5 [5.5-7.6] for death; 1.0 [0.7-1.3] and 1.0 [0.6-1.4] for MI; 0.6 [0.4-0.9] and 0.9 [0.5-1.2] for stroke; 1.3 [0.9-1.6] and 1.4 [0.9-1.9] for major bleeding. Event rates were stable over the 3 study years. Placebo patients in the PEGASUS-TIMI54 Study were younger, more often male and had lower event rates, especially for all-cause death and major bleeding. CONCLUSIONS: Patients selected using the criteria described in PEGASUS were older with more comorbidities, resulting in higher all cause death and bleeding rates, but similar MI recurrence rates. PMID- 28345155 TI - A nomogram for predicting prognostic value of inflammatory response biomarkers in decompensated cirrhotic patients without acute-on-chronic liver failure. AB - BACKGROUND: Inflammation plays a vital role in liver cirrhosis progression and prognosis. AIM: To investigate the prognostic significance of inflammatory response markers in decompensated cirrhotic patients without acute-on-chronic liver failure (ACLF). METHODS: Independent predictors were identified using multivariate Cox model and then assembled into a nomogram to predict survival. Concordance index (C-index) and time-dependent receiver operating characteristics (td-ROC) analysis were adopted to evaluate and compare the performance of nomogram, model for end-stage liver disease (MELD) scores, MELD-Na and Chronic Liver Failure-consortium score for acute decompensated (CLIF-C ADs). RESULTS: A total of 902 decompensated cirrhotic patients with different aetiologies were enrolled, with 6-month, 1-year and 3-year mortality of 18.6%, 24.4% and 34.8%, respectively. The cut-off values for neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) determined by X-tile program were 5.7 and 1.1 respectively. Patients with NLR>5.7 or LMR<=1.1 had significantly higher mortality (P < 0.001). Independent factors derived from multivariable Cox analysis of development cohort to predict mortality were age, NLR and LMR (hazard ratio (HR): 1.064, 95% confidence interval (CI): 1.045-1.084, P < 0.001; HR: 1.124, 95%CI: 1.091-1.158, P < 0.001; HR: 0.794, 95%CI: 0.702-0.898, P < 0.001, respectively). The C-indexes of nomogram were higher than that of MELD score, MELD-Na and CLIF-C ADs for predicting survival. The tdROC and decision curves showed that nomogram was superior to MELD score, MELD-Na and CLIF-C ADs. Similar results were observed in validation cohort. CONCLUSION: The proposed nomogram with neutrophil-to-lymphocyte ratio and lymphocyte-to-monocyte ratio resulted in accurate prognostic prediction for decompensated cirrhotic patients without ACLF. PMID- 28345156 TI - Evolving new concepts in the assessment of aortic stenosis. AB - Echocardiography has been pivotal in evaluating aortic stenosis (AS) over the past several decades. Recent experience has shown a wide spectrum in the clinical presentation of AS. A better understanding of the underlying hemodynamic principles has resulted in emergence of new subtypes of AS. New treatment modalities have also been introduced, requiring precise evaluation of aortic valve (AV) pathology for implementation of these therapies. This review will discuss new concepts and indices in the use of echocardiography in patients with AS. Specifically, we will address the hemodynamic characteristics, clinical presentation, and management of normal-flow, high-gradient; paradoxical low-flow, low-gradient; and classical low-flow, low-gradient aortic stenoses. PMID- 28345157 TI - Entecavir maleate versus entecavir in Chinese chronic hepatitis B predominantly genotype B or C: Results at week 144. AB - Reports on the efficacy and safety of long-term entecavir treatment in chronic hepatitis B (CHB) predominantly genotype B or C are insufficient. This study presents the efficacy and safety of entecavir maleate in Chinese CHB patients. Patients were randomly assigned to receive 48-week treatment with either 0.5 mg/day entecavir (group A) or 0.5 mg/day entecavir maleate (group B), and then all patients received treatment with 0.5 mg/day entecavir maleate from week 49. Two hundred and seventy-five patients with CHB (HBeAg-positive: 218) were analysed, predominantly (98.5%) with genotype B or C. Baseline characteristics were balanced. For the HBeAg-positive CHB patients, the mean HBV DNA level decreased similarly (A: by 6.36 log10 IU/mL vs B: by 6.31 log10 IU/mL) between groups at week 144. The percentages of patients who achieved undetectable HBV DNA were similar (A: 70.59% vs B: 66.67%) between groups. Similar HBeAg loss rates (A: 43.53% vs B: 40.23%; P>.05) and HBeAg seroconversion rates (A: 21.52% vs B: 21.18%) were achieved. For the HBeAg-negative CHB patients, similar reductions in HBV DNA levels from baseline (A: by 6.13 log10 IU/mL vs B: by 5.65 log10 IU/mL) and percentages of patients who achieved undetectable HBV DNA (A: 100% vs B: 100%) were achieved. The overall incidence of adverse events was comparable between groups. In conclusions, 48-week administration of entecavir maleate and entecavir showed similar efficacy and safety in Chinese patients with CHB. Long term entecavir maleate treatment was effective and safe in CHB patients. PMID- 28345158 TI - Circular RNAs in heart failure. AB - Cardiovascular disease, and particularly heart failure, is still a serious health care issue for which novel treatments and biomarkers are needed. The RNA family comprises different subgroups, among which the small-sized microRNAs and the larger long non-coding RNAs have shown some potential to aid in moving personalized health care of heart failure patients a step forward. Here, members of the Cardiolinc network review the recent findings suggesting that the less well-known circular RNAs may constitute a novel reservoir of therapeutic targets and biomarkers of heart failure. The knowledge of the mode of biogenesis of circular RNAs will first be reported, followed by a description of different features that make these RNA molecules of interest for the heart failure community. The functions of circular RNAs in the heart will be described, with some emphasis given to their regulation in the failing heart. Circulating in the bloodstream, circular RNAs have appeared as potential biomarkers and recent findings associated with the use of circular RNAs as heart failure biomarkers will be discussed. Finally, some directions for future research will be provided. PMID- 28345159 TI - Stereoselective Catalytic Synthesis of Active Pharmaceutical Ingredients in Homemade 3D-Printed Mesoreactors. AB - 3D-printed flow reactors were designed, fabricated from different materials (PLA, HIPS, nylon), and used for a catalytic stereoselective Henry reaction. The use of readily prepared and tunable 3D-printed reactors enabled the rapid screening of devices with different sizes, shapes, and channel dimensions, aimed at the identification of the best-performing reactor setup. The optimized process afforded the products in high yields, moderate diastereoselectivity, and up to 90 % ee. The method was applied to the continuous-flow synthesis of biologically active chiral 1,2-amino alcohols (norephedrine, metaraminol, and methoxamine) through a two-step sequence combining the nitroaldol reaction with a hydrogenation. To highlight potential industrial applications of this method, a multistep continuous synthesis of norephedrine has been realized. The product was isolated without any intermediate purifications or solvent switches. PMID- 28345160 TI - Increasing skeletal muscle carnitine availability does not alter the adaptations to high-intensity interval training. AB - Increasing skeletal muscle carnitine availability alters muscle metabolism during steady-state exercise in healthy humans. We investigated whether elevating muscle carnitine, and thereby the acetyl-group buffering capacity, altered the metabolic and physiological adaptations to 24 weeks of high-intensity interval training (HIIT) at 100% maximal exercise capacity (Wattmax ). Twenty-one healthy male volunteers (age 23+/-2 years; BMI 24.2+/-1.1 kg/m2 ) performed 2 * 3 minute bouts of cycling exercise at 100% Wattmax , separated by 5 minutes of rest. Fourteen volunteers repeated this protocol following 24 weeks of HIIT and twice-daily consumption of 80 g carbohydrate (CON) or 3 g l-carnitine+carbohydrate (CARN). Before HIIT, muscle phosphocreatine (PCr) degradation (P<.0001), glycogenolysis (P<.0005), PDC activation (P<.05), and acetylcarnitine (P<.005) were 2.3-, 2.1-, 1.5-, and 1.5-fold greater, respectively, in exercise bout two compared to bout 1, while lactate accumulation tended (P<.07) to be 1.5-fold greater. Following HIIT, muscle free carnitine was 30% greater in CARN vs CON at rest and remained 40% elevated prior to the start of bout 2 (P<.05). Following bout 2, free carnitine content, PCr degradation, glycogenolysis, lactate accumulation, and PDC activation were all similar between CON and CARN, albeit markedly lower than before HIIT. VO2max , Wattmax , and work output were similarly increased in CON and CARN, by 9, 15, and 23% (P<.001). In summary, increased reliance on non mitochondrial ATP resynthesis during a second bout of intense exercise is accompanied by increased carnitine acetylation. Augmenting muscle carnitine during 24 weeks of HIIT did not alter this, nor did it enhance muscle metabolic adaptations or performance gains beyond those with HIIT alone. PMID- 28345161 TI - A decrease in eukaryotic elongation factor 2 phosphorylation is required for local translation of sensorin and long-term facilitation in Aplysia. AB - Mechanistic target of rapamycin complex 1 (mTORC1)-dependent protein synthesis is required for many forms of synaptic plasticity and memory, but the downstream pathways important for synaptic plasticity are poorly understood. Long-term facilitation (LTF) in Aplysia is a form of synaptic plasticity that is closely linked to behavioral memory and an attractive model system for examining the important downstream targets for mTORC1 in regulating synaptic plasticity. Although mTORC1-regulated protein synthesis has been strongly linked to translation initiation, translation elongation is also regulated by mTORC1 and LTF leads to an mTORC1-dependent decrease in eukaryotic elongation factor 2 (eEF2) phosphorylation. The purpose of this study is to test the hypothesis that the decrease in eEF2 phosphorylation is required for mTORC1-dependent translation and plasticity. We show that the LTF-induced decrease in eEF2 phosphorylation is blocked by expression of an eEF2 kinase (eEF2K) modified to be resistant to mTORC1 regulation. We found that expression of this modified kinase blocked LTF. LTF requires local protein synthesis of the neuropeptide sensorin and importantly, local sensorin synthesis can be measured using a dendra fluorescent protein containing the 5' and 3' untranslated regions (UTRs) of sensorin. Using this construct, we show that blocking eEF2 dephosphorylation also blocks the increase in local sensorin synthesis. These results identify decreases in eEF2 phosphorylation as a critical downstream effector of mTOR required for long-term plasticity and identify an important translational target regulated by decreases in eEF2 phosphorylation. PMID- 28345163 TI - Pharmacokinetics and safety of letermovir, a novel anti-human cytomegalovirus drug, in patients with renal impairment. AB - AIMS: Human cytomegalovirus remains a significant issue for immunocompromised patients and existing viral polymerase targeting therapies are associated with significant toxicity. Accordingly, the viral terminase complex inhibitor, letermovir, is in development. We assessed letermovir pharmacokinetics in renal impairment. METHODS: This was a Phase 1, open-label, nonrandomised trial. Estimated glomerular filtration rate based on the Modification of Diet Renal Disease equation was used to create three groups of eight subjects: healthy function (estimated glomerular filtration rate >= 90 ml min-1 1.73m-2 ), moderate (30-59 ml min-1 1.73m-2 ) and severe (<30 ml min-1 1.73m-2 ) impairment. Oral letermovir 120 mg was dosed once-daily for 8 days and blood collected for pharmacokinetic analyses. RESULTS: All 24 subjects enrolled completed the trial. Moderate and severe renal impairment increased mean unbound letermovir fractions by 11% and 26%, respectively, vs. healthy subjects. Exposure (AUCtau,ss and Css,max ) was increased with renal impairment [least square mean ratios (90% confidence intervals) total letermovir vs. healthy subjects, AUCtau,ss 192% (143-258%) and 142% (83-243%) for moderate and severe impairment, respectively; Css,max 125% (87-182%) and 106% (75-151%), respectively]. Clearance was decreased vs. healthy subjects. Correlation analyses indicated a correlation between decreasing renal function and increased unbound letermovir concentration (R2 = 0.5076, P < 0.0001). Correlations were identified between decreased clearance with both decreased renal function (R2 = 0.0662, P = 0.2249 and R2 = 0.1861, P = 0.0353 total and unbound clearance, respectively) and increased age (R2 = 0.3548, P = 0.0021 and R2 = 0.3166, P = 0.0042 total and unbound clearance, respectively). Multiple-dose letermovir 120 mg was well tolerated across groups. CONCLUSIONS: Renal impairment increased exposure to letermovir, although age was a confounding factor. PMID- 28345162 TI - Reduction of postprandial glucose by lixisenatide vs sitagliptin treatment in Japanese patients with type 2 diabetes on background insulin glargine: A randomized phase IV study (NEXTAGE Study). AB - AIM: To evaluate the pharmacodynamics of lixisenatide once daily vs sitagliptin once daily in Japanese patients with type 2 diabetes receiving insulin glargine U100. MATERIALS AND METHODS: This multicentre, open-label, phase IV study (NEXTAGE Study; ClinicalTrials.gov number, NCT02200991) randomly assigned 136 patients to either lixisenatide once daily via subcutaneous injection (10 ug initially increased weekly by 5 up to 20 ug) or once-daily oral sitagliptin 50 mg. The primary endpoint was the change in postprandial glucose (PPG) exposure 4 hours after a standardized breakfast (PPG area under the plasma glucose concentration-time curve [AUC0:00-4:00h ]) from baseline to day 29. RESULTS: Lixisenatide reduced PPG exposure to a statistically significantly greater extent than sitagliptin: least squares (LS) mean change from baseline in PPG AUC0:00 4:00h was -347.3 h.mg/dL (-19.3 h.mmol/L) in the lixisenatide group and -113.3 h.mg/dL (-6.3 h.mmol/L) in the sitagliptin group (LS mean between-group difference -234.0 h.mg/dL [-13.0 h.mmol/L], 95% confidence interval -285.02 to 183.00 h.mg/dL [-15.8 to -10.2 h.mmol/L]; P < .0001). Lixisenatide led to significantly greater LS mean reductions in maximum PPG excursion than sitagliptin (-122.4 vs -46.6 mg/dL [-6.8 vs -2.6 h.mmol/L]; P < .0001). Change from-baseline reductions in exposure to C-peptide, fasting glycoalbumin levels, and the gastric emptying rate were greater in the lixisenatide than in the sitagliptin group. The incidence of treatment-emergent adverse events was higher with lixisenatide (60.9%) than with sitagliptin (16.4%), with no serious events or severe hypoglycaemia reported. CONCLUSION: Lixisenatide reduced PPG significantly more than sitagliptin, when these agents were added to basal insulin glargine U100, and was well tolerated. PMID- 28345164 TI - Comparing functional MRI protocols for small, iron-rich basal ganglia nuclei such as the subthalamic nucleus at 7 T and 3 T. AB - The basal ganglia (BG) form a network of subcortical nuclei. Functional magnetic resonance imaging (fMRI) in the BG could provide insight in its functioning and the underlying mechanisms of Deep Brain Stimulation (DBS). However, fMRI of the BG with high specificity is challenging, because the nuclei are small and variable in their anatomical location. High resolution fMRI at field strengths of 7 Tesla (T) could help resolve these challenges to some extent. A set of MR protocols was developed for functional imaging of the BG nuclei at 3 T and 7 T. The protocols were validated using a stop-signal reaction task (Logan et al. []: J Exp Psychol: Human Percept Perform 10:276-291). Compared with sub-millimeter 7 T fMRI protocols aimed at cortex, a reduction of echo time and spatial resolution was strictly necessary to obtain robust Blood Oxygen Level Dependent (BOLD) sensitivity in the BG. An fMRI protocol at 3 T with identical resolution to the 7 T showed no robust BOLD sensitivity in any of the BG nuclei. The results suggest that the subthalamic nucleus, as well as the substantia nigra, red nucleus, and the internal and external parts of the globus pallidus show increased activation in failed stop trials compared with successful stop and go trials. Hum Brain Mapp 38:3226-3248, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28345166 TI - Demonstrating therapeutic equivalence of a new and established pharmaceutical or intervention: a guide for the non-statistician. PMID- 28345165 TI - Interleukin-1 inhibition facilitates recovery from liver injury and promotes regeneration of hepatocytes in alcoholic hepatitis in mice. AB - BACKGROUND & AIMS: Inflammation and impaired hepatocyte regeneration contribute to liver failure in alcoholic hepatitis (AH). Interleukin (IL)-1 is a key inflammatory cytokine in the pathobiology of AH. The role of IL-1 in liver regeneration in the recovery phase of alcohol-induced liver injury is unknown. METHODS: In this study, we tested IL-1 receptor antagonist to block IL-1 signalling in a mouse model of acute-on-chronic liver injury on liver inflammation and hepatocyte regeneration in AH. RESULTS: We observed that inhibition of IL-1 signalling decreased liver inflammation and neutrophil infiltration, and resulted in enhanced regeneration of hepatocytes and increased rate of recovery from liver injury in AH. CONCLUSION: Our novel findings suggest that IL-1 drives sustained liver inflammation and impaired hepatocyte regeneration even after cessation of ethanol exposure. PMID- 28345167 TI - A Dynamic Estimation of Obesity Using Nhanes Data: A Pseudo-Panel Approach. AB - In this analysis, we examine the effect of wages on obesity by constructing pseudo-panels to conduct a dynamic estimation of Grossman's human capital model. The results indicate that wages have an increasing effect on obesity status. After accounting for past health status, the protective effect of wages commonly disseminated in the literature reverses on obesity status. The results may also indicate possible asymmetric consumption behavior between foods/nutrients that improve diet quality versus those that degrade it. Individuals may be more keen to adhere to prophylactic diet strategies that abate consumption of unhealthy food/nutrients rather than measures which increase healthy nutrient consumption. Additionally, wages have an increasing effect on overall total calories consumed. These findings suggest that higher wage earners may focus their diet efforts on reducing consumption of specific nutrients but compensate by overconsuming other types of nutrients increasing overall calorie intake. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28345168 TI - Cardinal and anti-cardinal points, equalities and chromatic dependence. AB - PURPOSE: Cardinal points are used for ray tracing through Gaussian systems. Anti principal and anti-nodal points (which we shall refer to as the anti-cardinal points), along with the six familiar cardinal points, belong to a much larger set of special points. The purpose of this paper is to obtain a set of relationships and resulting equalities among the cardinal and anti-cardinal points and to illustrate them using Pascal's ring. METHODS: The methodology used relies on Gaussian optics and the transference T. We make use of two equations, obtained via the transference, which give the locations of the six cardinal and four anti cardinal points with respect to the system. We obtain equalities among the cardinal and anti-cardinal points. We utilise Pascal's ring to illustrate which points depend on frequency and their displacement with change in frequency. RESULTS: Pascal described a memory schema in the shape of a hexagon for remembering equalities among the points and illustrating shifts in these points when an aspect of the system changes. We modify and extend Pascal's ring to include the anti-cardinal points. We make use of Pascal's ring extended to illustrate which points are dependent on the frequency of light and the direction of shift of the equalities with change in frequency. For the reduced eye the principal and nodal points are independent of frequency, but the focal points and the anti-cardinal points depend on frequency. For Le Grand's four-surface model eye all six cardinal and four anti-cardinal points depend on frequency. This has implications for definitions, particularly of chromatic aberrations of the eye, that make use of cardinal points and that themselves depend on frequency. CONCLUSIONS: Pascal's ring and Pascal's ring extended are novel memory schema for remembering the equalities among the cardinal and anti-cardinal points. The rings are useful for illustrating changes among the equalities and direction of shift of points when an aspect of a system changes. Care should be taken when defining concepts that rely on cardinal points that depend on frequency. PMID- 28345170 TI - Trigger factors and consequence factors of shock therapy in Japanese patients with implantable cardioverter defibrillator. PMID- 28345169 TI - Alcohol use from adolescence through early adulthood: an assessment of measurement invariance by age and gender. AB - BACKGROUND AND AIMS: Studies on alcohol use and related constructs rarely test for measurement invariance to assess the reliability and validity of measures of alcohol use across different subpopulations of interest or ages. This failure to consider measurement invariance may result in biased parameter estimates and inferences. This study aimed to test measurement invariance of alcohol use across gender and age using a US nationally representative sample to inform future longitudinal studies assessing alcohol use. DESIGN: The National Longitudinal Study of Adolescent to Adult Health, a school-based, nationally representative longitudinal study conducted in 1994-95, 2001-02 and 2008. SETTING: All regions within the United States; participants were selected via a clustered sample design from 80 high schools that represented the national population. PARTICIPANTS: Youth and young adults aged 13-31 years who had valid data on all three alcohol items within wave: 18 923 from wave 1; 14 315 from wave 3; and 14 785 from wave 4. MEASUREMENTS: Alcohol use measurement models were constructed using past-year general drinking frequency, heavy episodic drinking frequency and average quantity when drinking. Configural (factor structure), metric (factor loadings) and scalar (item intercepts) measurement invariance models were tested by gender and for each year of age from 13 to 31 years. FINDINGS: All models passed the threshold for configural invariance. Comparisons between males and females demonstrated metric (and usually scalar) non-invariance for most ages beyond middle adolescence. Nearly all 1- and 2-year contrasts passed metric invariance. Scalar non-invariance was most prevalent in age comparisons between late adolescence and early adulthood, particularly for tests using 2-year age increments. CONCLUSIONS: Studies that do not account for the effects of gender and age on the measurement of alcohol use may be statistically biased. PMID- 28345171 TI - Spatio-angular consistent construction of neonatal diffusion MRI atlases. AB - Atlases constructed using diffusion-weighted imaging are important tools for studying human brain development. Atlas construction is in general a two-step process involving spatial registration and fusion of individual images. The focus of most studies so far has been on improving the accuracy of registration while image fusion is commonly performed using simple averaging, often resulting in fuzzy atlases. In this article, we propose a patch-based method for diffusion weighted (DW) atlas construction. Unlike other atlases that are based on the diffusion tensor model, our atlas is model-free and generated directly from the diffusion-weighted images. Instead of independently generating an atlas for each gradient direction and hence neglecting angular image correlation, we propose to construct the atlas by jointly considering DW images of neighboring gradient directions. We employ a group regularization framework where local patches of angularly neighboring images are constrained for consistent spatio-angular atlas reconstruction. Experimental results confirm that our atlas, constructed for neonatal data, reveals more structural details with higher fractional anisotropy than the atlas generated without angular consistency as well as the average atlas. Also the normalization of test subjects to the proposed atlas results in better alignment of brain structures. Hum Brain Mapp 38:3175-3189, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28345172 TI - International, prospective haemovigilance study on methylene blue-treated plasma. AB - BACKGROUND AND OBJECTIVES: Methylene blue is a phenothiazine dye, which in combination with visible light has virucidal and bactericidal properties, disrupting the replication of a broad range of enveloped viruses and some non enveloped viruses. The study objective was to collect data on adverse reactions occurring with methylene blue plasma administered in a routine clinical practice environment and document their characteristics and severity. MATERIALS AND METHODS: This was an open label, multicentre, non-controlled, non-randomized, non interventional study. Patients who receive a methylene blue plasma transfusion were observed for any signs and symptoms (adverse reactions) within 24 h safter the start of the transfusion, in different hospitals for a study duration of at least 1 year. RESULTS: A total of 19 315 methylene blue plasma units were transfused. There were eight patients with adverse reactions recorded during the study, one of them serious. Two had more than one reaction (two and four, respectively). Three patients had previous transfusions with methylene blue plasma only. CONCLUSION: Methylene blue plasma has a very acceptable safety profile with a rate of serious adverse reactions of 0.5/10 000 units. PMID- 28345173 TI - Increasing preferred step rate during running reduces plantar pressures. AB - Increasing preferred step rate during running is a commonly used strategy in the management of running-related injuries. This study investigated the effect of different step rates on plantar pressures during running. Thirty-two healthy runners ran at a comfortable speed on a treadmill at five step rates (preferred, +/-5%, and +/-10%). For each step rate, plantar pressure data were collected using the pedar-X in-shoe system. Compared to running with a preferred step rate, a 10% increase in step rate significantly reduced peak pressure (144.5+/-46.5 vs 129.3+/-51 kPa; P=.033) and maximum force (382.3+/-157.6 vs 334.0+/-159.8 N; P=.021) at the rearfoot, and reduced maximum force (426.4+/-130.4 vs 400.0+/ 116.6 N; P=.001) at the midfoot. In contrast, a 10% decrease in step rate significantly increased peak pressure (144.5+/-46.5 vs 161.5+/-49.3 kPa; P=.011) and maximum force (382.3+/-157.6 vs 425.4+/-155.3 N; P=.032) at the rearfoot. Changing step rate by 5% provided no effect on plantar pressures, and no differences in plantar pressures were observed at the medial forefoot, lateral forefoot or hallux between the step rates. This study's findings indicate that increasing preferred step rate by 10% during running will reduce plantar pressures at the rearfoot and midfoot, while decreasing step rate by 10% will increase plantar pressures at the rearfoot. However, changing preferred step rate by 5% will provide no effect on plantar pressures, and forefoot pressures are unaffected by changes in step rate. PMID- 28345174 TI - Overall evaluability of low dose protocol for computed tomography angiography of thoracic aorta using 80 kV and iterative reconstruction algorithm using different concentration contrast media. AB - INTRODUCTION: Multidetector Computed Tomography Angiography (MDCTA) is presently the imaging modality of choice for aortic disease. However, the effective radiation dose and the risk related to the use of contrast agents associated with MDCTA is an issue of concern. Aim of this study was to assess image quality of a low dose ECG-gated MDCTA of thoracic aorta using different concentration contrast media without tailored injection protocol. METHODS: Two-hundred patients were randomised into four different scan protocols: Group A (Iodixanol 320 and 80 Kvp tube voltage), Group B (Iodixanol 320 and 100 Kvp tube voltage), Group C (Iomeprol 400 and 80 Kvp tube voltage) and Group D (Iomeprol 400 and 100 Kvp tube voltage). Image quality, noise, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and effective dose (ED) were compared among groups. RESULTS: No significant differences in image noise, SNR and CNR between groups with the same tube voltage. Significant differences in SNR and CNR were found among groups with 80 kV versus groups using 100 kV but without differences in terms of image quality. ED was significantly lower in groups with 80 kV. CONCLUSIONS: Multidetector Computed Tomography Angiography protocols using 80 kV and low concentration contrast media are feasible without need of tailored injection protocols. PMID- 28345175 TI - Enantioselective Palladium-Catalyzed Carbonylative Carbocyclization of Enallenes via Cross-Dehydrogenative Coupling with Terminal Alkynes: Efficient Construction of alpha-Chirality of Ketones. AB - An enantioselective PdII /Bronsted acid-catalyzed carbonylative carbocyclization of enallenes ending with a cross-dehydrogenative coupling (CDC) with a terminal alkyne was developed. VAPOL phosphoric acid was found as the best co-catalyst among the examined 28 chiral acids, for inducing the enantioselectivity of alpha chiral ketones. As a result, a number of chiral cyclopentenones were easily synthesized in good to excellent enantiomeric ratio with good yields. PMID- 28345176 TI - Eye movement desensitisation and reprocessing therapy for posttraumatic stress disorder in a child and an adolescent with mild to borderline intellectual disability: A multiple baseline across subjects study. AB - BACKGROUND: This study explored the effectiveness of eye movement desensitisation and reprocessing (EMDR) therapy for post-traumatic stress disorder (PTSD) in persons with mild to borderline intellectual disability (MBID) using a multiple baseline across subjects design. METHODS: One child and one adolescent with MBID, who met diagnostic criteria for PTSD according to a PTSD clinical interview (i.e., ADIS-C PTSD section), adapted and validated for this target group, were offered four sessions of EMDR. PTSD symptoms were measured before, during and after EMDR, and at six weeks follow-up. RESULTS: For both participants, number of PTSD symptoms decreased in response to treatment and both no longer met PTSD criteria at post-treatment. This result was maintained at 6-week follow-up. CONCLUSIONS: The results of this study add further support to the notion that EMDR can be an effective treatment for PTSD in children and adolescents with MBID. Replication of this study in larger samples and using a randomized controlled design is warranted. PMID- 28345178 TI - Letter to the Editor. PMID- 28345179 TI - Transient epileptic amnesia without epileptic seizures: proposal of a new entity. PMID- 28345180 TI - Population-based study shows that teenage girls with asthma had impaired health related quality of life. AB - AIM: This study examined the health-related quality of life (HRQoL) of teenagers with and without asthma, including the impact of their sex, allergic conditions, smoking, living conditions and physical activity. METHODS: The Obstructive Lung Disease in Northern Sweden (OLIN) studies recruited a cohort of schoolchildren in 2006. The parents of all children aged seven to eight years in three municipalities were invited to complete a questionnaire and 2585 (96%) participated. The cohort was followed up at the ages of 11-12 years and 14-15 years with high participation rates. At 14-15 years, the HRQoL questionnaire KIDSCREEN-10 and Asthma Control Test were added. RESULTS: Girls with current asthma at 14-15 years had a lower mean HRQoL score than girls without asthma (46.4 versus 49.3, p < 0.001), but this was not seen among boys (53.8 versus 52.8, p = 0.373). Poor HRQoL was related to current asthma, uncontrolled asthma and teenage onset of asthma. It was also related to eczema, living in a single parent household, maternal smoking, daily smoking and inversely related to physical activity. CONCLUSION: Teenage girls with asthma had lower HRQoL than girls without asthma. Possible interventions to improve HRQoL among teenagers with asthma were identified as follows: increasing asthma control, preventing smoking and promoting physical activity. PMID- 28345177 TI - Pharmacogenomics of off-target adverse drug reactions. AB - Off-target adverse drug reactions (ADRs) are associated with significant morbidity and costs to the healthcare system, and their occurrence is not predictable based on the known pharmacological action of the drug's therapeutic effect. Off-target ADRs may or may not be associated with immunological memory, although they can manifest with a variety of shared clinical features, including maculopapular exanthema, severe cutaneous adverse reactions (SCARs), angioedema, pruritus and bronchospasm. Discovery of specific genes associated with a particular ADR phenotype is a foundational component of clinical translation into screening programmes for their prevention. In this review, genetic associations of off-target drug-induced ADRs that have a clinical phenotype suggestive of an immunologically mediated process and their mechanisms are highlighted. A significant proportion of these reactions lack immunological memory and current data are informative for these ADRs with regard to disease pathophysiology, therapeutic targets and biomarkers which may identify patients at greatest risk. Although many serious delayed immune-mediated (IM)-ADRs show strong human leukocyte antigen associations, only a small subset have successfully been implemented in screening programmes. More recently, other factors, such as drug metabolism, have been shown to contribute to the risk of the IM-ADR. In the future, pharmacogenomic targets and an understanding of how they interact with drugs to cause ADRs will be applied to drug design and preclinical testing, and this will allow selection of optimal therapy to improve patient safety. PMID- 28345181 TI - Hepatitis B s antigen kinetics during treatment with nucleos(t)ides analogues in patients with hepatitis B e antigen-negative chronic hepatitis B. AB - BACKGROUND/AIMS: Serum hepatitis B s antigen (HBsAg) levels might be used as a predictor of virological breakthrough or of sustained off-treatment virological response in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients. We evaluated the changes of HBsAg in those patients under nucleos(t)ide analogue(s) [NA(s)] therapy for >=12 months. METHODS: We included 99 HBeAg negative CHB patients treated with low-genetic barrier NA(s) for a mean of 66 months (lamivudine: 66, adefovir: 6, lamivudine plus adefovir: 11 and telbivudine: 16) and 86 HBeAg-negative CHB patients treated under entecavir or tenofovir for a mean of 30 months as the comparison group. RESULTS: Compared to baseline, HBsAg levels decreased by a median of 162, 1525, 943, 1545, 2163 and 3859 IU/mL at 6, 12, 24, 36, 48 and 60 months of therapy with low-genetic barrier NA(s) respectively. The 6-, 12-, 24-, 36-, 48- and 60-month cumulative rates of HBsAg<100 IU/mL were 2%, 3%, 3%, 5%, 5% and 5%, and <1000 IU/mL 6%, 9%, 15%, 19%, 24% and 61% respectively. Baseline HBsAg levels were the only significant variable associated with the time to HBsAg drop <1000 IU/mL. HBsAg loss occurred in 3.0% of patients. The high-genetic barrier NAs were not found to offer a greater or faster HBsAg decline. CONCLUSIONS: In HBeAg-negative CHB patients, long-term therapy with low-genetic barrier NA(s) decreases serum HBsAg levels, but the rate of decline is slow. Lower baseline HBsAg levels are significantly associated with on-therapy HBsAg drop <1000 IU/mL. Serum HBsAg decline is similar during therapy with low- or high-genetic barrier NAs. PMID- 28345182 TI - Can genomic data alone tell us whether speciation happened with gene flow? AB - The allopatric model, which requires a period of geographical isolation for speciation to complete, has been the standard model in the modern era. Recently, "speciation with gene flow" has been widely discussed in relation to the model of "strict allopatry" and the level of DNA divergence across genomic regions. We wish to caution that genomic data by themselves may only permit the rejection of the simplest form of allopatry. Even a slightly more complex and realistic model that starts with subdivided populations would be impossible to reject by the genomic data alone. To resolve this central issue of speciation, other forms of observations such as the sequencing of reproductive isolation genes or the identification of geographical barrier(s) will be necessary. PMID- 28345183 TI - Common femoral artery disease in antiphospholipid syndrome: histopathology. PMID- 28345185 TI - Overexpression of Yes-associated protein and its association with clinicopathological features of hepatocellular carcinoma: A meta-analysis. AB - BACKGROUND: Yes-associated protein (YAP) overexpression is reported to be associated with risk of hepatocellular carcinoma (HCC) but current studies have not explored the relationship between YAP expression with HCC clinicopathological features. METHODS: To assess these associations, a meta-analysis was performed which included four eligible studies including 391 HCC cases and 334 controls. There were eight eligible studies to investigate the association between YAP expression in HCC and clinicopathological features of liver cancer patients. Literature was obtained from PubMed, Embase, Wangfang and China National Knowledge Infrastructure. RESULTS: Analysis indicated that YAP expression in HCC was greater than in adjacent non-tumour tissue (odds ratio [OR], 15.80, 95% confidence interval [CI], 10.53-23.70, P<.00001; heterogeneity=.30). YAP overexpression in HCC was significantly associated with vascular invasion (OR, 2.21, 95% CI, 11.64-2.97, P<.00001, heterogeneity=.10), less cellular differentiation (OR, 2.38, 95% CI, 1.61-3.51, P<.00001, heterogeneity=.333), tumours larger than 5 cm (OR, 2.52, 95% CI, 1.75-3.62, P<.00001; heterogeneity=.17) and TNM tumour stage I + II (OR, 0.44, 95% CI, 0.28-0.75, P=.00003, heterogeneity=.12). CONCLUSIONS: Overexpression of YAP contributes to HCC formation, and its overexpression is associated with vascular invasion, low cellular differentiation tumours larger than 5 cm and TNM tumour stage III + IV. PMID- 28345186 TI - Fetal myocardial performance index in assessment and management of small-for gestational-age fetus: a cohort and nested case-control study. AB - OBJECTIVE: To assess the clinical utility of the fetal myocardial performance index (MPI) in assessment and management of the small-for-gestational-age (SGA) fetus/growth-restricted fetus (FGR). METHODS: This was a prospective cohort study in metropolitan Australia of patients referred in the period June 2012 to March 2015 to fetal medicine services at 24-38 weeks' gestation for suspected singleton SGA/FGR (estimated fetal weight (EFW) < 10th centile with or without abnormal umbilical artery (UA) Doppler) pregnancy. Patients had MPI assessed in addition to routine measures, and were followed through to birth. We compared MPI values against those of a local reference population and gestational age-matched controls, and assessed the correlation with perinatal outcome and other Doppler measures. RESULTS: Fifty-two cases were included, 38 diagnosed < 32 weeks and 14 diagnosed >= 32 weeks. None demonstrated significantly elevated left, right or delta MPI compared with the reference population or with gestational age-matched controls at the time of first MPI evaluation. There were no consistent longitudinal patterns in MPI that would suggest its clinical utility. The mean +/ SD gestational age at delivery was 34.6 +/- 3.8 weeks and birth weight was 1.7 +/- 0.6 kg, and the median neonatal hospital admission time was 27 days, confirming a pathological cohort. There were no significant correlations between left, right or delta-MPI and perinatal outcome, although there were significant correlations between UA, middle cerebral artery (MCA) and ductus venosus (DV) Doppler and perinatal outcome (birth weight, gestational age at birth and length of neonatal hospital stay). Exploratory subgroup comparisons (EFW < 3rd vs 3rd 10th centile; early- vs late-onset; abnormal vs normal UA Doppler) found only minor differences in MPI, reaching statistical, but not clinical, significance, only in the EFW < 3rd vs 3rd -10th centile comparison. CONCLUSIONS: MPI did not demonstrate clinical utility in either triage or longitudinal follow-up of an SGA/FGR cohort presenting to fetal medicine services. Given that prior research suggesting its utility originates from single-center cohorts, while multicenter, large cohorts have suggested little utility or no additional utility if routine UA/MCA/DV Doppler is performed, publication bias may have affected previous reports. It seems unlikely that MPI has clinical utility in assessment and management of SGA/FGR fetuses. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28345184 TI - Spatial molecular epidemiology of carbapenem-resistant and New Delhi metallo beta lactamase (blaNDM)-producing Escherichia coli in the piglets of organized farms in India. AB - AIM: A cross-sectional study was conducted in 10 government-organized pig farms between 2014 and 2016 representing seven states of India to understand the epidemiology of carbapenem resistance in the Escherichia coli. METHODS AND RESULTS: In this study, fecal sample (n = 673) from non-diarrheic (n = 501) and diarrheic (n = 172) piglets were processed for isolation of carbapenem resistant E. coli. Of 673, E. coli isolate (n = 112) was genotyped for confirming the carbapenem resistance and associated virulence factors. Of the 112 isolates, 23 were phenotypically resistant to carbapenem and 8 were carrying the New Delhi metallo beta-lactamase (blaNDM) gene. The carbapenem-resistant isolates also produced extended spectrum beta-lactamases and were multidrug resistant. The PCR based pathotyping revealed the presence of stx1, stx2, eae and hlyA genes. The enterobacterial repetitive intergenic consensus PCR dendrogram analysis of the isolates yielded three distinct clusters. The statistical analysis revealed no association between carriages of carbapenem-resistant E. coli in different breed of piglets however, location, sex, health status of piglets and age showed significant difference. The spatial analysis with SaTScan helped in identification of carbapenem-resistant clusters. CONCLUSIONS: The presence of carbapenem resistant E. coli isolates with virulence genes in the piglet poses a potential public health risk through possible access and spread via the food chain and environment. Efflux pump may also play an important role in carbapenem resistance in piglet E. coli isolates. Furthermore, identification of risk factors in relation to spatial clusters will help in designing preventive strategies for reducing the risk of spread of carbapenem resistant bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: 1. Piglets harbor carbapenem resistant E. coli and have great public health significance. 2. Apart from carbapenemase, efflux pump is also important for carbapenem resistance. 3. This is the first report of blaNDM in the piglets from India. PMID- 28345187 TI - Novel biomarkers for prostate cancer: An evidence-based review for use in clinical practice. AB - Prostate cancer is a heterogeneous disease with disparate outcomes. Traditional clinical parameters are limited in their ability to differentiate between these cases, and there is uncertainty regarding management strategies. A number of novel biomarkers have emerged, but how best to use them at the point of care remains confusing. In the present review, we describe the most common novel biomarkers, their key supporting literature, and propose a meaningful algorithm for their use in clinical practice. To identify commercially available prostate cancer diagnostic tests, we carried out a PubMed literature search (through May 2016). Only English-language studies were included. We restricted our search to studies published within the past 10 years in order to focus our review on novel data. Secondary sources were also examined. We identified 12 novel biomarkers and categorized them into broad areas of clinical practice: (i) early diagnosis and screening; (ii) staging and primary treatment selection; (iii) post-treatment risk stratification; (iv) advanced disease prognosis and treatment response; and (v) emerging tests. Most validation studies rely on small retrospective cohorts and carry a high risk of bias; furthermore, most cohorts are restricted to Caucasians, with little to no representation of other geographic, racial or ethnic populations. Novel biomarkers for prostate cancer management, while potentially helpful, should not replace standard clinical information and physician judgment. They are currently best suited to serve as an adjunct to existing management tools. Clinicians should have a sound grasp of each biomarker based test's indications and limitations. PMID- 28345188 TI - Treatment of gonorrhoea in Auckland, New Zealand: marked variation in prescriber adherence to treatment guidelines. AB - BACKGROUND: The relentless emergence and spread of strains of Neisseria gonorrhoeae that are resistant to many antimicrobial agents has led to frequent changes in treatment guidelines, with a consequent risk that prescribers may not be aware of current guidelines. AIM: To determine the proportion of patients with gonorrhoea who were treated with a regimen consistent with the New Zealand Sexual Health Society (NZSHS) guidelines. METHODS: We audited the treatment given to adult patients with laboratory-proven gonorrhoea in Auckland, New Zealand, during the first 6 months of 2015. RESULTS: Treatment compliant with the current NZSHS guidelines was administered in only 65% (458/706) episodes overall. Guideline compliant treatment was much more likely to be prescribed for patients who presented to a sexual health clinic (89%) than for patients who presented to either a general practice or other community clinic (52%) or to a hospital (56%) (P < 0.0001). Overall, 52 of 706 (7%) episodes were not treated with any antimicrobial regimen by the service that diagnosed the patients' gonorrhoea, 13 of 62 (21%) episodes in patients who presented to a hospital, 34 of 403 (8%) episodes in patients who presented to a general practice or other community clinic and 5 of 241 (2%) episodes in patients who presented to a sexual health clinic (P < 0.0001). CONCLUSION: Low levels of compliance with treatment guidelines increase the risk that antibiotic-resistant strains of N. gonorrhoeae will spread within the Auckland region. Improved compliance with treatment guidelines, particularly in patients who present either to general practice or to hospitals, is necessary to maintain the efficacy of current treatment regimens. PMID- 28345191 TI - Report of the 13th Annual International Pachyonychia Congenita Consortium Symposium. AB - The International Pachyonychia Congenita Consortium (IPCC) is a group of physicians and scientists from around the world dedicated to developing therapies for pachyonychia congenita, a rare autosomal dominant skin disorder. The research presented at the 13th Annual Research Symposium of the IPCC, held on 10-11 May 2016, in Scottsdale, AZ, U.S.A., is reported here. PMID- 28345190 TI - New medicinal products for chronic heart failure: advances in clinical trial design and efficacy assessment. AB - Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health-related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure. The draft version of the Guideline was released for public consultation in January 2016. The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two-day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline: (i) assessment of efficacy (i.e. endpoint selection and statistical analysis); (ii) clinical trial design (i.e. issues pertaining to patient population, optimal medical therapy, run-in period); and (iii) research approaches for testing novel therapeutic principles (i.e. cell therapy). This paper summarizes the key outputs from the workshop, reviews areas of expert consensus, and identifies gaps that require further research or discussion. Collaboration between regulators, industry, clinical trialists, cardiologists, health technology assessment bodies, payers, and patient organizations is critical to address the ongoing challenge of heart failure and to ensure the development and market access of new therapeutics in a scientifically robust, practical and safe way. PMID- 28345192 TI - Respirometry increases cortisol levels in rainbow trout Oncorhynchus mykiss: implications for measurements of metabolic rate. AB - This study aimed to assess the extent to which chasing, handling and confining Oncorhynchus mykiss to a small respirometer chamber during respirometric experiments is stressful and affects metabolic measurements. The study observed increased cortisol levels in animals tested using a chase protocol and subsequent intermittent-flow respirometry, suggesting that this procedural treatment may stress animals. PMID- 28345189 TI - Tuning face perception with electrical stimulation of the fusiform gyrus. AB - The fusiform gyrus (FG) is an important node in the face processing network, but knowledge of its causal role in face perception is currently limited. Recent work demonstrated that high frequency stimulation applied to the FG distorts the perception of faces in human subjects (Parvizi et al. []: J Neurosci 32:14915 14920). However, the timing of this process in the FG relative to stimulus onset and the spatial extent of FG's role in face perception are unknown. Here, we investigate the causal role of the FG in face perception by applying precise, event-related electrical stimulation (ES) to higher order visual areas including the FG in six human subjects undergoing intracranial monitoring for epilepsy. We compared the effects of single brief (100 MUs) electrical pulses to the FG and non-face-selective visual areas on the speed and accuracy of detecting distorted faces. Brief ES applied to face-selective sites did not affect accuracy but significantly increased the reaction time (RT) of detecting face distortions. Importantly, RT was altered only when ES was applied 100ms after visual onset and in face-selective but not place-selective sites. Furthermore, ES applied to face selective areas decreased the amplitude of visual evoked potentials and high gamma power over this time window. Together, these results suggest that ES of face-selective regions within a critical time window induces a delay in face perception. These findings support a temporally and spatially specific causal role of face-selective areas and signify an important link between electrophysiology and behavior in face perception. Hum Brain Mapp 38:2830-2842, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28345193 TI - Retention of gene diversity during the spread of a non-native plant species. AB - Spatial expansion, which is a crucial stage in the process to successful biological invasion, is anticipated to profoundly affect the magnitude and spatial distribution of genetic diversity in novel colonized areas. Here, we show that, contrasting common expectations, Pyrenean rocket (Sisymbrium austriacum), retained SNP diversity as this introduced plant species descended in the Meuse River Basin. Allele frequencies did not mirror between-population distances along the predominant expansion axis. Reconstruction of invasion history based on the genotypes of historical herbarium specimens indicated no influence of additional introductions or multiple points of entry on this nongradual pattern. Assignment analysis suggested the admixture of distant upstream sources in recently founded downstream populations. River dynamics seem to have facilitated occasional long distance dispersal which brought diversity to the expansion front and so maintained evolutionary potential. Our findings highlight the merit of a historical framework in interpreting extant patterns of genetic diversity in introduced species and underscore the need to integrate long-distance dispersal events in theoretical work on the genetic consequences of range expansion. PMID- 28345194 TI - Decay of the glycolytic pathway and adaptation to intranuclear parasitism within Enterocytozoonidae microsporidia. AB - Glycolysis and oxidative phosphorylation are the fundamental pathways of ATP generation in eukaryotes. Yet in microsporidia, endoparasitic fungi living at the limits of cellular streamlining, oxidative phosphorylation has been lost: energy is obtained directly from the host or, during the dispersive spore stage, via glycolysis. It was therefore surprising when the first sequenced genome from the Enterocytozoonidae - a major family of human and animal-infecting microsporidians - appeared to have lost genes for glycolysis. Here, we sequence and analyse genomes from additional members of this family, shedding new light on their unusual biology. Our survey includes the genome of Enterocytozoon hepatopenaei, a major aquacultural parasite currently causing substantial economic losses in shrimp farming, and Enterospora canceri, a pathogen that lives exclusively inside epithelial cell nuclei of its crab host. Our analysis of gene content across the clade suggests that Ent. canceri's adaptation to intranuclear life is underpinned by the expansion of transporter families. We demonstrate that this entire lineage of pathogens has lost glycolysis and, uniquely amongst eukaryotes, lacks any obvious intrinsic means of generating energy. Our study provides an important resource for the investigation of host-pathogen interactions and reductive evolution in one of the most medically and economically important microsporidian lineages. PMID- 28345195 TI - Diagnosing neonatal transphyseal fractures of the distal humerus. AB - A traumatic birth can cause significant upper limb injury; the presenting features are non-specific and the differential diagnosis long. Transphyseal fractures of the distal humerus are a rare but clinically important birth injury. This injury has typical radiographic findings, which due to the un-ossified nature of the distal humeral epiphysis can easily be misinterpreted. This article presents the radiographic appearance correlated with arthrography, ultrasound and MRI obtained from four cases of neonatal transphyseal fracture of the distal humerus. We hope that by demonstrating the appearances for each of these imaging techniques in relation to the underlying pathology will reduce errors of interpretation that may lead to inappropriate diagnosis and management of these children. PMID- 28345196 TI - Flupyradifurone effectively manages whitefly Bemisia tabaci MED (Hemiptera: Aleyrodidae) and tomato yellow leaf curl virus in tomato. AB - BACKGROUND: The cotton whitefly Bemisia tabaci (Gennadius) is among the most important pests of numerous crops and a vector of more than 100 plant viruses, causing significant crop losses worldwide. Managing this pest as well as inhibiting the transmission of major viruses such as tomato yellow leaf curl virus (TYLCV) are of utmost importance for sustainable yields. The efficacy against both whitefly and virus transmission of the novel systemic butenolide insecticide flupyradifurone was investigated in this study. RESULTS: The inhibition of TYLCV transmission by flupyradifurone was compared to that by thiamethoxam, a neonicotinoid insecticide reported to inhibit virus transmission. The experiment was performed under high virus pressure conditions (10 viruliferous insects per plant for 48 h) using a fully characterized field strain of B. tabaci. The insecticides were foliarly applied at recommended label rates under greenhouse conditions. Flupyradifurone suppressed virus transmission by 85% while levels of suppression after thiamethoxam treatments were just 25% and significantly lower. In untreated control plots, 100% of plants were infected by TYLCV. The observed difference in the potential to suppress virus transmission is linked to a strong knockdown effect as well as prolonged feeding inhibition in flupyradifurone treatments. CONCLUSION: Flupyradifurone is shown to be an extremely useful, fast-acting, new chemical tool in integrated crop management offering simultaneous control of whiteflies and strong suppression of viral infections via its rapid knockdown action and good residual activity. (c) 2017 Society of Chemical Industry. PMID- 28345198 TI - Corrigendum: Dysregulation of Wnt-Signaling and a Candidate Set of miRNAs Underlie the Effect of Metformin on Neural Crest Cell Development. PMID- 28345199 TI - Erratum. PMID- 28345197 TI - Attenuated intrinsic connectivity within cognitive control network among individuals with remitted depression: Temporal stability and association with negative cognitive styles. AB - Many individuals with major depressive disorder (MDD) experience cognitive dysfunction including impaired cognitive control and negative cognitive styles. Functional connectivity magnetic resonance imaging studies of individuals with current MDD have documented altered resting-state connectivity within the default mode network and across networks. However, no studies to date have evaluated the extent to which impaired connectivity within the cognitive control network (CCN) may be present in remitted MDD (rMDD), nor have studies examined the temporal stability of such attenuation over time. This represents a major gap in understanding stable, trait-like depression risk phenotypes. In this study, resting-state functional connectivity data were collected from 52 unmedicated young adults with rMDD and 47 demographically matched healthy controls, using three bilateral seeds in the CCN (dorsolateral prefrontal cortex, inferior parietal lobule, and dorsal anterior cingulate cortex). Mean connectivity within the entire CCN was attenuated among individuals with rMDD, was stable and reliable over time, and was most pronounced with the right dorsolateral prefrontal cortex and right inferior parietal lobule, results that were corroborated by supplemental independent component analysis. Attenuated connectivity in rMDD appeared to be specific to the CCN as opposed to representing attenuated within-network coherence in other networks (e.g., default mode, salience). In addition, attenuated connectivity within the CCN mediated relationships between rMDD status and cognitive risk factors for depression, including ruminative brooding, pessimistic attributional style, and negative automatic thoughts. Given that these cognitive markers are known predictors of relapse, these results suggest that attenuated connectivity within the CCN could represent a biomarker for trait phenotypes of depression risk. Hum Brain Mapp 38:2939-2954, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28345200 TI - All roads lead to weediness: Patterns of genomic divergence reveal extensive recurrent weedy rice origins from South Asian Oryza. AB - Weedy rice (Oryza spp.), a weedy relative of cultivated rice (O. sativa), infests and persists in cultivated rice fields worldwide. Many weedy rice populations have evolved similar adaptive traits, considered part of the 'agricultural weed syndrome', making this an ideal model to study the genetic basis of parallel evolution. Understanding parallel evolution hinges on accurate knowledge of the genetic background and origins of existing weedy rice groups. Using population structure analyses of South Asian and US weedy rice, we show that weeds in South Asia have highly heterogeneous genetic backgrounds, with ancestry contributions both from cultivated varieties (aus and indica) and wild rice. Moreover, the two main groups of weedy rice in the USA, which are also related to aus and indica cultivars, constitute a separate origin from that of Asian weeds. Weedy rice populations in South Asia largely converge on presence of red pericarps and awns and on ease of shattering. Genomewide divergence scans between weed groups from the USA and South Asia, and their crop relatives are enriched for loci involved in metabolic processes. Some candidate genes related to iconic weedy traits and competitiveness are highly divergent between some weed-crop pairs, but are not shared among all weed-crop comparisons. Our results show that weedy rice is an extreme example of recurrent evolution, and suggest that most populations are evolving their weedy traits through different genetic mechanisms. PMID- 28345201 TI - Start high, then go low: An effective strategy in the treatment of myasthenia gravis. PMID- 28345202 TI - Prognostic value of long-term blood pressure changes in patients with chronic heart failure. AB - BACKGROUND: Chronic heart failure (CHF) is the final stage of many heart diseases. To improve outcomes, important risk factors for adverse clinical events in the CHF population need to be identified. The aim of the present study was to delineate the influence of long-term blood pressure (BP) changes on prognosis and mortality in a real-world cohort of CHF patients. METHODS AND RESULTS: This is a retrospective longitudinal analysis. Repeated office BP measurements were scheduled during follow-up visits every 3-6 months. The primary endpoint was time to death or heart transplantation (HTx). A Cox regression with time-dependent strata was used to analyse the effect of systolic BP (SBP) values and its change during follow-up on the primary endpoint. A total of 927 patients presented with a median survival of 7.7 [95% confidence interval (CI) 6.6-9.8] years. During follow-up, 220 patients died and 70 patients underwent HTx. The BP stratum with the most stable values showed the best survival. Blood pressure changes with an increase or decrease greater than +/-10 mmHg per year led to a significantly worse outcome [hazard ratio (HR) 1.8 and 2.0, respectively]. The stratum with the lowest SBP levels (<90 mmHg) had the highest mortality. Multiple regression analysis showed a HR factor of 17 (95% CI 9.7-29) in comparison with the stratum with SBP >=130 mmHg. CONCLUSION: Low SBP (<90 mmHg) and pronounced long-term changes in SBP were associated with poor survival in patients with CHF. Additional prospective studies are warranted to further specify optimal BP targets in patients with CHF. PMID- 28345204 TI - Insight into Ion Transfer through the Sub-Nanometer Channels in Zeolitic Imidazolate Frameworks. AB - A crack-free sub-nanometer composite structure for the study of ion transfer was constructed by in situ growth of ZIF-90 [Zn(ICA)2 , ICA=Imidazole-2 carboxaldehyde] on the tip of a glass nanopipette. The potential-driven ion transfer through the sub-nanometer channels in ZIF-90 is strongly influenced by the pH of the solution. A rectification ratio over 500 is observed in 1 m KCl solution under alkaline conditions (pH 11.58), which is the highest value reported under such a high salt concentration. Fluorescence experiments show the super-high rectification ratio under alkaline conditions results from the strong electrostatic interaction between ions and the sub-nanometer channels of ZIF-90. In addition to providing a general pathway for further study of mass-transfer process through sub-nanometer channels, the approach enable all kinds of metal organic frameworks (MOFs) to be used as ionic permselectivity materials in nanopore-based analysis. PMID- 28345203 TI - Major electrocardiographic abnormality predicts support/care-need certification and/or death in community-dwelling older adults with no history of cardiovascular disease. AB - AIM: Not only cardiovascular disease (CVD) itself, but also subclinical major electrocardiographic (ECG) abnormalities are related to frailty in older adults. We investigated whether major ECG abnormality was associated with first support/care-need certification in Long-Term Care Insurance or death in community dwelling older adults. METHODS: We analyzed 1078 community-dwelling older adults with no history of certification aged 65-94 years. Relationships between baseline major ECG abnormality and risk of first certification or death were estimated using the Cox proportional hazards model. RESULTS: During 5 years, 135 first certifications and 53 deaths occurred. Among participants with no prior history of CVD (n = 875), those with major ECG abnormality (n = 282) showed significantly higher adjusted hazard ratios (HR) for certification (HR 2.42, 95% CI 1.58-3.69, P < 0.001) and for death (HR 2.44, 95% CI 1.27-4.69, P = 0.008) compared with control participants without major ECG abnormality (n = 593). The impact of major ECG abnormality on certification in this group was more evident in older adults with age >=75 years, female sex or hyperuricemia. Participants with either arrhythmia or ST/T abnormality on ECG examination tended to have higher HR for certification as a result of dementia. In participants with a prior history of CVD (n = 203), the impact of major ECG abnormality (n = 126) on certification was not significant. CONCLUSIONS: These observations show that subclinical major ECG abnormality predicts higher risk for later support/care-need certification in community-dwelling older adults with no prior history of CVD. Geriatr Gerontol Int 2017; 17: 1967-1976. PMID- 28345205 TI - para-Selective C-H Borylation of (Hetero)Arenes by Cooperative Iridium/Aluminum Catalysis. AB - para-Selective C-H borylation of benzamides and pyridines has been achieved by cooperative iridium/aluminum catalysis. A combination of iridium catalysts commonly employed for arene C-H borylation and bulky aluminum-based Lewis acid catalysts provides an unprecedented strategy for controlling the regioselectivity of C-H borylation to give variously substituted (hetero)arylboronates, which are versatile synthetic intermediates for complex multi-substituted aromatic compounds. PMID- 28345206 TI - Treatment with direct-acting antiviral agents of hepatitis C virus infection in injecting drug users: A prospective study. AB - In this prospective study, we evaluated the effectiveness and tolerability of novel therapies against hepatitis C virus (HCV) in a cohort of PWID enrolled at our centre from April 2015 to July 2016. In this analysis, a total of 174 patients were included: eleven (6.3%) were treated with pegylated interferon (PEG IFN) and ribavirin (RBV) containing regimens, 163 (93.7%) with IFN-free treatments. RBV has been used in 70 patients (40.2%); 59 (33.9%) patients were in opioid substitution therapy (OST) with methadone or buprenorphine. Overall, sustained virological response (SVR) has been observed in 162 subject (93.1%), breakthrough (BT) in three (1.7%), relapse in one (0.6%) and dropout in eight (4.6%). Treatment was interrupted for clinical conditions in seven patients: six (3.4%) had hepatic decompensation and one died for hepatocellular carcinoma (HCC). In multivariate analysis, predictive factors of treatment failure were as follows: albumin level below 3 g/dL (OR=7.190; 95% IC=1.236-41.837; P<.001), MELD score >10 (OR=5.886; 95% IC=1.411-35.994; P<.001) and years of HCV infection >20 (OR=1.286; 95% IC=0.556-9.455; P=.016). In conclusion, treatment with DAAs was effective and well tolerated in PWID; cirrhotic subjects with MELD > 10 and albumin low level showed a higher risk of developing serious adverse events and treatment failure. PMID- 28345207 TI - Autoinflammatory syndromes associated with hidradenitis suppurativa and/or acne. AB - Autoinflammatory syndromes associated with hidradenitis suppurativa (HS) and/or acne are rare but potentially debilitating disorders if not diagnosed and treated correctly. They share a common pathogenesis involving a dysregulated innate immune system with abnormal interleukin (IL)-1 signaling leading to sterile neutrophilic inflammation. The clinical features are recurrent episodes of fever, painful arthritis, and skin lesions consistent with HS, acne, and pyoderma gangrenosum (PG) accompanied by elevated systemic inflammatory markers in blood. So far, several clinically different syndromes have been reported in the literature including pyoderma gangrenosum, acne, and pyogenic arthritis (PAPA), pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH), pyoderma gangrenosum, acne, and spondyloarthritis (PASS), pyoderma gangrenosum, acne, pyogenic arthritis, and hidradenitis suppurativa (PAPASH), psoriatic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PsAPASH), and pyoderma gangrenosum, acne, and ulcerative colitis (PAC). The rarity of the syndromes complicates the establishment of evidence-based treatment guidelines. Furthermore, treatment can be challenging due to lack of response to standard treatment modalities. Therefore, it is important to increase the awareness about these diseases in order to optimize disease management and ultimately improve the quality of life of patients. PMID- 28345208 TI - Increased Synthetic Control-Gaining Access to Predicted Mg2 Si5 N8 and beta-Ca2 Si5 N8. AB - Nitridosilicates represent an intriguing class of materials and are typically made up of highly condensed tetrahedral network structures. Alkaline-earth nitridosilicates emerged as unique host materials for Eu2+ doped luminophores which found broad application in phosphor-converted (pc)-LEDs. In contrast to common strategies of preparing nitridosilicates by bottom-up syntheses, we have now succeeded to post-synthetically design nitridosilicates by ion exchange in metal halide melts. We describe the syntheses of hitherto unknown but predicted alkaline-earth nitridosilicates, Mg2 Si5 N8 and beta-Ca2 Si5 N8 . Both compounds were obtained by ion exchange starting from pre-synthesized nitridosilicates. In situ investigations of the ion-exchange process show that the Si-N network topology remains preserved. Therefore the reaction offers a significant increase of synthetic control with respect to classical bottom-up syntheses. PMID- 28345209 TI - High olfactory sensitivity to conspecific intestinal fluid in the chameleon cichlid Australoheros facetus: could faeces signal dominance? AB - The present study shows that the olfactory potency of intestinal and bile fluids taken from dominant male chameleon cichlids Australoheros facetus is greater than those from subordinate males. Thus, dominant status may be communicated by odorants released in the intestinal fluid and bile acids may contribute towards this. PMID- 28345210 TI - Geographic Disparities in Availability of Opioid Use Disorder Treatment for Medicaid Enrollees. AB - OBJECTIVE: To examine county-level geographic variation in treatment admissions among opioid treatment programs (OTPs) that accept Medicaid in the continental United States. DATA SOURCES/STUDY SETTING: Data come from the 2012 National Survey of Substance Abuse Treatment Services. STUDY DESIGN/DATA COLLECTION: We used local measures of spatial autocorrelation (LISA) analysis to identify (1) clusters of counties with higher and lower than average rates of opioid use disorders and (2) clusters of counties with higher and lower than average treatment admissions among OTPs that accept Medicaid, adjusting for county population size. PRINCIPAL FINDINGS: Our results reveal several clusters of counties with higher than average rates of opioid use disorder (OUD) and lower than average treatment admissions among OTPs that accept Medicaid. These clusters are highly concentrated in the Southeast region of the country and include Arkansas, Kentucky, Louisiana, Mississippi, and Tennessee. CONCLUSIONS: Medicaid enrollees in areas in the Southeast have the largest gaps between county-level OUD rates and estimated county-level capacity for treatment, as measured by county-level total treatment admissions among OTPs that accept Medicaid. Policy makers should consider strategies to increase the availability of OTPs with the capacity to serve Medicaid enrollees. PMID- 28345211 TI - 3D echocardiographic analysis of aortic annulus for transcatheter aortic valve replacement using novel aortic valve quantification software: Comparison with computed tomography. AB - BACKGROUND: With the increasing use of transcatheter aortic valve replacement (TAVR) in patients with aortic stenosis (AS), computed tomography (CT) remains the standard for annulus sizing. However, 3D transesophageal echocardiography (TEE) has been an alternative in patients with contraindications to CT. We sought to (1) test the feasibility, accuracy, and reproducibility of prototype 3DTEE analysis software (Philips) for aortic annular measurements and (2) compare the new approach to the existing echocardiographic techniques. METHODS: We prospectively studied 52 patients who underwent gated contrast CT, procedural 3DTEE, and TAVR. 3DTEE images were analyzed using novel semi-automated software designed for 3D measurements of the aortic root, which uses multiplanar reconstruction, similar to CT analysis. Aortic annulus measurements included area, perimeter, and diameter calculations from these measurements. The results were compared to CT-derived values. Additionally, 3D echocardiographic measurements (3D planimetry and mitral valve analysis software adapted for the aortic valve) were also compared to the CT reference values. RESULTS: 3DTEE image quality was sufficient in 90% of patients for aortic annulus measurements using the new software, which were in good agreement with CT (r-values: .89-.91) and small (<4%) inter-modality nonsignificant biases. Repeated measurements showed <10% measurements variability. The new 3D analysis was the more accurate and reproducible of the existing echocardiographic techniques. CONCLUSIONS: Novel semi-automated 3DTEE analysis software can accurately measure aortic annulus in patients with severe AS undergoing TAVR, in better agreement with CT than the existing methodology. Accordingly, intra-procedural TEE could potentially replace CT in patients where CT carries significant risk. PMID- 28345212 TI - Cardiac iodine-123-metaiodobenzylguanidine scintigraphy may be useful to identify pathologic from physiologic sinus bradycardia. AB - BACKGROUND: Sinus bradycardia includes pathologic sick sinus syndrome (SSS) and physiologic bradycardia such as athletes' heart. Pacemaker implantation is indicated for patients with symptomatic SSS; however, the indication remains difficult to determine in those with mild and/or unspecific symptoms. The sympathetic tone is increased in response to reduced cardiac output in SSS, whereas excessive vagal tone has been seen in physiological bradycardia. We sought to determine if cardiac iodine-123-metaiodobenzylguanidine scintigraphy (123 I-MIBG) was useful in differentiating pathologic from physiologic sinus bradycardia. METHODS: Twenty consecutive patients presenting with continuous sinus bradycardia (heart rate of <50 beats/min) in our outpatient clinic (male, eight patients; age, 70 +/- 12 years old) were enrolled. The indication for a pacemaker implantation was determined by an experienced electrophysiologist in compliance with the international guidelines. The sympathetic nervous tone was assessed by cardiac 123 I-MIBG. RESULTS: Eight patients (40%) were clinically diagnosed as SSS (type I) including four suffering from obvious symptoms (syncope or dizziness) and four suffering from mild symptoms (fatigue), and had an indication for a pacemaker implantation. The patients with SSS indicated for a pacemaker implantation had a lower early heart-to-mediastinum ratio (2.0 +/- 0.6 vs 2.5 +/- 0.2, P = 0.043), lower delayed heart to mediastinum ratio (2.0 +/- 0.8 vs 2.8 +/- 0.3, P = 0.026), and higher washout rate (34 +/- 6.0 vs 26 +/- 6.0, P = 0.008) than those without. CONCLUSION: Excessive sympathetic tone detected by 123 I-MIBG may serve as an adjunct to determine the indication for a pacemaker implantation in sinus bradycardia. PMID- 28345213 TI - Caries experience of children in primary schools with long-term tooth brushing programs: A pilot Australian study. AB - OBJECTIVE: The aim of this study was to evaluate a primary school-based tooth brushing (TB) program conducted in a low socio-economic area of Queensland, Australia, to determine its effectiveness in reducing caries. METHODS: Records kept at the central dental clinic of the district were used to analyse the caries experience (decayed, missing, filled teeth [dmft/DMFT]) and caries prevalence in children from two schools with long-term TB programs (TB) (N=1191) and three Non TB schools (N=553). The schools were matched by socio-economic indices. RESULTS: Historical records showed that the baseline caries experience in all TB and Non TB primary schools were similar at each primary school year. After a mean period of 5-9 years of the TB program, the caries experience (mean decayed, missing, filled teeth, dmft/DMFT) and prevalence were lower for TB group than Non-TB group. In the primary dentition, the overall mean dmft (+/-standard deviation) of TB group (2.53+/-3.00) was significantly lower than the Non-TB group (3.06+/ 3.30) (P<.001). Similarly, in the permanent dentition, the overall mean DMFT of TB group (0.47+/-1.05) was reduced significantly compared to the Non-TB group (1.15+/-1.72) (P<.001). The overall caries prevalence in the TB group was 68% compared to 78% in Non-TB (P<.001). Overall, the mean annual DMFT increments of children in the TB schools were also significantly less compared with children in the Non-TB schools (P<.001). CONCLUSION: A long-term primary school TB program significantly reduced caries experience and caries prevalence in an optimally fluoridated (1-ppm), very low socio-economic district. PMID- 28345214 TI - Effects from changes to the Medicare Benefits Schedule in 2014 on cone beam computed tomography and panoramic radiography scans across Australia. AB - INTRODUCTION: This study examines the effects of the new Medicare Benefits Schedule (MBS) operating from 1st November 2014 on the number of Medicare rebated panoramic radiography (PR) and cone beam computed tomography (CBCT) scans. METHODS: Data for rebated PR and CBCT scans were extracted from Medicare Australia Statistics online for four 12-month periods: November 2011-October 2012, November 2012-October 2013, November 2013-October 2014 and December 2014 November 2015. RESULTS: There was a reduction in the number of CBCT scans rebated across Australia under the new MBS. Nationally, December 2014-November 2015 showed a 65.3% reduction in the number of CBCT scans when compared to the peak in the previous 12 months under the old MBS. The number of rebated PR scans remained constant. CONCLUSION: The new MBS implemented on 1st November 2014 resulted in a reduction in the number of rebated CBCT scans, but had no effect on rebated PR scans. Overall, there has been considerable cost savings for Medicare due to the change in MBS. Additionally, the reduction in the number of rebated CBCT scans has resulted in a substantial reduction in the ionising radiation load to the Australian community as a whole, but especially the younger age groups. PMID- 28345215 TI - Temporal Discounting and the Tendency to Delay Gratification across the Eating Disorder Spectrum. AB - Bulimia nervosa (BN) and binge eating disorder (BED) have been associated with poorer reward-related inhibitory control, reflected by a reduced tendency to delay gratification. The opposite has been reported in anorexia nervosa (AN), but differences have not been directly compared across eating disorders (EDs). This study investigated self-reported (Delaying Gratification Inventory) and task based (temporal discounting) inhibitory control in 66 women with an ED and 28 healthy controls (HCs). Poorer task-based inhibitory control was observed in the BN compared with the AN group and poorer self-reported inhibitory control in the BN and in the BED groups compared with the AN and the HC groups, suggesting that reward-related inhibitory control varies across EDs. Symptom severity correlated with poorer self-reported (but not task-based) inhibitory control across the EDs. These data provide some support for transdiagnostic mechanisms and highlight the importance of addressing perceived loss of control in the treatment of EDs. Copyright (c) 2017 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 28345216 TI - Response to letter to the editor on shock anxiety among Japanese implantable cardioverter defibrillator patients. PMID- 28345217 TI - Fatigue and training of obstetrics and gynaecology trainees in Australia and New Zealand. AB - BACKGROUND: Several studies have linked doctor fatigue with adverse patient events and an increase in risk to doctors' personal safety and wellbeing. The present study assesses the rostering structure of Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) trainees and its association with trainees' reported fatigue levels, training opportunities and wellbeing, which were secondary outcomes of a larger study of trainee working hours which has been separately reported. METHODS: An anonymous, online survey of RANZCOG trainees was conducted. Demographic data collected included: age, gender, level of training and current rotation. Data were also collected on hours worked per week, long shifts (>12 h), self-reported fatigue levels, and opinions regarding current rostering and training. RESULTS: A majority (72.9%) of respondents regularly felt fatigued, with higher fatigue levels being associated with more hours worked per week (P = <0.001) and working long shifts (>12 h) (P = 0.007). Fatigue was associated with an increased risk of dozing while driving (P = 0.028), with 56.1% of respondents reporting that this occurs. Trainees appeared to be less confident in achieving their technical skill requirements, with increasing hours not increasing confidence in achieving these skills (P = 0.594). Trainees who worked under 50 h per week were less likely to report fatigue (P = <0.001) and more likely to report greater work enjoyment (P = 0.043), and working hours being conducive to learning (P = 0.015). CONCLUSION: Fatigue was frequently reported by RANZCOG trainees with increased working hours and long shifts being significant factors in fatigue levels. Strategies should be developed and trialled to enable trainees to obtain adequate case exposure and teaching without compromising patient and doctor safety. PMID- 28345218 TI - Nonadherence to antihypertensive medications in adults with high risk for obstructive sleep apnea. PMID- 28345219 TI - A Prototype of Mathematical Treatment of Pen Pressure Data for Signature Verification. AB - A prototype using simple mathematical treatment of the pen pressure data recorded by a digital pen movement recording device was derived. In this study, a total of 48 sets of signature and initial specimens were collected. Pearson's correlation coefficient was used to compare the data of the pen pressure patterns. From the 820 pair comparisons of the 48 sets of genuine signatures, a high degree of matching was found in which 95.4% (782 pairs) and 80% (656 pairs) had rPA > 0.7 and rPA > 0.8, respectively. In the comparison of the 23 forged signatures with their corresponding control signatures, 20 of them (89.2% of pairs) had rPA values < 0.6, showing a lower degree of matching when compared with the results of the genuine signatures. The prototype could be used as a complementary technique to improve the objectivity of signature examination and also has a good potential to be developed as a tool for automated signature identification. PMID- 28345220 TI - Boosting the Performance of the Nickel Anode in the Oxygen Evolution Reaction by Simple Electrochemical Activation. AB - The development of cost-effective and active water-splitting electrocatalysts that work at mild pH is an essential step towards the realization of sustainable energy and material circulation in our society. Its success requires a drastic improvement in the kinetics of the anodic half-reaction of the oxygen evolution reaction (OER), which determines the overall system efficiency to a large extent. A simple electrochemical protocol has been developed to activate Ni electrodes, by which a stable NiOOH phase was formed, which could weakly bind to alkali-metal cations. The electrochemically activated (ECA) Ni electrode reached a current of 10 mA at <1.40 V vs. the reversible hydrogen electrode (RHE) at practical operation temperatures (>75 degrees C) and a mild pH of ca. 10 with excellent stability (>24 h), greatly surpassing that of the state-of-the-art NiFeOx electrodes under analogous conditions. Water electrolysis was demonstrated with ECA-Ni and NiMo, which required an iR-free overall voltage of only 1.44 V to reach 10 mA cmgeo-2 . PMID- 28345221 TI - The effects of electromyostimulation application timing on denervated skeletal muscle atrophy. AB - INTRODUCTION: In this study we evaluated the effect of electromyostimulation (EMS) on myosin heavy chain (MHC) isoform expression in denervated rat muscles to determine the optimal timing for EMS application. METHODS: EMS was initiated on post-injury day 1 for the group with denervation receiving immediate EMS (DIEMS) and on post-injury day 15 for the group with denervation receiving delayed EMS (DDEMS) in rat denervated muscles. Muscle wet weight and muscle fiber cross sectional area (FCSA) were measured. MHC isoforms were analyzed in both protein homogenates and single muscle fibers. RESULTS: The expression levels of IIx and IIb isoforms of MHC were significantly lower and higher, respectively, in the gastrocnemius muscles of the DIEMS group, but not the DDEMS group. The DIEMS group also showed larger FCSA and a lower proportion of hybrid single fibers compared with the DDEMS group. DISCUSSION: These results indicate that immediate EMS is more effective than delayed EMS for aiding recovery of denervation-induced MHC changes. Muscle Nerve 56: E154-E161, 2017. PMID- 28345222 TI - Zein films with unoxidized or oxidized tannic acid. AB - BACKGROUND: Corn zein is a predominatly hydrophobic protein, forming films with relatively good water resistance. Tannic acid, especially in its oxidized form, is supposed to cross-link proteins including zein, which may be explored to further enhance the water resistance of zein films. The effects of different contents (0-8 wt%) of unoxidized and oxidized tannic acid (uTA and oTA, respectively) on the properties of zein films at different pH values (4-9) were studied, according to central composite designs. RESULTS: Increasing tannic acid contents and pH values resulted in decreased water solubility and increased tensile strength and modulus of films. The presence of tannic acid provided the films with a yellowish color and increased opacity. Paired t-tests indicated that oTA films presented higher tensile strength, lower water vapor permeability and lower water solubility than uTA films. CONCLUSION: Higher tannic acid contents and pH values resulted in films with better overall physical properties, which might be ascribed to cross-linking, although the films were still not water resistant. The resulting films have potential to be used for food packaging and coating applications. (c) 2017 Society of Chemical Industry. PMID- 28345223 TI - Impact of age and mismatch repair status on survival in colorectal cancer. AB - Previous studies have suggested that deficiencies in mismatch repair genes (dMMR) often occur in patients with colorectal cancer (CRC) and contribute to disease etiology. Here, we looked for a correlation of MMR status to disease outcomes from a large number of Chinese CRC patients stratified by the age of onset of disease. A total of 2233 CRC patients were analyzed and tissue biopsies of surgically removed tumors scored for MMR gene status. The patient distribution after classification consisted of 188 younger aged patients (20-39 years of age), 1024 middle aged patients (40-59 years of age), and 1020 older aged patients (60 85 years of age). In this analysis, the expression of four MMR genes was assessed by immunohistochemistry (IHC). We found that the young group of CRC patients with dMMR had higher overall survival (OS) than the young group of patients with proficient MMR (pMMR) (77% vs. 56%, P = 0.03). Middle-aged patients with dMMR also had higher OS than middle-aged group patients with pMMR (78% vs. 68%, P = 0.012). However, we found no statistical difference in OS between dMMR and pMMR status in the older group of patients (75% vs. 71%, P = 0.224). Finally, the middle- and older-aged group set of patients had higher OS than the young group of patients (69% vs. 71% vs. 59%, P = 0.008). These data demonstrated that the age of disease onset can be an important factor to help evaluate the prognosis of CRC when combined with the analysis of MMR status within tumor biopsied tissue. PMID- 28345224 TI - Involvement of multiple Chlamydia suis genotypes in porcine conjunctivitis. AB - Chlamydia suis has been detected in numerous disease conditions of pigs, particularly in eye infections. This study examined recurring conjunctivitis cases in five commercial pig farms in Japan. 40.5% of the cases were identified as Chlamydia positive using impression cytology of ocular smears and a genus specific direct fluorescent antibody. C. suis was detected in 59.5% of the samples using PCR tests targeting 16S-23S rRNA intergenic spacer region (ISR) and ompA gene. Genetic analysis of PCR amplicons revealed nine sequence variants of 16S-23S rRNA ISR and 20 sequence variants within ompA gene. Among C. suis positive conjunctivitis cases, 36.4% showed concurrent infection with 2-4 varied ompA sequence types and 9.1% showed multiple 16S-23S rRNA ISR sequence types of C. suis. Multiple genotypes were found circulating in four of five farms. All 20 detected strains and 25 previously reported C. suis strains were grouped into four clusters. Japanese C. suis strains were closely related to American and European strains indicating wide distribution of these genetically variant strains. This study is the first to show multiple and genetically diverse C. suis strain associations in pig conjunctivitis. PMID- 28345225 TI - Highly potent host external immunity acts as a strong selective force enhancing rapid parasite virulence evolution. AB - Virulence is often under selection during host-parasite coevolution. In order to increase fitness, parasites are predicted to circumvent and overcome host immunity. A particular challenge for pathogens are external immune systems, chemical defence systems comprised of potent antimicrobial compounds released by prospective hosts into the environment. We carried out an evolution experiment, allowing for coevolution to occur, with the entomopathogenic fungus, Beauveria bassiana, and the red flour beetle, Tribolium castaneum, which has a well documented external immune system with strong inhibitory effects against B. bassiana. After just seven transfers of experimental evolution we saw a significant increase in parasite induced host mortality, a proxy for virulence, in all B. bassiana lines. This apparent virulence increase was mainly the result of the B. bassiana lines evolving resistance to the beetles' external immune defences, not due to increased production of toxins or other harmful substances. Transcriptomic analyses of evolved B. bassiana implicated the up-regulation of oxidative stress resistance genes in the observed resistance to external immunity. It was concluded that external immunity acts as a powerful selective force for virulence evolution, with an increase in virulence being achieved apparently entirely by overcoming these defences, most likely due to elevated oxidative stress resistance. PMID- 28345226 TI - Decision making in the face of uncertainty: the challenge of emerging infectious diseases. PMID- 28345227 TI - The unmeasured cost of preterm labor screening programs. PMID- 28345228 TI - Asian collaboration to establish a provisional system to provide high-quality end of-life care by promoting advance care planning for older adults. PMID- 28345229 TI - Reply to Gulistan Bahat: Significance of population differences and the methodology in determining the muscle mass cut-off points for sarcopenia. PMID- 28345230 TI - Sensory neuropathy in a patient with low low-density lipoprotein cholesterol levels. PMID- 28345231 TI - Association of blood pressure and cognitive decline in older adults with diabetes mellitus during a 9-year observational study. PMID- 28345232 TI - Spanish translation of the Kihon Checklist (frailty index). PMID- 28345233 TI - Sleep apnea and lateral balance instability in older adults. PMID- 28345234 TI - Acute cerebral infarction after pyrethroid ingestion. PMID- 28345235 TI - Risk assessment and falls prevention in the older adult: Asian experience with the Falls Risk for Older People in the Community tool. PMID- 28345236 TI - Significance of population differences and the methodology in determining the muscle mass cut-off points for sarcopenia. PMID- 28345237 TI - Moving to Translational Proteomics. PMID- 28345239 TI - The anatomy of the blood vascular system of the giant vestimentiferan tubeworm Riftia pachyptila (Siboglinidae, Annelida). AB - The giant dimensions of vestimentiferan Riftia pachyptila (Jones, ) are achieved thanks to the well-developed vascular system. In the vestimentum, there is a complicated net of lacunae, including the brain blood supply and the ventral lacuna underlying the ciliary field. The trunk region has an extensive network of blood vessels feeding the gonads ("rete mirabile"). The thick muscular lining of the mesenterial vessels in the trunk and the dorsal vessel in the opisthosome serves as an additional pump, pushing blood into numerous vessels in the segments. It was hypothesized that the blood envelope of the ventral blood vessel in the trunk provides the blood supply to the trophosome. The 3D reconstruction has revealed that there are two vascular systems of the tentacular crown of R. pachyptila. Blood runs into the tentacles via axial afferent vessels, as described earlier only for Riftia, and also via basal ones, as described for other vestimentiferans except Riftia. The basal ones are poorly developed, and the number of lamellar blood vessels is small, indicating a lack of demand for these within huge R. pachyptila. It appears that the presence of these vessels is the preserved ancestral state of Vestimentifera. In different portions of the dorsal vessel, the morphology of the intravasal body varies, depending on function. PMID- 28345240 TI - Prenatal DNA Sequencing: Clinical, Counseling, and Diagnostic Laboratory Considerations. AB - Clinical diagnostic laboratories are producing next-generation sequencing-based test results that are becoming increasingly incorporated into patient care. Whole genome and exome sequencing on fetal material derived from amniocytes, chorionic villi, or products of conception is starting to be offered clinically in specialized centers, but it has not yet become routine practice. The technical, interpretation, and ethical challenges are greatest in the area of prenatal medicine because the fetus has a limited health history, and the physical examination is only indirectly available via prenatal sonography. Here, we provide an overview of these challenges and highlight the clinical utility, reporting, and counseling issues associated with prenatal DNA sequencing. Future considerations are also discussed. (c) 2017 John Wiley & Sons, Ltd. PMID- 28345241 TI - The new Swedish report on Shaken Baby Syndrome is misleading. PMID- 28345242 TI - Multi-Electron Oxidation of Anthracene Derivatives by Nonheme Manganese(IV)-Oxo Complexes. AB - Six-electron oxidation of anthracene to anthraquinone by a nonheme MnIV -oxo complex, [(Bn-TPEN)MnIV (O)]2+ , proceeds through a rate-determining electron transfer from anthracene to [(Bn-TPEN)MnIV (O)]2+ , followed by subsequent fast oxidation reactions to give anthraquinone. The reduced MnII complex ([(Bn TPEN)MnII ]2+ ) is oxidized by [(Bn-TPEN)MnIV (O)]2+ rapidly to produce the MU oxo dimer ([(Bn-TPEN)MnIII -O-MnIII (Bn-TPEN)]4+ ). The oxygen atoms of the anthraquinone product were found to derive from the manganese-oxo species by the 18 O-labelling experiments. In the presence of Sc3+ ion, formation of an anthracene radical cation was directly detected in the electron transfer from anthracene to a Sc3+ ion-bound MnIV (O) complex, [(Bn-TPEN)MnIV (O)-(Sc(OTf)3 )2 ]2+ , followed by subsequent further oxidation to yield anthraquinone. When anthracene was replaced by 9,10-dimethylanthracene, electron transfer from 9,10 dimethylanthracene to [(Bn-TPEN)MnIV (O)-(Sc(OTf)3 )2 ]2+ occurred rapidly to produce stable 9,10-dimethylanthracene radical cation. The driving force dependence of the rate constants of electron transfer from the anthracene derivatives to [(Bn-TPEN)MnIV (O)]2+ and [(Bn-TPEN)MnIV (O)-(Sc(OTf)3 )2 ]2+ was well-evaluated in light of the Marcus theory of electron transfer. PMID- 28345243 TI - Dehiscence of a pulmonary bioprosthesis with a focal dissection of the pulmonary artery in a patient with congenital pulmonic stenosis. AB - Pulmonary valve replacement (PVR) is the most common adult congenital cardiac operation performed. Valve degeneration leading to prosthetic stenosis and/or regurgitation is a long-term risk in this population and may be associated with paravalvular leak (PVL). Complications involving the proximal pulmonary artery, including dissection, are less clearly defined. Herein, we report the case of a 30-year-old patient with a history of multiple pulmonary valve interventions secondary to congenital pulmonic stenosis, who developed dehiscence of a bioprosthetic PVR associated with significant paravalvular leak (PVL) and further complicated by a focal dissection of the proximal pulmonary artery. PMID- 28345244 TI - Association between serum and oral matrix metalloproteinase-8 levels and periodontal health status. AB - BACKGROUND AND OBJECTIVE: Matrix metalloproteinase-8 (MMP-8) is involved in a wide range of pathologies including periodontitis and cardiovascular diseases (CVD). The association between periodontitis and CVD has been repeatedly recognized. The aim of the study was to analyze to what extent circulating active MMP-8 (aMMP-8) is associated with periodontal disease status and oral fluid aMMP 8 levels in otherwise healthy subjects. MATERIAL AND METHODS: In a cross sectional study, aMMP-8 was measured in serum of 59 volunteers, comprising 19 periodontally healthy subjects, 20 patients with gingivitis as well as 20 with periodontitis. All study subjects were characterized regarding aMMP-8 concentrations in different oral fluids as well as clinically and microbiologically with respect to periodontal disease. aMMP-8 levels in gingival crevicular fluid were measured using the enzyme-linked immunosorbent assay. Saliva enzyme levels as well as circulating aMMP-8 were determined by a time resolved immunofluorometric assay. Both methods utilized the same monoclonal antibodies. Correlation and regression analyses were performed to study the potential association between serum aMMP-8 and oral parameters. RESULTS: Oral aMMP-8 levels were significantly higher in patients with periodontitis compared to periodontally healthy or gingivitis subjects. Highest serum aMMP-8 concentration was also found in the periodontitis group. The serum levels correlated significantly with oral aMMP-8 as well as with clinical parameters in a dose-dependent manner. These results were confirmed in a multivariate regression analysis. After adjusting for potential confounders, saliva aMMP-8 concentrations as well as periodontitis severity were significant predictors of serum aMMP-8. CONCLUSION: The associations between circulating aMMP-8 and oral aMMP-8 as well as periodontal findings in a dose-dependent manner may contribute to linking periodontal disease with increased CVDsusceptibility. PMID- 28345245 TI - Pain, depressive symptoms and medication in German patients with rheumatoid arthritis-results from the linking patient-reported outcomes with claims data for health services research in rheumatology (PROCLAIR) study. AB - PURPOSE: Pain and depressive symptoms are common in patients with rheumatoid arthritis (RA). Information on the prevalence and treatment of both conditions in German RA patients is scarce. METHODS: Using data from a nationwide statutory health insurance fund (BARMER GEK), 6193 RA patients aged 18 to 79 years were provided with a questionnaire covering a variety of items such as demographics, medical condition and quality of life in 2015. Pain caused by the joint disorder (11-point scale) was classified as none existent/mild, moderate or severe. Depressive symptoms were determined using the World Health Organization's five item Well-being Index and categorized as none existent, mild or moderate/severe. Another item covered additional use of over-the-counter drugs. Data were linked to dispensation records. RESULTS: A total of 3140 RA patients were included. Median age was 66 years (79% female). About 70% of patients were classified as having moderate or severe pain. Depressive symptoms were found in 52% and were far more common among patients with higher pain levels. Analgesic treatment ranged from 45% to 76% (non-opioid analgesics) and from 6% to 33% (opioids) in patients with no/mild pain and those reporting severe pain, respectively. In patients reporting moderate or severe pain, substantially higher prevalences of opioid use were observed among those with depressive symptoms. Depending on depressive symptoms, antidepressant use ranged from 7% to 37%. Overall, over-the counter drug use varied between 30% and 59%. CONCLUSIONS: Pain and depressive symptoms are highly prevalent in German RA patients, often present together and influence each other's treatment. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28345246 TI - Effect of History and Context on Forensic Pathologist Interpretation of Photographs of Patterned Injury of the Skin. AB - In a previous study, a survey-based analysis of pathologist diagnoses of patterned injury was performed. Subjects were provided with photographs of "classic" injuries and asked to diagnose the lesion in the absence of history or context. There was a relatively low diagnostic consensus among respondents. A second survey suggested that the disparate answers were not due to a strong belief in different diagnoses, but instead reflected how the respondents dealt with ambiguity. A third survey was created that asked participants to evaluate patterned injuries of the skin, but provided history and contextual information. The addition of history and contextual information increased consensus from a median of 80% to 98% on a per-question basis. Confidence increased from a median of 56%-92%. These results demonstrate the importance of history and context in medical diagnosis of patterned injuries of the skin. PMID- 28345247 TI - Functional morphological adaptations of the bony labyrinth in marsupials (Mammalia, Theria). AB - Diprotodontia represents the largest and ecologically most distinct order of marsupials occurring in Australasian being highly divers in size, locomotion, habitat preferences, feeding, and activity pattern. The spatial orientation in the habitat and therefore the three-dimensional space is detected by the vestibular system of the inner ear, more precisely by the three semicircular canals. In this study, we investigated the bony labyrinth of diprotodontian and selected non-diprotodontian marsupial mammals of almost all genera with noninvasive micro-CT scanning and 3D-reconstructions. In principal component analyses, the subterranean taxon can be separated from gliding and saltatorial taxa, whereas arboreal species can be separated from saltatorial specimens. The highest PCA loadings of this functional distinction are clearly found in the diameter of the semicircular canals, whereas the overall shape (height, width, length) of the semicircular canals is less important. Additionally, the investigated arboreal and fossorial species of South America are nested in the morphospace of the Australasian taxa. Even if a phylogenetic signal in the anatomy of the bony labyrinth cannot be excluded entirely, the main functional morphological signal of the vestibular system is found in the diameter of the semicircular canals. With the large dataset of extant marsupial mammals analysed here, the locomotion mode of extinct taxa can be inferred in future studies independent of any evidence of postcranial material. PMID- 28345248 TI - Application of Thiol-yne/Thiol-ene Reactions for Peptide and Protein Macrocyclizations. AB - The application of thiol-yne/thiol-ene reactions to synthesize mono- and bicyclic stapled peptides and proteins is reported. First, a thiol-ene-based peptide stapling method in aqueous conditions was developed. This method enabled the efficient stapling of recombinantly expressed coil-coiled proteins. The resulting stapled protein demonstrated higher stability in its secondary structure than the unstapled version. Furthermore, a thiol-yne coupling was performed by using an alpha,omega-diyne to react with two cysteine residues to synthesize a stapled peptide with two vinyl sulfide groups. The stapled peptide could further react with another biscysteine peptide to yield a bicyclic stapled peptide with enhanced properties. For example, the cell permeability of a stapled peptide was further increased by appending an oligoarginine cell-penetrating peptide. The robustness and versatility of thiol-yne/thiol-ene reactions that can be applied to both synthetic and expressed peptides and proteins were demonstrated. PMID- 28345250 TI - The application of constitutively solvent-tolerant P. taiwanensis VLB120DeltaCDeltattgV for stereospecific epoxidation of toxic styrene alleviates carrier solvent use. AB - For whole-cell biotransformations involving toxic organic compounds, two-liquid phase setups are typically applied employing an apolar extractive phase. Bis(2 ethylhexyl)phthalate (BEHP) has proven to be an ideal solvent for stereospecific styrene epoxidation with recombinant E. coli, providing excellent extractive properties and a high biocompatibility. In eco-efficiency evaluations, BEHP, however, has been identified as a critical factor regarding costs and environmental impact. In this study, the constitutive solvent tolerance of Pseudomonas taiwanensis VLB120DeltaCDeltattgV is shown to enable high specific activities (up to 180 U gCDW-1 ) and extensive reduction of the BEHP amount in two-liquid phase setups and thus to constitute an excellent tool to improve the environmental and economic efficiency of such processes. At a 90% reduction of carrier solvent use and accordingly increased aqueous styrene concentrations, this strain still showed reasonably high specific styrene epoxidation activities (100 U gCDW-1 ), while the solvent-adaptable wildtype strain immediately was toxified. A moderate 55% reduction of BEHP enabled a specific activity of 150 U gCDW-1 and thus represents a good trade-off between volumetric productivity maximization and environmental impact minimization. These results for the first time show a clear benefit of a solvent-tolerant compared to solvent-sensitive host strains and how such a benefit can be achieved. PMID- 28345249 TI - A multinational, drug utilization study to investigate the use of dexmedetomidine (Dexdor(r)) in clinical practice in the EU. AB - AIMS: Dexmedetomidine (dexdor(r)) is approved in the European Union (EU) for sedation of adults in the intensive care unit (ICU). The present observational, retrospective study was requested by the European Medicines Agency to investigate dexmedetomidine use in clinical practice, with a particular focus on off-label use, including the paediatric population. METHODS: Study countries and sites were chosen from those with highest dexmedetomidine use, based on sales. Site selection (blind) was conducted by a multispecialist, independent group. Anonymized data on demographics, treatment indication, dexmedetomidine dosing, concomitant medications and treatment effectiveness were collected retrospectively from records of all dexmedetomidine-treated patients at the site during the enrolment period. Informed consent was waived, to avoid influencing the prescribing of dexmedetomidine. Recruitment was completed within 18 months of first site initiation. RESULTS: Data from 2000 patients were collected from 16 hospitals in four EU countries (Finland 750, Poland 505, Germany 470, Austria 275). The median age was 62 years, with more males (70.2%) than females. Dexmedetomidine was primarily used in the adult ICU (86.0%) for ICU sedation (78.6%) and mostly dosed according the product label. The intended sedative effect was obtained in 84.9% of administrations. Paediatric use (5.9% of patients, mostly in Austria and Finland) occurred mainly in the adult or paediatric ICU (75.6%) for sedation (67.2%). CONCLUSIONS: Overall, most patients were treated with dexmedetomidine according to the product labelling. Use in children was limited but significant and similar in scope to that in adults. Administrations not fully according to the product labelling usually occurred in an ICU environment and reflected extensively investigated clinical uses of dexmedetomidine. PMID- 28345251 TI - Complication of hybrid treatment in type B aortic dissection diagnosed by echocardiography. AB - This case illustrates an unusual and fatal complication after endovascular treatment of type B aortic dissection and highlights the role of echocardiography in the early diagnosis of complications. In this case, a patient with previous diagnosis of chronic type B aortic dissection and moderate aortic regurgitation underwent endovascular repair of the proximal descending aorta and conservative surgical correction of the aortic valve. On early postoperative, a transesophageal echocardiogram and aortic angiotomography demonstrated proximal endoleak by contrast extravasation around the proximal graft attachment site, causing compression of the stent in its middle portion, resulting in narrowing with reduced cross-sectional area. PMID- 28345252 TI - Amplification of FSH signalling by CFTR and nuclear soluble adenylyl cyclase in the ovary. AB - The cAMP/PKA pathway is one of the most important signalling pathways widely distributed in most eukaryotic cells. The activation of the canonical cAMP/PKA pathway depends on transmembrane adenylyl cyclase (tmAC). Recently, soluble adenylyl cyclase (sAC), which is activated by HCO3- or Ca2+ , emerges to provide an alternative way to activate cAMP/PKA pathway with the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated Cl- /HCO3- conducting anion channel, as a key player. This review summarizes new progress in the investigation of the CFTR/HCO3- -dependent sAC signalling and its essential role in various reproductive processes, particularly in ovarian functions. We present the evidence for a CFTR/HCO3- -dependent nuclear sAC signalling cascade that amplifies the FSH-stimulated cAMP/PKA pathway, traditionally thought to involve tmAC, in granulosa for the regulation of oestrogen production and granulosa cell proliferation. The implication of the CFTR/HCO3- /sAC pathway in amplifying other receptor-activated cAMP/PKA signalling in a wide variety of cell types and pathophysiological processes, including aging, is also discussed. PMID- 28345253 TI - Attending and avoiding dental appointments: Do "bright" and "dark" motivational paths have a role? AB - OBJECTIVE: The aim of this study was to test a self-determination theory (SDT) process model of the "bright" and the "dark" motivational pathways through dental attendance or avoidance to oral health. METHODS: A cross-sectional study was conducted among 322 students from all study disciplines at the University of Oslo. Participants responded to a survey with validated questionnaires. Structural equation modelling was used to test the SDT model, and a bootstrapping procedure was used to test the indirect links in the model. RESULTS: Along the "bright" path: Autonomy support at the dental clinic was positively associated with need satisfaction in treatment, which was positively associated with autonomous motivation for dental treatment and reappraisal of dental anxiety. Further, autonomous motivation was positively related to dental attendance, which in turn predicted oral health. Also, both autonomous motivation and reappraisal of anxiety were negatively related to avoiding dental appointments. Along the "dark" path: Conditional regard at the dental clinic positively predicted need frustration in treatment, which positively predicted dental anxiety. In turn, dental anxiety positively predicted avoiding appointments, along with the negative predictions by autonomy and anxiety reappraisal. Finally, oral health was negatively predicted by avoiding appointments. A bootstrapping procedure indicated that all indirect links in the model were supported. A SEM fit the data very well. CONCLUSIONS: Because of the high level of explained variances for dental attendance (42%) and avoiding dental appointments (52%), promoting autonomy support and avoiding conditional regard at the dental clinic may be important for patients' oral health. PMID- 28345254 TI - Direct Functionalization of Poly(spirophosphazene)s via the Regioselective Lithiation of the Aromatic Rings Using a Cooperative Superbase. AB - The direct chemical functionalization of poly(spirophosphazene) [N?P(O2 C12 H8 )]n (1) can be performed by the lithiation of the aromatic rings at low temperature using Schlosser's base (Lit Bu/KOt Bu or "superbase"), and the subsequent reaction with various electrophiles such as Cl?SiMe3 , Cl?PPh2 , or MeO?B(O2 C6 H12 ) (MeO?Bpin). The functionalized polymers, isolated in very high yields (>90%) and without degradation of the polymeric chains, have an average degree of substitution per repeat unit ranging from 0.3 (random copolymers) to a maximum of 1.0, which corresponds to the homopolymers [N?P(O2 C12 H7 ?FG)]n (FG (functional group) =?SiMe3 , ?PPh2 , and ?Bpin). NMR studies, including bidimensional high temperature experiments on silylated and deuterated polymers, show that the substitution is regioselectively occurring at the C3 carbon of the aromatic rings due to the coordination of the lithium cations to the nitrogen of the polyphosphazene chain. The introduction of functional groups on the aromatic rings leads to significant changes in the solubility (silylated polymers), Tg , and electronic properties of the material, showing how the change of substituents in the aromatic rings can lead to polyphosphazenes with properties markedly different from those of the precursor polymer. PMID- 28345255 TI - Lichenoid folliculitis: A unifying concept. AB - Skin diseases presenting with keratotic papules, atrophy, cicatricial alopecia and/or "lichenoid" histopathologic changes have been described under at least 30 names. This family of diseases contains 2 subgroups, largely based on clinical features: keratosis pilaris atrophicans (KPA; including keratosis pilaris atrophicans faciei/ulerythema ophryogenes, atrophoderma vermiculata, and keratosis follicularis spinulosa decalvans); and the lichen planopilaris (LPP) subgroup (including LPP, frontal fibrosing alopecia, Graham-Little-Piccardi Lassueur Syndrome and fibrosing alopecia in a pattern distribution). An interface dermatitis with lichenoid inflammation is characteristic of the LPP group of disorders, but the literature provides scant information about the histopathology of the KPA group. Our experience has been that the 2 subgroups show a unifying histologic similarity as well as considerable clinical overlap. Because these conditions overlap clinically and histologically, we propose that the term lichenoid folliculitis (LF) be used to refer to this group of diseases, thus simplifying cumbersome nomenclature and highlighting the possibility of shared pathogenesis and treatment options. PMID- 28345256 TI - Physician Competition in the Era of Accountable Care Organizations. AB - OBJECTIVE: To calculate physician concentration levels for all U.S. markets using detailed data on integration and accountable care organization (ACO) participation. DATA SOURCE: 2015 SK&A office-based physician survey linked to all commercial and public payer ACOs. STUDY DESIGN: We construct three separate Herfindahl-Hirschman Index (HHI) measures and plot their distributions. We then investigate how prevailing levels of concentration change when incorporating more detailed organizational features into the HHI measure. PRINCIPAL FINDINGS: Horizontal and vertical integration strongly influences measures of physician concentration; however, ACOs have limited impact overall. ACOs are often present in competitive markets, and only in a minority of these markets do ACOs substantively increase physician concentration. CONCLUSIONS: Monitoring ACO effects on physician competition will likely have to proceed on a case-by-case basis. PMID- 28345257 TI - The role of limb position in the interpretation of nerve conduction studies. PMID- 28345258 TI - Locus of control and frequency of physician visits: Results of a population-based longitudinal study in Germany. AB - OBJECTIVES: To examine the role of internal and external locus of control (LOC) in the frequency of physician visits longitudinally. DESIGN: A nationally representative, longitudinal cohort study of German households. Data were used from the years 2005 and 2010. METHODS: Data were gathered from the German Socio Economic Panel (GSOEP). The ten internal and external LOC items in the SOEP are based on a scale by Krampen. The number of physician visits in the last 3 months was used as outcome variable. According to Andersen's behavioural model, predisposing characteristics, enabling resources, and need factors were included as control variables. RESULTS: Fixed-effects Poisson regressions showed that physician visits increased with increasing external LOC, whereas changes in internal LOC were not associated with changes in physician visits. Furthermore, physician visits increased with need factors (decreased self-rated health; onset of disability), whereas predisposing characteristics and the enabling resources were not associated with physician visits. CONCLUSIONS: Our findings emphasize the meaning of changes in external LOC for physician visits. As there is evidence that interventions can change the LOC, efforts to modify external LOC might be beneficial for the health care system. Statement of contribution What is already known on this subject? A few cross-sectional studies have investigated the association between locus of control (LOC) and health care use. Longitudinal studies are needed to get a deeper understanding of the causal relationship between these factors. What does this study add? Our longitudinal study provides insights into the impact of general internal and external LOC on physician visits. This is the first study examining the long-term relation in Germany using a population-based sample. PMID- 28345259 TI - The role of complement inhibitors beyond controlling inflammation. AB - The complement system is an arm of innate immunity that aids in the removal of pathogens and dying cells. Due to its harmful, pro-inflammatory potential, complement is controlled by several soluble and membrane-bound inhibitors. This family of complement regulators has been recently extended by the discovery of several new members, and it is becoming apparent that these proteins harbour additional functions. In this review, the current state of knowledge of the physiological functions of four complement regulators will be described: cartilage oligomeric matrix protein (COMP), CUB and sushi multiple domains 1 (CSMD1), sushi domain-containing protein 4 (SUSD4) and CD59. Complement activation is involved in both the development of and defence against cancer. COMP expression is pro-oncogenic, whereas CSMD1 and SUSD4 act as tumour suppressors. These effects may be related in part to the complex influence of complement on cancer but also depend on unrelated functions such as the protection of cells from endoplasmic reticulum stress conveyed by intracellular COMP. CD59 is the main inhibitor of the membrane attack complex, and its deficiency leads to complement attack on erythrocytes and severe haemolytic anaemia, which is now amenable to treatment with an inhibitor of C5 cleavage. Unexpectedly, the intracellular pool of CD59 is crucial for insulin secretion from pancreatic beta-cells. This finding is one of several relating to the intracellular functions of complement proteins, which until recently were only considered to be present in the extracellular space. Understanding the alternative functions of complement inhibitors may unravel unexpected links between complement and other physiological systems, but is also important for better design of therapeutic complement inhibition. PMID- 28345260 TI - Resistance training and aerobic training improve muscle strength and aerobic capacity in chronic inflammatory demyelinating polyneuropathy. AB - INTRODUCTION: We investigated the effects of aerobic and resistance exercise in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Eighteen CIDP patients treated with subcutaneous immunoglobulin performed 12 weeks of aerobic exercise and 12 weeks of resistance exercise after a run-in period of 12 weeks without exercise. Three times weekly the participants performed aerobic exercise on an ergometer bike or resistance exercise with unilateral training of knee and elbow flexion/extension. Primary outcomes were maximal oxygen consumption velocity (VO2 -max) and maximal combined isokinetic muscle strength (cIKS) of knee and elbow flexion/extension. RESULTS: VO2 -max and muscle strength were unchanged during run-in (-4.9% +/- 10.3%, P = 0.80 and -3.7% +/- 10.1%, P = 0.17, respectively). Aerobic exercise increased VO2 -max by 11.0% +/- 14.7% (P = 0.02). Resistance exercise resulted in an increase of 13.8% +/- 16.0% (P = 0.0004) in cIKS. DISCUSSION: Aerobic exercise training and resistance exercise training improve fitness and strength in CIDP patients. Muscle Nerve 57: 70-76, 2018. PMID- 28345261 TI - Antibodies from plants for bionanomaterials. AB - Antibodies are produced as part of the vertebrate adaptive immune response and are not naturally made by plants. However, antibody DNA sequences can be introduced into plants, and together with laboratory technologies that allow the design of antibodies recognizing any conceivable molecular structure, plants can be used as 'green factories' to produce any antibody at all. The advent of plant based transient expression systems in particular allows the rapid, convenient, and safe production of antibodies, ranging from laboratory-scale expression to industrial-scale manufacturing. The key features of plant-based production include safety, speed, low cost, and convenience, allowing newcomers to rapidly master the technology and use it to its full advantage. Manufacturing in plants has recently achieved significant milestones and offers more than just an alternative to established microbial and mammalian cell platforms. The use of plants for product development in particular offers the power and flexibility to easily coexpress many different genes, allowing the plug-and-play construction of novel bionanomaterials, perfectly complementing existing approaches based on plant virus-like particles. As well as producing single antibodies for applications in medicine, agriculture, and industry, plants can be used to produce antibody-based supramolecular structures and scaffolds as a new generation of green bionanomaterials that promise a bright future based on clean and renewable nanotechnology applications. WIREs Nanomed Nanobiotechnol 2017, 9:e1462. doi: 10.1002/wnan.1462 For further resources related to this article, please visit the WIREs website. PMID- 28345262 TI - Purebreeding of Red Maasai and crossbreeding with Dorper sheep in different environments in Kenya. AB - The aim of this article was to study opportunities for improvement of the indigenous and threatened Red Maasai sheep (RM) in Kenya, by comparing purebreeding with crossbreeding with Dorper sheep (D) as a terminal breed, in two different environments (Env. A and a harsher Env. B), assuming different levels of genotype-by-environment interaction (G * E). Breeding goals differed between environments and breeds. Four scenarios of nucleus breeding schemes were stochastically simulated, with the nucleus in Env. A. Overall, results showed an increase in carcass weight produced per ewe by more than 10% over 15 years. Genetic gain in carcass weight was 0.17 genetic SD/year (0.2 kg/year) across scenarios for RM in the less harsh Env. A. For survival and milk yield, the gain was lower (0.04-0.05 genetic SD/year). With stronger G * E, the gain in the commercial tier for RM in the harsher Env. B became increasingly lower. Selection of females also within the commercial tier gave slightly higher genetic gain. The scenario with purebreeding of RM and a subnucleus in Env. B gave the highest total income and quantity of meat. However, quantity of meat in Env. A increased slightly from having crossbreeding with D, whereas that in Env. B decreased. A simple and well-designed nucleus breeding programme would increase the genetic potential of RM. Crossbreeding of RM with D is not recommended for harsh environmental conditions due to the large breed differences expected in that environment. PMID- 28345264 TI - Blood transcriptomes and de novo identification of candidate loci for mating success in lekking great snipe (Gallinago media). AB - We assembled the great snipe blood transcriptome using data from fourteen lekking males, in order to de novo identify candidate genes related to sexual selection, and determined the expression profiles in relation to mating success. The three most highly transcribed genes were encoding different haemoglobin subunits. All tended to be overexpressed in males with high mating success. We also called single nucleotide polymorphisms (SNPs) from the transcriptome data and found considerable genetic variation for many genes expressed during lekking. Among these, we identified 14 polymorphic candidate SNPs that had a significant genotypic association with mating success (number of females mated with) and/or mating status (mated or not). Four of the candidate SNPs were found in HBAA (encoding the haemoglobin alpha-chain). Heterozygotes for one of these and one SNP in the gene PABPC1 appeared to enjoy higher mating success compared to males homozygous for either of the alleles. In a larger data set of individuals, we genotyped 38 of the identified SNPs but found low support for consistent selection as only one of the zygosities of previously identified candidate SNPs and none of their genotypes were associated with mating status. However, candidate SNPs generally showed lower levels of spatial genetic structure compared to noncandidate markers. We also scored the prevalence of avian malaria in a subsample of birds. Males infected with avian malaria parasites had lower mating success in the year of sampling than noninfected males. Parasite infection and its interaction with specific genes may thus affect performance on the lek. PMID- 28345263 TI - NMR solution structure of the RED subdomain of the Sleeping Beauty transposase. AB - DNA transposons can be employed for stable gene transfer in vertebrates. The Sleeping Beauty (SB) DNA transposon has been recently adapted for human application and is being evaluated in clinical trials, however its molecular mechanism is not clear. SB transposition is catalyzed by the transposase enzyme, which is a multi-domain protein containing the catalytic and the DNA-binding domains. The DNA-binding domain of the SB transposase contains two structurally independent subdomains, PAI and RED. Recently, the structures of the catalytic domain and the PAI subdomain have been determined, however no structural information on the RED subdomain and its interactions with DNA has been available. Here, we used NMR spectroscopy to determine the solution structure of the RED subdomain and characterize its interactions with the transposon DNA. PMID- 28345265 TI - Cytokine and antioxidant gene profiles from peripheral blood mononuclear cells of Pelibuey lambs after Haemonchus contortus infection. AB - The expression profiles of cytokines and antioxidant genes were determined from an experimental infection with H. contortus in Pelibuey lambs. The infection was followed for 34 days (d) to determine the number of eggs per gram (epg) and the packed cell volume (PCV). Differential white cell counts and expression profile estimations of IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, FCepsilonR1A, GPX and SOD1 were determined at 0 hour, 4 hours, 2 days and 14 days post-infection (PI) in infected and control groups. Comparison of the fold change between 0 and 4 hours, 4-hours and 2-days and 2- and 14-days periods was performed. Significant differences (P<.05) between epg (>2000) and PCV (>30%) were determined after 21 days and were also observed with regard to monocyte and lymphocyte cells after 2 and 7 days PI. At 0 hour and 14 days PI, the GPX and IL-2 genes showed a 0.37- and 0.49-fold decrease in expression, respectively. In contrast, upregulation was observed at 4 hours of IL-8 (2.58) and FCepsilonR1A (2.71), at 2 days for IL-4 (2.14) and IL-8 (4.02) and at 14 days for IL-2 (0.41), IL-10 (2.35) and FCepsilonR1A (2.28). The comparison between the intervals of infection showed high expression values against H. contortus infection in Pelibuey sheep after the 2nd period of PI involving a dichotomy T cells. PMID- 28345266 TI - Cross-sectional study of equol producer status and cognitive impairment in older adults. AB - AIM: It is well known that consumption of isoflavones reduces the risk of cardiovascular disease. However, the effectiveness of isoflavones in preventing dementia is controversial. A number of intervention studies have produced conflicting results. One possible reason is that the ability to produce equol, a metabolite of a soy isoflavone, differs greatly in individuals. In addition to existing data, we sought to confirm whether an apparent beneficial effect in cognitive function is observed after soy consumption in equol producers compared with non-producers. METHODS: The present study was a cross-sectional, observational study of 152 (male/female = 61/91, mean age 69.2 +/- 9.2 years) individuals. Participants were divided into two groups according to equol production status, which was determined using urine samples collected after a soy challenge test. Cognitive function was assessed using two computer-based questionnaires (touch panel-type dementia assessment scale [TDAS] and mild cognitive impairment [MCI] screen). RESULTS: Overall, 60 (40%) of 152 participants were equol producers. Both TDAS and prevalence of MCI were significantly higher in the equol producer group than in the non-producer group. In univariate analyses, TDAS significantly correlated with age, serum creatinine, estimated glomerular filtration rate and low-density lipoprotein cholesterol. In multiple regression analysis using TDAS as a dependent variable, equol producer (beta = 0.236, P = 0.005) was selected as an independent variable. In addition, multiple logistic regression analysis to assess the presence of MCI showed that being an equol producer was an independent risk factor for MCI (odds ratio 3.961). CONCLUSIONS: Compared with equol non-producers, equol producers showed an apparent beneficial effect in cognitive function after soy intake. Geriatr Gerontol Int 2017; 17: 2103-2108. PMID- 28345267 TI - Color duplex ultrasonography versus handheld Doppler to plan anterior lateral thigh flaps. AB - BACKGROUND: The anterior lateral thigh flap (ALT) has become increasingly important in reconstructive surgery in the head and neck region. To cope with the problem of anatomical variability in the supplying blood vessels, preoperative evaluation is desirable. Purpose of the study is to compare the most commonly used Doppler devices Handheld Doppler (HD) and Color Doppler Ultrasonography (CDU) for their clinical reliability. METHODS: Forty five consecutive head and neck cancer patients (mean age 66.0 +/- 11.2 years) were included in the study. They all underwent a reconstruction via ALT flap for a defect in the head and neck area. Study period ranged from May 2014 to August 2015. We preoperatively conducted HD and CDU on the lateral thigh and compared the intraoperative findings by measuring presence of the perforator and distance to the estimated position. RESULTS: There were 95 perforators identified in 45 patients. The sensitivity and positive predictive value (PPV) were calculated as 97.9% and 100% for CDU and 90.5% and 80.4% for HD, respectively. Accuracy was significantly greater with the HD compared to the CDU device (P < 0.001) and was strongly associated with body mass index (BMI) (P < 0.001). This effect was stronger in HD than in CDU (r = 0.800; P < 0.001 versus r = 0.673; P < 0.001). CONCLUSIONS: Our results indicate CDU is more precise and reliable than HD with respect to detecting the anatomical position of perforating arteries. (c) 2017 Wiley Periodicals, Inc. Microsurgery 37:388-393, 2017. PMID- 28345268 TI - Target plasma factor levels for personalized treatment in haemophilia: a Delphi consensus statement. AB - BACKGROUND: Prophylactic replacement with factor concentrate is the optimal treatment for persons with severe haemophilia to avoid or minimize bleeding. This ultimately prevents or reduces joint disease and improves life expectancy and quality of life towards values matching those in the normal population. However, uncertainty still exists around the optimal regimens to be prescribed for prophylaxis. An increasing number of treating physicians and patients are showing interest in patient-tailored approaches to prophylaxis, which aim to harmonize the prophylaxis regimen with the patients' bleeding phenotype, levels of physical activity and a variety of other variables. METHODS: A modified Delphi technique was adopted to generate consensus. The expert panel met in person to set the objectives, be trained on the Delphi technique and agree on the desired level of consensus. Three iterations were used to identify the targets, the scenarios and their combinations. RESULTS: Twenty-eight scenarios and eight target levels were identified and used to issue recommendations. The panel reached the desired level of consensus on positive or negative recommendations. Areas where consensus was not reached were identified and proposed as areas for future research. Prospective assessment of the validity of most of the proposed targets is recommended. CONCLUSIONS: We have generated, by expert consensus, target plasma levels of factor concentrate to be used to tailor treatment for persons with haemophilia. PMID- 28345270 TI - False positive retroaortic left circumflex coronary artery in a patient with atrial septal defect. AB - Retroaortic course of coronary artery is a relative contraindication for device closure of an atrial septal defect. In this brief report, we demonstrate, for the first time, inferior aortic recess mimicking retroaortic left circumflex coronary artery in a patient with atrial septal defect. This distinction is important to avoid spurious diagnosis of anomalous coronary artery denying patient a chance of nonsurgical closure of atrial septal defect. PMID- 28345269 TI - Multi-task diagnosis for autism spectrum disorders using multi-modality features: A multi-center study. AB - Autism spectrum disorder (ASD) is a neurodevelopment disease characterized by impairment of social interaction, language, behavior, and cognitive functions. Up to now, many imaging-based methods for ASD diagnosis have been developed. For example, one may extract abundant features from multi-modality images and then derive a discriminant function to map the selected features toward the disease label. A lot of recent works, however, are limited to single imaging centers. To this end, we propose a novel multi-modality multi-center classification (M3CC) method for ASD diagnosis. We treat the classification of each imaging center as one task. By introducing the task-task and modality-modality regularizations, we solve the classification for all imaging centers simultaneously. Meanwhile, the optimal feature selection and the modeling of the discriminant functions can be jointly conducted for highly accurate diagnosis. Besides, we also present an efficient iterative optimization solution to our formulated problem and further investigate its convergence. Our comprehensive experiments on the ABIDE database show that our proposed method can significantly improve the performance of ASD diagnosis, compared to the existing methods. Hum Brain Mapp 38:3081-3097, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28345271 TI - Immunosuppression with mTOR inhibitors prevents the development of donor-specific antibodies after liver transplant. AB - BACKGROUND: Donor-specific antibodies (DSAs) are an important cause of complications after solid organ transplant. Risk factors and, thus, strategies for preventing DSA development are not well defined. METHODS: The DSA status of 400 patients who underwent liver transplant (LT) at the outpatient clinic of the University Hospital Essen was determined. Human leukocyte antigen (HLA) antibodies were detected by single-antigen bead technology. The strength of DSAs was reported as mean fluorescence intensity. RESULTS: Detectable DSAs were found in 74 (18.5%) patients and significantly more often in patients who underwent LT for autoimmune liver disease than for all other indications (29.3%; P=.022), but significantly less often found in patients who underwent LT for hepatocellular carcinoma (7.6%, P=.005). The incidence of DSAs increased with time after LT, and the risk was generally higher for female patients. The frequency of DSA detection was significantly lower (10.6%) for patients receiving immunosuppressive treatment with mammalian target of rapamycin (mTOR) inhibitors than for those receiving other regimens (20.5%; P=.025). CONCLUSION: Autoimmune liver diseases, female sex, and time of more than 8 years since LT predispose patients to the development of DSAs. Immunosuppression with the mTOR inhibitor everolimus protects against DSA development after liver transplant. PMID- 28345272 TI - Population health and the economy: Mortality and the Great Recession in Europe. AB - We analyze the evolution of mortality-based health indicators in 27 European countries before and after the start of the Great Recession. We find that in the countries where the crisis has been particularly severe, mortality reductions in 2007-2010 were considerably bigger than in 2004-2007. Panel models adjusted for space-invariant and time-invariant factors show that an increase of 1 percentage point in the national unemployment rate is associated with a reduction of 0.5% (p < .001) in the rate of age-adjusted mortality. The pattern of mortality oscillating procyclically is found for total and sex-specific mortality, cause specific mortality due to major causes of death, and mortality for ages 30-44 and 75 and over, but not for ages 0-14. Suicides appear increasing when the economy decelerates-countercyclically-but the evidence is weak. Results are robust to using different weights in the regression, applying nonlinear methods for detrending, expanding the sample, and using as business cycle indicator gross domestic product per capita or employment-to-population ratios rather than the unemployment rate. We conclude that in the European experience of the past 20 years, recessions, on average, have beneficial short-term effects on mortality of the adult population. PMID- 28345273 TI - Tuning Hole and Electron Transfer from Photoexcited CdSe Quantum Dots to Phenol Derivatives: Effect of Electron-Donating and -Withdrawing Moieties. AB - Charge-transfer processes from photoexcited CdSe quantum dots (QDs) to phenol derivatives with electron- donating (4-methoxy) and -withdrawing (4-nitro) moieties have been demonstrated by using steady-state and time- resolved emission and femtosecond transient absorption spectroscopy. Steady-state and time-resolved emission studies suggest that in the presence of both 4-nitrophenol (4NP) and 4 methoxyphenol (4MP) CdSe QDs luminescence is quenched. Stern-Volmer analysis suggests both static and dynamic mechanisms are active for both the QD/phenol composites. Cyclic voltammetric analysis recommends that photoexcited CdSe QDs can donate electrons to 4NP and holes to 4MP. To reconfirm both electron- and hole-transfer mechanisms, CdSe/CdS quasi-type II and CdSe/CdTe type II core-shell nanocrystals were synthesized and photoluminescence quenching was monitored in the absence and presence of both 4NP and 4MP, for which hole and electron transfer were systematically restricted. Results suggest that indeed electron and hole transfer take place from photoexcited CdSe to 4NP and 4MP, respectively. To monitor the charge-transfer dynamics in both systems on an early timescale, femtosecond transient absorption spectroscopic techniques have been employed. Electron and hole transfer and charge-recombination dynamics are discussed and the effect of electron-donating and -withdrawing groups has been demonstrated. PMID- 28345274 TI - Global model fitting to compare survival curves for faecal indicator bacteria and ruminant-associated genetic markers. AB - AIMS: To compare decay profiles of ruminant- and cattle-associated molecular markers for faecal contamination and Escherichia coli, facilitating their correct application in water quality studies. METHODS AND RESULTS: We generated decay profiles for cultivable E. coli, a general Bacteroidales genetic marker (GenBac3), ruminant markers (CF128, Rum2Bac) and cattle markers (CowM2, CowM3) using faeces-seeded mesocosms, and selected best fitting models for each decay profile. Global model fitting tested for differences between decay profiles. After normalizing for initial concentration, decay curves differed significantly between E. coli and all genetic markers except CowM3. Decay curves for CF128 differed from GenBac3 and Rum2Bac, but Rum2Bac and GenBac3 decay profiles did not differ. Despite similar survival profiles for some markers, highly varied initial concentrations affected time to nondetection. CONCLUSIONS: Decay curves and time until nondetection differed among markers from the same host. However, the Rum2Bac and GenBac3 markers had similar decay profiles and could potentially be investigated further for source allocation using the ratio method. SIGNIFICANCE AND IMPACT OF THE STUDY: As the use of genetic markers for microbial source tracking becomes increasingly common, caution is necessary. Both the shape of decay curves and time to nondetect may differ depending on the marker selected, resulting in possible misinterpretation of results and precluding application of a 'ratio method' of source allocation. PMID- 28345276 TI - A prospective evaluation of levofloxacin-based triple therapy for refractory Helicobacter pylori infection in Australia. AB - BACKGROUND: First-line Helicobacter pylori eradication failure is a common and challenging problem. AIM: To assess the efficacy of salvage levofloxacin-based triple therapy in Australia. METHODS: Prospective patients referred after prior treatment failure(s) were prescribed esomeprazole 40 mg, amoxicillin 1 g and levofloxacin 500 mg each twice daily for 10 days. All patients received detailed written and verbal adherence support. Outcome assessment was by 13 C-urea breath test and/or histology and urease test. RESULTS: In 150 consecutive, evaluable patients (66% female, mean age 54 +/- 14 years; six smokers), the main indications for treatment were peptic ulcer disease (17%), increased gastric cancer risk (20%), symptoms (35%) and other risk reduction (28%). The median number of previous treatments was 2 (range 1-7). Eradication of H. pylori was achieved in 90% (intention to treat (ITT)) and 91% (per-protocol (PP)) of patients. The eradication rate did not differ according to the type or number of prior treatments: 93% when <=2 (n = 107) compared with 84% after three or more prior treatments (n = 43; P = 0.13) or with age, ethnicity or indication for treatment but it was higher in females (ITT 94 vs 82%, P = 0.04). Adherence was excellent (95%). No serious adverse effects were observed; mild adverse effects were reported in 11%. No primary levofloxacin resistance was observed in 20 concurrent cases. CONCLUSION: The efficacy and safety of this levofloxacin-based triple therapy suggests it should be used as a salvage regimen in this region. Randomised comparative trials are unlikely to be done but these data compare favourably with local data for other salvage therapies. PMID- 28345278 TI - Remembering Eric Forest (1957-2017). From analytical chemistry to the rise of HDXMS for structural biology of complex protein systems. PMID- 28345277 TI - Evolution of antigenic diversity in the tick-transmitted bacterium Borrelia afzelii: a role for host specialization? AB - Antigenic diversity in pathogenic microbes can be a result of at least three different processes: diversifying selection by acquired immunity, host-pathogen coevolution and/or host specialization. Here, we investigate whether host specialization drives diversity at ospC (which encodes an immunodominant surface protein) in the tick-transmitted bacterium Borrelia afzelii. We determined prevalence and infection intensity of ospC strains in naturally infected wild mammals (rodents and shrews) by 454 amplicon sequencing in combination with qPCR. Neither prevalence nor infection intensity of specific ospC strains varied in a species-specific manner (i.e. there were no significant ospC * host species interactions). Rankings of ospC prevalences were strongly positively correlated across host species. Rankings of ospC infection intensities were correlated more weakly, but only in one case significantly < 1. ospC prevalences in the studied mammals were similar to those in ticks sampled at the study site, indicating that we did not miss any mammal species that are important hosts for specific ospC strains. Based on this, we conclude that there is at best limited host specialization in B. afzelii and that other processes are likely the main drivers of ospC diversity. PMID- 28345275 TI - Abnormal frontoparietal synaptic gain mediating the P300 in patients with psychotic disorder and their unaffected relatives. AB - The "dysconnection hypothesis" of psychosis suggests that a disruption of functional integration underlies cognitive deficits and clinical symptoms. Impairments in the P300 potential are well documented in psychosis. Intrinsic (self-)connectivity in a frontoparietal cortical hierarchy during a P300 experiment was investigated. Dynamic Causal Modeling was used to estimate how evoked activity results from the dynamics of coupled neural populations and how neural coupling changes with the experimental factors. Twenty-four patients with psychotic disorder, twenty-four unaffected relatives, and twenty-five controls underwent EEG recordings during an auditory oddball paradigm. Sixteen frontoparietal network models (including primary auditory, superior parietal, and superior frontal sources) were analyzed and an optimal model of neural coupling, explaining diagnosis and genetic risk effects, as well as their interactions with task condition were identified. The winning model included changes in connectivity at all three hierarchical levels. Patients showed decreased self inhibition-that is, increased cortical excitability-in left superior frontal gyrus across task conditions, compared with unaffected participants. Relatives had similar increases in excitability in left superior frontal and right superior parietal sources, and a reversal of the normal synaptic gain changes in response to targets relative to standard tones. It was confirmed that both subjects with psychotic disorder and their relatives show a context-independent loss of synaptic gain control at the highest hierarchy levels. The relatives also showed abnormal gain modulation responses to task-relevant stimuli. These may be caused by NMDA-receptor and/or GABAergic pathologies that change the excitability of superficial pyramidal cells and may be a potential biological marker for psychosis. Hum Brain Mapp 38:3262-3276, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28345279 TI - Use of a novel contact lens to improve fundal optical coherence tomographic images in keratoconus. PMID- 28345280 TI - Otoprotective effects of mouse nerve growth factor in DBA/2J mice with early onset progressive hearing loss. AB - As it displays progressive hair-cell loss and degeneration of spiral ganglion neurons (SGNs) characterized by early-onset progressive hearing loss (ePHL), DBA/2J is an inbred mouse strain widely used in hearing research. Mouse nerve growth factor (mNGF), as a common exogenous nerve growth factor (NGF), has been studied extensively for its ability to promote neuronal survival and growth. To determine whether mNGF can ameliorate progressive hearing loss (PHL) in DBA/2J mice, saline or mNGF was given to DBA/2J mice of either sex by daily intramuscular injection from the 1st to the 9th week after birth. At 5, 7, and 9 weeks of age, in comparison with vehicle groups, mNGF groups experienced decreased auditory-evoked brainstem response (ABR) thresholds and increased distortion product otoacoustic emission (DPOAE) amplitudes, the prevention of hair cell loss, and the inhibition of apoptosis of SGNs. Downregulation of Bak/Bax and Caspase genes and proteins in cochleae of mice receiving the mNGF treatment was detected by real-time PCR, Western blot, and immunohistochemistry. This suggests that the Bak-dependent mitochondrial apoptosis pathway may be involved in the otoprotective mechanism of mNGF in progressive hearing loss of DBA/2J mice. Our results demonstrate that mNGF can act as an otoprotectant in the DBA/2J mice for the early intervention of PHL and, thus, could become of great value in clinical applications. (c) 2017 Wiley Periodicals, Inc. PMID- 28345281 TI - Correlates of alcohol consumption on heavy drinking occasions of young risky drinkers: event versus personal characteristics. AB - AIMS: Risky single-occasion drinking (RSOD) by young people is a serious public health issue, yet little is known about the specific circumstances of risky drinking occasions. This study examined the independent effects of event- and individual-specific variables on RSOD. DESIGN: Longitudinal cohort study measuring self-reported RSOD and event- and individual-specific variables across two drinking occasions approximately 1 year apart. SETTING: Metropolitan Melbourne, Australia. PARTICIPANTS: A sample of 710 young risky drinkers aged between 18 and 25 years and defined as engaging in risky drinking practices (males: consumed alcohol in excess of 10 Australian Standard Drinks (ASD: 10 g ethanol) in a single occasion in the previous year; females: consumed alcohol in excess of seven ASD for females in a single occasion in the previous year). MEASUREMENTS: Random digit-dial telephone landline survey of the most recent heavy drinking occasion and socio-demographic variables. The primary outcome was the log of the total drinks consumed in the most recent heavy drinking occasion. Event-specific (e.g. number of drinking locations) and time-varying (e.g. weekly income) and time-invariant (e.g. sex) individual-specific variables were examined as correlates of total drinks consumed. FINDINGS: Changes in event-specific characteristics including the length of the drinking occasion (Likelihood Ratio chi2 (2) = 24.4, P < 0.001), the number of drinking locations (Wald chi2(1) = 7.6, P = 0.006) and the number of different drink types (Wald chi2(1) = 13.6, P < 0.001) were associated with increases in total drinks consumed, after adjustment for time-invariant and time-variant individual-specific variables such as gender, income level and weekly consumption. Few other effects were noted. CONCLUSIONS: Event-specific characteristics are important predictors of the number of drinks consumed during risky single occasion drinking (RSOD) and illustrate the importance of event contexts when considering interventions targeting RSOD. The total number of drinks consumed in a RSOD session appears to rise independently with the duration of the drinking event, the number of drinking locations and the number of different types of beverage consumed. PMID- 28345283 TI - Oxygen-Containing Amorphous Cobalt Sulfide Porous Nanocubes as High-Activity Electrocatalysts for the Oxygen Evolution Reaction in an Alkaline/Neutral Medium. AB - A novel OER electrocatalyst, namely oxygen-incorporated amorphous cobalt sulfide porous nanocubes (A-CoS4.6 O0.6 PNCs), show advantages over the benchmark RuO2 catalyst in alkaline/neutral medium. Experiments combining with calculation demonstrate that the desirable O* adsorption energy, associated with the distorted CoS4.6 O0.6 octahedron structure and the oxygen doping, contribute synergistically to the outstanding electrocatalytic activity. PMID- 28345282 TI - Neuroplasticity of language in left-hemisphere stroke: Evidence linking subsecond electrophysiology and structural connections. AB - The understanding of neuroplasticity following stroke is predominantly based on neuroimaging measures that cannot address the subsecond neurodynamics of impaired language processing. We combined behavioral and electrophysiological measures and structural-connectivity estimates to characterize neuroplasticity underlying successful compensation of language abilities after left-hemispheric stroke. We recorded the electroencephalogram from patients with stroke lesions to the left temporal lobe and from matched controls during context-driven word retrieval. Participants heard lead-in sentences that either constrained the final word ("He locked the door with the") or not ("She walked in here with the"). The last word was shown as a picture to be named. Individual-participant analyses were conducted, focusing on oscillatory power as a subsecond indicator of a brain region's functional neurophysiological computations. All participants named pictures faster following constrained than unconstrained sentences, except for two patients, who had extensive damage to the left temporal lobe. Left lateralized alpha-beta oscillatory power decreased in controls pre-picture presentation for constrained relative to unconstrained contexts. In patients, the alpha-beta power decreases were observed with the same time course as in controls but were lateralized to the intact right hemisphere. The right lateralization depended on the probability of white-matter connections between the bilateral temporal lobes. The two patients who performed poorly behaviorally showed no alpha-beta power decreases. Our findings suggest that incorporating direct measures of neural activity into investigations of neuroplasticity can provide important neural markers to help predict language recovery, assess the progress of neurorehabilitation, and delineate targets for therapeutic neuromodulation. Hum Brain Mapp 38:3151-3162, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28345285 TI - Enhancing oral health for better mental health: Exploring the views of mental health professionals. AB - The association between oral health, self-esteem and quality of life is well established yet there is limited research on the impact of addressing the poor oral health of people living with mental health disorders. Greater consideration is warranted on how enhancing oral health in the course of mental healthcare might reduce the burden of a person's ill health. The role of mental health professionals is important in this regard yet uncertainty persists about the role these providers can and should play in promoting oral health care for people with mental health disorders. This qualitative study explored the issue of oral health and mental health with community based mental health professionals in Perth, Western Australia. It examined their views on the oral health status and experiences of their clients, and the different and alternative ways to improve access to care, knowledge and preventative regimens. Findings indicated participants' ambivalence, reluctance and lack of training in raising oral health issues, despite its acknowledged importance, indicating a siloed approach to care. Findings offer an opportunity to reflect on whether a more integrated approach to oral health care for people with mental health disorders would improve health outcomes. PMID- 28345284 TI - Role of fine needle aspiration cytology in the diagnosis of a rare case of a poorly differentiated synovial sarcoma with "Rhabdoid" features, including treatment implications. AB - Synovial sarcoma is a high-grade, soft tissue sarcoma that is relatively chemosensitive. Its exact diagnosis is crucial, including differentiation from its closest diagnostic mimic, ie, Ewing sarcoma, in view of different treatment options, including chemotherapy regimens, for both these tumors. A 15-year-old girl presented with a recurrent soft tissue mass in her right popliteal region, which was diagnosed as Ewing sarcoma, based on positive immunoexpression of MIC2/CD99, Fli1 and negative expression of LCA and desmin. During her metastatic "work-up", a popliteal lymph node was identified, which was aspirated and examined. Fine needle aspiration cytology smears showed singly scattered and loose, cohesive clusters of cells containing round to polygonal, to short spindle shaped nuclei with prominent nuclei, and moderate to abundant cytoplasm, including several "rhabdoid" cells. These features prompted a review of the biopsy of the recurrent tumor, and additional immunohistochemical stains, which revealed positive co-expression of pan cytokeratin (AE1/AE3), epithelial membrane antigen (EMA), along with a characteristic variable staining pattern of INI11/SMARCB1. Subsequently, by fluorescent in situ hybridization (FISH) technique, performed on the paraffin section of the recurrent tumor, 100% tumor nuclei displayed SS18 rearrangement, while none of the tumor cells displayed EWSR1 rearrangement. Diagnosis of poorly differentiated SS with "rhabdoid" features was confirmed. This constitutes as the first case, describing cytopathologic features of a poorly differentiated SS with "rhabdoid" features, initially misdiagnosed as a Ewing sarcoma, on biopsy and confirmed as SS by FISH technique. The diagnostic and treatment implications in this case are discussed herewith. Diagn. Cytopathol. 2017;45:662-667. (c) 2017 Wiley Periodicals, Inc. PMID- 28345286 TI - Highly Selective Synthesis of cis-Enediynes on a Ag(111) Surface. AB - Cis-enediyne-type compounds have received much attention as potent antitumor antibiotics. The conventional synthesis of cis-enediynes in solution typically involves multiple steps and various side reactions. For the first time, selective one-step synthesis of cis-enediyne from a single reactant is reported on a Ag(111) surface with a yield up to 90 %. High selectivity for the formation of cis-enediyne originates from the steric effect posed by weak intermolecular interactions, which protect the cis-enediyne from further reaction. A series of comparative experiments and DFT-based transition-state calculations support the findings. The described synthetic approach for directing reaction pathways on surface may illuminate potential syntheses of other unstable organic compounds. PMID- 28345287 TI - Contribution of platelet P2Y12 receptors to chronic Complete Freund's adjuvant induced inflammatory pain. AB - : Essentials The role of platelet P2Y12 receptors in the regulation of chronic inflammatory pain is unknown. Complete Freund's Adjuvant (CFA)-induced chronic inflammatory pain model was used in mice. Gene deficiency and antagonists of P2Y12 receptors attenuate hyperalgesia and local inflammation. Platelet P2Y12 receptors contribute to these effects in the chronic phase of inflammation. SUMMARY: Background P2Y12 receptor antagonists are widely used in clinical practice to inhibit platelet aggregation. P2Y12 receptors are also known to regulate different forms of pain as well as local and systemic inflammation. However, it is not known whether platelet P2Y12 receptors contribute to these effects. Objectives To explore the contribution of platelet P2Y12 receptors to chronic inflammatory pain in mice. Methods Complete Freund's adjuvant (CFA) induced chronic inflammatory pain was induced in wild-type and P2ry12 gene deficient (P2ry12-/- ) mice, and the potent, direct-acting and reversible P2Y12 receptor antagonists PSB-0739 and cangrelor were used. Results CFA-induced mechanical hyperalgesia was significantly decreased in P2ry12-/- mice for up to 14 days, and increased neutrophil myeloperoxidase activity and tumor necrosis factor (TNF)-alpha and CXCL1 (KC) levels in the hind paws were also attenuated in the acute inflammation phase. At day 14, increased interleukin (IL)-1beta, IL-6, TNF-alpha and KC levels were attenuated in P2ry12-/- mice. PSB-0739 and cangrelor reversed hyperalgesia in wild-type mice but had no effect in P2ry12-/- mice, and PSB-0739 was also effective when applied locally. The effects of both local and systemic PSB-0739 were prevented by A-803467, a selective NaV1.8 channel antagonist, suggesting the involvement of NaV1.8 channels in the antihyperalgesic effect. Platelet depletion by anti-mouse CD41 antibody decreased hyperalgesia and attenuated the proinflammatory cytokine response in wild-type but not in P2ry12-/ mice on day 14. Conclusions In conclusion, P2Y12 receptors regulate CFA-induced hyperalgesia and the local inflammatory response, and platelet P2Y12 receptors contribute to these effects in the chronic inflammation phase. PMID- 28345288 TI - Single-tube tetradecaplex panel of highly polymorphic microsatellite markers < 1 Mb from F8 for simplified preimplantation genetic diagnosis of hemophilia A. AB - : Essentials Preimplantation genetic diagnosis (PGD) of severe hemophilia A relies on linkage analysis. Simultaneous multi-marker screening can simplify selection of informative markers in a couple. We developed a single-tube tetradecaplex panel of polymorphic markers for hemophilia A PGD use. Informative markers can be used for linkage analysis alone or combined with mutation detection. SUMMARY: Background It is currently not possible to perform single cell preimplantation genetic diagnosis (PGD) to directly detect the common inversion mutations of the factor VIII (F8) gene responsible for severe hemophilia A (HEMA). As such, PGD for such inversion carriers relies on indirect analysis of linked polymorphic markers. Objectives To simplify linkage-based PGD of HEMA, we aimed to develop a panel of highly polymorphic microsatellite markers located near the F8 gene that could be simultaneously genotyped in a multiplex PCR reaction. Methods We assessed the polymorphism of various microsatellite markers located <= 1 Mb from F8 in 177 female subjects. Highly polymorphic markers were selected for co-amplification with the AMELX/Y indel dimorphism in a single-tube reaction. Results Thirteen microsatellite markers located within 0.6 Mb of F8 were successfully co-amplified with AMELX/Y in a single-tube reaction. Observed heterozygosities of component markers ranged from 0.43 to 0.84, and ~70 80% of individuals were heterozygous for >= 5 markers. The tetradecaplex panel successfully identified fully informative markers in a couple interested in PGD for HEMA because of an intragenic F8 point mutation, with haplotype phasing established through a carrier daughter. In-vitro fertilization (IVF)-PGD involved single-tube co-amplification of fully informative markers with AMELX/Y and the mutation-containing F8 amplicon, followed by microsatellite analysis and amplicon mutation-site minisequencing analysis. Conclusions The single-tube multiplex-PCR format of this highly polymorphic microsatellite marker panel simplifies identification and selection of informative markers for linkage-based PGD of HEMA. Informative markers can also be easily co-amplified with mutation containing F8 amplicons for combined mutation detection and linkage analysis. PMID- 28345289 TI - Severe bleeding diatheses in an elderly patient with combined type autoantibody against factor XIII A subunit; novel approach to the diagnosis and classification of anti-factor XIII antibodies. AB - INTRODUCTION: Acquired factor XIII (FXIII) deficiency due to autoantibody is a rare, severe bleeding diathesis. Its laboratory diagnosis and classification represents a difficult task. AIM: Introduction of novel approaches into the diagnosis and characterization of anti-FXIII autoantibody and demonstration of their use in the diagnosis of a patient with autoimmune FXIII deficiency. METHODS: Factor XIII activity, FXIII antigen levels and the titre of anti-FXIII-A antibody were monitored throughout the course of the disease. FXIII activity was measured by ammonia release assay; FXIII-A2 B2 complex, total and free FXIII-B concentrations were determined by ELISAs. The binding constant for the interaction of the autoantibody with recombinant FXIII-A2 (rFXIII-A2 ) and FXIII A2 B2 was determined by surface plasmon resonance (SPR). The inhibitory capacity of IgG was expressed as the concentration exerting 50% inhibition of FXIII activation/activity (IC50). The truncation of FXIII-A by thrombin was monitored by western blotting. The inhibition of Ca2+ -induced FXIII activation and active FXIII (FXIIIa) were assessed by FXIII activity assay. RESULTS: The antibody bound to rFXIII-A2 and FXIII-A2 B2 with high affinity and accelerated the decay of supplemented FXIII concentrate. An IC50 value of 170.1 MUg IgG.mL-1 indicated effective FXIII neutralization. The main neutralizing effect of the autoantibody was the inhibition of FXIIIa. After 2 months, due to combined therapeutic modalities, the autoantibody disappeared and FXIII activity significantly elevated. CONCLUSION: The anti-FXIII-A autoantibody exerted a combined effect including inhibition of FXIIIa and acceleration of FXIII decay in the plasma. IC50 and binding constant determinations added important information to the characterization of the autoantibody. PMID- 28345290 TI - Telerehabilitation for COPD: Could pulmonary rehabilitation deliver on its promise? PMID- 28345291 TI - Association between mortality and blood pressure variability in hypertensive and normotensive elders: A cohort study. AB - To evaluate the association between blood pressure variability (BPV) and mortality in the elderly, all blood pressure measurements recorded in a cohort of individuals 65 years and older were collected and the association between BPV coefficient of variation (BPV divided by mean arterial pressure) was calculated. Mortality during a 10-year period was compared between BPV coefficient of variation quartiles. Overall, 39 502 individuals 65 years and older were included in the analysis, of which 31 737 (80.3%) were hypertensive; 12 817 (32.4%) individuals died during the study period. Mortality was lower in the second and third blood pressure quartiles compared with the first quartile in both the normotensive and hypertensive groups. In both normotensive and hypertensive individuals, mortality was higher in the fourth quartile, but it was more pronounced in normotensive individuals (odds ratio, 1.18; 95% confidence interval, 1.06-1.31 in hypertensive individuals vs odds ratio, 1.27; 95% confidence interval, 1.17-1.37 in normotensive individuals). High and low BPV are associated with mortality in both hypertensive and normotensive elders. PMID- 28345292 TI - The detection and phylogenetic analysis of porcine deltacoronavirus from Guangdong Province in Southern China. AB - Porcine deltacoronavirus (PDCoV) is a newly discovered coronavirus that causes diarrhoea, vomiting and dehydration in sucking and nursing piglets. It was first reported in Hong Kong in 2012 and has since been discovered in the United States, Canada, South Korea, mainland China, Thailand and Laos. PDCoV has been experimentally proved to lead to diarrhoea in swine and it was detected positive in pigs in Guangdong, southern China. In our study, 252 faecal and intestinal samples from sucking piglets and sows with diarrhoea were surveyed for common enteric viruses. We found a prevalence of PDCoV (21.8%), porcine epidemic diarrhoea virus (65.5%), transmissible gastroenteritis virus (0%), rotavirus group A (25.0%) and porcine kobuvirus (68.7%). We isolated 13 PDCoV strains and discovered that PDCoV infections were often co-infections with kobuvirus rather than the commonly linked porcine epidemic diarrhoea virus. Phylogenetic analysis of S gene and N gene revealed that 11 of 13 PDCoV strains belonged to Chinese lineage. As for the left two strains, one single strain (CHN-GD16-05) belonged to American and Korean lineages while another strain (CHN-GD16-03) was similar to a Thai strain, but only in the S gene. This suggested a possible recombination event between the Thai and the newly described Chinese strain. PMID- 28345293 TI - Detection of Zaire ebolavirus in swine: Assay development and optimization. AB - Ebolaviruses (family Filoviridae, order Mononegavirales) cause often fatal, haemorrhagic fever in primates including humans. Pigs have been identified as a species susceptible to Reston ebolavirus (RESTV) infection, with indicated transmission to humans in the Philippines; however, their role during Ebola outbreaks in Africa needs to be clarified. To perform surveillance studies, detection of ebolavirus requires a prerequisite validation of viral RNA and antibody detection methods in swine samples. These diagnostic tests also need to be suitable for deployment to low-level containment laboratories. In this study, we developed a set of tests for detection of antibodies against Zaire ebolavirus (EBOV) in swine. Recombinant EBOV nucleoprotein was produced using a baculovirus expression system for indirect ELISA development. Evaluation of this assay was performed using laboratory and field samples, achieving a diagnostic specificity of 99%. Importantly, the indirect ELISA was able to detect antibodies to EBOV at 7 dpi, 3 days earlier than virus neutralization tests (VNT). The format of the VNT in this work was modified to a microtitre plaque reduction neutralization assay (miPRNT) complemented with immunostaining to provide a more rapid and highly specific assay. Finally, a confirmatory immunoblot assay was generated to supplement the indirect ELISA results. PMID- 28345294 TI - Compact teleoperated laparoendoscopic single-site robotic surgical system: Kinematics, control, and operation. AB - BACKGROUND: To date a variety of teleoperated surgical robotic systems have been developed to improve a surgeon's ability to perform demanding single-port procedures. However typical large systems are bulky, expensive, and afford limited angular motion, while smaller designs suffer complications arising from limited motion range, speed, and force generation. This work was to develop and validate a simple, compact, low cost single site teleoperated laparoendoscopic surgical robotic system, with demonstrated capability to carry out basic surgical procedures. METHODS: This system builds upon previous work done at the University of Hawaii at Manoa and includes instrument and endoscope manipulators as well as compact articulated instruments designed to overcome single incision geometry complications. A robotic endoscope holder was used for the base, with an added support frame for teleoperated manipulators and instruments fabricated mostly from 3D printed parts. Kinematics and control methods were formulated for the novel manipulator configuration. RESULTS: Trajectory following results from an optical motion tracker and sample task performance results are presented. CONCLUSIONS: Results indicate that the system has successfully met the goal of basic surgical functionality while minimizing physical size, complexity, and cost. PMID- 28345296 TI - Boosting the Energy Density of Carbon-Based Aqueous Supercapacitors by Optimizing the Surface Charge. AB - The voltage of carbon-based aqueous supercapacitors is limited by the water splitting reaction occurring in one electrode, generally resulting in the promising but unused potential range of the other electrode. Exploiting this unused potential range provides the possibility for further boosting their energy density. An efficient surface charge control strategy was developed to remarkably enhance the energy density of multiscale porous carbon (MSPC) based aqueous symmetric supercapacitors (SSCs) by controllably tuning the operating potential range of MSPC electrodes. The operating voltage of the SSCs with neutral electrolyte was significantly expanded from 1.4 V to 1.8 V after simple adjustment, enabling the energy density of the optimized SSCs reached twice as much as the original. Such a facile strategy was also demonstrated for the aqueous SSCs with acidic and alkaline electrolytes, and is believed to bring insight in the design of aqueous supercapacitors. PMID- 28345295 TI - A National Swedish Longitudinal Twin-Sibling Study of alcohol use disorders among males. AB - AIMS: To examine whether genetic influences on the development of alcohol use disorders (AUD) among men during emerging adulthood through mid-adulthood are stable or dynamic. DESIGN: A twin study modeling developmental changes in the genetic and environmental influences on AUD during three age periods (18-25, 26 33 and 33-41) as a Cholesky decomposition. SETTING: Sweden. PARTICIPANTS: Swedish male twin pairs (1532 monozygotic and 1940 dizygotic) and 66 033 full male sibling pairs born less than 2 years apart. MEASUREMENTS: AUD was identified based on Swedish medical and legal registries. FINDINGS: The best-fitting model included additive genetic and unique environmental factors, with no evidence for shared environmental factors. Although the total heritability was stable over time, there were two major genetic factors contributing to AUD risk, one beginning at ages 18-25 with a modest decline in importance over time [0.84; confidence interval (CI) = 0.83-0.88], and another of less impact beginning at ages 26-33 with a modest increase in importance by ages 33-41 (0.31; CI = 0.05 0.47). CONCLUSIONS: The heritability of alcohol use disorders among Swedish men appears to be stable among three age periods: 18-25 years, 26-33 years, and 33-41 years. Two sets of genetic risk factors contribute to alcohol use disorders risk, with one originating during the ages 18-25 years and another coming online at 26 33 years, providing support for the developmentally dynamic hypothesis. PMID- 28345298 TI - Effects of T-loop modification on the PII-signalling protein: structure of uridylylated Escherichia coli GlnB bound to ATP. AB - To adapt to environments with variable nitrogen sources and richness, the widely distributed homotrimeric PII signalling proteins bind their allosteric effectors ADP/ATP/2-oxoglutarate, and experience nitrogen-sensitive uridylylation of their flexible T-loops at Tyr51, regulating their interactions with effector proteins. To clarify whether uridylylation triggers a given T-loop conformation, we determined the crystal structure of the classical paradigm of PII protein, Escherichia coli GlnB (EcGlnB), in fully uridylylated form (EcGlnB-UMP3 ). This is the first structure of a postranslationally modified PII protein. This required recombinant production and purification of the uridylylating enzyme GlnD and its use for full uridylylation of large amounts of recombinantly produced pure EcGlnB. Unlike crystalline non-uridylylated EcGlnB, in which T-loops are fixed, uridylylation rendered the T-loop highly mobile because of loss of contacts mediated by Tyr51, with concomitant abolition of T-loop anchoring via Arg38 on the ATP site. This site was occupied by ATP, providing the first, long sought snapshot of the EcGlnB-ATP complex, connecting ATP binding with T-loop changes. Inferences are made on the mechanisms of PII selectivity for ATP and of PII-UMP3 signalling, proposing a model for the architecture of the complex of EcGlnB-UMP3 with the uridylylation-sensitive PII target ATase (which adenylylates/deadenylylates glutamine synthetase [GS]) and with GS. PMID- 28345297 TI - Residual Cdk1/2 activity after DNA damage promotes senescence. AB - In response to DNA damage, a cell can be forced to permanently exit the cell cycle and become senescent. Senescence provides an early barrier against tumor development by preventing proliferation of cells with damaged DNA. By studying single cells, we show that Cdk activity persists after DNA damage until terminal cell cycle exit. This low level of Cdk activity not only allows cell cycle progression, but also promotes cell cycle exit at a decision point in G2 phase. We find that residual Cdk1/2 activity is required for efficient p21 production, allowing for nuclear sequestration of Cyclin B1, subsequent APC/CCdh1 -dependent degradation of mitotic inducers and induction of senescence. We suggest that the same activity that triggers mitosis in an unperturbed cell cycle enforces senescence in the presence of DNA damage, ensuring a robust response when most needed. PMID- 28345299 TI - A prospective study of health-related quality of life of boys with severe haemophilia A in China: comparing on-demand to prophylaxis treatment. AB - INTRODUCTION: Treatment for boys with haemophilia in China is rapidly improving; however, comprehensive outcomes have not been examined prospectively. AIM: The aim of this study was to evaluate the effect of short-term full-dose prophylaxis compared to on-demand treatment, on the Health-Related Quality of Life (HR-QoL) of boys with severe haemophilia A (HA) in China. METHODS: Boys with severe HA (FVIII<1%) completed 3 months of on-demand treatment and 3 months of full-dose prophylaxis (25 FVIII IU per kg 3x per week). The primary outcomes were child- and parent-reported Canadian Hemophilia Outcomes - Kids Life Assessment Tool (CHO KLAT) scores. The number and type of bleeds and Activities Scale for Kids (ASK) scores were also recorded. RESULTS: Analyses included 23 boys between 4 and 15.9 years of age. The number of bleeds decreased by 94% on prophylaxis (P < 0.0001, Wilcoxon Signed-Rank test). The mean child-reported CHO-KLAT scores for boys >=7 years (n = 20) was 61.4 (+/-10.9) during on-demand treatment and 61.9 (+/-11.4) following short-term prophylaxis (P = 0.72, paired t-test). The mean parent reported CHO-KLAT score during the on-demand phase was 54.4 (+/-10.5) with an increase of 3.8 points (+/-8.1; P = 0.04, paired t-test) following prophylaxis. CONCLUSIONS: Child-reported CHO-KLAT scores were lower in boys with severe HA in China than reported in countries with access to full-dose prophylaxis. Boys reported higher HR-QoL scores than their parents. Small improvements in ASK scores were noted following the prophylaxis phase. These changes were only significant in the parent-reported CHO-KLAT scores. Longer term prospective clinical trials are needed in China to determine the impact of prophylaxis on HR QoL in boys with severe HA. PMID- 28345300 TI - Primary intestinal lymphangiectasia: Multiple detector computed tomography findings after direct lymphangiography. AB - INTRODUCTION: To analyse the findings of multiple detector computed tomography (MDCT) after direct lymphangiography in primary intestinal lymphangiectasia (PIL). METHODS: Fifty-five patients with PIL were retrospectively reviewed. All patients underwent MDCT after direct lymphangiography. The pathologies of 16 patients were confirmed by surgery and the remaining 39 patients were confirmed by gastroendoscopy and/or capsule endoscopy. RESULTS: After direct lymphangiography, MDCT found intra- and extraintestinal as well as lymphatic vessel abnormalities. Among the intra- and extraintestinal disorders, 49 patients had varying degrees of intestinal dilatation, 46 had small bowel wall thickening, 9 had pleural and pericardial effusions, 21 had ascites, 41 had mesenteric oedema, 20 had mesenteric nodules and 9 had abdominal lymphatic cysts. Features of lymphatic vessel abnormalities included intestinal trunk reflux (43.6%, n = 24), lumbar trunk reflux (89.1%, n = 49), pleural and pulmonary lymph reflux (14.5%, n = 8), pericardial and mediastinal lymph reflux (16.4%, n = 9), mediastinal and pulmonary lymph reflux (18.2%, n = 10), and thoracic duct outlet obstruction (90.9%, n = 50). CONCLUSIONS: Multiple detector computed tomography after direct lymphangiography provides a safe and accurate examination method and is an excellent tool for the diagnosis of PIL. PMID- 28345301 TI - One-pot Reductive Amination of carbonyl Compounds with Nitro Compounds by Transfer Hydrogenation over Co-Nx as catalyst. AB - A new method was developed for the synthesis of secondary amines through the one pot reductive amination of carbonyl compounds with nitro compounds using formic acid as the hydrogen donor over a heterogeneous non-noble-metal catalyst (Co-Nx /C-800-AT, generated by the pyrolysis of the cobalt phthalocyanine/silica composite at 800 degrees C under a N2 atmosphere and subsequent etching by HF). Both nitrogen and cobalt were of considerable importance in the transfer hydrogenation reactions with formic acid. PMID- 28345302 TI - Outcome of subsequent pregnancies in patients with a history of peripartum cardiomyopathy. AB - AIMS: Subsequent pregnancies (SSPs) in patients with peripartum cardiomyopathy (PPCM) have a high risk of heart failure relapse. We report on outcome of SSPs in PPCM patients in Germany, Scotland, and South Africa. METHODS AND RESULTS: Among 34 PPCM patients with a SSP, pregnancy ended prematurely in four patients while it was full-term in 30. Overall relapse rate [left ventricular ejection fraction, (LVEF) <50% or death after at least 6-month follow-up] was 56% with 12% (4/34) mortality. Relapse of PPCM after SSP was not associated with differences in parity, twin pregnancy, gestational hypertension, or smoking. Persistently reduced LVEF (<50%) before entering SSP was present in 47% of patients while full recovery (LVEF >=50%) was present in 53%. The majority of patients entering SSP with persistently reduced LVEF were of African ethnicity (75%). Persistently reduced LVEF before SSP was associated with higher mortality (25% vs. 0%) and lower rate of full recovery at follow-up. Patients obtaining standard therapy for heart failure and bromocriptine immediately after delivery displayed significantly better LVEF at follow-up and a higher rate of full recovery with no patient dying compared with patients obtaining standard therapy for heart failure alone. This was independent of African or Caucasian race. CONCLUSION: Full recovery of LVEF before SSP was associated with lower mortality and better cardiac function at follow-up. Addition of bromocriptine to standard therapy for heart failure immediately after delivery was safe and seemed to be associated with a better outcome of SSP in African and Caucasian patients. PMID- 28345303 TI - Arterial ageing: from endothelial dysfunction to vascular calcification. AB - Complex structural and functional changes occur in the arterial system with advancing age. The aged artery is characterized by changes in microRNA expression patterns, autophagy, smooth muscle cell migration and proliferation, and arterial calcification with progressively increased mechanical vessel rigidity and stiffness. With age the vascular smooth muscle cells modify their phenotype from contractile to 'synthetic' determining the development of intimal thickening as early as the second decade of life as an adaptive response to forces acting on the arterial wall. The increased permeability observed in intimal thickening could represent the substrate on which low-level atherosclerotic stimuli can promote the development of advanced atherosclerotic lesions. In elderly patients the atherosclerotic plaques tend to be larger with increased vascular stenosis. In these plaques there is a progressive accumulation of both lipids and collagen and a decrease of inflammation. Similarly the plaques from elderly patients show more calcification as compared with those from younger patients. The coronary artery calcium score is a well-established marker of adverse cardiovascular outcomes. The presence of diffuse calcification in a severely stenotic segment probably induces changes in mechanical properties and shear stress of the arterial wall favouring the rupture of a vulnerable lesion in a less stenotic adjacent segment. Oxidative stress and inflammation appear to be the two primary pathological mechanisms of ageing-related endothelial dysfunction even in the absence of clinical disease. Arterial ageing is no longer considered an inexorable process. Only a better understanding of the link between ageing and vascular dysfunction can lead to significant advances in both preventative and therapeutic treatments with the aim that in the future vascular ageing may be halted or even reversed. PMID- 28345304 TI - Chemical evidence for the effect of Urochloa ruziziensis on glyphosate-resistant soybeans. AB - BACKGROUND: Soybean (Glycine max) is an important oleaginous legume that has been cultivated in new areas in Brazil, including pastures. Problems of reduced production yields have been reported by soybean growers when the crop is sown immediately after desiccation of pastures of Urochloa spp. using glyphosate. The objective of this work was to extract, isolate and identify the major chemicals from U. ruziziensis that have phytotoxic activity and to evaluate the possible relation between this effect and reduced soybean yield. RESULTS: U. ruziziensis plants at the flowering stage were desiccated using glyphosate at 1.44 kg ha-1 . The plants were collected between five and ten days after treatment. Extracts of dried and ground shoots were obtained by sequential extraction with hexane, dichloromethane and methanol. The results of wheat coleoptile bioassays indicated that the methanol extract was more inhibitory than the dichloromethane extract regardless of glyphosate application. CONCLUSION: Protodioscin, a steroidal saponin, was isolated from the extract as the major component and the activities of this compound were in good agreement with those found for the extract. The release of this compound into the soil is a plausible explanation for the decrease in production observed in transgenic soybean crop after desiccation of U. ruziziensis. (c) 2017 Society of Chemical Industry. PMID- 28345305 TI - Temperature-mediated local adaptation alters the symbiotic function in arbuscular mycorrhiza. AB - Variation in the symbiotic function of arbuscular mycorrhizal fungi (AM fungi) has been demonstrated among distinct biotic and abiotic interactions. However, there is little knowledge on how local temperature conditions influence the functional divergence of AM symbionts in alpine ecosystems. Here, we conduct a reciprocal inoculation experiment to explore the three-way interactions among plants, AM fungal inoculum and temperature at sites of contrasting elevation. Evidence of local adaptation of plant growth was found only under low temperature conditions, with no consistent local versus foreign effect found in AM fungal performance. The origin of either the plant or the inoculum relative to the temperature was important in explaining symbiotic function. Specifically, when inoculum and temperature were sympatric but allopatric to the plant, poor adaptation by the plant to the novel environment was clearly found under both temperature conditions. Further analysis found that the symbiotic function was inversely related to fungal diversity under high temperature conditions. These results suggest that local adaptation represents a powerful factor in the establishment of novel combinations of plant, inoculum and temperature, and confirms the importance of taking into account both biotic and abiotic interactions in the prediction of the response of symbionts to global environmental change. PMID- 28345306 TI - The burden and management of cytochrome P450 2D6 (CYP2D6)-mediated drug-drug interaction (DDI): co-medication of metoprolol and paroxetine or fluoxetine in the elderly. AB - PURPOSE: Metoprolol and paroxetine/fluoxetine are inevitably co-prescribed because cardiovascular disorders and depression often coexist in the elderly. This leads to CYP2D6-mediated drug-drug interactions (DDI). Because systematic evaluations are lacking, we assessed the burden of metoprolol paroxetine/fluoxetine interaction in the elderly and how these interactions are managed in Dutch community pharmacies. METHOD: Dispensing data were collected from the University of Groningen pharmacy database (IADB.nl, 1999-2014) for elderly patients (>=60 years) starting beta-blockers and/or antidepressants. Based on the two main DDI alert systems (G-Standard and Pharmabase), incidences were divided between signalled (metoprolol-fluoxetine/paroxetine) and not signalled (metoprolol-alternative antidepressants and alternative beta-blockers paroxetine/fluoxetine) combinations. Incident users were defined as patients starting at least one signalled or a non-signalled combination. G-Standard signalled throughout the study period, whereas Pharmabase stopped after 2005. RESULTS: A total of 1763 patients had 2039 metoprolol-paroxetine/fluoxetine co prescriptions, despite DDI alert systems, and about 57.3% were signalled. The number of metoprolol-alternative antidepressant combinations (incidences = 3150) was higher than alternative beta-blocker-paroxetine/fluoxetine combinations (incidences = 1872). Metoprolol users are more likely to be co-medicated with an alternative antidepressant (incidences = 2320) than paroxetine/fluoxetine users (incidences = 1232) are. The number of paroxetine/fluoxetine users co-prescribed with alternative beta-blockers was comparable to those co-medicated with metoprolol (about 50%). Less than 5% of patients received a substitute therapy after using metoprolol-paroxetine/fluoxetine. Most of the metoprolol users (90%) received a low dose (mean DDD = 0.47) regardless whether they were prescribed paroxetine/fluoxetine. CONCLUSION: Despite the signalling software, metoprolol paroxetine/fluoxetine combinations are still observed in the elderly population. The clinical impact of these interactions needs further investigation. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28345307 TI - Quality indicators for early stage Hodgkin's lymphoma. AB - INTRODUCTION: The purpose of this project was to devise simple, practicable quality indicators (QIs) for the treatment of early stage (I-II) Hodgkin's lymphoma (ESHL), and to test their applicability retrospectively at a single large teaching hospital. METHODS: Of the available treatment guidelines, we chose the two eviQ (evidence and Quality, Cancer Institute New South Wales) documents first published in early 2012 (updated in 2015) for ESHL favourable and ESHL unfavourable (based upon German Hodgkin Study Group practice) as being most relevant to the Australian setting, and selected nine QIs from them viz. baseline staging investigations, discussion in a multi-disciplinary meeting, chemotherapy type and number of cycles, radiotherapy (RT) planning technique, use of dose volume histograms, dose, treatment volume and timing. We identified all patients with ESHL treated radically with chemotherapy and/or RT at the Royal Adelaide Hospital between July 2009 and July 2014, and extracted relevant data from hospital records. QI score for each item was defined as the percentage of patients who received care as recommended in the eviQ guidelines, and improvement potential as an indicator score <90%. RESULTS: Raw QI scores varied between 74 100%. When corrected for clinical circumstances legitimising deviation from the guidelines, the range was 83-100%. Only number of chemotherapy cycles (87% corrected) and RT dose (83% corrected) had improvement potential. However, compliance after publication of the eviQ guidelines was virtually perfect for each item. CONCLUSIONS: The chosen QIs for ESHL proved to be practicable to apply in this single centre review where overall compliance was high, and excellent in the latter half of the study period. We would encourage reporting of raw and corrected QI scores. PMID- 28345309 TI - A survey of clinicians regarding respiratory physiotherapy intervention for intubated and mechanically ventilated patients with community-acquired pneumonia. What is current practice in Australian ICUs? AB - RATIONALE, AIMS, AND OBJECTIVES: Community-acquired pneumonia (CAP) is a common cause for intensive care unit (ICU) admission resulting in high morbidity and mortality. There is a paucity of evidence regarding respiratory physiotherapy for intubated and mechanically ventilated patients with CAP, and anecdotally clinical practice is variable in this cohort. The aims of this study were to identify the degree of variability in physiotherapy practice for intubated adult patients with CAP and to explore ICU physiotherapist perceptions of current practice for this cohort and factors that influence physiotherapy treatment mode, duration, and frequency. METHOD: A survey was developed based on common aspects of assessment, clinical rationale, and intervention for intubated and mechanically ventilated patients. Senior ICU physiotherapists across 88 Australian public and private hospitals were recruited. RESULTS: The response rate was 72%. Respondents (n = 75) stated their main rationale for providing a respiratory intervention were improved airway clearance (98%, n = 60/61), alveolar recruitment (74%, n = 45/61), and gas exchange (33%, n = 20/61). Respondents estimated that average intervention lasted between 16 and 30 minutes (70% of respondents, n = 41/59) and would be delivered once (44%) or twice (44%) daily. Results indicated large variability in reported practice; however, trends existed regarding positioning in alternate side-lying (81%, n = 52/64) or affected lung uppermost (83%, n = 53/64) and use of hyperinflation techniques (81%, 52/64). Decisions regarding duration were reported to be based on sputum volume (95%), viscosity (93%) and purulence (88%), cough effectiveness (95%), chest X-ray (87%), and auscultation (84%). Sixty percent reported that workload and staffing affected intervention duration and frequency. Intervention time was more likely increased when there was greater staffing (P = .03). CONCLUSION: Respiratory physiotherapy treatment varies for intubated patients with CAP. Further research is required to determine what is considered best practice for this patient population. PMID- 28345308 TI - Expeditious and Solvent-Free Nickel-Catalyzed C-H Arylation of Arenes and Indoles. AB - An efficient solvent-free nickel-catalyzed method for C-H bond arylation of arenes and indoles has been developed, which proceeds expeditiously through chelation assistance. The reaction is highly selective for mono-arylation and tolerates sensitive and structurally diverse functionalities, such as halides, ethers, amines, indole, pyrrole and carbazole. This reaction represents the first example of a nickel-catalyzed C-H arylation by monochelate assistance and symbolizes a rare precedent in solvent-free C-H arylation. Mechanistic investigations by various controlled reactions, kinetic studies, and deuterium labeling experiments suggest that the arylation follows a single electron transfer (SET) pathway involving the turnover-limiting C-H nickelation process. PMID- 28345310 TI - Individual factors that influence experiences and perceptions of stigma and discrimination towards people with mental illness in Ghana. AB - People with a mental illness often encounter stigma and discrimination from a variety of sources, reinforcing negative self-perceptions and influencing their health and well-being. Even though support systems and attitudes of the general public act as powerful sources of stigma, views and perceptions held by people with mental illness also influence their sensitivity to the experiences they encounter. The aim of the present qualitative study was to examine perceptions of stigma and discrimination and self-stigma in individuals diagnosed with a mental illness. This study adopted a narrative, descriptive method, using a semistructured interview guide to elicit participant perceptions regarding sources of stigma, discrimination, and personal factors that might influence their experiences. Twelve outpatients attending a clinic in Ghana were interviewed. Thematic content analysis was completed and augmented by field notes. Participants' perceptions about personal impacts of stigma were found to be influenced by self-stigma, anticipated stigma and discrimination, perceived discrimination, and their knowledge about their illness. For many participants, their views served to augment societal views, and thus reinforce negative self perceptions and their future. However, for other participants, their views served as a buffer in the face of environmental situations that reflect stigma and discrimination. Stigma is a complex, socially-sanctioned phenomenon that can seriously affect the health of people with mental illness. As such, it requires coordinated strategies among public policy makers, governmental bodies, and health-care providers to address stigma on a societal level, and to address its potential impacts on broad health outcomes for individuals with mental illness. PMID- 28345311 TI - Relationships among sense of coherence, oral health status, nutritional status and care need level of older adults according to path analysis. AB - AIM: Sense of coherence (SOC) is a measurement of ability of an individual to cope with psychological stress and remain in good health. The aim of the present study was to examine the relationships among SOC score, oral health status, nutritional status and care need level of older adults using path analysis. METHODS: We enrolled 53 older adults (17 men and 36 women) who were attending a day care service (mean age 80.4 +/- 6.5 years). SOC was assessed using a 13-item, seven-scale instrument. Oral health status (number of present teeth, denture use) and nutritional status (assessed with Mini-Nutritional Assessment Short-Form) were also evaluated. Path analysis was used to examine the relationship of SOC with other related factors, including care need level. RESULTS: The mean SOC score was 57.0 +/- 13.9. Mini-Nutritional Assessment Short-Form results showed that one participant (1.8%) was malnourished, 26 (49.1%) were at risk of malnutrition and 26 (49.1%) had normal nutritional status. Participants with high SOC scores showed a strong positive attitude, had a relatively large number of teeth, were in good nutritional condition and showed low care need levels. CONCLUSIONS: The present results showed that maintaining a high SOC level and good oral health help to reduce care need levels in older adults, and also prevent a worsening of their nutritional condition. Geriatr Gerontol Int 2017; 17: 2083-2088. PMID- 28345312 TI - Identification of the new HLA-DQA1*01:15N allele in an Italian patient. AB - The novel allele DQA1*01:15N differs from DQA1*01:03:01:01 by 1 nucleotide substitutions in exon 2. PMID- 28345313 TI - Acute Hyperglycemia Associated with Anti-Cancer Medication. AB - Hyperglycemia during chemotherapy occurs in approximately 10% to 30% of patients. Glucocorticoids and L-asparaginase are well known to cause acute hyperglycemia during chemotherapy. Long-term hyperglycemia is also frequently observed, especially in patients with hematologic malignancies treated with L-asparaginase based regimens and total body irradiation. Glucocorticoid-induced hyperglycemia often develops because of increased insulin resistance, diminished insulin secretion, and exaggerated hepatic glucose output. Screening strategies for this condition include random glucose testing, hemoglobin A1c testing, oral glucose loading, and fasting plasma glucose screens. The management of hyperglycemia starts with insulin or sulfonylurea, depending on the type, dose, and delivery of the glucocorticoid formulation. Mammalian target of rapamycin (mTOR) inhibitors are associated with a high incidence of hyperglycemia, ranging from 13% to 50%. Immunotherapy, such as anti-programmed death 1 (PD-1) antibody treatment, induces hyperglycemia with a prevalence of 0.1%. The proposed mechanism of immunotherapy induced hyperglycemia is an autoimmune process (insulitis). Withdrawal of the PD 1 inhibitor is the primary treatment for severe hyperglycemia. The efficacy of glucocorticoid therapy is not fully established and the decision to resume PD-1 inhibitor therapy depends on the severity of the hyperglycemia. Diabetic patients should achieve optimized glycemic control before initiating treatment, and glucose levels should be monitored periodically in patients initiating mTOR inhibitor or PD-1 inhibitor therapy. With regard to hyperglycemia caused by anti cancer therapy, frequent monitoring and proper management are important for promoting the efficacy of anti-cancer therapy and improving patients' quality of life. PMID- 28345314 TI - Prevalence and Clinical Characteristics of Dyslipidemia in Koreans. AB - The prevalence of hypercholesterolemia in Koreans 30 years old and over was 19.5% in 2015 according to the Korean Nutrition and Health Examination Survey, which means that one-fifth of adults had hypercholesterolemia. The prevalence of hypertriglyceridemia in adults 30 years of age and older was 16.8% in 2015, and men had a 2-fold higher prevalence of hypertriglyceridemia than women (23.9% vs. 10.4%). The awareness of hypercholesterolemia in Koreans was higher in women than among men (62.4% vs. 51.4%). It increased with age; the level of awareness in participants 30 to 49 years of age (32.1% in men and 32.6% in women) was less than half of that observed among respondents >=65 years old (77.5% in men and 78.0% in women). Regular check-ups for dyslipidemia and the active management thereof are urgent in Korean men aged 30 to 49. In women, the perimenopausal period is crucial for the prevention and management of metabolic syndrome, including dyslipidemia. Overall, improvements in awareness and treatment in the age group of 30 to 49 years in both men and women remain necessary. PMID- 28345315 TI - The Role of Macrophage Lipophagy in Reverse Cholesterol Transport. AB - Macrophage cholesterol efflux is a central step in reverse cholesterol transport, which helps to maintain cholesterol homeostasis and to reduce atherosclerosis. Lipophagy has recently been identified as a new step in cholesterol ester hydrolysis that regulates cholesterol efflux, since it mobilizes cholesterol from lipid droplets of macrophages via autophagy and lysosomes. In this review, we briefly discuss recent advances regarding the mechanisms of the cholesterol efflux pathway in macrophage foam cells, and present lipophagy as a therapeutic target in the treatment of atherosclerosis. PMID- 28345317 TI - How to Prepare Endocrinology and Metabolism for Reapplication to MEDLINE. PMID- 28345316 TI - The Implication of Coronary Artery Calcium Testing for Cardiovascular Disease Prevention and Diabetes. AB - Over the last two decades coronary artery calcium (CAC) scanning has emerged as a quick, safe, and inexpensive method to detect the presence of coronary atherosclerosis. Data from multiple studies has shown that compared to individuals who do not have any coronary calcifications, those with severe calcifications (i.e., CAC score >300) have a 10-fold increase in their risk of coronary heart disease events and cardiovascular disease. Conversely, those that have a CAC of 0 have a very low event rate (~0.1%/year), with data that now extends to 15 years in some studies. Thus, the most notable implication of identifying CAC in individuals who do not have known cardiovascular disease is that it allows targeting of more aggressive therapies to those who have the highest risk of having future events. Such identification of risk is especially important for individuals who are not on any therapies for coronary heart disease, or when intensification of treatment is being considered but has an uncertain role. This review will highlight some of the recent data on CAC testing, while focusing on the implications of those findings on patient management. The evolving role of CAC in patients with diabetes will also be highlighted. PMID- 28345318 TI - Articles in Endocrinology and Metabolism in 2016. PMID- 28345319 TI - Vascular Cell Adhesion Molecule 1, Intercellular Adhesion Molecule 1, and Cluster of Differentiation 146 Levels in Patients with Type 2 Diabetes with Complications. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is a multisystemic, chronic disease accompanied by microvascular complications involving various complicated mechanisms. Intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and cluster of differentiation-146 (CD146) are mainly expressed by endothelial cells, and facilitate the adhesion and transmigration of immune cells, leading to inflammation. In the present study, we evaluated the levels of soluble adhesion molecules in patients with microvascular complications of T2DM. METHODS: Serum and whole blood samples were collected from 58 T2DM patients with microvascular complications and 20 age-matched healthy subjects. Levels of soluble ICAM-1 (sICAM-1) and soluble VCAM-1 (sVCAM-1) were assessed using enzyme-linked immunosorbent assay, while flow cytometry was used to determine CD146 levels. RESULTS: Serum sICAM-1 levels were lower in T2DM patients with microvascular complications than in healthy controls (P<0.05). No significant differences were found in sVCAM-1 and CD146 levels between the study and the control group. Although patients were subdivided into groups according to the type of microvascular complications that they experienced, cell adhesion molecule levels were not correlated with the complication type. CONCLUSION: In the study group, most of the patients were on insulin therapy (76%), and 95% of them were receiving angiotensin-converting enzyme (ACE)-inhibitor agents. Insulin and ACE-inhibitors have been shown to decrease soluble adhesion molecule levels via various mechanisms, so we suggest that the decreased or unchanged levels of soluble forms of cellular adhesion molecules in our study group may have resulted from insulin and ACE-inhibitor therapy, as well as tissue-localized inflammation in patients with T2DM. PMID- 28345320 TI - Letter: Comparison of Age of Onset and Frequency of Diabetic Complications in the Very Elderly Patients with Type 2 Diabetes (Endocrinol Metab 2016;31:416-23, Bong Ki Lee et al.). PMID- 28345322 TI - Corrigendum: Correction of Acknowledgments: Epidemiology of Childhood Obesity in Korea. AB - This corrects the article on p. 510 in vol. 31, PMID: 27834078. PMID- 28345321 TI - Response: Comparison of Age of Onset and Frequency of Diabetic Complications in the Very Elderly Patients with Type 2 Diabetes (Endocrinol Metab 2016;31:416-23, Bong-Ki Lee et al.). PMID- 28345323 TI - Circulating Tumor BRAF Mutation and Personalized ThyroidCancer Treatment PMID- 28345325 TI - Potential Role of E4 Protein in Human Papillomavirus Screening: a Review AB - In 2006, cervical cancer was reported as the second most common cancer in women of Malaysia. This type ofcancer has been shown to correlate with persistent high risk human papillomavirus (HPV) infection. Although HPV iswell known to induce cervical cancer, knowledge of pathways that link the latent stage of the viral replication cycle toprecancerous and cancerous stages remains incomplete. However, it is interesting to note that the virus can be isolatedfrom tissues ranging from normal to low-grade squamous intraepithelial lesions as well as high grade intraepitheliallesions (HSILs), thus prompting scientists to develop HPV detection methods for screening. Detection of HPV usingviral proteins such as L1 and E1 is proposed to be very useful in assisting the management of high risk infection andcervical cancer. These tests however can lead to false positive results, largely due to the exisstence of asymptomatic ortransient HPV infections within any given individual. Somes observation indicate that use of HPV proteins such as E6and E7 might lead to false positive results. However, one particular HPV protein, E4 shows potential as an accuratemarker of the tissue state following HPV infection. E4 expression has been shown to correlate with the levels of HPVDNA incorporation by the host. Thus, it is possible that E4 could serve as a useful marker to define stages of viralcarcinogenesis. PMID- 28345326 TI - Patient-Linked Factors Associated with Delayed Reporting of Oral and Pharyngeal Carcinoma among Patients Attending National Cancer Institute, Maharagama, Sri Lanka AB - Background: Diagnosis of cancer at an early stage improves prognosis following treatment. Unfortunately a largeproportion of oral and pharyngeal cancer patients are diagnosed at late stages which require radical treatment withconsiderable morbidity and mortality. Many researchers have examined different types of delay that could occur betweenthe onset of symptoms and diagnosis. The objective of this research was to identify patient-linked delays between thetime of first noticing symptoms and definitive diagnosis, and its association with the stage at diagnosis among oraland pharyngeal carcinoma patients attending the National Cancer Institute, Maharagama, Sri Lanka. Methods: Ahospital-based descriptive cross-sectional study was carried out on 351 patients with histologically confirmed carcinomaof oral cavity and pharynx. Data were collected using an interviewer- administered questionnaire and a data extractionsheet. If a patient had taken more than three months to visit a Health Care Practitioner, it was considered as 'PatientDelay-1'. If a patient had taken more than two weeks following referral to reach for specialized cancer care, it wasconsidered as 'Patient Delay 2'. Results: Proportions of 'Patient Delay-1' and 'Patient Delay 2' were 19% (n=252)and 16% (n=322) respectively. Mean time duration between noticing symptoms to definitive diagnosis was 14.1weeks (SD=10.3). The proportion of advanced-stage cancers at diagnosis was 59.8%. Conclusion: Stage at diagnosiswas significantly associated with 'Patient Delay -1' (p = 0.001) but not with 'Patient Delay-2'. 'Patient Delay-1' wassignificantly associated with level of education (p = 0.001) and the cost of travelling (p = 0.048). PMID- 28345327 TI - Frequency of Epstein Barr Virus Type 1 Among Nasopharyngeal Carcinomas in Iranian Patients AB - Background: Around 95% of the world's population are infected with the Epstein Barr virus (EBV), whichcan persist latent in B lymphocytes and epithelial cells life-long. EBV has been linked with lymphoid and epithelialcancers and persistence of EBV infection in lymphoid or epithelial cells may result in virus associated B-celltumors or nasopharyngeal carcinomas (NPC). This study was conducted to determine the frequency of EBV DNA innasopharyngeal carcinoma tissue of Iranian patients. Materials and methods: A total of 50 blocks of formalin fixedparaffin-embedded tissue of NPCs from 38 (76 %) male and 12 (24%) female patients were collected from archivesof Ahvaz hospitals. Sections were cut at 5 MUm and DNA was extracted for detection of EBV DNA and EBV typing bymested PCR. DNA sequencing was performed to confirm PCR results. The distribution of EBV DNA was comparedamong WHO histological subtypes of NPC. Results: Some 3 female and 11 (22%) male NPC samples showed positivefor EBV DNA type 1, 2/14(22.2%)WHO histological type II and 12/41(29.3%) WHO histological type III. Conclusions:The frequency of EBV DNA among NPCs in Iranian patients was found to be 28%, EBV type I predominating. BothWHO histological type II and III NPC subtypes demonstrated approximately the same detection prevalence. PMID- 28345328 TI - Esophageal Cancer and associated Factors among Uzbek-Turkmen and Other Ethnic Groups in the Northern Part of Afghanistan AB - Background: A high incidence rate of esophageal cancer has been observed in the Northern part of Afghanistan,particularly among those of Uzbek-Turkmen ethnicity. However, there is a paucity of published data from which tocompare the prevalence of environmental risk factors for esophageal cancer between Uzbek-Turkmen and other ethnicgroups. Thus, we investigated the prevalence of environmental risk factors associated with esophageal cancer in theNorthern part of Afghanistan, focusing on ethnicity differences. Methods: This retrospective study covered 168 patientsdiagnosed with esophageal cancer based on endoscopic findings when attending an outpatient clinic from October2013 to April 2016. Demographic data and burden of relevant environmental risk factors were compared betweenUzbek Turkmen and other ethnic groups. Results: In the total of 168 patients (108 Uzbek Turkmen and 60 otherethnicities), males had significantly higher rates of opium use, chewing nass (a mixture of tobacco, ash and lime), andsmoking than female patients. The mean age of the Uzbek-Turkmen group was 62.9 years, while that of the other ethnicgroup cases was 59.1. The prevalence of opium use, chewing nass and hot tea consumption was significantly higher inthe Uzbek-Turkmen group. Conclusions: This study showed that there were significant differences in prevalence ofopium, nass, and hot tea consumption between Uzbek-Turkmen and the other ethnic group patients with esophagealcancer in the northern part of Afghanistan. PMID- 28345329 TI - Lycopene Extracts from Different Tomato-Based Food Products Induce Apoptosis in Cultured Human Primary Prostate Cancer Cells and Regulate TP53, Bax and Bcl-2 Transcript Expression AB - Carotenoids are the main tomato components, especially lycopene. Lycopene is more bioavailable in tomato processedproducts than in raw tomatos, since formation of lycopene cis-isomers during food processing and storage may increaseits biological activity. In the current study, we evaluated the influence of lycopene extracts (5 mg / mL) from differenttomato-based food products (paste, sauce, extract and ketchup) on cell viability and apoptosis on primary humanprostate cancer cells (PCa cels) for 96h. Using MTT assay, we observed a significant decrease on primary PCa cellviability upon treatment with lycopene extracted from either 4 tomato-based food products. Flow cytometeric analysisrevealed that lycopene from tomato extract and tomato sauce promoted up to fifty-fold increase on the proportion ofapoptotic cells, when compared to the control group. Using real time PCR assay, we found that lycopene promotedan upregulation of TP53 and Bax transcript expression and also downregulation of Bcl-2 expression in PCa cells. Inconclusion, our data demostrate that cis-lycopene promoted a significant inhibition on primary PCa cell viability, aswell as an increase on their apoptotic rates, evidencing that cis-lycopene contained in tomato sauce and extract cainmainly modulate of primary human prostate cancer cell survival. PMID- 28345324 TI - Cisplatin-Induced Nephrotoxicity; Protective Supplements and Gender Differences AB - Cisplatin (CDDP) has been widely used as a chemotherapeutic agent for solid tumors. The most common side effectof CDDP is nephrotoxicity, and many efforts have been made in the laboratory and the clinic to employ candidateadjuvants to CDDP to minimize this adverse influence. Many synthetic and herbal antioxidants as well as trace elementshave been investigated for this purpose in recent years and a variety of positive and negative results have been yielded.However, no definitive supplement has so far been proposed to prevent CDDP-induced nephrotoxicity; however, thiscondition is gender related and the sex hormone estrogen may protect the kidney against CDDP damage. In this review,the results of research related to the effect of different synthetic and herbal antioxidants supplements are presented anddiscussed with suggestions included for future work. PMID- 28345330 TI - Relationship of Lifetime Exposure to Tobacco, Alcohol and Second Hand Tobacco Smoke with Upper aero-digestive tract cancers in India: a Case-Control Study with a Life-Course Perspective AB - Background: Squamous cell carcinomas of the upper aero-digestive tract (UADTSCC) are a multifaceted publichealth problem. Effects of lifestyle risk factors, including tobacco (chewing and smoking), alcohol drinking and exposureto second hand tobacco smoke (SHS) at home and their association with UADT cancers was assessed in a case-controlstudy with a life-course perspective. The study was conducted at two different hospitals in Pune, India. Material andmethods: The total sample size (N=480) included 240 histopathologically confirmed cases of UADT cancers and anequal number of controls frequency matched with cases by gender and age distribution (+5 years). All the patients wereinterviewed face face using structured questionnaires. Self-reported information on socio demographic and lifestylerisk factors from childhood to the date of diagnosis of disease/cancer was obtained. Frequency, duration and age ofinitiation of habits were also recorded to study dose-response relationships. Odds ratios and their 95% confidenceintervals were calculated through unconditional logistic regression, adjusting for relevant potential confounders. Results:Chewing tobacco emerged as the strongest predictor for UADT cancers (OR=7.61; 95% CI 4.65-12.45) in comparisonto smoking and drinking alcohol. Exposure to SHS during childhood (<16 years) rather than >=16 years increased therisk (OR=4.05; 95% CI 2.06-7.95). Combined effects of tobacco and alcohol consumption habits elevated the risk bytwelve fold (OR=12.05; 95% 4.61-31.49) in comparison to never users of these habits. Furthermore, the combination ofthese lifestyle risk factors accounted for 86.8% of population attributable risk. Conclusions: Early exposure to variousmodifiable lifestyle risk factors has a strong positive association with UADT cancer incidence. Effective future publichealth interventions with focus on vital time points in life targeting these risk factors could possibly be a major step inprimary prevention and control of this cancer at the population level. PMID- 28345331 TI - Cervical Cancer Screening in Iranian Women: Healthcare Practitioner Perceptions and Views AB - Background: Although regular screening for cervical cancer with the Papanicolaou test is an important elementfor reducing the incidence and mortality of cervical cancer, the actual screening program in Iranian women is notsufficiently comprehensive at present. The purpose of this study was to explore healthcare provider perceptions of factorsaffecting cervical cancer screening in Iranian women. Methods: In this qualitative study performed from September2015 to August 2016 in Hamadan, Iran, we conducted semi-structured in depth interviews with 14 healthcare providersselected purposefully. All interviews were recorded, transcribed and analyzed according to a conventional thematicanalysis approach. MAXQDA10 software was employed for data analysis. Results: Four themes were extracted fromdata: "Inefficient management of cervical cancer screening process, Personal and professional characteristics of healthcare providers, Individual barriers and facilitators, Need for health system authorities to pay attention". Conclusion:Increased official attention to screening, and identifying challenges and providing strategies based on these challengeswill help in achieving a successful screening program. It is necessary to attend to professional features of medicalscience students and increase the skills of interaction with clients in addition to academic training. Efforts should bemade to increase trust in healthcare providers regarding the Pap test and receptiveness of society to this screeningmodality through informing the public, with encouragement through the media. PMID- 28345332 TI - Effects of Cisplatin-Loaded Niosomal Nanoparticleson BT-20 Human Breast Carcinoma Cells AB - Breast cancer is the fifth most common cause of death among women worldwide. Resistance to cisplatin is a mainchallenge in its treatment. Our present aim was to prepare nanoniosomated cisplatin and examine its efficacy in vitrousing the BT 20 cell line. Niosome nanoparticles containing cisplatin were prepared by reverse phase evaporation andcharacterized by dynamic light scattering (DLS), scanning electron microscopy (SEM), spectrophotometry and MTTassay. The size and zeta potential of the nanodrug were estimated as 489.3 +/- 23.66 nm and 23.4 +/- 2.1 mV, respectively.Drug encapsuies confirmed appropriate retention of particles. Nanoparticles also increased the cytotoxic effects ofcisplatin by 1.5 times compared to the standard drug. Findings of our study suggest that niosome nanoparticles aregood carriers for cisplatin delivery to breast cancer cells. PMID- 28345333 TI - Assessment of Anxiety and Depression Status in Turkish Cutaneous Melanoma Patients AB - Background: Even though anxiety and depression are two mood disorders encountered commonly in cancer patientsonly few trials have been carried out so far in melanoma patients. The aim of the study was to determine the clinicalprevalence of these disorders in Turkish cutaneous melanoma patients and to clarify possible clinicopathological factorsinfluencing them. Material and methods: A total of 100 consecutive outpatient melanoma patients were enrolled andasked to complete the Hospital Anxiety and Depression Scale (HADS) questionnaire immediately after scheduled visits.Results: A total of 24 participants had clinical anxiety and 8 were diagnosed with borderline anxiety. Fifteen werediagnosed with clinical depression and 20 with borderline depression. Prior to melanoma diagnosis the majority of thepatients, 93 and 86, were assessed as normal in terms of their anxiety and depression status, respectively (p<0.001).A statistically significant correlation was found between anxiety and depression scores (p<0.001). The patients withadvanced disease were significantly more anxious and depressive than those with early stage disease. None of the othersocio-demographic parameters was found to be correlated with anxiety and depression status. Conclusions: Becausea large group of Turkish melanoma patients, nearly one third of the cohort, was found to be suffering from relevantanxiety and depression, it is of uttermost importance that psychological support and pharmacological intervention forthese patients be commenced as soon as possible. PMID- 28345334 TI - Frequency of Head and Neck Squamous Cell Carcinomas and Related Variables in Southern Iran (Ahvaz City): 10-Year Retrospective Study AB - Objective: Squamous cell carcinoma (SCC) is a life threatening lesion but there has been only limited researchabout its frequency in Iran. The aim of this study was to evaluate the frequency of squamous cell carcinoma of thehead and neck in the records of the pathology department of Imam Khomeini hospital in Ahvaz between 2005 and2015. Methods: The retrospective and cross-sectional study was conducted using 55,708 medical records of cancerthroughout the body, accumulated in the pathology department of Imam Khomeini in Ahvaz in the designated period.Information about age, gender, site of involvement, histological characteristics, status of lymph node metastasis,smoking habit, family history, job and education level was extracted and data were analyzed with the Chi-square testwith SPSS version 22. Result: Of the total of 55,708 records, 582 patients (1.04%) had head and neck squamous cellcarcinomas. The male to female ratio was 2.85. The frequencies in the head, mouth and neck were 28.7%, 22% and49.3% respectively. Significant relationships between being male and location (neck) (p = 0.002), age (60 to 80 yearsold) and being a farmer (p = 0.001) was observed. The most important correlated risk factors were: smoking, sunlightexposure, rural residence, job and education level. Conclusion: Head and neck squamous cell carcinomas were foundto account for 1.04% of all cancers in Ahvaz, one of the southern provinces of Iran. PMID- 28345335 TI - VEGFR-3 Expression in Oral Lichen Planus AB - Background and objective: Given the postulated the role of inflammation and possible contribution oflymphangiogenesis in oral lichen planus, this study aimed to assess any associated presence of VEGFR-3. Materialand Methods: This cross sectional study was performed on 52 formalin fixed and paraffin embedded blocks of orallichen planus (pathological diagnosis based on Modified WHO criteria), comprising 25 of erosive and 27 of reticulartype, along with 60 samples of normal mucosa (with minimal inflammation from clinical and histopathological aspects)obtained at crown lengthening surgery. Four micron sections were cut from paraffin blocks and stained with H andE for confirmation of diagnosis and by immunohistochemistry with primary antibodies against VEGFR-3. Negativecontrols were provided by omission of primary antibody and placenta was considered as a positive control. Data wereanalyzed by Chi-square, Mann-Whitney and Kruskal wallis tests and P <0.05 was considered statistically significant.Findings: VEGFR 3 expression was apparent in 61.5% of lichen planus specimens and 5% of those from normalmucosa (p<0.001). Also, the average number of stained vessels was significantly higher in oral lichen planus than innormal mucosa (p<0.001). VEGFR 3 expression in oral lichen planus (p=0.262) and the average number of stainedvessels (p=0.092) demonstrated no significant difference according to the type. Conclusion: It appears that VEGFR-3expression might be involved in the pathogenesis of the oral lichen planus through increasing lymphatic vessels andlymphangiogenesis. PMID- 28345336 TI - Proteomic Identification of eEF1A1 as a Molecular Target of Curcumol for Suppressing Metastasis of MDA-MB-231 Cells. AB - Curcumol, a major volatile component in Rhizoma Curcumae, exhibits a potent antimetastatic effect on breast cancer cells. However, its molecular mechanism remains poorly understood. In this study, we employed two-dimensional gel electrophoresis-based proteomics to investigate the cellular targets of curcumol in MDA-MB-231 cells and identified 10 differentially expressed proteins. Moreover, Gene Ontology analysis revealed that these proteins are mainly involved in nine types of cellular components, seven different biological processes, and nine kinds of molecular functions, and 35 pathways (p < 0.05) were enriched by KEGG pathway analysis. Specially, eEF1A1, a well-characterized actin binding protein, draws our attention. Curcumol decreased eEF1A1 expression at both mRNA and protein levels. EEF1A1 expression was shown to be correlated with the invasiveness of cancer cells. Importantly, overexpression of eEF1A1 significantly reversed the inhibition of curcumol regarding the invasion and adhesion of MDA-MB 231 cells (p < 0.05). Together, our data suggest that eEF1A1 may be a potential molecular target underlying the antimetastatic effect of curcumol. PMID- 28345337 TI - Light-Up Mitophagy in Live Cells with Dual-Functional Theranostic Phosphorescent Iridium(III) Complexes. AB - Phosphorescent Ir(III) complexes are expected to be new multifunctional theranostic platforms that enable the integration of imaging capabilities and anticancer properties. Mitophagy is an important selective autophagic process that degrades dysfunctional mitochondria. Until now, the regulation of mitophagy is still poorly understood. Herein, we present two phosphorescent cyclometalated iridium(III) complexes (Ir1 and Ir2) that can accumulate in mitochondria and induce mitophagy. Because of their intrinsic phosphorescence, they can specially image mitochondria and track mitochondrial morphological alterations. Mechanism studies show that Ir1 and Ir2 induce mitophagy by depolarization of mitochondrial membrane potential, depletion of cellular ATP, perturbation in mitochondrial metabolic status, and induction of oxidative stress. Moreover, no sign of apoptosis is observed in Ir1- and Ir2-treated cells under the same conditions that an obvious mitophagic response is initiated. We demonstrate that Ir1 is a promising theranostic agent that can induce mitophagy and visualize changes in mitochondrial morphology simultaneously. PMID- 28345338 TI - Study of Arylamine-Substituted Porphyrins as Hole-Transporting Materials in High Performance Perovskite Solar Cells. AB - To develop new hole-transporting materials (HTMs) for efficient and stable perovskite solar cells (PSCs), 5,10,15,20-tetrakis{4-[N,N-di(4 methoxylphenyl)amino-phenyl]}-porphyrin was prepared in gram scale through the direct condensation of pyrrole and 4-[bis(4-methoxyphenyl)amino]benzaldehyde. Its Zn(II) and Cu(II) complexes exhibit excellent thermal and electrochemical stability, specifically a high hole mobility and very favorable energetics for hole extraction that render them a new class of HTMs in organometallic halide PSCs. As expected, ZnP as HTM in PSCs affords a competitive power conversion efficiency (PCE) of 17.78%, which is comparable to that of the most powerful HTM of Spiro-MeOTAD (18.59%) under the same working conditions. Meanwhile, the metal centers affect somewhat the photovoltaic performances that CuP as HTM produces a lower PCE of 15.36%. Notably, the PSCs employing ZnP show a much better stability than Spiro-OMeTAD. Moreover, the two porphyrin-based HTMs can be prepared from relatively cheap raw materials with a facile synthetic route. The results demonstrate that ZnP and CuP can be a new class of HTMs for efficient and stable PSCs. To the best of our knowledge, this is the best performance that porphyrin based solar cells could show with PCE > 17%. PMID- 28345339 TI - Synthesis of Positional Isomeric Phenylphenalenones. AB - A series of isomeric phenylphenalenones in which the phenyl ring is located at all possible peripheral positions of the phenalenone nuclei was synthesized. The structural characteristics of the series, in which topological variation is permitted with minimal electronic disturbance, could, in principle, allow for easy pharmacophore recognition when the compounds are aligned in steroidomimetic conformations. PMID- 28345340 TI - Excluded Volume Approach for Ultrathin Carbon Nanotube Network Stabilization: A Mesoscopic Distinct Element Method Study. AB - Ultrathin carbon nanotube films have gathered attention for flexible electronics applications. Unfortunately, their network structure changes significantly even under small applied strains. We perform mesoscopic distinct element method simulations and develop an atomic-scale picture of the network stress relaxation. On this basis, we put forward the concept of mesoscale design by the addition of excluded-volume interactions. We integrate silicon nanoparticles into our model and show that the nanoparticle-filled networks present superior stability and mechanical response relative to those of pure films. The approach opens new possibilities for tuning the network microstructure in a manner that is compatible with flexible electronics applications. PMID- 28345341 TI - Positron Annihilation Spectroscopic Investigation on the Origin of Temperature Dependent Electrical Response in Methylammonium Lead Iodide Perovskite. AB - Organic-inorganic hybrid perovskite has appeared as one of the leading materials for realizing solution-based high-performing optoelectronic devices. The charge transport properties in this class of material are quite intriguing and still need to be carefully investigated. The temperature-dependent electrical property of methylammonium lead iodide (CH3NH3PbI3) has been investigated by employing positron annihilation spectroscopy (PAS), which unambiguously reveals the gradual formation of open volume defects with the enhancement in temperature. The high temperature ionic conductivity is due to the generation of both cationic (CH3NH3+) and anionic (I-) vacancies, possibly because of the elimination of methylammonium iodide (CH3NH3I) as identified from the coincidence Doppler broadening (CDB) of the positron annihilation spectroscopy. Further, the evolution of temperature-dependent defect density and corresponding electrical responses has been correlated with the structural phase transitions of CH3NH3PbI3. This is the first ever report of temperature-dependent PAS measurement on hybrid lead halide perovskites to understand the nature and the origin of its electrical characteristics arising due to the variation in temperature. PMID- 28345342 TI - The Role of Strain in the Homoaromatization of Semibullvalenes. AB - The low activation barrier to the Cope rearrangement of semibullvalenes has been attributed to the inherent ring-strain of this nucleus. Appropriate, Dewar Hoffmann, substitution of semibullvalene results in the stabilization of the transition state and a further lowering of the Cope barrier. An alternative proposal for lowering/eliminating this barrier is the use of strain to destabilize the localized semibullvalene. Using density functional and Hartree Fock calculations, we predict that additionally straining the semibullvalene nucleus, by small ring annelations, will lead to a lowering of the Cope barrier and ultimately to ground state neutral homoaromatics. PMID- 28345343 TI - Electronic and Steric Optimization of Fluorogenic Probes for Biomolecular Imaging. AB - Fluorogenic probes are invaluable tools for spatiotemporal investigations within live cells. In common fluorogenic probes, the intrinsic fluorescence of a small molecule fluorophore is masked by esterification until entry into a cell, where endogenous esterases catalyze the hydrolysis of the masking groups, generating fluorescence. The susceptibility of masking groups to spontaneous hydrolysis is a major limitation of these probes. Previous attempts to address this problem have incorporated auto-immolative linkers at the cost of atom economy and synthetic adversity. Here, we report on a linker-free strategy that employs adventitious electronic and steric interactions in easy-to-synthesize probes. We find that X...C?O n->pi* interactions and acyl group size are optimized in 2',7' dichlorofluorescein diisobutyrate. This probe is relatively stable to spontaneous hydrolysis but is a highly reactive substrate for esterases both in vitro and in cellulo, yielding a bright, photostable fluorophore with utility in biomolecular imaging. PMID- 28345344 TI - Unravelling and Quantifying the "NMR-Invisible" Metabolites Interacting with Human Serum Albumin by Binding Competition and T2 Relaxation-Based Decomposition Analysis. AB - Quantitative profiling of low-molecular-weight metabolites (LMWMs) by 1H NMR is routinely used in high-throughput serum metabolomics. First, the protein background is attenuated using a T2 filter; then, the LMWM signals are resolved by line-shape fitting. However, protein-binding modifies the motional properties of LMWM, and their signal partially attenuates with the T2 filter, along with the protein background. Consequently, the quantified LMWM signals do not reflect the total concentration in serum but the nonbinding part. Here we present a novel strategy based on binding competition to promote the release of the "NMR invisible" metabolites from serum proteins and achieve quantifications closer to total concentrations. The study focuses on five clinically relevant amino acids with different binding properties (valine, isoleucine, leucine, tyrosine, and phenylalanine). We analyzed their binding affinity to human serum albumin (HSA) in serum mimic samples and promoted the release of their bound fraction by TSP titration. Furthermore, we used a novel combination of pseudo-2D CPMG and multivariate curve resolution analysis, allowing the separation of LMWM and protein signals and providing LMWM quantifications corrected for transverse relaxation effects. We found that TSP concentrations larger than 3 mM released most of the bound fraction and validated these findings in real serum/plasma samples. PMID- 28345345 TI - Continuously Electrotriggered Core Coalescence of Double-Emulsion Drops for Microreactions. AB - Microfluidically generated double emulsions are promising templates for microreactions, which protect the reaction from external disturbance and enable in vitro analyses with large-scale samples. Controlled combination of their inner droplets in a continuous manner is an essential requirement toward truly applications. Here, we first generate dual-cored double-emulsion drops with different inner encapsulants using a capillary microfluidic device; next, we transfer the emulsion drops into another electrode-integrated polydimethylsiloxane microfluidic device and utilize external AC electric field to continuously trigger the coalescence of inner cores inside these emulsion drops in continuous flow. Hundreds of thousands of monodisperse microreactions with nanoliter-scale reagents can be conducted using this approach. The performance of core coalescence is investigated as a function of flow rate, applied electrical signal, and core conductivity. The coalescence efficiency can reach up to 95%. We demonstrate the utility of this technology for accommodating microreactions by analyzing an enzyme catalyzed reaction and by fabricating cell laden hydrogel particles. The presented method can be readily used for the controlled triggering of microreactions with high flexibility for a wide range of applications, especially for continuous chemical or cell assays. PMID- 28345346 TI - Thermally Activated Delayed Fluorescence and Aggregation Induced Emission with Through-Space Charge Transfer. AB - Emissive molecules comprising a donor and an acceptor bridged by 9,9 dimethylxanthene, were studied (XPT, XCT, and XtBuCT). The structures position the donor and acceptor with cofacial alignment at distances of 3.3-3.5 A wherein efficient spatial charge transfer can occur. The quantum yields were enhanced by excluding molecular oxygen and thermally activated delayed fluorescence with lifetimes on the order of microseconds was observed. Although the molecules displayed low quantum yields in solution, higher quantum yields were observed in the solid state. Crystal structures revealed pi-pi intramolecular interactions between a donor and an acceptor, however, the dominant intermolecular interactions were C-H...pi, which likely restrict the molecular dynamics to create aggregation-induced enhanced emission. Organic light emitting devices using XPT and XtBuCT as dopants displayed electroluminescence external quantum efficiencies as high as 10%. PMID- 28345347 TI - A Systematic Evaluation of the N-F Bond Strength of Electrophilic N-F Reagents: Hints for Atomic Fluorine Donating Ability. AB - The recent discovery of the radical reactivity of a few traditionally electrophilic N-F reagents has sparked a renaissance of radical fluorination. A knowledge of the N-F bond dissociation enthalpies (BDE) of electrophilic N-F reagents is essential for understanding of their reactivities. However, a thorough literature survey revealed that such information is extremely sparse. This prompted us to carry out the first systematic computation on the N-F BDEs of electrophilic N-F reagents. The calculated N-F BDE scale of 88 electrophilic N-F reagents ranges from 49.3 to 80.0 kcal mol-1 in acetonitrile. The large variety of N-F reagents and wide span of N-F BDEs make the scale a useful tool not only for the future rational design of novel reagents but also for judicious selection of appropriate ones to explore new radical fluorinations. PMID- 28345348 TI - Mechanistic Insights into the Rh-Catalyzed Transannulation of Pyridotriazole with Phenylacetylene and Benzonitrile: A DFT Study. AB - Computational studies were carried out to explore the mechanisms of Rh2(OAc)4 catalyzed transannulation of pyridotriazole with phenylacetylene and benzonitrile, respectively. For the Rh2(OAc)4-catalyzed divergent cyclization with phenylacetylene, the major product (cyclopropene derivative) might be formed via [2 + 2] cycloaddition to yield a metallacyclobutene intermediate followed by a reductive elimination pathway, where carboxylate ligand lability is considered to release a vacant equatorial site for the formation of Rh-carbenoid. The cyclopropenation of phenylacetylene via a commonly proposed [2 + 1] cycloaddition pathway, where the tetrabridged framework of Rh2(OAc)4 is preserved, however, might not play a dominant role. This is because the competing formal [2 + 3] pathway leading to the indolizine as a minor product is more likely to occur. The main factors responsible for the chemoselectivity in cyclization with phenylacetylene are discussed. For the Rh2(OAc)4-catalyzed transannulation of pyridotriazole with benzonitrile, a stepwise formal [2 + 3] pathway via a ylide intermediate is proposed regardless of whether the tetrabridged framework of Rh2(OAc)4 is preserved or not. PMID- 28345349 TI - A Self-Assembled Ratiometric Polymeric Nanoprobe for Highly Selective Fluorescence Detection of Hydrogen Peroxide. AB - In this study, a dual-emission fluorescence resonance energy transfer (FRET) polymeric nanoprobe by single-wavelength excitation was developed for sensitive and selective hydrogen peroxide (H2O2) detection. Polymeric nanoprobe was prepared by simple self-assembly of functional lipopolymers, which were 4-carboxy 3-fluorophenylboronic acid (FPBA)-modified DSPE-PEG (DSPE-PEG-FPBA) and 7 hydroxycoumarin (HC)-conjugated DSPE-PEG (DSPE-PEG-HC). Subsequent binding of alizarin red S (ARS) to FPBA endowed the nanoprobe with a new fluorescence emission peak at around 600 nm. Because of the perfect match of the fluorescence emission spectra of HC with the absorbance spectra of ARS-FPBA, FRET was achieved between them. The sensing strategy for H2O2 was based on H2O2-induced deboronation reaction and boronic acid-mediated ARS fluorescence. Interaction between phenylboronic acid and ARS was revisited herein and it was found that electron-donating or -withdrawing group on phenylboronic acid (PBA) has significant influence on the fluorescence property of ARS, which enabled sensitive and selective H2O2 sensing. The nanoprobe displayed two well-separated emission bands (150 nm), providing high specificity and sensitivity for ratiometric detection of H2O2. Further application was exploited for the determination of glucose and the results demonstrated that the proposed strategy showed ratiometric response capability for glucose detection. The current method does not involve complicated organic synthesis and opens a new avenue for the construction of multifunctional polymeric fluorescent nanoprobe. PMID- 28345350 TI - Boron-Enhanced Growth of Micron-Scale Carbon-Based Nanowalls: A Route toward High Rates of Electrochemical Biosensing. AB - In this study, we have demonstrated the fabrication of novel materials called boron-doped carbon nanowalls (B:CNWs), which are characterized by remarkable electrochemical properties such as high standard rate constant (k degrees ), low peak-to-peak separation value (DeltaE) for the oxidation and reduction processes of the [Fe(CN)6]3-/4- redox system, and low surface resistivity. The B:CNW samples were deposited by the microwave plasma-assisted chemical vapor deposition (CVD) using a gas mixture of H2/CH4/B2H6 and N2. Growth results in sharp-edged, flat, and long CNWs rich in sp2 as well as sp3 hybridized phases. The achieved high values of k degrees (1.1 * 10-2 cm s-1) and DeltaE (85 mV) are much lower compared to those of the glassy carbon or undoped CNWs. The enhanced electrochemical performance of the B:CNW electrode facilitates the simultaneous detection of DNA purine bases: adenine and guanine. Both separated oxidation peaks for the independent determination of guanine and adenine were observed by means of cyclic voltammetry or differential pulse voltammetry. It is worth noting that the determined sensitivities and the current densities were about 1 order of magnitude higher than those registered by other electrodes. PMID- 28345351 TI - Shape Memory Characteristics of O157-Antigenic Cavities Generated on Nanocomposites Consisting of Copolymer-Encapsulated Gold Nanoparticles. AB - Nanometer-sized composite particles, which consisted of gold nanoparticles encapsulated by an N-isopropylacrylamide copolymer, were successfully synthesized using a one-step process. Shape complementary cavities of the O157-antigen were formed on the composite utilizing temperature-dependent affinity changes of the copolymer. The composite bound to enterohemorrhagic Escherichia coli (E. coli) O157 at 298 K and enhanced light-scattering intensity of the cell due to the optical properties of the gold nanoparticles. Moreover, the composite showed excellent selectivity (>15) against other types of E. coli such as O26 and O Rough. Recognition of the O157-antigen ceased upon heating to 313 K but was restored upon cooling to 298 K. During repeated temperature cycling around the phase transition temperature of the copolymer (305 K), the composite reproducibly showed recognition behavior at 298 K. The binding ability of the composite could be switched reversibly. Therefore, it was concluded that the molecular structure of the O157-antigen was memorized by the composite, rather than being molded into it. This technique is applicable not only for the detection of a target bacterium but also for an identification of new bacterial threats by the simple formation of the specific antigen-imprinted composite. PMID- 28345352 TI - Metal-Free Photoinduced Electron Transfer-Atom Transfer Radical Polymerization Integrated with Bioinspired Polydopamine Chemistry as a Green Strategy for Surface Engineering of Magnetic Nanoparticles. AB - Developing green and efficient technologies for surface modification of magnetic nanoparticles (MNPs) is of crucial importance for their biomedical and environmental applications. This study reports, for the first time, a novel strategy by integrating metal-free photoinduced electron transfer-atom transfer radical polymerization (PET-ATRP) with the bioinspired polydopamine (PDA) chemistry for controlled architecture of functional polymer brushes from MNPs. Conformal PDA encapsulation layers were initially generated on the surfaces of MNPs, which served as the protective shells while providing an ideal platform for tethering 2-bromo-2-phenylacetic acid (BPA), a highly efficient initiator. Metal free PET-ATRP technique was then employed for controlled architecture of poly(glycidyl methacrylate) (PGMA) brushes from the core-shell MNPs by using diverse organic dyes as photoredox catalysts. Impacts of light sources (including UV and visible lights), photoredox catalysts, and polymerization time on the composition and morphology of the PGMA brushes were investigated. Moreover, the versatility of the PGMA-functionalized core-shell MNPs was demonstrated by covalent attachment of ethylenediamine (EDA), a model functional molecule, which afforded the MNPs with improved hydrophilicity, dispersibility, and superior binding ability to uranyl ions. The green methodology by integrating metal-free PET-ATRP with facile PDA chemistry would provide better opportunities for surface modification of MNPs and miscellaneous nanomaterials for biomedical and electronic applications. PMID- 28345353 TI - A combined approach to decrease the technological and sensory defects caused by fat and sodium reduction in Bologna-type sausages. AB - The effect of the addition of fructooligosaccharides, transglutaminase, disodium inosinate, and disodium guanylate on some technological and sensory parameters of low-fat and low-salt Bologna-type sausages was evaluated. In the first experiment, sausages with a 25% and 50% fat reduction containing 0, 3%, or 6% fructooligosaccharides were manufactured. Fat reduction adversely affected the emulsion stability, hardness, and sensory properties; however, the addition of 6% fructooligosaccharides reduced the loss of quality associated with a lower fat content. In the second experiment, sausages with a 50% fat reduction containing 6% fructooligosaccharides were produced. Additionally, the salt content was reduced by 50% and transglutaminase, disodium inosinate, and disodium guanylate were added. The combination of transglutaminase (1%), disodium inosinate (0.03%), and disodium guanylate (0.03%) was efficient to supress the technological and sensory defects caused by NaCl reduction in low-fat Bologna-type sausages. PMID- 28345354 TI - Optimization of mold wheat bread fortified with soy flour, pea flour and whey protein concentrate. AB - The objective of this work was to study the effect of replacing a selected wheat flour for defatted soy flour, pea flour and whey protein concentrate on both dough rheological characteristics and the performance and nutritional quality of bread. A mixture design was used to analyze the combination of the ingredients. The optimization process suggested that a mixture containing 88.8% of wheat flour, 8.2% of defatted soy flour, 0.0% of pea flour and 3.0% of whey protein concentrate could be a good combination to achieve the best fortified-bread nutritional quality. The fortified bread resulted in high protein concentration, with an increase in dietary fiber content and higher calcium levels compared with those of control (wheat flour 100%). Regarding protein quality, available lysine content was significantly higher, thus contributing with the essential amino acid requirement. PMID- 28345355 TI - Coronary spasm secondary to cefuroxime injection, complicated with cardiogenic shock - a manifestation of Kounis syndrome: case report and literature review. AB - Kounis syndrome is defined as the coincidental occurrence of an acute coronary syndrome with hypersensitivity reactions following an allergic event. The three reported variants of Kounis syndrome are vasospastic allergic angina, allergic myocardial infarction and stent thrombosis with occluding thrombus. The syndrome is caused by various inflammatory mediators. The pathophysiological characteristics of Kounis syndrome involve coronary artery spasm and/or atheromatous plaque erosion or rupture during an allergic reaction. Several causes have been described to induce Kounis syndrome, and their number is increasing rapidly. The haemodynamic effect of the syndrome complicated by cardiogenic shock seems to combine allergic shock with extensive peripheral vasodilation and myocardial suppression with the characteristics of cardiogenic shock. Treatment of Kounis syndrome is challenging because it needs management of both cardiac and allergic manifestation simultaneously. We present a case report of type I Kounis syndrome, with coronary spasm secondary to cefuroxime injection complicated with cardiogenic shock. A brief review of the literature on the various facets of this condition is also provided. PMID- 28345356 TI - Dysregulation of Tissue Factor, Thrombin-Activatable Fibrinolysis Inhibitor, and Fibrinogen in Patients Undergoing Total Joint Arthroplasty. AB - Total joint arthroplasty (TJA) of the hip or knee (THA, TKA) has become an increasingly common procedure. While TJA is a successful treatment for individuals experiencing degenerative joint diseases, it is well known that one of the most common perioperative complications of TJA is deep venous thrombosis (DVT). To profile tissue factor (TF), microparticle-tissue factor (MP-TF), thrombin-activatable fibrinolysis inhibitor (TAFI), and fibrinogen levels in patients undergoing TJA to determine potential preexisting Hemostatic dysregulation. De-identified blood samples were obtained from patients undergoing TJA 1 day pre- and 1 day postprocedure. Plasma samples were analyzed using enzyme linked immunosorbent assay kits for fibrinogen, TAFI, TF, and MP-TF; fibrinogen levels were also assessed using a clot-based activity assay. In comparison with healthy controls, there were significant increases of fibrinogen and MP-TF levels, while there were significant decreases in TF and TAFI levels in the preoperative and postoperative patients. Comparing the pre versus postoperative patients, no significant differences were found; interestingly, however, surgical intervention exacerbated the changes found in the preoperative samples compared to the controls. The results of this study confirm that patients undergoing TJA have preexisting alterations in the fibrinolytic system. Surgical intervention tended to exacerbate these changes. The alterations observed in this study may provide insight as to why TJA is associated with higher rates of DVT and thromboembolism. PMID- 28345357 TI - New bisesquiterpenoid lactone from the wild rhizome of Atractylodes macrocephala Koidz grown in Qimen. AB - The rhizomes of Atractylodes macrocephala are used as both a food source and traditional Chinese medicine in China. A phytochemical investigation was carried out on wild A. macrocephala grown in Qimen County in eastern China, and yielded a novel bisesquiterpenoid lactone, namely, biatractylenolide II (1), along with two known compounds, atractylenolide II (2) and taraxeryl acetate (3). The structure and relative configuration of the new compound were elucidated mainly by 1D and 2D NMR spectroscopic methods in combination with HRESIMS experiments. This paper describes the isolation and structural elucidation of the new bisesquiterpenoid lactone (1). PMID- 28345358 TI - 'Instead of popping pills, perhaps you should add frog breathing': experiences of glossopharyngeal insufflation/breathing for people with cervical spinal cord injury. AB - BACKGROUND: People with cervical spinal cord injury have impaired function of the respiratory muscles, which results in reduced ventilation. Glossopharyngeal insufflation/breathing increases total lung capacity and improves cough function, however, knowledge of the experiences regarding learning and practicing glossopharyngeal insufflation in everyday life is missing. PURPOSE: To describe and explore the experiences of learning and practicing glossopharyngeal insufflation among people with cervical spinal cord injury. METHODS: Twenty six individuals with cervical spinal cord injury, who had participated in a previous intervention study on glossopharyngeal insufflation, were interviewed. Semi structured telephone interviews were analyzed with qualitative content analysis. RESULTS: An overall theme and seven categories emerged. Glossopharyngeal insufflation was perceived as a possibility to make a difference in one's life by improving respiratory function, both immediately and for time ahead and thereby ease everyday activities, and by increasing participation, independence, and overall health. The participants with cervical spinal cord injury described that they could learn glossopharyngeal insufflation, but it could be perceived as difficult. However, the use of glossopharyngeal insufflation could be experienced by the individual as being different, and there were sometimes doubts about its effectiveness. CONCLUSIONS: Use of glossopharyngeal insufflation can enable people with cervical spinal cord injury to increasingly participate in everyday activities. Increased autonomy might lead to improved self-esteem and provide well-being. However, ambivalence about the usefulness of glossopharyngeal insufflation may arise and the technique can be difficult to learn. Therefore, individualized information and instructions from health professionals are required. Implications for Rehabilitation Practicing glossopharyngeal insufflation leads to increased participation in everyday activities for people with cervical spinal cord injuries and provides the individual hope to influence future life situation. People with cervical spinal cord injuries therefore need support from health care professionals in order to be motivated to learn and then use the glossopharyngeal insufflation technique also as health promotion Glossopharyngeal insufflation can improve respiratory function and also increase awareness of breathing; health professionals should therefore be able to assess which patients who can benefit from glossopharyngeal insufflation in order to make the technique become an important part of the rehabilitation. The technique can be difficult to perform perfectly and is sometimes perceived as uncomfortable. It may also cause unpleasant side effects and therefore individualized information and instructions regarding glossopharyngeal insufflation are required. PMID- 28345359 TI - A new equation based on the 6-min walking test to predict VO2peak in women with obesity. AB - OBJECTIVE: The 6-min walking test (6 MWT) is commonly used to assess obese patients' aerobic fitness, but it has rarely been compared with a direct measurement of maximal aerobic capacities (VO2max or VO2peak) in obese adults. The aim of this study was to investigate the relationship between the distance covered during a 6 MWT with objectively measured VO2peak and to propose a new equation to predict VO2peak from this walking test in obese patients. METHODS: One hundred and thirty-seven obese patients (45.6 +/- 12.5 years) admitted to our hospital for a multidisciplinary rehabilitation program were enrolled. After assessment of their body composition, the participants were asked to perform a 6 MWT and their maximal aerobic capacities (VO2peak) were measured. RESULT: There is a significant linear relation between VO2peak and the distance covered during the 6 MWT (p < 0.001; r = 0.349). The determinant of VO2peak was body mass index, waist-to-hip ratio, fat free mass, leading to the follow prediction equation VO2peak such as VO2peak (l/min) = (body mass index *0.0150065) - (waist-to-hip ratio * 0.8595088) + (fat-free-mass * 0.0295478) + (6-min walk test *0.0020672) - 0.5853372. CONCLUSION: The 6-min walk test is a reliable method to reflect obese women's aerobic capacities and the distance covered can be used to accurately estimate VO2peak according to our newly proposed equation. Implication for rehabilitation Obesity is a worldwide disease and physical capacity evaluation is a key point for rehabilitation. The six minutes' walk test is commonly used in obese people to assess aerobic fitness. This study proposes a new equation using 6 MWT performance to estimate VO2peak. PMID- 28345360 TI - The effects of multimodal rehabilitation on pain-related sickness absence - an observational study. AB - PURPOSE: The aim of the current study was to examine the effects on sickness absence of multimodal rehabilitation delivered within the framework of a national implementation of evidence based rehabilitation, the rehabilitation guarantee for nonspecific musculoskeletal pain. METHOD: This was an observational matched controlled study of all persons receiving multimodal rehabilitation from the last quarter of 2009 until the end of 2010. The matching was based on age, sex, sickness absence the quarter before intervention start and pain-related diagnosis. The participants were followed by register data for 6 or 12 months. The matched controls received rehabilitation in accordance with treatment-as usual. RESULTS: Of the participants, 54% (N = 3636) were on registered sickness absence at baseline and the quarter before rehabilitation. The average difference in number of days of sickness absence between the participants who received multimodal rehabilitation and the matched controls was to the advantage of the matched controls, 14.7 days (CI 11.7; 17.7, p <= 0.001) at 6-month follow-up and 9.5 days (CI 6.7; 12.3, p <= 0.001) at 12-month follow-up. A significant difference in newly granted disability pensions was found in favor of the intervention. CONCLUSIONS: When implemented nationwide, multimodal rehabilitation appears not to reduce sickness absence compared to treatment-as-usual. Implications for Rehabilitation A nationwide implementation of multimodal rehabilitation was not effective in reducing sickness absence compared to treatment-as-usual for persons with nonspecific musculoskeletal pain. Multimodal rehabilitation was effective in reducing the risk of future disability pension for persons with nonspecific musculoskeletal pain compared to treatment-as-usual. To be effective in reducing sick leave multimodal rehabilitation must be started within 60 days of sick leave. The evidence for positive effect of multimodal rehabilitation is mainly for sick listed patients. Prevention of sick leave for persons not being on sick leave should not be extrapolated from evidence for multimodal rehabilitation. PMID- 28345361 TI - Implant of permanent pacemaker during acute coronary syndrome: Mortality and associated factors in the ARIAM registry. AB - BACKGROUND: Patients with acute coronary syndrome complicated with high degree atrioventricular block still have a high mortality. A low percentage of these patients need a permanent pacemaker (PPM) but mortality and associated factors with the PPM implant in acute coronary syndrome patients are not known. We assess whether PPM implant is an independent variable in the mortality of acute coronary syndrome patients. Also, we explored the variables that remain independently associated with PPM implantation. METHODS: This was an observational study on the Spanish ARIAM register. The inclusion period was from January 2001 to December 2011. This registry included all Andalusian acute coronary syndrome patients. Follow-up for global mortality was until November 2013. RESULTS: We selected 27,608 cases. In 62 patients a PPM was implanted (0.024%). The mean age in PPM patients was 70.71+/-11.214 years versus 64.46+/-12.985 years in patients with no PPM. PPM implant was associated independently with age (odds ratio (OR) 1.031, 95% confidence interval (CI) 1.007-1.055), with left ventricular branch block (OR 6.622, 95% CI 2.439-18.181), with any arrhythmia at intensive care unit admission (OR 2.754, 95% CI 1.506-5.025) and with heart failure (OR 3.344, 95% CI 1.78 8.333). PPM implant was independently associated with mortality (OR 11.436, 95% CI 1.576-83.009). In propensity score analysis PPM implant was still associated with mortality (OR 5.79, 95% CI 3.27-25.63). CONCLUSION: PPM implant is associated with mortality in the acute coronary syndrome population in the ARIAM registry. Advanced age, heart failure, arrhythmias and left ventricular branch block at intensive care unit admission were found associated factors with PPM implant in acute coronary syndrome patient. PMID- 28345362 TI - Mindfulness-Based Movement: A Polyvagal Perspective. AB - Compelling evidence suggests that physical activity is an effective intervention for cancer survivors, including for those undergoing active cancer treatments. However, to date most evidence has emerged from interventions that have promoted moderate to vigorous physical activity. In this conceptual review, we argue that attention should be given to the entire continuum of physical activity from reducing sedentary behavior to increasing higher levels of physical activity when possible. In addition, considerable evidence in the cancer literature supports the value of mindfulness-based interventions as a means of helping patients and survivors cope with the variety of threats that accompany this disease. Based on the success of these two areas of research, we argue for conceptualizing and promoting physical activity as Mindfulness-Based Movement, using Polyvagal Theory as a theoretical framework to understand the role and value of Mindfulness-Based Movement as a potential intervention for cancer care and control. PMID- 28345363 TI - Does Foot Position and Location of Measurement Influence Ankle Medial Clear Space? AB - PURPOSE: There is still controversy regarding normal and abnormal values of the medial clear space (MCS) of the ankle. The aim of this study was to assess how much different degrees of plantar flexion, with and without stress, influenced the MCS. METHODS: We submitted 30 volunteers to 6 different anteroposterior ankle radiographs in the following positions: neutral, neutral with external rotation stress, physiologic plantar flexion (FPF), physiologic plantar flexion with external rotation stress, maximum plantar flexion (MPF), and maximum plantar flexion with external rotation stress. The MCS oblique (MCSo) and perpendicular (MCSp) were measured in all images by an experienced foot and ankle surgeon. RESULTS: The data showed that the position of the foot does influence the value of MCSp and MCSo ( P < .05), except for 3 comparisons. MCSo did not change between FPF with stress and MPF with stress. MCSp did not change in 2 situations: between FPF and neutral with stress and between MPF and FPF with stress. CONCLUSIONS: This study is unique in showing that different ways of positioning the foot and performing stress radiographs results in different MCS values and that these values differ depending on the anatomical site where they are measured. LEVELS OF EVIDENCE: Diagnostic, Level IV. PMID- 28345364 TI - Anatomically Contoured Anterior Plating for Isolated Tibiotalar Arthrodesis: A Systematic Review. AB - INTRODUCTION: We performed a systematic review of the published literature to characterize patient demographic, surgical techniques, and functional outcomes to elucidate the complication and revision rates following isolated tibiotalar arthrodesis with anatomically contoured anterior plating. METHODS: A comprehensive literature search was performed. Inclusion criteria were peer reviewed studies in English, after 1990, at least 10 patients, and reporting clinical outcomes following contoured anterior plating and with follow-up of at least 80% and 1 year. Primary outcomes were fusion rate, time to fusion, return to activities, satisfaction, and functional outcome scores. Complication rates, reoperation, and revision were also extracted. RESULTS: Eight primary studies with 164 patients met the inclusion criteria. The average sample size was 21 +/- 10.0 patients and average age was 49.2 years with 61.6% male. Posttraumatic arthritis (49.4%) was the most common operative indication, followed by primary osteoarthrosis (18.9%). The average follow-up was 21.1 months. At this time, 97.6% of patients went on to uneventful union at a weighted average time of 18.7 weeks postoperatively. AOFAS scores improved significantly ( P < .05). 25% complication rate was reported with wound complication (7.9%) and hardware irritation (6.7%) most common. Overall, 21.3% of patients underwent reoperation; 4 for revision arthrodesis following nonunion. CONCLUSION: Isolated tibiotalar arthrodesis utilizing anatomically contoured anterior plating demonstrates excellent clinical and functional outcomes at short-term follow-up. Overall, 97.6% of patients went on to fusion and functional outcomes consistently improved following surgery. Furthermore, while one-quarter of patients experienced complications, wound complications were relatively uncommon and less than one quarter of these required surgical intervention. LEVELS OF EVIDENCE: Level IV: Systematic Review. PMID- 28345365 TI - Atrioventricular nodal ablation in patients with resynchronization therapy and atrial fibrillation - long term results. AB - OBJECTIVES: Atrioventricular nodal ablation (AVNA) is recommended for patients (pts) with cardiac resynchronization therapy (CRT) having atrial fibrillation (AF) and incomplete ventricular capture (Class IIa, level B). AVNA reduces mortality and improves the New York Heart Association (NYHA) functional class during intermediate term follow-up. The objectives were to study the long-term outcome regarding quality of life (QoL) and survival of our CRT pts after AVNA. DESIGN: 37 CRT-pts undergoing AVNA due to inadequate biventricular pacing were included in the study. Data were retrospectively obtained from clinical records and through telephone interviews. RESULTS: Twenty pts died during the follow-up period of average 30.6 +/- 24 months. After AVNA the ventricular capture improved significantly from 68.4 +/- 23% to 98.5 +/- 2% (p < 0.001). A significant and sustained improvement of average 0.3 +/- 0.5 (p = 0.001) in NYHA functional class was found. Additionally a large percentage of pts discontinued taking rate reducing drugs with potential severe side effects. CONCLUSION: AVNA in CRT pts was safe and effective. The treatment resulted in a sustained improvement in QoL, including long-term improvement in NYHA functional class. PMID- 28345366 TI - Reply to commentary on: History of erectile dysfunction as a predictor of poor physical performance after an acute myocardial infarction. PMID- 28345367 TI - The problem with non-adherence arising from medical practices. PMID- 28345368 TI - Sponsors' and investigative staffs' perceptions of the current investigational new drug safety reporting process in oncology trials. AB - BACKGROUND/AIMS: The Food and Drug Administration's final rule on investigational new drug application safety reporting, effective from 28 March 2011, clarified the reporting requirements for serious and unexpected suspected adverse reactions occurring in clinical trials. The Clinical Trials Transformation Initiative released recommendations in 2013 to assist implementation of the final rule; however, anecdotal reports and data from a Food and Drug Administration audit indicated that a majority of reports being submitted were still uninformative and did not result in actionable changes. Clinical Trials Transformation Initiative investigated remaining barriers and potential solutions to full implementation of the final rule by polling and interviewing investigators, clinical research staff, and sponsors. METHODS: In an opinion-gathering effort, two discrete online surveys designed to assess challenges and motivations related to management of expedited (7- to 15-day) investigational new drug safety reporting processes in oncology trials were developed and distributed to two populations: investigators/clinical research staff and sponsors. Data were collected for approximately 1 year. Twenty-hour-long interviews were also conducted with Clinical Trials Transformation Initiative-nominated interview participants who were considered as having extensive knowledge of and experience with the topic. Interviewees included 13 principal investigators/study managers/research team members and 7 directors/vice presidents of pharmacovigilance operations from 5 large global pharmaceutical companies. RESULTS: The investigative site's responses indicate that too many individual reports are still being submitted, which are time-consuming to process and provide little value for patient safety assessments or for informing actionable changes. Fewer but higher quality reports would be more useful, and the investigator and staff would benefit from sponsors'"filtering" of reports and increased sponsor communication. Sponsors replied that their greatest challenges include (1) lack of global harmonization in reporting rules, (2) determining causality, and (3) fear of regulatory repercussions. Interaction with the Food and Drug Administration has helped improve sponsors' adherence to the final rule, and sponsors would benefit from increased communication with the Food and Drug Administration and educational materials. CONCLUSION: The goal of the final rule is to minimize uninformative safety reports so that important safety signals can be captured and communicated early enough in a clinical program to make changes that help ensure patient safety. Investigative staff and sponsors acknowledge that the rule has not been fully implemented although they agree with the intention. Clinical Trials Transformation Initiative will use the results from the surveys and interviews to develop new recommendations and educational materials that will be available to sponsors to increase compliance with the final rule and facilitate discussion between sponsors, investigators, and Food and Drug Administration representatives. PMID- 28345369 TI - Pulmonary fibrosis, part II: state-of-the-art patient management. AB - INTRODUCTION: While many pharmacologic therapies for the treatment of idiopathic pulmonary fibrosis (IPF) have been evaluated via randomized, placebo-controlled clinical trials (RCTs) conducted over the past two decades, most therapies have been shown to be ineffective or even potentially harmful. However, a number of recently completed RCTs have shown significant efficacy for pirfenidone and nintedanib for the treatment of IPF. Areas covered: This manuscript reviews recent advances in the management of IPF and other forms of fibrosing interstitial lung disease (ILD) with an emphasis on IPF. The material upon which this discussion is based was obtained from various published texts and manuscripts identified via literature searching (e.g. PubMed). Expert commentary: Anti-fibrotic drugs are now available for clinical use and perceived as standard of-care therapies that have the potential to blunt disease progression for many patients with IPF. However, these agents do not necessarily stop disease progression or have a significant impact on mortality, and more effective pharmacologic therapies are needed for patients with IPF. Additionally, whether anti-fibrotic agents can be effective therapies for other forms of pulmonary fibrosis, which often have radiologic and histopathologic manifestations that mimic IPF, is being evaluated in a number of RCTs. PMID- 28345370 TI - An accurate and fast alignment-free method for profiling microbial communities. AB - Determining abundances of microbial genomes in metagenomic samples is an important problem in analyzing metagenomic data. Although homology-based methods are popular, they have shown to be computationally expensive due to the alignment of tens of millions of reads from metagenomic samples to reference genomes of hundreds to thousands of environmental microbial species. We introduce an efficient alignment-free approach to estimate abundances of microbial genomes in metagenomic samples. The approach is based on solving linear and quadratic programs, which are represented by genome-specific markers (GSM). We compared our method against popular alignment-free and homology-based methods. Without contamination, our method was more accurate than other alignment-free methods while being much faster than a homology-based method. In more realistic settings where samples were contaminated with human DNA, our method was the most accurate method in predicting abundance at varying levels of contamination. We achieve higher accuracy than both alignment-free and homology-based methods. PMID- 28345371 TI - EWMA Document: Negative Pressure Wound Therapy. AB - 1. Introduction Since its introduction in clinical practice in the early 1990's negative pressure wounds therapy (NPWT) has become widely used in the management of complex wounds in both inpatient and outpatient care.1 NPWT has been described as a effective treatment for wounds of many different aetiologies2,3 and suggested as a gold standard for treatment of wounds such as open abdominal wounds,4-6 dehisced sternal wounds following cardiac surgery7,8 and as a valuable agent in complex non-healing wounds.9,10 Increasingly, NPWT is being applied in the primary and home-care setting, where it is described as having the potential to improve the efficacy of wound management and help reduce the reliance on hospital-based care.11 While the potential of NPWT is promising and the clinical use of the treatment is widespread, highlevel evidence of its effectiveness and economic benefits remain sparse.12-14 The ongoing controversy regarding high level evidence in wound care in general is well known. There is a consensus that clinical practice should be evidence-based, which can be difficult to achieve due to confusion about the value of the various approaches to wound management; however, we have to rely on the best available evidence. The need to review wound strategies and treatments in order to reduce the burden of care in an efficient way is urgent. If patients at risk of delayed wound healing are identified earlier and aggressive interventions are taken before the wound deteriorates and complications occur, both patient morbidity and health-care costs can be significantly reduced. There is further a fundamental confusion over the best way to evaluate the effectiveness of interventions in this complex patient population. This is illustrated by reviews of the value of various treatment strategies for non-healing wounds, which have highlighted methodological inconsistencies in primary research. This situation is confounded by differences in the advice given by regulatory and reimbursement bodies in various countries regarding both study design and the ways in which results are interpreted. In response to this confusion, the European Wound Management Association (EWMA) has been publishing a number of interdisciplinary documents15-19 with the intention of highlighting: The nature and extent of the problem for wound management: from the clinical perspective as well as that of care givers and the patients Evidence based practice as an integration of clinical expertise with the best available clinical evidence from systematic research The nature and extent of the problem for wound management: from the policy maker and healthcare system perspectives The controversy regarding the value of various approaches to wound management and care is illustrated by the case of NPWT, synonymous with topical negative pressure or vacuum therapy and cited as branded VAC (vacuum-assisted closure) therapy. This is a mode of therapy used to encourage wound healing. It is used as a primary treatment of chronic wounds, in complex acute wounds and as an adjunct for temporary closure and wound bed preparation preceding surgical procedures such as skin grafts and flap surgery. Aim An increasing number of papers on the effect of NPWT are being published. However, due to the low evidence level the treatment remains controversial from the policy maker and health-care system's points of view-particularly with regard to evidence-based medicine. In response EWMA has established an interdisciplinary working group to describe the present knowledge with regard to NPWT and provide overview of its implications for organisation of care, documentation, communication, patient safety, and health economic aspects. These goals will be achieved by the following: Present the rational and scientific support for each delivered statement Uncover controversies and issues related to the use of NPWT in wound management Implications of implementing NPWT as a treatment strategy in the health-care system Provide information and offer perspectives of NPWT from the viewpoints of health-care staff, policy makers, politicians, industry, patients and hospital administrators who are indirectly or directly involved in wound management. PMID- 28345372 TI - Screening of Intestinal Crypt Organoids: A Simple Readout for Complex Biology. AB - Oral and intestinal mucositis is a debilitating side effect of radiation treatment. A mouse model of radiation-induced mucositis leads to weight loss and tissue damage, reflecting the human ailment as it responds to keratinocyte growth factor (KGF), the standard-of-care treatment. Cultured intestinal crypt organoids allowed the development of an assay monitoring the effect of treatments of intestinal epithelium to radiation-induced damage. This in vitro assay resembles the mouse model as KGF and roof plate-specific spondin-1 (RSPO1) enhanced crypt organoid recovery following radiation. Screening identified compounds that increased the survival of organoids postradiation. Testing of these compounds revealed that the organoids changed their responses over time. Unbiased transcriptome analysis was performed on crypt organoid cultures at various time points in culture to investigate this adaptive behavior. A number of genes and pathways were found to be modulated over time, providing a rationale for the altered sensitivity of the organoid cultures. This report describes an in vitro assay that reflects aspects of human disease. The assay was used to identify bioactive compounds, which served as probes to interrogate the biology of crypt organoids over prolonged culture. The pathways that are changing over time may offer potential targets for treatment of mucositis. PMID- 28345374 TI - Psychoticism in patients with panic disorder with or without comorbid agoraphobia. AB - OBJECTIVE: A few case-reports have previously described transient psychotic-like symptoms in non-psychotic patients with panic disorder (PD). We aimed to systematically explore whether PD patients without any current or past psychosis can be differentiated according to the severity of 'psychoticism' as a dimension, comprising clinical features such as psychotic-like experiences, increased social alienation, hostility and suspiciousness. METHODS: Sample included 35 (female = 26) medication-free, non-psychotic patients consecutively referred from our Department's Outpatient Clinic for acute symptoms of DSM-5 PD with (PDA; N = 29) or without concurrent agoraphobia. Psychometric measures included the Symptom Checklist-90-Revised (SCL-90-R), Agoraphobic Cognitions Questionnaire (ACQ), Body Sensations Questionnaire (BSQ), and panic attacks during last 21 days PA-21d. RESULTS: Multiple regression analysis (forward stepwise) revealed that, among all SCL-90-R subscales, the psychoticism-subscale was most significantly associated with panic-related beliefs included in the ACQ, while significant associations emerged between the paranoid ideation-subscale and the ACQ and BSQ measures. Moreover, significant correlations emerged between the SCL-90-R psychoticism subscale and all three measures of PD symptoms (ACQ, BSQ, PA-21d) and between the SCL-90-R paranoid ideation-subscale and both the ACQ and BSQ. CONCLUSIONS: This significant association between levels of psychoticism and severity of panic symptoms may reflect a more severe subtype of PD. PMID- 28345373 TI - Infarct topography and functional outcomes. AB - Acute ischemic stroke represents a major cause of long-term adult disability. Accurate prognostication of post-stroke functional outcomes is invaluable in guiding patient care, targeting early rehabilitation efforts, selecting patients for clinical research, and conveying realistic expectations to families. The involvement of specific brain regions by acute ischemia can alter post-stroke recovery potential. Understanding the influences of infarct topography on neurologic outcomes holds significant promise in prognosis of functional recovery. In this review, we discuss the recent evidence of the contribution of infarct location to patient management decisions and functional outcomes after acute ischemic stroke. PMID- 28345376 TI - Lessons from Metabonomics on the Neurobiology of Stroke. AB - The application of metabonomic science to interrogate stroke permits the study of metabolite entities, small enough to cross the blood-brain barrier, that provide insight into neuronal dysfunction, and may serve as reservoirs of biomarker discovery. This systematic review examines the applicability of metabolic profiling in ischemic stroke research. Six human studies utilizing metabolic profiling to analyze biofluids from ischemic stroke patients have been included, employing 1H-NMR and/or mass spectrometry to analyze plasma, serum, and/or urine in a targeted or untargeted fashion. Three are diagnostic studies, and one investigates prognostic biomarkers of stroke recurrence following transient ischemic attack. Two studies focus on metabolic distinguishers of depression or cognitive impairment following stroke. Identified biomarkers from blood and urine predominantly relate to homocysteine and folate, branched chain amino acid, and lipid metabolism. Statistical models are well fitted and reproducible, with excellent validation outcomes, demonstrating the feasibility of metabolic profiling to study a complex disorder with multicausal pathology, such as stroke. PMID- 28345375 TI - The chemo-prophylactic efficacy of an ethanol Moringa oleifera leaf extract against hepatocellular carcinoma in rats. AB - CONTEXT: Hepatocellular carcinoma (HCC) is among the most well-known threatening tumours around the world, and the outlook remains bleak. Moringa oleifera Lam. (Moringaceae) exhibits antitumor, antioxidant and hepatoprotective properties. OBJECTIVES: To assess the chemo-prophylactic proficiency and other likely activities of Moringa oleifera leaf ethanol extract (MOLEE) against diethyl nitrosamine (DEN)-induced HCC. MATERIALS AND METHODS: Wistar rats were gastrogavaged with MOLEE (500 mg/kg) for one week and then gastrogavaged with MOLEE and DEN (10 mg/kg) for the following 16 weeks. The progressions of the histological components, serum biomarkers and oxidation of DNA of the liver tissues were resolved to assess the prophylactic impacts. The lipid oxidative biomarker, the cancer prevention agent status and apoptotic proteins were surveyed to assess the potential mechanisms. RESULTS: The MOLEE LD50 was estimated to be 5585 mg/kg. MOLEE (500 mg/kg) administration fundamentally repressed the expansion event of knobs and the normal knob number per knob bearing livers prompted by DEN, enhanced hepatocellular appearance and altogether significantly decreased (p < 0.05) DEN-induced elevations in serum biochemical records and hepatic 8-hydroxy-2-deoxyguanosine (8-OHdG) levels by 29%. The robotic studies found that MOLEE disrupted the DEN-activated oxidative reactivity damage in rats by 46.8%. Curiously, the expression of Bcl-2, Bcl-xl and beta arrestin-2 were fundamentally diminished (p < 0.05); however, the expression of Bax and caspase-3 were essentially (p < 0.05) upregulated. DISCUSSION AND CONCLUSIONS: The outcomes presume that MOLEE inspired critical defensive impacts against DEN-induced hepatocarcinogenesis that might be identified with the implementation of antioxidant activity and actuation of apoptosis. PMID- 28345377 TI - Green microparticles based on a chitosan/lactobionic acid/linoleic acid association. Characterisation and evaluation as a new carrier system for cosmetics. AB - The association chitosan/linoleic acid/lactobionic acid in aqueous solution spontaneously led to the formation of stable microparticles with a liquid hydrophobic core consisting of linoleic acid surrounded by a shell of chitosan/lactobionic acid. The originality of the microparticles arises from the fact that they are formed by the association of three ingredients of cosmetic interest, including a skin penetration enhancer (linoleic acid). Dynamic light scattering (DLS) measurements showed microparticles with a mean diameter of 1-2 MUm. The presence of a hydrophobic liquid core was observed by transmission electron microscopy (TEM). The ability of these microparticles to encapsulate phenylethyl resorcinol, a hydrophobic skin lightener, was evaluated and its encapsulation was confirmed thanks to T2 measurements and nuclear Overhauser effects (nOe) signs. PMID- 28345378 TI - Probing the behavior of bovine serum albumin upon binding to atenolol: insights from spectroscopic and molecular docking approaches. AB - Molecular interaction of atenolol, a selective beta1 receptor antagonist with the major carrier protein, bovine serum albumin (BSA), was investigated under imitated physiological conditions (pH 7.4) by means of fluorescence spectroscopy, UV absorption spectroscopy, Fourier transform infrared spectroscopy (FT-IR), and molecular modeling studies. The steady-state fluorescence spectra manifested that static type, due to formation of the atenolol-BSA complex, was the dominant mechanism for fluorescence quenching. The characteristic information about the binding interaction of atenolol with BSA in terms of binding constant (Kb) were determined by the UV-vis absorption titration, and were found to be in the order of 103 M-1 at different temperatures, indicating the existence of a weak binding in this system. Thermodynamic analysis revealed that the binding process was primarily mediated by van der Waals force and hydrogen bonds due to the negative sign for enthalpy change (DeltaH0), entropy change (DeltaS0). The molecular docking results elucidated that atenolol preferred binding on the site II of BSA according to the findings observed in competitive binding experiments. Moreover, via alterations in synchronous fluorescence, three-dimensional fluorescence and FT-IR spectral properties, it was concluded that atenolol could arouse slight configurational and micro-environmental changes of BSA. PMID- 28345379 TI - The role of gammadelta T cells in pancreatic cancer: what could this mean for the clinic? PMID- 28345380 TI - Comparative Study of Ultraviolet Laser-Based Time-Resolved Photoacoustic Fingerprint Spectra and Thermal Decomposition Mechanisms of Energetic 1,2,3-1H Triazole Derivatives Under Controlled Pyrolysis. AB - We report the comparative study of photoacoustic (PA) fingerprint spectra, thermal decomposition, and stability mechanism of some phenyl and bis series energetic compounds named 1-(2-methoxy,-3,5-dinitrophenyl)-1H-1,2,3-triazole ( S5), 1-(3-methoxy, 2, 6 dinitrophenyl) 1H-1, 2, 3 triazole ( S10), 1-(4 nitrophenyl)-1H-1,2,3-triazole ( S8), and 2,6-bis ((4-(nitromethyl)-1H-1,2,3 triazol-1-yl)methyl) pyridine ( S9). Fourth harmonic wavelength, i.e., 266 nm of pulse duration 7 ns and 10 Hz repetition rate obtained from Q-switched Nd: YAG laser, was used to record the thermal PA spectra of these compounds under controlled pyrolysis condition in the range of 30-350 C. The PA fingerprint spectra are produced due to entire molecule vapor along with principal functional byproduct NO2 molecule. NO2 molecule is a major gas released during thermal decomposition due to weakest nature of C-NO2 bond. Further, NO2 molecules are involved in photodissociation process due to pi*<- n transition and converted into NO molecules inside the PA cell due to excitation by 266 nm wavelength. The combined results of PA and gas chromatography-mass spectrometry (GC-MS) spectra along with thermo gravimetric-differential thermal analysis (TG-DTA) data confirm the thermal decomposition mechanism process that can be completed in multiple steps. In addition, GC-MS spectra also confirm the release of NO and NO2 molecules. The effect of incident laser energy and data acquisition time has been carried out for understanding the behavior of acoustic modes. Finally, the thermal quality factor "Q" is measured to test the stability of compounds. PMID- 28345381 TI - Comparison of Fenton process and adsorption method for treatment of industrial container and drum cleaning industry wastewater. AB - The present study aims to explore the characterization of industrial container and drum cleaning (ICDC) industry wastewater and treatment alternatives of this wastewater using Fenton and adsorption processes. Wastewater derived from ICDC industry is usually treated by chemical coagulation and biological treatment in Turkey and then discharged in a centralized wastewater treatment facility. It is required that the wastewater COD is below 1500 mg/L to treat in a centralized wastewater treatment facility. The wastewater samples were characterized for parameters of pH, conductivity, COD, BOD5, TSS, NH3-N, TN, TOC, TP, Cd, Cr, Cu, Fe, Ni, Pb, Zn, and Hg. Initial COD values were in the range of 11,300-14,200 mg/L. The optimum conditions for Fenton treatment were 35-40 g/L for H2O2, 2-5 g/L for Fe2+, and 13-36 for H2O2/Fe2+ molar ratio. The optimum conditions of PAC doses and contact times in adsorption studies were 20-30 g/L and 5-12 h, respectively. Removal efficiencies of characterized parameters for the three samples were compared for both Fenton and adsorption processes under optimum conditions. The results suggest that these wastewaters are suitable for discharge to a centralized wastewater treatment plant. PMID- 28345382 TI - Identification of a novel nonsense mutation of the neurotrophic tyrosine kinase receptor type 1 gene in two siblings with congenital insensitivity to pain with anhidrosis. AB - Objective To explore the aetiology of congenital insensitivity to pain with anhidrosis (CIPA) in two Chinese siblings with typical CIPA symptoms including insensitivity to pain, inability to sweat, and self-mutilating behaviours. Methods Clinical examination and genetic testing were conducted of all available family members, and the findings were used to create a pedigree. Mutation screening using PCR amplification and DNA Sanger sequencing of the entire neurotrophic tyrosine kinase receptor type 1 gene ( NTRK1) including intron-exon boundaries was used to identify mutations associated with CIPA. Results A novel nonsense mutation (c.7C > T, p. Arg3Ter) and a known splice-site mutation (c.851 33 T > A) were detected in NTRK1 and shown to be associated with CIPA. Conclusion Our findings expand the known mutation spectrum of NTRK1 and provide insights into the aetiology of CIPA. PMID- 28345383 TI - Pulmonary fibrosis, part I: epidemiology, pathogenesis, and diagnosis. AB - INTRODUCTION: Many forms of interstitial lung disease (ILD) can progress to extensive fibrosis and respiratory failure. Idiopathic pulmonary fibrosis (IPF), which generally has a poor prognosis, has been thoroughly studied over the past two decades, and many important discoveries have been made that pertain to genetic predisposition, epidemiology, disease pathogenesis, diagnosis, and management. Additionally, non-IPF forms of ILD can have radiologic and histopathologic manifestations that mimic IPF, and making an accurate diagnosis is key to providing personalized medicine to patients with pulmonary fibrosis. Areas covered: This manuscript discusses current knowledge pertaining to the genetics, epidemiology, pathogenesis, and diagnosis of pulmonary fibrosis with an emphasis on IPF. The material upon which this discussion is based was obtained from various published texts and manuscripts identified via literature searching (e.g. PubMed). Expert commentary: Many genetic variants have been identified that are associated with risk of developing pulmonary fibrosis, and an improved understanding of the influence of both genomic and epigenomic factors in the development of pulmonary fibrosis is rapidly evolving. Because many forms of fibrosing ILD can have similar radiologic and histopathologic patterns yet have different responses to therapeutic interventions, making an accurate diagnosis of specific forms of pulmonary fibrosis is increasingly important. PMID- 28345384 TI - Parental evaluation of a telemonitoring service for children with Type 1 Diabetes. AB - Introduction In the past years, we developed a telemonitoring service for young patients affected by Type 1 Diabetes. The service provides data to the clinical staff and offers an important tool to the parents, that are able to oversee in real time their children. The aim of this work was to analyze the parents' perceived usefulness of the service. Methods The service was tested by the parents of 31 children enrolled in a seven-day clinical trial during a summer camp. To study the parents' perception we proposed and analyzed two questionnaires. A baseline questionnaire focused on the daily management and implications of their children's diabetes, while a post-study one measured the perceived benefits of telemonitoring. Questionnaires also included free text comment spaces. Results Analysis of the baseline questionnaires underlined the parents' suffering and fatigue: 51% of total responses showed a negative tendency and the mean value of the perceived quality of life was 64.13 in a 0-100 scale. In the post-study questionnaires about half of the parents believed in a possible improvement adopting telemonitoring. Moreover, the foreseen improvement in quality of life was significant, increasing from 64.13 to 78.39 ( p-value = 0.0001). The analysis of free text comments highlighted an improvement in mood, and parents' commitment was also proved by their willingness to pay for the service (median = 200 euro/year). Discussion A high number of parents appreciated the telemonitoring service and were confident that it could improve communication with physicians as well as the family's own peace of mind. PMID- 28345386 TI - Artifact Correction in Temperature-Dependent Attenuated Total Reflection Infrared (ATR-IR) Spectra. AB - A spectral processing method was developed and tested for analyzing temperature dependent attenuated total reflection infrared (ATR-IR) spectra of aliphatic polyesters. Spectra of a bio-based, biodegradable polymer, 3.9 mol% 3HHx poly[(R) 3-hydroxybutyrate- co-(R)-3-hydroxyhexanoate] (PHBHx), were analyzed and corrected prior to analysis using two-dimensional correlation spectroscopy (2D COS). Removal of the temperature variation of diamond absorbance, correction of the baseline, ATR correction, and appropriate normalization were key to generating more reliable data. Both the processing steps and order were important. A comparison to differential scanning calorimetry (DSC) analysis indicated that the normalization method should be chosen with caution to avoid unintentional trends and distortions of the crystalline sensitive bands. PMID- 28345385 TI - Activation of 5-HT1A receptors in the rat dorsomedial hypothalamus inhibits stress-induced activation of the hypothalamic-pituitary-adrenal axis. AB - Acute activation of the hypothalamic-pituitary-adrenal (HPA) axis, leading to the release of corticosteroid hormones into the circulation, is an adaptive response to perceived threats. Persistent activation of the HPA axis can lead to impaired physiological or behavioral function with maladaptive consequences. Thus, efficient control and termination of stress responses is essential for well being. However, inhibitory control mechanisms governing the HPA axis are poorly understood. Previous studies suggest that serotonergic systems, acting within the medial hypothalamus, play an important role in inhibitory control of stress induced HPA axis activity. To test this hypothesis, we surgically implanted chronic jugular cannulae in adult male rats and conducted bilateral microinjection of vehicle or the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n propylamino) tetralin hydrobromide (8-OH-DPAT; 8 nmol, 0.2 MUL, 0.1 MUL/min, per side) into the dorsomedial hypothalamus (DMH) immediately prior to a 40 min period of restraint stress. Repeated blood sampling was conducted using an automated blood sampling system and plasma corticosterone concentrations were determined using enzyme-linked immunosorbent assay. Bilateral intra-DMH microinjections of 8-OH-DPAT suppressed stress-induced increases in plasma corticosterone within 10 min of the onset of handling prior to restraint and, as measured by area-under-the-curve analysis of plasma corticosterone concentrations, during the 40 min period of restraint. These data support an inhibitory role for serotonergic systems, acting within the DMH, on stress induced activation of the HPA axis. Lay summary: Inhibitory control of the hypothalamic-pituitary-adrenal (HPA) stress hormone response is important for well-being. One neurochemical implicated in inhibitory control of the HPA axis is serotonin. In this study we show that activation of serotonin receptors, specifically inhibitory 5-HT1A receptors in the dorsomedial hypothalamus, is sufficient to inhibit stress-induced HPA axis activity in rats. PMID- 28345387 TI - Multimodal treatment in children and adolescents with attention deficit/hyperactivity disorder: a 6-month follow-up. AB - BACKGROUND: Different treatment approaches aimed at reducing attention deficit/hyperactivity disorder (ADHD) core symptoms are available. However, factors such as intolerance, side-effects, lack of efficacy, high new technology costs, and placebo effect have spurred on an increasing interest in alternative or complementary treatment. AIM: The aim of this study is to explore efficacy of multimodal treatment consisting of standard stimulant medication (methylphenidate) and neurofeedback (NF) in combination, and to compare it with the single treatment in 6-month follow-up in ADHD children and adolescents. METHODS: This randomized controlled trial with 6-month follow-up comprised three treatment arms: multimodal treatment (NF + MED), MED alone, and NF alone. A total of 130 ADHD children/adolescents participated, and 62% completed the study. ADHD core symptoms were recorded pre-/post-treatment, using parents' and teachers' forms taken from Barkley's Defiant Children: A Clinician's Manual for Assessment and Parent Training, and a self-report questionnaire. RESULTS: Significant ADHD core symptom improvements were reported 6 months after treatment completion by parents, teachers, and participants in all three groups, with marked improvement in inattention in all groups. However, no significant improvements in hyperactivity or academic performance were reported by teachers or self-reported by children/adolescents, respectively, in the three groups. Changes obtained with multimodal treatment at 6-month follow-up were comparable to those with single medication treatment, as reported by all participants. CONCLUSIONS: Multimodal treatment using combined stimulant medication and NF showed 6-month efficacy in ADHD treatment. More research is needed to explore whether multimodal treatment is suitable for ADHD children and adolescents who showed a poor response to single medication treatment, and for those who want to reduce the use of stimulant medication. PMID- 28345388 TI - Cortisol levels in fingernails, neurocognitive performance and clinical variables in euthymic bipolar I disorder. AB - OBJECTIVES: Neurocognitive impairment has been found in bipolar patients. Hypercortisolemia is one possible cause but there has been no agreement on this. Previous sampling methods assessed only acute cortisol levels, whereas the association between cortisol and psychopathology might be better understood by investigating chronic levels. Fingernails are a novel method for measuring chronic cortisol concentration (CCC). Here, we measured CCC in euthymic bipolar disorder I (BD-I) patients and healthy controls using fingernails to investigate whether differences in CCC influenced neurocognitive performance. We also investigated whether differences in clinical illness variables influenced CCC in euthymic BD-I patients. METHODS: A previous study demonstrated neurocognitive impairment in euthymic BD-I patients. The current study included a portion of this sample: 40 BD-I versus 42 matched controls who provided fingernail samples. RESULTS: There was no statistically significant difference in CCC between controls and BD-I (P = .09). Logistic regression analyses revealed that euthymic bipolar I subjects with more than five years of current euthymia had decreased odds of having higher fingernail cortisol concentration (>71.2 pg/mg) compared to those with less than 1.5 years (P = .04). There was no association between CCC and cognitive impairment in all domains before and after adjustment for age and sex. CONCLUSIONS: The current evidence suggests CCC is not a trait biomarker in euthymic BD-I (BD-I). Longer periods of stability in affective disorders are associated with lower CCC. Fingernail cortisol does not seem to be implicated in neurocognitive impairment and BD-I. Future studies may investigate CCC in different illness phases of BD-I. PMID- 28345389 TI - Ethnic status and engagement with health services: Attitudes toward help-seeking and intercultural willingness to interact among South East Asian students in Australia. AB - Previous research has demonstrated the importance of intercultural willingness to interact; however, these investigations have yet to be applied to a health context or to compare an ethnic minority with a majority sample. Consequently, the current study sought to better understand engagement with health services by investigating both attitudes towards seeking psychological help and intercultural willingness to interact within an ethnic minority South East Asian population, relative to an Anglo Australian sample. As predicted, negative attitudes towards seeking psychological help were higher in the South East Asian sample, with this relationship persisting across generations, despite significant differences in acculturation. In contrast, intercultural willingness to interact was not associated with ethnicity status but was associated with higher anxiety, uncertainty, ethnocentrism and help-seeking, consistent with current empirical and theoretical literature. The current study also sought to examine factors associated with help-seeking attitudes and found that ethnocentrism was a significant predictor, when accounting for previous health experience. PMID- 28345390 TI - Nitrogen removal and nitrous oxide emission from a step-feeding multiple anoxic and aerobic process. AB - The multiple anoxic and aerobic (AO) process is an advanced biological nitrogen removal process, and nitrous oxide (N2O) emission might affect its sustainable application. Nitrogen removal and N2O emission in a step-feeding multiple AO sequencing batch reactor (SBRS) was examined, in comparison with a one-feeding sequencing batch reactor (SBRO). Nitrogen removal was enhanced by 12.6% in SBRS compared to the removal percentage of 75.8% in SBRO. Activated sludge in SBRs possessed a higher N2O emission factor during nitrification, denitrification and simultaneous nitrification and denitrification (SND) than in SBRO. A high N2O emission factor was observed during SND in both reactors, with the emission factor of 4.38% in SBRS and 4.66% in SBRO. More N2O emission occurred in the presence of nitrite. Bacteroidetes and Proteobacteria dominated in both SBRS and SBRO. A similar abundance of Thauera, Dechloromonas and Zoogloea possible for denitrification was observed in SBRS and SBRO. Moreover, nosZ from Proteobacteria dominated in both SBRS and SBRO, with dominating genus of Acidovorax, Ralstonia, Thauera and Marinobacter. PMID- 28345391 TI - A retrospective study on rapid plasma reagin testing in patients with Pityriasis rosea. AB - Pityriasis rosea (PR) is an acute self-limited exanthem characterized by oval erythematous patches with scale and may be difficult to differentiate from secondary syphilis. A rapid plasma reagin (RPR) test can be used to rule in secondary syphilis with high sensitivity and specificity. A retrospective study was performed on patients at Weill Cornell Medicine, who were diagnosed with PR from 2000 to 2016 and also received RPR testing at the time of diagnosis. The objective was to assess the frequency of secondary syphilis when the initial clinical impression was PR. Only 2/142 patients (1.4%) had a reactive RPR test. Based on our results, we advocate that careful social and sexual histories be taken in all patients presenting with atypical PR and syphilis screening performed if risk factors are present. PMID- 28345392 TI - Informed consent for opt-in HIV testing via tablet kiosk: an assessment of patient comprehension and acceptability. AB - Although implementation of HIV testing in the emergency department has met with some success, one commonly cited challenge is the consent process. Kiosks offer one potential strategy to overcome this barrier. This pilot cross-sectional survey study examined patient comprehension of opt-in HIV testing consent and acceptability of using a kiosk to provide consent. Subjects were guided through a simulated consent process using a kiosk and then completed a survey of consent comprehension and acceptability of kiosk use. Subjects were 50.3% female, Black (74.4%), and had an education level of high school or less (61.3%). Subjects found the kiosk very easy or easy to use (83.9%) and reported they were very or mostly comfortable using the kiosk to consent to HIV testing (89.4%). Subjects understood the required aspects of consent: HIV testing was voluntary (93.0%, n = 185) and that refusal would not impact their care (98.5%, n = 196; 99.0%, n = 197). Following a simulated consent process, subjects demonstrated a high rate of comprehension about the vital components of HIV testing consent. Subjects reported they were comfortable using the kiosk, found the kiosk easy to use, and reported a positive experience using the kiosk to provide consent for HIV testing. PMID- 28345394 TI - Association of Novel Inflammatory and Oxidative Stress Biomarkers With In-Stent Restenosis. PMID- 28345393 TI - Inhibitory effects of 3alpha-hydroxy-lup-20(29)-en-23, 28-dioic acid on lipopolysaccharide-induced TNF-alpha, IL-1beta, and the high mobility group box 1 release in macrophages. AB - We investigated the anti-inflammatory effects of 3alpha-hydroxy-lup-20(29)-en-23, 28-dioic acid (HLEDA)-a lupane-type triterpene isolated from leaves of Acanthopanax gracilistylus W. W.Smith (AGS), as well as the underlying molecular mechanisms in lipopolysaccharide (LPS)-induced RAW264.7 cells. Our results demonstrated that HLEDA concentration-dependently reduced the production of nitric oxide (NO), significantly suppressed LPS-induced expression of TNF-alpha and IL-1beta at the mRNA and protein levels in RAW264.7 cells. Further analysis revealed that HLEDA could reduce the secretion of High Mobility Group Box 1 (HMGB1). Additionally, the results showed that HLEDA efficiently decreased nuclear factor-kappaB (NF-kappaB) activation by inhibiting the degradation and phosphorylation of IkappaBalpha. These results suggest that HLEDA exerts anti inflammatory properties in LPS-induced macrophages, possibly through inhibition of the NF-kappaB signaling pathway, which mediates the expression of pro inflammatory cytokines. These results warrant further studies that would concern candidate therapy for diseases, such as fulminant hepatitis and rheumatology of triterpenoids in AGS. PMID- 28345395 TI - Evaluation of the Predictive Value of CHA2DS2-VASc Score for In-Stent Restenosis. AB - The CHA2DS2-VASc (congestive heart failure, hypertension, age >=75 years, diabetes mellitus, previous stroke, vascular disease, age 65-74 years, female gender) score is used to estimate thromboembolic risk in atrial fibrillation (AF). Its usefulness in predicting in-stent restenosis (ISR) is unknown. We evaluated the predictive value of the CHA2DS2-VASc score in AF-free patients who have undergone stent implantation. A total of 1350 patients who underwent coronary angiography and successful bare-metal stent implantation were analyzed. The CHA2DS2-VASc score was calculated before percutaneous coronary intervention, and the association between the score and ISR was investigated. Patients (n = 700; mean age: 61.4 [8.7] years, 63% men) were divided in 2 subgroups according to the presence of ISR; 265 of 700 patients had ISR. Mean CHA2DS2-VASc score was significantly higher in the ISR (+) group than the ISR (-) group (3.7 [1.8] vs 2.1 [1.4], P < .001). According to multivariate logistic regression analysis, diabetes, hyperlipidemia, smoking, stent length, and CHA2DS2-VASc score were independent predictors of ISR. In conclusion, the CHA2DS2-VASc score may be useful as a new and simple tool to predict ISR. PMID- 28345396 TI - Re: "Prognostic Factors in Diabetic Foot Ulcer". PMID- 28345397 TI - Hepatitis B virus prevalence in rural areas in south-west Chad. AB - In Chad, hepatitis B virus (HBV) is thought to have a high prevalence and is consequently responsible for numerous acute and long-term complications. It is often detected during screening in potential blood donors. However, no general population-based study on the prevalence of hepatitis B has been performed. The aim of this study was to gain an impression of the HBV prevalence in rural areas in south-west Chad. A total of 1309 individuals (745 boys/men, 564 girls/women) with a median age of 15 years (age range, 6-81 years) were screened for the presence of the hepatitis B antigen (HBsAG). We found an overall prevalence of 22.9%. The youngest age group (6-15 years) and the boys/men showed a significantly higher HBsAG prevalence compared to the older groups and the girls/women, respectively ( P < 0.01). Vertical infection during birth and horizontal infection by sharing food, water and shelter are believed to be the main sources of infection. PMID- 28345398 TI - Challenges in the surgical management of ectopic pregnancy in a low-resource setting: Mpilo Central Hospital, Bulawayo, Zimbabwe. AB - Background Ectopic pregnancy contributes to maternal morbidity and mortality, especially in low-resourced countries with limited facilities for early diagnosis and treatment. It is a very challenging condition to diagnose. Patients may collapse and die while undergoing investigation. Aims To assess surgical treatment given to patients presenting at Mpilo Central Hospital, the challenges that are faced and the outcomes; and also to document how women survive this dangerous condition in a setting challenged by low resources. Results All the patients had prompt life-saving surgery within 48 h of admission despite the challenges faced. The survival rate was 100% during the period of the study. Conclusion It is possible to prevent maternal mortality in low-resource countries by maintaining basic clinical and surgical skills. PMID- 28345399 TI - Spontaneous resolution of a hepatogastric fistula. PMID- 28345401 TI - The Prosody of Topic Transition in Interaction: Pitch Register Variations. AB - In conversation, speakers can mobilize a variety of prosodic cues to signal a switch in topics. This paper uses a mixed-methods approach combining Conversation Analysis and Instrumental Prosody to investigate the prosody of topic transition in American English, and analyzes the ways in which speakers can play on register level and on register span. A cluster of three prosodic parameters was found to be predictive of transitions: a higher maximum fundamental frequency (F0), a higher median F0 (key), and an expanded register span. Relative to speakers' habitual profiles, the mobilization of such prosodic cues corresponds to a marked upgraded prosodic design. This finding is consistent with the general assumption that continuation constitutes the norm in conversation, and that departing from it, as in the case of a topic transition, requires a marked action and marked linguistic design. The disjunctive action of opening a new topic corresponds to the use of a marked prosodic cue. PMID- 28345400 TI - Combination of aerobic exercise and an arginine, alanine, and phenylalanine mixture increases fat mobilization and ketone body synthesis. AB - During exercise, blood levels of several hormones increase acutely. We hypothesized that consumption of a specific combination of amino acids (arginine, alanine, and phenylalanine; A-mix) may be involved in secretion of glucagon, and when combined with exercise may promote fat catabolism. Ten healthy male volunteers were randomized in a crossover study to ingest either A-mix (3 g/dose) or placebo (3 g of dextrin/dose). Thirty minutes after ingesting, each condition subsequently performed workload trials on a cycle ergometer at 50% of maximal oxygen consumption for 1 h. After oral intake of A-mix, the concentrations of plasma ketone bodies and adrenalin during and post-exercise were significantly increased. The area under the curve for glycerol and glucagon was significantly increased in the post-exercise by A-mix administration. These results suggest that pre-exercise ingestion of A-mix causes a shift of energy source from carbohydrate to fat combustion by increasing secretion of adrenalin and glucagon. PMID- 28345402 TI - Clinical and functional correlates of processing speed in pediatric Attention Deficit/Hyperactivity Disorder: a systematic review and meta-analysis. AB - It is well established that processing speed is negatively impacted in children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). Unfortunately, exactly how processing speed vulnerabilities manifest in daily functioning has not been well established. To support clinical care of youth with ADHD, it is important to better understand the functional consequences and relevant outcomes associated with processing speed deficits. This systematic review and meta-analysis sought to identify the association between processing speed and clinical or functional correlates among children or adolescents diagnosed with ADHD. A total of 409 abstracts were screened, of which, 60 full text articles were identified as potentially relevant, and 8 of these studies met inclusion criteria. Domains evaluated across these studies included reading skills, mathematics skills, written expression, anxiety, self-appraisals of competence, and adaptive functioning. Six studies reported an association between processing speed and reading skills, allowing for meta-analysis. Processing speed difficulties among youth with ADHD appear strongly associated with several clinical and functional correlates including weaker academic skills, poorer adaptive skills, increased self-reported anxiety, and overestimates of social competence. Meta-analytic results for studies reporting the association between processing speed and reading skills indicate a medium overall weighted mean effect size (r = 0.33, 95% CI = 0.28 -0.39) with minimal heterogeneity (I2 = 0.17). Clinical implications of these findings, limitations in the current knowledge base, and suggestions for future research are discussed. PMID- 28345403 TI - Intralesional Osteophyte Regrowth Following Autologous Chondrocyte Implantation after Previous Treatment with Marrow Stimulation Technique. AB - Objective Bone marrow stimulation surgeries are frequent in the treatment of cartilage lesions. Autologous chondrocyte implantation (ACI) may be performed after failed microfracture surgery. Alterations to subchondral bone as intralesional osteophytes are commonly seen after previous microfracture and removed during ACI. There have been no reports on potential recurrence. Our purpose was to evaluate the incidence of intralesional osteophyte development in 2 cohorts: existing intralesional osteophytes and without intralesional osteophytes at the time of ACI. Study Design We identified 87 patients (157 lesions) with intralesional osteophytes among a cohort of 497 ACI patients. Osteophyte regrowth was analyzed on magnetic resonance imaging and categorized as small or large (less or more than 50% of the cartilage thickness). Twenty patients (24 defects) without intralesional osteophytes at the time of ACI acted as control. Results Osteophyte regrowth was observed in 39.5% of lesions (34.4% of small osteophytes and 5.1% of large osteophytes). In subgroup analyses, regrowth was observed in 45.8% of periosteal-covered defects and in 18.9% of collagen membrane-covered defects. Large osteophyte regrowth occurred in less than 5% in either group. Periosteal defects showed a significantly higher incidence for regrowth of small osteophytes. In the control group, intralesional osteophytes developed in 16.7% of the lesions. Conclusions Even though intralesional osteophytes may regrow after removal during ACI, most of them are small. Small osteophyte regrowth occurs almost twice in periosteum-covered ACI. Large osteophytes occur only in 5% of patients. Intralesional osteophyte formation is not significantly different in preexisting intralesional osteophytes and control groups. PMID- 28345404 TI - Are Bone Bruise Characteristics and Articular Cartilage Pathology Associated with Inferior Outcomes 2 and 6 Years After Anterior Cruciate Ligament Reconstruction? AB - Objective To determine (1) if bone bruise characteristics seen on magnetic resonance imaging are associated with patient-reported outcomes prior to and following anterior cruciate ligament reconstruction and (2) if the combined presence of bone bruises with articular cartilage pathology results in inferior 2 or 6-year outcomes. Design Bone bruise volume and severity were measured on 81 patients' preoperative magnetic resonance imaging in the medial and lateral femoral condyle (MFC, LFC) and medial and lateral tibial plateau (MTP, LTP) using the Costa-Paz classification and a modified version of Roemer and Bohndorf's technique. The relationships between bone bruise volume and severity with Knee Injury and Osteoarthritis Outcome Score (KOOS) and International Knee Documentation Committee (IKDC) scores were assessed, and pre- and postoperative KOOS and IKDC scores were compared between those with bone bruises either with or without combined local articular cartilage pathology. Results All 81 patients had a bone bruise in at least 1 region and 70 (86%) had bone bruises in >=2 regions. LTP bruises were the most common (76/81, 94%), followed by the LFC (66, 81%), MTP (46, 57%), and MFC (20, 25%). Neither bone bruise volume nor severity was associated with inferior postoperative outcomes. The subset of 17 patients with bone bruises and combined articular cartilage pathology were 3.4 times more likely to be symptomatic at 6-year follow-up than those without articular cartilage pathology ( P = 0.04). Conclusions The volume and severity of preoperative bone bruises alone were not associated with 2- or 6-year outcomes; however, bone bruises combined with local articular cartilage pathology appear to be more symptomatic after ACL reconstruction. PMID- 28345405 TI - Thickness Distribution of Glenohumeral Joint Cartilage. AB - High-resolution 3-dimensional cartilage-specific magnetic resonance imaging (MRI) was performed at 3 T to test the following hypotheses: (1) there is a nonuniform cartilage thickness distribution both on the proximal humerus and on the glenoid surface and (2) the glenohumeral joint as a combined system is congruent with the level of the joint cartilage surface without substantial radial mismatch. Inclusion of 38 volunteers (19 females, mean age 24.34 +/- 2.22 years; range 21 29 years) in a prospective study. Measurements of: cartilage thickness in 3 regions and 3 zones; radius of both circles (glenoid and humeral cartilage) for congruency calculation using 3-T MRI with 3-dimensional dual-echo steady-state sequence with water excitation. A homogenous mean cartilage thickness (1.2-1.5 mm) and slightly higher values for the glenoidal articulating surface radii both in the mid-paracoronar section (2.4 vs. 2.1 cm, P < 0.001) and in the mid paraaxial section (2.4 vs. 2.1 cm, P < 0.001) compared with the humeral side were observed. The concept of a radial mismatch between the humeral head and the glenoid in healthy human subjects can be confirmed. This study provides normative data for the comparison of joint cartilage changes at the shoulder for future studies. PMID- 28345406 TI - Evaluation of the Quality, Accuracy, and Readability of Online Patient Resources for the Management of Articular Cartilage Defects. AB - Objective Patients commonly use the Internet to obtain their health-related information. The purpose of this study was to investigate the quality, accuracy, and readability of online patient resources for the management of articular cartilage defects. Design Three search terms ("cartilage defect," "cartilage damage," "cartilage injury") were entered into 3 Internet search engines (Google, Bing, Yahoo). The first 25 websites from each search were collected and reviewed. The quality and accuracy of online information were independently evaluated by 3 reviewers using predetermined scoring criteria. The readability was evaluated using the Flesch-Kincaid (FK) grade score. Results Fifty-three unique websites were evaluated. Quality ratings were significantly higher in websites with a FK score >11 compared to those with a score of <=11 ( P = 0.021). Only 10 websites (19%) differentiated between focal cartilage defects and diffuse osteoarthritis. Of these, 7 (70%) were elicited using the search term "cartilage defect" ( P = 0.038). The average accuracy of the websites was high (11.7 out of maximum 12), and the average FK grade level (13.4) was several grades higher than the recommended level for readable patient education material (eighth grade level). Conclusions The quality and readability of online patient resources for articular cartilage defects favor those with a higher level of education. Additionally, the majority of these websites do not distinguish between focal chondral defects and diffuse osteoarthritis, which can fail to provide appropriate patient education and guidance for available treatment. Clinicians should help guide patients toward high-quality, accurate, and readable online patient education material. PMID- 28345407 TI - Knee Menisci. AB - The menisci of the knees are semicircular fibrocartilaginous structures consisting of a hydrophilic extracellular matrix containing a network of collagen fibers, glycoproteins, and proteoglycans maintained by a cellular component. The menisci are responsible for more than 50% of load transmission across the knee and increase joint congruity thereby also aiding in fluid film lubrication of the joint. In the United Kingdom, meniscal tears are the most common form of intra articular knee injury and one of the commonest indications for orthopedic intervention. The management of these injuries is dependent on the location within the meniscus (relative to peripheral blood supply) and the pattern of tear. Removal of meniscus is known to place the knee at increased risk of osteoarthritis; therefore repair of meniscal tears is preferable. However, a significant proportion of tears are irreparable and can only be treated by partial or even complete meniscectomy. More recent studies have shown encouraging results with meniscal replacement in this situation, though further work is required in this area. PMID- 28345408 TI - Autologous Chondrocyte Implantation to Isolated Patella Cartilage Defects. AB - Background Autologous chondrocyte implantation (ACI) is a durable treatment for patients with chondral defects. This study presents the comprehensive evaluation of patients with patella defects treated with ACI at medium- to long-term follow up. Methods Thirty consecutive patients with isolated chondral lesions of the patella were enrolled prospectively. Primary outcome measures were validated patient reported outcome measures and objective magnetic resonance imaging. Results Nineteen of 30 patients underwent tibial tubercle osteotomy (TTO) to correct lateral maltracking in combination with soft tissue balancing. The defect sizes were large, averaging 4.7 +/- 2.1 cm2 (range 2.2-30.0 cm2). Pidoriano/Fulkerson classification revealed that 3 defects were type II (lateral), 9 were type III (medial), and 18 were type IV (central/panpatella). Age at the time of surgery was 32 +/- 10 years. At follow-up of 2 to 14 years, knee function was rated good to excellent in 25 (83%) patients, fair in 4 (13%) patients, and poor in 1 (3%) patient. Three patients failed treatment after a mean of 75 months (6.25 years). All 3 failures were Workers Compensation (WC) cases. They were older than the non-WC patients, 42 +/- 6 years compared with the non-WC 28 +/- 9 years ( P = 0.0019). Significant increases in all clinical and health utility outcome scores were seen. Magnetic resonance imaging demonstrated that the fill grade, surface and integrity of the repair tissue correlated with clinical scores. Conclusion ACI to isolated patella defects results in significant functional improvement at a minimum of 24 months, with the results remaining durable at latest follow-up of 15 years. Level of evidence Level 4. PMID- 28345411 TI - CORRIGENDUM to Depth-Dependent Glycosaminoglycan Concentration in Articular Cartilage by Quantitative Contrast-Enhanced Micro-Computed Tomography. AB - Owing to the errors made by the authors, Mittelstaedt D and Xia Y, the following article contains error. Mittelstaedt D, Xia Y. Depth-Dependent Glycosaminoglycan Concentration in Articular Cartilage by Quantitative Contrast-Enhanced Micro Computed Tomography. Cartilage. 2015;6:216-25. Original doi: 10.1177/1947603515596418. PMID- 28345410 TI - Transplantation of Chemically Processed Decellularized Meniscal Allografts. AB - Objective The aim of this study was to evaluate the chondroprotective effect of chemically decellularized meniscal allografts transplanted into the knee joints of adult merino sheep. Methods Lateral sheep meniscal allografts were chemically processed by a multistep method to yield acellular, sterile grafts. The grafts were transplanted into the knee joints of sheep that were treated by lateral meniscectomy. Joints treated by meniscectomy only and untreated joints served as controls. The joints were analyzed morphologically 6 and 26 weeks after surgery by the macroscopical and histological OARSI (Osteoarthritis Research Society International) score. Additionally, the meniscal grafts were biomechanically tested by cyclic indentation. Results Lateral meniscectomy was associated with significant degenerative changes of the articular cartilage of the lateral joint compartment. Transplanted lateral meniscal allografts retained their integrity during the observation period without inducing significant synovitis or foreign body reactions. Cellular repopulation of the grafts was only present on the surface and the periphery of the lateral meniscus, but was still completely lacking in the center of the grafts at week 26. Transplantation of processed meniscal allografts could not prevent degenerative changes of the articular cartilage in the lateral joint compartment. Compared with healthy menisci, the processed grafts were characterized by a significantly reduced dynamic modulus, which did not improve during the observation period of 26 weeks in vivo. Conclusion Chemically decellularized meniscal allografts proved their biocompatibility and durability without inducing immunogenic reactions. However, insufficient recellularization and inferior stiffness of the grafts hampered chondroprotective effects on the articular cartilage. PMID- 28345409 TI - Osteoarthritis in Football. AB - Football is currently the most popular sporting activity in the world. Multiple reports have shown that a high incidence of osteoarthritis is found in football players. Evidence clearly shows that traumatic injury significantly predisposes players for such pathophysiology. Injuries are frequent in amateur as well as professional football players, with knee and ankle accounting for the most severe injuries. Many professional athletes lose playing time due to injuries and many are forced into early retirement. Posttraumatic osteoarthritis is a common finding among ex-football players with numbers well above the normal population. Today's surgical techniques are advanced and capable of restoring the joint to a certain extent. However, a restitution ad integrum is reached only in very rare cases. Professional football players that return to play after serious injuries perform their extremely strenuous activity on morphologically compromised joints. Incomplete rehabilitation and pressure to return to play after an injurious event clearly put the athlete at an even higher risk for joint degeneration. Prevention strategies, improved surgical management, strict rehabilitation, as well as future aspects such as early suppression of inflammation, personalized medicine, and predictive genomics DNA profiling are needed to reduce incidence and improve the health perspectives of football players. PMID- 28345412 TI - Effect of Glucosamine Sulfate on Osteoarthritis in the Cruciate-Deficient Canine Model of Osteoarthritis. AB - Objective Osteoarthritis (OA) is a major cause of musculoskeletal pain and disability worldwide. The investigation of disease-modifying treatment options for OA has become an important aspect of orthopedic care. To assess the effect of intra-articular and oral glucosamine sulfate (GS) versus placebo on osteoarthritis in a canine model. Materials In this randomized, placebo controlled, double-blinded study, OA was induced by anterior cruciate ligament transection (ACLT) according to the Pond-Nuki model in 32 canines. All canines were allocated into 4 treatment subgroups with treatment administered for 8 weeks: GS (400 mg) intra-articular, placebo intra-articular, GS (200 mg/kg body weight) oral, and placebo oral. The contralateral nonoperated stifle (knee) served as control. After 8 weeks, the medial and lateral femoral condyles, the medial and lateral tibial plateau and patella were histologically examined and anatomic changes quantified by light microscopy using the modified Mankin score. Results After 8 weeks, mean Mankin score values significantly ( P < 0.002) decreased in the intra-articular GS group (8.1; range 7.9-8.8) compared with the intra-articular placebo group (13.9; range 11.6-15.9) and again significantly ( P < 0.002) in the oral GS group (12.1; range 9.9-12.7) compared with the oral placebo group (15.1; range 12.5-17.0). Mean Mankin score values were significantly ( P < 0.002) lower in the intra-articular GS group compared with the oral GS group. Conclusion Both, intra-articular and oral administered GS significantly reduced histological signs of OA in the Pond-Nuki model, with the intra-articular application being more effective compared to oral administration. PMID- 28345413 TI - Development of a Tool to Predict Outcome of Autologous Chondrocyte Implantation. AB - Objective The study had 2 objectives: first, to evaluate the success of autologous chondrocyte implantation (ACI) in terms of incidence of surgical re intervention, including arthroplasty, and investigate predictors of successful treatment outcome. The second objective was to derive a tool predicting a patient's arthroplasty risk following ACI. Design In this Level II, prognostic study, 170 ACI-treated patients (110 males [aged 36.8 +/- 9.4 years]; 60 females [aged 38.1 +/- 10.2 years]) completed a questionnaire about further surgery on their knee treated with ACI 10.9 +/- 3.5 years previously. Factors commonly assessed preoperatively (age, gender, defect location and number, previous surgery at this site, and the preoperative Lysholm score) were used as independent factors in regression analyses. Results At final follow-up (maximum of 19 years post-ACI), 40 patients (23.5%) had undergone surgical re-intervention following ACI. Twenty-six patients (15.3%) underwent arthroplasty, more commonly females (25%) than males (10%; P = 0.001). Cox regression analyses identified 4 factors associated with re-intervention: age at ACI, multiple operations before ACI, patellar defects, and lower pretreatment Lysholm scores (Nagelkerke's R2 = 0.20). Six predictive items associated with risk of arthroplasty following ACI (Nagelkerke's R2 = 0.34) were used to develop the Oswestry Risk of Knee Arthroplasty index with internal cross-validation. Conclusion In a single-center study, we have identified 6 factors (age, gender, location and number of defects, number of previous operations, and Lysholm score before ACI) that appear to influence the likelihood of ACI patients progressing to arthroplasty. We have used this information to propose a formula or "tool" that could aid treatment decisions and improve patient selection for ACI. PMID- 28345414 TI - Fresh Osteochondral Allograft Transplantation for Fractures of the Knee. AB - Objective The purpose of this study was to evaluate functional outcomes and allograft survivorship among patients with knee fracture who underwent fresh osteochondral allograft (OCA) transplantation as a salvage treatment option. Design Retrospective analysis of prospectively collected data. Setting Department of Orthopaedic Surgery at one hospital. Patients Fresh OCAs were implanted for osteochondral lesions after knee fracture in 24 males and 15 females with an average age of 34 years. Twenty-nine lesions (74%) were tibial plateau fractures, 6 (15%) were femoral condyle fractures, and 4 (10%) were patella fractures. Main Outcome Measurements Clinical evaluation included modified Merle d'Aubigne-Postel (18-point), International Knee Documentation Committee, and Knee Society function scores, and patient satisfaction. Failure of OCA was defined as revision OCA or conversion to total knee arthroplasty (TKA). Results Nineteen of 39 knees (49%) had further surgery. Ten knees (26%) were considered OCA failures (3 OCA revisions, 6 TKA, and 1 patellectomy). Survivorship of the OCA was 82.6% at 5 years and 69.6% at 10 years. Among the 29 knees (74%) that had the OCA still in situ, median follow-up was 6.6 years. Pain and function improved from preoperative to latest follow-up; 83% of patients reported satisfaction with OCA results. Conclusion OCA transplantation is a useful salvage treatment option for osteochondral lesions caused by knee fracture. Although the reoperation rate was high, successful outcome was associated with significant clinical improvement. PMID- 28345415 TI - Chondrogenic Gene Expression Differences between Chondrocytes from Osteoarthritic and Non-OA Trauma Joints in a 3D Collagen Type I Hydrogel. AB - Objective The purpose of the current study was to compare the donor age variation of chondrocytes from non-OA (osteoarthritic) trauma joints in patients of young to middle age (20.5 +/- 3.7, 31.8 +/- 1.9, 41.9 +/- 4.1 years) embedded in matrix associated autologous chondrocyte transplantation (MACT) grafts (CaReS). The chondrocyte-specific gene expression of CaReS grafts were then compared to chondrocytes from OA joints (in patients aged 63.8 +/- 10 years) embedded in a collagen type I hydrogel. Design OA chondrocytes and articular chondrocyte-laden grafts were cultured over 14 days in chondrogenic growth medium. We performed reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) to evaluate the mRNA expression levels of chondrocyte-specific and hypertrophic markers. Results Gene expression analysis with RT-qPCR revealed no significant difference in chondrocyte-specific genes ( COL2A1, ACAN, SOX9, SOX5, SOX6) among 3 different age group of patients with CaReS grafts. In a comparative analysis of OA chondrocytes to articular chondrocytes, chondrogenic markers ( COL2A1, SOX6) exhibited higher expression in OA chondrocytes ( P < 0.05). Hypertrophic or OA cartilage pathogenesis marker ( MMP3, MMP13) expression was higher and COL1A1 had significantly lower expression ( P < 0.05) in OA chondrocytes than articular chondrocytes when cultivated in collagen type I hydrogels. Conclusion In summary, we identify that donor age variation does not influence the chondrogenic gene expression of the CaReS system. We also identified that freshly isolated OA chondrocytes embedded in collagen type I hydrogels can exhibit chondrogenic gene expression as observed in articular chondrocytes on the CaReS grafts. Transforming OA chondrocytes to articular chondrocytes can be regarded as an alternative option in the MACT technique. PMID- 28345416 TI - Short-step syntheses of naturally occurring polyoxygenated aromatics based on site-selective transformation. AB - Wogonin and astringin were synthesized from inexpensive chrysin and piceid in short steps. The key feature of these syntheses is site-selective transformation. The target molecules were obtained in 27 and 62% yields from the starting materials, respectively. PMID- 28345417 TI - The Effect of Mechanical Loading Upon Extracellular Matrix Bioscaffold-Mediated Skeletal Muscle Remodeling. AB - Mounting evidence suggests that site-appropriate loading of implanted extracellular matrix (ECM) bioscaffolds and the surrounding microenvironment is an important tissue remodeling determinant, although the role at the cellular level in ECM-mediated skeletal muscle remodeling remains unknown. This study evaluates crosstalk between progenitor cells and macrophages during mechanical loading in ECM-mediated skeletal muscle repair. Myoblasts were exposed to solubilized ECM bioscaffolds and were mechanically loaded at 10% strain, 1 Hz for 5 h. Conditioned media was collected and applied to bone marrow-derived macrophages followed by immunolabeling for proinflammatory M1-like markers and proremodeling M2-like markers. Macrophages were subjected to the same loading protocol and their secreted products were collected for myoblast migration, proliferation, and differentiation analysis. A mouse hind limb unloading volumetric muscle loss model was used to evaluate the effect of loading upon the skeletal muscle microenvironment after ECM implantation. Animals were sacrificed at 14 or 180 days. Isometric torque production was tested and tissue sections were immunolabeled for macrophage phenotype and muscle fiber content. Results show that loading augments the ability of myoblasts to promote an M2-like macrophage phenotype following exposure to ECM bioscaffolds. Mechanically loaded macrophages promote myoblast chemotaxis and differentiation. Lack of weight bearing impaired muscle remodeling as indicated by Masson's Trichrome stain. Isometric torque was significantly increased following ECM implantation when compared to controls, a response not present in the hind limb-unloaded group. This work provides an important mechanistic insight of the effects of rehabilitation upon ECM-mediated remodeling and could have broader implications in clinical practice, advocating multidisciplinary approaches to regenerative medicine, emphasizing rehabilitation. PMID- 28345418 TI - A Coaxial Dual-element Focused Ultrasound Probe for Guidance of Epidural Catheterization: An Experimental Study. AB - Ultrasound guidance for epidural block has improved clinical blind-trial problems but the design of present ultrasonic probes poses operating difficulty of ultrasound-guided catheterization, increasing the failure rate. The purpose of this study was to develop a novel ultrasonic probe to avoid needle contact with vertebral bone during epidural catheterization. The probe has a central circular passage for needle insertion. Two focused annular transducers are deployed around the passage for on-axis guidance. A 17-gauge insulated Tuohy needle containing the self-developed fiber-optic-modified stylet was inserted into the back of the anesthetized pig, in the lumbar region under the guidance of our ultrasonic probe. The inner transducer of the probe detected the shallow echo signals of the peak-peak amplitude of 2.8 V over L3 at the depth of 2.4 cm, and the amplitude was decreased to 0.8 V directly over the L3 to L4 interspace. The outer transducer could detect the echoes from the deeper bone at the depth of 4.5 cm, which did not appear for the inner transducer. The operator tilted the probe slightly in left-right and cranial-caudal directions until the echoes at the depth of 4.5 cm disappeared, and the epidural needle was inserted through the central passage of the probe. The needle was advanced and stopped when the epidural space was identified by optical technique. The needle passed without bone contact. Designs of the hollow probe for needle pass and dual transducers with different focal lengths for detection of shallow and deep vertebrae may benefit operation, bone/nonbone identification, and cost. PMID- 28345419 TI - Commentary on Perez et al.: How to create a 21st century adverse event reporting system. PMID- 28345420 TI - Peroneal perforator pedicle propeller flap for lower leg soft tissue defect reconstruction: Clinical applications and treatment of venous congestion. AB - Objective To describe the characteristics of the perforator vessel in the peroneal artery of the lower leg and to explore the use of perforator pedicle propeller flaps to repair soft tissue defects in the lower leg, heel and foot. Methods This retrospective study enrolled patients with soft tissue defects of the distal lower leg, heel and foot who underwent surgery using peroneal perforator-based propeller flaps. The peroneal artery perforators were identified preoperatively by colour duplex Doppler ultrasound. The flap was designed based on the preoperatively-identified perforator location, with the posterior border of the fibula employed as an axis, and the perforator vessel as the pivot point of rotation. Patients were followed-up to determine the outcomes. Results The study analysed 36 patients (mean age, 39.7 years). The majority of the soft tissue defects were on the heel (20; 55.6%). The donor-site of the flap was closed in 11 patients by direct suturing and skin grafting was undertaken in 25 patients. Postoperative complications included venous congestion (nine patients), which was managed with delayed wound coverage and bleeding therapy. All wounds were eventually cured and the flaps were cosmetically acceptable. Conclusions The peroneal perforator pedicle propeller flap is an appropriate choice to repair soft tissue defects of the distal limbs. PMID- 28345421 TI - Clinical features and prognosis of patients with acute aortic dissection in China. AB - Objective To evaluate the clinical features, risk factors, and prognostic significance of different Stanford types of acute aortic dissection (AAD). Methods We retrospectively analyzed the clinical data and prognostic predictors in 105 patients with AAD (37 with Stanford type A and 68 with Stanford type B) at Tianjin Medical University General Hospital and Tianjin 4th Central Hospital from January 2014 to November 2015. Results Patients with Marfan syndrome and bicuspid aortic valve constituted 24.3% and 8.1%, respectively, of patients with type A AAD; these proportions were significantly higher than those of patients with type B AAD (7.4% and 0.0%, respectively). The proportion of iatrogenic causes of type A AAD (8.1%) was significantly higher than that of type B AAD (0.0%). Computed tomography angiography showed that the proportion of involvement of the aortic arch and pericardial effusion (86.5% and 18.9%, respectively) in patients with type A AAD were higher than those in patients with type B AAD (23.5% and 5.9%, respectively). Endovascular treatment was performed in a higher proportion of patients with type B than A AAD (70.6% vs. 5.4%, respectively). Conclusion Systolic blood pressure, pericardial effusion, periaortic hematoma, conservative treatment, and open surgery were independent predictors of increased mortality in patients with AAD. PMID- 28345422 TI - Predictors of preference for caesarean delivery among pregnant women in Beijing. AB - Objective To evaluate factors associated with preference for caesarean or vaginal delivery among pregnant Chinese nulliparous and parous women. Methods In this cross-sectional study, a self-administered questionnaire was used to collect information on sociodemographic characteristics, preference/reasons for delivery mode, and knowledge of delivery complications. Results Of the 450 participants, 85 (18.9%) reported a preference for caesarean section (CS) pre-partum. Compared with women who would prefer a vaginal delivery, nulliparous women who preferred CS were more likely to be: >=35 years; have no medical insurance; have had two or more pregnancies; have access to only one source of information about birthing options; knowledge of the complications of vaginal delivery and think doctors have no right to decide the type of delivery. For parous women who preferred CS, they were more likely to have had a previous caesarean delivery and live outside Beijing. Conclusions From this study conducted at a large, maternity centre in Beijing, the proportion of pregnant women with preference pre-partum for CS was moderate and their reasons were varied. PMID- 28345423 TI - Systemic Lupus Erythematosus and hearing disorders: Literature review and meta analysis of clinical and temporal bone findings. AB - Objective This literature review and meta-analysis was performed to evaluate the correlations among hearing and vestibular clinical symptoms, temporal bone findings, and pathological mechanisms in patients with systemic lupus erythematosus (SLE). Study design Relevant papers in the literature were retrospectively reviewed. Clinical hearing aspects in patients with SLE and relevant temporal bone studies in the same field were analyzed. Methods PubMed and Google Scholar searches were performed using the following keywords: "auto immune disease," "systemic lupus erythematosus (SLE)," "hearing loss," "temporal bone study," "vertigo," "dizziness," "tinnitus," "ear symptoms," "treatment," "diagnosis," "symptoms," "etiopathogenesis," "Wegener granulomatosis," "Sjogren," "polyarteritis nodosa," "Cogan syndrome," and "granulomatosis." Also included were reviews in which the following terms were present: "SLE," "temporal bone," and "hearing symptoms." Review and conclusion This literature review and meta analysis focused on the pathological mechanisms through which SLE can damage inner ear structures and determinate hearing and vestibular symptoms. The main mechanisms involved in inner ear damage include the autoimmune response, deposition of immune complexes in the vessels and, to a lesser extent, cytotoxic damage. PMID- 28345424 TI - Does a social/behavioural gradient in dental health exist among adults? A cross sectional study. AB - Objective To explore the potential presence of a social/behavioural gradient in dental health among Italian adults using a cross-sectional study. Methods Caries indices were recorded among 480 subjects (52.9% men, 47.1% women) who also completed a structured self-administered social and behavioural questionnaire. A social/behavioural gradient was generated as the sum of the worst circumstances recorded on the questionnaire (cariogenic diet, smoking, lowest occupational profile, brushing teeth < twice daily, lowest educational level, uneven dental examination attendance). Results Caries figures (DMFT) and the number of filled sound teeth (FS-T) were statistically significantly linked to the social/behavioural gradient (DMFT: chi2(9) = 20.17 p = 0.02, Z = 0.02 p = 0.99; FS-T: chi2(9) = 25.68 p < 0.01, Z = -4.31 p < 0.01). DMFT was statistically significantly associated with gender and with social and behavioural variables. FS-T was higher in women (p = 0.03) and was linked to smoking ( p < 0.01). Conclusions The proposed social/behavioural gradient demonstrated how subjects reporting the worst circumstances on the questionnaire exhibited the worst dental health. The use of the gradient demonstrates that health promotion and prevention cannot be compartmentalized. PMID- 28345425 TI - Efficacy and safety of topical diclofenac/menthol gel for ankle sprain: A randomized, double-blind, placebo- and active-controlled trial. AB - Purpose This study was performed to evaluate topical 1% diclofenac/3% menthol gel in treating ankle sprain. Design In this randomized, double-blind, placebo controlled trial, adolescents and adults with acute ankle sprain (N = 385) applied 4 g of gel containing 1% diclofenac/3% menthol (n = 117), 1% diclofenac (n = 112), 3% menthol (n = 77), or placebo (n = 75) four times daily. The primary outcome was the area under the curve of pain intensity (PI) on movement [0 (no pain) to 10 (extreme pain)] from 24 to 72 hours post-application (AUC1-3 days). Secondary outcomes included pain relief (PR); PI; time to onset of PR, meaningful PR, cooling, and complete recovery; PI difference; sum of PI difference; total PR; reduction in ankle swelling; and the patient's global assessment of response to treatment. Results There were no statistically significant differences in AUC1 3 between 1% diclofenac/3% menthol and placebo, diclofenac, or menthol gels and no meaningful advantages of 1% diclofenac/3% menthol for any secondary outcome. There was a higher incidence of skin and application-site events with 1% diclofenac/3% menthol than with placebo or 1% diclofenac. Conclusion No significant improvement was observed with topical 1% diclofenac/3% menthol gel compared with placebo, 1% diclofenac, or 3% menthol gel in treating pain from ankle sprain. ClinicalTrials.Gov Identifier: NCT02100670. PMID- 28345426 TI - Prevalence and risk factors of multi-drug resistant tuberculosis in Dalian, China. AB - Objectives To investigate the prevalence and risk factors associated with multi drug resistant tuberculosis (MDR-TB) in Dalian, China. Methods This was a retrospective review of data from patients attending a TB clinic in Dalian, China between 2012 and 2015. Demographic and drug susceptibility data were retrieved from TB treatment cards. Univariate logistic analysis was used to assess the association between risk factors and MDR-TB. Results Among the 3552 patients who were smear positive for Mycobacterium tuberculosis (MTB), 2918 (82.2%) had positive MTB cultures and 1106 (31.1%) had isolates that showed resistance to at least one drug. The overall prevalence of MDR-TB was 10.1% (359/3552; 131/2261 [5.8%] newly diagnosed and 228/1291 [17.7%] previously treated patients). Importantly, 75 extensively drug-resistant TB isolates were detected from 25 newly treated and 50 previously treated patients. In total, 215 (6.1%) patients were infected with a poly-resistant strain of MTB. Previously treated patients and older patients were more likely to develop MDR-TB. Conclusions The study showed a high prevalence of MDR-TB among the study population. History of previous TB treatment and older age were associated with MDR-TB. PMID- 28345427 TI - Emotional freedom techniques (EFT) as a practice for supporting chronic disease healthcare: a practitioners' perspective. AB - PURPOSE: The objective of the present study was to explore Emotional Freedom Techniques (EFT) practitioners' experiences of using EFT to support chronic disease patients. This was part of a larger study exploring chronic disease patients' and EFT practitioners' experiences of using EFT to support chronic disease healthcare. METHODS: A qualitative approach was deemed suitable for this study. Eight practitioners were interviewed using semi-structured interviews via telephone or Zoom (an online video-conferencing platform). Interviews were transcribed verbatim and data was analyzed using Interpretative Phenomenological Analysis methodology. RESULTS AND CONCLUSION: This article presents two super ordinate themes which explore application of EFT for addressing emotional issues faced by chronic disease patients, and for management of physical symptoms, respectively. Chronic disease patients may benefit from a holistic biopsychosocial, patient-centered healthcare approach. EFT offers potential as a technique that may be used by health practitioners to support the psychosocial aspect of chronic disease healthcare. Implications for Rehabilitation Rehabilitation professionals should incorporate suitable psychological interventions (e.g., EFT) to improve coping and acceptance in physical chronic disease patients and alleviate their fears about the future. Rehabilitation professionals are also recommended to address in chronic disease patients, long standing or unresolved emotional issues, including past traumas from early life, using EFT or another suitable intervention. Rehabilitation professionals should help improve patients' emotional states using EFT to enhance physical symptom management. PMID- 28345430 TI - Planning for sedentary behaviour interventions: office workers' survey and focus group responses. AB - AIMS: As sedentary behaviour is becoming more prominent in office-based work environments, this study aimed to explore office workers' perceptions of sedentary behaviour, explore potential behavioural strategies to reduce sedentary behaviour in the workplace and identify barriers which may hamper behaviour change. METHODS: A total of 140 office workers were recruited and surveyed from the same workplace. The survey included questions regarding perceptions of the relationship between sitting time and health. Following the survey, 12 employees also participated in focus groups to identify potential sedentary behaviour intervention strategies and barriers. The responses from the survey and focus groups were thematically analysed. RESULTS: In total, 88% of all participants surveyed agreed that there was a relationship between sitting time and their health. The most prominent theme identified was musculoskeletal complaints followed by general health and weight gain or obesity. The focus groups identified that interventions targeting reducing sitting time should include education, supportive and knowledgeable managers, and a variety of behaviour change strategies to address individual preferences and barriers. CONCLUSION: Multiple behavioural strategies were identified, which appear to be appropriate for sedentary behaviour change. PMID- 28345429 TI - Uric acid therapy improves the outcomes of stroke patients treated with intravenous tissue plasminogen activator and mechanical thrombectomy. AB - Background Numerous neuroprotective drugs have failed to show benefit in the treatment of acute ischemic stroke, making the search for new treatments imperative. Uric acid is an endogenous antioxidant making it a drug candidate to improve stroke outcomes. Aim To report the effects of uric acid therapy in stroke patients receiving intravenous thrombolysis and mechanical thrombectomy. Methods Forty-five patients with proximal vessel occlusions enrolled in the URICO-ICTUS trial received intravenous recombinant tissue plasminogen activator within 4.5 h after stroke onset and randomized to intravenous 1000 mg uric acid or placebo (NCT00860366). These patients also received mechanical thrombectomy because a brain computed tomogaphy angiography confirmed the lack of proximal recanalization at the end of systemic thrombolysis. The primary outcome was good functional outcome at 90 days (modified Rankin Score 0-2). Safety outcomes included mortality, symptomatic intracerebral bleeding, and gout attacks. Results The rate of successful revascularization was >80% in the uric acid and the placebo groups but good functional outcome was observed in 16 out of 24 (67%) patients treated with uric acid and 10 out of 21 (48%) treated with placebo (adjusted Odds Ratio, 6.12 (95% CI 1.08-34.56)). Mortality was observed in two out of 24 (8.3%) patients treated with uric acid and one out of 21 (4.8%) treated with placebo (adjusted Odds Ratio, 3.74 (95% CI 0.06-226.29)). Symptomatic cerebral bleeding and gout attacks were similar in both groups. Conclusions Uric acid therapy was safe and improved stroke outcomes in stroke patients receiving intravenous thrombolysis followed by thrombectomy. Validation of this simple strategy in a larger trial is urgent. PMID- 28345428 TI - Induction of T-Cell Infiltration and Programmed Death Ligand 2 Expression by Adeno-Associated Virus in Rhesus Macaque Skeletal Muscle and Modulation by Prednisone. AB - Use of adeno-associated virus (AAV) to transduce genes into skeletal muscles can be associated with T-cell responses to viral capsid and/or to transgenic protein. Intramuscular mononuclear cell infiltrates primarily consisting of CD8+ T cells and also containing FOXP3+ regulatory T cells were present in rhesus macaque skeletal muscle treated with rAAVrh74.MCK.GALGT2 by vascular delivery. Administration of oral prednisone prior to AAV gene delivery and throughout the study reduced such infiltrates by 60% at 24 weeks post AAV delivery compared with AAV-treated animals not receiving prednisone, regardless of the presence of pre existing AAV serum antibodies at the time of treatment. The majority of CD8+ T cells in AAV-treated muscles expressed activated caspase 3 and programmed cell death protein 1 (PD1), suggesting ongoing programmed cell death. AAV-transduced skeletal muscles also had elevated expression of programmed death ligand 2 (PDL2) on skeletal myofibers, and this increase in expression extended to muscles where transgene was not overexpressed. These data demonstrate that prednisone can reduce the extent of intramuscular T-cell infiltrates in AAV-treated muscles, which may aid in achieving long-term transgene expression, as may the induction of PDL2 expression on skeletal myofibers to promote PD1-mediated programmed T cell death. PMID- 28345431 TI - Collaterals 2016: Translating the collaterome around the globe. AB - Collaterals 2016 (third International Symposium on Collaterals to the Brain) was a multidisciplinary scientific conference focused on collateral circulation in acute ischemic stroke. Decisive challenges include generalizability of optimal triage and selection paradigms based on collateral status for definitive treatment of acute ischemic stroke, rapid dissemination of expert methods, and the urgent need to leverage networking opportunities for stroke science related to the hemodynamics of collaterals. The collaterome, or individual capacity to offset ischemia in the brain, and determination of a favorable collateral profile have become pivotal factors in consideration of the precision medicine of stroke decision-making. The conference convened over 50 invited faculty from around the world to connect on-site participants at a state-of-the-art facility with remote audiences in more than 22 countries and regions. The 21/2-day program was structured into 40-min sessions devoted to key issues in translating the collaterome in acute stroke therapy across the globe. This unique forum of expertise emphasized the timely impact of collaterals on a monumental scale, encouraging maximal participation, rapid diffusion and added value of a diverse networking resource. The meeting format established a model geographical framework and innovative videoconferencing platform for future scientific conferences. PMID- 28345432 TI - Utero-placental perfusion Doppler indices in growth restricted fetuses: effect of sildenafil citrate. AB - OBJECTIVE: To assess efficacy and tolerability of sildenafil citrate on utero placental blood flow and fetal growth in pregnancies complicated by fetal growth restriction (FGR). METHODS: From March 2015, a randomized controlled trial of 54 patients at 24 weeks or more complicated by FGR and abnormal Doppler indices were randomly allocated 1:1 into an intervention arm (receive sildenafil citrate, 50 mg) or a control arm (receive placebo). The primary outcomes were changes occurred in the Doppler parameters 2 h following drug administration. RESULTS: Baseline characteristics were similar between groups. Significant difference was observed in the Delta uterine and umbilical Doppler indices among sildenafil group as compared to placebo group (p < 0.001). Middle cerebral Doppler indices, however, decreased significantly after sildenafil, which could be the result of shifting more blood to improve the utero-placental perfusion. No difference regarding Delta cerebro-placental ratio among both groups (p = 0.979). Sildenafil was also associated with pregnancy prolongation (p = .0001), increased gestational age at delivery (p = .004), improved neonatal weight (p = .0001), and less admission to neonatal intensive care unit (p = .03). No adverse effects reported in both treatment arms. CONCLUSION: Sildenafil citrate, by its vasodilator effect, can improve utero-placental blood flow in pregnancies complicated by FGR and abnormal Doppler. CLINICAL TRIAL: gov Registry: NCT02362399. PMID- 28345433 TI - The contextual malleability of approach-avoidance training effects: approaching or avoiding fear conditioned stimuli modulates effects of approach-avoidance training. AB - Previous research showed that the repeated approaching of one stimulus and avoiding of another stimulus typically leads to more positive evaluations of the former stimuli. In the current study, we examined whether approach and avoidance training (AAT) effects on evaluations of neutral stimuli can be modulated by introducing a regularity between the approach-avoidance actions and a positive or negative (feared) stimulus. In an AAT task, participants repeatedly approached one neutral non-word and avoided another neutral non-word. Half of the participants also approached a negative fear-conditioned stimulus (CS+) and avoided a conditioned safe stimulus (CS-). The other half of the participants avoided the CS+ and approached the CS-. Whereas participants in the avoid CS+ condition exhibited a typical AAT effect, participants in the approach CS+ condition exhibited a reversed AAT effect (i.e. they evaluated the approached neutral non-word as more negative than the avoided non-word). These findings provide evidence for the malleability of the AAT effect when strongly valenced stimuli are approached or avoided. We discuss the practical and theoretical implications of our findings. PMID- 28345434 TI - Effect of Diabetes Treatment-Related Attributes on Costs to Type 2 Diabetes Patients in a Real-World Population. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) results in a substantial economic burden on patients, health care systems, and society. Most literature assessing the cost of T2DM focuses on the long-term complications of the disease, the association between glucose control and cost, and patient characteristics resulting in poor and costly outcomes. However, it is likely that attributes specific to diabetes therapy can affect the use of costly resources. OBJECTIVE: To estimate the effect of diabetes treatment-related attributes, such as improved efficacy, adherence, and reduced risk for hypoglycemia, on costs to T2DM patients. METHODS: An observational, retrospective study was conducted using the Optum Clinformatics Database, which links medical and pharmacy claims to laboratory results. Patients aged >= 18 years with T2DM who had >= 1 antidiabetic medication claim; >= 1 hemoglobin A1c (A1c) test result; continuous enrollment in the health plan from April 1, 2010, to March 31, 2011; and at least 1 follow-up day were included. Nondiabetes specific total, inpatient, outpatient, emergency room, and other costs (along with antidiabetes medication costs) were defined for each patient. Generalized linear models with logarithm link were used to predict the 1-year and cumulative 3-year costs. Demographic factors and comorbidities were included as covariates in addition to the diabetes treatment-related attributes. RESULTS: In the entire analysis cohort, the average 3-year cost per patient was $74,862. The percentage effect on cost of diabetes treatment-related variables ranged from -18% to 429%. Drug adherence was associated with lower inpatient, outpatient, and emergency room costs and higher drug costs. Hypoglycemia was associated with higher inpatient, outpatient, emergency room, and other direct costs (except antidiabetic drug costs). Compared with A1c values <= 7%, patients with higher levels were associated with higher total and drug costs. CONCLUSIONS: Study results demonstrate the association between diabetes treatment-related attributes and costs, including inpatient, outpatient, drug, and total costs. This association raises the question: what would the effect of a new diabetes therapy, with high efficacy, high adherence, and reduced risk of hypoglycemia have on economic outcomes? DISCLOSURES: Funding from Sanofi supported this study. Tong was an employee of ProUnlimited, under contract with Sanofi during the time of the study. Kitio-Dschassi was a Sanofi employee at time of the analysis. Meng, Casciano, Stern, and Gultyaev are employees of LASER Analytica, which received research funds from Sanofi to conduct this database analysis. Lee was an employee at LASER Analytica at the time of the analysis and has received grants from Sanofi. This manuscript was presented as a poster at the American Diabetes Association, 76th Scientific Sessions; New Orleans, Louisiana; June 10-14, 2016. Study concept and design were contributed by Meng, Casciano, Gultyaev, and Kitio-Dschassi. Meng and Stern collected the data, and data interpretation was performed by Casciano, Lee, Tong, and Kitio-Dschassi. The manuscript was written primarily by Lee, along with Meng and Stern, and revised by Stern, Meng, Tong, Kitio-Dschassi, and Lee. PMID- 28345435 TI - Predicting Adherence and Persistence with Oral Bisphosphonate Therapy in an Integrated Health Care Delivery System. AB - BACKGROUND: Examining drug exposure is essential to pharmacovigilance, especially for bisphosphonate (BP) therapy. OBJECTIVE: To examine differences in 4 measures of oral BP exposure: treatment discontinuation, adherence, persistence, and nonpersistence. METHODS: Among women aged >= 50 years who initiated oral BP therapy during 2002-2007 with at least 3 years of health plan membership follow up, discontinuation was defined by evidence of no further treatment during the study observation period. Among those with at least 2 filled BP prescriptions during the study period, adherence was calculated for each year of follow-up using the (modified) proportion of days covered (mPDC) metric that allows for stockpiling of prescription/refills overlap <= 30 days supply. Persistence was quantified by treatment duration, allowing a gap of up to 60 days between prescription/refill days covered. Nonpersistence was quantified by the periods without drugs outside this allowable gap. Multivariable logistic regression was used to compare age and race groups and the relationships of early adherence (adherence during the first year) with subsequent adherence. RESULTS: Among 48,390 women initiating oral BP therapy and followed for 3 years, 26.7% discontinued in year 1, and 14.7% of the remaining 35,456 women discontinued in year 2. Discontinuation rates were slightly higher (29.4%, P < 0.001) for women aged >= 75 years and somewhat lower (21.1%, P < 0.001) for Asian women. During the first year, 60.4% of the women achieved an mPDC of >= 75%, with demographic differences in adherence similar to that seen for treatment discontinuation. Over the 3 years, the median mPDC levels for BP therapy were 86%, 84%, and 85% in years 1, 2, and 3, respectively, for those receiving treatment. Cumulative persistence was 2.3 years (median, IQR = 1.0-3.0) overall and slightly greater for Asian versus white women and lower for older women. There were 18,174 (42.9%) women with at least 1 period of nonpersistence during 3 years follow-up in excess of the 60-day allowable gap between prescription/refills (median cumulative nonpersistence = 0.65, IQR = 0.30-1.25 years). Women with mPDC >= 75% during the first year had a 12-fold and 6-fold increased odds of mPDC >= 75% during year 2 and year 3, respectively. CONCLUSIONS: BP discontinuation rates are highest for women during the first year. Among those continuing treatment in subsequent years, adherence rates were relatively stable. Persistence and adherence varied slightly by age and was somewhat higher in Asians, contributing to differences in cumulative BP exposure. We also found evidence that optimal adherence in the first year was highly predictive of optimal adherence in the subsequent 1-2 years. Hence, subgroups of patients receiving oral BP drugs may require different levels of support and monitoring to maximize treatment benefit, especially based on early patterns of use. DISCLOSURES: This study was supported by grants from the Kaiser Permanente Northern California Community Benefit Program and the National Institutes of Health, 1R01AG047230-01A1. The opinions expressed in this publication are solely the responsibility of the authors and do not represent the official views of Kaiser Permanente or the National Institutes of Health. Hui, Yi, and Chandra have received past research funding from Amgen not related to the current study. Adams has received research funding from Amgen, Merck, and Otsuka not related to the current study. Niu has received research funding from Bristol Myers Squibb not related to the current study. Ettinger has received past legal fees in litigation involving Fosamax. Lo has received past research funding from Amgen and current research funding from Sanofi not related to the current study. The data from this study were presented at the Academy of Managed Care Pharmacy Annual Meeting; April 19-22, 2016; San Francisco, California. Study concept and design were contributed primarily by Hui and Lo, along with Adams, Niu, Yi, and Ettinger. Hui took the lead in data collection, along with Chandra, and data interpretation was performed by Niu, Yi, and Lo, along with the other authors. The manuscript was written by Hui, Adams, and Lo, along with Niu, Yi, and Ettinger, and revised by Ettinger, Hui, Lo, and Niu, along with the other authors. PMID- 28345436 TI - Characterizing Health Care Utilization, Direct Costs, and Comorbidities Associated with Interstitial Cystitis: A Retrospective Claims Analysis. AB - BACKGROUND: Interstitial cystitis (IC) is a debilitating condition that affects up to 5% of the U.S. POPULATION: This condition is characterized by bladder pain, urinary urgency and frequency, nocturia, and, in some patients, bladder lesions called Hunner's lesions (HL). IC patients who have HL experience a clinical course that is distinct from those without HL and, as a result, respond differently to existing treatments. Without effective and lasting therapeutic options, IC patients are expected to experience a reduced quality of life and be a significant economic burden. Previous research describing the burden of IC is not only outdated but lacks stratification by HL. OBJECTIVES: To (a) characterize health care utilization, direct costs, and comorbidities associated with IC and (b) elucidate differences between patients with and without HL. METHODS: A retrospective analysis was conducted using health care claims from the Truven Health MarketScan Research Databases. Adults with an incident IC diagnosis between 2009 and 2014 were identified and matched 1:4 to non-IC patients on age, gender, and geographic region. Health care utilization, direct costs, and comorbidities during the first 12 months after diagnosis were compared between the 2 groups, as well as between IC subgroups with and without HL. Associations were evaluated after adjustment for potential confounders using regression models. RESULTS: A total of 24,836 IC patients were identified and matched to 99,344 non-IC patients. Patients were predominantly female (92%), with a mean age of 49.0 (SD = 15.3) years. IC patients used significantly more health care resources across all categories compared with non-IC patients. On average, having IC was associated with $7,223 higher total health care costs than not having IC (95% CI = $6,650-$7,796), with outpatient costs contributing to 71% of the difference, after adjusting for baseline age, gender, region, insurance type, plan type, and Charlson Comorbidity Index (CCI) score. The odds of developing select comorbidities were 2.61 times greater in IC patients compared with non-IC patients (95% CI = 2.52-2.70), adjusting for baseline age, sex, region, and CCI score. Among IC patients, the HL subgroup (n = 292) used more health care resources, and having HL was associated with $6,895 higher total health care costs compared with not having HL (95% CI = $3,770-$10,020) after adjusting for baseline age, gender, region, insurance type, and plan type. CONCLUSIONS: Findings suggest that patients with IC have significantly higher health care utilization, costs, and comorbidities compared with non-IC patients. This economic burden is further amplified in those with HL. DISCLOSURES: Funding for this study was contributed by Allergan. Tung was supported by a training grant from Allergan at the time of this study. Hepp was an Allergan employee at the time this study was conducted. The other authors have nothing to disclose. This research was previously presented, in part, as a poster presentation at the International Society for Pharmacoeconomics and Outcomes Research 21st Annual International Meeting; Washington, DC; May 23, 2016. Study concept and design were primarily contributed by Hepp, along with Tung and Devine. Tung took the lead in data collection, with assistance from Hepp, and data interpretation was performed by Tung, along with Bansal and Devine. The manuscript was prepared primarily by Tung, along with Devine, Bansal, and Hepp. PMID- 28345438 TI - CORRECTIONS. PMID- 28345437 TI - Clinical Profile, Dosing, and Quality-of-Life Outcomes in Primary Immune Deficiency Patients Treated at Home with Immunoglobulin G: Data from the IDEaL Patient Registry. AB - BACKGROUND: Patients with primary immune deficiency (PID) often require immunoglobulin G (IgG, commonly referred to as Ig) replacement therapy to prevent infections and associated comorbidities. Ig therapy can be given either through intravenous or subcutaneous routes, and both can be done in the home setting. There is limited information available on the real-world diagnosis, management, and outcomes of this patient population, given the variable disease presentation and treatment options. The Immunoglobulin Diagnosis, Evaluation, and key Learnings (IDEaL) Patient Registry is designed to capture nursing, pharmacy, and patient-reported data for patients receiving Ig at home. OBJECTIVES: To (a) present a real-world population of patients with PID who have received Ig at home and (b) examine how differences in administration, dosing, and insurance affect health and quality-of-life outcomes in these patients. METHODS: As of July 2015, 383 patients receiving Ig therapy from Coram/CVS specialty infusion services, across multiple disease states, signed consent forms and enrolled in the IDEaL Patient Registry. Patients' referral paperwork, including lab values, and standard of care nursing and pharmacy follow-up forms were collected. Patients were mailed quality-of-life surveys at the time of enrollment and every 6 months after their enrollment. RESULTS: The most common diagnosis (78%) in these PID patients was common variable immunodeficiency (CVID). For Ig-naive adult patients, the average age at the start of treatment was 59 years. For pediatric patients, average age at start of treatment was 9 years. A majority of these PID patients (80%) received subcutaneous Ig (SCIg) at home, and 20% received intravenous Ig (IVIg). The average SCIg dose was 10 grams per week, or 130 mg per kg, and the average IVIg dose was 36 grams every 4 weeks, or 472 mg per kg. In the IVIg patient population, 34% had a dose or frequency change while on treatment, while 30% of the SCIg patients had a dose or frequency change. Patient reported health and quality-of-life scores were generally positive. Route of administration did not affect patient perception of cost (P = 0.171), but whether the patient had private or government-backed health care did affect perception of cost (P = 0.036). CONCLUSIONS: For a disease state with an extremely variable presentation, data from the IDEaL Patient Registry provides further insights into the real-world clinical and diagnostic characteristics of this population, as well as dosing and treatment outcomes of home administration of Ig therapy. The majority of patients received SCIg infusions. SCIg dosing was on the lower end of the recommended mg per kg dose range, while IVIg patients were more in the middle of the recommended dose range. Patient outcomes on treatment were correlated with baseline status, suggesting that earlier detection and treatment of primary immune deficiencies may be critical in achieving beneficial outcomes on Ig therapy. DISCLOSURES: No outside funding supported this study. Seidu was compensated by Coram Clinical Trials for acting as primary investigator and reviewing data. Study concept and design were contributed by all the authors. Kearns, Kristofek, and Kiles collected the data, and data interpretation was performed by Kearns, Seidu, and Kristofek, along with Bolgar. The manuscript was written and revised primarily by Kearns, along with Kristofek, Bolgar, and Seidu. PMID- 28345439 TI - Primary Nonadherence to Overactive Bladder Medications in an Integrated Managed Care Health Care System. AB - BACKGROUND: Treatment for overactive bladder (OAB) remains suboptimal, in part because of patient nonadherence to medications. Primary nonadherence is when patients fail to pick up their initial prescriptions. OBJECTIVE: To measure primary nonadherence to OAB medications within 30 days of a first OAB prescription order using electronic medical records from a U.S. managed care health care system METHODS: A retrospective cohort study was conducted using electronic medical records from the Kaiser Permanente Southern California (KPSC) database to identify patients with new OAB prescriptions between January 1, 2007, and December 31, 2013. The index date was defined as the first order of an OAB prescription. Patients had to be aged >= 18 years on the index date and were required to have 12 months of continuous membership with drug benefit eligibility before, during, and after the index date. Patients were defined as primary nonadherent if they did not pick up their new OAB prescriptions within 30 days of the order date. Descriptive statistics and a multivariable logistic regression analysis with backward selection were conducted to identify factors associated with patients who were primary nonadherent versus adherent. RESULTS: There were 9,050 patients with a new OAB prescription order; 1,662 (18%) of these were primary nonadherent. Patients with primary nonadherence were younger in age (56.9 [SD +/- 16.0] years vs. 63.9 [SD +/- 14.8] years; P < 0.001) and more likely to have commercial insurance (65.9% vs. 46.2%; P < 0.001). They also had lower mean Charlson Comorbidity Index (CCI) scores (1.99 vs. 2.70; P < 0.001), fewer OAB related comorbidities, fewer concomitant medications (P < 0.005), and fewer overall prescriptions dispensed in the previous 12 months (P < 0.001) compared with adherent patients. Significant factors such as commercial insurance (P = 0.013), race other than white (P = 0.020), CCI = 0 versus CCI >= 2 (P = 0.001), urinary tract infections (P < 0.001), and falls (P = 0.047) were associated with a higher likelihood of primary nonadherence versus adherence. CONCLUSIONS: Nearly 1 in 5 patients did not pick up their new OAB medications within 30 days of the order date. Knowledge of factors associated with primary nonadherence may inform strategies for improving management of OAB. DISCLOSURES: This study was supported by a research grant provided by Astellas Pharma Global Development. Rashid and Lin do not have any financial interests or potential conflict of interest with regard to the work. Vassilakis, Kristy, and Ng were employees of Astellas Pharma Global Development when this study was conducted. Study concept and design were contributed by Rashid and Ng, along with the other authors. Rashid and Lin collected the data, and data interpretation was performed by Rashid, Ng, and Lin, along with Vassilakis and Kristy. The manuscript was written by Rashid and Ng, along with Vassilakis and Lin, and revised by Rashid, Ng, and Lin. PMID- 28345440 TI - The Economic Burden of Opioid Abuse: Updated Findings. AB - BACKGROUND: Opioid pain relievers can be highly effective in providing relief for patients suffering from pain. At the same time, prescription opioid abuse, dependence, overdose, and poisoning (hereinafter "abuse") have become a national public health concern. Opioid abuse is also costly: previous estimates of the annual excess costs of opioid abuse to payers range from approximately $10,000 to $20,000 per patient. OBJECTIVES: To (a) provide a comprehensive, current estimate of the economic burden of opioid abuse to commercial payers and (b) explore the drivers of these excess costs of abuse. METHODS: Administrative claims from beneficiaries covered by large self-insured companies throughout the United States were used to identify patients diagnosed with opioid abuse, dependence, and overdose/poisoning ("abuse") between 2012 and 2015. Sample selection criteria identified patients most likely to be misusing opioids. Abusers and nonabuser controls were matched using propensity scores. Excess health care costs were assessed over the 18-month study period. Drivers of excess costs were then evaluated by place of service and medical condition (identified as 3-digit ICD-9 CM groupings). RESULTS: 9,342 matched abuser/nonabuser pairs were analyzed. Relative to nonabusers, abusers had significantly higher annual health care resource utilization, leading to $14,810 in per-patient incremental annual health care costs. Excess costs began accumulating 5 months before the formal, incident diagnosis of abuse, driven by alcohol and nonopioid substance abuse. Major drivers of excess costs of abuse included opioid and other substance abuse disorders, mental health conditions, and painful conditions. Many patients had diagnoses for other substance abuse that predated their opioid abuse diagnoses. CONCLUSIONS: Opioid abuse imposes a substantial economic burden on payers and often occurs in the context of other substance abuse. Poly-substance abuse often precedes the diagnosis of opioid abuse. DISCLOSURES: This study was funded by Purdue Pharma. Mayne is an employee of Purdue Pharma. Kirson, Scarpati, and Birnbaum are employees of Analysis Group, which received funding from Purdue Pharma to conduct this study. Enloe and Dincer were employees of Analysis Group at the time this research was conducted. Study concept and design were contributed by Kirson, Birnbaum, Mayne, and Scarpati, along with Enloe and Dincer. Enloe and Dincer took the lead in data collection, along with Birnbaum and assisted by Kirson and Scarpati. Data interpretation was performed by all the authors. The manuscript was written and revised by Kirson and Scarpati, along with Mayne and Birnbaum. PMID- 28345441 TI - Prevalence and Cost of Subsequent Fractures Among U.S. Patients with an Incident Fracture. AB - BACKGROUND: The prevalence and cost of subsequent fractures among patients with an incident fracture are not well defined. OBJECTIVE: To assess the prevalence of, and costs associated with, subsequent fractures in the year after an incident fracture. METHODS: This was a retrospective claims database analysis using data from Humana Medicare Advantage claims (Medicare group) and Optum Insight Clinformatics Data Mart commercial claims (commercial group). Patients included in the study had a claim for a qualifying fracture occurring between January 2008 and December 2013 (index fracture), were continuously enrolled in the health plan for >= 1 year before and after the index fracture, and were aged >= 65 years in the Medicare group or >= 50 years in the commercial group at the time of the index fracture. Subsequent fractures were identified by ICD-9-CM codes and were defined as the second fracture occurring >= 3 to <= 12 months after the index fracture (>= 6 to <= 12 months for fractures at the same site as the index fracture). Rates of subsequent fractures were calculated as the number of patients who had a subsequent fracture divided by the total sample size. After propensity matching of demographic and clinical variables, we determined the total medical and pharmacy costs accrued within 1 year of the index fracture by patients with and without a subsequent fracture. Health care costs were compared between patients with and without a subsequent fracture using McNemar's test. RESULTS: A total of 45,603 patients were included in the Medicare group, and 54,145 patients were included in the commercial group. In the Medicare group, 7,604 (16.7%) patients experienced a subsequent fracture. The proportion of patients with a subsequent fracture was highest among patients with multiple index fractures (26.2%, n = 905), followed by those with hip (25.5%, n = 1,280) and vertebral (20.2%, n = 1,908) index fractures. In the commercial group, 6,256 (11.6%) patients experienced a subsequent fracture. The proportion of patients with a subsequent fracture paralleled those observed in the Medicare group: 24.5% (n = 808) in patients with multiple index fractures, 22.0% (n = 525) in those with hip fracture, and 14.5% (n = 841) in those with vertebral fracture. For vertebral, hip, and nonhip nonvertebral fractures, subsequent fractures were most frequently of the same type as the index fracture. The mean total health care cost (sum of medical and pharmacy costs) in the year following the incident fracture for the Medicare group was $27,844 and differed significantly between patients with and without a subsequent fracture ($34,897 vs. $20,790; P < 0.001). The mean total health care cost in the year following the incident fracture for the commercial group was $29,316 and also differed significantly between patients with and without a subsequent fracture ($39,501 vs. $19,131; P < 0.001). CONCLUSIONS: Among patients with an incident fracture, those who experienced a subsequent fracture in the following year had significantly higher health care costs than those who did not. A subsequent fracture is most likely to be of the same type as the initial fracture. DISCLOSURES: This study was funded by Merck & Co. Other than through the employer relationships disclosed here, Merck & Co did not have a role in the study design, data collection, interpretation of the data, in writing of the manuscript, or in the decision to submit the manuscript for publication. Weaver and Marvos are employees of Merck & Co. Sajjan was an employee of Merck & Co. and owned stock in the company at the time of the study. Lewiecki has received consulting and/or speaker honoraria from Merck, AbbVie, AgNovos Healthcare, Alexion Pharmaceuticals, Amgen, Eli Lilly and Company, Radius Health, Shire, and TheraNova. Lewiecki has received research grant support from Merck, Amgen, and Eli Lilly and Company and serves as a board member for the National Osteoporosis Foundation, the International Society for Clinical Densitometry, and the Osteoporosis Foundation of New Mexico. Harris has received consulting honoraria from Merck, Alexion Pharmaceuticals, Amgen, Eli Lilly and Company, Gilead Sciences, Primus Pharmaceuticals, and Radius Health. Study concept and design were contributed by Weave and Sajjan. Lewiecki collected the data, and data interpretation was performed by all the authors. The manuscript was written and revised by Weaver, Lewiecki, and Harris. PMID- 28345442 TI - Predicting 1-Year Statin Adherence Among Prevalent Users: A Retrospective Cohort Study. AB - BACKGROUND: Attempts to predict who is at risk of future nonadherence have largely focused on predictions at the time of therapy initiation; however, these users are only a small proportion of all patients on therapy at any point in time. Methods to predict nonadherence for established medication users, which have not been previously described in the literature, would be helpful to guide efforts to enhance the use of evidence-based therapies. OBJECTIVE: To test approaches for adherence prediction among prevalent statin users, namely the use of short-term filling behavior, investigator-specified predictors from medical and pharmacy administrative claims, and the empirical selection of potential predictors using the high-dimensional propensity score variable selection algorithm. METHODS: Medical and prescription claims data from a large national health insurer were used to create a cohort of patients who filled statin medication prescriptions in January 2012. We defined 6 groups of adherence predictors and estimated 10 main models to predict medication adherence in the full cohort. The same was done for the population stratified based on the days supply of the index statin prescription (<= 30 days vs. > 30 days). RESULTS: The study cohort consisted of 93,777 individuals, 58.4% of which were adherent to statins during follow-up. The use of 3 pre-index adherence predictors alone achieved a c-statistic of 0.70. Investigator-specified and empirically selected pharmacy, medical, and demographic variables did substantially worse (0.57-0.60). The use of 3 indicators of post-index adherence achieved a higher c-statistic than the best-performing model using pre-index information (0.74 vs. 0.72). The addition of 3 pre-index adherence predictors further improved discrimination (0.78). CONCLUSIONS: This analysis demonstrated the ability to predict adherence among medication users using filling behavior before and immediately after an index prescription fill. DISCLOSURES: This work was supported by an unrestricted grant from CVS Health to Brigham and Women's Hospital. Shrank, Brennan, and Matlin were employees and shareholders at CVS Health at the time of this manuscript preparation; they report no financial interests in products or services that are related to the subject of the manuscript. Franklin has received consulting fees from Aetion. Chourdry has received grants from the National Heart, Lung, and Blood Institute, PhRMA Foundation, Merck, Sanofi, AstraZeneca, and MediSafe. Spettell is an employee of, and shareholder in, Aetna. The other authors have nothing to disclose. Krumme, Choudhry, Tong, and Franklin contributed to the study design, interpretation of results, and manuscript drafting. Tong prepared and analyzed the data. Isaman, Spettell, Shrank, Brennan, and Matlin provided interpretation of results and critical manuscript revisions. PMID- 28345443 TI - Economic Burden of Irritable Bowel Syndrome with Diarrhea: Retrospective Analysis of a U.S. Commercially Insured Population. AB - BACKGROUND: The economic burden associated with irritable bowel syndrome with diarrhea (IBS-D) is not well understood. OBJECTIVES: To (a) evaluate total annual all-cause, gastrointestinal (GI)-related, and symptom-related (i.e., IBS, diarrhea, abdominal pain) health care resource use and costs among IBS-D patients in a U.S. commercially insured population and (b) estimate incremental all-cause health care costs of IBS-D patients versus matched controls. METHODS: Patients aged >= 18 years with 12 months of continuous medical and pharmacy benefit eligibility in 2013 were identified from the Truven Health MarketScan research database. The study sample included patients with >= 1 medical claim with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code in any position for IBS (ICD-9-CM 564.1x) and either (a) >= 2 claims for diarrhea (ICD-9-CM 787.91, 564.5x) on different service dates in 2013, or (b) >= 1 claim for diarrhea plus >= 1 claim for abdominal pain (ICD-9 CM 789.0x) on different service dates in 2013, or (c) >= 1 claim for diarrhea plus >= 1 pharmacy claim for a symptom-related prescription on different service dates in 2013. Controls included patients with no claims for IBS, diarrhea, abdominal pain, or symptom-related prescriptions in 2013. Controls were randomly selected and matched with IBS-D patients in a 1:1 ratio based on age (+/- 4 years), gender, geographic location, and health plan type. All-cause health care resource utilization included medical and pharmacy claims for health care services associated with any condition. Total health care costs were defined as the sum of health plan-paid and patient-paid direct health care costs from prescriptions and medical services, including inpatient, emergency department (ED), and physician office visits, and other outpatient services. A total cost approach was used to assess all-cause, GI-related, and symptom-related health care costs for IBS-D patients. An incremental cost approach via generalized linear models was used to assess the excess all-cause costs attributable to IBS-D after adjusting for demographics and general and GI comorbidities. RESULTS: Of 39,306 patients (n = 19,653 each for IBS-D and matched controls) included, mean (+/- SD) age was 47 (+/- 17) years and 76.5% were female. Compared with controls, IBS-D patients had a significantly higher mean annual number of hospitalizations, ED visits, office visits, and monthly (30-day) prescription fills. Mean annual all-cause health care costs for IBS-D patients were $13,038, with over half (58.4%) attributable to office visits and other outpatient services (e.g., diagnostic tests and laboratory or radiology services), and remaining costs attributable to prescriptions (19.5%), inpatient admissions (13.6%), and ED visits (8.5%). GI-related ($3,817) and symptom-related ($1,693) costs were also primarily driven by other outpatient service costs. After adjusting for demographics and comorbidities, incremental annual all-cause costs associated with IBS-D were $2,268 ($9,436 for IBS-D patients vs. $7,169 for matched controls; P < 0.001) per patient/year, of which 78% were from medical costs and 22% were from prescription costs. CONCLUSIONS: IBS-D was associated with a substantial burden in direct costs in this population. Compared with matched controls, IBS-D patients had greater medical service use and incurred significantly more annual all-cause health care costs, even after controlling for demographics and comorbidities. Incremental costs associated with IBS-D were primarily attributable to increased use of medical services rather than pharmacy costs. DISCLOSURES: This study was funded by Allergan. The authors received no compensation related to the development of the manuscript. Buono and Andrae are employees of Allergan. Mathur is an employee of Axtria. Averitt was an employee of Axtria at the time this study was conducted. Data from this manuscript have previously been presented in poster format by Buono at the American College of Gastroenterology Annual Scientific Meeting; Honolulu, Hawaii; October 16-21, 2015. Mathur and Averitt were involved in conducting the study analyses. All authors were involved in the study design, interpretation of the data, and preparation of the manuscript. The authors take full responsibility for the scope, direction, and content of the manuscript and have approved the submitted manuscript. PMID- 28345444 TI - Budgetary Impact of Cabazitaxel Use After Docetaxel Treatment for Metastatic Castration-Resistant Prostate Cancer. AB - BACKGROUND: With the approval of several new treatments for metastatic castration resistant prostate cancer (mCRPC), budgetary impact is a concern for health plan decision makers. Budget impact models (BIMs) are becoming a requirement in many countries as part of formulary approval or reimbursement decisions. Cabazitaxel is a second-generation taxane developed to overcome resistance to docetaxel and is approved for the treatment of patients with mCRPC previously treated with a docetaxel-containing regimen. OBJECTIVE: To estimate a 1-year projected budget impact of varying utilization rates of cabazitaxel as a second-line treatment for mCRPC following docetaxel, using a hypothetical U.S. private managed care plan with 1 million members. METHODS: A BIM was developed to evaluate costs for currently available treatment options for patients with mCRPC previously treated with docetaxel. Treatments included in the model were cabazitaxel, abiraterone acetate, enzalutamide, and radium-223, with utilization rates derived from market research data. Medication costs were calculated according to published pricing benchmarks factored by dosing and duration of therapy as stated in the prescribing information for each agent. Published rates and costs of grade 3-4 adverse events were also factored into the model. In addition, the model reports budget impact under 2 scenarios. In the first base-case scenario, patient out-of pocket costs were subtracted from the total cost of treatment. In the second scenario, all treatment costs were assumed to be paid by the plan. RESULTS: In a hypothetical 1 million-member health plan population, 100 patients were estimated to receive second-line treatment for mCRPC after treatment with docetaxel. Using current utilization rates for the 4 agents of interest, the base-case scenario estimated the cost of second-line treatment after docetaxel to be $6,331,704, or $0.528 per member per month (PMPM). In a scenario where cabazitaxel use increases from the base-rate case of 24% to a hypothetical rate of 33%, the PMPM cost would decrease to $0.524, reflecting a cost saving of $0.004 PMPM and equating to incremental savings of $49,546, or $497 per patient per year (PPPY). In the second scenario, when out-of-pocket costs were not considered, the cost of second line treatment after docetaxel was estimated as $6,733,594, or $0.561 PMPM. With a hypothetical increase in cabazitaxel use (24%-33%), the PMPM cost would decrease to $0.554, reflecting savings of $0.007 PMPM and equating to incremental savings of $86,136, or $864 PPPY. The primary driver of cost savings with increased cabazitaxel use was lower acquisition cost. One-way sensitivity analyses revealed that the model results were robust over a wide range of input values (utilization, prevalence, and population parameters). CONCLUSIONS: In the presented BIM, an increase in cabazitaxel use is expected to result in modest cost savings to the health plan. Patient coinsurance savings may also be realized based on applicable Medicare Part B and Part D calculations. This BIM presents an objective, comprehensive, robust, and user-adaptable tool that health plans and medical decision makers may use to evaluate potential economic impact of formulary and reimbursement decisions. DISCLOSURES: Research and analysis were funded by Sanofi US. The sponsor had the opportunity to review the final draft; however, the authors were responsible for all content and editorial decisions. Flannery, Drea, Hudspeth, and Miao are employees of Sanofi. Miao is an owner of stock in Sanofi. Corman, Gao, and Xue are employees of Pharmerit International and served as consultants to Sanofi during this study. All authors contributed to study design and data collection and analysis. The manuscript was written by Flannery, along with the other authors, and revised by all the authors. PMID- 28345445 TI - The Role of Patient Financial Assistance Programs in Reducing Costs for Cancer Patients. AB - BACKGROUND: Limited transparency exists regarding eligibility and benefits for patient financial assistance programs (PAPs). OBJECTIVE: To describe oral anticancer medication costs, insurance coverage, and the degree of financial assistance provided by PAPs. METHODS: This was a retrospective study of prescription anticancer medication costs and PAP coverage. The study used data from an academic cancer center's specialty pharmacy. Medication, cost, and coverage data were collected from the specialty pharmacy database for prescriptions filled from January 2013 to November 2015. Prescriptions with missing copayments, insurance, or financial assistance amounts were excluded. Descriptive statistics summarized prescription characteristics. RESULTS: Of 9,388 anticancer medication prescriptions filled, 8,212 (87%) had complete cost data and were included. The 5 most common medications prescribed were capecitabine (20%), temozolomide (13%), enzalutamide (10%), letrozole (6%), and tamoxifen (4%). Most prescriptions were covered by commercial insurance or Part D (41.6%, n = 3,418). The median copayment was $20 per prescription (interquartile range [IQR] = $10.00-$80.30). When considering all prescriptions that received PAP assistance, the median amount of financial assistance provided by PAPs per prescription was $411.0 (IQR = $302.80-$523.40), amounting to 15% of the median prescription cash price. When considering all prescriptions, the median amount of financial assistance provided by PAPs per prescription was $0, and the mean was $79.30 (SD = $389.90). CONCLUSIONS: A minority of prescriptions received financial assistance from PAPs. The proportion of financial assistance was small relative to the price billed to insurance. PAPs play a modest role in reducing anticancer prescription-related costs. DISCLOSURES: Support of this project by The Duke Biostatistics Core was made possible by Grant Number UL1TR001117 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Zullig is supported by a VA Health Services Research and Development (HSR&D) Career Development Award (CDA 13-025). Zullig also reports a financial relationship with Novartis. Zafar reports financial relationships with Novartis, Genentech-Roche, and Vivor. Vlastelica, Shankaran, and Wolf have nothing to disclose. The views in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs, Duke University, NCATS, or NIH. This abstract was previously presented at the 2016 ASCO Annual Meeting; Chicago, Illinois; June 3-7, 2016. Study concept and design were contributed by Zafar, Zullig, and Vlastelica, with assistance from Shankaran. Vlastelica and Wolf took the lead in data collection, along with Zafar, and data interpretation was performed by Zullig, Zafar, and Wolf, along with Vlastelica and Shankaran. The manuscript was written and revised by Zullig and Zafar, along with the other authors. PMID- 28345446 TI - Inter-species comparative antioxidant assay and HPTLC analysis of sakuranetin in the chloroform and ethanol extracts of aerial parts of Rhus retinorrhoea and Rhus tripartita. AB - CONTEXT: Extensive research on Rhus (Anacardiaceae) shows their antioxidant potential, which warrants further evaluation of its other species. OBJECTIVE: To perform a comparative antioxidant assay on extracts of R. retinorrhoea and R. tripartita, including sakuranetin quantification by a validated HPTLC method. MATERIALS AND METHODS: In vitro antioxidant assay was performed on chloroform and ethanol extracts of R. retinorrhoea Steud. ex Oliv. (RRCE and RREE) and R. tripartita (Ucria) Grande (RTCE and RTEE) by DPPH radical scavenging (at 31.25, 62.5, 125, 250 and 500 MUg/mL concentrations) and beta-carotene-linoleic acid bleaching methods at 500 MUg/mL concentration. Densitometric HPTLC method was developed and validated using toluene: ethyl acetate: methanol (8:2:0.2; v/v/v) as mobile phase, executed on glass-backed silica gel F254 plate and scanned at 292 nm. RESULTS: Antioxidant activity of Rhus extracts tested by the two methods (DPPH/BCB) was found in order of RTEE > RREE > RTCE > RRCE with IC50 118.67/256.26, 315.75/82.35, 827.92/380.0 and 443.69/292.75, respectively. Scanning of the HPTLC plate provided an intense peak of sakuranetin at Rf = 0.59. The estimated sakuranetin content in the dry weight of the extracts was highest in RREE (27.95 MUg/mg) followed by RRCE (25.22 MUg/mg), RTEE (0.487 MUg/mg) and RTCE (0.0 MUg/mg). Presence of sakuranetin in RREE, RRCE and RTEE supported the highest antioxidant property of the two Rhus species. Nonetheless, low sakuratenin in R. tripartita indicated the presence of other bioactive constituents responsible for synergistic antioxidant activity. CONCLUSION: The developed HPTLC method therefore guarantees its application in quality control of commercialized herbal drugs and formulations containing sakuranetin. PMID- 28345447 TI - Urea enhances cell lysis of Schizosaccharomyces pombe ura4 mutants. AB - Cell lysis is induced in Schizosaccharomyces pombe ?ura4 cells grown in YPD medium, which contains yeast extract, polypeptone, and glucose. To identify the medium components that induce cell lysis, we first tested various kinds of yeast extracts from different suppliers. Cell lysis of ?ura4 cells on YE medium was observed when yeast extracts from OXOID, BD, Oriental, and Difco were used, but not when using yeast extract from Kyokuto. To determine which compounds induced cell lysis, we subjected yeast extract and polypeptone to GC-MS analysis. Ten kinds of compounds were detected in OXOID and BD yeast extracts, but not in Kyokuto yeast extract. Among them was urea, which was also present in polypeptone, and it clearly induced cell lysis. Deletion of the ure2 gene, which is responsible for utilizing urea, abolished the lytic effect of urea. The effect of urea was suppressed by deletion of pub1, and a similar phenotype was observed in the presence of polypeptone. Thus, urea is an inducer of cell lysis in S. pombe ?ura4 cells. PMID- 28345449 TI - Biocompatibility of PCL/PLGA-BCP porous scaffold for bone tissue engineering applications. AB - In this study, biomimic porous polycaprolactone/poly (lactide-co-glycolide) loading biphasic tricalcium phosphate (PCL/PLGA-BCP) scaffolds were fabricated successfully by solvent evaporation method. The distribution of biphasic tricalcium phosphate (BCP) in polycaprolactone/poly (lactide-co-glycolide) (PCL/PLGA) scaffold was confirmed by micro-computed tomography (micro-CT) scanning, scanning electron microscope (SEM) observation and Energy-dispersive X ray Spectroscopy (EDS) analysis. The hydrophilicity of the scaffolds was confirmed by contact angle measurement. In in vitro experiments, proliferation of human bone marrow mesenchymal stem cell (hBMSCs) and its osteoblastic differentiation on scaffold were assessed for 1, 2 and 3 weeks using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, fluorescence observation, hematoxylin & eosin (H&E) staining and real-time polymerase chain reaction (RT-PCR). In in vivo experiments, ossification was observed using micro CT analysis and histological staining. PMID- 28345450 TI - Erratum. AB - Weber, K. (2017). Differences in Types and Incidence of Neoplasms in Wistar Han and Sprague-Dawley Rats. J Toxicol Pathol45, 64-75. (Original DOI: 10.1177/0192623316672075) In the January 2017 issue of Toxicologic Pathology, a number of in text Table citations were incorrectly labeled. The following are the sentences with corrected Table number (this has also been corrected in the online version): Many fewer neoplasms are recorded for the endocrine pancreas compared with islet cell tumor incidences (Table 3). The data presented in Table 4 are consistent with the high incidences mentioned for keratoacanthomas by various authors for SD (M. Chandra, Riley, and Johnson 1992; Nakazawa et al. 2001) and Wistar (Poteracki and Walsh 1998) rats. Mammary gland neoplasms are considered a major cause of morbidity/death (Weber et al. 2011; Table 6). The most common tumor in male F344 rats is the interstitial (Leydig) cell tumor at a mean incidence of 81% (Mitsumori and Elwell 1998; NTP 2010) but is also reported to reach almost 100% (Nolte et al. 2010; Table 6). Incidences at >0.5% are only reported for granulosa cell tumors or theca granulosa cell tumors, and the highest incidences are noted in Wistar strains (Table 7). Stromal sarcoma and leiomyoma were noted also at incidences >0.5% (Table 9). In Table 9, adenomas of the pars intermedia and anterior are combined due to the fact that several pathologists did not differentiate between these tumor types. PMID- 28345451 TI - The impact of advanced proteomics in the search for markers and therapeutic targets of bladder cancer. AB - Bladder cancer is the most common cancer of the urinary tract and can be avoided through proper surveillance and monitoring. Several genetic factors are known to contribute to the progression of bladder cancer, many of which produce molecules that serve as cancer biomarkers. Blood, urine, and tissue are commonly analyzed for the presence of biomarkers, which can be derived from either the nucleus or the mitochondria. Recent advances in proteomics have facilitated the high throughput profiling of data generated from bladder cancer-related proteins or peptides in parallel with high sensitivity and specificity, providing a wealth of information for biomarker discovery and validation. However, the transmission of screening results from one laboratory to another remains the main disadvantage of these methods, a fact that emphasizes the need for consistent and standardized procedures as suggested by the Human Proteome Organization. This review summarizes the latest discoveries and progress of biomarker identification for the early diagnosis, projected prognosis, and therapeutic response of bladder cancer, informs the readers of the current status of proteomic-based biomarker findings, and suggests avenues for future work. PMID- 28345452 TI - l-Glutamine supplementation promotes an improved energetic balance in Walker-256 tumor-bearing rats. AB - We evaluated the effects of supplementation with oral l-glutamine in Walker-256 tumor-bearing rats. A total of 32 male Wistar rats aged 54 days were randomly divided into four groups: rats without Walker-256 tumor, that is, control rats (C group); control rats supplemented with l-glutamine (CG group); Walker-256 tumor rats without l-glutamine supplementation (WT group); and WT rats supplemented with l-glutamine (WTG group). l-Glutamine was incorporated into standard food at a proportion of 2 g/100 g (2%). After 10 days of the experimental period, the jejunum and duodenum were removed and processed. Protein expression levels of key enzymes of gluconeogenesis, that is, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, were analyzed by western blot and immunohistochemical techniques. In addition, plasma corticosterone, glucose, insulin, and urea levels were evaluated. The WTG group showed significantly increased plasma glucose and insulin levels ( p < 0.05); however, plasma corticosterone and urea remained unchanged. Moreover, the WTG group showed increased immunoreactive staining for jejunal phosphoenolpyruvate carboxykinase and increased expression of duodenal glucose-6-phosphatase. Furthermore, the WTG group presented with less intense cancer cachexia and slower tumor growth. These results could be attributed, at least partly, to increased intestinal gluconeogenesis and insulinemia, and better glycemia maintenance during fasting in Walker-256 tumor rats on a diet supplemented with l-glutamine. PMID- 28345453 TI - Tumor suppressor miR-29c regulates radioresistance in lung cancer cells. AB - Radiotherapy is an important treatment option for non-small cell lung carcinoma patients. Despite the appropriate use of radiotherapy, radioresistance is a biological behavior of cancer cells that limits the efficacy of this treatment. Deregulation of microRNAs contributes to the molecular mechanism underlying resistance to radiotherapy in cancer cells. Although the functional roles of microRNAs have been well described in lung cancer, their functional roles in radioresistance are largely unclear. In this study, we established a non-small cell lung carcinoma Calu-1 radioresistant cell line by continuous exposure to therapeutic doses of ionizing radiation as a model to investigate radioresistance associated microRNAs. Our data show that 50 microRNAs were differentially expressed in Calu-1 radioresistant cells (16 upregulated and 34 downregulated); furthermore, well-known and novel microRNAs associated with resistance to radiotherapy were identified. Gene ontology and enrichment analysis indicated that modulated microRNAs might regulate signal transduction, cell survival, and apoptosis. Accordingly, Calu-1 radioresistant cells were refractory to radiation by increasing cell survival and reducing the apoptotic response. Among deregulated microRNAs, miR-29c was significantly suppressed. Reestablishment of miR-29c expression in Calu-1 radioresistant cells overcomes the radioresistance through the activation of apoptosis and downregulation of Bcl-2 and Mcl-1 target genes. Analysis of The Cancer Genome Atlas revealed that miR-29c is also suppressed in tumor samples of non-small cell lung carcinoma patients. Notably, we found that low miR-29c levels correlated with shorter relapse-free survival of non-small cell lung carcinoma patients treated with radiotherapy. Together, these results indicate a new role of miR-29c in radioresistance, highlighting their potential as a novel biomarker for outcomes of radiotherapy in lung cancer. PMID- 28345454 TI - Genome-wide profiling of micro-RNA expression in gefitinib-resistant human lung adenocarcinoma using microarray for the identification of miR-149-5p modulation. AB - To understand the mechanism involved in gefitinib resistance, we established gefitinib-resistant human HCC827/GR-8-1 cell line from the parental HCC827 cell line. We compared the micro-RNA expression profiles of the HCC827 cells HCC827/GR 8-1 using Agilent micro-RNA microarrays. The micro-RNAs, such as the miR-149-5p, were up- or downregulated and associated with acquired gefitinib resistance. Quantitative real-time polymerase chain reaction was then performed to verify the expression patterns of different micro-RNAs. The result showed that miR-149-5p was upregulated in the HCC827/GR-8-1 cell line. To investigate the biological function of miR-149-5p in non-small cell lung cancer cells acquired gefitinib resistance, we examined cell proliferation using a cell counting kit-8 assay. Cell viability was evaluated after the miR-149-5p mimics, inhibitors, and negative control were separately transfected into the non-small cell lung cancer cells. The results showed that the non-small cell lung cancer cells transfected with miR-149-5p mimics exhibited reduced cell motility. The drug-sensitivity assay results revealed that the overexpression of miR-149-5p effectively evaluates the half maximal inhibitory concentration values of the cell in response to gefitinib, and the downregulation of miR-149-5p can attenuate the half maximal inhibitory concentration values of the cell lines in response to gefitinib. Furthermore, the levels of miR-149-5p in the HCC827 and HCC827/GR-8-1 cells were inversely correlated with caspase-3 expression. In conclusion, this study revealed that miR-149-5p is upregulated in the HCC827/GR-8-1 cells and involved in the acquired gefitinib resistance. PMID- 28345455 TI - Recurrent epigenetic silencing of the PTPRD tumor suppressor in laryngeal squamous cell carcinoma. AB - Cellular processes like differentiation, mitotic cycle, and cell growth are regulated by tyrosine kinases with known oncogenic potential and tyrosine phosphatases that downmodulate the first. Therefore, tyrosine phosphatases are recurrent targets of gene alterations in human carcinomas. We and others suggested recently a tumor suppressor function of the PTPRD tyrosine phosphatase and reported homozygous deletions of the PTPRD locus in laryngeal squamous cell carcinoma. In this study, we investigated other gene-inactivating mechanisms potentially targeting PTPRD, including loss-of-function mutations and also epigenetic alterations like promoter DNA hypermethylation. We sequenced the PTPRD gene in eight laryngeal squamous cell carcinoma cell lines but did not identify any inactivating mutations. In contrast, by bisulfite pyrosequencing of the gene promoter region, we identified significantly higher levels of methylation (p = 0.001 and p = 0.0002, respectively) in 9/14 (64%) laryngeal squamous cell carcinoma cell lines and 37/79 (47%) of primary laryngeal squamous cell carcinoma tumors as compared to normal epithelium of the upper aerodigestive tract. There was also a strong correlation (p = 0.0001) between methylation and transcriptional silencing for the PTPRD gene observed in a cohort of 497 head and neck tumors from The Cancer Genome Atlas dataset suggesting that DNA methylation is the main mechanism of PTPRD silencing in these tumors. In summary, our data provide further evidence of the high incidence of PTPRD inactivation in laryngeal squamous cell carcinoma. We suggest that deletions and loss-of-function mutations are responsible for PTPRD loss only in a fraction of cases, whereas DNA methylation is the dominating mechanism of PTPRD inactivation. PMID- 28345456 TI - Overexpression of miR-10b in colorectal cancer patients: Correlation with TWIST-1 and E-cadherin expression. AB - MicroRNAs are emergent players of epigenetics that function as oncogenes or tumor suppressors and that have been implicated in regulating diverse cellular pathways. MiR-10b is an oncogenic microRNA involved in tumor invasion and metastasis in various cancers. Our data have shown that miR-10b is overexpressed in colorectal cancer samples in comparison with non-tumorous adjacent mucosa (p = 0.0025) and that it is associated with severe features such as tumor size >5 cm (p = 0.023), distant metastasis (p = 0.0022), non-differentiated tumors (p = 0.016), and vascular invasion (p = 0.01). Regarding the regulation of its expression, positive correlation between the loss of miR-10b and aberrant DNA methylation (p = 0.02) as well as a loss of TWIST-1 messenger RNA (p = 0.018) have been observed. Furthermore, expression analysis of the downstream miR-10b targets has shown that there are associations between low HOXD10 messenger RNA and E-cadherin protein levels (p < 0.0001, p = 0.0008, respectively) and overexpression of miR-10b. Our data suggests that overexpression of miR-10b results from high levels of TWIST-1 and may induce a decrease of E-cadherin membranous protein levels, thus contributing to the acquisition of metastatic phenotypes in colorectal cancer. PMID- 28345457 TI - Special AT-rich sequence binding protein 1 promotes tumor growth and metastasis of esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma is one of the most aggressive malignancies worldwide. Special AT-rich sequence binding protein 1 is a nuclear matrix attachment region binding protein which participates in higher order chromatin organization and tissue-specific gene expression. However, the role of special AT rich sequence binding protein 1 in esophageal squamous cell carcinoma remains unknown. In this study, western blot and quantitative real-time polymerase chain reaction analysis were performed to identify differentially expressed special AT rich sequence binding protein 1 in a series of esophageal squamous cell carcinoma tissue samples. The effects of special AT-rich sequence binding protein 1 silencing by two short-hairpin RNAs on cell proliferation, migration, and invasion were assessed by the CCK-8 assay and transwell assays in esophageal squamous cell carcinoma in vitro. Special AT-rich sequence binding protein 1 was significantly upregulated in esophageal squamous cell carcinoma tissue samples and cell lines. Silencing of special AT-rich sequence binding protein 1 inhibited the proliferation of KYSE450 and EC9706 cells which have a relatively high level of special AT-rich sequence binding protein 1, and the ability of migration and invasion of KYSE450 and EC9706 cells was distinctly suppressed. Special AT-rich sequence binding protein 1 could be a potential target for the treatment of esophageal squamous cell carcinoma and inhibition of special AT-rich sequence binding protein 1 may provide a new strategy for the prevention of esophageal squamous cell carcinoma invasion and metastasis. PMID- 28345458 TI - Proteasome expression and activity in cancer and cancer stem cells. AB - Proteasome is a multi-protein organelle that participates in cellular proteostasis by destroying damaged or short-lived proteins in an organized manner guided by the ubiquitination signal. By being in a central place in the cellular protein complement homeostasis, proteasome is involved in virtually all cell processes including decisions on cell survival or death, cell cycle, and differentiation. These processes are important also in cancer, and thus, the proteasome is an important regulator of carcinogenesis. Cancers include a variety of cells which, according to the cancer stem cell theory, descend from a small percentage of cancer stem cells, alternatively termed tumor-initiating cells. These cells constitute the subsets that have the ability to propagate the whole variety of cancer and repopulate tumors after cytostatic therapies. Proteasome plays a role in cellular processes in cancer stem cells, but it has been found to have a decreased function in them compared to the rest of cancer cells. This article will discuss the transcriptional regulation of proteasome sub-unit proteins in cancer and in particular cancer stem cells and the relationship of the proteasome with the pluripotency that is the defining characteristic of stem cells. Therapeutic opportunities that present from the understanding of the proteasome role will also be discussed. PMID- 28345459 TI - N6-Isopentenyladenosine promoted HeLa cell apoptosis through inhibitions of AKT and transforming growth factor beta-activated kinase 1 activation. AB - N6-Isopentenyladenosine, a member of the family of plant hormones, possesses anti cancer activities on a number of cancer cell lines. However, its mode of action in cervical cancer cell remains poorly understood. Our computational docking studies showed that N6-Isopentenyladenosine could bind with the really interesting new gene domain of tumor necrosis factor receptor-associated factor 6, which is an ubiquitination E3 ligase. Tumor necrosis factor receptor associated factor 6-mediated ubiquitination is known to activate both protein kinase B (also known as AKT) and transforming growth factor beta-activated kinase 1, and the really interesting new gene domain comprises the core of the ubiquitin ligase catalytic domain. First, we evaluated the effects of iPA on cervical cancer cell line HeLa using MTT and flow cytometry. Second, we examined the effects of iPA on activation of tumor necrosis factor receptor-associated factor 6-mediated downstream targets using western blot or immunoprecipitation. iPA could reduce HeLa cell proliferation through apoptosis, and such anti-cancer activity is associated with inhibitions of both AKT and transforming growth factor beta-activated kinase 1 signaling pathways. In addition, suppression of the anti-apoptotic protein Bcl-2 and elevation of the pro-apoptotic protein Bax were also observed. Anti-proliferation properties of iPA are likely due to its binding at the really interesting new gene domain of tumor necrosis factor receptor-associated factor 6 and loss of AKT and transforming growth factor beta activated kinase 1 activities as a result of functional modulations of tumor necrosis factor receptor-associated factor 6. These results support the emerging notion that tumor necrosis factor receptor-associated factor 6 could serve as a viable target for developing new cancer therapeutics. PMID- 28345460 TI - Coactivator-associated arginine methyltransferase 1 promotes cell growth and is targeted by microRNA-195-5p in human colorectal cancer. AB - The pathogenesis of colorectal cancer remains poorly understood. Here, we show that coactivator-associated arginine methyltransferase 1 is frequently upregulated in colorectal cancer tissues and promotes cell growth in vitro and in vivo. Using bioinformatics-based prediction and luciferase reporter system, we found that coactivator-associated arginine methyltransferase 1 is post transcriptionally targeted by microRNA-195-5p in colorectal cancer. Ectopic expression of microRNA-195-5p led to the suppression of the coactivator associated arginine methyltransferase 1 3'-untranslated regions activity and downregulation of the endogenous coactivator-associated arginine methyltransferase 1 protein in colorectal cancer cells. Expression analysis verified that microRNA-195-5p was markedly downregulated in human colorectal cancer tissues, which was negatively correlated with the elevated levels of coactivator-associated arginine methyltransferase 1 protein. Enhanced levels of microRNA-195-5p in colorectal cancer cells resulted in a sharp reduction of cell proliferative and colony-formative capacities in vitro. Remarkably, restoration of coactivator-associated arginine methyltransferase 1 in microRNA-195-5p transfected colorectal cancer cells partially abrogated the inhibition of cell proliferation and colony formation mediated through microRNA-195-5p. These data confirm that microRNA-195-5p might function as an anti-tumor microRNA in colorectal cancer exerting critical control over coactivator-associated arginine methyltransferase 1 expression. The newly identified microRNA-195-5p/coactivator associated arginine methyltransferase 1 axis may act as a novel promising therapeutic target for colorectal cancer treatment. PMID- 28345461 TI - Expression and prognostic value of soluble CD97 and its ligand CD55 in intrahepatic cholangiocarcinoma. AB - The incidence rate of intrahepatic cholangiocarcinoma is rising, and treatment options are limited. Therefore, new biological markers of intrahepatic cholangiocarcinoma are needed. Immunohistochemistry and enzyme-linked immunosorbent assay were applied to analyze the expressions of CD97, CD55, and soluble CD97 in 71 patients with intrahepatic cholangiocarcinoma and 10 patients with hepatolithiasis. CD97 and CD55 were not expressed in hepatolithiatic tissues, but positive expression was observed in 76.1% (54/71) and 70.4% (50/71) of intrahepatic cholangiocarcinoma patients. The univariate analyses indicated that the positive expressions of CD97 and CD55 were related to short intrahepatic cholangiocarcinoma survival of patients (both p = 0.001). Furthermore, CD97 and CD55 expressions and biliary soluble CD97 levels were significantly associated with histological grade (p = 0.004, 0.002, and 0.012, respectively), lymph node metastases (p = 0.020, 0.038, and 0.001, respectively), and venous invasion (p = 0.003, 0.002, and 0.001, respectively). The multivariate analyses indicated that lymph node metastases (hazard ratio: 2.407, p = 0.003), positive CD55 expression (hazard ratio: 4.096, p = 0.003), and biliary soluble CD97 levels (hazard ratio: 2.434, p = 0.002) were independent risk factors for the intrahepatic cholangiocarcinoma survival. The receiver operating characteristic (ROC) curve analysis indicated that when the cutoff values of biliary soluble CD97 were 1.15 U/mL, the diagnostic value for predicting lymph node metastasis had a sensitivity of 87.5% and a specificity of 51.3%. For intrahepatic cholangiocarcinoma patient death within 60 months at a cutoff value of 0.940 U/mL, the diagnostic value sensitivity was 89.3% and the specificity was 93.3%. Biliary soluble CD97 may be a new biological marker for early diagnosis, prediction of lymph node metastasis and poor prognosis, and discovery of a therapeutic target. PMID- 28345462 TI - Functional interaction of fibroblast growth factor 8b and androgen in prostate cancer cell proliferation. AB - Fibroblast growth factor 8b and androgen play important roles in cell proliferation of prostate cancer. We investigated the effects of fibroblast growth factor 8b and androgen on the proliferation of prostate cell lines and the corresponding intracellular mechanisms. It is found that dihydrotestosterone and fibroblast growth factor 8b stimulated Lncap cell mitosis in a concentration responsive manner, with 30 ng/mL as the most suitable concentration, respectively. Dihydrotestosterone treatment alone did not enhance the expression and phosphorylation level of fibroblast growth factor receptor but significantly enhanced the level of fibroblast growth factor receptor phosphorylation elicited by fibroblast growth factor 8b. Phosphorylations of extracellular signal regulated kinase, p38, and c-Jun NH2-terminal kinase were stimulated by dihydrotestosterone or fibroblast growth factor 8b. Among these major downstream pathways for mitogen-activated protein kinase, c-Jun NH2-terminal kinase signaling was most significantly enhanced. Protein kinase C phosphorylation was higher than AKT by the combined stimulation of dihydrotestosterone and fibroblast growth factor 8b. The phosphorylation of CDC2 was significantly induced by dihydrotestosterone and fibroblast growth factor 8b synergetically, and Smad underwent the same induction as CDC2. So the promoting effect of fibroblast growth factor 8b on cell cycle might contribute to the G2/M transition. This study indicated that the functional interaction between fibroblast growth factor 8b and androgen was essential for the prostate cancer cell proliferation. PMID- 28345463 TI - Computational and mechanistic studies on the effect of galactoxyloglucan: Imatinib nanoconjugate in imatinib resistant K562 cells. AB - Imatinib mesylate, a BCR/ABL fusion protein inhibitor, is the first-line treatment against chronic myelogenous leukemia. In spite of its advantageous viewpoints, imatinib still has genuine impediments like undesirable side effects and tumor resistance during chemotherapy. Nanoparticles with sustainable release profile will help in targeted delivery of anticancer drugs while minimizing deleterious side effects and drug resistance. The use of biopolymers like galactoxyloglucan (PST001) for the fabrication of imatinib mesylate nanoparticles could impart its use in overcoming multidrug resistance in chronic myelogenous leukemia patients with minimal side effects. This study involved in the synthesis of PST-Imatinib nanoconjugates with appreciable drug payload and excellent cytotoxicity against drug-resistant chronic myelogenous leukemia cell line (K562) in comparison with free drug. The use of bioinformatics tool revealed better binding affinity for the drug-polysaccharide complex than the drug alone with three proteins: 3QX3 (Topoisomerase), 1M17 (EGFR tyrosine kinase domain), and 3QRJ (ABL1 kinase domain). Assessment of the biochemical, hematological, and histopathological parameters in mice upheld the security and adequacy of the nanoconjugate compared to free drug. Although perspective investigations are warranted, in a condition like drug resistance in leukemia, this nanoconjugate would display a productive approach in cancer therapeutics. PMID- 28345464 TI - MicroRNA-590-3p promotes cell proliferation and invasion by targeting inositol polyphosphate 4-phosphatase type II in human prostate cancer cells. AB - Inositol polyphosphate 4-phosphatase type II emerges as a tumor suppressor in prostate cancer, and its loss of expression is associated with poor prognosis for prostate cancer. However, the mechanism of downregulation of inositol polyphosphate 4-phosphatase type II in prostate cancer development has not yet been fully clarified. In this study, microRNA-590-3p was found to be upregulated in both prostate cancer tissues and cell lines. Overexpression of microRNA-590-3p by microRNA-590-3p mimics promoted prostate cancer cell proliferation and invasion and accelerated the growth of xenografted tumors, while microRNA-590-3p inhibitors contributed to inhibition of cellular proliferation and invasion as well as tumor growth. A dual-luciferase reporter assay and expression analysis further confirmed that inositol polyphosphate 4-phosphatase type II was a direct target of microRNA-590-3p. Enforced expression of microRNA-590-3p led to repression of inositol polyphosphate 4-phosphatase type II messenger RNA and protein expression, as well as upregulation of p-Akt, p-FoxO3a, and cyclin D1 and downregulation of p21 expression in prostate cancer cell lines. Overexpression of inositol polyphosphate 4-phosphatase type II could reduce microRNA-590-3p-induced cell proliferation and invasion as well as tumor growth, and decrease microRNA 590-3p-mediated upregulation of cyclin D1 and downregulation of p21 expression in prostate cancer cells. Taken together, our findings reveal that microRNA-590-3p is a potential onco-microRNA that participates in carcinogenesis of human prostate cancer by suppressing inositol polyphosphate 4-phosphatase type II expression and involving the Akt/FoxO3a pathway. MicroRNA-590-3p may represent a potential therapeutic target for prostate cancer patients. PMID- 28345465 TI - Demethoxycurcumin inhibited human epithelia ovarian cancer cells' growth via up regulating miR-551a. AB - Curcumin is a natural agent that has ability to dampen tumor cells' growth. However, the natural form of curcumin is prone to degrade and unstable in vitro. Here, we demonstrated that demethoxycurcumin (a curcumin-related demethoxy compound) could inhibit cell proliferation and induce apoptosis of ovarian cancer cells. Moreover, IRS2/PI3K/Akt axis was inactivated in cells treated with demethoxycurcumin. Quantitative real-time reverse transcription polymerase chain reaction demonstrated that miR-551a was down-regulated in ovarian cancer tissues and ovarian cancer cell lines. Over-expression of miR-551a inhibited cell proliferation and induced apoptosis of ovarian cancer cells, whereas down regulation of miR-551a exerted the opposite function. Luciferase assays confirmed that there was a binding site of miR-551a in IRS2, and we found that miR-551a exerted tumor-suppressive function by targeting IRS2 in ovarian cancer cells. Remarkably, miR-551a was up-regulated in the cells treated with demethoxycurcumin, and demethoxycurcumin suppressed IRS2 by restoration of miR 551a. In conclusion, demethoxycurcumin hindered ovarian cancer cells' malignant progress via up-regulating miR-551a. PMID- 28345466 TI - Tumor-associated calcium signal transducer 2 regulates neovascularization of non small-cell lung cancer via activating ERK1/2 signaling pathway. AB - Lung cancer, especially the non-small-cell lung cancer, is a highly aggressive vascular cancer with excessively activated signaling pathways. Tumor-associated calcium signal transducer 2, also known as trop2, was identified to be correlated with tumor proliferation and invasion of non-small-cell lung cancer; however, the biological role of trop2 in neovascularization of non-small-cell lung cancer remained elusive. In this study, we first verified that trop2 was overexpressed in non-small-cell lung cancer tissues as well as cell lines and that the increased expression of trop2 promoted non-small-cell lung cancer cell proliferation and invasion. Then, we expanded the biological role of trop2 by in vitro and in vivo angiogenesis assay. The tubular formation analysis revealed that trop2 promoted non-small-cell lung cancer angiogenesis in vitro, and the immunohistochemistry staining of vascular markers (CD31 and CD34) provided evidences that trop2 promoted in vivo neovascularization. The results of polymerase chain reaction array revealed that trop2 promoted the expression level of two well-known angiogenesis factors MMP13 and PECAM1. By screening the trop2 related signaling pathways, we observed that excessive angiogenesis was correlated with activation of ERK1/2 signaling pathway, and ERK1/2 inhibitor (U0126) could suppress the tubular formation ability induced by trop2 expression. These results suggested that trop2 facilitated neovascularization of non-small cell lung cancer via activating ERK1/2 signaling pathway. Targeting trop2 might provide novel anti-angiogenesis strategy for non-small-cell lung cancer treatment. PMID- 28345467 TI - Mitochondrial DNA alteration in primary and metastatic colorectal cancer: Different frequency and association with selected clinicopathological and molecular markers. AB - This study attempts to determine whether primary tumor tissue could reliably represent metastatic colorectal cancer in therapy-guiding analysis of mitochondrial microsatellite instability. Therefore, we investigated the concordance of microsatellite instability in D310, D514, and D16184 (mitochondrial DNA displacement loop), and its association with selected clinical categories and KRAS/NRAS/BRAF/PIK3CA/TP53 mutation status between primary and metastatic colorectal cancer tissue from 119 patients. Displacement loop microsatellite instability was significantly more frequently seen in lymph node metastases (53.1%) compared to primary tumors (37.5%) and distant metastases (21.4%) ( p = 0.0183 and p = 0.0005). The discordant rate was significantly higher in lymph node metastases/primary tumor pairs (74.6%) than in distant metastases/primary tumor pairs (52.4%) or lymph node metastases/distant metastases pairs (51.6%) ( p = 0.0113 and p = 0.0261) with more gain (86.7%) than loss (61.1%) of microsatellite instability in the discordant lymph node metastases ( p = 0.0024). Displacement loop instability occurred significantly more frequently in lymph node metastases and distant metastases of patients with early colorectal cancer onset age <60 years ( p = 0.0122 and p = 0.0129), was found with a significant high rate in a small cohort of TP53-mutated distant metastases ( p = 0.0418), and was associated with TP53 wild-type status of primary tumors ( p = 0.0009), but did not correlate with KRAS, NRAS, BRAF, or PIK3CA mutations. In conclusion, mitochondrial microsatellite instability and its association with selected clinical and molecular markers are discordant in primary and metastatic colorectal cancer, which could have importance for surveillance and therapeutic strategies. PMID- 28345468 TI - Surface-bound galectin-4 regulates gene transcription and secretion of chemokines in human colorectal cancer cell lines. AB - One long-term complication of chronic intestinal inflammation is the development of colorectal cancer. However, the mechanisms linking inflammation to the colorectal tumorigenesis are poorly defined. Previously, we have demonstrated that galectin-4 is predominantly expressed in the luminal epithelia of the gastrointestinal tract, and its loss of expression plays a key role in the colorectal tumorigenesis. However, the mechanism by which galectin-4 regulates inflammation-induced tumorigenesis is unclear. Here, we show that galectin-4 secreted by the colorectal cancer cell lines was bound to the cell surface. Neutralization of surface-bound galectin-4 with anti-galectin-4 antibody resulted in increased cell proliferation with concomitant secretion of several chemokines into the extracellular medium. Neutralization of the surface-bound galectin-4 also resulted in the up-regulation of transcription of 29 genes, several of which are components of multiple inflammation signaling pathways. In an alternate experiment, binding of recombinant galectin-4 protein to cell surface of the galectin-4-negative colorectal cancer cells resulted in increased p27, and decreased cyclin D1 and c-Myc levels, leading to cell cycle arrest and apoptosis. Together, these data demonstrated that surface-bound galectin-4 is a dual function protein-down-regulating cell proliferation and chemokine secretion in galectin-4-expressing colorectal cancer cells on one hand and inducing apoptosis in galectin-4-negative colorectal cancer cells on the other hand. PMID- 28345469 TI - The role of estradiol metabolism in urogenital schistosomiasis-induced bladder cancer. AB - Urogenital schistosomiasis is a neglected tropical disease that can lead to bladder cancer. How urogenital schistosomiasis induces carcinogenesis remains unclear, although there is evidence that the human blood fluke Schistosoma haematobium, the infectious agent of urogenital schistosomiasis, releases estradiol-like metabolites. These kind of compounds have been implicated in other cancers. Aiming for enhanced understanding of the pathogenesis of the urogenital schistosomiasis-induced bladder cancer, here we review, interpret, and discuss findings of estradiol-like metabolites detected in both the parasite and in the human urine during urogenital schistosomiasis. Moreover, we predict pathways and enzymes that are involved in the production of these metabolites emphasizing their potential effects on the dysregulation of the tumor suppressor gene p53 expression during urogenital schistosomiasis. Enhanced understanding of these potential carcinogens may not only shed light on urogenital schistosomiasis induced neoplasia of the bladder, but would also facilitate development of interventions and biomarkers for this and other infection-associated cancers at large. PMID- 28345470 TI - The role and safe use of the ambulatory syringe pump in palliative and end-of life care. PMID- 28345472 TI - Politics and palliative care: Sierra Leone. AB - Dion Smyth's review of palliative nursing on the internet. PMID- 28345473 TI - Exploring end-of-life care for South Asian kidney patients: interviewer reflections. AB - The reduction of inequalities in access to quality care has been a central tenet of UK health policy. Ethnic minorities may experience additional inequalities because of language and other cultural barriers. This article reports interviewer reflections of conducting interviews with South Asian kidney patients about their experiences of end-of-life care. It explores themes which emerged from the analysis of a focus group held with eight bilingual research interviewers. The relevance of these themes to understanding inequalities and access to end-of-life care is discussed; together with the potential for the research process to contribute to service improvement. PMID- 28345474 TI - Assessment, treatment goals and interventions for oedema/lymphoedema in palliative care. AB - BACKGROUND: Little is known about the treatment of oedema in palliative care patients. AIM: To outline the assessment, goals, and interventions for patients with oedema. METHOD: A 6-month chart review of a specialist physiotherapy-led oedema service was carried out. RESULTS: Of the sample group (n=63), 28.6% of patients had lymphoedema, 15.9% had non-lymphatic oedema, 46% had mixed oedema and 9.8% had lymphorrhoea; 58 patients (92%) had cancer. The most common interventions were providing education (100%, n=63), using compression garments (58%, n=37), bandaging (51%, n=32), exercise (38%, n=24), lymphatic massage and kinesio-taping (35%, n=22 each). Treatment regime differed depending on the type of oedema present. Treatment goals were pragmatic: the most common were to maintain skin quality (54%, n=34), reduce limb volume (52%, n=32), and improve quality of life (48%, n=30). CONCLUSION: Palliative care oedema can be treated using manual methods, including compression and massage. Goals differ from other oedema populations. Research is hampered by lack of suitable measures to record skin changes and quality of life. PMID- 28345475 TI - Understanding bladder management on a palliative care unit: a grounded theory study. AB - BACKGROUND: Research regarding factors associated with nursing-initiated changes to bladder management at end-of-life is sparse. OBJECTIVES: To explore the process of Palliative Care Unit (PCU) nurses' approach to bladder management changes. METHODS: Nursing staff from one PCU in London, Canada were interviewed regarding bladder management care practices. A constructivist grounded theory was generated. RESULTS: Four interconnected themes emerged: humanity (compassionate support of patients); journey (making the most of a finite timeline); health condition (illness, functional decline); and context (orders, policies, supplies). These overlapping themes must be considered in light of ongoing changes which prompt recycling through the framework. While bladder management necessitates shared decision-making and individualised care, nurses' phronetic experience may serve to detect the presence of change and the need to consider other alternatives. CONCLUSION: End-of-life bladder management requires nurses to continually reconsider the significance of humanity, journey, health condition and context in light of ongoing changes. PMID- 28345476 TI - The association between nurses' coordination with physicians and clients' place of death. AB - AIM: Over 60% of Japanese people hope to die at home; hence, assisting clients in achieving this outcome is an important responsibility of home care providers. This study investigated the effects of nurses' relational coordination with physicians on clients' place of death in home visiting nursing (HVN) agencies. METHOD: Secondary analysis of a public survey conducted in 2015 by local governments in Kurume city, Fukuoka prefecture, Western Japan. Manager nurses from 17 HVN agencies provided data about themselves and their relational coordination with community physicians and 85 deceased clients. RESULTS: Among 85 deceased clients, 52 (61.2%) had died at home. Four regression models showed significant positive effects of HVN nurse managers' relational coordination on clients' home death (the odds ratios (95% CI) were 2.488 (1.442-4.293), 2.111 (1.014-4.396), 2.562 (1.409-4.658) and 2.275 (1.079-4.796) in models 1-4, respectively. CONCLUSION: Measuring relational coordination among HVN nursing managers and physicians indicated readiness for home death among HVN clients in an agency or community. PMID- 28345477 TI - Death cafes: another way to unlock the fear of death. PMID- 28345478 TI - The importance of interdisciplinary communication in the process of anticipatory prescribing. AB - In the UK there has been a widespread introduction of 'anticipatory prescribing' in community based palliative care. This involves general practitioners (GPs) writing prescriptions in anticipation of them being needed and has been encouraged to try to minimise the risk of patients suffering uncontrolled symptoms and distress; a key reason why terminally ill patients are admitted to hospital in contradiction of most people's preferences. This paper presents the findings from an ethnographic study of healthcare professionals across four care homes and four community sites in two regions (East Midlands and Lancashire/South Cumbria) of the UK. Data were collected from a range of community health professionals, resulting in 83 episodes of observation and 72 interviews. Findings highlight how essential good interdisciplinary communication is to the process of anticipatory prescribing and end-of-life care. This study found that when interdisciplinary communication worked well the anticipatory prescribing process could be carried out smoothly, optimising patient care. PMID- 28345480 TI - Ultrasound in the management of pleural disease. AB - INTRODUCTION: Pleural disease encompasses a large range of conditions, is a common presentation to the acute medical take and often requires comprehensive investigation and treatment. Ultrasound is well recognised as a useful investigative tool in pleural disease especially in the field of pleural effusion, pleural thickening and interventional procedures. Thoracic ultrasound (TUS) has gained widespread use by physicians as evidence has shown a reduced rate of complications when performing pleural procedures with ultrasound guidance. Areas covered: This article will review studies assessing the role of TUS in the management of pleural disease and examine ongoing research into how TUS could advance our knowledge and understanding over the next decade. Expert commentary: Physician lead thoracic ultrasound has become commonplace over the last decade, and now represents a minimum standard of safety in conducting the majority of 'bedside' pleural procedures. The current evidence points to important diagnostic and procedural roles of the use of bedside thoracic ultrasound. In the future, research developments are likely to lead to the use of thoracic ultrasound in prognostication, targeted treatment and understanding pathogenesis in pleural disease. PMID- 28345481 TI - Cost-effectiveness analysis of implementing an antimicrobial stewardship program in critical care units. AB - AIMS: To evaluate the cost-effectiveness of antimicrobial stewardship (AS) program implementation focused on critical care units based on assumptions for the Spanish setting. MATERIALS AND METHODS: A decision model comparing costs and outcomes of sepsis, community-acquired pneumonia, and nosocomial infections (including catheter-related bacteremia, urinary tract infection, and ventilator associated pneumonia) in critical care units with or without an AS was designed. Model variables and costs, along with their distributions, were obtained from the literature. The study was performed from the Spanish National Health System (NHS) perspective, including only direct costs. The Incremental Cost-Effectiveness Ratio (ICER) was analysed regarding the ability of the program to reduce multi drug resistant bacteria. Uncertainty in ICERs was evaluated with probabilistic sensitivity analyses. RESULTS: In the short-term, implementing an AS reduces the consumption of antimicrobials with a net benefit of ?71,738. In the long-term, the maintenance of the program involves an additional cost to the system of ?107,569. Cost per avoided resistance was ?7,342, and cost-per-life-years gained (LYG) was ?9,788. Results from the probabilistic sensitivity analysis showed that there was a more than 90% likelihood that an AS would be cost-effective at a level of ?8,000 per LYG. LIMITATIONS: Wide variability of economic results obtained from the implementation of this type of AS program and short information on their impact on patient evolution and any resistance avoided. CONCLUSIONS: Implementing an AS focusing on critical care patients is a long-term cost effective tool. Implementation costs are amortized by reducing antimicrobial consumption to prevent infection by multidrug-resistant pathogens. PMID- 28345479 TI - Imaging the physiological evolution of the ischemic penumbra in acute ischemic stroke. AB - We review the hemodynamic, metabolic and cellular parameters affected during early ischemia and their changes as a function of approximate cerebral blood flow ( CBF) thresholds. These parameters underlie the current practical definition of an ischemic penumbra, namely metabolically affected but still viable brain tissue. Such tissue is at risk of infarction under continuing conditions of reduced CBF, but can be rescued through timely intervention. This definition will be useful in clinical diagnosis only if imaging techniques exist that can rapidly, and with sufficient accuracy, visualize the existence of a mismatch between such a metabolically affected area and regions that have suffered cell depolarization. Unfortunately, clinical data show that defining the outer boundary of the penumbra based solely on perfusion-related thresholds may not be sufficiently accurate. Also, thresholds for CBF and cerebral blood volume ( CBV) differ for white and gray matter and evolve with time for both inner and outer penumbral boundaries. As such, practical penumbral imaging would involve parameters in which the physiology is immediately displayed in a manner independent of baseline CBF or CBF threshold, namely pH, oxygen extraction fraction ( OEF), diffusion constant and mean transit time ( MTT). Suitable imaging technologies will need to meet this requirement in a 10-20 min exam. PMID- 28345482 TI - Glu-Phe from onion (Allium Cepa L.) attenuates lipogenesis in hepatocytes. AB - A Glu-Phe (EF) was isolated from onion (Allium cepa L. cv. Sunpower). The chemical structure of EF was determined by nuclear magnetic resonance and electrospray ionization-mass (ESI-MS) spectroscopy. We showed that EF reduced lipid accumulation in mouse hepatocytes by inhibiting the expression of sterol regulatory element-binding protein-1c (SREBP-1c) and its lipogenic target genes. We also found that AMP-activated protein kinase (AMPK) was required for the inhibitory effect of EF on lipid accumulation in mouse hepatocytes. Furthermore, EF was qualified in nine onion cultivars by selective multiple reaction monitoring detection of liquid chromatography-ESI-MS. These results suggest that EF could contribute to the beneficial effect of onion supplement in maintaining hepatic lipid homeostasis. PMID- 28345483 TI - Spinal Epidural Stimulation Strategies: Clinical Implications of Locomotor Studies in Spinal Rats. AB - Significant advancements in spinal epidural stimulation (ES) strategies to enable volitional motor control in persons with a complete spinal cord injury (SCI) have generated much excitement in the field of neurorehabilitation. Still, an obvious gap lies in the ability of ES to effectively generate a robust locomotor stepping response after a complete SCI in rodents, but not in humans. In order to reveal potential discrepancies between rodent and human studies that account for this void, in this review, we summarize the findings of studies that have utilized ES strategies to enable successful hindlimb stepping in spinal rats. Recent clinical and preclinical evidence indicates that motor training with ES plays a crucial role in tuning spinal neural circuitry to generate meaningful motor output. Concurrently administered pharmacology can also facilitate the circuitry to provide near optimal motor performance in SCI rats. However, as of today, the evidence for pharmacological agents to enhance motor function in persons with complete SCI is insignificant. These and other recent findings discussed in this review provide insight into addressing the translational gap, guide the design of relevant preclinical experiments, and facilitate development of new approaches for motor recovery in patients with complete SCIs. PMID- 28345484 TI - Removal of fouling species from brackish water reverse osmosis reject stream. AB - Brine disposal from reverse osmosis (RO) systems remains a major challenge for the desalination industry especially in inland areas where discharge options are very limited. Solutions will entail the introduction of economic treatment processes that will alleviate the brine's negative impact on the environment and reduce its discharge volume. Such processes could act as an intermediary treatment process for the recycling of the brine through an additional RO stage which, for brackish water (BW) desalination, could lead to saving valuable water while reducing the amount of brine discharge. In this context, the study at hand attempts to evaluate the effectiveness of a one-step chemical process for the treatment of BWRO brine. This study seeks to determine optimal operating conditions relative to type, ratio, and dosage of alkalizing chemicals, pH and temperature, for substantially reducing the concentrations of scaling parameters such as calcium, magnesium, silica, and strontium. The results indicate that precipitation softening at pH = 11.5 using combined chemical dosages of NaOH and Na2CO3 in a ratio of 2:1 leads to substantial removal of calcium and magnesium (>95%) and moderately high removal of strontium and silica (>71%). PMID- 28345485 TI - The Effect of Tamoxifen on Thin Endometrium in Patients Undergoing Frozen-Thawed Embryo Transfer. AB - Tamoxifen has played a vital role in endocrine therapy for the treatment of estrogen receptor-positive breast cancer. We examined the effect of tamoxifen in patients with a thin endometrium in frozen-thawed embryo transfer (FET) cycles and compared the improvement in endometrial thickness (EMT) and pregnancy outcomes stratified by different etiologies of thin endometrium. A total of 226 women were recruited for a new tamoxifen protocol; all had an EMT of less than 7.5 mm in previous cycles, including natural cycle (NC), hormone replacement treatment (HRT), and ovulation induction (OI) cycles. Compared with previous cycles, tamoxifen cycles showed a significantly increased EMT (from 6.11 +/- 0.98 mm to 7.87 +/- 1.48 mm in the NC group, from 6.24 +/- 1.01 mm to 8.22 +/- 1.67 mm in the HRT group, and from 6.34 +/- 1.03 mm to 8.05 +/- 1.58 mm in the OI group; all P < .001). Patients were further divided into 3 groups based on the causes of their thin endometrium: (1) history of intrauterine adhesion (n = 34), (2) history of uterine curettage (n = 141), and (3) polycystic ovary syndrome (PCOS; n = 51). Patients with PCOS obtained the thickest EMT (9.31 +/- 1.55 mm), the lowest cycle cancellation rate (11.76%), and the highest rate of clinical pregnancy (60%) and live birth (55.56%) per transfer ( P < .001). Multivariable regression analysis showed that EMT was related to live birth (odds ratio: 1.487; 95% confidence interval: 1.172-1.887). A tamoxifen protocol improves EMT in patients after NC, HRT, and OI cycles during FET. Patients with PCOS show the most benefit from tamoxifen and achieve better pregnancy outcomes. PMID- 28345486 TI - Objective Analysis of Vaginal Ultrasound Video Clips for Exploring Uterine Peristalsis Post Vaginal and Cesarean Section Deliveries. AB - The nonpregnant uterus is characterized by cyclic contractions that assist in sperm transport to the fallopian tube, embryo transport to implantation site, and expulsion of menstrual debris. The effect of post-Cesarean section (CS) scar on uterine peristalsis is unclear, while worldwide the prevalence of CS deliveries is increasing. In this study, we developed a new objective method for analysis of dynamic characteristics of the nonpregnant uterus from transvaginal ultrasound (TVUS) recordings when the uterine cavity is not clearly observed, as may be the case in post-CS uteri. The method of active contours was utilized to detect the contours of the endometrium-myometrium interface (EMI) from sagittal cross section TVUS images of nonpregnant uteri. The contours were straightened along the uterus centerline and registered with respect to the fundal end in order to reduce the noise due to movements of the physician and the participant. A dynamic analysis was conducted on these time-dependent contours in order to explore the frequency and amplitude of the EMI motility. The analysis was conducted on TVUS video clips from 12 nonpregnant participants, 7 post-CS and 5 controls. The frequencies of the EMI motility was 0.010 to 0.064 Hz at days 8 to 17 in the control participants and 0.014 to 0.073 Hz at days 9 to 15 in post-CS participants. The maximal amplitude of motility was 0.67 to 2.00 mm and 0.48 to 2.58 mm for the control and post-CS participants, respectively. In this preliminary study, we have not observed significant difference between the EMI motility of healthy and post-CS uteri. PMID- 28345487 TI - Extranuclear Translocation of High-Mobility Group A1 Reduces the Invasion of Extravillous Trophoblasts Involved in the Pathogenesis of Preeclampsia: New Aspect of High-Mobility Group A1. AB - OBJECTIVE: High-mobility group A1 (HMGA1) protein is known to express in trophoblast; however, the role of migration has not been reported to date. In this study, we investigated the role of HMGA1 on the pathogenesis of preeclampsia using immortalized human trophoblast cell (HTR-8/SVneo). MATERIALS AND METHODS: We investigated HMGA1 expression in cytotrophoblasts derived from our preeclampsia model mouse, the CD40L mouse, using immunofluorescence. Wound healing and transwell migration assays were also performed using HTR-8/SVneo (extravillous trophoblast) cells transfected with DNA or siRNA of HMGA1. The effect of extranuclear translocation of HMGA1 on the migration of extravillous trophoblastic cells was evaluated using deoxycholic acid (DCA). RESULTS: HMGA1 was expressed exclusively in the nuclei of trophoblasts derived from control mice; cytoplasmic expression was observed only in CD40L mice with preeclampsia. Furthermore, overexpression of HMGA1 in the nuclei of HTR-8/SVneo cells stimulated cell proliferation and migration. Translocation of nuclear HMGA1 to cytoplasm treated with DCA reduced cell migration. CONCLUSIONS: Collectively, these findings demonstrate that proper subcellular localization of HMGA1 is important for its function in trophoblast cells, and suggest that aberrant cytoplasmic expression of HMGA1 contributes to the pathogenesis of preeclampsia through impairment of trophoblast migration. PMID- 28345488 TI - Deep Infiltrating Endometriosis and Endometrial Adenocarcinoma Express High Levels of Myostatin and Its Receptors Messenger RNAs. AB - Myostatin is a growth factor member of the transforming growth factor beta superfamily, which is known to play major roles in cell proliferation and differentiation. The present study investigated the messenger RNA (mRNA) expression of myostatin and myostatin receptors (activin receptor-like kinase 4 [ALK4], transforming growth factor (TGF)-beta type I receptor kinase [ALK5] and activin receptor type IIB [ActRIIB]) in endometrium of healthy women during menstrual cycle as well as in benign (endometriosis, polyps) and malignant (endometrial adenocarcinoma) conditions. Endometrial specimens were collected by hysteroscopy, whereas endometriotic lesions were collected by laparoscopy, and adenocarcinomas were sampled after hysterectomy. Total RNA was extracted from tissue homogenates, and gene expression was assessed by quantitative real-time polymerase chain reaction. Myostatin and myostatin receptors mRNAs were expressed by healthy endometrium throughout the menstrual cycle, with no differences between the proliferative and secretory phase. The highest myostatin mRNA expression was found in patients with deep infiltrating endometriosis (DIE) and in endometrial carcinoma; expression was also found in ovarian endometrioma (OMA ) and endometrial polyps. Myostatin receptors mRNA expression was higher in DIE and adenocarcinomas compared to control endometrium. The expression of ALK5 and ActRIIB in OMA was higher than in controls, whereas polyps had an increased expression of ALK5 mRNA. In conclusion, the present data showed for the first time the expression of myostatin in healthy endometrium and a higher expression in endometriosis and endometrial cancer, suggesting myostatin involvement in human endometrial physiology and related pathologies. PMID- 28345489 TI - Primary Culture of Human Cumulus Cells Requires Stearoyl-Coenzyme A Desaturase 1 Activity for Steroidogenesis and Enhancing Oocyte In Vitro Maturation. AB - Stearoyl-coenzyme A desaturase 1 (SCD1) is a key enzyme in lipid metabolism and is expressed in cumulus cells. The objective of the present study was to evaluate the effect of SCD1 inhibition in human cumulus cells on triglyceride content, steroidogenesis, and oocyte in vitro maturation. Human cumulus cells were exposed to SCD1 inhibitor CAY10566 (SCDinhib) alone or in combination with oleic acid in primary culture. The SCDinhib markedly suppressed triglyceride accumulation ( 47%, P = .01), aromatase gene expression (-36%, P = .02), and estradiol production (-49%, P = .01) even at a dose not affecting cell viability and apoptosis. Human immature oocytes at the germinal vesicle (GV) stage were cocultured with pretreated cumulus cells. The rate of oocytes reaching the metaphase II stage was significantly lower in coculture with SCDinhib-treated cumulus cells than with control cumulus cells (-18%, P < .01), which recovered by oleic acid supplementation. This finding on in vitro maturation rate was also reproducible with mouse GV oocytes. The results suggest that SCD1 activity is required for cumulus cell lipid storage and steroidogenesis. In addition, oocyte maturation is negatively affected by SCD1 inhibition in cumulus cells, possibly due to a deficient lipid-mediated paracrine support. PMID- 28345490 TI - Challenges and complexity of functionality evaluation of flavan-3-ol derivatives. AB - Flavan-3-ol derivatives are common plant-derived bioactive compounds. In particular, (-)-epigallocatechin-3-O-gallate shows various moderate biological activities without severe toxicity, and its health-promoting effects have been widely studied because it is a main ingredient in green tea and is commercially available at low cost. Although various biologically active flavan-3-ol derivatives are present as minor constituents in plants as well as in green tea, their biological activities have yet to be revealed, mainly due to their relative unavailability. Here, I outline the major factors contributing to the complexity of functionality studies of flavan-3-ol derivatives, including proanthocyanidins and oligomeric flavan-3-ols. I emphasize the importance of conducting structure activity relationship studies using synthesized flavan-3-ol derivatives that are difficult to obtain from plant extracts in pure form to overcome this challenge. Further discovery of these minor constituents showing strong biological activities is expected to produce useful information for the development of functional health foods. PMID- 28345491 TI - A comparison of toxicities in acute myeloid leukemia patients with and without renal impairment treated with decitabine. AB - Purpose There are limited data regarding the clinical use of decitabine for the treatment of acute myeloid leukemia in patients with a serum creatinine of 2 mg/dL or greater. Methods We retrospectively evaluated 111 patients with acute myeloid leukemia who had been treated with decitabine and compared the development of toxicities during cycle 1 in those with normal renal function (creatinine clearance greater than or equal to 60 mL/min) to those with renal dysfunction (creatinine clearance less than 60 mL/min). Results Notable differences in the incidence of grade >=3 cardiotoxicity (33% of renal dysfunction patients vs. 16% of normal renal function patients, p = 0.042) and respiratory toxicity (40% of renal dysfunction patients vs. 14% of normal renal function patients, p = 0.0037) were observed. The majority of heart failure, myocardial infarction, and atrial fibrillation cases occurred in the renal dysfunction group. The odds of developing grade >=3 cardiotoxicity did not differ significantly between patients with and without baseline cardiac comorbidities (OR 1.43, p = 0.43). Conclusions This study noted a higher incidence of grade >=3 cardiac and respiratory toxicities in decitabine-treated acute myeloid leukemia patients with renal dysfunction compared to normal renal function. This may prompt closer monitoring, regardless of baseline cardiac comorbidities. Further evaluation of decitabine in patients with renal dysfunction is needed. PMID- 28345492 TI - Rasburicase-induced methemoglobinemia: The eyes do not see what the mind does not know. AB - Rasburicase is indicated for the prevention and treatment of tumor lysis syndrome which can be a potentially life-threatening emergency. The drug has oxidizing potential and as an adverse effect, it can convert the ferrous form of iron in erythrocytes to its ferric form resulting in the formation of methemoglobin which makes the heme component incapable of carrying oxygen. Patients with glucose-6 phosphate dehydrogenase enzyme deficiency are at high risk of methemoglobinemia from oxidizing agents. Symptoms of methemoglobinemia range from none to life threatening hypoxemia, cyanosis and respiratory compromise. Treatment is indicated at levels above 20% and at lower levels if the patient is significantly anemic. We present a case of a 60-year-old male with diffuse large B cell lymphoma at high risk of tumor lysis syndrome. Rasburicase was administered to prevent renal failure and further rise in uric acid. Twenty-four hours later, a bedside pulse oximetry showed an oxygen saturation ranging from 60 to 65% with minimal cyanosis. Co-oximetry revealed a methemoglobin level of 9.8%. Methylene blue was administered and the methemoglobin level decreased to 2.6%. However, the patient developed hemolysis several hours later, likely secondary to rasburicase and methylene blue, requiring transfusion support. We discuss this potentially fatal and initially asymptomatic adverse effect of rasburicase along with diagnostic and treatment considerations, and review the cases described in the current literature. PMID- 28345493 TI - Genetic risk scores, sex and dietary factors interact to alter serum uric acid trajectory among African-American urban adults. AB - Serum uric acid (SUA), a causative agent for gout among others, is affected by both genetic and dietary factors, perhaps differentially by sex. We evaluated cross-sectional (SUAbase) and longitudinal (SUArate) associations of SUA with a genetic risk score (GRS), diet and sex. We then tested the interactive effect of GRS, diet and sex on SUA. Longitudinal data on 766 African-American urban adults participating in the Healthy Aging in Neighborhood of Diversity across the Lifespan study were used. In all, three GRS for SUA were created from known SUA associated SNP (GRSbase (n 12 SNP), GRSrate (n 3 SNP) and GRStotal (n 15 SNP)). Dietary factors included added sugar, total alcohol, red meat, total fish, legumes, dairy products, caffeine and vitamin C. Mixed-effects linear regression models were conducted. SUAbase was higher among men compared with that among women, and increased with GRStotal tertiles. SUArate was positively associated with legume intake in women (gamma=+0.14; 95 % CI +0.06, +0.22, P=0.001) and inversely related to dairy product intake in both sexes combined (gamma=-0.042; 95 % CI -0.075, -0.009), P=0.010). SUAbase was directly linked to alcohol consumption among women (gamma=+0.154; 95 % CI +0.046, +0.262, P=0.005). GRSrate was linearly related to SUArate only among men. Legume consumption was also positively associated with SUArate within the GRStotal's lowest tertile. Among women, a synergistic interaction was observed between GRSrate and red meat intake in association with SUArate. Among men, a synergistic interaction between low vitamin C and genetic risk was found. In sum, sex-diet, sex-gene and gene-diet interactions were detected in determining SUA. Further similar studies are needed to replicate our findings. PMID- 28345494 TI - Adaptation and validation of the Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog) in a low-literacy setting in sub-Saharan Africa. AB - OBJECTIVE: This study aimed to assess the feasibility of a low-literacy adaptation of the Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog) for use in rural sub-Saharan Africa (SSA) for interventional studies in dementia. No such adaptations currently exist. METHODS: Tanzanian and Nigerian health professionals adapted the ADAS-Cog by consensus. Validation took place in a cross sectional sample of 34 rural-dwelling older adults with mild/moderate dementia alongside 32 non-demented controls in Tanzania. Participants were oversampled for lower educational level. Inter-rater reliability was conducted by two trained raters in 22 older adults (13 with dementia) from the same population. Assessors were blind to diagnostic group. RESULTS: Median ADAS-Cog scores were 28.75 (interquartile range (IQR), 22.96-35.54) in mild/moderate dementia and 12.75 (IQR 9.08-16.16) in controls. The area under the receiver operating characteristic curve (AUC) was 0.973 (95% confidence interval (CI) 0.936-1.00) for dementia. Internal consistency was high (Cronbach's alpha 0.884) and inter-rater reliability was excellent (intra-class correlation coefficient 0.905, 95% CI 0.804-0.964). CONCLUSION: The low-literacy adaptation of the ADAS-Cog had good psychometric properties in this setting. Further evaluation in similar settings is required. PMID- 28345495 TI - People with dementia as peer workers, challenges, and benefits: a thematic analysis and nominal groups study. AB - BACKGROUND: There are national initiatives to involve service users in service delivery. However, programs employing people with dementia as peer support workers (PSWs) in memory services are in their infancy. This study is the first to explore the challenges and benefits to staff and peers involved in such a program. METHODS: Focus groups, structured based on nominal groups (NG) methodology were run with PSWs and clinical staff from two memory services. In total, there were 12 participants, with three focus groups: PSWs alone (n = 3); staff members alone (n = 6); and PSWs and staff members combined (n = 6). Data were analyzed through thematic analysis of recorded session content and the ranking of themes inherent in an NG approach. RESULTS: Perceived benefits of the PSW program were similar for staff and PSWs and included personal benefits for PSWS and stereotype reduction for staff. More challenges were reported by staff than PSWs, but both groups agreed that role definition and dealing with the cognitive deterioration inherent in dementia were key issues. CONCLUSIONS: The PSW program does have benefits for involved staff and PSWs. However, the challenges identified highlight the need for careful and consensual setup and consideration of power dynamics, with agreed roles and clear guidelines to deal with cognitive deterioration. PMID- 28345496 TI - Toward a Better Nutritional Aiding in Disasters: Relying on Lessons Learned during the Bam Earthquake. AB - : Introduction Examining various problems in the aftermath of disasters is very important to the disaster victims. Managing and coordinating food supply and its distribution among the victims is one of the most important problems after an earthquake. Therefore, the purpose of this study was to recognize problems and experiences in the field of nutritional aiding during an earthquake. METHODS: This qualitative study was of phenomenological type. Using the purposive sampling method, 10 people who had experienced nutritional aiding during the Bam Earthquake (Iran; 2003) were interviewed. Colaizzi's method of analysis was used to analyze interview data. RESULTS: The findings of this study identified four main categories and 19 sub-categories concerning challenges in the nutritional aiding during the Bam Earthquake. The main topics included managerial, aiding, infrastructural, and administrative problems. CONCLUSIONS: The major problems in nutritional aiding include lack of prediction and development of a specific program of suitable nutritional pattern and nutritional assessment of the victims in critical conditions. Forming specialized teams, educating team members about nutrition, and making use of experts' knowledge are the most important steps to resolve these problems in the critical conditions; these measures are the duties of the relevant authorities. Nekouie Moghadam M , Amiresmaieli M , Hassibi M , Doostan F , Khosravi S . Toward a better nutritional aiding in disasters: relying on lessons learned during the Bam Earthquake. Prehosp Disaster Med. 2017;32(4):382-386. PMID- 28345497 TI - Scoping the role and education needs of practice nurses in London. AB - : Aims To identify education priorities for practice nursing across eight London Clinical Commissioning Groups (CCGs); to identify the education, training, development and support needs of practice nurses in undertaking current and future roles. BACKGROUND: The education needs of practice nurses have long been recognised but their employment status means that accessing education requires the support of their GP employer. This study scopes the educational requirements of the practice nurse workforce and working with educational providers and commissioners describes a coherent educational pathway for practice nurses. METHOD: A survey of practice nurses to scope their educational attainment needs was undertaken. Focus groups were carried out which identified the education, training, development and support needs of practice nurses to fulfil current and future roles. Findings A total of 272 respondents completed the survey. Practice nurses took part in three focus groups (n=34) and one workshop (n=39). Findings from this research indicate a practice nurse workforce which lacked career progression, role autonomy or a coherent educational framework. Practice nurses recognised the strength of their role in building relationship-centred care with patients over an extended period of time. They valued this aspect of their role and would welcome opportunities to develop this to benefit patients. CONCLUSION: This paper demonstrates an appetite for more advanced education among practice nurses, a leadership role by the CCGs in working across the whole system to address the education needs of practice nurses, and a willingness on the part of National Health Service education commissioners to commission education which meets the education needs of the practice nurse workforce. Evidence is still required, however, to inform the scope of the practice nurse role within an integrated system of care and to identify the impact of practice nursing on improving health outcomes and care of local populations. PMID- 28345498 TI - The effects of payments for pharmaceuticals: a systematic literature review. AB - The existence of different forms of out-of-pocket payments (OOPs) for pharmaceuticals across the globe provokes the question whether they can achieve more negative or positive consequences. A systematic literature review was conducted to assess the association between drug cost sharing and health care services utilization, health care costs as well as health outcomes. Studies published in The Cochrane Library, PubMed, Embase were searched with such keywords as: drug, pharmaceutical, cost sharing, out of pocket, co-payments paired with the following: impact, health outcomes, health care costs and utilization. The final review included 18 articles. A total of 11 publications reported the association between drug cost sharing and health care utilization patterns, of which nine found a statistically significant direct relationship. In all 10 publications concerned the association between drug copayments and health care costs. Majority were limited to the impact on the drug budget. Seven studies looked into the link between drug cost sharing and health outcomes, of which five reported statistically significant inverse relationship. There is some evidence for the association between drug copayments, health outcomes and health care services consumption. The optimal system of OOPs' payments for pharmaceuticals needs to prevent drugs' overconsumption and mitigate the risks of excessive cost sharing's burden. PMID- 28345499 TI - Synbiotic supplementation in lean patients with non-alcoholic fatty liver disease: a pilot, randomised, double-blind, placebo-controlled, clinical trial. AB - Although non-alcoholic fatty liver disease (NAFLD) is the leading aetiology of liver disorders in the world, there is no proven treatment for NAFLD patients with normal or low BMI. The aim of this study was to evaluate the efficacy of synbiotics supplementation in NAFLD patients with normal or low BMI. In this randomised, double-blind, placebo-controlled, clinical trial, fifty patients with NAFLD were assigned to take either a synbiotic supplement or a placebo capsule for 28 weeks. Both groups were advised to follow a healthy lifestyle. At the end of the study, hepatic steatosis and fibrosis reduced in both groups; however, the mean reduction was significantly greater in the synbiotic group rather than in the placebo group (P<0.001). Furthermore, serum levels of fasting blood sugar, TAG and most of the inflammatory mediators reduced in the synbiotic group significantly compared with the placebo group (P<0.05). Our results provide evidence that synbiotic supplementation improves the main features of NAFLD in patients with normal and low BMI, at least partially through reduction in inflammatory indices. Further studies are needed to address the exact mechanism of action of these effects. PMID- 28345500 TI - Avian malaria, ecological host traits and mosquito abundance in southeastern Amazonia. AB - Avian malaria is a vector transmitted disease caused by Plasmodium and recent studies suggest that variation in its prevalence across avian hosts is correlated with a variety of ecological traits. Here we examine the relationship between prevalence and diversity of Plasmodium lineages in southeastern Amazonia and: (1) host ecological traits (nest location, nest type, flocking behaviour and diet); (2) density and diversity of avian hosts; (3) abundance and diversity of mosquitoes; and (4) season. We used molecular methods to detect Plasmodium in blood samples from 675 individual birds of 120 species. Based on cytochrome b sequences, we recovered 89 lineages of Plasmodium from 136 infected individuals sampled across seven localities. Plasmodium prevalence was homogeneous over time (dry season and flooding season) and space, but heterogeneous among 51 avian host species. Variation in prevalence among bird species was not explained by avian ecological traits, density of avian hosts, or mosquito abundance. However, Plasmodium lineage diversity was positively correlated with mosquito abundance. Interestingly, our results suggest that avian host traits are less important determinants of Plasmodium prevalence and diversity in southeastern Amazonia than in other regions in which they have been investigated. PMID- 28345501 TI - Evaluating the submission of digital images as a method of surveillance for Ixodes scapularis ticks. AB - Widespread access to the internet is offering new possibilities for data collection in surveillance. We explore, in this study, the possibility of using an electronic tool to monitor occurrence of the tick vector of Lyme disease, Ixodes scapularis. The study aimed to compare the capacity for ticks to be identified in web-based submissions of digital images/photographs, to the traditional specimen-based identification method used by the provincial public health laboratory in Quebec, Canada. Forty-one veterinary clinics participated in the study by submitting digital images of ticks collected from pets via a website for image-based identification by an entomologist. The tick specimens were then sent to the provincial public health laboratory to be identified by the 'gold standard' method using a microscope. Of the images submitted online, 74.3% (284/382) were considered of high-enough quality to allow identification. The laboratory identified 382 tick specimens from seven different species, with I. scapularis representing 76% of the total submissions. Of the 284 ticks suitable for image-based species identification, 276 (97.2%) were correctly identified (Kappa statistic of 0.92, Z = 15.46, P < 0.001). This study demonstrates that image-based tick identification may be an accurate and useful method of detecting ticks for surveillance when images are of suitable quality. PMID- 28345502 TI - Reporting Correct p Values in VEGAS Analyses. AB - VEGAS (versatile gene-based association study) is a popular methodological framework to perform gene-based tests based on summary statistics from single variant analyses. The approach incorporates linkage disequilibrium information from reference panels to account for the correlation of test statistics. The gene based test can utilize three different types of tests. In 2015, the improved framework VEGAS2, using more detailed reference panels, was published. Both versions provide user-friendly web- and offline-based tools for the analysis. However, the implementation of the popular top-percentage test is erroneous in both versions. The p values provided by VEGAS2 are deflated/anti-conservative. Based on real data examples, we demonstrate that this can increase substantially the rate of false-positive findings and can lead to inconsistencies between different test options. We also provide code that allows the user of VEGAS to compute correct p values. PMID- 28345503 TI - Physical fitness and shapes of subcortical brain structures in children. AB - A few studies have recently reported that higher cardiorespiratory fitness is associated with higher volumes of subcortical brain structures in children. It is, however, unknown how different fitness measures relate to shapes of subcortical brain nuclei. We aimed to examine the association of the main health related physical fitness components with shapes of subcortical brain structures in a sample of forty-four Spanish children aged 9.7 (sd 0.2) years from the NUtraceuticals for a HEALthier life project. Cardiorespiratory fitness, muscular strength and speed agility were assessed using valid and reliable tests (ALPHA fitness test battery). Shape of the subcortical brain structures was assessed by MRI, and its relationship with fitness was examined after controlling for a set of potential confounders using a partial correlation permutation approach. Our results showed that all physical fitness components studied were significantly related to the shapes of subcortical brain nuclei. These associations were both positive and negative, indicating that a higher level of fitness in childhood is related to both expansions and contractions in certain regions of the accumbens, amygdala, caudate, hippocampus, pallidum, putamen and thalamus. Cardiorespiratory fitness was mainly associated with expansions, whereas handgrip was mostly associated with contractions in the structures studied. Future randomised controlled trials will confirm or contrast our findings, demonstrating whether changes in fitness modify the shapes of brain structures and the extent to which those changes influence cognitive function. PMID- 28345504 TI - The association between Dietary Inflammatory Index scores and the prevalence of colorectal adenoma. AB - OBJECTIVE: The Dietary Inflammatory Index (DII)TM, which was developed to characterize the inflammatory potential of a person's diet, has been shown to be associated with inflammatory conditions such as cancer. The present study aimed to investigate the association between DII scores and colorectal adenoma (CRA), a pre-cancerous condition. DESIGN: Responses to baseline dietary questionnaires were used calculate DII scores. In a cross-sectional study design, the association between DII scores and CRA prevalence was determined in men and women separately using logistic regression models. SETTING: Ten cancer screening centres across the USA. SUBJECTS: Participants were those included in the screening arm of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. RESULTS: Among the 44 278 individuals included in these analyses, men with diets in the most inflammatory quartile of DII scores had higher odds of all types of CRA (advanced, non-advanced and multiple (>1)) compared with those with diets in the least inflammatory quartile of DII scores. In fully adjusted models, compared with those with DII scores in quartile 1 (least inflammatory), males with DII scores in quartile 3 (adjusted odds ratio (aOR)=1.28; 95 % CI 1.12, 1.47) and quartile 4 (aOR=1.41; 95 % CI 1.23, 1.62) were more likely to have prevalent distal CRA. Higher DII scores, representing a more inflammatory diet, also were weakly associated with a higher prevalence of CRA in women. CONCLUSIONS: Implementing an anti-inflammatory diet may be an effective means of primary prevention of CRA, especially in men. PMID- 28345505 TI - International recognition of the Chronic Otitis Media Questionnaire 12. AB - OBJECTIVE: The Chronic Otitis Media Questionnaire 12 was developed initially in the UK to assess patient-reported health-related quality of life associated with chronic otitis media. This study aimed to determine whether this tool is applicable to the Russian population, which has a materially different healthcare system. METHOD: A total of 108 patients with different forms of chronic otitis media completed the Russian Chronic Otitis Media Questionnaire 12. RESULTS: The average Russian Chronic Otitis Media Questionnaire 12 score was 19.4 (standard deviation = 8.3). The internal consistency of the Russian Chronic Otitis Media Questionnaire 12 was high, with a Cronbach's alpha value of 0.860. CONCLUSION: The Russian version of the Chronic Otitis Media Questionnaire 12 was found to be a reliable tool for the assessment of health-related quality of life in patients with chronic otitis media. This sets the scene for international collaboration, using this tool to assess the effectiveness of surgical treatments even amongst countries with different healthcare systems. PMID- 28345506 TI - Parasite performance and host alternation: is there a negative effect in host specific and host-opportunistic parasites? AB - Environmental fluctuations are expected to require special adaptations only if they are associated with a decrease in fitness. We compared reproductive performance between fleas fed on alternating (preferred and non-preferred) hosts and fleas fed solely on either a preferred or a non-preferred host to determine whether (1) host alternation incurs an immediate negative effect, and, if yes, then (2) whether this effect is greater in a host specialist (Parapulex chephrenis) than in host generalists (Xenopsylla conformis and Synosternus cleopatrae). We also compared flea performance under alternating host regimes with different host order (initial feeding on either a preferred or a non preferred host). An immediate negative effect of alternating hosts on reproductive performance was found in P. chephrenis only. These fleas produced 44.3% less eggs that were 3.6% smaller when they fed on alternating hosts as compared with a preferred host. In contrast, X. conformis and S. cleopatrae appeared to be able to adapt their reproductive strategy to host alternation by producing higher quality offspring (on average, 3.1% faster development and 2.1% larger size) without compromising offspring number. However, the former produced eggs that were slightly, albeit significantly, smaller when it fed on alternating hosts as compared with a preferred host. Moreover, host order affected reproductive performance in host generalists (e.g. 2.8% larger eggs when the first feeding was performed on a non-preferred host), but not in a host specialist. We conclude that immediate effects of environmental fluctuation on parasite fitness depend on the degree of host specialization. PMID- 28345507 TI - Plasmodium knowlesi invasion following spread by infected mosquitoes, macaques and humans. AB - Plasmodium knowlesi is increasingly recognized as a major cause of malaria in Southeast Asia. Anopheles leucosphyrous group mosquitoes transmit the parasite and natural hosts include long-tailed and pig-tailed macaques. Despite early laboratory experiments demonstrating successful passage of infection between humans, the true role that humans play in P. knowlesi epidemiology remains unclear. The threat posed by its introduction into immunologically naive populations is unknown despite being a public health priority for this region. A two-host species mathematical model was constructed to analyse this threat. Global sensitivity analysis using Monte Carlo methods highlighted the biological processes of greatest influence to transmission. These included parameters known to be influential in classic mosquito-borne disease models (e.g. vector longevity); however, interesting ecological components that are specific to this system were also highlighted: while local vectors likely have intrinsic preferences for certain host species, how plastic these preferences are, and how this is shaped by local conditions, are key determinants of parasite transmission potential. Invasion analysis demonstrates that this behavioural plasticity can qualitatively impact the probability of an epidemic sparked by imported infection. Identifying key vector sub/species and studying their biting behaviours constitute important next steps before models can better assist in strategizing disease control. PMID- 28345508 TI - Use of a Novel, Portable, LED-Based Capillary Refill Time Simulator within a Disaster Triage Context. AB - : Introduction A simple, portable capillary refill time (CRT) simulator is not commercially available. This device would be useful in mass-casualty simulations with multiple volunteers or mannequins depicting a variety of clinical findings and CRTs. The objective of this study was to develop and evaluate a prototype CRT simulator in a disaster simulation context. METHODS: A CRT prototype simulator was developed by embedding a pressure-sensitive piezo crystal, and a single red light-emitting diode (LED) light was embedded, within a flesh-toned resin. The LED light was programmed to turn white proportionate to the pressure applied, and gradually to return to red on release. The time to color return was adjustable with an external dial. The prototype was tested for feasibility among two cohorts: emergency medicine physicians in a tabletop exercise and second year medical students within an actual disaster triage drill. The realism of the simulator was compared to video-based CRT, and participants used a Visual Analog Scale (VAS) ranging from "completely artificial" to "as if on a real patient." The VAS evaluated both the visual realism and the functional (eg, tactile) realism. Accuracy of CRT was evaluated only by the physician cohort. Data were analyzed using parametric and non-parametric statistics, and mean Cohen's Kappas were used to describe inter-rater reliability. RESULTS: The CRT simulator was generally well received by the participants. The simulator was perceived to have slightly higher functional realism (P=.06, P=.01) but lower visual realism (P=.002, P=.11) than the video-based CRT. Emergency medicine physicians had higher accuracy on portrayed CRT on the simulator than the videos (92.6% versus 71.1%; P<.001). Inter-rater reliability was higher for the simulator (0.78 versus 0.27; P<.001). CONCLUSIONS: A simple, LED-based CRT simulator was well received in both settings. Prior to widespread use for disaster triage training, validation on participants' ability to accurately triage disaster victims using CRT simulators and video-based CRT simulations should be performed. Chang TP , Santillanes G , Claudius I , Pham PK , Koved J , Cheyne J , Gausche-Hill M , Kaji AH , Srinivasan S , Donofrio JJ , Bir C . Use of a novel, portable, LED-based capillary refill time simulator within a disaster triage context. Prehosp Disaster Med. 2017;32(4):451-456. PMID- 28345509 TI - Correction: Perceptual decisions are biased by the cost to act. PMID- 28345510 TI - A cephalometric study to establish the relationship of the occlusal plane to the three different ala-tragal lines and the Frankfort horizontal plane in different head forms. AB - BACKGROUND: The aim of the study is to compare the relationship of the occlusal plane to 3 different ala-tragal lines, namely the superior, middle and inferior lines, in individuals having different head forms and its relation to the Frankfort horizontal plane. METHODOLOGY: A total of 75 lateral cephalometric radiographs of subjects with natural dentition, having full complement of teeth, between the age group of 18-25 were screened and selected. Lateral cephalogram were made for each subjects in an open mouth position. Prior to making the lateral cephalogram, radiopaque markers were placed on the superior, middle and inferior tragus points and on the inferior border of the ala of the nose. Cephalometric tracing was done over each cephalogram. RESULTS: In mesiocephalic head form the middle ala-tragal line was most parallel to the occlusal plane having a mean angle of (1.96 degrees ). In dolichocephalic headform, the superior ala-tragal line was most parallel to the occlusal plane having a mean angle of (0.48 degrees ). In brachycephalic head form, the middle ala-tragal line was most parallel to the occlusal plane having a mean angle of (2.08 degrees ). The mean angulations of occlusal plane to FH plane is 11.04 degrees , 10.16 degrees and 10.60 degrees in mesiocephalic, dolichocephalic and brachycephalic head forms, respectively. RESULTS AND CONCLUSION: The study concludes that the middle ala tragal line can be used as a reference for the mesiocephalic head form and the superior ala-tragal line for the dolichocephalic and brachycephalic head form as a reference to establish the occlusal plane. PMID- 28345511 TI - [Complete removable denture retained by symphyseal implant]. AB - INTRODUCTION: Edentulous patients often hope for stable and retentive prostheses. In very unfavorable anatomophysiological circumstances, the implant-retained removable full denture is a simple and reliable option that considerably optimizes the prosthetic balance. We present the case of one of those patients taken in charge in our department. OBSERVATION: A full edentulous 82 years old male patient was referred for a prosthetic rehabilitation. He presented with a negative mandibular crest and a very tonic peri-prosthetic musculature in the anterior region. He refused a bone augmentation surgery; we performed a piezographic mandibular prosthesis retained by a single symphyseal implant in a lingual position. The denture was stable and retentive. Comfort and masticatory efficiency were satisfactory and the psychological integration of the prosthesis was improved. DISCUSSION: Several studies focusing on octogenarian patients concluded that a complete removable denture retained by a single symphyseal implant is a simple, efficient and cost-effective option. Studies including more patients are needed. PMID- 28345512 TI - Calcifying odontogenic cysts. AB - INTRODUCTION: Calcifying odontogenic cysts (COC) represent 0.3-0.8% of all odontogenic cysts. We describe the finding and the treatment of a COC in a 67 year-old female. OBSERVATION: An asymptomatic well-limited radioluscent mandibular lesion was fortuitously discovered on the panoramic X-ray in the periapical region of teeth No. 33 and 34. Treatment consisted in enucleation and curettage. Histologic examination was in favour of a COC. At 6 years follow-up, X ray control showed new bone formation and the patient was free of symptoms. Pulp vitality was maintained in all teeth in the operated area. DISCUSSION: Total enucleation is the preferred treatment of COC. Absence of recurrence is attested by X-ray controls and pulp vitality tests. PMID- 28345513 TI - [Schizophrenia and oral health]. AB - Mental health is an essential component of general health. Schizophrenia is a severe and chronic mental illness that affects higher brain functions. It is characterized by the presence of a mental dissociation, dampened or inappropriate affects, hallucinations and delirium. Schizophrenia has also a negative impact on oral health. As schizophrenia affects 1% of the population, every practitioner concerned with oral sphere will be confronted one day or another with a patient suffering from this disease. It is therefore important to acquire essential notions. The aim of our work was to make an update about factors that may affect oral health in patients with schizophrenia. PMID- 28345514 TI - A soft-tissue mass of the anterior maxilla. PMID- 28345515 TI - Treatment of salivary stones by intraductal pneumatic lithotripsy: A preliminary presentation of the StoneBreaker with sterile bag covering. AB - INTRODUCTION: Sialendoscopy has changed the management of obstructive sialadenitis. Nowadays, minimally invasive techniques evolve to preserve salivary gland function. Intraductal lithotripsy allows stones fragmentation and retrieval without opening the salivary duct. We report our experience with the StoneBreaker (SB), a new lithotripter with improvement using a sterile bag that permits reuse of the SB without passing to sterilization. TECHNICAL NOTE: The non-sterilized SB was used into a sterile camera sleeve in 5 patients, 3 submandibular lithiases and 2 parotid lithiases. Technique and outcomes were described with a review of the literature. An explanatory video of the procedure was performed. DISCUSSION: Complete fragmentation was achieved and all fragments were extracted without any ductal damage. Utilization of the sterile sleeve did not change the SB efficiency and the procedure duration. The use of a sterile bag allowed several consecutive procedures with a single non-sterilized handpiece. However, the gas cartridge change may be more delicate when more than 80 impacts are needed. Patients remained symptoms and stones free one month after surgery. PMID- 28345516 TI - A case of bilateral megaducts: Diagnostic and treatment methods. AB - INTRODUCTION: The pathology of the saliva glands comprises both tumoral and obstructive disorders. The latter include lithiasis, stenosis and megaduct. In this paper, we describe a clinical case of bilateral megaduct, a rare pathology, using sialo-MRI imaging and a conservative diagnostic-cum-therapeutic technique, sialendoscopy with dilation followed by catheterization. CLINICAL CASE: Our female patient presented oversized parotids with an unsightly deformation of the face (parotid ducts visible beneath the skin) and itchy cheeks, from which she had suffered for several years. Sialo-MRI revealed bilateral hypertrophied parotid saliva glands. We opted to perform diagnostic sialendoscopy to explore the branches of the salivary gland system and found ducts shaped like strings of sausages associated with mucous plugs. The treatment procedure was combined with rinsing of both parotid ducts in physiological serum followed by initiation of antibiotic-corticotherapy within the saliva ducts and, lastly, by placement of transpapillary drains, which were left in place for 10 days. Immediately following the procedure, the patient felt a considerable improvement regarding both local discomfort and her cheek deformation. Postoperative control at 10 weeks by sialo-MRI confirmed the reduction of the dilation of the salivary ducts. At 3 months, the patient continued to display a marked clinical improvement despite her saliva retaining a thick consistency. She no longer suffered from pruritis or deformation of the cheeks. DISCUSSION: Sialendoscopy could become the reference treatment tool since it is both efficient and conservative. Duration of her postoperative catheterization remains to be defined. PMID- 28345517 TI - Ptosis and vertical diplopia after ligation of ethmoidal arteries. AB - The treatment of epistaxis is well codified, ligation of the ethmoidal arteries being the last resort. We report the case of a 25-year-old pregnant patient, who has had a ligation of the anterior and posterior ethmoidal arteries after a persistent epistaxis. Postoperatively, she presented a complete ptosis and an impaired eye elevation without any visual acuity disorders, evoking a lesion of the upper branch of the common oculomotor nerve (third cranial nerve). The patient totally recovered after 3 months. Anatomical study shows that the upper branch of the third cranial nerve is lying very close to the optic nerve and cannot be affected by surgery without any associated damage of the optic nerve. Thus, a vascular etiology seems to be the best explanation of the complication experienced by our patient. Ligation of the posterior ethmoidal artery should be done with caution. PMID- 28345518 TI - Oropharyngeal squamous cell carcinoma and HPV. Systematic review on overall management. AB - INTRODUCTION: Oral human papillomavirus infection amplifies the risk for oropharyngeal cancer. Human papillomavirus-associated cancers in otorhinolaryngology have typical characteristics. PATIENTS AND METHODS: To improve understanding of management, therapy and prognosis of patients with oropharyngeal human papillomavirus-associated cancers a systematic review of the literature was reported. Medline, The Cochrane Library, Embase and Scielo electronic databases were searched. The search included published articles up to December 2006. A wide search strategy was employed in order to avoid publication biases and to assess studies in which the main aspects concerning oropharyngeal squamous cell carcinoma and human papillomavirus management are analyzed. RESULTS: A total of 120 articles were identified, of which 16 matched the inclusion criteria. DISCUSSION: Patients with human papillomavirus-associated oropharyngeal cancers have distinctive risk factors such as a high number of sex partners. They are typically younger, nonusers of tobacco and alcohol and have a better prognosis. PMID- 28345519 TI - Anatomical landmarks for maxillary nerve block in the pterygopalatine fossa: A radiological study. AB - INTRODUCTION: The aim of this study was to describe the anatomical landmarks for maxillary nerve block in the pterygopalatine fossa. The risk of injury to the skull base and maxillary artery was assessed. METHODS: This retrospective study was based on the analysis of 61 consecutive computed tomography angiographies obtained from patients suffering from different pathologies. Anatomical relationships between optic canal (OC), foramen rotundum (FR), inferior orbital fissure (IOF) and puncture point (PP) were assessed. A "maxillary section" was virtually carried out on the CTs, following a plane passing through PP, IOF and FR in order to mimic the anaesthesia needle route. RESULTS: No gender difference was observed except for the PP-OC distance that was longer in men. The mean PP IOF distance was of 31.9 (+/- 0.7mm). PP-OC (43.9+/-0.5) and PP-FR (44.2+/-0.7) distances increased significantly with the patients height (PP FR=17.25+0.16*height (cm); PP-OC=20.54+0.13*height (cm)). The route to the skull base was curved, with an angle of 168+/-1.6 degrees at the FR level. The angle to reach the OC was greater than 7 degrees . DISCUSSION: With a 35-mm needle length, the probability to reach the IOF was high (79%), while the risk to injure the skull base (2%) and the optical nerve (0%) was low. Artery injuries were only found in 13% of cases. Therefore, a 35-mm needle length allows for the best efficacy/risk ratio in maxillary nerve block. PMID- 28345520 TI - [Management of patients with bradykinin-mediated angioedema in oral and maxillofacial surgery]. AB - Bradykinin-mediated angioedema (AE) is a rare disease characterized by recurrent cutaneous or mucosal angioedema. This hereditary or acquired disease is of rapid installation, non-pruritic, usually painless and can affect the face, lips, larynx, gastrointestinal tract or extremities. When the affected area involves the upper respiratory tract, laryngeal angioedema can lead to imminent death by asphyxia. This is the reason for the high mortality rate (30 %) in undiagnosed or improperly managed patients. High-risk situations in oral and maxillofacial surgery procedures should be identified preoperatively. Short-term prophylaxis must be carried-out prior to any procedure that may trigger an attack. A multi site reference center (CREAK) has been created to help clinicians to manage this disease. This article reviews the pathophysiologic mechanisms, the clinical presentations, the possible treatments, the acute strategies for attacks and different prophylactic possibilities in oral and maxillofacial surgery. PMID- 28345521 TI - [An obstructive soft palate tumor]. PMID- 28345522 TI - Regulatory B cells and Allergy: uncovering the link. PMID- 28345523 TI - A practical formula for determining growth. AB - PURPOSE: We aimed to establish a practical method to evaluate skeletal age using cervical vertebrae. METHODS: The study consisted of hand-wrist and cephalometric radiographs of 324 subjects (167 girls, 157 boys; age range, 7.3-17.2 years). Skeletal ages of the subjects were calculated from hand-wrist radiographs, and cervical vertebral bodies were measured using cephalometric radiographs. A single formula based on C3 and C4 vertebral body heights with different coefficients for each gender was derived using ridge regression analysis. RESULTS: The correlation coefficients for vertebral and hand-wrist bone age were 0.825 and 0.856 for girls and boys, respectively. The correlations among vertebral bone age and C3 and C4 vertebral body heights were also found to be significant. The intraclass correlation (ICC) score was found to be 0.914, which shows high consistency between the two measurements of the same investigator for each C3 and C4 vertebral body height result. CONCLUSION: The formula derived for evaluating skeletal age in cephalometric radiographs is reliable and can be applied to both girl and boy subjects for legal requirements or therapeutic needs of age estimation. PMID- 28345525 TI - Tolerance of monocytes and macrophages in response to bacterial endotoxin. AB - Monocytes belong to myeloid effector cells, which constitute the first line of defense against pathogens, also called the nonspecific immune system and play an important role in the maintenance of tissue homeostasis. In response to stimulation, monocytes differentiate into macrophages capable of microorganism phagocytosis and secrete factors that play a key role in the regulation of immune responses. However excessive exposure of monocytes/macrophages to the lipopolysaccharide (LPS) of Gram negative bacteria leads to the acquisition of immune tolerance by these cells. Such state results from disruption of different biological processes, for example intracellular signaling pathways and is accompanied by a number of disease states (immune, inflammatory or neoplastic conditions). Regulation of monocytes/macrophages activity is controlled by miRNAs, which are involved in the modulation of immune tolerance acquired by these cells. Moreover, the tolerance to endotoxin is conditioned by the posttranscriptional processes and posttranslational epigenetic modifications leading to the impairment of normal immune response for example by alterations in the expression of many genes encoding immune signaling mediators. The aim of this paper is to provide an overview existing knowledge on the modulation of activity of monocytes/macrophages in response to bacterial endotoxin and impaired immune responses. PMID- 28345524 TI - Conventional MRI features for predicting the clinical outcome of patients with invasive placenta. AB - PURPOSE: We aimed to evaluate whether morphologic magnetic resonance imaging (MRI) features could help to predict the maternal outcome after uterine artery embolization (UAE)-assisted cesarean section (CS) in patients with invasive placenta previa. METHODS: We retrospectively reviewed the MRI data of 40 pregnant women who have undergone UAE-assisted cesarean section due to suspected high risk of massive hemorrhage caused by invasive placenta previa. Patients were divided into two groups based on the maternal outcome (good-outcome group: minor hemorrhage and uterus preserved; poor-outcome group: significant hemorrhage or emergency hysterectomy). Morphologic MRI features were compared between the two groups. Multivariate logistic regression analysis was used to identify the most valuable variables, and predictive value of the identified risk factor was determined. RESULTS: Low signal intensity bands on T2-weighted imaging (P < 0.001), placenta percreta (P = 0.011), and placental cervical protrusion sign (P = 0.002) were more frequently observed in patients with poor outcome. Low signal intensity bands on T2-weighted imaging was the only significant predictor of poor maternal outcome in multivariate analysis (P = 0.020; odds ratio, 14.79), with 81.3% sensitivity and 84.3% specificity. CONCLUSION: Low signal intensity bands on T2-weighted imaging might be a predictor of poor maternal outcome after UAE assisted cesarean section in patients with invasive placenta previa. PMID- 28345526 TI - Aspects of pericytes and their potential therapeutic use. AB - Pericytes, which are multi-potential stem cells, co-create the walls of the microvessels: capillaries, terminal arterioles and postcapillary venules. These cells are localized under the basement membrane, tightly encircling the endothelium. The most frequently mentioned molecular markers of pericytes include NG2 (neural-glial antigen 2), beta-type platelet-derived growth factor receptor (PDGFRbeta), smooth muscle alpha-actin (alpha-SMA), regulator of G protein signalling 5 (RGS5), the adhesion protein CD146 and nestin. Different functions in physiological processes are assigned to pericytes such as maintaining the integrity and senescence of endothelial cells, transregulation of vascular tone or the potential to differentiate into other cells. Probably they are also involved in pathological processes such as tissues fibrosis. In this review, we focus on the participation of pericytes in the process of blood vessel formation, the regeneration of skeletal muscle tissue and fibrosis. Strong evidence for pericytes' participation in endothelial homeostasis, as well as in pathological conditions such as fibrosis, reveals a broad potential for the therapeutic use of these cells. Targeted pharmacological modulation of pericytes, leading to blocking signalling pathways responsible for the differentiation of pericytes into myofibroblasts, seems to be a promising strategy for the treatment of fibrosis in the early stages. PMID- 28345527 TI - Prevalence and factors promoting the occurrence of vitamin D deficiency in the elderly. AB - Vitamin D deficiency affects a large part of the population of elderly people, especially women, who live in moderate climate countries due to a reduced amount of vitamin D in the diet (small sea fish consumption) and reduced content of 7 dehydrocholesterol, which causes decreased skin synthesis. The lowest seasonal concentration of 25(OH)D3 is usually observed during winter and spring. Sun exposure influences 25(OH)D3 concentration more strongly in men than in women. Sociodemographic factors that increase the risk of vitamin D deficiency in the elderly include poor environmental conditions, low economic status, lower educational level, drug exposure (smoking), reduced physical activity, overall poor health and obesity, which causes reduced skin exposure to sunlight. The use of medications or supplements that contain vitamin D and staying in a nursing home that employ such supplementation are factors that prevent deficiency. Significant prevalence of diseases of the gastrointestinal tract may contribute to cholecalciferol and ergocalciferol malabsorption or impair their liver transformation. In addition, the high incidence of chronic kidney disease in old age reduces processing hydroxylation of vitamin D and the formation of active metabolites. Vitamin D deficiency can not only cause bone mineralization disorders, but also increase incidence of cardiovascular diseases, cancers, type 2 diabetes and depression. The aim of this study was to summarize current knowledge about the risk factors of vitamin D deficiency development in the elderly population. PMID- 28345528 TI - Genetic and psychosocial factors for benzodiazepine addiction. An analysis based on the results of the authors' own research conducted in a group of benzodiazepine addicted and non-addicted individuals. AB - PURPOSE: In spite of the fact that the addictive potential of benzodiazepine (BDZ) drugs has been known for a long time, benzodiazepine addiction remains a common problem for psychiatry to deal with. The etiology of benzodiazepine addiction is very complex. Among the risk factors, the course of the treatment, demographic status and psychological features of a patient seem to play an important role. The aim of this study was to investigate both psychological and genetic factors differentiating benzodiazepine addicts from non-addicted users. METHODS: We analysed a cohort of 120 individuals treated with benzodiazepines divided into two groups: benzodiazepine addicts and non-addicted benzodiazepine users (the control group). In both groups we measured genetic polymorphisms of GABA A2 and MAOA. In both groups some psychometric measurements were performed - we investigated the level of depression, anxiety as a state and as a trait, personality features and the dominant coping style using the Beck Depression Scale, Hamilton Anxiety Scale, Five-Factor Personality Inventory NEO-FFI and the Coping Inventory for Stressful Situations [4,10,17,36,41,44]. RESULTS: There are some psychological and situational risk factors for benzodiazepine addiction such as high neuroticism, introversion and lack of the ability to release tension through interpersonal contacts, dominance of emotional coping style and high accumulation of critical life events during both childhood and adulthood. The genetic background still remains a field for further exploration. PMID- 28345529 TI - Diversity of extended-spectrum beta-lactamase-producing Escherichia coli rods. AB - INTRODUCTION: The aim of the study was to evaluate genetic relatedness and antimicrobial susceptibility of extended-spectrum beta-lactamase-producing E. coli strains isolated from patients hospitalized in the University Hospital in Bydgoszcz (Poland). MATERIAL AND METHODS: The study included 33 extended-spectrum beta-lactamase-producing E. coli strains isolated from 31 patients. The chromosomal DNA was extracted from the strains and separated by pulsed-field gel electrophoresis. Antimicrobial susceptibility testing was performed by the agar dilution method and carried out according to the European Committee on Antimicrobial Susceptibility Testing recommendations. RESULTS: According to the pulsed-field gel electrophoresis results, 32 distinct pulsotypes were revealed. Based on Molecular Analyst Fingerprinting software analysis, the studied isolates were divided into four subgroups: 6 (18.2%) isolates showing similarity greater than 90% (group A); 19 (57.6%) showing 80-90% similarity (group B); 7 (21.2%) showing 70-79% similarity (group C); and one isolate with less than 70% similarity (group D). Among E. coli isolates showing similarity greater than 90%, four antimicrobial patterns were noted. Among the isolates showing 80-90% similarity, 18 antimicrobial patterns were observed. E. coli isolates showing 70 79% similarity presented 6 antimicrobial patterns. CONCLUSIONS: Our results show a high degree of genetic diversity of extended-spectrum beta-lactamase-producing E. coli isolates. However, based on a similarity of >=80%, almost 75% of E. coli isolates were clonally related. Although it is difficult to identify definitive transmission events based on the recovery of indistinguishable pulsed-field gel electrophoresis types alone, we speculate that extended-spectrum beta-lactamase producing E. coli strains may have disseminated throughout the hospital. PMID- 28345530 TI - Fecal microbiota transplantation - methods of treatment of recurrent Clostridium difficile infections and other diseases. AB - Clostridium difficile is a serious epidemiological problem and particularly dangerous microorganism causing hospital infections. Currently, the treatment of C. difficile infections is the use of metronidazole or vancomycin. However, in some patients, recurrent infection difficult to treat occurs. Fecal microbiota transplantation (FMT) is a new method used to treat the recurrent CDI. FMT consists in the infusion of the fecal suspension from a healthy donor into the gastrointestinal tract of a patient with CDI to restore the natural intestinal microflora. FMT is safe and effective treatment of recurrent CDI. FMT is extensively described around the world, but to date only two randomized studies confirming the effectiveness of FMT have been conducted. This method was also applied in the treatment of diseases such as pseudomembranous colitis, ulcerative colitis, Crohn's disease and irritable bowel syndrome. The review describes the procedure for FMT and the current state of knowledge about the effectiveness of FMT in the treatment of recurrent CDI. PMID- 28345531 TI - Polyphenols in preventing endothelial dysfunction. AB - One of the main causes of mortality in developed countries is atherosclerosis. The pathogenesis of atherosclerosis is associated with endothelial dysfunction. Consumption of food rich in natural antioxidants including polyphenols significantly improves endothelial cells functions. Polyphenols have a beneficial effect on the human body and play an important part in protecting the cardiovascular system. Polyphenols present in food have antioxidant, anti inflammatory, antihypertensive, antithrombotic and antiproliferative properties. Catechins cause an increase in the activity of endothelial nitric oxide synthase (eNOS) and increased production of nitric oxide (NO) and decrease in blood pressure. Catechins also reduce platelet adhesion, lower the concentration of C reactive protein and tumor necrosis factor alpha and interleukin-6. Resveratrol inhibits NADPH oxidase expression, increases the expression of eNOS and NO production as well as decreases the expression of proinflammatory cytokines, and also lowers the concentration of the soluble forms of adhesion molecules - sICAM 1 and sVCAM-1 in blood. Quercetin reduces the blood level of low density lipoprotein cholesterol, lowers blood pressure, reduces the concentration of C reactive protein and F2-isoprostane level. Curcumin has antagonistic activity to homocysteine. Curcumin increases the expression of eNOS and reduces oxidative DNA damage in rat cardiomyocytes. Numerous attempts are taken for improving the bioavailability of polyphenols in order to increase their use in the body. PMID- 28345532 TI - Observation of variable hybridized-band gaps in Eu-intercalated graphene. AB - We report europium (Eu)-induced changes in the pi-band of graphene (G) formed on the 6H-SiC(0001) surface by a combined study of photoemission measurements and density functional theory (DFT) calculations. Our photoemission data reveal that Eu intercalates upon annealing at 120 degrees C into the region between the graphene and the buffer layer (BL) to form a G/Eu/BL system, where a band gap of 0.29 eV opens at room temperature. This band gap is found to increase further to 0.48 eV upon cooling down to 60 K. Our DFT calculations suggest that the increased band gap originates from the enhanced hybridization of the graphene pi band with the Eu 4f band due to the increased magnetic ordering upon cooling. These Eu atoms continue to intercalate further down below the BL to produce bilayer graphene (G/BL/Eu) upon annealing at 300 degrees C. The pi-band stemming from the BL then exhibits another band gap of 0.37 eV, which appears to be due to the strong hybridization between the pi-band of the BL and the Eu 4f band. The Eu intercalated graphene thus illustrates an example of versatile band gaps formed under different thermal treatments, which may play a critical role for future applications in graphene-based electronics. PMID- 28345533 TI - Fabrication of plasmonic cavity arrays for SERS analysis. AB - The plasmonic cavity arrays are ideal substrates for surface enhanced Raman scattering analysis because they can provide hot spots with large volume for analyte molecules. The large area increases the probability to make more analyte molecules on hot spots and leads to a high reproducibility. Therefore, to develop a simple method for creating cavity arrays is important. Herein, we demonstrate how to fabricate a V and W shape cavity arrays by a simple method based on self assembly. Briefly, the V and W shape cavity arrays are respectively fabricated by taking KOH etching on a nanohole and a nanoring array patterned silicon (Si) slides. The nanohole array is generated by taking a reactive ion etching on a Si slide assembled with monolayer of polystyrene (PS) spheres. The nanoring array is generated by taking a reactive ion etching on a Si slide covered with a monolayer of octadecyltrichlorosilane before self-assembling PS spheres. Both plasmonic V and W cavity arrays can provide large hot area, which increases the probability for analyte molecules to deposit on the hot spots. Taking 4-Mercaptopyridine as analyte probe, the enhancement factor can reach 2.99 * 105 and 9.97 * 105 for plasmonic V cavity and W cavity array, respectively. The relative standard deviations of the plasmonic V and W cavity arrays are 6.5% and 10.2% respectively according to the spectra collected on 20 random spots. PMID- 28345535 TI - Photoactivated processes in optical fibers: generation and conversion mechanisms of twofold coordinated Si and Ge atoms. AB - In this work we present an extensive investigation of nanoscale physical phenomena related to oxygen-deficient centers (ODCs) in silica and Ge-doped silica by means of first-principles calculations, including nudged-elastic band, electron paramagnetic resonance parameters calculations, and many-body perturbation theory (GW and Bethe-Salpeter equation) techniques. We show that by neutralizing positively charged oxygen monovacancies we can obtain model structures of twofold Si and Ge defects of which the calculated absorption spectra and singlet-to-triplet transitions are in excellent agreement with the experimental optical absorption and photo-luminescence data. In particular we provide an exhaustive analysis of the main exciton peaks related to the presence of twofold defects including long-range correlation effects. By calculating the reaction pathways and energy barriers necessary for the interconversion, we advance a double precursory origin of the [Formula: see text] and Ge(2) centers as due to the ionization of neutral oxygen monovacancies (Si-Si and Ge-Si dimers) and as due to the ionization of twofold Si and Ge defects. Furthermore two distinct structural conversion mechanisms are found to occur between the neutral oxygen monovacancy and the twofold Si (and Ge) atom configurations. Such conversion mechanisms allow to explain the radiation induced generation of the ODC(II) centers, their photobleaching, and also their generation during the drawing of optical fibers. PMID- 28345534 TI - Electron transfer processes occurring on platinum neural stimulating electrodes: calculated charge-storage capacities are inaccessible during applied stimulation. AB - OBJECTIVE: Neural prostheses employing platinum electrodes are often constrained by a charge/charge-density parameter known as the Shannon limit. In examining the relationship between charge injection and observed tissue damage, the electrochemistry at the electrode-tissue interface should be considered. The charge-storage capacity (CSC) is often used as a predictor of how much charge an electrode can inject during stimulation, but calculating charge from a steady state i-E curve (cyclic voltammogram) over the water window misrepresents how electrodes operate during stimulation. We aim to gain insight into why CSC predictions from classic i-E curves overestimate the amount of charge that can be injected during neural stimulation pulsing. APPROACH: In this study, we use a standard electrochemical technique to investigate how platinum electrochemistry depends on the potentials accessed by the electrode and on the electrolyte composition. MAIN RESULTS: The experiments indicate: (1) platinum electrodes must be subjected to a 'cleaning' procedure in order to expose the maximum number of surface platinum sites for hydrogen adsorption; (2) the 'cleaned' platinum surface will likely revert to an obstructed condition under typical neural stimulation conditions; (3) irreversible oxygen reduction may occur under neural stimulation conditions, so the consequences of this reaction should be considered; and (4) the presence of the chloride ion (Cl-) or proteins (bovine serum albumin) inhibits oxide formation and alters H adsorption. SIGNIFICANCE: These observations help explain why traditional CSC calculations overestimate the charge that can be injected during neural stimulation. The results underscore how careful electrochemical examination of the electrode-electrolyte interface can result in more accurate expectations of electrode performance during applied stimulation. PMID- 28345536 TI - Tuning the work function of stepped metal surfaces by adsorption of organic molecules. AB - Understanding the binding mechanisms for aromatic molecules on transition-metal surfaces, especially with defects such as vacancies, steps and kinks, is a major challenge in designing functional interfaces for organic devices. One important parameter in the performance of organic/inorganic devices is the barrier of charge carrier injection. In the case of a metallic electrode, tuning the electronic interface potential or the work function for electronic level alignment is crucial. Here, we use density-functional theory (DFT) calculations with van der Waals (vdW) interactions treated with both screened pairwise (vdWsurf) and many-body dispersion (MBD) methods, to systematically study the interactions of benzene with a variety of stepped surfaces. Our calculations confirm the physisorptive character of Ag(2 1 1), Ag(5 3 3), Ag(3 2 2), Ag(7 5 5) and Ag(5 4 4) surfaces upon the adsorption of benzene. The MBD effects reduce the adsorption energies by about 0.15 eV per molecule compared to the results from the DFT + vdWsurf method. In addition, we find that the higher the step density, the larger the reduction of the work function upon the adsorption of benzene. We also study the effect of vdW interactions on the electronic structure using a fully self-consistent implementation of the vdWsurf method in the Kohn Sham DFT framework. We find that the self-consistent vdWsurf effects increase the work function due to the lowered Fermi level and the increased vacuum level. As a result, the benzene/Ag(2 1 1) system has the lowest work function (3.67 eV) among the five adsorption systems, significantly smaller than the work function of the clean Ag(1 1 1) surface (4.74 eV). Our results provide important insights into the stability and electronic properties of molecules adsorbed on stepped metal surfaces, which could help in designing more appropriate interfaces with low work functions for electron transfer. PMID- 28345537 TI - Hyperuniformity variation with quasicrystal local isomorphism class. AB - Hyperuniformity is the suppression of long-wavelength density fluctuations, relative to typical structurally disordered systems. In this paper, we examine how the degree of hyperuniformity [[Formula: see text]] in quasicrystals depends on the local isomorphism class. By studying the continuum of pentagonal quasicrystal tilings obtained by direct projection from a five-dimensional hypercubic lattice, we find that [Formula: see text] is dominantly determined by the local distribution of vertex environments (e.g. as measured by Voronoi cells) but also exhibits a non-negligible dependence on the restorability. We show that the highest degree of hyperuniformity [smallest [Formula: see text]] corresponds to the Penrose local isomorphism class. The difference in the degree of hyperuniformity is expected to affect physical characteristics, such as transport properties. PMID- 28345538 TI - Current Trends for ST-segment Elevation Myocardial Infarction during the Past 5 Years in Rural Areas of China's Liaoning Province: A Multicenter Study. AB - BACKGROUND: Since 2010, two versions of National Guidelines aimed at promoting the management of ST-segment elevation myocardial infarction (STEMI) have been formulated by the Chinese Society of Cardiology. However, little is known about the changes in clinical characteristics, management, and in-hospital outcomes in rural areas. METHODS: In the present multicenter, cross-sectional study, participants were enrolled from rural hospitals located in Liaoning province in Northeast China, during two different periods (from June 2009 to June 2010 and from January 2015 to December 2015). Data collection was conducted using a standardized questionnaire. In total, 607 and 637 STEMI patients were recruited in the 2010 and 2015 cohorts, respectively. RESULTS: STEMI patients in rural hospitals were older in the second group (63 years vs. 65 years, P = 0.039). We found increases in the prevalence of hypertension, prior percutaneous coronary intervention (PCI), and prior stroke. Over the past 5 years, the cost during hospitalization almost doubled. The proportion of STEMI patients who underwent emergency reperfusion had significantly increased from 42.34% to 54.47% (P < 0.0001). Concurrently, the proportion of primary PCI increased from 3.62% to 10.52% (P < 0.0001). The past 5 years have also seen marked increases in the use of guideline-recommended drugs and clinical examinations. However, in-hospital mortality and major adverse cardiac events did not significantly change over time (13.01% vs. 10.20%, P = 0.121; 13.34% vs. 13.66%, P = 0.872). CONCLUSIONS: Despite the great progress that has been made in guideline-recommended therapies, in-hospital outcomes among rural STEMI patients have not significantly improved. Therefore, there is still substantial room for improvement in the quality of care. PMID- 28345539 TI - Admission Glucose and In-hospital Mortality after Acute Myocardial Infarction in Patients with or without Diabetes: A Cross-sectional Study. AB - BACKGROUND: Hyperglycemia on admission has been found to elevate risk for mortality and adverse clinical events after acute myocardial infarction (AMI), but there are evidences that the relationship of blood glucose and mortality may differ between diabetic and nondiabetic patients. Prior studies in China have provided mixed results and are limited by statistical power. Here, we used data from a large, nationally representative sample of patients hospitalized with AMI in China in 2001, 2006, and 2011 to assess if admission glucose is of prognostic value in China and if this relationship differs depending on the presence or absence of diabetes. METHODS: Using a nationally representative sample of patients with AMI in China in 2001, 2006, and 2011, we categorized patients according to their glucose levels at admission (Results: Compared to patients with euglycemia (5.8%), patients with moderate hyperglycemia (13.1%, odds ratio [OR] = 2.44, 95% confidence interval [CI, 2.08-2.86]), severe hyperglycemia (21.5%, OR = 4.42, 95% CI [3.78-5.18]), and hypoglycemia (13.8%, OR = 2.59, 95% CI [1.68-4.00]), all had higher crude in-hospital mortality after AMI regardless of the presence of recognized diabetes mellitus. After adjustment for patients' characteristics and clinical status, however, the relationship between admission glucose and in-hospital mortality was different for diabetic and nondiabetic patients (P for interaction = 0.045). Among diabetic patients, hypoglycemia (OR = 3.02, 95% CI [1.20-7.63]), moderate hyperglycemia (OR = 1.75, 95% CI [1.04 2.92]), and severe hyperglycemia (OR = 2.97, 95% CI [1.87-4.71]) remained associated with elevated risk for mortality, but among nondiabetic patients, only patients with moderate hyperglycemia (OR = 2.34, 95% CI [1.93-2.84]) and severe hyperglycemia (OR = 3.92, 95% CI [3.04-5.04]) were at elevated mortality risk and not hypoglycemia (OR = 1.12, 95% CI [0.60-2.08]). This relationship was consistent across different study years (P for interaction = 0.900). CONCLUSIONS: The relationship between admission glucose and in-hospital mortality differs for diabetic and nondiabetic patients. Hypoglycemia was a bad prognostic marker among diabetic patients alone. The study results could be used to guide risk assessment among AMI patients using admission glucose. TRIAL REGISTRATION: www.clinicaltrials.gov, NCT01624883; https://clinicaltrials.gov/ct2/show/NCT01624883. PMID- 28345540 TI - Epidemiological Features of Nontraumatic Spontaneous Subarachnoid Hemorrhage in China: A Nationwide Hospital-based Multicenter Study. AB - BACKGROUND: Nontraumatic spontaneous subarachnoid hemorrhage (SAH) is associated with a high mortality. This study was conducted to investigate the epidemiological features of nontraumatic spontaneous SAH in China. METHODS: From January 2006 to December 2008, the clinical data of patients with nontraumatic SAH from 32 major neurosurgical centers of China were evaluated. Emergent digital subtraction angiography (DSA) was performed for the diagnosis of SAH sources in the acute stage of SAH (<=3 days). The results and complications of emergent DSA were analyzed. Repeated DSA or computed tomography angiography (CTA) was suggested 2 weeks later if initial angiographic result was negative. RESULTS: A total of 2562 patients were enrolled, including 81.4% of aneurysmal SAH and 18.6% of nonaneurysmal SAH. The total complication rate of emergent DSA was 3.9% without any mortality. Among the patients with aneurysmal SAH, 321 cases (15.4%) had multiple aneurysms, and a total of 2435 aneurysms were detected. The aneurysms mostly originated from the anterior communicating artery (30.1%), posterior communicating artery (28.7%), and middle cerebral artery (15.9%). Among the nonaneurysmal SAH cases, 76.5% (n = 365) had negative initial DSA, including 62 cases with peri-mesencephalic nonaneurysmal SAH (PNSAH). Repeated DSA or CTA was performed in 252 patients with negative initial DSA, including 45 PNSAH cases. Among them, the repeated angiographic results remained negative in 45 PNSAH cases, but 28 (13.5%) intracranial aneurysms were detected in the remaining 207 cases. In addition, brain arteriovenous malformation (AVM, 7.5%), Moyamoya disease (7.3%), stenosis or sclerosis of the cerebral artery (2.7%), and dural arteriovenous fistula or carotid cavernous fistula (2.3%) were the major causes of nonaneurysmal SAH. CONCLUSIONS: DSA can be performed safely for pathological diagnosis in the acute stage of SAH. Ruptured intracranial aneurysms, AVM, and Moyamoya disease are the major causes of SAH detected by emergent DSA in China. PMID- 28345541 TI - A Risk Prediction Model for In-hospital Mortality in Patients with Suspected Myocarditis. AB - BACKGROUND: Myocarditis is an inflammatory disease of the myocardium that may lead to cardiac death in some patients. However, little is known about the predictors of in-hospital mortality in patients with suspected myocarditis. Thus, the aim of this study was to identify the independent risk factors for in hospital mortality in patients with suspected myocarditis by establishing a risk prediction model. METHODS: A retrospective study was performed to analyze the clinical medical records of 403 consecutive patients with suspected myocarditis who were admitted to Ningbo First Hospital between January 2003 and December 2013. A total of 238 males (59%) and 165 females (41%) were enrolled in this study. We divided the above patients into two subgroups (survival and nonsurvival), according to their clinical in-hospital outcomes. To maximize the effectiveness of the prediction model, we first identified the potential risk factors for in-hospital mortality among patients with suspected myocarditis, based on data pertaining to previously established risk factors and basic patient characteristics. We subsequently established a regression model for predicting in hospital mortality using univariate and multivariate logistic regression analyses. Finally, we identified the independent risk factors for in-hospital mortality using our risk prediction model. RESULTS: The following prediction model for in-hospital mortality in patients with suspected myocarditis, including creatinine clearance rate (Ccr), age, ventricular tachycardia (VT), New York Heart Association (NYHA) classification, gender and cardiac troponin T (cTnT), was established in the study: P = ea/(1 + ea) (where e is the exponential function, P is the probability of in-hospital death, and a = -7.34 + 2.99 * [Ccr <60 ml/min = 1, Ccr >=60 ml/min = 0] + 2.01 * [age >=50 years = 1, age <50 years = 0] + 1.93 * [VT = 1, no VT = 0] + 1.39 * [NYHA >=3 = 1, NYHA <3 = 0] + 1.25 * [male = 1, female = 0] + 1.13 * [cTnT >=50 MUg/L = 1, cTnT <50 MUg/L = 0]). The area under the receiver operating characteristic curve was 0.96 (standard error = 0.015, 95% confidence interval [CI]: 0.93-0.99). The model demonstrated that a Ccr <60 ml/min (odds ratio [OR] = 19.94, 95% CI: 5.66-70.26), an age >=50 years (OR = 7.43, 95% CI: 2.18-25.34), VT (OR = 6.89, 95% CI: 1.86-25.44), a NYHA classification >=3 (OR = 4.03, 95% CI: 1.13-14.32), male gender (OR = 3.48, 95% CI: 0.99-12.20), and a cTnT level >=50 MUg/L (OR = 3.10, 95% CI: 0.91-10.62) were the independent risk factors for in-hospital mortality. CONCLUSIONS: A Ccr <60 ml/min, an age >=50 years, VT, an NYHA classification >=3, male gender, and a cTnT level >=50 MUg/L were the independent risk factors resulting from the prediction model for in-hospital mortality in patients with suspected myocarditis. In addition, sufficient life support during the early stage of the disease might improve the prognoses of patients with suspected myocarditis with multiple risk factors for in-hospital mortality. PMID- 28345542 TI - Association between Self-reported Snoring and Prediabetes among Adults Aged 40 Years and Older without Diabetes. AB - BACKGROUND: Several previous studies have shown that snoring is associated with glucose metabolism and the development of diabetes, but rare study has shown the association between snoring frequency and prediabetes, particularly in China. We hypothesized that individuals who snore might have a higher risk of prediabetes. This study aimed to investigate the association between self-reported snoring and prediabetes in a Chinese population. METHODS: A cross-sectional study was performed in three large communities of Beijing from December 2011 to August 2012 by recruiting individuals aged >=40 years old. All participants were requested to complete a detailed questionnaire and undergo anthropometric measurements. A 75 g oral glucose tolerance test was performed in individuals without diabetes. Blood samples of all participants were collected; blood glucose and blood fat levels were measured. Multivariate logistic regression models were built to assess the association between snoring frequency and prediabetes. RESULTS: A total of 13,592 participants (female: 66.56%; mean age: 56.8 +/- 7.9 years; mean body mass index: 25.5 +/- 3.4 kg/m2) were included in the final analysis. Of these, 30.9% were diagnosed with prediabetes, while 41.3% and 25.4% had occasional and habitual snoring, respectively. Habitual snoring was associated with an increased risk of prediabetes (odds ratio [OR]: 1.3, 95% confidence interval [CI]: 1.1-1.4, P< 0.001), after adjusting for diabetes and sleep-related confounders in the multivariable models. Habitual snoring was also associated with isolated impaired fasting glucose (IFG; OR: 1.3, 95% CI: 1.0-1.6; P< 0.001) and isolated impaired glucose tolerance (IGT; OR: 1.3, 95% CI: 1.2-1.5; P< 0.001), but not IFG + IGT (OR: 1.1, 95% CI: 0.9-1.4; P = 0.281). When stratified by total cholesterol (TC) levels, this association between habitual snoring and prediabetes was observed only in individuals with TC <5.6 mmol/L (OR: 1.4, 95% CI: 1.2-1.6; P< 0.001). CONCLUSIONS: Habitual snoring is associated with prediabetes, but only in individuals with TC <5.6 mmol/L. Further prospective studies are needed to confirm this finding. PMID- 28345543 TI - Use of First-phase Insulin Secretion in Early Diagnosis of Thyroid Diabetes and Type 2 Diabetes Mellitus. AB - BACKGROUND: A relationship between hyperthyroidism and insulin secretion in type 2 diabetes mellitus (T2DM) has been reported. Therefore, this study explored the use of first-phase insulin secretion in the differential diagnosis of thyroid diabetes (TDM) and T2DM. METHODS: In total, 101 patients with hyperthyroidism were divided into hyperthyroidism with normal glucose tolerance (TNGT), hyperthyroidism with impaired glucose regulation (TIGR), and diabetes (TDM) groups. Furthermore, 96 patients without hyperthyroidism were recruited as control groups (normal glucose tolerance [NGT], impaired glucose regulation [IGR], and T2DM). The following parameters were evaluated: homeostasis model assessment (HOMA)-IR, HOMA-beta, modified beta-cell function index (MBCI), peak insulin/fasting insulin (IP/I0), AUCins-OGTT, and AUCins-OGTT/AUCglu-OGTTfrom the oral glucose tolerance test (OGTT) insulin release test were utilized to assess the second-phase insulin secretion, while the IP/I0, AIR0'~10', and AUCins IVGTTfrom the intravenous glucose tolerance test (IVGTT) insulin release test were used to assess the first-phase insulin secretion. RESULTS: In the OGTT, the HOMA-beta values of the TNGT and TDM groups were higher than those of the NGT and T2DM groups (all P< 0.05). In the hyperthyroidism groups, the MBCI of the TDM group was lower than that of the TNGT and TIGR groups (all P< 0.05). Among the control groups, the MBCI values of the IGR and T2DM groups were lower than that of the normal glucose tolerance (NGT) group (all P< 0.05). In the IVGTT, insulin secretion peaked for all groups at 2-4 min, except for the T2DM group, which showed a low plateau and no secretion peak. The IP values of the TNGT, TIGR, and TDM groups were higher than those of the NGT, IGR, and T2DM groups (all P< 0.05). The Ip/I0, AIR0'~10', and AUCins-IVGTTvalues of the TDM group were higher than those of the T2DM group but were lower than those of the TNGT, TIGR, NGR, and IGR groups (all P< 0.05). Compared with the other five groups, the Ip/I0, AIR0'~10', and AUCins-IVGTTvalues of the T2DM group were significantly decreased (all P< 0.05). The Ip/I0and AUCins-IVGTTvalues of the TNGT group were higher than those of the NGT group (all P< 0.05). CONCLUSIONS: beta-cell function in TDM patients is superior to that in T2DM patients. First-phase insulin secretion could be used as an early diagnostic marker to differentiate TDM and T2DM. PMID- 28345545 TI - Diagnostic Significance of Mycobacterium tuberculosis T-cell Assays for Active Tuberculosis. AB - BACKGROUND: Active tuberculosis (TB) with negative results of sputum smear is difficult to be identified. Till now, there is no effective and noninvasive diagnostic method. This study evaluated the diagnostic power of Mycobacterium tuberculosis T-cell (T.SPOT(r).TB) assays for active TB. METHODS: We retrospectively screened 450 suspected TB patients that were hospitalized in the Respiratory Department of Henan Province People's Hospital from June 2015 to June 2016. The patients were divided into the active, previous, and non-TB groups according to their final diagnosis. We evaluated the diagnostic value of the T SPOT(r).TB assay by constructing receiver operating characteristic (ROC) curves and calculating the optimal diagnostic cutoff value. In addition, we compared the levels of A antigen (ESAT-6) and B antigen (CFP-10) in active TB. RESULTS: The sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio of T-SPOT(r).TB for active TB were 89.78%, 63.16%, 0.56, 0.92, 2.47, and 0.16, respectively. For active TB, the area under the ROC curve (AUC) of the A antigen (0.89) was higher than that of the B antigen (0.86). The AUC of the A antigen for active TB was largest at a cutoff value of 13.5 spot-forming cells (SFCs) per 2.5 * 105 peripheral blood mononuclear cells (PBMCs). The AUC of the A and B antigens was 0.60 and 0.58 for previous TB. The levels of A and B antigen in the active TB group were significantly different from those in the previous- and non-TB groups (A antigen: chi2 = 105.41, P< 0.01 and B antigen: chi2 = 91.03, P< 0.01; A antigen: chi2 = 12.99, P< 0.01 and B antigen: chi2 = 8.56, P< 0.01, respectively). There were no significant differences in the levels of A and B antigens between the non-TB group and previous TB group (A antigen: chi2 = 1.07, P> 0.05 and B antigen: chi2 = 0.77, P> 0.05). CONCLUSIONS: T-SPOT(r).TB has high sensitivity and specificity for the diagnosis of active TB at a cutoff value of 13.5 SFCs per 2.5 * 105 PBMCs and is not influenced by previous TB. PMID- 28345544 TI - Retinal Vascular Morphological Changes in Patients with Extremely Severe Obstructive Sleep Apnea Syndrome. AB - BACKGROUND: Obstructive sleep apnea syndrome (OSAS) has been shown to generate hypertension and endothelial dysfunction. Retinal vessel is the only vessel that can be observed directly and noninvasively; retinal vascular abnormalities can serve as a predictive marker for the occurrence, clinical course, and prognosis of cardiovascular and cerebrovascular diseases. The objective of this study was to identify the effect of OSAS severity on the morphological changes of retinal vessels. METHODS: Adult patients complained of snoring were included in this study. The patients' general information, polysomnography, and fundus photography parameters including central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), and arteriole-to-venule ratio (AVR) were collected. Patients were divided into four groups according to their apnea-hypopnea index (AHI) results: Group I, AHI <=5/h; Group II, 5/h < AHI <=30/h; Group III, 30/h < AHI <=60/h; and Group IV, AHI> 60/h. RESULTS: A total of 133 patients were included in this study with 111 males (83.5%) and 22 females (16.5%). Mean age was 41.6 +/- 9.9 years, and the mean body mass index was 28.1 +/- 4.0 kg/m2. AHI ranged between 0 and 130.8/h with a mean of 39.1 +/- 30.7/h. There were 24, 34, 35, and 40 patients in Group I, Group II, Group III, and Group IV, respectively. Significant differences were found for AHI (F = 388.368, P< 0.001), minimal pulse oxygen saturation (F = 91.902, P< 0.001), and arousal index (F = 31.014, P< 0.001) among four groups; no significant differences were found for CRAE (F = 0.460, P = 0.599) and CRVE (F = 0.404, P = 0.586) among groups; there were significant differences for AVR between Group I and Group IV (63.6 +/- 5.1% vs. 67.2 +/- 5.5%, P = 0.010) Group II and Group IV (64.5 +/- 6.0% vs. 67.2 +/- 5.5%, P = 0.030), and Group III and Group IV (64.7 +/- 4.1% vs. 67.2 +/- 5.5%, P = 0.043). A main group-by-AHI effect was found on the AVR: patients with higher AHI showed higher AVR results (r = 0.225, P = 0.009). Multivariate logistic regression analysis was used for multi-variable factors. A group-by-age effect was found on the AVR: younger patients showed higher AVR results (beta = -0.001, P = 0.020). CONCLUSIONS: This study indicated that increased AVR of retinal vessel can be observed in extremely severe OSAS patients. For patients with OSAS, retinal vascular abnormalities may become an early indication for further cardiovascular abnormalities. PMID- 28345546 TI - High-resolution 3T Magnetic Resonance Imaging of the Triangular Fibrocartilage Complex in Chinese Wrists: Correlation with Cross-sectional Anatomy. AB - BACKGROUND: The injury of the triangular fibrocartilage complex (TFCC) is a common cause of ulnar-sided wrist pain. The aim of this study was to investigate if the high-resolution 3T magnetic resonance imaging (MRI) could demonstrate the detailed complex anatomy of TFCC in Chinese. METHODS: Fourteen Chinese cadaveric wrists (from four men and three women; age range at death from 30 to 60 years; mean age at 46 years) and forty healthy Chinese wrists (from 20 healthy volunteers, male/female: 10/10; age range from 21 to 53 years with a mean age of 32 years) in Beijing Jishuitan Hospital from March 2014 to March 2016 were included in this study. All cadavers and volunteers had magnetic resonance (MR) examination of the wrist with coronal T1-weighted and proton density-weighted imaging with fat suppression in three planes, respectively. MR arthrography (MRAr) was performed on one of the cadaveric wrists. Subsequently, all 14 cadaveric wrists were sliced into 2 mm thick slab with band saw (six in coronal plane, four in sagittal plane, and four in axial plane). The MRI features of normal TFCC were analyzed in these specimens and forty healthy wrists. RESULTS: Triangular fibrocartilage, the ulnar collateral ligament, and the meniscal homolog could be best observed on images in coronal plane. The palmar and dorsal radioulnar ligaments were best evaluated in transverse plane. The ulnotriquetral and ulnolunate ligaments were best visualized in sagittal plane. The latter two structures and the volar and dorsal capsules were better demonstrated on MRAr. CONCLUSION: High-resolution 3T MRI is capable to show the detailed complex anatomy of the TFCC and can provide valuable information for the clinical diagnosis in Chinese. PMID- 28345547 TI - Contrast Dose and Radiation Dose Reduction in Abdominal Enhanced Computerized Tomography Scans with Single-phase Dual-energy Spectral Computerized Tomography Mode for Children with Solid Tumors. AB - BACKGROUND: Contrast dose and radiation dose reduction in computerized tomography (CT) scan for adult has been explored successfully, but there have been few studies on the application of low-concentration contrast in pediatric abdominal CT examinations. This was a feasibility study on the use of dual-energy spectral imaging and adaptive statistical iterative reconstruction (ASiR) for the reduction of radiation dose and iodine contrast dose in pediatric abdominal CT patients with solid tumors. METHODS: Forty-five patients with solid tumors who had initial CT (Group B) and follow-up CT (Group A) after chemotherapy were enrolled. The initial diagnostic CT scan (Group B) was performed using the standard two-phase enhanced CT with 320 mgI/ml concentration contrast, and the follow-up scan (Group A) was performed using a single-phase enhanced CT at 45 s after the beginning of the 270 mgI/ml contrast injection using spectral mode. Forty percent ASiR was used for the images in Group B and monochromatic images with energy levels >=60 keV in Group A. In addition, filtered back-projection (FBP) reconstruction was used for monochromatic images <60 keV in Group A. The total radiation dose, total iodine load, contrast injection speed, and maximum injection pressure were compared between the two groups. The 40 keV and 60 keV spectral CT images of Group A were compared with the images of Group B to evaluate overall image quality. RESULTS: The total radiation dose, total iodine load, injection speed, and maximum injection pressure for Group A were decreased by 19%, 15%, 34.4%, and 18.3%, respectively. The optimal energy level in spectral CT for displaying the abdominal vessels was 40 keV. At this level, the CT values in the abdominal aorta and its three branches, the portal vein and its two branches, and the inferior vena cava were all greater than 340 hounsfield unit (HU). The abdominal organs of Groups A and B had similar degrees of absolute and relative enhancement (t = 0.36 and -1.716 for liver, -0.153 and -1.546 for pancreas, and 2.427 and 0.866 for renal cortex, all P> 0.05). Signal-to-noise ratio of the abdominal organs was significantly lower in Group A than in Group B (t = -8.11 for liver, -7.83 for pancreas, and -5.38 for renal cortex, all P< 0.05). However, the subjective scores for the 40 keV (FBP) and 60 keV (40% ASiR) spectral CT images determined by two radiologists were all> 3, indicating clinically acceptable image quality. CONCLUSIONS: Single-phase, dual-energy spectral CT used for children with solid abdominal tumors can reduce contrast dose and radiation dose and can also maintain clinically acceptable image quality. PMID- 28345548 TI - Polyglycolic Acid Fibrous Scaffold Improving Endothelial Cell Coating and Vascularization of Islet. AB - BACKGROUND: Improving islet graft revascularization has become a crucial task for prolonging islet graft survival. Endothelial cells (ECs) are the basis of new microvessels in an isolated islet, and EC coating has been demonstrated to improve the vascularization and survival of an islet. However, the traditional method of EC coating of islets has low efficiency in vitro. This study was conducted to evaluate the effect of a polyglycolic acid (PGA) scaffold on the efficiency of islet coating by ECs and the angiogenesis in the coated islet graft. METHODS: A PGA fibrous scaffold was used for EC coating of islet culture and was evaluated for its efficiency of EC coating on islets and islet graft angiogenesis. RESULTS: In in vitro experiments, we found that apoptosis index of ECs-coating islet in PGA group (27% +/- 8%) was significantly lower than that in control group (83% +/- 20%, P < 0.05) after 7 days culture. Stimulation index was significantly greater in the PGA group than in the control group at day 7 after ECs-coating (2.07 +/- 0.31 vs. 1.80 +/- 0.23, P < 0.05). vascular endothelial growth factor (VEGF) level in the PGA group was significantly higher than the coating in the control group after 7 days culture (52.10 +/- 13.50 ng/ml vs. 16.30 +/- 8.10 ng/ml, P < 0.05). Because of a tight, circumvallated, adhesive and three-dimensional growth microenvironment, islet cultured in a PGA scaffold had higher coating efficiency showing stronger staining intensity of enzyme than those in the control group after 14 days of culture following ECs-coating. For in vivo study, PGA scaffold significantly prolonged the average survival time of EC coated islet graft after transplantation compared with control group (15.30 +/- 5.60 days vs. 8.30 +/- 2.45 days, P < 0.05). The angiogenesis and area of survived grafts were more in the PGA group compared with the control group by measuring the mean microvessel density (8.60 +/- 1.21/mm2 vs. 5.20 +/- 0.87/mm2, P < 0.05). In addition, expression of VEGF and tyrosin-protein kinase receptor (Tie-2) gene increased in PGA scaffold group than that in control group by real time reverse transcription-polymerase chain reaction analysis. CONCLUSIONS: These results demonstrate that the efficiency of EC coating of islets was successfully increased by culturing ECs on a PGA scaffold. This method enhances the function, survival, and vascularization of isolated islets in vitro and in vivo. PMID- 28345550 TI - Recombinant Human Erythropoietin Augments Neovascularization Responses in a Neonatal Rat Model of Premature Brain Damage by Phosphatidylinositol 3 Kinase/Akt Pathway. AB - BACKGROUND: Recombinant human-erythropoietin (rh-EPO) has therapeutic efficacy for premature infants with brain damage during the active rehabilitation and anti inflammation. In the present study, we found that the rh-EPO was related to the promotion of neovascularization. Our aim was to investigate whether rh-EPO augments neovascularization in the neonatal rat model of premature brain damage through the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway. METHODS: Postnatal day 5 (PD5), rats underwent permanent ligation of the right common carotid artery and were exposed to hypoxia for 2 h. All the rat pups were randomized into five groups as follows: (1) control group; (2) hypoxia ischemic (HI) group; (3) HI + LY294002 group; (4) HI + rh-EPO group; and (5) HI + rh-EPO + LY294002 group. The phospho-Akt protein was tested 90 min after the whole operation, and CD34, vascular endothelial growth factor receptor 2 (VEGFR2), and vascular endothelial growth factor (VEGF) were also tested 2 days after the whole operation. RESULTS: In the hypoxic and ischemic zone of the premature rat brain, the rh-EPO induced CD34+ cells to immigrate to the HI brain zone (P < 0.05) and also upregulated the VEGFR2 protein expression (P < 0.05) and VEGF mRNA level (P < 0.05) through the PI3K/Akt (P < 0.05) signaling pathway when compared with other groups. CONCLUSIONS: The rh-EPO treatment augments neovascularization responses in the neonatal rat model of premature brain damage through the PI3K/Akt signaling pathway. Besides, the endogenous EPO may exist in the HI zone of rat brain and also has neovascularization function through the PI3K/Akt signaling pathway. PMID- 28345549 TI - Sub-anesthesia Dose of Isoflurane in 60% Oxygen Reduces Inflammatory Responses in Experimental Sepsis Models. AB - BACKGROUND: Sepsis is a major cause of mortality in Intensive Care Units. Anesthetic dose isoflurane and 100% oxygen were proved to be beneficial in sepsis; however, their application in septic patients is limited because long term hyperoxia may induce oxygen toxicity and anesthetic dose isoflurane has potential adverse consequences. This study was scheduled to find the optimal combination of isoflurane and oxygen in protecting experimental sepsis and its mechanisms. METHODS: The effects of combined therapy with isoflurane and oxygen on lung injury and sepsis were determined in animal models of sepsis induced by cecal ligation and puncture (CLP) or intraperitoneal injection of lipopolysaccharide (LPS) or zymosan. Mouse RAW264.7 cells or human peripheral blood mononuclear cells (PBMCs) were treated by LPS to probe mechanisms. The nuclear factor kappa B (NF-kappaB) signaling molecules were examined by Western blot and cellular immunohistochemistry. RESULTS: The 0.5 minimum alveolar concentration (MAC) isoflurane in 60% oxygen was the best combination of oxygen and isoflurane for reducing mortality in experimental sepsis induced by CLP, intraperitoneal injection of LPS, or zymosan. The 0.5 MAC isoflurane in 60% oxygen inhibited proinflammatory cytokines in peritoneal lavage fluids (tumor necrosis factor-alpha [TNF-beta]: 149.3 vs. 229.7 pg/ml, interleukin [IL]-1beta: 12.5 vs. 20.6 pg/ml, IL-6: 86.1 vs. 116.1 pg/ml, and high-mobility group protein 1 [HMGB1]: 323.7 vs. 449.3 ng/ml; all P< 0.05) and serum (TNF-beta: 302.7 vs. 450.7 pg/ml, IL-1beta: 51.7 vs. 96.7 pg/ml, IL-6: 390.4 vs. 722.5 pg/ml, and HMGB1: 592.2 vs. 985.4 ng/ml; all P< 0.05) in septic animals. In vitro experiments showed that the 0.5 MAC isoflurane in 60% oxygen reduced inflammatory responses in mouse RAW264.7 cells, after LPS stimulation (all P< 0.05). Suppressed activation of NF-kappaB pathway was also observed in mouse RAW264.7 macrophages and human PBMCs after LPS stimulation or plasma from septic patients. The 0.5 MAC isoflurane in 60% oxygen also prevented the increases of phospho IKKbeta/beta, phospho-IkappaBbeta, and phospho-p65 expressions in RAW264.7 macrophages after LPS stimulation (all P< 0.05). CONCLUSION: Combined administration of a sedative dose of isoflurane with 60% oxygen improves survival of septic animals through reducing inflammatory responses. PMID- 28345551 TI - Biliverdin Protects the Isolated Rat Lungs from Ischemia-reperfusion Injury via Antioxidative, Anti-inflammatory and Anti-apoptotic Effects. AB - BACKGROUND: Biliverdin (BV) has a protective role against ischemia-reperfusion injury (IRI). However, the protective role and potential mechanisms of BV on lung IRI (LIRI) remain to be elucidated. Thus, we aimed to investigate the protective role and potential mechanisms of BV on LIRI. METHODS: Lungs were isolated from Sprague-Dawley rats to establish an ex vivo LIRI model. After an initial 15 min stabilization period, the isolated lungs were subjected to ischemia for 60 min, followed by 90 min of reperfusion with or without BV treatment. RESULTS: Lungs in the I/R group exhibited significant decrease in tidal volume (1.44 +/- 0.23 ml/min in I/R group vs. 2.41 +/- 0.31 ml/min in sham group; P< 0.001), lung compliance (0.27 +/- 0.06 ml/cmH2O in I/R group vs. 0.44 +/- 0.09 ml/cmH2O in sham group; P< 0.001; 1 cmH2O=0.098 kPa), and oxygen partial pressure (PaO2) levels (64.12 +/- 12 mmHg in I/R group vs. 114 +/- 8.0 mmHg in sham group; P< 0.001; 1 mmHg = 0.133 kPa). In contrast, these parameters in the BV group (2.27 +/- 0.37 ml/min of tidal volume, 0.41 +/- 0.10 ml/cmH2O of compliance, and 98.7 +/- 9.7 mmHg of PaO2) were significantly higher compared with the I/R group (P = 0.004, P< 0.001, and P< 0.001, respectively). Compared to the I/R group, the contents of superoxide dismutase were significantly higher (47.07 +/- 7.91 U/mg protein vs. 33.84 +/- 10.15 U/mg protein; P = 0.005) while the wet/dry weight ratio (P < 0.01), methane dicarboxylic aldehyde (1.92 +/- 0.25 nmol/mg protein vs. 2.67 +/- 0.46 nmol/mg protein; P< 0.001), and adenosine triphosphate contents (297.05 +/- 47.45 nmol/mg protein vs. 208.09 +/- 29.11 nmol/mg protein; P = 0.005) were markedly lower in BV-treated lungs. Histological analysis revealed that BV alleviated LIRI. Furthermore, the expression of inflammatory cytokines (interleukin-1beta, interleukin-6, and tumor necrosis factor-beta) was downregulated and the expression of cyclooxygenase-2, inducible nitric oxide synthase, and Jun N-terminal kinase was significantly reduced in BV group (all P< 0.01 compared to I/R group). Finally, the apoptosis index in the BV group was significantly decreased (P < 0.01 compared to I/R group). CONCLUSION: BV protects lung IRI through its antioxidative, anti-inflammatory, and anti-apoptotic effects. PMID- 28345553 TI - Two Cases of Spinal Tanycytic Ependymoma Associated with Neurofibromatosis Type 2. PMID- 28345552 TI - Relationship between Hepatitis C Virus Infection and Iron Overload. AB - OBJECTIVE: The aim of this study was to summarize the interactions between hepatitis C virus (HCV) infection and iron overload, and to understand the mechanisms of iron overload in chronic hepatitis C (CHC) and the role iron plays in HCV life cycle. DATA SOURCES: This review was based on data in articles published in the PubMed databases up to January 28, 2017, with the keywords "hepatitis C virus", "iron overload", "iron metabolism", "hepcidin", "translation", and "replication". STUDY SELECTION: Articles related to iron metabolism, iron overload in patients with CHC, or the effects of iron on HCV life cycle were selected for the review. RESULTS: Iron overload is common in patients with CHC. The mechanisms involve decreased hepcidin levels caused by HCV through signal transducer and activator of transcription 3, mitogen-activated protein kinase, or bone morphogenetic protein/SMAD signaling pathways, and the altered expression of other iron-metabolism-related genes. Some studies found that iron increases HCV replication, while other studies found the opposite result. Most of the studies suggest the positive role of iron on HCV translation, the mechanisms of which involve increased expression levels of factors associated with HCV internal ribosome entry site-dependent translation, such as eukaryotic initiation factor 3 and La protein. CONCLUSION: The growing literature demonstrates that CHC leads to iron overload, and iron affects the HCV life cycle in turn. Further research should be conducted to clarify the mechanism involved in the complicated interaction between iron and HCV. PMID- 28345554 TI - Robot-assisted Living-donor Left Lateral Sectionectomy. PMID- 28345555 TI - Squamous Cell Carcinoma of the Nail Bed. PMID- 28345556 TI - Dural Venous Sinus Angioplasty and Stenting for Treatment of Idiopathic Intracranial Hypertension. PMID- 28345557 TI - Surgical Treatment of Double Outlet Right Ventricle with Absent Pulmonary Valve and Bronchiarctia. PMID- 28345558 TI - Celebrating excellence. PMID- 28345559 TI - Dr. Rajendra Prasad Centre celebrates golden jubilee. PMID- 28345560 TI - Fifty glorious years of Dr. Rajendra Prasad Centre. PMID- 28345562 TI - Definition of blindness under National Programme for Control of Blindness: Do we need to revise it? AB - A review appropriateness of the current definition of blindness under National Programme for Control of Blindness (NPCB), Government of India. Online search of peer-reviewed scientific published literature and guidelines using PubMed, the World Health Organization (WHO) IRIS, and Google Scholar with keywords, namely blindness and visual impairment, along with offline examination of reports of national and international organizations, as well as their cross-references was done until December 2016, to identify relevant documents on the definition of blindness. The evidence for the historical and currently adopted definition of blindness under the NPCB, the WHO, and other countries was reviewed. Differences in the NPCB and WHO definitions were analyzed to assess the impact on the epidemiological status of blindness and visual impairment in India. The differences in the criteria for blindness under the NPCB and the WHO definitions cause an overestimation of the prevalence of blindness in India. These variations are also associated with an over-representation of refractive errors as a cause of blindness and an under-representation of other causes under the NPCB definition. The targets for achieving elimination of blindness also become much more difficult to achieve under the NPCB definition. Ignoring differences in definitions when comparing the global and Indian prevalence of blindness will cause erroneous interpretations. We recommend that the appropriate modifications should be made in the NPCB definition of blindness to make it consistent with the WHO definition. PMID- 28345561 TI - Insight into high myopia and the macula. AB - The incidence of myopia is constantly on the rise. Patients of high myopia and pathological myopia are young and can lose vision due to a number of degenerative changes occurring at the macula. With the emergence of new technologies such as swept-source optical coherence tomography (OCT) and OCT angiography, our understanding of macular pathology in myopia has improved significantly. New conditions such as myopic traction maculopathy have been defined. Early, noninvasive detection of myopic choroidal neovascularization and its differentiation from lacquer cracks is possible with a greater degree of certainty. We discuss the impact of these new exciting and promising technologies and management of macular pathology in myopia. Incorporation of OCT in the microscope has also improved macular surgery. New concepts such as fovea-sparing internal limiting membrane peeling have emerged. A review of literature and our experience in managing all these conditions are discussed. PMID- 28345563 TI - Chlamydial eye infections: Current perspectives. AB - Chlamydia trachomatis, an obligate intraocular bacteria causing trachoma, adult and neonatal inclusion conjunctivitis, was the leading cause of blindness in the last century worldwide. Improvement in socioeconomic and living conditions, availability of antibiotics, and introduction of National Trachoma Control Programmes reduced the prevalence in developed countries, but it persisted in resource-poor settings of Africa and Asia, including India. In 2016, as per the WHO report, trachoma is restricted to 42 countries, causing blindness/visual impairment in ~1.9 million people. India is one of the five countries with nearly half of total active trachoma patients. Introduction of Global Elimination of Trachoma 2020 program by the WHO, using SAFE strategy (surgery for trachomatous trichiasis; Antibiotics for C. trachomatis; Facial cleanliness; and environmental improvement) greatly reduced the prevalence, but trachoma still persists in India. Global increase in the reproductive tract infection by C. trachomatis urogenital serotypes (D-K) has led to concurrent increase in C. trachomatis eye infections. Therefore, kerato eye infections due to chlamydial infections continue to be seen in hospitals. Over the years, there have been advances in laboratory diagnostics, in understanding the pathogenesis, tissue tropism, C. trachomatis genomics, and treatment modalities. Due attention and research is still needed for the study of C. trachomatis eye infections. PMID- 28345564 TI - Innovations in glaucoma surgery from Dr. Rajendra Prasad Centre for Ophthalmic Sciences. AB - Trabeculectomy surgery is the current standard of care in glaucoma for achieving a low target intraocular pressure if medical therapy is not adequate. Augmentation of trabeculectomy with antimetabolites brought a revolutionary change in the long-term success rates of trabeculectomy, but along with it came a plethora of complications. There still is a big window for therapeutic innovations on this subject. The foremost target for these innovations is to modulate the wound healing response after glaucoma drainage surgery. Achieving the desired balance between long-term success of filtering blebs versus early failure due to scarring of blebs and hypotony due to dysfunctional filtering blebs poses a unique challenge to the ophthalmologists. Alternatives to trabeculectomy such as glaucoma drainage devices and minimally invasive glaucoma surgeries cannot solve the problem of glaucoma blindness in our country, mainly due to their unpredictable results and unfavorable cost-benefit ratio. In this article, we present a summary of our innovations in glaucoma surgery to advance patient care by making it more effective, safer, and economical. PMID- 28345565 TI - Upgradation and modernization of eye banking services: Integrating tradition with innovative policies and current best practices. AB - PURPOSE: The purpose of this study is to review the history and evolution of the National Eye Bank (NEB) and analyze the impact over the years and report the outcome of the invested resources. METHODS: Review of archival material, records, project reports, policy and procedures' manuals, and publications was done. Descriptive and analytical processing of data obtained was undertaken. Parameters evaluated included total collection, transplantation, utilization rates of donor cornea, changing trends over time in terms of numbers and duration of recipients waiting, impactful research translated into changes in standard operating protocols, new facilities, and subsequent effects on numbers or quality assurance measures and overview of major achievements. Periodic situational analysis with contextual relevance and interpretation of outcomes was done pertaining to national goals and international standards. RESULTS: The NEB and cornea services have played a key leadership role in furthering the development of eye banking and corneal transplantation services. The contribution extends beyond routine patient care to education, training, generation of resources, advocacy, and policymaking. In quantifiable terms, the overall performance has steadily increased over the years. Major contributions include training of doctors, eye bank staff and corneal surgeons, introduction of innovative techniques for corneal transplantation, setting of national standards for eye banking and provision of preservation media, customized corneal, and ocular surface cell replacement therapy in collaboration with other departments and institutes. CONCLUSION: The eye banking and corneal transplantation facilities have evolved with time providing quality services, modernized as appropriate with updated knowledge and incorporating technological advances supported by the systematic evidence-based approach. PMID- 28345566 TI - Intraoperative optical coherence tomography in anterior segment surgeries. AB - Intraoperative optical coherence tomography (iOCT) is a noninvasive imaging modality that provides a real-time dynamic feedback of the various surgical steps. Comprehensive literature search was performed in MEDLINE using "intraoperative optical coherence tomography" and "iOCT" as keywords. The use of iOCT as an aid to decision-making has been successfully reported in cases undergoing keratoplasty, implantable Collamer lens (ICL) implantation as well as cataract surgery. iOCT helps to assess the graft-host relationship in penetrating keratoplasty. It helps confirm the presence of a big bubble, detect subclinical big bubbles and guide layer by layer stromal dissection in cases of deep anterior lamellar keratoplasty. It acts as a guide during crucial surgical steps in endothelial keratoplasty, right from scoring of the Descemet membrane to ensuring graft apposition at the end of surgery. The morphological features of the corneal incision in phacoemulsification may be assessed. iOCT is a useful tool in assessing the status of the posterior capsule and may help identify preexisting posterior capsular defects during cataract surgery in various clinical scenarios such as posterior polar cataract, traumatic cataract, and vitrectomized eyes. It allows on-table assessment of the ICL vault and potentially facilitates exchange of ICL in the same sitting in extremes of vault. Ocular surface disorders such as ocular surface squamous neoplasia, pterygium, and dermoid may find an application for iOCT, wherein an iOCT-guided stromal dissection will ensure adequate depth of dissection. Further technological advancements may allow for automatic centration and tracking and address the present limitation of instrument-induced shadowing. PMID- 28345567 TI - Retina and the tubercle Bacillus: Four decades of our journey and current understanding. AB - Tuberculosis continues to be a major pandemic with enormous public health implication. Involvement of ocular tissues in the form of tubercles, tuberculomas, panophthalmitis, and iris granulomas are well recognized as definitive manifestations of tuberculosis. For these lesions, confirmatory evidence is available in the form of demonstration of acid-fast Bacillus on Ziehl Neelsen staining. For other retinochoroidal disorders such as central serous chorioretinopathy, retinal vasculitis, and presumed ocular tuberculosis, hard evidence about the role of Mycobacterium tuberculosis is lacking. In this review, work done at our center over the past four decades in the form of experimental animal studies, nucleic acid amplification assays and clinical studies regarding the above retinochoroidal pathologies and the tubercle Bacillus is presented. It is possible that revisiting experimental animal studies may be a way forward in the current scenario of ambiguity about the cause-effect relationship between M. tuberculosis and few of the retinochoroidal disorders. PMID- 28345568 TI - Prognosis of different glaucomas seen at a tertiary center: A 10-year overview. AB - AIM: This study aims to determine treatment patterns, long-term intraocular pressure (IOP) and perimetric control in different glaucomas seen at a tertiary eye center. SETTINGS AND DESIGN: Hospital-based, cross-sectional chart review of patients routinely following up at an outpatient glaucoma service. METHODS: Patients with a follow-up of at least 10 years were evaluated. Their mean IOP, visual field (VF) status, and medications/surgery required at final assessment were noted. STATISTICAL ANALYSIS: Descriptive statistics (mean, standard deviation, and range) were used for all parameters. RESULTS: A total of 230 patients met our inclusion and exclusion criteria, 79 having ocular hypertension with open angles or primary angle closure (PAC), 35 primary open angle glaucoma (POAG), 50 PAC glaucoma (PACG), 20 primary congenital glaucoma (PCG), 46 secondary glaucoma patients. Ocular hypertensives with open angles showed progression to POAG in 3.7%, those with PAC in 5.2%, at a mean IOP of 17.3 +/- 3.37 mmHg and 17.13 +/- 4.41 mmHg, respectively. A progression on Humphrey Field Analyzer was seen in 11% of POAG and PACG eyes at a mean IOP of 13.50 +/- 5.07 and 13.09 +/- 3.95 mmHg, respectively. Fifteen percent of primary congenital glaucomas (PCGs) showed a glaucomatous VF defect after 10 years. In secondary glaucoma eyes, the mean IOP at last follow-up visit was 12.38 +/- 3.74 mmHg, with progression noted in 7.69% of eyes. CONCLUSION: This study provides evidence that routine delivery of care can provide well controlled IOP in glaucomas, both primary and secondary, and the VF stabilized in about 90% of patients over a period of 10 years, with the currently available glaucoma medications and trabeculectomy. PMID- 28345569 TI - Recent advances and challenges in the management of retinoblastoma. AB - The treatment of retinoblastoma (Rb) has improved significantly in recent times. Worldwide, there is an increasing trend to use conservative treatment modalities that aim to preserve the globe as well as vision with minimum morbidity. Recently, the use of targeted delivery of chemotherapy to the eye in the form of selective intra-arterial and intravitreal chemotherapy has shown promising results. Radiotherapy is beneficial in selected cases, either in the form of plaque brachytherapy or as external beam radiotherapy. Orbital disease carries a poor prognosis for survival. However, a multimodal treatment protocol has improved survival in children with extraocular disease. Nevertheless, challenges remain, especially for the developing world. This review aims to highlight recent advances in the management of Rb that have contributed towards improving treatment outcomes and also discuss the challenges ahead, with special reference to the Indian scenario. PMID- 28345570 TI - Appraising the spectrum of firework trauma and the related laws during Diwali in North India. AB - PURPOSE: To evaluate the epidemiological characteristics and outcomes of ocular injuries resulting from the use of firecrackers during the Diwali festival in all age groups. MATERIALS AND METHODS: A single-center, retrospective, hospital-based case series presenting with ocular trauma consequent to fireworks usage in a tertiary eye care center in North India during the 5 days of Diwali festival from 2011 to 2015 was conducted. RESULTS: A total of 53 eyes of 45 patients were included in the study, out of which the vast majority (39/87%) were males. The mean age was 20.55 years. Almost an equal number of bystanders (25/55.5%) were affected as compared to people handling the fireworks (20/44.44%). Five (9.43%) eyes had open-globe injury, whereas 48 (90.56%) eyes had closed-globe injury. Eighteen (33.96%) eyes underwent surgical intervention. Thirty-three (62.26%) eyes had final vision >20/200 with eight (15.09%) eyes being vision <3/60 in the affected eye. CONCLUSION: Firework-related ocular trauma can lead to serious visual impairment. Mandatory legislative laws pertaining to the manufacture, sale, and use of fireworks and creating public awareness can reduce the incidence of this preventable cause of blindness in the society. Initiating new policies for retailers involved in sale of these firecrackers can also bring in decrease of such morbidities. PMID- 28345571 TI - Laser capsulotomy following cataract surgery: Comparing time to capsulotomy with implantation of two broadly used intraocular lenses. AB - PURPOSE: The aim of this study is to compare the length of time from uneventful cataract surgery using one of two common posterior chamber intraocular lenses (IOLs) (hydrophilic versus hydrophobic acrylic) to laser capsulotomy. MATERIALS AND METHODS: Retrospective analysis of all patients who underwent neodymium: yttrium-aluminum-garnet laser capsulotomy between 2011 and 2014 following uneventful phacoemulsification surgery at a tertiary university-affiliated medical center. Medical records were reviewed for demographics, ocular comorbidities, operative details, postoperative follow-up, and findings of the precapsulotomy ophthalmologic examination. Parameters, including age, sex, laterality, visual acuity, surgeon's experience, and time from cataract surgery to capsulotomy, were compared between patients who received hydrophilic (SeeLens AF, Kibbutz Hanita, Israel) or hydrophobic (AcrySof SA60AT, Alcon Laboratories, Fort Worth, TX, USA) IOLs. RESULTS: The cohort included 222 patients (255 eyes), of which, 107 were male and 115 female, of mean age 73 +/- 8 years. Mean interval from cataract surgery to laser capsulotomy was 24 months (range 2-70) and was significantly shorter in patients with SeeLens (23 +/- 13 months) than AcrySof IOL implantation (28 +/- 13 months, P = 0.04). Lens type remained significant in multivariate analysis after including surgeon's experience and age as potential confounders (P = 0.04). CONCLUSION: The hydrophilic SeeLens IOL is associated with a significantly shorter time interval from cataract surgery to laser capsulotomy than the hydrophobic AcrySof IOL. PMID- 28345572 TI - Late dislocation of in-the-bag intraocular lenses in uveitic eyes: An analysis of management and complications. AB - AIM: An analysis of late in-the-bag dislocation of intraocular lenses (IOL), in uveitic eyes. SETTING: Referral uveitis clinic. DESIGN: Retrospective case series. MATERIALS AND METHODS: All case records of eyes with chronic uveitis that had phacoemulsification with IOL implantation, at a referral uveitis clinic between February 1997 and January 2015 were retrieved and analyzed. Only those eyes with no documented intraoperative complication and no predisposing risks to IOL dislocation, such as pseudoexfoliation, high myopia, trauma, and prior VR surgery were included in this study. RESULTS: A total of 581 eyes with chronic uveitis underwent phacoemulsification with IOL implantation under steroid cover from February 1997 to December 2015. Out of these 581 eyes, 10 patients (11 eyes) had experienced late in-the-bag IOL dislocation (1.89%). All 11 eyes had chronic intermediate uveitis. The mean duration from the time of cataract surgery to IOL dislocation was 11.24 years. 5 out of 11 eyes had pars plana vitrectomy (PPV) with IOL removal with 4-point sutured scleral fixated IOL. Two out of 11 eyes had PPV with in-the-bag IOL re-fixation. Out of 11, 2 eyes had PPV with IOL removal only. Remaining 2 eyes of 2 patients did not opt for surgery. Out of 11, 8 eyes had improved vision at last follow-up. CONCLUSIONS: In-the-bag dislocation of IOL is a rare late complication in uveitic eyes. With tight perioperative inflammatory control, scleral-fixated posterior chamber intraocular lens or IOL re-fixation are good options of restoring vision in these high-risk eyes. PMID- 28345573 TI - Clinical correlation of imaging findings in congenital cranial dysinnervation disorders involving abducens nerve. AB - PURPOSE: High-resolution magnetic resonance imaging (MRI) of intracranial parts of sixth nerve and seventh nerve and the extraocular muscles (EOMs) in orbit to correlate the clinical characteristics in patients with two special forms of strabismus in congenital cranial dysinnervation disorders which are Duane's retraction syndrome (DRS) and Mobius syndrome. MATERIALS AND METHODS: Morphological analysis by 3T MRI of orbit (using surface coils) and brain (using 32 channel head coil) was performed on 6 patients with clinical DRS (1 bilateral), 2 cases with Mobius syndrome, and 1 case with congenital sixth nerve palsy. These were compared with findings in five controls. RESULTS: We observed absence/hypoplasia of sixth nerve in five out of seven eyes with DRS (71.42%), anomalous course in one eye, sixth and seventh nerve absence/hypoplasia in affected eyes with Mobius syndrome and bilateral absence/hypoplasia of the sixth nerve in congenital sixth nerve palsy. For EOMs we calculated maximum diameter, area, and circumference of muscles using Osirix software, and noticed significant hypoplasia of lateral rectus in comparison to controls (P < 0.001). CONCLUSIONS: MRI gives useful information regarding confirmation of clinical diagnosis and its neurological anomalies in complex cases and helps to plan tailor made surgical management. PMID- 28345574 TI - Differential cataract blindness by sex in India: Evidence from two large national surveys. AB - AIMS: Women suffer disproportionately more from cataract blindness compared to males in low- and middle-income countries. Two large population-based surveys have been undertaken in India at an interval of 7 years and data from these surveys provided an opportunity to assess the trends in gender differentials in cataract blindness. MATERIALS AND METHODS: Data were extracted from the surveys to discern sex differences in cataract blindness. Multivariate analysis was performed to adjust for confounders and their impact on gender differences in cataract blindness. Blindness was defined as presenting vision <20/400 in the better eye, and a cataract blind person was defined as a blind person where the principal cause of loss of vision was cataract. RESULTS: Prevalence of cataract blindness was higher in females compared to males in both surveys. The odds of cataract blindness for females did not change over time as observed in the surveys (1999-2001 and 2006-2007). Adjusted odds ratio from logistic regression analysis revealed that females continued to be at a higher risk of cataract blindness. CONCLUSIONS: Sex differences continued in India in relation to cataract blindness despite the gains made by the national program. PMID- 28345575 TI - Missed punctal foreign body: A cause for chronic ocular irritation. PMID- 28345576 TI - Congenital nasolacrimal duct obstruction: Should we continue lacrimal massage till 1 year or perform an office probing at 6 months? A clinical decision analysis approach. PMID- 28345577 TI - Comment on: Comparison of serum sodium and potassium levels in patients with senile cataract and age-matched individuals without cataract. PMID- 28345578 TI - Comment on: Comparison of serum sodium and potassium levels in patients with senile cataract and age-matched individuals without cataract. PMID- 28345579 TI - Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer's disease. AB - delta-secretase, also known as asparagine endopeptidase (AEP) or legumain, is a lysosomal cysteine protease that cleaves both amyloid precursor protein (APP) and tau, mediating the amyloid-beta and tau pathology in Alzheimer's disease (AD). Here we report the therapeutic effect of an orally bioactive and brain permeable delta-secretase inhibitor in mouse models of AD. We performed a high-throughput screen and identified a non-toxic and selective delta-secretase inhibitor, termed compound 11, that specifically blocks delta-secretase but not other related cysteine proteases. Co-crystal structure analysis revealed a dual active site directed and allosteric inhibition mode of this compound class. Chronic treatment of tau P301S and 5XFAD transgenic mice with this inhibitor reduces tau and APP cleavage, ameliorates synapse loss and augments long-term potentiation, resulting in protection of memory. Therefore, these findings demonstrate that this delta secretase inhibitor may be an effective clinical therapeutic agent towards AD. PMID- 28345581 TI - Potential of biosynthesized silver nanoparticles using Stenotrophomonas sp. BHU S7 (MTCC 5978) for management of soil-borne and foliar phytopathogens. AB - Stenotrophomonas sp. is emerging as a popular microbe of global concern with various potential ecological roles. Biosynthesis of gold and silver nanoparticles (AgNPs) using this bacterial strain has shown promising applications in life sciences. However, there is no report on efficient agricultural applications of biosynthesized AgNPs using Stenotrophomonas sp. In this regard, successful biosynthesis of AgNPs using Stenotrophomonas sp. BHU-S7 (MTCC 5978) was monitored by Uv-visible spectrum showing surface plasmon resonance (SPR) peak at 440 nm. The biosynthesized AgNPs were spherical with an average mean size of ~12 nm. The antifungal efficacy of biosynthesized AgNPs against foliar and soil-borne phytopathogens was observed. The inhibitory impact of AgNPs (2, 4, 10 MUg/ml) on conidial germination was recorded under in vitro conditions. Interestingly, sclerotia of Sclerotium rolfsii exposed to AgNPs failed to germinate on PDA medium and in soil system. Moreover, AgNPs treatment successfully managed collar rot of chickpea caused by S. rolfsii under greenhouse conditions. The reduced sclerotia germination, phenolic acids induction, altered lignification and H2O2 production was observed to be the probable mechanisms providing protection to chickpea against S. rolfsii. Our data revealed that AgNPs treated plants are better equipped to cope with pathogen challenge pointing towards their robust applications in plant disease management. PMID- 28345583 TI - Synergistic Effects of Micro-electrolysis-Photocatalysis on Water Treatment and Fish Performance in Saline Recirculating Aquaculture System. AB - A new physico-chemical process for TAN (total ammonia nitrogen) removal and disinfection is introduced in saline recirculating aquaculture system (RAS), in which the biofilter is replaced with an integrated electrolysis cell and an activated carbon filter. The electrolysis cell which is based on micro current electrolysis combined with UV-light was self-designed. After the fundamental research, a small pilot scale RAS was operated for 30 days to verify the technical feasibility. The system was stocked by 42 GIFT tilapia (Oreochromis niloticus) fish with the rearing density of 13 kg/m3. During the experiments, the TAN concentration remained below 1.0 mg/L. The nitrite concentration was lower than 0.2 mg/L and the nitrate concentration had increased continuously to 12.79 mg/L at the end. Furthermore, the concentration of residual chlorine in culture ponds remained below 0.3 mg/L, ORP maintained slight fluctuations in the range of 190~240 mV, and pH of the water showed the downtrend. Tilapia weight increased constantly to 339.3 +/- 10 g. For disinfection, the active chlorine generated by electrochemical treatment caused Escherichia coli inactivation. Enzyme activity assay indicated that the activity of glutamate dehydrogenase, carbonic anhydrase and glutamic pyruvic transaminase increased within the normal range. The preliminary feasibility was verified by using this physico-chemical technology in the RAS. PMID- 28345580 TI - Differential roles of caspase-1 and caspase-11 in infection and inflammation. AB - Caspase-1, also known as interleukin-1beta (IL-1beta)-converting enzyme (ICE), regulates antimicrobial host defense, tissue repair, tumorigenesis, metabolism and membrane biogenesis. On activation within an inflammasome complex, caspase-1 induces pyroptosis and converts pro-IL-1beta and pro-IL-18 into their biologically active forms. "ICE-/-" or "Casp1-/-" mice generated using 129 embryonic stem cells carry a 129-associated inactivating passenger mutation on the caspase-11 locus, essentially making them deficient in both caspase-1 and caspase-11. The overlapping and unique functions of caspase-1 and caspase-11 are difficult to unravel without additional genetic tools. Here, we generated caspase 1-deficient mouse (Casp1Null) on the C57BL/6 J background that expressed caspase 11. Casp1Null cells did not release IL-1beta and IL-18 in response to NLRC4 activators Salmonella Typhimurium and flagellin, canonical or non-canonical NLRP3 activators LPS and ATP, Escherichia coli, Citrobacter rodentium and transfection of LPS, AIM2 activators Francisella novicida, mouse cytomegalovirus and DNA, and the infectious agents Listeria monocytogenes and Aspergillus fumigatus. We further demonstrated that caspase-1 and caspase-11 differentially contributed to the host defense against A. fumigatus infection and to endotoxemia. PMID- 28345582 TI - Enhancing titres of therapeutic viral vectors using the transgene repression in vector production (TRiP) system. AB - A key challenge in the field of therapeutic viral vector/vaccine manufacturing is maximizing production. For most vector platforms, the 'benchmark' vector titres are achieved with inert reporter genes. However, expression of therapeutic transgenes can often adversely affect vector titres due to biological effects on cell metabolism and/or on the vector virion itself. Here, we exemplify the novel 'Transgene Repression In vector Production' (TRiP) system for the production of both RNA- and DNA-based viral vectors. The TRiP system utilizes a translational block of one or more transgenes by employing the bacterial tryptophan RNA-binding attenuation protein (TRAP), which binds its target RNA sequence close to the transgene initiation codon. We report enhancement of titres of lentiviral vectors expressing Cyclo-oxygenase-2 by 600-fold, and adenoviral vectors expressing the pro-apoptotic gene Bax by >150,000-fold. The TRiP system is transgene-independent and will be a particularly useful platform in the clinical development of viral vectors expressing problematic transgenes. PMID- 28345584 TI - Terahertz and mid-infrared plasmons in three-dimensional nanoporous graphene. AB - Two-dimensional (2D) graphene emerged as an outstanding material for plasmonic and photonic applications due to its charge-density tunability, high electron mobility, optical transparency and mechanical flexibility. Recently, novel fabrication processes have realised a three-dimensional (3D) nanoporous configuration of high-quality monolayer graphene which provides a third dimension to this material. In this work, we investigate the optical behaviour of nanoporous graphene by means of terahertz and infrared spectroscopy. We reveal the presence of intrinsic 2D Dirac plasmons in 3D nanoporous graphene disclosing strong plasmonic absorptions tunable from terahertz to mid-infrared via controllable doping level and porosity. In the far-field the spectral width of these absorptions is large enough to cover most of the mid-Infrared fingerprint region with a single plasmon excitation. The enhanced surface area of nanoporous structures combined with their broad band plasmon absorption could pave the way for novel and competitive nanoporous-graphene based plasmonic-sensors. PMID- 28345585 TI - Direct amidation of esters with nitroarenes. AB - Esters are one of the most common functional groups in natural and synthetic products, and the one-step conversion of the ester group into other functional groups is an attractive strategy in organic synthesis. Direct amidation of esters is particularly appealing due to the omnipresence of the amide moiety in biomolecules, fine chemicals, and drug candidates. However, efficient methods for direct amidation of unactivated esters are still lacking. Here we report nickel catalysed reductive coupling of unactivated esters with nitroarenes to furnish in one step a wide range of amides bearing functional groups relevant to the development of drugs and agrochemicals. The method has been used to expedite the syntheses of bio-active molecules and natural products, as well as their post synthetic modifications. Preliminary mechanistic study indicates a reaction pathway distinct from conventional amidation methods using anilines as nitrogen sources. The work provides a novel and efficient method for amide synthesis. PMID- 28345586 TI - New insights into mononuclear phagocyte biology from the visual system. AB - Major advances in mononuclear phagocyte biology have been made but key questions pertinent to their roles in health and disease remain, including in the visual system. One problem concerns how dendritic cells can trigger immune responses from certain tightly regulated immune- privileged sites of the eye. Another, albeit separate, problem involves whether there are functional specializations for microglia versus monocytes in retinal neurodegeneration. In this Review, we examine novel insights in eye immune privilege and, separately, we discuss recent inroads concerning retinal degeneration. Both themes have been extensively studied in the visual system and show parallels with recent findings concerning mononuclear phagocytes in the central nervous system and in the periphery. PMID- 28345587 TI - Derivation of Functional Human Astrocytes from Cerebral Organoids. AB - Astrocytes play a critical role in the development and homeostasis of the central nervous system (CNS). Astrocyte dysfunction results in several neurological and degenerative diseases. However, a major challenge to our understanding of astrocyte physiology and pathology is the restriction of studies to animal models, human post-mortem brain tissues, or samples obtained from invasive surgical procedures. Here, we report a protocol to generate human functional astrocytes from cerebral organoids derived from human pluripotent stem cells. The cellular isolation of cerebral organoids yielded cells that were morphologically and functionally like astrocytes. Immunolabelling and proteomic assays revealed that human organoid-derived astrocytes express the main astrocytic molecular markers, including glutamate transporters, specific enzymes and cytoskeletal proteins. We found that organoid-derived astrocytes strongly supported neuronal survival and neurite outgrowth and responded to ATP through transient calcium wave elevations, which are hallmarks of astrocyte physiology. Additionally, these astrocytes presented similar functional pathways to those isolated from adult human cortex by surgical procedures. This is the first study to provide proteomic and functional analyses of astrocytes isolated from human cerebral organoids. The isolation of these astrocytes holds great potential for the investigation of developmental and evolutionary features of the human brain and provides a useful approach to drug screening and neurodegenerative disease modelling. PMID- 28345589 TI - Rational Design of 1-D Co3O4 Nanofibers@Low content Graphene Composite Anode for High Performance Li-Ion Batteries. AB - Cobalt oxide that has high energy density, is the next-generation candidate as the anode material for LIBs. However, the practical use of Co3O4 as anode material has been hindered by limitations, especially, low electrical conductivity and pulverization from large volume change upon cycling. These features lead to hindrance to its electrochemical properties for lithium-ion batteries. To improve electrochemical properties, we synthesized one-dimensional (1-D) Co3O4 nanofibers (NFs) overed with reduced graphene oxide (rGO) sheets by electrostatic self-assembly (Co3O4 NFs@rGO). The flexible graphene oxide sheets not only prevent volume changes of active materials upon cycling as a clamping layer but also provide efficient electrical pathways by three-dimensional (3-D) network architecture. When applied as an anode for LIBs, the Co3O4 NFs@rGO exhibits superior electrochemical performance: (i) high reversible capacity (615 mAh g-1 and 92% capacity retention after 400 cycles at 4.0 A g-1) and (ii) excellent rate capability. Herein, we highlighted that the enhanced conversion reaction of the Co3O4 NFs@rGO is attributed to effective combination of 1-D nanostructure and low content of rGO (~3.5 wt%) in hybrid composite. PMID- 28345590 TI - Associations of parental age with health and social factors in adult offspring. Methodological pitfalls and possibilities. AB - Parental age is increasing rapidly in many countries. Analysis of this potentially important influence on offspring well-being is hampered by strong secular trends and socioeconomic patterning and by a shortage of follow-up data for adult offspring. We used Swedish national data on up to 3,653,938 offspring to consider the associations of parental age with a suite of outcomes in adult offspring, comparing the results from an array of statistical methods for optimal causal inference. The offspring of older mothers had higher BMI, blood pressure, height, intelligence, non-cognitive ability and socioeconomic position. They were less likely to smoke or to be left-handed. Associations with paternal age were strongly, but not completely, attenuated by adjustment for maternal age. Estimates from the commonly-used sibling comparison method were driven primarily by a pathway mediated by offspring date of birth when outcomes showed strong secular trends. These results suggest that the intra-uterine and early life environments provided by older mothers may be detrimental to offspring cardiovascular health, but that their greater life experience and social position may bring intellectual and social advantages to their offspring. The analysis of parental age presents particular challenges, and further methodological developments are needed. PMID- 28345588 TI - Macrophages induce AKT/beta-catenin-dependent Lgr5+ stem cell activation and hair follicle regeneration through TNF. AB - Skin stem cells can regenerate epidermal appendages; however, hair follicles (HF) lost as a result of injury are barely regenerated. Here we show that macrophages in wounds activate HF stem cells, leading to telogen-anagen transition (TAT) around the wound and de novo HF regeneration, mostly through TNF signalling. Both TNF knockout and overexpression attenuate HF neogenesis in wounds, suggesting dose-dependent induction of HF neogenesis by TNF, which is consistent with TNF induced AKT signalling in epidermal stem cells in vitro. TNF-induced beta-catenin accumulation is dependent on AKT but not Wnt signalling. Inhibition of PI3K/AKT blocks depilation-induced HF TAT. Notably, Pten loss in Lgr5+ HF stem cells results in HF TAT independent of injury and promotes HF neogenesis after wounding. Thus, our results suggest that macrophage-TNF-induced AKT/beta-catenin signalling in Lgr5+ HF stem cells has a crucial role in promoting HF cycling and neogenesis after wounding. PMID- 28345591 TI - Activation of the mechanosensitive ion channel MscL by mechanical stimulation of supported Droplet-Hydrogel bilayers. AB - The droplet on hydrogel bilayer (DHB) is a novel platform for investigating the function of ion channels. Advantages of this setup include tight control of all bilayer components, which is compelling for the investigation of mechanosensitive (MS) ion channels, since they are highly sensitive to their lipid environment. However, the activation of MS ion channels in planar supported lipid bilayers, such as the DHB, has not yet been established. Here we present the activation of the large conductance MS channel of E. coli, (MscL), in DHBs. By selectively stretching the droplet monolayer with nanolitre injections of buffer, we induced quantifiable DHB tension, which could be related to channel activity. The MscL activity response revealed that the droplet monolayer tension equilibrated over time, likely by insertion of lipid from solution. Our study thus establishes a method to controllably activate MS channels in DHBs and thereby advances studies of MS channels in this novel platform. PMID- 28345592 TI - Community temporal variability increases with fluctuating resource availability. AB - An increase in the quantity of available resources is known to affect temporal variability of aggregate community properties. However, it is unclear how might fluctuations in resource availability alter community-level temporal variability. Here we conduct a microcosm experiment with laboratory protist community subjected to manipulated resource pulses that vary in intensity, duration and time of supply, and examine the impact of fluctuating resource availability on temporal variability of the recipient community. The results showed that the temporal variation of total protist abundance increased with the magnitude of resource pulses, as protist community receiving infrequent resource pulses (i.e., high-magnitude nutrients per pulse) was relatively more unstable than community receiving multiple resource pulses (i.e., low-magnitude nutrients per pulse), although the same total amounts of nutrients were added to each community. Meanwhile, the timing effect of fluctuating resources did not significantly alter community temporal variability. Further analysis showed that fluctuating resource availability increased community temporal variability by increasing the degree of community-wide species synchrony and decreasing the stabilizing effects of dominant species. Hence, the importance of fluctuating resource availability in influencing community stability and the regulatory mechanisms merit more attention, especially when global ecosystems are experiencing high rates of anthropogenic nutrient inputs. PMID- 28345593 TI - Microstructural tissue-engineering in the rachis and barbs of bird feathers. AB - Feathers do not have to be especially strong but they do need to be stiff and at the same time resilient and to have a high work of fracture. Syncitial barbule fibres are the highest size-class of continuous filaments in the cortex of the rachis of the feather. However, the rachis can be treated as a generalized cone of rapidly diminishing volume. This means that hundreds of syncitial barbule fibres of the rachis may have to be terminated before reaching the tip - creating potentially thousands of inherently fatal crack-like defects. Here I report a new microstructural architecture of the feather cortex in which most syncitial barbule fibres deviate to the right and left edges of the feather rachis from far within its borders and extend into the barbs, side branches of the rachis, as continuous filaments. This novel morphology adds significantly to knowledge of beta-keratin self-assembly in the feather and helps solve the potential problem of fatal crack-like defects in the rachidial cortex. Furthermore, this new complexity, consistent with biology's robust multi-functionality, solves two biomechanical problems at a stroke. Feather barbs deeply 'rooted' within the rachis are also able to better withstand the aerodynamic forces to which they are subjected. PMID- 28345595 TI - Fundamental properties of resonances. AB - All resonances, from hydrogen nuclei excited by the high-energy gamma rays in deep space to newly discovered particles produced in Large Hadron Collider, should be described by the same fundamental physical quantities. However, two distinct sets of properties are used to describe resonances: the pole parameters (complex pole position and residue) and the Breit-Wigner parameters (mass, width, and branching fractions). There is an ongoing decades-old debate on which one of them should be abandoned. In this study of nucleon resonances appearing in the elastic pion-nucleon scattering we discover an intricate interplay of the parameters from both sets, and realize that neither set is completely independent or fundamental on its own. PMID- 28345594 TI - Serum lactate dehydrogenase predicts prognosis and correlates with systemic inflammatory response in patients with advanced pancreatic cancer after gemcitabine-based chemotherapy. AB - Serum lactate dehydrogenase (LDH) concentrations correlate with tumor progression and poor outcome. We evaluated the predictive value of serum LDH level for overall survival (OS) of patients with advanced pancreatic cancer after gemcitabine-based chemotherapy. We retrospectively enrolled 364 patients with locally advanced or metastatic pancreatic adenocarcinoma who were then allocated to training (n = 139) and validation cohorts (n = 225). We evaluated the association between serum LDH levels and OS as well as with markers of systemic inflammation, including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and lymphocyte/monocyte ratio (LMR). Kaplan-Meier analyses revealed that low serum LDH levels in the training cohort significantly correlated with longer OS. Multivariate analysis identified the serum LDH levels as an independent prognostic predictor of OS (p = 0.005). Serum LDH levels correlated positively with NLR and PLR and correlated negatively with LMR. Similar results were obtained for the validation cohort, except that multivariate analysis identified the serum LDH level as a significant prognostic predictor and only a statistical trend for OS (p = 0.059). We conclude that serum LDH levels were associated with the systemic inflammatory response and served as a significant prognostic predictor of OS. Serum LDH levels predicted OS in patients with advanced pancreatic cancer after gemcitabine-based palliative chemotherapy. PMID- 28345596 TI - Crystal structure of Zika virus NS5 RNA-dependent RNA polymerase. AB - The current Zika virus (ZIKV) outbreak became a global health threat of complex epidemiology and devastating neurological impacts, therefore requiring urgent efforts towards the development of novel efficacious and safe antiviral drugs. Due to its central role in RNA viral replication, the non-structural protein 5 (NS5) RNA-dependent RNA-polymerase (RdRp) is a prime target for drug discovery. Here we describe the crystal structure of the recombinant ZIKV NS5 RdRp domain at 1.9 A resolution as a platform for structure-based drug design strategy. The overall structure is similar to other flaviviral homologues. However, the priming loop target site, which is suitable for non-nucleoside polymerase inhibitor design, shows significant differences in comparison with the dengue virus structures, including a tighter pocket and a modified local charge distribution. PMID- 28345598 TI - Novel 1, 4-dihydropyridines for L-type calcium channel as antagonists for cadmium toxicity. AB - The present study, we design and synthesize the novel dihydropyridine derivatives, i.e., 3 (a-e) and 5 (a-e) and evaluated, anticonvulsant activity. Initially due to the lacuna of LCC, we modeled the protein through modeller 9.15v and evaluated through servers. Docking studies were performed with the synthesized compounds and resulted two best compounds, i.e., 5a, 5e showed the best binding energies. The activity of intracellular Ca2+ measurements was performed on two cell lines: A7r5 (rat aortic smooth muscle cells) and SH-SY5Y (human neuroblastoma cells). The 5a and 5e compounds was showing the more specific activity on L-type calcium channels, i.e. A7r5 (IC50 = 0.18 +/- 0.02 and 0.25 +/- 0.63 MUg/ml, respectively) (containing only L-type channels) than SH SY5Y (i.e. both L-type and T-type channels) (IC50 = 8 +/- 0.23 and 10 +/- 0.18 MUg/ml, respectively) with intracellular calcium mobility similar to amlodipine. Finally, both in silico and in vitro results exploring two derivatives 5a and 5e succeeded to treat cadmium toxicity. PMID- 28345597 TI - Post-Traumatic Osteoarthritis in Mice Following Mechanical Injury to the Synovial Joint. AB - We investigated the spectrum of lesions characteristic of post-traumatic osteoarthritis (PTOA) across the knee joint in response to mechanical injury. We hypothesized that alteration in knee joint stability in mice reproduces molecular and structural features of PTOA that would suggest potential therapeutic targets in humans. The right knees of eight-week old male mice from two recombinant inbred lines (LGXSM-6 and LGXSM-33) were subjected to axial tibial compression. Three separate loading magnitudes were applied: 6N, 9N, and 12N. Left knees served as non-loaded controls. Mice were sacrificed at 5, 9, 14, 28, and 56 days post-loading and whole knee joint changes were assessed by histology, immunostaining, micro-CT, and magnetic resonance imaging. We observed that tibial compression disrupted joint stability by rupturing the anterior cruciate ligament (except for 6N) and instigated a cascade of temporal and topographical features of PTOA. These features included cartilage extracellular matrix loss without proteoglycan replacement, chondrocyte apoptosis at day 5, synovitis present at day 14, osteophytes, ectopic calcification, and meniscus pathology. These findings provide a plausible model and a whole-joint approach for how joint injury in humans leads to PTOA. Chondrocyte apoptosis, synovitis, and ectopic calcification appear to be targets for potential therapeutic intervention. PMID- 28345599 TI - Location, location &size: defects close to surfaces dominate fatigue crack initiation. AB - Metallic cast components inevitably contain defects such as shrinkage cavities which are inherent to the solidification process. Those defects are known to significantly alter the fatigue life of components. Yet very little is known, quantitatively, on the dangerosity of internal casting defects compared to surface ones. In this study, fatigue specimens containing controlled internal defects (shrinkage pores) are used to foster internal cracking. In situ fatigue tests monitored by X ray synchrotron tomography revealed that the internal nucleation and propagation of cracks was systematically overran by surface cracking initiated at castings defects up to ten times smaller than the internal ones. These findings indicate that the presence of internal defects in cast components can be tolerated to a larger extent than is allowed by nowadays standards. PMID- 28345600 TI - The structure of Zika virus NS5 reveals a conserved domain conformation. AB - The recent outbreak of Zika virus (ZIKV) has imposed a serious threat to public health. Here we report the crystal structure of the ZIKV NS5 protein in complex with S-adenosyl-L-homocysteine, in which the tandem methyltransferase (MTase) and RNA-dependent RNA polymerase (RdRp) domains stack into one of the two alternative conformations of flavivirus NS5 proteins. The activity of this NS5 protein is verified through a de novo RdRp assay on a subgenomic ZIKV RNA template. Importantly, our structural analysis leads to the identification of a potential drug-binding site of ZIKV NS5, which might facilitate the development of novel antivirals for ZIKV. PMID- 28345601 TI - Towards reproducible MRM based biomarker discovery using dried blood spots. AB - There is an increasing interest in the use of dried blood spot (DBS) sampling and multiple reaction monitoring in proteomics. Although several groups have explored the utility of DBS by focusing on protein detection, the reproducibility of the approach and whether it can be used for biomarker discovery in high throughput studies is yet to be determined. We assessed the reproducibility of multiplexed targeted protein measurements in DBS compared to serum. Eighty-two medium to high abundance proteins were monitored in a number of technical and biological replicates. Importantly, as part of the data analysis, several statistical quality control approaches were evaluated to detect inaccurate transitions. After implementing statistical quality control measures, the median CV on the original scale for all detected peptides in DBS was 13.2% and in Serum 8.8%. We also found a strong correlation (r = 0.72) between relative peptide abundance measured in DBS and serum. The combination of minimally invasive sample collection with a highly specific and sensitive mass spectrometry (MS) technique allows for targeted quantification of multiple proteins in a single MS run. This approach has the potential to fundamentally change clinical proteomics and personalized medicine by facilitating large-scale studies. PMID- 28345602 TI - A primary human macrophage-enteroid co-culture model to investigate mucosal gut physiology and host-pathogen interactions. AB - Integration of the intestinal epithelium and the mucosal immune system is critical for gut homeostasis. The intestinal epithelium is a functional barrier that secludes luminal content, senses changes in the gut microenvironment, and releases immune regulators that signal underlying immune cells. However, interactions between epithelial and innate immune cells to maintain barrier integrity and prevent infection are complex and poorly understood. We developed and characterized a primary human macrophage-enteroid co-culture model for in depth studies of epithelial and macrophage interactions. Human intestinal stem cell-derived enteroid monolayers co-cultured with human monocyte-derived macrophages were used to evaluate barrier function, cytokine secretion, and protein expression under basal conditions and following bacterial infection. Macrophages enhanced barrier function and maturity of enteroid monolayers as indicated by increased transepithelial electrical resistance and cell height. Communication between the epithelium and macrophages was demonstrated through morphological changes and cytokine production. Intraepithelial macrophage projections, efficient phagocytosis, and stabilized enteroid barrier function revealed a coordinated response to enterotoxigenic and enteropathogenic E. coli infections. In summary, we have established the first primary human macrophage enteroid co-culture system, defined conditions that allow for a practical and reproducible culture model, and demonstrated its suitability to study gut physiology and host responses to enteric pathogens. PMID- 28345603 TI - PJA2 ubiquitinates the HIV-1 Tat protein with atypical chain linkages to activate viral transcription. AB - Transcription complexes that assemble at the HIV-1 promoter efficiently initiate transcription but generate paused RNA polymerase II downstream from the start site. The virally encoded Tat protein hijacks positive transcription elongation factor b (P-TEFb) to phosphorylate and activate this paused polymerase. In addition, Tat undergoes a series of reversible post-translational modifications that regulate distinct steps of the transcription cycle. To identify additional functionally important Tat cofactors, we performed RNAi knockdowns of sixteen previously identified Tat interactors and found that a novel E3 ligase, PJA2, ubiquitinates Tat in a non-degradative manner and specifically regulates the step of HIV transcription elongation. Interestingly, several different lysine residues in Tat can function as ubiquitin acceptor sites, and variable combinations of these lysines support both full transcriptional activity and viral replication. Further, the polyubiquitin chain conjugated to Tat by PJA2 can itself be assembled through variable ubiquitin lysine linkages. Importantly, proper ubiquitin chain assembly by PJA2 requires that Tat first binds its P-TEFb cofactor. These results highlight that both the Tat substrate and ubiquitin modification have plastic site usage, and this plasticity is likely another way in which the virus exploits the host molecular machinery to expand its limited genetic repertoire. PMID- 28345604 TI - Mind-wandering and alterations to default mode network connectivity when listening to naturalistic versus artificial sounds. AB - Naturalistic environments have been demonstrated to promote relaxation and wellbeing. We assess opposing theoretical accounts for these effects through investigation of autonomic arousal and alterations of activation and functional connectivity within the default mode network (DMN) of the brain while participants listened to sounds from artificial and natural environments. We found no evidence for increased DMN activity in the naturalistic compared to artificial or control condition, however, seed based functional connectivity showed a shift from anterior to posterior midline functional coupling in the naturalistic condition. These changes were accompanied by an increase in peak high frequency heart rate variability, indicating an increase in parasympathetic activity in the naturalistic condition in line with the Stress Recovery Theory of nature exposure. Changes in heart rate and the peak high frequency were correlated with baseline functional connectivity within the DMN and baseline parasympathetic tone respectively, highlighting the importance of individual neural and autonomic differences in the response to nature exposure. Our findings may help explain reported health benefits of exposure to natural environments, through identification of alterations to autonomic activity and functional coupling within the DMN when listening to naturalistic sounds. PMID- 28345605 TI - Extracellular matrix protein Reelin promotes myeloma progression by facilitating tumor cell proliferation and glycolysis. AB - Reelin is an extracellular matrix protein that is crucial for neuron migration, adhesion, and positioning. We examined the expression of Reelin in a large cohort of multiple myeloma patients recorded in Gene Expression Omnibus (GEO) database and used over-expression and siRNA knockdown of Reelin to investigate the role of Reelin in myeloma cell growth. We find that Reelin expression is negatively associated with myeloma prognosis. Reelin promotes myeloma cell proliferation in vitro as well as in vivo. The Warburg effect, evidenced by increased glucose uptake and lactate production, is also enhanced in Reelin-expressing cells. The activation of FAK/Syk/Akt/mTOR and STAT3 pathways contributes to Reelin-induced cancer cell growth and metabolic reprogramming. Our findings further reveal that activated Akt and STAT3 pathways induce the upregulation of HIF1alpha and its downstream targets (LDHA and PDK1), leading to increased glycolysis in myeloma cells. Together, our results demonstrate the critical contributions of Reelin to myeloma growth and metabolism. It presents an opportunity for myeloma therapeutic intervention by inhibiting Reelin and its signaling pathways. PMID- 28345606 TI - 53BP1 contributes to regulation of autophagic clearance of mitochondria. AB - Autophagy, the primary recycling pathway within cells, plays a critical role in mitochondrial quality control under normal growth conditions and in the cellular response to stress. Here we provide evidence that 53BP1, a DNA damage response protein, is involved in regulating mitochondrial clearance from the cell via a type of autophagy termed mitophagy. We found that when either human or mouse cells were 53BP1-deficient, there was an increase in mitochondrial abnormalities, as observed through staining intensity, aggregation, and increased mass. Moreover, a 53BP1-depleted cell population included an increased number of cells with a high mitochondrial membrane potential (DeltaPsim) relative to controls, suggesting that the loss of 53BP1 prevents initiation of mitophagy thereby leading to the accumulation of damaged mitochondria. Indeed, both 53BP1 and the mitophagy-associated protein LC3 translocated to mitochondria in response to damage induced by the mitochondrial uncoupler carbonyl cyanide m chlorophenylhydrazone (CCCP). The recruitment of parkin, an E3-ubiquitin ligase, to mitochondria in response to CCCP treatment was significantly decreased in 53BP1-deficient cells. And lastly, using p53-deficient H1299 cells, we confirmed that the role of 53BP1 in mitophagy is independent of p53. These data support a model in which 53BP1 plays an important role in modulating mitochondrial homeostasis and in the clearance of damaged mitochondria. PMID- 28345608 TI - MAOA rs1137070 and heroin addiction interactively alter gray matter volume of the salience network. AB - The rs1137070 polymorphism of monoamine oxidase A (MAOA) is associated with alcoholism and smoking behavior. However, the association between rs1137070 and heroin addiction remains unclear. In this study, we examined the allelic distribution of rs1137070 in 1,035 heroin abusers and 2,553 healthy controls and investigated the interactive effects of rs1137070 and heroin addiction on gray matter volume (GMV) based on 78 heroin abusers and 79 healthy controls. The C allele frequency of rs1137070 was significantly higher in heroin abusers. Heroin addiction and the rs1137070 variant interactively altered measures of GMV in the anterior cingulate cortex, orbital frontal cortex, temporal pole, and insula, which were correlated with cognitive function. Heroin abusers with the C allele had lower measures of GMV in these regions than the healthy controls with the same allele, whereas those with the T allele displayed a different trend. The altered brain regions were connected with white matter tracts, yielding a structural network that partially overlapped with the salience network. These findings suggest that the low activity-related C allele of MAOA rs1137070 is associated with an increase in the sensitivity to heroin addiction and the damaging effects of heroin abuse on cognition and the salience network. PMID- 28345607 TI - Time- and dose dependent actions of cardiotonic steroids on transcriptome and intracellular content of Na+ and K+: a comparative analysis. AB - Recent studies demonstrated that in addition to Na+,K+-ATPase inhibition cardiotonic steroids (CTSs) affect diverse intracellular signaling pathways. This study examines the relative impact of [Na+]i/[K+]i-mediated and -independent signaling in transcriptomic changes triggered by the endogenous CTSs ouabain and marinobufagenin (MBG) in human umbilical vein endothelial cells (HUVEC). We noted that prolongation of incubation increased the apparent affinity for ouabain estimated by the loss of [K+]i and gain of [Na+]i. Six hour exposure of HUVEC to 100 and 3,000 nM ouabain resulted in elevation of the [Na+]i/[K+]i ratio by ~15 and 80-fold and differential expression of 258 and 2185 transcripts, respectively. Neither [Na+]i/[K+]i ratio nor transcriptome were affected by 6-h incubation with 30 nM ouabain. The 96-h incubation with 3 nM ouabain or 30 nM MBG elevated the [Na+]i/[K+]i ratio by ~14 and 3-fold and led to differential expression of 880 and 484 transcripts, respectively. These parameters were not changed after 96-h incubation with 1 nM ouabain or 10 nM MBG. Thus, our results demonstrate that elevation of the [Na+]i/[K+]i ratio is an obligatory step for transcriptomic changes evoked by CTS in HUVEC. The molecular origin of upstream [Na+]i/[K+]i sensors involved in transcription regulation should be identified in forthcoming studies. PMID- 28345609 TI - Environmental DNA in subterranean biology: range extension and taxonomic implications for Proteus. AB - Europe's obligate cave-dwelling amphibian Proteus anguinus inhabits subterranean waters of the north-western Balkan Peninsula. Because only fragments of its habitat are accessible to humans, this endangered salamander's exact distribution has been difficult to establish. Here we introduce a quantitative real time polymerase chain reaction-based environmental DNA (eDNA) approach to detect the presence of Proteus using water samples collected from karst springs, wells or caves. In a survey conducted along the southern limit of its known range, we established a likely presence of Proteus at seven new sites, extending its range to Montenegro. Next, using specific molecular probes to discriminate the rare black morph of Proteus from the closely related white morph, we detected its eDNA at five new sites, thus more than doubling the known number of sites. In one of these we found both black and white Proteus eDNA together. This finding suggests that the two morphs may live in contact with each other in the same body of groundwater and that they may be reproductively isolated species. Our results show that the eDNA approach is suitable and efficient in addressing questions in biogeography, evolution, taxonomy and conservation of the cryptic subterranean fauna. PMID- 28345610 TI - Early loss of subchondral bone following microfracture is counteracted by bone marrow aspirate in a translational model of osteochondral repair. AB - Microfracture of cartilage defects may induce alterations of the subchondral bone in the mid- and long-term, yet very little is known about their onset. Possibly, these changes may be avoided by an enhanced microfracture technique with additional application of bone marrow aspirate. In this study, full-thickness chondral defects in the knee joints of minipigs were either treated with (1) debridement down to the subchondral bone plate alone, (2) debridement with microfracture, or (3) microfracture with additional application of bone marrow aspirate. At 4 weeks after microfracture, the loss of subchondral bone below the defects largely exceeded the original microfracture holes. Of note, a significant increase of osteoclast density was identified in defects treated with microfracture alone compared with debridement only. Both changes were significantly counteracted by the adjunct treatment with bone marrow. Debridement and microfracture without or with bone marrow were equivalent regarding the early cartilage repair. These data suggest that microfracture induced a substantial early resorption of the subchondral bone and also highlight the potential value of bone marrow aspirate as an adjunct to counteract these alterations. Clinical studies are warranted to further elucidate early events of osteochondral repair and the effect of enhanced microfracture techniques. PMID- 28345612 TI - Wafer-scale Fabrication of Non-Polar Mesoporous GaN Distributed Bragg Reflectors via Electrochemical Porosification. AB - Distributed Bragg reflectors (DBRs) are essential components for the development of optoelectronic devices. For many device applications, it is highly desirable to achieve not only high reflectivity and low absorption, but also good conductivity to allow effective electrical injection of charges. Here, we demonstrate the wafer-scale fabrication of highly reflective and conductive non polar gallium nitride (GaN) DBRs, consisting of perfectly lattice-matched non polar (11-20) GaN and mesoporous GaN layers that are obtained by a facile one step electrochemical etching method without any extra processing steps. The GaN/mesoporous GaN DBRs exhibit high peak reflectivities (>96%) across the entire visible spectrum and wide spectral stop-band widths (full-width at half-maximum >80 nm), while preserving the material quality and showing good electrical conductivity. Such mesoporous GaN DBRs thus provide a promising and scalable platform for high performance GaN-based optoelectronic, photonic, and quantum photonic devices. PMID- 28345611 TI - Copy number variation profile in the placental and parental genomes of recurrent pregnancy loss families. AB - We have previously shown an extensive load of somatic copy number variations (CNVs) in the human placental genome with the highest fraction detected in normal term pregnancies. Hereby, we hypothesized that insufficient promotion of CNVs may impair placental development and lead to recurrent pregnancy loss (RPL). RPL affects ~3% of couples aiming at childbirth and idiopathic RPL represents ~50% of cases. We analysed placental and parental CNV profiles of idiopathic RPL trios (mother-father-placenta) and duos (mother-placenta). Consistent with the hypothesis, the placental genomes of RPL cases exhibited 2-fold less CNVs compared to uncomplicated 1st trimester pregnancies (P = 0.02). This difference mainly arose from lower number of duplications. Overall, 1st trimester control placentas shared only 5.3% of identified CNV regions with RPL cases, whereas the respective fraction with term placentas was 35.1% (P = 1.1 * 10-9). Disruption of the genes NUP98 (embryonic stem cell development) and MTRR (folate metabolism) was detected exclusively in RPL placentas, potentially indicative to novel loci implicated in RPL. Interestingly, genes with higher overall expression were prone to deletions (>3-fold higher median expression compared to genes unaffected by CNVs, P = 6.69 * 10-20). Additionally, large pericentromeric and subtelomeric CNVs in parental genomes emerged as a risk factor for RPL. PMID- 28345613 TI - Nano-inspired smart interfaces: fluidic interactivity and its impact on heat transfer. AB - Interface-inspired convection is a key heat transfer scheme for hot spot cooling and thermal energy transfer. An unavoidable trade-off of the convective heat transfer is pressure loss caused by fluidic resistance on an interface. To overcome this limitation, we uncover that nano-inspired interfaces can trigger a peculiar fluidic interactivity, which can pursue all the two sides of the coin: heat transfer and fluidic friction. We demonstrate the validity of a quasi-fin effect of Si-based nanostructures based on conductive capability of heat dissipation valid under the interactivity with fluidic viscous sublayer. The exclusive fluid-interface friction is achieved when the height of the nanostructures is much less than the thickness of the viscous sublayers in the turbulent regime. The strategic nanostructures show an enhancement of heat transfer coefficients in the wall jet region by more than 21% without any significant macroscale pressure loss under single-phase impinging jet. Nanostructures guaranteeing fluid access via an equivalent vacancy larger than the diffusive path length of viscid flow lead to local heat transfer enhancement of more than 13% at a stagnation point. Functional nanostructures will give shape to possible breakthroughs in heat transfer and its optimization can be pursued for engineered systems. PMID- 28345614 TI - Prognosis and value of preoperative radiotherapy in locally advanced rectal signet-ring cell carcinoma. AB - As well known, signet-ring cell carcinoma (SRCC) is a rare histological subtype of colorectal adenocarcinoma, which has been associated with poor prognosis and resistant to non-surgery therapy compared with common adenocarcinoma. In this study, we assessed the effect of preoperative radiotherapy (PRT) for locally advanced rectal SRCC in a large patient group from the Surveillance, Epidemiology, and End Results program (SEER, 1988-2011) database. SRCC was found in 0.9% (n = 622) rectal cancer (RC) patients in our study. In the PRT setting, SRCC had significantly worse cancer-specific survival than mucinous adenocarcinoma and nonmucinous adenocarcinoma patients (log-rank, P < 0.001). In terms of SRCC, stage III RC patients benefited from PRT (log-rank, P < 0.001) while stage II did not (P = 0.095). The multivariate Cox proportional hazard model showed that PRT was an independent benefit factor in stage III rectal SRCC patients (HR, 0.611; 95% CI, 0.407-0.919; P = 0.018). In conclusion, SRCC was an independent predictor of poor prognosis in stage III RC patients, but not in stage II. In the PRT setting of locally advanced RC, SRCC patients had significantly worse prognosis. PRT was an independent prognostic factor associated with improved survival in stage III rectal SRCC. PMID- 28345615 TI - Transcriptome analysis of molecular mechanisms responsible for light-stress response in Mythimna separata (Walker). AB - Light is an important environmental signal for most insects. The Oriental Armyworm, Mythimna separata, is a serious pest of cereal crops worldwide, and is highly sensitive to light signals during its developmental and reproductive stages. However, molecular biological studies of its response to light stress are scarce, and related genomic information is not available. In this study, we sequenced and de novo assembled the transcriptomes of M. separata exposed to four different light conditions: dark, white light (WL), UV light (UVL) and yellow light (YL). A total of 46,327 unigenes with an average size of 571 base pairs (bp) were obtained, among which 24,344 (52.55%) matched to public databases. The numbers of genes differentially expressed between dark vs WL, dark vs UVL, dark vs YL, and UVL vs YL were 12,012, 12,950, 14,855, and 13,504, respectively. These results suggest that light exposure altered gene expression patterns in M. separata. Putative genes involved in phototransduction-fly, phototransduction, circadian rhythm-fly, olfactory transduction, and taste transduction were identified. This study thus identified a series of candidate genes and pathways potentially related to light stress in M. separata. PMID- 28345616 TI - Shoulder Stretching Intervention Reduces the Incidence of Shoulder and Elbow Injuries in High School Baseball Players: a Time-to-Event Analysis. AB - We prospectively evaluated the effects of a prevention program on the incidence of shoulder and elbow injuries in high school baseball pitchers. Ninety-two pitchers participated in this study and were taught to perform stretching and strength exercises aimed at improving shoulder external rotation strength in the preseason. The pitchers freely chose to participate in one of four groups [SM group: performed both exercises, S-group: performed stretching exercise only, M group: performed strength training only, and N-group: performed neither intervention]. Injury was defined as inability to play for >=8 days because of shoulder/elbow symptoms. Kaplan-Meier survival curves were generated and hazard ratios (HRs) for injury occurrence were calculated using multivariate Cox regression. Log-rank test was used for between-group comparisons of survival distributions. The injuries occurred in 25, 35, and 57% of participants and median times to injury were 89, 92, and 29.5 days in the S- (n = 32), SM- (n = 46), and N- (n = 14) group, respectively. Nobody chose M-group. HRs were 0.36 and 0.47 for the S- and SM-group, respectively, based on the N-group. The incidence of injury was significantly lower in the S-group than in the N-group (p = 0.04). Daily posterior shoulder stretching may reduce the incidence of the injuries in high school baseball pitchers. PMID- 28345617 TI - Stimulation of adult hippocampal neurogenesis by physical exercise and enriched environment is disturbed in a CADASIL mouse model. AB - In the course of CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), a dysregulated adult hippocampal neurogenesis has been suggested as a potential mechanism for early cognitive decline. Previous work has shown that mice overexpressing wild type Notch3 and mice overexpressing Notch3 with a CADASIL mutation display impaired cell proliferation and survival of newly born hippocampal neurons prior to vascular abnormalities. Here, we aimed to elucidate how the long-term survival of these newly generated neurons is regulated by Notch3. Knowing that adult neurogenesis can be robustly stimulated by physical exercise and environmental enrichment, we also investigated the influence of such stimuli as potential therapeutic instruments for a dysregulated hippocampal neurogenesis in the CADASIL mouse model. Therefore, young-adult female mice were housed in standard (STD), environmentally enriched (ENR) or running wheel cages (RUN) for either 28 days or 6 months. Mice overexpressing mutated Notch3 and developing CADASIL (TgN3R169C), and mice overexpressing wild type Notch3 (TgN3WT) were used. We found that neurogenic stimulation by RUN and ENR is apparently impaired in both transgenic lines. The finding suggests that a disturbed neurogenic process due to Notch3 dependent micromilieu changes might be one vascular-independent mechanism contributing to cognitive decline observed in CADASIL. PMID- 28345618 TI - PTPIP51 regulates mouse cardiac ischemia/reperfusion through mediating the mitochondria-SR junction. AB - Protein tyrosine phosphatase interacting protein 51 (PTPIP51) participates in multiple cellular processes, and dysfunction of PTPIP51 is implicated in diseases such as cancer and neurodegenerative disorders. However, there is no functional evidence showing the physiological or pathological roles of PTPIP51 in the heart. We have therefore investigated the role and mechanisms of PTPIP51 in regulating cardiac function. We found that PTPIP51 was markedly upregulated in ischemia/reperfusion heart. Upregulation of PTPIP51 by adenovirus-mediated overexpression markedly increased the contact of mitochondria-sarcoplasmic reticulum (SR), elevated mitochondrial Ca2+ uptake from SR release through mitochondrial Ca2+uniporter. Inhibition or knockdown of mitochondrial Ca2+uniporter reversed PTPIP51-mediated increase of mitochondrial Ca2+ and protected cardiomyocytes against PTPIP51-mediated apoptosis. More importantly, cardiac specific knockdown of PTPIP51 largely reduced myocardium infarction size and heart injury after ischemia/reperfusion. Our study defines a novel and essential function of PTPIP51 in the cardiac ischemia/reperfusion process by mediating mitochondria-SR contact. Downregulation of PTPIP51 improves heart function after ischemia/reperfusion injury, suggesting PTPIP51 as a therapeutic target for ischemic heart diseases. PMID- 28345619 TI - Impact of molecular subtypes on metastatic breast cancer patients: a SEER population-based study. AB - To investigate the significance and impact of molecular subtyping stratification on metastatic breast cancer patients, we identified 159,344 female breast cancer patients in the Surveillance, Epidemiology and End Results (SEER) database with known hormone receptor (HoR) and human epidermal growth factor receptor 2 (HER2) status. 4.8% of patients were identified as having stage IV disease, and were more likely to be HER2+/HoR-, HER2+/HoR+, or HER2-/HoR-. Stage IV breast cancer patients with a HER2+/HoR+ status exhibited the highest median overall survival (OS) (44.0 months) and those with a HER2-/HoR- status exhibited the lowest median OS (13.0 months). Patients with a HER2-/HoR+ status had more bone metastasis, whereas patients with a HER2+/HoR- status had an increased incidence of liver metastasis. Brain and lung metastasis were more likely to occur in women with a HER2-/HoR- status. The multivariable analysis revealed a significant interaction between single metastasis and molecular subtype. No matter which molecular subtype, women who did not undergo primary tumour surgery had worse survival than those who experienced primary tumour surgery. Collectively, our findings advanced the understanding that molecular subtype might lead to more tailored and effective therapies in metastatic breast cancer patients. PMID- 28345621 TI - Two-dimensional electronic spectra of the photosynthetic apparatus of green sulfur bacteria. AB - Advances in time resolved spectroscopy have provided new insight into the energy transmission in natural photosynthetic complexes. Novel theoretical tools and models are being developed in order to explain the experimental results. We provide a model calculation for the two-dimensional electronic spectra of Cholorobaculum tepidum which correctly describes the main features and transfer time scales found in recent experiments. From our calculation one can infer the coupling of the antenna chlorosome with the environment and the coupling between the chlorosome and the Fenna-Matthews-Olson complex. We show that environment assisted transport between the subunits is the required mechanism to reproduce the experimental two-dimensional electronic spectra. PMID- 28345620 TI - Acute and chronic mitochondrial respiratory chain deficiency differentially regulate lysosomal biogenesis. AB - Mitochondria are key cellular signaling platforms, affecting fundamental processes such as cell proliferation, differentiation and death. However, it remains unclear how mitochondrial signaling affects other organelles, particularly lysosomes. Here, we demonstrate that mitochondrial respiratory chain (RC) impairments elicit a stress signaling pathway that regulates lysosomal biogenesis via the microphtalmia transcription factor family. Interestingly, the effect of mitochondrial stress over lysosomal biogenesis depends on the timeframe of the stress elicited: while RC inhibition with rotenone or uncoupling with CCCP initially triggers lysosomal biogenesis, the effect peaks after few hours and returns to baseline. Long-term RC inhibition by long-term treatment with rotenone, or patient mutations in fibroblasts and in a mouse model result in repression of lysosomal biogenesis. The induction of lysosomal biogenesis by short-term mitochondrial stress is dependent on TFEB and MITF, requires AMPK signaling and is independent of calcineurin signaling. These results reveal an integrated view of how mitochondrial signaling affects lysosomes, which is essential to fully comprehend the consequences of mitochondrial malfunction, particularly in the context of mitochondrial diseases. PMID- 28345622 TI - Comprehensive track-structure based evaluation of DNA damage by light ions from radiotherapy-relevant energies down to stopping. AB - Track structures and resulting DNA damage in human cells have been simulated for hydrogen, helium, carbon, nitrogen, oxygen and neon ions with 0.25-256 MeV/u energy. The needed ion interaction cross sections have been scaled from those of hydrogen; Barkas scaling formula has been refined, extending its applicability down to about 10 keV/u, and validated against established stopping power data. Linear energy transfer (LET) has been scored from energy deposits in a cell nucleus; for very low-energy ions, it has been defined locally within thin slabs. The simulations show that protons and helium ions induce more DNA damage than heavier ions do at the same LET. With increasing LET, less DNA strand breaks are formed per unit dose, but due to their clustering the yields of double-strand breaks (DSB) increase, up to saturation around 300 keV/MUm. Also individual DSB tend to cluster; DSB clusters peak around 500 keV/MUm, while DSB multiplicities per cluster steadily increase with LET. Remarkably similar to patterns known from cell survival studies, LET-dependencies with pronounced maxima around 100-200 keV/MUm occur on nanometre scale for sites that contain one or more DSB, and on micrometre scale for megabasepair-sized DNA fragments. PMID- 28345623 TI - Liposomes loaded with bioactive lipids enhance antibacterial innate immunity irrespective of drug resistance. AB - Phagocytosis is a key mechanism of innate immunity, and promotion of phagosome maturation may represent a therapeutic target to enhance antibacterial host response. Phagosome maturation is favored by the timely and coordinated intervention of lipids and may be altered in infections. Here we used apoptotic body-like liposomes (ABL) to selectively deliver bioactive lipids to innate cells, and then tested their function in models of pathogen-inhibited and host impaired phagosome maturation. Stimulation of macrophages with ABLs carrying phosphatidic acid (PA), phosphatidylinositol 3-phosphate (PI3P) or PI5P increased intracellular killing of BCG, by inducing phagosome acidification and ROS generation. Moreover, ABLs carrying PA or PI5P enhanced ROS-mediated intracellular killing of Pseudomonas aeruginosa, in macrophages expressing a pharmacologically-inhibited or a naturally-mutated cystic fibrosis transmembrane conductance regulator. Finally, we show that bronchoalveolar lavage cells from patients with drug-resistant pulmonary infections increased significantly their capacity to kill in vivo acquired bacterial pathogens when ex vivo stimulated with PA- or PI5P-loaded ABLs. Altogether, these results provide the proof of concept of the efficacy of bioactive lipids delivered by ABL to enhance phagosome maturation dependent antimicrobial response, as an additional host-directed strategy aimed at the control of chronic, recurrent or drug-resistant infections. PMID- 28345625 TI - Assortative Mating: Encounter-Network Topology and the Evolution of Attractiveness. AB - We model a social-encounter network where linked nodes match for reproduction in a manner depending probabilistically on each node's attractiveness. The developed model reveals that increasing either the network's mean degree or the "choosiness" exercised during pair formation increases the strength of positive assortative mating. That is, we note that attractiveness is correlated among mated nodes. Their total number also increases with mean degree and selectivity during pair formation. By iterating over the model's mapping of parents onto offspring across generations, we study the evolution of attractiveness. Selection mediated by exclusion from reproduction increases mean attractiveness, but is rapidly balanced by skew in the offspring distribution of highly attractive mated pairs. PMID- 28345624 TI - The effects of self-selected light-dark cycles and social constraints on human sleep and circadian timing: a modeling approach. AB - Why do we go to sleep late and struggle to wake up on time? Historically, light dark cycles were dictated by the solar day, but now humans can extend light exposure by switching on artificial lights. We use a mathematical model incorporating effects of light, circadian rhythmicity and sleep homeostasis to provide a quantitative theoretical framework to understand effects of modern patterns of light consumption on the human circadian system. The model shows that without artificial light humans wakeup at dawn. Artificial light delays circadian rhythmicity and preferred sleep timing and compromises synchronisation to the solar day when wake-times are not enforced. When wake-times are enforced by social constraints, such as work or school, artificial light induces a mismatch between sleep timing and circadian rhythmicity ('social jet-lag'). The model implies that developmental changes in sleep homeostasis and circadian amplitude make adolescents particularly sensitive to effects of light consumption. The model predicts that ameliorating social jet-lag is more effectively achieved by reducing evening light consumption than by delaying social constraints, particularly in individuals with slow circadian clocks or when imposed wake-times occur after sunrise. These theory-informed predictions may aid design of interventions to prevent and treat circadian rhythm-sleep disorders and social jet-lag. PMID- 28345626 TI - Elevated angiopoietin 2 in aqueous of patients with neovascular age related macular degeneration correlates with disease severity at presentation. AB - Angiopoietin 2 (ANG2) is a proangiogenic cytokine which may have an implication in neovascular age related macular degeneration (nAMD). In 24 eyes of 24 subjects presenting with treatment naive nAMD and 26 eyes of 26 control patients, aqueous humor samples were collected at the time of intervention (intravitreal injection of anti-vascular endothelial growth factor or cataract extraction). Best corrected visual acuity (BCVA) with and central macular thickness (CMT) using optical coherence tomography (OCT) were measured before each injection in the nAMD group. Aqueous cytokine levels were determined by immunoassay using a multiplex array (Quansys Biosciences, Logan, UT). Levels of ANG2 in the aqueous were significantly higher in nAMD patients than those of the control group (p < 0.0001), so were hepatocyte growth factor (HGF), interleukin-8 (IL-8) and tissue inhibitor of metalloproteinase 1 (TIMP 1), all with p < 0.001. ANG2 correlated with worse BCVA (r = 0.44, p-value = 0.027) and greater CMT (r = 0.66, p-value < 0.0001) on optical coherence tomography (OCT). ANG2 is upregulated in patients with nAMD and correlates with severity of disease at presentation. PMID- 28345627 TI - Heterologous protein-DNA interactions lead to biased allelic expression of circadian clock genes in interspecific hybrids. AB - Genomic interactions in allopolyploids create expression variation of homoeologous alleles through protein-protein and protein-DNA interactions. However, the molecular basis for this is largely unknown. Here we investigated the protein-protein and protein-DNA interactions among homoeologous transcription factors in the circadian-clock feedback loop, consisting of CCA1 HIKING EXPEDITION (CHE), CIRCADIAN CLOCK ASSOCIATED1 (CCA1), and TIMING OF CAB EXPRESSION1 (TOC1), plus the interaction with a chromatin factor, HISTONE DEACETYLASE1 (HD1). In the allotetraploids formed between A. thaliana (At) and Arabidopsis arenosa (Aa), AtCCA1 is expressed at lower levels than AaCCA1, which could alter clock output traits. The reduced AtCCA1 expressions in the allotetraploids are consistent with the biochemical data that AaCHE showed preferential binding to the AtCCA1 promoter, in which AaCHE interacts with a higher affinity to AtHD1 than AtCHE. AaCHE also showed a higher affinity to TOC1 than AtCHE, consistent with the effect of TOC1 on repressing CCA1. Thus, stronger AaCHE-TOC1 and AaCHE-AtHD1 interactions reduce AtCC1 allelic expression. Our current data suggest a biochemical basis for protein interactions in trans with a preference to the cis-acting elements in heterologous combinations to reduce AtCCA1 expression, while altered CCA1 expression has been shown to affect metabolic and biomass heterosis in interspecific hybrids or allotetraploids. PMID- 28345628 TI - Tissue resident memory T cells in the human conjunctiva and immune signatures in human dry eye disease. AB - Non-recirculating resident memory (TRM) and recirculating T cells mount vigorous immune responses to both self and foreign antigens in barrier tissues like the skin, lung and gastrointestinal tract. Using impression cytology followed by flow cytometry we identified two TRM subsets and four recirculating T-subsets in the healthy human ocular surface. In dry eye disease, principal component analysis (PCA) revealed two clusters of patients with distinct T-cell signatures. Increased conjunctival central memory and naive T cells characterized Cluster-1 patients, and increased CD8+ TRMs and CD4+ recirculating memory T cells characterized Cluster-2 patients. Interestingly these T-cell signatures are associated with different clinical features: the first signature correlated with increased ocular redness, and the second with reduced tear break up times. These findings open the door to immune-based characterization of dry eye disease and T subset specific immunotherapies to suppress T-subsets involved in disease. They may also help with patient stratification during clinical trials of immunomodulators. PMID- 28345629 TI - WT1 expression in breast cancer disrupts the epithelial/mesenchymal balance of tumour cells and correlates with the metabolic response to docetaxel. AB - WT1 is a transcription factor which regulates the epithelial-mesenchymal balance during embryonic development and, if mutated, can lead to the formation of Wilms' tumour, the most common paediatric kidney cancer. Its expression has also been reported in several adult tumour types, including breast cancer, and usually correlates with poor outcome. However, published data is inconsistent and the role of WT1 in this malignancy remains unclear. Here we provide a complete study of WT1 expression across different breast cancer subtypes as well as isoform specific expression analysis. Using in vitro cell lines, clinical samples and publicly available gene expression datasets, we demonstrate that WT1 plays a role in regulating the epithelial-mesenchymal balance of breast cancer cells and that WT1-expressing tumours are mainly associated with a mesenchymal phenotype. WT1 gene expression also correlates with CYP3A4 levels and is associated with poorer response to taxane treatment. Our work is the first to demonstrate that the known association between WT1 expression in breast cancer and poor prognosis is potentially due to cancer-related epithelial-to-mesenchymal transition (EMT) and poor chemotherapy response. PMID- 28345632 TI - Immune regulation: Immune cell social networks. PMID- 28345630 TI - Identification and comparative analysis of the epidermal differentiation complex in snakes. AB - The epidermis of snakes efficiently protects against dehydration and mechanical stress. However, only few proteins of the epidermal barrier to the environment have so far been identified in snakes. Here, we determined the organization of the Epidermal Differentiation Complex (EDC), a cluster of genes encoding protein constituents of cornified epidermal structures, in snakes and compared it to the EDCs of other squamates and non-squamate reptiles. The EDC of snakes displays shared synteny with that of the green anole lizard, including the presence of a cluster of corneous beta-protein (CBP)/beta-keratin genes. We found that a unique CBP comprising 4 putative beta-sheets and multiple cysteine-rich EDC proteins are conserved in all snakes and other squamates investigated. Comparative genomics of squamates suggests that the evolution of snakes was associated with a gene duplication generating two isoforms of the S100 fused-type protein, scaffoldin, the origin of distinct snake-specific EDC genes, and the loss of other genes that were present in the EDC of the last common ancestor of snakes and lizards. Taken together, our results provide new insights into the evolution of the skin in squamates and a basis for the characterization of the molecular composition of the epidermis in snakes. PMID- 28345633 TI - T cells: Successful checkpoint blockade requires positive co-stimulation. PMID- 28345631 TI - Structure of the Cyanuric Acid Hydrolase TrzD Reveals Product Exit Channel. AB - Cyanuric acid hydrolases are of industrial importance because of their use in aquatic recreational facilities to remove cyanuric acid, a stabilizer for the chlorine. Degradation of excess cyanuric acid is necessary to maintain chlorine disinfection in the waters. Cyanuric acid hydrolase opens the cyanuric acid ring hydrolytically and subsequent decarboxylation produces carbon dioxide and biuret. In the present study, we report the X-ray structure of TrzD, a cyanuric acid hydrolase from Acidovorax citrulli. The crystal structure at 2.19 A resolution shows a large displacement of the catalytic lysine (Lys163) in domain 2 away from the active site core, whereas the two other active site lysines from the two other domains are not able to move. The lysine displacement is proposed here to open up a channel for product release. Consistent with that, the structure also showed two molecules of the co-product, carbon dioxide, one in the active site and another trapped in the proposed exit channel. Previous data indicated that the domain 2 lysine residue plays a role in activating an adjacent serine residue carrying out nucleophilic attack, opening the cyanuric acid ring, and the mobile lysine guides products through the exit channel. PMID- 28345634 TI - HIV: Marking the HIV hideout. PMID- 28345635 TI - Viral infection: The mother of all viruses. PMID- 28345636 TI - Viral infections: Reinvigorating exhausted T cells in hepatitis B infection. PMID- 28345637 TI - Rattusin structure reveals a novel defensin scaffold formed by intermolecular disulfide exchanges. AB - Defensin peptides are essential for innate immunity in humans and other living systems, as they provide protection against infectious pathogens and regulate the immune response. Here, we report the solution structure of rattusin (RTSN), an alpha-defensin-related peptide, which revealed a novel C2-symmetric disulfide linked dimeric structure. RTSN was synthesized by solid-phase peptide synthesis (SPPS) and refolded by air oxidation in vitro. Dimerization of the refolded RTSN (r-RTSN) resulted from five intermolecular disulfide (SS) bond exchanges formed by ten cysteines within two protomer chains. The SS bond pairings of r-RTSN were determined by mass analysis of peptide fragments cleaved by trypsin digestion. In addition to mass analysis, nuclear magnetic resonance (NMR) experiments for a C15S mutant and r-RTSN confirmed that the intermolecular SS bond structure of r RTSN showed an I-V', II-IV', III-III', IV-II', V-I' arrangement. The overall structure of r-RTSN exhibited a cylindrical array, similar to that of beta sandwich folds, with a highly basic surface. Furthermore, fluorescence spectroscopy results suggest that r-RTSN exerts bactericidal activity by damaging membrane integrity. Collectively, these results provide a novel structural scaffold for designing highly potent peptide-based antibiotics suitable for use under various physiological conditions. PMID- 28345638 TI - Lectin-like oxidized low-density lipoprotein receptor-1 facilitates metastasis of gastric cancer through driving epithelial-mesenchymal transition and PI3K/Akt/GSK3beta activation. AB - Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a pattern recognition receptor that plays a critical role in vascular diseases and host immune response. Recently, our research discovered that LOX-1 could facilitate the uptake of dying cells and cross-presentation of cellular antigen via binding with heat shock proteins, which have a close relationship with gastric neoplasia. Therefore, we speculated that LOX-1 may serve as an oncogene in gastric cancer (GC) development and progression. In this study, through immunohistochemistry staining assay and cancer-related databases, we found that LOX-1 expression was up-regulated in GC tissues and correlated with a poor prognosis in GC patients. The expression of LOX-1 was an independent prognostic factor for OS in GC patients, and the incorporation of LOX-1 with TNM stage is more accurate for predicting prognosis. Additionally, in vitro study by transwell assay and western blot analysis confirmed that LOX-1 could promote the migration and invasion of GC cells by driving epithelial-mesenchymal transition and PI3K/Akt/GSK3beta activation. Taken together, we first explored the expression profiles, clinical significance and biological function of LOX-1 in GC, and these data suggest that LOX-1 may represent a promising prognostic biomarker for GC and offer a novel molecular target for GC therapies. PMID- 28345639 TI - Genomic characterization of Nontuberculous Mycobacteria. AB - Mycobacterium tuberculosis and Mycobacterium leprae have remained, for many years, the primary species of the genus Mycobacterium of clinical and microbiological interest. The other members of the genus, referred to as nontuberculous mycobacteria (NTM), have long been underinvestigated. In the last decades, however, the number of reports linking various NTM species with human diseases has steadily increased and treatment difficulties have emerged. Despite the availability of whole genome sequencing technologies, limited effort has been devoted to the genetic characterization of NTM species. As a consequence, the taxonomic and phylogenetic structure of the genus remains unsettled and genomic information is lacking to support the identification of these organisms in a clinical setting. In this work, we widen the knowledge of NTMs by reconstructing and analyzing the genomes of 41 previously uncharacterized NTM species. We provide the first comprehensive characterization of the genomic diversity of NTMs and open new venues for the clinical identification of opportunistic pathogens from this genus. PMID- 28345640 TI - Degree of functionalisation dependence of individual Raman intensities in covalent graphene derivatives. AB - Covalent functionalisation of graphene is a continuously progressing field of research. The optical properties of such derivatives attract particular attention. In virtually all optical responses, however, an enhancement in peak intensity with increase of sp3 carbon content, and a vanishing of the peak position shift in monolayer compared to few-layer systems, is observed. The understanding of these seemingly connected phenomena is lacking. Here we demonstrate, using Raman spectroscopy and in situ electrostatic doping techniques, that the intensity is directly modulated by an additional contribution from photoluminescent pi-conjugated domains surrounded by sp3 carbon regions in graphene monolayers. The findings are further underpinned by a model which correlates the individual Raman mode intensities to the degree of functionalisation. We also show that the position shift in the spectra of solvent based and powdered functionalised graphene derivatives originates predominantly from the presence of edge-to-edge and edge-to-basal plane interactions and is by large functionalisation independent. PMID- 28345641 TI - III-nitride core-shell nanorod array on quartz substrates. AB - We report the fabrication of near-vertically elongated GaN nanorods on quartz substrates. To control the preferred orientation and length of individual GaN nanorods, we combined molecular beam epitaxy (MBE) with pulsed-mode metal-organic chemical vapor deposition (MOCVD). The MBE-grown buffer layer was composed of GaN nanograins exhibiting an ordered surface and preferred orientation along the surface normal direction. Position-controlled growth of the GaN nanorods was achieved by selective-area growth using MOCVD. Simultaneously, the GaN nanorods were elongated by the pulsed-mode growth. The microstructural and optical properties of both GaN nanorods and InGaN/GaN core-shell nanorods were then investigated. The nanorods were highly crystalline and the core-shell structures exhibited optical emission properties, indicating the feasibility of fabricating III-nitride nano-optoelectronic devices on amorphous substrates. PMID- 28345643 TI - Thermal Resistance Variations of Fly Ash Geopolymers: Foaming Responses. AB - This paper presents a comparative study of the characteristic of unfoamed and foamed geopolymers after exposure to elevated temperatures (200-800 degrees C). Unfoamed geopolymers were produced with Class F fly ash and sodium hydroxide and liquid sodium silicate. Porous geopolymers were prepared by foaming with hydrogen peroxide. Unfoamed geopolymers possessed excellent strength of 44.2 MPa and degraded 34% to 15 MPa in foamed geopolymers. The strength of unfoamed geopolymers decreased to 5 MPa with increasing temperature up to 800 degrees C. Foamed geopolymers behaved differently whereby they deteriorated to 3 MPa at 400 degrees C and increased up to 11 MPa at 800 degrees C. Even so, the geopolymers could withstand high temperature without any disintegration and spalling up to 800 degrees C. The formation of crystalline phases at higher temperature was observed deteriorating the strength of unfoamed geopolymers but enhance the strength of foamed geopolymers. In comparison, foamed geopolymer had better thermal resistance than unfoamed geopolymers as pores provide rooms to counteract the internal damage. PMID- 28345644 TI - Vitamin D both facilitates and attenuates the cellular response to lipopolysaccharide. AB - Vitamin D has a range of non-skeletal health effects and has been implicated in the response to respiratory infections. The aim of this study was to assess the effect of vitamin D on the response of epithelial cells, neutrophils and macrophages to lipopolysaccharide (LPS) stimulation. BEAS-2B cells (airway epithelial cell line) and primary neutrophils and macrophages isolated from blood samples were cultured and exposed to LPS with and without vitamin D (1,25(OH)2D). The production of IL-6, IL-8, IL-1beta and TNF-alpha of all cells and the phagocytic capacity of neutrophils and macrophages to E. coli were assessed. Vitamin D had no effect on BEAS-2B cells but enhanced the production of IL-8 in neutrophils (p = 0.007) and IL-1beta in macrophages (p = 0.007) in response to LPS. Both vitamin D (p = 0.019) and LPS (p < 0.001) reduced the phagocytic capacity of macrophages. These data suggest that the impact of vitamin D on responses to infection are complex and that the net effect will depend on the cells that respond, the key response that is necessary for resolution of infection (cytokine production or phagocytosis) and whether there is pre-existing inflammation. PMID- 28345645 TI - Influence of Anthropogenic Climate Change on Planetary Wave Resonance and Extreme Weather Events. AB - Persistent episodes of extreme weather in the Northern Hemisphere summer have been shown to be associated with the presence of high-amplitude quasi-stationary atmospheric Rossby waves within a particular wavelength range (zonal wavenumber 6 8). The underlying mechanistic relationship involves the phenomenon of quasi resonant amplification (QRA) of synoptic-scale waves with that wavenumber range becoming trapped within an effective mid-latitude atmospheric waveguide. Recent work suggests an increase in recent decades in the occurrence of QRA-favorable conditions and associated extreme weather, possibly linked to amplified Arctic warming and thus a climate change influence. Here, we isolate a specific fingerprint in the zonal mean surface temperature profile that is associated with QRA-favorable conditions. State-of-the-art ("CMIP5") historical climate model simulations subject to anthropogenic forcing display an increase in the projection of this fingerprint that is mirrored in multiple observational surface temperature datasets. Both the models and observations suggest this signal has only recently emerged from the background noise of natural variability. PMID- 28345642 TI - Dynamic Changes in Amygdala Psychophysiological Connectivity Reveal Distinct Neural Networks for Facial Expressions of Basic Emotions. AB - The quest to characterize the neural signature distinctive of different basic emotions has recently come under renewed scrutiny. Here we investigated whether facial expressions of different basic emotions modulate the functional connectivity of the amygdala with the rest of the brain. To this end, we presented seventeen healthy participants (8 females) with facial expressions of anger, disgust, fear, happiness, sadness and emotional neutrality and analyzed amygdala's psychophysiological interaction (PPI). In fact, PPI can reveal how inter-regional amygdala communications change dynamically depending on perception of various emotional expressions to recruit different brain networks, compared to the functional interactions it entertains during perception of neutral expressions. We found that for each emotion the amygdala recruited a distinctive and spatially distributed set of structures to interact with. These changes in amygdala connectional patters characterize the dynamic signature prototypical of individual emotion processing, and seemingly represent a neural mechanism that serves to implement the distinctive influence that each emotion exerts on perceptual, cognitive, and motor responses. Besides these differences, all emotions enhanced amygdala functional integration with premotor cortices compared to neutral faces. The present findings thus concur to reconceptualise the structure-function relation between brain-emotion from the traditional one-to-one mapping toward a network-based and dynamic perspective. PMID- 28345648 TI - Preface for the Special Issue dedicated to Professor Julian E. Davies. PMID- 28345647 TI - Sexual epigenetics: gender-specific methylation of a gene in the sex determining region of Populus balsamifera. AB - Methylation has frequently been implicated in gender determination in plants. The recent discovery of the sex determining region (SDR) of balsam poplar, Populus balsamifera, pinpointed 13 genes with differentiated X and Y copies. We tested these genes for differential methylation using whole methylome sequencing of xylem tissue of multiple individuals grown under field conditions in two common gardens. The only SDR gene to show a marked pattern of gender-specific methylation is PbRR9, a member of the two component response regulator (type-A) gene family, involved in cytokinin signalling. It is an ortholog of Arabidopsis genes ARR16 and ARR17. The strongest patterns of differential methylation (mostly male-biased) are found in the putative promoter and the first intron. The 4th intron is strongly methylated in both sexes and the 5th intron is unmethylated in both sexes. Using a statistical learning algorithm we find that it is possible accurately to assign trees to gender using genome-wide methylation patterns alone. The strongest predictor is the region coincident with PbRR9, showing that this gene stands out against all genes in the genome in having the strongest sex specific methylation pattern. We propose the hypothesis that PbRR9 has a direct, epigenetically mediated, role in poplar sex determination. PMID- 28345646 TI - Association of high normal HbA1c and TSH levels with the risk of CHD: a 10-year cohort study and SVM analysis. AB - This study aimed to determine the association between the clinical reference range of serum glycated hemoglobin A1c (HbA1c) and thyrotropin (TSH) and the risk of coronary heart disease (CHD) in non-diabetic and euthyroid patients. We examined baseline HbA1c and TSH in 538 healthy participants, and then analyzed the associations and potential value of these indicators for predicting CHD using Cox proportional hazard and support vector machine analyses. During the median follow-up of 120 months, 39 participants later developed CHD. The baseline HbA1c and TSH within the reference range were positively associated with CHD risk. No correlation and interaction were found between the baseline HbA1c and TSH for the development of CHD. Disease event-free survival varied among participants with different baseline HbA1c quintiles, whereas disease event-free survival was similar for different TSH tertiles. The combination of these baselines showed sensitivity of 87.2%, specificity of 92.7%, and accuracy of 92.3% for identifying the participants who will later develop CHD. Relatively high but clinically normal HbA1c and TSH levels may increase the risk of CHD. Therefore, the combination of these indicators can serve as a biomarker for identifying healthy individuals from those who would later develop CHD. PMID- 28345649 TI - Proteomic analysis indicates that mitochondrial energy metabolism in skeletal muscle tissue is negatively correlated with feed efficiency in pigs. AB - Feed efficiency (FE) is a highly important economic trait in pig production. Investigating the molecular mechanisms of FE is essential for trait improvement. In this study, the skeletal muscle proteome of high-FE and low-FE pigs were investigated by the iTRAQ approach. A total of 1780 proteins were identified, among which 124 proteins were differentially expressed between the high- and low FE pigs, with 74 up-regulated and 50 down-regulated in the high-FE pigs. Ten randomly selected differentially expressed proteins (DEPs) were validated by Western blotting and quantitative PCR (qPCR). Gene ontology (GO) analysis showed that all the 25 DEPs located in mitochondria were down-regulated in the high-FE pigs. Furthermore, the glucose-pyruvate-tricarboxylic acid (TCA)-oxidative phosphorylation energy metabolism signaling pathway was found to differ between high- and low-FE pigs. The key enzymes involved in the conversion of glucose to pyruvate were up-regulated in the high-FE pigs. Thus, our results suggested mitochondrial energy metabolism in the skeletal muscle tissue was negatively correlated with FE in pigs, and glucose utilization to generate ATP was more efficient in the skeletal muscle tissue of high-FE pigs. This study offered new targets and pathways for improvement of FE in pigs. PMID- 28345650 TI - Rational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy. AB - Both anti-PD1/PD-L1 therapy and oncolytic virotherapy have demonstrated promise, yet have exhibited efficacy in only a small fraction of cancer patients. Here we hypothesized that an oncolytic poxvirus would attract T cells into the tumour, and induce PD-L1 expression in cancer and immune cells, leading to more susceptible targets for anti-PD-L1 immunotherapy. Our results demonstrate in colon and ovarian cancer models that an oncolytic vaccinia virus attracts effector T cells and induces PD-L1 expression on both cancer and immune cells in the tumour. The dual therapy reduces PD-L1+ cells and facilitates non-redundant tumour infiltration of effector CD8+, CD4+ T cells, with increased IFN-gamma, ICOS, granzyme B and perforin expression. Furthermore, the treatment reduces the virus-induced PD-L1+ DC, MDSC, TAM and Treg, as well as co-inhibitory molecules double-positive, severely exhausted PD-1+CD8+ T cells, leading to reduced tumour burden and improved survival. This combinatorial therapy may be applicable to a much wider population of cancer patients. PMID- 28345651 TI - Epigenome mapping highlights chromatin-mediated gene regulation in the protozoan parasite Trichomonas vaginalis. AB - Trichomonas vaginalis is an extracellular flagellated protozoan parasite that causes trichomoniasis, one of the most common non-viral sexually transmitted diseases. To survive and to maintain infection, T. vaginalis adapts to a hostile host environment by regulating gene expression. However, the mechanisms of transcriptional regulation are poorly understood for this parasite. Histone modification has a marked effect on chromatin structure and directs the recruitment of transcriptional machinery, thereby regulating essential cellular processes. In this study, we aimed to outline modes of chromatin-mediated gene regulation in T. vaginalis. Inhibition of histone deacetylase (HDAC) alters global transcriptional responses and induces hyperacetylation of histones and hypermethylation of H3K4. Analysis of the genome of T. vaginalis revealed that a number of enzymes regulate histone modification, suggesting that epigenetic mechanisms are important to controlling gene expression in this organism. Additionally, we describe the genome-wide localization of two histone H3 modifications (H3K4me3 and H3K27Ac), which we found to be positively associated with active gene expression in both steady and dynamic transcriptional states. These results provide the first direct evidence that histone modifications play an essential role in transcriptional regulation of T. vaginalis, and may help guide future epigenetic research into therapeutic intervention strategies against this parasite. PMID- 28345652 TI - Synergistic infection of BrYV and PEMV 2 increases the accumulations of both BrYV and BrYV-derived siRNAs in Nicotiana benthamiana. AB - Viral synergism is caused by co-infection of two unrelated viruses, leading to more severe symptoms or increased titres of one or both viruses. Synergistic infection of phloem-restricted poleroviruses and umbraviruses has destructive effects on crop plants. The mechanism underlying this synergy remains elusive. In our study, synergism was observed in co-infections of a polerovirus Brassica yellows virus (BrYV) and an umbravirus Pea enation mosaic virus 2 (PEMV 2) on Nicotiana benthamiana, which led to (1) increased titres of BrYV, (2) appearance of severe symptoms, (3) gain of mechanical transmission capacity of BrYV, (4) broader distribution of BrYV to non-vascular tissues. Besides, profiles of virus derived small interfering RNAs (vsiRNAs) from BrYV and PEMV 2 in singly and doubly infected plants were obtained by small RNA deep sequencing. Our results showed that accumulation of BrYV vsiRNAs increased tremendously and ratio of positive to negative strand BrYV vsiRNAs differed between singly infected and co infected plants. Positions to which the BrYV vsiRNAs mapped to the viral genome varied considerably during synergistic infection. Moreover, target genes of vsiRNAs were predicted and annotated. Our results revealed the synergistic characteristics during co-infection of BrYV and PEMV 2, and implied possible effects of synergism have on vsiRNAs. PMID- 28345653 TI - Temporally dependent pollinator competition and facilitation with mass flowering crops affects yield in co-blooming crops. AB - One of the greatest challenges in sustainable agricultural production is managing ecosystem services, such as pollination, in ways that maximize crop yields. Most efforts to increase services by wild pollinators focus on management of natural habitats surrounding farms or non-crop habitats within farms. However, mass flowering crops create resource pulses that may be important determinants of pollinator dynamics. Mass bloom attracts pollinators and it is unclear how this affects the pollination and yields of other co-blooming crops. We investigated the effects of mass flowering apple on the pollinator community and yield of co blooming strawberry on farms spanning a gradient in cover of apple orchards in the landscape. The effect of mass flowering apple on strawberry was dependent on the stage of apple bloom. During early and peak apple bloom, pollinator abundance and yield were reduced in landscapes with high cover of apple orchards. Following peak apple bloom, pollinator abundance was greater on farms with high apple cover and corresponded with increased yields on these farms. Spatial and temporal overlap between mass flowering and co-blooming crops alters the strength and direction of these dynamics and suggests that yields can be optimized by designing agricultural systems that avoid competition while maximizing facilitation. PMID- 28345655 TI - Large Electrocaloric Effect in Relaxor Ferroelectric and Antiferroelectric Lanthanum Doped Lead Zirconate Titanate Ceramics. AB - Both relaxor ferroelectric and antiferroelectric materials can individually demonstrate large electrocaloric effects (ECE). However, in order to further enhance the ECE it is crucial to find a material system, which can exhibit simultaneously both relaxor ferroelectric and antiferroelectric properties, or easily convert from one into another in terms of the compositional tailoring. Here we report on a system, in which the structure can readily change from antiferroelectric into relaxor ferroelectric and vice versa. To this end relaxor ferroelectric Pb0.89La0.11(Zr0.7Ti0.3)0.9725O3 and antiferroelectric Pb0.93La0.07(Zr0.82Ti0.18)0.9825O3 ceramics were designed near the antiferroelectric-ferroelectric phase boundary line in the La2O3-PbZrO3-PbTiO3 phase diagram. Conventional solid state reaction processing was used to prepare the two compositions. The ECE properties were deduced from Maxwell relations and Landau-Ginzburg-Devonshire (LGD) phenomenological theory, respectively, and also directly controlled by a computer and measured by thermometry. Large electrocaloric efficiencies were obtained and comparable with the results calculated via the phenomenological theory. Results show great potential in achieving large cooling power as refrigerants. PMID- 28345654 TI - The soybean GmSNAP18 gene underlies two types of resistance to soybean cyst nematode. AB - Two types of resistant soybean (Glycine max (L.) Merr.) sources are widely used against soybean cyst nematode (SCN, Heterodera glycines Ichinohe). These include Peking-type soybean, whose resistance requires both the rhg1-a and Rhg4 alleles, and PI 88788-type soybean, whose resistance requires only the rhg1-b allele. Multiple copy number of PI 88788-type GmSNAP18, GmAAT, and GmWI12 in one genomic segment simultaneously contribute to rhg1-b resistance. Using an integrated set of genetic and genomic approaches, we demonstrate that the rhg1-a Peking-type GmSNAP18 is sufficient for resistance to SCN in combination with Rhg4. The two SNAPs (soluble NSF attachment proteins) differ by only five amino acids. Our findings suggest that Peking-type GmSNAP18 is performing a different role in SCN resistance than PI 88788-type GmSNAP18. As such, this is an example of a pathogen resistance gene that has evolved to underlie two types of resistance, yet ensure the same function within a single plant species. PMID- 28345656 TI - Structure and function of the Zika virus full-length NS5 protein. AB - The recent outbreak of Zika virus (ZIKV) has infected over 1 million people in over 30 countries. ZIKV replicates its RNA genome using virally encoded replication proteins. Nonstructural protein 5 (NS5) contains a methyltransferase for RNA capping and a polymerase for viral RNA synthesis. Here we report the crystal structures of full-length NS5 and its polymerase domain at 3.0 A resolution. The NS5 structure has striking similarities to the NS5 protein of the related Japanese encephalitis virus. The methyltransferase contains in-line pockets for substrate binding and the active site. Key residues in the polymerase are located in similar positions to those of the initiation complex for the hepatitis C virus polymerase. The polymerase conformation is affected by the methyltransferase, which enables a more efficiently elongation of RNA synthesis in vitro. Overall, our results will contribute to future studies on ZIKV infection and the development of inhibitors of ZIKV replication. PMID- 28345657 TI - Multicolor bioimaging with biosynthetic zinc nanoparticles and their application in tumor detection. AB - Because they generate excellent images, nanoparticles (NPs), especially biosynthesized NPs, provide a new solution for tumor imaging. In this research, we unveil a novel type of biosynthesized NPs featuring multicolor fluorescence. These NPs exhibit little cytotoxicity to cells. The explored NPs, designated Zn ZFP-GST NPs (Zinc NPs in abbreviation), are generated from leukemia cells treated with a Zn2+ solution, while zinc-finger protein and glutathione S-transferase (GST) were also identified in the Zinc NPs. Under near-UV illumination, the Zinc NPs simultaneously emit green, yellow, and red fluorescence. In addition, the intensity of the fluorescence increases with the existence of sulfides. Besides, the NPs are encapsulated by microvesicles (MVs) shed from the plasma membrane. As observed in whole-body research of nude mice, the NP-MVs migrate via blood circulation and are distinguished by their fluorescent signals. Furthermore, the folic acid (FA) &AVR2 (human VEGF antibody)-coated NP-MVs are exploited to target the tumor location, and the feasibility of this approach has been confirmed empirically. The Zinc NPs shed light on an alternative solution to tumor detection. PMID- 28345658 TI - Nephronectin plays critical roles in Sox2 expression and proliferation in dental epithelial stem cells via EGF-like repeat domains. AB - Tooth development is initiated by epithelial-mesenchymal interactions via basement membrane (BM) and growth factors. In the present study, we found that nephronectin (Npnt), a component of the BM, is highly expressed in the developing tooth. Npnt localizes in the BM on the buccal side of the tooth germ and shows an expression pattern opposite that of the dental epithelial stem cell marker Sox2. To identify the roles of Npnt during tooth development, we performed knockdown and overexpression experiments using ex vivo organ and dental epithelial cell cultures. Our findings showed that loss of Npnt induced ectopic Sox2-positive cells and reduced tooth germ size. Over expression of Npnt showed increased proliferation, whereas the number of Sox2-positive cells was decreased in dental epithelial cells. Npnt contains 5 EGF-like repeat domains, as well as an RGD sequence and MAM domain. We found that the EGF-like repeats are critical for Sox2 expression and cell proliferation. Furthermore, Npnt activated the EGF receptor (EGFR) via the EGF-like repeat domains and induced the PI3K-Akt signaling pathway. Our results indicate that Npnt plays a critical scaffold role in dental epithelial stem cell differentiation and proliferation, and regulates Sox2 expression during tooth development. PMID- 28345659 TI - Oral chromium picolinate impedes hyperglycemia-induced atherosclerosis and inhibits proatherogenic protein TSP-1 expression in STZ-induced type 1 diabetic ApoE-/- mice. AB - Increasing evidence suggests thrombospondin-1 (TSP-1), a potent proatherogenic matricellular protein, as a putative link between hyperglycemia and atherosclerotic complications in diabetes. We previously reported that the micronutrient chromium picolinate (CrP), with long-standing cardiovascular benefits, inhibits TSP-1 expression in glucose-stimulated human aortic smooth muscle cells in vitro. Here, we investigated the atheroprotective action of orally administered CrP in type 1 diabetic apolipoprotein E-deficient (ApoE-/-) mice and elucidated the role of TSP-1 in this process. CrP decreased lipid burden and neointimal thickness in aortic root lesions of hyperglycemic ApoE-/- mice; also, smooth muscle cell (SMC), macrophage and leukocyte abundance was prevented coupled with reduced cell proliferation. Attenuated lesion progression was accompanied with inhibition of hyperglycemia-induced TSP-1 expression and reduced protein O-glycosylation following CrP treatment; also, PCNA and vimentin (SMC synthetic marker) expression were reduced while SM-MHC (SMC contractile marker) levels were increased. To confirm a direct role of TSP-1 in diabetic atherosclerosis, hyperglycemic TSP-1-/-/ApoE-/- double knockout mice were compared with age-matched hyperglycemic ApoE-/- littermates. Lack of TSP-1 prevented lesion formation in hyperglycemic ApoE-/- mice, mimicking the atheroprotective phenotype of CrP-treated mice. These results suggest that therapeutic TSP-1 inhibition may have important atheroprotective potential in diabetic vascular disease. PMID- 28345660 TI - Zinc deficiency and low enterocyte zinc transporter expression in human patients with autism related mutations in SHANK3. AB - Phelan McDermid Syndrome (PMDS) is a genetic disorder characterized by features of Autism spectrum disorders. Similar to reports of Zn deficiency in autistic children, we have previously reported high incidence of Zn deficiency in PMDS. However, the underlying mechanisms are currently not well understood. Here, using inductively coupled plasma mass-spectrometry to measure the concentration of Zinc (Zn) and Copper (Cu) in hair samples from individuals with PMDS with 22q13.3 deletion including SHANK3 (SH3 and multiple ankyrin repeat domains 3), we report a high rate of abnormally low Zn/Cu ratios. To investigate possible underlying mechanisms, we generated enterocytes from PMDS patient-derived induced pluripotent stem cells and used Caco-2 cells with knockdown of SHANK3. We detected decreased expression of Zn uptake transporters ZIP2 and ZIP4 on mRNA and protein level correlating with SHANK3 expression levels, and found reduced levels of ZIP4 protein co-localizing with SHANK3 at the plasma membrane. We demonstrated that especially ZIP4 exists in a complex with SHANK3. Furthermore, we performed immunohistochemistry on gut sections from Shank3alphabeta knockout mice and confirmed a link between enterocytic SHANK3, ZIP2 and ZIP4. We conclude that apart from its well-known role in the CNS, SHANK3 might play a specific role in the GI tract. PMID- 28345661 TI - Stepwise analysis of MIR9 loci identifies miR-9-5p to be involved in Oestrogen regulated pathways in breast cancer patients. AB - miR-9 was initially identified as an epigenetically regulated miRNA in tumours, but inconsistent findings have been reported so far. We analysed the expression of miR-9-5p, miR-9-3p, pri-miRs and MIR9 promoters methylation status in 131 breast cancer cases and 12 normal breast tissues (NBTs). The expression of both mature miRs was increased in tumours as compared to NBTs (P < 0.001) and negatively correlated with ER protein expression (P = 0.005 and P = 0.003, for miR-9-3p and miR-9-5p respectively). In addition, miR-9-5p showed a significant negative correlation with PgR (P = 0.002). Consistently, miR-9-5p and miR-9 3p were differentially expressed in the breast cancer subgroups identified by ER and PgR expression and HER2 amplification. No significant correlation between promoter methylation and pri-miRNAs expressions was found either in tumours or in NBTs. In the Luminal breast cancer subtype the expression of miR-9-5p was associated with a worse prognosis in both univariable and multivariable analyses. Ingenuity Pathway Analysis exploring the putative interactions among miR-9-5p/miR 9-3p, ER and PgR upstream and downstream regulators suggested a regulatory loop by which miR-9-5p but not miR-9-3p is induced by steroid hormone receptor and acts within hormone-receptor regulated pathways. PMID- 28345662 TI - Brain arousal regulation as response predictor for antidepressant therapy in major depression. AB - A tonically high level of brain arousal and its hyperstable regulation is supposed to be a pathogenic factor in major depression. Preclinical studies indicate that most antidepressants may counteract this dysregulation. Therefore, it was hypothesized that responders to antidepressants show a) a high level of EEG-vigilance (an indicator of brain arousal) and b) a more stable EEG-vigilance regulation than non-responders. In 65 unmedicated depressed patients 15-min resting-state EEGs were recorded off medication (baseline). In 57 patients an additional EEG was recorded 14 +/- 1 days following onset of antidepressant treatment (T1). Response was defined as a >=50% HAMD-17-improvement after 28 +/- 1 days of treatment (T2), resulting in 29 responders and 36 non-responders. Brain arousal was assessed using the Vigilance Algorithm Leipzig (VIGALL 2.1). At baseline responders and non-responders differed in distribution of overall EEG vigilance stages (F2,133 = 4.780, p = 0.009), with responders showing significantly more high vigilance stage A and less low vigilance stage B. The 15 minutes Time-course of EEG-vigilance did not differ significantly between groups. Exploratory analyses revealed that responders showed a stronger decline in EEG vigilance levels from baseline to T1 than non-responders (F2,130 = 4.978, p = 0.005). Higher brain arousal level in responders to antidepressants supports the concept that dysregulation of brain arousal is a possible predictor of treatment response in affective disorders. PMID- 28345664 TI - Hierarchical viscosity of aqueous solution of tilapia scale collagen investigated via dielectric spectroscopy between 500 MHz and 2.5 THz. AB - Aqueous solutions of biomolecules such as proteins are very important model systems for understanding the functions of biomolecules in actual life processes because interactions between biomolecules and the surrounding water molecules are considered to be important determinants of biomolecules' functions. Globule proteins have been extensively studied via dielectric spectroscopy; the results indicate three relaxation processes originating from fluctuations in the protein molecule, the bound water and the bulk water. However, the characteristics of aqueous solutions of collagens have rarely been investigated. In this work, based on broadband dielectric measurements between 500 MHz and 2.5 THz, we demonstrate that the high viscosity of a collagen aqueous solution is due to the network structure being constructed of rod-like collagen molecules surrounding free water molecules and that the water molecules are not responsible for the viscosity. We determine that the macroscopic viscosity is related to the mean lifetime of the collagen-collagen interactions supporting the networks and that the local viscosity of the water surrounded by the networks is governed by the viscosity of free water as in the bulk. This hierarchical structure in the dynamics of the aqueous solution of biomolecules has been revealed for the first time. PMID- 28345663 TI - Nuclear localization of Beclin 1 promotes radiation-induced DNA damage repair independent of autophagy. AB - Beclin 1 is a well-established core mammalian autophagy protein that is embryonically indispensable and has been presumed to suppress oncogenesis via an autophagy-mediated mechanism. Here, we show that Beclin 1 is a prenatal primary cytoplasmic protein but rapidly relocated into the nucleus during postnatal development in mice. Surprisingly, deletion of beclin1 in in vitro human cells did not block an autophagy response, but attenuated the expression of several DNA double-strand break (DSB) repair proteins and formation of repair complexes, and reduced an ability to repair DNA in the cells exposed to ionizing radiation (IR). Overexpressing Beclin 1 improved the repair of IR-induced DSB, but did not restore an autophagy response in cells lacking autophagy gene Atg7, suggesting that Beclin 1 may regulate DSB repair independent of autophagy in the cells exposed to IR. Indeed, we found that Beclin 1 could directly interact with DNA topoisomerase IIbeta and was recruited to the DSB sites by the interaction. These findings reveal a novel function of Beclin 1 in regulation of DNA damage repair independent of its role in autophagy particularly when the cells are under radiation insult. PMID- 28345665 TI - Oscillating Electric Field Measures the Rotation Rate in a Native Rotary Enzyme. AB - Rotary enzymes are complex, highly challenging biomolecular machines whose biochemical working mechanism involves intersubunit rotation. The true intrinsic rate of rotation of any rotary enzyme is not known in a native, unmodified state. Here we use the effect of an oscillating electric (AC) field on the biochemical activity of a rotary enzyme, the vacuolar proton-ATPase (V-ATPase), to directly measure its mean rate of rotation in its native membrane environment, without any genetic, chemical or mechanical modification of the enzyme, for the first time. The results suggest that a transmembrane AC field is able to synchronise the steps of ion-pumping in individual enzymes via a hold-and-release mechanism, which opens up the possibility of biotechnological exploitation. Our approach is likely to work for other transmembrane ion-transporting assemblies, not only rotary enzymes, to determine intrinsic in situ rates of ion pumping. PMID- 28345666 TI - Members of Gammaproteobacteria as indicator species of healthy banana plants on Fusarium wilt-infested fields in Central America. AB - Culminating in the 1950's, bananas, the world's most extensive perennial monoculture, suffered one of the most devastating disease epidemics in history. In Latin America and the Caribbean, Fusarium wilt (FW) caused by the soil-borne fungus Fusarium oxysporum f. sp. cubense (FOC), forced the abandonment of the Gros Michel-based export banana industry. Comparative microbiome analyses performed between healthy and diseased Gros Michel plants on FW-infested farms in Nicaragua and Costa Rica revealed significant shifts in the gammaproteobacterial microbiome. Although we found substantial differences in the banana microbiome between both countries and a higher impact of FOC on farms in Costa Rica than in Nicaragua, the composition especially in the endophytic microhabitats was similar and the general microbiome response to FW followed similar rules. Gammaproteobacterial diversity and community members were identified as potential health indicators. Healthy plants revealed an increase in potentially plant beneficial Pseudomonas and Stenotrophomonas, while diseased plants showed a preferential occurrence of Enterobacteriaceae known for their plant-degrading capacity. Significantly higher microbial rhizosphere diversity found in healthy plants could be indicative of pathogen suppression events preventing or minimizing disease expression. This first study examining banana microbiome shifts caused by FW under natural field conditions opens new perspectives for its biological control. PMID- 28345667 TI - The toxicity of angiotensin converting enzyme inhibitors to larvae of the disease vectors Aedes aegypti and Anopheles gambiae. AB - The control of mosquitoes is threatened by the appearance of insecticide resistance and therefore new control chemicals are urgently required. Here we show that inhibitors of mosquito peptidyl dipeptidase, a peptidase related to mammalian angiotensin-converting enzyme (ACE), are insecticidal to larvae of the mosquitoes, Aedes aegypti and Anopheles gambiae. ACE inhibitors (captopril, fosinopril and fosinoprilat) and two peptides (trypsin-modulating oostatic factor/TMOF and a bradykinin-potentiating peptide, BPP-12b) were all inhibitors of the larval ACE activity of both mosquitoes. Two inhibitors, captopril and fosinopril (a pro-drug ester of fosinoprilat), were tested for larvicidal activity. Within 24 h captopril had killed >90% of the early instars of both species with 3rd instars showing greater resistance. Mortality was also high within 24 h of exposure of 1st, 2nd and 3rd instars of An. gambiae to fosinopril. Fosinopril was also toxic to Ae. aegypti larvae, although the 1st instars appeared to be less susceptible to this pro-drug even after 72 h exposure. Homology models of the larval An. gambiae ACE proteins (AnoACE2 and AnoACE3) reveal structural differences compared to human ACE, suggesting that structure based drug design offers a fruitful approach to the development of selective inhibitors of mosquito ACE enzymes as novel larvicides. PMID- 28345668 TI - C9ORF135 encodes a membrane protein whose expression is related to pluripotency in human embryonic stem cells. AB - Human embryonic stem cells (hESCs) are a unique population of cells defined by their capacity for self-renewal and pluripotency. Here, we identified a previously uncharacterized gene in hESCs, C9ORF135, which is sharply downregulated during gastrulation and gametogenesis, along with the pluripotency factors OCT4, SOX2, and NANOG. Human ESCs express two C9ORF135 isoforms, the longer of which encodes a membrane-associated protein, as determined by immunostaining and western blotting of fractionated cell lysates. Moreover, the results of chromatin immunoprecipitation (ChIP), mass spectrometry (MS), and co immunoprecipitation (co-IP) analyses demonstrated that C9ORF135 expression is regulated by OCT4 and SOX2 and that C9ORF135 interacts with non-muscle myosin IIA and myosin IIB. Collectively, these data indicated that C9ORF135 encodes a membrane-associated protein that may serve as a surface marker for undifferentiated hESCs. PMID- 28345669 TI - A coupled human-Earth model perspective on long-term trends in the global marine fishery. AB - The global wild marine fish harvest increased fourfold between 1950 and a peak value near the end of the 20th century, reflecting interactions between anthropogenic and ecological forces. Here, we examine these interactions in a bio energetically constrained, spatially and temporally resolved model of global fisheries. We conduct historical hindcasts with the model, which suggest that technological progress can explain most of the 20th century increase of fish harvest. In contrast, projections extending this rate of technological progress into the future under open access suggest a long-term decrease in harvest due to over-fishing. Climate change is predicted to gradually decrease the global fish production capacity, though our model suggests that this is of secondary importance to social and economic factors. Our study represents a novel way to integrate human-ecological interactions within a single model framework for long term simulations. PMID- 28345670 TI - Domain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression. AB - Despite a high degree of homology, insulin receptor (IR) and IGF-1 receptor (IGF1R) mediate distinct cellular and physiological functions. Here, we demonstrate how domain differences between IR and IGF1R contribute to the distinct functions of these receptors using chimeric and site-mutated receptors. Receptors with the intracellular domain of IGF1R show increased activation of Shc and Gab-1 and more potent regulation of genes involved in proliferation, corresponding to their higher mitogenic activity. Conversely, receptors with the intracellular domain of IR display higher IRS-1 phosphorylation, stronger regulation of genes in metabolic pathways and more dramatic glycolytic responses to hormonal stimulation. Strikingly, replacement of leucine973 in the juxtamembrane region of IR to phenylalanine, which is present in IGF1R, mimics many of these signalling and gene expression responses. Overall, we show that the distinct activities of the closely related IR and IGF1R are mediated by their intracellular juxtamembrane region and substrate binding to this region. PMID- 28345671 TI - Spatiotemporal expression of osteopontin in the striatum of rats subjected to the mitochondrial toxin 3-nitropropionic acid correlates with microcalcification. AB - Our aim was to elucidate whether osteopontin (OPN) is involved in the onset of mineralisation and progression of extracellular calcification in striatal lesions due to mitochondrial toxin 3-nitropropionic acid exposure. OPN expression had two different patterns when observed using light microscopy. It was either localised to the Golgi complex in brain macrophages or had a small granular pattern scattered in the affected striatum. OPN labelling tended to increase in number and size over a 2-week period following the lesion. Ultrastructural investigations revealed that OPN is initially localised to degenerating mitochondria within distal dendrites, which were then progressively surrounded by profuse OPN on days 7-14. Electron probe microanalysis of OPN-positive and calcium-fixated neurites indicated that OPN accumulates selectively on the surfaces of degenerating calcifying dendrites, possibly via interactions between OPN and calcium. In addition, 3-dimensional reconstruction of OPN-positive neurites revealed that they are in direct contact with larger OPN-negative degenerating dendrites rather than with fragmented cell debris. Our overall results indicate that OPN expression is likely to correlate with the spatiotemporal progression of calcification in the affected striatum, and raise the possibility that OPN may play an important role in the initiation and progression of microcalcification in response to brain insults. PMID- 28345673 TI - Sex-dependent effects on gut microbiota regulate hepatic carcinogenic outcomes. AB - Emerging evidence points to a strong association between sex and gut microbiota, bile acids (BAs), and gastrointestinal cancers. Here, we investigated the mechanistic link between microbiota and hepatocellular carcinogenesis using a streptozotocin-high fat diet (STZ-HFD) induced nonalcoholic steatohepatitis hepatocellular carcinoma (NASH-HCC) murine model and compared results for both sexes. STZ-HFD feeding induced a much higher incidence of HCC in male mice with substantially increased intrahepatic retention of hydrophobic BAs and decreased hepatic expression of tumor-suppressive microRNAs. Metagenomic analysis showed differences in gut microbiota involved in BA metabolism between normal male and female mice, and such differences were amplified when mice of both sexes were exposed to STZ-HFD. Treating STZ-HFD male mice with 2% cholestyramine led to significant improvement of hepatic BA retention, tumor-suppressive microRNA expressions, microbial gut communities, and prevention of HCC. Additionally the sex-dependent differences in BA profiles in the murine model can be correlated to the differential BA profiles between men and women during the development of HCC. These results uncover distinct male and female profiles for gut microbiota, BAs, and microRNAs that may contribute to sex-based disparity in liver carcinogenesis, and suggest new possibilities for preventing and controlling human obesity related gastrointestinal cancers that often exhibit sex differences. PMID- 28345672 TI - Cyclophilins and nucleoporins are required for infection mediated by capsids from circulating HIV-2 primary isolates. AB - HIV-2 groups have emerged from sooty mangabey SIV and entered the human population in Africa on several separate occasions. Compared to world pandemic HIV-1 that arose from the chimpanzee SIVcpz virus, the SIVsm-derived HIV-2, largely confined to West Africa, is less replicative, less transmissible and less pathogenic. Here, we evaluated the interactions between host cellular factors, which control HIV-1 infection and target the capsid, and HIV-2 capsids obtained from primary isolates from patients with different disease progression status. We showed that, like HIV-1, all HIV-2 CA we tested exhibited a dependence on cyclophilin A. However, we observed no correlation between HIV-2 viremia and susceptibility to hu-TRIM5alpha or dependence to CypA. Finally, we found that all CA from HIV-2 primary isolates exploit Nup358 and Nup153 for nucleus transposition. Altogether, these findings indicate that the ability to use the two latter nucleoporins is essential to infection of human cells for both HIV-1 and HIV-2. This dependence provides another molecular target that could be used for antiviral strategies against both HIV-1 and 2, based on both nucleoporins. PMID- 28345674 TI - Skeletal Muscle Pump Drives Control of Cardiovascular and Postural Systems. AB - The causal interaction between cardio-postural-musculoskeletal systems is critical in maintaining postural stability under orthostatic challenge. The absence or reduction of such interactions could lead to fainting and falls often experienced by elderly individuals. The causal relationship between systolic blood pressure (SBP), calf electromyography (EMG), and resultant center of pressure (COPr) can quantify the behavior of cardio-postural control loop. Convergent cross mapping (CCM) is a non-linear approach to establish causality, thus, expected to decipher nonlinear causal cardio-postural-musculoskeletal interactions. Data were acquired simultaneously from young participants (25 +/- 2 years, n = 18) during a 10-minute sit-to-stand test. In the young population, skeletal muscle pump was found to drive blood pressure control (EMG -> SBP) as well as control the postural sway (EMG -> COPr) through the significantly higher causal drive in the direction towards SBP and COPr. Furthermore, the effect of aging on muscle pump activation associated with blood pressure regulation was explored. Simultaneous EMG and SBP were acquired from elderly group (69 +/- 4 years, n = 14). A significant (p = 0.002) decline in EMG -> SBP causality was observed in the elderly group, compared to the young group. The results highlight the potential of causality to detect alteration in blood pressure regulation with age, thus, a potential clinical utility towards detection of fall proneness. PMID- 28345675 TI - A MYB transcription factor, DcMYB6, is involved in regulating anthocyanin biosynthesis in purple carrot taproots. AB - Carrots are widely grown and enjoyed around the world. Purple carrots accumulate rich anthocyanins in the taproots, while orange, yellow, and red carrots accumulate rich carotenoids in the taproots. Our previous studies indicated that variation in the activity of regulatory genes may be responsible for variations in anthocyanin production among various carrot cultivars. In this study, an R2R3 type MYB gene, designated as DcMYB6, was isolated from a purple carrot cultivar. In a phylogenetic analysis, DcMYB6 was grouped into an anthocyanin biosynthesis related MYB clade. Sequence analyses revealed that DcMYB6 contained the conserved bHLH-interaction motif and two atypical motifs of anthocyanin regulators. The expression pattern of DcMYB6 was correlated with anthocyanin production. DcMYB6 transcripts were detected at high levels in three purple carrot cultivars but at much lower levels in six non-purple carrot cultivars. Overexpression of DcMYB6 in Arabidopsis led to enhanced anthocyanin accumulation in both vegetative and reproductive tissues and upregulated transcript levels of all seven tested anthocyanin-related structural genes. Together, these results show that DcMYB6 is involved in regulating anthocyanin biosynthesis in purple carrots. Our results provide new insights into the regulation of anthocyanin synthesis in purple carrot cultivars. PMID- 28345676 TI - Bioconversion of stilbenes in genetically engineered root and cell cultures of tobacco. AB - It is currently possible to transfer a biosynthetic pathway from a plant to another organism. This system has been exploited to transfer the metabolic richness of certain plant species to other plants or even to more simple metabolic organisms such as yeast or bacteria for the production of high added value plant compounds. Another application is to bioconvert substrates into scarcer or biologically more interesting compounds, such as piceatannol and pterostilbene. These two resveratrol-derived stilbenes, which have very promising pharmacological activities, are found in plants only in small amounts. By transferring the human cytochrome P450 hydroxylase 1B1 (HsCYP1B1) gene to tobacco hairy roots and cell cultures, we developed a system able to bioconvert exogenous t-resveratrol into piceatannol in quantities near to mg L-1. Similarly, after heterologous expression of resveratrol O-methyltransferase from Vitis vinifera (VvROMT) in tobacco hairy roots, the exogenous t-resveratrol was bioconverted into pterostilbene. We also observed that both bioconversions can take place in tobacco wild type hairy roots (pRiA4, without any transgene), showing that unspecific tobacco P450 hydroxylases and methyltransferases can perform the bioconversion of t-resveratrol to give the target compounds, albeit at a lower rate than transgenic roots. PMID- 28345677 TI - Relationships of work-related psychosocial risks, stress, individual factors and burnout - Questionnaire survey among emergency physicians and nurses. AB - BACKGROUND: Psychosocial risks represent a great challenge for safety and health protection at work in Europe. The purpose of this study has been to determine the relationships of psychosocial risks arising from work, stress, personal characteristics and burnout among physicians and nurses in the Emergency Medical Service (EMS). MATERIAL AND METHODS: We performed a cross-sectional study based on a questionnaire survey which contained the Copenhagen Psychosocial Questionnaire (COPSOQ) and Copenhagen Burnout Inventory (CBI). RESULTS: A total of 88 physicians and 80 nurses completed the survey. Physicians demonstrated higher emotional (mean (M) +/- standard deviation (SD) = 74.57+/-16.85) and cognitive (M+/-SD = 75.95+/-13.74) demands as compared to nurses. Both groups had high sensory demands and responsibilities at work, in spite of the low degree of their autonomy. The meaning of work, commitment to the workplace, and insecurity at work were high for both groups. Among all participants, stressful behavior and reactions were within the limits of low values (< 40) and coping strategies showed high values (> 60). Personal and patient-related burnout was high for both groups, where physicians were significantly affected by work-related burnout. The influence at work, degree of freedom at work, social support, sense of coherence, mental health, and problem-focused coping are negatively related to work-related burnout. CONCLUSIONS: Based on personal factors and coping styles, emergency physicians and nurses are representing a self-selective professional group that meets high work demands, great responsibility, strong commitment and insecurity at work. Burnout of physicians and nurses in the EMS tends to be ignored, although it has severe consequences on their mental and general health. Med Pr 2017;68(2):178-178. PMID- 28345678 TI - Laryngeal manual therapy palpatory evaluation scale: A preliminary study to examine its usefulness in diagnosis of occupational dysphonia. AB - BACKGROUND: The aim of this study has been to assess the larynx and soft tissue around the vocal tract in a group of people with healthy voice, and in a group of patients with occupational dysphonia using the new laryngeal manual therapy palpatory evaluation scale (LMTPE). MATERIAL AND METHODS: The examinations were performed in a study (dysphonic) group of professional voice users who had developed voice disorders (N = 51) and in the control group of normophonic subjects (N = 50). All the participants underwent perceptual voice assessment and examination by means of the LMTPE scale. Additionally, phoniatric examination including VHI (Voice Handicap Index) questionnaire, GRBAS (the Grade of hoarseness, Roughness, Breathiness, Asthenic, Strained) perceptual evaluation, maximum phonation time (MPT) measurement and videostroboscopy was performed in the study group. RESULTS: The comparison of the LMTPE total score showed that the results of the study group were significantly poorer than those of controls (p < 0.001). In the study group, correlations were found between the LMTPE results and the VHI scores (p < 0.05), perceptual evaluation by the GRBAS (p < 0.05) and the objective parameter MPT (p < 0.05). CONCLUSIONS: The study has proven that the LMTPE scale is characterized by the high score of Cronbach's alpha ratio estimating the reliability of the test. The results have confirmed that the LMTPE scale seems to be a valuable tool, useful in diagnostics of occupational dysphonia, particularly of hyperfunction origin. Med Pr 2017;68(2):179-188. PMID- 28345679 TI - Impact of climate conditions on hospital admissions for subcategories of cardiovascular diseases. AB - BACKGROUND: The aim of this study has been to examine the association between climate conditions (CC) and hospital admissions for the subcategories of cardiovascular diseases (CVD), according to patients' age. MATERIAL AND METHODS: From January 2010 through December 2011, the daily number of hospital admissions for angina pectoris (AP), essential hypertension (EH), acute myocardial infarction (AMI) and ischemic heart diseases (IHD) for adults (19-64 years old) and the elderly (>= 65 years old), as well as for the CC (N = 728 days) was collected for multivariate Poisson regression analysis, confounding with season and weekends. The results were expressed by using the relative risk with the corresponding 95% confidence interval. RESULTS: The risk for the AMI among the adults and the elderly is significantly higher for 41.8% and 38.9%, respectively on the days with lower ambient temperature and lesser for 32.7% and 29.8%, respectively on the days with lower air pressure values. The risk for the IHD among the elderly is significantly higher on the days with lower ambient temperature and lower relative humidity for 50.6% and 37.4%, respectively. CONCLUSIONS: Our findings explain how the CC and subcategories of CVD are associated, which could be used for adequate public awareness of the risk for hospitalization due to climate conditions. Med Pr 2017;68(2):189-197. PMID- 28345681 TI - [Studies on Lyme disease incidence rates in selected groups of forestry workers in West Pomerania, 2005-2014]. AB - BACKGROUND: The data collected by sanitary-epidemiological stations in 2005-2014 were analyzed to determine the incidence rates of borreliosis Lyme disease in the West Pomerania group of workers exposed to tick bites. MATERIAL AND METHODS: It was assumed that an adequate comparison of official epidemiological data with the data concerning the number of exposed people, is an indispensable condition for assessing properly the trend in Lyme disease incidence rates, concerning at the same time a real scale of occupational exposure. The study covered a selected group of forestry workers, i.e., white-collar staff employed in different units of the State Forests National Forest Holding with their seats in West Pomerania. The aim of the research was to process and analyze the data on workers employed in the forest sector and their positions, requested from district sanitary epidemiological stations. RESULTS: In the years concerned 282 cases of the occupational disease were recorded mainly in the groups of forest rangers, junior foresters and forest service inspectors. The values of the incidence factor exhibit high variability with the major share of cases recorded in the years 2008 2010 that accounted for 61.8% of the total occurrences concerned. The incidence in the years 2008, 2009 and 2010 amounted to 2418, 2828 and 2646 cases per 100 000 employees, respectively. CONCLUSIONS: The results show that previously published information about the incidence of Lyme disease in the agriculture, forestry and hunting sector, did not fully illustrate a real scale of occupational risk. Med Pr 2017;68(2):211-220. PMID- 28345680 TI - Personal and occupational risk factors for carpal tunnel syndrome in meat processing industry workers in Northern Italy. AB - BACKGROUND: Carpal tunnel syndrome (CTS) is a musculoskeletal condition that often impairs the fitness to work. Our aim is to retrospectively evaluate the association between physical exposures in meat processing industry in Northern Italy and the CTS, taking into account non-occupational factors. MATERIAL AND METHODS: A cross-sectional study was performed to include 434 workers (236 males, 198 females, 37.0+/-10.6 years old, working age: 12.6+/-10.8 years) from meat processing industries. Signs and symptoms were collected at the compulsory occupational medical surveillance. Occupational risk factors were assessed through a questionnaire and direct assessment by investigators. Adjusted odds ratios (ORadj) for factors of interest were estimated through binary logistic regression. RESULTS: Diagnosis of the CTS was reported for 61 out of 434 subjects (14.1%) for an incidence of 11.3/1000 person- years. In general, signs and symptoms for the CTS were associated with the following demographic factors: smoking history (OR = 1.909, 95% confidence interval (CI): 1.107-3.293), previous traumas of the upper limb (OR = 3.533, 95% CI: 1.743-7.165), hypothyroidism status (OR = 7.897, 95% CI: 2.917-21.38) and, in the case of female participants only, previous pregnancies (OR = 2.807, 95% CI: 1.200-6.566) as well as a personal history of oral contraceptive therapy and/or steroidal replacement therapy (OR = 11.57, 95% CI: 4.689-28.56). The carpal tunnel syndrome cases were associated with the following occupational factors (> 4 h/day): forceful hand exertion (ORadj = 3.548, 95% CI: 1.379-9.131), repeated trauma of the hand (ORadj = 3.602, 95% CI: 1.248- 10.395), repeated movements of the wrist (ORadj = 2.561, 95% CI: 1.100-5.960). CONCLUSIONS: Increasing levels of hand activity and force were associated with the increased CTS prevalence among participants. Recommendations have to be provided in order to reduce occupational exposure to these risk factors and improve medical surveillance. Med Pr 2017;68(2):199-209. PMID- 28345682 TI - [Occupational exposure in orthopedic procedures under fluoroscopic control]. AB - BACKGROUND: In interventional radiology the highest radiation doses are usually recorded for both the medical staff and the patients. Interventional procedures with X-rays are implemented in a number of medical specializations. This paper concerns the exposure of interventional teams performing orthopedic procedures under X-rays control. MATERIAL AND METHODS: Doses for interventional teams were measured in the 3 Lodz hospitals. Thermoluminescent dosemeters were applied to measure the following dose equivalents: Hp(3) for eye lens, Hp(0.07) for palm skin, Hp(10) at the level of the neck without a protective shield (i.e., collar) and Hp(10) for the whole body on the front surface of the trunk (measured under the protective apron at the level of the chest). RESULTS: Doses for the operator who performs surgery, assisting physicians and scrub nurse were measured during 95 procedures. The highest doses were received by the operator the dose for eyes per 1 procedure did not exceed 0.1 mSv, the highest dose for hands was 1.6 mSv and the highest recorded effective dose was 0.02 mSv. CONCLUSIONS: On the basis of the results of measurements and their comparison with the values reported in the literature it may be concluded that the obtained results fall within the published reference range (for non-vascular procedures). This proves the compatibility of practice in the monitored Lodz hospitals with routine methodology applied in other interventional departments. The measurement results confirm that the usage of thermoluminescent dosimetry is fully adequate for the evaluation of exposure in interventional radiology and that the usage of at least 2 dosemeters for that staff is necessary. Med Pr 2017;68(2):221-227. PMID- 28345683 TI - [Workplace health promotion in Poland in 2015 - Diagnosis based on a representative survey of companies employing more than 50 employees]. AB - BACKGROUND: The workplace health promotion (WHP) activity of enterprises in Poland was examined. The findings referred to how many companies implemented non obligatory actions for health and what actions were taken, what were the reasons and obstacles in the implementation, whether companies evaluated their activity, how they motivated staff to WHP, and whether the size and economic standing differentiated their activity. MATERIAL AND METHODS: Representative survey, consisted of computer assisted telephone interviews with delegates of the boards of 1000 companies employing > 50 employees, held in November-December 2015. RESULTS: Every second company undertook voluntary actions for workers health. Most often they offered medical care, supported physical activity and took care about the work environment in a higher range than required by binding regulations. They promoted health to build company's good image, improve productivity and reduce costs. The tradition of WHP in the company, attitudes of employers and intention to boost the vitality of employees also played a role . Despite good financial standing of companies, the shortage of funds was the main barrier in the implementation of WHP activities. Other impediments, such as lack of sufficient state incentives, workload of the management staff, lack of knowledge about WHP benefits and lack of good pro-health services were observed as well. Few companies motivated employees to WHP and carried out its evaluation. CONCLUSIONS: The development of WHP requires dissemination of its benefits among employers, human resources and safety personnel trainings in WHP management, implementation of the system of relief and prestigious awards for active companies, increase in the number and scope of research works on WHP conditions and effectiveness. Crucial herein is the role of the state in cooperation with other major WHP actors. Med Pr 2017;68(2):229-246. PMID- 28345684 TI - [Analysis of changes in radiographic lung image and lung ventilation disorders in workers occupationally exposed to chrysotile in the past]. AB - BACKGROUND: The adverse health effects of occupational exposure to asbestos dust may occur several years after first exposure. The objective of the study was to assess the relationship between lesions in the respiratory system and the factors contributing to occupational exposure to asbestos described in the first medical examination as well as to analyze the factors responsible for the progression of these changes in further medical tests. MATERIAL AND METHODS: The study group comprised 591 former workers of asbestos processing plant "Gambit" in Lubawka. The results of medical examinations carried out in 2001-2012 were assessed. Statistical inference was performed based on bilateral significance tests at the 0.05 level of significance. RESULTS: A higher risk of interstitial lung changes along with an increase in the cumulative concentration of asbestos was indicated; for the employees with the highest exposure, the adjusted odds ratio (OR) was 1.63 (95% confidence interval (CI): 0.99-2.71), while for changes with the severity degree qualifying for asbestosis diagnosis, the risk was significantly increased, over fivefold higher, compared to subjects employed in the lowest exposure. The analysis of the relationship between the progression of interstitial changes and the exposure to asbestos dust showed a fourfold higher risk of the progression in workers employed in the highest exposure. Mean values of FEV1 (forced expiratory volume in 1 s), FVC (forced vital capacity), FEV1/FVC (forced expiratory volume in 1 s to forced vital capacity) were significantly lower in the subjects working in a higher asbestos exposure. The effect of tobacco smoking on the occurrence of interstitial lung changes and their progression was also confirmed. CONCLUSIONS: The results of prophylactic medical examinations of the health status of workers formerly employed in the plants using chrysotile indicate the importance andthe need for a long-term clinical follow-up and the promotion of anti-smoking prevention in this group of former employees. Med Pr 2017;68(2):247-258. PMID- 28345685 TI - [Carbon nanotubes - Characteristic of the substance, biological effects and occupational exposure levels]. AB - Carbon nanotubes (CNTs) are a diverse group of nano-objects in terms of structure, size (length, diameter), shape and characteristics. The growing interest in these structures is due to the increasing number of people working in exposure to CNTs. Occupational exposure to carbon nanotubes may occur in research laboratories, as well as in plants producing CNTs and their nanocomposites. Carbon nanotubes concentration at the emission source may reach 107 particles/cm3. These values, however, are considerably reduced after the application of adequate ventilation. Animal studies suggest that the main route of exposure is inhalation. Carbon nanotubes administered orally are largely excreted in the feces. In animals exposed by inhalation, CNTs caused mainly inflammation, as a result of oxidative stress, leading above all to changes in the lungs. The main effect of animal dermal exposure is oxidative stress causing local inflammation. In animals exposed by ingestion the mild or no toxicity was observed. Carbon nanotubes did not induce mutations in the bacterial tests, but they were genotoxic in a series of tests on cells in vitro, as well as in exposed mice in vivo. Embryotoxicity of nanotubes depends mainly on their modifications and carcinogenicity - primarily on the CNT size and its rigidity. Occupational exposure limits for CNTs proposed by world experts fall within the range of 1-80 MUg/m3. The different effects of various kinds of CNT, leads to the conclusion that each type of nanotube should be treated as a separate substance with individual estimation of hygienic normative. Med Pr 2017;68(2):259-276. PMID- 28345686 TI - [Effectiveness of physical activity intervention at workplace]. AB - A physical activity is a key factor contributing to the improvement and maintenance of one's general health. Although this issue is by no means limited to the workplace, it is precisely the work environment that can provide the basis for keeping and reinforcing more health-conscious attitudes and lifestyles, including programs promoting a physical activity. The paper presents an analysis of the literature on the effectiveness of physical activity intervention at the workplace. Particular attention is paid to the impact of the physical activity programs on musculoskeletal disorders, absenteeism, work ability, physical capacity and body weight of the participants. Given a marginal extent of programs of this kind in Poland, the authors' intention was to show the benefits resulting from implementation of and participation in such initiatives. Med Pr 2017;68(2):277-301. PMID- 28345688 TI - A vacuum ultraviolet laser pulsed field ionization-photoion study of methane (CH4): determination of the appearance energy of methylium from methane with unprecedented precision and the resulting impact on the bond dissociation energies of CH4 and CH4. AB - We report on the successful implementation of a high-resolution vacuum ultraviolet (VUV) laser pulsed field ionization-photoion (PFI-PI) detection method for the study of unimolecular dissociation of quantum-state- or energy selected molecular ions. As a test case, we have determined the 0 K appearance energy (AE0) for the formation of methylium, CH3+, from methane, CH4, as AE0(CH3+/CH4) = 14.32271 +/- 0.00013 eV. This value has a significantly smaller error limit, but is otherwise consistent with previous laboratory and/or synchrotron-based studies of this dissociative photoionization onset. Furthermore, the sum of the VUV laser PFI-PI spectra obtained for the parent CH4+ ion and the fragment CH3+ ions of methane is found to agree with the earlier VUV pulsed field ionization-photoelectron (VUV-PFI-PE) spectrum of methane, providing unambiguous validation of the previous interpretation that the sharp VUV-PFI-PE step observed at the AE0(CH3+/CH4) threshold ensues because of higher PFI detection efficiency for fragment CH3+ than for parent CH4+. This, in turn, is a consequence of the underlying high-n Rydberg dissociation mechanism for the dissociative photoionization of CH4, which was proposed in previous synchrotron based VUV-PFI-PE and VUV-PFI-PEPICO studies of CH4. The present highly accurate 0 K dissociative ionization threshold for CH4 can be utilized to derive accurate values for the bond dissociation energies of methane and methane cation. For methane, the straightforward application of sequential thermochemistry via the positive ion cycle leads to some ambiguity because of two competing VUV-PFI-PE literature values for the ionization energy of methyl radical. The ambiguity is successfully resolved by applying the Active Thermochemical Tables (ATcT) approach, resulting in D0(H-CH3) = 432.463 +/- 0.027 kJ mol-1 and D0(H-CH3+) = 164.701 +/- 0.038 kJ mol-1. PMID- 28345689 TI - Can there be a multi-bond between noble gas and metal? A theoretical study of F2XeMoF2. AB - A new noble gas compound containing a Xe-Mo double bond, F2XeMoF2, was theoretically constructed and studied based on DFT and ab initio calculations. The CCSD(T)-calculated Xe-Mo bond length of 2.518 A was comparable to the standard value of 2.56 A. The bonding energy (32.3 kcal mol-1) was even higher than that of the Xe-Au bond in the well-known XeAuF complex (24.1 kcal mol-1). The result of natural bond orbital (NBO) analysis indicates that there is a sigma bond and a pi-bond between the Xe and Mo atoms in F2XeMoF2. The properties of the Xe-Mo double bond were also analyzed with the atoms in molecules (AIM) approach and natural resonance theory (NRT). PMID- 28345690 TI - Expedient synthesis of a phenanthro-imidazo-pyridine fused heteropolynuclear framework via CDC coupling: a new class of luminophores. AB - We herein report the design and synthesis of a group of fused phenanthro imidazo[1,2-a]pyridine derivatives as a new class of luminescent materials through a Pd(ii) catalyzed intramolecular CDC (cross dehydrogenative coupling) reaction. This method thus unlocked a convenient & expedient way for the synthesis of a new molecular framework containing pi-extended fused heteropolycycles. The heteropolycycles showed very good fluorescence properties both in solid and solution phases which were further utilized in live cell imaging. These kinds of molecules have potential to be used as therapeutic probes and also their solid state luminescence properties can be further utilized for making optoelectronic devices. PMID- 28345691 TI - Surface plasmon resonance imaging for ABH antigen detection on red blood cells and in saliva: secretor status-related ABO subgroup identification. AB - Low antigenic expression of ABO subgroup system on red blood cell (RBC) is cause of discrepancy between forward and reverse blood typing in the standard agglutination technique. Neutralization agglutination is employed for verification of the detection of ABH substances in saliva. However, the neutralization technique is complicated, time-consuming and requires expertise. To overcome these drawbacks, surface plasmon resonance (SPR) imaging was developed for ABH antigen detection on RBCs and in saliva. An antibody array was designed to classify the ABO subgroups by anti-A, anti-B, and anti-H antibodies; the array was immobilized on a carboxymethyl-dextran sensor-surface. RBCs and saliva specimens from sixty-four donors were analysed by passing them over the antibody array, where the secretor status and blood group could be simultaneously identified. Consequently, the immobilized antibodies could specifically and quantitatively detect the ABH antigen on RBCs. Using the direct assay, the SPR signal of saliva detection was weaker than that of RBC detection. However, a sandwich assay with a mixture of anti-A, anti-B, and anti-H antibodies could efficiently enhance the signal. The sensor chip provided high specificity (cut off at 100 to 175 micro refractive index units) and high precision at 0.06%-4.9% CV. The blood group results of the sixty-four donor specimens obtained by SPR agreed with the standard agglutination test with 100% accuracy. SPR could indicate different ABH antigen densities on the RBCs and nearly the same amounts of ABH substances in the saliva of strong and weak subgroups. Finally, we also demonstrated reduced assay time and fewer complications with the SPR imaging platform compared to the neutralization technique. PMID- 28345687 TI - Recent advances in high-performance fluorescent and bioluminescent RNA imaging probes. AB - RNA plays an important role in life processes. Imaging of messenger RNAs (mRNAs) and micro-RNAs (miRNAs) not only allows us to learn the formation and transcription of mRNAs and the biogenesis of miRNAs involved in various life processes, but also helps in detecting cancer. High-performance RNA imaging probes greatly expand our view of life processes and enhance the cancer detection accuracy. In this review, we summarize the state-of-the-art high-performance RNA imaging probes, including exogenous probes that can image RNA sequences with special modification and endogeneous probes that can directly image endogenous RNAs without special treatment. For each probe, we review its structure and imaging principle in detail. Finally, we summarize the application of mRNA and miRNA imaging probes in studying life processes as well as in detecting cancer. By correlating the structures and principles of various probes with their practical uses, we compare different RNA imaging probes and offer guidance for better utilization of the current imaging probes and the future design of higher performance RNA imaging probes. PMID- 28345692 TI - The cyclopropanation of [60]fullerobenzofurans via electrosynthesis. AB - The electrochemical cyclopropanation of [60]fullerobenzofurans with diethyl dibromomalonate has been investigated. Controlled by the steric effect, the sterically favored e bisadducts are obtained as the major products along with two trans-3 bisadducts as minor products. The addition sites and patterns of this reaction are very different from those of our previously reported reaction with benzyl bromide, providing insights into the controlling factors for the electrophilic reactions of dianionic fullerene derivatives. PMID- 28345694 TI - Metal-organic frameworks for the removal of toxic industrial chemicals and chemical warfare agents. AB - Owing to the vast diversity of linkers, nodes, and topologies, metal-organic frameworks can be tailored for specific tasks, such as chemical separations or catalysis. Accordingly, these materials have attracted significant interest for capture and/or detoxification of toxic industrial chemicals and chemical warfare agents. In this paper, we review recent experimental and computational work pertaining to the capture of several industrially-relevant toxic chemicals, including NH3, SO2, NO2, H2S, and some volatile organic compounds, with particular emphasis on the challenging issue of designing materials that selectively adsorb these chemicals in the presence of water. We also examine recent research on the capture and catalytic degradation of chemical warfare agents such as sarin and sulfur mustard using metal-organic frameworks. PMID- 28345695 TI - Anion-dependent self-assembly of copper coordination polymers based on pyrazole 3,5-dicarboxylate and 1,2-di(4-pyridyl)ethylene. AB - By utilizing a pyrazole-3,5-dicarboxylic acid (H3pzdc) and flexible 1,2-di(4 pyridyl)ethylene (dpe) with various copper(ii) salts under the same solvothermal synthetic conditions, six novel coordination polymers, namely, {[Cu2(pzdc)(dpe)2]X}n (X = NO3- (1), ClO4- (2), BF4- (3), SCN- (4)), {[Cu(ii)4Cu(i)4(pzdc)4(dpe)6](H2O)4}2n (5), and {[Cu5(HPO4)2 (pzdc)2(dpe)3](H2O)5}n (6) were obtained. The structural diversity of compounds 1 6 depends on the starting Cu(ii) salts. Compounds 1-4 are isostructural and exhibit a 3D porous cationic pillar-layered coordination framework with lattice monoanions incorporated into the channels of the framework. When using copper(ii) sulfate as a reagent, a neutral mixed-valence Cu(i,ii) 2D + 2D -> 2D parallel interpenetrated layer of 5 was obtained. In the case of a phosphate trianion, compound 6 shows a 3D coordination framework which contains MU4-HPO42- linking between Cu(ii) centers. The anion-exchange properties of 1-4 were studied. Interestingly, compounds 1-4 exhibit the irreversible chemisorption of the thiocyanate anion instead of anion exchange without the destruction of their structural framework as confirmed by PXRD, IR, UV-Vis, and AA spectroscopy. Moreover, the anion-induced structural transformation of 1-4 was observed when exchanging with an azide anion. The luminescent properties of 1-6 and exchanged products were also investigated. PMID- 28345697 TI - The role of ion-water interactions in determining the Soret coefficient of LiCl aqueous solutions. AB - The application of a thermal gradient to an aqueous electrolyte solution induces the Soret effect, and the salt migrates towards hot (thermophilic) or cold regions (thermophobic). Experimental studies of LiCl reported changes in the sign of the Soret coefficient as well as a minimum in this coefficient at specific salt concentrations and temperatures. At the minimum the thermodiffusive response of the solution is enhanced significantly. We have performed non-equilibrium molecular dynamics simulations of LiCl solutions to quantify the dependence of the sign change and minimum of the Soret coefficient with salt concentration and temperature. We find that the ion mass plays a secondary role in determining the magnitude of the Soret coefficient, while the diameter of the cation has a significant impact on the coefficient and on the observation of the minimum. Our simulations show that the ordering of water around Li+ plays a key role in determining the Soret coefficient of LiCl salts. PMID- 28345696 TI - Interfacially Al-doped ZnO nanowires: greatly enhanced near band edge emission through suppressed electron-phonon coupling and confined optical field. AB - Aluminium (Al)-doped zinc oxide (ZnO) nanowires (NWs) with a unique core-shell structure and a Delta-doping profile at the interface were successfully grown using a combination of chemical vapor deposition re-growth and few-layer AlxOy atomic layer deposition. Unlike the conventional heavy doping which degrades the near-band-edge (NBE) luminescence and increases the electron-phonon coupling (EPC), it was found that there was an over 20-fold enhanced NBE emission and a notably-weakened EPC in this type of interfacially Al-doped ZnO NWs. Further experiments revealed a greatly suppressed nonradiative decay process and a much enhanced radiative recombination rate. By comparing the finite-difference time domain simulation with the experimental results from intentionally designed different NWs, this enhanced radiative decay rate was attributed to the Purcell effect induced by the confined and intensified optical field within the interfacial layer. The ability to manipulate the confinement, transport and relaxation dynamics of ZnO excitons can be naturally guaranteed with this unique interfacial Delta-doping strategy, which is certainly desirable for the applications using ZnO-based nano-photonic and nano-optoelectronic devices. PMID- 28345698 TI - Ethylcellulose oleogels for lipophilic bioactive delivery - effect of oleogelation on in vitro bioaccessibility and stability of beta-carotene. AB - The in vitro lipolysis and beta-carotene (BC) transfer from oil to aqueous phase of canola oil ethylcellulose (EC) oleogels were measured using a static monocompartmental model simulating oral, gastric, and duodenal digestive stages. The effects of EC oleogelation on gel in vitro digestibility were examined, using un-structured canola oil as a control. The physicochemical properties of oleogels containing BC were also measured. It was found that oleogels made with 10% 10 cP and 10% 20 cP did not differ significantly in their extent of lipolysis or BC transfer compared to canola oil; however 10% 45 cP and 15.5% 20 cP had a significantly lower extent of lipolysis and BC transfer compared to other formulations. The structure and mechanical strength of the oleogels were both determined to be factors affecting lipolysis and transfer. The presence of BC did not significantly affect the mechanical strength of the gels and EC oleogelation delayed BC degradation under accelerated storage conditions compared to a heated canola oil control. These findings could contribute to the development of new applications for EC oleogels, specifically for the effective delivery of lipophilic molecules. PMID- 28345699 TI - Gold and iodine diffusion in large area perovskite solar cells under illumination. AB - Operational stability is the main issue hindering the commercialisation of perovskite solar cells. Here, a long term light soaking test was performed on large area hybrid halide perovskite solar cells to investigate the morphological and chemical changes associated with the degradation of photovoltaic performance occurring within the devices. Using Scanning Transmission Electron Microscopy (STEM) in conjunction with EDX analysis on device cross sections, we observe the formation of gold clusters in the perovskite active layer as well as in the TiO2 mesoporous layer, and a severe degradation of the perovskite due to iodine migration into the hole transporter. All these phenomena are associated with a drastic drop of all the photovoltaic parameters. The use of advanced electron microscopy techniques and data processing provides new insights on the degradation pathways, directly correlating the nanoscale structure and chemistry to the macroscopic properties of hybrid perovskite devices. PMID- 28345700 TI - Electronic structure and magnetic properties of penta-graphene nanoribbons. AB - 2D penta-graphene sheets were cut along typical crystallographic orientations in order to construct various penta-graphene nanoribbon (P-GNR) models, and their electronic structures and magnetic properties were systemically investigated. It was demonstrated that P-GNRs are very versatile with rich and unique electronic and magnetic properties. In particular, bipolar magnetic semiconducting features can be achieved in the ferromagnetic state for all magnetic P-GNRs, which makes P GNRs valuable for developing next-generation information storage devices. More interestingly, studies on the electric-magnetic coupling revealed that an applied transverse electric field can transform a P-GNR from a magnetic semiconductor to a half-metal with a wide band gap of 0.88 eV, which can achieve complete spin filtering even at room temperature. Important advantages of magnetism over graphene nanoribbons are thus expected. PMID- 28345701 TI - The effect of natural iron oxide and oxalic acid on the photocatalytic degradation of isoproturon: a kinetics and analytical study. AB - The photocatalytic degradation of isoproturon, a persistent toxic herbicide, was investigated in the presence of natural iron oxide and oxalic acid and under UV irradiation. The influence of the relevant parameters such as the pH and the iron oxide and oxalic acid concentrations has been studied. The presence of natural iron oxide and oxalic acid in the system effectively allow the degradation of isoproturon, whereas the presence of t-butyl alcohol adversely affects the phototransformation of the target pollutant, thus indicating that an OH radical initiated the degradation mechanism. The degradation mechanism of isoproturon was investigated by means of GC-MS analysis. Oxidation of both the terminal N-(CH3)2 and isopropyl groups is the initial process leading to N-monodemethylated (NHCH3), N-formyl (N(CH3)CHO), and CHCH3OH as the main intermediates. The substitution of the isopropyl group by an OH group is also observed as a side process. PMID- 28345702 TI - The role of conformational heterogeneity in regulating the apoptotic activity of BAX protein. AB - While activation of BAX is required for initiating mitochondria-mediated apoptosis, the underlying mechanisms remain unsettled. We studied conformations of BAX protein using pressure- and temperature-resolved ESR techniques and obtained the thermodynamic properties of the conformations. We show that inactive BAX is structurally heterogeneous and exists in equilibrium between two major populations of the conformations, UM and UM', of which the former is thermodynamically favored at room temperature. An increase in the population of UM', induced by either pressure or point mutations of BAX, renders BAX susceptible to oligomerization, which leads to cell death. This study uncovers the biological significance of BAX conformations and shows that the pro-apoptotic activity of BAX can be triggered by altering the equilibrium between the two states. It suggests that therapeutic intervention may focus on shifting the balance in the conformational heterogeneity. PMID- 28345703 TI - Phoretic motion of colloids in a phase separating medium. AB - The enhanced motion of dispersed particles driven by a concentration gradient is the basis for diffusiophoresis. Here we present the dynamics of colloids in a phase separating medium probed by X-Ray Photon Correlation Spectroscopy (XPCS) in the ultra-small angle scattering range. Charge stabilized silica colloids suspended in a binary mixture of 3-methylpyridine and water/heavy water are preferentially wetted by 3-methylpyridine and consequently display a phoretic motion towards that phase upon demixing. This activity lasts for hundreds of seconds before the phase separation is complete and the enhanced motion is arrested as the colloids return to normal diffusive dynamics. PMID- 28345704 TI - Atomic layer deposition of nickel-cobalt spinel thin films. AB - We report the atomic layer deposition (ALD) of high-quality crystalline thin films of the spinel-oxide system (Co1-xNix)3O4. These spinel oxides are ferrimagnetic p-type semiconductors, and promising material candidates for several applications ranging from photovoltaics and spintronics to thermoelectrics. The spinel phase is obtained for Ni contents exceeding the x = 0.33 limit for bulk samples. It is observed that the electrical resistivity decreases continuously with x while the magnetic moment increases up to x = 0.5. This is in contrast to bulk samples where a decrease of resistivity is not observed for x > 0.33 due to the formation of a rock-salt phase. From UV-VIS-NIR absorption measurements, a change from distinct absorption edges for the parent oxide Co3O4 to a continuous absorption band ranging deep into the near infrared for 0 < x <= 0.5 was observed. The conformal deposition of dense films on high aspect-ratio patterns is demonstrated. PMID- 28345705 TI - Activating efficient room temperature phosphorescence of carbon dots by synergism of orderly non-noble metals and dual structural confinements. AB - Obtaining high efficiency room temperature phosphorescence (RTP) by employing non noble metals poses two challenges: (1) strengthening spin-orbit coupling of excitons to improve the rate of intersystem crossing (ISC) by using non-noble metals with small-atomic-number; (2) employing structural confinement to enhance radiation relaxation because harsh conditions, including carefully selected matrices, rigid solid-state crystalline structure and low temperature, are commonly needed. Here, layered double hydroxides (LDHs) with orderly non-noble metal arrangements were used as an inorganic matrix to activate RTP of carbon dots (CDs). The Zn orderly arranged on the LDH layer contributes to the enhancement in spin-orbit coupling of excitons and the decrease in the energy gap for the singlet-triplet state. The structural confinements of the LDH layer and nano-interlayer testify that the phosphorescence of CDs-LDHs originates from the suppressed radiationless relaxation processes. Using the high tunability of metal species and ratios on the LDH layer, this method can be widely applied to optimize ISC and phosphorescence properties. PMID- 28345706 TI - Topochemical synthesis of cation ordered double perovskite oxynitrides. AB - Topochemical nitridation in ammonia at moderate temperatures of cation ordered Sr2FeWO6 produces new antiferromagnetic double perovskite oxynitrides Sr2FeWO6 xNx with 0 < x <= 1. Nitrogen introduction induces the oxidation of Fe2+ to Fe3+ and decreases TN from 38 K (x = 0) to 13 K for Sr2FeWO5N which represents the first example of a double perovskite oxynitride with both high cationic order and nitrogen content. This synthetic approach can be extended to other cation combinations expanding the possibility of new materials in the large group of double perovskites. PMID- 28345707 TI - Selectivity control between Mizoroki-Heck and homo-coupling reactions for synthesising multinuclear metal complexes: unique addition effects of tertiary phosphines and O2. AB - The addition of a tertiary phosphine and O2 to reaction solutions strongly affected the reactivity and selectivity of coupling reactions between transition metal complexes. The Mizoroki-Heck reaction between metal complexes with bromo and those with vinyl groups in the diimine ligand did not proceed using Pd(OAc)2 in the presence of 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (Sphos) under Ar but proceeded selectively after injection of air into the reaction vessel. In the absence of the phosphine ligand, on the other hand, not only the Mizoroki Heck reaction but also a homo-coupling reaction between the metal complexes with the bromo groups proceeded at the same time. Mechanistic investigation showed that nanoparticles of Pd species were produced in the absence of the phosphine ligand and worked as catalysts for both the Mizoroki-Heck and homo-coupling reactions. On the other hand, larger Pd particles, which were produced in the presence of Sphos but after addition of air for oxidising Sphos, selectively catalysed the Mizoroki-Heck reaction. 'Molecular' Pd species that were stabilised in the presence of non-oxidised Sphos could not catalyse both coupling reactions under the reaction conditions. Based on these results, reaction conditions were established for the selective progress of the Mizoroki-Heck and the homo-coupling reactions. PMID- 28345708 TI - Evaluation of two- and three-dimensional electrode platforms for the electrochemical characterization of organometallic catalysts incorporated in non conducting metal-organic frameworks. AB - The development of a reliable platform for the electrochemical characterization of a redox-active molecular diiron complex, [FeFe], immobilized in a non conducting metal organic framework (MOF), UiO-66, based on glassy-carbon electrodes is reported. Voltammetric data with appreciable current responses can be obtained by the use of multiwalled carbon nanotubes (MWCNT) or mesoporous carbon (CB) additives that function as conductive scaffolds to interface the MOF crystals in "three-dimensional" electrodes. In the investigated UiO-66-[FeFe] sample, the low abundance of [FeFe] in the MOF and the intrinsic insulating properties of UiO-66 prevent charge transport through the framework, and consequently, only [FeFe] units that are in direct physical contact with the electrode material are electrochemically addressable. PMID- 28345709 TI - A study of asymmetrical mixed-valent Mo2-Mo2 complexes in the class III regime. AB - Three novel asymmetrical dimolybdenum dimers, [Mo2(DAniF)3]2(MU-OOCCOS) (DAniF = N,N'-di(p-anisyl)formamidinate) ([OO-OS]), [Mo2(DAniF)3]2(MU-S2CCO2) ([SS-OO]), and [Mo2(DAniF)3]2(MU-SSCCOS) ([SS-OS]), have been synthesized and characterized by either single-crystal X-ray crystallography or 1H NMR spectroscopy. The structural asymmetry for these compounds gives rise to a redox asymmetry, which enlarges the potential separation (DeltaE1/2) between the two [Mo2] units. The mixed-valance (MV) species [OO-OS]+, [SS-OO]+ and [SS-OS]+, prepared by one electron chemical oxidation of the neutral precursors, exhibit an intense and symmetrical intervalence charge transfer (IVCT) absorption band in the near-IR region, along with the high energy metal (delta) to ligand (pi*) (ML) and ligand (pi) to metal (delta) charge transfer (LMCT) absorptions. The LMCT band, which is absent in the neutral precursors, is reflective of the cationic [Mo2]+ unit in the MV species; therefore, it is evidenced that in the MV complexes optical electron transfer from the electron donor to acceptor occurs, while the thermal process is energetically unfavorable. The C(1)-C(2) bonds (1.44-1.48 A) that connect the two [Mo2] units are significantly shorter than a C-C single bond, showing that the two Mo2 centers are strongly coupled. For the series, TD-DFT calculations show that the molecular orbitals have an unsymmetrical charge density distribution over the two dimolybdenum sites. For each of the complex systems, the calculated orbital energy gaps, SOMO(delta - delta)-LUMO(bridging ligand pi*), HOMO-8(bridging ligand pi)-SOMO(delta - delta) and SOMO(delta - delta)-HOMO-1(delta + delta), are in good agreement with the observed MLCT, LMCT and IVCT absorption band energies, respectively. The consistency in energy between the IVCT band and the SOMO(delta - delta)-HOMO-1(delta + delta) gap permits assignment of the MV complexes to Class III in the Robin-Day scheme. PMID- 28345710 TI - Desktop NMR for structure elucidation and identification of strychnine adulteration. AB - Elucidating the structure of complex molecules is difficult at low magnetic fields due to the overlap of different peak multiplets and second-order coupling effects. This is even more challenging for rigid molecules with small chemical shift differences and with prochiral centers. Since low-field NMR spectroscopy is sometimes presumed as restricted to the analysis of only small and simple molecules, this paper aims at countering this misconception: it demonstrates the use of low-field NMR spectroscopy in chemical forensics for identifying strychnine and its counterions by exploring the chemical shift as a signature in different 1D 1H and 13C experiments. Hereby the applied methodologies combine various 1D and 2D experiments such as 1D 1H, 13C, DEPT, and 2D COSY, HETCOR, HSQC, HMBC and J-resolved spectroscopy to elucidate the molecular structure and skeleton of strychnine at 1 Tesla. Strychnine is exemplified here, because it is a basic precursor in the chemistry of natural products and is employed as a chemical weapon and as a doping agent in sports including the Olympics. In our study, the molecular structure of the compound could be identified either with a 1D experiment at high magnetic field or with HMBC and HSQC experiments at 1 T. In conclusion, low-field NMR spectroscopy enables the chemical elucidation of the strychnine structure through a simple click with a computer mouse. In situations where a high-field NMR spectrometer is unavailable, compact NMR spectrometers can nevertheless generate knowledge of the structure, important for identifying the different chemical reaction mechanisms associated with the molecule. Desktop NMR is a cost-effective viable option in chemical forensics. It can prove adulteration and identify the origin of different strychnine salts, in particular, the strychnine free base, strychnine hemisulphate and strychnine hydrochloride. The chemical shift signatures report the chemical structure of the molecules due to the impact of the counterions on the chemical shift of the protons adjacent to the heteroatoms. This can serve as a methodology for the structure elucidation of complex molecules at lower-magnetic fields. PMID- 28345711 TI - Metal-free synthesis of 2-aminonaphthalenes by intramolecular transannulation of 1-sulfonyl-4-(2-alkenylphenyl)-1,2,3-triazoles. AB - A facile metal-free synthesis of naphthalenes by intramolecular transannulation of 1-sulfonyl-4-(2-alkenylphenyl)-1,2,3-triazoles was realized. The in situ formed ketenimine was proposed as the key intermediate, and the desired 2 aminonaphthalenes were generated in up to 87% yield in refluxing 1,2 dichloroethane without any catalyst or additive. PMID- 28345712 TI - Metal-free phosphonation of heteroarene N-oxides with trialkyl phosphite at room temperature. AB - A new protocol is described for the conversion of heteroarene N-oxides to heteroarylphosphonates through in situ activation with bromotrichloromethane. The N-oxides of isoquinoline, quinoline, quinoxaline and 1,10-phenanthroline were fast transformed into the corresponding heteroarylphosphonates in up to 92% yield under mild conditions in the absence of solvent and metal catalysts. The good functional group tolerance, low cost, feasibility of scale up, and wide availability of reagents make this method a prominent complement to the Hirao coupling. PMID- 28345714 TI - A novel symmetric TTF-pyridyl thiolato zinc complex: synthesis, characterization and crystal structure analysis. AB - We report the first preparation of a symmetric tetrathiafulvalene (TTF)-pyridyl thiolato zinc(ii) complex in which two TTF parts connect to the central zinc atom through pyridines and thiolates. We also discuss the crystal structure analysis and physical properties of the complex, especially photocurrent generations measured on its thin-film sample and single crystal. PMID- 28345713 TI - Real-time quantification of endothelial response to shear stress and vascular modulators. AB - Quiescence is commonly used to describe the inactive state of endothelial cells (ECs) in monolayers that have reached homeostasis. Experimentally quiescence is usually described in terms of the relative change in cell activity (e.g. turnover, speed, etc.) in response to a perturbation (e.g. solute, shear stress, etc.). The objective of this study is to provide new insight into EC quiescence by quantitatively defining the morphology and activity of confluent cell monolayers in response to shear stress and vascular modulators. Confluent monolayers of human umbilical vein ECs (HUVECs) were subjected to a range of shear stresses (4-16 dyne cm-2) under steady flow. Using phase contrast, time lapse microscopy and image analysis, we quantified EC morphology, speed, proliferation, and apoptosis rates over time and detected differences in monolayer responses under various media conditions: basal media supplemented with growth factors, interleukin-8, or cyclic AMP. In all conditions, we observed a transition from cobblestone to spindle-like morphology in a dose-dependent manner due to shear stress. Cyclic AMP enhanced the elongation and alignment of HUVECs due to shear stress and reduced steady state cell speed. We observed the lowest proliferation rates below 8 dyne cm-2 and found that growth factors and cyclic AMP reduced proliferation and apoptosis; interleukin-8 similarly decreased proliferation, but increased apoptosis. We have quantified the response of ECs in confluent monolayers to shear stress and vascular modulators in terms of morphology, speed, proliferation and apoptosis and have established quantifiable metrics of cell activity to define vascular quiescence under shear stress. PMID- 28345715 TI - Ultralow-power near-infrared excited neodymium-doped nanoparticles for long-term in vivo bioimaging. AB - Lanthanide-doped luminescent nanoparticles with both emission and excitation in the near-infrared (NIR-to-NIR) region hold great promise for bioimaging. Herein, core@shell structured LiLuF4:Nd@LiLuF4 (named as Nd@Lu) nanoparticles (NPs) with highly efficient NIR emission were developed for high-performance in vivo bioimaging. Strikingly, the absolute quantum yield of Nd@Lu NPs reached as high as 32%. After coating with polyethylene glycol (PEG), the water-dispersible Nd@Lu NPs showed good bio-compatibility and low toxicity. With efficient NIR emission, the Nd@Lu NPs were clearly detectable in tissues at depths of up to 20 mm. In addition, long-term in vivo biodistribution with a high signal-to-noise ratio of 25.1 was distinctly tracked upon an ultralow-power-density excitation (10 mW cm 2) of 732 nm for the first time. PMID- 28345716 TI - Spontaneous NaCl-doped ice at seawater conditions: focus on the mechanisms of ion inclusion. AB - Molecular dynamics simulations on the microsecond time scale have been performed on an aqueous solution of TIP4P/2005 water and NaCl by using the direct coexistence technique to study the ice growth and the ice/liquid interface water. At ambient pressure, for temperatures above the eutectic point of the salt and at seawater concentrations the brine rejection phenomenon and the spontaneous growth of an ice slab doped by the salt are obtained, as found in natural terrestrial and planetary environments. Experiments indicate that Cl- goes via substitution to ice sites. In line with this evidence we find a new result: the Cl- ion included in the lattice always substitutes not one but two water molecules, leaving the surrounding ice structure not distorted. The Na+ ion shows a lower probability of being included in the ice and it occupies an interstitial site, causing a local distortion of the lattice. No signs of significant ion diffusion are observed in the lattice. PMID- 28345718 TI - Probing the binding affinity of plasma proteins adsorbed on Au nanoparticles. AB - Nanoparticle (NP) surfaces are modified immediately by the adsorption of proteins when exposed to human blood, leading to the formation of a protein corona. The adsorption of serum proteins is the key process for exploring the bioapplication and biosafety of NPs. In this study, NP-protein binding affinity (Ka) was investigated. Some serum proteins, such as human serum albumin (HSA), trypsin (TRP), hemoglobin (Hb), myoglobin (MB), immunoglobulin G (IgG), carbonic anhydrase (CA), fibrinogen (FIB), chymotrypsin and r-globulin, were used with gold nanoparticles (AuNPs) to address binding affinity according to isothermal titration calorimetry (ITC) combined with dynamic light scattering (DLS) and fluorescence quenching. The NP protein binding affinities determined by the two methods were in agreement, and depended on the protein properties and size of the NPs. The two methods are convenient, and the results are highly comparable. These methods can be extended to determine the binding affinity of NP protein interactions. The adsorption of proteins upon the AuNP surface is a complex process and depends on several factors, but the binding affinities are higher for proteins with more cysteine residues located on the surface. PMID- 28345719 TI - New insight into binary TiO2@C nanocomposites: the crucial effect of an interfacial microstructure. AB - Combining with carbon materials is a common and efficient strategy to improve the photocatalytic performance of TiO2. But the fundamental nature of the interfacial microstructures between carbon and TiO2 and how they affect the photocatalysis process remain controversial. In this work, hybrid TiO2@C nanocomposites with different carbon contents are synthesized. It is found that an interfacial disorder region with interfacial Ti-O-C bonds and abundant defects (oxygen vacancies, VO) can be generally formed from the chemical interactions between carbon and Ti-O-Ti skeletons. These interfacial VO sites are well stabilized by the carbon complex coating, and maintain their intrinsic nature in visible light absorption and electron trapping. Moreover, the synergistic effect of interfacial bonding, defective sites and the components on the visible photocatalysis of TiO2@C composites has been carefully investigated, and a corresponding mechanism is also proposed. PMID- 28345720 TI - Partitioning of 2-phenylethanol and limonene cosurfactants in C12E4. AB - Avoided level-crossing muon spin resonance (ALC-MUSR) has been used to study the dynamics and local environment of spin probes formed by muonium (Mu) addition to 2-phenylethanol (PEA) and limonene (1-methyl-4-(1-methylethenyl)-cyclohexene) in an aqueous dispersion of the nonionic surfactant C12E4 (tetra(ethylene glycol) n dodecyl ether). The spin probes derived from both cosurfactants reside within the micelles in the L1 phase and the bilayers in the Lalpha phase rather than in the aqueous region. The local polarity measured by the different isomers of the Mu adducts of PEA suggests there is a water gradient within the micelles and bilayers. Slow rotation of the micelles broadened the Delta1 resonances with increasing temperature in the L1 phase while narrower Delta1 resonances were observed in the Lalpha phase due to the rapid rotation of the spin probes around a preferred axis, which was wobbling within a cone. PMID- 28345721 TI - Dissecting the structural basis for the intracellular delivery of OSW-1 by fluorescent probes. AB - The structural basis for the intracellular delivery of OSW-1 is investigated using fluorescent derivatives of OSW-1 and its closely related congeners. Despite the large differences in activity, all the fluorescent probes are found to translocate across the plasma membrane to the ER and Golgi apparatus. This observation suggests that the glycosylated cholestane moiety plays an important role in the cell internalization and intracellular localization property of OSW 1. PMID- 28345722 TI - Eu2+-Eu3+ valence transition in double, Eu-, and Na-doped PbSe from transport, magnetic, and electronic structure studies. AB - The Eu atoms in Pb1-xEuxSe have long been assumed to be divalent. We show that p type doping of this magnetic semiconductor alloy with Na can modify the effective Eu valence: a mixed, Eu2+-Eu3+ state appears in Pb1-x-yEuxNaySe at particular values of y. Magnetization, carrier concentration, resistivity, and thermopower of Pb1-x-yEuxNaySe are reported for a number of samples with different x and y. A pronounced increase in thermopower at a given carrier concentration was identified and attributed to the presence of enhanced ionized impurity scattering. A strong decrease in the hole concentration is observed in Pb1-yNaySe when Eu is added to the system, which we attribute to a Eu2+-Eu3+ self-ionization process. This is evidenced by magnetization measurements, which reveal a significant reduction of the magnetic moment of Pb1-xEuxSe upon alloying with Na. Further, a deviation of magnetization from a purely paramagnetic state, described by a Brillouin function, identifies antiferromagnetic interactions between the nearest-neighbor Eu atoms: a value of Jex/kB = -0.35 K was found for the exchange coupling parameter. The conclusion of a Eu2+-Eu3+ self-ionization process being in effect is supported further by the electronic structure calculations, which show that an instability of the 4f7 configuration of the Eu2+ ion appears with Na doping. Schematically, it was found that the Eu 4f levels form states near enough to the Fermi energy that hole doping can lower the Fermi energy and trigger a reconfiguration of a 4f electronic shell. PMID- 28345726 TI - Structural analyses of isolated cyclic tetrapeptides with varying amino acid residues. AB - Cyclic peptides represent a large class of substances that occur in nature with important biological and medical functions. Synthetic cyclic peptides are used as artificial receptors due to a series of advantages over conventional receptors. In order to optimize their binding abilities, investigations of their intrinsic structural properties especially with regard to the influence of different amino acid residues are fundamental. Here we report the structural analysis of two synthetic cyclic tetrapeptides cyclo[l-Tyr(Me)-d-Pro-l-Ala-d-Pro] (CPAla) and cyclo[l-Tyr(Me)-d-Pro-l-Glu(Me)-d-Pro] (CPGlu) in a molecular beam by means of combined IR/UV spectroscopic techniques. Structural assignments were achieved by comparing experimentally obtained vibrations and harmonically calculated frequencies including dispersion corrections (B3LYP-D3/TZVP). The investigated cyclic peptides contain an arrangement of an amino acid sequence which is no longer symmetric compared to the former investigations of the cyclo[l-Tyr(Me)-d Pro]2 peptide. It turns out that all investigated compounds prefer conformations stabilized by two internal hydrogen bonds. In the case of CPGlu containing a flexible side chain with a terminal hydrogen bond acceptor an additional structure was observed in which a hydrogen bond between the terminal carboxylate group and a ring NH group is formed. PMID- 28345727 TI - Intrinsic defects and their effects on the optical properties in the nonlinear optical crystal CdSiP2: a first-principles study. AB - In view of their high nonlinear optical coefficients and good phase-matching properties, CdSiP2 (CSP) crystals are considered as one of the most promising materials in the field of nonlinear optical applications. However, the slight absorption losses around 1.34 MUm and 1.78 MUm under e-polarized light have been affecting its performance. In this study, first-principles calculations were performed to identify the effects of various charge defects on the absorption properties. Different intrinsic defects in the CSP crystal were calculated using the HSE method and compared according to the specific chemical environments in the experiments. The results show that the point defects of V, Si, and V, which can be spontaneously formed, are dominant in the Cd-poor environment. The combination of Si and V defects is the most favorable cluster in the Cd-poor case because of its relatively low formation energy. Furthermore, the antisite defect SiCd was found to be responsible for the main absorption peaks at 1.34 and 1.78 MUm in the experimental spectra, whereas other defects and clusters, such as the defects Si and V, also contribute to these red shifted absorptions. Our results intend to provide a guideline for adjusting the optical absorption in CSP by modifying its defects. PMID- 28345728 TI - Embedding 1D or 2D cobalt-carboxylate substrates in 3D coordination polymers exhibiting slow magnetic relaxation behaviors: crystal structures, high-field EPR, and magnetic studies. AB - By utilizing well-designed bifunctional ligands derived from 1H-imidazole-4,5 dicarboxylic acid, magnetic coordination polymers (CPs) that exhibit slow magnetic relaxation at the low temperature regions were constructed and further structurally characterized. In 1, 1D cobalt-carboxyl chains were stabilized in the final structure. In contrast, by adjusting the length of the substituted arms on imidazole-4,5-dicarboxylic acid, a novel 3D CP, 2 containing 2D 63 cobalt carboxyl layer was obtained. A combination of Quantum Monte Carlo (QMC) simulations and the first-principles Density functional theory (DFT) calculations showed that compound 2 features weak ferro- and antiferro-magnetic coupling mechanisms with two different super-exchange paths of -/+/- for syn-anti carboxylate bridges and -/-/- for syn-syn carboxylate bridges. Through HF-EPR measurements performed on polycrystalline samples over the frequency range of 60 260 GHz and field range of 0-12 T, the effective g-values of 1 and 2 were all larger than 2.00, and the signs of their D values were probably positive. PMID- 28345729 TI - Medication adherence among cardiac patients in Khartoum State, Sudan: a cross sectional study. AB - INTRODUCTION: Non-adherence to medication among cardiac patients is often the major risk factor for poor clinical outcomes, increased mortality rates and higher healthcare costs. The literature evaluating the prevalence of and reasons for non-adherence in resource-poor settings is extremely limited compared to resource-rich settings. There is a scarcity of data about medication adherence in Sudan hence this study was performed to identify prevalence, predictors and barriers of non-adherence to medication among cardiac patients in Khartoum State. METHODS: A descriptive, cross-sectional survey was performed using a pre-tested, self-administered questionnaire on a sample of 433 randomly selected cardiac patients attending the largest three cardiac centres located in Khartoum State. Descriptive and multivariate logistic regression analyses were used for data analysis. RESULTS: The response rate was 89.1%. The mean (+/- SD) number of chronic diseases among respondents was 2.3 ( +/- 1.3) and that of medication use was 4.2 ( +/- 1.9). The mean ( +/- SD) duration of medication use among participants was 6.4 ( +/- 5.4) years. Optimal adherence was defined as having a score of greater than six on the eight-item Morisky medication adherence scale. Using this cut-off point, 49% (95% CI: 43.9-54.1) of respondents had optimal adherence and 51% (95% CI: 45.9-56.1) had poor adherence. Respondents with a high level of education, low and middle income levels, and those taking five or more medications daily were found to be significantly more non-adherent to medication use than those with low to intermediate education levels (p < 0.001), those with high income levels (p < 0.001), and those taking one to four medications daily (p = 0.039). The top four barriers for poor medication adherence among the study participants were the high cost of drugs, polypharmacy and lack of pharmacist and physician communication with patients about their drug therapy. CONCLUSIONS: The current findings highlight the need for urgent, multifaceted interventions, given the burden of cardiovascular diseases and the clinical and economic consequences of medication non-adherence. These interventions include affordable medications, easy-to-use medication regimens with fewer daily doses, ongoing communication between patients and healthcare providers, and improvement of the patient provider partnership. PMID- 28345731 TI - English Translation of the Minutes of the Invitational Workshop Goals, Contents and Methods for Education in Medical Informatics. PMID- 28345730 TI - Electrocardiographic abnormalities in treatment-naive HIV subjects in south-east Nigeria. AB - BACKGROUND: Cardiac complications of human immunodeficiency virus (HIV) infection are important causes of morbidity and mortality. We set out to determine the electrocardiographic (ECG) abnormalities in treatment-naive HIV-positive patients in Enugu, south-east Nigeria. METHODS: This was a cross-sectional study involving 250 HIV-positive and 200 HIV-negative subjects. Demographic and anthropometric data, relevant investigations and ECG results were compared between the groups. RESULTS: An abnormal ECG was present in 70% of the HIV-positive patients, sinus bradycardia in 64%, QTC prolongation in 48%, T-wave inversion in 21.6%, Wolf Parkinson-White syndrome in 0.8%, abnormal P waves in 12.8%, 1st degree heart block in 2.4%, ST depression in 30%, and left-axis deviation in 1.6%. Underweight was associated with ECG abnormalities (p = 0.001). The HIV-positive patients had more ECG abnormalities than the HIV-negative subjects (p = 0.001). CONCLUSION: Electrocardiographic abnormalities were common in treatment-naive HIV-positive patients in Enugu, Nigeria. The 70% prevalence of ECG abnormalities in treatment naive HIV-positive patients was high. There is a need to evaluate HIV-positive patients at onset for cardiac and non-cardiac abnormalities detectable by ECG. PMID- 28345732 TI - Comparative analysis in continuous expansion of bovine and human primary nucleus pulposus cells for tissue repair applications. AB - Autologous NP cell implantation is a potential therapeutic avenue for intervertebral disc (IVD) degeneration. However, monolayer expansion of cells isolated from surgical samples may negatively impact matrix production by way of dedifferentiation. Previously, we have used a continuous expansion culture system to successfully preserve a chondrocyte phenotype. In this work, we hypothesised that continuous expansion culture could also preserve nucleus pulposus (NP) phenotype. We confirmed that serial passaging drove NP dedifferentiation by significantly decreasing collagen type II, aggrecan and chondroadherin (CHAD) gene expression, compared to freshly isolated cells. Proliferation, gene expression profile and matrix production in both culture conditions were compared using primary bovine NP cells. Both standard culture and continuous culture produced clinically relevant cell populations. However, continuous culture cells maintained significantly higher collagen type II, aggrecan and CHAD transcript expression levels. Also, continuous expansion cells generated greater amounts of proteoglycan, collagen type II and aggrecan protein deposition in pellet cultures. To our surprise, continuous expansion of human intervertebral disc cells - isolated from acute herniation tissue - produced less collagen type II, aggrecan and CHAD genes and proteins, compared to standard culture. Also, continuous culture of cells isolated from young non-degenerate tissue did not preserve gene and protein expression, compared to standard culture. These data indicated that primary bovine and human NP cells responded differently to continuous culture, where the positive effects observed for bovine cells did not translate to human cells. Therefore, caution must be exercised when choosing animal models and cell sources for pre-clinical studies. PMID- 28345733 TI - [Hand fine motor skills and use of both hand and arm in subjects after a stroke: a systematic review]. AB - INTRODUCTION: In clinical practice it is important to be able to assess the function of the upper limb of the patient who has suffered a stroke. There is currently no systemic review that could identify assessment tools for the 'fine use of the hand' and 'use of both hand and arm'. AIMS: Primary, to identify observational tools which can assess the fine use of the hand and the use of both hand and arm in patients with stroke sequels. Secondary, to analyze the bias risk in the included articles, describing and categorizing the clinical utility, validity and reliability. PATIENTS AND METHODS: A search was carried in Medline, LILACS, SciELO and Open Grey, which included articles published until October 2015. Studies that validate assessing tools of the upper limb in subjects with a stroke sequel which evaluate the fine use of the hand and the use of both hand and arm were included. RESULTS: Eleven tools in evaluate observational haven been selected, which assess the fine use of the hand and the use of hand and arm. CONCLUSIONS: In every case both validity and reliability have been reported, but clinical utility has been less considered for assessment. The studies that researched these tools showed a high risk of bias in their development. ARAT-19 showed a lower bias risk, but when it has to do with applicability and the reference trial is taken into account, the level of concern is high. PMID- 28345734 TI - [Restless legs syndrome in patients diagnosed with attention deficit hyperactivity disorder]. AB - INTRODUCTION: Restless legs syndrome (RLS) is a common neurological disease. RLS has been linked to various psychiatric disorders, especially with attention deficit hyperactivity disorder (ADHD). AIMS: The main objective was to describe the frequency of RLS in pediatric patients diagnosed with ADHD. Secondary objectives of the study were describe other sleep disorders in ADHD patients. PATIENTS AND METHODS: A multicentre prospective study was conducted in nine Spanish centers. We included children aged 6-18 years diagnosed with ADHD between January and June 2015. Data were collected by 13 researchers doctors through an interview with the parent/caregiver and with the child. To assess the degree of functioning of patients with ADHD we used the Children's Global Assessment Scale. The Sleep Disturbance Scale for Children was applied to screening sleep disorders in childhood. RESULTS: A sample of 73 patients was collected. Five patients (6.8%) met diagnostic criteria for RLS: four of them definitive and one probable. CONCLUSIONS: RLS is a frequent condition in adulthood but also in adolescence and childhood. ADHD patients have an increased risk of an RLS. PMID- 28345735 TI - [Supratentorial cavernous malformations in an Argentinian institution: experience with surgical treatment]. AB - INTRODUCTION: Cavernous malformations are vascular malformations of the central nervous system formed by a group of capillaries not covered by pia mater and communicated to the vascular system at very low pressure with very slow flow. Surgery or radiosurgery are the treatment modalities. AIMS: To analyze our results after surgical treatment of supratentorial cavernous malformations, reviewing clinical presentation, surgical indications and postoperative complications. PATIENTS AND METHODS: Analytical retrospective study of medical records and images of patients who underwent resection of supratentorial cavernomas at FLENI from January 1996 until December 2013. RESULTS: We evaluated 51 patients, mean age 34 years, followed for an average of 30 months. In 1.96% of patients diagnosis was incidental, the rest all presented symptoms. Bleeding at diagnosis was observed in 23.52%. Total excision of supratentorial cavernous malformations was possible in all cases. The only postoperative complication was one case of meningitis. CONCLUSIONS: The bleeding rate of supratentorial cavernous malformations in our series was 1.38% per patient per year. Surgical treatment effectively eliminated, or at least reduced symptoms, prevented rebleeding, and decreased need for antiepileptic drug therapy. Surgery have a low complication rate and good outcome. PMID- 28345736 TI - [Kleine-Levin syndrome: differential diagnosis in recurrent encephalitic syndromes in adolescence]. AB - INTRODUCTION: The Kleine-Levin syndrome is a rare disease of unknown origin characterized by recurrent and self-limited episodes of hypersomnia that are also accompanied by a cognitive and behavioral dysfunction. Patients present normal sleeping and behavior patterns between episodes. CASE REPORTS: We present three patients who are 14 years old: two boys and one girl. They started having the episodes after a predisposing factor (vaccine, influenza B and menstruation). During the episode they presented hypersomnolence and while wakefulness they were bradipsychic, in motor restlessness and with emotional liability. They also presented a tendency towards crying and claimed the presence of relatives constantly. The episodes lasted between 10 and 15 days and they appeared monthly, being asymptomatic between episodes. All three patients were attended initially by pediatricians, diagnosed and treated as autoimmune encephalitis. Only one of our cases had the three typical symptoms of hypersomnia, hyperfagia and hypersexuality. However, none of the three had been asked initially and the family only referred to it after the directed anamnesis. CONCLUSIONS: The Kleine Levin syndrome presents neurologic symptoms initially more frequently than psychiatric ones. Hypersomnia and behavioural disturbances during wakefulness, bradypsychia, apatheia and emotional liability make us suspect that it could be an encephalitis process. We should be aware of this entity if we face a patient with recurrent encephalitis of unknown origin. PMID- 28345737 TI - [Meningeal carcinomatosis in breast cancer: from diagnosis to treatment]. AB - The appearance of meningeal carcinomatosis in breast cancer is an event that is being reported increasingly more frequently in the literature. It seems to be related with the lengthening of the patients' lives, improved sensitivity to diagnostic imaging and impermeability of the blood-brain barrier to the chemotherapeutic agents. It is an evolutionary form that affirms the metastatic invasion of the subarachnoidal space and is correlated with limited survival. Its diagnosis is difficult, due to the lack of specificity of the clinical signs dominated by headaches, cognitive disorders and possible signs and symptoms of progressive focal lesions. Magnetic resonance imaging of the brain and the spinal cord interpreted by a specialist in neuro-oncology is the preferred examination in this indication, in the search for an increase in meningeal enhancement. Biological analysis of the cerebrospinal fluid is an essential element in the diagnosis. In addition to the biochemical study, the presence of neoplastic cells is in itself enough to confirm the diagnosis. False negatives are very common and represent an important diagnostic problem that entails the need to repeat the lumbar punctures. The therapeutic methods are standard, often invasive, dominated by intrathecal chemotherapy and are based on low-level scientific evidence. This study analyses the epidemiology, the prognostic factors, the diagnostic tools, currently available treatments and the possible future therapies of meningeal carcinomatosis in breast cancer. PMID- 28345738 TI - [Exploring the dark continent: medical image and brain]. AB - INTRODUCTION: Until the late 19th century, direct observation of the central nervous system was practically impossible. The discovery of X-rays in 1895 and their subsequent application in the field of medicine brought about a shift of paradigm that completely revolutionised the way in which neurology was practised. The possibility of viewing the inside of the brain had a pronounced impact on clinical practice, and enriched the diagnosis and treatment of brain pathologies in a manner that was unimaginable up until then. DEVELOPMENT: The aim of this study is to describe the birth and development of medical imaging of the brain, from the discovery of X-rays and the early days of radiography to the appearance of computerised tomography and magnetic resonance in the 60s, both of which are techniques that were to change the world of diagnostic imaging forever. This brief overview of the history of radiology also includes the origins of angiography and other techniques that are no longer in use, but which were ground breaking innovations in their time, such as ventriculography or pneumoencephalography. CONCLUSIONS: The procedures and techniques described in this article made it possible to view the inside of the brain, thereby facilitating the diagnosis and treatment of a number of neurological processes. PMID- 28345739 TI - [Cervantes and Shakespeare, two Renaissance neurologists]. PMID- 28345740 TI - [Polymyositis secondary to a non-Hodgkin's lymphoma]. PMID- 28345742 TI - A qualitative exploration of chronic pain and opioid treatment among HIV patients with drug use disorders. AB - OBJECTIVE: The study explored high-risk participants' experiences with pain management regarding clinical access to and use of prescription opioids. DESIGN: Qualitative semistructured interviews and focus groups. SETTING: Data were collected August 2014 to May 2015 at an urban community-based research facility in Baltimore City, MD. PARTICIPANTS: HIV participants with chronic pain and a history of illicit drug use. METHODS: Qualitative coding and analysis used an iterative, inductive, and thematic approach and coders achieved inter-coder consistency. RESULTS: The authors identified two major themes. First, participants had positive and negative interactions with healthcare providers regarding chronic pain treatment. Participants perceived that providers lacked empathy for their pain and/or were not adequately managing their pain. These interactions resulted in participants seeking new providers or mistrusting the medical system. Further, providers' surveillance of participants' pain treatment regimen contributed to distress surrounding pain management. The second theme centered on participants' pain management experiences with prescribed opioid analgesics. Participants felt they were receiving dosages and classes of analgesics that did not sufficiently address their pain, and consequently modified their dosages or rationed prescription opioids. Other participants were reluctant to take analgesics due to their history of illicit drug use. Some participants relapsed to illicit drug use when they felt their prescription opioids did not adequately address their pain needs. CONCLUSIONS: Participant struggles with receiving and managing prescribed opioid analgesics suggest a need for: therapies beyond these medications; guidelines for providers specific to this population; and harm reduction trainings for providers. PMID- 28345743 TI - Opioids and nonopioids for postoperative pain control in patients with chronic kidney disease. AB - OBJECTIVES: To evaluate postoperative pain management (POPM) practices by anesthesiologists caring for patients with chronic kidney disease (CKD). DESIGN: Prospective one-time survey endorsed by the French Society of Anesthesia and Intensive Care (SFAR). SETTING: A self-administered online questionnaire was distributed to members of SFAR nationally. PARTICIPANTS: Three hundred seven SFAR members participated in the study. INTERVENTION: Close-ended questions concerned: standard test used to assess renal function, analgesic agent selection and dose adjustment based on the CKD functional stage, and the availability of standard operating procedures. MAIN OUTCOMES MEASURES: The primary end-point was to identify the most frequently prescribed analgesics in case of CKD, variations in practice based on different stages of CKD, and drug dosing adjustments. The secondary end-point was to identify the most commonly used tests to evaluate kidney function. RESULTS: The most commonly used postoperative analgesics were paracetamol (acetaminophen) and morphine. The most commonly used opioid was morphine, relative to oxycodone and sufentanil. Modification of diet in renal disease (MDRD) and Cockcroft equations were used by 39 and 40 percent of anesthesiologists, respectively, to measure kidney function. Six percent of anesthesiologists declared following standard operating procedures for POPM in patients with CKD. CONCLUSIONS: There is considerable variability in POPM practices for patients with all stages of CKD. Morphine is favored even in end stage renal disease. Departments of anesthesiology are insufficiently involved in drafting standard operating procedures. PMID- 28345744 TI - Eleven years of children methadone poisoning in a referral center: A review of 453 cases. AB - OBJECTIVES: Methadone can be fatal due to respiratory failure even in little doses. This study aimed to evaluate the possible risk factors of death and/or intubation in methadone-poisoned children of 12 years or younger. DESIGN: Retrospective routine database study. SETTING: The only tertiary hospital for children poisoning in Tehran. PATIENTS: Four hundred fifty-three methadone poisoned patients aged 12 or younger were studied between 2001 and 2012. MAIN OUTCOME MEASURES: In-hospital mortality and intubation/mechanical ventilation. RESULTS: Of a total of 475 children included, 22 were excluded due to coingestion of other drugs. Three (0.66 percent) expired and 12 (2.65 percent) were intubated during the course of hospital stay. Intubation (p < 0.001), fever (T axillary >= 37.5 degrees C, p = 0.01), being unresponsive at presentation (p = 0.02), tachycardia (p = 0.01), acidosis (p = 0.03), leukocytosis (p = 0.02), and longer hospital stay (p = 0.01) associated with death. Mortality (p < 0.001), fever (p = 0.004), aspartate aminotransferase (AST; p = 0.006), alanine transaminase (p = 0.04), creatinine (p = 0.005), corrected QT (QTc) interval in triage electrocardiogram (p = 0.02), and longer hospital stay (p = 0.005) associated with intubation in univariate analysis. However, after running regression analysis, only fever, QTc >= 480 ms, tachycardia, and AST independently associated with intubation and death. Axillary T >= 37.45 degrees C with an accuracy of 91.9 (95% confidence interval [CI] 88.8-94.2) and odds ratio of 9.3 (95% CI 2.5-34.9) predicted intubation, and T >= 37.75 with an accuracy of 96.0 (95% CI 93.5-97.5) and odds ratio of 47.4 (95% CI 4.1-550.1) predicted death. CONCLUSION: A methadone-poisoned child presenting with tachycardia, fever, abnormal AST, or an initial prolonged QTc interval should be managed with great caution. PMID- 28345745 TI - In vitro and in vivo assessment of the abuse potential of PF614, a novel BIO-MDTM prodrug of oxycodone. AB - OBJECTIVE: The need for pain medication which will not lead to abuse is well recognized. Ensysce has designed prodrug analogs of the commonly used pain medications including hydromorphone, oxycodone (OC), hydrocodone, and morphine that limit their use to oral delivery, two of which are in clinical development. This study was undertaken to demonstrate that PF614, an extended-release prodrug of OC, allows the release of OC as designed when delivered orally, yet it resists ex vivo extraction with household chemicals and is pharmacologically inactive when administered by nonoral routes (nasal and parenteral), thereby substantially reducing its intravenous (IV) and intranasal abuse potential. METHODS: In vitro and in vivo methods were used to determine release of OC from PF614 and to show potential u-opioid receptor activity. Plasma and cerebral spinal fluid levels of OC were evaluated following in vivo IV administration of PF614 in rats. In vitro extraction of OC from PF614 was explored using enzymes, common solvents, and household chemicals at room temperature and elevated temperature over time to determine release of OC from the prodrug. RESULTS: PF614 was stable with in vitro exposure to human plasma, saliva, and liver microsomes or culinary enzyme preparations. PF614 was stable (>=90 percent remaining as intact prodrug) under all room temperature conditions evaluated for 24 hours. At 80 degrees C for 1 hour, no OC was released. Incubation at 80 degrees C for 24 hours in vinegar or vodka produced a conversion to OC of 6 percent. Incubation with trypsin at 37 degrees C converted PF614 approximately stoichiometric to OC with half-life of 4 hours. PF614's penetration of the central nervous system was 83-fold lower than OC and it had a 6.5-fold reduced potency as a u-opioid agonist. Finally, oral PF614 delivers OC into plasma with an extended-release profile in dogs (reduced Cmax; delayed Tmax). CONCLUSIONS: The Bio-Activated Molecular Delivery prodrug design limits the use of PF614 to the intended oral route of delivery with reduced potential for IV or nasal abuse, as it cannot be activated intravenously or nasally to provide an active opioid. Unlike existing opioid formulations, the extended-release profile of PF614 cannot be accelerated by chewing or ex vivo extraction to pharmacologically active substances. PMID- 28345747 TI - Survey of opioid tapering practices of pediatric healthcare providers: A national perspective. AB - OBJECTIVE: The purpose of this study was to describe the current opioid tapering practice. DESIGN: Cross-sectional, online, survey research. PARTICIPANTS: Pediatric healthcare providers from a national sample of practicing nurse practitioners, physician assistants, and physicians who participate in five different pediatric pain and/or palliative care list serves. RESULTS: One hundred four participants responded to the survey. The respondents were predominantly physicians (n = 58, 62 percent). The majority of respondents worked in an academic children's medical center (n = 50, 52 percent). The average number of years in pediatric practice was 16 (mean = 16.33, range of 0-45 years). Of the 104 respondents, only 22 (27 percent) had a written protocol for opioid tapering. Use of expert consultants such as pharmacists or pediatric pain management teams varied. The majority of respondents (n = 46, 44 percent) seldom or never consult a pharmacist. Only 22 percent (n = 17) almost always or always consult a pediatric pain team. There was a wide range of personal tapering rate preferences. CONCLUSIONS: This study provided a baseline assessment of pediatric opioid tapering practices by pediatric healthcare providers. Results revealed a marked variation in practice patterns that may indicate deficits in the assessment and management of opioid withdrawal in children. The need for the development of assessment-based opioid tapering guidelines for the pediatric population is long overdue. PMID- 28345746 TI - An analysis of errors, discrepancies, and variation in opioid prescriptions for adult outpatients at a teaching hospital. AB - OBJECTIVE: To determine opioid-prescribing patterns and rate of three types of errors, discrepancies, and variation from ideal practice. DESIGN: Retrospective review of opioid prescriptions processed at an outpatient pharmacy. SETTING: Tertiary institutional medical center. PATIENTS: We examined 510 consecutive opioid medication prescriptions for adult patients processed at an institutional outpatient pharmacy in June 2016 for patient, provider, and prescription characteristics. MAIN OUTCOME MEASURE(S): We analyzed prescriptions for deviation from best practice guidelines, lack of two patient identifiers, and noncompliance with Drug Enforcement Agency (DEA) rules. RESULTS: Mean patient age (standard deviation) was 47.5 years (17.4). The most commonly prescribed opioid was oxycodone (71 percent), usually not combined with acetaminophen. Practitioners prescribed tablet formulation to 92 percent of the sample, averaging 57 (47) pills. We identified at least one error on 42 percent of prescriptions. Among all prescriptions, 9 percent deviated from best practice guidelines, 21 percent failed to include two patient identifiers and 41 percent were noncompliant with DEA rules. Errors occurred in 89 percent of handwritten prescriptions, 0 percent of electronic health record (EHR) computer-generated prescriptions, and 12 percent of non-EHR computer-generated prescriptions. Interrater reliability by kappa was 0.993. CONCLUSIONS: Inconsistencies in opioid prescribing remain common. Handwritten prescriptions continue to demonstrate higher associations of errors, discrepancies, and variation from ideal practice and government regulations. All computer-generated prescriptions adhered to best practice guidelines and contained two patient identifiers, and all EHR prescriptions were fully compliant with DEA rules. PMID- 28345748 TI - Risk perception and perceived self-efficacy of deaf and hard-of-hearing seniors and young adults in emergencies. AB - OBJECTIVES: The authors explored the factors influencing risk perception and perceived self-efficacy before and during an emergency for deaf and hard-of hearing (Deaf/HH) seniors and young adults. METHODS: The authors collected demographic survey data and conducted four focus groups with 38 Deaf/HH residents of the San Francisco Bay Area; two groups were with young adults (ages 18-35), including one group of college students and one group of young professionals, and two were with older adults (ages 50-90). RESULTS: Significant differences were found between Deaf/HH young adults and seniors in both the sources of self efficacy and risk perception and their attitudes toward preparedness. All groups demonstrated high resilience. Deaf/HH young professionals expressed more concern about their risk in an emergency than Deaf/HH college students. Alternately, the risk perception of Deaf/HH older adults was often rooted in their past experiences (survival of past emergencies, inaccessibility of communications during drills). CONCLUSIONS: Policy implications include the need to dedicate more resources to increasing accessibility and relevance of emergency communications technology for Deaf/HH populations. This could help increase adaptability before, during, and after emergencies among all groups of Deaf/HH people, particularly among young Deaf/HH professionals. PMID- 28345749 TI - The use of social media for campus safety. AB - As public safety communication evolved, each disaster or emergency presented unique challenges for emergency managers and others response to disasters. Yet, a foundational focus is the timely dissemination of accurate information to keep communities informed and able to prepare, mitigate, respond, and recover. For the campus community, the increase in bomb threats, active shooter incidents, and geographic-based natural disasters call for the discovery of reliable and cost effective solutions for emergency information management. Social media is becoming a critical asset in this endeavor. This article examines the evolution of public safety communication, the unique setting of the campus community, and social media's role in campus disaster resilience. In addition, an exploratory study was done to better understand the perception of social media use for public safety within the campus community. The findings provide practical recommendations for campus emergency management professions; however, future research is needed to provide specific, actionable ways to achieve these goals as well as understand how diverse universities utilize a variety of platforms. PMID- 28345750 TI - Subway emergency preparedness in Shanghai: A focused group and interview study exploring the perceived experiences of senior citizens and the disabled. AB - As Shanghai's population increases and currently being boosted by an influx of foreigners, there has been pressure on the subway system and this has led to a great concern for the aged and disabled people (including foreigners) who use the subway during emergency situations. The present study uses an exploratory research approach including a focus group discussion (FGD) and interviews to uncover the experiences, safety concerns, and challenges that the aged and disabled faces when using the subway. A total of 38 participants were involved in the study, which comprises of three FGDs and interviews conducted in the city of Shanghai. The findings reveal that most aged and disabled subway riders have little or no knowledge about emergency safety measures or safety symbols, the administering of first aid and have language barrier concerns. This study recommends that policy makers and sub-way operators should get the aged and disabled people involved in developing more educational programs that will help them to better the concept of safety prevention measures and it also suggests holding more emergency drills involving the aged and disabled. Braille language symbols, sign languages on TV screens, specially designed sub-way maps, low frequency alarms with flashing lights, and information printed in multiple international languages should also be provided to help foreigners understand the instructions and information in the subways. Additionally, these measures could help all commuters to feel safer when using the subway. PMID- 28345751 TI - Tsunami evacuation buildings and evacuation planning in Banda Aceh, Indonesia. AB - Indonesia, a country of more than 17,000 islands, is exposed to many hazards. A magnitude 9.1 earthquake struck off the coast of Sumatra, Indonesia, on December 26, 2004. It triggered a series of tsunami waves that spread across the Indian Ocean causing damage in 11 countries. Banda Aceh, the capital city of Aceh Province, was among the most damaged. More than 31,000 people were killed. At the time, there were no early warning systems nor evacuation buildings that could provide safe refuge for residents. Since then, four tsunami evacuation buildings (TEBs) have been constructed in the Meuraxa subdistrict of Banda Aceh. Based on analysis of evacuation routes and travel times, the capacity of existing TEBs is examined. Existing TEBs would not be able to shelter all of the at-risk population. In this study, additional buildings and locations for TEBs are proposed and residents are assigned to the closest TEBs. While TEBs may be part of a larger system of tsunami mitigation efforts, other strategies and approaches need to be considered. In addition to TEBs, robust detection, warning and alert systems, land use planning, training, exercises, and other preparedness strategies are essential to tsunami risk reduction. PMID- 28345752 TI - Recent field experiments with commercial satellite imagery direct downlink. AB - US Pacific Command's strategy includes assistance to United States government relief agencies and nongovernment organizations during humanitarian aid and disaster relief operations in the Asia-Pacific region. Situational awareness during these operations is enhanced by broad interagency access to unclassified commercial satellite imagery. The Remote Ground Terminal-a mobile satellite downlink ground station-has undergone several technology demonstrations and participated in an overseas deployment exercise focused on a natural disaster scenario. This ground station has received new commercial imagery within 20 minutes, hastening a normally days-long process. The Army Geospatial Center continues to manage technology development and product improvement for the Remote Ground Terminal. Furthermore, this ground station is now on a technology transition path into the Distributed Common Ground System-Army program of record. PMID- 28345753 TI - Outcomes of women diagnosed and treated for low-risk gestational trophoblastic neoplasia at the Queensland Trophoblast Centre (QTC). AB - BACKGROUND: Gestational trophoblastic neoplasia (GTN) is classified as a highly curable group of pregnancy-related malignancies; however, approximately 15% will be persistent and require chemotherapy. Up to 25% of these women will develop resistance and 2% will develop disease relapse after initial chemotherapy. Despite the need for further chemotherapy in these women, cure rates are high. OBJECTIVE: To evaluate the outcomes of women diagnosed with low-risk GTN, assessing the type of treatment, the number of chemotherapy cycles received, development of resistance or disease relapse, survival, and to assess the feasibility of changing to a new drug regimen. METHODS: From March 2012 until February 2015, a retrospective study was conducted and 38 cases with low-risk GTN were reviewed. The number of cycles, type of treatment received, duration of treatment, development of resistance and disease relapse, and adverse side effects were analysed. RESULTS: The median duration of follow-up was 12 months. Disease-free survival was 100% and primary complete remission rates were achieved in 85.3% of patients who were treated with actinomycin D and 25% patients who were treated with methotrexate (MTX). A change in chemotherapy was required for nine patients. One patient developed disease relapse. Nausea, fatigue and constipation were the most frequent adverse events reported with actinomycin D. All women were cured of their disease. CONCLUSION: All women were successfully treated and achieved complete remission. Changing from MTX to actinomycin D as first-line chemotherapy for women with low-risk GTN was feasible and safe. PMID- 28345754 TI - Second-to-fourth digit ratio (2D:4D) is unrelated to measures of somatic reproductive effort among young men from Cebu, the Philippines. AB - OBJECTIVES: A low second-to-fourth (2D:4D) digit ratio, a retrospective marker of high prenatal androgens, predicts increased investment in costly sexually dimorphic traits in men in some studies, although results are mixed. Here we test the hypothesis that the association of low 2D:4D ratios with increased muscularity and decreased adiposity depends on current testosterone (T) levels, such that digit ratio will be a particularly strong predictor of outcomes among men exhibiting a mating-effort-oriented endocrinological profile (high T). We also test the association between 2D:4D and somatic traits independently of T. MATERIALS AND METHODS: We related 2D:4D digit ratios, and their interaction with T, to handgrip strength, lean mass, arm muscle area, and skinfold thickness in a sample of young, childess men (20-22 y) from Cebu, Philippines (N = 623). RESULTS: Digit ratio did not significantly predict men's T-dependent somatic traits. Interactions between 2D:4D and morning T, similarly, did not predict male muscularity or adiposity. Although two of the interactions were significant or marginally significant (p < .1), after adjusting for multiple testing the evidence in support of our hypothesis was weak. DISCUSSION: We found no evidence that 2D:4D predicted measures of somatic reproductive effort in this sample of young men from Cebu, who as a group could be considered mostly mating-oriented. These relationships were also not contingent upon, or stronger, when considering the moderating effect of concurrent T levels. In this sample, 2D:4D was therefore either a poor proxy of prenatal androgen exposure or prenatal androgens had limited influence on adult somatic outcomes. PMID- 28345755 TI - Chilblain lupus erythematosus treated successfully with mycophenolate mofetil. PMID- 28345756 TI - The dawn of dentistry in the late upper Paleolithic: An early case of pathological intervention at Riparo Fredian. AB - OBJECTIVES: Early evidence for the treatment of dental pathology is found primarily among food-producing societies associated with high levels of oral pathology. However, some Late Pleistocene hunter-gatherers show extensive oral pathology, suggesting that experimentation with therapeutic dental interventions may have greater antiquity. Here, we report the second earliest probable evidence for dentistry in a Late Upper Paleolithic hunter-gatherer recovered from Riparo Fredian (Tuscany, Italy). MATERIALS AND METHODS: The Fredian 5 human consists of an associated maxillary anterior dentition with antemortem exposure of both upper first incisor (I1 ) pulp chambers. The pulp chambers present probable antemortem modifications that warrant in-depth analyses and direct dating. Scanning electron microscopy, microCT and residue analyses were used to investigate the purported modifications of external and internal surfaces of each I1 . RESULTS: The direct date places Fredian 5 between 13,000 and 12,740 calendar years ago. Both pulp chambers were circumferentially enlarged prior to the death of this individual. Occlusal dentine flaking on the margin of the cavities and striations on their internal aspects suggest anthropic manipulation. Residue analyses revealed a conglomerate of bitumen, vegetal fibers, and probable hairs adherent to the internal walls of the cavities. DISCUSSION: The results are consistent with tool assisted manipulation to remove necrotic or infected pulp in vivo and the subsequent use of a composite, organic filling. Fredian 5 confirms the practice of dentistry-specifically, a pathology-induced intervention-among Late Pleistocene hunter-gatherers. As such, it appears that fundamental perceptions of biomedical knowledge and practice were in place long before the socioeconomic changes associated with the transition to food production in the Neolithic. PMID- 28345757 TI - Parasites of orangutans (primates: ponginae): An overview. AB - Wild orangutan populations exist in an increasingly fragile state. As numbers continue to decline and populations became fragmented, the overall health of remaining individuals becomes increasingly at risk. Parasitic infections can have a serious impact on the health of wild orangutans, and can be fatal. It has been reported that rehabilitated individuals demonstrate a higher prevalence of parasitic diseases, and it is possible that they may spread these infections to wild orangutans upon reintroduction. In order to ensure the success of reintroduction and conservation efforts, it is crucial to understand the potential risks by fully understanding what parasites they have been reported to be infected with. Using this knowledge, future conservation strategies can be adapted to minimize the risk and prevalence of parasite transmission in the remaining orangutan populations. There is still limited information available on orangutan parasites, with several still not identified to the species level. Based on comprehensive literature review, we found 51 parasite taxa known to infect wild, semi-wild, and captive orangutans, including newly reported species. Here, we summarize methods used to identify parasites and draw conclusions relative to their reported prevalence. We also recommend fecal sample preservation and analytical methods to obtain best result in the future. PMID- 28345758 TI - Biodegradable gelatin/beta-tricalcium phosphate sponges incorporating recombinant human fibroblast growth factor-2 for treatment of recession-type defects: A split mouth study in dogs. AB - BACKGROUND AND OBJECTIVE: Tissue engineering by using recombinant human (rh) growth factor technology may offer a promising therapeutic approach for treatment of gingival recession. Fibroblast growth factor-2 (FGF-2) has shown the ability to promote periodontal regeneration. Gelatin/beta-tricalcium phosphate (gelatin/beta-TCP) sponges have been developed to control the release of growth factors. The present study evaluated the periodontal regenerative efficacy of rhFGF-2 by comparing gelatin/beta-TCP sponges incorporated with rhFGF-2 to the scaffolds alone in artificially created recession-type defects in dogs. MATERIAL AND METHODS: Critically sized buccal gingival recession defects were surgically created on maxillary canine teeth of five dogs. In each animal, defects were randomized to receive either a gelatin/beta-TCP sponge soaked with rhFGF-2 (gelatin/beta-TCP/rhFGF-2) or phosphate-buffered saline (gelatin/beta-TCP). Eight weeks after surgery, biopsy specimens were obtained and subjected to microcomputed tomography and histological analyses. RESULTS: Complete root coverage was achieved in both groups. Microcomputed tomography revealed significantly greater new bone volume in the gelatin/beta-TCP/rhFGF-2 group. Histologically, both groups achieved periodontal regeneration; however, gelatin/beta-TCP/rhFGF-2 sites exhibited more tissue regeneration, characterized by significantly larger amounts of new cementum and new bone. Gelatin/beta-TCP sites featured increased long junctional epithelium and connective tissue attachment. In the gelatin/beta-TCP/rhFGF-2 sites, new bone exhibited many haversian canals and circumferential lamellae as well as remarkably thick periosteum with blood vascularization and hypercellularity. CONCLUSION: Within the limitations of this study, rhFGF-2 in gelatin/beta-TCP sponges exhibits an increased potential to support periodontal wound healing/regeneration in canine recession-type defects. PMID- 28345759 TI - Stable carbon, oxygen, and nitrogen, isotope analysis of plants from a South Asian tropical forest: Implications for primatology. AB - Stable isotope analysis of primate tissues in tropical forest contexts is an increasingly popular means of obtaining information about niche distinctions among sympatric species, including preferences in feeding height, forest canopy density, plant parts, and trophism. However, issues of equifinality mean that feeding height, canopy density, as well as the plant parts and plant species consumed, may produce similar or confounding effects. With a few exceptions, researchers have so far relied largely on general principles and/or limited plant data from the study area as references for deducing the predominant drivers of primate isotope variation. Here, we explore variation in the stable carbon (delta13 C), nitrogen (delta15 N), and oxygen (delta18 O) isotope ratios of 288 plant samples identified as important to the three primate species from the Polonnaruwa Nature Sanctuary, Sri Lanka, relative to plant part, season, and canopy height. Our results show that plant part and height have the greatest effect on the delta13 C and delta18 O measurements of plants of immediate relevance to the primates, Macaca sinica, Semnopithecus priam thersites, and Trachypithecus vetulus, living in this monsoonal tropical forest. We find no influence of plant part, height or season on the delta15 N of measured plants. While the plant part effect is particularly pronounced in delta13 C between fruits and leaves, differential feeding height, and plant taxonomy influence plant delta13 C and delta18 O differences in addition to plant organ. Given that species composition in different regions and forest types will differ, the results urge caution in extrapolating general isotopic trends without substantial local baselines studies. PMID- 28345760 TI - Effect of temperature on lysosomal enzyme activity during preparation and storage of dried blood spots. AB - BACKGROUND: The use of dried blood spots (DBS) for the assay of lysosomal enzymes has facilitated the implementation of pilot studies for newborn screening for lysosomal storage disorders in various developed countries. The aim of the study was to determine the influence of ambient temperature during DBS preparation and storage on lysosomal enzyme activity in a developing, tropical country. METHODS: Blood samples from 12 healthy subjects collected on a S&S 903 filter paper were dried and stored at different temperatures for different periods of time. Activities of five lysosomal enzymes (acid alpha-glucosidase, acid alpha galactosidase, acid beta-glucocerebrosidase, acid sphingomyelinase, and galactocerebrosidase) were determined by tandem mass spectrometric and fluorimetric (acid alpha-glucosidase and acid beta-glucocerebrosidase only) assays. RESULTS: The mean activities of all five enzymes decreased significantly when DBS was dried at temperatures above 24 degrees C (P<.0001). DBS stored at 4 degrees C, 24 degrees C, 30 degrees C, 37 degrees C, and 45 degrees C for 10 days and more, also showed significant reduction in activities of all five enzymes (P<.0001). CONCLUSION: The results highlight the importance of maintaining the correct ambient temperature during DBS preparation and storage to avoid false positive results when screening for lysosomal storage disorders. PMID- 28345761 TI - Shifting diet, shifting culture? A bioarchaeological approach to island dietary development on Iron-Age Oland, Baltic Sea. AB - OBJECTIVES: The diet and subsistence in Iron-Age Oland is debated as earlier studies and different archaeological sources seemingly provide conflicting interpretations. The objectives of this study are therefore to: (i) add new insights on diet and (ii) investigate the chronological variation in detail. It is common in studies of diet to investigate differences between datasets defined by archaeological periods (determined by artefact typology), but it is rare to explore whether these dietary changes are, in fact, well correlated with these temporal categories or not. MATERIALS AND METHODS: Stable isotope analysis of 108 individuals and 25 animals was used to interpret diet in comparison with data from earlier studies. Different values of TLE (Trophic Level Effect) for delta15 N were compared for interpretations of diet. Of the 108 individuals, 42 were subjected to 14 C analysis in this study. RESULTS: The isotopes from Iron-Age animals on Oland indicate that the local, contemporary ecology is specific. The human isotope values show chronological development both when pooled in chronological groups by typology and by more specific 14 C chronology. DISCUSSION: The new samples of animals as well as the use of 50/00 TLE for delta15 N values results in the diet reinterpreted as mainly domesticate-based, with at least two shifts in diet occurring in the Iron Age. The use of 14 C dates in connection with the stable isotope results indicates a dietary transition occurring between 200 BC and AD 200, a date range that spans two typologically determined time periods. PMID- 28345762 TI - Short-term effects of a low carbohydrate diet on glycaemic variables and cardiovascular risk markers in patients with type 1 diabetes: A randomized open label crossover trial. AB - The aim of the present study was to assess the effects of a high carbohydrate diet (HCD) vs a low carbohydrate diet (LCD) on glycaemic variables and cardiovascular risk markers in patients with type 1 diabetes. Ten patients (4 women, insulin pump-treated, median +/- standard deviation [s.d.] age 48 +/- 10 years, glycated haemoglobin [HbA1c] 53 +/- 6 mmol/mol [7.0% +/- 0.6%]) followed an isocaloric HCD (>=250 g/d) for 1 week and an isocaloric LCD (<=50 g/d) for 1 week in random order. After each week, we downloaded pump and sensor data and collected fasting blood and urine samples. Diet adherence was high (225 +/- 30 vs 47 +/- 10 g carbohydrates/d; P < .0001). Mean sensor glucose levels were similar in the two diets (7.3 +/- 1.1 vs 7.4 +/- 0.6 mmol/L; P = .99). The LCD resulted in more time with glucose values in the range of 3.9 to 10.0 mmol/L (83% +/- 9% vs 72% +/- 11%; P = .02), less time with values <=3.9 mmol/L (3.3% +/- 2.8% vs 8.0% +/- 6.3%; P = .03), and less glucose variability (s.d. 1.9 +/- 0.4 vs 2.6 +/ 0.4 mmol/L; P = .02) than the HCD. Cardiovascular markers were unaffected, while fasting glucagon, ketone and free fatty acid levels were higher at end of the LCD week than the HCD week. In conclusion, the LCD resulted in more time in euglycaemia, less time in hypoglycaemia and less glucose variability than the HCD, without altering mean glucose levels. PMID- 28345763 TI - The role of Runx2 in facilitating autophagy in metastatic breast cancer cells. AB - Breast cancer metastases cause significant patient mortality. During metastases, cancer cells use autophagy, a catabolic process to recycle nutrients via lysosomal degradation, to overcome nutritional stress for their survival. The Runt-related transcription factor, Runx2, promotes cell survival under metabolic stress, and regulates breast cancer progression and bone metastases. Here, we identify that Runx2 enhances autophagy in metastatic breast cancer cells. We defined Runx2 function in cellular autophagy by monitoring microtubule-associated protein light chain (LC3B-II) levels, an autophagy-specific marker. The electron and confocal microscopic analyses were utilized to identify alterations in autophagic vesicles. The Runx2 knockdown cells accumulate LC3B-II protein and autophagic vesicles due to reduced turnover. Interestingly, Runx2 promotes autophagy by enhancing trafficking of LC3B vesicles. Our mechanistic studies revealed that Runx2 promotes autophagy by increasing acetylation of alpha-tubulin sub-units of microtubules. Inhibiting autophagy decreased cell adhesion and survival of Runx2 knockdown cells. Furthermore, analysis of LC3B protein in clinical breast cancer specimens and tumor xenografts revealed significant association between high Runx2 and low LC3B protein levels. Our studies reveal a novel regulatory mechanism of autophagy via Runx2 and provide molecular insights into the role of autophagy in metastatic cancer cells. PMID- 28345764 TI - The tarsal-metatarsal complex of caviomorph rodents: Anatomy and functional adaptive analysis. AB - Caviomorph rodents represent a major adaptive radiation of Neotropical mammals. They occupy a variety of ecological niches, which is also reflected in their wide array of locomotor behaviors. It is expected that this radiation would be mirrored by an equivalent disparity of tarsal-metatarsal morphology. Here, the tarsal-metatarsal complex of Erethizontidae, Cuniculidae, Dasyproctidae, Caviidae, Chinchillidae, Octodontidae, Ctenomyidae, and Echimyidae was examined, in order to evaluate its anatomical variation and functional-adaptive relevance in relation to locomotor behaviors. A qualitative study in functional morphology and a geometric morphometric analysis were performed. We recognized two distinct tarsal-metatarsal patterns that represent the extremes of anatomical variation in the foot. The first, typically present in arboreal species, is characterized by features that facilitate movements at different levels of the tarsal-metatarsal complex. The second pattern, typically present in cursorial caviomorphs, has a set of features that act to stabilize the joints, improve the interlocking of the tarsal bones, and restrict movements to the parasagittal plane. The morphological disparity recognized in this study seems to result from specific locomotor adaptations to climb, dig, run, jump and swim, as well as phylogenetic effects within and among the groups studies. PMID- 28345765 TI - A Synthetic Route to beta-Hydroxytyrosine-Derived Tetramic Acids: Total Synthesis of the Fungal Metabolite F-14329. AB - 3-Acyltetramic acids derived from beta-hydroxytyrosine are synthetically challenging. The first route to this structural motif, based upon a condensation between a Meldrum's acid conjugate bearing the acyl side chain, and a beta hydroxytyrosinate, N-protected by an ortho-nitrobenzyl group is presented. This group enables the Dieckmann cyclization of the resulting N-(beta-ketoacyl)amino ester, after which it can be removed photolytically without compromising the delicate 3'-hydroxy group. This strategy was applied to the first total synthesis of the fungal metabolite F-14329 (1). PMID- 28345766 TI - alpha-Linolenic acid and exercise training independently, and additively, decrease blood pressure and prevent diastolic dysfunction in obese Zucker rats. AB - KEY POINTS: alpha-linolenic acid (ALA) and exercise training both attenuate hyperlipidaemia-related cardiovascular derangements, however, there is a paucity of information pertaining to their mechanisms of action when combined. We investigated both the independent and combined effects of exercise training and ALA consumption in obese Zucker rats, aiming to determine the potential for additive improvements in cardiovascular function. ALA and exercise training independently improved cardiac output, end-diastolic volume, left ventricular fibrosis and mean blood pressure following a 4 week intervention. Combining ALA and endurance exercise yielded greater improvements in these parameters, independent of changes in markers of oxidative stress or endogenous anti oxidants. We postulate that divergent mechanisms of action may explain these changes: ALA increases peripheral vasodilation, and exercise training stimulates angiogenesis. ABSTRACT: Although alpha-linolenic acid (ALA) and endurance exercise training independently attenuate hyperlipidaemia-related cardiovascular derangements, there is a paucity of information pertaining to their mechanisms of action and efficacy when combined as a preventative therapeutic approach. Therefore, we used obese Zucker rats to investigate the independent and combined effects of these interventions on cardiovascular disease. Specifically, animals were randomly assigned to one of the following groups: control diet-sedentary, ALA supplemented-sedentary, control diet-exercise trained or ALA supplemented exercise trained. Following a 4 week intervention, although the independent and combined effects of ALA and exercise reduced (P < 0.05) the serum free/esterified cholesterol ratio, only the ALA supplemented-exercise trained animals displayed a reduction in the content of both serum free and esterified cholesterol. Moreover, although ALA and endurance training individually increased cardiac output, stroke volume and end-diastolic volume, as well as reduced left ventricle fibrosis, mean blood pressure and total peripheral resistance, these responses were all greater following the combined intervention (ALA supplemented-exercise trained). These effects occurred independent of changes in oxidative phosphorylation proteins, markers of oxidative stress or endogenous anti-oxidant capacity. We propose that the beneficial effects of a combined intervention occur as a result of divergent mechanisms of action elicited by ALA and endurance exercise because only exercise training increased the capillary content in the left ventricle and skeletal muscle, and tended to decrease protein carbonylation in the left ventricle (P = 0.06). Taken together, our data indicate that combining ALA and endurance exercise provides additional improvements in cardiovascular disease risk reduction compared to singular interventions in the obese Zucker rat. PMID- 28345767 TI - NLRP3 inflammasome: Its regulation and involvement in atherosclerosis. AB - Inflammasomes are intracellular complexes involved in the innate immunity that convert proIL-1beta and proIL-18 to mature forms and initiate pyroptosis via cleaving procaspase-1. The most well-known inflammasome is NLRP3. Several studies have indicated a decisive and important role of NLRP3 inflammasome, IL-1beta, IL 18, and pyroptosis in atherosclerosis. Modern hypotheses introduce atherosclerosis as an inflammatory/lipid-based disease and NLRP3 inflammasome has been considered as a link between lipid metabolism and inflammation because crystalline cholesterol and oxidized low-density lipoprotein (oxLDL) (two abundant components in atherosclerotic plaques) activate NLRP3 inflammasome. In addition, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and lysosome rupture, which are implicated in inflammasome activation, have been discussed as important events in atherosclerosis. In spite of these clues, some studies have reported that NLRP3 inflammasome has no significant effect in atherogenesis. Our review reveals that some molecules such as JNK-1 and ASK-1 (upstream regulators of inflammasome activation) can reduce atherosclerosis through inducing apoptosis in macrophages. Notably, NLRP3 inflammasome can also cause apoptosis in macrophages, suggesting that NLRP3 inflammasome may mediate JNK-induced apoptosis, and the apoptotic function of NLRP3 inflammasome may be a reason for the conflicting results reported. The present review shows that the role of NLRP3 in atherogenesis can be significant. Here, the molecular pathways of NLRP3 inflammasome activation and the implications of this activation in atherosclerosis are explained. PMID- 28345768 TI - Mycophenolate Mofetil and Rapamycin Induce Apoptosis in the Human Monocytic U937 Cell Line Through Two Different Pathways. AB - Transplant vasculopathy may be considered as an accelerated form of atherosclerosis resulting in chronic rejection of vascularized allografts. After organ transplantation, a diffuse intimal thickening is observed, leading to the development of an atherosclerosis plaque due to a significant monocyte infiltration. This results from a chronic inflammatory process induced by the immune response. In this study, we investigated the impact of two immunosuppressive drugs used in therapy initiated after organ transplantation, mycophenolate mofetil, and rapamycin, on the apoptotic response of monocytes induced or not by oxidized LDL. Here we show the pro-apoptotic effect of these two drugs through two distinct signaling pathways and we highlight a synergistic effect of rapamycin on apoptosis induced by oxidized LDL. In conclusion, since immunosuppressive therapy using mycophenolate mofetil or rapamycin can increase the cell death in a monocyte cell line, this treatment could exert similar effects on human monocytes in transplant patients, and thus, prevent transplant vasculopathy, atherosclerosis development, and chronic allograft rejection. J. Cell. Biochem. 118: 3480-3487, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28345769 TI - Best practice policy statement on urodynamic antibiotic prophylaxis in the non index patient. AB - AIMS: Antibiotic prophylaxis before urodynamic testing (UDS) is widely utilized to prevent urinary tract infection (UTI) with only limited guidance. The Society of Urodynamics, Female Pelvic Medicine, and Urogenital Reconstruction (SUFU) convened a Best Practice Policy Panel to formulate recommendations on the urodynamic antibiotic prophylaxis in the non-index patient. METHODS: Recommendations are based on a literature review and the Panel's expert opinion, with all recommendations graded using the Oxford grading system. RESULTS: All patients should be screened for symptoms of UTI and undergo dipstick urinalysis. If the clinician suspects a UTI, the UDS should be postponed until it has been treated. The first choice for prophylaxis is a single oral dose of trimethoprim sulfamethoxazole before UDS, with alternative antibiotics chosen in case of allergy or intolerance. Individuals who do NOT require routine antibiotic prophylaxis include those without known relevant genitourinary anomalies, diabetics, those with prior genitourinary surgery, a history of recurrent UTI, post-menopausal women, recently hospitalized patients, patients with cardiac valvular disease, nutritional deficiencies or obesity. Identified risk factors that increase the potential for UTI following UDS and for which the panel recommends peri-procedure antibiotics include: known relevant neurogenic lower urinary tract dysfunction, elevated PVR, asymptomatic bacteriuria, immunosuppression, age over 70, and patients with any indwelling catheter, external urinary collection device, or performing intermittent catheterization. Patients with orthopedic implants have a separate risk stratification. CONCLUSIONS: These recommendations can assist urodynamic providers in the appropriate use of antibiotics for UDS testing. Clinical judgment of the provider must always be considered. PMID- 28345770 TI - Effect of 1,25(OH)2 D3 and 20(OH)D3 on interleukin-1beta-stimulated interleukin-6 and -8 production by human gingival fibroblasts. AB - BACKGROUND AND OBJECTIVE: Vitamin D-1,25(OH)2 D3 or 1,25D3-maintains healthy osseous tissue, stimulates the production of the antimicrobial peptide cathelicidin and has anti-inflammatory effects, but it can cause hypercalcemia. Evidence links diminished serum levels of 1,25D3 with increased gingival inflammation. Periodontitis progression is associated with increased local production of inflammatory mediators by immune cells and gingival fibroblasts. These include interleukin (IL)-6, a regulator of osteoclastic bone resorption, and the neutrophil chemoattractant IL-8, both regulated by signaling pathways, including NF-kappaB and MAPK/AP-1. The objectives were to determine the effects of 1,25D3 or a non-calcemic analog, 20-hydroxyvitamin D3 -20(OH)D3 or 20D3-on IL 1beta-stimulated IL-6 and IL-8 production, and NF-kappaB and MAPK/AP-1 activation, by human gingival fibroblasts. MATERIAL AND METHODS: Human gingival fibroblasts were incubated +/- IL-1beta, with or without exposure to 1,25D3 or 20D3. IL-6 and IL-8 in culture supernatants were measured by enzyme-linked immunosorbent assay. NF-kappaB (p65) and AP-1 (phospho-cJun) and were measured in nuclear extracts via binding to specific oligonucleotides. Data were analyzed using ANOVA and Scheffe's F procedure for post hoc comparisons. RESULTS: IL-1beta stimulated IL-6 and IL-8 levels were both significantly inhibited (40%-60%) (P<.045) by 1,25D3, but not 20D3 (0%-15% inhibition, not statistically significant). Both 1,25D3 and 20D3 significantly and similarly inhibited IL-1beta stimulated nuclear levels of p65 and phospho-cJun (P<.02). CONCLUSION: Reduction of the activation of NF-kappaB and AP-1 alone is not able to inhibit strongly the IL-1beta stimulated IL-6 and IL-8 gene expression. 1,25D3 but not 20D3 may affect some of the many other factors/processes/pathways that in turn regulate the expression of these genes. However, the results suggest that topical application of ligands of the vitamin D receptor may be useful in the local treatment of periodontitis while reducing adverse systemic effects. PMID- 28345772 TI - The novel KIR3DS1*085 allele identified in a southern Chinese Han individual. AB - KIR3DS1*085 allele differs from the closest allele KIR3DS1*01301 at nucleotide 934 C>T in exon 5. PMID- 28345771 TI - Effect of intra-cellular trafficking on flow cytometric measurement of neutrophil's oxidative status in iron deficient pregnant females. AB - BACKGROUND: Iron deficiency and iron deficiency anemia are prevalent among pregnant women particularly in developing countries. This study aimed to evaluate the iron status among Egyptian pregnant women and its impact on their neutrophil's count and antimicrobial functions. METHOD: Ninety pregnant females underwent complete blood count, iron profile, flow cytometric studies for neutrophil myeloperoxidase expression & oxidative burst using dihydrorhodamine 123 (DHR) after phorbol-12-myristate-13-acetate (PMA) stimulation as well as neutrophil phagocytic and lytic indices. RESULTS: According to percent saturation 54/90 women (60%) were iron deficient (<15% saturation) (cases) and 36/90 (40%) were iron sufficient (controls). A higher proportion of iron deficient pregnant women were in their third trimester compared to controls. No significant difference was found between the iron deficient & sufficient groups as regards anemia despite a positive correlation between haemoglobin level and percent saturation (P=.02). Both the phagocytic and lytic indices were significantly lower among the cases compared to controls (P=.014 & .002 respectively). Cases and controls were comparable as regards flow cytometric studies of neutrophils' myeloperoxidase and oxidative burst (P>.05). No significant correlation was found between any of the iron profile parameters and the oxidative burst by flow cytometry. CONCLUSION: Functional microphage assay (phagocytic and lytic indices) may be more relevant and cost effective than flow cytometry assays of myeloperoxidase and oxidative burst in reflecting either iron status or cellular immunity in pregnancy. PMID- 28345773 TI - Screening for malnutrition in hospitalised older people: Comparison of the Mini Nutritional Assessment with its short-form versions. AB - OBJECTIVE: To determine how well the Mini Nutritional Assessment (MNA) Short Form (MNA-SF) performed as a nutritional screening tool when calf circumference replaced body mass index (BMI) as the included anthropometric measurement. METHODS: A total of 100 patients >=70 years were recruited from a Geriatric Evaluation and Management Unit. RESULTS: Mean age of patients was 85.2 (6.1) years. By the full MNA, 40% of patients were malnourished. The MNA correlated highly with both of its short-form versions (r = 0.87 and r = 0.90 for the BMI and calf circumference versions, respectively). Both MNA-SF versions also showed high accuracy in identifying malnutrition (auROC values >0.89). CONCLUSIONS: The MNA-SF is a rapid and accurate way to screen for malnutrition in hospitalised older adults. Substitution of BMI measurement with the time-efficient calf circumference measurement maintained MNA-SF accuracy. It is recommended that calf circumference measurement be used for nutritional screening by MNA-SF in a hospital setting. PMID- 28345775 TI - Quantification of the position and depth of the flexor hallucis longus groove in euarchontans, with implications for the evolution of primate positional behavior. AB - OBJECTIVE: On the talus, the position and depth of the groove for the flexor hallucis longus tendon have been used to infer phylogenetic affinities and positional behaviors of fossil primates. This study quantifies aspects of the flexor hallucis longus groove (FHLG) to test if: (1) a lateral FHLG is a derived strepsirrhine feature, (2) a lateral FHLG reflects inverted and abducted foot postures, and (3) a deeper FHLG indicates a larger muscle. METHODS: We used linear measurements of microCT-generated models from a sample of euarchontans (n = 378 specimens, 125 species) to quantify FHLG position and depth. Data are analyzed with ANOVA, Ordinary and Phylogenetic Generalized Least Squares, and Bayesian Ancestral State Reconstruction (ASR). RESULTS: Extant strepsirrhines, adapiforms, plesiadapiforms, dermopterans, and Ptilocercus exhibit lateral FHLGs. Extant anthropoids, subfossil lemurs, and Tupaia have medial FHLGs. FHLGs of omomyiforms and basal fossil anthropoids are intermediate between those of strepsirrhines and extant anthropoids. FHLG position has few correlations with pedal inversion features. Relative FHLG depth is not significantly correlated with body mass. ASRs support a directional model for FHLG position and a random walk model for FHLG depth. CONCLUSIONS: The prevalence of lateral FHLGs in many non-euprimates suggests a lateral FHLG is not a derived strepsirrhine feature. The lack of correlations with pedal inversion features suggests a lateral FHLG is not a sufficient indicator of strepsirrhine-like foot postures. Instead, a lateral FHLG may reduce the risk of tendon displacement in abducted foot postures on large diameter supports. A deep FHLG does not indicate a larger muscle, but likely reduces bowstringing during plantarflexion. PMID- 28345774 TI - Clinical features of trisomy 12 mosaicism-Report and review. AB - Trisomy 12 mosaicism is a rare condition. Herein, we report a patient with mosaic trisomy 12 who was conceived by in vitro fertilization. She presented with mild dysmorphic features at birth, including down-slanting palpebral fissures, a depressed and creased nasal bridge, and mild rhizomelic shortening of the limbs. She had age-appropriate development at 6 months of age, but displayed slightly more dysmorphic features than at birth. Chromosome analysis on peripheral blood revealed a normal female karyotype in 50 metaphases. A concurrent genomic microarray analysis showed trisomy 12 in about 25% of the specimen, which was also confirmed by fluorescence in situ hybridization analysis with the CEP12 probe. Our findings further delineate the clinical features in trisomy 12 mosaicism in liveborns and demonstrate the utility of genomic microarray analysis in identification of mosaic aneuploidies. PMID- 28345776 TI - Red blood cell distribution width and neutrophil to lymphocyte ratio are correlated with disease activity of dermatomyositis and polymyositis. AB - BACKGROUND: Previous studies indicated that both red blood cell distribution width (RDW) and neutrophil to lymphocyte ratio (NLR) were useful indices in assessing the disease activity of autoimmune diseases. However, the evidence for the association between RDW, NLR and dermatomyositis (DM) and polymyositis (PM) is limited. The aim of this study is to investigate the association between the disease activity of PM/DM and both RDW and NLR. METHODS: Medical records of 114 PM/DM patients and 114 healthy controls were retrospectively reviewed, and their RDW, NLR and myositis disease activity assessment visual analogue scale (MYOACT) on admission were extracted. The correlations between RDW, NLR and MYOACT were analyzed using the Spearman approach and multivariable model. RESULTS: PM/DM patients had significantly higher RDW and NLR. Increased RDW in PM/DM patients was not completely attributed to decreased hemoglobin or therapeutic agents. Both RDW and NLR are independently and positively correlated MYOACT. CONCLUSION: Both RDW and NLR are useful indices in assessing the disease activity of PM/DM. PMID- 28345777 TI - The relationship between cancer patients' place of death and bereaved caregivers' mental health status. AB - BACKGROUND: Although place of death has been recognized as a risk factor in caregivers' bereavement adjustment, the estimation of the effect of the place of death needs careful consideration about many potential cofounders. PATIENTS AND METHODS: This study was a nationwide cross-sectional questionnaire survey for bereaved family caregivers of patients with cancer who died in 3 settings: (1) hospice at home; (2) palliative care units (PCUs); and (3) acute hospitals. We assessed bereaved caregivers' depression, grief, insomnia, and the quality of dying of deceased patients across the 3 groups using propensity score weighting. RESULTS: A total of 8968 responses were analyzed. According to scores on Patient Health Questionnaire 9, depressive symptoms were significantly higher in bereaved caregivers of patients who had died in acute hospitals (5.7; 95% confidence interval [CI]: 5.3-6.2) than for those of patients who had died in hospice at home (4.8; 95% CI: 4.4-5.1) or PCU (5.1; 95% CI: 5.0-5.2). Grief symptoms measured by Brief Grief Questionnaire were also significantly higher in caregivers of patients who had died in acute hospitals (5.0; 95% CI: 4.8-5.2) than those of patients who had died in hospice at home (4.7; 95% CI: 4.5-4.9) or PCU (4.7; 95% CI: 4.7-4.8). Deceased patients' quality of dying was highest in hospice at home, and worst in acute hospital. CONCLUSIONS: The place where a cancer patient dies influences not only their quality of dying and death but also the mental health of their family caregivers. However, the absolute difference is not large after adjustment of multiple variables. PMID- 28345778 TI - Comparison of the efficacy of perineal and intravaginal biofeedback assisted pelvic floor muscle exercises in women with urodynamic stress urinary incontinence. AB - OBJECTIVE: To assess the effectiveness of intravaginal pressure biofeedback (P BF) and perineal electromyographic biofeedback (EMG-BF) assisted pelvic floor muscle (PFM) exercises in women with stress urinary incontinence (SUI). MATERIAL AND METHODS: Fifty-three women with SUI were randomized into three groups as follows: the Group 1 received PFM home exercise program alone (n:18); the Group 2 received PFM home exercise program plus intravaginal P-BF assisted PFM exercise program (n:17); and the Group 3 received PFM home exercise program plus perineal EMG-BF assisted PFM exercise program (n:18). Subjects were also assessed with the 1-h pad test (severity of incontinence), perineometer (PFM strength), social activity index (SAI), IIQ7 (quality of life associated with incontinence), treatment success (cure and improvement rate) and treatment satisfaction. RESULTS: A statistically significant improvement was found in all parameters for all groups at 4th week and 8th week compared to the baseline values. It was found that severity of incontinence, PFM strength, and SAI scores were significantly improved in both BF groups compared to the Group 1 at 8th week. Also, statistically higher cure and improvement rate and treatment satisfaction values were detected in both BF groups compared to the Group 1. There was no statistically significant difference between Group 2 and Group 3 in all parameters evaluated at the follow-up period. CONCLUSIONS: We conclude that both the home exercises plus intravaginal P-BF and home exercises plus perineal EMG-BF are superior to home exercises in women with SUI. Intravaginal P-BF and perineal EMG-BF were similarly effective and they can be used as their alternatives. PMID- 28345779 TI - Sacral neuromodulation for detrusor hyperactivity with impaired contractility. AB - INTRODUCTION: Detrusor hyperactivity with impaired contractility (DHIC) is a challenging condition to manage. Sacral neuromodulation (SNM) is a proven treatment modality for both the individual aspects of DHIC. To date, data reporting the outcome of SNM for DHIC are lacking. MATERIALS AND METHODS: Consecutive patients undergoing SNM for DHIC were followed prospectively, from April 2013 to October 2016. Patient demographics, bladder diaries, subjective response rates, ICIQ-OAB, and PGI-I scores were recorded. Success was defined as greater than 50% improvement in storage symptoms and a 50% improvement in voided volume or reduction of post-void residual volumes. RESULTS: Twenty patients underwent stage 1 trial of SNM for DHIC. Median age was 68.5, IQR (54.25-76.25). Thirteen (65%) patients were female. A total of 14/20 (70%) of patients had a significant treatment response, 9/20 had a response to both elements of DHIC, 4/20 patients had a response to the detrusor overactivity (DO) alone, and 1/20 had a response to the voiding component alone. A total of 12/20 (60%) patients proceeded to insertion of an IPG. At mean follow-up of 17 months, IQR (1.5-35), 11/12 (91.7%) of patients are still using the SNM for DHIC. Median PGI score is 2, IQR (2-4). SNM for DHIC resulted in statistically significant improvements in voided volume (P = 0.016), PVR (P = 0.0296), ICIQ-OAB score (P < 0.0001), and ICIQ-OAB bother score (P = 0.016) CONCLUSION: This is the first study we know of to report the results of SNM for DHIC. SNM is associated with satisfactory success rates, treating both the detrusor hyperactivity, and impaired contractility components of this condition. PMID- 28345780 TI - Lewis Acid Mediated Nazarov Cyclization as a Convergent and Enantioselective Entry to C-nor-D-homo-Steroids. AB - A straightforward synthesis of C-nor-D-homo steroids starting from (+)-Wieland Miescher ketone is reported. This convergent synthetic strategy utilizes a scalable diastereoselective Nazarov cyclization of functionalized chiral aryl vinyl ketones, allowing for further functionalization. The ability to conduct this key transformation on a multi-gram scale paves the way for the synthesis of a variety of completely new C-nor-D-homo steroids, without the need of a classic steran steroid rearrangement or achiral linear reaction sequences. PMID- 28345781 TI - Apoptotic pathways of macrophages within osteolytic interface membrane in periprosthestic osteolysis after total hip replacement. AB - Macrophage apoptosis in interface membrane, which occurs through either death receptor, mitochondrion, or endoplasmic reticulum (ER) stress pathways, has been suggested to play an important role in promoting osteolysis. However, how and why macrophage apoptosis originates and the correlation among these apoptotic pathways is not yet clear. The objective of this study was to identify the apoptotic mechanism of macrophages, and to explore the relationship between the apoptotic pathways and progression of osteolysis. Transmission electron microscopy (TEM) was utilized to analyze the tissue ultrastructure of wear particles, and in situ apoptotic macrophage identification was performed by TUNEL staining. We analyzed the expression of the key biomarkers of apoptotic pathways via immunohistochemistry and Western blotting. Our results demonstrated that the majority of wear particles within osteolytic interface membrane was in the 30-60 nm range, and that macrophage apoptotic ratio increased along with osteolysis progression. Normal hip dysplasia and mechanical loosening of tissues showed low expression levels of biomarkers for ER stress (Ca2+ , JNK, cleaved Caspase-4, IRE1-alpha, Grp78/Bip, and CHOP), mitochondrion (Bcl-2, Bax, and Cytochrome c), and death receptor (Fas and cleaved Caspase-8) pathways, while osteolytic interface membrane tissues expressed high levels of these biomarkers. In addition, we found that the ER stress intensity was in complete conformity with mitochondrial dysfunction and was consistent with the results of death receptor activation. Thus, our findings suggested that wear particles generated at implant interface can accelerate macrophage apoptosis through changes in apoptotic pathways and ultimately aggravate the symptom of osteolysis. These data represent a preferential apoptotic signaling pathway of macrophages as specific target points for the prevention and therapeutic modulation of periprosthetic osteolysis. PMID- 28345783 TI - Natural tolerance development in cow's milk allergic children: IgE and IgG4 epitope binding. AB - BACKGROUND: Although most of cow's milk (CM) allergic children will outgrow their allergy, the pathomechanism of the natural development of tolerance remains poorly understood. It has been suggested that the balance between milk-specific IgE and IgG4 plays a major role. OBJECTIVE: We aimed to investigate differences in IgE and IgG4 antibody binding to CM epitopes between patients with persistent CM allergy (CMA) and those that naturally became tolerant. METHODS: Sera from 35 children with proven CMA (median age at inclusion of 10 months) were analyzed retrospectively; 22 patients have become tolerant (median age at tolerance acquisition of 51 months) during the study period as confirmed by a negative oral food challenge. IgE and IgG4 binding to sequential epitopes derived from five major CM proteins were measured with a peptide microarray-based immunoassay. RESULTS: At baselines, greater intensity and broader diversity of IgE and IgG4 binding have been found in children with persistent CMA beyond 5 years of age compared to patients with transient CMA. Moreover, children with transient CMA had IgE and IgG4 antibodies that more often recognized the same epitopes, compared to those with persistent CMA. From baseline to the time of tolerance development, both IgE and IgG4 binding intensity decreased significantly, particularly in areas of alpha-s- and beta-casein (P<.01, false discovery rate [FDR]<.1). Interestingly, differences between IgE and IgG4 binding intensity to CM peptides decreased when the patients became tolerant. CONCLUSIONS: Our results suggest that the overlap between IgE and IgG4 might be important in natural tolerance acquisition. Further studies are needed to confirm our data and can eventually lead to development of more targeted treatment of food allergy. PMID- 28345782 TI - Red cell distribution width as a novel predictor of postoperative respiratory adverse events after adenotonsillectomy. AB - BACKGROUND: Respiratory adverse events are commonly observed after adenotonsillectomy in children with sleep-disordered breathing. Preoperative prediction of these events enhances quality of care and resource management in facilities while encouraging precautions against them. Red cell distribution width, a measure of erythrocyte size variability, has recently been linked to adverse outcomes in a variety of disorders. Red cell distribution width has also been found to be associated with severity of obstructive sleep apnea in adults due to hypoxia-mediated inflammation. AIM: The objective of this study was to evaluate whether elevated red cell distribution width is associated with postoperative respiratory adverse events in children with symptoms of sleep disordered breathing. METHODS: A prospective, observational, assessor-blinded study was conducted with consecutive children undergoing elective adenotonsillectomy for treatment of sleep-disordered breathing. Under general anesthesia, adenoidectomy was performed by curettage, and tonsillectomy was carried out by dissection. The primary outcome was the occurrence of an adverse event during emergence or in the postanesthesia care unit (PACU). RESULTS: Among 287 patients, with mean +/- sd age 7.49 +/- 3.21, the frequency of respiratory complications during emergence was 62 (22.30%) and in PACU was 56 (20.14%). Mean +/- sd red cell distribution width was 14.36 +/- 1.06 in patients with complications and higher than that in those without complications 13.53 +/- 0.59. Red cell distribution width had an adjusted odds ratio 7.28 (95% CI: 4.30-13.28) and area under the curve value 0.74 (95% CI: 0.67-0.81) to predict postoperative complications. A cutoff value for red cell distribution width was found to be 14.7. CONCLUSION: Our study showed that preoperative elevated red cell distribution width is associated with an increased risk of respiratory adverse events in children undergoing adenotonsillectomy for sleep-disordered breathing. PMID- 28345784 TI - Quality of Life in Cervical Cancer Survivors and Healthy Women: Thai Urban Population Study AB - Background : To determine a baseline quality of life (QoL) in cervical cancer survivors compared to that of healthysubjects in the tertiary Thammasat University Hospital, Thailand. Materials and Methods: The investigation wasconducted at the outpatient gynecological department of Thammasat University Hospital between January and June2016. A total of 192 women were entered into the study (97 cervical cancer survivors; 37 after radical hysterectomy(RH), 43 with concurrent chemoradiation (CRT), and 17 featuring both RH and CRT; and 95 control subjects from thesame outpatient department with no history of malignancy). Participant QoL was assessed using a Thai version of theEORTC-QLQ-C30 (European Organization for Research Treatment of Cancer Quality-of-Life) and a general survey forthe assessment of sociodemographic data was also conducted. Results: There were significant differences in physical,role, emotional and social functions between cervical cancer survivor and control groups. Global health, fatigue, pain,appetite loss, and financial difficulties also demonstrated statistically significant variation. Cervical cancer survivorstreated by RH had higher scores for emotional and social function and global health than the control group. Moreover,they had less appetite loss, fatigue and financial difficulties. However, patients treated with CRT experienced morepain than the control group. All cervical cancer survivors had lower physical function scores than the control group.Conclusion: Quality of life in cervical cancer survivors is better than in healthy peers in some domains. Cervical cancersurvivors treated with RH may have a better QoL than healthy peers. Early detection for early stage cervical cancerremains most important because treatment in early stages does not cause lowering of the QoL. PMID- 28345785 TI - NANOG overexpression and its correlation with stem cell and differentiation markers in meningiomas of different WHO grades. AB - NANOG, as a key regulator of pluripotency and acting synergistically with other factors, has been described as a crucial transcription factor in various types of cancer. In meningiomas the expression of this marker has not yet been described. With our study, we aimed to identify and localize NANOG and other possible markers of pluripotency, stem cell properties and differentiation in meningioma tissue, to elucidate a possible effect on tumorigenesis. The gene expression levels of NANOG (NANOG1 and NANOGP8), SOX2, OCT4, KLF4, ABCG2, CMYC, MSI1, CD44, NOTCH1, NES, SALL4B, TP53, and EPAS1 were quantitatively examined using RT-qPCR in 33 surgical specimens of low- (WHO grade I) as well as in high-grade (WHO grade II/III) meningiomas with dural tissue as reference. Immunofluorescence co localization analysis following confocal fluorescence microscopy for NANOG, OCT4, SOX2, Nestin, KI-67, and CD44 was also performed. There was a significant overexpression of NANOG, MSI1, and EPAS1 and a downregulation of NES in all examined tumors. Subgroup analysis (WHO grade I versus grade II/III) revealed differences in the expression of NANOG, CD44, and MSI1. We found 1% NANOG positive (NANOG+) cells in low-grade and 2% in grade II/III meningiomas co expressing the other mentioned markers in various compositions. In particular, NANOG+ cells expressing SOX2 and OCT4 were successfully identified (26% low-grade versus 20% high-grade). Our data reveal an overexpression of NANOG and other markers of pluripotency and stemness in meningiomas. Such potentially pluripotent "stem cell-like" cells may have an impact on tumorigenesis and progression in human meningiomas. PMID- 28345786 TI - A de novo nonsense mutation in ZBTB18 plus a de novo 15q13.3 microdeletion in a 6 year-old female. AB - ZBTB18 has been proposed as candidate gene for microcephaly and abnormalities of the corpus callosum based on overlapping microdeletions of 1q43q44. More recently, de novo mutations of ZBTB18 have been identified in patients with syndromic and non-syndromic intellectual disability. Heterozygous microdeletions of 15q13.3 encompassing the candidate gene CHRNA7 are associated with developmental delay or intellectual disability with speech problems, hypotonia, and seizures. They are characterized by significant variability and reduced penetrance. We report on a patient with a de novo ZBTB18 nonsense mutation and a de novo 15q13.3 microdeletion, both in a heterozygous state, identified by next generation sequencing and array-CGH. The 6-year-old girl showed global developmental delay, absent speech, therapy-refractory seizures, ataxia, muscular hypotonia, and discrete facial dysmorphisms. Almost all of these features have been reported for both genetic aberrations, but the severity could hardly been explained by the microdeletion 15q13.3 alone. We assume an additive effect of haploinsufficiency of ZBTB18 and CHRNA7 in our patient. Assembling the features of our patient and the published patients, we noted that only one of them showed mild anomalies of the corpus callosum. Moreover, we hypothesize that nonsense mutations of ZBTB18 are associated with a more severe phenotype than missense mutations. This report indicates that haploinsufficiency of additional genes beside ZBTB18 causes the high frequency of corpus callosum anomalies in patients with microdeletions of 1q43q44 and underlines the importance of an NGS-based molecular diagnostic in complex phenotypes. PMID- 28345787 TI - Non-motor symptoms and quality of life in subjects with mild parkinsonian signs. AB - BACKGROUND: Mild parkinsonian signs (MPS) are frequent in the elderly population and associated with the presence of risk markers for Parkinson's disease (PD). Both MPS and non-motor signs may be present in prodromal PD and may significantly impair quality of life (QoL). OBJECTIVE: To disentangle the contribution of motor impairment and extra-motor manifestations to QoL in subjects with MPS (n=63), manifest PD (n=69), disorders with motor symptoms due to non-neurodegenerative diseases (n=213) and healthy controls (n=258). METHODS: Subjects with MPS, healthy controls, disease controls (patients with motor impairment due to, eg, arthrosis and spondylosis), and PD patients (total n=603) were selected from a large epidemiological longitudinal study, the EPIPARK cohort. Motor function was determined using the UPDRSIII protocol, and information on depressive symptoms, anxiety, sleep, and QoL was assessed via rating scales and data were analyzed. RESULTS: Depressive symptoms, anxiety, and sleep problems were equally frequent in the MPS group and controls. Health-related QoL was slightly reduced in the MPS group. Motor impairment and its extent was comparable between the MPS group and disease controls (UPDRSIII 5-6 points). Higher motor dysfunction was associated with lower QoL. Depressive symptoms, but not anxiety and daytime sleepiness, was significant predictors of general QoL, independent of motor function. CONCLUSIONS: Quality of life is slightly decreased in an elderly population with MPS. QoL is associated with severity of motor impairment but also with non-motor aspects, ie, depressive symptoms. Follow-up studies in large cohorts are warranted to determine the natural course of MPS and its impact on QoL. PMID- 28345788 TI - Horticultural activity predicts later localized limb status in a contemporary pre industrial population. AB - OBJECTIVES: Modern humans may have gracile skeletons due to low physical activity levels and mechanical loading. Tests using pre-historic skeletons are limited by the inability to assess behavior directly, while modern industrialized societies possess few socio-ecological features typical of human evolutionary history. Among Tsimane forager-horticulturalists, we test whether greater activity levels and, thus, increased loading earlier in life are associated with greater later life bone status and diminished age-related bone loss. MATERIALS AND METHODS: We used quantitative ultrasonography to assess radial and tibial status among adults aged 20+ years (mean +/- SD age = 49 +/- 15; 52% female). We conducted systematic behavioral observations to assess earlier-life activity patterns (mean time lag between behavioural observation and ultrasound = 12 years). For a subset of participants, physical activity was again measured later in life, via accelerometry, to determine whether earlier-life time use is associated with later-life activity levels. Anthropometric and demographic data were collected during medical exams. RESULTS: Structural decline with age is reduced for the tibia (female: -0.25 SDs/decade; male: 0.05 SDs/decade) versus radius (female: 0.56 SDs/decade; male: -0.20 SDs/decade), which is expected if greater loading mitigates bone loss. Time allocation to horticulture, but not hunting, positively predicts later-life radial status (betaHorticulture = 0.48, p = 0.01), whereas tibial status is not significantly predicted by subsistence or sedentary leisure participation. DISCUSSION: Patterns of activity- and age-related change in bone status indicate localized osteogenic responses to loading, and are generally consistent with the logic of bone functional adaptation. Nonmechanical factors related to subsistence lifestyle moderate the association between activity patterns and bone structure. PMID- 28345789 TI - Childhood body mass index and development of type 2 diabetes throughout adult life-A large-scale danish cohort study. AB - OBJECTIVE: This study investigated how a wide spectrum of body mass index (BMI) values at ages 7 to 13 years are associated with type 2 diabetes throughout adulthood, including potential modifying effects of sex and birth weight. METHODS: From the Copenhagen School Health Records Register, 292,827 individuals, born between 1930 and 1989, were followed in national registers for type 2 diabetes (women, n = 7,472; men, n = 11,548). Heights and weights were measured at ages 7 to 13 years. RESULTS: Below-average BMIs, with few exceptions, were not associated with type 2 diabetes. Above-average BMIs had positive associations that were stronger in women than men, stronger in younger birth cohorts, and weaker with older age at diagnosis. Women born 1930-1947, 1948-1965, and 1966 1983 with above-average BMIs at 13 years (>=18.2 kg/m2 ) had hazard ratios (95% confidence intervals) ranging from 2.12 (1.91-2.36) to 2.84 (2.31-3.49) per z score when diagnosed at 30 to 47 years. Birth weight did not modify these associations. CONCLUSIONS: Childhood BMIs below average are not associated with type 2 diabetes, whereas childhood BMIs above average are strongly associated with type 2 diabetes in adulthood, corresponding to excess risks even at levels below international definitions of overweight. The associations are stronger in women than men but are not affected by birth weight. PMID- 28345791 TI - Trichoscopic diagnosis of cutaneous Pelodera strongyloides infestation in a dog. AB - BACKGROUND: Pelodera strongyloides infestation has rarely been reported in dogs. It is a saprophytic free-living nematode, found in moist decaying organic matter, whose L3 larval stages occasionally can invade the skin of dogs and humans. Larvae penetrate the follicular infundibula causing an erythematous and pruritic dermatitis. The disease is usually diagnosed by deep skin scraping or histopathology, with large numbers of parasites readily identified in hair follicles. CASE REPORT: Pelodera strongyloides dermatitis was diagnosed in a six year-old mixed breed dog presenting with alopecia, erythema and severe pruritus on the ventrum and limbs. The infestation was diagnosed by microscopic examination of plucked hair shafts and confirmed on microscopic examination of skin biopsies collected for histopathology. Only two of 10 deep skin scrapings gave positive findings. The nematode infestation was eradicated following two applications, 2 weeks apart, of a moxidectin/imidacloprid spot-on product. CONCLUSION AND CLINICAL IMPORTANCE: Skin scrapings are considered the diagnostic test of choice for P. strongyloides infestations. In this case, parasites were identified by hair trichograms more readily than by skin scrapings. PMID- 28345790 TI - Metabolic responses to exogenous ghrelin in obesity and early after Roux-en-Y gastric bypass in humans. AB - AIMS: Ghrelin is a gastric-derived hormone that stimulates growth hormone (GH) secretion and has a multi-faceted role in the regulation of energy homeostasis, including glucose metabolism. Circulating ghrelin concentrations are modulated in response to nutritional status, but responses to ghrelin in altered metabolic states are poorly understood. We investigated the metabolic effects of ghrelin in obesity and early after Roux-en-Y gastric bypass (RYGB). MATERIALS AND METHODS: We assessed central and peripheral metabolic responses to acyl ghrelin infusion (1 pmol kg-1 min-1 ) in healthy, lean subjects (n = 9) and non-diabetic, obese subjects (n = 9) before and 2 weeks after RYGB. Central responses were assessed by GH and pancreatic polypeptide (surrogate for vagal activity) secretion. Peripheral responses were assessed by hepatic and skeletal muscle insulin sensitivity during a hyperinsulinaemic-euglycaemic clamp. RESULTS: Ghrelin stimulated GH secretion was attenuated in obese subjects, but was restored by RYGB to a response similar to that of lean subjects. The heightened pancreatic polypeptide response to ghrelin infusion in the obese was attenuated after RYGB. Hepatic glucose production and hepatic insulin sensitivity were not altered by ghrelin infusion in RYGB subjects. Skeletal muscle insulin sensitivity was impaired to a similar degree in lean, obese and post-RYGB individuals in response to ghrelin infusion. CONCLUSIONS: These data suggest that obesity is characterized by abnormal central, but not peripheral, responsiveness to ghrelin that can be restored early after RYGB before significant weight loss. Further work is necessary to fully elucidate the role of ghrelin in the metabolic changes that occur in obesity and following RYGB. PMID- 28345793 TI - Small Molecules from Deep within the Gut. AB - Although the influence of the human microbiome on host functions is widely recognized, the underlying molecular mechanisms are still largely unknown. A recent study by the Fischbach group now provides an experimental workflow for characterizing and evaluating the impact of microbiome-derived small molecules on host physiology. PMID- 28345794 TI - The relationship between the biovars and the antimicrobial resistance of Ureaplasma urealyticum in female patients with urogenital infections. AB - BACKGROUND: Ureaplasma urealyticum is considered as one of the main pathogens found in women with urogenital infection. This study aimed to investigate the relationship between the biovars, serovars, and their antimicrobial resistance against antibiotics in female patients with urogenital infection. METHODS: Two hundred and forty-six cervical secretion samples (125 female outpatients as the patient group, 121 healthy female subjects as the control group) were first collected and analyzed for U. urealyticum using the Mycoplasma Identification and Antimicrobial Susceptibility Testing; then polymerase chain reaction (PCR) was carried out to identify the biovars and serovars of U. urealyticum-positive samples. RESULTS: The prevalence of U. urealyticum in the patient group (57. 60%) was higher than that in the control group (24.79%, P<.01). The main biovar was biovar 1, and the main serovars were 1 (S1), 3 (S3), 6 (S6) in biovar 1. Mixed infection was observed in biovar 2. According to the results of Antimicrobial Susceptibility Testing in the patient group, biovar 1 shows more resistance to minocycline, doxycycline, and azithromycin than biovar 2 (P<.05). Serovars S1, S3 and S6 have the highest resistant rate to ofloxacin (84.38%), roxithromycin (84.62%), and azithromycin (90.90%), respectively. CONCLUSIONS: A high prevalence of U. urealyticum was observed in female patients with urogenital infections. And the biovar 1 and the serovars 1, 3, 6 were the main types of pathogens. PMID- 28345792 TI - Adding fast-acting insulin aspart to basal insulin significantly improved glycaemic control in patients with type 2 diabetes: A randomized, 18-week, open label, phase 3 trial (onset 3). AB - AIM: To confirm glycaemic control superiority of mealtime fast-acting insulin aspart (faster aspart) in a basal-bolus (BB) regimen vs basal-only insulin. MATERIALS AND METHODS: In this open-label, randomized, 18-week trial (51 sites; 6 countries), adults (n = 236) with inadequately controlled type 2 diabetes (T2D; mean glycosylated haemoglobin [HbA1c] +/- SD: 7.9% +/- 0.7% [63.1 +/- 7.5 mmol/mol]) receiving basal insulin and oral antidiabetic drugs underwent 8-week optimization of prior once-daily basal insulin followed by randomization 1:1 to either a BB regimen with faster aspart (n = 116) or continuation of once-daily basal insulin (n = 120), both with metformin. Primary endpoint was HbA1c change from baseline after 18 weeks of treatment. Secondary endpoints included: postprandial plasma glucose (PPG) change and overall PPG increment (all meals); weight; treatment-emergent adverse events; hypoglycaemic episodes. RESULTS: HbA1c decreased from 7.9% (63.2 mmol/mol) to 6.8% (50.7 mmol/mol; BB group) and from 7.9% (63.2 mmol/mol) to 7.7% (60.7 mmol/mol; basal-only group); estimated treatment difference [95% confidence interval] -0.94% [-1.17; -0.72]; -10.3 mmol/mol [-12.8; -7.8]; P < .0001. Reductions from baseline in overall mean 2 hour PPG and overall PPG increment for all meals (self-measured plasma glucose profiles) were statistically significant in favour of BB treatment ( P < .0001). Severe/blood glucose confirmed hypoglycaemia rate (12.8 vs 2.0 episodes per patient-years of exposure), total daily insulin (1.2 vs 0.6 U/kg) and weight gain (1.8 vs 0.2 kg) were greater with BB than with basal-only treatment. CONCLUSIONS: In T2D, faster aspart in a BB regimen provided superior glycaemic control as compared with basal-only insulin, but with an increase in the frequency of hypoglycaemia and modest weight gain. PMID- 28345795 TI - Is the Lateralized Categorical Perception of Color a Situational Effect of Language on Color Perception? AB - This study investigated whether and how a person's varied series of lexical categories corresponding to different discriminatory characteristics of the same colors affect his or her perception of colors. In three experiments, Chinese participants were primed to categorize four graduated colors-specifically dark green, light green, light blue, and dark blue-into green and blue; light color and dark color; and dark green, light green, light blue, and dark blue. The participants were then required to complete a visual search task. Reaction times in the visual search task indicated that different lateralized categorical perceptions (CPs) of color corresponded to the various priming situations. These results suggest that all of the lexical categories corresponding to different discriminatory characteristics of the same colors can influence people's perceptions of colors and that color perceptions can be influenced differently by distinct types of lexical categories depending on the context. PMID- 28345797 TI - Metabolomics strategy for the mapping of volatile exometabolome from Saccharomyces spp. widely used in the food industry based on comprehensive two dimensional gas chromatography. AB - Saccharomyces spp. are widely used in the food and beverages industries. Their cellular excreted metabolites are important for general quality of products and can contribute to product differentiation. This exploratory study presents a metabolomics strategy for the comprehensive mapping of cellular metabolites of two yeast species, Saccharomyces cerevisiae and S. pastorianus (both collected in an industrial context) through a multidimensional chromatography platform. Solid phase microextraction was used as a sample preparation method. The yeast viability, a specific technological quality parameter, was also assessed. This untargeted analysis allowed the putative identification of 525 analytes, distributed over 14 chemical families, the origin of which may be explained through the pathways network associated with yeasts metabolism. The expression of the different metabolic pathways was similar for both species, event that seems to be yeast genus dependent. Nevertheless, these species showed different growth rates, which led to statistically different metabolites content. This was the first in-depth approach that characterizes the headspace content of S. cerevisiae and S. pastorianus species cultures. The combination of a sample preparation method capable of providing released volatile metabolites directly from yeast culture headspace with comprehensive two-dimensional gas chromatography was successful in uncovering a specific metabolomic pattern for each species. PMID- 28345796 TI - Establishing nucleosome architecture and stability at promoters: Roles of pioneer transcription factors and the RSC chromatin remodeler. AB - Improvements in deep sequencing, together with methods to rapidly deplete essential transcription factors (TFs) and chromatin remodelers, have recently led to a more detailed picture of promoter nucleosome architecture in yeast and its relationship to transcriptional regulation. These studies revealed that ~40% of all budding yeast protein-coding genes possess a unique promoter structure, where we propose that an unusually unstable nucleosome forms immediately upstream of the transcription start site (TSS). This "fragile" nucleosome (FN) promoter architecture relies on the combined action of the essential RSC (Remodels Structure of Chromatin) nucleosome remodeler and pioneer transcription factors (PTFs). FNs are associated with genes whose expression is high, coupled to cell growth, and characterized by low cell-to-cell variability (noise), suggesting that they may promote these features. Recent studies in metazoans suggest that the presence of dynamic nucleosomes upstream of the TSS at highly expressed genes may be conserved throughout evolution. PMID- 28345799 TI - George Lincoln Blackburn, MD, PhD (1936-2017). PMID- 28345798 TI - Multimetallic and Mixed Environment Iridium(III) Complexes: A Modular Approach to Luminescence Tuning Using a Host Platform. AB - Mononuclear and trinuclear bis-cyclometallated IrIII complexes of the host ligands tris(4-[4'-methyl-2,2'-bipyridyl]methyl)cyclotriguaiacylene (L1) and tris(4-(4'-methyl-2,2'- bipyridyl)carboxy)cyclotriguaiacylene (L2) have been prepared. Complexes [{Ir(ppy)2 }3 (L1)](PF6 )3 (1.1), [{Ir(ppy)2 }(L1)](PF6 )3 (1.2), [{Ir(ppy)2 }3 (L2)](PF6 )3 (2.1) and [{Ir(ppy)2 }(L2)](PF6 )3 (2.2) (where ppy=phenylpyridinato) showed distinct photophysical properties depending on the L ligand. Complexes featuring the L1 ligand were comparatively blue-shifted in solution, with longer lifetimes and higher quantum yields. The mixed bis cyclometallated IrIII complexes [{Ir(ppy)2 }{Ir(dFppy)2 }2 (L1)](PF6 )3 (1.3), [{Ir(ppy)2 }{Ir(dFppy)2 }2 (L2)](PF6 )3 (2.3), [{Ir(ppy)2 }2 {Ir(dFppy)2 }(L1)](PF6 )3 (1.4) and [{Ir(ppy)2 }2 {Ir(dFppy)2 }(L2)](PF6 )3 (2.4) (where dFppy=2,4-difluorophenylpyrinato) were also synthesised. Steady-state and time resolved spectroscopy, along with electrochemical investigations, show that the Ir(III) chromophores within these mixed Ir-environment species behave as isolated centres, with no energy transfer or electronic communication between them. PMID- 28345800 TI - Ancestry dynamics in a South American population: The impact of gene flow and preferential mating. AB - OBJECTIVES: European ancestry in many populations in Latin America at autosomal loci is often higher than that from X-linked loci indicating more European male ancestry and more Amerindian female ancestry. Generally, this has been attributed to more European male gene flow but could also result from an advantage to European mating or reproductive success. METHODS: Population genetic models were developed to investigate the dynamics of gene flow and mating or reproductive success. Using estimates of autosomal and X-chromosome European ancestry, the amount of male gene flow or mating or reproductive advantage for Europeans, or those with European ancestry, was estimated. RESULTS: In a population from Antioquia, Colombia with an estimated 79% European autosomal ancestry and an estimated 69% European X-chromosome ancestry, about 15% male gene flow from Europe or about 20% mating or reproductive advantage of Europeans over Amerindians resulted in these levels of European ancestry in the contemporary population. Combinations of gene flow and mating advantage were nearly additive in their impact. CONCLUSIONS: Gene flow, mating advantage, or a combination of both factors, are consistent with observed levels of European ancestry in a Latin American population. This approach provides a general methodology to determine the levels of gene flow and mating differences that can explain the observed contemporary differences in ancestry from autosomes and X-chromosomes. PMID- 28345801 TI - ZC4H2 deletions can cause severe phenotype in female carriers. AB - ZC4H2 is involved in human brain development, and, if mutated, can be responsible for a rare X-linked disorder, originally presented in literature as Wieacker Wolff syndrome and Miles-Carpenter syndrome. In males, severe intellectual disability is associated with variable symptoms of central and peripheral nervous system involvement, such as spasticity, hyperreflexia, muscle weakness, and arthrogryposis. Female carriers are usually described as asymptomatic or only mildly affected. Here, we report on a girl carrying a de novo deletion of ZC4H2 detected by array-CGH analysis. She showed a complex neurodevelopmental disorder resembling the clinical picture commonly observed in male patients. X inactivation was found to be random. Additionally, she had an unusual appearance of fingers and hand creases, and electromyography showed a peculiar pattern of both neurogenic and myopathic anomalies. The present patient confirms that female carriers can also be severely affected. Systematic clinical investigations of both males and females are needed to define the variety in nature and severity of phenotypes related to ZC4H2 variants. PMID- 28345803 TI - An evolving approach to delirium: A mixed-methods process evaluation of a hospital-wide delirium program in New Zealand. AB - OBJECTIVE: A process evaluation was carried out to assess and potentially improve the design and implementation of a hospital-wide delirium program. METHODS: A mixed-methods sequential-explanatory design was used; retrospective chart reviews for 100 older (75+) medical inpatients were conducted to measure nurses', doctors' and coders' adherence to key program processes following which interviews were conducted to identify potential barriers to implementation. RESULTS: Delirium occurred in 49% of patients. Chart reviews revealed suboptimal adherence to the delirium risk assessment (66%), the Short Confusion Assessment Method (50% on admission, 58% during admission), documentation of delirium in clinical records (80%) and discharge letters (38%) and coding for delirium (49%). The major barriers to implementation identified were failure to recruit non nursing staff, unclear goals and instructions, difficulties using the Short-CAM, time constraints with competing priorities and lack of outcome expectancy. CONCLUSION: A new delirium program was needed based on these findings. PMID- 28345802 TI - The association between caudal anesthesia and increased risk of postoperative surgical complications in boys undergoing hypospadias repair. AB - INTRODUCTION: Recent reports have suggested that caudal anesthesia may be associated with an increased risk of postoperative surgical complications. We examined our experience with caudal anesthesia in hypospadias repair to evaluate for increased risk of urethrocutaneous fistula or glanular dehiscence. METHODS: All hypospadias repairs performed by a single surgeon in 2001-2014 were reviewed. Staged or revision surgeries were excluded. Patient age, weight, hypospadias severity, surgery duration, month and year of surgery, caudal anesthesia use, and postoperative complications were recorded. Bivariate and multivariate statistical analyses were performed. RESULTS: We identified 395 single-stage primary hypospadias repairs. Mean age was 15.6 months; 326 patients had distal (83%) and 69 had proximal (17%) hypospadias. Caudal anesthetics were used in 230 (58%) cases; 165 patients (42%) underwent local penile block at the discretion of the surgeon and/or anesthesiologist. Complications of urethrocutaneous fistula or glanular deshiscence occurred in 22 patients (5.6%) and were associated with caudal anesthetic use (OR 16.5, 95% CI 2.2-123.8, P = 0.007), proximal hypospadias (OR 8.2, 95% CI 3.3-20.0, P < 0.001), increased surgical duration (OR 1.01, 95% CI 1.01-1.02, P < 0.001), and earlier year of practice (OR 3.0, 95% CI 1.2-7.9, P = 0.03 for trend). After adjusting for confounding variables via multivariable logistic regression, both caudal anesthetic use (OR 13.4, 95% CI 1.8-101.8, P = 0.01) and proximal hypospadias (OR 6.8, 95% CI 2.7-16.9, P < 0.001) remained highly associated with postoperative complications. CONCLUSIONS: In our experience, caudal anesthesia was associated with an over 13-fold increase in the odds of developing postoperative surgical complications in boys undergoing hypospadias repair even after adjusting for urethral meatus location. Until further investigation occurs, clinicians should carefully consider the use of caudal anesthesia for children undergoing hypospadias repair. PMID- 28345804 TI - Mycobacterium szulgai: an unusual cause of skin and soft tissue infection after breast augmentation. PMID- 28345806 TI - Obituary. PMID- 28345805 TI - Promoter hypermethylation-mediated downregulation of miR-770 and its host gene MEG3, a long non-coding RNA, in the development of gastric cardia adenocarcinoma. AB - Maternally expressed gene 3 (MEG3) is an imprinted gene located at 14q32 which encodes an lncRNA and is downregulated in an expanding list of cancer cell lines and primary human cancers. The miR-770 is transcribed from the intronic sequence of MEG3 and MEG3 may be the host gene for miR-770. However, the biological role of MEG3 and miR-770 in gastric cardia adenocarcinoma (GCA) development and prognosis is poorly defined. The present study was to investigate the function and methylation status of MEG3 in GCA, and further to detect the functional association of miR-770 and its host gene MEG3 in GCA carcinogenesis and prognosis. MEG3 and miR-770 was significantly downregulated in GCA patients and cell lines, and their expression was associated with TNM stage and lymph node metastasis. Overexpression of MEG3 and miR-770 inhibited gastric cancer cell proliferation and invasion in vitro. Furthermore, the expression level of MEG3 and miR-770 was significantly increased in cancer cells after treated with 5-Aza dC. The aberrant hypermethylation of proximal promoter and enhancer region of MEG3 was detected in GCA tissues. In addition, the proximal promoter and enhancer region hypermethylation and dysregulation of MEG3 and miR-770 were associated with poorer GCA patients' survival. These findings suggest that miR-770 and its host gene MEG3 may play tumor suppressor role and hypermethylation of proximal promoter and enhancer region may be one of the critical mechanisms in inactivation of MEG3 and miR-770 in GCA development. MEG3 and miR-770 may be used as potential biomarkers in predicting GCA patients' prognosis. PMID- 28345807 TI - Low FODMAP in 2017: Lessons learned from clinical trials and mechanistic studies. AB - Given the prevalence of irritable bowel syndrome (IBS) and the suboptimal response to most therapeutic approaches, there has been increasing interest in and adoption of dietary treatment strategies, such as the low Fermentable Oligo-, Di-, & Mono-Saccharides and Polyols (FODMAP) diet. FODMAPs are a diverse group of carbohydrates that exert effects in the gastrointestinal tract not only via fermentation but likely via alterations in the microbiota, metabolome, permeability, and intestinal immunity as well. Clinical evidence for efficacy of this diet is mounting, but there are significant questions regarding short- and long-term safety and effects on the microbiota and nutrition that remain unanswered. This review article interprets the recent findings reported in this issue of Neurogastroenterology and Motility and summarizes the mechanistic and clinical efficacy data of the low FODMAP diet in IBS patients to date. PMID- 28345809 TI - Effect of lorcaserin on glycemic parameters in patients with type 2 diabetes mellitus. AB - OBJECTIVE: Lorcaserin, a 5-HT2C receptor agonist approved for chronic weight management, is also associated with improvements in glycemic parameters in patients with/without type 2 diabetes mellitus (T2DM), but the extent to which these effects are mediated by weight loss is unknown. This post hoc analysis further examines glycemic data from the Phase III BLOOM-DM study stratified by weight changes. METHODS: Patients with T2DM were randomized to lorcaserin 10 mg twice daily or placebo. Glycemic parameters were reported by Week (W) 12 weight loss status >=5% (Group >=5%) or <5% (Group <5%). Glycemic parameter changes were analyzed using ANCOVA; the relationship between glycemic parameter changes and percent weight loss was assessed by simple regression modeling. RESULTS: Group >=5% receiving lorcaserin had greater improvements in fasting plasma glucose (FPG) at W2 (prior to significant weight loss) and greater improvements in glycated hemoglobin (HbA1c) at W12 versus placebo. These improvements were maintained through W52 (FPG, -29.3 mg/dL vs. -24.2 mg/dL; HbA1c, -1.2% vs. 1.1%). Group <5% treated with lorcaserin also had larger decreases in FPG (-28.3 mg/dL vs. -10.0 mg/dL) and HbA1c (-0.8% vs. -0.4%) at W52 versus placebo despite limited weight loss. CONCLUSIONS: Lorcaserin may have beneficial effects on glycemic control with or without weight loss. PMID- 28345810 TI - An Untrodden Path: Versatile Fabrication of Self-Supporting Polymer-Stabilized Percolation Membranes (PSPMs) for Gas Separation. AB - The preparation and scalability of zeolite or metal organic framework (MOF) membranes remains a major challenge, and thus prevents the application of these materials in large-scale gas separation. Additionally, several zeolite or MOF materials are quite difficult or nearly impossible to grow as defect-free layers, and require expensive macroporous ceramic or polymer supports. Here, we present new self-supporting zeolite and MOF composite membranes, called Polymer Stabilized Percolation Membranes (PSPMs), consisting of a pressed gas selective percolation network (in our case ZIF-8, NaX and MIL-140) and a gas-impermeable infiltrated epoxy resin for cohesion. We demonstrate the performance of these PSPMs by separating binary mixtures of H2 /CO2 and H2 /CH4 . We report the brickwork-like architecture featuring selective percolation pathways and the polymer as a stabilizer, compare the mechanical stability of said membranes with competing materials, and give an outlook on how economic these membranes may become. PMID- 28345808 TI - Molecular genetic analysis of the melanoma regulatory locus in Xiphophorus interspecies hybrids. AB - Development of spontaneous melanoma in Xiphophorus interspecies backcross hybrid progeny, (X. hellerii * [X. maculatus Jp 163 A * X. hellerii]) is due to Mendelian segregation of a oncogene (xmrk) and a molecularly uncharacterized locus, called R(Diff), on LG5. R(Diff) is thought to suppresses the activity of xmrk in healthy X. maculatus Jp 163 A parental species that rarely develop melanoma. To better understand the molecular genetics of R(Diff), we utilized RNA Seq to study allele-specific gene expression of spontaneous melanoma tumors and corresponding normal skin samples derived from 15 first generation backcross (BC1 ) hybrids and 13 fifth generation (BC5 ) hybrids. Allele-specific expression was determined for all genes and assigned to parental allele inheritance for each backcross hybrid individual. Results showed that genes residing in a 5.81 Mbp region on LG5 were exclusively expressed from the X. hellerii alleles in tumor bearing BC1 hybrids. This observation indicates this region is consistently homozygous for X. hellerii alleles in tumor bearing animals, and therefore defines this region to be the R(Diff) locus. The R(Diff) locus harbors 164 gene models and includes the previously characterized R(Diff) candidate, cdkn2x. Twenty-one genes in the R(Diff) region show differential expression in the tumor samples compared to normal skin tissue. These results further characterize the R(Diff) locus and suggest tumor suppression may require a multigenic region rather than a single gene variant. Differences in gene expression between tumor and normal skin tissue in this region may indicate interactions among several genes are required for backcross hybrid melanoma development. PMID- 28345811 TI - Importance of laboratory parameters in patients with obstructive sleep apnea and their relationship with cardiovascular diseases. AB - BACKGROUND: Ostructive sleep apnea (OSA) is an independent risk factor for the development of cardiovascular events. Platelet activation and inflammation are the mechanisms involved in the association between OSA and cardiovascular disease (CVD). The markers of platelet activation and inflammation are the mean platelet volume (MPV), platelet-lymphocyte ratio (PLR), red cell distribution width (RDW), neutrophil- lymphocyte ratio (NLR). We aimed to define the association of NLR, PLR, RDW, and MPV with the severity of disease and the presence of CVD. METHODS: This study consisted of 300 patients who were admitted to the sleep laboratory. The patients were classified according to their apnea- hypopnea index (AHI) scores as OSA negative (Group A: AHI<5), mild (Group B: AHI: 5-15), moderate (Group C: AHI=15-30), and severe OSA (Group D: AHI >30). RESULTS: There were no significant differences in the NLR, PLR, and MPV among the groups (P>.05); only RDW differed significantly (P=.04). RDW was significantly higher in patients with than without risk factors for CVD [15.6% (15.4-15.7) vs 15.3% (15.1-15.3), respectively; P=.02]. CONCLUSIONS: NLR, PLR, MPV, and RDW are widely available and easily obtained from a routinely performed hemogram. Among these laboratory parameters, only RDW can demonstrate the reverse consequences of OSA-associated comorbidities, because vascular damage due to systemic inflammation is an important underlying mechanism in these diseases. RDW might be used as a marker of the response and patient compliance with continuous positive airway pressure treatment. PMID- 28345812 TI - Reduced expression of let-7f activates TGF-beta/ALK5 pathway and leads to impaired ischaemia-induced neovascularization after cigarette smoke exposure. AB - This study sought to determine the potential role of microRNAs (miRNAs) in the detrimental effects of cigarette smoke on angiogenesis and neovascularization. Using large-scale miRNA profiling and qRT-PCR analyses, we identified let-7f as a pro-angiogenic miRNA which expression is significantly reduced in HUVECs treated with cigarette smoke extracts (CSE), and in the ischemic muscles of mice that are exposed to cigarette smoke (MES). In a mouse model of hindlimb ischaemia, intramuscular injection of let-7f mimic restored ischaemia-induced neovascularization in MES. Doppler flow ratios and capillary density in ischemic muscles were significantly improved in MES treated with let-7f mimic. Clinically, this was associated with reduced ambulatory impairment and hindlimb ischaemic damage. Treatment with let-7f mimic could also rescue pro-angiogenic cell (PAC) number and function (attachment, proliferation, migration) in MES. ALK5 (TGF betaR1), an important modulator of angiogenesis, is a target of let-7f. Here we show that ALK5 is increased in HUVECs exposed to CSE and in the ischaemic muscles of MES. This is associated with a downstream activation of the anti-angiogenic factors SMAD2/3 and PAI-1. Importantly, treatment with let-7f mimic reduces the expression of ALK5, SMAD2/3 and PAI-1 both in vitro and in vivo. Moreover, let-7f overexpression or ALK5 inhibition can rescue angiogenesis in HUVECs exposed to CSE. Cigarette smoke exposure is associated with reduced expression of let-7f and activation of the anti-angiogenic TGF-beta/ALK5 pathway. Overexpression of let-7f using a miRNA mimic could constitute a novel therapeutic strategy to improve ischaemia-induced neovascularization in pathological conditions. PMID- 28345813 TI - Effect of the interaction between MiR-200b-3p and DNMT3A on cartilage cells of osteoarthritis patients. AB - The aim of this research is to explore the effect of miR-200b-3p targeting DNMT3A on the proliferation and apoptosis of osteoarthritis (OA) cartilage cells. Quantitative RT-PCR was performed to analyse the expression of miR-200b-3p, DNMT3A, MMP1, MMP3, MMP9, MMP13 and COL II in normal and OA cartilage tissues. The dual-luciferase reporter assay and Western blot assay were conducted to confirm the targeting relationship between miR-200b-3p and DNMT3A. We also constructed eukaryotic expression vector to overexpress miR-200b-3p and DNMT3A. We detected the expression level of MMPs and COL II in stable transfected cartilage cells using RT-PCR and Western blot. Cell proliferation and apoptosis were evaluated using the MTS, pellet culture and Hoechst 33342 staining method. Finally, we explored the effect of miR-200b-3p targeting DNMT3A on the proliferation and apoptosis of OA cartilage cells. The results of RT-PCR indicated that both miR-200b-3p and COL II were down-regulated in OA cartilage tissues, while the expression of DNMT3A and MMPs was up-regulated in OA cartilage tissues. The expressions of DNMT3A, MMPs and COL II detected by Western blot showed the same trend of the results of RT-PCR. The dual-luciferase reporter assay and Western blot assay confirmed the targeting relationship between miR 200b-3p and DNMT3A. In overexpressed miR-200b-3p cartilage cells, DNMT3A and MMPs were significantly down-regulated, COL II was significantly up-regulated, cell viability was enhanced and apoptosis rate was decreased (P < 0.05). In overexpressed DNM3T cartilage cells, MMPs were significantly up-regulated, COL II was significantly down-regulated, cell viability was weakened and apoptosis rate was increased (P < 0.05). MiR-200b-3p inhibited the secretion of MMPs, promoted the synthesis of COL II and enhanced the growth and proliferation of OA cartilage cells through inhibiting the expression of DNMT3A. PMID- 28345815 TI - Description of the novel HLA-A allele, HLA-A*11:229, identified by sequence-based typing in a Chinese individual. AB - HLA-A*11:229 differs from HLA-A*11:01:01:01 by 1 nucleotide exchange at position 556 (G > A) with an amino exchange. PMID- 28345814 TI - Dapagliflozin once daily plus exenatide once weekly in obese adults without diabetes: Sustained reductions in body weight, glycaemia and blood pressure over 1 year. AB - AIMS: Dapagliflozin and exenatide reduce body weight by differing mechanisms. Dual therapy with these agents reduces body weight, adipose tissue volume, glycaemia and systolic blood pressure (SBP) over 24 weeks. Here, we examined these effects over 1 year in obese adults without diabetes. MATERIALS AND METHODS: Obese adults without diabetes (N = 50; aged 18-70 years; body mass index, 30-45 kg/m2 ) were initially randomized to double-blind oral dapagliflozin 10 mg once daily plus subcutaneous long-acting exenatide 2 mg once weekly or to placebo. They entered an open-label extension from 24 to 52 weeks during which all participants received active treatment. RESULTS: Of the original 25 dapagliflozin + exenatide-treated and 25 placebo-treated participants, respectively, 21 (84%) and 17 (68%) entered the open-label period and 16 (64%) and 17 (68%) completed 52 weeks of treatment. At baseline, mean body weight was 104.6 kg, and 73.5% of participants had prediabetes (impaired fasting glucose or impaired glucose tolerance). Reductions with dapagliflozin + exenatide at 24 weeks were sustained at 52 weeks, respectively, for body weight (-4.5 and -5.7 kg), total adipose tissue volume (-3.8 and -5.3 L), proportion with prediabetes (34.8% and 35.3%), and SBP (-9.8 and -12.0 mm Hg). Effects on body weight, SBP and glycaemia at 52 weeks with placebo -> dapagliflozin + exenatide were similar to those observed with continuation of dapagliflozin + exenatide. Nausea and injection-site reactions were more frequent with dapagliflozin + exenatide than with placebo and diminished over time. Safety and tolerability were similar to that in previous diabetes trials with these agents. No clear difference in adverse event-related withdrawals between placebo and active treatment periods was observed. CONCLUSIONS: Dapagliflozin + exenatide dual therapy produced sustained reductions in body weight, prediabetes and SBP over 52 weeks and was well tolerated in obese adults without diabetes. PMID- 28345816 TI - Germline variation in the 3'-untranslated region of the POU2AF1 gene is associated with susceptibility to lymphoma. AB - Genetic variations in certain genes may alter the susceptibility to lymphoma. We searched electronic databases and selected candidate single-nucleotide polymorphisms (SNPs) located within 3'-untranslated regions (3'-UTRs) that might affect miRNA-binding ability in the 50 most dysregulated genes in lymphoma for further study. We found that rs1042752-located in the 3'-UTR of POU2AF1, which plays a vital role in lymphomagenesis-was significantly associated with lymphoma risk in a case-control study with 793 patients and 939 controls. Compared with individuals with the rs1042752TT genotype, those with the rs1042752CC genotype had a higher risk of lymphoma (OR = 2.14, 95% CI: 1.55-2.95, P < 0.001), even in stratified analysis for non-Hodgkin lymphoma (OR = 4.58, 95% CI: 2.38-8.81, P < 0.001), B-cell lymphoma (OR = 4.89, 95% CI: 2.46-9.73, P < 0.001), T-cell lymphoma (OR = 4.20, 95% CI: 1.76-10.05, P = 0.001), and Hodgkin lymphoma (OR = 3.62, 95% CI: 1.25-10.46, P = 0.018). Similar results were also observed in a recessive genetic model. Database findings suggested that rs1042752 might affect the interaction of POU2AF1 mRNA with hsa-miR-633. Functional assays confirmed that rs1042752C altered the binding site of hsa-miR-633 and increased POU2AF1 expression in Ramos, HuT 102, and Jurkat E6-1 cell lines. These findings demonstrate for the first time that functional polymorphism in the 3'-UTR of POU2AF1 is associated with susceptibility, and that SNP interaction with hsa-miR 633 affects gene expression and increases the risk of lymphoma. PMID- 28345818 TI - Retraction: Predicting New Ugi-Smiles Couplings: A Combined Experimental and Theoretical Study. PMID- 28345817 TI - Simultaneous determination of multiple active components in rat plasma using ultra-fast liquid chromatography with tandem mass spectrometry and application to a comparative pharmacokinetic study after oral administration of Suan-Zao-Ren decoction and Suan-Zao-Ren granule. AB - Suan-Zao-Ren decoction has been used to treat insomnia for many years. In this work, a rapid and sensitive ultra-fast liquid chromatography with tandem mass spectrometry method was first developed and fully validated for the simultaneous quantification of seven main active components, spinosin, mangiferin, neomangiferin, ferulic acid, liquiritin, isoliquiritin, and liquiritin apioside in rat plasma. The method was also successfully applied to compare the pharmacokinetics of these active ingredients after oral administration of Suan Zao-Ren decoction and Suan-Zao-Ren granule. The separation was achieved on a Venusil MP C18 column and the detection was conducted by the multiple reaction monitoring mode using negative ion mode. Each calibration curve had good linearity over a wide concentration range. The precision of intra- and interday were all within 15%, and the extraction recoveries at different analyte concentrations were all above 82.0%. The established method was successfully applied to compare the pharmacokinetic profiles of the analytes between Suan-Zao Ren decoction and Suan-Zao-Ren granule groups. The results indicated that all the analytes had similar mean concentration-time curves trend between two groups. No significant differences were observed in pharmacokinetic parameters of mangiferin, while the others had significant differences. PMID- 28345819 TI - Outbreak investigations and molecular characterization of foot-and-mouth disease viruses circulating in south-west Niger. AB - In Niger, the epidemiological situation regarding foot-and-mouth disease is unclear as many outbreaks are unreported. This study aimed (i) to identify Foot and-mouth disease virus (FMDV) strains currently circulating in cattle herds, and (ii) to identify risk factors associated with Foot-and-mouth disease (FMD) seropositive animals in clinical outbreaks. Epithelial tissues (n = 25) and sera (n = 227) were collected from cattle in eight districts of the south-western part of Niger. Testing of clinical material revealed the presence of FMDV serotype O that was characterized within the O/WEST AFRICA topotype. The antigenic relationship between one of the FMDV isolates from Niger (O/NGR/4/2015) and three reference vaccine strains was determined by the two-dimensional virus neutralization test (2dmVNT), revealing a close antigenic match between the field isolate from Niger and three FMDV serotype O vaccine strains. Serological analyses using a non-structural protein (NSP) test provided evidence for previous FMDV infection in 70% (158/227) of the sera tested. Multivariate logistic regression analysis revealed that only the herd composition (presence of both cattle and small ruminants) was significantly associated with FMDV seropositivity as defined by NSP-positive results (p-value = .006). Of these positive sera, subsequent testing by liquid-phase blocking ELISA (LPBE) showed that 86% (136/158) were positive for one (or more) of four FMDV serotypes (A, O, Southern African Territories (SAT) 1 and SAT 2). This study provides epidemiological information about FMD in the south-western part of Niger and highlights the complex transboundary nature of FMD in Africa. These findings may help to develop effective control and preventive strategies for FMD in Niger as well, as other countries in West Africa. PMID- 28345820 TI - Meta-Analysis of Serum Gastrin-Releasing Peptide Precursor as a Biomarker for Diagnosis of Small Cell Lung Cancer AB - Background: The serum level of gastrin-releasing peptide precursor (proGRP) is generally. elevated in patients withsmall cell lung cancer (SCLC). However, the diagnostic sensitivity and specificity of serum proGRP in SCLC casesremains controversial. The study aimed to assess the diagnostic value of this biomarker by meta-analysis. Materials andMethods: The Cochrane, Clinical trials, Pubmed, Web of Science and Embase databases were searched and diagnosticvalues were calculated or extracted. Statistical analysis was accomplished with RevMan 5.3 and STATA 12.0 software.Results: A total of 27 studies with 7268 participants were included. The pooled sensitivity, specificity, PLR, NLRand DOR were 0.754 (95% CI: 0.700-0.802), 0.945 (95% CI: 0.916-0.965), 13.804 (95% CI: 9.096 20.948), 0.260(95% CI: 0.213-0.317) and 53.101 (95% CI: 34.327-82.145) respectively. The AUC was 0.910 (95% CI: 0.880-0.930).Significant publication bias was not found (P =0.622). Conclusions: The meta-analysis indicated that serum proGRPis indeed a useful biomarker with good sensitivity and high specificity for diagnosis of SCLC. Therefore proGRP canbe expected to be widely applied in the clinic for identification of lung cancer patients. PMID- 28345821 TI - Antioxidant and Antiproliferative Activities of an Ethylacetate Fraction of Picria Fel-Terrae Lour. Herbs AB - Background: Excessive production of oxygen free radicals and imbalance in the mechanisms responsible forantioxidant protection may result in the onset of many diseases including breast cancer. Objective: To evaluateantiproliferative and antioxidant activity of an ethylacetate fraction (EAF) of Picria fel-terrae Lour. Herbs in the T47Dcell line. Methods: Phenolic and total flavonoid contents in EAF were determined. EAF was tested for cytotoxicity andeffects on the cell cycle and apoptosis, as well as antioxidant activity. Results: EAF was found to contain high levels ofphenolic agents (92.88 +/- 0.50 mg GAE/g), total flavonoid (84.39 +/- 0.07 mg QE/g). The EAF of Picria fel-terrae Lour.herbs was found to have an IC50 of 62.98MUg/mL, caused accumulation in G0-G1 and S phase and increased early andlate apoptosis. Antioxidant activity in DPPH assays gave an IC50 of 166.90 +/- 0.10 MUg/mL. Conclusions: The resultsreveal that EAF of Picria fel-terrae Lour. herbs has antiproliferative activity and strong antioxidant potential. Furtherstudies are now needed to isolate the responsible antiproliferative and antioxidant components. PMID- 28345822 TI - The Optimal Cut-Off Level of The Fecal Immunochemical Test For Colorectal Cancer Screening in a Country with Limited Colonoscopy Resources: A Multi-Center Study from Thailand AB - Background: Selecting the cut-off point for the fecal immunochemical test (FIT) for colorectal cancer (CRC)screening programs is of prime importance. The balance between the test performance for detecting advanced neoplasiaand the available colonoscopy resources should be considered. We aimed to identify the optimal cut off of FIT foradvanced neoplasia in order to minimize colonoscopy burden. Methods: We conducted a multi-center study in 6hospitals from diverse regions of Thailand. Asymptomatic participants, aged 50-75 years, were tested with one timequantitative FIT (OC-SENSOR, Eiken Chemical Co.,Ltd., Tokyo, Japan) and all participants underwent colonoscopy.We assessed test performance in detecting advanced neoplasia (advanced adenoma and CRC) and measured the burdenof colonoscopy with different cut-offs [25 (FIT25), 50 (FIT50), 100 (FIT100), 150 (FIT150), and 200 (FIT200)ng/ml].Results: Among 1,479 participants, advanced neoplasia and CRC were found in 137 (9.3%) and 14 (0.9%), respectively.From FIT25 to FIT200, the positivity rate decreased from 18% to 4.9%. For advanced neoplasia, an increased cut-offdecreased sensitivity from 42.3% to 16.8% but increased specificity from 84.2% to 96.3%. The increased cut-offincreased the positive predictive value (PPV) from 21.5% to 31.5%. However, all cut-off points provided a high negativepredictive value (NPV) (>90%). For CRC, the miss rate for FIT25 to FIT 150 was the same (n=3, 21%), whereas thatwith FIT200 increased to 35% (n=5). Conclusions: In a country with limited-colonoscopy resources, using FIT150may be preferred because it offers both high PPV and NPV for advanced neoplasia detection. It could also decreasecolonoscopy workload, while maintaining a CRC miss rate similar to those with lower cut-offs. PMID- 28345823 TI - Mutation Analysis of Isocitrate Dehydrogenase (IDH1/2) and DNA Methyltransferase 3A (DNMT3A) in Thai Patients with Newly Diagnosed Acute Myeloid Leukemia AB - Acute myeloid leukemia (AML) is a clonal hematopoietic stem/progenitor cell disorder which features severalgenetic mutations. Recurrent genetic alterations identified in AML are recognized as causes of the disease, findingapplication as diagnostic, prognostic and monitoring markers, with potential use as targets for cancer therapy. Here, weperformed a pyrosequencing technique to investigate common mutations of IDH1, IDH2 and DNMT3A in 81 newlydiagnosed AML patients. The prevalences of IDH1, IDH2 and DNMT3A mutations were 6.2%, 18.5%, and 7.4%,respectively. In addition, exclusive mutations in IDH1 codon 132 (R132H, R132C, R132G and R132S) were identifiedin all IDH1-mutated cases indicating that these are strongly associated with AML. Interestingly, higher median blast cellcounts were significantly associated with IDH1/2 and DNMT3A mutations. In summary, we could establish a routinerobust pyrosequencing method to detect common mutations in IDH1/2 and DNMT3A and demonstrate the frequencyof those mutations in adult Thai AML patients. PMID- 28345824 TI - Epidemiological Characteristics of Retinoblastoma in Children Attending Almouassat University Hospital, Damascus, Syria, 2012-2016 AB - Retinoblastoma (Rb) is a malignant tumor that originates from the developing retina. Diagnosis is based on clinicalsigns and symptoms and usually children under the age of five years are affected. Early diagnosis and treatment of Rband non-ocular tumors can reduce morbidity and increase longevity. Treatment in the early stages may allow a goodprognosis and salvage of visual function.The aim of this study is to present descriptive epidemiological aspects ofretinoblastomas in children seen at Almouassat University Hospital (AUH) in Damascus, Syria from 1 January 2012 to31 October 2016In this retrospective, observational hospital survey, medical records of 37 retinoblastoma cases werereviewed. The male/female (M/F) ratio was 1.6. The most frequent presenting sign was leukocoria (56.7%) and 81%of cases were diagnosed between the ages of 4 months and 3 years. More than 73% of cases were diagnosed early atstages I and II. PMID- 28345825 TI - Comparison of Hypersensitivity Reactions to Carboplatin Retreatment in Gynecologic Cancer Patients between One and Two Hour Infusions: a Randomized Trial Study AB - Objective: To compare the incidence rate of carboplatin hypersensitivity reactions (HSRs) in gynecologic cancerpatients receiving one-hour or two-hour carboplatin retreatment infusions. Setting: A Prospective RandomizedControlled Trial. Methods: Recurrent gynecologic cancer patients 25 to 80-years of age who were scheduled to receivecarboplatin retreatment after previously receiving at least six cycles of carboplatin without a history of platinum allergywere invited to enroll. They were randomized to receive either a one-hour or two-hour carboplatin infusion in eachcycle. The nurses recorded any occurrence of HSR. Patients who developed carboplatin HSR were discontinued fromthe study. Results: Forty-five patients were enrolled and randomized to receive either a one-hour carboplatin infusionarm in 69 cycles or a two-hour infusion arm in 67 cycles. Both groups were well balanced regarding median age, bodymass index, type of cancer, history of drug allergy, median platinum free interval time, median total number of previouscarboplatin cycles, premedication type, regimen and median total dose of carboplatin. Five (3.67%) of the 136 cyclesresulted in carboplatin HSR, all of which were Grade 1. Of these, four cycles developed HSR during the one-hourinfusion and only one cycle with a two-hour infusion (P=0.37). The onset of carboplatin HSR occurred within 30-105minutes after infusion start. Conclusion: Extending the carboplatin infusion time to two hours from one hour did notsignificantly decrease carboplatin HSR. PMID- 28345826 TI - Value of Sentinel Lymph Node (SLN) Mapping and Biopsy using Combined Intracervical Radiotracers and Blue Dye Injections for Endometrial Cancer AB - Background: Lymphadenectomy, as part of the initial surgical staging of patients with endometrial carcinoma,remains a controversial topic in gynecologic oncology. Sentinel lymph node (SLN) mapping has become a well-acceptedprocedure for melanomas and breast cancer; a number of investigators have begun to explore the utility and accuracyof this technique with regard to endometrial cancer. Aim: This study was conducted to evaluate SLN mapping ofearly stage endometrial cancer with blue dye in conjunction with a radioactive tracer. Subjects and methods: In thisprospective cross-sectional study, patients with stage I and II endometrial cancer who were candidates for systemiclymph node dissection during surgery were enrolled, some underwent lymph node mapping and SLN biopsy usingcombined intra cervical radiotracer and blue dye injections and some applying only an intra cervical radiotracer. SLNsand other lymph nodes were sent for pathological assessment. Sensitivity, specificity, the positive predictive value, andthe negative predictive value were calculated as predictive values for the radiotracer and blue dye. Results: Pre-operativelymph node mapping showed SLN in 29 out of 30 patients. Intra operations in 29/30 patients, SLNs were harvested bygamma probe; in 13 out of 19 patients SLNs were detected by blue dye. The median number of SLNs per patient was3 and the total number of SLNs detected was 81. Four patients had positive pelvic lymph nodes. All of the positivenodes were SLNs. Using this technique (radiotracer and blue dye) an overall detection rate of 96.7%, an NPV of 100%,a sensitivity of 100% and a specificity of 3.85% were achieved. Conclusion: Results of SLN research for endometrialcancer are promising and make feasible the possibility of avoiding unnecessary aggressive surgical procedures in nearfuture by advances in SLN mapping. PMID- 28345828 TI - Effects of a Self-Encouragement Program on Stress of Mothers of Children with Cancer Referred to Imam Ali Hospital, Zahedan, In 2015 AB - Introduction: In addition to the physical problems for the patients themselves, cancer can cause several socialand psychological problems to the family, especially the mother in pediatric cases. This study aimed to investigate theeffects of a self-encouragement program on stress of mothers of children with cancer referred to Imam Ali Hospitalof Zahedan in 2015. Materials and Methods: This case-control study was performed on 44 mothers with childrensuffering from cancer, referred to the hospital during October and November of 2015. Convenience sampling was used,and the mothers were randomly allocated into two 22-member groups. The Impact of Event Scale - Revised (IES-R)was the data collection instrument. Educational classes were held in the hospital. Confidentiality and mutual respectwere observed by each and every member of the group. Data obtained before and after the intervention were analyzedusing the independent t-test, paired t-test and ANOVA. The significance level was set at 0.05. Findings: The mostfrequent diseases were acute lymphoblastic leukemia (47%) and brain tumors (16%). The results indicated that themean score of stress in the control group did not significantly between the two time points (P=0.106). In the interventiongroup, however, there was a significant difference in stress mean scores before (54.3+/-2.0) and after (37.1+/-1.8) theintervention (P<0.001). Conclusion: Self-encouragement can help mothers dealing with a diseased child to feel lessstressed. Therefore, they may be able to act more effectively when faced with problems. PMID- 28345827 TI - Polycyclic Aromatic Hydrocarbons In Edible Mushrooms from Niger Delta, Nigeria: Carcinogenic and Non-Carcinogenic Health Risk Assessment AB - In the oil-rich Niger Delta, hydrocarbon pollution and oil spillages, gas flaring and sundry anthropogenic activitiesconstitute sources of polycyclic aromatic hydrocarbons (PAHs), with food contamination playing a major role in humanexposure. In this study we assessed PAH levels in wild and cultivated edible mushroom species consumed by the generalpopulation from the oil producing Niger Delta, Nigeria. The concentrations of USEPA-16 PAHs were determinedby gas chromatography and carcinogenic and non-carcinogenic health risks were calculated. The concentrations ofUSEPA-16 PAHs ranged from 0.02 mg/kg - 3.37 mg/kg. The dietary intake of carcinogenic and non-carcinogenicUSEPA-16 PAHs (Naphthalene, Acenaphthylene, Acenaphthene, Anthracene, Phenanthrene, Flourene, Flouranthene,Pyrene, Benzo[a]Anthracene, Chrysene, Benzo[a]Pyrene, Benzo[b]Flouranthene, Benzo[K]Flouranthene, Benzo[g,h,i]Perylene, Dibenz[a,h]Anthracene and Ideno[1,2,3-cd]Pyrene) for adults, adolescents and seniors ranged from 0.00 - 0.05mg/kg/day, 0.00 - 0.06 mg/kg/day and 0.00 - 0.07 mg/kg/day. The BaPeq ranged from 0.02 - 2.76 with margin ofexposure MOE values of BaP ranging from 3,500,000 to 700,000, 3,500,000 and 3,500,000 to 7,000,000 for adults,adolescents and seniors indicating very insignificant health risk. The incremental lifetime cancer risk was within thesafe range of 1.56x10-8 - 1.73x10 6 with the highest calculated risk found for wild Pleurotus ostreatus mushroomspecies from the study area. PMID- 28345829 TI - High Fluoroquinolone Resistant Strains of Helicobacter pylori in the Golden triangle AB - Background and aims: Helicobacter pylori (H. pylori) infections, associated with fatal GI diseases such as gastriccancer and MALT lymphoma, remain a major health problem in ASEAN countries. The Golden triangle has long beenknown as one of Asia's main opium-producing areas. There have been no prior studies of H. pylori infection in this area.The major objectives of this project were therefore to establish prevalence, antibiotic resistance patterns and associatedpredictive in the Golden triangle. Methods: We recruited dyspeptic patients in Chiang khong and Chiang saen districts,Chiangrai province of Thailand. All subjects underwent gastroscopy, and 3 antral gastric biopsies were collected forrapid urease tests and H. pylori culture. E-tests were used to evaluate the MICs for metronidazole (MNZ), levofloxacin(LVX), ciprofloxacin (CIP), amoxicillin(AMX), tetracycline (TET) and clarithromycin (CLR). Results: Total of 148patients was included. H. pylori infection was present in 36.3%(37/102) of Chiang khong and 34.8 % (16/46) of Chiangsaen subjects and the overall H. pylori infection rate was 35.8% (53/148). Antibiotic resistance was demonstrated in44%, including 2% for CLR and 26% for MNZ, whereas fluoroquinolone resistance was demonstrated to be as highas 25% in Chiang khong. Multi-drug resistant H. pylori was detected in 4%. There was no AMX and TET resistancein this study. The prevalence of CLR resistance on a background of gastritis was significantly higher than peptic ulcerdisease in the golden triangle area (100%vs 0%: P= 0.04). Conclusions: H. pylori remains a common infection in theGolden triangle. MNZ resistance appears to be high, whereas fluoroquinolone resistance is prevalent and is becominga significant problem in this area. Diagnosis of gastritis might be a predictor of CLR resistance in the Golden triangle.H. pylori eradication with an appropriate regimen by using the local antibiotic resistant pattern is a key important toolto reduce H. pylori associated GI diseases in this particular part of the world. PMID- 28345830 TI - Histopathologic Evolution of Urothelial Carcinoma Recurrence in Transurethral Resection of the Urinary Bladder:35 Consecutive Cases And Literature Review AB - Background: Urothelial carcinoma (UC) is the malignancy most frequently encountered in the urinary bladder.Theprimary aim of this study was to make a reappraisal of histopathologic features, recurrence and progression. Materialsand Methods: The records of cases consecutively diagnosed with UC in the state hospital pathology laboratory werecollected. Cases were classified according to age, gender, histologic grade, pathologic staging [primary Tumor (pT)],tumor configuration, primary or recurrent status, and progression. Results: A total of 35 (29 male and 6 female) caseswere examined. The mean age was 68.9 years with a male-to-female incidence ratio of 4.8:1. Low-grade UCs accountedfor 20 (57.1%) and high-grade for 15 (42.9%). A papillary pattern was observed in 80% of the UCs, classified into thefollowing pathological stages: 11 (31.4%) pTa, 22 (62.9%) pT1, and 2 (5.9%) pT2 cases. Eleven patients progressedto a higher stage (pT1 to pT2), and three cases from low to higher grade. We analyzed results for 26 (74.3%) casesaged 65 years or older. Conclusions: UCs have a great tendency for recurrence but potentially may be amenable toeffective local or systemic treatments. PMID- 28345831 TI - Anxiety Disorders in Family Caregivers of Breast Cancer Patients Receiving Oncologic Treatment in Malaysia AB - Background: Anxiety is recognized as a normal psychological reaction of those caring for cancer patients. However,anxiety disorders in caregivers may interfere with their care-giving role and require further clinical attention. Objectives:To determine the prevalence and associated factors of anxiety disorders among caregivers of breast cancer patientsreceiving oncologic treatment in Kuala Lumpur Hospital. Methodology: A cross-sectional study was conducted on 130caregiver patient dyads, recruited by non-random sampling at Kuala Lumpur Hospital. Data were collected in 2 stages:1) the caregivers were screened for psychological distress using the Depression, Anxiety, Stress, Scale (DASS-21) whileother related factors for the patients and their caregivers were obtained; 2) the identified distressed caregivers (n=64)were then administered the Mini International Neuropsychiatric Interview (MINI) to diagnose anxiety disorders. Results:A total of 11.5% (n=15) of the caregivers reported suffering from anxiety disorders. Bivariate analysis found durationof caregiving (OR=3.31; CI=2.21 11.93), shared caregiving (OR=4.07; CI=1.34-12.36), and patients' treatment type(OR=3.42; CI=1.92-12.76) were significantly associated with anxiety disorders (p value <0.05), with shared caregivingand patient's treatment type remaining significant using logistic regression (p value < 0.05, R2 = 0.255). Conclusions:Every one in ten of the caregivers in this study had a diagnosable anxiety disorder, associated with certain care-givingfactors and patients' treatment. This should alert clinicians to such risk and indicates psychological support needs forfamily caregivers. PMID- 28345832 TI - Metformin Inhibits Migration and Invasion of Cholangiocarcinoma Cells AB - Background: Metformin is an oral anti-diabetic agent that has been widely prescribed for treatment of type II diabetes.Anti-cancer properties of metformin have been revealed for numerous human malignancies including cholangiocarcinoma(CCA) with anti-proliferative effects in vitro. However, effects on CCA cell migration and invasion have not beenfully investigated. The present study aimed to explore the inhibitory effects of metformin on motility, migration andinvasion of the CCA cell line HuCCT1, and examine molecular mechanisms underlying metformin effects. Methods:HuCCT1 cells were exposed to increasing doses of metformin. Viability and growth of HuCCT1 cells were assessedby MTS and colony formation assays, respectively. Motility, migration and invasion of metformin-treated HuCCT1cells were determined in vitro using wound healing, transwell migration and matrigel invasion assays. Expression ofsignaling molecules and epithelial-mesenchymal transition (EMT) markers was assessed by Western blotting. Results:It was observed that metformin significantly decreased HuCCT1 cell viability and colony formation. The agent alsomarkedly reduced wound closure, migration and invasion of HuCCT1 cells. Furthermore, metformin exposure resultedin decreased STAT3 activation and down-regulation of anti-apoptotic protein Bcl-2 and Mcl-1 expression. In addition,it upregulated the expression of E-cadherin, while downregulating that of N-cadherin, Snail, and MMP-2. Conclusion:These results demonstrated inhibitory effects of metformin on CCA cell migration and invasion, possibly involvingthe STAT3 pathway and reversal of EMT markers expression. They further suggest that metformin may be useful forCCA management. PMID- 28345833 TI - Efficacy and Toxicity of Low-Dose versus Conventional-Dose Chemotherapy for Malignant Tumors: a Meta-Analysis of 6 Randomized Controlled Trials AB - Low-dose chemotherapy has emerged as a new strategy for control of cancer. However, there is a controversy as to whetherlow-dose chemotherapy is an effective way to manage many human malignancies. To shed light on this controversy,we performed a meta-analysis of relative merits between low-dose and conventional-dose chemotherapy in differentcarcinomas. Studies published before February 29, 2016 were reviewed for the meta-analysis and selected according todefined criteria. The effect levels of low-dose chemotherapy regarding overall survival (OS), progression-free survival(PFS) and severe adverse events (SAEs) (Grade>=3) were calculated as risk ratios (ORs) or adjusted hazard ratios (HRs).Six randomized controlled studies (RCTs) have provided data for low-dose chemotherapy versus conventional-dosechemotherapy for 838 cases and 833 cases, respectively. Interestingly, low-dose chemotherapy achieved the samedesired potency as conventional-dose chemotherapy, with no differences in pooled ORR (RR=1.00, 95%CI [0.89,1.13]; (P=0.97), OS (HR=1.07, 95%CI [0.90, 1.26]; P=0.44) and PFS (HR=1.02, 95%CI [0.84, 1.23]; P=0.87) values.Furthermore, pooled data for common SAEs showed that, compared with conventional-dose chemotherapy regimen,low dose chemotherapy regimen resulted in significant less mucositis (P<0.0001), thrombocytopenia (P<0.00001),anemia (P=0.0001) and febrile neutropenia (P=0.004). At the same time, no statistically significant differences wereobserved with regard to treatment-related death (P=0.36), diarrhea (P=0.49), leucopenia (P=0.11), neutropenia (P=0.74)and nausea/vomiting ("P"=0.21). Publication bias was assessed by Egger's test and the funnel plot. In conclusion, themeta-analysis seems to support the idea that low-dose chemotherapy may play an important role in achieving the samedesired potency as conventional-dose chemotherapy in managing malignant tumors. Moreover, low-dose regimen seemsto possess positive advantages of lower toxicity which is a particular concern for most patients. PMID- 28345834 TI - Hyperuricemia at The Time Of Diagnosis is a Factor for Poor Prognosis in Patients With Stage II and III Colorectal Cancer (Uric Acid and Colorectal Cancer) AB - Purpose: In this pilot study we investigated whether serum levels of uric acid, the final breakdown product ofpurine metabolism, might influence cancer-related events in stage II and III colorectal cancer patients. Material andmethods: In this cross-sectional retrospective study, a total of 150 stage II and III colorectal adenocarcinoma patientswith no exclusion criteria were included. Serum uric acid levels of the patients measured at diagnosis and demographic,clinical, laboratory analyses were performed and histologically features recorded. Patients were stratified into quartilesaccording to serum uric acid level with different cut-off values. Results: The mean serum uric acid level of all patientswas determined o be 6.97+/-2.87 md/dL (range, 3.1-12.4). Median follow-up time was 98 (range 9-98) months and theproportion of patients who did not relapse was 22%. It was determined that majority of the patients who had serum uricacid levels over 8.37 mg/dL had stage IIIB lesions, were smokers, were among those who lost weight, with metastasisto the liver and with significantly leukocyte and platelet counts. Conclusions: Serum uric acid levels measured at thetime of diagnosis may be associated PMID- 28345835 TI - Evolution of the Histo-Epidemiological Profile of Urological Cancers in Togo AB - Background: Urological cancers are an important public health issue and pose problems with diagnosis andadequate management in developing countries. Our aim was to determine and report epidemiological and histologicalfeatures of urological cancers in Togo. Materials and methods: A retrospective descriptive study was conducted ofcases of urological cancers observed in the laboratory of pathological anatomy of the CHU Tokoin over the last 4 years(2012-2016). The parameters studied were frequency, age, sex, sites of development and histological type. Results:Epidemiological data were collected for 182 cases, representing 16.4% of all cancers (1108 cases). The annual frequencywas 45.5+/ 1.1 cases on average. The male:female sex ratio was 8.6 with a mean age of 60.2 years. Regarding location,in decreasing order of frequency, the tumors were found in the prostate (n=121 cases; 66.5%), bladder (n=28; 15.4%),kidney (n=19; 10.4%), testis (n=10; 5%), penis (n=3; 1.7%) and scrotum (n=1; 0.5%). Histologically, prostate cancerswere predominantly adenocarcinomas (n=116 cases; 95.8%) with a Gleason score of 6 (n=46; 39.7%) predominant.Bladder cancers were mainly squamous cell carcinomas (n=11; 39.3%) followed by transitional carcinomas (n=9cases; 32.1%) and adenocarcinomas (n=7; 25%). Kidney cancers were predominantly nephroblastomas (n=10, 52.6%)in children and clear cell carcinomas (n=8 cases; 42.1%) in adults. Testicular cancers were Burkitt lymphomas in 5cases. The cases of penis and scrotum cancers were all squamous cell carcinomas. Conclusion: Urological cancersare experiencing an upsurge in frequency in Togo, dominated by prostate cancer, with a high frequency of squamouscell carcinoma of the bladder due to endemic bilharziasis. PMID- 28345837 TI - Association of the Asp1312Gly Thyroglobulin Gene Polymorphism with Susceptibility to Differentiated Thyroid Cancer in an Iranian Population AB - Background and aim: While the causes of thyroid cancer in most patients remain largely unknown, it has recentlybeen reported that there may be links to particular chromosome regions. In particular, polymorphisms (SNPs) in thethyroglobulin (TG) gene could be susceptibility factors. Methods: In this case control study, any association of theAsp1312Gly single nucleotide polymorphism (SNP) in the TG gene (rs2069556) with susceptibility to differentiatedthyroid cancer (DTC) was investigated among 103 Iranian patients and 100 controls who had no history of any type ofcancer. Genomic DNA was extracted from the whole blood by salting out procedure. High Resolution Melting (HRM)technique was used to detect this SNP. Results: Data were analyzed with SPSS software and the results showed thatthe recessive GG genotype was associated with an increased risk of differentiated thyroid carcinoma when compared tothe AA+AG genotypes (OR: 2.06; CI: 1.09-3.89; P-value: 0.025). Conclusion: Although our study demonstrated thatdifferentiated thyroid cancer is significantly associated with this polymorphism, further studies with larger populationsare required to confirm our findings. PMID- 28345838 TI - ERCC1 Expression in Metastatic Triple Negative Breast Cancer Patients Treated with Platinum-Based Chemotherapy AB - Background: Possible targeted therapies for metastatic triple negative breast cancer (TNBC) include cytotoxicchemotherapy that causes interstrand breaks (platinum-based drugs). The excision repair cross-complementation 1(ERCC1) enzyme plays an essential role in the nucleotide excision repair pathway, removing platinum-induced DNAadducts and contributing to cisplatin resistance. Detecting ERCC1 overexpression is important in considering treatmentoptions for metastatic TNBC, including individualized approaches to therapy, and may facilitate improved responses orreduction of unnecessary toxicity. We hypothesized that assigning cisplatin based on pretreatment ERCC1 expressionwould improve response and survival. This study was conducted to assess the impact of ERCC1 expression on PFS,OS and response rates in metastatic triple negative breast cancer patients treated with platinum-based chemotherapy.Methods: From June 2012 to November 2013, 52 metastatic triple negative breast cancer patients were enrolled.ERCC1 protein expression was detected from pretreatment biopsies by Immunohistochemistry. All patients receivedcisplatin plus paclitaxel. The primary end point was the impact of ERCC1 expression on PFS and OS. Results: 34patients (65.4%) showed positive ERCC1 expression while 18 (34.6%) proved negative. Positive ERCC1 expressionwas associated with short PFS (median, 5 months vs. 7 months; P = 0.043), short OS (median, 9 months vs. 11 months;P = 0.033) and poor response to cisplatin based chemotherapy (P = 0.046). Conclusions: This prospective study furthervalidated ERCC1 as a reliable biomarker for customized chemotherapy in metastatic triple negative breast cancerpatients. High expression of ERCC1 was thereby fond to be significantly associated with poor outcome in patientstreated with platinum based chemotherapy. PMID- 28345836 TI - Assessing the Effect of Waterpipe Smoking on Cancer Outcome - a Systematic Review of Current Evidence AB - Background: Waterpipe smoking (WPS) is widely believed to be a safe and hazard free tobacco habit. However,a number of studies have indicated that exposure to several toxicants and carcinogens through WPS is strongly relatedto serious health hazards. The current paper presents a narrative review on the effects of WPS on cancer outcome.Methods: The addressed focused question was "Is there an association between waterpipe smoking and cancer outcome?"PubMed, Medline, EMBASE, ISI Web of Science and the Cochrane databases were searched until June 2015 using thekey words "Waterpipe", "Hookah", "Narghileh", "Shisha", "Hubbly Bubbly" "cancer" in various combinations. Lettersto the Editor, review articles, case-reports and unpublished articles were excluded. Results: A total of 16 studies wereincluded: six on lung cancer, three on oesophageal cancer, two on gastric cancer, two on bladder cancer, and one eachon nasopharyngeal, pancreatic and prostate cancers. Our search did not yield any study that evaluated the risk of oralcancer in WPS users. The available evidence showed a significant association of WPS with lung cancer (UOR 6.0, 95%CI 1.78-20.26); however, no association was observed with bladder, nasopharyngeal, pancreatic and prostate cancers.Gastric (OR 3.4, 95% CI 1.7-7.1) and oesophageal cancers (OR 1.85, 95% CI 1.41-2.44) were observed to have weakassociations with WPS. Conclusion: Regardless of the limitations, there is sufficient evidence to suggest associationsof WPS with cancer, particularly in the lung. Future well-designed studies are required to identify and quantify withconfidence all the health effects of this form of smoking. PMID- 28345839 TI - Validation of an Indonesian Version of the Breast Cancer Awareness Scale (BCAS-I) AB - Background: Raising breast cancer awareness is a key strategy to reduce associated mortality. While a paucityof adequately validated instruments for breast cancer awareness is applicable across cultures, even outside the healthcare setting such instruments have been developed. Objective: This study investigated the validity and psychometricproperties of a breast cancer awareness scale in Indonesia (BCAS-I). Methods: This cross-sectional study was carriedout among Indonesian women conveniently selected within three provinces (Yogyakarta, South of Sumatera and EastNusa Tenggara) located in rural-urban areas using stratified random sampling. First, we translated all questionnairesfrom English to the local language and then back-translated. The third step was to perform psychometric testing ofthe adapted instrument by establishing internal consistency (Cronbach's alpha score 0.79) and construct validity byconfirmatory factor analysis (CFA). Results: In the 856 participants who responded (responded rate = 98.28%), theage ranged from 18 to 80 years old (mean = 30, SD = 11). The BCAS-I was shown to have good internal consistency,and CFA demonstrated the model fit data adequately (chi2 = 922.267, df = 515, p <0.001, comparative fit index = 0.965,Tucker-Lewis Index = 0.96, goodness-of-fit index = 0.97, adjusted goodness of-fit index = 0.97, root-mean-squareerror of approximation = 0.03 95% confidence interval: 0.027, 0.034). The final version of BCAS-I consists of 33items across 5 domains that cover most key aspects of breast cancer awareness for this population. Conclusion: TheBCAS-I demonstrated good psychometric properties and was found to be valid to provide a measurement of breastcancer awareness in Asian women in general and Indonesian women in particular. PMID- 28345840 TI - Correlation between Epstein-Barr Virus Infection and Disease Activity of Systemic Lupus Erythematosus: a Cross-Sectional Study AB - Background: Systemic lupus erythematosus (SLE) is an autoimmune disease for whose pathogenesis viral infectionsare important. The Epstein-Barr virus (EBV) is the main infectious etiological agent. This study aimed to quantitativeevaluation of EBV in SLE patients. Materials and Methods: In this cross-sectional study, 40 patients with SLE diagnosedbased on American College of Rheumatology criteria were selected using purposive sampling. All were included in thestudy after obtaining informed consent for participation. Whole blood samples were taken and buffy coat preparationswere isolated to determine viral load using the real-time polymerase chain reaction method and assessment with the SLEdisease activity index (SLE-DAI). Results: From a total of 40 patients, 37 cases (92.5%) were women. The EBV testwas positive in 67.5% and mean viral load was 5396 +/- 1891.9 copy/ml. Twenty of forty patients had active and 50%inactive disease, mean EBV viral loads being 6798 and 28.25 copy/ml, respectively (P-value = 0.003). In terms of theseverity of disease activity, 17.5 % of female patients had mild to moderate activity, whilst 32.5% of them had severeactivity, with respective viral loads of 5,803.3 and 29.73 copy/ml (P-value = 0.003). Conclusion: The Epstein Barrviral load in SLE patients with active disease was found to be markedly higher than in inactive cases. Thus, EBV mayhave an important role in the pathogenesis and activity of SLE. PMID- 28345841 TI - Carcinogenic Liver Fluke and Others Contaminated in Pickled Fish of Northeastern Thailand AB - Twenty provinces in northeastern Thailand were investigated for fluke metacercariae contamination in pickled fish,or pla-som, during January -June 2016. A total of 129 pickled fish shops were randomly chosen. Samples were digestedwith acid-pepsin and those found to be infected with metacercariae were fed to hamsters to test for metacercariaeinfectivity. The results demonstrated that only 20.2% of the pla-som samples were infected with fluke metacercariae(mc), at various levels (1 to 268 mc/kg). All recovered fluke metacercariae were inactive, degenerated and could notdevelop to adults in the animal model. In conclusion, the fluke mc infection status in pla-som was correlated with theprevalence of fluke infection in this region known for high O.viverrini and cholangiocarcinoma development. Clearly,systematic control of the fluke life cycle is needed. Whether pickling is an effective preventive measure needs furtherassessment. PMID- 28345842 TI - Bone Mineral Density in Survivors of Childhood Acute Lymphoblastic Leukemia AB - Background: The objective of this study was to evaluate bone mineral density (BMD) after completion of treatmentfor childhood acute lymphoblastic leukemia (ALL). Methods: In this cross-sectional study, 103 survivors of ALLaged 13.5 +/- 0.45 who completed their treatment at least one year earlier were enrolled. Among these, 49.5% and51.5% received chemotherapy alone and chemotherapy plus cranial radiotherapy, respectively. Bone mineral content,BMD, and bone mineral apparent density in the lumbar spine (LS), femoral neck (FN) and forearm were assessedusing dual-energy X-ray absorptiometry (DEXA). BMD Z-scores were classified according to International Societyfor Clinical Densitometry (ISCD) criteria. Results: The mean BMD Z-scores +/- SD forLS, FN and forearm were 1.60+/- 0.12, -1.21 +/- 0.9 and -2.43 +/- 0.14 respectively with significant differences (P<0.001). Considering the lowest BMDZ-score in LS and FN areas (at any site) and according to the ISCD classification, 62.1%, 33% and 4.9% of the patientshad normal BMD, low BMD and osteoporosis, respectively. Also, 8.7% of patients had developed fractures aftercompletion of the treatment period, 4.9% having BMD Z-Scores <-2 SD at any site. A direct relationship was apparentbetween BMD Z-scores at LS and FN at any sites and risk of fracture (P<0.001). Conclusions: ALL patients are atrisk for low BMD and fracture. Therefore, applying DEXA scanning is recommended after completion of therapy forprevention of BMD reduction and osteoporosis. PMID- 28345843 TI - Diagnostic Value of Fine-Needle Aspiration Biopsies and Pathologic Methods for Benign and Malignant Breast Masses and Axillary Node Assessment AB - Bacground: The goal of this study was to evaluate the fine needle aspiration (FNA) preoperatively together withTouch Print, Crush Print, frozen section and pathologic methods to reach a diagnosis for patients with breast andaxillary masses. Methods: This study was conducted on 107 patients, and included 111 samples of breast and 43 ofaxillary masses taken at surgery. Data on epidemiological and clinical features of the patients were collected usinga questionnaire. The results of the methods of FNA, Touch Print, and Crush Print were compared with the results ofpathology after operations. Results: Comparison between the diagnosis values of FNA with pathology for breast cancershowed sensitivity, sensitivity, positive predictive values, negative predictive values, positive mendacious percentages,and negative mendacious percentages of 80.4%, 98%, 97.3%, 87.6%, 2%, and 19.6% , respectively, and for metastaticaxillary lymph nodes, 80%, 95.6%, 94.1%, 84.6%, 4.4%, and 20%. Comparison of diagnosis values of FNA withTouch Print and Crush Print for breast cancer gave values of 82.2%, 89%, 97.3%, 89%, 1.6%, and 17.8%, respectively,and for metastatic axillary lymph nodes 84.2%, 95.8%, 94.1%, 88.4%, 14.2%, and 15.8%. Conclusion: Use of thesemethods, compared with pathology, can decrease cost, time, and a need for a second surgery and related complications. PMID- 28345844 TI - Association between the DNA Repair Gene XRCC3 rs861539 Polymorphism and Risk of Osteosarcoma: a Systematic Review and Meta-Analysis AB - Objective: Although there are a few studies investigating the relation between X Ray Repair Cross Complementing 3(XRCC3) gene rs861539 polymorphism and osteosarcoma (OSA), the results are inconsistent. Therefore, we performedthis systematic review and meta-analysis to clarify the associations between XRCC3 rs861539 polymorphism and OSArisk. Methods: We have retrieved published literature from PubMed, Google scholar, and ISI Web of Knowledge up to25 January 2017. Odds ratios were pooled using either fixed-effects or random effects models. Overall and subgroupanalyses were performed. Statistical analysis was performed running comprehensive meta-analysis (CMA) 2.0 software.Results: A total of four studies with 515 cases and 1,109 controls were identified in order to investigate the associationbetween XRCC3 rs861539 polymorphism and OSA risk. The results showed that XRCC3 rs861539 polymorphismwas associated with OSA in allelic (T vs. C: OR= 1.563, 95% CI: 1.244-1.963, p= <0.001), homozygote (TT vs. CC:OR= 2.574, 95% CI: 1.573-4.212, p= <0.001), dominant (TT+TC vs. CC: OR= 1.255, 95% CI: 1.011-1.558, p= 0.039),and recessive (TT vs. TC+CC: OR= 2.224, 95% CI: 1.393 3.552, p= 0.001), but not with heterozygote (TC vs. CC:OR= 1.361, 95% CI: 0.982 1.885, p= 0.064). The XRCC3 rs861539 polymorphism conferred susceptibility to OSA inAsians, but not in Caucasians. Additionally, we observed no evidence of publication bias. Conclusion: To the best ofour knowledge, this is the first meta analysis investigating the association between XRCC3 rs861539 polymorphismand OSA risk. Our results revealed a significant association between the XRCC3 rs861539 polymorphism and risk ofOSA, especially in Asian populations. Future more comprehensive and well-designed case control studies with largersample size are needed to warrant these findings. PMID- 28345846 TI - Compliance with Tobacco Promotion and Sale Laws in School Neighbourhoods in India AB - Objective: Regulation of sale of tobacco has given sufficient attention in India and little information exists aboutthe impact of bans near schools. Our study aim was to check the levels of tobacco promotion, advertising and salesin school neighborhoods' of Central Delhi. Methods: Using multistage random sampling 15 schools were selectedin Central Delhi. Areas 100 meters around each were mapped using a map tool and screened using a self designedquestionnaire consisting of 26 questions, both closed and open ended, to determine the details of outlets, sales of tobaccoand tobacco products, advertising, promotions, school roles, and children seeking tobacco. The data were subjectedto statistical analysis. Results: The response rate was 65%. Outlet licenses were present in only 6 (3.47%). The pointsale of tobacco was most frequently in tea stalls and a total of 173 (41.2%) outlets had some form of tobacco sale. Thebrands of smokeless tobacco sold more were shikar (50%) and classic citrus (30%). Advertisement or promotion ofsales was mainly in the form of signs and displays (53%). Major schools did not have any no tobacco boards displayed.Conclusion: Sale of tobacco continues in central Delhi with a lack of compliance with the rules of COPTA. Theimplications of this non compliance in the Capital region is of major significance for the rest of the country. PMID- 28345845 TI - The Pre-Treatment Neutrophil-Lymphocyte Ratio: a Useful Tool in Predicting Non Sentinel Lymph Node Metastasis in Breast Cancer Cases AB - Background: The sentinel lymph node (SLN) biopsy is a highly accurate predictor of overall axillary nodal statusin early breast cancer patients. There is however, still a debate on which patients with a positive SLN can benefit fromaxillary lymph node dissection (ALND). Numerous studies have been designed to identify variables that are predictiveof non-SLN metastasis to avoid a complete ALND. The aim of this study was to determine whether the pre-treatmentneutrophil lymphocyte ratio (NLR) can be a predictive factor of non-SLN metastasis in early breast cancer patients.Materials and Methods: The records of 214 consecutive patients with cT1-3N0 invasive breast cancer who hadundergone intraoperative SLN evaluation at Songklanagarind Hospital between the 1stof March 2011 and the 30thofMay 2016 were examined. Data on patient demographics, tumor variables and NLR were collected and factors fornon-SLN metastasis were analyzed using multivariate logistic regression. The power of the NLR was quantified withreceiver operating characteristics (ROC) curves as measured by the areas under curves (AUC). Results: Multivariateanalysis established presence of lymphovascular invasion (OR 8.4, 95%CI 2.3-31.3, p=0.002), macrometastasis(OR 6.6, 95%CI 1.8-24.7, p=0.005), and NLR (OR 2.3, 95%CI 1.1-4.8, p=0.033) as predictive factors of non-SLNmetastasis with statistical significance. The AUC for NLR was 0.7 (95%CI 0.6-0.8) with an optimal cut-off of 2.6giving a sensitivity of 62%, a specificity of 83.8%, a positive predictive value of 77.3% and a negative predictive valueof 70.5%. Conclusion: Pre-treatment NLR is a useful diagnostic aid for predicting additional non-SLN metastasis. PMID- 28345847 TI - Five-Year Survival is Not a Useful Measure for Cancer Control in the Population: an Analysis Based on UK Data AB - Background: Five-year survival is an important metric for progress in cancer control broadly used both in thecancer literature and by the public. In order to assess its validity and relation to other common metrics, we analyzedthe relationship between 5-year survival, incidence and mortality using publicly available cancer registry data fromEngland and Wales. Methods: Five-year survival, incidence and mortality data were obtained from the online databaseof a registered charity, Cancer Research UK. We extracted sex-specific age standardized mortality, incidence, and5-year survivalfor16 types of cancer over the period from 1976 to 1995. The relationships between 5-year survival,incidence and mortality were estimated using both Pearson and Spearman correlation coefficients. Results: All 16cancertypes showed an increase in 5-year survival for both genders from 1976 to 1995, ranging from 0.2% (pancreas andlung cancer) to 16.6% (prostate cancer) for males and 0.2% (pancreas cancer) to 16.6% (leukemia) for females. From1976 to 1995, there was no significant correlation between changes in 5-year survival and cancer mortality for eithersex (males, Pearson r=0.16, Spearman r=-0.06; females, Pearson r=-0.33, Spearman r=-0.43). A positive relationshipbetween 5-year survival and incidence was noted among males, but not among females (males, Pearson r=0.61,Spearman r=0.53; females, Pearson r=0.03, Spearman r=0.11). However, after excluding breast and prostate cancer,the positive association became weaker and became statistically non-significant for males (Pearson r=0.47; Spearmanr=0.41). Conclusions: Our findings suggest that there are no reliable relationships between changes in 5-year survivaland cancer incidence or mortality. Increases in 5-year survival might therefore represent poor indicators of progress incancer control at the population level. In the absence of over-diagnosis, 5-year survival might only indicate improveddiagnosis and treatment in clinical practice. PMID- 28345851 TI - High-Resolution Adhesion Mapping of the Odd-Even Effect on a Layer-by-Layer Coated Biomaterial by Atomic-Force-Microscopy. AB - The adhesion behavior of polyelectrolyte multilayers consisting of poly(diallyldimethylammonium chloride), PDDA, and poly(styrenesulfonate), PSS, toward a silicon AFM tip was studied during their build-up on wood, a chemically heterogeneous, micrometer rough biomaterial and compared with a nanometer rough substrate, namely quartz. The atomic force microscopy-based force mapping approach generated high-resolution topography-, and adhesion maps within the first bilayers, which point toward a homogeneous layer-by-layer build-up on the biomaterial surface, and therefore indicate an even charge distribution. By analyzing the force-distance curves in every pixel of the mapping, new insights into the specific interactions of the polyelectrolyte multilayers at the surface were achieved. The characteristic odd-even effect of polyelectrolyte multilayers cannot only be determined on quartz, but also on the biomaterial wood, however, only after an offset of two bilayers. This is potentially due to the specific roughness and charge of wood in comparison to commonly used quartz. PMID- 28345852 TI - Layer-Number Dependent Antibacterial and Osteogenic Behaviors of Graphene Oxide Electrophoretic Deposited on Titanium. AB - Graphene oxide has attracted widespread attention in the biomedical fields due to its excellent biocompatibility. Herein we investigated the layer-number dependent antibacterial and osteogenic behaviors of graphene oxide in biointerfaces. Graphene oxide with different layer numbers was deposited on the titanium surfaces by cathodal electrophoretic deposition with varied deposition voltages. The initial cell adhesion and spreading, cell proliferation, and osteogenic differentiation were observed from all the samples using rat bone mesenchymal stem cells. Both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus were used to investigate the antibacterial effect of the modified titanium surfaces. Cocultures of human gingival fibroblasts (HGF) cells with Escherichia coli and Staphylococcus aureus were conducted to simulate the conditions of the clinical practice. The results show that the titanium surfaces with graphene oxide exhibited excellent antibacterial and osteogenic effects. Increasing the layer-number of graphene oxide resulted in the augment of reactive oxygen species levels and the wrinkling, which led to the antibacterial and osteogenic effects, respectively. Compared to pure titanium surface in the cells-bacteria coculture process, the modified titanium surfaces with graphene oxide exhibited higher surface coverage percentage of cells. PMID- 28345853 TI - Single-Crystal-like Perovskite for High-Performance Solar Cells Using the Effective Merged Annealing Method. AB - We report a simple, low cost, and quite effective method for achieving single crystal-like CH3NH3PbI3 perovskite leading to a significant enhancement in the performance and stability of inverted planar perovskite solar cells (IPSCs). By employing a merged annealing method during the fabrication of an IPSC for preparing the perovskite CH3NH3PbI3 film, we remarkably increase the crystallinity of the CH3NH3PbI3 film and enhance the device performance and stability. An IPSC with the indium tin oxide/poly(3,4-ethylenedioxythiophene) poly(styrenesulfonate)/CH3NH3PbI3 (active layer)/[6,6]-phenyl-C61-butyric acid methyl ester/Al structure was fabricated using the merged annealing method and exhibited significantly enhanced performance with a high power conversion efficiency of 18.27% and a fill factor of 81.34%. Moreover, since two separate annealing processes are merged in the proposed annealing method, the fabrication step becomes much simpler and easier, leading to a reduction in fabrication costs. PMID- 28345854 TI - Flexible P-Doped Carbon Cloth: Vacuum-Sealed Preparation and Enhanced Na-Storage Properties as Binder-Free Anode for Sodium Ion Batteries. AB - In this work, a flexible and self-supporting P-doped carbon cloth (FPCC), which is composed of interwoven mesh of hollow microtubules with porous carbon walls, is prepared via a vacuum-sealed doping technology by employing the commercially available cotton cloth as sustainable and scalable raw material. When directly used as binder-free anode for sodium-ion batteries, the as-prepared FPCC delivers superior Na-storage properties in terms of specific capacity up to 242.4 mA h g 1, high initial Coulombic efficiency of ~72%, excellent rate capabilities (e.g., 123.1 mA h g-1 at a high current of 1 A g-1), and long-term cycle life (e.g., ~88% capacity retention after even 600 cycles). All these electrochemical data are better than the undoped carbon cloth control, demonstrating the significance of P-doping to enhance the Na-storage properties of cotton-derived carbon anode. Furthermore, the technologies of electrochemical impedance spectroscopy and galvanostatic intermittent titration technique are implemented to disclose the decrease of charge transfer resistance and improvement of Na-migration kinetics, respectively. PMID- 28345855 TI - Surface Modification of Na3V2(PO4)3 by Nitrogen and Sulfur Dual-Doped Carbon Layer with Advanced Sodium Storage Property. AB - Nitrogen and sulfur dual-doped carbon layer wrapped Na3V2(PO4)3 nanoparticles (NVP@NSC) have been successfully fabricated by the facile solid-state method. In this hierarchical structure, the Na3V2(PO4)3 nanoparticles are well dispersed and closely coated by nitrogen and sulfur dual-doped carbon layer, constructing an effective and interconnected conducting network to reduce the internal resistance. Furthermore, the uniform coating layers alleviate the agglomeration of Na3V2(PO4)3 as well as mitigate the side reaction between electrode and electrolyte. Because of the excellent electron transfer mutually enhancing sodium diffusion for this extraordinary structure, the NVP@NSC composite delivers an impressive discharge capacity of 113.0 mAh g-1 at 1 C and shows a capacity retention of 82.1% after 5000 cycles at an ultrahigh rate of 50 C, suggesting the remarkable rate capability and long cyclicity. Surprisingly, a reversible capacity of 91.1 mAh g-1 is maintained after 1000 cycles at 5 C under the elevated temperature of 55 degrees C. The approach of nitrogen and sulfur dual doped carbon-coated Na3V2(PO4)3 provides an effective and promising strategy to enhance the ultrahigh rate and ultralong life property of cathode, which can be used for large-scale commercial production in sodium ion batteries. PMID- 28345856 TI - Instantaneous Pulsed-Light Cross-Linking of a Polymer Gate Dielectric for Flexible Organic Thin-Film Transistors. AB - We report the instantaneous pulsed-light cross-linking of polymer gate dielectrics on a flexible substrate by using intensely pulsed white light (IPWL) irradiation. Irradiation with IPWL for only 1.8 s of a poly(4-vinylphenol) (PVP) thin film with the cross-linking agent poly(melamine-co-formaldehyde) (PMF) deposited on a plastic substrate was found to yield fully cross-linked PVP films. It was confirmed that the IPWL-cross-linked PVP films have smooth pinhole-free surfaces and exhibit a low leakage current density, organic solvent resistance, and good compatibility with organic semiconductor, and that they can be used as replacements for typical PVP dielectrics that are cross-linked with time and energy intensive thermal heating processes. The synchronization of the IPWL irradiation with substrate transfer was found to enable the preparation of cross linked PVP films on large area substrates with a highly uniform capacitance. Flexible OTFT based on IPWL-cross-linked PVP dielectrics were found to exhibit good electrical performance that is comparable to that of devices with thermally cross-linked PVP dielectric, as well as excellent deformation stability even at a bending radius of 3 mm. PMID- 28345857 TI - Self-Cleaning Membranes from Comb-Shaped Copolymers with Photoresponsive Side Groups. AB - In this study, we present a novel self-cleaning, photoresponsive membrane that is capable of removing predeposited foulant layers upon changes in surface morphology in response to UV or visible light irradiation while maintaining stable pore size and water permeance. These membranes were prepared by creating thin film composite (TFC) membranes by coating a porous support membrane with a thin layer of novel comb-shaped graft copolymers at two side-chain lengths featuring polyacrylonitrile (PAN) backbones and photoreactive side chains, synthesized by atom transfer radical polymerization (ATRP). Photoregulated control over membrane properties is attained through a light-induced transition, where the side chains switch between a hydrophobic spiropyran (SP) state and a zwitterionic, hydrophilic merocyanine (MC) state. The light-induced switch between the SP and MC forms changes surface hydrophilicity and causes morphological changes on the membrane surface as evidenced by atomic force microscopy (AFM). Before any phototreatment, the as-coated membrane surface comprises mostly hydrophobic SP groups that allow the adsorption of organic solutes such as proteins the membrane surface, reducing flow rate. Once exposed to UV light, conversion of the SP groups to hydrophilic MC groups leads to the release of adsorbed molecules and the full recovery of the initial water flux. A fouled membrane in the more hydrophilic MC form is also capable of self-cleaning upon conversion to the less hydrophilic SP form by visible light irradiation. The self-cleaning behavior observed for this system, where the surface became less hydrophilic but also experienced a morphological change, demonstrates a novel mechanism that has a mechanical component in addition to the changes in hydrophilicity. It is also the first report, to our knowledge, of self-cleaning performance accompanied by a decrease in hydrophilicity. PMID- 28345858 TI - Enhanced Absorption Performance of Carbon Nanostructure Based Metamaterials and Tuning Impedance Matching Behavior by an External AC Electric Field. AB - Metamaterials have surprisingly broadened the range of available practical applications in new devices such as shielding, microwave absorbing, and novel antennas. More research has been conducted related to tuning DNG frequency bands of ordered or disordered metamaterials, and far less research has focused on the importance of impedance matching behavior, with little effort and attention given to adjusting the magnitude of negative permittivity values. This is particularly important if devices deal with low-amplitude signals such as radio or TV antennas. The carbon/hafnium nickel oxide (C/Hf0.9Ni0.1Oy) nanocomposites with simultaneously negative permittivity and negative permeability, excellent metamaterial performance, and good impedance matching could become an efficient alternative for the ordered metamaterials in wave-transparent, microwave absorbing, and solar energy harvesting fields. In this study, we prepared C/Hf0.9Ni0.1Oy nanocomposites by the solvothermal method, and we clarified how the impedance matching and double-negative (DNG) behaviors of C/Hf0.9Ni0.1Oy can be tuned by an external AC electric field created by an electric quadrupole system. An external electric field allows for the alignment of the well-dispersed nanoparticles of carbon with long-range orientations order. We believe that this finding broadens our understanding of moderate conductive material-based random metamaterials (MCMRMs) and provides a novel strategy for replacing high-loss ordered or disordered metamaterials with MCMRMs. PMID- 28345859 TI - Aqueous Nanoparticle Polymer Solar Cells: Effects of Surfactant Concentration and Processing on Device Performance. AB - Polymer solar cells based on PDPP5T and PCBM as donor and acceptor materials, respectively, were processed from aqueous nanoparticle dispersions. Careful monitoring and optimization of the concentration of free and surface-bound surfactants in the dispersion, by measuring the conductivity and zeta-potential, is essential to avoid aggregation of nanoparticles at low concentration and dewetting of the film at high concentration. The surfactant concentration is crucial for creating reproducible processing conditions that aid in further developing aqueous nanoparticle processed solar cells. In addition, the effects of adding ethanol, of aging the dispersion, and of replacing [60]PCBM with [70]PCBM to enhance light absorption were studied. The highest power conversion efficiencies (PCEs) obtained are 2.0% for [60]PCBM and 2.4% for [70]PCBM-based devices. These PCEs are limited by bimolecular recombination of photogenerated charges. Cryo-TEM reveals that the two components phase separate in the nanoparticles, forming a PCBM-rich core and a PDPP5T-rich shell and causing a nonoptimal film morphology. PMID- 28345860 TI - Instant, Visual, and Instrument-Free Method for On-Site Screening of GTS 40-3-2 Soybean Based on Body-Heat Triggered Recombinase Polymerase Amplification. AB - On-site monitoring the plantation of genetically modified (GM) crops is of critical importance in agriculture industry throughout the world. In this paper, a simple, visual and instrument-free method for instant on-site detection of GTS 40-3-2 soybean has been developed. It is based on body-heat recombinase polymerase amplification (RPA) and followed with naked-eye detection via fluorescent DNA dye. Combining with extremely simplified sample preparation, the whole detection process can be accomplished within 10 min and the fluorescent results can be photographed by an accompanied smart phone. Results demonstrated a 100% detection rate for screening of practical GTS 40-3-2 soybean samples by 20 volunteers under different ambient temperatures. This method is not only suitable for on-site detection of GM crops but also demonstrates great potential to be applied in other fields. PMID- 28345862 TI - Quantification of Lipid Metabolism in Living Cells through the Dynamics of Lipid Droplets Measured by Stimulated Raman Scattering Imaging. AB - Dysregulation of lipid metabolism is associated with many diseases including cancer. Lipid droplet (LD), a ubiquitous organelle in mammalian cells, serves as a hub for lipid metabolism. Conventional assays on the measurement of lipid metabolism rely on the quantification of the lipid composition or amount. Such methods cannot distinguish LDs having different biofunctionalities in living cells, and thus could be inaccurate in measuring the instantaneous lipogenesis of the living cells. We applied label-free stimulated Raman scattering microscopy to quantify the LDs' spatial-temporal dynamics, which showed direct links to cellular lipid metabolisms and can separate LDs involved in different metabolic events. In human cancer cells, we found that changes in the maximum displacement of LDs reflected variations in cellular lipogenic activity, and changes in the average speed of LDs revealed alterations in LD size. The LD dynamics analysis allowed for more accurate measurement in the lipogenesis and LD dimensions, and can break the optical diffraction limit to detect small variation in lipid metabolism that was conventionally undetectable. By this method, we revealed changes in the lipogenic activity and LD sizes during glucose starvation of HeLa cells and transforming growth factor beta-induced epithelial-to-mesenchymal transition of SKOV-3 cells. This method opens a way to quantify lipid metabolism in living cells during cellular development and transition. PMID- 28345861 TI - Identification of Gene Transcription Start Sites and Enhancers Responding to Pulmonary Carbon Nanotube Exposure in Vivo. AB - Increased use of nanomaterials in industry, medicine, and consumer products has raised concerns over their toxicity. To ensure safe use of nanomaterials, understanding their biological effects at the molecular level is crucial. In particular, the regulatory mechanisms responsible for the cascade of genes activated by nanomaterial exposure are not well-characterized. To this end, we profiled the genome-wide usage of gene transcription start sites and linked active enhancer regions in lungs of C57BL/6 mice 24 h after intratracheal instillation of a single dose of the multiwalled carbon nanotube (MWCNT) Mitsui 7. Our results revealed a massive gene regulatory response, where expression of key inflammatory genes (e.g., Csf3, Il24, and Fgf23) was increased >100-fold 24 h after Mitsui-7 exposure. Many of the Mitsui-7-responsive transcription start sites were alternative transcription start sites for known genes, and the number of alternative transcription start sites used in a given gene was correlated with overall Mitsui-7 response. Strikingly, genes that were up-regulated after Mitsui 7 exposure only through their main annotated transcription start site were linked to inflammatory and defense responses, while genes up-regulated only through alternative transcription start sites were functionally heterogeneous and not inflammation-associated. Furthermore, we identified almost 12 000 active enhancers, many of which were Mitsui-7-responsive, and we identified similarly responding putative target genes. Overall, our study provides the location and activity of Mitsui-7-induced enhancers and transcription start sites, providing a useful resource for targeted experiments elucidating the biological effects of nanomaterials and the identification of biomarkers for early detection of MWCNT induced inflammation. PMID- 28345863 TI - Native Mass Spectrometry of Recombinant Proteins from Crude Cell Lysates. AB - Determining the properties of proteins prior to purification saves time and labor. Here, we demonstrate a native mass spectrometry approach for rapid characterization of overexpressed proteins directly in crude cell lysates. The method provides immediate information on the identity, solubility, oligomeric state, overall structure, and stability, as well as ligand binding, without the need for purification. PMID- 28345865 TI - Human Milk Oligosaccharide Specificities of Human Galectins. Comparison of Electrospray Ionization Mass Spectrometry and Glycan Microarray Screening Results. AB - The affinities of thirty-two free human milk oligosaccharides (HMOs) for four human galectin proteins, a stable mutant of hGal1 (hGal-1), a C-terminal fragment of hGal-3 (hGal-3C), hGal-7, and an N-terminal fragment of hGal-9 (hGal-9N), were measured using electrospray ionization mass spectrometry (ESI-MS). The binding data show that each of the four galectins recognize the majority of the HMOs tested (hGal-1 binds thirty-two HMOs, hGal-3C binds twenty-six, hGal-7 binds thirty-one, and hGal-9N binds twenty-six). Twenty-five of the HMOs tested bind all four galectins, with affinities ranging from 103 to 105 M-1. The reliability of the ESI-MS assay for quantifying the affinities of HMOs for lectins was established from the agreement found between the ESI-MS data and affinities of a small number of HMOs for hGal-1, hGal-3C, and hGal-7 measured by isothermal titration calorimetry (ITC). Comparison of the relative affinities (of 14 HMOs) measured by ESI-MS with the reported specificities of hGal-1, hGal-3, hGal-7, and hGal-9 for these same HMOs established using the shotgun human milk glycan microarray (HM-SGM-v2) showed fair-to-poor correlation, with evidence of false positives and false negatives in the microarray data. The results of this study suggest that HMO specificities of lectins established using microarrays may not accurately reflect their true HMO-binding properties and that the use of "in solution" assays such as ESI-MS and ITC is to be preferred. PMID- 28345864 TI - Triple-Stage Mass Spectrometry Unravels the Heterogeneity of an Endogenous Protein Complex. AB - Protein complexes often represent an ensemble of different assemblies with distinct functions and regulation. This increased complexity is enabled by the variety of protein diversification mechanisms that exist at every step of the protein biosynthesis pathway, such as alternative splicing and post transcriptional and translational modifications. The resulting variation in subunits can generate compositionally distinct protein assemblies. These different forms of a single protein complex may comprise functional variances that enable response and adaptation to varying cellular conditions. Despite the biological importance of this layer of complexity, relatively little is known about the compositional heterogeneity of protein complexes, mostly due to technical barriers of studying such closely related species. Here, we show that native mass spectrometry (MS) offers a way to unravel this inherent heterogeneity of protein assemblies. Our approach relies on the advanced Orbitrap mass spectrometer capable of multistage MS analysis across all levels of protein organization. Specifically, we have implemented a two-step fragmentation process in the inject flatapole device, which was converted to a linear ion trap, and can now probe the intact protein complex assembly, through its constituent subunits, to the primary sequence of each protein. We demonstrate our approach on the yeast homotetrameric FBP1 complex, the rate-limiting enzyme in gluconeogenesis. We show that the complex responds differently to changes in growth conditions by tuning phosphorylation dynamics. Our methodology deciphers, on a single instrument and in a single measurement, the stoichiometry, kinetics, and exact position of modifications, contributing to the exposure of the multilevel diversity of protein complexes. PMID- 28345866 TI - Biocompatible Hydroxylated Boron Nitride Nanosheets/Poly(vinyl alcohol) Interpenetrating Hydrogels with Enhanced Mechanical and Thermal Responses. AB - Poly(vinyl alcohol) (PVA) hydrogels with tissue-like viscoelasticity, excellent biocompatibility, and high hydrophilicity have been considered as promising cartilage replacement materials. However, lack of sufficient mechanical properties is a critical barrier to their use as load-bearing cartilage substitutes. Herein, we report hydroxylated boron nitride nanosheets (OH BNNS)/PVA interpenetrating hydrogels by cyclically freezing/thawing the aqueous mixture of PVA and highly hydrophilic OH-BNNS (up to 0.6 mg/mL, two times the highest reported so far). Encouragingly, the resulting OH-BNNS/PVA hydrogels exhibit controllable reinforcements in both mechanical and thermal responses by simply varying the OH-BNNS contents. Impressive 45, 43, and 63% increases in compressive, tensile strengths and Young's modulus, respectively, can be obtained even with only 0.12 wt% (OH-BNNS:PVA) OH-BNNS addition. Meanwhile, exciting improvements in the thermal diffusivity (15%) and conductivity (5%) can also be successfully achieved. These enhancements are attributed to the synergistic effect of intrinsic superior properties of the as-prepared OH-BNNS and strong hydrogen bonding interactions between the OH-BNNS and PVA chains. In addition, excellent cytocompatibility of the composite hydrogels was verified by cell proliferation and live/dead viability assays. These biocompatible OH-BNNS/PVA hydrogels are promising in addressing the mechanical failure and locally overheating issues as cartilage substitutes and may also have broad utility for biomedical applications, such as drug delivery, tissue engineering, biosensors, and actuators. PMID- 28345867 TI - Correction to Recent Advances in the Analysis of Single Cells. PMID- 28345868 TI - Immune System Activation and Depression: Roles of Serotonin in the Central Nervous System and Periphery. AB - Serotonin (5-hydroxytryptamine, 5-HT) has long been recognized as a key contributor to the regulation of mood and anxiety and is strongly associated with the etiology of major depressive disorder (MDD). Although more known for its roles within the central nervous system (CNS), 5-HT is recognized to modulate several key aspects of immune system function that may contribute to the development of MDD. Copious amounts of research have outlined a connection between alterations in immune system function, inflammation status, and MDD. Supporting this connection, peripheral immune activation results in changes in the function and/or expression of many components of 5-HT signaling that are associated with depressive-like phenotypes. How 5-HT is utilized by the immune system to effect CNS function and ultimately behaviors related to depression is still not well understood. This Review summarizes the evidence that immune system alterations related to depression affect CNS 5-HT signaling that can alter MDD relevant behaviors and that 5-HT regulates immune system signaling within the CNS and periphery. We suggest that targeting the interrelationships between immune and 5-HT signaling may provide more effective treatments for subsets of those suffering from inflammation-associated MDD. PMID- 28345869 TI - Characterization of the Aerosol-Based Synthesis of Uranium Particles as a Potential Reference Material for Microanalytical Methods. AB - A process for production of micrometer-sized particles composed of uranium oxide using aerosol spray pyrolysis is characterized with respect to the various production parameters. The aerosol is generated using a vibrating orifice aerosol generator providing monodisperse droplets, which are oxidized in a subsequent heat treatment. The final particles are characterized with microanalytical methods to determine size, shape, internal morphology, and chemical and structural properties in order to assess the suitability of the produced particles as a reference material for microanalytical methods, in particular, for mass spectrometry. It is demonstrated that physicochemical processes during particle formation and the heat treatment to chemically transform particles into an oxide strongly influence the particle shape and the internal morphology. Synchrotron MU-X-ray based techniques combined with MU-Raman spectroscopy have been applied to demonstrate that the obtained microparticles consist of a triuranium octoxide phase. Our studies demonstrate that the process is capable of delivering spherical particles with determined uniform size and elemental as well as chemical composition. The particles therefore represent a suitable base material to fulfill the homogeneity and stability requirements of a reference material for microanalytical methods applied in, for example, international safeguards or nuclear forensics. PMID- 28345870 TI - Ultrafast Separation and Analysis of Monoclonal Antibody Aggregates Using Membrane Chromatography. AB - We discuss a method for rapid and cost-effective analysis of monoclonal antibody (mAb) aggregates. Hydrophobic interaction membrane chromatography, which was previously shown to be highly suitable for such separation and analysis, was used in a recently developed format referred to as laterally fed membrane chromatography (or LFMC). A stack of rectangular polyvinylidene fluoride (or PVDF) membranes having 0.22 MUm pores housed within a modified analytical-scale LFMC device was used for analyzing aggregate types and content in different monoclonal antibody samples. High-resolution separations could be achieved in less than 1.5 min, this being faster than other currently available techniques such as size exclusion ultraperformance liquid chromatography (SE-UPLC). Moreover, the operating pressure was less than 200 kPa, which eliminated the need for an expensive high-pressure pump and chromatography system. The resolution obtained using the LFMC was comparable to that obtained using SE-UPLC. The effect of design variations such as change in dead volume and pillar size within the lateral channels within the LFMC device was also examined. PMID- 28345872 TI - Intrinsically Stretchable and Conductive Textile by a Scalable Process for Elastic Wearable Electronics. AB - The prosperous development of stretchable electronics poses a great demand on stretchable conductive materials that could maintain their electrical conductivity under tensile strain. Previously reported strategies to obtain stretchable conductors usually involve complex structure-fabricating processes or utilization of high-cost nanomaterials. It remains a great challenge to produce stretchable and conductive materials via a scalable and cost-effective process. Herein, a large-scalable pyrolysis strategy is developed for the fabrication of intrinsically stretchable and conductive textile in utilizing low-cost and mass produced weft-knitted textiles as raw materials. Due to the intrinsic stretchability of the weft-knitted structure and the excellent mechanical and electrical properties of the as-obtained carbonized fibers, the obtained flexible and durable textile could sustain tensile strains up to 125% while keeping a stable electrical conductivity (as shown by a Modal-based textile), thus ensuring its applications in elastic electronics. For demonstration purposes, stretchable supercapacitors and wearable thermal-therapy devices that showed stable performance with the loading of tensile strains have been fabricated. Considering the simplicity and large scalability of the process, the low-cost and mass production of the raw materials, and the superior performances of the as-obtained elastic and conductive textile, this strategy would contribute to the development and industrial production of wearable electronics. PMID- 28345871 TI - In Vivo Targeting and Positron Emission Tomography Imaging of Tumor with Intrinsically Radioactive Metal-Organic Frameworks Nanomaterials. AB - Nanoscale metal-organic frameworks (nMOF) materials represent an attractive tool for various biomedical applications. Due to the chemical versatility, enormous porosity, and tunable degradability of nMOFs, they have been adopted as carriers for delivery of imaging and/or therapeutic cargos. However, the relatively low stability of most nMOFs has limited practical in vivo applications. Here we report the production and characterization of an intrinsically radioactive UiO-66 nMOF (89Zr-UiO-66) with incorporation of positron-emitting isotope zirconium-89 (89Zr). 89Zr-UiO-66 was further functionalized with pyrene-derived polyethylene glycol (Py-PGA-PEG) and conjugated with a peptide ligand (F3) to nucleolin for targeting of triple-negative breast tumors. Doxorubicin (DOX) was loaded onto UiO 66 with a relatively high loading capacity (1 mg DOX/mg UiO-66) and served as both a therapeutic cargo and a fluorescence visualizer in this study. Functionalized 89Zr-UiO-66 demonstrated strong radiochemical and material stability in different biological media. Based on the findings from cellular targeting and in vivo positron emission tomography (PET) imaging, we can conclude that 89Zr-UiO-66/Py-PGA-PEG-F3 can serve as an image-guidable, tumor-selective cargo delivery nanoplatform. In addition, toxicity evaluation confirmed that properly PEGylated UiO-66 did not impose acute or chronic toxicity to the test subjects. With selective targeting of nucleolin on both tumor vasculature and tumor cells, this intrinsically radioactive nMOF can find broad application in cancer theranostics. PMID- 28345873 TI - Impact of Semiconducting Perylene Diimide Nanoparticle Size on Lymph Node Mapping and Cancer Imaging. AB - Semiconducting molecules of perylene diimide (PDI) with strong light absorption properties in the near-infrared region and good biocompatibility have received increasing attention in the field of theranostics, especially as photoacoustic (PA) imaging agents. Herein, we report a series of [64Cu]-labeled PDI nanoparticles (NPs) of different sizes (30, 60, 100, and 200 nm) as dual positron emission tomography (PET) and PA imaging probes and photothermal therapy agents. The precise size control of the PDI NPs can be achieved by adjusting the initial concentration of PDI molecules in the self-assembly process, and the photophysical property of different sized PDI NPs was studied in detail. Furthermore, we systematically investigated the size-dependent accumulation of the PDI NPs in the lymphatic system after local administration and in tumors after intravenous injection by PA and PET imaging. The results revealed that 100 nm is the best size for differentiating popliteal and sciatic LNs since the interval is around 60 min for the NPs to migrate from popliteal LNs to sciatic LNs, which is an ideal time window to facilitate surgical sentinel LN biopsy and pathological examination. Furthermore, different migration times of the different sized PDI NPs will provide more choices for surgeons to map the specific tumor relevant LNs. PDI NP theranostics can also be applied to imaging-guided cancer therapy. The NPs with a size of 60 nm appear to be the best for tumor imaging and photothermal cancer therapy due to the maximum tumor accumulation efficiency. Thus, our study not only presents organic PDI NP theranostics but also introduces different-sized NPs for multiple bioapplications. PMID- 28345874 TI - Delivery of Pesticides to Plant Parasitic Nematodes Using Tobacco Mild Green Mosaic Virus as a Nanocarrier. AB - Plant parasitic nematodes are a major burden to the global agricultural industry, causing a $157 billion loss each year in crop production worldwide. Effective treatment requires large doses of nematicides to be applied, putting the environment and human health at risk. Challenges are to treat nematodes that are located deep within the soil, feeding on the roots of plants. To attack the problem at its roots, we propose the use of tobacco mild green mosaic virus (TMGMV), an EPA-approved herbicide as a carrier to deliver nematicides. TMGMV self-assembles into a 300 * 18 nm soft matter nanorod with a 4 nm-wide hollow channel. This plant virus is comprised of 2130 identical coat protein subunits, each of which displays solvent-exposed carboxylate groups from Glu/Asp as well as Tyr side chains, enabling the functionalization of the carrier with cargo. We report (1) the successful formulation and characterization of TMGMV loaded with ~1500 copies of the anthelmintic drug crystal violet (CV), (2) the bioavailability and treatment efficacy of CVTMGMV vs CV to nematodes in liquid cultures, and (3) the superior soil mobility of CVTMGMV compared to free CV. PMID- 28345876 TI - Engineering Cellular Microenvironments with Photo- and Enzymatically Responsive Hydrogels: Toward Biomimetic 3D Cell Culture Models. AB - Conventional cell culture techniques using 2D polystyrene or glass have provided great insight into key biochemical mechanisms responsible for cellular events such as cell proliferation, differentiation, and cell-cell interactions. However, the physical and chemical properties of 2D culture in vitro are dramatically different than those found in the native cellular microenvironment in vivo. Cells grown on 2D substrates differ significantly from those grown in vivo, and this explains, in part, why many promising drug candidates discovered through in vitro drug screening assays fail when they are translated to in vivo animal or human models. To overcome this obstacle, 3D cell culture using biomimetic hydrogels has emerged as an alternative strategy to recapitulate native cell growth in vitro. Hydrogels, which are water-swollen polymers, can be synthetic or naturally derived. Many methods have been developed to control the physical and chemical properties of the hydrogels to match those found in specific tissues. Compared to 2D culture, cells cultured in 3D gels with the appropriate physicochemical cues can behave more like they naturally do in vivo. While conventional hydrogels involve modifications to the bulk material to mimic the static aspects of the cellular microenvironment, recent progress has focused on using more dynamic hydrogels, the chemical and physical properties of which can be altered with external stimuli to better mimic the dynamics of the native cellular microenvironment found in vivo. In this Account, we describe our progress in designing stimuli-responsive, optically transparent hydrogels that can be used as biomimetic extracellular matrices (ECMs) to study cell differentiation and migration in the context of modeling the nervous system and cancer. Specifically, we developed photosensitive agarose and hyaluronic acid hydrogels that are activated by single or two-photon irradiation for biomolecule immobilization at specific volumes within the 3D hydrogel. By controlling the spatial location of protein immobilization, we created 3D patterns and protein concentration gradients within these gels. We used the latter to study the effect of VEGF-165 concentration gradients on the interactions between endothelial cells and retinal stem cells. Hyaluronic acid (HA) is particularly compelling as it is naturally found in the ECM of many tissues and the tumor microenvironment. We used Diels Alder click chemistry and cryogelation to alter the chemical and physical properties of these hydrogels. We also designed HA hydrogels to study the invasion of breast cancer cells. HA gels were chemically cross-linked with matrix metalloproteinase (MMP)-degradable peptides that degrade in the presence of cancer cell-secreted MMPs, thus allowing cells to remodel their local microenvironment and invade into HA/MMP-degradable gels. PMID- 28345877 TI - Direct Analysis of Metal Ions in Solutions with High Salt Concentrations by Total Reflection X-ray Fluorescence. AB - Total reflection X-ray fluorescence (TXRF) is becoming more and more popular for elemental analysis in academia and industry. However, simplification of the procedures for analyzing samples with complex compositions and residual matrix effects is still needed. In this work, the effect of an inorganic (CaCl2) and an organic (tetraalkylphosphonium chloride) matrix on metals quantification by TXRF was investigated for liquid samples. The samples were spiked with up to 20 metals at concentrations ranging from 3 to 50 mg L-1 per element, including elements with spectral peaks near the peaks of the matrix elements or near the Raleigh and Compton scattering peaks of the X-ray source (molybdenum anode). The recovery rate (RR) and the relative standard deviation (RSD) were calculated to express the accuracy and the precision of the measured element concentrations. In samples with no matrix effects, good RRs are obtained regardless of the internal standard selected. However, in samples with moderate matrix content, the use of an optimum internal standard (OIS) at a concentration close to that of the analyte significantly improved the quantitative analysis. In samples with high concentrations of inorganic ions, using a Triton X-100 aqueous solution to dilute the sample during the internal standardization resulted in better RRs and lower RSDs compared to using only water. In samples with a high concentration of organic material, pure ethanol gave slightly better results than when a Triton X 100-ethanol solution was used for dilution. Compared to previous methods reported in the literature, the new sample-preparation method gave better accuracy, precision, and sensitivity for the elements tested. Sample dilution with an OIS and the surfactant Triton X-100 (inorganic media) or ethanol (organic media) is recommended for fast routine elemental determination in matrix containing samples, as it does not require special equipment, experimentally derived case dependent mathematical corrections, or physicochemical removal of interfering elements. PMID- 28345875 TI - Reactive Oxygen Species Synergize To Potently and Selectively Induce Cancer Cell Death. AB - A distinctive feature of cancer cells is their elevated levels of reactive oxygen species (ROS), a trait that can cause cancer cells to be more sensitive to ROS inducing agents than normal cells. ROS take several forms, each with different reactivity and downstream consequence. Here we show that simultaneous generation of superoxide and hydrogen peroxide within cancer cells results in significant synergy, potently and selectively causing cancer cell death. In these experiments superoxide is generated using the NAD(P)H quinone oxidoreductase 1 (NQO1) substrate deoxynyboquinone (DNQ), and hydrogen peroxide is generated using the lactate dehydrogenase A (LDH-A) inhibitor NHI-Glc-2. This combination reduces tumor burden and prolongs survival in a mouse model of lung cancer. These data suggest that simultaneous induction of superoxide and hydrogen peroxide can be a powerful and selective anticancer strategy. PMID- 28345879 TI - Vibrational Probes: From Small Molecule Solvatochromism Theory and Experiments to Applications in Complex Systems. AB - The vibrational frequency of a chosen normal mode is one of the most accurately measurable spectroscopic properties of molecules in condensed phases. Accordingly, infrared absorption and Raman scattering spectroscopy have provided valuable information on both distributions and ensemble-average values of molecular vibrational frequencies, and these frequencies are now routinely used to investigate structure, conformation, and even absolute configuration of chemical and biological molecules of interest. Recent advancements in coherent time-domain nonlinear vibrational spectroscopy have allowed the study of heterogeneous distributions of local structures and thermally driven ultrafast fluctuations of vibrational frequencies. To fully utilize IR probe functional groups for quantitative bioassays, a variety of biological and chemical techniques have been developed to site-specifically introduce vibrational probe groups into proteins and nucleic acids. These IR-probe-labeled biomolecules and chemically reactive systems are subject to linear and nonlinear vibrational spectroscopic investigations and provide information on the local electric field, conformational changes, site-site protein contacts, and/or function-defining features of biomolecules. A rapidly expanding library of data from such experiments requires an interpretive method with atom-level chemical accuracy. However, despite prolonged efforts to develop an all-encompassing theory for describing vibrational solvatochromism and electrochromism as well as dynamic fluctuations of instantaneous vibrational frequencies, purely empirical and highly approximate theoretical models have often been used to interpret experimental results. They are, in many cases, based on the simple assumption that the vibrational frequency of an IR reporter is solely dictated by electric potential or field distribution around the vibrational chromophore. Such simplified description of vibrational solvatochromism generally referred to as vibrational Stark effect theory has been considered to be quite appealing and, even in some cases, e.g., carbonyl stretch modes in amide, ester, ketone, and carbonate compounds or proteins, it works quantitatively well, which makes it highly useful in determining the strength of local electric field around the IR chromophore. However, noting that the vibrational frequency shift results from changes of solute-solvent intermolecular interaction potential along its normal coordinate, Pauli exclusion repulsion, polarization, charge transfer, and dispersion interactions, in addition to the electrostatic interaction between distributed charges of both vibrational chromophore and solvent molecules, are to be properly included in the theoretical description of vibrational solvatochromism. Since the electrostatic and nonelectrostatic intermolecular interaction components have distinctively different distance and orientation dependences, they affect the solvatochromic vibrational properties in a completely different manner. Over the past few years, we have developed a systematic approach to simulating vibrational solvatochromic data based on the effective fragment potential approach, one of the most accurate and rigorous theories on intermolecular interactions. We have further elucidated the interplay of local electric field with the general vibrational solvatochromism of small IR probes in either solvents or complicated biological systems, with emphasis on contributions from non-Coulombic intermolecular interactions to vibrational frequency shifts and fluctuations. With its rigorous foundation and close relation to quantitative interpretation of experimental data, this and related theoretical approaches and experiments will be of use in studying and quantifying the structure and dynamics of biomolecules with unprecedented time and spatial resolution when combined with time-resolved vibrational spectroscopy and chemically sensitive vibrational imaging techniques. PMID- 28345878 TI - Multispectral Optical Tweezers for Biochemical Fingerprinting of CD9-Positive Exosome Subpopulations. AB - Extracellular vesicles (EVs), including exosomes, are circulating nanoscale particles heavily implicated in cell signaling and can be isolated in vast numbers from human biofluids. Study of their molecular profiling and materials properties is currently underway for purposes of describing a variety of biological functions and diseases. However, the large, and as yet largely unquantified, variety of EV subpopulations differing in composition, size, and likely function necessitates characterization schemes capable of measuring single vesicles. Here we describe the first application of multispectral optical tweezers (MS-OTs) to single vesicles for molecular fingerprinting of EV subpopulations. This versatile imaging platform allows for sensitive measurement of Raman chemical composition (e.g., variation in protein, lipid, cholesterol, nucleic acids), coupled with discrimination by fluorescence markers. For exosomes isolated by ultracentrifugation, we use MS-OTs to interrogate the CD9-positive subpopulations via antibody fluorescence labeling and Raman spectra measurement. We report that the CD9-positive exosome subset exhibits reduced component concentration per vesicle and reduced chemical heterogeneity compared to the total purified EV population. We observed that specific vesicle subpopulations are present across exosomes isolated from cell culture supernatant of several clonal varieties of mesenchymal stromal cells and also from plasma and ascites isolated from human ovarian cancer patients. PMID- 28345880 TI - Detecting Proteins Glycosylation by a Homogeneous Reaction System with Zwitterionic Gold Nanoclusters. AB - Homogeneous gold nanoclusters (Au NCs) have been widely utilized in drug delivery, chemical sensing, bioassays, and biolabeling due to their unique physical and chemical properties. However, little attention has been paid to their application in detecting protein post-translational modifications. Herein, we describe the development of a homogeneous reaction system with water-soluble zwitterionic Au NCs to capture glycopeptides from complex biological samples. The unique characteristics of Au NCs, such as their molecular-like properties, the excellent homogeneity in aqueous solution, the organic solvent responsive precipitation, and the easy preparation in only 4.5 h, contribute to the high efficiency and high throughput for capturing the targeted glycopeptides. Compared with the conventional heterogeneous system with solid-state adsorbents, the number of characterized glycosylation sites was improved by 35%. Finally, an MS detection limit as low as 50 amol was achieved for the standard glycoprotein (IgG), and 1576 glycosylation sites from 713 glycoproteins were identified from only 60 MUg of mouse liver protein. Data are available via ProteomeXchange with identifier PXD005635. PMID- 28345881 TI - Silane and Germane Molecular Electronics. AB - This Account provides an overview of our recent efforts to uncover the fundamental charge transport properties of Si-Si and Ge-Ge single bonds and introduce useful functions into group 14 molecular wires. We utilize the tools of chemical synthesis and a scanning tunneling microscopy-based break-junction technique to study the mechanism of charge transport in these molecular systems. We evaluated the fundamental ability of silicon, germanium, and carbon molecular wires to transport charge by comparing conductances within families of well defined structures, the members of which differ only in the number of Si (or Ge or C) atoms in the wire. For each family, this procedure yielded a length dependent conductance decay parameter, beta. Comparison of the different beta values demonstrates that Si-Si and Ge-Ge sigma bonds are more conductive than the analogous C-C sigma bonds. These molecular trends mirror what is seen in the bulk. The conductance decay of Si and Ge-based wires is similar in magnitude to those from pi-based molecular wires such as paraphenylenes However, the chemistry of the linkers that attach the molecular wires to the electrodes has a large influence on the resulting beta value. For example, Si- and Ge-based wires of many different lengths connected with a methyl-thiomethyl linker give beta values of 0.36-0.39 A-1, whereas Si- and Ge-based wires connected with aryl-thiomethyl groups give drastically different beta values for short and long wires. This observation inspired us to study molecular wires that are composed of both pi- and sigma-orbitals. The sequence and composition of group 14 atoms in the sigma chain modulates the electronic coupling between the pi end-groups and dictates the molecular conductance. The conductance behavior originates from the coupling between the subunits, which can be understood by considering periodic trends such as bond length, polarizability, and bond polarity. We found that the same periodic trends determine the electric field-induced breakdown properties of individual Si-Si, Ge-Ge, Si-O, Si-C, and C-C bonds. Building from these studies, we have prepared a system that has two different, alternative conductance pathways. In this wire, we can intentionally break a labile, strained silicon silicon bond and thereby shunt the current through the secondary conduction pathway. This type of in situ bond-rupture provides a new tool to study single molecule reactions that are induced by electric fields. Moreover, these studies provide guidance for designing dielectric materials as well as molecular devices that require stability under high voltage bias. The fundamental studies on the structure/function relationships of the molecular wires have guided the design of new functional systems based on the Si- and Ge-based wires. For example, we exploited the principle of strain-induced Lewis acidity from reaction chemistry to design a single molecule switch that can be controllably switched between two conductive states by varying the distance between the tip and substrate electrodes. We found that the strain intrinsic to the disilaacenaphthene scaffold also creates two state conductance switching. Finally, we demonstrate the first example of a stereoelectronic conductance switch, and we demonstrate that the switching relies crucially on the electronic delocalization in Si-Si and Ge-Ge wire backbones. These studies illustrate the untapped potential in using Si- and Ge-based wires to design and control charge transport at the nanoscale and to allow quantum mechanics to be used as a tool to design ultraminiaturized switches. PMID- 28345883 TI - Cluster Organic Frameworks Constructed from Heterometallic Supertetrahedral Cluster Secondary Building Units. AB - The two novel cluster organic frameworks based on heterometallic supertetrahedral cluster secondary building units (SBUs) [Cd4Cu6(L)4(Ac)7(H2O)4](Ac).7H2O (1) and [Mn4Cu6(L)4(Ac)4.5(H2O)9]CuCN(Ac)3.5.H2O (2), where H3L = 2-(hydroxymethyl)-2 (pyridin-4-yl)-1,3-propanediol and Ac = CH3COO-, have been prepared under solvothermal conditions. 1 and 2 are the first cases of cluster organic frameworks containing Cd-Cu/Mn-Cu heterometallic supertetrahedral cluster SBUs. Furthermore, 1 and 2 show an integration of magnetic properties and adsorption properties from both the heterometallic cluster secondary building units and the framework in a porous material. PMID- 28345882 TI - Covalent Allosteric Inactivation of Protein Tyrosine Phosphatase 1B (PTP1B) by an Inhibitor-Electrophile Conjugate. AB - Protein tyrosine phosphatase 1B (PTP1B) is a validated drug target, but it has proven difficult to develop medicinally useful, reversible inhibitors of this enzyme. Here we explored covalent strategies for the inactivation of PTP1B using a conjugate composed of an active site-directed 5-aryl-1,2,5-thiadiazolidin-3-one 1,1-dioxide inhibitor connected via a short linker to an electrophilic alpha bromoacetamide moiety. Inhibitor-electrophile conjugate 5a caused time-dependent loss of PTP1B activity consistent with a covalent inactivation mechanism. The inactivation occurred with a second-order rate constant of (1.7 +/- 0.3) * 102 M 1 min-1. Mass spectrometric analysis of the inactivated enzyme indicated that the primary site of modification was C121, a residue distant from the active site. Previous work provided evidence that covalent modification of the allosteric residue C121 can cause inactivation of PTP1B [Hansen, S. K., Cancilla, M. T., Shiau, T. P., Kung, J., Chen, T., and Erlanson, D. A. (2005) Biochemistry 44, 7704-7712]. Overall, our results are consistent with an unusual enzyme inactivation process in which noncovalent binding of the inhibitor-electrophile conjugate to the active site of PTP1B protects the nucleophilic catalytic C215 residue from covalent modification, thus allowing inactivation of the enzyme via selective modification of allosteric residue C121. PMID- 28345884 TI - Canted Antiferromagnetism on Rectangular Layers of Fe2+ in Polymorphic CaFeSeO. AB - From stoichiometric amounts of CaO, Fe, and Se, pure powders and single crystals of quaternary [Formula: see text] can be obtained by solid-state reaction and self-flux growth, respectively. The as-synthesized compound exhibits a polymorphic crystal structure, where the two modifications have different stacking sequences of [Formula: see text] layers. The two polymorphs have similar unit cells but different crystal symmetries (Cmc21 and Pnma), of which the former is non-centrosymmetric. Fe is divalent (d6) and high-spin, as proven by X-ray spectroscopy, Mossbauer spectroscopy, and powder neutron diffraction data. The latter two, in combination with magnetic susceptibility and specific heat data, reveal a long-range antiferromagnetic spin order (TN = 160 K) with a minor spin canting. CaFeSeO is an electronic insulator, as confirmed by resistivity measurements and density functional theory calculations. The latter also suggest a relatively small energy difference between the two polymorphs, explaining their intimate intergrowth. PMID- 28345885 TI - Synthesis of Highly Uniform and Compact Lithium Zinc Ferrite Ceramics via an Efficient Low Temperature Approach. AB - LiZn ferrite ceramics with high saturation magnetization (4piMs) and low ferromagnetic resonance line widths (DeltaH) represent a very critical class of material for microwave ferrite devices. Many existing approaches emphasize promotion of the grain growth (average size is 10-50 MUm) of ferrite ceramics to improve the gyromagnetic properties at relatively low sintering temperatures. This paper describes a new strategy for obtaining uniform and compact LiZn ferrite ceramics (average grains size is ~2 MUm) with enhanced magnetic performance by suppressing grain growth in great detail. The LiZn ferrites with a formula of Li0.415Zn0.27Mn0.06Ti0.1Fe2.155O4 were prepared by solid reaction routes with two new sintering strategies. Interestingly, results show that uniform, compact, and pure spinel ferrite ceramics were synthesized at a low temperature (~850 degrees C) without obvious grain growth. We also find that a fast second sintering treatment (FSST) can further improve their gyromagnetic properties, such as higher 4piMs and lower DeltaH. The two new strategies are facile and efficient for densification of LiZn ferrite ceramics via suppressing grain growth at low temperatures. The sintering strategy reported in this study also provides a referential experience for other ceramics, such as soft magnetism ferrite ceramics or dielectric ceramics. PMID- 28345886 TI - Synthesis and Crystal Structures of the First Antimony(III) Aziridinides. AB - The first antimony(III) aziridinyl derivatives are reported. Treatment of anhydrous SbCl3 with N-lithioaziridine Li(Azn) (Azn = NC2H4) afforded the structurally unique heterobimetallic lithium/antimony(III) amide complex [Li3Sb(MU3-Cl)2(MU-Azn)4(THF)2]infinity (1). Homoleptic Sb2(Azn)6 (2) has become available for the first time through an amide group exchange reaction between Sb(NMe2)3 and 3 equiv of aziridine. The low-melting Sb2(Azn)6 exhibits a "weak dimer" structure in the crystal. PMID- 28345887 TI - From Detection to Resection: Photoacoustic Tomography and Surgery Guidance with Indocyanine Green Loaded Gold Nanorod@liposome Core-Shell Nanoparticles in Liver Cancer. AB - Conventional imaging methods encounter challenges in diagnosing liver cancer that is less than 10 mm or without typical hypervascular features. With deep penetration and high spatial resolution imaging capability, the emerging photoacoustic tomography may offer better diagnostic efficacy for noninvasive liver cancer detection. Moreover, near-infrared fluorescence imaging-guided hepatectomy was proven to be able to identify nodules at the millimeter level. Thus, suitable photoacoustic and fluorescence dual-modality imaging probe may benefit patients in early diagnosis and complete resection. In this study, we fabricated indocyanine green loaded gold nanorod@liposome core-shell nanoparticles (Au@liposome-ICG) to integrate both imaging strategies. These nanoparticles exhibit superior biocompatibility, high stability, and enhanced dual-model imaging signals. Next, we explored their effectiveness of tumor detection and surgery guidance in orthotopic liver cancer mouse models. Histological analysis confirmed the accuracy of the probe in liver cancer detection and resection. This novel dual-modality nanoprobe holds promise for early diagnosis and better surgical outcome of liver cancer and has great potential for clinical translation. PMID- 28345888 TI - Influence of Ring Strain and Bond Polarization on the Ring Expansion of Phosphorus Homocycles. AB - Heterolytic cleavage of homoatomic bonds is a challenge, as it requires separation of opposite charges. Even highly strained homoatomic rings (e.g., cyclopropane and cyclobutane) are kinetically stable and do not react with nucleophiles or electrophiles. In contrast, cycloalkanes bearing electron donating/withdrawing substituents on adjacent carbons have polarized C-C bonds and undergo numerous heterolytic ring-opening and expansion reactions. Here we show that upon electrophile activation phosphorus homocycles exhibit analogous reactivity, which is modulated by the amount of ring strain and extent of bond polarization. Neutral rings (tBuP)3, 1, or (tBuP)4, 2, show no reactivity toward nitriles, but the cyclo-phosphinophosphonium derivative [(tBuP)3Me]+, [3Me]+, undergoes addition to nitriles giving five-membered P3CN heterocycles. Because of its lower ring strain, the analogous four-membered ring, [(tBuP)4Me]+, [4Me]+, is thermodynamically stable with respect to cycloaddition with nitriles, despite similar P-P bond polarization. We also report the first example of isonitrile insertion into cyclophosphines, which is facile for polarized derivatives [3Me]+ and [4Me]+, but does not proceed for neutral 1 or 2, despite the calculated exothermicity of the process. Finally, we assessed the reactions of [4R]+ R = H, Cl, F toward 4-dimethylaminopyridine (dmap), which suggest that the site of nucleophilic attack varies with the extent of P-P bond polarization. These results deconvolute the influence of ring strain and bond polarization on the chemistry of inorganic homocycles and unlock new synthetic possibilities. PMID- 28345890 TI - Relationship of Microbiota and Cyanobacterial Secondary Metabolites in Planktothricoides-Dominated Bloom. AB - The identification of phytoplankton species and microbial biodiversity is necessary to assess water ecosystem health and the quality of water resources. We investigated the short-term (2 days) vertical and diel variations in bacterial community structure and microbially derived secondary metabolites during a cyanobacterial bloom that emerged in a highly urbanized tropical reservoir. The waterbody was largely dominated by the cyanobacteria Planktothricoides spp., together with the Synechococcus, Pseudanabaena, Prochlorothrix, and Limnothrix. Spatial differences (i.e., water depth) rather than temporal differences (i.e., day versus night) better-explained the short-term variability in water quality parameters and bacterial community composition. Difference in bacterial structure suggested a resource-driven distribution pattern for the community. We found that the freshwater bacterial community associated with cyanobacterial blooms is largely conserved at the phylum level, with Proteobacteria (beta-proteobateria), Bacteroidetes, and Actinobacteria as the main taxa despite the cyanobacterial species present and geographical (Asia, Europe, Australia, and North America) or climatic distinctions. Through multivariate statistical analyses of the bacterial community, environmental parameters, and secondary metabolite concentrations, we observed positive relationships between the occurrences of cyanobacterial groups and off-flavor compounds (2-methyisoborneol and beta-ionone), suggesting a cyanobacterial origin. This study demonstrates the potential of 16S rRNA gene amplicon sequencing as a supporting tool in algal bloom monitoring or water resource management. PMID- 28345889 TI - AP-Endonuclease 1 Accelerates Turnover of Human 8-Oxoguanine DNA Glycosylase by Preventing Retrograde Binding to the Abasic-Site Product. AB - A major product of oxidative DNA damage is 8-oxoguanine. In humans, 8-oxoguanine DNA glycosylase (hOGG1) facilitates removal of these lesions, producing an abasic (AP) site in the DNA that is subsequently incised by AP-endonuclease 1 (APE1). APE1 stimulates turnover of several glycosylases by accelerating rate-limiting product release. However, there have been conflicting accounts of whether hOGG1 follows a similar mechanism. In pre-steady-state kinetic measurements, we found that addition of APE1 had no effect on the rapid burst phase of 8-oxoguanine excision by hOGG1 but accelerated steady-state turnover (kcat) by ~10-fold. The stimulation by APE1 required divalent cations, could be detected under multiple turnover conditions using limiting concentrations of APE1, did not require flanking DNA surrounding the hOGG1 lesion site, and occurred efficiently even when the first 49 residues of APE1's N-terminus had been deleted. Stimulation by APE1 does not involve relief from product inhibition because thymine DNA glycosylase, an enzyme that binds more tightly to AP sites than hOGG1 does, could not effectively substitute for APE1. A stimulation mechanism involving stable protein-protein interactions between free APE1 and hOGG1, or the DNA-bound forms, was excluded using protein cross-linking assays. The combined results indicate a mechanism whereby dynamic excursions of hOGG1 from the AP site allow APE1 to invade the site and rapidly incise the phosphate backbone. This mechanism, which allows APE1 to access the AP site without forming specific interactions with the glycosylase, is a simple and elegant solution to passing along unstable intermediates in base excision repair. PMID- 28345891 TI - Tailored Chemical Properties of 4-Arm Star Shaped Poly(d,l-lactide) as Cell Adhesive Three-Dimensional Scaffolds. AB - Biodegradable poly(lactic acid) (PLA) is widely used to fabricate 3D scaffolds for tissue regeneration. However, PLA lacks cell adhering functional moieties, which limit its successful application in tissue engineering. Herein, we have tailored the cell adhesive properties of star shaped poly(d,l-lactide) (ss-PDLLA) by grafting gelatin to their 4 arms. Grafting of gelatin on PDLLA backbone was confirmed by 1H NMR and FTIR. The synthesized star shaped poly(d,l-lactide)-b gelatin (ss-pLG) exhibited enhanced wettability and protein adsorption. The modification also facilitated better cell adhesion and proliferation on their respective polymer coated 2D substrates, compared to their respective unmodified ss-PDLLA. Further, 3D scaffolds were fabricated from gelatin grafted and unmodified polymers. The fabricated scaffolds were shown to be cytocompatible to 3T3-L1 cells and hemocompatible to red blood cells (RBCs). Cell proliferation was increased up to 2.5-fold in ss-pLG scaffolds compared to ss-PDLLA scaffolds. Furthermore, a significant increase in cell number reveals a high degree of infiltration of cells into the scaffolds, forming a viable and healthy 3D interconnected cell community. In addition to that, burst release of docetaxal (DTX) was observed from ss-pLG scaffolds. Hence, this new system of grafting polymers followed by fabricating 3D scaffolds could be utilized as a successful approach in a variety of applications where cell-containing depots are used. PMID- 28345893 TI - Fluorescent Recognition of Zn2+ by Two Diastereomeric Salicylaldimines: Dramatically Different Responses and Spectroscopic Investigation. AB - Fluorescence responses of two BINOL-based diastereomeric salicylaldimines toward a variety of metal cations have been studied in methanol solution. It is revealed that both compounds show great fluorescence enhancements in the presence of Zn2+ but not with any other metal ions. Moreover, these two diastereomers exhibit dramatically different responses toward Zn2+ under the same conditions. That is, one can produce much stronger fluorescence enhancement also at a longer wavelength than the other. This fluorescence recognition of Zn2+ also shows distinctive color changes under a UV lamp. Mass and NMR spectroscopic analyses have been used to study the mechanism, which indicates the formation of 2+nZn2+ complexes (n = 2, 3). This work has shed new light on the mechanism of an enantioselective fluorescent recognition of chiral amines promoted by Zn2+. PMID- 28345892 TI - A Silver-Specific DNAzyme with a New Silver Aptamer and Salt-Promoted Activity. AB - Most RNA-cleaving DNAzymes require a metal ion to interact with the scissile phosphate for activity. Therefore, few unmodified DNAzymes work with thiophilic metals because of their low affinity for phosphate. Recently, an Ag+-specific Ag10c DNAzyme was reported via in vitro selection. Herein, Ag10c is characterized to rationalize the role of the strongly thiophilic Ag+. Systematic mutation studies indicate that Ag10c is a highly conserved DNAzyme and its Ag+ binding is unrelated to C-Ag+-C interaction. Its activity is enhanced by increasing Na+ concentrations in buffer. At the same metal concentration, activity decreases in the following order: Li+ > Na+ > K+. Ag10c binds one Na+ ion and two Ag+ ions for catalysis. The pH-rate profile has a slope of ~1, indicating a single deprotonation step. Phosphorothioate substitution at the scissile phosphate suggests that Na+ interacts with the pro-Rp oxygen of the phosphate, and dimethyl sulfate footprinting indicates that the DNAzyme loop is a silver aptamer binding two Ag+ ions. Therefore, Ag+ exerts its function allosterically, while the scissile phosphate interacts with Na+, Li+, Na+, or Mg2+. This work suggests the possibility of isolating thiophilic metal aptamers based on DNAzyme selection, and it also demonstrates a new Ag+ aptamer. PMID- 28345894 TI - Rich Coordination Chemistry of pi-Acceptor Dibenzoarsole Ligands. AB - A series of dibenzoarsole (also known as 9-arsafluorene) derivatives have been prepared, and their coordination chemistry has been investigated. The different ligand topology and the arsenic substituents govern the reactivity of the ligands. We report various crystal structures of palladium and platinum complexes derived from this family of ligands. The biphenyl backbone of the bridged bidentate ligands allows very flexible coordination. We have also studied the application of an allylic Pd complex in nucleophilic substitution reactions, revealing that the benzoarsole substituent is susceptible to metal insertion. PMID- 28345896 TI - Transcriptomics and Lipidomics of the Environmental Strain Rhodococcus ruber Point out Consumption Pathways and Potential Metabolic Bottlenecks for Polyethylene Degradation. AB - Polyethylene (PE), one of the most prominent synthetic polymers used worldwide, is very poorly biodegradable in the natural environment. Consequently, PE represents by itself more than half of all plastic wastes. PE biodegradation is achieved through the combination of abiotic and biotic processes. Several microorganisms have been shown to grow on the surface of PE materials, among which are the species of the Rhodococcus genus, suggesting a potent ability of these microorganisms to use, at least partly, PE as a potent carbon source. However, most of them, if not all, fail to induce a clear-cut degradation of PE samples, showing that bottlenecks to reach optimal biodegradation clearly exist. To identify the pathways involved in PE consumption, we used in the present study a combination of RNA-sequencing and lipidomic strategies. We show that short-term exposure to various forms of PE, displaying different molecular weight distributions and oxidation levels, lead to an increase in the expression of 158 genes in a Rhodococcus representative, R. ruber. Interestingly, one of the most up-regulated pathways is related to alkane degradation and beta-oxidation of fatty acids. This approach also allowed us to identify metabolic limiting steps, which could be fruitfully targeted for optimized PE consumption by R. ruber. PMID- 28345895 TI - Asymmetric Anchoring Is Required for Efficient Omega-Loop Opening and Closing in Cytosolic Phosphoenolpyruvate Carboxykinase. AB - Mobile Omega-loops play essential roles in the function of many enzymes. Here we investigated the importance of a residue lying outside of the mobile Omega-loop element in the catalytic function of an H477R variant of cytosolic phosphoenolpyruvate carboxykinase using crystallographic, kinetic, and computational analysis. The crystallographic data suggest that the efficient transition of the Omega-loop to the closed conformation requires stabilization of the N-terminus of the loop through contacts between R461 and E588. In contrast, the C-terminal end of the Omega-loop undergoes changing interactions with the enzyme body through contacts between H477 at the C-terminus of the loop and E591 located on the enzyme body. Potential of mean force calculations demonstrated that altering the anchoring of the C-terminus of the Omega-loop via the H477R substitution results in the destabilization of the closed state of the Omega-loop by 3.4 kcal mol-1. The kinetic parameters for the enzyme were altered in an asymmetric fashion with the predominant effect being observed in the direction of oxaloacetate synthesis. This is exemplified by a reduction in kcat for the H477R mutant by an order of magnitude in the direction of OAA synthesis, while in the direction of PEP synthesis, it decreased by a factor of only 2. The data are consistent with a mechanism for loop conformational exchange between open and closed states in which a balance between fixed anchoring of the N-terminus of the Omega-loop and a flexible, unattached C-terminus drives the transition between a disordered (open) state and an ordered (closed) state. PMID- 28345897 TI - A Smart Molecule for Selective Sensing of Nitric Oxide: Conversion of NO to HSNO; Relevance of Biological HSNO Formation. AB - A smart molecule, QT490, containing thiosemicarbazide moiety acts as a highly selective turn-on in vitro NO sensor through the unprecedented NO-induced transformation of thiosemicarbazide moiety to 1,3,4-oxadiazole heterocycle with the concomitant release of HSNO, thereby eliminating any interference from various endogenous biomolecules including dehydroascorbic acid, ascorbic acid, etc. The kinetic studies of the reactions between QT490 and NO provide a mechanistic insight into formation of HSNO/RSNO from the reaction between H2S/RSH and NO in the biological system. This novel probe is non-cytotoxic, cell permeable, water-soluble, and appropriate for intracellular cytoplasmic NO sensing with the possibilities of in vivo applications. PMID- 28345898 TI - Hydrolysis of Ionic Phthalic Acid Based Polyesters by Wastewater Microorganisms and Their Enzymes. AB - Water-soluble polyesters are used in a range of applications today and enter wastewater treatment plants after product utilization. However, little is known about extracellular enzymes and aquatic microorganisms involved in polyester biodegradation and mineralization. In this study, structurally different ionic phthalic acid based polyesters (the number-average molecular weights (Mn) 1770 to 10 000 g/mol and semi crystalline with crystallinity below 1%) were synthesized in various combinations. Typical wastewater microorganisms like Pseudomonas sp. were chosen for in-silico screening toward polyester hydrolyzing enzymes. Based on the in-silico search, a cutinase from Pseudomonas pseudoalcaligenes (PpCutA) and a putative lipase from Pseudomonas pelagia (PpelaLip) were identified. The enzymes PpCutA and PpelaLip were demonstrated to hydrolyze all structurally different polyesters. Activities on all the polyesters were also confirmed with the strains P. pseudoalcaligenes and P. pelagia. Parameters identified to enhance hydrolysis included increased water solubility and polyester hydrophilicity as well as shorter diol chain lengths. For example, polyesters containing 1,2 ethanediol were hydrolyzed faster than polyesters containing 1,8-octanediol. Interestingly, the same trend was observed in biodegradation experiments. This information is important to gain a better mechanistic understanding of biodegradation processes of polyesters in WWTPs where the extracellular enzymatic hydrolysis seems to be the limiting step. PMID- 28345899 TI - Ammonia Borane Dehydrogenation Catalyzed by (kappa4-EP3)Co(H) [EP3 = E(CH2CH2PPh2)3; E = N, P] and H2 Evolution from Their Interaction with NH Acids. AB - Two Co(I) hydrides containing the tripodal polyphosphine ligand EP3, (kappa4 EP3)Co(H) [E(CH2CH2PPh2)3; E = N (1), P (2)], have been exploited as ammonia borane (NH3BH3, AB) dehydrogenation catalysts in THF solution at T = 55 degrees C. The reaction has been analyzed experimentally through multinuclear (11B, 31P{1H}, 1H) NMR and IR spectroscopy, kinetic rate measurements, and kinetic isotope effect (KIE) determination with deuterated AB isotopologues. Both complexes are active in AB dehydrogenation, albeit with different rates and efficiency. While 1 releases 2 equiv of H2 per equivalent of AB in ca. 48 h, with concomitant borazine formation as the final "spent fuel", 2 produces 1 equiv of H2 only per equivalent of AB in the same reaction time, along with long-chain poly(aminoboranes) as insoluble byproducts. A DFT modeling of the first AB dehydrogenation step has been performed, at the M06//6-311++G** level of theory. The combination of the kinetic and computational data reveals that a simultaneous B-H/N-H activation occurs in the presence of 1, after a preliminary AB coordination to the metal center. In 2, no substrate coordination takes place, and the process is better defined as a sequential BH3/NH3 insertion process on the initially formed [Co]-NH2BH3 amidoborane complex. Finally, the reaction of 1 and 2 with NH-acids [AB and Me2NHBH3 (DMAB)] has been followed via VT-FTIR spectroscopy (in the -80 to +50 degrees C temperature range), with the aim of gaining a deeper experimental understanding of the dihydrogen bonding interactions that are at the origin of the observed H2 evolution. PMID- 28345901 TI - Recyclable Single-Component Rare-Earth Metal Catalysts for Cycloaddition of CO2 and Epoxides at Atmospheric Pressure. AB - Ionic rare-earth metal complexes 1-4 bearing an imidazolium cation were synthesized, which, as single-component catalysts, showed good activity in catalyzing cyclic carbonate synthesis from epoxides and CO2. In the presence of 0.2 mol % catalyst, monosubstituted epoxides bearing different functional groups were converted into cyclic carbonates in 60-97% yields under atmospheric pressure. In addition, bulky/internal epoxides with low reactivity yielded cyclic carbonates in 40-95% yields. More importantly, the readily available samarium complex 2 was reused for six successive cycles without any significant loss in its catalytic activity. This is the first recyclable rare-earth metal-based catalyst in cyclic carbonate synthesis. PMID- 28345900 TI - Fluorescence- and Radiolabeling of [Lys4,Nle17,30]hPP Yields Molecular Tools for the NPY Y4 Receptor. AB - The neuropeptide Y (NPY) Y4 receptor (Y4R) is involved in energy homeostasis and considered a potential drug target for the treatment of obesity. Only a few molecular tools, i.e., radiolabeled and fluorescent ligands, for the investigation of the Y4R were reported. Previously, [Lys4]hPP proved to be an appropriate full-length PP analog to prepare a fluorescent ligand by derivatization at the epsilon-amino group. To preclude oxidation upon long-term storage, we replaced the two methionine residues in [Lys4]hPP by norleucine and prepared the corresponding [3H]propionylated ([3H]12) and cyanine labeled (13) peptides, which were characterized and compared with a set of reference compounds in binding (Y1, Y2, Y4, and Y5 receptors) and functional (luciferase gene reporter, beta-arrestin-1,2) Y4R assays. Both molecular probes proved to be useful in radiochemical and flow cytometric saturation and competition Y4R binding experiments. Most strikingly, there was a different influence of the composition of buffer on equilibrium binding and kinetics: [3H]12 affinity (Kd in Na+-free buffer: 1.1 nM) clearly decreased with increasing sodium ion concentration, whereas dissociation and Y4R-mediated internalization of 13 (Kd in Na+-free buffer: 10.8 nM) were strongly affected by the osmolarity of the buffer as demonstrated by confocal microscopy. Displacement of [3H]12 and 13 revealed a tendency to higher apparent affinities for a set of reference peptides in hypotonic (Na+-free) compared to isotonic buffers. The differences were negligible in the case of hPP but up to 270-fold in the case of GW1229 (GR231118). By contrast, no relevant influence of Na+ on Y5R affinity became obvious, when the radioligands [H]12 and [3H]propionyl-pNPY were investigated in saturation binding and competition binding. PMID- 28345902 TI - Hyaluronate-Peanut Agglutinin Conjugates for Target-Specific Bioimaging of Colon Cancer. AB - Colon cancer is one of the most common death-related cancers in the world. For treating colon cancer, it is crucial to detect and remove malignant lesions early. Here, we developed hyaluronate (HA)-peanut agglutinin (PNA) conjugates for the bioimaging of colon cancer. The HA-PNA conjugates were successfully synthesized by the coupling reaction between aldehyde-modified HA and the N terminal amine group of PNA. For diagnostic imaging, rhodamine B (RhoB) was chemically conjugated onto PNA in HA-PNA conjugates. After intraluminal injection of HA-PNA-RhoB conjugates into tumor-bearing mice, small-sized colon cancers could be effectively visualized by ex vivo imaging with an in vivo imaging system (IVIS) and a two-photon microscope. With these results taken together, we could confirm the feasibility of HA-PNA-RhoB conjugates as a bioimaging agent for detecting colon cancers. PMID- 28345903 TI - Molecular Imprinting on Inorganic Nanozymes for Hundred-fold Enzyme Specificity. AB - Enzyme-mimicking nanomaterials (nanozymes) are more cost-effective and robust than protein enzymes, but they lack specificity. Herein, molecularly imprinted polymers were grown on Fe3O4 nanozymes with peroxidase-like activity to create substrate binding pockets. Electron microscopy confirmed a shell of nanogel. By imprinting with an adsorbed substrate, moderate specificity was achieved with neutral monomers. Further introducing charged monomers led to nearly 100-fold specificity for the imprinted substrate over the nonimprinted compared to that of bare Fe3O4. Selective substrate binding was further confirmed by isothermal titration calorimetry. The same method was also successfully applied for imprinting on gold nanoparticles (peroxidase mimics) and nanoceria (oxidase mimics). Molecular imprinting furthers the functional enzyme mimicking aspect of nanozymes, and such hybrid materials will find applications in biosensor development, separation, environmental remediation, and drug delivery. PMID- 28345904 TI - Ligand Selectivity Mechanism and Conformational Changes in Guanine Riboswitch by Molecular Dynamics Simulations and Free Energy Calculations. AB - Riboswitches regulate gene expression through direct and specific interactions with small metabolite molecules. Binding of a ligand to its RNA target is high selectivity and affinity and induces conformational changes of the RNA's secondary and tertiary structure. The structural difference of two purine riboswitches aptamers is caused by only one single mutation, where cytosine 74 in the guanine riboswitch is corresponding to a uracil 74 in adenine riboswitch. Here we employed molecular dynamics (MD) simulation, molecular mechanics Poisson Boltzmann surface area (MM-PBSA) and thermodynamic integration computational methodologies to evaluate the energetic and conformational changes of ligands binding to purine riboswitches. The snapshots used in MM-PBSA calculation were extracted from ten 50 ns MD simulation trajectories for each complex. These free energy results are in consistent with the experimental data and rationalize the selectivity of the riboswitches for different ligands. In particular, it is found that the loss in binding free energy upon mutation is mainly electrostatic in guanine (GUA) and riboswitch complex. Furthermore, new hydrogen bonds are found in mutated complexes. To reveal the conformational properties of guanine riboswitch, we performed a total of 6 MUs MD simulations in both the presence and the absence of the ligand GUA. The MD simulations suggest that the conformation of guanine riboswitch depends on the distance of two groups in the binding pocket of ligand. The conformation is in a close conformation when U51-A52 is close to C74-U75. PMID- 28345905 TI - MetaTox: Web Application for Predicting Structure and Toxicity of Xenobiotics' Metabolites. AB - A new freely available web-application MetaTox ( http://www.way2drug.com/mg ) for prediction of xenobiotic's metabolism and calculation toxicity of metabolites based on the structural formula of chemicals has been developed. MetaTox predicts metabolites, which are formed by nine classes of reactions (aliphatic and aromatic hydroxylation, N- and O-glucuronidation, N-, S- and C-oxidation, and N- and O-dealkylation). The calculation of probability for generated metabolites is based on analyses of "structure-biotransformation reactions" and "structure modified atoms" relationships using a Bayesian approach. Prediction of LD50 values is performed by GUSAR software for the parent compound and each of the generated metabolites using quantitative structure-activity relationahip (QSAR) models created for acute rat toxicity with the intravenous type of administration. PMID- 28345906 TI - Malonylginsenosides with Potential Antidiabetic Activities from the Flower Buds of Panax ginseng. AB - LC-MS-guided phytochemical isolation of malonylginsenosides, featuring neutral elimination of CO2 and C3H2O3 by the negative mode collision-induced dissociation, from the flower buds of Panax ginseng led to the isolation of 19 malonyl-substituted triterpenoid saponins. They include 15 new malonylginsenosides, malonylfloralginsenosides-Re1-Re3 (1-3), -Rb1 and -Rb2 (4, 5), -Rd1-Rd6 (6-11), and -Rc1-Rc4 (12-15), and the known m-Rb1, m-Rc, m-Rb2, and m-Rd (16-19). Compound 11 represents the first dimalonyl saponin isolated from the Panax genus, while 2-4, 9, and 10 are five ginsenosides with single malonylation at the C-20 sugar chain. The antidiabetic activities of nine of these malonyl-substituted ginsenosides (1, 3, 4, 8, 13, and 16-19) and five of the corresponding non-malonyl ginsenosides (Re, Rb1, Rb2, Rc, and Rd) were evaluated by L6 myotubes' glucose consumption and AMPKalpha2beta1gamma1 activation. Ginsenoside Rb2, 1, and 18 promoted glucose consumption of differentiated L6 myotubes, while ginsenosides Rb1, Rb2, and Rd and the malonylginsenosides 4, 8, 13, 16, 17, and 19 activated AMPKalpha2beta1gamma1 (EC50: 0.0168-2.8 MUM, fold: 1.7-4.7). PMID- 28345908 TI - Rapid, Low Temperature Formation of Imine-Linked Covalent Organic Frameworks Catalyzed by Metal Triflates. AB - Imine-linked two-dimensional covalent organic frameworks (2D COFs) are crystalline polymer networks with enhanced stability compared to boronate ester linked systems and with broad monomer scope. They are traditionally prepared by condensing polyfunctional aldehydes and amines at elevated temperature in a mixture of organic solvents and aqueous CH3CO2H, which catalyzes imine formation and exchange. Here we employ metal triflates, which are water-tolerant Lewis acids, to accelerate 2D imine-linked COF synthesis and improve their materials quality. Low catalyst loadings provide crystalline polymer networks in nearly quantitative yields. These conditions are demonstrated for several COFs, including heteroatom-containing systems of interest for optoelectronic applications. PMID- 28345907 TI - Simulating Protein Mediated Hydrolysis of ATP and Other Nucleoside Triphosphates by Combining QM/MM Molecular Dynamics with Advances in Metadynamics. AB - The protein mediated hydrolysis of nucleoside triphosphates such as ATP or GTP is one of the most important and challenging biochemical reactions in nature. The chemical environment (water structure, catalytic metal, and amino acid residues) adjacent to the hydrolysis site contains hundreds of atoms, usually greatly limiting the amount of the free energy sampling that one can achieve from computationally demanding electronic structure calculations such as QM/MM simulations. Therefore, the combination of QM/MM molecular dynamics with the recently developed transition-tempered metadynamics (TTMetaD), an enhanced sampling method that can provide a high-quality free energy estimate at an early stage in a simulation, is an ideal approach to address the biomolecular nucleoside triphosphate hydrolysis problem. In this work the ATP hydrolysis process in monomeric and filamentous actin is studied as an example application of the combined methodology. The performance of TTMetaD in these demanding QM/MM simulations is compared with that of the more conventional well-tempered metadynamics (WTMetaD). Our results show that TTMetaD exhibits much better exploration of the hydrolysis reaction free energy surface in two key collective variables (CVs) during the early stages of the QM/MM simulation than does WTMetaD. The TTMetaD simulations also reveal that a key third degree of freedom, the O-H bond-breaking and proton transfer from the lytic water, must be biased for TTMetaD to converge fully. To perturb the NTP hydrolysis dynamics to the least extent and to properly focus the MetaD free energy sampling, we also adopt here the recently developed metabasin metadynamics (MBMetaD) to construct a self limiting bias potential that only applies to the lytic water after its nucleophilic attack of the phosphate of ATP. With these new, state-of-the-art enhanced sampling metadynamics techniques, we present an effective and accurate computational strategy for combining QM/MM molecular dynamics simulation with free energy sampling methodology, including a means to analyze the convergence of the calculations through robust numerical criteria. PMID- 28345909 TI - Rapid and Simultaneous Analysis of 360 Pesticides in Brown Rice, Spinach, Orange, and Potato Using Microbore GC-MS/MS. AB - A multiresidue method for the simultaneous and rapid analysis of 360 pesticides in representative agricultural produce (brown rice, orange, spinach, and potato) was developed using a modified QuEChERS procedure combined with gas chromatography-tandem mass spectrometry (GC-MS/MS). Selected reaction monitoring transition parameters (e.g., collision energy, precursor and product ions) in MS/MS were optimized to achieve the best selectivity and sensitivity for a wide range of GC-amenable pesticides. A short (20 m) microbore (0.18 mm i.d.) column resulted in better signal-to-noise ratio with reduced analysis time than a conventional narrowbore column (30 m * 0.25 mm i.d.). The priming injection dramatically increased peak areas by masking effect on a new GC liner. The limit of quantitation was <0.01 mg/kg, and the correlation coefficients (r2) of matrix matched standards were >0.99 within the range of 0.0025-0.1 mg/kg. Acetonitrile with 0.1% formic acid without additional buffer salts was used for pesticide extraction, whereas only primary-secondary amine (PSA) was used for dispersive solid phase extraction (dSPE) cleanup, to achieve good recoveries for most of the target analytes. The recoveries ranged from 70 to 120% with relative standard deviations of <=20% at 0.01 and 0.05 mg/kg spiking levels (n = 6) in all samples, indicating acceptable accuracy and precision of the method. Seventeen real samples from local markets were analyzed by using the optimized method, and 14 pesticides in 11 incurred samples were found at below the maximum residue limits. PMID- 28345910 TI - PyCGTOOL: Automated Generation of Coarse-Grained Molecular Dynamics Models from Atomistic Trajectories. AB - Development of coarse-grained (CG) molecular dynamics models is often a laborious process which commonly relies upon approximations to similar models, rather than systematic parametrization. PyCGTOOL automates much of the construction of CG models via calculation of both equilibrium values and force constants of internal coordinates directly from atomistic molecular dynamics simulation trajectories. The derivation of bespoke parameters from atomistic simulations improves the quality of the CG model compared to the use of generic parameters derived from other molecules, while automation greatly reduces the time required. The ease of configuration of PyCGTOOL enables the rapid investigation of multiple atom-to bead mappings and topologies. Although we present PyCGTOOL used in combination with the GROMACS molecular dynamics engine its use of standard trajectory input libraries means that it is in principle compatible with other software. The software is available from the URL https://github.com/jag1g13/pycgtool as the following doi: 10.5281/zenodo.259330 . PMID- 28345911 TI - Subtle Microwave-Induced Overheating Effects in an Industrial Demethylation Reaction and Their Direct Use in the Development of an Innovative Microwave Reactor. AB - A systematic study of the conventional and microwave (MW) kinetics of an industrially relevant demethylation reaction is presented. In using industrially relevant reaction conditions the dominant influence of the solvent on the MW energy dissipation is avoided. Below the boiling point, the effect of MWs on the activation energy Ea and k0 is found nonexistent. Interestingly, under reflux conditions, the microwave-heated (MWH) reaction displays very pronounced zero order kinetics, displaying a much higher reaction rate than observed for the conventionally thermal-heated (CTH) reaction. This is related to a different gas product (methyl bromide, MeBr) removal mechanism, changing from classic nucleation into gaseous bubbles to a facilitated removal through escaping gases/vapors. Additionally, the use of MWs compensates better for the strong heat losses in this reaction, associated with the boiling of HBr/water and the loss of MeBr, than under CTH. Through modeling, MWH was shown to occur inhomogeneously around gas/liquid interfaces, resulting in localized overheating in the very near vicinity of the bubbles, overall increasing the average heating rate in the bubble vicinity vis-a-vis the bulk of the liquid. Based on these observations and findings, a novel continuous reactor concept is proposed in which the escaping MeBr and the generated HBr/water vapors are the main driving forces for circulation. This reactor concept is generic in that it offers a viable and low cost option for the use of very strong acids and the managed removal/quenching of gaseous byproducts. PMID- 28345912 TI - Fluorogenic Templated Reaction Cascades for RNA Detection. AB - Nucleic acids detection is essential to the study of biological processes and to diagnosis of pathological states. Although PCR is highly effective in vitro, methods that can function without prior sample preparation, thermal cycling, or enzymes are of interest due to their simplicity. Most current non-PCR detection methods rely on linear signal amplification, which hinders the detection of small amounts of genetic material. To address this limitation, we tested a new strategy for attaining higher-order signal amplification, in which a target sequence templates a chemical ligation, and the product of this reaction is in turn detected with a second templated reaction. The method is nonenzymatic, isothermal, and fluorogenic, allowing the direct detection of nucleic acids in complex matrices. Using this approach, as little as 500 attomoles (10 pM) could be detected with single nucleotide resolution. In a test of selectivity, single nucleotide substitutions and deletions could successfully be detected, including a deletion that is associated with tetracycline resistance in Helicobacter pylori. Compatibility with biological matrices was demonstrated by the direct detection of rRNA in bacterial lysate. Imaging and detection of target sequences on a solid support further illustrates the potential of the new approach for high throughput analysis. PMID- 28345913 TI - Molecular Engineering of Phytoalexins in Plants: Benefits and Limitations for Food and Agriculture. PMID- 28345914 TI - Photoreductive Elimination of Chlorine from Antimony in an [SbPd]VII Complex. AB - As part of our ongoing interest in main group species that support the photoreductive elimination of halogens, we have synthesized [Cl3SbVPdIICl2(o dppp)2] (o-dppp = o-(Ph2P)C6H4), a palladium dichloride complex featuring a Lewis acidic trichlorostiborane moiety positioned within the ligand architecture. Upon UV irradiation, this complex undergoes a clean photoreductive chlorine elimination reaction which produces [Cl2SbIVPdICl(o-dppp)2], a complex with a covalent Sb-Pd bond. This transformation illustrates the viability of antimony as an element from which a halogen can be photoeliminated; it also shows that a metal halide can be photolytically coupled with a main group halide to generate a metal-element bond. PMID- 28345915 TI - Observation of pH-Induced Protein Reorientation at the Water Surface. AB - Hydrophobins are surface-active proteins that form a hydrophobic, water-repelling film around aerial fungal structures. They have a compact, particle-like structure, in which hydrophilic and hydrophobic regions are spatially separated. This surface property renders them amphiphilic and is reminiscent of synthetic Janus particles. Here we report surface-specific chiral and nonchiral vibrational sum-frequency generation spectroscopy (VSFG) measurements of hydrophobins adsorbed to their natural place of action, the air-water interface. We observe that hydrophobin molecules undergo a reversible change in orientation (tilt) at the interface when the pH is varied. We explain this local orientation toggle from the modification of the interprotein interactions and the interaction of hydrophobin with the water solvent, following the pH-induced change of the charge state of particular amino acids. PMID- 28345916 TI - Molecular Mechanism of Nucleotide-Dependent Allosteric Regulation in AMP Activated Protein Kinase. AB - The AMP-activated protein kinase (AMPK), a central enzyme in the regulation of energy homeostasis, is an important drug target for type 2 diabetes, obesity, and cancer. Binding of adenosine nucleotides to the regulatory gamma-subunit tightly regulates the activity of this enzyme. Though recent crystal structures of AMPK have provided important insights into the allosteric activation of AMPK, molecular details of the regulatory mechanism of AMPK activation is still elusive. Here, we have performed extensive all-atom molecular dynamics (MD) simulations and shown that the kinase domain (KD) and gamma-subunit come closer resulting in a more compact heterotrimeric AMPK complex in AMP-bound state compared to the ATP-bound state. The binding of ATP at site 3 of regulatory gamma subunit allosterically inhibits AMPK by destabilizing different regulatory regions of alpha-subunit: the autoinhibitory domain, the linker region, and the activation loop of the kinase core. The catalytically important residues experience a change in mechanical stress, and major rearrangements in community structure derived from residue-residue interaction energy-based network are observed in KD and alpha-linker region upon binding of different nucleotides. Our results also highlight the role of conserved charged residues forming an ionic network near the site 3 of gamma-subunit in allosteric communications. PMID- 28345917 TI - Enantiodivergent Synthesis of Tertiary alpha-Aryl 1-Indanones: Evidence Toward Disparate Mechanisms in the Palladium-Catalyzed Decarboxylative Asymmetric Protonation. AB - Herein, we describe a study into the scope and origin of an enantiodivergent effect in the palladium-catalyzed decarboxylative asymmetric protonation. By switching the achiral proton source, both enantiomers of a series of tertiary alpha-aryl-1-indanones are readily accessed from the corresponding alpha-aryl beta-keto allyl esters. In this example of dual stereocontrol, enantioselectivities up to 94% (S) and 92% (R) were achieved using Meldrum's acid and formic acid, respectively. In an attempt to rationalize this switch in absolute configuration an investigation of the ambiguous mechanism of the decarboxylative asymmetric protonation was conducted. A novel catalytic cycle for the reaction with formic acid is proposed and subjected to a variety of experimental studies. PMID- 28345918 TI - Direct S0->T Excitation of a Conjugated Polymer Repeat Unit: Unusual Spin Forbidden Transitions Probed by Time-Resolved Electron Paramagnetic Resonance Spectroscopy. AB - A detailed understanding of the electronic structure of semiconducting polymers and their building blocks is essential to develop efficient materials for organic electronics. (Time-resolved) electron paramagnetic resonance (EPR) is particularly suited to address these questions, allowing one to directly detect paramagnetic states and to reveal their spin-multiplicity, besides its clearly superior resolution compared to optical methods. We present here evidence for a direct S0->T optical excitation of distinct triplet states in the repeat unit of a conjugated polymer used in organic photovoltaics. These states differ in their electronic structure from those populated via intersystem crossing from excited singlet states. This is an additional and so far unconsidered route to triplet states with potentially high impact on efficiency of organic electronic devices. PMID- 28345919 TI - Photocontrol of Clustering, Retaining, and Releasing of Microbeads Concomitant with Phototransformation of Supramolecular Architecture of Amphiphilic Diarylethene. AB - Photoinduced clustering of polystyrene microbeads and photocontrol of their diffusion was achieved in water with the assistance of photoinduced transformation of supramolecular architecture of amphiphilic diarylethene between sphere and fiber states. When a suspension of polystyrene beads containing the sphere state of diarylethene was UV-irradiated from beneath, clustering of the polystyrene beads by thermal convection was observed. The velocity of clustering was dependent on the amount of photogenerated nanofibers that determines the viscosity of the water. Diffusion of the clustered polymer beads was suppressed by the surrounding fibers, but was restored to regular Brownian motion upon irradiation with visible light. It was suggested that the diffusion of the microbeads was controlled by the transformation of aggregates between the more viscous fiber state and the less viscous sphere state. These results provide new insight into the photocontrol of particle motion in fluidic media. PMID- 28345921 TI - Constructing 24(23->22)-abeo-Cholestane from Tigogenin in a 20(22->23)-abeo-Way via a PhI(OAc)2-mediated Favorskii Rearrangement. AB - Transforming tigogenin, a steroidal sapogenin, to a 24(23->22)-abeo-cholestane, which is an unusual structural feature shared by the aglycons of saundersiosides and candicanoside A, is described. The spiroketal of tigogenin was unfolded and the resulting C22-ketone was subjected to Favorskii rearrangement mediated by PhI(OAc)2/KOH/MeOH to squeeze out the C22 from the side chain, thus reaching the 24(23->22)-abeo-cholestane structure. PMID- 28345920 TI - Tuning the Continuum of Structural States in the Native Ensemble of a Regulatory Protein. AB - The mesoscale nature of proteins allows for an efficient coupling between environmental cues and conformational changes, enabling their function as molecular transducers. Delineating the precise structural origins of such a connection and the expected spectroscopic response has, however, been challenging. In this work, we perform a combination of urea-temperature double perturbation experiments and theoretical modeling to probe the conformational landscape of Cnu, a natural thermosensor protein. We observe unique ensemble signatures that point to a continuum of conformational substates in the native ensemble and that respond intricately to perturbations upon monitoring secondary and tertiary structures, distances between an intrinsic FRET pair, and hydrodynamic volumes. Binding assays further reveal a weakening of the Cnu functional complex with temperature, highlighting the molecular origins of signal transduction critical for pathogenic response in enterobacteriaceae. PMID- 28345922 TI - Synthetic Access Toward Cycloastragenol Glycosides. AB - The first efficient synthetic approach toward four types of the cycloartane glycosides, the cycloastragenol 25-O; 3-O; 3,6-O-bis; and 3,25-O-bisglycoside, have been established, which featured the PPY-mediated, concentration-controlled acetylation and Au(I)-catalyzed Yu glycosylation. Through the synthetic investigation, the reactivity sequence of the four OHs in cycloastragenol was fixed for the first time and a detour strategy for the highly efficient removal of bulky pivaloyl protecting groups was discovered. PMID- 28345923 TI - Geometry and Topology of Two-Dimensional Dry Foams: Computer Simulation and Experimental Characterization. AB - Pseudo-two-dimensional (2D) foams are commonly used in foam studies as it is experimentally easier to measure the bubble size distribution and other geometric and topological properties of these foams than it is for a 3D foam. Despite the widespread use of 2D foams in both simulation and experimental studies, many important geometric and topological relationships are still not well understood. Film size, for example, is a key parameter in the stability of bubbles and the overall structure of foams. The relationship between the size distribution of the films in a foam and that of the bubbles themselves is thus a key relationship in the modeling and simulation of unstable foams. This work uses structural simulation from Surface Evolver to statistically analyze this relationship and to ultimately formulate a relationship for the film size in 2D foams that is shown to be valid across a wide range of different bubble polydispersities. These results and other topological features are then validated using digital image analysis of experimental pseudo-2D foams produced in a vertical Hele-Shaw cell, which contains a monolayer of bubbles between two plates. From both the experimental and computational results, it is shown that there is a distribution of sizes that a film can adopt and that this distribution is very strongly dependent on the sizes of the two bubbles to which the film is attached, especially the smaller one, but that it is virtually independent of the underlying polydispersity of the foam. PMID- 28345924 TI - A Ligand-Directed Catalytic Regioselective Hydrocarboxylation of Aryl Olefins with Pd and Formic Acid. AB - An effective Pd-catalyzed hydrocarboxylation of aryl olefins with Ac2O and formic acid is described. A variety of 2- and 3-arylpropanoic acids can be regioselectively formed by the judicious choice of ligand without the use of toxic CO gas. PMID- 28345925 TI - Metal Insertion in a Methylamine-Functionalized Zirconium Metal-Organic Framework for Enhanced Carbon Dioxide Capture. AB - The reaction of ZrCl4 with 2',3',5',6'-tetramethylamino-p-terphenyl-4,4" dicarboxylic acid (H2tpdc-4CH2NH2.3HCl) in the presence of NaF affords Zr6O4(OH)2.1F1.9(tpdc-4CH2NH2.3HCl)6 (1), which is a new member of the Zr6O4(OH)4(dicarboxylate linker)12 or UiO-68 family, and exhibits high porosity with BET and Langmuir surface areas of 1910 m2/g and 2220 m2/g, respectively. Remarkably, fluoride ion incorporation in the zirconium clusters results in increased thermal stability, marking the first example of enhancement in the stability of a UiO framework by this defect-restoration approach. Although material 1 features four alkylamine groups on each organic linker, the framework does not exhibit the high CO2 uptake that would be expected for reaction between CO2 and the amine groups to form carbamic acid or ammonium carbamate species. The absence of strong CO2 adsorption can likely be attributed to protonation at some of the amine sites and the presence of counterions. Indeed, exposure of material 1 to acetonitrile solutions of the organic bases 1,8 bis(dimethylamino)naphthalene (DMAN) or trimethylamine, affords a partially deprotonated material, which exhibits enhanced CO2 uptake. Exposure of basic amine sites also facilitates the postsynthetic chelation of copper(I) ([Cu(MeCN)4].CF3SO3) to yield material 2 with an enhanced CO2 uptake of 4 wt % at 0.15 bar, which is double that of the parent framework 1. PMID- 28345926 TI - Band Gap Opening Induced by the Structural Periodicity in Epitaxial Graphene Buffer Layer. AB - The epitaxial graphene buffer layer on the Si face of hexagonal SiC shows a promising band gap, of which the precise origin remains to be understood. In this work, we correlate the electronic to the atomic structure of the buffer layer by combining angle resolved photoemission spectroscopy (ARPES), scanning tunneling microscopy (STM), and high-resolution scanning transmission electron microscopy (HR-STEM). We show that the band structure in the buffer has an electronic periodicity related to the structural periodicity observed in STM images and published X-ray diffraction. Our HR-STEM measurements show the bonding of the buffer layer to the SiC at specific locations separated by 1.5 nm. This is consistent with the quasi 6 * 6 periodic corrugation observed in the STM images. The distance between buffer C and SiC is 1.9 A in the bonded regions and up to 2.8 A in the decoupled regions, corresponding to a 0.9 A corrugation of the buffer layer. The decoupled regions are sp2 hybridized. Density functional tight binding (DFTB) calculations demonstrate the presence of a gap at the Dirac point everywhere in the buffer layer, even in the decoupled regions where the buffer layer has an atomic structure close to that of graphene. The surface periodicity also promotes band in the superperiodic Brillouin zone edges as seen by photoemission and confirmed by our calculations. PMID- 28345927 TI - Stable Superwetting Meshes for On-Demand Separation of Immiscible Oil/Water Mixtures and Emulsions. AB - Oil-water separation is of great importance for the treatment of oily wastewater, including immiscible light/heavy oil-water mixtures, oil-in-water, or water-in oil emulsions. Recently, interfacial materials (especially filtration membranes) with special wettability have been broadly developed to solve the environmental problems by virtue of their advantages in energy saving, high flux, and good selectivity. However, the given wetting property (superhydrophilicity or superhydrophobicity) and pore size and poor stability of filtration membranes limit their widespread applications, which is far from meeting a wide variety of oil-polluted water. Here polypyrrole-coated meshes with underwater superoleophobicity and underoil superhydrophobicity as well as controllable pore size were prepared by adopting cyclic voltammetry. It is found that the surface micro/nanohierarchical structures play a critical role in the formation of underwater superoleophobicity and underoil superhydrophobicity. HCl is advantageous to the construction of highly rough surface rather than H2SO4 and H3PO4. The obtained filtration membranes can be used for the on-demand separation of oil-water mixtures, showing outstanding stability in harsh conditions, such as high temperature (80 degrees C), low temperature (0 degrees C), salt (0.5 M NaCl), and acid (1 M HCl), except for alkali (1 M NaOH). PMID- 28345928 TI - Enantioselective Synthesis of 4H-Pyran via Amine-Catalyzed Formal (3 + 3) Annulation of delta-Acetoxy Allenoate. AB - The formal (3 + 3) annulations of delta-acetoxy allenoates and 1C,3O bisnucleophiles are reported with the use of 6'-deoxy-6'-perfluorobenzamido quinine (4g) as a catalyst, which provide rapid access to 4H-pyrans with excellent enantioselectivity. The reaction features a wide reaction scope and mild reaction conditions. The crucial roles of amide NH of 4g as a H-bond donor have also been elucidated, which not only activates allenoate to facilitate formation of cationic intermediate A but also enhances the electrophilicity of its delta-position for nucleophilic 1,6-addition. PMID- 28345930 TI - Palladium-Catalyzed Formal (5 + 2) Annulation between ortho-Alkenylanilides and Allenes. AB - 2-Alkenyltriflylanilides react with allenes upon treatment with catalytic amounts of Pd(OAc)2 and Cu(II) to give highly valuable 2,3-dihydro-1H-benzo[b]azepines, in good yields, and with very high regio- and diastereoselectivities. Density functional theory (DFT) calculations suggest that the C-H activation of the alkenylanilide involves a classical concerted metalation-deprotonation (CMD) mechanism. PMID- 28345929 TI - Utility of CYP3A4 and PXR-CAR-CYP3A4/3A7 Transgenic Mouse Models To Assess the Magnitude of CYP3A4 Mediated Drug-Drug Interactions. AB - Species differences in the expression, activity, regulation, and substrate specificity of metabolizing enzymes preclude the use of animal models to predict clinical drug-drug interactions (DDIs). The objective of this work is to determine if the transgenic (Tg) Cyp3a-/-Tg-3A4Hep/Int and Nr1i2/Nr1i3-/--Cyp3a-/ Tg-PXR-CAR-3A4/3A7Hep/Int (PXR-CAR-CYP3A4/3A7) mouse models could be used to predict in vivo DDI of 10 drugs; alprazolam, bosutinib, crizotinib, dasatinib, gefitinib, ibrutinib, regorafenib, sorafenib, triazolam, and vandetinib (as victims); with varying magnitudes of reported CYP3A4 clinical DDI. As an assessment of the effect of CYP3A4 inhibition, these drugs were coadministered to Cyp3a-/-Tg-3A4Hep/Int mice with the CYP3A inhibitor, itraconazole. For crizotinib, regorafenib, sorafenib, and vandetanib, there was no significant increase of AUC observed; with alprazolam, bosutinib, ibrutinib, dasatinib, and triazolam, pretreatment with itraconazole resulted in a 2-, 4-, 17-, 7-, and 15 fold increase in AUC, respectively. With the exception of gefinitib for which the DDI effect was overpredicted (12-fold in Tg-mice vs 2-fold in the clinic), the magnitude of AUC increase observed in this study was consistent (within 2-fold) with the clinical DDI observed following administration with itraconazole/ketoconazole. As an assessment of CYP3A4 induction, following rifampin pretreatment to PXR-CAR-3A4/3A7Hep/Int mice, an 8% decrease in vandetanib mean AUC was observed; 39-52% reduction in AUC were observed for dasatinib, ibrutinib, regorafenib, and sorafenib compared to vehicle treated mice. The greatest effect of rifampin induction was observed with alprazolam, bosutinib, crizotinib, gefitinib, and triazolam where 72-91% decrease in AUC were observed. With the exception of vandetanib for which rifampin induction was under predicted, the magnitude of induction observed in this study was consistent (within 2-fold) with clinical observations. These data sets suggest that, with two exceptions, these transgenic mice models were able to exclude or capture the magnitude of CYP3A4 clinical inhibition and induction. Data generated in transgenic mice may be used to gain confidence and complement in vitro and in silico methods for assessing DDI potential/liability. PMID- 28345931 TI - Predictable Conformational Diversity in Foldamers of Sugar Amino Acids. AB - A systematic conformational search was carried out for monomers and homohexamers of furanoid beta-amino acids: cis-(S,R) and trans-(S,S) stereoisomers of aminocyclopentane carboxylic acid (ACPC), two different aminofuranuronic acids (AFUalpha and AFUbeta), their isopropylidene derivatives (AFU(ip)), and the key intermediate beta-aminotetrahydrofurancarboxylic acid (ATFC). The stereochemistry of the building blocks was chosen to match that of the natural sugar amino acid (xylose and ribose) precursors (XylAFU and RibAFU). The results show that hexamers of cis-furanoid beta-amino acids show great variability: while hydrophobic cyclopentane (cis-ACPC)6 and hydrophilic (XylAFUalpha/beta)6 foldamers favor two different zigzagged conformation as hexamers, the backbone fold turns into a helix in the case of (cis-ATFC)6 (10-helix) and (XylAFU(ip))6 (14-helix). Trans stereochemistry resulted in hexamers exclusively with the right handed helix conformation, (H12P)6, regardless of their polarity. We found that the preferred oligomeric structure of XylAFUalpha/beta is conformationally compatible with beta-pleated sheets, while that of the trans/(S,S) units matches with alpha-helices of proteins. PMID- 28345932 TI - Formation of Turmeric-Based Thin Films: Universal, Transparent Coatings. AB - Curry stains on clothes and dishes in daily life inspired us to investigate the potential use of turmeric powder, the major ingredient in curry, as a universal coating material. After condition optimization, the coating solution was made by boiling and filtering a turmeric slurry, and the coating was formed at pH 3, leading to the formation of ultrathin, transparent films. Various inorganic and polymeric substrates were successfully coated with turmeric-based materials, including gold, TiO2, SiO2, glass, stainless steel, indium tin oxide, nylon, polyethylene, polycarbonate, polypropylene, acryl, and poly(ethylene terephthalate). The turmeric-based coating was also applied to poly(tetrafluoroethylene) (PTFE, Teflon) and cyclic olefin copolymer (COC), and after double dip-coating, the water contact angle was changed from 118.2 degrees to 49.1 degrees for PTFE and from 91.2 degrees to 44.7 degrees for COC. The water contact angles for the other substrates converged to 35 degrees after coating, confirming the substrate-independent universal coating capability of turmeric. The X-ray photoelectron spectroscopic analysis indicated the presence of nitrogen in the film, and the possible involvement of amines in film formation was investigated with several amine compounds. PMID- 28345933 TI - Structure-Energy Relationships of Halogen Bonds in Proteins. AB - The structures and stabilities of proteins are defined by a series of weak noncovalent electrostatic, van der Waals, and hydrogen bond (HB) interactions. In this study, we have designed and engineered halogen bonds (XBs) site-specifically to study their structure-energy relationship in a model protein, T4 lysozyme. The evidence for XBs is the displacement of the aromatic side chain toward an oxygen acceptor, at distances that are equal to or less than the sums of their respective van der Waals radii, when the hydroxyl substituent of the wild-type tyrosine is replaced by a halogen. In addition, thermal melting studies show that the iodine XB rescues the stabilization energy from an otherwise destabilizing substitution (at an equivalent noninteracting site), indicating that the interaction is also present in solution. Quantum chemical calculations show that the XB complements an HB at this site and that solvent structure must also be considered in trying to design molecular interactions such as XBs into biological systems. A bromine substitution also shows displacement of the side chain, but the distances and geometries do not indicate formation of an XB. Thus, we have dissected the contributions from various noncovalent interactions of halogens introduced into proteins, to drive the application of XBs, particularly in biomolecular design. PMID- 28345934 TI - Amphiphilic Nucleating Agents to Enhance Calcium Phosphate Growth on Polymeric Surfaces. AB - Poly(epsilon-caprolactone) (PCL) is an aliphatic polyester widely explored in the preparation of guided bone regeneration (GBR) membranes because of its interesting mechanical properties and biodegradability. However, PCL high hydrophobicity often impairs cell adhesion and proliferation as well as calcium phosphate growth, all of which are crucial to achieving suitable bone-tissue integration. In this work, aimed at achieving less-hydrophobic surfaces, amphiphilic molecules were added at low concentrations to the polymeric dope solutions that generated the GBR membranes. During membrane formation, these molecules migrate to the solution/air interface in such a way that, upon liquid solid phase transition, the negatively charged heads are exposed while the apolar tails are anchored to the polymer bulk. As a consequence, these molecules became nucleating agents for subsequent calcium phosphate growth using an alternating soaking process. Herein, PCL porous membranes containing different amphiphilic molecules, such as stearic acid and bis(2-ethylhexyl) phosphate, were investigated. This new, simple, and atoxic method to superficially treat polymeric membranes could be extended to a wide range of polymers and applications. PMID- 28345935 TI - Targeting Self-Binding Peptides as a Novel Strategy To Regulate Protein Activity and Function: A Case Study on the Proto-oncogene Tyrosine Protein Kinase c-Src. AB - : Previously, we have reported a new biomolecular phenomenon spanning between protein folding and binding, termed as self-binding peptides (SBPs), where a short peptide segment in monomeric protein functions as a molecular switch by dynamically binding to/unbinding from its cognate domain in the monomer (Yang et al. J. Chem. Inf. MODEL: 2015, 55, 329-342). Here, we attempt to raise the SBP as a new class of druggable targets to regulate the biological activity and function of proteins. A case study was performed on the proto-oncogene nonreceptor tyrosine kinase, c-Src, which contains two SBPs that bind separately to SH3 and SH2 domains of the kinase. State-of-the-art molecular dynamics (MD) simulations and post binding energetics analysis revealed that disrupting the kinase intramolecular interactions of SH3 and SH2 domains with their cognate SBP ligands can result in totally different effects on the structural dynamics of c-Src kinase architecture; targeting the SH2 domain unlocks the autoinhibitory form of the kinase-this is very similar to the pTyr527 dephosphorylation that functionally activates the kinase, whereas targeting the SH3 domain can only release the domain from the tightly packed kinase but has a moderate effect on the kinase activity. Subsequently, based on the cognate SBP sequence we computationally designed a number of SH2-binding phosphopeptides using a motif grafting strategy. Fluorescence polarization (FP) assay observed that most of the designed phosphopeptides have higher binding affinity to SH2 domain as compared to the native SBP segment (Kd = 53 nM). Kinase assay identified a typical dose response relationship of phosphopeptides against kinase activation, substantiating that disruption of SH2-SBP interaction can mimic c-Src dephosphorylation and activate the kinase. Two rationally designed phosphopeptides, namely EPQpYEEIEN and EPQpYEELEN, were determined as strong binders of SH2 domain (Kd = 8.3 and 15 nM, respectively) and potent activators of c-Src kinase (EC50 = 3.2 and 41 MUM, respectively). PMID- 28345936 TI - Co-Registered Molecular Logic Gate with a CO-Releasing Molecule Triggered by Light and Peroxide. AB - Co-registered molecular logic gates combine two different inputs and outputs, such as light and matter. We introduce a biocompatible CO-releasing molecule (CORM, A) as Mn(I) tricarbonyl complex with the ligand 5-(dimethylamino)-N, N bis(pyridin-2-ylmethyl) naphthalene-1-sulfonamide (L). CO release is chaperoned by turn-on fluorescence and can be triggered by light (405 nm) as well as with hydrogen peroxide in aqueous phosphate buffer. Complex A behaves as a logic "OR" gate via co-registering the inputs of irradiation (light) and peroxide (matter) into the concomitant outputs fluorescence (light) and CO (matter). Cell viability assays confirm the low toxicity of A toward different human cell lines. The CORM has been used to track the inclusion of A into cancer cells. PMID- 28345937 TI - Asymmetric Synthesis of (-)-Pterocarine and (-)-Galeon via Chiral Phase Transfer Catalyzed Atropselective Formation of Diarylether Cyclophane Skeleton. AB - Pterocarine and galeon are typical examples of diarylether heptanoids (DAEHs) with planar chirality due to the strictly constrained conformations in their molecular skeletons. The characterized oxa[1,7]metapara-cyclophane motifs in DAEHs impose great challenges for their enantioselective synthesis. The asymmetric syntheses of (-)-pterocarine and (-)-galeon are demonstrated by employing a chiral phase transfer-catalyzed highly enantioselective SNAr cyclization as the key step for the formation of a diarylether cyclophane skeleton. PMID- 28345938 TI - Mimicking pH-Gated Ionic Channels by Polyelectrolyte Complex Confinement Inside a Single Nanopore. AB - Biological channels have served as inspiration to design stimuli-response artificial nanopores. Here we propose an original approach to design a pH-gate nanopore based on polyethylenimine and chondroitin-4-sulfate (ChS) layer-by-layer self-assembly. This approach is interesting because it is rapid and permits monitoring in real time of functionalization. The study of ionic transport through these single nanopores reveals a selectivity on anions and pH-gate properties at low salt concentration. It is open at pH below 4 or 5 depending on salt concentration. These properties are explained by the modification of both charge and conformation of ChS as well as swelling of the polyelectrolyte complex. PMID- 28345939 TI - Macrophilone A: Structure Elucidation, Total Synthesis, and Functional Evaluation of a Biologically Active Iminoquinone from the Marine Hydroid Macrorhynchia philippina. AB - A previously uncharacterized pyrroloiminoquinone natural product, macrophilone A, was isolated from the stinging hydroid Macrorhynchia philippina. The structure was assigned utilizing long-range NMR couplings and DFT calculations and proved by a concise, five-step total synthesis. Macrophilone A and a synthetic analogue displayed potent biological activity, including increased intracellular reactive oxygen species levels and submicromolar cytotoxicity toward lung adenocarcinoma cells. PMID- 28345940 TI - Early development of mechanisms of change as a predictor of subsequent change and treatment outcome: The case of working alliance. AB - OBJECTIVE: Advanced statistical tools have created the opportunity to systematically examine the effect of early trajectories in predictors of therapeutic change, such as early alliance development patterns, on outcome. To date, however, these methods have been used almost exclusively to examine the effect of the development of early symptoms on later ones. Development patterns of alliance early in treatment, and their association with treatment outcome, have received much theoretical attention, but few systematic examinations have been conducted so far. METHOD: We integrated exploratory cluster analysis with the accumulated theoretical and empirical knowledge on patterns of alliance development to identify distinct patterns of early alliance development across the 1st 4 sessions of treatment in a sample of 166 patients receiving psychotherapy. RESULTS: Three patterns of early alliance development were identified: early gradual strengthening, early repaired rupture, and early unrepaired rupture. The gradual strengthening and the repaired rupture patterns early in treatment predicted alliance strengthening later in treatment, whereas the unrepaired rupture pattern early in treatment predicted alliance stability later in treatment. The effect of early alliance development patterns on treatment outcome was moderated by pretreatment interpersonal problems: For patients with better interpersonal functioning at intake, the gradual strengthening and the repaired rupture patterns showed better outcomes, whereas for those with poorer interpersonal functioning at intake, the early unrepaired rupture pattern showed better outcomes. CONCLUSIONS: Findings suggest that early alliance development patterns affect treatment process and outcome. (PsycINFO Database Record PMID- 28345941 TI - The roles of negative affect and goal adjustment capacities in breast cancer survivors: Associations with physical activity and diurnal cortisol secretion. AB - OBJECTIVE: This study examined whether within-person changes of breast cancer survivors' high-arousal negative affect (e.g., feeling scared, upset, anxious, or guilty) could predict high levels of diurnal cortisol secretion and moderate-to vigorous physical activity (MVPA). In addition, goal adjustment capacities (goal disengagement and goal reengagement) were expected to buffer the effect of negative affect on cortisol and to increase its effect on MVPA. METHOD: High arousal negative affect, self-reported MVPA, area-under-the-curve of diurnal cortisol secretion, and goal adjustment capacities were assessed in a longitudinal sample of 145 female breast cancer survivors. RESULTS: Based on hierarchical linear modeling, breast cancer survivors reported increased levels of both MVPA and cortisol secretion if they experienced higher (as compared with lower) levels of high-arousal negative affect than their personal average. Furthermore, within-person negative affect was associated with: (a) higher MVPA among participants with high (but not low) goal reengagement capacities; and (b) elevated cortisol secretion among participants with low (but not high) goal reengagement capacities. CONCLUSIONS: High-arousal negative affect may exert differing functions among breast cancer survivors in that it can trigger adaptive health behaviors, yet simultaneously elevate diurnal cortisol secretion. In addition, being able to engage in new goals may be a necessary condition for breast cancer survivors to experience the beneficial behavioral effects of high arousal negative affect, and it may prevent the adverse effect of negative affect on enhanced cortisol output. (PsycINFO Database Record PMID- 28345942 TI - Implicit spatial-numerical associations: Negative numbers and the role of counting direction. AB - It has been debated whether negative number concepts are cognitively represented on the same mental number line as positive number concepts. The present study reviews this debate and identifies limitations of previous studies. A method with nonspatial stimuli and responses is applied to overcome these limitations and to document a systematic implicit association of negative numbers with left space, thus indicating a leftward extension of the mental number line. Importantly, this result only held for left-to-right counting adults. Implications for the experiential basis of abstract conceptual knowledge are discussed. (PsycINFO Database Record PMID- 28345943 TI - The role of predictability in cooperative and competitive joint action. AB - Predictability may be an important component of cooperative action, or it may arise as a by-product of involuntary entrainment with another's behavior. Further, differences previously observed in cooperative versus competitive actions may represent a fundamental distinction between behaviors with opposite goals, or they may simply reflect the output of different physical actions. The role of predictability in cooperative versus competitive behavior was directly tested using a joint sequential button-pressing task in which Participant 1 (P1) pressed a key followed by P2 pressing a key. In the cooperative condition, both actors shared the goal of minimizing P2's response times (RTs). In the competitive condition, P1 tried to maximize P2's RTs, whereas P2 continued to try to minimize them. It was found that P1 was much more predictable in the timing of his or her presses in the cooperative condition than in the competitive condition, and this coincided with faster P2 responses when cooperating than when competing. A 2nd experiment showed the effects of the predictability of P1's responses on the speed of P2 responses were similar when P1 was replaced by a schematic hand, showing the responses could not have been due to the transmission of subtle nonverbal cues by P1. These results demonstrate that being predictable is an important strategy in the timing of cooperative joint action, whereas being unpredictable is an important strategy in competition, and that they have opposite effects on a coactor's ability to respond quickly. (PsycINFO Database Record PMID- 28345944 TI - Enhanced integration of multisensory body information by proximity to "habitual action space". AB - Previous research suggests integration of visual and somatosensory inputs is enhanced within reaching (peripersonal) space. In such experiments, somatosensory inputs are presented on the body while visual inputs are moved relatively closer to, or further from the body. It is unclear, therefore, whether enhanced integration in "peripersonal space" is truly due to proximity of visual inputs to the body space, or, simply the distance between the inputs (which also affects integration). Using a modified induction of the rubber hand illusion, here we measured proprioceptive drift as an index of visuosomatosensory integration when distance between the two inputs was constrained, and absolute distance from the body was varied. Further, we investigated whether integration varies with proximity of inputs to the habitual action space of the arm-rather than the actual arm itself. In Experiment 1, integration was enhanced with inputs proximal to habitual action space, and reduced with lateral distance from this space. This was not attributable to an attentional or perceptual bias of external space because the pattern of proprioceptive drift was opposite for left and right hand illusions, that is, consistently maximal at the shoulder of origin (Experiment 2). We conclude that habitual patterns of action modulate visuosomatosensory integration. It appears multisensory integration is modulated in locations of space that are functionally relevant for behavior, whether an actual body part resides within that space or not. (PsycINFO Database Record PMID- 28345945 TI - Gaze control during interceptive actions with different spatiotemporal demands. AB - It is widely accepted that the sources of information used to guide interceptive actions depend on conflicting spatiotemporal task demands. However, there is a paucity of evidence that shows how information pick-up during interceptive actions is adapted to such conflicting constraints. The present study therefore examined the effects of systematic manipulations of spatiotemporal constraints on performance, timing and gaze in an in situ interceptive action. To this end, expert futsal goalkeepers faced penalty kicks taken from 10 m and 6 m. With the more lenient spatiotemporal constraints (i.e., kicks from 10 m), the goalkeepers saved more kicks, initiated their actions later, and looked longer toward ball relative to the penalty takers' body. Furthermore, analysis of gaze patterns showed that interindividual variations in information pick-up were related to the unfolding of the penalty taker's action, revealing a less variable, funnel-like gaze pattern toward the end of the action. These findings are interpreted to reflect that changes in spatiotemporal demands induce the differential use of information for the accurate control of interceptive actions. (PsycINFO Database Record PMID- 28345946 TI - Objective effects of knowledge on visual perception. AB - To what extent is what we perceive influenced by what we know? Although a large literature purports to show effects of knowledge, expectations, and other cognitive states on various aspects of perception, strong counterarguments have been advanced that these demonstrations are confounded by nonperceptual factors. For example, although letters are easier to recognize in meaningful words than meaningless letter strings, skepticism remains that such effects of knowledge on visual recognition mean that knowledge literally helps people see. In Experiment 1, a perceptual matching task is used to show that meaningful words look sharper than meaningless letter strings. In Experiments 2 through 4, it is shown that people are more accurate in detecting subtle changes in blur when they occur in meaningful words compared with meaningless letter strings. In Experiment 5, it is shown that this improvement in performance cannot be explained solely by differences in visual familiarity, but is predicted by semantic factors such as word imageability. These results provide a strong empirical rejoinder to claims that perception is encapsulated from knowledge. (PsycINFO Database Record PMID- 28345947 TI - Distinct cognitive control mechanisms as revealed by modality-specific conflict adaptation effects. AB - Cognitive control is essential to resolve conflict in stimulus-response compatibility (SRC) tasks. The SRC effect in the current trial is reduced after an incongruent trial as compared with a congruent trial, a phenomenon being termed conflict adaptation (CA). The CA effect is found to be domain-specific, such that it occurs when adjacent trials contain the same type of conflict, but disappears when the conflicts are of different types. Similar patterns have been observed when tasks involve different modalities, but the modality-specific effect may have been confounded by task switching. In the current study, we investigated whether or not cognitive control could transfer across auditory and visual conflicts when task-switching was controlled. Participants were asked to respond to a visual or auditory (Experiments 1A/B) stimulus, with conflict coming from either the same or a different modality. CA effects showed modality-specific patterns. To account for potential confounding effects caused by differences in task-irrelevant properties, we specifically examined the influence of task irrelevant properties on CA effects within the visual modality (Experiments 2A/B). Significant CA effects were observed across different conflicts from distinct task-irrelevant properties, ruling out that the lack of cross-modal CA effects in Experiments 1A/B resulted from differences in task-irrelevant information. Task-irrelevant properties were further matched in Experiments 3A/B to examine the pure effect of modality. Results replicated Experiments 1A/B showing robust modality-specific CA effects. Taken together, we provide supporting evidences that modality affects cognitive control in conflict resolution, which should be taken into account in theories of cognitive control. (PsycINFO Database Record PMID- 28345948 TI - The impact of cross-modal correspondences on working memory performance. AB - Cross-modal correspondences influence perceptual performance in adults, infants, and even nonhuman primates across a variety of different sensory modalities, including tasks involving speeded detection and categorization. However, to date, it is still unclear whether and how correspondences could modulate post perceptual processes, such as working memory (WM). We investigated this issue using an audiovisual two-back task. In Experiment 1, 3 kinds of correspondences were used: audio/visual numerosity, pitch/shape, and pitch/elevation, each presented congruently (e.g., for numerosity: 3 tones along with 3 shapes) or incongruently (3 tones/2 shapes). Participants attended to the visual or auditory modalities, or both, simultaneously. The results revealed faster target-detection latencies following congruent as compared to incongruent stimulation, especially for numerosity congruence. In Experiment 2, we focused on numerosity, varying the correspondence of the unattended modality, thus having correspondences at both sample (e.g., 3 tones/3 shapes) and target (e.g., 3 tones/3 shapes), only at sample (sample: 3 tones/3 shapes; target: 3 tones/2 shapes), only at target (sample: 3 tones/2 shapes; target: 3 tones/3 shapes), or never. To investigate the information format we included "symbolic" quantities (i.e., visually/auditorily presented digits). The results confirmed the congruence effects, specifically when the correspondence operates at the target display, thus affecting response selection. The experiment revealed modal effects, showing how task-irrelevant digits affect performance only in the auditory modality, while task-irrelevant quantities affect it only when presented visually. Overall, these findings highlight the impact of cross-modal correspondences on WM, adding new light on the link between perceptual and post-perceptual stages of human information processing. (PsycINFO Database Record PMID- 28345949 TI - The spatial representation of time can be flexibly oriented in the frontal or lateral planes from an early age. AB - The perception of time is strongly influenced by spatial context. The longer the distance of a stimulus' trajectory, the longer its duration is perceived to be. This effect has primarily been investigated in the lateral (left-right) axis despite the fact that spatial metaphors for time most commonly invoke the frontal (front-back) axis. We therefore explored how spatial distance, depth, and direction influenced perceived duration of stimuli moving in the frontal or lateral axes. Moreover, we compared the developmental trajectories of frontal versus lateral representations of time by testing children (5, 7, or 10 years old) and adults. Results showed that perceived duration of the interval between 2 consecutive stimuli in a temporal bisection task was biased by distance in the frontal, as well as lateral, plane across all age groups. Even the mere impression of distance in depth (Ponzo illusion), was sufficient to produce these effects. These findings indicate that the spatial representation of time can be oriented flexibly in either frontal or lateral planes from the age of 5 years and even precedes the development of explicit timing mechanisms. Motion direction in the frontal plane (looming/receding) had little effect on perceived duration in adults, though children temporally underestimated looming stimuli, possibly due to attentional mechanisms. (PsycINFO Database Record PMID- 28345950 TI - Introduction to special issue on animal models of neuropsychiatric disorders and substance use disorders: Progress and gaps. AB - This is an introduction to the special issue, "Animal Models of Neuropsychiatric Disorders and Substance Use Disorders: Progress and Gaps." This issue presents 6 original research reports describing the use of mice and rats to model neurodevelopmental disorders, depressive disorders, anxiety disorders, and substance use disorders. Collectively, these studies demonstrate the progress of the field and the gaps and challenges that remain. They also illustrate the range of conditions that are informed by animal models and identify the clinical populations that stand to benefit from their use in preclinical research. (PsycINFO Database Record PMID- 28345951 TI - Stereotactic Ablative Radiotherapy Induces Peripheral T-Cell Activation in Patients with Early-Stage Lung Cancer. PMID- 28345953 TI - Reperfusion ventricular arrhythmia bursts identify larger infarct size in spite of optimal epicardial and microvascular reperfusion using cardiac magnetic resonance imaging. AB - AIMS: Ventricular arrhythmia (VA) bursts following recanalisation in acute ST elevation myocardial infarction (STEMI) are related to larger infarct size (IS). Inadequate microvascular reperfusion, as determined by microvascular obstruction (MVO) using cardiac magnetic resonance imaging (CMR), is also known to be associated with larger IS. This study aimed to test the hypothesis that VA bursts identify larger infarct size in spite of optimal microvascular reperfusion. METHODS: All 65 STEMI patients from the Maastricht ST elevation (MAST) study with brisk epicardial flow (TIMI 3), complete ST recovery post-percutaneous coronary intervention and early CMR were included. Using 24-hour Holter registrations from the time of admission, VA bursts were identified against subject-specific Holter background VA rates using a statistical outlier method. MVO and final IS were determined using delayed enhancement CMR. RESULTS: MVO was present in 37/65 (57%) of patients. IS was significantly smaller in the group without MVO (median 9.4% vs. 20.5%; p < 0.001). IS in the group with MVO did not differ depending on VA burst ( n = 28/37; median 20.8% vs. 19.7%; p = 0.64). However, in the group without MVO, VA burst was associated with significantly larger IS ( n = 17/28; median 10.5% vs. 4.1%; p = 0.037). In multivariable analyses, VA burst as well as anterior infarct location remained independent predictors of larger infarct size. CONCLUSION: In the presence of suboptimal reperfusion with MVO by CMR, VA burst does not further define MI size. However, with optimal TIMI 3 reperfusion and optimal microvascular perfusion (i.e. no MVO), VA burst is associated with larger IS, indicating that VA burst is a marker of additional cell death. PMID- 28345952 TI - The Timing of Early Antibiotics and Hospital Mortality in Sepsis. AB - RATIONALE: Prior sepsis studies evaluating antibiotic timing have shown mixed results. OBJECTIVES: To evaluate the association between antibiotic timing and mortality among patients with sepsis receiving antibiotics within 6 hours of emergency department registration. METHODS: Retrospective study of 35,000 randomly selected inpatients with sepsis treated at 21 emergency departments between 2010 and 2013 in Northern California. The primary exposure was antibiotics given within 6 hours of emergency department registration. The primary outcome was adjusted in-hospital mortality. We used detailed physiologic data to quantify severity of illness within 1 hour of registration and logistic regression to estimate the odds of hospital mortality based on antibiotic timing and patient factors. MEASUREMENTS AND MAIN RESULTS: The median time to antibiotic administration was 2.1 hours (interquartile range, 1.4-3.1 h). The adjusted odds ratio for hospital mortality based on each hour of delay in antibiotics after registration was 1.09 (95% confidence interval [CI], 1.05-1.13) for each elapsed hour between registration and antibiotic administration. The increase in absolute mortality associated with an hour's delay in antibiotic administration was 0.3% (95% CI, 0.01-0.6%; P = 0.04) for sepsis, 0.4% (95% CI, 0.1-0.8%; P = 0.02) for severe sepsis, and 1.8% (95% CI, 0.8-3.0%; P = 0.001) for shock. CONCLUSIONS: In a large, contemporary, and multicenter sample of patients with sepsis in the emergency department, hourly delays in antibiotic administration were associated with increased odds of hospital mortality even among patients who received antibiotics within 6 hours. The odds increased within each sepsis severity strata, and the increased odds of mortality were greatest in septic shock. PMID- 28345954 TI - Chest Radiographic Screening for Sarcoidosis in the Diagnosis of Patients with Active Uveitis. AB - RATIONALE: Although chest radiography is currently recommended for the initial evaluation of patients with new-onset uveitis, the efficacy of this diagnostic screening modality is not known. OBJECTIVES: To evaluate the diagnostic value of chest radiographs in patients with active uveitis of recent onset in a tertiary center in Western Europe. METHODS: A retrospective cross-sectional study was conducted by reviewing all chest imaging for adults with new-onset (<1 yr) uveitis of unknown origin undergoing initial evaluation in the Department of Ophthalmology at Erasmus University Medical Center (Rotterdam, the Netherlands). Radiographic findings were related to clinical and other imaging characteristics and to final diagnoses. RESULTS: Screening chest radiographs were abnormal for 30 of 200 patients (15%) included in this study. Twenty-two of the 200 patients (11%) had biopsy-confirmed sarcoidosis, and an additional 12 patients were presumed to have sarcoidosis. The finding of chest radiographic abnormalities interpreted as typical of sarcoidosis was specific (91%; 95% confidence interval, 85.9-94.4%) but not sensitive (64%; 95% confidence interval, 43.0-80.3%) for biopsy-confirmed sarcoidosis. The combination of elevated serum angiotensin converting enzyme level and chest radiographic findings typical of sarcoidosis increased the sensitivity to 79%. Biopsy-confirmed sarcoidosis was more common in patients with panuveitis (17 of 84; 20%) compared to patients with other anatomical locations of uveitis (5 of 116, 4%; P < 0.001). One patient was diagnosed with active pulmonary and ocular tuberculosis. CONCLUSIONS: Abnormal chest radiographs were found in 15% of patients with active uveitis of unknown origin and onset within 1 year of referral to a tertiary center in the Netherlands. A majority of the abnormal chest radiographs showed findings compatible with a diagnosis of sarcoidosis. PMID- 28345956 TI - Modulation of steroidogenesis by vitamin D3 in granulosa cells of the mouse model of polycystic ovarian syndrome. AB - : Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of women of reproductive age characterized by polycystic ovarian morphology, anovulation or oligomenorrhea, and hyperandrogenism. It is shown that disruption in the steroidogenesis pathway caused by excess androgen in PCOS is a critical element of abnormal folliculogenesis and failure in dominant follicle selection. Vitamin D plays an important role in the regulation of ovulatory dysfunction and can influence genes involved in steroidogenesis in granulosa cells. In the present study, we investigated the effects of vitamin D3 on steroidogenic enzyme expression and activities in granulosa cell using a PCOS mouse model. In our study, the PCOS mouse model was developed by the injection of dehydroepiandrosterone (DHEA) for 20 days. The mRNA and protein expression levels of genes involved in steroidogenesis in granulosa cells were compared between polycystic and normal ovaries using real-time PCR and Western blotting assays. Granulosa cells of DHEA-induced PCOS mice were then cultured with and without vitamin D3 and mRNA and protein expression levels of steroidogenic enzymes and serum 17beta-estradiol and progesterone levels were investigated using qRT-PCR, western blot, and radioimmunoassay, respectively. Steroidogenic enzymes including Cyp11a1, StAR, Cyp19a1, and 3beta-HSD were upregulated in granulosa cells of PCOS mice when compared to normal mice. Treatment with vitamin D3 decreased mRNA and protein expression levels of steroidogenic enzymes in cultured granulosa cells. Vitamin D3 also decreased aromatase and 3beta-HSD activity that leads to decreased 17beta-estradiol and progesterone release. This study suggests that vitamin D3 could modulate the steroidogenesis pathway in granulosa cells of PCOS mice that may lead to improving follicular development and maturation. This is a step towards a possible conceivable treatment for PCOS. ABBREVIATIONS: AMHR-II: anti-mullerian hormone receptor-II; 3beta-HSD: 3beta-hydroxysteroid dehydrogenase; Cyp11a1: Cytochrome P450 Family 11 Subfamily A Member 1; Cyp19a1: cytochrome P450 aromatase; DHEA: dehydroepiandrosterone; FSH: follicle stimulating hormone; FSHR: follicle stimulating hormone receptor; IVF: in vitro fertilization; 25OHD: 25-hydroxy vitamin D; OHSS: ovarian hyperstimulation syndrome; PCOS: polycystic ovarian syndrome; P450scc: P450 side-chain cleavage enzyme; StAR: steroidogenic acute regulatory protein; VDRs: vitamin D receptors. PMID- 28345955 TI - Smoking-Dependent Distal-to-Proximal Repatterning of the Adult Human Small Airway Epithelium. AB - RATIONALE: Small airways are the primary site of pathologic changes in chronic obstructive pulmonary disease (COPD), the major smoking-induced lung disorder. OBJECTIVES: On the basis of the concept of proximal-distal patterning that determines regional specialization of the airway epithelium during lung development, we hypothesized that a similar program operates in the adult human lung being altered by smoking, leading to decreased regional identity of the small airway epithelium (SAE). METHODS: The proximal and distal airway signatures were identified by comparing the transcriptomes of large and small airway epithelium samples obtained by bronchoscopy from healthy nonsmokers. The expression of these signatures was evaluated in the SAE of healthy smokers and smokers with COPD compared with that of healthy nonsmokers. The capacity of airway basal stem cells (BCs) to maintain region-associated phenotypes was evaluated using the air-liquid interface model. MEASUREMENTS AND MAIN RESULTS: The distal and proximal airway signatures, containing 134 and 233 genes, respectively, were identified. These signatures included known developmental regulators of airway patterning, as well as novel regulators such as epidermal growth factor receptor, which was associated with the proximal airway phenotype. In the SAE of smokers with COPD, there was a dramatic smoking-dependent loss of the regional transcriptome identity with concomitant proximalization. This repatterning phenotype was reproduced by stimulating SAE BCs with epidermal growth factor, which was up-regulated in the SAE of smokers, during differentiation of SAE BCs in vitro. CONCLUSIONS: Smoking-induced global distal to-proximal reprogramming of the SAE represents a novel pathologic feature of COPD and is mediated by exaggerated epidermal growth factor/epidermal growth factor receptor signaling in SAE BCs. PMID- 28345957 TI - Xyloglucan, hibiscus and propolis for the prevention of urinary tract infections: results of in vitro studies. AB - AIM: To assess the properties of a medical device containing xyloglucan, propolis and hibiscus to create a bioprotective barrier to avoid the contact of uropathogenic Escherichia coli strains on cell walls in models of intestinal (CacoGoblet) and uroepithelial (RWPE-1) cells (derived from normal human prostate epithelium). MATERIALS & METHODS: Two uropathogenic E. coli strains (expressing type 1 fimbriae and P fimbriae) were used to assess, by electronic microscopy and ELISA, the barrier properties of the medical device. The antimicrobial activity was assessed in broth dilution assays. RESULTS: The three components (xyloglucan, propolis and hibiscus) did not alter E. coli cell integrity in intestinal and uroepithelial cell models and were devoid of antibacterial activity. The three components avoided bacterial contact in both cell monolayers. CONCLUSION: The nonpharmacological barrier properties of xyloglucan, propolis and hibiscus confirm the role of the medical device for the management of urinary tract infections. PMID- 28345959 TI - Ventilatory Inefficiency and Exertional Dyspnea in Early Chronic Obstructive Pulmonary Disease. AB - Exertional dyspnea is present across the spectrum of chronic obstructive pulmonary disease (COPD) severity. However, without realizing it themselves, patients may decrease daily physical activity to avoid distressing respiratory sensations. Dyspnea also may be associated with deconditioning. Cardiopulmonary exercise testing can uncover exertional dyspnea and its physiological determinants in patients with preserved or only mildly reduced FEV1. Dyspnea in mild COPD can largely be explained by increased "wasted" ventilation in the physiological dead space, which heightens the drive to breathe and worsens the inspiratory mechanical constraints. During incremental exercise testing, this is readily identified as an excessive ventilation-to-metabolic demand, that is, a high ventilation ([Formula: see text]e) to carbon dioxide output ([Formula: see text]co2) relationship. Linking increases in [Formula: see text]e/[Formula: see text]co2 to exertional dyspnea may provide objective evidence that a patient's poor exercise tolerance is not just a consequence of deconditioning. This information should prompt a proactive therapeutic approach to increase the available ventilatory reserve by, for example, giving inhaled bronchodilators. Considering that the structural determinants of ventilatory inefficiency (early emphysema, ventilation-perfusion mismatching, and microvascular disease) may progress despite only modest changes in FEV1, serial [Formula: see text]e/[Formula: see text]co2 measurements might also prove valuable to track disease progression in these symptomatic patients. PMID- 28345958 TI - Macrophage Elastase Induces TRAIL-mediated Tumor Cell Death through Its Carboxy Terminal Domain. AB - RATIONALE: Macrophage elastase (matrix metalloproteinase [MMP]-12) is a potent protease that contributes to the lung destruction that accompanies cigarette smoking; it simultaneously inhibits lung tumor angiogenesis and metastasis by catalyzing the formation of antiangiogenic peptides. Recent studies have revealed novel nonproteolytic functions of MMP12, including antimicrobial activity through a peptide within its C-terminal domain (CTD). OBJECTIVES: To determine whether the MMP12 CTD contributes to its antitumor activity in lung cancer. METHODS: We used recombinant MMP12 peptide fragments, including its catalytic domain, CTD, and a 20 amino acid peptide within the CTD (SR20), in an in vitro system to delineate their effects on non-small cell lung cancer cell proliferation and apoptosis. We translated our findings to two murine models of lung cancer, including orthotopic human xenograft and KrasLSL/G12D mouse models of lung cancer. MEASUREMENTS AND MAIN RESULTS: We show that SR20 triggers tumor apoptosis by up-regulation of gene expression of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and its receptor, death receptor 4, sensitizing cells to an autocrine loop of TRAIL-mediated cell death. We then demonstrate the therapeutic efficacy of SR20 against two murine models of lung cancer. CONCLUSIONS: The MMP12 CTD initiates TRAIL-mediated tumor cell death through its conserved SR20 peptide. PMID- 28345960 TI - Graft Utilization in the Bridging Reconstruction of Irreparable Rotator Cuff Tears: A Systematic Review. AB - BACKGROUND: Rotator cuff tears are one of the most common conditions affecting the shoulder. Because of the difficulty in managing massive rotator cuff tears and the inability of standard techniques to prevent arthropathy, surgeons have developed several novel techniques to improve outcomes and ideally alter the natural history. PURPOSE: To systematically review the existing literature and analyze reported outcomes to evaluate the effectiveness of using a bridging graft reconstruction technique to treat large to massive irreparable rotator cuff tears. STUDY DESIGN: Systematic review. METHODS: A systematic search of PubMed, EMBASE, CINAHL, and CENTRAL was employed with the key terms "tear," "allograft," and "rotator cuff." Eligibility was determined by a 3-phase screening process according to the outlined inclusion/exclusion criteria. Data in relation to the primary and secondary outcomes were summarized. The results were synthesized according to the origin of the graft and the level of evidence. RESULTS: Fifteen studies in total were included in this review: 2 comparative studies and 13 observational case series. Both the biceps tendon and the fascia lata autograft groups had significantly superior structural integrity rates on magnetic resonance imaging at 12-month minimum follow-up when compared with their partial primary repair counterparts (58% vs 26%, P = .036; 79% vs 58%, P < .05), respectively. Multiple noncomparative case series investigating allografts, xenografts, and synthetic materials for bridging reconstruction of large to massive rotator cuff tears demonstrated high structural healing rates (74%-90%, 73%-100%, and 60%-90%, respectively). Additionally, both comparative studies and case series demonstrated a general improvement of patients' functional outcome scores. CONCLUSION: Using a graft for an anatomic bridging rotator cuff repair results in improved function on objective testing and may be functionally better than nonanatomic or partial repair of large to massive rotator cuff tears. Allograft or xenograft techniques appear to be favorable options, given demonstrated functional improvement, imaging-supported graft survival, and lack of harvest complication risk. More high-quality randomized controlled studies are needed to further assess this technique. PMID- 28345961 TI - The Short-Term Efficacy of an Unguided Internet-Based Cognitive-Behavioral Therapy for Insomnia: A Randomized Controlled Trial With a Six-Month Nonrandomized Follow-Up. AB - OBJECTIVE: Insomnia is a major health problem, and the need for effective and accessible treatment is urgent. The aim of the current study was to evaluate the short-term efficacy of an unguided Internet-based cognitive-behavioral treatment program for insomnia (CBTi), called SHUTi (Sleep Healthy Using the Internet). METHODS: This study used a parallel arm randomized controlled trial in Norway. Participants were randomly allocated to the SHUTi condition or a Web-based patient education condition. Both groups were assessed before and after the nine week intervention period (online sleep diaries and questionnaires). The SHUTi participants were reassessed in a six-month nonrandomized follow-up. Primary outcome measures were the Insomnia Severity Index (ISI) and the Bergen Insomnia Scale (BIS). RESULTS: A total of 181 participants were included in the study; SHUTi condition (n = 95), patient education condition (n = 86). Intention-to treat mixed-model repeated-measures analysis revealed that the SHUTi group had better short-term outcomes compared with the patient education group on most sleep measures. The SHUTi group showed a significant decrease on the primary outcomes, the ISI (dbetween = -1.77, 95% CI = -2.23, -1.31) and the BIS (dbetween = -1.00, 95% CI = -1.32, -.68). Improvements were maintained among the completing SHUTi participants at the six-month nonrandomized follow-up. However, dropout attrition was high. CONCLUSION: Unguided Internet-based CBTi produced significant short-term improvements in sleep in patients with chronic insomnia. This highlights the benefits of making Internet-delivered CBTi programs available as a standard first-line treatment option in public health services. Nevertheless, the rate of dropout attrition (participants not completing post-assessment) in this trial limits the generalizability of the findings. PMID- 28345963 TI - Accumulation and speciation of Cd in Avicennia marina tissues. AB - Avicennia marina is a high-Cd-tolerant species in the mangrove wetlands. A hydroponic experiment was carried out to research the accumulation and chemical form distribution of Cd in the tissues of A. marina under different concentrations and durations of Cd stress. It was found that the concentrations of Cd in plant tissues followed the order of root > stem > leaf. The data suggested that root activity decreased, Cd accumulation ability weakened in roots, and the translocation factor increased in stems and leaves with the increase of stress duration. With a proactive defense mechanism, most Cd was bound to pectates, organic acids, and protein, especially in roots and stems with the most proportion of 88.51 and 78.91%, respectively, having lower biological activities. The Cd bounded to water-soluble organic acid and free inorganic aminophenol-Cd showed the lowest concentration. The pectates, organic acids, and protein-integrated Cd seem the most important in affecting Cd detoxification for A. marina; this mechanism of change in Cd biological activities decreases the toxicity of this aggressive pollutant and presents new knowledge about the tolerance of mangrove plants. PMID- 28345962 TI - Immune responses to vaccination and infection with Mycoplasma gallisepticum in turkeys. AB - Infection with Mycoplasma gallisepticum induces severe lymphoproliferative lesions in multiple sites along the respiratory tract in chickens and turkeys. These immunopathological responses have been well-characterized in chickens, but have not been studied closely in turkeys. The aim of the study described here was to examine the immune responses of turkeys after live vaccination and infection with M. gallisepticum. In a strain comparison study, the mean log10 antibody titre of birds exposed to an aerosol culture of M. gallisepticum strain Ap3AS was found to be significantly higher at day 14 than that of birds exposed to strain 100809/31. In a dose-response study, there was a significant difference in the mean log10 antibody titre between birds exposed to mycoplasma broth and birds exposed to the highest dose of strain Ap3AS at day 7 after exposure. Immunohistochemical analysis of the tracheal mucosa and the air sacs revealed similar patterns of distribution of CD4+ and CD8+ lymphocytes to those seen in the tracheal mucosa of chickens, implicating these cell types in the pathogenesis of respiratory mycoplasmosis in turkeys. Turkeys that had been vaccinated with M. gallisepticum GapA+ ts-11 had significantly higher antibody titres than unvaccinated birds at both 7 and 14 days after challenge with strain Ap3AS. Vaccination with GapA+ ts-11 protected against the lymphoproliferative response to infection with virulent M. gallisepticum in both the tracheal mucosa and the air sacs, suggesting that this strain may be a useful vaccine candidate for use in turkeys. PMID- 28345964 TI - End-Tidal Carbon Dioxide as a Prognostic Feature in Pulmonary Arterial Hypertension. AB - RATIONALE: Pulmonary arterial hypertension (PAH) is characterized in part by increased dead space ventilation, which can be estimated noninvasively at the bedside by measurement of end-tidal CO2 (ETco2). OBJECTIVES: Prior work has demonstrated that ETco2 is lower in patients with PAH than in control patients, but whether ETco2 has prognostic value is unknown. We hypothesized that lower measurements of ETco2 in patients with PAH correlate with worse long-term outcomes. METHODS: Patients with PAH seen in our referral clinic were prospectively recruited for ETco2 measurement between September 2009 and February 2010. Vital status as of July 2015 was documented using medical records and the Social Security Death Index. RESULTS: Eighty-two patients were followed for a median of 60 months. Twenty-six patients died, and two were lost to follow-up. Patients who died were more likely to be older (58.5 +/- 14.9 vs. 47.6 +/- 12.2 yr; P < 0.05) and to have shorter 6-minute walk distance (296 +/- 127 vs. 401 +/- 92 m; P < 0.05). Mean ETco2 in survivors was 30.5 +/- 4.8 mm Hg, whereas mean ETco2 in patients who died was 27.1 +/- 4.2 mm Hg (P = 0.004). After stratification by median baseline ETco2 of 29 mm Hg, survival in each group was analyzed. Patients with lower ETco2 had shorter survival (P = 0.006). Cox regression analysis with ETco2 as a continuous variable revealed the hazard ratio to be 0.88 (95% confidence interval, 0.80-0.97; P = 0.006). In 52 patients with more than one measurement a median of 17 months apart, ETco2 was unchanged. CONCLUSIONS: Our single-center data suggest that lower ETco2 is associated with shorter survival and that ETco2 is stable over time in patients with PAH. PMID- 28345965 TI - Experiences of attending day care services designed for people with dementia - a qualitative study with individual interviews. AB - OBJECTIVES: Day care is assumed to promote independence in home-dwelling people with dementia, increase well-being and enhance social stimulation. Few studies have directly engaged people with dementia to better understand the benefits and impacts of such services. The aim of this study was to explore attendees' experiences with day care designed for people with dementia. METHOD: This study had a qualitative descriptive design and included individual interviews with 17 users attending day care. The analysis was undertaken using content analyses. RESULTS: The participants reported that day care had a positive influence on their physical functioning, cognition, well-being, and situation at home because they were provided with social stimulation, meals, and activities. Day care contributed to the maintenance of a rhythm and structure in everyday life. Furthermore, the staff contributed to making the day care a safe place to be and enhanced a sense of belonging. CONCLUSION: This study reveals the positive impact of day care on the daily lives of people with dementia because this service contributes to the enhancement of activities and social support, prevents isolation, and enhances practical and cognitive functioning as experienced by the users. The staff has a major impact on the experience of the participants in the day care. PMID- 28345966 TI - The importance of standardization of stimuli for functional MRI tasks to evaluate substance use disorder pathology. PMID- 28345967 TI - Deaths from Nonmalignant Respiratory Disease in Styrene-Exposed Workers: Does Obliterative Bronchiolitis Contribute to Mortality? PMID- 28345968 TI - Relationship between phospholipase C-zeta, semen parameters, and chromatin status. AB - The need for additional tests to complement basic sperm analysis in clinics is well appreciated. In this regard, a number of tests such as sperm DNA integrity test as a tool in diagnosis and treatment of infertility are suggested. But recent studies have focused on main sperm factors involved in oocyte activation such as phospholipase C-zeta (PLCzeta) that initiate intracellular Ca2+ signaling and embryogenesis. Therefore, this study aimed to investigate the relationship between PLCzeta, basic semen parameters, sperm DNA fragmentation (SDF), and protamine deficiency in men with normal (n=32) and abnormal (n=23) semen parameters. Unlike SDF and protamine deficiency, as negative factors related to fertility, the mean value of PLCzeta as positive factor related to infertility was significantly lower in men with abnormal semen parameters compared to men with normal semen parameters. Significant correlations were also observed between sperm concentration, motility, and abnormal morphology with the percentage of PLCzeta positive spermatozoa. In addition, logistic regression analysis revealed that sperm morphology is more predictive than sperm motility and concentration for PLCzeta presence. In addition, a statistically significant negative relationship was observed between the percentage of PLCzeta positive spermatozoa and SDF. These findings suggested during ICSI, selection of sperm based on morphology has a profound effect on its ability to induce oocyte activation based on the likelihood of PLCzeta expression. Therefore, assessment of PLCzeta as an index for fertilization potential of a semen sample in men with severe teratozoospermia may define individuals who are candidates for artificial oocyte activation (AOA) and may avoid failed fertilization post ICSI. PMID- 28345970 TI - Pressure ulcer over pressure injury. PMID- 28345969 TI - Foot ulceration in patients with diabetes: a risk analysis. AB - The study reported in this article aimed to analyse factors associated with the risk of ulceration in the feet of patients with diabetes using a conceptual hierarchic model. It was a cross-sectional study carried out with 1515 people with diabetes mellitus aged 40 years and older. The risk of foot ulceration was of higher significance in male patients with diabetes (adjusted odds ratio (OR)=1.39 (95% confidence interval (CI) 1.11 to 1.73); p=0.020), who did not practise a regular physical activity (adjusted OR=1.58 (95% CI 1.15 to 2.15); p=0.013), with time since diagnosis over 10 years (adjusted OR=1.42 (95% CI 1.10 to 1.86); p=0.011), who used insulin (adjusted OR=1.40 (95% CI 1.09 to 1.84); p=0.012), with retinopathy (adjusted OR=1.84 (95% CI 1.38 to 2.45); p=0.001) and who had had a previous stroke (adjusted OR=1.47 (95% CI 1.09 to 2.04); p=0.018). Mycosis on the nails and the interdigital spaces of the feet was statistically associated with ulceration risk independent of other variables of the model (adjusted OR=2.48 (95%CI 1.70 to 3.63); p=0.001). Finding the factors associated with ulceration contributes to the provision of quality care by nurses. PMID- 28345971 TI - Change for the better? AB - Jackie Stephen-Haynes, Professor in Tissue Viability, Professional Development Unit, Birmingham City University and Consultant Nurse, Worcestershire Health and Care NHS Trust. PMID- 28345972 TI - Domestic violence against men. PMID- 28345973 TI - Patient satisfaction with clinicians in colorectal 2-week wait clinics. AB - AIM: To determine if patient satisfaction is affected by the clinician (nurse or doctor), conducting the colorectal 2-week wait (2ww) clinics. METHODS: A prospective non-randomised comparative cohort study of 339 consecutive patients (divided by blind allocation into nurse-led (n=216) and doctor-led (n=123) cohorts) conducted over a 3-month period. Patient satisfaction in both cohorts was assessed by an adapted version of the Grogan et al validated patient satisfaction questionnaire. The questionnaire was piloted first and was found to have high internal reliability (Cronbach's alpha=0.91). RESULTS: The study had a response rate of 78% (n=258/331) and overall satisfaction scores showed 85% (n=149/175) of patients in the nurse-led cohort and 65% (n=54/83) of patients in the doctor-led cohort strongly agreed that they were satisfied with the care they received. Mean overall satisfaction scores in the two cohorts revealed that the nurse-led cohort achieved significantly more 'strongly agree' responses than the doctor-led cohort (p<0.001, CI: 95%). Further analysis of the responses to each question demonstrated statistical significance when comparing the two cohorts. CONCLUSIONS: The study offered patients the opportunity to reflect on service delivery enabling a more responsive approach to health care within the colorectal 2ww service. It found that patient satisfaction was affected by the clinician conducting the 2ww clinic, in that the nurse-led cohort displayed significantly higher patient satisfaction. However, there are areas that merit further research. PMID- 28345974 TI - The provision of therapy mattresses for pressure ulcer prevention. AB - Preventing pressure ulcers is complex and involves skin care, the provision of therapy mattresses, repositioning, the management of incontinence and adequate nutritional support. This article describes a model of therapy mattress provision that is based on non-powered products. Evaluating the efficiency of this model is challenging, due to the complexities of care, but Safety Thermometer data and incidents reports offer reassurance that non-powered therapy mattresses can provide adequate pressure ulcer prevention. Therapy mattress provision is only one of the five interventions and these are described in details to give readers a fuller picture of the model used at the author's trust. PMID- 28345975 TI - Pressure ulcer prevention is everyone's business: the PUPS project. AB - Prevention of pressure ulcers is one of the greatest healthcare challenges in terms of reducing patient harm. The literature shows that although numerous reports and policy documents have been published, pressure ulcer prevention remains an ongoing challenge. A number of innovations have been published offering practising nurses and managers ideas for raising awareness of skin care and preventing pressure ulcers. The majority of these have focused on patients in hospital settings with very little in the literature related to care-home and community initiatives. This article reports on an innovative approach to education for pressure ulcer prevention through collaboration between patients, carers and health and social care professionals. PMID- 28345976 TI - Evaluating the performance of a new carboxymethyl cellulose dressing in the community setting. AB - This article describes a single-centre, non-comparative evaluation set out to assess the clinical performance and patient acceptability of a new carboxymethyl cellulose (CMC) wound dressing. Twenty patients in a community setting, aged between 34-97 years, were recruited. The progression of various types of wounds with different levels of exudate was documented over 4 weeks. No adherence to the wound bed or painful removal was reported in 18 patients, and the peri-wound skin was the same or had improved in all patients. When compared with the previous CMC dressing used by the authors, the new CMC dressing reported a longer wear time. These findings show a positive clinical performance and suggest a potential financial advantage when using the new dressing. PMID- 28345977 TI - Spinal cord injuries: overcoming barriers to seamless care for patients. AB - Patients with spinal cord injuries (SCIs) often have complex needs that require multidisciplinary support in specialist centres. Optimal management depends on seamless transitions between service providers. Delays at any point potentially compromise clinical outcomes and efficient resource utilisation. The Spinal Advisory Working Group aims to develop and implement practical initiatives to improve SCI care, initially focusing on admission and discharge. A literature review identified few relevant papers. In addition, the generalisability of the findings of these papers to SCI centres in the UK is unclear. Therefore, further research is needed to, for example: establish best practice in the UK; quantify the associations between admission criteria and clinical and economic outcomes from a UK perspective; and determine the extent and impact of barriers that influence the transition of SCI patients between NHS care providers. Such research would enable the development of evidence-based strategies to overcome or minimise these barriers. In the meantime, pragmatic consensus guidelines would help standardise management, aid service optimisation, overcome inequities and, potentially, reduce bed blocking. The working group agreed that the robust inclusion and exclusion criteria developed by the Welsh Spinal Cord Injury Rehabilitation Centre could form the basis of a consensus guideline, to be piloted across the five SCI centres represented by members of the group. PMID- 28345978 TI - From staff nurse to nurse consultant - Clinical leadership part 12: series summary. AB - John Fowler, independent education consultant, summarises his series which has explored the importance of leadership for clinically based nurses. PMID- 28345979 TI - Assessment and treatment options for patients with constipation. AB - Constipation is a common complaint for people of all ages, with prevalence increasing with age and during pregnancy. Women are more likely to be affected than men. Severity of constipation varies from person to person; most people experience short periods of constipation during their lives, including possibly after surgery, while others have constipation as a chronic long-term condition that can significantly affect their quality of life. There are a number of factors that can contribute to developing constipation including diets low in fibre, changes in lifestyle, side effects of certain medications and low fluid intake. People can successfully treat constipation by making changes to their diet and lifestyle. However, medication may be required to manage constipation for some. PMID- 28345980 TI - Palliative care nursing for patients with neurological diseases: what makes the difference? AB - Neurodegenerative diseases progress slowly, creating increasing physical disability with unpredictable disease trajectories. The disease's life threatening nature often places these patients in palliative care. There are several factors that complicate the care of patients with neurodegenerative diseases in palliative care units. Owing to physical impairments, there are many communication barriers between patients and staff. Nurses are not able to duplicate the patient's meticulous daily routine leading to caregiver mistrust in the nurse's competencies. Even if the patient is hospitalised, caregivers may not take the much-needed time off to recuperate. The placement of patients with neurodegenerative diseases in palliative care is confusing, since they rarely die during in-hospital treatment but might even get better due to multidisciplinary treatment. Finally, patients and caregivers lack adequate knowledge about disease progression and available help and support programmes. Patients with neurodegenerative diseases urgently need palliative care and nurses and caregivers need better preparation to appropriately deal with these diseases. PMID- 28345981 TI - Health promotion for patients and their families. AB - Michelle Gracia, Third Year Student Nurse (Adult), School of Health Studies, Gibraltar Health Authority. PMID- 28345982 TI - Managing conflict appropriately to benefit staff and organisations. PMID- 28345983 TI - The voice of healthcare education and research. PMID- 28345984 TI - Clinical supervision: an important part of every nurse's practice. AB - Clinical supervision involves a supportive relationship between supervisor and supervisee that facilitates reflective learning and is part of professional socialisation. Clinical supervision can take many different forms and may be adapted to suit local circumstances. A working agreement is required between the parties to the supervision and issues surrounding confidentiality must be understood. High-quality clinical supervision leads to greater job satisfaction and less stress. When it is absent or inadequate, however, the results can be serious and it is particularly important that student nurses are well supported in this way. Further research in this area is necessary. PMID- 28345985 TI - Reviewing the investigative landscape to move towards a learning culture. AB - John Tingle, Reader in Health Law at Nottingham Trent University, discusses the Public Administration and Constitutional Affairs Committee follow up to the report, Learning from Mistakes, on the NHS in England. PMID- 28345986 TI - Children and young people with diabetes: recognition and management. AB - Diabetes mellitus (type 1) is an autoimmune condition leading to absolute insulin deficiency resulting in hyperglycaemia and its associated manifestations. It is the most common type of diabetes seen in children, characterised by the 4Ts (toilet, thinner, thirsty, tired). The signs and symptoms can sometimes be non specific and a delay or missed diagnosis may be catastrophic to the health of the child. Children with an established diagnosis of diabetes often present to the health service with issues such as hypoglycaemia, hyperglycaemia, or diabetic ketoacidosis. The condition requires life-long monitoring and strict control of blood glucose levels with insulin replacement therapy, with the aim of achieving an HbA1c level of 48 mmol/mol. There are often physical and psychosocial issues that arise from the diagnosis leading to poor control. Nurses working in different clinical settings play a vital role in raising suspicions of diabetes leading to timely diagnosis and rapid initiation of treatment. They are best placed to provide essential support in helping children and their families to come to terms with the diagnosis, as well as manage this chronic condition by addressing the common issues that arise in the ongoing management, with a particular emphasis on managing the various day-to-day challenges. Two case studies are included to highlight some of the challenges that nurses may encounter while managing children with diabetes. PMID- 28345987 TI - Walk this way: improving activity levels. AB - Emeritus Professor Alan Glasper, from the University of Southampton, discusses ways of increasing daily exercise, especially walking, as a way of tackling obesity and its effects on health. PMID- 28345988 TI - The experiences of students in interprofessional learning. AB - This article explores the experiences of undergraduate healthcare students within interprofessional education (IPE) using a qualitative research study. The motive to undertake this study was as a result of mixed evaluations of IPE sessions. The study aimed to analyse student experiences of IPE, and as a result provide greater insight into how this type of education could be enhanced. Participants were selected through voluntary recruitment and data were collected using a focus group involving 12 participants who responded. Data analysis identified two key themes highlighting the barriers to engagement in IPE and factors that enable participants to engage. The study provides guidance for further developments and improvements when designing and delivering IPE. PMID- 28345989 TI - Making decisions for patient safety. AB - Sam Foster, Chief Nurse at Heart of England NHS Foundation Trust, looks at providing leadership and taking appropriate action when a fitness-to-practise concern is raised. PMID- 28345990 TI - Erratum: Jeong, Kim, and Lee (2015). AB - In the article by Jeong, M., Kim, S-Y., & Lee, E., "Parents' beliefs and intentions toward supporting physical activity participation for their children with disabilities," in Adapted Physical Activity Quarterly, 32(2), 93-105, the third author's name was misspelled in the print version. It was printed as Euikyung Lee, but the correct spelling is Eunkyung Lee. PMID- 28345991 TI - Correlation between serum homocysteine concentration and severity of mitral valve disease in dogs. AB - OBJECTIVE To measure serum homocysteine concentrations in dogs with myxomatous mitral valve disease (MMVD) and identify any association between this variable and stage of MMVD. ANIMALS 53 client-owned dogs with MMVD and 10 healthy control Beagles. PROCEDURES Dogs with MMVD were allocated to 3 groups in accordance with the staging system for chronic valvular heart disease in dogs and cats of the American College of Veterinary Internal Medicine. Blood samples were collected from all dogs, and serum homocysteine and cardiac troponin 1 concentrations were measured by enzyme immunoassay and chemiluminescence immunoassay, respectively. Analyte values were tested for associations with each other and with stage of MMVD. RESULTS A significant correlation was identified between serum homocysteine concentration and stage of MMVD. Mean +/- SD concentrations were 6.72 +/- 1.65 MUmol/L for control dogs, 13.37 +/- 4.16 MUmol/L for dogs with stage B MMVD, 18.86 +/- 6.73 MUmol/L for dogs with stage C disease, and 28.26 +/- 4.48 MUmol/L for dogs with stage D disease. In addition, serum homocysteine concentration was correlated with serum cardiac troponin 1 (r = 0.34) and creatinine (r = 0.46) concentrations, systolic blood pressure (r = 0.57), and left atrium-to-aortic root ratio (r = 0.28), all of which were positively correlated with stage of MMVD. CONCLUSIONS AND CLINICAL RELEVANCE Serum homocysteine concentrations of dogs with MMVD were significantly higher than those of control dogs, and significant correlations were identified between these values and several risk factors for heart failure. Measurement of serum homocysteine concentration may be useful in the prediction of severity of disease in dogs with MMVD. PMID- 28345994 TI - Immunologic responses in corn snakes (Pantherophis guttatus) after experimentally induced infection with ferlaviruses. AB - OBJECTIVE To measure immunologic responses of snakes after experimentally induced infection with ferlaviruses. ANIMALS 42 adult corn snakes (Pantherophis guttatus) of both sexes. PROCEDURES Snakes were inoculated intratracheally with genogroup A (n = 12), B (12), or C (12) ferlavirus (infected groups) or cell-culture supernatant (6; control group) on day 0. Three snakes from each infected group were euthanized on days 4, 16, 28, and 49, and 3 snakes from the control group were euthanized on day 49. Blood samples were collected from live snakes on days 6 (baseline), 4, 16, 28, and 49. Hematologic tests were performed and humoral responses assessed via hemagglutination-inhibition assays and ELISAs. Following euthanasia, gross pathological and histologic evaluations and virus detection were performed. RESULTS Severity of clinical signs of and immunologic responses to ferlavirus infection differed among snake groups. Hematologic values, particularly WBC and monocyte counts, increased between days 4 and 16 after infection. A humoral response was identified between days 16 and 28. Serum IgM concentrations increased from baseline earlier than IgY concentrations, but the IgY relative increase was higher at the end of the study. The hemagglutination inhibition assay revealed that the strongest reactions in all infected groups were against the strain with which they had been infected. Snakes infected with genogroup A ferlavirus had the strongest immune response, whereas those infected with genogroup B had the weakest responses. CONCLUSIONS AND CLINICAL RELEVANCE Results of this experimental study suggested that the ferlavirus strain with the highest virulence induced the weakest immune response in snakes. PMID- 28345992 TI - Evaluation of a hypervariable octameric oligonucleotide fingerprints assay for identification of and discrimination between wild-type and vaccine strains of Brucella melitensis. AB - OBJECTIVE To evaluate a hypervariable octameric oligonucleotide fingerprints (HOOF-Prints) assay for identification of and discrimination between wild-type and vaccine strains of Brucella melitensis. SAMPLE Brucella melitensis vaccine strain M5 and wild-type strain M43. PROCEDURES 8 pairs of primers (alterable, octameric nucleotides) were designed on the basis of a biological analysis of 8 flanking sequences in the DNA of B melitensis. The HOOF-Prints technique was used to identify wild-type and vaccine strains of B melitensis. Phylogenetic analysis of short, polymorphic fragments of DNA from B melitensis strains M5 and M43 was performed. RESULTS Variable-number tandem repeat DNA segments of B melitensis vaccine strain M5 and wild-type strain M43 were successfully amplified by means of PCR assay. All target gene fragments ranged in size from 100 to 300 bp. Separate phylogenetic analysis of each Brucella strain revealed considerable differences between the vaccine and wild-type strains. CONCLUSIONS AND CLINICAL RELEVANCE The results of this study suggested the HOOF-Prints assay may be useful for discriminating vaccine strains of B melitensis from wild-type strains. This ability could allow discrimination between animals that are seropositive because of vaccination against B melitensis and those that are seropositive because of B melitensis infection and could decrease the likelihood of importing Brucella infected animals. PMID- 28345995 TI - Description and comparison of excretory urography performed during radiography and computed tomography for evaluation of the urinary system in healthy New Zealand White rabbits (Oryctolagus cuniculus). AB - OBJECTIVE To evaluate the usefulness of excretory urography performed during radiography (REU) and CT (CTEU) in healthy rabbits, determine timings of urogram phases, and compare sensitivities of REU and CTEU for detection of these phases. ANIMALS 13 New Zealand White rabbits (Oryctolagus cuniculus). PROCEDURES Rabbits were screened for signs of systemic and urinary tract disease. An REU examination of each was performed, followed >= 5 days later by a CTEU examination. Contrast images from each modality were evaluated for quality of opacification and intervals between initiation of contrast medium administration and detection of various urogram phases. RESULTS Excretory urograms of excellent diagnostic quality were achieved with both imaging modalities. For all rabbits, the nephrographic phase of the urogram appeared in the first postcontrast REU image (obtained between 34 and 40 seconds after initiation of contrast medium administration) and at a median interval of 20 seconds in CTEU images. The pyelographic phase began at a median interval of 1.63 minutes with both imaging modalities. Contrast medium was visible within the urinary bladder at a median interval of 2.20 minutes. Median interval to the point at which the nephrogram and pyelogram were no longer visible in REU images was 8 hours and 2.67 hours, respectively. The CTEU technique was better than the REU technique for evaluating renal parenchyma. CONCLUSIONS AND CLINICAL RELEVANCE Findings suggested that REU and, particularly, CTEU may be valuable tools for the diagnosis of renal and urinary tract disease in rabbits; however, additional evaluation in diseased rabbits is required. PMID- 28345996 TI - Effects of repeated use and resterilization on structural and functional integrity of microwave ablation antennas. AB - OBJECTIVE To determine effects of repeated use and resterilization on structural and functional integrity of microwave ablation (MWA) antennas. SAMPLE 17 cooled shaft MWA antennas (3 groups of 5 antennas/group and 2 control antennas). PROCEDURES 1, 2, and 3 ablations in the livers of bovine cadavers were performed at the maximum recommended settings. Antennas were cleaned and sterilized in hydrogen peroxide plasma, and the process was repeated (reprocessing cycle; n = 6). Control antennas were only sterilized (6 times). Aerobic and anaerobic bacterial cultures were performed, and antennas were microscopically assessed for damage. RESULTS 6 cycles were completed. Thirteen of 15 MWA antennas remained functional for up to 4 cycles, 10 were functional after 5 cycles, and only 7 were functional after 6 cycles. Progressive tearing of the silicone coating of the antennas was observed, with a negative effect of the number of cycles for silicone tearing. Size of the ablation zone decreased mildly over time after cycles 5 and 6; however, this was not considered clinically relevant. No significant changes in the shape of ablation zones were detected. All cultures yielded negative results, except for an isolated case, which was considered a contaminant. CONCLUSIONS AND CLINICAL RELEVANCE Structural and functional integrity of the microwave antennas remained acceptable during repeated use and reprocessing for up to 4 cycles. However, there was a decrease in functional integrity at cycles 5 and 6. We suggest that these microwave antennas be subjected to > 3 reprocessing cycles. Antennas should be carefully examined before reuse. PMID- 28345997 TI - Evaluation of a new method to determine the tibial tuberosity advancement distance required to reduce the patellar tendon-tibial plateau angle to 90 degrees with the modified Maquet technique in dogs. AB - OBJECTIVE To assess use of a new radiographic method to determine the distance by which the tibial tuberosity should be advanced to reduce the patellar tendon tibial plateau angle (PTA) to 90 degrees by means of the modified Maquet technique (MMT) in dogs. SAMPLE 24 pelvic limbs from 12 adult medium-sized to large-breed canine cadavers. PROCEDURES Radiographs of stifle joints at 135 degrees extension in true lateral position were used to determine tibial tuberosity advancement distances for use in the MMT. A method was devised to incorporate the planned osteotomy axis; distal patellar translations of 0, 3, 5, or 10 mm; and advancement cage implant application level along the osteotomy site in advancement planning measurements. Concordance correlation coefficients (CCCs) were calculated to compare these adjusted advancement measurements with true advancement measurements obtained for the same joints in another study after treatment by MMT. Intraobserver, interobserver, and total agreement for selected measurements were determined by assessment of CCCs for results obtained by 3 blinded observers. RESULTS Agreement between true advancement measurements and measurements obtained with osteotomy axis and cage position method calculations that incorporated a 5-mm distal patellar translation distance was excellent (CCC, 0.96). Intraobserver and interobserver agreements for the planning measurements evaluated were good to excellent (CCC, 0.83 to 0.96). CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that the osteotomy axis and cage position method incorporating a 5-mm distal patellar translation distance has the potential to improve success rates for achieving a PTA of 90 degrees in medium-sized to large breed dogs undergoing MMT for treatment of cranial cruciate ligament rupture. Further research is warranted. PMID- 28345998 TI - Pharmacokinetics of a single dose of voriconazole administered orally with and without food to red-tailed hawks (Buteo jamaicensus). AB - OBJECTIVE To determine the pharmacokinetics of voriconazole administered PO with or without food to red-tailed hawks (Buteo jamaicensus) and whether any observed variability could be explained by measured covariates to inform dose adjustments. ANIMALS 7 adult red-tailed hawks. PROCEDURES In a crossover study design, hawks were randomly assigned to first receive voriconazole (15 mg/kg, PO) injected into a dead mouse (n = 3; fed birds) or without food (4; unfed birds). Sixteen days later, treatments were reversed. Blood samples were collected at various points to measure plasma voriconazole concentrations by ultraperformance liquid chromatography. Pharmacokinetic data were analyzed by noncompartmental methods and fit to a compartmental model through nonlinear mixed-effects regression, with feeding status and body weight investigated as covariates. RESULTS Voriconazole was well absorbed, with quantifiable plasma concentrations up to 24 hours after administration. Mean plasma half-life was approximately 2 hours in fed and unfed birds. Administration of the voriconazole in food delayed absorption, resulting in a significant delay in time to maximum plasma concentration. The final compartmental model included a categorical covariate to account for this lag in absorption as well as body weight as a covariate of total body clearance (relative to unknown bioavailability). CONCLUSIONS AND CLINICAL RELEVANCE A single dose of voriconazole (15 mg/kg) administered PO to red-tailed hawks resulted in mean plasma voriconazole concentrations greater than the targeted value (1 MUg/mL). Additional studies with larger sample sizes and multidose regimens are required before the model developed here can be applied in clinical settings. PMID- 28345999 TI - Variance associated with walking velocity during force platform gait analysis of a heterogeneous sample of clinically normal dogs. AB - OBJECTIVE To determine whether walking at specific ranges of absolute and relative (V*) velocity would aid efficient capture of gait trial data with low ground reaction force (GRF) variance in a heterogeneous sample of dogs. ANIMALS 17 clinically normal dogs of various breeds, ages, and sexes. PROCEDURES Each dog was walked across a force platform at its preferred velocity, with controlled acceleration within 0.5 m/s2. Ranges in V* were created for height at the highest point of the shoulders (withers; WHV*). Variance effects from 8 walking absolute velocity ranges and associated WHV* ranges were examined by means of repeated measures ANCOVA. RESULTS The individual dog effect provided the greatest contribution to variance. Narrow velocity ranges typically resulted in capture of a smaller percentage of valid trials and were not consistently associated with lower variance. The WHV* range of 0.33 to 0.46 allowed capture of valid trials efficiently, with no significant effects on peak vertical force and vertical impulse. CONCLUSIONS AND CLINICAL RELEVANCE Dogs with severe lameness may be unable to trot or may have a decline in mobility with gait trial repetition. Gait analysis involving evaluation of individual dogs at their preferred absolute velocity, such that dogs are evaluated at a similar V*, may facilitate efficient capture of valid trials without significant effects on GRF. Use of individual velocity ranges derived from a WHV* range of 0.33 to 0.46 can account for heterogeneity and appears suitable for use in clinical trials involving dogs at a walking gait. PMID- 28346000 TI - Assessment of the potential efficacy of blind perineural injection techniques for blockade of the saphenous, obturator, and lateral cutaneous femoral nerves in dog cadavers. AB - OBJECTIVE To evaluate the potential efficacy of blind perineural injection techniques to provide nerve blockade of the saphenous, obturator, and lateral cutaneous femoral nerves by assessing the distribution along those nerves of 3 volumes of an injected staining solution in dog cadavers. ANIMALS 18 canine cadavers. PROCEDURES The anatomic characteristics of the target nerves were evaluated by dissection in 3 cadavers. The saphenous nerve was located by the use of superficial anatomic landmarks and a loss-of-resistance test. The obturator and lateral cutaneous femoral nerves were located by the use of superficial anatomic landmarks. Following perineural administration of 3 volumes (0.1, 0.2, and 0.3 mL/kg) of staining solution near the target nerves in 15 cadavers, the distribution of the staining solution along the nerves was evaluated. Staining that extended >= 2 cm along the target nerves was considered to be compatible with an effective clinical nerve block. RESULTS In all cadavers, nerves were appropriately stained by the blind techniques used here. The staining distribution along the nerves was considered to be optimal after perineural injection of 0.2 mL of staining solution/kg in the obturator and lateral cutaneous femoral nerves and 0.3 mL of staining solution/kg in the saphenous nerve. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that the evaluated blind perineural injection techniques may be an inexpensive, safe, and clinically effective method to block the saphenous, obturator, and lateral cutaneous femoral nerves in dogs. PMID- 28346001 TI - Assessment of contrast-enhanced ultrasonography of the hepatic vein for detection of hemodynamic changes associated with experimentally induced portal hypertension in dogs. AB - OBJECTIVE To assess the use of contrast-enhanced ultrasonography (CEUS) of the hepatic vein for the detection of hemodynamic changes associated with experimentally induced portal hypertension in dogs. ANIMALS 6 healthy Beagles. PROCEDURES A prospective study was conducted. A catheter was surgically placed in the portal vein of each dog. Hypertension was induced by intraportal injection of microspheres (10 to 15 mg/kg) at 5-day intervals via the catheter. Microsphere injections were continued until multiple acquired portosystemic shunts were created. Portal vein pressure (PVP) was measured through the catheter. Contrast enhanced ultrasonography was performed before and after establishment of hypertension. Time-intensity curves were generated from the region of interest in the hepatic vein. Perfusion variables measured for statistical analysis were hepatic vein arrival time, time to peak, time to peak phase (TTPP), and washout ratio. The correlation between CEUS variables and PVP was assessed by use of simple regression analysis. RESULTS Time to peak and TTPP were significantly less after induction of portal hypertension. Simple regression analysis revealed a significant negative correlation between TTPP and PVP. CONCLUSIONS AND CLINICAL RELEVANCE CEUS was useful for detecting hemodynamic changes associated with experimentally induced portal hypertension in dogs, which was characterized by a rapid increase in the intensity of the hepatic vein. Furthermore, TTPP, a time dependent variable, provided useful complementary information for predicting portal hypertension. IMPACT FOR HUMAN MEDICINE Because the method described here induced presinusoidal portal hypertension, these results can be applied to idiopathic portal hypertension in humans. PMID- 28346002 TI - Quality assessment of fluconazole capsules and oral suspensions compounded by pharmacies located in the United States. AB - OBJECTIVE To evaluate pharmaceutical characteristics (strength or concentration, accuracy, and precision), physical properties, and bacterial contamination of fluconazole compounded products. SAMPLE Fluconazole compounded products (30- and 240-mg capsules; 30- and 100-mg/mL oral suspensions) from 4 US veterinary compounding pharmacies. PROCEDURES Fluconazole compounded products were ordered 3 times from each of 4 pharmacies at 7- or 10-day intervals. Generic fluconazole products (50- and 200-mg tablets; 10- and 40-mg/mL oral suspensions) served as references. Compounded products were evaluated at the time of receipt; suspensions also were evaluated 3 months later and at beyond-use dates. Evaluations included assessments of strength (concentration), accuracy, precision, physical properties, and bacterial contamination. Acceptable accuracy was defined as within +/- 10% of the labeled strength (concentration) and acceptable precision as within +/- 10%. Fluconazole was quantified by use of high performance liquid chromatography. RESULTS Physical characteristics of compounded products differed among pharmacies. Aerobic bacterial cultures yielded negative results. Capsules (30 and 240 mg) had acceptable accuracy (median, 96.3%; range, 87.3% to 135.2%) and precision (mean +/- SD, 7.4 +/- 6.0%). Suspensions (30 and 100 mg/mL) had poor accuracy (median, 73.8%; range, 53.9% to 95.2%) and precision (mean +/- SD, 15.0 +/- 6.9%). Accuracy and precision were significantly better for capsules than for suspensions. CONCLUSIONS AND CLINICAL RELEVANCE Fluconazole compounded products, particularly suspensions, differed in pharmaceutical and physical qualities. Studies to evaluate the impact of inconsistent quality on bioavailability or clinical efficacy of compounded fluconazole products are indicated, and each study should include data on the quality of the compounded product evaluated. PMID- 28346003 TI - Randomized, controlled clinical trial of safety and plasma concentrations of diclofenac in healthy neonatal foals after repeated topical application of 1% diclofenac sodium cream. AB - OBJECTIVE To determine the plasma pharmacokinetics and safety of 1% diclofenac sodium cream applied topically to neonatal foals every 12 hours for 7 days. ANIMALS Twelve 2- to 14-day old healthy Arabian and Arabian-pony cross neonatal foals. PROCEDURES A 1.27-cm strip of cream containing 7.3 mg of diclofenac sodium (n = 6 foals) or an equivalent amount of placebo cream (6 foals) was applied topically to a 5-cm square of shaved skin over the anterolateral aspect of the left tarsometatarsal region every 12 hours for 7 days. Physical examination, CBC, serum biochemistry, urinalysis, gastric endoscopy, and ultrasonographic examination of the kidneys and right dorsal colon were performed before and after cream application. Venous blood samples were collected at predefined intervals following application of the diclofenac cream, and plasma diclofenac concentrations were determined by liquid chromatography-mass spectrometry. RESULTS No foal developed any adverse effects attributed to diclofenac application, and no significant differences in values of evaluated variables were identified between treatment groups. Plasma diclofenac concentrations peaked rapidly following application of the diclofenac cream, reaching a maximum of < 1 ng/mL within 2 hours, and declined rapidly after application ceased. CONCLUSIONS AND CLINICAL RELEVANCE Topical application of the 1% diclofenac sodium cream to foals as described appeared safe, and low plasma concentrations of diclofenac suggested minimal systemic absorption. Practitioners may consider use of this medication to treat focal areas of pain and inflammation in neonatal foals. PMID- 28346005 TI - Plasma coenzyme Q10 concentration, antioxidant status, and serum N-terminal pro brain natriuretic peptide concentration in dogs with various cardiovascular diseases and the effect of cardiac treatment on measured variables. AB - OBJECTIVE To determine the plasma total antioxidant capacity, erythrocyte superoxide dismutase activity, whole blood glutathione peroxidase activity, and plasma coenzyme Q10 (CoQ10) concentration in dogs with various stages of cardiovascular diseases and in healthy dogs; assess the influence of cardiac treatment on the levels of antioxidant variables, plasma CoQ10 concentration, and serum N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration, and determine any correlation between the disease severity (NT-proBNP concentration) and antioxidant variables or CoQ10 concentration. ANIMALS 43 dogs with various types and stages of cardiovascular diseases (congenital and acquired) and 29 healthy dogs. PROCEDURES Blood samples were collected from all dogs for spectrophotometric assessment of antioxidant variables. Plasma CoQ10 concentration was determined with a high-performance liquid chromatography atmospheric pressure chemical ionization-tandem mass spectrometry method. Serum NT-proBNP concentration was measured with an ELISA. RESULTS Values for antioxidant variables did not differ among groups of dogs with cardiovascular diseases, regardless of disease stage or treatment. Plasma CoQ10 concentration was significantly increased in treated dogs with congestive heart failure (CHF), compared with untreated patients. However, plasma CoQ10 concentration did not differ among heart failure classes. A significant, negative correlation between serum NT-proBNP and plasma CoQ10 concentrations was identified in treated CHF affected dogs, suggesting that low plasma CoQ10 concentration may be associated with increased severity of CHF. CONCLUSIONS AND CLINICAL RELEVANCE The antioxidant variables evaluated were not altered in dogs with CHF, regardless of cardiac disease stage or treatment. Further investigation into the possible effects of CoQ10 supplementation in dogs with advanced stages of CHF is warranted. PMID- 28346006 TI - Magnetic resonance imaging susceptibility artifacts in the cervical vertebrae and spinal cord related to monocortical screw-polymethylmethacrylate implants in canine cadavers. AB - OBJECTIVE To characterize and compare MRI susceptibility artifacts related to titanium and stainless steel monocortical screws in the cervical vertebrae and spinal cord of canine cadavers. SAMPLE 12 canine cadavers. PROCEDURES Cervical vertebrae (C4 and C5) were surgically stabilized with titanium or stainless steel monocortical screws and polymethylmethacrylate. Routine T1-weighted, T2-weighted, and short tau inversion recovery sequences were performed at 3.0 T. Magnetic susceptibility artifacts in 20 regions of interest (ROIs) across 4 contiguous vertebrae (C3 through C6) were scored by use of an established scoring system. RESULTS Artifact scores for stainless steel screws were significantly greater than scores for titanium screws at 18 of 20 ROIs. Artifact scores for titanium screws were significantly higher for spinal cord ROIs within the implanted vertebrae. Artifact scores for stainless steel screws at C3 were significantly less than at the other 3 cervical vertebrae. CONCLUSIONS AND CLINICAL RELEVANCE Evaluation of routine MRI sequences obtained at 3.0 T revealed that susceptibility artifacts related to titanium monocortical screws were considered mild and should not hinder the overall clinical assessment of the cervical vertebrae and spinal cord. However, mild focal artifacts may obscure small portions of the spinal cord or intervertebral discs immediately adjacent to titanium screws. Severe artifacts related to stainless steel screws were more likely to result in routine MRI sequences being nondiagnostic; however, artifacts may be mitigated by implant positioning. PMID- 28346007 TI - Lipid emulsion improves survival in animal models of local anesthetic toxicity: a meta-analysis. AB - INTRODUCTION: The Lipid Emulsion Therapy workgroup, organized by the American Academy of Clinical Toxicology, recently conducted a systematic review, which subjectively evaluated lipid emulsion as a treatment for local anesthetic toxicity. We re-extracted data and conducted a meta-analysis of survival in animal models. METHODS: We extracted survival data from 26 publications and conducted a random-effect meta-analysis based on odds ratio weighted by inverse variance. We assessed the benefit of lipid emulsion as an independent variable in resuscitative models (16 studies). We measured Cochran's Q for heterogeneity and I2 to determine variance contributed by heterogeneity. Finally, we conducted a funnel plot analysis and Egger's test to assess for publication bias in studies. RESULTS: Lipid emulsion reduced the odds of death in resuscitative models (OR =0.24; 95%CI: 0.1-0.56, p = .0012). Heterogeneity analysis indicated a homogenous distribution. Funnel plot analysis did not indicate publication bias in experimental models. DISCUSSION: Meta-analysis of animal data supports the use of lipid emulsion (in combination with other resuscitative measures) for the treatment of local anesthetic toxicity, specifically from bupivacaine. Our conclusion differed from the original review. Analysis of outliers reinforced the need for good life support measures (securement of airway and chest compressions) along with prompt treatment with lipid. PMID- 28346008 TI - Wnt/beta-catenin signaling is required for distraction osteogenesis in rats. AB - OVERVIEW: The Wnt signaling pathway plays crucial roles in embryonic skeletal development and postnatal bone regeneration. However, mechanisms of Wnt signaling functioning in distraction osteogenesis (DO) haven't been well characterized. MATERIALS AND METHODS: We established a DO model using Sprague-Dawley rat tibia. And a Wnt signaling blocking agent, recombinant rat Dickkopf-related protein 1 (rrDkk1), was locally applied in the distracted gap to study the role of Wnt signaling during DO process. Animals in the experimental group received rrDkk1 injections (dose = 25 MUg/kg) once daily during distraction period and every third day during consolidation stage (n = 48). Animals in the control group received saline under the same injection strategy (n = 48). Animals at different time points during DO process (1, 3, 6, 12 days after distraction, 10 days and 6 weeks after consolidation) were killed and tissues in the distraction region were harvested for radiography, dual energy X-ray absorptiometry, micro-computed tomography (micro-CT), and histological analyses. RESULTS: Most Wnt ligands, cofactors, receptors, and antagonists were widely expressed in the distraction callus and were significantly upregulated during DO process. After rrDkk1 administration, the majority of these factors were downregulated at the mRNA level, except sFRP and GSK-3beta. At the protein level, both beta-catenin and Lef 1 were also suppressed by rrDkk1. In the long term, restricted bone healing was observed in the distracted callus in the rrDkk1 injection group. These findings were confirmed by histological and micro-CT analyses. CONCLUSIONS: Our findings suggest that Wnt signaling participates in the process of DO, and clinical therapeutic approaches of DO may do well to avoid Wnt pathway suppression. PMID- 28346009 TI - Reactions with Antisera and Pathological Effects of Staphylococcus aureus Gamma Toxin in the Cornea. AB - PURPOSE: This study analyzed the toxicity of purified gamma-toxin from Staphylococcus aureus and the protectiveness of antisera to gamma-toxin in the rabbit cornea. MATERIALS AND METHODS: Gamma-toxin was purified from cultures of alpha-toxin deficient S. aureus strain Newman Deltahla. Antisera to native gamma toxin (Hlg) were produced in rabbits. These antisera and a commercial polyclonal antibody to recombinant HlgB (rHlgB) were analyzed for specificity and toxin neutralization. Heat-inactivated gamma-toxin, active gamma-toxin either alone or with antisera or with commercial antibody to rHlgB, was injected into the rabbit cornea to observe the pathological effects using slit lamp examination scoring (SLE) and histological analyses. RESULTS: Eyes with intrastromal injection of gamma-toxin developed SLE scores that were significantly higher than eyes injected with heat-inactivated gamma-toxin (p <= 0.003). Slit lamp and histological examination of eyes revealed that gamma-toxin injected into the cornea mediated conjunctival injection and chemosis, iritis, fibrin accumulation in the anterior chamber, and polymorphonuclear neutrophil infiltration of the cornea and iris. Also, eyes injected with gamma-toxin plus antisera to native whole gamma-toxin or HlgB, but not with commercial antibody to rHlgB, yielded significantly lower SLE scores than eyes injected with gamma-toxin alone (p <= 0.003). CONCLUSIONS: This study illustrates that S. aureus gamma-toxin is capable of causing significant corneal pathology. Furthermore, the use of polyclonal antisera specific for native gamma-toxin was found to inhibit the damaging effects of the toxin in the rabbit cornea. PMID- 28346010 TI - Non-Healing Perianal Ulcers in a Healthy Elderly Male: An Unusual Case of Perforating Dermatosis. AB - BACKGROUND: Perforating dermatoses are a rare group of dermatologic conditions characterized by transepidermal elimination of dermal material that can be primary or acquired secondary to systemic disease. OBJECTIVE: We present an atypical case of perforating dermatosis resembling elastosis perforans serpiginosa (EPS) presenting with perianal ulcers in an elderly male with no systemic disease or medications and outline his successful treatment course. CONCLUSIONS: Perianal ulcers in an otherwise healthy individual is an unusual presentation for perforating disorders but should be considered in cases not responding to traditional treatment options. PMID- 28346011 TI - Various plus unique: Viral protein U as a plurifunctional protein for HIV-1 replication. AB - Human immunodeficiency virus type 1 (HIV-1), the causative agent of acquired immunodeficiency syndrome, encodes four accessory genes, one of which is viral protein U (Vpu). Recently, the study of Vpu has been of great interest. For instance, various cellular proteins are degraded (e.g. CD4) and down-modulated (e.g. tetherin) by Vpu. Vpu also antagonizes the function of tetherin and inhibits NF-kappaB. Moreover, Vpu is a viroporin forming ion channels and may represent a promising target for anti-HIV-1 drugs. In this review, we summarize the domains/residues that are responsible for Vpu's functions, describe the current understanding of the role of Vpu in HIV-1-infected cells, and review the effect of Vpu on HIV-1 in replication and pathogenesis. Future investigations that simultaneously assess a combination of Vpu functions are required to clearly delineate the most important functions for viral replication. Impact statement Viral protein U (Vpu) is a unique protein encoded by human immunodeficiency virus type 1 (HIV-1) and related lentiviruses, playing multiple roles in viral replication and pathogenesis. In this review, we briefly summarize the most up-to date knowledge of HIV-1 Vpu. PMID- 28346013 TI - The physiology of blood loss and shock: New insights from a human laboratory model of hemorrhage. AB - The ability to quickly diagnose hemorrhagic shock is critical for favorable patient outcomes. Therefore, it is important to understand the time course and involvement of the various physiological mechanisms that are active during volume loss and that have the ability to stave off hemodynamic collapse. This review provides new insights about the physiology that underlies blood loss and shock in humans through the development of a simulated model of hemorrhage using lower body negative pressure. In this review, we present controlled experimental results through utilization of the lower body negative pressure human hemorrhage model that provide novel insights on the integration of physiological mechanisms critical to the compensation for volume loss. We provide data obtained from more than 250 human experiments to classify human subjects into two distinct groups: those who have a high tolerance and can compensate well for reduced central blood volume (e.g. hemorrhage) and those with low tolerance with poor capacity to compensate.We include the conceptual introduction of arterial pressure and cerebral blood flow oscillations, reflex-mediated autonomic and neuroendocrine responses, and respiration that function to protect adequate tissue oxygenation through adjustments in cardiac output and peripheral vascular resistance. Finally, unique time course data are presented that describe mechanistic events associated with the rapid onset of hemodynamic failure (i.e. decompensatory shock). Impact Statement Hemorrhage is the leading cause of death in both civilian and military trauma. The work submitted in this review is important because it advances the understanding of mechanisms that contribute to the total integrated physiological compensations for inadequate tissue oxygenation (i.e. shock) that arise from hemorrhage. Unlike an animal model, we introduce the utilization of lower body negative pressure as a noninvasive model that allows for the study of progressive reductions in central blood volume similar to those reported during actual hemorrhage in conscious humans to the onset of hemodynamic decompensation (i.e. early phase of decompensatory shock), and is repeatable in the same subject. Understanding the fundamental underlying physiology of human hemorrhage helps to test paradigms of critical care medicine, and identify and develop novel clinical practices and technologies for advanced diagnostics and therapeutics in patients with life-threatening blood loss. PMID- 28346012 TI - Lymphangiogenesis: fuel, smoke, or extinguisher of inflammation's fire? AB - Lymphangiogenesis is a recognized hallmark of inflammatory processes in tissues and organs as diverse as the skin, heart, bowel, and airways. In clinical and animal models wherein the signaling processes of lymphangiogenesis are manipulated, most studies demonstrate that an expanded lymphatic vasculature is necessary for the resolution of inflammation. The fundamental roles that lymphatics play in fluid clearance and immune cell trafficking from the periphery make these results seemingly obvious as a mechanism of alleviating locally inflamed environments: the lymphatics are simply providing a drain. Depending on the tissue site, lymphangiogenic mechanism, or induction timeframe, however, evidence shows that inflammation-associated lymphangiogenesis (IAL) may worsen the pathology. Recent studies have identified lymphatic endothelial cells themselves to be local regulators of immune cell activity and its consequential phenotypes - a more active role in inflammation regulation than previously thought. Indeed, results focusing on the immunocentric roles of peripheral lymphatic function have revealed that the basic drainage task of lymphatic vessels is a complex balance of locally processed and transported antigens as well as interstitial cytokine and immune cell signaling: an interplay that likely defines the function of IAL. This review will summarize the latest findings on how IAL impacts a series of disease states in various tissues in both preclinical models and clinical studies. This discussion will serve to highlight some emerging areas of lymphatic research in an attempt to answer the question relevant to an array of scientists and clinicians of whether IAL helps to fuel or extinguish inflammation. Impact statement Inflammatory progression is present in acute and chronic tissue pathologies throughout the body. Lymphatic vessels play physiological roles relevant to all medical fields as important regulators of fluid balance, immune cell trafficking, and immune identity. Lymphangiogenesis is often concurrent with inflammation and can potentially aide or worsen disease progression. How new lymphatic vessels impact inflammation and by which mechanism is an important consideration in current and future clinical therapies targeting inflammation and/or vasculogenesis. This review identifies, across a range of tissue-specific pathologies, the current understanding of inflammation-associated lymphangiogenesis in the progression or resolution of inflammation. PMID- 28346015 TI - The role of exosomes derived from cerebrospinal fluid of spinal cord injury in neuron proliferation in vitro. AB - Exosomes is a key component of cell paracrine secretion and can exert important effects in various disease models. However, the role of exosomes in neuron repair of spinal cord injury (SCI) has rarely been reported. In this study, Exosomes were isolated from cerebrospinal fluid of SCI and normal, and incubated neuron in vitro respectively to research its biological function in cell proliferation. The results demonstrated these exosomes all expressed CD9, CD63, CD81, Alix and Tsg101; however, only exosomes derived from cerebrospinal fluid of SCI could promote proliferation of neuron via ERK signaling pathway, and decrease cell apoptosis. Exosomes contain cytosolic content, including proteins, mRNAs and non cording RNAs, and play a role in important biological function. Our research showed exosomes derived from cerebrospinal fluid of SCI, they can influence neuron cell proliferation in vitro, we did not observe these characters in exosome derived from normal cerebrospinal fluid. PMID- 28346014 TI - Intestinal absorption and renal reabsorption of calcium throughout postnatal development. AB - Calcium is vital for many physiological functions including bone mineralization. Postnatal deposition of calcium into bone is greatest in infancy and continues through childhood and adolescence until peek mineral density is reached in early adulthood. Thereafter, bone mineral density remains static until it eventually declines in later life. A positive calcium balance, i.e. more calcium absorbed than excreted, is crucial to bone deposition during growth and thus to peek bone mineral density. Dietary calcium is absorbed from the intestine into the blood. It is then filtered by the renal glomerulus and either reabsorbed by the tubule or excreted in the urine. Calcium can be (re)absorbed across intestinal and renal epithelia via both transcellular and paracellular pathways. Current evidence suggests that significant intestinal and renal calcium transport changes occur throughout development. However, the molecular details of these alterations are incompletely delineated. Here we first briefly review the current model of calcium transport in the intestine and renal tubule in the adult. Then, we describe what is known with regard to calcium handling through postnatal development, and how alterations may aid in mediating a positive calcium balance. The role of transcellular and paracellular calcium transport pathways and the contribution of specific intestinal and tubular segments vary with age. However, the current literature highlights knowledge gaps in how specifically intestinal and renal calcium (re)absorption occurs early in postnatal development. Future research should clarify the specific changes in calcium transport throughout early postnatal development including mediators of these alterations enabling appropriate bone mineralization. Impact statement This mini review outlines the current state of knowledge pertaining to the molecules and mechanisms maintaining a positive calcium balance throughout postnatal development. This process is essential to achieving optimal bone mineral density in early adulthood, thereby lowering the lifetime risk of osteoporosis. PMID- 28346016 TI - DSL prescriptive targets for bone conduction devices: adaptation and comparison to clinical fittings. AB - OBJECTIVE: To develop an algorithm that prescribes targets for bone conduction frequency response shape, compression, and output limiting, along with a clinical method that ensures accurate transforms between assessment and verification stages of the clinical workflow. DESIGN: Technical report of target generation and validation. STUDY SAMPLE: We recruited 39 adult users of unilateral percutaneous bone conduction hearing aids with a range of unilateral, bilateral, mixed and conductive hearing losses across the sample. RESULTS: The initial algorithm over-prescribed output compared to the user's own settings in the low frequencies, but provided a good match to user settings in the high frequencies. Corrections to the targets were derived and implemented as a low-frequency cut aimed at improving acceptance of the wearer's own voice during device use. CONCLUSIONS: The DSL-BCD prescriptive algorithm is compatible with verification of devices and fine-tuning to target for percutaneous bone conduction hearing devices that can be coupled to a skull simulator. Further study is needed to investigate the appropriateness of this prescriptive algorithm for other input levels, and for other clinical populations including those with single-sided deafness, bilateral devices, children and users of transcutaneous bone conduction hearing aids. PMID- 28346017 TI - Strong in the Face of Adversity. AB - Palliative care provides holistic care to individuals in life-threatening or life limiting conditions. This narrative describes the journey of Kanchan. A strong lady and a doting mother, she came to the hospital by choice, in immense pain and with swelling. Her narrative illustrates how the palliative approach draws out the inner strengths of individuals by focusing on their issues and needs. Kanchan was able to benefit from physiotherapy to reduce the risk of lymphoedema after surgery for breast cancer. Her narrative illustrates how she found comfort and relief, ably supported by the dedicated hospital team. Although a chance encounter led her to the hospital, her story emphasizes the need for greater awareness about palliative services to ensure early intervention. PMID- 28346018 TI - Antiretroviral treatment in HIV-infected children who require a rifamycin containing regimen for tuberculosis. AB - INTRODUCTION: In high prevalence settings, tuberculosis and HIV dual infection and co-treatment is frequent. Rifamycins, especially rifampicin, in combination with isoniazid, ethambutol and pyrazinamide are key components of short-course antituberculosis therapy. Areas covered: We reviewed available data, for which articles were identified by a Pubmed search, on rifamycin-antiretroviral interactions in HIV-infected children. Rifamycins have potent inducing effects on phase I and II drug metabolising enzymes and transporters. Antiretroviral medications are often metabolised by the enzymes induced by rifamycins or may suppress specific enzyme activity leading to drug-drug interactions with rifamycins. These may cause significant alterations in their phamacokinetic and pharmacodynamic properties, and sometimes that of the rifamycin. Recommended strategies to adapt to these interactions include avoidance and dose adjustment. Expert opinion: Despite the importance and frequency of tuberculosis as an opportunistic disease in HIV-infected children, current data on the management of co-treated children is based on few studies. We need new strategies to rapidly assess the use of rifamycins, new anti-tuberculosis drugs and antiretroviral drugs together as information on safety and dosing of individual drugs becomes available. PMID- 28346020 TI - Erratum. AB - In the article by Pedlar CR, Whyte GP, Burden R, et al, "A Case Study of an Iron Deficient Female Olympic 1500-m Runner," in Int J Sport Physiol Perform. 8(6), p. 696, we printed an incorrect version of Figure 1, without the *'s and +'s referred to in the caption. Please see below for the correct version of the figure, along with the caption. PMID- 28346019 TI - Fallopian Tube Involvement by Disseminated Peritoneal Adenomucinosis, Mimicking Mucinous Tubal Metaplasia. PMID- 28346022 TI - Erratum: Rhodes et al (2015). AB - In the article by Rhodes JM, Mason BS, Perrat B, et al, "Activity Profiles of Elite Wheelchair Rugby Players During Competition," in Int J Sport Physiol Perform. 10(3), the character for "less than/equal to" (<=) was printed incorrectly. In text-twice on p. 319, twice on p. 320, and once on p. 323-it appears as a small box with an "X" in it (L). Five times in Table 3, on p. 320, it appears as the British pound sign (L). PMID- 28346021 TI - Erratum. AB - In the article by Muggeridge DJ, Howe C CF, Spendiff O, Pedlar C, James PE, Easton C, "The effects of a single dose of concentrated beetroot juice on performance in trained flatwater kayakers," in the International Journal of Sport Nutrition and Exercise Metabolism 23(5), Figures 2 and 3 were incorrectly labeled due to an error in the production process. The online version of the article had been corrected. We apologize for the error. PMID- 28346023 TI - Why are new antidepressants failing to make the grade for approval? PMID- 28346024 TI - Increased IL-4- and IL-17-producing CD8+ cells are related to decreased CD39+CD4+Foxp3+ cells in allergic asthma. AB - OBJECTIVE: In allergic asthma, regulatory T cell (Treg) number and function are decreased. Antigen-primed CD8+ T cells play an indispensable role in the full development of airway inflammation and airway hyper-responsiveness (AHR) occurring in asthma. In this study, we investigated the relationship between subpopulations of CD8+ T cells and CD39+ Tregs. METHODS: Female C57BL/6 mice were used to develop the model of allergic asthma. Experimental mice were immunized with ovalbumin (OVA) by intra-peritoneal (i.p) injection and then challenged with OVA by intra-tracheal administration. Control mice were immunized with vehicle by i.p injection and challenged with OVA. Airway inflammation was determined by histology and AHR was measured by an invasive method. Levels of interferon (IFN) gamma, IL-4, and IL-17 in bronchoalveolar lavage fluid (BALF) were determined by enzyme-linked immunosorbent assay. The frequencies of CD8+IFN-gamma+ cells (Tc1), CD8+IL-4+ cells (Tc2), CD8+IL-17+cells (Tc17), and CD39+Tregs were measured by flow cytometry. The correlation between CD39+Tregs and Tc subsets was analyzed by Pearson's test. RESULTS: Experimental mice displayed phenotypes of allergic asthma, including inflammatory cell infiltration into the lungs, goblet cell hyperplasia, increased airway resistance, and increased IL-4 and IL-17 in BALF. Compared to control mice, experimental mice displayed lower CD39+Tregs and Tc1 but higher Tc2 and Tc17. There was a negative correlation between CD39+Tregs and Tc2 or Tc17. CONCLUSION: In allergic asthma, increased Tc2 and Tc17 are possibly related to insufficient CD39+Tregs. PMID- 28346026 TI - Erratum. AB - In the article by Aloui A, Chaouachi A, Chtourou H, et al, "Effects of Ramadan on the Diurnal Variations of Repeated-Sprint Performance," in Int J Sport Physiol Perform. 8(3), p. 255, we printed two incorrect times of day. In the second paragraph under the Participants heading, "dinner between 10 and 11 PM) and sleeping habits (sleeping between 8 and 9 PM" should read "dinner between 8 and 9 PM) and sleeping habits (sleeping between 10 and 11 PM." We apologize for the error. PMID- 28346025 TI - Guidance on radiation dose limits for the lens of the eye: overview of the recommendations in NCRP Commentary No. 26. AB - PURPOSE: This review summarizes the conclusions and recommendations of the new National Council on Radiation Protection and Measurements (NCRP) Commentary No. 26 guidance on radiation dose limits for the lens of the eye. The NCRP addressed radiation protection principles in respect to the lens of the eye, discussed the current understanding of eye biology and lens effects, reviewed and evaluated epidemiology, and assessed exposed populations with the potential for significant radiation exposures to the lens while suggesting monitoring and protection practices. CONCLUSIONS: Radiation-induced damage to the lens of the eye can include the loss of clarity resulting in opacification or clouding several years after exposure. The impact is highly dependent on the type of radiation, how the exposure of the lens was delivered, the genetic susceptibilities of the individual exposed, and the location of the opacity relative to the visual axis of the individual. The preponderance of epidemiological evidence suggests that lens damage could occur at lower doses than previously considered and the NCRP has determined that it is prudent to reduce the recommended annual lens of the eye occupational dose limit from an equivalent dose of 150 mSv to an absorbed dose of 50 mGy. Significant additional research is still needed in the following areas: comprehensive evaluation of the overall effects of ionizing radiation on the eye, dosimetry methodology and dose-sparing optimization techniques, additional high quality epidemiology studies, and a basic understanding of the mechanisms of cataract development. PMID- 28346027 TI - Biologically-based mechanistic models of radiation-related carcinogenesis applied to epidemiological data. AB - PURPOSE: Biologically-based mechanistic models that are used in combining current understanding of human carcinogenesis with epidemiological studies were reviewed. Assessment was made of how well they fit the data, whether they account for non linear radiobiological low-dose effects, and whether they suggest any implications for the dose response at low doses and dose rates. However, the present paper does not make an attempt to provide a complete review of the existing literature on biologically-based models and their application to epidemiological data. CONCLUSION: In most studies the two-stage clonal expansion (TSCE) model of carcinogenesis was used. The model provided robust estimates of identifiable parameters and radiation risk. While relatively simple, it is flexible, so that more stages can easily be added, and tests made of various types of radiation action. In general, the model performed similarly or better than descriptive excess absolute and excess relative risk models, in terms of quality of fit and number of parameters. Only very rarely the shape of dose response predicted by the models was investigated. For some tumors, when more detailed biological information was known, additional pathways were included in the model. The future development of these models will benefit from growing knowledge on carcinogenesis processes, and in particular from use of biobank tissue samples and advances in omics technologies. Their use appears a promising approach to investigate the radiation risk at low doses and low dose rates. However, the uncertainties involved are still considerable, and the models provide only a simplified description of the underlying complexity of carcinogenesis. Current assumptions in radiation protection including the linear non-threshold (LNT) model are not in contradiction to what is presently known on the process of cancer development. PMID- 28346028 TI - Prevalence and associated factors for self-reported asthma in a Canadian population: The Canadian Community Health Survey, 2014. AB - BACKGROUND: Asthma prevalence is increasing among adults, yet limited information regarding the association between adult asthma and environmental and personal exposures is available using large nationally representative population-based survey. OBJECTIVE: To determine the prevalence of asthma and associated factors for self-reported asthma in a Canadian population aged 12 years and older by using the Canadian Community Health Survey (CCHS) 2014 cross-sectional cohort. METHODS: We used data from the 2014 CCHS. Asthma was determined through self reported health professional diagnosis. Information regarding covariates of importance, such as socio-economic status, life style variables, was obtained. A weighted logistic regression analysis was performed with appropriate technique for clustering effects. RESULTS: Estimated self-reported asthma prevalence of 8.1% in the greater than 12 years old Canadian population was observed. We found that a substantial proportion of Canadians (aged 12 and older) reported having asthma and geographical differences and differences between specific provinces in asthma prevalence. Women had higher prevalence of asthma than men, but the relationship depended on age and body mass index (BMI). Interactions between household income and smoking status were observed to predict the probability of asthma. CONCLUSIONS: Additional studies are needed to determine which factors influence the asthma prevalence between sex, BMI as well as smoking status and household income and its interactions with each other. PMID- 28346029 TI - Reasons for using power tilt: perspectives from clients and therapists. AB - PURPOSE: A power tilt wheelchair allows independence in changing body position to address a variety of needs throughout the day; however, literature and clinical practice suggest that actual use varies greatly. This grounded theory study examined how power tilt was used in daily life from the perspectives of adults who used power tilt and therapists who prescribed this technology. METHODS: A constant comparative approach was used to collect and analyze interview data from five people who use power tilt and six therapists who prescribe this technology. RESULTS: This paper presents the findings specific to understanding the reasons why power tilt was used, focusing on the relationships between tilt use and (1) the reasons for use, (2) the reasons for prescribing power tilt and (3) the associated amplitudes of tilt. CONCLUSIONS: This study advances knowledge related to how power tilt is used in daily life by elucidating that how the reasons for use are conceptualized is complex. The three relationships related to the reason for power tilt use identified in this paper have the potential to influence the quality of communication about power tilt use in clinical practice between therapist and client and in research between researcher and participant. Implications for Rehabilitation: Understanding the inconsistencies and variations in how power tilt is used in daily life is dependent on exploring the reasons beyond the words or terms expressed to describe use. Reasons for tilt use are context dependent, particularly the activity occurring at the time of tilt use, the associated amplitude of tilt and the influence of other reasons occurring at the same time. PMID- 28346030 TI - Antimicrobial activity of eugenol and essential oils containing eugenol: A mechanistic viewpoint. AB - Eugenol is a hydroxyphenyl propene, naturally occurring in the essential oils of several plants belonging to the Lamiaceae, Lauraceae, Myrtaceae, and Myristicaceae families. It is one of the major constituents of clove (Syzygium aromaticum (L.) Merr. & L.M. Perry, Myrtaceae) oil and is largely used in both foods and cosmetics as a flavoring agent. A large body of recent scientific evidence supports claims from traditional medicine that eugenol exerts beneficial effects on human health. These effects are mainly associated with antioxidant and anti-inflammatory activities. Eugenol has also shown excellent antimicrobial activity in studies, being active against fungi and a wide range of gram-negative and gram-positive bacteria. The aim of this review is to analyze scientific data from the main published studies describing the antibacterial and antifungal activities of eugenol targeting different kind of microorganisms, such as those responsible for human infectious diseases, diseases of the oral cavity, and food borne pathogens. This article also reports the effects of eugenol on multi-drug resistant microorganisms. On the basis of this collected data, eugenol represents a very interesting bioactive compound with broad spectrum antimicrobial activity against both planktonic and sessile cells belonging to food-decaying microorganisms and human pathogens. PMID- 28346031 TI - Chromogranin A cell density in the large intestine of Asian and European patients with irritable bowel syndrome. AB - OBJECTIVE: Patients with irritable bowel syndrome (IBS) in Asia show distinctive differences from those in the western world. The gastrointestinal endocrine cells appear to play an important role in the pathophysiology of IBS. The present study aimed at studying the density of chromogranin A (CgA) cells in the large intestine of Thai and Norwegian IBS patients. METHODS: Thirty Thai IBS patients and 20 control subjects, and 47 Norwegian IBS patients and 20 control subjects were included. A standard colonoscopy was performed in both the patients and controls, and biopsy samples were taken from the colon and the rectum. The biopsy samples were stained with hematoxylin-eosin and immunostained for CgA. The density of CgA cells was determined by computerized image analysis. RESULTS: In the colon and rectum, the CgA cell densities were far higher in both IBS and healthy Thai subjects than in Norwegians. The colonic CgA cell density was lower in Norwegian IBS patients than in controls, but did not differ between Thai IBS patients and controls. In the rectum, the CgA cell densities in both Thai and Norwegian patients did not differ from those of controls. CONCLUSIONS: The higher densities of CgA cells in Thai subjects than Norwegians may be explained by a higher exposure to infections at childhood and the development of a broad immune tolerance, by differences in the intestinal microbiota, and/or differing diet habits. The normal CgA cell density in Thai IBS patients in contrast to that of Norwegians may be due to differences in pathophysiology. PMID- 28346033 TI - Erratum. AB - In the article by Davis P, Wittekind A, and Beneke R, "Amateur Boxing: Activity Profile of Winners and Losers," in Int J Sport Physiol Perform. 8(1), pp. 84-91, the digit zero was inadvertently deleted from some of the figures in the tables. Table 1, Total punches, Round 1 winners should be 20.7 not 2.7, and Round 3 winners should be 20.3 not 2.3. Table 2, Air punches, Round 1 winners should be 10.1 not 1.1, and Round 3 losers should be 10.6 not 1.6. Table 2, Punches/min, Round 2 should be 20.2 not 2.2, and Round 1 losers should be 20.2 not 2.2. Table 4, 2-punch-combinations, Round 2 winners should be 10.4 not 1.4, and Round 3 winners should be 10.2 not 1.2. We apologize for the error. PMID- 28346032 TI - Presence of Vision Impairment and Risk of Hospitalization among Elderly Medicare Beneficiaries. AB - PURPOSE: To examine the association between vision impairment and all-cause hospitalization among elderly Medicare beneficiaries. METHODS: A population-based study (N = 22,681) of community-dwelling Medicare beneficiaries aged 65 years and older who participated in the Medicare Current Beneficiary Survey for the years 2001-2007. Beneficiaries were classified into self-reported presence of vision impairment versus no vision impairment. Inpatient hospitalizations were identified using Medicare claims data. A multivariable Cox proportional hazard model examined the association between presence of vision impairment and time to first hospitalization within 3 years of survey entry after adjusting for sociodemographics, comorbidities, hearing impairment, and activity limitation stages derived from difficulty performing the activities of daily living. RESULTS: Medicare beneficiaries who self-reported the presence of vision impairment were significantly more likely to be hospitalized over 3 years compared to beneficiaries without vision impairment even after adjustment for potentially influential covariates (hazard ratio = 1.14 and 95% confidence interval: 1.05-1.23). CONCLUSIONS: Medicare beneficiaries with self-reported vision impairment were at higher risk of hospitalization during a 3-year period. Further research may identify reasons that are amenable to policy interventions. PMID- 28346034 TI - Evidence of binaural integration benefits following ARIA training for children and adolescents diagnosed with amblyaudia. AB - OBJECTIVE: The purpose of this study was to demonstrate the efficacy of Auditory Rehabilitation for Interaural Asymmetry (ARIA) to improve dichotic listening scores in children and adolescents diagnosed with amblyaudia and other binaural integration deficits. DESIGN: The study is a field experiment without randomisation. STUDY: Participants placed into groups based on dichotic listening test scores received four sessions of ARIA training. Baseline scores were compared to performance during the final session of training and to scores obtained 2 or more months after completion of ARIA. SAMPLE: A total of 125 children participated at five different clinical sites. RESULTS: Dichotic listening scores improved across all participants. Post hoc analyses demonstrated highly significant gains in non-dominant ear performance and reductions of interaural asymmetry among participants diagnosed with amblyaudia at both post ARIA measurements. Participants in other diagnostic groups also showed significant benefits for some post-ARIA measures. CONCLUSIONS: Results demonstrate that ARIA training is an effective method for improving binaural integration skills among children and adolescents identified with dichotic listening weaknesses during assessments for auditory processing disorder (APD), especially for those diagnosed with amblyaudia. Benefits achieved following ARIA training remain stable across several months. PMID- 28346035 TI - One Needle is Better Than Two: The Philosophy Surrounding Use of Local Anesthesia in Northern India. AB - The author, an internal medicine resident in the United States, participated in an international elective through her postgraduate training program in a rural hospital in northern India. While performing a thoracentesis, she notes that local anesthesia has not been administered, which is seemingly the standard of care at this hospital. Several questionnaire studies about pain services and pain management in India are reviewed, and they reveal insights and severe limitations to effective management of hospitalized patients' pain. PMID- 28346036 TI - Assessing the Relationship Between Mental Distress and Tobacco Use in Post Katrina and Rita Louisiana. AB - BACKGROUND: The relationship between mental health status and smoking is complicated and often confounded by bi-directionality, yet most research on this relationship assumes exogeneity. OBJECTIVES: The goal of this article is to implement an instrumental variable approach to (1) test the exogeneity assumption and (2) report on the association between mental health status and smoking post disaster. METHODS: This analysis utilizes the 2006 and 2007 Louisiana Behavioral Risk Factor Surveillance Survey to examine the link between mental distress and smoking in areas affected by Hurricanes Katrina and Rita. Residence in a hurricane-affected parish (county) was used as an instrumental variable for mental distress. RESULTS: Just over 22% of the sample resided in a hurricane affected parish. Residents of hurricane-affected parishes were significantly more likely to report occasional and frequent mental distress. Residence in a hurricane-affected parish was not significantly associated with smoking status. With residence established as a salient instrumental variable for mental distress, the exogeneity assumption was tested and confirmed in this sample. A dose-response relationship existed between mental distress and smoking, with smoking prevalence increasing directly (and non-linearly) with mental distress. CONCLUSIONS: In this sample, the relationship between mental distress and smoking status was exogenous and followed a dose-response relationship, suggesting that the disasters did not result in an uptake of smoking initiation, but that the higher amounts of mental distress may lead to increased use among smokers. The findings suggest that tobacco control programs should devise unique strategies to address mentally distressed populations. PMID- 28346037 TI - Prognostic significance of granulomas in children with Crohn's disease. AB - OBJECTIVES: Granulomas have long been considered the histological hallmark of Crohn's disease (CD). Currently, there is considerable dispute with regards to their prognostic implications. We aimed to determine the effect of granulomas on phenotypic features and disease's long-term outcomes in a large cohort of pediatric CD patients. MATERIALS AND METHODS: Medical records of pediatric CD patients diagnosed at the Schneider Children's Medical Center were reviewed retrospectively. Patients were categorized into two groups based on the presence or absence of granulomas at diagnosis. Baseline characteristics included anthropometric, clinical, laboratory, radiological and endoscopic data. Outcome measures included flares, hospitalizations, biological therapy and surgery. RESULTS: Of 289 CD patients diagnosed between 2001 and 2015, 99 patients (34%) had granulomas. Median age of the entire cohort at diagnosis was 14.2 years (females, 42.6%), with a median follow-up of 8.5 years. Patients with granulomas had a significantly higher percentage (47.5% vs. 23.7%, p = .001) of upper gastrointestinal involvement and ileo-colonic disease (64.9% vs. 49.5%, p = .01). Extraintestinal manifestations were twice as common in patients without granulomas (16.3% vs. 8.1%, p = .05). Patients with granulomas were more likely to be hospitalized (HR =1.43, 95% CI: 1.0-2.0) and to receive biologic therapy (HR = 1.52, 95% CI: 1.1-2.11). Additionally, both of these disease outcomes occurred significantly earlier (p = .013 and p = .027, respectively). In contrast, patients with granulomas did not exhibit increased risk of flares or bowel resection. CONCLUSION: Patients with granulomas exhibited a distinct phenotype at diagnosis and demonstrated a more severe disease course. PMID- 28346040 TI - Erratum: Callahan et al (2014). AB - In the article by Callahan LF, Cleveland RJ, Shreffler J, et al, "Evaluation of Active Living Every Day in Adults With Arthritis," in J Phys Act Health, 11(2), p. 285, two authors were omitted from the author byline for the article. Those authors are Teresa Brady and Todd Schwartz. The authors apologize for the error. PMID- 28346038 TI - Recruitment and Testing Protocol in the National Eye Health Survey: A Population Based Eye Study in Australia. AB - PURPOSE: To present the recruitment and testing methodology of the National Eye Health Survey (NEHS), a population-based study that aimed to determine the prevalence and causes of vision impairment and blindness in Australia. METHODS: Non-Indigenous Australians aged 50 years and older and Indigenous Australians aged 40 years and older were recruited using a door-to-door approach from 30 randomly selected geographical areas, stratified by remoteness. Participants underwent a vision examination, anterior segment assessment, intraocular pressure testing, perimetry, and fundus photography. RESULTS: In total, recruiters approached 23,235 residences, and 11,883 residents were successfully contacted (51.1%). Of these, 6760 (56.9%) were deemed eligible and 5764 agreed to participate (positive response rate = 85.3%). Of those who agreed, 4836 residents attended the examination (4836/6760 = 71.5%). This included 1738 Indigenous Australians (41.1% male) aged 40-92 years (mean +/- standard deviation = 55.0 +/- 10.0 years) and 3098 non-Indigenous Australians (46.4% male), aged 50-98 years (mean +/- standard deviation = 66.6 +/- 9.7 years). CONCLUSIONS: The NEHS achieved an excellent positive response rate, and the data collected from 4836 Australians will provide the first population-based national estimate of the prevalence of vision impairment and blindness. This data will guide future economic analysis, policy formulation, and eye health service delivery in Australia. PMID- 28346039 TI - Comparison Between Urinalysis Results and Self-Reported Heroin Use Among Patients Undergoing Methadone Maintenance Treatment in China. AB - BACKGROUND: The validity and concordance of two main measures of drug use behavior, self-report and urinalysis, has long been discussed. More understanding is needed about the underlying factors associated with discordance between these two methods. OBJECTIVES: Describe the pattern and associated factors of discordance between self-reported heroin use and the urinalysis results of opiate use among methadone maintenance therapy (MMT) patients in China. METHODS: A total of 2,448 MMT patients from 68 clinics in five provinces of China participated in a survey, which collected information on demographics, drug use and MMT-related factors, depressive symptoms, and drug avoidance self-efficacy. The most recent urine morphine test result was obtained from medical records and compared with self-reported heroin use. Participants who had urinalysis within 14 days of the survey were included in the analysis. RESULTS: Among the 1,092 participants, 70 (6.4%) self-reported heroin use and 195 (17.9%) had positive urinalysis results. The over-reporters group had significantly higher education, and the under reporters had significantly higher level of drug-avoidance self-efficacy and lower level of depressive symptoms. Among the participants who either self reported heroin use or had positive urinalysis results, being young, having higher education, and having lower level of depressive symptoms were associated with discordance between self-reports and urinalysis results. CONCLUSION: The combination of both measures in assessing drug use behavior seems necessary. The validity of self-report should be considered differently based on demographic and psychosocial characteristics. PMID- 28346041 TI - Enhancing tolerability of a measure of social perception in schizophrenia: comparison of short and long Norwegian versions of the Relationships Across Domains test. AB - INTRODUCTION: Relationship perception focuses on social interactions, is reduced in schizophrenia and is related to daily functioning. It can be assessed with the Relationships Across Domains (RAD) test, built on Relational Models Theory which states that people use four relational models to interpret social interaction. RAD is time consuming, low on tolerability and only used in English-speaking countries. We evaluated the psychometric properties of a translated, abbreviated Norwegian version. METHODS: Sixty-two schizophrenia participants and 56 healthy controls underwent assessments of social and non-social cognition. The schizophrenia group completed functional and clinical measures. RAD's internal consistency was investigated with Cronbach's alphas, group differences with logistic regressions and associations between study variables with Pearson's correlations. RESULTS: RAD was reduced from 25 (Cronbach's alpha = .809) to 12 vignettes (Cronbach's alpha = .815). Schizophrenia participants had significant impairments, with larger effect sizes for the full version. Associations of RAD with study variables were similar for the two versions: smaller for clinical measures and larger for functional and cognitive measures. Results were comparable to results for the English version. CONCLUSIONS: The length of the Norwegian RAD was reduced while retaining its psychometric properties, which were similar to the English version. This suggests the test's cross-cultural utility. PMID- 28346044 TI - Erratum. AB - In issue 10(1) of JPAH, in Iannotti RJ, Chen R, Kololo H, Petronyte G, Haug E, & Roberts C, Motivations for Adolescent Participation in Leisure-Time Physical Activity: International Differences, the publisher incorrectly omitted the article's tables. This has been corrected in the online version of the article which appears on the JPAH website. The publisher regrets this error and encourages readers to view the corrected version of the article published online. PMID- 28346042 TI - Decreased expression of ALDH5A1 predicts prognosis in patients with ovarian cancer. AB - Aldehyde dehydrogenase 5 family, member A1 (ALDH5A1) belongs to the superfamily of aldehyde dehydrogenases (ALDHs). However, the prognostic value of ALDH5A1 in ovarian cancer remains unclear. The aim of this study was to explore the relationship between ALDH5A1 and the prognosis of patients with ovarian cancer (OC). We compared the expression of ALDH5A1 in OC to that innormal controls, using GSE40595 profiling data. Tissue microarray analysis was conducted for192 OC patients, 14 adjacent normal ovary tissues, and 2 normal ovary tissues. Using the "Kaplan-Meier plotter" (KM plotter) database, updated gene expression data and survival information of a total of 1583 OC patients were used to evaluate the prognostic value of ALDH5A1 in OC patients. We found that ALDH5A1 mRNA expression was downregulated in OC patients compared with that innormal tissues. In survival analyses, we found that ALDH5A1 was positively linked to prognosis in patients with OC, particularly in those with serous ovarian cancer (SOC). In addition, high Ctranscription activity of ALDH5A1 was correlated with better overall survival in SOC patients expressing mutatedTP53, but not in those expressing wild type TP53. In pathological grades II/III, a high mRNA level of ALDH5A1 was associated with improved overall survival. The positive association between ALDH5A1 and prognosis was found not only in early stages(I and II), but also in advanced stages (III and IV) of SOC patients. results indicate that ALDH5A1 is an excellent predictive factor of OC and may play crucial roles in OC progression. PMID- 28346043 TI - Structural abnormalities in the primary somatosensory cortex and a normal behavioral profile in Contactin-5 deficient mice. AB - Contactin-5 (Cntn5) is an immunoglobulin cell adhesion molecule that is exclusively expressed in the central nervous system. In view of its association with neurodevelopmental disorders, particularly autism spectrum disorder (ASD), this study focused on Cntn5-positive areas in the forebrain and aimed to explore the morphological and behavioral phenotypes of the Cntn5 null mutant (Cntn5-/-) mouse in relation to these areas and ASD symptomatology. A newly generated antibody enabled us to elaborately describe the spatial expression pattern of Cntn5 in P7 wild type (Cntn5+/+) mice. The Cntn5 expression pattern included strong expression in the cerebral cortex, hippocampus and mammillary bodies in addition to described previously brain nuclei of the auditory pathway and the dorsal thalamus. Thinning of the primary somatosensory (S1) cortex was found in Cntn5-/- mice and ascribed to a misplacement of Cntn5-ablated cells. This phenotype was accompanied by a reduction in the barrel/septa ratio of the S1 barrel field. The structure and morphology of the hippocampus was intact in Cntn5 /- mice. A set of behavioral experiments including social, exploratory and repetitive behaviors showed that these were unaffected in Cntn5-/- mice. Taken together, these data demonstrate a selective role of Cntn5 in development of the cerebral cortex without overt behavioral phenotypes. PMID- 28346045 TI - A modular and adaptive mass spectrometry-based platform for support of bioprocess development toward optimal host cell protein clearance. AB - A modular and adaptive mass spectrometry (MS)-based platform was developed to provide fast, robust and sensitive host cell protein (HCP) analytics to support process development. This platform relies on one-dimensional ultra-high performance liquid chromatography (1D UHPLC) combined with several different MS data acquisition strategies to meet the needs of purification process development. The workflow was designed to allow HCP composition and quantitation for up to 20 samples per day, a throughput considered essential for real time bioprocess development support. With data-dependent acquisition (DDA), the 1D UHPLC-MS/MS method had excellent speed and demonstrated robustness in detecting unknown HCPs at >= 50 ng/mg (ppm) level. Combining 1D UHPLC with sequential window acquisition of all theoretical spectra (SWATH) MS enabled simultaneous detection and quantitation of all HCPs in single-digit ng/mg range within 1 hour, demonstrating for the first time the benefit of SWATH MS as a technique for HCP analysis. As another alternative, a targeted MS approach can be used to track the clearance of specific known HCP under various process conditions. This study highlights the importance of designing a robust LC-MS/MS workflow that not only allows HCP discovery, but also affords greatly improved process knowledge and capability in HCP removal. As an orthogonal and complementary detection approach to traditional HCP analysis by enzyme-linked immunosorbent assay, the reported LC MS/MS workflow supports the development of bioprocesses with optimal HCP clearance and the production of safe and high quality therapeutic biopharmaceuticals. PMID- 28346047 TI - Erratum. AB - In the article by Huiszoon, E., et al., "Assessment of Daily Activity Performance: Exploring the Option of Shortening the Test," in the Journal of Aging and Physical Activity, 22(1), pp. 44-51, http://dx.doi.org/10.1123/JAPA.2011-0410, the affiliation listed for the second author, Paul L. de Vreede, was incorrect. The correct affiliation for this author at the time the article was written was Utrecht University Medical Center, Utrecht, Netherlands. The online version of the article has been corrected. PMID- 28346046 TI - Erratum: Harkey et al (2014). AB - In Table 2 in the article by Harkey M, McLeod M, Van Scoit A, et al, "The Immediate Effects of an Anterior-to-Posterior Talar Mobilization on Neural Excitability, Dorsiflexion Range of Motion, and Dynamic Balance in Patients With Chronic Ankle Instability," in J Sport Rehabil. 23(4):351-359, the composite and anterior scores for the Star Excursion Balance Test in the joint-mobilization group were transposed. Printed here is the correct version of the table. PMID- 28346049 TI - Adverse Childhood Experiences among Veterinary Medical Students: A Multi-Site Study. AB - This research explores Adverse Childhood Experiences (ACEs) among veterinary medical students across six academic institutions of veterinary medicine, and their relationship with depression, stress, and desire to become a veterinarian. Between April 1, 2016, and May 23, 2016, 1,118 veterinary medical students in all 4 years of the curriculum (39% response rate) completed an anonymous web-based questionnaire about ACEs, depression using the Center for Epidemiological Studies Depression scale (CESD), stress using the Perceived Stress Scale (PSS), and the age at which they wanted to become a veterinarian. Sixty-one percent (677) of respondents reported having at least one ACE. The most prevalent ACE reported was living with a household member with a mental illness (31%). Students who had experienced four or more ACEs had an approximately threefold increase in signs of clinical depression and higher than average stress when compared to students who had experienced no ACEs. The number of ACEs showed an overall graded relationship to signs of clinical depression and higher than average stress. There was no statistically significant relationship between age at which a student wanted to become a veterinarian and exposure to ACEs. Veterinary students report being exposed to ACEs before age 18 at a rate similar to that of other population-based studies. These findings do not suggest that veterinary students enter the veterinary medical education system more at risk for poor mental health due to ACEs than the general population. PMID- 28346051 TI - Erratum. AB - In the article by Joseph MF et al, "Incidence of Morphologic Changes in Asymptomatic Achilles Tendons in an Active Young Adult Population," in J Sport Rehabil. 21(3), 249-252, 3 authors were omitted from the byline. The full list of authors is Michael F. Joseph, Thomas H. Trojian, Jeffrey M. Anderson, John Crowley, Lindsay Dilieto, Brian O'Neil, and Craig R. Denegar. PMID- 28346048 TI - MAbDelivery: Administration routes for antibody therapy Third LabEx MAbImprove industrial workshop, July 2, 2015 Tours, France. AB - The annual "LabEx MAbImprove Industrial Workshops" are primarily intended to provide a comprehensive view about topics of interest for the pharmaceutical industry to scientists involved in research on therapeutic antibodies. The third workshop in this series, held July 2, 2015 in Tours, was dedicated to the optimization of delivery, namely all processes leading monoclonal antibodies to reach their target site. The commonly used intravenous (IV) route, although advantageous in terms of pharmacokinetics and pharmacodynamics, presents some disadvantages in terms of patients' convenience, therapeutic target access or treatment cost. Such problems led pharmaceutical companies to consider more straightforward and patient-friendly administration routes, bringing the need for specific formulations adapted to the specific inherent physicochemical challenges. In this context, the workshop provided an overview of these advances and opened discussion on new administration routes and formulation development. In the first session, the opportunities and challenges of 3 main routes of administration (IV, subcutaneous (SC), and pulmonary) were discussed, integrating protein stability issues. The next session was dedicated to medical devices intended for SC and pulmonary administration. The last session focused on specific formulations for monoclonal antibodies, particularly to successfully protect antibodies upon aerosolization, to develop highly concentrated formulations for SC administration, and to use formulation as a mean to overcome the barriers to oral protein delivery. As in the previous editions, this workshop gathered people from the academic and industrial spheres and allowed rich debates and discussions. PMID- 28346052 TI - Erratum for the article by Taverno Ross et al in PES 25(2). AB - In the article by Taverno Ross S, Dowda M, Saunders R, Pate R, "Double dose: The cumulative effect of TV viewing at home and in preschool on children's activity patterns and weight status," in Pediatr Exerc Sci. 25(2), p. 262-272, the authors incorrectly stated that children in the High TV-Combined group had significantly lower levels of MVPA compared with children in the Low TV-Combined group. However, as shown in Table 3, children in the High TV-Combined group had higher MVPA than the Low TV-Combined group. Given that all other differences between High TV and Low TV groups were not significantly different and the erroneously interpreted difference was marginally significant (p =.047), the authors believe that the proper interpretation of the findings is that TV exposure was not associated with children's physical activity. PMID- 28346050 TI - Perception of Canine Welfare Concerns among Veterinary Students, Practitioners, and Behavior Specialists in Spain. AB - Veterinarians are well placed to supervise and ensure canine welfare. However, the perception of animal welfare among veterinarians may vary depending on the level of training and professional practice, including the specialization in animal behavior and welfare. The aim of this study was to survey the perception of canine welfare among veterinarians, including students, practitioners, and behavior specialists. A scale-based questionnaire including 12 issues affecting canine welfare was adapted from Yeates and Main and distributed to first-year (n=50) and fifth-year veterinary students (n=50), as well as veterinary practitioners (n=260) and specialists in behavioral medicine (n=50). For each issue, respondents were asked to rate how much they perceived each issue to affect canine welfare (on a scale of 0 to 4). A General Linear Model test was used to assess the effect of the studied group on scores. "Physical abuse or cruelty" was the highest-scoring problem in all groups and "breed-related conditions" was the lowest. In general, specialists in behavioral medicine assigned significantly higher scores to most items, particularly "behavioral problems" and "lack of sufficient company." In contrast, fifth-year students assigned significantly lower scores to most items. This study shows that situations clearly affecting canine welfare represent an important concern for veterinarians, both undergraduates and professionals. However, the level of professional experience and specialization might influence the perception of more subtle examples of poor welfare. Raising awareness regarding canine welfare, including concern for breed- or behavior-related problems, should be emphasized within university programs. PMID- 28346053 TI - Rapid Prototyping of a Cyclic Olefin Copolymer Microfluidic Device for Automated Oocyte Culturing. AB - Assisted reproductive technology (ART) can benefit from the features of microfluidic technologies, such as the automation of time-consuming labor intensive procedures, the possibility to mimic in vivo environments, and the miniaturization of the required equipment. To date, most of the proposed approaches are based on polydimethylsiloxane (PDMS) as platform substrate material due to its widespread use in academia, despite certain disadvantages, such as the elevated cost of mass production. Herein, we present a rapid fabrication process for a cyclic olefin copolymer (COC) monolithic microfluidic device combining hot embossing-using a low-temperature cofired ceramic (LTCC) master-and micromilling. The microfluidic device was suitable for trapping and maturation of bovine oocytes, which were further studied to determine their ability to be fertilized. Furthermore, another COC microfluidic device was fabricated to store sperm and assess its quality parameters over time. The study herein presented demonstrates a good biocompatibility of the COC when working with gametes, and it exhibits certain advantages, such as the nonabsorption of small molecules, gas impermeability, and low fabrication costs, all at the prototyping and mass production scale, thus taking a step further toward fully automated microfluidic devices in ART. PMID- 28346054 TI - Genomic Regions in Local Endangered Sheep Encode Potentially Favorable Genes. AB - The economic evaluation of farm animal genetic resources plays a key role in developing conservation programs. However, to date, the link between diversity as assessed by neutral genetic markers and the functional diversity is not yet understood. Two genome-wide comparisons, using over 44,000 Single Nucleotide Polymorphisms, identified the markers with the highest difference in allele frequency between the Alpago endangered breed and two clusters, composed of four specialized dairy sheep, and four meat breeds respectively. The genes in proximity of these markers were mapped to known pathways of the Gene Ontology to determine which ones were most represented. Our results indicated that the differences of the Alpago breed from the more productive sheep rely upon genes involved in cellular defense and repair mechanisms. A higher number of different markers and genes were detected in the comparison with the specialized dairy sheep. These genes play a role in complex biological processes: metabolic, homeostatic, neurological system, and macromolecular organization; such processes may possibly explain the evolution of gene function as a result of selection to improve milk yield. PMID- 28346056 TI - Alcohol and Drug Use and Aberrant Drug-Related Behavior Among Patients on Chronic Opioid Therapy. AB - OBJECTIVE: To better identify individuals on chronic opioid therapy (COT) at high risk for aberrant-drug related behavior (ADRB). We examine whether patients with low level alcohol and drug use have similar characteristics to those with alcohol and drug disorders. We then examined the relationship of alcohol and drug use to ADRBs among COT patients. METHODS: The sample was 972 randomly selected COT patients (age 21-80 years old) from a large health system in Northern California, USA, and interviewed in 2009. Logistic regression models were used to model the dependent variables of: alcohol use, illicit drug use, alcohol disorders, illicit drug disorders, and ADRBs. RESULTS: The odds of daily/weekly alcohol use were lower for those with a high daily opioid dose (120+ mg/day vs. <20 mg/day) (OR = 0.32, p < 0.010). Illicit drug disorders were associated with depression (OR = 2.31, p < .001) and being on a high daily opioid dose (OR = 5.51, p < .01). Participants with illicit drug use had higher odds of giving (OR = 2.57, p < 0.01) and receiving opioids from friends or family (OR = 3.25, p < 0.001), but disorder diagnoses were not associated with ADRBs. CONCLUSIONS: Findings reinforce that illicit drug use should be of high concern to clinicians prescribing opioids, and suggest it should be considered separately from alcohol use and alcohol disorders in the evaluation of ADRBs. Frequent alcohol use is low, but not uncommon, and suggests a need to discuss specific issues regarding safe use of opioids among persons who use alcohol that may differ from their risk of drug use. PMID- 28346057 TI - The role of germline variants in chemotherapy outcome in brain tumors: a systematic review of pharmacogenetic studies. AB - AIM: This systematic review provides an overview of publications concerning pharmacogenetic research in pediatric patients with medulloblastoma and low-grade glioma. MATERIALS & METHODS: Three electronic databases searches including a manual search were performed to identify studies investigating potential interactions between germline variants and chemotherapy efficacy and toxicity. RESULTS: Out of 3570 citations, 21 studies were included. Outcomes include overall survival, progression-free survival and treatment-related adverse events (n = 5), cisplatin-induced ototoxicity (n = 13) and vincristine-induced neurotoxicity (n = 3). CONCLUSION: This review shows that the number of pharmacogenetic studies in well-defined pediatric brain tumor cohorts is poor and studies often report conflicting results. Large-scale international collaborations allowing analysis of sufficiently sized cohorts are therefore very important for the future of personalized medicine in brain tumors. PMID- 28346055 TI - A to I editing in disease is not fake news. AB - Adenosine deaminases acting on RNA (ADARs) are zinc-containing enzymes that deaminate adenosine bases to inosines within dsRNA regions in transcripts. In short, structured dsRNA hairpins individual adenosine bases may be targeted specifically and edited with up to one hundred percent efficiency, leading to the production of alternative protein variants. However, the majority of editing events occur within longer stretches of dsRNA formed by pairing of repetitive sequences. Here, many different adenosine bases are potential targets but editing efficiency is usually much lower. Recent work shows that ADAR-mediated RNA editing is also required to prevent aberrant activation of antiviral innate immune sensors that detect viral dsRNA in the cytoplasm. Missense mutations in the ADAR1 RNA editing enzyme cause a fatal auto-inflammatory disease, Aicardi Goutieres syndrome (AGS) in affected children. In addition RNA editing by ADARs has been observed to increase in many cancers and also can contribute to vascular disease. Thus the role of RNA editing in the progression of various diseases can no longer be ignored. The ability of ADARs to alter the sequence of RNAs has also been used to artificially target model RNAs in vitro and in cells for RNA editing. Potentially this approach may be used to repair genetic defects and to alter genetic information at the RNA level. In this review we focus on the role of ADARs in disease development and progression and on their potential use to artificially modify RNAs in a targeted manner. PMID- 28346059 TI - Deferasirox pharmacogenetic influence on pharmacokinetic, efficacy and toxicity in a cohort of pediatric patients. AB - AIM: We aimed to evaluate the influence of genetic polymorphisms involved in deferasirox metabolism and transport on its pharmacokinetics and treatment toxicity, in a cohort of beta-thalassaemic children. PATIENTS & METHODS: Drug plasma concentrations were measured by a HPLC-UV method. Allelic discrimination for UGT1A1, UGT1A3, CYP1A1, CYP1A2, CYP2D6, MRP2 and BCRP1 polymorphisms was performed by real-time PCR. RESULTS: CYP1A1 rs2606345AA influenced Ctrough (p = 0.001) and t1/2 (p = 0.042), CYP1A1 rs4646903TC/CC (p = 0.005) and BCRP1 rs2231142GA/AA (p = 0.005) influenced Tmax and CYP2D6 rs1135840CG/GG influenced Cmax (p = 0.044). UGT1A1 rs887829TT (p = 0.002) and CYP1A2 rs762551CC (p = 0.019) resulted as predictive factor of ferritin levels and CYP1A1 rs2606345CA/AA (p = 0.021) and CYP1A2 rs762551AC/CC (p = 0.027) of liver iron concentration. CONCLUSION: Our data suggest the usefulness of deferasirox pharmacogenetics in pediatric treatment optimization. PMID- 28346060 TI - Stem cell-derived neurons in the development of targeted treatment for schizophrenia and bipolar disorder. AB - The recent advent of induced pluripotent stem cells has enabled the study of patient-specific and disease-related neurons in vitro and has facilitated new directions of inquiry into disease mechanisms. With these approaches, we now have the possibility of correlating ex vivo cellular phenotypes with individual patient response to treatment and/or side effects, which makes targeted treatments for schizophrenia and bipolar disorder a distinct prospect in the coming years. Here, we briefly review the current state of stem cell-based models and explore studies that are providing new insights into the disease biology of schizophrenia and bipolar disorder, which are laying the foundations for the development of novel targeted therapies. PMID- 28346061 TI - Understanding the contamination of food with mineral oil: the need for a confirmatory analytical and procedural approach. AB - The contamination of food by mineral oil hydrocarbons (MOHs) found in packaging is a long-running concern. A main source of MOHs in foods is the migration of mineral oil from recycled board into the packed food products. Consequently, the majority of food manufacturers have taken protective measures, e.g., by using virgin board instead of recycled fibres and, where feasible, introducing functional barriers to mitigate migration. Despite these protective measures, MOHs may still be observed in low amounts in certain food products, albeit due to different entry points across the food supply chain. In this study, we successfully apply gas chromatography coupled to mass spectrometry (GC-MS) to demonstrate, through marker compounds and the profile of the hydrocarbon response, the possible source of contamination using mainly chocolate and cereals as food matrices. The conventional liquid chromatography-one-dimensional GC coupled to a flame ionisation detector (LC-GC-FID) is a useful screening method, but in cases of positive samples it must be complemented by a confirmatory method such as, for example, GC-MS, allowing a verification of mineral oil contamination. The procedural approach proposed in this study entails profile analysis, marker identification, and interpretation and final quantification. PMID- 28346058 TI - Promising pharmacogenetic targets for treating alcohol use disorder: evidence from preclinical models. AB - Inherited genetic variants contribute to risk factors for developing an alcohol use disorder, and polymorphisms may inform precision medicine strategies for treating alcohol addiction. Targeting genetic mutations linked to alcohol phenotypes has provided promising initial evidence for reducing relapse rates in alcoholics. Although successful in some studies, there are conflicting findings and the reports of adverse effects may ultimately limit their clinical utility, suggesting that novel pharmacogenetic targets are necessary to advance precision medicine approaches. Here, we describe promising novel genetic variants derived from preclinical models of alcohol consumption and dependence that may uncover disease mechanisms that drive uncontrolled drinking and identify novel pharmacogenetic targets that facilitate therapeutic intervention for the treatment of alcohol use disorder. PMID- 28346062 TI - Dietary exposures for the safety assessment of seven emulsifiers commonly added to foods in the United States and implications for safety. AB - Dietary exposure assessment using food-consumption data and ingredient-use level is essential for assessing the safety of food ingredients. Dietary exposure estimates are compared with safe intake levels, such as the acceptable daily intake (ADI). The ADI is estimated by applying a safety factor to an experimentally determined no-observed-adverse-effect level of a test substance. Two food ingredients classified as emulsifiers, carboxymethylcellulose (CMC) and polysorbate 80 (P80), received attention recently due to their putative adverse effects on gut microbiota. Because no published dietary exposure estimates for commonly used emulsifiers exist for the US population, the current investigation focused on the estimation of dietary exposure to seven emulsifiers: CMC, P80, lecithin, mono- and diglycerides (MDGs), stearoyl lactylates, sucrose esters, and polyglycerol polyricinoleate. Using maximum-use levels obtained from publicly available sources, dietary exposures to these emulsifiers were estimated for the US population (aged 2 years and older) for two time periods (1999-2002 and 2003 10) using 1- and 2-day food-consumption data from the National Health and Nutrition Examination Survey, and 10-14-day food-consumption data from NPD Group, Inc.'s National Eating Trends - Nutrient Intake Database. Our analyses indicated that among the emulsifiers assessed, lecithin and MDGs have the highest mean exposures at about 60 and about 80 mg kg-1 bw day-1, respectively, whereas the exposure to CMC is half to one-third that of lecithin or MDGs; and the exposure to P80 is approximately half that of CMC. The review of available safety information such as ADIs established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA), in light of our updated dietary exposure estimates for these seven emulsifiers, did not raise safety concerns at the current specified levels of use. Additionally, by examining two time periods (1999-2002, 2003-10), it was concluded that there is no evidence that exposure levels to emulsifiers have substantially increased. PMID- 28346063 TI - Playing Some Video Games but Not Others Is Related to Cognitive Abilities: A Critique of Unsworth et al. (2015). PMID- 28346064 TI - Modeling and Simulation of Two Wheelchair Accessories for Pushing Doors. AB - Independent mobility is vital to individuals of all ages, and wheelchairs have proven to be great personal mobility devices. The tasks of opening and navigating through a door are trivial for healthy people, while the same tasks could be difficult for some wheelchair users. A wide range of intelligent wheelchair controllers and systems, robotic arms, or manipulator attachments integrated with wheelchairs have been developed for various applications, including manipulating door knobs. Unfortunately, the intelligent wheelchairs and robotic attachments are not widely available as commercial products. Therefore, the current manuscript presents the modeling and simulation of a novel but simple technology in the form of a passive wheelchair accessory (straight, arm-like with a single wheel, and arc-shaped with multiple wheels) for pushing doors open from a wheelchair. From the simulations using different wheel shapes and sizes, it was found that the arc-shaped accessory could push open the doors faster and with almost half the required force as compared to the arm-like accessory. Also, smaller spherical wheels were found to be best in terms of reaction forces on the wheels. Prototypes based on the arc-shaped accessory design will be manufactured and evaluated for pushing doors open and dodging or gliding other obstacles. PMID- 28346065 TI - Effect of ultrasonic treatment of palygorskite on the catalytic performance of Pd Cu/palygorskite catalyst for room temperature CO oxidation in humid circumstances. AB - Pd-Cu/palygorskite catalysts were prepared by a wet impregnation method using palygorskite (PC/N-Pal) and ultrasonic-treated palygorskite (PC/U-Pal) as the support. Their catalytic activities toward CO oxidation at room temperature and in humid circumstances were investigated. PC/U-Pal exhibits much higher catalytic activity and stability than PC/N-Pal under the conditions of 1.0 vol.% CO and 3.3 vol.% H2O in the feed gas. The X-ray diffraction results indicate that quartz impurities were eliminated from the Pal after the ultrasonic treatment, and more copper species exist in the form of Cu2Cl(OH)3 in PC/U-Pal. The temperature programmed reduction results suggest that there is an enhanced reducibility of PC/U-Pal after ultrasonic treatment. Furthermore, the ultrasonic treatment can properly decrease the hydrophilicity of the support and catalyst, which may also contribute to the excellent catalytic performance. PMID- 28346066 TI - Gratitude, psychological well-being, and perceptions of posttraumatic growth in adults who lost a parent in childhood. AB - Findings from an online survey of 350 adults who experienced early parental death showed that current dispositional gratitude was positively correlated with psychological well-being and posttraumatic growth and negatively correlated with depression. Further, 281 participants produced textual responses indicating they could remember the time following their parent's death. Increases in gratitude attributable to the experience of losing a parent were reported by 79% of these participants. They associated their increased gratitude with a newfound belief that life is precious and with greater appreciation for loved ones. Direction of change in gratitude was associated with psychological well-being, posttraumatic growth, and depression. PMID- 28346067 TI - Horseback riding therapy for a deafblind individual enabled by a haptic interface. AB - We present a haptic interface to help deafblind people to practice horseback riding as a recreational and therapeutic activity. Horseback riding is a form of therapy which can improve self-esteem and sensation of independence. It has been shown to benefit people with various medical conditions-including autism. However, in the case of deafblind riders, an interpreter must stand by at all times to communicate with the rider by touch. We developed a simple interface that enables deafblind people to enjoy horseback riding while the instructor is remotely providing cues, which improves their independence. Experiments demonstrated that an autistic deafblind individual exhibits similar responses to navigational cues as an unimpaired rider. Motivation is an important factor in therapy, and is frequently determinant of its outcome; therefore, the user attitude toward the therapy methods is key. The answers to questionnaires filled by the rider, family, and the instructor show that our technique gives the rider a greater sense of independence and more joy compared to standard riding where the instructor is walking along with the horse. PMID- 28346069 TI - The Rationale for Rejuvenation Research: Structuring the Debate. PMID- 28346068 TI - Institutional profile: University of Florida Health Personalized Medicine Program. AB - The University of Florida (UF) Health Personalized Medicine Program launched in 2012 with CYP2C19 genotyping for clopidogrel response at UF Health Shands Hospital. We have since expanded CYP2C19 genotyping to UF Health Jacksonville and established the infrastructure at UF Health to support clinical implementation for five additional gene-drug pairs: TPMT-thiopurines, IFNL3 (IL28B)-PEG IFN alpha-based regimens, CYP2D6-opioids, CYP2D6/CYP2C19-antidepressants and CYP2C19 proton pump inhibitors. We are contributing to the evidence based on outcomes with genotype-guided therapy through pragmatic studies of our clinical implementations. In addition, we have developed a broad array of educational programs for providers, trainees and students that incorporate personal genotype evaluation to enhance participant learning. PMID- 28346070 TI - Origin of disinfection by-products in cheese. AB - The disinfection of water, equipment and surfaces in a cheese factory is one of the factors that can originate disinfection by-products (DBPs) in cheese. This research has focused on studying cheese factories in order to evaluate the individual contribution of each step of the cheese-making process that can contribute to the presence of DBPs in cheese. Ten factories were selected according to their salting processes (brine or dry salting). Each factory was monitored by the collection of six representative samples (factory water supply, brine solution, milk, whey, curd and cheese) in which the concentrations of up to eight chemicals were detected. The study shows that contact with brine solutions containing significant levels of DBPs is the main source of these chemicals in cheese. A minor factor is the pasteurised milk used in their manufacture. PMID- 28346071 TI - Mineral composition and toxic element levels of muscle, liver and kidney of intensive (Swedish Landrace) and extensive (Mangulica) pigs from Serbia. AB - Mineral composition (Fe, Zn, Cu, Mn, Se, Cr, Co, Ni, Na, K, Mg, Ca) and toxic element levels (Cd, Pb, Hg, As) of soil, feed and tissue (muscle, liver and kidney) from intensive (Swedish Landrace, housed indoors, fed a known diet, 4 years) and extensive (Mangulica, free-roaming, non-specified diet, 7-8 months) pigs were determined by inductively coupled plasma mass spectrometry (ICP-MS). Controlled nutrition produced pigs with higher concentrations of most minerals (muscle: Mn, Se, K, Mg; liver: Zn, Cu, Mn, Se, Cr, Ca; kidney: Zn, Cu, Mn, Se, K, Mg), but for Fe the opposite trend was found. Long-term free-ranging pigs have a higher risk of contamination by toxic elements (Cd exceeded the maximum residue level in kidney). Principal component analysis and cluster analysis were used to assess the effect of different pig breed/lifestyle (pig type) on element composition of muscle, liver and kidney of pigs. Multivariate data analysis showed good discriminating capabilities. PMID- 28346072 TI - Regaining my new life: Daily lives of suicide-bereaved individuals. AB - This study aimed to develop a conceptual framework of the experience of persons who have lost a family member to suicide in Japan. The authors conducted in-depth interviews with 24 such family members. They conceptualized their experience as a process of regaining my new life. Initially, their lives were out of their hands, but gradually they learned striving skills and recuperative conditioning, and integrated the skills to regain their lives. Some participants eventually reached a state of living a redefined life. How individuals underwent this process varied. The authors identified two types of people dealing with this issue: dialoguers and mood changers. PMID- 28346073 TI - Detection of Clinically Significant Prostate Cancer: Short Dual-Pulse Sequence versus Standard Multiparametric MR Imaging-A Multireader Study. AB - Purpose To compare the diagnostic performance of a short dual-pulse sequence magnetic resonance (MR) imaging protocol versus a standard six-pulse sequence multiparametric MR imaging protocol for detection of clinically significant prostate cancer. Materials and Methods This HIPAA-compliant study was approved by the regional ethics committee. Between July 2013 and March 2015, 63 patients from a prospectively accrued study population who underwent MR imaging of the prostate including transverse T1-weighted; transverse, coronal, and sagittal T2-weighted; diffusion-weighted; and dynamic contrast material-enhanced MR imaging with a 3-T imager at a single institution were included in this retrospective study. The short MR imaging protocol image set consisted of transverse T2-weighted and diffusion-weighted images only. The standard MR imaging protocol image set contained images from all six pulse sequences. Three expert readers from different institutions assessed the likelihood of prostate cancer on a five-point scale. Diagnostic performance on a quadrant basis was assessed by using areas under the receiver operating characteristic curves, and differences were evaluated by using 83.8% confidence intervals. Intra- and interreader agreement was assessed by using the intraclass correlation coefficient. Transperineal template saturation biopsy served as the standard of reference. Results At histopathologic evaluation, 84 of 252 (33%) quadrants were positive for cancer in 38 of 63 (60%) men. There was no significant difference in detection of tumors larger than or equal to 0.5 mL for any of the readers of the short MR imaging protocol, with areas under the curve in the range of 0.74-0.81 (83.8% confidence interval [CI]: 0.64, 0.89), and for readers of the standard MR imaging protocol, areas under the curve were 0.71-0.77 (83.8% CI: 0.62, 0.86). Ranges for sensitivity were 0.76-0.95 (95% CI: 0.53, 0.99) and 0.76-0.86 (95% CI: 0.53, 0.97) and those for specificity were 0.84-0.90 (95% CI: 0.79, 0.94) and 0.82-0.90 (95% CI: 0.77, 0.94) for the short and standard MR protocols, respectively. Ranges for interreader agreement were 0.48-0.60 (83.8% CI: 0.41, 0.66) and 0.49 0.63 (83.8% CI: 0.42, 0.68) for the short and standard MR imaging protocols. Conclusion For the detection of clinically significant prostate cancer, no difference was found in the diagnostic performance of the short MR imaging protocol consisting of only transverse T2-weighted and diffusion-weighted imaging pulse sequences compared with that of a standard multiparametric MR imaging protocol. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28346075 TI - Hope and hopelessness as predictors of suicide ideation in Hungarian college students. AB - This study investigated whether hopelessness and dispositional hope predict suicide ideation in 395 Hungarian college students. Both hopelessness and hope uniquely predicted suicide ideation, a pattern that remained unchanged even after controlling for psychological symptoms. Moreover, a significant Hopelessness * Hope interaction predicted suicide ideation. Present findings highlight how hope buffers the association between hopelessness and suicide risk in college students. PMID- 28346076 TI - Meaning making after a near-death experience: The relevance of intrapsychic and interpersonal dynamics. AB - This study aims to investigate the processes used by individuals to integrate a near-death experience (NDE) and to discuss the use of a meaning-making component to help people who have had such experiences. A psychotherapist interviewed six individuals who reported having had a NDE. Transcripts of the interviews were coded using an interpretative phenomenological analysis. The authors identified intrapsychic and interpersonal dynamics implicated in the individuals' meaning making processes, and the problems encountered during their integration of the experience. Meaning-based approaches are a feasible theoretical framework for shedding light on the NDE and providing support for people who have lived through them. PMID- 28346074 TI - Germline genetic predictors of aromatase inhibitor concentrations, estrogen suppression and drug efficacy and toxicity in breast cancer patients. AB - The third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, are highly effective for the treatment of estrogen receptor-positive breast cancer in postmenopausal women. AIs inhibit the aromatase (CYP19A1) mediated production of estrogens. Most patients taking AIs achieve undetectable blood estrogen concentrations resulting in drug efficacy with tolerable side effects. However, some patients have suboptimal outcomes, which may be due, in part, to inherited germline genetic variants. This review summarizes published germline genetic associations with AI treatment outcomes including systemic AI concentrations, estrogenic response to AIs, AI treatment efficacy and AI treatment toxicities. Significant associations are highlighted with commentary about prioritization for future validation to identify pharmacogenetic predictors of AI treatment outcomes that can be used to inform personalized treatment decisions in patients with estrogen receptor-positive breast cancer. PMID- 28346078 TI - Molecular dynamics simulation of three plastic additives' diffusion in polyethylene terephthalate. AB - Accurate diffusion coefficient data of additives in a polymer are of paramount importance for estimating the migration of the additives over time. This paper shows how this diffusion coefficient can be estimated for three plastic additives [2-(2'-hydroxy-5'-methylphenyl) (UV-P), 2,6-di-tert-butyl-4-methylphenol (BHT) and di-(2-ethylhexyl) phthalate (DEHP)] in polyethylene terephthalate (PET) using the molecular dynamics (MD) simulation method. MD simulations were performed at temperatures of 293-433 K. The diffusion coefficient was calculated through the Einstein relationship connecting the data of mean-square displacement at different times. Comparison of the diffusion coefficients simulated by the MD simulation technique, predicted by the Piringer model and experiments, showed that, except for a few samples, the MD-simulated values were in agreement with the experimental values within one order of magnitude. Furthermore, the diffusion process for additives is discussed in detail, and four factors - the interaction energy between additive molecules and PET, fractional free volume, molecular shape and size, and self-diffusion of the polymer - are proposed to illustrate the microscopic diffusion mechanism. The movement trajectories of additives in PET cell models suggested that the additive molecules oscillate slowly rather than hopping for a long time. Occasionally, when a sufficiently large hole was created adjacently, the molecule could undergo spatial motion by jumping into the free-volume hole and consequently start a continuous oscillation and hop. The results indicate that MD simulation is a useful approach for predicting the microstructure and diffusion coefficient of plastic additives, and help to estimate the migration level of additives from PET packaging. PMID- 28346077 TI - Effects of Brief Messages About Antiretroviral Therapy and Condom Use Benefits Among Black and Latino MSM in Three U.S. Cities. AB - This pilot study examined effects of HIV prevention messages about self and partner benefits of antiretroviral therapy (ART) and condom effectiveness on increased intentions for behavior change. Data were from Messages4Men, a study examining prevention messages among 320 HIV-positive and 605 HIV-negative Black and Latino MSM. Men completed a computer-based assessment after message exposure, and multivariable models controlled for risky sex and demographics. A majority of HIV-positive men reported increased intentions for ART use; 22% reported partner benefit information was new. HIV-positive men with a detectable viral load had significantly greater adjusted odds of reporting intentions for ART use. Over half of HIV-negative MSM reported ART benefit information was new, and 88% reported increased intentions to discuss ART use with infected partners. Black MSM anticipated they would increase condom use in response to the self and partner benefit messages. Tailored messages on benefits of ART are needed for MSM. PMID- 28346079 TI - Patterns of Mental Health Care Utilization Among Sexual Orientation Minority Groups. AB - Prior studies of the utilization of mental health professionals by sexual minority populations have relied on data that are now dated or not nationally representative. These studies have also provided mixed findings regarding gender differences in the utilization of mental health professionals among sexual minority individuals. Using data from the 2013-2015 National Health Interview Surveys, this study investigates (1) how sexual minority individuals compare to heterosexual participants in their utilization of mental health professionals; and (2) gender differences in that utilization. The results indicate sexual minority individuals utilize mental health care professionals at higher rates than heterosexual individuals even after controlling for measures of mental health and other demographic characteristics; this is true for both men and women. However, gender moderates the sexual minority effect on utilization rates. Sexual minority men utilize mental health professionals at a high rate, such that their utilization rates are similar to sexual minority women, contrary to the gender gap seen among heterosexuals. PMID- 28346080 TI - A descriptive quantitative study of 7- and 8-year-old children's outdoor recreation, cold exposure and symptoms in winter in Northern Finland. AB - BACKGROUND: In Finland, children spend a lot of time outdoors in winter. Outdoor recreation in winter has a wide variety of effects on children's well-being. Although children are a subgroup that is vulnerable to cold exposure, remarkably little research has been done on the subject. OBJECTIVE: The aim of this study was to describe children's outdoor recreation, cold exposure and symptoms in winter in Northern Finland. DESIGN: This was a descriptive quantitative study. The participants consisted of 30 children aged 7-8 years who were living in the provinces of Lapland and Northern Ostrobothnia in Finland. Data were collected by using electronic data-logging thermometers fixed on children's outerwear for a month. The thermometers recorded the environmental temperature every five minutes and from that temperature data, we were able to discern the exact amount and duration of children's outdoor recreation. In addition, information on the children's cold symptoms was collected with structured daily entries. RESULTS: Cold weather was not an obstacle to children's outdoor activities in Finland. However, the duration of outdoor recreation shortened when the outdoor air temperature decreased. There were no significant differences between boys and girls in terms of time spent outdoors. Remarkably, every child reported symptoms associated with cold. Almost half of the children reported experiencing respiratory symptoms and some children also experienced cold pain and numbness. CONCLUSIONS: The results of this study illustrate the many and varied effects that cold exposure can have on children's health and well-being. In order to prevent negative health effects of cold exposure on children, structured prevention strategies are needed: therefore, children's exposure to cold should be studied more. Future research should also bring out more the positive health effects of outdoor recreation on children's growth and development.. PMID- 28346081 TI - Pneumocystis jiroveci pneumonia (PJP) in non-HIV immunocompromised individuals. AB - OBJECTIVES: PJP is a major cause of morbidity and mortality in immunocompromised individuals. Diagnosing PJP is often difficult because respiratory signs might be minimal or absent and the sensitivity of a chest X-ray (CXR) is low. We studied the clinical risk factors in order to increase awareness and facilitate the diagnosis. METHODS: We studied a prospective case series over a one year period (from 1 January 2015 to 1 January 2016) and did a retrospective analysis (from 2013 to 2016) of all PJP positive bronchoalveolar lavage (BAL) analysis. RESULTS: Seven patients with metastatic solid tumors were diagnosed with symptomatic PJP (based on positive polymerase chain reaction) over a one year period. The median age was 61 years. Three patients had brain metastasis. Four of them were on steroids, the median dose was 16 mg methylprednisolone with three of them at a tapered dose. Respiratory failure developed in four cases and prompted intensive care monitoring. Two patients needed non-invasive ventilation and the third patient was intubated and mechanically ventilated. No patient died of PJP. A retrospective analysis on microbiological results obtained from BAL in our hospital from 2013 to 2016 shows a striking high percentage PJP positivity in cancer patients (including hematologic cancers) of nearly 22% (15/69) as opposed to the overall number of PJP-positives 7.3% (59/803). DISCUSSION: The incidence of clinical PJP in patients treated for metastatic cancer is substantial. A high index of suspicion, especially in cases with unexplained respiratory symptoms, concurrent or recent use of steroids, a normal CXR and otherwise unexplained increased lactate dehydrogenase levels, is critical. The threshold for performing a CT-scan must be low and the diagnosis needs to be confirmed microbiologically. PMID- 28346082 TI - Depression and Risk for Problem Drinking in Latino Migrant Day Laborers. AB - BACKGROUND: Given the structural vulnerability of Latino migrant day laborers (LMDLs) to unstable and poorly paying work, harsh living conditions and frequent inability to support or even visit families in country of origin, psychological distress is a common response and one frequently implicated in risky outcomes such as problem drinking. OBJECTIVES: The purpose of this study was to examine the relation of three different forms of psychological distress to problem drinking in LMDLs: depression, anxiety, and desesperacion, the latter a popular Latino culture-based idiom of psychological distress. METHODS: A cross sectional survey of 344 LMDLs was conducted in the San Francisco Bay Area from January to June of 2014. Independent contributions of depression, anxiety, and desesperacion in explaining problem drinking as measured by a modified version of the AUDIT, were assessed using multiple linear regression analysis. RESULTS: Depression was significantly associated with risk for problem drinking while other forms of psychological distress were not. Conclusion/Importance: Findings provide stronger empirical support for the association between depression and problem drinking, a long suspected but under-demonstrated relationship in the literature on LMDLs. Implications for preventing problem drinking as well as mitigating psychological distress more generally for LMDLs are discussed. PMID- 28346083 TI - Logistic Regression Likelihood Ratio Test Analysis for Detecting Signals of Adverse Events in Post-market Safety Surveillance. AB - The Vaccine Adverse Event Reporting System (VAERS) and other product surveillance systems compile reports of product-associated adverse events (AEs), and these reports may include a wide range of information including age, gender, and concomitant vaccines. Controlling for possible confounding variables such as these is an important task when utilizing surveillance systems to monitor post market product safety. A common method for handling possible confounders is to compare observed product-AE combinations with adjusted baseline frequencies where the adjustments are made by stratifying on observable characteristics. Though approaches such as these have proven to be useful, in this article we propose a more flexible logistic regression approach which allows for covariates of all types rather than relying solely on stratification. Indeed, a main advantage of our approach is that the general regression framework provides flexibility to incorporate additional information such as demographic factors and concomitant vaccines. As part of our covariate-adjusted method, we outline a procedure for signal detection that accounts for multiple comparisons and controls the overall Type 1 error rate. To demonstrate the effectiveness of our approach, we illustrate our method with an example involving febrile convulsion, and we further evaluate its performance in a series of simulation studies. PMID- 28346084 TI - Is there a role for pharmacogenetics in the dosing of fentanyl? PMID- 28346085 TI - SLAS Discovery. PMID- 28346086 TI - A Small-Molecule Microarray Approach for the Identification of E2 Enzyme Inhibitors in Ubiquitin-Like Conjugation Pathways. AB - E2 enzymes in ubiquitin-like conjugation pathways are important, highly challenging pharmacological targets, and despite significant efforts, few noncovalent modulators have been discovered. Small-molecule microarray (SMM) based screening was employed to identify an inhibitor of the "undruggable" small ubiquitin-like modifier (SUMO) E2 enzyme Ubc9. The inhibitor, a degradation product from a commercial screening collection, was chemically synthesized and evaluated in biochemical, mechanistic, and structure-activity relationship studies. Binding to Ubc9 was confirmed through the use of ligand-detected nuclear magnetic resonance, and inhibition of sumoylation in a reconstituted enzymatic cascade was found to occur with an IC50 of 75 uM. This work establishes the utility of the SMM approach for identifying inhibitors of E2 enzymes, targets with few known small-molecule modulators. PMID- 28346087 TI - PubChem BioAssay: A Decade's Development toward Open High-Throughput Screening Data Sharing. AB - High-throughput screening (HTS) is now routinely conducted for drug discovery by both pharmaceutical companies and screening centers at academic institutions and universities. Rapid advance in assay development, robot automation, and computer technology has led to the generation of terabytes of data in screening laboratories. Despite the technology development toward HTS productivity, fewer efforts were devoted to HTS data integration and sharing. As a result, the huge amount of HTS data was rarely made available to the public. To fill this gap, the PubChem BioAssay database ( https://www.ncbi.nlm.nih.gov/pcassay/ ) was set up in 2004 to provide open access to the screening results tested on chemicals and RNAi reagents. With more than 10 years' development and contributions from the community, PubChem has now become the largest public repository for chemical structures and biological data, which provides an information platform to worldwide researchers supporting drug development, medicinal chemistry study, and chemical biology research. This work presents a review of the HTS data content in the PubChem BioAssay database and the progress of data deposition to stimulate knowledge discovery and data sharing. It also provides a description of the database's data standard and basic utilities facilitating information access and use for new users. PMID- 28346088 TI - A 1536-Well 3D Viability Assay to Assess the Cytotoxic Effect of Drugs on Spheroids. AB - Evaluation of drug cytotoxicity traditionally relies on use of cell monolayers, which are easily miniaturized to the 1536-well plate format. Three-dimensional (3D) cell culture models have recently gained popularity thanks to their ability to better mimic the complexity of in vivo systems. Despite growing interest in these more physiologically relevant and highly predictive cell-based models for compound profiling and drug discovery, 3D assays are currently performed in a medium- to low-throughput format, either in 96-well or 384-well plates. Here, we describe the design and implementation of a novel high-throughput screening (HTS) compatible 1536-well plate assay that enables the parallel formation, size monitoring and viability assessment of 3D spheroids in a highly consistent manner. Custom-made plates featuring an ultra-low-attachment surface and round bottom wells were evaluated for their compatibility with HTS requirements through a luminescence-based cytotoxicity pilot screen of ~3300 drugs from approved drug and National Cancer Institute (NCI) collections. As anticipated, results from this screen were significantly different from a parallel screen performed on cell monolayers. With the ability to achieve an average Z' factor greater than 0.5, this automation-friendly assay can be implemented to either profile lead compounds in a more economical plate format or to interrogate large compound libraries by ultra-HTS (uHTS). PMID- 28346089 TI - A Chemogenomic Screening Platform Used to Identify Chemotypes Perturbing HSP90 Pathways. AB - Compounds that modulate the heat shock protein (HSP) network have potential in a broad range of research applications and diseases. A yeast-based liquid culture assay that measured time-dependent turbidity enabled the high-throughput screening of different Saccharomyces cerevisae strains to identify HSP modulators with unique molecular mechanisms. A focused set of four strains, with differing sensitivities to Hsp90 inhibitors, was used to screen a compound library of 3680 compounds. Computed turbidity curve functions were used to classify strain responses and sensitivity to chemical effects across the compound library. Filtering based on single-strain selectivity identified nine compounds as potential heat shock modulators, including the known Hsp90 inhibitor macbecin. Haploid yeast deletion strains (360), mined from previous Hsp90 inhibitor yeast screens and heat shock protein interaction data, were screened for differential sensitivities to known N-terminal ATP site-directed Hsp90 inhibitors to reveal functional distinctions. Strains demonstrating differential sensitivity (13) to Hsp90 inhibitors were used to prioritize primary screen hit compounds, with NSC145366 emerging as the lead hit. Our follow-up biochemical and functional studies show that NSC145366 directly interacts and inhibits the C-terminus of Hsp90, validating the platform as a powerful approach for early-stage identification of bioactive modulators of heat shock-dependent pathways. PMID- 28346090 TI - Identifying Inhibitors of the Hsp90-Aha1 Protein Complex, a Potential Target to Drug Cystic Fibrosis, by Alpha Technology. AB - Deletion of a single phenylalanine residue at position 508 of the protein CFTR (cystic fibrosis transmembrane conductance regulator), a chloride channel in lung epithelium, is the most common cause for cystic fibrosis. As a consequence, folding of the CFTRDeltaF508 protein and delivery to the cell surface are compromised, resulting in degradation of the polypeptide. Accordingly, decreased surface presence of CFTRDeltaF508 causes impaired chloride ion conductivity and is associated with mucus accumulation, a hallmark of cystic fibrosis. Molecular chaperones such as Hsp90 and its co-chaperone partner Aha1 are thought to play a key role in targeting folding-deficient CFTRDeltaF508 for degradation. Thus, pharmacologic manipulation to inhibit Hsp90-Aha1 chaperone complex formation appears beneficial to inhibit proteolysis of CFTRDeltaF508 and rescue its residual chloride channel activity. Therefore, we have screened a collection of 14,400 druglike chemical compounds for inhibitors of the Hsp90-Aha1 complex by amplified luminescence proximity homogeneous assay (Alpha). We identified two druglike molecules that showed promising results when we tested their ability to restore chloride channel activity in culture cells expressing the mutant CFTRDeltaF508 protein. The two molecules were most effective in combination with the corrector VX-809 and may therefore serve as a lead compound that can be further developed into a drug to treat cystic fibrosis patients. PMID- 28346091 TI - A High-Throughput Screening Model of the Tumor Microenvironment for Ovarian Cancer Cell Growth. AB - The tumor microenvironment plays an important role in the processes of tumor growth, metastasis, and drug resistance. We have used a multilayered 3D primary cell culture model that reproduces the human ovarian cancer metastatic microenvironment to study the effect of the microenvironment on the pharmacological responses of different classes of drugs on cancer cell proliferation. A collection of oncology drugs was screened to identify compounds that inhibited the proliferation of ovarian cancer cells growing as monolayers or forming spheroids, on plastic and on a 3D microenvironment culture model of the omentum metastatic site, and also cells already in preformed spheroids. Target based analysis of the pharmacological responses revealed that several classes of targets were more efficacious in cancer cells growing in the absence of the metastatic microenvironment, and other target classes were less efficacious in cancer cells in preformed spheres compared to forming spheroid cultures. These findings show that both the cellular context of the tumor microenvironment and cell adhesion mode have an essential role in cancer cell drug resistance. Therefore, it is important to perform screens for new drugs using model systems that more faithfully recapitulate the tissue composition at the site of tumor growth and metastasis. PMID- 28346092 TI - Screening for Protein-Protein Interaction Inhibitors Using a Bioluminescence Resonance Energy Transfer (BRET)-Based Assay in Yeast. AB - The bioluminescence resonance energy transfer (BRET) technology is a widely used live cell-based method for monitoring protein-protein interactions as well as conformational changes within proteins or molecular complexes. Considering the emergence of protein-protein interactions as a new promising class of therapeutic targets, we have adapted the BRET method in budding yeast. In this technical note, we describe the advantages of using this simple eukaryotic model rather than mammalian cells to perform high-throughput screening of chemical compound collections: genetic tractability, tolerance to solvent, rapidity, and no need of expensive robotic systems. Here, the HDM2/p53 interaction, related to cancer, is used to highlight the interest of this technology in yeast. Sharing the protocol of this BRET-based assay with the scientific community will extend its application to other protein-protein interactions, even though it is toxic for mammalian cells, in order to discover promising therapeutic candidates. PMID- 28346093 TI - A Label-Free Continuous Fluorescence-Based Assay for Monitoring Ornithine Decarboxylase Activity with a Synthetic Putrescine Receptor. AB - Polyamines play an important role in cell growth, differentiation, and cancer development, and the biosynthetic pathway of polyamines is established as a drug target for the treatment of parasitic diseases, neoplasia, and cancer chemoprevention. The key enzyme in polyamine biosynthesis is ornithine decarboxylase (ODC). We report herein an analytical method for the continuous fluorescence monitoring of ODC activity based on the supramolecular receptor cucurbit[6]uril (CB6) and the fluorescent dye trans-4-[4-(dimethylamino)styryl]-1 methylpyridinium iodide (DSMI). CB6 has a significantly higher binding constant to the ODC product putrescine (>107 M-1) than to the substrate L-ornithine (340 M 1). This enables real-time monitoring of the enzymatic reaction through a continuous fluorescence change caused by dye displacement from the macrocycle by the formed product, which allowed a straightforward determination of enzyme kinetic parameters ( kcat = 0.12 s-1 and KM = 24 uM) and inhibition constants of the two ODC inhibitors alpha-difluoromethylornithine (DFMO) and epigallocatechin gallate (EGCG). The potential for high-throughput screening (HTS) was demonstrated by excellent Z' factors (>0.9) in a microplate reader format, and the sensitivity of the assay is comparable to or better than most established complementary methods, which invariably have the disadvantage of not being compatible with direct implementation and upscaling to HTS format in the drug discovery process. PMID- 28346094 TI - Drug Library Screening for the Identification of Ionophores That Correct the Mistrafficking Disorder Associated with Oxalosis Kidney Disease. AB - Primary hyperoxaluria is the underlying cause of oxalosis and is a life threatening autosomal recessive disease, for which treatment may require dialysis or dual liver-kidney transplantation. The most common primary hyperoxaluria type 1 (PH1) is caused by genetic mutations of a liver-specific enzyme alanine:glyoxylate aminotransferase (AGT), which results in the misrouting of AGT from the peroxisomes to the mitochondria. Pharmacoperones are small molecules with the ability to modify misfolded proteins and route them correctly within the cells, which may present an effective strategy to treat AGT misrouting in PH1 disorders. We miniaturized a cell-based high-content assay into 1536-well plate format and screened ~4200 pharmacologically relevant compounds including Food and Drug Administration, European Union, and Japanese-approved drugs. This assay employs CHO cells stably expressing AGT-170, a mutant that predominantly resides in the mitochondria, where we monitor for its relocation to the peroxisomes through automated image acquisition and analysis. The miniaturized 1536-well assay yielded a Z' averaging 0.70 +/- 0.07. Three drugs were identified as potential pharmacoperones from this pilot screen, demonstrating the applicability of this assay for large-scale high-throughput screening. PMID- 28346095 TI - Identification by High-Throughput Screening of Pseudomonas Acyl-Coenzyme A Synthetase Inhibitors. AB - Pseudomonas infections are common among hospitalized, immunocompromised, and chronic lung disease patients. These infections are recalcitrant to common antibacterial therapies due to inherent antibiotic resistance. To meet the need of new anti- Pseudomonas drugs, a sensitive, homogenous, and robust assay was developed with the aim of identifying inhibitors of acyl-coenzyme A synthetases (ACSs) from Pseudomonas. Given the importance of fatty acids for in vivo nutrition of Pseudomonas, such inhibitors might have the potential to reduce the bacterial fitness during infection. The assay, based on a coupled reaction between the Pseudomonas spp. ACS and the firefly luciferase, allowed the identification of three classes of inhibitors by screening of a diverse compound collection. These compounds were confirmed to reversibly bind ACS with potencies in the micromolar range. Two classes were found to compete with acyl-coenzyme A, while the third one was competitive with fatty acid binding. Although these compounds inhibit the bacterial ACS in cell-free assays, they show modest or no effect on Pseudomonas growth in vitro. PMID- 28346096 TI - A Novel Multiparametric Drug-Scoring Method for High-Throughput Screening of 3D Multicellular Tumor Spheroids Using the Celigo Image Cytometer. AB - Three-dimensional (3D) tumor models have been increasingly used to investigate and characterize cancer drug compounds. The ability to perform high-throughput screening of 3D multicellular tumor spheroids (MCTS) can highly improve the efficiency and cost-effectiveness of discovering potential cancer drug candidates. Previously, the Celigo Image Cytometer has demonstrated a novel method for high-throughput screening of 3D multicellular tumor spheroids. In this work, we employed the Celigo Image Cytometer to examine the effects of 14 cancer drug compounds on 3D MCTS of the glioblastoma cell line U87MG in 384-well plates. Using parameters such as MCTS diameter and invasion area, growth and invasion were monitored for 9 and 3 d, respectively. Furthermore, fluorescent staining with calcein AM, propidium iodide, Hoechst 33342, and caspase 3/7 was performed at day 9 posttreatment to measure viability and apoptosis. Using the kinetic and endpoint data generated, we created a novel multiparametric drug-scoring system for 3D MCTS that can be used to identify and classify potential drug candidates earlier in the drug discovery process. Furthermore, the combination of quantitative and qualitative image data can be used to delineate differences between drugs that induce cytotoxic and cytostatic effects. The 3D MCTS-based multiparametric scoring method described here can provide an alternative screening method to better qualify tested drug compounds. PMID- 28346097 TI - An Optimized 3D Coculture Assay for Preclinical Testing of Pro- and Antiangiogenic Drugs. AB - Angiogenesis is a promising target for anticancer therapies, but also for treating other diseases with pathologic vessel development. Targeting the vascular endothelial growth factor (VEGF) pathway did not proof as effective as expected due to emerging intrinsic resistance mechanisms, as well as stromal contributions leading to drug insensitivity. Therefore, alternative strategies affecting the interaction of endothelial cells (ECs) with other stromal cells seem to be more promising. Human preclinical in vitro angiogenesis models successfully recapitulating these interactions are rare, and two-dimensional (2D) cell cultures cannot mimic tissue architecture in vivo. Consequently, models combining three-dimensionality with heterotypic cell interaction seem to be better suited. Here, we report on an improved human fibroblast-EC coculture assay mimicking sprouting angiogenesis from EC-covered microbeads resembling existing endothelial structures. Culture conditions were optimized to assess pro- and antiangiogenic compounds. Important characteristics of angiogenesis, that is, the number of sprouts and branch points, sprout length protrusion, and overall vessel structure areas, were quantified. Notably, the endothelial sprouts display lumen formation and basal membrane establishment. In this model, angiogenesis can be inhibited by genetic interference of pro-angiogenic factors expressed in the fibroblasts. Moreover, bona fide antiangiogenic drugs decreased, whereas pro angiogenic factors increased vessel formation in 24-well and 96-well settings, demonstrating the applicability for screening approaches. PMID- 28346098 TI - Filter Plate-Based Screening of MIP SPE Materials for Capture of the Biomarker Pro-Gastrin-Releasing Peptide. AB - Affinity-based solid-phase extraction (SPE) is an attractive low-cost sample preparation strategy for biomarker analysis. Molecularly imprinted polymers (MIPs) as affinity sorbents offer unique opportunities for affinity SPE, due to their low manufacturing cost and high robustness. A limitation is the prediction of their affinity; therefore, screening of analyte recovery and specificity within a large range of SPE conditions is important in order to ensure high sensitivity detection and assay reproducibility. Here, a u-SPE method for screening of the MIP-SPE materials using a commercial 384-well filter plate is presented. The method allows for rapid and automated screening using 10-30 uL of packed SPE sorbent per well and sample volumes in the range of 10-70 uL. This enables screening of many different SPE sorbents while simultaneously identifying optimal SPE conditions. In addition, the 384-well format also facilitates detection with a multitude of analytical platforms. Performance of the u-MIP-SPE method was investigated using a series of MIPs designed to capture pro-gastrin releasing peptide (ProGRP). Fractions coming from sample load, cartridge wash, and elution were collected and analyzed using mass spectrometry (MS). The top performing MIPs were identified, together with proper SPE conditions. PMID- 28346100 TI - Robotic Mammosphere Assay for High-Throughput Screening in Triple-Negative Breast Cancer. AB - In order to identify novel treatment principles specifically affecting cancer stem cells in triple-negative breast cancer, we have developed a high-throughput screening method based on the mammosphere and anoikis resistance assays allowing us to screen compounds using a functional readout. The assay was validated against manual protocols and through the use of positive controls, such as the response to hypoxia and treatment with the known cancer stem cell-targeting compound salinomycin. Manual and robotic procedures were compared and produced similar results in cell handling, cell cultures, and counting techniques, with no statistically significant difference produced from either method. The variance between samples processed manually versus robotically was no greater than 0.012, while Levene's test of significance was 0.2, indicating no significant difference between mammosphere data produced manually or robotically. Through the screening of 989 FDA-approved drugs and a follow-up screen assessing the antineoplastic subgroup, we have identified three therapeutic compounds with the ability to modulate the breast cancer stem cell fraction in the triple-negative breast cancer cell line MDA-MB-231, highlighting their potential usage as stem cell specific adjuvant treatments. PMID- 28346101 TI - Semiautomatic High-Content Analysis of Complex Images from Cocultures of Vascular Smooth Muscle Cells and Macrophages: A CellProfiler Showcase. AB - Automatization in microscopy, cell culture, and the ease of digital imagery allow obtainment of more information from single samples and upscaling of image-based analysis to high-content approaches. Simple segmentation algorithms of biological imagery are nowadays widely spread in biomedical research, but processing of complex sample structures, for example, variable sample compositions, cell shapes, and sizes, and rare events remains a difficult task. As there is no perfect method for image segmentation and fully automatic image analysis of complex content, we aimed to succeed by identification of unique and reliable features within the sample. Through exemplary use of a coculture of vascular smooth muscle cells (VSMCs) and macrophages (MPs), we demonstrate how rare interactions within this highly variable sample type can be analyzed. Because of limitations in immunocytochemistry in our specific setup, we developed a semiautomatic approach to examine the interaction of lipid-laden MPs with VSMCs under hypoxic conditions based on nuclei morphology by high-content analysis using the open-source software CellProfiler ( www.cellprofiler.org ). We provide evidence that, in comparison with fully automatic analysis, a low threshold within the analysis workflow and subsequent manual control save time, while providing more objective and reliable results. PMID- 28346099 TI - Development of Novel Cell Lines for High-Throughput Screening to Detect Estrogen Related Receptor Alpha Modulators. AB - Estrogen-related receptor alpha (ERRalpha), the first orphan nuclear receptor discovered, is crucial for the control of cellular energy metabolism. ERRalpha and its coactivator, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha), are required for rapid energy production in response to environmental challenges. They have been implicated in the etiology of metabolic disorders such as type 2 diabetes and metabolic syndrome. ERRalpha also plays a role in the pathogenesis of breast cancer. Identification of compounds that modulate ERRalpha signaling may elucidate environmental factors associated with these diseases. Therefore, we developed stable cell lines containing an intact ERRalpha signaling pathway, with and without the coactivator PGC-1alpha, to use as high-throughput screening tools to detect ERRalpha modulators. The lentiviral PGC-1alpha expression constructs and ERRalpha multiple hormone response element (MHRE) reporters were introduced into HEK293T cells that express endogenous ERRalpha. A cell line expressing the reporter alone was designated "ERR." A second cell line expressing both reporter and PGC-1alpha was named "PGC/ERR." Initial screenings of the Library of Pharmacologically Active Compounds (LOPAC) identified 33 ERR and 22 PGC/ERR agonists, and 54 ERR and 15 PGC/ERR antagonists. Several potent ERRalpha agonists were dietary plant compounds (e.g., genistein). In conclusion, these cell lines are suitable for high-throughput screens to identify environmental chemicals affecting metabolic pathways and breast cancer progression. PMID- 28346102 TI - Phage Display-Derived Ligand for Mucosal Transcytotic Receptor GP-2 Promotes Antigen Delivery to M Cells and Induces Antigen-Specific Immune Response. AB - Successful oral immunization depends on efficient delivery of antigens (Ags) to the mucosal immune induction site. Glycoprotein-2 (GP-2) is an integral membrane protein that is expressed specifically on M cells within follicle-associated epithelium (FAE) and serves as transcytotic receptor for luminal Ags. In this study, we selected peptide ligands against recombinant human GP-2 by screening a phage display library and evaluated their interaction with GP-2 in vitro and ex vivo. Selected peptides were conjugated to the C-terminal of enhanced green fluorescence protein (EGFP) and evaluated for their ability to induce an immune response in mice. One of our selected peptides, Gb-1, showed high binding affinity to GP-2 and, when fused to EGFP, significantly increased the uptake of EGFP by M cells compared to EGFP alone. After oral administration, the Gb1-EGFP fusion induced efficient mucosal and systemic immune responses in mice measured at the level of antigen-specific serum and fecal antibodies, cytokine secretion, and lymphocyte proliferation. Furthermore, the IgG subclasses and cytokine secretion showed that ligand Gb-1 induced a Th2-type immune response. Collectively, our findings suggest that the ligand we selected through phage library screening is capable of targeting Ags to GP-2 on M cells and can be used as an oral vaccine adjuvant. PMID- 28346103 TI - Discovery of Novel Gq-Biased LPA1 Negative Allosteric Modulators. AB - Lysophosphatidic acid (LPA) activates the G-protein-coupled receptor LPA1, which regulates various cellular processes, including cell proliferation and migration. Although LPA1 transduces cellular responses via Gq, Gi, and G12/13, associations between these signaling molecules and cellular phenotypes remain poorly characterized due to the lack of signal-specific pharmacological tools. Here, we characterized novel signal-biased modulators using multiple assays, including label-free impedance assays. LPA caused dramatic changes in cellular impedance in LPA1-expressing recombinant cells, which were susceptible to G-protein and protein kinase inhibitors. Subsequently, Gq-biased LPA1 negative allosteric modulators (NAMs) were identified using high-throughput screening, and a nonbiased antagonist differently affected the LPA-induced cellular impedance. These NAMs provide pharmacological tools for further investigations of the biology of LPA1. PMID- 28346104 TI - Bioengineered 3D Glial Cell Culture Systems and Applications for Neurodegeneration and Neuroinflammation. AB - Neurodegeneration and neuroinflammation are key features in a range of chronic central nervous system (CNS) diseases such as Alzheimer's and Parkinson's disease, as well as acute conditions like stroke and traumatic brain injury, for which there remains significant unmet clinical need. It is now well recognized that current cell culture methodologies are limited in their ability to recapitulate the cellular environment that is present in vivo, and there is a growing body of evidence to show that three-dimensional (3D) culture systems represent a more physiologically accurate model than traditional two-dimensional (2D) cultures. Given the complexity of the environment from which cells originate, and their various cell-cell and cell-matrix interactions, it is important to develop models that can be controlled and reproducible for drug discovery. 3D cell models have now been developed for almost all CNS cell types, including neurons, astrocytes, microglia, and oligodendrocyte cells. This review will highlight a number of current and emerging techniques for the culture of astrocytes and microglia, glial cell types with a critical role in neurodegenerative and neuroinflammatory conditions. We describe recent advances in glial cell culture using electrospun polymers and hydrogel macromolecules, and highlight how these novel culture environments influence astrocyte and microglial phenotypes in vitro, as compared to traditional 2D systems. These models will be explored to illuminate current trends in the techniques used to create 3D environments for application in research and drug discovery focused on astrocytes and microglial cells. PMID- 28346105 TI - High-Throughput Clonogenic Analysis of 3D-Cultured Patient-Derived Cells with a Micropillar and Microwell Chip. AB - A high-throughput clonogenic assay with a micropillar-microwell chip platform is proposed by using the colony area of glioblastoma multiforme (GBM) patient derived cells (PDCs) from colony images. Unlike conventional cell lines, PDCs from the tumor are composed of heterogeneous cell populations, and some clonogenic populations form colonies during culture while the rest die off or remain unchanged, thus causing the diverse distribution of colony size. Therefore, area-based analysis of the total colonies is not sufficient to estimate total cell viability or toxicity responses. In this work, the average and standard deviation of an individual colony's area calculated from the colony images were used as indicators for cell clonogenicity and heterogeneity, respectively. Two parameters (the total and average area of colonies) were compared to draw the colony's growth curve and measure a doubling time and dose response curve (IC50). Based on both analyses of two PDCs, 464T PDCs show a higher heterogeneity and clonogenicity than 448T PDCs. The differences in the doubling time and the IC50 according to the analysis methods suggest that the average area of colonies, rather than their total area, is suitable for heterogeneous and clonogenic samples. PMID- 28346106 TI - Isolation and Characterization of a Distinct Subpopulation from the WM115 Cell Line That Resembles In Vitro Properties of Melanoma Cancer Stem Cells. AB - Despite key advances in cancer therapies, malignant tumors, such as melanoma, continue to be one of the leading causes of mortality. Recent debate on whether cancer can originate from a tumor-initiating subpopulation has permeated oncology and stem cell research. It has been well established that primary and immortalized tumor cells consist of heterogeneous cell populations. The profound effect of tumor heterogeneity on tumor growth and drug resistance remains elusive, but it is highly likely that subpopulations of cancer cells have different capabilities of self-renewal and drug resistance. Discrepancies between excellent in vitro potency and efficacy and poor patient response have been observed on multiple cancer therapeutics. Although this observation can be attributed to many factors, a better understanding of the contribution from subpopulations within a cancer will help bridge the gap between in vitro assay results and patient prognosis. To comprehend this impact, it is critical to isolate and characterize cancer subpopulations that possess higher growth and drug resistance properties so that novel therapeutics can be developed to eventually eradicate all cancer cells. In this article, we describe a method to enrich a subpopulation, CB4, from the melanoma cell line WM115. CB4 exhibited higher anchorage-independent growth, higher survival under serum starvation condition, and lower drug sensitivity to commonly used melanoma treatment compared with WM115. Details of functional properties and gene expression of CB4 compared with WM115 are reported. Our study demonstrates that it is feasible to isolate and enrich a subpopulation that exhibits higher growth capacity and treatment resistance from an immortalized tumor cell line. PMID- 28346107 TI - A High-Throughput Method for Measuring Drug Residence Time Using the Transcreener ADP Assay. AB - Analysis of drug-target residence times during drug development can result in improved efficacy, increased therapeutic window, and reduced side effects. Residence time can be estimated as the reciprocal of the dissociation rate ( koff) of an inhibitor from its target. The traditional methods for measuring koff require synthesis of labeled ligands or low-throughput label-free methods. To provide an alternative that is better suited to an automated high-throughput screening (HTS) environment, we adapted a classic "jump dilution" catalytic assay method for determination of koff values for kinase inhibitor drugs. We used the Transcreener ADP2 Kinase assay as a universal, homogenous method to monitor the recovery of kinase activity as the drugs dissociated from preformed inhibitor kinase complexes. We measured residence times for several drugs that bind the epidermal growth factor receptor (EGFR), ABL1, and Aurora kinases and found that the rank ordering of inhibitor koff values correlated with literature values determined using ligand binding assays. Moreover, very similar results were obtained using the Transcreener assay with fluorescence polarization (FP), fluorescence intensity (FI), and time-resolved Forster resonance energy transfer (TR-FRET) detection modes. This HTS-compatible, generic assay method should facilitate the use of residence time as a parameter for compound prioritization and optimization early in kinase drug discovery programs. PMID- 28346108 TI - Don't Shoot the Messenger: Still No Evidence That Video-Game Experience Is Related to Cognitive Abilities-A Reply to Green et al. (2017). PMID- 28346109 TI - Assessing process of paediatric care in a resource-limited setting: a cross sectional audit of district hospitals in Rwanda. AB - BACKGROUND: Routine assessment of quality of care helps identify deficiencies which need to be improved. While gaps in the emergency care of children have been documented across sub-Saharan Africa, data from Rwanda are lacking. OBJECTIVE: To assess the care of sick infants and children admitted to Rwandan district hospitals and the extent to which it follows currently recommended clinical practice guidelines in Rwanda. METHODS: Data were gathered during a retrospective cross-sectional audit of eight district hospitals across Rwanda in 2012/2013. Medical records were randomly selected from each hospital and were reviewed to assess the process of care, focusing on the leading causes of under-5 mortality, including neonatal conditions, pneumonia, malaria and dehydration/diarrhoea. RESULTS: Altogether, 522 medical records were reviewed. Overall completion of a structured neonatal admission record was above 85% (range 78.6-90.0%) and its use was associated with better documentation of key neonatal signs (median score 6/8 and 2/8 when used and not used, respectively). Deficiencies in the processes of care were identified across hospitals and there were rural/urban disparities for some indicators. For example, neonates admitted to urban district hospitals were more likely to receive treatment consistent with currently recommended guidelines [e.g. gentamicin (OR 2.52, 95% CI 1.03-6.43) and fluids (OR 2.69, 95% CI 1.2 6.2)] than those in rural hospitals. Likewise, children with pneumonia admitted to urban hospitals were more likely to receive the correct dosage of gentamicin (OR 4.47, 95% CI 1.21-25.1) and to have their treatment monitored (OR 3.75, 95% CI 1.57-8.3) than in rural hospitals. Furthermore, children diagnosed with malaria and admitted to urban hospitals were more likely to have their treatment (OR 2.7, 95% CI 1.15-6.41) monitored than those in rural hospitals. CONCLUSIONS: Substantial gaps were identified in the process of neonatal and paediatric care across district hospitals in Rwanda. There is a need to (i) train health care professionals in providing neonatal and paediatric care according to nationally adopted clinical practice guidelines (e.g. ETAT+); (ii) establish a supervision and mentoring programme to ensure that the guidelines are available and used appropriately in district hospitals; and (iii) use admission checklists (e.g. neonatal and paediatric admission records) in district hospitals. PMID- 28346110 TI - FDA Approval of Nusinersen for Spinal Muscular Atrophy Makes 2016 the Year of Splice Modulating Oligonucleotides. PMID- 28346111 TI - Seeing and Thinking in Studies of Embodied "Perception". PMID- 28346112 TI - A Growing Disconnection From Nature Is Evident in Cultural Products. AB - Human connection with nature is widely believed to be in decline even though empirical evidence is scarce on the magnitude and historical pattern of the change. Studying works of popular culture in English throughout the 20th century and later, we have documented a cultural shift away from nature that begins in the 1950s. Since then, references to nature have been decreasing steadily in fiction books, song lyrics, and film storylines, whereas references to the human made environment have not. The observed temporal pattern is consistent with the explanatory role of increased virtual and indoors recreation options (e.g., television, video games) in the disconnect from nature, and it is inconsistent with a pure urbanization account. These findings are cause for concern, not only because they imply foregone physical and psychological benefits from engagement with nature, but also because cultural products are agents of socialization that can evoke curiosity, respect, and concern for the natural world. PMID- 28346113 TI - Wisdom in Context. AB - Philosophers and psychological scientists have converged on the idea that wisdom involves certain aspects of thinking (e.g., intellectual humility, recognition of uncertainty and change), enabling application of knowledge to life challenges. Empirical evidence indicates that people's ability to think wisely varies dramatically across experiential contexts that they encounter over the life span. Moreover, wise thinking varies from one situation to another, with self-focused contexts inhibiting wise thinking. Experiments can show ways to buffer thinking against bias in cases in which self-interests are unavoidable. Specifically, an ego-decentering cognitive mind-set enables wise thinking about personally meaningful issues. It appears that experiential, situational, and cultural factors are even more powerful in shaping wisdom than previously imagined. Focus on such contextual factors sheds new light on the processes underlying wise thought and its development, helps to integrate different approaches to studying wisdom, and has implications for measurement and development of wisdom-enhancing interventions. PMID- 28346114 TI - Status-Based Identity. AB - Psychological research on socioeconomic status (SES) has grown significantly over the past decade. In this article, we build upon and integrate existing approaches to direct greater attention toward investigating the subjective meaning and value that people attach to understanding their own SES as an identity. We use the term status-based identity to organize relevant research and examine how people understand and make meaning of their SES from moment to moment in real time. Drawing from multiple areas of research on identity, we suggest that even temporary shifts in how people construe their status-based identities predict changes in thought, affect, motivation, and behavior. This novel focus is positioned to examine the psychological effects of status transitions (e.g., upward or downward mobility). Further, in initial empirical work, we introduce a new measure to assess uncertainty regarding one's SES (i.e., status-based identity uncertainty) and offer evidence that greater uncertainty regarding one's status-based identity is associated with lower individual well-being. In sum, we argue that insight from the literature on identity will both expand and serve to organize the burgeoning literature on the psychology of SES and, in so doing, reveal promising new directions for research. PMID- 28346115 TI - The Malevolent Side of Human Nature. AB - The term dark triad refers to the constellation of narcissism, Machiavellianism, and psychopathy. Over the past few years, the concept has gained momentum, with many researchers assuming that the dark triad is a prominent antecedent of transgressive and norm-violating behavior. Our purpose in this meta-analytic review was to evaluate (a) interrelations among narcissism, Machiavellianism, and psychopathy; (b) gender differences in these traits; (c) how these traits are linked to normal personality factors; and (d) the psychosocial correlates of the dark triad. Our findings show that dark triad traits are substantially intercorrelated, somewhat more prevalent among men than women, predominantly related to the Big Five personality factor of agreeableness and the HEXACO factor of honesty-humility, and generally associated with various types of negative psychosocial outcomes. We question whether dark triad traits are sufficiently distinct and argue that the way they are currently measured is too simple to capture the malevolent sides of personality. Because most research in this domain is cross-sectional and based on self-reports, we recommend using a cross informant approach and prospective, longitudinal research designs for studying the predictive value of dark triad features. PMID- 28346116 TI - No Magic Bullet in Sight. PMID- 28346117 TI - On the Communicative Function of Body Odors. AB - Humans use multiple senses to navigate the social world, and the sense of smell is arguably the most underestimated one. An intriguing aspect of the sense of smell is its social communicative function. Research has shown that human odors convey information about a range of states (e.g., emotions, sickness) and traits (e.g., individuality, gender). Yet, what underlies the communicability of these states and traits via smell? We fill this explanatory gap with a framework that highlights the dynamic and flexible aspects of human olfactory communication. In particular, we explain how chemical profiles, associative learning (i.e., the systematic co-occurrence of chemical profiles with state- or trait-related information), and top-down contextual influences could interact to shape human odor perception. Our model not only helps to integrate past research on human olfactory communication but it also opens new avenues for future research on this fascinating, yet to date poorly understood, field. PMID- 28346118 TI - Social and Contextual Constraints on Embodied Perception. AB - A number of papers have challenged research on physiological and psychological influences on perception by claiming to show that such findings can be explained by nonperceptual factors such as demand characteristics. Relatedly, calls for separating perception from judgment have been issued. However, such efforts fail to consider key processes known to shape judgment processes: people's inability to report accurately on their judgments, conversational dynamics of experimental research contexts, and misattribution and discounting processes. Indeed, the fact that initially observed effects of embodied influences disappear is predicted by an extensive amount of literature on judgments studied within social psychology. Thus, findings from such studies suggest that the initially presumed underlying processes are at work-namely, functional considerations that are informative in the context of preparing the body for action. In this article, I provide suggestions on how to conduct research on perception within the social constraints of experimental contexts. PMID- 28346119 TI - Counterpoint. AB - Claims about alterations in perception based on manipulations of the energetics hypothesis (and other influences) are often framed as interesting specifically because they affect our perceptual experience. Many control experiments conducted on such perceptual effects suggest, however, that they are the result of attribution effects and other kinds of judgmental biases influencing the reporting process rather than perception itself. Schnall (2017, this issue), appealing to Heider's work on attribution, argues that it is fruitless to try to distinguish between perception and attribution. This makes the energetics hypothesis less interesting. PMID- 28346120 TI - Investigation of Consensually Nonmonogamous Relationships. AB - We proposed that the premise that monogamy is the exemplary form of romantic partnership underlies much theory and research on relationship quality, and we addressed how this bias has prompted methodological issues that make it difficult to effectively address the quality of nonmonogamous relationships. Because the idea that consensually nonmonogamous (CNM) relationships are functional (i.e., satisfying and of high quality) is controversial, we included a basic study to assess, in a variety of ways, the quality of these relationships. In that study, we found few differences in relationship functioning between individuals engaged in monogamy and those in CNM relationships. We then considered how existing theories could help researchers to understand CNM relationships and how CNM relationships could shed light on relationship processes, and we proposed a model of how CNM and monogamous relationships differ. Finally, in a second study, we determined that even researchers who present data about CNM are affected by the stigma surrounding such relationships. That is, researchers presenting findings favoring polyamory were perceived as more biased than researchers presenting findings favoring monogamy. PMID- 28346121 TI - Can Memories of Traumatic Experiences or Addiction Be Erased or Modified? A Critical Review of Research on the Disruption of Memory Reconsolidation and Its Applications. AB - Recent research suggests that the mere act of retrieving a memory can temporarily make that memory vulnerable to disruption. This process of "reconsolidation" will typically restabilize the neural representation of the memory and foster its long term storage. However, the process of reconsolidating the memory takes time to complete, and during this limited time window, the original memory may be modified either by the presentation of new information or with pharmacological agents. Such findings have prompted rising interest in using disruption during reconsolidation as a clinical intervention for anxiety, posttraumatic stress, and substance use disorders. However, "boundary conditions" on memory reconsolidation may pose significant obstacles to clinical translation. The aim of this article is to critically examine the nature of these boundary conditions, their neurobiological substrates, and the potential effect they may have on disruption of reconsolidation as a clinical intervention. These boundary conditions also highlight potential constraints on the reconsolidation phenomenon and suggest a limited role for memory updating consistent with evolutionary accounts of associative learning for threat and reward. We conclude with suggestions for future research needed to elucidate the precise conditions under which reconsolidation disruption may be clinically useful. PMID- 28346122 TI - Non-targeted metabolomics in sport and exercise science. AB - Metabolomics incorporates the study of metabolites that are produced and released through physiological processes at both the systemic and cellular levels. Biological compounds at the metabolite level are of paramount interest in the sport and exercise sciences, although research in this field has rarely been referred to with the global 'omics terminology. Commonly studied metabolites in exercise science are notably within cellular pathways for adenosine triphosphate production such as glycolysis (e.g., pyruvate and lactate), beta-oxidation of free fatty acids (e.g., palmitate) and ketone bodies (e.g., beta hydroxybutyrate). Non-targeted metabolomic technologies are able to simultaneously analyse the large numbers of metabolites present in human biological samples such as plasma, urine and saliva. These analytical technologies predominately employ nuclear magnetic resonance spectroscopy and chromatography coupled to mass spectrometry. Performing experiments based on non targeted methods allows for systemic metabolite changes to be analysed and compared to a particular physiological state (e.g., pre-/post-exercise) and provides an opportunity to prospect for metabolite signatures that offer beneficial information for translation into an exercise science context, for both elite performance and public health monitoring. This narrative review provides an introduction to non-targeted metabolomic technologies and discusses current and potential applications in sport and exercise science. PMID- 28346123 TI - Panfungal Polymerase Chain Reaction for Identification of Fungal Pathogens in Formalin-Fixed Animal Tissues. AB - Identification of fungal organisms often poses a problem for pathologists because the histomorphology of some fungal organisms is not specific, fresh tissues may not be available, and isolation and identification in culture may take a long time. The purpose of this study was to validate the use of panfungal polymerase chain reaction (PCR) to identify fungal organisms from formalin-fixed paraffin embedded (FFPE) tissues. Formalin-fixed paraffin-embedded curls were tested from 128 blocks containing canine, feline, equine, and bovine tissues with cutaneous, nasal, pulmonary, and systemic fungal infections, identified by the presence of fungi in histologic sections. Quantitative scoring of histologic sections identified rare (11.9%), occasional (17.5%), moderate (17.5%), or abundant (53.1%) fungal organisms. DNA was isolated from FFPE tissues and PCR was performed targeting the internal transcribed spacer 2 (ITS-2) region, a segment of noncoding DNA found in all eukaryotes. Polymerase chain reaction products were sequenced and identified at >=97% identity match using the Basic Local Alignment Search Tool and the NCBI database of ITS sequences. Of the 128 blocks, 117 (91.4%) yielded PCR products and high-quality sequences were derived from 89 (69.5%). Sequence and histologic identifications matched in 79 blocks (61.7%). This assay was capable of providing genus- and species-level identification when histopathology could not and, thus, is a beneficial complementary tool for diagnosis of fungal diseases. PMID- 28346124 TI - Pax8, Napsin A, and CD10 as Immunohistochemical Markers of Canine Renal Cell Carcinoma. AB - Pax8, napsin A, and CD10 are useful immunohistochemical markers of human renal cell carcinoma (RCC); however, their diagnostic utility in canine RCC is unclear. Forty formalin-fixed paraffin-embedded renal cell carcinomas from dogs (15 papillary, 12 solid, and 13 tubular) and 10 metastases were evaluated for expression of Pax8, napsin A, and CD10. Thirty-nine (98%), 24 (60%), and 19 (50%) tumors expressed Pax8 (nuclear labeling), napsin A (cytoplasmic labeling), and CD10 (cytoplasmic and membranous labeling), respectively. Pax8 was expressed in 92% of solid, 100% of papillary, and 100% of tubular tumors. Napsin A was expressed in 58% of solid, 60% of papillary, and 62% of tubular RCC. CD10 was expressed in 33% of solid, 47% of papillary, and 62% of tubular RCC. Pax8 was expressed in 80% of the metastatic tumors, napsin A in 60%, and CD10 in 50%. Additionally, Pax8 immunoreactivity was stronger overall than that of napsin A or CD10. In summary, Pax8 is a more sensitive marker than napsin A or CD10 for primary and metastatic canine RCC; its nuclear and more intense reactivity also makes it easier to interpret. Tubular and papillary RCCs were more likely than solid RCC to express all 3 markers. These findings highlight the utility of Pax8 as an immunohistochemical marker in diagnosing all major subtypes of canine primary and metastatic renal cell carcinoma. PMID- 28346125 TI - Canine Neutrophil Extracellular Traps Enhance Clot Formation and Delay Lysis. AB - Autoimmune diseases increase the risk of thrombosis. Neutrophil extracellular traps (NETs) are webs of DNA and protein that may mediate thrombosis in autoimmune diseases. Human and murine studies show NET-releasing neutrophils within a thrombus promote its growth, but it is unclear to what extent NET fragments released into circulation during inflammation are prothrombotic. This study hypothesized that canine NETs promote clot formation and impair lysis even in the absence of neutrophils. NETs were prepared from PMA-stimulated neutrophils and added to fibrinogen and thrombin or to recalcified pooled canine platelet poor plasma, tissue factor, and tissue plasminogen activator. Clot formation and lysis were measured spectrophotometrically. NETs did not alter fibrin clot formation, but NETs increased maximum clot formation velocity ( P = .001) and delayed lysis ( P = .009) of plasma clots compared with supernatants from nonstimulated neutrophils. DNase digestion of NETs reduced their effect on clot lysis but not maximum clot formation velocity. This suggested impaired lysis was principally mediated by DNA within NETs but that NET proteins were principally responsible for increased speed of clot formation. Previous reports suggested elastase or histones might be responsible for the effect of NETs on clot formation. Elastase activity was greatly reduced by plasma, and addition of histones to plasma did not increase formation velocity, suggesting these proteins were not responsible for increasing maximum formation velocity. This study showed that NETs enhanced clot formation and impaired clot lysis in canine platelet-poor plasma. These in vitro findings suggest both NET proteins and DNA may contribute to thrombosis in inflammatory disease. PMID- 28346127 TI - In this issue: everything you wanted to know about electronic health exchange, diversity and ethnicity. PMID- 28346126 TI - Agreement Between Cytology and Histopathology for Regional Lymph Node Metastasis in Dogs With Melanocytic Neoplasms. AB - Melanocytic neoplasms are common in dogs and frequently occur within the oral cavity or in haired skin. The behavior of melanocytic neoplasms is variable and depends on tumor location, size, and histopathologic features. This study compared cytopathology and histopathology of 32 lymph nodes from 27 dogs diagnosed with melanocytic neoplasms. Agreement between the original cytology report, cytology slide review, original histopathology report, and histopathology slide review was determined for each lymph node. A subset of lymph nodes was subjected to immunohistochemistry (Melan-A) and additional histochemical stains/techniques (Prussian blue, bleach) to assist in differentiation of melanocytes and melanophages. Agreement ranged from slight to fair for each of the variables evaluated with weighted kappa (kappaw) or kappa (kappa) analysis (original cytology vs cytology review kappaw = 0.24; original cytology vs original histopathology kappaw = 0.007; original cytology vs histopathology review kappaw = 0.23; cytology review vs original histopathology kappaw = 0.008; cytology review vs histopathology review kappaw = 0.006; and original histopathology vs histopathology review kappa = 0.18). The diagnoses (metastatic, equivocal, or negative for metastasis) of the original report and slide review for both cytology and histopathology were not significantly correlated with survival in this population of patients. Overall, agreement between cytology and histopathology was poor even with a single clinical or anatomic pathologist performing slide review. Consensus between routine cytology and histopathology for staging of lymph nodes in patients with melanocytic neoplasms is poor and does not correlate with survival. PMID- 28346128 TI - Ethnicity Recording in Primary Care Computerised Medical Record Systems: An Ontological Approach. AB - BACKGROUND: Ethnicity recording within primary care computerised medical record (CMR) systems is suboptimal, exacerbated by tangled taxonomies within current coding systems.Objective To develop a method for extending ethnicity identification using routinely collected data. METHODS: We used an ontological method to maximise the reliability and prevalence of ethnicity information in the Royal College of General Practitioner's Research and Surveillance database. Clinical codes were either directly mapped to ethnicity group or utilised as proxy markers (such as language spoken) from which ethnicity could be inferred. We compared the performance of our method with the recording rates that would be identified by code lists utilised by the UK pay for the performance system, with the help of the Quality and Outcomes Framework (QOF). RESULTS: Data from 2,059,453 patients across 110 practices were included. The overall categorisable ethnicity using QOF codes was 36.26% (95% confidence interval (CI): 36.20% 36.33%). This rose to 48.57% (CI:48.50%-48.64%) using the described ethnicity mapping process. Mapping increased across all ethnic groups. The largest increase was seen in the white ethnicity category (30.61%; CI: 30.55%-30.67% to 40.24%; CI: 40.17%-40.30%). The highest relative increase was in the ethnic group categorised as the other (0.04%; CI: 0.03%-0.04% to 0.92%; CI: 0.91%-0.93%). CONCLUSIONS: This mapping method substantially increases the prevalence of known ethnicity in CMR data and may aid future epidemiological research based on routine data. PMID- 28346129 TI - Health Information Exchange as a Complex and Adaptive Construct: Scoping Review. AB - OBJECTIVE: To understand how the concept of Health Information Exchange (HIE) has evolved over time. METHODS: Supplementary analysis of data from a systematic scoping review of definitions of HIE from 1900 to 2014, involving temporal analysis of underpinning themes. RESULTS: The search identified 268 unique definitions of HIE dating from 1957 onwards; 103 in scientific databases and 165 in Google. These contained consistent themes, representing the core concept of exchanging health information electronically, as well as fluid themes, reflecting the evolving policy, business, organisational and technological context of HIE (including the emergence of HIE as an organisational 'entity'). These are summarised graphically to show how the concept has evolved around the world with the passage of time. The term HIE emerged in 1957 with the establishment of Occupational HIE, evolving through the 1990s with concepts such as electronic data interchange and mobile computing technology; then from 2006-10 largely aligning with the US Government's health information technology strategy and the creation of HIEs as organisational entities, alongside the broader interoperability imperative, and continuing to evolve today as part of a broader international agenda for sustainable, information-driven health systems. CONCLUSIONS: The concept of HIE is an evolving and adaptive one, reflecting the ongoing quest for integrated and interoperable information to improve the efficiency and effectiveness of health systems, in a changing technological and policy environment. PMID- 28346130 TI - Defining Health Information Exchange: Scoping Review of Published Definitions. AB - OBJECTIVE: The term Health Information Exchange (HIE) is often used in health informatics, yet uncertainties remain about its precise meaning. This study aimed to capture and analyse existing definitions in order to map variations in its use and the concepts associated with it. METHODS: Systematic literature search to identify published definitions of HIE and equivalent terms such as Clinical Information Exchange. Medline, Web of Science, Library Information Science and Technology Abstracts, EMBASE and CINAHL Plus were searched to identify relevant research, and Google to identify grey literature. Searches were not limited by language or date of publication. In order to warrant inclusion documents had to either define the concept explicitly or do so via a concrete description. Included references were tabulated by author affiliation, source of quote, year of publication, country of origin and definitions and the definitions themselves were analysed thematically. RESULTS: Searches revealed 603 scientific articles and 5981 website links. From these, a total of 268 unique definitions of HIE were identified and extracted: 103 from scientific databases and 165 from Google. Eleven constructs emerged from the thematic analysis. Contextual factors influenced the emphasis of the definitions and the framing of HIE as a concept/process, a set of enabling technologies, or an entity/organisation.ConclusionsHIE is a complex and evolving concept and uses of the term vary across settings, presenting challenges for communication. Developing a generic term is difficult, given the importance of context, but the authors suggest one covering key attributes of HIE, which may be helpful. PMID- 28346131 TI - Lack of Diversity in Personal Health Record Evaluations with Older Adult Participants: A Systematic Review of Literature. AB - BACKGROUND: Older adults are not adopting personal health records (PHRs) at the same rates as other adult populations. Disparities in adoption rates are also reported in older adult subgroups. The variability in adoption may be because PHRs are not designed to meet older adult users. OBJECTIVE: We analyzed PHR evaluation studies to examine the characteristics and perspectives of older adult study participants to identify their self-reported needs. METHOD: We searched Medline, CINAHL, PsycINFO, and Embase for PHR evaluation studies that involved older adult participants. RESULTS: 1017 abstracts were identified, and 179 publications went through full text review. 10 publications met inclusion criteria. These publications described studies conducted in 3 countries, and evaluated 7 PHRs. Homogeneity was found in the study populations and participant opinions of the systems. DISCUSSION: Many PHR evaluations do not include diverse older adult participants. This may lead to consistency in outcomes, but it also may create gaps in identifying user needs. Additional studies, specifically targeting diverse older adult participants, are needed to gain a more comprehensive understanding of the opinions of older adults on PHRs and how these systems could benefit older adult healthcare consumers. CONCLUSION: The body of research shows that older adults are highly satisfied using PHRs. These outcomes may be generalizable because most PHR evaluation studies do not include diverse older adult participants. This lack of participant diversity may be contributing to the disparities observed in PHR adoption rates. PMID- 28346132 TI - Electronic Health Record's Effects on the Outpatient Office Visit and Clinical Education. AB - BACKGROUND: During an office visit, the provider has the important cognitive task of attending to the patient while actively using the electronic health record (EHR). Prior literature suggests that EHR may have a positive effect on simple tasks, but a negative effect on tasks that require complex cognitive processes. No study has examined the provider's perception of EHR on multiple distinct aspects of the office visit. METHODS: We surveyed providers/preceptors regarding their perception of EHR on multiple aspects of the office visit. We summarized their EHR utilization history and their perceptions of the EHR during the visit using descriptive statistics. We tested for associations between time spent using the EHR and distinct aspects of the visit using Chi-square tests of association. RESULTS: In total, 83 providers/preceptors reported use of EHR (response rate 52%). Provider/preceptors reported an overall negative effect of EHR on the patient-provider connection, but an overall positive effect on the review of medications/medical records, communication between providers, review of results with patients and review of follow-up to testing results with patients. The effect of EHR on history taking and teaching students was neutral. We observed no correlation between the provider's time spent using the EHR and their perception of its effectiveness. CONCLUSIONS: Providers reported a positive perception of EHR on aspects of the office visit that involved a single cognitive task. However, providers reported a negative perception of EHR on patient provider connection, which involves a high degree of cognitive processing. PMID- 28346133 TI - Creating a climate that catalyses healthcare innovation in the United Kingdom - learning lessons from international innovators. AB - BACKGROUND: The United Kingdom (UK) lags behind other high-income countries in relation to technological innovation in healthcare. In order to inform UK strategy on how to catalyse innovation, we sought to understand what national strategies can help to promote a climate for innovation in healthcare settings by extracting lessons for the UK from international innovators. METHODS: We undertook a series of qualitative semi-structured interviews with senior international innovators from a range of health related policy, care/service delivery, commercial and academic backgrounds. Thematic analysis helped to explore how different stakeholder groups could facilitate/inhibit innovation at individual, organisational, and wider societal levels. RESULTS: We conducted 14 interviews and found that a conducive climate for healthcare innovation comprised of national/regional strategies stimulating commercial competition, promoting public/private relationships, and providing central direction (e.g. incentives for adoption and regulation through standards) without being restrictive. Organisational attitudes with a willingness to experiment and to take risks were also seen as important, but a bottom-up approach to innovation, based on the identification of clinical need, was seen as a crucial first step to construct relevant national policies. CONCLUSIONS: There is now a need to create mechanisms through which frontline National Health Service staff in relation can raise ideas/concerns and suggest opportunities for improvement, and then build national innovation environments that seek to address these needs. This should be accompanied by creating competitive health technology markets to stimulate a commercial environment that attracts high-quality health information technology experts and innovators working in partnership with staff and patients. PMID- 28346134 TI - Five key recommendations for the implementation of Hospital Electronic Prescribing and Medicines Administration systems in Scotland. AB - NHS Scotland is about to embark on the implementation of Hospital Electronic Prescribing and Medicines Administration (HEPMA) systems. There are a number of risks associated with such ventures, thus drawing on existing experiences from other settings is crucial in informing deployment.Drawing on our previous and ongoing work in English settings as well as the international literature, we reflect on key lessons that NHS Scotland may wish to consider in going forward. These deliberations include recommendations surrounding key aspects of deployment strategy surrounding: 1) the way central coordination should be conceptualised, 2) how flexibility in can be ensured, 3) paying attention to optimising systems from the outset, 4) how expertise should be developed and centrally shared, and 5) ways in which learning from experience can be maximised.Our five recommendations will, we hope, provide a starting point for the strategic deliberations of policy makers. Throughout this journey, it is important to view the deployment of HEPMA as part of a wider strategic goal of creating integrated digital infrastructures across Scotland. PMID- 28346135 TI - Polo-like kinase-dependent phosphorylation of the synaptonemal complex protein SYP-4 regulates double-strand break formation through a negative feedback loop. AB - The synaptonemal complex (SC) is an ultrastructurally conserved proteinaceous structure that holds homologous chromosomes together and is required for the stabilization of pairing interactions and the completion of crossover (CO) formation between homologs during meiosis I. Here, we identify a novel role for a central region component of the SC, SYP-4, in negatively regulating formation of recombination-initiating double-strand breaks (DSBs) via a feedback loop triggered by crossover designation in C. elegans. We found that SYP-4 is phosphorylated dependent on Polo-like kinases PLK-1/2. SYP-4 phosphorylation depends on DSB formation and crossover designation, is required for stabilizing the SC in pachytene by switching the central region of the SC from a more dynamic to a less dynamic state, and negatively regulates DSB formation. We propose a model in which Polo-like kinases recognize crossover designation and phosphorylate SYP-4 thereby stabilizing the SC and making chromosomes less permissive for further DSB formation. PMID- 28346136 TI - Environment determines evolutionary trajectory in a constrained phenotypic space. AB - Constraints on phenotypic variation limit the capacity of organisms to adapt to the multiple selection pressures encountered in natural environments. To better understand evolutionary dynamics in this context, we select Escherichia coli for faster migration through a porous environment, a process which depends on both motility and growth. We find that a trade-off between swimming speed and growth rate constrains the evolution of faster migration. Evolving faster migration in rich medium results in slow growth and fast swimming, while evolution in minimal medium results in fast growth and slow swimming. In each condition parallel genomic evolution drives adaptation through different mutations. We show that the trade-off is mediated by antagonistic pleiotropy through mutations that affect negative regulation. A model of the evolutionary process shows that the genetic capacity of an organism to vary traits can qualitatively depend on its environment, which in turn alters its evolutionary trajectory. PMID- 28346137 TI - Histone gene replacement reveals a post-transcriptional role for H3K36 in maintaining metazoan transcriptome fidelity. AB - Histone H3 lysine 36 methylation (H3K36me) is thought to participate in a host of co-transcriptional regulatory events. To study the function of this residue independent from the enzymes that modify it, we used a 'histone replacement' system in Drosophila to generate a non-modifiable H3K36 lysine-to-arginine (H3K36R) mutant. We observed global dysregulation of mRNA levels in H3K36R animals that correlates with the incidence of H3K36me3. Similar to previous studies, we found that mutation of H3K36 also resulted in H4 hyperacetylation. However, neither cryptic transcription initiation, nor alternative pre-mRNA splicing, contributed to the observed changes in expression, in contrast with previously reported roles for H3K36me. Interestingly, knockdown of the RNA surveillance nuclease, Xrn1, and members of the CCR4-Not deadenylase complex, restored mRNA levels for a class of downregulated, H3K36me3-rich genes. We propose a post-transcriptional role for modification of replication-dependent H3K36 in the control of metazoan gene expression. PMID- 28346138 TI - Dilation of fusion pores by crowding of SNARE proteins. AB - Hormones and neurotransmitters are released through fluctuating exocytotic fusion pores that can flicker open and shut multiple times. Cargo release and vesicle recycling depend on the fate of the pore, which may reseal or dilate irreversibly. Pore nucleation requires zippering between vesicle-associated v SNAREs and target membrane t-SNAREs, but the mechanisms governing the subsequent pore dilation are not understood. Here, we probed the dilation of single fusion pores using v-SNARE-reconstituted ~23-nm-diameter discoidal nanolipoprotein particles (vNLPs) as fusion partners with cells ectopically expressing cognate, 'flipped' t-SNAREs. Pore nucleation required a minimum of two v-SNAREs per NLP face, and further increases in v-SNARE copy numbers did not affect nucleation rate. By contrast, the probability of pore dilation increased with increasing v SNARE copies and was far from saturating at 15 v-SNARE copies per face, the NLP capacity. Our experimental and computational results suggest that SNARE availability may be pivotal in determining whether neurotransmitters or hormones are released through a transient ('kiss and run') or an irreversibly dilating pore (full fusion). PMID- 28346139 TI - Oncometabolite D-2-Hydroxyglutarate enhances gene silencing through inhibition of specific H3K36 histone demethylases. AB - Certain mutations affecting central metabolism cause accumulation of the oncometabolite D-2-hydroxyglutarate which promotes progression of certain tumors. High levels of D-2-hydroxyglutarate inhibit the TET family of DNA demethylases and Jumonji family of histone demethylases and cause epigenetic changes that lead to altered gene expression. The link between inhibition of DNA demethylation and changes in expression is strong in some cancers, but not in others. To determine whether D-2-hydroxyglutarate can affect gene expression through inhibiting histone demethylases, orthologous mutations to those known to cause accumulation of D-2-hydroxyglutarate in tumors were generated in Saccharomyces cerevisiae, which has histone demethylases but not DNA methylases or demethylases. Accumulation of D-2-hydroxyglutarate caused inhibition of several histone demethylases. Inhibition of two of the demethylases that act specifically on histone H3K36me2,3 led to enhanced gene silencing. These observations pinpointed a new mechanism by which this oncometabolite can alter gene expression, perhaps repressing critical inhibitors of proliferation. PMID- 28346140 TI - EM connectomics reveals axonal target variation in a sequence-generating network. AB - The sequential activation of neurons has been observed in various areas of the brain, but in no case is the underlying network structure well understood. Here we examined the circuit anatomy of zebra finch HVC, a cortical region that generates sequences underlying the temporal progression of the song. We combined serial block-face electron microscopy with light microscopy to determine the cell types targeted by HVC(RA) neurons, which control song timing. Close to their soma, axons almost exclusively targeted inhibitory interneurons, consistent with what had been found with electrical recordings from pairs of cells. Conversely, far from the soma the targets were mostly other excitatory neurons, about half of these being other HVC(RA) cells. Both observations are consistent with the notion that the neural sequences that pace the song are generated by global synaptic chains in HVC embedded within local inhibitory networks. PMID- 28346144 TI - Surrealistic sleep. PMID- 28346142 TI - The neuropeptide F/nitric oxide pathway is essential for shaping locomotor plasticity underlying locust phase transition. AB - Behavioral plasticity is widespread in swarming animals, but little is known about its underlying neural and molecular mechanisms. Here, we report that a neuropeptide F (NPF)/nitric oxide (NO) pathway plays a critical role in the locomotor plasticity of swarming migratory locusts. The transcripts encoding two related neuropeptides, NPF1a and NPF2, show reduced levels during crowding, and the transcript levels of NPF1a and NPF2 receptors significantly increase during locust isolation. Both NPF1a and NPF2 have suppressive effects on phase-related locomotor activity. A key downstream mediator for both NPFs is nitric oxide synthase (NOS), which regulates phase-related locomotor activity by controlling NO synthesis in the locust brain. Mechanistically, NPF1a and NPF2 modify NOS activity by separately suppressing its phosphorylation and by lowering its transcript level, effects that are mediated by their respective receptors. Our results uncover a hierarchical neurochemical mechanism underlying behavioral plasticity in the swarming locust and provide insights into the NPF/NO axis. PMID- 28346143 TI - Action of CMG with strand-specific DNA blocks supports an internal unwinding mode for the eukaryotic replicative helicase. AB - Replicative helicases are ring-shaped hexamers that encircle DNA for duplex unwinding. The currently accepted view of hexameric helicase function is by steric exclusion, where the helicase encircles one DNA strand and excludes the other, acting as a wedge with an external DNA unwinding point during translocation. Accordingly, strand-specific blocks only affect these helicases when placed on the tracking strand, not the excluded strand. We examined the effect of blocks on the eukaryotic CMG and, contrary to expectations, blocks on either strand inhibit CMG unwinding. A recent cryoEM structure of yeast CMG shows that duplex DNA enters the helicase and unwinding occurs in the central channel. The results of this report inform important aspects of the structure, and we propose that CMG functions by a modified steric exclusion process in which both strands enter the helicase and the duplex unwinding point is internal, followed by exclusion of the non-tracking strand. PMID- 28346141 TI - Insights into electrosensory organ development, physiology and evolution from a lateral line-enriched transcriptome. AB - The anamniote lateral line system, comprising mechanosensory neuromasts and electrosensory ampullary organs, is a useful model for investigating the developmental and evolutionary diversification of different organs and cell types. Zebrafish neuromast development is increasingly well understood, but neither zebrafish nor Xenopus is electroreceptive and our molecular understanding of ampullary organ development is rudimentary. We have used RNA-seq to generate a lateral line-enriched gene-set from late-larval paddlefish (Polyodon spathula). Validation of a subset reveals expression in developing ampullary organs of transcription factor genes critical for hair cell development, and genes essential for glutamate release at hair cell ribbon synapses, suggesting close developmental, physiological and evolutionary links between non-teleost electroreceptors and hair cells. We identify an ampullary organ-specific proneural transcription factor, and candidates for the voltage-sensing L-type Cav channel and rectifying Kv channel predicted from skate (cartilaginous fish) ampullary organ electrophysiology. Overall, our results illuminate ampullary organ development, physiology and evolution. PMID- 28346145 TI - Commentary on National Sleep Foundation sleep quality recommendations. PMID- 28346146 TI - Social support, social strain, sleep quality, and actigraphic sleep characteristics: evidence from a national survey of US adults. AB - OBJECTIVE: To determine the associations between average family and friend social support and strain over 10 years and sleep quality, sleep efficiency, total sleep time, and night-to-night total sleep time variability. PARTICIPANTS: Non institutionalized English-speaking US adults aged 34-81 who participated in the MacArthur Study on Aging: Midlife in the United States. MEASUREMENTS: Sleep quality was assessed by the Pittsburgh Sleep Quality Index and by a 7-day daily diary. Sleep efficiency, total sleep time, and night-to-night total sleep time variability were assessed by actigraphy (MiniMitter 64). RESULTS: Social support, but not social strain, was significantly associated with both self-reported measures of quality (social support beta=-1.239, P=.019 for global Pittsburgh Sleep Quality Index scores; social support beta=-0.248, P=.016 for diary assessed quality). Lower scores on both quality measures indicate better sleep. In contrast, social strain, but not social support, was significantly associated with sleep efficiency (social strain beta=-3.780, P=.007). Social strain, but not social support, was significantly associated with night-to-night sleep variability (social strain beta=0.421, P=.034); however, the overall model was not significant. Neither social support nor social strain was significantly associated with total sleep time. CONCLUSION: Social support was significant for self-reported sleep, whereas only social strain was significantly associated with objective sleep parameters. Future research on social relationships and sleep should analyze both positive and negative aspects of relationships in tandem because effects appear to differ based on outcome. PMID- 28346147 TI - Differences in short and long sleep durations between blacks and whites attributed to emotional distress: analysis of the National Health Interview Survey in the United States. AB - OBJECTIVES: The current study examined the role of emotional distress in explaining racial/ethnic differences in unhealthy sleep duration. DESIGN: Data from the 2004-2013 National Health Interview Survey were analyzed using SPSS 20. SETTING: Data were collected through personal household interviews in the United States. PARTICIPANTS: Of the total 261,686 participants (age>=18 years), 17.0% were black, 83.0% were white, and the mean age was 48 years (SE=0.04). MEASUREMENTS: To ascertain total sleep duration, participants were asked, "How many hours of sleep do you get on average in a 24-hour period?" Sleep duration was coded as short sleep (<7hours), average sleep (7-8hours), or long sleep (>8hours). Emotional distress-feeling sad, nervous, restless, hopeless, worthless, and burdened over a 30-day period-was measured using Kessler-6, a 6 item screening scale. RESULTS: Of the participants reporting significant emotional distress (4.0% black, 3.5% white), chi2 analyses revealed that a higher percentage of blacks, compared with whites, reported unhealthy sleep durations. Relative to Whites, Blacks had increased prevalence of short sleep (prevalence ratio=1.32, P<.001) or long sleep (odds ratio =1.189, P<.001). The interaction between race/ethnicity and emotional distress was significantly associated with short (prevalence ratio=0.99, P<.001) and long sleep (odds ratio=0.98, P<.001) durations. CONCLUSIONS: Individuals of the black race/ethnicity or those reporting greater levels of emotional distress are more likely to report short or long sleep duration. Emotional distress might partially explain racial/ethnic differences in unhealthy sleep duration between blacks and whites. PMID- 28346149 TI - Sleep health of Australian adults in 2016: results of the 2016 Sleep Health Foundation national survey. AB - OBJECTIVE: To measure the prevalence and social impacts of sleep problems in Australia. DESIGN: Cross-sectional national adult online survey. SETTING: Community-based sample. PARTICIPANTS: Australian adults >=18 years, n=1011. RESULTS: Self-reported inadequate sleep, of either duration or quality, and its daytime consequences affect 33%-45% of adults. Diagnosed sleep apnea is reported by 8%, significant insomnia by 20%, and restless legs by18% of adults. Besides specific clinical sleep disorders, poor sleep habits were common. Average reported sleep time is 7 hours, although 12% sleep less than 51/2hours and 8% over 9 hours. Three-quarters (76%) of those who sleep less than 51/2hours report frequent daytime impairment or sleep-related symptoms. Frequent, loud snoring is reported by 24% of men and 17% of women. Among these, 70% report daytime impairment or other sleep-related symptoms. Twenty-six percent report Internet use most or every night just before bed and frequent sleep difficulties or daytime impairments. Similarly, 16% of working adults do work just before bed and also have frequent sleep difficulties or daytime sleep-related symptoms. Younger adults (18-34 years) sleep around 1 hour longer before non-work days than working days compared with 18 minutes in older age groups. In the past 3 months, 29% of adults report making errors at work due to sleepiness or sleep problems. Driving while drowsy at least every month is reported by 29% of people, 20% have nodded off while driving, and 5% have had an accident in the past year because they dozed off. CONCLUSION: Sleep problems and daytime consequences are endemic among Australian adults. A focus on healthy sleep at a policy level as well as increased clinician and public awareness may be warranted. PMID- 28346150 TI - Factors contributing to poor satisfaction with sleep and healthcare seeking behavior in older adults. AB - OBJECTIVE: To identify factors influencing older adults' poor satisfaction with sleep and their current healthcare seeking behaviors. DESIGN: Cross-sectional study. SETTING: Pittsburgh Claude D. Pepper Older Americans Independence Center Community Registry. PARTICIPANTS: Individuals aged 60 or older enrolled in the registry that completed a cross-sectional mailed survey (N = 1026). MEASUREMENTS: Participant demographics (age, gender, marital status, race, education), overall health (self-rated health, pain, and comorbidities), and health behaviors (physical activity, smoking, drinking behaviors) were collected from the registry database. A mail survey was used to collect self-report on sleep problems and their current healthcare seeking behaviors. Simple and multiple logistic regression models were used to evaluate associations between variables. RESULTS: A total of 19.3% of participants reported being "dissatisfied" or "very dissatisfied" with their overall sleep quality. Participants who reported poor sleep satisfaction were more likely to be single and report poorer overall health compared to participants who were satisfied with their sleep quality. They were also more likely to report using over-the-counter (OTC) and prescription sleep medications, discuss sleep problems with a healthcare provider, and use strategies to improve their sleep (P < .05). A higher proportion of participants with trouble sleeping throughout the night reported they had discussions with a healthcare provider (47.2%), and used OTC (38.6%) or prescription (20.1%) sleep aids. CONCLUSIONS: These results underscore the possible linkage between poor satisfaction with sleep and older adults' current healthcare seeking behaviors and self-treatment methods, particularly using OTC medications to cope with sleep problems without consulting a healthcare provider. PMID- 28346151 TI - Bidirectional associations of accelerometer-determined sedentary behavior and physical activity with reported time in bed: Women's Health Study. AB - OBJECTIVE: To examine the day-to-day, bidirectional associations of accelerometer derived sedentary behavior and physical activity (PA) with reported time in bed in a large cohort of older women. METHODS: Data are from 10086 Women's Health Study participants (aged 71.6 years; SD, 5.7) who agreed to wear an accelerometer and complete a diary for 7 consecutive days. Generalized linear (multilevel) models with repeated measures were used to examine the adjusted associations of the following: (1) reported time in bed with next-day accelerometer-determined counts and time spent sedentary and in light- and moderate-to-vigorous-intensity PA (MVPA) and (2) accelerometer estimates with reported time in bed that night, expressed as short (<7 hours), optimal (7-9 hours), and long (>9 hours) sleep. RESULTS: Across days, short sleep was associated with an average of 5500 (SE, 1352) higher accelerometer counts the following day but was also related to higher average sedentary (46.5 [SE, 1.5] minutes) and light-intensity PA (11.9 [SE, 1.2] minutes) than optimal sleep (all P<.001). Long sleep was associated with lower accelerometer counts, time spent sedentary and in light-intensity PA, and a reduced likelihood of engaging in >=20 minutes of MVPA (all P<.001) than optimal sleep. Higher PA during the day (higher accelerometer counts and >=20 minutes of accumulated MVPA) was associated with a reduced likelihood of reporting short or long sleep that night (all P<.001). CONCLUSIONS: Findings support the bidirectional associations of accelerometer-determined sedentary behavior and PA with reported time in bed in older women. Future studies are needed to confirm findings with sleep actigraphy in older women. PMID- 28346152 TI - Associations between physical activity and sedentary behavior with sleep quality and quantity in young adults. AB - OBJECTIVES: Intensity and duration of physical activity (PA) and sedentary behavior are individually associated with sleep, but their independent associations are poorly characterized. The objectives of this study were to determine if PA and/or sedentary behavior are/is associated with sleep quality and/or quantity in a young adult sample. DESIGN: Cross-sectional. SETTING: Montreal, Canada. PARTICIPANTS: Participants (n=658) from the Nicotine Dependence in Teens Study. MEASUREMENTS: PA measures included total minutes of light, moderate, and vigorous PA in the past week; sedentary measures included number of hours per day watching television (TV) and using the computer for leisure activities in the past week. Sleep measures included (1) the Pittsburgh Sleep Quality Index, which assesses sleep quality in the past month, and (2) number of hours of sleep per night in the past month. Data were analyzed using multiple logistic regression adjusting for age, sex, and mother's education. RESULTS: In multivariable analyses, each additional hour of TV and computer use per day was associated with a 17% and 13% increase, respectively, in the odds of reporting poor sleep quality. After additionally adjusting for PA, the association between TV use and poor sleep quality remained significant (odds ratio: 1.15, 95% confidence interval: 1.01-1.28). Sedentary behavior was not associated with sleep quantity. PA intensity and duration were not associated with sleep quality or quantity. CONCLUSIONS: More time spent doing sedentary activities was associated with poorer sleep quality, but PA was not associated. Clinicians treating young adults with sleep problems should inquire about sedentary behavior. PMID- 28346153 TI - National Sleep Foundation's sleep quality recommendations: first report. AB - OBJECTIVES: To provide evidence-based recommendations and guidance to the public regarding indicators of good sleep quality across the life-span. METHODS: The National Sleep Foundation assembled a panel of experts from the sleep community and representatives appointed by stakeholder organizations (Sleep Quality Consensus Panel). A systematic literature review identified 277 studies meeting inclusion criteria. Abstracts and full-text articles were provided to the panelists for review and discussion. A modified Delphi RAND/UCLA Appropriateness Method with 3 rounds of voting was used to determine agreement. RESULTS: For most of the sleep continuity variables (sleep latency, number of awakenings >5minutes, wake after sleep onset, and sleep efficiency), the panel members agreed that these measures were appropriate indicators of good sleep quality across the life span. However, overall, there was less or no consensus regarding sleep architecture or nap-related variables as elements of good sleep quality. CONCLUSIONS: There is consensus among experts regarding some indicators of sleep quality among otherwise healthy individuals. Education and public health initiatives regarding good sleep quality will require sustained and collaborative efforts from multiple stakeholders. Future research should explore how sleep architecture and naps relate to sleep quality. Implications and limitations of the consensus recommendations are discussed. PMID- 28346154 TI - Text message intervention improves objective sleep hours among adolescents: the moderating role of race-ethnicity. AB - OBJECTIVES: This 10-day study aimed to (1) assess the effectiveness of a text message-based sleep intervention and (2) determine whether the intervention was equally effective for non-Hispanic whites and racial-ethnic minority adolescents. PARTICIPANTS: Participants were 46 (50% female) adolescents (13-18 years; mean=15.75 years old, SD=0.98) from a public high school in the Midwest. INTERVENTION: Participants were randomly assigned to a control or text message intervention condition. Only participants in the intervention condition received 2 text messages outlining individualized bedtime goals daily, for 8 weekdays. MEASUREMENTS: All participants attended a sleep lecture, wore a sleep monitor, and completed baseline and exit surveys that assessed demographics, subjective sleep, lifestyle, and psychosocial adjustment variables. RESULTS: Results of a 2 (intervention, control) * 2 (pre-intervention, postintervention) analysis of variance test revealed no significant intervention * time interaction effect (F1,38=0.020, P=.889) in the full sample. This effect, however, was significantly moderated by race-ethnicity: Results indicated a significant intervention * time * race interaction (F1,36=8.050, P=.007, partial eta2=.183) such that the intervention significantly improved sleep hours (by approximately 1 hour) only among non-Hispanic whites (and not among adolescents of racial-ethnic minority status). CONCLUSIONS: Adolescents from racial-ethnic minority groups may face significant barriers that interfere with their ability to successfully alter their sleep-wake patterns and maximize sleep hours. PMID- 28346155 TI - Objectively measured sleep and health-related quality of life in older adults with type 2 diabetes: a cross-sectional study from the Alberta's Caring for Diabetes Study. AB - BACKGROUND AND AIM: Sleep is an important behavior for metabolic control and mental health in type 2 diabetes. The aim was to examine the relationship of objective estimates of sleep quantity and quality with health-related quality of life (HRQL) in adults with type 2 diabetes. MATERIALS AND METHODS: Participants completed a survey where HRQL was measured using the EQ-5D-5 L index score, and the SF-12 v2, which provides physical and mental composite summary (PCS and MCS) scores. Participants also wore wrist actigraphy (Actigraph GT3X+) during sleep to derive estimates of total sleep time (TST), sleep latency (SLAT), and sleep efficiency (SEFF) and wake after sleep onset (WASO). Adjusted multivariable linear regression models were used to examine the associations among actigraphy derived sleep parameters with PCS, MCS, and EQ-5D-5 L index scores. RESULTS: On average, participants (N=168) were 65 years old (standard deviation [SD] 10), 46% were female, with a diabetes duration of 13 years (SD 9) and body mass index of 31 kg/m2 (SD 6.5). Mean (SD) TST and SLAT were 7.5 (1.0) hours and 9.9 (7.6) minutes, respectively, SEFF was 82.7 (6.1) percent and WASO was 86.7 (53.4) minutes. An inverse association between TST and PCS was found where every additional 60 minutes of sleep was associated with 1.3-unit lower PCS (P=.04). SEFF was positively associated with both PCS and MCS, where a 10% greater SEFF was associated with 2.6-unit higher PCS (P=.008), and 1.8-unit higher MCS (P=.056). CONCLUSIONS: Among this population, better sleep efficiency was associated with better physical and mental health. PMID- 28346157 TI - Earlier school start times are associated with higher rates of behavioral problems in elementary schools. AB - BACKGROUND: Early school start times may curtail children's sleep and inadvertently promote sleep restriction. The current study examines the potential implications for early school start times for behavioral problems in public elementary schools (student ages 5-12 years) in Kentucky. METHOD: School start times were obtained from school Web sites or by calling school offices; behavioral and disciplinary problems, along with demographic information about schools, were obtained from the Kentucky Department of Education. Estimated associations controlled for teacher/student ratio, racial composition, school rank, enrollment, and Appalachian location. RESULTS: Associations between early school start time and greater behavioral problems (harassment, in-school removals, suspensions, and expulsions) were observed, although some of these associations were found only for schools serving the non-Appalachian region. CONCLUSIONS: Findings support the growing body of research showing that early school start times may contribute to student problems, and extend this research through a large-scale examination of elementary schools, behavioral outcomes, and potential moderators of risk. PMID- 28346156 TI - Association of sleep characteristics with cardiovascular and metabolic risk factors in a population sample: the Chicago Area Sleep Study. AB - OBJECTIVES: To investigate the association of sleep characteristics with prevalent hypertension, diabetes, and obesity in a multiethnic cohort. DESIGN: This study used a population-based cross-sectional study design. SETTING: Participants were recruited between 2009 and 2011 from Chicago, Illinois, and the surrounding suburbs. PARTICIPANTS: Participants were 492 adults aged 35 to 64years who self-reported as white, black, Hispanic, or Asian and who had a low likelihood of sleep apnea based on the apnea screening questionnaires and 1 night of apnea screening using an in-home device (apnea hypopnea index <15 or oxygen desaturation index <10). MEASUREMENTS: Participants wore a wrist actigraphy monitor (ActiwatchTM) for 7days. During a clinical examination, participants completed questionnaires about sleep, other health behaviors, and medical history and had their blood pressure, anthropometric measures, and fasting blood glucose measured; metabolic risk factors were determined based on standard clinical guidelines. RESULTS: The prevalence of hypertension, obesity, and diabetes was 17.1%, 5.5%, and 35.4%, respectively. Sleep duration was not associated with any cardiovascular risk factor. There was a significantly increased odds for hypertension (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.01-1.08) and obesity (OR, 1.03; 95% CI, 1.00-1.05) associated with higher sleep fragmentation (per 1%). There was also a significantly increased odds for hypertension associated with poorer self-reported sleep quality (OR, 1.14 [95% CI, 1.05-1.24] per 1-unit higher Pittsburgh Sleep Quality Index global score). CONCLUSION: Objective and self-reported sleep quality may be more important than duration in relation to prevalent hypertension. PMID- 28346158 TI - Delayed high school start times later than 8:30am and impact on graduation rates and attendance rates. AB - OBJECTIVES: The first purpose of this study was to investigate changes in high school graduation rates with a delayed school start time of later than 8:30am. The second aim of the study was to analyze the association between a delayed high school start time later than 8:30am and attendance rates. DESIGN: In the current study, a pre-post design using a repeated-measures analysis of variance was used to examine changes in attendance and graduation rates 2 years after a delayed start was implemented. SETTING: Public high schools from 8 school districts (n=29 high schools) located throughout 7 different states. Schools were identified using previous research from the Children's National Medical Center's Division of Sleep Medicine Research Team. PARTICIPANTS AND MEASUREMENTS: A total membership of more than 30,000 high school students enrolled in the 29 schools identified by the Children's National Medical Center's Research Team. A pre-post design was used for a within-subject design, controlling for any school-to-school difference in the calculation of the response variable. This is the recommended technique for a study that may include data with potential measurement error. RESULTS: Findings from this study linked a start time of later than 8:30am to improved attendance rates and graduation rates. CONCLUSIONS: Attendance rates and graduation rates significantly improved in schools with delayed start times of 8:30am or later. School officials need to take special notice that this investigation also raises questions about whether later start times are a mechanism for closing the achievement gap due to improved graduation rates. PMID- 28346159 TI - Using actigraphy feedback to improve sleep in soldiers: an exploratory trial. AB - OBJECTIVES: The objective of this study was to assess the impact of wearing an actigraph and receiving personalized feedback on the sleep of a high-risk occupational group: United States soldiers recently returned from a combat deployment. DESIGN: Following a baseline survey with a full sample, a subsample of soldiers wore an actigraph, received feedback, and completed a brief survey. Two months later, the full sample completed a follow-up survey. The actigraph intervention involved wearing an actigraph for 3 weeks and then receiving a personalized report about sleep patterns and an algorithm-based estimate of cognitive functioning derived from individual sleep patterns. RESULTS: Propensity score matching with a genetic search algorithm revealed that subjects in the actigraph condition (n=43) reported fewer sleep problems (t value = -2.55, P<.01) and getting more sleep hours (t value =1.97, P<.05) at follow-up than those in a matched comparison condition (n=43, weighted). There were no significant differences in functioning, somatic symptoms, and mental health outcomes (posttraumatic stress disorder symptoms and depression). A significant interaction indicated that the actigraph had a more beneficial effect on those with more somatic symptoms at baseline but not those with more sleep problems. Most participants rated the personalized report as helpful. CONCLUSION: Actigraphs combined with personalized reports may offer a useful, simple intervention to improve the sleep patterns of large, high-risk occupational groups. PMID- 28346160 TI - Sleep under a mother's protective gaze. PMID- 28346161 TI - Gender differences in sleep hygiene practices and sleep quality in New Zealand adolescents aged 15 to 17 years. AB - AIM: To examine, in a nationwide sample of New Zealand adolescents, self-reported sleep hygiene, and specifically evening technology and caffeine use, and body mass index, in relation to sleep quality. DESIGN: Cross-sectional survey. PARTICIPANTS: A total of 692 adolescents (59% girls), predominantly European (78%), with an average age of 16 years 9 months were recruited through schools, community advertising, and social media. MEASURES: All participants completed the Pittsburgh Sleep Quality Index and Adolescent Sleep Hygiene Scale online, and questions about their height, weight, evening technology use, and caffeine consumption. RESULTS: Fifty-six percent of adolescents had poor sleep quality with a higher prevalence in girls (63.1%) than in boys (44.5%), and sleep hygiene (Adolescent Sleep Hygiene Scale) was significantly worse in girls. Caffeine after dinner was associated with increased adjusted odds of a poorer score for Pittsburgh Sleep Quality Index-evaluated daytime dysfunction (P=.002). A higher proportion of girls drank hot caffeinated drinks (51.8%) after dinner than did boys (38.1%), and although more boys (12.1% vs 9.2%) drank energy drinks, the difference was not significant. A 1-hour increase in evening technology time increased the odds of poor sleep efficiency by 20% (P=.04). A 1-zscore increase in body mass index resulted in a 38% higher adjusted odds of poor sleep efficiency (P=.015) and 21% higher adjusted odds of long sleep latency (P=.032). DISCUSSION: The findings highlight gender differences in sleep quality and some presleep behaviors of New Zealand youth, and support the role for good sleep hygiene practices to promote healthy sleep in adolescents. PMID- 28346163 TI - Sleep and mental health: the moderating role of perceived adolescent-parent attachment. AB - OBJECTIVE: The present study investigated whether the effects of sleep duration and quality on adolescent adjustment were moderated by perceived attachment to mothers and fathers. DESIGN: The study used a cross-sectional design. SETTING: Participants were recruited from small town and semirural communities in Alabama. PARTICIPANTS: Participants were 106 adolescents (mean age=13.61 years, SD=.73; 55% girls; 28% African American, 72% European American) and their parents. MEASUREMENTS: Sleep duration (minutes) and sleep quality (efficiency, number of long wake episodes) were derived using actigraphy, and subjective sleep/wake problems were derived with adolescent reports. Adolescents also reported on perceived attachment to mothers and fathers, internalizing symptoms, and self esteem. Mothers and fathers reported on externalizing behaviors. RESULTS: Path model analyses indicated that perceived attachment to parents moderated relations between adolescents' sleep quality and their adjustment. For externalizing symptoms and self-esteem, adolescents at greatest risk for maladjustment were those who reported poor quality sleep (ie, more sleep/wake problems, lower sleep efficiency) coupled with less secure attachment to parents. Conversely, adolescents who experienced better actigraphy-based sleep quality (ie, higher sleep efficiency, fewer long wake episodes) in conjunction with more secure attachment to parents experienced the lowest levels of anxiety symptoms. Less secure attachment was associated with high levels of anxiety symptoms independent of sleep quality. Similar patterns of associations emerged for attachment to mothers and fathers. CONCLUSIONS: Findings highlight the importance of examining the conjoint influence of sleep and adolescent-parent relationships toward explication of adolescent's mental health. PMID- 28346162 TI - Household chaos and sleep-disturbing behavior of family members: results of a pilot study of African American early adolescents. AB - BACKGROUND: Although disorganized, chaotic households have been linked to poorer sleep outcomes, how household chaos actually manifests itself in the behaviors of others around the bedtime of a child or adolescent is not well understood. OBJECTIVE: To determine whether household chaos was associated with specific, nightly sleep-disturbing activities of adolescents' family members. DESIGN: Longitudinal study. PARTICIPANTS: Twenty-six African American or multiethnic early adolescent (ages 11-12 years) and parent dyads, recruited from local schools and social-service agencies in greater Cleveland, OH. MEASUREMENTS: Over 14 days, each night at bedtime, adolescents identified family-member activities keeping them awake or making it difficult to sleep by using a smart phone administered survey. Household organization was assessed via parent-completed, validated instruments. A generalized linear mixed model examined associations between each activity and household-organization measures. RESULTS: Adjusted for the effect of school being in session the next day, an increasingly chaotic household was associated with increased odds of household members disturbing adolescents' efforts to fall asleep by watching TV/listening to music (odds ratio [OR]=1.8, 95% confidence interval [CI]=1.2-3.2), phoning/texting (OR=1.7, 95% CI =1.2-2.9), or having friends/relatives over visiting at the home (OR=1.6, 95% CI =1.0-3.0). Conversely, a more chaotic household was associated with decreased odds of adolescents reporting that "nothing" was keeping them awake or making it more difficult to sleep (OR=0.6, 95% CI =0.4-0.8). Enforced sleep rules were inconsistently associated with sleep-disturbing behaviors. CONCLUSION: Improving early-adolescent sleep may benefit from considering the nighttime behavior of all household members and encouraging families to see that improving early-adolescent sleep requires the household's participation. PMID- 28346164 TI - Affiliative interpersonal behaviors during stress are associated with sleep quality and presleep arousal in young, healthy adults. AB - OBJECTIVES: This study examined the association between stress-related interpersonal behaviors, presleep arousal (PSA), and sleep quality. METHODS: Sixty-four participants (53% female) described a recent stressful interpersonal event that was coded for overall degree of affiliation (warmth vs hostility) and autonomy (independence vs interdependence). Cognitive and somatic PSA and sleep quality were examined using regression with affiliation and autonomy scores as predictors. Specific interpersonal behaviors that comprise overall affiliation were also examined. RESULTS: More affiliation (warmth) was associated with lower cognitive PSA (beta=-.32) and better sleep quality (beta=-.28). Autonomy was not associated with sleep quality or PSA. The specific behavior trust in others was associated with better sleep quality (rs=-.25). CONCLUSIONS: Behaviors during stress reflect underlying dimensions of interpersonal security. Findings underscore importance of interpersonal frameworks for understanding associations between stress and sleep, and provide support for the anthropological theory that interpersonal security is necessary for healthy sleep. PMID- 28346165 TI - Department of Error. PMID- 28346166 TI - November 8-14, 2014. PMID- 28346167 TI - Antibiotic research priorities: ready, set, now go. PMID- 28346169 TI - Corrections. PMID- 28346168 TI - Vaccine compliance and the 2016 Arkansas mumps outbreak. PMID- 28346170 TI - Corrections. PMID- 28346171 TI - The need for randomised controlled trials of isoniazid monoresistant tuberculosis treatment. PMID- 28346172 TI - FATE: the new partnership to Fight Against TB in Central and Eastern Europe. PMID- 28346173 TI - Drawbacks of communicating refugee vaccination rates. PMID- 28346174 TI - Surveillance of Crimean-Congo haemorrhagic fever in Pakistan. PMID- 28346175 TI - HPV screening in Islamic countries. PMID- 28346176 TI - Until eradication, awareness. PMID- 28346177 TI - Biomarker tests for bacterial infection-a costly wait for the holy grail. PMID- 28346178 TI - Duration of surgical antibiotic prophylaxis in patients with asymptomatic bacteriuria - Authors' reply. PMID- 28346179 TI - Duration of surgical antibiotic prophylaxis in patients with asymptomatic bacteriuria. PMID- 28346180 TI - HIV vaccines: where are we now? PMID- 28346181 TI - Highlights from the 24th CROI. PMID- 28346182 TI - Social otitis media: ear infection and disparity in Australia. PMID- 28346185 TI - Neisseria meningitidis and purpura fulminans in a woman with chronic liver disease. PMID- 28346186 TI - Epithelioid cell granuloma in the bone marrow secondary to Epstein-Barr virus infection. PMID- 28346187 TI - Re: The role of Th1/Th2 cells and associated cytokines in autoimmune hepatitis. PMID- 28346188 TI - Seroprevalance of hepatitis B and C infections in Turkey. PMID- 28346189 TI - Etiology and comorbidities of childhood obesity. PMID- 28346190 TI - Retraction Notice. AB - This retracts the article DOI: 10.4318/tjg.2011.0208. PMID- 28346192 TI - Menopausal Symptom Relief and Side Effects Experienced by Women Using Compounded Bioidentical Hormone Replacement Therapy and Synthetic Conjugated Equine Estrogen and/or Progestin Hormone Replacement Therapy, Part 3. AB - The use of compounded bioidentical hormone replacement therapy by menopausal women has become a popular alternative to traditional synthetic conjugated equine estrogen and progestin hormone replacement therapy due to safety concerns raised by recent studies. However, due to the lack of randomized, large-scale trials to evaluate the efficacy and side-effect profile of compounded bioidentical hormone replacement therapy many healthcare providers are reluctant to prescribe such therapy. The purpose of this study was to compare women's menopausal symptom relief and side effects experienced when using compounded bioidentical hormone replacement therapy and traditional hormone replacement therapy. A descriptive comparative design was used. Inferential and descriptive statistical procedures including a paired difference t-test, two-sample t-test, and f-tests (percentage, mean, standard deviation, frequency) were run on the Statistical Package for the Social Sciences. The framework used to guide this study was Lenz and Pugh's Theory of Unpleasant Symptoms. Surveys were distributed once to a convenient sample of women aged 35 and older when they dropped off or picked up their prescriptions at a pharmacy. Of the 216 surveys distributed, 70 were returned from those women taking compounded bioidentical hormone replacement therapy and 53 from traditional hormone replacement therapy. The survey contained 15 questions pertaining to age, duration of hormone replacement therapy, type and formulation of hormone replacement therapy, reasons for initiating hormone replacement therapy, symptoms before and one month after hormone replacement therapy, and side effects related to hormone replacement therapy. Included in part 1 of this series of articles was the introduction to the study conducted and the results of the literature review that was conducted for the purpose of examining the current data related to the topic of hormone replacement therapy. Part 2 provided a brief discussion on the significance of this study to nursing and provided the methods used in this study. The results and conclusion of this study are provided within this article. PMID- 28346193 TI - When to Compound Medications for Veterinary Patients. AB - This article serves as a brief discussion about some of the restrictions applicable to compounding medications for veterinary patients based on U. S. Food and Drug Administration compliance policy guidelines and provides a brief summary of when it is appropriate to compound medications for veterinary patients. PMID- 28346194 TI - Case Report: Diabetic Foot Ulcer Infection Treated with Topical Compounded Medications. AB - An adult diabetic male with three toes amputated on his right foot presented with an ulcer infection on his left foot, unresponsive to conventional antifungal oral medication for over two months. The ulcerated foot wound had a large impairment on the patient's quality of life, as determined by the Wound-QoL questionnaire. The compounding pharmacist recommended and the physician prescribed two topical compounded medicines, which were applied twice a day, free of charge at the compounding pharmacy. The foot ulcer infection was completely resolved following 13 days of treatment, with no longer any impairment on the patient's quality of life. This scientific case study highlights the value of pharmaceutical compounding in current therapeutics, the importance of the triad relationship, and the key role of the compounding pharmacist in diabetes care. PMID- 28346195 TI - Why You Should Become an International Academy of Compounding Pharmacists Member. PMID- 28346196 TI - Analytic Methods Used in Quality Control in a Compounding Pharmacy. AB - Analytical testing will no doubt become a more important part of pharmaceutical compounding as the public and regulatory agencies demand increasing documentation of the quality of compounded preparations. Compounding pharmacists must decide what types of testing and what amount of testing to include in their quality control programs, and whether testing should be done in-house or outsourced. Like pharmaceutical compounding, analytical testing should be performed only by those who are appropriately trained and qualified. This article discusses the analytical methods that are used in quality control in a compounding pharmacy. PMID- 28346197 TI - Basics of Compounding with Dilutions and Concentrates. AB - Pharmacists use various sources for obtaining the active pharmaceutical ingredient for compounding medications. In many cases, it is the pure drug (United States Pharmacopeia, National Formulary, or similar grade); in some cases, it can be a commercial dosage form; and, in some cases, it may be a dilution or concentrate. If the drug is not present at full strength, then adjustments may be necessary to obtain the required quantity of drug. Also, in many cases, it is necessary to use a dilution or a concentrate of a drug due to safety and quality reasons. Presented within this article are new sources of active pharmaceutical ingredients that are now available to aid pharmacists in meeting future United States Pharmacopeia <800> standards. It is critical that the pharmacist be aware of the strength of the drug and any other excipients that may be available. PMID- 28346198 TI - Basics of Sterile Compounding: Biopharmaceutics of Injectable Dosage Forms. AB - Biopharmaceutics studies the relationship between the drug product and what happens after the product is administered. Since the majority of injectables are administered by the intravenous route, thus avoiding the need for drug absorption, not many articles are published compared to other routes of drug administration. However, other routes of administration for drug injection are becoming more frequent because of greater commercial availability of sustained- and controlled-release drug delivery systems. This article reviews basic principles of drug absorption, distribution, metabolism, and elimination of injectable drugs and certain physicochemical and physiological factors affecting injectable drug biopharmaceutics. PMID- 28346199 TI - Compatibility and Stability of Rolapitant Injectable Emulsion Admixed with Dexamethasone Sodium Phosphate. AB - Neurokinin-1 receptor antagonist, 5-hydroxytryptamine-3 receptor antagonist, and dexamethasone combination therapy is the standard of care for the prevention of chemotherapy-induced nausea and vomiting. Herein, we describe the physical and chemical stability of an injectable emulsion of the Neurokinin-1 receptor antagonist rolapitant 185 mg in 92.5 mL (free base, 166.5 mg in 92.5 mL) admixed with either 2.5 mL of dexamethasone sodium phosphate (10 mg) or 5 mL of dexamethasone sodium phosphate (20 mg). Admixtures were prepared and stored in two types of container closures (glass and Crystal Zenith plastic bottles) and four types of intravenous administration tubing sets (or intravenous tubing sets). The assessment of the physical and chemical stability was conducted on admixtures packaged in bottled samples stored at room temperature (20 degrees C to 25 degrees C under fluorescent light) and evaluated at 0, 1, and 6 hours. For admixtures in intravenous tubing sets, the assessment of physicochemical stability was performed after 0 and 7 hours of storage at 20 degrees C to 25 degrees C, and then after 20 hours (total 27 hours) under refrigeration (2 degrees C to 8 degrees C) and protected from light. Physical stability was assessed by visually examining the bottle contents under normal room light and measuring turbidity and particulate matter. Chemical stability was assessed by measuring the pH of the admixture and determining drug concentrations through high-performance liquid chromatographic analysis. Results showed that all samples were physically compatible throughout the duration of the study. The admixtures stayed within narrow and acceptable ranges in pH, turbidity, and particulate matter. Admixtures of rolapitant and dexamethasone were chemically stable when stored in glass and Crystal Zenith bottles for at least 6 hours at room temperature, as well as in the four selected intravenous tubing sets for 7 hours at 20 degrees C to 25 degrees C and then for 20 (total 27 hours) hours at 2 degrees C to 8 degrees C. No loss of potency of any admixed component occurred in the samples stored at the temperature ranges studied. PMID- 28346200 TI - Compatibility and Stability of Rolapitant Injectable Emulsion Admixed with Intravenous Palonosetron Hydrochloride. AB - Neurokinin-1 receptor antagonist, 5-hydroxytryptamine-3 RA, and dexamethasone combination therapy is standard of care for the prevention of chemotherapy induced nausea and vomiting. Herein we describe the physical and chemical stability of rolapitant injectable emulsion 166.5 mg in 92.5 mL (185 mg hydrochloride salt) admixed with palonosetron injection 0.25 mg in 5 mL (0.28 mg hydrochloride salt). Admixtures were prepared and stored in two types of container closures (110-mL Crystal Zenith plastic and glass bottles) and four types of intravenous administration sets (or intravenous tubing sets). Assessment of the physical and chemical stability was conducted on the admixtures in the ready-to-use container closure systems as supplied by the manufacturer, stored at room temperature (20 degrees C to 25 degrees C under fluorescent light), and evaluated at 0, 1, and 6 hours; 1 and 2 days; and under refrigeration (2 degrees C to 8 degrees C protected from light) after 1, 3, and 7 days. For admixtures in intravenous tubing sets, the assessment of physicochemical stability was performed after 0 and 7 hours of storage at 20 degrees C to 25 degrees C initially, and then after 20 hours (total 27 hours) at 2 degrees C to 8 degrees C protected from light. Physical stability was assessed by visual examination of the container contents under normal room light, and measuring turbidity and particulate matter. Chemical stability was assessed by measuring the pH of the admixture and determining drug concentrations and impurity levels with high performance liquid chromatographic analysis. The results indicated that all samples were physically compatible throughout the duration of the study. The pH, turbidity, and particulate matter of the admixture stayed within narrow and acceptable ranges. Rolapitant admixed with palonosetron was chemically stable when admixed in glass and Crystal Zenith bottles for at least 48 hours at room temperature and for 7 days under refrigeration, as well as in the four selected intravenous tubing sets for 7 hours at 20 degrees C to 25 degrees C and then for 20 hours at 2 degrees C to 8 degrees C. No loss of potency of any admixed components occurred in the samples stored at the two temperature ranges and time period studied. PMID- 28346201 TI - A Pilot Stability Study of Dehydroepiandrosterone Rapid-dissolving Tablets Prepared by Extemporaneous Compounding. AB - Dehydroepiandrosterone supplementation is used to treat a variety of conditions. Rapid-dissolving tablets are a relatively novel choice for compounded dehydroepiandrosterone dosage forms. While rapid-dissolving tablets offer ease of administration, there are uncertainties about the physical and chemical stability of the drug and dosage form during preparation and over long-term storage. This study was designed to evaluate the stability of dehydroepiandrosterone rapid dissolving tablets just after preparation and over six months of storage. The Professional Compounding Centers of America rapid-dissolving tablet mold and base formula were used to prepare 10-mg strength dehydroepiandrosterone rapid dissolving tablets. The formulation was heated at 100 degrees C to 110 degrees C for 30 minutes, released from the mold, and cooled at room temperature for 30 minutes. The resulting rapid-dissolving tablets were individually packaged in amber blister packs and stored in a stability chamber maintained at 25 degrees C and 60% relative humidity. The stability samples were pulled at pre-determined time points for evaluation, which included visual inspection, tablet weight check, United States Pharmacopeia disintegration test, and stability-indicating high-performance liquid chromatography. The freshly prepared dehydroepiandrosterone rapiddissolving tablets exhibited satisfactory chemical and physical stability. Time 0 samples disintegrated within 40 seconds in water kept at 37 degrees C. The high-performance liquid chromatographic results confirmed that the initial potency was 101.9% of label claim and that there was no chemical degradation from the heating procedure. Over six months of storage, there were no significant changes in visual appearance, physical integrity, or disintegration time for any of the stability samples. The high-performance liquid chromatographic results also indicated that dehydroepiandrosterone rapid dissolving tablets retained >95% label claim with no detectable degradation products. The dehydroepiandrosterone rapid-dissolving tablets investigated in this pilot study were physically and chemically stable during preparation and over six months of storage at 25 degrees C and 60% relative humidity. PMID- 28346202 TI - PreScription: Whatever Happened to Common Sense? PMID- 28346203 TI - U.S. Food and Drug Administration Inspections: Guide to a Successful Outcome for 503A Sterile Compounding Pharmacies. AB - The reasons for which pharmaceutical compounding is the focus of intense state and federal scrutiny are now well known. Compounders are faced with an ever increasing need to prove, by objective standards, the safety, purity, and potency of the formulations they dispense. They must also demonstrate their compliance with regulations often based on current good compounding practices designed for the pharmaceutical industry. In the U.S. today, rigorous unannounced state and federal inspections of compounding facilities are occurring more and more frequently. To achieve a successful outcome, communicating clearly and effectively with inspectors and having ready access to the information they request are as critical as proving compliance. This article describes the author's experience with an unannounced United States Food and Drug Administration inspection of his 503A compounding facility and his response to the findings. Readers will learn what to expect during such an inspection, how to prepare for that event, and how to achieve an excellent outcome. Those who would like more information about any of the topics presented are invited to contact the author at the address provided at the close of this article. PMID- 28346204 TI - Restructuring the Art of Health by Pharmacists: Formulation Designs with Oral Vehicles--Teaching Pharmacy Students. AB - Compounding pharmacists, responsible for appropriate preparation of medications, coordinate with other professionals to reach optimal therapeutic options for patients. This review summarizes proprietary oral vehicles or suspensions focusing on available information or updated data from suppliers. Research has advanced methods with revised applications, cutting-edge safety considerations, beyond-use dating provisions for technical assistance, and evidence to review and teach pharmacy students the opportunities in the choices of an oral vehicle. Current marketing, competitive, and scientific trends necessitate that manufacturers shift further to research of product or integrated product mixes to sustain their independence in pharmacies. PMID- 28346205 TI - Consultation for Human, Veterinary, and Compounded Medications. AB - Providing consultation on medications is a daily responsibility for pharmacists. However, counseling components for veterinary or compounded medications can differ from those for manufactured medications for humans. This article lists the content that should be provided during consultation, describes differences between counseling for human and veterinary patients, and provides references that can be used. Because many veterinary medications are compounded, this article also provides information that should accompany compounded preparations. PMID- 28346206 TI - The International Academy of Compounding Pharmacists Introduces a New President. PMID- 28346207 TI - Quality Control: (Material) Safety Data Sheets. AB - Safety Data Sheets (formerly Material Safety Data Sheets) are a system for cataloging information on chemicals, chemical compounds, and chemical mixtures and include instructions for the safe use and potential hazards associated with a particular material or product. At present, there are 16 sections of Safety Data Sheets, and these sections are discussed in this article. Two United States Pharmacopeia compounding-related chapters (<795> and <800>) refer to Safety Data Sheets, and this article provides a brief discussion on the terminology contained within those chapters. PMID- 28346208 TI - Basics of Compounding: 3D Printing--Pharmacy Applications, Part 1. AB - Three-dimensional printing quickly became a standard tool in the automotive, aerospace, and consumer goods industries and, recently, has begun gaining traction in pharmaceutical manufacturing. 3D printing has steadily grown, introducing a new element into dosage form development, and has received a boost with U.S. Food and Drug Administration (FDA) approval of the 3D-printed orodispersible tablet, Spritam (levetiracetam). This part 1 of a 3-part article introduces 3D printing and its application to pharmacy. PMID- 28346209 TI - Accuracy Considerations in Sterile Compounding. AB - Published information about the accuracy of filling and closing operations of sterile products is limited and guidelines on the topic are very general. This article highlights the basic principles in sterile-product filling of syringes and vials. Also covered in this article are descriptions of some of the available devices for filling containers, a brief discussion of the advances in vial and syringe filling, a discussion on the advantages and disadvantages of sterile product filling methods, and a discussion on possible problems encountered during filling operations. Because of the extremely high costs of some new drugs, especially biopharmaceuticals, compounding pharmacies may prefer to fill small batches to reduce the risk of unacceptable monetary losses in the event of a manufacturing deviation that results in batch rejection. PMID- 28346210 TI - Stability of Alprostadil in 0.9% Sodium Chloride Stored in Polyvinyl Chloride Containers. AB - The stability of alprostadil diluted in 0.9% sodium chloride stored in polyvinyl chloride (VIAFLEX) containers at refrigerated temperature, protected from light, is reported. Five solutions of alprostadil 11 mcg/mL were prepared in 250 mL 0.9% sodium chloride polyvinyl chloride (PL146) containers. The final concentration of alcohol was 2%. Samples were stored under refrigeration (2 degrees C to 8 degrees C) with protection from light. Two containers were submitted for potency testing and analyzed in duplicate with the stability-indicating high-performance liquid chromatography assay at specific time points over 14 days. Three containers were submitted for pH and visual testing at specific time points over 14 days. Stability was defined as retention of 90% to 110% of initial alprostadil concentration, with maintenance of the original clear, colorless, and visually particulate-free solution. Study results reported retention of 90% to 110% initial alprostadil concentration at all time points through day 10. One sample exceeded 110% potency at day 14. pH values did not change appreciably over the 14 days. There were no color changes or particle formation detected in the solutions over the study period. This study concluded that during refrigerated, light protected storage in polyvinyl chloride (VIAFLEX) containers, a commercial alcohol-containing alprostadil formulation diluted to 11 mcg/mL with 0.9% sodium chloride 250 mL was stable for 10 days. PMID- 28346211 TI - Stability of Two Antifungal Agents, Fluconazole and Miconazole, Compounded in HUMCO RECURA Topical Cream to Determine Beyond-Use Date. AB - A novel compounding vehicle (RECURA) has previously been proven to penetrate the nail bed when compounded with the antifungal agent miconazole or fluconazole, providing for an effective treatment for onychomycosis. In this study, miconazole and fluconazole were compounded separately in RECURA compounding cream, and they were tested at different time points (0, 7, 14, 28, 45, 60, 90, and 180 days) to determine the beyond-use date of those formulations. The beyond-use date testing of both formulations (10% miconazole in RECURA and 10% fluconazole in RECURA) proved them to be physically, chemically, and microbiologically stable under International Conference of Harmonisation controlled room temperature (25 degrees C +/- 2 degrees C/60% RH +/-5%) for at least 180 days from the date of compounding. Stability-indicating analytical method validation was completed for the simultaneous determination of miconazole and fluconazole in RECURA base using high-performance liquid chromatography coupled with photodiode array detector prior to the study. PMID- 28346212 TI - Stability of Extemporaneously Prepared Hydroxycarbamide Oral Suspensions. AB - Hydroxycarbamide, available as tablets, is a pharmacological agent for fetal hemoglobin induction such as sickle cell anemia. The need for alternative dosage form options for patients unable to take tablets led hospital pharmacies to prepare solutions and suspensions. The objective of this study was to determine the stability of hydroxycarbamide in Ora-Plus in combination with either Ora Sweet or Ora-Sweet SF, Ora-Blend, or Ora-Blend SF suspending agents. The studied samples were compounded into 100-mg/mL suspensions and stored in 60-mL amber glass bottles at room (22 degrees C to 25 degrees C) or refrigerated (4 degrees C to 8 degrees C) temperature. Samples were assayed at each time point out to 120 days by a stability-indicating high-performance liquid chromatography method. The samples were examined for any change in color, odor, visual microbiology, and pH on initial and final day of analysis. At least 90% of hydroxycarbamide concentration remained in all suspensions at the end of the 120-day study period in both conditions. There was no appreciable change in color, odor, or taste. The pH values of suspensions stored at 25 degrees C changed by at least 1 unit at the end of the study period. Based on the data collected, the beyond-use date of these suspensions is 120 days when stored in 60-mL amber glass bottles at both temperature storage conditions. PMID- 28346213 TI - Development and Application of a High-Performance Liquid Chromatography Stability Indicating Assay for Beyond-Use Date Determination of Compounded Topical Gels Containing Multiple Active Drugs. AB - Topical gels compounded by pharmacists are important clinical tools for the management of pain. Nevertheless, there is often a dearth of information about the chemical stability of drugs included in these topical formulations, complicating the assignment of beyond-use dating. The purpose of this study was to develop a high-performance liquid chromatography photodiode array-based stability-indicating assay that could simultaneously resolve six drugs (amitriptyline, baclofen, clonidine, gabapentin, ketoprofen, lidocaine) commonly included in topical gels for pain management and their potential degradation products. Furthermore, this method was applied to the determination of beyond-use dating of combinations of these drugs prepared in commonly utilized bases (Lipobase, Lipoderm, Pluronic organogel). Gabapentin was determined to be the least stable component in all formulations tested. Measured stability ranged between 7 to 49 days depending on the base and other active drugs present in the formulation. In the absence of gabapentin, baclofen was the next least stable component, lasting for 120 days, regardless of the type of formulating base used. PMID- 28346214 TI - Suspensions as a Valuable Alternative to Extemporaneously Compounded Capsules. AB - The objective of this study was to determine the variation in content of 74 different active pharmaceutical ingredients (APIs) and compare it with what is known in the literature for the content uniformity of extemporaneous prepared capsules. Active pharmaceutical ingredients quantification was performed by high performance liquid chromatography, via a stability-indicating method. Samples for all active pharmaceutical ingredients were taken throughout a 90-day period and the content was determined. In total, 5,190 different samples were analyzed for 74 different active pharmaceutical ingredients at room (15 degrees C to 25 degrees C) or controlled refrigerated temperature (2 degrees C to 8 degrees C). Each of these datasets was analyzed according to the United States Pharmacopeia Content Uniformity monograph, corrected for the sample number. The mean acceptance values were well within specifications. In addition, all suspensions complied with the criteria defined by the British Pharmacopoeia monograph for Content Uniformity of Liquid Dispersions for both room and controlled refrigerated temperature. In previous studies, it was found that a routine weight variation check is often not sufficient for quality assurance of extemporaneous prepared capsules. Compounded oral liquids show little variation in content for 74 different active pharmaceutical ingredients; therefore, compounded oral liquids are a suitable alternative when compounding individualized medications for patients. PMID- 28346215 TI - Enhanced optoelectronic quality of perovskite films with excess CH3NH3I for high efficiency solar cells in ambient air. AB - Solution-processed polycrystalline perovskite films contribute critically to the high photovoltaic performance of perovskite-based solar cells (PSCs). The inevitable electronic trap states at grain boundaries and intrinsic defects such as metallic lead (Pb0) and halide vacancies in perovskite films cause serious carrier recombination loss. Furthermore, the film can easily decompose into PbI2 in a moist atmosphere. Here, we introduce a simple strategy, through a small increase in methylammonium iodide (CH3NH3I, MAI), molar proportion (5%), for perovskite fabrication in ambient air with ~50% relative humidity. Analysis of the morphology and crystallography demonstrates that excess MAI significantly promotes grain growth without decomposition. X-ray photoemission spectroscopy shows that no metallic Pb0 exists in the perovskite film and the I/Pb ratio is improved. A time-resolved photoluminescence measurement indicates efficient suppression of non-radiative recombination in the perovskite layer. As a result, the device yields improved power conversion efficiency from 14.06% to 18.26% with reduced hysteresis and higher stability under AM1.5G illumination (100 mW cm-2). This work strongly provides a feasible and low-cost way to develop highly efficient PSCs in ambient air. PMID- 28346216 TI - Non-linear conduction due to depinning of charge order domains in Fe3O2BO3. AB - The oxyborate Fe3O2BO3 presents a charge density wave (CDW) transition close to room temperature. As we show here, this is associated with a well defined anomaly in the specific heat. Below this transition, when applying in a single crystal of Fe3O2BO3 a DC voltage above a temperature dependent threshold, a high current is liberated in this material. We study the conduction in single crystals of Fe3O2BO3 with voltage applied parallel and perpendicular to the crystallographic c axis direction. The observed currents are attributed to the depinning of charge ordered domains above a threshold voltage V T2 that gives rise to a collective conduction due to coherent domains. Compliance limited DC data shows that above a lower threshold voltage depinning is smooth and follows a power law scaling. Similar depinning with power law scaling is also revealed in the AC conductivity. PMID- 28346217 TI - The possibility of multi-layer nanofabrication via atomic force microscope-based pulse electrochemical nanopatterning. AB - Pulse electrochemical nanopatterning, a non-contact scanning probe lithography process using ultrashort voltage pulses, is based primarily on an electrochemical machining process using localized electrochemical oxidation between a sharp tool tip and the sample surface. In this study, nanoscale oxide patterns were formed on silicon Si (100) wafer surfaces via electrochemical surface nanopatterning, by supplying external pulsed currents through non-contact atomic force microscopy. Nanoscale oxide width and height were controlled by modulating the applied pulse duration. Additionally, protruding nanoscale oxides were removed completely by simple chemical etching, showing a depressed pattern on the sample substrate surface. Nanoscale two-dimensional oxides, prepared by a localized electrochemical reaction, can be defined easily by controlling physical and electrical variables, before proceeding further to a layer-by-layer nanofabrication process. PMID- 28346218 TI - Wafer-scale production of highly uniform two-dimensional MoS2 by metal-organic chemical vapor deposition. AB - Semiconducting two-dimensional (2D) materials, particularly extremely thin molybdenum disulfide (MoS2) films, are attracting considerable attention from academia and industry owing to their distinctive optical and electrical properties. Here, we present the direct growth of a MoS2 monolayer with unprecedented spatial and structural uniformity across an entire 8 inch SiO2/Si wafer. The influences of growth pressure, ambient gases (Ar, H2), and S/Mo molar flow ratio on the MoS2 layered growth were explored by considering the domain size, nucleation sites, morphology, and impurity incorporation. Monolayer MoS2 based field effect transistors achieve an electron mobility of 0.47 cm2 V-1 s-1 and on/off current ratio of 5.4 * 104. This work demonstrates the potential for reliable wafer-scale production of 2D MoS2 for practical applications in next generation electronic and optical devices. PMID- 28346219 TI - Semiconductor devices for entangled photon pair generation: a review. AB - Entanglement is one of the most fascinating properties of quantum mechanical systems; when two particles are entangled the measurement of the properties of one of the two allows the properties of the other to be instantaneously known, whatever the distance separating them. In parallel with fundamental research on the foundations of quantum mechanics performed on complex experimental set-ups, we assist today with bourgeoning of quantum information technologies bound to exploit entanglement for a large variety of applications such as secure communications, metrology and computation. Among the different physical systems under investigation, those involving photonic components are likely to play a central role and in this context semiconductor materials exhibit a huge potential in terms of integration of several quantum components in miniature chips. In this article we review the recent progress in the development of semiconductor devices emitting entangled photons. We will present the physical processes allowing the generation of entanglement and the tools to characterize it; we will give an overview of major recent results of the last few years and highlight perspectives for future developments. PMID- 28346220 TI - Magnetocrystalline two-fold symmetry in CaFe2O4 single crystal. AB - Understanding of magnetocrystalline anisotropy in CaFe2O4 is a matter of importance for its future applications. A high quality single crystal CaFe2O4 sample is studied by using synchrotron x-ray diffraction, a magnetometer and the electron spin resonance (ESR) technique. A broad feature of the susceptibility curve around room temperature is observed, indicating the development of 1D spin interactions above the on-set of antiferromagnetic transition. The angular dependency of ESR reveals an in-plane two-fold symmetry, suggesting a strong correlation between the room temperature spin structure and magnetocrystalline anisotropy. This finding opens an opportunity for the device utilizing the anisotropy field of CaFe2O4. PMID- 28346221 TI - Direct nucleation, morphology and compositional tuning of InAs1-x Sb x nanowires on InAs (111) B substrates. AB - III-V ternary nanowires are interesting due to the possibility of modulating their physical and material properties by tuning their material composition. Amongst them InAs1-x Sb x nanowires are good candidates for applications such as Infrared detectors. However, this material has not been grown directly from substrates, in a large range of material compositions. Since the properties of ternaries are alterable by tuning their composition, it is beneficial to gain access to a wide range of composition tunability. Here we demonstrate direct nucleation and growth of InAs1-x Sb x nanowires from Au seed particles over a broad range of compositions (x = 0.08-0.75) for different diameters and surface densities by means of metalorganic vapor phase epitaxy. We investigate how the nucleation, morphology, solid phase Sb content, and growth rate of these nanowires depend on the particle dimensions, and on growth conditions such as the vapor phase composition, V/III ratio, and temperature. We show that the solid phase Sb content of the nanowires remains invariant towards changes of the In precursor flow. We also discuss that at relatively high In flows the growth mechanism alters from Au-seeded to what is referred to as semi In-seeded growth. This change enables growth of nanowires with a high solid phase Sb content of 0.75 that are not feasible via Au-seeded growth. Independent of the growth conditions and morphology, we report that the nanowire Sb content changes over their length, from lower Sb contents at the base, increasing to higher amounts towards the tip. We correlate the axial Sb content variations to the axial growth rate measured in situ. We also report spontaneous core-shell formation for Au seeded nanowires, where the core is Sb-rich in comparison to the Sb-poor shell. PMID- 28346222 TI - Sign determination methods for the respiratory signal in data-driven PET gating. AB - Patient respiratory motion during PET image acquisition leads to blurring in the reconstructed images and may cause significant artifacts, resulting in decreased lesion detectability, inaccurate standard uptake value calculation and incorrect treatment planning in radiation therapy. To reduce these effects data can be regrouped into (nearly) 'motion-free' gates prior to reconstruction by selecting the events with respect to the breathing phase. This gating procedure therefore needs a respiratory signal: on current scanners it is obtained from an external device, whereas with data driven (DD) methods it can be directly obtained from the raw PET data. DD methods thus eliminate the use of external equipment, which is often expensive, needs prior setup and can cause patient discomfort, and they could also potentially provide increased fidelity to the internal movement. DD methods have been recently applied on PET data showing promising results. However, many methods provide signals whose direction with respect to the physical motion is uncertain (i.e. their sign is arbitrary), therefore a maximum in the signal could refer either to the end-inspiration or end-expiration phase, possibly causing inaccurate motion correction. In this work we propose two novel methods, CorrWeights and CorrSino, to detect the correct direction of the motion represented by the DD signal, that is obtained by applying principal component analysis (PCA) on the acquired data. They only require the PET raw data, and they rely on the assumption that one of the major causes of change in the acquired data related to the chest is respiratory motion in the axial direction, that generates a cranio-caudal motion of the internal organs. We also implemented two versions of a published registration-based method, that require image reconstruction. The methods were first applied on XCAT simulations, and later evaluated on cancer patient datasets monitored by the Varian Real-time Position ManagementTM (RPM) device, selecting the lower chest bed positions. For each patient different time intervals were evaluated ranging from 50 to 300 s in duration. The novel methods proved to be generally more accurate than the registration-based ones in detecting the correct sign of the respiratory signal, and their failure rates are lower than 3% when the DD signal is highly correlated with the RPM. They also have the advantage of faster computation time, avoiding reconstruction. Moreover, CorrWeights is not specifically related to PCA and considering its simple implementation, it could easily be applied together with any DD method in clinical practice. PMID- 28346223 TI - Early rectal cancer: a choice between local excision and transabdominal resection. A review of the literature and current guidelines. AB - INTRODUCTION: Indication for Local Excision (LE) or Trans Abdominal Resections with Total Mesorectal Excision (TAR) in Early Rectal Cancer (ERC) are still controversial. MATERIAL OF STUDY: We reviewed meta-analyses, scientific societies guidelines, randomized and controlled clinical trials from 1999 to 2016 for a total of 146,231 patients. We included in our analysis the accuracy of different tools of investigation, the reliability of the endoscopic biopsies and compared the results of the various LE and TAR. RESULTS: The Endo Rectal Ultra Sound (ERUS) is the most accurate technique for the preoperative staging with an 18% of understaging and a 17.3% of overstaging. Endoscopic biopsies do not provide reliable data on unfavorable histopathological features in a significant percentage of cases. The Transanal Excision Microsurgery (TEM) is the best technique among LE but with worse overall results than TAR in terms of R0, local recurrence and overall 5-years survival in T2 cancers. DISCUSSION: The ERUS is the diagnostic technique most appropriate in the preoperative staging of the ERC; the employment of Magnetic Resonance Imaging (MRI) has to be limited to uncertain T2 patients. The ERUS shows significant understaging rate which expose to inadequate treatment, particularly in T2 patients. Endoscopic biopsies risk to disregard unfavorable histological features, resulting in inadequate therapeutic indications to LE. The use of TAR guarantees overall better results than the use of LE on T2 and T1 with unfavorable histological findings. CONCLUSIONS: The TAR still shows best results in the ERC treatment especially in T2 and T1 with unfavorable histological findings. KEY WORDS: Early Rectal Cancer (ERC), Local Excision (LE), Trans Abdominal Resection with Total Mesorectal Excision (TAR TME). PMID- 28346224 TI - Mutant alpha2-chimaerin signals via bidirectional ephrin pathways in Duane retraction syndrome. AB - Duane retraction syndrome (DRS) is the most common form of congenital paralytic strabismus in humans and can result from alpha2-chimaerin (CHN1) missense mutations. We report a knockin alpha2-chimaerin mouse (Chn1KI/KI) that models DRS. Whole embryo imaging of Chn1KI/KI mice revealed stalled abducens nerve growth and selective trochlear and first cervical spinal nerve guidance abnormalities. Stalled abducens nerve bundles did not reach the orbit, resulting in secondary aberrant misinnervation of the lateral rectus muscle by the oculomotor nerve. By contrast, Chn1KO/KO mice did not have DRS, and embryos displayed abducens nerve wandering distinct from the Chn1KI/KI phenotype. Murine embryos lacking EPH receptor A4 (Epha4KO/KO), which is upstream of alpha2 chimaerin in corticospinal neurons, exhibited similar abducens wandering that paralleled previously reported gait alterations in Chn1KO/KO and Epha4KO/KO adult mice. Findings from Chn1KI/KI Epha4KO/KO mice demonstrated that mutant alpha2 chimaerin and EphA4 have different genetic interactions in distinct motor neuron pools: abducens neurons use bidirectional ephrin signaling via mutant alpha2 chimaerin to direct growth, while cervical spinal neurons use only ephrin forward signaling, and trochlear neurons do not use ephrin signaling. These findings reveal a role for ephrin bidirectional signaling upstream of mutant alpha2 chimaerin in DRS, which may contribute to the selective vulnerability of abducens motor neurons in this disorder. PMID- 28346225 TI - Long telomeres protect against age-dependent cardiac disease caused by NOTCH1 haploinsufficiency. AB - Diseases caused by gene haploinsufficiency in humans commonly lack a phenotype in mice that are heterozygous for the orthologous factor, impeding the study of complex phenotypes and critically limiting the discovery of therapeutics. Laboratory mice have longer telomeres relative to humans, potentially protecting against age-related disease caused by haploinsufficiency. Here, we demonstrate that telomere shortening in NOTCH1-haploinsufficient mice is sufficient to elicit age-dependent cardiovascular disease involving premature calcification of the aortic valve, a phenotype that closely mimics human disease caused by NOTCH1 haploinsufficiency. Furthermore, progressive telomere shortening correlated with severity of disease, causing cardiac valve and septal disease in the neonate that was similar to the range of valve disease observed within human families. Genes that were dysregulated due to NOTCH1 haploinsufficiency in mice with shortened telomeres were concordant with proosteoblast and proinflammatory gene network alterations in human NOTCH1 heterozygous endothelial cells. These dysregulated genes were enriched for telomere-contacting promoters, suggesting a potential mechanism for telomere-dependent regulation of homeostatic gene expression. These findings reveal a critical role for telomere length in a mouse model of age dependent human disease and provide an in vivo model in which to test therapeutic candidates targeting the progression of aortic valve disease. PMID- 28346227 TI - Reducing expression of synapse-restricting protein Ephexin5 ameliorates Alzheimer's-like impairment in mice. AB - Accumulation of amyloid-beta (Abeta) protein may cause synapse degeneration and cognitive impairment in Alzheimer's disease (AD) by reactivating expression of the developmental synapse repressor protein Ephexin5 (also known as ARHGEF15). Here, we have reported that Abeta is sufficient to acutely promote the production of Ephexin5 in mature hippocampal neurons and in mice expressing human amyloid precursor protein (hAPP mice), a model for familial AD that produces high brain levels of Abeta. Ephexin5 expression was highly elevated in the hippocampi of human AD patients, indicating its potential relevance to AD. We also observed elevated Ephexin5 expression in the hippocampi of hAPP mice. Removal of Ephexin5 expression eliminated hippocampal dendritic spine loss and rescued AD-associated behavioral deficits in the hAPP mice. Furthermore, selective reduction of Ephexin5 expression using shRNA in the dentate gyrus of presymptomatic adolescent hAPP mice was sufficient to protect these mice from developing cognitive impairment. Thus, pathological elevation of Ephexin5 expression critically drives Abeta-induced memory impairment, and strategies aimed at reducing Ephexin5 levels may represent an effective approach to treating AD. PMID- 28346226 TI - A TLR9-dependent checkpoint governs B cell responses to DNA-containing antigens. AB - Mature B cell pools retain a substantial proportion of polyreactive and self reactive clonotypes, suggesting that activation checkpoints exist to reduce the initiation of autoreactive B cell responses. Here, we have described a relationship among the B cell receptor (BCR), TLR9, and cytokine signals that regulate B cell responses to DNA-containing antigens. In both mouse and human B cells, BCR ligands that deliver a TLR9 agonist induce an initial proliferative burst that is followed by apoptotic death. The latter mechanism involves p38 dependent G1 cell-cycle arrest and subsequent intrinsic mitochondrial apoptosis and is shared by all preimmune murine B cell subsets and CD27- human B cells. Survival or costimulatory signals rescue B cells from this fate, but the outcome varies depending on the signals involved. B lymphocyte stimulator (BLyS) engenders survival and antibody secretion, whereas CD40 costimulation with IL-21 or IFN-gamma promotes a T-bet+ B cell phenotype. Finally, in vivo immunization studies revealed that when protein antigens are conjugated with DNA, the humoral immune response is blunted and acquires features associated with T-bet+ B cell differentiation. We propose that this mechanism integrating BCR, TLR9, and cytokine signals provides a peripheral checkpoint for DNA-containing antigens that, if circumvented by survival and differentiative cues, yields B cells with the autoimmune-associated T-bet+ phenotype. PMID- 28346231 TI - Optimizing patients undergoing surgery (OPUS): Part II - still a matter of 'eminence-based medicine'? PMID- 28346228 TI - Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans. AB - It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile alpha motif domain-containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (-7), deletions of 7q (7q-), and secondary somatic loss of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with -7 and 7q- developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized. PMID- 28346229 TI - Clinical efficacy of gene-modified stem cells in adenosine deaminase-deficient immunodeficiency. AB - BACKGROUND: Autologous hematopoietic stem cell transplantation (HSCT) of gene modified cells is an alternative to enzyme replacement therapy (ERT) and allogeneic HSCT that has shown clinical benefit for adenosine deaminase-deficient (ADA-deficient) SCID when combined with reduced intensity conditioning (RIC) and ERT cessation. Clinical safety and therapeutic efficacy were evaluated in a phase II study. METHODS: Ten subjects with confirmed ADA-deficient SCID and no available matched sibling or family donor were enrolled between 2009 and 2012 and received transplantation with autologous hematopoietic CD34+ cells that were modified with the human ADA cDNA (MND-ADA) gamma-retroviral vector after conditioning with busulfan (90 mg/m2) and ERT cessation. Subjects were followed from 33 to 84 months at the time of data analysis. Safety of the procedure was assessed by recording the number of adverse events. Efficacy was assessed by measuring engraftment of gene-modified hematopoietic stem/progenitor cells, ADA gene expression, and immune reconstitution. RESULTS: With the exception of the oldest subject (15 years old at enrollment), all subjects remained off ERT with normalized peripheral blood mononuclear cell (PBMC) ADA activity, improved lymphocyte numbers, and normal proliferative responses to mitogens. Three of nine subjects were able to discontinue intravenous immunoglobulin replacement therapy. The MND-ADA vector was persistently detected in PBMCs (vector copy number [VCN] = 0.1-2.6) and granulocytes (VCN = 0.01-0.3) through the most recent visits at the time of this writing. No patient has developed a leukoproliferative disorder or other vector-related clinical complication since transplant. CONCLUSION: These results demonstrate clinical therapeutic efficacy from gene therapy for ADA deficient SCID, with an excellent clinical safety profile. TRIAL REGISTRATION: ClinicalTrials.gov NCT00794508. FUNDING: Food and Drug Administration Office of Orphan Product Development award, RO1 FD003005; NHLBI awards, PO1 HL73104 and Z01 HG000122; UCLA Clinical and Translational Science Institute awards, UL1RR033176 and UL1TR000124. PMID- 28346232 TI - The future is now: neuroprotection during cardiopulmonary resuscitation. AB - PURPOSE OF REVIEW: Survival with favorable neurological function after cardiac arrest remains low. The purpose of this review is to identify recent advances that focus on neuroprotection during cardiopulmonary resuscitation (CPR). RECENT FINDINGS: Multiple strategies have been shown to enhance neuroprotection during CPR. Brain perfusion during CPR is increased with therapies such as active compression decompression CPR and intrathoracic pressure regulation that improve cardiac preload and decrease intracranial pressure. Head Up CPR has been shown to decrease intracranial pressure thereby increasing cerebral perfusion pressure and cerebral blood flow. Sodium nitroprusside enhanced CPR increases cerebral perfusion, facilitates heat exchange, and improves neurologic survival in swine after cardiac arrest. Postconditioning has been administered during CPR in laboratory settings. Poloxamer 188, a membrane stabilizer, and ischemic postconditioning have been shown to improve cardiac and neural function after cardiac arrest in animal models. Postconditioning with inhaled gases protects the myocardium, with more evidence mounting for the potential for neural protection. SUMMARY: Multiple promising neuroprotective therapies are being developed in animal models of cardiac arrest, and are in early stages of human trials. These therapies have the potential to be bundled together to improve rates of favorable neurological survival after cardiac arrest. PMID- 28346230 TI - Glutaminase and poly(ADP-ribose) polymerase inhibitors suppress pyrimidine synthesis and VHL-deficient renal cancers. AB - Many cancer-associated mutations that deregulate cellular metabolic responses to hypoxia also reprogram carbon metabolism to promote utilization of glutamine. In renal cell carcinoma (RCC), cells deficient in the von Hippel-Lindau (VHL) tumor suppressor gene use glutamine to generate citrate and lipids through reductive carboxylation (RC) of alpha-ketoglutarate (alphaKG). Glutamine can also generate aspartate, the carbon source for pyrimidine biosynthesis, and glutathione for redox balance. Here we have shown that VHL-/- RCC cells rely on RC-derived aspartate to maintain de novo pyrimidine biosynthesis. Glutaminase 1 (GLS1) inhibitors depleted pyrimidines and increased ROS in VHL-/- cells but not in VHL+/+ cells, which utilized glucose oxidation for glutamate and aspartate production. GLS1 inhibitor-induced nucleoside depletion and ROS enhancement led to DNA replication stress and activation of an intra-S phase checkpoint, and suppressed the growth of VHL-/- RCC cells. These effects were rescued by administration of glutamate, alphaKG, or nucleobases with N-acetylcysteine. Further, we observed that the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib synergizes with GLS1 inhibitors to suppress the growth of VHL-/- cells in vitro and in vivo. This work describes a mechanism that explains the sensitivity of RCC tumor growth to GLS1 inhibitors and supports the development of therapeutic strategies for targeting VHL-deficient RCC. PMID- 28346233 TI - Clinical efficacy and tolerability of direct-acting antivirals in elderly patients with chronic hepatitis C. AB - BACKGROUND: There is a lack of evidence-based data on aged patients with newer direct-acting antivirals (DAAs) and with shorter duration of treatment regimens involving DAAs with or without ribavirin (RBV) and pegylated interferon (Peg IFN). PATIENTS AND METHODS: Medical records of 240 patients treated with DAAs with or without Peg IFN and RBV between January 2013 and July 2015 were retrospectively analyzed. Patients were divided into two groups: patients aged 65 years and older (N=84) and patients aged younger than 65 years (N=156). Pretreatment baseline patient characteristics, treatment efficacy, factors affecting sustained virologic response at 12 weeks after treatment, and adverse reactions were compared between the groups. RESULTS: No statistically significant difference was observed with end of treatment response (98.8 vs. 98%, P=0.667) and sustained virologic response at 12 weeks after treatment (93.1 vs. 94.1%, P=0.767) between patients aged 65 and older and those younger than 65 years of age. Fatigue was the most common adverse event recorded (32.5%), followed by anemia (19.6%), leukopenia (11.7%), thrombocytopenia (10%), skin rash (8.3%), and headache (7.9%). The RBV dose was reduced in eight (8%) patients and four patients discontinued the RBV treatment because of severe anemia. RBV dose reduction or discontinuation did not reach statistical significance (P=0.913). Increased fibrosis, cirrhosis, aspartate aminotransferase, alanine aminotransferase, hemoglobin, and platelet levels seem to affect the sustained virologic response in the elderly. Twelve (6.28%) patients failed to respond to treatment and the failure rate was not significant (P=0.767) between the groups. CONCLUSION: DAAs with or without IFN and RBV in the standard recommended 12 or 24 week treatment regimens are effective, well tolerated, and may be safely extended to elderly patients infected with chronic hepatitis C. PMID- 28346235 TI - Advances in hepatology. PMID- 28346236 TI - Current concepts in ischemic hepatitis. AB - PURPOSE OF REVIEW: The current review seeks to define ischemic hepatitis and its associated comorbidities. It means to review the pathophysiology, clinical presentation, clinical course, outcomes, and any potential therapies. RECENT FINDINGS: Ischemic hepatitis has long been associated with cardiovascular disease; recent reports have found a substantial link between preexisting cardiovascular disease and the risk for developing ischemic hepatitis. A proposed mechanism by which hepatic congestion predisposes the liver to hemodynamic injury further defines this link. Treatment is aimed at the underlying hemodynamic disturbance; however, efforts to better predict mortality and improve outcomes continue to arise. The Acute Liver Failure Study Group proposed that, though uncommon, ischemic hepatitis may result in acute liver failure. With numerous studies identifying the multiple comorbid conditions associated with ischemic hepatitis, the sequela of acute liver failure is called into question. SUMMARY: Ischemic hepatitis is a clinical syndrome frequently encountered in critically ill patients that represents a complication of underlying cardiac, circulatory, or respiratory failure. The pathogenesis of ischemic hepatitis appears to occur as a result of a 'two-hit' mechanism when the liver, which is at risk, is subsequently exposed to systemic hypoperfusion and ischemia, ultimately resulting in a marked but transient elevation in aspartate aminotransferase and alanine aminotransferase. Mortality is high and is dependent largely on the underlying cause of hypotension. Treatment is directed at the underlying cause of hemodynamic disturbance. PMID- 28346234 TI - Outstanding animal studies in allergy I. From asthma to food allergy and anaphylaxis. AB - PURPOSE OF REVIEW: Animal models published within the past 18 months on asthma, food allergy and anaphylaxis, all conditions of rising public health concern, were reviewed. RECENT FINDINGS: While domestic animals spontaneously develop asthma, food allergy and anaphylaxis, in animal models, divergent sensitization and challenge routes, dosages, intervals and antigens are used to induce asthmatic, food allergic or anaphylactic phenotypes. This must be considered in the interpretation of results. Instead of model antigens, gradually relevant allergens such as house dust mite in asthma, and food allergens like peanut, apple and peach in food allergy research were used. Novel engineered mouse models such as a mouse with a T-cell receptor for house dust mite allergen Der p 1, or with transgenic human hFcgammaR genes, facilitated the investigation of single molecules of interest. Whole-body plethysmography has become a state-of-the-art in-vivo readout in asthma research. In food allergy and anaphylaxis research, novel techniques were developed allowing real-time monitoring of in-vivo effects following allergen challenge. Networks to share tissues were established as an effort to reduce animal experiments in allergy which cannot be replaced by in vitro measures. SUMMARY: Natural and artificial animal models were used to explore the pathophysiology of asthma, food allergy and anaphylaxis and to improve prophylactic and therapeutic measures. Especially the novel mouse models mimicking molecular aspects of the complex immune network in asthma, food allergy and anaphylaxis will facilitate proof-of-concept studies under controlled conditions. PMID- 28346238 TI - Management of hypertension in 2017: targets and therapies. AB - PURPOSE OF REVIEW: Approximately one-fourth of the adult population is diagnosed with hypertension, which has been associated with increased cardiovascular morbidity and mortality including cardiovascular death, myocardial infarction, heart failure and stroke. Early detection and treatment is key and can lead to a significant reduction in cardiovascular morbidity and mortality. RECENT FINDINGS: In this review, we discuss the management and treatment strategies in patients with hypertension in the current era. Blood pressure (BP) targets will be reviewed in accordance with the recent literature and current guidelines. There is a controversy about lower BP target in patients with coronary artery disease with some studies showing a J-curve relationship but a recent randomized trial (SPRINT) showing a benefit, albeit with controversy as to how BP was measured in the trial. Nevertheless, lower BP targets come with a price of needing more medication (thus impacting cost and compliance) and increases in medication related adverse effects. There is a growing recognition that angiotensin converting enzyme inhibitors or angiotensin receptor blockers, calcium antagonists or thiazide diuretics can be used a first-line therapy for hypertension. Evidence also supports the use of combination drug therapy as opposed to monotherapy for more synergistic effect on lowering of BP, offsetting side effects and for improved adherence to a drug regimen. SUMMARY: Overall, we aim to review BP targets and medical therapies for hypertension in the current era, recognizing varying clinical characteristics such as comorbidities and patient-risk profile. PMID- 28346237 TI - Current and future pharmacologic treatment of nonalcoholic steatohepatitis. AB - PURPOSE OF REVIEW: Nonalcoholic steatohepatitis (NASH), the aggressive form of nonalcoholic fatty liver disease (NAFLD), can progress to cirrhosis and hepatocellular cancer in 5-15% of patients and is rapidly becoming the leading cause for end-stage liver disease. Dietary caloric restriction and exercise, currently the cornerstone of therapy for NAFLD, can be difficult to achieve and maintain, underscoring the dire need for pharmacotherapy. This review presents the agents currently used in managing NAFLD and their pharmacologic targets. It also provides an overview of NAFLD agents currently under development. RECENT FINDINGS: Therapies for NASH can be broadly classified into agents that target the metabolic perturbations driving disease pathogenesis (such as insulin resistance and de novo lipogenesis) and agents that target downstream processes including cell stress, apoptosis, inflammation, and fibrosis. Modulation of peroxisome proliferator-activator receptors, farnesoid-X-receptors, and the glucagon-like peptide 1 pathway have been shown to improve liver histology. The intestinal microbiome and metabolic endotoxemia are novel targets that are currently under review. Antioxidants such as vitamin E, and more recently anti inflammatory agents such as apoptosis signal-regulating kinase 1 inhibitors show promise as therapy for NASH. Several antifibrotic agents including cysteine cysteine motif chemokine receptor type 2 and type 5 antagonists have been shown to inhibit the progression of fibrosis toward cirrhosis. SUMMARY: There are currently several agents in the drug pipeline for NASH. Within the next few years, the availability of therapeutic options for NAFLD will hopefully curb the rising trend of NAFLD-related end stage liver disease. PMID- 28346239 TI - Elevated Expression of Kin17 in Cervical Cancer and Its Association With Cancer Cell Proliferation and Invasion. AB - BACKGROUND: Cervical cancer is one of the most common cancers in women worldwide. Emerging evidence suggests that kin17 is a tumor-promoting protein in some types of solid tumors. However, whether kin17 contributes to cervical cancer carcinogenesis remains unknown. METHODS: Kin17 expression in clinical samples from Guangdong Women and Children's Hospital and Health Institute was detected by immunohistochemical staining. A series of functional experiments including 3-(4,5 dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay, 5-bromo-2' deoxyuridine assay, colony formation, transwell assay, flow cytometry of apoptosis, and cell cycle were performed to explore the roles of kin17 in cervical cancer cells HeLa. RESULTS: In this study, we showed for the first time that the expression of kin17 was significantly increased in clinical cervical cancer samples, and associated with tumor differentiation, lymph node metastasis, and ki-67 expression in a clinicopathologic characteristics review. Furthermore, silence of kin17 in HeLa cells inhibited cell proliferation, clone formation, cell cycle progression, migration, and invasion, and also promoted cell apoptosis. CONCLUSION: Our findings demonstrate that kin17 is closely related to the cell proliferation and invasion of cervical cancer and could be a novel diagnostic and therapeutic target for cervical cancer management. The underlying mechanisms should be elucidated in future research. PMID- 28346240 TI - Combined Oral Medroxyprogesterone/Levonorgestrel-Intrauterine System Treatment for Women With Grade 2 Stage IA Endometrial Cancer. AB - OBJECTIVE: The aim of this study was to evaluate the oncologic and pregnancy outcomes of combined oral medroxyprogesterone acetate (MPA)/levonorgestrel intrauterine system (LNG-IUS) treatment in young women with grade 2 differentiated stage IA endometrial adenocarcinoma who wish to preserve fertility. METHODS: We retrospectively reviewed the medical records of patients with grade 2 stage IA endometrial adenocarcinoma who had received fertility sparing treatment at CHA Gangnam Medical Center between 2011 and 2015. All of the patients were treated with combined oral MPA (500 mg/d)/LNG-IUS, and follow-up dilatation and curettage were performed every 3 months. RESULTS: A total of 5 patients were included in the study. The mean age was 30.4 +/- 5.3 years (range, 25-39 years). After a mean treatment duration of 11.0 +/- 6.2 months (range, 6-18 months), complete response (CR) was shown in 3 of the 5 patients, with partial response (PR) in the other 2 patients. One case of recurrence was reported 14 months after achieving CR. This patient was treated again with combined oral MPA/LNG-IUS and achieved CR by 6 months. The average follow-up period was 44.4 +/ 26.2 months (range, 12-71 months). There were no cases of progressive disease. No treatment-related complications arose. CONCLUSIONS: Combined oral MPA/LNG-IUS treatment is considered to be a reasonably effective fertility-sparing treatment of grade 2 stage IA endometrial cancer. Although our results are encouraging, it is preliminary and should be considered with experienced oncologists in well defined protocol and with close follow-up. PMID- 28346241 TI - Hemodynamic responses to magnetic stimulation of carotid sinus in normotensive rabbits. AB - OBJECTIVES: Carotid baroreflex plays a crucial role in regulating arterial pressure. Based on this knowledge, electrical stimulation of carotid sinus was designed for treating resistant hypertension. However, the clinical implication of electrical stimulation of carotid sinus is largely restrained due to obvious invasiveness. This study aimed to evaluate the efficacy of magnetic stimulation of carotid sinus (MSCS), a noninvasive strategy, for lowering blood pressure in rabbits. METHODS: MSCS with graded intensities and frequencies were systematically attempted in normotensive rabbits. Blood pressure was recorded dynamically. Sinoaortic denervation and plasma hormone level analyses were performed. RESULTS: When the right carotid sinus was stimulated at 1 Hz frequency, a dose-effect relationship was observed between stimulation intensity (100-250% motor threshold) and mean arterial pressure (MAP) decrement (3.6 +/- 1.0 to 10.4 +/- 2.3 mmHg). When stimulation intensity was fixed at 200% motor threshold, the median reduction of MAP in 1-Hz group [10.8 (8.6-14.9) mmHg] was significantly higher than that in other frequency groups (all P < 0.05). Heart rates declined transiently after the initiation of MSCS. Compared with baseline (33.9 +/- 5.5 pg/ml), plasma epinephrine level increased during MSCS (88.1 +/- 9.6, P = 0.002). After ipsilateral sinoaortic denervation, MAP decrement (7.0 +/- 0.8 mmHg) was remarkably blunted compared with that in sham animals (13.0 +/- 1.1 mmHg, P = 0.001). CONCLUSION: The current study demonstrated that MSCS treatment can lower the arterial pressure in normotensive rabbits. This preliminarily result warrants further studies to establish the efficacy of MSCS in treating refractory hypertension. PMID- 28346242 TI - Genetic variation in GABRbeta1 and the risk for developing alcohol dependence. AB - Associations between the gamma-aminobutyric acid type-A receptors (GABAA) and alcohol dependence risk have been reported, although the receptor subunit driving the association is unclear. Recent work in mice has highlighted a possible role for variants in the Gabr beta1 subunit (Gabrbeta1) in alcohol dependence risk, although this gene does not contain any common nonsynonymous variants in humans. However, the GABAA receptor is a heteropentamer so multiple potential variants within the gene complex could generate the alcohol dependence phenotype. The association between GABRbeta1 variants and alcohol dependence risk was explored in a British and Irish population of alcohol-dependent cases (n=450) and ancestrally-matched controls screened to exclude current or historical alcohol misuse (n=555). Twelve common single nucleotide polymorphisms (SNPs) and a rare nonsynonymous variant, rs41311286, were directly genotyped; imputation was then performed across the whole gene. No allelic association was observed between alcohol dependence risk and any of the directly genotyped or imputed SNPs. However, post-hoc testing for genotypic association identified five common intronic SNPs that showed modest evidence for association after correction for multiple testing; two, rs76112682 and rs141719901, were in complete linkage disequilibrium [Pcorrected=0.02, odds ratio (95% confidence interval)=5.9 (1.7 2.06)]. These findings provide limited support for an association between GABRbeta1 and the risk for developing alcohol dependence; further testing in expanded cohorts may be warranted. PMID- 28346243 TI - Modeling Flowsheet Data to Support Secondary Use. AB - The purpose of this study was to create information models from flowsheet data using a data-driven consensus-based method. Electronic health records contain a large volume of data about patient assessments and interventions captured in flowsheets that measure the same "thing," but the names of these observations often differ, according to who performs documentation or the location of the service (eg, pulse rate in an intensive care, the emergency department, or a surgical unit documented by a nurse or therapist or captured by automated monitoring). Flowsheet data are challenging for secondary use because of the existence of multiple semantically equivalent measures representing the same concepts. Ten information models were created in this study: five related to quality measures (falls, pressure ulcers, venous thromboembolism, genitourinary system including catheter-associated urinary tract infection, and pain management) and five high-volume physiological systems: cardiac, gastrointestinal, musculoskeletal, respiratory, and expanded vital signs/anthropometrics. The value of the information models is that flowsheet data can be extracted and mapped for semantically comparable flowsheet measures from a clinical data repository regardless of the time frame, discipline, or setting in which documentation occurred. The 10 information models simplify the representation of the content in flowsheet data, reducing 1552 source measures to 557 concepts. The amount of representational reduction ranges from 3% for falls to 78% for the respiratory system. The information models provide a foundation for including nursing and interprofessional assessments and interventions in common data models, to support research within and across health systems. PMID- 28346244 TI - A Six Sigma Approach to Analyze Time-to-Assembly Variance of Surgical Trays in a Sterile Services Department. AB - INTRODUCTION: We analyze the assembly of surgical trays in a hospital's sterile services department. The department assembles 520 different tray setups. However, tray assembly times are unknown, imposing a challenge to production planners. To respond to demand, workers from other departments are often called, leading to higher operational costs and more frequent quality problems due to workers' poor training and inconsistency. METHODS: Conducting traditional time-motion studies is infeasible in such a high variety production setting. Thus, we used design of experiments to optimize the data acquisition. Assembly times of 36 trays were sampled using a 2-factor nested factorial design. Through regression analysis, we built a model to estimate completion times of trays not sampled in the experiment. RESULTS: A prediction model with 90.8% accuracy was obtained from the experimental data. The model was validated with assembly times from several trays not included in the experiment. Predicted assembly times had an absolute error of 7.83% on average compared with observed assembly times. CONCLUSIONS: Design of experiments and regression analysis combined were able to optimize time data acquisition using a small sample of trays, resulting in a model that predicted assembly times within an acceptable margin of error. PMID- 28346245 TI - Hospitalist Versus Subspecialist Perspectives on Reasons, Timing, and Impact of Consultation. AB - BACKGROUND: Hospitalists frequently consult medical subspecialists in the management of inpatients. Given the potential impact on health resource utilization, it is important to understand the working relationship between these groups. METHODS: A cross-sectional survey of hospitalists, n = 655, and subspecialists across Ohio (nephrologists and endocrinologists), n = 293, was conducted to investigate perceptions and communication about reasons, timing, and impact of hospital consultations. RESULTS: Survey response rate was 13.3%. Hospitalists were more likely to report subspecialty request to serve as admitting physician with subsequent consultation 63.2% versus 26.7%, p < .001. Hospitalists with a daily workload >=15 patients per day were more likely to report that this impeded their ability to manage details of patient care versus hospitalists with <15 patients per day, 53.2% versus 24.1%, p = .02, and resulted in subspecialty consultation for problems manageable by the hospitalist, 38.3% versus 6.9%, p = .003. Hospitalists were less likely than subspecialists to report major impact from consultation 50.0% versus 81.0%, p = .001 and they were more likely to report direct communication for urgent consults 97.3% versus 48.8%, p < .001. CONCLUSIONS: Future work should be aimed at addressing hospitalist workload, improving communication, and ensuring appropriate need and timing of consultation. PMID- 28346246 TI - Analysis of a Patient Intervention to Reduce Patients Who Leave Without Being Seen in an Ophthalmology-Dedicated Emergency Room. AB - Patients who leave without being seen (LWBS) by a medical provider in emergency care settings are a concern because their urgent complaints remain unaddressed. This study aims to characterize the LWBS population in an ophthalmology-dedicated emergency room and to evaluate an intervention designed to decrease the number of these patients. A program of rounding and patient contact in the waiting room of our emergency room was initiated to this end. A patient database was used retrospectively to review 13,124 charts and collect clinical and demographic data on 71 LWBS patients. The percentage of LWBS patients decreased from 0.74% to 0.33% after the intervention (p = 0.00158). Of the LWBS patients, 27% were seen in an ophthalmology clinic within 2 weeks, and 4% were seen back in the emergency room. Of these patients, 49% had some ophthalmology follow-up after leaving. Among those with follow-up, 14% had concerning pathology. Of all LWBS patients, 63% had a primary care physician. We conclude that frequent rounding in an emergency room waiting room can decrease the number of LWBS patients and as such reduce morbidity. This strategy offers potential to improve healthcare outcomes in emergency settings. PMID- 28346247 TI - Lymphatic Drainages to the Paravertebral and Pararenal Lymph Nodes in Breast Cancer Patients. AB - An efficient evaluation of the lymphatic drainage from the breasts (thoracic wall) and/or the upper limbs is essential in the management of patients with breast cancer (BC) and/or BC-related lymphedema. Lymphoscintigraphy was performed in 2 patients with lymphedema. Lymphatic drainage was observed from the upper limb or breast to the posterior paravertebral and/or pararenal lymph nodes. The cases demonstrate lymphatic drainage pathways toward unusual and mostly unrecognized lymph nodes, which may be at risk for further evolution of BC and may be important for the physical treatment of BC-related lymphedema. PMID- 28346248 TI - 68Ga-PSMA PET/CT in Osteosarcoma in Fibrous Dysplasia. AB - Fibrous dysplasia (FD) is a benign bone lesion with a rare but potential for malignant transformation. Neither Tc-MDP nor F-FDG PET/CT can differentiate between FD and areas of malignant transformation in FD. We described a case of osteosarcoma developing in FD with selective uptake of tracer in malignant transformation areas demonstrated on a Ga-PSMA PET/CT scan. Our case highlights the ability of Ga-PSMA PET/CT to map tumor neoangiogenesis in osteosarcoma arising in FD, which can have potential implications in prognostication, possibility of antiangiogenesis-based therapeutic options, and in response assessment following chemotherapy. PMID- 28346249 TI - Usefulness of 68Ga-DOTA-RGD (alphavbeta3) PET/CT Imaging in Thyroglobulin Elevation With Negative Iodine Scintigraphy. AB - TENIS (thyroglobulin elevation with negative iodine scintigraphy) syndrome in patients with differentiated thyroid carcinoma is not a rare finding. In such patients, F-FDG PET/CT can help in disease evaluation. RGD tripeptide, used for imaging angiogenesis, may also help in disease detection in patients with negative radioiodine whole-body scan. We present 1 such case in whom Ga-RGD tripeptide imaging was helpful in disease detection in the setting of negative radioiodine whole-body scan. PMID- 28346250 TI - Reconstruction of Combined Upper and Lower Eyelid Defects in a Patient With Lentigo Maligna. PMID- 28346251 TI - Histological Mohs Maps Improve the Accuracy of Dermatology Residents' Interpretations of Mohs Slides: A Pilot Study. AB - BACKGROUND: Effective Mohs surgery depends on accurate histopathological identification and mapping of tumor burden to ensure complete removal of tumor. OBJECTIVE: The purpose of this study is to evaluate whether using a photograph of the histopathological slide as the Mohs map improves mapping accuracy. MATERIALS AND METHODS: Single-blinded pilot study. Five dermatology residents at one academic institution mapped 11 cases of basal cell carcinoma using both traditional hand-drawn maps and color photographic maps. Residents' marked maps were assessed for global diagnostic accuracy, sensitivity, and specificity compared with the Mohs map verified by the attending surgeon on the day of surgery. RESULTS: Diagnostic accuracy, sensitivity, and specificity were higher using the photographic Mohs maps compared with using the traditional hand-drawn maps (58.2% vs 29.1%, 84.5% vs 76.4%, and 87.1% vs 70.8%, respectively). These results were statistically significant for accuracy and specificity, but not for sensitivity. CONCLUSION: Using histopathological photographs as the Mohs map significantly improved accuracy and specificity within a small group of residents with limited Mohs experience. More research is warranted to evaluate whether using histopathological photographs improves accuracy of Mohs mapping for experienced Mohs surgeons in a real-world setting, and whether this translates to improved clinical outcomes. PMID- 28346252 TI - Commentary on A Retrospective Case-Matched Cost Comparison of Surgical Treatment of Melanoma and Nonmelanoma Skin Cancer in the Outpatient Versus Operating Room Setting. PMID- 28346253 TI - A Retrospective Case-Matched Cost Comparison of Surgical Treatment of Melanoma and Nonmelanoma Skin Cancer in the Outpatient Versus Operating Room Setting. AB - BACKGROUND: To date, no study has used authentic billing data in a case-control matched fashion to examine the cost of treating skin cancer in different settings. OBJECTIVE: To compare the cost of surgical treatment of skin cancer in the outpatient versus operating room setting using matched cases based on patient and skin cancer characteristics. METHODS: ICD-9 diagnosis codes for skin cancers were used to find patients who had a malignant excision current procedural terminology code in the operating room setting during 2010 to 2014. Patient and skin cancer characteristics were used to match cases to those treated as an outpatient. A total of 36 cases (18 operating room and 18 outpatient) had the required information and characteristics to be matched and analyzed for cost. Health status was determined using the American Society of Anesthesiologists anesthesia grading scale. RESULTS: No statistically significant differences were found in the age (p > 0.9) or American Society of Anesthesiologists scores (p > 0.6) of the outpatient and operating room cases. The median cost for outpatient cases was $1,745. For operating room cases, the median cost was $11,323. This was a statistically significant difference (p < 0.001). CONCLUSION: The outpatient setting remains a cost-effective location to treat skin cancer compared with the operating room. PMID- 28346254 TI - Toluidine Blue Stain of Dermatofibrosarcoma Protuberans: Highlighting Its Use in Mohs. PMID- 28346255 TI - Splash Safety During Dermatologic Procedures Among US Dermatology Residents. AB - BACKGROUND: Dermatologists are at potential risk of acquiring infections from contamination of the mucous membranes by blood and body fluids. However, there are little data on splash safety during procedural dermatology. OBJECTIVE: To determine dermatology resident perceptions about splash risk during dermatologic procedures and to quantify the rate of protective equipment use. METHODS: An anonymous on-line survey was sent to 108 United States ACGME-approved dermatology residency programs assessing frequency of facial protection during dermatologic procedures, personal history of splash injury, and, if applicable, reasons for not always wearing facial protection. RESULTS: A total of 153 dermatology residents responded. Rates of facial protection varied by procedure, with the highest rates during surgery and the lowest during local anesthetic injection. Over 54% of respondents reported suffering facial splash while not wearing facial protection during a procedure. In contrast, 88.9% of respondents correctly answered that there is a small risk of acquiring infection from mucosal splash. Residency program recommendations for facial protection seem to vary by procedure. CONCLUSION: The authors' results demonstrate that although facial splash is a common injury, facial protection rates and protective recommendations vary significantly by procedure. These data support the recommendation for enhanced facial protection guidelines during procedural dermatology. PMID- 28346256 TI - Reconstruction of a Full-Thickness Superior Auricular Defect. PMID- 28346257 TI - Dermal Piercing Removal: Searching for an Optimal Technique. PMID- 28346258 TI - MANAGEMENT OF METASTATIC BREAST CARCINOMA OF IRIS WITH INTRAOCULAR BEVACIZUMAB INJECTIONS. AB - PURPOSE: To describe intraocular use of bevacizumab for a metastatic breast carcinoma of the iris resistant to advanced systemic chemotherapy protocols, for which conventional treatment would be local radiotherapy or brachytherapy. METHODS: Case report. RESULTS: A 65-year-old woman, who was previously diagnosed with breast carcinoma and treated with radical mastectomy coupled with radiotherapy and chemotherapy, presented with an iris mass in her left eye. Four successive intravitreal injections of bevacizumab resulted in progressive regression of the tumor to an almost indiscernible size at 8 months, along with blunting of the highly complex tumor vascular network on fluorescein angiography. At 12 months, the patient's visual acuity remained 20/20, and no ocular or systemic adverse effects were encountered. CONCLUSION: Intravitreal bevacizumab can offer a simpler and safer solution to treat metastatic iris tumors compared with other treatment options. This report of bevacizumab for treating iris metastasis from breast carcinoma may broaden the treatment options for similar neoplasms of the iris. PMID- 28346259 TI - IGG4-RELATED OPHTHALMIC DISEASE PRESENTING AS CHOROIDAL AND ORBITAL LESIONS. AB - PURPOSE: To report a case of IgG4-related ophthalmic disease (IgG4-ROD) which presented as choroidal and orbital lesions. METHODS: Case report. RESULTS: A 64 year-old man presented with left eye photopsias and a history of IgG4-related perirenal fibrosis. Fundoscopic examination showed multiple bilateral yellow choroidal lesions, and optical coherence tomography showed multiple choroidal lesions. Magnetic resonance imaging of the orbits showed an enhancing lesion present circumferential to the optic nerve, but greater medially, abutting the posterior surface of the left globe. Workup for infectious, autoimmune, and malignant etiologies was negative, and the patient has responded well to treatment with rituximab. CONCLUSION: IgG4-related disease is a systemic fibroinflammatory disease, which often presents in another location, as in our patient. In cases of uncertain choroidal and orbital lesions, a thorough workup for other etiologies is indicated, and lymphoma must be ruled out. Steroids are the mainstay of treatment for IgG4-ROD, however, small case series and our patient responded well to rituximab. To our knowledge, this is the first reported case of choroidal and orbital lesions secondary to IgG4-ROD. PMID- 28346260 TI - Effectiveness Analysis of a Part-Time Rapid Response System During Operation Versus Nonoperation. AB - OBJECTIVES: To evaluate the effect of a part-time rapid response system on the occurrence rate of cardiopulmonary arrest by comparing the times of rapid response system operation versus nonoperation. DESIGN: Retrospective cohort study. SETTING: A 1,360-bed tertiary care hospital. PATIENTS: Adult patients admitted to the general ward were screened. Data were collected over 36 months from rapid response system implementation (October 2012 to September 2015) and more than 45 months before rapid response system implementation (January 2009 to September 2012). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The rapid response system operates from 7 AM to 10 PM on weekdays and from 7 AM to 12 PM on Saturdays. Primary outcomes were the difference of cardiopulmonary arrest incidence between pre-rapid response system and post-rapid response system periods and whether the rapid response system operating time affects the cardiopulmonary arrest incidence. The overall cardiopulmonary arrest incidence (per 1,000 admissions) was 1.43. Although the number of admissions per month and case-mix index were increased (3,555.18 vs 4,564.72, p < 0.001; 1.09 vs 1.13, p = 0.001, respectively), the cardiopulmonary arrest incidence was significantly decreased after rapid response system (1.60 vs 1.23; p = 0.021), and mortality (%) was unchanged (1.38 vs 1.33; p = 0.322). After rapid response system implementation, the cardiopulmonary arrest incidence significantly decreased by 40% during rapid response system operating times (0.82 vs 0.49/1,000 admissions; p = 0.001) but remained similar during rapid response system nonoperating times (0.77 vs 0.73/1,000 admissions; p = 0.729). CONCLUSIONS: The implementation of a part-time rapid response system reduced the cardiopulmonary arrest incidence based on the reduction of cardiopulmonary arrest during rapid response system operating times. Further analysis of the cost effectiveness of part-time rapid response system is needed. PMID- 28346262 TI - Modeling Outcomes: Modified Aortic Arch Advancement for Neonatal Hypoplastic Arch. AB - OBJECTIVE: Numerous surgical approaches regarding aortic arch advancement for neonatal arch hypoplasia have been described. These repairs can be classified into two categories: those that incorporate a patch and those that do not. The decision between repairs remains largely experiential, rather than empirical, because of the limited number of reported outcomes. We report early outcomes from neonates undergoing modified aortic arch advancement with an anterior patch and our experience using computational fluid dynamic modeling to better understand the hemodynamic consequences associated with this repair. METHODS: A retrospective review of neonates undergoing aortic arch advancement with anterior patch in 2014 at a single institution was performed. Anatomical, perioperative, and follow-up data were collected. Three-dimensional cardiac magnetic resonance images were used to generate computational fluid dynamic models of the modified anterior patch and direct end-to-side repairs. Cardiac waveform inputs were simulated and hemodynamic analyzed. RESULTS: Ten neonates underwent modified aortic arch advancement. No hemodynamically significant gradients were observed at a median follow-up of 0.77 (0.30-1.2) years. Asymmetrical flow was observed in the end-to-side repair, whereas more concentric laminar flow was observed throughout the modified model. Spatial variations in velocities immediately distal to the anastomosis were greater in the end-to-side model (0.35 vs 0.17 m/s, P < 0.001). Time-averaged variations in wall shear stress during systole were greater in the end-to-side model at the same location (3.44 vs 1.98 dynes/cm, P < 0.001). CONCLUSIONS: Early outcomes after the use of an anterior patch for neonatal hypoplastic aortic arch repair show favorable hemodynamic outcomes. PMID- 28346261 TI - Advantages of Minimal Access Versus Conventional Aortic Valve Replacement in Elderly or Severely Obese Patients. AB - OBJECTIVE: The aim of our study was to investigate potential clinical advantages of minimal access versus conventional surgical approach in older and severely obese patients undergoing isolated aortic valve replacement (AVR). METHODS: One hundred thirty-five patients undergoing isolated primary AVR were enrolled. Propensity score matching was used to compare 42 selected patients operated on ministernotomy (MS, group B) with 42 selected patients operated on full sternotomy (FS, group A). RESULTS: After propensity score matching, the two groups were comparable in terms of preoperative characteristics. Cardiopulmonary bypass time was significantly longer in MS group compared with the FS group [median (95% confidence level or CL), 103 (98.7-106.4) vs 94 (83.6-99) minutes, respectively; P = 0.0019]. No significant difference was observed in aortic cross clamp time [median (95% CL), 73 (71.1-78.2) vs 69.5 (62.7-83) minutes; P = 0.4]. Significantly shorter ventilation time [median (95% CL), 13 (12-16.4) vs 24 (22 25) hours; P = 0.00018], intensive care unit stay [median (95% CL), 1 vs 2 days; P = 0.00017], and hospital stay [median (95% CL), 8.5 (8-10.8) vs 13.5 (11.1-14) days; P = 0.00030] were shown in the MS group. The age subgroup analysis showed that statistical significance for mechanical ventilation, intensive care unit, and hospital stay was specific for patients older than 75 years. The analysis of body mass index quartile showed that statistical significance for mechanical ventilation was specific for patients in the fourth quartile. CONCLUSIONS: Minimal access AVR is a reproducible, safe, and effective surgical option in patients candidate for isolated AVR, and our study suggests a faster recovery when used in severely obese or older patients. PMID- 28346263 TI - Minimally Invasive Aortic Valve Replacement via Right Anterior Minithoracotomy and Central Aortic Cannulation: A 13-Year Experience. AB - OBJECTIVE: This study reports the evolution of a minimally invasive aortic valve replacement (mini-AVR) technique that uses a right anterior minithoracotomy approach with central cannulation, for a 13-year period. This technique has become our standard approach for isolated primary AVR in nearly all patients. METHODS: This observational study evaluated perioperative clinical outcomes of patients 18 years or older who underwent mini-AVR from November 2003 to June 2015. RESULTS: The mini-AVR technique was used in 202 patients during two periods of 2003 to 2009 (n = 65, "early") and 2010 to 2015 (n = 137, "late"). The mean +/ SD age was 72.5 +/- 12.9 years and 60% were male. Demographic parameters were statistically similar between the study periods, except for increased body weight in the later period (75.3 +/- 14.7 vs 80.9 +/- 20.8 kg, P = 0.03). The mean cardiopulmonary bypass and aortic cross-clamp times were significantly different by each year and Bonferroni adjustment, with significant decreases in cardiopulmonary bypass and aortic cross-clamp times beginning 2006. Compared with the early study period, late study period patients were more often extubated intraoperatively (52% vs 12%, P < 0.001), had less frequent prolonged ventilator use postoperatively (6% vs 16%, P = 0.018), required fewer blood transfusions (mean, 2.0 +/- 2.3 U vs 3.6 +/- 3.0 U; P = 0.011), and had shorter postoperative stay (6.3 +/- 4.5 days vs 8.0 +/- 5.9 days, P = 0.026). Numerically, fewer postoperative strokes (1% vs 6%, P = 0.09) and fewer reoperations for bleeding (3% vs 6%, P = 0.3) occurred in the late period. In-hospital mortality did not differ (1/65 early vs 3/137 late). CONCLUSIONS: Overall mini-AVR intraoperative and postoperative clinical outcomes improved for this 13-year experience. PMID- 28346264 TI - Re: Biases in Randomized Trials: A Conversation Between Trialists and Epidemiologists. PMID- 28346265 TI - The Authors Respond. PMID- 28346266 TI - "All Generalizations Are Dangerous, Even This One."-Alexandre Dumas. PMID- 28346269 TI - Cohort Variation in Selection During Pregnancy and Risk of Selected Birth Defects Among Males. AB - BACKGROUND: The literature theorizes, but does not test, that variation over time in selective loss in utero affects the observed count of live-born birth defects cases. We test the hypothesis that the risk of birth defects among live-born males varies inversely with the strength of selection against males in utero. METHODS: We identified a subset of six birth defect phenotypes among males from the California Birth Defects Monitoring Program, an active surveillance system for over 490,000 male singletons born in eight California counties from 1986 to 2004. We assigned each birth defect case infant to a monthly conception cohort at risk of selection in utero. We used the monthly sex ratio at birth (M:F), derived from each conception cohort, as the indicator of selection against males. We analyzed the odds ratio of birth defects with both individual-level logistic regression and aggregate time-series methods. RESULTS: Consistent with selection in utero, male infants from conception cohorts with low outlying sex ratios (i.e., stronger selectivity) exhibit fewer than expected birth defects (adjusted odds ratio [OR] = 0.86; 95% confidence interval [CI] = 0.76, 0.98). Aggregate time-series tests also yield similar findings (OR = 0.81; 95% CI = 0.71, 0.90). CONCLUSIONS: Our findings among males indicate that variation in the strength of selectivity in utero accounts for a portion of observed cohort differences in morbidity due to birth defects. These findings suggest that "revealed prevalence" of morbidity across birth cohorts varies, at least in part, from selective loss in utero. See video abstract at, http://links.lww.com/EDE/B209. PMID- 28346267 TI - Generalizing Study Results: A Potential Outcomes Perspective. AB - Great care is taken in epidemiologic studies to ensure the internal validity of causal effect estimates; however, external validity has received considerably less attention. When the study sample is not a random sample of the target population, the sample average treatment effect, even if internally valid, cannot usually be expected to equal the average treatment effect in the target population. The utility of an effect estimate for planning purposes and decision making will depend on the degree of departure from the true causal effect in the target population due to problems with both internal and external validity. Herein, we review concepts from recent literature on generalizability, one facet of external validity, using the potential outcomes framework. Identification conditions sufficient for external validity closely parallel identification conditions for internal validity, namely conditional exchangeability; positivity; the same distributions of the versions of treatment; no interference; and no measurement error. We also require correct model specification. Under these conditions, we discuss how a version of direct standardization (the g-formula, adjustment formula, or transport formula) or inverse probability weighting can be used to generalize a causal effect from a study sample to a well-defined target population, and demonstrate their application in an illustrative example. PMID- 28346270 TI - Repair of Partly Misspecified Causal Diagrams. AB - Errors in causal diagrams elicited from experts can lead to the omission of important confounding variables from adjustment sets and render causal inferences invalid. In this report, a novel method is presented that repairs a misspecified causal diagram through the addition of edges. These edges are determined using a data-driven approach designed to provide improved statistical efficiency relative to de novo structure learning methods. Our main assumption is that the expert is "directionally informed," meaning that "false" edges provided by the expert would not create cycles if added to the "true" causal diagram. The overall procedure is cast as a preprocessing technique that is agnostic to subsequent causal inferences. Results based on simulated data and data derived from an observational cohort illustrate the potential for data-assisted elicitation in epidemiologic applications. See video abstract at, http://links.lww.com/EDE/B208. PMID- 28346268 TI - Long-term Recall of Pregnancy-related Events. AB - BACKGROUND: Early-life factors can be associated with future health outcomes and are often measured by maternal recall. METHODS: We used data from the North Carolina Early Pregnancy Study and Follow-up to characterize long-term maternal recall. We used data from the Early Pregnancy Study as the gold standard to evaluate the accuracy of prepregnancy weight, early pregnancy behaviors, symptoms and duration of pregnancy, and child's birthweight reported at follow-up, for 109 women whose study pregnancies had resulted in a live birth. RESULTS: Most (81%) participants reported a prepregnancy weight at follow-up that correctly classified them by BMI category. Women reported experiencing pregnancy symptoms later at follow-up than what they reported in the Early Pregnancy Study. Accuracy of reporting of early pregnancy behaviors varied based on exposure. Overall, women who had abstained from a behavior were more likely to be classified correctly. Sensitivity of reporting was 0.14 for antibiotics, 0.30 for wine, 0.71 for brewed coffee, and 0.82 for vitamins. Most misclassification at follow-up was due to false-negative reporting. Among women who gave birth to singletons, 94% could report their child's correct birthweight within 1/2 pound and 86% could report duration of pregnancy within 7 days at follow-up. CONCLUSIONS: Self-report of prepregnancy weight, duration of pregnancy, and child's birthweight after almost 30 years was good, whereas self-reported pregnancy-related exposures resulted in higher levels of reporting error. Social desirability appeared to influence women's report of their behaviors at follow-up. Self-reported assessment of confidence in the recalled information was unrelated to accuracy. PMID- 28346271 TI - Primary and Repeat Cesarean Deliveries: A Population-based Study in the United States, 1979-2010. AB - BACKGROUND: Despite the temporal increase in cesarean deliveries, the extent to which maternal age, period, and maternal birth cohorts may have contributed to these trends remains unknown. METHODS: We performed an analysis of 123 million singleton deliveries in the United States (1979-2010). We estimated rate ratio (RR) with 95% confidence interval (CI) for primary and repeat cesarean deliveries. We examined changes in cesarean rates with weighted Poisson regression models across three time-scales: maternal age, year of delivery, and birth cohort (mother's birth year). RESULTS: The primary cesarean rate increased by 68% (95% confidence interval [CI]: 67%, 69%) between 1979 (11.0%) and 2010 (18.5%). Repeat cesarean deliveries increased by 178% (95% CI: 176, 179) from 5.2% in 1979 to 14.4% in 2010. Cesarean rates increased with advancing age. Compared with 1979, the RR for the period effect in primary and repeat cesarean deliveries increased up to 1990, fell to a nadir at 1993, and began to rise thereafter. A small birth cohort effect was evident, with women born before 1950 at increased risk of primary cesarean; no cohort effect was seen for repeat cesarean deliveries. Adjustment for maternal BMI had a small effect on these findings. Period effects in primary cesarean were explained by a combination of trends in obesity and chronic hypertension, as well as demographic shifts over time. CONCLUSIONS: Maternal age and period appear to have important contributions to the temporal increase in the cesarean rates, although the effect of parity on these associations remains undetermined. PMID- 28346272 TI - Influenza in children. AB - PURPOSE OF REVIEW: We review the current information and evidence available on the global burden of disease in the pediatric population, clinical presentation and complications, testing, treatment, and immunization. RECENT FINDINGS: In addition to multiple other risk factors for influenza complications, children with neurologic and neuromuscular disorders are significantly higher risk for serious complications. In practice, there is no lower age limit for children with influenza who can be treated with oseltamivir. The quadrivalent live attenuated influenza vaccine was not recommended for use during the 2016-2017 season due to poor effectiveness. SUMMARY: Influenza infection causes a significant burden of disease each year in the pediatric population worldwide. Both healthy and chronically ill children can fall prey to complications either due to the virus itself or secondary bacterial infection. Children within high-risk groups should be tested and treated with neuraminidase inhibitors. Immunization against influenza is well tolerated and effective. PMID- 28346273 TI - Preoperative Extraintestinal Manifestations Associated with Chronic Pouchitis in Japanese Patients with Ulcerative Colitis After Ileal Pouch-anal Anastomosis: A Retrospective Study. AB - BACKGROUND: Pouchitis is a major problem after ileal pouch-anal anastomosis in patients with ulcerative colitis. Chronic pouchitis is particularly troublesome. This study aimed to identify risk factors for the development of chronic pouchitis in a Japanese population. METHODS: We retrospectively reviewed 100 patients who underwent pouchoscopy for a functioning ileal pouch. The diagnosis of pouchitis was made according to the modified pouchitis disease activity index. The incidence of pouchitis was estimated using the Kaplan-Meier curve, and Cox regression analysis was used to identify risk factors for the development of chronic pouchitis. RESULTS: Twenty-two patients developed pouchitis; 12 of them had chronic pouchitis. The incidences of chronic pouchitis were 3.3%, 7.6%, and 16.6% at 2, 5, and 10 years, respectively, after the pouch operation. The incidence of pouchitis was significantly higher in patients with preoperative extraintestinal manifestations (EIMs) than in those without (log-rank test, P = 0.002 and P = 0.005 for overall and chronic pouchitis, respectively). Cox regression analysis revealed that the presence of extraintestinal manifestations was an independent risk factor for the development of overall (hazard ratio: 4.48, 95% confidence interval, 1.77-11.30, P = 0.002) and chronic (hazard ratio: 5.81, 95% confidence interval, 1.67-20.23, P = 0.006) pouchitis. CONCLUSIONS: The presence of preoperative extraintestinal manifestations was found to be an independent risk factor for the development of overall and chronic pouchitis. PMID- 28346274 TI - The Effect of Disease Activity on Birth Outcomes in a Nationwide Cohort of Women with Moderate to Severe Inflammatory Bowel Disease. AB - BACKGROUND: Active inflammatory bowel disease (IBD) during conception and pregnancy may increase the risk of adverse birth outcomes. Former studies have examined heterogeneous groups of women with varying degrees of IBD severity. We aimed to examine the effect of active IBD on birth outcomes in a more homogeneous group of women with a moderate to severe disease course. Since in Denmark, moderate to severe IBD is an indication for use of anti-tumor necrosis factor alpha therapy, we examined all women who used anti-tumor necrosis factor therapy during pregnancy. METHODS: We identified a nationwide cohort of 219 singleton pregnancies in women treated with anti-tumor necrosis factor-alpha therapy during pregnancy (2005-2014). Pregnancies with clinical disease activity (65.8%) constituted the exposed cohort and pregnancies without disease activity constituted the unexposed (34.2%). Disease activity scores were supported by levels of fecal calprotectin. Outcomes included low birth weight, preterm birth, and congenital anomalies. RESULTS: In women with IBD, disease activity was associated with adjusted odds ratio of low birth weight and preterm birth; 2.05 (95% confidence interval, 0.37-11.35) and 2.64 (95% confidence interval, 0.85 8.17), respectively. In those with clinical moderate to severe disease activity, the odds ratio for preterm birth was 3.60 (95% confidence interval, 1.14-11.36). In women with ulcerative colitis and disease activity, 19.5% had a child with low birth weight and 29.3% gave birth preterm. CONCLUSION: In women with moderate to severe IBD, 66% experienced disease activity during pregnancy. In those with the highest degree of disease activity, the risk of preterm birth was increased 3 to 4 folds. The proportion of adverse birth outcomes was high, particularly among women with ulcerative colitis and disease activity. PMID- 28346275 TI - Committee Opinion No. 704: Human Papillomavirus Vaccination. AB - Human papillomavirus (HPV) is associated with anogenital cancer (including cervical, vaginal, vulvar, penile, and anal), oropharyngeal cancer, and genital warts. The HPV vaccination significantly reduces the incidence of anogenital cancer and genital warts. Despite the benefits of HPV vaccines, only 41.9% of girls in the recommended age group, and only 28.1% of males in the recommended age group have received all recom-mended doses. Compared with many other countries, HPV vaccination rates in the United States are unacceptably low. The U.S. Food and Drug Administration has approved three vaccines that are effective at preventing HPV infection. These vaccines cover 2, 4, or 9 HPV serotypes, respectively. Safety data for all three HPV vaccines are reassuring. The HPV vaccines are recommended for girls and boys aged 11-12 years and can be given to females and males up to age 26 years. The Advisory Committee on Immunization Practices and the American College of Obstetricians and Gynecologists recommend routine HPV vaccination for girls and boys at the target age of 11-12 years (but it may be given from the age of 9 years) as part of the adolescent immunization platform in order to help reduce the incidence of anogenital cancer and genital warts associated with HPV infection. Obstetrician-gynecologists and other health care providers should stress to parents and patients the benefits and safety of HPV vaccination and offer HPV vaccines in their offices. PMID- 28346276 TI - Comparison of Noncontact Specular and Confocal Microscopy for Evaluation of Corneal Endothelium. AB - PURPOSE: To compare endothelial cell analysis obtained by noncontact specular and confocal microscopy, using the Konan NSP-9900 and Nidek ConfoScan4 systems, respectively. METHODS: Three groups including 70 healthy eyes, 49 eyes with Fuchs endothelial corneal dystrophy (FECD), and 78 eyes with glaucoma were examined with both the Konan NSP-9900 specular microscope and the Nidek ConfocScan4 confocal microscope. Certified graders at the Doheny Image Reading Center compared corneal endothelial images from both instruments side by side to assess image quality. Endothelial cell density (ECD) measurements were calculated and compared using three different modalities: (1) each instrument's fully automated analysis; (2) each instrument's semiautomatic analysis with grader input; and (3) manual grading methods by certified grader. RESULTS: All normal eyes yielded gradable endothelial images, and most but not all glaucomatous eyes yielded images with high enough image quality to allow grading. In addition, in corneas with severe FECD, poor image quality precluded ECD grading by specular microscopy in 20 eyes (40.8%) but in only 4 (8.2%) confocal images from the same eyes. For the gradable images, the ECD values obtained using the manual grading method from either device were comparable with no statistically significant difference (P>0.05) between specular and confocal devices. Machine-generated ECD values were significantly different from manual results, measuring greater in all cases with specular microscopy. Machine-generated ECD values from confocal microscopy also differed significantly from manual determinations, but not in a consistent direction. Semiautomatic methods for both instruments obtained clinically acceptable ECD values. CONCLUSIONS: Automatic machine-generated ECD measurements differed significantly from manual assessments of corneal endothelium by both specular and confocal microscopy, suggesting that automated results should be used with caution. But ECD values derived manually were comparable between the two devices in both normal and glaucomatous eyes, suggesting that manually graded images from the two instruments can be used interchangeably for reliable ECD measurements. Because of a higher proportion of gradable images, confocal microscopy may be superior to specular microscopy for ECD measurements in FECD. PMID- 28346277 TI - Myopic Laser Corneal Refractive Surgery Reduces Interdevice Agreement in the Measurement of Anterior Corneal Curvature. AB - OBJECTIVES: To investigate interdevice differences and agreement in the measurement of anterior corneal curvature obtained by different technologies after laser corneal refractive surgery. METHODS: The prospective study comprised 109 eyes of 109 consecutive patients who had undergone laser-assisted in situ keratomileusis (LASIK). Preoperative and postoperative corneal parameters were measured by Scheimpflug imaging (Pentacam), Placido-slit-scanning (Orbscan) and auto-keratometry (IOLMaster). Preoperative and postoperative anterior corneal curvatures (K readings) were compared between devices. Interdevice agreement was evaluated by Bland-Altman analysis. RESULTS: Preoperatively, the difference of K reading for Pentacam-IOLMaster (0.04+/-0.20 D) was not statistically significant (P=0.059). The differences between Pentacam-Orbscan and Orbscan-IOLMaster were 0.20+/-0.34 D (P<0.001) and -0.17+/-0.29 D (P<0.001), respectively. After surgery, no difference was found for Pentacam-Orbscan (-0.05+/-0.38, P=0.136). The differences between Pentacam-IOLMaster and Orbscan-IOLMaster were 0.13+/-0.29 D (P<0.001) and 0.19+/-0.34 D (P<0.001). Preoperative interdevice agreement (95% limit of agreement [LOA]) between Pentacam and Orbscan, Pentacam and IOLMaster, and Orbscan and IOLMaster were 1.31 D, 0.79 D and 1.14 D, respectively. The 95% LOAs decreased to 1.47 D, 1.14 D, and 1.34 D after refractive surgery. CONCLUSION: Corneal refractive surgery changed the preoperative and postoperative interdevice differences in corneal curvature measurements and reduced interdevice agreement, indicating that the devices are not interchangeable. PMID- 28346278 TI - Effects of Myopic Orthokeratology on Visual Performance and Optical Quality. AB - OBJECTIVES: To analyze the changes in visual performance and optical quality after orthokeratology (ortho-k) treatment and its correlation with the magnitude of lens decentration and the diameter of treatment zone (TxZ). METHODS: A prospective study was conducted in 27 eyes of 27 patients wearing ortho-k contact lens. Area under log contrast sensitivity function (AULCSF), modulation transfer function cutoff values (MTFcutoff), Strehl ratio (SR), and objective scattering index (OSI) were measured and compared before and 1 month after ortho-k lens treatment. Refractive sphere, astigmatism, and diameter and decentration of TxZ were tested against the change in AULCSF, MTFcutoff, SR, and OSI after ortho-k treatment in stepwise multiple linear regression models. RESULTS: Objective scattering index significantly increased and AULCSF, MTFcutoff, and SR significantly decreased after ortho-k lens wear (all P<0.001). The mean TxZ diameter was 3.61+/-0.26 mm, and the mean magnitude of TxZ decentration was 0.60+/-0.16 mm. The amount of lens decentration significantly correlated with the change in AULCSF and MTFcutoff (P=0.027 and P=0.005, respectively). The diameter of TxZ significantly correlated with the change in MTFcutoff and SR (P=0.005 and P=0.024, respectively). CONCLUSIONS: Visual and optical quality decreases after ortho-k treatment, which can be alleviated by a larger TxZ diameter and a smaller lens decentration. PMID- 28346280 TI - Conjunctivochalasis and Related Factors in an Adult Population of Iran. AB - OBJECTIVES: To determine the prevalence of conjunctivochalasis and its determinants in a middle-aged Iranian population. METHODS: This population-based study was conducted in the context of the second phase of Shahroud Eye Cohort Study in 2014. Of 4,737 participants aged 45 to 69 years who participated in the second phase, the data of 4,702 participants were available for this report. A diagnosis of conjunctivochalasis was made based on the physician's judgment on ophthalmic examinations. RESULTS: Diagnosis of conjunctivochalasis in at least one eye was confirmed in 295 (6.2%) participants. The prevalence of unilateral and bilateral conjunctivochalasis was 0.7% and 5.5%, respectively. Older age (odds ratio [OR] = 1.96, 95% confidence interval [CI]: 1.22-3.15), use of Losartan (an angiotensin II receptor antagonist) (OR=1.47, 95% CI: 1.05-2.08), Meibomian Gland Dysfunction (OR=2.32, 95% CI: 1.78-3.03), Pinguecula (OR=0.57, 95% CI: 0.42-0.77), and blepharitis (OR=0.24, 95% CI: 0.07-0.77) had a significant association with conjunctivochalasis. CONCLUSION: The prevalence of conjunctivochalasis in our study was less than other reports from Asian population. Conjunctivochalasis has a significant association with some eyelid disorders and the use of Losartan which should be noted when diagnosing and treating this disease. PMID- 28346281 TI - Recognition and management of Clostridium difficile in older adults. AB - Clostridium difficile infection (CDI) is increasing in the outpatient setting, and older adults are at a higher risk for contracting CDI and experiencing poor outcomes. NPs may see this infection in the primary care setting. This article focuses on the presentation, treatment, and clinical practice implications for CDI in community-dwelling older adults. PMID- 28346279 TI - Sub-basal Corneal Nerve Plexus Analysis Using a New Software Technology. AB - PURPOSE: To study sub-basal corneal nerve plexus (SCNP) parameters by in vivo corneal confocal microscopy using a new software technology and examine the effect of demographics and diabetes mellitus (DM) on corneal nerves morphology. METHODS: A Confoscan 4 (Nidek Technologies) was used in this cross-sectional study to image the SCNP in 84 right eyes at the Miami Veterans Affairs eye clinic. Images were analyzed using a new semiautomated nerve analysis software program (The Corneal Nerve Analysis tool) which evaluated 9 parameters including nerve fibers length (NFL) and nerve fibers length density (NFLD). The main outcome measure was the examination of SCNP morphology by demographics, comorbidities, and HbA1c level. RESULTS: Interoperator and intraoperator reproducibility were good for the 9 parameters studied (Intraclass Correlations [ICCs] 0.73-0.97). Image variability between two images within the same scan was good for all parameters (ICC 0.66-0.80). Older individuals had lower SCNP parameters with NFL and NFLD negatively correlating with age (r=-0.471, and 0.461, respectively, P<0.01 for all). Patients with diabetes had lower mean NFLD 10987.6 MUm/mm (+/-3,284.6) and NFL 1,289.5 MUm/frame (+/-387.2) compared with patients without diabetes (mean NFLD 15077.1 MUm/mm [+/-4,261.3] and NFL 1750.0 MUm/frame [+/-540.7]) (P<0.05 for all). HbA1c levels in patients with diabetes were inversely correlated with NFL and NFLD (r= -0.568, and -0.569, respectively, P<0.05 for all). CONCLUSIONS: The Corneal Nerve Analysis tool is a reproducible diagnostic software technique for the analysis of the SCNP with confocal microscopy. Older age, DM, and higher level of HbA1c were associated with a significant reduction in SCNP parameters. PMID- 28346282 TI - Screening tools to assess risk of opioid abuse in the Canadian primary healthcare setting. AB - Opioid therapy for patients with chronic pain is increasing in frequency along with rates of opioid abuse. Many screening tools are available to assess for the risk of opioid abuse. NPs should use screening tools that are cross-validated for use in chronic pain patients in the Canadian primary healthcare setting. PMID- 28346283 TI - Nonvisualized sentinel lymph nodes on lymphoscintigraphy in melanoma: predictive factors and surgical outcomes. AB - PURPOSE: Preoperative lymphoscintigraphy is the standard for the identification of sentinel lymph nodes (SLNs) in melanoma. The impact of negative scintigraphy [nonvisualization (NV) of the SLN] on surgical outcomes is inadequately reported in the literature. The objectives of this study were to determine the incidence, predictive factors, and surgical outcomes of NV in clinically node-negative melanoma patients. PATIENTS AND METHODS: A retrospective review of a prospective, Institutional Review Board approved, melanoma sentinel node database from January 2005 to August 2015 was performed. RESULTS: Twenty-seven of the 897 (3%) patients had negative scintigraphy. Single-photon emission computed tomography/computed tomography was performed in addition to planar imaging in four patients and failed to locate the SLN in all cases. NV was associated with older age (71 vs. 59 years, P<0.001), head and neck primaries (41%), and previous operations adjacent to the primary tumor or nodal beds (37%). NV was not associated with sex, BMI, or T stage. Despite a negative scintigram, the SLN was still found at operation in 10 of the 27 (37%) patients using the hand-held gamma probe, with one (10%) patient having nodal metastasis. Two patients with NV had nodal recurrence, with a mean follow-up of 3 years. DISCUSSION: Preoperative lymphoscintigraphy in clinically node-negative melanoma patients is associated with a low NV rate. Predictors for NV include age, head and neck location, and previous operations at adjacent sites. NV should not preclude surgical exploration as the SLN can still be found at operation in over one-third of patients. PMID- 28346284 TI - An electronic cardiac rehabilitation referral system increases cardiac rehabilitation referrals. AB - AIM: Although cardiac rehabilitation attendance is associated with improved clinical outcomes for patients after acute myocardial infarction (AMI), it remains underutilized nationally. We sought to determine whether replacing traditional, paper-based referrals for cardiac rehabilitation for patients with AMI with an electronic referral system would increase utilization. METHODS AND RESULTS: We implemented the change from traditional, paper-based referrals to electronic referrals at the Massachusetts General Hospital on 10 December 2013. Using a segmented regression approach to control for other secular effects, we assessed an association between the intervention and inpatient referrals, total referrals, cardiac rehabilitation attendance at Massachusetts General Hospital, and the rate of inpatient referral to cardiac rehabilitation after AMI. We analyzed 1895 referral records over a 30-month period. After the intervention, the total referrals to our cardiac rehabilitation program increased by a factor of 1.8, largely attributable to a 17-fold increase in inpatient referrals (P<0.0001 for both). CONCLUSION: Even relative to pre-existing secular trends, switching to an electronic referral system was associated with an increase in referral volume for cardiac rehabilitation for patients with AMI. Electronic care innovations may improve the ability of provider organizations to provide guideline-oriented care for patients with coronary artery disease. PMID- 28346285 TI - Effect of prompt revascularization on outcomes in diabetic patients with stable ischemic heart disease and previous myocardial infarction in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. AB - BACKGROUND: Survivors of a myocardial infarction (MI) are at a considerable risk of developing further cardiovascular events, including recurrent MI, heart failure, stroke, and death. Patients with type 2 diabetes mellitus and stable ischemic heart disease (SIHD) have worse outcomes than their nondiabetic counterparts, and those with previous MI may be at particularly high risk. Yet, little is known about the effect of adding prompt revascularization to intensive medical therapy in this high-risk group. PATIENTS AND METHODS: We carried out a post-hoc analysis of the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial, which randomized patients with type 2 diabetes mellitus and SIHD to prompt revascularization with percutaneous coronary intervention or coronary artery bypass grafting in addition to intensive medical therapy or intensive medical therapy alone. Previous MI status was defined by a history of MI or pathologic Q-waves. The primary endpoints were death, nonfatal or fatal MI, nonfatal or fatal stroke, congestive heart failure, and a composite of death/MI/stroke. RESULTS: Of the 2280 patients with evaluable data, 936 had previous MI. In these patients, there were no differences in the 5-year event free rates of all-cause death, MI, stroke, congestive heart failure, or death/MI/stroke between those who were randomized to prompt revascularization in addition to intensive medical therapy and those who were randomized to intensive medical therapy alone. CONCLUSION: In diabetic patients with SIHD and previous MI, adding prompt revascularization to intensive medical therapy yielded no benefit compared with intensive medical therapy alone. These findings underscore the importance of intensive medical therapy in mitigating further ischemic events. PMID- 28346286 TI - Delayed coronary obstruction following Portico in Freedom Solo valve-in-valve implantation. PMID- 28346287 TI - The Impact of Laparoscopic-assisted Colorectal Surgery Using 3-dimensional Reconstruction for Highly Obese Patients With Colorectal Cancer. AB - OBJECTIVES: During laparoscopic-assisted colorectal surgery (LACS), precise recognition of the anatomic variations and relationships among tumor and vessels is required. However, in highly obese patients, it is more difficult to grasp the surgical anatomy due to the presence of dense mesenteric fat tissue. We utilized a 3-dimensional (3D) reconstructed image for preoperative simulation and intraoperative navigation for LACS. In this study, we examined the correlation between patient obesity and 3D-simulated perioperative outcomes. MATERIALS AND METHODS: We retrospectively analyzed 124 patients who underwent LACS using 3D surgical simulation at Tsukuba Medical Center Hospital. We sequentially divided our cohort into 2 groups: patients with a low body mass index (BMI<25 kg/m, n=60) and patients with a high BMI (BMI >=25 kg/m, n=64). Patient characteristics and perioperative outcomes, including conversion rate, postoperative complications, operating time, intraoperative blood loss, and length of postoperative hospital stay, were compared for these 2 groups. RESULTS: There were no significant differences in patient background between the 2 groups.We found it more difficult to grasp the surgical anatomy, including vessel arrangement, for high-BMI patients than for low-BMI patients because of the dense mesenteric fat tissue in high-BMI patients. There were no significant differences between the 2 groups with respect to perioperative outcomes. CONCLUSIONS: The utilized reconstructed 3D images were useful for understanding anatomic relationships, including vessel arrangement, during LACS, particularly in highly obese patients. PMID- 28346288 TI - Day Surgery for Acute Appendicitis in Adults: A Prospective Series of 102 Patients. AB - AIM: To report the results of a consecutive series of day surgery appendectomy (DSA) for acute appendicitis. METHODS: Selection criteria for DSA were as follows: body mass index<28 kg/m, white cell count <15,000/mL, C-reactive protein<30 mg/L, no radiological signs of perforation, and appendix diameter <=10 mm. All patients with radiologically proven appendicitis and 4 or 5 criteria were proposed for DSA and prospectively included. RESULTS: A total of 102 patients (female=39.2%) were operated between January 1, 2013 and January 5, 2015 with a median age of 29.5 years [interquartile range (IQR), 23 to 37 y]. Diagnosis was mainly supported by computed tomographic scan (75.5%). About 60 patients (59%) were reconvened on the next morning for surgery with oral antibiotics. The median operative time was 40 minutes (IQR, 30 to 52 min), and 92 (90%) patients were discharged on day 0 after a postoperative period of 5h:12min (IQR, 4h:14min to 6h:33min). The overall median hospital length of stay was 8h:04min (IQR, 6h:46min to 10h:23min). Surgical morbidity was 6.9% (n=7), with 1.9% (n=2) major complications. CONCLUSIONS: DSA is a safe procedure for selected patients; it reduces the hospital length of stay without increasing morbidity. PMID- 28346289 TI - beta-Blocker use and reduced disease progression in patients with thick melanoma: 8 years of follow-up. AB - Previous observational studies have reported the protective effect of beta blockers on the progression of different types of cancers. In 2011, we published a prospective study, including patients with histologically confirmed malignant melanoma in stage II-IIIA. In total, 25% of them reported previous use of beta blockers that were administered at any time for any other diseases. After a median follow-up of 2.5 years, 34% of the patients in the untreated group showed disease progression. In contrast, only 3% of the patients in the treated group showed progression. We report the findings obtained in the same cohort after a longer period of beta-blocker therapy and follow-up (8 years). We prospectively reviewed data of the patients enrolled in the original prospective study. Disease progression was assessed by evaluating the presence of lymphatic, in-transit or visceral metastases. Deaths by any cause and deaths because of melanoma were recorded. A multivariate Cox proportional hazards model was used to evaluate the effect of beta-blocker use on disease-free survival and overall survival, adjusting for significant confounders. After a median follow-up of 8 years and a median duration of beta-blocker use of 7.6 years, 45% of the patients in the untreated group and 30% of the patients in the treated group showed disease progression. Notably, in the untreated group 35% patients died from melanoma and only 17% patients died from melanoma in the treated group. Results of this hospital-based prospective cohort study with a median follow-up of 8 years confirmed our previous results that the use of beta-blockers significantly reduced the risk of recurrence and mortality in melanoma patients. PMID- 28346290 TI - Endoscopic Ear Surgery for External Auditory Canal Cholesteatoma. AB - BACKGROUND: Treatment of external auditory canal cholesteatoma (EACC) has been a question of debate. To our knowledge and according to a systematic review of endoscopic ear surgery (EES) in 2015, this study describes for the first time the technique and outcome by solely transcanal EES for EACC. STUDY METHOD: Retrospective case series, level of evidence IV. METHODS: Between October 2014 and December 2016, nine patients with unilateral EACC have been treated by EES. Using a bimanual technique, canaloplasty has been performed using tragal perichondrium, cartilage, or artificial bone. Symptoms, signs, and reconstruction technique have been assessed and the primary endpoint: healing time was compared with benchmark values in the literature. RESULTS: During the 26 months study period all of our nine Naim stage III EACCs were successfully treated by EES with median healing time of 23.8 days. EACC limited to the external auditory canal (Naim stage III) represented an ideal target for EES minimizing tissue damage and thus median healing time compared with retroauricular (42-56 d) or endaural (59 d) surgical techniques. DISCUSSION: Shorter healing time helped to reduce skepticism toward a surgical treatment of EACC from the patient's perspective. Moreover, EES relied on reduced bulky equipment, dressing time, and complex maintenance compared with microscopic techniques. CONCLUSION: Transcanal endoscopic surgery is a valid treatment option for EACC up to Naim stage III. Moreover, the described procedure fosters in our eyes the teaching of our residence to get familiar with the basic steps of EES. PMID- 28346291 TI - Round and Oval Window Anatomic Variability: Its Implication for the Vibroplasty Technique. AB - OBJECTIVE: The objective of this study is to evaluate the anatomical variability of round and oval window regions and its relationship with their closest structures, to determine its implication on the fitting and stabilization of the middle ear implant Vibrant Soundbridge. METHODS: Variations of the anatomy of round and oval window regions were assessed in a total of 85 human dissected temporal bones. Afterward, we evaluated the adaptation and subsequent stabilization of the floating mass transducer (FMT) of the Vibrant Soundbridge in 67 cases in round window (RW) and in 22 cases in oval window (OW), and the influence that the variability of the different anatomical features examined had on this stabilization. We also assessed access and surgeon's view of the RW niche through the facial recess approach. RESULTS: Stabilization of the FMT in the RW was achieved in 53 (79%) of the 67 cases; we found that the less favorable anatomical conditions for stabilization were: membrane smaller than 1.5 mm, presence of a high jugular bulb and a narrow or very narrow RW niche. Frequently, two or more of these conditions happened simultaneously. In seven cases (22%) access to the RW through facial recess approach did not allow positioning the FMT in place. OW stabilization succeeded in 18 (82%) of the 22 cases. CONCLUSION: Round and oval window vibroplasty are difficult surgical techniques. To place the FMT directly on the OW may be easier as we do not have to drill the niche. In both regions there are some anatomical conditions that hinder fitting the FMT and even make it impossible. Once fitted, the main problem is to achieve good stabilization of the device. PMID- 28346292 TI - Bilateral Labyrinthine and Internal Auditory Canal Enhancement in an Infant With Severe Labyrinthine Dysplasia: A Previously Unreported Phenomenon. AB - OBJECTIVE: To describe a novel case of congenital profound bilateral sensorineural hearing loss in a patient with bilateral nodular internal auditory canal and labyrinthine enhancement and temporal bone dysplasia. PATIENTS: A 76 day-old female was referred to the authors' center for evaluation of congenital deafness. Behavioral observations and objective audiometric evaluation demonstrated bilateral profound sensorineural hearing loss and a comprehensive multidisciplinary evaluation identified compound heterozygous pathogenic variants in MYO7A, a gene associated with Usher Syndrome Type 1B or DFNB2. Computed tomography and contrast-enhanced magnetic resonance imaging studies demonstrated bilateral temporal bone anomalies with unique middle and inner ear malformations, as well as unique contrast enhancement in the membranous labyrinth, internal auditory canals, and cranial nerves, which have not been previously described with MYO7A variants. INTERVENTIONS: Given the potential risk for progressive bilateral labyrinthitis ossificans, bilateral simultaneous cochlear implantation was performed at 4 months of age. MAIN OUTCOME MEASURES: Subsequent audiologic follow up after implantation shows significantly improved access to auditory information and increased vocalizations. At last testing, speech and language skills for both receptive and expressive language abilities were found to be commensurate with her chronological age. CONCLUSION: We report a novel presentation and imaging findings of congenital bilateral profound sensorineural hearing loss in a patient with nodular internal auditory canal and labyrinthine enhancement and coexisting inner ear dysplasia. Despite the multiple radiologic abnormalities, the patient has demonstrated good benefit from cochlear implantation. Future study of rare variants of congenital deafness, such as this, is critical toward defining new disease processes and determining optimal treatment. PMID- 28346293 TI - Comparison of Experts and Residents Performing a Complex Procedure in a Temporal Bone Surgery Simulator. AB - OBJECTIVE: To investigate the use of automated metrics from a virtual reality (VR) temporal bone surgery simulator to determine how the performance of experts and trainees differs when performing a complex otological procedure (mastoidectomy with posterior tympanotomy and cochleostomy). STUDY DESIGN: Cohort study. METHODS: Using the University of Melbourne VR temporal bone surgery simulator, seven ENT consultants and seven ENT residents performed two trials of the surgical approach to cochlear implantation on a virtual temporal bone. Simulator recordings were used to calculate a range of automated metrics for each stage of the procedure, capturing efficiency, technique characteristics, drilled bone regions, and damage to vital anatomical structures. RESULTS: Results confirm that experts drilled more efficiently than residents. Experts generally used larger burrs and applied higher forces, resulting in faster material removal. However, they exercised more caution when drilling close to anatomical structures. Residents opened the temporal bone more widely, but neglected important steps in obtaining a clear view toward the round window, such as thinning the external ear canal wall and skeletonizing the medial aspect of the facial nerve. Residents used higher magnification and reoriented the temporal bone more often than experts. CONCLUSION: VR simulation provides metrics that allow the objective analysis of surgical technique, and identification of differences between the performance of surgical residents and their senior colleagues. The performance of residents could be improved with more guidance regarding how much force they should apply, what burr size they should use, how they should orient the bone, and for cochlear implant surgery guidance regarding anatomical regions requiring particular attention, to visualize the round window. PMID- 28346294 TI - Diagnosis and Treatment of Vestibular Neuritis/Neuronitis or Peripheral Vestibulopathy (PVP)? Open Questions and Possible Answers. AB - : The acute vestibular syndrome is a clinically defined entity consisting of vertigo or dizziness that develops acutely over minutes to hours and is accompanied by nausea/vomiting, gait instability, head motion intolerance, and nystagmus, while persisting over a day or more. When it is caused by a peripheral vestibular lesion and is not associated with clinically manifest auditory deficits, it is mostly labeled vestibular neuritis/neuronitis/neuropathy or sometimes peripheral vestibulopathy. Here, we propose hypotheses and discuss current research advances on viral or vascular factors in the pathogenesis, the recurrence, the site of lesion, old and new treatment options, contraindicated measures, the differential diagnosis, and the prognosis of vestibular neuritis/neuronitis/neuropathy or vestibulopathy. Possibly, other structures than the vestibular nerve are also involved in the pathogenetic process and the label peripheral vestibulopathy would be more apt. PMID- 28346295 TI - A Correlational Study of Spiritual Well-being and Depression in the Adult Cancer Patient. AB - Depression in adult cancer patients has been widely studied, along with spiritual effects of traumatic events and even spiritual growth after a diagnosis of cancer. There has been limited research determining a direct correlation between spiritual well-being and depression in adult cancer patients. The purpose of this research study was to examine the relationship between spiritual well-being and depression in adult cancer patients. This was a descriptive correlational study using 59 patients older than 18 years from an outpatient cancer center. The researchers hypothesized that patients with a low spiritual well-being score would be more likely to have a high depressive symptom score, thus providing support for a correlation between cancer patient's spiritual well-being and risk of depression. Implications of this study lead to evidence for better screening processes for cancer patients regarding spiritual well-being. PMID- 28346296 TI - Antipsychotic drug use in nursing home residents with and without dementia: keep an eye on the pro re nata medication. AB - Behavioral and psychological symptoms of dementia often lead to the prescription of antipsychotics, especially in nursing homes, but their use remains controversial. This study aimed to assess antipsychotic drug use in residents with dementia compared with those without dementia. Data were obtained through the cross-sectional 'inappropriate medication in patients with renal insufficiency in nursing homes' (IMREN) study including data from 21 nursing homes. Descriptive statistics were used and factors associated with the prescription of antipsychotics were identified by logistic regression. Overall, 57.5% of the 837 residents had a diagnosis of dementia and 47.0% of residents with dementia and 19.5% of those without dementia received antipsychotics. 35.9% of all antipsychotics in residents with dementia were prescribed as pro re nata (PRN) compared with 23.0% for residents without dementia. Typical antipsychotics were prescribed more commonly than atypical ones. The adjusted logistic regression showed a significant association between the prescription of antipsychotics and dementia (odds ratio: 3.58, 95% confidence interval: 2.45 5.25) as well as severe care dependency (odds ratio: 1.68, 95% confidence interval: 1.10-2.55). Despite safety warnings, antipsychotics are still frequently prescribed to residents with dementia. Almost half received antipsychotics and about a third of the antipsychotics are prescribed as PRN. Further studies should assess the use of PRN antipsychotics and guidelines for PRN prescriptions are clearly needed. PMID- 28346298 TI - Defining Sepsis in Burn Patients: Still a Long Way to Go. PMID- 28346297 TI - Exposure to Mycophenolate and Fatherhood. AB - BACKGROUND: Mycophenolic acid (MPA) is the active immunosuppressive substance in both mycophenolate mofetil and mycophenolate sodium, and it is widely used after organ transplantation. In women, taking MPA is teratogenic and may also influence spermatogenesis. There is a lack of knowledge regarding outcome of pregnancies fathered by men exposed to MPA. METHODS: We compared outcomes in pregnancies fathered by renal transplant men per whether they had been exposed to MPA or not at time of conception. A nationwide population-based retrospective cohort study was performed. Data from the Norwegian Renal Registry with all renal transplanted men alive between January 1, 1995 and December 31, 2015 were included, and relevant outcome data were extracted from the Medical Birth Registry of Norway. RESULTS: During the given time, 230 immunosuppressed renal transplanted men fathered 350 children (155 on MPA/195 not on MPA). There were no significant increased risks of malformation (3.9% vs. 2.6%, P = 0.49) in MPA exposed versus unexposed cohorts of children. The average dose (+/-SD) of mycophenolate was 1.42 +/- 0.3 g/day and the individual median MPA trough concentration in the time period of anticipated conception and pregnancy was 2.8 +/- 1.6 mg/L. Birth weight was similar in exposed and unexposed cohorts of children; 3381 +/- 681 g vs. 3429 +/- 714 g (P = 0.53). CONCLUSIONS: Paternal exposure to MPA did not increase the risk of adverse birth outcomes in children fathered by male kidney transplanted patients. These results are reassuring and support the continuation of paternal MPA treatment before, during, and after conception. PMID- 28346299 TI - Burn Survivor Focus Group. PMID- 28346301 TI - Psychological Outcomes Following Burn Injuries. PMID- 28346300 TI - The Burn Survivor Perspective. PMID- 28346302 TI - The Benefit of Microskin in Combination With Autologous Keratinocyte Suspension to Treat Full Skin Loss In Vivo. AB - Patients with extensive deep burns often lack enough autologous skin to cover the wounds. This study explores a new method using microskin in combination with autologous keratinocytes in the treatment of extensive deep burn. Wounds in the combination group were treated with automicroskin at an area expansion ratio of 20:1 (wound area to automicroskin area) and autologous keratinocyte suspension, which were compared with the following treatments: no autotransplant, only allografts (control group); autologous keratinocyte suspension only (keratinocyte only group); automicroskin at an area expansion ratio of 20:1 (20:1 group); and automicroskin at an area expansion ratio of 10:1 (10:1 group, positive control). The authors used epithelialization rate (epithelialized area on day 21 divided by original wound area), hematoxylin and eosin staining, laminin, and type IV collagen immunohistochemistry to assess wound healing. The epithelialization rate of combination group (74.2% +/- 8.0%) was similar to that of 10: 1 group (84.3% +/- 11.9%, P = .085) and significantly (P < .05) higher than that of 20:1 group (59.2% +/- 10.8%), keratinocyte only group (53.8% +/- 11.5%), and control group (22.7% +/- 5.5%). The hematoxylin and eosin staining and immunohistochemistry showed the epithelialization in the combination group was better than that in the keratinocyte only group and control group. Microskin in combination with autologous keratinocyte suspension can promote the reepithelialization of full thickness wounds and reduce the requirements for automircoskin, and it is a useful option in the treatment of extensive deep burns. PMID- 28346303 TI - Eccrine Syringofibroadenoma in Association With Acquired Epidermodysplasia Verruciformis. AB - A 75-year-old man with human immunodeficiency virus infection and numerous biopsy proven warts for 10 years, refractory to cryosurgery, cimetidine, and topical imiquimod, presented with numerous pink to hypopigmented verrucous papules and plaques involving the face, trunk, buttocks, and groin. Laboratory evaluation revealed a CD4 T-cell count of 62 cells per microliter and human immunodeficiency virus viral load of <117 copies per milliliter. Biopsy of a plaque groin lesion was performed. Histopathology revealed vertically oriented anastomosing strands of basaloid epithelium arising from multiple points along the epidermis in a background fibrovascular stroma. Ductal differentiation was identified. Areas of epidermis showed compact orthokeratosis, coarse hypergranulosis, and keratinocytes with abundant steel-blue-gray cytoplasm, indicative of viral cytopathic changes. Cytologic atypia was not identified. Human papillomavirus (HPV) genotyping of this lesion was positive for types 5 and 14. Overall, the findings were consistent with epidermodysplasia verruciformis in association with eccrine syringofibroadenoma (ESFA). The patient was subsequently treated with acitretin and showed clinical improvement. ESFA is an uncommon benign adnexal tumor with unknown pathogenesis. Although its association with HPV has rarely been reported, ESFA in the setting of acquired epidermodysplasia verruciformis has not been described. The development of ESFA in this case may be the result of HPV-induced cellular transformation. PMID- 28346304 TI - Lamotrigine Induces Hair Loss in a Patient With Treatment-Resistant Major Depressive Disorder. PMID- 28346307 TI - Ultrasound-Guided Selective Cervical Root Injection for Postherpetic Neuralgia. PMID- 28346308 TI - Atypical Fatty Infiltration in a Below-Knee Amputation. PMID- 28346309 TI - Sacral Insufficiency Fracture in an Elderly Woman With Hip Pain. PMID- 28346310 TI - The Potential for Gabapentinoid Abuse in Pain Management. PMID- 28346311 TI - Latissimus Dorsi Flap Breast Reconstruction-A Nationwide Inpatient Sample Review. AB - INTRODUCTION: The latissimus dorsi (LD) myocutaneous flap has been a long term standard for breast reconstruction. The variable indications for the LD flap have not been statistically examined because of the relative infrequency of its use by any single surgeon or institution. METHODS: The Nationwide Inpatient Sample data set was queried for all patient encounters involving a LD myocutaneous flap procedure. The study population was further restricted to female patients with a history of breast cancer or previous mastectomy. Demographics, Charlson Comorbidity Index scores, previous radiation history, and additional simultaneous procedures were extracted. Analysis was performed using nonparametric correlation coefficients and linear regression models. RESULTS: In total, 2304 LD breast reconstruction hospitalizations were identified between 2008 and 2010. Average patient age was 52.1 years, average hospital length of stay (LOS) was 2.8 days, bilateral latissimus reconstruction was performed in 252 (10.9%) patients, and 1414 patients (61.4%) were delayed reconstruction. Previous irradiation was present in 389 (16.9%) patients and was correlated with delayed reconstruction (P < 0.001).Younger age was associated with bilateral latissimus reconstructions (P < 0.05), contralateral free flap reconstruction (P < 0.0001), and combination with implants or tissue expanders (both P < 0.0001).After adjustment for age and Charlson Comorbidity Index, increased LOS was observed in patients undergoing contralateral free flap reconstruction (+1.29 days, P < 0.05) and immediate reconstruction (mastectomy, +0.39 days unilateral, P < 0.05; +0.64 days, bilateral, P < 0.001). The use of tissue expanders and implants were found to decrease hospital LOS (bilateral implant, -0.65 days, P < 0.001; bilateral expander, -0.72 days, P < 0.001), likely from confounding comorbidities. Charlson Comorbidity Index was strongly related to LOS (+0.08 days per point, P < 0.005), whereas age was not statistically significant when considered with comorbidity. CONCLUSIONS: The LD is most commonly used for delayed or salvage breast reconstruction, with particular utility in irradiated patients. Younger patients tend to undergo more involved LD variants with bilateral reconstructions and expanders or implants. After adjusting for comorbidity, age and the use of bilateral latissimus flaps with implants or expanders have no adverse impact on LOS. PMID- 28346312 TI - Using Technology to Enhance Discharge Teaching and Improve Coping for Patients After Stroke. AB - BACKGROUND: A diagnosis of stroke is a life-changing event. Effective discharge teaching after a stroke is crucial for recovery, but the overload of information can be overwhelming for patients and caregivers. PURPOSE: The purpose of this study was to examine differences in discharge readiness and postdischarge coping in patients admitted for stroke after the use of individualized postdischarge information/education provided via a technology package (including patient online portal access, e-mail/secure messaging) compared with current standard discharge teaching methods (verbal/written instructions). METHODS: This study used a descriptive comparative design to evaluate the difference between the nonintervention group A and the intervention group B. Patients in group B received additional discharge information via secured e-mail messaging at postdischarge days 2, 6, and 10. Two validated tools, Readiness for Hospital Discharge Form and Post-Discharge Coping Difficulty Scale, were used. RESULTS: One hundred patients were recruited for the study, but the final number of complete data sets collected was 86-42 in group A and 44 in group B. There was no statistically significant difference between the groups in discharge readiness. There was a significant difference in coping scores between the 2 groups, with the technology group exhibiting higher coping. CONCLUSIONS: New technology affords new options to improve discharge readiness and contribute to positive patient coping after stroke. The researchers hope that this study will contribute to the growing body of evidence showing success using aspects of technology to enhance discharge teaching and follow-up after discharge. PMID- 28346313 TI - Population Pharmacokinetics of Gemcitabine and dFdU in Pancreatic Cancer Patients Using an Optimal Design, Sparse Sampling Approach. AB - BACKGROUND: Gemcitabine remains a pillar in pancreatic cancer treatment. However, toxicities are frequently observed. Dose adjustment based on therapeutic drug monitoring might help decrease the occurrence of toxicities. In this context, this work aims at describing the pharmacokinetics (PK) of gemcitabine and its metabolite dFdU in pancreatic cancer patients and at identifying the main sources of their PK variability using a population PK approach, despite a sparse sampled population and heterogeneous administration and sampling protocols. METHODS: Data from 38 patients were included in the analysis. The 3 optimal sampling times were determined using KineticPro and the population PK analysis was performed on Monolix. Available patient characteristics, including cytidine deaminase (CDA) status, were tested as covariates. Correlation between PK parameters and occurrence of severe hematological toxicities was also investigated. RESULTS: A two-compartment model best fitted the gemcitabine and dFdU PK data (volume of distribution and clearance for gemcitabine: V1 = 45 L and CL1 = 4.03 L/min; for dFdU: V2 = 36 L and CL2 = 0.226 L/min). Renal function was found to influence gemcitabine clearance, and body surface area to impact the volume of distribution of dFdU. However, neither CDA status nor the occurrence of toxicities was correlated to PK parameters. CONCLUSIONS: Despite sparse sampling and heterogeneous administration and sampling protocols, population and individual PK parameters of gemcitabine and dFdU were successfully estimated using Monolix population PK software. The estimated parameters were consistent with previously published results. Surprisingly, CDA activity did not influence gemcitabine PK, which was explained by the absence of CDA-deficient patients enrolled in the study. This work suggests that even sparse data are valuable to estimate population and individual PK parameters in patients, which will be usable to individualize the dose for an optimized benefit to risk ratio. PMID- 28346315 TI - The Effects of 10-week Integrated Neuromuscular Training on Fundamental Movement Skills and Physical Self-efficacy in 6-7-Year-Old Children. AB - Duncan, MJ, Eyre, ELJ, and Oxford, SW. The effects of 10-week integrated neuromuscular training on fundamental movement skills and physical self-efficacy in 6-7-year-old children. J Strength Cond Res 32(12): 3348-3356, 2018-Integrated neuromuscular training (INT) has been suggested as an effective means to enhance athletic potential in children. However, few studies have reported the effects of school-based INT programs. This study examined the effect of INT on process and product fundamental movement skill measures and physical self-efficacy in 6-7 year-old children. Ninety-four children from 2 primary schools were randomized into either a 10-week INT program or a control group (CON) (n = 41). Results indicated significantly greater increases in process fundamental movement skill (FMS) scores in INT vs. CON (p = 0.001). For product measures of FMS, 10-m sprint time, counter movement jump, seated medicine ball throw and standing long jump (all p = 0.001), all significantly increased to a greater extent in the INT group vs. CON. A significant group (INT vs. CON) * time (pre vs. post) * gender interaction for physical self-efficacy revealed increased physical self-efficacy pre to post INT, compared with CON but only for boys (p = 0.001). For girls, physical self-efficacy was not significantly different before to after the 10 week period for INT and CON groups. The results of this study suggest that replacing 1 of the 2 weekly statutory physical education (PE) lessons with an INT program over a 10-week period results in positive improvements in fundamental movement skill quality and outcomes in 6-7-year-old children. Integrated neuromuscular training also appears to increase physical self-esteem to a greater extent than statutory PE but only in boys. PMID- 28346314 TI - Radiographic Review of Helical Blade Versus Lag Screw Fixation for Cephalomedullary Nailing of Low-Energy Peritrochanteric Femur Fractures: There is a Difference in Cutout. AB - OBJECTIVES: To compare the rate of cutout of helical blades and lag screws in low energy peritrochanteric femur fractures treated with a cephalomedullary nail (CMN). DESIGN: Retrospective review. SETTING: Academic medical center. PATIENTS: Overall, this study included 362 patients with an average age of 83 year old, a majority of whom were women, and had sustained a low-energy peritrochanteric femur fracture treated with a CMN. All patients had at least 3 months of clinical and radiographic follow, with an average follow-up of 11 months and a range of 3 88 months follow-up. INTERVENTION: Cephalomedullary nailing with the use of a helical blade or single lag screw for proximal fixation. MAIN OUTCOME MEASUREMENTS: Cutout of the helical blade or lag screw. RESULTS: Twenty-two cutouts occurred, 14 (15.1%) of 93 patients with helical blades and 8 (3.0%) of 269 patients with lag screws. Cutout with the helical blade was significantly more frequent than with the lag screw (P = 0.0001). The average tip-apex distance (TAD) was significantly greater for those patients who experienced cutout both for the helical blades (23.5 vs. 19.7 mm; P = 0.0194) and lag screws (24.5 vs. 20.0 mm; P = 0.0197). An absolute TAD predictive of cutout could not be determined. CONCLUSIONS: When the helical blade was used, implant cutout occurred at a significantly higher rate compared with lag screw fixation. There was not a threshold TAD that was predictive of cutout for either implant. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28346316 TI - Impact of Direction of Unloading Influence on Template Rate of Perceived Exertion. AB - Greer, BK, Young, PR, Thompson, B, Rickert, BJ, and Moran, MF. Impact of direction of unloading influence on template rate of perceived exertion. J Strength Cond Res 32(12): 3407-3413, 2018-It is suggested that exercisers engage in a process of teleoanticipation and create an exercise template based on previous experience with the exercise task that guides their perceptions of the amount of effort required for task completion. This study examined how altering workload intensity during a positive-pressure treadmill task may impact Rating of Perceived Exertion (RPE). In a counterbalanced design, 15 collegiate cross country runners (7 men and 8 women) performed 2 25-minute runs at a constant velocity, while body mass (BM) was either increased from 60 to 100% (low-to-high progression trial [INC]) or decreased from 100 to 60% (high-to-low progression trial) in 5-minutes increments. Oxygen consumption (V[Combining Dot Above]O2), heart rate (HR), and respiratory exchange ratio (RER) were collected. RPE was recorded at the end of each stage, and energy expenditure (EE) was calculated with V[Combining Dot Above]O2 and RER data. There were no significant differences between direction of loading conditions for V[Combining Dot Above]O2, EE, HR, and RER (p > 0.05). Between-trial differences in RPE at 100, 90, and 80% BM were statistically significant (p < 0.001), with higher RPEs observed during the INC. Differences in RPE observed between conditions cannot be explained by physiological mechanisms. These findings suggest that RPE is a multifaceted construct that can be impacted by subjectively based anticipatory factors such as exercise intensity. PMID- 28346317 TI - The CSF Immune Response in HIV-1-Associated Cryptococcal Meningitis: Macrophage Activation, Correlates of Disease Severity, and Effect of Antiretroviral Therapy. AB - BACKGROUND: Immune modulation may improve outcome in HIV-associated cryptococcal meningitis. Animal studies suggest alternatively activated macrophages are detrimental but human studies are limited. We performed a detailed assessment of the cerebrospinal fluid (CSF) immune response and examined immune correlates of disease severity and poor outcome, and the effects of antiretroviral therapy (ART). METHODOLOGY: We enrolled persons >=18 years with first episode of HIV associated cryptococcal meningitis. CSF immune response was assessed using flow cytometry and multiplex cytokine analysis. Principal component analysis was used to examine relationships between immune response, fungal burden, intracranial pressure and mortality, and the effects of recent ART initiation (<12 weeks). FINDINGS: CSF was available from 57 persons (median CD4 34/MUL). CD206 (alternatively activated macrophage marker) was expressed on 54% CD14 and 35% CD14 monocyte-macrophages. High fungal burden was not associated with CD206 expression but with a paucity of CD4, CD8, and CD4CD8 T cells and lower interleukin-6, G-CSF, and interleukin-5 concentrations. High intracranial pressure (>=30 cm H2O) was associated with fewer T cells, a higher fungal burden, and larger Cryptococcus organisms. Mortality was associated with reduced interferon-gamma concentrations and CD4CD8 T cells but lost statistical significance when adjusted for multiple comparisons. Recent ART was associated with increased CSF CD4/CD8 ratio and a significantly increased macrophage expression of CD206. CONCLUSIONS: Paucity of CSF T cell infiltrate rather than alternative macrophage activation was associated with severe disease in HIV associated cryptococcosis. ART had a pronounced effect on the immune response at the site of disease. PMID- 28346318 TI - Predictors of Impaired HDL Function in HIV-1 Infected Compared to Uninfected Individuals. AB - OBJECTIVE: High-density lipoprotein (HDL) function rather than absolute level may be a more accurate indicator for cardiovascular disease (CVD). Novel methods can measure HDL function using patient samples. The objective of this study is to identify factors that may contribute to HDL dysfunction in chronic treated HIV-1 infection. DESIGN: Retrospective study of HDL function measured in 2 ways in HIV 1-infected men with low overall CVD risk and healthy men with no known CVD risk matched by race to the HIV-1-infected participants. METHODS: We examined patient level factors associated with 2 different measures of HDL dysfunction: reduced antioxidant function (oxidized HDL, HDLox) and reduced HDL-apoA-I exchange (HAE), a measure of HDL remodeling, in the HIV infected and control men. Multivariable adjusted linear regression analyses were used adjusting for false discovery rate, age, race, body mass index (BMI), CD4 count, viremia, CVD risk, smoking, lipids, apoA-I, and albumin. RESULTS: In multivariate analysis among HIV-1-infected men (n = 166) (median age 45 years, CD4 T-cell count 505 cells/mm, 30.1% were viremic), higher BMI, lower apoA-I, and lower albumin were among the most notable correlates of higher HDLox and lower HAE (P < 0.05). In HIV-1 uninfected participants, lower albumin and higher BMI were associated with lower HAE and higher HDLox, respectively (P <= 0.05). HDLox was inversely related to HAE in HIV 1-infected individuals (P < 0.001). CONCLUSIONS: Increased HDLox correlates with reduced HAE in chronic HIV-1 infection. Higher BMI, lower apoA-I, and albumin were identified as factors associated with HDL dysfunction in chronic HIV-1 infection using 2 independent methods. PMID- 28346319 TI - Effect of Combination Antiretroviral Therapy on HIV-1-specific Antibody-Dependent Cellular Cytotoxicity Responses in Subtype B- and Subtype C-Infected Cohorts. AB - BACKGROUND: There is growing interest in immune therapies to clear the latent HIV 1 after combination antiretroviral therapy (cART). There is limited information on the effect of cART on antibody-dependent cellular cytotoxicity (ADCC), and no studies have directly compared ADCC in HIV-1 subtype B- and subtype C-infected subjects. The effect of improving immunocompetence on ADCC to influenza also remains unexplored. METHODS: The effect of cART on HIV-1- and influenza-specific ADCC was analyzed in 2 cohorts (39 subtype B- and 47 subtype C-infected subjects) before and after 2 years of cART. ADCC analyses included an enzyme-linked immunosorbent assay-based dimeric recombinant soluble (rs) FcgammaRIIIa-binding assay, antibody-dependent natural killer cell activation assay, and ADCC-mediated killing assays. RESULTS: HIV-1 subtype B and C Env-specific antibody binding to dimeric rsFcgammaRIIIa were reduced in subtypes B- and C-infected cohorts after 2 years of cART (both P < 0.05). Reduced ADCC-mediated killing of target cells expressing subtype B Env in the subtype B-infected cohort (P = 0.003) was observed after 96 weeks of cART, but not of subtype C Env in the subtype C infected cohort. A greater reduction in ADCC was detected in subjects with baseline CD4 counts >300 cells/MUL (P < 0.05). The resolving immunodeficiency after 96 weeks of cART resulted in improved HA-specific ADCC to 6 strains of influenza (all P < 0.01). CONCLUSIONS: cART results in HIV-1 antigen loss and reductions in HIV-1 Env-specific antibodies with Fc functionality in both subtype B- and C-infected subjects, particularly in immunocompetent subjects. Simultaneously, cART improves ADCC to diverse strains of influenza, suggesting reduction in influenza disease after cART. PMID- 28346321 TI - Growth Arrest and DNA-damage-inducible Protein 45beta-mediated DNA Demethylation of Voltage-dependent T-type Calcium Channel 3.2 Subunit Enhances Neuropathic Allodynia after Nerve Injury in Rats. AB - BACKGROUND: Growth arrest and DNA-damage-inducible protein 45beta reactivates methylation-silenced neural plasticity-associated genes through DNA demethylation. However, growth arrest and DNA-damage-inducible protein 45beta dependent demethylation contributes to neuropathic allodynia-associated spinal plasticity remains unclear. METHODS: Adult male Sprague-Dawley rats (654 out of 659) received a spinal nerve ligation or a sham operation with or without intrathecal application of one of the following: growth arrest and DNA-damage inducible protein 45beta messenger RNA-targeted small interfering RNA, lentiviral vector expressing growth arrest and DNA-damage-inducible protein 45beta, Ro 25 6981 (an NR2B-bearing N-methyl-D-aspartate receptor antagonist), or KN-93 (a calmodulin-dependent protein kinase II antagonist) were used for behavioral measurements, Western blotting, immunofluorescence, dot blots, detection of unmodified cytosine enrichment at cytosine-phosphate-guanine site, chromatin immunoprecipitation quantitative polymerase chain reaction analysis, and slice recordings. RESULTS: Nerve ligation-enhanced growth arrest and DNA-damage inducible protein 45beta expression (n = 6) in ipsilateral dorsal horn neurons accompanied with behavioral allodynia (n = 7). Focal knockdown of growth arrest and DNA-damage-inducible protein 45beta expression attenuated ligation-induced allodynia (n = 7) by reducing the binding of growth arrest and DNA-damage inducible protein 45beta to the voltage-dependent T-type calcium channel 3.2 subunit promoter (n = 6) that decreased expression of and current mediated by the voltage-dependent T-type calcium channel 3.2 subunit (both n = 6). In addition, NR2B-bearing N-methyl-D-aspartate receptors and calmodulin-dependent protein kinase II act in an upstream cascade to increase growth arrest and DNA-damage inducible protein 45beta expression, hence enhancing demethylation at the voltage dependent T-type calcium channel 3.2 subunit promoter and up-regulating voltage dependent T-type calcium channel 3.2 subunit expression. Intrathecal administration of Ro 25-6981, KN-93, or a growth arrest and DNA-damage-inducible protein 45beta-targeting small interfering RNA (n = 6) reversed the ligation induced enrichment of unmodified cytosine at the voltage-dependent T-type calcium channel 3.2 subunit promoter by increasing the associated 5-formylcytosine and 5 carboxylcytosine levels. CONCLUSIONS: By converting 5-formylcytosine or 5 carboxylcytosine to unmodified cytosine, the NR2B-bearing N-methyl-D-aspartate receptor, calmodulin-dependent protein kinase II, or growth arrest and DNA-damage inducible protein 45beta pathway facilitates voltage-dependent T-type calcium channel 3.2 subunit gene demethylation to mediate neuropathic allodynia. PMID- 28346323 TI - Isolated Persistent Left-sided Superior Vena Cava. PMID- 28346324 TI - T-wave Alternans and Long QT Syndrome. PMID- 28346325 TI - Clinical Judgment Is Not Reliable for Reducing Whole-body Computed Tomography Scanning after Isolated High-energy Blunt Trauma. AB - BACKGROUND: The purpose of this study was to test the diagnostic performance of clinical judgment for the prediction of a significant injury with whole-body computed tomography scanning after high-energy trauma. METHODS: The authors conducted an observational prospective study in a single level-I trauma center. Adult patients were included if they had an isolated high-energy injury. Senior trauma leaders were asked to make a clinical judgment regarding the likelihood of a significant injury before performance of a whole-body computed tomography scan. Clinical judgments were recorded using a probability diagnosis scale. The primary endpoint was the diagnosis of a serious-to-critical lesion on the whole-body computed tomography scan. Diagnostic performance was assessed using receiver operating characteristic analysis. RESULTS: Of the 354 included patients, 127 patients (36%) had at least one injury classified as abbreviated injury score greater than or equal to 3. The area under the receiver operating characteristic curve of the clinical judgment to predict a serious-to-critical lesion was 0.70 (95% CI, 0.64 to 0.75%). The sensitivity of the clinical judgment was 82% (95% CI, 74 to 88%), and the specificity was 49% (95% CI, 42 to 55%). No patient with a strict negative clinical examination had a severe lesion (n = 19 patients). The sensitivity of the clinical examination was 100% (95% CI, 97 to 100%) and its specificity was 8% (95% CI, 5 to 13%). CONCLUSIONS: Clinical judgment alone is not sufficient to reduce whole-body computed tomography scan use. In patients with a strictly normal physical examination, whole-body computed tomography scanning might be avoided, but this result deserves additional study in larger and more diverse populations of trauma patients. PMID- 28346326 TI - Sarcomas With CIC-rearrangements Are a Distinct Pathologic Entity With Aggressive Outcome: A Clinicopathologic and Molecular Study of 115 Cases. AB - CIC-DUX4 gene fusion, resulting from either a t(4;19) or t(10;19) translocation, is the most common genetic abnormality detected in EWSR1-negative small blue round cell tumors. Following their discovery it was debated if these tumors should be classified as variants of Ewing sarcoma (ie, atypical Ewing sarcoma) or as a stand-alone pathologic entity. As such the WHO classification temporarily grouped the CIC-rearranged tumors under undifferentiated sarcomas with round cell phenotype, until further clinical evidence was available. However, most studies reported so far include small series with limited follow-up information, which preclude a more definitive assessment. The present work investigates the clinicopathologic features of a large cohort of sarcomas with CIC gene rearrangement, to define their clinical presentation, morphologic spectrum, and outcome. Our study further examines the overall survival of the CIC-positive cohort compared with a control group of EWSR1-rearranged Ewing sarcoma matched for age and stage. The study cohort included 115 patients, with a mean age of 32 years and a slight male predominance. Most tumors occurred in the soft tissue (86%), predominantly deep-seated and equally divided among trunk and extremity, followed by visceral locations (12%) and rarely in the bone (3%). Microscopically, most tumors showed round to ovoid cytomorphology but half of the cases showed also focal areas of spindling and epithelioid/rhabdoid phenotype, with frequent myxoid stromal changes. Variable CD99 reactivity was seen in 84% cases, with a diffuse pattern only in 23% of cases, whereas nuclear WT1 was seen in 92%. A CIC-DUX4 fusion was detected in 57% of cases, with either DUX4 on 4q35 (35%) or on 10q26 in 25 (22%) cases. No FOXO4 gene rearrangements were present in 39 cases tested. Clinical follow-up was available in 57 patients, with a 5-year survival of 43%, which was significantly lower than the 77% 5-year survival in the control Ewing sarcoma group (P=0.002). Our findings show that CIC-DUX4 sarcomas occur most commonly in young adults within the somatic soft tissues, having a wide spectrum of morphology including round, epithelioid and spindle cells, and associated with an aggressive clinical course, with an inferior overall survival compared with Ewing sarcoma. The results support the classification of CIC-rearranged tumors as an independent molecular and clinical subset of small blue round cell tumors distinct from Ewing sarcoma. PMID- 28346328 TI - Guided Growth: A Novel Treatment for Anterolateral Bowing of the Tibia. AB - BACKGROUND: Tibial pseudoarthrosis is a source of considerable morbidity in children with neurofibromatosis. Preventing the progression of anterolateral bowing of the tibia (ALBT) to tibial pseudoarthrosis is difficult. The aim of this paper is to report the successful use of guided growth to prevent tibial pseudoarthrosis in a child with neurofibromatosis. METHODS: With local ethical approval, we reviewed the case notes and radiographs of a child with pronounced ALBT who was treated with guided growth to correct the deformity and prevent fracture. RESULTS: At 4-year follow-up guided growth has successfully corrected the deformity and prevented tibial pseudoarthrosis. CONCLUSIONS: This is the first report of the use of guided growth to prevent the progression of ALBT to pseudoarthrosis of the tibia in a child with neurofibromatosis. LEVEL OF EVIDENCE: Level IV. PMID- 28346327 TI - Development of a New Outcome Prediction Model in Early-stage Squamous Cell Carcinoma of the Oral Cavity Based on Histopathologic Parameters With Multivariate Analysis: The Aditi-Nuzhat Lymph-node Prediction Score (ANLPS) System. AB - The aim of this study was to evaluate the histopathologic parameters that predict lymph node metastasis in patients with oral squamous cell carcinoma (OSCC) and to design a new assessment score on the basis of these parameters that could ultimately allow for changes in treatment decisions or aid clinicians in deciding whether there is a need for close follow-up or to perform early lymph node dissection. Histopathologic parameters of 336 cases of OSCC with stage cT1/T2 N0M0 disease were analyzed. The location of the tumor and the type of surgery used for the management of the tumor were recorded for all patients. The parameters, including T stage, grading of tumor, tumor budding, tumor thickness, depth of invasion, shape of tumor nest, lymphoid response at tumor-host interface and pattern of invasion, eosinophilic reaction, foreign-body giant cell reaction, lymphovascular invasion, and perineural invasion, were examined. Ninety-two patients had metastasis in lymph nodes. On univariate and multivariate analysis, independent variables for predicting lymph node metastasis in descending order were depth of invasion (P=0.003), pattern of invasion (P=0.007), perineural invasion (P=0.014), grade (P=0.028), lymphovascular invasion (P=0.038), lymphoid response (P=0.037), and tumor budding (P=0.039). We designed a scoring system on the basis of these statistical results and tested it. Cases with scores ranging from 7 to 11, 12 to 16, and >=17 points showed LN metastasis in 6.4%, 22.8%, and 77.1% of cases, respectively. The difference between these 3 groups in relation to nodal metastasis was very significant (P<0.0001). A patient at low risk for lymph node metastasis (score, 7 to 11) had a 5-year survival of 93%, moderate risk patients (score, 12 to 16) had a 5-year survival of 67%, and high-risk patients (score, 17 to 21) had a 5-year survival of 39%. The risk of lymph node metastasis in OSCC is influenced by many histologic parameters that are not routinely analyzed in pathologic reports. These significant independent factors were graded to design a scoring system that permits accurate evaluation of the risk of metastasis with accuracy independent of the traditional TNM system or isolated histologic parameters. The need for neck node dissection can be predicted depending upon the scores obtained. PMID- 28346329 TI - Cardiac Computed Tomography Radiomics: A Comprehensive Review on Radiomic Techniques. AB - Radiologic images are vast three-dimensional data sets in which each voxel of the underlying volume represents distinct physical measurements of a tissue-dependent characteristic. Advances in technology allow radiologists to image pathologies with unforeseen detail, thereby further increasing the amount of information to be processed. Even though the imaging modalities have advanced greatly, our interpretation of the images has remained essentially unchanged for decades. We have arrived in the era of precision medicine where even slight differences in disease manifestation are seen as potential target points for new intervention strategies. There is a pressing need to improve and expand the interpretation of radiologic images if we wish to keep up with the progress in other diagnostic areas. Radiomics is the process of extracting numerous quantitative features from a given region of interest to create large data sets in which each abnormality is described by hundreds of parameters. From these parameters datamining is used to explore and establish new, meaningful correlations between the variables and the clinical data. Predictive models can be built on the basis of the results, which may broaden our knowledge of diseases and assist clinical decision making. Radiomics is a complex subject that involves the interaction of different disciplines; our objective is to explain commonly used radiomic techniques and review current applications in cardiac computed tomography imaging. PMID- 28346331 TI - Reverse Attenuation Gradient Sign. PMID- 28346330 TI - Differentiation of Impaired From Preserved Hemodynamics in Patients With Fontan Circulation Using Real-time Phase-velocity Cardiovascular Magnetic Resonance. AB - PURPOSE: Progressive impairment of hemodynamics in patients with Fontan circulation is common, multifactorial, and associated with decreased quality of life and increased morbidity. We sought to assess hemodynamic differences between patients with preserved (preserved Fontans) and those with impaired circulation (impaired Fontans) after pulmonary vasodilation using oxygen and under forced breathing conditions. MATERIALS AND METHODS: Real-time phase-contrast cardiovascular magnetic resonance was performed using non-ECG triggered echo planar imaging (temporal resolution=24 to 28 ms) in the ascending aorta (AAo) and superior vena cava (SVC)/inferior vena cava (IVC) on room air, after 100% oxygen inhalation (4 L/min; 10 min) and on forced breathing in 29 Fontan patients (17.2+/-7.3 y) and in 32 controls on room air (13.4+/-3.7 y). The simultaneously recorded patients' respiratory cycle was divided into 4 segments (expiration, end expiration, inspiration, and end-inspiration) to generate respiratory-dependent stroke volumes (SVs). The imaging data were matched with physiological data and analyzed with home-made software. RESULTS: The mean SVi (AAo) was 46.1+/-11.1 mL/m in preserved Fontans versus 30.4+/-6.2 mL/m in impaired Fontans (P=0.002) and 51.1+/-6.9 mL/m in controls (P=0.107). The cutoff value for differentiation of Fontan groups was SVi (AAo, end-expiratory) of 32.1 mL/m. After hyperoxygenation, the mean SVi (AAo) increased to 48.7+/-12.7 mL/m in preserved Fontans (P=0.045) but remained unchanged in impaired Fontans (31.1+/-5.8 mL/m, P=0.665). Simultaneously, heart rates decreased from 75.2+/-15.9 to 70.8+/-16.4 bpm (preserved; P=0.000) but remained unchanged in impaired circulation (baseline: 84.1+/-9.8 bpm, P=0.612). Compared with physiological respiration, forced breathing increased the maximum respiratory-related cardiac index difference (DeltaCImax) in preserved Fontans (SVC: 2.5-fold, P=0.000; and IVC: 1.8-fold, P=0.000) and to a lower extent in impaired Fontans (both veins, 1.5 fold; P(SVC)=0.011, P(IVC)=0.013). There was no impact on mean blood flow. CONCLUSIONS: Oxygen affected the pulmonary vascular system by vasodilation and increased SVi in preserved Fontans but had no effect on impaired Fontans. Forced breathing increased DeltaCImax but did not change the mean blood flow by sole activation of the ventilatory pump. End-expiratory aortic SVi represents a valuable measure for classifying the severity of Fontan hemodynamics impairment. PMID- 28346332 TI - Venom Profiling of a Population of the Theraphosid Spider Phlogius crassipes Reveals Continuous Ontogenetic Changes from Juveniles through Adulthood. AB - Theraphosid spiders (tarantulas) are venomous arthropods found in most tropical and subtropical regions of the world. Tarantula venoms are a complex cocktail of toxins with potential use as pharmacological tools, drugs and bioinsecticides. Although numerous toxins have been isolated from tarantula venoms, little research has been carried out on the venom of Australian tarantulas. We therefore investigated the venom profile of the Australian theraphosid spider Phlogius crassipes and examined whether there are ontogenetic changes in venom composition. Spiders were divided into four ontogenic groups according to cephalothorax length, then the venom composition of each group was examined using gel electrophoresis and mass spectrometry. We found that the venom of P. crassipes changes continuously during development and throughout adulthood. Our data highlight the need to investigate the venom of organisms over the course of their lives to uncover and understand the changing functions of venom and the full range of toxins expressed. This in turn should lead to a deeper understanding of the organism's ecology and enhance the potential for biodiscovery. PMID- 28346334 TI - Outdoor Cultivation of Marine Diatoms for Year-Round Production of Biofuels. AB - Biofuel production using microalgae is believed to have the advantage of continuous year-round production over crop plants, which have strong seasonality. However, actual year-round production of microalgal lipids using outdoor mass cultivation has rarely been demonstrated. In our previous study, it was demonstrated that the oleaginous diatom, Fistulifera solaris, was culturable in outdoor bioreactors from spring to autumn, whereas biomass and lipid production in winter failed because F. solaris did not grow below 15 degrees C. Therefore, another candidate strain that is culturable in winter is required. In this study, a cold-tolerant diatom, Mayamaea sp. JPCC CTDA0820, was selected as a promising candidate for biofuel production in winter. Laboratory-scale characterization revealed that this diatom was culturable at temperatures as low as 10 degrees C. Subsequently, F. solaris (April-October) and Mayamaea sp. JPCC CTDA0820 (November March) were cultured in outdoor open-pond bioreactors, wherein year-round production of diatom lipids was successfully demonstrated. The maximal values of areal productivities of biomass and lipids reached to 9.79 and 1.80 g/(m2 day) for F. solaris, and 8.62 and 0.92 g/(m2 day) for Mayamaea sp. JPCC CTDA0820, respectively. With the combined use of these two diatom species, stable year round production of microalgal lipids became possible. PMID- 28346333 TI - Clinical Benefits of n-3 PUFA and ?-Linolenic Acid in Patients with Rheumatoid Arthritis. AB - (1) Background: Marine n-3 polyunsaturated fatty acids (PUFA) and ?-linolenic acid (GLA) are well-known anti-inflammatory agents that may help in the treatment of inflammatory disorders. Their effects were examined in patients with rheumatoid arthritis; (2) Methods: Sixty patients with active rheumatoid arthritis were involved in a prospective, randomized trial of a 12 week supplementation with fish oil (group I), fish oil with primrose evening oil (group II), or with no supplementation (group III). Clinical and laboratory evaluations were done at the beginning and at the end of the study; (3) Results: The Disease Activity Score 28 (DAS 28 score), number of tender joints and visual analogue scale (VAS) score decreased notably after supplementation in groups I and II (p < 0.001). In plasma phospholipids the n-6/n-3 fatty acids ratio declined from 15.47 +/- 5.51 to 10.62 +/- 5.07 (p = 0.005), and from 18.15 +/- 5.04 to 13.50 +/- 4.81 (p = 0.005) in groups I and II respectively. The combination of n-3 PUFA and GLA (group II) increased ?-linolenic acid (0.00 +/- 0.00 to 0.13 +/- 0.11, p < 0.001), which was undetectable in all groups before the treatments; (4) Conclusion: Daily supplementation with n-3 fatty acids alone or in combination with GLA exerted significant clinical benefits and certain changes in disease activity. PMID- 28346335 TI - Apparent Interfacial Tension Effects in Protein Stabilized Emulsions Prepared with Microstructured Systems. AB - Proteins are mostly used to stabilize food emulsions; however, production of protein containing emulsions is notoriously difficult to capture in scaling relations due to the complex behavior of proteins in interfaces, in combination with the dynamic nature of the emulsification process. Here, we investigate premix membrane emulsification and use the Ohnesorge number to derive a scaling relation for emulsions prepared with whey protein, bovine serum albumin (BSA), and a standard emulsifier Tween 20, at various concentrations (0.1%, 0.5%, 1.25% and 2%). In the Ohnesorge number, viscous, inertia, and interfacial tension forces are captured, and most of the parameters can be measured with great accuracy, with the exception of the interfacial tension. We used microfluidic Y junctions to estimate the apparent interfacial tension at throughputs comparable to those in premix emulsification, and found a unifying relation. We next used this relation to plot the Ohnesorge number versus P-ratio defined as the applied pressure over the Laplace pressure of the premix droplet. The measured values all showed a decreasing Ohnesorge number at increasing P-ratio; the differences between regular surfactants and proteins being systematic. The surfactants were more efficient in droplet size reduction, and it is expected that the differences were caused by the complex behavior of proteins in the interface (visco-elastic film formation). The differences between BSA and whey protein were relatively small, and their behavior coincided with that of low Tween concentration (0.1%), which deviated from the behavior at higher concentrations. PMID- 28346337 TI - A Smart Sensor for Defending against Clock Glitching Attacks on the I2C Protocol in Robotic Applications. AB - This paper presents a study about hardware attacking and clock signal vulnerability. It considers a particular type of attack on the clock signal in the I2C protocol, and proposes the design of a new sensor for detecting and defending against this type of perturbation. The analysis of the attack and the defense is validated by means of a configurable experimental platform that emulates a differential drive robot. A set of experimental results confirm the interest of the studied vulnerabilities and the efficiency of the proposed sensor in defending against this type of situation. PMID- 28346336 TI - Enzymatic Processes in Marine Biotechnology. AB - In previous review articles the attention of the biocatalytically oriented scientific community towards the marine environment as a source of biocatalysts focused on the habitat-related properties of marine enzymes. Updates have already appeared in the literature, including marine examples of oxidoreductases, hydrolases, transferases, isomerases, ligases, and lyases ready for food and pharmaceutical applications. Here a new approach for searching the literature and presenting a more refined analysis is adopted with respect to previous surveys, centering the attention on the enzymatic process rather than on a single novel activity. Fields of applications are easily individuated: (i) the biorefinery value-chain, where the provision of biomass is one of the most important aspects, with aquaculture as the prominent sector; (ii) the food industry, where the interest in the marine domain is similarly developed to deal with the enzymatic procedures adopted in food manipulation; (iii) the selective and easy extraction/modification of structurally complex marine molecules, where enzymatic treatments are a recognized tool to improve efficiency and selectivity; and (iv) marine biomarkers and derived applications (bioremediation) in pollution monitoring are also included in that these studies could be of high significance for the appreciation of marine bioprocesses. PMID- 28346338 TI - SmartFluo: A Method and Affordable Adapter to Measure Chlorophyll a Fluorescence with Smartphones. AB - In order to increase the monitoring capabilities of inland and coastal waters, there is a need for new, affordable, sensitive and mobile instruments that could be operated semi-automatically in the field. This paper presents a prototype device to measure chlorophyll a fluorescence: the SmartFluo. The device is a combination of a smartphone offering an intuitive operation interface and an adapter implying a cuvette holder, as well as a suitable illumination source. SmartFluo is based on stimulated fluorescence of water constituents such as chlorophyll a. The red band of the digital smartphone camera is sensitive enough to detect quantitatively the characteristic red fluorescence emission. The adapter contains a light source, a strong light emitting diode and additional filters to enhance the signal-to-noise ratio and to suppress the impact of scattering. A novel algorithm utilizing the red band of the camera is provided. Laboratory experiments of the SmartFluo show a linear correlation (R 2 = 0.98) to the chlorophyll a concentrations measured by reference instruments, such as a high-performance benchtop laboratory fluorometer (LS 55, PerkinElmer). PMID- 28346339 TI - A Power Planning Algorithm Based on RPL for AMI Wireless Sensor Networks. AB - The advanced metering infrastructure (AMI) is an architecture for two-way communication between electric, gas and water meters and city utilities. The AMI network is a wireless sensor network that provides communication for metering devices in the neighborhood area of the smart grid. Recently, the applicability of a routing protocol for low-power and lossy networks (RPL) has been considered in AMI networks. Some studies in the literature have pointed out problems with RPL, including sub-optimal path selection and instability. In this paper, we defend the viewpoint that careful planning of the transmission power in wireless RPL networks can significantly reduce the pointed problems. This paper presents a method for planning the transmission power in order to assure that, after convergence, the size of the parent set of the RPL nodes is as close as possible to a predefined size. Another important feature is that all nodes in the parent set offer connectivity through links of similar quality. PMID- 28346340 TI - A Place to Call Home: An Analysis of the Bacterial Communities in Two Tethya rubra Samaai and Gibbons 2005 Populations in Algoa Bay, South Africa. AB - Sponges are important sources of bioactive secondary metabolites. These compounds are frequently synthesized by bacterial symbionts, which may be recruited from the surrounding seawater or transferred to the sponge progeny by the parent. In this study, we investigated the bacterial communities associated with the sponge Tethya rubra Samaai and Gibbons 2005. Sponge specimens were collected from Evans Peak and RIY Banks reefs in Algoa Bay, South Africa and taxonomically identified by spicule analysis and molecular barcoding. Crude chemical extracts generated from individual sponges were profiled by ultraviolet high performance liquid chromatography (UV-HPLC) and subjected to bioactivity assays in mammalian cells. Next-generation sequencing analysis of 16S rRNA gene sequences was used to characterize sponge-associated bacterial communities. T. rubra sponges collected from the two locations were morphologically and genetically indistinguishable. Chemical extracts from sponges collected at RIY banks showed mild inhibition of the metabolic activity of mammalian cells and their UV-HPLC profiles were distinct from those of sponges collected at Evans Peak. Similarly, the bacterial communities associated with sponges from the two locations were distinct with evidence of vertical transmission of symbionts from the sponge parent to its embryos. We conclude that these distinct bacterial communities may be responsible for the differences observed in the chemical profiles of the two Algoa Bay T. rubra Samaai and Gibbons 2005 populations. PMID- 28346342 TI - The Structure-Antioxidant Activity Relationship of Ferulates. AB - The antioxidant activity of ferulic acid (1), iso-ferulic acid (2), coniferyl aldehyde (3), methyl ferulate (4), and ethyl ferulate (5) were investigated using 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and ferric-reducing antioxidant power (FRAP) assays and autoxidation of triacylglycerols of commercially available sunflower oil (TGSO). The compounds tested for ability to scavenge ABTS radical cations was in the order of ferulic acid > coniferyl aldehyde ~ iso-ferulic acid > ethyl ferulate ~ methyl ferulate. The results of the FRAP assay for ferulic acid, iso-ferulic acid, and coniferyl aldehyde were similar to and higher than those of methyl ferulate and ethyl ferulate. In the lipid system, iso-ferulic acid showed weak antioxidant activity. The other ferulates exhibited much stronger, yet similar, activities. PMID- 28346341 TI - Subcritical Fluid Extraction of Chinese Quince Seed: Optimization and Product Characterization. AB - Chinese quince seed (CQS) is an underutilized oil source and a potential source of unsaturated fatty acids and alpha-tocopherol-rich oil. Subcritical fluid (SCF) extraction is executed at lower pressures and temperatures than the pressures and temperatures used in supercritical fluid extraction. However, no studies on the SCF extraction of CQS oil are reported. Therefore, the objective of this study was to evaluate the use of SCF for the extraction of CQS oil and to compare the use of SCF with the classical Soxhlet (CS) and supercritical CO2 (SC-CO2) extraction methods. Response surface methodology (RSM) was used to investigate the extraction conditions: temperature (45-65 degrees C), time (30-50 min), and solvent/solid ratio (5-15 mL/g). The optimization results showed that the highest yield (27.78%) was obtained at 56.18 degrees C, 40.20 min, and 12.57 mL/g. The oil extracted by SCF had a higher unsaturated fatty acid content (86.37%-86.75%), higher alpha-tocopherol content (576.0-847.6 mg/kg), lower acid value (3.97 mg/g), and lower peroxide value (0.02 meq O2/kg) than extractions using CS and SC CO2 methods. The SCF-defatted meal of oilseed exhibited the highest nitrogen solubility index (49.64%) and protein dispersibility index (50.80%), demonstrating that SCF extraction was a promising and efficient technique as an alternative to CS and SC-CO2 methods, as very mild operating conditions and an eco-friendly solvent can be used in the process with maximum preservation of the quality of the meal. PMID- 28346343 TI - Lifetime Exposure to a Constant Environment Amplifies the Impact of a Fructose Rich Diet on Glucose Homeostasis during Pregnancy. AB - The need to refine rodent models of human-related disease is now being recognized, in particular the rearing environment that can profoundly modulate metabolic regulation. Most studies on pregnancy and fetal development purchase and transport young females into the research facility, which after a short period of acclimation are investigated (Gen0). We demonstrate that female offspring (Gen1) show an exaggerated hyperinsulinemic response to pregnancy when fed a standard diet and with high fructose intake, which continues throughout pregnancy. Markers of maternal hepatic metabolism were differentially influenced, as the gene expression of acetyl-CoA-carboxylase was raised in Gen1 given fructose and controls, whereas glucose transporter 5 and fatty acid synthase expression were only raised with fructose. Gen1 rats weighed more than Gen0 throughout the study, although fructose feeding raised the percent body fat but not body weight. We show that long-term habituation to the living environment has a profound impact on the animal's metabolic responses to nutritional intervention and pregnancy. This has important implications for interpreting many studies investigating the influence of maternal consumption of fructose on pregnancy outcomes and offspring to date. PMID- 28346344 TI - Increased Force Variability Is Associated with Altered Modulation of the Motorneuron Pool Activity in Autism Spectrum Disorder (ASD). AB - Force control deficits have been repeatedly documented in autism spectrum disorder (ASD). They are associated with worse social and daily living skill impairments in patients suggesting that developing a more mechanistic understanding of the central and peripheral processes that cause them may help guide the development of treatments that improve multiple outcomes in ASD. The neuromuscular mechanisms underlying force control deficits are not yet understood. Seventeen individuals with ASD and 14 matched healthy controls completed an isometric index finger abduction test at 60% of their maximum voluntary contraction (MVC) during recording of the first dorsal interosseous (FDI) muscle to determine the neuromuscular processes associated with sustained force variability. Central modulation of the motorneuron pool activation of the FDI muscle was evaluated at delta (0-4 Hz), alpha (4-10 Hz), beta (10-35 Hz) and gamma (35-60 Hz) frequency bands. ASD patients showed greater force variability than controls when attempting to maintain a constant force. Relative to controls, patients also showed increased central modulation of the motorneuron pool at beta and gamma bands. For controls, reduced force variability was associated with reduced delta frequency modulation of the motorneuron pool activity of the FDI muscle and increased modulation at beta and gamma bands. In contrast, delta, beta, and gamma frequency oscillations were not associated with force variability in ASD. These findings suggest that alterations of central mechanisms that control motorneuron pool firing may underlie the common and often impairing symptoms of ASD. PMID- 28346346 TI - An Effective Terrain Aided Navigation for Low-Cost Autonomous Underwater Vehicles. AB - Terrain-aided navigation is a potentially powerful solution for obtaining submerged position fixes for autonomous underwater vehicles. The application of terrain-aided navigation with high-accuracy inertial navigation systems has demonstrated meter-level navigation accuracy in sea trials. However, available sensors may be limited depending on the type of the mission. Such limitations, especially for low-grade navigation sensors, not only degrade the accuracy of traditional navigation systems, but further impact the ability to successfully employ terrain-aided navigation. To address this problem, a tightly-coupled navigation is presented to successfully estimate the critical sensor errors by incorporating raw sensor data directly into an augmented navigation system. Furthermore, three-dimensional distance errors are calculated, providing measurement updates through the particle filter for absolute and bounded position error. The development of the terrain aided navigation system is elaborated for a vehicle equipped with a non-inertial-grade strapdown inertial navigation system, a 4-beam Doppler Velocity Log range sensor and a sonar altimeter. Using experimental data for navigation performance evaluation in areas with different terrain characteristics, the experiment results further show that the proposed method can be successfully applied to the low-cost AUVs and significantly improves navigation performance. PMID- 28346345 TI - Unconventional Transport Routes of Soluble and Membrane Proteins and Their Role in Developmental Biology. AB - Many proteins and cargoes in eukaryotic cells are secreted through the conventional secretory pathway that brings proteins and membranes from the endoplasmic reticulum to the plasma membrane, passing through various cell compartments, and then the extracellular space. The recent identification of an increasing number of leaderless secreted proteins bypassing the Golgi apparatus unveiled the existence of alternative protein secretion pathways. Moreover, other unconventional routes for secretion of soluble or transmembrane proteins with initial endoplasmic reticulum localization were identified. Furthermore, other proteins normally functioning in conventional membrane traffic or in the biogenesis of unique plant/fungi organelles or in plasmodesmata transport seem to be involved in unconventional secretory pathways. These alternative pathways are functionally related to biotic stress and development, and are becoming more and more important in cell biology studies in yeast, mammalian cells and in plants. The city of Lecce hosted specialists working on mammals, plants and microorganisms for the inaugural meeting on "Unconventional Protein and Membrane Traffic" (UPMT) during 4-7 October 2016. The main aim of the meeting was to include the highest number of topics, summarized in this report, related to the unconventional transport routes of protein and membranes. PMID- 28346347 TI - Biosynthesis of alpha-Glucosidase Inhibitors by a Newly Isolated Bacterium, Paenibacillus sp. TKU042 and Its Effect on Reducing Plasma Glucose in a Mouse Model. AB - Paenibacillus sp. TKU042, a bacterium isolated from Taiwanese soil, produced alpha-glucosidase inhibitors (aGIs) in the culture supernatant when commercial nutrient broth (NB) was used as the medium for fermentation. The supernatant of fermented NB (FNB) showed stronger inhibitory activities than acarbose, a commercial anti-diabetic drug. The IC50 and maximum alpha-glucosidase inhibitory activities (aGIA) of FNB and acarbose against alpha-glucosidase were 81 MUg/mL, 92% and 1395 MUg/mL, 63%, respectively. FNB was found to be strongly thermostable, retaining 95% of its relative activity, even after heating at 100 degrees C for 30 min. FNB was also stable at various pH values. Furthermore, FNB demonstrated antioxidant activity (IC50 = 2.23 mg/mL). In animal tests, FNB showed remarkable reductions in the plasma glucose of ICR (Institute of Cancer Research) mice at a concentration of 200 mg/kg. Combining FNB and acarbose enhanced the effect even more, with an added advantage of eliminating diarrhea. According to HPLC (High-performance liquid chromatography) fingerprinting, the Paenibacillus sp. TKU042 aGIs were not acarbose. All of the results suggest that Paenibacillus sp. TKU042 FNB could have potential use as a health food or to treat type 2 diabetes. PMID- 28346349 TI - Electrodes for Semiconductor Gas Sensors. AB - The electrodes of semiconductor gas sensors are important in characterizing sensors based on their sensitivity, selectivity, reversibility, response time, and long-term stability. The types and materials of electrodes used for semiconductor gas sensors are analyzed. In addition, the effect of interfacial zones and surface states of electrode-semiconductor interfaces on their characteristics is studied. This study describes that the gas interaction mechanism of the electrode-semiconductor interfaces should take into account the interfacial zone, surface states, image force, and tunneling effect. PMID- 28346348 TI - Vitamin D in Chronic Kidney Disease and Dialysis Patients. AB - Vitamin D deficiency (<20 ng/mL) and insufficiency (20-29 ng/mL) are common among patients with chronic kidney disease (CKD) or undergoing dialysis. In addition to nutritional and sunlight exposure deficits, factors that affect vitamin D deficiency include race, sex, age, obesity and impaired vitamin D synthesis and metabolism. Serum 1,25(OH)2D levels also decrease progressively because of 25(OH)D deficiency, together with impaired availability of 25(OH)D by renal proximal tubular cells, high fibroblast growth factor (FGF)-23 and decreased functional renal tissue. As in the general population, this condition is associated with increased morbidity and poor outcomes. Together with the progressive decline of serum calcitriol, vitamin D deficiency leads to secondary hyperparathyroidism (SHPT) and its complications, tertiary hyperparathyroidism and hypercalcemia, which require surgical parathyroidectomy or calcimimetics. Kidney Disease Outcomes Quality Initiative (KDOQI) and Kidney Disease Improving Global Outcomes (KDIGO) experts have recognized that vitamin D insufficiency and deficiency should be avoided in CKD and dialysis patients by using supplementation to prevent SHPT. Many vitamin D supplementation regimens using either ergocalciferol or cholecalciferol daily, weekly or monthly have been reported. The benefit of native vitamin D supplementation remains debatable because observational studies suggest that vitamin D receptor activator (VDRA) use is associated with better outcomes and it is more efficient for decreasing the serum parathormone (PTH) levels. Vitamin D has pleiotropic effects on the immune, cardiovascular and neurological systems and on antineoplastic activity. Extra-renal organs possess the enzymatic capacity to convert 25(OH)D to 1,25(OH)2D. Despite many unanswered questions, much data support vitamin D use in renal patients. This article emphasizes the role of native vitamin D replacement during all-phases of CKD together with VDRA when SHPT persists. PMID- 28346350 TI - Fast and Selective Plasmonic Serotonin Detection with Aptamer-Gold Nanoparticle Conjugates. AB - Neurotransmitters detection is critical to understanding communication between the brain and peripheral tissue. Serotonin is a key neurotransmitter linked to a number of conditions, but a full understanding of its role in disease is still lacking. The development of fast and selective serotonin detection platforms will provide researchers with tools to monitor serotonin in individuals before and after treatment for the condition of interest. Aptamer-gold nanoparticles conjugates that responded colorimetrically to serotonin with minimal response to its metabolite and other neurotransmitters were designed by simply adsorbing the DNA on the surface of AuNPs. A plasmonic assay for serotonin detection was designed with a response to biologically relevant serotonin levels. Importantly, the assay performance was not compromised when tested in filtered spiked fetal bovine serum as a mimic of biofluids. This work shows that these simple and stable Apt-AuNP conjugates are promising tools to develop fast assays for point of-care and personalized diagnostics applications. PMID- 28346352 TI - DOA Estimation of Coherent Signals on Coprime Arrays Exploiting Fourth-Order Cumulants. AB - This paper considers the problem of direction-of-arrival (DOA) estimation of coherent signals on passive coprime arrays, where we resort to the fourth-order cumulants of the received signal to explore more information. A fourth-order cumulant matrix (FCM) is introduced for the coprime array. The special structure of the FCM is combined with the array configuration to resolve the coherent signals. Since each sparse array of a coprime array is uniform, a series of overlapping identical subarrays can be extracted. Using this property, we propose a generalized spatial smoothing scheme applied to the FCM. From the smoothed FCM, the DOAs of both the coherent and independent signals can be successfully estimated on the pseudo-spectrum generated by the fourth-order MUSIC algorithm. To overcome the problem of occasional false peaks appearing on the pseudo spectrum, we use a supplementary sparse array whose inter-sensor spacing is coprime to that of either existing sparse array. From the combined spectrum aided by the supplementary sensors, the false peaks are removed while the true peaks remain. The effectiveness of the proposed methods is demonstrated by simulation examples. PMID- 28346351 TI - In Vitro and In Vivo Studies on the Structural Organization of Chs3 from Saccharomyces cerevisiae. AB - Chitin biosynthesis in yeast is accomplished by three chitin synthases (Chs) termed Chs1, Chs2 and Chs3, of which the latter accounts for most of the chitin deposited within the cell wall. While the overall structures of Chs1 and Chs2 are similar to those of other chitin synthases from fungi and arthropods, Chs3 lacks some of the C-terminal transmembrane helices raising questions regarding its structure and topology. To fill this gap of knowledge, we performed bioinformatic analyses and protease protection assays that revealed significant information about the catalytic domain, the chitin-translocating channel and the interfacial helices in between. In particular, we identified an amphipathic, crescent-shaped alpha-helix attached to the inner side of the membrane that presumably controls the channel entrance and a finger helix pushing the polymer into the channel. Evidence has accumulated in the past years that chitin synthases form oligomeric complexes, which may be necessary for the formation of chitin nanofibrils. However, the functional significance for living yeast cells has remained elusive. To test Chs3 oligomerization in vivo, we used bimolecular fluorescence complementation. We detected oligomeric complexes at the bud neck, the lateral plasma membrane, and in membranes of Golgi vesicles, and analyzed their transport route using various trafficking mutants. PMID- 28346353 TI - Intake and Dietary Food Sources of Fibre in Spain: Differences with Regard to the Prevalence of Excess Body Weight and Abdominal Obesity in Adults of the ANIBES Study. AB - The aim was to study the intake and food sources of fibre in a representative sample of Spanish adults and to analyse its association with excess body weight and abdominal obesity. A sample of 1655 adults (18-64 years) from the ANIBES ("Anthropometric data, macronutrients and micronutrients intake, practice of physical activity, socioeconomic data and lifestyles") cross-sectional study was analysed. Fibre intake and dietary food sources were determined by using a three day dietary record. Misreporters were identified using the protocol of the European Food Safety Authority. Mean (standard deviation) fibre intake was 12.59 (5.66) g/day in the whole sample and 15.88 (6.29) g/day in the plausible reporters. Mean fibre intake, both in the whole sample and the plausible reporters, was below the adequate intake established by European Food Safety Authority (EFSA) and the Institute of Medicine of the United States (IOM). Main fibre dietary food sources were grains, followed by vegetables, fruits, and pulses. In the whole sample, considering sex, and after adjusting for age and physical activity, mean (standard error) fibre intake (adjusted by energy intake) was higher in subjects who had normal weight (NW) 13.40 (0.184) g/day, without abdominal obesity 13.56 (0.192) g/day or without excess body weight and/or abdominal obesity 13.56 (0.207) g/day compared to those who were overweight (OW) 12.31 (0.195) g/day, p < 0.001 or obese (OB) 11.83 (0.266) g/day, p < 0.001, with abdominal obesity 12.09 (0.157) g/day, p < 0.001 or with excess body weight and/or abdominal obesity 12.22 (0.148) g/day, p < 0.001. There were no significant differences in relation with the fibre intake according to the body mass index (BMI), presence or absence of abdominal obesity or excess body weight and/or abdominal obesity in the plausible reporters. Fibre from afternoon snacks was higher in subjects with NW (6.92%) and without abdominal obesity (6.97%) or without excess body weight and/or abdominal obesity (7.20%), than those with OW (5.30%), p < 0.05 or OB (4.79%), p < 0.05, with abdominal obesity (5.18%), p < 0.01, or with excess body weight and/or abdominal obesity (5.21%), p < 0.01, in the whole sample. Conversely, these differences were not observed in the plausible reporters. The present study demonstrates an insufficient fibre intake both in the whole sample and in the plausible reporters and confirms its association with excess body weight and abdominal obesity only when the whole sample was considered. PMID- 28346354 TI - Anti-Inflammatory Properties of Irisin, Mediator of Physical Activity, Are Connected with TLR4/MyD88 Signaling Pathway Activation. AB - Irisin, an adipomiokine known as a mediator of physical activity, induces the browning of adipose tissue and it has potentially protective properties in the development of obesity-related states, such as insulin resistance, arteriosclerosis, and type 2 diabetes. Despite numerous studies conducted on this factor, still little is known about its impact on the functioning of immunocompetent cells, but its potential anti-inflammatory properties were previously suggested. In the current study we investigated the role of irisin (0 100 nM) in the downstream pathway activation of Toll-like receptor 4 (TLR4) in RAW 264.7 macrophages stimulated with lipopolysaccharide (LPS; 100 ng/mL). The results have shown that irisin in high concentrations (50, 100 nM) significantly decreased the TLR4 and MyD88 protein levels, as well as the phosphorylation of nuclear factor-kappaB (NF-kappaB), consequently leading to the reduction in the release of crucial pro-inflammatory cytokines. The above was confirmed for interleukin 1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), interleukin 6 (IL-6), keratinocyte chemoattractant (KC), monocyte chemotactic protein 1 (MCP 1), as well as for high mobility group box 1 (HMGB1). Moreover, our results indicate that this effect is connected with irisin's impact on the phosphorylation of mitogen-activated protein kinases (MAPKs), where a significant reduction in p-JNK and p-ERK but not p-p38 was observed. In conclusion, these data suggest that irisin has potentially anti-inflammatory properties connected with the downregulation of downstream pathways of TLR4/MyD88. PMID- 28346355 TI - Characterization of Active Anthocyanin Degradation in the Petals of Rosa chinensis and Brunfelsia calycina Reveals the Effect of Gallated Catechins on Pigment Maintenance. AB - Anthocyanin degradation decreases ornamental or nutritional values of horticultural products. To investigate factors that may influence colour change in flower development, anthocyanin degradation was compared between the flowers of Brunfelsia calycina and Rosa chinensis, which show rapid and slow degradation, respectively. In-gel activity assays, high performance liquid chromatography (HPLC) analysis of tannins, enzyme kinetics measurement and immune-detection of anthocyanin degradation related-perioxidases (PODs) were carried out for the comparison. Rose petals possessed significantly lower anthocyanin degradation related POD activities than Brunfelsia petals, which may be related to the high tannin contents. Epicatechin gallate (ECG) and gallocatechin gallate (GCG) were detected in rose as 161.3 +/- 12.34 and 273.56 +/- 41.23 MUg/g FW (Fresh Weight) respectively, while not detected in Brunfelsia. ECG and GCG inhibited the activities of the Brunfelsia POD with half maximal inhibitory concentrations (IC50s) as 21.5 and 29.7 MUM respectively, and increased the colour intensities of the anthocyanins. Catechin and epicatechin did not inhibit the POD activity, while serving as POD substrates, with Km (the Michaelis constant) as 0.48 and 1.23 mM. Similar protein levels of the anthocyanin degradation-related 40-kDa PODs were detected in Brunfelsia and rose. In summary, high amount of tannins, particularly ECG and GCG, in red rose petals may inhibit the degradation-related enzymes, leading to the maintenance of anthocyanins in vivo. PMID- 28346356 TI - Microinjection of Antibodies Targeting the Lamin A/C Histone-Binding Site Blocks Mitotic Entry and Reveals Separate Chromatin Interactions with HP1, CenpB and PML. AB - Lamins form a scaffold lining the nucleus that binds chromatin and contributes to spatial genome organization; however, due to the many other functions of lamins, studies knocking out or altering the lamin polymer cannot clearly distinguish between direct and indirect effects. To overcome this obstacle, we specifically targeted the mapped histone-binding site of A/C lamins by microinjecting antibodies specific to this region predicting that this would make the genome more mobile. No increase in chromatin mobility was observed; however, interestingly, injected cells failed to go through mitosis, while control antibody-injected cells did. This effect was not due to crosslinking of the lamin polymer, as Fab fragments also blocked mitosis. The lack of genome mobility suggested other lamin-chromatin interactions. To determine what these might be, mini-lamin A constructs were expressed with or without the histone-binding site that assembled into independent intranuclear structures. HP1, CenpB and PML proteins accumulated at these structures for both constructs, indicating that other sites supporting chromatin interactions exist on lamin A. Together, these results indicate that lamin A-chromatin interactions are highly redundant and more diverse than generally acknowledged and highlight the importance of trying to experimentally separate their individual functions. PMID- 28346357 TI - Comparison of the In Vivo Biotransformation of Two Emerging Estrogenic Contaminants, BP2 and BPS, in Zebrafish Embryos and Adults. AB - Zebrafish embryo assays are increasingly used in the toxicological assessment of endocrine disruptors. Among other advantages, these models are 3R-compliant and are fit for screening purposes. Biotransformation processes are well-recognized as a critical factor influencing toxic response, but major gaps of knowledge exist regarding the characterization of functional metabolic capacities expressed in zebrafish. Comparative metabolic studies between embryos and adults are even scarcer. Using 3H-labeled chemicals, we examined the fate of two estrogenic emerging contaminants, benzophenone-2 (BP2) and bisphenol S (BPS), in 4-day embryos and adult zebrafish. BPS and BP2 were exclusively metabolized through phase II pathways, with no major qualitative difference between larvae and adults except the occurrence of a BP2-di-glucuronide in adults. Quantitatively, the biotransformation of both molecules was more extensive in adults. For BPS, glucuronidation was the predominant pathway in adults and larvae. For BP2, glucuronidation was the major pathway in larvae, but sulfation predominated in adults, with ca. 40% conversion of parent BP2 and an extensive release of several conjugates into water. Further larvae/adults quantitative differences were demonstrated for both molecules, with higher residue concentrations measured in larvae. The study contributes novel data regarding the metabolism of BPS and BP2 in a fish model and shows that phase II conjugation pathways are already functional in 4-dpf-old zebrafish. Comparative analysis of BP2 and BPS metabolic profiles in zebrafish larvae and adults further supports the use of zebrafish embryo as a relevant model in which toxicity and estrogenic activity can be assessed, while taking into account the absorption and fate of tested substances. PMID- 28346358 TI - Genomic Evidence for Bacterial Determinants Influencing Obesity Development. AB - Obesity is a major global public health problem requiring multifaceted interventional approaches including dietary interventions with probiotic bacteria. High-throughput genome sequencing of microbial communities in the mammalian gastrointestinal system continues to present diverse protein function information to understand the bacterial determinants that influence obesity development. The goal of the research reported in this article was to identify biological processes in probiotic bacteria that could influence the mechanisms for the extraction of energy from diet in the human gastrointestinal system. Our research strategy of combining bioinformatics and visual analytics methods was based on the identification of operon gene arrangements in genomes of Lactobacillus species and Akkermansiamuciniphila that include at least a gene for a universal stress protein. The two major findings from this research study are related to Lactobacillus plantarum and Akkermansia muciniphila bacteria species which are associated with weight-loss. The first finding is that Lactobacillus plantarum strains have a two-gene operon that encodes a universal stress protein for stress response and the membrane translocator protein (TSPO), known to function in mitochondrial fatty acid oxidation in humans. The second finding is the presence of a three-gene operon in Akkermansia muciniphila that includes a gene whose human mitochondrial homolog is associated with waist-hip ratio and fat distribution. From a public health perspective, elucidation of the bacterial determinants influencing obesity will help in educating the public on optimal probiotic use for anti-obesity effects. PMID- 28346359 TI - New Acorane-Type Sesquiterpene from Acorus calamus L. AB - A new sesquiterpene, named neo-acorane A (1), and two known ones, acoric acid (2) and calamusin D (3), were isolated from a 95% ethanol extract of the rhizome parts of Acorus calamus L. Their structures were elucidated by spectroscopic methods, and the absolute configurations were determined by single-crystal X-ray diffraction analysis. Compounds 1 and 2 are nonisoprenoid sesquiterpenoids, likely biosynthesized from an acorane-type sesquiterpene by oxidative fission of the six- or five-membered ring. Moreover, compounds 1 (10 MUM), 2 (5 MUM and 10 MUM) and 3 (10 MUM) showed cell proliferation activity on the SK-N-BE (2) cell line. PMID- 28346360 TI - Functional Analysis of the Ser149/Thr149 Variants of Human Aspartylglucosaminidase and Optimization of the Coding Sequence for Protein Production. AB - Aspartylglucosaminidase (AGA) is a lysosomal hydrolase that participates in the breakdown of glycoproteins. Defects in the AGA gene result in a lysosomal storage disorder, aspartylglucosaminuria (AGU), that manifests mainly as progressive mental retardation. A number of AGU missense mutations have been identified that result in reduced AGA activity. Human variants that contain either Ser or Thr in position 149 have been described, but it is unknown if this affects AGA processing or activity. Here, we have directly compared the Ser149/Thr149 variants of AGA and show that they do not differ in terms of relative specific activity or processing. Therefore, Thr149 AGA, which is the rare variant, can be considered as a neutral or benign variant. Furthermore, we have here produced codon-optimized versions of these two variants and show that they are expressed at significantly higher levels than AGA with the natural codon-usage. Since optimal AGA expression is of vital importance for both gene therapy and enzyme replacement, our data suggest that use of codon-optimized AGA may be beneficial for these therapy options. PMID- 28346362 TI - Nutrition Assessment of B-Vitamins in Highly Active and Sedentary Women. AB - BACKGROUND: Female athletes and active women require adequate nutrition for optimal health and performance. Nutrition assessments are needed to identify potential nutrients of concern. Folate, vitamin B6, and vitamin B12 function in important pathways used during physical activity and female athletes may be at risk for poor status of these micronutrients. This cross-sectional study described a comprehensive nutrition assessment of the B-vitamins (folate, vitamin B6, and vitamin B12) using both dietary (food and dietary supplements) and biochemical assessments among highly active and sedentary women. METHODS: Highly active (n = 29; age 20 +/- 2 years; body mass index (BMI) 23.8 +/- 3.5 kg/m2) and sedentary (n = 29; age 24 +/- 3 years; BMI 22.6 +/- 3.0 kg/m2) women were recruited for this study. Participants completed 7-day weighed food records and a fasting blood draw. RESULTS: Although the highly active women reported higher intakes of energy (p < 0.01), folate (p < 0.01), vitamin B6 (p < 0.01), and vitamin B12 (p < 0.01), no significant differences were found between the groups for biomarkers of folate, vitamin B6, and vitamin B12. All of the highly active women had biomarkers within the desired reference ranges, suggesting good status. In general, most participants were able to meet the 1998 Recommended Daily Allowance (RDA) from food alone. For the women that reported using dietary supplements, micronutrient intakes met the 1998 RDA and in some cases, exceeded the Tolerable Upper Intake Level. CONCLUSION: This nutrition assessment documented good status for folate, vitamin B6, and vitamin B12 in the highly active women. Similar assessment approaches (food, dietary supplements, and biomarkers) should to completed with other nutrients of concern for the female athlete. PMID- 28346363 TI - Rapid and Low-Cost CRP Measurement by Integrating a Paper-Based Microfluidic Immunoassay with Smartphone (CRP-Chip). AB - Traditional diagnostic tests for chronic diseases are expensive and require a specialized laboratory, therefore limiting their use for point-of-care (PoC) testing. To address this gap, we developed a method for rapid and low-cost C reactive protein (CRP) detection from blood by integrating a paper-based microfluidic immunoassay with a smartphone (CRP-Chip). We chose CRP for this initial development because it is a strong biomarker of prognosis in chronic heart and kidney disease. The microfluidic immunoassay is realized by lateral flow and gold nanoparticle-based colorimetric detection of the target protein. The test image signal is acquired and analyzed using a commercial smartphone with an attached microlens and a 3D-printed chip-phone interface. The CRP-Chip was validated for detecting CRP in blood samples from chronic kidney disease patients and healthy subjects. The linear detection range of the CRP-Chip is up to 2 MUg/mL and the detection limit is 54 ng/mL. The CRP-Chip test result yields high reproducibility and is consistent with the standard ELISA kit. A single CRP-Chip can perform the test in triplicate on a single chip within 15 min for less than 50 US cents of material cost. This CRP-Chip with attractive features of low-cost, fast test speed, and integrated easy operation with smartphones has the potential to enable future clinical PoC chronic disease diagnosis and risk stratification by parallel measurements of a panel of protein biomarkers. PMID- 28346364 TI - New Benzimidazole-1,2,4-Triazole Hybrid Compounds: Synthesis, Anticandidal Activity and Cytotoxicity Evaluation. AB - Owing to the growing need for antifungal agents, we synthesized a new series 2 ((5-(4-(5-substituted-1H-benzimidazol-2-yl)phenyl)-4-substituted-4H-1,2,4-triazol 3-yl)thio)-1-(substitutedphenyl)ethan-1-one derivatives, which were tested against Candida species. The synthesized compounds were characterized and elucidated by FT-IR, 1H-NMR, 13C-NMR and HR-MS spectroscopies. The synthesized compounds were screened in vitro anticandidal activity against Candida species by broth microdiluation methods. In vitro cytotoxic effects of the final compounds were determined by MTT assay. Microbiological studies revealed that compounds 5m, 5o, 5r, 5t, 5y, 5ab, and 5ad possess a good antifungal profile. Compounds 5w was the most active derivative and showed comparable antifungal activity to those of reference drugs ketoconazole and fluconazole. Cytotoxicity evaluation of compounds 5m, 5o, 5r, 5w, 5y, 5ab and 5ad showed that compounds 5w and 5ad were the least cytotoxic agents. Effects of these two compounds against ergosterol biosynthesis were observed by LC-MS-MS method, which is based on quantification of ergosterol level in C. albicans. Compounds 5w and 5d inhibited ergosterol biosynthesis concentration dependently. A fluorescence microscopy study was performed to visualize effect of compound 5w against C. albicans at cellular level. It was determined that compound 5w has a membrane damaging effect, which may be related with inhibition of biosynthesis of ergosterol. PMID- 28346365 TI - An Amylase-Like Protein, AmyD, Is the Major Negative Regulator for alpha-Glucan Synthesis in Aspergillus nidulans during the Asexual Life Cycle. AB - alpha-Glucan affects fungal cell-cell interactions and is important for the virulence of pathogenic fungi. Interfering with production of alpha-glucan could help to prevent fungal infection. In our previous study, we reported that an amylase-like protein, AmyD, could repress alpha-glucan accumulation in Aspergillus nidulans. However, the underlying molecular mechanism was not clear. Here, we examined the localization of AmyD and found it was a membrane-associated protein. We studied AmyD function in alpha-glucan degradation, as well as with other predicted amylase-like proteins and three annotated alpha-glucanases. AmyC and AmyE share a substantial sequence identity with AmyD, however, neither affects alpha-glucan synthesis. In contrast, AgnB and MutA (but not AgnE) are functional alpha-glucanases that also repress alpha-glucan accumulation. Nevertheless, the functions of AmyD and these glucanases were independent from each other. The dynamics of alpha-glucan accumulation showed different patterns between the AmyD overexpression strain and the alpha-glucanase overexpression strains, suggesting AmyD may not be involved in the alpha-glucan degradation process. These results suggest the function of AmyD is to directly suppress alpha glucan synthesis, but not to facilitate its degradation. PMID- 28346366 TI - Automatic Camera Calibration Using Active Displays of a Virtual Pattern. AB - Camera calibration plays a critical role in 3D computer vision tasks. The most commonly used calibration method utilizes a planar checkerboard and can be done nearly fully automatically. However, it requires the user to move either the camera or the checkerboard during the capture step. This manual operation is time consuming and makes the calibration results unstable. In order to solve the above problems caused by manual operation, this paper presents a full-automatic camera calibration method using a virtual pattern instead of a physical one. The virtual pattern is actively transformed and displayed on a screen so that the control points of the pattern can be uniformly observed in the camera view. The proposed method estimates the camera parameters from point correspondences between 2D image points and the virtual pattern. The camera and the screen are fixed during the whole process; therefore, the proposed method does not require any manual operations. Performance of the proposed method is evaluated through experiments on both synthetic and real data. Experimental results show that the proposed method can achieve stable results and its accuracy is comparable to the standard method by Zhang. PMID- 28346361 TI - Specificity in Legume-Rhizobia Symbioses. AB - Most species in the Leguminosae (legume family) can fix atmospheric nitrogen (N2) via symbiotic bacteria (rhizobia) in root nodules. Here, the literature on legume rhizobia symbioses in field soils was reviewed and genotypically characterised rhizobia related to the taxonomy of the legumes from which they were isolated. The Leguminosae was divided into three sub-families, the Caesalpinioideae, Mimosoideae and Papilionoideae. Bradyrhizobium spp. were the exclusive rhizobial symbionts of species in the Caesalpinioideae, but data are limited. Generally, a range of rhizobia genera nodulated legume species across the two Mimosoideae tribes Ingeae and Mimoseae, but Mimosa spp. show specificity towards Burkholderia in central and southern Brazil, Rhizobium/Ensifer in central Mexico and Cupriavidus in southern Uruguay. These specific symbioses are likely to be at least in part related to the relative occurrence of the potential symbionts in soils of the different regions. Generally, Papilionoideae species were promiscuous in relation to rhizobial symbionts, but specificity for rhizobial genus appears to hold at the tribe level for the Fabeae (Rhizobium), the genus level for Cytisus (Bradyrhizobium), Lupinus (Bradyrhizobium) and the New Zealand native Sophora spp. (Mesorhizobium) and species level for Cicer arietinum (Mesorhizobium), Listia bainesii (Methylobacterium) and Listia angolensis (Microvirga). Specificity for rhizobial species/symbiovar appears to hold for Galega officinalis (Neorhizobium galegeae sv. officinalis), Galega orientalis (Neorhizobium galegeae sv. orientalis), Hedysarum coronarium (Rhizobium sullae), Medicago laciniata (Ensifer meliloti sv. medicaginis), Medicago rigiduloides (Ensifer meliloti sv. rigiduloides) and Trifolium ambiguum (Rhizobium leguminosarum sv. trifolii). Lateral gene transfer of specific symbiosis genes within rhizobial genera is an important mechanism allowing legumes to form symbioses with rhizobia adapted to particular soils. Strain-specific legume rhizobia symbioses can develop in particular habitats. PMID- 28346367 TI - Transplantation of Menstrual Blood-Derived Mesenchymal Stem Cells Promotes the Repair of LPS-Induced Acute Lung Injury. AB - Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with high morbidity and mortality. Menstrual blood-derived stem cells (MenSCs) have been shown to be good therapeutic tools in diseases such as ovarian failure and cardiac fibrosis. However, relevant studies of MenSCs in ALI have not yet proceeded. We hypothesized that MenSC could attenuate the inflammation in lipopolysaccharide (LPS)-induced ALI and promote the repair of damaged lung. ALI model was induced by LPS in C57 mice, and saline or MenSCs were administered via tail vein after four hours. The MenSCs were subsequently detected in the lungs by a live imaging system. The MenSCs not only improved pulmonary microvascular permeability and attenuated histopathological damage, but also mediated the downregulation of IL-1beta and the upregulation of IL-10 in bronchoalveolar lavage fluid (BALF) and the damaged lung. Immunohistochemistry revealed the increased expression of proliferating cell nuclear antigen (PCNA) and the reduced expression of caspase-3 indicating the beneficial effect of MenSCs. Keratinocyte growth factor (KGF) was also upregulated after MenSCs administrated. As shown using transwell co-culture, the MenSCs also could improve the viability of BEAS 2B cells and inhibit LPS-induced apoptosis. These findings suggest that MenSC based therapies could be promising strategies for treating ALI. PMID- 28346368 TI - Pathophysiological Significance of Dermatan Sulfate Proteoglycans Revealed by Human Genetic Disorders. AB - The indispensable roles of dermatan sulfate-proteoglycans (DS-PGs) have been demonstrated in various biological events including construction of the extracellular matrix and cell signaling through interactions with collagen and transforming growth factor-beta, respectively. Defects in the core proteins of DS PGs such as decorin and biglycan cause congenital stromal dystrophy of the cornea, spondyloepimetaphyseal dysplasia, and Meester-Loeys syndrome. Furthermore, mutations in human genes encoding the glycosyltransferases, epimerases, and sulfotransferases responsible for the biosynthesis of DS chains cause connective tissue disorders including Ehlers-Danlos syndrome and spondyloepimetaphyseal dysplasia with joint laxity characterized by skin hyperextensibility, joint hypermobility, and tissue fragility, and by severe skeletal disorders such as kyphoscoliosis, short trunk, dislocation, and joint laxity. Glycobiological approaches revealed that mutations in DS-biosynthetic enzymes cause reductions in enzymatic activities and in the amount of synthesized DS and also disrupt the formation of collagen bundles. This review focused on the growing number of glycobiological studies on recently reported genetic diseases caused by defects in the biosynthesis of DS and DS-PGs. PMID- 28346369 TI - Metabolic Impact of Light Phase-Restricted Fructose Consumption Is Linked to Changes in Hypothalamic AMPK Phosphorylation and Melatonin Production in Rats. AB - Recent studies show that the metabolic effects of fructose may vary depending on the phase of its consumption along with the light/dark cycle. Here, we investigated the metabolic outcomes of fructose consumption by rats during either the light (LPF) or the dark (DPF) phases of the light/dark cycle. This experimental approach was combined with other interventions, including restriction of chow availability to the dark phase, melatonin administration or intracerebroventricular inhibition of adenosine monophosphate-activated protein kinase (AMPK) with Compound C. LPF, but not DPF rats, exhibited increased hypothalamic AMPK phosphorylation, glucose intolerance, reduced urinary 6 sulfatoxymelatonin (6-S-Mel) (a metabolite of melatonin) and increased corticosterone levels. LPF, but not DPF rats, also exhibited increased chow ingestion during the light phase. The mentioned changes were blunted by Compound C. LPF rats subjected to dark phase-restricted feeding still exhibited increased hypothalamic AMPK phosphorylation but failed to develop the endocrine and metabolic changes. Moreover, melatonin administration to LPF rats reduced corticosterone and prevented glucose intolerance. Altogether, the present data suggests that consumption of fructose during the light phase results in out-of phase feeding due to increased hypothalamic AMPK phosphorylation. This shift in spontaneous chow ingestion is responsible for the reduction of 6-S-Mel and glucose intolerance. PMID- 28346370 TI - De Novo Assembly, Annotation, and Characterization of Root Transcriptomes of Three Caladium Cultivars with a Focus on Necrotrophic Pathogen Resistance/Defense Related Genes. AB - Roots are vital to plant survival and crop yield, yet few efforts have been made to characterize the expressed genes in the roots of non-model plants (root transcriptomes). This study was conducted to sequence, assemble, annotate, and characterize the root transcriptomes of three caladium cultivars (Caladium * hortulanum) using RNA-Seq. The caladium cultivars used in this study have different levels of resistance to Pythiummyriotylum, the most damaging necrotrophic pathogen to caladium roots. Forty-six to 61 million clean reads were obtained for each caladium root transcriptome. De novo assembly of the reads resulted in approximately 130,000 unigenes. Based on bioinformatic analysis, 71,825 (52.3%) caladium unigenes were annotated for putative functions, 48,417 (67.4%) and 31,417 (72.7%) were assigned to Gene Ontology (GO) and Clusters of Orthologous Groups (COG), respectively, and 46,406 (64.6%) unigenes were assigned to 128 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. A total of 4518 distinct unigenes were observed only in Pythium-resistant "Candidum" roots, of which 98 seemed to be involved in disease resistance and defense responses. In addition, 28,837 simple sequence repeat sites and 44,628 single nucleotide polymorphism sites were identified among the three caladium cultivars. These root transcriptome data will be valuable for further genetic improvement of caladium and related aroids. PMID- 28346371 TI - Modulation of TRP Channel Activity by Hydroxylation and Its Therapeutic Potential. AB - Two transient receptor potential (TRP) channels-TRPA1 and TRPV3-are post translationally hydroxylated, resulting in oxygen-dependent regulation of channel activity. The enzymes responsible are the HIF prolyl hydroxylases (PHDs) and the asparaginyl hydroxylase factor inhibiting HIF (FIH). The PHDs and FIH are well characterized for their hydroxylation of the hypoxic inducible transcription factors (HIFs), mediating their hypoxic regulation. Consequently, these hydroxylases are currently being targeted therapeutically to modulate HIF activity in anemia, inflammation, and ischemic disease. Modulating the HIFs by targeting these hydroxylases may result in both desirable and undesirable effects on TRP channel activity, depending on the physiological context. For the best outcomes, these hydroxylases could be therapeutically targeted in pathologies where activation of both the HIFs and the relevant TRP channels are predicted to independently achieve positive outcomes, such as wound healing and obesity. PMID- 28346372 TI - "Bligh and Dyer" and Folch Methods for Solid-Liquid-Liquid Extraction of Lipids from Microorganisms. Comprehension of Solvatation Mechanisms and towards Substitution with Alternative Solvents. AB - Bligh and Dyer (B & D) or Folch procedures for the extraction and separation of lipids from microorganisms and biological tissues using chloroform/methanol/water have been used tens of thousands of times and are "gold standards" for the analysis of extracted lipids. Based on the Conductor-like Screening MOdel for realistic Solvatation (COSMO-RS), we select ethanol and ethyl acetate as being potentially suitable for the substitution of methanol and chloroform. We confirm this by performing solid-liquid extraction of yeast (Yarrowia lipolytica IFP29) and subsequent liquid-liquid partition-the two steps of routine extraction. For this purpose, we consider similar points in the ternary phase diagrams of water/methanol/chloroform and water/ethanol/ethyl acetate, both in the monophasic mixtures and in the liquid-liquid miscibility gap. Based on high performance thin layer chromatography (HPTLC) to obtain the distribution of lipids classes, and gas chromatography coupled with a flame ionisation detector (GC/FID) to obtain fatty acid profiles, this greener solvents pair is found to be almost as effective as the classic methanol-chloroform couple in terms of efficiency and selectivity of lipids and non-lipid material. Moreover, using these bio-sourced solvents as an alternative system is shown to be as effective as the classical system in terms of the yield of lipids extracted from microorganism tissues, independently of their apparent hydrophilicity. PMID- 28346373 TI - Harmful Use of Alcohol: A Shadow over Sub-Saharan Africa in Need of Workable Solutions. AB - Alcohol consumption and alcohol-attributable burden of disease in Africa are expected to rise in the near future, yet. increasing alcohol-related harm receives little attention from policymakers and from the population in general. Even where new legislation is proposed it is rarely enacted into law. Being at the center of social and cultural activities in many countries, alcohol's negative role in society and contribution to countries' burden of disease are rarely questioned. After the momentum created by the adoption in 2010 of the WHO Global Strategy and the WHO Regional Strategy (for Africa) to Reduce the Harmful Use of Alcohol, and the WHO Global Action Plan for the Prevention and Control of Non-Communicable Diseases, in 2013, little seems to have been done to address the increasing use of alcohol, its associated burden and the new challenges that derive from the growing influence of the alcohol industry in Africa. In this review, we argue that to have a positive impact on the health of African populations, action addressing specific features of alcohol policy in the continent is needed, namely focusing on particularities linked to alcohol availability, like unrecorded and illicit production, outlet licensing, the expansion of formal production, marketing initiatives and taxation policies. PMID- 28346374 TI - Minimized Bolus-Type Wireless Sensor Node with a Built-In Three-Axis Acceleration Meter for Monitoring a Cow's Rumen Conditions. AB - Monitoring rumen conditions in cows is important because a dysfunctional rumen system may cause death. Sub-acute ruminal acidosis (SARA) is a typical disease in cows, and is characterized by repeated periods of low ruminal pH. SARA is regarded as a trigger for rumen atony, rumenitis, and abomasal displacement, which may cause death. In previous studies, rumen conditions were evaluated by wireless sensor nodes with pH measurement capability. The primary advantage of the pH sensor is its ability to continuously measure ruminal pH. However, these sensor nodes have short lifetimes since they are limited by the finite volume of the internal liquid of the reference electrode. Mimicking rumen atony, we attempt to evaluate the rumen condition using wireless sensor nodes with three-axis accelerometers. The theoretical life span of such sensor nodes depends mainly on the transmission frequency of acceleration data and the size of the battery, and the proposed sensor nodes are 30.0 mm in diameter and 70.0 mm in length and have a life span of over 600 days. Using the sensor nodes, we compare the rumen motility of the force transducer measurement with the three-axis accelerometer data. As a result, we can detect discriminative movement of rumen atony. PMID- 28346376 TI - Blend Hydrogel Microspheres of Carboxymethyl Chitosan and Gelatin for the Controlled Release of 5-Fluorouracil. AB - Carboxymethyl chitosan (CMCS) was synthesized and blended with gelatin (GE) to prepare hydrogel microspheres by w/o emulsion cross-linking in the presence of glutaraldehyde (GA), which acted as a cross-linker. 5-Fluorouracil (5-FU) was encapsulated to investigate its controlled release (CR) characteristics in acidic (pH 1.2) and alkaline (pH 7.4) buffer media. The microspheres which formed were spherical in nature, with smooth surfaces, as judged by the scanning electron microscopy (SEM). Fourier transform infrared spectroscopy (FTIR) confirmed the carboxymethylation of CS and the chemical stability of 5-FU in the formulations. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) confirmed the physical state and molecular level dispersion of 5-FU. Equilibrium swelling of microspheres was performed in water, in order to understand the water uptake properties. The in vitro release of 5-FU was extended up to 12 h in pH 7.4 phosphate buffer, revealing an encapsulation efficiency of 72%. The effects of blend composition, the extent of cross-linking, and initial drug loading on the in vitro release properties, were investigated. When analyzed through empirical equations, the release data suggested a non-Fickian transport mechanism. PMID- 28346377 TI - Impact of Beamforming on the Path Connectivity in Cognitive Radio Ad Hoc Networks. AB - This paper investigates the impact of using directional antennas and beamforming schemes on the connectivity of cognitive radio ad hoc networks (CRAHNs). Specifically, considering that secondary users use two kinds of directional antennas, i.e., uniform linear array (ULA) and uniform circular array (UCA) antennas, and two different beamforming schemes, i.e., randomized beamforming and center-directed to communicate with each other, we study the connectivity of all combination pairs of directional antennas and beamforming schemes and compare their performances to those of omnidirectional antennas. The results obtained in this paper show that, compared with omnidirectional transmission, beamforming transmission only benefits the connectivity when the density of secondary user is moderate. Moreover, the combination of UCA and randomized beamforming scheme gives the highest path connectivity in all evaluating scenarios. Finally, the number of antenna elements and degree of path loss greatly affect path connectivity in CRAHNs. PMID- 28346375 TI - Liposomal Formulations in Clinical Use: An Updated Review. AB - Liposomes are the first nano drug delivery systems that have been successfully translated into real-time clinical applications. These closed bilayer phospholipid vesicles have witnessed many technical advances in recent years since their first development in 1965. Delivery of therapeutics by liposomes alters their biodistribution profile, which further enhances the therapeutic index of various drugs. Extensive research is being carried out using these nano drug delivery systems in diverse areas including the delivery of anti-cancer, anti-fungal, anti-inflammatory drugs and therapeutic genes. The significant contribution of liposomes as drug delivery systems in the healthcare sector is known by many clinical products, e.g., Doxil(r), Ambisome(r), DepoDurTM, etc. This review provides a detailed update on liposomal technologies e.g., DepoFoamTM Technology, Stealth technology, etc., the formulation aspects of clinically used products and ongoing clinical trials on liposomes. PMID- 28346378 TI - DNA Repair Pathway Alterations in Bladder Cancer. AB - Most bladder tumors have complex genomes characterized by a high mutation burden as well as frequent copy number alterations and chromosomal rearrangements. Alterations in DNA repair pathways-including the double-strand break (DSB) and nucleotide excision repair (NER) pathways-are present in bladder tumors and may contribute to genomic instability and drive the tumor phenotype. DNA damaging such as cisplatin, mitomycin C, and radiation are commonly used in the treatment of muscle-invasive or metastatic bladder cancer, and several recent studies have linked specific DNA repair pathway defects with sensitivity to DNA damaging-based therapy. In addition, tumor DNA repair defects have important implications for use of immunotherapy and other targeted agents in bladder cancer. Therefore, efforts to further understand the landscape of DNA repair alterations in bladder cancer will be critical in advancing treatment for bladder cancer. This review summarizes the current understanding of the role of DNA repair pathway alterations in bladder tumor biology and response to therapy. PMID- 28346379 TI - The Economic Cost of Suicide and Non-Fatal Suicide Behavior in the Australian Workforce and the Potential Impact of a Workplace Suicide Prevention Strategy. AB - Suicide and non-fatal suicide behavior (NFSB) are significant problems faced by most countries. The objective of this research is to quantify the economic cost of suicide and NFSB in the Australian workforce and to examine the potential impact of introducing a workplace suicide prevention intervention to reduce this burden. The analysis used the best available suicide data, a well-established costing methodology, and a proven workplace intervention. In 2014, 903 workers died by suicide, 2303 workers harmed themselves resulting in full incapacity, and 11,242 workers harmed themselves resulting in a short absence from work. The present value of the economic cost of suicide and NFSB is estimated at $6.73 billion. Our analysis suggests the economic benefit of implementing a universal workplace strategy would considerably outweigh the cost of the strategy. For every one dollar invested, the benefits would be in excess of $1.50 ($1.11 $3.07), representing a positive economic investment. All variations of the key parameter hold the positive benefit-cost ratio. Rates of suicide and NFSB are far too high in Australia and elsewhere. More needs to be done to reduce this burden. Although workplace strategies are appropriate for those employed, these interventions must be used within a multifaceted approach that reflects the complex nature of self-harming behavior. PMID- 28346380 TI - Constituents of the Roots of Dichapetalum pallidum and Their Anti-Proliferative Activity. AB - As part of our search for bioactive compounds from the Dichapetalaceae, repeated chromatographic purification of the roots of a hitherto unexamined species, Dichapetalum pallidum, led to the isolation of the newly occurring 7 hydroxydichapetalin P (1) and the known dichapetalins A (2) and X (3). Also isolated were the known compounds friedelin-2,3-lactone (4), friedelan-3-one (6), friedelan-3beta-ol (7) and pomolic (8), as well as the dipeptide aurantiamide acetate (5). The compounds were characterized by direct interpretation of their IR, 1D NMR and 2D NMR spectral data and by comparison of their physico-chemical data, including their chromatographic profiles, with the literature and authentic samples in our compound library for the genus Dichapetalum. The compounds were assayed for their anti-proliferative activities against the human T-lymphocytic leukemia (Jurkat), acute promyelocytic leukemia (HL-60) and T-lymphoblast-like leukemia (CEM) cell lines. Overall, dichapetalin X showed the strongest (3.14 MUM) and broadest cytotoxic activities against all the leukemic cell lines tested, exhibiting even stronger activities than the standard compound, curcumin. PMID- 28346382 TI - The Balloon-Based Manometry Evaluation of Swallowing in Patients with Amyotrophic Lateral Sclerosis. AB - The aim of the study was to analyse the disturbances of the oro-pharyngeal swallowing phase of dysphagia in amyotrophic lateral sclerosis (ALS) patients with the use of specific manometric measurements and to evaluate their plausible association with the duration of the disease. Seventeen patients with ALS were evaluated with manometric examinations of the oral and pharyngeal part of the gastrointestinal tract. Tests were carried out by using the oesophageal balloon based method with four balloon transducers located 5 cm away from each other. The following manometric parameters were analysed: the base of tongue contraction (BTC) and the upper oesophageal sphincter pressure (UESP), and the hypopharyngeal suction pump (HSP) as well as the oro-pharyngeal, pharyngeal and hypopharyngeal transit time and average pharyngeal bolus velocity (oropharyngeal transit time (OTT), pharyngeal transit time (PTT), hypopharyngeal transit time (HTT) and average pharyngeal bolus velocity (APBV), respectively). Manomatric examinations during swallowing in patients with ALS showed significant weakness of BTC, a decrease of HSP and a decrease of the velocity of bolus transit inside the pharynx which were particularly marked between the first and the third examination. Manometric examinations of the oro-pharyngeal part of the gastrointestinal tract are useful and supportive methods in the analysis of swallowing disturbances in ALS patients. PMID- 28346383 TI - Novel Antihypertensive Peptides Derived from Adlay (Coix larchryma-jobi L. var. ma-yuen Stapf) Glutelin. AB - n/a. PMID- 28346381 TI - Multifaceted Applications of Chitosan in Cancer Drug Delivery and Therapy. AB - Chitosan is a versatile polysaccharide of biological origin. Due to the biocompatible and biodegradable nature of chitosan, it is intensively utilized in biomedical applications in scaffold engineering as an absorption enhancer, and for bioactive and controlled drug release. In cancer therapy, chitosan has multifaceted applications, such as assisting in gene delivery and chemotherapeutic delivery, and as an immunoadjuvant for vaccines. The present review highlights the recent applications of chitosan and chitosan derivatives in cancer therapy. PMID- 28346384 TI - Intensive Sleep Re-Training: From Bench to Bedside. AB - Intensive sleep re-training is a promising new therapy for chronic insomnia. Therapy is completed over a 24-h period during a state of sleep deprivation. Improvements of sleep and daytime impairments are comparable to the use of stimulus control therapy but with the advantage of a rapid reversal of the insomnia. The initial studies have been laboratory based and not readily accessible to the patient population. However, new smart phone technology, using a behavioral response to external stimuli as a measure of sleep/wake state instead of EEG determination of sleep, has made this new therapy readily available. Technological improvements are still being made allowing the therapy to provide further improvements in the effectiveness of Intensive Sleep Re training. PMID- 28346385 TI - Intelligent Diagnosis Method for Rotating Machinery Using Dictionary Learning and Singular Value Decomposition. AB - Rotating machinery is widely used in industrial applications. With the trend towards more precise and more critical operating conditions, mechanical failures may easily occur. Condition monitoring and fault diagnosis (CMFD) technology is an effective tool to enhance the reliability and security of rotating machinery. In this paper, an intelligent fault diagnosis method based on dictionary learning and singular value decomposition (SVD) is proposed. First, the dictionary learning scheme is capable of generating an adaptive dictionary whose atoms reveal the underlying structure of raw signals. Essentially, dictionary learning is employed as an adaptive feature extraction method regardless of any prior knowledge. Second, the singular value sequence of learned dictionary matrix is served to extract feature vector. Generally, since the vector is of high dimensionality, a simple and practical principal component analysis (PCA) is applied to reduce dimensionality. Finally, the K-nearest neighbor (KNN) algorithm is adopted for identification and classification of fault patterns automatically. Two experimental case studies are investigated to corroborate the effectiveness of the proposed method in intelligent diagnosis of rotating machinery faults. The comparison analysis validates that the dictionary learning-based matrix construction approach outperforms the mode decomposition-based methods in terms of capacity and adaptability for feature extraction. PMID- 28346386 TI - A Mixed-Methods Examination of Physical Activity and Sedentary Time in Overweight and Obese South Asian Men Living in the United Kingdom. AB - South Asian men living in the UK have higher rates of central obesity and Type 2 Diabetes Mellitus (T2DM) compared with their white British counterparts. Physical activity (PA) and sedentary time (ST) are important risk factors for the development of T2DM. The purpose of this study was to objectively measure PA, ST, and to explore the factors influencing these behaviours in this high-risk population. A mixed-methods cross-sectional research design was employed, including the quantification of PA and ST using the self-report International Physical Activity Questionnaire (IPAQ)-long form and accelerometry in overweight and obese UK South Asian men (n = 54), followed by semi-structured interviews in a purposive sub-sample to explore the factors influencing PA and ST (n = 31). Accelerometer-derived moderate-to-vigorous PA (MVPA) and ST were 298.9 +/- 186.6 min/week and 551.4 +/- 95.0 min/day, respectively. IPAQ-derived MVPA was significantly lower than accelerometer-derived MVPA (p < 0.001). IPAQ-derived ST was significantly higher than accelerometer-derived ST (p < 0.001). Lack of time and family commitments were identified as the main barriers to being more physically active, with group exercise identified as an important facilitator to being more active. A cultural norm of focusing on promoting education over sport participation during childhood was identified as an important factor influencing long-term PA behaviours. Work commitments and predominantly sedentary jobs were identified as the main barriers to reducing ST. Healthcare professionals and researchers need to consider the socio-cultural factors which affect PA engagement in overweight and obese South Asian men living in the UK, to ensure that advice and future interventions are tailored to address the needs of this population. PMID- 28346387 TI - OPRM1 c.118A>G Polymorphism and Duration of Morphine Treatment Associated with Morphine Doses and Quality-of-Life in Palliative Cancer Pain Settings. AB - Despite increased attention on assessment and management, pain remains the most persistent symptom in patients with cancer, in particular in end-of-life settings, with detrimental impact on their quality-of-life (QOL). We conducted this study to evaluate the added value of determining some genetic and non genetic factors to optimize cancer pain treatment. Eighty-nine patients were included in the study for the evaluation of palliative cancer pain management. The regression analysis showed that age, OPRM1 single nucleotide polymorphism (SNP), as well as the duration of morphine treatment were significantly associated with morphine doses at 24 h (given by infusion pump; p = 0.043, 0.029, and <0.001, respectively). The mean doses of morphine decreased with age but increased with the duration of morphine treatment. In addition, patients with AG genotype c.118A>G OPRM1 needed a higher dose of morphine than AA patients. Moreover, metastases, OPRM1 SNP, age, and gender were significantly associated with the QOL in our population. In particular, AA patients for OPRM1 SNP had significantly lower cognitive function than AG patients, a result not previously reported in the literature. These findings could help increase the effectiveness of morphine treatment and enhance the QOL of patients in regards to personalized medicine. PMID- 28346388 TI - Thermal Condensation of Glycine and Alanine on Metal Ferrite Surface: Primitive Peptide Bond Formation Scenario. AB - The amino acid condensation reaction on a heterogeneous mineral surface has been regarded as one of the important pathways for peptide bond formation. Keeping this in view, we have studied the oligomerization of the simple amino acids, glycine and alanine, on nickel ferrite (NiFe2O4), cobalt ferrite (CoFe2O4), copper ferrite (CuFe2O4), zinc ferrite (ZnFe2O4), and manganese ferrite (MnFe2O4) nanoparticles surfaces, in the temperature range from 50-120 degrees C for 1-35 days, without applying any wetting/drying cycles. Among the metal ferrites tested for their catalytic activity, NiFe2O4 produced the highest yield of products by oligomerizing glycine to the trimer level and alanine to the dimer level, whereas MnFe2O4 was the least efficient catalyst, producing the lowest yield of products, as well as shorter oligomers of amino acids under the same set of experimental conditions. It produced primarily diketopiperazine (Ala) with a trace amount of alanine dimer from alanine condensation, while glycine was oligomerized to the dimer level. The trend in product formation is in accordance with the surface area of the minerals used. A temperature as low as 50 degrees C can even favor peptide bond formation in the present study, which is important in the sense that the condensation process is highly feasible without any sort of localized heat that may originate from volcanoes or hydrothermal vents. However, at a high temperature of 120 degrees C, anhydrides of glycine and alanine formation are favored, while the optimum temperature for the highest yield of product formation was found to be 90 degrees C. PMID- 28346389 TI - Artesunate Enhances the Cytotoxicity of 5-Aminolevulinic Acid-Based Sonodynamic Therapy against Mouse Mammary Tumor Cells In Vitro. AB - Sonodynamic therapy (SDT) kills tumor cells through the synergistic effects of ultrasound (US) and a sonosensitizer agent. 5-Aminolevulinic acid (5-ALA) has been used as a sonodynamic sensitizer for cancer treatment. However, studies have shown that 5-ALA-based SDT has limited efficacy against malignant tumors. In this study, we examined whether artesunate (ART) could enhance the cytotoxicity of 5 ALA-based SDT against mouse mammary tumor (EMT-6) cells in vitro. In the ART, ART + US, ART + 5-ALA, and ART + 5-ALA + US groups, the cell survival rate correlated with ART concentration, and decreased with increasing concentrations of ART. Morphologically, many apoptotic and necrotic cells were observed in the ART + 5 ALA + US group. The percentage of reactive oxygen species-positive cells in the ART + 5-ALA + US group was also significantly higher than that in the 5-ALA group (p = 0.0228), and the cell death induced by ART + 5-ALA + US could be inhibited by the antioxidant N-acetylcysteine. These results show that ART offers great potential in enhancing the efficacy of 5-ALA-based SDT for the treatment of cancer. However, these results are only based on in vitro studies, and further in vivo studies are required. PMID- 28346390 TI - The Effect and Mechanism of Transdermal Penetration Enhancement of Fu's Cupping Therapy: New Physical Penetration Technology for Transdermal Administration with Traditional Chinese Medicine (TCM) Characteristics. AB - BACKGROUND: In this paper, a new type of physical penetration technology for transdermal administration with traditional Chinese medicine (TCM) characteristics is presented. Fu's cupping therapy (FCT), was established and studied using in vitro and in vivo experiments and the penetration effect and mechanism of FCT physical penetration technology was preliminarily discussed. METHODS: With 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-ylacetic acid (indomethacin, IM) as a model drug, the establishment of high, medium, and low references was completed for the chemical permeation system via in vitro transdermal tests. Furthermore, using chemical penetration enhancers (CPEs) and iontophoresis as references, the percutaneous penetration effect of FCT for IM patches was evaluated using seven species of in vitro diffusion kinetics models and in vitro drug distribution; the IM quantitative analysis method in vivo was established using ultra-performance liquid chromatography-tandem mass spectrometry technology (UPLC-MS/MS), and pharmacokinetic parameters: area under the zero and first moment curves from 0 to last time t (AUC0-t, AUMC0-t), area under the zero and first moment curves from 0 to infinity (AUC0-infinity, AUMC0 infinity), maximum plasma concentration (Cmax) and mean residence time (MRT), were used as indicators to evaluate the percutaneous penetration effect of FCT in vivo. Additionally, we used the 3K factorial design to study the joint synergistic penetration effect on FCT and chemical penetration enhancers. Through scanning electron microscopy (SEM) and transmission electron microscope (TEM) imaging, micro- and ultrastructural changes on the surface of the stratum corneum (SC) were observed to explore the FCT penetration mechanism. RESULTS: In vitro and in vivo skin permeation experiments revealed that both the total cumulative percutaneous amount and in vivo percutaneous absorption amount of IM using FCT were greater than the amount using CPEs and iontophoresis. Firstly, compared with the control group, the indomethacin skin percutaneous rate of the FCT low intensity group (FCTL) was 35.52%, and the enhancement ratio (ER) at 9 h was 1.76X, roughly equivalent to the penetration enhancing effect of the CPEs and iontophoresis. Secondly, the indomethacin percutaneous ratio of the FCT middle intensity group (FCTM) and FCT high-intensity group (FCTH) were 47.36% and 54.58%, respectively, while the ERs at 9 h were 3.58X and 8.39X, respectively. Thirdly, pharmacokinetic data showed that in vivo indomethacin percutaneous absorption of the FCT was much higher than that of the control, that of the FCTM was slightly higher than that of the CPE, and that of the FCTM group was significantly higher than all others. Meanwhile, variance analysis indicated that the combination of the FCT penetration enhancement method and the CPE method had beneficial effects in enhancing skin penetration: the significance level of the CPE method was 0.0004, which was lower than 0.001, meaning the difference was markedly significant; the significance level of the FCT was also below 0.0001 and its difference markedly significant. The significance level of factor interaction A * B was lower than 0.0001, indicating that the difference in synergism was markedly significant. Moreover, SEM and TEM images showed that the SC surfaces of Sprague-Dawley rats treated with FCT were damaged, and it was difficult to observe the complete surface structure, with SC pores growing larger and its special "brick structure" becoming looser. This indicated that the barrier function of the skin was broken, thus revealing a potentially major route of skin penetration. CONCLUSION: FCT, as a new form of transdermal penetration technology, has significant penetration effects with TCM characteristics and is of high clinical value. It is worth promoting its development. PMID- 28346391 TI - Hydrogen Sulphide Production in Healthy and Ulcerated Gastric Mucosa of Rats. AB - Hydrogen sulphide (H2S) is produced endogenously via two enzymes dependent on pyridoxal phosphate (PLP): cystathionine beta-synthase (CBS, EC 4.2.1.22), cystathionase gamma-liase (CTH, EC 4.4.1.1), and a third, 3-mercaptopyruvate sulfurtransferase (MPST, EC 2.8.1.2). H2S strengthens the defence mechanisms of the gastric mucosal barrier, and plays an important role in gastroprotection, including the increased resistance to damage caused by various irritants and non steroidal anti-inflammatory drugs. The study was conducted to determine the role of H2S in ulcerated gastric mucosa of rats caused by immobilization in cold water (WRS). The activity and expression of gamma-cystathionase, cystathionine beta synthase, 3-mercaptopyruvate sulfurtransferase, and rhodanese was compared with healthy mucosa, together with H2S generation, and cysteine, glutathione, and cystathionine levels. The results showed that the defence mechanism against stress is associated with stimulation of the production of H2S in the tissue and confirmed the observed advantageous effect of H2S on healing of gastric ulcers. In case of animals pretreated with exogenous sources of H2S and NaHS, and some changes observed in the ulcerated gastric mucosa tend to return to values found in the healthy tissue, a finding that is in accordance with the previously determined gastroprotective properties of H2S. The results presented in this paper point to the possible role of rhodanese in H2S production in the gastric mucosa of rats, together with the earlier mentioned three enzymes, which are all active in this tissue. PMID- 28346393 TI - Choerosponins A and B, Two New Cytotoxic Bridged-Ring Ketones and the Determination of Their Absolute Configurations. AB - Bioactivity-directed fractionation of antitumor compounds from the stem barks of Choerospondias axillaries (Roxb.) Burtt et Hill (Anacardiaceae) afforded two new cytotoxic bridged-ring ketones, choerosponins A (1) and B (2), and their structures were elucidated by spectroscopic methods; their stereochemistry was determined by NOE difference experiments, CD spectra and the modified Mosher's method. Compound 1 has a rare dioxatricyclo skeleton. Flow cytometry and SRB methods were employed to evaluate the antitumor activity of the two compounds against tsFT210, HCT-15, HeLa, A2780 and MCF-7 cell lines, and both of them showed strong cytotoxicity. MTT and paper disc methods were also used to evaluate their anti-hypoxia and antibacterial activities, and both of them showed no apparent activities. PMID- 28346392 TI - Impact of Novel Sorghum Bran Diets on DSS-Induced Colitis. AB - We have demonstrated that polyphenol-rich sorghum bran diets alter fecal microbiota; however, little is known regarding their effect on colon inflammation. Our aim was to characterize the effect of sorghum bran diets on intestinal homeostasis during dextran sodium sulfate (DSS)-induced colitis. Male Sprague-Dawley rats (N = 20/diet) were provided diets containing 6% fiber from cellulose, or Black (3-deoxyanthocyanins), Sumac (condensed tannins) or Hi Tannin Black (both) sorghum bran. Colitis was induced (N = 10/diet) with three separate 48-h exposures to 3% DSS, and feces were collected. On Day 82, animals were euthanized and the colon resected. Only discrete mucosal lesions, with no diarrhea or bloody stools, were observed in DSS rats. Only bran diets upregulated proliferation and Tff3, Tgfbeta and short chain fatty acids (SCFA) transporter expression after a DSS challenge. DSS did not significantly affect fecal SCFA concentrations. Bran diets alone upregulated repair mechanisms and SCFA transporter expression, which suggests these polyphenol-rich sorghum brans may suppress some consequences of colitis. PMID- 28346395 TI - A Correlation-Based Joint CFAR Detector Using Adaptively-Truncated Statistics in SAR Imagery. AB - Traditional constant false alarm rate (CFAR) detectors only use the contrast information between ship targets and clutter, and they suffer probability of detection (PD) degradation in multiple target situations. This paper proposes a correlation-based joint CFAR detector using adaptively-truncated statistics (hereafter called TS-2DLNCFAR) in SAR images. The proposed joint CFAR detector exploits the gray intensity correlation characteristics by building a two dimensional (2D) joint log-normal model as the joint distribution (JPDF) of the clutter, so joint CFAR detection is realized. Inspired by the CFAR detection methodology, we design an adaptive threshold-based clutter truncation method to eliminate the high-intensity outliers, such as interfering ship targets, side lobes, and ghosts in the background window, whereas the real clutter samples are preserved to the largest degree. A 2D joint log-normal model is accurately built using the adaptively-truncated clutter through simple parameter estimation, so the joint CFAR detection performance is greatly improved. Compared with traditional CFAR detectors, the proposed TS-2DLNCFAR detector achieves a high PD and a low false alarm rate (FAR) in multiple target situations. The superiority of the proposed TS-2DLNCFAR detector is validated on the multi-look Envisat-ASAR and TerraSAR-X data. PMID- 28346394 TI - Engineered Resistant-Starch (ERS) Diet Shapes Colon Microbiota Profile in Parallel with the Retardation of Tumor Growth in In Vitro and In Vivo Pancreatic Cancer Models. AB - BACKGROUND/AIMS: Pancreatic cancer (PC) is ranked as the fourth leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, a modest impact on the outcome of the disease is observed so far. We have previously demonstrated that short-term fasting cycles have the potential to improve the efficacy of chemotherapy against PC. The aim of this study was to assess the effect of an engineered resistant-starch (ERS) mimicking diet on the growth of cancer cell lines in vitro, on the composition of fecal microbiota, and on tumor growth in an in vivo pancreatic cancer mouse xenograft model. MATERIALS AND METHODS: BxPC-3, MIA PaCa-2 and PANC-1 cells were cultured in the control, and in the ERS-mimicking diet culturing condition, to evaluate tumor growth and proliferation pathways. Pancreatic cancer xenograft mice were subjected to an ERS diet to assess tumor volume and weight as compared to mice fed with a control diet. The composition and activity of fecal microbiota were further analyzed in growth experiments by isothermal microcalorimetry. RESULTS: Pancreatic cancer cells cultured in an ERS diet-mimicking medium showed decreased levels of phospho ERK1/2 (extracellular signal-regulated kinase proteins) and phospho-mTOR (mammalian target of rapamycin) levels, as compared to those cultured in standard medium. Consistently, xenograft pancreatic cancer mice subjected to an ERS diet displayed significant retardation in tumor growth. In in vitro growth experiments, the fecal microbial cultures from mice fed with an ERS diet showed enhanced growth on residual substrates, higher production of formate and lactate, and decreased amounts of propionate, compared to fecal microbiota from mice fed with the control diet. CONCLUSION: A positive effect of the ERS diet on composition and metabolism of mouse fecal microbiota shown in vitro is associated with the decrease of tumor progression in the in vivo PC xenograft mouse model. These results suggest that engineered dietary interventions could be supportive as a synergistic approach to enhance the efficacy of existing cancer treatments in pancreatic cancer patients. PMID- 28346396 TI - A PCR-Based Molecular Detection of Strongyloides stercoralisin Human Stool Samples from Tabriz City, Iran. AB - : Strongyloides stercoralis is a nematode causing serious infections in immunocompromised patients. In chronically infected patients, the low parasitic content as well as the resemblance of the larvae to several other species make diagnosis basedonmorphology difficult. In the present study, a PCR-based method targeting the internal transcribed sequence 2 (ITS2) of the rDNA region was examined for the molecular detection of S. stercoralis infection from the stool samples. A total of 1800 patients were included. Three fresh stool samples were collected per patient, and S. stercoralis isolates were identified by the morphological method. A subset of isolates was later used in the PCR-based method as positive controls. Additionally, negative and no-template controls were included. Data analysis was accomplished using an x2 test. Ap-value less than 0.05 was considered significant. In total, fivestool samples were found to be infected with S. stercoralis using the morphology method. PCR method detected S. stercoralis DNA target from all of the fiveDNA samples extracted from positive fecal samples. CONCLUSIONS: The PCR method used for amplifying a short fragment was successful for diagnosis of S. stercoralis in fecal samples and can be reliable for directly detecting the parasite bypassing morphological method. PMID- 28346398 TI - Sirtuin 1 (Sirt1) Overexpression in BaF3 Cells Contributes to Cell Proliferation Promotion, Apoptosis Resistance and Pro-Inflammatory Cytokine Production. AB - BACKGROUND B lymphocyte hyperactivity is a main characteristic of systemic lupus erythematosus (SLE), and B lymphocytes play a prominent pathogenic role in the development and progression of SLE. The aim of this study was to investigate the role of Sirtuin 1 (Sirt1) in B lymphocytes. MATERIAL AND METHODS Mouse B lymphocytes BaF3 was transfected with Sirt1 vector or shRNA against Sirt1. Then the transfected cells viability and apoptosis were respectively determined by MTT assay and flow cytometry. In addition, the mRNA levels of three pro-inflammatory cytokines and p53 were detected by RT-PCR. Furthermore, the expression levels of nuclear factor-kappa B (NF-kappaB) pathway proteins were measured by Western blot. RESULTS Overexpression of Sirt1 significantly increased cell proliferation (p<0.05 or p<0.01) and significantly suppressed apoptosis (p<0.05). The mRNA level expressions of interleukin 1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-alpha) were significantly upregulated (p<0.05 or p<0.01), whereas p53 was significantly downregulated (p<0.05) by Sirt1 overexpression. In addition, the inhibitory subunit of NF-kappaB (IkappaBalpha) and p65 were significantly activated and phosphorylated (p<0.01 or p<0.001), and B-Cell CLL/Lymphoma 3 (Bcl 3) was significantly upregulated (p<0.05) by Sirt1 overexpression. CONCLUSIONS These results suggested that Sirt1 overexpression could promote BaF3 cell proliferation, inhibit apoptosis, and upregulate pro-inflammatory cytokines. The NF-kappaB pathway might be involved in these effects of Sirt1 on BaF3 cells, and Sirt1 might be a potential risk factor of SLE. PMID- 28346399 TI - Endothelial cell-specific activation of transforming growth factor-beta signaling in mice induces cutaneous, visceral, and microvascular fibrosis. AB - In this study, we tested the hypothesis that constitutive endothelial cell specific activation of TGF-beta signaling induces tissue fibrosis and vasculopathy resembling the characteristic fibrotic and vascular alterations of systemic sclerosis. Transgenic mice with inducible expression of a constitutively active TGF-beta receptor I specifically in endothelial cells were generated by intercrossing mice harboring a constitutively active TGF-beta receptor I with a mouse strain containing the endothelial cell-specific Cdh5 gene promoter directing the tamoxifen-inducible expression of the Cre-ERT2 cassette. Administration of tamoxifen to these mice would result in constitutive TGF-beta activation and signaling confined to endothelial lineage cells. The effects of constitutive TGF-beta endothelial cell activation were assessed by histopathological examination of skin and various internal organs, tissue hydroxyproline analysis, and assessment of expression of myofibroblast differentiation and TGF-beta signaling genes employing real-time PCR and immunohistochemical staining of lung vessels for endothelial- and myofibroblast specific proteins. Constitutive TGFbeta-1 signaling in endothelial cells resulted in cutaneous and visceral fibrosis with prominent fibrotic involvement of the lungs and severe perivascular and subendothelial fibrosis of small arterioles. A marked increase in the expression of fibrosis-associated genes and of genes indicative of myofibroblast activation was also found. Confocal microscopy of lung vessels showed evidence consistent with the induction of endothelial-to mesenchymal transition (EndoMT). Taken together, our data indicate that transgenic mice with constitutive endothelial cell-specific activation of TGF beta signaling display severe cutaneous, pulmonary, and microvascular fibrosis resembling the fibrotic and microvascular alterations characteristic of systemic sclerosis. PMID- 28346397 TI - The Process and Regulatory Components of Inflammation in Brain Oncogenesis. AB - Central nervous system tumors comprising the primary cancers and brain metastases remain the most lethal neoplasms and challenging to treat. Substantial evidence points to a paramount role for inflammation in the pathology leading to gliomagenesis, malignant progression and tumor aggressiveness in the central nervous system (CNS) microenvironment. This review summarizes the salient contributions of oxidative stress, interleukins, tumor necrosis factor-alpha (TNF alpha), cyclooxygenases, and transcription factors such as signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-light-chain enhancer of activated B-cells (NF-kappaB) and the associated cross-talks to the inflammatory signaling in CNS cancers. The roles of reactive astrocytes, tumor associated microglia and macrophages, metabolic alterations, microsatellite instability, O6-methylguanine DNA methyltransferase (MGMT) DNA repair and epigenetic alterations mediated by the isocitrate dehydrogenase 1 (IDH1) mutations have been discussed. The inflammatory pathways with relevance to the brain cancer treatments have been highlighted. PMID- 28346401 TI - Targeted base editing in rice and tomato using a CRISPR-Cas9 cytidine deaminase fusion. AB - We applied a fusion of CRISPR-Cas9 and activation-induced cytidine deaminase (Target-AID) for point mutagenesis at genomic regions specified by single guide RNAs (sgRNAs) in two crop plants. In rice, we induced multiple herbicide resistance point mutations by multiplexed editing using herbicide selection, while in tomato we generated marker-free plants with homozygous heritable DNA substitutions, demonstrating the feasibility of base editing for crop improvement. PMID- 28346402 TI - Large-scale design of robust genetic circuits with multiple inputs and outputs for mammalian cells. AB - Engineered genetic circuits for mammalian cells often require extensive fine tuning to perform as intended. We present a robust, general, scalable system, called 'Boolean logic and arithmetic through DNA excision' (BLADE), to engineer genetic circuits with multiple inputs and outputs in mammalian cells with minimal optimization. The reliability of BLADE arises from its reliance on recombinases under the control of a single promoter, which integrates circuit signals on a single transcriptional layer. We used BLADE to build 113 circuits in human embryonic kidney and Jurkat T cells and devised a quantitative, vector-proximity metric to evaluate their performance. Of 113 circuits analyzed, 109 functioned (96.5%) as intended without optimization. The circuits, which are available through Addgene, include a 3-input, two-output full adder; a 6-input, one-output Boolean logic look-up table; circuits with small-molecule-inducible control; and circuits that incorporate CRISPR-Cas9 to regulate endogenous genes. BLADE enables execution of sophisticated cellular computation in mammalian cells, with applications in cell and tissue engineering. PMID- 28346403 TI - Near-infrared optogenetic pair for protein regulation and spectral multiplexing. AB - Multifunctional optogenetic systems are in high demand for use in basic and biomedical research. Near-infrared-light-inducible binding of bacterial phytochrome BphP1 to its natural PpsR2 partner is beneficial for simultaneous use with blue-light-activatable tools. However, applications of the BphP1-PpsR2 pair are limited by the large size, multidomain structure and oligomeric behavior of PpsR2. Here, we engineered a single-domain BphP1 binding partner, Q-PAS1, which is three-fold smaller and lacks oligomerization. We exploited a helix-PAS fold of Q-PAS1 to develop several near-infrared-light-controllable transcription regulation systems, enabling either 40-fold activation or inhibition. The light induced BphP1-Q-PAS1 interaction allowed modification of the chromatin epigenetic state. Multiplexing the BphP1-Q-PAS1 pair with a blue-light-activatable LOV domain-based system demonstrated their negligible spectral crosstalk. By integrating the Q-PAS1 and LOV domains in a single optogenetic tool, we achieved tridirectional protein targeting, independently controlled by near-infrared and blue light, thus demonstrating the superiority of Q-PAS1 for spectral multiplexing and engineering of multicomponent systems. PMID- 28346400 TI - T-lymphocyte homing: an underappreciated yet critical hurdle for successful cancer immunotherapy. AB - Advances in cancer immunotherapy have offered new hope for patients with metastatic disease. This unfolding success story has been exemplified by a growing arsenal of novel immunotherapeutics, including blocking antibodies targeting immune checkpoint pathways, cancer vaccines, and adoptive cell therapy (ACT). Nonetheless, clinical benefit remains highly variable and patient specific, in part, because all immunotherapeutic regimens vitally hinge on the capacity of endogenous and/or adoptively transferred T-effector (Teff) cells, including chimeric antigen receptor (CAR) T cells, to home efficiently into tumor target tissue. Thus, defects intrinsic to the multi-step T-cell homing cascade have become an obvious, though significantly underappreciated contributor to immunotherapy resistance. Conspicuous have been low intralesional frequencies of tumor-infiltrating T-lymphocytes (TILs) below clinically beneficial threshold levels, and peripheral rather than deep lesional TIL infiltration. Therefore, a Teff cell 'homing deficit' may arguably represent a dominant factor responsible for ineffective immunotherapeutic outcomes, as tumors resistant to immune targeted killing thrive in such permissive, immune-vacuous microenvironments. Fortunately, emerging data is shedding light into the diverse mechanisms of immune escape by which tumors restrict Teff cell trafficking and lesional penetrance. In this review, we scrutinize evolving knowledge on the molecular determinants of Teff cell navigation into tumors. By integrating recently described, though sporadic information of pivotal adhesive and chemokine homing signatures within the tumor microenvironment with better established paradigms of T-cell trafficking under homeostatic or infectious disease scenarios, we seek to refine currently incomplete models of Teff cell entry into tumor tissue. We further summarize how cancers thwart homing to escape immune-mediated destruction and raise awareness of the potential impact of immune checkpoint blockers on Teff cell homing. Finally, we speculate on innovative therapeutic opportunities for augmenting Teff cell homing capabilities to improve immunotherapy-based tumor eradication in cancer patients, with special focus on malignant melanoma. PMID- 28346405 TI - Structural and functional insight into human O-GlcNAcase. AB - O-GlcNAc hydrolase (OGA) removes O-linked N-acetylglucosamine (O-GlcNAc) from a myriad of nucleocytoplasmic proteins. Through co-expression and assembly of OGA fragments, we determined the three-dimensional structure of human OGA, revealing an unusual helix-exchanged dimer that lays a structural foundation for an improved understanding of substrate recognition and regulation of OGA. Structures of OGA in complex with a series of inhibitors define a precise blueprint for the design of inhibitors that have clinical value. PMID- 28346404 TI - Chemical screening identifies ATM as a target for alleviating senescence. AB - Senescence, defined as irreversible cell-cycle arrest, is the main driving force of aging and age-related diseases. Here, we performed high-throughput screening to identify compounds that alleviate senescence and identified the ataxia telangiectasia mutated (ATM) inhibitor KU-60019 as an effective agent. To elucidate the mechanism underlying ATM's role in senescence, we performed a yeast two-hybrid screen and found that ATM interacted with the vacuolar ATPase V1 subunits ATP6V1E1 and ATP6V1G1. Specifically, ATM decreased E-G dimerization through direct phosphorylation of ATP6V1G1. Attenuation of ATM activity restored the dimerization, thus consequently facilitating assembly of the V1 and V0 domains with concomitant reacidification of the lysosome. In turn, this reacidification induced the functional recovery of the lysosome/autophagy system and was coupled with mitochondrial functional recovery and metabolic reprogramming. Together, our data reveal a new mechanism through which senescence is controlled by the lysosomal-mitochondrial axis, whose function is modulated by the fine-tuning of ATM activity. PMID- 28346406 TI - Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase. AB - Obesity-associated insulin resistance plays a central role in type 2 diabetes. As such, tyrosine phosphatases that dephosphorylate the insulin receptor (IR) are potential therapeutic targets. The low-molecular-weight protein tyrosine phosphatase (LMPTP) is a proposed IR phosphatase, yet its role in insulin signaling in vivo has not been defined. Here we show that global and liver specific LMPTP deletion protects mice from high-fat diet-induced diabetes without affecting body weight. To examine the role of the catalytic activity of LMPTP, we developed a small-molecule inhibitor with a novel uncompetitive mechanism, a unique binding site at the opening of the catalytic pocket, and an exquisite selectivity over other phosphatases. This inhibitor is orally bioavailable, and it increases liver IR phosphorylation in vivo and reverses high-fat diet-induced diabetes. Our findings suggest that LMPTP is a key promoter of insulin resistance and that LMPTP inhibitors would be beneficial for treating type 2 diabetes. PMID- 28346407 TI - Insights into activity and inhibition from the crystal structure of human O GlcNAcase. AB - O-GlcNAc hydrolase (OGA) catalyzes removal of betaalpha-linked N-acetyl-D glucosamine from serine and threonine residues. We report crystal structures of Homo sapiens OGA catalytic domain in apo and inhibited states, revealing a flexible dimer that displays three unique conformations and is characterized by subdomain alpha-helix swapping. These results identify new structural features of the substrate-binding groove adjacent to the catalytic site and open new opportunities for structural, mechanistic and drug discovery activities. PMID- 28346408 TI - Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes. AB - Gut dysbiosis might underlie the pathogenesis of type 1 diabetes. In mice of the non-obese diabetic (NOD) strain, we found that key features of disease correlated inversely with blood and fecal concentrations of the microbial metabolites acetate and butyrate. We therefore fed NOD mice specialized diets designed to release large amounts of acetate or butyrate after bacterial fermentation in the colon. Each diet provided a high degree of protection from diabetes, even when administered after breakdown of immunotolerance. Feeding mice a combined acetate- and butyrate-yielding diet provided complete protection, which suggested that acetate and butyrate might operate through distinct mechanisms. Acetate markedly decreased the frequency of autoreactive T cells in lymphoid tissues, through effects on B cells and their ability to expand populations of autoreactive T cells. A diet containing butyrate boosted the number and function of regulatory T cells, whereas acetate- and butyrate-yielding diets enhanced gut integrity and decreased serum concentration of diabetogenic cytokines such as IL-21. Medicinal foods or metabolites might represent an effective and natural approach for countering the numerous immunological defects that contribute to T cell-dependent autoimmune diseases. PMID- 28346409 TI - The metabolic ER stress sensor IRE1alpha suppresses alternative activation of macrophages and impairs energy expenditure in obesity. AB - Obesity is associated with metabolic inflammation and endoplasmic reticulum (ER) stress, both of which promote metabolic disease progression. Adipose tissue macrophages (ATMs) are key players orchestrating metabolic inflammation, and ER stress enhances macrophage activation. However, whether ER stress pathways underlie ATM regulation of energy homeostasis remains unclear. Here, we identified inositol-requiring enzyme 1alpha (IRE1alpha) as a critical switch governing M1-M2 macrophage polarization and energy balance. Myeloid-specific IRE1alpha abrogation in Ern1f/f; Lyz2-Cre mice largely reversed high-fat diet (HFD)-induced M1-M2 imbalance in white adipose tissue (WAT) and blocked HFD induced obesity, insulin resistance, hyperlipidemia and hepatic steatosis. Brown adipose tissue (BAT) activity, WAT browning and energy expenditure were significantly higher in Ern1f/f; Lyz2-Cre mice. Furthermore, IRE1alpha ablation augmented M2 polarization of macrophages in a cell-autonomous manner. Thus, IRE1alpha senses protein unfolding and metabolic and immunological states, and consequently guides ATM polarization. The macrophage IRE1alpha pathway drives obesity and metabolic syndrome through impairing BAT activity and WAT browning. PMID- 28346410 TI - Quality of TCR signaling determined by differential affinities of enhancers for the composite BATF-IRF4 transcription factor complex. AB - Variable strengths of signaling via the T cell antigen receptor (TCR) can produce divergent outcomes, but the mechanism of this remains obscure. The abundance of the transcription factor IRF4 increases with TCR signal strength, but how this would induce distinct types of responses is unclear. We compared the expression of genes in the TH2 subset of helper T cells to enhancer occupancy by the BATF IRF4 transcription factor complex at varying strengths of TCR stimulation. Genes dependent on BATF-IRF4 clustered into groups with distinct TCR sensitivities. Enhancers exhibited a spectrum of occupancy by the BATF-IRF4 ternary complex that correlated with the sensitivity of gene expression to TCR signal strength. DNA sequences immediately flanking the previously defined AICE motif controlled the affinity of BATF-IRF4 for direct binding to DNA. Analysis by the chromatin immunoprecipitation-exonuclease (ChIP-exo) method allowed the identification of a previously unknown high-affinity AICE2 motif at a human single-nucleotide polymorphism (SNP) of the gene encoding the immunomodulatory receptor CTLA-4 that was associated with resistance to autoimmunity. Thus, the affinity of different enhancers for the BATF-IRF4 complex might underlie divergent signaling outcomes in response to various strengths of TCR signaling. PMID- 28346411 TI - The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue. AB - Brown adipose tissue (BAT) and beige adipose tissue combust fuels for heat production in adult humans, and so constitute an appealing target for the treatment of metabolic disorders such as obesity, diabetes and hyperlipidemia. Cold exposure can enhance energy expenditure by activating BAT, and it has been shown to improve nutrient metabolism. These therapies, however, are time consuming and uncomfortable, demonstrating the need for pharmacological interventions. Recently, lipids have been identified that are released from tissues and act locally or systemically to promote insulin sensitivity and glucose tolerance; as a class, these lipids are referred to as 'lipokines'. Because BAT is a specialized metabolic tissue that takes up and burns lipids and is linked to systemic metabolic homeostasis, we hypothesized that there might be thermogenic lipokines that activate BAT in response to cold. Here we show that the lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) is a stimulator of BAT activity, and that its levels are negatively correlated with body-mass index and insulin sensitivity. Using a global lipidomic analysis, we found that 12,13 diHOME was increased in the circulation of humans and mice exposed to cold. Furthermore, we found that the enzymes that produce 12,13-diHOME were uniquely induced in BAT by cold stimulation. The injection of 12,13-diHOME acutely activated BAT fuel uptake and enhanced cold tolerance, which resulted in decreased levels of serum triglycerides. Mechanistically, 12,13-diHOME increased fatty acid (FA) uptake into brown adipocytes by promoting the translocation of the FA transporters FATP1 and CD36 to the cell membrane. These data suggest that 12,13-diHOME, or a functional analog, could be developed as a treatment for metabolic disorders. PMID- 28346413 TI - Skin allograft for severe chronic GvHD. PMID- 28346412 TI - VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. AB - To date, anti-CTLA-4 (ipilimumab) or anti-PD-1 (nivolumab) monotherapy has not been demonstrated to be of substantial clinical benefit in patients with prostate cancer. To identify additional immune-inhibitory pathways in the prostate-tumor microenvironment, we evaluated untreated and ipilimumab-treated tumors from patients in a presurgical clinical trial. Levels of the PD-L1 and VISTA inhibitory molecules increased on independent subsets of macrophages in treated tumors. Our data suggest that VISTA represents another compensatory inhibitory pathway in prostate tumors after ipilimumab therapy. PMID- 28346414 TI - Nivolumab before and after allogeneic hematopoietic cell transplantation. PMID- 28346416 TI - JACIE accreditation for blood and marrow transplantation: past, present and future directions of an international model for healthcare quality improvement. AB - Blood and marrow transplantation (BMT) is a complex and evolving medical speciality that makes substantial demands on healthcare resources. To meet a professional responsibility to both patients and public health services, the European Society for Blood and Marrow Transplantation (EBMT) initiated and developed the Joint Accreditation Committee of the International Society for Cellular Therapy and EBMT-better known by the acronym, JACIE. Since its inception, JACIE has performed over 530 voluntary accreditation inspections (62% first time; 38% reaccreditation) in 25 countries, representing 40% of transplant centres in Europe. As well as widespread professional acceptance, JACIE has become incorporated into the regulatory framework for delivery of BMT and other haematopoietic cellular therapies in several countries. In recent years, JACIE has been validated using the EBMT registry as an effective means of quality improvement with a substantial positive impact on survival outcomes. Future directions include development of Europe-wide risk-adjusted outcome benchmarking through the EBMT registry and further extension beyond Europe, including goals to faciliate access for BMT programmes in in low- and middle-income economies (LMIEs) via a 'first-step' process. PMID- 28346415 TI - Haplo-Cord transplantation compared to haploidentical transplantation with post transplant cyclophosphamide in patients with AML. AB - For patients with AML, the best alternative donor remains to be defined. We analyze outcomes of patients who underwent myeloablative umbilical cord blood or haploidentical hemopoietic stem cell transplantation (HSCT) in Spain. Fifty-one patients underwent single umbilical cord blood transplantation supported by a third party donor (Haplo-Cord) between 1999 and 2012, and 36 patients received an haploidentical HSCT with post-transplant cyclophosphamide (PTCY-haplo) between 2012 and 2014 in GETH centers. The Haplo-Cord cohort included a higher proportion of patients with high disease risk index and use of TBI in the conditioning regimen, and hematopoietic cell transplantation-age Comorbidity Age Index was higher in PTCY-haplo patients. Cumulative incidence of neutrophil engraftment was 97% in the Haplo-Cord and 100% in the PTCY-haplo group, achieved in a median of 12 and 17 days, respectively (P=0.01). Grade II-IV acute GvHD rate was significantly higher in the PTCY-haplo group (9.8% vs 29%, P=0.02) as well as chronic GvHD rates (20% vs 38%, P=0.03). With a median follow-up of 61 months for the Haplo-Cord group and 26 months for the PTCY-haplo cohort, overall survival at 2 years was 55% and 59% (P=0.66), event-free survival was 45% vs 56% (P=0.46), relapse rate was 27% vs 21% (P=0.79), and non-relapse mortality was 17% vs 23% (P=0.54), respectively. In this multicenter experience, Haplo-Cord and PTCY-haplo HSCT offer valid alternatives for patients with AML. Neutrophil engraftment was faster in the Haplo-Cord cohort, with similar survival rates, with higher GvHD rates after haploidentical HSCT. PMID- 28346418 TI - First experience of hematopoietic stem cell transplantation treatment of Shwachman-Diamond syndrome using unaffected HLA-matched sibling donor produced through preimplantation HLA typing. AB - The only proven cure for Shwachman-Diamond syndrome (SDS) bone marrow failure is allogeneic hematopoietic stem cell transplantation (HSCT). However HSCT with donors other than HLA-identical siblings is associated with high mortality and unfavorable prognosis. This paper presents the first experience of HSCT treatment of SDS using an unaffected HLA-identical sibling produced through preimplantation genetic diagnosis (PGD). The patient was a 6-year-old blood transfusion-dependent SDS baby girl with secondary myelodysplastic syndrome, for whom no HLA-identical donor was available. As a result of PGD, two unaffected HLA matched embryos were identified; one of them was randomly selected for transfer, resulting in a clinical pregnancy and birth of an apparently healthy child. The patient underwent allogeneic transplantation of cord blood hematopoietic stem cells, together with bone marrow from this sibling, resulting in complete hemopoietic recovery. The patient was no longer transfusion-dependent and had normal blood values 160 days after transplantation. PMID- 28346417 TI - Bacterial bloodstream infections in the allogeneic hematopoietic cell transplant patient: new considerations for a persistent nemesis. AB - Bacterial bloodstream infections (BSI) cause significant transplant-related morbidity and mortality following allogeneic hematopoietic cell transplantation (allo-HCT). This manuscript reviews the risk factors for and the bacterial pathogens causing BSIs in allo-HCT recipients in the contemporary transplant period. In addition, it offers insight into emerging resistant pathogens and reviews clinical management considerations to treat and strategies to prevent BSIs in allo-HCT patients. PMID- 28346419 TI - Evolving concepts in prognostic scoring of chronic GvHD. AB - Chronic GvHD (cGvHD) remains one of the most complex and challenging complications after allogeneic hematopoietic cell transplantation. Emerging knowledge about the clinical manifestations and associated organ involvement of cGvHD has led to the establishment of prognostic parameters for post-transplant survival among affected allograft recipients. Studies employing the pre-National Institutes of Health (NIH) consensus data on cGvHD incidence and its risks have led to development of the CIBMTR's cGvHD risk stratification, which serves as the most refined and validated prognostic tool for estimating survival of patients with cGvHD. However, cGvHD global severity scoring has recently evolved as a powerful prognostic tool for patient survival in the post-NIH consensus era. Current use of the substantially redefined NIH criteria of cGvHD diagnosis and measurements of its severity makes it challenging to interpret prognostic scoring systems generated in the pre-NIH era. Some of the pre-NIH prognostic parameters, however, appear to retain their significance in predicting survival independently from the NIH global severity score. Thus, future analyses of prospective cohorts of patients with cGvHD defined by NIH consensus criteria will be critical in reconciling and integrating various prognostic scoring systems of cGvHD. PMID- 28346420 TI - Hepatic cyclooxygenase-2 overexpression induced spontaneous hepatocellular carcinoma formation in mice. AB - Cyclooxygenase (COX)-2 is upregulated in hepatocellular carcinoma (HCC). However, the direct causative effect of COX-2 in spontaneous HCC formation remains unknown. We thus investigate the role and molecular pathogenesis of COX-2 in HCC by using liver-specific COX-2 transgenic (TG) mice. We found spontaneous HCC formation with elevated inflammatory infiltrates and neovessels in male TG mice (3/21, 14.3%), but not in any of male WT mice (0/19). Reduced representation bisulfite sequencing (RRBS) and gene expression microarrays were performed in the HCC tumor and non-HCC liver tissues to investigate the molecular mechanisms of COX-2-driven HCC. By RRBS, DNA promoter hypermethylation was identified in HCC from TG mice. Induction of promoter hypermethylation was associated with reduced tet methylcytosine dioxygenase 1 (TET1) expression by COX-2. TET1 could catalyze the conversion of 5-methylcytosine into 5-hydroxymethylcytosine (5hmC) and prevents DNA hypermethylation. In keeping with this, loss of 5hmC was demonstrated in COX-2-induced HCC. Consistently, COX-2 overexpression in human HCC cell lines could reduce both TET1 expression and 5hmc levels. Integrative analyses of DNA methylation and gene expression profiles further identified significantly downregulated genes including LTBP1, ADCY5 and PRKCZ by promoter methylation in COX-2-induced HCC. Reduced expression of LTBP1, ADCY5 and PRKCZ by promoter hypermethylation was further validated in human HCCs. Bio-functional investigation revealed that LTBP1 inhibited cell proliferation in HCC cell lines, suggesting its potential role as a tumor suppressor in HCC. Gene expression microarrays revealed that signaling cascades (AKT (protein kinase B), STK33 (Serine/Threonine kinase 33) and MTOR (mechanistic target of rapamycin) pathways) were enriched in COX-2-induced HCC. In conclusion, this study demonstrated for the first time that enhanced COX-2 expression in hepatocytes is sufficient to induce HCC through inducing promoter hypermethylation by reducing TET1, silencing tumor-suppressive genes and activating key oncogenic pathways. Inhibition of COX 2 represents a mechanism-based target for HCC prevention. PMID- 28346421 TI - SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer. AB - Pancreatic cancer has a devastating prognosis, with an overall 5-year survival rate of ~8%, restricted treatment options and characteristic molecular heterogeneity. SerpinB2 expression, particularly in the stromal compartment, is associated with reduced metastasis and prolonged survival in pancreatic ductal adenocarcinoma (PDAC) and our genomic analysis revealed that SERPINB2 is frequently deleted in PDAC. We show that SerpinB2 is required by stromal cells for normal collagen remodelling in vitro, regulating fibroblast interaction and engagement with collagen in the contracting matrix. In a pancreatic cancer allograft model, co-injection of PDAC cancer cells and SerpinB2-/- mouse embryonic fibroblasts (MEFs) resulted in increased tumour growth, aberrant remodelling of the extracellular matrix (ECM) and increased local invasion from the primary tumour. These tumours also displayed elevated proteolytic activity of the primary biochemical target of SerpinB2-urokinase plasminogen activator (uPA). In a large cohort of patients with resected PDAC, we show that increasing uPA mRNA expression was significantly associated with poorer survival following pancreatectomy. This study establishes a novel role for SerpinB2 in the stromal compartment in PDAC invasion through regulation of stromal remodelling and highlights the SerpinB2/uPA axis for further investigation as a potential therapeutic target in pancreatic cancer. PMID- 28346422 TI - The metastatic suppressor NDRG1 inhibits EMT, migration and invasion through interaction and promotion of caveolin-1 ubiquitylation in human colorectal cancer cells. AB - N-myc downstream-regulated gene 1 (NDRG1) has been reported to act as a key regulatory molecule in tumor progression-related signaling pathways, especially in tumor metastasis. However, the related mechanism has not been fully discovered yet. Herein we demonstrated that the novel molecule of cell migration and invasion, caveolin-1, has direct interaction with NDRG1 in human colorectal cancer (CRC) cells. Moreover, we discovered that NDRG1 reduces caveolin-1 protein expression through promoting its ubiquitylation and subsequent degradation via the proteasome in CRC cells. In addition, caveolin-1 mediates the suppressive function of NDRG1 in epithelial-mesenchymal transition, migration and invasion in vitro and metastasis in vivo. These results help to fulfill the potential mechanisms of NDRG1 in anti-metastatic treatment for human colorectal cancer. PMID- 28346423 TI - MOB1-YAP1/TAZ-NKX2.1 axis controls bronchioalveolar cell differentiation, adhesion and tumour formation. AB - Mps One Binder Kinase Activator (MOB)1A/1B are core components of the Hippo pathway. These proteins, which coactivate LArge Tumour Suppressor homologue kinases, are also tumour suppressors. To investigate MOB1A/B's roles in normal physiology and lung cancer, we generated doxycycline (Dox)-inducible, bronchioalveolar epithelium-specific, null mutations of MOB1A/B in mice (SPC rtTA/(tetO)7-Cre/Mob1aflox/flox/Mob1b-/-; termed luMob1DKO mice). Most mutants (70%) receiving Dox in utero (luMob1DKO (E6.5-18.5) mice) died of hypoxia within 1 h post-birth. Their alveolar epithelial cells showed increased proliferation, impaired YAP1/TAZ-dependent differentiation and decreased surfactant protein production, all features characteristic of human respiratory distress syndrome. Intriguingly, mutant mice that received Dox postnatally (luMob1DKO (P21-41) mice) did not develop spontaneous lung adenocarcinomas, and urethane treatment-induced lung tumour formation was decreased (rather than increased). Lungs of luMob1DKO (P21-41) mice exhibited increased detachment of bronchiolar epithelial cells and decreased numbers of the bronchioalveolar stem cells thought to initiate lung adenocarcinomas. YAP1/TAZ-NKX2.1-dependent expression of collagen XVII, a key hemidesmosome component, was also reduced. Thus, a MOB1-YAP1/TAZ-NKX2.1 axis is essential for normal lung homeostasis and expression of the collagen XVII protein necessary for alveolar stem cell maintenance in the lung niche. PMID- 28346424 TI - Skp2 deficiency restricts the progression and stem cell features of castration resistant prostate cancer by destabilizing Twist. AB - Castration-resistant prostate cancer (CRPC) remains a major clinical challenge because of the lack of effective targeted therapy for its treatment. The mechanism underlying how CRPC gains resistance toward hormone depletion and other forms of chemotherapy is poorly understood. Research on understanding the factors that drive these processes is desperately needed to generate new therapies to cure the disease. Here, we discovered a fundamental role of S-phase protein kinase 2 (Skp2) in the formation and progression of CRPC. In transgenic adenocarcinoma mouse prostate model, Skp2 depletion leads to a profound repression of prostate tumor growth and distal metastasis and substantially prolonged overall survival. We revealed that Skp2 regulates CRPC through Twist mediated oncogenic functions including epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) acquisitions. Mechanistically, Skp2 interacted with Twist and promoted the non-degradative ubiquitination of Twist. Consequently, Skp2 stabilized Twist protein expression by preventing proteasomal degradation of Twist by beta-TrCP. We found that Twist overexpression augments CSC self-renewal and population and that Skp2 inhibition reverts Twist's effects on CSC regulation. Furthermore, genetically depleting or pharmacologically inactivating Skp2 synergistically re-sensitized CRPC cells toward chemotherapies such as paclitaxel or doxorubicin. Together, this study uncovering Skp2-mediated Twist stabilization and oncogenic functions in CRPC offers new knowledge on how CRPC progresses and acquires chemoresistance during tumor progression. It provides proof of principle that Skp2 targeting is a promising approach to combat metastatic CRPC by targeting Twist and CSCs. PMID- 28346425 TI - CHIP/Stub1 regulates the Warburg effect by promoting degradation of PKM2 in ovarian carcinoma. AB - Tumor cells preferentially adopt aerobic glycolysis for their energy supply, a phenomenon known as the Warburg effect. It remains a matter of debate as to how the Warburg effect is regulated during tumor progression. Here, we show that CHIP (carboxyl terminus of Hsc70-interacting protein), a U-box E3 ligase, suppresses tumor progression in ovarian carcinomas by inhibiting aerobic glycolysis. While CHIP is downregulated in ovarian carcinoma, induced expression of CHIP results in significant inhibition of the tumor growth examined by in vitro and in vivo experiments. Reciprocally, depletion of CHIP leads to promotion of tumor growth. By a SiLAD proteomics analysis, we identified pyruvate kinase isoenzyme M2 (PKM2), a critical regulator of glycolysis in tumors, as a target that CHIP mediated for degradation. Accordingly, we show that CHIP regulates PKM2 protein stability and thereafter the energy metabolic processes. Depletion or knockout of CHIP increased the glycolytic products in both tumor and mouse embryonic fibroblast cells. Simultaneously, we observed that CHIP expression inversely correlated with PKM2 levels in human ovarian carcinomas. This study reveals a mechanism that the Warburg effect is regulated by CHIP through its function as an E3 ligase, which mediates the degradation of PKM2 during tumor progression. Our findings shed new light into understanding of ovarian carcinomas and may provide a new therapeutic strategy for ovarian cancer. PMID- 28346426 TI - MRL proteins cooperate with activated Ras in glia to drive distinct oncogenic outcomes. AB - The Mig10/RIAM/Lpd (MRL) adapter protein Lpd regulates actin dynamics through interactions with Scar/WAVE and Ena/VASP proteins to promote the formation of cellular protrusions and to stimulate invasive migration. However, the ability of MRL proteins to interact with multiple actin regulators and to promote serum response factor (SRF) signalling has raised the question of whether MRL proteins employ alternative downstream mechanisms to drive oncogenic processes in a context-dependent manner. Here, using a Drosophila model, we show that overexpression of either human Lpd or its Drosophila orthologue Pico can promote growth and invasion of RasV12-induced cell tumours in the brain. Notably, effects were restricted to two populations of Repo-positive glial cells: an invasive population, characterized by JNK-dependent elevation of Mmp1 expression, and a hyperproliferative population lacking elevated JNK signalling. JNK activation was not triggered by reactive immune cell signalling, implicating the involvement of an intrinsic stress response. The ability to promote dissemination of RasV12 induced tumours was shared by a subset of actin regulators, including, most prominently, Chicadee/Profilin, which directly interacts with Pico, and, Mal, a cofactor for serum response factor that responds to changes in G:F actin dynamics. Suppression of Mal activity partially abrogated the ability of pico to promote invasion of RasV12 tumours. Furthermore, we found that larval glia are enriched for serum response factor expression, explaining the apparent sensitivity of glial cells to Pico/RasV12 overexpression. Taken together, our findings indicate that MRL proteins cooperate with oncogenic Ras to promote formation of glial tumours, and that, in this context, Mal/serum response factor activation is rate-limiting for tumour dissemination. PMID- 28346427 TI - MiR-21 is required for anti-tumor immune response in mice: an implication for its bi-directional roles. AB - Here we show that miR-21, a microRNA known for its oncogenic activity, is also essential for mediating immune responses against tumor. Knockout of miR-21 in mice slowed the proliferation of both CD4+ and CD8+ cells, reduced their cytokine production and accelerated the grafted tumor growth. Further investigations indicated that miR-21 could activate CD4+ and CD8+ T cells via the PTEN/Akt pathway in response to stimulations. Taken together, these data suggest the key functions of miR-21 in mediating anti-tumor immune response and thereby uncover a bi-directional role of this traditionally known 'oncomiR' in tumorigenesis. Our study may provide new insights for the design of cancer therapies targeting microRNAs, with an emphasis on the dynamic and possibly unexpected role of these molecules. PMID- 28346428 TI - Autophagy is required for cell survival under L-asparaginase-induced metabolic stress in acute lymphoblastic leukemia cells. AB - L-asparaginase has been used for more than three decades in acute lymphoblastic leukemia (ALL) patients and remains an essential drug in the treatment of ALL. Poor response to L-asparaginase is associated with increased risk of therapeutic failure in ALL. However, both the metabolic perturbation and molecular context of L-asparaginase-treated ALL cells has not been fully elucidated. Here we identify that treatment with L-asparaginase results in metabolic shutdown via the reduction of both glycolysis and oxidative phosphorylation, accompanied by mitochondrial damage and activation of autophagy. The autophagy is involved in reducing reactive oxygen species (ROS) level by eliminating injured mitochondria. Inhibition of autophagy enhances L-asparaginase-induced cytotoxicity and overcomes the acquired resistance to L-asparaginase in ALL cells. The ROS-p53 positive feedback loop is an essential mechanism of this synergistic cytotoxicity. Thus, our findings provide the rationale for the future development of combined treatment of L-asparaginase and anti-autophagy drug in ALL patients. PMID- 28346429 TI - Deletion of endothelial cell-specific liver kinase B1 increases angiogenesis and tumor growth via vascular endothelial growth factor. AB - Liver kinase B1 (LKB1) is a serine/threonine protein kinase ubiquitously expressed in mammalian cells. It was first identified in Peutz-Jeghers syndrome as a tumor suppressor gene. Whether endothelial LKB1 regulates angiogenesis and tumor growth is unknown. In this study, we generated endothelial cell-specific LKB1-knockout (LKB1endo-/-) mice by crossbreeding vascular endothelial-cadherin Cre mice with LKB1flox/flox mice. Vascular endothelial growth factor (VEGF) level was highly co-stained in endothelial cells but not in macrophages in LKB1endo-/- mice. Consistently, LKB1endo-/- mouse tissues including the lung, skin, kidney and liver showed increased vascular permeability. Tumors implanted in LKB1endo-/- mice but not macrophage-specific LKB1-knockout mice grew faster and showed enhanced vascular permeability and increased angiogenesis as compared with those implanted in wild-type mice. Injection of VEGF-neutralizing antibody but not the isotype-matched control antibody decreased endothelial-cell angiogenesis and tumor growth in vivo. Furthermore, LKB1 deletion enhanced mouse retinal and cell angiogenesis, and knockdown of VEGF by small-interfering RNA decreased endothelial cell proliferation and migration. Re-expression of LKB1 or knockdown of VEGF receptor 2 decreased the overproliferation and -migration observed in LKB1endo-/- cells. Mechanistically, LKB1 could bind to the VEGF transcription factor, specificity protein 1 (Sp1), which then inhibited the binding of Sp1 to the VEGF promoter to reduce VEGF expression. Endothelial LKB1 may regulate endothelial angiogenesis and tumor growth by modulating Sp1-mediated VEGF expression. PMID- 28346431 TI - Real-time impedance monitoring of oxygen reduction during surface modification of thin film cathodes. AB - Improvement of solid oxide fuel cells strongly relies on the development of cathode materials with high catalytic activity for the oxygen reduction reaction. Excellent activity was found for perovskite-type oxides such as La1-xSrxCoO3 delta (LSC), but performance degradation, probably caused by surface composition changes, hinders exploitation of the full potential of LSC. This study reveals that the potentially very high activity of the LSC surface can be traced back to few very active sites. Already tiny amounts of SrO, for example, 4% of a monolayer, deposited on an LSC surface, lead to severe deactivation. Co, on the other hand, causes (re-)activation, suggesting that active sites are strongly related to Co being present at the surface. These insights could be gained by a novel method to measure changes of the electrochemical performance of thin film electrodes in situ, while modifying their surface: impedance spectroscopy measurements during deposition of well-defined fractions of monolayers of Sr-, Co and La-oxides by single laser pulses in a pulsed laser deposition chamber. PMID- 28346430 TI - IL-17C mediates the recruitment of tumor-associated neutrophils and lung tumor growth. AB - Chronic obstructive pulmonary disease (COPD) is associated with an increased risk for lung cancer and an aberrant microbiota of the lung. Microbial colonization contributes to chronic neutrophilic inflammation in COPD. Nontypeable Haemophilus influenzae (NTHi) is frequently found in lungs of stable COPD patients and is the major pathogen triggering exacerbations. The epithelial cytokine interleukin-17C (IL-17C) promotes the recruitment of neutrophils into inflamed tissues. The purpose of this study was to investigate the function of IL-17C in the pulmonary tumor microenvironment. We subjected mice deficient for IL-17C (IL-17C-/-) and mice double deficient for Toll-like receptor 2 and 4 (TLR-2/4-/-) to a metastatic lung cancer model. Tumor proliferation and growth as well as the number of tumor associated neutrophils was significantly decreased in IL-17C-/- and TLR-2/4-/- mice exposed to NTHi. The NTHi-induced pulmonary expression of IL-17C was dependent on TLR-2/4. In vitro, IL-17C increased the NTHi- and tumor necrosis factor-alpha-induced expression of the neutrophil chemokines keratinocyte-derived chemokine and macrophage inflammatory protein 2 in lung cancer cells but did not affect proliferation. Human lung cancer samples stained positive for IL-17C, and in non-small cell lung cancer patients with lymph node metastasis, IL-17C was identified as a negative prognostic factor. Our data indicate that epithelial IL 17C promotes neutrophilic inflammation in the tumor microenvironment and suggest that IL-17C links a pathologic microbiota, as present in COPD patients, with enhanced tumor growth. PMID- 28346432 TI - Nanoscale capillary freezing of ionic liquids confined between metallic interfaces and the role of electronic screening. AB - Room-temperature ionic liquids (RTILs) are new materials with fundamental importance for energy storage and active lubrication. They are unusual liquids, which challenge the classical frameworks of electrolytes, whose behaviour at electrified interfaces remains elusive, with exotic responses relevant to their electrochemical activity. Using tuning-fork-based atomic force microscope nanorheological measurements, we explore here the properties of confined RTILs, unveiling a dramatic change of the RTIL towards a solid-like phase below a threshold thickness, pointing to capillary freezing in confinement. This threshold is related to the metallic nature of the confining materials, with more metallic surfaces facilitating freezing. This behaviour is interpreted in terms of the shift of the freezing transition, taking into account the influence of the electronic screening on RTIL wetting of the confining surfaces. Our findings provide fresh views on the properties of confined RTIL with implications for their properties inside nanoporous metallic structures, and suggests applications to tune nanoscale lubrication with phase-changing RTILs, by varying the nature and patterning of the substrate, and application of active polarization. PMID- 28346433 TI - A cytosolic Ezh1 isoform modulates a PRC2-Ezh1 epigenetic adaptive response in postmitotic cells. AB - The evolution of chromatin-based epigenetic cell memory may be driven not only by the necessity for cells to stably maintain transcription programs, but also by the need to recognize signals and allow plastic responses to environmental stimuli. The mechanistic role of the epigenome in adult postmitotic tissues, however, remains largely unknown. In vertebrates, two variants of the Polycomb repressive complex (PRC2-Ezh2 and PRC2-Ezh1) control gene silencing via methylation of histone H3 on Lys27 (H3K27me). Here we describe a reversible mechanism that involves a novel isoform of Ezh1 (Ezh1beta). Ezh1beta lacks the catalytic SET domain and acts in the cytoplasm of skeletal muscle cells to control nuclear PRC2-Ezh1 activity in response to atrophic oxidative stress, by regulating Eed assembly with Suz12 and Ezh1alpha (the canonical isoform) at their target genes. We report a novel PRC2-Ezh1 function that utilizes Ezh1beta as an adaptive stress sensor in the cytoplasm, thus allowing postmitotic cells to maintain tissue integrity in response to environmental changes. PMID- 28346434 TI - Optimization of adeno-associated virus vector-mediated gene transfer to the respiratory tract. AB - An efficient adeno-associated virus (AAV) vector was constructed for the treatment of respiratory diseases. AAV serotypes, promoters and routes of administration potentially influencing the efficiency of gene transfer to airway cells were examined in the present study. Among the nine AAV serotypes (AAV1-9) screened in vitro and four serotypes (AAV1, 2, 6, 9) evaluated in vivo, AAV6 showed the strongest transgene expression. As for promoters, the cytomegalovirus (CMV) early enhancer/chicken beta-actin (CAG) promoter resulted in more robust transduction than the CMV promoter. Regarding delivery routes, intratracheal administration resulted in strong transgene expression in the lung, whereas the intravenous and intranasal administration routes yielded negligible expression. The combination of the AAV6 capsid and CAG promoter resulted in sustained expression, and the intratracheally administered AAV6-CAG vector transduced bronchial cells and pericytes in the lung. These results suggest that AAV6-CAG vectors are more promising than the previously preferred AAV2 vectors for airway transduction, particularly when administered into the trachea. The present study offers an optimized strategy for AAV-mediated gene therapy for lung diseases, such as cystic fibrosis and pulmonary fibrosis. PMID- 28346435 TI - AAV9-mediated engineering of autotransplanted kidney of non-human primates. AB - Ex vivo gene transfer to the graft before transplantation is an attractive option for circumventing systemic side effects of chronic antirejection therapy. Gene delivery of the immunomodulatory protein cytotoxic T-lymphocyte-associated protein 4-immunoglobulin (CTLA4-Ig) prevented chronic kidney rejection in a rat model of allotransplantation without the need for systemic immunosuppression. Here we generated adeno-associated virus type 2 (AAV2) and AAV9 vectors encoding for LEA29Y, an optimized version of CTLA4-Ig. Both LEA29Y vectors were equally efficient for reducing T-cell proliferation in vitro. Serotype 9 was chosen for in vivo experiments owing to a lower frequency of preformed antibodies against the AAV9 capsid in 16 non-human primate tested sera. AAV9-LEA29Y was able to transduce the kidney of non-human primates in an autotransplantation model. Expression of LEA29Y mRNA by renal cells translated into the production of the corresponding protein, which was confined to the graft but not detected in serum. Results in non-human primates represent a step forward in maintaining the portability of this strategy into clinics. PMID- 28346436 TI - Detailed comparison of retroviral vectors and promoter configurations for stable and high transgene expression in human induced pluripotent stem cells. AB - Correction of patient-specific induced pluripotent stem cells (iPSC) upon gene delivery through retroviral vectors offers new treatment perspectives for monogenetic diseases. Gene-modified iPSC clones can be screened for safe integration sites and differentiated into transplantable cells of interest. However, the current bottleneck is epigenetic vector silencing. In order to identify the most suitable retroviral expression system in iPSC, we systematically compared vectors from different retroviral genera, different promoters and their combination with ubiquitous chromatin opening elements (UCOE), and several envelope pseudotypes. Lentiviral vectors (LV) pseudotyped with vesicular stomatitis virus glycoprotein were superior to gammaretroviral and alpharetroviral vectors and other envelopes tested. The elongation factor 1alpha short (EFS) promoter mediated the most robust expression, whereas expression levels were lower from the potent but more silencing-prone spleen focus forming virus (SFFV) promoter. Both full-length (A2UCOE) and minimal (CBX3) UCOE juxtaposed to two physiological and one viral promoter reduced transgene silencing with equal efficiency. However, a promoter-specific decline in expression levels was not entirely prevented. Upon differentiation of transgene positive iPSC into endothelial cells, A2UCOE.EFS and CBX3.EFS vectors maintained highest transgene expression in a larger fraction of cells as compared with all other constructs tested here. The function of UCOE diminished, but did not fully counteract, vector silencing and possibilities for improvements remain. Nevertheless, the CBX3.EFS in a LV background exhibited the most promising promoter and vector configuration for both high titer production and long-term genetic modification of human iPSC and their progeny. PMID- 28346437 TI - Friction forces position the neural anlage. AB - During embryonic development, mechanical forces are essential for cellular rearrangements driving tissue morphogenesis. Here, we show that in the early zebrafish embryo, friction forces are generated at the interface between anterior axial mesoderm (prechordal plate, ppl) progenitors migrating towards the animal pole and neurectoderm progenitors moving in the opposite direction towards the vegetal pole of the embryo. These friction forces lead to global rearrangement of cells within the neurectoderm and determine the position of the neural anlage. Using a combination of experiments and simulations, we show that this process depends on hydrodynamic coupling between neurectoderm and ppl as a result of E cadherin-mediated adhesion between those tissues. Our data thus establish the emergence of friction forces at the interface between moving tissues as a critical force-generating process shaping the embryo. PMID- 28346438 TI - Basolateral protrusion and apical contraction cooperatively drive Drosophila germ band extension. AB - Throughout development, tissues undergo complex morphological changes, resulting from cellular mechanics that evolve over time and in three-dimensional space. During Drosophila germ-band extension (GBE), cell intercalation is the key mechanism for tissue extension, and the associated apical junction remodelling is driven by polarized myosin-II-dependent contraction. However, the contribution of the basolateral cellular mechanics to GBE remains poorly understood. Here, we characterize how cells coordinate their shape from the apical to the basal side during rosette formation, a hallmark of cell intercalation. Basolateral rosette formation is driven by cells mostly located at the dorsal/ventral part of the rosette (D/V cells). These cells exhibit actin-rich wedge-shaped basolateral protrusions and migrate towards each other. Surprisingly, the formation of basolateral rosettes precedes that of the apical rosettes. Basolateral rosette formation is independent of apical contractility, but requires Rac1-dependent protrusive motility. Furthermore, we identified Src42A as a regulator of basolateral rosette formation. Our data show that in addition to apical contraction, active cell migration driven by basolateral protrusions plays a pivotal role in rosette formation and contributes to GBE. PMID- 28346440 TI - Endocytic proteins are partitioned at the edge of the clathrin lattice in mammalian cells. AB - Dozens of proteins capture, polymerize and reshape the clathrin lattice during clathrin-mediated endocytosis (CME). How or if this ensemble of proteins is organized in relation to the clathrin coat is unknown. Here, we map key molecules involved in CME at the nanoscale using correlative super-resolution light and transmission electron microscopy. We localize 19 different endocytic proteins (amphiphysin1, AP2, beta2-arrestin, CALM, clathrin, DAB2, dynamin2, EPS15, epsin1, epsin2, FCHO2, HIP1R, intersectin, NECAP, SNX9, stonin2, syndapin2, transferrin receptor, VAMP2) on thousands of individual clathrin structures, generating a comprehensive molecular architecture of endocytosis with nanoscale precision. We discover that endocytic proteins distribute into distinct spatial zones in relation to the edge of the clathrin lattice. The presence or concentrations of proteins within these zones vary at distinct stages of organelle development. We propose that endocytosis is driven by the recruitment, reorganization and loss of proteins within these partitioned nanoscale zones. PMID- 28346439 TI - Hippo signalling governs cytosolic nucleic acid sensing through YAP/TAZ-mediated TBK1 blockade. AB - The Hippo pathway senses cellular conditions and regulates YAP/TAZ to control cellular and tissue homeostasis, while TBK1 is central for cytosolic nucleic acid sensing and antiviral defence. The correlation between cellular nutrient/physical status and host antiviral defence is interesting but not well understood. Here we find that YAP/TAZ act as natural inhibitors of TBK1 and are vital for antiviral physiology. Independent of transcriptional regulation and through the transactivation domain, YAP/TAZ associate directly with TBK1 and abolish virus induced TBK1 activation, by preventing TBK1 Lys63-linked ubiquitylation and the binding of adaptors/substrates. Accordingly, YAP/TAZ deletion/depletion or cellular conditions inactivating YAP/TAZ through Lats1/2 kinases relieve TBK1 suppression and boost antiviral responses, whereas expression of the transcriptionally inactive YAP dampens cytosolic RNA/DNA sensing and weakens the antiviral defence in cells and zebrafish. Thus, we describe a function of YAP/TAZ and the Hippo pathway in innate immunity, by linking cellular nutrient/physical status to antiviral host defence. PMID- 28346441 TI - Altering the threshold of an excitable signal transduction network changes cell migratory modes. AB - The diverse migratory modes displayed by different cell types are generally believed to be idiosyncratic. Here we show that the migratory behaviour of Dictyostelium was switched from amoeboid to keratocyte-like and oscillatory modes by synthetically decreasing phosphatidylinositol-4,5-bisphosphate levels or increasing Ras/Rap-related activities. The perturbations at these key nodes of an excitable signal transduction network initiated a causal chain of events: the threshold for network activation was lowered, the speed and range of propagating waves of signal transduction activity increased, actin-driven cellular protrusions expanded and, consequently, the cell migratory mode transitions ensued. Conversely, innately keratocyte-like and oscillatory cells were promptly converted to amoeboid by inhibition of Ras effectors with restoration of directed migration. We use computational analysis to explain how thresholds control cell migration and discuss the architecture of the signal transduction network that gives rise to excitability. PMID- 28346445 TI - Potential energy landscapes identify the information-theoretic nature of the epigenome. AB - Epigenetics is the study of biochemical modifications carrying information independent of DNA sequence, which are heritable through cell division. In 1940, Waddington coined the term "epigenetic landscape" as a metaphor for pluripotency and differentiation, but methylation landscapes have not yet been rigorously computed. Using principles from statistical physics and information theory, we derive epigenetic energy landscapes from whole-genome bisulfite sequencing (WGBS) data that enable us to quantify methylation stochasticity genome-wide using Shannon's entropy, associating it with chromatin structure. Moreover, we consider the Jensen-Shannon distance between sample-specific energy landscapes as a measure of epigenetic dissimilarity and demonstrate its effectiveness for discerning epigenetic differences. By viewing methylation maintenance as a communications system, we introduce methylation channels and show that higher order chromatin organization can be predicted from their informational properties. Our results provide a fundamental understanding of the information theoretic nature of the epigenome that leads to a powerful approach for studying its role in disease and aging. PMID- 28346447 TI - Synthetic control of flowering in rice independent of the cultivation environment. AB - For genetically homogeneous crops, the timing of flowering is determined largely by the cultivation environment and is strongly associated with the yield and quality of the harvest1. Flowering time and other agronomical traits are often tightly correlated, which can lead to difficulty excluding the effects of flowering time when evaluating the characteristics of different genetic varieties2. Here, we describe the development of transgenic rice plants whose flowering time can be controlled by specific agrochemicals. We first developed non-flowering rice plants by overexpressing a floral repressor gene, Grain number, plant height and heading date 7 (Ghd7)3,4, to inhibit any environmentally induced spontaneous flowering. We then co-transformed plants with a rice florigen gene, Heading date 3a (Hd3a)5, which is induced by the application of specific agrochemicals. This permitted the flowering time to be experimentally controlled regardless of the cultivation environment: some transgenic plants flowered only after agrochemical treatment. Furthermore, plant size and yield-related traits could, in some cases, be increased owing to both a longer duration of vegetative growth and an increased panicle size. This ability to control flowering time experimentally, independently of environmental variables, may lead to production of crops suitable for growth in different climates and facilitate breeding for various agronomical traits. PMID- 28346444 TI - Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility. AB - The Y chromosome is frequently lost in hematopoietic cells, which represents the most common somatic alteration in men. However, the mechanisms that regulate mosaic loss of chromosome Y (mLOY), and its clinical relevance, are unknown. We used genotype-array-intensity data and sequence reads from 85,542 men to identify 19 genomic regions (P < 5 * 10-8) that are associated with mLOY. Cumulatively, these loci also predicted X chromosome loss in women (n = 96,123; P = 4 * 10-6). Additional epigenome-wide methylation analyses using whole blood highlighted 36 differentially methylated sites associated with mLOY. The genes identified converge on aspects of cell proliferation and cell cycle regulation, including DNA synthesis (NPAT), DNA damage response (ATM), mitosis (PMF1, CENPN and MAD1L1) and apoptosis (TP53). We highlight the shared genetic architecture between mLOY and cancer susceptibility, in addition to inferring a causal effect of smoking on mLOY. Collectively, our results demonstrate that genotype-array-intensity data enables a measure of cell cycle efficiency at population scale and identifies genes implicated in aneuploidy, genome instability and cancer susceptibility. PMID- 28346443 TI - Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors. AB - Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 * 10-9, odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 * 10-10, OR = 1.24), 16p13.3 (rs2562152; P = 1.93 * 10-8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 * 10-11, OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 * 10-10, OR = 1.15), as well as eight loci for non GBM tumors at 1q32.1 (rs4252707; P = 3.34 * 10-9, OR = 1.19), 1q44 (rs12076373; P = 2.63 * 10-10, OR = 1.23), 2q33.3 (rs7572263; P = 2.18 * 10-10, OR = 1.20), 3p14.1 (rs11706832; P = 7.66 * 10-9, OR = 1.15), 10q24.33 (rs11598018; P = 3.39 * 10-8, OR = 1.14), 11q21 (rs7107785; P = 3.87 * 10-10, OR = 1.16), 14q12 (rs10131032; P = 5.07 * 10-11, OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 * 10 9, OR = 1.18). These data substantiate that genetic susceptibility to GBM and non GBM tumors are highly distinct, which likely reflects different etiology. PMID- 28346449 TI - Desiccation tolerance: Seedy origins of resurrection. PMID- 28346446 TI - Dengue virus NS2B protein targets cGAS for degradation and prevents mitochondrial DNA sensing during infection. AB - During the last few decades, the global incidence of dengue virus (DENV) has increased dramatically, and it is now endemic in more than 100 countries. To establish a productive infection in humans, DENV uses different strategies to inhibit or avoid the host innate immune system. Several DENV proteins have been shown to strategically target crucial components of the type I interferon system. Here, we report that the DENV NS2B protease cofactor targets the DNA sensor cyclic GMP-AMP synthase (cGAS) for lysosomal degradation to avoid the detection of mitochondrial DNA during infection. Such degradation subsequently results in the inhibition of type I interferon production in the infected cell. Our data demonstrate a mechanism by which cGAS senses cellular damage upon DENV infection. PMID- 28346448 TI - A footprint of desiccation tolerance in the genome of Xerophyta viscosa. AB - Desiccation tolerance is common in seeds and various other organisms, but only a few angiosperm species possess vegetative desiccation tolerance. These 'resurrection species' may serve as ideal models for the ultimate design of crops with enhanced drought tolerance. To understand the molecular and genetic mechanisms enabling vegetative desiccation tolerance, we produced a high-quality whole-genome sequence for the resurrection plant Xerophyta viscosa and assessed transcriptome changes during its dehydration. Data revealed induction of transcripts typically associated with desiccation tolerance in seeds and involvement of orthologues of ABI3 and ABI5, both key regulators of seed maturation. Dehydration resulted in both increased, but predominantly reduced, transcript abundance of genomic 'clusters of desiccation-associated genes' (CoDAGs), reflecting the cessation of growth that allows for the expression of desiccation tolerance. Vegetative desiccation tolerance in X. viscosa was found to be uncoupled from drought-induced senescence. We provide strong support for the hypothesis that vegetative desiccation tolerance arose by redirection of genetic information from desiccation-tolerant seeds. PMID- 28346450 TI - Structural modeling of protein-RNA complexes using crosslinking of segmentally isotope-labeled RNA and MS/MS. AB - Ribonucleoproteins (RNPs) are key regulators of cellular function. We established an efficient approach, crosslinking of segmentally isotope-labeled RNA and tandem mass spectrometry (CLIR-MS/MS), to localize protein-RNA interactions simultaneously at amino acid and nucleotide resolution. The approach was tested on polypyrimidine tract binding protein 1 and U1 small nuclear RNP. Our method provides distance restraints to support integrative atomic-scale structural modeling and to gain mechanistic insights into RNP-regulated processes. PMID- 28346451 TI - SC3: consensus clustering of single-cell RNA-seq data. AB - Single-cell RNA-seq enables the quantitative characterization of cell types based on global transcriptome profiles. We present single-cell consensus clustering (SC3), a user-friendly tool for unsupervised clustering, which achieves high accuracy and robustness by combining multiple clustering solutions through a consensus approach (http://bioconductor.org/packages/SC3). We demonstrate that SC3 is capable of identifying subclones from the transcriptomes of neoplastic cells collected from patients. PMID- 28346454 TI - Viral pathogenesis: Dengue virus takes on cGAS. PMID- 28346452 TI - Purine synthesis promotes maintenance of brain tumor initiating cells in glioma. AB - Brain tumor initiating cells (BTICs), also known as cancer stem cells, hijack high-affinity glucose uptake active normally in neurons to maintain energy demands. Here we link metabolic dysregulation in human BTICs to a nexus between MYC and de novo purine synthesis, mediating glucose-sustained anabolic metabolism. Inhibiting purine synthesis abrogated BTIC growth, self-renewal and in vivo tumor formation by depleting intracellular pools of purine nucleotides, supporting purine synthesis as a potential therapeutic point of fragility. In contrast, differentiated glioma cells were unaffected by the targeting of purine biosynthetic enzymes, suggesting selective dependence of BTICs. MYC coordinated the control of purine synthetic enzymes, supporting its role in metabolic reprogramming. Elevated expression of purine synthetic enzymes correlated with poor prognosis in glioblastoma patients. Collectively, our results suggest that stem-like glioma cells reprogram their metabolism to self-renew and fuel the tumor hierarchy, revealing potential BTIC cancer dependencies amenable to targeted therapy. PMID- 28346453 TI - Activity-induced histone modifications govern Neurexin-1 mRNA splicing and memory preservation. AB - Epigenetic mechanisms regulate the formation, consolidation and reconsolidation of memories. However, the signaling path from neuronal activation to epigenetic modifications within the memory-related brain circuit remains unknown. We report that learning induces long-lasting histone modifications in hippocampal memory activated neurons to regulate memory stability. Neuronal activity triggers a late onset shift in Nrxn1 splice isoform choice at splicing site 4 by accumulating a repressive histone marker, H3K9me3, to modulate the splicing process. Activity dependent phosphorylation of p66alpha via AMP-activated protein kinase recruits HDAC2 and Suv39h1 to establish repressive histone markers and changes the connectivity of the activated neurons. Removal of Suv39h1 abolished the activity dependent shift in Nrxn1 splice isoform choice and reduced the stability of established memories. We uncover a cell-autonomous process for memory preservation in which memory-related neurons initiate a late-onset reduction of their rewiring capacities through activity-induced histone modifications. PMID- 28346455 TI - Collective helicity switching of a DNA-coat assembly. AB - Hierarchical assemblies of biomolecular subunits can carry out versatile tasks at the cellular level with remarkable spatial and temporal precision. As an example, the collective motion and mutual cooperation between complex protein machines mediate essential functions for life, such as replication, synthesis, degradation, repair and transport. Nucleic acid molecules are far less dynamic than proteins and need to bind to specific proteins to form hierarchical structures. The simplest example of these nucleic acid-based structures is provided by a rod-shaped tobacco mosaic virus, which consists of genetic material surrounded by coat proteins. Inspired by the complexity and hierarchical assembly of viruses, a great deal of effort has been devoted to design similarly constructed artificial viruses. However, such a wrapping approach makes nucleic acid dynamics insensitive to environmental changes. This limitation generally restricts, for example, the amplification of the conformational dynamics between the right-handed B form to the left-handed Z form of double-stranded deoxyribonucleic acid (DNA). Here we report a virus-like hierarchical assembly in which the native DNA and a synthetic coat undergo repeated collective helicity switching triggered by pH change under physiological conditions. We also show that this collective helicity inversion occurs during translocation of the DNA coat assembly into intracellular compartments. Translating DNA conformational dynamics into a higher level of hierarchical dynamics may provide an approach to create DNA-based nanomachines. PMID- 28346456 TI - Sub-10-nm patterning via directed self-assembly of block copolymer films with a vapour-phase deposited topcoat. AB - Directed self-assembly (DSA) of the domain structure in block copolymer (BCP) thin films is a promising approach for sub-10-nm surface patterning. DSA requires the control of interfacial properties on both interfaces of a BCP film to induce the formation of domains that traverse the entire film with a perpendicular orientation. Here we show a methodology to control the interfacial properties of BCP films that uses a polymer topcoat deposited by initiated chemical vapour deposition (iCVD). The iCVD topcoat forms a crosslinked network that grafts to and immobilizes BCP chains to create an interface that is equally attractive to both blocks of the underlying copolymer. The topcoat, in conjunction with a chemically patterned substrate, directs the assembly of the grating structures in BCP films with a half-pitch dimension of 9.3 nm. As the iCVD topcoat can be as thin as 7 nm, it is amenable to pattern transfer without removal. The ease of vapour-phase deposition, applicability to high-resolution BCP systems and integration with pattern-transfer schemes are attractive properties of iCVD topcoats for industrial applications. PMID- 28346459 TI - Directed self-assembly: A dress code for block copolymers. PMID- 28346460 TI - Lithium-oxygen batteries: The reaction mechanism revealed. PMID- 28346458 TI - Revealing the reaction mechanisms of Li-O2 batteries using environmental transmission electron microscopy. AB - The performances of a Li-O2 battery depend on a complex interplay between the reaction mechanism at the cathode, the chemical structure and the morphology of the reaction products, and their spatial and temporal evolution; all parameters that, in turn, are dependent on the choice of the electrolyte. In an aprotic cell, for example, the discharge product, Li2O2, forms through a combination of solution and surface chemistries that results in the formation of a baffling toroidal morphology. In a solid electrolyte, neither the reaction mechanism at the cathode nor the nature of the reaction product is known. Here we report the full-cycle reaction pathway for Li-O2 batteries and show how this correlates with the morphology of the reaction products. Using aberration-corrected environmental transmission electron microscopy (TEM) under an oxygen environment, we image the product morphology evolution on a carbon nanotube (CNT) cathode of a working solid-state Li-O2 nanobattery and correlate these features with the electrochemical reaction at the electrode. We find that the oxygen-reduction reaction (ORR) on CNTs initially produces LiO2, which subsequently disproportionates into Li2O2 and O2. The release of O2 creates a hollow nanostructure with Li2O outer-shell and Li2O2 inner-shell surfaces. Our findings show that, in general, the way the released O2 is accommodated is linked to lithium-ion diffusion and electron-transport paths across both spatial and temporal scales; in turn, this interplay governs the morphology of the discharging/charging products in Li-O2 cells. PMID- 28346457 TI - Confined space facilitates G-quadruplex formation. AB - Molecular simulations suggest that the stability of a folded macromolecule increases in a confined space due to entropic effects. However, due to the interactions between the confined molecular structure and the walls of the container, clear-cut experimental evidence for this prediction is lacking. Here, using DNA origami nanocages, we show the pure effect of confined space on the property of individual human telomeric DNA G-quadruplexes. We induce targeted mechanical unfolding of the G-quadruplex while leaving the nanocage unperturbed. We find that the mechanical and thermodynamic stabilities of the G-quadruplex inside the nanocage increase with decreasing cage size. Compared to the case of diluted or molecularly crowded buffer solutions, the G-quadruplex inside the nanocage is significantly more stable, showing a 100 times faster folding rate. Our findings suggest the possibility of co-replicational or co-transcriptional folding of G-quadruplex inside the polymerase machinery in cells. PMID- 28346461 TI - Geometry can provide long-range mechanical guidance for embryogenesis. AB - Downstream of gene expression, effectors such as the actomyosin contractile machinery drive embryo morphogenesis. During Drosophila embryonic axis extension, actomyosin has a specific planar-polarised organisation, which is responsible for oriented cell intercalation. In addition to these cell rearrangements, cell shape changes also contribute to tissue deformation. While cell-autonomous dynamics are well described, understanding the tissue-scale behaviour challenges us to solve the corresponding mechanical problem at the scale of the whole embryo, since mechanical resistance of all neighbouring epithelia will feedback on individual cells. Here we propose a novel numerical approach to compute the whole-embryo dynamics of the actomyosin-rich apical epithelial surface. We input in the model specific patterns of actomyosin contractility, such as the planar-polarisation of actomyosin in defined ventro-lateral regions of the embryo. Tissue strain rates and displacements are then predicted over the whole embryo surface according to the global balance of stresses and the material behaviour of the epithelium. Epithelia are modelled using a rheological law that relates the rate of deformation to the local stresses and actomyosin anisotropic contractility. Predicted flow patterns are consistent with the cell flows observed when imaging Drosophila axis extension in toto, using light sheet microscopy. The agreement between model and experimental data indicates that the anisotropic contractility of planar-polarised actomyosin in the ventro-lateral germband tissue can directly cause the tissue-scale deformations of the whole embryo. The three-dimensional mechanical balance is dependent on the geometry of the embryo, whose curved surface is taken into account in the simulations. Importantly, we find that to reproduce experimental flows, the model requires the presence of the cephalic furrow, a fold located anteriorly of the extending tissues. The presence of this geometric feature, through the global mechanical balance, guides the flow and orients extension towards the posterior end. PMID- 28346463 TI - Changes in soil bacterial community structure as a result of incorporation of Brassica plants compared with continuous planting eggplant and chemical disinfection in greenhouses. AB - Greenhouse eggplant monocropping in China has contributed to the aggravation of soil-borne diseases, reductions in crop quality and yield, and the degradation of physical and chemical soil properties. Crop rotation is one effective way of alleviating the problems of continuous cropping worldwide; however, few studies have reported changes in soil bacterial community structures and physical and chemical soil properties after Brassica vegetables had been rotated with eggplant in greenhouses. In this experiment, mustard-eggplant (BFN) and oilseed rape eggplant (BFC) rotations were studied to identify changes in the physicochemical properties and bacterial community structure in soil that was previously subject to monocropping. Samples were taken after two types of Brassica plants incorporated into soil for 15 days to compare with continually planted eggplant (control, CN) and chemical disinfection of soil (CF) in greenhouses. MiSeq pyrosequencing was used to analyze soil bacterial diversity and structure in the four different treatments. A total of 55,129 reads were identified, and rarefaction analysis showed that the soil treatments were equally sampled. The bacterial richness of the BFC treatment and the diversity of the BFN treatment were significantly higher than those of the other treatments. Further comparison showed that the bacterial community structures of BFC and BFN treatments were also different from CN and CF treatments. The relative abundance of several dominant bacterial genera in the BFC and BFN treatments (such as Flavobacteria, Stenotrophomonas, Massilia and Cellvibrio, which played different roles in improving soil fertility and advancing plant growth) was distinctly higher than the CN or CF treatments. Additionally, the total organic matter and Olsen-P content of the BFC and BFN treatments were significantly greater than the CN treatment. We conclude that Brassica vegetables-eggplant crop rotations could provide a more effective means of solving the problems of greenhouse eggplant monocultures. PMID- 28346464 TI - Sympathetic nervous system activity and anti-lipolytic response to iv-glucose load in subcutaneous adipose tissue of obese and obese type 2 diabetic subjects. AB - The study aim was to investigate the effect of endogenous insulin release on lipolysis in subcutaneous adipose tissue after adrenergic stimulation in obese subjects diagnosed with type 2 diabetes (T2D). In 14 obese female T2D subjects, or 14 obese non-T2D controls, glycerol concentration was measured in response to the alpha1,2,beta-agonist norepinephrine, the alpha1-agonist norfenefrine and the beta2-agonist terbutaline (each 10-4 M), using the microdialysis technique. After 60 minutes of stimulation, an intravenous glucose load (0.5 g/kg lean body mass) was given. Local blood flow was monitored by means of the ethanol technique. Norepinephrine and norfenefrine induced a four and three fold rise in glycerol dialysate concentration (p<0.001, each), with a similar pattern in adipose tissue. Following agonist stimulation and glucose infusion, endogenous insulin release inhibited lipolysis in the presence of norepinephrine, which was more rapid and pronounced in healthy obese controls than in T2D subjects (p = 0.024 obese vs T2D subjects). Insulin-induced inhibition of lipolysis in the presence of norfenefrine was similar in all study participants. In the presence of terbutaline the lipolysis rate increased two fold until the effect of endogenous insulin (p<0.001). A similar insulin-induced decrease in lipolysis was observed for each of the norfenefrine groups and the terbutaline groups, respectively. Adipose tissue blood flow remained unchanged after the iv-glucose load. Both norepinephrine and norfenefrine diminished blood flow slightly, but insulin reversed this response (p<0.001 over the entire time). Terbutaline alone and terbutaline plus increased endogenous insulin augmented local blood flow (p<0.001 over the entire time). In conclusion, a difference in insulin-induced inhibition of lipolysis was observed in obese T2D subjects compared to obese healthy controls following modulation of sympathetic nervous system activity and is assumed to be due to beta1-adrenoceptor mediated stimulation by norepinephrine. PMID- 28346462 TI - Wnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus. AB - Understanding the mechanisms regulating cell cycle, proliferation and potency of pluripotent stem cells guarantees their safe use in the clinic. Embryonic stem cells (ESCs) present a fast cell cycle with a short G1 phase. This is due to the lack of expression of cell cycle inhibitors, which ultimately determines naive pluripotency by holding back differentiation. The canonical Wnt/beta-catenin pathway controls mESC pluripotency via the Wnt-effector Tcf3. However, if the activity of the Wnt/beta-catenin controls the cell cycle of mESCs remains unknown. Here we show that the Wnt-effector Tcf1 is recruited to and triggers transcription of the Ink4/Arf tumor suppressor locus. Thereby, the activation of the Wnt pathway, a known mitogenic pathway in somatic tissues, restores G1 phase and drastically reduces proliferation of mESCs without perturbing pluripotency. Tcf1, but not Tcf3, is recruited to a palindromic motif enriched in the promoter of cell cycle repressor genes, such as p15Ink4b, p16Ink4a and p19Arf, which mediate the Wnt-dependent anti-proliferative effect in mESCs. Consistently, ablation of beta-catenin or Tcf1 expression impairs Wnt-dependent cell cycle regulation. All together, here we showed that Wnt signaling controls mESC pluripotency and proliferation through non-overlapping functions of distinct Tcf factors. PMID- 28346465 TI - SEPT12 phosphorylation results in loss of the septin ring/sperm annulus, defective sperm motility and poor male fertility. AB - Septins are critical for numerous cellular processes through the formation of heteromeric filaments and rings indicating the importance of structural regulators in septin assembly. Several posttranslational modifications (PTMs) mediate the dynamics of septin filaments in yeast. However, little is known about the role of PTMs in regulating mammalian septin assembly, and the in vivo significance of PTMs on mammalian septin assembly and function remains unknown. Here, we showed that SEPT12 was phosphorylated on Ser198 using mass spectrometry, and we generated SEPT12 phosphomimetic knock-in (KI) mice to study its biological significance. The homozygous KI mice displayed poor male fertility due to deformed sperm with defective motility and loss of annulus, a septin-based ring structure. Immunohistochemistry of KI testicular sections suggested that SEPT12 phosphorylation inhibits septin ring assembly during annulus biogenesis. We also observed that SEPT12 was phosphorylated via PKA, and its phosphorylation interfered with SEPT12 polymerization into complexes and filaments. Collectively, our data indicate that SEPT12 phosphorylation inhibits SEPT12 filament formation, leading to loss of the sperm annulus/septin ring and poor male fertility. Thus, we provide the first in vivo genetic evidence characterizing importance of septin phosphorylation in the assembly, cellular function and physiological significance of septins. PMID- 28346442 TI - Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer. AB - To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC. PMID- 28346467 TI - Characterization and interstrain transfer of prophage pp3 of Pseudomonas aeruginosa. AB - Prophages are major contributors to horizontal gene transfer and drive the evolution and diversification of bacteria. Here, we describe the characterization of a prophage element designated pp3 in the clinical Pseudomonas aeruginosa isolate PA1. pp3 spontaneously excises from the PA1 genome and circularizes at a very high frequency of 25%. pp3 is likely to be a defective prophage due to its inability to form plaques on P. aeruginosa indicator strains, and no phage particles could be detected in PA1 supernatants. The pp3-encoded integrase is essential for excision by mediating site-specific recombination at the 26-bp attachment sequence. Using a filter mating experiment, we demonstrated that pp3 can transfer into P. aeruginosa recipient strains that do not possess this element naturally. Upon transfer, pp3 integrates into the same attachment site as in PA1 and maintains the ability to excise and circularize. Furthermore, pp3 significantly promotes biofilm formation in the recipient. Sequence alignment reveals that the 26-bp attachment site recognized by pp3 is conserved in all P. aeruginosa strains sequenced to date, making it possible that pp3 could be extensively disseminated in P. aeruginosa. This work improves our understanding of the ways in which prophages influence bacterial behavior and evolution. PMID- 28346468 TI - Endoluminal dilatation for embedded hemodialysis catheters: A case-control study of factors associated with embedding and clinical outcomes. AB - BACKGROUND: With the increasing frequency of tunneled hemodialysis catheter use there is a parallel increase in the need for removal and/or exchange. A small but significant minority of catheters become embedded or 'stuck' and cannot be removed by traditional means. Management of embedded catheters involves cutting the catheter, burying the retained fragment with a subsequent increased risk of infections and thrombosis. Endoluminal dilatation may provide a potential safe and effective technique for removing embedded catheters, however, to date, there is a paucity of data. OBJECTIVES: 1) To determine factors associated with catheters becoming embedded and 2) to determine outcomes associated with endoluminal dilatation. METHODS: All patients with endoluminal dilatation for embedded catheters at our institution since Jan. 2010 were included. Patients who had an embedded catheter were matched 1:3 with patients with uncomplicated catheter removal. Baseline patient and catheter characteristics were compared. Outcomes included procedural success and procedure-related infection. Logistic regression models were used to determine factors associated with embedded catheters. RESULTS: We matched 15 cases of embedded tunneled catheters with 45 controls. Among patients with embedded catheters, there were no complications with endoluminal dilatation. Factors independently associated with embedded catheters included catheter dwell time (> 2 years) and history of central venous stenosis. CONCLUSION: Embedded catheters can be successfully managed by endoluminal dilatation with minimal complications and factors associated with embedding include dwell times > 2 years and/or with a history of central venous stenosis. PMID- 28346466 TI - Common and rare exonic MUC5B variants associated with type 2 diabetes in Han Chinese. AB - Genome-wide association studies have identified over one hundred common genetic risk variants associated with type 2 diabetes (T2D). However, most of the heritability of T2D has not been accounted for. In this study, we investigated the contribution of rare and common variants to T2D susceptibility by analyzing exome array data in 1,908 Han Chinese genotyped with Affymetrix Axiom(r) Exome Genotyping Arrays. Based on the joint common and rare variants analysis of 57,704 autosomal SNPs within 12,244 genes using Sequence Kernel Association Tests (SKAT), we identified significant associations between T2D and 25 variants (9 rare and 16 common) in MUC5B, p-value 1.01*10-14. This finding was replicated (p = 0.0463) in an independent sample that included 10,401 unrelated individuals. Sixty-six of 1,553 possible haplotypes based on 25 SNPs within MUC5B showed significant association with T2D (Bonferroni corrected p values < 3.2*10-5). The expression level of MUC5B is significantly higher in pancreatic tissues of persons with T2D compared to those without T2D (p-value = 5*10-5). Our findings suggest that dysregulated MUC5B expression may be involved in the pathogenesis of T2D. As a strong candidate gene for T2D, MUC5B may play an important role in the mechanisms underlying T2D etiology and its complications. PMID- 28346469 TI - Computational identifying and characterizing circular RNAs and their associated genes in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is currently still a major factor leading to death, lacking of reliable biomarkers. Therefore, deep understanding the pathogenesis for HCC is of great importance. The emergence of circular RNA (circRNA) provides a new way to study the pathogenesis of human disease. Here, we employed the prediction tool to identify circRNAs based on RNA-seq data. Then, to investigate the biological function of the circRNA, the candidate circRNAs were associated with the protein-coding genes (PCGs) by GREAT. We found significant candidate circRNAs expression alterations between normal and tumor samples. Additionally, the PCGs associated with these candidate circRNAs were also found have discriminative expression patterns between normal and tumor samples. The enrichment analysis illustrated that these PCGs were predominantly enriched for liver/cardiovascular-related diseases such as atherosclerosis, myocardial ischemia and coronary heart disease, and participated in various metabolic processes. Together, a further network analysis indicated that these PCGs play important roles in the regulatory and the PPI network. Finally, we built a classification model to distinguish normal and tumor samples by using candidate circRNAs and their associated genes, respectively. Both of them obtained satisfactory results (~ 0.99 of AUC for circRNA and PCG). Our findings suggested that the circRNA could be a critical factor in HCC, providing a useful resource to explore the pathogenesis of HCC. PMID- 28346470 TI - Relationship of microbial communities and suppressiveness of Trichoderma fortified composts for pepper seedlings infected by Phytophthora nicotianae. AB - The understanding of the dynamic of soil-borne diseases is related to the microbial composition of the rhizosphere which is the key to progress in the field of biological control. Trichoderma spp. is commonly used as a biological control agent. The use of next generation sequencing approaches and quantitative PCR are two successful approaches to assess the effect of using compost as substrate fortified with two Trichoderma strains (Trichoderma harzianum or Trichoderma asperellum) on bacterial and fungal communities in pepper rhizosphere infected with Phytophthora nicotianae. The results showed changes in the bacterial rhizosphere community not attributed to the Trichoderma strain, but to the pathogen infection, while, fungi were not affected by pathogen infection and depended on the type of substrate. The Trichoderma asperellum fortified compost was the most effective combination against the pathogen. This could indicate that the effect of fortified composts is greater than compost itself and the biocontrol effect should be attributed to the Trichoderma strains rather than the compost microbiota, although some microorganisms could help with the biocontrol effect. PMID- 28346471 TI - Effect of functional sympathetic nervous system impairment of the liver and abdominal visceral adipose tissue on circulating triglyceride-rich lipoproteins. AB - BACKGROUND: Interruption of sympathetic innervation to the liver and visceral adipose tissue (VAT) in animal models has been reported to reduce VAT lipolysis and hepatic secretion of very low density lipoprotein (VLDL) and concentrations of triglyceride-rich lipoprotein particles. Whether functional impairment of sympathetic nervous system (SNS) innervation to tissues of the abdominal cavity reduce circulating concentrations of triglyceride (TG) and VLDL particles (VLDL P) was tested in men with spinal cord injury (SCI). METHODS: One hundred-three non-ambulatory men with SCI [55 subjects with neurologic injury at or proximal to the 4th thoracic vertebrae (?T4); 48 subjects with SCI at or distal to the 5th thoracic vertebrae (?T5)] and 53 able-bodied (AB) subjects were studied. Fasting blood samples were obtained for determination of TG, VLDL-P concentration by NMR spectroscopy, serum glucose by autoanalyzer, and plasma insulin by radioimmunoassay. VAT volume was determined by dual energy x-ray absorptiometry imaging with calculation by a validated proprietary software package. RESULTS: Significant group main effects for TG and VLDL-P were present; post-hoc tests revealed that serum TG concentrations were significantly higher in ?T5 group compared to AB and ?T4 groups [150+/-9 vs. 101+/-8 (p<0.01) and 112+/-8 mg/dl (p<0.05), respectively]. VLDL-P concentration was significantly elevated in ?T5 group compared to AB and ?T4 groups [74+/-4 vs. 58+/-4 (p<0.05) and 55+/-4 MUmol/l (p<0.05)]. VAT volume was significantly higher in both SCI groups than in the AB group, and HOMA-IR was higher and approached significance in the SCI groups compared to the AB group. A linear relationship between triglyceride rich lipoproteins (i.e., TG or Large VLDL-P) and VAT volume or HOMA-IR was significant only in the ?T5 group. CONCLUSIONS: Despite a similar VAT volume and insulin resistance in both SCI groups, the ?T5 group had significantly higher serum TG and VLDL-P values than that observed in the ?T4 and the AB control groups. Thus, level of injury is an important determinate of the concentration of circulating triglyceride rich lipoproteins, which may play a role in the genesis of cardiometabolic dysfunction. PMID- 28346472 TI - Can group-based reassuring information alter low back pain behavior? A cluster randomized controlled trial. AB - BACKGROUND: Low back pain (LBP) is common in the population and multifactorial in nature, often involving negative consequences. Reassuring information to improve coping is recommended for reducing the negative consequences of LBP. Adding a simple non-threatening explanation for the pain (temporary muscular dysfunction) has been successful at altering beliefs and behavior when delivered with other intervention elements. This study investigates the isolated effect of this specific information on future occupational behavior outcomes when delivered to the workforce. DESIGN: A cluster-randomized controlled trial. METHODS: Publically employed workers (n = 505) from 11 Danish municipality centers were randomized at center-level (cluster) to either intervention (two 1-hour group-based talks at the workplace) or control. The talks provided reassuring information together with a simple non-threatening explanation for LBP-the 'functional-disturbance' model. Data collections took place monthly over a 1-year period using text message tracking (SMS). Primary outcomes were self-reported days of cutting down usual activities and work participation. Secondary outcomes were self-reported back beliefs, work ability, number of healthcare visits, bothersomeness, restricted activity, use of pain medication, and sadness/depression. RESULTS: There was no between-group difference in the development of LBP during follow-up. Cumulative logistic regression analyses showed no between-group difference on days of cutting down activities, but increased odds for more days of work participation in the intervention group (OR = 1.83 95% CI: 1.08-3.12). Furthermore, the intervention group was more likely to report: higher work ability, reduced visits to healthcare professionals, lower bothersomeness, lower levels of sadness/depression, and positive back beliefs. CONCLUSION: Reassuring information involving a simple non-threatening explanation for LBP significantly increased the odds for days of work participation and higher work ability among workers who went on to experience LBP during the 12-month follow-up. Our results confirm the potential for public-health education for LBP, and add to the discussion of simple versus multidisciplinary interventions. PMID- 28346473 TI - Oral administration of Bifidobacterium bifidum G9-1 alleviates rotavirus gastroenteritis through regulation of intestinal homeostasis by inducing mucosal protective factors. AB - Human rotavirus (RV) infection is a leading cause of dehydrating diarrhea in infants and young children worldwide. Since therapeutic approaches to RV gastroenteritis are limited to alleviation of dehydration with oral rehydration solutions, more direct approaches to palliate symptoms of RV gastroenteritis are required. Treatments with probiotics have been increasingly recognized as alternative safe and low cost treatments for moderate infectious diarrhea. In this study, Bifidobacterium bifidum G9-1 (BBG9-1), which has been used as an intestinal drug for several decades, was shown to have a remarkable protective effect against RV gastroenteritis in a suckling mice model. As well as prophylactic oral administration of BBG9-1 from 2 days before RV infection, therapeutic oral administration of BBG9-1 from 1 day after RV infection significantly alleviated RV-induced diarrhea. Therapeutic administration of BBG9 1 reduced various types of damage in the small intestine, such as epithelial vacuolization and villous shortening, and significantly diminished the infectious RV titer in mixtures of cecal contents and feces. It was also shown that therapeutic administration of BBG9-1 significantly increased the number of acidic mucin-positive goblet cells and the gene expression of mucosal protective factors including MUC2, MUC3, MUC4, TGFbeta1 and TFF3 in the small intestine. This led to alleviation of low gut permeability shown as decreased gene expression levels of occludin, claudin-1 and villin-1 after RV infection. Furthermore, in the small intestine, therapeutic administration of BBG9-1 significantly palliated the decreased gene expression of SGLT-1, which plays an important role in water absorption. In the large intestine, administered BBG9-1 was shown to replicate to assimilate undigested nutrients, resulting in normalization of the abnormally high osmotic pressure. These results suggested that water malabsorption caused by RV infection was alleviated in mice administered BBG9-1. Thus, the present study showed that oral administration of BBG9-1 palliated diarrhea partly through protection against RV-induced lesions by inducing mucosal protective factors. Oral administration of BBG9-1 is thought to be an efficient method for management of an RV epidemic for both prophylactic and therapeutic purposes. PMID- 28346474 TI - The microRNA-205-5p is correlated to metastatic potential of 21T series: A breast cancer progression model. AB - MicroRNA is a class of noncoding RNAs able to base pair with complementary messenger RNA sequences, inhibiting their expression. These regulatory molecules play important roles in key cellular processes including cell proliferation, differentiation and response to DNA damage; changes in miRNA expression are a common feature of human cancers. To gain insights into the mechanisms involved in breast cancer progression we conducted a microRNA global expression analysis on a 21T series of cell lines obtained from the same patient during different stages of breast cancer progression. These stages are represented by cell lines derived from normal epithelial (H16N2), atypical ductal hyperplasia (21PT), primary in situ ductal carcinoma (21NT) and pleural effusion of a lung metastasis (21MT-1 and 21MT-2). In a global microRNA expression analysis, miR-205-5p was the only miRNA to display an important downregulation in the metastatic cell lines (21MT 1; 21MT-2) when compared to the non-invasive cells (21PT and 21NT). The lower amounts of miR-205-5p found also correlated with high histological grades biopsies and with higher invasion rates in a Boyden chamber assay. This work pinpoints miR-205-5p as a potential player in breast tumor invasiveness. PMID- 28346475 TI - Treatment of blunt thoracic aortic injury in Germany-Assessment of the TraumaRegister DGU(r). AB - PURPOSE: Using the data delivered by the German Trauma Register DGU(r) from 2002 till 2013, the value of different therapies of blunt thoracic aortic injury (BTAI) in Germany was analyzed. METHODS: Prospectively collected data of patients suffering from BTAI were retrospectively analyzed with focus on the different treatment modalities for grade I-IV injuries. RESULTS: 821 patients suffering from BTAI were identified: 51.6% (424) grade I injury, 35.4% (291) grade II or III injury and 12.9% (106) grade IV injury (77.5% men [44.94 +/- 20.6 years]). The main patterns of injury were high- speed accidents and falls (78.0% [n = 640], 21.8% [n = 171] respectively). Significant differences between grade I and grade II/III as well as IV injuries could be assessed for the incidence of cardiopulmonary resuscitation, a Glasgow Coma Scale score below 8 and a systolic blood pressure below 90 mmHg (p-value: <0.001). In the primary admission subgroup, 44.1% (197/447) of the patients received best medical treatment, 55.9% received surgical intervention (250/447): Thereof 37.2% (93/250) received open surgery and 62.8% (147/250) had been treated by endovascular means. Significantly lower 24-h- and in-hospital-mortality rates were encountered after endovascular treatment for all gradings of BTAI (p-value: <0.001). Yet this subgroup of patients showed the lowest incidence of further severe injuries and cardiac arrest. CONCLUSION: Endovascular therapy became the treatment of choice for BTAI in Germany. Patients who have been treated by surgical means showed the highest survival rate, especially endovascular therapy showed a favorable low mortality rate. PMID- 28346476 TI - Reduced dosage of beta-catenin provides significant rescue of cardiac outflow tract anomalies in a Tbx1 conditional null mouse model of 22q11.2 deletion syndrome. AB - The 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome; DiGeorge syndrome) is a congenital anomaly disorder in which haploinsufficiency of TBX1, encoding a T-box transcription factor, is the major candidate for cardiac outflow tract (OFT) malformations. Inactivation of Tbx1 in the anterior heart field (AHF) mesoderm in the mouse results in premature expression of pro-differentiation genes and a persistent truncus arteriosus (PTA) in which septation does not form between the aorta and pulmonary trunk. Canonical Wnt/beta-catenin has major roles in cardiac OFT development that may act upstream of Tbx1. Consistent with an antagonistic relationship, we found the opposite gene expression changes occurred in the AHF in beta-catenin loss of function embryos compared to Tbx1 loss of function embryos, providing an opportunity to test for genetic rescue. When both alleles of Tbx1 and one allele of beta-catenin were inactivated in the Mef2c-AHF Cre domain, 61% of them (n = 34) showed partial or complete rescue of the PTA defect. Upregulated genes that were oppositely changed in expression in individual mutant embryos were normalized in significantly rescued embryos. Further, beta-catenin was increased in expression when Tbx1 was inactivated, suggesting that there may be a negative feedback loop between canonical Wnt and Tbx1 in the AHF to allow the formation of the OFT. We suggest that alteration of this balance may contribute to variable expressivity in 22q11.2DS. PMID- 28346477 TI - Disruption of SorCS2 reveals differences in the regulation of stereociliary bundle formation between hair cell types in the inner ear. AB - Behavioural anomalies suggesting an inner ear disorder were observed in a colony of transgenic mice. Affected animals were profoundly deaf. Severe hair bundle defects were identified in all outer and inner hair cells (OHC, IHC) in the cochlea and in hair cells of vestibular macular organs, but hair cells in cristae were essentially unaffected. Evidence suggested the disorder was likely due to gene disruption by a randomly inserted transgene construct. Whole-genome sequencing identified interruption of the SorCS2 (Sortilin-related VPS-10 domain containing protein) locus. Real-time-qPCR demonstrated disrupted expression of SorCS2 RNA in cochlear tissue from affected mice and this was confirmed by SorCS2 immuno-labelling. In all affected hair cells, stereocilia were shorter than normal, but abnormalities of bundle morphology and organisation differed between hair cell types. Bundles on OHC were grossly misshapen with significantly fewer stereocilia than normal. However, stereocilia were organised in rows of increasing height. Bundles on IHC contained significantly more stereocilia than normal with some longer stereocilia towards the centre, or with minimal height differentials. In early postnatal mice, kinocilia (primary cilia) of IHC and of OHC were initially located towards the lateral edge of the hair cell surface but often became surrounded by stereocilia as bundle shape and apical surface contour changed. In macular organs the kinocilium was positioned in the centre of the cell surface throughout maturation. There was disruption of the signalling pathway controlling intrinsic hair cell apical asymmetry. LGN and Galphai3 were largely absent, and atypical Protein Kinase C (aPKC) lost its asymmetric distribution. The results suggest that SorCS2 plays a role upstream of the intrinsic polarity pathway and that there are differences between hair cell types in the deployment of the machinery that generates a precisely organised hair bundle. PMID- 28346480 TI - Stationarity of the inter-event power-law distributions. AB - A number of human activities exhibit a bursty pattern, namely periods of very high activity that are followed by rest periods. Records of these processes generate time series of events whose inter-event times follow a probability distribution that displays a fat tail. The grounds for such phenomenon are not yet clearly understood. In the present work we use the freely available Wikipedia's editing records to unravel some features of this phenomenon. We show that even though the probability to start editing is conditioned by the circadian 24 hour cycle, the conditional probability for the time interval between successive edits at a given time of the day is independent from the latter. We confirm our findings with the activity of posting on the social network Twitter. Our results suggest that there is an intrinsic humankind scheduling pattern: after overcoming the encumbrance of starting an activity, there is a robust distribution of new related actions, which does not depend on the time of day at which the activity started. PMID- 28346478 TI - Association of eNOS and Cav-1 gene polymorphisms with susceptibility risk of large artery atherosclerotic stroke. AB - Endothelial nitric oxide synthase (eNOS) is localized in caveole and has important effects on caveolar coordination through its interaction with caveolin 1 (Cav-1), which supports normal functioning of vascular endothelial cells. However, the relationship between genotypic polymorphisms of e-NOS and Cav-1 genes and ischemic stroke (IS) remains lesser reported. This hospital-based case control study aimed to determine the genetic polymorphisms of the eNOS (Glu298Asp) and Cav-1 (G14713A and T29107A) genes in association with susceptibility risk in patients who had suffered from a large artery atherosclerotic (LAA) stroke. Genotyping determination for these variant alleles was performed using the TaqMan assay. The distributions of observed allelic and genotypic frequencies for the polymorphisms were in Hardy-Weinberg equilibrium in healthy controls. The risk for an LAA stroke in the Asp298 variant was 1.72 (95% CI = 1.09-2.75) versus Glu298 of the eNOS. In the GA/AA (rs3807987) variant, it was 1.79 (95% CI = 1.16-2.74) versus GG and in TA/AA (rs7804372) was 1.61 (95% CI = 1.06-2.43) versus TT of the Cav-1, respectively. A tendency toward an increased LAA stroke risk was significant in carriers with the eNOS Glu298Asp variant in conjunction with the G14713 A and T29107A polymorphisms of the Cav-1 (aOR = 2.03, P-trend = 0.002). A synergistic effect between eNOS and Cav-1 polymorphisms on IS risk elevation was significantly influenced by alcohol drinking, heavy cigarette smoking (P-trend<0.01), and hypercholesterolemia (P-trend < 0.001). In conclusion, genotypic polymorphisms of the eNOS Glu298Asp and Cav-1 14713A/29107A polymorphisms are associated with the elevated risk of LAA stroke among Han Chinese in Taiwan. PMID- 28346479 TI - Rare variants in fox-1 homolog A (RBFOX1) are associated with lower blood pressure. AB - Many large genome-wide association studies (GWAS) have identified common blood pressure (BP) variants. However, most of the identified BP variants do not overlap with the linkage evidence observed from family studies. We thus hypothesize that multiple rare variants contribute to the observed linkage evidence. We performed linkage analysis using 517 individuals in 130 European families from the Cleveland Family Study (CFS) who have been genotyped on the Illumina OmniExpress Exome array. The largest linkage peak was observed on chromosome 16p13 (MLOD = 2.81) for systolic blood pressure (SBP). Follow-up conditional linkage and association analyses in the linkage region identified multiple rare, coding variants in RBFOX1 associated with reduced SBP. In a 17 member CFS family, carriers of the missense variant rs149974858 are normotensive despite being obese (average BMI = 60 kg/m2). Gene-based association test of rare variants using SKAT-O showed significant association with SBP (p-value = 0.00403) and DBP (p-value = 0.0258) in the CFS participants and the association was replicated in large independent replication studies (N = 57,234, p-value = 0.013 for SBP, 0.0023 for PP). RBFOX1 is expressed in brain tissues, the atrial appendage and left ventricle in the heart, and in skeletal muscle tissues, organs/tissues which are potentially related to blood pressure. Our study showed that associations of rare variants could be efficiently detected using family information. PMID- 28346481 TI - Edaravone protects against hyperosmolarity-induced oxidative stress and apoptosis in primary human corneal epithelial cells. AB - An increase in the osmolarity of tears induced by excessive evaporation of the aqueous tear phase is a major pathological mechanism behind dry eye. Exposure of epithelial cells on the surface of the human eye to hyperosmolarity leads to oxidative stress, mitochondrial dysfunction, and apoptosis. Edaravone, a hydroxyl radical scavenging agent, is clinically used to reduce neuronal damage following ischemic stroke. In this study, we found that treatment with hyperosmotic media at 400 and 450 mOsM increased the levels of ROS and mitochondrial oxidative damage, which were ameliorated by edaravone treatment in a dose-dependent manner. We also found that edaravone could improve mitochondrial function in HCEpiCs by increasing the levels of ATP and mitochondrial membrane potential. MTT and LDH assays indicated that edaravone could attenuate hyperosmolarity-induced cell death. It was found that edaravone prevented apoptosis by decreasing the level of cleaved caspase-3, and attenuating the release of cytochrome C. Mechanistically, we found that edaravone augmented the expression of Nrf2 and its target genes, such as HO-1, GPx-1, and GCLC. PMID- 28346482 TI - 24S-hydroxycholesterol and 25-hydroxycholesterol differentially impact hippocampal neuronal survival following oxygen-glucose deprivation. AB - N-methyl-D-aspartate receptors (NMDARs), a major subtype of glutamate receptor mediating excitatory transmission throughout the CNS, participate in ischemia induced neuronal death. Unfortunately, undesired side effects have limited the strategy of inhibiting/blocking NMDARs as therapy. Targeting endogenous positive allosteric modulators of NMDAR function may offer a strategy with fewer downsides. Here, we explored whether 24S-hydroxycholesterol (24S-HC), an endogenous positive NMDAR modulator characterized recently by our group, participates in NMDAR-mediated excitotoxicity following oxygen-glucose deprivation (OGD) in primary neuron cultures. 24S-HC is the major brain cholesterol metabolite produced exclusively in neurons near sites of glutamate transmission. By selectively potentiating NMDAR current, 24S-HC may participate in NMDAR-mediated excitotoxicity following energy failure, thus impacting recovery after stroke. In support of this hypothesis, our findings indicate that exogenous application of 24S-HC exacerbates NMDAR-dependent excitotoxicity in primary neuron culture following OGD, an ischemic-like challenge. Similarly, enhancement of endogenous 24S-HC synthesis reduced survival rate. On the other hand, reducing endogenous 24S-HC synthesis alleviated OGD-induced cell death. We found that 25-HC, another oxysterol that antagonizes 24S-HC potentiation, partially rescued OGD-mediated cell death in the presence or absence of exogenous 24S-HC application, and 25-HC exhibited NMDAR-dependent/24S-HC-dependent neuroprotection, as well as NMDAR-independent neuroprotection in rat tissue but not mouse tissue. Our findings suggest that both endogenous and exogenous 24S-HC exacerbate OGD-induced damage via NMDAR activation, while 25-HC exhibits species dependent neuroprotection through both NMDAR-dependent and independent mechanisms. PMID- 28346483 TI - Effect of miR-146 targeted HDMCP up-regulation in the pathogenesis of nonalcoholic steatohepatitis. AB - BACKGROUNDS/AIMS: Mitochondrial dysfunction plays an important role inthe pathogenesis of nonalcoholic steatohepatitis (NASH), where uncoupling protein (UCP) is actively involved. We previously reported the uncoupling activity of HDMCP and its role in liver steatosis. We now aim to investigate the degree and therapeutic effect of HDMCP in NASH and the regulatory role of miR-146 on HDMCP. METHODS: NASH animal model was established by feeding BALB/c mice with MCD diet while L02 cell was cultured with high concentration of fatty acid (HFFA) for 72h to mimic the steatosis and inflammation of NASH in-vitro appearance. The steatosis level was assessed by H-E/oil-red staining and serum/supernatant marker detection. The inflammation activity was evaluated by levels of Hepatic activity index, transwell, apoptosis degree (TUNEL/flow cytometry) and serum/supernatant marker. HDMCP level was detected by western blot and miRNA expression was tested by qRT-PCR. NASH severity change was recorded after RNA interference while the regulatory role of miR-146 on HDMCP was confirmed by dual luciferase report system. The H2O2 and ATP levels were measured for mechanism exploration. RESULTS: Increased HDMCP expression was identified in NASH animal model and HFFA-72h cultured L02 cell. Moreover, under regulation of miR-146, NASH alleviation was achieved after HDMCP downregulation in both in vivo and in vitro, according to the declination of steatosis and inflammation related markers. Though H2O2 and ATP levels were increased and decreased in NASH models, HDMCP down regulation both increased their levels. CONCLUSIONS: The miR-146-HDMCP-ATP/H2O2 pathway may provide novel mechanism and treatment option for NASH. PMID- 28346484 TI - A Neighborhood-Wide Association Study (NWAS): Example of prostate cancer aggressiveness. AB - PURPOSE: Cancer results from complex interactions of multiple variables at the biologic, individual, and social levels. Compared to other levels, social effects that occur geospatially in neighborhoods are not as well-studied, and empiric methods to assess these effects are limited. We propose a novel Neighborhood-Wide Association Study(NWAS), analogous to genome-wide association studies(GWAS), that utilizes high-dimensional computing approaches from biology to comprehensively and empirically identify neighborhood factors associated with disease. METHODS: Pennsylvania Cancer Registry data were linked to U.S. Census data. In a successively more stringent multiphase approach, we evaluated the association between neighborhood (n = 14,663 census variables) and prostate cancer aggressiveness(PCA) with n = 6,416 aggressive (Stage>=3/Gleason grade>=7 cases) vs. n = 70,670 non-aggressive (Stage<3/Gleason grade<7) cases in White men. Analyses accounted for age, year of diagnosis, spatial correlation, and multiple testing. We used generalized estimating equations in Phase 1 and Bayesian mixed effects models in Phase 2 to calculate odds ratios(OR) and confidence/credible intervals(CI). In Phase 3, principal components analysis grouped correlated variables. RESULTS: We identified 17 new neighborhood variables associated with PCA. These variables represented income, housing, employment, immigration, access to care, and social support. The top hits or most significant variables related to transportation (OR = 1.05;CI = 1.001-1.09) and poverty (OR = 1.07;CI = 1.01 1.12). CONCLUSIONS: This study introduces the application of high-dimensional, computational methods to large-scale, publically-available geospatial data. Although NWAS requires further testing, it is hypothesis-generating and addresses gaps in geospatial analysis related to empiric assessment. Further, NWAS could have broad implications for many diseases and future precision medicine studies focused on multilevel risk factors of disease. PMID- 28346485 TI - Identification and discrimination of Toxoplasma gondii, Sarcocystis spp., Neospora spp., and Cryptosporidium spp. by righ-resolution melting analysis. AB - The objective of this study was to standardize the high-resolution melting method for identification and discrimination of Toxoplasma gondii, Sarcocystis spp., Neospora spp., and Cryptosporidium spp. by amplification of 18S ribosomal DNA (rDNA) using a single primer pair. The analyses were performed on individual reactions (containing DNA from a single species of a protozoan), on duplex reactions (containing DNA from two species of protozoa in each reaction), and on a multiplex reaction (containing DNA of four parasites in a single reaction). The proposed method allowed us to identify and discriminate the four species by analyzing the derivative, normalized, and difference melting curves, with high reproducibility among and within the experiments, as demonstrated by low coefficients of variation (less than 2.2% and 2.0%, respectively). This is the first study where this method is used for discrimination of these four species of protozoa in a single reaction. PMID- 28346486 TI - GREM1 is expressed in the cancer-associated myofibroblasts of basal cell carcinomas. AB - Cancer-associated fibroblasts (CAFs) play important roles in cancer progression through their complex interactions with cancer cells. The secreted bone morphogenetic protein antagonist, gremlin1 (GREM1) is expressed by the CAFs of basal cell carcinomas (BCCs), and promotes the growth of cancer cells. In this study, we investigated the expression of GREM1 mRNAs in various benign and malignant skin tumors, including various BCC subtypes. Analysis by RNA in situ hybridization (ISH) revealed that fibroblasts in the scar tissue expressed GREM1 and alpha-smooth muscle actin (alpha-SMA), whereas resident fibroblasts in the dermis of the normal skin did not express GREM1. Real-time polymerase chain reaction analysis showed significantly higher GREM1 expression in skin cancers and pilomatricomas (PMCs) than in other benign skin tumors. Tissue microarrays analyzed by RNA ISH for GREM1 expression also demonstrated that 23% of BCCs, 42% of squamous cell carcinomas, 20% of melanomas, and 90% of PMCs were positive for GREM1 expression, whereas trichoepitheliomas, eccrine poromas, hidradenomas, and spiradenomas were negative for GREM1 expression. Most BCCs that were GREM1 expression positive were of desmoplastic or mixed subtypes, and GREM1 expression was localized to activated myofibroblasts at the tumoral-stromal interface. Interestingly, most PMCs harbored GREM1-expressing fibroblasts, probably because of the inflammatory responses caused by foreign body reactions to keratin. Additionally, in BCCs, stromal GREM1 expression had a strong correlation with CD10 expression. In conclusion, GREM1 is frequently expressed by myofibroblasts in scars or in the stroma of basal cell carcinomas, suggesting that GREM1 expression can be a marker for activated myofibroblasts in the cancer stroma or in scar tissue. PMID- 28346487 TI - ML2Motif-Reliable extraction of discriminative sequence motifs from learning machines. AB - High prediction accuracies are not the only objective to consider when solving problems using machine learning. Instead, particular scientific applications require some explanation of the learned prediction function. For computational biology, positional oligomer importance matrices (POIMs) have been successfully applied to explain the decision of support vector machines (SVMs) using weighted degree (WD) kernels. To extract relevant biological motifs from POIMs, the motifPOIM method has been devised and showed promising results on real-world data. Our contribution in this paper is twofold: as an extension to POIMs, we propose gPOIM, a general measure of feature importance for arbitrary learning machines and feature sets (including, but not limited to, SVMs and CNNs) and devise a sampling strategy for efficient computation. As a second contribution, we derive a convex formulation of motifPOIMs that leads to more reliable motif extraction from gPOIMs. Empirical evaluations confirm the usefulness of our approach on artificially generated data as well as on real-world datasets. PMID- 28346488 TI - Comparison of chest CT findings in nontuberculous mycobacterial diseases vs. Mycobacterium tuberculosis lung disease in HIV-negative patients with cavities. AB - OBJECTIVES: This article focuses on the differences between CT findings of HIV negative patients who have cavities with nontuberculous mycobacteria (NTM) disease and those with Mycobacterium tuberculosis infections (TB). METHODS: We retrospectively reviewed 128 NTM disease patients (79 males and 49 females) with cavities in chest CT, matched for age and gender with 128 TB patients in the same period. Sputum cultures of all patients were positive for pathogens. Two independent chest radiologists evaluated the characteristics of the largest cavity and related factors. RESULTS: Interobserver agreement was excellent (kappa value, 0.853-0.938). Cavity walls in NTM disease were significantly thinner (6.9+/-4 mm vs 10.9+/-6 mm, P<0.001) and more even (the ratio of thickness, 2.6+/ 1 vs 3.7+/-2, P<0.001) than those in TB. The thickening of adjacent pleura next to the cavity was also significantly thicker in NTM than TB (P<0.001). However, in the multivariate analysis, thickening of adjacent pleura was the only significant factor among the representative cavity findings (Odds ratio [OR], 6.49; P<0.001). In addition, ill-defined tree-in-bud nodules (OR, 8.82; P<0.001), number of non-cavitary nodules (>=10mm) (OR, 0.72; P = 0.003), and bronchiectasis in the RUL (OR, 5.3; P = 0.002) were significantly associated ancillary findings with NTM disease in the multivariate analysis. CONCLUSIONS: The major cavities in NTM disease generally have thinner and more even walls than those in TB. When cavities are associated with adjacent pleural thickening, ill-defined satellite tree-in-bud nodules, or fewer non-cavitary nodules >=10 mm, these CT findings are highly suggestive of NTM disease rather than TB. PMID- 28346489 TI - Gonadotropin-releasing hormone receptor (Gnrhr) gene knock out: Normal growth and development of sensory, motor and spatial orientation behavior but altered metabolism in neonatal and prepubertal mice. AB - Gonadotropin-releasing hormone (GnRH) is important in the control of reproduction, but its actions in non-reproductive processes are less well known. In this study we examined the effect of disrupting the GnRH receptor in mice to determine if growth, metabolism or behaviors that are not associated with reproduction were affected. To minimize the effects of other hormones such as FSH, LH and sex steroids, the neonatal-prepubertal period of 2 to 28 days of age was selected. The study shows that regardless of sex or phenotype in the Gnrhr gene knockout line, there was no significant difference in the daily development of motor control, sensory detection or spatial orientation among the wildtype, heterozygous or null mice. This included a series of behavioral tests for touch, vision, hearing, spatial orientation, locomotory behavior and muscle strength. Neither the daily body weight nor the final weight on day 28 of the kidney, liver and thymus relative to body weight varied significantly in any group. However by day 28, metabolic changes in the GnRH null females compared with wildtype females showed a significant reduction in inguinal fat pad weight normalized to body weight; this was accompanied by an increase in glucose compared with wildtype females shown by Student-Newman-Keuls Multiple Comparison test and Student's unpaired t tests. Our studies show that the GnRH-GnRHR system is not essential for growth or motor/sensory/orientation behavior during the first month of life prior to puberty onset. The lack of the GnRH-GnRHR axis, however, did affect females resulting in reduced subcutaneous inguinal fat pad weight and increased glucose with possible insulin resistance; the loss of the normal rise of estradiol at postnatal days 15-28 may account for the altered metabolism in the prepubertal female pups. PMID- 28346490 TI - Effect of HIV and malaria parasites co-infection on immune-hematological profiles among patients attending anti-retroviral treatment (ART) clinic in Infectious Disease Hospital Kano, Nigeria. AB - BACKGROUND: Human immunodeficiency virus (HIV) and malaria co-infection may present worse health outcomes in the tropics. Information on HIV/malaria co infection effect on immune-hematological profiles is critical for patient care and there is a paucity of such data in Nigeria. OBJECTIVE: To evaluate immune hematological profiles among HIV infected patients compared to HIV/malaria co infected for ART management improvement. METHODS: This was a cross sectional study conducted at Infectious Disease Hospital, Kano. A total of 761 consenting adults attending ART clinic were randomly selected and recruited between June and December 2015. Participants' characteristics and clinical details including two previous CD4 counts were collected. Venous blood sample (4ml) was collected in EDTA tube for malaria parasite diagnosis by rapid test and confirmed with microscopy. Hematological profiles were analyzed by Sysmex XP-300 and CD4 count by Cyflow cytometry. Data was analyzed with SPSS 22.0 using Chi-Square test for association between HIV/malaria parasites co-infection with age groups, gender, ART, cotrimoxazole and usage of treated bed nets. Mean hematological profiles by HIV/malaria co-infection and HIV only were compared using independent t-test and mean CD4 count tested by mixed design repeated measures ANOVA. Statistical significant difference at probability of <0.05 was considered for all variables. RESULTS: Of the 761 HIV infected, 64% were females, with a mean age of +/- (SD) 37.30 (10.4) years. Prevalence of HIV/malaria co-infection was 27.7% with Plasmodium falciparum specie accounting for 99.1%. No statistical significant difference was observed between HIV/malaria co-infection in association to age (p = 0.498) and gender (p = 0.789). A significantly (p = 0.026) higher prevalence (35.2%) of co-infection was observed among non-ART patients compared to (26%) ART patients. Prevalence of co-infection was significantly lower (20.0%) among cotrimoxazole users compared to those not on cotrimoxazole (37%). The same significantly lower co-infection prevalence (22.5%) was observed among treated bed net users compared to those not using treated bed nets (42.9%) (p = 0.001). Out of 16 hematology profiles evaluated, six showed significant difference between the two groups (i) packed cell volume (p = <0.001), (ii) mean cell volume (p = 0.005), (iii) mean cell hemoglobin concentration (p = 0.011), (iv) absolute lymphocyte count (p = 0.022), (v) neutrophil percentage count (p = 0.020) and (vi) platelets distribution width (p = <0.001). Current mean CD4 count cell/MUl (349+/-12) was significantly higher in HIV infected only compared to co-infected (306+/-17), (p = 0.035). A significantly lower mean CD4 count (234.6 +/- 6.9) was observed among respondents on ART compared to non-ART (372.5 +/- 13.2), p<0.001, mean difference = -137.9). CONCLUSION: The study revealed a high burden of HIV and malaria co-infection among the studied population. Co-infection was significantly lower among patients who use treated bed nets as well as cotrimoxazole chemotherapy and ART. Six hematological indices differed significantly between the two groups. Malaria and HIV co-infection significantly reduces CD4 count. In general, to achieve better management of all HIV patients in this setting, diagnosing malaria, prompt antiretroviral therapy, monitoring CD4 and some hematology indices on regular basis is critical. PMID- 28346492 TI - Dual energy X-ray absorptiometry body composition reference values of limbs and trunk from NHANES 1999-2004 with additional visualization methods. AB - Body Mass Index has traditionally been used as a measure of health, but Fat Mass Index (FMI) and Lean Mass Index (LMI) have been shown to be more predictive of mortality and health risk. Total body FMI and LMI reference curves have particularly been useful in quantifying sarcopenia and sarcopenic obesity. Research has shown regional composition has significant associations to health outcomes. We derived FMI and LMI reference curves of the regions of the body (leg, arm, and trunk) for 15,908 individuals in the 1999-2004 National Health and Nutrition Examination Survey data for each sex and ethnicity using the Lambda-Mu Sigma (LMS) method and developed software to visualize this regional composition. These reference curves displayed differentiation between males and females during puberty and sharper limb LMI declines during late adulthood for males. For adults ages 30-50, females had 39%, 83%, and 47% larger arm, leg, and trunk FMI values than males, respectively. Males had 49%, 20%, and 15% higher regional LMI values than females for the arms, legs, and trunk respectively. The leg FMI and LMI of black females were 14% and 15% higher respectively than those of Hispanic and white females. White and Hispanic males had 37% higher trunk FMI values than black males. Hispanic females had 20% higher trunk FMI than white and black females. These data underscore the importance of accounting for sex and ethnicity in studies of regional composition. This study is the first to produce regional LMI and FMI reference tables and curves from the NHANES dataset. These reference curves provide a framework useful in studies and research involving sarcopenia, obesity, sarcopenic obesity, and other studies of compositional phenotypes. Further, the software tool we provide for visualizing regional composition will prove useful in monitoring progress in physical therapy, diets, or other attempts to attain healthier compositions. PMID- 28346494 TI - The effects of surface structure mutations in Arabidopsis thaliana on the polarization of reflections from virus-infected leaves. AB - The way in which light is polarized when reflected from leaves can be affected by infection with plant viruses. This has the potential to influence viral transmission by insect vectors due to altered visual attractiveness of infected plants. The optical and topological properties of cuticular waxes and trichomes are important determinants of how light is polarized upon reflection. Changes in expression of genes involved in the formation of surface structures have also been reported following viral infection. This paper investigates the role of altered surface structures in virus-induced changes to polarization reflection from leaves. The percentage polarization of reflections from Arabidopsis thaliana cer5, cer6 and cer8 wax synthesis mutants, and the gl1 leaf hair mutant, was compared to those from wild-type (WT) leaves. The cer5 mutant leaves were less polarizing than WT on the adaxial and abaxial surfaces; gl1 leaves were more polarizing than WT on the adaxial surfaces. The cer6 and cer8 mutations did not significantly affect polarization reflection. The impacts of Turnip vein clearing virus (TVCV) infection on the polarization of reflected light were significantly affected by cer5 mutation, with the reflections from cer5 mutants being higher than those from WT leaves, suggesting that changes in CER5 expression following infection could influence the polarization of the reflections. There was, however, no significant effect of the gl1 mutation on polarization following TVCV infection. The cer5 and gl1 mutations did not affect the changes in polarization following Cucumber mosaic virus (CMV) infection. The accumulation of TVCV and CMV did not differ significantly between mutant and WT leaves, suggesting that altered expression of surface structure genes does not significantly affect viral titres, raising the possibility that if such regulatory changes have any adaptive value it may possibly be through impacts on viral transmission. PMID- 28346491 TI - A genetic switch controls the production of flagella and toxins in Clostridium difficile. AB - In the human intestinal pathogen Clostridium difficile, flagella promote adherence to intestinal epithelial cells. Flagellar gene expression also indirectly impacts production of the glucosylating toxins, which are essential to diarrheal disease development. Thus, factors that regulate the expression of the flgB operon will likely impact toxin production in addition to flagellar motility. Here, we report the identification a "flagellar switch" that controls the phase variable production of flagella and glucosylating toxins. The flagellar switch, located upstream of the flgB operon containing the early stage flagellar genes, is a 154 bp invertible sequence flanked by 21 bp inverted repeats. Bacteria with the sequence in one orientation expressed flagellum and toxin genes, produced flagella, and secreted the toxins ("flg phase ON"). Bacteria with the sequence in the inverse orientation were attenuated for flagellar and toxin gene expression, were aflagellate, and showed decreased toxin secretion ("flg phase OFF"). The orientation of the flagellar switch is reversible during growth in vitro. We provide evidence that gene regulation via the flagellar switch occurs post-transcription initiation and requires a C. difficile-specific regulatory factor to destabilize or degrade the early flagellar gene mRNA when the flagellar switch is in the OFF orientation. Lastly, through mutagenesis and characterization of flagellar phase locked isolates, we determined that the tyrosine recombinase RecV, which catalyzes inversion at the cwpV switch, is also responsible for inversion at the flagellar switch in both directions. Phase variable flagellar motility and toxin production suggests that these important virulence factors have both advantageous and detrimental effects during the course of infection. PMID- 28346493 TI - Aberrant neuronal activity-induced signaling and gene expression in a mouse model of RASopathy. AB - Noonan syndrome (NS) is characterized by reduced growth, craniofacial abnormalities, congenital heart defects, and variable cognitive deficits. NS belongs to the RASopathies, genetic conditions linked to mutations in components and regulators of the Ras signaling pathway. Approximately 50% of NS cases are caused by mutations in PTPN11. However, the molecular mechanisms underlying cognitive impairments in NS patients are still poorly understood. Here, we report the generation and characterization of a new conditional mouse strain that expresses the overactive Ptpn11D61Y allele only in the forebrain. Unlike mice with a global expression of this mutation, this strain is viable and without severe systemic phenotype, but shows lower exploratory activity and reduced memory specificity, which is in line with a causal role of disturbed neuronal Ptpn11 signaling in the development of NS-linked cognitive deficits. To explore the underlying mechanisms we investigated the neuronal activity-regulated Ras signaling in brains and neuronal cultures derived from this model. We observed an altered surface expression and trafficking of synaptic glutamate receptors, which are crucial for hippocampal neuronal plasticity. Furthermore, we show that the neuronal activity-induced ERK signaling, as well as the consecutive regulation of gene expression are strongly perturbed. Microarray-based hippocampal gene expression profiling revealed profound differences in the basal state and upon stimulation of neuronal activity. The neuronal activity-dependent gene regulation was strongly attenuated in Ptpn11D61Y neurons. In silico analysis of functional networks revealed changes in the cellular signaling beyond the dysregulation of Ras/MAPK signaling that is nearly exclusively discussed in the context of NS at present. Importantly, changes in PI3K/AKT/mTOR and JAK/STAT signaling were experimentally confirmed. In summary, this study uncovers aberrant neuronal activity-induced signaling and regulation of gene expression in Ptpn11D61Y mice and suggests that these deficits contribute to the pathophysiology of cognitive impairments in NS. PMID- 28346495 TI - The incidence and prevalence of pterygium in South Korea: A 10-year population based Korean cohort study. AB - Although numerous population-based studies have reported the prevalences and risk factors for pterygium, information regarding the incidence of pterygium is scarce. This population-based cohort study aimed to evaluate the South Korean incidence and prevalence of pterygium. We retrospectively obtained data from a nationally representative sample of 1,116,364 South Koreans in the Korea National Health Insurance Service National Sample Cohort (NHIS-NSC). The associated sociodemographic factors were evaluated using multivariable Cox regression analysis, and the hazard ratios and confidence intervals were calculated. Pterygium was defined based on the Korean Classification of Diseases code, and surgically removed pterygium was defined as cases that required surgical removal. We identified 21,465 pterygium cases and 8,338 surgically removed pterygium cases during the study period. The overall incidences were 2.1 per 1,000 person-years for pterygium and 0.8 per 1,000 person-years for surgically removed pterygium. Among subjects who were >=40 years old, the incidences were 4.3 per 1,000 person years for pterygium and 1.7 per 1,000 person-years for surgically removed pterygium. The overall prevalences were 1.9% for pterygium and 0.6% for surgically removed pterygium, and the prevalences increased to 3.8% for pterygium and 1.4% for surgically removed pterygium among subjects who were >=40 years old. The incidences of pterygium decreased according to year. The incidence and prevalence of pterygium were highest among 60-79-year-old individuals. Increasing age, female sex, and living in a relatively rural area were associated with increased risks of pterygium and surgically removed pterygium in the multivariable Cox regression analysis. Our analyses of South Korean national insurance claims data revealed a decreasing trend in the incidence of pterygium during the study period. PMID- 28346497 TI - Determinants of infant nutritional status in Dabat district, North Gondar, Ethiopia: A case control study. AB - BACKGROUND: Malnutrition is the top cause of global burden of disease, disability and mortality among infants. Over two-thirds of deaths of children globally occur during the first year of life (infancy). Malnutrition among infants is substantially high in Ethiopia. Therefore, this study is aimed to assess determinants of infant nutritional status. METHODS: A community based nested case control study was conducted from February to June 2013 in Dabat district. A total of 80 cases and 320 controls (1:4 ratios) were studied. Relevant data was extracted from the community based survey data set. Anthroplus software was used to identify cases and controls. Determinants of infant nutritional status were identified using multivariate analysis. RESULTS: Among the total of 80 cases and 320 controls, more than half (52.5%) of the cases and the controls (53.8%) were males and females, respectively. Breast Feeding (BF) was started immediately after birth in only 43.8% of the cases. Nearly 94% of the mothers of the cases had no breast feeding information as part of Ante Natal Care (ANC) follow up. Maternal age (AOR: 0.29; 95% CI: 0.11-0.76), having radio (AOR: 0.43; 95% CI: 0.22-0.82), lack of toilet facility (AOR: 2.24; 95% CI: 1.16-4.33), deprivation of colostrum (AOR: 1.76; 95% CI: 1.01-1.06) and method of complementary feeding (AOR: 2.82; 95% CI: 1.33-5.99) were associated with wasting. CONCLUSIONS: This study has found that inappropriate infant feeding; nutritional information gap and lack of toilet facility as significant predictors of malnutrition. Hence, joint interventions, including counseling of mothers about benefits of colostrum feeding and use of appropriate feeding method, toilet utilization and mass media such as radio possession, are needed to address the problem in Dabat district. PMID- 28346499 TI - A farm-level precision land management framework based on integer programming. AB - Farmland management involves several planning and decision making tasks including seed selection and irrigation management. A farm-level precision farmland management model based on mixed integer linear programming is proposed in this study. Optimal decisions are designed for pre-season planning of crops and irrigation water allocation. The model captures the effect of size and shape of decision scale as well as special irrigation patterns. The authors illustrate the model with a case study on a farm in the state of California in the U.S. and show the model can capture the impact of precision farm management on profitability. The results show that threefold increase of annual net profit for farmers could be achieved by carefully choosing irrigation and seed selection. Although farmers could increase profits by applying precision management to seed or irrigation alone, profit increase is more significant if farmers apply precision management on seed and irrigation simultaneously. The proposed model can also serve as a risk analysis tool for farmers facing seasonal irrigation water limits as well as a quantitative tool to explore the impact of precision agriculture. PMID- 28346498 TI - Characteristics of seasonal influenza A and B in Latin America: Influenza surveillance data from ten countries. AB - INTRODUCTION: The increased availability of influenza surveillance data in recent years justifies an actual and more complete overview of influenza epidemiology in Latin America. We compared the influenza surveillance systems and assessed the epidemiology of influenza A and B, including the spatio-temporal patterns of influenza epidemics, in ten countries and sub-national regions in Latin America. METHODS: We aggregated the data by year and country and characteristics of eighty two years were analysed. We calculated the median proportion of laboratory confirmed influenza cases caused by each virus strain, and compared the timing and amplitude of the primary and secondary peaks between countries. RESULTS: 37,087 influenza cases were reported during 2004-2012. Influenza A and B accounted for a median of 79% and, respectively, 21% of cases in a year. The percentage of influenza A cases that were subtyped was 82.5%; for influenza B, 15.6% of cases were characterized. Influenza A and B were dominant in seventy five (91%) and seven (9%) years, respectively. In half (51%) of the influenza A years, influenza A(H3N2) was dominant, followed by influenza A(H1N1)pdm2009 (41%) and pre-pandemic A(H1N1) (8%). The primary peak of influenza activity was in June September in temperate climate countries, with little or no secondary peak. Tropical climate countries had smaller primary peaks taking place in different months and frequently detectable secondary peaks. CONCLUSIONS: We found that good influenza surveillance data exists in Latin America, although improvements can still be made (e.g. a better characterization of influenza B specimens); that influenza B plays a considerable role in the seasonal influenza burden; and that there is substantial heterogeneity of spatio-temporal patterns of influenza epidemics. To improve the effectiveness of influenza control measures in Latin America, tropical climate countries may need to develop innovative prevention strategies specifically tailored to the spatio-temporal patterns of influenza in this region. PMID- 28346500 TI - Night-time lights: A global, long term look at links to socio-economic trends. AB - We use a parallelized spatial analytics platform to process the twenty-one year totality of the longest-running time series of night-time lights data-the Defense Meteorological Satellite Program (DMSP) dataset-surpassing the narrower scope of prior studies to assess changes in area lit of countries globally. Doing so allows a retrospective look at the global, long-term relationships between night time lights and a series of socio-economic indicators. We find the strongest correlations with electricity consumption, CO2 emissions, and GDP, followed by population, CH4 emissions, N2O emissions, poverty (inverse) and F-gas emissions. Relating area lit to electricity consumption shows that while a basic linear model provides a good statistical fit, regional and temporal trends are found to have a significant impact. PMID- 28346496 TI - Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies. AB - Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype. PMID- 28346501 TI - A tissue-specific role for intraflagellar transport genes during craniofacial development. AB - Primary cilia are nearly ubiquitous, cellular projections that function to transduce molecular signals during development. Loss of functional primary cilia has a particularly profound effect on the developing craniofacial complex, causing several anomalies including craniosynostosis, micrognathia, midfacial dysplasia, cleft lip/palate and oral/dental defects. Development of the craniofacial complex is an intricate process that requires interactions between several different tissues including neural crest cells, neuroectoderm and surface ectoderm. To understand the tissue-specific requirements for primary cilia during craniofacial development we conditionally deleted three separate intraflagellar transport genes, Kif3a, Ift88 and Ttc21b with three distinct drivers, Wnt1-Cre, Crect and AP2-Cre which drive recombination in neural crest, surface ectoderm alone, and neural crest, surface ectoderm and neuroectoderm, respectively. We found that tissue-specific conditional loss of ciliary genes with different functions produces profoundly different facial phenotypes. Furthermore, analysis of basic cellular behaviors in these mutants suggests that loss of primary cilia in a distinct tissue has unique effects on development of adjacent tissues. Together, these data suggest specific spatiotemporal roles for intraflagellar transport genes and the primary cilium during craniofacial development. PMID- 28346503 TI - External validity of randomized controlled trials in older adults, a systematic review. AB - BACKGROUND: To critically assess the external validity of randomized controlled trials (RCTs) it is important to know what older adults have been enrolled in the trials. The aim of this systematic review is to study what proportion of trials specifically designed for older patients report on somatic status, physical and mental functioning, social environment and frailty in the patient characteristics. METHODS: PubMed was searched for articles published in 2012 and only RCTs were included. Articles were further excluded if not conducted with humans or only secondary analyses were reported. A random sample of 10% was drawn. The current review analyzed this random sample and further selected trials when the reported mean age was >= 60 years. We extracted geriatric assessments from the population descriptives or the in- and exclusion criteria. RESULTS: In total 1396 trials were analyzed and 300 trials included. The median of the reported mean age was 66 (IQR 63-70) and the median percentage of men in the trials was 60 (IQR 45-72). In 34% of the RCTs specifically designed for older patients somatic status, physical and mental functioning, social environment or frailty were reported in the population descriptives or the in- and exclusion criteria. Physical and mental functioning was reported most frequently (22% and 14%). When selecting RCTs on a mean age of 70 or 80 years the report of geriatric assessments in the patient characteristics was 46% and 85% respectively but represent only 5% and 1% of the trials. CONCLUSION: Somatic status, physical and mental functioning, social environment and frailty are underreported even in RCTs specifically designed for older patients published in 2012. Therefore, it is unclear for clinicians to which older patients the results can be applied. We recommend systematic to transparently report these relevant characteristics of older participants included in RCTs. PMID- 28346502 TI - EBV induces persistent NF-kappaB activation and contributes to survival of EBV positive neoplastic T- or NK-cells. AB - Epstein-Barr virus (EBV) has been detected in several T- and NK-cell neoplasms such as extranodal NK/T-cell lymphoma nasal type, aggressive NK-cell leukemia, EBV-positive peripheral T-cell lymphoma, systemic EBV-positive T-cell lymphoma of childhood, and chronic active EBV infection (CAEBV). However, how this virus contributes to lymphomagenesis in T or NK cells remains largely unknown. Here, we examined NF-kappaB activation in EBV-positive T or NK cell lines, SNT8, SNT15, SNT16, SNK6, and primary EBV-positive and clonally proliferating T/NK cells obtained from the peripheral blood of patients with CAEBV. Western blotting, electrophoretic mobility shift assays, and immunofluorescent staining revealed persistent NF-kappaB activation in EBV-infected cell lines and primary cells from patients. Furthermore, we investigated the role of EBV in infected T cells. We performed an in vitro infection assay using MOLT4 cells infected with EBV. The infection directly induced NF-kappaB activation, promoted survival, and inhibited etoposide-induced apoptosis in MOLT4 cells. The luciferase assay suggested that LMP1 mediated NF-kappaB activation in MOLT4 cells. IMD-0354, a specific inhibitor of NF-kappaB that suppresses NF-kappaB activation in cell lines, inhibited cell survival and induced apoptosis. These results indicate that EBV induces NF-kappaB mediated survival signals in T and NK cells, and therefore, may contribute to the lymphomagenesis of these cells. PMID- 28346504 TI - Diagnostic accuracy of two multiplex real-time polymerase chain reaction assays for the diagnosis of meningitis in children in a resource-limited setting. AB - INTRODUCTION: Accurate etiological diagnosis of meningitis is important, but difficult in resource-limited settings due to prior administration of antibiotics and lack of viral diagnostics. We aimed to develop and validate 2 real-time multiplex PCR (RT-PCR) assays for the detection of common causes of community acquired bacterial and viral meningitis in South African children. METHODS: We developed 2 multiplex RT- PCRs for detection of S. pneumoniae, N. meningitidis, H. influenzae, enteroviruses, mumps virus and herpes simplex virus. We tested residual CSF samples from children presenting to a local paediatric hospital over a one-year period, whose CSF showed an abnormal cell count. Results were compared with routine diagnostic tests and the final discharge diagnosis. We calculated accuracy of the bacterial RT-PCR assay compared to CSF culture and using World Health Organisation definitions of laboratory-confirmed bacterial meningitis. RESULTS: From 292 samples, bacterial DNA was detected in 12 (4.1%) and viral nucleic acids in 94 (32%). Compared to CSF culture, the sensitivity and specificity of the bacterial RT-PCR was 100% and 97.2% with complete agreement in organism identification. None of the cases positive by viral RT-PCR had a bacterial cause confirmed on CSF culture. Only 9/90 (10%) of patients diagnosed clinically as bacterial meningitis or partially treated bacterial meningitis tested positive with the bacterial RT-PCR. DISCUSSION: In this population the use of 2 multiplex RT-PCRs targeting 6 common pathogens gave promising results. If introduced into routine diagnostic testing, these multiplex RT-PCR assays would supplement other diagnostic tests, and have the potential to limit unnecessary antibiotic therapy and hospitalisation. PMID- 28346505 TI - Long-duration effect of multi-factor stresses on the cellular biochemistry, oil yielding performance and morphology of Nannochloropsis oculata. AB - Microalga Nannochloropsis oculata is a promising alternative feedstock for biodiesel. Elevating its oil-yielding capacity is conducive to cost-saving biodiesel production. However, the regulatory processes of multi-factor collaborative stresses (MFCS) on the oil-yielding performance of N. oculata are unclear. The duration effects of MFCS (high irradiation, nitrogen deficiency and elevated iron supplementation) on N. oculata were investigated in an 18-d batch culture. Despite the reduction in cell division, the biomass concentration increased, resulting from the large accumulation of the carbon/energy-reservoir. However, different storage forms were found in different cellular storage compounds, and both the protein content and pigment composition swiftly and drastically changed. The analysis of four biodiesel properties using pertinent empirical equations indicated their progressive effective improvement in lipid classes and fatty acid composition. The variation curve of neutral lipid productivity was monitored with fluorescent Nile red and was closely correlated to the results from conventional methods. In addition, a series of changes in the organelles (e.g., chloroplast, lipid body and vacuole) and cell shape, dependent on the stress duration, were observed by TEM and LSCM. These changes presumably played an important role in the acclimation of N. oculata to MFCS and accordingly improved its oil-yielding performance. PMID- 28346506 TI - Specific expression of novel long non-coding RNAs in high-hyperdiploid childhood acute lymphoblastic leukemia. AB - Pre-B cell childhood acute lymphoblastic leukemia (pre-B cALL) is a heterogeneous disease involving many subtypes typically stratified using a combination of cytogenetic and molecular-based assays. These methods, although widely used, rely on the presence of known chromosomal translocations, which is a limiting factor. There is therefore a need for robust, sensitive, and specific molecular biomarkers unaffected by such limitations that would allow better risk stratification and consequently better clinical outcome. In this study we performed a transcriptome analysis of 56 pre-B cALL patients to identify expression signatures in different subtypes. In both protein-coding and long non coding RNAs (lncRNA), we identified subtype-specific gene signatures distinguishing pre-B cALL subtypes, particularly in t(12;21) and hyperdiploid cases. The genes up-regulated in pre-B cALL subtypes were enriched in bivalent chromatin marks in their promoters. LncRNAs is a new and under-studied class of transcripts. The subtype-specific nature of lncRNAs suggests they may be suitable clinical biomarkers to guide risk stratification and targeted therapies in pre-B cALL patients. PMID- 28346507 TI - Olive oil bioactives protect pigs against experimentally-induced chronic inflammation independently of alterations in gut microbiota. AB - Subclinical chronic inflammation (SCI) is associated with impaired animal growth. Previous work has demonstrated that olive-derived plant bioactives exhibit anti inflammatory properties that could possibly counteract the growth-depressing effects of SCI. To test this hypothesis and define the underlying mechanism, we conducted a 30-day study in which piglets fed an olive-oil bioactive extract (OBE) and their control counterparts (C+) were injected repeatedly during the last 10 days of the study with increasing doses of Escherichia coli lipopolysaccharides (LPS) to induce SCI. A third group of piglets remained untreated throughout the study and served as a negative control (C-). In C+ pigs, SCI increased the circulating concentration of interleukin 1 beta (p < 0.001) and decreased feed ingestion (p < 0.05) and weight gain (p < 0.05). These responses were not observed in OBE animals. Although intestinal inflammation and colonic microbial ecology was not altered by treatments, OBE enhanced ileal mRNA abundance of tight and adherens junctional proteins (p < 0.05) and plasma recovery of mannitol (p < 0.05) compared with C+ and C-. In line with these findings, OBE improved transepithelial electrical resistance (p < 0.01) in TNF alpha-challenged Caco-2/TC-7 cells, and repressed the production of inflammatory cytokines (p < 0.05) in LPS-stimulated macrophages. In summary, this work demonstrates that OBE attenuates the suppressing effect of SCI on animal growth through a mechanism that appears to involve improvements in intestinal integrity unrelated to alterations in gut microbial ecology and function. PMID- 28346508 TI - Most women recover from psychological distress after postoperative complications following implant or DIEP flap breast reconstruction: A prospective long-term follow-up study. AB - BACKGROUND: Substantial complication rates after postmastectomy breast reconstruction (BR) in breast cancer patients have been reported. Few studies have reported on the resulting psychological distress (PD) and satisfaction with the aesthetic result in relation to postoperative complications after completion of implant or DIEP flap BR. The present study investigated whether women were able to recover from complication related distress in the long term. METHODS: PD was prospectively measured using questionnaires regarding anxiety, depression and cancer distress. Eligible patients completed questionnaires before BR (T0, n = 144), after one month (T1, n = 139) and after completion of BR, approximately 21 months after initial reconstructive surgery (T2, n = 119). Satisfaction with the aesthetic result was assessed 21 months after BR. Data concerning complications, subsequent additional surgery and total reconstruction failure up to T2 were collected from the medical records. Analyses were performed using multi-level regression analyses correcting for age. RESULTS: One or more complications occurred in 61 patients (42%) and 50 women required subsequent surgery (35%). In time, mean PD significantly declined towards baseline scores independent of complications. However, a total reconstruction failure (n = 10) was significantly associated with a large temporary increase in depression scores. After additional surgery due to complications patients were less satisfied with aesthetic outcome, although patient satisfaction was independent of PD. CONCLUSIONS: PD outcomes generally declined to normal levels after completion of the entire BR course. Patients experiencing a total reconstruction failure reported more depression after this loss, but in the long term recovered to the same level as women without complications. These findings indicate that women generally can cope efficiently with these serious adverse events, even if they were less satisfied with the aesthetic result. PMID- 28346510 TI - Study on the biodegradation of crude oil by free and immobilized bacterial consortium in marine environment. AB - Five strains of bacteria, namely, Exiguobacterium sp. ASW-1, Pseudomonas aeruginosa strain ASW-2, Alcaligenes sp. ASW-3, Alcaligenes sp. ASS-1, and Bacillus sp. ASS-2, were isolated from the Zhejiang coast in China. The mixed flora of the five strains performed well with degrading 75.1% crude oil (1%, w/v) in 7 days. The calcium alginate-activated carbon embedding carrier was used to immobilize bacterial consortium. Immobilized cells performed better than free ones in variations of environmental factors containing incubated temperature, initial pH, salinity of the medium and crude oil concentration. The degradation process of crude oil by immobilized bacteria was accelerated compared with that of the free ones. Bacterial consortium showed better performance on biodegradation of normal alkanes than that of PAHs. Improvement of immobilization on the biodegradation efficiency of normal alkanes (31.9%) was apparently high than that of PAHs (1.9%). PMID- 28346509 TI - Systematic identification of phosphorylation-mediated protein interaction switches. AB - Proteomics techniques can identify thousands of phosphorylation sites in a single experiment, the majority of which are new and lack precise information about function or molecular mechanism. Here we present a fast method to predict potential phosphorylation switches by mapping phosphorylation sites to protein protein interactions of known structure and analysing the properties of the protein interface. We predict 1024 sites that could potentially enable or disable particular interactions. We tested a selection of these switches and showed that phosphomimetic mutations indeed affect interactions. We estimate that there are likely thousands of phosphorylation mediated switches yet to be uncovered, even among existing phosphorylation datasets. The results suggest that phosphorylation sites on globular, as distinct from disordered, parts of the proteome frequently function as switches, which might be one of the ancient roles for kinase phosphorylation. PMID- 28346511 TI - Is manure an alternative to topsoil in road embankment restoration? AB - One of the main steps in road and railway embankment restoration is the spreading of previously removed topsoil, which provides an input of seeds, organic matter and microorganisms and encourages the establishment of a vegetation cover, essential to stabilise the embankment and blend it with the landscape. However, topsoil is a scarce resource, prompting the search for economic alternatives with similar results. The present study compares the results of spreading topsoil with an organic amendment (manure) for the soil's physico-chemical properties, erosion resistance and microbial activity, floristic richness and composition, and bare soil cover. For this purpose, experimental plots with three treatments (Control, Topsoil and Manure) were maintained on a recently built embankment in Central Spain for 20 months. Manure was found to be an effective alternative to topsoil for the improvement of soil fertility (organic matter content and total nitrogen). The two types of organic amendment produced similar reductions in bare soil cover and erosion rates. However, plots with topsoil showed greater soil respiration and species richness and a different floristic composition in comparison to those treated with manure, which was closer to control plots. These results suggest that manure can be used to replace topsoil to enhance embankment stability during the early stages of restoration. However, if the aim of the restoration process is to promote plant diversity, topsoil is recommended. PMID- 28346512 TI - Bacterial and viral pathogen spectra of acute respiratory infections in under-5 children in hospital settings in Dhaka city. AB - The study aimed to examine for the first time the spectra of viral and bacterial pathogens along with the antibiotic susceptibility of the isolated bacteria in under-5 children with acute respiratory infections (ARIs) in hospital settings of Dhaka, Bangladesh. Nasal swabs were collected from 200 under-five children hospitalized with clinical signs of ARIs. Nasal swabs from 30 asymptomatic children were also collected. Screening of viral pathogens targeted ten respiratory viruses using RT-qPCR. Bacterial pathogens were identified by bacteriological culture methods and antimicrobial susceptibility of the isolates was determined following CLSI guidelines. About 82.5% (n = 165) of specimens were positive for pathogens. Of 165 infected cases, 3% (n = 6) had only single bacterial pathogens, whereas 43.5% (n = 87) cases had only single viral pathogens. The remaining 36% (n = 72) cases had coinfections. In symptomatic cases, human rhinovirus was detected as the predominant virus (31.5%), followed by RSV (31%), HMPV (13%), HBoV (11%), HPIV-3 (10.5%), and adenovirus (7%). Streptococcus pneumoniae was the most frequently isolated bacterial pathogen (9%), whereas Klebsiella pneumaniae, Streptococcus spp., Enterobacter agglomerans, and Haemophilus influenzae were 5.5%, 5%, 2%, and 1.5%, respectively. Of 15 multidrug-resistant bacteria, a Klebsiella pneumoniae isolate and an Enterobacter agglomerans isolate exhibited resistance against more than 10 different antibiotics. Both ARI incidence and predominant pathogen detection rates were higher during post-monsoon and winter, peaking in September. Pathogen detection rates and coinfection incidence in less than 1-year group were significantly higher (P = 0.0034 and 0.049, respectively) than in 1-5 years age group. Pathogen detection rate (43%) in asymptomatic cases was significantly lower compared to symptomatic group (P<0.0001). Human rhinovirus, HPIV-3, adenovirus, Streptococcus pneumonia, and Klebsiella pneumaniae had significant involvement in coinfections with P values of 0.0001, 0.009 and 0.0001, 0.0001 and 0.001 respectively. Further investigations are required to better understand the clinical roles of the isolated pathogens and their seasonality. PMID- 28346513 TI - Cystatin C estimated glomerular filtration rate to assess renal function in early stages of autosomal dominant polycystic kidney disease. AB - BACKGROUND/AIMS: Height-adjusted total kidney volume (htTKV) is the best marker of disease progression in early autosomal dominant polycystic kidney disease (ADPKD) when renal function still remains normal. The usefulness of cystatin-C as a biomarker to assess renal function according to renal volume has not been studied in ADPKD patients. METHODS: Observational and cross-sectional study of 62 ADPKD patients. htTKV, creatinine and cystatin-C estimated glomerular filtration rate (eGFR) were determined. Correlations between htTKV and eGFR were studied. A control group was used to determine the association between renal function differences and htTKV. RESULTS: htTKV significantly correlated with cystatin-C eGFR (r = -0.384, p = 0.002) but not with creatinine-eGFR (r = -0.225, p = 0.078). With htTKV stratified into tertiles, a significant difference of cystatin C-eGFR but not in creatinine-eGFR was detected in the third tertile when compared with the first tertile group (110.0+/-22.2 vs 121.3+/-7.2; p = 0.023 and 101.8+/ 17.2 vs 106.9+/-15.1; p = 0.327 respectively). When cystatin-C-eGFR of the controls was used as the reference, htTKV above 605 ml/m identified with a 75% sensitivity and 84.9% specificity those patients with a significant worse kidney function. However, this cut-off value could not be identified using creatinine eGFR. CONCLUSIONS: Cystatin-C-eGFR but not creatinine-eGFR correlated with htTKV in ADPKD patients in early stages of the disease. Differences in cystatin-C-eGFR but not in creatinine-eGFR have been identified through htTKV tertiles. A htTKV above 605 ml/m is associated with a worse renal function only if cystatin-C-eGFR is used. Cystatin-C-eGFR should be studied in prospective studies of early stages of ADPKD to determine its usefulness as an early marker of disease progression. PMID- 28346514 TI - Valence, arousal, familiarity, concreteness, and imageability ratings for 292 two character Chinese nouns in Cantonese speakers in Hong Kong. AB - Words are frequently used as stimuli in cognitive psychology experiments, for example, in recognition memory studies. In these experiments, it is often desirable to control for the words' psycholinguistic properties because differences in such properties across experimental conditions might introduce undesirable confounds. In order to avoid confounds, studies typically check to see if various affective and lexico-semantic properties are matched across experimental conditions, and so databases that contain values for these properties are needed. While word ratings for these variables exist in English and other European languages, ratings for Chinese words are not comprehensive. In particular, while ratings for single characters exist, ratings for two-character words-which often have different meanings than their constituent characters, are scarce. In this study, ratings for 292 two-character Chinese nouns were obtained from Cantonese speakers in Hong Kong. Affective variables, including valence and arousal, and lexico-semantic variables, including familiarity, concreteness, and imageability, were rated in the study. The words were selected from a film subtitle database containing word frequency information that could be extracted and listed alongside the resulting ratings. Overall, the subjective ratings showed good reliability across all rated dimensions, as well as good reliability within and between the different groups of participants who each rated a subset of the words. Moreover, several well-established relationships between the variables found consistently in other languages were also observed in this study, demonstrating that the ratings are valid. The resulting word database can be used in studies where control for the above psycholinguistic variables is critical to the research design. PMID- 28346515 TI - Gender differences in reward and punishment for monetary and social feedback in children: An ERP study. AB - Gender differences in feedback processing have been observed among adolescents and adults through event-related potentials. However, information on whether and how this feedback processing is affected by feedback valence, feedback type, and individual sensitivity in reward/punishment among children remains minimal. In this study, we used a guessing game task coupled with electroencephalography to investigate gender differences in feedback processing, in which feedback to reward and punishment was presented in the context of monetary and social conditions. Results showed that boys were less likely to switch their response after punishment, had generally less feedback-related negativity (FRN) amplitude, and longer FRN latency in monetary and punishment conditions than girls. Moreover, FRN for monetary punishment, which is related to individual difference in reward sensitivity, was observed only in girls. The study provides gender specific evidence for the neural processing of feedback, which may offer educational guidance for appropriate feedback for girls and boys. PMID- 28346517 TI - CD22 is required for formation of memory B cell precursors within germinal centers. AB - CD22 is a BCR co-receptor that regulates B cell signaling, proliferation and survival and is required for T cell-independent Ab responses. To investigate the role of CD22 during T cell-dependent (TD) Ab responses and memory B cell formation, we analyzed Ag-specific B cell responses generated by wild-type (WT) or CD22-/- B cells following immunization with a TD Ag. CD22-/- B cells mounted normal early Ab responses yet failed to generate either memory B cells or long lived plasma cells, whereas WT B cells formed both populations. Surprisingly, B cell expansion and germinal center (GC) differentiation were comparable between WT and CD22-/- B cells. CD22-/- B cells, however, were significantly less capable of generating a population of CXCR4hiCD38hi GC B cells, which we propose represent memory B cell precursors within GCs. These results demonstrate a novel role for CD22 during TD humoral responses evident during primary GC formation and underscore that CD22 functions not only during B cell maturation but also during responses to both TD and T cell-independent antigens. PMID- 28346518 TI - What do people with aphasia want to be able to say? A content analysis of words identified as personally relevant by people with aphasia. AB - BACKGROUND: Word finding is a common difficulty for people with aphasia. Targeting words that are relevant to the individual could maximise the usefulness and impact of word finding therapy. AIMS: To provide insights into words that people with aphasia perceive to be personally relevant. METHODS AND PROCEDURES: 100 people with aphasia were each asked to identify 100 words that would be particularly important for them to be able to say. Two speech and language therapist researchers conducted a quantitative content analysis of the words selected. The words were coded into a framework of topics and subtopics. The frequency with which different words and topics were selected was then calculated. OUTCOMES AND RESULTS: 100 participants representing 20 areas of the United Kingdom ranged in age from 23 to 85 years. Word finding difficulties ranged from mild to severe. The sample of 9999 words selected for practice included 3095 different words in 27 topics. The majority of words selected (79.4%) were from the topics 'food and drink' (30.6%), 'nature and gardening' (10.3%), 'entertainment' (9.4%), 'places' (7.3%), 'people' (6.7%), 'house' (6.5%), 'clothes' (5.2%) and 'travel' (3.5%). The 100 words types chosen with the greatest frequency were identified. These account for 27 percent of the 9999 words chosen by the participants. DISCUSSION: Personally relevant vocabulary is unique to each individual and is likely to contain specific or specialist words for which material needs to be individually prepared. However there is some commonality in the words chosen by people with aphasia. This could inform pre prepared materials for use in word finding therapy from which personally relevant words could be selected for practice. PMID- 28346516 TI - Protective immune responses against Schistosoma mansoni infection by immunization with functionally active gut-derived cysteine peptidases alone and in combination with glyceraldehyde 3-phosphate dehydrogenase. AB - BACKGROUND: Schistosomiasis, a severe disease caused by parasites of the genus Schistosoma, is prevalent in 74 countries, affecting more than 250 million people, particularly children. We have previously shown that the Schistosoma mansoni gut-derived cysteine peptidase, cathepsin B1 (SmCB1), administered without adjuvant, elicits protection (>60%) against challenge infection of S. mansoni or S. haematobium in outbred, CD-1 mice. Here we compare the immunogenicity and protective potential of another gut-derived cysteine peptidase, S. mansoni cathepsin L3 (SmCL3), alone, and in combination with SmCB1. We also examined whether protective responses could be boosted by including a third non-peptidase schistosome secreted molecule, glyceraldehyde 3-phosphate dehydrogenase (SG3PDH), with the two peptidases. METHODOLOGY/PRINCIPAL FINDINGS: While adjuvant-free SmCB1 and SmCL3 induced type 2 polarized responses in CD-1 outbred mice those elicited by SmCL3 were far weaker than those induced by SmCB1. Nevertheless, both cysteine peptidases evoked highly significant (P < 0.005) reduction in challenge worm burden (54-65%) as well as worm egg counts and viability. A combination of SmCL3 and SmCB1 did not induce significantly stronger immune responses or higher protection than that achieved using each peptidase alone. However, when the two peptidases were combined with SG3PDH the levels of protection against challenge S. mansoni infection reached 70-76% and were accompanied by highly significant (P < 0.005) decreases in worm egg counts and viability. Similarly, high levels of protection were achieved in hamsters immunized with the cysteine peptidase/SG3PDH-based vaccine. CONCLUSIONS/SIGNIFICANCE: Gut-derived cysteine peptidases are highly protective against schistosome challenge infection when administered subcutaneously without adjuvant to outbred CD-1 mice and hamsters, and can also act to enhance the efficacy of other schistosome antigens, such as SG3PDH. This cysteine peptidase based vaccine should now be advanced to experiments in non-human primates and, if shown promise, progressed to Phase 1 safety trials in humans. PMID- 28346519 TI - Views of senior health personnel about quality of emergency obstetric care: A qualitative study in Nigeria. AB - BACKGROUND: Late arrival in hospital by women experiencing pregnancy complications is an important background factor leading to maternal mortality in Nigeria. The use of effective and timely emergency obstetric care determines whether women survive or die, or become near-miss cases. Healthcare managers have the responsibility to deploy resources for implementing emergency obstetric care. OBJECTIVES: To determine the nature of institutional policies and frameworks for managing obstetric complications and reducing maternal deaths in Nigeria. METHODS: Thirty-six hospital managers, heads of obstetrics department and senior midwives were interviewed about hospital infrastructure, resources, policies and processes relating to emergency obstetric care, whilst allowing informants to discuss their thoughts and feelings. The interviews were audiotaped, transcribed and analyzed using Atlas ti 6.2software. RESULTS: Hospital managers are aware of the seriousness of maternal mortality and the steps to improve maternal healthcare. Many reported the lack of policies and specific action-plans for maternal mortality prevention, and many did not purposely disburse budgets or resources to address the problem. Although some reported that maternal/perinatal audit take place in their hospitals, there was no substantive evidence and no records of maternal/perinatal audits were made available. Respondents decried the lack of appropriate data collection system in the hospitals for accurate monitoring of maternal mortality and identification of appropriate remediating actions. CONCLUSION: Healthcare managers are handicapped to properly manage the healthcare system for maternal mortality prevention. Relevant training of healthcare managers would be crucial to enable the development of strategic implementation plans for the prevention of maternal mortality. PMID- 28346520 TI - Downregulation of miR-139-5p contributes to the antiapoptotic effect of liraglutide on the diabetic rat pancreas and INS-1 cells by targeting IRS1. AB - Liraglutide is administered as glucagon-like peptide-1 (GLP-1) receptor agonist for diabetic patients and can protect pancreatic beta-cells by inhibiting their apoptosis. MicroRNA-139-5p (miRNA-139-5p) participates in the regulation of cancer cell apoptosis. However, it is not clear whether miR-139-5p contributes to the anti-apoptotic effect of liraglutide in beta-cells. The objective of the present study was to investigate the role of miR-139-5p on apoptosis of pancreatic beta-cells. MicroRNA levels in pancreatic tissue from diabetic rats and INS-1 cells treated with liraglutide were measured by real-time quantitative RT-PCR. The role of miR-139-5p on apoptosis was studied by transfecting INS-1 cells with miR-139-5p mimics. The mRNA and protein expression of the target gene, insulin receptor substrate-1 (IRS1), were measured by qRT-PCR and Western blot, respectively. Apoptosis in rat pancreatic tissue and INS-1 cells was detected by TUNEL and annexin V/propidium iodide costaining. Apoptosis of pancreatic tissue from diabetic rats and INS-1 cells was decreased by administration of liraglutide. The expression of miR-139-5p increased in the pancreas of diabetic rats and decreased with liraglutide treatment. Incubation with liraglutide (100 nM) for 48 h attenuated the expression of miR-139-5p and increased the mRNA and protein levels of IRS1. Direct regulatory effects of miR-139-5p on IRS1 were found by a dual-luciferase reporter assay. Transfection of INS-1 cells with miR 139-5p mimics led to decreases in the mRNA and protein expression of IRS1. In conclusion, our observations suggest that decreased miR-139-5p expression contributes to the anti-apoptotic effect of liraglutide on the diabetic rat pancreas and INS-1 cells by targeting IRS1. PMID- 28346521 TI - HIV-1 gp120 envelope glycoprotein determinants for cytokine burst in human monocytes. AB - The first step of HIV infection involves the interaction of the gp120 envelope glycoprotein to its receptor CD4, mainly expressed on CD4+ T cells. Besides its role on HIV-1 entry, the gp120 has been shown to be involved in the production of IL-1, IL-6, CCL20 and other innate response cytokines by bystander, uninfected CD4+ T cells and monocytes. However, the gp120 determinants involved in these functions are not completely understood. Whether signalling leading to cytokine production is due to CD4 or other receptors is still unclear. Enhanced chemokine receptor binding and subsequent clustering receptors may lead to cytokine production. By using a comprehensive panel of gp120 mutants, here we show that CD4 binding is mandatory for cytokine outburst in monocytes. Our data suggest that targeting monocytes in HIV-infected patients might decrease systemic inflammation and the potential tissue injury associated with the production of inflammatory cytokines. Understanding how gp120 mediates a cytokine burst in monocytes might help develop new approaches to improve the chronic inflammation that persists in these patients despite effective suppression of viremia by antiretroviral therapy. PMID- 28346522 TI - Decline in lung function rather than baseline lung function is associated with the development of metabolic syndrome: A six-year longitudinal study. AB - This study was conducted to investigate whether baseline lung function or change in lung function is associated with the development of metabolic syndrome (MS) in Koreans. We analyzed clinical and laboratory data from 3,768 Koreans aged 40-60 years who underwent medical check-ups over a six-year period between 2006 and 2012. We calculated the percent change in forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) over the study period. We tested for an association between baseline lung function or lung function change during the follow-up period and the development of MS. The 533 subjects (14.1%) developed MS after the six-year follow-up. The baseline FVC and FEV1 were not different between the subjects who developed MS after six years and the subject without MS after six years. The percent change in FVC over six years in subjects who developed MS after six years was higher than that in subjects who did not develop MS (-5.75 [-10.19 --1.17], -3.29 [-7.69-1.09], respectively, P = 0.001). The percent change in FVC over six years was associated with MS development after adjusting for age, sex, body mass index (BMI), glucose, HDL, triglyceride, waist circumferences (WC), and systolic blood pressure. However, these association was not significant after adjusting for change of BMI and change of WC over six years (P = 0.306). The greater change in vital capacity over six years of follow-up was associated with MS development, predominantly due to obesity and abdominal obesity. The prospective study is needed to determine the relationship between lung function decline and MS. PMID- 28346523 TI - A moderate diet restriction during pregnancy alters the levels of endocannabinoids and endocannabinoid-related lipids in the hypothalamus, hippocampus and olfactory bulb of rat offspring in a sex-specific manner. AB - Undernutrition during pregnancy has been associated to increased vulnerability to develop metabolic and behavior alterations later in life. The endocannabinoid system might play an important role in these processes. Therefore, we investigated the effects of a moderate maternal calorie-restricted diet on the levels of the endocannabinoid 2-arachidonoyl glycerol (2-AG), arachidonic acid (AA) and the N-acylethanolamines (NAEs) anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) in the brain of newborn rat offspring. We focused on brain structures involved in metabolism, feeding behavior, as well as emotional and cognitive responses. Female Wistar rats were assigned during the entire pregnancy to either control diet (C) or restriction diet (R), consisting of a 20% calorie-restricted diet. Weight gain and caloric intake of rat dams were monitored and birth outcomes were assessed. 2-AG, AA and NAE levels were measured in hypothalamus, hippocampus and olfactory bulb of the offspring. R dams displayed lower gain weight from the middle pregnancy and consumed less calories during the entire pregnancy. Offspring from R dams were underweight at birth, but litter size was unaffected. In hypothalamus, R male offspring displayed decreased levels of AA and OEA, with no change in the levels of the endocannabinoids 2-AG and AEA. R female exhibited decreased 2-AG and PEA levels. The opposite was found in the hippocampus, where R male displayed increased 2-AG and AA levels, and R female exhibited elevated levels of AEA, AA and PEA. In the olfactory bulb, only R female presented decreased levels of AEA, AA and PEA. Therefore, a moderate diet restriction during the entire pregnancy alters differentially the endocannabinoids and/or endocannabinoid-related lipids in hypothalamus and hippocampus of the underweight offspring, similarly in both sexes, whereas sex specific alterations occur in the olfactory bulb. Consequently, endocannabinoid and endocannabinoid-related lipid signaling alterations might be involved in the long-term and sexual dimorphism effects commonly observed after undernutrition and low birth weight. PMID- 28346524 TI - Rare mutations and potentially damaging missense variants in genes encoding fibrillar collagens and proteins involved in their production are candidates for risk for preterm premature rupture of membranes. AB - Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm birth with ~ 40% of preterm births being associated with PPROM and occurs in 1% - 2% of all pregnancies. We hypothesized that multiple rare variants in fetal genes involved in extracellular matrix synthesis would associate with PPROM, based on the assumption that impaired elaboration of matrix proteins would reduce fetal membrane tensile strength, predisposing to unscheduled rupture. We performed whole exome sequencing (WES) on neonatal DNA derived from pregnancies complicated by PPROM (49 cases) and healthy term deliveries (20 controls) to identify candidate mutations/variants. Genotyping for selected variants from the WES study was carried out on an additional 188 PPROM cases and 175 controls. All mothers were self-reported African Americans, and a panel of ancestry informative markers was used to control for genetic ancestry in all genetic association tests. In support of the primary hypothesis, a statistically significant genetic burden (all samples combined, SKAT-O p-value = 0.0225) of damaging/potentially damaging rare variants was identified in the genes of interest-fibrillar collagen genes, which contribute to fetal membrane strength and integrity. These findings suggest that the fetal contribution to PPROM is polygenic, and driven by an increased burden of rare variants that may also contribute to the disparities in rates of preterm birth among African Americans. PMID- 28346525 TI - Modeling timelines for translational science in cancer; the impact of technological maturation. AB - This work examines translational science in cancer based on theories of innovation that posit a relationship between the maturation of technologies and their capacity to generate successful products. We examined the growth of technologies associated with 138 anticancer drugs using an analytical model that identifies the point of initiation of exponential growth and the point at which growth slows as the technology becomes established. Approval of targeted and biological products corresponded with technological maturation, with first approval averaging 14 years after the established point and 44 years after initiation of associated technologies. The lag in cancer drug approvals after the increases in cancer funding and dramatic scientific advances of the 1970s thus reflects predictable timelines of technology maturation. Analytical models of technological maturation may be used for technological forecasting to guide more efficient translation of scientific discoveries into cures. PMID- 28346528 TI - Correction: Identification of a Putative Quantitative Trait Gene for Resistance to Obesity in Mice Using Transcriptome Analysis and Causal Inference Tests. AB - [This corrects the article DOI: 10.1371/journal.pone.0170652.]. PMID- 28346526 TI - Plasma potassium, diuretic use and risk of developing chronic kidney disease in a predominantly White population. AB - OBJECTIVE: Both hypokalemia and hyperkalemia are associated with disease progression in patients with chronic kidney disease (CKD). It is unclear whether similar associations are present in the general population. Our aim was to examine the association of plasma potassium with risk of developing CKD and the role of diuretics in this association in a population-based cohort. RESEARCH DESIGN AND METHODS: We studied 5,130 subjects free of CKD at baseline of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, a prospective, population-based cohort of Dutch men and women aged 28-75 years. Hypokalemia was defined as plasma potassium <3.5 mmol/L, and hyperkalemia as plasma potassium >=5.0 mmol/L. Risk of CKD was defined as de novo development of eGFR <60 ml/min/1.73m2 and/or albuminuria >30 mg/24h. RESULTS: Mean baseline plasma potassium was 4.4+/-0.3 mmol/L. The prevalences of hypokalemia and hyperkalemia were 0.5% and 3.8%, respectively; 3.0% of the subjects used diuretics. During a median follow-up of 10.3 years (interquartile range: 6.3-11.4 years), 753 subjects developed CKD. The potassium-CKD association was modified by diuretic use (Pinteraction = 0.02). Both hypokalemia without (HR, 7.74, 95% CI, 3.43-17.48) or with diuretic use (HR, 4.32, 95% CI, 1.77-10.51) were associated with an increased CKD risk as compared to plasma potassium 4.0-4.4 mmol/L without diuretic use. Plasma potassium concentrations >=3.5 mmol/L were associated with an increased CKD risk among subjects using diuretics (Ptrend = 0.01) but not among subjects not using diuretics (Ptrend = 0.74). CONCLUSION: In this population-based cohort, hypokalemia was associated with an increased CKD risk, regardless of diuretic use. In the absence of hypokalemia, plasma potassium was not associated with an increased CKD risk, except among subjects using diuretics. PMID- 28346527 TI - A qualitative study of secondary distribution of HIV self-test kits by female sex workers in Kenya. AB - Promoting awareness of serostatus and frequent HIV testing is especially important among high risk populations such as female sex workers (FSW) and their sexual partners. HIV self-testing is an approach that is gaining ground in sub Saharan Africa as a strategy to increase knowledge of HIV status and promote safer sexual decisions. However, little is known about self-test distribution strategies that are optimal for increasing testing access among hard-to-reach and high risk individuals. We conducted a qualitative study with 18 FSW who participated in a larger study that provided them with five oral fluid-based self tests, training on how to use the tests, and encouragement to offer the self tests to their sexual partners using their discretion. Women demonstrated agency in the strategies they used to introduce self-tests to their partners and to avoid conflict with partners. They carefully considered with whom to share self tests, often assessing the possibility for negative reactions from partners as part of their decision making process. When women faced negative reactions from partners, they drew on strategies they had used before to avoid conflict and physical harm from partners, such as not responding to angry partners and forgoing payment to leave angry partners quickly. Some women also used self-tests to make more informed sexual decisions with their partners. PMID- 28346529 TI - Human amnion epithelial cells modulate the inflammatory response to ventilation in preterm lambs. AB - Ventilation of preterm neonates causes pulmonary inflammation that can contribute to lung injury, propagate systemically and result in long-term disease. Modulation of this initial response may reduce lung injury and its sequelae. We aimed to determine the effect of human amnion epithelial cells (hAECs) on immune activation and lung injury in preterm neonatal lambs. Preterm lambs received intratracheal hAECs (90x106) or vehicle, prior to 2 h of mechanical ventilation. Within 5 min of ventilation onset, lambs also received intravenous hAECs (90x106) or vehicle. Lung histology, bronchoalveolar lavage (BAL) cell phenotypes, and cytokine profiles were examined after 2 h of ventilation, and in unventilated controls. Histological indices of lung injury were higher than control, in vehicle-treated ventilated lambs but not in hAEC-treated ventilated lambs. Ventilation-induced pulmonary leukocyte recruitment was greater in hAEC-treated lambs than in vehicle-treated lambs. Lung IL-1beta and IL-6 mRNA expression was higher in vehicle- and hAEC-treated ventilated lambs than in controls but IL-8 mRNA levels were greater than control only in vehicle-treated ventilated lambs. Numbers of CD44+ and CD21+ lymphocytes and macrophages from the lungs were altered in vehicle- and hAEC-treated ventilated lambs. Numbers of CD8+ macrophages were lower in hAEC-treated ventilated lambs than in vehicle-treated ventilated lambs. Indices of systemic inflammation were not different between vehicle- and hAEC-treated lambs. Human amnion epithelial cells modulate the pulmonary inflammatory response to ventilation in preterm lambs, and reduce acute lung injury. Immunomodulatory effects of hAECs reduce lung injury in preterm neonates and may protect against longer-term respiratory disease. PMID- 28346530 TI - Quantification of left coronary bifurcation angles and plaques by coronary computed tomography angiography for prediction of significant coronary stenosis: A preliminary study with dual-source CT. AB - PURPOSE: To evaluate the diagnostic performance of left coronary bifurcation angles and plaque characteristics for prediction of coronary stenosis by dual source CT. METHODS: 106 patients suspected of coronary artery disease undergoing both coronary computed tomography angiography (CCTA) and invasive coronary angiography (CAG) within three months were included. Left coronary bifurcation angles including the angles between the left anterior descending artery and left circumflex artery (LAD-LCx), left main coronary artery and left anterior descending artery (LM-LAD), left main coronary artery and left circumflex artery (LM-LCx) were measured on CT images. CCTA plaque parameters were calculated by plaque analysis software. Coronary stenosis >= 50% by CAG was defined as significant. RESULTS: 106 patients with 318 left coronary bifurcation angles and 126 vessels were analyzed. The bifurcation angle of LAD-LCx was significantly larger in left coronary stenosis >= 50% than stenosis < 50%, and significantly wider in the non-calcified plaque group than calcified. Multivariable analyses showed the bifurcation angle of LAD-LCx was an independent predictor for significant left coronary stenosis (OR = 1.423, P = 0.002). In ROC curve analysis, LAD-LCx predicted significant left coronary stenosis with a sensitivity of 66.7%, specificity of 78.4%, positive predictive value of 85.2% and negative predictive value of 55.8%. The lipid plaque volume improved the diagnostic performance of CCTA diameter stenosis (AUC: 0.854 vs. 0.900, P = 0.045) in significant coronary stenosis. CONCLUSIONS: The bifurcation angle of LAD-LCx could predict significant left coronary stenosis. Wider LAD-LCx is related to non calcified lesions. Lipid plaque volume could improve the diagnostic performance of CCTA for coronary stenosis prediction. PMID- 28346533 TI - Correction: A Cross-Sectional Study of Colonization Rates with Methicillin Resistant Staphylococcus aureus (MRSA) and Extended-Spectrum Beta-Lactamase (ESBL) and Carbapenemase-Producing Enterobacteriaceae in Four Swiss Refugee Centres. AB - [This corrects the article DOI: 10.1371/journal.pone.0170251.]. PMID- 28346531 TI - The prevalence of trichomoniasis and associated factors among women treated at a university hospital in southern Brazil. AB - BACKGROUND: Trichomoniasis is the most prevalent non-viral sexually transmitted disease (STD) in the world; however, it remains a neglected parasitic disease. This study aimed to determine the prevalence of trichomoniasis and its associated epidemiological factors among women treated at a hospital in southern Brazil. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional study was performed to determine the prevalence of this infection in women treated at Hospital Universitario (HU) in Rio Grande, Rio Grande do Sul, Brazil, between January 2012 and January 2015. This study consisted a self-administered questionnaire regarding demographic, clinical, and behavioural data and a molecular diagnosis with polymerase chain reaction (PCR) using the TVK3/7 primer set, which was confirmed with sequence analysis. Of the 345 women surveyed, the overall prevalence of Trichomonas vaginalis (T. vaginalis) was 4.1% (14/345). The prevalence rates were 5.9% among pregnant women, 8.5% among HIV-positive women, and 10.1% among HIV-positive pregnant women. The rates for groups with other significant demographic and clinical features were as follows: 6.6% among women with white skin, 12.3% among women with an income below the minimum monthly wage, 7.4% among women with a vaginal pH greater than or equal to 4.6, and 7.9% among women with a comorbid STD. The multivariate analysis confirmed that pregnant women who were HIV-positive (p = 0.001) and had low incomes (p = 0.026) were the most likely to have this infection. CONCLUSIONS: A multivariate analysis confirmed that HIV-positive pregnant women with low incomes were the participants most likely to have trichomoniasis. These results are important because this Brazilian region presents a high prevalence of HIV-1 subtype C, which is associated with greater transmissibility. Additionally, low family income reveals a socioeconomic fragility that might favour the transmission of this STD. PMID- 28346532 TI - Decline in changing Montreal Cognitive Assessment (MoCA) scores is associated with post-stroke cognitive decline determined by a formal neuropsychological evaluation. AB - OBJECTIVES: We aimed to examine changes in the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) scores within a one-year period after stroke/transient ischemic attack (TIA) in associating cognitive decline determined by a formal neuropsychological test battery. METHODS: Patients with ischemic stroke/TIA received MoCA and MMSE at baseline within 14 days after stroke/TIA, at 3-6 months and 1-year follow-ups. The scores of MoCA and MMSE were considered to have declined if there were a reduction of >=2 points in the respective scores measured across two time points. The decline in neuropsychological diagnosis transitional status was defined by a category transition from no cognitive impairment or any cognitive impairment to a more severe cognitive impairment or dementia. RESULTS: 275 patients with a mean age of 59.8 +/- 11.6 years, and education of 7.7 +/- 4.3 years completed all the assessments at baseline, 3-6 months and 1-year follow-ups. A decline in MoCA scores from 3-6 months to 1 year was associated with higher risk of decline in diagnosis transitional status (odd ratio = 3.21, p = 0.004) in the same time period whereas there was no association with a decline in MMSE scores. CONCLUSIONS: The decline in MoCA scores from 3-6 months to 1 year after stroke/TIA has three times higher risk for decline in the diagnosis transitional status. The decline of MoCA scores (reduction >= 2points) is associated with the decline in neuropsychological diagnosis transitional status. PMID- 28346534 TI - Spatial and temporal changes in leaf coloring date of Acer palmatum and Ginkgo biloba in response to temperature increases in South Korea. AB - Understanding shifts in autumn phenology associated with climate changes is critical for preserving forest ecosystems. This study examines the changes in the leaf coloring date (LCD) of two temperate deciduous tree species, Acer palmatum (Acer) and Ginkgo biloba (Ginkgo), in response to surface air temperature (Ts) changes at 54 stations of South Korea for the period 1989-2007. The variations of Acer and Ginkgo in South Korea are very similar: they show the same mean LCD of 295th day of the year and delays of about 0.45 days year-1 during the observation period. The delaying trend is closely correlated (correlation coefficient > 0.77) with increases in Ts in mid-autumn by 2.8 days degrees C-1. It is noted that the LCD delaying and temperature sensitivity (days degrees C-1) for both tree species show negligible dependences on latitudes and elevations. Given the significant LCD-Ts relation, we project LCD changes for 2016-35 and 2046-65 using a process-based model forced by temperature from climate model simulation. The projections indicate that the mean LCD would be further delayed by 3.2 (3.7) days in 2016-35 (2046-65) due to mid-autumn Ts increases. This study suggests that the mid-autumn warming is largely responsible for the observed LCD changes in South Korea and will intensify the delaying trends in the future. PMID- 28346535 TI - Caudwell Xtreme Everest: A prospective study of the effects of environmental hypoxia on cognitive functioning. AB - BACKGROUND: The neuropsychological consequences of exposure to environmental hypobaric hypoxia (EHH) remain unclear. We thus investigated them in a large group of healthy volunteers who trekked to Mount Everest base camp (5,300 m). METHODS: A neuropsychological (NP) test battery assessing memory, language, attention, and executive function was administered to 198 participants (age 44.5+/-13.7 years; 60% male). These were studied at baseline (sea level), 3,500 m (Namche Bazaar), 5,300 m (Everest Base Camp) and on return to 1,300 m (Kathmandu) (attrition rate 23.7%). A comparable control group (n = 25; age 44.5+/-14.1 years; 60% male) for comparison with trekkers was tested at/or near sea level over an equivalent timeframe so as to account for learning effects associated with repeat testing. The Reliable Change Index (RCI) was used to calculate changes in cognition and neuropsychological function during and after exposure to EHH relative to controls. RESULTS: Overall, attention, verbal ability and executive function declined in those exposed to EHH when the performance of the control group was taken into account (RCI .05 to -.95) with decline persisting at descent. Memory and psychomotor function showed decline at highest ascent only (RCI -.08 to -.56). However, there was inter-individual variability in response: whilst NP performance declined in most, this improved in some trekkers. Cognitive decline was greater amongst older people (r = .42; p < .0001), but was otherwise not consistently associated with socio-demographic, mood, or physiological variables. CONCLUSIONS: After correcting for learning effects, attention, verbal abilities and executive functioning declined with exposure to EHH. There was considerable individual variability in the response of brain function to sustained hypoxia with some participants not showing any effects of hypoxia. This might have implications for those facing sustained hypoxia as a result of any disease. PMID- 28346536 TI - Water, Sanitation and Hygiene (WASH) and environmental risk factors for soil transmitted helminth intensity of infection in Timor-Leste, using real time PCR. AB - BACKGROUND: No investigations have been undertaken of risk factors for intensity of soil-transmitted helminth (STH) infection in Timor-Leste. This study provides the first analysis of risk factors for intensity of STH infection, as determined by quantitative PCR (qPCR), examining a broad range of water, sanitation and hygiene (WASH) and environmental factors, among communities in Manufahi District, Timor-Leste. METHODS: A baseline cross-sectional survey of 18 communities was undertaken as part of a cluster randomised controlled trial, with additional identically-collected data from six other communities. qPCR was used to assess STH infection from stool samples, and questionnaires administered to collect WASH, demographic, and socioeconomic data. Environmental information was obtained from open-access sources and linked to infection outcomes. Mixed-effects multinomial logistic regression was undertaken to assess risk factors for intensity of Necator americanus and Ascaris infection. RESULTS: 2152 participants provided stool and questionnaire information for this analysis. In adjusted models incorporating WASH, demographic and environmental variables, environmental variables were generally associated with infection intensity for both N. americanus and Ascaris spp. Precipitation (in centimetres) was associated with increased risk of moderate-intensity (adjusted relative risk [ARR] 6.1; 95% confidence interval [CI] 1.9-19.3) and heavy-intensity (ARR 6.6; 95% CI 3.1-14.1) N. americanus infection, as was sandy-loam soil around households (moderate intensity ARR 2.1; 95% CI 1.0-4.3; heavy-intensity ARR 2.7; 95% CI 1.6-4.5; compared to no infection). For Ascaris, alkaline soil around the household was associated with reduced risk of moderate-intensity infection (ARR 0.21; 95% CI 0.09-0.51), and heavy-intensity infection (ARR 0.04; 95% CI 0.01-0.25). Few WASH risk factors were significant. CONCLUSION: In this high-prevalence setting, strong risk associations with environmental factors indicate that anthelmintic treatment alone will be insufficient to interrupt STH transmission, as conditions are favourable for ongoing environmental transmission. Integrated STH control strategies should be explored as a priority. PMID- 28346538 TI - Discrimination of rippled-spectrum patterns in noise: A manifestation of compressive nonlinearity. AB - In normal-hearing listeners, rippled-spectrum discrimination was psychophysically investigated in both silence and with a simultaneous masker background using the following two paradigms: measuring the ripple density resolution with the phase reversal test and measuring the ripple-shift threshold with the ripple-shift test. The 0.5-oct wide signal was centered on 2 kHz, the signal levels were 50 and 80 dB SPL, and the masker levels varied from 30 to 100 dB SPL. The baseline ripple density resolutions were 8.7 oct-1 and 8.6 oct-1 for the 50-dB and 80-dB signals, respectively. The baseline ripple shift thresholds were 0.015 oct and 0.018 oct for the 50-dB and 80-dB signals, respectively. The maskers were 0.5-oct noises centered on 2 kHz (on-frequency) or 0.75 to 1.25 oct below the signal (off frequency maskers). The effects of the maskers were as follows: (i) both on- and low-frequency maskers reduced the ripple density resolution and increased the ripple shift thresholds, (ii) the masker levels at threshold (the ripple density resolution decrease down to 3 oct-1 or ripple shift threshold increased up to 0.1 oct) increased with increasing frequency spacing between the signal and masker, (iii) the masker levels at threshold were higher for the 80-dB signal than for the 50-dB signal, and (iv) the difference between the masker levels at threshold for the 50-dB and 80-dB signals decreased with increasing frequency spacing between the masker and signal. Within the 30-dB (from 50 to 80 dB SPL) signal level, the growth of the masker level at threshold was 27.8 dB for the on frequency masker and 9 dB for the low-frequency masker. It is assumed that the difference between the on- and low-frequency masking of the rippled-spectrum discrimination reflects the cochlear compressive non-linearity. With this assumption, the compression was 0.3 dB/dB. PMID- 28346537 TI - Deep mutational scanning identifies sites in influenza nucleoprotein that affect viral inhibition by MxA. AB - The innate-immune restriction factor MxA inhibits influenza replication by targeting the viral nucleoprotein (NP). Human influenza virus is more resistant than avian influenza virus to inhibition by human MxA, and prior work has compared human and avian viral strains to identify amino-acid differences in NP that affect sensitivity to MxA. However, this strategy is limited to identifying sites in NP where mutations that affect MxA sensitivity have fixed during the small number of documented zoonotic transmissions of influenza to humans. Here we use an unbiased deep mutational scanning approach to quantify how all single amino-acid mutations to NP affect MxA sensitivity in the context of replication competent virus. We both identify new sites in NP where mutations affect MxA resistance and re-identify mutations known to have increased MxA resistance during historical adaptations of influenza to humans. Most of the sites where mutations have the greatest effect are almost completely conserved across all influenza A viruses, and the amino acids at these sites confer relatively high resistance to MxA. These sites cluster in regions of NP that appear to be important for its recognition by MxA. Overall, our work systematically identifies the sites in influenza nucleoprotein where mutations affect sensitivity to MxA. We also demonstrate a powerful new strategy for identifying regions of viral proteins that affect inhibition by host factors. PMID- 28346540 TI - Fragment library screening identifies hits that bind to the non-catalytic surface of Pseudomonas aeruginosa DsbA1. AB - At a time when the antibiotic drug discovery pipeline has stalled, antibiotic resistance is accelerating with catastrophic implications for our ability to treat bacterial infections. Globally we face the prospect of a future when common infections can once again kill. Anti-virulence approaches that target the capacity of the bacterium to cause disease rather than the growth or survival of the bacterium itself offer a tantalizing prospect of novel antimicrobials. They may also reduce the propensity to induce resistance by removing the strong selection pressure imparted by bactericidal or bacteriostatic agents. In the human pathogen Pseudomonas aeruginosa, disulfide bond protein A (PaDsbA1) plays a central role in the oxidative folding of virulence factors and is therefore an attractive target for the development of new anti-virulence antimicrobials. Using a fragment-based approach we have identified small molecules that bind to PaDsbA1. The fragment hits show selective binding to PaDsbA1 over the DsbA protein from Escherichia coli, suggesting that developing species-specific narrow spectrum inhibitors of DsbA enzymes may be feasible. Structures of a co-complex of PaDsbA1 with the highest affinity fragment identified in the screen reveal that the fragment binds on the non-catalytic surface of the protein at a domain interface. This biophysical and structural data represent a starting point in the development of higher affinity compounds, which will be assessed for their potential as selective PaDsbA1 inhibitors. PMID- 28346539 TI - Is there a relation between novelty seeking, striatal dopamine release and frontal cortical thickness? AB - BACKGROUND: Novelty-seeking (NS) and impulsive personality traits have been proposed to reflect an interplay between fronto-cortical and limbic systems, including the limbic striatum (LS). Although neuroimaging studies have provided some evidence for this, most are comprised of small samples and many report surprisingly large effects given the challenges of trying to relate a snapshot of brain function or structure to an entity as complex as personality. The current work tested a priori hypotheses about associations between striatal dopamine (DA) release, cortical thickness (CT), and NS in a large sample of healthy adults. METHODS: Fifty-two healthy adults (45M/7F; age: 23.8+/-4.93) underwent two positron emission tomography scans with [11C]raclopride (specific for striatal DA D2/3 receptors) with or without amphetamine (0.3 mg/kg, p.o.). Structural magnetic resonance image scans were acquired, as were Tridimensional Personality Questionnaire data. Amphetamine-induced changes in [11C]raclopride binding potential values (DeltaBPND) were examined in the limbic, sensorimotor (SMS) and associative (AST) striatum. CT measures, adjusted for whole brain volume, were extracted from the dorsolateral sensorimotor and ventromedial/limbic cortices. RESULTS: BPND values were lower in the amphetamine vs. no-drug sessions, with the largest effect in the LS. When comparing low vs. high LS DeltaBPND groups (median split), higher NS2 (impulsiveness) scores were found in the high DeltaBPND group. Partial correlations (age and gender as covariates) yielded a negative relation between ASTS DeltaBPND and sensorimotor CT; trends for inverse associations existed between DeltaBPND values in other striatal regions and frontal CT. In other words, the greater the amphetamine-induced striatal DA response, the thinner the frontal cortex. CONCLUSIONS: These data expand upon previously reported associations between striatal DA release in the LS and both NS related impulsiveness and CT in the largest sample reported to date. The findings add to the plausibility of these associations while suggesting that the effects are likely weaker than has been previously proposed. PMID- 28346542 TI - Unusual behaviour of phototrophic picoplankton in turbid waters. AB - Autotrophic picoplankton (APP) abundance and contribution to phytoplankton biomass was studied in Hungarian shallow lakes to test the effect of inorganic turbidity determining the size distribution of the phytoplankton. The studied lakes displayed wide turbidity (TSS: 4-2250 mg l-1) and phytoplankton biomass (chlorophyll a: 1-460 MUg l-1) range, as well as APP abundance (0 and 100 million cells ml-1) and contribution (0-100%) to total phytoplankton biomass. Inorganic turbidity had a significant effect on the abundance and contribution of APP, resulting in higher values compared to other freshwater lakes with the same phytoplankton biomass. Our analysis has provided empirical evidence for a switching point (50 mg l-1 inorganic turbidity), above which turbidity is the key factor causing APP predominance regardless of phytoplankton biomass in shallow turbid lakes. Our results have shown that turbid shallow lakes are unique waters, where the formerly and widely accepted model (decreasing APP contribution with increasing phytoplankton biomass) is not applicable. We hypothesize that this unusual behaviour of APP in turbid waters is a result of either diminished underwater light intensity or a reduced grazing pressure due to high inorganic turbidity. PMID- 28346541 TI - Quality of life and objective outcome assessment in women with tape division after surgery for stress urinary incontinence. AB - BACKGROUND: Midurethral tapes may cause long-term complications such as voiding dysfunction, groin pain, de novo urgency or mesh erosion, which necessitate a reoperation. There is a paucity of data regarding health related quality of life in patients undergoing tape removal. The aim of the study was to evaluate quality of life (QoL) and objective outcome after midurethral tape division or excision. METHODS: All patients who underwent a midurethral tape division for voiding difficulties, pain or therapy resistant de novo overactive bladder between 1999 and 2014 were invited for follow-up. A control group with a suburethral tape without division was established in a 1:2 ratio and matched for age, tape used and year of tape insertion. Patients completed the Kings' Health Questionnaire (KHQ), Incontinence Outcome Questionnaire, Female Sexual Function Index Questionnaire and the Patient Global Impression of Improvement score. RESULTS: Tape division or excision was performed in 32 women. Overall, 15 (60%) of 25 women who were alive were available for clinical examination and completed the questionnaires. Tape division was performed for voiding dysfunction (n = 7), overactive bladder (n = 2), mesh extrusion (n = 3) and ongoing pain (n = 3). Median time to tape division/excision was 10 months. Three women in the tape division group had undergone reoperation for stress urinary incontinence (SUI). At a median follow-up of 11 years (IQR 9-13) subjective SUI rate was 53% (8/15 women) in the tape division group and 17% (5/30) in the control group (p = 0.016), with no significant differences in objective SUI rates between groups. With regard to quality of life, the study group had significantly worse scores in the SUI related domains role limitation, physical limitation, severity measures and social limitations (KHQ) compared to the control group. CONCLUSIONS: Women needing tape division or excision have lower SUI related QoL scores compared to controls mostly because of higher subjective SUI rates. PMID- 28346543 TI - Prevalence of non-alcoholic fatty liver disease and risk factors for advanced fibrosis and mortality in the United States. AB - In the United States, non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and associated with higher mortality according to data from earlier National Health and Nutrition Examination Survey (NHANES) 1988-1994. Our goal was to determine the NAFLD prevalence in the recent 1999-2012 NHANES, risk factors for advanced fibrosis (stage 3-4) and mortality. NAFLD was defined as having a United States Fatty Liver Index (USFLI) > 30 in the absence of heavy alcohol use and other known liver diseases. The probability of low/high risk of having advanced fibrosis was determined by the NAFLD Fibrosis Score (NFS). In total, 6000 persons were included; of which, 30.0% had NAFLD and 10.3% of these had advanced fibrosis. Five and eight-year overall mortality in NAFLD subjects with advanced fibrosis was significantly higher than subjects without NAFLD ((18% and 35% vs. 2.6% and 5.5%, respectively) but not NAFLD subjects without advanced fibrosis (1.1% and 2.8%, respectively). NAFLD with advanced fibrosis (but not those without) is an independent predictor for mortality on multivariate analysis (HR = 3.13, 95% CI 1.93-5.08, p<0.001). In conclusion, in this most recent NHANES, NAFLD prevalence remains at 30% with 10.3% of these having advanced fibrosis. NAFLD per se was not a risk factor for increased mortality, but NAFLD with advanced fibrosis was. Mexican American ethnicity was a significant risk factor for NAFLD but not for advanced fibrosis or increased mortality. PMID- 28346544 TI - Epigenetic silencing of V(D)J recombination is a major determinant for selective differentiation of mucosal-associated invariant t cells from induced pluripotent stem cells. AB - Mucosal-associated invariant T cells (MAITs) are innate-like T cells that play a pivotal role in the host defense against infectious diseases, and are also implicated in autoimmune diseases, metabolic diseases, and cancer. Recent studies have shown that induced pluripotent stem cells (iPSCs) derived from MAITs selectively redifferentiate into MAITs without altering their antigen specificity. Such a selective differentiation is a prerequisite for the use of MAITs in cell therapy and/or regenerative medicine. However, the molecular mechanisms underlying this phenomenon remain unclear. Here, we performed methylome and transcriptome analyses of MAITs during the course of differentiation from iPSCs. Our multi-omics analyses revealed that recombination activating genes (RAG1 and RAG2) and DNA nucleotidylexotransferase (DNTT) were highly methylated with their expression being repressed throughout differentiation. Since these genes are essential for V(D)J recombination of the T cell receptor (TCR) locus, this indicates that nascent MAITs are kept from further rearrangement that may alter their antigen specificity. Importantly, we found that the repression of RAGs was assured in two layers: one by the modulation of transcription factors for RAGs, and the other by DNA methylation at the RAG loci. Together, our study provides a possible explanation for the unaltered antigen specificity in the selective differentiation of MAITs from iPSCs. PMID- 28346547 TI - A controllable water signal transistor. AB - We performed molecular dynamics simulations to study the regulating ability of water chains confined in a Y-shaped nanochannel. It was shown that a signal at the molecular level could be controlled by two other charge-induced signals when the water chains were confined in a Y-shaped nanochannel, demonstrating promising applications as water signal transistors in nanosignal systems. The mechanism of a water signal transistor is similar to a signal logic device. This remarkable ability to control the water signal is attributed to the strong dipole-ordering of the water chains in the nanochannel. The controllable water signal process of the Y-shaped nanochannel provides opportunities for future application in the design of molecular-scale signal devices. PMID- 28346546 TI - Antimicrobial susceptibility and multilocus sequence typing of Mycoplasma capricolum subsp. capricolum. AB - Mycoplasma capricolum subsp. capricolum is one of the causative agents of contagious agalactia (CA). Nevertheless, there is still a lack of information about its antimicrobial susceptibility and genetic characteristics. Therefore, the aim of this work was to study the antimicrobial and genetic variability of different Mycoplasma capricolum subsp. capricolum field isolates. For this purpose, the growth inhibition effect of 18 antimicrobials and a multilocus sequence typing (MLST) scheme based on five housekeeping genes (fusA, glpQ, gyrB, lepA and rpoB) were performed on 32 selected field isolates from Italy and Spain.The results showed a wide range of growth inhibitory effects for almost all the antimicrobials studied. Macrolides presented lower efficacy inhibiting Mcc growth than in previous works performed on other CA-causative mycoplasmas. Erythromycin was not able to inhibit the growth of any of the studied strains, contrary to doxycycline, which inhibited the growth of all of them from low concentrations. On the other hand, the study of the concatenated genes revealed a high genetic variability among the different Mcc isolates. Hence, these genetic variations were greater than the ones reported in prior works on other mycoplasma species. PMID- 28346548 TI - Kinetics of light-induced ordering and deformation in LC azobenzene-containing materials. AB - Azobenzene-containing smart materials are able to transform the energy of light into directional mechanical stress. We develop a theory of time-dependent light induced ordering and deformation in azobenzene materials starting from the kinetic equations of photoisomerization. The liquid crystalline (LC) interactions between rod-like trans-isomers are taken into account. Angular selectivity of the photoisomerization known as an "angular hole burning" or the Weigert effect leads to the light-induced ordering and deformation of the azobenzene materials. The time evolution of ordering and deformation is found as a function of intensity of light depending on the opto-mechanical characteristics of the materials, such as probabilities of the optical excitation of trans- and cis-isomers, angular jump during the single isomerization event, viscosity of the materials, strength of the LC interactions in both the isotropic and LC materials, and the angular distribution of chromophores in polymer chains. Established structural-property relationships are in agreement with a number of experiments and can be used for the construction of light-controllable smart materials for practical applications. PMID- 28346545 TI - Aqueous cytokine levels are associated with reduced macular thickness after intravitreal ranibizumab for diabetic macular edema. AB - PURPOSE: It is controversial whether the administration of anti-vascular endothelial growth factor drugs for diabetic macular edema (DME) affects intraocular inflammatory cytokines. In this study, we measured cytokine concentration in aqueous humor before and after intravitreal injection of ranibizumab (IVR). The aim was to determine changes in cytokine concentration and their effects on DME reduction. METHODS: Twelve patients (13 eyes) with DME received two IVR (0.5 mg) with a 1 month interval, and a total of 26 aqueous humor samples were obtained. Macular thickness was measured with an optical coherence tomography (OCT) using thickness-map mode with an Early Treatment Diabetic Retinopathy Study (ETDRS) 9-zone grid that was divided into two zones: a central circle with a diameter of 1 mm (zone1); and an outer circle with a diameter of 6 mm (zone2). RESULTS: The concentration of eotaxin-1 in aqueous humor samples decreased significantly after IVR. Baseline cytokine concentration was associated with IVR-induced DME reduction. In zone1, higher baseline concentration of interferon-induced protein (IP)-10, and in zone 2, higher baseline concentration of granulocyte-macrophage colony-stimulating factor, IP 10, and tumor necrosis factor (TNF) alpha; and lower baseline concentration of eotaxin-1, interleukin (IL)-5, and IL-8 were associated with improved DME. Cytokine changes were associated with IVR-induced DME reduction. In zone1, lower concentration of IP-10 compared to baseline or higher concentration of macrophage inflammatory protein (MIP) -alpha, and in zone 2, lower concentration of IL-5 compared to baseline, IL-8, and IP-10 or higher concentration of eotaxin-1 and MIP-1beta were associated with improved DME. CONCLUSIONS: These findings suggest that ranibizumab affects the concentration of cytokines in aqueous humor. Various cytokines contribute to a decrease in retinal thickness, both in the center of the macula and in a larger area of the retina. PMID- 28346551 TI - Infrared spectra of HSCS+, c-HSCS, and HCS2- produced on electron bombardment of CS2 in solid para-hydrogen. AB - We report infrared (IR) spectra of HSCS+, c-HSCS, HCS2-, and other species produced on electron bombardment of a mixture of CS2 and para-hydrogen (p-H2) during deposition at 3.2 K. After maintenance of the deposited matrix in darkness for 12 h, the intensities of the absorption lines of HSCS+ at 2477.2 (nu1), 1525.6 (nu2), and 919.6 cm-1 (nu3) decreased through neutralization of HSCS+ with trapped electrons. During this period, the intensities of the lines of HCS2- at 2875.7 (nu1), 1249.9 (nu5), 1003.2 (nu6), and 814.3 cm-1 (nu4) increased due to reaction between H and CS2-. The intensities of the lines observed at 2312.7 and 889.0 cm-1, which are assigned to the c-HSCS radical, increased after maintenance in darkness and greatly diminished after irradiation at 373 nm. The IR spectra of HSCS+, HCS2-, and c-HSCS are reported for the first time. The IR absorption lines of the t-HSCS radical, t-HC(S)SH, and c-HC(S)SH were also identified; their wavenumbers are similar to those reported for these species in an Ar matrix. The corresponding spectra of the 13C, 34S, and D isotopic variants of these species were observed. The assignments were made according to the expected chemical behavior, predicted potential energies of associated reactions, and a comparison of observed and predicted wavenumbers and their 13C, 34S, and D isotopic ratios. In contrast to the observed significant red shifts of the OH-stretching wavenumbers of HOCO+ and HOCS+ in solid p-H2 compared to those in the gaseous phase due to proton sharing with H2, the wavenumber of the HS-stretching mode of HSCS+ in solid p-H2 (2477.2 cm-1) is similar to the anharmonic wavenumber of HSCS+ (2424 cm-1) predicted with the B3LYP/aug-cc-pVTZ method, indicating that the sharing of a proton between HSCS+ and neighboring H2 molecules is insignificant. PMID- 28346549 TI - Asymmetric synthesis of vinylogous beta-amino acids and their incorporation into mixed backbone oligomers. AB - Chiral vinylogous beta-amino acids (VBAA) were synthesized using enantioselective Mannich reactions of aldehydes with in situ generated N-carbamoyl imines followed by a Horner-Wadsworth-Emmons reaction. The efficiency with which these units could be incorporated into oligomers with different moieties on the C- and N terminal sides was established, as was the feasibility of sequencing oligomers containing VBAAs by tandem mass spectrometry. The data show that VBAAs will be useful building blocks for the construction of combinatorial libraries of peptidomimetic compounds. PMID- 28346552 TI - Incorporation of vanadium into the framework of hydroxyapatites: importance of the vanadium content and pH conditions during the precipitation step. AB - Even though vanadium-modified hydroxyapatite (V-HAp) samples are very promising systems for oxidative dehydrogenation of propane, the incorporation of vanadium into the hydroxyapatite framework was reported to be limited and to lead to over stoichiometric compounds. Here, the synthesis of a Ca10(PO4)6-x(VO4)x(OH)2 stoichiometric solid solution using a co-precipitation method is monitored in the whole composition range (0 <= x <= 6) by controlling the pH of the precipitation medium, with continuous (the first series of samples) or periodic (the second series of samples) addition of NH4OH during the precipitation step or during the maturation step, respectively. It is demonstrated that the changes in pH conditions result in materials of a substantial difference in terms of the final composition. From XRD patterns and Rietveld refinements, a solid solution V-HAp phase was found to be exclusively obtained for the first series of samples for x varying from 0 to 6. This also occurred in the second series of samples but only for x lower than 4. For 4 <= x <= 5.22, the materials were composed of a mixture of V-HAp and Ca2V2O7, whereas for a x value of 6 only Ca2V2O7 was formed. The predominance of polymeric V species in solution at a high vanadium concentration deduced from the diagram of speciation of vanadium accounts for the preferential formation of Ca2V2O7 under these particular conditions. However, provided that a higher pH value was maintained, isolated VO3(OH)2- species are predominant, which accounts for the incorporation of isolated vanadates into the hydroxyapatite framework and for the well-controlled stoichiometry with Ca/(P + V) ratios found to be close to 1.67. Such a very good accommodation of vanadium in the hydroxyapatite framework is illustrated by the characterization of the local surrounding of phosphorus and vanadium species using 31P and 51V NMR, Raman and UV-vis spectroscopies. PMID- 28346554 TI - Fundamental insights into interfacial catalysis. AB - Surface and interfacial catalysis plays a vital role in chemical industries, electrochemistry and photochemical reactions. The challenges of modern chemistry are to optimize the chemical reaction processes and understand the detailed mechanism of chemical reactions. Since the early 1960s, the foundation of surface science systems has allowed the study of surface and interfacial phenomena on atomic/molecular level, and thus brought a number of significant developments to fundamental and technological processes, such as catalysis, material science and biochemistry, just to name a few. This themed issue describes the recent advances and developments in the fundamental understanding of surface and interfacial catalysis, encompassing areas of knowledge from metal to metal oxide, carbide, graphene, hexagonal boron nitride, and transition metal dichalcogenides under ultrahigh vacuum conditions, as well as under realistic reaction conditions. PMID- 28346555 TI - Modulation of the cooperativity in the assembly of multistranded supramolecular polymers. AB - It is highly desirable that supramolecular polymers self-assemble following small changes in the environment. The degree of responsiveness depends on the degree of cooperativity at play during the assembly. Understanding how to modulate and quantify cooperativity is therefore highly desirable for the study and design of responsive polymers. Here we show that the cooperative assembly of a porphyrin based, double-stranded polymer is triggered by changes in building blocks and in salt concentration. We develop a model that accounts for this responsiveness by assuming the binding of the salt countercations to the double-stranded polymer. Using our assembly model we generate plots that show the increase in concentration of polymer versus the normalized concentration of monomer. These plots are ideally suited to appreciate changes in cooperativity, and show that, for our system, these changes are consistent with the increase in polymer length observed experimentally. Unexpectedly, we find that polymer stability increases when cooperativity decreases. We attribute this behaviour to the fact that increasing salt concentration stabilizes the overall polymer more than the nucleus. In other words, the cooperativity factor alpha, defined as the ratio between the growth constant Kg and the nucleation constant Kn decreases as the overall stability of the polymer increases. Using our model to simulate the data, we generate cooperativity plots to explore changes in cooperativity for multistranded polymers. We find that, for the same pairwise association constants, the cooperativity sharply increases with the number of strands in the polymer. We attribute this dependence to the fact that the larger the number of strands, the larger is the nucleus necessary to trigger polymer growth. We show therefore that the cooperativity factor alpha does not properly account for the cooperativity behaviour of multistranded polymers, or any supramolecular polymer with a nucleus composed of more than 2 building blocks, and propose the use of the corrected cooperativity factor alpham. Finally, we show that multistranded polymers display highly cooperative polymerisation with pairwise association constants as low as 10 M-1 between the building blocks, which should simplify the design of responsive supramolecular polymers. PMID- 28346558 TI - Simple synthesis of multiple length-scale structured Nb2O5 with functional macrodomain-integrated mesoporous frameworks. AB - We report the simple synthesis of macro- and mesostructured Nb2O5 that have functional submicrometer-sized particles (macrodomain) embedded in mesoporous frameworks (nanodomain). Resol can macrophase-separate by self-polymerization and co-assemble with niobia sol into mesostructured frameworks. The resultant materials increase the power conversion efficiency due to light-scattering capability of submicrometer-sized particles. PMID- 28346559 TI - Mechanism of degradation of a nitrogenous heterocycle induced by a reductive radical: decomposition of a sym-triazine ring. AB - Cyanuric acid is a major component of many materials and chemicals, and is the most important intermediate in the degradation processes of sym-triazine compounds in the natural environment, as well as being used for water treatment. However, the degradation mechanism of cyanuric acid is still unclear in various advanced oxidation processes (AOPs), where OH is usually regarded as the dominant radical. Here, using a combination of density functional theory calculations and experimental observations, we unexpectedly show that the sym-triazine ring structure is broken efficiently by reductive free radicals - hydrogen radicals (H), rather than traditional OH. The energy barrier of cyanuric acid reacting with H to form the -NH2 group and break the sym-triazine ring is only 4.96 kcal mol-1, which is clearly lower than that of cyanuric acid reacting with OH (13.32 kcal mol-1). Our theoretical predictions are further confirmed by gamma photon irradiation experiments, which show that when H is present in the reaction, the nitrogen in cyanuric acid (or other nitrogenous compounds including primidone and bezafibrate) rapidly degrades into NH4+. In contrast, when H is scavenged, cyanuric acid stops degrading into NH4+. Our results provide new insight for understanding the decomposition of nitrogenous materials, and we are the first to shed light on the key role of H in organic transformation processes. PMID- 28346561 TI - Reduced Intestinal Motility, Mucosal Barrier Function, and Inflammation in Aged Monkeys. AB - OBJECTIVE: We aimed to examine the general health and intestinal physiology of young and old non-human primates with comparable life histories and dietary environments. DESIGN: Vervet monkeys (Chlorcebus aethiops sabaeus) in stable and comparable social and nutritional environments were selected for evaluation. Health phenotype, circulating cytokines and biomarkers of microbial translocation (MT) were measured (n=26-44). Subsets of monkeys additionally had their intestinal motility, intestinal permeability, and fecal microbiomes characterized. These outcomes document age-related intestinal changes present in the absence of nutritional stressors, which are all known to affect gastrointestinal motility, microbiome, and MT. RESULTS: We found that old monkeys have greater systemic inflammation and poor intestinal barrier function as compared to young monkeys. Old monkeys have dramatically reduced intestinal motility, and all changes in motility and MT are present without large differences in fecal microbiomes. CONCLUSION: We conclude that deteriorating intestinal function is a feature of normal aging and could represent the source of inflammatory burden yet to be explained by disease or diet in normal aging human primate populations. Intestinal changes were seen independent of dietary influences and aging within a consistent environment appears to avoid major microbiome shifts. Our data suggests interventions to promote intestinal motility and mucosal barrier function have the potential to support better health with aging. PMID- 28346562 TI - Joint Association of Obesity and Hypertension with Disability in the Elderly-- A Community-Based Study of Residents in Shanghai, China. AB - BACKGROUND: Although both obesity and hypertension are known risk factors for disability, the joint association of obesity and hypertension with risk of disability is unknown. This paper is aim to examine the joint association of obesity and hypertension with risk of disability. METHODS: Cross-sectional study with 8060 elderly community-dwelling individuals participating in the survey initiated by Shanghai Health and Family Planning Commission from March to September 2013. Obesity was measured using the body mass index (BMI) in World Health Organization (WHO) Asia criteria. Hypertension, based on the doctor's diagnosis, was obtained through face-to-face interview. Disability was measured using the self-reported physical self-maintenance scale (PSMS) and the instrumental activities of daily living (IADL) scale developed by Lawton and Brody. RESULTS: A total of 8.97% of participants reported ADL disability, and 15.18% for IADL disability. After adjusting social demographics and chronic conditions, the risk of ADL disability was progressively greater in obese persons with hypertension (OR=1.40, 95% CI=1.05-1.89), underweight persons without hypertension (OR=2.05, 95% CI=1.29-3.25), and underweight persons with hypertension (OR=2.14, 95% CI=1.36-3.36). For IADL disability, only underweight persons with hypertension were significantly associated (OR=1.65, 95% CI=1.23 2.21). CONCLUSIONS: Low or extremely high BMI, independent of its metabolic consequences, is a risk factor for disability among the elderly. Simple hypertension wasn't significantly associated with disability. In addition, having hypertension significantly increased the risk of ADL disability in obese individuals and IADL disability in underweight individuals. PMID- 28346563 TI - Delivery of Nutritious Meals to Elderly Receiving Home Care: Feasibility and Effectiveness. AB - BACKGROUND/OBJECTIVES: Elderly with functional disabilities are at increased risk of inadequate dietary intake. Little is known about the effectiveness of interventions aimed at improving their dietary intake and nutritional status, nor about the determinants of successful implementation. We performed a feasibility study to evaluate the implementation and effectiveness of a home delivery service providing nutritious meals. DESIGN: Quasi-experimental, with participants allocated to treatment group based on municipality of residence. SETTING AND PARTICIPANTS: Functionally disabled home-dwelling elderly receiving home care. INTERVENTION: Three-month daily meal service consisting of dinner and snacks (intervention). The control group sustained habitual food intake. MEASUREMENTS: Data on satisfaction and problems regarding the meal service were collected by structured interviews. Dietary intake (2-day estimated food diary), nutritional status (anthropometry), handgrip strength, and quality of life (questionnaire based) was measured at baseline, three months (end of intervention), and six months (follow-up). RESULTS: Forty-four elderly were included (intervention group: 25, control group: 19). For most aspects of the meal service, approximately 90% of participants indicated being satisfied, and the large majority (70%) was interested in receiving a similar meal service in the future. At the end of the 3-month intervention, the intervention group showed a greater increase than the control group in body weight (P< 0.005), body mass index (P< 0.005), upper leg circumference (P< 0.01) and fat free mass (FFM, P< 0.03). Three months post-intervention, only the increase in FFM remained statistically significant (P< 0.05). Except for calcium intake, no positive intervention effect was observed for any of the other outcomes. CONCLUSION: Our study stresses the feasibility as well as the potential of healthy and tasteful meals to support home-dwelling elderly, by showing that a high-quality meal service was highly appreciated and had a rapid effect on FFM. PMID- 28346564 TI - The Relationship between Body Mass Index and 10-Year Trajectories of Physical Functioning in Middle-Aged and Older Russians: Prospective Results of the Russian HAPIEE Study. AB - OBJECTIVE: To investigate the associations of overweight and obesity with longitudinal decline in physical functioning (PF) among middle-aged and older Russians. DESIGN: Prospective cohort study. SETTING: Four rounds of data collection in the Russian Health, Alcohol and Psychosocial factors In Eastern Europe study with up to 10 years of follow-up. PARTICIPANTS: 9,222 men and women aged 45-69 years randomly selected from the population of two districts of Novosibirsk, Russia. MEASUREMENTS: PF score (range 0-100) was measured by the Physical Functioning Subscale (PF-10) of the 36-item Short Form Health Survey (SF 36) at baseline and three subsequent occasions. Body mass index (BMI), derived from objectively measured body height and weight at baseline, was classified into normal weight (BMI 18.5-24.9), overweight (BMI 25.0-29.9), obesity class I (BMI 30.0-34.9), and obesity class II+ (BMI>=35.0). RESULTS: The mean annual decline in the PF score during the follow-up was -1.92 (95% confidence interval -2.17; 1.68) in men and -1.91 (-2.13; -1.68) in women. At baseline, compared with normal weight, obesity classes I and II+ (but not overweight) were associated with significantly lower PF in both sexes. In prospective analyses, the decline in PF was faster in overweight men (difference from normal weight subjects -0.38 [ 0.63; -0.14]), class I obese men and women (-0.49 [-0.82; -0.17] and -0.44 [ 0.73; -0.15] respectively) and class II+ obese men and women (-1.13 [-1.73; 0.53] and -0.43 [-0.77; -0.09] respectively). Adjustment for physical activity and other covariates did not materially change the results. CONCLUSIONS: PF decreased more rapidly in obese men and women than among those with normal weight. The adverse effect of high BMI on PF trajectories appeared to be more pronounced in men than in women, making more extremely obese Russian men an important target population to prevent/slow down the process of decline in PF. PMID- 28346565 TI - Anticholinergic Burden and Functional Status in Older People with Cognitive Impairment: Results from the Regal Project. AB - OBJECTIVE: The use of drugs with intrinsic anticholinergic properties is widespread among old age persons. A growing body of evidences suggest that a high anticholinergic burden is associated with physical and cognitive impairment. However, the association between anticholinergic drug use and functional status is still poorly investigated, particularly among subjects with initial cognitive impairment. DESIGN: Cross-sectional study examining the association between drug related anticholinergic burden and functional status in cognitively healthy (CH) (n=691), mild cognitive impairment (MCI) (n=541) or mild Alzheimer's diseases (AD) (n=1127) subjects. SETTING: Data were gathered from the ReGAl project (Rete Geriatrica Alzheimer-Geriatric Network on Alzheimer's disease), a large longitudinal Italian multicentric clinical-based study, promoted by the Italian Society of Gerontology and Geriatrics (SIGG). PARTICIPANTS: 2359 outpatients, older than 65 years, admitted to memory clinics. The total sample size, estimated according to a global effect size of 25% with type I error of 0.05 and a power of 95% is 2010 subjects. MEASUREMENT: Functional status was evaluated by the Katz Index of Independence in Activities of Daily Living (ADL) and the Lawton-Brody Instrumental Activities of Daily Living (IADL) scales. The drug-related anticholinergic burden was estimated by the Anticholinergic Risk Scale (ARS). RESULTS: The 15.9 % (n=375) of total population used at least one drug with anticholinergic properties. Such a drug use was associated with partially dependence in ADL (OR:1.42, CI95%: 1.10-1.83; p=0.006), independently of gender, number of drugs, comorbidity index, presence of clinically relevant neuropsychiatric symptoms and adjusted MMSE. Anticholinergic drug use was associated with un-ability at each IADL task only in male MCI subjects, with significant impairment in shopping (p=0.011), and drug management (p=0.05). CONCLUSIONS: The use of medications with anticholinergic properties is common among older persons cognitively health as well as with cognitive impairment. Our results suggest that the use of anticholinergic drugs is associated with functional impairment, especially in old age subjects with initial cognitive impairment. Minimizing anticholinergic burden should result in maintaining daily functioning, especially in a vulnerable population, such as MCI and mild AD. PMID- 28346566 TI - Gene- Gene Interaction between PPARG and APOE Gene on Late-Onset Alzheimer's Disease: A Case- Control Study in Chinese Han Population. AB - AIMS: The aim was to investigate the impact of PPARG and APOE gene single nucleotide polymorphisms (SNPs) and additional gene- gene interaction on late onset Alzheimer's disease (LOAD) risk based on Chinese Han population. METHODS: A total of 928 participants (466 males, 462 females), with a mean age of 81.3 +/- 16.4 years old, were included in the study, including 460 LOAD patients and 468 normal controls participants. Logistic regression was performed to investigate association between SNP and LOAD risk and generalized multifactor dimensionality reduction (GMDR) was used to analysis the gene-gene interaction. RESULTS: Logistic regression analysis showed that LOAD risk was significantly higher in carriers of G allele of the rs405509 polymorphism than those with AA (AG+ GG versus AA, adjusted OR (95%CI) =1.54(1.20-1.89), and higher in carriers of G allele of the rs1805192 polymorphism than those with CC (CG+ GG versus CC, adjusted OR (95%CI) =1.32(1.16-2.43). We also found that there was a potential gene-gene interaction between rs405509 and rs1805192. Participants with AG or GG of rs405509 and CG or GG of rs1805192 genotype have the highest AD risk, compared to participants with AA of rs405509 and CC of rs1805192 genotype, OR (95%CI) was 2.62(1.64 -3.58), after covariates adjustment. CONCLUSIONS: G allele of the rs405509 of APOE and G allele of the rs1805192 of PPAR G polymorphism were associated with increased LOAD risk, and participants with AG or GG of rs405509 and CG or GG of rs1805192 genotype have the highest AD risk. PMID- 28346567 TI - Effect of a Low Glycemic Index Mediterranean Diet on Non-Alcoholic Fatty Liver Disease. A Randomized Controlled Clinici Trial. AB - INTRODUCTION: Non-Alcoholic Fatty Liver Disease (NAFLD) is currently the most common form of liver disease worldwide affecting all ages and ethnic groups and it has become a consistent threat even in young people. Our aim was to estimate the effect of a Low Glycemic Index Mediterranean Diet (LGIMD) on the NAFLD score as measured by a Liver Ultrasonography (LUS). DESIGN: NUTRIzione in EPAtologia (NUTRIEPA) is a population-based Double-Blind RCT. Data were collected in 2011 and analyzed in 2013-14. SETTING/PARTICIPANTS: 98 men and women coming from Putignano (Puglia, Southern Italy) were drawn from a previous randomly sampled population-based study and identified as having moderate or severe NAFLD. INTERVENTION: The intervention strategy was the assignment of a LGIMD or a control diet. OUTCOME MEASURES: The main outcome measure was NAFLD score, defined by LUS. RESULTS: After randomization, 50 subjects were assigned to a LGIMD and 48 to a control diet. The study lasted six months and all participants were subject to monthly controls/checks. Adherence to the LGIMD as measured by Mediterranean Adequacy Index (MAI) showed a median of 10.1. A negative interaction between time and LGIMD on the NAFLD score (-4.14, 95% CI -6.78,-1.49) was observed, and became more evident at the sixth month (-4.43, 95%CI -7.15, -1.71). A positive effect of the interaction among LGIMD, time and age (Third month: 0.07, 95% CI 0.02, 0.12; Sixth month: 0.08, 95% CI 0.03,0.13) was also observed. CONCLUSIONS: LGIMD was found to decrease the NAFLD score in a relatively short time. Encouraging those subjects who do not seek medical attention but still have NAFLD to follow a LGIMD and other life-style interventions, may reduce the degree of severity of the disease. Dietary intervention of this kind, could also form the cornerstone of primary prevention of Type 2 Diabetes Mellitus (T2DM) and cardiovascular disease. PMID- 28346568 TI - Impact of 3-Monthly Vitamin D Supplementation Plus Exercise on Survival after Surgery for Osteoporotic Hip Fracture in Adult Patients over 50 Years: A Pragmatic Randomized, Partially Blinded, Controlled Trial. AB - OBJECTIVE: To determine whether 3-monthly supplementation of an oral vitamin D widely used in Spain (calcifediol) plus daily exercise could influence survival at one and four years after surgery for osteoporotic hip fracture. DESIGN: A pragmatic, randomized, partially single-blind placebo-controlled study. SETTING: Patients admitted to a tertiary university hospital for acute hip fracture. PARTICIPANTS: 675 healthy adult patients undergoing surgery for osteoporotic hip fracture were recruited from January 2004 to December 2007. INTERVENTION: Patients were randomized to receive either 3-monthly oral doses of 3 mg calcifediol (Hidroferol Choque(r)) or placebo in the 12 months postsurgery. Patients who received calcifediol were also given an exercise programme. The placebo group received standard health recommendations only. MEASUREMENTS: The primary endpoint was survival at 1 year and at 4 year follow-up. We also recorded new fractures, medical complications and anti-osteoporotic treatment compliance. RESULTS: We included a total of 88 patients, aged 62 to 99 years. Mean age was 82 years and 88.6% were women. At 12 months, 10 (11.3%) patients had died, 9 of them, from the non-intervention group. At 4 years after surgery, 20 (22.7%) had died, 3 (3.4%) from the intervention group and 17 (19.3%) from the non intervention group. At this time, survival curve analysis showed 93% survival in the intervention group and 62% in the non-intervention group (p=0.001). At 12 month follow up, there were 18 new fractures, 9 in each group. The non intervention group had more medical complications, with significant differences at visit 2 (p = 0.04) and 3 (p = 0.02) but not at visit 4 (p = 0.18). No significant differences between groups were found regarding treatment compliance. CONCLUSION: 3-monthly, oral supplements of 3 mg calcifediol plus daily exercise improved survival at one-year and four-year follow up after surgery for an osteoporotic hip fracture. PMID- 28346569 TI - Vitamin D Supplementation in Nursing Home Residents: Randomized Single Cholecalciferol Loading Protocol vs. Individualized Loading Dose Regimen. AB - OBJECTIVE: To assess the efficacy and safety of a single cholecalciferol loading protocol in nursing home (NH) residents taking no VitD supplementation at regular basis. DESIGN: Randomized single-blind controlled study. SETTING: One NH. PARTICIPANTS: All residents. INTERVENTION: From March 21st to May 19th, 2015, NH residents were randomly assigned to either 4x100'000IU to be taken every 2 weeks (treatment group) or an individualized regimen according to baseline 25(OH)VitD level (control group). MEASUREMENTS: 25(OH)VitD, calcium, phosphorus, parathyroid hormone, alkaline phosphatase, and creatinine serum levels were centrally measured at day 7 after the last dose in both groups, and at baseline in the control group. RESULTS: 111 residents (mean age 85.1+/-6.7 years) were randomized to the treatment (N=53) or the control group (N=58). No significant difference in terms of demographic characteristics, risk for osteoporosis, and past history of VitD supplementation was measured. At baseline, 37.9%, 25.5% and 5.2% were respectively sub-optimal, insufficient, and deficient for VitD. Whatever the study group, at the 7th day after the last dose of cholecalciferol, 100% of residents reached serum values >=20ng/mL (p value for non-inferiority <0.001 and p value for superiority p=1.00) and 93.6 vs. 88.2% reached values >=30ng/mL in the treatment and control group respectively (p value for non-inferiority <0.01 and p value for superiority p=0.48). While mean value was higher in the treatment group (50.2+/-615.4 vs. 35.8+/-66.5ng/mL; p<0.0001), none of participants have seen their value >150 ng/mL. Not any biological adverse effects was measured. CONCLUSION: This study confirmed that a single loading protocol is at least as effective and safe as tailored regimen in terms of the ability to rapidly normalize 25(OH)VitD values. The often required dosage of 25(OH)VitD is reasonably not necessary to initiate VitD supplementation protocol in this vulnerable population. PMID- 28346570 TI - Tolerance and Long-Term Efficacy of Polyethylene Glycol 4000 (Forlax(r)) Compared to Lactulose in Elderly Patients with Chronic Constipation. AB - OBJECTIVES: To assess the tolerance and potential nutritional consequences of long-term repeated doses of PEG 4000 (10 to 30 g/day) in elderly patients with chronic constipation as compared to lactulose (10-30 g/day). DESIGN: Single blind, randomised, multicentre, parallel group comparative study. SETTING: Community-dwelling patients and nursing homes residents aged 70 years and older with a history of chronic constipation. Treatment intervention: PEG 4000 (10-30 g/day) or lactulose (10-30 g/day) for six months. ASSESSMENTS: Clinical nutritional status (Mini Nutritional Assessment), blood and stool samples were taken at baseline and after three and six months for assay of nutritional and absorption parameters. A patient diary documented digestive symptoms and adverse events were recorded. Information on efficacy (stool frequency and consistency) was collected as a secondary outcome measure. RESULTS: Of the 316 patients screened, 245 eligible patients constituted the ITT population (PEG 4000: N = 118; lactulose group: N = 127). The proportion of patients receiving PEG 4000 with abnormal levels of electrolytes, nutritional markers or vitamins did not significantly change in the six months after initiating laxative treatment and do not differ between the two groups. After a D-xylose challenge test, the proportion of patients with abnormally low xylosaemia (suggesting malabsorption) varied from 24.6% at baseline to 35.8% after six months in the PEG 4000 group and from 29.1% to 42.4% in the lactulose group, with no significant between-group or within-group differences. The proportion of patients with poor nutritional status (MNA score <17) varied from 8.5% at baseline to 9.8% after 6 months in the PEG 4000 group and from 3.9% to 5.0% in the lactulose group. No changes in stool fat or total or soluble stool nitrogen were observed in the minority of patients for whom stool analysis was performed. A significantly higher stool frequency (p <0.05) and improved stool consistency (p <0.05) was observed in the PEG 4000 group compared to the lactulose group at each monthly evaluation period. CONCLUSIONS: After six months of treatment with PEG 4000, no clinically relevant changes in biochemical and nutritional parameters and no unanticipated treatment related adverse events were detected, demonstrating the good clinical tolerance of PEG 4000 in this population of elderly constipated patients. This tolerance was associated with a better clinical efficacy of PEG 4000 compared to lactulose. PMID- 28346572 TI - Effectiveness of Cardiac Rehabilitation for Prevention and Treatment of Sarcopenia in Patients with Cardiovascular Disease - A Retrospective Cross Sectional Analysis. AB - OBJECTIVE: Sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength, with the risk of frailty and poor quality of life. This study aimed to clarify the clinical characteristics of sarcopenia and to investigate the effects of comprehensive cardiac rehabilitation (CCR), including nutrition, physical exercise and medication, in patients with cardiovascular disease (CVD). METHODS: We retrospectively studied 322 inpatients with CVD (age 72+/-12 years). Muscle mass, muscle strength and physical performance were assessed before and after exercise training in patients with and without sarcopenia, which was defined as either a gait speed of <0.8 m/s or reduced handgrip strength (<26 kg in males and <18 kg in females), together with lower skeletal muscle index (SMI) (<7.0 kg/m2 in males and <5.7 kg/m2 in females). The actual daily total calorie and nutrient intake was also calculated. RESULTS: Sarcopenia was identified in 28% of patients with CVD, these patients having a higher prevalence of symptomatic chronic heart failure and chronic kidney disease. SMI was significantly associated with protein intake and statin treatment. The ratio of peak VO2 and SMI was significantly higher in the statin treatment group. Handgrip strength, gait speed, leg weight bearing index, and nutritional intake improved after exercise training in patients both with and without sarcopenia. CONCLUSIONS: The present findings suggest that CCR is a promising strategy for prevention and treatment of sarcopenia in patients with CVD. PMID- 28346571 TI - Is the Ergogenicity of Caffeine Affected by Increasing Age? The Direct Effect of a Physiological Concentration of Caffeine on the Power Output of Maximally Stimulated EDL and Diaphragm Muscle Isolated from the Mouse. AB - INTRODUCTION: Caffeine is a well-established performance enhancing nutritional supplement in a young healthy population, however far less is known about how its ergogenicity is affected by increasing age. A recent review has highlighted the value of studies examining the direct effect of caffeine on isolated skeletal muscle contractility, but the present work is the first to assess the direct effect of 70uM caffeine (physiological maximum) on the maximal power output of isolated mammalian muscle from an age range representing developmental to early ageing. METHOD: Female CD1 mice were aged to 3, 10, 30 and 50 weeks (n = 20 in each case) and either whole EDL or a section of the diaphragm was isolated and maximal power output determined using the work loop technique. Once contractile performance was maximised, each muscle preparation was treated with 70uM caffeine and its contractile performance was measured for a further 60 minutes. RESULTS: In both mouse EDL and diaphragm 70uM caffeine treatment resulted in a significant increase in maximal muscle power output that was greatest at 10 or 30 weeks (up to 5% and 6% improvement respectively). This potentiation of maximal muscle power output was significantly lower at the early ageing time point, 50 weeks (up to 3% and 2% improvement respectively), and in mice in the developmental stage, at 3 weeks of age (up to 1% and 2% improvement respectively). CONCLUSION: Uniquely, the present findings indicate a reduced age specific sensitivity to the performance enhancing effect of caffeine in developmental and aged mice which is likely to be attributed to age related muscle growth and degradation, respectively. Importantly, the findings indicate that caffeine may still provide a substantial ergogenic aid in older populations which could prove important for improving functional capacity in tasks of daily living. PMID- 28346574 TI - Size Matters! Differences in Nutritional Care between Small, Medium and Large Nursing Homes in Germany. AB - OBJECTIVES: The aim of this study is to comprehensively describe nutritional care in German nursing homes (NHs) and to examine if nutritional care differs between small, medium and large NHs. DESIGN: Nationwide cross-sectional postal survey. SETTING: Nursing homes. PARTICIPANTS: 541 NHs across Germany. MEASUREMENTS: Information on structural NH characteristics and nutritional care (food provision and menu planning, nursing care, and management and quality assurance) was collected by means of a questionnaire addressed to the management of a random sample of German NHs. NHs were grouped by size as small (<= 50 beds), medium (50 100 beds) or large (> 100 beds) institutions. Frequencies were used to describe nutritional care, and Chi2-test to identify differences in nutritional care by NH size. RESULTS: Aspects in the domain of food provision and menu planning regarding food variety and choice were widely implemented in German NHs (77 - 100 %). Best results were achieved in the domain of nursing care, where all aspects were implemented in at least 68 % of the NHs. Aspects regarding management and quality assurance, especially those concerning staffing, i.e. the availability of an interface manager (14 %), an interdisciplinary nutrition team (12 %) and a dietician (42 %), were only rarely implemented. Differences by NH size were found between small and medium or large NHs. On the one hand, small NHs stated more often to consider individual capabilities of the residents with texture-modified food (81 % vs. 60 %, p<0.05) and produce more often hot meals at ward level on a regular base (46 % vs. 32 %, p<0.05) than large NHs. On the other hand, several aspects regarding food provision and menu planning, and management and quality assurance were significantly more often implemented in larger than smaller NHs. CONCLUSION: Whereas kitchen and nursing-related aspects of nutritional care seem to be widely implemented in German NHs, management and quality assurance demands are often not met. The differences found by NH size support the hypothesis that the number of residents living in a NH has an impact on how nutritional care is performed. PMID- 28346573 TI - Assessment of Glycemic Control in Nursing Home Residents with Diabetes. AB - OBJECTIVE: To describe glycemic control in nursing home residents with diabetes and to evaluate the relevance of HbA1c in the detection of hypoglycemia risk. DESIGN AND METHODS: Diabetes treatment, geriatric assessment, blood capillary glucose (n= 24,682), and HbA1c were collected from medical charts of 236 southern France nursing home residents during a 4-month period. Glycemic control was divided into four categories: tight, fair, and moderate or severe chronic hyperglycemia using the High Blood Glucose Index or the analysis of blood glucose frequency distribution. Hypoglycemia episodes were identified by medical or biological records. RESULTS: Glucose control was tight in 59.3 % and fair in 19.1 % of the residents. Chronic exposure to hyperglycemia was observed in 21.6 % of the residents (severe in 9.7 % and moderate in 11.9 %). Hypoglycemia was noticed in 42/236 (17.8%), in all categories of glycemic control. Relative hypoglycemia risk was significantly (P = 0.0095) higher in residents with moderate chronic hyperglycemia compared with those with tight control. The majority of residents with hypoglycemia (39/42) or chronic hyperglycemia (45/51) were insulin-treated. The relative risk of hypoglycemia was not significantly associated with HbA1c values. CONCLUSION: Hypoglycemia risk in nursing home residents is observed in all categories of glycemic control. In tight control, the potency of antidiabetic treatment should be reduced. In chronic hyperglycemia, diet and treatment should be reevaluated in order to reduce glucose variability. HbA1c is not sufficient for hypoglycemia risk detection; capillary blood glucose monitoring is warranted for nursing homes residents with diabetes. PMID- 28346576 TI - A New Sign of Intracerebral Hematoma Expansion. PMID- 28346577 TI - Medicaid Expenditures and Estimated Rebates for Epinephrine Autoinjectors, 2012 to 2016. PMID- 28346575 TI - Perceptions of Healthcare Professionals on the Usage of Percutaneous Endoscopic Gastrostomy in a Teaching Hospital from a Middle-Income South East Asian Country. AB - OBJECTIVE: To explore the perceptions of healthcare professionals' (HCPs) in a South East Asian nation towards percutaneous endoscopic gastrostomy (PEG) feeding. DESIGN: Semi-structured, qualitative interviews. SETTINGS: A teaching hospital in Kuala Lumpur, Malaysia. PARTICIPANTS: A total of 17 healthcare professionals aged 23-43 years, 82% women. RESULTS: Thematic analysis revealed five themes that represent HCPs' perceptions in relation to the usage of PEG feeding: 1) knowledge of HCPs, 2) communication, 3) understanding among patients, and 4) financial and affordability. CONCLUSION: The rationale for reluctance towards PEG feeding observed in this regions was explained by lack of education, knowledge, communication, team work, and financial support. Future studies should assess the effects of educational programmes among HCPs and changes in policies to promote affordability on the utilization of PEG feeding in this region. PMID- 28346579 TI - Seeing the Effect of Health Care Delivery Innovation in the Safety Net. PMID- 28346578 TI - Association of Plasma Neurofilament Light With Neurodegeneration in Patients With Alzheimer Disease. AB - Importance: Existing cerebrospinal fluid (CSF) or imaging (tau positron emission tomography) biomarkers for Alzheimer disease (AD) are invasive or expensive. Biomarkers based on standard blood test results would be useful in research, drug development, and clinical practice. Plasma neurofilament light (NFL) has recently been proposed as a blood-based biomarker for neurodegeneration in dementias. Objective: To test whether plasma NFL concentrations are increased in AD and associated with cognitive decline, other AD biomarkers, and imaging evidence of neurodegeneration. Design, Setting, and Participants: In this prospective case control study, an ultrasensitive assay was used to measure plasma NFL concentration in 193 cognitively healthy controls, 197 patients with mild cognitive impairment (MCI), and 180 patients with AD dementia from the Alzheimer's Disease Neuroimaging Initiative. The study dates were September 7, 2005, to February 13, 2012. The plasma NFL analysis was performed in September 2016. Main Outcomes and Measures: Associations were tested between plasma NFL and diagnosis, Abeta pathologic features, CSF biomarkers of neuronal injury, cognition, brain structure, and metabolism. Results: Among 193 cognitively healthy controls, 197 patients with mild cognitive impairment, and 180 patients with AD with dementia, plasma NFL correlated with CSF NFL (Spearman rho = 0.59, P < .001). Plasma NFL was increased in patients with MCI (mean, 42.8 ng/L) and patients with AD dementia (mean, 51.0 ng/L) compared with controls (mean, 34.7 ng/L) (P < .001) and had high diagnostic accuracy for patients with AD with dementia vs controls (area under the receiver operating characteristic curve, 0.87, which is comparable to established CSF biomarkers). Plasma NFL was particularly high in patients with MCI and patients with AD dementia with Abeta pathologic features. High plasma NFL correlated with poor cognition and AD related atrophy (at baseline and longitudinally) and with brain hypometabolism (longitudinally). Conclusions and Relevance: Plasma NFL is associated with AD diagnosis and with cognitive, biochemical, and imaging hallmarks of the disease. This finding implies a potential usefulness for plasma NFL as a noninvasive biomarker in AD. PMID- 28346580 TI - Searching for Neurodegeneration in the Blood of Patients With Alzheimer Disease. PMID- 28346581 TI - Home-Based Hypnotherapy Self-exercises vs Individual Hypnotherapy With a Therapist for Treatment of Pediatric Irritable Bowel Syndrome, Functional Abdominal Pain, or Functional Abdominal Pain Syndrome: A Randomized Clinical Trial. AB - Importance: Individual gut-directed hypnotherapy (HT) is effective in pediatric irritable bowel syndrome (IBS) and functional abdominal pain or functional abdominal pain syndrome (FAP[S]). It is, however, unavailable to many children. Objective: To compare the effectiveness of HT by means of home-based self exercises using a CD with that of individual HT (iHT) performed by qualified therapists. Design, Setting, and Participants: This noninferiority randomized clinical trial with a follow-up of 1 year after the end of treatment was conducted from July 15, 2011, through June 24, 2013, at 9 secondary and tertiary care centers throughout the Netherlands. A total of 303 children were eligible to participate. Of those, 260 children (aged 8-18 years) with IBS or FAP(S) were included in this study. Children were randomized (1:1 ratio) to home-based HT with a CD (CD group) or iHT performed by qualified therapists (iHT group). No children withdrew from the study because of adverse effects. Interventions: The CD group was instructed to perform exercises 5 times per week or more for 3 months. The iHT group consisted of 6 sessions during 3 months. Main Outcomes and Measures: Primary outcomes were treatment success directly after treatment and after 1-year follow-up. Treatment success was defined as a 50% or greater reduction in pain frequency and intensity scores. The noninferiority limit was set at 50% treatment success in the CD group, with a maximum of 25% difference in treatment success with the iHT group after 1-year follow-up. Modified intention to-treat analyses were performed. Results: A total of 132 children were assigned to the CD group and 128 to the iHT group; 250 children were analyzed (126 in the CD group and 124 in the iHT group) (mean [SD] age, 13.4 [2.9] years in the CD group and 13.3 [2.8] years in the iHT group; 94 female [74.6%] in the CD group and 85 [68.5%] in the iHT group). Directly after treatment, 46 children (36.8%) in the CD group and 62 (50.1%) in the iHT group were successfully treated. After 1-year follow-up, the 62.1% treatment success in the CD group was noninferior to the 71.0% in the iHT group (difference, -8.9%; 90% CI, -18.9% to 0.7%; P = .002). Conclusions and Relevance: Long-term effectiveness of home-based HT with a CD is noninferior to iHT performed by therapists in pediatric IBS or FAP(S). Treatment with hypnosis using a CD provides an attractive treatment option for these children. Trial Registration: trialregister.nl Identifier: NTR2725. PMID- 28346583 TI - Staging CT Scans in Early-Stage Chronic Lymphocytic Leukemia. PMID- 28346582 TI - Rates and Characteristics of Paid Malpractice Claims Among US Physicians by Specialty, 1992-2014. AB - Importance: Although physician concerns about medical malpractice are substantial, national data are lacking on the rate of claims paid on behalf of US physicians by specialty. Objective: To characterize paid malpractice claims by specialty. Design, Setting, and Participants: A comprehensive analysis was conducted of all paid malpractice claims, with linkage to physician specialty, from the National Practitioner Data Bank from January 1, 1992, to December 31, 2014, a period including an estimated 19.9 million physician-years. All dollar amounts were inflation adjusted to 2014 dollars using the Consumer Price Index. The dates on which this analysis was performed were from May 1, 2015, to February 20, 2016, and from October 25 to December 16, 2016. Main Outcomes and Measures: For malpractice claims (n = 280 368) paid on behalf of physicians (in aggregate and by specialty): rates per physician-year, mean compensation amounts, the concentration of paid claims among a limited number of physicians, the proportion of paid claims that were greater than $1 million, severity of injury, and type of malpractice alleged. Results: From 1992-1996 to 2009-2014, the rate of paid claims decreased by 55.7% (from 20.1 to 8.9 per 1000 physician-years; P < .001), ranging from a 13.5% decrease in cardiology (from 15.6 to 13.5 per 1000 physician years; P = .15) to a 75.8% decrease in pediatrics (from 9.9 to 2.4 per 1000 physician-years; P < .001). The mean compensation payment was $329 565. The mean payment increased by 23.3%, from $286 751 in 1992-1996 to $353 473 in 2009-2014 (P < .001). The increases ranged from $17 431 in general practice (from $218 350 in 1992-1996 to $235 781 in 2009-2014; P = .36) to $114 410 in gastroenterology (from $276 128 in 1992-1996 to $390 538 in 2009-2014; P < .001) and $138 708 in pathology (from $335 249 in 1992-1996 to $473 957 in 2009-2014; P = .005). Of 280 368 paid claims, 21 271 (7.6%) exceeded $1 million (4304 of 69 617 [6.2%] in 1992 1996 and 4322 of 54 081 [8.0%] in 2009-2014), and 32.1% (35 293 of 109 865) involved a patient death. Diagnostic error was the most common type of allegation, present in 31.8% (35 349 of 111 066) of paid claims, ranging from 3.5% in anesthesiology (153 of 4317) to 87.0% in pathology (915 of 1052). Conclusions and Relevance: Between 1992 and 2014, the rate of malpractice claims paid on behalf of physicians in the United States declined substantially. Mean compensation amounts and the percentage of paid claims exceeding $1 million increased, with wide differences in rates and characteristics across specialties. A better understanding of the causes of variation among specialties in paid malpractice claims may help reduce both patient injury and physicians' risk of liability. PMID- 28346584 TI - Stimulant Use and Bone Mineral Density-Reply. PMID- 28346585 TI - Improving Public Health by Making Cities Friendly to Walking and Biking: Safer, More Active Transportation Starts With the Street. PMID- 28346586 TI - Human Immunodeficiency Virus Presenting as Progressive Multifocal Leukoencephalopathy Restricted to the Posterior Fossa. PMID- 28346587 TI - A New Sign of Intracerebral Hematoma Expansion-Reply. PMID- 28346588 TI - Association Between Childhood-Onset Epilepsy and Amyloid Burden 5 Decades Later. AB - Importance: The effect of childhood epilepsy on later-life cognitive and brain health is an unclear and little-explored issue. Objective: To determine whether adults with a history of childhood-onset epilepsy exhibit increased brain amyloid accumulation, possibly predisposing to accelerated cognitive impairment or even frank cognitive disorders in later life. Design, Setting, and Participants: Forty one adults from a population-based cohort of individuals with childhood-onset epilepsy in southwestern Finland, together with 46 matched population-based controls, underwent amyloid ligand carbon 11-labeled Pittsburgh Compound B (PiB) positron emission tomography after long-term prospective follow-up. The PiB uptake was quantified as a region to cerebellar cortex ratio. Tracer uptake was evaluated visually and analyzed voxel by voxel over the entire brain to investigate the spatial distribution of amyloid deposition. The study was conducted from May 2011 to October 2013; data analysis was performed from January 2014 to October 2016. Main Outcomes and Measures: Brain amyloid accumulation. Results: The 41 individuals with epilepsy were originally enrolled in the Turku Adult Childhood Onset Epilepsy study at the mean (SD) age of 5.1 (4.5) years (range, 0-14 years). After a mean 52.5 (4.0) years of follow-up, the participants were evaluated (26 [63%] were women; the mean [SD] age was 56.0 [4.3] years). Nine individuals with childhood-onset epilepsy (22%) and 3 control participants (7%) had a visually abnormal PiB scan showing high cortical uptake in at least 1 of the evaluated brain regions (P = .04). In semiquantitative analyses, there was a significant interaction effect indicating higher prefrontal cortex uptake in apolipoprotein E (APOE) epsilon4 allele carriers than in noncarriers in participants (mean [SD], 1.66 [0.41] vs 1.43 [0.15]) compared with controls (1.40 [0.26) vs 1.41 [0.12]) (group * APOE interaction, F = 6.8; P = .01). In addition, there was a significant group effect showing higher tracer uptake in participants compared with controls (group effect, F = 8.0; P = .006). Conclusions and Relevance: Adults with childhood-onset epilepsy, particularly APOE epsilon4 carriers, have an increased brain amyloid load at late middle age. Thus, epilepsy is linked with a biomarker that might be related to accelerated brain aging and can be considered a neurobiological predisposition to later-life cognitive disorders. PMID- 28346589 TI - Comparison of Antibiotic Therapy and Appendectomy for Acute Uncomplicated Appendicitis in Children: A Meta-analysis. AB - Importance: Antibiotic therapy for acute uncomplicated appendicitis is effective in adult patients, but its application in pediatric patients remains controversial. Objective: To compare the safety and efficacy of antibiotic treatment vs appendectomy as the primary therapy for acute uncomplicated appendicitis in pediatric patients. Data Sources: The PubMed, MEDLINE, EMBASE, and Cochrane Library databases and the Cochrane Controlled Trials Register for randomized clinical trials were searched through April 17, 2016. The search was limited to studies published in English. Search terms included appendicitis, antibiotics, appendectomy, randomized controlled trial, controlled clinical trial, randomized, placebo, drug therapy, randomly, and trial. Study Selection: Randomized clinical trials and prospective clinical controlled trials comparing antibiotic therapy with appendectomy for acute uncomplicated appendicitis in pediatric patients (aged 5-18 years) were included in the meta-analysis. The outcomes included at least 2 of the following terms: success rate of antibiotic treatment and appendectomy, complications, readmissions, length of stay, total cost, and disability days. Data Extraction and Synthesis: Data were independently extracted by 2 reviewers. The quality of the included studies was examined in accordance with the Cochrane guidelines and the Newcastle-Ottawa criteria. Data were pooled using a logistic fixed-effects model, and the subgroup pooled risk ratio with or without appendicolith was estimated. Main Outcomes and Measures: The primary outcome was the success rate of treatment. The hypothesis was formulated before data collection. Results: A total of 527 articles were screened. In 5 unique studies, 404 unique patients with uncomplicated appendicitis (aged 5-15 years) were enrolled. Nonoperative treatment was successful in 152 of 168 patients (90.5%), with a Mantel-Haenszel fixed-effects risk ratio of 8.92 (95% CI, 2.67-29.79; heterogeneity, P = .99; I2 = 0%). Subgroup analysis showed that the risk for treatment failure in patients with appendicolith increased, with a Mantel-Haenszel fixed-effects risk ratio of 10.43 (95% CI, 1.46-74.26; heterogeneity, P = .91; I2 = 0%). Conclusions and Relevance: This meta-analysis shows that antibiotics as the initial treatment for pediatric patients with uncomplicated appendicitis may be feasible and effective without increasing the risk for complications. However, the failure rate, mainly caused by the presence of appendicolith, is higher than for appendectomy. Surgery is preferably suggested for uncomplicated appendicitis with appendicolith. PMID- 28346590 TI - Implementation and Evaluation of a Large-Scale Teleretinal Diabetic Retinopathy Screening Program in the Los Angeles County Department of Health Services. AB - Importance: Diabetic retinopathy (DR) is the leading cause of blindness in adults of working age in the United States. In the Los Angeles County safety net, a nonvertically integrated system serving underinsured and uninsured patients, the prevalence of DR is approximately 50%, and owing to limited specialty care resources, the average wait times for screening for DR have been 8 months or more. Objective: To determine whether a primary care-based teleretinal DR screening (TDRS) program reduces wait times for screening and improves timeliness of needed care in the Los Angeles County safety net. Design, Setting, and Participants: Quasi-experimental, pretest-posttest evaluation of exposure to primary care-based TDRS at 5 of 15 Los Angeles County Department of Health Services safety net clinics from September 1, 2013, to December 31, 2015, with a subgroup analysis of random samples of 600 patients before and after the intervention (1200 total). Exposure: Primary care clinic-based teleretinal screening for DR. Main Outcomes and Measures: Annual rates of screening for DR before and after implementation of the TDRS program across the 5 clinics, time to screening for DR in a random sample of patients from these clinics, and a description of the larger framework of program implementation. Results: Among the 21 222 patients who underwent the screening (12 790 female, 8084 male, and 348 other gender or not specified; mean [SD] age, 57.4 [9.6] years), the median time to screening for DR decreased from 158 days (interquartile range, 68-324 days) before the intervention to 17 days (interquartile range, 8-50 days) after initiation of the program (P < .001). Overall annual screening rates for DR increased from 5942 of 14 633 patients (40.6%) before implementation to 7470 of 13 133 patients (56.9%) after initiation of the program at all 15 targeted clinics (odds ratio, 1.9; 95% CI, 1.3-2.9; P = .002). Of the 21 222 patients who were screened, 14 595 (68.8%) did not require referral to an eye care professional, 4160 (19.6%) were referred for treatment or monitoring of DR, and 2461 (11.6%) were referred for other ophthalmologic conditions. Conclusions and Relevance: A digital TDRS program was successfully implemented for the largest publicly operated county safety net population in the United States, resulting in the elimination of the need for more than 14 000 visits to specialty care professionals, a 16.3% increase in annual rates of screening for DR, and an 89.2% reduction in wait times for screening. Teleretinal DR screening programs have the potential to maximize access and efficiency in the safety net, where the need for such programs is most critical. PMID- 28346591 TI - Out-of-Pocket Spending Among Commercially Insured Patients for Epinephrine Autoinjectors Between 2007 and 2014. PMID- 28346592 TI - Medical Treatment of Pediatric Appendicitis: Are We There Yet? PMID- 28346593 TI - Parental Sharing on the Internet: Child Privacy in the Age of Social Media and the Pediatrician's Role. PMID- 28346594 TI - Stimulant Use and Bone Mineral Density. PMID- 28346596 TI - Withholding Proton Pump Inhibitors to Prevent Recurrent Clostridium difficile: Time for a Randomized Trial. PMID- 28346595 TI - Association of Gastric Acid Suppression With Recurrent Clostridium difficile Infection: A Systematic Review and Meta-analysis. AB - Importance: Gastric acid suppression has been associated with an increased risk of primary Clostridium difficile infection (CDI), but the risk of recurrent CDI in patients taking gastric acid suppressant medications is unclear. Objective: To perform a systematic review and meta-analysis to evaluate the association between gastric acid suppressants and recurrent CDI. Data Sources: MEDLINE, EMBASE, the Cochrane Central Register, the Cochrane Database, and Web of Science were searched from January 1, 1995, to September 30, 2015, for studies assessing the association between gastric acid suppressant exposure and recurrent CDI. Search terms included Clostridium difficile, pseudomembranous colitis, proton pump inhibitor, and histamine H2 blocker. Study Selection: Case-control studies, cohort studies, and clinical trials that included patients with CDI who did or did not receive gastric acid suppressant therapy and who were evaluated for recurrent CDI were included, with no restriction on study setting (inpatient or outpatient). Data Extraction and Synthesis: The Newcastle-Ottawa scale was used to assess the methodologic quality of included studies. In this scale, case control and cohort studies were scored on selection, comparability, and ascertainment of the outcome of interest. Data were independently abstracted to a predetermined collection form by 2 investigators. Summary odds ratio estimates with 95% CIs were calculated using the random-effects model and software to calculate the pooled effect size of studies reporting multivariate analyses. Main Outcomes and Measures: Risk of recurrent infection in patients with CDI and its association with use of gastric acid suppressant medication. Results: Sixteen observational studies were included, together reporting 7703 patients with CDI; among these, 1525 patients (19.8%) developed recurrent CDI. The rate of recurrent CDI in patients with gastric acid suppression was 22.1% (892 of 4038 patients) compared with 17.3% (633 of 3665) in patients without gastric acid suppression, which indicated an increased risk by meta-analysis (odds ratio [OR], 1.52; 95% CI, 1.20-1.94; P < .001). There was significant heterogeneity among the studies, with an I2 value of 64%. Subgroup analyses of studies adjusting for age and potential confounders confirmed an increased risk of recurrent CDI with use of gastric acid suppressants (OR, 1.38; 95% CI, 1.08-1.76; P = .02). Conclusions and Relevance: Meta-analyses of observational studies suggest that patients who receive gastric acid suppressants may be at increased risk for recurrent CDI. These data should be interpreted with caution because they may be confounded owing to the observational design of the individual studies. It may be reasonable to re-evaluate the need for these medications in patients with CDI. PMID- 28346598 TI - Association Between Family Characteristics and the Effect of Timing of Regular Egg Introduction in Infant Egg Allergy. PMID- 28346599 TI - Genomics, Health Disparities, and Missed Opportunities for the Nation's Research Agenda. PMID- 28346600 TI - Changes in Osteopathic Medical Education: The Journey Continues. PMID- 28346597 TI - Association of Risk of Viremia, Immunosuppression, Serious Clinical Events, and Mortality With Increasing Age in Perinatally Human Immunodeficiency Virus Infected Youth. AB - Importance: As perinatally human immunodeficiency virus-infected youth (PHIVY) in the United States grow older and more treatment experienced, clinicians need updated information about the association of age, CD4 cell count, viral load (VL), and antiretroviral (ARV) drug use with risk of opportunistic infections, key clinical events, and mortality to understand patient risks and improve care. Objective: To examine the incidence or first occurrence during follow-up of key clinical events (including Centers for Disease Control and Prevention stage B [CDC-B] and stage C [CDC-C] events) and mortality among PHIVY stratified by age, CD4 cell count, and VL and ARV status. Design, Setting, and Participants: Combining data from the Pediatric HIV/AIDS Cohort Study (PHACS) Adolescent Master Protocol and International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1074 multicenter cohort studies (March 2007 through April 2015), we estimated event rates during person-time spent in key strata of age (7-12, 13-17, and 18-30 years), CD4 cell count (<200, 200-499, and >=500/MUL), and a combined measure of VL and ARV status (VL <400 or >=400 copies/mL; ARV therapy or no ARV therapy). A total of 1562 participants in the PHACS Adolescent Master Protocol and IMPAACT P1074 were eligible, and 1446 PHIVY from 41 ambulatory sites in the 12 US states, including Puerto Rico were enrolled. The dates of analysis were March 2015 through January 2017. Main Outcomes and Measures: Clinical event rates stratified by person-time in age, CD4 cell count, and VL and ARV categories. Results: A total of 1446 PHIVY participated in the study (mean [SD] age, 14.6 [4.6] years; 759 female [52.5%]; 953 black [65.9%]). During a mean (SD) follow-up of 4.9 (1.3) years, higher incidences of CDC-B events, CDC-C events, and mortality were observed as participants aged. Older PHIVY (aged 13-17 and 18-30 years) spent more time with a VL of 400 copies/mL or more and with a CD4 cell count of less than 200/uL compared with 7- to 12-year-old participants (30% and 44% vs 22% of person-time with a VL>=400 copies/mL; 5% and 18% vs 2% of person time with CD4 cell count <200/uL; P < .001 for each comparison). We observed higher rates of CDC-B events, CDC-C events, bacterial infections, and mortality at lower CD4 cell counts, as expected. The mortality rate among older PHIVY was 6 to 12 times that among the general US population. Higher rates of sexually transmitted infections were also observed at lower CD4 cell counts after adjusting for age. Conclusions and Relevance: Older PHIVY were at increased risk of viremia, immunosuppression, CDC-B events, CDC-C events, and mortality. Interventions to improve ARV therapy adherence and optimize models of care for PHIVY as they age are urgently needed to improve long-term outcomes among PHIVY. PMID- 28346601 TI - Single Accreditation System Update: Gaining Momentum. AB - In July 2014, the American Osteopathic Association House of Delegates endorsed the establishment of a new, single graduate medical education accreditation system in collaboration with the Accreditation Council for Graduate Medical Education and the American Association of Colleges of Osteopathic Medicine. Since that time, the osteopathic medical community has made substantial headway in the transition to the new system. This article provides an update on the transition. PMID- 28346602 TI - Attitudes of Family Medicine Program Directors Toward Osteopathic Residents Under the Single Accreditation System. AB - BACKGROUND: Between 2015 and 2020, residency programs accredited through the American Osteopathic Association (AOA) are preparing the single graduate medical education (GME) system through the Accreditation Council for Graduate Medical Education (ACGME). OBJECTIVES: (1) To assess the attitudes of family medicine program directors in programs accredited dually by the AOA and ACGME (AOA/ACGME) or ACGME only toward the clinical and academic preparedness of osteopathic residency candidates and (2) to determine program director attitudes toward the perceived value of osteopathic-focused education, including osteopathic manipulative treatment (OMT) curricula. METHODS: A survey was sent to program directors of AOA/ACGME and ACGME-only accredited family medicine residency programs. Items concerned program directors' perception of the academic and clinical strength of osteopathic residents at the onset of residency, the presence of osteopathic faculty and residents currently in the program, and the presence of formal curricula for teaching OMT. The perceived value of osteopathic focus was obtained through a composite score of 5 items. RESULTS: A total of 38 AOA/ACGME family medicine residency program directors (17%) and 211 ACGME family medicine residency program directors (45.6%) completed the survey (N=249). No difference was found in the ranking of the perceived clinical preparation of osteopathic residents vs allopathic residents in programs with and without OMT curricula (P=.054). Directors of programs with OMT curricula perceived the academic preparation of their osteopathic residents vs allopathic residents more highly than those without OMT curricula (P=.039). Directors of AOA/ACGME programs perceived both the academic preparation and clinical preparation of their osteopathic residents more highly than those at ACGME-only programs (P=.004 and P=.002, respectively). CONCLUSION: Directors of AOA/ACGME programs, as well as those whose programs have an osteopathic focus in curricular offerings, were more likely to rank the academic preparation of osteopathic residents higher than directors of ACGME-only programs and those without OMT curricula. Further research is needed to determine the value of osteopathic recognition in attracting strong family medicine residency candidates. PMID- 28346603 TI - Residency Program Directors' Interview Methods and Satisfaction With Resident Selection Across Multiple Specialties. AB - CONTEXT: Competition for postdoctoral training positions is at an all-time high, and residency program directors continue to have little direction when it comes to structuring an effective interview process. OBJECTIVES: To examine whether a relationship existed between interview methods used and program director satisfaction with resident selection decisions and whether programs that used methods designed to assess candidate personal characteristics were more satisfied with their decisions. METHODS: Residency directors from the Statewide Campus System at the Michigan State University College of Osteopathic Medicine were invited to complete a 20-item survey regarding their recent interview methods and proportion of resident selections later regretted. Data analyses examined relationships between interview methods used, frequency of personal characteristics evaluated, and subsequent satisfaction with selected residents. RESULTS: Of the 186 program director surveys distributed, 83 (44.6%) were returned, representing 11 clinical specialty areas. In total, 69 responses (83.1%) were from programs accredited by the American Osteopathic Association only, and 14 (16.9%) were from programs accredited dually by the American Osteopathic Association and Accreditation Council for Graduate Medical Education. The most frequent interview method reported was faculty or peer resident interview. No statistically significant correlational relationships were found between type of interview methods used and subsequent satisfaction with selected residents, either within or across clinical specialties. Although program directors rated ethical behavior/honesty as the most highly prioritized characteristic in residents, 27 (32.5%) reported using a specific interview method to assess this trait. Program directors reported later regrets concerning nearly 1 of every 12 resident selection decisions. CONCLUSION: The perceived success of an osteopathic residency program's interview process does not appear to be related to methods used and is not distinctively different from that of programs dually accredited. The findings suggest that it may not be realistic to aim for standardization of a common set of best interview methods or ideal personal characteristics for all programs. Each residency program's optimal interview process is likely unique, more dependent on analyzing why some resident selections are regretted and developing an interview process designed to assess for specific desirable and unwanted characteristics. PMID- 28346604 TI - Blended Learning Educational Format for Third-Year Pediatrics Clinical Rotation. AB - CONTEXT: Traditional medical education is shifting to incorporate learning technologies and online educational activities with traditional face-to-face clinical instruction to engage students, especially at remote clinical training sites. OBJECTIVE: To describe and evaluate the effectiveness of the blended learning format (combining online and face-to-face instruction) for third-year osteopathic medical students during their pediatric rotation. METHODS: Third-year medical students who completed the 4-week clerkship in pediatrics during the 2014 2015 academic year were divided into a standard learning group and a blended learning group with online activities (discussion boards, blogs, virtual patient encounters, narrated video presentations, and online training modules). Comprehensive Osteopathic Medical Achievement Test scores and final course grades were compared between the standard learning and blended learning groups. Students in the blended learning group completed a postsurvey regarding their experiences. RESULTS: Of 264 third-year students who completed the 4-week clerkship in pediatrics during the 2014-2015 academic year, 78 (29.5%) participated in the blended learning supplement with online activities. Of 53 students who completed the postsurvey in the blended learning group, 44 (83.0%) agreed or strongly agreed that "The integration of e-learning and face-to-face learning helped me learn pediatrics." Open-ended comments supported this overall satisfaction with the course format; however, 26 of 100 comments reflected a desire to increase the amount of clinical exposure and face-to-face time with patients. No statistical differences were seen between the standard learning (n=186) and blended learning (n=78) groups with regard to Comprehensive Osteopathic Medical Achievement Test scores (P=.321). Compared with the standard learning group, more students in the blended learning group received a final course grade of honors (P=.015). CONCLUSION: Results of this study support the use of blended learning in a clinical training environment. As more medical educators use blended learning, it is important to investigate the best balance between learning with technology and learning in a face-to-face setting. Online activities may enhance but should never fully replace face-to-face learning with real patients. PMID- 28346605 TI - Does Including Public Health Students on Interprofessional Teams Increase Attainment of Interprofessional Practice Competencies? AB - CONTEXT: Interprofessional education (IPE) creates dynamic experiential learning that can address social determinants of health that influence health outcomes. OBJECTIVE: To examine the effects of including public health students on IPE teams on the interprofessional practice domain constructs (values/ethics, roles/responsibilities, interprofessional communication, and teams and teamwork). METHODS: This single-case, mixed-methods study was performed using a grounded theory approach. Students from 8 graduate health sciences programs participated in an asynchronous, 6-week, online IPE learning activity. Three of the 4 interprofessional practice domain constructs were examined as outcome variables: participants' biomedical vs biopsychosocial patient approach (values/ethics); reported change in attitudes, beliefs, or values about other health professions (roles/responsibilities); and anticipated changes in future professional behaviors/interactions/approaches (teams and teamwork). Predictor variables were having an MPH participant on the IPE team, participants' enrollment in a clinical or nonclinical program, and student perception of the online format (interprofessional communication). RESULTS: Three hundred nineteen students were included, 261 from clinical and 58 from nonclinical programs. A significant association was found between having an MPH participant on the IPE teams and participants' awareness of the influence of social determinants of health (OR, 2.04; 95% CI, 1.13-3.66; P<.05). Program type was also significantly associated with awareness of the influence of social determinants of health, such that participants in nonclinical programs were significantly more likely to report the importance of social determinants of health in the care plan (OR, 3.68; 95% CI, 1.38-9.84; P<.01). Participants were significantly less likely to report future behavior change if they were in clinical programs (OR, 0.44; 95% CI, 0.23-0.86; P<.05) or if they disliked the online format (OR, 0.25; 95% CI, 0.14-0.42; P<.01). The model fit the data well (chi23=30.80; P<.001). CONCLUSION: Inclusion of MPH students on IPE teams has the potential to increase clinical participants' awareness of the influence of social determinants of health and interest in incorporating a biopsychosocial approach to health care. PMID- 28346607 TI - Appendix 1: Osteopathic Graduate Medical Education, 2017. PMID- 28346606 TI - Evidence-Based Redesign of the COMLEX-USA Series. AB - To ensure that the Comprehensive Osteopathic Medical Licensing Examination-USA (COMLEX-USA) reflects the evolving practice of osteopathic medicine, the National Board of Osteopathic Medical Examiners has developed new content and format specifications for an enhanced, competency-based examination program to be implemented with COMLEX-USA Level 3 in 2018. This article summarizes the evidence based design processes that served as the foundation for blueprint development and the evidence supporting its validity. An overview is provided of the blueprint's 2 dimensions: Competency Domains and Clinical Presentations. The authors focus on the evidence that supports interpretation of test scores for the primary and intended purpose of COMLEX-USA, which is osteopathic physician licensure. Important secondary uses and the educational and catalytic effect of assessments are also described. This article concludes with the National Board of Osteopathic Medical Examiners' plans to ensure that the COMLEX-USA series remains current and meets the needs of its stakeholders-the patients who seek care from osteopathic physicians. PMID- 28346608 TI - Appendix 2: American Osteopathic Association Specialty Board Certification. PMID- 28346609 TI - Massive Incarcerated Paraesophageal Hiatal Hernia. PMID- 28346610 TI - Can the Humanities Humanize Health Care? PMID- 28346613 TI - Protective Effect of Met12, a Small Peptide Inhibitor of Fas, on the Retinal Pigment Epithelium and Photoreceptor After Sodium Iodate Injury. AB - Purpose: A major problem in macular degeneration is the inability to reduce RPE and photoreceptor death. These cells die by necroptosis and apoptosis, respectively, but the upstream activator(s) of these death pathways is unknown. In this study, we use the sodium iodate (NaIO3) model of oxidative stress to test the hypothesis that activation of the Fas receptor contributes to the death of the RPE and photoreceptors. Methods: Sodium iodate was injected in Brown-Norway rats via femoral vein injection. Both in vivo (fundus photography, optical coherence tomography, and fluorescein angiography) and ex vivo (histology, immunohistochemistry, Western blot, and RT-PCR) analyses of the RPE and retina were conducted at baseline, as well as at various times post NaIO3 injection. The ability of intravitreal injection of Met12, a small peptide inhibitor of the Fas receptor, to prevent RPE and photoreceptor cell death was assessed. Results: Injection of NaIO3 led to Fas-mediated activation of both necroptosis and apoptosis in the RPE and photoreceptors, respectively. This was accompanied by a significant increase in the number of microglia/macrophages in the outer retina. Met12 significantly reduced the activation of the Fas-mediated death pathways, resulting in reduced RPE and photoreceptor death and a decreased immune response. Conclusions: Our results demonstrate that NaIO3 activates Fas-mediated cell death, both in the RPE and photoreceptor, and that a small peptide antagonist of the Fas receptor, Met12, significantly reduces the extent of this cell death. These findings suggest a role for Fas inhibition to protect the RPE and photoreceptors from death due to oxidative stress. PMID- 28346616 TI - Unilateral Amblyopia Affects Two Eyes: Fellow Eye Deficits in Amblyopia. AB - Unilateral amblyopia is a visual disorder that arises after selective disruption of visual input to one eye during critical periods of development. In the clinic, amblyopia is understood as poor visual acuity in an eye that was deprived of pattern vision early in life. By its nature, however, amblyopia has an adverse effect on the development of a binocular visual system and the interactions between signals from two eyes. Visual functions aside from visual acuity are impacted, and many studies have indicated compromised sensitivity in the fellow eye even though it demonstrates normal visual acuity. While these fellow eye deficits have been noted, no overarching theory has been proposed to describe why and under what conditions the fellow eye is impacted by amblyopia. Here, we consider four explanations that may account for decreased fellow eye sensitivity: the fellow eye is adversely impacted by treatment for amblyopia; the maturation of the fellow eye is delayed by amblyopia; fellow eye sensitivity is impacted for visual functions that rely on binocular cortex; and fellow eye deficits reflect an adaptive mechanism that works to equalize the sensitivity of the two eyes. To evaluate these ideas, we describe five visual functions that are commonly reported to be deficient in the amblyopic eye (hyperacuity, contrast sensitivity, spatial integration, global motion, and motion-defined form), and unify the current evidence for fellow eye deficits. Further research targeted at exploring fellow eye deficits in amblyopia will provide us with a broader understanding of normal visual development and how amblyopia impacts the developing visual system. PMID- 28346615 TI - Cross Talk Between TGF-beta2 and TLR-4. PMID- 28346614 TI - Crosstalk Between Transforming Growth Factor Beta-2 and Toll-Like Receptor 4 in the Trabecular Meshwork. AB - Purpose: The trabecular meshwork (TM) is involved in the outflow of aqueous humor and intraocular pressure (IOP) regulation. Regulation of the extracellular matrix (ECM) by TGFbeta2 signaling pathways in the TM has been extensively studied. Recent evidence has implicated toll-like receptor 4 (TLR4) in the regulation of ECM and fibrogenesis in liver, kidney, lung, and skin. Here, we investigated the role of TGFbeta2-TLR4 signaling crosstalk in the regulation of the ECM in the TM and ocular hypertension. Methods: Cross sections of human donor eyes, primary human TM cells in culture, and dissected mouse TM rings were used to determine Tlr4 expression in the TM. Trabecular meshwork cells in culture were treated with TGFbeta2 (5 ng/mL), TLR4 inhibitor (TAK-242, 15 MUM), and a TLR4 ligand (cellular fibronectin isoform [cFN]-EDA). A/J (n = 13), AKR/J (n = 7), BALBc/J (n = 8), C3H/HeJ (n = 20), and C3H/HeOuJ (n = 10) mice were injected intravitreally with adenovirus 5 (Ad5).hTGFbeta2c226s/c228s in one eye, with the uninjected contralateral eye serving as a control. Conscious IOP measurements were taken using a TonoLab rebound tonometer. Results: Toll-like receptor 4 is expressed in the human and mouse TM. Inhibition of TLR4 signaling in the presence of TGFbeta2 decreases fibronectin expression. Activation of TLR4 by cFN-EDA in the presence of TGFbeta2 further increases fibronectin, laminin, and collagen-1 expression, and TLR4 signaling inhibition blocks this effect. Ad5.hTGFbeta2c226s/c228s induces ocular hypertension in wild-type mice but has no effect in Tlr4 mutant (C3H/HeJ) mice. Conclusions: These studies identify TGFbeta2-TLR4 crosstalk as a novel pathway involved in ECM regulation in the TM and ocular hypertension. These data further explain the complex mechanisms involved in the development of glaucomatous TM damage. PMID- 28346617 TI - Taking Responsibility for Family Medicine Student Interest. PMID- 28346618 TI - What Is Happening in America? A Family Medicine Perspective From Overseas. PMID- 28346619 TI - Scope of Practice and Family Medicine Match Rates: Results From a CERA Clerkship Directors' Survey. AB - BACKGROUND AND OBJECTIVES: Family medicine clerkship directors depend on community preceptors to teach and attract medical students to family medicine. Many community preceptors do not provide the full range of family medicine services, and some are not family physicians. This study aimed to determine the types of practices in which family medicine clerkship students train and whether scope of practice is associated with family medicine Match rates. METHODS: Data were collected as part of the 2014 Council of Academic Family Medicine Educational Research Alliance (CERA) Family Medicine Clerkship Director Survey. Clerkship directors estimated the percentage of their preceptor sites providing each of nine clinical services and the percentage of students placed with internal medicine physicians for their family medicine rotations. We devised a Scope of Practice Index (SPI) to assess scope of practice and measured the association between a clerkship's SPI and family medicine Match rate. RESULTS: Limited scopes of practice were common. SPI was lowest in the Northeast and highest in the West. In bivariate and multivariable analyses, a lower SPI was associated with lower family medicine Match rates. Preventive gynecological care was the service most highly associated with family medicine Match rates. Family medicine Match rates were lower when programs used internal medicine sites for their family medicine rotations. CONCLUSIONS: Many clerkship students are exposed to practices with limited scopes of family medicine practice, and this is associated with lower family medicine Match rates. These findings have implications for the specialty as preceptor scope of practice declines. PMID- 28346620 TI - Varied Rates of Implementation of Patient-Centered Medical Home Features and Residents' Perceptions of Their Importance Based on Practice Experience. AB - BACKGROUND AND OBJECTIVES: Little is known about how the patient-centered medical home (PCMH) is being implemented in residency practices. We describe both the trends in implementation of PCMH features and the influence that working with PCMH features has on resident attitudes toward their importance in 14 family medicine residencies associated with the P4 Project. METHODS: We assessed 24 residency continuity clinics annually between 2007-2011 on presence or absence of PCMH features. Annual resident surveys (n=690) assessed perceptions of importance of PCMH features using a 4-point scale (not at all important to very important). We used generalized estimating equations logistic regression to assess trends and ordinal-response proportional odds regression models to determine if resident ratings of importance were associated with working with those features during training. RESULTS: Implementation of electronic health record (EHR) features increased significantly from 2007-2011, such as email communication with patients (33% to 67%), preventive services registries (23% to 64%), chronic disease registries (63% to 82%), and population-based quality assurance (46% to 79%). Team-based care was the only process of care feature to change significantly (54% to 93%). Residents with any exposure to EHR-based features had higher odds of rating the features more important compared to those with no exposure. We observed consistently lower odds of the resident rating process of care features as more important with any exposure compared to no exposure. CONCLUSIONS: Residencies engaged in educational transformation were more successful in implementing EHR-based PCMH features, and exposure during training appears to positively influence resident ratings of importance, while exposure to process of care features are slower to implement with less influence on importance ratings. PMID- 28346621 TI - Current Status of Family Medicine Faculty Development in Sub-Saharan Africa. AB - BACKGROUND AND OBJECTIVES: Reducing the shortage of primary care physicians in sub-Saharan Africa requires expansion of training programs in family medicine. Challenges remain in preparing, recruiting, and retaining faculty qualified to teach in these pioneering programs. Little is known about the unique faculty development needs of family medicine faculty within the sub-Saharan African context. The purpose of this study was to assess the current status and future needs for developing robust family medicine faculty in sub-Saharan Africa. The results are reported in two companion articles. METHODS: A cross-sectional study design was used to conduct a qualitative needs assessment comprising 37 in-depth, semi-structured interviews of individual faculty trainers from postgraduate family medicine training programs in eight sub-Saharan African countries. Data were analyzed according to qualitative description. RESULTS: While faculty development opportunities in sub-Saharan Africa were identified, current faculty note many barriers to faculty development and limited participation in available programs. Faculty value teaching competency, but institutional structures do not provide adequate support. CONCLUSIONS: Sub-Saharan African family physicians and postgraduate trainee physicians value good teachers and recognize that clinical training alone does not provide all of the skills needed by educators. The current status of limited resources of institutions and individuals constrain faculty development efforts. Where faculty development opportunities do exist, they are too infrequent or otherwise inaccessible to provide trainers the necessary skills to help them succeed as educators. PMID- 28346623 TI - Family Medicine Maternity Care Call to Action: Moving Toward National Standards for Training and Competency Assessment. AB - BACKGROUND: Maternity care is an integral part of family medicine, and the quality and cost-effectiveness of maternity care provided by family physicians is well documented. Considering the population health perspective, increasing the number of family physicians competent to provide maternity care is imperative, as is working to overcome the barriers discouraging maternity care practice. A standard that clearly defines maternity care competency and a systematic set of tools to assess competency levels could help overcome these barriers. National discussions between 2012 and 2014 revealed that tools for competency assessment varied widely. These discussions resulted in the formation of a workgroup, culminating in a Family Medicine Maternity Care Summit in October 2014. This summit allowed for expert consensus to describe three scopes of maternity practice, draft procedural and competency assessment tools for each scope, and then revise the tools, guided by the Family Medicine and OB/GYN Milestones documents from the respective residency review committees. The summit group proposed that achievement of a specified number of procedures completed should not determine competency; instead, a standardized competency assessment should take place after a minimum number is performed. The traditionally held required numbers for core procedures were reassessed at the summit, and the resulting consensus opinion is proposed here. Several ways in which these evaluation tools can be disseminated and refined through the creation of a learning collaborative across residency programs is described. The summit group believed that standardization in training will more clearly define the competencies of family medicine maternity care providers and begin to reduce one of the barriers that may discourage family physicians from providing maternity care. PMID- 28346622 TI - Future of Family Medicine Faculty Development in Sub-Saharan Africa. AB - BACKGROUND AND OBJECTIVES: High-quality family medicine education is needed in sub-Saharan Africa to facilitate the future growth of primary care health systems. Current faculty educators recognize the value of dedicated teacher training and ongoing faculty development. However, they are constrained by inadequate faculty development program availability and institutional support. METHODS: A cross-sectional study design was used to conduct a qualitative needs assessment comprised of 37 in-depth, semi-structured interviews of individual faculty trainers from postgraduate family medicine training programs in eight sub Saharan African countries. Data were analyzed according to qualitative description. RESULTS: Informants described desired qualities for a family medicine educator in sub-Saharan Africa: (1) pedagogical expertise in topics and perspectives unique to family medicine, (2) engagement in self-directed, lifelong learning, and (3) exemplary character and behavior that inspires others. Informant recommendations to guide the development of faculty development programs include: (1) sustainability, partnership, and responsiveness to the needs of the institution, (2) intentional faculty development must begin early and be supported with high-quality mentorship, (3) presumptions of teaching competence based on clinical training must be overcome, and (4) evaluation and feedback are critical components of faculty development. CONCLUSIONS: High quality faculty development in family medicine is critically important to the primary care workforce in sub-Saharan Africa. Our study describes specific needs and recommendations for family medicine faculty development in sub-Saharan Africa. Next steps include piloting and evaluating innovative models of faculty development that respond to specific institutional or regional needs. PMID- 28346624 TI - Association of Group Prenatal Care in US Family Medicine Residencies With Maternity Care Practice: A CERA Secondary Data Analysis. AB - BACKGROUND AND OBJECTIVES: Group prenatal care has been shown to improve both maternal and neonatal outcomes. With increasing adaption of group prenatal care by family medicine residencies, this model may serve as a potential method to increase exposure to and interest in maternity care among trainees. This study aims to describe the penetration, regional and program variations, and potential impacts on future maternity care practice of group prenatal care in US family medicine residencies. METHODS: The CAFM Educational Research Alliance (CERA) conducted a survey of all US family medicine residency program directors in 2013 containing questions about maternity care training. A secondary data analysis was completed to examine relevant data on group prenatal care in US family medicine residencies and maternity care practice patterns. RESULTS: 23.1% of family medicine residency programs report provision of group prenatal care. Programs with group prenatal care reported increased number of vaginal deliveries per resident. Controlling for average number of vaginal deliveries per resident, programs with group prenatal care had a 2.35 higher odds of having more than 10% of graduates practice obstetrics and a 2.93 higher odds of having at least one graduate in the past 5 years enter an obstetrics fellowship. CONCLUSIONS: Residency programs with group prenatal care models report more graduates entering OB fellowships and practicing maternity care. Implementing group prenatal care in residency training can be one method in a multifaceted approach to increasing maternity care practice among US family physicians. PMID- 28346625 TI - A Point System as Catalyst to Increase Resident Scholarship: An MPCRN Study. AB - INTRODUCTION: Encouraging resident scholarly activity has been a longstanding challenge for medical educators. The Accreditation Council for Graduate Medical Education (ACGME) has been increasing its emphasis on scholarly activity, forcing programs to evaluate their existing processes. This study sought to evaluate the impact of a scholarly activity point system on the resident scholarly productivity at multiple programs. METHODS: Five military family medicine residencies evaluated resident outcomes 2 years before and 2 years after the introduction of a scholarly activity point system. Outcome measures included peer reviewed publications with a resident as first author, peer-reviewed publications with a resident as any author, resident presentation of scholarship at a regional, national, and international conference, IRB-approved protocols with a resident as principal investigator, and IRB-approved protocols with a resident in any role. RESULTS: Four of the five programs experienced substantial increases in nearly every outcome. The fifth program, which had a more robust culture of inquiry at baseline, did not experience an increase in resident scholarly productivity. CONCLUSIONS: A scholarly activity point system was associated with an increase in resident scholarly production in family medicine programs. It appears to work best in programs that start from a lower level of scholarly productivity at baseline. A point system appears to be a useful addition to scholarly activity curricula. PMID- 28346626 TI - Preparing Residents for Teaching Careers: The Faculty for Tomorrow Resident Workshop. AB - BACKGROUND AND OBJECTIVES: Progress toward growing the primary care workforce is at risk of being derailed by an emerging crisis: a critical shortage of family medicine faculty. In response to the faculty shortage, the Society of Teachers of Family Medicine (STFM) launched a 2-year initiative called "Faculty for Tomorrow" (F4T). The F4T Task Force created a workshop designed to increase residents' interest in, and prepare them for, careers in academic family medicine. We aimed to evaluate the effectiveness of this workshop. METHODS: Participants were family medicine residents who preregistered for and attended the F4T Resident Workshop at the 2016 STFM Annual Spring Conference. The intervention was a full-day, 9 hour preconference workshop delivered by a multi-institutional faculty team. Participants were asked to complete a questionnaire before and immediately after the workshop. Data collected included demographics, residency program characteristics, future career plans, self-reported confidence in skills, and general knowledge relevant to becoming faculty. RESULTS: A total of 75 participants attended the workshop. The proportion of those who were "extremely likely" to pursue a career in academic family medicine increased from 58% to 72%. Participants reported statistically significant improvements in their confidence in clinical teaching, providing feedback to learners, writing an effective CV, knowledge about the structure of academic family medicine, and knowledge about applying for a faculty position. CONCLUSIONS: The STFM F4T Resident Workshop was effective at increasing participants' interest in academic careers, as well as self-reported confidence in skills and knowledge relevant to becoming faculty. The data collected from participants regarding their career plans may inform future interventions. PMID- 28346627 TI - Just Another Drug Seeker. PMID- 28346628 TI - Dear Juan/From Your Inconsequential Doctor. PMID- 28346629 TI - The Marcus Welby Moment (MWM). PMID- 28346632 TI - Behavioral Health Emphasis Critical for Rural Family Physician Training. PMID- 28346633 TI - One-stage Posterior Approach in the Treatment of Consecutive Multi-segment Thoracic Tuberculosis with Kyphosis. AB - AIM: To evaluate the clinical efficacy of the one-stage posterior approach in treating consecutive multiple-segment thoracic tuberculosis with kyphosis. MATERIAL AND METHODS: A retrospective study was performed. The data of 22 patients with consecutive multi-level thoracic tuberculosis and kyphosis who underwent the one-stage posterior approach of debridement, bone grafting, drainage and pedicle screws fixation were collected. The kyphotic angle was 61.6 degrees +/-3.1 degrees pre-operatively. The neurologic status based on American Spinal Injury Association (ASIA) scoring was A in 5 cases, B in 4 cases, C in 9 cases, D in 3 cases and E in 1 case. RESULTS: The average follow-up period was 43.4+/-5.0 months. The kyphotic angle was 19.8 degrees +/-0.7 degrees after operation (p < 0.01), and 21.9 degrees +/-1.2 degrees at the last visit (p < 0.01). No neurological deterioration was observed in any patients after surgery. A significant difference in ASIA score was detected when the state before the operation and at the last visit was compared (p < 0.01). There was no recurrent paravertebral abscess of thoracic tuberculosis in any of these cases. CONCLUSION: The one-stage posterior approach of debridement and drainage is a feasible surgical option for consecutive multisegment thoracic tuberculosis with kyphosis. It can achieve debridement, decompression, and stabilization simultaneously. PMID- 28346634 TI - The otolaryngology residency application problem. PMID- 28346635 TI - 25 years of powered endoscopic maxillary antrostomy. PMID- 28346636 TI - Airway foreign body occurring during in-office vocal fold injection. PMID- 28346637 TI - Unusual case of chronic maxillary rhinosinusitis. PMID- 28346638 TI - Repair of the dilated earlobe. PMID- 28346639 TI - Unusual case of sleep apnea in a child. PMID- 28346640 TI - Presbyphonia: What can be done? PMID- 28346641 TI - Speech perception and auditory performance following cochlear implantation in elderly Koreans. AB - The benefits of cochlear implantation (CI) in the elderly remain debatable in terms of sound and speech perception. Moreover, the results of CI may be affected by the intensity and pitch of spoken language. We conducted a retrospective study to evaluate surgical and hospitalization times, postoperative complications, and hearing outcomes after CI in elderly Koreans. Our study population was made up of 55 postlingually deafened adults who underwent unilateral CI. They were divided into two groups based on age; an older group consisted of 21 patients aged 65 years or older (mean 71.8) at the time of CI, and a comparison group was made up of 34 patients aged 18 to 64 years (mean: 47.5). The mean surgical and hospitalization times and the mean number of postoperative complications in the two groups were comparable. Auditory outcomes were quantified by the speech reception threshold (SRT), the speech discrimination test (SDT), scores on the Korean version of the Glendonald Auditory Screening Procedure (GASP-K), and categories of auditory performance (CAP) scores. The SDT and GASP-K values were significantly lower in the older group at 3 months, 1 year, and 2 years; there were no significant differences in mean SRT and CAP values. We conclude that elderly patients may obtain appreciable benefits from CI without experiencing serious surgical complications. Nevertheless, difficulties in speech perception should be taken into consideration in older patients. PMID- 28346642 TI - Nasal, oral, and pharyngolaryngeal manifestations of pemphigus vulgaris: Endoscopic ororhinolaryngologic examination. AB - Pemphigus vulgaris is an autoimmune blistering disorder that involves the skin and mucous membranes. Few reports have described nasal and oropharyngolaryngeal lesions in pemphigus vulgaris using an endoscopic ororhinolaryngologic examination. We retrospectively reviewed the clinical records of 11 patients with pemphigus vulgaris between 2001 and 2013 with respect to their symptoms, lesion sites, lesion features, and treatments received. All patients had undergone an endoscopic ororhinolaryngologic examination. Their mucosa-related symptoms were sore throat, oral pain, odynophagia, gingival bleeding, hoarseness, and epistaxis. The most frequent sites were the oral cavity (gingiva and buccal mucosa), larynx (epiglottis and vocal fold), oropharynx (soft palate), and nasal cavity (nasal septum). Lesions were typically characterized by erosion, erosion with a whitish exudate, and erythematous patches. Thus, our study findings reveal that pemphigus vulgaris involves both the nasal and oropharyngolaryngeal regions. Patients with pemphigus vulgaris should undergo an endoscopic ororhinolaryngologic examination to determine the range of their lesions. PMID- 28346643 TI - Evaluating the quality and readability of Internet information sources regarding the treatment of swallowing disorders. AB - The Internet has become a popular resource for patient education. The information it provides, however, is rarely peer-reviewed, and its quality may be a concern. Since the average American reads at an 8th grade level, the American Medical Association and the National Institutes of Health have recommended that health information be written at a 4th to 6th grade level. We performed a study to assess the quality and readability of online information regarding the treatment of swallowing disorders. A Google search for "swallowing treatment" was conducted. We studied the first 50 websites that appeared on the search engine's results with the use of the DISCERN quality index tool, the Flesch Ease of Reading Score (FRES), and the Flesch-Kincaid Grade Level (FKGL) readability test. DISCERN is a validated 16-item questionnaire used to assess the quality of written health information; FRES and FKGL are used to assess readability. We classified the websites as either patient-targeted or professional-targeted sites, as well as either major or minor. The overall DISCERN score was 1.61 +/- 0.61 (range: 1 to 5), the overall FRES was 39.1 +/- 19.0 (range: 1 to 100), and the overall FKGL was 11.8 +/- 3.4 (range: 3 to 12). As would be expected, patient targeted websites had significantly higher FRES and significantly lower FKGL scores than did the professional-targeted websites (p = 0.01 and p = 0.04, respectively); there was no significant difference between the two in DISCERN scores. The major websites had significantly higher DISCERN scores than did the minor sites (p = 0.002); there were no significant differences in FRES and FKGL scores. We conclude that online information sources regarding the treatment of swallowing disorders were of suboptimal quality in that information was written at a level too difficult for the average American to easily understand. Also, the patient-targeted websites were written at a lower reading level, and the major websites contained a higher quality of information. PMID- 28346644 TI - Laryngoceles: Concepts of diagnosis and management. AB - A laryngocele is an abnormal dilatation of the laryngeal saccule. It is a rare benign lesion of the larynx. Various modalities of treatment have been advocated for its management. We present our treatment results and outcomes of a series of cases of laryngoceles and discuss the concepts of their management. This study included patients with different laryngocele types. Patients with an internal laryngocele underwent endoscopic CO2 laser resection, while those with a combined laryngocele underwent resection via a V-shaped lateral thyrotomy approach. Seven patients had an internal laryngocele, and 4 patients had a combined laryngocele. Hoarseness and neck swelling were the most common symptoms. The mean follow-up period was 8.5 months. None of the patients needed a tracheostomy either preoperatively or postoperatively, or had recurrence of laryngocele. We advocate the lateral thyrotomy approach for combined laryngoceles as it provides safe, precise, and complete resection under direct visualization via a single approach, while we favor the endoscopic laser approach for the internal ones as it allows resection of the entire lesion with minimal laryngeal trauma, less operative time, and a shorter hospital stay. PMID- 28346645 TI - Facial trauma caused by electronic cigarette explosion. AB - Electronic cigarettes are increasingly popular as a supposed safer alternative to tobacco cigarettes or a smoking cessation tool. Research and debate have focused primarily on possible adverse effects caused by the inhaled aerosol produced by electronic cigarettes and on smoking cessation efficacy. Few reports in the medical literature describe injuries secondary to device malfunction. We present a case of electronic cigarette explosion, with a projectile fracturing the patient's right naso-orbital-ethmoid complex and anterior and posterior frontal sinus tables, with frontal sinus outflow tract involvement. The patient underwent combined open and endoscopic repair, including open reduction internal fixation, with reconstitution and preservation of the frontal sinus and frontal sinus outflow tract. Additionally, we review the available data on electronic cigarette malfunction-including fires, explosions, associated injuries, and possible reasons for device malfunction-and discuss new 2016 U.S. Food and Drug Administration regulations pertaining to electronic cigarettes. PMID- 28346646 TI - Metastatic chordoma of the tongue: Case report. AB - Chordomas are rare bone tumors that arise from notochord remnants. They most commonly occur in the sacrum, but they also can be seen in the skull base, cervical spine, and thoracolumbar vertebrae. Chordomas account for 1 to 4% of all primary skeletal tumors. They are usually indolent, locally growing tumors. Distant metastasis has been reported in 3 to 48% of cases. When metastasis occurs, it is usually observed in the lung, bone, and liver. To the best of our knowledge, no case of a chordoma metastasis to the tongue has been previously reported in the literature. We report such a case in a 61-year-old man. PMID- 28346647 TI - Validation of olfactory threshold testing methods. AB - In patients with chemosensory complaints, a head-to-head comparison of unilateral olfaction threshold testing with the Phenyl Ethyl Alcohol Smell Threshold Test (PEA) and the OLFACT-RL Odor Threshold Test (OLFACT-RL) was undertaken. The charts of 23 consecutive patients presenting with chemosensory complaints seen at the Smell and Taste Treatment and Research Foundation were reviewed and information extracted per Institutional Review Board guidelines. All patients had undergone olfactory testing with the PEA test and the OLFACT-RL test in accordance with their published administration manuals. Using Spearman correlation coefficients to measure the statistical correlation between tests, we found evidence of a correlation between PEA and OLFACT-RL values on the left side only, overall (r = 0.49, p = 0.0184); in those who had hyposmia and did not have anosmia (r = 0.42, p = 0.0668); in those who did not have burning mouth syndrome (r = 0.46, p = 0.0304); and in those who did not have dysosmia (r = 0.47, p = 0.0553). There is no evidence of a correlation on the right side. The correlation for the left nostril suggests that these tests may be interchangeable. However, lack of correlation with the right nostril requires further investigation. PMID- 28346648 TI - Glomus faciale tumors: A report of 3 cases and literature review. AB - Our objectives in reporting this case series are to familiarize readers with the rare occurrence of paragangliomas originating along the facial nerve and to provide a literature review. We describe 3 such cases that occurred at our tertiary care academic medical center. Two women and 1 man presented with a tumor adjacent to the vertical segment of the facial nerve. The first patient, a 48 year-old woman, presented with what appeared to be a parotid tumor at the stylomastoid foramen; she underwent a parotidectomy, transmastoid facial nerve decompression, and a shave biopsy of the tumor. The second patient, a 66-year-old man, underwent surgery via a postauricular infratemporal fossa approach, and a complete tumor resection was achieved. The third patient, a 56-year-old woman, presented with a middle ear mass; she underwent complete tumor removal through a transmastoid transcanal approach. All 3 patients exhibited normal facial nerve function both before and after surgery. Paragangliomas of the facial nerve are extremely rare, and their signs and symptoms are unlike those of any other temporal bone glomus tumors. Management options include surgical resection, radiologic surveillance, and radiotherapy. The facial nerve can be spared in selected cases. PMID- 28346649 TI - The rising incidence of major salivary gland cancer in the United States. AB - We performed a population-based historical cohort study using the Surveillance, Epidemiology, and End Results (SEER) database to determine trends in the incidence of major salivary gland cancer and to evaluate the effect of sex, tumor size, histology, primary site, and extent of disease. Participants were men and women with major salivary gland cancer, diagnosed 1973-2009. The incidence of major salivary gland cancer increased from 10.4 per 1,000,000 in 1973 to 16 per 1,000,000 in 2009 (annual percent change [APC] 0.99; 95% confidence interval [CI] 0.78 to 1.20; p < 0.05). The incidence of parotid cancers increased (APC 1.13; 95% CI 0.88 to 1.39; p < 0.05) and paralleled the increase in major salivary gland cancer overall. There was an increase in the incidence of tumors measuring 0 to 2.0 cm (APC 1.99; 95% CI 0.61 to 3.38; p < 0.05), but no change in tumors measuring 2.1 to 4.0 cm (APC 1.02; 95% CI -0.46 to 2.52; p > 0.05) and tumors measuring > 4 cm (APC -0.52; 95% CI -1.72 to 0.69; p > 0.05). There was an increase in the incidence of regional (APC 0.77; 95% CI 0.32 to 1.23; p < 0.05) and distant (APC 2.43; 95% CI 1.43 to 3.45; p < 0.05) disease, but not localized disease (APC 0.35; 95% CI 0 to 0.71; p > 0.05). We conclude that the incidence of major salivary gland cancer is increasing, especially small parotid tumors. The incidence of tumors with regional and distant metastasis is also increasing. These findings highlight the need for further research on the etiology of salivary gland cancer, which may reveal opportunities for further public health efforts aimed at prevention. PMID- 28346650 TI - Submandibular salivary gland tumors: Clinical course and outcome of a 20-year multicenter study. AB - The purpose of this retrospective chart review study was to review the nature and clinical course of benign and malignant submandibular gland tumors at 2 major university-affiliated tertiary medical centers. All patients who underwent submandibular salivary gland excision between 1990 and 2010 were included. Clinical and disease-related data were collected from the medical charts. One hundred ninety-three patients were identified, of whom 108 (56%) had non neoplastic disorders (sialolithiasis and sialadenitis). The remaining 85 patients (44%) had a submandibular salivary gland tumor. The most common benign neoplasm was pleomorphic adenoma (53 patients). Twenty tumors (24%) were malignant: adenoid cystic carcinoma in 11 patients, mucoepidermoid carcinoma in 6 patients, and adenocarcinoma in 3 patients. Recurrence was noted in 7 patients with submandibular gland malignancy and in 2 patients with pleomorphic adenoma. The 5 year disease-free survival rate was 63%. Tumors of the submandibular gland are infrequently malignant. Recurrent submandibular salivary gland pleomorphic adenoma is rare compared with recurrences in the parotid gland. PMID- 28346651 TI - Breast cancer metastases to the head and neck: Case series and literature review. AB - Breast cancer is the most common cancer in women and is the second most common cause of cancer-related death. Despite the relatively high prevalence of this disease, breast cancer manifestations in the head and neck are relatively rare. Supraclavicular lymphadenopathy and bony metastases to the mandible and maxilla are the most common manifestation of breast cancer in the head and neck. Head and neck metastases are the first presentation of distant disease in approximately one-third of cases. The prognosis of breast cancer with distant metastases to the head and neck is generally poor, and the management of these lesions is controversial. Overall extent of disease and individual patient prognosis must guide treatment decisions. Atypical cases including maxillary sinus mass, jugular foramen mass, and dermal metastases are presented. Metastatic breast cancer is a rare diagnosis in the head and neck, yet metastatic disease from an infraclavicular primary deserves inclusion on any comprehensive differential diagnosis list. In women, breast carcinoma is the most common infraclavicular primary to metastasize to the head and neck. PMID- 28346652 TI - Treatment success with titratable thermoplastic mandibular advancement devices for obstructive sleep apnea: A comparison of patient characteristics. AB - A titratable thermoplastic mandibular advancement device (MAD) is clearly an effective treatment option in some patients with obstructive sleep apnea (OSA). Determining which patients may be more likely to respond to treatment with thermoplastic MADs and to adhere to treatment would be of obvious clinical relevance. This was an experimental descriptive study (N = 60). Patients with OSA were instructed to wear a titratable thermoplastic MAD for 3 months. Treatment success was defined as a >=50% reduction from baseline in the apnea-hypopnea index (AHI) or AHI <10 when wearing MAD. Adherence was defined as MAD use >=5 nights/week. Treatment was successful in 66.7% of patients and 60.0% were adherent. All polysomnographic parameters and visual analogue scale scores (sleep quality, snoring, waking refreshed) were significantly improved after treatment. The patients in whom treatment failed had significantly higher neck circumferences (39.3 cm vs. 37.5 cm, p = 0.014), higher baseline AHI values (26.6 vs. 18.0, p = 0.016), and smaller AHI reduction (-31.8 vs -53.1, p < 0.001) than those in the group in whom treatment succeeded. There were no significant differences in polysomnographic, cephalometric, or visual analogue scale measures between patients for whom treatment was and was not successful, regardless of baseline values or the change rates after the MAD was placed. Titratable thermoplastic MADs can improve indicators of sleep quality, even in patients in whom treatment is considered to have failed. PMID- 28346653 TI - How successful is the fitting of digital hearing aids? Implications for the allocation of resources within national health systems. AB - We conducted a retrospective study to determine the success rate of initial fittings in digital hearing aid (DHA) users. We also addressed the implications of national health systems' continuing to provide access to these devices. We identified 1,597 consecutively presenting adults who had undergone a first fitting or a new fitting (i.e., an upgrade from an analogue hearing aid in the first or second ear) of a behind-the-ear DHA during the previous year. We further sought to identify all nominal reprogram appointments that had taken place within 6 months after the first or new fitting; we found 460 such appointments (28.8%). Of these, 419 appointments had been for typical reasons other than patient dissatisfaction with the fitting itself-for example, poor hearing, a further hearing loss, an uncomfortably loud hearing aid level, difficulty with speech in noise, an imbalance between bilateral hearing aids, and a faulty or lost hearing aid. Only 41 of the 1,597 first or new fittings (2.6%) were considered unsatisfactory by patients and necessitated a follow-up reprogramming appointment. Overall, DHA fittings were generally successful, as most patients (1,137/1,597 [71.2%]) did not require any follow-up appointment during the study period. Principles of cost-effectiveness demand the maximum practicable efficiency in the utilization of resources to ensure the continuous delivery of high-quality audiologic services through national health systems. This can be achieved by scheduling group appointments to reduce costs and to increase the time allocated to fitting and training patients. PMID- 28346654 TI - Glomus jugulare manifesting as angiogenesis of the external ear canal. PMID- 28346655 TI - High prevalence of alcohol use disorders in patients with inflammatory skin diseases. AB - BACKGROUND: There is a known association between psoriasis and heavy alcohol consumption. The association between heavy alcohol consumption and other inflammatory skin diseases remains to be defined. OBJECTIVES: To examine the prevalence of heavy drinking using the Alcohol Use Disorders Identification Test (AUDIT) in patients with inflammatory skin disease. METHODS: We conducted an observational cross-sectional study in a single hospital outpatient department. We recruited 609 patients with either psoriasis, eczema, cutaneous lupus or other inflammatory disorders, and a reference population with skin lesions. Primary outcome was the proportion of patients in each group with an alcohol use disorder (AUD). RESULTS: The observed prevalence of AUD was 30.6% in patients with psoriasis, 33.3% in those with eczema, 12.3% in those with cutaneous lupus, 21.8% in those with other inflammatory disease and 14.3% in those with non-inflammatory disease. Odds ratios (OR) for AUD in patients in the inflammatory groups compared with those in the noninflammatory groups, adjusted for age and sex, were as follows: psoriasis 1.65 [95% confidence interval (CI) 0.86-3.17], eczema 2.00 (95% CI 1.03-3.85), lupus 1.03 (95% CI 0.39-2.71), other inflammatory disease 1.32 (95% CI 0.68-2.56). ORs were reduced if also adjusted for Dermatology Life Quality Index (DLQI). The prevalence of DLQI >= 11 was 31.1% for psoriasis, 43.7% for eczema, 17.5% for cutaneous lupus, 17.2% for other inflammatory disease and 2.8% for noninflammatory disease. CONCLUSIONS: Patients with eczema attending a hospital clinic have been shown to have high levels of AUD of a similar level to patients with psoriasis and higher than patients with noninflammatory skin diseases. PMID- 28346657 TI - Across the Pond. PMID- 28346656 TI - 7-year follow-up after stereotactic ablative radiotherapy for patients with stage I non-small cell lung cancer: Results of a phase 2 clinical trial. AB - BACKGROUND: The authors evaluated the efficacy, patterns of failure, and toxicity of stereotactic ablative radiotherapy (SABR) for patients with medically inoperable, clinical stage I non-small cell lung cancer (NSCLC) in a prospective clinical trial with 7 years of follow-up. Clinical staging was performed according to the seventh edition of the American Joint Committee on Cancer TNM staging system. METHODS: Eligible patients with histologically confirmed NSCLC of clinical stage I as determined using positron emission tomography staging were treated with SABR (50 grays in 4 fractions). The primary endpoint was progression free survival. Patients were followed with computed tomography and/or positron emission tomography/computed tomography every 3 months for the first 2 years, every 6 months for the next 3 years, and then annually thereafter. RESULTS: A total of 65 patients were eligible for analysis. The median age of the patients was 71 years, and the median follow-up was 7.2 years. A total of 18 patients (27.7%) developed disease recurrence at a median of 14.5 months (range, 4.3-71.5 months) after SABR. Estimated incidences of local, regional, and distant disease recurrence using competing risk analysis were 8.1%, 10.9%, and 11.0%, respectively, at 5 years and 8.1%, 13.6%, and 13.8%, respectively, at 7 years. A second primary lung carcinoma developed in 12 patients (18.5%) at a median of 35 months (range, 5-67 months) after SABR. Estimated 5-year and 7-year progression free survival rates were 49.5% and 38.2%, respectively; the corresponding overall survival rates were 55.7% and 47.5%, respectively. Three patients (4.6%) experienced grade 3 treatment-related adverse events. No patients developed grade 4 or 5 adverse events (toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]). CONCLUSIONS: With long-term follow-up, the results of the current prospective study demonstrated outstanding local control and low toxicity after SABR in patients with clinical stage I NSCLC. Regional disease recurrence and distant metastases were the dominant manifestations of failure. Surveillance for second primary lung carcinoma is recommended. Cancer 2017;123:3031-39. (c) 2017 American Cancer Society. PMID- 28346658 TI - Spatially heterogeneous selection in nature favors phenotypic plasticity in anuran larvae. AB - Theory holds that adaptive phenotypic plasticity evolves under spatial or temporal variation in natural selection. I tested this prediction in a classic system of predator-induced plasticity: frog tadpoles (Rana temporaria) reacting to predaceous aquatic insects. An outdoor mesocosm experiment manipulating exposure to Aeshna dragonfly larvae revealed plasticity in most characters: growth, development, behavior, and external morphology. I measured selection by placing 1927 tadpoles into enclosures within natural ponds; photographs permitted identification of the survivors six to nine days later. Fitness was defined as a linear combination of growth, development, and survival that correlates with survival to age 2 in another anuran species. In enclosures with many predators, selection-favored character values similar to those induced by exposure to Aeshna in mesocosms. The shift in selection along the predation gradient was strongest for characters that exhibited high predator-induced plasticity. A field survey of 50 ponds revealed that predator density changes over a spatial scale relevant for movement of individual adults and larvae: 17% of variation in predation risk was among ponds separated by tens to thousands of meters and 81% was among sites <=10 m apart within ponds. These results on heterogeneity in the selection regime confirm a key tenant of the standard model for the evolution of plasticity. PMID- 28346660 TI - Clinicodermoscopic features of Spitz naevi by age and anatomical site: a study of 378 Spitz naevi. PMID- 28346659 TI - Is universal HLA-B*15:02 screening a cost-effective option in an ethnically diverse population? A case study of Malaysia. AB - BACKGROUND: A strong association has been documented between HLA-B*15:02 and carbamazepine-induced severe cutaneous adverse reactions (SCARs) in Asians. Human leucocyte antigen testing is potentially valuable in many countries to facilitate early recognition of patient susceptibility to SCARs. OBJECTIVES: To determine the cost-effectiveness of universal HLA-B*15:02 screening in preventing carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in an ethnically diverse Malaysian population. METHODS: A hybrid model of a decision tree and Markov model was developed to evaluate three strategies for treating newly diagnosed epilepsy among adults: (i) carbamazepine initiation without HLA B*15:02 screening (current practice); (ii) universal HLA-B*15:02 screening prior to carbamazepine initiation; and (iii) alternative treatment [sodium valproate (VPA)] prescribing without HLA-B*15:02 screening. Base-case analysis and sensitivity analyses were performed over a lifetime time horizon. Incremental cost-effectiveness ratios were calculated. RESULTS: Both universal HLA-B*15:02 screening and VPA prescribing were dominated by current practice. Compared with current practice, universal HLA-B*15:02 screening resulted in a loss of 0.0255 quality-adjusted life years (QALYs) at an additional cost of 707 U.S. dollars (USD); VPA prescribing resulted in a loss of 0.2622 QALYs at an additional cost of USD 4127, owing to estimated differences in antiepileptic treatment efficacy. CONCLUSIONS: Universal HLA-B*15:02 screening is unlikely to be a cost-effective intervention in Malaysia. However, with the emergence of an ethnically diverse population in many other countries, this may render HLA-B*15:02 screening a viable intervention when an increasing proportion of the population is at risk and an equally effective yet safer antiepileptic drug is available. PMID- 28346661 TI - A major shift in diversification rate helps explain macroevolutionary patterns in primate species diversity. AB - Primates represent one of the most species rich, wide ranging, and ecologically diverse clades of mammals. What major macroevolutionary factors have driven their diversification and contributed to the modern distribution of primate species remains widely debated. We employed phylogenetic comparative methods to examine the role of clade age and evolutionary rate heterogeneity in the modern distribution of species diversity of Primates. Primate diversification has accelerated since its origin, with decreased extinction leading to a shift to even higher evolutionary rates in the most species rich family (Cercopithecidae). Older primate clades tended to be more diverse, however a shift in evolutionary rate was necessary to adequately explain the imbalance in species diversity. Species richness was also poorly explained by geographic distribution, especially once clade age and evolutionary rate shifts were accounted for, and may relate instead to other ecological factors. The global distribution of primate species diversity appears to have been strongly impacted by heterogeneity in evolutionary rates. PMID- 28346662 TI - Intravenous immunoglobulin contributes to the control of antimelanoma differentiation-associated protein 5 antibody-associated dermatomyositis with palmar violaceous macules/papules. AB - Autoantibodies to melanoma differentiation-associated protein 5 (MDA5) are associated with a subset of patients with dermatomyositis (DM) who have rapidly progressive interstitial lung disease (RP-ILD) with poor prognosis. Intensive immunosuppressive therapy is initiated before irreversible lung damage can occur; however, there are few lines of evidence for the treatment of RP-ILD. Here, we report three cases of anti-MDA5 antibody-associated DM with RP-ILD in which the patients were treated with combined-modality therapy, including high-dose prednisolone, tacrolimus, intravenous cyclophosphamide and intravenous immunoglobulin (IVIG). In all three cases, serum ferritin levels, which are known to represent the disease activity of RP-ILD, were decreased after IVIG administration. IVIG might contribute to the control of the disease activity of anti-MDA5 antibody-positive DM. Moreover, palmar violaceous macules/papules around the interphalangeal joints, which was observed in all three cases in the incipient stage, might be a useful sign in suggesting a diagnosis of anti-MDA5 antibody-associated DM. PMID- 28346663 TI - Management of stage III colon cancer in the elderly: Practice patterns and outcomes in the general population. AB - BACKGROUND: Clinical trials have established surgical resection and adjuvant chemotherapy (ACT) as the standard management for stage III colon cancer; however, the extent to which these results apply to elderly patients in routine practice is unclear. This article describes the management and outcomes of elderly patients with stage III colon cancer. METHODS: All cases of surgically resected colon cancer from 2002 to 2008 were identified with the population-based Ontario Cancer Registry. Pathology reports were obtained for a random sample (25% of all cases); those with stage III disease constituted the study population. The utilization of ACT, cancer-specific survival (CSS), and overall survival (OS) in elderly patients (>=70 years) and nonelderly patients (<70 years) were compared. RESULTS: The study population included 2920 patients, and 1521 (52%) were elderly. The 30- and 90-day mortality rates increased with advanced age: <70 years, 2% and 5%; 70 to 74 years, 3% and 7%; 75 to 79 years, 5% and 8%, and >=80 years, 9% and 16% (P < .001). ACT was delivered to 48% of elderly patients and to 81% of younger patients (P < .001). Factors independently associated with ACT utilization among the elderly were a younger age (P < .001), male sex (P = .041), and no comorbidities (P = .001). Among elderly patients, ACT was associated with improved CSS (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.60-0.88) and OS (HR, 0.71; 95% CI, 0.60-0.83); however, the magnitude of the benefit was smaller for elderly patients than younger patients (HR for CSS, 0.53; 95% CI, 0.42-0.67; HR for OS 0.56; 95% CI, 0.45-0.69). CONCLUSIONS: Half of elderly patients with stage III colon cancer do not receive ACT. Although the effect size is smaller than that in younger patients, ACT is associated with improved long term survival. Cancer 2017;123:2840-49. (c) 2017 American Cancer Society. PMID- 28346665 TI - Effects of ovarian structures identified at OvsynchTM enrolment, disease history and lactation variables on odds of pregnancy to a fixed-time artificial insemination after OvsynchTM. AB - OBJECTIVE: To determine the effects of ovarian structures present at OvsynchTM enrolment, disease history, lactation variables and times bred on pregnancy per fixed-time artificial insemination (FTAI) following fixed-time insemination after Ovsynch and to determine the relationship between the size of ovarian follicular structures and concurrent presence of a corpus luteum (CL). METHODS: The study was conducted in a 3000-cow Holstein dairy herd. Over a 6-month period, 886 non pregnant cows were examined by transrectal ultrasound and enrolled into 1132 Ovsynch events. Enrolled cows were synchronised using an Ovsynch-56 protocol. At enrolment, both ovaries were scanned by transrectal ultrasound to identify and record the presence and size of ovarian structures. Cows that did not return to oestrus were pregnancy tested 32-38 days post-insemination. Univariable and multivariable generalised linear mixed models (GLMMs) were used to determine the effect of each variable on pregnancy per FTAI. A univariable GLMM was also used to analyse the relationship between size of the dominant follicular structure and concurrent presence of a CL. RESULTS: CL size (P = 0.039) and presence of a luteal cyst (P = 0.002) at Ovsynch enrolment significantly increased the odds of pregnancy. Occurrence of lameness (P = 0.035) or mastitis (P = 0.008) between calving and enrolment significantly decreased the odds of pregnancy. Neither the presence nor size of a follicular structure significantly affected the odds of pregnancy, although cows with larger follicular structures were less likely to have a concurrent CL (P < 0.001). CONCLUSION: Presence of luteal tissue at Ovsynch enrolment and recent disease events affected pregnancy per FTAI in cows inseminated after Ovsynch. PMID- 28346664 TI - A cross-sectional comparison of three guidelines for intrapartum cardiotocography. AB - OBJECTIVE: To compare the cardiotocography classification systems outlined by the International Federation of Gynecology and Obstetrics (FIGO) in 2015 and the UK National Institute for Health and Care Excellence (NICE) in 2007 and 2014. METHODS: A cross-sectional observational study of cardiotocography practices at a UK hospital was conducted among labor ward staff (n=21) from November 1 to November 31, 2015. All observers classified ten cardiotocography traces according to the three guidelines using a bespoke form. Outcome measures included interobserver agreement (kappa values), percentage agreement, intervention rate, and perceived ease of use. RESULTS: The kappa values were 0.38 (FIGO 2015), 0.37 (NICE 2007), and 0.34 (NICE 2014). The percentage agreement was identical across the three systems for both normal cardiotocography results (100.0%) and for intermediate or suspicious results (80.9%). By contrast, the percentage agreement for abnormal or pathological findings was 47.6% for NICE 2014, 76.2% for FIGO 2015, and 91.0% for NICE 2007 guidelines. Among 210 observations, intervention was deemed necessary for 48 (22.9%) for FIGO 2015, 29 (13.8%) for NICE 2014, and 56 (26.7%) for NICE 2007 guidelines. The FIGO 2015 system was considered the easiest to use by 13 (61.9%) observers. CONCLUSION: Interobserver agreement of cardiotocography classification is suboptimal. The FIGO 2015 system offered favorable agreement scores, perceived ease of use, and a moderate intervention rate. PMID- 28346666 TI - Disseminated peripheral neuroblastoma in a Rhodesian Ridgeback dog. AB - CASE REPORT: A 4-year-old neutered male Rhodesian Ridgeback dog with right-sided Horner's syndrome, bilateral laryngeal paralysis, neck pain and bilateral hindlimb ataxia was euthanased following deterioration of its neurological status. Necropsy examination revealed an off-white retropharyngeal neoplastic mass (100 * 30 * 30 mm) attached to the base of the skull on the right side and macroscopic nodular metastases in the spleen and three vertebral bodies (C6, C7 and T6), including a nodule attached to the dura at C7. Histological evidence of neuroblastic tumour was detected in these macroscopic lesions, a regional lymph node, bone marrow of a femur and all 15 vertebral bodies (C1-T8) examined, including the three with macroscopic metastases, and in the lumens of small blood vessels in the lungs and liver. Ganglion cell differentiation was detected only in the primary retropharyngeal mass, one splenic nodule and the C7 dural nodule. Neoplastic cells were immunoreactive to neurofilament protein (ganglion cells only), vimentin and synaptophysin, and were negative for S100 protein, GFAP, CD3 and Pax5. CONCLUSION: The diagnosis was disseminated peripheral neuroblastoma, differentiating subtype (International Neuroblastoma Pathology Classification), with likely primary involvement of the right cranial cervical ganglion. This appears to be the first report of neuroblastoma in a dog with widespread occult haematogenous metastasis to bone marrow. PMID- 28346668 TI - Demographic and preliminary employment data of the first two graduate cohorts from a rural veterinary school. AB - OBJECTIVE: To report initial career experiences and graduate employment destinations 1 and 5 years following graduation of the 67 graduates from the first two graduating classes of the veterinary science program at Charles Sturt University. DESIGN: Online survey of graduates from the 2010 and 2011 cohorts undertaken 12 months following course completion and descriptive data on graduate practice locations 5 years post-graduation. PROCEDURE: Questions covered general demographic information, issues relating to work-life balance and factors influencing vocational choices. Descriptive statistics and qualitative responses are reported, with comparisons between continuous variables by two-sample t-test and between categories by Chi-square analyses. Significance was set at P < 0.05. Graduates' locations 5 years after graduation were obtained from veterinary registration details and staff contact with graduates. RESULTS: Complete survey responses were received from 39 graduates of whom 34 were employed in regional areas, 1 in a very remote area, 3 in major cities and 1 overseas. Hours worked and salary received were consistent with other survey data, with new graduates working in regional practices earning slightly more than those working in metropolitan practices. At 5 years following graduation, the majority (56/61, 92%) remained in rural or regional Australian veterinary practices, with a further five graduates overseas and one lost to follow-up. CONCLUSION: This study supported the selection criteria and educational approaches at CSU in establishing most of the new graduates in rural and regional mixed veterinary practice. PMID- 28346669 TI - Evaluation of a point-of-care electrochemical meter to detect subclinical ketosis and hypoglycaemia in lactating dairy cows. AB - OBJECTIVES: To evaluate and validate a hand-held electrochemical meter (Precision Xtra(r)) as a screening test for subclinical ketosis and hypoglycaemia in lactating dairy cattle. DESIGN: Method comparison study using a convenience sample. PROCEDURE: Blood samples were collected into plain tubes from the coccygeal vessels of 181 Holstein cows at 2-4 weeks of lactation during summer in Iran. Blood beta-hydroxybutyrate concentration (BHB) and glucose concentration were immediately measured by the electrochemical meter after applying 20 MUL of blood to the reagent strip. Passing-Bablok regression and Bland-Altman plots were used to determine the accuracy of the meter against laboratory reference methods (BHB dehydrogenase and glucose oxidase). RESULTS: Serum BHB ranged from 0.1 to 7.3 mmol/L and serum glucose ranged from 0.9 to 5.1 mmol/L. Passing-Bablok regression analysis indicated that the electrochemical meter and reference methods were linearly related for BHB and glucose, with a slope estimate that was not significantly different from 1.00. Clinically minor, but statistically significant, differences were present for the intercept value for Passing-Bablok regression analysis for BHB and glucose, and bias estimates in the Bland-Altman plots for BHB and glucose. CONCLUSION: The electrochemical meter provided a clinically useful method to detect subclinical ketosis and hypoglycaemia in lactating dairy cows. Compared with other method validation studies using the meter, we attributed the improved performance of the electrochemical meter to application of a fixed volume of blood (20 MUL) to the reagent strip, use of the meter in hot ambient conditions and use of glucose oxidase as the reference method for glucose analysis. PMID- 28346670 TI - Neospora caninum in beef herds in New South Wales, Australia. 2: analysis of risk factors. AB - OBJECTIVE: To determine the influence of farm-level and animal-level factors on the seroprevalence of antibodies to Neospora caninum and associations between seropositivity and reproductive outcomes. METHODS: A questionnaire for a cross sectional survey was posted to the 63 properties with a herd size >=50 beef breeding cows that had participated in a previous seroprevalence study. Correspondence analysis, which does not appear to have been used previously in any Australian studies of livestock diseases, was used in conjunction with logistic regression to analyse the data. RESULTS: Geographic factors that increased the risk of seropositivity included higher rainfall North Coast location. Herd management factors that increased the risk of seropositivity included the use of Bos indicus genetics, cross-breeding and running several breeds in the one herd. Using fox control measures was found to be protective against infection with N. caninum. The risk of abortion was 12-fold greater in individual animals that were seropositive for N. caninum. Within a herd, the calving rate was 10.4% lower in herds with one or more N. caninum-positive animals (P = 0.03), but the difference in abortion rate was not significant between seropositive and seronegative herds (0.3% higher, P > 0.3). CONCLUSIONS: This study confirmed previous observations of increased risks for N. caninum seropositivity with being located in the coastal subtropics, some styles of herd management and canid exposure. In addition, it suggested that cross-breeding and proximity to an urban area may increase the risk, and that having pet dogs may reduce the risk of seropositivity. PMID- 28346672 TI - Congenital bilateral anterior nasal atresia in 16 half-sibling Holstein-Friesian calves. AB - CASE REPORT: Cases of bilateral anterior nasal atresia, sometimes referred to as arhinia or partial arhinia, are extremely rare in cattle and have only been reported as single events. This report describes the birth of 16 Holstein Friesian calves over a 3-month period, all affected with bilateral atresia of the nares and anterior nasal cavity, with 2 calves having additional severe deviation of the nasomaxillary bones and nasal septum. One affected calf was born with an anatomically normal twin. Parentage testing demonstrated that a single Holstein Friesian bull sired all cases tested. CONCLUSION: This is the first report of multiple cases of bilateral anterior nasal atresia in cattle with evidence that demonstrates a heritable condition. PMID- 28346674 TI - ERRATUM: Genetic Variants in Transcription Factors Are Associated With the Pharmacokinetics and Pharmacodynamics of Metformin. PMID- 28346673 TI - Clinical features of Bim deletion polymorphism and its relation with crizotinib primary resistance in Chinese patients with ALK/ROS1 fusion-positive non-small cell lung cancer. AB - BACKGROUND: The authors' previous study demonstrated that the B-cell chronic lymphocytic leukemia/lymphoma (Bcl-2)-like 11 (BCL2L11) (Bim) deletion polymorphism was associated with poor clinical response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC) with EGFR mutations. The objective of the current study was to investigate the impact of the Bim deletion polymorphism among patients with anaplastic lymphoma kinase (ALK)-positive or ROS proto-oncogene 1, receptor tyrosine kinase (ROS1)-positive NSCLC who were treated with crizotinib. METHODS: A total of 55 patients with ALK-positive NSCLC and 14 patients with ROS1-positive NSCLC who were treated with crizotinib were enrolled into the current study. The Bim deletion polymorphism was analyzed by polymerase chain reaction. The clinical features of the Bim deletion polymorphism and its impact on the effect of crizotinib were investigated. RESULTS: The Bim deletion polymorphism was present in 9 of 69 patients with ALK-positive or ROS1-positive NSCLC (13.0%). There were no differences noted with regard to clinicopathological features between patients with and without the Bim deletion polymorphism. Patients with the Bim deletion polymorphism had a significantly shorter progression-free survival (PFS) and lower objective response rate compared with those without (median PFS, 182 days vs 377 days [P = .008]) (objective response rate, 44.4% vs 81.7% [P =.041]) in all populations. The significant difference in PFS was observed in patients with ALK-positive NSCLC (83 days vs 305 days [P =.0304]) compared with those with ROS1 positive NSCLC (218 days vs not reached [P =.082]). Multivariate analysis indicated that the Bim deletion polymorphism was an independent predictive factor for patients with ALK-positive NSCLC who were treated with crizotinib (hazard ratio, 4.786 [P =.006]). CONCLUSIONS: The Bim deletion polymorphism was found to be associated with poor clinical response to crizotinib in patients with ALK fusion-positive NSCLC. Cancer 2017;123:2927-35. (c) 2017 American Cancer Society. PMID- 28346676 TI - CORRIGENDUM: Genetic Variations in GRIA1 on Chromosome 5q33 Related to Asparaginase Hypersensitivity. PMID- 28346678 TI - CORRIGENDUM: Identification and Characterization of a Defective CYP3A4 Genotype in a Kidney Transplant Patient With Severely Diminished Tacrolimus Clearance. PMID- 28346680 TI - Human papillomavirus in cervical cancer and oropharyngeal cancer: One cause, two diseases. AB - Human papillomavirus (HPV) causes greater than 5% of cancers worldwide, including all cervical cancers and an alarmingly increasing proportion of oropharyngeal cancers (OPCs). Despite markedly reduced cervical cancer incidence in industrialized nations with organized screening programs, cervical cancer remains the second most common cause of death from cancer in women worldwide, as developing countries lack resources for universal, high-quality screening. In the United States, HPV-related OPC is only 1 of 5 cancers with a rising incidence since 1975 and now has taken over the cervix as the most common site of HPV related cancer. Similar trends follow throughout North America and Europe. The need for early detection and prevention is paramount. Despite the common etiologic role of HPV in the development of cervical cancer and HPV-associated OPC, great disparity exists between incidence, screening modalities (or lack thereof), treatment, and prevention in these 2 very distinct cohorts. These differences in cervical cancer and HPV-associated OPC and their impact are discussed here. Cancer 2017;123:2219-2229. (c) 2017 American Cancer Society. PMID- 28346681 TI - Obstructive sleep apnea and postoperative complications among patients undergoing gynecologic oncology surgery. AB - OBJECTIVE: To investigate the prevalence of obstructive sleep apnea (OSA), physiological or risk factors associated with OSA, and OSA-associated postoperative complications among patients undergoing gynecologic oncology surgery. METHODS: A prospective observational study enrolled gynecologic oncology patients undergoing abdominal surgery at a center in the UK between August 2009 and January 2013. All patients underwent perioperative sleep oximetry for the diagnosis of OSA. Data assessed included the body mass index, the STOP-Bang score, the Epworth Sleepiness Scale score, the apnea-hypopnea index, and postoperative complications. Associations were determined between preoperative OSA and postoperative OSA, postoperative complications, and risk factors such as body mass index, age, STOP-Bang score, and Epworth score. RESULTS: Among 160 participants, 72 (45.0%) were obese and 80 (50.0%) had OSA. Obesity, older age (more than 65 years), and a neck circumference of 40 cm or more were significantly associated with OSA. Overall, 58 (36.3%) patients had postoperative complications; 21 (13.1%) had surgical complications and 37 (23.1%) had medical complications. Complications were not associated with OSA (P=0.612). Four (2.5%) patients died; mortality was not associated with OSA (P=0.810). CONCLUSION: OSA is common among gynecologic oncology patients. Portable sleep oximetry identifies gynecology patients who have OSA or require postoperative critical care. Obesity is associated with OSA, but OSA is not associated with postoperative complications in gynecologic oncology patients. PMID- 28346682 TI - Age-related variation in the cellular composition of equine bronchoalveolar lavage fluid. AB - BACKGROUND: Previous reports reveal variation in the cellular composition of equine bronchoalveolar lavage fluid (BALF). OBJECTIVES: The purpose of this study was to compare the profiles of BALF from horses to assess age-related differences. Serial BALF samples were collected from the same individuals over a one-year period to identify changes in individual animals as they aged. METHODS: Collection of BALF was performed on horses aged one week and one, 2, 6, and 12 months. Total nucleated cell count (TNCC), protein concentration, and cytology were assessed. Longitudinal analysis was performed and compared to healthy adults. RESULTS: Foals at one week and 6 months of age had significantly higher TNCC than adults (medians: 320/MUL, 285/MUL, and 90/MUL, respectively); no differences in total protein were found. Foals at one month had the highest proportion of macrophages (median: 87.3%), differing significantly from both yearlings and adults (medians: 45.5% and 48.7%, respectively). Foals aged one week and one month had significantly lower proportions of lymphocytes than yearlings and adults (medians: 3.2% and 4.7% vs 43.2% and 45.8%, respectively). Eosinophil percentage was lowest in foals aged one week, one month, and 2 months (median: 0.0%) and highest in foals aged 6 months (median: 2.2%). Mast cell percentages were highest in yearlings and adults (medians: 2.2% and 3.3%, respectively) and neutrophil percentage was highest in foals aged one week (13.7%). CONCLUSIONS: Cytologic profiles of BALF from foals and adult horses differed considerably. Significant changes in TNCC and percentages of lymphocytes, macrophages, and eosinophils occurred with age. PMID- 28346683 TI - Obituary Robert H. Horwich (1940-2017). PMID- 28346685 TI - Experience of Shame Mediates the Relationship Between Pathological Narcissism and Suicidal Ideation in Psychiatric Outpatients. AB - OBJECTIVE: Pathological narcissism, described by 2 dysfunctional phenotypic forms grandiosity and vulnerability-has often been connected to suicidal tendencies in theoretical and clinical literatures. Furthermore, shame proneness has been implicated as a key mechanism that links these 2 constructs. However, empirical evidence for the presumed relationship between pathological narcissism and suicidal tendencies is sparse, and no prior research has investigated the role of shame proneness in this relationship. The objective of the present research was to investigate the complex relations among pathological narcissism, experience of shame, and suicidal ideation in psychiatric outpatients. METHOD: A sample of 250 adult psychiatric outpatients (61% female; mean age 39.15 years) were assessed between January and May 2014. The participants filled out the Pathological Narcissism Inventory, the Experience of Shame Scale, and the Suicide Assessment Scale-self-rating. RESULTS: Narcissistic vulnerability was found to have unique positive associations with acute suicidal ideation, whereas narcissistic grandiosity exhibited substantially weaker relations with the same construct. Two dimensions of shame-characterological and bodily shame-mediated the relationship between narcissistic vulnerability and suicidal ideation. The mediating role of behavioral shame was not demonstrated. CONCLUSIONS: Narcissistic vulnerability seems to be more strongly related to suicidal tendencies than narcissistic grandiosity, while experience of shame represents one of the underlying mechanisms of this relationship among psychiatric outpatients. The implications of these findings are discussed in relation to the role of pathological narcissism in the psychotherapeutic management of suicidality. PMID- 28346686 TI - Effects of Catechins and Their Related Compounds on Cellular Accumulation and Efflux Transport of Mitoxantrone in Caco-2 Cell Monolayers. AB - The ability of catechins and their related compounds to inhibit breast cancer resistance protein (BCRP) function in Caco-2 cell monolayers was investigated with mitoxantrone as a BCRP substrate. The gallate or pyrogallol moiety on the catechin structure seemed to promote increased cellular accumulation and inhibit efflux transport of mitoxantrone. The ability of gallate catechins such as (-) epigallocatechin gallate (EGCG) and (-)-epicatechin gallate (ECG) to increase cellular accumulation and inhibit efflux transport of mitoxantrone was greater than that of nongallate catechins. Gallic acid octyl ester (GAO) also increased intracellular mitoxantrone accumulation. Experiments using GAO derivatives indicated that the gallate moiety required the presence of a long carbon chain for BCRP inhibition. Cellular accumulation and reduced efflux transport of mitoxantrone were greater with epigallocatechin 3-(3"-O-butyl) gallate than with EGCG. EGCG inhibition of BCRP seemed to be restricted by hydrophobicity. The co administration of catechins, particularly EGCG and related compounds, with greater hydrophobicity may increase the therapeutic activities of BCRP substrates such as mitoxantrone. PMID- 28346687 TI - ITADE flap after mastectomy for locally advanced breast cancer: A good choice for mid-sized defects of the chest wall, based on a systematic review of thoracoabdominal flaps. AB - BACKGROUND: Locally advanced breast cancer (LABC) is still a common problem in developing countries. Extensive resections are aimed at local control and improving quality of life. Dermofat flaps are an option for medium-sized defects. OBJECTIVES: Evaluate the results of a new thoracoabdominal flap (TAF). METHODS: We describe and evaluate an ipsilateral, thoracoabdominal horizontal, dermofat (ITADE) flap performed in patients submitted to mastectomy and immediate reconstruction. A systematic review of the flaps used in this situation was performed. RESULTS: A total of 23 patients underwent the ITADE flap. The average flap size was 360 cm2 . One (4.3%) patient presented extensive loss of the flap. In the literature review, we observed 354 patients with 159 TAFs. We added our cases to the evaluation. A significant reduction in the risk of necrosis using myocutaneous flaps versus TAFs was observed (P < 0.001). Comparing other TAFs and ITADE flaps, considering all necrosis, a significant difference was apparent (P = 0.02), which disappeared when evaluating only larger necrosis (P = 0.13). Multivariate analysis showed that the resected area was the best variable related to the presence of necrosis. CONCLUSIONS: ITADE allows extensive coverage areas, an early start of adjuvant treatment and it can be performed without requiring a reconstructive team. PMID- 28346688 TI - How far do Neotropical primates disperse seeds? AB - Seed dispersal distance (SDD) is a vital component of vertebrate-mediated seed dispersal process: the average distance at which seeds are deposited away from the parent plant represents the starting template of plant regeneration. We present a simple model to explain and predict observed measures of average dispersal distance and we hypothesize that it is a consequence of how long seeds are retained in the disperser's gut, how rapidly the disperser moves per unit time and how twisted the animal travel path is relative to the straight-line distance moved away from the seed source. We retrieved data on dispersal distances from 26 published studies including nine primate species dispersing up to 112 plant species per study. We used gut transit time (TT) as a proxy for residence time inside the gut, the disperser's travel path per hour as proxy for movement rate, and the daily path length relative to the home range area as a correlate of path twisting (PT). We illustrate this model with comparative data on Neotropical primates. These three variables explained 90% of the variation in the average SDD. Path analysis indicates that additional variables exerted only indirect effects. Our model can be applied to primate populations for which detailed seed dispersal data are missing, and help evaluate conservation priorities for primate species according to the potential service they provide in terms of forest regeneration. PMID- 28346689 TI - Peripheral and central fatigue after high intensity resistance circuit training. AB - INTRODUCTION: The aim of this study was to investigate the effects of high intensity resistance circuit (HIRC) and traditional strength training (TST) on neuromuscular fatigue and metabolic responses. METHODS: Twelve trained young subjects performed HIRC and TST in a counterbalanced order with 1 week rest in between. The amount of workload and the inter-set time for each local muscle group were matched (180 s), however, the time between successive exercises differed. The twitch interpolation technique was used to test neuromuscular function of the knee extensor muscles. Blood lactate concentration was used to evaluate metabolic responses. RESULTS: Maximum voluntary contraction and resting potentiated twitch amplitude (Qtw ) were significantly reduced after HIRC, but there were not changes after TST, while reductions in voluntary activation were similar. Lactate concentration increased significantly more after HIRC. CONCLUSIONS: The higher lactate concentration after HIRC probably impaired excitation-contraction coupling, indicating larger peripheral fatigue than after TST. Muscle Nerve 56: 152-159, 2017. PMID- 28346690 TI - The benefits and limitations of cell-free DNA screening for 47, XXY (Klinefelter syndrome). AB - OBJECTIVE: The purpose of this paper is to provide an overview of the 47, XXY syndrome, which is the most commonly occurring X and Y chromosomal variation. This paper seeks to review what is currently known of noninvasive prenatal testing (NIPT) and 47, XXY and investigate potential risks and benefits of prenatal identification. METHOD: A literature review of NIPT and 47, XXY was performed to identify limitations of current NIPT techniques. RESULTS: As NIPT becomes an increasingly more routine procedure, prenatal findings of 47, XXY may increase. Awareness of this disorder and appropriate genetic counseling is necessary. CONCLUSION: X and Y chromosomal variations will be identified through this screening, and the benefits and limitations to this finding need to be thoughtfully considered. (c) 2017 John Wiley & Sons, Ltd. PMID- 28346691 TI - Reproductive status affects the feeding ecology and social association patterns of female squirrel monkeys (Saimiri collinsi) in an Amazonian rainforest. AB - When making foraging decisions, female primates may follow specific behavioral strategies that reflect their reproductive state. Lactation is considered the most energetically costly phase for females, but we argue that gestation is also energetically expensive for squirrel monkeys. In this study, we examined whether female squirrel monkeys (a seasonally breeding primate) in different reproductive phases showed significant differences in their foraging ecology. We sampled two wild groups of squirrel monkeys (Saimiri collinsi) using the focal animal method, during 12 months (June 2014 to May 2015). During this time, we quantified the effect of reproductive state (mating, gestation, and lactation) and sex (females vs. males) on activity budgets, foraging efficiency, dietary composition, and nearest neighbors. We found significant effects of both sex and reproductive phase on the mean proportion of time spent foraging, resting, traveling, and being social. Females consumed more insects than did males at all times; among females, time spent eating prey and fruit varied according to reproductive state. These data suggest that, due to their life history and seasonal breeding, reproduction is a costly activity for female Saimiri, and not only during lactation. Therefore, adopting the appropriate behavioral strategies is essential to reduce energetic deficits in females. PMID- 28346692 TI - Embraces are lateralized in spider monkeys (Ateles fusciceps rufiventris). AB - Side biases observed in behavior are thought to reflect underlying asymmetric brain function or hemispheric specialization. Previous work in multiple species identified left side biases (associated with the right hemisphere) for processing social behavior. In highly social species such as primates, many behaviors may be categorized as social, yet differences between such behaviors have not been examined as a test of asymmetric brain function. Using Colombian spider monkeys (Ateles fusciceps rufiventris), we observed lateral positioning during two types of behaviors widely categorized as social affiliative: embracing and grooming, and identified a left bias for embracing, but not grooming. Our findings partially support prior research in hemispheric specialization, but suggest that there may be differences between social behaviors that drive specialization. We discuss these results in light of current theory on hemispheric specialization and highlight differences between embracing and grooming. PMID- 28346694 TI - "Holy anorexia"-relevant or relic? Religiosity and anorexia nervosa among Finnish women. AB - Since medieval times, an association between religiosity and anorexia nervosa has been suggested, but few systematic studies exist. This study examines in a nationwide setting whether personal or family religiosity is associated with lifetime anorexia nervosa among women in adolescence and early adulthood. Women (N = 2,825) from the 1975 to 1979 birth cohorts of Finnish twins were screened for lifetime DSM-5 anorexia nervosa (N = 92). Parental religiosity was assessed by self-report when the women were aged 16 years. The women self-reported their religiosity at ages 16 and 22 to 27 years. Parental religiosity did not increase the risk of lifetime anorexia nervosa, and neither did religiosity of the women themselves in adolescence. In early adulthood, a J-shaped curve was compatible with the data, indicating increased risk both at low and high levels of religiosity, but this result was statistically non-significant. Religiosity was weakly negatively correlated with body dissatisfaction. There was some suggestive evidence for socioregional variation in the association of religiosity with lifetime anorexia nervosa. In this first population study to directly address religiosity and anorexia nervosa, no evidence was found for a significant association of religiosity with anorexia nervosa either at the personal or family level. Some regional differences are possible. A modest protective association of religiosity with body dissatisfaction is also possible. Despite compelling case descriptions of "holy anorexia," religiosity does not appear to be a central factor in the development of anorexia nervosa in Finland, a highly secularized Christian country. PMID- 28346693 TI - Using a novel NQO1 bioactivatable drug, beta-lapachone (ARQ761), to enhance chemotherapeutic effects by metabolic modulation in pancreatic cancer. AB - Novel, tumor-selective therapies are needed to increase the survival rate of pancreatic cancer patients. K-Ras-mutant-driven NAD(P)H:quinone oxidoreductase 1 (NQO1) is over-expressed in pancreatic tumor versus associated normal tissue, while catalase expression is lowered compared to levels in associated normal pancreas tissue. ARQ761 undergoes a robust, futile redox cycle in NQO1+ cancer cells, producing massive hydrogen peroxide (H2 O2 ) levels; normal tissues are spared by low NQO1 and high catalase expression. DNA damage created by ARQ761 in pancreatic cancer cells "hyperactivates" PARP1, causing metabolic catastrophe and NAD +/- keresis cell death. NQO1: catalase levels (high in tumor, low in normal tissue) are an attractive therapeutic window to treat pancreatic cancer. Based on a growing body of literature, we are leading a clinical trial to evaluate the combination of ARQ761 and chemotherapy in patients with pancreatic cancer. PMID- 28346695 TI - Contribution of small conductance K+ channels to sinoatrial node pacemaker activity: insights from atrial-specific Na+ /Ca2+ exchange knockout mice. AB - KEY POINTS: Repolarizing currents through K+ channels are essential for proper sinoatrial node (SAN) pacemaking, but the influence of intracellular Ca2+ on repolarization in the SAN is uncertain. We identified all three isoforms of Ca2+ activated small conductance K+ (SK) channels in the murine SAN. SK channel blockade slows repolarization and subsequent depolarization of SAN cells. In the atrial-specific Na+ /Ca2+ exchanger (NCX) knockout mouse, cellular Ca2+ accumulation during spontaneous SAN pacemaker activity produces intermittent hyperactivation of SK channels, leading to arrhythmic pauses alternating with bursts of pacing. These findings suggest that Ca2+ -sensitive SK channels can translate changes in cellular Ca2+ into a repolarizing current capable of modulating pacemaking. SK channels are a potential pharmacological target for modulating SAN rate or treating SAN dysfunction, particularly under conditions characterized by abnormal increases in diastolic Ca2+ . ABSTRACT: Small conductance K+ (SK) channels have been implicated as modulators of spontaneous depolarization and electrical conduction that may be involved in cardiac arrhythmia. However, neither their presence nor their contribution to sinoatrial node (SAN) pacemaker activity has been investigated. Using quantitative PCR (q PCR), immunostaining and patch clamp recordings of membrane current and voltage, we identified all three SK isoforms (SK1, SK2 and SK3) in mouse SAN. Inhibition of SK channels with the specific blocker apamin prolonged action potentials (APs) in isolated SAN cells. Apamin also slowed diastolic depolarization and reduced pacemaker rate in isolated SAN cells and intact tissue. We investigated whether the Ca2+ -sensitive nature of SK channels could explain arrhythmic SAN pacemaker activity in the atrial-specific Na+ /Ca2+ exchange (NCX) knockout (KO) mouse, a model of cellular Ca2+ overload. SAN cells isolated from the NCX KO exhibited higher SK current than wildtype (WT) and apamin prolonged their APs. SK blockade partially suppressed the arrhythmic burst pacing pattern of intact NCX KO SAN tissue. We conclude that SK channels have demonstrable effects on SAN pacemaking in the mouse. Their Ca2+ -dependent activation translates changes in cellular Ca2+ into a repolarizing current capable of modulating regular pacemaking. This Ca2+ dependence also promotes abnormal automaticity when these channels are hyperactivated by elevated Ca2+ . We propose SK channels as a potential target for modulating SAN rate, and for treating patients affected by SAN dysfunction, particularly in the setting of Ca2+ overload. PMID- 28346696 TI - Do people trust dentists? Development of the Dentist Trust Scale. AB - BACKGROUND: This study aimed to adapt a measure of trust in physicians to trust in dentists and to assess the reliability and validity of the measure. METHODS: Questionnaire data were collected from a simple random sample of 596 Australian adults. The 11-item General Trust in Physicians Scale was modified to apply to dentists. RESULTS: The Dentist Trust Scale (DTS) had good internal consistency (alpha = 0.92) and exploratory factor analysis revealed a single-factor solution. Lower DTS scores were associated with less trust in the dentist last visited, having previously changed dentists due to unhappiness with the care received, currently having dental pain, usual visiting frequency, dental avoidance, and with past experiences of discomfort, gagging, fainting, embarrassment and personal problems with the dentist. CONCLUSIONS: The majority of people appear to exhibit trust in dentists. The DTS shows promising reliability and validity evidence. PMID- 28346698 TI - How do rivers, geographic distance, and dispersal behavior influence genetic structure in two sympatric New World monkeys? AB - Dispersal, one of the major factors affecting the gene flow between populations, shapes the spatial distribution of genetic diversity within species. Alouatta macconnelli and Saguinus midas are two Neotropical monkey species that sympatrically inhabit the Guiana shield in northern Amazonia and are likely to differ in their dispersal behavior and vagility. We took advantage of their sympatry to investigate, over a fine geographical scale (~50 km long), the relationship between spatial genetic structure, on the one hand, and geographical features and the species' dispersal behavior on the other. A total of 84 A. macconnelli individuals from 25 social units and 76 S. midas individuals from 19 social units were genotyped for nine microsatellite markers. Both species displayed high genetic diversity and allelic richness. However, patterns of genetic structure differed between the two species. In A. macconnelli, no genetic substructuring was observed, while in S. midas we detected significant structuring, but this structuring was not correlated with geographical features, such as the location of individuals relative to the river and/or the distance between them. Instead, the geographical distribution of genetic variation observed for each species is predominantly explained by each species' dispersal pattern. We identified bisexual dispersal for both species, but with significant differences, either in the distance or in the rate of dispersal, between species and sexes. Genetic relatedness within social units was higher in S. midas than in A. macconnelli: gene flow between social units seems limited in S. midas, especially for females, while high dispersal characterizes A. macconnelli, where females seem to disperse at lower rate but at a longer distance than males. PMID- 28346699 TI - The SORG nomogram accurately predicts 3- and 12-months survival for operable spine metastatic disease: External validation. AB - BACKGROUND AND OBJECTIVES: Externally validate the SORG12 nomogram and SORG classic algorithm at estimating survival in patients with spine metastatic disease, and compare predictive accuracy with other survival algorithms. METHODS: We received data from 100 patients who had surgery for spine metastatic disease at an external institution. Algorithms were accurate if the Area Under Curve (AUC) was >0.70, and we used Receiver Operating Characteristic (ROC) analysis to compare predictive accuracy with other algorithms. RESULTS: The SORG nomogram accurately estimated 3-months (AUC = 0.74) and 12-months survival (AUC = 0.78); it did not accurately estimate 1-month survival (AUC = 0.65). There was no difference in 1-month survival accuracy between the SORG nomogram and SORG classic algorithm (P = 0.162). The SORG nomogram was best at predicting 3-months survival, compared with the Tokuhashi score and SORG classic algorithm (P = 0.009). The SORG nomogram was best at predicting 12-months survival, compared with the Tomita score, Ghori score, Bauer modified score, Tokuhashi score, and SORG classic algorithm (P = 0.033). CONCLUSIONS: The SORG nomogram accurately estimated 3- and 12-months survival for operable spine metastatic disease, and is therefore, useful in clinical practice. PMID- 28346700 TI - Vitamin D status in wild toque macaques (Macaca sinica) in Sri Lanka. AB - The vitamin D receptor is found on most cells, including active immune cells, implying that vitamin D has important biological functions beyond calcium metabolism and bone health. Although captive primates should be given a dietary source of vitamin D, under free-living conditions vitamin D is not a required nutrient, but rather is produced in skin when exposed to UV-B light. The circulating level of 25 hydroxyvitamin D (25-OH-D) considered adequate for humans is a topic of current controversy. Levels of circulating 25-OH-D sufficient for good health for macaques and other Old World anthropoids are assumed to be the same as human values, but data from free-living animals are scant. This study reports values for 25-OH-D and the active vitamin D metabolite, 1,25 dihydroxyvitamin D (1,25[OH]2 D) for wild, forest-ranging toque macaques (Macaca sinica) in Sri Lanka. Plasma samples were obtained from eight adult males, seven juvenile males, six young nulliparous females, nine adult females not pregnant or lactating, eleven lactating adult females, and four pregnant females. Mean values for the complete sample were 61.3 +/- 4.0 ng/ml for 25-OH-D and 155.6 +/- 8.7 pg/ml for 1,25[OH]2 D. There were no significant differences for either metabolite among age and sex classes, nor between lactating and non-reproductive females. Values from the literature for circulating 25-OH-D in captive macaques are three times higher than those found in this wild population, however, 1,25[OH]2 D values in captive animals were similar to the wild values. The data from this study indicate that anthropoid primates exposed to extensive sunlight will have circulating values of 25-OH-D generally above 30 ng/ml, providing some support for the Endocrine Society recommendations for humans. Current dietary vitamin D supplementation of captive macaques likely exceeds requirement. This may affect metabolism and immune function, with possible consequences for macaque health and biomedical research results. PMID- 28346697 TI - CAR T-cell therapy for pancreatic cancer. AB - Chimeric antigen receptor (CAR) T-cell therapy utilizes genetic engineering to redirect a patient's own T cells to target cancer cells. The remarkable results in hematological malignancies prompted investigating this approach in solid tumors such as pancreatic cancer. The complex tumor microenvironment, stromal hindrance in limiting immune response, and expression of checkpoint blockade on T cells pose hurdles. Herein, we summarize the opportunities, challenges, and state of knowledge in targeting pancreatic cancer with CAR T-cell therapy. PMID- 28346701 TI - Effect of resistance training with vibration and compression on the formation of muscle and bone. AB - INTRODUCTION: In this study we investigated the effects of resistance training with vibration in combination with leg compression to restrict blood flow on strength, muscle oxygenation, muscle mass, and bone formation. METHODS: Twelve participants were tested before and after 12 weeks of resistance training with application of vibration (VIBRA; 1-2 mm, 30 Hz) to both legs and compression (~35 mm Hg, VIBRA+COMP) to only 1 leg. RESULTS: VIBRA+COMP and VIBRA improved 1 repetition maximum (1-RM), increased the number of repetitions preceding muscle exhaustion, enhanced cortical bone mass, and lowered the mass and fat fraction in the thigh, with no changes in total muscle mass. The mass of cancellous bone decreased to a similar extent after VIBRA and VIBRA+COMP. DISCUSSION: Resistance training with VIBRA+COMP and VIBRA improved 1-RM, increased the number of repetitions preceding muscular exhaustion, and enhanced formation of cortical bone, with no alteration of muscle mass. Muscle Nerve 56: 1137-1142, 2017. PMID- 28346702 TI - Evaluation of the effects of time, temperature, and specimen storage on in vitro lactate concentrations in healthy dogs. AB - BACKGROUND: Lactate concentrations increase significantly under certain storage conditions, except for when glycolysis-arresting agents are used. Evaluation of time and storage conditions on heparinized whole blood lactate concentrations without glycolysis-arresting agents have not been evaluated in dogs. OBJECTIVES: The purpose of the study was to determine the effects of preanalytic storage conditions on the in vitro concentration of lactate in heparinized canine venous blood specimens. METHODS: In this prospective study, blood collected from 30 healthy dogs was aliquoted and stored under different conditions: anaerobic refrigerated (3 degrees C), aerobic refrigerated, anaerobic room temperature (RT), and aerobic RT. Whole blood lactate was analyzed at 15-25, 30-40, 60-70, and 120-130 minutes from time 0 (T0) under all storage conditions. Percent increases from the T0 specimen were calculated. RESULTS: There were significantly increased lactate concentrations at all time points within the anaerobic refrigerated specimens compared to T0, and in the anaerobic RT specimens after 15 25 minutes. The aerobic refrigerated specimens did not have significant changes in lactate when compared to anaerobic refrigerated specimens, while the aerobic RT specimens had significant increases at all time points. Anaerobically refrigerated specimens stored < 40 minutes and aerobically refrigerated specimens stored < 25 minutes had in vitro lactate increases of < 20%. CONCLUSIONS: Results support analyzing lactate specimens immediately. If lactate analysis is delayed, anaerobic refrigerated specimens should be analyzed within 40 minutes, and aerobic refrigerated specimens should be analyzed within 25 minutes. Room temperature specimens stored either aerobically or anaerobically should be avoided as lactate concentrations may be falsely increased. PMID- 28346703 TI - Tunable GLUT-Hexose Binding and Transport via Modulation of Hexose C-3 Hydrogen Bonding Capabilities. AB - The importance of the hydrogen bonding interactions in the GLUT-hexose binding process (GLUT=hexose transporter) has been demonstrated by studying the binding of structurally modified d-fructose analogues to GLUTs, and in one case its transport into cells. The presence of a hydrogen bond donor at the C-3 position of 2,5-anhydro-d-mannitol derivatives is essential for effective binding to GLUT5 and transport into tumor cells. Surprisingly, installation of a group that can function only as a hydrogen bond acceptor at C-3 resulted in selective recognition by GLUT1 rather than GLUT5. A fluorescently labelled analogue clearly showed GLUT-mediated transport and low efflux properties of the probe. This study reveals that a single positional modification of a 2,5-anhydro-d-mannitol derivative is sufficient to switch its binding preference from GLUT5 to GLUT1, and uncovers general scaffolds that are suitable for the potential selective delivery of molecular payloads into tumor cells via GLUT transport machinery. PMID- 28346704 TI - The chloroplast RNA helicase ISE2 is required for multiple chloroplast RNA processing steps in Arabidopsis thaliana. AB - INCREASED SIZE EXCLUSION LIMIT2 (ISE2) is a chloroplast-localized RNA helicase that is indispensable for proper plant development. Chloroplasts in leaves with reduced ISE2 expression have previously been shown to exhibit reduced thylakoid contents and increased stromal volume, indicative of defective development. It has recently been reported that ISE2 is required for the splicing of group II introns from chloroplast transcripts. The current study extends these findings, and presents evidence for ISE2's role in multiple aspects of chloroplast RNA processing beyond group II intron splicing. Loss of ISE2 from Arabidopsis thaliana leaves resulted in defects in C-to-U RNA editing, altered accumulation of chloroplast transcripts and chloroplast-encoded proteins, and defective processing of chloroplast ribosomal RNAs. Potential ISE2 substrates were identified by RNA immunoprecipitation followed by next-generation sequencing (RIP seq), and the diversity of RNA species identified supports ISE2's involvement in multiple aspects of chloroplast RNA metabolism. Comprehensive phylogenetic analyses revealed that ISE2 is a non-canonical Ski2-like RNA helicase that represents a separate sub-clade unique to green photosynthetic organisms, consistent with its function as an essential protein. Thus ISE2's evolutionary conservation may be explained by its numerous roles in regulating chloroplast gene expression. PMID- 28346705 TI - Performance of a polymer coated silicon microarray for simultaneous detection of food allergen-specific IgE and IgG4. AB - BACKGROUND: Microarray-based component-resolved diagnostics (CRD) has become an accepted tool to detect allergen-specific IgE sensitization towards hundreds of allergens in parallel from one drop of serum. Nevertheless, specificity and sensitivity as well as a simultaneous detection of allergen-specific IgG4 , as a potential parameter for tolerance development, remain to be optimized. OBJECTIVE: We applied the recently introduced silicon chip coated with a functional polymer named copoly(DMA-NAS-MAPS) to the simultaneous detection of food allergen specific IgE and IgG4 , and compared it with ImmunoCAP and ImmunoCAP ISAC. Inter- and intraslide variation, linearity of signal and working range, sensitivity and application of internal calibrations for IgE and IgG4 were assessed. METHODS: Native and recombinant allergenic proteins from hen's egg and cow's milk were spotted on silicon chips coated with copoly(DMA-NAS-MAPS) along with known concentrations for human IgE and IgG4 . A serum pool and 105 patient samples were assessed quantitatively and semi-quantitatively with the ImmunoCAP and ImmunoCAP ISAC and correlated with IgE- and IgG4 -specific fluorescence on silicon microarrays. RESULTS: Allergen-specific IgE and IgG4 were detected in parallel using two fluorescent dyes with no crosstalk. Results from the ImmunoCAP correlated better with microarray fluorescence than with ImmunoCAP ISAC except for the allergen ovomucoid. The working range of the silicon microarray for total hen's egg-specific IgE was comparable to the range of 0.1 to >100 kUA /L of the ImmunoCAP system, whereas for total cow's milk, the silicon microarray was less sensitive. Detectable allergen-specific IgG4 could be determined only for low concentrations, but still correlated positively with ImmunoCAP results. CONCLUSIONS: We confirmed the ability of the polymer coated silicon microarray to be comparably sensitive to the ImmunoCAP ISAC for various food allergens. This suggests that the copoly(DMA-NAS-MAPS) microarray is a low-cost, self-producible alternative to the commercial ImmunoCAP ISAC in allergy research. PMID- 28346706 TI - Tooth loss in generalized aggressive periodontitis: Prognostic factors after 17 years of supportive periodontal treatment. AB - AIM: This retrospective longitudinal study assessed the risk of and prognostic factors for tooth loss in patients with generalized aggressive periodontitis (GAgP) after periodontal treatment in a university setting. METHODS: Fifty-seven patients (1,505 teeth) were examined before (T0) and after active periodontal therapy (APT, T1) as well as after 17.4 +/- 4.8 [range: 9-28] years of supportive periodontal therapy (SPT, T2). Descriptive statistics and a Cox-proportional hazards shared-frailty model were applied. RESULTS: Overall, 98 and 134 teeth were lost during APT and SPT, respectively, with 0.14 +/- 0.18 teeth being lost per patient and year. During SPT, three patients (5%) lost >=10 teeth, 14 (25%) lost 4-9 teeth, 40 lost 0-3 (70%) teeth, respectively. One-third (n = 19) of all patients lost no teeth. Mean PPD of the teeth surviving SPT was stable from T1 (3.5 +/- 1.1 mm) to T2 (3.4 +/- 1.1 mm). Nearly, 84% of all survived teeth showed stable or improved bone level at T2. Risk of tooth loss was significantly increased in active smokers (HR[95% CI]: 4.94[1.91/12.75]), the upper dental arch (1.94[1,16/3.25]), with each mm of residual PPD (1.41[1.29/1.53]), teeth with furcation involvement (FI) (HR 4.00-4.44 for different degrees) and mobility (5.39 [2.06/14.1] for degree III). CONCLUSION: Within the provided conservative treatment regimen, GAgP patients lost only few teeth. PMID- 28346707 TI - Periurethral muscle-derived mononuclear cell injection improves urethral sphincter restoration in rats. AB - AIMS: Investigate the effect of a novel cell-based therapy with skeletal muscle derived mononuclear cells (SMDMCs) in a rat model of stress urinary incontinence. METHODS: Male Wistar-Kyoto rats' hind limb muscles were enzymatically dissociated, and SMDMCs were isolated without needing expansion. The cell population was characterized. Twenty female rats underwent urethrolysis. One week later, 10 rats received periurethral injection of 106 cells (SMDMC group), and 10 rats received saline injections (Saline group). Ten rats underwent sham surgery (Sham group). Four weeks after injection, animals were euthanized and the urethra was removed. The incorporation of SMDMCs in the female urethra was evaluated with fluorescence in situ hybridization for the detection of Y-chromosomes. Hematoxylin and eosin, Masson's trichrome staining, and immunohistochemistry for actin and myosin were performed. The muscle/connective tissue, actin and myosin ratios were calculated. Morphological evaluation of the urethral diameters and fractional areas of the lumen, mucosa, and muscular layer was performed. RESULTS: SMDMCs population was consistent with the presence of muscle cells, muscle satellite cells, perivascular cells, muscle progenitor cells, and endothelial cells. SMDMCs were incorporated into the urethra. A significant decrease in the muscle/connective tissue ratio was observed in the Saline group compared with the SMDMC and Sham groups. The proportions of actin and myosin were significantly decreased in the Saline group. No differences were observed in the morphometric parameters. CONCLUSIONS: SDMSC were incorporated into the rat urethra and promoted histological recovery of the damaged urethral sphincter, resulting in decreased connective tissue deposition and increased muscle content. PMID- 28346708 TI - High-resolution isotopic monitoring of cave air CO2. AB - RATIONALE: CO2 is the main driver of many chemical processes in cave environments. Understanding CO2 fluxes in a given cave system through monitoring campaigns has become a standard procedure in a wide variety of fields such as paleoclimatology or show cave management. However, conventional methods lack the resolution of isotopic data to capture many transient processes occurring in caves. METHODS: A novel approach using isotope ratio infrared spectrometry (IRIS) to monitor cave air pCO2 , delta13 C and delta18 O values in situ was tested and compared with conventional monitoring methods (handheld pCO2 meter and discrete cave air samples for conventional isotope ratio mass spectrometry). This also involved the development of a field-deployable experimental setup to operate the equipment in rough cave environments. RESULTS: Comparison between data obtained by means of a Thermo Fisher Scientific Delta Ray IRIS instrument shows overall good agreement with conventional monitoring methods in terms of pCO2 and delta13 C values. In addition, IRIS allows the delta18 O values of cave air CO2 to be measured. CONCLUSIONS: IRIS allows identification and tracking of processes at various timescales ranging from transient visitor impact on the cave atmosphere to seasonal trends in cave ventilation. However, the need for an uninterrupted power supply (110/220 V AC) and the relatively large dimensions of the equipment (698 * 1092 * 704 mm, 80 kg) limit the number of caves where deployment of the instrument is feasible. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28346709 TI - Synthetic beta-nitrostyrene derivative CYT-Rx20 as inhibitor of oral cancer cell proliferation and tumor growth through glutathione suppression and reactive oxygen species induction. AB - BACKGROUND: The beta-nitrostyrene family possesses anticancer properties. In this study, beta-nitrostyrene derivative CYT-Rx20 (3'-hydroxy-4'-methoxy-beta-methyl beta-nitrostyrene) was synthesized and investigated its anticancer activity in oral cancer. METHODS: Anticancer activity of CYT-Rx20 and the underlying mechanisms were analyzed using cell viability assay, reactive oxygen species (ROS) generation assay, fluorescence-activated cell sorter analysis, annexin V staining, comet assay, glutathione (GSH)/glutathione disulfide (GSSG) ratio, immunoblotting, soft agar assay, nude mice xenograft study, and immunohistochemistry. RESULTS: CYT-Rx20-induced cell apoptosis via ROS generation and mitochondrial membrane potential reduction, associated with release of mitochondrial cytochrome C to cytosol and activation of downstream caspases and poly ADP-ribose polymerase (PARP). Furthermore, CYT-Rx20 induced mitochondrial ROS accumulation and mitochondrial dysfunction, followed by GSH downregulation. CYT-Rx20-induced cell apoptosis, ROS generation, and DNA damage were reversed by thiol antioxidants. In nude mice, CYT-Rx20 inhibited oral tumor growth accompanied by increased expression of gammaH2AX, GSH reductase, and cleaved caspase-3. CONCLUSION: CYT-Rx20 has the potential to be further developed into an antioral cancer drug clinically. (c) 2017 Wiley Periodicals, Inc. Head Neck 39: 1055-1064, 2017. PMID- 28346711 TI - Comment on the IUGA/ICS joint report on the terminology for the conservative and nonpharmacological management of female pelvic floor dysfunction. PMID- 28346710 TI - The Arabidopsis thiamin-deficient mutant pale green1 lacks thiamin monophosphate phosphatase of the vitamin B1 biosynthesis pathway. AB - Thiamin diphosphate (TPP, vitamin B1 ) is an essential coenzyme present in all organisms. Animals obtain TPP from their diets, but plants synthesize TPPde novo. We isolated and characterized an Arabidopsis pale green1 (pale1) mutant that contained higher concentrations of thiamin monophosphate (TMP) and less thiamin and TPP than the wild type. Supplementation with thiamin, but not the thiazole and pyrimidine precursors, rescued the mutant phenotype, indicating that the pale1 mutant is a thiamin-deficient mutant. Map-based cloning and whole-genome sequencing revealed that the pale1 mutant has a mutation in At5g32470 encoding a TMP phosphatase of the TPP biosynthesis pathway. We further confirmed that the mutation of At5g32470 is responsible for the mutant phenotypes by complementing the pale1 mutant with constructs overexpressing full-length At5g32470. Most plant TPP biosynthetic enzymes are located in the chloroplasts and cytosol, but At5g32470-GFP localized to the mitochondrion of the root, hypocotyl, mesophyll and guard cells of the 35S:At5g32470-GFP complemented plants. The subcellular localization of a functional TMP phosphatase suggests that the complete vitamin B1 biosynthesis pathway may involve the chloroplasts, mitochondria and cytosol in plants. Analysis of PALE1 promoter-uidA activity revealed that PALE1 is mainly expressed in vascular tissues of Arabidopsis seedlings. Quantitative RT-PCR analysis of TPP biosynthesis genes and genes encoding the TPP-dependent enzymes pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and transketolase revealed that the transcript levels of these genes were upregulated in the pale1 mutant. These results suggest that endogenous levels of TPP may affect the expression of genes involved in TPP biosynthesis and TPP-dependent enzymes. PMID- 28346712 TI - Comparison of three methods to analyze detrusor contraction during micturition in men over 50 years of age. AB - AIMS: To grade detrusor voiding contraction three parameters are used: the Schafer pressure-flow nomogram (LinPURR), the bladder contractility index (BCI) and the maximum Watt factor (Wmax ). Because these methods to quantify detrusor contraction and/or to diagnose detrusor underactivity (DU) have not yet been mutually compared, this study compares these three methods of grading detrusor contraction. MATERIALS AND METHODS: Evaluated were 1420 urodynamic pressure-flow studies from 1222 men (aged >50 years) with lower urinary tract symptoms (LUTS). Excluded were patients with abnormal urinalysis, neurological disorders, surgical correction of congenital anomalies, pelvic surgery, post radical prostatectomy, or with evidence of urethral stricture. Contractility was graded with the LinPURR, the BCI, and Wmax, making a distinction between "strong," "normal," "weak," and "very weak" contractility. We calculated agreement between LinPURR and both BCI and Wmax . RESULTS: The contractility groups LinPURR and BCI, as well as LinPURR and Wmax , showed a high agreement of 97.5% and 80.9%, respectively. CONCLUSION: This study demonstrates a significant correlation in grading detrusor contractility when comparing LinPURR with the BCI (97.5% agreement) and the Wmax (80.9% agreement). The LinPURR is plausible, and applicable in clinical practice and BCI is (intrinsically) well associating with the LinPURR classes, on a more continuous scale. Both are relevant to define clinically relevant patients groups. PMID- 28346713 TI - Re: Sheng W, Zhang H, Kirschner-Hermanns R. Could urinary nerve growth factor be a biomarker for overactive bladder? A meta-analysis. Neurourol Urodyn. 2017;9999:1-8. doi: 10.1002/nau.23210. AB - Sheng et al (Neurourology and Urodynamics 2017; DOI: 10.1002/nau.23210) presented a meta-analysis based on 17 publications to show that urinary nerve growth factor (NGF) may be a useful biomarker for overactive bladder syndrome (OAB). Unfortunately, 13 of the 17 studies used an unspecifc enzyme-linked immunosorbent assay (ELISA), the Promega NGF Emax Immunoassay, to quantify NGF in urine. This assay did not detect NGF in urine, but other urinary components, such as immunoglobulin G, and in 2014, it was withdrawn from the market. With other NGF ELISAs, urinary NGF concentrations were found to be below detection level for both, OAB and healthy controls. Currently, ELISA techniques are not sensitive enough to detect NGF in urine, and urinary NGF cannot be used as a biomarker for OAB. PMID- 28346715 TI - Cabergoline-related impulse control disorder in an adolescent with a giant prolactinoma. PMID- 28346714 TI - Discrepant serological assays for Pneumococcus in renal transplant recipients - a prospective study. AB - Vaccine immunoprotection for Streptococcus pneumoniae is mediated by opsonizing antibodies targeting serotype-specific capsular polysaccharides. Quantitative antibody levels enzyme-linked immunosorbent assay (ELISA) and antibody-mediated opsonophagocytic assays (OPA) measure vaccine-induced protection; correlation of these assays in transplantation requires investigation. This study examines the laboratory assessment of antibody titers in vaccinated renal recipients. Streptococcus pneumoniae 19A is common in immunocompromised hosts and is represented in protein-conjugate vaccines (PCV) and polysaccharide vaccines (PSV). Antibodies to 19A in serial sera from 30 vaccinated renal transplant recipients were compared using ELISA and OPA assays. Subject titers were classified as protected or not by ELISA (>0.35 MUg/ml) and OPA titer (>1:8). Antibody titers analyzed using McNemar's test indicate that protection measured by the two assays are not the same (P = 0.0078); simple linear regression of within-subject geometric means of 19A enzyme-linked immunosorbent assay (ELISA) antibody levels versus 19A opsonophagocytic assays (OPA) titers demonstrates significant correlation between the two assays (P < 0.001). Vaccination is increasingly important given increasing antimicrobial resistance worldwide. OPA and ELISA antibody assays do not correlate well using current values for protective immunity against the Pneumococcus in immunosuppressed transplant recipients. Future studies of vaccination in transplant recipients should evaluate protective antibody levels using both functional antibody assays and standard ELISA antibody titers. (ClinicalTrials.gov: NCT00307125). PMID- 28346716 TI - Vinylpyridines as Building Blocks for the Photocatalyzed Synthesis of Alkylpyridines. AB - The photocatalyzed addition of several hydrogen donors (ethers, aldehydes, alkanes, amides) onto vinylpyridines was achieved. This approach provided access to alkylpyridines, which are important building blocks for the preparation of compounds with biological activity. The strategy was very simple and straightforward because it required only a small amount of a cheap decatungstate salt as photocatalyst. As an added advantage, the reaction could be performed under sunlight irradiation as well as under flow conditions. PMID- 28346717 TI - Characterization of two novel antimicrobial peptides from the cuticular extracts of the ant Trichomyrmex criniceps (Mayr), (Hymenoptera: Formicidae). AB - Antimicrobial peptides (AMPs) from cuticular extracts of worker ants of Trichomyrmex criniceps (Mayr, Hymenoptera: Formicidae) were isolated and evaluated for their antimicrobial activity. Eight peptides ranging in mass from 804.42 to 1541.04 Da were characterized using a combination of analytical and bioinformatics approach. All the eight peptides were novel with no similarity to any of the AMPs archived in the Antimicrobial Peptide Database. Two of the eight novel peptides, the smallest and the largest by mass were named Crinicepsin-1 and Crinicepsin-2 and were chemically synthesized by solid phase peptide synthesis. The two synthetic peptides had antibacterial and weak hemolytic activity. PMID- 28346718 TI - Modulation of the rat micturition reflex with transcutaneous ultrasound. AB - INTRODUCTION: Low intensity focused ultrasound has recently been identified as a novel method of stimulating targeted neurons. We hypothesized that ultrasound stimulation of the posterior tibial nerve would inhibit bladder contractions in an established rat model of rhythmic bladder contractions. METHODS: Cyclical detrusor contractions were initiated by placing a transurethral catheter in female rats and infusing saline into the bladder. Transcutaneous ultrasound pulses were then delivered to the lower extremity of a rat (overlying the posterior tibial nerve) using a single element spherically focused 250 kHz transducer. Sixty-three cycles were repeated at 2 kHz for 300 ms at peak negative pressure of 900 kPa pulsed at 0.5 Hz. RESULTS: We report successful suppression of bladder contractions using ultrasound stimulation in 10 animals. The average latency between the initiation of ultrasound and suppression of bladder contractions was 3 min 23 s (+/-51 s), the average time of contraction suppression was 13 min and 50 s (+/-2 min 25 s) and the average time from the end of ultrasound to return of contractions was 9 min 37 s (+/-2 min and 30 s). CONCLUSION: In this work, we demonstrate the ability of targeted transcutaneous ultrasound to inhibit rhythmic bladder contractions in anesthetized rats. Due to its non-invasive nature and ease of application, we believe ultrasound mediated suppression of the micturition reflex is potentially an ideal outpatient treatment of overactive bladder and dysfunctional elimination. PMID- 28346719 TI - Reduced Th22 cell proportion and prevention of atopic dermatitis in infants following maternal probiotic supplementation. AB - BACKGROUND: In the randomized, controlled study Probiotics in the Prevention of Allergy among Children in Trondheim (ProPACT), maternal probiotic supplementation reduced the incidence of atopic dermatitis (AD) in the offspring. In the current study, we hypothesized that the effect was mediated by a shift in the T helper (Th) cells in the children. OBJECTIVE: To examine whether Th cell proportions were affected by maternal probiotic supplementation and thus could mediate the preventive effect of probiotics on AD. METHODS: A total of 415 pregnant women were randomized to ingest a combination of Lactobacillus rhamnosus GG (LGG), Bifidobacterium animalis subsp. lactis Bb-12 (Bb-12) and Lactobacillus acidophilus La-5 (La-5) or placebo, and their offspring were assessed for AD during the first 2 years of life. Peripheral blood collected at 3 months of age was analysed for regulatory T cells (n=140) and Th subsets (n=77) including Th1, Th2, Th9, Th17 and Th22. RESULTS: The proportion of Th22 cells was reduced in children in the probiotic group compared to the placebo group (median 0.038% vs 0.064%, P=.009). The difference between the probiotic and placebo groups was also observed in the children who did not develop AD during the 2-year follow-up. The proportion of Th22 cells was increased in children who developed AD compared to the children who did not develop AD (0.090% vs 0.044%, P<.001). Mediation analysis indicated that the preventive effect of probiotics was partially mediated through the reduction in Th22 cells. CONCLUSION: Perinatal maternal probiotic supplementation with a combination of LGG, Bb-12 and La-5 reduced the proportion of Th22 cells in 3-month-old children. This may partially explain the preventive effect of probiotics on AD. PMID- 28346720 TI - Videourodynamic analysis of the urethral sphincter overactivity and the poor relaxing pelvic floor muscles in women with voiding dysfunction. AB - AIMS: Voiding dysfunction due to dysfunctional voiding (DV) and poor relaxation of the external sphincter (PRES) are commonly found among adult women with lower urinary tract symptoms (LUTS) during videourodynamic study (VUDS). This study analyzed the VUDS characteristics of DV and PRES in female voiding dysfunction. METHODS: This retrospective study involved 1914 women aged >18 years with refractory LUTS. The medical records and the VUDS parameters were reviewed. Patients diagnosed with DV and PRES participated in the study. The VUDS characteristics and urethral sphincter activities were compared with those of urodynamically normal women. RESULTS: Of the 1914 women, 325 (17.0%) and 336 (17.6%) were diagnosed with DV and PRES, respectively. Detrusor overactivity (DO) occurred in 60% of the women with DV and in 5.7% of the women with PRES. Patients with DV had significantly increased bladder sensation, lower cystometric bladder capacity (CBC), lower bladder compliance, higher voiding detrusor pressure, smaller voided volume (VV), larger post-void residual volume (PVR), lower voiding efficiency (VE), and higher bladder outlet obstruction index (BOOI) than the women with PRES and the control individuals. Patients with PRES had significantly increased bladder sensation, lower CBC, lower maximum flow rate, smaller VV, larger PVR, and lower VE than the control individuals. CONCLUSIONS: DV and PRES were highly prevalent among the adult women with voiding dysfunction. Patients with DV had VUDS characteristics of BOO and urodynamic DO. The clinical symptoms of PRES were similar to those of DV, but the patients had low detrusor contractility and low DO rates. PMID- 28346721 TI - Dynamic lumbopelvic stabilization for treatment of stress urinary incontinence in women: Controlled and randomized clinical trial. AB - OBJECTIVES: To compare the results of the dynamic lumbopelvic stabilization (DLS) exercises with exercises for the pelvic floor muscles (PFM) in women with stress urinary incontinence. METHODS: Randomized controlled clinical trial comparing 17 women submitted to the DLS with 16 women submitted to the exercises for the PFM. The evaluated outcomes were incontinence severity, quality of life (QoL), and impression of improvement in three moments. Significance was set at 5%. RESULTS: For socio-demographic and clinical variables, only climacteric was more prevalent in the DLS group (82% vs. 44%, P = 0.02). Soon after the intervention, there was no difference between the groups in relation to the outcomes evaluated. In the evaluation after 90 days, the DLS group presented better values for the severity of the losses (4.1 +/- 2.6 vs. 5.7 +/- 2.4, P = 0.006, d = 0.64), daytime frequency (4.6 +/- 0.4 vs. 6.2 +/- 0.6, P < 0.001, d = 2.67), and nighttime frequency (0.4 +/- 0.3 vs. 1.4 +/- 0.5, P < 0.001, d = 2.50), QoL and impression of improvement (P < 0.001). CONCLUSIONS: After treatment, the DLS plus PFM exercise patients had results similar to those performing PFM exercises alone. However, the DLS plus PFM exercises were superior in the outcomes of incontinence severity, QoL, and impression of improvement in the post-90-day evaluation, showing longer lasting effect. PMID- 28346722 TI - A Simple Tetraminocalix[4]arene as a Highly Efficient Catalyst under "On-Water" Conditions through Hydrophobic Amplification of Weak Hydrogen Bonds. AB - The simple tetraminocalix[4]arene 1, which contains weak H-bond-donor NH2 groups, is reported to be a highly efficient organocatalyst for the Vinylogous Mukaiyama Aldol Reaction (VMAR) of 2-(trimethylsilyloxy)furan 5 with alpha-ketoesters 6 a-l under "on-water" conditions owing to the hydrophobic amplification of weak H-bond interactions. The catalytic efficiency of calixarene catalyst 1 was shown to be closely related to its recognition abilities towards the reactants 5 and 6 through a multipoint recognition model. The proposed model provided good explanations for the differences on the reaction rate acceleration and on the stereoselectivity observed with different substrates. PMID- 28346723 TI - A systematic review of genetic syndromes with obesity. AB - Syndromic monogenic obesity typically follows Mendelian patterns of inheritance and involves the co-presentation of other characteristics, such as mental retardation, dysmorphic features and organ-specific abnormalities. Previous reviews on obesity have reported 20 to 30 syndromes but no systematic review has yet been conducted on syndromic obesity. We searched seven databases using terms such as 'obesity', 'syndrome' and 'gene' to conduct a systematic review of literature on syndromic obesity. Our literature search identified 13,719 references. After abstract and full-text review, 119 relevant papers were eligible, and 42 papers were identified through additional searches. Our analysis of these 161 papers found that 79 obesity syndromes have been reported in literature. Of the 79 syndromes, 19 have been fully genetically elucidated, 11 have been partially elucidated, 27 have been mapped to a chromosomal region and for the remaining 22, neither the gene(s) nor the chromosomal location(s) have yet been identified. Interestingly, 54.4% of the syndromes have not been assigned a name, whereas 13.9% have more than one name. We report on organizational inconsistencies (e.g. naming discrepancies and syndrome classification) and provide suggestions for improvements. Overall, this review illustrates the need for increased clinical and genetic research on syndromes with obesity. PMID- 28346724 TI - Acclimation of bloom-forming and perennial seaweeds to elevated pCO2 conserved across levels of environmental complexity. AB - Macroalgae contribute approximately 15% of the primary productivity in coastal marine ecosystems, fix up to 27.4 Tg of carbon per year, and provide important structural components for life in coastal waters. Despite this ecological and commercial importance, direct measurements and comparisons of the short-term responses to elevated pCO2 in seaweeds with different life-history strategies are scarce. Here, we cultured several seaweed species (bloom forming/nonbloom forming/perennial/annual) in the laboratory, in tanks in an indoor mesocosm facility, and in coastal mesocosms under pCO2 levels ranging from 400 to 2,000 MUatm. We find that, across all scales of the experimental setup, ephemeral species of the genus Ulva increase their photosynthesis and growth rates in response to elevated pCO2 the most, whereas longer-lived perennial species show a smaller increase or a decrease. These differences in short-term growth and photosynthesis rates are likely to give bloom-forming green seaweeds a competitive advantage in mixed communities, and our results thus suggest that coastal seaweed assemblages in eutrophic waters may undergo an initial shift toward communities dominated by bloom-forming, short-lived seaweeds. PMID- 28346726 TI - Predictive value of p63, ki-67, and survivin expression in oral leukoplakia: A tissue microarray study. AB - The aim of this study was to analyze the immunohistochemical expression of survivin, ki-67, and p63 in oral leukoplakic lesions, histopathologically differentiated into dysplastic and nondysplastic. A tissue microarray containing 57 samples of biopsies from clinically classified lesions, such as leukoplakia, was immunolabeled for survivin, ki-67, and p63. Samples were scored for percentage of positively stained. Scores were designated as follows: low = less than 25% of positive cells; and high = more than 25% of positive cells. On performing histopathological diagnosis, 20 dysplastic lesions and 37 nondysplastic lesions were seen, in which female patients (56.1%) were predominant with an average age of 58.27 years. The study showed a high expression of 37.5% for survivin, 43.7% for ki-67, and 88.2% for p63 in dysplastic lesions. However, there was a high expression of 16.7% for survivin, 16.7% for ki-67, and 92% for p63 in nondysplastic lesions. There is a positive correlation of expression among the three antibodies. In the association of immunoreactivity, in both dysplastic and nondysplastic lesions, increased expression of survivin reflects on the increased expression of ki-67, and there is an overexpression of p63. In leukoplakia, the expression of survivin associated with that of ki-67 reinforces the assumption that all these lesions are potentially malignant, regardless of histopathology; and the overexpression of p63 may indicate carcinogenic potential. These findings may help in the treatment of patients with this type of lesion. PMID- 28346727 TI - Sulforaphene enhances radiosensitivity of hepatocellular carcinoma through suppression of the NF-kappaB pathway. AB - Sulforaphene (SFE), a naturally occurring isothiocyanate found in cruciferous vegetables, has attracted increasing attention for its anti-cancer effect in many cancers, including hepatocellular carcinoma (HCC). However, the precise role of SFE in the radiosensitivity of HCC is still unclear. Here, cell proliferation and apoptosis were detected by MTT and flow cytometry assay, respectively. The activity of NF-kappaB was further evaluated by ELISA. We also observed the effect of SFE and/or radiation on tumor growth. The results showed that SFE inhibited cell proliferation and induced apoptosis in HCC cells. Radiation increased NF-kB activity, while PDTC, a NF-kB inhibitor, enhanced radiation-induced cell death. SFE inhibited NF-kB activity and the downstream gene expressions of the NF-kB pathway in HCC cells. Moreover, SFE enhanced the inhibitory effect of radiation on tumor growth both in vitro and in vivo. This study indicated that SFE sensitized the radiosensitivity of HCC by blocking the NF-kB pathway. PMID- 28346728 TI - NUBPL, a novel metastasis-related gene, promotes colorectal carcinoma cell motility by inducing epithelial-mesenchymal transition. AB - Nucleotide binding protein-like, NUBPL, is an assembly factor for human mitochondrial complex I, which is the biggest member of the mitochondrial respiratory chain. However, the relationship between NUBPL and carcinoma progression remains unknown. In this study, NUBPL was characterized for its role in colorectal cancer (CRC) and the underlying molecular mechanisms. Data (n = 197) from the Oncomine database revealed that mRNA levels of NUBPL were remarkably overexpressed in CRC tissues compared with normal tissues. In addition, immunohistochemical analysis of 75 pairs of CRC and non-tumor tissues showed that the expression level of NUBPL was significantly higher in CRC tissues, and its expression level was positively associated with lymph node metastasis (P = 0.028) and advanced staging (P = 0.030). Expression of NUBPL in metastatic lymph nodes of CRC patients was also detected by immunohistochemical staining and high expression levels of NUBPL were observed. Overexpression of NUBPL significantly promoted the migration and invasion ability of CRC cell lines SW480 and SW620, whereas knockdown of NUBPL lead to an opposite effect. Our further study found that NUBPL could induce epithelial-mesenchymal transition (EMT), characterized by downregulation of epithelial markers (E-cadherin) and upregulation of mesenchymal markers (N-cadherin and vimentin). Moreover, NUBPL was able to activate ERK, which is believed to promote EMT and tumor metastasis. Inhibition of ERK suppressed the NUBPL-induced changes in EMT and cell motility. These data showed that NUBPL plays a vital role in CRC migration and invasion by inducing EMT and activating ERK. It might be a novel therapeutic target for CRC. PMID- 28346729 TI - Comparison of the safety of electrotome, Harmonic scalpel, and LigaSure for management of thyroid surgery. AB - BACKGROUND: Energy-based surgical devices, including electrotome, the Harmonic scalpel, and LigaSure, have been widely applied in thyroid surgery, although a comparison of their safety and efficacy has not been reported yet. In this study, we investigated the feasibility of using hemostatic energy-based surgical devices during thyroid surgery in a canine model. METHODS: Twenty-four beagle dogs were randomly divided into the following groups: electrotome (30 kW), electrotome (15 kW), the Harmonic scalpel (output level 3), and LigaSure (middle gear). The hemostatic devices were applied on the thyroid surface for 3 seconds and then near the recurrent laryngeal nerve (RLN; distance of 5 mm, 3 mm, or 1 mm) for 3 seconds. Evoked electromyography (EMG) amplitudes were recorded by intraoperative neuromonitoring (IONM). Acute microstructural morphological damage to thyroid tissues and the RLN were evaluated immediately after the procedure by light and electron microscopy. RESULTS: Electrotome caused a significant decrease in evoked EMG amplitudes when applied at a vertical distance of 1 mm from the RLN, both at 30 kW (1046 +/- 404.3 MUV vs 153 +/- 245.5 MUV; p < .001) and 15 kW (1197 +/- 589.2 MUV vs 986.3 +/- 797.3 MUV; p = .037), compared with those evoked under normal conditions. Furthermore, distinct acute microstructural morphological changes of the RLNs were observed by light and electron microscopy. However, no significant functional or histological changes were induced by the electrotome at a vertical distance of 5 mm or 3 mm from the RLN. The Harmonic scalpel and LigaSure induced neither marked changes in evoked EMG amplitudes when applied at vertical distances of 5 mm, 3 mm, or 1 mm (all p > .05) nor microstructural morphological changes in the RLNs. The electrotome (15 kW) caused more serious thermal damage to thyroid tissues than that caused by either the Harmonic scalpel or LigaSure (thermal damaged depth: 0.951 +/- 0.061 vs 0.756 +/- 0.074, p < .001; 0.951 +/- 0.061 vs 0.724 +/- 0.116, p < .001). Nevertheless, there were no differences between the Harmonic scalpel and LigaSure groups (p = .435). CONCLUSION: LigaSure and the Harmonic scalpel might be safer than electrotome when used in thyroid operations. LigaSure generates less heat than the Harmonic scalpel and electrotome. (c) 2017 Wiley Periodicals, Inc. Head Neck 39: 1078 1085, 2017. PMID- 28346730 TI - Cheese supplemented with probiotics reduced the Candida levels in denture wearers RCT. AB - OBJECTIVES: The access to probiotics should be facilitated in order to encourage their usage. We evaluated the effect of consumption of two experimental probiotic containing cheeses on the oral colonization of Candida in denture wearers. METHODS: Sixty denture wearers harboring oral Candida were randomly allocated in groups who received cheese supplemented with Lactobacillus acidophilus NCFM (T1) or Lactobacillus rhamnosus Lr-32 (T2), daily for 8 weeks, and a control group (C) who received a control cheese. Oral samples were obtained through a mouthwash, and Candida levels were determined (CFU/mL) at baseline and after the 8-week experimental period. RESULTS: At baseline, the mean levels of Candida spp. (log CFU/mL) were similar among the groups. However, the mean levels of Candida were significantly reduced in groups T1 and T2 but not in C (Tukey, p<.05). The reduction in Candida oral levels occurred independently on the colonizing Candida species, participant age, and use of bi- or unimaxillary dentures. CONCLUSIONS: Daily consumption of cheese supplemented with probiotics, with either L. acidophilus NCFM or L. rhamnosus Lr-32, was able to reduce the colonization of oral Candida in complete denture wearers, suggesting its potential in reducing the risk of oral candidiasis in this highly susceptible population. PMID- 28346731 TI - Exploring the influence of MPA-capped CdTe quantum dots on the structure and function of lysozyme probing by spectroscopic and calorimetric methods. AB - The effect of 3-mercaptopropionic acid (MPA)-capped CdTe quantum dots (QDs) on lysozyme was systematically investigated by spectroscopic methods, enzyme activity assay, and calorimetry techniques. Results show that the MPA-capped CdTe QDs binded to lysozyme through van der Walls forces and hydrogen bondings, causing the decrement of alpha-helical content (~7%) and increment of beta-sheet content (~11%) of lysozyme. The binding caused static quenching of the fluorescence, while the microenvironment of aromatic amino acid residues did not show any significant alteration. The lysozyme activity was affected by the increasing exposure of QDs, it was inhibited to 53.77% under a 6 * 10-7 M exposure compared with the control group. This work will provide direct evidence about enzyme toxicity of QDs to lysozyme in vitro. PMID- 28346732 TI - Asiaticoside hinders the invasive growth of keloid fibroblasts through inhibition of the GDF-9/MAPK/Smad pathway. AB - Higher expression of growth differentiation factor-9 (GDF-9) in keloids compared with hypertrophic scars and normal skin tissues has been reported recently. The present study was performed to investigate the role of GDF-9 in keloid pathogenesis, and to elucidate its implication for asiaticoside in the keloid management. The data showed that GDF-9 could enhance the proliferation, migration, and invasion of keloid fibroblasts (KFs), while it only slightly elevated collagen expression, indicating that the effect of GDF-9 was opposite to that of TGF-beta1. The bioactivity difference between GDF-9 and TGF-beta1 could be explained by the different phosphorylated sites on the downstream Smad2/3. Moreover, asiaticoside could inhibit GDF-9-induced activation of MAPKs and Smad pathway in KFs. In conclusion, GDF-9 enhanced the invasive growth of KFs, which was achieved by phosphorylation of Smad 2/3 at the linker region through activation of MAPKs pathway. Asiaticoside hindered the invasive growth of KFs by inhibiting the GDF-9/MAPK/Smad pathway. PMID- 28346733 TI - The ontogeny and population variability of human hepatic dihydronicotinamide riboside:quinone oxidoreductase (NQO2). AB - Dihydronicotinamide riboside:quinone oxidoreductase (NQO2) is an enzyme that performs reduction reactions involved in antioxidant defense. We hypothesized that NQO2 hepatic drug clearance would develop in children over time, similar to NQO1. Using human liver cytosol (n = 117), the effects of age, sex, ethnicity, and weight on NQO2 expression and activity were probed. No significant correlations were observed. Biochemical activity of NQO2 was as high at birth as in adults (0.23 +/- 0.04 nmol/min/mg protein, mean +/- SEM, range 0-1.83). In contrast, modeled hepatic clearance through the NQO2 pathway was up to 10% of adult levels at birth, reaching predicted adult levels (0.3 +/- 0.03 L/h) at 14 years of age. Comparisons between NQO1 and NQO2 in the same livers showed that neither protein (P = 0.32) nor activity (P = 0.23) correlated, confirming both orthologs are independently regulated. Because hepatic clearance through NQO2 does not mature until teenage years, compounds detoxified by this enzyme may be more deleterious in children. PMID- 28346734 TI - When meta-analysis fails: A case about stomata. PMID- 28346735 TI - Carbenes as Electron-Pair Donors for P???C Pnicogen Bonds. AB - Ab initio MP2/aug'-cc-pVTZ calculations were performed on the P???C pnicogen bonded complexes of the singlet carbene molecules C(NH2 )2 , C(OH)2 , and cyclic C(OCH)2 [OHC] with H2 XP molecules, with X=F, Cl, NC, OH, CH3 , CN, CCH, and H. The H2 XP:C(NH2 )2 and H2 XP:C(OH)2 complexes have Cs symmetry and two different structures: one in which the symmetry plane of the complex and the local symmetry plane of the carbene are non-coplanar, and the other in which they are coplanar. The non-coplanar H2 XP:C(NH2 )2 and H2 XP:C(OH)2 complexes arise only when X is one of the more electronegative substituents. Coplanar H2 XP:C(NH2 )2 complexes form when X is one of the more electropositive substituents, whereas coplanar H2 XP:C(OH)2 complexes exist for all X. H2 XP:C(NH2 )2 and H2 XP:C(OH)2 are stabilized by covalent P-C bonds or P???C pnicogen bonds, but co-planar H2 (CH3 )P:C(OH)2 and H3 P:C(OH)2 are stabilized by O-H???P hydrogen bonds. The H2 XP:OHC complexes have non-coplanar structures that are also stabilized by P-C covalent bonds or pnicogen bonds. The H2 (CH3 )P:OHC and H3 P:OHC complexes in which the symmetry plane of the complex and the local symmetry plane of the carbene are perpendicular are stabilized by P???pi bonds with P acting as the electron-pair donor to the OHC pi system. The H2 XP:C(NH2 )2 , H2 XP:C(OH)2 , and H2 XP:OHC complexes are described in terms of their binding energies, charge-transfer energies, electron density properties, and equation-of-motion coupled cluster singles and doubles spin-spin coupling constants. PMID- 28346736 TI - Loss of predator species, not intermediate consumers, triggers rapid and dramatic extinction cascades. AB - Ecological networks are tightly interconnected, such that loss of a single species can trigger additional species extinctions. Theory predicts that such secondary extinctions are driven primarily by loss of species from intermediate or basal trophic levels. In contrast, most cases of secondary extinctions from natural systems have been attributed to loss of entire top trophic levels. Here, we show that loss of single predator species in isolation can, irrespective of their identity or the presence of other predators, trigger rapid secondary extinction cascades in natural communities far exceeding those generally predicted by theory. In contrast, we did not find any secondary extinctions caused by intermediate consumer loss. A food web model of our experimental system a marine rocky shore community-could reproduce these results only when biologically likely and plausible nontrophic interactions, based on competition for space and predator-avoidance behaviour, were included. These findings call for a reassessment of the scale and nature of extinction cascades, particularly the inclusion of nontrophic interactions, in forecasts of the future of biodiversity. PMID- 28346738 TI - Overlooked small apes need more attention! PMID- 28346739 TI - A Novel Approach to Limit Chemical Deterioration of Gilthead Sea Bream (Sparus aurata) Fillets: Coating with Electrospun Nanofibers as Characterized by Molecular, Thermal, and Microstructural Properties. AB - Coating of sea bream fillets with thymol loaded chitosan based electrospun nanofibers (TLCN) and chitosan based nanafibers (CN) has been presented a novel approach to delay chemical deterioration. We assessed CN and TLCN with respect of scanting of total volatile basic nitrogen (TVBN), trimethylamine (TMA), thiobarbituric acid (TBA) deterioration during cold storage condition. Electrospinning process was applied to obtain TLCN and CN. Both of nanofibers obtained from biopolymer and bioactive material were cylindrical, smooth, beadless. Thermal, molecular, zeta potential (ZP), and surface properties of the groups were investigated, revealing that CN indicated molecular interactions with thymol in nanofibers, reduce in physical properties of these structures, thermal decomposition (an alteration in mass of CN and TLCN at temperatures below 190 degrees C, corresponding to 20.53% and 19.97%, respectively) and also dispersion stabilities (zeta potential) of CN and TLCN were determined 33.68 +/- 3.35 and 21.85 +/- 1.96 mV, respectively. TVBN and TMA stability analyses demonstrated that CN and TLCN were both effective in delaying chemical deterioration of fish fillets, furthermore TLCN was more effective against chemical deterioration. TBA analyses results of fish fillets indicated that CN and TLCN delayed rancidity in fish meat as compared to control group samples. The presented study results suggested that coating of the sea bream fillets with CN and TLCN would be a promising approach to delay the chemical deterioration of fish fillets. PMID- 28346737 TI - EASL and AASLD recommendations for the diagnosis of HCC to the test of daily practice. AB - AIMS: To evaluate the diagnostic performance of CT, MRI and CEUS alone and in combination, for the diagnosis of HCC between 10 and 30 mm, in a large population of cirrhotic patients. PATIENTS AND METHODS: In a multicentre prospective trial, 442 patients have been enrolled. Within a month, CEUS, CT and MRI were performed for all patients. A composite algorithm was defined to obtain the more accurate gold standard. RESULTS: A total of 544 nodules in 381 patients have been retained for the performance analysis. Eighty-two percent of the patients were male, mean age was 62 years. For the 10-20 mm nodules (n=342), the sensitivity (Se) and specificity (Sp) for the diagnosis of HCC were, respectively, 70.6% and 83.2% for MRI, 67.9% and 76.8% for CT and 39.6% and 92.9% for CEUS. For the 20-30 mm nodules (n=202), the Se and Sp were, respectively, 72.3% and 89.4% for MRI, 71.6% and 93.6% for CT and 52.9% and 91.5% for CEUS. THE BEST COMBINATION FOR THE 10-20 MM NODULES WAS MRI + CT (SE: 55.1%, SP: 100.0%).: After a first inconclusive technique, CEUS as second image technique allowed the highest specificity with only a slight drop of sensitivity for 10-20 mm nodules and the highest sensitivity and specificity for 20-30 mm nodules. CONCLUSION: This large multicentre study validates the EASL/AASLD recommendations in daily practice. Specificity using CT or MRI in 10-20 mm HCC was low, but we do not recommend combined imaging at first as sensitivity would be very low. The best sequential approach combined MRI and CEUS. PMID- 28346740 TI - Are Various sigma-Hole Bonds Steered by the Same Mechanisms? AB - Representative Lewis acid-Lewis base complexes linked by tetrel, pnicogen, chalcogen, and halogen bonds have been studied within the quantum theory of atoms in molecules (QTAIM) approach and the hybrid variation-perturbation theory (HVPT) to analyze possible relationships between these sigma-hole dimers. Results obtained at the MP2/aug-cc-pVTZ level indicate numerous correlations similar to hydrogen-bonded systems. PMID- 28346741 TI - Small Molecules Targeting Human N-Acetylmannosamine Kinase. AB - N-Acetylmannosamine kinase (MNK) plays a key role in the biosynthesis of sialic acids and glycosylation of proteins. Sialylated glycoconjugates affect a large number of biological processes, including immune modulation and cancer transformation. In search of effective inhibitors of MNK we applied high throughput screening of drug-like small molecules. By applying different orthogonal assays for their validation we identified four potential MNK-specific inhibitors with IC50 values in the low-micromolar range. Molecular modelling of the inhibitors into the active site of MNK supports their binding to the sugar or the ATP-binding pocket of the enzyme or both. These compounds are promising for downregulation of the sialic acid content of glycoconjugates and for studying the functional contribution of sialic acids to disease development. PMID- 28346742 TI - Economic and hydraulic divergences underpin ecological differentiation in the Bromeliaceae. AB - Leaf economic and hydraulic theories have rarely been applied to the ecological differentiation of speciose herbaceous plant radiations. The role of character trait divergences and network reorganization in the differentiation of the functional types in the megadiverse Neotropical Bromeliaceae was explored by quantifying a range of leaf economic and hydraulic traits in 50 diverse species. Functional types, which are defined by combinations of C3 or Crassulacean acid metabolism (CAM) photosynthesis, terrestrial or epiphytic habits, and non specialized, tank-forming or atmospheric morphologies, segregated clearly in trait space. Most classical leaf economic relationships were supported, but they were weakened by the presence of succulence. Functional types differed in trait network architecture, suggesting that rewiring of trait-networks caused by innovations in habit and photosynthetic pathway is an important aspect of ecological differentiation. The hydraulic data supported the coupling of leaf hydraulics and gas exchange, but not the hydraulic safety versus efficiency hypothesis, and hinted at an important role for the extra-xylary compartment in the control of bromeliad leaf hydraulics. Overall, our findings highlight the fundamental importance of structure-function relationships in the generation and maintenance of ecological diversity. PMID- 28346743 TI - Fabrication of a mechanically anisotropic poly(glycerol sebacate) membrane for tissue engineering. AB - Poly(glycerol sebacate) (PGS) has been used successfully as a scaffolding material for soft tissue engineering. PGS scaffolds, however, are usually mechanically isotropic, which may restrict their use in tissue repairs as many soft tissues in the body have anisotropic mechanical behaviors. Although various methods have been used to fabricate anisotropic scaffolds, it remains challenging to make anisotropic scaffolds from thermoset PGS. Here a new, simple method to fabricate an anisotropic PGS membrane which can then be used to construct thicker three-dimensional anisotropic scaffolds was developed. First, an aligned sacrificial poly(vinyl alcohol) fibrous membrane was prepared by electrospinning. The fibrous membrane was then partially immersed in PGS prepolymer solution, resulting in a composite membrane upon drying. After curing, the sacrificial fibers within the membrane were removed by water, supposedly leaving aligned cylindrical pores in the membrane. Both SEM and AFM illustrated aligned grooves on the surface of the resultant PGS membrane, indicating the successful removal of sacrificial fibers. The PGS membrane was validated to be mechanically anisotropic using uniaxial tensile testing along and perpendicular to the predominant pore direction. The in vitro cytocompatibility of the PGS membrane was confirmed. As a demonstration of its potential application in vascular tissue engineering, a tubular scaffold was constructed by wrapping a stack of two axisymmetric pieces of the anisotropic PGS membranes on a mandrel. The compliance of the scaffold was found to depend on the pitch angle of its double helical structure, imitating the anisotropic mechanical behavior of the arterial media. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 760-770, 2018. PMID- 28346744 TI - Radiopaque UHMWPE sublaminar cables for spinal deformity correction: Preclinical mechanical and radiopacifier leaching assessment. AB - Polymeric sublaminar cables have a number of advantages over metal cables in the field of spinal deformity surgery, with decreased risk of neurological injury and potential for higher correction forces as the two most predominant. However, currently available polymer cables are radiolucent, precluding postoperative radiological assessment of instrumentation stability and integrity. This study provides a preclinical assessment of a woven UHMWPE cable made with radiopaque UHMWPE fibers. Our primary goal was to determine if the addition of a radiopacifier negatively affects the mechanical properties of UHMWPE woven cables. Tensile mechanical properties were determined and compared to suitable controls. Radiopacity was evaluated and radiopacifier leaching was assessed in vitro and in vivo. Finally, in vivo bismuth organ content was quantified after a 24-week implantation period in sheep. Results show that the mechanical properties of woven UHMWPE cables were not deleteriously affected by the addition of homogenously dispersed bismuth oxide particles within each fiber. Limited amounts of bismuth oxide were released in vitro, well below the toxicological threshold. Tissue concentrations lower than generally accepted therapeutic dosages for use against gastrointestinal disorders, well below toxic levels, were discovered in vivo. These results substantiate controlled clinical introduction of these radiopaque UHMWPE cables. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 771-779, 2018. PMID- 28346745 TI - Emp10 encodes a mitochondrial PPR protein that affects the cis-splicing of nad2 intron 1 and seed development in maize. AB - In higher plants, many mitochondrial genes contain group II-type introns that are removed from RNAs by splicing to produce mature transcripts that are then translated into functional proteins. However, the factors involved in the splicing of mitochondrial introns and their biological functions are not well understood in maize. Here, we isolated an empty pericarp 10 (emp10) mutant and identified the underlying gene by map-based cloning. Emp10 encodes a P-type mitochondria-targeted pentatricopeptide repeat (PPR) protein with 10 PPR motifs. Loss of Emp10 function results in splicing defect of the first intron of nad2, a gene encoding subunit 2 of NADH dehydrogenase (also called complex I). The emp10 mutant has undetectable activity of complex I and has arrested development of embryo and endosperm, and thus defective seeds with empty pericarp. Additionally, the basal endosperm transfer layer cells were severely affected, indicating the deficiency of cell wall ingrowths in the emp10 kernels. Moreover, the alternative respiratory pathway involving alternative oxidase was significantly induced in the emp10 mutant. These results suggest that EMP10 is specifically required for the cis-splicing of mitochondrial nad2 intron 1, embryogenesis and endosperm development in maize. PMID- 28346746 TI - Simultaneous determination of 4-hydroxyphenyl lactic acid, 4-hydroxyphenyl acetic acid, and 3,4-hydroxyphenyl propionic acid in human urine by ultra-high performance liquid chromatography with fluorescence detection. AB - A simple and reliable method was established for simultaneous determination of 4 hydroxyphenyl acetic acid, 4-hydroxyphenyl lactic acid, and 3,4-hydroxyphenyl propionic acid in human urine by high-performance liquid chromatography with fluorescence detection. Solid-phase extraction was used to eliminate the interferences in urine. The separation of three analytes was achieved using a C18 column and a mobile phase formed by a 95:5 v/v mixture of 50 mmol/L ammonium acetate buffer at pH 6.8 that contained 5 mmol/L tetrabutyl ammonium bromide and acetonitrile. Under the optimized conditions, the detection limits of 4 hydroxyphenyl acetic acid, 4-hydroxyphenyl lactic acid, and 3,4-hydroxyphenyl propionic acid were 4.8 * 10-3 , 8.80 * 10-3 , and 9.00 * 10-3 mg/L, respectively, and the recoveries were in the range of 85.0-120.0% with relative standard deviations of 1.5-3.1%. This method was used to analyze urine samples from breast cancer patients, healthy people and post-surgery breast cancer patients. Significant differences in urinary levels of 4-hydroxyphenyl acetic acid and 4-hydroxyphenyl lactic acid could be found between the breast cancer patients group and other two groups. No effect of age and sex was observed on the urinary levels of 4-hydroxyphenyl acetic acid and 4-hydroxyphenyl lactic acid. This method might be helpful for cancer biomarkers discovery in urine. PMID- 28346747 TI - Agreement between cytotechnologists and cytopathologists as a new measure of cytopathologist performance in gynecologic cytology. AB - BACKGROUND: Although objective measures of cytotechnologist (CT) and cytopathologist (CP) performance exist, challenges remain. Two assumptions deserve examination: CPs' interpretations are correct, and CTs and CPs render interpretations independently of each other. This study presents a CT-CP interpretation comparison and provides insight into these assumptions. METHODS: Every gynecologic cytology specimen examined by both a CT and a CP from December 2004 to March 2015 was extracted from the laboratory information system; glandular interpretations were excluded. Excel and SAS were used for CT-CP pair analysis. CT-CP pairs with fewer than 32 specimens (the lowest quartile) were excluded. For the remaining CT-CP pairs, 30 specimens or 10% of the specimens (whichever was higher) were randomly selected for comparison by a weighted kappa statistic. kappa values greater than 0.6 represented good agreement within CT-CP pairs. RESULTS: This study evaluated 7116 of 53,241 gynecologic cytology specimens (13.4%) that received CT and CP interpretations. This resulted in 155 pair-specific kappa values from 15 CTs and 16 CPs. In aggregate, the kappa values had a mean of 0.64, a standard deviation of 0.14, a median of 0.65, and a range of 0.27 to 0.91. Nine CTs exhibited good agreement in the majority of their pair specific kappa values with CPs (high-concordance CTs; 88 pair-specific kappa values). This allowed us to identify outlier CPs who did not demonstrate good agreement with high-concordance CTs (16 of 88 pair-specific kappa values [18.2%]). CONCLUSIONS: Laboratories can use this kappa to determine when CP levels of agreement with CTs depart from those of their peers. Adding this to established metrics can give a more nuanced impression of CP performance. Cancer Cytopathol 2017;125:576-80. (c) 2017 American Cancer Society. PMID- 28346748 TI - The Brain of the Giraffe (Giraffa Camelopardalis): Surface Configuration, Encephalization Quotient, and Analysis of the Existing Literature. AB - The anatomy of the giraffe (Giraffa camelopardalis Linnaeus, 1758) has been poorly studied, except for the circulatory system. In particular, only a handful of studies have concerned the brain of this species since the first description in 1839. Accordingly, only a very few articles discussing encephalization mentioned the giraffe or used it in their calculations. In this article, we performed a thorough examination of the literature including old and grey, regarding the central nervous system of the giraffe. Furthermore, we examined the brain of 3 giraffes, and calculated the encephalization quotient (EQ) of the species, based on our own data and the values found in the literature. We also revised the pre-existing literature and re-mapped the main sulci based on current comparative interpretation and anatomical nomenclature. Our results were compared to those of other selected significant mammals. The mean brain weight was of 719.9 +/- 12.5 g. Our data indicate that the EQ of the giraffe is 0.64 and matches that of the typical ungulate, despite having the largest brain among terrestrial Cetartiodactyla. This emphasizes that the giraffe is a highly specialized mammal, within the limitations of its clad. Anat Rec, 300:1502-1511, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28346750 TI - Intuitive Understanding of sigma Delocalization in Loose and sigma Localization in Tight Helical Conformations of an Oligosilane Chain. AB - Conformational effects on the sigma-electron delocalization in oligosilanes are addressed by Hartree-Fock and time-dependent density functional theory calculations (B3LYP, 6-311G**) at MP2 optimized geometries of permethylated uniformly helical linear oligosilanes (all-omega-Sin R2n+2 ) up to n=16 and for backbone dihedral angles omega=55-180 degrees . The extent of sigma delocalization is judged by the partition ratio of the highest occupied molecular orbital and is reflected in the dependence of its shape and energy and of UV absorption spectra on n. The results agree with known spectra of all-transoid loose-helix conformers (all-[+/-165]-Sin Me2n+2 ) and reveal a transition at omega~90 degrees from the "sigma-delocalized" limit at omega=180 degrees toward and close to the physically non-realizable "sigma-localized" tight-helix limit omega=0 with entirely different properties. The distinction is also obtained in the Huckel Ladder H and C models of sigma delocalization. An easy intuitive way to understand the origin of the two contrasting limits is to first view the linear chain as two subchains with alternating primary and vicinal interactions (sigma hyperconjugation), one consisting of the odd and the other of the even sigma(SiSi) bonds, and then allow the two subchains to interact by geminal interactions (sigma conjugation). PMID- 28346752 TI - Atrophoderma of Pasini and Pierini in a blaschkoid pattern. PMID- 28346751 TI - d-Fructose Modification Enhanced Internalization of Mixed Micelles in Breast Cancer Cells via GLUT5 Transporters. AB - d-Fructose modified poly(epsilon-caprolactone)-polyethylene glycol (PCL-PEG-Fru) diblock amphiphile is synthesized via Cu(I)-catalyzed click chemistry, which self assembles with D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) into PCL-PEG-Fru/TPGS mixed micelles (PPF MM). It has been proven that glucose transporter (GLUT)5 is overexpressed in MCF-7 cells other than L929 cells. In this study, PPF MM exhibit a significantly higher uptake efficiency than fructose free PCL-PEG-N3 /TPGS mixed micelles in both 2D MCF-7 cells and 3D tumor spheroids. Also, the presence of free d-fructose competitively inhibits the internalization of PPF MM in MCF-7 cells other than L929 cells. PPF MM show selective tumor accumulation in MCF-7 breast tumor bearing mice xenografts. Taken together, PPF MM represent a promising nanoscale carrier system to achieve GLUT5 mediated cell specific delivery in cancer therapy. PMID- 28346753 TI - Association between diabetes mellitus/hyperglycaemia and peri-implant diseases: Systematic review and meta-analysis. AB - AIM: This systematic review investigates whether hyperglycaemia/diabetes mellitus is associated with peri-implant diseases (peri-implant mucositis and peri implantitis). MATERIALS AND METHODS: Electronic and manual literature searching was conducted. An a priori case definition for peri-implantitis was used as an inclusion criterion to minimize risk of bias. The Newcastle-Ottawa Scale was used for quality assessment; random effect models were applied; and results were reported according to the PRISMA Statement. RESULTS: Twelve studies were eligible for qualitative and seven of them for quantitative analyses. Meta-analyses detected the risk of peri-implantitis was about 50% higher in diabetes than in non-diabetes (RR = 1.46; 95% CI: 1.21-1.77 and OR = 1.89; 95% CI: 1.31-2.46; z = 5.98; p < .001). Importantly, among non-smokers, those with hyperglycaemia had 3.39-fold higher risk for peri-implantitis compared with normoglycaemia (95% CI: 1.06-10.81). Conversely, the association between diabetes and peri-implant mucositis was not statistically significant (RR = 0.92; 95% CI: 0.72-1.16 and OR = 1.06; 95% CI: 0.84-1.27; z = 1.06, p = .29). CONCLUSIONS: Within its limits that demand great caution when interpreting its findings, this systematic review suggests that diabetes mellitus/hyperglycaemia is associated with greater risk of peri-implantitis, independently of smoking, but not with peri-implant mucositis. PMID- 28346754 TI - Commentary: What makes a life go well? Moral functioning and quality of life measurement in neurodevelopmental disorders - reflections on Jonsson et al. (2017). AB - Jonsson et al.'s excellent review of the literature on quality of life (QoL) and childhood mental and behavioural disorders (Jonsson et al., ) highlights the need for studies that utilise child self-reported QoL, in contrast to parent or proxy QoL measures, and further challenges the field to develop QoL measures that 'put the child's own views and priorities first'. PMID- 28346755 TI - Editorial: Child psychology and psychiatry - using science to make a difference. AB - The Journal of Child Psychology and Psychiatry has, I think it is fair to say, a special place in the hearts of scientists and scientist-practitioners working broadly in the field of developmental psychopathology. How would you put into words what it is we all love about the journal? Answers on a postcard please! For me, in addition to the high quality of the science, there is something unique about JCPP's open-minded, eclectic yet rigorous and methodologically pluralistic style that makes it stand out from the rest. PMID- 28346756 TI - Commentary: All that glisters is not gold - reflections on Hollis et al. 2017. AB - Digital Health Innovations have great potential to improve access to evidence based psychological therapies. This comprehensive review and meta-analysis sets out the current state of the field including the efficacy of the interventions for different types of mental health problems and the desirability of the interventions from the patients' perspective. It also highlights the poor methodology of much of the research and suggests important ways forward to improve the quality of the data. The importance of assessing and understanding the potential negative impact of such interventions is emphasised both in the review and the commentary, and suggestions are made to maximise the likelihood that such interventions are accessible within routine services. PMID- 28346757 TI - Commentary: Extraordinary environments, extreme neuroplasticity and mental disorder - reflections on pathways from adversity to mental disorder prompted by McCrory, Gerin, and Viding (2017). AB - Neuroplasticity, the brain's capacity to be shaped in response to environmental experience, has been claimed to resemble a double-edged sword - potentiating growth and healing when individuals are exposed to normative, benign or therapeutic environments on the one hand, mediating mental disorder development in those exposed to adversity, on the other. However, questions about the scope and limits of neuroplasticity and, especially, its clinical significance, remain unanswered. PMID- 28346758 TI - Commentary: Distillation and element-based design of psychological treatments in global mental health - a commentary on Brown et al. (2017). AB - This commentary reflects on the "elements" approach in psychological treatment research, and its specific application to a systematic review of psychosocial interventions for youth in conflict-affected areas. We discuss three key questions for the field. First, what psychological treatment elements are necessary and/or sufficient to achieve clinically significant change for a given population? Second, how should elements be sequenced to achieve optimal outcomes? Third, what might account for the large heterogeneity observed in psychological treatment trials, other than the constituent practice elements? We conclude by describing a new research programme that aims to develop a transdiagnostic intervention targeting common mental health difficulties among school-going adolescents in India. The initial experience of this programme affirms the utility of aligning an elements approach with contextually-sensitive formative research. PMID- 28346759 TI - Commentary: What's in a word (or words) - on the relations among self-regulation, self-control, executive functioning, effortful control, cognitive control, impulsivity, risk-taking, and inhibition for developmental psychopathology - reflections on Nigg (2017). AB - In Nigg's excellent article, he deals with a variety of complex conceptual issues related to the constructs of self-regulation and executive functioning (EF). Overall, I agree that the terminology proposed by Nigg should be adopted; moreover, the conceptual distinctions he provides should help the field to move forward with regard to the understanding of varied constructs related to self regulation. In the spirit of further clarification, I questioned Nigg's suggestions that (a) working memory should be considered as part of the construct of top-down regulation and (b) planning is a higher level component of EF but not part of effortful control. In addition, I discussed my perspective on the role of automaticity in defining top-down versus bottom-up self-regulatory processes and the role of flexibility in top-down self-regulatory processes and their relation to personality resiliency. PMID- 28346760 TI - Commentary: Critical considerations for studying low-functioning autism. AB - Jack and Pelphrey provide a systematic review of neuroimaging studies in understudied populations within the autistic spectrum, focussing specifically on those with minimal verbal ability, intellectual disability and developmental regression. Despite accounting for nearly a third of the autistic spectrum, the number of studies focussing on these populations is extremely low. This review highlights a critical need for further neuroimaging research on these populations, and provides practical suggestions for overcoming the challenges posed by it. In this commentary, I discuss some of the theoretical questions that arise from the review, on the conceptualisation of the autistic spectrum as well as on optimising experimental design and analysis. PMID- 28346761 TI - Commentary: Information-processing in anxiety and depression - novel targets for translational research, a reflection on Lau and Waters (2017). AB - Understanding psychopathology in the context of a developmental cognitive neuroscience approach entails the notion that specific individual differences in information processing can serve as both etiologic and maintaining factors in the development of specific disorders. It is posited that such mechanistic understanding of neurocognitive aberrations during development can then serve focused translational efforts in the form of cognitive bias modification treatments. In the review by Lau and Waters (this issue), an astute developmental model is suggested regarding the role of potential neurocognitive mechanisms in depression and anxiety in youth. PMID- 28346763 TI - Direct Noncovalent Activation of alpha,beta-Unsaturated Aldehydes for the Stereodivergent Synthesis of Substituted Cyclohexenes. AB - HOMO-raising noncovalent activation of alpha-aryl alpha,beta-unsaturated aldehydes using a bifunctional Bronsted base catalyst is achieved. The catalytically generated dienolate intermediate undergoes all-carbon [4+2] cyclizations with nitroolefins, leading to chiral cyclohexenes with four contiguous stereocenters in high yields and with excellent enantioseletivity. Furthermore, the diastereodivergent synthesis of the products is realized by introducing a second steric control to the bifunctional catalyst; 4 isomers out of 16 possible stereoisomers of the products were selectively produced by simple use of two catalysts and their (pseudo)enantiomers. The results presented here provide new insights into the remote activation of the carbonyl functionality as well as the stereodivergent synthesis of complex chiral molecules with multiple stereocenters. PMID- 28346762 TI - Predicting the pain continuum after adolescent idiopathic scoliosis surgery: A prospective cohort study. AB - BACKGROUND: Chronic postsurgical pain (CPSP) affects half a million children annually in the United States, with dire socioeconomic consequences, including long-term disability into adulthood. The few studies of CPSP in children are limited by sample size, follow-up duration, non-homogeneity of surgical procedure and factors evaluated. METHODS: In a prospective study of 144 adolescents undergoing a single major surgery (spine fusion), we evaluated demographic, perioperative, surgical and psychosocial factors as predictors of a continuum of postsurgical pain: immediate, pain maintenance at 2-3 months (chronic pain/CP) and persistence of pain a year (persistent pain/PP) after surgery. RESULTS: We found an incidence of 37.8% and 41.8% for CP and PP. CP and acute pain were both significant predictors for developing PP (p-value <0.001 and 0.003). Preoperative pain and higher postoperative opioid requirement was significantly associated with CP (p = 0.015, p = 0.002), while Childhood Anxiety Sensitivity Index (p = 0.002) and surgical duration (p = 0.014) predicted PP. The final regression models had reasonable predictive accuracy (c-statistic of 0.73 and 0.83 for CP and PP, respectively). Anxiety scores and catastrophizing for child and parent were found to be significantly correlated (p = 0.005, p = 0.013 respectively). Pain trajectories revealed that 65% of patients who developed PP reported CP and high pain trends; however, 33% of those who developed PP could not be identified using solely pain criteria. CONCLUSION: Persistent postsurgical pain in children is a significant problem. It can be predicted in part by combinations of psychological and clinical variables, which may provide evidence-based measures to prevent development of CPSP in the future. SIGNIFICANCE: In a homogeneous cohort of adolescents undergoing spine fusion, we report a high incidence of persistent postsurgical pain (41.8%) predicted by child anxiety, perioperative pain, and surgical duration. Our results stress timely preventive and therapeutic strategies. PMID- 28346764 TI - Mapping the Interactions of Selective Biochemical Probes of Antibody Conformation by Hydrogen-Deuterium Exchange Mass Spectrometry. AB - Protein-based pharmaceuticals represent the fastest growing group of drugs in development in the pharmaceutical industry. One of the major challenges in the discovery, development, and distribution of biopharmaceuticals is the assessment of changes in their higher-order structure due to chemical modification. Here, we investigated the interactions of three different biochemical probes (Fab s) generated to detect conformational changes in a therapeutic IgG1 antibody (mAbX) by local hydrogen-deuterium exchange mass spectrometry (HDX-MS). We show that two of the probes target the Fc part of the antibody, whereas the third probe binds to the hinge region. Through HDX-ETD, we could distinguish specific binding patterns of the Fc -binding probes on mAbX at the amino-acid level. Preliminary surface plasmon resonance (SPR) experiments showed that these domain-selective Fab probes are sensitive to conformational changes in distinct regions of a full length therapeutic antibody upon oxidation. PMID- 28346765 TI - The medial temporal memory system in Down syndrome: Translating animal models of hippocampal compromise. AB - Recent studies have highlighted the dentate gyrus as a region of increased vulnerability in mouse models of Down syndrome (DS). It is unclear to what extent these findings are reflected in the memory profile of people with the condition. We developed a series of novel tasks to probe distinct medial temporal functions in children and young adults with DS, including object, spatial, and temporal order memory. Relative to mental age-matched controls (n = 45), individuals with DS (n = 28) were unimpaired on subtests involving short-term object or configural recall that was divorced from spatial or temporal contexts. By contrast, the DS group had difficulty recalling spatial locations when contextual information was salient and recalling the order in which objects were serially presented. Results are consistent with dysfunction of spatial and temporal contextual pattern separation abilities in individuals with DS, mediated by the hippocampus, including the dentate gyrus. Amidst increasing calls to bridge human and animal work, the memory profile demonstrated here in humans with DS is strikingly similar to that of the Ts65Dn mouse model of DS. The study highlights the trisynaptic circuit as a potentially fruitful intervention target to mitigate cognitive impairments associated with DS. PMID- 28346766 TI - Maternal thyroid parameters in pregnant women with different ethnic backgrounds: Do ethnicity-specific reference ranges improve the diagnosis of subclinical hypothyroidism? AB - OBJECTIVE: Guidelines on the management of thyroid dysfunction during pregnancy have recently been updated and, for the diagnosis of subclinical hypothyroidism (SCH), a thyroid-stimulating hormone (TSH) upper reference limit (cut-off) of 4.0 mIU/L has been proposed when no institutional values are available. It is also suggested that serum TSH and thyroid autoimmunity (TAI) may be different according to the ethnic background of the women. We therefore determined the prevalence of TAI and SCH in pregnant women with different ethnic backgrounds and, to define SCH, we used different first trimester TSH upper reference cut offs (institutional, ethnicity-specific, 2.5 mIU/L [Endocrine Society] and 4.0 mIU/L [American Thyroid Association]). DESIGN: Cross-sectional data analysis of 1683 pregnant women nested within an ongoing prospective database of pregnant women. METHOD: The study was performed in a single centre in Brussels, Belgium. During the first antenatal visit, thyroid peroxidase antibodies (TPO-abs), TSH and free T4 (FT4) were measured and baseline characteristics recorded. Data from 481 women with sub-Saharan (SaBg; 28.6%), 754 North African (NaBg; 44.8%) and 448 Caucasian (CaBg; 26.6%) backgrounds were analysed. For the calculation of TSH reference ranges, women with TAI, outliers, twin and assisted pregnancies were excluded. RESULTS: The prevalence of TAI was significantly lower in the SaBg group than in NaBg and CaBg groups (3.3% vs 8.6% and 11.1%; P<.001, respectively). Median TSH was significantly lower in SaBg and NaBg groups as compared with the CaBg group (1.3 and 1.4 vs 1.5 mIU/L; P=.006 and .014, respectively). The prevalence of women with SCH was comparable between all groups when 2.5 mIU/L was used as cut-off, but when 4.0 mIU/L or the institutional cut off (3.74 mIU/L) was used, it was significantly higher in the CaBg group vs the NaBg group (5.4% vs 2.1% and 7.1% vs 3.3%, P=.008 and .013, respectively). The use of ethnicity-specific cut-offs did not change the prevalence of SCH as compared to the use of institutional cut-offs. However, when these cut-offs were used, the prevalence of SCH reduced by >70% (4.5% instead of 16.7%; P<.001) relative to the 2.5 mIU/L cut-off. CONCLUSIONS: Pregnant women with a sub-Saharan African background had a lower prevalence of TAI and TSH levels as compared with women from other backgrounds. The use of ethnicity-specific TSH cut-offs in early pregnancy was not more specific for the diagnosis of SCH as compared to the use of the institutional cut-off. PMID- 28346767 TI - Hormone replacement therapy for chronic tinnitus in menopausal women: Our experience with 13 cases. PMID- 28346769 TI - Have Your Say! PMID- 28346768 TI - Defining the role of SGAs in the long-term treatment of bipolar disorder. PMID- 28346770 TI - A core outcome set for localised prostate cancer effectiveness trials. AB - OBJECTIVE: To develop a core outcome set (COS) applicable for effectiveness trials of all interventions for localised prostate cancer. Many treatments exist for localised prostate cancer, although it is unclear which offers the optimal therapeutic ratio; which is confounded by inconsistencies in the selection, definition, measurement and reporting of outcomes in clinical trials. PATIENTS, SUBJECTS AND METHODS: A list of 79 outcomes was derived from a systematic review of published localised prostate cancer effectiveness studies and semi-structured interviews with 15 patients with prostate cancer patients. A two-stage consensus process involving 118 patients and 56 international healthcare professionals (HCPs; cancer specialist nurses, urological surgeons and oncologists) was undertaken, consisting of a three-round Delphi survey followed by a face-to-face consensus panel meeting of 13 HCPs and eight patients. RESULTS: The final COS included 19 outcomes. In all, 12 apply to all interventions: death from prostate cancer, death from any cause, local disease recurrence, distant disease recurrence/metastases, disease progression, need for salvage therapy, overall quality of life, stress urinary incontinence, urinary function, bowel function, faecal incontinence, and sexual function. Seven were intervention-specific: perioperative deaths (surgery), positive surgical margin (surgery), thromboembolic disease (surgery), bothersome or symptomatic urethral or anastomotic stricture (surgery), need for curative treatment (active surveillance), treatment failure (ablative therapy), and side-effects of hormonal therapy (hormone therapy). The UK-centric participants may limit the generalisability to other countries, but trialists should reason why the COS would not be applicable. The default position should not be that a COS developed in one country will automatically not be applicable elsewhere. CONCLUSION: We have established a COS for trials of effectiveness in localised prostate cancer, applicable across all interventions that should be measured in all localised prostate cancer effectiveness trials. PMID- 28346772 TI - Tools in science. PMID- 28346771 TI - Cohort study of oncologic emergencies in patients with head and neck cancer. AB - BACKGROUND: Treatments for head and neck squamous cell carcinoma (HNSCC) are associated with toxicities that lead to emergency department presentation. METHODS: We utilized data from an ongoing prospective cohort of newly diagnosed, previously untreated patients (N = 298) with HNSCC to evaluate the association between clinical and epidemiologic factors and risk for and frequency of emergency department presentation. Time to event was calculated from the date of treatment initiation to emergency department presentation, date of death, or current date. Frequency of emergency department presentation was the sum of emergency department visits during the follow-up time. RESULTS: History of hypertension, normal/underweight body mass index (BMI), and probable depression predicted increased risk for emergency department presentation. BMI and severe pain were associated with higher frequency of emergency department presentations. CONCLUSION: Clinical and epidemiologic factors can help predict patients with HNSCC who will present to the emergency department. Such knowledge may improve treatment-related patient outcomes and quality of life. (c) 2017 Wiley Periodicals, Inc. Head Neck 39: 1195-1204, 2017. PMID- 28346773 TI - Noninterventional, Naturalistic, Retrospective Study to Describe Prescription Patterns of Long-Acting Injectable Antipsychotics and the Impact of Introducing a New Atypical Antipsychotic in the Spanish Province of Tarragona Catchment Area. AB - Background: We studied the patterns and predictors of long-acting injectable (LAI) antipsychotic (AP) use in the treatment of schizophrenia and the effect of introducing a new LAI (paliperidone palmitate [paliperidone-LAI]) in the Spanish province of Tarragona. Methods: This noninterventional, naturalistic, retrospective study included electronic medical record data from a large population-based database of 1,646 patients who were diagnosed with schizophrenia according to ICD-10 criteria and treated between January 2011 and December 2013. Results: During the study period, 42.0% of patients were treated with an LAI AP. The most frequently prescribed initial LAI was risperidone (52.0% of patients). A total of 23% of patients initially treated with an oral AP were switched to an LAI AP, a change that was associated with younger age (P = .001), undifferentiated schizophrenia (P = .015), substance abuse (P < .001), and neuropsychiatric comedication with the following agents: anticonvulsants (P = .004), anticholinergics (P < .001), and hypnotics/sedatives (P = .03). The change from an oral AP to paliperidone-LAI was predicted by younger age (P < .001). Overall, 27.5% of patients switched to another LAI AP, and paliperidone-LAI was the preferred option in 64.7% of cases. The most frequent change involved patients taking risperidone-LAI, many of whom transitioned to paliperidone-LAI (85.0% of cases), particularly patients with a disease duration > 5 years (P = .019). Conclusions: There was a progressive increase in the use of LAI formulations in our catchment area. These agents were preferentially prescribed to patients with chronic disease and a history of substance abuse, as well as patients receiving neuropsychiatric comedication. One-month LAI formulations were commonly used in young patients. PMID- 28346774 TI - Geriatric-Onset Olfactory Reference Syndrome Successfully Treated with Duloxetine and Memantine. PMID- 28346775 TI - Hyperinsulinism-Causing Mutations Cause Multiple Molecular Defects in SUR1 NBD1. AB - The sulfonylurea receptor 1 (SUR1) protein forms the regulatory subunit in ATP sensitive K+ (KATP) channels in the pancreas. SUR proteins are members of the ATP binding cassette (ABC) superfamily of proteins. Binding and hydrolysis of MgATP at the SUR nucleotide binding domains (NBDs) lead to channel opening. Pancreatic KATP channels play an important role in insulin secretion. SUR1 mutations that result in increased levels of channel opening ultimately inhibit insulin secretion and lead to neonatal diabetes. In contrast, SUR1 mutations that disrupt trafficking and/or decrease gating of KATP channels cause congenital hyperinsulinism, where oversecretion of insulin occurs even in the presence of low glucose levels. Here, we present data on the effects of specific congenital hyperinsulinism-causing mutations (G716V, R842G, and K890T) located in different regions of the first nucleotide binding domain (NBD1). Nuclear magnetic resonance (NMR) and fluorescence data indicate that the K890T mutation affects residues throughout NBD1, including residues that bind MgATP, NBD2, and coupling helices. The mutations also decrease the MgATP binding affinity of NBD1. Size exclusion and NMR data indicate that the G716V and R842G mutations cause aggregation of NBD1 in vitro, possibly because of destabilization of the domain. These data describe structural characterization of SUR1 NBD1 and shed light on the underlying molecular basis of mutations that cause congenital hyperinsulinism. PMID- 28346776 TI - Proton Exchange in a Paramagnetic Chemical Exchange Saturation Transfer Agent from Experimental Studies and ab Initio Metadynamics Simulation. AB - The proton-exchange process between water and a carbamate has been studied experimentally and theoretically in a lanthanide-based paramagnetic chemical exchange saturation transfer agent endowed with potential multimodality detection capabilities (optical imaging, or T1 MRI for the Gd(III) analogue). In addition to an in-depth structural analysis by a combined approach (using X-ray crystallography, NMR, and molecular dynamics), our ab initio simulation in aqueous solution sheds light on the reaction mechanism for this proton exchange, which involves structural Grotthuss diffusion. PMID- 28346777 TI - Effect of Intrinsic Disorder and Self-Association on the Translational Diffusion of Proteins: The Case of alpha-Casein. AB - Translational diffusion is the major mode of macromolecular transport in leaving organisms, and therefore it is vital to many biological and biotechnological processes. Although translational diffusion of proteins has received considerable theoretical and experimental scrutiny, much of that attention has been directed toward the description of globular proteins. The translational diffusion of intrinsically disordered proteins (IDPs), however, is much less studied. Here, we use a pulsed-gradient nuclear magnetic resonance technique (PFG NMR) to investigate the translational diffusion of a disordered protein in a wide range of concentrations using alpha-casein that belongs to the class of natively disordered proteins as an example. PMID- 28346778 TI - Direct Measurement of the Angular Pair Correlation Coefficients in Molecular Liquids Using NMR. Benchmarking Force Fields for Atomistic Simulations. AB - High-field deuterium NMR spectroscopy is used to characterize a number of molecular liquids and their mixtures in order to probe the directional part of the intermolecular interactions through the orientational ordering induced in the isotropic liquid phase by the spectrometer magnetic field. The systems studied include benzene, chloroform, hexafluorobenzene, and thiophene at various concentrations and in mixtures. Dilution with the magnetically isotropic tetramethylsilane provides quantification of ordering at "infinite magnetic dilution", that is, in the absence of magnetic intermolecular correlations, and thereby allows identification of the contribution of these correlations to the orientational ordering in neat phases and at various degrees of magnetic dilution. Such contributions are conveyed by angular pair correlation coefficients, which, in addition to being accessible to direct NMR measurement, are also possible to evaluate directly from molecular dynamics simulations. By using various force fields, simulations provide benchmark quantities for testing and possibly further improving the force field performance, particularly with respect to the directional components of the intermolecular interactions. The latter are critical for the simulation of self-assembly generally and particularly in biological systems. PMID- 28346779 TI - Quantum Dynamics Study of the Potential Energy Minima Effect on Energy Efficiency for the F- + CH3Cl -> FCH3 + Cl- Reaction. AB - The Polanyi rules on the energy efficiency on reactivity are summarized solely from the locations of barriers on the potential energy surfaces. Here, our quantum dynamics study for the F- + CH3Cl -> FCH3 + Cl- reaction shows that the two potential energy minima in the entrance channel on the potential energy surface play an essential role in energy efficiency on reactivity. The reactivity of this reaction is dominated by the low collision energies where two distinctive reaction mechanisms involve the two minima in the entrance channel. Overall, the Cl-CH3 stretching motion and C-H3 umbrella motion both are more efficient than the translational motion in promoting this reaction. Although this reaction has a negative energy barrier, our study shows that it is the minima in the entrance channel, together with the energy barrier relative to these minima, that determine the energy efficacy on reactivity. PMID- 28346780 TI - High-Spin Polymers: Ferromagnetic Coupling of S = 1 Hexaazacyclophane Units up to a Pure S = 2 Polycyclophane. AB - Triarylamines oxidized to radical cations can be used as stable spins sources for the design of high-spin compounds. Here, we present the synthesis of the polyarylamine-containing hexaazacyclophanes linked via meta-terphenyl bridges. Spins, created after oxidation of the polymer, can be coupled magnetically in cyclophane moieties via meta-phenyl and along the polymer chain via meta terphenyl units. The formation of a quintet spin state was evidenced by pulsed EPR nutation spectroscopy. Two exchange coupling constants via both couplers were determined experimentally and corresponded to J/k = 89 K in the cyclophane moiety and j/k = 17 K via meta-terphenyl. Most importantly, in this polymer, four spins can be ferromagnetically ordered via both couplers, which leads to the high spin state. PMID- 28346781 TI - Metabolism of Ibuprofen by Phragmites australis: Uptake and Phytodegradation. AB - This study explores ibuprofen (IBP) uptake and transformation in the wetland plant species Phragmites australis and the underlying mechanisms. We grew P. australis in perlite under greenhouse conditions and treated plants with 60 MUg/L of IBP. Roots and rhizomes (RR), stems and leaves (SL), and liquid samples were collected during 21 days of exposure. Results show that P. australis can take up, translocate, and degrade IBP. IBP was completely removed from the liquid medium after 21 days with a half-life of 2.1 days. IBP accumulated in RR and was partly translocated to SL. Meanwhile, four intermediates were detected in the plant tissues: hydroxy-IBP, 1,2-dihydroxy-IBP, carboxy-IBP and glucopyranosyloxy hydroxy-IBP. Cytochrome P450 monooxygenase was involved in the production of the two hydroxy intermediates. We hypothesize that transformation of IBP was first catalyzed by P450, and then by glycosyltransferase, followed by further storage or metabolism in vacuoles or cell walls. No significant phytotoxicity was observed based on relative growth of plants and stress enzyme activities. In conclusion, we demonstrated for the first time that P. australis degrades IBP from water and is therefore a suitable species for application in constructed wetlands to clean wastewater effluents containing IBP and possibly also other micropollutants. PMID- 28346782 TI - kappa-Carrageenan Enhances the Biomineralization and Osteogenic Differentiation of Electrospun Polyhydroxybutyrate and Polyhydroxybutyrate Valerate Fibers. AB - Novel electrospun materials for bone tissue engineering were obtained by blending biodegradable polyhydroxybutyrate (PHB) or polyhydroxybutyrate valerate (PHBV) with the anionic sulfated polysaccharide kappa-carrageenan (kappa-CG) in varying ratios. In both systems, the two components phase separated as shown by FTIR, DSC and TGA. According to the contact angle data, kappa-CG was localized preferentially at the fiber surface in PHBV/kappa-CG blends in contrast to PHB/kappa-CG, where the biopolymer was mostly found within the fiber. In contrast to the neat polyester fibers, the blends led to the formation of much smaller apatite crystals (800 nm vs 7 MUm). According to the MTT assay, NIH3T3 cells grew in higher density on the blend mats in comparison to neat polyester mats. The osteogenic differentiation potential of the fibers was determined by SaOS-2 cell culture for 2 weeks. Alizarin red-S staining suggested an improved mineralization on the blend fibers. Thus, PHBV/kappa-CG fibers resulted in more pronounced bioactive and osteogenic properties, including fast apatite-forming ability and deposition of nanosized apatite crystals. PMID- 28346783 TI - Dicarbonyls of Carbon and Methylidyne Cations. AB - The carbon suboxide cation C3O2+ and the protonated carbon suboxide HC3O2+/DC3O2+ were produced in the gas phase. The vibrational spectra were measured via infrared photodissociation spectroscopy of their argon- or CO-tagged complexes. Spectroscopic evidence combined with state-of-the-art quantum chemical calculations indicate that both cations have a bent C2v symmetry and can be designated as dicarbonyls of a carbon cation and methylidyne cation, respectively. PMID- 28346785 TI - Infrared Spectroscopy of Ionic Liquids Consisting of Imidazolium Cations with Different Alkyl Chain Lengths and Various Halogen or Molecular Anions with and without a Small Amount of Water. AB - Infrared spectroscopy was performed on ionic liquids (ILs) that had imidazolium cations with different alkyl chain lengths and various halogen or molecular anions with and without a small amount of water. The molar concentration normalized absorbance due to +C-H vibrational modes in the range of 3000 to 3200 cm-1 was nearly identical for ILs that had imidazolium cations with different alkyl chain lengths and the same anions. A close correlation was found between the red-shifted +C-H vibrational modes, the chemical shift of +C(2)-H proton, and the energy stabilization of the hydrogen-bonding interaction. The vibrational modes of the water molecules interacting with anions in the range between 3300 and 3800 cm-1 was examined. The correlation between the vibrational frequencies of water, the frequencies of +C-H vibrational modes, and the center frequency of intermolecular vibrational modes due to ion pairs was discussed. PMID- 28346784 TI - Structure Determination of Mycobacterium tuberculosis Serine Protease Hip1 (Rv2224c). AB - The Mycobacterium tuberculosis (Mtb) serine protease Hip1 (hydrolase important for pathogenesis; Rv2224c) promotes tuberculosis (TB) pathogenesis by impairing host immune responses through proteolysis of a protein substrate, Mtb GroEL2. The cell surface localization of Hip1 and its immunomodulatory functions make Hip1 a good drug target for new adjunctive immune therapies for TB. Here, we report the crystal structure of Hip1 to a resolution of 2.6 A and the kinetic studies of the enzyme against model substrates and the protein GroEL2. The structure shows a two domain protein, one of which contains the catalytic residues that are the signature of a serine protease. Surprisingly, a threonine is located within the active site close enough to hydrogen bond with the catalytic residues Asp463 and His490. Mutation of this residue, Thr466, to alanine established its importance for function. Our studies provide insights into the structure of a member of a novel family of proteases. Knowledge of the Hip1 structure will aid in designing inhibitors that could block Hip1 activity. PMID- 28346787 TI - Assembly and Speed in Ion-Exchange-Based Modular Phoretic Microswimmers. AB - We report an experimental study on ion-exchange-based modular microswimmers in low-salt water. Cationic ion-exchange particles and passive cargo particles assemble into self-propelling complexes, showing self-propulsion at speeds of several micrometers per second over extended distances and times. We quantify the assembly and speed of the complexes for different combinations of ion-exchange particles and cargo particles, substrate types, salt types and concentrations, and cell geometries. Irrespective of the experimental boundary conditions, we observe a regular development of the assembly shape with increasing number of cargo. Moreover, the swimming speed increases stepwise upon increasing the number of cargo and then saturates at a maximum speed, indicating the active role of cargo in modular swimming. We propose a geometric model of self-assembly to describe the experimental observations in a qualitative way. Our study also provides some constraints for future theoretical modeling and simulation. PMID- 28346786 TI - Break Down in Order To Build Up: Decomposing Small Molecules for Fragment-Based Drug Design with eMolFrag. AB - Constructing high-quality libraries of molecular building blocks is essential for successful fragment-based drug discovery. In this communication, we describe eMolFrag, a new open-source software to decompose organic compounds into nonredundant fragments retaining molecular connectivity information. Given a collection of molecules, eMolFrag generates a set of unique fragments comprising larger moieties, bricks, and smaller linkers connecting bricks. These building blocks can subsequently be used to construct virtual screening libraries for targeted drug discovery. The robustness and computational performance of eMolFrag is assessed against the Directory of Useful Decoys, Enhanced database conducted in serial and parallel modes with up to 16 computing cores. Further, the application of eMolFrag in de novo drug design is illustrated using the adenosine receptor. eMolFrag is implemented in Python, and it is available as stand-alone software and a web server at www.brylinski.org/emolfrag and https://github.com/liutairan/eMolFrag . PMID- 28346788 TI - Three-Step Catalytic Asymmetric Total Syntheses of 13 Methyltetrahydroprotoberberine Alkaloids. AB - (S,R)-N-PINAP was identified to be the chiral ligand for highly enantioselective CuI-catalyzed reaction of tetrahydroisoquinolines (THIQs), alkynes, and 2 bromobenzaldehyde derivatives. This enables us to accomplish the first asymmetric total synthesis of 12 natural 13-methyltetrahydroprotoberberine (13-MeTHPB) alkaloids in only three catalytic steps with 47-64% overall yields. In addition, the Pd-catalyzed reductive Heck cyclization was successfully extended to three Pd catalyzed domino reactions (Heck/Suzuki, Heck/Sonogashira, and Heck/Heck), which greatly expands the synthetic utility of this catalytic strategy and allows expeditious access to 13-substituted tetrahydroprotoberberines for further bioactivity evaluation. PMID- 28346789 TI - Resolving Ultrafast Photoinduced Deactivations in Water-Solvated Pyrimidine Nucleosides. AB - For the first time, ultrafast deactivations of photoexcited water-solvated pyrimidine nucleosides are mapped employing hybrid QM(CASPT2)/MM(AMBER) optimizations that account for explicit solvation, sugar effects, and dynamically correlated potential energy surfaces. Low-energy S1/S0 ring-puckering and ring opening conical intersections (CIs) are suggested to drive the ballistic coherent subpicosecond (<200 fs) decays observed in each pyrimidine, the energetics controlling this processes correlating with the lifetimes observed. A second bright 1pi2pi* state, promoting excited-state population branching and leading toward a third CI with the ground state, is proposed to be involved in the slower ultrafast decay component observed in Thd/Cyd. The transient spectroscopic signals of the competitive deactivation channels are computed for the first time. A general unified scheme for ultrafast deactivations, spanning the sub- to few picosecond time domain, is eventually delivered, with computed data that matches the experiments and elucidates the intrinsic photoprotection mechanism in solvated pyrimidine nucleosides. PMID- 28346790 TI - Synthesis of Chiral gamma-Lactams via in Situ Elimination/Iridium-Catalyzed Asymmetric Hydrogenation of Racemic gamma-Hydroxy gamma-Lactams. AB - Chiral gamma-lactams have been synthesized in excellent yields and enantioselectivities (up to 99% yield and 96% ee) from easily accessible racemic gamma-hydroxy gamma-lactams via an iridium-phosphoramidite catalyzed asymmetric hydrogenation. The reaction was designed based on insight into the reaction mechanism demonstrated in previous work and can be carried out at a reduced catalyst loading of 0.1 mol % on a gram scale. Several potential bioactive compounds can be synthesized from the reduced products. Mechanistic studies indicated that the reduced products were obtained via the hydrogenation of the N acyliminium cations, generated from gamma-hydroxy gamma-lactams. PMID- 28346791 TI - Hydroxy-Directed Enantioselective Hydroxyalkylation in the Carbocyclic Ring of Indoles. AB - A Cinchona-derived squaramide catalyzes the reaction between hydroxyindoles and isatins leading to enantioenriched indoles substituted in the carbocyclic ring. The reaction proceeds efficiently with differently substituted isatins, yielding the desired products with excellent regioselectivity, good yields, and high enantiocontrol. Moreover, every position of the carbocyclic ring of the indole can be functionalized by using the appropriate starting hydroxyindole. The OH group was removed smoothly upon hydrogenolysis of the corresponding triflate. PMID- 28346792 TI - Effects of IFN-gamma on cell growth and the expression of ADAM33 gene in human embryonic lung Mrc-5 fibroblasts in vitro. AB - OBJECTIVE: To investigate the effects of interferon-gamma (IFN-gamma) on the proliferation and viability of human embryonic lung Mrc-5 fibroblasts in vitro and the expression of the A Disintegrin and Metalloprotease 33 (ADAM33) gene and to explore the mechanism of airway remodeling. METHODS: Mrc-5 fibroblasts were sensitized with Dermatophagoides farinae 1 (Derf1) in vitro to mimic in vivo conditions observed in bronchial asthma. An inverted fluorescence microscope was used to observe changes in cell morphology before and after treatment. The viability of Mrc-5 cells was tested using the Cell Counting kit-8 (CCK8). Expression of the ADAM33 gene and protein in Mrc-5 cells was assessed using qPCR and Western blotting, respectively. RESULTS: Different concentrations of Derf1 increased cell growth and the expression of the ADAM33 gene in Mrc-5 cells, and these changes were most obvious in the 10 ug/ml group. In contrast, IFN-gamma decreased cell growth and the expression of the ADAM33 gene in both Mrc-5 cells and Derf1-induced Mrc-5 cells, and these changes were most obvious in the 10 ng/ml group. The negative effects of 10 ng/ml IFN-gamma were the most significant at 32 hours. CONCLUSIONS: Derf1-induced Mrc-5 cells successfully imitated the in vivo conditions observed in patients with asthma. IFN-gamma inhibited the proliferation and viability of Mrc-5 cells, and Derf1-induced Mrc-5 cells were more sensitive to IFN-gamma treatment. IFN-gamma treatment significantly downregulated the expression of the ADAM33 gene in a concentration- and time dependent manner. IFN-gamma may participate in airway remodeling in asthma by regulating the expression of the ADAM33 gene. PMID- 28346793 TI - Early Immune Responses to Marek's Disease Vaccines. AB - Marek's disease virus (MDV), a highly cell-associated lymphotropic alpha herpesvirus, is the causative agent of Marek's disease (MD) in domestic chickens. MDV replicates in chicken cells and establishes a latent infection within CD4+ T cells. Although MD vaccines have been in use for several decades, the exact mechanism of vaccine-induced protection is unclear. It is believed that the innate immune system plays a role in vaccine-induced immunity against pathogenic strains of MDV. To shed light on the possible function of the innate immunity in vaccine-mediated protection, we investigated the effect of vaccination, Rispens/CVI988, on the activation of cellular components of the innate immune system by analyzing the expression pattern of select immune-related genes in the cecal tonsils (CT) and duodenum of two MD-susceptible and MD-resistant chicken lines at 3, 5, and 10 days postvaccination (dpv). The differential expression patterns of the tested genes within the CT and duodenum of vaccinated birds revealed the activation of the innate immune system in both the susceptible and resistant lines. Stronger innate immune response was induced within the CT of the vaccinated birds of the susceptible line at 5 dpv. Upregulation of some of the tested genes at 10 dpv was likely due to the activation and response of the adaptive immune system to vaccination. Immunohistochemical analysis showed no increase in the number of CD3+ T cells in the CT and duodenum of the vaccinated birds of either line at 5 dpv. There was, however, an increase in the macrophage populations within the duodenum of the vaccinated birds of both the susceptible and resistant lines at 5 dpv. The vaccine strain antigen was detected in the CT and duodenum of the susceptible line, but not the resistant line at 5 dpv. PMID- 28346794 TI - Comparative Study of Xenobiotic-Free Media for the Cultivation of Human Limbal Epithelial Stem/Progenitor Cells. AB - The culture of human limbal epithelial stem/progenitor cells (LSCs) in the presence of animal components poses the risk of cross-species contamination in clinical applications. We quantitatively compared different xenobiotic-free culture media for the cultivation of human LSCs. LSCs were cultured from 2 * 2 mm limbal tissue explants on denuded human amniotic membrane with different xenobiotic-free culture media: CnT-Prime (CnT-PR) supplemented with 0%, 1%, 5%, and 10% human serum (HS), embryonic stem cell medium (ESCM) alone or in combination with the standard supplemented hormonal epithelium medium (SHEM, control) at a 1:1 dilution ratio, and modified SHEM (mSHEM), in which cholera toxin and dimethyl sulfoxide (DMSO) were removed, isoproterenol was added, and the epidermal growth factor concentration was reduced. Several parameters were quantified to assess the LSC phenotype: cell morphology, cell growth, cell size, outgrowth size, and expression of the undifferentiated LSC markers cytokeratin (K) 14, and p63alpha high-expressing (p63alphabright) cells, a mature keratinocyte marker K12, epithelial marker pancytokeratin (PanK), and stromal cell marker vimentin (Vim). Compared with the standard SHEM control, CnT-PR base medium was associated with a lower cell growth and reduction in the proportion of stem cells generated regardless of the amount of HS supplemented (p < 0.05); ESCM resulted in an increased proportion of PanK-/Vim+ stromal cells (p < 0.05) and a decreased proportion of p63alphabright cells (p < 0.05); mSHEM supported a similar cell growth (p > 0.05), increased the number of small cells (diameter <=12 MUm; p < 0.05), and provided a similar proportion of p63alphabright cells (p > 0.05). Among all the conditions tested, mSHEM was the most efficient and consistent in supporting the LSC phenotype and growth. PMID- 28346795 TI - Understanding the emission impacts of high-occupancy vehicle (HOV) to high occupancy toll (HOT) lane conversions: Experience from Atlanta, Georgia. AB - : Converting a congested high-occupancy vehicle (HOV) lane into a high-occupancy toll (HOT) lane is a viable option for improving travel time reliability for carpools and buses that use the managed lane. However, the emission impacts of HOV-to-HOT conversions are not well understood. The lack of emission impact quantification for HOT conversions creates a policy challenge for agencies making transportation funding choices. The goal of this paper is to evaluate the case study of before-and-after changes in vehicle emissions for the Atlanta, Georgia, I-85 HOV/HOT lane conversion project, implemented in October 2011. The analyses employed the Motor Vehicle Emission Simulator (MOVES) for project-level analysis with monitored changes in vehicle activity data collected by Georgia Tech researchers for the Georgia Department of Transportation (GDOT). During the quarterly field data collection from 2010 to 2012, more than 1.5 million license plates were observed and matched to vehicle class and age information using the vehicle registration database. The study also utilized the 20-sec, lane-specific traffic operations data from the Georgia NaviGAtor intelligent transportation system, as well as a direct feed of HOT lane usage data from the State Road and Tollway Authority (SRTA) managed lane system. As such, the analyses in this paper simultaneously assessed the impacts associated with changes in traffic volumes, on-road operating conditions, and fleet composition before and after the conversion. Both greenhouse gases and criteria pollutants were examined. IMPLICATIONS: A straight before-after analysis showed about 5% decrease in air pollutants and carbon dioxide (CO2). However, when the before-after calendar year of analysis was held constant (to account for the effect of 1 yr of fleet turnover), mass emissions at the analysis site during peak hours increased by as much as 17%, with little change in CO2. Further investigation revealed that a large percentage decrease in criteria pollutants in the straight before-after analysis was associated with a single calendar year change in MOVES. Hence, the Atlanta, Georgia, results suggest that an HOV-to-HOT conversion project may have increased mass emissions on the corridor. The results also showcase the importance of obtaining on-road data for emission impact assessment of HOV-to-HOT conversion projects. PMID- 28346797 TI - * Substituted Borosilicate Glasses with Improved Osteogenic Capacity for Bone Tissue Engineering. AB - Borosilicate bioactive glasses (BBGs) have shown the capacity to promote higher formation of new bone when compared with silicate bioactive glasses. Herein, we assessed the capacity of BBGs to induce osteogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs) as a function of their substituted divalent cations (Mg2+, Ca2+, Sr2+). To this purpose, we synthesized BBG particles by melt quenching. The cell viability, proliferation, and morphology (i.e., PrestoBlue(r), PicoGreen(r), and DAPI and Phalloidin stainings, respectively), as well as protein expression (i.e., alkaline phosphatase, ALP; osteopontin, OP; and osteocalcin, OC), of BM-MSCs in contact with BBGs were evaluated for 21 days. We observed an enhanced expression of bone-specific proteins (ALP, OP, and OC) and high mineralization of BM-MSCs under BBG-Mg and BBG-Sr-conditioned osteogenic media for concentrations of 20 and 50 mg/mL with low cytotoxic effects. Moreover, BBG-Sr, at a concentration of 50 mg/mL, was able to increase the mineralization and expression of the same bone-specific proteins even under basal medium conditions. These results indicated that the proposed BBGs improved osteogenic differentiation of BM-MSCs, therefore showing their potential as relevant biomaterials for bone tissue regeneration, not only by bonding to bone tissue but also by stimulating new bone formation. PMID- 28346796 TI - * Harnessing External Cues: Development and Evaluation of an In Vitro Culture System for Osteochondral Tissue Engineering. AB - Over the last decade, engineered structures have been developed for osteochondral (OC) tissue regeneration. While the optimal structure design is yet to be determined, these scaffolds require in vitro evaluation before clinical use. However, the means by which complex scaffolds, such as OC scaffolds, can be tested are limited. Taking advantage of a mesenchymal stem cell's (MSC's) ability to respond to its surrounding we harness external cues, such as the cell's mechanical environment and delivered factors, to create an in vitro culture system for OC tissue engineering with a single cell source on a gradient yet integrated scaffold system. To do this, the effect of hydrogel stiffness on the expression of human MSCs (hMSCs) chondrogenic differentiation was studied using histological analysis. Additionally, hMSCs were also cultured in different combinations of chondrogenic and osteogenic media to develop a co-differentiation media suitable for OC lineage differentiation. A uniquely graded (density gradient matrix) OC scaffold with a distal cartilage hydrogel phase specifically tailored to support chondrogenic differentiation was cultured using a newly developed "simulated in vivo culture method." The scaffold's culture in co differentiation media models hMSC infiltration into the scaffold and subsequent differentiation into the distal cartilage and proximal bone layers. Cartilage and bone marker staining along with specific matrix depositions reveal the effect of external cues on the hMSC differentiation. As a result of these studies a model system was developed to study and culture OC scaffolds in vitro. PMID- 28346798 TI - Priming Adipose Stem Cells with Tumor Necrosis Factor-Alpha Preconditioning Potentiates Their Exosome Efficacy for Bone Regeneration. AB - Mesenchymal stem cells (MSCs) have been widely used for tissue repair and regeneration. However, the inherent drawbacks, including limited cell survival after cell transplantation, have hindered direct MSC transplantation for tissue repair and regeneration. The aim of this study was to investigate if exosomes isolated from MSCs can promote the proliferation and differentiation of human primary osteoblastic cells (HOBs) and be potentially used for bone tissue regeneration. We showed that adipose tissue-derived MSC (ASC)-derived exosomes (ASC-EXO) were able to promote the proliferation and osteogenic differentiation in HOBs; and the trophic effects of ASC-EXO on HOBs were further harnessed when ASCs were preconditioned with tumor necrosis factor-alpha (TNF-alpha) for 3 days, which mimics the acute inflammatory phase upon bone injury. In addition, we showed that Wnt-3a content was elevated in ASC-EXO when ASCs were preconditioned by TNF-alpha, and inhibiting Wnt signaling decreased the osteogenic gene expression levels in HOBs which were cultured in TNF-alpha preconditioned ASCs conditioned medium. In conclusion, it was demonstrated that ASC-EXO, especially primed by TNF-alpha preconditioning on ASCs, offer a promising approach to replace direct stem cell transplantation for bone repair and regeneration. PMID- 28346799 TI - Activation of Macrophages by Lipopolysaccharide for Assessing the Immunomodulatory Property of Biomaterials. AB - The design paradigm of biomaterials has been changed to ones with favorable immunomodulatory effects, indicating the importance of accurately evaluating the immunomodulatory properties of biomaterials. Among all the immune cells macrophages receive most attention, due to their plasticity and multiple roles in the materials and host interactions, and thereby become model immune cells for the evaluation of immunomodulatory properties of biomaterials in many studies. Lipopolysaccharides (LPS), a polysaccharide in the outer membrane of Gram negative bacteria, elicit strong immune responses, which was often applied to activate macrophages, resulting in a proinflammatory M1 phenotype, and the release of proinflammatory cytokines, including tumor necrosis factor alpha (TNFalpha), interleukin (IL)-1, and IL-6. However, there is no consensus on how to apply macrophages and LPS to detect the immunomodulatory properties of biomaterials. The lack of scientific consideration of this issue has led to some inaccurate and insufficient conclusions on the immunomodulatory properties of biomaterials, and inconsistences between different research groups. In this study, we carried out a systemic study to investigate the stimulatory effects of LPS with different times, doses, and conditions on the activation of macrophages. An experimental pathway was proposed accordingly for the activation of macrophages using LPS for assessing the immunomodulatory property of biomaterials. PMID- 28346800 TI - Using Chemoinformatics, Bioinformatics, and Bioassay to Predict and Explain the Antibacterial Activity of Nonantibiotic Food and Drug Administration Drugs. AB - Discovering of new and effective antibiotics is a major issue facing scientists today. Luckily, the development of computer science offers new methods to overcome this issue. In this study, a set of computer software was used to predict the antibacterial activity of nonantibiotic Food and Drug Administration (FDA)-approved drugs, and to explain their action by possible binding to well known bacterial protein targets, along with testing their antibacterial activity against Gram-positive and Gram-negative bacteria. A three-dimensional virtual screening method that relies on chemical and shape similarity was applied using rapid overlay of chemical structures (ROCS) software to select candidate compounds from the FDA-approved drugs database that share similarity with 17 known antibiotics. Then, to check their antibacterial activity, disk diffusion test was applied on Staphylococcus aureus and Escherichia coli. Finally, a protein docking method was applied using HYBRID software to predict the binding of the active candidate to the target receptor of its similar antibiotic. Of the 1,991 drugs that were screened, 34 had been selected and among them 10 drugs showed antibacterial activity, whereby drotaverine and metoclopramide activities were without precedent reports. Furthermore, the docking process predicted that diclofenac, drotaverine, (S)-flurbiprofen, (S)-ibuprofen, and indomethacin could bind to the protein target of their similar antibiotics. Nevertheless, their antibacterial activities are weak compared with those of their similar antibiotics, which can be potentiated further by performing chemical modifications on their structure. PMID- 28346801 TI - Our 15th Anniversary Issue. PMID- 28346802 TI - Metabolome Profiling of Partial and Fully Reprogrammed Induced Pluripotent Stem Cells. AB - Acquisition of proper metabolomic fate is required to convert somatic cells toward fully reprogrammed pluripotent stem cells. The majority of induced pluripotent stem cells (iPSCs) are partially reprogrammed and have a transcriptome different from that of the pluripotent stem cells. The metabolomic profile and mitochondrial metabolic functions required to achieve full reprogramming of somatic cells to iPSC status have not yet been elucidated. Clarification of the metabolites underlying reprogramming mechanisms should enable further optimization to enhance the efficiency of obtaining fully reprogrammed iPSCs. In this study, we characterized the metabolites of human fully reprogrammed iPSCs, partially reprogrammed iPSCs, and embryonic stem cells (ESCs). Using capillary electrophoresis time-of-flight mass spectrometry-based metabolomics, we found that 89% of analyzed metabolites were similarly expressed in fully reprogrammed iPSCs and human ESCs (hESCs), whereas partially reprogrammed iPSCs shared only 74% similarly expressed metabolites with hESCs. Metabolomic profiling analysis suggested that converting mitochondrial respiration to glycolytic flux is critical for reprogramming of somatic cells into fully reprogrammed iPSCs. This characterization of metabolic reprogramming in iPSCs may enable the development of new reprogramming parameters for enhancing the generation of fully reprogrammed human iPSCs. PMID- 28346803 TI - Carbapenemase-Producing Aeromonas veronii Disseminated in the Environment of an Equine Specialty Hospital. AB - The emergence of bacterial resistance to carbapenem antibiotics is an urgent public health threat. Carbapenem drugs are a last resort treatment option for life-threatening infections. The frequent use of broad-spectrum antibiotics to treat hospitalized patients provides significant selection pressure favoring the emergence and dissemination of resistant organisms, including carbapenem resistant Enterobacteriaceae (CRE). CREs have been reported in animal populations, but only rarely in horses. Our objective was to determine the prevalence of CRE in the environment of a referral equine specialty hospital. Environmental samples were collected on seven different sampling dates. Four clonal carbapenemase-producing Aeromonas veronii were recovered from 315 sampled surfaces (1.3%). All four isolates harbored the carbapenemase-producing, metallo beta-lactamase gene blacphA, although corresponding minimum inhibitory concentrations were within the susceptible range for imipenem and meropenem. All had an identical multilocus sequence type with a previously unreported allelic profile and contained multiple plasmids. To our knowledge, this recovery of blacphA-harboring A. veronii is the first report of carbapenemase-producing bacteria in the environment of an equine veterinary hospital. However, the low recovery rate suggests that environmental contamination is uncommon. Appropriate hospital cleaning and disinfection protocols are necessary to maintain a low risk of contamination for patients and personnel. PMID- 28346804 TI - Hepatitis B and C Virus Infections Among Human Immunodeficiency Virus-Infected People Who Inject Drugs in Lahore, Pakistan. AB - Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the major cause of the global burden of hepatitis. One of the main routes of transmission for both viruses is through exposure to infected blood, which includes sharing blood contaminated syringes and needles. Human immunodeficiency virus (HIV) attacks the immune system and results in acquired immune deficiency syndrome and opportunistic infections. The objective of this study was to assess the epidemiology of HBV and HCV infections among HIV-infected people who inject drugs (PWID). The study enrolled 100 PWID from different addiction centers of the city of Lahore in Pakistan. All subjects were HIV-infected males and were above 16 years of age. Screening of HBV and HCV infections was performed through immunochromatography tests and enzyme-linked immunosorbent assays. The prevalence of HCV and HBV infections among the 100 HIV-infected PWID was 55% and 6%, respectively. HIV monoinfection was found in 37% of the subjects, while triple infection was detected in 2% of the subjects. Majority of the HIV-infected PWID were using heroin and Avil injections (65%). Half of the subjects had used injection drugs for 1-5 years, while 32% had used injection drugs for 6-10 years. HCV infection was more common than HBV infection among the enrolled subjects. Most of the PWID were practicing heroin and Avil injections. PMID- 28346805 TI - Brachytherapy for Patients With Prostate Cancer: American Society of Clinical Oncology/Cancer Care Ontario Joint Guideline Update. AB - Purpose To jointly update the Cancer Care Ontario guideline on brachytherapy for patients with prostate cancer to account for new evidence. Methods An Update Panel conducted a targeted systematic literature review and identified more recent randomized controlled trials comparing dose-escalated external beam radiation therapy (EBRT) with brachytherapy in men with prostate cancer. Results Five randomized controlled trials provided the evidence for this update. Recommendations For patients with low-risk prostate cancer who require or choose active treatment, low-dose rate brachytherapy (LDR) alone, EBRT alone, and/or radical prostatectomy (RP) should be offered to eligible patients. For patients with intermediate-risk prostate cancer choosing EBRT with or without androgen deprivation therapy, brachytherapy boost (LDR or high-dose rate [HDR]) should be offered to eligible patients. For low-intermediate risk prostate cancer (Gleason 7, prostate-specific antigen < 10 ng/mL or Gleason 6, prostate-specific antigen, 10 to 20 ng/mL), LDR brachytherapy alone may be offered as monotherapy. For patients with high-risk prostate cancer receiving EBRT and androgen-deprivation therapy, brachytherapy boost (LDR or HDR) should be offered to eligible patients. Iodine-125 and palladium-103 are each reasonable isotope options for patients receiving LDR brachytherapy; no recommendation can be made for or against using cesium-131 or HDR monotherapy. Patients should be encouraged to participate in clinical trials to test novel or targeted approaches to this disease. Additional information is available at www.asco.org/Brachytherapy-guideline and www.asco.org/guidelineswiki . PMID- 28346807 TI - Is Low-Risk Prostate Cancer More Indolent in Younger Patients? PMID- 28346806 TI - Active Surveillance in Younger Men With Prostate Cancer. AB - Purpose The suitability of younger patients with prostate cancer (PCa) for initial active surveillance (AS) has been questioned on the basis of eventual treatment necessity and concerns of safety; however, the role of age on surveillance outcomes has not been well defined. Patients and Methods We identified men managed with AS at our institution with a minimum follow-up of 6 months. The primary study objective was to examine the association of age with risk of biopsy-based Gleason score upgrade during AS. We also examined the association of age with related end points, including overall biopsy-determined progression, definitive treatment, and pathologic and biochemical outcomes after delayed radical prostatectomy (RP), using descriptive statistics, the Kaplan Meier method, and multivariable Cox proportional hazards regression. Results A total of 1,433 patients were followed for a median of 49 months; 74% underwent initial biopsy at a referring institution. Median age at diagnosis was 63 years, including 599 patients (42%) <= 60 years old and 834 (58%) > 60 years old. The 3- and 5-year biopsy-based Gleason score upgrade-free rates were 73% and 55%, respectively, for men <= 60 years old compared with 64% and 48%, respectively, for men older than 60 years ( P < .01). On Cox regression analysis, younger age was independently associated with lower risk of biopsy-based Gleason score upgrade (hazard ratio per 1-year decrease, 0.969 [95% CI, 0.956 to 0.983]; P < .01), and persisted upon restriction to men meeting strict AS inclusion criteria. There was no significant association between younger age and risk of definitive treatment or risk of biochemical recurrence after delayed RP. Conclusion Younger patient age was associated with decreased risk of biopsy-based Gleason score upgrade during AS but not with risk of definitive treatment in the intermediate term. AS represents a strategy to mitigate overtreatment in young patients with low-risk PCa in the early term. PMID- 28346810 TI - An Automated Multiplexed Hepatotoxicity and CYP Induction Assay Using HepaRG Cells in 2D and 3D. AB - Drug-induced liver injury (DILI) and drug-drug interactions (DDIs) are concerns when developing safe and efficacious compounds. We have developed an automated multiplex assay to detect hepatotoxicity (i.e., ATP depletion) and metabolism (i.e., cytochrome P450 1A [CYP1A] and cytochrome P450 3A4 [CYP3A4] enzyme activity) in two-dimensional (2D) and three-dimensional (3D) cell cultures. HepaRG cells were cultured in our proprietary micromold plates and produced spheroids. HepaRG cells, in 2D or 3D, expressed liver-specific proteins throughout the culture period, although 3D cultures consistently exhibited higher albumin secretion and CYP1A/CYP3A4 enzyme activity than 2D cultures. Once the spheroid hepatic quality was assessed, 2D and 3D HepaRGs were challenged to a panel of DILI- and CYP-inducing compounds for 7 days. The 3D HepaRG model had a 70% sensitivity to liver toxins at 7 days, while the 2D model had a 60% sensitivity. In both the 2D and 3D HepaRG models, 83% of compounds were predicted to be CYP inducers after 7 days of compound exposure. Combined, our results demonstrate that an automated multiplexed liver spheroid system is a promising cell-based method to evaluate DILI and DDI for early-stage drug discovery. PMID- 28346808 TI - Patient-Reported Outcomes 1 Year After Immediate Breast Reconstruction: Results of the Mastectomy Reconstruction Outcomes Consortium Study. AB - Purpose The goals of immediate postmastectomy breast reconstruction are to minimize deformity and optimize quality of life as perceived by patients. We prospectively evaluated patient-reported outcomes (PROs) in women undergoing immediate implant-based or autologous reconstruction. Methods Women undergoing immediate postmastectomy reconstruction for invasive cancer and/or carcinoma in situ were enrolled at 11 sites. Women underwent implant-based or autologous tissue reconstruction. Patients completed the BREAST-Q, a condition-specific PRO measure for breast surgery patients, and Patient-Reported Outcomes Measurement Information System-29, a generic PRO measure, before and 1 year after surgery. Mean changes in PRO scores were summarized. Mixed-effects regression models were used to compare PRO scores across procedure types. Results In total, 1,632 patients (n = 1,139 implant, n = 493 autologous) were included; 1,183 (72.5%) responded to 1-year questionnaires. After analysis was controlled for baseline values, patients who underwent autologous reconstruction had greater satisfaction with their breasts than those who underwent implant-based reconstruction (difference, 6.3; P < .001), greater sexual well-being (difference, 4.5; P = .003), and greater psychosocial well-being (difference, 3.7; P = .02) at 1 year. Patients in the autologous reconstruction group had improved satisfaction with breasts (difference, 8.0; P = .002) and psychosocial well-being (difference, 4.6; P = .047) compared with preoperative baseline. Physical well-being of the chest was not fully restored in either the implant group (difference, -3.8; P = .001) or autologous group (-2.2; P = .04), nor was physical well-being of the abdomen in patients who underwent autologous reconstruction (-13.4; P < .001). Anxiety and depression were mitigated at 1 year in both groups. Compared with their baseline reports, patients who underwent implant reconstruction had decreased fatigue (difference, -1.4; P = .035), whereas patients who underwent autologous reconstruction had increased pain interference (difference, 2.0; P = .006). Conclusion At 1 year after mastectomy, patients who underwent autologous reconstruction were more satisfied with their breasts and had greater psychosocial and sexual well-being than those who underwent implant reconstruction. Although satisfaction with breasts was equal to or greater than baseline levels, physical well-being was not fully restored. This information can help patients better understand expected outcomes and may guide innovations to improve outcomes. PMID- 28346809 TI - MALAT1 promotes osteosarcoma development by regulation of HMGB1 via miR-142-3p and miR-129-5p. AB - Recently, emerging evidence has demonstrated that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long non-coding RNAs (lncRNAs), contributes to the initiation and development of tumors, including osteosarcoma (OS). Multiple studies have suggested an oncogenic role of MALAT1 and high mobility group protein B1 (HMGB1) in OS tumorigenesis and metastasis, but the effects and mechanisms are not unanimous. Here, we showed that MALAT1 and HMGB1 were significantly increased in human OS cell lines and knockdown of MALAT1 reduced HMGB1 expression. By using online tools, we screen out 2 candidate miRNAs, miR-142-3p and miR-129-5p which may be associated with both MALAT1 and HMGB1. Luciferase reporter assay revealed a direct interaction between the 2 miRNAs and MALAT1, respectively, via a putative binding site within MALAT1. Meanwhile, both the 2 miRNAs could bind to HMGB1 3'-untranslated region (3'-UTR) and regulate HMGB1 expression. Moreover, knockdown of MALAT1 decreased HMGB1 expression, inhibited OS cell growth and promoted apoptosis, while miR-142-3p and miR-129-5p inhibitor partly restored the inhibitory effect of MALAT1 knockdown on HMGB1 expression, OS cell growth and the promotion of apoptosis. In OS tissues, the expression of MALAT1 and HMGB1 was upregulated while the expression of miR 142-3p and miR-129-5p was downregulated. Together, our results support a MALAT1/miR-142-3p/miR-129-5p/HMGB1 axis in OS cell proliferation and tumor progression. MALAT1 promoted OS cell growth through inhibition of miR-142-3p or miR-129-5p and by targeting HMGB1. PMID- 28346811 TI - Improved Soluble ScFv ELISA Screening Approach for Antibody Discovery Using Phage Display Technology. AB - Phage display technology (PDT) is a powerful tool for the isolation of recombinant antibody (Ab) fragments. Using PDT, target molecule-specific phage-Ab clones are enriched through the "biopanning" process. The individual specific binders are screened by the monoclonal scFv enzyme-linked immunosorbent assay (ELISA) that may associate with inevitable false-negative results. Thus, in this study, three strategies were investigated for optimization of the scFvs screening using Tomlinson I and J libraries, including (1) optimizing the expression of functional scFvs, (2) improving the sensitivity of ELISA, and (3) preparing different samples containing scFvs. The expression of all scFv Abs was significantly enhanced when scFv clones were cultivated in the terrific broth (TB) medium at the optimum temperature of 30 degrees C. The protein A-conjugated with horseradish peroxidase (HRP) was found to be a well-suited reagent for the detection of Ag-bound scFvs in comparison with either anti-c-myc Ab or the mixing procedure. Based on our findings, it seems there is no universal media supplement for an improved expression of all scFvs derived from both Tomlinson I and J libraries. We thus propose that expression of scFv fragments in a microplate scale is largely dependent on a variety of parameters, in particular the scFv clones and relevant sequences. PMID- 28346812 TI - Identification of a Novel Benzimidazole Pyrazolone Scaffold That Inhibits KDM4 Lysine Demethylases and Reduces Proliferation of Prostate Cancer Cells. AB - Human lysine demethylase (KDM) enzymes (KDM1-7) constitute an emerging class of therapeutic targets, with activities that support growth and development of metastatic disease. By interacting with and co-activating the androgen receptor, the KDM4 subfamily (KDM4A-E) promotes aggressive phenotypes of prostate cancer (PCa). Knockdown of KDM4 expression or inhibition of KDM4 enzyme activity reduces the proliferation of PCa cell lines and highlights inhibition of lysine demethylation as a possible therapeutic method for PCa treatment. To address this possibility, we screened the ChemBioNet small molecule library for inhibitors of the human KDM4E isoform and identified several compounds with IC50 values in the low micromolar range. Two hits, validated as active by an orthogonal enzyme linked immunosorbent assay, displayed moderate selectivity toward the KDM4 subfamily and exhibited antiproliferative effects in cellular models of PCa. These compounds were further characterized by their ability to maintain the transcriptionally silent histone H3 tri-methyl K9 epigenetic mark at subcytotoxic concentrations. Taken together, these efforts identify and validate a hydroxyquinoline scaffold and a novel benzimidazole pyrazolone scaffold as tractable for entry into hit-to-lead chemical optimization campaigns. PMID- 28346813 TI - Protein Supplementation Does Not Affect Myogenic Adaptations to Resistance Training. AB - : It has been proposed that protein supplementation during resistance exercise training enhances muscle hypertrophy. The degree of hypertrophy during training is controlled in part through the activation of satellite cells and myonuclear accretion. PURPOSE: This study aimed to determine the efficacy of protein supplementation (and the type of protein) during traditional resistance training on myofiber cross-sectional area, satellite cell content, and myonuclear addition. METHODS: Healthy young men participated in supervised whole-body progressive resistance training 3 d.wk for 12 wk. Participants were randomized to one of three groups ingesting a daily 22-g macronutrient dose of soy-dairy protein blend (PB, n = 22), whey protein isolate (WP, n = 15), or an isocaloric maltodextrin placebo (MDP, n = 17). Lean mass, vastus lateralis myofiber-type specific cross-sectional area, satellite cell content, and myonuclear addition were assessed before and after resistance training. RESULTS: PB and the pooled protein treatments (PB + WP = PRO) exhibited a greater whole-body lean mass %change compared with MDP (P = 0.057 for PB) and (P = 0.050 for PRO), respectively. All treatments demonstrated similar leg muscle hypertrophy and vastus lateralis myofiber-type-specific cross-sectional area (P < 0.05). Increases in myosin heavy chain I and II myofiber satellite cell content and myonuclei content were also detected after exercise training (P < 0.05). CONCLUSION: Protein supplementation during resistance training has a modest effect on whole-body lean mass as compared with exercise training without protein supplementation, and there was no effect on any outcome between protein supplement types (blend vs whey). However, protein supplementation did not enhance resistance exercise-induced increases in myofiber hypertrophy, satellite cell content, or myonuclear addition in young healthy men. We propose that as long as protein intake is adequate during muscle overload, the adaptations in muscle growth and function will not be influenced by protein supplementation. PMID- 28346814 TI - Nicotinamide riboside, a form of vitamin B3 and NAD+ precursor, relieves the nociceptive and aversive dimensions of paclitaxel-induced peripheral neuropathy in female rats. AB - Injury to sensory afferents may contribute to the peripheral neuropathies that develop after administration of chemotherapeutic agents. Manipulations that increase levels of nicotinamide adenine dinucleotide (NAD) can protect against neuronal injury. This study examined whether nicotinamide riboside (NR), a third form of vitamin B3 and precursor of NAD, diminishes tactile hypersensitivity and place escape-avoidance behaviors in a rodent model of paclitaxel-induced peripheral neuropathy. Female Sprague-Dawley rats received 3 intravenous injections of 6.6 mg/kg paclitaxel over 5 days. Daily oral administration of 200 mg/kg NR beginning 7 days before paclitaxel treatment and continuing for another 24 days prevented the development of tactile hypersensitivity and blunted place escape-avoidance behaviors. These effects were sustained after a 2-week washout period. This dose of NR increased blood levels of NAD by 50%, did not interfere with the myelosuppressive effects of paclitaxel, and did not produce adverse locomotor effects. Treatment with 200 mg/kg NR for 3 weeks after paclitaxel reversed the well-established tactile hypersensitivity in a subset of rats and blunted escape-avoidance behaviors. Pretreatment with 100 mg/kg oral acetyl-L carnitine (ALCAR) did not prevent paclitaxel-induced tactile hypersensitivity or blunt escape-avoidance behaviors. ALCAR by itself produced tactile hypersensitivity. These findings suggest that agents that increase NAD, a critical cofactor for mitochondrial oxidative phosphorylation systems and cellular redox systems involved with fuel utilization and energy metabolism, represent a novel therapeutic approach for relief of chemotherapy-induced peripheral neuropathies. Because NR is a vitamin B3 precursor of NAD and a nutritional supplement, clinical tests of this hypothesis may be accelerated. PMID- 28346815 TI - Improvement of identification methods for honeybee specific Lactic Acid Bacteria; future approaches. AB - Honeybees face many parasites and pathogens and consequently rely on a diverse set of individual and group-level defenses to prevent disease. The crop microbiota of Apis mellifera, composed of 13 Lactic Acid Bacterial (LAB) species within the genera Lactobacillus and Bifidobacterium, form a beneficial symbiotic relationship with each other and the honeybee to protect their niche and their host. Possibly playing a vital role in honeybee health, it is important that these honeybee specific Lactic Acid Bacterial (hbs-LAB) symbionts can be correctly identified, isolated and cultured, to further investigate their health promoting properties. We have previously reported successful identification to the strain level by culture-dependent methods and we recently sequenced and annotated the genomes of the 13 hbs-LAB. However, the hitherto applied techniques are unfortunately very time consuming, expensive and not ideal when analyzing a vast quantity of samples. In addition, other researchers have constantly failed to identify the 13 hbs-LAB from honeybee samples by using inadequate media and/or molecular techniques based on 16S rRNA gene sequencing with insufficient discriminatory power. The aim of this study was to develop better and more suitable methods for the identification and cultivation of hbs-LAB. We compared currently used bacterial cultivation media and could for the first time demonstrate a significant variation in the hbs-LAB basic requirements for optimal growth. We also present a new bacterial identification approach based on amplicon sequencing of a region of the 16S rRNA gene using the Illumina platform and an error correction software that can be used to successfully differentiate and rapidly identify the 13 hbs-LAB to the strain level. PMID- 28346816 TI - Child-Adult Differences in Using Dual-Task Paradigms to Measure Listening Effort. AB - Purpose: The purpose of the project was to investigate the effects modifying the secondary task in a dual-task paradigm to measure objective listening effort. To be specific, the complexity and depth of processing were increased relative to a simple secondary task. Method: Three dual-task paradigms were developed for school-age children. The primary task was word recognition. The secondary task was a physical response to a visual probe (simple task), a physical response to a complex probe (increased complexity), or word categorization (increased depth of processing). Sixteen adults (22-32 years, M = 25.4) and 22 children (9-17 years, M = 13.2) were tested using the 3 paradigms in quiet and noise. Results: For both groups, manipulations of the secondary task did not affect word recognition performance. For adults, increasing depth of processing increased the calculated effect of noise; however, for children, results with the deep secondary task were the least stable. Conclusions: Manipulations of the secondary task differentially affected adults and children. Consistent with previous findings, increased depth of processing enhanced paradigm sensitivity for adults. However, younger participants were more likely to demonstrate the expected effects of noise on listening effort using a secondary task that did not require deep processing. PMID- 28346818 TI - Regulation of low temperature stress in plants by microRNAs. AB - Low temperature is one of the most common environmental stresses that seriously affect the growth and development of plants. However, plants have the plasticity in their defence mechanisms enabling them to tolerate and, sometimes, even survive adverse environmental conditions. MicroRNAs (miRNAs) are small non-coding RNAs, approximately 18-24 nucleotides in length, and are being increasingly recognized as regulators of gene expression at the post-transcriptional level and have the ability to influence a broad range of biological processes. There is growing evidence in the literature that reprogramming of gene expression mediated through miRNAs is a major defence mechanism in plants enabling them to respond to stresses. To date, numerous studies have established the importance of miRNA based regulation of gene expression under low temperature stress. Individual miRNAs can modulate the expression of multiple mRNA targets, and, therefore, the manipulation of a single miRNA has the potential to affect multiple biological processes. Numerous functional studies have attempted to identify the miRNA target interactions and have elaborated the role of several miRNAs in cold-stress regulation. This review summarizes the current understanding of miRNA-mediated modulation of the expression of key genes as well as genetic and regulatory pathways, involved in low temperature stress responses in plants. PMID- 28346817 TI - The psychosocial work environment is associated with risk of stroke at working age. AB - Objective The aim of this study was to explore the relation between the risk of first-ever stroke at working age and psychological work environmental factors. Methods A consecutive multicenter matched 1:2 case-control study of acute stroke cases (N=198, age 30-65 years) who had been working full-time at the time of their stroke and 396 sex- and age-matched controls. Stroke cases and controls answered questionnaires on their psychosocial situation during the previous 12 months. The psychosocial work environment was assessed using three different measures: the job-control-demand model, the effort-reward imbalance (ERI) score, and exposures to conflict at work. Results Among 198 stroke cases and 396 controls, job strain [odds ratio (OR) 1.30, 95% confidence interval (95% CI) 1.05 1.62], ERI (OR 1.28, 95% CI 1.01-1.62), and conflict at work (OR 1.75, 95% CI 1.07-2.88) were independent risk factors of stroke in multivariable regression models. Conclusions Adverse psychosocial working conditions during the past 12 months were more frequently observed among stroke cases. Since these factors are presumably modifiable, interventional studies targeting job strain and emotional work environment are warranted. PMID- 28346819 TI - Parametric overdispersed frailty models for current status data. AB - Frailty models have a prominent place in survival analysis to model univariate and multivariate time-to-event data, often complicated by the presence of different types of censoring. In recent years, frailty modeling gained popularity in infectious disease epidemiology to quantify unobserved heterogeneity using Type I interval-censored serological data or current status data. In a multivariate setting, frailty models prove useful to assess the association between infection times related to multiple distinct infections acquired by the same individual. In addition to dependence among individual infection times, overdispersion can arise when the observed variability in the data exceeds the one implied by the model. In this article, we discuss parametric overdispersed frailty models for time-to-event data under Type I interval-censoring, building upon the work by Molenberghs et al. (2010) and Hens et al. (2009). The proposed methodology is illustrated using bivariate serological data on hepatitis A and B from Flanders, Belgium anno 1993-1994. Furthermore, the relationship between individual heterogeneity and overdispersion at a stratum-specific level is studied through simulations. Although it is important to account for overdispersion, one should be cautious when modeling both individual heterogeneity and overdispersion based on current status data as model selection is hampered by the loss of information due to censoring. PMID- 28346820 TI - Blastomyces dermatitidis serine protease dipeptidyl peptidase IVA (DppIVA) cleaves ELR+ CXC chemokines altering their effects on neutrophils. AB - Blastomycosis elicits a pyogranulomatous inflammatory response that involves a prominent recruitment of neutrophils to the site of infection. Although neutrophils are efficiently recruited to the site of infection, this event is paradoxically coupled with the host's inability to control infection by Blastomyces dermatitidis, the causative agent. The mechanisms underlying this characteristic pyogranulomatous response and inability of neutrophils to kill the yeast are poorly understood. We recently reported that the fungal protease dipeptidyl peptidase IVA (DppIVA) promotes B. dermatitidis virulence by cleaving a dipeptide from the N-terminus of C-C chemokines and granulocyte/macrophage colony stimulating factor, thereby inactivating them. Herein, we present evidence that DppIVA can also truncate the N-terminus of members of the ELR+ CXC chemokine family, which are known to modulate neutrophil function. We show that the DppIVA cleaved form of human (h) CXCL-2, for example, hCXCL-2 (3-73), is a more potent neutrophil chemoattractant than its intact counterpart, but hCXCL-2 (3-73) is conversely impaired in its ability to prime the reactive oxygen species response of neutrophils. Thus, DppIVA action on ELR+ CXC chemokines may promote the pyogranulomatous response that is typical of blastomycosis, while also explaining the inability of neutrophils to control infection. PMID- 28346822 TI - Sensitivity analysis for matched pair analysis of binary data: From worst case to average case analysis. AB - In matched observational studies where treatment assignment is not randomized, sensitivity analysis helps investigators determine how sensitive their estimated treatment effect is to some unmeasured confounder. The standard approach calibrates the sensitivity analysis according to the worst case bias in a pair. This approach will result in a conservative sensitivity analysis if the worst case bias does not hold in every pair. In this paper, we show that for binary data, the standard approach can be calibrated in terms of the average bias in a pair rather than worst case bias. When the worst case bias and average bias differ, the average bias interpretation results in a less conservative sensitivity analysis and more power. In many studies, the average case calibration may also carry a more natural interpretation than the worst case calibration and may also allow researchers to incorporate additional data to establish an empirical basis with which to calibrate a sensitivity analysis. We illustrate this with a study of the effects of cellphone use on the incidence of automobile accidents. Finally, we extend the average case calibration to the sensitivity analysis of confidence intervals for attributable effects. PMID- 28346823 TI - Design and monitoring of multi-arm multi-stage clinical trials. AB - Two-arm group sequential designs have been widely used for over 40 years, especially for studies with mortality endpoints. The natural generalization of such designs to trials with multiple treatment arms and a common control (MAMS designs) has, however, been implemented rarely. While the statistical methodology for this extension is clear, the main limitation has been an efficient way to perform the computations. Past efforts were hampered by algorithms that were computationally explosive. With the increasing interest in adaptive designs, platform designs, and other innovative designs that involve multiple comparisons over multiple stages, the importance of MAMS designs is growing rapidly. This article provides break-through algorithms that can compute MAMS boundaries rapidly thereby making such designs practical. For designs with efficacy-only boundaries the computational effort increases linearly with number of arms and number of stages. For designs with both efficacy and futility boundaries the computational effort doubles with successive increases in number of stages. PMID- 28346821 TI - Structure-Activity Relationships on Cinnamoyl Derivatives as Inhibitors of p300 Histone Acetyltransferase. AB - Human p300 is a polyhedric transcriptional coactivator that plays a crucial role in acetylating histones on specific lysine residues. A great deal of evidence shows that p300 is involved in several diseases, including leukemia, tumors, and viral infection. Its involvement in pleiotropic biological roles and connections to diseases provide the rationale to determine how its modulation could represent an amenable drug target. Several p300 inhibitors (i.e., histone acetyltransferase inhibitors, HATis) have been described so far, but they all suffer from low potency, lack of specificity, or low cell permeability, which thus highlights the need to find more effective inhibitors. Our cinnamoyl derivative, 2,6-bis(3-bromo 4-hydroxybenzylidene)cyclohexanone (RC56), was identified as an active and selective p300 inhibitor and was proven to be a good hit candidate to investigate the structure-activity relationship toward p300. Herein, we describe the design, synthesis, and biological evaluation of new HATis structurally related to our hit; moreover, we investigate the interactions between p300 and the best-emerged hits by means of induced-fit docking and molecular-dynamics simulations, which provided insight into the peculiar chemical features that influence their activity toward the targeted enzyme. PMID- 28346825 TI - Fabrication of NiCo2-Anchored Graphene Nanosheets by Liquid-Phase Exfoliation for Excellent Microwave Absorbers. AB - Graphene nanosheets (GNSs) were prepared by an efficient liquid-phase exfoliation method, and then the NiCo2/GNS nanohybrids were fabricated using the single-mode microwave-assisted hydrothermal technique. The NiCo2/GNS composites with different GNS proportions were investigated as microwave absorbers. Morphology investigation suggested that NiCo2 nanocrystals were uniformly anchored on the GNS without aggregation. The electromagnetic parameters of NiCo2/GNS nanohybrids could be artificially adjusted by changing the GNS proportion, which led to an exceptional microwave-absorbing performance. A reflection loss (RL) exceeding -20 dB was obtained in the frequency range of 5.3-16.4 GHz for the absorber thicknesses of 1.2-3.2 mm, while an optimal RL of -30 dB was achieved at 11.7 GHz for a thickness of 1.6 mm. The enhanced microwave-absorbing performance indicated that the NiCo2/10 wt % GNS composite has great potential for use as an excellent microwave absorber. PMID- 28346824 TI - Weighted pseudolikelihood for SNP set analysis with multiple secondary outcomes in case-control genetic association studies. AB - We propose a weighted pseudolikelihood method for analyzing the association of a SNP set, example, SNPs in a gene or a genetic pathway or network, with multiple secondary phenotypes in case-control genetic association studies. To boost analysis power, we assume that the SNP-specific effects are shared across all secondary phenotypes using a scaled mean model. We estimate regression parameters using Inverse Probability Weighted (IPW) estimating equations obtained from the weighted pseudolikelihood, which accounts for case-control sampling to prevent potential ascertainment bias. To test the effect of a SNP set, we propose a weighted variance component pseudo-score test. We also propose a penalized IPW pseudolikelihood method for selecting a subset of SNPs that are associated with the multiple secondary phenotypes. We show that the proposed variable selection procedure has the oracle properties and is robust to misspecification of the correlation structure among secondary phenotypes. We select the tuning parameter using a weighted Bayesian Information-like Criterion (wBIC). We evaluate the finite sample performance of the proposed methods via simulations, and illustrate the methods by the analysis of the multiple secondary smoking behavior outcomes in a lung cancer case-control genetic association study. PMID- 28346826 TI - Imaging Successive Intermediate States of the On-Surface Ullmann Reaction on Cu(111): Role of the Metal Coordination. AB - The in-depth knowledge about on-surface reaction mechanisms is crucial for the tailor-made design of covalently bonded organic frameworks, for applications such as nanoelectronic or -optical devices. Latest developments in atomic force microscopy, which rely on functionalizing the tip with single CO molecules at low temperatures, allow to image molecular systems with submolecular resolution. Here, we are using this technique to study the complete reaction pathway of the on-surface Ullmann-type coupling between bromotriphenylene molecules on a Cu(111) surface. All steps of the Ullmann reaction, i.e., bromotriphenylenes, triphenylene radicals, organometallic intermediates, and bistriphenylenes, were imaged with submolecular resolution. Together with density functional theory calculations with dispersion correction, our study allows to address the long standing question of how the organometallic intermediates are coordinated via Cu surface or adatoms. PMID- 28346827 TI - Effects of Cerium Oxide and Ferrocene Nanoparticles Addition As Fuel-Borne Catalysts on Diesel Engine Particulate Emissions: Environmental and Health Implications. AB - This study systematically examined the potential impacts of doping CeO2 and Fe(C5H5)2 nanoparticles as fuel-borne catalysts (FBCs) to ultralow sulfur diesel (ULSD) fuel on the physical, chemical and toxicological characteristics of diesel particulate matter (DPM). The FBCs-doped fuels are effective in promoting soot oxidation and reducing the DPM mass emissions, but lead to a significant increase in the total particle counts due to the formation of self-nucleated metallic nanoparticles. Compared to undoped ULSD, the FBCs-doped fuels result in higher concentrations of particle-phase polycyclic aromatic hydrocarbons (PAHs) and n alkanes, higher fractions of organic carbon (OC) and water-soluble organic carbon (WSOC) in particles, show slight alterations in soot nanostructure, reduce soot ignition temperature and activation energy. Exposure of the human-type II cell alveolar epithelial cells (A549) to DPM derived from FBCs-doped fuels shows a decrease in cell viability and alterations in the global gene expression with a broad range of biochemical pathways. The overall variations in DPM characteristics are mainly caused by the catalytic combustion process, and are related to the type, properties and contents of FBCs used in diesel fuel as well as the engine operating conditions. Environmental and health implications of the study are highlighted. PMID- 28346828 TI - Chemical Transformation of Colloidal Nanostructures with Morphological Preservation by Surface-Protection with Capping Ligands. AB - When nanocrystals are made to undergo chemical transformations, there are often accompanying large mechanical deformations and changes to overall particle morphology. These effects can constrain development of multistep synthetic methods through loss of well-defined particle morphology and functionality. Here, we demonstrate a surface protection strategy for solution phase chemical conversion of colloidal nanostructures that allows for preservation of overall particle morphology despite large volume changes. Specifically, via stabilization with strong coordinating capping ligands, we demonstrate the effectiveness of this method by transforming beta-FeOOH nanorods into magnetic Fe3O4 nanorods, which are known to be difficult to produce directly. The surface-protected conversion strategy is believed to represent a general self-templating method for nanocrystal synthesis, as confirmed by applying it to the chemical conversion of nanostructures of other morphologies (spheres, rods, cubes, and plates) and compositions (hydroxides, oxides, and metal organic frameworks). PMID- 28346829 TI - Polymorphisms in the Glucocorticoid Receptor Gene and Associations with Glucocorticoid-Induced Avascular Osteonecrosis of the Femoral Head. AB - AIMS: Individual sensitivity to glucocorticoid (GC) therapy might play a pivotal role in the development of GC-induced avascular necrosis of the femoral head (GANFH). In a growing number of studies, common polymorphisms of the glucocorticoid receptor gene (nuclear receptor subfamily 3 group C member 1 [NR3C1]) have been associated with variability in the individual sensitivity to GCs. However, whether the NR3C1 gene polymorphisms actually influence the susceptibility of GANFH remains unknown. METHODS: In this study, we report the findings of a case-control study to investigate the role of the NR3C1 gene single nucleotide polymorphisms (SNPs) in GANFH susceptibility among 78 GANFH patients (GCs sensitive) and 115 GC-resistant controls. RESULTS: Our results found no significant associations between the SNPs N363S, Tth111I, BclI, ER22/23EK, and A3669G with GANFH susceptibility. The G allele frequency, both homozygous and heterozygous, of SNP BclI was significantly different between control and GANFH combined with osteopenia subgroups (odds ratios [OR] = 1.81; 95% confidence intervals [CI] = 1.05-3.10; OR = 2.04; 95% CI = 1.03-4.07, respectively). CONCLUSIONS: Most of these common SNPs in the NR3C1 gene likely do not play critical roles in the susceptibility of GANFH. However, the G allele at the SNP Bcll, irrespective of dosage, may increase risk for the development of GANFH combined with osteopenia in the Chinese population. PMID- 28346830 TI - Synergetic Neuroprotective Effect of Docosahexaenoic Acid and Aspirin in SH-Y5Y by Inhibiting miR-21 and Activating RXRalpha and PPARalpha. AB - Parkinson's disease (PD) is a serious neurodegenerative disorder that lacks effective therapeutic methods. In this research, expressions of PPARalpha, RXRalpha, and miR-21 were evaluated in PD patients and normal controls. To investigate the effects of miR-21, docosahexaenoic acid (DHA) and aspirin (ASA) on PD, as well as the relationships between them, SH-Y5Y cells were treated with DHA, ASA, or both for 24 h. The assay showed that levels of miR-21 were increased and levels of PPARalpha were decreased in PD patients compared with normal controls. miR-21 was negatively correlated with PPARalpha in PD patients. DHA and ASA could activate RXRalpha and PPARalpha, respectively. Additionally, DHA upregulated PPARalpha expression by inhibiting miR-21 in SH-Y5Y cells. A combination of DHA and ASA efficiently enhanced heterodimer formations of PPARalpha and RXRalpha and increased the expression of neurotrophic factors PSD 95, brain-derived neurotrophic factor (BDNF), and glial cell-derived neurotrophic factor (GDNF), while inhibiting NFkappaB and COX2. These findings suggest that a combination of DHA and ASA could significantly improve the expression of PSD-95, BDNF, and GDNF by promoting heterodimerization of PPARalpha and RXRalpha, thus supplying a new therapeutic method for PD. PMID- 28346831 TI - Anxiety and Depression as Longitudinal Predictors of Mild Cognitive Impairment in Older Adults. AB - INTRODUCTION: Few studies have dealt with the potential correlation between anxiety, depression, and cognitive impairment in community-dwelling older adults. METHOD: This longitudinal study was conducted in the city of Montreal, Canada, with 352 older adults aged 55 years or more. The participants were interviewed at baseline and again 2 years later. The Montreal Cognitive Assessment (MoCA) score was estimated and compared between the 2 time points, the Composite International Diagnostic Interview (CIDI) was used to assess major depression and anxiety, and the K10 measured high psychological distress. Likewise, major depression, anxiety disorders, and psychological distress were evaluated at the 2 study time points. RESULTS: In older adults with a diagnosis of depression or anxiety at baseline, no significant reduction in the MoCA score indicating deterioration in cognitive function was found 2 years later. Nevertheless, in individuals with a high level of psychological distress at baseline, there was a significant reduction in MoCA scores 2 years later, indicating deterioration in cognition. The findings of the present study suggest that a high level of psychological distress in addition to environmental factors may constitute important predictors for cognitive health. PMID- 28346833 TI - Arthroscopic Hip Surgery in the Elite Athlete: Comparison of Female and Male Competitive Athletes. AB - BACKGROUND: Few studies have published the results of hip arthroscopic surgery in elite athletes and none studying a significant number of elite female athletes. PURPOSE: (1) To compare sex-based differences in the ability to return to prior competitive sports activity after arthroscopic hip surgery. (2) To compare sex based differences in the type of sports activity, diagnosis, and treatment in athletes requiring hip arthroscopic surgery. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Data on all elite athletes who underwent primary hip arthroscopic surgery between 2007 and 2014 were included. Athletes with a Hip Sports Activity Scale (HSAS) score of over 6 were identified. The preoperative evaluation included a medical history, history of sports activity, and hip specific outcome scores (Modified Harris Hip Score [MHHS] and International Hip Outcome Tool-33 [iHOT-33]). Surgical findings and time to return to competitive sports were documented. RESULTS: Of 547 hips in 484 consecutive patients, 98 elite athletes (49 female) with a mean follow-up of 18.9 +/- 12.8 months were identified. Eighty patients desired to return to their original competitive activity: 38 were female (42 hips; mean age, 21.5 +/- 3.9 years), and 42 were male (54 hips; mean age, 20.5 +/- 1.9 years). Moreover, 84.2% of female athletes and 83.3% of male athletes were able to return to the same level of competition at a mean of 8.3 +/- 3.0 and 8.8 +/- 2.9 months, respectively. Significant improvements between preoperative and postoperative outcome scores were seen in both groups (all P < .0001). Female athletes had more pincer femoroacetabular impingement (FAI) ( P = .0004) and instability ( P < .0001). Conversely, male athletes were diagnosed more commonly with combined FAI ( P < .0001), demonstrated greater acetabular cartilage damage ( P = .0004), and required microfracture more often ( P = .0014). Female athletes competed more frequently in flexibility (4/38, 11%; P = .047) and endurance (9/38, 24%) sports, while male athletes participated in cutting (14/42, 33%), contact (6/42, 14%), and asymmetric (13/42, 31%) sports more often. Patients who returned to their baseline level of competition had a shorter duration of symptoms preoperatively ( P = .001). Microfracture status did not affect the ability to return to sports. CONCLUSION: Female and male elite athletes were able to return to competitive sports activity at the same or higher level after hip arthroscopic surgery at a similar rate, although their performance in sports was not measured. Distinct differences in the diagnosis, treatment, and type of sports activity between sexes were seen. The duration of symptoms negatively correlated with outcomes. Microfracture did not affect the return to sports. PMID- 28346832 TI - TCF21 rs12190287 Polymorphisms Are Associated with Ventricular Septal Defects in a Chinese Population. AB - AIMS: TCF21 knockout mice display cardiac defects, including ventricular septal defects (VSDs). Functional rs12190287 polymorphisms located within the 3' untranslated region (3'-UTR) of TCF21 were associated with a risk of coronary heart disease in the European and Eastern populations. However, whether rs12190287 polymorphisms in the TCF21-3'UTR confer predisposition to congenital heart disease (CHD) is unclear. METHODS: A case-control study was designed consisting of 781 nonsyndromic VSD patients and 867 non-CHD control subjects. The genotype frequency of rs12190287 polymorphisms was determined by real-time polymerase chain reaction. RESULTS: There were significant differences in the genotype and allele frequencies of rs12190287 between the cases and controls in a Chinese population. Allele G of rs12190287 was significantly associated with an increased risk of VSD in a Chinese population. CONCLUSIONS: Our results demonstrate that rs12190287 polymorphisms confer predisposition to VSDs in the Chinese population studied here. PMID- 28346834 TI - Outcomes of Inside-out Meniscal Repair in the Setting of Multiligament Reconstruction in the Knee. AB - BACKGROUND: Limited evidence exists for meniscal repair outcomes in a multiligament reconstruction setting. Purpose/Hypothesis: The purpose of this study was to assess outcomes and failure rates of meniscal repair in patients who underwent multiligament reconstruction compared with patients who underwent multiligament reconstruction but lacked meniscal tears. The authors hypothesized that the outcomes of meniscal repair associated with concomitant multiligament reconstruction would significantly improve from preoperatively to postoperatively at a minimum of 2 years after the index surgery. Secondarily, they hypothesized that this cohort would demonstrate similar outcomes and failure rates compared with the cohort that did not have meniscal lesions at the time of multiligament reconstruction. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Inclusion criteria for the study included radiographically confirmed skeletally mature patients of at least 16 years of age who underwent multiligamentous reconstruction of the knee without previous ipsilateral osteotomy, intra articular infections, or intra-articular fractures. Patients were included in the experimental group if they underwent inside-out meniscal suture repair with concurrent multiligament reconstruction. Those included in the control group (multiligament reconstruction without a meniscal tear) underwent multiligament reconstruction but did not undergo any type of meniscal surgery. Lysholm, Western Ontario and McMaster Universities Osteoarthritis Index, Short Form-12 physical component summary and mental component summary, Tegner activity scale, and patient satisfaction scores were recorded preoperatively and postoperatively. The failure of meniscal repair was defined as a retear of the meniscus that was confirmed arthroscopically. RESULTS: There were 43 patients (16 female, 27 male) in the meniscal repair group and 62 patients (25 female, 37 male) in the control group. Follow-up was obtained in 93% of patients with a mean of 3.0 years (range, 2.0-4.7 years). There was a significant improvement between all preoperative and postoperative outcome scores ( P < .05) for both groups. The meniscal repair group had significantly lower preoperative Lysholm and Tegner scores ( P = .009 and P = .02, respectively). There were no significant differences between any other outcome scores preoperatively. The failure rate of the meniscal repair group was 2.7%, consisting of 1 symptomatic meniscal retear. There was no significant difference in any postoperative outcome score at a minimum 2-year follow-up between the 2 groups. CONCLUSION: Good to excellent patient-reported outcomes were reported for both groups with no significant differences in outcomes between the cohorts. Additionally, the failure rate for inside-out meniscal repair with concomitant multiligament reconstruction was low, regardless of meniscus laterality and tear characteristics. The use of multiple vertical mattress sutures and the biological augmentation resulting from intra-articular cruciate ligament reconstruction tunnel reaming may be partially responsible for the stability of the meniscal repair construct and thereby contribute to the overall improved outcomes and the low failure rate of meniscal repair, despite lower preoperative Lysholm and Tegner scores in the meniscal repair group. PMID- 28346838 TI - Short Communication: HIV-1 Transmission Networks Across South Korea. AB - Molecular epidemiology can help clarify the properties and dynamics of HIV-1 transmission networks in both global and regional scales. We studied 143 HIV-1 infected individuals recruited from four medical centers of three cities in South Korea between April 2013 and May 2014. HIV-1 env V3 sequence data were generated (337-793 bp) and analyzed using a pairwise distance-based clustering approach to infer putative transmission networks. Participants whose viruses were <=2.0% divergent according to Tamura-Nei 93 genetic distance were defined as clustering. We collected demographic, risk, and clinical data and analyzed these data in relation to clustering. Among 143 participants, we identified nine putative transmission clusters of different sizes (range 2-4 participants). The reported risk factor of participants were concordant in only one network involving two participants, that is, both individuals reported homosexual sex as their risk factor. The participants in the other eight networks did not report concordant risk factors, although they were phylogenetically linked. About half of the participants refused to report their risk factor. Overall, molecular epidemiology provides more information to understand local transmission networks and the risks associated with these networks. PMID- 28346839 TI - Characterization of Vancomycin-Resistant Enterococcus faecalis and Enterococcus faecium Isolated from Fresh Produces and Human Fecal Samples. AB - Increased enterococcal infections in hospitals and multidrug-resistant and vancomycin-resistant enterococci (VRE) isolated from humans, animals, and food sources raised public health concern on the presence of VRE in multiple sources. We performed a comparative analysis of the antimicrobial resistance and genetics of VRE isolates derived from fresh produce and human fecal samples. Of 389 Enterococcus isolates, 8 fecal and 3 produce isolates were resistant to vancomycin and teicoplanin; all harbored vanA gene. The VRE isolates showed multidrug-resistant properties. The isolates from fresh produce in this study showed to have the common shared characteristics with the isolates from humans by the results of antimicrobial resistance, multilocus sequence typing, and Tn 1546 transposon analysis. Therefore, VRE isolates from fresh produce are likely related to VRE derived from humans. The results suggested that VRE may contaminate vegetables through the environment, and the contaminated vegetables could then act as a vehicle for human infections. Ongoing nationwide surveillance of antibiotic resistance and the promotion of the proper use of antibiotics are necessary. PMID- 28346840 TI - Fabrication and evaluation of Phytomenadione as a nanostructure lipid carrier for enhancement of bioavailability. AB - Owing to its limited aqueous solubility, Phytomenadione (vitamin K) undergoes a low bioavailability (50%) with a large inter-individual variability after oral administration. Therefore, the aim of this work was to incorporate vitamin K into nanostructure lipid carrier systems to improve its aqueous solubility and bioavailability. Phytomenadione was used as a liquid lipid; Precirol ATO5, and Compritol ATO were used as solid lipids; Labrasol and Cremophore EL as water soluble surfactants; Capryol 90 and Lauroglycol as lipid soluble surfactants. Eight formulas were prepared and characterized for their particle sizes, zeta potential, entrapment efficiencies, and drug release. Those formulas had particle sizes ranging from 25.4 to 68.3 nm. The best formula, consisting of 15% Phytomenadione, 45% Precirol ATO5, 30% Cremophore EL, and 10% Lauroglycol 90, was selected for stability study and characterized by the techniques mentioned above and scanning electron microscopy. It had the highest drug loading and an acceptable in vitro release profile (94.54% within 30 min). This formula was also chemically and physically stable, and it recorded a relative bioavailability of 645.5% in rabbits compared to the commercial conventional tablet. This formula could be a promising carrier regarding its ease of preparation, dosage form versatility and enhanced bioavailability. PMID- 28346841 TI - Rapid and Reliable Genotyping of HLA-B*57:01 in Four Chinese Populations Using a Single-Tube Duplex Real-Time Polymerase Chain Reaction Assay. AB - HLA-B*57:01 is strongly associated with severe adverse drug reaction induced by the anti-HIV drug abacavir (ABC) and antibiotic flucloxacillin. This study was dedicated to establishing a new method for HLA-B*57:01 genotyping and investigating the HLA-B*57:01 distribution pattern in four Chinese populations. A single-tube duplex real-time polymerase chain reaction (PCR) system was established by combining the amplification refractory mutation system and TaqMan probe. The reliability of this assay was validated by comparing the genotyping results with those by sequence-based typing. With this assay, the distribution of HLA-B*57:01 in 354 blood samples from four ethnic groups, namely, Han, Tibetan, Uighur, and Buyei, was determined. A 100% concordance was observed between the results of real-time PCR and sequence-based typing in 50 Uighur samples. As low as 0.016 ng DNA that carried HLA-B*57:01 could be detected with this assay. HLA B*57:01 carriers identified in 100 Northern Han Chinese, 104 Buyeis, 100 Tibetans, and 50 Uighurs were 0, 1 (0.96%), 3 (3%), and 6 (12%), respectively. The carrier rate of HLA-B*57:01 in Uighur was significantly higher than those in Northern Han (p = .001) and Buyei (p = .005). The newly established real-time PCR assay provides a rapid and reliable tool for HLA-B*57:01 allele screening before the prescription of ABC and flucloxacillin in clinical practice. PMID- 28346842 TI - Reconnecting the Body in Eastern and Western Medicine. PMID- 28346843 TI - Analgesic Effect of Maternal Human Milk Odor on Premature Neonates: A Randomized Controlled Trial. AB - BACKGROUND: Two studies have demonstrated an analgesic effect of maternal milk odor in preterm neonates, without specifying the method of olfactory stimulation. Research aim: This study aimed to assess the analgesic effect of maternal milk odor in preterm neonates by using a standardized method of olfactory stimulation. METHODS: This trial was prospective, randomized, controlled, double blinded, and centrally administered. The inclusion criteria for breastfed infants included being born between 30 and 36 weeks + 6 days gestational age and being less than 10 days postnatal age. There were two groups: (a) A maternal milk odor group underwent a venipuncture with a diffuser emitting their own mother's milk odor and (2) a control group underwent a venipuncture with an odorless diffuser. The primary outcome was the Premature Infant Pain Profile (PIPP) score, with secondary outcomes being the French scale of neonatal pain-Douleur Aigue du Nouveau-ne (DAN) scale-and crying duration. All neonates were given a dummy. RESULTS: Our study included 16 neonates in the maternal milk odor group and 17 in the control group. Neonates exposed to their own mother's milk odor had a significantly lower median PIPP score during venipuncture compared with the control group (6.3 [interquartile range (IQR) = 5-10] versus 12.0 [IQR = 7-13], p = .03). There was no significant difference between the DAN scores in the two groups ( p = .06). Maternal milk odor significantly reduced crying duration after venipuncture (0 [IQR = 0-0] versus 0 [IQR = 0-18], p = .04). CONCLUSION: Maternal milk odor has an analgesic effect on preterm neonates. PMID- 28346844 TI - Inactivation of Clostridium difficile spore outgrowth by synergistic effects of nisin and lysozyme. AB - Inactivating Clostridium difficile spores is difficult, as they are resistant to heat, chemicals, and antimicrobials. However, this note describes inactivation of C. difficile spore outgrowth by incubation in a solution containing a germinant (1% (m/v) sodium taurocholate), co-germinants (1% (m/v) tryptose and 1% (m/v) NaCl), and natural antimicrobials (20 nmol.L-1 nisin and 0.2 mmol.L-1 lysozyme). Clostridium difficile spores were resistant to nisin and lysozyme but became susceptible during germination and outgrowth triggered and promoted by sodium taurocholate, tryptose, and NaCl. The degree of inactivation of germinated and outgrowing C. difficile spores by both nisin and lysozyme was greater than the sum of that by nisin and lysozyme individually, suggesting synergistic inactivation of C. difficile spores. The germinant, co-germinants, and natural antimicrobials used in this study are safe for human contact and consumption. Therefore, these findings will facilitate the development of a safe and effective method to inactivate C. difficile spore. PMID- 28346845 TI - Commentary on Kang et al.: Single-Port Laparoscopic Surgery Can Be Performed Safely and Appropriately for Colon Cancer: Short-Term Results of a Pilot Randomized Controlled Trial. PMID- 28346846 TI - DNA Methylation of the PDGFD Gene Promoter Increases the Risk for Intracranial Aneurysms and Brain Arteriovenous Malformations. AB - The aim of this study was to determine the role of DNA methylation of the platelet-derived growth factor-D (PDGFD) gene promoter in the development of intracranial aneurysms (IAs) and brain arteriovenous malformations (BAVMs). A total of 70 patients with IAs or BAVMs and 26 control individuals were enrolled for this study. The PDGFD level in the plasma was determined using enzyme-linked immunosorbent assay. DNA methylation levels of seven cytosine-phosphate-guanine (CpG) dinucleotides present in the PDGFD gene promoter were measured using bisulfite pyrosequencing technology. The plasma PDGFD levels in IA and BAVM were significantly lower than those in the control group (p = 0.0008 and 0.002, respectively). CpG1 methylation levels of the PDGFD gene promoter were significantly higher in IA patients (4.63 +/- 0.35, p = 0.017) than in the control group (3.36 +/- 0.35). CpG1 methylation of the PDGFD gene promoter in BAVM patients (6.00 +/- 0.86, p = 0.003) was also significantly higher than that in the control group, although these differences were seen in both male and female patients (p = 2.81E-04 and p = 0.017, respectively). In addition, CpG1 methylation of the PDGFD promoter was associated with apolipoprotein E (APOE) levels in IA patients (p = 0.013). In conclusion, our study has demonstrated significant correlations between DNA methylation of the PDGFD gene promoter and the risk of developing either IA or BAVM. Furthermore, PDGFD gene promoter CpG1 methylation shows a significant correlation with APOE in IAs. Further functional studies on these relationships and correlations are warranted. PMID- 28346847 TI - Does Acute Normobaric Hypoxia Induce Anapyrexia in Adult Humans? AB - Seo, Yongsuk, Hayden D. Gerhart, Jeremiah Vaughan, Jung-Hyun Kim, and Ellen L. Glickman. Does acute normobaric hypoxia induce anapyrexia in adult humans? High Alt Med Biol. 18:185-190, 2017.-Exposure to hypoxia is known to induce a reduction in core body temperature as a protective mechanism, which has been shown in both animals and humans. The purpose of this study was to test if acute exposure to normobaric hypoxia (NH) induces anapyrexia in adult humans in association with decreased peripheral oxygen saturation (SpO2). Ten healthy male subjects were seated in atmospheres of normobaric normoxia 21% (NN21), NH 17% (NH17), and 13% (NH13) O2 for 60 minutes in a counterbalanced manner. Rectal temperature (Tre) was continuously monitored together with the quantification of metabolic heat production (MHP) and body heat storage (S). Baseline physiological measurements showed no differences between the three conditions. SpO2 was significantly decreased in NH17 and NH13 compared with NN21 (p <= 0.001). Tre decreased following 60 minutes of resting in all conditions, but, independent of the conditions, showed no association between Tre and levels of hypoxic SpO2. There was also no significant difference in either MHP or S between conditions. The present results showed no evidence of hypoxia-induced anapyrexia in adult humans during 1 hour of resting after exposure to NH either at 13% or 17% O2. PMID- 28346849 TI - Clostridium perfringens Type A Isolates of Animal Origin with Decreased Susceptibility to Metronidazole Show Extensive Genetic Diversity. AB - Metronidazole (MTZ) is a first-line drug for the treatment of human infections caused by anaerobic bacteria. Although most Clostridium perfringens isolates are susceptible to metronidazole, a number of strains with decreased susceptibility have been obtained in clinical and environmental surveys. However, little is known yet about the toxinotype and genetic diversity of metronidazole-resistant C. perfringens strains. We tested for susceptibility to metronidazole and assessed the toxigenic status and amplified fragment length polymorphism (AFLP) diversity of a collection of 80 C. perfringens isolates of animal origin. In vitro susceptibility testing by the standard agar dilution technique revealed that 22 isolates (27.5% of total) were susceptible to metronidazole, 54 (67.5%) intermediate susceptible, and four (5%) resistant. All isolates belonged to toxinotype A, and two, 41 and 17, of them yielded a positive PCR result for presence of the gene encoding for enterotoxin (cpe), the consensus form of beta2 toxin (cpb2) and the atypical form of beta2 toxin, respectively. AFLP fingerprinting classified isolates into 65 genotypes indicating a high molecular diversity among isolates in this study, and this diversity was reflected among isolates from each susceptibility category. In conclusion, the results of this study revealed extensive genetic diversity among C. perfringens type A isolates regardless of their susceptibility to metronidazole. PMID- 28346848 TI - Cardiovascular Protective Effects and Clinical Applications of Resveratrol. AB - Resveratrol is a naturally occurring phenol that is generated by plant species following injury or attack by bacterial and fungal pathogens. This compound was first described as the French Paradox in 1992. Later in 2003, resveratrol was reported to activate sirtuins in yeast cells. Recent experimental studies have found that resveratrol offers a variety of benefits that include both anticarcinogenic and anti-inflammatory effects in addition to the ability to reverse obesity, attenuate hyperglycemia and hyperinsulinemia, protect heart and endothelial function, and increase the life span. Multiple molecular targets are associated with the cardioprotective capabilities of resveratrol, and therefore, resveratrol has potential for a wide range of new therapeutic strategies for atherosclerosis, ischemia/reperfusion, metabolic syndrome, cardiac failure, and inflammatory alterations during aging. Expectations for application in human patients, however, suffer from a lack of sufficient clinical evidence in support of these beneficial effects. This article reviews recently reported basic research results that describe the beneficial effects of resveratrol in an attempt to condense the evidence observed in clinical trials and provide support for the future development of novel clinical therapeutics in patients with cardiovascular diseases. PMID- 28346850 TI - Risk Factors Related to Lower Limb Edema, Compression, and Physical Activity During Pregnancy: A Retrospective Study. AB - OBJECTIVE: The aim of the article was to assess risk factors and to analyze methods applied in the prevention and treatment of lower limb edema in pregnant women with a particular focus on compression therapy and exercise. MATERIALS AND METHODS: Fifty-four women during the early 24-hour period following delivery were assigned to two groups-either to a group with swellings of lower limbs during pregnancy, located mostly in the region of feet and lower legs (Group A, n = 42), or to a group without edema (Group B, n = 12). Two subgroups, namely A1 and A2, were additionally distinguished in Group A. Compression therapy that consisted in wearing circular-knit compression garments, usually at compression level 1 (ccl1), with three cases of compression level 2 (ccl2) was applied only in Group A1 (n = 18 women). RESULTS: The analysis has led to a conclusion that there is a link between the occurrence of edema during pregnancy on the one hand and the pregravidity episodes of venous conditions (vascular insufficiency and thrombosis, p < 0.05) and the lack of physical exercise during pregnancy (p = 0.01) on the other hand. However, interdependence between the occurrence of edema and the number of times a female had been pregnant, physical activity before gravidity, or body mass index before gravidity has not been identified. Only 33% of the analyzed women applied compression therapy during pregnancy; a half of them continued to apply compression during the postpartum period. CONCLUSIONS: Compression therapy in combination with proper physical exercises appears to be an effective means to prevent and treat venous thrombosis and lower limb edema in pregnant women, yet further research in line with the principles of evidence based medicine is required. PMID- 28346851 TI - Aquatic Therapy for People with Lymphedema: A Systematic Review and Meta analysis. AB - BACKGROUND: Aquatic therapy has several proposed benefits for people with lymphedema. A systematic review of the evidence for aquatic therapy in lymphedema management has not been conducted. METHOD AND RESULTS: Systematic review and meta analysis were conducted. Five electronic databases were searched to identify randomized controlled trials (RCTs) of people with lymphedema, which compared aquatic therapy with other lymphedema interventions. Qualitative analysis was undertaken where quantitative analysis was not possible. Study quality was assessed using physiotherapy evidence database (PEDro) scores. The strength of evidence was evaluated using the Grades of Recommendations Assessment, Development and Evaluation (GRADE) approach. Four RCTs of moderate quality (average PEDro score 6.5/10) were included in the review. Two studies provided results for inclusion in meta-analysis. There was moderate-level evidence of no significant short-term differences in lymphedema status (as measured by lymphedema relative volume) between patients who completed aqua lymphatic therapy (ALT) compared to land-based standard care (standardized mean difference [SMD]: 0.14; 95% confidence interval [CI]: -0.37 to 0.64, I2 = 0%, p = 0.59); and low quality evidence of no significant difference between ALT and standard care for improving upper limb (UL) physical function (SMD -0.27, 95% CI: -0.78 to 0.23, I2 = 0%, p = 0.29). No adverse events reported. CONCLUSIONS: Current evidence indicates no significant benefit of ALT over standard land-based care for improving lymphedema status or physical function in people with UL lymphedema. Patient preference should guide the choice of care to facilitate adherence. Further research is required to strengthen the evidence from four studies in people with UL lymphedema, and to establish the efficacy of this intervention in people with lower limb lymphedema. Review registration: PROSPERO (CRD42015019900). PMID- 28346852 TI - Preoperative Lymphedema-Related Risk Factors in Early-Stage Breast Cancer. AB - BACKGROUND: Prolongation of survival in patients with breast cancer due to early diagnosis and modern methods of treatment has turned the attention on lymphedema, which is the most important morbidity secondary to the treatment of the disease. Determination of lymphedema and related risk factors in patients before a surgical intervention may provide protection for patients and early treatment. The aim of this study was to determine the presence of lymphedema before surgery by bioimpedance analysis in patients with breast cancer and to establish risk factors associated with lymphedema. PATIENTS AND METHODS: A total of 277 patients who were diagnosed as having breast cancer, were planned to undergo a surgical intervention, and had no clinical lymphedema were included in the study. The presence of lymphedema was evaluated with clinical examination, measurement of arm circumference, and bioimpedance analysis. RESULTS: Lymphedema was found in 59 (21.3%) patients with no detected differences in arm circumferences. A significant relationship was found between the presence of lymphedema and body mass index (BMI), number of positive lymph nodes, and capsule invasion of the tumor (p = 0.001, p = 0.003, p = 0.002, respectively). Multiple regression analysis revealed that BMI and the number of positive lymph nodes were independent variables (p = 0.024, p = 0.002). ROC curve analysis resulted in an increased risk of preoperative lymphedema when the number of positive lymph nodes was >=8. Correlation analysis revealed a positive correlation between the number of positive lymph nodes and L-dex score (p = 0.001, r = 0.219). CONCLUSION: Preoperative bioimpedance analysis demonstrated that ~1/5 of the patients had subclinical lymphedema. Preoperative subclinical lymphedema is associated with obesity and the number of positive lymph nodes, and thus, treatment of the axilla in patients who are preoperatively detected to have subclinical lymphedema should be revised. PMID- 28346853 TI - High Prevalence of Vitamin D Deficiency and Correlation of Serum Vitamin D with Cardiovascular Risk in Patients with Metabolic Syndrome. AB - BACKGROUND: Metabolic syndrome (MetS) identifies subjects with increased risk of cardiovascular disease when they have a combination of insulin resistance, obesity, hypertension, hyperglycemia, low high-density lipoprotein cholesterol (HDL-C), and elevated triglycerides (TGs). Increasing evidence suggests that vitamin D deficiency could be associated with diabetes and MetS. The aim is to assess if 25-hydroxyvitamin D (25-OHD) is correlated with cardiovascular risk components of MetS. METHODS: A cross-sectional study involved 124 diabetic patients with MetS according to International Diabetes Federation definition. 25 OHD was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Fasting insulin, lipid profile, glucose, and hemoglobin-A1c (HbA1c) were determined using routinely standard laboratory methods. Insulin resistance was assessed using homeostatic model assessment (HOMA). RESULTS: 59.68% and 27.42% of patients have vitamin D deficiency and insufficiency, respectively. Systolic blood pressure (SBP) was significantly higher in patients with vitamin D deficiency compared to patients with sufficient vitamin D (P < 0.05). Serum log (25-OHD) was inversely correlated with SBP, HbA1c, low-density lipoprotein cholesterol (LDL-C), TGs, and total cholesterol and directly correlated with pancreatic beta cell function (HOMA-beta) (P < 0.05). Multiple linear regression analysis has shown that SBP can be predicted from log (25-OHD) (B = -9.388, P < 0.05), while HbA1c, LDL-C, TGs, total cholesterol, and HOMA-beta cannot be predicted from log (25-OHD), (P > 0.05). CONCLUSIONS: Vitamin D deficiency was very prevalent among patients with MetS. 25-OHD was inversely correlated with glycemic control and cardiovascular risk components of MetS except HDL-C, insulin resistance, and obesity. SBP was the only cardiovascular risk component that can be predicted from vitamin D concentrations. PMID- 28346854 TI - Breast Cancer-Related Lymphedema: Differentiating Fat from Fluid Using Magnetic Resonance Imaging Segmentation. AB - BACKGROUND: Lymphedema is an iatrogenic complication after breast cancer treatment in which lymph fluid in the affected limb progresses to fat deposition and fibrosis that are amenable to liposuction treatment. Magnetic resonance imaging (MRI) for lymphedema can differentiate fat tissue from fluid, but estimating relative volumes remains problematic. METHODS AND RESULTS: Patients underwent routine bilateral arm MRI both before and after liposuction for advanced lymphedema. The threshold-based level set (TLS) segmentation method was applied to segment the geometric image data and to measure volumes of soft tissue (fat, muscle, and lymph fluid) and bone. Bioimpedance testing (L-Dex(r)) to detect extracellular fluid was also used. Volumes derived by using TLS or girth measurement were evaluated and showed consistent agreement, whereas L-Dex showed no significant reduction between pre- and postoperative measures. The percentage median volume difference between the affected and unaffected sides was 132.4% for girth measures compared with 137.2% for TLS (p = 0.175) preoperatively, and 99.8% and 98.5%, respectively (p = 0.600), postoperatively. MRI segmentation detected reductions in fat (median 52.6%, p = 0.0163) and lymph fluid (median 66%, p = 0.094), but the volumes of muscle and bone were relatively constant. CONCLUSIONS: MRI imaging with TLS technology may be a useful tool to quantitatively measure fat tissue and fluid for patients with advanced lymphedema and may assist in the selection of eligible liposuction candidates at initial assessment and follow-up of patients who proceed with surgery. PMID- 28346855 TI - TSHR/IGF-1R Cross-Talk, Not IGF-1R Stimulating Antibodies, Mediates Graves' Ophthalmopathy Pathogenesis. PMID- 28346856 TI - An Experiential Service-Learning Project on Observed Smoking Behavior to Teach Practical Epidemiologic Skills to MPH Students, Philadelphia, 2015. PMID- 28346857 TI - The Influence of Epicardial Fat and Nonalcoholic Fatty Liver Disease on Heart Rate Recovery in Metabolic Syndrome. AB - BACKGROUND: Epicardial adipose tissues reflecting visceral fat accumulations of the heart are associated with metabolic syndrome (MetS) and can be a predictor of other cardiometabolic diseases. It can adversely influence autonomic nervous system (ANS) of heart. Heart rate recovery (HRR) is an easy method for measuring ANS dysfunction. The purpose of this study was to determine whether epicardial fat thickness (EFT) and nonalcoholic fatty liver disease (NAFLD) are related to HRR in patients with MetS. METHODS: We enrolled 772 consecutive patients from a health-screening center who underwent abdominal ultrasonography, treadmill test, and cardiac echocardiography. EFT using echocardiography and HRR by symptom limited exercise testing was assessed. According to the presence of MetS and NAFLD, patients were classified into the four groups. RESULTS: In NAFLD patients, EFT was higher and HRR was lower, especially in patients with MetS and NAFLD, compared to non-MetS participants without NAFLD (MetS with NAFLD, EFT 7.5 +/- 4.4 mm, HRR 31.9 +/- 12.7; MetS without NAFLD, EFT 4.9 +/- 3.0 mm, HRR 39.5 +/- 11.1; non-MetS with NAFLD, EFT 5.9 +/- 3.6 mm, HRR 36.6 +/- 12.7; and non-MetS without NAFLD, EFT 4.4 +/- 3.5 mm, HRR 43.4 +/- 14.5, p < 0.001). Patients with severe liver steatosis (LS) showed significantly higher EFT than those with moderate LS (14.2 +/- 2.0 vs. 7.5 +/- 3.1 mm, P < 0.001), and EFT was positively correlated with severity of LS (r = 0.431, P < 0.001). HRR was significantly correlated with EFT (r = -0.386, P < 0.001) and severity of LS (r = -0.324, P < 0.001). CONCLUSIONS: EFT and NAFLD were significantly correlated with HRR in patients with MetS and they may be highly related to increased cardiovascular risk. These results suggest a cross-link among EFT, NAFLD, and cardiac autonomic dysfunction in patients with MetS. PMID- 28346858 TI - Circulating Soluble IL-6 Receptor Concentration and Visceral Adipocyte Size Are Related to Insulin Resistance in Taiwanese Adults with Morbid Obesity. AB - BACKGROUND: Morbid obesity is related to chronic inflammation and many metabolic complications. Interleukin (IL)-6 plays a pivotal pathophysiological role in obesity, and IL-6 trans-signaling through the soluble IL-6 receptor (sIL-6R) has a major proinflammatory effect. The aim of this study was to investigate the association between sIL-6R, adipocyte size, and insulin resistance in morbidly obese individuals. METHODS: We measured concentrations of sIL-6R, high sensitivity C-reactive protein, and lipid parameters and estimated homeostasis model assessment of insulin resistance (HOMA-IR) before the patients underwent bariatric surgery. Mesenteric adipose tissue was collected during surgery, and adipocyte size and concentrations of membrane-bound IL-6 receptor (mIL-6R) were evaluated. In total, 35 adults (20 men and 15 women) were recruited. RESULTS: The subjects with high HOMA-IR (>=2.4) had higher fasting glucose/insulin, triglycerides, sIL-6R, and adipocyte size and lower high-density lipoprotein cholesterol and mIL-6R than those with low HOMA-IR (<2.4). Adipocyte size positively correlated with sIL-6R (r = 0.559, P = 0.001) and HOMA-IR (r = 0.773, P <= 0.001) independent of age, gender, body mass index (BMI), waist, and use of diabetic drugs. In addition, every 1 ng/mL increase in sIL-6R concentration corresponded to a 10.2% decrease in the likelihood of maintaining lower insulin resistance. Furthermore, an sIL-6R level of 77.45 ng/mL was a reasonable cutoff level to propose lower insulin resistance in morbidly obese subjects. CONCLUSIONS: Circulating sIL-6R is more closely associated with insulin resistance status than waist-to-hip ratio or BMI in morbidly obese Taiwanese adults. sIL-6R may be a useful biomarker to assess insulin resistance among morbidly obese subjects. PMID- 28346859 TI - Circulating Zbed3 Levels in Subjects With and Without Metabolic Syndrome. AB - BACKGROUND: Zinc-finger BED domain-containing 3 (Zbed3) is a member of the zinc finger domain protein superfamily. Recent studies have shown that Zbed3 is associated with insulin resistance and type 2 diabetes mellitus. However, no report has demonstrated the association of Zbed3 with metabolic syndrome (MetS) in humans. The purpose of this study is to examine the association between Zbed3 and MetS in a cross-sectional study. METHODS: We conducted a cross-sectional study of a Chinese population, including 167 non-MetS subjects and 144 newly diagnosed MetS (nMetS) patients. Circulating Zbed3 levels were examined by enzyme linked immunosorbent assay. The relationship between circulating Zbed3 levels and the components of MetS was assessed. RESULTS: Circulating Zbed3 levels were significantly higher in nMetS patients than in non-MetS subjects (134.6 +/- 32.1 vs. 106.5 +/- 26.1 ng/L, P < 0.01). Circulating Zbed3 correlated positively with markers of adiposity (waist circumference, P < 0.01). It also correlated with glucose and lipid parameters (increasing fasting blood glucose and triglycerides and decreasing high-density lipoprotein cholesterol, all P < 0.01) and blood pressure (elevating systolic blood pressure and diastolic blood pressure, both P < 0.01) and inflammatory marker (elevating tumor necrosis factor alpha, P < 0.01). The relative risks for MetS showed significant elevation with an increase in Zbed3 quartiles. Circulating levels of Zbed3 were progressively elevated with an increased number of components of MetS. CONCLUSIONS: These data suggest that Zbed3 may correlate with the pathogenesis of MetS in humans. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-OCC-11001422. PMID- 28346860 TI - Comparison of Short-Term Effects of Diquafosol and Rebamipide on Mucin 5AC Level on the Rabbit Ocular Surface. AB - PURPOSE: To investigate the short-term effects of 2 new secretagogue eye drops for dry eye, 3% diquafosol tetrasodium ophthalmic solution (diquafosol) and 2% rebamipide ophthalmic suspension (rebamipide), on the concentration of mucin 5AC (MUC5AC) in rabbit tear fluid and conjunctival goblet cells. METHODS: One dose of artificial tears, diquafosol or rebamipide, was instilled into 8 eyes of Japanese white rabbits. MUC5AC concentration in the tear fluid was examined using the enzyme-linked immunosorbent assay 15 min after instillation and compared with 8 untreated controls. Impression cytology was performed to measure the number of periodic acid Schiff (PAS)-positive cells and the ratio of the PAS-positive area using image analysis software. Statistical comparison was performed using ANOVA with post hoc analysis with the Tukey's test. RESULTS: After 15 min, only diquafosol significantly (P <= 0.01) increased the MUC5AC level in the tear fluid. Although no drug affected the number of PAS-positive cells, the ratio of the PAS-positive area decreased significantly (P <= 0.01) only in the diquafosol group. CONCLUSIONS: These data indicated that more PAS-positive MUC5AC was released into the tear fluid from the goblet cells by diquafosol than by rebamipide. There is a difference in the induction pattern of MUC5AC into the tears from the goblet cells between these eye drops. PMID- 28346861 TI - Biomimetic Remineralization of Carious Lesions by Self-Assembling Peptide. AB - Caries is the most common disease in the world. Great efforts have been undertaken for prevention and to identify a regenerative treatment solution for dental caries. Self-assembling beta-sheet forming peptides have previously shown to form 3-dimensional fiber networks supporting tissue regeneration. In particular, the self-assembling peptide P11-4 has shown potential in the treatment and prevention of dental caries. It has previously been shown that application of monomeric P11-4 solution to early carious lesions can increase net mineral gain by forming de novo hydroxyapatite crystals. The hypothesis for the mode of action was that monomeric self-assembling peptide P11-4 diffuses into the subsurface lesion body and assembles therein into higher order fibrils, facilitating mineralization of the subsurface volume by mimicking the natural biomineralization of the tooth enamel, and it remains within the lesion body as a scaffold built-in by the newly formed hydroxyapatite. The aim of the present study was to investigate the mechanism of action of the self-assembling peptide P11-4 supporting mineralization of carious enamel. By various analytical methods, it could be shown that the self-assembling peptide P11-4 diffuses into the subsurface lesion, assembles into higher formed aggregates throughout the whole volume of the lesion, and supports nucleation of de novo hydroxyapatite nanocrystals and consequently results in increased mineral density within the subsurface carious lesion. The results showed that the application of self assembling peptide P11-4 can facilitate the subsurface regeneration of the enamel lesion by supporting de novo mineralization in a similar mode of action as has been shown for the natural formation of dental enamel. PMID- 28346862 TI - Communication About Dying, Death, and Bereavement: A Systematic Review of Children's Literature. AB - BACKGROUND: Children's books have the potential to facilitate communication about death for children living with a serious illness and for children coping with the death of a loved one. OBJECTIVES: This study examines the content of children's literature relevant to the topic of dying and death and identifies books providers can share with children and their families. DESIGN: A search of children's literature was conducted using four electronic databases and one additional search engine using the word "Death" or "Dying." Storybooks about dying, death, and bereavement published in English, French, or Spanish between 1995 and 2015 were included. MEASUREMENTS: Each book underwent content analysis by at least two independent reviewers. Strict PRISMA standard was followed. Full protocol is available as PROSPERO #CRD42016042129. RESULTS: Two hundred ten books met inclusion criteria. The dying subject was primarily a grandparent (n = 78) or pet (n = 44). Books on the experience of a child dying were scarce (n = 5). The word death or dying was used in 75% of the books (n = 158), while others utilized euphemisms. The majority of books featured animals (n = 40) or Caucasian subjects (n = 122) and included spiritual elements such as heaven (n = 122). Less than one quarter of the books included tools for readers to address the topic of death. CONCLUSIONS: Storybooks can be a helpful tool to introduce communication about dying and death with children. Gaps exist in current children's literature to effectively enable children to reflect on their own dying process. A general summary of available books is provided to assist those caring for children and families facing end-of-life issues. PMID- 28346863 TI - Lymph Node Dissection Using Bipolar Vessel-Sealing Device During Reduced Port Laparoscopic Distal Gastrectomy for Gastric Cancer: Result of a Pilot Study from a Single Institute. AB - INTRODUCTION: The electrothermal bipolar vessel-sealing device (BVSD) is known to supply a strong vessel-sealing power. However, only few studies have reported lymph node dissection (LND) using only BVSD during laparoscopic surgery for gastric cancer. The purpose of this study was to investigate the feasibility of LND using BVSD during reduced port laparoscopic distal gastrectomy for gastric cancer. METHODS: From May 2015, patients in whom three- or single-port laparoscopic distal gastrectomy had been engaged for gastric cancer were enrolled in this study. We performed D1+ or D2 LND using only LigaSureTM Maryland (Medtronics, Minneapolis, MN), a recently developed BVSD. Clinical outcomes of these patients were investigated. RESULTS: From May 2015 to November 2016, 20 patients were enrolled in this study. The mean operation time was 262.6 +/- 36.6 (200-340) minutes. The mean time for LND was 124.7 +/- 19.2 (93-171) minutes. Only one patient had a morbidity of Clavien-Dindo grade more than II. No mortality was observed in all patients. The mean number of retrieved lymph nodes was 46.8 +/- 22.8 (15-105). CONCLUSIONS: LND using the Maryland jaw type BVSD was feasible during reduced port (single- or three-port) laparoscopic distal gastrectomy for gastric cancer. Objectively evaluating the potential advantages of BVSD in reduced port laparoscopic surgery is necessary. PMID- 28346864 TI - Application of the L-Dex Score for the Assessment of Bilateral Leg Edema. AB - BACKGROUND: We evaluated a modified L-Dex score by using the right arm as a reference (LDSrarm), to determine whether it could be used for the assessment of leg edema in place of the usual L-Dex score calculated by using the contralateral normal leg as a reference (LDScont). METHODS: Bioimpedance analysis was performed in the legs and right arms of 38 patients with unilateral leg edema and in 42 healthy volunteers by using a standard equipotential electrode arrangement. RESULTS: The impedance ratio in the right arms of patients (2.6 +/- 0.4) was lower than that in their contralateral normal legs (3.0 +/- 0.8, p < 0.05), but it was similar to that in the legs (right: 2.4 +/- 0.7, left 2.5 +/- 0.8) of normal subjects. There was a significant correlation between LDScont and LDSrarm in legs with edema (right: r = 0.80, left: r = 0.93). No such correlation was found in the legs of normal subjects, but the mean +/- 2 standard deviation of their LDSrarm ranged from -3 to 37, which was similar to LDSrarm values in legs with edema corresponding to the normal range of LDScont (-10 to 10), that is, from 1 to 34. CONCLUSIONS: LDSrarm could be used as an alternative for LDScont in the assessment of leg edema. PMID- 28346866 TI - Prevalence and Potential Risk Factors for Bartonella Infection in Tunisian Stray Dogs. AB - Bartonellae are blood-borne and vector-transmitted pathogens, some are zoonotic, which have been reported in several Mediterranean countries. Transmission from dogs to humans is suspected, but has not been clearly demonstrated. Our objectives were to determine the seroprevalence of Bartonella henselae, Bartonella vinsonii subsp. berkhoffii, Bartonella clarridgeiae, and Bartonella bovis (as a proxy for Candidatus Bartonella merieuxii) in stray dogs from Tunisia, identify the Bartonella species infecting the dogs and evaluate potential risk factors for canine infection. Blood samples were collected between January and November 2013 from 149 dogs in 10 Tunisian governorates covering several climatic zones. Dog-specific and geographic variables were analyzed as potential risk factors for Bartonella spp. seropositivity and PCR-positivity. DNA was extracted from the blood of all dogs and tested by PCR for Bartonella, targeting the ftsZ and rpoB genes. Partial sequencing was performed on PCR positive dogs. Twenty-nine dogs (19.5%, 95% confidence interval: 14-27.4) were seropositive for one or more Bartonella species, including 17 (11.4%) for B. vinsonii subsp. berkhoffii, 14 (9.4%) for B. henselae, 13 (8.4%) for B. clarridgeiae, and 7 (4.7%) for B. bovis. Statistical analysis revealed a few potential risk factors, mainly dog's age and breed, latitude and average winter temperature. Twenty-two (14.8%) dogs, including 8 of the 29 seropositive dogs, were PCR-positive for Bartonella based on the ftsZ gene, with 18 (81.8%) of these 22 dogs also positive for the rpoB gene. Partial sequencing showed that all PCR positive dogs were infected with Candidatus B. merieuxii. Dogs from arid regions and regions with cold average winter temperatures were less likely to be PCR positive than dogs from other climatic zones. The widespread presence of Bartonella spp. infection in Tunisian dogs suggests a role for stray dogs as potential reservoirs of Bartonella species in Tunisia. PMID- 28346865 TI - Repetitive Transcranial Magnetic Stimulation for the Treatment of Executive Function Deficits in Autism Spectrum Disorder: Clinical Trial Approach. AB - OBJECTIVE: Executive function (EF) deficits in patients with autism spectrum disorder (ASD) are ubiquitous and understudied. Further, there are no effective, neuroscience-based treatments to address this impairing feature of ASD. Repetitive transcranial magnetic stimulation (rTMS) has demonstrated promise in addressing EF deficits in adult neuropsychiatric disorders. This article will outline the design of a novel randomized-controlled trial of bilateral, 20 Hz, rTMS applied to the dorsolateral prefrontal cortex (DLPFC) for treatment of EF deficits in ASD that is currently ongoing. We describe prior therapeutic rTMS research for ASD and prior rTMS trials targeting EFs in adult neuropsychiatric disorders. A neurophysiological rationale for rTMS treatment of EF deficits in ASD is presented. METHODS: An ongoing protocol will enroll participants aged 16 35 with ASD and no intellectual disability. Psychotropic medications will be continued during the 4-week trial of active 20 Hz versus sham rTMS applied to the DLPFC. Twenty, active treatment sessions consisting of 25 stimulation trains at a 90% motor threshold will be administered. The primary outcome measure is the Cambridge Neuropsychological Test Automated Battery (CANTAB) spatial working memory task. At present, recruitment, enrollment, and treatment within the described clinical trial are ongoing. CONCLUSIONS: EF deficits are common and impairing symptoms of ASD. There are no evidence-based treatments for EF deficits in ASD. The protocol described here will provide important preliminary data on the feasibility and efficacy of 20 Hz rTMS to DLPFC for EF deficits in ASD. PMID- 28346867 TI - The Challenges and Advances in Diagnosis of Vector-Borne Diseases: Where Do We Stand? AB - Vector-borne diseases (VBD) are of major importance to human and animal health. In recent years, VBD have been emerging or re-emerging in many geographical areas, alarming new disease threats and economic losses. The precise diagnosis of many of these diseases still remains a major challenge because of the lack of comprehensive data available on accurate and reliable diagnostic methods. Here, we conducted a systematic and in-depth review of the former, current, and upcoming techniques employed for the diagnosis of VBD. PMID- 28346868 TI - Circulation of Zoonotic Arboviruses in Equine Populations of Mallorca Island (Spain). AB - The presence of major arbovirus vector species, climate change that promotes the expansion and increase of their populations, and potential animal reservoirs mean that vector-borne diseases represent a significant health risk for Mallorca's inhabitants. Microbiological monitoring of circulating arboviruses, particularly flaviviruses causing encephalitis, was initiated using domestic horses from localities near wetlands as "sentinel" hosts. A total of 291 blood samples were taken from 172 horses between 2011 and 2012, using paired samples to highlight seroconversion events. A multiplex immunoassay and confirmatory reference serological assays were used to screen sera for immunoglobulin G antibodies against West Nile (WNV), Usutu (USUV), and tick-borne encephalitis (TBEV) viruses. The seroprevalence was 6.4% (confidence interval [95% CI] 3.2%-11.0%) for WNV, 1.2% (95% CI 0.1%-4.1%) for USUV, and 0.6% (95% CI 0.0%-3.2%) for TBEV. In addition, eight horses (4.6%; 95% CI 2.0%-8.9%) were found positive for unidentified flaviviruses. Seroconversion events were detected for WNV and USUV, reflecting recent arboviral infections. These results highlight the active transmission of zoonotic arboviruses in Mallorca wetlands. PMID- 28346869 TI - Multisensory object perception in infancy: 4-month-olds perceive a mistuned harmonic as a separate auditory and visual object. AB - Infants learn to use auditory and visual information to organize the sensory world into identifiable objects with particular locations. Here we use a behavioural method to examine infants' use of harmonicity cues to auditory object perception in a multisensory context. Sounds emitted by different objects sum in the air and the auditory system must figure out which parts of the complex waveform belong to different sources (auditory objects). One important cue to this source separation is that complex tones with pitch typically contain a fundamental frequency and harmonics at integer multiples of the fundamental. Consequently, adults hear a mistuned harmonic in a complex sound as a distinct auditory object (Alain, Theunissen, Chevalier, Batty, & Taylor, 2003). Previous work by our group demonstrated that 4-month-old infants are also sensitive to this cue. They behaviourally discriminate a complex tone with a mistuned harmonic from the same complex with in-tune harmonics, and show an object-related event related potential (ERP) electrophysiological (EEG) response to the stimulus with mistuned harmonics. In the present study we use an audiovisual procedure to investigate whether infants perceive a complex tone with an 8% mistuned harmonic as emanating from two objects, rather than merely detecting the mistuned cue. We paired in-tune and mistuned complex tones with visual displays that contained either one or two bouncing balls. Four-month-old infants showed surprise at the incongruous pairings, looking longer at the display of two balls when paired with the in-tune complex and at the display of one ball when paired with the mistuned harmonic complex. We conclude that infants use harmonicity as a cue for source separation when integrating auditory and visual information in object perception. PMID- 28346870 TI - 'To the victor go the spoils': Infants expect resources to align with dominance structures. AB - Previous research has found that within the first year of life infants possess rich knowledge about social structures (i.e., that some individuals are dominant over other individuals) as well as expectations about resource distributions (i.e., that resources are typically distributed equally to recipients). We investigated whether infants' expectations about resource distribution can be modulated by information about the dominance structure between the recipients. We first replicated the finding that infants attribute a stable dominance hierarchy to a pair of individuals when their goals conflicted and one individual yielded to the other (Expt. 1), and that this sensitivity is not driven by lower-level perceptual factors (Expt. 2). In Experiments 3-5, we tested our main hypothesis that infants' attention to equal and unequal distributions varies as a function of prior social dominance information. We first replicated and extended prior work by establishing that infants looked significantly longer to unequal than equal resource distributions when no prior information about dominance was provided about recipients (Expt. 3). Critically, following social dominance information, infants looked significantly longer to an equal distribution of resources than a distribution that favored the dominant individual (Expt. 4), and looked significantly longer when the submissive individual received more resources compared to when the dominant individual received more resources (Expts. 4 and 5). Together, these findings suggest that infants expect resources to align with social dominance structures. PMID- 28346871 TI - Synthesis, in vitro evaluation and molecular docking studies of novel amide linked triazolyl glycoconjugates as new inhibitors of alpha-glucosidase. AB - A series of N-substituted amide linked triazolyl beta-d-glucopyranoside derivatives (4a-l) were synthesized and their in vitro inhibitory activity against yeast alpha-glucosidase enzyme [EC.3.2.1.20] was assessed. Compounds 4e (IC50=156.06MUM), 4f (IC50=147.94MUM), 4k (IC50=127.71MUM) and 4l (IC50=121.33MUM) were identified as the most potent inhibitors for alpha glucosidase as compared to acarbose (IC50=130.98MUM) under the same in vitro experimental conditions. Kinetic study showed that both 4e and 4f inhibit the enzyme in a competitive manner with p-nitrophenyl alpha-d-glucopyranoside as substrate. Molecular docking studies of 4e, 4f, 4k and 4l were also carried out using homology model of alpha-glucosidase to find out the binding modes responsible for the inhibitory activity. This study revealed that the binding affinity of compounds 4e, 4f, 4k and 4l for alpha-glucosidase were -8.2, -8.6, 8.3 and -8.5kcal/mol respectively, compared to that of acarbose (-8.9kcal/mol). The results suggest that the N-substituted amide linked triazole glycoconjugates can reasonably mimic the substrates for the yeast alpha-glucosidase. PMID- 28346872 TI - 5-Bromo-2-aryl benzimidazole derivatives as non-cytotoxic potential dual inhibitors of alpha-glucosidase and urease enzymes. AB - On the basis of previous report on promising alpha-glucosidase inhibitory activity of 5-bromo-2-aryl benzimidazole derivatives, these derivatives were further screened for urease inhibitory and cytotoxicity activity in order to get more potent and non-cytotoxic potential dual inhibitor for the patients suffering from diabetes as well as peptic ulcer. In this study, all compounds showed varying degree of potency in the range of (IC50=8.15+/-0.03-354.67+/-0.19MUM) as compared to standard thiourea (IC50=21.25+/-0.15MUM). It is worth mentioning that derivatives 7 (IC50=12.07+/-0.05MUM), 8 (IC50=10.57+/-0.12MUM), 11 (IC50=13.76+/ 0.02MUM), 14 (IC50=15.70+/-0.12MUM) and 22 (IC50=8.15+/-0.03MUM) were found to be more potent inhibitors than standard. All compounds were also evaluated for cytotoxicity towards 3T3 mouse fibroblast cell line and found to be completely non-toxic. Previously benzimidazole 1-25 were also showed alpha-glucosidase inhibitory potential. In silico studies were performed on the lead molecules i.e.2, 7, 8, 11, 14, and 22, in order to rationalize the binding interaction of compounds with the active site of urease enzyme. PMID- 28346873 TI - Design, synthesis, docking studies and biological evaluation of novel chalcone derivatives as potential histone deacetylase inhibitors. AB - A group of novel chalcone derivatives comprising hydroxamic acid or 2 aminobenzamide group as zinc binding groups (ZBG) were synthesized. The structure of the prepared compounds was fully characterized by IR, NMR and elemental microanalyses. Most of the tested compounds displayed strong to moderate HDAC inhibitory activity. Some of these compounds showed potent anti-proliferative activity against human HepG2, MCF-7 and HCT-116 cell lines. In particular, compounds 4a and 4b exhibited significant anti-proliferative activity against the three cell lines compared to SAHA as reference drug and displayed promising profile as anti-tumor candidates. The results indicated that these chalcone derivatives could serve as a promising lead compounds for further optimization as antitumor agents. PMID- 28346874 TI - Protective effects of hepatocyte-specific glycyrrhetic derivatives against carbon tetrachloride-induced liver damage in mice. AB - Glycyrrhetic acid (GA), the main hydrolysate of glycyrrhizic acid extracted from the roots of the Chinese herb Glycyrrhiza glabra, was reported to be accumulated in hepatocytes due to the extensive distribution of GA receptors in liver. A series of hepatocyte-specific derivatives on the basis of anetholtrithione and glycyrrhizic were designed and synthesized. The potential beneficial effect was evaluated in carbon tetrachloride (CCl4)-induced liver injury model. In addition, the hepatoprotective activity of these derivatives was assessed by measuring levels of serum marker enzymes, including serum glutamate oxaloacetate transaminase (GOT), serum glutamate pyruvate transaminase (GPT), alkaline phosphatase (AKP), lactate dehydrogenase (LDH) and the ratio of GSH to GSSG. Gratifyingly, compounds 5a-c (100mg/kg, p.o.) markedly prevented CCl4-induced elevation of levels of serum GPT, GOT. A comparative histopathological study of liver exhibited almost a normal liver lobular architecture and cell structure of the livers, as compared to CCl4-treated group. These findings were confirmed with the histopathological observations, where hepatocyte-specific glycyrrhetic acid derivatives 5a-c were capable of reversing the toxic effects of CCl4 on hepatocytes. PMID- 28346875 TI - Helicobacter Pylori infection detection from gastric X-ray images based on feature fusion and decision fusion. AB - In this paper, a fully automatic method for detection of Helicobacter pylori (H. pylori) infection is presented with the aim of constructing a computer-aided diagnosis (CAD) system. In order to realize a CAD system with good performance for detection of H. pylori infection, we focus on the following characteristic of stomach X-ray examination. The accuracy of X-ray examination differs depending on the symptom of H. pylori infection that is focused on and the position from which X-ray images are taken. Therefore, doctors have to comprehensively assess the symptoms and positions. In order to introduce the idea of doctors' assessment into the CAD system, we newly propose a method for detection of H. pylori infection based on the combined use of feature fusion and decision fusion. As a feature fusion scheme, we adopt Multiple Kernel Learning (MKL). Since MKL can combine several features with determination of their weights, it can represent the differences in symptoms. By constructing an MKL classifier for each position, we can obtain several detection results. Furthermore, we introduce confidence based decision fusion, which can consider the relationship between the classifier's performance and the detection results. Consequently, accurate detection of H. pylori infection becomes possible by the proposed method. Experimental results obtained by applying the proposed method to real X-ray images show that our method has good performance, close to the results of detection by specialists, and indicate that the realization of a CAD system for determining the risk of H. pylori infection is possible. PMID- 28346876 TI - A fluid-structure interaction model of the internal carotid and ophthalmic arteries for the noninvasive intracranial pressure measurement method. AB - Accurate and clinically safe measurements of intracranial pressure (ICP) are crucial for secondary brain damage prevention. There are two methods of ICP measurement: invasive and noninvasive. Invasive methods are clinically unsafe; therefore, safer noninvasive methods are being developed. One of the noninvasive ICP measurement methods implements the balance principle, which assumes that if the velocity of blood flow in both ophthalmic artery segments - the intracranial (IOA) and extracranial (EOA) - is equal, then the acting ICP on the IOA and the external pressure (Pe) on the EOA are also equal. To investigate the assumption of the balance principle, a generalized computational model incorporating a fluid structure interaction (FSI) module was created and used to simulate noninvasive ICP measurement by accounting for the time-dependent behavior of the elastic internal carotid (ICA) and ophthalmic (OA) arteries and their interaction with pulsatile blood flow. It was found that the extra balance pressure term, which incorporates the hydrodynamic pressure drop between measurement points, must be added into the balance equation, and the corrections on a difference between the velocity of blood flow in the IOA and EOA must be made, due to a difference in the blood flow rate. PMID- 28346877 TI - Stevia rebaudiana Bertoni effect on the hemolytic potential of Listeria monocytogenes. AB - The effect of Stevia rebaudiana Bertoni on the hemolytic potential of Listeria monocytogenes was studied by means of the assessment of the Listeriolysin O (LLO) production. The three factors under study, stevia concentration in the range [0 2.5] % (w/v), incubation temperature (10 and 37 degrees C), and exposure time (0 65h) significantly affected (p<=0.05) the hemolytic activity of L. monocytogenes. Results showed that at the lower incubation temperature the hemolytic potential of the bacterium was significantly reduced, from 100% at 37 degrees C to 8% at 10 degrees C (after 65h of incubation) in unsupplemented substrate (0% stevia). Irrespective of the temperature, 10 or 37 degrees C, supplementation of the medium with stevia at 2.5 % (w/v) reduced the bacterium's hemolytic activity by a maximum of 100%. Furthermore, the time of exposure to 2.5 % (w/v) stevia concentration was also a significant factor reducing the hemolytic capability of L. monocytogenes. The possibility of reducing the pathogenic potential of L. monocytogenes (hemolysis) by exposure to stevia should be confirmed in real food matrices, opening a research niche with a valuable future impact on food safety. PMID- 28346878 TI - How appropriate are the English language test requirements for non-UK-trained nurses? A qualitative study of spoken communication in UK hospitals. AB - BACKGROUND: Non-native speakers of English who hold nursing qualifications from outside the UK are required to provide evidence of English language competence by achieving a minimum overall score of Band 7 on the International English Language Testing System (IELTS) academic test. OBJECTIVES: To describe the English language required to deal with the daily demands of nursing in the UK. To compare these abilities with the stipulated levels on the language test. DESIGN: A tracking study was conducted with 4 nurses, and focus groups with 11 further nurses. The transcripts of the interviews and focus groups were analysed thematically for recurrent themes. These findings were then compared with the requirements of the IELTS spoken test. SETTINGS: The study was conducted outside the participants' working shifts in busy London hospitals. PARTICIPANTS: The participants in the tracking study were selected opportunistically;all were trained in non-English speaking countries. Snowball sampling was used for the focus groups, of whom 4 were non-native and 7 native speakers of English. METHODS: In the tracking study, each of the 4 nurses was interviewed on four occasions, outside the workplace, and as close to the end of a shift as possible. They were asked to recount their spoken interactions during the course of their shift. The participants in the focus groups were asked to describe their typical interactions with patients, family members, doctors, and nursing colleagues. They were prompted to recall specific instances of frequently-occurring communication problems. All interactions were audio-recorded, with the participants' permission,and transcribed. RESULTS: Nurses are at the centre of communication for patient care. They have to use appropriate registers to communicate with a range of health professionals, patients and their families. They must elicit information, calm and reassure, instruct, check procedures, ask for and give opinions,agree and disagree. Politeness strategies are needed to avoid threats to face. They participate in medical team discussions, and provide information. They have to be able to translate between everyday and medical registers. This requires socio-pragmatic competence, much of which is not tested by IELTS. CONCLUSIONS: In addition to linguistic knowledge and fluency, nursing requires considerable cultural and pragmatic knowledge and competence. Our findings support arguments for including socio-pragmatic competence in language tests specifically designed for nurses. They also indicate a need for further research to find or design more appropriate assessment, and greater awareness amongst policy makers of the principles of language test design and use. PMID- 28346879 TI - The spatial relations between stimulus and response determine an absolute visuo haptic calibration in pantomime-grasping. AB - Pantomime-grasps entail a response to an area adjacent to (i.e., spatially dissociated pantomime-grasp), or previously occupied by (i.e., no-target pantomime-grasp) a target. Previous work has reported that pantomime-grasps differ kinematically from naturalistic grasps (i.e., grasping a physical target object) - a result taken to evince that pantomime-grasps are perception-based and mediated via relative visual information. However, such actions differ not only in terms of their visual properties, but also because the former precludes haptic feedback related to a target's absolute size. The current study provides four experiments examining whether experimenter-induced haptic feedback influences the information mediating spatially dissociated and no-target pantomime-grasps. Just noticeable-difference scores were computed to determine whether grasps adhered to, or violated, the relative psychophysical properties of Weber's law. Spatially dissociated pantomime-grasps performed with haptic feedback adhered to Weber's law (Experiments 1-3), whereas their no-target pantomime-grasp counterparts violated the law (Experiment 4). Accordingly, we propose that the top-down demands of decoupling stimulus-response relations in spatially dissociated pantomime-grasping renders aperture shaping via a visual percept that is not directly influenced by the integration of haptic feedback. In turn, the decreased top-down demands of no-target pantomime-grasps allows haptic feedback to serve as a reliable sensory resource supporting an absolute visuo-haptic calibration. PMID- 28346880 TI - Human exposure to Bisphenol A and liver health status: Quantification of urinary and circulating levels by LC-MS/MS. AB - A selective and highly sensitive analytical methodology for determination of Bisphenol A in human plasma was developed and validated. The method was based on selective liquid/solid extraction, combined with liquid chromatography electrospray ionization tandem mass spectrometry in the multiple reaction monitoring mode and negative ionization. The linearity of the detector response was verified in human plasma over the concentration range 0.100-200ngmL-1. The detection limit was 0.03ngmL-1 and the quantification limit was 0.100ngmL-1. The analytical features of the proposed in-house validated method were satisfactory: precision was <10% and recoveries were around 84-104%. The matrix effect was studied and compensated using deuterated labeled standard. The applicability of the proposed method was demonstrated analyzing human plasma samples from individuals affected by non-alcoholic fatty liver disease. Bisphenol A was detected above the detection limit in all samples. The data show a persistence of unconjugated Bisphenol A levels in plasma and indicate a chronic Bisphenol A exposure of the target organ, suggesting an association between liver health status and Bisphenol A exposure. The results from our study are valuable for further investigation with large sample size and longitudinal study designs, necessary to confirm the observed association. PMID- 28346881 TI - Heparin and homogeneous model heparin oligosaccharides form distinct complexes with protamine: Light scattering and zeta potential analysis. AB - Large multimolecular complexes of heparin with positively charged proteins such as platelet factor 4 (PF4) or protamine can initiate immune responses associated with heparin use in patients, including the most significant adverse event, heparin-induced thrombocytopenia (HIT). Current evidence suggests that platelet activating antibodies that recognize large multi-molecular complexes (300-700kDa) of PF4 bound to heparin cause HIT [1] and in very rare cases anti-protamine heparin antibodies can induce thrombocytopenia [2]. Heparin is administered as a mixture of sulfated glycosaminoglycans of variable lengths and sulfation levels. To date the potential impact of chain length, sulfation level and impurities on the formation, size and immunogenicity of heparin-protamine complexes has not been addressed due to the lack of purified, homogenous heparin chains for testing purposes. Here, a set of well-characterized model heparin oligosaccharides was used with protamine sulfate to evaluate the physicochemical properties of the resulting complexes. Hydrodynamic radii and zeta potential profiles of heparin protamine complexes were observed to be dependent upon the sulfation location, size and concentration of the model heparin oligosaccharides. The well characterized oligosaccharide-protamine complexes analyzed in this work will be useful for establishing links between heparin-protamine complex physiochemical attributes to their potential to illicit cellular immunogenicity. PMID- 28346882 TI - Determination of prodrug treosulfan and its biologically active monoepoxide in rat plasma, liver, lungs, kidneys, muscle, and brain by HPLC-ESI-MS/MS method. AB - A prodrug treosulfan (TREO) is currently investigated in clinical trials for conditioning prior to hematopoietic stem cell transplantation. Bioanalysis of TREO and its active derivatives, monoepoxide (S,S-EBDM) and diepoxide, in plasma and urine underlay the pharmacokinetic studies of these compounds but cannot explain an organ pharmacological action or toxicity. Recently, distribution of TREO and S,S-EBDM into brain, cerebrospinal fluid, and aqueous humor of the eye has been investigated in animal models and the obtained results presented clinical relevance. In this paper, a selective and rapid HPLC-ESI-MS/MS method was elaborated and validated for the studies of disposition of TREO and S,S-EBDM in rat plasma, liver, lungs, kidneys, muscle, and brain. The two analytes and codeine, internal standard (IS), were isolated from 50MUL of plasma and 100MUL of supernatants of the tissues homogenates using ultrafiltration Amicon vials. Chromatographic resolution was accomplished on C18 column with isocratic elution. The limits of quantitation of TREO and S,S-EBDM in the studied matrices ranged from 0.11 to 0.93MUM. The HPLC-MS/MS method was adequately precise and accurate within and between runs. The IS-normalized matrix effect differed among the tissues and was the most pronounced in a liver homogenate supernatant (approximately 0.55 for TREO and 0.35 for S,S-EBDM). Stability of the analytes in experimental samples was also established. The validated method for the first time enabled determination of TREO and S,S-EBDM in the six life-important tissues in rats following administration of the prodrug. PMID- 28346883 TI - Identification and characterization of a thermally cleaved fragment of monoclonal antibody-A detected by sodium dodecyl sulfate-capillary gel electrophoresis. AB - This report describes a novel, comprehensive approach to identifying a fragment peak of monoclonal antibody-A (mAb-A), detected by sodium dodecyl sulfate capillary gel electrophoresis (SDS-cGE). The fragment migrated close to the internal standard (10kDa marker) of SDS-cGE and increased about 0.5% under a 25 degrees C condition for 6 months. Generally, identification of fragments observed in SDS-cGE is challenging to carry out due to the difficulty of collecting analytical amounts of fractionations from the capillary. In this study, in-gel digestion peptide mapping and reversed phase liquid chromatography-mass spectrometry (RPLC-MS) were employed to elucidate the structure of the fragment. In addition, a Gelfree 8100 fractionation system was newly introduced to collect the fragment and the fraction was applied to the structural analysis of a mAb for the first time. These three analytical methods showed comparable results, proving that the fragment was a fraction of heavy chain HC1-104. The fragment contained complementarity determining regions (CDRs), which are significant to antigen binding, and thus would affect the efficacy of mAb-A. In addition, SDS-cGE without the 10kDa marker was demonstrated to clarify the increased amount of the fragment, and the experiment revealed that the fragment increases 0.2% per year in storage at 5 degrees C. The combination of the three analytical methodologies successfully identified the impurity peak detected by SDS-cGE, providing information critical to assuring the quality and stability of the biotherapeutics. PMID- 28346884 TI - Automatic measurement of melanoma depth of invasion in skin histopathological images. AB - Measurement of melanoma depth of invasion (DoI) in skin tissues is of great significance in grading the severity of skin disease and planning patient's treatment. However, accurate and automatic measurement of melanocytic tumor depth is a challenging problem mainly due to the difficulty of skin granular identification and melanoma detection. In this paper, we propose a technique for measuring melanoma DoI in microscopic images digitized from MART1 (i.e., meleanoma-associated antigen recognized by T cells) stained skin histopathological sections. The technique consists of four modules. First, skin melanoma areas are detected by combining color features with the Mahalanobis distance measure. Next, skin epidermis is segmented by a multi-thresholding method. The skin granular layer is then identified based on Bayesian classification of segmented skin epidermis pixels. Finally, the melanoma DoI is computed using a multi-resolution approach with Hausdorff distance measurement. Experimental results show that the proposed technique provides a superior performance in measuring the melanoma DoI than two closely related techniques. PMID- 28346885 TI - Plasma and brain pharmacokinetics of ganoderic acid A in rats determined by a developed UFLC-MS/MS method. AB - Ganoderic acid A (GAA), an active triterpenoid of the traditional Chinese herbal medicine Lingzhi, has been reported to exhibit antinociceptive, antioxidative, and anti-cancer activities. The present study aims to establish a sensitive and rapid UPLC-MS/MS method for studying the plasma and brain pharmacokinetics of GAA in rats. The analytes were separated on a C18 column eluted with a gradient mobile phase consisting of acetonitrile and 0.1% aqueous formic acid at 0.3mL/min. The eluate was monitored by a mass detector using an MRM (m/z, 515.3 285.1) model in negative electrospray ionization. The calibration curve showed good linearity (r2>0.99), with limits of detection and quantification of 0.25 and 2.00 nmol/L, respectively. The intra- and inter-day precision and accuracy were less than 9.99% and ranged from 97.45% to 114.62%, respectively. The extraction recovery from plasma was between 92.89% and 98.87%. GAA was found to be stable in treated samples at room temperature (22 degrees C) for 12h and in plasma at -20 degrees C for 7d. The developed method was successfully applied to a pharmacokinetic study of GAA in rats. GAA could be rapidly absorbed into the circulation (Tmax, 0.15h) and eliminated relatively slowly (t1/2, 2.46h) after orally dosing, and could also be detected in the brain lateral ventricle (Tmax, 0.25h and t1/2, 1.40h) after intravenously dosing. The absolute oral bioavailability and brain permeability of GAA were estimated to be 8.68% and 2.96%, respectively. PMID- 28346886 TI - Simultaneous determination of amitraz, chlordimeform, formetanate and their main metabolites in human urine by high performance liquid chromatography-tandem mass spectrometry. AB - A rapid, simple and reliable high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for simultaneous determination of amitraz, chlordimeform, formetanate and their main metabolites, N-(2,4 dimethylphenyl)-N-methyl-formamidine (DMPF), 2,4-dimethylformamidine (DMF), 2,4 dimethylaniline (DMA), 4-chloro-2-methylaniline and 3-hydroxyacetanilide in human urine. The urine samples were mixed with buffer solutions (pH 8) and subsequently cleaned up by solid supported liquid/liquid extraction (SLE). The target analytes were efficiently separated with a Waters Atlantis T3 column (150mm*4.6mm, 5MUm), ionized with electrospray ion source in positive mode, and quantitatively determined by tandem mass spectrometry in the multiple reaction monitoring (MRM) mode. In order to minimize matrix effects, the matrix-matched calibration curves of eight analytes were adopted with correlation coefficients (R2) above 0.99. The method were further validated by determining the limits of detection (LODs, 0.3 0.6ng/mL), the limits of quantitation (LOQs, 1.0-2.0ng/mL) and recoveries (89.1% 108.4%) with intra-day and inter-day relative standard deviation (RSD, <11%). The established method was applied and demonstrated in a real case by assaying a urine sample from a female poisoned by formetanate. The achieved results proved this method to be rapid, sensitive and accurate for simultaneous quantitation of eight analytes in human urine for intended forensic cases of human poisoning. PMID- 28346887 TI - High-resolution mass spectrometry as an alternative detection method to tandem mass spectrometry for the analysis of endogenous steroids in serum. AB - Recently, steroid hormones quantification in blood showed a promising ability to detect testosterone doping and interesting complementarities with the urinary module of the Athlete Biological Passport (ABP). In this work, an ultra-high pressure liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) method was developed for the quantification of eleven endogenous steroids in serum. The performance of the full scan and targeted SIM acquisition modes was evaluated and compared to the performance of tandem mass spectrometry (MS/MS). Passing-Bablok regressions and Bland-Altman plots were assessed for each analyte of interest, and concentration values measured by HRMS showed high correlation with the ones obtained by MS/MS for all target hormones, with low absolute differences in the majority of cases. A slight decrease in terms of sensitivity was observed with HRMS in both acquisition modes, but performing an analysis of variance multiblock orthogonal partial least squares (AMOPLS) on the dataset obtained with all three methods revealed that only 0.8% of the total variance was related to instrumentation and acquisition methods. Moreover, the evaluation of the testosterone administration effect over time highlighted testosterone itself and dihydrotestosterone as the most promising biomarkers of exogenous testosterone administration. This conclusion suggests that HRMS could provide suitable performance for blood steroid analysis in the anti-doping field. PMID- 28346888 TI - Oxidative and nitrosative stress biomarkers in chronic schizophrenia. AB - There is evidence that the acute phase of schizophrenia (SCZ) is accompanied by specific changes in oxidative and nitrosative stress (O&NS) biomarkers. There are, however, no firm data regarding these biomarkers in chronic SCZ. Therefore, this study aimed to delineate O&NS biomarkers in patients with chronic SCZ. 125 outpatients with SCZ and 118 controls were enrolled. The markers included lipid hydroperoxides (LOOH), advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), total radical-trapping antioxidant parameter (TRAP) and paraoxonase 1 (PON-1) activity. Immune-inflammatory markers known to be altered in SCZ were also measured: leptin, IL-6, soluble TNF receptors (sTNF-Rs) and the chemokines CCL-11 and CCL-3. There were no significant associations between chronic SCZ and the O&NS markers (AOPP, NOx, LOOH) and the anti-oxidants PON-1 and TRAP. Leptin, sTNF-R, CCL-3 and CCL-11 were significantly higher in SCZ. There were significant associations between pro-inflammatory and O&NS biomarkers (leptin/CCL-8 and AOPP; IL-6 and NOx; CCL-3 and LOOH; CCL-3/IL-6/NOx and TRAP). In conclusion, there were significant intercorrelations between inflammatory and O&NS pathways, which play a role in the pathophysiology of chronic SCZ. O&NS markers and the enzyme PON-1 are not useful as biomarkers in chronic stable polymedicated SCZ patients. PMID- 28346889 TI - Quantifying the dynamics of emotional expressions in family therapy of patients with anorexia nervosa. AB - Emotional interactions have been considered dynamical processes involved in the affective life of humans and their disturbances may induce mental disorders. Most studies of emotional interactions have focused on dyadic behaviors or self reports of emotional states but neglected the dynamical processes involved in family therapy. The main objective of this study is to quantify the dynamics of emotional expressions and their changes using the family therapy of patients with anorexia nervosa as an example. Nonlinear methods characterize the variability of the dynamics at the level of the whole therapeutic system and reciprocal influence between the participants during family therapy. Results show that the variability of the dynamics is higher at the end of the therapy than at the beginning. The reciprocal influences between therapist and each member of the family and between mother and patient decrease with the course of family therapy. Our results support the development of new interpersonal strategies of emotion regulation during family therapy. The quantification of emotional dynamics can help understanding the emotional processes underlying psychopathology and evaluating quantitatively the changes achieved by the therapeutic intervention. PMID- 28346890 TI - High-throughput system-wide engineering and screening for microbial biotechnology. AB - Genetic engineering and screening of large number of cells or populations is a crucial bottleneck in today's systems biology and applied (micro)biology. Instead of using standard methods in bottles, flasks or 96-well plates, scientists are increasingly relying on high-throughput strategies that miniaturize their experiments to the nanoliter and picoliter scale and the single-cell level. In this review, we summarize different high-throughput system-wide genome engineering and screening strategies for microbes. More specifically, we will emphasize the use of multiplex automated genome evolution (MAGE) and CRISPR/Cas systems for high-throughput genome engineering and the application of (lab-on chip) nanoreactors for high-throughput single-cell or population screening. PMID- 28346891 TI - Spatial transcriptomics: paving the way for tissue-level systems biology. AB - The tissues in our bodies are complex systems composed of diverse cell types that often interact in highly structured repeating anatomical units. External gradients of morphogens, directional blood flow, as well as the secretion and absorption of materials by cells generate distinct microenvironments at different tissue coordinates. Such spatial heterogeneity enables optimized function through division of labor among cells. Unraveling the design principles that govern this spatial division of labor requires techniques to quantify the entire transcriptomes of cells while accounting for their spatial coordinates. In this review we describe how recent advances in spatial transcriptomics open the way for tissue-level systems biology. PMID- 28346893 TI - Biochemical transformation of lignin for deriving valued commodities from lignocellulose. AB - The biochemical properties of lignin present major obstacles to deriving societally beneficial entities from lignocellulosic biomass, an abundant and renewable feedstock. Similar to other biopolymers such as polysaccharides, polypeptides, and ribonucleic acids, lignin polymers are derived from multiple types of monomeric units. However, lignin's renowned recalcitrance is largely attributable to its racemic nature and the variety of covalent inter-unit linkages through which its aromatic monomers are linked. Indeed, unlike other biopolymers whose monomers are consistently inter-linked by a single type of covalent bond, the monomeric units in lignin are linked via non-enzymatic, combinatorial radical coupling reactions that give rise to a variety of inter unit covalent bonds in mildly branched racemic polymers. Yet, despite the chemical complexity and stability of lignin, significant strides have been made in recent years to identify routes through which valued commodities can be derived from it. This paper discusses emerging biological and biochemical means through which degradation of lignin to aromatic monomers can lead to the derivation of commercially valuable products. PMID- 28346892 TI - Characterizing regression in Phelan McDermid Syndrome (22q13 deletion syndrome). AB - PURPOSE: To describe the frequency and characteristics of developmental regression in a sample of 50 patients with Phelan McDermid Syndrome (PMS) and investigate the possibility of association between regression, epilepsy, and electroencephalogram (EEG) abnormalities and deletion size. METHODS: The Autism Diagnostic Interview-Revised (ADI-R) was used to evaluate regression in patients with a confirmed diagnosis of PMS. Information on seizure history and EEGs was obtained from medical record review. Deletion size was determined by DNA microarray. RESULTS: A history of regression at any age was present in 43% of all patients. Among those exhibiting regression, 67% had onset after the age of 30 months, affecting primarily motor and self-help skills. In 63% of all patients there was a history of seizures and a history of abnormal EEG was also present in 71%. No significant associations were found between regression and seizures or EEG abnormalities. Deletion size was significantly associated with EEG abnormalities, but not with regression or seizures. CONCLUSION: This study found a high rate of regression in PMS. In contrast to regression in autism, that often occurs earlier in development and affects language and social skills, we found regression in PMS most frequently has an onset in mid-childhood, affecting motor and self-help skills. We also found high rates of seizures and abnormal EEGs in patients with PMS. However, a history of abnormal EEG and seizures was not associated with an increased risk of regression. Larger deletion sizes were found to be significantly associated with a history of abnormal EEG. PMID- 28346894 TI - The Romberg ratio in people with multiple sclerosis. AB - Postural control relies on the integration of inputs from the visual, somatosensory and vestibular systems which are frequently impaired in people with Multiple Sclerosis (PwMS). In this situation, examining the Romberg ratio can be useful. This parameter can be interpreted as a gross indicator of a vestibular and proprioceptive contribution to postural control. Therefore, the primary objective of the current study was to examine whether the Romberg ratio differs between MS fallers, non-fallers and neurological disability levels. In addition, we clarified the association between the Romberg ratio values with validated gait and the balance tests in PwMS. Romberg ratio values were calculated according to the sway rate, total sway area and center of pressure (CoP) path length. The patient group included 542 PwMS (337 women) with a mean age of 42.3 (S.D=13.8). In terms of fall status, significant differences were observed between the faller (n=287) and non-faller (n=255) groups solely in terms of the Romberg ratio ellipse sway area: 2.76 (S.D=2.46) vs. 2.24 (S.D=2.01), P-value=0.01. A significant increase in the Romberg ratio was found between the severe group (n=50), the very mild (n=245), mild (n=186) and moderate (n=61) groups for each of the three Romberg ratio quotients. Significant weak correlation scores were found between the Romberg ratio-ellipse sway area and all walking and balance outcome measures; the Pearson's rho ranged from 0.172 to 0.270. The present data suggest that an elevated Romberg ratio quotient, especially according to the sway area, is an indicator of poor walking and balance capabilities in PwMS. PMID- 28346895 TI - Wheat genomics comes of age. AB - Advances in wheat genomics have lagged behind other major cereals (e.g., rice and maize) due to its highly repetitive and large polyploid genome. Recent technological developments in sequencing and assembly methods, however, have largely overcome these barriers. The community now moves to an era centred on functional characterisation of the genome. This includes understanding sequence and structural variation as well as how information is integrated across multiple homoeologous genomes. This understanding promises to uncover variation previously hidden from natural and human selection due to the often observed functional redundancy between homoeologs. Key functional genomic resources will enable this, including sequenced mutant populations and gene editing technologies which are now available in wheat. Training the next-generation of genomics-enabled researchers will be essential to ensure these advances are quickly translated into farmers' fields. PMID- 28346896 TI - Weak size dependence of resuspended radiocesium adsorbed on soil particles collected after the Fukushima nuclear accident. AB - Most studies of the properties of airborne radionuclides emitted from the Fukushima Daiichi Nuclear Power Plant have focused on the relatively early stages of the accident, and little is known about the characteristics of radiocesium in the long-term. In this study, we analyzed activity size distributions of airborne radiocesium collected over 5 months in Tsukuba, Japan. Radiocesium in the accumulation mode size range (0.1-2 MUm in aerodynamic diameter) was overwhelming in the early aerosol samples and decreased with time, while that associated with coarse aerosols remained airborne. We examined the radiocesium adsorbed onto airborne soil particles, and found that the size dependence of 137Cs surface density adsorbed on soil particles was weak. That is, radiocesium was distributed homogeneously throughout the aerodynamic diameter range of 2.1-11 MUm. This characteristic may be related to the reported structure of radiocesium-bearing soil particles collected from the ground, which consisted of an aggregate of specific clay minerals and other non-cesium adsorbing particles. The resuspension factors for the first two aerosol samples collected during late April and May 2011 were close to those in European cities in the months following the Chernobyl accident, despite different soil and weather conditions. PMID- 28346897 TI - Absence of the right common carotid artery: a rare case without separate origins of the internal and external carotid arteries. AB - Absence of the common carotid artery (CCA) is a rare anomaly. In the few cases described in the literature, it has been typically associated with separate origins of the internal carotid artery (ICA) and external carotid artery (ECA) Fife (1921), Boyd (1934), Rossiti and Raininko (2001), Cerase et al. (2009), Drazin et al. (2010), Yim et al. (2009), Monaco et al. (2009), Jerius et al. (1995), Dahn et al. (1999), Cakirer et al. (2002), Choi et al. (2015), Bryan et al. (1978), Horowitz et al. (2003), Roberts and Gerald (1978), Rajeshwari (2013), Purkayastha et al. (2006), Maybody et al. (2003), Wood et al. (2011) . To the best of our knowledge, absence of the CCA without separate origins of the ECA and ICA has only been described five times before, one of them in conjunction with a persistent proatlantal intersegmental artery (PIA) Cao et al. (2011) and four with agenesis of the ICA Kobayashi et al. (2013), Kunishio et al. (1987), Chen et al. (2008), Xie et al. (2010) . We present a case of a previously undescribed variation of this rare vascular anomaly. PMID- 28346898 TI - Modelling of Escherichia coli concentrations in bathing water at microtidal coasts. AB - Monitoring of the quality of bathing water in line with the European Commission bathing water directive (Directive 2006/7/EC) is a significant economic expense for those countries with great lengths of coastline. In this study a numerical model based on finite elements is generated whose objective is partially substituting the microbiological analysis of the quality of coastal bathing waters. According to a study of the concentration of Escherichia coli in 299 Spanish Mediterranean beaches, it was established that the most important variables that influence the concentration are: monthly sunshine hours, mean monthly precipitation, number of goat cattle heads, population density, presence of Posidonia oceanica, UV, urbanization level, type of sediment, wastewater treatment ratio, salinity, distance to the nearest discharge, and wave height perpendicular to the coast. Using these variables, a model with an absolute error of 10.6+/-1.5CFU/100ml is achieved. With this model, if there are no significant changes in the beach environment and the variables remain more or less stable, the concentration of E. coli in bathing water can be determined, performing only specific microbiological analyses to verify the water quality. PMID- 28346899 TI - Multi-scale approach to Euro-Atlantic climatic cycles based on phenological time series, air temperatures and circulation indexes. AB - The spectral periods in North Atlantic Oscillation (NAO), Atlantic Multidecadal Oscillation (AMO) and El Nino Southern Oscillation (ENSO) were analyzed and has been verified how they imprint a time series of European temperature anomalies (ETA), two European temperature time series and some phenological series (dates of cherry flowering and grapevine harvest). Such work had as reference scenario the linear causal chain MCTP (Macroscale Circulation->Temperature->Phenology of crops) that links oceanic and atmospheric circulation to surface air temperature which in its turn determines the earliness of appearance of phenological phases of plants. Results show that in the three segments of the MCTP causal chain are present cycles with the following central period in years (the % of the 12 analyzed time series interested by these cycles are in brackets): 65 (58%), 24 (58%), 20.5 (58%), 13.5 (50%), 11.5 (58%), 7.7 (75%), 5.5 (58%), 4.1 (58%), 3 (50%), 2.4 (67%). A comparison with short term spectral peaks of the four El Nino regions (nino1+2, nino3, nino3.4 and nino4) show that 10 of the 12 series are imprinted by periods around 2.3-2.4yr while 50-58% of the series are imprinted by El Nino periods of 4-4.2, 3.8-3.9, 3-3.1years. The analysis highlights the links among physical and biological variables of the climate system at scales that range from macro to microscale whose knowledge is crucial to reach a suitable understanding of the ecosystem behavior. The spectral analysis was also applied to a time series of spring - summer precipitation in order to evaluate the presence of peaks common with other 12 selected series with result substantially negative which brings us to rule out the existence of a linear causal chain MCPP (Macroscale Circulation->Precipitation->Phenology). PMID- 28346900 TI - Growing season variability in carbon dioxide exchange of irrigated and rainfed soybean in the southern United States. AB - Measurement of carbon dynamics of soybean (Glycine max L.) ecosystems outside Corn Belt of the United States (U.S.) is lacking. This study examines the seasonal variability of net ecosystem CO2 exchange (NEE) and its components (gross primary production, GPP and ecosystem respiration, ER), and relevant controlling environmental factors between rainfed (El Reno, Oklahoma) and irrigated (Stoneville, Mississippi) soybean fields in the southern U.S. during the 2016 growing season. Grain yield was about 1.6tha-1 for rainfed soybean and 4.9tha-1 for irrigated soybean. The magnitudes of diurnal NEE (~2-weeks average) reached seasonal peak values of -23.18 and -34.78MUmolm-2s-1 in rainfed and irrigated soybean, respectively, approximately two months after planting (i.e., during peak growth). Similar thresholds of air temperature (Ta, slightly over 30 degrees C) and vapor pressure deficit (VPD, ~2.5kPa) for NEE were observed at both sites. Daily (7-day average) NEE, GPP, and ER reached seasonal peak values of -4.55, 13.54, and 9.95gCm-2d-1 in rainfed soybean and -7.48, 18.13, and 14.93gCm-2d-1 in irrigated soybean, respectively. The growing season (DOY 132 243) NEE, GPP, and ER totals were -54, 783, and 729gCm-2, respectively, in rainfed soybean. Similarly, cumulative NEE, GPP, and ER totals for DOY 163-256 (flux measurement was initiated on DOY 163, missing first 45days after planting) were -291, 1239, and 948gCm-2, respectively, in irrigated soybean. Rainfed soybean was a net carbon sink for only two months, while irrigated soybean appeared to be a net carbon sink for about three months. However, grain yield and the magnitudes and seasonal sums of CO2 fluxes for irrigated soybean in this study were comparable to those for soybean in the U.S. Corn Belt, but they were lower for rainfed soybean. PMID- 28346901 TI - Boundary work for implementing adaptive management: A water sector application. AB - Boundary work, defined as effort to mediate between knowledge and action, is a promising approach for facilitating knowledge co-production for sustainable development. Here, we investigate a case study of knowledge co-production, to assess the applicability of boundary work as a conceptual framework to support implementing adaptive management in the water sector. We refer to a boundary work classification recently proposed by Clark et al., (2016), based on three types of knowledge uses, i.e. enlightenment, decision-, and negotiation-support, and three types of sources, i.e. personal expertise, single, and multiple communities of expertise. Our empirical results confirm boundary work has been crucial for the three types of knowledge use. For enlightenment and decision-support, effective interaction among knowledge producers and users was achieved through diverse boundary work practices, including joint agenda setting, and sharing of data and expertise. This initial boundary work eased subsequent knowledge co-production for decision-support and negotiations, in combination with stepping up of cooperation between relevant actors, suitable legislation and pressure for problem solving. Our analysis highlighted the temporal dimension matters - building trust around enlightenment first, and then using this as a basis for managing knowledge co-production for decision-, and negotiation support. We reconfirmed that boundary work is not a single time achievement, rather is a dynamic process, and we emphasized the importance of key actors driving the process, such as water utilities. Our results provide a rich case study of how strategic boundary work can facilitate knowledge co-production for adaptive management in the water sector. The boundary work practices employed here could also be transferred to other cases. Water utilities, as intermediaries between providers and beneficiaries of the important water-related ecosystem service of clean water provision, can indeed serve as key actors for initiating such boundary work practices. PMID- 28346902 TI - In situ synthesis of cobalt ferrites-embedded hollow N-doped carbon as an outstanding catalyst for elimination of organic pollutants. AB - Using polydopamine-metal ions complex as precursor, hollow mesoporous N-doped carbon microspheres encapsulating spinel ferrites nanocrystals (HM-NC/CoFe2O4) were facilely prepared with the aim of creating a novel heterogeneous catalyst for sulfate radical-based oxidation of organic contaminants. The surface morphology, structure and composition of HM-NC/CoFe2O4 catalyst were thoroughly investigated. The applicability of the catalyst was systematically assessed through numerous controlled trials, several operating parameters, as well as different model pollutants by means of peroxymonosulfate (PMS) activation. Outstanding efficiency and excellent reusability were achieved due to the unique structure and composition of HM-NC/CoFe2O4. The HM-NC scaffold with high porosity and surface area not only stabilizes the CoFe2O4 nanoparticles but also greatly facilitates the accessibility and adsorption of substrates to the active sites. In addition, both HM-NC and CoFe2O4 on the material surface can act as active sites. Sulfate radicals and hydroxyl radicals are identified as main active species and a possible enhancement mechanism of catalytic performance is also proposed. Due to the simple synthesis method, low-cost precursors, unique structure and excellent catalytic activity and stability, this novel composite have great potential as new strategic materials for remediation of water pollution. PMID- 28346903 TI - The Oceanus statue of the Fontana di Trevi (Rome): The analysis of black crust as a tool to investigate the urban air pollution and its impact on the stone degradation. AB - This paper deals with the analysis of black crust coming from the statue of Oceanus belonging to the Fontana di Trevi (Rome). This monument is undoubtedly one of the main touristic attractions of Rome. During the restoration held between 2014 and 2015, some diagnostic analyses had been carried out. It has been highlighted that the sheltered surfaces suffer the formation of black crust, especially on the marble statues. The possibility to sample those degradation products, together with the unaltered substrate, represented an excellent opportunity to characterize the marble itself, to assess the impact of the urban air pollution on the stone material, and to detect the pollutant on a precise timescale. In fact, it is known that the previous restoration of the fountain had been carried out between 1989 and 1991 then, information about the air pollution over the last 25years can be highlighted, because it has been proved that black crusts act as passive samplers of pollution. In order to fully characterize those samples, several techniques were used, including optical and scanning electron microscopy, X-ray diffraction, laser ablation inductively coupled plasma mass spectrometry, infrared spectroscopy and ion chromatography. Furthermore, a new methodology based on CHN (Carbon, Hydrogen, Nitrogen) analysis has been developed for the quantification of the two main constituents of the carbonaceous fraction present in the black crusts, i.e. OC (organic carbon) and EC (elemental carbon). This integrated approach proposed in the present study allowed us to gain information about the mineralogical phases and the elements within the crusts and at the crust-substrate interface, giving the possibility to identify the pollution sources causing the stone decay within the monument. PMID- 28346904 TI - Single particle mass spectral signatures from vehicle exhaust particles and the source apportionment of on-line PM2.5 by single particle aerosol mass spectrometry. AB - In order to accurately apportion the many distinct types of individual particles observed, it is necessary to characterize fingerprints of individual particles emitted directly from known sources. In this study, single particle mass spectral signatures from vehicle exhaust particles in a tunnel were performed. These data were used to evaluate particle signatures in a real-world PM2.5 apportionment study. The dominant chemical type originating from average positive and negative mass spectra for vehicle exhaust particles are EC species. Four distinct particle types describe the majority of particles emitted by vehicle exhaust particles in this tunnel. Each particle class is labeled according to the most significant chemical features in both average positive and negative mass spectral signatures, including ECOC, NaK, Metal and PAHs species. A single particle aerosol mass spectrometry (SPAMS) was also employed during the winter of 2013 in Guangzhou to determine both the size and chemical composition of individual atmospheric particles, with vacuum aerodynamic diameter (dva) in the size range of 0.2-2MUm. A total of 487,570 particles were chemically analyzed with positive and negative ion mass spectra and a large set of single particle mass spectra was collected and analyzed in order to identify the speciation. According to the typical tracer ions from different source types and classification by the ART-2a algorithm which uses source fingerprints for apportioning ambient particles, the major sources of single particles were simulated. Coal combustion, vehicle exhaust, and secondary ion were the most abundant particle sources, contributing 28.5%, 17.8%, and 18.2%, respectively. The fraction with vehicle exhaust species particles decreased slightly with particle size in the condensation mode particles. PMID- 28346905 TI - Modeling the terrestrial N processes in a small mountain catchment through INCA N: A case study in Taiwan. AB - Riverine dissolved inorganic nitrogen (DIN) is an important indicator of trophic status of aquatic ecosystems. High riverine DIN export in Taiwan, ~3800kg-Nkm-2yr 1, which is ~18 times higher than the global average, urges the need of thorough understanding of N cycling processes. We applied INCA-N (Integrated Nitrogen Catchment Model) to simulate riverine DIN export and infer terrestrial N processes using weekly rainwater and streamwater samples collected at the Fushan Experimental Forest (FEF) of northern Taiwan. Results showed that the modeled discharge and nitrate export are in good agreement with observations, suggesting the validity of our application. Based on our modeling, the three main N removal processes, in the order of descending importance, were plant uptake, riverine N transport and denitrification at FEF. The high plant uptake rate, 4920kg-Nkm-2yr 1, should have led to accumulation of large biomass but biomass at FEF was relatively small compared to other tropical forests, likely due to periodic typhoon disruptions. The low nitrate concentration but high DIN export highlights the importance of hydrological control over DIN export, particularly during typhoons. The denitrification rate, 750kg-Nkm-2yr-1, at FEF was also low compared to other tropical forest ecosystems, likely resulting from quick water drainage through the coarse-loamy top soils. The high DIN export to atmospheric deposition ratio, 0.45, suggests that FEF may be in advanced stages of N excess. This simulation provides useful insights for establishing monitoring programs and improves our understanding N cycling in subtropical watersheds. PMID- 28346906 TI - Long-term exposure to high air pollution induces cumulative DNA damages in traffic policemen. AB - The specific effects of long-term exposure to high air pollution on human health and biological remain unclear. To explore the adverse health effects as well as biological mechanisms and biomarkers for durative exposure to air pollution, 183 traffic policemen and 88 office policemen were enrolled in this study. The concentration of PM2.5 in both the traffic and office policemen's working environments were obtained. Detailed personal questionnaires were completed and levels of inflammation, oxidative stress and DNA damage markers of all participants were analyzed in this study. The average PM2.5 concentration of the intersections of main roads and the offices of control group were 132.4+/ 48.9MUg/m3 and 50.80+/-38.6MUg/m3, respectively. The traffic policemen, who stably exposed to at least 2 times higher PM2.5 in their work area as compared with the control group, have a median average duration of 7.00years, and average cumulative intersection duty time reached 8030h. No statistically significant differences in the levels of inflammation markers were observed between the traffic and office policemen. However, the DNA damage markers in traffic policemen shared significant positive correlation with cumulative intersection duty time and higher than those in the office policemen. Multiple linear regression analysis demonstrated that the increase of cumulative intersection duty time by 1h per day for one year was associated with the increase in 8 hydroxy-20-deoxyguanosine of 0.329% (95% CI: 0.249% to 0.409%), tail DNA of 0.051% (95% CI: 0.041% to 0.061%), micronucleus frequency of 0.0360/00 (95% CI: 0.030/00 to 0.0430/00), and a decrease in glutathione of 0.482% (95% CI: -0.652% to -0.313%). These findings suggest that long-term exposure to high air pollution could induce cumulative DNA damages, supporting the hypothesis that durative exposure to air pollution is associated with an increased risk of cancer. PMID- 28346907 TI - Long-term associations of modeled and self-reported measures of exposure to air pollution and noise at residence on prevalent hypertension and blood pressure. AB - Air pollution, traffic noise and noise annoyance are suggested to be associated with hypertension and blood pressure (BP); however, the evidence remains inconsistent. Our study examined the long-term associations of modeled and self reported measures of air pollution and traffic noise on prevalent hypertension and BP. We analyzed cross-sectional data from 2552 participants aged 31-72years from the KORA F4 (2006-2008) study conducted in the region of Augsburg, Germany. Land-use regression models were used to estimate residential long-term exposure to particulate matter <2.5MUm (PM2.5), soot content of PM2.5 (PM2.5abs) and nitrogen dioxide (NO2). Road traffic noise levels at the facade of the dwellings were estimated for the participants' residences. Participants filled-in a questionnaire on noise annoyance and heavy traffic passing their residence. Linear and logistic regression models adjusting for confounders were used to assess the association between exposure measures and hypertension and BP. An interquartile increase in annual mean PM2.5 (1MUg/m3) was significantly associated with 15% higher prevalence of hypertension, without (95% CI: 2.5; 28.0%) and with (95% CI: 0.7; 30.8%) adjustment for traffic noise. Diastolic blood pressure (DBP) was associated with air pollutants and traffic noise with percent increases in mean of 0.7 (95% CI: 0.2; 1.2), 0.6 (95% CI: 0.1; 1.1) and 0.3 (95% CI: 0.0; 0.7) for an interquartile increase in PM2.5 (1MUg/m3) and PM2.5abs (0.2*10-5/m), and 5dB(A) increase in 24-hour road traffic noise, respectively. Associations of PM2.5abs and NO2 with hypertension or DBP were stronger in men and diabetic individuals. No clear associations were seen with systolic BP or noise annoyance. In conclusion, self-reported measures of air pollution or noise did not perform better than the objective measures. Our findings provide further evidence for a link between air pollution, noise and cardiovascular disease and indicate a stronger association for men and diabetic individuals. PMID- 28346908 TI - Different effects of biochar and a nitrification inhibitor application on paddy soil denitrification: A field experiment over two consecutive rice-growing seasons. AB - Biochar and nitrification inhibitors are increasingly being proposed as amendments to improve nitrogen use efficiency (NUE). However, their effects on soil denitrification and the major N loss in rice paddies over an entire rice growing season are not well understood. In this study, using intact soil core incubation combined with N2/Ar technique, the impacts of biochar and a nitrification inhibitor (Ni), 2-chloro-6-(trichloromethyl)-pyridine, on rice yield and soil denitrification, as well as ammonia (NH3) volatilization, were investigated over two rice-growing seasons in the Taihu Lake region of China. Field experiments were designed with four treatments: N0 (no N applied), N270 (270kg N ha-1 applied), N270+C (25tha-1 biochar applied) and N270+Ni (2-chloro-6- [trichloromethyl] -pyridine, 1.35kgha-1N applied). Compared with single application of N fertilizer alone (N270), biochar (N270+C) and Ni (N270+Ni) applications increased rice yields by 4.2-5.2% and 6.2-7.3%, respectively. The cumulative N2-N and NH3-N losses in different treatments varied from 11.9 to 21.8% and from 11.5 to 22.0% of the applied N, respectively. Compared with the single application of N fertilizer, the Ni application increased total NH3 emission by 4.0-20.6% and significantly decreased total N2-N emission by 9.7 19.4% (p<0.05), while the biochar application increased total NH3 and N2-N emissions by 8.6-17.9% and 3.3-9.7%, respectively. Overall, the biochar application resulted in an 11-15% higher net gaseous N than the Ni application. Although the biochar application may increase the rice yield and consequently the plant N uptake, it also promoted N loss more than Ni. Therefore biochar may not be good for maintaining soil fertility over a long period. Instead, applying Ni may be an optimal practice to ensure food security, while decreasing gaseous N loss, for rice production in the Taihu Lake region of China. PMID- 28346909 TI - Bioaugmentaton in Technosols created in abandoned pyritic tailings can contribute to enhance soil C sequestration and plant colonization. AB - Creation of Technosols in combination with phytostabilization may be a sustainable strategy to minimize the environmental and human health hazards derived from mine tailings. Bioaugmentation can facilitate plant establishment and growth for efficient phytostabilization. In order to assess if bioaugmentation can increase soil quality and fertility, decrease metal(loid) mobility and accelerate plant colonization, a one-year field experiment was designed with creation of Technosols in two tailings ponds with different pH (acidic (AT) and neutral (NT)), with addition of marble waste (MaW) and two organic materials (pig manure (PM) and sewage sludge (SS), without or with inoculation of effective microorganisms (EM) at three rates. Results showed that MaW was the main factor responsible for maintaining pH ~7 in AT and ~8 in NT, decreasing salinity, and decreasing the soluble fraction of metals (70-99%). The soluble fraction of As decreased ~45% in AT, related to increases in pH up to neutrality, while increased ~90% in NT with PM due to pH>8 and higher content of organic compounds. The addition of PM and SS significantly increased soil organic C (SOC), nutrient contents and microbial biomass and activity in both tailings, being PM more effective. However, a positive priming effect was observed in NT with SS addition likely due to higher C/N ratio and lack of nutrients. There was a significant effect of EM rate on inorganic C, SOC, N, K and microbial biomass and activity, with higher values as rate increased. Vegetation richness and density directly increased with increasing EM rate. Multivariate analyses showed that the most important properties contributing to increase richness and plant density were microbial biomass and N. Thus, bioaugmentation contributed to soil C sequestration (as organic and inorganic C) and soil fertility, related to high soil microbial biomass and activity, which facilitated an effective colonization of vegetation. PMID- 28346911 TI - Conserved Patterns of Trigeminal Somatosensory System Organization in Mammals. PMID- 28346910 TI - Occurrence, temporal variation, and estrogenic burden of five parabens in sewage sludge collected across the United States. AB - Five parabens used as preservatives in pharmaceuticals and personal care products (PPCPs) were measured in sewage sludges collected at 14 U.S. wastewater treatment plants (WWTPs) located in nine states. Detected concentration ranges (ng/g, dry weight) and frequencies were as follows: methyl paraben (15.9 to 203.0; 100%), propyl paraben (0.5 to 7.7; 100%), ethyl paraben (<0.6 to 2.6; 63%), butyl paraben (<0.4 to 4.3; 42%) and benzyl paraben (<0.4 to 3.3; 26%). The estrogenicity inherent to the sum of parabens detected in sewage sludge (ranging from 10.1 to 500.1pg/kg 17beta-estradiol equivalents) was insignificant when compared to the 106-times higher value calculated for natural estrogens reported in the literature to occur in sewage sludge. Temporal monitoring at one WWTP provided insights into temporal and seasonal variations in paraben concentrations. This is the first report on the occurrence of five parabens in sewage sludges from across the U.S., and internationally, the first on temporal variations of paraben levels in sewage sludge. Study results will help to inform the risk assessment of sewage sludge destined for land application (biosolids). PMID- 28346912 TI - Optimizing the Dose of Erythropoietin Required to Prevent Acute Ventilation Induced Cerebral White Matter Injury in Preterm Lambs. AB - Erythropoietin (EPO) is being trialed in preterm neonates for neuroprotection. We have recently demonstrated that a single high bolus dose (5,000 IU/kg) of recombinant human EPO amplified preterm lung and brain ventilation-induced injury. We aimed to determine the optimal dose of EPO to reduce ventilation induced cerebral white matter inflammation and injury in preterm lambs. Lambs (0.85 gestation) were ventilated with an injurious strategy for 15 min followed by conventional ventilation for 105 min. Lambs were randomized to no treatment (VENT; n = 8) or received a bolus dose of EPO (EPREX(r)): 300 IU/kg (EPO 300; n = 5), 1,000 IU/kg (EPO 1,000; n = 5), or 3,000 IU/kg (EPO 3,000; n = 5). Physiological parameters were measured throughout the study. After 2 h, brains were collected for analysis; real-time quantitative polymerase chain reaction and immunohistochemistry were used to assess inflammation, cell death, and vascular leakage in the periventricular and subcortical white matter (PVWM; SCWM). Molecular and histological inflammatory indices in the PVWM were not different between groups. EPO 300 lambs had higher IL-6 (p = 0.006) and caspase-3 (p = 0.025) mRNA expression in the SCWM than VENT lambs. Blood-brain barrier (BBB) occludin mRNA levels were higher in EPO 3,000 lambs in the PVWM and SCWM than VENT lambs. The number of blood vessels with protein extravasation in the SCWM was lower in EPO 1,000 (p = 0.010) and EPO 3,000 (p = 0.025) lambs compared to VENT controls but not different between groups in the PVWM. Early administration of EPO at lower doses neither reduced nor exacerbated cerebral white matter inflammation or injury. 3,000 IU/kg EPO may provide neuroprotection by improving BBB integrity. PMID- 28346913 TI - Selected Food Consumption Mediates the Association between Education Level and Metabolic Syndrome in Korean Adults. AB - BACKGROUND/AIMS: Low socioeconomic status (SES) is linked to higher incidence/mortality of cardiovascular disease, but emerging evidence inconsistently reported that education level, a proxy for SES, is related to cardiovascular risk and metabolic syndrome (MetS) in Koreans. Furthermore, limited information is available on whether dietary components would mediate the relationship between education level and cardiovascular risk. We hypothesized that selected food consumption mediates the association between education level and MetS prevalence. METHODS: Data from the Korea National Health and Nutritional Examination Survey (2008-2011) were included in cross-sectional analyses (n = 11,029, 30-64 years). The possible mediating effect of selected food groups (fruits, raw vegetables, red meat, milk, and soft drinks) on the association between education level and MetS was tested using a multiple mediation model. RESULTS: Education level was negatively associated with MetS prevalence. The association between lower education level and higher MetS prevalence was partially mediated by selected food consumption (lower intakes of fruit, red meat and milk; higher intakes of vegetable and soft drink) after adjusted for covariates. Gender also modified the association between education level and MetS prevalence that was more prominent in women than in men. CONCLUSIONS: Selected food consumption substantially contributes to the association between education level and MetS in Korean adults, especially among women. PMID- 28346914 TI - TOP: Prospective Evaluation of a Volume Based, Computer Assisted Method for Transperineal Optimized Prostate Biopsy. AB - OBJECTIVE: This study is a prospective evaluation of a volume-based, computer assisted method for transperineal optimized prostate (TOP) biopsy. The TOP algorithm automates core planning for systematic prostate biopsies using the 3 dimensional organ contour and an alterable volume for tumors to be excluded. SUBJECTS AND METHODS: MRI-transrectal ultrasound fusion biopsy with MRI-targeted biopsies (TBs) and systematic-TOP biopsies were performed on 172 men between October 2013 and March 2014. Systematic biopsies were placed according to TOP for detection of tumor volumes >0.5 mL with a minimum of 80% organ coverage in prostates up to 50 mL (70% in larger organs). RESULTS: Median 24 TOP cores and 3 MRI-TBs have been placed. Prostate cancer (PCa) was detected in 112 of 172 (65%) of men; TOP detected 109 (97%) and TB 62 (55%). Significant cancer (Gleason score >=7) was detected in 75 (44%) of men and of these TOP detected 73 of 75 (97%) and TB 51 of 75 (68%). Overall, systematic-TOP sampling significantly outperformed TB for the detection of both, all PCa as well as significant PCa (p < 0.0001, p = 0.0005). CONCLUSION: The TOP method is innovative by integrating the individual prostate volume and PCa volume detection thresholds. In the present cohort, it diagnosed more significant tumors than TB alone. However, at the same time, more low-risk tumors are detected. PMID- 28346915 TI - Safety and Efficacy of Flexible Ureteroscopy in Combination with Holmium Laser Lithotripsy for the Treatment of Bilateral Upper Urinary Tract Calculi. AB - OBJECTIVE: To retrospectively evaluate the safety and efficacy of flexible ureteroscopy (FURS) in combination with holmium laser lithotripsy for the treatment of bilateral upper urinary calculi. MATERIALS AND METHODS: The stone free status was defined as the absence of any stones or asymptomatic status, or the presence of clinically insignificant residual fragments <4 mm, and was assessed by plain kidney, ureter, and bladder X-ray. The operative time, stone free rates (SFRs), serum creatinine (SCr), and complications were recorded. RESULTS: During the operation, there was no bleeding, ureteral perforation, avulsion, and rupture. Postoperative hematuria was observed in 2 patients. SCr increased significantly on the first day after the procedure compared with the preoperative SCr, but after 4 weeks, the renal function significantly improved (p < 0.05). The SFR was 71.6% (63/88) on the first day after the first surgical procedure; it then increased to 86.4% (76/88) in the fourth week, and rose to 97.4% (76/78) after the second operation. CONCLUSION: The results demonstrated that FURS in combination with holmium laser lithotripsy represented a favorable less-invasive alternative with high SFR and acceptable complication rates in the treatment of bilateral upper urinary tract calculi. PMID- 28346916 TI - PD-1/PD-L1 Pathway in Breast Cancer. AB - The programmed cell death-1 receptor (PD-1) is an immune checkpoint inhibitor which is expressed on the surface of immune effector cells. It is activated mainly by PD-L1 which can be expressed by all human cells. The PD-1/PD-L1 pathway plays a subtle role in maintaining peripheral T-lymphocyte tolerance and regulating inflammation. In cancer, the expression of PD-L1 seems to be one of the major immune escape mechanisms. Many studies have shown efficacy of blocking PD-1 or PD-L1 with specific antibodies like pembrolizumab or atezulizumab. In breast cancer, potential response was demonstrated in metastatic triple-negative breast cancers. PMID- 28346917 TI - Endocrine Long-Term Follow-Up of Children with Neurofibromatosis Type 1 and Optic Pathway Glioma?. AB - BACKGROUND/AIMS: Children with optic pathway glioma (OPG) face sequelae related to tumour location and treatment modalities. We aimed to assess the prevalence of hypothalamic-pituitary dysfunctions in children with neurofibromatosis type 1 (NF1) and OPG who did not receive radiotherapy or surgical resection. The causative role of tumour location on endocrinopathy development is investigated. METHODS: A retrospective follow-up study of 40 children with NF1 and OPG evaluated between August 1996 and May 2015 was undertaken. Patients who underwent radiotherapy or surgical resection were excluded and 36 patients were studied. Tumour location was classified according to the Dodge criteria: stage I, optic nerve alone; stage II, optic chiasm with or without optic nerve involvement; and stage III, involvement of the hypothalamus or other adjacent structures. RESULTS: Endocrinopathies were diagnosed in 20/36 (55.6%) children during a mean follow-up of 9.1 (0.2-13.6) years: 0/4 OPGs were Dodge stage I, 12/21 (57.1%) stage II, and 8/11 (72.7%) stage III. The first endocrinopathy was found at a mean age of 7.4 (5.0-13.2) years, 2.4 (0-6.7) years after tumour diagnosis. We found growth hormone deficiency (GHD; 36.1%), central precocious puberty (33.3%), obesity with insulin resistance/impaired glucose tolerance (11.1%), early puberty (5.5%), GH excess (5.5%), ACTH deficiency (5.5%), hypogonadotropic hypogonadism (2.7%), and thyrotropin deficiency (2.7%). GHD was transient in all of those who were retested. CONCLUSION: This population is at high risk of endocrinopathies due to tumour location. Lifelong endocrine follow-up is recommended.?. PMID- 28346919 TI - The Pregnancy Microbiome. AB - In recent years, microbiome research has revealed multiple essential roles of the microorganisms residing within the human body in host metabolism, immunity, and overall health. Numerous physiological and pathological states, including obesity and the metabolic syndrome, have been correlated with microbial changes, termed dysbiosis. Our microbiomes change in response to our environment, diet, weight, hormones, and other factors. It is, therefore, not surprising that there are also significant changes in the microbiome during pregnancy when dramatic weight gain and metabolic and immunological changes occur. In this review, we summarize the known changes in microbial composition throughout pregnancy at a variety of body sites, including the gut, vagina, oral cavity, and placenta, and we describe several studies that have linked pregnancy complications with microbial changes. Unlike the case of certain disease states, such as obesity, where dysbiosis is considered to have negative effects, we believe that the microbial alterations observed during pregnancy are vital for a healthy pregnancy. While more research in this field is required to reveal specific mechanisms and pathways regulating these alterations, the microbial changes during pregnancy are likely coordinated with the immune, endocrine, and metabolic states. PMID- 28346918 TI - 5-HT1A Receptors Mediate Analgesia Induced by Emulsified Sevoflurane in Thermal Nociception but Have Little Effect on Chemical Nociception. AB - OBJECTIVE: The study aimed to investigate the relationship between the analgesic effect of sevoflurane and 5-serotonin receptor 1A (5-HT1A R) in the spinal cords of mice. METHODS: Analgesic mouse models were established by intraperitoneal injection of emulsified sevoflurane, and the influence of p-MPPF (a specific antagonist of 5-HT1A Rs) intrathecal injection on the changes in tail-flick latency in tail-withdrawal test, pain threshold in hot-plate test (HPPT), and writhing times in acetic acid-induced writhing test were recorded. RESULTS: Intraperitoneal injection of emulsified sevoflurane alone produced an analgesic effect (p < 0.05). p-MPPF (2, 4, and 8 MUg) alone had no impact on tail-flick latency, HPPT, and writhing times in mice (p > 0.05). The 3 doses of p-MPPF reduced the tail-flick latency or HPPT. p-MPPF 8 MUg can increase the writhing times (p < 0.05) in analgesic mice with sevoflurane, while p-MPPF 2 and 4 MUg did not affect the writhing times. CONCLUSION: 5-HT1A Rs in the spinal cord may be an important target for the analgesic effect of sevoflurane on the thermal nociception, but it has little relation to the anti-chemical chemical nociceptive effect of sevoflurane. PMID- 28346920 TI - Microbial Composition of the Initial Colonization of Newborns. AB - Early-life interaction with indigenous intestinal microbes is a prerequisite for healthy immune and metabolic maturation. Human infants acquire their gut microbiota predominantly from the mother. A considerable inoculum of microbes is received by the neonate during vaginal delivery. Recent observations suggest that human gut colonization may be initiated prenatally by microbes in amniotic fluid, but the significance of this phenomenon remains unknown. After birth, neonatal gut colonization is guided by human milk factors, which selectively promote the growth of specific microbes, as well as by live microbes present in human milk. Aberrant gut colonization in early life has been associated with an increased risk of noncommunicable diseases in later life. Epidemiological and experimental studies suggest a causal relationship between early-life gut microbiota perturbations and disease risk. Perinatal antibiotic exposure, cesarean section delivery, postnatal antibiotic administration, and formula feeding, which may disrupt intestinal microecology, have been associated with disease development in later life. The modulation of gut microbiota in the perinatal period by pre- and probiotics, for example, may offer a means to reduce the risk of chronic diseases. PMID- 28346921 TI - Bacterial Colonization of the Newborn Gut, Immune Development, and Prevention of Disease. AB - We now know that the fetus does not reside in a sterile intrauterine environment but is exposed to commensal bacteria from the maternal gut which cross the placenta and infiltrate the amniotic fluid. This exposure to colonizing bacteria continues at birth and during the first year of life, and it has a profound influence on lifelong health. Why is this important? Cross talk with colonizing bacteria in the developing neonatal intestine helps in the initial adaptation of the infant to extrauterine life, particularly in acquiring immune homeostasis, and provides protection against disease expression (e.g., allergy, autoimmune disease, and obesity) later in life. Colonizing intestinal bacteria are critical to the development of host defense during the neonatal period. Disrupted colonization (dysbiosis) due to cesarean section delivery, perinatal antibiotics, or premature delivery may adversely affect the development of host defense mechanisms in the gut and predispose to inflammation leading to increased susceptibility to disease later in life. Clinical evidence suggests that babies born by cesarean section have higher incidence rates of allergy, type 1 diabetes, and obesity. Infants given repeated antibiotic regimens are more likely to have asthma as adolescents. This observation helps to explain the disease paradigm shift in children from developed countries. PMID- 28346922 TI - Epigenetics in Gastrointestinal Health and Disease: Spotlight on DNA Methylation in the Intestinal Epithelium. AB - Epigenetics can be defined as stable, potentially heritable changes in cellular phenotype caused by mechanisms other than alterations in the underlying DNA sequence. DNA methylation is amongst the most intensely studied epigenetic mechanisms and has been shown to play a major role in regulating fundamental aspects of cell biology including cellular differentiation, organ development, and cell type-specific gene expression. Importantly, it is becoming increasingly clear that epigenetic mechanisms operate at the interface between the genetic code and our environment and are able to mediate environmental changes into stable phenotypic alterations. Given existing evidence supporting the important effects of environmental factors (e.g., diet, nutrition, and infections) on human health, epigenetic mechanisms provide a plausible mechanistic framework for the development of many multifactorial diseases including inflammatory bowel disease (IBD). Impaired function of the intestinal epithelium has been implicated in IBD pathogenesis, yet underlying mechanisms remain ill defined. The work of our group focuses on investigating the role of DNA methylation in regulating cellular function of the human intestinal epithelium during gastrointestinal health and IBD. In addition to performing an analysis of primary human intestinal epithelium, we utilize human intestinal organoid culture systems allowing us to perform functional analysis in a patient-derived ex vivo model. PMID- 28346924 TI - Early-Life Antibiotic Exposure, Gut Microbiota Development, and Predisposition to Obesity. AB - Antibiotics are often prescribed inappropriately to infants and young children, with potentially adverse effects on the developing gut microbiota and related metabolic processes. We review evidence from 17 epidemiologic studies suggesting that antibiotic exposure during critical periods of early development may influence weight gain and the development of obesity. Complementary research in both humans and rodents indicates that gut microbiota play a key role in this process, although further research is needed to confirm and characterize the causal mechanisms involved. Obesity is a complex and multifactorial condition; thus, a multipronged prevention strategy will be required to curb the current obesity epidemic. Evidence to date suggests this strategy should include the judicious use of antibiotics, especially in early life when the developing gut microbiota is particularly susceptible to perturbations with long-lasting implications for metabolic programming and obesity risk. PMID- 28346923 TI - Gut-Brain Axis and Behavior. AB - In the last 5 years, interest in the interactions among the gut microbiome, brain, and behavior has exploded. Preclinical evidence supports a role of the gut microbiome in behavioral responses associated with pain, emotion, social interactions, and food intake. Limited, but growing, clinical evidence comes primarily from associations of gut microbial composition and function to behavioral and clinical features and brain structure and function. Converging evidence suggests that the brain and the gut microbiota are in bidirectional communication. Observed dysbiotic states in depression, chronic stress, and autism may reflect altered brain signaling to the gut, while altered gut microbial signaling to the brain may play a role in reinforcing brain alterations. On the other hand, primary dysbiotic states due to Western diets may signal to the brain, altering ingestive behavior. While studies performed in patients with depression and rodent models generated by fecal microbial transfer from such patients suggest causation, evidence for an influence of acute gut microbial alterations on human behavioral and clinical parameters is lacking. Only recently has an open-label microbial transfer therapy in children with autism tentatively validated the gut microbiota as a therapeutic target. The translational potential of preclinical findings remains unclear without further clinical investigation. PMID- 28346925 TI - Microbiota and Necrotizing Enterocolitis. AB - Necrotizing enterocolitis (NEC) is an acquired gastrointestinal inflammatory condition with significant mortality and morbidity in preterm very low birth weight infants. The interplay between toll-like receptors, bacterial endotoxins, developmentally regulated excessive proinflammatory responses of the immature innate immune system, hypoxia, ischemia, reperfusion, free radicals, and the presence of substrates and bacterial endotoxins is thought to play an important role in the pathogenesis of NEC. The association (cause?) of various microbes (bacteria, viruses, and fungi) with NEC has intrigued researchers for many years. Availability of newer molecular methods (e.g., 16S ribosomal RNA gene-specific primers/pyrosequencing of fecal DNA) is expected to improve our understanding of the role of gut microbiota in the pathogenesis of NEC. Recent studies employing such methods to assess fecal microbiota are reviewed. Current evidence suggests that dysbiosis of the gut microbiota precedes the development of NEC in preterm infants. Further research is required to understand the significance of changes in the gut microbiome over the early postnatal period including the relative abundance of Gammaproteobacteria and the paucity of strict anaerobic bacteria that precedes NEC in preterm infants. Assessing the reproducibility of previous findings in large prospective studies with standardized methodology (e.g. sample processing, PCR primer, and DNA extraction) is important. PMID- 28346926 TI - Microbiota and Obesity. AB - Obesity is globally the most prevalent nutritional disorder. Multifaceted therapeutic approaches are called for to halt the cascade from neonatal adiposity/high birth weight to childhood excessive weight gain/adult obesity with comorbidities. Recent experimental and clinical data provide one new target for interventions aiming to close this vicious circle: the microbiota. An aberrant gut microbiota, dysbiosis, induces immune and metabolic disturbances both locally and, consequent upon impaired gut barrier function, also systemic low-grade inflammation, which is causally linked to insulin resistance. The gut microecology could thus fill the gap between energy intake and expenditure by processing nutrients and regulating their access to and storage in the body, producing chemicals of hormonal nature and controlling the secretion of proinflammatory mediators locally and systemically. Conversely, being highly sensitive to environmental impacts, particularly to early feeding, the compositional development of the gut microbiota may prove the target of choice in efforts to reduce the risk of obesity. It has been demonstrated that a lower number of bifidobacteria precedes the development of obesity, and a dearth of butyrate-producing bacteria and an overall richness of bacteria increase the risk of metabolic disease; moreover, recognition that practices known to disrupt the early gut microbiota, e.g., cesarean section delivery and antibiotic exposure, contribute to obesity, encourages to pursue this line of research. PMID- 28346927 TI - Microbiota in Functional Gastrointestinal Disorders in Infancy: Implications for Management. AB - The complex and diverse intestinal microbiome is recognized as important in promoting human health. An altered gut microflora, referred to as dysbiosis, is increasingly recognized as having an etiologic role in a variety of conditions, including functional gastrointestinal disorders: colic in infants and irritable bowel syndrome in older children. Probiotics are defined as live microorganisms that, if ingested in sufficient amounts, restore microbial homeostasis and have a benefit on health. Randomized controlled trials indicate that probiotics can be effective in a variety of intestinal conditions, including colic and irritable bowel syndrome. Probiotics may promote gut microbial diversity, but timing of the intervention appears crucial. Strain-specific effects on colonization resistance, epithelial barrier integrity, modulation of signal transduction, impacts on innate and adaptive immune responses, and effects on visceral hyperalgesia likely explain the observed variability in various probiotic strains. In the future, probiotics are likely to be chosen for use in a defined clinical setting based on underlying mechanism(s) of action. The precise component of the probiotic agent mediating observed effects is the subject of current research. Unresolved issues relate to optimal dosages, timing of ingestion, single versus combination formulations, maintenance of viability in storage, and the merits of employing probiotic-derived products. PMID- 28346928 TI - Diet and Gut Microbiota in Health and Disease. AB - Gut microbiota plays an important role in host health maintenance and disease pathogenesis. The development of a stable and diverse gut microbiota is essential to various host physiologic functions such as immunoregulation, pathogen prevention, energy harvest, and metabolism. At the same time, a dysbiotic gut microbiota associated with disease is altered in structure and function, and often characterized by a decrease in species richness and proliferation of pathogenic bacterial taxa. As a shared substrate between the host and the gut microbiota, diet significantly impacts the health and disease states of the host both directly and through gut microbial metabolite production. This is demonstrated in the examples of short-chain fatty acid and trimethylamine production via bacterial metabolism of dietary complex carbohydrates and choline, respectively. In disorders related to mucosal immune dysregulation such as inflammatory bowel disease, the dysbiotic gut microbiota and diet contribute to its pathogenesis. Reversal of dysbiosis through fecal microbiota transplantation and dietary interventions may thus represent important strategies to modify the gut microbiota and its metabolite production for health maintenance as well as disease prevention and management. PMID- 28346929 TI - Summary of Normal Development of Gut Microbiota and Dysbiosis. PMID- 28346930 TI - Enzymes in Human Milk. AB - Milk proteins are a complex and diverse source of biological activities. Beyond their function, intact milk proteins also act as carriers of encrypted functional sequences that, when released as peptides, exert biological functions, including antimicrobial and immunomodulatory activity, which could contribute to the infant's competitive success. Research has now revealed that the release of these functional peptides begins within the mammary gland itself. A complex array of proteases produced in mother's milk has been shown to be active in the milk, releasing these peptides. Moreover, our recent research demonstrates that these milk proteases continue to digest milk proteins within the infant's stomach, possibly even to a larger extent than the infant's own proteases. As the neonate has relatively low digestive capacity, the activity of milk proteases in the infant may provide important assistance to digesting milk proteins. The coordinated release of these encrypted sequences is accomplished by selective proteolytic action provided by an array of native milk proteases and infant produced enzymes. The task for scientists is now to discover the selective advantages of this protein-protease-based peptide release system. PMID- 28346931 TI - Compositional Analysis and Metabolism of Human Milk Oligosaccharides in Infants. AB - It is a great success that biotechnological means are available today to produce amounts of single human milk oligosaccharides (HMOs) in a purity which allows performing metabolic and functional studies even in humans. As recent data indicate that there is a link between the Lewis blood group and the secretor status of an individual and certain inflammatory diseases, this review will also focus on the metabolic fate of secretor- and Lewis blood group-specific components. We conclude that there is no simple urinary or fecal excretion pattern of HMOs, although the pattern in urine often reflects the mother's secretor/nonsecretor status. However, there are deviations for single HMOs which deserve special attention. In feces, the variation in excretion is much higher than in urine, which may be caused by variations in the infant's intestinal microbiota. A gradual decrease in HMO excretion with time as proposed earlier does not take place as even after 7 months of exclusive breastfeeding often intact HMOs can be detected in feces and urine. In addition, we found that whenever oligosaccharides were detected in feces, LNT, the major core structure of HMOs, was present. Hence, our data do not support speculations that LNT is a preferable source for the microbiota. PMID- 28346932 TI - Regulatory Aspects of Human Milk Oligosaccharides. AB - Human milk oligosaccharides are key components of human milk and appear in various compositions and concentrations in all human milks. In regulatory sense human milk oligosaccharides are classified as novel foods or novel food ingredients requiring safety assessment. In addition, if any health messages are intended to be used also health claim regulations apply. This chapter reviews the regulatory settings and studies human milk oligosaccharides are required to fulfill to be able to enter markets in European Union or United States or elsewhere. Examples include Lacto-N-neotetraose and 2-fucosyllactose with safety assessment in European Union and United States. PMID- 28346934 TI - Summary of Evolution of Human Microbiota. PMID- 28346933 TI - Summary on Human Milk Oligosaccharides. PMID- 28346935 TI - Dysbiosis in the Neonatal Period: Role of Cesarean Section. AB - From epidemiological studies and studies done evaluating microbiomes in infants, there is a strong signal that the infants born by elective cesarean section (C section) develop microbiota that differs from those babies born by vaginal delivery. Epidemiological studies show increased odds ratios for the development of immunological disorders such as type 1 diabetes, celiac disease, asthma, allergic diseases as well as metabolic diseases such as obesity in babies born by C-section. These are interesting associations, and if supported by additional studies that rigorously control for confounding factors, they will have major public health implications. Such studies represent major challenges because the confounding factors are numerous. The fact that provision of vaginal bacteria to C-section-delivered babies using a mouth swab that may actually transmit these bacteria to the infant is of interest and supports the concept that this can be done to alter the infant microbiota. However, significant caution needs to be taken, and alternative approaches that are safe as well as effective need to be considered; follow-up studies showing efficacy as well as safety need to be evaluated in the long term. PMID- 28346936 TI - Differential Establishment of Bifidobacteria in the Breastfed Infant Gut. AB - The composition of an infant's gut microbiome can impact their immediate and long term health. Bifdobacteria play a major role in structuring the gut microbiome of breastfed infants due to their ability to consume oligosaccharides found in human milk. However, recent studies have revealed that bifidobacteria are often absent in the gut microbiome of breastfed infants in some locations. This lack of colonization may be due either to differences in the environmental conditions in the gastrointestinal tract of uncolonized infants which prohibit the growth of bifidobacteria or a dearth of sources from which infants may acquire these specialized bacterial species. Potential mechanisms by which these broad factors may lead to lower colonization of infants by bifidobacteria are discussed herein. Environmental conditions which may select against bifidobacteria include low rates/duration of breastfeeding, milk glycan composition, and antimicrobial use. Routes of colonization by bifidobacteria which may be disrupted include maternal transfer via vaginal birth, fecal-oral routes, or via breast milk itself. A careful contemplation of the conditions experienced by bifidobacteria over human evolutionary history may lead to further hypotheses as to the causative factors of the differential colonization by this foundation genus in some contemporary locations. PMID- 28346937 TI - In-crystal reaction cycle of a toluene-bound diiron hydroxylase. AB - Electrophilic aromatic substitution is one of the most important and recognizable classes of organic chemical transformation. Enzymes create the strong electrophiles that are needed for these highly energetic reactions by using O2, electrons, and metals or other cofactors. Although the nature of the oxidants that carry out electrophilic aromatic substitution has been deduced from many approaches, it has been difficult to determine their structures. Here we show the structure of a diiron hydroxylase intermediate formed during a reaction with toluene. Density functional theory geometry optimizations of an active site model reveal that the intermediate is an arylperoxo Fe2+/Fe3+ species with delocalized aryl radical character. The structure suggests that a carboxylate ligand of the diiron centre may trigger homolytic cleavage of the O-O bond by transferring a proton from a metal-bound water. Our work provides the spatial and electronic constraints needed to propose a comprehensive mechanism for diiron enzyme arene hydroxylation that accounts for many prior experimental results. PMID- 28346938 TI - Star formation inside a galactic outflow. AB - Recent observations have revealed massive galactic molecular outflows that may have the physical conditions (high gas densities) required to form stars. Indeed, several recent models predict that such massive outflows may ignite star formation within the outflow itself. This star-formation mode, in which stars form with high radial velocities, could contribute to the morphological evolution of galaxies, to the evolution in size and velocity dispersion of the spheroidal component of galaxies, and would contribute to the population of high-velocity stars, which could even escape the galaxy. Such star formation could provide in situ chemical enrichment of the circumgalactic and intergalactic medium (through supernova explosions of young stars on large orbits), and some models also predict it to contribute substantially to the star-formation rate observed in distant galaxies. Although there exists observational evidence for star formation triggered by outflows or jets into their host galaxy, as a consequence of gas compression, evidence for star formation occurring within galactic outflows is still missing. Here we report spectroscopic observations that unambiguously reveal star formation occurring in a galactic outflow at a redshift of 0.0448. The inferred star-formation rate in the outflow is larger than 15 solar masses per year. Star formation may also be occurring in other galactic outflows, but may have been missed by previous observations owing to the lack of adequate diagnostics. PMID- 28346945 TI - Virtual Glucose Management in the Hospital Setting. PMID- 28346946 TI - Association Between a Virtual Glucose Management Service and Glycemic Control in Hospitalized Adult Patients: An Observational Study. AB - Background: Inpatient hyperglycemia is common and is linked to adverse patient outcomes. New methods to improve glycemic control are needed. Objective: To determine whether a virtual glucose management service (vGMS) is associated with improved inpatient glycemic control. Design: Cross-sectional analyses of three 12 month periods (pre-vGMS, transition, and vGMS) between 1 June 2012 and 31 May 2015. Setting: 3 University of California, San Francisco, hospitals. Patients: All nonobstetric adult inpatients who underwent point-of-care glucose testing. Intervention: Hospitalized adult patients with 2 or more glucose values of 12.5 mmol/L or greater (>=225 mg/dL) (hyperglycemic) and/or a glucose level less than 3.9 mmol/L (<70 mg/dL) (hypoglycemic) in the previous 24 hours were identified using a daily glucose report. Based on review of the insulin/glucose chart in the electronic medical record, recommendations for insulin changes were entered in a vGMS note, which could be seen by all clinicians. Measurements: Proportion of patient-days classified as hyperglycemic, hypoglycemic, and at-goal (all measurements >=3.9 and <=10 mmol/L [>=70 and <=180 mg/dL] during the pre-vGMS, transition, and vGMS periods). Results: The proportion of hyperglycemic patients decreased by 39%, from 6.6 per 100 patient-days in the pre-vGMS period to 4.0 per 100 patient-days in the vGMS period (difference, -2.5 [95% CI, -2.7 to -2.4]). The hypoglycemic proportion in the vGMS period was 36% lower than in the pre-vGMS period (difference, -0.28 [CI, -0.35 to -0.22]). Forty severe hypoglycemic events (<2.2 mmol/L [<40 mg/dL]) occurred during the pre-vGMS period compared with 15 during the vGMS period. Limitation: Information was not collected on patients' concurrent illnesses and treatment or physicians' responses to the vGMS notes. Conclusion: Implementation of the vGMS was associated with decreases in hyperglycemia and hypoglycemia. Primary Funding Source: National Institutes of Health, the Wilsey Family Foundation, and the UCSF Clinical & Translational Science Institute. PMID- 28346939 TI - A B12-dependent radical SAM enzyme involved in oxetanocin A biosynthesis. AB - Oxetanocin A (OXT-A) is a potent antitumour, antiviral and antibacterial compound. Biosynthesis of OXT-A has been linked to a plasmid-borne Bacillus megaterium gene cluster that contains four genes: oxsA, oxsB, oxrA and oxrB. Here we show that both the oxsA and oxsB genes are required for the production of OXT A. Biochemical analysis of the encoded proteins, a cobalamin (Cbl)-dependent S adenosylmethionine (AdoMet) radical enzyme, OxsB, and an HD-domain phosphohydrolase, OxsA, reveals that OXT-A is derived from a 2'-deoxyadenosine phosphate in an OxsB-catalysed ring contraction reaction initiated by hydrogen atom abstraction from C2'. Hence, OxsB represents the first biochemically characterized non-methylating Cbl-dependent AdoMet radical enzyme. X-ray analysis of OxsB reveals the fold of a Cbl-dependent AdoMet radical enzyme, a family of enzymes with an estimated 7,000 members. Overall, this work provides a framework for understanding the interplay of AdoMet and Cbl cofactors and expands the catalytic repertoire of Cbl-dependent AdoMet radical enzymes. PMID- 28346947 TI - Health and Public Policy to Facilitate Effective Prevention and Treatment of Substance Use Disorders Involving Illicit and Prescription Drugs: An American College of Physicians Position Paper. AB - Substance use disorders involving illicit and prescription drugs are a serious public health issue. In the United States, millions of individuals need treatment for substance use disorders but few receive it. The rising number of drug overdose deaths and the changing legal status of marijuana pose new challenges. In this position paper, the American College of Physicians maintains that substance use disorder is a treatable chronic medical condition and offers recommendations on expanding treatment options, the legal status of marijuana, addressing the opioid epidemic, insurance coverage of substance use disorders treatment, education and workforce, and public health interventions. PMID- 28346948 TI - Putting Patients First by Reducing Administrative Tasks in Health Care: A Position Paper of the American College of Physicians. AB - This American College of Physicians (ACP) position paper, initiated and written by ACP's Medical Practice and Quality Committee and approved by the Board of Regents on 21 January 2017, reports policy recommendations to address the issue of administrative tasks to mitigate or eliminate their adverse effects on physicians, their patients, and the health care system as a whole. The paper outlines a cohesive framework for analyzing administrative tasks through several lenses to better understand any given task that a clinician and his or her staff may be required to perform. In addition, a scoping literature review and environmental scan were done to assess the effects on physician time, practice and system cost, and patient care due to the increase in administrative tasks. The findings from the scoping review, in addition to the framework, provide the backbone of detailed policy recommendations from the ACP to external stakeholders (such as payers, governmental oversight organizations, and vendors) regarding how any given administrative requirement, regulation, or program should be assessed, then potentially revised or removed entirely. PMID- 28346949 TI - Designing and Regulating Wisely: Removing Barriers to Joy in Practice. PMID- 28346950 TI - A Tale of Two Countries: How I Saw More Patients With More Joy in Internal Medicine Practice. PMID- 28346952 TI - Web Exclusives. Annals Graphic Medicine - Anatomy of a Donut Hole. PMID- 28346951 TI - Professionalism Charter Provides Guidance to Health Care Organizations in These Troubled Times. PMID- 28346953 TI - Lennox-Gastaut Syndrome: A State of the Art Review. AB - Lennox-Gastaut syndrome (LGS) is a severe age-dependent epileptic encephalopathy usually with onset between 1 and 8 years of age. Functional neuroimaging studies recently introduced the concept of Lennox-Gastaut as "secondary network epilepsy" resulting from dysfunctions of a complex system involving both cortical and subcortical structures (default-mode network, corticoreticular connections, and thalamus). These dysfunctions are produced by different disorders including hypoxic-ischemic encephalopathies, meningoencephalitis, cortical malformations, neurocutaneous disorders, or tumors. The list of etiologies was expanded to pathogenic copy number variants at whole-genome array comparative genomic hybridization associated with late-onset cases or pathogenic mutations involving genes, such as GABRB3, ALG13, SCN8A, STXBP1, DNM1, FOXG1, or CHD2. Various clinical trials demonstrated the usefulness of different drugs (including rufinamide, clobazam, lamotrigine, topiramate, or felbamate), ketogenic diet, resective surgery, corpus callosotomy, and vagus nerve stimulation in the treatment of epileptic manifestations. The outcome of LGS often remains disappointing regarding seizure control or cognitive functioning. The realization of animal models, which are still lacking, and the full comprehension of molecular mechanisms involved in epileptogenesis and cognitive impairment would give a relevant support to further improvements in therapeutic strategies for LGS patients. PMID- 28346954 TI - Evaluation of Probably Benign Adnexal Masses in Postmenopausal Women. AB - Background Preoperatively identification of malignancy potential of a postmenopausal adnexal masses is important. Aim To evaluate the effectiveness of the Risk of Malignancy Index-2 in presumably benign adnexal masses in postmenopausal women. Study Design Retrospective, observational study. Methods 119 women with postmenopausal adnexal masses with a preliminary diagnosis of benign tumors according to the Risk of Malignancy Index-2 were included. Age, duration of menopause, ultrasonographic findings, and serum CA-125 levels were recorded preoperatively. The definitive diagnosis was based on postoperative histopathological examination. Results Of 119 adnexal mass, 10 were malignant and 109 were benign. There was no statistically significant difference with regard to age and tumor size between the groups. The two significant ultrasonographic parameter between groups were the presence of solid area in the mass and bilaterality. Moreover, if the cut off point for serum CA-125 was adjusted to 14.75 IU/mL according to ROC curve, a sensitivity value of 80% and a specificity value of 72% could be achieved to discriminate benign and malign cysts. Conclusion In the differential diagnosis of benign and malignant adnexal masses in postmenopausal women, the presence of a solid component, bilaterallity based on ultrasonography and high CA-125 values may be used as discriminative criteria. There is no direct relation between the size of the adnexal mass and malignancy potential. Therefore, in the malignancy indexes of postmenopausal women, we recommend lower cut-off values of CA-125 to increase the sensitivity of preoperative evaluation tests without having a great impact on negative predictive values. PMID- 28346955 TI - Nonischemic Priapism in Childhood: A Case Series and Review of Literature. AB - INTRODUCTION: Nonischemic priapism (NIP) in childhood is a very rare affection. In the literature, patients with NIP are described mainly incidental after perineal trauma. Many of them underwent embolization of either internal pudendal artery or bulbocavernosal arteries. PATIENTS AND METHODS: We report on six boys between 4 and 13 years of age with NIP, treated at our institution between 2008 and 2014. Color Doppler ultrasound (CDU) was performed in all patients as emergency diagnostic evaluation. Patients were treated conservatively, including bed rest, local cooling, and perineal compression. History, etiological factors, clinical findings, diagnostics, and follow-up are presented. RESULTS: Out of the six patients, only one boy had a history of perineal injury with subsequent arteriocavernosal fistula, revealed in CDU. Five patients were circumcised, and one of them suffered from thalassemia minor, but no other underlying disease or etiological factors could be found. In all patients, normal to high blood flow velocities were detected in the cavernosal arteries. Detumescence started with nonoperative treatment within 24 hours in five boys and in one patient with recurrent priapism after 1 week. All six patients remained painless without evidence for an ischemic priapism. None of them suffered from relapse and further erections were observed during follow-up from 3 to 87 months. CONCLUSION: In contrast to the literature, five out of six boys developed NIP without a previous perineal trauma. The etiology of idiopathic NIP in childhood remains unclear; however, circumcision may play a role as a conditional factor. One etiological thesis could be the release of the neurotransmitter nitric oxide after stimulation of the corpora cavernosa. Conservative treatment proved to be successful in all six patients. During a median follow-up of 55 months (3-87 months), none of the patients showed signs of erectile dysfunction. PMID- 28346956 TI - Early Nephrectomy in Unilateral Multicystic Dysplastic Kidney in Children Cures Hypertension Early: An Observation. AB - Objective Surgery is still indicated as the treatment of choice in subset of patients with unilateral multicystic dysplastic kidney (UMCDK) because of its potential complications and malignant change. The purpose of this study is to present our observation that early nephrectomy may cure hypertension early in children with UMCDK and review the literature. Materials and Methods We report here four children (two males and two females) with antenatally diagnosed UMCDK with hypertension, treated in the past 4 years. All have antenatal diagnosis of UMCDK and referred to us after their birth. Diagnosis of hypertension (blood pressure > 95th percentile) was made after 3 months of follow-up in all patients. Nephrectomy was performed in all children in variable time duration. Hypertension, urinary tract infection, and desire of parents were the main indication of surgery. Results All children showed decrease in the size of their dysplastic kidney with time, but hypertension was persistent and needed antihypertensive drugs; even increase in the doses in successive follow-up. After nephrectomy, three children who were operated early got cured having normal blood pressure within variable time duration, while a child, operated late, still had high blood pressure and needed antihypertensive drugs. Conclusion Early nephrectomy in recently diagnosed hypertension in UMCDK is advisable and can cure hypertension early. Levels of Evidence The level of evidence is IV (case series with no comparison group). PMID- 28346957 TI - [A Young Asylum Seeker with Hemoptysis and Positive Tuberculosis Screening: Not Always Tuberculosis!] AB - This paper reports on the case of a 19 year old asylum seeker from Eritrea who presented with hemoptysis, a positive tuberculosis screening (Enzyme Linked Immuno Spot Assay - EliSpot) and mushy faeces submitted with a suspected diagnosis of tuberculosis. Laboratory testing revealed thrombopenia, leukopenia and eosinophilia, while the chest X-ray was inconspicuous. Acid-proof rod bacteria were neither evident in bronchoscopy samples nor in expectorated sputum samples. However, sonographic findings showed a profound splenomegaly, and laboratory testing revealed a Schistosoma mansoni infection. This case demonstrates that in asylum seekers with suspected tuberculosis endemic diseases of the home country need to be considered as alternative diagnoses. PMID- 28346958 TI - [Role of Laser Resection in Pulmonary Metastasectomy]. AB - Objectives This review presents laser resection as treatment option in pulmonary metastasectomy and summarizes the current evidence. Moreover, it includes the comparison of laser resection and common techniques used in lung metastasectomy. Methods We performed a systematic literature research in Medline and the Cochrane library to detect case series and even randomized trials. All included studies underwent qualitative analysis. Results Laser metastasectomy is a safe procedure. Data regarding relevant clinical end points as hospitalization, duration of chest tube drainage and long-term survival are heterogeneous and still controversial. Laser enucleation decreases the resection volume. Therefore, it leads to a significant reduction of parenchymal loss. Survival rates after laser metastasectomy are equal to the outcome after resection using other techniques. Conclusions Laser resection is a parenchyma-sparing method. Hence, it offers radical metastasectomy even in case of multiple pulmonary lesions or impaired lung capacity. PMID- 28346959 TI - Mirtazapine Induces Nightmares in Depressed Patients. PMID- 28346960 TI - 2016 Eberhard F. Mammen Award Announcements: Part II-Young Investigator Awards. PMID- 28346961 TI - Laboratory Assessment of Hemostatic and Anticoagulant Therapy. PMID- 28346962 TI - Response to "Comment on State-of-the-Art Imaging in Pulmonary Embolism: Ventilation/Perfusion Single-Photon Emission Computed Tomography versus Computed Tomography Angiography-Controversies, Results, and Recommendations from a Systematic Review". PMID- 28346963 TI - Point-of-Care Testing in Neurosurgery. AB - Coagulation disorders can have a major impact on the outcome of neurosurgical patients. The central nervous system is located within the closed space of the skull, and therefore, intracranial hemorrhage can lead to intracranial hypertension. Acute brain injury has been associated with alterations of various hemostatic parameters. Point-of-care (POC) techniques such as rotational thromboelastometry are able to identify markers of coagulopathy which are not reflected by standard assessment of hemostasis (e.g., hyperfibrinolysis). In patients with acute brain injury, POC test results have been associated with important outcome parameters such as mortality and need for neurosurgical intervention. POC devices have also been used to rapidly identify and quantify the effects of antithrombotic medication. In cases of life-threatening intracranial hemorrhage, this information can be valuable when deciding over administration of prohemostatic substances or immediate neurosurgical intervention. In elective neurosurgical procedures, POC devices can provide important information when unexpected bleeding occurs or in cases of prolonged operative time with subsequent blood loss. Initial experiences with POC devices in neurosurgical care have shown promising results but further studies are needed to characterize their full potential and limitations. PMID- 28346964 TI - Lipoprotein(a) as a Risk Factor for Venous Thromboembolism: A Systematic Review and Meta-analysis of the Literature. AB - Elevated plasma levels of lipoprotein(a) (Lp(a)) are associated with increased cardiovascular risk in several clinical studies. However, there is a lack of data supporting a positive association between elevated Lp(a) levels and venous thromboembolism (VTE). Thus, we conducted a systematic review of the literature to better clarify its role as a risk factor for VTE. Medline and the Embase (up to May 2015) electronic databases were used to identify potentially eligible studies. Studies measuring Lp(a) values in adult patients with deep vein thrombosis and/or pulmonary embolism and in a population of patients without a VTE were selected. Studies on patients with major venous thromboembolic events occurring at other unusual site, case reports, and case series were excluded. The odds ratios (ORs) of the association between high values of Lp(a) and VTE and the weighted mean difference (WMD) in Lp(a) levels in cases and in controls were calculated using a random-effect model. Results were presented with 95% confidence interval (CI). Fourteen studies for a total of more than 14,000 patients were finally included in our analysis. Lp(a) was slightly but significantly associated with an increased risk of VTE (OR: 1.56, 95% CI: 1.36, 1.79; 10 studies, 13,541 patients). VTE patients had significantly higher Lp(a) values compared with controls (WMD: 14.46 mg/L, 95% CI: 12.14, 16.78; 4 studies, 470 patients). Lp(a) appeared to be significantly associated with increased risk of VTE. However, Lp(a) levels were only slightly increased in VTE patients compared with controls. PMID- 28346965 TI - Point-of-Care Coagulation Tests Monitoring of Direct Oral Anticoagulants and Their Reversal Therapy: State of the Art. AB - Direct oral anticoagulants (DOACs) exert similar anticoagulant effects to vitamin K antagonists and are increasingly used worldwide. Nevertheless, an evidence based approach to patients receiving DOACs when any unplanned urgent surgery or bleeding (either spontaneous or traumatic) occurs is still missing. In this review, we investigate the role of point-of-care coagulation tests when other, more specific tests are not available. Indeed, thromboelastography and activated clotting time can detect dabigatran-induced coagulopathy, while their accuracy is limited for apixaban and rivaroxaban, mostly in cases of low drug plasma concentrations. These tests can also be used to guide the reversal of DOAC induced coagulopathy providing a quick, before-and-after picture in case of therapeutic use of hemostatic compounds. PMID- 28346966 TI - Factor XII Contact Activation. AB - Contact activation is the surface-induced conversion of factor XII (FXII) zymogen to the serine protease FXIIa. Blood-circulating FXII binds to negatively charged surfaces and this contact to surfaces triggers a conformational change in the zymogen inducing autoactivation. Several surfaces that have the capacity for initiating FXII contact activation have been identified, including misfolded protein aggregates, collagen, nucleic acids, and platelet and microbial polyphosphate. Activated FXII initiates the proinflammatory kallikrein-kinin system and the intrinsic coagulation pathway, leading to formation of bradykinin and thrombin, respectively. FXII contact activation is well characterized in vitro and provides the mechanistic basis for the diagnostic clotting assay, activated partial thromboplastin time. However, only in the past decade has the critical role of FXII contact activation in pathological thrombosis been appreciated. While defective FXII contact activation provides thromboprotection, excess activation underlies the swelling disorder hereditary angioedema type III. This review provides an overview of the molecular basis of FXII contact activation and FXII contact activation-associated disease states. PMID- 28346968 TI - Corrigendum. PMID- 28346967 TI - Anticoagulation Therapy in Children. AB - Venous thromboembolism (VTE) is very uncommon in children and adolescents compared with older adults, though its incidence has significantly increased over the past two decades. Given the rarity of the condition, the data on pediatric VTE lag behind the adult experience and consequently the management of VTE in children is, in large part, modeled on the adult strategies. This approach has certain limitations, given that young children have developmental particularities of the hemostatic system and differences in the pharmacokinetics and pharmacodynamics of various anticoagulant agents. The most commonly used anticoagulants in children continue to be the heparins and the vitamin K antagonists. Direct intravenous thrombin inhibitors, argatroban, bivalirudin, have very limited pediatric use. The non-vitamin K antagonist oral anticoagulant drugs (novel oral anticoagulants) present potential advantages in terms of efficacy, safety, and convenience, though pediatric data are limited to preclinical and small phase I trials. There are several ongoing phase I, II, and III trials for dabigatran rivaroxaban, apixaban, and edoxaban, the results of which are likely to change the future management of pediatric thromboses. PMID- 28346970 TI - Erratum. PMID- 28346969 TI - The comparison of laparoscopic and microsurgical varicocoelectomy in infertile men with varicocoele on paternity rate 12 months after surgery: a prospective randomized controlled trial. AB - The best surgical approach for varicocoelectomy is still unknown, however more and more physicians favour subinguinal microsurgery. The aim of this study was to find whether microsurgical approach is superior to laparoscopic varicocoelectomy in terms of pregnancy rate, fertility potential, endocrinological function of the testis, erectile dysfunction and testicle volume increase. It was a prospective, non-masked, parallel-group randomized controlled trial with one to one allocation. It was conducted at authors' institution and designed as per protocol study. From 2012 till 2015 84 patients were randomly allocated to two groups. First group consisted of 42 patients who underwent laparoscopic varicocoelectomy, whereas patients from the second group underwent microsurgical varicocoelectomy. The indications for varicocoelectomy consisted of infertility >1 year, palpable left-sided varicocoele and at least one impaired semen parameter (sperm concentration <15 mln/mL; total motility<40%; progressive motility <32%, vitality <58% or normal morphology <4%). The primary goal was to show superiority of microsurgical varicocoelectomy over laparoscopic varicocoelectomy in terms of pregnancy rate. The secondary endpoints comprised assessment of sperm parameters in three-month intervals after intervention until one year. Other points included, LH, FSH and testosterone levels as well as testicle volume and International Index of Erectile Function. From each group five patients were lost during the follow-up period. The primary endpoint was not achieved - pregnancy rate in first and second group was 29.7% and 40.5% respectively (p = 0.34). Analysis of the sperm parameters after surgery revealed significant statistical difference in total motility, progressive motility and morphology in favour of microsurgical approach. Both methods showed improvement in all sperm parameters. There were no differences in hormonal levels as well as in erectile function and testicle volume between groups. Small number of patients in both groups are the main limitation of our study. PMID- 28346971 TI - Correction to "Linear mixed function-on-function regression models," by Wei Wang; 70, xxx-xxx, December 2014. PMID- 28346973 TI - Erratum. PMID- 28346972 TI - Erratum. PMID- 28346974 TI - American Journal of Transplantation: Volume 14, Number 8, August 2014. PMID- 28346976 TI - Erratum. PMID- 28346977 TI - Erratum. PMID- 28346975 TI - Hypothyroidism is associated with all-cause mortality in a national cohort of chronic haemodialysis patients. AB - AIM: The prevalence of hypothyroidism is high in haemodialysis (HD) patients and hypothyroidism increases all-cause mortality in HD patients. Comorbidities are common in HD patients and are associated with both mortality and hypothyroidism. The aim of the study is to explore the effect of the interactions of comorbidities and hypothyroidism on all-cause mortality in HD patients. METHOD: Patients with hypothyroidism (ICD-9-CM 244.0, 244.1, and 244.9) and matched patients without hypothyroidism in the Registry for Catastrophic Illness Patient Database of Taiwan Health Insurance from 2000 to 2010 were analyzed. The association of hypothyroidism and risk of all-cause mortality was analyzed using Cox proportional hazard regression. RESULT: Nine hundred and eight HD patients with hypothyroidism and 3632 sex-, age-, gender- matched HD patients without hypothyroidism were analyzed. Hypothyroidism was associated with increased all cause mortality with an adjusted hazard ratio of 1.22 [95% confidence interval (CI): 1.10-1.36, P < 0.001]. TRT may decrease mortality associated with hypothyroidism (P < 0.001). There was a significant interaction (P = 0.04) between diabetes and hypothyroidism. There was no significant interaction found in hypothyroidism and the following comorbidities: hyperlipidaemia, hypertension, chronic obstructive pulmonary disease, coronary artery disease, stroke, peripheral arterial disease, asthma, congestive heart failure and cancer. CONCLUSION: Hypothyroidism is associated with increased all-cause mortality in chronic HD patients. The interaction of hypothyroidism and diabetes, but not other common comorbidities in HD patients, has an effect on mortality risks. PMID- 28346978 TI - American Journal of Transplantation: Volume 14, Number 6, June 2014. PMID- 28346979 TI - Erratum for "Outsourced cataract surgery and postoperative endophthalmitis" in Acta Ophthalmol. 2013: 91: 701-708. PMID- 28346983 TI - Editorial Comment. PMID- 28346980 TI - Ecological intensification to mitigate impacts of conventional intensive land use on pollinators and pollination. AB - Worldwide, human appropriation of ecosystems is disrupting plant-pollinator communities and pollination function through habitat conversion and landscape homogenisation. Conversion to agriculture is destroying and degrading semi natural ecosystems while conventional land-use intensification (e.g. industrial management of large-scale monocultures with high chemical inputs) homogenises landscape structure and quality. Together, these anthropogenic processes reduce the connectivity of populations and erode floral and nesting resources to undermine pollinator abundance and diversity, and ultimately pollination services. Ecological intensification of agriculture represents a strategic alternative to ameliorate these drivers of pollinator decline while supporting sustainable food production, by promoting biodiversity beneficial to agricultural production through management practices such as intercropping, crop rotations, farm-level diversification and reduced agrochemical use. We critically evaluate its potential to address and reverse the land use and management trends currently degrading pollinator communities and potentially causing widespread pollination deficits. We find that many of the practices that constitute ecological intensification can contribute to mitigating the drivers of pollinator decline. Our findings support ecological intensification as a solution to pollinator declines, and we discuss ways to promote it in agricultural policy and practice. PMID- 28346985 TI - Editorial Comment. PMID- 28346984 TI - Editorial Comment. PMID- 28346987 TI - Reply by Authors. PMID- 28346986 TI - Editorial Comment. PMID- 28346988 TI - Editorial Comment. PMID- 28346989 TI - Editorial Comment. PMID- 28346991 TI - An integrated assessment framework for the analysis of multiple pressures in aquatic ecosystems and the appraisal of management options. AB - The contribution illustrates an integrated assessment framework aimed at evaluating the relationships between multiple pressures and water body status for the purposes of river basin management. The framework includes the following steps. (1) Understanding how the different pressures affect the status of water bodies. This entails the characterization of biophysical state variables and the definition of a causal relationship between pressures and status. Therefore this step involves interaction between experts bearing ecological understanding and experts providing models to represent the effect of pressures. (2) Identifying the relevant pressures to be addressed through appropriate measures to improve the status of water bodies. (3) Evaluating reduction targets for the relevant pressures identified in a river basin, by weighting the effort associated to reducing individual pressures and the potential benefits in terms of water body status. (4) Designing management measures through a creative process and political discussion of alternative options, balancing costs, benefits and effectiveness based on engineering and economic analysis. (5) Simulating scenarios of implementation of a programme of measures in order to check their effectiveness and robustness against climate and land use change. We discuss the five steps of the assessment framework, and particularly the interaction between science and policy at the different stages. We review the assessment tools required at each step and, for setting optimal pressure reduction targets (step 3), we propose and illustrate a simplified multicriteria approach based on semi quantitative assessment, which produces frontiers of optimal trade-offs between effort spent on measures, and achievements. PMID- 28346992 TI - Longitudinal assessment of hydropeaking impacts on various scales for an improved process understanding and the design of mitigation measures. AB - Hydropeaking is one of the main pressures on the aquatic ecology in alpine rivers. Beside studies on abiotic process and biotic response on the local scale there is a lack in process understanding on the reach scale. Especially longitudinal changes of hydropeaking impacts based on retention processes have not been studied yet. Thus, based on unsteady one-dimensional and two-dimensional depth averaged modelling it was targeted to investigate possible changes in vertical ramping velocity for the discussion of possible mitigation measures at the local scale. Here, we compared artificial and natural sheltering habitats in terms of peak flow. Additionally, the hydropeaking assessment on various river scales was supported by an evaluation of tributaries in an alpine river system. Based on the modelling results and the discussion of the impact assessment of hydropeaking in different case studies we state, that on the first 5km downstream of the turbine outlet a significant decrease in vertical ramping velocity occurs. In this reach, habitat improvements should focus on increasing retention processes considering the higher risk of stranding for juvenile fish and macroinvertebrates. For morphological mitigation measures at the local scale, it turned out that self-formed, near-natural morphology should be targeted in terms of mitigation measure design compared to artificial sheltering habitats. Abundance and biomass of macroinvertebrates are directly linked to substrate variability in self-formed sheltering habitats downstream of gravel bars. Moreover, we ascertained that tributaries are able to contribute to the 'ecological potential' in multi-stressed hydropeaking rivers by providing spawning and rearing habitats for fish. However, for a sustainable improvement of the aquatic environment on all relevant scales, both sediment and flood dynamics have to be considered as important drivers to establish self-formed sheltering habitats in terms of hydropeaking. PMID- 28346993 TI - Artemisia sieberi Besser essential oil and treatment of fungal infections. AB - A. sieberi essential oil has been used for treatment of hardly curable infectious ulcers in Middle East Medicine and has been famous due to its wormicide effects. In this review, we evaluated the potency of A. sieberi essential oil in treatment of fungal infections. We searched in PubMed Central, Science direct, Wiley, Springer, SID, and accessible books, reports, thesis. There is a lot of mixed information on chemical compositions of A. sieberi essential oil, but most articles reported alpha, beta-thujones as the main components of essential oils. In vitro studies confirmed the antifungal activity of A. sieberi essential oil against saprophytes fungi, dermatophytes, Malassezia sp. and Candida sp. and these results were confirmed in six clinical studies. The clinical studies confirmed the superiority of A. sieberi essential oil (5%) lotion in improvement of clinical signs of fungal superficial diseases, and mycological laboratory examinations of dermatophytosis and pityriasis versicolor diseases than clotrimazole (1%) topical treatment. The recurrence rate of superficial fungal infections with dermatophytosis and pityriasis versicolor was statistically lower in A. sieberi essential oil (5%) lotion than clotrimazole. There are no adverse effects due to the application of A. sieberi essential oil in clinical studies. Despite, the efficacy of A. sieberi essential oil against Candida sp., there is no clinical study about their related infections. Investigation about the effects of A. sieberi essential oil on fungal virulence factors in order to identifying the exact mechanism of antifungal activity and clinical trials on Candida related diseases are recommended. PMID- 28346994 TI - GC/MS analysis and potential cytotoxic activity of Calyptranthes grandifolia (O. Berg), Calyptranthes tricona (D. Legrand) and Myrciaria plinioides (D. Legrand) essential oil in RAW264.7 and CHO-K1 cells. AB - The search for new bioactive substances derived from natural products is daily growing. Among biologically active products used in therapeutic approaches, essential oils are described with wide range of therapeutic and pharmacological potential. Plants from Myrtaceae family have the presence of essential oils in its composition. Calyptranthes grandifolia, Calyptranthes tricona and Myrciaria plinioides species belong to this family and are used by the local population. However, there are no reports in the literature describing relevant characteristics about the potential and possible activities of these species. The aim of this study was to identify the main compounds, evaluate the antioxidant potential and investigate, in RAW264.7 and CHO-K1 cells, the cytotoxic activity of the essential oils from the leaves of C. grandifolia, C. tricona and M. plinioides plants, in order to ensure their use. The compounds were identified by GC-MS, antioxidant activity was determined by DPPH method and cytotoxicity was assessed by the Alamar Blue method, at 48 and 72h. The main compounds found in the essential oils were sesquiterpenes. None of the essential oils have antioxidant potential. In cytotoxicity assays, the essential oils from the plants in analysis showed moderate activity in the proposed conditions. The alterations observed between the data provided by the essential oils in question, between different cell lines, may be associated with their composition, suggesting action of minor compounds. These results may suggest that the essential oils from C. grandifolia, C. tricona and M. plinioides have considerable potential to be explored. Future studies will be conducted to obtain more information about the action pathway and potential of the identified compounds. PMID- 28346996 TI - Synthesis, Characterization, and Mechanism of Formation of Janus-Like Nanoparticles of Tantalum Silicide-Silicon (TaSi2/Si). AB - Metal-semiconductor Janus-like nanoparticles with the composition tantalum silicide-silicon (TaSi2/Si) were synthesized for the first time by means of an evaporation method utilizing a high-power electron beam. The composition of the synthesized particles were characterized using high-resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD), selective area electron diffraction (SAED), and energy dispersive X-ray fluorescence (EDX) analysis. The system is compared to previously synthesized core-shell type particles in order to show possible differences responsible for the Janus-like structure forming instead of a core-shell architecture. It is proposed that the production of Janus like as opposed to core-shell or monophase particles occurs due to the ability of Ta and Si to form compounds and the relative content of Ta and Si atoms in the produced vapour. Based on the results, a potential mechanism of formation for the TaSi2/Si nanoparticles is discussed. PMID- 28346995 TI - Rare Earth Ion-Doped Upconversion Nanocrystals: Synthesis and Surface Modification. AB - The unique luminescent properties exhibited by rare earth ion-doped upconversion nanocrystals (UCNPs), such as long lifetime, narrow emission line, high color purity, and high resistance to photobleaching, have made them widely used in many areas, including but not limited to high-resolution displays, new-generation information technology, optical communication, bioimaging, and therapy. However, the inherent upconversion luminescent properties of UCNPs are influenced by various parameters, including the size, shape, crystal structure, and chemical composition of the UCNPs, and even the chosen synthesis process and the surfactant molecules used. This review will provide a complete summary on the synthesis methods and the surface modification strategies of UCNPs reported so far. Firstly, we summarize the synthesis methodologies developed in the past decades, such as thermal decomposition, thermal coprecipitation, hydro/solvothermal, sol-gel, combustion, and microwave synthesis. In the second part, five main streams of surface modification strategies for converting hydrophobic UCNPs into hydrophilic ones are elaborated. Finally, we consider the likely directions of the future development and challenges of the synthesis and surface modification, such as the large-scale production and actual applications, stability, and so on, of the UCNPs. PMID- 28346997 TI - A Novel Arch-Shape Nanogenerator Based on Piezoelectric and Triboelectric Mechanism for Mechanical Energy Harvesting. AB - A simple and cost-effective approach was developed to fabricate piezoelectric and triboelectric nanogenerator (P-TENG) with high electrical output. Additionally, pyramid micro structures fabricated atop a polydimethylsiloxane (PDMS) surface were employed to enhance the device performance. Furthermore, piezoelectric barium titanate (BT) nanoparticles and multiwalled carbon nanotube (MWCNT) were mixed in the PDMS film during the forming process. Meanwhile, the composition of the film was optimized to achieve output performance, and favorable toughness was achieved after thermal curing. An arch-shape ITO/PET electrode was attached to the upper side of the polarized composite film and an aluminum film was placed under it as the bottom electrode. With periodic external force at 20 Hz, electrical output of this P-TENG, reached a peak voltage of 22 V and current of 9 MUA with a peak current density of 1.13 MUA/cm2, which was six times that of the triboelectric generator without BT and MWCNT nanoparticles. The nanogenerator can be directly used to lighten 28 commercial light-emitting diodes (LEDs) without any energy storage unit or rectification circuit under human footfalls. PMID- 28346998 TI - Cellular Uptake of Tile-Assembled DNA Nanotubes. AB - DNA-based nanostructures have received great attention as molecular vehicles for cellular delivery of biomolecules and cancer drugs. Here, we report on the cellular uptake of tubule-like DNA tile-assembled nanostructures 27 nm in length and 8 nm in diameter that carry siRNA molecules, folic acid and fluorescent dyes. In our observations, the DNA structures are delivered to the endosome and do not reach the cytosol of the GFP-expressing HeLa cells that were used in the experiments. Consistent with this observation, no elevated silencing of the GFP gene could be detected. Furthermore, the presence of up to six molecules of folic acid on the carrier surface did not alter the uptake behavior and gene silencing. We further observed several challenges that have to be considered when performing in vitro and in vivo experiments with DNA structures: (i) DNA tile tubes consisting of 42 nt-long oligonucleotides and carrying single- or double-stranded extensions degrade within one hour in cell medium at 37 degrees C, while the same tubes without extensions are stable for up to eight hours. The degradation is caused mainly by the low concentration of divalent ions in the media. The lifetime in cell medium can be increased drastically by employing DNA tiles that are 84 nt long. (ii) Dyes may get cleaved from the oligonucleotides and then accumulate inside the cell close to the mitochondria, which can lead to misinterpretation of data generated by flow cytometry and fluorescence microscopy. (iii) Single-stranded DNA carrying fluorescent dyes are internalized at similar levels as the DNA tile-assembled tubes used here. PMID- 28347000 TI - Magnetic Properties of Magnetic Nanoparticles for Efficient Hyperthermia. AB - Localized magnetic hyperthermia using magnetic nanoparticles (MNPs) under the application of small magnetic fields is a promising tool for treating small or deep-seated tumors. For this method to be applicable, the amount of MNPs used should be minimized. Hence, it is essential to enhance the power dissipation or heating efficiency of MNPs. Several factors influence the heating efficiency of MNPs, such as the amplitude and frequency of the applied magnetic field and the structural and magnetic properties of MNPs. We discuss some of the physics principles for effective heating of MNPs focusing on the role of surface anisotropy, interface exchange anisotropy and dipolar interactions. Basic magnetic properties of MNPs such as their superparamagnetic behavior, are briefly reviewed. The influence of temperature on anisotropy and magnetization of MNPs is discussed. Recent development in self-regulated hyperthermia is briefly discussed. Some physical and practical limitations of using MNPs in magnetic hyperthermia are also briefly discussed. PMID- 28347001 TI - Recent Advances on Carbon Nanotubes and Graphene Reinforced Ceramics Nanocomposites. AB - Ceramics suffer the curse of extreme brittleness and demand new design philosophies and novel concepts of manufacturing to overcome such intrinsic drawbacks, in order to take advantage of most of their excellent properties. This has been one of the foremost challenges for ceramic material experts. Tailoring the ceramics structures at nanometre level has been a leading research frontier; whilst upgrading via reinforcing ceramic matrices with nanomaterials including the latest carbon nanotubes (CNTs) and graphene has now become an eminent practice for advanced applications. Most recently, several new strategies have indeed improved the properties of the ceramics/CNT nanocomposites, such as by tuning with dopants, new dispersions routes and modified sintering methods. The utilisation of graphene in ceramic nanocomposites, either as a solo reinforcement or as a hybrid with CNTs, is the newest development. This article will summarise the recent advances, key difficulties and potential applications of the ceramics nanocomposites reinforced with CNTs and graphene. PMID- 28347002 TI - Alumina Matrix Composites with Non-Oxide Nanoparticle Addition and Enhanced Functionalities. AB - The addition of SiC or TiC nanoparticles to polycrystalline alumina matrix has long been known as an efficient way of improving the mechanical properties of alumina-based ceramics, especially strength, creep, and wear resistance. Recently, new types of nano-additives, such as carbon nanotubes (CNT), carbon nanofibers (CNF), and graphene sheets have been studied in order not only to improve the mechanical properties, but also to prepare materials with added functionalities, such as thermal and electrical conductivity. This paper provides a concise review of several types of alumina-based nanocomposites, evaluating the efficiency of various preparation methods and additives in terms of their influence on the properties of composites. PMID- 28347003 TI - The Nucleotide Capture Region of Alpha Hemolysin: Insights into Nanopore Design for DNA Sequencing from Molecular Dynamics Simulations. AB - Nanopore technology for DNA sequencing is constantly being refined and improved. In strand sequencing a single strand of DNA is fed through a nanopore and subsequent fluctuations in the current are measured. A major hurdle is that the DNA is translocated through the pore at a rate that is too fast for the current measurement systems. An alternative approach is "exonuclease sequencing", in which an exonuclease is attached to the nanopore that is able to process the strand, cleaving off one base at a time. The bases then flow through the nanopore and the current is measured. This method has the advantage of potentially solving the translocation rate problem, as the speed is controlled by the exonuclease. Here we consider the practical details of exonuclease attachment to the protein alpha hemolysin. We employ molecular dynamics simulations to determine the ideal (a) distance from alpha-hemolysin, and (b) the orientation of the monophosphate nucleotides upon release from the exonuclease such that they will enter the protein. Our results indicate an almost linear decrease in the probability of entry into the protein with increasing distance of nucleotide release. The nucleotide orientation is less significant for entry into the protein. PMID- 28347004 TI - Cysteine-Functionalized Chitosan Magnetic Nano-Based Particles for the Recovery of Light and Heavy Rare Earth Metals: Uptake Kinetics and Sorption Isotherms. AB - Cysteine-functionalized chitosan magnetic nano-based particles were synthesized for the sorption of light and heavy rare earth (RE) metal ions (La(III), Nd(III) and Yb(III)). The structural, surface, and magnetic properties of nano-sized sorbent were investigated by elemental analysis, FTIR, XRD, TEM and VSM (vibrating sample magnetometry). Experimental data show that the pseudo second order rate equation fits the kinetic profiles well, while sorption isotherms are described by the Langmuir model. Thermodynamic constants (DeltaG degrees , DeltaH degrees ) demonstrate the spontaneous and endothermic nature of sorption. Yb(III) (heavy RE) was selectively sorbed while light RE metal ions La(III) and Nd(III) were concentrated/enriched in the solution. Cationic species RE(III) in aqueous solution can be adsorbed by the combination of chelating and anion-exchange mechanisms. The sorbent can be efficiently regenerated using acidified thiourea. PMID- 28347005 TI - DNA-Protected Silver Clusters for Nanophotonics. AB - DNA-protected silver clusters (AgN-DNA) possess unique fluorescence properties that depend on the specific DNA template that stabilizes the cluster. They exhibit peak emission wavelengths that range across the visible and near-IR spectrum. This wide color palette, combined with low toxicity, high fluorescence quantum yields of some clusters, low synthesis costs, small cluster sizes and compatibility with DNA are enabling many applications that employ AgN-DNA. Here we review what is known about the underlying composition and structure of AgN DNA, and how these relate to the optical properties of these fascinating, hybrid biomolecule-metal cluster nanomaterials. We place AgN-DNA in the general context of ligand-stabilized metal clusters and compare their properties to those of other noble metal clusters stabilized by small molecule ligands. The methods used to isolate pure AgN-DNA for analysis of composition and for studies of solution and single-emitter optical properties are discussed. We give a brief overview of structurally sensitive chiroptical studies, both theoretical and experimental, and review experiments on bringing silver clusters of distinct size and color into nanoscale DNA assemblies. Progress towards using DNA scaffolds to assemble multi-cluster arrays is also reviewed. PMID- 28347006 TI - Polymorphic Ring-Shaped Molecular Clusters Made of Shape-Variable Building Blocks. AB - Self-assembling molecular building blocks able to dynamically change their shapes, is a concept that would offer a route to reconfigurable systems. Although simulation studies predict novel properties useful for applications in diverse fields, such kinds of building blocks, have not been implemented thus far with molecules. Here, we report shape-variable building blocks fabricated by DNA self assembly. Blocks are movable enough to undergo shape transitions along geometrical ranges. Blocks connect to each other and assemble into polymorphic ring-shaped clusters via the stacking of DNA blunt-ends. Reconfiguration of the polymorphic clusters is achieved by the surface diffusion on mica substrate in response to a monovalent salt concentration. This work could inspire novel reconfigurable self-assembling systems for applications in molecular robotics. PMID- 28347008 TI - New Insights into Understanding Irreversible and Reversible Lithium Storage within SiOC and SiCN Ceramics. AB - Within this work we define structural properties of the silicon carbonitride (SiCN) and silicon oxycarbide (SiOC) ceramics which determine the reversible and irreversible lithium storage capacities, long cycling stability and define the major differences in the lithium storage in SiCN and SiOC. For both ceramics, we correlate the first cycle lithiation or delithiation capacity and cycling stability with the amount of SiCN/SiOC matrix or free carbon phase, respectively. The first cycle lithiation and delithiation capacities of SiOC materials do not depend on the amount of free carbon, while for SiCN the capacity increases with the amount of carbon to reach a threshold value at ~50% of carbon phase. Replacing oxygen with nitrogen renders the mixed bond Si-tetrahedra unable to sequester lithium. Lithium is more attracted by oxygen in the SiOC network due to the more ionic character of Si-O bonds. This brings about very high initial lithiation capacities, even at low carbon content. If oxygen is replaced by nitrogen, the ceramic network becomes less attractive for lithium ions due to the more covalent character of Si-N bonds and lower electron density on the nitrogen atom. This explains the significant difference in electrochemical behavior which is observed for carbon-poor SiCN and SiOC materials. PMID- 28347007 TI - Synthesis of Upconversion beta-NaYF4:Nd3+/Yb3+/Er3+ Particles with Enhanced Luminescent Intensity through Control of Morphology and Phase. AB - Hexagonal NaYF4:Nd3+/Yb3+/Er3+ microcrystals and nanocrystals with well-defined morphologies and sizes have been synthesized via a hydrothermal route. The rational control of initial reaction conditions can not only result in upconversion (UC) micro and nanocrystals with varying morphologies, but also can produce enhanced and tailored upconversion emissions from the Yb3+/Er3+ ion pairs sensitized by the Nd3+ ions. The increase of reaction time converts the phase of NaYF4:Nd3+/Yb3+/Er3+ particles from the cubic to the hexagonal structure. The added amount of oleic acid plays a critical role in the shape evolution of the final products due to their preferential attachment to some crystal planes. The adjustment of the molar ratio of F-/Ln3+ can range the morphologies of the beta NaYF4:Nd3+/Yb3+/Er3+ microcrystals from spheres to nanorods. When excited by 808 nm infrared laser, beta-NaYF4:Nd3+/Yb3+/Er3+ microplates exhibit a much stronger UC emission intensity than particles with other morphologies. This phase- and morphology-dependent UC emission holds promise for applications in photonic devices and biological studies. PMID- 28347010 TI - Retraction: Begum et al. Potential Impact of Multi-Walled Carbon Nanotubes Exposure to the Seedling Stage of Selected Plant Species. Nanomaterials 2014, 4, 203-221. AB - We have become aware that a substantial part of the main text of [1] is copied from multiple other publications. In total, 46% of the main text was taken from publications by the same authors [2,3] and 10% from other papers [4,5]. Because of the extent of text taken verbatim from previously published articles, we have made the decision to retract the article. All the authors of [1] have agreed to this decision. This paper is thus declared retracted and shall be marked accordingly for the scientific record.[...]. PMID- 28347011 TI - DNA-Assisted Solubilization of Carbon Nanotubes and Construction of DNA-MWCNT Cross-Linked Hybrid Hydrogels. AB - A simple method for preparation of DNA-carbon nanotubes hybrid hydrogel based on a two-step procedure including: (i) solubilization of multi-walled carbon nanotubes (MWCNT) in aqueous solution of DNA, and (ii) chemical cross-linking between solubilized MWCNT via adsorbed DNA and free DNA by ethylene glycol diglycidyl ether is reported. We show that there exists a critical concentration of MWCNT below which a homogeneous dispersion of MWCNT in hybrid hydrogel can be achieved, while at higher concentrations of MWCNT the aggregation of MWCNT inside hydrogel occurs. The strengthening effect of carbon nanotube in the process of hydrogel shrinking in solutions with high salt concentration was demonstrated and significant passivation of MWCNT adsorption properties towards low-molecular weight aromatic binders due to DNA adsorption on MWCNT surface was revealed. PMID- 28347009 TI - DNA under Force: Mechanics, Electrostatics, and Hydration. AB - Quantifying the basic intra- and inter-molecular forces of DNA has helped us to better understand and further predict the behavior of DNA. Single molecule technique elucidates the mechanics of DNA under applied external forces, sometimes under extreme forces. On the other hand, ensemble studies of DNA molecular force allow us to extend our understanding of DNA molecules under other forces such as electrostatic and hydration forces. Using a variety of techniques, we can have a comprehensive understanding of DNA molecular forces, which is crucial in unraveling the complex DNA functions in living cells as well as in designing a system that utilizes the unique properties of DNA in nanotechnology. PMID- 28347012 TI - DNA/Ag Nanoparticles as Antibacterial Agents against Gram-Negative Bacteria. AB - Silver (Ag) nanoparticles were produced using DNA extracted from salmon milt as templates. Particles spherical in shape with an average diameter smaller than 10 nm were obtained. The nanoparticles consisted of Ag as the core with an outermost thin layer of DNA. The DNA/Ag hybrid nanoparticles were immobilized over the surface of cotton based fabrics and their antibacterial efficiency was evaluated using E. coli as the typical Gram-negative bacteria. The antibacterial experiments were performed according to the Antibacterial Standard of Japanese Association for the Functional Evaluation of Textiles. The fabrics modified with DNA/Ag nanoparticles showed a high enough inhibitory and killing efficiency against E. coli at a concentration of Ag >= 10 ppm. PMID- 28347015 TI - In Situ Self Assembly of Nanocomposites: Competition of Chaotic Advection and Interfacial Effects as Observed by X-Ray Diffreaction. AB - The effects of chaotic advection on the in situ assembly of a hierarchal nanocomposite of Poly Amide 6, (nylon 6 or PA6) and platelet shape nanoparticles (NPs) were studied. The assemblies were formed by chaotic advection, where melts of pristine PA6 and a mixture of PA6 with NPs were segregated into discrete layers and extruded into film in a continuous process. The process assembles the nanocomposite into alternating pristine-polymer and oriented NP/polymer layers. The structure of these hierarchal assemblies was probed by X-rays as a processing parameter, N, was varied. This parameter provides a measure of the extent of in situ structuring by chaotic advection. We found that all assemblies are semi crystalline at room temperature. Increasing N impacts the ratio of alpha to gamma crystalline forms. The effects of the chaotic advection vary with the concentration of the NPs. For nanocomposites with lower NP concentrations the amount of the gamma crystalline form increased with N. However, at higher NP concentrations, interfacial effects of the NP play a significant role in determining the structure, where the NPs oriented along the melt flow direction and the polymer chains oriented perpendicular to the NP surfaces. PMID- 28347016 TI - On the Mass Fractal Character of Si-Based Structural Networks in Amorphous Polymer Derived Ceramics. AB - The intermediate-range packing of SiNxC4-x (0 <= x <= 4) tetrahedra in polysilycarbodiimide and polysilazane-derived amorphous SiCN ceramics is investigated using 29Si spin-lattice relaxation nuclear magnetic resonance (SLR NMR) spectroscopy. The SiCN network in the polysilylcarbodiimide-derived ceramic consists predominantly of SiN4 tetrahedra that are characterized by a 3 dimensional spatial distribution signifying compact packing of such units to form amorphous Si3N4 clusters. On the other hand, the SiCN network of the polysilazane derived ceramic is characterized by mixed bonded SiNxC4-x tetrahedra that are inefficiently packed with a mass fractal dimension of Df ~2.5 that is significantly lower than the embedding Euclidean dimension (D = 3). This result unequivocally confirms the hypothesis that the presence of dissimilar atoms, namely, 4-coordinated C and 3-coordinated N, in the nearest neighbor environment of Si along with some exclusion in connectivity between SiCxN4-x tetrahedra with widely different N:C ratios and the absence of bonding between C and N result in steric hindrance to an efficient packing of these structural units. It is noted that similar inefficiencies in packing are observed in polymer-derived amorphous SiOC ceramics as well as in proteins and binary hard sphere systems. PMID- 28347014 TI - Hybrids of Nucleic Acids and Carbon Nanotubes for Nanobiotechnology. AB - Recent progress in the combination of nucleic acids and carbon nanotubes (CNTs) has been briefly reviewed here. Since discovering the hybridization phenomenon of DNA molecules and CNTs in 2003, a large amount of fundamental and applied research has been carried out. Among thousands of papers published since 2003, approximately 240 papers focused on biological applications were selected and categorized based on the types of nucleic acids used, but not the types of CNTs. This survey revealed that the hybridization phenomenon is strongly affected by various factors, such as DNA sequences, and for this reason, fundamental studies on the hybridization phenomenon are important. Additionally, many research groups have proposed numerous practical applications, such as nanobiosensors. The goal of this review is to provide perspective on biological applications using hybrids of nucleic acids and CNTs. PMID- 28347017 TI - Unidirectional Wave Propagation in Low-Symmetric Colloidal Photonic-Crystal Heterostructures. AB - We show theoretically that photonic crystals consisting of colloidal spheres exhibit unidirectional wave propagation and one-way frequency band gaps without breaking time-reversal symmetry via, e.g., the application of an external magnetic field or the use of nonlinear materials. Namely, photonic crystals with low symmetry such as the monoclinic crystal type considered here as well as with unit cells formed by the heterostructure of different photonic crystals show significant unidirectional electromagnetic response. In particular, we show that the use of scatterers with low refractive-index contrast favors the formation of unidirectional frequency gaps which is the optimal route for achieving unidirectional wave propagation. PMID- 28347018 TI - Synthesis of Silver-Strontium Titanate Hybrid Nanoparticles by Sol-Gel Hydrothermal Method. AB - Silver (Ag) nanoparticle-loaded strontium titanate (SrTiO3) nanoparticles were attempted to be synthesized by a sol-gel-hydrothermal method. We prepared the titanium oxide precursor gels incorporated with Ag+ and Sr2+ ions with various molar ratios, and they were successfully converted into the Ag-SrTiO3 hybrid nanoparticles by the hydrothermal treatment at 230 degrees C in strontium hydroxide aqueous solutions. The morphology of the SrTiO3 nanoparticles is dendritic in the presence and absence of Ag+ ions. The precursor gels, which act as the high reactive precursor, give rise to high nucleation and growth rates under the hydrothermal conditions, and the resultant diffusion-limited aggregation phenomena facilitate the dendritic growth of SrTiO3. From the field emission transmission electron microscope observation of these Ag-SrTiO3 hybrid nanoparticles, the Ag nanoparticles with a size of a few tens of nanometers are distributed without severe agglomeration, owing to the competitive formation reactions of Ag and SrTiO3. PMID- 28347019 TI - Separator Membrane from Crosslinked Poly(Vinyl Alcohol) and Poly(Methyl Vinyl Ether-alt-Maleic Anhydride). AB - In this work, we report separator membranes from crosslinking of two polymers, such as poly vinyl alcohol (PVA) with an ionic polymer poly(methyl vinyl ether alt-maleic anhydride) (PMVE-MA). Such interpolymer-networked systems were extensively used for biomedical and desalination applications but they were not examined for their potential use as membranes or separators for batteries. Therefore, the chemical interactions between these two polymers and the influence of such crosslinking on physicochemical properties of the membrane are systematically investigated through rheology and by critical gel point study. The hydrogen bonding and the chemical interaction between PMVE-MA and PVA resulted in highly cross-linked membranes. Effect of the molecular weight of PVA on the membrane properties was also examined. The developed membranes were extensively characterized by studying their physicochemical properties (water uptake, swelling ratio, and conductivity), thermal and electrochemical properties using differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), thermo-gravimetric analysis (TGA) and electrochemical impedance spectroscopy (EIS). The DSC study shows the presence of a single Tg in the membranes indicating compatibility of the two polymers in flexible and transparent films. The membranes show good stability and ion conductivity suitable for separator applications. PMID- 28347021 TI - Meso-Structuring of SiCN Ceramics by Polystyrene Templates. AB - A simple one-pot synthesis of well-defined PS-silazane nano-composites (polystyrene, PS) is described. In contrast to the, thus far, used two-step procedure ((1) assembly of a PS template bed and (2) careful filling of the voids between the PS spheres), which is restricted to macro structuring, we are able to simply mix the PS template and a commercially available silazane precursor HTT 1800 in toluene. The key is the alteration of the zeta potential of the PS template leading to a homogeneous dispersion in the silazane-toluene mixture. Removal of solvent gives rise to a highly ordered PS-silazane nano-composites and subsequent pyrolysis leads to mesoporous silicon carbonitride (SiCN) materials. The one-pot procedure has two advantages: easy upscaling and the use of PS spheres smaller than 100 nm in diameter, here 60 nm. The PS template was characterized by photon correlation spectroscopy, zeta potential measurements, scanning electron microscopy (SEM), and thermal gravimetric analysis (TGA). The resulting mesoporous SiCN materials were analyzed by SEM, transmission electron microscopy (TEM), nitrogen sorption analysis, and Fourier transform infrared measurements (FT-IR). PMID- 28347020 TI - Fabrication and Cell Responsive Behavior of Macroporous PLLA/Gelatin Composite Scaffold with Hierarchical Micro-Nano Pore Structure. AB - Scaffolds providing a 3D environment which can effectively promote the adhesion, proliferation and differentiation of cells are crucial to tissue regeneration. In this study, the poly-l-lactic acid (PLLA) scaffold with hierarchical pore structural was fabricated via two-step thermally induced phase separation (TIPS). To mimic both physical architecture and chemical composite of natural bone extracellular matrix (ECM), gelatin fibers were introduced into the pores of PLLA scaffolds and formed 3D network structure via TIPS. Human adipose tissue-derived stem cells (ADSCs) were harvested and seeded into PLLA/gel hybrid scaffolds and cultured in vitro for biocompatibility assay. The surface morphology, porosity and compressive modulus of scaffolds were characterized by scanning electron microscopy (SEM), density analysis and compression test respectively. The results showed that hybrid scaffolds had high porosity (91.62%), a good compressive modulus (2.79 +/- 0.20 MPa), nanometer fibers (diameter around 186.39~354.30 nm) and different grades of pore size from 7.41 +/- 2.64 nm to 387.94 +/- 102.48 nm. The scaffolds with mild hydrolysis by NaOH were modified by 1-ethyl-3-(3-dimethyl ami-nopropyl) carbodiimide/N-hydroxysuccinimide (EDC/NHS). Gelatin was performed onto PLLA scaffold via TIPS aiming at enhancement cell-material interaction. In comparison with PLLA scaffold, the PLLA/gel scaffold had better biological performance and the mechanical properties because the gelatin fibers homogeneously distributed in each pore of PLLA scaffold and formed 3D network structure. PMID- 28347024 TI - Band Structure Simulations of the Photoinduced Changes in the MgB2:Cr Films. AB - An approach for description of the photoinduced nonlinear optical effects in the superconducting MgB2:Cr2O3 nanocrystalline film is proposed. It includes the molecular dynamics step-by-step optimization of the two separate crystalline phases. The principal role for the photoinduced nonlinear optical properties plays nanointerface between the two phases. The first modified layers possess a form of slightly modified perfect crystalline structure. The next layer is added to the perfect crystalline structure and the iteration procedure is repeated for the next layer. The total energy here is considered as a varied parameter. To avoid potential jumps on the borders we have carried out additional derivative procedure. PMID- 28347023 TI - Ceramic Nanocomposites from Tailor-Made Preceramic Polymers. AB - The present Review addresses current developments related to polymer-derived ceramic nanocomposites (PDC-NCs). Different classes of preceramic polymers are briefly introduced and their conversion into ceramic materials with adjustable phase compositions and microstructures is presented. Emphasis is set on discussing the intimate relationship between the chemistry and structural architecture of the precursor and the structural features and properties of the resulting ceramic nanocomposites. Various structural and functional properties of silicon-containing ceramic nanocomposites as well as different preparative strategies to achieve nano-scaled PDC-NC-based ordered structures are highlighted, based on selected ceramic nanocomposite systems. Furthermore, prospective applications of the PDC-NCs such as high-temperature stable materials for thermal protection systems, membranes for hot gas separation purposes, materials for heterogeneous catalysis, nano-confinement materials for hydrogen storage applications as well as anode materials for secondary ion batteries are introduced and discussed in detail. PMID- 28347022 TI - Gene Expression, Protein Function and Pathways of Arabidopsis thaliana Responding to Silver Nanoparticles in Comparison to Silver Ions, Cold, Salt, Drought, and Heat. AB - Silver nanoparticles (AgNPs) have been widely used in industry due to their unique physical and chemical properties. However, AgNPs have caused environmental concerns. To understand the risks of AgNPs, Arabidopsis microarray data for AgNP, Ag+, cold, salt, heat and drought stresses were analyzed. Up- and down-regulated genes of more than two-fold expression change were compared, while the encoded proteins of shared and unique genes between stresses were subjected to differential enrichment analyses. AgNPs affected the fewest genes (575) in the Arabidopsis genome, followed by Ag+ (1010), heat (1374), drought (1435), salt (4133) and cold (6536). More genes were up-regulated than down-regulated in AgNPs and Ag+ (438 and 780, respectively) while cold down-regulated the most genes (4022). Responses to AgNPs were more similar to those of Ag+ (464 shared genes), cold (202), and salt (163) than to drought (50) or heat (30); the genes in the first four stresses were enriched with 32 PFAM domains and 44 InterPro protein classes. Moreover, 111 genes were unique in AgNPs and they were enriched in three biological functions: response to fungal infection, anion transport, and cell wall/plasma membrane related. Despite shared similarity to Ag+, cold and salt stresses, AgNPs are a new stressor to Arabidopsis. PMID- 28347025 TI - Synthesis and Adsorption Property of SiO2@Co(OH)2 Core-Shell Nanoparticles. AB - Silica nanoparticles were directly coated with cobalt hydroxide by homogeneous precipitation of slowly decomposing urea in cobalt nitrate solution. The cobalt hydroxide was amorphous, and its morphology was nanoflower-like. The BET (Brunauer-Emmett-Teller) surface area of the core-shell composite was 221 m2/g. Moreover, the possible formation procedure is proposed: the electropositive cobalt ions were first adsorbed on the electronegative silica nanoparticles surface, which hydrolyzed to form cobalt hydroxide nanoparticles. Then, the cobalt hydroxide nanoparticles were aggregated to form nanoflakes. Finally, the nanoflakes self-assembled, forming cobalt hydroxide nanoflowers. Adsorption measurement showed that the core-shell composite exhibited excellent adsorption capability of Rhodamine B (RB). PMID- 28347026 TI - Metal Organic Framework Micro/Nanopillars of Cu(BTC).3H2O and Zn(ADC).DMSO. AB - In this work, we report the optical and thermal properties of Cu(BTC).3H2O (BTC = 1,3,5-benzenetricarboxylic acid) and Zn(ADC).DMSO (ADC = 9,10- anthracenedicarboxylic acid, DMSO = dimethyl sulfoxide) metal-organic frameworks (MOFs) micro/nanopillars. The morphologies of MOFs on surfaces are most in the form of micro/nanopillars that were vertically oriented on the surface. The size and morphology of the pillars depend on the evaporation time, concentration, solvent, substrate, and starting volume of solutions. The crystal structures of the nanopillars and micropillars are the same, confirmed by powder XRD. Zn(ADC).DMSO pillars have a strong blue fluorescence. Most of ADC in the pillars are in the form of monomers, which is different from ADC in the solid powder. PMID- 28347028 TI - Optical and Structural Properties of Si Nanocrystals in SiO2 Films. AB - Optical and structural properties of Si nanocrystals (Si-nc) in silica films are described. For the SiOx (x < 2) films annealed above 1000 degrees C, the Raman signal of Si-nc and the absorption coefficient are proportional to the amount of elemental Si detected by X-ray photoelectron spectroscopy. A good agreement is found between the measured refractive index and the value estimated by using the effective-medium approximation. The extinction coefficient of elemental Si is found to be between the values of crystalline and amorphous Si. Thermal annealing increases the degree of Si crystallization; however, the crystallization and the Si-SiO2 phase separation are not complete after annealing at 1200 degrees C. The 1.5-eV PL quantum yield increases as the amount of elemental Si decreases; thus, this PL is probably not directly from Si-nc responsible for absorption and detected by Raman spectroscopy. Continuous-wave laser light can produce very high temperatures in the free-standing films, which changes their structural and optical properties. For relatively large laser spots, the center of the laser annealed area is very transparent and consists of amorphous SiO2. Large Si-nc (up to ~300 nm in diameter) are observed in the ring around the central region. These Si-nc lead to high absorption and they are typically under compressive stress, which is connected with their formation from the liquid phase. By using strongly focused laser beams, the structural changes in the free-standing films can be made in submicron areas. PMID- 28347027 TI - Magneto-Plasmonics and Resonant Interaction of Light with Dynamic Magnetisation in Metallic and All-Magneto-Dielectric Nanostructures. AB - A significant interest in combining plasmonics and magnetism at the nanoscale gains momentum in both photonics and magnetism sectors that are concerned with the resonant enhancement of light-magnetic-matter interaction in nanostructures. These efforts result in a considerable amount of literature, which is difficult to collect and digest in limited time. Furthermore, there is insufficient exchange of results between the two research sectors. Consequently, the goal of this review paper is to bridge this gap by presenting an overview of recent progress in the field of magneto-plasmonics from two different points of view: magneto-plasmonics, and magnonics and magnetisation dynamics. It is expected that this presentation style will make this review paper of particular interest to both general physical audience and specialists conducting research on photonics, plasmonics, Brillouin light scattering spectroscopy of magnetic nanostructures and magneto-optical Kerr effect magnetometry, as well as ultrafast all-optical and THz-wave excitation of spin waves. Moreover, readers interested in a new, rapidly emerging field of all-dielectric nanophotonics will find a section about all-magneto-dielectric nanostructures. PMID- 28347029 TI - Structural Ceramic Nanocomposites: A Review of Properties and Powders' Synthesis Methods. AB - Ceramic nanocomposites are attracting growing interest, thanks to new processing methods enabling these materials to go from the research laboratory scale to the commercial level. Today, many different types of nanocomposite structures are proposed in the literature; however, to fully exploit their exceptional properties, a deep understanding of the materials' behavior across length scales is necessary. In fact, knowing how the nanoscale structure influences the bulk properties enables the design of increasingly performing composite materials. A further key point is the ability of tailoring the desired nanostructured features in the sintered composites, a challenging issue requiring a careful control of all stages of manufacturing, from powder synthesis to sintering. This review is divided into four parts. In the first, classification and general issues of nanostructured ceramics are reported. The second provides basic structure property relations, highlighting the grain-size dependence of the materials properties. The third describes the role of nanocrystalline second-phases on the mechanical properties of ordinary grain sized ceramics. Finally, the fourth part revises the mainly used synthesis routes to produce nanocomposite ceramic powders, underlining when possible the critical role of the synthesis method on the control of microstructure and properties of the sintered ceramics. PMID- 28347030 TI - Dealloying of Cu-Based Metallic Glasses in Acidic Solutions: Products and Energy Storage Applications. AB - Dealloying, a famous ancient etching technique, was used to produce nanoporous metals decades ago. With the development of dealloying techniques and theories, various interesting dealloying products including nanoporous metals/alloys, metal oxides and composites, which exhibit excellent catalytic, optical and sensing performance, have been developed in recent years. As a result, the research on dealloying products is of great importance for developing new materials with superior physical and chemical properties. In this paper, typical dealloying products from Cu-based metallic glasses after dealloying in hydrofluoric acid and hydrochloric acid solutions are summarized. Several potential application fields of these dealloying products are discussed. A promising application of nanoporous Cu (NPC) and NPC-contained composites related to the energy storage field is introduced. It is expected that more promising dealloying products could be developed for practical energy storage applications. PMID- 28347031 TI - Titration of DNA/Carbon Nanotube Complexes with Double-Chained Oppositely Charged Surfactants. AB - 1/1 dispersions of ss-DNA/CNT complexes in mass ratios were investigated in a mixture with didodecyldimethylammonium bromide, DDAB. Depending on the amounts of the surface-active agent and of the complexes, solutions, precipitates, or re dissolution occur. DDAB titrates the phosphate groups on the outer surface of the complex and controls the phase sequence in these systems. The combination of different experimental methods determined the phases that occur therein. The results are based on optical absorbance, Dynamic Light Scattering, ionic conductivity, zeta-potential, optical microscopy and AFM. From the above findings a (pseudo)-binary phase diagram is attained. The system has strong similarities with polymer-surfactant mixtures. In fact, its properties conform to cases in which interactions between rigid rod-like polyelectrolytes and oppositely charged species take place. The peculiarities of double-chained DDAB in the process imply significant differences with respect to the behavior of single chain surfactants. In fact, DDAB associates into vesicular entities, when the homologous single chain species forms small micellar aggregates. PMID- 28347032 TI - Synthesis, Characterization and Gas Sensing Properties of Ag@alpha-Fe2O3 Core Shell Nanocomposites. AB - Ag@alpha-Fe2O3 nanocomposite having a core-shell structure was synthesized by a two-step reduction-sol gel approach, including Ag nanoparticles synthesis by sodium borohydride as the reducing agent in a first step and the subsequent mixing with a Fe+3 sol for alpha-Fe2O3 coating. The synthesized Ag@alpha-Fe2O3 nanocomposite has been characterized by various techniques, such as SEM, TEM and UV-Vis spectroscopy. The electrical and gas sensing properties of the synthesized composite towards low concentrations of ethanol have been evaluated. The Ag@alpha Fe2O3 nanocomposite showed better sensing characteristics than the pure alpha Fe2O3. The peculiar hierarchical nano-architecture and the chemical and electronic sensitization effect of Ag nanoparticles in Ag@alpha-Fe2O3 sensors were postulated to play a key role in modulating gas-sensing properties in comparison to pristine alpha-Fe2O3 sensors. PMID- 28347033 TI - Frontiers in Nucleic Acid Nanotechnology. AB - This Special Issue of Nanomaterials highlights innovative work from around the world focused on harnessing the physical, chemical and topological properties of nucleic acids. [...]. PMID- 28347035 TI - Modeling the Dispersibility of Single Walled Carbon Nanotubes in Organic Solvents by Quantitative Structure-Activity Relationship Approach. AB - The knowledge of physico-chemical properties of carbon nanotubes, including behavior in organic solvents is very important for design, manufacturing and utilizing of their counterparts with improved properties. In the present study a quantitative structure-activity/property relationship (QSAR/QSPR) approach was applied to predict the dispersibility of single walled carbon nanotubes (SWNTs) in various organic solvents. A number of additive descriptors and quantum chemical descriptors were calculated and utilized to build QSAR models. The best predictability is shown by a 4-variable model. The model showed statistically good results (R2training = 0.797, Q2 = 0.665, R2test = 0.807), with high internal and external correlation coefficients. Presence of the X0Av descriptor and its negative term suggest that small size solvents have better SWCNTs solubility. Mass weighted descriptor ATS6m also indicates that heavier solvents (and small in size) most probably are better solvents for SWCNTs. The presence of the Dipole Z descriptor indicates that higher polarizability of the solvent molecule increases the solubility. The developed model and contributed descriptors can help to understand the mechanism of the dispersion process and predictorganic solvents that improve the dispersibility of SWNTs. PMID- 28347034 TI - Multifunctional Carbon Nanostructures for Advanced Energy Storage Applications. AB - Carbon nanostructures-including graphene, fullerenes, etc.-have found applications in a number of areas synergistically with a number of other materials. These multifunctional carbon nanostructures have recently attracted tremendous interest for energy storage applications due to their large aspect ratios, specific surface areas, and electrical conductivity. This succinct review aims to report on the recent advances in energy storage applications involving these multifunctional carbon nanostructures. The advanced design and testing of multifunctional carbon nanostructures for energy storage applications specifically, electrochemical capacitors, lithium ion batteries, and fuel cells are emphasized with comprehensive examples. PMID- 28347036 TI - Phosphorothioate DNA Stabilized Fluorescent Gold and Silver Nanoclusters. AB - Unmodified single-stranded DNA has recently gained popularity for the templated synthesis of fluorescent noble metal nanoclusters (NCs). Bright, stable, and biocompatible clusters have been developed primarily through optimization of DNA sequence. However, DNA backbone modifications have not yet been investigated. In this work, phosphorothioate (PS) DNAs are evaluated in the synthesis of Au and Ag nanoclusters, and are employed to successfully template a novel emitter using T15 DNA at neutral pH. Mechanistic studies indicate a distinct UV-dependent formation mechanism that does not occur through the previously reported thymine N3. The positions of PS substitution have been optimized. This is the first reported use of a T15 template at physiological pH for AgNCs. PMID- 28347037 TI - Thermal Emission Control via Bandgap Engineering in Aperiodically Designed Nanophotonic Devices. AB - Aperiodic photonic crystals can open up novel routes for more efficient photon management due to increased degrees of freedom in their design along with the unique properties brought about by the long-range aperiodic order as compared to their periodic counterparts. In this work we first describe the fundamental notions underlying the idea of thermal emission/absorption control on the basis of the systematic use of aperiodic multilayer designs in photonic quasicrystals. Then, we illustrate the potential applications of this approach in order to enhance the performance of daytime radiative coolers and solar thermoelectric energy generators. PMID- 28347038 TI - Graphene Oxide Synthesis from Agro Waste. AB - A new method of graphene oxide (GO) synthesis via single-step reforming of sugarcane bagasse agricultural waste by oxidation under muffled atmosphere conditions is reported. The strong and sharp X-ray diffraction peak at 2theta = 11.6 degrees corresponds to an interlayer distance of 0.788 nm (d002) for the AB stacked GOs. High-resolution transmission electron microscopy (HRTEM) and selected-area electron diffraction (SAED) confirm the formation of the GO layer structure and the hexagonal framework. This is a promising method for fast and effective synthesis of GO from sugarcane bagasse intended for a variety of energy and environmental applications. PMID- 28347039 TI - Toxicity and Biokinetics of Colloidal Gold Nanoparticles. AB - Gold nanoparticles (Au-NPs) have promising potential for diverse biological application, but it has not been completely determined whether Au-NP has potential toxicity in vitro and in vivo. In the present study, toxicity of Au-NP was evaluated in human intestinal cells as well as in rats after 14-day repeated oral administration. Biokinetic study was also performed to assess oral absorption and tissue distribution. The results demonstrated that Au-NP did not cause cytotoxic effects on cells after 24 h exposure in terms of inhibition of cell proliferation, membrane damage, and oxidative stress. However, when a small number of cells were exposed to Au-NP for seven days, colony forming ability remarkably decreased by Au-NP treatment, suggesting its potential toxicity after long-term exposure at high concentration. Biokinetic study revealed that Au-NP slowly entered the blood stream and slightly accumulated only in kidney after oral administration to rats. Whereas, orally administered Au ions were rapidly absorbed, and then distributed in kidney, liver, lung, and spleen at high levels, suggesting that the biological fate of Au-NP is primarily in nanoparticulate form, not in ionic Au. Fourteen-day repeated oral toxicity evaluation showed that Au-NP did not cause severe toxicity in rats based on histopathological, hematological, and serum biochemical analysis. PMID- 28347041 TI - Targeting of Apoptotic Cells Using Functionalized Fe2O3 Nanoparticles. AB - Fe2O3 nanoparticles (NPs) have been synthesized and functionalized with SiO2 and NH2 group, respectively. Conjugation to fluorescently-labeled poly-caspase inhibitor (SR-FLIVO) has been carried out for better cellular uptake studies of apoptosis arising from brain focal cerebral ischemia. Highest conjugation affinity to SR-FLIVO was found to be ca. 80% for Fe2O3-SiO-NH2 functionalized nanoparticles (FNPs). Tracking of SR-FLIVO conjugated functionalized nanoparticles (SR-FLIVO-FNPs) in vivo and in vitro has been carried out and detected using microscopic techniques after histochemical staining methods. Experimental results revealed that SR-FLIVO-FNPs probe could passively cross the blood brain barrier (BBB) and accumulated within the apoptotic cell. Optimization of SR-FLIVO-FNPs probe can effectively promise to open a new era for intracellular drug delivery and brain diagnosis. PMID- 28347042 TI - Electronic Structure and Magnetism of Mn-Doped ZnO Nanowires. AB - The geometric structures, electronic and magnetic properties of Mn-doped ZnO nanowires were investigated using density functional theory. The results indicated that all the calculated energy differences were negative, and the energy of the ground state was 0.229 eV lower than ferromagnetic coupling, which show higher stability in antiferromagnetic coupling. The calculated results indicated that obvious spin splitting phenomenon occurred near the Femi level. The Zn atoms on the inner layer of ZnO nanowires are easily substituted by Mn atoms along the [0001] direction. It was also shown that the Mn2+-O2--Mn2+ magnetic coupling formed by intermediate O atom was proved to be caused by orbital hybridization between Mn 3d and O 2p states. The magnetic moments were mainly attributed to the unpaired Mn 3d orbitals, but not relevant with doping position of Mn atoms. Moreover, the optical properties of Mn-doped ZnO nanowires exhibited a novel blue-shifted optical absorption and enhanced ultraviolet-light emission. The above results show that the Mn-doped ZnO nanowires are a new type of magneto-optical materials with great promise. PMID- 28347040 TI - Penetration and Toxicity of Nanomaterials in Higher Plants. AB - Nanomaterials (NMs) comprise either inorganic particles consisting of metals, oxides, and salts that exist in nature and may be also produced in the laboratory, or organic particles originating only from the laboratory, having at least one dimension between 1 and 100 nm in size. According to shape, size, surface area, and charge, NMs have different mechanical, chemical, electrical, and optical properties that make them suitable for technological and biomedical applications and thus they are being increasingly produced and modified. Despite their beneficial potential, their use may be hazardous to health owing to the capacity to enter the animal and plant body and interact with cells. Studies on NMs involve technologists, biologists, physicists, chemists, and ecologists, so there are numerous reports that are significantly raising the level of knowledge, especially in the field of nanotechnology; however, many aspects concerning nanobiology remain undiscovered, including the interactions with plant biomolecules. In this review we examine current knowledge on the ways in which NMs penetrate plant organs and interact with cells, with the aim of shedding light on the reactivity of NMs and toxicity to plants. These points are discussed critically to adjust the balance with regard to the risk to the health of the plants as well as providing some suggestions for new studies on this topic. PMID- 28347043 TI - Emission Properties of Fluorescent Nanoparticles Determined by Their Optical Environment. AB - The emission rate of a radiating dipole within a nanoparticle is crucially dependent on its surrounding refractive index environment. In this manuscript, we present numerical results on how the emission rates are affected for nanoparticles in a homogenous and substrate environment. These results are general, applicable to any refractive index distribution and emitter. PMID- 28347045 TI - Synthesis of Helical Carbon Fibers and Related Materials: A Review on the Past and Recent Developments. AB - Helical carbon fibers (HCFs) have been widely studied due to their unique helical morphology and superior properties, which make them efficient materials for several potential applications. This review summarizes the past and current advancement on the synthesis of HCFs. The review focuses and discusses synthesis strategies and effect of experimental parameters on the growth of HCFs. The effect of preparation method of catalyst, catalyst nature, catalyst composition, catalyst size, catalyst initial and final shape, reaction temperature, reaction time, carbon source, impurities, and electromagnetic field on the growth of HCFs is reviewed. We also discuss the growth mechanism for HCFs and the synthesis of HCFs related materials. Finally, we conclude with a brief summary and an outlook on the challenges and future prospects of HCFs. PMID- 28347046 TI - Kinetic Uptake Studies of Powdered Materials in Solution. AB - Challenges exist for the study of time dependent sorption processes for heterogeneous systems, especially in the case of dispersed nanomaterials in solvents or solutions because they are not well suited to conventional batch kinetic experiments. In this study, a comparison of batch versus a one-pot setup in two variable configurations was evaluated for the study of uptake kinetics in heterogeneous (solid/solution) systems: (i) conventional batch method; (ii) one pot system with dispersed adsorbent in solution with a semi-permeable barrier (filter paper or dialysis tubing) for in situ sampling; and (iii) one-pot system with an adsorbent confined in a semi-permeable barrier (dialysis tubing or filter paper barrier) with ex situ sampling. The sorbent systems evaluated herein include several cyclodextrin-based polyurethane materials with two types of phenolic dyes: p-nitrophenol and phenolphthalein. The one-pot kinetics method with in situ (Method ii) or ex situ (Method iii) sampling described herein offers significant advantages for the study of heterogeneous sorption kinetics of highly dispersed sorbent materials with particles sizes across a range of dimensions from the micron to nanometer scale. The method described herein will contribute positively to the development of advanced studies for heterogeneous sorption processes where an assessment of the relative uptake properties is required at different experimental conditions. The results of this study will be advantageous for the study of nanomaterials with significant benefits over batch kinetic studies for a wide range of heterogeneous sorption processes. PMID- 28347044 TI - Nanostructured Electrode Materials for Electrochemical Capacitor Applications. AB - The advent of novel organic and inorganic nanomaterials in recent years, particularly nanostructured carbons, conducting polymers, and metal oxides, has enabled the fabrication of various energy devices with enhanced performance. In this paper, we review in detail different nanomaterials used in the fabrication of electrochemical capacitor electrodes and also give a brief overview of electric double-layer capacitors, pseudocapacitors, and hybrid capacitors. From a materials point of view, the latest trends in electrochemical capacitor research are also discussed through extensive analysis of the literature and by highlighting notable research examples (published mostly since 2013). Finally, a perspective on next-generation capacitor technology is also given, including the challenges that lie ahead. PMID- 28347047 TI - Nano-Sized Cyclodextrin-Based Molecularly Imprinted Polymer Adsorbents for Perfluorinated Compounds-A Mini-Review. AB - Recent efforts have been directed towards the design of efficient and contaminant selective remediation technology for the removal of perfluorinated compounds (PFCs) from soils, sediments, and aquatic environments. While there is a general consensus on adsorption-based processes as the most suitable methodology for the removal of PFCs from aquatic environments, challenges exist regarding the optimal materials design of sorbents for selective uptake of PFCs. This article reviews the sorptive uptake of PFCs using cyclodextrin (CD)-based polymer adsorbents with nano- to micron-sized structural attributes. The relationship between synthesis of adsorbent materials and their structure relate to the overall sorption properties. Hence, the adsorptive uptake properties of CD-based molecularly imprinted polymers (CD-MIPs) are reviewed and compared with conventional MIPs. Further comparison is made with non-imprinted polymers (NIPs) that are based on cross-linking of pre-polymer units such as chitosan with epichlorohydrin in the absence of a molecular template. In general, MIPs offer the advantage of selectivity, chemical tunability, high stability and mechanical strength, ease of regeneration, and overall lower cost compared to NIPs. In particular, CD-MIPs offer the added advantage of possessing multiple binding sites with unique physicochemical properties such as tunable surface properties and morphology that may vary considerably. This mini-review provides a rationale for the design of unique polymer adsorbent materials that employ an intrinsic porogen via incorporation of a macrocyclic compound in the polymer framework to afford adsorbent materials with tunable physicochemical properties and unique nanostructure properties. PMID- 28347048 TI - Antitumor Activities of Metal Oxide Nanoparticles. AB - Nanoparticles have received much attention recently due to their use in cancer therapy. Studies have shown that different metal oxide nanoparticles induce cytotoxicity in cancer cells, but not in normal cells. In some cases, such anticancer activity has been demonstrated to hold for the nanoparticle alone or in combination with different therapies, such as photocatalytic therapy or some anticancer drugs. Zinc oxide nanoparticles have been shown to have this activity alone or when loaded with an anticancer drug, such as doxorubicin. Other nanoparticles that show cytotoxic effects on cancer cells include cobalt oxide, iron oxide and copper oxide. The antitumor mechanism could work through the generation of reactive oxygen species or apoptosis and necrosis, among other possibilities. Here, we review the most significant antitumor results obtained with different metal oxide nanoparticles. PMID- 28347049 TI - Plasmonics Meets Biology through Optics. AB - Plasmonic metallic nanoparticles (NPs) represent a relevant class of nanomaterials, which is able to achieve light localization down to nanoscale by exploiting a phenomenon called Localized Plasmon Resonance. In the last few years, NPs have been proposed to trigger DNA release or enhance ablation of diseased tissues, while minimizing damage to healthy tissues. In view of the therapeutic relevance of such plasmonic NPs; a detailed characterization of the electrostatic interaction between positively charged gold nanorods (GNRs) and a negatively charged whole-genome DNA solution is reported. The preparation of the hybrid biosystem has been investigated as a function of DNA concentration by means of zeta-potential; hydrodynamic diameter and gel electrophoresis analysis. The results have pointed out the specific conditions to achieve the most promising GNRs/DNA complex and its photo-thermal properties have been investigated. The overall study allows to envisage the possibility to ingeniously combine plasmonic and biological materials and, thus, enable design and development of an original non invasive all-optical methodology for monitoring photo-induced temperature variation with high sensitivity. PMID- 28347050 TI - Crosslinked Carbon Nanotubes/Polyaniline Composites as a Pseudocapacitive Material with High Cycling Stability. AB - The poor cycling stability of polyaniline (PANI) limits its practical application as a pseudocapacitive material due to the volume change during the charge discharge procedure. Herein, crosslinked carbon nanotubes/polyaniline (C CNTs/PANI) composites had been designed by the in situ chemical oxidative polymerization of aniline in the presence of crosslinked carbon nanotubes (C CNTs), which were obtained by coupling of the functionalized carbon nanotubes with 1,4-benzoquinone. The composite showed a specific capacitance of 294 F/g at the scan rate of 10 mV/s, and could retain 95% of its initial specific capacitance after 1000 CV cycles. Such high electrochemical cycling stability resulting from the crosslinked skeleton of the C-CNTs makes them potential electrode materials for a supercapacitor. PMID- 28347051 TI - Origin and Future of Plasmonic Optical Tweezers. AB - Plasmonic optical tweezers can overcome the diffraction limits of conventional optical tweezers and enable the trapping of nanoscale objects. Extension of the trapping and manipulation of nanoscale objects with nanometer position precision opens up unprecedented opportunities for applications in the fields of biology, chemistry and statistical and atomic physics. Potential applications include direct molecular manipulation, lab-on-a-chip applications for viruses and vesicles and the study of nanoscale transport. This paper reviews the recent research progress and development bottlenecks and provides an overview of possible future directions in this field. PMID- 28347052 TI - Examination of Single-Walled Carbon Nanotubes Uptake and Toxicity from Dietary Exposure: Tracking Movement and Impacts in the Gastrointestinal System. AB - Previous studies indicate that exposure of fish to pristine single-walled carbon nanotubes (SWCNTs) by oral gavage, causes no overt toxicity, and no appreciable absorption has been observed. However, in the environment, SWCNTs are likely to be present in dietary sources, which may result in differential impacts on uptake and biological effects. Additionally, the potential of these materials to sorb nutrients (proteins, carbohydrates, and lipids) while present in the gastrointestinal (GI) tract may lead to nutrient depletion conditions that impact processes such as growth and reproduction. To test this phenomenon, fathead minnows were fed a commercial diet either with or without SWCNTs for 96 h. Tracking and quantification of SWCNTs using near-infrared fluorescence (NIRF) imaging during feeding studies showed the presence of food does not facilitate transport of SWCNTs across the intestinal epithelia. Targeting genes shown to be responsive to nutrient depletion (peptide transporters, peptide hormones, and lipases) indicated that pept2, a peptide transporter, and cck, a peptide hormone, showed differential mRNA expression by 96 h, a response that may be indicative of nutrient limitation. The results of the current study increase our understanding of the movement of SWCNTs through the GI tract, while the changes in nutrient processing genes highlight a novel mechanism of sublethal toxicity in aquatic organisms. PMID- 28347053 TI - Hybrid Mesoporous Silicas and Microporous POSS-Based Frameworks Incorporating Evaporation-Induced Self-Assembly. AB - We fabricated a series of mesoporous silicas and mesoporous organosilicates with hierarchical porosity through evaporation-induced self-assembly using Pluronic F127 as a template in this study. We could tailor the mesophase of each mesoporous silica sample by varying the weight ratio of its two silica sources: tetraethyl orthosilicate (TEOS) and triethoxysilane hydrosilylated octavinyl polyhedral oligomeric silsesquioxane (OV-POSS-SILY). The mesophases ranged from an ordered body-centered cubic (bcc) structure (TEOS alone) to ordered face centered cubic (fcc) structure (10 and 20 wt.% of OV-POSS-SILY) and finally to disordered spherical pores (>=30 wt.% of OV-POSS-SILY). We used small-angle X-ray scattering (SAXS) and transmission electron microscopy (TEM) to study the transformations of these mesophases, while N2 isotherm sorption curves revealed the porosities of these mesoporous silicate samples. Moreover, 29Si CP/MAS solid state nuclear magnetic resonance spectroscopy allowed us to analyze the compositions of the POSS-containing silicate frameworks. Such functional mesoporous silica samples incorporating microporous POSS building units have potential applications in various systems, including optical and electronic devices. PMID- 28347055 TI - A Sustainable Approach to Fabricating Ag Nanoparticles/PVA Hybrid Nanofiber and Its Catalytic Activity. AB - Ag nanoparticles were synthesized by using Ficus altissimaBlume leaf extract as a reducing agent at room temperature. The resulting Ag nanoparticles/PVA mixture was employed to create Ag nanoparticles/PVA (polyvinyl alcohol) hybrid nanofibers via an electrospinning technique. The obtained nanofibers were confirmed by means of UV-Vis spectroscopy, The X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and then tested to catalyze KBH4 reduction of methylene blue (MB). The catalytic results demonstrate that the MB can be reduced completely within 15 min. In addition, the Ag nanoparticles/PVA hybrid nanofibers show reusability for three cycles with no obvious losses in degradation ratio of the MB. PMID- 28347054 TI - Dynamism of Stimuli-Responsive Nanohybrids: Environmental Implications. AB - Nanomaterial science and design have shifted from generating single passive nanoparticles to more complex and adaptive multi-component nanohybrids. These adaptive nanohybrids (ANHs) are designed to simultaneously perform multiple functions, while actively responding to the surrounding environment. ANHs are engineered for use as drug delivery carriers, in tissue-engineered templates and scaffolds, adaptive clothing, smart surface coatings, electrical switches and in platforms for diversified functional applications. Such ANHs are composed of carbonaceous, metallic or polymeric materials with stimuli-responsive soft-layer coatings that enable them to perform such switchable functions. Since ANHs are engineered to dynamically transform under different exposure environments, evaluating their environmental behavior will likely require new approaches. Literature on polymer science has established a knowledge core on stimuli responsive materials. However, translation of such knowledge to environmental health and safety (EHS) of these ANHs has not yet been realized. It is critical to investigate and categorize the potential hazards of ANHs, because exposure in an unintended or shifting environment could present uncertainty in EHS. This article presents a perspective on EHS evaluation of ANHs, proposes a principle to facilitate their identification for environmental evaluation, outlines a stimuli based classification for ANHs and discusses emerging properties and dynamic aspects for systematic EHS evaluation. PMID- 28347056 TI - Mechanical Dispersion of Nanoparticles and Its Effect on the Specific Heat Capacity of Impure Binary Nitrate Salt Mixtures. AB - In this study, the effect of nanoparticle concentration was tested for both CuO and TiO2 in eutectic mixture of sodium and potassium nitrate. Results showed an enhancement in specific heat capacity (Cp) for both types of nanoparticles (+10.48% at 440 degrees C for 0.1 wt % CuO and +4.95% at 440 degrees C for 0.5 wt % TiO2) but the behavior toward a rise in concentration was different with CuO displaying its highest enhancement at the lowest concentration whilst TiO2 showed no concentration dependence for three of the four different concentrations tested. The production of cluster of nanoparticles was visible in CuO but not in TiO2. This formation of nanostructure in molten salt might promote the enhancement in Cp. However, the size and shape of these structures will most likely impact the energy density of the molten salt. PMID- 28347057 TI - Nano-Sized Secondary Organic Aerosol of Diesel Engine Exhaust Origin Impairs Olfactory-Based Spatial Learning Performance in Preweaning Mice. AB - The aims of our present study were to establish a novel olfactory-based spatial learning test and to examine the effects of exposure to nano-sized diesel exhaust origin secondary organic aerosol (SOA), a model environmental pollutant, on the learning performance in preweaning mice. Pregnant BALB/c mice were exposed to clean air, diesel exhaust (DE), or DE-origin SOA (DE-SOA) from gestational day 14 to postnatal day (PND) 10 in exposure chambers. On PND 11, the preweaning mice were examined by the olfactory-based spatial learning test. After completion of the spatial learning test, the hippocampus from each mouse was removed and examined for the expressions of neurological and immunological markers using real time RT-PCR. In the test phase of the study, the mice exposed to DE or DE-SOA took a longer time to reach the target as compared to the control mice. The expression levels of neurological markers such as the N-methyl-d-aspartate (NMDA) receptor subunits NR1 and NR2B, and of immunological markers such as TNF-alpha, COX2, and Iba1 were significantly increased in the hippocampi of the DE-SOA exposed preweaning mice as compared to the control mice. Our results indicate that DE-SOA exposure in utero and in the neonatal period may affect the olfactory based spatial learning behavior in preweaning mice by modulating the expressions of memory function-related pathway genes and inflammatory markers in the hippocampus. PMID- 28347059 TI - Neural Cell Chip Based Electrochemical Detection of Nanotoxicity. AB - Development of a rapid, sensitive and cost-effective method for toxicity assessment of commonly used nanoparticles is urgently needed for the sustainable development of nanotechnology. A neural cell with high sensitivity and conductivity has become a potential candidate for a cell chip to investigate toxicity of environmental influences. A neural cell immobilized on a conductive surface has become a potential tool for the assessment of nanotoxicity based on electrochemical methods. The effective electrochemical monitoring largely depends on the adequate attachment of a neural cell on the chip surfaces. Recently, establishment of integrin receptor specific ligand molecules arginine-glycine aspartic acid (RGD) or its several modifications RGD-Multi Armed Peptide terminated with cysteine (RGD-MAP-C), C(RGD)4 ensure farm attachment of neural cell on the electrode surfaces either in their two dimensional (dot) or three dimensional (rod or pillar) like nano-scale arrangement. A three dimensional RGD modified electrode surface has been proven to be more suitable for cell adhesion, proliferation, differentiation as well as electrochemical measurement. This review discusses fabrication as well as electrochemical measurements of neural cell chip with particular emphasis on their use for nanotoxicity assessments sequentially since inception to date. Successful monitoring of quantum dot (QD), graphene oxide (GO) and cosmetic compound toxicity using the newly developed neural cell chip were discussed here as a case study. This review recommended that a neural cell chip established on a nanostructured ligand modified conductive surface can be a potential tool for the toxicity assessments of newly developed nanomaterials prior to their use on biology or biomedical technologies. PMID- 28347060 TI - The Application of Gas Dwell Time Control for Rapid Single Wall Carbon Nanotube Forest Synthesis to Acetylene Feedstock. AB - One aspect of carbon nanotube (CNT) synthesis that remains an obstacle to realize industrial mass production is the growth efficiency. Many approaches have been reported to improve the efficiency, either by lengthening the catalyst lifetime or by increasing the growth rate. We investigated the applicability of dwell time and carbon flux control to optimize yield, growth rate, and catalyst lifetime of water-assisted chemical vapor deposition of single-walled carbon nanotube (SWCNT) forests using acetylene as a carbon feedstock. Our results show that although acetylene is a precursor to CNT synthesis and possesses a high reactivity, the SWCNT forest growth efficiency is highly sensitive to dwell time and carbon flux similar to ethylene. Through a systematic study spanning a wide range of dwell time and carbon flux levels, the relationship of the height, growth rate, and catalyst lifetime is found. Further, for the optimum conditions for 10 min growth, SWCNT forests with ~2500 MUm height, ~350 MUm/min initial growth rates and extended lifetimes could be achieved by increasing the dwell time to ~5 s, demonstrating the generality of dwell time control to highly reactive gases. PMID- 28347058 TI - Nanotoxicity: An Interplay of Oxidative Stress, Inflammation and Cell Death. AB - Nanoparticles are emerging as a useful tool for a wide variety of biomedical, consumer and instrumental applications that include drug delivery systems, biosensors and environmental sensors. In particular, nanoparticles have been shown to offer greater specificity with enhanced bioavailability and less detrimental side effects as compared to the existing conventional therapies in nanomedicine. Hence, bionanotechnology has been receiving immense attention in recent years. However, despite the extensive use of nanoparticles today, there is still a limited understanding of nanoparticle-mediated toxicity. Both in vivo and in vitro studies have shown that nanoparticles are closely associated with toxicity by increasing intracellular reactive oxygen species (ROS) levels and/or the levels of pro-inflammatory mediators. The homeostatic redox state of the host becomes disrupted upon ROS induction by nanoparticles. Nanoparticles are also known to up-regulate the transcription of various pro-inflammatory genes, including tumor necrosis factor-alpha and IL (interleukins)-1, IL-6 and IL-8, by activating nuclear factor-kappa B (NF-kappaB) signaling. These sequential molecular and cellular events are known to cause oxidative stress, followed by severe cellular genotoxicity and then programmed cell death. However, the exact molecular mechanisms underlying nanotoxicity are not fully understood. This lack of knowledge is a significant impediment in the use of nanoparticles in vivo. In this review, we will provide an assessment of signaling pathways that are involved in the nanoparticle- induced oxidative stress and propose possible strategies to circumvent nanotoxicity. PMID- 28347061 TI - Facile Attachment of TAT Peptide on Gold Monolayer Protected Clusters: Synthesis and Characterization. AB - High affinity thiolate-based polymeric capping ligands are known to impart stability onto nanosized gold nanoparticles. Due to the stable gold-sulfur bond, the ligand forms a protective layer around the gold core and subsequently controls the physicochemical properties of the resultant nanogold mononuclear protected clusters (AuMPCs). The choice of ligands to use as surfactants for AuMPCs largely depends on the desired degree of hydrophilicity and biocompatibility of the MPCs, normally dictated by the intended application. Subsequent surface modification of AuMPCs allows further conjugation of additional biomolecules yielding bilayer or multilayered clusters suitable for bioanalytical applications ranging from targeted drug delivery to diagnostics. In this study, we discuss our recent laboratory findings on a simple route for the introduction of Trans-Activator of Transcription (TAT) peptide onto the surface of biotin-derivatised gold MPCs via the biotin-strepavidin interaction. By changing the surface loading of biotin, controlled amounts of TAT could be attached. This bioconjugate system is very attractive as a carrier in intercellular delivery of various delivery cargoes such as antibodies, proteins and oligonucleotides. PMID- 28347062 TI - Hydrothermal Fabrication of WO3 Hierarchical Architectures: Structure, Growth and Response. AB - Recently hierarchical architectures, consisting of two-dimensional (2D) nanostructures, are of great interest for potential applications in energy and environmental. Here, novel rose-like WO3 hierarchical architectures were successfully synthesized via a facile hydrothermal method. The as-prepared WO3 hierarchical architectures were in fact assembled by numerous nanosheets with an average thickness of ~30 nm. We found that the oxalic acid played a significant role in governing morphologies of WO3 during hydrothermal process. Based on comparative studies, a possible formation mechanism was also proposed in detail. Furthermore, gas-sensing measurement showed that the well-defined 3D WO3 hierarchical architectures exhibited the excellent gas sensing properties towards CO. PMID- 28347063 TI - Effects of Primary Processing Techniques and Significance of Hall-Petch Strengthening on the Mechanical Response of Magnesium Matrix Composites Containing TiO2 Nanoparticulates. AB - In the present study, Mg (1.98 and 2.5) vol % TiO2 nanocomposites are primarily synthesized utilizing solid-phase blend-press-sinter powder metallurgy (PM) technique and liquid-phase disintegrated melt deposition technique (DMD) followed by hot extrusion. Microstructural characterization of the synthesized Mg-TiO2 nanocomposites indicated significant grain refinement with DMD synthesized Mg nanocomposites exhibiting as high as ~47% for 2.5 vol % TiO2 NPs addition. X-ray diffraction studies indicated that texture randomization of pure Mg depends not only on the critical amount of TiO2 NPs added to the Mg matrix but also on the adopted synthesis methodology. Irrespective of the processing technique, theoretically predicted tensile yield strength of Mg-TiO2 nanocomposites was found to be primarily governed by Hall-Petch mechanism. Among the synthesized Mg materials, solid-phase synthesized Mg 1.98 vol % TiO2 nanocomposite exhibited a maximum tensile fracture strain of ~14.5%. Further, the liquid-phase synthesized Mg-TiO2 nanocomposites exhibited higher tensile and compression properties than those primarily processed by solid-phase synthesis. The tensile-compression asymmetry values of the synthesized Mg-TiO2 nanocomposite was found to be lower than that of pure Mg with solid-phase synthesized Mg 1.98 vol % TiO2 nanocomposite exhibiting as low as 1.06. PMID- 28347064 TI - Microwave-Assisted Hydrothermal Rapid Synthesis of Calcium Phosphates: Structural Control and Application in Protein Adsorption. AB - Synthetic calcium phosphate (CaP)-based materials have attracted much attention in the biomedical field. In this study, we have investigated the effect of pH values on CaP nanostructures prepared using a microwave-assisted hydrothermal method. The hierarchical nanosheet-assembled hydroxyapatite (HAP) nanostructure was prepared under weak acidic conditions (pH 5), while the HAP nanorod was prepared under neutral (pH 7) and weak alkali (pH 9) condition. However, when the pH value increases to 11, a mixed product of HAP nanorod and tri-calcium phosphate nanoparticle was obtained. The results indicated that the pH value of the initial reaction solution played an important role in the phase and structure of the CaP. Furthermore, the protein adsorption and release performance of the as prepared CaP nanostructures were investigated by using hemoglobin (Hb) as a model protein. The sample that was prepared at pH = 11 and consisted of mixed morphologies of nanorods and nanoprisms showed a higher Hb protein adsorption capacity than the sample prepared at pH 5, which could be explained by its smaller size and dispersed structure. The results revealed the relatively high protein adsorption capacity of the as-prepared CaP nanostructures, which show promise for applications in various biomedical fields such as drug delivery and protein adsorption. PMID- 28347065 TI - Conjugation of Polymer-Coated Gold Nanoparticles with Antibodies-Synthesis and Characterization. AB - The synthesis of polymer-coated gold nanoparticles with high colloidal stability is described, together with appropriate characterization techniques concerning the colloidal properties of the nanoparticles. Antibodies against vascular endothelial growth factor (VEGF) are conjugated to the surface of the nanoparticles. Antibody attachment is probed by different techniques, giving a guideline about the characterization of such conjugates. The effect of the nanoparticles on human adenocarcinoma alveolar basal epithelial cells (A549) and human umbilical vein endothelial cells (HUVECs) is probed in terms of internalization and viability assays. PMID- 28347066 TI - An Investigation of the Cytotoxicity and Caspase-Mediated Apoptotic Effect of Green Synthesized Zinc Oxide Nanoparticles Using Eclipta prostrata on Human Liver Carcinoma Cells. AB - Cancer is a leading cause of death worldwide and sustained focus is on the discovery and development of newer and better tolerated anticancer drugs, especially from plants. In the present study, a simple, eco-friendly, and inexpensive approach was followed for the synthesis of zinc oxide nanoparticles (ZnO NPs) using the aqueous leaf extract of Eclipta prostrata. The synthesized ZnO NPs were characterized by UV-visible absorption spectroscopy, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), Scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX), High resolution transmission electron microscopy (HRTEM), and Selected area (electron) diffraction (SAED). The HRTEM images confirmed the presence of triangle, radial, hexagonal, rod, and rectangle, shaped with an average size of 29 +/- 1.3 nm. The functional groups for synthesized ZnO NPs were 3852 cm-1 for H-H weak peak, 3138 cm-1 for aromatic C-H extend, and 1648 cm-1 for Aromatic ring stretch. The 3-(4,5 Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT), caspase and DNA fragmentation assays were carried out using various concentrations of ZnO NPs ranging from 1 to 100 mg/mL. The synthesized ZnO NPs showed dose dependent cytopathic effects in the Hep-G2 cell line. At 100 mg/mL concentration, the synthesized ZnO NPs exhibited significant cytotoxic effects and the apoptotic features were confirmed through caspase-3 activation and DNA fragmentation assays. PMID- 28347067 TI - Impact of Carbon Nano-Onions on Hydra vulgaris as a Model Organism for Nanoecotoxicology. AB - The toxicological effects of pristine and chemically modified carbon nano-onions (CNOs) on the development of the freshwater polyp Hydra vulgaris were investigated in order to elucidate the ecotoxicological effects of CNOs. Chemical modifications of the CNOs were accomplished by surface functionalization with benzoic acid, pyridine and pyridinium moieties. thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FT-IR) and Raman spectroscopy confirmed the covalent surface functionalization of CNOs. Hydra specimens were exposed to the carbon nanomaterials by prolonged incubation within their medium. Uptake was monitored by optical microscopy, and the toxicological effects of the CNOs on Hydra behavior, morphology, as well as the long-term effects on the development and reproductive capability were examined. The obtained data revealed the absence of adverse effects of CNOs (in the range 0.05-0.1 mg/L) in vivo at the whole animal level. Together with previously performed in vitro toxicological analyses, our findings indicate the biosafety of CNOs and the feasibility of employing them as materials for biomedical applications. PMID- 28347069 TI - Carbon Nanotube/Alumina/Polyethersulfone Hybrid Hollow Fiber Membranes with Enhanced Mechanical and Anti-Fouling Properties. AB - Carbon nanotubes (CNTs) were incorporated into alumina/polyethersulfone hollow fibre membranes to enhance the mechanical property and the efficiency of water treatment. Results show that the incorporation of CNTs can greatly limit the formation of large surface pores, decrease the void size in support layers and improve the porosity and pore connectivity of alumina/polyethersulfone membranes. As a result of such morphology change and pore size change, both improved flux and rejection were achieved in such CNTs/alumina/polyethersulfone membranes. Moreover, the CNTs/alumina/PES membranes show higher antifouling ability and the flux recoveries after being fouled by bovine serum albumin (BSA) and humic acid were improved by 84.1% and 53.2% compared to the samples without CNT incorporation. Besides the improvement in water treatment performance, the incorporation of CNTs enhanced the tensile properties of inorganic/polymer membranes. Therefore, such CNTs/alumina/PES hollow fiber membranes are very promising candidates for good filter media in industry, considering their high efficiency and high mechanical properties. PMID- 28347068 TI - Role of Physicochemical Properties in Nanoparticle Toxicity. AB - With the recent rapid growth of technological comprehension in nanoscience, researchers have aimed to adapt this knowledge to various research fields within engineering and applied science. Dramatic advances in nanomaterials marked a new epoch in biomedical engineering with the expectation that they would have huge contributions to healthcare. However, several questions regarding their safety and toxicity have arisen due to numerous novel properties. Here, recent studies of nanomaterial toxicology will be reviewed from several physiochemical perspectives. A variety of physiochemical properties such as size distribution, electrostatics, surface area, general morphology and aggregation may significantly affect physiological interactions between nanomaterials and target biological areas. Accordingly, it is very important to finely tune these properties in order to safely fulfill a bio-user's purpose. PMID- 28347070 TI - Hyaluronic Acid-Chitosan Nanoparticles to Deliver Gd-DTPA for MR Cancer Imaging. AB - Molecular imaging is essential to increase the sensitivity and selectivity of cancer diagnosis especially at the early stage of tumors. Recently, polyionic nanocomplexes (PICs), which are composed of polyanions and opposite polycations, have been demonstrated to be a promising strategy for biomedical applications. In this work, chitosan-hyaluronic acid nanoparticles (GCHN) were developed to deliver Gd-DTPA as MRI contrast agents for tumor diagnosis. The Gd-labeled conjugates (CS-DTPA-Gd) were successfully synthesized by carbodiimide reaction, and then GCHN were prepared by ionic gelation using the obtained CS-DTPA-Gd and hyaluronic acid. The morphology of GCHN was spherical or ellipsoidal, which is observed by transmission electronic microscopy (TEM). The mean particle size and zeta potential of GCHN were 213.8 +/- 2.6 nm and 19.92 +/- 1.69 mV, respectively. The significant enhancement of signal intensity induced by GCHN was observed both in vitro and in vivo. Also, compared with Magnevist, GCHN was witnessed for a prolonged imaging time in the B16 tumor-bearing mice model. Furthermore, GCHN were verified as below toxic both in vitro and in vivo. These results indicated that GCHN could potentially be an alternative to current MRI contrast agents for tumor diagnosis. PMID- 28347071 TI - Preparation and Photocatalytic Activity of Potassium- Incorporated Titanium Oxide Nanostructures Produced by the Wet Corrosion Process Using Various Titanium Alloys. AB - Nanostructured potassium-incorporated Ti-based oxides have attracted much attention because the incorporated potassium can influence their structural and physico-chemical properties. With the aim of tuning the structural and physical properties, we have demonstrated the wet corrosion process (WCP) as a simple method for nanostructure fabrication using various Ti-based materials, namely Ti 6Al-4V alloy (TAV), Ti-Ni (TN) alloy and pure Ti, which have 90%, 50% and 100% initial Ti content, respectively. We have systematically investigated the relationship between the Ti content in the initial metal and the precise condition of WCP to control the structural and physical properties of the resulting nanostructures. The WCP treatment involved various concentrations of KOH solutions. The precise conditions for producing K-incorporated nanostructured titanium oxide films (nTOFs) were strongly dependent on the Ti content of the initial metal. Ti and TAV yielded one-dimensional nanowires of K-incorporated nTOFs after treatment with 10 mol/L-KOH solution, whereas TN required a higher concentration (20 mol/L-KOH solution) to produce comparable nanostructures. The obtained nanostructures revealed a blue-shift in UV absorption spectra due to the quantum confinement effects. A significant enhancement of the photocatalytic activity was observed via the chromomeric change and the intermediate formation of methylene blue molecules under UV irradiation. This study demonstrates the WCP as a simple, versatile and scalable method for the production of nanostructured K incorporated nTOFs to be used as high-performance photocatalysts for environmental and energy applications. PMID- 28347073 TI - Synthesis of Mesoporous Metal Oxides by Structure Replication: Thermal Analysis of Metal Nitrates in Porous Carbon Matrices. AB - A variety of metal nitrates were filled into the pores of an ordered mesoporous CMK-3 carbon matrix by solution-based impregnation. Thermal conversion of the metal nitrates into the respective metal oxides, and subsequent removal of the carbon matrix by thermal combustion, provides a versatile means to prepare mesoporous metal oxides (so-called nanocasting). This study aims to monitor the thermally induced processes by thermogravimetric analysis (TGA), coupled with mass ion detection (MS). The highly dispersed metal nitrates in the pores of the carbon matrix tend to react to the respective metal oxides at lower temperature than reported in the literature for pure, i.e., carbon-free, metal nitrates. The subsequent thermal combustion of the CMK-3 carbon matrix also occurs at lower temperature, which is explained by a catalytic effect of the metal oxides present in the pores. This catalytic effect is particularly strong for oxides of redox active metals, such as transition group VII and VIII metals (Mn, Fe, Co, Ni), Cu, and Ce. PMID- 28347072 TI - Comparison of the in Vitro Uptake and Toxicity of Collagen- and Synthetic Polymer Coated Gold Nanoparticles. AB - We studied the physico-chemical properties (size, shape, zeta-potential), cellular internalization and toxicity of gold nanoparticles (NPs) stabilized with the most abundant mammalian protein, collagen. The properties of these gold NPs were compared to the same sized gold NPs coated with synthetic poly(isobutylene alt-maleic anhydride) (PMA). Intracellular uptake and cytotoxicity were assessed in two cell lines (cervical carcinoma and lung adenocarcinoma cells) by employing inductively-coupled plasma-mass spectrometry (ICP-MS) analysis and a cell viability assay based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), respectively. We found that the collagen-coated gold NPs exhibit lower cytotoxicity, but higher uptake levels than PMA-coated gold NPs. These results demonstrate that the surface coating of Au NPs plays a decisive role in their biocompatibility. PMID- 28347074 TI - Surface Wettability Modification of Cyclic Olefin Polymer by Direct Femtosecond Laser Irradiation. AB - The effect of laser irradiation on surface wettability of cyclic olefin polymer (COP) was investigated. Under different laser parameters, a superhydrophilic or a superhydrophobic COP surface with a water contact angle (WCA) of almost 0 degrees or 163 degrees , respectively, could be achieved by direct femtosecond laser irradiation. The laser power deposition rate (PDR) was found to be a key factor on the wettability of the laser-treated COP surface. The surface roughness and surface chemistry of the laser-irradiated samples were characterized by surface profilometer and X-ray photoelectron spectroscopy, respectively; they were found to be responsible for the changes of the laser-induced surface wettability. The mechanisms involved in the laser surface wettability modification process were discussed. PMID- 28347075 TI - Synthesis of Water-Based Dispersions of Polymer/TiO2 Hybrid Nanospheres. AB - We develop a strategy for preparing water-based dispersions of polymer/TiO2 nanospheres that can be used to form composite materials applicable in various fields. The formed hybrid nanospheres are monodisperse and possess a hierarchical structure. It starts with the primary TiO2 nanoparticles of about 5 nm, which first assemble to nanoclusters of about 30 nm and then are integrated into monomer droplets. After emulsion polymerization, one obtains the water-based dispersions of polymer/TiO2 nanospheres. To achieve universal size, it is necessary to have treatments with intense turbulent shear generated in a microchannel device at different stages. In addition, a procedure combining synergistic actions of steric and anionic surfactants has been designed to warrant the colloidal stability of the process. Since the formed polymer/TiO2 nanospheres are stable aqueous dispersions, they can be easily mixed with TiO2 free polymeric nanoparticle dispersions to form new dispersions, where TiO2 containing nanospheres are homogeneously distributed in the dispersions at the nanoscale, thus leading to various applications. As an example, the proposed strategy has been applied to generate polystyrene/TiO2 nanospheres of about 100 nm in diameter. PMID- 28347076 TI - High Performance Li4Ti5O12/Si Composite Anodes for Li-Ion Batteries. AB - Improving the energy capacity of spinel Li4Ti5O12 (LTO) is very important to utilize it as a high-performance Li-ion battery (LIB) electrode. In this work, LTO/Si composites with different weight ratios were prepared and tested as anodes. The anodic and cathodic peaks from both LTO and silicon were apparent in the composites, indicating that each component was active upon Li+ insertion and extraction. The composites with higher Si contents (LTO:Si = 35:35) exhibited superior specific capacity (1004 mAh.g-1) at lower current densities (0.22 A.g-1) but the capacity deteriorated at higher current densities. On the other hand, the electrodes with moderate Si contents (LTO:Si = 50:20) were able to deliver stable capacity (100 mAh.g-1) with good cycling performance, even at a very high current density of 7 A.g-1. The improvement in specific capacity and rate performance was a direct result of the synergy between LTO and Si; the former can alleviate the stresses from volumetric changes in Si upon cycling, while Si can add to the capacity of the composite. Therefore, it has been demonstrated that the addition of Si and concentration optimization is an easy yet an effective way to produce high performance LTO-based electrodes for lithium-ion batteries. PMID- 28347077 TI - Graphene/Sulfur/Carbon Nanocomposite for High Performance Lithium-Sulfur Batteries. AB - Here, we report a two-step synthesis of graphene/sulfur/carbon ternary composite with a multilayer structure. In this composite, ultrathin S layers are uniformly deposited on graphene nanosheets and covered by a thin layer of amorphous carbon derived from beta-cyclodextrin on the surface. Such a unique microstructure, not only improves the electrical conductivity of sulfur, but also effectively inhibits the dissolution of polysulfides during charging/discharging processes. As a result, this ternary nanocomposite exhibits excellent electrochemical performance. It can deliver a high initial discharge and charge capacity of 1410 mAh.g-1 and 1370 mAh.g-1, respectively, and a capacity retention of 63.8% can be achieved after 100 cycles at 0.1 C (1 C = 1675 mA.g-1). A relatively high specific capacity of 450 mAh.g-1 can still be retained after 200 cycles at a high rate of 2 C. The synthesis process introduced here is simple and broadly applicable to the modification of sulfur cathode for better electrochemical performance. PMID- 28347080 TI - Layer-by-Layer Self-Assembling Gold Nanorods and Glucose Oxidase onto Carbon Nanotubes Functionalized Sol-Gel Matrix for an Amperometric Glucose Biosensor. AB - A novel amperometric glucose biosensor was fabricated by layer-by-layer self assembly of gold nanorods (AuNRs) and glucose oxidase (GOD) onto single-walled carbon nanotubes (SWCNTs)-functionalized three-dimensional sol-gel matrix. A thiolated aqueous silica sol containing SWCNTs was first assembled on the surface of a cleaned Au electrode, and then the alternate self-assembly of AuNRs and GOD were repeated to assemble multilayer films of AuNRs-GOD onto SWCNTs functionalized silica gel for optimizing the biosensor. Among the resulting glucose biosensors, the four layers of AuNRs-GOD-modified electrode showed the best performance. The sol-SWCNTs-(AuNRs- GOD)4/Au biosensor exhibited a good linear range of 0.01-8 mM glucose, high sensitivity of 1.08 MUA/mM, and fast amperometric response within 4 s. The good performance of the proposed glucose biosensor could be mainly attributed to the advantages of the three-dimensional sol-gel matrix and stereo self-assembly films, and the natural features of one dimensional nanostructure SWCNTs and AuNRs. This study may provide a new facile way to fabricate the enzyme-based biosensor with high performance. PMID- 28347079 TI - Surface Evolution of Nano-Textured 4H-SiC Homoepitaxial Layers after High Temperature Treatments: Morphology Characterization and Graphene Growth. AB - Nano-textured 4H-SiC homoepitaxial layers (NSiCLs) were grown on 4H-SiC(0001) substrates using a low pressure chemical vapor deposition technique (LPCVD), and subsequently were subjected to high temperature treatments (HTTs) for investigation of their surface morphology evolution and graphene growth. It was found that continuously distributed nano-scale patterns formed on NSiCLs which were about submicrons in-plane and about 100 nanometers out-of-plane in size. After HTTs under vacuum, pattern sizes reduced, and the sizes of the remains were inversely proportional to the treatment time. Referring to Raman spectra, the establishment of multi-layer graphene (MLG) on NSiCL surfaces was observed. MLG with sp2 disorders was obtained from NSiCLs after a high temperature treatment under vacuum at 1700 K for two hours, while MLG without sp2 disorders was obtained under Ar atmosphere at 1900 K. PMID- 28347078 TI - Textile-Based Electronic Components for Energy Applications: Principles, Problems, and Perspective. AB - Textile-based electronic components have gained interest in the fields of science and technology. Recent developments in nanotechnology have enabled the integration of electronic components into textiles while retaining desirable characteristics such as flexibility, strength, and conductivity. Various materials were investigated in detail to obtain current conductive textile technology, and the integration of electronic components into these textiles shows great promise for common everyday applications. The harvest and storage of energy in textile electronics is a challenge that requires further attention in order to enable complete adoption of this technology in practical implementations. This review focuses on the various conductive textiles, their methods of preparation, and textile-based electronic components. We also focus on fabrication and the function of textile-based energy harvesting and storage devices, discuss their fundamental limitations, and suggest new areas of study. PMID- 28347081 TI - A Paper-Based Sandwich Format Hybridization Assay for Unlabeled Nucleic Acid Detection Using Upconversion Nanoparticles as Energy Donors in Luminescence Resonance Energy Transfer. AB - Bioassays based on cellulose paper substrates are gaining increasing popularity for the development of field portable and low-cost diagnostic applications. Herein, we report a paper-based nucleic acid hybridization assay using immobilized upconversion nanoparticles (UCNPs) as donors in luminescence resonance energy transfer (LRET). UCNPs with intense green emission served as donors with Cy3 dye as the acceptor. The avidin functionalized UCNPs were immobilized on cellulose paper and subsequently bioconjugated to biotinylated oligonucleotide probes. Introduction of unlabeled oligonucleotide targets resulted in a formation of probe-target duplexes. A subsequent hybridization of Cy3 labeled reporter with the remaining single stranded portion of target brought the Cy3 dye in close proximity to the UCNPs to trigger a LRET-sensitized emission from the acceptor dye. The hybridization assays provided a limit of detection (LOD) of 146.0 fmol and exhibited selectivity for one base pair mismatch discrimination. The assay was functional even in undiluted serum samples. This work embodies important progress in developing DNA hybridization assays on paper. Detection of unlabeled targets is achieved using UCNPs as LRET donors, with minimization of background signal from paper substrates owing to the implementation of low energy near-infrared (NIR) excitation. PMID- 28347082 TI - Preparation of GST Inhibitor Nanoparticle Drug Delivery System and Its Reversal Effect on the Multidrug Resistance in Oral Carcinoma. AB - During the chemotherapy of cancer, drug resistance is the first issue that chemotherapeutic drugs cannot be effectively used for the treatment of cancers repeatedly for a long term, and the main reason for this is that tumor cell detoxification is mediated by GSH (glutathione) catalyzed by GST (glutathione-S transferase). In this study, a GST inhibitor, ethacrynic acid (ECA), was designed to be coupled with methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA) by disulfide bonds to prepare methoxy poly(ethylene glycol)-poly(lactide)-disulphide bond-mthacrynic acid (MPEG-PLA-SS-ECA) as a carrier material of the nanoparticles. Nanoparticles of pingyangmycin (PYM) and carboplatin (CBP) were prepared, respectively, and their physicochemical properties were investigated. The ECA at the disulfide could be released in the presence of GSH, the pingyangmycin, carboplatin and ECA were all uniformly released, and the nanoparticles could release all the drugs completely within 10 days. The half maximal inhibitory concentration (IC50) of the prepared MPEG-PLA-SS-ECA/CBP and MPEG-PLA-SS-ECA/PYM nanoparticles in drug-resistant oral squamous cell carcinoma cell lines SCC15/CBP and SCC15/PYM cells was 12.68 MUg.mL-1 and 12.76 MUg.mL-1, respectively; the resistant factor RF of them in the drug-resistant cells were 1.51 and 1.24, respectively, indicating that MPEG-PLA-SS-ECA nanoparticles can reverse the drug resistance of these two drug-resistant cells. PMID- 28347084 TI - Controllable Synthesis of Copper Oxide/Carbon Core/Shell Nanowire Arrays and Their Application for Electrochemical Energy Storage. AB - Rational design/fabrication of integrated porous metal oxide arrays is critical for the construction of advanced electrochemical devices. Herein, we report self supported CuO/C core/shell nanowire arrays prepared by the combination of electro deposition and chemical vapor deposition methods. CuO/C nanowires with diameters of ~400 nm grow quasi-vertically to the substrates forming three-dimensional arrays architecture. A thin carbon shell is uniformly coated on the CuO nanowire cores. As an anode of lithium ion batteries, the resultant CuO/C nanowire arrays are demonstrated to have high specific capacity (672 mAh.g-1 at 0.2 C) and good cycle stability (425 mAh.g-1 at 1 C up to 150 cycles). The core/shell arrays structure plays positive roles in the enhancement of Li ion storage due to fast ion/electron transfer path, good strain accommodation and sufficient contact between electrolyte and active materials. PMID- 28347083 TI - Iron Oxide Nanoparticles Coated with a Phosphorothioate Oligonucleotide and a Cationic Peptide: Exploring Four Different Ways of Surface Functionalization. AB - The superparamagnetic iron oxide nanoparticles (SPIONs) have great potential in therapeutic and diagnostic applications. Due to their superparamagnetic behavior, they are used clinically as a Magnetic Resonance Imaging (MRI) contrast agent. Iron oxide nanoparticles are also recognized todays as smart drug-delivery systems. However, to increase their specificity, it is essential to functionalize them with a molecule that effectively targets a specific area of the body. Among the molecules that can fulfill this role, peptides are excellent candidates. Oligonucleotides are recognized as potential drugs for various diseases but suffer from poor uptake and intracellular degradation. In this work, we explore four different strategies, based on the electrostatic interactions between the different partners, to functionalize the surface of SPIONs with a phosphorothioate oligonucleotide (ODN) and a cationic peptide labeled with a fluorophore. The internalization of the nanoparticles has been evaluated in vitro on RAW 264.7 cells. Among these strategies, the ""one-step assembly"", i.e., the direct complexation of oligonucleotides and peptides on iron oxide nanoparticles, provides the best way of coating for the internalization of the nanocomplexes. PMID- 28347086 TI - High Rate Performance Nanocomposite Electrode of Mesoporous Manganese Dioxide/Silver Nanowires in KI Electrolytes. AB - In recent years, manganese dioxide has become a research hotspot as an electrode material because of its low price. However, it has also become an obstacle to industrialization due to its low ratio of capacitance and the low rate performance which is caused by the poor electrical conductivity. In this study, a KI solution with electrochemical activity was innovatively applied to the electrolyte, and we systematically investigated the rate performance of the mesoporous manganese dioxide and the composite electrode with silver nanowires in supercapacitors. The results showed that when mesoporous manganese dioxide and mesoporous manganese dioxide/silver nanowires composite were used as electrodes, the strength of the current was amplified five times (from 0.1 to 0.5 A/g), the remaining rates of specific capacitance were 95% (from 205.5 down to 197.1 F/g) and 92% (from 208.1 down to 191.7 F/g) in the KI electrolyte, and the rate performance was much higher than which in an Na2SO4 electrolyte with a remaining rate of 25% (from 200.3 down to 49.1 F/g) and 60% (from 187.2 down to 113.1 F/g). The morphology and detail structure were investigated by Scanning electron microscopy, X-ray diffraction, Fourier transform infrared spectrometry and Nitrogen adsorption-desorption isotherms. The electrochemical performance was assessed by cyclic voltammograms, galvanostatic charge/discharge and electrochemical impedance spectroscopy. PMID- 28347087 TI - Computational Evaluation of Amorphous Carbon Coating for Durable Silicon Anodes for Lithium-Ion Batteries. AB - We investigate the structural, mechanical, and electronic properties of graphite like amorphous carbon coating on bulky silicon to examine whether it can improve the durability of the silicon anodes of lithium-ion batteries using molecular dynamics simulations and ab-initio electronic structure calculations. Structural models of carbon coating are constructed using molecular dynamics simulations of atomic carbon deposition with low incident energies (1-16 eV). As the incident energy decreases, the ratio of sp2 carbons increases, that of sp3 decreases, and the carbon films become more porous. The films prepared with very low incident energy contain lithium-ion conducting channels. Also, those films are electrically conductive to supplement the poor conductivity of silicon and can restore their structure after large deformation to accommodate the volume change during the operations. As a result of this study, we suggest that graphite-like porous carbon coating on silicon will extend the lifetime of the silicon anodes of lithium-ion batteries. PMID- 28347085 TI - Metal Oxide Nanomaterial QNAR Models: Available Structural Descriptors and Understanding of Toxicity Mechanisms. AB - Metal oxide nanomaterials are widely used in various areas; however, the divergent published toxicology data makes it difficult to determine whether there is a risk associated with exposure to metal oxide nanomaterials. The application of quantitative structure activity relationship (QSAR) modeling in metal oxide nanomaterials toxicity studies can reduce the need for time-consuming and resource-intensive nanotoxicity tests. The nanostructure and inorganic composition of metal oxide nanomaterials makes this approach different from classical QSAR study; this review lists and classifies some structural descriptors, such as size, cation charge, and band gap energy, in recent metal oxide nanomaterials quantitative nanostructure activity relationship (QNAR) studies and discusses the mechanism of metal oxide nanomaterials toxicity based on these descriptors and traditional nanotoxicity tests. PMID- 28347088 TI - Mesoporous Transition Metal Oxides for Supercapacitors. AB - Recently, transition metal oxides, such as ruthenium oxide (RuO2), manganese dioxide (MnO2), nickel oxides (NiO) and cobalt oxide (Co3O4), have been widely investigated as electrode materials for pseudo-capacitors. In particular, these metal oxides with mesoporous structures have become very hot nanomaterials in the field of supercapacitors owing to their large specific surface areas and suitable pore size distributions. The high specific capacities of these mesoporous metal oxides are resulted from the effective contacts between electrode materials and electrolytes as well as fast transportation of ions and electrons in the bulk of electrode and at the interface of electrode and electrolyte. During the past decade, many achievements on mesoporous transition metal oxides have been made. In this mini-review, we select several typical nanomaterials, such as RuO2, MnO2, NiO, Co3O4 and nickel cobaltite (NiCo2O4), and briefly summarize the recent research progress of these mesoporous transition metal oxides-based electrodes in the field of supercapacitors. PMID- 28347090 TI - Voltammetric Determination of Ferulic Acid Using Polypyrrole-Multiwalled Carbon Nanotubes Modified Electrode with Sample Application. AB - A polypyrrole-multiwalled carbon nanotubes modified glassy carbon electrode-based sensor was devised for determination of ferulic acid (FA). The fabricated sensor was prepared electrochemically using cyclic voltammetry (CV) and characterized using CV and scanning electron microscope (SEM). The electrode shows an excellent electrochemical catalytic activity towards FA oxidation. Under optimal conditions, the anodic peak current correlates linearly to the FA concentration throughout the range of 3.32 * 10-6 to 2.59 * 10-5 M with a detection limit of 1.17 * 10-6 M (S/N = 3). The prepared sensor is highly selective towards ferulic acid without the interference of ascorbic acid. The sensor applicability was tested for total content determination of FA in a commercial popcorn sample and showed a robust functionality. PMID- 28347089 TI - Multifunctional Nanomaterials and Their Applications in Drug Delivery and Cancer Therapy. AB - The field of nanotechnology has led to the development of many innovative strategies for effective detection and treatment of cancer, overcoming limitations associated with conventional cancer diagnosis and therapy. Multifunctional nanoparticle systems can integrate imaging, targeting and treatment moieties on the surface and in the core, resulting in targeted delivery of the imaging or treatment modalities, specifically to the tumor. Multifunctional nanoparticles also enable simultaneous delivery of multiple treatment agents, resulting in effective combinatorial therapeutic regimens against cancer. In this review, various multifunctional nanoparticle systems that feature a variety of targeting moieties for in vitro and/or in vivo cancer imaging and therapy are discussed. PMID- 28347091 TI - Dendrimer-Functionalized Laponite Nanodisks as a Platform for Anticancer Drug Delivery. AB - In this study, we synthesized dendrimer-functionalized laponite (LAP) nanodisks for loading and delivery of anticancer drug doxorubicin (DOX). Firstly, LAP was modified with silane coupling agents and succinic anhydride to render abundant carboxyl groups on the surface of LAP. Then, poly(amidoamine) (PAMAM) dendrimer of generation 2 (G2) were conjugated to form LM-G2 nanodisks. Anticancer drug DOX was then loaded on the LM-G2 with an impressively high drug loading efficiency of 98.4% and could be released in a pH-sensitive and sustained manner. Moreover, cell viability assay results indicate that LM-G2/DOX complexes could more effectively inhibit the proliferation of KB cells (a human epithelial carcinoma cell line) than free DOX at the same drug concentration. Flow cytometry analysis and confocal laser scanning microscope demonstrated that LM-G2/DOX could be uptaken by KB cells more effectively than free DOX. Considering the exceptional high drug loading efficiency and the abundant dendrimer amine groups on the surface that can be further modified, the developed LM-G2 nanodisks may hold a great promise to be used as a novel platform for anticancer drug delivery. PMID- 28347093 TI - Direct Growth of Bismuth Film as Anode for Aqueous Rechargeable Batteries in LiOH, NaOH and KOH Electrolytes. AB - As promising candidates for next-generation energy storage devices, aqueous rechargeable batteries are safer and cheaper than organic Li ion batteries. But due to the narrow voltage window of aqueous electrolytes, proper anode materials with low redox potential and high capacity are quite rare. In this work, bismuth electrode film was directly grown by a facile hydrothermal route and tested in LiOH, NaOH and KOH electrolytes. With low redox potential (reduction/oxidation potentials at ca. -0.85/-0.52 V vs. SCE, respectively) and high specific capacity (170 mAh.g-1 at current density of 0.5 A.g-1 in KOH electrolyte), Bi was demonstrated as a suitable anode material for aqueous batteries. Furthermore, by electrochemical impedance spectroscopy (EIS) analysis, we found that with smaller Rs and faster ion diffusion coefficient, Bi electrode film in KOH electrolyte exhibited better electrochemical performance than in LiOH and NaOH electrolytes. PMID- 28347092 TI - Single-Walled Carbon Nanohorns for Energy Applications. AB - With the growth of the global economy and population, the demand for energy is increasing sharply. The development of environmentally a benign and reliable energy supply is very important and urgent. Single-walled carbon nanohorns (SWCNHs), which have a horn-shaped tip at the top of single-walled nanotube, have emerged as exceptionally promising nanomaterials due to their unique physical and chemical properties since 1999. The high purity and thermal stability, combined with microporosity and mesoporosity, high surface area, internal pore accessibility, and multiform functionalization make SWCNHs promising candidates in many applications, such as environment restoration, gas storage, catalyst support or catalyst, electrochemical biosensors, drug carrier systems, magnetic resonance analysis and so on. The aim of this review is to provide a comprehensive overview of SWCNHs in energy applications, including energy conversion and storage. The commonly adopted method to access SWCNHs, their structural modifications, and their basic properties are included, and the emphasis is on their application in different devices such as fuel cells, dye sensitized solar cells, supercapacitors, Li-ion batteries, Li-S batteries, hydrogen storage, biofuel cells and so forth. Finally, a perspective on SWCNHs' application in energy is presented. PMID- 28347094 TI - Control of Partial Coalescence of Self-Assembled Metal Nano-Particles across Lyotropic Liquid Crystals Templates towards Long Range Meso-Porous Metal Frameworks Design. AB - The formation of purely metallic meso-porous metal thin films by partial interface coalescence of self-assembled metal nano-particles across aqueous solutions of Pluronics triblock lyotropic liquid crystals is demonstrated for the first time. Small angle X-ray scattering was used to study the influence of the thin film composition and processing conditions on the ordered structures. The structural characteristics of the meso-structures formed demonstrated to primarily rely on the lyotropic liquid crystal properties while the nature of the metal nano-particles used as well as the their diameters were found to affect the ordered structure formation. The impact of the annealing temperature on the nano particle coalescence and efficiency at removing the templating lyotropic liquid crystals was also analysed. It is demonstrated that the lyotropic liquid crystal is rendered slightly less thermally stable, upon mixing with metal nano-particles and that low annealing temperatures are sufficient to form purely metallic frameworks with average pore size distributions smaller than 500 nm and porosity around 45% with potential application in sensing, catalysis, nanoscale heat exchange, and molecular separation. PMID- 28347096 TI - Organic Phase Change Nanoparticles for in-Product Labeling of Agrochemicals. AB - There is an urgent need to develop in-product covert barcodes for anti counterfeiting of agrochemicals. This paper reports a new organic nanoparticle based in-product barcode system, in which a panel of organic phase change nanoparticles is added as a barcode into in a variety of chemicals (herein agrochemicals). The barcode is readout by detecting melting peaks of organic nanoparticles using differential scanning calorimetry. This method has high labeling capacity due to small sizes of nanoparticles, sharp melting peaks, and large scan range of thermal analysis. The in-product barcode can be effectively used to protect agrochemical products from being counterfeited due to its large coding capacity, technical readiness, covertness, and robustness. PMID- 28347095 TI - Enhancing Solar Cell Efficiency Using Photon Upconversion Materials. AB - Photovoltaic cells are able to convert sunlight into electricity, providing enough of the most abundant and cleanest energy to cover our energy needs. However, the efficiency of current photovoltaics is significantly impeded by the transmission loss of sub-band-gap photons. Photon upconversion is a promising route to circumvent this problem by converting these transmitted sub-band-gap photons into above-band-gap light, where solar cells typically have high quantum efficiency. Here, we summarize recent progress on varying types of efficient upconversion materials as well as their outstanding uses in a series of solar cells, including silicon solar cells (crystalline and amorphous), gallium arsenide (GaAs) solar cells, dye-sensitized solar cells, and other types of solar cells. The challenge and prospect of upconversion materials for photovoltaic applications are also discussed. PMID- 28347097 TI - Chalcopyrite Nanoparticles as a Sustainable Thermoelectric Material. AB - In this report, copper iron sulfide nanoparticles with various composition were synthesized by a thermolysis based wet chemical method. These inherently sustainable nanoparticles were then fully characterized in terms of composition, structure, and morphology, as well as for suitability as a thermoelectric material. The merits of the material preparation include a straightforward bulk material formation where particles do not require any specialized treatment, such as spark plasma sintering or thermal heating. The Seebeck coefficient of the materials reveals P-type conductivity with a maximum value of 203 uV/K. The results give insight into how to design and create a new class of sustainable nanoparticle material for thermoelectric applications. PMID- 28347098 TI - Effects of Annealing Temperature on Properties of Ti-Ga-Doped ZnO Films Deposited on Flexible Substrates. AB - An investigation is performed into the optical, electrical, and microstructural properties of Ti-Ga-doped ZnO films deposited on polyimide (PI) flexible substrates and then annealed at temperatures of 300 degrees C, 400 degrees C, and 450 degrees C, respectively. The X-ray diffraction (XRD) analysis results show that all of the films have a strong (002) Ga doped ZnO (GZO) preferential orientation. As the annealing temperature is increased to 400 degrees C, the optical transmittance increases and the electrical resistivity decreases. However, as the temperature is further increased to 450 degrees C, the transmittance reduces and the resistivity increases due to a carbonization of the PI substrate. Finally, the crystallinity of the ZnO film improves with an increasing annealing temperature only up to 400 degrees C and is accompanied by a smaller crystallite size and a lower surface roughness. PMID- 28347099 TI - Structural Stability of Diffusion Barriers in Cu/Ru/MgO/Ta/Si. AB - Various structures of Cu (50 nm)/Ru (2 nm)/MgO (0.5-3 nm)/Ta (2 nm)/Si were prepared by sputtering and electroplating techniques, in which the ultra-thin trilayer of Ru (2 nm)/MgO (0.5-3 nm)/Ta (2 nm) is used as the diffusion barrier against the interdiffusion between Cu film and Si substrate. The various structures of Cu/Ru/MgO/Ta/Si were characterized by four-point probes for their sheet resistances, by X-ray diffractometers for their crystal structures, by scanning electron microscopes for their surface morphologies, and by transmission electron microscopes for their cross-section and high resolution views. The results showed that the ultra-thin tri-layer of Ru (2 nm)/MgO (0.5-3 nm)/Ta (2 nm) is an effective diffusion barrier against the interdiffusion between Cu film and Si substrate. The MgO, and Ta layers as deposited are amorphous. The mechanism for the failure of the diffusion barrier is that the Ru layer first became discontinuous at a high temperature and the Ta layer sequentially become discontinuous at a higher temperature, the Cu atoms then diffuse through the MgO layer and to the substrate at the discontinuities, and the Cu3Si phases finally form. The maximum temperature at which the structures of Cu (50 nm)/Ru (2 nm)/MgO (0.5-3 nm)/Ta (2 nm)/Si are annealed and still have low sheet resistance is from 550 to 750 degrees C for the annealing time of 5 min and from 500 to 700 degrees C for the annealing time of 30 min. PMID- 28347101 TI - T1-MRI Fluorescent Iron Oxide Nanoparticles by Microwave Assisted Synthesis. AB - Iron oxide nanoparticles have long been studied as a T2 contrast agent in MRI due to their superparamagnetic behavior. T1-based positive contrast, being much more favorable for clinical application due to brighter and more accurate signaling is, however, still limited to gadolinium- or manganese-based imaging tools. Though being the only available commercial positive-contrast agents, they lack an efficient argument when it comes to biological toxicity and their circulatory half-life in blood. The need arises to design a biocompatible contrast agent with a scope for easy surface functionalization for long circulation in blood and/or targeted imaging. We hereby propose an extremely fast microwave synthesis for fluorescein-labeled extremely-small iron oxide nanoparticles (fdIONP), in a single step, as a viable tool for cell labeling and T1-MRI. We demonstrate the capabilities of such an approach through high-quality magnetic resonance angiographic images of mice. PMID- 28347102 TI - Nanoporous Carbon Nanofibers Decorated with Platinum Nanoparticles for Non Enzymatic Electrochemical Sensing of H2O2. AB - We describe the preparation of nanoporous carbon nanofibers (CNFs) decorated with platinum nanoparticles (PtNPs) in this work by electrospining polyacrylonitrile (PAN) nanofibers and subsequent carbonization and binding of PtNPs. The fabricated nanoporous CNF-PtNP hybrids were further utilized to modify glass carbon electrodes and used for the non-enzymatic amperometric biosensor for the highly sensitive detection of hydrogen peroxide (H2O2). The morphologies of the fabricated nanoporous CNF-PtNP hybrids were observed by scanning electron microscopy, transmission electron microscopy, and their structure was further investigated with Brunauer-Emmett-Teller (BET) surface area analysis, X-ray photoelectron spectroscopy, X-ray diffraction, and Raman spectrum. The cyclic voltammetry experiments indicate that CNF-PtNP modified electrodes have high electrocatalytic activity toward H2O2 and the chronoamperometry measurements illustrate that the fabricated biosensor has a high sensitivity for detecting H2O2. We anticipate that the strategies utilized in this work will not only guide the further design and fabrication of functional nanofiber-based biomaterials and nanodevices, but also extend the potential applications in energy storage, cytology, and tissue engineering. PMID- 28347100 TI - Gold Nanotheranostics: Proof-of-Concept or Clinical Tool? AB - Nanoparticles have been making their way in biomedical applications and personalized medicine, allowing for the coupling of diagnostics and therapeutics into a single nanomaterial-nanotheranostics. Gold nanoparticles, in particular, have unique features that make them excellent nanomaterials for theranostics, enabling the integration of targeting, imaging and therapeutics in a single platform, with proven applicability in the management of heterogeneous diseases, such as cancer. In this review, we focus on gold nanoparticle-based theranostics at the lab bench, through pre-clinical and clinical stages. With few products facing clinical trials, much remains to be done to effectively assess the real benefits of nanotheranostics at the clinical level. Hence, we also discuss the efforts currently being made to translate nanotheranostics into the market, as well as their commercial impact. PMID- 28347104 TI - Cytotoxicity, Uptake Behaviors, and Oral Absorption of Food Grade Calcium Carbonate Nanomaterials. AB - Calcium is the most abundant mineral in human body and essential for the formation and maintenance of bones and teeth as well as diverse cellular functions. Calcium carbonate (CaCO3) is widely used as a dietary supplement; however, oral absorption efficiency of CaCO3 is extremely low, which may be overcome by applying nano-sized materials. In this study, we evaluated the efficacy of food grade nano CaCO3 in comparison with that of bulk- or reagent grade nano CaCO3 in terms of cytotoxicity, cellular uptake, intestinal transport, and oral absorption. Cytotoxicity results demonstrated that nano-sized CaCO3 particles were slightly more toxic than bulk materials in terms of oxidative stress and membrane damage. Cellular uptake behaviors of CaCO3 nanoparticles were different from bulk CaCO3 or Ca2+ ions in human intestinal epithelial cells, showing efficient cellular internalization and elevated intracellular Ca2+ levels. Meanwhile, CaCO3 nanoparticles were efficiently transported by microfold (M) cells in vitro model of human intestinal follicle-associated epithelium, in a similar manner as Ca2+ ions did. Biokinetic study revealed that the biological fate of CaCO3 particles was different from Ca2+ ions; however, in vivo, its oral absorption was not significantly affected by particle size. These findings provide crucial information to understand and predict potential toxicity and oral absorption efficiency of food grade nanoparticles. PMID- 28347105 TI - Surface Properties and Photocatalytic Activities of the Colloidal ZnS:Mn Nanocrystals Prepared at Various pH Conditions. AB - Water-dispersible ZnS:Mn nanocrystals (NC) were synthesized by capping the surface with mercaptoacetic acid (MAA) molecules at three different pH conditions. The obtained ZnS:Mn-MAA NC products were physically and optically characterized by corresponding spectroscopic methods. The UV-Visible absorption spectra and PL emission spectra showed broad peaks at 310 and 590 nm, respectively. The average particle sizes measured from the HR-TEM images were 5 nm, which were also supported by the Debye-Scherrer calculations using the X-ray diffraction (XRD) data. Moreover, the surface charges and the degrees of aggregation of the ZnS:Mn-MAA NCs were determined by electrophoretic and hydrodynamic light scattering methods, indicating formation of agglomerates in water with various sizes (50-440 nm) and different surface charge values accordingly the preparation conditions of the NCs (-7.59 to -24.98 mV). Finally, the relative photocatalytic activities of the ZnS:Mn-MAA NCs were evaluated by measuring the degradation rate of methylene blue (MB) molecule in a pseudo first order reaction condition under the UV-visible light irradiation. As a result, the ZnS:Mn-MAA NC prepared at the pH 7 showed the best photo-degradation efficiency of the MB molecule with the first-order rate constant (kobs) of 2.0 * 10-3.min-1. PMID- 28347106 TI - Synthesis of Ordered Mesoporous CuO/CeO2 Composite Frameworks as Anode Catalysts for Water Oxidation. AB - Cerium-rich metal oxide materials have recently emerged as promising candidates for the photocatalytic oxygen evolution reaction (OER). In this article, we report the synthesis of ordered mesoporous CuO/CeO2 composite frameworks with different contents of copper(II) oxide and demonstrate their activity for photocatalytic O2 production via UV-Vis light-driven oxidation of water. Mesoporous CuO/CeO2 materials have been successfully prepared by a nanocasting route, using mesoporous silica as a rigid template. X-ray diffraction, electron transmission microscopy and N2 porosimetry characterization of the as-prepared products reveal a mesoporous structure composed of parallel arranged nanorods, with a large surface area and a narrow pore size distribution. The molecular structure and optical properties of the composite materials were investigated with Raman and UV-Vis/NIR diffuse reflectance spectroscopy. Catalytic results indicated that incorporation of CuO clusters in the CeO2 lattice improved the photochemical properties. As a result, the CuO/CeO2 composite catalyst containing ~38 wt % CuO reaches a high O2 evolution rate of ~19.6 umol.h-1 (or 392 umol.h 1.g-1) with an apparent quantum efficiency of 17.6% at lambda = 365 +/- 10 nm. This OER activity compares favorably with that obtained from the non-porous CuO/CeO2 counterpart (~1.3 umol.h-1) and pure mesoporous CeO2 (~1 umol.h-1). PMID- 28347103 TI - Smart Mesoporous Nanomaterials for Antitumor Therapy. AB - The use of nanomaterials for the treatment of solid tumours is receiving increasing attention by the scientific community. Among them, mesoporous silica nanoparticles (MSNs) exhibit unique features that make them suitable nanocarriers to host, transport and protect drug molecules until the target is reached. It is possible to incorporate different targeting ligands to the outermost surface of MSNs to selectively drive the drugs to the tumour tissues. To prevent the premature release of the cargo entrapped in the mesopores, it is feasible to cap the pore entrances using stimuli-responsive nanogates. Therefore, upon exposure to internal (pH, enzymes, glutathione, etc.) or external (temperature, light, magnetic field, etc.) stimuli, the pore opening takes place and the release of the entrapped cargo occurs. These smart MSNs are capable of selectively reaching and accumulating at the target tissue and releasing the entrapped drug in a specific and controlled fashion, constituting a promising alternative to conventional chemotherapy, which is typically associated with undesired side effects. In this review, we overview the recent advances reported by the scientific community in developing MSNs for antitumor therapy. We highlight the possibility to design multifunctional nanosystems using different therapeutic approaches aimed at increasing the efficacy of the antitumor treatment. PMID- 28347107 TI - Lithium-Excess Research of Cathode Material Li2MnTiO4 for Lithium-Ion Batteries. AB - Lithium-excess and nano-sized Li2+xMn1-x/2TiO4 (x = 0, 0.2, 0.4) cathode materials were synthesized via a sol-gel method. The X-ray diffraction (XRD) experiments indicate that the obtained main phases of Li2.0MnTiO4 and the lithium excess materials are monoclinic and cubic, respectively. The scanning electron microscope (SEM) images show that the as-prepared particles are well distributed and the primary particles have an average size of about 20-30 nm. The further electrochemical tests reveal that the charge-discharge performance of the material improves remarkably with the lithium content increasing. Particularly, the first discharging capacity at the current of 30 mA g-1 increases from 112.2 mAh g-1 of Li2.0MnTiO4 to 187.5 mAh g-1 of Li2.4Mn0.8TiO4. In addition, the ex situ XRD experiments indicate that the monoclinic Li2MnTiO4 tends to transform to an amorphous state with the extraction of lithium ions, while the cubic Li2MnTiO4 phase shows better structural reversibility and stability. PMID- 28347108 TI - Electrochemical Characterization of Graphene and MWCNT Screen-Printed Electrodes Modified with AuNPs for Laccase Biosensor Development. AB - The aim of this work is to show how the integration of gold nanoparticles (AuNPs) into multi-wall-carbon-nanotubes (MWCNTs) based screen-printed electrodes and into graphene-based screen-printed electrodes (GPHs) could represent a potential way to further enhance the electrochemical properties of those electrodes based on nanoparticles. Laccase from Trametes versicolor (TvL) was immobilized over MWCNTs and GPH previously modified with AuNPs (of 5 and 10 nm). The characterization of the modified electrode surface has been carried out by cyclic voltammetry. The results showed that the use of AuNPs for modification of both graphene and MWCNTs screen-printed electrode surfaces would increase the electrochemical performances of the electrodes. MWCNTs showed better results than GPH in terms of higher electroactive area formation after modification with AuNPs. The two modified nanostructured electrodes were successively proven to efficiently immobilize the TvL; the electrochemical sensing properties of the GPH and MWCNT-based AuNPs-TvL biosensors were investigated by choosing 2,2'-Azino bis(3-ethylbenzothiazoline-6-sulfonic-acid diammonium salt (ABTS), catechol and caffeic acid as laccase mediators; and the kinetic parameters of the laccase biosensor were carefully evaluated. PMID- 28347109 TI - Nanostructuring of Palladium with Low-Temperature Helium Plasma. AB - Impingement of high fluxes of helium ions upon metals at elevated temperatures has given rise to the growth of nanostructured layers on the surface of several metals, such as tungsten and molybdenum. These nanostructured layers grow from the bulk material and have greatly increased surface area over that of a not nanostructured surface. They are also superior to deposited nanostructures due to a lack of worries over adhesion and differences in material properties. Several palladium samples of varying thickness were biased and exposed to a helium helicon plasma. The nanostructures were characterized as a function of the thickness of the palladium layer and of temperature. Bubbles of ~100 nm in diameter appear to be integral to the nanostructuring process. Nanostructured palladium is also shown to have better catalytic activity than not nanostructured palladium. PMID- 28347110 TI - Recent Advance on Mesoporous Silica Nanoparticles-Based Controlled Release System: Intelligent Switches Open up New Horizon. AB - Mesoporous silica nanoparticle (MSN)-based intelligent transport systems have attracted many researchers' attention due to the characteristics of uniform pore and particle size distribution, good biocompatibility, high surface area, and versatile functionalization, which have led to their widespread application in diverse areas. In the past two decades, many kinds of smart controlled release systems were prepared with the development of brilliant nano-switches. This article reviews and discusses the advantages of MSN-based controlled release systems. Meanwhile, the switching mechanisms based on different types of stimulus response are systematically analyzed and summarized. Additionally, the application fields of these devices are further discussed. Obviously, the recent evolution of smart nano-switches promoted the upgrading of the controlled release system from the simple "separated" switch to the reversible, multifunctional, complicated logical switches and selective switches. Especially the free-blockage switches, which are based on hydrophobic/hydrophilic conversion, have been proposed and designed in the last two years. The prospects and directions of this research field are also briefly addressed, which could be better used to promote the further development of this field to meet the needs of mankind. PMID- 28347112 TI - Performance Evaluation of a Nanofluid-Based Direct Absorption Solar Collector with Parabolic Trough Concentrator. AB - Application of solar collectors for hot water supply, space heating, and cooling plays a significant role in reducing building energy consumption. For conventional solar collectors, solar radiation is absorbed by spectral selective coating on the collectors' tube/plate wall. The poor durability of the coating can lead to an increased manufacturing cost and unreliability for a solar collector operated at a higher temperature. Therefore, a novel nanofluid-based direct absorption solar collector (NDASC) employing uncoated collector tubes has been proposed, and its operating characteristics for medium-temperature solar collection were theoretically and experimentally studied in this paper. CuO/oil nanofluid was prepared and used as working fluid of the NDASC. The heat-transfer mechanism of the NDASC with parabolic trough concentrator was theoretically evaluated and compared with a conventional indirect absorption solar collector (IASC). The theoretical analysis results suggested that the fluid's temperature distribution in the NDASC was much more uniform than that in the IASC, and an enhanced collection efficiency could be achieved for the NDASC operated within a preferred working temperature range. To demonstrate the feasibility of the proposed NDASC, experimental performances of an NDASC and an IASC with the same parabolic trough concentrator were furthermore evaluated and comparatively discussed. PMID- 28347113 TI - Upconverting NIR Photons for Bioimaging. AB - Lanthanide-doped upconverting nanoparticles (UCNPs) possess uniqueanti-Stokes optical properties, in which low energy near-infrared (NIR) photons can beconverted into high energy UV, visible, shorter NIR emission via multiphoton upconversionprocesses. Due to the rapid development of synthesis chemistry, lanthanide-doped UCNPscan be fabricated with narrow distribution and tunable multi-color optical properties. Theseunique attributes grant them unique NIR driven imaging/drug delivery/therapeuticapplications, especially in the cases of deep tissue environments. In this brief review, weintroduce both the basic concepts of and recent progress with UCNPs in material engineeringand theranostic applications in imaging, molecular delivery, and tumor therapeutics. The aimof this brief review is to address the most typical progress in basic mechanism, materialdesign as bioimaging tools. PMID- 28347115 TI - Morphological, Chemical Surface, and Diffusive Transport Characterizations of a Nanoporous Alumina Membrane. AB - Synthesis of a nanoporous alumina membrane (NPAM) by the two-step anodization method and its morphological and chemical surface characterization by analyzing Scanning Electron Microscopy (SEM) micrographs and X-Ray Photoelectron Spectroscopy (XPS) spectra is reported. Influence of electrical and diffusive effects on the NaCl transport across the membrane nanopores is determined from salt diffusion measurements performed with a wide range of NaCl concentrations, which allows the estimation of characteristic electrochemical membrane parameters such as the NaCl diffusion coefficient and the concentration of fixed charges in the membrane, by using an appropriated model and the membrane geometrical parameters (porosity and pore length). These results indicate a reduction of ~70% in the value of the NaCl diffusion coefficient through the membrane pores with respect to solution. The transport number of ions in the membrane pores (Na+ and Cl-, respectively) were determined from concentration potential measurements, and the effect of concentration-polarization at the membrane surfaces was also considered by comparing concentration potential values obtained with stirred solutions (550 rpm) and without stirring. From both kinds of results, a value higher than 0.05 M NaCl for the feed solution seems to be necessary to neglect the contribution of electrical interactions in the diffusive transport. PMID- 28347116 TI - Hydrothermal Synthesis of Ultrasmall Pt Nanoparticles as Highly Active Electrocatalysts for Methanol Oxidation. AB - Ultrasmall nanoparticles, with sizes in the 1-3 nm range, exhibit unique properties distinct from those of free molecules and larger-sized nanoparticles. Demonstrating that the hydrothermal method can serve as a facile method for the synthesis of platinum nanoparticles, we successfully synthesized ultrasmall Pt nanoparticles with an average size of 2.45 nm, with the aid of poly(vinyl pyrrolidone) (PVP) as reducing agents and capping agents. Because of the size effect, these ultrasmall Pt nanoparticles exhibit a high activity toward the methanol oxidation reaction. PMID- 28347114 TI - Utilization of Enzyme-Immobilized Mesoporous Silica Nanocontainers (IBN-4) in Prodrug-Activated Cancer Theranostics. AB - To develop a carrier for use in enzyme prodrug therapy, Horseradish peroxidase (HRP) was immobilized onto mesoporous silica nanoparticles (IBN-4: Institute of Bioengineering and Nanotechnology), where the nanoparticle surfaces were functionalized with 3-aminopropyltrimethoxysilane and further conjugated with glutaraldehyde. Consequently, the enzymes could be stabilized in nanochannels through the formation of covalent imine bonds. This strategy was used to protect HRP from immune exclusion, degradation and denaturation under biological conditions. Furthermore, immobilization of HRP in the nanochannels of IBN-4 nanomaterials exhibited good functional stability upon repetitive use and long term storage (60 days) at 4 degrees C. The generation of functionalized and HRP immobilized nanomaterials was further verified using various characterization techniques. The possibility of using HRP-encapsulated IBN-4 materials in prodrug cancer therapy was also demonstrated by evaluating their ability to convert a prodrug (indole-3- acetic acid (IAA)) into cytotoxic radicals, which triggered tumor cell apoptosis in human colon carcinoma (HT-29 cell line) cells. A lactate dehydrogenase (LDH) assay revealed that cells could be exposed to the IBN-4 nanocomposites without damaging their membranes, confirming apoptotic cell death. In summary, we demonstrated the potential of utilizing large porous mesoporous silica nanomaterials (IBN-4) as enzyme carriers for prodrug therapy. PMID- 28347117 TI - Structural and Morphological Tuning of LiCoPO4 Materials Synthesized by Solvo Thermal Methods for Li-Cell Applications. AB - Olivine-type lithium metal phosphates (LiMPO4) are promising cathode materials for lithium-ion batteries. LiFePO4 (LFP) is commonly used in commercial Li-ion cells but the Fe3+/Fe2+ couple can be usefully substituted with Mn3+/Mn2+, Co3+/Co2+, or Ni3+/Ni2+, in order to obtain higher redox potentials. In this communication we report a systematic analysis of the synthesis condition of LiCoPO4 (LCP) using a solvo-thermal route at low temperature, the latter being a valuable candidate to overcome the theoretical performances of LFP. In fact, LCP shows higher working potential (4.8 V vs. 3.6 V) compared to LFP and similar theoretical capacity (167 mAh.g-1). Our goal is to show the effect of the synthesis condition of the ability of LCP to reversibly cycle lithium in electrochemical cells. LCP samples have been prepared through a solvo-thermal method in aqueous-non aqueous solvent blends. Different Co2+ salts have been used to study the effect of the anion on the crystal growth as well as the effect of solution acidity, temperature and reaction time. Materials properties have been characterized by Fast-Fourier transform infrared spectroscopy, X-ray diffraction and scanning electron microscopies. The correlation between structure/morphology and electrochemical performances has been investigated by galvanostatic charge discharge cycles. PMID- 28347111 TI - Composites of Polymer Hydrogels and Nanoparticulate Systems for Biomedical and Pharmaceutical Applications. AB - Due to their unique structures and properties, three-dimensional hydrogels and nanostructured particles have been widely studied and shown a very high potential for medical, therapeutic and diagnostic applications. However, hydrogels and nanoparticulate systems have respective disadvantages that limit their widespread applications. Recently, the incorporation of nanostructured fillers into hydrogels has been developed as an innovative means for the creation of novel materials with diverse functionality in order to meet new challenges. In this review, the fundamentals of hydrogels and nanoparticles (NPs) were briefly discussed, and then we comprehensively summarized recent advances in the design, synthesis, functionalization and application of nanocomposite hydrogels with enhanced mechanical, biological and physicochemical properties. Moreover, the current challenges and future opportunities for the use of these promising materials in the biomedical sector, especially the nanocomposite hydrogels produced from hydrogels and polymeric NPs, are discussed. PMID- 28347119 TI - Electric Field-Responsive Mesoporous Suspensions: A Review. AB - This paper briefly reviews the fabrication and electrorheological (ER) characteristics of mesoporous materials and their nanocomposites with conducting polymers under an applied electric field when dispersed in an insulating liquid. Smart fluids of electrically-polarizable particles exhibit a reversible and tunable phase transition from a liquid-like to solid-like state in response to an external electric field of various strengths, and have potential applications in a variety of active control systems. The ER properties of these mesoporous suspensions are explained further according to their dielectric spectra in terms of the flow curve, dynamic moduli, and yield stress. PMID- 28347118 TI - Magnetic Nanoparticles Cross the Blood-Brain Barrier: When Physics Rises to a Challenge. AB - The blood-brain barrier is a physical and physiological barrier that protects the brain from toxic substances within the bloodstream and helps maintain brain homeostasis. It also represents the main obstacle in the treatment of many diseases of the central nervous system. Among the different approaches employed to overcome this barrier, the use of nanoparticles as a tool to enhance delivery of therapeutic molecules to the brain is particularly promising. There is special interest in the use of magnetic nanoparticles, as their physical characteristics endow them with additional potentially useful properties. Following systemic administration, a magnetic field applied externally can mediate the capacity of magnetic nanoparticles to permeate the blood-brain barrier. Meanwhile, thermal energy released by magnetic nanoparticles under the influence of radiofrequency radiation can modulate blood-brain barrier integrity, increasing its permeability. In this review, we present the strategies that use magnetic nanoparticles, specifically iron oxide nanoparticles, to enhance drug delivery to the brain. PMID- 28347120 TI - Simulation of the Impact of Si Shell Thickness on the Performance of Si-Coated Vertically Aligned Carbon Nanofiber as Li-Ion Battery Anode. AB - Micro- and nano-structured electrodes have the potential to improve the performance of Li-ion batteries by increasing the surface area of the electrode and reducing the diffusion distance required by the charged carriers. We report the numerical simulation of Lithium-ion batteries with the anode made of core shell heterostructures of silicon-coated carbon nanofibers. We show that the energy capacity can be significantly improved by reducing the thickness of the silicon anode to the dimension comparable or less than the Li-ion diffusion length inside silicon. The results of simulation indicate that the contraction of the silicon electrode thickness during the battery discharge process commonly found in experiments also plays a major role in the increase of the energy capacity. PMID- 28347121 TI - Nanoscience Supporting the Research on the Negative Electrodes of Li-Ion Batteries. AB - Many efforts are currently made to increase the limited capacity of Li-ion batteries using carbonaceous anodes. The way to reach this goal is to move to nano-structured material because the larger surface to volume ratio of particles and the reduction of the electron and Li path length implies a larger specific capacity. Additionally, nano-particles can accommodate such a dilatation/contraction during cycling, resulting in a calendar life compatible with a commercial use. In this review attention is focused on carbon, silicon, and Li4Ti5O12 materials, because they are the most promising for applications. PMID- 28347122 TI - Mesoporous Silica Nanoparticles Loaded with Cisplatin and Phthalocyanine for Combination Chemotherapy and Photodynamic Therapy in vitro. AB - Mesoporous silica nanoparticles (MSNs) have been synthesized and loaded with both aluminum chloride phthalocyanine (AlClPc) and cisplatin as combinatorial therapeutics for treating cancer. The structural and photophysical properties of the MSN materials were characterized by different spectroscopic and microscopic techniques. Intracellular uptake and cytotoxicity were evaluated in human cervical cancer (HeLa) cells by confocal laser scanning microscopy (CLSM) and 3 (4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium (MTS) assays, respectively. The CLSM experiments showed that the MSN materials can be readily internalized in HeLa cells. The cytotoxic experiments demonstrated that, after light exposure, the combination of both AlClPc and cisplatin compounds in the same MSN platform potentiate the toxic effect against HeLa cells in comparison to the control AlClPc-MSN and cisplatin-MSN materials. These results show the potential of using MSN platforms as nanocarriers for combination photodynamic and chemotherapies to treat cancer. PMID- 28347123 TI - Nanocarriers for DNA Vaccines: Co-Delivery of TLR-9 and NLR-2 Ligands Leads to Synergistic Enhancement of Proinflammatory Cytokine Release. AB - Adjuvants enhance immunogenicity of vaccines through either targeted antigen delivery or stimulation of immune receptors. Three cationic nanoparticle formulations were evaluated for their potential as carriers for a DNA vaccine, and muramyl dipeptide (MDP) as immunostimulatory agent, to induce and increase immunogenicity of Mycobacterium tuberculosis antigen encoding plasmid DNA (pDNA). The formulations included (1) trimethyl chitosan (TMC) nanoparticles, (2) a squalene-in-water nanoemulsion, and (3) a mineral oil-in-water nanoemulsion. The adjuvant effect of the pDNA-nanocomplexes was evaluated by serum antibody analysis in immunized mice. All three carriers display a strong adjuvant effect, however, only TMC nanoparticles were capable to bias immune responses towards Th1. pDNA naturally contains immunostimulatory unmethylated CpG motifs that are recognized by Toll-like receptor 9 (TLR-9). In mechanistic in vitro studies, activation of TLR-9 and the ability to enhance immunogenicity by simultaneously targeting TLR-9 and NOD-like receptor 2 (NLR-2) was determined by proinflammatory cytokine release in RAW264.7 macrophages. pDNA in combination with MDP was shown to significantly increase proinflammatory cytokine release in a synergistic manner, dependent on NLR-2 activation. In summary, novel pDNA-Ag85A loaded nanoparticle formulations, which induce antigen specific immune responses in mice were developed, taking advantage of the synergistic combinations of TLR and NLR agonists to increase the adjuvanticity of the carriers used. PMID- 28347124 TI - Facile and Eco-Friendly Synthesis of Finger-Like Co3O4 Nanorods for Electrochemical Energy Storage. AB - Co3O4 nanorods were prepared by a facile hydrothermal method. Eco-friendly deionized water rather than organic solvent was used as the hydrothermal media. The as-prepared Co3O4 nanorods are composed of many nanoparticles of 30-50 nm in diameter, forming a finger-like morphology. The Co3O4 electrode shows a specific capacitance of 265 F g-1 at 2 mV s-1 in a supercapacitor and delivers an initial specific discharge capacity as high as 1171 mAh g-1 at a current density of 50 mA g-1 in a lithium ion battery. Excellent cycling stability and electrochemical reversibility of the Co3O4 electrode were also obtained. PMID- 28347125 TI - Size Effect of Ordered Mesoporous Carbon Nanospheres for Anodes in Li-Ion Battery. AB - The present work demonstrates the application of various sizes of ordered mesoporous carbon nanospheres (OMCS) with diameters of 46-130 nm as an active anode material for Li-ion batteries (LIB). The physical and chemical properties of OMCS have been evaluated by performing scanning electron microscopy (SEM), transmission electron microscopy (TEM), N2 adsorption-desorption analysis; small angle scattering system (SAXS) and X-ray diffraction (XRD). The electrochemical analysis of using various sizes of OMCS as anode materials showed high capacity and rate capability with the specific capacity up to 560 mA.h.g-1 at 0.1 C after 85 cycles. In terms of performance at high current rate compared to other amorphous carbonaceous materials; a stable and extremely high specific capacity of 240 mA.h.g-1 at 5 C after 15 cycles was achieved. Such excellent performance is mainly attributed to the suitable particle size distribution of OMCS and intimate contact between OMCS and conductive additives; which can be supported from the TEM images. Results obtained from this study clearly indicate the excellence of size distribution of highly integrated mesoporous structure of carbon nanospheres for LIB application. PMID- 28347127 TI - Freestanding rGO-SWNT-STN Composite Film as an Anode for Li Ion Batteries with High Energy and Power Densities. AB - Freestanding Si-Ti-Ni alloy particles/reduced graphene oxide/single wall carbon nanotube composites have been prepared as an anode for lithium ion batteries via a simple filtration method. This composite electrode showed a 9% increase in reversible capacity, a two-fold higher cycle retention at 50 cycles and a two fold higher rate capability at 2 C compared to pristine Si-Ti-Ni (STN) alloy electrodes. These improvements were attributed to the suppression of the pulverization of the STN active material by the excellent mechanical properties of the reduced graphene oxide-single wall carbon nanotube networks and the enhanced kinetics associated with both electron and Li ion transport. PMID- 28347126 TI - Non-Cytotoxic Quantum Dot-Chitosan Nanogel Biosensing Probe for Potential Cancer Targeting Agent. AB - Quantum dot (Qdot) biosensors have consistently provided valuable information to researchers about cellular activity due to their unique fluorescent properties. Many of the most popularly used Qdots contain cadmium, posing the risk of toxicity that could negate their attractive optical properties. The design of a non-cytotoxic probe usually involves multiple components and a complex synthesis process. In this paper, the design and synthesis of a non-cytotoxic Qdot-chitosan nanogel composite using straight-forward cyanogen bromide (CNBr) coupling is reported. The probe was characterized by spectroscopy (UV-Vis, fluorescence), microscopy (Fluorescence, Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM) and Dynamic Light Scattering. This activatable ("OFF"/"ON") probe contains a core-shell Qdot (CdS:Mn/ZnS) capped with dopamine, which acts as a fluorescence quencher and a model drug. Dopamine capped "OFF" Qdots can undergo ligand exchange with intercellular glutathione, which turns the Qdots "ON" to restore fluorescence. These Qdots were then coated with chitosan (natural biocompatible polymer) functionalized with folic acid (targeting motif) and Fluorescein Isothiocyanate (FITC; fluorescent dye). To demonstrate cancer cell targetability, the interaction of the probe with cells that express different folate receptor levels was analyzed, and the cytotoxicity of the probe was evaluated on these cells and was shown to be nontoxic even at concentrations as high as 100 mg/L. PMID- 28347128 TI - Temperature and Wavelength Dependence of Energy Transfer Process Between Quantized States and Surface States in CdSe Quantum Dots. AB - Temperature and wavelength dependence of energy transfer (ET) process between quantized states and surface trap states of CdSe quantum dots was investigated, respectively. The experimental results demonstrate that the photoluminescence (PL) intensity of the quantized states decreases with respect to the trap state emission, especially at lower temperatures. The observed ET process between quantized states and trap states which is influenced by the thermal population behavior. At the same temperature, the silver films can greatly enhance the energy transfer (ET) rate from the quantized states to trap states due to surface plasmonic coupling effect. PMID- 28347129 TI - Bi-layer Channel AZO/ZnO Thin Film Transistors Fabricated by Atomic Layer Deposition Technique. AB - This letter demonstrates bi-layer channel Al-doped ZnO/ZnO thin film transistors (AZO/ZnO TFTs) via atomic layer deposition process at a relatively low temperature. The effects of annealing in oxygen atmosphere at different temperatures have also been investigated. The ALD bi-layer channel AZO/ZnO TFTs annealed in dry O2 at 300 degrees C exhibit a low leakage current of 2.5 * 10 13A, I on/I off ratio of 1.4 * 107, subthreshold swing (SS) of 0.23 V/decade, and high transmittance. The enhanced performance obtained from the bi-layer channel AZO/ZnO TFT devices is explained by the inserted AZO front channel layer playing the role of the mobility booster. PMID- 28347130 TI - New tracers to the clinic. PMID- 28347131 TI - Preclinical in vivo cancer, straightway to patients? AB - Detection of useful cellular targets has strongly stimulated personalized tumor targeted imaging and therapy approaches, also involving synthesis and evaluation of nuclear imaging probes with potential for clinical applications. Reviews of preclinical and translational studies concerning such probes, including radiolabeled antibodies, nanobodies, affibodies, peptides, small molecule inhibitors, and nanoparticles, are presented in this issue. As most tracers described in these articles have been developed for the field of cancer imaging and radionuclide therapy, the current article on preclinical studies will focus on cancer research as well. The main steps in developing a nuclear probe for clinical application for radionuclide imaging and therapy, after identification of a suitable molecular target on tumor cells, comprise: 1) synthesis and radiolabeling of the probe; 2) in vitro characterization, such as the evaluation of target binding affinity; 3) in vivo evaluation to assess the biodistribution and tumor targeting capability, for radionuclide therapy purposes also dosimetry studies to determine the absorbed doses and efficacy; 4) radiolabeled probes that successfully pass such tests as well as toxicological studies may enter clinical evaluation. For preclinical testing of radiolabeled probes various relevant in vitro and in vivo models dedicated to oncological research have been developed along with preclinical imaging platforms, including positron emission tomography (PET) and single photon emission computed tomography (SPECT) systems, in combination with magnetic resonance imaging (MRI) or computed tomography (CT). These developments hold great promise for fast translation of new candidate probes from preclinical validation into the clinic. This overview article describes preclinical studies typically being performed to bring a new radiopharmaceutical into clinical oncology practice. It also aims to raise awareness of confounding factors during translation of preclinical studies and ways to overcome them. PMID- 28347132 TI - Radiolabeled peptides: current and new perspectives. AB - Radiolabeled peptides have been the subject of research for over 20 years and during that time possibility/variety of peptide receptor imaging and later targeted radiotherapy increased significantly. The targeted receptors belong to the large family of G-protein-coupled receptors or tyrosine kinases receptors partially connected with them. They both regulate large signaling networks, control multiple cell functions and are implicated in many diseases including cancers. The essential feature of peptides used in nuclear medicine involves their ability to binding with high affinity and specify to their receptors overexpressed on tumor cells. Currently most important peptide radiotracers are somatostatin, GLP-1, bombesin, gastrin/cholecystokinin-2, neurokinin type 1, CXCR4, EGF, VEGF and integrins. These tracers are mainly based on nuclides which are radiometals or on 18F and may be used in both SPECT or PET techniques as well as for hybrid imaging. Using of chelators suitable for peptide labeling with diagnostic and therapeutic radionuclids enables the theranostic approach. In this review we will provide a brief overview over currently available radiopharmaceuticals based on different groups of peptides. PMID- 28347133 TI - Antimony and Arsenic Behavior during Fe(II)-Induced Transformation of Jarosite. AB - Jarosite can be an important scavenger for arsenic (As) and antimony (Sb) in acid mine drainage (AMD) and acid sulfate soil (ASS) environments. When subjected to reducing conditions, jarosite may undergo reductive dissolution, thereby releasing As, Sb, and Fe2+ coincident with a rise in pH. These conditions can also trigger the Fe2+-induced transformation of jarosite to more stable Fe(III) minerals, such as goethite. However, the consequences of this transformation process for As and Sb are yet to be methodically examined. We explore the effects of abiotic Fe2+-induced transformation of jarosite on the mobility, speciation, and partitioning of associated As(V) and Sb(V) under anoxic conditions at pH 7. High concentrations of Fe2+ (10 and 20 mM) rapidly (<10 min) transformed jarosite to a green rust intermediary, prior to the subsequent precipitation of goethite within 24 h. In contrast, lower concentrations of Fe2+ (1 and 5 mM) led to the formation of lepidocrocite. As K-edge XANES spectroscopy revealed some reduction of As(V) to As(III) at higher concentrations of Fe2+, while Sb L1-edge XANES spectroscopy indicated no reduction of Sb(V). The transformation processes enhanced Sb mobilization into the aqueous phase, while As was instead repartitioned to a surface-bound exchangeable phase. The results imply that Fe2+ induced transformation of As/Sb-jarosite can increase Sb mobility and exert major influences on As partitioning and speciation. PMID- 28347134 TI - Evaluating Droplet Digital Polymerase Chain Reaction for the Quantification of Human Genomic DNA: Lifting the Traceability Fog. AB - Digital polymerase chain reaction (dPCR) end point platforms directly estimate the number of DNA target copies per reaction partition, lambda, where the partitions are fixed-location chambers (cdPCR) or aqueous droplets floating in oil (ddPCR). For use in the certification of target concentration in primary calibrant certified reference materials (CRMs), both lambda and the partition volume, V, must be metrologically traceable to some accessible reference system, ideally, the International System of Units (SI). The fixed spatial distribution of cdPCR chambers enables real-time monitoring of PCR amplification. Analysis of the resulting reaction curves enables validation of the critical dPCR assumptions that are essential for establishing the SI traceability of lambda. We know of no direct method for validating these assumptions for ddPCR platforms. The manufacturers of the cdPCR and ddPCR systems available to us do not provide traceable partition volume specifications. Our colleagues at the National Institute of Standards and Technology (NIST) have developed a reliable method for determining ddPCR droplet volume and have demonstrated that different ddPCR reagents yield droplets of somewhat different size. Thus, neither dPCR platform by itself provides metrologically traceable estimates of target concentration. We show here that evaluating split samples with both cdPCR and ddPCR platforms can transfer the lambda traceability characteristics of a cdPCR assay to its ddPCR analogue, establishing fully traceable ddPCR estimates of CRM target concentration. PMID- 28347136 TI - A Dynamic Three-Dimensional Covalent Organic Framework. AB - A guest-induced reversible crystal-structure transformation is identified in a new 3D covalent organic framework (COF) by comprehensive analyses using powder X ray diffraction, organic vapor sorption isotherm, and 129Xe NMR spectroscopy. The revolving imine bond in interpenetrating 3D networks is uncovered as the key to the dynamic behavior, the potential applications of which are illustrated by gas separation and heterogeneous catalysis, thus paving the way to the design of stimuli-responsive and multifunctional COF materials. PMID- 28347135 TI - Manganese-Cobalt Oxido Cubanes Relevant to Manganese-Doped Water Oxidation Catalysts. AB - Incorporation of Mn into an established water oxidation catalyst based on a Co(III)4O4 cubane was achieved by a simple and efficient assembly of permanganate, cobalt(II) acetate, and pyridine to form the cubane oxo cluster MnCo3O4(OAc)5py3 (OAc = acetate, py = pyridine) (1-OAc) in good yield. This allows characterization of electronic and chemical properties for a manganese center in a cobalt oxide environment, and provides a molecular model for Mn-doped cobalt oxides. The electronic properties of the cubane are readily tuned by exchange of the OAc- ligand for Cl- (1-Cl), NO3- (1-NO3), and pyridine ([1-py]+). EPR spectroscopy, SQUID magnetometry, and DFT calculations thoroughly characterized the valence assignment of the cubane as [MnIVCoIII3]. These cubanes are redox-active, and calculations reveal that the Co ions behave as the reservoir for electrons, but their redox potentials are tuned by the choice of ligand at Mn. This MnCo3O4 cubane system represents a new class of easily prepared, versatile, and redox-active oxido clusters that should contribute to an understanding of mixed-metal, Mn-containing oxides. PMID- 28347138 TI - Identification of Early Represented Gluten Proteins during Durum Wheat Grain Development. AB - The time course of biosynthesis and accumulation of storage proteins in developing grains of durum wheat (Triticum turgidum ssp. durum (Desf.) Husn.) pasta-quality reference cv. Svevo was investigated at the protein level for the first time. Seeds were harvested at key kernel developmental stages, namely, 3 (seed increase 3-fold in size), 5 (kernel development, water-ripe stage), 11 (kernel development, water-ripe stage), 16 (kernel full development, water-ripe stage), 21 (milk-ripe stage), and 30 (dough stage) days postanthesis (dpa). Gliadins and glutenins were fractionated according to their different solubility and individually analyzed after fractionation by reversed-phase high performance liquid chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Proteins were identified by liquid chromatography-tandem mass spectrometry of proteolytic peptides. The alpha- and gamma-gliadin were already detected at 3 dpa. The biosynthesis of high molecular mass glutenin Bx7 was slightly delayed (11 dpa). Most of the gluten proteins accumulated rapidly between 11 and 21 dpa, with a minor further increase up to 30 dpa. The expression pattern of gluten proteins in Triticum durum at the early stages of synthesis provides reference data sets for future applications in crop breeding and growth monitoring. PMID- 28347137 TI - Quantitative Proteomics and Immunohistochemistry Reveal Insights into Cellular and Molecular Processes in the Infarct Border Zone One Month after Myocardial Infarction. AB - Postinfarction remodeling and expansion of the peri-infarct border zone (BZ) directly correlate with mortality following myocardial infarction (MI); however, the cellular and molecular mechanisms underlying remodeling processes in the BZ remain unclear. Herein, we utilized a label-free quantitative proteomics approach in combination with immunohistochemical analyses to gain a better understanding of processes contributing to postinfarction remodeling of the peri-infarct BZ in a swine model of MI with reperfusion. Our analysis uncovered a significant down regulation of proteins involved in energy metabolism, indicating impaired myocardial energetics and possibly mitochondrial dysfunction, in the peri-scar BZ. An increase in endothelial and vascular smooth muscles cells, as well as up regulation of proteins implicated in vascular endothelial growth factor (VEGF) signaling and marked changes in the expression of extracellular matrix and subendothelial basement membrane proteins, is indicative of active angiogenesis in the infarct BZ. A pronounced increase in macrophages in the peri-infarct BZ was also observed, and proteomic analysis uncovered evidence of persistent inflammation in this tissue. Additional evidence suggested an increase in cellular proliferation that, concomitant with increased nestin expression, indicates potential turnover of endogenous stem cells in the BZ. A marked up regulation of pro-apoptotic proteins, as well as the down-regulation of proteins important for adaptation to mechanical, metabolic, and oxidative stress, likely contributes to increased apoptosis in the peri-infarct BZ. The cellular processes and molecular pathways identified herein may have clinical utility for therapeutic intervention aimed at limiting remodeling and expansion of the BZ myocardium and preventing the development of heart failure post-MI. PMID- 28347139 TI - Single-Protein Tracking Reveals That NADPH Mediates the Insertion of Cytochrome P450 Reductase into a Biomimetic of the Endoplasmic Reticulum. AB - Cytochrome P450 reductase (CPR) is the redox partner for most human cytochrome P450 enzymes. It is also believed that CPR is an integral membrane protein exclusively. Herein, we report that, contrary to this belief, CPR can exist as a peripheral membrane protein in the absence of NADPH and will transition to an integral membrane protein in the presence of stoichiometric amounts of NADPH or greater. All experiments were performed in a solid-supported cushioned lipid bilayer that closely matched the chemical composition of the human endoplasmic reticulum and served as an ER biomimetic. The phase characteristics and fluidity of the ER biomimetic was characterized with fluorescence micrographs and temperature-dependent fluorescence recovery after photobleaching. The interactions of CPR with the ER biomimetic were directly observed by tracking single CPR molecules using time-lapse single-molecule fluorescence imaging and subsequent analysis of tracks. These studies revealed dramatic changes in diffusion coefficient and the degree of partitioning of CPR as a function of NADPH concentration. PMID- 28347140 TI - Strain Engineering for Anion Arrangement in Perovskite Oxynitrides. AB - Mixed-anion perovskites such as oxynitrides, oxyfluorides, and oxyhydrides have flexibility in their anion arrangements, which potentially enables functional material design based on coordination chemistry. However, difficulty in the control of the anion arrangement has prevented the realization of this concept. In this study, we demonstrate strain engineering of the anion arrangement in epitaxial thin films of the Ca1-xSrxTaO2N perovskite oxynitrides. Under compressive epitaxial strain, the axial sites in TaO4N2 octahedra tend to be occupied by nitrogen rather than oxygen, which was revealed by N and O K-edge linearly polarized X-ray absorption near-edge structure (LP-XANES) and scanning transmission electron microscopy combined with electron energy loss spectroscopy. Furthermore, detailed analysis of the LP-XANES indicated that the high occupancy of nitrogen at the axial sites is due to the partial formation of a metastable trans-type anion configuration. These results are expected to serve as a guide for the material design of mixed-anion compounds based on their anion arrangements. PMID- 28347141 TI - Reversible Capture and Release of Cl2 and Br2 with a Redox-Active Metal-Organic Framework. AB - Extreme toxicity, corrosiveness, and volatility pose serious challenges for the safe storage and transportation of elemental chlorine and bromine, which play critical roles in the chemical industry. Solid materials capable of forming stable nonvolatile compounds upon reaction with elemental halogens may partially mitigate these challenges by allowing safe halogen release on demand. Here we demonstrate that elemental halogens quantitatively oxidize coordinatively unsaturated Co(II) ions in a robust azolate metal-organic framework (MOF) to produce stable and safe-to-handle Co(III) materials featuring terminal Co(III) halogen bonds. Thermal treatment of the oxidized MOF causes homolytic cleavage of the Co(III)-halogen bonds, reduction to Co(II), and concomitant release of elemental halogens. The reversible chemical storage and thermal release of elemental halogens occur with no significant losses of structural integrity, as the parent cobaltous MOF retains its crystallinity and porosity even after three oxidation/reduction cycles. These results highlight a material operating via redox mechanism that may find utility in the storage and capture of other noxious and corrosive gases. PMID- 28347142 TI - Polyethylenimine-mediated synthetic insertion of gold nanoparticles into mesoporous silica nanoparticles for drug loading and biocatalysis. AB - Mesoporous silica nanoparticles (MSNPs) have been used as an efficient and safe carrier for drug delivery and biocatalysis. The surface modification of MSNPs using suitable reagents may provide a robust framework in which two or more components can be incorporated to give multifunctional capabilities (e.g., synthesis of noble metal nanoparticles within mesoporous architecture along with loading of a bioactive molecule). In this study, the authors reported on a new synthetic route for the synthesis of gold nanoparticles (AuNPs) within (1) unmodified MSNPs and (2) 3-trihydroxysilylpropyl methylphosphonate-modified MSNPs. A cationic polymer, polyethylenimine (PEI), and formaldehyde were used to mediate synthetic incorporation of AuNPs within MSNPs. The AuNPs incorporated within the mesoporous matrix were characterized by transmission electron microscopy, energy dispersive x-ray analysis, and high-resolution scanning electron microscopy. PEI in the presence of formaldehyde enabled synthetic incorporation of AuNPs in both unmodified and modified MSNPs. The use of unmodified MSNPs was associated with an increase in the polycrystalline structure of the AuNPs within the MSNPs. The AuNPs within modified MSNPs showed better catalytic activity than those within unmodified MSNPs. MSNPs with an average size of 200 nm and with a pore size of 4-6 nm were used for synthetic insertion of AuNPs. It was found that the PEI coating enabled AuNPs synthesis within the mesopores in the presence of formaldehyde or tetrahydrofuran hydroperoxide at a temperature between 10 and 25 degrees C or at 60 degrees C in the absence of organic reducing agents. The as-made AuNP-inserted MSNPs exhibited enhanced catalytic activity. For example, these materials enabled rapid catalytic oxidation of the o-dianisidine substrate to produce a colored solution in proportion to the amount of H2O2 generated as a function of glucose oxidase catalyzed oxidation of glucose; a linear concentration range from 80 to 800 MUM and a detection limit as low as 80 MUM were observed. The mesoscale pores of the as developed AuNP-inserted MSNPs were also used to entrap the hydrophobic drug paclitaxel. The results of this study indicate the potential use of the AuNP inserted MSNPs in biocatalysis and drug delivery. PMID- 28347144 TI - Compassion Fatigue Among Palliative Care Clinicians: Findings on Personality Factors and Years of Service. AB - OBJECTIVES: Palliative medicine is a rewarding field, but providers encounter patient trauma on a routine basis. Compassion fatigue, marked by burnout, secondary traumatic stress, and low satisfaction may result. However, professionals differ markedly in how they respond to patient trauma. The objective of the current study was to determine whether personality traits of neuroticism and agreeableness relate to aspects of compassion fatigue, after accounting for time spent working in the field. METHODS: Sixty-six palliative medicine physicians, nurses, social workers, and chaplains completed validated measures of personality traits, compassion fatigue, and work background. RESULTS: Providers who had worked longer reported higher levels of satisfaction and lower levels of burnout. Neuroticism demonstrated strong significant associations with secondary traumatic stress and burnout ( Ps < .001). Agreeableness was significantly and strongly associated with compassion satisfaction ( P < .001). These associations held after accounting for years spent working in the field. SIGNIFICANCE OF RESULTS: Personality traits of neuroticism and agreeableness may convey risk and resilience, respectively, for palliative care professionals. More research is needed to determine if assessing personality traits can help identify providers at risk for adverse reactions to patient trauma. PMID- 28347145 TI - Here and Now Aboriginal Assessment (HANAA): a follow-up survey of users. AB - OBJECTIVES: To explore users' views of, and experience with, the Here and Now Aboriginal Assessment (HANAA), an instrument developed for screening social and emotional wellbeing (SEWB) in Aboriginal adults. Over the last few years the HANAA has been widely disseminated across Australia. METHODS: All those on our database who had requested the HANAA package were contacted by email and invited to participate in the evaluation by completing an online survey. RESULTS: A total of 38 responses were received; the response rate was 36%. All 10 HANAA domains were highly rated by respondents; the overall mean score was 8.3/10. Each domain was assessed using a dichotomous scale of 'problem' or 'no problem' which respondents rated as being very useful; the mean score was 8.4/10. The mean score for the 'recommendation' section at the end of the HANAA was 7.2/10. CONCLUSIONS: Respondents reported a high level of utility and cultural applicability of the HANAA's assessment domains, semi-structured narrative style of administration and simple rating system. The HANAA is making a useful and practical contribution to the assessment of Aboriginal SEWB at a community level. Recommendations for future work on the HANAA include consideration of addition of a personality domain and development of a child and adolescent version. PMID- 28347146 TI - Complex PTSD - a better description for borderline personality disorder? AB - OBJECTIVE: To consider the use of the diagnostic category 'complex posttraumatic stress disorder' (c-PTSD) as detailed in the forthcoming ICD-11 classification system as a less stigmatising, more clinically useful term, instead of the current DSM-5 defined condition of 'borderline personality disorder' (BPD). CONCLUSIONS: Trauma, in its broadest definition, plays a key role in the development of both c-PTSD and BPD. Given this current lack of differentiation between these conditions, and the high stigma faced by people with BPD, it seems reasonable to consider using the diagnostic term 'complex posttraumatic stress disorder' to decrease stigma and provide a trauma-informed approach for BPD patients. PMID- 28347147 TI - Oxytocin Augmentation in Spontaneously Laboring, Nulliparous Women: Multilevel Assessment of Maternal BMI and Oxytocin Dose. AB - BACKGROUND: Synthetic oxytocin, the primary tool for labor augmentation, is less effective among obese women, leading to more unplanned cesarean deliveries for slow labor progress. It is not known if obese women require higher doses of oxytocin due to maternal, fetal, or labor factors related to maternal obesity. OBJECTIVES: This study had two main objectives: (1) examine the influence of maternal body mass index (BMI) on hourly doses of oxytocin from augmentation initiation until vaginal delivery in obese women; and (2) examine the influence of other maternal, fetal, and labor factors on hourly doses of oxytocin in obese women. STUDY DESIGN: Longitudinal study of a cohort ( N = 136) of healthy, nulliparous, spontaneously laboring obese women (BMI >= 30 kg/m2) who received oxytocin augmentation and achieved vaginal delivery. We performed iterative multilevel analyses to examine the influence of maternal BMI and other factors on hourly oxytocin doses. RESULTS: Maternal BMI explained 16.56% (95% confidence interval [CI] = [13.7, 20.04], p < .001) of the variance in hourly oxytocin doses received in a multilevel model controlling for influence of maternal, fetal, and labor characteristics. Maternal age, gestational age, status of amniotic membranes at hospital admission, and admission cervical dilation examination were not significant; however, neonatal birthweight and cervical dilation at oxytocin initiation were significant predictors of hourly oxytocin dose in these women ( p < .001). CONCLUSIONS: Even when parturition preparation has progressed adequately for spontaneous labor initiation, there still may be some obesity-related blunting of myometrial contractility and response to oxytocin used for augmentation. PMID- 28347148 TI - Minimising compassion fatigue in obstetrics/gynaecology doctors: exploring an intervention for an occupational hazard. AB - AIM: To explore the indicators of occupational stress in a group of obstetrics and gynaecology doctors and to investigate the impact of work-focused discussion groups over a 6 month period. METHODS: The ProQOL questionnaire was used to measure the efficacy of monthly psychiatrist-led Balint style discussion groups on minimising Compassion Fatigue (consisting of Secondary Traumatic Stress and Burnout). The 25 doctors were given the given the ProQOL questionnaire to complete: (a) at the initiation of the intervention in July 2015, (b) in October 2015, and (c) in December 2015. RESULTS: Significantly decreased levels of Secondary Traumatic Stress ( p=0.008), Burnout ( p=0.010), as well as significantly increased rates of Compassion Satisfaction ( p=0.035) were recorded. Participants requested that the groups be continued. CONCLUSIONS: Psychiatrist-led work focused discussion groups were associated with improved rates of Secondary Traumatic Stress, Burnout, and Compassion Satisfaction in this sample group. PMID- 28347149 TI - Psychometric Testing of Two Chinese-Version Scales on Attitudes Toward and Caregiving Behaviors for End-of-Life Patients and Families. AB - The study purpose was to examine the validities and reliabilities of the Chinese versions Frommelt Attitudes Toward Care of the Dying Scale (Attitudes Scale) and Caregiving Behaviors Scale for End-of-Life Patients and Families (Behaviors Scale). The scales were tested in a convenience sample of 318 nurses with >=6 months work experience at three hospitals. Cronbach's alphas of the Attitudes and Behaviors Scales were .90 and .96, respectively. Each scale had Kaiser-Meyer Olkin index >.85 and Bartlett's test of sphericity >4000 ( p < .001). Attitudes Scale loaded on three factors: respecting and caring for dying patients and families, avoiding care of the dying, and involving patients and families in end of-life care. The Behaviors Scale loaded on two factors: supporting dying patients and families, and helping families cope with grief. Factor loadings for both scales were >=.49. Both Attitudes and Behaviors Scales are reliable and valid for evaluating nurses' attitudes and caregiving behaviors for the dying. PMID- 28347150 TI - Taxometric Analysis of the Toronto Structured Interview for Alexithymia. AB - Alexithymia is a clinically relevant personality construct characterized by difficulties identifying and describing feelings, externally oriented thinking, and impoverished imaginal processes. Previous taxometric investigations provided evidence that alexithymia is best conceptualized as a continuous dimension rather than a discrete type, at least when assessed with the self-report 20-Item Toronto Alexithymia Scale. The aim of the current study was to test the categorical versus dimensional structure of alexithymia using the recently developed Toronto Structured Interview for Alexithymia. Three nonredundant taxometric procedures (MAXCOV, MAMBAC, and L-Mode) were performed on the Toronto Structured Interview for Alexithymia subscale scores from a multinational sample of 842 adults. All taxometric procedures produced unambiguously dimensional solutions, providing further evidence that the core alexithymia features are continuously distributed in the population. Discussion focuses on the theoretical, assessment, and clinical implications of these findings for the alexithymia construct. PMID- 28347151 TI - Dowry-related domestic violence and complex posttraumatic stress disorder: a case report. AB - OBJECTIVES: This paper draws attention to the mental health impact of coercive practice of dowry demands, associated with domestic violence (DV) in an immigrant woman. METHODS: This study was based on a case report and selective literature review. RESULTS: This case history illustrates the serious mental health impacts of repeated emotional and physical trauma inflicted by a husband who was dissatisfied with his wife's dowry. Bio-psycho-social / cultural aspects of mental health treatments needed to be augmented with attention to safety, advocacy, and access to support networks. CONCLUSIONS: Cultural factors are important determinants of mental illness. Psychiatrists need to be aware of DV and dowry when treating immigrant women. PMID- 28347152 TI - [Dieting pitfalls - psychological factors]. AB - INTRODUCTION: Eating is one of the fundamental sources of happiness. Slimming diets would deprive you of this very enjoyment without granting something else instead, for example, proper eating behaviours for life or a permanent solution for overweight-related problems. AIM: This paper aims to investigate the psycho dynamic relationships that might be the reason for the failure of all diets and slimming diets. METHOD: Analysing overweight, obesity and the failure of slimming diets with the help of the cognitive behavioral therapeutic approach. RESULTS: By applying the principles confirmed and laid down by the cognitive behavioral therapy, we can identify specific ethological causes present in dieting and gaining weight behaviours that can successfully be used in curative symptom and problem oriented psychotherapy. CONCLUSION: In summary it can be stated that it is advised to approach the defined objective slowly, in small steps. With the help of learning methods and the continual transformation of the environment, obese individuals, having shred their own unwanted behavioral attitudes, can not only build up new attitudes and transform them into new desirable habits but will also have their personalities chiselled. Orv. Hetil., 2017, 158(13), 499-507. PMID- 28347153 TI - [Live birth resulting from abdominal pregnancy]. AB - Advanced abdominal pregnancy is extremely rare. Symptoms are often nonspecific, and the diagnosis is frequently missed. Maternal mortality and morbidity are also very high especially if the condition is not diagnosed and managed properly. In abdominal pregnancy there is a high incidence of fetal malformations. We are presenting a case of a 38 year old primigravida with an undiagnosed advanced abdominal pregnancy carried beyond 36 weeks of gestation. We delivered a 2090 g baby from the abdomen. A relaparotomy was necessary on the third postoperative day because of abdominal bleeding. At the time of discharge both mother and baby were doing well. The publication also provides a literature overview, including definition, epidemiology, diagnosis and therapy. Orv. Hetil., 2017, 158(13), 508 511. PMID- 28347155 TI - [Miscellaneous]. PMID- 28347154 TI - [Circulating microRNAs in the diagnostics of endocrine neoplasms]. AB - MicroRNAs (miRNA, miR) are short - 19-25 nucleotide long - single stranded (in their mature form), non-coding RNA molecules that regulate gene expression mostly at the posttranscriptional level. microRNAs are involved in the regulation of various physiological processes such as cell differentiation and proliferation, development, haematopoesis, cell death, while their aberrant expression is observed in numerous diseases, like autoimmune disorders, inflammations, vascular diseases or tumorigenesis. microRNAs are expressed in a tissue specific fashion. Beyond their appearance in tissues, they can be found in body fluids as well. microRNAs are present in blood, mother milk, semen, saliva, urine, etc. MicroRNAs in body fluids, especially the blood-borne circulating microRNAs can be exploited as minimally invasive biomarkers of tumor diagnosis. The number of endocrine tumor-associated circulating microRNA alterations is relatively low, mostly described for papillary thyroid cancer, adrenocortical cancer, ovarian and neuroendocrine tumors. As the histological diagnosis including the establishment of malignancy of some of these neoplasms is difficult, studies on circulating microRNAs might have great perspectives. Orv. Hetil., 2017, 158(13), 483-490. PMID- 28347156 TI - [Prof. Dr. Geza Jako - academian (1930-2015)]. PMID- 28347158 TI - Effective dose in low-dose CT compared with radiography for templating of total hip arthroplasty. AB - Background Recently, total hip arthroplasty (THA) has come to focus on restoration of individual anatomy including femoral neck anteversion and global offset (femoral and acetabular offset). Three-dimensional (3D) computed tomography (CT) data could provide a better basis for preoperative templating. The use of CT has been hampered by high radiation dose. Purpose To evaluate the effective dose used in pelvis and hip CT for THA templating. Material and Methods CT data from two clinical trials of THA were evaluated for CT scan length and volume CT dose index (CTDIvol). The effective doses from hip-knee-ankle CT and pelvis and hip radiography were compared. Conversion factors for effective dose for radiography were calculated using the PCXMC software. Results A reduced dose CT protocol for pelvis imaging gave a substantial dose reduction compared with standard CT, while maintaining sufficient image quality. Between the two clinical trials there was a significant reduction in effective CT dose corresponding to changes in the CT protocol ( P < 0.01). The CT dose for the latter group was similar to, but nevertheless significantly higher than for, radiography ( P < 0.01). However, in the latter group the theoretical minimum dose for CT, using the minimum scan length required by the templating software, was equal to the dose from radiography. Conclusion Although the CT dose remained higher than for radiography, potential reductions in scan length could reduce the dose further so that CT would have a comparable level of risk to radiography with the added benefit of 3D templating. PMID- 28347157 TI - Bacterial adhesion capacity on food service contact surfaces. AB - The aim of this study was to analyse the adhesion of E. coli, P. aeruginosa and S. aureus on food contact materials, such as polyethylene terephthalate, silicone, aluminium, Teflon and glass. Surface roughness, streaming potential and contact angle were measured. Bacterial properties by contact angle and specific charge density were characterised. The bacterial adhesion analysis using staining method and scanning electron microscopy showed the lowest adhesion on smooth aluminium and hydrophobic Teflon for most of the bacteria. However, our study indicates that hydrophobic bacteria with high specific charge density attach to those surfaces more intensively. In food services, safety could be increased by selecting material with low adhesion to prevent cross contamination. PMID- 28347159 TI - Stenotic lesion level did not affect outcomes of carotid endarterectomy. AB - Background Carotid endarterectomy is the established treatment for carotid artery stenosis, and remains the primary surgical option due to its superior outcomes compared to carotid arterial stenting. However, Japanese patients are known to have unfavorable anatomical conditions for carotid endarterectomy, with a relatively higher level of the carotid artery bifurcation than in the Western population. We investigated the outcomes of carotid endarterectomy in our institute and evaluated the procedural quality by comparing patients based on higher or lower lesion levels. Methods The clinical data of 65 patients who underwent carotid endarterectomy were collected retrospectively. The outcomes reviewed included stroke-free survival and stroke-free rate. The patients were divided into a higher group ( n = 25) and a lower group ( n = 40), based on lesion location in respect of the 2nd cervical vertebral level. Results There was no perioperative death and only one case of stroke in the higher group within 30 days after carotid endarterectomy. At 5 years after carotid endarterectomy, the stroke-free survival rates were 83.4% in the higher group and 87.8% in the lower group, while the stroke-free rates were 96.0% and 94.0%, respectively; there were no significant differences between groups. Conclusions Stenotic lesion level did not affect the outcome or procedural quality of carotid endarterectomy. PMID- 28347160 TI - Primary prevention of Clostridium difficile infections - how difficult can it be? AB - INTRODUCTION: C. difficile infections (CDI) have been a challenging disease to treat, much less to prevent, for decades. Efforts for primary prevention have mainly focused on improving infection control practices, but CDI outbreaks continue to plague healthcare facilities. Areas covered: A literature search from 1970-December 2016 found 13 facility-level and 2 patient-level strategies that were evidence-based. The aim of this manuscript is to assess the current state of the literature on primary prevention of CDI and offer insights into which strategies may be more effective. Expert commentary: The strongest evidence for primary prevention is based on multi-faceted infection control bundles, while there is promising moderate evidence involving facility-wide use of specific probiotics. Moderate-level evidence was found for patient-level use of specific probiotics and low level evidence for vaccines. Future suggestions include use of consistent outcome metrics, measurements of implementation compliance and program sustainability. PMID- 28347161 TI - Unravelling the mechanisms behind the persistent gastrointestinal symptoms in celiac disease - how can they lead to better treatment outcomes? PMID- 28347162 TI - Biomarkers in hepatocellular carcinoma: an overview. AB - INTRODUCTION: Current methods for HCC diagnosis have not an optimal diagnostic accuracy. The detection of more than one biomarker seems to improve their individual performance and provide an accurate HCC diagnosis approach. Individual gene expression seems to influence whether or not the treatment is successful, since several molecules have interfere with cancer associated pathways and have been related to poor prognosis which condition the lack of effective treatment options. Areas covered: Novel biomarkers have been proposed as a useful tool in each patient prognosis. This article aims to review the recent evidence based on HCC biomarkers which seems to have a regulative role according to tumor cell development leading to a specific biological response. Epigenetic regulation, miRNAs, and genome sequencing analysis propose molecular expression signatures as novel biomarkers which allowed achieve the major goal for the use of biomarkers in clinical practice. Moreover, a deeper analysis for determine the diagnostic accuracy of biomarkers has been made. Expert commentary: To improve of methodological designs and sample sizes are needed in order to support the role of biomarkers in HCC. Furthermore, is necessary to consider HCC etiologies and all clinic disease context to carried out clinical phase studies to thrust biomarkers application. PMID- 28347163 TI - Mediating role of maternal serum interleukin-1beta and tumor necrosis factor alpha in the association between environmental tobacco smoke exposure in pregnancy and low birth weight at term. AB - OBJECTIVES: To explore the mediation effects of maternal serum interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) on the association between environmental tobacco smoke (ETS) exposure during pregnancy and low birth weight (LBW) at term. METHODS: ETS exposure, birth weight, blood sample and covariates were collected from 195 pregnant women delivered term LBW infants and 195 controls delivered normal birth weight infants in two Maternity and Child Hospitals in Guangdong, China. Maternal serum IL-1beta and TNF-alpha were measured by flow cytometry. Logistic regression models and path analyses explored the mediation effects of maternal IL-1beta and TNF-alpha on the association between ETS exposure and LBW. RESULTS: LBW was significantly associated with maternal ETS exposure (OR = 2.14 (95% CI =1.06-4.32)). TNF-alpha and IL-1beta were significantly associated with both LBW (OR = 1.87 (1.41-2.47) and OR = 1.53 (1.14-2.05)) and ETS (beta = 0.32 (0.04-0.60) and beta = 0.27 (0.05-0.49)). Traditional mediation analyses indicated the separate mediation effect of TNF alpha and IL-1beta was 32.2% and 24.6%, respectively. Path analysis revealed the combined mediation effects of TNF-alpha and IL-1beta as 29.4% in the pathway from ETS exposure to LBW. CONCLUSIONS: Maternal serum IL-1beta and TNF-alpha may play a mediating role in the association between maternal ETS exposure during pregnancy and term LBW. PMID- 28347164 TI - Inflammatory biomarkers for asthma endotyping and consequent personalized therapy. AB - INTRODUCTION: We argue that asthma be considered a syndrome caused by multiple inflammatory pathogenic processes. Bronchial hyperresponsiveness, reversible airflow limitation, and chronic airway inflammation characterize asthma pathophysiology. Personalized Medicine, i.e. a tailored management approach, is appropriate for asthma management and is based on the identification of discrete phenotypes and endotypes. Biomarkers can help define phenotypes and endotypes. Several biomarkers have been described in asthma, but most of them are not commonly available or still need external validation. Areas covered: This review presents useful pragmatic biomarkers available in daily clinical practice for assessing airway inflammation in asthmatic patients. Expert commentary: Eosinophil counts and serum allergen-specific IgE assessments are the most reliable biomarkers. Lung function, mainly concerning FEF25-75, and nasal cytology may be envisaged as ancillary biomarkers in asthma management. In conclusion, biomarkers have a clinical relevance in asthma in identifying asthma endotypes to direct personalized therapy. PMID- 28347165 TI - Synthetic cathinones in Southern Germany - characteristics of users, substance patterns, co-ingestions, and complications. AB - OBJECTIVE: To define the characteristics of synthetic cathinone users admitted to hospital including clinical and laboratory parameters and the complications of use. DESIGN: Retrospective single-center study of patients treated for acute cathinone intoxication and complications of cathinone use between January 2010 and January 2016. SETTING: A specialized clinical toxicology unit at an academic tertiary care center in Southern Germany serving a population of about 4 million. PATIENTS AND METHODS: 81 consecutive patients with laboratory-confirmed use of cathinones who presented for acute intoxication or complications of cathinone use were retrospectively analyzed. RESULTS AND CONCLUSIONS: The patients were predominantly male (64%, 52/81) with a median age of 34 years. 60 were admitted for signs of acute intoxication while 21 suffered from complications of cathinone use. 70% of acutely intoxicated patients had an increased creatinine phosphokinase. Only a minority of patients presented with a sympathomimetic toxidrome. Three patients had infectious complications, 10 prolonged psychosis, 6 rhabdomyolyses and/or kidney failure, and two patients died. Based on presentations, cathinone use has increased with the first cases seen in 2010. Opiates/opioids are the main co-ingested drugs of abuse. The pattern of cathinone use shifted from methylone in 2010/2011 to 3,4-methylenedioxypyrovalerone (MDPV) and 3-methylmethcathinone (3-MMC) in 2014/2015. We conclude that in our setting "typical" cathinone users are males in their thirties. They are seldom drug naive and regularly co-ingest illicit drugs. Preventive measures have to be tailored to these difficult to reach patients. Present efforts to educate young clubbers in their late teens may fail to reach the pertinent demographic. PMID- 28347167 TI - Caragasinin C: a new oligostilbene from the roots of Caragana sinica. AB - A new oligostilbene, caragasinin C (1), and seven known compounds, betulinic acid (2), 4-hydroxybenzaldehyde (3), (-)-medicarpin (4), wistin (5), (2E,4S)-4-hydroxy 2-nonenoic acid (6), pallidol (7), and (+)-alpha-viniferin (8), were isolated from the roots of Caragana sinica. The structure of caragasinin C was established on the basis of spectroscopic techniques, including HRESIMS, 1D and 2D-NMR. PMID- 28347168 TI - Live demonstrations. Addendum to the WFITN ethics charter of 2016. PMID- 28347166 TI - Oleuropein improves glucose tolerance and lipid profile in rats with simultaneous renovascular hypertension and type 2 diabetes. AB - Oleuropein mediates most of the beneficial effects of olive products. This study examined the role of oxidative stress in the effects of oleuropein on lipid profile and blood glucose in rats with simultaneous renovascular hypertension and type 2 diabetes. Eight groups (n = 7-9 each) of male Sprague-Dawley rats including a control, a type 2 diabetic, a renovascular hypertensive, a sham, a simultaneously hypertensive diabetic receiving vehicle, and 3 simultaneously hypertensive-diabetic receiving 20, 40, or 60 mg/kg/day oleuropein were used. Four weeks after treatment, blood glucose, lipid profile, and biomarkers of oxidative stress were measured, and glucose tolerance test (GTT) was performed. Simultaneously hypertensive diabetic rats had significantly higher blood pressure, blood glucose, and serum total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglyceride and malondialdehyde. They also had lower serum high-density lipoprotein cholesterol, erythrocyte superoxide dismutase, and impaired glucose tolerance. Oleuropein significantly reduced blood pressure, blood glucose, and serum total cholesterol, LDL-C, triglyceride and malondoaldehyde. It also increased serum high-density lipoprotein cholesterol, erythrocyte superoxide dismutase, and improved glucose tolerance. The findings show that the model is associated with impaired glucose tolerance, and adverse lipid profile. They also show that oleuropein, partly by an antioxidant mechanism, improves glucose tolerance and changed lipid profile favorably. PMID- 28347169 TI - Three new areca alkaloids from the nuts of Areca catechu. AB - Three new areca alkaloids arecatemines A-C (1-3), together with five known ones (4-8), were isolated from the nuts of Areca catechu. The structures of new compounds including absolute configurations were elucidated using comprehensive spectroscopic and electronic circular dichroism (ECD). The known compounds were identified by comparing with data in the literature. PMID- 28347170 TI - Stress distribution in cylindrical and conical implants under rotational micromovement with different boundary conditions and bone properties: 3-D FEA. AB - Factors related to micromovements at bone-implant interface have been studied because they are considered adverse to osseointegration. Simplifications are commonly observed in these FEA evaluations. The aim of this study was to clarify the influence of FEA parameters (boundary conditions and bone properties) on the stress distribution in peri-implant bone tissue when micromovements are simulated in implants with different geometries. Three-dimensional models of an anterior section of the jaw with cylindrical or conical titanium implants (4.1 mm in width and 11 mm in length) were created. Micromovement (50, 150, or 250 MUm) was applied to the implant. The FEA parameters studied were linear vs. non-linear analyses, isotropic vs. orthogonal anisotropic bone, friction coefficient (0.3) vs. frictionless bone-implant contact. Data from von Mises, shear, maximum, and minimum principal stresses in the peri-implant bone tissue were compared. Linear analyses presented a relevant increase of the stress values, regardless of the bone properties. Frictionless contact reduced the stress values in non-linear analysis. Isotropic bone presented lower stress than orthogonal anisotropic. Conical implants behave better, in regard to compressive stresses (minimum principal), than cylindrical ones, except for nonlinear analyses when micromovement of 150 and 250 MUm were simulated. The stress values raised as the micromovement amplitude increased. Non-linear analysis, presence of frictional contact and orthogonal anisotropic bone, evaluated through maximum and minimum principal stress should be used as FEA parameters for implant-micromovement studies. PMID- 28347171 TI - A simple, reliable method to determine the mean gait speed using heel markers on a treadmill. AB - Gait speed is an essential parameter of gait analysis. Our study proposed a simple and accurate method to extract a mean gait speed during walking on a treadmill using only kinematic data from markers placed on the heels of the participants' feet. This method provided an attractive, simple method that remains resistant to errors in treadmill calibration. In addition, this method required only two markers, since heel markers are essential to gait analysis, and the proposed method is robust enough to differentiate among various gait speeds (mean error <1%). PMID- 28347172 TI - Ultrastructural changes in Raillietina (Platyhelminthes: cestoda), exposed to sulfonoquinovosyldiacylglyceride (SQDG), isolated from Neem (Azadirachta indica). AB - Neem (Azadirachta indica), has been known to be a curative for various ailments and diseases in the traditional Indian medicinal system from times immemorial. A glycolipid sulfonoquinovosyldiacylglyceride (SQDG) isolated from the leaves of neem has been found to be a proactive antibacterial and antiviral agent in previous studies. The current communication pertains to the anthelmintic activity of SQDG in vitro against a model cestode Raillietina spp. The results of efficacy tests showed a paralysis time of 1.0 +/- 0.1 and 0.7 +/- 0.01 h, whereas death time of 1.6 +/- 0.3 and 0.9 +/- 0.02 h, following treatments with dosages of 0.5 and 1.0 mg/mL, respectively. The scanning electron microscopic studies showed significant and unique changes in the ultrastructure of the worms with prominent breakages and furrows on the surface. PMID- 28347173 TI - Self-Reported Outcomes for Patients Undergoing Revision Carpal Tunnel Surgery With or Without Hypothenar Fat Pad Transposition. AB - BACKGROUND: Carpal tunnel surgery is the most common surgical procedure performed on the hand. Although complications are rare, recurrent or persistent carpal tunnel syndrome can be a significant problem after primary decompression. Various procedures have been described for the treatment of these patients including repeat decompression and hypothenar fat pad transposition. The purpose of this study is to compare the outcomes of patients undergoing revision carpal tunnel decompression with and without hypothenar fat pad transposition. METHODS: We performed a retrospective review of all patients undergoing revision carpal tunnel surgery at our institution between 2002 and 2014. Identified patients were contacted by telephone. A Boston Carpal Tunnel Questionnaire (BCTQ) was administered to all participants. RESULTS: Seventy-six patients underwent revision carpal tunnel surgery over the study period. Twenty-nine of 45 potential participants provided a survey response (64.9%) representing a total of 33 carpal tunnel revision surgeries. Seventeen hands underwent repeat decompression alone, and 16 hands underwent repeat decompression with hypothenar fat pad transposition. A trend toward improved overall BCTQ score was noted for patients undergoing decompression alone; however, no significant difference was determined for total survey score by procedure type. Similarly, total symptom severity and functional scores were not statistically significant between groups; however, a trend toward significance for improved symptom severity score was observed in patients undergoing decompression alone. CONCLUSIONS: Our results reveal no difference in self-reported symptom severity and functional scores between patients undergoing revision carpal tunnel surgery with repeat decompression alone or decompression with fat pad transposition. PMID- 28347174 TI - Autophagy as a target for development of anti-diabetes drugs derived from natural compounds. AB - Patients with diabetes have a high level of blood glucose because their body cannot produce enough insulin or properly respond to this hormone. In both situations, it has become evident that persistent high concentrations of glucose, insulin, insulin-like growth factor, and insulin resistance lead to dysfunction and destruction of autophagic activity in the cells of islet and other organs involved in complications of diabetes, including the liver, cardiovascular, and nervous systems. Accumulating evidences have revealed that autophagy is a novel therapeutic target with a wide range of beneficial effects on diabetes and that plenty of drugs and natural products are involved in autophagy modulation, either inducing or inhibiting autophagy, through multiple signaling pathways. In this review, we summarize the roles of several clinical drugs and compounds derived from natural products in diabetes and its complications through regulation of autophagy, expecting to inspire further investigation of the underlying mechanisms of these compounds and to facilitate their better clinical application. PMID- 28347175 TI - Bioactive capacity of some Romanian wild edible mushrooms consumed mainly by local communities. AB - Wild edible mushrooms are considered as a cheap food source, but rich in bioactive compounds, especially in phenolic compounds. The purpose of the study was to determine the antioxidant and antimicrobial activity and the content of polyphenolcarboxylic acids in 10 species of mushrooms commonly used (consumed) in Romania and two controls. The effect against free radicals, lipid peroxidation and reducing power were determined. The antimicrobial effect was revealed on some strains with pathogenic effect by disk diffusion assay. The antioxidant capacity expressed in vitro was correlated both with the presence of the main polyphenolcarboxylic acids, and also with the presence of other bioactive molecules (flavonoids, carotenoid compounds, etc.). PMID- 28347177 TI - New mechanistic insights into the motile-to-sessile switch in various bacteria with particular emphasis on Bacillus subtilis and Pseudomonas aeruginosa: a review. AB - A biofilm is a complex assemblage of microbial communities adhered to a biotic or an abiotic surface which is embedded within a self-produced matrix of extracellular polymeric substances. Many transcriptional regulators play a role in triggering a motile-sessile switch and in consequently producing the biofilm matrix. This review is aimed at highlighting the role of two nucleotide signaling molecules (c-di-GMP and c-di-AMP), toxin antitoxin modules and a novel transcriptional regulator BolA in biofilm formation in various bacteria. In addition, it highlights the common themes that have appeared in recent research regarding the key regulatory components and signal transduction pathways that help Bacillus subtilis and Pseudomonas aeruginosa to acquire the biofilm mode of life. PMID- 28347178 TI - Current Evidence Regarding Routine Antibiotic Prophylaxis in Hand Surgery. AB - BACKGROUND: Although routine antibiotic prophylaxis immediately preceding an orthopedic surgery has become the standard of care in most cases, this practice is poorly defined in hand surgery. The purpose of this analysis is to review the most current literature of antibiotic use in hand surgery. METHODS: A careful review of the literature regarding routine antibiotic prophylaxis in hand surgery was made. Current relevant resources were used in the construction of this review. RESULTS: There is a mixed consensus on the role for prophylactic antibiotics in hand surgery with some resources and data showing support and others opposed. CONCLUSIONS: Based on the current literature, the authors recommend the following patient characteristics not receive antibiotics: clean hygienic patients, without autoimmune disease, and those not taking steroid medication. Surgical characteristics that would render prophylaxis unnecessary include those without hardware, those without reasonable risk of hematoma formation, or those performed at an ambulatory surgery center as opposed to a large hospital. However, the decision should be made on a case-by-case basis weighing the evidence presented. PMID- 28347179 TI - A Sphingosine-type cerebroside in Clavicorona pyxidata induce fruit body formation. AB - Clavicorona pyxidata is a wild edible and medicinal mushroom that is rich in bioactive natural products and has thus been extensively used as traditional medicine in China. The present study has determined that the organic crude extract prepared from a fermented culture of C. pyxidata imparted auto-inhibitory effects on mycelial growth and then induced the formation of fruiting bodies. By monitoring bioactivity, one compound was isolated via successive chromatography over silica gel, Sephadex LH-20, and Cl8-reversed phase silica gel and was identified as a known sphingosine-type cerebroside by nuclear magnetic resonance (NMR) and physicochemical data, namely, (4E, 8E)-N-D-2'-hydroxypalmitoyl-1-O-beta D-glucopyranosyl-9-methyl-4,8-sphingadienine. The application of this cerebroside at a concentration of 200 MUg/disc paper resulted in the inhibition of aerial hyphal growth of C. pyxidata. The findings of the present study indicated that this C. pyxidata cerebroside is a fruiting body-inducing substance (FIS). PMID- 28347180 TI - Seeking new anti-cancer agents from autophagy-regulating natural products. AB - Natural products are an important original source of many widely used drugs, including anti-cancer drugs. Early research efforts for seeking anti-cancer therapy from the natural products are mainly focused on the compounds with cytotoxicity capability. The good examples include vinblastine, vincristine, the camptothecin derivatives; topotecan, irinotecan, epipodophyllotoxin derivatives and paclitaxel. In a recent decade, the fundamental progression has been made in the understanding of molecular and cellular mechanisms regarding tumor initiation, metastasis, therapeutic resistance, immune escape, and relapse, which provide a great opportunity for the development of new mechanism-based anticancer drugs, especially drugs against new molecular and cellular targets. Autophagy, a critical cell homeostasis mechanism and promising drug target involved in a verity of human diseases including cancer, can be modulated by many compounds derived from natural products. In this review, we'll give a short introduction of autophagy and discuss the roles of autophagy in the tumorigenesis and progression. And then, we summarize the accumulated evidences to show the anti tumor effects of several compounds derived from natural products through modulation of autophagy activity. PMID- 28347181 TI - Verification of key odorants in rose oil by gas chromatography-olfactometry/aroma extract dilution analysis, odour activity value and aroma recombination. AB - Rose oil is much too expensive but very popular. It's well known that the flower oil's aroma profile hasn't been intensively investigated. In order to verify the aroma profile of rose oil, the synthetic blend of odorants was prepared and then compared with the original rose oil using electronic nose analysis (ENA) combined with quantitative descriptive analysis (QDA). The odorants from rose oils were screened out by Gas Chromatography-Olfactometry/aroma extract dilution analysis (GC-O/AEDA) combined with odour activity value (OAV). Both ENA and QDA indicated the recombination model derived from OAV and GC-O/AEDA closely resembled the original rose oil. The experiment results show that rose oxide, linalool, alpha pinene, beta-pinene, nonanal, heptanal citronellal, phenyl ethyl alcohol, benzyl alcohol, eugenol, methyl eugenol, beta-citronellol, hexyl acetate, beta-ionone, nerol, etc. are very important constituent to rose oil aroma profile. PMID- 28347182 TI - The experience of voice hearing and the role of self-help group: An interpretative phenomenological analysis. AB - BACKGROUND: Auditory verbal hallucinations (AVHs) played an important role in the psychiatric diagnostics, but in the last few decades the diagnostic-free complex phenomenological understanding of the phenomena of voice hearing became the focus of studies. MATERIALS: Six semi-structured interviews with recovering voice hearers were conducted and analysed using interpretative phenomenological analysis (IPA). DISCUSSION: The self-help group gives significant help in identification and dealing with the voices; therefore, it serves as turning point in the life story of voice hearers. CONCLUSION: Applying self-help group in clinical context contributes to better outcomes in treatment of voice hearers. PMID- 28347183 TI - The role of perceived social support after psychiatric hospitalisation: Post hoc analysis of a randomised controlled trial testing the effectiveness of a transitional intervention. AB - BACKGROUND: The association between social support, readmissions and psychopathology following discharge from psychiatric hospitals is not clear. AIMS: To examine the prospective effects of perceived social support on rehospitalisation rates and psychopathology and to focus on the moderators of a transitional intervention. METHOD: This post hoc analysis of a multisite randomised controlled trial included 151 patients with no more than three hospitalisations within the last 3 years, a Global Assessment of Functioning (GAF) score <=60 and aged 18-64 years, assessed at two psychiatric hospitals from Zurich, Switzerland, between September 2011 and February 2014. Participants received either a transitional intervention aimed at improving social support during the transition from inpatient to outpatient care provided by a social worker or treatment as usual. RESULTS: Lack of perceived social support at discharge significantly predicted subsequent rehospitalisation rates and increased psychopathological impairment across 12-month follow-up. Significant interaction effects between patient characteristics and the intervention on perceived social support comprised living at parent's home, having no children and being of younger age. CONCLUSION: Perceived social support at discharge from inpatient care may reduce rehospitalisation rates and psychopathological impairment in the long term. A transitional intervention aimed at improving social support may negatively impact on the perceived social support in some patient groups. PMID- 28347184 TI - Effects of testosterone replacement therapy on hypogonadal men with osteopenia or osteoporosis: a subanalysis of a prospective randomized controlled study in Japan (EARTH study). AB - OBJECTIVE: We investigated the effects of testosterone replacement therapy (TRT) on bone mineral density (BMD) among hypogonadal men with osteopenia/osteoporosis. METHODS: From our previous EARTH study population, 74 patients with a clinical diagnosis of osteopenia or osteoporosis and hypogonadism were included in this study, as the TRT (n = 35) and control (n = 34) groups. The TRT group was administered 250 mg of testosterone enanthate injection every 4 weeks for 12 months. The BMD, waist circumference, body mass index, body fat percentage, and muscle volume were measured at baseline and at 12 months. Blood biochemical data, including total cholesterol, triglycerides, HDL-cholesterol, hemoglobin A1c, and adiponectin values were also evaluated. RESULTS: At the 12-month visit, BMD significantly increased in both groups. However, comparisons on changes of parameter values from baseline to the 12-month visit between the TRT and control groups were significantly different in BMD (5.0 +/- 5.0 vs. 3.0 +/- 3.2; p = .0434) and in adiponectin value (-0.90 +/- 3.33 vs. 0.10 +/- 2.04; p = .0192). There were no significant changes in other parameters. CONCLUSIONS: TRT for 12 months could improve BMD with a decrease in adiponectin levels among hypogonadal men with osteopenia/osteoporosis. PMID- 28347186 TI - Aryl Hydrocarbon Receptor Deficiency Alters Circadian and Metabolic Rhythmicity. AB - PAS domain-containing proteins can act as environmental sensors that capture external stimuli to allow coordination of organismal physiology with the outside world. These proteins permit diverse ligand binding and heterodimeric partnership, allowing for varied combinations of PAS-dependent protein-protein interactions and promoting crosstalk among signaling pathways. Previous studies report crosstalk between circadian clock proteins and the aryl hydrocarbon receptor (AhR). Activated AhR forms a heterodimer with the circadian clock protein Bmal1 and thereby functionally inhibits CLOCK/Bmal1 activity. If physiological activation of AhR through naturally occurring, endogenous ligands inhibits clock function, it seems plausible to hypothesize that decreased AhR expression releases AhR-induced inhibition of circadian rhythms. Because both AhR and the clock are important regulators of glucose metabolism, it follows that decreased AhR will also alter metabolic function. To test this hypothesis, rhythms of behavior, metabolic outputs, and circadian and metabolic gene expression were measured in AhR-deficient mice. Genetic depletion of AhR enhanced behavioral responses to changes in the light-dark cycle, increased rhythmic amplitude of circadian clock genes in the liver, and altered rhythms of glucose and insulin. This study provides evidence of AhR-induced inhibition that influences circadian rhythm amplitude. PMID- 28347185 TI - Chemical composition and biological activities of Helicteres vegae and Heliopsis sinaloensis. AB - CONTEXT: Helicteres vegae Cristobal (Sterculiaceae) (Hv) and Heliopsis sinaloensis B.L. Turner (Asteraceae) (Hs) are endangered and poorly studied plant species; related plants have been used against chronic-degenerative and infectious diseases. Therefore, Hv and Hs could be sources of bioactive compounds against these illnesses. OBJECTIVE: To determine the chemical composition and biological activities (antioxidant, antimutagenic and antimicrobial) of Hv and Hs leaves (L) and stems (S). MATERIALS AND METHODS: Methanol extracts (ME) of each plant/tissue were evaluated for their phytochemicals; phenolics (HPLC-DAD-ESI MS); antioxidant activity (AA) (0.125-4 mg/mL) (DPPH, ABTS, ORAC and beta carotene discoloration); antimutagenicity (0.5 and 1 mg/plate) (Ames assay, tester strain Salmonella enterica serovar Typhimurium YG1024, 1-nitropyrene as mutagen); activity against human pathogens (1 mg/mL); and toxicity (0.01-2 mg/mL) (Artemia salina assay). RESULTS: All ME showed flavonoids and triterpenes/steroids. The ME-SHv had the highest content of total phenolics (TP) (2245.82 +/- 21.45 mg GAE/100 g d.w.) and condensed tannins (603.71 +/- 1.115 mg CE/100 g d.w.). The compounds identified were flavonoids (kaempferol 7-O coumaroylhexoside, and two kaempferol 7-O-rhamnosylhexosides) and phenolics [rosmarinic acid, and 3'-O-(8"-Z-caffeoyl) rosmarinic acid]. The ME-LHs showed the highest content of flavonoids (357.88 mg RE/g d.w.) and phenolic acids (238.58 mg CAE/g d.w.) by HPLC. The ME-SHv showed the highest AA. All ME were strong antimutagens (63.3-85.7%). Only the Hs extracts were toxic (ME-LHs, LC50 = 94.9 +/- 1.7 MUg/mL; ME-SHs, LC50 = 89.03 +/- 4.42 MUg/mL). DISCUSSION AND CONCLUSIONS: Both Hv and Hs are potential sources of preventive and therapeutic agents against chronic-degenerative diseases. PMID- 28347187 TI - Second-trimester amniotic fluid corticotropin-releasing hormone and urocortin in relation to maternal stress and fetal growth in human pregnancy. AB - This study explored the association between the acute psychobiological stress response, chronic social overload and amniotic fluid corticotropin-releasing hormone (CRH) and urocortin (UCN) in 34 healthy, second-trimester pregnant women undergoing amniocentesis. The study further examined the predictive value of second-trimester amniotic fluid CRH and UCN for fetal growth and neonatal birth outcome. The amniocentesis served as a naturalistic stressor, during which maternal state anxiety and salivary cortisol was measured repeatedly and an aliquot of amniotic fluid was collected. The pregnant women additionally completed a questionnaire on chronic social overload. Fetal growth parameters were obtained at amniocentesis using fetal ultrasound biometry and at birth from medical records. The statistical analyzes revealed that the acute maternal psychobiological stress response was unassociated with the amniotic fluid peptides, but that maternal chronic overload and amniotic CRH were positively correlated. Moreover, amniotic CRH was negatively associated with fetal size at amniocentesis and positively with growth in size from amniocentesis to birth. Hardly any studies have previously explored whether acute maternal psychological stress influences fetoplacental CRH or UCN levels significantly. Our findings suggest that (i) chronic, but not acute maternal stress may affect fetoplacental CRH secretion and that (ii) CRH is complexly involved in fetal growth processes as previously shown in animals. PMID- 28347189 TI - Arylamine N-acetyltransferase 2 gene polymorphism in an Algerian population. AB - BACKGROUND: The arylamine N-acetyltransferase 2 (NAT2) is a key enzyme in the biotransformation of xenobiotics. NAT2 gene polymorphisms have been associated with the risk of isoniazid hepatotoxicity and these polymorphisms change among different populations. AIM: The objective of this study is to investigate NAT2 polymorphisms in order to predict the prevalence of NAT2 phenotype in an Algerian population. SUBJECTS AND METHODS: Genotyping of NAT2 was done using a PCR-RFLP method. Haplotype was analysed using the software package PHASE, version 2.0. RESULTS: The major haplotypes were NAT2*5B (23.72%), NAT2*6 A (18.61%), NAT2*4 (14.60%) and NAT2*5 F (10%). The average of the expected slow acetylator phenotype was 53%. CONCLUSION: Our results suggest that the high frequency of slow acetylator phenotype requires investigation into its possible association with ATDH. PMID- 28347188 TI - Circadian Misalignment Increases C-Reactive Protein and Blood Pressure in Chronic Shift Workers. AB - Shift work is a risk factor for inflammation, hypertension, and cardiovascular disease. This increased risk cannot be fully explained by classical risk factors. Shift workers' behavioral and environmental cycles are typically misaligned relative to their endogenous circadian system. However, there is little information on the impact of acute circadian misalignment on cardiovascular disease risk in shift workers, independent of differences in work stress, food quality, and other factors that are likely to differ between night and day shifts. Thus, our objectives were to determine the independent effect of circadian misalignment on 24-h high-sensitivity C-reactive protein (hs-CRP; a marker of systemic inflammation) and blood pressure levels-cardiovascular disease risk factors-in chronic shift workers. Chronic shift workers undertook two 3-day laboratory protocols that simulated night work, comprising 12-hour inverted behavioral and environmental cycles (circadian misalignment) or simulated day work (circadian alignment), using a randomized, crossover design. Circadian misalignment increased 24-h hs-CRP by 11% ( p < 0.0001). Circadian misalignment increased 24-h systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 1.4 mmHg and 0.8 mmHg, respectively (both p <= 0.038). The misalignment mediated increase in 24-h SBP was primarily explained by an increase in SBP during the wake period (+1.7 mmHg; p = 0.017), whereas the misalignment-mediated increase in 24-h DBP was primarily explained by an increase in DBP during the sleep opportunity (+1.8 mmHg; p = 0.005). Circadian misalignment per se increases hs-CRP and blood pressure in shift workers. This may help explain the increased inflammation, hypertension, and cardiovascular disease risk in shift workers. PMID- 28347190 TI - Anti-inflammatory activity of standardized dichloromethane extract of Salvia connivens on macrophages stimulated by LPS. AB - CONTEXT: A previous study demonstrated that the chloroform extract of Salvia connivens Epling (Lamiaceae) has anti-inflammatory activity. OBJECTIVE: Identification of the active components in the dicholorometane extract (DESC), and, standardization of the extract based in ursolic acid. MATERIAL AND METHODS: DESC was prepared by percolation with dichlromethane and after washed with hot hexane, its composition was determined by CG-MS and NMR, and standardized by HPLC. The anti-inflammatory activity was tested on acute TPA-induced mouse ear oedema at doses of 2.0 mg/ear. The cell viability of macrophages was evaluated by MTT method, and pro- and anti-inflammatory interleukin levels were measured using an ELISA kit. RESULTS: Ursolic acid, oleanolic acid, dihydroursolic acid and eupatorin were identified in DESC, which was standardized based on the ursolic acid concentration (126 mg/g). The anti-inflammatory activities of DESC, the acid mixture, and eupatorin (2 mg/ear) were 60.55, 57.20 and 56.40% inhibition, respectively, on TPA-induced ear oedema. The IC50 of DESC on macrophages was 149.4 MUg/mL. DESC (25 MUg/mL) significantly reduced TNF-alpha (2.0-fold), IL 1beta (2.2-fold) and IL-6 (2.0-fold) in macrophages stimulated with LPS and increased the production of IL-10 (1.9-fold). DISCUSSION: Inflammation is a basic response to injuries, and macrophages are involved in triggering inflammation. Macrophage cells exhibit a response to LPS, inducing inflammatory mediators, and DESC inhibits the biosynthesis of the pro-inflammatory and promote anti inflammatory cytokines. CONCLUSION: DESC has an anti-inflammatory effect; reduced the levels of IL-1beta, Il-6 and TNF-alpha; and increases IL-10 in macrophages stimulated with LPS. Ursolic acid is a good phytochemical marker. PMID- 28347191 TI - Transferring two grades I cleavage-stage embryo might not be a good protocol. AB - PURPOSE: The aim of this study was to explore whether transferring two grades I cleavage-stage embryo was suitable for the patients in the first fresh transfer. METHODS: This study included 202 single grades I cleavage-stage, 229 single grades III cleavage-stage, 743 single excellent blastocyst, 522 double grades I cleavage-stage, and 596 double grades III cleavage-stage embryo transfers. Main clinical outcomes: clinical pregnancy and twin-pregnancy rate. RESULTS: Among single excellent blastocyst, single grades I and single grades III group, the clinical pregnancy rate was significantly higher in single excellent blastocyst group than single grades I and grades III group (67.16% versus 42.08% versus 23.97%; p < 0.001). When transferred double grades I cleavage-stage embryos, the clinical pregnancy rate reached 68.20% which was no significant difference compared with the single excellent blastocyst group (67.16%). However, the twin pregnancy rate was significantly higher in double grades I group than double grades III and single excellent blastocyst group (43.26% versus 26.70% versus 0.60%; p < 0.001). CONCLUSIONS: Because of higher twin-pregnancy incidence rate, transferring two grades I cleavage-stage embryo might not be a good protocol. Extended culture to blastocyst-stage could be considered for the patient with only two grades I cleavage-stage embryos. PMID- 28347192 TI - A review of recent developments on micro/nanostructured pharmaceutical systems for intravesical therapy of the bladder cancer. AB - Bladder cancer (BC) is the most common tumor type of genitourinary tract, which affects more men than women. The conventional treatment is through chemotherapy or immunotherapy, but the radiotherapy and surgery may be necessary in cases of invasive cancer. The search for less invasive, safe and effective therapies has attracted researchers to the development of new drug delivery systems to carry drugs to be administered by catheter into the bladder. The research on intravesical systems for the BC treatment continues at a rapid pace and a variety of micro or nanostructured systems have been used. Micro/nanoparticles, liposomes, micelles, carbon nanotubes, hydrogels and nanogels can contribute to reduce the number of intravesical administrations due to the extended drug release as well as to reduce the adverse effects and to increase the patient adherence to the treatment. Thus, this article reviews relevant studies regarding these systems, which have shown promising perspectives for the treatment of BC. It is hoped that in a near future they can prove to be safe and efficient to benefit patients with BC. PMID- 28347193 TI - Placebo prescription and empathy of the physician: A cross-sectional study. AB - BACKGROUND: Empathy in the patient-physician relationship is a major component in an effective placebo treatment, as in every medical treatment. Understanding the role of empathy of the physician in the placebo effect may help dissect some of the context variables responsible for the effectiveness of the placebo. OBJECTIVES: To determine the frequency of placebo prescription, doctors' beliefs, motivation, and attitudes to placebos in general practice in northern Portugal and to test the association between placebo prescription and physician empathy. METHODS: A cross-sectional study was conducted between November 2014 and January 2015 among general practice specialists and interns from 14 health centres in a northern Portuguese health region. The self-report questionnaire included the Portuguese version of the Jefferson scale of physician empathy (JSPE) and a questionnaire about placebo prescription. Associations between demographic variables, JSPE score, prescription of placebo, and the attitudes to placebo score were tested with the chi-squared statistic, student t-tests for independent samples, and Pearson correlation. RESULTS: The study included 93 general practitioners (GP) (response rate: 74%). Placebos were prescribed by 73% (n = 68) of the respondents. GPs who prescribe placebo are significantly younger (mean age = 38.4 years; SD = 11.1; t (90) = 2.98, P <.05, d = 0.67) than non-prescribers (mean age =46.5 years; SD =13.3). Favourable attitudes towards placebo prescription are associated with higher empathy scores (R = 0.310, P <.01). CONCLUSION: Placebo prescription is frequent and associated with empathy from the prescriber, especially among younger GPs. PMID- 28347195 TI - Endometriosis doubles the risk of sexual dysfunction: a cross-sectional study in a large amount of patients. AB - INTRODUCTION: Endometriosis affects several aspects of a woman's life, including sexual function, but which specific aspects of sexual function remains unclear. METHODS: A cross-sectional study was performed involving 1001 women divided into two groups, according to the presence or absence of endometriosis. We assessed sexual function, anxiety and depression of patients and correlated these findings with symptoms, locations and types of endometriosis and the affected domains of sexual function. Eighteen completed the forms incorrectly, 294 women (29.9%) were excluded due to severe anxiety and depression. One hundred and six patients had symptoms that could have any relation to endometriosis, so they were also excluded. The final cohort was composed of 254 patients with endometriosis and 329 patients without the disease. Sexual function score was assessed using the female sexual quotient (FSQ); Beck inventories were used to assess anxiety and depression. RESULTS: Patients with endometriosis were affected in all phases of sexual response: desire, sexual arousal, genital-pelvic pain/ penetration and orgasm/ sexual satisfaction. In the overall assessment, 43.3% of patients with endometriosis had sexual dysfunction, while the population without endometriosis sexual dysfunction occurred in 17.6% of women. CONCLUSIONS: Patients with endometriosis have more than twice sexual dysfunctions as compared to women without the disease. PMID- 28347194 TI - The Q192R polymorphism of the paraoxonase-1 (PON1) gene is associated with susceptibility to gestational diabetes mellitus in the Greek population. AB - A key factor protecting from oxidative stress in gestational diabetes mellitus (GDM) and in type 2 diabetes (T2D) is paraoxonase-1 (PON1). Inconclusive and limited data exist regarding the effect of a coding polymorphism (Q192R) of the PON1 gene in conferring susceptibility to both states. In the present study, we investigated the association between the PON1 gene and the risk for GDM in the Greek population and assessed for the first time its transcriptional efficiency. We studied 185 women with GDM and 104 non-diabetic controls for the PON1 polymorphism. For PON1 mRNA expression, peripheral leucocytes were harvested from 20 GDM and 20 control women, harboring different genotypes for the polymorphism, using real-time quantitative PCR. The RR genotype and the R allele of the PON1 Q192R polymorphism were significantly associated with an increased risk for GDM (p = 0.012 and p < 0.0001, respectively). Furthermore, there was no statistical correlation between the individual metabolic parameters tested and the three genotypes. Finally, the expression levels of PON1 mRNA in GDM patients did not exhibit any statistical difference compared with normal controls (p = 0.138). These data independently document that the Q192R polymorphism is closely associated with GDM susceptibility, while the PON1 gene expression is not impaired in GDM. PMID- 28347196 TI - Distribution of Subchondral Bone Puncture Strength in the Talus and Tibial Plafond: A Biomechanical Study. AB - : We investigated talus and tibial plafond subchondral bone puncture strength based on surface location. Puncture tests of the subchondral bone were performed in 9 equal zones on the articular surface of 12 cadaver specimens aged 49.1 years (range, 36-56 years). Compressive load was applied through a microfracture awl at 2 mm/min. Puncture strength was defined as the first load drop in load-deflection curves. In the talus, zone 1 (215 +/- 91 N) and zone 2, the anterior medial and anterior middle zones, had significantly greater puncture strength than zones 7, 8, and 9, the posterior medial, middle, and lateral zones (104 +/- 43 N, 115 +/- 43 N, and 102 +/- 35 N, respectively; P < .001). In the tibial plafond, zone 3, the anterior-lateral zone, and zone 7, the posterior medial zone, had significantly greater strength than zone 8, the posterior middle zone (202 +/- 72 N, 206 +/- 121 N, and 112 +/- 65 N, respectively; P < .001) These results suggest that the subchondral bone is significantly weaker to penetrative force in the posterior region than in the anterior region of the talar dome and of the tibial plafond. These findings may have implications for microfracture awl design and for understanding the complex anatomy and physiology of the ankle joint. LEVELS OF EVIDENCE: Controlled laboratory study. PMID- 28347197 TI - Forty to fifty-five-year-old women and iron deficiency: clinical considerations and quality of life. AB - Between the age of 40 and 55 years, women experience important changes in their lives. This period, which corresponds to the perimenopause for most women, is associated with the risk of iron deficiency anemia (IDA). The clinical presentation of anemia can be misleading, and the underlying cause, particularly bleeding, is frequently treated without concomitant iron prescription. Iron deficiency (ID) remains a social and economic burden in European countries. Underdiagnosed and undertreated, this problem has a strong negative impact on women's quality of life. The risk factors for ID are well known. The physician's role is essential in recognizing the symptoms, identifying the risk factors, detecting IDA by testing hemoglobin, and evaluating the degree of ID by measuring serum ferritin (SF). Iron therapy treats the anemia and restores iron stores, thus decreasing symptoms such as fatigue and restoring quality of life. Among the available forms of iron, evidence is in favor of ferrous sulfate in a slow release formulation, which is well-tolerated and results in good adherence, a key factor for efficacious supplementation. PMID- 28347198 TI - Endomyometritis after cesarean delivery in the era of antibiotic prophylaxis: incidence and risk factors. AB - PURPOSE: To identify the rate of postpartum endomyometritis (PPE) after cesarean delivery (CD) in the era of antibiotic prophylaxis and determine risk factors. METHODS: A single institution retrospective study was performed in women undergoing CD. Data regarding obstetrical and surgical variables were collected. Diagnosis of PPE was made clinically. RESULTS: Among 2419 patients, the rate of PPE was 1.6% (n = 38) and was associated with lower age (27.0 versus 31.0; p < .001). 65.7% of patients having chorioamnionitits developed PPE, but only 5.4% of patients without PPE had chorioamnionitis (p < .001). On multivariate analysis, PPE was higher in emergent versus scheduled CD (OR: 5.89; p = .0081). There was no difference in PPE for cefazolin 2 g versus 1 g (OR: 1.91; p = .17) or 3 g versus 1 g (OR: 3.69; p = .29), gentamicin/clindamycin versus cefazolin (OR: 5.60; p < .001) had higher PPE. Women with PPE were more likely to have labor arrest (OR: 4.336; p = .001), sexually transmitted infection during the pregnancy (OR: 4.197; p = .02) or blood transfusion (OR: 9.50; p < .0001). CONCLUSIONS: While the overall rate of PPE was low, several risk factors were identified. Preoperative diagnosis of chorioamnionitits is associated with a higher rate of PPE. Further studies are needed to identify optimal regimens for antimicrobial prophylaxis in women undergoing CD. PMID- 28347199 TI - The use of cellular and molecular biomarkers to manage COPD exacerbations. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) exacerbations are a common cause of respiratory morbidity and mortality, and have various etiologies. Multiple cellular and molecular biomarkers have been associated with exacerbations. Quantitative sputum cell counts are able to identify the presence and type of bronchitis, which is an important contributor to exacerbations. Their utility to monitor bronchitis and to help treat exacerbations has been evaluated, yet they are not used in routine clinical practice. Areas covered: This review will provide a brief summary of biomarkers utilized in COPD, with a focus on the application of cellular markers for the management of exacerbations. A case study will demonstrate the application of these methods. With quantitative sputum cell counts, the presence of eosinophilic bronchitis predicts corticosteroid responsiveness, while neutrophilic bronchitis identifies infection and suggests the need for antibiotics. Gastroesophageal reflux-related aspiration and heart failure can also be identified by examining sputum. Expert commentary: Quantitative sputum cytometry is an essential tool in the management of exacerbations of COPD, particularly those prone to frequent exacerbations. Treatment based on sputum cell counts is superior to current guideline-based recommendations to prevent future exacerbations and hospitalizations in observational and single-centre controlled trials. Large multicentre clinical trials are necessary to confirm this. PMID- 28347200 TI - Personality type influence the gestational weight gain. AB - Pregnancy is frequently followed by the development of obesity. Aside from psychological factors, hormonal changes influence weight gain in pregnant women. We attempted to assess the potential association between personality type and the extent of gestational weight gain. The study group involved 773 women after term delivery (age 26.3 +/- 3.9 years, body mass before pregnancy 61.2 +/- 11.1 kg). Weight gain during pregnancy was calculated by using self-reported body mass prior to and during the 38th week of pregnancy. Personality type was assessed using the Polish version of the Framingham Type A Behavior Patterns Questionnaire (adapted by Juczynski). Two hundred forty-six (31.8%) study subjects represented type A personalities, 272 (35.2%) type B and 255 (33.0%) an indirect type. Gestational weight gain was related to the behavior patterns questionnaire score and age. In women <30 years with type A personality, the weight gain was higher than in women with type B behavior of the same age. In women >30, the gestational weight gain was larger for type B personalities. Type A personality and increased urgency in younger pregnant women increases the risk of developing obesity during pregnancy in women below 30 years old. A higher level of competitiveness demonstrates a risk factor of excessive weight gain during pregnancy regardless of age. PMID- 28347201 TI - The relationship between the helicobacter pylori seropositivity with systemic and local oxidative status and hyperemesis gravidarum: a pilot study. AB - OBJECTIVES: The aim of study was to determine the helicobacter pylori (HP) seropositivity and oxidative parameters in serum and saliva of pregnant women with poor oral hygiene and hyperemesis gravidarum (HG). METHODS: A case-control study was conducted involving 50 pregnant women in their first trimester of pregnancy. Twenty-five subjects had a diagnosis of HG, and remaining 25 were healthy pregnant women who served as control subjects were included. The groups were adjusted for age, parity and gestational week. All patients were subjected to the measurement of total oxidant status (TOS) and total antioxidant status in serum and saliva. Also HP seropositivity was investigated. RESULTS: Serum TAS and TOS values were similar, although oxidative burden in saliva of women with HG were significantly higher than controls. HP seropositivity was found to be 24% in women with HG and 4% of controls. CONCLUSIONS: Our results suggest that significantly increased oxidative burden and slightly decreased antioxidative capacity of saliva may be involved in the pathogenesis of HG and this condition may be the result of HP infection which was found to be significantly more common in women with poor oral hygiene and HG. PMID- 28347202 TI - Pediatric concussion: biomechanical differences between outcomes of transient and persistent (> 4 weeks) postconcussion symptoms. AB - OBJECTIVE Currently, little is known about the biomechanics of head impact for concussion in youths (ages 5 to 18 years). Even less is known about the biomechanical characteristics and variables related to head impacts that may be useful in differentiating between transient and persistent postconcussion symptoms in a youth population. The purpose of this research was to examine the differences in biomechanics of youth head impact for transient postconcussion symptoms (TPCSs) and persistent postconcussion symptoms (PPCSs) by using data from a hospital population. METHODS In a laboratory setting and using physical, computational, and finite element models, the authors reconstructed falling events in a large cohort of patients who had sustained a brain injury that resulted in transient or persistent postconcussion symptoms. The falling events and resulting concussions for the TPCS and PPCS patient groups were analyzed in terms of force, energy, peak resultant linear and rotational accelerations, and maximum principal strain in the gray and white matter of the brain, as well as measurements of cumulative strain damage. RESULTS The results indicated that there were no significant differences between the groups for any of the variables analyzed. CONCLUSIONS With methods derived for use in an adult population, the magnitudes of peak linear acceleration for the youth data set were determined to be above the 50% risk of injury. The youth data set showed higher brain tissue strain responses for lower energy and impact velocities than measured in adults, suggesting that youths are at higher risk of concussive injury at lower event severities. A trend shown by some variables indicated that larger magnitudes of response were associated with PPCSs, but no single measurement variable consistently differentiated between the TPCS and PPCS groups. It is possible that using the biomechanics of head and brain responses to predict a subjective symptom load may not be appropriate. To enhance future biomechanical analyses, further investigations should include the use of quantifiable measures of brain injury linked to clinical outcomes and possible confounding factors such as history of brain injury and patient predisposition. PMID- 28347203 TI - Thromboelastometric assessment of hemostasis in newborn Piemontese calves. AB - We investigated possible age-related differences in coagulation profiles in bovine species by means of rotational thromboelastometric (ROTEM) analysis. We evaluated hemostasis by ROTEM in newborn Piemontese calves at birth (T0), 8 d (T8), and 15 d (T15) of age and compared the ROTEM results obtained in 16 newborn calves with 28 adult Piemontese cattle. Hemostasis was evaluated using standard coagulation tests and ROTEM analysis, obtaining in-TEM, ex-TEM, and fib-TEM profiles. Statistically significant differences in the ROTEM profiles of newborn calves were found between T0 and T8 and between T0 and T15 ( p < 0.05) but not between T8 and T15. Differences between ROTEM profiles of calves and adults were statistically significant at T0 ( p < 0.05) but no differences were found at T15 ( p < 0.05). Hence, ROTEM reference intervals for adult cattle can be used to evaluate profiles in Piemontese calves >=8 d of age. PMID- 28347204 TI - The effect of Echis coloratus venom on biochemical and molecular markers of the antioxidant capacity in human fibroblasts. AB - This study was undertaken to examine the activities and levels of major antioxidants/oxidants in cultured human fibroblasts incubated with a sublethal dose of Echis coloratus venom (EcV). Glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD) and glutathione reductase (GR) activities and gene expression levels as well as reduced glutathione (GSH) levels, and the concurrent hydrogen peroxide (H2O2), superoxide anions (SOA), lipid peroxides (LPO) and oxidized glutathione (GSSG) generation rates were assayed in fibroblast cultures and sonicates incubated with 0.5 ug ml-1 medium EcV for 4 h at 37 degrees C. Data indicated that the activities of all antioxidant enzymes were significantly decreased and their corresponding transcripts downregulated in EcV incubated cells compared to controls (p < 0.001). In contrast, there were parallel equally significant increases in H2O2, SOA and LPO generation rates in venom-incubated cells compared to controls (p < 0.001). Additionally, GSH levels were significantly decreased and those of GSSG were equally significantly increased in venom-incubated cultures compared to controls (p < 0.001) leading to a lowered GSH/GSSG ratio. In conclusion, incubation of fibroblast cultures with EcV resulted in a shift towards oxidative metabolism causing severe OS. This correlated with significant downregulation in the expression levels of all investigated antioxidant genes. PMID- 28347205 TI - Preparation of collagen/polyurethane/knitted silk as a composite scaffold for tendon tissue engineering. AB - The main objective of this study was to prepare a hybrid three-dimensional scaffold that mimics natural tendon tissues. It has been found that a knitted silk shows good mechanical strength; however, cell growth on the bare silk is not desirable. Hence, electrospun collagen/polyurethane combination was used to cover knitted silk. A series of collagen and polyurethane solutions (4%-7% w/v) in aqueous acetic acid were prepared and electrospun. According to obtained scanning electron microscopy images from pure collagen and polyurethane nanofibers, concentration was set constant at 5% (w/v) for blend solutions of collagen/polyurethane. Afterward, blend solutions with the weight ratios of 75/25, 50/50 and 25/75 were electrospun. Scanning electron microscopy images demonstrated the smooth and uniform morphology for the optimized nanofibers. The least fibers diameter among three weight ratios was found for collagen/polyurethane (25/75) which was 100.86 +/- 40 nm and therefore was selected to be electrospun on the knitted silk. Attenuated total reflectance Fourier transform infrared spectra confirmed the chemical composition of obtained electrospun nanofibers on the knitted silk. Tensile test of the specimens including blend nanofiber, knitted silk and commercial tendon substitute examined and indicated that collagen/polyurethane-coated knitted silk has appropriate mechanical properties as a scaffold for tendon tissue engineering. Then, Alamar Blue assay of the L929 fibroblast cell line seeded on the prepared scaffolds demonstrated appropriate viability of the cells with a significant proliferation on the scaffold containing more collagen content. The results illustrate that the designed structure would be promising for being used as a temporary substitute for tendon repair. PMID- 28347206 TI - Patients With Mitochondrial Disease Have an Inadequate Nutritional Intake. AB - BACKGROUND: Mitochondrial disease (MD) is a group of disorders caused by dysfunctional mitochondria, the organelles that generate energy for the cell. Malnutrition in patients with MD may lead to increased mitochondrial dysfunction, which may enhance already existing symptoms. The aim of this study was to investigate whether patients with MD have an insufficient or unbalanced food intake and to establish which nutrients and product groups are particularly compromised in this patient group. METHODS: In this observational, cross sectional, retrospective study, sixty 3-day nutrition diaries of adult patients with MD were analyzed and compared with the Dutch recommended daily allowance and the Dutch National Food Consumption Survey (DNFCS). RESULTS: The intake of all macronutrients and micronutrients of patients with MD was significantly different from Dutch recommended daily allowance values with the exception of fat and iron. In particular, protein and calcium intake in patients with MD was significantly lower when compared with the DNFCS. Interindividual differences were high. Also, intake of fiber, sugars, saturated fat, and vitamin D differed from recommendations for the overall population. In comparison with DNFCS, the intake of dairy products and drinks was significant lower in patients. CONCLUSIONS: Our study demonstrates that many patients with MD have an inadequate diet. Specifically, intake of protein, calcium, dairy products, and fluids were low. Overall, eating a healthy diet seems as difficult for patients with MD as for the general population. Since interindividual differences are high, individual diet counseling is recommended for all adult patients with MD. PMID- 28347207 TI - Evaluation of the effectiveness of transcranial direct current stimulation (tDCS) and psychosensory stimulation through DOCS scale in a minimally conscious subject. AB - The aim of our study was to assess the effectiveness of transcranial direct current stimulation (tDCS) on alertness improvement in a patient in a minimally conscious state (MCS) by means of disorders of consciousness scale combined with psycho-sensory stimulation. The effects of tDCS on muscle hypertonia through the Ashworth scale were also examined. tDCS was performed through a two-channel intra cephalic stimulator. After stimulation, the patient followed a psychosensory stimulation training. Results pointed out an increase in DOCunit score, as well as an increase in alertness maintenance and an improvement in muscle hypertonia, although a MCS state persisted. PMID- 28347208 TI - Cum Scientia Caritas: written on the body. PMID- 28347209 TI - Stability of glomerular and tubular renal injury biomarkers in canine urine after 4 years of storage. AB - Urine biomarkers are sensitive indicators of early-stage renal injury, consequently, research in this area is expanding in both human and veterinary medicine. However, studies investigating the impact of preanalytical factors, such as storage conditions, on urine biomarker concentrations are largely lacking in veterinary medicine. Therefore, we evaluated the stability of several renal injury biomarkers in canine urine after storage for 4 y at -72 degrees C. Urine samples were collected from 26 dogs: 18 dogs with babesiosis and 8 healthy dogs. Concentrations of urine immunoglobulin G (uIgG), urine C-reactive protein (uCRP), and urine retinol-binding protein (uRBP) were measured, using validated commercial immunoassays, at the start of the study and 4 y later. To investigate the effect of long-term storage, absolute and relative differences between both measurements were compared. Additionally, dogs with babesiosis were compared with the healthy controls at both time points. Storage caused significant absolute and relative decreases in concentrations of all 3 biomarkers. Significant differences between dogs with babesiosis and healthy dogs were found in uIgG and uRBP at both times; however, the difference in uCRP between both groups lost significance after storage. Because the main goal of these urine biomarkers is to detect early stage renal injury, the statistically significant decrease in their concentrations will be clinically relevant when a mild degree of renal injury is present. Our data indicate that the investigated urine biomarkers show significant decay after 4 y of storage at -72 degrees C, adversely affecting their diagnostic utility. PMID- 28347210 TI - Poly(glycerol methacrylate)-based degradable nanoparticles for delivery of small interfering RNA. AB - Nucleic acids therapeutic efficiency is generally limited by their low stability and intracellular bioavailability, and by the toxicity of the carriers used to deliver them to the target sites. Aminated poly(glycerol methacrylate) polymers are biodegradable and pH-sensitive polymers that have been used previously to deliver antisense oligonucleotide and show high transfection efficiency. The purpose of this study is to compare the efficiency and toxicity of aminated linear poly(glycerol methacrylate) (ALT) biodegradable polymer to the most commonly used cationic degradable (i.e. chitosan) and non-degradable (i.e. polyethylenimine (PEI)) polymers for delivery of short interfering RNA (siRNA). ALT, PEI and chitosan polymers were able to form nanosized particles with siRNA. Size, size-distribution and zeta-potential were measured over a wide range of nitrogen-to-phosphate (N/P) ratios, and the stability of the formed nanoparticles in saline and upon freeze-drying was also assessed. No significant cytotoxicity at the range of the tested concentrations of ALT and chitosan nanoparticles was observed, whereas the non-degradable PEI showed significant toxicity in huh-7 hepatocyte-derived carcinoma cell line. The safety profiles of the degradable polymers (ALT and chitosan) over non-degradable PEI were demonstrated in vitro and in vivo. In addition, ALT nanoparticles were able to deliver siRNA in vivo with significantly higher efficiency than chitosan nanoparticles. The results in the present study give evidence of the great implications of ALT nanoparticles in biomedical applications due to their biocompatibility, low cytotoxicity, high stability and simple preparation method. PMID- 28347211 TI - Use of Multichannel Near Infrared Spectroscopy to Study Relationships Between Brain Regions and Neurocognitive Tasks of Selective/Divided Attention and 2-Back Working Memory. AB - While dichotic listening (DL) was originally intended to measure bottom-up selective attention, it has also become a tool for measuring top-down selective attention. This study investigated the brain regions related to top-down selective and divided attention DL tasks and a 2-back task using alphanumeric and Japanese numeric sounds. Thirty-six healthy participants underwent near-infrared spectroscopy scanning while performing a top-down selective attentional DL task, a top-down divided attentional DL task, and a 2-back task. Pearson's correlations were calculated to show relationships between oxy-Hb concentration in each brain region and the score of each cognitive task. Different brain regions were activated during the DL and 2-back tasks. Brain regions activated in the top-down selective attention DL task were the left inferior prefrontal gyrus and left pars opercularis. The left temporopolar area was activated in the top-down divided attention DL task, and the left frontopolar area and left dorsolateral prefrontal cortex were activated in the 2-back task. As further evidence for the finding that each task measured different cognitive and brain area functions, neither the percentages of correct answers for the three tasks nor the response times for the selective attentional task and the divided attentional task were correlated to one another. Thus, the DL and 2-back tasks used in this study can assess multiple areas of cognitive, brain-related dysfunction to explore their relationship to different psychiatric and neurodevelopmental disorders. PMID- 28347212 TI - Mapping nouns and finite verbs in left hemisphere tumors: a direct electrical stimulation study. AB - Neurosurgical mapping studies with nouns and finite verbs are scarce and subcortical data are nonexistent. We used a new task that uses finite verbs in six Italian-speaking patients with gliomas in the left language-dominant hemisphere. Language-relevant positive areas were detected only with nouns in four patients, with both tasks yet in distinct cortical areas in one patient, and only with finite verbs in another patient. Positive areas and types of errors varied across participants. Finite verbs provide complementary information to nouns, and permit more accurate mapping of language production when nouns are unaffected by electrical stimulation. PMID- 28347213 TI - Limb Misidentification: A Clinical-Anatomical Prospective Study. AB - The misidentification of one's own limb (LM) after right hemisphere stroke is a striking phenomenon that is incompletely understood. The authors prospectively studied the natural history and anatomy of LM in 36 patients with hyperacute right middle cerebral artery infarct. Unlike in previous studies, rapid clinical assessment was prioritized. The authors found LM to be common and transient, involving 61% at onset, evolving to 15% at 1 week. Voxel-based lesion-symptom mapping found supramarginal gyrus (SMG) damage associated with LM. This substantiates the SMG's importance in LM and has broader implications for lesion analysis: timing matters. Rapid assessment of transient disorders minimizes false negatives, which can improve lesion analysis. PMID- 28347214 TI - Delusions and the Right Hemisphere: A Review of the Case for the Right Hemisphere as a Mediator of Reality-Based Belief. AB - Delusions are beliefs that remain fixed despite evidence that they are incorrect. Although the precise neural mechanism of delusional belief remains to be elucidated, there is a predominance of right-hemisphere lesions among patients with delusional syndromes accompanied by structural pathology, suggesting that right-hemisphere lesions, or networks with key nodes in the right hemisphere, may be playing a role. The authors discuss the potential theoretical basis and empiric support for a specific right-hemisphere role in delusion production, drawing on its roles in pragmatic communication; perceptual integration; attentional surveillance and anomaly/novelty detection; and belief updating. PMID- 28347215 TI - Platelet function testing in pediatric patients. AB - INTRODUCTION: Platelets play a key role in primary hemostasis and are also intricately linked to secondary hemostasis. Investigation of platelet function in children, especially in neonates, is seriously challenged by the volumes required to perform the majority of platelet function tests and due to the lack of standardization of these tests for use in children. Areas covered: The present review summarizes developmental hemostasis with a focus on the differences in platelet adhesion, activation and aggregation, between preterm neonates, full term neonates, during childhood and in adults. Some of the most widely used platelet function tests are presented, including novel tests requiring only a small blood volume. Expert commentary: Currently available platelet function tests are limited as regards to investigation of neonates due to difficulties in obtaining adequate blood volume, poor standardization, lack of reference intervals for neonates and children, and an incomplete understanding of the functional phenotype of neonatal platelets, especially preterm neonatal platelets. PMID- 28347216 TI - Research or evaluation - does the difference matter? AB - There appears to be an insatiable appetite to develop and improve medical education. A quick perusal of the abstracts of any recent conference or publication reveals the high frequency with which the terms 'research' and 'evaluation' occurs, although there often appears to be little to distinguish between the two. In this article, we will highlight the key conceptual differences between research and evaluation and discuss the importance of clear distinction between the two processes; a distinction which is often blurred. We aim to explore some of the possible reasons why this is the case. Finally, we will plea for greater awareness of how the strengths of evaluation can be applied to both understand and improve medical education. PMID- 28347217 TI - The evolution of publication hotspots in the field of telemedicine from 1962 to 2015 and differences among six countries. AB - Introduction Telemedicine has been implemented in many countries and has captured the attention of many researchers. Herein, we aim to quantify publication hotspots in the field of telemedicine, analyse their evolution, compare them in different countries, and provide visual representations. Methods We used software tools to process PubMed entries for a 54-year period and identified publication hotspots using keyword frequency analysis. We employed a keyword co-occurrence analysis, principal component analysis, multidimensional scaling analysis, and network visualization technology. Results The number of Medical Subject Heading (MeSH) terms increased with time. The most common subcategories of telemedicine between 1962 and 2015 were Remote Consultation, Teleradiology, and Telepathology. The most popular information communication technologies in telemedicine publications were related to the Internet and cell phones. The topics of Patient Satisfaction, Treatment Outcomes, and Home Care Services associated with telemedicine were highlighted after the 1990s. Use frequency of the terms Cell Phones and Self-Care increased drastically in the past six years, and the publication focus in six countries that had the highest output was different. Knowledge network maps and perceptual maps show the relationship between high frequency MeSH terms. Discussion The telemedicine field has experienced significant growth and expansion in knowledge and innovation in the last 54 years. Publication hotspots for telemedicine lean towards clinical treatment, home care services, and personal care, and countries emphasize publishing in areas related to their national characteristics. This study quantitatively discusses publication hotspots, provides an objective and systematic understanding of this field, and suggests directions for future telemedicine research. PMID- 28347218 TI - Enablers and barriers to using two-way information technology in the management of adults with diabetes: A descriptive systematic review. AB - Background This systematic review aimed to explore the enablers and barriers faced by adults with diabetes using two-way information communication technologies to support diabetes self-management. Methods Relevant literature was obtained from five databases using search strategies combining four major constructs: adults with diabetes, biomedical technology, communication technology and patient utilisation. Results Of 8430 unique articles identified, 48 were included for review. Risk of bias was assessed using either the Newcastle-Ottowa or Cochrane risk of bias assessment tools. Seventy-one percent of studies were of cohort design with the majority of studies assessed at high or unclear risk of bias. Consistently identified barriers included poorly designed interfaces requiring manual data entry and systems that lacked functionalities valued by patients. Commonly cited enablers included access to reliable technology, highly automated data entry and transmission, graphical display of data with immediate feedback, and supportive health care professionals and family members. Conclusions People with diabetes face a number of potentially modifiable barriers in using technology to support their diabetes management. In order to address these barriers, end users should be consulted in the design process and consideration given to theories of technology adoption to inform design and implementation. Systems should be designed to solve clinical or behavioural problems that are identified by patients as priorities. Technology should be as automated, streamlined, mobile, low cost and integrated as possible in order to limit the burden of usage for the patient and maximise clinical usefulness. PMID- 28347219 TI - The National Football League-225 Bench Press Test and the Size-Weight Illusion. AB - The purpose of this study was to test reports that size and arrangement manipulations of weight plates (i.e., inducing a size-weight illusion [SWI]) effect athletic weightlifting performance. The participants were 72 experienced, weight-trained collegiate American football players. Across three weeks, each athlete performed three different repetitions-to-fatigue bench press tests (NFL 225, SWI-225, and SWI-215). A multiple regression revealed a positive association between participants' strength relative to the test load and repetitions for NFL 225 and SWI-215, but no association with SWI-225. To explore these results, players were ranked into quartiles based on their one-repetition maximum relative to 102.27 kg (225 lb), and a 3 * 4 repeated measures analysis of variance was conducted. The primary finding was a significant Test Condition * Quartile interaction ( p = .004). Bonferroni-corrected pairwise comparisons revealed that Quartile 4 (those with lowest strength relative to test load) completed more repetitions for SWI-225 compared with NFL-225 ( p = .049). These results suggest that alternate weight plate arrangements may be beneficial for those whose bench press load is near the lifter's one-repetition maximum. However, variations of the SWI do not appear to affect the performance of repetitions-to-fatigue bench press tests for the majority of collegiate American football players. PMID- 28347220 TI - Letter to the Editor: Re: Allergic Rhinitis Is Associated With Periodontitis: A Population-Based Study. PMID- 28347222 TI - 2016 Balint Orban Memorial Program Abstracts - Clinical Science. PMID- 28347223 TI - Authors' Response. PMID- 28347224 TI - Crocodile choline from Crocodylus siamensis induces apoptosis of human gastric cancer. AB - Crocodile choline, an active compound isolated from Crocodylus siamensis, was found to exert potent anti-cancer activities against human gastric cancer cells in vitro and in vivo. Our study revealed that crocodile choline led to cell cycle arrest at the G2/M phase through attenuating the expressions of cyclins, Cyclin B1, and CDK-1. Furthermore, crocodile choline accelerated apoptosis through the mitochondrial apoptotic pathway with the decrease in mitochondrial membrane potential, the increase in reactive oxygen species production and Bax/Bcl-2 ratio, and the activation of caspase-3 along with the release of cytochrome c. In addition, this study, for the first time, shows that Notch pathway is remarkably deregulated by crocodile choline. The combination of crocodile choline and Notch1 short interfering RNA led to dramatically increased cytotoxicity than observed with either agent alone. Notch1 short interfering RNA sensitized and potentiated the capability of crocodile choline to suppress the cell progression and invasion of gastric cancer. Taken together, these data suggested that crocodile choline was a potent progression inhibitor of gastric cancer cells, which was correlated with mitochondrial apoptotic pathway and Notch pathway. Combining Notch1 inhibitors with crocodile choline might represent a novel approach for gastric cancer. PMID- 28347225 TI - Magnetic resonance imaging tumor regression shrinkage patterns after neoadjuvant chemotherapy in patients with locally advanced breast cancer: Correlation with tumor biological subtypes and pathological response after therapy. AB - The objective of this study is to analyze magnetic resonance imaging shrinkage pattern of tumor regression after neoadjuvant chemotherapy and to evaluate its relationship with biological subtypes and pathological response. We reviewed the magnetic resonance imaging studies of 51 patients with single mass-enhancing lesions (performed at time 0 and at the II and last cycles of neoadjuvant chemotherapy). Tumors were classified as Luminal A, Luminal B, HER2+, and Triple Negative based on biological and immunohistochemical analysis after core needle biopsy. We classified shrinkage pattern, based on tumor regression morphology on magnetic resonance imaging at the II cycle, as concentric, nodular, and mixed. We assigned a numeric score (0: none; 1: low; 2: medium; 3: high) to the enhancement intensity decrease. Pathological response on the surgical specimen was classified as complete (grade 5), partial (grades 4-3), and non-response (grades 1-2) according to Miller and Payne system. Fisher test was used to relate shrinkage pattern with biological subtypes and final pathological response. Seventeen patients achieved complete response, 25 partial response, and 9 non-response. A total of 13 lesions showed nodular pattern, 20 concentric, and 18 mixed. We found an association between concentric pattern and HER2+ (p < 0.001) and mixed pattern and Luminal A lesions (p < 0.001). We observed a statistical significant correlation between concentric pattern and complete response (p < 0.001) and between mixed pattern and non-response (p = 0.005). Enhancement intensity decrease 3 was associated with complete response (p < 0.001). Shrinkage pattern and enhancement intensity decrease may serve as early response indicators after neoadjuvant chemotherapy. Shrinkage pattern correlates with tumor biological subtypes. PMID- 28347226 TI - Colorectal polypoid lesions and expression of vascular endothelial growth factor in a consecutive series of endoscopic and surgical patients. AB - Colorectal cancer incidence in patients undergoing screening protocols is decreasing because of the higher rate of discovered preneoplastic colonic lesions; however, adenomatous polyps may not always be removable endoscopically and surgery may still be necessary. The aim of this study was to assess the vascular endothelial growth factor expression in the different steps of colorectal carcinogenesis to explore its potential role as a marker of malignancy in polypoid lesions. A total of 92 subjects with colonic adenoma or cancer who underwent screening colonoscopy or surgery were prospectively enrolled. Real-time reverse transcription polymerase chain reaction for VEGF-A messenger RNA expression and immunohistochemistry for VEGF-A were performed. Immunoassays for VEGF-A, VEGF-C, VEGFR-1, VEGFR-2, and VEGFR-3 were also performed. Non-parametric statistics, receiver operating characteristic curve analysis, and logistic multiple regression analysis were used. VEGF-A messenger RNA expression was higher in patients with high-grade dysplasia or colorectal cancer than in those with low-grade dysplasia adenomas (p = 0.01). At immunohistochemistry, VEGF-A expression was significantly higher in colorectal cancer patients compared to dysplastic adenomas (p < 0.001), and the accuracy of VEGF-A expression for prediction of malignancy was 91.7 (95% confidence interval = 78.7-97.9). VEGF-C protein expression was lower in colorectal cancer patients than in simple adenomas (p = 0.02). VEGF-A levels were directly correlated to polyp size (rho = 0.73, p = 0.0062). Multivariate analysis demonstrated that malignancy and polyp size were independent predictors of VEGF-A mucosal levels. This study demonstrated that the VEGF-A expression changes along the colorectal carcinogenesis pathway showing a neat step up at the passage from high-grade dysplasia to invasive cancer. This feature might potentially be useful to stratify colorectal polyps in different risks of progression classes. Moreover, the high level of VEGF-A expression predicted the presence of lymphovascular invasion with good accuracy. PMID- 28347227 TI - Comparative proteomics-network analysis of proteins responsible for ursolic acid induced cytotoxicity in colorectal cancer cells. AB - Ursolic acid is a key active compound present in many medicinal herbs that have been widely used in traditional Chinese medicine for the clinical treatment of various cancers. However, the precise mechanisms of its antitumor activity have been poorly understood. To identify the cellular targets of ursolic acid, two dimensional gel electrophoresis combined with mass spectrometry was performed in this study, which identified 15 proteins with significantly altered levels in protein expression. This demonstrated that ursolic acid-induced cytotoxicity in colorectal cancer cells involves dysregulation in protein folding, signal transduction, cell proliferation, cell cycle, and apoptosis. Corresponding protein regulation was also confirmed by Western blotting. Furthermore, the study of functional association between these 15 proteins revealed that 10 were closely related in a protein-protein interaction network, whereby the proteins either had a direct interaction with each other or were associated via only one intermediary protein. In this instance, the ATP5B/CALR/HSP90B1/HSPB1/HSPD1-signaling network was revealed as the predominant target which was associated with the majority of the observed protein-protein interactions. As a result, the identified targets may be useful in explaining the anticancer mechanisms of ursolic acid and as potential targets for colorectal cancer therapy. PMID- 28347228 TI - EMP2 re-expression inhibits growth and enhances radiosensitivity in nasopharyngeal carcinoma. AB - Although radiation therapy is the primary treatment for nasopharyngeal carcinoma, radioresistance remains a major obstacle to successful treatment in many cases, and the exact underlying molecular mechanisms are still ill-defined. EMP2, epithelial membrane protein-2, was a recently identified potential oncogene involved in multiple biological processes including cell migration and cell proliferation. This study was to explore the potential relationship between EMP2 expression, nasopharyngeal carcinoma genesis, and radioresistance. EMP2 expression status in 98 nasopharyngeal carcinoma clinical samples was examined by immunohistochemical staining. As a result, most of the nasopharyngeal carcinoma tumor samples were weakly or negatively stained, while paired adjacent normal tissues were moderately or strongly stained. Moreover, patients with higher expression of EMP2 had significant longer survival times. EMP2 re-expression suppresses cell growth, induces S-phase cell cycle arrest, and promotes radiosensitivity and apoptosis in nasopharyngeal carcinoma cells. These results support that loss of EMP2 is common, and its re-expression may serve as an approach to enhance radiation sensitivity in nasopharyngeal carcinoma. PMID- 28347229 TI - High expression of G-protein signaling modulator 2 in hepatocellular carcinoma facilitates tumor growth and metastasis by activating the PI3K/AKT signaling pathway. AB - The aim of this study was to investigate the role of G-protein signaling modulator 2 in the carcinogenesis and progression of hepatocellular carcinoma. We previously showed that G-protein signaling modulator 2 was upregulated in hepatitis B virus-related hepatocellular carcinoma tissues through a hierarchical clustering analysis. With this study, we first assessed the expression pattern of G-protein signaling modulator 2 in hepatocellular carcinoma specimens and adjacent noncancerous tissues; clinical data were analyzed, along survival times, utilizing the Kaplan-Meier method. Moreover, the functions of G-protein signaling modulator 2 were examined using small-interfering RNAs in vitro. The results showed that G-protein signaling modulator 2 was clearly overexpressed in hepatocellular carcinoma tissues and cell lines and that the G-protein signaling modulator 2 expression level was related to tumor size and hepatitis B virus infection. Furthermore, G-protein signaling modulator 2 knockdown studies suggested that G-protein signaling modulator 2 accelerates cell growth, cell cycle, migration, and invasion and inhibits apoptosis, acting as an oncogene in hepatocellular carcinoma. Western blotting indicated that silencing of G-protein signaling modulator 2 in HepG2 and SMMC-7721 cells increased the expression levels of Bax, caspase-3, and E-cadherin, while notably suppressing the cyclin dependent kinase 4, cyclin-dependent kinase 6, CyclinD1, Snail1, Vimentin, and matrix metallopeptidase 9 expression levels, compared with that in the control groups. In addition, we found that G-protein signaling modulator 2 can affect the expression of key proteins involved in protein kinase B activation. In conclusion, high expression of G-protein signaling modulator 2 was involved in the pathological processes of hepatocellular carcinoma through activation of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway, which may provide an attractive potential diagnostic biomarker and therapeutic target for treatment of hepatocellular carcinoma. PMID- 28347231 TI - Animal models as a tool in hepatocellular carcinoma research: A Review. AB - Cancer is the first cause of death in developed countries and the second in developing countries. Concerning the most frequent worldwide-diagnosed cancer, primary liver cancer represents approximately 4% of all new cancer cases diagnosed globally. However, among primary liver cancer, hepatocellular carcinoma is by far the most common histological subtype. Notwithstanding the health promotion and disease prevention campaigns, more than half a million new hepatocellular carcinoma cases are reported yearly, being estimated to growth continuously until 2020. Taking this scenario under consideration and the fact that some aspects concerning hepatocellular carcinoma evolution and metastasize process are still unknown, animal models assume a crucial role to understand this disease. The animal models have also provided the opportunity to screen new therapeutic strategies. The present review was supported on research and review papers aiming the complexity and often neglected chemically induced animal models in hepatocarcinogenesis research. Despite the ongoing debate, chemically induced animal models, namely, mice and rat, can provide unique valuable information on the biotransformation mechanisms against xenobiotics and apprehend the deleterious effects on DNA and cell proteins leading to carcinogenic development. In addition, taking under consideration that no model achieves all hepatocellular carcinoma research purposes, criteria to define the " ideal" animal model, depending on the researchers' approach, are also discussed in this review. PMID- 28347230 TI - Inhibition of microRNA-21 via locked nucleic acid-anti-miR suppressed metastatic features of colorectal cancer cells through modulation of programmed cell death 4. AB - Colorectal cancer is among the most lethal of malignancies, due to its propensity to metastatic spread and multifactorial-chemoresistance. The latter property supports the need to identify novel therapeutic approaches for the treatment of colorectal cancer. MicroRNAs are endogenous non-coding small RNA molecules that function as post-transcriptional regulators of gene expression. Recently, programmed cell death 4 has been identified as a protein that increases during apoptosis. This gene is among the potential targets of miR-21 (OncomiR). Locked nucleic acid-modified oligonucleotides have recently emerged as a potential therapeutic option for targeting microRNAs. The aim of this study was to explore the functional role of locked nucleic acid-anti-miR-21 in the LS174T cell line in vitro and in vivo models. LS174T cells were treated with locked nucleic acid-anti miR-21 for 24, 48, and 72 h in vitro. The expression of miR-21 and PDCD4 at messenger RNA (mRNA) level was evaluated by quantitative real-time polymerase chain reaction, while the protein level of PDCD4 was determined by Western blotting. Cell migratory behavior and the cluster-forming ability of cells were assessed before and after therapy. The disseminated tumor cells were assessed in the chick chorioallantoic membrane model by Alu quantitative polymerase chain reaction. Locked nucleic acid-anti-miR-21 was transfected successfully into the LS174T cells and inhibited the expression of miR-21. Locked nucleic acid-anti-miR 21 inhibited the migration and the number of cells forming clusters. Moreover, we found that locked nucleic acid-anti-miR-21 transfection was associated with a significant reduction in metastatic properties as assessed by the in ovo model. Our findings demonstrated the novel therapeutic potential of locked nucleic acid anti-miR-21 in colon adenocarcinoma with high miR-21 expression. PMID- 28347232 TI - Expression of RNA-binding motif 10 is associated with advanced tumor stage and malignant behaviors of lung adenocarcinoma cancer cells. AB - This study assessed RNA-binding motif 10 expression in lung adenocarcinoma tissues and examined the role and mechanism of RNA-binding motif 10 in the regulation of lung adenocarcinoma malignancy. Lung adenocarcinoma and corresponding adjacent non-tumor lung tissues from 41 patients were subjected to reverse transcription-polymerase chain reaction and Western blot assessment to detect RNA-binding motif 10 expression. Recombinant lentivirus carrying RNA binding motif 10 complementary DNA was used to infect lung adenocarcinoma cell lines, A549 and H1299 cells. Complementary DNA microarray was used to profile RNA binding motif 10-regulated genes. Levels of RNA-binding motif 10 messenger RNA and protein were significantly lower in lung adenocarcinoma tissues than those in paired non-tumor tissues (p < 0.001). Reduced RNA-binding motif 10 expression was found to be associated with an advanced tumor stage. RNA-binding motif 10 overexpression inhibited viability and colony formation capacity of lung adenocarcinoma cell lines and induced cell-cycle arrest at G0/G1 phase in A549 cells and at S phase in H1299 cells. Complementary DNA microarray analysis identified 304 upregulated and 386 downregulated genes induced by RNA-binding motif 10 overexpression, which may be involved in cancer, focal adhesion, peroxisome proliferator-activated receptor-regulated gene pathway, cytokine cytokine receptor interaction, mitogen-activated protein kinase signaling, complement and coagulation cascades, platelet amyloid precursor protein pathway, extracellular matrix-receptor interaction, and small cell lung cancer-related genes. Expression of FGF2, EGFR, WNT5A, NF-kappaB, and RAP1A was downregulated, whereas expression of AKT2, BIRC3, and JUN was upregulated. RNA-binding motif 10 messenger RNA and protein were reduced in lung adenocarcinoma tissues, and RNA binding motif 10 overexpression inhibited lung adenocarcinoma cancer cell malignant behavior in vitro. Molecularly, RNA-binding motif 10 regulates many gene pathways involving in the tumor development or progression. PMID- 28347233 TI - Glycolysis-related protein expression in thyroid cancer. AB - We aimed to demonstrate the differences in the expression of glucose metabolism related proteins according to the thyroid cancer subtypes and investigate the implications of these differences. A total of 566 thyroid cancer patients, including 342 cases of papillary thyroid carcinoma, 112 cases of follicular carcinoma, 70 cases of medullary carcinoma, 23 cases of poorly differentiated carcinoma, 19 cases of anaplastic carcinoma, and 152 cases of follicular adenoma, were enrolled in the study. Immunohistochemical staining for glucose transporter 1, hexokinase II, carbonic anhydrase IX, and monocarbonylate transporter 4 was performed, and the relationship between immunoreactivity and clinicopathologic parameters was analyzed. Glucose transporter 1 and tumoral monocarbonylate transporter 4 expression levels were shown to be the highest in anaplastic carcinoma, and medullary carcinoma showed the highest carbonic anhydrase IX and lowest hexokinase II levels compared with other subtypes. Stromal expression of monocarbonylate transporter 4 was observed in papillary thyroid carcinoma and anaplastic carcinoma samples. Conventional papillary thyroid carcinoma tumors expressed higher levels of glucose transporter 1, and tumoral and stromal monocarbonylate transporter 4, than the follicular variant, which showed a higher expression of carbonic anhydrase IX. Papillary thyroid carcinoma samples with BRAF V600E mutation were shown to have higher glucose transporter 1, hexokinase II, carbonic anhydrase IX, and tumoral monocarbonylate transporter 4 expression levels. Univariate analysis showed that papillary thyroid carcinoma cases with glucose transporter 1 positivity had shorter overall survival, patients with medullary carcinoma and hexokinase II positivity were shown to have a shorter disease-free survival and overall survival, and tumoral monocarbonylate transporter 4 positivity was associated with shorter overall survival compared with papillary thyroid carcinoma patients with negativity for each marker. Disease-free survival and overall survival of patients with poorly differentiated carcinoma were shown to be significantly decreased when glucose transporter 1 and tumoral monocarbonylate transporter 4 are expressed. We demonstrated that the expression levels of glycolysis-related proteins differ between thyroid cancer subtypes and are correlated with poorer prognosis, depending on the subtype. PMID- 28347234 TI - Clinical value of miR-145-5p in NSCLC and potential molecular mechanism exploration: A retrospective study based on GEO, qRT-PCR, and TCGA data. AB - MicroRNAs have been reported to be involved in various biological processes. Here, we performed a systematic analysis to explore the clinical value and potential molecular mechanism of miR-145-5p in non-small cell lung cancer. First, a meta-analysis was performed with eligible literature, followed by microRNA microarrays in the Gene Expression Omnibus database, to verify the diagnostic and prognostic values of miR-145-5p. A cohort of 125 clinical paired non-small cell lung cancer samples was next used to detect the level of miR-145-5p and to explore the relationship of miR-145-5p with clinicopathological parameters. The Cancer Genome Atlas database was additionally applied to investigate the role of miR-145-5p in non-small cell lung cancer. The potential targets of miR-145-5p were predicted using 12 online prediction databases to explore the prospective molecular mechanism of miR-145-5p in non-small cell lung cancer. The expression of miR-145-5p in non-small cell lung cancer was significantly lower than that in healthy tissues. And miR-145-5p tended to show better diagnostic performance in lung squamous cell carcinoma than in lung adenocarcinoma. Furthermore, the expression of miR-145-5p was closely associated with lymph node metastasis in non small cell lung cancer. Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the target genes were mainly enriched with enzyme-linked receptor protein signaling pathways, SH3 domain binding, cell leading edge, and adherens junction. The protein-protein interaction network showed that eight hub genes (SMAD4, SMAD2, IRS1, FOXO1, ERBB4, NRAS, ACTB, and ACTG1) might be the key target genes of miR-145-5p in non-small cell lung cancer. The information we obtained might offer new perspectives for clinical diagnosis and treatment for non-small cell lung cancer. PMID- 28347235 TI - Selection of single chain antibody fragments binding to the extracellular domain of 4-1BB receptor by phage display technology. AB - The 4-1BB is a surface glycoprotein that pertains to the tumor necrosis factor receptor family. There is compelling evidence suggesting important roles for 4 1BB in the immune response, including cell activation and proliferation and also cytokine induction. Because of encouraging results of different agonistic monoclonal antibodies against 4-1BB in the treatment of cancer, infectious, and autoimmune diseases, 4-1BB has been suggested as an attractive target for immunotherapy. In this study, single chain variable fragment phage display libraries, Tomlinson I+J, were screened against specific synthetic oligopeptides (peptides I and II) designed from 4-1BB extracellular domain. Five rounds of panning led to selection of four 4-1BB specific single chain variable fragments (PI.12, PI.42, PII.16, and PII.29) which showed specific reaction to relevant peptides in phage enzyme-linked immunosorbent assay. The selected clones were successfully expressed in Escherichia coli Rosetta-gami 2, and their expression was confirmed by western blot analysis. Enzyme-linked immunosorbent assay experiments indicated that these antibodies were able to specifically recognize 4 1BB without any cross-reactivity with other antigens. Flow cytometry analysis demonstrated an acceptable specific binding of the single chain variable fragments to 4-1BB expressed on CCRF-CEM cells, while no binding was observed with an irrelevant antibody. Anti-4-1BB single chain variable fragments enhanced surface CD69 expression and interleukin-2 production in stimulated CCRF-CEM cells which confirmed the agonistic effect of the selected single chain variable fragments. The data from this study have provided a rationale for further experiments involving the biological functions of anti-4-1BB single chain variable fragments in future studies. PMID- 28347236 TI - High mobility group box 1/toll-like receptor 4/myeloid differentiation factor 88 signaling promotes progression of gastric cancer. AB - High mobility group box 1 and toll-like receptor 4/myeloid differentiation factor 88 signaling pathway have been indicated to have oncogenic effects in many cancers. However, the role of high mobility group box 1/toll-like receptor 4/myeloid differentiation factor 88 signaling pathway in the development of gastric cancer remains unclear. In this study, we demonstrated that high mobility group box 1, toll-like receptor 4, and myeloid differentiation factor 88 were overexpressed in gastric cancer tumors compared with the adjacent non-tumor tissues. The overexpression of high mobility group box 1, toll-like receptor 4, and myeloid differentiation factor 88 were correlated with tumor-node-metastasis stage (p = 0.0068, p = 0.0063, p = 0.0173) and lymph node metastasis (p = 0.0272, p = 0.0382, and p = 0.0495). Furthermore, we observed that knockdown of high mobility group box 1 by high mobility group box 1-small interfering RNA suppressed the expression of toll-like receptor 4 and myeloid differentiation factor 88. Blockage of high mobility group box 1/toll-like receptor 4/myeloid differentiation factor 88 signaling by high mobility group box 1-small interfering RNA resulted in elevation of apoptotic ratio and inhibition of cell growth, migration, and invasion by upregulating Bax expression and downregulating Bcl-2, matrix metalloproteinase-2, nuclear factor kappa B/p65 expression, and the nuclear translocation of nuclear factor kappa B/p65 in gastric cancer cells. Our findings suggest that high mobility group box 1/toll-like receptor 4/myeloid differentiation factor 88 signaling pathway may contribute to the development and progression of gastric cancer via the nuclear factor kappa B pathway and it also represents a novel potential therapeutic target for gastric cancer. PMID- 28347237 TI - Specific tumor-derived CCL2 mediated by pyruvate kinase M2 in colorectal cancer cells contributes to macrophage recruitment in tumor microenvironment. AB - Development of colorectal cancer has been considered as a result of imbalance of pro- and anti-inflammatory intestinal microenvironment accompanied by macrophage recruitment. Despite macrophages are implicated in remodeling tumor microenvironment, the mechanism of macrophage recruitment is not fully elucidated yet. In this study, we reported clinical association of highly expressed pyruvate kinase M2 in colorectal cancer with macrophage attraction. The conditioned medium from Caco-2 and HT-29 cells with depleted pyruvate kinase M2 dramatically reduced macrophage recruitment, which is reversed by addition of, a critical chemotaxis factor to macrophage migration, rCCL2. Silencing of endogenous pyruvate kinase M2 markedly decreased CCL2 expression and secretion by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Endogenous pyruvate kinase M2 interacted with p65 and mediated nuclear factor-kappaB signaling pathway and mainly regulated phosphorylation of Ser276 on p65 nuclear factor-kappaB. In addition, inhibition of macrophage recruitment caused by pyruvate kinase M2 silencing was rescued by ectopic expression of p65. Interestingly, pyruvate kinase M2 highly expressed in colorectal cancer tissue, which is correction with macrophage distribution. Taken together, we revealed a novel mechanism of pyruvate kinase M2 in promoting colorectal cancer progression by recruitment of macrophages through p65 nuclear factor-kappaB-mediated expression of CCL2. PMID- 28347239 TI - Impact of microRNA dynamics on cancer hallmarks: An oral cancer scenario. AB - MicroRNAs are endogenous small noncoding RNAs that negatively regulate gene expression at posttranscriptional level. The discovery of microRNAs has identified a new layer of gene regulation mechanisms, which play a pivotal role in development as well as in various cellular processes, such as proliferation, differentiation, cell growth, and cell death. Deregulated microRNA expression favors acquisition of cancer hallmark traits as well as transforms the tumor microenvironment, leading to tumor development and progression. Many recent studies have revealed altered expression of microRNAs in oral carcinoma with several microRNAs shown to have key biological role in tumorigenesis functioning either as tumor suppressors or as tumor promoters. MicroRNA expression levels correlate with clinicopathological variables and have a diagnostic and prognostic value in oral carcinoma. For these reasons, microRNA has been a hot topic in oral cancer research for the last few years. In this review, we attempt to summarize the present understanding of microRNA deregulation in oral carcinoma, their role in acquiring cancer hallmarks, and their potential diagnostic and prognostic value for oral cancer management. PMID- 28347238 TI - The predicted target gene validation, function, and prognosis studies of miRNA-22 in colorectal cancer tissue. AB - MicroRNAs are known as small, non-coding, and single-stranded RNAs which can regulate cell proliferation, differentiation, and apoptosis and involve in the development of tumors. In this study, colorectal cancer tissue morphological change in different prognosis in patients was observed by hematoxylin and eosin staining. Thereafter, differentially expressed miR-22 and TIAM1 gene were detected using quantitative polymerase chain reaction and western blot in different colorectal cancer tissues. Meanwhile, luciferase reporter gene system was used to verify the relationship between miR-22 and TIAM1. Eventually, the survival curve was plotted according to follow-up records of patients with colorectal cancer and the expression levels of miR-22 and TIAM1 in different tumor tissues. The hematoxylin and eosin results showed the poor pathological features in the 1-year survival group. The expression level of miR-22 was upregulated and TIAM1 was inhibited, correlating with the extension of patients' survival time. Our results indicated that miR-22 and TIAM1 might play a regulatory role in the occurrence and development of colorectal cancer which were consistent with the survival curve analysis results. Furthermore, the luciferase in miR-22 co-transfected with pmiR-RB-REPORT- TIAM1 group was significantly lower than pmiR-RB-REPORT- TIAM1-mut and Si groups. Collectively, these data suggest that miR-22 may suppress the expression of its target gene TIAM1. The low miR-22 level or the high TIAM1 level will indicate the poor prognosis in colorectal cancer patients. PMID- 28347240 TI - Computer-aided prognosis on breast cancer with hematoxylin and eosin histopathology images: A review. AB - With the advance of digital pathology, image analysis has begun to show its advantages in information analysis of hematoxylin and eosin histopathology images. Generally, histological features in hematoxylin and eosin images are measured to evaluate tumor grade and prognosis for breast cancer. This review summarized recent works in image analysis of hematoxylin and eosin histopathology images for breast cancer prognosis. First, prognostic factors for breast cancer based on hematoxylin and eosin histopathology images were summarized. Then, usual procedures of image analysis for breast cancer prognosis were systematically reviewed, including image acquisition, image preprocessing, image detection and segmentation, and feature extraction. Finally, the prognostic value of image features and image feature-based prognostic models was evaluated. Moreover, we discussed the issues of current analysis, and some directions for future research. PMID- 28347241 TI - Nestin and cluster of differentiation 146 expression in breast cancer: Predicting early recurrence by targeting metastasis? AB - The purpose of this study was to investigate the relationship between the expression of stem-cell markers nestin and cluster of differentiation 146 with clinicopathological characteristics in breast cancer and to determine whether a prognostic impact of nestin and CD146 expression exists regarding occurrence of disease relapse in breast cancer. A total of 141 patients who were histologically diagnosed with breast cancer and underwent radical operations from November 2006 to October 2013 in Laiko General Hospital, National and Kapodistrian University of Athens, were enrolled in the study. CD146 and nestin protein expression were evaluated using immunohistochemistry. Nestin expression was observed in 18.4% (26/141) of the cases, while CD146 expression was observed in 35.5% (50/141) of the cases. Nestin expression is significantly higher in younger patients with breast cancer. Nestin and CD146 expression were not correlated with the tumor size and the presence of lymph node metastasis. On the contrary, a significantly higher expression of nestin and CD146 was observed with triple-negative cancers (p < 0.0001 for both markers), low differentiated tumors (p = 0.021 for nestin and p = 0.008 for CD146), and increased Ki-67 expression (p = 0.007 for nestin and p < 0.0001 for CD146). The nestin-positive group of patients and the CD146 positive group of patients presented significantly higher rates of disease recurrence (log-rank test, p = 0.022 for nestin and p = 0.003 for CD146) with a distant metastasis, 30 months after the primary treatment. CD146 but not nestin, however, predicted independently (p = 0.047) disease recurrence. Nestin and CD146 are expressed in breast cancer cells with highly aggressive potency. They might contribute to disease relapse in breast cancer by activating the epithelial mesenchymal transition pathway and assist tumor neovascularization. PMID- 28347242 TI - Clinical, cellular, and bioinformatic analyses reveal involvement of WRAP53 overexpression in carcinogenesis of lung adenocarcinoma. AB - Lung cancer, of which non-small cell lung cancer accounts for 80%, remains a leading cause of cancer-related mortality and morbidity worldwide. Our study revealed that the expression of WD repeat containing antisense to P53 (WRAP53) is higher in lung-adenocarcinoma specimens than in specimens from adjacent non-tumor tissues. The prevalence of WRAP53 overexpression was significantly higher in patients with tumor larger than 3.0 cm than in patients with tumor smaller than 3.0 cm. The depletion of WRAP53 inhibits the proliferation of lung-adenocarcinoma A549 and SPC-A-1 cells via G1/S cell-cycle arrest. Several proteins interacting with WRAP53 were identified through co-immunoprecipitation and liquid chromatography/mass spectrometry. These key proteins indicated previously undiscovered functions of WRAP53. These observations strongly suggested that WRAP53 should be considered a promising target in the prevention or treatment of lung adenocarcinoma. PMID- 28347243 TI - Evidence for circulating cancer stem-like cells and epithelial-mesenchymal transition phenotype in the pleurospheres derived from lung adenocarcinoma using liquid biopsy. AB - Lung cancer stem cells are supposed to be the main drivers of tumor initiation, maintenance, drug resistance, and relapse of the disease. Hence, identification of the cellular and molecular aspects of these cells is a prerequisite for targeted therapy of lung cancer. Currently, analysis of circulating tumor cells has the potential to become the main diagnostic technique to monitor disease progression or therapeutic response as it is non-invasive. However, accurate detection of circulating tumor cells has remained a challenge, as epithelial cell markers used so far are not always trustworthy for detecting circulating tumor cells, especially during epithelial-mesenchymal transition. As cancer stem cells are the only culprit to initiate metastatic tumors, our aim was to isolate and characterize circulating tumor stem cells rather than circulating tumor cells from the peripheral blood of NSCLC adenocarcinoma as limited data are available addressing the gene expression profiling of lung cancer stem cells. Here, we reveal that CD44(+)/CD24(-) population in circulation not only exhibit stem cell related genes but also possess epithelial-mesenchymal transition characteristics. In conclusion, the use of one or more cancer stem cell markers along with epithelial, mesenchymal and epithelial mesenchymal transition markers will prospectively provide the most precise assessment of the threat for recurrence and metastatic disease and has a great potential for forthcoming applications in harvesting circulating tumor stem cells and their downstream applications. Our results will aid in developing diagnostic and prognostic modalities and personalized treatment regimens like dendritic cell-based immunotherapy that can be utilized for targeting and eliminating circulating tumor stem cells, to significantly reduce the possibility of relapse and improve clinical outcomes. PMID- 28347244 TI - The miR-30 family: Versatile players in breast cancer. AB - The microRNA family, miR-30, plays diverse roles in regulating key aspects of neoplastic transformation, metastasis, and clinical outcomes in different types of tumors. Accumulating evidence proves that miR-30 family is pivotal in the breast cancer development by controlling critical signaling pathways and relevant oncogenes. Here, we review the roles of miR-30 family members in the tumorigenesis, metastasis, and drug resistance of breast cancer, and their application to predict the prognosis of breast cancer patients. We think miR-30 family members would be promising biomarkers for breast cancer and may bring a novel insight in molecular targeted therapy of breast cancer. PMID- 28347245 TI - Cancer stem cells: The potential role of autophagy, proteolysis, and cathepsins in glioblastoma stem cells. AB - One major obstacle in cancer therapy is chemoresistance leading to tumor recurrence and metastasis. Cancer stem cells, in particular glioblastoma stem cells, are highly resistant to chemotherapy, radiation, and immune recognition. In case of immune recognition, several survival mechanisms including, regulation of autophagy, proteases, and cell surface major histocompatibility complex class I molecules, are found in glioblastoma stem cells. In different pathways, cathepsins play a crucial role in processing functional proteins that are necessary for several processes and proper cell function. Consequently, strategies targeting these pathways in glioblastoma stem cells are promising approaches to interfere with tumor cell survival and will be discussed in this review. PMID- 28347246 TI - MicroRNA-125b predicts clinical outcome and suppressed tumor proliferation and migration in human gallbladder cancer. AB - We intended to investigate the functional role and clinical relevance of microRNA 125b in human gallbladder cancer. Quantitative real-time polymerase chain reaction was used to examine microRNA-125b expression in gallbladder cancer cell lines, and 79 pairs of gallbladder cancer and normal gallbladder clinical tissues. Clinical correlations between tumorous microRNA-125b expression and gallbladder cancer patients' clinicopathological variances or overall survivals were statistically analyzed. In gallbladder cancer cell lines, TYGBK-8 and G-415 cells, microRNA-125b was upregulated to examine its regulatory effect on gallbladder cancer proliferation and migration in vitro. MicroRNA-125b was significantly downregulated in gallbladder cancer cell lines and human gallbladder cancer tumors. MicroRNA-125b in gallbladder cancer was significantly correlated with patients' clinical stage, tumor differentiation, lymph metastasis, and tumor invasion. Low tumorous microRNA-125b expression was also found to be associated with poor overall survivals among gallbladder cancer patients. In vitro studies demonstrated that microRNA-125b upregulation significantly suppressed proliferation and migration in TYGBK-8 and G-415 cells. Tumorous microRNA-125b is an independent prognostic biomarker for patients with gallbladder cancer and possibly acts as a tumor suppressor in gallbladder cancer. PMID- 28347247 TI - Decreased RNA-binding motif 5 expression is associated with tumor progression in gastric cancer. AB - RNA-binding motif 5 is a putative tumor suppressor gene that modulates cell cycle arrest and apoptosis. We recently demonstrated that RNA-binding motif 5 inhibits cell growth through the p53 pathway. This study evaluated the clinical significance of RNA-binding motif 5 expression in gastric cancer and the effects of altered RNA-binding motif 5 expression on cancer biology in gastric cancer cells. RNA-binding motif 5 protein expression was evaluated by immunohistochemistry using the surgical specimens of 106 patients with gastric cancer. We analyzed the relationships of RNA-binding motif 5 expression with clinicopathological parameters and patient prognosis. We further explored the effects of RNA-binding motif 5 downregulation with short hairpin RNA on cell growth and p53 signaling in MKN45 gastric cancer cells. Immunohistochemistry revealed that RNA-binding motif 5 expression was decreased in 29 of 106 (27.4%) gastric cancer specimens. Decreased RNA-binding motif 5 expression was correlated with histological differentiation, depth of tumor infiltration, nodal metastasis, tumor-node-metastasis stage, and prognosis. RNA-binding motif 5 silencing enhanced gastric cancer cell proliferation and decreased p53 transcriptional activity in reporter gene assays. Conversely, restoration of RNA-binding motif 5 expression suppressed cell growth and recovered p53 transactivation in RNA binding motif 5-silenced cells. Furthermore, RNA-binding motif 5 silencing reduced the messenger RNA and protein expression of the p53 target gene p21. Our results suggest that RNA-binding motif 5 downregulation is involved in gastric cancer progression and that RNA-binding motif 5 behaves as a tumor suppressor gene in gastric cancer. PMID- 28347248 TI - SIRT3 functions as a tumor suppressor in hepatocellular carcinoma. AB - Hepatocellular carcinoma is one of the leading causes for cancer-related mortality worldwide. SIRT3 may function as either oncogene or tumor suppressor in a panel of cancers; however, the role of SIRT3 in hepatocellular carcinoma remains unclear. In this study, we assayed the expression level of SIRT3 in hepatocellular carcinoma tissues by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. A loss-of-function approach was used to examine the effects of SIRT3 on biological activity, including cell proliferative activity and invasive potential. The results demonstrated that the expression levels of SIRT3 protein in hepatocellular carcinoma tissues were significantly downregulated compared with those in adjacent non-cancerous tissues. Furthermore, SIRT3 could decrease cell proliferation and inhibit cell migration/invasion in hepatocellular carcinoma cell line. Taken together, these results elucidated the function of SIRT3 in hepatocellular carcinoma development and suggested that SIRT3 might function as tumor suppressor in hepatocellular carcinoma by targeting PI3K/Akt pathway. PMID- 28347249 TI - Chemoresistance is associated with overexpression of HAX-1, inhibition of which resensitizes drug-resistant breast cancer cells to chemotherapy. AB - Acquired resistance to standard chemotherapy is the common and critical limitation for cancer therapy. Hematopoietic cell-specific protein 1-associated protein X-1 (HAX-1) has been reported to be upregulated in numerous cancers. However, the role of HAX-1 in oncotherapy remains unclear. In this study, we established MDA-MB-231 cell lines which were resistant to cisplatin (MDA-MB 231/CR) or doxorubicin (MDA-MB-231/DR) to study the chemoresistance in breast cancer. As a result, the HAX-1 which is an apoptosis-associated protein was observed to be overexpressed in both MDA-MB-231/CR and MDA-MB-231/DR compared with the routine MDA-MB-231 cells. Moreover, knockdown of HAX-1 via RNA interference decreased IC50 level of cisplatin by 70.91% in MDA-MB-231/CR cells, and the IC50 level of doxorubicin was decreased by 76.46% in MDA-MB-231/DR cells when the HAX-1 was downregulated. Additionally, we found that the knockdown of HAX-1 induced the release of cytochrome C from mitochondria, resulting in the activation of caspases. Taken together, our study indicates that the overexpression of HAX-1 is essential in the development of chemoresistance in breast cancer. Furthermore, we identify that HAX-1 may become the target for cancer therapy. PMID- 28347250 TI - Chimeric antigen receptor-engineered T cells for liver cancers, progress and obstacles. AB - Chimeric antigen receptor-engineered T cells therapy has become the hottest topic of immunotherapy, as its great successes achieved in treating refractory hematological malignancies. These successes also paved the road to novel strategies of treating various solid tumors including liver cancer. Many specific proteins can be expressed aberrantly in liver cancers; therefore, a series of experimental and clinical researches exploring chimeric antigen receptor engineered T cells and liver cancer are in progress, acquiring obvious antitumor effect and revealing its feasibility in treating liver cancer. However, lots of challenges and obstacles are emerging simultaneously, such as low infiltration, side effects, safety of chimeric antigen receptor-engineered T cells, and limited data of studies or clinical trials. Researchers have been working out many innovative ways to directly stroke these obstacles, theoretically or practically. This review focuses more on the progress and obstacles from chimeric antigen receptor-engineered T cells therapy to treat liver cancer, summarizing new breakthroughs in shooting those obstacles, meanwhile, hoping to provide enlightenment to this promising immunotherapeutic method. PMID- 28347252 TI - The critical role and potential target of the autotaxin/lysophosphatidate axis in pancreatic cancer. AB - Autotaxin, an ecto-lysophospholipase D encoded by the human ENNP2 gene, is expressed in multiple tissues, and participates in numerous critical physiologic and pathologic processes including inflammation, pain, obesity, embryo development, and cancer via the generation of the bioactive lipid lysophosphatidate. Overwhelming evidences indicate that the autotaxin/lysophosphatidate signaling axis serves key roles in the numerous processes central to tumorigenesis and progression, including proliferation, survival, migration, invasion, metastasis, cancer stem cell, tumor microenvironment, and treatment resistance by interacting with a series of at least six G-protein-coupled receptors (LPAR1-6). This review provides an overview of the autotaxin/lysophosphatidate axis and collates current knowledge regarding its specific role in pancreatic cancer. With a deeper understanding of the critical role of the autotaxin/lysophosphatidate axis in pancreatic cancer, targeting autotaxin or lysophosphatidate receptor may be a potential and promising strategy for cancer therapy. PMID- 28347251 TI - Feedback regulation of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 via ATM/Chk2 pathway contributes to the resistance of MCF-7 breast cancer cells to cisplatin. AB - The methyl methanesulfonate and ultraviolet-sensitive gene clone 81 protein is a structure-specific nuclease that plays important roles in DNA replication and repair. Knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 has been found to sensitize cancer cells to chemotherapy. However, the underlying molecular mechanism is not well understood. We found that methyl methanesulfonate and ultraviolet-sensitive gene clone 81 was upregulated and the ATM/Chk2 pathway was activated at the same time when MCF-7 cells were treated with cisplatin. By using lentivirus targeting methyl methanesulfonate and ultraviolet-sensitive gene clone 81 gene, we showed that knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 enhanced cell apoptosis and inhibited cell proliferation in MCF-7 cells under cisplatin treatment. Abrogation of ATM/Chk2 pathway inhibited cell viability in MCF-7 cells in response to cisplatin. Importantly, we revealed that ATM/Chk2 was required for the upregulation of methyl methanesulfonate and ultraviolet-sensitive gene clone 81, and knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 resulted in inactivation of ATM/Chk2 pathway in response to cisplatin. Meanwhile, knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 activated the p53/Bcl-2 pathway in response to cisplatin. These data suggest that the ATM/Chk2 may promote the repair of DNA damage caused by cisplatin by sustaining methyl methanesulfonate and ultraviolet-sensitive gene clone 81, and the double-strand breaks generated by methyl methanesulfonate and ultraviolet-sensitive gene clone 81 may activate the ATM/Chk2 pathway in turn, which provide a novel mechanism of how methyl methanesulfonate and ultraviolet sensitive gene clone 81 modulates DNA damage response and repair. PMID- 28347253 TI - Carboxymethyl chitosan nanoparticles coupled with CD59-specific ligand peptide for targeted delivery of C-phycocyanin to HeLa cells. AB - The combination of nanotechnology and medicine will be the next generation of vehicles for targeted drug delivery. Carboxymethyl chitosan loaded with the anticancer drug C-phycocyanin and the CD59-specific ligand peptide for cancer cell targeting were used to create C-phycocyanin/carboxymethyl chitosan-CD59 specific ligand peptide nanoparticles using the ionic-gelation method. Optimal synthesis conditions, selected by response surface methodology, comprised the ratio carboxymethyl chitosan:C-phycocyanin = 3:1, and carboxymethyl chitosan and CaCl2 concentrations of 2.0 and 1.0 mg/mL, respectively. The resulting nanoparticles were spherical, with diameters of approximately 200 nm; the entrapment efficient was about 65%; and the drug loading was about 20%. The release of C-phycocyanin from C-phycocyanin/carboxymethyl chitosan nanoparticles was pH sensitive and had a sustainable effect in vitro. Guided by the CD59 specific ligand peptide, the nanoparticles efficiently targeted the surface of HeLa cells and had an obvious inhibitory effect on HeLa cell proliferation as determined by methyl thiazolyl tetrazolium assays. The nanoparticles were hemocompatible and induced apoptosis by upregulation of cleaved caspase-3 and cleaved polyADP-ribose polymerase proteins, and downregulation of Bcl-2 proteins. Our study provides a novel approach to the research and development of marine drugs, and support for targeted therapy using anticancer drugs. PMID- 28347254 TI - Epigenetic perturbation driving asleep telomerase reverse transcriptase: Possible therapeutic avenues in carcinoma. AB - In the last decade, implications of human telomerase reverse transcriptase (hTERT), a component of ribonucleoprotein telomerase in aging, senescence, and stem cell are highly evident. Besides, the activation of hTERT is also being documented several cancer types including carcinoma. The awakening of telomerase during carcinoma initiation and development is being seen with different perspectives including genetic and epigenetic tools and events. In view of several tumor progenitors genes (also referred as epigenetic mediators), telomerase is placed as key enzyme to achieve the carcinoma phenotype and sustain during the progression. It is true that swaying of telomerase in carcinoma could be facilitated with dedicated set of epigenetic modulators and modifiers players. These epigenetic alterations are heritable, potentially reversible, and seen as the epigenetic signature of carcinoma. Several papers converge to suggest that DNA methylation, histone modification, and small non-coding RNAs are the widely appreciated epigenetic changes towards hTERT modulation. In this review, we summarize the contribution of epigenetic factors in the telomerase activation and discuss potential avenues to achieve therapeutic intervention in carcinoma. PMID- 28347256 TI - Sleep deprivation as an experimental model system for psychosis: Effects on smooth pursuit, prosaccades, and antisaccades. AB - Current antipsychotic medications fail to satisfactorily reduce negative and cognitive symptoms and produce many unwanted side effects, necessitating the development of new compounds. Cross-species, experimental behavioural model systems can be valuable to inform the development of such drugs. The aim of the current study was to further test the hypothesis that controlled sleep deprivation is a safe and effective model system for psychosis when combined with oculomotor biomarkers of schizophrenia. Using a randomized counterbalanced within subjects design, we investigated the effects of 1 night of total sleep deprivation in 32 healthy participants on smooth pursuit eye movements (SPEM), prosaccades (PS), antisaccades (AS), and self-ratings of psychosis-like states. Compared with a normal sleep control night, sleep deprivation was associated with reduced SPEM velocity gain, higher saccadic frequency at 0.2 Hz, elevated PS spatial error, and an increase in AS direction errors. Sleep deprivation also increased intra-individual variability of SPEM, PS, and AS measures. In addition, sleep deprivation induced psychosis-like experiences mimicking hallucinations, cognitive disorganization, and negative symptoms, which in turn had moderate associations with AS direction errors. Taken together, sleep deprivation resulted in psychosis-like impairments in SPEM and AS performance. However, diverging somewhat from the schizophrenia literature, sleep deprivation additionally disrupted PS control. Sleep deprivation thus represents a promising but possibly unspecific experimental model that may be helpful to further improve our understanding of the underlying mechanisms in the pathophysiology of psychosis and aid the development of antipsychotic and pro-cognitive drugs. PMID- 28347255 TI - Inhibition of l-type amino acid transporter 1 activity as a new therapeutic target for cholangiocarcinoma treatment. AB - Unlike normal cells, cancer cells undergo unlimited growth and multiplication, causing them to require massive amounts of amino acid to support their continuous metabolism. Among the amino acid transporters expressed on the plasma membrane, l type amino acid transporter-1, a Na+-independent neutral amino acid transporter, is highly expressed in many types of human cancer including cholangiocarcinoma. Our previous study reported that l-type amino acid transporter-1 and its co functional protein CD98 were highly expressed and implicated in cholangiocarcinoma progression and carcinogenesis. Therefore, this study determined the effect of JPH203, a selective inhibitor of l-type amino acid transporter-1 activity, on cholangiocarcinoma cell inhibition both in vitro and in vivo. JPH203 dramatically suppressed [14C]l-leucine uptake as well as cell growth in cholangiocarcinoma cell lines along with altering the expression of l type amino acid transporter-1 and CD98 in response to amino acid depletion. We also demonstrated that JPH203 induced both G2/M and G0/G1 cell cycle arrest, as well as reduced the S phase accompanied by altered expression of the proteins in cell cycle progression: cyclin D1, CDK4, and CDK6. There was also cell cycle arrest of the related proteins, P21 and P27, in KKU-055 and KKU-213 cholangiocarcinoma cells. Apoptosis induction, detected by an increase in trypan blue-stained cells along with a cleaved caspase-3/caspase-3 ratio, occurred in JPH203-treated cholangiocarcinoma cells at the highest concentration tested (100 uM). As expected, daily intravenous administration of JPH203 (12.5 and 25 mg/kg) significantly inhibited tumor growth in KKU-213 cholangiocarcinoma cell xenografts in the nude mice model in a dose-dependent manner with no statistically significant change in the animal's body weight and with no differences in the histology and appearance of the internal organs compared with the control group. Our study demonstrates that suppression of l-type amino acid transporter-1 activity using JPH203 might be used as a new therapeutic strategy for cholangiocarcinoma treatment. PMID- 28347257 TI - Antipsychotic treatment of schizotypy and schizotypal personality disorder: a systematic review. AB - Schizotypal personality disorder (SPD) is characterised by thought disorders, experiences of illusions, obsessive ruminations, bizarre or eccentric behaviour, cognitive problems and deficits in social functioning - symptoms that SPD shares with schizophrenia. Efforts have been undertaken to investigate the relationship between these conditions regarding genetics, pathophysiology, and phenomenology. However, treatment of SPD with antipsychotics has received less scientific attention. Embase and PubMed databases were searched using all known generic names of antipsychotics as search terms in combination with the following diagnostic terms: latent schizophrenia, schizotypal disorder, latent type schizophrenia, or SPD. Studies were categorised according to evidence level on the basis of their methodology from A, being the best, to E, being the worst. Five hundred and nine studies were retrieved and scrutinised. Sixteen studies, from the period 1972 to 2012, on antipsychotic treatment of SPD were extracted. Four studies were categorised as evidence level A, two as level B, six as level C and three as level D, with one study level E. Only four randomised, double-blind, placebo-controlled trials, on subjects with well-defined diagnoses, exists. Only amisulpride, risperidone and thiothixene have been studied according to evidence level A. This result warrants further high quality studies of the effects of antipsychotic treatment of SPD. PMID- 28347258 TI - Depot risperidone-induced adverse metabolic alterations in female rats. AB - Atypical antipsychotics are associated with adverse metabolic effects including weight gain, increased adiposity, dyslipidaemia, alterations in glucose metabolism and insulin resistance. Increasing evidence suggests that metabolic dysregulation precedes weight gain development. The aim of this study was to evaluate alterations in adipokines, hormones and basic serum biochemical parameters induced by chronic treatment with depot risperidone at two doses (20 and 40 mg/kg) in female Sprague-Dawley rats. Dose-dependent metabolic alterations induced by risperidone after 6 weeks of treatment were revealed. Concomitant to weight gain and increased liver weight, an adverse lipid profile with an elevated triglyceride level was observed in the high exposure group, administered a 40 mg/kg dose repeatedly, while the low dose exposure group, administered a 20 mg/kg dose, developed weight gain without alterations in the lipid profile and adipokine levels. An initial peak in leptin serum level after the higher dose was observed in the absence of weight gain. This finding may indicate that the metabolic alterations observed in this study are not consequent to body weight gain. Taken together, these data may support the primary effects of atypical antipsychotics on peripheral tissues. PMID- 28347259 TI - Metformin for antipsychotic-induced weight gain: Statistical curiosities. PMID- 28347260 TI - A drug-drug conditioning paradigm reveals multiple antipsychotic-nicotine interactions. AB - Clinical studies indicate a reciprocal impact between nicotine use and antipsychotic medications in patients with schizophrenia. The present study used a conditioned avoidance response (CAR) test (a behavioral test of antipsychotic effect) and examined the specific drug-drug interactions between nicotine and haloperidol or clozapine. Following acquisition of the avoidance response, rats were first tested under either vehicle, nicotine (0.2, 0.4 mg/kg, sc), haloperidol (0.025, 0.05 mg/kg, sc), clozapine (5.0, 10.0 mg/kg, sc), or a combination of nicotine and haloperidol or nicotine and clozapine for seven consecutive days. Afterward, they were challenged with nicotine (0.2 mg/kg), haloperidol (0.025 mg/kg), or clozapine (5.0 mg/kg) in the CAR to assess if haloperidol or clozapine affected the behavioral effect of nicotine on avoidance response and if nicotine altered the avoidance suppressive effect of haloperidol and clozapine. During the seven avoidance drug test days, nicotine did not alter the avoidance suppressive effect of haloperidol or clozapine. However, in the challenge test, prior nicotine treatment (0.2 mg/kg) attenuated haloperidol's (0.05 mg/kg) sensitized effect on avoidance response. On the other hand, prior haloperidol treatment increased nicotine's (0.2 mg/kg) avoidance disruptive effect, and even engendered nicotine 0.4 mg/kg to exhibit an "acquired" avoidance suppressive effect. The combined nicotine and clozapine treatment did not produce any detectable interactive effects on avoidance response and motor activity. These findings suggest that nicotine is capable of altering the long-term antipsychotic efficacy of haloperidol, while haloperidol can alter the behavioral effects of nicotine. Clozapine and nicotine are less likely to influence each other. PMID- 28347261 TI - Dopamine D4 receptor stimulation contributes to novel object recognition: Relevance to cognitive impairment in schizophrenia. AB - Several atypical antipsychotic drugs (APDs) have high affinity for the dopamine (DA) D4 receptor, but the relevance to the efficacy for the treatment of cognitive impairment associated with schizophrenia (CIAS) is poorly understood. The aim of this study was to investigate the effects of D4 receptor stimulation or blockade on novel object recognition (NOR) in normal rats and on the sub chronic phencyclidine (PCP)-induced novel object recognition deficit. The effect of the D4 agonist, PD168077, and the D4 antagonist, L-745,870, were studied alone, and in combination with clozapine and lurasidone. In normal rats, L 745,870 impaired novel object recognition, whereas PD168077 had no effect. PD168077 acutely reversed the sub-chronic phencyclidine-induced novel object recognition deficit. Co-administration of a sub-effective dose (SED) of PD168077 with a sub-effective dose of lurasidone also reversed this deficit, but a sub effective dose of PD168077 with a sub-effective dose of clozapine, a more potent D4 antagonist than lurasidone, did not reverse the sub-chronic phencyclidine induced novel object recognition deficit. At a dose that did not induce a novel object recognition deficit, L-745,870 blocked the ability of clozapine, but not lurasidone, to reverse the novel object recognition deficit. D4 receptor agonism has a beneficial effect on novel object recognition in sub-chronic PCP-treated rats and augments the cognitive enhancing efficacy of an atypical antipsychotic drug that lacks affinity for the D4 receptor, lurasidone. PMID- 28347262 TI - A review of evolution of electrospun tissue engineering scaffold: From two dimensions to three dimensions. AB - The potential of electrospinning process to fabricate ultrafine fibers as building blocks for tissue engineering scaffolds is well recognized. The scaffold construct produced by electrospinning process depends on the quality of the fibers. In electrospinning, material selection and parameter setting are among many factors that contribute to the quality of the ultrafine fibers, which eventually determine the performance of the tissue engineering scaffolds. The major challenge of conventional electrospun scaffolds is the nature of electrospinning process which can only produce two-dimensional electrospun mats, hence limiting their applications. Researchers have started to focus on overcoming this limitation by combining electrospinning with other techniques to fabricate three-dimensional scaffold constructs. This article reviews various polymeric materials and their composites/blends that have been successfully electrospun for tissue engineering scaffolds, their mechanical properties, and the various parameters settings that influence the fiber morphology. This review also highlights the secondary processes to electrospinning that have been used to develop three-dimensional tissue engineering scaffolds as well as the steps undertaken to overcome electrospinning limitations. PMID- 28347263 TI - Editor's Note. PMID- 28347264 TI - Inquiry Concerning Which Polyclonal Goat Antibody for Detection of FLAG-tag in Formalin-Fixed and Paraffin-Embedded Specimens. PMID- 28347265 TI - Response to: Inquiry Concerning Which Polyclonal Goat Antibody for Detection of FLAG-tag in Formalin-Fixed and Paraffin-Embedded Specimens. PMID- 28347266 TI - Formulation and pH of the Buffered Ethanol Fixative BE70. PMID- 28347267 TI - Buffered Ethanol Fixative. PMID- 28347269 TI - The autophagy interaction network of the aging model Podospora anserina. AB - BACKGROUND: Autophagy is a conserved molecular pathway involved in the degradation and recycling of cellular components. It is active either as response to starvation or molecular damage. Evidence is emerging that autophagy plays a key role in the degradation of damaged cellular components and thereby affects aging and lifespan control. In earlier studies, it was found that autophagy in the aging model Podospora anserina acts as a longevity assurance mechanism. However, only little is known about the individual components controlling autophagy in this aging model. Here, we report a biochemical and bioinformatics study to detect the protein-protein interaction (PPI) network of P. anserina combining experimental and theoretical methods. RESULTS: We constructed the PPI network of autophagy in P. anserina based on the corresponding networks of yeast and human. We integrated PaATG8 interaction partners identified in an own yeast two-hybrid analysis using ATG8 of P. anserina as bait. Additionally, we included age-dependent transcriptome data. The resulting network consists of 89 proteins involved in 186 interactions. We applied bioinformatics approaches to analyze the network topology and to prove that the network is not random, but exhibits biologically meaningful properties. We identified hub proteins which play an essential role in the network as well as seven putative sub-pathways, and interactions which are likely to be evolutionary conserved amongst species. We confirmed that autophagy-associated genes are significantly often up-regulated and co-expressed during aging of P. anserina. CONCLUSIONS: With the present study, we provide a comprehensive biological network of the autophagy pathway in P. anserina comprising PPI and gene expression data. It is based on computational prediction as well as experimental data. We identified sub-pathways, important hub proteins, and evolutionary conserved interactions. The network clearly illustrates the relation of autophagy to aging processes and enables further specific studies to understand autophagy and aging in P. anserina as well as in other systems. PMID- 28347268 TI - Illumina MiSeq sequencing analysis of fungal diversity in stored dates. AB - BACKGROUND: Date palm has been a major fruit tree in the Middle East over thousands of years, especially in the Arabian Peninsula. Dates are consumed fresh (Rutab) or after partial drying and storage (Tamar) during off-season. The aim of the study was to provide in-depth analysis of fungal communities associated with the skin (outer part) and mesocarp (inner fleshy part) of stored dates (Tamar) of two cultivars (Khenizi and Burny) through the use of Illumina MiSeq sequencing. RESULTS: The study revealed the dominance of Ascomycota (94%) in both cultivars, followed by Chytridiomycota (4%) and Zygomycota (2%). Among the classes recovered, Eurotiomycetes, Dothideomycetes, Saccharomycetes and Sordariomycetes were the most dominant. A total of 54 fungal species were detected, with species belonging to Penicillium, Alternaria, Cladosporium and Aspergillus comprising more than 60% of the fungal reads. Some potentially mycotoxin-producing fungi were detected in stored dates, including Aspergillus flavus, A. versicolor and Penicillium citrinum, but their relative abundance was very limited (<0.5%). PerMANOVA analysis revealed the presence of insignificant differences in fungal communities between date parts or date cultivars, indicating that fungal species associated with the skin may also be detected in the mesocarp. It also indicates the possible contamination of dates from different cultivars with similar fungal species, even though if they are obtained from different areas. CONCLUSION: The analysis shows the presence of different fungal species in dates. This appears to be the first study to report 25 new fungal species in Oman and 28 new fungal species from date fruits. The study discusses the sources of fungi on dates and the presence of potentially mycotoxin producing fungi on date skin and mesocarp. PMID- 28347270 TI - Inclusion of the fitness sharing technique in an evolutionary algorithm to analyze the fitness landscape of the genetic code adaptability. AB - BACKGROUND: The canonical code, although prevailing in complex genomes, is not universal. It was shown the canonical genetic code superior robustness compared to random codes, but it is not clearly determined how it evolved towards its current form. The error minimization theory considers the minimization of point mutation adverse effect as the main selection factor in the evolution of the code. We have used simulated evolution in a computer to search for optimized codes, which helps to obtain information about the optimization level of the canonical code in its evolution. A genetic algorithm searches for efficient codes in a fitness landscape that corresponds with the adaptability of possible hypothetical genetic codes. The lower the effects of errors or mutations in the codon bases of a hypothetical code, the more efficient or optimal is that code. The inclusion of the fitness sharing technique in the evolutionary algorithm allows the extent to which the canonical genetic code is in an area corresponding to a deep local minimum to be easily determined, even in the high dimensional spaces considered. RESULTS: The analyses show that the canonical code is not in a deep local minimum and that the fitness landscape is not a multimodal fitness landscape with deep and separated peaks. Moreover, the canonical code is clearly far away from the areas of higher fitness in the landscape. CONCLUSIONS: Given the non-presence of deep local minima in the landscape, although the code could evolve and different forces could shape its structure, the fitness landscape nature considered in the error minimization theory does not explain why the canonical code ended its evolution in a location which is not an area of a localized deep minimum of the huge fitness landscape. PMID- 28347272 TI - Genome-wide identification of conserved intronic non-coding sequences using a Bayesian segmentation approach. AB - BACKGROUND: Computational identification of non-coding RNAs (ncRNAs) is a challenging problem. We describe a genome-wide analysis using Bayesian segmentation to identify intronic elements highly conserved between three evolutionarily distant vertebrate species: human, mouse and zebrafish. We investigate the extent to which these elements include ncRNAs (or conserved domains of ncRNAs) and regulatory sequences. RESULTS: We identified 655 deeply conserved intronic sequences in a genome-wide analysis. We also performed a pathway-focussed analysis on genes involved in muscle development, detecting 27 intronic elements, of which 22 were not detected in the genome-wide analysis. At least 87% of the genome-wide and 70% of the pathway-focussed elements have existing annotations indicative of conserved RNA secondary structure. The expression of 26 of the pathway-focused elements was examined using RT-PCR, providing confirmation that they include expressed ncRNAs. Consistent with previous studies, these elements are significantly over-represented in the introns of transcription factors. CONCLUSIONS: This study demonstrates a novel, highly effective, Bayesian approach to identifying conserved non-coding sequences. Our results complement previous findings that these sequences are enriched in transcription factors. However, in contrast to previous studies which suggest the majority of conserved sequences are regulatory factor binding sites, the majority of conserved sequences identified using our approach contain evidence of conserved RNA secondary structures, and our laboratory results suggest most are expressed. Functional roles at DNA and RNA levels are not mutually exclusive, and many of our elements possess evidence of both. Moreover, ncRNAs play roles in transcriptional and post-transcriptional regulation, and this may contribute to the over-representation of these elements in introns of transcription factors. We attribute the higher sensitivity of the pathway focussed analysis compared to the genome-wide analysis to improved alignment quality, suggesting that enhanced genomic alignments may reveal many more conserved intronic sequences. PMID- 28347271 TI - The ST131 Escherichia coli H22 subclone from human intestinal microbiota: Comparison of genomic and phenotypic traits with those of the globally successful H30 subclone. AB - BACKGROUND: In 2006, we found healthy subjects carrying ST131 Escherichia coli in their intestinal microbiota consisting of two populations: a subdominant population of fluoroquinolone-resistant E. coli belonging to subclone H30 (H30-R or subclade C1), the current worldwide dominant ST131 subclone, and a dominant E. coli population composed of antibiotic-susceptible E. coli belonging to subclone H22 (clade B), the precursor of subclone H30. We sequenced the whole genome of fecal H22 strain S250, compared it to the genomes of ExPEC ST131 H30-Rx strain JJ1886 and commensal ST131 H41 strain SE15, sought the H22-H30 genomic differences in our fecal strains and assessed their phenotypic consequences. RESULTS: We detected 173 genes found in the Virulence Factor Database, of which 148 were shared by the three ST131 genomes, whereas some were genome-specific, notably those allowing determination of virotype (D for S250 and C for JJ1886). We found three sequences of the FimH site involved in adhesion: two in S250 and SE15 close and identical, respectively, to that previously reported to confer strong intestinal adhesion, and one in JJ1886, corresponding to that commonly present in uropathogenic E. coli. Among the genes involved in sugar metabolism, one encoding a gluconate kinase lacked in S250 and JJ1886. Although this gene was also absent in both our fecal H22 and H30-R strains, H22 strains showed a higher capacity to grow in minimal medium with gluconate. Among the genes involved in gluconate metabolism, only the ghrB gene differed between S250/H22 and JJ1886/H30 R strains, resulting in different gluconate reductases. Of the genes involved in biofilm formation, two were absent in the three genomes and one, fimB, in the JJ1886 genome. Our fecal H30-R strains lacking intact fimB displayed delayed biofilm formation relative to our fecal H22 strains. The H22 strains differed by subclade B type and plasmid content, whereas the H30-R strains were identical. CONCLUSIONS: Phenotypic analysis of our fecal strains based on observed genomic differences between S250 and JJ1886 strains suggests the presence of traits related to bacterial commensalism in our H22 strains and traits commonly found in uropathogenic E. coli in our H30-R strains. PMID- 28347274 TI - Erratum to: How can functional annotations be derived from profiles of phenotypic annotations? PMID- 28347273 TI - Stage IVb thymic carcinoma: patients with lymph node metastases have better prognoses than those with hematogenous metastases. AB - BACKGROUND: This study aimed to analyze the pattern of lymphogenous and hematogenous metastases in patients with stage IVb thymic carcinomas and identify prognostic factors for their survivals. METHODS: Between September 1978 and October 2014, 68 patients with pathologically confirmed stage IVb thymic carcinomas were treated at Fudan University Shanghai Cancer Center. Forty-three patients had lymph node involvement without distant metastases, and the remaining 25 patients had hematogenous metastases. Clinical-pathological characteristics, including age, sex, histologic subtype, tumor size, metastasis, treatment modalities, such as surgical resection, radiotherapy, and chemotherapy, and clinical outcomes, such as overall survival (OS) and progression free survival (PFS), were analyzed. RESULTS: The median follow-up time was 22 months (range, 1 126 months). The median OS of all patients with stage IVb thymic carcinomas was 30 months, and the 5-year overall survival rate was 25.1%. The median PFS was 11 months, and the 5-year PFS was 17.9%. Stage IVb patients with lymph node involvement had a better survival than those with distant metastasis (40 vs. 20 months, p = 0.002). Patients with myasthenia gravis had a worse prognosis (p = 0.033). Multivariate analysis identified metastatic status as an independent prognostic factor for OS in patients with stage IVb thymic carcinomas. CONCLUSIONS: Patients with lymph node involvement had a better survival than those with distant metastases. Much work remains to investigate the prognosis of patients with stage IVb thymic carcinomas and to explore different treatment strategies for patients with lymph node involvement and distant metastases. PMID- 28347275 TI - Exploring structural variation and gene family architecture with De Novo assemblies of 15 Medicago genomes. AB - BACKGROUND: Previous studies exploring sequence variation in the model legume, Medicago truncatula, relied on mapping short reads to a single reference. However, read-mapping approaches are inadequate to examine large, diverse gene families or to probe variation in repeat-rich or highly divergent genome regions. De novo sequencing and assembly of M. truncatula genomes enables near comprehensive discovery of structural variants (SVs), analysis of rapidly evolving gene families, and ultimately, construction of a pan-genome. RESULTS: Genome-wide synteny based on 15 de novo M. truncatula assemblies effectively detected different types of SVs indicating that as much as 22% of the genome is involved in large structural changes, altogether affecting 28% of gene models. A total of 63 million base pairs (Mbp) of novel sequence was discovered, expanding the reference genome space for Medicago by 16%. Pan-genome analysis revealed that 42% (180 Mbp) of genomic sequences is missing in one or more accession, while examination of de novo annotated genes identified 67% (50,700) of all ortholog groups as dispensable - estimates comparable to recent studies in rice, maize and soybean. Rapidly evolving gene families typically associated with biotic interactions and stress response were found to be enriched in the accession specific gene pool. The nucleotide-binding site leucine-rich repeat (NBS-LRR) family, in particular, harbors the highest level of nucleotide diversity, large effect single nucleotide change, protein diversity, and presence/absence variation. However, the leucine-rich repeat (LRR) and heat shock gene families are disproportionately affected by large effect single nucleotide changes and even higher levels of copy number variation. CONCLUSIONS: Analysis of multiple M. truncatula genomes illustrates the value of de novo assemblies to discover and describe structural variation, something that is often under-estimated when using read-mapping approaches. Comparisons among the de novo assemblies also indicate that different large gene families differ in the architecture of their structural variation. PMID- 28347277 TI - 'Let food be thy medicine...': lessons from low-protein diets from around the world. AB - In this editorial we present the special issue dedicated to low-protein diets (LPDs) in chronic kidney disease, from a global perspective.The experiences gathered from several countries across all continents have created an issue which we hope you will find insightful, and lead to further discussion on this interesting topic.We discover that LPDs are feasible in both developed and low income countries, in patients where literacy is an issue, and are also safe, including during pregnancy and in old age.Patients prescribed a low protein diet are more inclined to follow and adhere to this change in lifestyle, provided the diet has been adapted to meet their own individual needs. With an increasing list of different menu options and better medical advice being offered we no longer need to identify low protein diets with a specific menu, ingredient or supplement, or with a specific level of protein restriction. Evidence shows how the best diet is often the one chosen by the patients, which doesn't drastically affect their day-to-day life, and delays the start of dialysis for as long as is safe under careful clinical control. The colourful menus gathered from all over the world remind us that a low protein diet does not necessarily mean that the pleasure of preparing a delicious meal is lost. The final comment is therefore dedicated to our patients: low protein diets can be beautiful. PMID- 28347278 TI - Validity of anthropometric equations to estimate infant fat mass at birth and in early infancy. AB - BACKGROUND: In newborns and children, body fat estimation equations are often used at different ages than the age used to develop the equations. Limited validation studies exist for newborn body fat estimation equations at birth or later in infancy. The study purpose was to validate 4 newborn fat mass (FM) estimation equations in comparison to FM measured by air displacement plethysmography (ADP; the Pea Pod) at birth and 3 months. METHODS: Ninety-five newborns (1-3 days) had their body composition measured by ADP and anthropometrics assessed by skinfolds. Sixty-three infants had repeat measures taken (3 months). FM measured by ADP was compared to FM from the skinfold estimation equations (Deierlein, Catalano, Lingwood, and Aris). Paired t-tests assessed mean differences, linear regression assessed accuracy, precision was assessed by R2 and standard error of the estimate (SEE), and bias was assessed by Bland-Altman plots. RESULTS: At birth, FM measured by ADP differed from FM estimated by Deierlein, Lingwood and Aris equations, but did not differ from the Catalano equation. At 3 months, FM measured by ADP was different from all equations. At both time points, poor precision and accuracy was detected. Bias was detected in most all equations. CONCLUSIONS: Poor agreement, precision, and accuracy were found between prediction equations and the criterion at birth and 3 months. PMID- 28347276 TI - Herboxidiene triggers splicing repression and abiotic stress responses in plants. AB - BACKGROUND: Constitutive and alternative splicing of pre-mRNAs from multiexonic genes controls the diversity of the proteome; these precisely regulated processes also fine-tune responses to cues related to growth, development, and stresses. Small-molecule inhibitors that perturb splicing provide invaluable tools for use as chemical probes to uncover the molecular underpinnings of splicing regulation and as potential anticancer compounds. RESULTS: Here, we show that herboxidiene (GEX1A) inhibits both constitutive and alternative splicing. Moreover, GEX1A activates genome-wide transcriptional patterns involved in abiotic stress responses in plants. GEX1A treatment -activated ABA-inducible promoters, and led to stomatal closure. Interestingly, GEX1A and pladienolide B (PB) elicited similar cellular changes, including alterations in the patterns of transcription and splicing, suggesting that these compounds might target the same spliceosome complex in plant cells. CONCLUSIONS: Our study establishes GEX1A as a potent splicing inhibitor in plants that can be used to probe the assembly, dynamics, and molecular functions of the spliceosome and to study the interplay between splicing stress and abiotic stresses, as well as having potential biotechnological applications. PMID- 28347279 TI - Simultaneous detection of respiratory syncytial virus and human metapneumovirus by one-step multiplex real-time RT-PCR in patients with respiratory symptoms. AB - BACKGROUND: Both respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are important viral pathogens causing respiratory tract infection (RTI) in the pediatric population. However, the clinical manifestations of RSV and hMPV infections are similar. Therefore, a reliable and rapid diagnostic tool is needed for diagnostic performance. METHODS: In order to optimize diagnosis efficiency of RTI, the aim of this study is to establish a rapid and advanced method for simultaneous detecting RSV and hMPV in nasopharyngeal aspirates specimens from patients. We designed a one-step triplex real-time RT-PCR (qRT-PCR) protocol using TaqMan probes for detecting RSV and hMPV. The plasmid clones containing RSV nucleoprotein gene and hMPV fusion gene were established as reference standards. We used virus culture supernatants from 86 known pediatric RTI patient to test the specificity and sensitivity of our assay. Then we used total 222 nasopharyngeal aspirates specimens from pediatric patients hospitalized with respiratory symptoms to evaluate our assay. RESULTS: Our one-step triplex qRT-PCR assay showed 100% sensitivity and specificity in testing RSV and hMPV in 86 known virus culture supernatants, with excellent linearity (R2 > 0.99) and reliable reproducibility (CV lower than 1.04%). This assay has a wide dynamic range 102 109copies/reaction (limit of detection; LOD = 100 copies/reaction). A total of 222 patients hospitalized with respiratory symptoms were enrolled for clinical evaluation. In these samples, our qRT-PCR assay detected 68 RSV positive and 18 hMPV positive cases. However, standard virus culture only detected 8 RSV positive cases and 0 hMPV cases. Based on this improved triplex qRT-PCR assay, we found that RSV infection was associated with severe inflammation by chest X-ray and occurrence of pneumonia which were not observed previously. CONCLUSIONS: In summary, we have developed a highly specific and sensitive one-step triplex qRT PCR assay to detect hMPV and RSV simultaneously. This assay offers a valuable tool for routine diagnosis. PMID- 28347281 TI - A structural equation analysis on the relationship between maternal health services utilization and newborn health outcomes: a cross-sectional study in Eastern Uganda. AB - BACKGROUND: Neonatal and maternal health services have a bearing on neonatal mortality. Direct and indirect factors affecting neonatal health outcomes therefore require understanding to enable well-targeted interventions. This study, therefore, assessed the interrelationship between newborn health outcomes and maternal service utilization factors. METHODS: We investigated maternal health utilization factors using health facility delivery and at least four Antenatal Care (ANC) visits; and newborn health outcomes using newborn death and low birth weight (LBW). We used data from a household cross-sectional survey that was conducted in 2015 in Kamuli, Pallisa and Kibuku districts. We interviewed 1946 women who had delivered in the last 12 months. The four interrelated (Endogenous) outcomes were ANC attendance, health facility delivery, newborn death, and LBW. We performed analysis using a structural equation modeling technique. RESULTS: A history of newborn death (aOR = 12.64, 95% CI 5.31-30.10) and birth of a LBW baby (aOR = 3.51, 95% CI 1.48-8.37) were directly related to increased odds of newborn death. Factors that reduced the odds of LBW as a mediating factor for newborn death were ANC fourth time attendance (aOR = 0.62, 95% CI 0.45-0.85), having post-primary level education (aOR = 0.68, 95% CI 0.46 0.98) compared to none and being gravida three (aOR = 0.49, 95% CI 0.26-0.94) compared to being gravida one. Mother's age group, 20-24 (aOR = 0.24, 95% CI 0.08 0.75) and 25-29 years (aOR = 0.20, 95% CI 0.05-0.86) compared to 15-19 years was also associated with reduced odds of LBW. Additionally, ANC visits during the first trimester (aOR = 2.04, 95% CI 1.79-2.34), and village health teams (VHTs) visits while pregnant (aOR = 1.14, 95% CI 1.01-1.30) were associated with increased odds of at least four ANC visits, which is a mediating factor for health facility delivery, LBW and newborn death. Surprisingly, newborn death was not significantly different between health facility and community deliveries. CONCLUSIONS: Attending ANC at least four times was a mediating factor for reduced newborn death and low birth weight. Interventions in maternal health and newborn health should focus on factors that increase ANC fourth time attendance and those that reduce LBW especially in resource-limited settings. Targeting women with high-risk pregnancies is also crucial for reducing newborn deaths. PMID- 28347280 TI - Comparison of two commercial broad-range PCR and sequencing assays for identification of bacteria in culture-negative clinical samples. AB - BACKGROUND: Culturing has long been the gold standard for detecting aetiologic agents in bacterial infections. In some cases, however, culturing fails to detect the infection. To further investigate culture-negative samples, amplification and subsequent sequencing of the 16S rRNA gene is often applied. The aim of the present study was to compare the current method used at our Department of Clinical Microbiology, based on the MicroSeq ID system (Applied Biosystems, USA) with the Universal Microbe Detection (UMD) SelectNA kit (Molzym, Germany). METHODS: 76 culture-negative samples were first processed with the MicroSeq ID analysis, where total DNA was extracted and the 16S gene amplified and sequenced with the MicroSeq ID system. Samples were subsequently processed with the UMD SelectNA analysis, where human DNA was removed during the DNA extraction procedure and the 16S gene amplified in a real-time PCR and sequenced. RESULTS: 22 of 76 samples (28.9%) were positive for bacteria with the UMD SelectNA, which was significantly more (p = 0.0055) than the MicroSeq ID where 11 of 76 samples (14.5%) were positive. The UMD SelectNA assay identified more relevant bacterial pathogens than the MicroSeq ID analysis (p = 0.0233), but also found a number of species that were considered contaminations. CONCLUSIONS: The UMD SelectNA assay was valuable for the identification of pathogens in culture-negative samples; however, due to the sensitive nature of the assay, extreme care is suggested in order to avoid false positives. PMID- 28347282 TI - Hyperuricemia after orthotopic liver transplantation: divergent associations with progression of renal disease, incident end-stage renal disease, and mortality. AB - BACKGROUND: Although hyperuricemia is common after orthotopic liver transplantation (OLT), its relationship to mortality, progressive kidney disease, or the development of end stage renal disease (ESRD) is not well-described. METHODS: Data from 304 patients undergoing OLT between 1996 and 2010 were used to assess the association of mean serum uric acid (UA) level in the 3-months post OLT with mortality, doubling of creatinine, and ESRD incidence. Post-OLT survival to event outcomes according to UA level and eGFR was assessed using the Kaplan Meier method and multivariate Cox proportional hazards models. RESULTS: Mean UA level among the 204 patients with an eGFR level >=60 ml/min/1.73 m2 was 6.4 mg/dl compared to 7.9 mg/dl among the 100 patients with eGFR <60 (p < 0.0001). During a median of 4.6 years of follow-up, mortality rate, doubling of creatinine, and ESRD incidence were 48.9, 278.2, and 20.7 per 1000 person-years, respectively. In the first 5 years of follow-up, elevated UA was associated with mortality (Hazard Ratio, HR = 1.7; p = 0.045). However, among those with eGFR >= 60, UA level did not predict mortality (HR = 1.0; p = 0.95), and among those with eGFR < 60, elevated UA was a strong predictor of mortality (HR = 3.7[1.1, 12.0]; p = 0.03). UA was not associated with ESRD, but was associated with doubling of creatinine among diabetics (HR = 2.2[1.1, 4.3]; p = 0.025). CONCLUSION: In this post-OLT cohort, hyperuricemia independently predicted mortality, particularly among patients with eGFR < 60, and predicted doubling of creatinine among diabetics. PMID- 28347283 TI - Healthcare resource use and costs of multiple sclerosis patients in Germany before and during fampridine treatment. AB - BACKGROUND: Multiple sclerosis (MS) patients often suffer from gait impairment and fampridine is indicated to medically improve walking ability in this population. Patient characteristics, healthcare resource use, and costs of MS patients on fampridine treatment for 12 months in Germany were analyzed. METHODS: A retrospective claims database analysis was conducted including MS patients who initiated fampridine treatment (index date) between July 2011 and December 2013. Continuous insurance enrollment during 12 months pre- and post-index date was required, as was at least 1 additional fampridine prescription in the fourth quarter after the index date. Patient characteristics were evaluated and pre- vs post-index MS-related healthcare utilization and costs were compared. RESULTS: A total of 562 patients were included in this study. The mean (standard deviation [SD]) age was 50.5 (9.8) years and 63% were female. In the treatment period, almost every patient had at least 1 MS-related outpatient visit, 24% were hospitalized due to MS, and 79% utilized MS-specific physical therapy in addition to the fampridine treatment. Total MS-related healthcare costs were significantly higher in the fampridine treatment period than in the period prior to fampridine initiation (?17,392 vs ?10,960, P < 0.001). While this difference was driven primarily by prescription costs, MS-related inpatient costs were lower during fampridine treatment (?1,333 vs ?1,565, P < 0.001). CONCLUSIONS: Physical therapy is mainly used concomitant to fampridine treatment. While healthcare costs were higher during fampridine treatment compared to the pre-treatment period, inpatient costs were lower. Further research is necessary to better understand the fampridine influence. PMID- 28347284 TI - How does the media portray drinking water security in Indigenous communities in Canada? An analysis of Canadian newspaper coverage from 2000-2015. AB - BACKGROUND: Drinking water insecurity and related health outcomes often disproportionately impact Indigenous communities internationally. Understanding media coverage of these water-related issues can provide insight into the ways in which public perceptions are shaped, with potential implications for decision making and action. This study aimed to examine the extent, range, and nature of newspaper coverage of drinking water security in Canadian Indigenous communities. METHODS: Using ProQuest database, we systematically searched for and screened newspaper articles published from 2000 to 2015 from Canadian newspapers: Windspeaker, Toronto Star, The Globe and Mail, and National Post. We conducted descriptive quantitative analysis and thematic qualitative analysis on relevant articles to characterize framing and trends in coverage. RESULTS: A total of 1382 articles were returned in the search, of which 256 articles were identified as relevant. There was limited coverage of water challenges for Canadian Indigenous communities, especially for Metis (5%) and Inuit (3%) communities. Most stories focused on government responses to water-related issues, and less often covered preventative measures such as source water protection. Overall, Indigenous peoples were quoted the most often. Double-standards of water quality between Indigenous and non-Indigenous communities, along with conflict and cooperation efforts between stakeholders were emphasized in many articles. CONCLUSION: Limited media coverage could undermine public and stakeholder interest in addressing water-related issues faced by many Canadian Indigenous communities. PMID- 28347285 TI - Whole-exome sequencing and digital PCR identified a novel compound heterozygous mutation in the NPHP1 gene in a case of Joubert syndrome and related disorders. AB - BACKGROUND: Joubert syndrome and related disorders (JSRD) is a clinically and genetically heterogeneous condition with autosomal recessive or X-linked inheritance, which share a distinctive neuroradiological hallmark, the so-called molar tooth sign. JSRD is classified into six clinical subtypes based on associated variable multiorgan involvement. To date, 21 causative genes have been identified in JSRD, which makes genetic diagnosis difficult. CASE PRESENTATION: We report here a case of a 28-year-old Japanese woman diagnosed with JS with oculorenal defects with a novel compound heterozygous mutation (p.Ser219*/deletion) in the NPHP1 gene. Whole-exome sequencing (WES) of the patient identified the novel nonsense mutation in an apparently homozygous state. However, it was absent in her mother and heterozygous in her father. A read depth based copy number variation (CNV) detection algorithm using WES data of the family predicted a large heterozygous deletion mutation in the patient and her mother, which was validated by digital polymerase chain reaction, indicating that the patient was compound heterozygous for the paternal nonsense mutation and the maternal deletion mutation spanning the site of the single nucleotide change. CONCLUSION: It should be noted that analytical pipelines that focus purely on sequence information cannot distinguish homozygosity from hemizygosity because of its inability to detect large deletions. The ability to detect CNVs in addition to single nucleotide variants and small insertion/deletions makes WES an attractive diagnostic tool for genetically heterogeneous disorders. PMID- 28347286 TI - Malignant acrospiroma: a case report in the era of next generation sequencing. AB - BACKGROUND: Malignant acrospiroma is a rare tumor of the eccrine sweat glands accounting for around 6% of all malignant eccrine tumors. Typically, it presents as large ulcerated nodules, and diagnosis can be challenging as it has great overlap with its benign counterpart. CASE PRESENTATION: We herein report a case of acral malignant acrospiroma, initially treated with surgical excision and adjuvant radiotherapy. After metastatic disease was confirmed, subject received multiple lines of chemo- as well as targeted therapy. Genomic testing was also done using next generation sequencing. CONCLUSION: To the best of our knowledge, this is the first case of acral malignant acrospiroma with reported next generation sequencing results. PMID- 28347287 TI - Unraveling the complexity of transcriptomic, metabolomic and quality environmental response of tomato fruit. AB - BACKGROUND: The environment has a profound influence on the organoleptic quality of tomato (Solanum lycopersicum) fruit, the extent of which depends on a well regulated and dynamic interplay among genes, metabolites and sensorial attributes. We used a systems biology approach to elucidate the complex interacting mechanisms regulating the plasticity of sensorial traits. To investigate environmentally challenged transcriptomic and metabolomic remodeling and evaluate the organoleptic consequences of such variations we grown three tomato varieties, Heinz 1706, whose genome was sequenced as reference and two "local" ones, San Marzano and Vesuviano in two different locations of Campania region (Italy). RESULTS: Responses to environment were more pronounced in the two "local" genotypes, rather than in the Heinz 1706. The overall genetic composition of each genotype, acting in trans, modulated the specific response to environment. Duplicated genes and transcription factors, establishing different number of network connections by gaining or losing links, play a dominant role in shaping organoleptic profile. The fundamental role of cell wall metabolism in tuning all the quality attributes, including the sensorial perception, was also highlighted. CONCLUSIONS: Although similar fruit-related quality processes are activated in the same environment, different tomato genotypes follow distinct transcriptomic, metabolomic and sensorial trajectories depending on their own genetic makeup. PMID- 28347288 TI - ABCG2 is a potential prognostic marker of overall survival in patients with clear cell renal cell carcinoma. AB - BACKGROUND: ATP-binding cassette sub-family G member 2 (ABCG2) is a semi transport protein that plays a major role in multidrug resistance. We aimed to evaluate the prognostic significance of ABCG2 expression in patients with clear cell renal cell carcinoma. METHODS: From 2008 to 2013, 120 patients with clear cell kidney cancer underwent surgery with paraffin-embedded specimens and necessary clinical information available. Immunohistochemistry staining was performed to grade the expression of ABCG2 as ABCG2(-): less than 10% of tumor cells stained; ABCG2(+): weak membrane staining; and ABCG2(++): moderate or strong membrane staining. The overall survival was analyzed using Kaplan-Meier method. Multivariable Cox regression evaluated the independent predictors for overall survival. RESULTS: ABCG2(-) was diagnosed in 57 (48%) patients, ABCG2(+) in 52 (43%) patients, and ABCG2 (++) in 11(9.2%) patients. ABCG2 expression significantly correlated with the five-year survival (p < 0.001) and distant metastasis (p = 0.001). In the multivariable analysis, besides Fuhrman grade, the ABCG2 expression was an independent prognostic marker for overall survival (p < 0.001) when incorporating other relevant tumor and clinical parameters (HR = 3.84, 95% CI: 1.92-7.70). CONCLUSION: The current data suggests that ABCG2 may serve as a prognostic marker for overall survival in patients with clear cell renal cell carcinoma. Further studies with large cohorts of patients will be essential for validating these findings and defining the clinical utility of ABCG2 in the patient population. PMID- 28347289 TI - DNA alterations in Cd133+ and Cd133- tumour cells enriched from intra-operative human colon tumour biopsies. AB - BACKGROUND: Tumour stem cells are considered important to promote disease progression, recurrence and treatment resistance following chemotherapy in colon cancer. However, genomic analyses of colorectal cancer have mainly been performed on integrated tumour tissue consisting of several different cell types in addition to differentiated tumour cells. The purpose of the present study was to compare genomic alterations in two cell fractions enriched of CD133+ and CD133 /EpCAM+ cells, respectively, obtained from fresh intraoperative human tumour biopsies. METHODS: The tumour biopsies were fractionated into CD133+ and CD133 /EpCAM+ cells by immunomagnetic separation, confirmed by immunocytochemistry and Q-PCR. DNA were extracted and used for array comparative genome hybridization (aCGH) after whole genome amplification. Frozen tumour tissue biopsies were used for DNA/RNA extraction and Q-PCR analyses to check for DNA alterations detected in the cell fractions. RESULTS: The number and size of DNA alterations were equally distributed across the cell fractions; however, large deletions were detected on chromosome 1, 7 and 19 in CD133-/EpCAM+ cells. Deletions were frequent in both cell fractions and a deletion on chromosome 19p was confirmed in 90% of the patients. CONCLUSION: Isolation of enriched cells derived from tumour tissue revealed mainly genomic deletions, which were not observed in tumour tissue DNA analyses. CD133+ cells were genetically heterogeneous among patients without any defined profile compared to CD133-/EpCAM+ cells. PMID- 28347290 TI - A possible association of baseline serum IL-17A concentrations with progression free survival of metastatic colorectal cancer patients treated with a bevacizumab based regimen. AB - BACKGROUND: Colorectal cancer is a major public health issue worldwide. Interleukin-17 (IL-17) and Th17 (T-helper cell type 17)-related molecules are involved in tumor development and in resistance to bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody used in association with chemotherapy in metastatic colorectal cancer. Some studies have previously shown that IL-17A and IL-17F polymorphisms, respectively rs2275913 and rs763780, are associated with gastric or colorectal cancer risk. Here we aimed at studying the influence of IL-17A-related individual factors on overall survival and progression-free survival in patients with metastatic colorectal cancer treated with a bevacizumab-based chemotherapy. METHODS: Pre-treatment serum biomarkers were retrospectively evaluated in 122 metastatic colorectal cancer patients treated by bevacizumab in combination with chemotherapy at 2-weeks intervals in a prospective cohort study (NCT00489697). The polymorphisms of IL-17A and IL-17F were analyzed by polymerase chain reaction - restriction fragment length polymorphism. Serum concentrations of Th17-related cytokines were measured by MultiPlex. The impact of individual parameters on overall survival and progression-free survival was assessed using multivariate Cox models. RESULTS: High baseline IL-17A serum concentrations were significantly associated with shorter progression-free survival [p = 0.043]. Other baseline serum Th17-related cytokines and polymorphisms of IL-17 were not associated with overall survival or progression-free survival. CONCLUSIONS: In this ancillary study, baseline serum IL-17A concentration is the only Th17/IL-17 related factor that was significantly associated with the response of patients with metastatic colorectal cancer to bevacizumab. But this main significant result is highly dependent on one case which, if left out, weakens the data. Other clinical studies are required to confirm this association. TRIAL REGISTRATION: NCT00489697 . June 20, 2007. PMID- 28347291 TI - Design of a randomized controlled trial of physical training and cancer (Phys Can) - the impact of exercise intensity on cancer related fatigue, quality of life and disease outcome. AB - BACKGROUND: Cancer-related fatigue is a common problem in persons with cancer, influencing health-related quality of life and causing a considerable challenge to society. Current evidence supports the beneficial effects of physical exercise in reducing fatigue, but the results across studies are not consistent, especially in terms of exercise intensity. It is also unclear whether use of behaviour change techniques can further increase exercise adherence and maintain physical activity behaviour. This study will investigate whether exercise intensity affects fatigue and health related quality of life in persons undergoing adjuvant cancer treatment. In addition, to examine effects of exercise intensity on mood disturbance, adherence to oncological treatment, adverse effects from treatment, activities of daily living after treatment completion and return to work, and behaviour change techniques effect on exercise adherence. We will also investigate whether exercise intensity influences inflammatory markers and cytokines, and whether gene expressions following training serve as mediators for the effects of exercise on fatigue and health related quality of life. METHODS/DESIGN: Six hundred newly diagnosed persons with breast, colorectal or prostate cancer undergoing adjuvant therapy will be randomized in a 2 * 2 factorial design to following conditions; A) individually tailored low-to moderate intensity exercise with or without behaviour change techniques or B) individually tailored high intensity exercise with or without behaviour change techniques. The training consists of both resistance and endurance exercise sessions under the guidance of trained coaches. The primary outcomes, fatigue and health related quality of life, are measured by self-reports. Secondary outcomes include fitness, mood disturbance, adherence to the cancer treatment, adverse effects, return to activities of daily living after completed treatment, return to work as well as inflammatory markers, cytokines and gene expression. DISCUSSION: The study will contribute to our understanding of the value of exercise and exercise intensity in reducing fatigue and improving health related quality of life and, potentially, clinical outcomes. The value of behaviour change techniques in terms of adherence to and maintenance of physical exercise behaviour in persons with cancer will be evaluated. TRIAL REGISTRATION: NCT02473003 , October, 2014. PMID- 28347292 TI - Protocol for a randomized, double blind, placebo controlled, crossover trial of Melatonin for treatment of Nocturia in adults with Multiple Sclerosis (MeNiMS). AB - BACKGROUND: Nocturia (the symptom of needing to wake up to pass urine) is common in progressive Multiple Sclerosis (MS) patients. Moderate-to-severe nocturia affects quality of life, can exacerbate fatigue and may affect capacity to carry out daily activities. Melatonin is a natural hormone regulating circadian cycles, released by the pineal gland at night-time, and secretion is impaired in MS. Melatonin levels can be supplemented by administration in tablet form at bedtime. The aim of this study is to evaluate the effect of melatonin on mean number of nocturia episodes per night in MS patients. Secondary outcome measures will assess impact upon quality of life, urinated volumes, lower urinary tract symptoms (LUTS), cognition, sleep quality and sleep disturbance of partners. METHODS: A randomized, double blind, placebo controlled, crossover trial consisting of two, six week treatment phases (active drug melatonin 2 mg or placebo), with a 1 month wash-out period in between. The primary outcome (change in nocturia episodes per night) in this two arm, two treatment, two period crossover design, will be objectively measured using frequency volume charts (FVC) at baseline and following both treatment phases. Questionnaires will be used to assess quality of life, sleep quality, safety and urinary tract symptoms. Qualitative interviews of participants and partners will explore issues including quality of life, mechanisms of sleep disturbance and impact of nocturia on partners. DISCUSSION: This study will evaluate whether melatonin reduces the frequency of nocturia episodes in MS patients, and therefore whether 'Circadin' has the potential to reduce LUTS and fatigue, and improve cognition and overall quality of life. TRIAL REGISTRATION: (EudraCT reference) 2012-00418321 registered: 25/01/13. ISRCTN Registry: ISRCTN38687869. PMID- 28347293 TI - Comparison of a novel microcrystalline tyrosine adjuvant with aluminium hydroxide for enhancing vaccination against seasonal influenza. AB - BACKGROUND: Vaccination against seasonal influenza strains is recommended for "high risk" patient groups such as infants, elderly and those with respiratory or circulatory diseases. However, efficacy of the trivalent influenza vaccine (TIV) is poor in many cases and in the event of an influenza pandemic, mono-valent vaccines have been rapidly developed and deployed. One of the main issues with use of vaccine in pandemic situations is the lack of a suitable quantity of vaccine early enough during the pandemic to exert a major influence on the transmission of virus and disease outcome. One approach is to use a dose-sparing regimen which inevitably involves enhancing the efficacy using adjuvants. METHODS: In this study we compare the use of a novel microcrystalline tyrosine (MCT) adjuvant, which is currently used in a niche area of allergy immunotherapy, for its ability to enhance the efficacy of a seasonal TIV preparation. The efficacy of the MCT adjuvant formulation was compared to alum adjuvanted TIV and to TIV administered without adjuvant using a ferret challenge model to determine vaccine efficacy. RESULTS: The MCT was found to possess high protein-binding capacity. In the two groups where TIV was formulated with adjuvant, the immune response was found to be higher (as determined by HAI titre) than vaccine administered without adjuvant and especially so after challenge with a live influenza virus. Vaccinated animals exhibited lower viral loads (as determined using RT-PCR) than control animals where no vaccine was administered. CONCLUSIONS: The attributes of each adjuvant in stimulating single-dose protection against a poorly immunogenic vaccine was demonstrated. The properties of MCT that lead to the reported effectiveness warrants further exploration in this and other vaccine targets - particularly where appropriate immunogenic, biodegradable and stable alternative adjuvants are sought. PMID- 28347294 TI - From good health to illness with post-infectious fatigue syndrome: a qualitative study of adults' experiences of the illness trajectory. AB - BACKGROUND: Municipal drinking water contaminated with the parasite Giardia lamblia in Bergen, Norway, in 2004 caused an outbreak of gastrointestinal infection in 2500 people, according to the Norwegian Prescription Database. In the aftermath a minor group subsequently developed post-infectious fatigue syndrome (PIFS). Persons in this minor group had laboratory-confirmed parasites in their stool samples, and their enteritis had been cured by one or more courses of antibiotic treatment. The study's purpose was to explore how the affected persons experienced the illness trajectory and various PIFS disabilities. METHODS: A qualitative design with in-depth interviews was used to obtain first hand experiences of PIFS. To get an overall understanding of their perceived illness trajectory, the participants were asked to retrospectively rate their functional level at different points in time. A maximum variation sample of adults diagnosed with PIFS according to the international 1994 criteria was recruited from a cohort of persons diagnosed with PIFS at a tertiary Neurology Outpatient Clinic in Western Norway. The sample comprised 19 women and seven men (mean age 41 years, range 26-59). The interviews were fully transcribed and subjected to a qualitative content analysis. RESULTS: All participants had been living healthy lives pre-illness. The time to develop PIFS varied. Multiple disabilities in the physical, cognitive, emotional, neurological, sleep and intolerance domains were described. Everyone more or less dropped out from studies or work, and few needed to be taken care of during the worst period. The severity of these disabilities varied among the participants and during the illness phases. Despite individual variations, an overall pattern of illness trajectory emerged. Five phases were identified: prodromal, downward, turning, upward and chronic phase. All reached a nadir followed by varying degrees of improvement in their functional ability. None regained pre-illness health or personal and professional abilities. CONCLUSIONS: The needs of persons with this condition are not met. Early diagnosis and interdisciplinary rehabilitation could be beneficial in altering the downward trajectory at an earlier stage, avoiding the most severe disability and optimising improvement. Enhanced knowledge among health professionals, tailored treatment, rest as needed, financial support and practical help would likely improve prognosis. PMID- 28347295 TI - Factors associated with anemia among Sri Lankan primary school children in rural North Central Province. AB - BACKGROUND: Despite interventions, childhood anemia is still a major public health problem in low and middle income countries. Purpose of the present study is to determine factors associated with anemia among rural primary school children in Sri Lanka, a country undergoing rapid socioeconomic changes. METHODS: Multi stage cluster sampling was used to select 100 rural schools in NCP and a maximum of 50 children aged 60-131 months were enrolled from each school. Self administered questionnaires were sent to parents. Anthropometric measurements and blood samples were obtained by trained investigators. Blood reports were analyzed in a commercial laboratory with external quality control measures. RESULTS: Total of 4412 children were included in the analysis. A Multiple regression was performed for hemoglobin. Only 4.2% of the change in hemoglobin could be explained by the model. District (p > 0.001), age (p > 0.001), timing of warm treatment(p = 0.026) and BMI for age (p = 0.002) uniquely contributed 1.12%, 1.19%, 0.13% and 0.26% to change in hemoglobin level respectively whereas, sex, monthly family income and frequency of meat and green leaf consumption didn't contribute significantly. Peripheral blood film analyses were available for 146 anemic children. Blood film was reported as normal in 19.9% while evidence of iron deficiency (18.5%), early iron deficiency (32.5%) and thalassemia trait with iron deficiency (29.5%) were reported in the rest. Serum ferritin level was available for 417 children with hemoglobin less than 12 g/dl. Mean ferritin level was 63.7 microgram/l. Only 0.5% had depleted iron stores. A multiple regression was performed for serum ferritin and R2 was 0.123 (p < 0.001). Area under the curve for serum ferritin and anemia was 0.436. CONCLUSION: Anemia among rural primary school children in NCP cannot be well explained by routinely assessed socioeconomic characteristics which mainly provide clues to access for food. Commonly used anemia related investigations have low validity in detecting and explaining anemia in this population. Since behavioral factors have been shown to affect nutrition of younger children in Sri Lanka, studying weather behaviors are related to anemia in primary school children is important. Possible etiologies including but not limited to nutritional deficiencies need to be studied further. PMID- 28347296 TI - The effect of postal questionnaire burden on response rate and answer patterns following admission to intensive care: a randomised controlled trial. AB - BACKGROUND: The effects of postal questionnaire burden on return rates and answers given are unclear following treatment on an intensive care unit (ICU). We aimed to establish the effects of different postal questionnaire burdens on return rates and answers given. METHODS: Design: A parallel group randomised controlled trial. We assigned patients by computer-based randomisation to one of two questionnaire packs (Group A and Group B). SETTING: Patients from 26 ICUs in the United Kingdom. INCLUSION CRITERIA: Patients who had received at least 24 h of level 3 care and were 16 years of age or older. Patients did not know that there were different questionnaire burdens. The study included 18,490 patients. 12,170 were eligible to be sent a questionnaire pack at 3 months. We sent 12,105 questionnaires (6112 to group A and 5993 to group B). INTERVENTIONS: The Group A pack contained demographic and EuroQol group 5 Dimensions 3 level (EQ-5D-3 L) questionnaires, making four questionnaire pages. The Group B pack also contained the Hospital Anxiety and Depression Score (HADS) and the Post-Traumatic Stress Disorder Check List-Civilian (PCL-C) questionnaires, making eight questionnaire pages in total. MAIN OUTCOME MEASURE: Questionnaire return rate 3 months after ICU discharge by group. RESULTS: In group A, 2466/6112 (40.3%) participants responded at 3 months. In group B 2315/ 5993 (38.6%) participants responded (difference 1.7% CI for difference 0-3.5% p = 0.053). Group A reported better functionality than group B in the EQ-5D-3 L mobility (41% versus 37% reporting no problems p = 0.003) and anxiety/depression (59% versus 55% reporting no problems p = 0.017) domains. CONCLUSIONS: In survivors of intensive care, questionnaire burden had no effect on return rates. However, questionnaire burden affected answers to the same questionnaire (EQ-5D-3 L). TRIAL REGISTRATION: ISRCTN69112866 (assigned 02/05/2006). PMID- 28347298 TI - Erratum to: Local intra-uterine Ang-(1-7) infusion attenuates PGE2 and 6-keto PGF1alpha in decidualized uterus of pseudopregnant rats. PMID- 28347297 TI - Factors affecting the long-term outcomes of idiopathic membranous nephropathy. AB - BACKGROUND: We attempted to describe the clinical features and determine the factors associated with renal survival in idiopathic membranous nephropathy (iMN) patients with nephrotic syndrome (NS) and to determine the factors associated with spontaneous complete remission (sCR) and progression to NS in iMN patients with subnephrotic proteinuria. METHODS: This retrospective study involved 166 iMN patients with NS and 65 patients with subnephrotic proteinuria. The primary end point was a doubling of serum creatinine or initiation of dialysis. In patients with subnephrotic proteinuria, we determined the factors associated with sCR and factors associated with progression to NS. RESULTS: Remission of NS was achieved in 125 out of 166 patients (75.3%). Of those who reached remission, 26 patients (20.8%) experienced relapse that was followed by second remission. The relapse or persistence of proteinuria was associated with the primary end points (hazard ratio [HR] = 12.40, P = 0.037, HR = 173, P < 0.001, respectively). In patients with subnephrotic proteinuria, sCR occurred in 35.4% of the patients. The patients with sCR had lower proteinuria and serum creatinine levels and higher serum albumin concentrations at baseline. The serum albumin level at diagnosis was a prognostic factor for progression to NS (Odds ratio [OR] = 0.015, P < 0.001). CONCLUSIONS: The occurrence of relapse or persistence of proteinuria had negative effects on renal survival in iMN patients with NS, and low serum albumin levels at baseline were associated with non-achievement of sCR and progression to NS. PMID- 28347299 TI - Erratum to: Integrin-FAK signaling rapidly and potently promotes mitochondrial function through STAT3. PMID- 28347300 TI - Students' attitudes and perceptions of teaching and assessment of evidence-based practice in an occupational therapy professional Master's curriculum: a mixed methods study. AB - BACKGROUND: Most health professions, including occupational therapy, have made the application of evidence-based practice a desired competency and professional responsibility. Despite the increasing emphasis on evidence-based practice for improving patient outcomes, there are numerous research-practice gaps in the health professions. In addition to efforts aimed at promoting evidence-based practice with clinicians, there is a strong impetus for university programs to design curricula that will support the development of the knowledge, attitudes, skills and behaviours associated with evidence-based practice. Though occupational therapy curricula in North America are becoming increasingly focused on evidence-based practice, research on students' attitudes towards evidence based practice, their perceptions regarding the integration and impact of this content within the curricula, and the impact of the curriculum on their readiness for evidence-based practice is scarce. The present study examined occupational therapy students' perceptions towards the teaching and assessment of evidence based practice within a professional master's curriculum and their self-efficacy for evidence-based practice. METHODS: The study used a mixed methods explanatory sequential design. The quantitative phase included a cross-sectional questionnaire exploring attitudes towards evidence-based practice, perceptions of the teaching and assessment of evidence-based practice and evidence-based practice self-efficacy for four cohorts of students enrolled in the program and a cohort of new graduates. The questionnaire was followed by a focus group of senior students aimed at further exploring the quantitative findings. RESULTS: All student cohorts held favourable attitudes towards evidence-based practice; there was no difference across cohorts. There were significant differences with regards to perceptions of the teaching and assessment of evidence-based practice within the curriculum; junior cohorts and students with previous education had less favourable perceptions. Students' self-efficacy for evidence-based practice was significantly higher across cohorts. Four main themes emerged from the focus group data: (a) Having mixed feelings about the value of evidence-based practice (b) Barriers to the application of evidence-based practice; (c) Opposing worlds and (d) Vital and imperfect role of the curriculum. CONCLUSION: This study provides important data to support the design and revision of evidence-based practice curricula within professional rehabilitation programs. PMID- 28347301 TI - Does social distinction contribute to socioeconomic inequalities in diet: the case of 'superfoods' consumption. AB - BACKGROUND: The key mechanisms underlying socioeconomic inequalities in dietary intake are still poorly understood, hampering the development of interventions. An important, but sparsely mentioned mechanism is that of 'social distinction', whereby those in a higher socioeconomic position adopt dietary patterns by which they can distinguish themselves from lower socioeconomic groups. We investigated the importance of distinction as a mechanism, by testing the socioeconomic gradient in the consumption of so-called 'superfoods' and the contribution of a well-established indicator of distinction, cultural participation. METHODS: Data from participants (25-75 years) of the 2014 survey of the Dutch population-based GLOBE study were used (N = 2812). Multivariable regression models were used to analyse the association between education, income and cultural participation (e.g. visits to museums, opera, theatre, concerts) and the consumption of superfoods (spelt, quinoa and goji berries, chia seeds or wheatgrass). RESULTS: The consumption of superfoods is far more prevalent among higher socioeconomic groups. Adjusting for cultural participation strongly attenuated the educational and income gradient in superfoods consumption, whereas cultural participation remained strongly associated with superfoods consumption. Those in the highest quintile of cultural participation reported the highest consumption of spelt products (OR = 2.97, 95% CI = 2.10;4.18), quinoa (OR = 3.50, 95% CI = 2.12;5.79) and goji berries, chia seeds or wheatgrass (OR = 2.69, 95% CI = 1.73;4.17). CONCLUSIONS: The associations between socioeconomic position and the consumption of 'superfoods' seem to be partially driven by a process of social distinction. These findings suggest that distinction may be an important, but currently neglected mechanism in generating socioeconomic inequalities in dietary intake. It deserves a more prominent role in interventions to reduce these inequalities. PMID- 28347302 TI - Development and validation of a high-throughput calcium mobilization assay for the orphan receptor GPR88. AB - BACKGROUND: GPR88 is an orphan G protein-coupled receptor highly expressed in the striatum and is implicated in basal ganglia-associated disorders. However, the receptor functions of GPR88 are still largely unknown due to the lack of potent and selective ligands appropriate for central nervous system investigation. Development of a high-throughput screening assay for GPR88 should facilitate the discovery of novel ligands to probe GPR88 functions. METHODS: In this paper, we describe the development of a CHO-Galphaqi5-GPR88 cell-based calcium mobilization assay. The assay takes advantage of functional coupling of GPR88 with the promiscuous Galphaqi5 protein and consequent mobilization of intracellular calcium, which can be measured in a 384-well format with a Fluorescent Imaging Plate Reader. RESULTS: The CHO-Galphaqi5-GPR88 cell-based calcium mobilization assay was validated by the structure-activity relationship study of known GPR88 agonist (1R,2R)-2-PCCA analogues. The assay was automated and miniaturized to a 384-well format, and was deemed robust and reproducible with a Z'-factor of 0.72 and tolerated dimethyl sulfoxide to a final concentration of 2%. Screening a pilot neurotransmitter library consisting of 228 compounds yielded 10 hits, but none of the hits were confirmed as GPR88 agonists in follow-up assays. CONCLUSIONS: We have developed a high-throughput calcium mobilization assay for the orphan receptor GPR88. This calcium mobilization assay can be used to identify several different types of GPR88 ligands including agonists, competitive and noncompetitive antagonists, inverse agonists, and allosteric modulators. These ligands will serve as valuable tools to probe signaling mechanisms and in vivo functions of GPR88, and could expedite development of novel therapies for diseases potentially mediated by GPR88. PMID- 28347303 TI - Satisfaction with dental care among patients who receive invasive or non-invasive treatment for non-cavitated early dental caries: findings from one region of the National Dental PBRN. AB - BACKGROUND: The objectives were to: (1) quantify patient satisfaction with treatment for early dental caries overall, and according to whether or not (2a) the patient received invasive treatment; (2b) was high-risk for dental caries, and had dental insurance; and (3) encourage practitioners to begin using non invasive approaches to early caries management. METHODS: Ten practitioners recorded patient, lesion, and treatment information about non-cavitated early caries lesions. Information on 276 consecutive patients with complete data was included, who received either non-invasive (no dental restoration) or invasive (dental restoration) treatment. Patients completed a patient satisfaction questionnaire and were classified as dissatisfied if they did not "agree" or "strongly agree" with any of 14 satisfaction items. RESULTS: Patients had a mean (+/- SD) age of 41.8 (+/-15.8) years, 64% were female and 88% were white. Twenty five percent (n = 68) were dissatisfied in at least one of the 14 satisfaction items. Satisfaction levels did not significantly vary by patient's gender, race, caries risk category, or affected tooth surface location. Overall, 11% (28 of 276) received invasive treatment; satisfaction did not differ between patients who had invasive or non-invasive treatment. Seven patients received invasive treatment at their request even though that was not what their practitioner recommended; 5 out of 6 were satisfied with their treatment nonetheless. CONCLUSIONS: About one-fourth of patients treated for non-cavitated early caries were dissatisfied with at least some aspect of their dental care experience. Satisfaction of patients who received invasive treatment did not differ from those who received non-invasive treatment. PMID- 28347304 TI - Implementing an online pharmaceutical service using design science research. AB - BACKGROUND: The rising prevalence of chronic diseases is pressing health systems to introduce reforms. Primary healthcare and multidisciplinary models have been suggested as approaches to deal with this challenge, with new roles for nurses and pharmacists being advocated. More recently, implementing healthcare based on information systems and technologies (e.g. eHealth) has been proposed as a way to improve health services. However, implementing online pharmaceutical services, including their adoption by pharmacists and patients, is still an open research question. In this paper we present ePharmacare, a new online pharmaceutical service implemented using Design Science Research. METHODS: The Design Science Research Methodology (DSRM) was chosen to implement this online service for chronic diseases management. In the paper, DSRM's different activities are explained, from the definition of the problem to the evaluation of the artifact. During the design and development activities, surveys, observations, focus groups, and eye-tracking glasses were used to validate pharmacists' and patients' requirements. During the demonstration and evaluation activities the new service was used with real-world pharmacists and patients. RESULTS: The results show the contribution of DSRM in the implementation of online services for pharmacies. We found that pharmacists spend only 50% of their time interacting with patients, uncovering a clear opportunity to implement online pharmaceutical care services. On the other hand, patients that regularly visit the same pharmacy recognize the value in patient follow-up demanding to use channels such as the Internet for their pharmacy interactions. Limitations were identified regarding the high workload of pharmacists, but particularly their lack of know-how and experience in dealing with information systems (IST) for the provision of pharmaceutical services. CONCLUSIONS: This paper summarizes a research project in which an online pharmaceutical service was proposed, designed, developed, demonstrated and evaluated using DSRM. The main barriers for pharmacists' adoption of online pharmaceutical services provision were the lack of time, time management and information systems usage skills, as well as a precise role definition within pharmacies. These problems can be addressed with proper training and services reorganization, two proposals to be investigated in future works. PMID- 28347305 TI - Abnormal gene expression in regular and aggregated somatic cell nuclear transfer placentas. AB - BACKGROUND: Placental defects in somatic cell nuclear transfer (SCNT) are a major cause of complications during pregnancy. One of the most critical factors for the success of SCNT is the successful epigenetic reprogramming of donor cells. Recently, it was reported that the placental weight in mice cloned with the aggregated SCNT method was significantly reduced. Here, we examine the profile of abnormal gene expression using microarray technology in both regular SCNT and aggregated SCNT placentas as well as in vivo fertilization placentas. One SCNT embryo was aggregated with two 2 to 4 -cell stage tetraploid embryos from B6D2F1 mice (C57BL/6 * DBA/2). RESULTS: In SCNT placentas, 206 (1.6%) of the 12,816 genes probed were either up-regulated or down-regulated by more than two-fold. However, 52 genes (0.4%) showed differential expression in aggregated SCNT placentas compared to that in controls. In comparison of both types of SCNT placentas with the controls, 33 (92%) out of 36 genes were found to be up regulated (>2-fold) in SCNT placentas. Among 36 genes, 13 (36%) genes were up regulated in the aggregated SCNT placentas. Eighty-five genes were down-regulated in SCNT placentas compared with the controls. However, only 9 (about 10.5%) genes were down-regulated in the aggregated SCNT placentas. Of the 34 genes known as imprinted genes, expression was lower in SCNT placentas than that in the controls. Thus, these genes may be the cause of placentomegaly in mice produced post SCNT. CONCLUSIONS: These results suggest that placentomegaly in the SCNT placentas was probably caused by abnormal expression of multiple genes. Taken together, these results suggest that abnormal gene expression in cloned placentas was reduced in a genome-wide manner using the aggregation method with tetraploid embryos. PMID- 28347307 TI - Use of indocyanine green for detecting sentinel lymph nodes in breast cancer: letter to the editor. AB - In a previous issue of the journal, Oldrich Coufal and Vuk Fait reported a pilot study that specifically addressed the use of indocyanine green for detecting sentinel lymph nodes in breast cancer within a European population. They concluded that fluorescence method cannot currently be considered a method fully comparable with using radioisotopes in this setting. We consider that the absence of a learning curve, the low mean of retrieved sentinel nodes, and the possibility that migration of indocyanine green occurred after the initial biopsy limit the strength of their conclusion. PMID- 28347306 TI - Accessibility of long-term family planning methods: a comparison study between Output Based Approach (OBA) clients verses non-OBA clients in the voucher supported facilities in Kenya. AB - BACKGROUND: The study seeks to evaluate the difference in access of long-term family planning (LTFP) methods among the output based approach (OBA) and non-OBA clients within the OBA facility. METHODS: The study utilises a quasi experimental design. A two tailed unpaired t-test with unequal variance is used to test for the significance variation in the mean access. The difference in difference (DiD) estimates of program effect on long term family planning methods is done to estimate the causal effect by exploiting the group level difference on two or more dimensions. The study also uses a linear regression model to evaluate the predictors of choice of long-term family planning methods. Data was analysed using SPSS version 17. RESULTS: All the methods (Bilateral tubal ligation-BTL, Vasectomy, intrauterine contraceptive device -IUCD, Implants, and Total or combined long-term family planning methods -LTFP) showed a statistical significant difference in the mean utilization between OBA versus non-OBA clients. The difference in difference estimates reveal that the difference in access between OBA and non OBA clients can significantly be attributed to the implementation of the OBA program for intrauterine contraceptive device (p = 0.002), Implants (p = 0.004), and total or combined long-term family planning methods (p = 0.001). The county of residence is a significant determinant of access to all long-term family planning methods except vasectomy and the year of registration is a significant determinant of access especially for implants and total or combined long-term family planning methods. The management level and facility type does not play a role in determining the type of long-term family planning method preferred; however, non-governmental organisations (NGOs) as management level influences the choice of all methods (Bilateral tubal ligation, intrauterine contraceptive device, Implants, and combined methods) except vasectomy. The adjusted R2 value, representing the percentage of the variance explained by various models, is larger than 18% for implants and total or combined long-term family planning. CONCLUSION: The study showed that the voucher services in Kenya has been effective in providing long-term family planning services and improving access of care provided to women of reproductive age. Therefore, voucher scheme can be used as a tool for bridging the gap of unmet needs of family planning in Kenya and could potentially be more effective if rolled out to other counties. PMID- 28347308 TI - Erratum to: Assessment of myocardial injury after reperfused infarction by T1rho cardiovascular magnetic resonance. PMID- 28347309 TI - Chemical composition and pharmacological activities of Pisum sativum. AB - BACKGROUND: Consumption of vegetables has been proven to be effective in the prevention of different diseases. Traditionally edible aerial part of Pisum sativum L. subsp. sativum (Fabaceae) is used to treat diabetes, heart diseases and as blood purifier. Present study was aimed to explore the traditional use of aerial parts of P. sativum as a source of antidiabetic agent. In addition, antioxidant activity and chemical composition was carried out. METHODS: Total polyphenol content was spectrophotometrically determined using Folin Chiocalteu's reagent while the flavonoids by aluminum chloride colorimetric assay. Identification of compounds of the extract was made through HPLC and LCMS. Antihyperglycemic activity was assessed by oral glucose tolerance test in mice. Antioxidant activity was determined by DPPH free radical scavenging and reducing power assay. RESULTS: Total polyphenol and total flavonoids content were found to be 51.23 mg gallic acid equivalent and 30.88 mg quercetin equivalent per gram of dried plant extract respectively. Ellagic acid and p-coumeric acid were detected through HPLC. A total of eight compounds including naringenin, beta-sitosterol were indentified through LCMS. In OGTT, extract (200 mg/kg bw) showed a 30.24% decrease (P< 0.05) in blood glucose levels at 30 min compared to the normal control. The extract showed IC50 value of 158.52 MUg/mL in DPPH scavenging assay and also showed comparable reducing power. CONCLUSION: Along with other compounds ellagic acid and beta-sitosterol present in the extract may be responsible for its antioxidant as well as antihyperglycemic activities. Altogether these results rationalize the use of this vegetable in traditional medicine. PMID- 28347310 TI - A novel in vitro model reveals distinctive modulatory roles of Plasmodium falciparum and Plasmodium vivax on naive cell-mediated immunity. AB - BACKGROUND: To date, human peripheral blood mononuclear cells (PBMCs) have been used mainly in immune stimulation assays and the interpretation of data can be influenced by the previous immunological history of donors and cross reactivity with other infectious agents. Resolving these limitations requires an alternative in vitro model to uncover the primary response profiles. METHODS: A novel in vitro model of mononuclear cells (MNCs) generated from haematopoietic stem cells (HSCs) was developed and these cells were then co-cultured with various antigens from Plasmodium falciparum and Plasmodium vivax to investigate the response of naive immune cells to malaria antigens by flow cytometry. RESULTS: In vitro stimulation of naive lymphocytes showed that CD4+ and CD8+ T lymphocytes were significantly reduced (P < 0.01) by exposure to lysates of infected erythrocytes or intact erythrocytes infected with P. falciparum. The depletion was associated with the expression of CD95 (Fas receptor) on the surface of T lymphocytes. Maturation of T lymphocytes was affected differently, showing elevated CD3+CD4+CD8+ and CD3+CD4-CD8- T lymphocytes after stimulation with cell lysates of P. falciparum and P. vivax, respectively. In addition, antigen presenting monocytes and dendritic cells derived from haematopoietic stem cells showed impaired HLA-DR expression as a consequence of exposure to different species of malaria parasites. CONCLUSION: These results suggest that naive mononuclear cells differentiated in vitro from HSCs could provide a valid model for the assessment of immunity. P. falciparum and P. vivax malaria parasites could modulate various populations of immune cells starting from newly differentiated mononuclear cells. PMID- 28347311 TI - Predictors of the use of interventions to prevent malaria in pregnancy in Cameroon. AB - BACKGROUND: Malaria in pregnancy is common in sub-Saharan Africa where it contributes to perinatal morbidity and mortality. Use of insecticide-treated bed nets and intermittent preventive therapy with sulfadoxine-pyrimethamine during pregnancy are effective but underutilized interventions to prevent infection. Factors associated with bed net ownership and usage, and use of prophylaxis among recently pregnant women in Cameroon were investigated. METHODS: National data from the 2011 Cameroon Demographic Health Survey was used to identify women with a pregnancy within the previous 5 years. Logistic regression models were created to assess for independent predictors of reported bed net ownership, bed net usage, and the use of malaria prophylaxis medications during pregnancy. RESULTS: Nearly one in two women surveyed had a recent pregnancy (n = 7647). In this group, bed net ownership and usage rates were low (33.7 and 16.9%, respectively); 61.6% used medication for malaria prophylaxis during pregnancy. Bed net ownership and usage were associated with maternal literacy (aOR 1.4 for net usage, 95% CI 1.1-1.8) and the presence of children under age 5 in the home (aOR 2.3 for net usage, 95% CI 1.6-3.3). The use of malaria prophylaxis medication was associated with measures of healthcare access (aOR 17.8, 95% CI 13-24.5 for >=4 antenatal care visits), higher maternal education (aOR 1.5, 95% CI 1.1-2.1) and maternal literacy (aOR 1.4, 95% CI 1.1-1.7). CONCLUSIONS: Women in Cameroon and their antenatal providers missed many opportunities to prevent malaria in pregnancy. Efforts toward ensuring universal bed net provision, consistent antenatal care and the education of girls are likely to improve birth outcomes attributable to malaria infection. PMID- 28347312 TI - Phenotyping and comparing the immune cell populations of free-ranging Atlantic bottlenose dolphins (Tursiops truncatus) and dolphins under human care. AB - BACKGROUND: Studies suggest that free-ranging bottlenose dolphins exhibit a suppressed immune system because of exposure to contaminants or microorganisms. However, due to a lack of commercially available antibodies specific to marine mammal immune cell surface markers, the research has been indecisive. The purpose of this study was to identify cross-reactive terrestrial-specific antibodies in order to assess the changes in the immune cell populations of dolphins under human care and free-ranging dolphins. The blood and PBMC fraction of blood samples from human care and free-ranging dolphins were characterized by H&E staining of cytospin slides and flow cytometry using a panel of terrestrial specific antibodies. RESULTS: In this study, we show that out of 65 terrestrial specific antibodies tested, 11 were cross-reactive and identified dolphin immune cell populations within their peripheral blood. Using these antibodies, we found significant differences in the absolute number of cells expressing specific markers within their lymphocyte and monocyte fractions. Interestingly, the peripheral blood mononuclear cell profile of free-ranging dolphins retained an additional population of cells that divided them into two groups showing a low (<27%) or high (>56%) percentage of smaller cells resembling granulocytes. CONCLUSIONS: We found that the cross-reactive antibodies not only identified specific changes in the immune cells of free-ranging dolphins, but also opened the possibility to investigate the causal relationship between immunosuppression and mortality seen in free-ranging dolphins. PMID- 28347313 TI - Estimating genome-wide regulatory activity from multi-omics data sets using mathematical optimization. AB - BACKGROUND: Gene regulation is one of the most important cellular processes, indispensable for the adaptability of organisms and closely interlinked with several classes of pathogenesis and their progression. Elucidation of regulatory mechanisms can be approached by a multitude of experimental methods, yet integration of the resulting heterogeneous, large, and noisy data sets into comprehensive and tissue or disease-specific cellular models requires rigorous computational methods. Recently, several algorithms have been proposed which model genome-wide gene regulation as sets of (linear) equations over the activity and relationships of transcription factors, genes and other factors. Subsequent optimization finds those parameters that minimize the divergence of predicted and measured expression intensities. In various settings, these methods produced promising results in terms of estimating transcription factor activity and identifying key biomarkers for specific phenotypes. However, despite their common root in mathematical optimization, they vastly differ in the types of experimental data being integrated, the background knowledge necessary for their application, the granularity of their regulatory model, the concrete paradigm used for solving the optimization problem and the data sets used for evaluation. RESULTS: Here, we review five recent methods of this class in detail and compare them with respect to several key properties. Furthermore, we quantitatively compare the results of four of the presented methods based on publicly available data sets. CONCLUSIONS: The results show that all methods seem to find biologically relevant information. However, we also observe that the mutual result overlaps are very low, which contradicts biological intuition. Our aim is to raise further awareness of the power of these methods, yet also to identify common shortcomings and necessary extensions enabling focused research on the critical points. PMID- 28347314 TI - Reemergence of chloroquine-sensitive pfcrt K76 Plasmodium falciparum genotype in southeastern Cameroon. AB - BACKGROUND: Chloroquine had been used extensively during the last five decades in Cameroon. Its decreasing clinical effectiveness, supported by high proportions of clinical isolates carrying the mutant pfcrt haplotype (CVIET), led the health authorities to resort to amodiaquine monotherapy in 2002 and artemisinin-based combination therapy (ACT) in 2004 (artesunate-amodiaquine, with artemether lumefantrine as an alternative since 2006) as the first-line treatment of uncomplicated malaria. The aim of the present study was to investigate whether the withdrawal of chloroquine was associated with a reduction in pfcrt mutant parasite population and reemergence of chloroquine-sensitive parasites in southeastern Cameroon between 2003 and 2012. METHODS: The frequency of pfcrt haplotypes at positions 72-76 in Plasmodium falciparum isolates collected from individuals in 2003 and 2012 in southeastern Cameroon was determined by sequence specific oligonucleotide probes-enzyme linked immunosorbent assay (SSOP-ELISA). RESULTS: The proportions of parasites carrying the mutant haplotype CVIET and the wild-type CVMNK were 53.0 and 28.0% in 2003, respectively. The proportion of the mutant haplotype in samples collected 9 years later decreased to 25.3% whereas the proportion of parasites carrying the wild-type CVMNK haplotype was 53.7%. CONCLUSIONS: Even though the proportion of chloroquine-sensitive parasites seems to be increasing in southeastern Cameroon, a reintroduction of chloroquine cannot be recommended at present in Cameroon. The current national anti-malarial drug policy should be implemented and reinforced to combat drug-resistant malaria. PMID- 28347315 TI - 5alpha-reductase activity in women with polycystic ovary syndrome: a systematic review and meta-analysis. AB - BACKGROUND: 5alpha-reductase activity might be important during the development of polycystic ovary syndrome (PCOS). However, the changes of 5alpha-reductase activity in PCOS subjects and the relationship between 5alpha-reductase activity and body mass index (BMI), insulin resistance (IR) remain largely unknown. METHODS: We performed a meta-analysis to examine 5alpha-reductase activity in women with PCOS; exploratory subgroup analyses were also performed. RESULTS: Five articles (with 356 cases and 236 controls) reporting 5alpha-reductase activity in patients with PCOS were selected for the meta-analysis. We observed significantly higher ratios of 5alphaTHF/THF (5alpha-reduced tetrahydrocortisol to 5beta reduced tetrahydrocortisol) and An/Et (androsteroneto/etiocholanolone) levels, which were used to assess 5alpha-reductase activity, among the patients with PCOS, [standardized mean differences (SMD) =0.43, 95%confidence intervals (95%CI) =0.25-0.61, P < 0.00001; SMD = 0.86, 95% CI = 0.29-1.44, P = 0.003]. We observed significant heterogeneity between studies for An/Et (I2 = 89% and P < 0.00001). According to the group analysis, women with PCOS exhibited increased 5alpha reductase activity which was significantly associated with homeostasis model assessment of insulin resistance (HOMA-IR) regardless of obesity. CONCLUSIONS: 5alpha-reductase activity was enhanced in women with PCOS. Increased 5alpha reductase activity in patients with PCOS was related to IR. PMID- 28347316 TI - Trends of testis-sparing surgery for pediatric testicular tumors in South China. AB - BACKGROUND: Testis-sparing surgery is not popular in South China. This study aimed to investigate this procedure for pediatric testicular tumors. METHODS: Children with testicular benign tumors were retrospectively analyzed from January 2001 to June 2015 in the Sun Yat-sen University Cancer Center (SYSUCC) and the First Affiliated Hospital (SYSU-1st). Follow-up was performed until June 2016, and the proportions of TSS in the two hospitals during the different periods were compared. RESULTS: Forty-seven children with testicular benign tumors were enrolled, and 16 cases underwent testis-sparing surgery. All patients were cured and discharged, which included mature teratoma (n = 37), testicular adrenal rest tumors (n = 4), epidermal cysts (n = 3), granulomatous inflammation (n = 2) and adenomatoid tumors (n = 1). Inguinal testis-sparing surgery was performed in 16 children, and no recurrence was detected during follow-up. It was performed more frequently in SYSUCC than in SYSU-1st (P = 0.031), and the tumor size of these patients was smaller than those of patients who underwent radical orchiectomy (P = 0.044). Moreover, testis-sparing surgery has become more common in the past 5 years, although differences over time have not reached significance (P = 0.051). CONCLUSIONS: Testis-sparing surgery is reliable, and tumor size and special hospitals affect its success. Additionally, its use has become more popular in recent years. However, advocacy is still needed for the use of this technique in pediatric testicular benign tumors that are small sized. PMID- 28347317 TI - Erratum to: Metabotropic glutamate receptor 5 may be involved in macrophage plasticity. PMID- 28347318 TI - Pharmacokinetics of surotomycin from phase 1 single and multiple ascending dose studies in healthy volunteers. AB - BACKGROUND: Surotomycin, a novel, orally administered, cyclic, lipopeptide antibacterial in development for the treatment of Clostridium difficile associated diarrhea, has demonstrated minimal intestinal absorption in animal models. METHODS: Safety, tolerability, and plasma pharmacokinetics of single and multiple ascending oral doses (SAD/MAD) of surotomycin in healthy volunteers were characterized in two randomized, double-blind, placebo-controlled, phase 1 studies. RESULTS: Participants were sequentially enrolled into one of four SAD (500, 1000, 2000, 4000 mg surotomycin) or three MAD (250, 500, 1000 mg surotomycin twice/day for 14 days) cohorts. Ten subjects were randomized 4:1 into each cohort to receive surotomycin or placebo. Surotomycin plasma concentrations rose as dose increased (maximum plasma concentration [Cmax]: 10.5, 21.5, 66.6, and 86.7 ng/mL). Systemic levels were generally low, with peak median surotomycin plasma concentrations observed 6-12 h after the first dose. In the MAD study, surotomycin plasma concentrations were higher on day 14 (Cmax: 25.5, 37.6, and 93.5 ng/mL) than on day 1 (Cmax: 6.8, 11.0, and 21.1 ng/mL for increasing doses), indicating accumulation. In the SAD study, <0.01% of the administered dose was recovered in urine. Mean surotomycin stool concentration from the 1000 mg MAD cohort was 6394 MUg/g on day 5. Both cohorts were well tolerated with all adverse events reported as mild to moderate. CONCLUSION: Both SAD and MAD studies of surotomycin demonstrated minimal systemic exposure, with feces the primary route of elimination following oral administration; consistent with observations with similar compounds, such as fidaxomicin. Results of these phase 1 studies support the continued clinical development of surotomycin for the treatment of Clostridium difficile-associated diarrhea. TRIAL REGISTRATION: NCT02835118 and NCT02835105 . Retrospectively registered, July 13 2016. PMID- 28347319 TI - Applying the Theoretical Domains Framework to identify barriers and targeted interventions to enhance nurses' use of electronic medication management systems in two Australian hospitals. AB - BACKGROUND: Medication errors harm hospitalised patients and increase health care costs. Electronic Medication Management Systems (EMMS) have been shown to reduce medication errors. However, nurses do not always use EMMS as intended, largely because implementation of such patient safety strategies requires clinicians to change their existing practices, routines and behaviour. This study uses the Theoretical Domains Framework (TDF) to identify barriers and targeted interventions to enhance nurses' appropriate use of EMMS in two Australian hospitals. METHODS: This qualitative study draws on in-depth interviews with 19 acute care nurses who used EMMS. A convenience sampling approach was used. Nurses working on the study units (N = 6) in two hospitals were invited to participate if available during the data collection period. Interviews inductively explored nurses' experiences of using EMMS (step 1). Data were analysed using the TDF to identify theory-derived barriers to nurses' appropriate use of EMMS (step 2). Relevant behaviour change techniques (BCTs) were identified to overcome key barriers to using EMMS (step 3) followed by the identification of potential literature-informed targeted intervention strategies to operationalise the identified BCTs (step 4). RESULTS: Barriers to nurses' use of EMMS in acute care were represented by nine domains of the TDF. Two closely linked domains emerged as major barriers to EMMS use: Environmental Context and Resources (availability and properties of computers on wheels (COWs); technology characteristics; specific contexts; competing demands and time pressure) and Social/Professional Role and Identity (conflict between using EMMS appropriately and executing behaviours critical to nurses' professional role and identity). The study identified three potential BCTs to address the Environmental Context and Resources domain barrier: adding objects to the environment; restructuring the physical environment; and prompts and cues. Seven BCTs to address Social/Professional Role and Identity were identified: social process of encouragement; pressure or support; information about others' approval; incompatible beliefs; identification of self as role model; framing/reframing; social comparison; and demonstration of behaviour. It proposes several targeted interventions to deliver these BCTs. CONCLUSIONS: The TDF provides a useful approach to identify barriers to nurses' prescribed use of EMMS, and can inform the design of targeted theory-based interventions to improve EMMS implementation. PMID- 28347321 TI - The 150 most important questions in cancer research and clinical oncology series: questions 6-14 : Edited by Chinese Journal of Cancer. AB - To accelerate our endeavors to overcome cancer, Chinese Journal of Cancer has launched a program of publishing 150 most important questions in cancer research and clinical oncology. In this article, nine more questions are presented as followed. Question 6. Why do nasopharyngeal carcinomas rarely metastasize to the brain? Question 7. Can distant spread of cancer cells be blocked by inhibiting the remodeling of high endothelial venules in the sentinel lymph node? Question 8. What sort of live-imaging techniques can be developed to directly observe the dynamic processes of metastasis? Question 9. How does chronic hepatitis prevent liver metastasis from colorectal cancer? Question 10. How many types of host cells contribute to forming the pre-metastatic niche in the lung favorable for metastasis? Question 11. Why do cancers rarely metastasize to the small bowel? Question 12. Why do glioblastomas rarely metastasize outside the central nervous system? Question 13. Despite increased understanding of the molecular genetic events leading to the development and progression of high-grade gliomas, these tumors are the most therapeutically refractory among all human cancers. What then would be the most effective therapeutic approaches to treat what in essence can be regarded as a whole brain malignancy, since even a surgical resection of greater than 99% of tumor tissues is invariably associated with recurrence? Question 14. The blood-brain barrier (BBB) effectively limits a wide variety of potential therapeutic agents from reaching glioma cells widely dispersed in the brain. What therapeutic approaches can be used to breach the BBB and allow therapeutic agents to seek out and kill these tumor cells? PMID- 28347320 TI - Life-threatening massive pulmonary embolism rescued by venoarterial extracorporeal membrane oxygenation. AB - BACKGROUND: Despite quick implementation of reperfusion therapies, a few patients with high-risk, acute, massive, pulmonary embolism (PE) remain highly hemodynamically unstable. Others have absolute contraindication to receive reperfusion therapies. Venoarterial-extracorporeal membrane oxygenation (VA-ECMO) might lower their right ventricular overload, improve hemodynamic status, and restore tissue oxygenation. METHODS: ECMO-related complications and 90-day mortality were analyzed for 17 highly unstable, ECMO-treated, massive PE patients admitted to a tertiary-care center (2006-2015). Hospital- discharge survivors were assessed for long-term health-related quality of life. A systematic review of this topic was also conducted. RESULTS: Seventeen high-risk PE patients [median age 51 (range 18-70) years, Simplified Acute Physiology Score II (SAPS II) 78 (45-95)] were placed on VA-ECMO for 4 (1-12) days. Among 15 (82%) patients with pre-ECMO cardiac arrest, seven (41%) were cannulated during cardiopulmonary resuscitation, and eight (47%) underwent pre-ECMO thrombolysis. Pre-ECMO median blood pressure, pH, and blood lactate were, respectively: 42 (0-106) mmHg, 6.99 (6.54-7.37) and 13 (4-19) mmol/L. Ninety-day survival was 47%. Fifteen (88%) patients suffered in-ICU severe hemorrhages with no impact on survival. Like other ECMO-treated patients, ours reported limitations of all physical domains but preserved mental health 19 (4-69) months post-ICU discharge. CONCLUSIONS: VA ECMO could be a lifesaving rescue therapy for patients with high-risk, acute, massive PE when thrombolytic therapy fails or the patient is too sick to benefit from surgical thrombectomy. Because heparin-induced clot dissolution and spontaneous fibrinolysis allows ECMO weaning within several days, future studies should investigate whether VA-ECMO should be the sole therapy or completed by additional mechanical clot-removal therapies in this setting. PMID- 28347322 TI - A theoretical analysis of the barriers and facilitators to the implementation of school-based physical activity policies in Canada: a mixed methods scoping review. AB - BACKGROUND: Given the potential impact school-based daily physical activity (DPA) policies can have on the health outcomes of Canadian children, it is surprising that such little research has examined the implementation and student-level effectiveness of these policies, and that even less have used theory to understand the barriers and facilitators affecting uptake of this policy by teachers. This review descriptively summarizes the implementation status, approaches used to implement DPA, and the effectiveness of DPA at increasing the physical activity of children at school. In addition, the Theoretical Domains Framework (TDF) was used to explore the barriers and facilitators to DPA implementation. METHODS: A scoping review of English articles using ERIC, CINAHL, and Google Scholar (2005 to 2016) was conducted. Only studies that evaluated the implementation and/or student-level effectiveness of DPA policies in Canadian elementary schools were included. Only articles that examined DPA implementation barriers and facilitators by teachers, principals, and/or administration were eligible for the TDF analysis. Data on study characteristics and major findings regarding implementation status, implementation approach used, and impact on student's physical activity were extracted and were summarized descriptively, including study quality indicators. Two coders extracted and categorized implementation barriers and facilitators into TDF domains. RESULTS: The search resulted in 66 articles being retrieved and 38 being excluded for not meeting the eligibility criteria, leaving 15 eligible for review (10 of which examined barriers and facilitators to implementation from DPA deliverers' perspective). Eleven of 15 studies examined the Ontario DPA policy, and 2 studies were from both Alberta and British Columbia. Thirteen studies examined implementation, and only two examined effectiveness. DPA implementation status, approaches to delivery, and effectiveness on student's PA levels are inconsistent across the three provinces. A total of 203 barriers/facilitators were extracted across the ten implementation studies, most of which related to the environmental context and resources (ECR; n = 86; 37.4%), beliefs about consequences (n = 41; 17.8%), and social influences (n = 36; 15.7%) TDF domains. CONCLUSIONS: With the limited research examining the DPA policy in Canada, the current status and approaches used to implement DPA and the student-level effectiveness is not well understood; however, this review revealed that DPA deliverers often report many barriers to DPA implementation. Most importantly, in conducting a TDF-based analysis of the barriers/facilitators affecting implementation, this review provides a theoretical basis by which researchers and policy-makers can design interventions to better target these problems in the future. REGISTRATION: A protocol for this review was not registered. PMID- 28347323 TI - Blood-feeding patterns of native mosquitoes and insights into their potential role as pathogen vectors in the Thames estuary region of the United Kingdom. AB - BACKGROUND: The range of vertebrate hosts on which species of mosquito blood-feed is an important parameter for identifying potential vectors and in assessing the risk of incursion and establishment of vector-borne pathogens. In the United Kingdom, studies of mosquito host range have collected relatively few specimens and used techniques that could only broadly identify host species. This study conducted intensive collection and analysis of mosquitoes from a grazing marsh environment in southeast England. This site provides extensive wetland habitat for resident and migratory birds and has abundant human nuisance biting mosquitoes. The aim was to identify the blood-feeding patterns of mosquito species present at the site which could contribute to the transmission of pathogens. METHODS: Twice-weekly collections of mosquitoes were made from Elmley Nature Reserve, Kent, between June and October 2014. Mosquitoes were collected using resting boxes, by aspiration from man-made structures and using a Mosquito Magnet Pro baited with 1-octen-3-ol. Blood-fed specimens were classified according to the degree of blood meal digestion using the Sella scale and vertebrate origin determined using sequencing of a fragment of the mitochondrial cytochrome C oxidase subunit I gene. Mosquitoes that were morphologically cryptic were identified to species level using multiplex PCR and sequencing methods. RESULTS: A total of 20,666 mosquitoes of 11 species were collected, and 2,159 (10.4%) were blood-fed (Sella scale II-VI); of these 1,341 blood-fed specimens were selected for blood meal analysis. Vertebrate origin was successfully identified in 964 specimens (72%). Collections of blood-fed individuals were dominated by Anopheles maculipennis complex (73.5%), Culiseta annulata (21.2%) and Culex pipiens form pipiens (10.4%). Nineteen vertebrate hosts comprising five mammals and 14 birds were identified as hosts for mosquitoes, including two migratory bird species. Feeding on birds by Culex modestus and Anopheles atroparvus populations in England was demonstrated. CONCLUSIONS: This study expands the vertebrate host range of mosquitoes in the Thames estuary region of the UK. Feeding on both resident and migratory bird species by potential arbovirus vectors including Cx. pipiens f. pipiens and Cx. modestus indicates the potential for enzootic transmission of an introduced arbovirus between migratory and local bird species by native mosquito species. PMID- 28347324 TI - PMS2 gene mutation results in DNA mismatch repair system failure in a case of adult granulosa cell tumor. AB - BACKGROUND: Granulosa cell tumors are rare ovarian malignancies. Their characteristics include unpredictable indolent growth with malignant potential and late recurrence. Approximately 95% are of adult type. Recent molecular studies have characterized the FOXL2 402C > G mutation in adult granulosa cell tumor. Our previous case report showed that unique FOXL2 402C > G mutation and defective DNA mismatch repair system are associated with the development of adult granulosa cell tumor. FINDINGS: In this study, the DNA sequences of four genes, MSH2, MLH1, MSH6, and PMS2, in the DNA mismatch repair system were determined via direct sequencing to elucidate the exact mechanism for the development of this granulosa cell tumor. The results showed that two missense germline mutations, T485K and N775L, inactivate the PMS2 gene. CONCLUSIONS: The results of this case study indicated that although FOXL2 402C > G mutation determines the development of granulosa cell tumor, PMS2 mutation may be the initial driver of carcinogenesis. Immunohistochemistry-based tumor testing for mismatch repair gene expression may be necessary for granulosa cell tumors to determine their malignant potential or if they are part of Lynch syndrome. PMID- 28347325 TI - Potential of Aedes aegypti and Aedes albopictus populations in the Central African Republic to transmit enzootic chikungunya virus strains. AB - BACKGROUND: Major chikungunya outbreaks have affected several Central African countries during the past decade. The chikungunya virus (CHIKV) was isolated from humans and sylvan mosquitoes in the Central African Republic (CAR) during the 1970 and 1980s but has not been found recently, despite the presence of Aedes albopictus since 2010. The risk of a massive chikungunya epidemic is therefore potentially high, as the human populations are immunologically naive and because of the presence of the mosquito vector. In order to estimate the risk of a large outbreak, we assessed the vector competence of local Ae. aegypti and Ae. albopictus populations for ancient local strains of CHIKV in CAR. Mosquitoes were orally infected with the virus, and its presence in mosquito saliva was analysed 7 and 14 days post-infection (dpi) by quantitative reverse transcriptase polymerase chain reaction. RESULTS: The two species had similar infection rates at 7 and 14 days, and the dissemination rate of both vectors was >= 80% at 14 dpi. Only females followed up to 14 dpi had CHKV in their saliva. CONCLUSION: These results confirm the risk of transmission of enzootic CHIKV by anthropophilic vectors such as Ae. aegypti and Ae. albopictus. PMID- 28347326 TI - First report of the Phe1534Cys kdr mutation in natural populations of Aedes albopictus from Brazil. AB - BACKGROUND: Knockdown resistance (kdr), caused by alterations in the voltage gated sodium channel (NaV), is one of the mechanisms responsible for pyrethroid (PY) resistance. In the Asian tiger mosquito, Aedes albopictus, at least four different mutations were described in the IIIS6 NaV segment in populations from Asia, North America and Europe. In contrast, in Aedes aegypti at least 12 non synonymous mutations have been reported at nine different codons, mostly in the IIS6 and IIIS6 NaV segments. The Phe1534Cys kdr mutation in the IIIS6 NaV segment is the most prevalent in populations of Ae. aegypti worldwide, also found in Ae. albopictus from Singapore. Herein, we investigated the DNA diversity corresponding to the IIS6 and IIIS6 NaV segments in natural populations of Ae. albopictus from Brazil. METHODS: DNA from eight Brazilian Ae. albopictus natural populations were individually extracted and pooled by states of origin, amplified, cloned and sequenced for the corresponding IIS6 and IIIS6 NaV segments. Additionally, samples from each location were individually genotyped by an allelic specific PCR (AS-PCR) approach to obtain the genotypic and allelic frequencies for the 1534 NaV site. RESULTS: No non-synonymous substitutions were observed in the IIS6 sequences. However, the Phe1534Cys kdr mutation was evidenced in the Ae. albopictus NaV IIIS6 segment sequences from Parana (PR) and Rondonia (RO) states, but not from Mato Grosso (MT) state. The 1534Cys kdr allele varied from 3% (Marilena/PR and Porto Velho/RO) to 10% (Foz do Iguacu/PR). To our knowledge, this paper reports the first occurrence and provides distribution data of a possible kdr mutation in Ae. albopictus in South America. CONCLUSION: The emergence of a likely kdr mutation in Ae. albopitus natural populations is a signal of alert for vector control measures since PY are the most popular insecticides adopted by residents. Additionally, once the kdr allele is present, its frequency tends to increase faster under exposition to those compounds. Although the Asian tiger mosquito is not incriminated as an important vector of dengue, chikungunya and Zika viruses in South America, its importance in this regard has been extensively discussed since Ae. albopictus is rapidly spreading and can also migrate between sylvatic and urban environments. Therefore, insecticide resistance monitoring initiatives should also be extended to Ae. albopictus in Brazil in order to maintain chemical compounds as an efficient vector control tool when needed. PMID- 28347328 TI - A rare case report of early bioprosthetic valve thrombosis presenting with acute heart failure salvaged by thrombectomy. AB - BACKGROUND: Bioprosthetic valve thrombosis is previously considered as an extremely rare complication which hasn't been systemically recognized and understood. CASE PRESENTATION: Herein, we present an unusual case of a patient manifesting with acute heart failure, secondary to thrombus formation in a porcine aortic bioprosthesis which was implanted 11 months prior to hospitalization. Due to the patient's poor heart function and intraoperative findings, thrombectomy was performed. For our best knowledge, cases of early bioprosthetic valve thrombosis presenting with acute heart failure have seldomly been reported. CONCLUSION: Our study reviews predisposing factors, typical echocardiographic features and treatment for bioprosthetic valve thrombosis and it should be considered as a reason for bioprosthetic malfunction. A combination of clinical and echocardiographic features can help for diagnosis preoperatively. In some certain circumstances, early reoperation can be avoided if anticoagulant therapy works. PMID- 28347327 TI - Mechanistic model for predicting the seasonal abundance of Culicoides biting midges and the impacts of insecticide control. AB - BACKGROUND: Understanding seasonal patterns of abundance of insect vectors is important for optimisation of control strategies of vector-borne diseases. Environmental drivers such as temperature, humidity and photoperiod influence vector abundance, but it is not generally known how these drivers combine to affect seasonal population dynamics. METHODS: In this paper, we derive and analyse a novel mechanistic stage-structured simulation model for Culicoides biting midges-the principle vectors of bluetongue and Schmallenberg viruses which cause mortality and morbidity in livestock and impact trade. We model variable life-history traits as functional forms that are dependent on environmental drivers, including air temperature, soil temperature and photoperiod. The model is fitted to Obsoletus group adult suction-trap data sampled daily at five locations throughout the UK for 2008. RESULTS: The model predicts population dynamics that closely resemble UK field observations, including the characteristic biannual peaks of adult abundance. Using the model, we then investigate the effects of insecticide control, showing that control strategies focussing on the autumn peak of adult midge abundance have the highest impact in terms of population reduction in the autumn and averaged over the year. Conversely, control during the spring peak of adult abundance leads to adverse increases in adult abundance in the autumn peak. CONCLUSIONS: The mechanisms of the biannual peaks of adult abundance, which are important features of midge seasonality in northern Europe and are key determinants of the risk of establishment and spread of midge-borne diseases, have been hypothesised over for many years. Our model suggests that the peaks correspond to two generations per year (bivoltine) are largely determined by pre-adult development. Furthermore, control strategies should focus on reducing the autumn peak since the immature stages are released from density-dependence regulation. We conclude that more extensive modelling of Culicoides biting midge populations in different geographical contexts will help to optimise control strategies and predictions of disease outbreaks. PMID- 28347329 TI - Incidence and burden of comorbid pain and depression in patients with chronic rhinosinusitis awaiting endoscopic sinus surgery in Canada. AB - BACKGROUND: This study sheds important light on the association between sino nasal symptoms and global quality of life in patients with chronic rhinosinusitis waiting for endoscopic sinus surgery. Using patient-reported information collected pre-operatively, the primary objective was to report on patients' pre surgical sino-nasal symptoms and their association with self-reported pain and depression. The secondary objective was to report on levels of depression and pain among patients in the sample reporting severe sleep problems. METHODS: This is a cross-sectional study of patient-reported outcomes collected prospectively from a cohort of 261 patients assigned to the wait list for elective endoscopic sinus surgery in a large urban region of Canada. RESULTS: Younger patients and patients with other medical comorbidities were most likely to report significant symptoms of chronic rhinosinusitis and substantial associated pain and depression. In the primary analyses, patients reporting significant symptoms of chronic rhinosinusitis were more likely to report moderate depression or high pain (p < 0.01). Subsequently, chronic rhinosinusitis patients with severe sleep problems were 82% likely to report moderate or severe depression and pain. CONCLUSION: Preoperative management of depression and pain may be considered in order to improve the health-related quality of life of patients waiting for ESS. As depression and pain were highly prevalent, patients with severe sleep problems may be candidates for prioritized access. PMID- 28347330 TI - Erratum to: HIV integration sites in latently infected cell lines: evidence of ongoing replication. PMID- 28347331 TI - Progressive multifocal exophytic pontine glioblastoma: a case report with literature review. AB - Multifocal pontine glioblastoma exhibiting an exophytic growth pattern in the cerebello-pontine angle (CPA) is rare. We present a case of a 5-year-old girl with consecutive neurological imaging and other clinical findings indicating progressive multifocal exophytic pontine glioblastoma. Three lesions were reported, of which two were initially presented, and one was developed 2 months later. One lesion demonstrated a progressing exophytic extension in the cistern of the left side of the CPA. The other two lesions were located and confined within the pons. Initial magnetic resonance imaging and positron emission tomography-computed tomography indicated low-grade glioma or inflammatory disease. However, 2 and 3 months later, subsequent magnetic resonance spectroscopy (MRS) displayed elevated choline and depressed N-acetyl aspartate peaks compared with the peaks on the initial MRS, indicating a high-grade glioma. Subtotal resection was performed for the CPA lesion. Histopathologic examination showed discrepant features of different parts of the CPA lesion. The patient received no further chemotherapy or radiotherapy and died 2 months after surgery. The multifocal and exophytic features of this case and the heterogeneous manifestations on neurological images were rare and confusing for both diagnosis and surgical decision-making. Our case report may contribute knowledge and helpful guidance for other medical doctors. PMID- 28347332 TI - An outbreak vector-host epidemic model with spatial structure: the 2015-2016 Zika outbreak in Rio De Janeiro. AB - BACKGROUND: A deterministic model is developed for the spatial spread of an epidemic disease in a geographical setting. The disease is borne by vectors to susceptible hosts through criss-cross dynamics. The model is focused on an outbreak that arises from a small number of infected hosts imported into a subregion of the geographical setting. The goal is to understand how spatial heterogeneity of the vector and host populations influences the dynamics of the outbreak, in both the geographical spread and the final size of the epidemic. METHODS: Partial differential equations are formulated to describe the spatial interaction of the hosts and vectors. The partial differential equations have reaction-diffusion terms to describe the criss-cross interactions of hosts and vectors. The partial differential equations of the model are analyzed and proven to be well-posed. A local basic reproduction number for the epidemic is analyzed. RESULTS: The epidemic outcomes of the model are correlated to the spatially dependent parameters and initial conditions of the model. The partial differential equations of the model are adapted to seasonality of the vector population, and applied to the 2015-2016 Zika seasonal outbreak in Rio de Janeiro Municipality in Brazil. CONCLUSIONS: The results for the model simulations of the 2015-2016 Zika seasonal outbreak in Rio de Janeiro Municipality indicate that the spatial distribution and final size of the epidemic at the end of the season are strongly dependent on the location and magnitude of local outbreaks at the beginning of the season. The application of the model to the Rio de Janeiro Municipality Zika 2015-2016 outbreak is limited by incompleteness of the epidemic data and by uncertainties in the parametric assumptions of the model. PMID- 28347333 TI - A phase II study of preoperative chemoradiation with tegafur-uracil plus leucovorin for locally advanced rectal cancer with pharmacogenetic analysis. AB - BACKGROUND: This study aimed to evaluate the efficacy of a high dose of oral tegafur-uracil (400 mg/m2) plus leucovorin with preoperative chemoradiation of locally advanced rectal cancer and to explore the impact of polymorphisms of cytochrome P 2A6 (CYP2A6), uridine monophosphate synthetase (UMPS), and ATP binding cassette B1 (ABCB1) on clinical outcome. METHODS: Patients with cT3 or cT4 rectal cancer were enrolled and were given tegafur-uracil 400 mg/m2/day and leucovorin 90 mg/m2/day for 7 days a week during preoperative chemoradiation (50.4 Gy/28 fractions) in this phase II trial. Primary endpoint was pathologic complete response rate, and the secondary endpoint was to explore the association between clinical outcomes and genetic polymorphisms CYP2A6 (*4, *7, *9 and *10), UMPS G638C, and three ABCB1 genotypes (C1236T, C3435T, and G2677T). RESULTS: Ninety-one patients were given study treatment, and 90 underwent surgery. Pathologic complete response was noted in 10 patients (11.1%). There was no grade 4 or 5 toxicity; 20 (22.0%) experienced grade 3 toxicities, including diarrhea (10, 11.0%), abdominal pain (2, 2.2%), and anemia (2, 2.2%). Relapse-free survival and overall survival at 5 years were 88.6% and 94.2%, respectively. Patients with the UMPS 638 CC genotype experienced significantly more frequent grade 2 or 3 diarrhea (p for trend = 0.018). CONCLUSIONS: Preoperative chemoradiation with tegafur-uracil 400 mg/m2/day with leucovorin was feasible, but did not meet the expected pathologic complete response rate. The UMPS 638 CC genotype might be a candidate biomarker predicting toxicity in patients receiving tegafur-uracil/leucovorin-based preoperative chemoradiation for locally advanced rectal cancer. TRIAL REGISTRATION: ISRCTN11812525 , registered on 25 July 2016. Retrospectively registered. PMID- 28347334 TI - Is the hypothesis of preimplantation genetic screening (PGS) still supportable? A review. AB - The hypothesis of preimplantation genetic diagnosis (PGS) was first proposed 20 years ago, suggesting that elimination of aneuploid embryos prior to transfer will improve implantation rates of remaining embryos during in vitro fertilization (IVF), increase pregnancy and live birth rates and reduce miscarriages. The aforementioned improved outcome was based on 5 essential assumptions: (i) Most IVF cycles fail because of aneuploid embryos. (ii) Their elimination prior to embryo transfer will improve IVF outcomes. (iii) A single trophectoderm biopsy (TEB) at blastocyst stage is representative of the whole TE. (iv) TE ploidy reliably represents the inner cell mass (ICM). (v) Ploidy does not change (i.e., self-correct) downstream from blastocyst stage. We aim to offer a review of the aforementioned assumptions and challenge the general hypothesis of PGS. We reviewed 455 publications, which as of January 20, 2017 were listed in PubMed under the search phrase < preimplantation genetic screening (PGS) for aneuploidy>. The literature review was performed by both authors who agreed on the final 55 references. Various reports over the last 18 months have raised significant questions not only about the basic clinical utility of PGS but the biological underpinnings of the hypothesis, the technical ability of a single trophectoderm (TE) biopsy to accurately assess an embryo's ploidy, and suggested that PGS actually negatively affects IVF outcomes while not affecting miscarriage rates. Moreover, due to high rates of false positive diagnoses as a consequence of high mosaicism rates in TE, PGS leads to the discarding of large numbers of normal embryos with potential for normal euploid pregnancies if transferred rather than disposed of. We found all 5 basic assumptions underlying the hypothesis of PGS to be unsupported: (i) The association of embryo aneuploidy with IVF failure has to be reevaluated in view how much more common TE mosaicism is than has until recently been appreciated. (ii) Reliable elimination of presumed aneuploid embryos prior to embryo transfer appears unrealistic. (iii) Mathematical models demonstrate that a single TEB cannot provide reliable information about the whole TE. (iv) TE does not reliably reflect the ICM. (v) Embryos, likely, still have strong innate ability to self-correct downstream from blastocyst stage, with ICM doing so better than TE. The hypothesis of PGS, therefore, no longer appears supportable. With all 5 basic assumptions underlying the hypothesis of PGS demonstrated to have been mistaken, the hypothesis of PGS, itself, appears to be discredited. Clinical use of PGS for the purpose of IVF outcome improvements should, therefore, going forward be restricted to research studies. PMID- 28347335 TI - TriPer, an optical probe tuned to the endoplasmic reticulum tracks changes in luminal H2O2. AB - BACKGROUND: The fate of hydrogen peroxide (H2O2) in the endoplasmic reticulum (ER) has been inferred indirectly from the activity of ER-localized thiol oxidases and peroxiredoxins, in vitro, and the consequences of their genetic manipulation, in vivo. Over the years hints have suggested that glutathione, puzzlingly abundant in the ER lumen, might have a role in reducing the heavy burden of H2O2 produced by the luminal enzymatic machinery for disulfide bond formation. However, limitations in existing organelle-targeted H2O2 probes have rendered them inert in the thiol-oxidizing ER, precluding experimental follow-up of glutathione's role in ER H2O2 metabolism. RESULTS: Here we report on the development of TriPer, a vital optical probe sensitive to changes in the concentration of H2O2 in the thiol-oxidizing environment of the ER. Consistent with the hypothesized contribution of oxidative protein folding to H2O2 production, ER-localized TriPer detected an increase in the luminal H2O2 signal upon induction of pro-insulin (a disulfide-bonded protein of pancreatic beta cells), which was attenuated by the ectopic expression of catalase in the ER lumen. Interfering with glutathione production in the cytosol by buthionine sulfoximine (BSO) or enhancing its localized destruction by expression of the glutathione-degrading enzyme ChaC1 in the lumen of the ER further enhanced the luminal H2O2 signal and eroded beta-cell viability. CONCLUSIONS: A tri-cysteine system with a single peroxidatic thiol enables H2O2 detection in oxidizing milieux such as that of the ER. Tracking ER H2O2 in live pancreatic beta-cells points to a role for glutathione in H2O2 turnover. PMID- 28347337 TI - The effect of intervening hospitalizations on the benefit of structured physical activity in promoting independent mobility among community-living older persons: secondary analysis of a randomized controlled trial. AB - BACKGROUND: Among older persons, disability is often precipitated by intervening illnesses and injuries leading to hospitalization. In the Lifestyle Interventions and Independence for Elders (LIFE) Study, a structured moderate-intensity physical activity program, compared with a health education program, was shown to significantly reduce the amount of time spent with major mobility disability (MMD) over the course of 3.5 years. We aimed to determine whether the benefit of the physical activity program in promoting independent mobility was diminished in the setting of intervening hospitalizations. METHODS: We analyzed data from a single-blinded, parallel group randomized trial (ClinicalTrials.gov: NCT01072500). In this trial, 1635 sedentary persons, aged 70-89 years, who had functional limitations but were able to walk 400 m, were randomized from eight US centers between February 2010 and December 2013: 818 to physical activity (800 received intervention) and 817 to health education (805 received intervention). Intervening hospitalizations and MMD, defined as the inability to walk 400 m, were assessed every 6 months for up to 3.5 years. RESULTS: For both the physical activity and health education groups, intervening hospitalizations were strongly associated with the initial onset of MMD and inversely associated with recovery from MMD, defined as a transition from initial MMD onset to no MMD. The benefit of the physical activity intervention did not differ significantly based on hospital exposure. For onset of MMD, the hazard ratios (HR) were 0.79 (95% confidence interval [CI] 0.58-1.1) and 0.77 (0.62-0.95) in the presence and absence of intervening hospitalizations, respectively (P-interaction, 0.903). For recovery of MMD, the magnitude of effect was modestly greater among participants who were hospitalized (HR 1.5, 95% CI 0.71-3.0) than in those who were not hospitalized (HR 1.2, 95% CI 0.88-1.7), but this difference did not achieve statistical significance (P-interaction, 0.670). CONCLUSIONS: Intervening hospitalizations had strong deleterious effects on the onset of MMD and recovery from MMD, but did not diminish the beneficial effect of the LIFE physical activity intervention in promoting independent mobility. To achieve sustained benefits over time, structured physical activity programs should be designed to accommodate acute illnesses and injuries leading to hospitalizations given their high frequency in older persons with functional limitations. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01072500 . PMID- 28347336 TI - Quantifying the impact of current and future concentrations of air pollutants on respiratory disease risk in England. AB - BACKGROUND: Estimating the long-term health impact of air pollution in a spatio temporal ecological study requires representative concentrations of air pollutants to be constructed for each geographical unit and time period. Averaging concentrations in space and time is commonly carried out, but little is known about how robust the estimated health effects are to different aggregation functions. A second under researched question is what impact air pollution is likely to have in the future. METHODS: We conducted a study for England between 2007 and 2011, investigating the relationship between respiratory hospital admissions and different pollutants: nitrogen dioxide (NO2); ozone (O3); particulate matter, the latter including particles with an aerodynamic diameter less than 2.5 micrometers (PM2.5), and less than 10 micrometers (PM10); and sulphur dioxide (SO2). Bayesian Poisson regression models accounting for localised spatio-temporal autocorrelation were used to estimate the relative risks (RRs) of pollution on disease risk, and for each pollutant four representative concentrations were constructed using combinations of spatial and temporal averages and maximums. The estimated RRs were then used to make projections of the numbers of likely respiratory hospital admissions in the 2050s attributable to air pollution, based on emission projections from a number of Representative Concentration Pathways (RCP). RESULTS: NO2 exhibited the largest association with respiratory hospital admissions out of the pollutants considered, with estimated increased risks of between 0.9 and 1.6% for a one standard deviation increase in concentrations. In the future the projected numbers of respiratory hospital admissions attributable to NO2 in the 2050s are lower than present day rates under 3 Representative Concentration Pathways (RCPs): 2.6, 6.0, and 8.5, which is due to projected reductions in future NO2 emissions and concentrations. CONCLUSIONS: NO2 concentrations exhibit consistent substantial present-day health effects regardless of how a representative concentration is constructed in space and time. Thus as concentrations are predicted to remain above limits set by European Union Legislation until the 2030s in parts of urban England, it will remain a substantial health risk for some time. PMID- 28347338 TI - The prevalence, characteristics, and factors associated with purchasing Chinese herbal medicine among adults in Taiwan. AB - BACKGROUND: The objective of this study was to investigate the prevalence and factors associated with purchasing Chinese herbal medicine (CHM) without a physician's prescription among adults. METHODS: Using data from the 2005 National Health Interview Survey and National Health Insurance, we identified 16,756 individuals aged 20 years and older. Socio-demographic factors, lifestyle, medical services utilization and health behaviors were compared between people with and without a history of purchasing CHM by calculating adjusted odds ratios (ORs) and 95% confidence intervals (CIs) in a multiple logistic regression analysis. RESULTS: The one-month prevalence of purchasing CHM without a physician' prescription was 5.2% in Taiwan. People more likely to purchase CHM included people aged >=70 years (OR 2.84, 95% CI 2.03-3.99), women (OR 1.28, 95% CI 1.11-1.48), non-indigenous people (OR 2.61, 95% CI 1.29-5.30), and people with an illness not receiving medical care (OR 2.69, 95% CI 2.19-3.31). CONCLUSION: The prevalence of purchasing CHM without a physician's prescription is high in Taiwan and is correlated with factors such as socio-demographics, disease history, and behaviors surrounding the utilization of medical care. PMID- 28347339 TI - Antibacterial activity of the stem bark of Tieghemella Heckelii Pierre ex. A Chev against methicillin-resistant Staphylococcus aureus. AB - BACKGROUND: Tieghemella heckelii (Sapotaceae) is a medicinal plant used in Africa, particularly in Cote d'Ivoire for treating various diseases including infections. Identification of prospective antibacterial compounds from stem bark of this plant as a result of its medicinal virtue, led to screening activity against methicillin resistant bacteria. METHODS: Six extracts (hexane, chloroform, ethyl acetate, ethanol, methanol and sterile distilled water) were prepared and tested on methicillin resistant Staphylococcus aureus (MRSA) using broth microdilution method for activity assessment. From this experiment, the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of the plant extracts were determined in sterile 96-well microplates in order to search for both bacteriostatic and bactericidal effects. Afterwards, data analysis was performed using GraphPad Prism5 software (One-way ANOVA and Turkey Multiple Comparison test). The results were then presented as Mean +/- SD for experiment repeated three times. RESULTS: Four extracts (ethyl acetate, methanol, ethanol and sterile distilled water) showed credible potency, with strong, significant, and moderate growth inhibition of the MRSA tested. The MIC values which varied from 45 MUg/mL to 97 MUg/mL according to microbial phenotype, resolutely established the activity of the plant extracts. Additionally, the MBC values which varied, depending on the type of bacteria strain, revealed the bacteriostatic and bactericidal effects of the active extracts against Methicillin-resistant Staphylococcus aureus. CONCLUSION: The present study is a confirmation of the therapeutic potential of Tieghemella heckelii and its promising contribution to the discovery of a novel antibacterial drug pertaining to these resistant strains. PMID- 28347340 TI - Expanding metabolic pathway for de novo biosynthesis of the chiral pharmaceutical intermediate L-pipecolic acid in Escherichia coli. AB - BACKGROUND: The six-carbon circular non-proteinogenic compound L-pipecolic acid is an important chiral drug intermediate with many applications in the pharmaceutical industry. In the present study, we developed a metabolically engineered strain of Escherichia coli for the overproduction of L-pipecolic acid from glucose. RESULTS: The metabolic pathway from L-lysine to L-pipecolic acid was constructed initially by introducing lysine cyclodeaminase (LCD). Next, L lysine metabolic flux from glucose was amplified by the plasmid-based overexpression of dapA, lysC, and lysA under the control of the strong trc promoter to increase the biosynthetic pool of the precursor L-lysine. Additionally, since the catalytic efficiency of the key enzyme LCD is limited by the cofactor NAD+, the intracellular pyridine nucleotide concentration was rebalanced by expressing the pntAB gene encoding the transhydrogenase, which elevated the proportion of LCD with bound NAD+ and enhanced L-pipecolic acid production significantly. Further, optimization of Fe2+ and surfactant in the fermentation process resulted in 5.33 g/L L-pipecolic acid, with a yield of 0.13 g/g of glucose via fed-batch cultivation. CONCLUSIONS: We expanded the metabolic pathway for the synthesis of the chiral pharmaceutical intermediate L-pipecolic acid in E. coli. Using the engineered E. coli, a fast and efficient fermentative production of L-pipecolic acid was achieved. This strategy could be applied to the biosynthesis of other commercially and industrially important chiral compounds containing piperidine rings. PMID- 28347341 TI - Validation of the Pittsburgh sleep quality index in community dwelling Ethiopian adults. AB - BACKGROUND: The applicability of the Pittsburgh Sleep Quality Index (PSQI) in screening of insomnia is demonstrated in various populations. But, the tool has not been validated in a sample of Ethiopians. Therefore, this study aimed to assess its psychometric properties in community dwelling Ethiopian adults. MATERIAL AND METHODS: Participants (n = 311, age = 25.5 +/- 6.0 years and body mass index = 22.1 +/- 2.3 kg/m2) from Mizan-Aman town, Southwest Ethiopia completed the PSQI and a semi-structured questionnaire for socio-demographics. Clinical interview for screening of insomnia according to the International Classification of Sleep Disorders was carried out as a concurrent validation measure. RESULTS: Overall, the PSQI scale did not have floor effect and ceiling effects. Moderate internal consistency (Cronbach's alpha was 0.59) and sufficient internal homogeneity as indicated by correlation coefficient between component scores and the global PSQI score was found. The PSQI was of good value for screening insomnia with optimal cut-off scores of 5.5 (sensitivity 82%, specificity 56.2%) and the area under the curve, 0.78 (p < 0.0001). The PSQI has unidimensional factor structure in the Ethiopian community adults for screening insomnia. CONCLUSION: The PSQI has good psychometric validity in screening for insomnia among Ethiopians adults. PMID- 28347342 TI - Identification and analysis of genomic islands in Burkholderia cenocepacia AU 1054 with emphasis on pathogenicity islands. AB - BACKGROUND: Genomic islands (GIs) are genomic regions that reveal evidence of horizontal DNA transfer. They can code for many functions and may augment a bacterium's adaptation to its host or environment. GIs have been identified in strain J2315 of Burkholderia cenocepacia, whereas in strain AU 1054 there has been no published works on such regions according to our text mining and keyword search in Medline. RESULTS: In this study, we identified 21 GIs in AU 1054 by combining two computational tools. Feature analyses suggested that the predictions are highly reliable and hence illustrated the advantage of joint predictions by two independent methods. Based on putative virulence factors, four GIs were further identified as pathogenicity islands (PAIs). Through experiments of gene deletion mutants in live bacteria, two putative PAIs were confirmed, and the virulence factors involved were identified as lipA and copR. The importance of the genes lipA (from PAI 1) and copR (from PAI 2) for bacterial invasion and replication indicates that they are required for the invasive properties of B. cenocepacia and may function as virulence determinants for bacterial pathogenesis and host infection. CONCLUSIONS: This approach of in silico prediction of GIs and subsequent identification of potential virulence factors in the putative island regions with final validation using wet experiments could be used as an effective strategy to rapidly discover novel virulence factors in other bacterial species and strains. PMID- 28347343 TI - Modeling electrical stimulation of retinal ganglion cell with optimizing additive noises for reducing threshold and energy consumption. AB - BACKGROUND: Epiretinal prosthesis is one device for the treatment of blindness, which target retinal ganglion cells (RGCs) by electrodes on retinal surface. The stimulating current of epiretinal prosthesis is an important factor that influences the safety threshold and visual perception. Stochastic resonance (SR) can be used to enhance the detection and transmission of subthreshold stimuli in neurons. Here, it was assumed that SR was a potential way to improve the performance of epiretinal prosthesis. The effect of noises on the response of RGCs to electrical stimulation and the energy of stimulating current was studied based on a RGC model. METHODS: The RGC was modeled as a multi-compartment model consisting of dendrites and its branches, soma and axon. To evoke SR, a subthreshold signal, a series of bipolar rectangular pulse sequences, plus stochastic biphasic pulse sequences as noises, were used as a stimulus to the model. The SR-type behavior in the model was characterized by a "power norm" measure. To decrease energy consumption of the stimulation waveform, the stochastic biphasic pulse sequences were only added to the cathode and anode phase of the subthreshold pulse and the noise parameters were optimized by using a genetic algorithm (GA). RESULTS: When certain intensity of noise is added to the subthreshold signal, RGC model can fire. With the noise's RMS amplitudes increased, more spikes were elicited and the curve of power norm presents the inverted U-like graph. The larger pulse width of stochastic biphasic pulse sequences resulted in higher power norm. The energy consumption and charges of the single bipolar rectangular pulse without noise in threshold level are 468.18 pJ, 15.30 nC, and after adding optimized parameters's noise to the subthreshold signal, they became 314.8174 pJ, 11.9281 nC and were reduced by 32.8 and 22.0%, respectively. CONCLUSIONS: The SR exists in the RGC model and can enhance the representation of RGC model to the subthreshold signal. Adding the stochastic biphasic pulse sequences to the cathode and anode phase of the subthreshold signal helps to reduce stimulation threshold, energy consumption and charge of RGC stimulation. These may be helpful for improving the performance of epiretinal prosthesis. PMID- 28347346 TI - 7-day weighed food diaries suggest patients with hereditary hemorrhagic telangiectasia may spontaneously modify their diet to avoid nosebleed precipitants. AB - Hereditary hemorrhagic telangiectasia (HHT) poses substantial burdens due to nosebleeds and iron deficiency resulting from recurrent hemorrhagic iron losses. Recent studies by our group found surprising links between HHT nosebleeds and certain food groups. In this letter, we report 7-day weighed food diary assessments of an unselected group of 25 UK patients with HHT whose nosebleeds ranged from mild to severe (median epistaxis severity score 4.66, range 0.89- 9.11). The diaries provide evidence that food items most commonly reported to provoke nosebleeds were ingested by fewer HHT patients, compared to food items less commonly reported to provoke nosebleeds (chi-squared p <0.001). PMID- 28347344 TI - Quantification of the relative contribution of the different right ventricular wall motion components to right ventricular ejection fraction: the ReVISION method. AB - Three major mechanisms contribute to right ventricular (RV) pump function: (i) shortening of the longitudinal axis with traction of the tricuspid annulus towards the apex; (ii) inward movement of the RV free wall; (iii) bulging of the interventricular septum into the RV and stretching the free wall over the septum. The relative contribution of the aforementioned mechanisms to RV pump function may change in different pathological conditions.Our aim was to develop a custom method to separately assess the extent of longitudinal, radial and anteroposterior displacement of the RV walls and to quantify their relative contribution to global RV ejection fraction using 3D data sets obtained by echocardiography.Accordingly, we decomposed the movement of the exported RV beutel wall in a vertex based manner. The volumes of the beutels accounting for the RV wall motion in only one direction (either longitudinal, radial, or anteroposterior) were calculated at each time frame using the signed tetrahedron method. Then, the relative contribution of the RV wall motion along the three different directions to global RV ejection fraction was calculated either as the ratio of the given direction's ejection fraction to global ejection fraction and as the frame-by-frame RV volume change (?V/?t) along the three motion directions.The ReVISION (Right VentrIcular Separate wall motIon quantificatiON) method may contribute to a better understanding of the pathophysiology of RV mechanical adaptations to different loading conditions and diseases. PMID- 28347347 TI - A rare case of biventricular myxoma. AB - BACKGROUND: Cardiac myxoma is the most common primary cardiac tumor. Approximately 75-80% of myxomas are located in the left atrium. Occurrence of multiple myxomas is extremely rare. CASE PRESENTATION: We describe a rare case of biventricular myxomas resulting in right ventricular inflow and tricuspid valve obstruction. The lesions were detected by echocardiography and thoracic computerized tomography (CT) and confirmed on positron emission tomography computed tomography. CONCLUSION: The patient underwent successful surgical resection of the multiple cardiac myxomas. This kind of biventricular case has not been previously reported. The patient is asymptomatic as of the 10-month follow-up. PMID- 28347345 TI - Serotonergic system in hypoxic ventilatory response in unilateral rat model of Parkinson's disease. AB - BACKGROUND: Malfunctioning of the serotonergic system in Parkinson's disease may contribute to non-motor symptoms such as respiratory complications. Thus the aim of our study was to investigate the role of serotonin 5-HT2 receptors in the modulation of normoxic breathing and the hypoxic ventilatory response (HVR) in rat model of Parkinson's disease. METHODS: Wistar rats were lesioned unilaterally with double 6-hydroxydopamine (6-OHDA) injection to the right medial forebrain bundle (MFB). Before lesion and two weeks later animals were put in whole body plethysmography chamber and exposed to hypoxia (8% O2). Before hypoxic tests animals received intraperitoneal injections of DOI and ketanserin. Efficacy of lesion was confirmed by cylinder test, assessing limb use asymmetry. RESULTS: Degeneration of the nigrostriatal pathway augmented response of tidal volume and minute ventilation to hypoxia. DOI administration in control and lesion state caused a significant rise in normoxic respiratory rate and minute ventilation. Yet, ventilatory response of these parameters to hypoxia was attenuated. Post-DOI magnitude of HVR in lesioned state was decreased in compare to pre-lesion control. Subsequent ketanserin injection reverted DOI-induced respiratory effects. We demonstrated that 6-OHDA treatment decreased the content of serotonin in the injured striatum and on both sides of the brainstem, leaving the concentration of noradrenaline on unchanged level. CONCLUSIONS: These observations showed that damage of the nigrostriatal system initiates changes in the serotonergic system, confirmed by reduced concentration of serotonin in the striatum and brainstem, which affects the magnitude of respiratory response to hypoxia after activation of 5-HT2 receptors. PMID- 28347348 TI - Targeted sequencing may facilitate differential diagnostics of pulmonary tumours: a case series. AB - BACKGROUND: Histopathological diagnosis is important for prognostication and choice of treatment in patients with cancer in the lung. Metastases to the lungs are common and need to be distinguished from primary lung cancer. Furthermore, cases with synchronous or metachronous primary lung cancers (although infrequent) are often handled differently than cases with lung cancer with intrapulmonary metastasis or relapse, respectively. In some cases, morphology and immunohistochemical staining is not sufficient for certain diagnosis. METHODS: The present study included six cases where molecular genetic analysis in form of pyrosequencing or targeted next-generation sequencing was of value for certain diagnosis of selected tumours in the lung. RESULTS: Two of the included cases were rare metastases to the lung; colorectal cancer with IHC profile consistent with primary lung cancer and malignant adenomyoepithelioma of the breast, respectively, where molecular genetic analysis was of aid for proving the relationship to the primary tumour. The other four cases were multiple lung adenocarcinomas where molecular genetic analysis was of aid to distinguish between intrapulmonary metastasis and synchronous tumour. CONCLUSIONS: Comparison of molecular genetic profile may be an important tool for determination of relationship between tumours in some situations and should always be considered in unclear cases. Further studies on concordance and discordance of molecular genetic profiles between spatially or temporally different tumours with common origin may be helpful for improved diagnostics of pulmonary tumours. PMID- 28347349 TI - Use of crystal methamphetamine among male adolescents in Cape Town, South Africa: Caregivers' experiences. AB - BACKGROUND: Against the background that crystal methamphetamine (colloquially known as "tik") is extensively used by the emerging working class Coloured youth in Cape Town, South Africa, this exploratory qualitative study was conducted to explore the experience of mothers whose children use methamphetamine. METHODS: The researchers conducted one-to-one semi-structured in-depth interviews with sixteen (16) purposively selected caregivers (mothers) whose sons use methamphetamine. Interviews were recorded and simultaneously translated and transcribed. Thematic analysis was used to identify themes related to the experiences of caregivers of youth with methamphetamine problems. RESULTS: Findings showed that youth misbehaviour provided a context that led to feelings of shame and embarrassment. Participants also experienced personal challenges which included emotional problems, fear and self-blame. Participants also expressed family disruptions and financial drain as adverse experiences as a results of their sons' misbehaviour. CONCLUSION: The study results highlight the psychosocial challenges for caregivers of children who use methamphetamine. These findings underscore the need for effort to be directed at the development of formal support interventions for mothers of youth who are troubled with addiction. PMID- 28347350 TI - The association between age of onset of opioid use and comorbidity among opioid dependent patients receiving methadone maintenance therapy. AB - BACKGROUND: Opioid use disorder (OUD) affects approximately 21.9 million people worldwide. This study aims to determine the association between age of onset of opioid use and comorbid disorders, both physical and psychiatric, in patients receiving methadone maintenance treatment (MMT) for OUD. Understanding this association may inform clinical practice about important prognostic factors of patients on MMT, enabling clinicians to identify high-risk patients. METHODS: This study includes data collected between June 2011 and August 2016 for the Genetics of Opioid Addiction research collaborative between McMaster University and the Canadian Addiction Treatment Centers. All patients were interviewed by trained health professionals using the Mini-International Neuropsychiatric Interview and case report forms. Physical comorbidities were verified using patients' electronic medical records. A multi-variable logistic regression model was constructed to determine the strength of the association between age of onset of opioid use and the presence of physical or psychiatric comorbidity while adjusting for current age, sex, body mass index, methadone dose and smoking status. RESULTS: Data from 627 MMT patients with a mean age of 38.8 years (SD = 11.07) were analyzed. Individuals with an age of onset of opioid use younger than 18 years were found to be at higher odds for having a physical or psychiatric comorbid disorder compared to individuals with an age of onset of opioid use of 31 years or older (odds ratio 2.94, 95% confidence interval 1.20, 7.19, p = 0.02). A significant association was not found between the risk of having a comorbidity and an age of onset of opioid use between 18 and 25 years or 26 and 30 years, compared to an age of onset of opioid use of 31 years or older. CONCLUSION: Our study demonstrates that the younger one begins to use opioids, the greater their chance of having a physical or psychiatric co-morbidity. Understanding the risk posed by an earlier onset of opioid use for the later development of comorbid disorders informs clinical practice about important prognostic predictors and aids in the identification of high-risk patients. PMID- 28347351 TI - The effectiveness of health care provider physical activity recommendations in cancer survivors: a systematic review and meta-analysis protocol. AB - BACKGROUND: Cancer survivors face a range of negative physical and psychological effects that can be mitigated by participating in physical activity. Despite this, most do not meet recommended levels. Health care providers may be in a unique position to promote participation in physical activity among cancer survivors. The aim of this systematic review and meta-analysis is to synthesize the findings from randomized controlled trials and controlled clinical trials investigating the effectiveness of health care provider-administered physical activity recommendations on participation in physical activity among cancer survivors. METHODS/DESIGN: Ten electronic databases (CINAHL, CENTRAL, Education Source, EMBASE, LILACS, MEDLINE, OTSeeker, PEDro, PsycINFO, SPORTDiscus) will be searched to identify relevant studies. The electronic searches will be supplemented by scanning the reference lists of relevant articles retrieved during these searches to ensure all potentially relevant studies are identified. Two reviewers will independently screen all titles and abstracts resulting from the searches to identify potentially eligible studies. They will then screen the full-text articles passing the first screen to identify studies for inclusion using predetermined inclusion/exclusion criteria, extract data from studies meeting all criteria, and assess the risk of bias of these studies. Results will be summarized narratively and statistically. DISCUSSION: By summarizing the best available evidence for the effectiveness of health care provider physical activity recommendations for increasing participation in physical activity among cancer survivors, the results of this systematic review and meta-analysis will help determine if making physical activity recommendations effectively changes cancer survivors behaviour. It will also help to identify knowledge gaps and highlight areas in need of additional research. PMID- 28347352 TI - Combined target site (kdr) mutations play a primary role in highly pyrethroid resistant phenotypes of Aedes aegypti from Saudi Arabia. AB - BACKGROUND: Pyrethroid resistance is a threat to effective vector control of Aedes aegypti, the vector of dengue, Zika and other arboviruses, but there are many major knowledge gaps on the mechanisms of resistance. In Jeddah and Makkah, the principal dengue-endemic areas of Saudi Arabia, pyrethroids are used widely for Ae. aegypti control but information about resistance remains sparse, and the underlying genetic basis is unknown. Findings from an ongoing study in this internationally significant area are reported here. METHODS: Aedes aegypti collected from each city were raised to adults and assayed for resistance to permethrin, deltamethrin (with and without the synergist piperonyl butoxide, PBO), fenitrothion, and bendiocarb. Two fragments of the voltage-gated sodium channel (Vgsc), encompassing four previously identified mutation sites, were sequenced and subsequently genotyped to determine associations with resistance. Expression of five candidate genes (CYP9J10, CYP9J28, CYP9J32, CYP9M6, ABCB4) previously associated with pyrethroid resistance was compared between assay survivors and controls. RESULTS: Jeddah and Makkah populations exhibited resistance to multiple insecticides and a similarly high prevalence of resistance to deltamethrin compared to a resistant Cayman strain, with a significant influence of age and exposure duration on survival. PBO pre-exposure increased pyrethroid mortality significantly in the Jeddah, but not the Makkah strain. Three potentially interacting Vgsc mutations were detected: V1016G and S989P were in perfect linkage disequilibrium in each strain and strongly predicted survival, especially in the Makkah strain, but were in negative linkage disequilibrium with 1534C, though some females with the Vgsc triple mutation were detected. The candidate gene CYP9J28 was significantly over-expressed in Jeddah compared to two susceptible reference strains, but none of the candidate genes was consistently up-regulated to a significant level in the Makkah strain. CONCLUSIONS: Despite their proximity, Makkah and Jeddah exhibit significant differences in pyrethroid resistance phenotypes, with some evidence to suggest a different balance of mechanisms, for example with more impact associated with CYP450s in the Jeddah strain, and the dual kdr mutations 989P and 1016G in the more resistant Makkah strain. The results overall demonstrate a major role for paired target site mutations in pyrethroid resistance and highlight their utility for diagnostic monitoring. PMID- 28347353 TI - Two synchronous malignant tumors of the pancreas: a case report. AB - BACKGROUND: Only a limited number of multiple synchronous primary malignancies of the pancreas have been reported in the medical literature. We report a case of two solid malignant tumors of the pancreas diagnosed preoperatively. CASE PRESENTATION: We describe a 65-year-old Sri Lankan woman who presented with progressive obstructive jaundice. Initial contrast-enhanced computed tomography imaging detected a malignant tumor at the tail of her pancreas. A second tumor of the pancreatic head was detected with integrated imaging using multidetector computed tomography and multimodal magnetic resonance imaging. She underwent total pancreaticoduodenectomy and splenectomy. Gross examination of the specimen confirmed the presence of two separate tumors. Histology of the ampullary tumor showed pancreatic-type adenocarcinoma and the tumor in the tail of her pancreas showed a colloid-type adenocarcinoma. CONCLUSION: The possibility of multiple primary malignant solid tumors of different types with malignant potential has to be considered even without background pathology when managing multiple tumors in the pancreas. PMID- 28347354 TI - Equipoise across the patient population: optimising recruitment to a randomised controlled trial. AB - BACKGROUND: This paper proposes a novel perspective on the value of qualitative research for improving trial design and optimising recruitment. We report findings from a qualitative study set within the OPEN trial, a surgical randomised controlled trial (RCT) comparing two interventions for recurrent bulbar urethral stricture, a common cause of urinary problems in men. METHODS: Interviews were conducted with men meeting trial eligibility criteria (n = 19) to explore reasons for accepting or declining participation and with operating urologists (n = 15) to explore trial acceptability. RESULTS: Patients expressed various preferences and understood these in the context of relative severity and tolerability of their symptoms. Accounts suggest a common trajectory of worsening symptoms with a particular window within which either treatment arm would be considered acceptable. Interviews with clinician recruiters found that uncertainty varied between general and specialist sites, which reflect clinicians' relative exposure to different proportions of the patient population. CONCLUSION: Recruitment post referral, at specialist sites, was challenging due to patient (and clinician) expectations. Trial design, particularly where there are fixed points for recruitment along the care pathway, can enable or constrain the possibilities for effective accrual depending on how it aligns with the optimum point of patient equipoise. Qualitative recruitment investigations, often focussed on information provision and patient engagement, may also look to better understand the target patient population in order to optimise the point at which patients are approached. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN98009168 . Registered on 29 November 2012. PMID- 28347355 TI - The potential of health literacy to address the health related UN sustainable development goal 3 (SDG3) in Nepal: a rapid review. AB - BACKGROUND: Health literacy has been linked to health outcomes across population groups around the world. Nepal, a low income country, experiences the double burden of highly prevalent communicable as well as non-communicable diseases. The World Health Organization (WHO) has positioned health literacy as a key mechanism to meet the health-related Sustainable Development Goal (SDG3). However, there is little known about the status of health literacy in developing countries such as Nepal. This paper aims to review the potential of health literacy to address SDG3 in Nepal. METHODS: A rapid review was conducted using the knowledge to action evidence summary approach. Articles included in the review were those reporting on barriers to health care engagements in Nepal published in English language between January 2000 and December 2015. RESULTS: Barriers for healthcare engagement included knowledge and education as strong factors, followed by culture, gender roles, quality of service and cost of services. These barriers influence the Nepalese community to access and engage with services, and make and enact healthcare decisions, not only at the individual level but at the family level. These factors are directly linked to health literacy. Health literacy is a pivotal determinant of understanding, accessing and using health information and health services, it is important that the health literacy needs of the people be addressed. CONCLUSION: Locally identified and developed health literacy interventions may provide opportunities for systematic improvements in health to address impediments to healthcare in Nepal. Further research on health literacy and implementation of health literacy interventions may help reduce inequalities and increase the responsiveness of health systems which could potentially facilitate Nepal to meet the sustainable development goals. While there is currently little in place for health literacy to impact on the SDG3, this paper generates insights into health literacy's potential role. PMID- 28347356 TI - Surgical resection of cardiac myxoma-a 30-year single institutional experience. AB - BACKGROUND: Primary cardiac tumors are rare and myxoma constitutes the majority. The present study summarizes our 30-year clinical outcomes of surgical myxoma resection. METHODS: Between January 1986 and December 2015, 93 patients (30 men, 63 women; mean age, 54.7 +/- 16.6 years) underwent surgical myxoma resection. The most common origin site was the left atrium. Surgery was performed via a biatrial approach in 74.2%, atrial septotomy through right atriotomy in 17.2%, and left atriotomy only in 8.6%. Mean myxoma size based on longest length was 4.73 +/- 1.92 cm (range, 1.2-11.0 cm). RESULTS: The mean follow-up duration was 9.9 +/- 7.8 years (range, 0-29 years). In-hospital mortality was 3.2%. The most common postoperative complication was atrial fibrillation (4.3%). The 5-, 10-, and 30 year survival rates were 92.9%, 87.2%, and 75.5%, respectively. Recurrence occurred in two patients (2.1%), which were detected at 20 and 79 months after the first surgery, respectively. CONCLUSIONS: Long-term survival after myxoma resection was excellent and recurrence was rare. Based on our experience, surgical method did not affect the outcome. PMID- 28347357 TI - Prevalence and risk factors associated with female anal sex in the context of HIV/AIDS in the selected districts of Tanzania. AB - BACKGROUND: Female anal sex is a receptive type of sexual practice among heterosexual couples where the penis is inserted into the anus of a female partner. In the Western world, a number of studies and interventions have been carried out on anal sex among men due to its potential risks to HIV transmission. In African countries, including Tanzania, there is dearth of information on the risks inherent in practices associated with female anal sex in the general population. The objective of this study was to determine the prevalence and risk factors associated with female anal sex in fuelling HIV transmission in selected districts of Tanzania. METHODS: This study was conducted in four districts of Tanzania of Kinondoni, Tanga Urban, Makete and Siha. Both quantitative and qualitative methods i.e. household interviews and focus group discussions were employed in data collection. Study participants included community members of aged 15 and above such as heads of the household, adolescents, bar workers and commercial sex workers. FINDINGS: A total of 903 individuals were interviewed, 60.6% of whom were females. When respondents were asked to indicate whether they had ever been tempted to practise FAS, 167 (18.5%) reported to have been tempted in the past 12 months. Of these, 44 (26.3%) respondents had at least practised FAS. Risky practices associated with FAS were forced sex, multiple partners, frequency of engaging in FAS, low use of condoms during FAS, low rates of HIV testing among partakers, poor perception of the risks to acquire HIV through FAS and use of lubricants. CONCLUSIONS: In this population, the frequency of FAS practice was rather low. And yet, FAS practice attendant risk factors are likely to exacerbate HIV transmission. As such, there is a need for further exploratory studies to determine and document drivers of FAS. In addition, public health education should be provided with regard to the risks of contracting HIV associated with FAS practices. PMID- 28347360 TI - GANEing on emotion and emotion regulation. AB - The function of emotion and its underlying neural mechanisms are often left underspecified. I extend the GANE (glutamate amplifies noradrenergic effects) model by examining its success in accounting for findings in emotion regulation. I also identify points of alignment with construction models of emotion and with the hypothesis that emotion states function to push neural activity toward rapid and efficient action. PMID- 28347359 TI - The association of trajectories of protein intake and age-specific protein intakes from 2 to 22 years with BMI in early adulthood. AB - No study has analysed how protein intake from early childhood to young adulthood relate to adult BMI in a single cohort. To estimate the association of protein intake at 2, 11, 15, 19 and 22 years with age- and sex-standardised BMI at 22 years (early adulthood), we used linear regression models with dietary and anthropometric data from a Filipino birth cohort (1985-2005, n 2586). We used latent growth curve analysis to identify trajectories of protein intake relative to age-specific recommended daily allowance (intake in g/kg body weight) from 2 to 22 years, then related trajectory membership to early adulthood BMI using linear regression models. Lean mass and fat mass were secondary outcomes. Regression models included socioeconomic, dietary and anthropometric confounders from early life and adulthood. Protein intake relative to needs at age 2 years was positively associated with BMI and lean mass at age 22 years, but intakes at ages 11, 15 and 22 years were inversely associated with early adulthood BMI. Individuals were classified into four mutually exclusive trajectories: (i) normal consumers (referent trajectory, 58 % of cohort), (ii) high protein consumers in infancy (20 %), (iii) usually high consumers (18 %) and (iv) always high consumers (5 %). Compared with the normal consumers, 'usually high' consumption was inversely associated with BMI, lean mass and fat mass at age 22 years whereas 'always high' consumption was inversely associated with male lean mass in males. Proximal protein intakes were more important contributors to early adult BMI relative to early-childhood protein intake; protein intake history was differentially associated with adulthood body size. PMID- 28347361 TI - For better or worse, or for a change? AB - The noradrenergic system is intimately related to the autonomic system and is thought to play a key role at the interface between arousal and cognition. The GANE (glutamate amplifies noradrenergic effects) theory proposes a complete account of that role, with an emphasis on the quantitative effect of noradrenaline on stimulus processing. This is in marked contrast to network reset theory, which emphasizes the qualitative effect of noradrenaline of updating the representation of the environment. PMID- 28347362 TI - What BANE can offer GANE: Individual differences in function of hotspot mechanisms. AB - In this commentary we focus on individual differences in proposed mechanisms underlying arousal-based enhancement of prioritized stimuli. We discuss the potential of genotyping studies for examining effects of noradrenergic processes on stimulus prioritization in humans and stress the importance of potential individual differences in the activity of specific receptor subtypes in hotspot processes proposed by the GANE model. PMID- 28347363 TI - Locus coeruleus reports changes in environmental contingencies. AB - The GANE (glutamate amplifies noradrenergic effects) model proposed by Mather et al. attempts to explain how norepinephrine enhances processing in highly activated brain regions. Careful perusal of the sparse data available from recording studies in animals reveals that noradrenergic neurons are excited mainly by any change in the environment - a salient, novel, or unexpected sensory stimulus or a change in behavioral contingencies. This begets the "network reset hypothesis" supporting the notion that norepinephrine promotes rapid cognitive and behavioral adaption. PMID- 28347364 TI - Cognitive control, dynamic salience, and the imperative toward computational accounts of neuromodulatory function. AB - We draw attention to studies indicating that phasic arousal increases interference effects in tasks necessitating the recruitment of cognitive control. We suggest that arousal-biased competition models such as GANE (glutamate amplifies noradrenergic effects) may be able to explain these findings by taking into account dynamic, within-trial changes in the relative salience of task relevant and task-irrelevant features. However, testing this hypothesis requires a computational model. PMID- 28347365 TI - Emotional memory: From affective relevance to arousal. AB - Arousal is typically conceived as a key component of emotional response. We describe here the psychological processes thought to elicit arousal - in particular, the processes involved in the appraisal of affective relevance. The key role of relevance in attentional and memory processing, and its links with arousal, is discussed with respect to the GANE (glutamate amplifies noradrenergic effects) model described by Mather et al. PMID- 28347366 TI - Why we forget our dreams: Acetylcholine and norepinephrine in wakefulness and REM sleep. AB - The ascending fibers releasing norepinephrine and acetylcholine are highly active during wakefulness. In contrast, during rapid-eye-movement sleep, the neocortical tone is sustained mainly by acetylcholine. By comparing the different physiological features of the norepinephrine and acetylcholine systems in the light of the GANE (glutamate amplifies noradrenergic effects) model, we suggest how to interpret some functional differences between waking and rapid-eye movement sleep. PMID- 28347367 TI - Contemplating the GANE model using an extreme case paradigm. AB - Early experiences play a crucial role in programming brain function, affecting selective attention, learning, and memory. Infancy literature suggests an extension of the GANE (glutamate amplifies noradrenergic effects) model to conditions with minimal priority-map inputs, yet suggests qualifications by noting that its efficacy is increased when tonic levels of arousal are maintained in an optimal range, in manners that are age and exposure dependent. PMID- 28347358 TI - Genetic pleiotropy between age-related macular degeneration and 16 complex diseases and traits. AB - BACKGROUND: Age-related macular degeneration (AMD) is a common condition of vision loss with disease development strongly influenced by environmental and genetic factors. Recently, 34 loci were associated with AMD at genome-wide significance. So far, little is known about a genetic overlap between AMD and other complex diseases or disease-relevant traits. METHODS: For each of 60 complex diseases/traits with publicly available genome-wide significant association data, the lead genetic variant per independent locus was extracted and a genetic score was calculated for each disease/trait as the weighted sum of risk alleles. The association with AMD was estimated based on 16,144 AMD cases and 17,832 controls using logistic regression. RESULTS: Of the respective disease/trait variance, the 60 genetic scores explained on average 4.8% (0.27 20.69%) and 16 of them were found to be significantly associated with AMD (Q values < 0.01, p values from < 1.0 * 10-16 to 1.9 * 10-3). Notably, an increased risk for AMD was associated with reduced risk for cardiovascular diseases, increased risk for autoimmune diseases, higher HDL and lower LDL levels in serum, lower bone-mineral density as well as an increased risk for skin cancer. By restricting the analysis to 1824 variants initially used to compute the 60 genetic scores, we identified 28 novel AMD risk variants (Q-values < 0.01, p values from 1.1 * 10-7 to 3.0 * 10-4), known to be involved in cardiovascular disorders, lipid metabolism, autoimmune diseases, anthropomorphic traits, ocular disorders, and neurological diseases. The latter variants represent 20 novel AMD associated, pleiotropic loci. Genes in the novel loci reinforce previous findings strongly implicating the complement system in AMD pathogenesis. CONCLUSIONS: We demonstrate a substantial overlap of the genetics of several complex diseases/traits with AMD and provide statistically significant evidence for an additional 20 loci associated with AMD. This highlights the possibility that so far unrelated pathologies may have disease pathways in common. PMID- 28347368 TI - Bodily arousal differentially impacts stimulus processing and memory: Norepinephrine in interoception. AB - Bodily arousal modulates stimulus processing and memory, contributing to expression of emotional salience. The "glutamate amplifies noradrenergic effects" (GANE) model proposed by Mather and colleagues can be extended to account for the differential impact of interoceptive (notably cardiac afferent) signals on sensory processing. However, some emotion-specific effects, for example, for fear, may further depend on functional anatomical organisation of affect-related brain structures. PMID- 28347369 TI - Effect of arousal on perception as studied through the lens of the motor correlates of sexual arousal. AB - The study of sexual arousal is at the interface of affective and social neurosciences. Recent results regarding the motor correlates of sexual arousal demonstrating an early freezing response are in perfect accordance with the GANE (glutamate amplifies noradrenergic effects) model's sustaining the double role of the arousal dimension on emotional processing. PMID- 28347370 TI - Emotionally arousing context modulates the ERP correlates of neutral picture processing: An ERP test of the GANE model. AB - The time scale of the effects of emotional arousal on neutral information processing is crucial for the predictions of the glutamate amplifies noradrenergic effects (GANE) model. GANE suggests that when emotional and neutral stimuli are presented in a sequence, neutral information processing will change. We review the literature on event-related potentials, including our own data set, to test this prediction. PMID- 28347371 TI - Use of biomarkers to assess fruit and vegetable intake. AB - A high intake of fruit and vegetables (FV) has been associated with reduced risk of a number of chronic diseases, including CVD. The aim of this review is to describe the potential use of biomarkers to assess FV intake. Traditional methods of assessing FV intake have limitations, and this is likely to impact on observed associations with disease outcomes and markers of disease risk. Nutritional biomarkers may offer a more objective and reliable method of assessing dietary FV intake. Some single blood biomarkers, such as plasma vitamin C and serum carotenoids, are well established as indicators of FV intake. Combining potential biomarkers of intake may more accurately predict overall FV intake within intervention studies than the use of any single biomarker. Another promising approach is metabolomic analysis of biological fluids using untargeted approaches to identify potential new biomarkers of FV intake. Using biomarkers to measure FV intake may improve the accuracy of dietary assessment. PMID- 28347372 TI - The Fluency Amplification Model supports the GANE principle of arousal enhancement. AB - The GANE (glutamate amplifies noradrenergic effects) model described by Mather et al. offers a neurophysiological basis for the arousal mechanism which is essential for empirical aesthetics and Gestalt processing. More generally, the core principle of perception can be interpreted as a continuous processing of competing arousal states, yielding selective amplification and inhibition of percepts to deduce the meaning of a scene. PMID- 28347373 TI - Using stable isotope techniques in nutrition assessments and tracking of global targets post-2015. AB - Stable isotopes are non-radioactive, safe and are applied for various purposes in human health assessment in trace amounts that minimally disturb normal physiology. The International Atomic Energy Agency supports the use of stable isotope techniques to design and evaluate interventions addressing malnutrition in all its forms with focus on infant and young child feeding; maternal and adolescent nutrition; diet quality; prevention and control of non-communicable diseases; healthy ageing and gut function. These techniques can be used to objectively measure: (1) amount of human milk consumed and whether an infant is exclusively breastfed; (2) body composition in the context of re-feeding programmes for moderate and severe acute malnutrition and as an indicator of the risk for obesity; (3) bioavailability and bioconversion of pro-vitamin A and vitamin A body stores following vitamin A intervention programmes; (4) absorption and retention of iron, zinc and protein; (5) total energy expenditure for validation of physical activity measurement and dietary assessment tools and (6) diagnosis of Helicobacter pylori. Stable isotope techniques will be invaluable in the tracking of global targets on exclusive breast-feeding childhood obesity and anaemia among women. Efforts are underway to make nuclear techniques more affordable, field-friendly and less invasive, and to develop less sophisticated but precise equipment. Advocacy for the wide adoption of the techniques is needed. PMID- 28347374 TI - Interactions of noradrenaline and cortisol and the induction of indelible memories. AB - The glutamate amplifies noradrenergic effects (GANE) model emphasizes the role of focal glutamate-noradrenaline interactions in creating functional hotspots for prioritized processing of salient stimuli. Here, we briefly outline current evidence that synergistic action of noradrenaline and cortisol enables emotional stimuli to gain privileged access to amygdala-hippocampus circuits, eventually resulting in the formation of indelible memories and posttraumatic stress disorder (PTSD). PMID- 28347375 TI - Does arousal enhance apical amplification and disamplification? AB - We summarize evidence that input to the apical tufts of neocortical pyramidal cells modulates their response to basal input. Because this apical amplification and disamplification provide intracortical mechanisms for prioritization, Mather and colleagues' arguments suggest that their effects are enhanced by noradrenergic arousal. Though that is likely, it has not yet been adequately studied. Their article shows that it should be. PMID- 28347376 TI - Dentate gyrus and hilar region revisited. AB - It is suggested that the dentate gyrus and hilar region in the hippocampus perform memory selection and that the selectivity of the gating of memory by this circuit is modulated by the norepinephrine-glutamate loop described by Mather et al. PMID- 28347377 TI - A Pilot Evaluation of a Strengths-Based CBT Intervention Module with College Students. AB - BACKGROUND: Interventions focusing on positive experiences have moderate effects on distress, protective factors and quality of life. AIMS: To evaluate the 'Personal Model of Resilience' (PMR) intervention by Padesky and Mooney (2012) with a focus on resilience strategies the person already possesses. METHOD: In a pre-post design, intervention and control samples of college students (n = 53) are compared with regard to distress, protective factors and quality of life. RESULTS: Compared with the control group, the PMR group shows significant improvements in distress, protective factors and quality of life with medium to large effect sizes. CONCLUSIONS: The PMR is a promising intervention module. It requires further evaluation in clinical contexts, with larger samples, and long term follow-up assessments. PMID- 28347379 TI - Evaluation of a Trauma-Focused CBT Training Programme for IAPT services. AB - BACKGROUND: Therapists in Improving Access to Psychological Therapies (IAPT) services are often expected to treat complex presentations of post-traumatic stress disorder (PTSD), such as individuals with multiple, prolonged or early life trauma histories and significant co-morbidity, for which they have received minimal training. Although high recovery rates for PTSD have been demonstrated in randomized controlled trials, these are not always replicated in routine practice, suggesting that training interventions are required to fill the research-practice gap. AIMS: This study investigated the outcomes of a therapist training programme on treating PTSD with trauma-focused cognitive behavioural therapy (TF-CBT). METHOD: Twenty therapists from ten IAPT services participated in the training, which consisted of workshops, webinars and consultation sessions over a 6-month period. RESULTS: Feedback indicated that participants found the training highly acceptable. PTSD knowledge and self- and supervisor-rated competence on TF-CBT measures improved following the training and improvements were maintained a year later. Client outcomes on a PTSD measure improved following the training. Participants reported attempts to disseminate learning from the course back to their teams. CONCLUSIONS: The findings indicate that the training programme was successful in improving TF-CBT knowledge, skills and outcomes for IAPT therapists. Tentative support for training 'trauma experts' within IAPT services was found, although institutional constraints and staff turnover may limit the sustainability of the model. PMID- 28347378 TI - Vitamin D deficiency as a public health issue: using vitamin D2 or vitamin D3 in future fortification strategies. AB - The role of vitamin D in supporting the growth and maintenance of the skeleton is robust; with recent research also suggesting a beneficial link between vitamin D and other non-skeletal health outcomes, including immune function, cardiovascular health and cancer. Despite this, vitamin D deficiency remains a global public health issue, with a renewed focus in the UK following the publication of Public Health England's new Dietary Vitamin D Requirements. Natural sources of vitamin D (dietary and UVB exposure) are limited, and thus mechanisms are needed to allow individuals to achieve the new dietary recommendations. Mandatory or voluntary vitamin D food fortification may be one of the mechanisms to increase dietary vitamin D intakes and subsequently improve vitamin D status. However, for the food industry and public to make informed decisions, clarity is needed as to whether vitamins D2 and D3 are equally effective at raising total 25 hydroxyvitamin D (25(OH)D) concentrations as the evidence thus far is inconsistent. This review summarises the evidence to date behind the comparative efficacy of vitamins D2 and D3 at raising 25(OH)D concentrations, and the potential role of vitamin D food fortification as a public health policy to support attainment of dietary recommendations in the UK. The comparative efficacy of vitamins D2 and D3 has been investigated in several intervention trials, with most indicating that vitamin D3 is more effective at raising 25(OH)D concentrations. However, flaws in study designs (predominantly under powering) mean there remains a need for a large, robust randomised-controlled trial to provide conclusive evidence, which the future publication of the D2-D3 Study should provide (BBSRC DRINC funded: BB/I006192/1). This review also highlights outstanding questions and gaps in the research that need to be addressed to ensure the most efficacious and safe vitamin D food fortification practices are put in place. This further research, alongside cost, availability and ethical considerations (vitamin D3 is not suitable for vegans), will be instrumental in supporting government, decision-makers, industry and consumers in making informed choices about potential future vitamin D policy and practice. PMID- 28347380 TI - Behavioural and Cognitive Psychotherapy: A Descriptive Review (2000 to July 2016). AB - BACKGROUND: The Behavioural and Cognitive Psychotherapy (BCP) Journal is the main academic publication of the British Association for Behavioural and Cognitive Psychotherapies. It publishes empirical studies, reviews and theoretical papers, brief reports and single cases. AIM: To describe the main areas of interest and focus in BCP papers. METHOD: All the papers published in BCP from 2000 to July 2016 were analysed. A categorization procedure was followed with 813 contributions in six main areas: main author country; main author gender; kind of contribution; kind of therapeutic approaches; kind of samples; kind of focus/topic. RESULTS: Although the journal's scope is international, first authors tend to come from English-speaking countries. Since 2009, females contribute more than males. Empirical studies surpass theoretical studies and reviews, while the main therapy denomination is cognitive behavioural therapy. Variability of samples is wide, and ranges from analogues to main disorders. Finally, the main focus of papers is to study change and psychopathology, therapists' training and improvement of CBT. CONCLUSION: Given the total number of categorized papers, it can be tentatively assumed that they could exemplify some main areas of interest and evolvement in the cognitive and behavioural field. PMID- 28347381 TI - Live music intervention for cancer inpatients: The Music Givers format. AB - OBJECTIVE: The present study intended to evaluate the impact of a standardized format-called the "Music Givers," based on a single session of music intervention followed by a buffet-on the psychological burden and well-being of hospitalized cancer patients. METHOD: The Distress Thermometer (DT), the Hospital Anxiety and Depression Scale (HADS), and self-reported visual analogue scales (score range = 1-10) to assess pain, fatigue, and five areas of well-being (i.e., physical, psychological, relational, spiritual, and overall well-being) were administered to 242 cancer patients upon admission to and at discharge from the hospital. Among them, 103 were hospitalized during which time a live concert took place (intervention group), whereas 139 patients were hospitalized when it did not (control group). RESULTS: Compared to the control group, patients in the intervention group demonstrated less distress at discharge according to the DT (adjusted estimate of difference = -0.8, p = 0.001), lower HADS-Anxiety (-1.7, p < 0.001) and HADS-Depression scores (-1.3, p = 0.001), and higher scores on all the well-being scales, with the exception of spiritual well-being. In addition, no between-group differences were found in terms of pain and fatigue scores at discharge. SIGNIFICANCE OF RESULTS: The one-session format of the Music Givers intervention is an effective, standardized, easy-to-replicate, and low-cost intervention that reduces psychological burden and improves the well-being of hospitalized cancer patients. Listening to live music and the opportunity to establish better relationships between patients and staff could explain these results. PMID- 28347382 TI - Glutamate and norepinephrine interaction: Relevance to higher cognitive operations and psychopathology. AB - Mather and colleagues present an impressive interdisciplinary model of arousal induced norepinephrine release and its role in selectively enhancing/inhibiting perception, attention, and memory consolidation. This model will require empirical investigation to test its validity and generalizability beyond classic norepinephrine circuits because it simplifies extremely complex and heterogeneous actions including norepinephrine mechanisms related to higher cognitive circuits and psychopathology. PMID- 28347383 TI - The role of arousal in predictive coding. AB - Within a predictive coding approach, the arousal/norepinephrine effects described by the GANE (glutamate amplifies noradrenergic effects) model seem to modulate the precision attributed to prediction errors, favoring the selective updating of predictive models with larger prediction errors. However, to explain how arousal effects are triggered, it is likely that different kinds of prediction errors (including interoceptive/affective) need to be considered. PMID- 28347384 TI - An Empirical Assessment of REBT Models of Psychopathology and Psychological Health in the Prediction of Anxiety and Depression Symptoms. AB - AIMS: This study aimed to assess the validity of two models which integrate the cognitive (satisfaction with life) and affective (symptoms of anxiety and depression) aspects of subjective well-being within the framework of rational emotive behaviour therapy (REBT) theory; specifically REBT's theory of psychopathology and theory of psychological health. METHOD: 397 Irish and Northern Irish undergraduate students completed measures of rational/irrational beliefs, satisfaction with life, and anxiety/depression symptoms. Structural equation modelling techniques were used in order to test our hypothesis within a cross-sectional design. RESULTS: REBT's theory of psychopathology (chi2 = 373.78, d.f. = 163, p < .001; comparative fit index (CFI) = .92; Tucker Lewis index (TLI) = .91; root mean square error of approximation (RMSEA) = .06 (95% CI = .05 to .07); standardized root mean square residual (SRMR) = .07) and psychological health (chi2 = 371.89, d.f. = 181, p < .001; CFI = .93; TLI = .92; RMSEA = .05 (95% CI = .04 to .06); SRMR = .06) provided acceptable fit of the data. Moreover, the psychopathology model explained 34% of variance in levels of anxiety/depression, while the psychological health model explained 33% of variance. CONCLUSIONS: This study provides important findings linking the fields of clinical and positive psychology within a comprehensible framework for both researchers and clinicians. Findings are discussed in relation to the possibility of more effective interventions, incorporating and targeting not only negative outcomes, but also positive concepts within the same model. PMID- 28347385 TI - Importance of amygdala noradrenergic activity and large-scale neural networks in regulating emotional arousal effects on perception and memory. AB - Mather and colleagues postulate that norepinephrine promotes selective processing of emotionally salient information through local "hotspots" where norepinephrine release interacts with glutamatergic activity. However, findings in rodents and humans indicate that norepinephrine is ineffective in modulating mnemonic processes in the absence of a functional amygdala. We therefore argue that emphasis should shift toward modulatory effects of amygdala-driven changes at the network level. PMID- 28347386 TI - Are there "local hotspots?" When concepts of cognitive psychology do not fit with physiological results. AB - Mather and colleagues' arguments require rethinking at the mechanistic level. The arguments on the physiological effects of norepinephrine at the cortical level are inconsistent with large parts of the literature. There is no evidence that norepinephrine induces local "hotspots": Norepinephrine mainly decreases evoked responses; facilitating effects are rare and not localized. More generally, the idea that perception benefits from "local hotspots" is hardly compatible with the fact that neural representations involve largely distributed activation of cortical and subcortical networks. PMID- 28347387 TI - Adaptive memory systems for remembering the salient and the seemingly mundane. AB - In an adaptive memory system, events should be prioritized in memory based on their own significance, as well as the significance of preceding or following events. Here we argue that tag-and-capture models complement the GANE (glutamate amplifies noradrenergic effects) model by describing a mechanism that supports the transfer of memory benefits from one event to the next. PMID- 28347388 TI - Arousal-biased preferences for sensory input: An agent-centered and multisource perspective. AB - I argue that the GANE (glutamate amplifies noradrenergic effects) model basically explains an arousal-based amplification of emotional stimuli, whereas effects on neutral stimuli indicate a contextualization process aiming to reduce stimulus ambiguity. To extend the model's validity, I suggest distinguishing between internal and external emotional sources, as well considering the stimulus valence and addressing age-related differences in attention and memory preferences. PMID- 28347389 TI - Competition elicits arousal and affect. AB - The emotion-cognition integration in Mather et al. can be extended by specifying the relationship between competition and arousal in the reverse direction. According to affective monitoring, competition raises arousal, which, when sustained, results in negative affect, evoking theta oscillations, and when resolved, in positive affect, evoking gamma oscillations. Competition should be considered a core process in both cognition and emotion. PMID- 28347390 TI - Once more with feeling: On the explanatory limits of the GANE model and the missing role of subjective experience. AB - We applaud Mather and colleagues' model, which emphasizes the neurobiological pathways by which affective arousal tunes attention and memory. This commentary offers a friendly discussion of several potential limitations of the theory. We suggest the model is strong when predicting task-driven demands but is limited when predicting the impact of individual biases, interpretations, and experiential feelings. PMID- 28347391 TI - 'Biracial'-Looking Twins: A New Twin Type?/Twin Research: Twins with Cystic Teratomas; Sleep Quality and Body Mass Index; Previable Membrane Rupture/Print and Online Reports: Twins Born to a Sister Surrogate; NASA Twin Study; African Cosmopolitan Twin Fashion Inspirations; Triplet Hockey Stars. AB - Dizygotic (DZ) co-twins born to mothers and fathers from different racial or ethnic backgrounds often resemble one parent much more than the other. As such, these pairs comprise a unique subset of twins for investigating how others' responses to their different looks may affect their personalities and self esteem. This article describes some of these twin pairs and some challenges of raising them, and suggests ways they may be used in research. Next, recent twin research on cystic teratomas, relations between sleep quality and body mass index, and previable membrane rupture is described. The final section concerns twins, twin studies, and related events in the media, namely: twins born to a sister surrogate, the NASA twin investigation, inspiring African-Cosmopolitan twins in fashion, and triplet Hockey Stars. PMID- 28347392 TI - Amplified selectivity in cognitive processing implements the neural gain model of norepinephrine function. AB - Previous work has suggested that an interaction between local selective (e.g., glutamatergic) excitation and global gain modulation (via norepinephrine) amplifies selectivity in information processing. Mather et al. extend this existing theory by suggesting that localized gain modulation may further mediate this effect - an interesting prospect that invites new theoretical and experimental work. PMID- 28347393 TI - Brain volume changes over the first year of treatment in schizophrenia: relationships to antipsychotic treatment. AB - BACKGROUND: Progressive brain volume reductions have been described in schizophrenia, and an association with antipsychotic exposure has been reported. METHODS: We compared percentage changes in grey and white matter volume from baseline to month 12 in 23 previously antipsychotic-naive patients with a first episode of schizophrenia or schizophreniform disorder who were treated with the lowest effective dose of flupenthixol decanoate depot formulation, with 53 matched healthy individuals. Total antipsychotic dose was precisely calculated and its relationship with brain volume changes investigated. Relationships between volumetric changes and treatment were further investigated in terms of treatment response (changes in psychopathology and functionality) and treatment related adverse-events (extrapyramidal symptoms and weight gain). RESULTS: Excessive cortical volume reductions were observed in patients [-4.6 (6.6)%] v. controls [-1.12 (4.0)%] (p = 0.009), with no significant group differences for changes in subcortical grey matter and white matter volumes. In a multiple regression model, the only significant predictor of cortical volume change was total antipsychotic dose received (p = 0.04). Cortical volume change was not significantly associated with the changes in psychopathology, functionality, extrapyramidal symptoms and body mass index or age, gender and duration of untreated psychosis. CONCLUSIONS: Brain volume reductions associated with antipsychotic treatment are not restricted to poor outcome patients and occur even with the lowest effective dose of antipsychotic. The lack of an association with poor treatment response or treatment-related adverse effects counts against cortical volume reductions reflecting neurotoxicity, at least in the short term. On the other hand, the volume reductions were not linked to the therapeutic benefits of antipsychotics. PMID- 28347394 TI - "What have we GANEd?" A theoretical construct to explain experimental evidence for noradrenergic regulation of sensory signal processing. AB - The GANE (glutamate amplifies noradrenergic effects) theory posits a mechanism for amplifying noradrenergic modulatory actions and enhancing the processing of high-priority sensory signals for immediate or future experience-guided action. This theoretical construct is thought provoking with respect to the central processing of high-priority versus low-priority stimuli, but it requires some refinement to account for physiological fluctuations in NE efflux as a function of naturally occurring transitions in behavioral state and the experimentally observed phenomena associated with noradrenergic regulation of sensory signal transfer. PMID- 28347395 TI - What do we GANE with age? AB - Mather and colleagues provide an impressive cross-level account of how arousal levels modulate behavior, and they support it with data ranging from receptor pharmacology to measures of cognitive function. Here we consider two related questions: (1) Why should the brain engage in different arousal levels? and (2) What are the predicted consequences of age-related changes in norepinephrine signaling for cognitive function? PMID- 28347397 TI - To Move Health Care to Health Caring: A Conversation With Julie Kennedy Oehlert, DNP, RN. AB - The complex nature of health care requires a culture of interprofessionality that supports high-functioning interprofessional teams. Wolf and Prince (2014) wrote, "Culture is the foundation on which any healthcare encounter is delivered" (p. 3). It is therefore important for nursing to elevate thought leaders who can address the culture of health care organizations and how culture can be transformed. Julie Kennedy Oehlert is one of these leaders. PMID- 28347396 TI - Perceived Family Cohesion Moderates Environmental Influences on Prosocial Behavior in Nigerian Adolescent Twins. AB - Research shows that perceived family cohesion is positively related to prosocial behavior in adolescents. In this study, we investigated heritability of prosocial behavior (PB) and perceived family cohesion (FC) among Nigerian twins attending public schools in Lagos State, Nigeria (mean age = 14.7 years, SD = 1.7 years), and explored the issue of whether children's perception of cohesive family environment moderated genetic and environmental influences on (PB). The PB scale of the Strengths and Difficulties Questionnaire and the FC scale of the Family Adaptability and Cohesion Evaluation Scale III were completed by 2,376 twins (241 monozygotic (MZ) male, 354 MZ female, 440 dizygotic (DZ) male, 553 DZ female, and 788 opposite-sex DZ twins). A general sex-limitation and the bivariate genotype by environment interaction (G*E) models were applied to the data. The general sex limitation model showed no significant sex differences, indicating that additive genetic and non-shared environmental influences were, 38% (95% CI = 31, 46) and 62% (95% CI = 54, 69) for PB and 33% (95% CI = 24, 40) and 67% (95% CI = 60, 76) for FC in both sexes. These estimates were similar to those found in Western and Asian twin studies to date. The correlation between PB and FC was 0.36. The best fitting bivariate G*E model indicated that FC significantly moderated non-shared environmental influence unique to PB (E*E interaction). Specifically, non-shared environmental contributions to PB were highest when FC was lowest, and decreased as the levels of FC increased. However, genetic variances in PB were stable across all levels of FC. These findings suggest that FC reduces individual differences in PB by changing non-shared environmental experiences rather than genetic factors in PB. PMID- 28347398 TI - Person and Family Centered Care. PMID- 28347399 TI - Role of GALNT14 in lung metastasis of breast cancer. AB - Aberrant expression of the polypeptide N-acetyl-galactosaminyltransferase (GALNTs) has been associated with cancer, but their function(s) in metastasis remains elusive. We have recently identified GALNT14, one of the O-GalNAc glycosylationinitiating enzymes, as a prognostic marker for pulmonary relapse in breast cancer patients. Furthermore, we showed that GALNT14 promotes lung metastasis by the following novel mechanisms: 1) enhancing metastasis initiation by inhibiting the anti-metastatic effect of BMP produced from the lung stroma, 2) exploiting growth signals (e.g. FGF) supplied by macrophages, for their growth into macrometastases in the lung environment. These multi-faceted roles of GALNT14 in lung metastasis are achieved by GALNT14-mediated inhibition and activation of the BMP and FGF signaling pathways, respectively. The link among GALNT14, its downstream pathways and lung metastasis, provides us with an opportunity to develop effective therapeutic intervention for breast cancer. [BMB Reports 2017; 50(5): 233-234]. PMID- 28347400 TI - Monoacylglycerol O-acyltransferase 1 (MGAT1) localizes to the ER and lipid droplets promoting triacylglycerol synthesis. AB - Monoacylglycerol acyltransferase 1 (MGAT) is a microsomal enzyme that catalyzes the synthesis of diacylglycerol (DAG) and triacylglycerol (TAG). However, the subcellular localization and catalytic function domain of this enzyme is poorly understood. In this report, we identified that murine MGAT1 localizes to the endoplasmic reticulum (ER) under normal conditions, whereas MGAT1 co-localize to the lipid droplets (LD) under conditions of enriching fatty acids, contributing to TAG synthesis and LD expansion. For the enzyme activity, both the N-terminal transmembrane domain and catalytic HPHG motif are required. We also show that the transmembrane domain of MGAT1 consists of two hydrophobic regions in the N terminus, and the consensus sequence FLXLXXXn, a putative neutral lipid-binding domain, exists in the first transmembrane domain. Finally, MGAT1 interacts with DGAT2, which serves to synergistically increase the TAG biosynthesis and LD expansion, leading to enhancement of lipid accumulation in the liver and fat. [BMB Reports 2017; 50(7): 367-372]. PMID- 28347401 TI - Tracking zoonotic pathogens using blood-sucking flies as 'flying syringes'. AB - About 60% of emerging infectious diseases in humans are of zoonotic origin. Their increasing number requires the development of new methods for early detection and monitoring of infectious agents in wildlife. Here, we investigated whether blood meals from hematophagous flies could be used to identify the infectious agents circulating in wild vertebrates. To this aim, 1230 blood-engorged flies were caught in the forests of Gabon. Identified blood meals (30%) were from 20 vertebrate species including mammals, birds and reptiles. Among them, 9% were infected by different extant malaria parasites among which some belonged to known parasite species, others to new parasite species or to parasite lineages for which only the vector was known. This study demonstrates that using hematophagous flies as 'flying syringes' constitutes an interesting approach to investigate blood-borne pathogen diversity in wild vertebrates and could be used as an early detection tool of zoonotic pathogens. PMID- 28347402 TI - Chlamydia trachomatis-containing vacuole serves as deubiquitination platform to stabilize Mcl-1 and to interfere with host defense. AB - Obligate intracellular Chlamydia trachomatis replicate in a membrane-bound vacuole called inclusion, which serves as a signaling interface with the host cell. Here, we show that the chlamydial deubiquitinating enzyme (Cdu) 1 localizes in the inclusion membrane and faces the cytosol with the active deubiquitinating enzyme domain. The structure of this domain revealed high similarity to mammalian deubiquitinases with a unique alpha-helix close to the substrate-binding pocket. We identified the apoptosis regulator Mcl-1 as a target that interacts with Cdu1 and is stabilized by deubiquitination at the chlamydial inclusion. A chlamydial transposon insertion mutant in the Cdu1-encoding gene exhibited increased Mcl-1 and inclusion ubiquitination and reduced Mcl-1 stabilization. Additionally, inactivation of Cdu1 led to increased sensitivity of C. trachomatis for IFNgamma and impaired infection in mice. Thus, the chlamydial inclusion serves as an enriched site for a deubiquitinating activity exerting a function in selective stabilization of host proteins and protection from host defense. PMID- 28347404 TI - Maternal determinants of renal mass and function in the fetus and neonate. AB - The impact of adverse maternal and early gestational issues, ranging from maternal-fetal interactions all the way through to premature birth, are recognized as having influence on the subsequent development of chronic diseases later in life. The development of chronic kidney disease (CKD) as a direct result of early life renal injury or a sequela of diseases such as hypertension or diabetes is a good model example of the potential impact that early life events may have on renal development and lifelong function. The global monetary and human resource cost of CKD is exorbitant. Socio-economic factors, along with other factors (genetic and environmental) may significantly influence the timing and display of phenotypic expression in fetuses and neonates at risk for developing CKD, yet very few of these factors are studied or well understood. In general our focus has been directed at treatment once CKD is established. This strategy has been and remains short-sighted and costly. Earlier understanding of the intrauterine determinants of renal mass development (i.e. environmental "biomes", poor maternal-fetal health, socio-economic factors impacting early life events, diet, access to value based health care and educational opportunities on disease evolution) may allow us an opportunity for earlier intervention. This article aims to provide some foundation for improved understanding of the maternal determinants of renal mass and function in the fetus and neonate. PMID- 28347405 TI - [Another 'last word' on Rowell's syndrome]. PMID- 28347403 TI - Lack of IL-1R8 in neurons causes hyperactivation of IL-1 receptor pathway and induces MECP2-dependent synaptic defects. AB - Inflammation modifies risk and/or severity of a variety of brain diseases through still elusive molecular mechanisms. Here we show that hyperactivation of the interleukin 1 pathway, through either ablation of the interleukin 1 receptor 8 (IL-1R8, also known as SIGIRR or Tir8) or activation of IL-1R, leads to up regulation of the mTOR pathway and increased levels of the epigenetic regulator MeCP2, bringing to disruption of dendritic spine morphology, synaptic plasticity and plasticity-related gene expression. Genetic correction of MeCP2 levels in IL 1R8 KO neurons rescues the synaptic defects. Pharmacological inhibition of IL-1R activation by Anakinra corrects transcriptional changes, restores MeCP2 levels and spine plasticity and ameliorates cognitive defects in IL-1R8 KO mice. By linking for the first time neuronal MeCP2, a key player in brain development, to immune activation and demonstrating that synaptic defects can be pharmacologically reversed, these data open the possibility for novel treatments of neurological diseases through the immune system modulation. PMID- 28347408 TI - Selection of the Best in 2016 in Congenital Heart Diseases. PMID- 28347409 TI - Selection of the Best of 2016 in Implantable Defibrillators. PMID- 28347410 TI - Selection of the Best of 2016 in Catheter Ablation. PMID- 28347411 TI - Selection of the Best of 2016 in Mechanical Circulatory Support. PMID- 28347412 TI - Selection of the Best of 2016 in the Treatment of Pulmonary Hypertension. PMID- 28347413 TI - On how hydrogen bonds affect foam stability. AB - Do intermolecular H-bonds between surfactant head groups play a role for foam stability? From the literature on the foam stability of various surfactants with C12 alkyl chains but different head groups a clear picture emerges: stable foams are only generated when hydrogen bonds can form between the head groups, i.e. when the polar head group has a hydrogen bond donor and a proton acceptor. Stable foams can therefore be generated with surfactants having a sugar unit, a glycine, an amine oxide (at pH~5), or a carboxylic acid (at pH~pKa) as polar head group. On the other hand, aqueous foams stabilized with surfactants having oligo(ethylene oxide), phosphine oxide, quaternary ammonium, sulfate, sarcosine, amine oxide (at pH?5), or carboxylic acid (at pH?pKa) are not very stable. These observations suggest that hydrogen bonds between neighbouring molecules at the surface enhance foam stability. Formation of hydrogen bonds between surfactant head groups gives rise to a short-range attractive interaction that may restrict the surfactant's mobility while providing a more elastic surfactant layer which can counteract deformations. To support our hypothesis we carried out a systematic foaming study of two types of surfactants, one of them being capable of forming H-bonds and the other one not. Generating foams of all surfactants mentioned above with the same foaming conditions we found that stable foams are obtained when the head group is capable of forming intersurfactant H-bonds. The outcome of this study constitutes a new step towards the implementation of H bonds in the future design of surfactants. PMID- 28347414 TI - Gas adsorption properties of graphene-based materials. AB - Clean energy sources and global warming are among the major challenges of the 21st century. One of the possible actions toward finding alternative energy sources and reducing global warming are storage of H2 and CH4, and capture of CO2 by using highly efficient and low-cost adsorbents. Graphene and graphene-based materials attracted a great attention around the world because of their potential for a variety applications ranging from electronics, gas sensing, energy storage and CO2 capture. Large specific surface area of these materials up to ~3000m2/g and versatile modification make them excellent adsorbents for diverse applications. Here, graphene-based adsorbents are reviewed with special emphasis on their adsorption affinity toward CO2, H2 and CH4. This review shows that graphene derivatives obtained mainly via "chemical exfoliation" of graphite and further modification with polymers and/or metal species can be very effective sorbents for CO2 and other gases and can compete with the currently used carbonaceous or non-carbonaceous adsorbents. The high adsorption capacities of graphene-based materials are mainly determined by their unique nanostructures, high specific surface areas and tailorable surface properties, which make them suitable for storage or capture of various molecules relevant for environmental and energy-related applications. PMID- 28347415 TI - Congenital and Hereditary Diseases of the Spinal Cord. AB - Congenital anomalies of the spinal cord can pose a diagnostic dilemma to the radiologist. Several classification systems of these anomalies exist. Antenatal ultrasound and fetal magnetic resonance imaging is playing an increasingly important role in the early diagnosis and management of patients. Understanding the underlying anatomy as well as embryology of these disorders can be valuable in correctly identifying the type of spinal cord dysraphic defect. Hereditary spinal cord diseases are rare but can be devastating. When the onset is in adulthood, delay in diagnosis is common. Although the spine findings are nonspecific, some imaging features combined with brain imaging findings can be distinctive. Sometimes, the radiologist may be the first to raise the possibility of these disorders. PMID- 28347416 TI - Pediatric Spinal Ultrasound: Neonatal and Intraoperative Applications. AB - The purpose of this article is to review the use of ultrasound as a screening tool for spinal diseases in neonates and infants and its intraoperative value in selected pediatric neurosurgical disorders. A review of spinal embryology followed by a description of common spinal diseases in neonates assessed with ultrasound is presented. Indications for spinal ultrasound in neonates, commonly identified conditions, and the importance of magnetic resonance imaging in selected cases are emphasized. Additionally, the use of ultrasound in selected neurosurgical spinal diseases in pediatric patients is presented with magnetic resonance imaging and intraoperative correlation. Technique, limitations, and pitfalls are discussed. PMID- 28347417 TI - Vascular Imaging Techniques of the Spinal Cord. AB - The various imaging techniques used to depict vascular lesions of the spinal cord are described in this article with particular emphasis on magnetic resonance imaging (MRI), vascular sequences, and advantages of high-field MRI. Technical vascular protocols are discussed in computed tomography, MRI, and conventional angiography. The diverse magnetic resonance angiography protocols are presented as well as their findings, specificities, and pitfalls. A review of the vascular anatomy and the most common pathologies analyzed by magnetic resonance angiography and conventional angiography is described. PMID- 28347418 TI - The Application of Human Spinal Cord Magnetic Resonance Spectroscopy to Clinical Studies: A Review. AB - This article reviews the current state of magnetic resonance spectroscopy applied in the human spinal cord with respect to its clinical applications and challenges in comparison to investigations in the human brain. Results from several disease processes affecting the spinal cord are presented, and potential advantages of applying clinical MRS in their investigation are emphasized. PMID- 28347419 TI - Advanced Neuroimaging in the Evaluation of Spinal Cord Tumors and Tumor Mimics: Diffusion Tensor and Perfusion-Weighted Imaging. AB - Spinal cord tumors are an important component of pathologic diseases involving the spinal cord. Conventional magnetic resonance (MR) imaging only provides anatomical information. MR diffusion tensor imaging (DTI) and MR perfusion weighted imaging (PWI) may detect microstructure diffusion and hemodynamic changes in these tumors. We review recent application studies of MR DTI and PWI in spinal cord tumors. Overall, MR DTI and MR PWI are promising imaging tools that are especially useful in improving differential diagnosis between spinal cord tumors and tumor mimics, preoperative evaluation of resectability, and providing assistance in surgical navigation. PMID- 28347420 TI - Functional Magnetic Resonance Imaging of the Spinal Cord: Current Status and Future Developments. AB - Although functional magnetic resonance imaging has become popular for brain imaging, it is still difficult to apply this technique to the spinal cord because of complex issues related to the physiology of the spinal cord and technical challenges related to magnetic resonance imaging hardware, pulse sequences, and image processing techniques. In this article, we examine these key aspects and discuss their present status, unresolved issues, and future directions. PMID- 28347421 TI - Letter from the Guest Editor: Spinal Cord Imaging II-Pediatrics and Advanced Techniques. PMID- 28347422 TI - Cord Cystic Cavities: Syringomyelia and Prominent Central Canal. AB - Syringomyelia is the term given to cystic cavities in the spinal cord, most of which are associated with congenital malformations of the craniocervical junction and represent dilation of the central canal of the cord. As such, syrinxes can be considered analogous to hydrocephalus. The exact etiology of syrinx formation remains a subject of debate, but there is ample evidence that they are the result of obstruction of the normal flow of cerebrospinal fluid between the intracranial and spinal compartments. The chances that a syrinx will progress over time are much greater when they are associated with a causative lesion (Chiari malformation, tumor, infection, and trauma), but asymptomatic central canal dilation may be a stable incidental finding. Although spinal cord neoplasms are a recognized etiology for syrinx formation, especially in adults, it is not always necessary to administer contrast when evaluating a syrinx for the first time with magnetic resonance imaging. PMID- 28347423 TI - AEDV Primary Cutaneous Lymphoma Registry. PMID- 28347424 TI - Psychiatry unlocked. PMID- 28347425 TI - Strengthening community mental health services in Japan. PMID- 28347426 TI - Neuroscience-based nomenclature (NbN). PMID- 28347427 TI - An emerging approach to supporting the mental health of refugee and conflict exposed populations. PMID- 28347428 TI - An emerging approach to supporting the mental health of refugee and conflict exposed populations - Authors' reply. PMID- 28347429 TI - The IMPACT trial - Authors' reply. PMID- 28347430 TI - The IMPACT trial. PMID- 28347433 TI - Joshua Gordon: an interdisciplinary approach to mental health. PMID- 28347431 TI - Mental illness and mental health. PMID- 28347434 TI - Orange. PMID- 28347435 TI - Expanding engagement with the ethical implications of changing definitions of Alzheimer's disease. PMID- 28347436 TI - Cochrane for global mental health. PMID- 28347437 TI - Neural mechanisms of functional impairment across the lifespan: The 15th Biennial Meeting of the International Neurotoxicology Association and 39th Annual Meeting of the Neurobehavioral Teratology Society. PMID- 28347438 TI - Corrigendum to "Obesity is associated with higher absolute tibiofemoral contact and muscle forces during gait with and without knee osteoarthritis" [Clin. Biomech. Jan; 31 (2016) 79-86]. PMID- 28347439 TI - Online social support for obese adults: Exploring the role of forum activity. AB - PURPOSE: Worldwide, the number of obese persons continues to grow. Online mediated self-help groups represent an opportunity for obese persons to support each other. The aim of our study was to evaluate whether and how the use of and active participation in online self-help groups is associated with perceived informational and emotional support among obese adults. METHODS: We conducted an online-based questionnaire (N=230) with users of online self-help groups for obese adults in Germany. RESULTS: Findings revealed that forum activity is significantly correlated with perceived informational and emotional support. While asking questions was strongly correlated with both types of social support, sharing opinions and answering posts were more strongly correlated with perceived emotional support. CONCLUSION: The level of social support in online communities depends on an individual's forum activity. Our findings offer a foundation for professionals in the health care sector to enhance their understanding, make recommendations, and further develop online self-help groups. PMID- 28347440 TI - Rate of electronic health record adoption in South Korea: A nation-wide survey. AB - OBJECTIVE: The adoption rate of electronic health record (EHR) systems in South Korea has continuously increased. However, in contrast to the situation in the United States (US), where there has been a national effort to improve and standardize EHR interoperability, no consensus has been established in South Korea. The goal of this study was to determine the current status of EHR adoption in South Korean hospitals compared to that in the US. METHODS: All general and tertiary teaching hospitals in South Korea were surveyed regarding their EHR status in 2015 with the same questionnaire as used previously. The survey form estimated the level of adoption of EHR systems according to 24 core functions in four categories (clinical documentation, result view, computerized provider order entry, and decision supports). The adoption level was classified into comprehensive and basic EHR systems according to their functionalities. RESULTS: EHRs and computerized physician order entry systems were used in 58.1% and 86.0% of South Korean hospitals, respectively. Decision support systems and problem list documentation were the functions most frequently missing from comprehensive and basic EHR systems. The main barriers cited to adoption of EHR systems were the cost of purchasing (48%) and the ongoing cost of maintenance (11%). DISCUSSION: The EHR adoption rate in Korean hospitals (37.2%) was higher than that in US hospitals in 2010 (15.1%), but this trend was reversed in 2015 (58.1% vs. 75.2%). The evidence suggests that these trends were influenced by the level of financial and political support provided to US hospitals after the HITECH Act was passed in 2009. CONCLUSIONS: The EHR adoption rate in Korea has increased, albeit more slowly than in the US. It is logical to suggest that increased funding and support tied to the HITECH Act in the US partly explains the difference in the adoption rates of EHRs in both countries. PMID- 28347443 TI - Digital disease detection: A systematic review of event-based internet biosurveillance systems. AB - BACKGROUND: Internet access and usage has changed how people seek and report health information. Meanwhile,infectious diseases continue to threaten humanity. The analysis of Big Data, or vast digital data, presents an opportunity to improve disease surveillance and epidemic intelligence. Epidemic intelligence contains two components: indicator based and event-based. A relatively new surveillance type has emerged called event-based Internet biosurveillance systems. These systems use information on events impacting health from Internet sources, such as social media or news aggregates. These systems circumvent the limitations of traditional reporting systems by being inexpensive, transparent, and flexible. Yet, innovations and the functionality of these systems can change rapidly. AIM: To update the current state of knowledge on event-based Internet biosurveillance systems by identifying all systems, including current functionality, with hopes to aid decision makers with whether to incorporate new methods into comprehensive programmes of surveillance. METHODS: A systematic review was performed through PubMed, Scopus, and Google Scholar databases, while also including grey literature and other publication types. RESULTS: 50 event based Internet systems were identified, including an extraction of 15 attributes for each system, described in 99 articles. Each system uses different innovative technology and data sources to gather data, process, and disseminate data to detect infectious disease outbreaks. CONCLUSIONS: The review emphasises the importance of using both formal and informal sources for timely and accurate infectious disease outbreak surveillance, cataloguing all event-based Internet biosurveillance systems. By doing so, future researchers will be able to use this review as a library for referencing systems, with hopes of learning, building, and expanding Internet-based surveillance systems. Event-based Internet biosurveillance should act as an extension of traditional systems, to be utilised as an additional, supplemental data source to have a more comprehensive estimate of disease burden. PMID- 28347442 TI - Clinical impact and value of workstation single sign-on. AB - BACKGROUND: CHRISTUS Health began implementation of computer workstation single sign-on (SSO) in 2015. SSO technology utilizes a badge reader placed at each workstation where clinicians swipe or "tap" their identification badges. OBJECTIVE: To assess the impact of SSO implementation in reducing clinician time logging in to various clinical software programs, and in financial savings from migrating to a thin client that enabled replacement of traditional hard drive computer workstations. METHODS: Following implementation of SSO, a total of 65,202 logins were sampled systematically during a 7day period among 2256 active clinical end users for time saved in 6 facilities when compared to pre implementation. Dollar values were assigned to the time saved by 3 groups of clinical end users: physicians, nurses and ancillary service providers. RESULTS: The reduction of total clinician login time over the 7day period showed a net gain of 168.3h per week of clinician time - 28.1h (2.3 shifts) per facility per week. Annualized, 1461.2h of mixed physician and nursing time is liberated per facility per annum (121.8 shifts of 12h per year). The annual dollar cost savings of this reduction of time expended logging in is $92,146 per hospital per annum and $1,658,745 per annum in the first phase implementation of 18 hospitals. Computer hardware equipment savings due to desktop virtualization increases annual savings to $2,333,745. Qualitative value contributions to clinician satisfaction, reduction in staff turnover, facilitation of adoption of EHR applications, and other benefits of SSO are discussed. CONCLUSIONS: SSO had a positive impact on clinician efficiency and productivity in the 6 hospitals evaluated, and is an effective and cost-effective method to liberate clinician time from repetitive and time consuming logins to clinical software applications. PMID- 28347441 TI - Assessment of a personalized and distributed patient guidance system. AB - OBJECTIVES: The MobiGuide project aimed to establish a ubiquitous, user-friendly, patient-centered mobile decision-support system for patients and for their care providers, based on the continuous application of clinical guidelines and on semantically integrated electronic health records. Patients would be empowered by the system, which would enable them to lead their normal daily lives in their regular environment, while feeling safe, because their health state would be continuously monitored using mobile sensors and self-reporting of symptoms. When conditions occur that require medical attention, patients would be notified as to what they need to do, based on evidence-based guidelines, while their medical team would be informed appropriately, in parallel. We wanted to assess the system's feasibility and potential effects on patients and care providers in two different clinical domains. MATERIALS AND METHODS: We describe MobiGuide's architecture, which embodies these objectives. Our novel methodologies include a ubiquitous architecture, encompassing a knowledge elicitation process for parallel coordinated workflows for patients and care providers; the customization of computer-interpretable guidelines (CIGs) by secondary contexts affecting remote management and distributed decision-making; a mechanism for episodic, on demand projection of the relevant portions of CIGs from a centralized, backend decision-support system (DSS), to a local, mobile DSS, which continuously delivers the actual recommendations to the patient; shared decision-making that embodies patient preferences; semantic data integration; and patient and care provider notification services. MobiGuide has been implemented and assessed in a preliminary fashion in two domains: atrial fibrillation (AF), and gestational diabetes Mellitus (GDM). Ten AF patients used the AF MobiGuide system in Italy and 19 GDM patients used the GDM MobiGuide system in Spain. The evaluation of the MobiGuide system focused on patient and care providers' compliance to CIG recommendations and their satisfaction and quality of life. RESULTS: Our evaluation has demonstrated the system's capability for supporting distributed decision-making and its use by patients and clinicians. The results show that compliance of GDM patients to the most important monitoring targets - blood glucose levels (performance of four measurements a day: 0.87+/-0.11; measurement according to the recommended frequency of every day or twice a week: 0.99+/ 0.03), ketonuria (0.98+/-0.03), and blood pressure (0.82+/-0.24) - was high in most GDM patients, while compliance of AF patients to the most important targets was quite high, considering the required ECG measurements (0.65+/-0.28) and blood pressure measurements (0.75+/-1.33). This outcome was viewed by the clinicians as a major potential benefit of the system, and the patients have demonstrated that they are capable of self-monitoring - something that they had not experienced before. In addition, the system caused the clinicians managing the AF patients to change their diagnosis and subsequent treatment for two of the ten AF patients, and caused the clinicians managing the GDM patients to start insulin therapy earlier in two of the 19 patients, based on system's recommendations. Based on the end-of-study questionnaires, the sense of safety that the system has provided to the patients was its greatest asset. Analysis of the patients' quality of life (QoL) questionnaires for the AF patients was inconclusive, because while most patients reported an improvement in their quality of life in the EuroQoL questionnaire, most AF patients reported a deterioration in the AFEQT questionnaire. DISCUSSION: Feasibility and some of the potential benefits of an evidence-based distributed patient-guidance system were demonstrated in both clinical domains. The potential application of MobiGuide to other medical domains is supported by its standards-based patient health record with multiple electronic medical record linking capabilities, generic data insertion methods, generic medical knowledge representation and application methods, and the ability to communicate with a wide range of sensors. Future larger scale evaluations can assess the impact of such a system on clinical outcomes. CONCLUSION: MobiGuide's feasibility was demonstrated by a working prototype for the AF and GDM domains, which is usable by patients and clinicians, achieving high compliance to self measurement recommendations, while enhancing the satisfaction of patients and care providers. PMID- 28347444 TI - Use of a computerized arthroplasty registry to generate operative reports decreases transcription errors. AB - OBJECTIVES: Despite the clear importance of the operative report in the electronic medical record, few studies have addressed the quality. METHODS: We prospectively evaluated 300 consecutive patients undergoing primary total joint arthroplasties for operative report errors utilizing three different forms of documentation (standard dictation vs. templated dictation vs. a computer registry database generated operative report). The three types of reports were evaluated for errors which were classified as either major or minor. RESULTS: There were significantly more total errors in the standard dictation group compared to both the computer registry database generated (p<0.001) and the templated operative reports (p<0.001). Major errors were significantly reduced in the database generated reports compared to the templated (p<0.001) and standard dictation groups (p<0.001). There were significantly more minor errors in the standard dictation group (p<0.001) compared to the other two groups. No statistically significant differences in major errors were noted when comparing standard vs. templated operative reports. There was no difference in minor or total errors between the database generated and templated operative reports. CONCLUSIONS: The use of a computer registry database generated operative report resulted in fewer major errors versus a templated or standard dictated operative report. Further research is warranted in this area to validate these findings across subspecialties and institutions. PMID- 28347446 TI - Pharmacist-led admission medication reconciliation before and after the implementation of an electronic medication management system. AB - AIMS: To investigate the impact of the introduction of an electronic medication management system on the proportion of patients with a recorded medication reconciliation on admission, the time from admission to when medication reconciliation was performed, and the characteristics of patients receiving this intervention pre-and post-implementation. METHODS: An electronic medication management system was implemented in an Australian hospital from May to July 2015. A retrospective observational study was conducted in three wards across two phases; pre- (August 2014) and post- (August 2015) implementation. The study sample included every second patient admitted to these wards. RESULTS: A total of 370 patients were included, 179 pre- and 191 post-implementation. The proportion of recorded admission medication reconciliation significantly increased post implementation in all study wards; coronary care unit (40 vs 68%, p=0.004), gastroenterology ward (39 vs 59%, p=0.015), and the neurology ward (19 vs 45%, p=0.002). The proportion of patients with recorded medication reconciliation within 24h of weekday admissions, or 48-72h of weekend admissions, increased from 47% pre- to 84% post-implementation. Admission medication reconciliation was recorded within a median of 1.0day for weekday admissions pre- and post implementation (IQR 1.1 vs 0.2, respectively), and 3.5days (IQR 2.0) pre implementation vs 1.5days (IQR 2.0) post-implementation for weekend admissions. Overall, across both phases pre-and post-implementation, admission medication reconciliation was recorded for patients who were significantly older (median 77 and 71 years, p<0.001), had a higher number of preadmission medications (median 6.5 and 5.0 medicines, p=0.001), and had a longer hospital stay (median 6.5 and 5.1days, p=0.003). A significantly higher proportion of patients with recorded medication reconciliation in the pre-implementation phase experienced polypharmacy (61%, p=0.002), hyperpolypharmacy (15%, p=0.001), and used a high risk medication (44%, p=0.007). CONCLUSIONS: Implementing an electronic medication management system facilitates the medication reconciliation process leading to more high risk patients receiving this service on admission to hospital and in a more timely manner. The impact of electronic medication reconciliation on patient safety and clinical outcomes remains unknown. PMID- 28347445 TI - Scoping review and evaluation of SMS/text messaging platforms for mHealth projects or clinical interventions. AB - OBJECTIVES: Mobile technology supporting text messaging interventions (TMIs) continues to evolve, presenting challenges for researchers and healthcare professionals who need to choose software solutions to best meet their program needs. The objective of this review was to systematically identify and compare text messaging platforms and to summarize their advantages and disadvantages as described in peer-reviewed literature. METHODS: A scoping review was conducted using four steps: 1) identify currently available platforms through online searches and in mHealth repositories; 2) expand evaluation criteria of an mHealth mobile messaging toolkit and integrate prior user experiences as researchers; 3) evaluate each platform's functions and features based on the expanded criteria and a vendor survey; and 4) assess the documentation of platform use in the peer review literature. Platforms meeting inclusion criteria were assessed independently by three reviewers and discussed until consensus was reached. The PRISMA guidelines were followed to report findings. RESULTS: Of the 1041 potentially relevant search results, 27 platforms met inclusion criteria. Most were excluded because they were not platforms (e.g., guides, toolkits, reports, or SMS gateways). Of the 27 platforms, only 12 were identified in existing mHealth repositories, 10 from Google searches, while five were found in both. The expanded evaluation criteria included 22 items. Results indicate no uniform presentation of platform features and functions, often making these difficult to discern. Fourteen of the platforms were reported as open source, 10 focused on health care and 16 were tailored to meet needs of low resource settings (not mutually exclusive). Fifteen platforms had do-it-yourself setup (programming not required) while the remainder required coding/programming skills or setups could be built to specification by the vendor. Frequently described features included data security and access to the platform via cloud-based systems. Pay structures and reported targeted end-users varied. Peer-reviewed publications listed only 6 of the 27 platforms across 21 publications. The majority of these articles reported the name of the platform used but did not describe advantages or disadvantages. CONCLUSIONS: Searching for and comparing mHealth platforms for TMIs remains a challenge. The results of this review can serve as a resource for researchers and healthcare professionals wanting to integrate TMIs into health interventions. Steps to identify, compare and assess advantages and disadvantages are outlined for consideration. Expanded evaluation criteria can be used by future researchers. Continued and more comprehensive platform tools should be integrated into mHealth repositories. Detailed descriptions of platform advantages and disadvantages are needed when mHealth researchers publish findings to expand the body of research on TMI tools for healthcare. Standardized descriptions and features are recommended for vendor sites. PMID- 28347448 TI - Computer-aided diagnosis: A survey with bibliometric analysis. AB - Computer-aided diagnosis (CAD) has been a promising area of research over the last two decades. However, CAD is a very complicated subject because it involves a number of medicine and engineering-related fields. To develop a research overview of CAD, we conducted a literature survey with bibliometric analysis, which we report here. Our study determined that CAD research has been classified and categorized according to disease type and imaging modality. This classification began with the CAD of mammograms and eventually progressed to that of brain disease. Furthermore, based on our results, we discuss future directions and opportunities for CAD research. First, in contrast to the typical hypothetical approach, the data-driven approach has shown promise. Second, the normalization of the test datasets and an evaluation method is necessary when adopting an algorithm and a system. Third, we discuss opportunities for the co evolution of CAD research and imaging instruments-for example, the CAD of bones and pancreatic cancer. Fourth, the potential of synergy with CAD and clinical decision support systems is also discussed. PMID- 28347447 TI - User Requirements for a Chronic Kidney Disease Clinical Decision Support Tool to Promote Timely Referral. AB - BACKGROUND: Timely referral of patients with CKD has been associated with cost and mortality benefits, but referrals are often done too late in the course of the disease. Clinical decision support (CDS) offers a potential solution, but interventions have failed because they were not designed to support the physician workflow. We sought to identify user requirements for a chronic kidney disease (CKD) CDS system to promote timely referral. METHODS: We interviewed primary care physicians (PCPs) to identify data needs for a CKD CDS system that would encourage timely referral and also gathered information about workflow to assess risk factors for progression of CKD. Interviewees were general internists recruited from a network of 14 primary care clinics affiliated with Brigham and Women's Hospital (BWH). We then performed a qualitative analysis to identify user requirements and system attributes for a CKD CDS system. RESULTS: Of the 12 participants, 25% were women, the mean age was 53 (range 37-82), mean years in clinical practice was 27 (range 11-58). We identified 21 user requirements. Seven of these user requirements were related to support for the referral process workflow, including access to pertinent information and support for longitudinal co-management. Six user requirements were relevant to PCP management of CKD, including management of risk factors for progression, interpretation of biomarkers of CKD severity, and diagnosis of the cause of CKD. Finally, eight user requirements addressed user-centered design of CDS, including the need for actionable information, links to guidelines and reference materials, and visualization of trends. CONCLUSION: These 21 user requirements can be used to design an intuitive and usable CDS system with the attributes necessary to promote timely referral. PMID- 28347449 TI - Mobile application for diabetes self-management in China: Do they fit for older adults? AB - OBJECTIVES: Despite the exponential proliferation of Chinese diabetes applications, none are designed to meet the needs of the largest potential user population. The purpose of this study is to examine the features and contents of Chinese diabetes mobile applications in terms of their suitability for use by older adults with diabetes. METHODS: A search of the Apple application store and the 360 Mobile Assistant was conducted to identify Chinese diabetes applications. Next, we compared the features and contents of all the included and most popular diabetes applications with both the International Diabetes Federation (IDF) clinical guideline and recommended usability criteria for older adults respectively. RESULTS: Seventy-one diabetes apps were randomly selected (from a pool of 552 diabetes apps) and reviewed. The features of most apps failed to include content areas of known importance for managing diabetes in older adults. Usability of all tested applications was rated moderate to good. CONCLUSIONS: Designing maximally effective medical applications would benefit from attention to both usability and content guidelines targeted for the largest potential user population. Despite the preponderance of older adults in the potential user group, failing to consider the relevance of content, in addition to usability for the specific population will ultimately limit the usefulness of the app. PMID- 28347450 TI - Understanding factors influencing the adoption of mHealth by the elderly: An extension of the UTAUT model. AB - BACKGROUND: mHealth (mobile health) services are becoming an increasingly important form of information and communication technology (ICT) enabled delivery for healthcare, especially in low-resource environments such as developing countries like Bangladesh. Despite widespread adoption of mobile phones and the acknowledged potential of using them to improve healthcare services, the adoption and acceptance of this technology among the elderly is significantly low. However, little research has been done to draw any systematic study of the elderly's intention to adopt mHealth services. OBJECTIVE: The aim of this study was to develop a theoretical model based on the Unified Theory of Acceptance and Use of Technology (UTAUT) and then empirically test it for determining the key factors influencing elderly users' intention to adopt and use the mHealth services. METHODS: A face-to-face structured questionnaire survey method was used to collect data from nearly 300 participants of age 60 years and above from the capital city of Bangladesh. The data were analyzed using the Partial Least Squares (PLS) method, a statistical analysis technique based upon Structural Equation Modeling (SEM). RESULTS: The study determined that performance expectancy, effort expectancy, social influence, technology anxiety, and resistance to change (p<0.05) had a significant impact on the users' behavioral intention to adopt mHealth services. The study, however, revealed no significant relation between the facilitating condition and the users' behavioral intention to use the mHealth services (p>0.05). CONCLUSIONS: This study confirms the applicability of UTAUT model in the context of mHealth services among the elderly in developing countries like Bangladesh. It provides valuable information for mHealth service providers and policy makers in understanding the adoption challenges and the issues and also provides practical guidance for the successful implementation of mHealth services. Additionally the empirical findings identify implications related to the design and development of mHealth services that influence potential users. Furthermore, due to a generic approach, the findings of this study could be easily modified to assist other developing countries in the planning and up-take of mHealth services. PMID- 28347451 TI - The role of computerized diagnostic proposals in the interpretation of the 12 lead electrocardiogram by cardiology and non-cardiology fellows. AB - INTRODUCTION: Most contemporary 12-lead electrocardiogram (ECG) devices offer computerized diagnostic proposals. The reliability of these automated diagnoses is limited. It has been suggested that incorrect computer advice can influence physician decision-making. This study analyzed the role of diagnostic proposals in the decision process by a group of fellows of cardiology and other internal medicine subspecialties. MATERIALS AND METHODS: A set of 100 clinical 12-lead ECG tracings was selected covering both normal cases and common abnormalities. A team of 15 junior Cardiology Fellows and 15 Non-Cardiology Fellows interpreted the ECGs in 3 phases: without any diagnostic proposal, with a single diagnostic proposal (half of them intentionally incorrect), and with four diagnostic proposals (only one of them being correct) for each ECG. Self-rated confidence of each interpretation was collected. RESULTS: Availability of diagnostic proposals significantly increased the diagnostic accuracy (p<0.001). Nevertheless, in case of a single proposal (either correct or incorrect) the increase of accuracy was present in interpretations with correct diagnostic proposals, while the accuracy was substantially reduced with incorrect proposals. Confidence levels poorly correlated with interpretation scores (rho~2, p<0.001). Logistic regression showed that an interpreter is most likely to be correct when the ECG offers a correct diagnostic proposal (OR=10.87) or multiple proposals (OR=4.43). CONCLUSION: Diagnostic proposals affect the diagnostic accuracy of ECG interpretations. The accuracy is significantly influenced especially when a single diagnostic proposal (either correct or incorrect) is provided. The study suggests that the presentation of multiple computerized diagnoses is likely to improve the diagnostic accuracy of interpreters. PMID- 28347452 TI - Quality of routine health data collected by health workers using smartphone at primary health care in Ethiopia. AB - BACKGROUND: Mobile phone based applications are considered by many as potentially useful for addressing challenges and improving the quality of data collection in developing countries. Yet very little evidence is available supporting or refuting the potential and widely perceived benefits on the use of electronic forms on smartphones for routine patient data collection by health workers at primary health care facilities. METHODS: A facility based cross sectional study using a structured paper checklist was prepared to assess the completeness and accuracy of 408 electronic records completed and submitted to a central database server using electronic forms on smartphones by 25 health workers. The 408 electronic records were selected randomly out of a total of 1772 maternal health records submitted by the health workers to the central database over a period of six months. Descriptive frequencies and percentages of data completeness and error rates were calculated. RESULTS: When compared to paper records, the use of electronic forms significantly improved data completeness by 209 (8%) entries. Of a total 2622 entries checked for completeness, 2602 (99.2%) electronic record entries were complete, while 2393 (91.3%) paper record entries were complete. A very small percentage of error rates, which was easily identifiable, occurred in both electronic and paper forms although the error rate in the electronic records was more than double that of paper records (2.8% vs. 1.1%). More than half of entry errors in the electronic records related to entering a text value. CONCLUSIONS: With minimal training, supervision, and no incentives, health care workers were able to use electronic forms for patient assessment and routine data collection appropriately and accurately with a very small error rate. Minimising the number of questions requiring text responses in electronic forms would be helpful in minimizing data errors. PMID- 28347453 TI - Creation of a simple natural language processing tool to support an imaging utilization quality dashboard. AB - BACKGROUND: Testing for venous thromboembolism (VTE) is associated with cost and risk to patients (e.g. radiation). To assess the appropriateness of imaging utilization at the provider level, it is important to know that provider's diagnostic yield (percentage of tests positive for the diagnostic entity of interest). However, determining diagnostic yield typically requires either time consuming, manual review of radiology reports or the use of complex and/or proprietary natural language processing software. OBJECTIVES: The objectives of this study were twofold: 1) to develop and implement a simple, user-configurable, and open-source natural language processing tool to classify radiology reports with high accuracy and 2) to use the results of the tool to design a provider specific VTE imaging dashboard, consisting of both utilization rate and diagnostic yield. METHODS: Two physicians reviewed a training set of 400 lower extremity ultrasound (UTZ) and computed tomography pulmonary angiogram (CTPA) reports to understand the language used in VTE-positive and VTE-negative reports. The insights from this review informed the arguments to the five modifiable parameters of the NLP tool. A validation set of 2,000 studies was then independently classified by the reviewers and by the tool; the classifications were compared and the performance of the tool was calculated. RESULTS: The tool was highly accurate in classifying the presence and absence of VTE for both the UTZ (sensitivity 95.7%; 95% CI 91.5-99.8, specificity 100%; 95% CI 100-100) and CTPA reports (sensitivity 97.1%; 95% CI 94.3-99.9, specificity 98.6%; 95% CI 97.8 99.4). The diagnostic yield was then calculated at the individual provider level and the imaging dashboard was created. CONCLUSIONS: We have created a novel NLP tool designed for users without a background in computer programming, which has been used to classify venous thromboembolism reports with a high degree of accuracy. The tool is open-source and available for download at http://iturrate.com/simpleNLP. Results obtained using this tool can be applied to enhance quality by presenting information about utilization and yield to providers via an imaging dashboard. PMID- 28347454 TI - Minerals in thalassaemia major patients: An overview. AB - Thalassaemia major (TM) is a hereditary blood disease characterised by reduced or absent production of beta globin chains. Erythrocyte transfusions are given to raise the haemoglobin level in patients with thalassaemia major. However, transfusions have been related to increased risk of iron overload and tissue damage related to excess iron. Both elevated oxidative stress due to iron overload and increased hemolysis lead to over utilisation of minerals required for antioxidant enzymes activities. Iron chelators have been used to prevent iron overload in thalassaemia major patients, but these chelators have the possibility of removing minerals from the body. Thalassaemia patients are more at risk for mineral deficiency because of increased oxidative stress and iron chelation therapies. Growth and maturational delay, cardiomyopathy, endocrinopathies and osteoporosis are the complications of thalassaemia. Minerals may play a particular role to prevent these complications. In the current review, we provide an overview of minerals including zinc (Zn), copper (Cu), selenium (Se), magnesium (Mg) and calcium (Ca) in thalassaemia major patients. We, also, underline that some complications of thalassaemia can be caused by an increased need for minerals or lack of the minerals. PMID- 28347455 TI - Domain specific effects of postnatal toenail methylmercury exposure on child behaviour. AB - OBJECTIVE: Very little is known about the relationship between postnatal methylmercury concentrations (via toenails as bioindicator) and behavioural characteristics of Pacific Island children living in New Zealand. The aim of this study was to explore the association between total mercury exposure and different domains of behavioural problems in Pacific children. MATERIALS AND METHODS: A sample of nine-year-old Pacific Island children resident in Auckland, New Zealand participated in this study. Total mercury was determined in biological samples (toenail clippings) on behavioural problems as identified by mothers (using the child behaviour checklist). Specific behavioural domains, particularly aggression, rule breaking, attention and social problems were studied in relation to mercury exposure using toenails. The determination of mercury concentration in toenail clippings, after acid digestion was carried out using inductively coupled plasma mass spectrometry. RESULTS: The observational study was conducted between July 2010 and July 2011 in which 278 eligible nine-year-old Pacific Island children were enrolled (Girls n=58%; boys n=42%). FINDINGS: showed that 21% of the children had total toenail mercury concentrations (1.5MUg/g to 6MUg/g) higher than the United State Environmental Protection Agency recommended levels (RfD; 1MUg/g Hg) for optimal health in children. Aggressive behaviour was associated with total toenail mercury exposure after adjusting for gender, ethnicity and income levels (OR: 2.15 95% CI 1.45, 3.18 p-value <0.05; OR 1.38 95% CI 0.83, 1.2 p value <0.05, respectively). CONCLUSIONS: Overall, this research contributes to the understanding of total toenail mercury concentrations for Pacific people in New Zealand using toenail clippings as biomarkers in terms of associations with child behavioural problems. Mercury in toenails demonstrated a moderate association with a specific behavioural domain - aggressive behaviour. PMID- 28347456 TI - Long-term release of fluoride from fissure sealants-In vitro study. AB - The intensity of the cariostatic activity of fluoride ions can be attributed to their multidirectional influence on the caries process. They are an irreplaceable factor that helps sustain mineral balance of dental tissues, simultaneously demonstrating antibacterial properties. As a consequence, many manufacturers of fissure sealants include fluoride ions in their products. The aim of this in vitro study was to determine long-term fluoride release from four fissure sealants (Conseal F, Fissurit FX, Delton Fs+, Admira Seal). During a 14-week-long observation, all the materials showed a relatively constant level of F- release; however, it is crucial to mention that within the first 48h, the most significant increase in fluoride release was found for Fissurit and Delton sealants. Based on the overall assessment, the highest total amount of the released fluoride ions was observed for Delton, and the lowest level was reported for Admira Seal. PMID- 28347457 TI - Iron as a catalyst of human low-density lipoprotein oxidation: Critical factors involved in its oxidant properties. AB - Iron-induced human LDL oxidation, which is relevant to atherosclerosis, has not yet been properly investigated. We addressed such issue using iron(II) and (III) basically in the presence of phosphates, which are present in vivo and influence iron oxidative properties, at pH 4.5 and 7.4, representative, respectively, of the lysosomal and plasma environment. In 10mM phosphate buffered saline (PBS), iron(II) induces substantial LDL oxidation at pH 4.5 at low micromolar concentrations, while at pH 7.4 has low oxidative effects; iron(III) promotes small LDL oxidation only at pH 4.5. In 10mM sodium acetate/NaCl buffer, pH 4.5, iron-induced LDL oxidation is far higher than in PBS, highlighting the relevance of phosphates in the inhibitory modulation of iron-induced LDL oxidation. LDL oxidation is related to iron binding to the protein and lipid moiety of LDL, and requires the presence of iron(II) bound to LDL together with iron(III). Chemical modification of LDL carboxyl groups, which could bind iron especially at pH 4.5, decreases significantly iron binding to LDL and iron-induced LDL oxidation. Hydroxyl radical scavengers are ineffective on iron-induced LDL oxidation, which is inhibited by metal chelation, scavengers of alkoxyl/peroxyl radicals, or removal of LDL lipid hydroperoxides (LOOH). Overall, substantial human LDL oxidation is induced LOOH-dependently by iron(II) at pH 4.5 even in the presence of phosphates, suggesting the occurrence of iron(II)-induced LDL oxidation in vivo within lysosomes, where pH is about 4.5, iron(II) and phosphates coexist, plasma with its antioxidants is absent, and glutathione peroxidase is poorly expressed resulting in LOOH accumulation. PMID- 28347458 TI - Desferrioxamine and desferrioxamine-caffeine as carriers of aluminum and gallium to microbes via the Trojan Horse Effect. AB - Iron acquisition by bacteria and fungi involves in several cases the promiscuous usage of siderophores. Thus, antibiotic resistance from these microorganisms can be circumvented through a strategy of loading toxic metals into siderophores (Trojan Horse Effect). Desferrioxamine (dfo) and its cell-permeant derivative desferrioxamine-caffeine (dfcaf) were complexed with aluminum or gallium for this purpose. The complexes Me(dfo) and Me(dfcaf) (Me=Al3+ and Ga3+) were synthesized and characterized by mass spectroscopy and cyclic voltammetry. Their relative stabilities were studied through competitive equilibria with fluorescent probes calcein, fluorescein-desferrioxamine and 8-hydroxyquinoline. Me(dfo) and Me(dfcaf) were consistently more toxic than free Me3+ against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans, demonstrating the Trojan Horse Effect. Wide spectrum antimicrobial action can be obtained by loading non-essential or toxic metal ions to microbes via a convenient siderophore carrier. PMID- 28347459 TI - Selenium-mediated protection in reversing the sensitivity of bacterium to the bactericidal antibiotics. AB - Inducing production of damaging reactive oxygen species (ROS) is an important criterion to distinguish the bactericidal antibiotics from bacteriostatic antibiotics. Selenoenzymes were generally recognized to be a powerful antioxidant capable of scavenging free radicals, protecting the cells from the harmful effects of ROS. Therefore, the present study was carried out to investigate the selenium (Se)-mediated protection in reversing antibiotic sensitivity and the role of selenoenzymes in alleviating the negative effects of oxidative stress. The cellular antioxidant activity of Se-enriched bacteria was analyzed, as well as intracellular ROS production and elimination when Se-enriched bacteria in the presence of various antibiotics. Compared to complete inhibition of the parental strain by bactericidal antibiotics, it only exhibited slight and reversible inhibition of Se-enriched Escherichia coli ATCC25922 and Staphylococcus aureus ATCC25923 at the same conditions, which indicated that intracellular selenium provided substantial protection against antibiotics. ROS generation caused by bactericidal antibiotics was confirmed by fluorescence spectrophotometry using 2', 7'-dichloro- uorescein diacetate (DCFH-DA) as substrate. The time course experiments of pretreatment with selenium showed significant decrease of ROS level at 2h. In summary, the present study provides experimental evidence supporting selenoenzymes has good scavenging effect to ROS and can protect bacteria from oxidative stress injury induced by bactericidal antibiotics. PMID- 28347460 TI - The effect of the zinc concentration in breast milk on neonatal weight gain. AB - The change in breast milk zinc (Zn) concentration in a feeding period during lactation may affect neonatal weight gain. The aim of this study was to determine how to change the Zn concentrations in breast milk during a feeding period in early and late lactation periods and identify the relationship between the differences in the Zn levels in breast milk during lactation and neonatal weight gain. Breast milk was collected in the early and late lactation periods with samples being obtained before (foremilk) and after (hindmilk) a feeding period. Then, we determined the Zn concentrations in the breast milk and measured the weight of the infants before and after the same feeding period. The study was composed of 37 newborns and their mothers. During the feeding period, the Zn concentrations in both the transitional and mature milk decreased significantly. During the lactation period, the Zn levels were markedly lower in only the hindmilk. The body weights of the infants both before and after feeding in the early lactation period were negatively correlated with the delta Zn concentration in the same period, but the delta body weights in the early lactation period were positively correlated with the Zn levels in the hindmilk in the same period. In addition, body weights before feeding in the late lactation period were also positively correlated with Zn levels in hindmilk in the early lactation period. This study suggests that the Zn concentrations in both the transitional and mature milk decreased, which suggests that changes in the Zn content of breast milk during lactation might play a role in the weight gain of healthy neonates. PMID- 28347461 TI - Application of ICP-MS and HPLC-ICP-MS for diagnosis and therapy of a severe intoxication with hexavalent chromium and inorganic arsenic. AB - ICP-MS and HPLC-ICP-MS were applied for diagnosis and therapeutic monitoring in a severe intoxication with a liquid containing hexavalent chromium (Cr(VI)) and inorganic arsenic (iAs). In this rare case a liver transplantation of was considered as the only chance of survival. We developed and applied methods for the determination of Cr(VI) in erythrocytes and total chromium (Cr) and arsenic (As) in blood, plasma, urine and liver tissue by ICP-MS. Exposure to iAs was diagnosed by determination of iAs species and their metabolites in urine by anion exchange HPLC-ICP-MS. Three days after ingestion of the liquid the total Cr concentrations were 2180 and 1070MUg/L in whole blood and plasma, respectively, and 4540MUg/L Cr(VI) in erythrocytes. The arsenic concentration in blood was 206MUg/L. The urinary As species concentrations were <0.5, 109, 115, 154 and 126MUg/L for arsenobetaine, As(III), As(V), methylarsonate (V) and dimethylarsinate (V), respectively. Total Cr and As concentrations in the explanted liver were 11.7 and 0.9mg/kg, respectively. Further analytical results of this case study are tabulated and provide valuable data for physicians and toxicologists. PMID- 28347463 TI - Level of minerals and trace elements in the urine of the participants of mountain ultra-marathon race. AB - The aim of the present study was to explore impact of endurance exercise on urinary level of minerals and trace elements as well as on some oxidative stress and biochemical parameters. Urine samples were collected from participants (n=21) of mountain ultra-marathon race (53km; Medvednica, Zagreb, Croatia), before (baseline value), immediately after, 12h and 24h after the race. In urine samples level of minerals (Ca, P, K and Na) and trace elements (Se, Zn, Mn, Cu, Fe and Co) were assessed using the bench top Total reflection X-ray Fluorescence (TXRF) spectrometer. Oxidative stress was determined as level of malondialdehyde (MDA). Immediately after the race level of minerals, trace elements, MDA, creatinine, ketones, erythrocytes and specific gravity increased compared to their baseline value. In 24h follow-up trace elements involved in antioxidant defence, MDA and biochemical parameters returned to their baseline values, Cu and Co remained increased as after the race, Fe and K tended to return to baseline values while Ca, P and Na continued to increase. Mountain ultra-marathon resulted in alteration of physiologically important minerals and trace elements that for some minerals and trace elements persist, indicating their involvement in recovery processes. However, due to their loss in urine, level of minerals and trace elements in athletes participating in endurance exercise should be monitored. PMID- 28347462 TI - Interactions of iron with manganese, zinc, chromium, and selenium as related to prophylaxis and treatment of iron deficiency. AB - Iron (Fe) deficiency is considered as the most common nutritional deficiency. Iron deficiency is usually associated with low Fe intake, blood loss, diseases, poor absorption, gastrointestinal parasites, or increased physiological demands as in pregnancy. Nutritional Fe deficiency is usually treated with Fe tablets, sometimes with Fe-containing multimineral tablets. Trace element interactions may have a significant impact on Fe status. Existing data demonstrate a tight interaction between manganese (Mn) and Fe, especially in Fe-deficient state. The influence of Mn on Fe homeostasis may be mediated through its influence on Fe absorption, circulating transporters like transferrin, and regulatory proteins. The existing data demonstrate that the influence of zinc (Zn) on Fe status may be related to their competition for metal transporters. Moreover, Zn may be involved in regulation of hepcidin production. At the same time, human data on the interplay between Fe and Zn especially in terms of Fe-deficiency and supplementation are contradictory, demonstrating both positive and negative influence of Zn on Fe status. Numerous data also demonstrate the possibility of competition between Fe and chromium (Cr) for transferrin binding. At the same time, human data on the interaction between these metals are contradictory. Therefore, while managing hypoferremia and Fe-deficiency anemia, it is recommended to assess the level of other trace elements in parallel with indices of Fe homeostasis. It is supposed that simultaneous correction of trace element status in Fe deficiency may help to decrease possible antagonistic or increase synergistic interactions. PMID- 28347464 TI - Establishing human heart chromium, cobalt and vanadium concentrations by inductively coupled plasma mass spectrometry. AB - OBJECTIVE: Chromium, cobalt, and vanadium are used in metallic joint prosthesis. Case studies have associated elevated heart tissue cobalt concentrations with myocardial injury. To document the long term heart metal ion concentrations, a validated inductively coupled plasma mass spectroscopy (ICP-MS) method was needed. METHOD: The method utilized a closed-vessel microwave digestion system to digest the samples. An ICP-MS method utilizing Universal Cell Technology was used to determine our target analyte concentrations. Accuracy was verified using reference materials. Precision, sensitivity, recovery and linearity studies were performed. This method was used to establish a reference range for a non-implant containing cohort of 80 autopsy human heart tissues RESULTS: This method demonstrated an analytic measurement range of 0.5-100ng/mL for each element. Accuracy was within +/-10% of target value for each element. Within-run precision for each element was below 20% CV. The chromium, vanadium and cobalt concentrations (mean+/-SD) were 0.1523+/-0.2157MUg/g, 0.0094+/-0.0211MUg/g and 0.1039+/-0.1305MUg/g respectively in 80 non-implant containing human heart tissue samples. CONCLUSIONS: This method provides acceptable recovery of the chromium, cobalt and vanadium in heart tissue; allowing assessment of the effects of metallic joint prosthesis on myocardial health. PMID- 28347465 TI - Zn2+ reduction induces neuronal death with changes in voltage-gated potassium and sodium channel currents. AB - In the present study, cultured rat primary neurons were exposed to a medium containing N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), a specific cell membrane-permeant Zn2+ chelator, to establish a model of free Zn2+ deficiency in neurons. The effects of TPEN-mediated free Zn2+ ion reduction on neuronal viability and on the performance of voltage-gated sodium channels (VGSCs) and potassium channels (Kvs) were assessed. Free Zn2+ deficiency 1) markedly reduced the neuronal survival rate, 2) reduced the peak amplitude of INa, 3) shifted the INa activation curve towards depolarization, 4) modulated the sensitivity of sodium channel voltage-dependent inactivation to a depolarization voltage, and 5) increased the time course of recovery from sodium channel inactivation. In addition, free Zn2+ deficiency by TPEN notably enhanced the peak amplitude of transient outward K+ currents (IA) and delayed rectifier K+ currents (IK), as well as caused hyperpolarization and depolarization directional shifts in their steady-state activation curves, respectively. Zn2+ supplementation reversed the effects induced by TPEN. Our results indicate that free Zn2+ deficiency causes neuronal damage and alters the dynamic characteristics of VGSC and Kv currents. Thus, neuronal injury caused by free Zn2+ deficiency may correlate with its modulation of the electrophysiological properties of VGSCs and Kvs. PMID- 28347466 TI - Zinc concentrations in human milk and infant serum during the first six months of lactation. AB - Normal supply of zinc to the newborn via milk is essential for normal development. Using ICP-OES, we analyzed changes in the level of Zn in milk and infant serum in the neonatal period (Day 1 and Day 28 post partum) and at 6 months after delivery, in the cohort of 60 mothers and exclusively breastfed babies. Zn level in the serum showed increase (significant at 6 months) during this period (mg/mL): Day 1: 0.52+/-0.12; Day 28: 0.59+/-0.19; 6 months: 0.68+/ 0.28. The concentration of Zn in the milk showed an opposite (decreasing) trend during the follow up: Day 1: 4.70+/-1.74mg/L; Day 28: 2.65+/-1.06; 6 months: 0.46+/-0.36. A significant negative correlation was established between serum and milk [Zn] at day 28 (R=-0.338; p=0.008), whereas a positive correlation was found at 6 months between these parameters (R=0.306; p=0.018). There was no significant correlation between [Zn] in the milk and serum and infants' body mass, mothers' age and mass at delivery. The level of Zn in the milk at 6 months of lactation is not sufficient to meet the recommended values. This implies that in Serbian population, Zn supplementation might be needed in the later phase of lactation. PMID- 28347467 TI - Protective effects of cerium oxide and yttrium oxide nanoparticles on reduction of oxidative stress induced by sub-acute exposure to diazinon in the rat pancreas. AB - Diazinon is a kind of organophosphorus (OP) compound that is broadly used against different species of insects and pests. Oxidative stress can occur at very early stages of diazinon exposure and the pancreas is one of the main target organs for toxicity by diazinon. The aim of this study was to evaluate the protective effects of cerium oxide nanoparticles (CeO2 NPs) and yttrium oxide nanoparticles (Y2O3 NPs) against the pancreatic damage from sub-acute exposure of diazinon. Diazinon at a dose of 70mg/kg/day was given through gavage to rats once a day. Along with diazinon, trace amounts of CeO2 NPs and Y2O3 NPs (35mg/kg and 45mg/kg per day, respectively) were administered by intraperitoneal injection once a day for 2 weeks. Animals weight and blood glucose were measured during the treatment, and oxidative stress biomarkers, diabetes physiology, function and viability of cells were investigated at the end of the treatment in serum and pancreas tissues. Apoptosis of islets was examined by the flow cytometry. The high blood glucose level and significant weight loss resulting from diazinon were modified as a result of the application of the NPs. A significant recovery in oxidative stress markers, pro-insulin, insulin, C-peptide, adenosine diphosphate/adenosine triphosphate (ATP/ADP) ratio, caspase-3 and -9 activities and apoptosis-necrosis in the islets was observed. In conclusion, administration of CeO2 NPs or Y2O3 NPs only or their combination with suitable and defined dose will help to overcome the consequences from oxidant agents. PMID- 28347468 TI - Trace element status in patients with type 2 diabetes in Norway: The HUNT3 Survey. AB - Several epidemiological studies have indicated that a number of trace elements may play a role in type 2 diabetes (T2D). We investigated the association between prevalent T2D and the concentrations of 25 trace elements in whole blood, and the relationships between T2D duration and blood levels of the trace elements that we found to be related to T2D prevalence. In this population based case-control study, 267 patients with self-reported T2D and 609 controls (frequency matched), were selected from the third Nord-Trondelag Health Survey. Trace element blood levels were determined by high resolution inductively coupled plasma-mass spectrometry. Multivariable conditional logistic regression and multivariable linear regression were used to estimate associations. The prevalence of T2D was positively associated with boron, calcium and silver, and inversely associated with indium, lead and magnesium (Ptrend<0.05). We found no statistical evidence for associations between blood levels of arsenic, bromine, cadmium, cesium, chromium, copper, gallium, gold, manganese, mercury, molybdenum, nickel, rubidium, selenium, strontium, tantalum, thallium, tin and zinc and T2D prevalence. After corrections for multiple testing, associations remained significant for calcium and lead (Qtrend<0.05), and borderline significant for magnesium, silver and boron. With increasing disease duration, higher calcium levels were observed (P<0.05). This study suggests an association between prevalent T2D and blood levels of boron, calcium, indium, lead, magnesium and silver. PMID- 28347470 TI - Genomics and Sleep Disorders. PMID- 28347469 TI - Biological monitoring of welders' exposure to chromium, molybdenum, tungsten and vanadium. AB - BACKGROUND: Welders are exposed to a number of metallic elements during work. Bioaccessability, that is important for element uptake, has been little studied. This study addresses bioaccessability and uptake of chromium (Cr), molybdenum (Mo), tungsten (W) and vanadium (V) among welders. METHODS: Bioaccessability of Cr, Mo, V and W was studied in airborne particulate matter collected by personal sampling of the workroom air among shipyard welders by using the lung lining fluid simulant Hatch solution. Associations between concentrations of Hatch soluble and non-soluble elements (Hatchsol and Hatchnon-sol) and concentrations of the four elements in whole blood, serum, blood cells and urine were studied. RESULTS: Air concentrations of the four elements were low. Only a small fraction of Cr, V and W was Hatchsol, while similar amounts of Mo were Hatchsol and Hatchnon-sol. Welders (N=70) had statistically significantly higher concentrations of all four elements in urine and serum when compared to referents (N=74). Highly statistically significant associations were observed between urinary W and Hatchsol W (p<0.001) and serum V and Hatchsol V (p<0.001), in particular when air samples collected the day before collection of biological samples were considered. CONCLUSIONS: Associations between Hatchsol elements in air and their biological concentrations were higher than when Hatchnon-sol concentrations were considered. Associations were generally higher when air samples collected the day before biological sampling were considered as compared to air samples collected two days before. PMID- 28347471 TI - Double strand break repair and gamma-H2AX formation in erythrocytes of medaka (Oryzias latipes) after gamma-irradiation. AB - The study of the DNA damage response in erythrocytes after gamma-irradiation may provide evidence for its effectiveness as a biomarkers for genotoxic environmental stress. We previously reported various malformations in erythrocytes of medaka irradiated with10 Gy, but not in their micronuclei. In this study, we optimized an assay method for gamma-H2AX and double strand breaks in erythrocytes of adult medaka fish after 15 Gy of gamma-irradiation. The highest level of apoptosis and nuclear abnormalities, including in micronuclei, were recorded 4 h after gamma-irradiation, as was the highest level of gamma-H2AX foci in erythrocytes. These results suggest that recognition and repair processes occur as a response to DNA damage in erythrocytes in medaka. PMID- 28347472 TI - The design of delay-dependent wide-area DOFC with prescribed degree of stability alpha for damping inter-area low-frequency oscillations in power system. AB - In this paper, the delay-dependent wide-area dynamic output feedback controller (DOFC) with prescribed degree of stability is proposed for interconnected power system to damp inter-area low-frequency oscillations. Here, the prescribed degree of stability alpha is used to maintain all the poles on the left of s=-alpha in the s-plane. Firstly, residue approach is adopted to select input-output control signals and the schur balanced truncation model reduction method is utilized to obtain the reduced power system model. Secondly, based on Lyapunov stability theory and transformation operation in complex plane, the sufficient condition of asymptotic stability for closed-loop power system with prescribed degree of stability alpha is derived. Then, a novel method based on linear matrix inequalities (LMIs) is presented to obtain the parameters of DOFC and calculate delay margin of the closed-loop system considering the prescribed degree of stability alpha. Finally, case studies are carried out on the two-area four machine system, which is controlled by classical wide-area power system stabilizer (WAPSS) in reported reference and our proposed DOFC respectively. The effectiveness and advantages of the proposed method are verified by the simulation results under different operating conditions. PMID- 28347473 TI - A systematic review investigating the association of microRNAs with human abdominal aortic aneurysms. AB - BACKGROUND AND AIMS: There is increasing interest in identifying novel methods for abdominal aortic aneurysm (AAA) diagnosis. Non-coding RNA molecules such as microRNAs (miRNAs) are stable within the circulation and may serve as biomarkers for AAA. This systematic review aimed to identify miRNAs associated with a diagnosis of human AAA based on currently published original research. METHODS: A systematic search of the MEDLINE and EMBASE databases identified studies assessing miRNA expression in abdominal aortic tissue or circulating blood from human AAA cases compared to non-aneurysmal controls. Data from included studies were extracted to assess methods and results after independent quality assessment by two reviewers. RESULTS: 15 studies were included in this review. 11 studies obtained aortic tissue samples from 195 AAA cases and 104 controls with normal aortas. Nine studies obtained circulating blood samples from 526 AAA cases and 441 controls. miR-21 was differentially expressed in AAA tissue in five separate studies, with four studies reporting upregulation and one reporting downregulation. Seven other miRNAs were differentially expressed in AAA tissue in two separate studies. 15 circulating miRNAs were differentially expressed in two or more separate studies. miR-155 and miR-29b were the only miRNAs differentially expressed in two separate tissue- and blood-based studies. 11 studies offered mechanistic explanations of the role of miRNAs in AAA pathology through exploration of gene targets. Three studies assessed the diagnostic potential of circulating miRNAs with receiver operating characteristic curves. Only one study assessed the prognostic potential of circulating miRNAs in predicting AAA growth. CONCLUSIONS: Several miRNAs have been found to be associated with human AAA. Their utility as AAA biomarkers requires further investigation. PMID- 28347474 TI - Platelet activation of mechanical versus bioprosthetic heart valves during systole. AB - Thrombus formation is a major concern for recipients of mechanical heart valves (MHVs), which requires them to take anticoagulant drugs for the rest of their lives. Bioprosthetic heart valves (BHVs) do not require life-long anticoagulant therapy but deteriorate after 10-15years. The thrombus formation is initiated by the platelet activation which is thought to be mainly generated in MHVs by the flow through the hinge and the leakage flow during the diastole. However, our results show that the activation in the bulk flow during the systole phase might play an essential role as well. This is based on our results obtained by comparing the thrombogenic performance of a MHV and a BHV (as control) in terms of shear induced platelet activation under exactly the same conditions. Three different mathematical activation models including linear level of activation, damage accumulation, and Soares model are tested to quantify the platelet activation during systole using the previous simulations of the flow through MHV and BHV in a straight aorta under the same physiologic flow conditions. Results indicate that the platelet activation in the MHV at the beginning of the systole phase is slightly less than the BHV. However, at the end of the systole phase the platelet activation by the bulk flow for the MHV is several folds (1.41, 5.12, and 2.81 for linear level of activation, damage accumulation, and Soares model, respectively) higher than the BHV for all tested platelet activation models. PMID- 28347476 TI - Breastfeeding or formula feeding and iron status in the second 6 months of life: A critical role for complementary feeding. PMID- 28347475 TI - Current trends in vasopressor use to the operating room: A pharmacoepidemiologic study in French teaching and military hospitals. AB - OBJECTIVES: Phenylephrine, ephedrine and norepinephrine are the vasopressors most commonly used in the operating room to treat anaesthesia-induced hypotension. Two new diluted forms of phenylephrine were released in 2011 (500MUg/10mL and 500MUg/5mL). We initiated a study to evaluate trends in the use of vasopressors in the operating room in French hospitals over the period 2011-2014. METHODS: We conducted a longitudinal, retrospective, observational study between 2011 and 2014 in French teaching and military hospitals. A questionnaire was sent in February 2015 to hospital pharmacists of each centre to retrospectively collect the consumption of each type of vasopressor. Yearly numbers of vasopressor ampoules were divided by the yearly numbers of anaesthetics recorded. For each vasopressor, we calculated the number of ampoules per 100 anaesthetics recorded (/100A). RESULTS: Thirty-two hospitals (82%) completed the questionnaire. One hundred per cent of hospitals had registered the diluted form of phenylephrine (61% had chosen the dilution 500MUg/10mL), whereas concentrated ampoules were available in 68% of hospitals. Over the period, an exponential increase in the use of diluted phenylephrine was observed (from 1.0 ampoule/100A in 2012 to 31.7 in 2014), the use of ephedrine remained stable (26 ampoules and 17 prefilled syringe/100A), and use of norepinephrine trended upwards (from 6.7 to 8.2 ampoules/100A). CONCLUSIONS: The use of diluted phenylephrine has exponentially increased without reducing consumption of other vasopressors. This trend might be secondary to practice changes in hypotension treatment following the release of French guidelines in 2013 related to fluid management, the restriction of indications of hydroxylethyl-starch solutions in 2013, and a better knowledge of the benefit of blood pressure optimisation to reduce postoperative morbidity. PMID- 28347477 TI - Evolving Childhood Melanoma Monitored by Parental Photodocumentation. PMID- 28347478 TI - Changing P-wave morphology: What is the mechanism? AB - A 76-year-old woman, affected by drugs resistant focal atrial tachycardia, underwent a catheter ablation procedure in our Hospital. During ablations we observed on the surface ECG a progressive modification of the second component of the P wave (delayed and then negative in inferior leads). These findings demonstrated, compared to the beginning of the procedure, a different propagation of the activation wave from the right to the left atrium, helped to identify the true origin of a focal atrial tachycardia. Moreover, this case underlined the importance of the Bachmann's bundle for the impulse propagation through the interatrial septum in normal hearts. PMID- 28347479 TI - Artifactual ECG changes induced by electrocautery in a patient with coronary artery disease. AB - Continuous monitoring of 5-lead electrocardiogram is a basic standard of care (included under standard ASA monitor) in the operating room and electrocautery interference is a common phenomenon. Clinical signs, along with monitored waveforms from other simultaneously monitored parameters may provide us clues to differentiate artifacts from true changes on the electrocardiogram. An improved understanding of the artifacts generated by electrocautery and their identifying characteristics is important to avoid misinterpretation, misdiagnosis, and hence mismanagement. This case report highlights the artifacts in electrocardiogram induced by electrocautery. PMID- 28347480 TI - Electrocardiographic interference by a sacral neuromodulation device. PMID- 28347481 TI - Ventricular repolarization duration and dispersion adaptation after atropine induced rapid heart rate increase in healthy adults. AB - BACKGROUND: Proper adaptation of ventricular repolarization (VR) to rapid heart rate (HR) increase is crucial for cardiac electro-mechanical function. The pattern and temporal aspects of this adaptation and its components (duration and dispersion) during normal conduction are, however, incompletely known in humans and were the topic of this study. METHODS & RESULTS: The VR duration (QT & QTpeak) and dispersion (Tamplitude, Tarea & ventricular gradient; VG) responses were studied by continuous vectorcardiogram after a bolus injection of atropine 0.04mg/kg b.w. in 31 healthy young adults (16 men). The primary measure (T90 End) was the time to reach 90% change from baseline to end value 300s later. Mean (SD) of T90 End was 23 (9) s for a 41% RR decrease, 130 (35) s for a 16% QTend decrease and 110 (36) s for a 19% QTpeak decrease; the response was single exponential for these measures. For 35-43% decreases of Tamplitude, Tarea & VG, mean (SD) of T90 End were 21 (10), 38 (20) and 40 (23) s and the response pattern was double-exponential with varying overshoot. CONCLUSIONS: VR duration and dispersion responses to a very rapid HR increase during normal conduction differed substantially. In contrast to the well-known single-exponential delay in VR duration adaptation the responses of VR dispersion measures were double exponential and much more rapid. We describe a new and completely non-invasive phenotypic characterization of different components of VR adaptation. PMID- 28347482 TI - Robotics in Sinus and Skull Base Surgery. AB - Transoral robotic surgery (TORS) has been proven to be safe and to yield acceptable oncological and functional outcomes for surgery of the oropharynx, hypopharynx, supraglottis, and glottis. TORS has been successful at reducing morbidity, improving quality of life, and providing access to areas that previously required mandibulotomy or other more radical approaches in the past. This has changed the paradigm of management of tumors in these anatomic locations. In this article, the authors review the recent literature discussing the role of robotic surgery in managing sinonasal and skull base pathology and discuss its current advantages and limitations. PMID- 28347483 TI - The legacy of William Morgan: The PNNL years. PMID- 28347484 TI - In search of the smoking gun in calcific aortic valve disease. PMID- 28347485 TI - Pump thrombosis: Do we have the answer to the riddle? PMID- 28347486 TI - Comparison of Coronary Intimal Plaques by Optical Coherence Tomography in Arteries With Versus Without Internal Running Vasa Vasorum. AB - It has been reported that the internal running vasa vasorum (VV) was associated with plaque vulnerability, and microchannels in optical coherence tomography (OCT) are consistent pathologically with VV. We investigated plaque vulnerability and incidence of slow flow during percutaneous coronary intervention of the internal longitudinal running VV. Subjects were 71 lesions that underwent OCT before percutaneous coronary intervention. Internal running VV was defined as intraplaque neovessels running from the adventitia to plaque. Lesions with internal running VV were found in 47% (33 of 71). Compared with lesions without internal running VV, lesions with internal running VV showed significantly higher incidence of intimal laceration (64% [21 of 33] vs 16% [6 of 38], p <0.001), lipid-rich plaque (79% [26 of 33] vs 26% [10 of 38], p <0.001), plaque rupture (52% [17 of 33] vs 13% [5 of 38], p <0.001), thin-cap fibroatheroma (58% [19 of 33] vs 11% [4 of 38], p <0.001), macrophage accumulation (61% [20 of 33] vs 26% [10 of 38], p = 0.004), intraluminal thrombus (36% [12 of 33] vs 3% [1 of 38], p <0.001), and slow flow after stent implantation (42% [14 of 33] vs 13% [5 of 38], p = 0.007). The multivariable analysis showed that internal running VV was an independent predictor of slow flow after stent implantation (odds ratio 4.23, 95% confidence interval 1.05 to 17.01, p = 0.042). In conclusion, compared with those without, plaques with internal running VV in OCT had high plaque vulnerability with more intimal laceration, lipid-rich plaque, plaque rupture, thin-cap fibroatheroma, macrophage accumulation, and intraluminal thrombus, and they had high incidence of slow flow after stent implantation. PMID- 28347487 TI - Is age a predisposing factor of postoperative complications after lung resection for primary pulmonary neoplasms? AB - INTRODUCTION: Age has been classically considered as a determining factor for the development of postoperative complications related to lung resection for bronchogenic carcinoma. The Postoperative Complications Study Group of the Spanish Society of Thoracic Surgery has promoted a registry to analyze this factor. METHODS: A total of 3,307 patients who underwent any type of surgical resection for bronchogenic carcinoma have been systematically and prospectively recorded in any of the 24 units that are part of the group. Several variables related to comorbidity and age, as well as postoperative complications, were analyzed. RESULTS: The mean age of patients was 65,44. Men were significantly more common than female. The most frequent complication was prolonged air leak, which was observed in more than one third of patients. In a univariant analysis, air leak presence and postsurgical atelectasis showed statistical association with patient age, when stratified in age groups. In a multivariate analysis, age was recognized as an independent prognostic factor in relation to air leak onset. However, this could not be confirmed for postoperative atelectasis. CONCLUSION: Age is a predisposing factor for the development of postoperative complications after lung resection. Other associated factors also influence the occurrence of these complications. PMID- 28347489 TI - Preprosthetic surgery, fault-lines, and scholarly leadership. PMID- 28347490 TI - Environmental impacts of genetically modified plants: A review. AB - Powerful scientific techniques have caused dramatic expansion of genetically modified crops leading to altered agricultural practices posing direct and indirect environmental implications. Despite the enhanced yield potential, risks and biosafety concerns associated with such GM crops are the fundamental issues to be addressed. An increasing interest can be noted among the researchers and policy makers in exploring unintended effects of transgenes associated with gene flow, flow of naked DNA, weediness and chemical toxicity. The current state of knowledge reveals that GM crops impart damaging impacts on the environment such as modification in crop pervasiveness or invasiveness, the emergence of herbicide and insecticide tolerance, transgene stacking and disturbed biodiversity, but these impacts require a more in-depth view and critical research so as to unveil further facts. Most of the reviewed scientific resources provide similar conclusions and currently there is an insufficient amount of data available and up until today, the consumption of GM plant products are safe for consumption to a greater extent with few exceptions. This paper updates the undesirable impacts of GM crops and their products on target and non-target species and attempts to shed light on the emerging challenges and threats associated with it. Underpinning research also realizes the influence of GM crops on a disturbance in biodiversity, development of resistance and evolution slightly resembles with the effects of non-GM cultivation. Future prospects are also discussed. PMID- 28347488 TI - Targeted Interneuron Depletion in the Dorsal Striatum Produces Autism-like Behavioral Abnormalities in Male but Not Female Mice. AB - BACKGROUND: Interneuronal pathology is implicated in many neuropsychiatric disorders, including autism spectrum disorder (ASD) and Tourette syndrome (TS). Interneurons of the striatum, including the parvalbumin-expressing fast-spiking interneurons (FSIs) and the large cholinergic interneurons (CINs), are affected in patients with TS and in preclinical models of both ASD and TS. METHODS: To test the causal importance of these neuronal abnormalities, we recapitulated them in vivo in developmentally normal mice using a combination transgenic-viral strategy for targeted toxin-mediated ablation. RESULTS: We found that conjoint ~50% depletion of FSIs and CINs in the dorsal striatum of male mice produces spontaneous stereotypy and marked deficits in social interaction. Strikingly, these behavioral effects are not seen in female mice; because ASD and TS have a marked male predominance, this observation reinforces the potential relevance of the finding to human disease. Neither of these effects is seen when only one or the other interneuronal population is depleted; ablation of both is required. Depletion of FSIs, but not of CINs, also produces anxiety-like behavior, as has been described previously. Behavioral pathology in male mice after conjoint FSI and CIN depletion is accompanied by increases in activity-dependent signaling in the dorsal striatum; these alterations were not observed after disruption of only one interneuron type or in doubly depleted female mice. CONCLUSIONS: These data indicate that disruption of CIN and FSI interneurons in the dorsal striatum is sufficient to produce network and behavioral changes of potential relevance to ASD, in a sexually dimorphic manner. PMID- 28347491 TI - Diffusion of technology: Trends in robotic-assisted colorectal surgery. AB - Following FDA approval, robotic-assisted colorectal surgery (RACS) has increased in prevalence. We aimed to identify trends in utilization and patient characteristics of RACS in the United States using the University HealthSystem Consortium database between October 2011-September 2015. Outcome measures were number and percentage of procedures performed with robotic-assistance. 7100 patients were identified. The most common procedures were low anterior resection, sigmoid colectomy, abdominoperineal resection, right colectomy, rectopexy, left colectomy, and total colectomy. There was a 158% increase in RACS procedures. As a percentage of all approaches, RACS increased from 2.6% to 6.6%. The number of centers performing RACS increased from 105 to 140. Over the study period, the complexity of patients increased, with the percentage of patients with >=3 comorbidities rising from 18% to 24% (p = 0.03) and patients with a moderate severity of illness score increasing from 35% to 41% (p = 0.04). RACS has expanded significantly in volume, number of centers, and patient selection. Further studies evaluating outcomes and cost of RACS are required to determine whether these increases are justified by improved clinical outcomes. PMID- 28347492 TI - Tests used in the diagnostic evaluation of infertility: from ubiquitous to obsolete. AB - The only true wisdom is in knowing you know nothing. -Socrates. PMID- 28347493 TI - Transvaginal ultrasound to guide embryo transfer: a randomized controlled trial. AB - OBJECTIVE: To compare sonographic visualization and patient pain in conventional transabdominal ultrasound (TAUS) with transvaginal ultrasound (TVUS) sonographic guided embryo transfer (ET). DESIGN: Prospective, randomized, controlled study. SETTING: Tertiary medical center, in vitro fertilization (IVF) unit. PATIENT(S): One hundred and twenty patients younger than 40 years old scheduled for ET. INTERVENTION(S): Patients (32.9 +/- 4.5 years old) undergoing fresh cleavage stage ET were randomly assigned to the study group (TVUS; n = 60) or control group (TAUS; n = 60). After ET each patient filled out a questionnaire based on a visual analogue scale (VAS) to evaluate pain and discomfort before, during, and after the procedure. The physician assessed the quality of sonographic visualization. The follow-up observation lasted 12 months and included pregnancy rates. MAIN OUTCOME MEASURE(S): Visualization of the uterus and ET location and pain before, during, and after the ET procedure. RESULT(S): Visualization of the uterus and the ET location by the physician was statistically significantly better in the TVUS than in the TAUS group (9.57 vs. 8.42 and 9.58 vs. 8.82, respectively). Pain sensation assessed by a visual analogue scale (VAS) before, during, and after the procedure was statistically significantly lower in the study group compared with the control group (5.45 vs. 1.48, 5.03 vs. 2.42 and 2.97 vs. 1.52). The implantation and live-birth rates did not differ between the two groups (32.9% vs. 23.4%, OR 1.61; 95% CI, 0.85-3.07; 31.6% vs. 25.0%, OR 1.39; 95% CI, 0.63-3.09, respectively). CONCLUSION(S): TVUS guidance to facilitate ET is superior to TAUS in visualization of ET location and in lessening the pain and discomfort of the patients. CLINICAL TRIAL REGISTRATION NUMBER: NCT008263312. PMID- 28347494 TI - Using family members as gamete donors or gestational carriers. AB - The use of adult intrafamilial gamete donors and gestational surrogates is generally ethically acceptable when all participants are fully informed and counseled, but consanguineous arrangements or ones that simulate incestuous unions should be prohibited. Adult child-to-parent arrangements require caution in order to avoid coercion, and parent-to-adult child arrangements are acceptable in limited situations. Programs that choose to participate in intrafamilial arrangements should be prepared to spend additional time counseling participants and ensuring that they have made free, informed decisions. This document replaces the document of the same name, last published in 2012 (Fertil Steril 2012;98:797 803). PMID- 28347495 TI - Comparative feasibility study on retrofitting ballast water treatment system for a bulk carrier. AB - Use of ballast water in ships causes harmful effects on marine environment accompanied by economic loss and negative impact on ecosystem and human health. To solve these problems, the international convention on ballast water management will take into force in September 2017. In this study, a comprehensive feasibility of retrofitting the ballast water treatment system for an ocean-going bulk carrier was conducted. The technologies involved, installation and operational aspects of direct flow and side stream electrolysis, UV, and ozone type BWTS are described in detail. The principal concept of each BWTS is explained and probable arrangements of retrofitting in engine room are suggested. The cost analysis is carried out for retrofitting 4 types of BWTS onboard the target ship by examining each processes of installation and operation. PMID- 28347496 TI - Spatial patterns in coastal lagoons related to the hydrodynamics of seawater intrusion. AB - Marine intrusion was simulated in a choked and in a restricted coastal lagoon by using a 3D-hydrodynamic model. To study the spatiotemporal progression of seawater intrusion and its mixing efficiency with lagoon waters we define Marine Mixed Volume (VMM) as a new hydrodynamic indicator. Spatial patterns in both lagoons were described by studying the time series and maps of VMM taking into account the meteorological conditions encountered during a water year. The patterns comprised well-mixed zones (WMZ) and physical barrier zones (PBZ) that act as hydrodynamic boundaries. The choked Bages-Sigean lagoon comprises four sub basins: a PBZ at the inlet, and two WMZ's separated by another PBZ corresponding to a constriction zone. The volumes of the PBZ were 2.1 and 5.4 millions m3 with characteristic mixing timescale of 68 and 84days, respectively. The WMZ were 12.3 and 43.3 millions m3 with characteristics mixing timescale of 70 and 39days, respectively. PMID- 28347499 TI - Fears over health of doctor imprisoned without trial in Iran. PMID- 28347497 TI - Diabetes and Ramadan: Practical guidelines. AB - Ramadan fasting is one of the five pillars of Islam and is compulsory for all healthy Muslims from puberty onwards. Exemptions exist for people with serious medical conditions, including many with diabetes, but a large number will participate, often against medical advice. Ensuring the optimal care of these patients during Ramadan is crucial. The International Diabetes Federation (IDF) and Diabetes and Ramadan (DAR) International Alliance have come together to deliver comprehensive guidelines on this subject. The key areas covered include epidemiology, the physiology of fasting, risk stratification, nutrition advice and medication adjustment. The IDF-DAR Practical Guidelines should enhance knowledge surrounding the issue of diabetes and Ramadan fasting, thereby empowering healthcare professionals to give the most up-to-date advice and the best possible support to their patients during Ramadan. PMID- 28347498 TI - Jules and Augusta Dejerine, Pierre Marie, Joseph Babinski, Georges Guillain and their students during World War I. AB - World War I (1914-1918), however tragic, was nonetheless an "edifying school of nervous system experimental pathology" not only because of the various types of injuries, but also because their numbers were greater than any physician could have foreseen. The peripheral nervous system, the spine and the brain were all to benefit from the subsequent advances in clinical and anatomo-functional knowledge. Neurosurgeons took on nerve sutures, spinal injury exploration, and the localization and extraction of intracranial foreign bodies. Little by little, physical medicine and rehabilitation were established. A few of the most famous Parisian neurologists at the time-Jules and Augusta Dejerine, Pierre Marie, Joseph Babinski and Georges Guillain, who directed the military neurology centers took up the physically and emotionally exhausting challenge of treating thousands of wounded soldiers. They not only cared for them, but also studied them scientifically, with the help of a small but devoted band of colleagues. The examples presented here reveal their courage and their efforts to make discoveries for which we remain grateful today. PMID- 28347500 TI - Versatility of peroxisomes: An evolving concept. AB - Research spanning almost 50 years has highlighted unique characteristics and irreplaceable list of diverse functions performed by peroxisomes in various model systems. Peroxisomes are single membrane bound highly dynamic organelles ubiquitous to most eukaryotic cells. Proliferation by division of pre-existing organelles and the role of endoplasmic reticulum in the biogenesis of these organelles is now well established. The earliest identified conserved functions of peroxisomes are beta-oxidation of fatty acids and reactive oxygen species metabolism. Several studies over the last few decades have reported the importance of this organelle and its numerous cell type, tissue and environment dependent functions. Their role in several aspects of human health and disease is now under investigation. Studies related to peroxisome biology and functions are now also extended to diverse model systems like Drosophila melanogaster, trypanosomatids, etc. Peroxisomes also intricately collaborate and carry out these functions together with several other organelles in a cell. In this review, we aim to present an overview of our current knowledge of the repertoire of functions of peroxisomes in various model systems. PMID- 28347502 TI - Modern technology: The preferred biosecurity strategy? PMID- 28347501 TI - Knowledge, attitudes, beliefs, and behaviors of university students, faculty, and staff during a meningococcal serogroup B outbreak vaccination program. AB - OBJECTIVES: During an outbreak of invasive meningococcal B disease on a university campus, we explored the knowledge, attitudes, beliefs, and behaviors of members of the university community in relation to the disease, the vaccine, and the vaccination program. DESIGN: All students, faculty and staff were invited by email to participate in a 71-item online survey, which was administered after completion of the mass clinics for the first and second doses of a meningococcal B vaccination program. RESULTS: A total of 404 individuals responded to the survey; 75.7% were students. Knowledge about meningococcal disease and vaccine was generally high; more than 70% correct responses were received on each knowledge question except for one question about the different meningococcal serogroups. Gender (female) and higher knowledge scores were significantly associated with either being immunized or intending to be immunized (p<0.05). Positive attitudes about immunization, concern about meningococccal infection, a sense of community responsibility, and trust in public health advice also correlated with being vaccinated or intending to be vaccinated (p<0.05). CONCLUSIONS: A successful mass vaccination program in a Nova Scotia university was associated with high levels of knowledge, positive attitudes toward vaccination, and positive attitudes toward public health recommendations. PMID- 28347503 TI - Informing pneumococcal conjugate vaccine policy in middle-income countries: The case of Malaysia. PMID- 28347504 TI - Platform technologies for modern vaccine manufacturing. AB - Improved understanding of antigenic components and their interaction with the immune system, as supported by computational tools, permits a sophisticated approach to modern vaccine design. Vaccine platforms provide an effective tool by which strategically designed peptide and protein antigens are modularized to enhance their immunogenicity. These modular vaccine platforms can overcome issues faced by traditional vaccine manufacturing and have the potential to generate safe vaccines, rapidly and at a low cost. This review introduces two promising platforms based on virus-like particle and liposome, and discusses the methodologies and challenges. PMID- 28347505 TI - Complexity Assessed by the INTERMED in Patients With Somatic Symptom Disorder Visiting a Specialized Outpatient Mental Health Care Setting: A Cross-sectional Study. AB - BACKGROUND: Somatic symptom disorders (SSD), a new classification in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition is associated with problematic diagnostic procedures and treatment that lead to complex care. In somatic health care, the INTERMED has been used to assess levels of complexity; however, in SSD this instrument has not yet been applied. OBJECTIVE: This study aims to explore complexity in patients with SSD using the INTERMED, hereby contributing to an increased comprehension of this new patient group. METHOD: In this cross-sectional study, the INTERMED was used to assess complexity in outpatients with SSD at the Clinical Centre of Excellence for Body, Mind, and Health (The Netherlands), along biologic, psychologic, social, and health care domains. This was done retrospectively with patient files from consecutive patients from 2011 until 2015. RESULTS: In the total SSD sample (N = 187), 63% was female, the mean age (standard deviation) was 42 (+/-12.4) years, with an average educational level. The mean INTERMED score was 23.5 indicating high overall complexity in this population. A high proportion of our sample (69%) scored as highly complex (>20). High complexity was associated with higher depression and anxiety scores, but not with a higher number of physical symptoms. CONCLUSIONS: This study demonstrates that patients with SSD form a high-complex group, with higher scores compared with literature about multiple sclerosis, rheumatoid arthritis, or patient waiting for a liver transplant. INTERMED outcomes indicate a need for extensive diagnostic procedures and integrated multidisciplinary care for patients with SSD. Attention should especially be paid to mental disorders (depression and anxiety), given their association with high complexity. PMID- 28347506 TI - Antidepressant-Associated Microscopic Colitis: A Case Report and Literature Review. PMID- 28347507 TI - [Management of residual macular edema post-embolization of dural carotid cavernous fistula: A case report]. PMID- 28347508 TI - Ultrasonic-assisted extrusion of ZK60Mg alloy micropins at room temperature. AB - A new model of ZK60 magnesium micropins formed through ultrasonic-assisted extrusion at room temperature was developed. The billet was transmitted by the ultrasonic wave during the micropin-forming process. A self-designed apparatus was applied for the ultrasonic-assisted extrusion experiments. The effects of amplitude on the load-displacement curve, load reduction, temperature, microstructure, diameter after extrusion, microhardness, and compressibility of micropins were investigated. The results showed that the punch was always in contact with the billet when the displacement of the punch was larger than the amplitude. The maximum reduction of load was approximately 80% because of the dynamic recrystallization and ultrasonic softening. In addition, load reduction was almost similar under different amplitudes when the diameters of micropins after extrusion were 0.3 and 0.5mm as a result of the size effect. The microhardness of the micropins increased at the amplitude of 39 and 42MUm as compared with the traditional extrusion. This finding was inconsistent with the results for copper and aluminum. The compression ratio of micropins prepared through ultrasonic-assisted extrusion improved by 14-20% on average at room temperature. PMID- 28347509 TI - Sonochemical growth of nanomaterials in carbon nanotube. AB - Recent achievements in investigations of carbon nanotubes (CNTs) filled with ternary chalcohalides (antimony sulfoiodide (SbSI) and antimony selenoiodide (SbSeI)) are presented. Parameters of sonochemical encapsulation of nanocrystalline semiconducting ferroelectric SbSI-type materials in CNTs are reported. This low temperature technology is convenient, fast, efficient and environmentally friendly route for producing novel type of hybrid materials useful for nanodevices. Structure as well as optical and electrical properties of SbSI@CNTs and SbSeI@CNTs are described. Advantages of ultrasonic joining of such filled CNTs with metal microelectrodes are emphasized. The possible applications of these nanomaterials as gas sensors are shown. PMID- 28347510 TI - [Good's syndrome and congenital toxoplasmosis due to maternal reactivation during pregnancy]. AB - INTRODUCTION: Good syndrome is a rare condition in which thymoma is associated with hypogammaglobulinemia. It is characterized by an increased susceptibility to infections. CASE REPORT: We report a woman with Good's syndrome diagnosed after severe congenital toxoplasmosis in her daughter, even though she was immunized against this infection during pregnancy. CONCLUSION: This presentation is very unusual by its early diagnosis and to our knowledge is the first report of parasitic infection in this syndrome. PMID- 28347511 TI - [An unusal cause of lower limb claudication]. PMID- 28347512 TI - Characterization of immune regulatory molecules B7-H4 and PD-L1 in low and high grade endometrial tumors. AB - BACKGROUND: The objective of this investigation was to characterize the expression landscape of immune regulatory molecules programmed death-ligand-1 (PD L1, B7-H1) and B7-H4 in a cohort of endometrial tumors across the spectrum of grade and histology. MATERIALS AND METHODS: With institutional review board approval, 70 endometrial tumors from patients with known clinical outcomes were identified representing a spectrum of grade and histology. Immunohistochemistry (IHC) was performed for PD-L1 and B7-H4 and scored. Microsatellite instability (MSI) status was assessed for endometrioid tumors using the institutional IHC assay for expression of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2. RNA sequencing data from the Cancer Genome Atlas was queried for expression levels of CD274 (PD-L1 protein) and VTCN1 (B7-H4) across molecular subtypes of endometrial carcinoma and were correlated with a T cell infiltration index. RESULTS: We identified 40 low grade endometrioid tumors and a cohort of 30 high grade tumors. PD-L1 expression was observed in both high and low grade endometrial tumors (56% vs 35%, p=0.07). In the low grade tumors, PD-L1 expression was associated with MSI status (p<0.01). The high grade cohort had similar rates of PD-L1 expression compared to low grade MSI tumor (56% and 62% respectively), and both were distinct from low grade MSS tumors (22%, p<0.05). High (3+) B7-H4 positive cells were observed in both high and low grade carcinomas (33% and 31% respectively). RNA profiling data from confirmed highest CD274 expression in POLE and MSI tumors that was linearly correlated with T cell infiltration, while VTCN1 expression appeared consistent across molecular subtypes. CONCLUSIONS: While PD-L1 expression correlated with MSI and high grade tumors, B7-H4 expression was independent of grade, histology and immune cell infiltration. The development and testing of multi-agent therapeutics targeting PD-L1 and B7-H4 may be a novel strategy for endometrial tumors. PMID- 28347513 TI - Cost-effectiveness of Maintaining Daily Intake of Oat beta-Glucan for Coronary Heart Disease Primary Prevention. AB - PURPOSE: Oat beta-glucan reduces cholesterol levels and thus reduces the risk for coronary heart disease (CHD). However, its economic impact has not been well studied. We examined the economic impact of daily intake of >=3 g of oat beta glucan in primary prevention of CHD in patients receiving statins or no pharmacologic treatment. METHODS: A decision model was developed to compare costs and outcomes associated with lowering cholesterol levels with no pharmacologic treatment and normal diet, no pharmacologic treatment plus >=3 g/d of oat beta glucan, and statin therapy plus >=3 g/d of oat beta-glucan. The population comprised men 45, 55, or 65 years of age with no history of cardiovascular disease and a 10-year risk for CHD of 5%, 7.5%, or 10%. Clinical efficacy data were gathered from meta-analyses; safety data, costs, and utilities were gathered from published literature. Cost per quality-adjusted life years and number of first events were reported. FINDINGS: Maintaining >=3 g/d of beta-glucan may be cost-effective in men aged 45, 55, and 65 years with 10-year CHD risks of 5.0%, 7.5%, and 10.0% taking no pharmacologic treatment or on statins. It may also reduce first events of myocardial infarction and CHD death. Results are sensitive to oat beta-glucan cost but insensitive to changes in other parameters. Maintaining >=3 g of oat beta-glucan daily remains cost-effective within plausible range of values. IMPLICATIONS: beta-glucan may be cost-effective for preventing CHD events in middle-aged men with no history of cardiovascular events whose 10-year CHD risk is >=5%. Maintaining daily beta-glucan intake may have considerable impact on first events. PMID- 28347514 TI - Use of Lipid-modifying Therapy and LDL-C Goal Attainment in a High-Cardiovascular Risk Population in the Netherlands. AB - PURPOSE: This study investigates lipid-modifying therapy (LMT) and LDL-C goal attainment in a real-world, high-cardiovascular-risk population in the Netherlands. METHODS: From the PHARMO Database Network, patients aged >=18 years with an LDL-C measurement in 2012 (index date) were selected and hierarchically classified into the following mutually exclusive high-cardiovascular-risk categories: familial hypercholesterolemia (FH), recent acute coronary syndrome (ACS), coronary heart disease, ischemic stroke, peripheral arterial disease, and diabetes mellitus. LMT use and LDL-C goal attainment at the index date was assessed. FINDINGS: Of 61 839 patients who met the inclusion criteria, 1132 (2%) had FH, 2431 (4%) had recent ACS, 6292 (10%) had coronary heart disease, 2868 (5%) had ischemic stroke, 3017 (5%) had peripheral arterial disease, and 46 099 (75%) had diabetes mellitus. Overall, 67% of patients were receiving LMT. Use of LMT ranged from 77% for recent ACS to 53% for FH, and standard-potency statins were the most prescribed. The percentage attaining an LDL-C goal of <100 mg/dL was 55%, ranging from 23% (FH) to 58% (recent ACS). Among LMT users, 69% taking high-potency statins, 70% taking standard-potency statins, and 20% receiving nonstatin LMTs attained an LDL-C goal of <100 mg/dL. IMPLICATIONS: LMT use among high-cardiovascular-risk patients was modest, which contributed to 46% of the cohort failing to reach LDL-C goals <100 mg/dL. Underuse and suboptimal use of LMTs in this cohort represent opportunities for quality improvement programs aimed at reducing the risk of cardiovascular events. PMID- 28347515 TI - An immobilized titanium (IV) ion affinity chromatography adsorbent for solid phase extraction of phosphopeptides for phosphoproteome analysis. AB - In this study, we developed a centrifugation assisted solid phase extraction (SPE) method for the selective enrichment of phosphopeptides using a new Ti4+ IMAC material synthesized in-house. This new material has the feature of big size and large specific surface area which makes it more suitable to enrich phosphopeptides in a SPE way. The spin tips loaded with the Ti4+-IMAC material were applied to enrich phosphopeptides from the complex protein digests. It was found that phosphopeptides can be specifically enriched from tryptic digest of bovine serum albumin and beta-casein at a molar ratio up to 1000:1. And about 4700 unique phosphorylated peptides can be identified with the specificity as high as 99% from the tryptic digest of HeLa cell proteins. This tip was demonstrated to have good column-to-column reproducibility. Furthermore, it is fitted to analyze minute amount of sample. Compared with the conventional solution method, the SPE method facilitated the rapid and complete separation of the material with solution, which making it a time-saving and convenient method for phosphopeptide enrichment. Compared with the commercial TiO2 material, this new materials yielded much more phosphopeptide identifications and much higher enrichment specificity. PMID- 28347516 TI - Aqueous and non-aqueous microchip electrophoresis with on-chip electrospray ionization mass spectrometry on replica-molded thiol-ene microfluidic devices. AB - This work describes aqueous and non-aqueous capillary electrophoresis on thiol ene-based microfluidic separation devices that feature fully integrated and sharp electrospray ionization (ESI) emitters. The chip fabrication is based on simple and low-cost replica-molding of thiol-ene polymers under standard laboratory conditions. The mechanical rigidity and the stability of the materials against organic solvents, acids and bases could be tuned by adjusting the respective stoichiometric ratio of the thiol and allyl ("ene") monomers, which allowed us to carry out electrophoresis separation in both aqueous and non-aqueous (methanol- and ethanol-based) background electrolytes. The stability of the ESI signal was generally <=10% RSD for all emitters. The respective migration time repeatabilities in aqueous and non-aqueous background electrolytes were below 3 and 14% RSD (n=4-6, with internal standard). The analytical performance of the developed thiol-ene microdevices was shown in mass spectrometry (MS) based analysis of peptides, proteins, and small molecules. The theoretical plate numbers were the highest (1.2-2.4*104m-1) in ethanol-based background electrolytes. The ionization efficiency also increased under non-aqueous conditions compared to aqueous background electrolytes. The results show that replica-molding of thiol-enes is a feasible approach for producing ESI microdevices that perform in a stable manner in both aqueous and non-aqueous electrophoresis. PMID- 28347517 TI - Ion-imprinted magnetic nanoparticles for specific separation and concentration of ultra-trace methyl mercury from aqueous sample. AB - For rapidly and sensitively determining ultra-trace methyl mercury (MeHg) in aqueous environment, we herein synthesized a MeHg ion-imprinted magnetic nanoparticle (MeHg IIMN) to simply and specifically extract/concentrate ultra trace MeHg from water samples. The MeHg IIMN employed core-shell Fe3O4@SiO2 nanoparticles (Fe3O4@SiO2 NPs) as supporting structure, the complex ion of 1 pyrrolidinecarbodithioic acid and MeHg (PDC-CH3Hg+) as template, methacrylic acid (MAA) as functional monomer and trimethylolpropane trimethacrylate (TMPTM) as cross linker. The MeHg IIMN offered obvious advantages such as low cost, easy manipulation, better specificity and stability, and recycling characteristics. It can be used to separate/concentrate ultra-trace MeHg from natural water sample within 30min with a recovery >95%, an enrichment factor of 250, a relative standard deviation (RSD, n=5) <7%, a 25mg MeHg/g of maximum adsorption capacity, 50 times of recycling, and without obvious interference of other ions. Combining with capillary electrophoresis-inductively coupled plasma mass spectrometry (CE ICP-MS), it can be used for the accurate detection of ultra-trace methyl mercury in natural water samples with a limit of detection of 0.084pg/mL, a recovery of 92-99% and a RSD (n=5)<8%. The success of this study promises a valuable technique for relatively simple detection of ultra-trace methyl mercury in aqueous environment. PMID- 28347518 TI - Semi-automated screen for global protein conformational changes in solution by ion mobility spectrometry-massspectrometry combined with size-exclusion chromatography and differential hydrogen-deuterium exchange. AB - Development of methodologies for studying protein higher-order structure in solution helps to establish a better understanding of the intrinsic link between protein conformational structure and biological function and activity. The goal of this study was to demonstrate a simultaneous screening approach for global protein conformational changes in solution through the combination of ion mobility spectrometry-mass spectrometry (IMS-MS) with differential hydrogen deuterium exchange (DeltaHDX) on the size-exclusion chromatography (SEC) platform in a single on-line workflow. A semi-automated experimental setup based on the use of SEC on-column conditions allowed for tracking of protein conformational changes in solution as a function of acetonitrile concentration. In this setup, the SEC protein elution data was complemented by the DeltaHDX profile which showed global protein conformational changes as a difference in the number of deuterons exchanged to protons. The DeltaHDX data, in turn, was complemented by the changes in the drift time by IMS-MS. All three orthogonal techniques were applied for studying global higher-order structure of the proteins ubiquitin, cytochrome c and myoglobin, in solution simultaneously. The described approach allows for the use of a crude sample (or mixture of proteins) and could be suitable for rapid comparison of protein batch-to-batch higher-order structure or for optimizing conditions for enzymatic reactions. PMID- 28347519 TI - Meta-analyses of the sensitivity and specificity of ante-mortem and post-mortem diagnostic tests for bovine tuberculosis in the UK and Ireland. AB - Bovine Tuberculosis (bTB) in cattle is a global health problem and eradication of the disease requires accurate estimates of diagnostic test performance to optimize their efficiency. The objective of this study was, through statistical meta-analyses, to obtain estimates of sensitivity (Se) and specificity (Sp), for 14 different ante-mortem and post-mortem diagnostic tests for bTB in cattle. Using data from a systematic review of the scientific literature (published 1934 2009) diagnostic Se and Sp were estimated using Bayesian logistic regression models adjusting for confounding factors. Random effect terms were used to account for unexplained heterogeneity. Parameters in the models were implemented using Markov Chain Monte Carlo (MCMC), and posterior distributions for the diagnostic parameters with adjustment for covariates (confounding factors) were obtained using the inverse logit function. Estimates for Se and/or Sp of the tuberculin skin tests and the IFN-gamma blood test were compared with estimates published 2010-2015. Median Se for the single intradermal comparative cervical tuberculin skin (SICCT) test (standard interpretation) was 0.50 and Bayesian credible intervals (CrI) were wide (95% CrI 0.26, 0.78). Median Sp for the SICCT test was 1.00 (95% CrI 0.99, 1.00). Estimates for the IFN-gamma blood test Bovine Purified Protein Derivative (PPD)-Avian PPD and Early Secreted Antigen target 6 and Culture Filtrate Protein 10 (ESAT-6/CFP10) ESAT6/CFP10 were 0.67 (95% CrI 0.49, 0.82) and 0.78 (95% CrI 0.60, 0.90) respectively for Se, and 0.98 (95% CrI 0.96, 0.99) and 0.99 (95% CrI 0.99, 1.00) for Sp. The study provides an overview of the accuracy of a range of contemporary diagnostic tests for bTB in cattle. Better understanding of diagnostic test performance is essential for the design of effective control strategies and their evaluation. PMID- 28347520 TI - "Some of them shut the door with a single word, but she was different" - A migrant patient's culture, a physician's narrative humility and a researcher's bias. PMID- 28347521 TI - [Detection and early treatment of subjects at high risk of clinical psychosis: Definitions and recommendations]. AB - In children and adolescents, psychotic disorders already represent one of the leading causes of disability-adjusted life years. During the past two decades, early detection of risk for psychosis has been intensively investigated, and in particular, predictive power for early signs of risk has been initiated and translated into clinical practice. In particular, the attenuated and transient positive symptoms of the ultra-high risk criteria, and the basic symptom criterion "cognitive disturbances", open promising routes to an indicated prevention and have recently been considered by the European Psychiatric Association (EPA) as diagnostic criteria of a psychosis-risk syndrome. The EPA recently provided evidence-based recommendations on the early detection of clinical high risk (CHR) for psychosis in patients with mental distress. In 2015, experts in the field of early detection conducted a meta-analysis reporting on studies examining conversion rates to psychosis in non-overlapping samples meeting at least one of the main CHR criteria: ultra-high risk (UHR) and/or basic symptoms criteria, examining the effects of potential moderators (different UHR criteria definitions, single UHR criteria and age) on conversion rates. In the 42 identified samples, comprising more than 4000 CHR patients who had been mainly identified by means of UHR criteria and/or the basic symptom criterion 'cognitive disturbances' (COGDIS), conversion rates showed considerable heterogeneity. While UHR and COGDIS criteria were related to comparable conversion rates until a 2 year follow-up, rates for COGDIS were significantly higher for follow-up periods beyond 2 years. Differences in onset and frequency requirements of symptomatic UHR criteria, or in their different consideration of functional decline, substance use and co-morbidity, did not seem to have an impact on conversion rates. The 'genetic risk and functional decline' UHR criterion was rarely met and only showed an insignificant pooled sample effect. However, age significantly affected UHR conversion rates with lower rates in children and adolescents. Although more research into potential sources of heterogeneity in conversion rates is needed to facilitate improvement of CHR criteria, six evidence-based recommendations for the early detection of psychosis were developed as a basis for the EPA guidance on early intervention in CHR states. The EPA guidance on early intervention aimed to provide evidence-based recommendations on early intervention in CHR states of psychosis, assessed according to the EPA guidance on early detection. The recommendations were also made by experts in the field of early intervention in psychoses and derived from a meta-analysis of current empirical evidence on the efficacy of psychological and pharmacological interventions in CHR samples. Eligible studies had to investigate conversion rate and/or functioning as a treatment outcome in CHR patients defined by the ultra high risk and/or basic symptom criteria. In addition to analyses of treatment effects on conversion rate and functional outcome, age and type of intervention were examined as potential moderators. Based on data from 15 studies (n=1394), early intervention generally produced significantly reduced conversion rates at 6 to 48-month follow-up compared to control conditions. However, early intervention failed to achieve significantly greater functional improvements because both early intervention and control conditions produced similar positive effects. With regard to the type of intervention, both psychological and pharmacological interventions produced significant effects on conversion rates but not on functional outcome relative to the control conditions. Early intervention in youth samples was generally less effective than in predominantly adult samples. Seven evidence-based recommendations for early intervention in CHR samples have been formulated, although more studies are needed to investigate the specificity of treatment effects and potential age effects in order to tailor interventions to the individual treatment needs and risk status. Overall, age related specificities and developmental transitions in the early detection and intervention in psychoses should be better accounted for in future research. PMID- 28347522 TI - Keep calm and carry on: Mental disorder is not more "organic" than any other medical condition. AB - Psychiatry as a discipline should no longer be grounded in the dualistic opposition between organic and mental disorders. This non-dualistic position refusing the partition along functional versus organic lines is in line with Jean Delay, and with Robert Spitzer who wanted to include in the definition of mental disorder discussed by the DSM-III task force the statement that "mental disorders are a subset of medical disorders". However, it is interesting to note that Spitzer and colleagues ingeniously introduced the definition of "mental disorder" in the DSM-III in the following statement: "there is no satisfactory definition that specifies precise boundaries for the concept "mental disorder" (also true for such concepts as physical disorder and mental and physical health)". Indeed, as for "mental disorders", it is as difficult to define what they are as it is to define what constitutes a "physical disorder". The problem is not the words "mental" or "organic" but the word "disorder". In this line, Wakefield has proposed a useful "harmful dysfunction" analysis of mental disorder. They raise the issue of the dualistic opposition between organic and mental disorders, and situate the debate rather between the biological/physiological and the social. The paper provides a brief analysis of this shift on the question of what is a mental disorder, and demonstrates that a mental disorder is not more "organic" than any other medical condition. While establishing a dichotomy between organic and psychiatry is no longer intellectually tenable, the solution is not to reduce psychiatric and non-psychiatric disorders to the level of "organic disorders" but rather to continue to adopt both a critical and clinically pertinent approach to what constitutes a "disorder" in medicine. PMID- 28347523 TI - [Early detection of mental health disorders at school: The Fil Harmonie pilot program]. AB - OBJECTIVE: Most psychiatric disorders arise during adolescence, a period of life during which school takes an important place. School in France has an official mission of health education and prevention, and early detection of mental disorders is part of these goals. The aim of this study is to describe an innovative service operating in Paris that helps educational staff to deal with students having psychological or psychiatric symptoms. The Fil Harmonie program was launched in 2011. It consists of a telephone line available to all educational staff working for high schools in Paris. METHODS: When in need of assistance, a member of the educational staff can call the dedicated hotline and expose the situation of their student to a trained psychologist. Over the course of the study, data concerning these phone calls were collected such as: socio demographic characteristics of the student, the reason behind the call, the caller's professional role within the school, and care pathway information. All data collected during the phone calls were anonymized and computerized. We performed an observational descriptive study based on this data by using mixed methods: we integrated quantitative analysis and qualitative research in order to provide a better understanding of the Fil Harmonie program. RESULTS: Between 18 September 2013 and 12 May 2014, the Fil Harmonie program handled 68 calls from educational staff. Students concerned by the calls were aged between 11 and 22 and the average age was 17.3 years. Over half (52.5%) of the pupils concerned had never seen a mental health professional before the call. In more than 70% of cases, the caller was a school nurse while other professionals such as teachers or headmasters represented only a minority of the callers. Approximately two thirds (67.2%) of students were described by the caller as socially isolated and 48.2% were described as sad or anhedonic. One out of four (26.7%) had repeated a school year at least once, and 55.9% of young people for whom a member of staff contacted Fil Harmonie had been missing class. In 56.7% of cases, there had been no contact with the student's family about the psychological situation. The qualitative analysis particularly highlighted the complexity of the collaboration between the family and the educational staff. CONCLUSION: Schooling is an important opportunity to seize in mental health regarding early detection and access to care. By fostering collaboration between educational professionals and mental health services, Fil Harmonie meets a public health objective of prevention and should contribute to the reduction of care delays thus leading to better treatment outcome. Our study shows that such programs are feasible and answer a real need in our current health care system. PMID- 28347524 TI - [The pain-emotion: Advocating pain as an emotion]. AB - OBJECTIVES: Pain is a common experience, both physical and emotional. However we often feel powerless with our patients suffering pain. This paper aims to give a new heuristic and psychological understanding of pain. METHODOLOGY: According to new theories, recent researches as well as different points of view, we form an analogy between pain and emotion. Throughout historical considerations pain has always been perceived through theories and beliefs, changing its definition. This is also the case for emotion. Could they be two ways of expressing a single phenomenon? RESULTS: First, we must clarify the definition of emotion. In past, emotion was considered as a multiple-conditioned notion. To be considered as an emotion the pain had to fill numerous features, which differ according to the scientific opinions. The emotion may be considered as a physical expression or perceived only as the consequences of a real emotion, i.e., the subjective feeling. We propose as a way of thinking that emotion brings together these two concepts. We support a flexible vision of emotion. To investigate the field of the emotion different mental steps may be thought of: we should conceive of the emotion as a stimulus, as an emotional evaluation and as a tendency to action, which becomes an emotional response. These steps are colored by subjective feelings. It can be summarized in three levels: the situation decoding (1), the response organization (2) and the effectiveness of the response (3). Second pain can be considered as a complex notion involving personal and subjective feelings. We can use multidimensional patterns and consider emotion with its multiple features: the generating mechanisms, the pain perception, the pain behavior and the environment. Each stage can be divided in different ways. Hence pain treatment could be approached as an emotional treatment. Indeed, we can make a link between generating mechanisms and emotion situation decoding, between pain perception and emotion situation decoding and response organization, between pain behavior and environment and emotion response effectiveness and consequences. A heuristic analogy can be formed enriching therapeutic possibilities. First, emotion and pain could be considered as a unique phenomenon that can be expressed in different ways. We can let aside the opposition between psychological and physiological: these are two different levels of a same phenomenon. This point of view can be helpful to treat pain disorders because the skills to manage emotion disorders are well known. PMID- 28347525 TI - Tumor regression grade and survival after neoadjuvant treatment in gastro esophageal cancer: A meta-analysis of 17 published studies. AB - INTRODUCTION: Major pathologic regression after neoadjuvant therapy is a strong and favorable prognostic factor in several types of cancer (breast, rectal and bladder). This information is less clear and has yet to be systematically evaluated in upper gastrointestinal tumors. We performed a meta-analysis to evaluate the prognostic impact of tumor regression after preoperative therapy on disease-free survival (DFS) and overall survival (OS) in gastro-esophageal cancer patients. METHODS: we searched for relevant articles in PubMed, SCOPUS, Web of Science, CINAHL, LILACS, Ovid, Cochrane Library, Google Scholar and Embase up to June 2, 2016. Data of tumor regression (complete or near-complete pathologic response) that independently correlated with OS and DFS in multivariate analysis were extracted, and the proper hazard ratios (HRs) with corresponding 95% confidence intervals (95% CIs) were pooled according to the random effect model. RESULTS: a total of 17 studies-which included 3145 patients-were considered in the final analysis. Major pathologic response was significantly related with better OS (HR 0.46, 95% CI 0.32-0.66, P < 0.001) and DFS (HR = 0.40, 95% CI 0.26 0.62, P < 0.001). Pathologic complete response (pCR) or major tumor regression were associated with the same degree of benefit in outcome compared to no or minimal pathologic regression, regardless of histology. CONCLUSION: major pathologic response is associated with a significant improvement in OS compared to no response or minor pathologic changes after neoadjuvant therapy in gastro esophageal cancers. This should be considered a robust prognostic factor to guide postoperative treatment and follow-up. PMID- 28347526 TI - The role of imaging in the preoperative assessment of children with inflammatory colitis. AB - BACKGROUND: Accurate diagnosis of Crohn's disease or ulcerative colitis is essential for surgical planning. This study compared the accuracy, safety, and utility of small bowel follow-through (SBFT) and magnetic resonance enterography (MRE) for detecting small bowel (SB) involvement preoperatively. METHODS: A retrospective review of children who underwent colectomy for inflammatory bowel disease (2000-2014) was performed. Preoperative SBFT and MRE were independently reviewed by two radiologists blinded to clinical data. Gold standard for diagnosis was surgical pathology. RESULTS: 68 patients (36 female) were included. 45 patients had SBFT prior to colectomy, 17 patients had MRE, and 6 both. Interrater reliability for radiologic interpretation was 90% (SBFT) and 91% (MRE). Mean study durations were 190min (SBFT) and 59min (MRE). Median effective dose for SBFT was 1.5mSv, while MRE involved no ionizing radiation. Specificities for diagnosing SB involvement were 87.5% (SBFT) and 94% (MRE). 54 patients underwent subtotal colectomy and ileostomy, 12 restorative proctocolectomy, and 2 colectomy with ileorectal anastomosis. Preoperative imaging correlated with surgical pathology in 83% (SBFT) and 90% (MRE). CONCLUSION: MRE is at least as effective as SBFT for assessing SB disease in children with colitis prior to colectomy. MRE requires less time and does not expose children to ionizing radiation. Retrospective Case Series, Level 4 Evidence. PMID- 28347527 TI - Thyroid neoplasms: incidental findings on extent of disease evaluation CT for other pediatric malignancies. AB - PURPOSE: We performed a retrospective analysis to evaluate the risk of thyroid cancer in incidental thyroid nodules (ITNs) discovered on CT in patients with a history of pediatric cancer. METHODS: With IRB approval we reviewed the records of pediatric oncology patients age <=21y with newly detected thyroid nodules on surveillance CT of the neck, chest, chest/abdomen/pelvis, or PET/CT performed between April 2008 and March 2015. Patients with <6months of follow-up after incidental findings, a history of primary thyroid malignancy, or incomplete records were excluded. RESULTS: The final cohort (N=68) included 35 females and 33 males (mean age 16.0+/-4.3[SD] years) with a mean follow-up time of 3.7+/ 1.9[SD] years after CT detection of ITN(s). Twenty patients (29.4%) received a follow-up thyroid ultrasound, eleven (16.2%) of whom underwent fine needle aspiration (FNA) for cytopathologic diagnosis. Among these, six (8.8%) underwent thyroid resection, with final pathology demonstrating papillary carcinoma in five (7.4%) and benign pathology in one. CONCLUSIONS: Despite the low incidence of thyroid nodules and low risk of thyroid malignancy in the general pediatric population, we found a significant rate of malignancy in CT-detected ITNs in our pediatric oncology patients, and recommend ultrasound and FNA of these nodules in this high-risk population. LEVEL OF EVIDENCE: Level IV, retrospective study with no comparison group. PMID- 28347528 TI - Vascular invasion is a prognostic indicator in hepatoblastoma. AB - INTRODUCTION: The data regarding vascular invasion as a prognostic factor in hepatoblastoma (HB) are conflicted. The purpose of this study is to examine the relationship between vascular invasion and outcomes. METHODS: This is a retrospective review of patients <18 years old who underwent resection for hepatoblastoma from 1998 to 2015. Pathology reports were used to identify patients who had pathologic vascular invasion (VI), and those who did not (NVI). RESULTS: Sixty-six children were identified with a median age at diagnosis of 21months (interquartile range: 10-33months). Pathologic vascular invasion was present in 42/66 (64%) patients. A significant difference (P=0.02) in 3-year overall survival (3YOS) was detected between NVI (95%) and VI (61%). Recurrent disease was present in 8/66 (12%) patients. A marginally significant difference (P=0.08) was found in 3-year recurrence free survival (3YRFS) between NVI (94%) and the VI (76%) groups. Patients with NVI had no metastatic disease, had a lower recurrence rate, universally responded to neoadjuvant chemotherapy, and were less likely to have small cell undifferentiated histology. Twenty-one children underwent orthotopic liver transplant (OLT), with no difference in 3YROS or 3YRFS. CONCLUSION: Pathologic vascular invasion is associated with significantly worse 3YOS in HB, and lack of vascular invasion was associated with more favorable disease characteristics. The presence of pathologic vascular invasion did not confer a worse outcome in patients treated with liver transplantation in this cohort of patients. TYPE OF STUDY: Retrospective review. LEVEL OF EVIDENCE: Level III. PMID- 28347529 TI - Resource savings and outcomes associated with outpatient laparoscopic appendectomy for nonperforated appendicitis. AB - BACKGROUND: Postoperative admission for acute appendicitis utilizes health care system resources. We evaluated outcomes and hospital charges for children with nonperforated appendicitis who underwent outpatient laparoscopic appendectomy. METHODS: A retrospective chart review was performed for patients <=18years old who underwent laparoscopic appendectomy for acute appendicitis in 2015. Patients were categorized into discharge from postanesthesia care unit (PACU) (outpatient), admission for <24-h, and admission for >24-h. Continuous variables were compared using analysis of variance and categorical variables were compared using chi-square test, with p<0.05 considered significant. RESULTS: Of the 171 patients identified, 63 (37%) were discharged from the PACU, 94 (55%) were admitted <24-h, and 14 (8%) were admitted >24-h. There were no differences in postoperative emergency department/clinic visits, complications, or readmissions. Hospital charges for admission <24-h and >24-h were $1007 and $2237 more per patient than the PACU-discharge group, respectively. Outpatient laparoscopic appendectomies became more common over time, occurring in only 20% of patients with acute appendicitis in the first quarter of the year versus 49% of patients in the last quarter. CONCLUSION: Outpatient laparoscopic appendectomy for nonperforated appendicitis in children is a safe practice that decreases length of stay and hospital charges. Adoption of an outpatient strategy allows for better standardization of care and can lead to savings in health care resources. LEVEL OF EVIDENCE: III (Treatment: retrospective comparative study). PMID- 28347530 TI - Upper gastrointestinal bleeding secondary to vigorous physical exercise. PMID- 28347532 TI - Lobectomy for Lung Cancer at Veterans Administration Medical Center Versus Academic Medical Center. AB - BACKGROUND: Hospital and surgeon volume each have an association with postoperative outcomes. The volume of lung cancer surgery at our Veterans Administration Medical Center (VAMC) is lower than at our academic medical center (AMC). We compared the outcomes after lobectomy at VAMC versus AMC to identify specific areas of clinical care requiring quality improvement. METHODS: To keep surgeon experience constant, data were derived from a prospective database from a single surgeon. Included were all male patients undergoing lobectomy for non small cell lung cancer. Postoperative morbidity, mortality, and overall survival were compared after propensity score matching. RESULTS: From 2004 to 2013, 419 patients were evaluated (338 AMC, 81 VAMC). Outcomes comparison after propensity score matching of 81 AMC patients with 81 VAMC patients found a higher rate of major complications (12% versus 27%, p = 0.02) and longer hospital stay (median 6.0 versus 7.5 days, p < 0.001) for VAMC, but no difference in 90-day mortality (AMC 5% versus VAMC 6%, p > 0.99). Pneumonia was the specific complication found to be higher at VAMC (11% versus AMC 1.2%, p = 0.01). There was no difference in 5-year overall survival for stage I disease (AMC 68% versus VAMC 69%, p = 0.95). CONCLUSIONS: Keeping surgeon experience constant, and after adjusting for patient factors, the rate of major complication after lobectomy is higher at VAMC. The difference is largely attributable to a higher rate of postoperative pneumonia at VAMC. Complications after pulmonary resection at VAMC could be reduced by implementing quality improvement initiatives aimed at reducing the rate of postoperative pneumonia. PMID- 28347531 TI - Ultrasound Stimulation of Insulin Release from Pancreatic Beta Cells as a Potential Novel Treatment for Type 2 Diabetes. AB - Type 2 diabetes mellitus is a complex metabolic disease that has reached epidemic proportions in the United States and around the world. This disease is characterized by loss of insulin secretion and, eventually, destruction of insulin-producing pancreatic beta cells. Controlling type 2 diabetes is often difficult as pharmacological management routinely requires complex therapy with multiple medications, and loses its effectiveness over time. The objective of this study was to explore the effectiveness of a novel, non-pharmacological approach that uses the application of ultrasound energy to augment insulin release from rat INS 832/13 beta cells. The cells were exposed to unfocused ultrasound for 5 min at a peak intensity of 1 W/cm2 and frequencies of 400 kHz, 600 kHz, 800 kHz and 1 MHz. Insulin release was measured with enzyme-linked immunosorbent assay and cell viability was assessed via the trypan blue dye exclusion test. A marked release (approximately 150 ng/106 cells, p < 0.05) of insulin was observed when beta cells were exposed to ultrasound at 400 and 600 kHz as compared with their initial control values; however, this release was accompanied by a substantial loss in cell viability. Ultrasound application at frequencies of 800 kHz resulted in 24 ng/106 cells released insulin (p < 0.05) as compared with its unstimulated base level, while retaining cell viability. Insulin release from beta cells caused by application of 800-kHz ultrasound was comparable to that reported by the secretagogue glucose, thus operating within physiological secretory capacity of these cells. Ultrasound has potential as a novel and alternative method to current approaches aimed at correcting secretory deficiencies in patients with type 2 diabetes. PMID- 28347533 TI - Influence of Drugs Carried in Lipid Nanoparticles in Coronary Disease of Rabbit Transplanted Heart. AB - BACKGROUND: Coronary allograft vasculopathy is an inflammatory-proliferative process that compromises the long-term success of heart transplantation and currently has no effective prevention and treatment. Lipid nanoparticles, termed LDE can carry chemotherapeutic agents in the circulation and concentrates them in the heart. METHODS: Twenty-eight rabbits fed a cholesterol-rich diet and submitted to heterotopic heart transplantation were treated with cyclosporine A (10 mg/kg daily) and allocated to four groups of 7 animals treated with intravenous LDE-methotrexate (MTX; 4 mg/kg weekly), with LDE-paclitaxel (PACLI; 4 mg/kg weekly), or with LDE-PACLI (4 mg/kg weekly) and LDE-MTX (4 mg/kg weekly). A control group was treated with only weekly intravenous saline solution. Animals were euthanized 6 weeks later for morphometric, histologic, immunohistochemical, and gene expression analysis of the graft and native hearts. RESULTS: Compared with controls, grafts of rabbits treated with LDE-PACLI showed 50% reduction of coronary stenosis, and in the LDE-MTX and LDE-MTX/PACLI stenosis was approximately 18% less than in control, but this difference was not statistically significant. In the three treatment groups, macrophage infiltration was decreased. In the LDE-MTX group, gene expression of proinflammatory factors tumor necrosis factor-alpha, monocyte chemoattractant protein 1, interleukin 18, vascular cellular adhesion molecule 1, and matrix metalloproteinase 12 was strongly diminished, whereas expression of antiinflammatory interleukin 10 increased. In the LDE-PACLI and LDE-PACLI/MTX groups, proinflammatory and antiinflammatory gene expressions were not consistently changed by the treatments. CONCLUSIONS: LDE-PACLI promoted strong improvement of cardiac allograft vasculopathy, but the decrease in coronary stenosis by LDE-MTX and LDE MTX/PACLI was not significant. All three treatments decreased macrophage infiltration in the graft. These results may encourage future clinical trials to test this new therapeutic approach to coronary allograft vasculopathy. PMID- 28347534 TI - Interstage Weight Gain Is Associated With Survival After First-Stage Single Ventricle Palliation. AB - BACKGROUND: Low birth and operative weight have been identified as risk factors for death after first-stage single-ventricle palliation. We hypothesize that weight gain after the first-stage operation is associated with transplant-free interstage survival to admission for the second-stage operation. METHODS: We used historical data from the National Pediatric Cardiology Quality Improvement Collaborative database to conduct a longitudinal study to assess the association between weight gain and transplant-free interstage survival. The primary predictor was weight gain. The primary outcome was transplant-free survival. We constructed a repeated-measures logistic regression model using the general estimating equation method to examine the association between weight gain and transplant-free interstage survival. RESULTS: The study population included 1,501 infants who were discharged alive from the first-stage single-ventricle palliation between June 2008 and January 2015. Patients who underwent a hybrid operation (n = 132) or were lost to follow-up (n = 11) were excluded. Transplant free interstage survival was 90% (1,228 of 1,358). The mean weight gain was 2.5 (SD, 1.0) kg. Adjusted for age at the time of each measurement, the number of measurements, age at discharge from the first-stage operation, sex, diagnosis, postoperative arrhythmia, postoperative complications, and discharge antibiotic therapy, each 100-g increase in weight was associated with an odds ratio of transplant-free interstage survival of 1.03 (95% confidence limit, 1.01, 1.05). CONCLUSIONS: After first-stage single-ventricle palliation, interstage weight gain is significantly associated with transplant-free interstage survival. PMID- 28347535 TI - Incidence and Predictors of Aggravation of Mitral Regurgitation After Atrial Septal Defect Closure. AB - BACKGROUND: The association between atrial septal defect (ASD) and mitral regurgitation (MR) is well known. However, data about the predictors of changes in MR after ASD closure are limited. The purpose of this study was to clarify the chronological changes in MR after ASD closure and the predictors of aggravation of MR. METHODS: In this single-center cohort study, we retrospectively investigated 129 consecutive adult patients (mean age, 53 +/- 14 years) who underwent surgical ASD closure between 1987 and 2014. The MR grade was qualitatively classified as none, mild, moderate, or severe by echocardiography. Aggravation of MR was defined as an increase by two or more grades after ASD closure. Clinical factors and echocardiographic and catheterization data were evaluated. RESULTS: The mean follow-up period was 77 months. Aggravation of MR after ASD closure occurred in 16 patients (12%). The rate of perioperative atrial fibrillation was higher (odds ratio, 5.89), the anterior mitral leaflet was thicker (odds ratio, 1.91), and the posterior mitral leaflet length was shorter (odds ratio, 1.58) in patients with aggravation of MR than in the remaining 113 patients. The mechanism of aggravated MR was poor coaptation associated with annular dilatation, thickened anterior mitral leaflet, and shortened posterior mitral leaflet. CONCLUSIONS: A thickened anterior mitral leaflet and shortened posterior mitral leaflet, combined with mitral annular dilation associated with atrial fibrillation and restored left ventricular geometry, may aggravate MR after ASD closure. Careful follow-up is needed for patients with atrial fibrillation, a thickened anterior mitral leaflet, or a shortened posterior mitral leaflet. PMID- 28347536 TI - Left Ventricular Unloading by Impella Device Versus Surgical Vent During Extracorporeal Life Support. AB - BACKGROUND: Patients supported with extracorporeal life support (ECLS) can experience severe complications from increased left ventricular (LV) afterload. The Impella (Abiomed, Danvers, MA) percutaneous ventricular assist device (PVAD) may offer an attractive option for unloading the LV in these patients. This study describes the efficacy and outcomes of PVAD use during ECLS compared with surgically placed LV vent. METHODS: In this retrospective study, we reviewed patients supported by ECLS with PVAD or surgical LV vent for cardiogenic shock between April 2010 and May 2016. Included were 23 patients with PVADs and 22 with surgical vents. Patients' baseline characteristics, hemodynamic data, and outcomes were collected immediately preceding combined support initiation, at 48 hours, intensive care unit discharge, and 30 days. RESULTS: After 48 hours, pulmonary artery diastolic pressure was significantly reduced in the PVAD (23.3 +/- 8.4 vs 15.6 +/- 4.2, p = 0.02) and surgical vent groups (20.1 +/- 5.9 vs 15.6 +/- 5.4, p = 0.01), and radiographic evidence of pulmonary edema was reduced or unchanged in 90% of PVAD patients and in 76% of surgical vent patients. The primary end points of survival to 30 days (43% vs 32%, p = 0.42) and intensive care unit discharge (35% vs 23%, p = 0.37) were not different between the two methods of support. The PVAD and surgical vent groups were also not significantly different in the rate of vascular complications or in the number decannulated from ECLS and transitioned to durable LV assist device. CONCLUSIONS: PVAD use in ECLS patients is an effective means of LV unloading and preventing worsened pulmonary edema, with outcomes and complications that are comparable to surgical LV vent. PMID- 28347537 TI - Relevance Between Programmed Death Ligand 1 and Radiologic Invasiveness in Pathologic Stage I Lung Adenocarcinoma. AB - BACKGROUND: Programmed death ligand 1 (PD-L1) was reported to predict the response of immunotherapy; however, the association between PD-L1 expression and radiologic and pathologic features has yet to be elucidated. METHODS: In all, 292 patients with resected pathologic stage I adenocarcinoma were analyzed for PD-L1 expression by immunohistochemistry and evaluated to determine the association between PD-L1 expression and the radiologic/pathologic invasiveness. Specifically, the radiologic invasiveness and noninvasiveness were determined based on the consolidation/tumor ratio, with a cutoff value of 0.25 by thin section computed tomography. RESULTS: Among 292 patients, 47 (16.1%) were positive for PD-L1 expression; the remaining 245 patients (83.9%) were negative for PD-L1 expression. Fisher's exact test demonstrated that PD-L1 expression was significantly associated with a higher consolidation/tumor ratio (p = 0.029) and higher maximum standardized uptake value (p = 0.004). The mean values of consolidation/tumor ratio and maximum standardized uptake in patients with and without PD-L1 expression were 0.845 +/- 0.052 and 7.241 +/- 0.795, and 0.607 +/- 0.023 and 3.60 +/- 0.364, respectively (p < 0.001 and p < 0.001, respectively). Among 47 adenocarcinomas harboring PD-L1 expression, the frequencies of PD-L1 expression for consolidation/tumor ratios of 0, 0.1 to 0.25, 0.26 to 0.5, and 0.51 or more were 6.4%, 2.1%, 4.3%, and 87.2%, respectively (p = 0.007). Pathologically, PD-L1 was identified exclusively only in more invasive subtypes, not in less invasive ones, such as atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant ones (p < 0.001). CONCLUSIONS: Expression of PD-L1 was significantly associated with radiologic/pathologic invasive adenocarcinomas. This study provides the first evidence of the radiologic and pathologic invasiveness in resected pathologic stage I adenocarcinoma with PD-L1 expression. PMID- 28347538 TI - Infant Motor Skills After a Cardiac Operation: The Need for Developmental Monitoring and Care. AB - BACKGROUND: Neurodevelopmental dysfunction is increasingly recognized as a common outcome of congenital heart defects and their treatment in infancy. The effects of the intensive care unit (ICU) experience and environment on these infants are unknown and potentially modifiable, but no validated metric is available for objective evaluation of early motor impairments in the ICU/hospital setting. The purpose of this study was to characterize the motor status of hospitalized infants after cardiac operations, including the development and field-testing of the Congenital Heart Assessment of Sensory and Motor Status (CHASMS) metric. METHODS: CHASMS item generation was based on review of the literature, focused interviews with parents, and expert consensus. A nurse administered CHASMS to 100 infants aged younger than 10 months old undergoing cardiac operations. Preoperative and postoperative CHASMS scores were compared, and associations between CHASMS scores and patient characteristics were examined. Physical therapists assessed neuromotor skills by using the Test of Infant Motor Performance or the Alberta Infant Motor Scales for correlation with CHASMS scores. RESULTS: CHASMS gross motor scores declined postoperatively in 64% (25 of 39). Lower CHASMS scores, after adjusting for age, were associated with longer duration of mechanical ventilation (p < 0.001) and ICU length of stay (p = 0.001). Gross motor CHASMS scores were significantly correlated with Test of Infant Motor Performance (r = 0.70, p < 0.001) and Alberta Infant Motor Scales scores (r = 0.88, p < 0.001). CONCLUSIONS: Motor impairments in infants after cardiac operations are common and may be exacerbated by longer intubation and prolonged exposure to the ICU environment. The feasibility, reliability, and validity of CHASMS were supported for the evaluation of motor skills in this at risk population. PMID- 28347540 TI - Study on Perioperative Administration of a Neutrophil Elastase Inhibitor for Interstitial Pneumonias. AB - BACKGROUND: Although acute exacerbation of idiopathic interstitial pneumonias (IIPs) is a lethal complication after pulmonary resection for lung cancer with IIPs, there are no established methods to prevent its occurrence. This prospective randomized study was conducted to evaluate whether perioperative administration of the neutrophil elastase inhibitor sivelestat prevents acute exacerbation after surgery. METHODS: The IIP patients with suspected lung cancers were randomly assigned to two groups before surgery: in group A (n = 65), sivelestat was perioperatively administered for 5 days; in group B (n = 65), no medications were administered. The primary endpoint was the frequency of acute exacerbation of IIPs. The secondary endpoints were perioperative changes in the lactate dehydrogenase, C-reactive protein, sialylated carbohydrate antigen, surfactant protein D and surfactant protein A values, and the safety of preoperative administration of sivelestat. Multivariate analyses were performed using a logistic regression model to identify the factors that predicted acute exacerbation. RESULTS: Acute exacerbation developed in 2 patients in group A and 1 patient in group B (p = 0.559). Administration of sivelestat did not contribute to decreasing the acute exacerbation as well as short- and long-term mortality. The differences were not statistically significant in perioperative lactate dehydrogenase, C-reactive protein, sialylated carbohydrate antigen, and surfactant protein D and A levels. No subjective adverse events were observed. A preoperative partial pressure oxygen level of less than 70 mm Hg was the only predictive factor identified in the logistic analysis (p = 0.019, hazard ratio 19.2). CONCLUSIONS: Perioperative administration of neutrophil elastase inhibitor appeared to be safe; however, it could not prevent the development of acute exacerbation after surgery in lung cancer patients with IIPs. PMID- 28347539 TI - A Novel Murine Model of Marfan Syndrome Accelerates Aortopathy and Cardiomyopathy. AB - BACKGROUND: Marfan syndrome (MFS) represents a genetic disorder with variable phenotypic expression. The main cardiovascular sequelae of MFS include aortic aneurysm/dissection and cardiomyopathy. Although significant advances in the understanding of transforming growth factor beta signaling have led to promising therapeutic targets for the treatment of aortopathy, clinical studies have tempered this optimism. In particular, these studies suggest additional signaling pathways that play a significant role in disease progression. To date, studies aimed at elucidating molecular mechanisms involved in MFS-induced disease progression have been hampered by the lack of an accelerated disease model. METHODS: Wild-type B6.129 mice and MFS Fbn1C1039G/+ mice underwent subcutaneous, cervical osmotic minipump installation with sodium chloride (wild-type mice, n = 39; MFS mice, n = 12) or angiotensin II, 4.5 mg/kg daily (wild-type mice, n = 11; MFS mice; n = 35) for as long as 28 days. Hemodynamic measurements were obtained throughout the experiment. Aortas and hearts were analyzed by transthoracic echocardiography and histopathology study. RESULTS: This accelerated murine MFS model replicates increased mortality from MFS-related maladies (20.0%, 39.3%, and 52.9% at 10, 14, and 28 days, respectively). Aortic diameters in accelerated MFS mice were significantly enlarged at 10 days after minipump implantation and correlated with a higher degree of elastin fragmentation. Accelerated MFS mice also demonstrated dilated cardiomyopathy at 14 days, even without aortic insufficiency, suggesting an intrinsic etiology. CONCLUSIONS: A novel in vivo model consisting of subcutaneously delivered angiotensin II in MFS mice reproducibly causes accelerated aortic aneurysm formation and cardiomyopathy. This model allows for better investigation of MFS sequelae by rapid experimental processes. PMID- 28347541 TI - Stroke Volume Ratio Predicts Redilatation of the Right Ventricle After Pulmonary Valve Replacement. AB - BACKGROUND: This study aimed to identify the prognostic value of the preoperative stroke volume ratio (right ventricular stroke volume/left ventricular stroke volume) for redilatation of the right ventricle after pulmonary valve replacement in patients with repaired tetralogy of Fallot. METHODS: From April 2004 to November 2013, 20 patients with repaired tetralogy of Fallot underwent pulmonary valve replacement for pulmonary valve regurgitation and right ventricular dilatation. Serial changes in ventricular volume were examined by cardiac magnetic resonance or computed tomography imaging. The redilatation ratio was calculated for right ventricular end-diastolic and end-systolic volume indices by dividing the increment in right ventricular volume from the first (median, 1.1 years) to the second (median, 3.2 years) evaluations after pulmonary valve replacement by the first evaluation. The relationships between the stroke volume ratio and redilatation ratio were assessed. The degree of right ventricular myocardial fibrosis was examined in 13 patients and compared with the stroke volume ratio. RESULTS: Right ventricular volume (redilatation) significantly increased from a median of 1.1 to 3.2 years after pulmonary valve replacement. Significant positive correlations were detected between the stroke volume ratio and redilatation ratio of the right ventricular end-diastolic (r = 0.50. p = 0.02) and end-systolic volume indices (r = 0.49, p = 0.03). The stroke volume ratio also showed a significant positive correlation with the degree of right ventricular myocardial fibrosis (r = 0.73, p = 0.005). CONCLUSIONS: The preoperative stroke volume ratio can predict redilatation of the right ventricle after pulmonary valve replacement and the degree of right ventricular myocardial fibrosis. PMID- 28347542 TI - Managing obesity in pregnancy - An obstetric and midwifery perspective. AB - Overweight and obesity during pregnancy and childbirth represent a significant health burden, placing women and their infants at increased risk of almost all documented adverse outcomes. Research efforts have focused on strategies to limit gestational weight gain, including dietary and lifestyle interventions, as well as the use of adjuvant therapies such as metformin. However, there remain many barriers to behavioural change for women during pregnancy, and current care recommendations largely reflect good clinical practice, rather than being based on strong evidence. PMID- 28347543 TI - Ondrej Krivanek: A pioneering visionary in electron microscopy. AB - This article is a short biographical sketch of the life and times of Ondrej Krivanek. The story starts with his early days in Prague, Czechia, and briefly outlines various events from a PhD in Cambridge to post-docs in Kyoto, Bell Labs, and building his first spectrometer at UC Berkeley. Ondrej's pioneering contributions to electron microscopy as Assistant Professor at Arizona State University and later as Director of R&D at Gatan are covered, as well as his return to academia and focusing on aberration correction. The story wraps up with the founding of Nion, the early success of the Nion aberration correctors, and subsequent progress such as building a complete cutting-edge electron microscope and later a record-breaking monochromator. Ondrej continues to be actively involved in design and in running Nion, and while this article ends at the present, further breakthroughs can be expected from him. PMID- 28347544 TI - Ocular involvement in atypical haemolytic uraemic syndrome. AB - CASE REPORT: The case is presented of a young man with an atypical haemolytic uraemic syndrome (aHUS), complicated with bilateral serous retinal detachment, cotton wool spots, and a branch artery occlusion. Treatment with plasmapheresis, haemodialysis and systemic eculizumab led to the blood and urine parameters returning to normal, as well as resolution of the retinal anomalies. Genetic analysis show both mutations in complement factor H and C3. DISCUSSION: Haemolytic-uraemic syndrome (HUS) is a thrombotic microangiopathy characterised by microangiopathic haemolytic anaemia, thrombocytopenia, and acute renal failure. Atypical HUS is caused by genetic mutation of complement system. Ocular involvement is an unusual manifestation of this rare syndrome. PMID- 28347545 TI - Intraocular tuberculosis. PMID- 28347546 TI - Burn-related peripheral neuropathy: A systematic review. AB - Peripheral neuropathy is the most frequent disabling neuromuscular complication of burns. However, the insidious and progressive onset of burn neuropathy makes it often undiagnosed or overlooked. In our study, we reviewed the current studies on the burn-related peripheral neuropathy to summarize the morbidity, mechanism, detecting method and management of peripheral neuropathy in burn patients. Of the 1533 burn patients included in our study, 98 cases (6.39%) were presented with peripheral neuropathy. Thermal and electrical burns were the most common etiologies. Surgical procedures, especially nerve decompression, showed good effect on functional recovery of both acute and delayed peripheral neuropathy in burn patients. It is noteworthy that, for early detection and prevention of peripheral neuropathy, electrodiagnostic examinations should be performed on burn patients independent of symptoms. Still, the underlying mechanisms of burn related peripheral neuropathy remain to be clarified. PMID- 28347547 TI - PACE4 is an important driver of ZR-75-1 estrogen receptor-positive breast cancer proliferation and tumor progression. AB - Breast cancer is the most frequent and deadly malignancy in women worldwide. Despite national screening programs combined with new treatments relapse rate remain high and new therapies are needed. From previous work, we identified PACE4, a member of the proprotein convertase (PCs) family of endoproteases, as a novel therapeutic target in prostate cancer. In the present study we asked the question if PACE4 could also be a potential target in breast cancer. In clinical samples of breast adenocarcinoma, we observed a specific overexpression of PACE4 in the estrogen-receptor (ER) positive subtype. We therefore looked for a breast cancer cell line model which would be representative and thus focused on the ZR 75-1 since it both expresses PACE4 and is estrogen-receptor positive. We compared stable knockdowns of furin, PACE4 and PC7 in the estrogen-receptor-positive cell line ZR-75-1 to evaluate their respective contribution to cell growth and tumor progression. PACE4 was the only PC displaying an impact on cell growth. A PACE4 peptide-based inhibitor (C23) was tested and shown to decrease proliferation of ZR-75-1 cells in cell based assays. C23 also had potent effects of tumor progression in vivo on xenografts of the ZR-75-1 cell line in athymic nude mice. Thus, PACE4-silencing and systemic administration of a PACE4 inhibitor resulted in hindered tumor progression with reduction in proliferative indices and increased cell quiescence assessed with biomarkers. Our results suggest that PACE4 is a promising target for estrogen-receptor-positive breast cancer. PMID- 28347548 TI - Rapid detection of enriched uranium in food. AB - We have developed a quadrupole ICP-MS method for detecting sub-picogram quantities of 235U in contaminated foods. Notable features included elimination of the requirement for possessing licensed nuclear materials so that non radiochemical laboratories may perform this analysis in the event of a large scale nuclear or radiological emergency calling for high sample surge capacity, elimination of several extremely hazardous reagents in sample analysis e.g. aqua regia and hydrofluoric acid, and the method was developed for applying a moderately priced, and widely used quadrupole inductively coupled plasma mass spectrometer (Q-ICP-MS). This method could be quickly implemented at many laboratories to increase emergency response capability. PMID- 28347549 TI - Idiopathic decreased bispectral index during anaesthesia emergence: Possible causes for the phenomenon of paradoxical arousal. AB - In a small percentage of patients, sound, touch and even nociceptive stimulation in the presence of a light anaesthetic depth does not cause an electroencephalogram wave pattern of cortical activation (alpha, beta waves) as would be expected, but leads to a slowed electroencephalogram pattern instead. We report the case of a patient who on emerging from anaesthesia showed very slowed brain activity on the electroencephalogram and reduced algorithmic value, that lasted approximately 5min coinciding with sound and tactile stimulation. After keeping her under observation for 24h during the postoperative period she did not present any brain disorder that could justify that event. PMID- 28347550 TI - Unexpected obstetric haemorrhage. Krukenberg tumour. AB - Obstetric haemorrhage can endanger the lives of mother and foetus. It often occurs unexpectedly without clear predictors. A high degree of suspicion helps to avoid delaying resuscitation measures. We present the case of a ruptured ovarian metastasis that occurred during labour. It caused a massive bleed forcing a caesarean section due to non-reassuring foetal status. This was an unprecedented and undescribed onset of Krukenberg tumour formation. Malignant tumours in pregnancy are rare and difficult to diagnose due to their clinical manifestations which often overlap with those of pregnancy itself (dyspepsia, nausea and bloating). Despite the available therapeutic measures, a delay in diagnosis is a determining factor for long-term prognosis. We review the causes of obstetric bleeding, and underline how rare Krukenberg tumours concomitant to pregnancy are. PMID- 28347551 TI - Multimodal analgesia and regional anaesthesia. AB - Multimodal analgesia provides quality analgesia, with fewer side effects due to the use of combined analgesics or analgesic techniques. Regional anaesthesia plays a fundamental role in achieving this goal. The different techniques of regional anaesthesia that include both peripheral and central blocks in either a single dose or in continuous infusion help to modulate the nociceptive stimuli that access the central level. The emergence of the ultrasound as an effective system to perform regional anaesthesia techniques has allowed the development of new regional anaesthesia techniques that formerly could not be carried out since only neurostimulation or skin references were used. It is essential to take into account that even with effective blocking it is advisable to associate other drugs by other routes, in this way we will be able to reduce the required doses individually and attempt to achieve a synergistic, not purely additive, effect. PMID- 28347552 TI - Learning outcomes evaluation of a simulation-based introductory course to anaesthesia. AB - OBJECTIVE: An increased number of errors and reduced patient safety have been reported during the incorporation of residents, as this period involves learning new skills. The objectives were to evaluate the learning outcomes of an immersive simulation boot-camp for incoming residents before starting the clinical rotations. Airway assessment, airway control with direct laryngoscopy, and epidural catheterization competencies were evaluated. MATERIAL AND METHOD: Twelve first-year anaesthesiology residents participated. A prospective study to evaluate transfer of endotracheal intubation skills learned at the simulation centre to clinical practice (primary outcome) was conducted. A checklist of 28 skills and behaviours was used to assess the first supervised intubation performed during anaesthesia induction in ASA I/II patients. Secondary outcome was self-efficacy to perform epidural catheterization. A satisfaction survey was also performed. RESULTS: Seventy-five percent of residents completed more than 21 out of 28 skills and behaviours to assess and control the airway during their first intubation in patients. Twelve items were performed by all residents and 5 by half of them. More than 83% of participants reported a high level of self efficacy in placing an epidural catheter. All participants would recommend the course to their colleagues. CONCLUSIONS: A focused intensive simulation-based boot-camp addressing key competencies required to begin anaesthesia residency was well received, and led to transfer of airway management skills learned to clinical settings when performing for first time on patients, and to increased self-reported efficacy in performing epidural catheterization. PMID- 28347553 TI - Patent haemostasis prevents radial artery occlusion in patients with an acute coronary syndrome. AB - BACKGROUND: A haemostatic technique that maintains radial artery flow ("patent haemostasis") following transradial catheterization reduces rates of radial artery occlusion (RAO) in patients with stable coronary disease. It is unclear whether this benefit extends to patients with an acute coronary syndrome (ACS). METHODS: Patients undergoing inpatient transradial catheterization for an ACS were prospectively enrolled in a consecutive cohort study (n=300). Radial haemostasis was obtained using standard radial compression (cohort 1; n=150) or patent haemostasis (cohort 2; n=150). An end-of-case activated clotting time (ACT) was recorded and radial artery patency assessed within 24 hours of sheath removal by reverse Barbeau's test. RESULTS: The incidence of RAO was 16.0% following standard radial compression and 5.3% following patent haemostasis (p=0.003). Univariate predictors of RAO were patent haemostasis (OR 0.30; [0.13 0.68], p=0.004), hyperlipidaemia (OR 0.46; [0.21-0.98], p=0.04), history of current smoking (OR 2.86; [1.3-6.0], p=0.015) and longer procedure times (OR 1.03/additional minute; [1.01-1.05], p=0.003). There was no association between the end-of-case ACT and RAO (OR 1.00; [0.9-1.01] p=1.00). After adjusting for covariates, patent haemostasis reduced the risk of RAO by 70% compared to standard compression (OR 0.30; [0.12-0.77], p=0.12). The c-statistic for model discrimination was 0.79 (95% CI [0.71-0.86], p<0.001). Inverse probability treatment weighted analysis also confirmed patent haemostasis as an independent predictor of reduced RAO (OR 0.38 [0.15-0.95], p=0.039). CONCLUSION: Patent haemostasis is highly effective in preventing early RAO in patients with ACS. PMID- 28347554 TI - Long-Term Mortality of Emergency Medical Services Patients. AB - STUDY OBJECTIVE: Emergency medical services (EMS) provides out-of-hospital care to patients with life-threatening conditions, but the long-term outcomes of EMS patients are unknown. We seek to determine the long-term mortality of EMS patients in Denmark. METHODS: We analyzed linked EMS, hospital, and vital status data from 3 of 5 geographic regions in Denmark. We included events from July 1, 2011, to December 31, 2012. We classified EMS events according to primary dispatch category (unconsciousness/cardiac arrest, accidents/trauma, chest pain, dyspnea, neurologic symptoms, and other EMS patients). The primary outcome was 1 year mortality adjusted for age, sex, and Charlson comorbidity index. RESULTS: Among 142,125 EMS events, primary dispatch categories were unconsciousness or cardiac arrest 5,563 (3.9%), accidents or trauma 40,784 (28.7%), chest pain 20,945 (14.7%), dyspnea 9,607 (6.8%), neurologic symptoms 17,804 (12.5%), and other EMS patients 47,422 (33.4%). One-year mortality rates were unconscious or cardiac arrest 54.7% (95% confidence interval [CI] 53.4% to 56.1%), accidents or trauma 7.8 (95% CI 7.5% to 8.1%), chest pain 8.5% (95% CI 8.1% to 9.0%), dyspnea 27.7% (95% CI 26.7% to 28.7%), neurologic symptoms 14.1% (95% CI 13.6% to 14.7%), and other EMS patients 11.1% (95% CI 10.8% to 11.4%). Compared with other EMS conditions, adjusted 1-year mortality was higher in unconsciousness or cardiac arrest (risk ratio [RR] 2.6; 95% CI 2.5 to 2.7), dyspnea (RR 1.5; 95% CI 1.4 to 1.5), and in neurologic symptoms (RR 1.1; 95% CI 1.0 to 1.1), but lower in chest pain (RR 0.6; 95% CI 0.6 to 0.7) and accidents or trauma (RR 0.8; 95% CI 0.8 to 0.8). CONCLUSION: EMS patients with unconsciousness or cardiac arrest, dyspnea, and neurologic symptoms are at highest risk of long-term mortality. Our results suggest a potential for outcome improvement in these patients. PMID- 28347555 TI - Update: D-dimer Test for Excluding the Diagnosis of Pulmonary Embolism. PMID- 28347556 TI - Paramedic Intubation Experience Is Associated With Successful Tube Placement but Not Cardiac Arrest Survival. AB - STUDY OBJECTIVE: Paramedic experience with intubation may be an important factor in skill performance and patient outcomes. Our objective is to examine the association between previous intubation experience and successful intubation. In a subcohort of out-of-hospital cardiac arrest cases, we also measure the association between patient survival and previous paramedic intubation experience. METHODS: We analyzed data from Ambulance Victoria electronic patient care records and the Victorian Ambulance Cardiac Arrest Registry for January 1, 2008, to September 26, 2014. For each patient case, we defined intubation experience as the number of intubations attempted by each paramedic in the previous 3 years. Using logistic regression, we estimated the association between intubation experience and (1) successful intubation and (2) first-pass success. In the out-of-hospital cardiac arrest cohort, we determined the association between previous intubation experience and patient survival. RESULTS: During the 6.7-year study period, 769 paramedics attempted intubation in 14,857 patients. Paramedics typically performed 3 intubations per year (interquartile range 1 to 6). Most intubations were successful (95%), including 80% on the first attempt. Previous intubation experience was associated with intubation success (odds ratio 1.04; 95% confidence interval 1.03 to 1.05) and intubation first-pass success (odds ratio 1.02; 95% confidence interval 1.01 to 1.03). In the out-of-hospital cardiac arrest subcohort (n=9,751), paramedic intubation experience was not associated with patient survival. CONCLUSION: Paramedics in this Australian cohort performed few intubations. Previous experience was associated with successful intubation. Among out-of-hospital cardiac arrest patients for whom intubation was attempted, previous paramedic intubation experience was not associated with patient survival. PMID- 28347557 TI - HIV Prevention and Treatment: The Evolving Role of the Emergency Department. AB - Historically, the role of the emergency physician in HIV care has been constrained to treating sick patients with opportunistic infections and postexposure prophylaxis for occupational exposures. However, advances in HIV care have led to medications that have substantially fewer issues with toxicity and resistance, opening up an exciting new opportunity for emergency physicians to participate in treating the HIV virus itself. With this new role, it is crucial that emergency physicians be familiar with the advances in testing and medications for HIV prevention and treatment. To our knowledge, to date there has not yet been an article addressing this expansion of practice. We have compiled a summary of what the emergency physician needs to know, including misconceptions associated with antiretroviral therapy, medication complexity, toxicity, resistance, and usability. Additionally, we review potential indications for prescribing these drugs in the emergency department, including the role of the emergency physician in postexposure prophylaxis, preexposure prophylaxis, and treatment of acute HIV, as well as how emergency physicians can engage with chronic HIV infection. PMID- 28347558 TI - Nursing home-acquired pneumonia, dysphagia and associated diseases in nursing home residents: A retrospective, cross-sectional study. AB - BACKGROUND: Nursing home-acquired pneumonia (NHAP) is a common infection among nursing home residents. There is also a high prevalence of dysphagia in nursing home residents and they suffer more often from comorbidity and multimorbidity. This puts nursing home residents at higher risk of (mortality from) NHAP. Therefore it is important to gain more insight into the incidence of NHAP and the associated medical conditions in nursing home residents with dysphagia. OBJECTIVE: To investigate possible associations between NHAP and dysphagia in nursing home residents and to search for a medical risk profile for NHAP. DESIGN: A retrospective cross-sectional study. SETTING: Three nursing homes in The Netherlands. PARTICIPANTS: 416 electronic medical files of nursing home residents aged 65 or older living in 3 nursing homes. METHODS: Data about age, gender, diagnosis of dysphagia and/or pneumonia, medical diagnosis and possible cause of death of the nursing home residents were extracted from electronic medical files. RESULTS: The data of 373 electronic medical files were analyzed. A significant difference in the prevalence of dysphagia was found between the nursing homes (p < 0.001). The incidence of NHAP was 5-12% in the participating nursing homes. Statistically significant higher incidence of NHAP was found in residents with dysphagia (p = 0.046). Residents with dysphagia had statistically significantly more diseases compared to residents without dysphagia (p = 0.001). Logistic regression analyses revealed no statistically significant associations between NHAP and the number of diseases and the ICD-10 diseases. CONCLUSIONS: Dysphagia was found to be a risk factor for NHAP. Awareness of the signs of dysphagia by nurses and other care providers is important for early recognition and management of dysphagia and prevention of NHAP. PMID- 28347559 TI - Characteristics of the Chinese rural elderly living in nursing homes who have suicidal ideation: A multiple regression model. AB - BACKGROUND: Chinese rural elderly are at higher risk of committing suicide. However, little is known about the suicidal ideation (SI) of institutional elderly residents in rural China. METHODS: 250 participants aged 60 or above living in Chinese rural nursing homes were recruited. Data were collected on subjects' SI, social-demographic characters, physical illness and psychological factors. Univariate comparisons and path analysis were conducted then. RESULTS: 19.5% (40/205) of the participants reported a current SI. Hopelessness and depression had significant direct impacts on SI, and self-esteem and loneliness can impact SI through the mediating of depression and hopelessness. Visiting frequency of children, number of physical illnesses and social activities can also affect SI through the mediating of loneliness or self-esteem. CONCLUSION: As the first study on path analysis of SI of rural institutional elderly, the findings are significant. All these factors in our model should be considered when interventions are being conducted. PMID- 28347560 TI - [Can dermoscopy be used in place of capillaroscopy?] PMID- 28347561 TI - [The value of reflectance confocal microscopy in detection of Demodex mites]. PMID- 28347562 TI - Automatic segmentation of liver tumors from multiphase contrast-enhanced CT images based on FCNs. AB - This paper presents a novel, fully automatic approach based on a fully convolutional network (FCN) for segmenting liver tumors from CT images. Specifically, we designed a multi-channel fully convolutional network (MC-FCN) to segment liver tumors from multiphase contrast-enhanced CT images. Because each phase of contrast-enhanced data provides distinct information on pathological features, we trained one network for each phase of the CT images and fused their high-layer features together. The proposed approach was validated on CT images taken from two databases: 3Dircadb and JDRD. In the case of 3Dircadb, using the FCN, the mean ratios of the volumetric overlap error (VOE), relative volume difference (RVD), average symmetric surface distance (ASD), root mean square symmetric surface distance (RMSD) and maximum symmetric surface distance (MSSD) were 15.6+/-4.3%, 5.8+/-3.5%, 2.0+/-0.9%, 2.9+/-1.5mm, 7.1+/-6.2mm, respectively. For JDRD, using the MC-FCN, the mean ratios of VOE, RVD, ASD, RMSD, and MSSD were 8.1+/-4.5%, 1.7+/-1.0%, 1.5+/-0.7%, 2.0+/-1.2mm, 5.2+/-6.4mm, respectively. The test results demonstrate that the MC-FCN model provides greater accuracy and robustness than previous methods. PMID- 28347563 TI - Structural and elemental characterization of traditional Indian Siddha formulation: Thalagak karuppu. AB - BACKGROUND: The traditional Indian medicine 'Siddha' uses metals, metalloids and minerals including toxic ones with no proven toxicity. Thalagak karuppu (TK) is remarkably stable over a century and used for treating Suram (Fever), Kaasam (Cough), Elai (Tuberculosis) and Eraippu Erumal (Bronchial Asthma). OBJECTIVE: The present study addresses elemental and morphological characterization of therapeutic Siddha formulation: Thalagak karuppu (TK). MATERIALS AND METHODS: TK was purchased from the Indian Medical Practitioners Co-operative Pharmacy and Stores (IMCOPS) Ltd, Chennai, Tamilnadu, India. The physicochemical properties were evaluated using UV-visible spectrophotometer, Fourier Transform Infrared Spectrometer (FTIR), Scanning Electron Microscope (SEM) with Energy Dispersive X ray analysis (EDX), Zeta sizer and X-ray diffractometer (XRD). RESULTS: The mixed nature of arsenic was analyzed using UV-visible spectroscopy. The fingerprint region for arsenic derivatives was inferred from IR spectroscopy and X-ray diffraction patterns. The shape and size heterogeneity in the anisotropic mixture was observed in SEM images and the polydispersity was analyzed by Zeta sizer. CONCLUSIONS: The structural, elemental and morphological analyses suggests that the arsenic may predominantly exist either as orpiment (As2S2) or realgar (As2S4) form. The possibility is less for the toxic arsenolite. Hence, the formulation may be considered safe. PMID- 28347564 TI - The gut microbiota metabolism of pomegranate or walnut ellagitannins yields two urolithin-metabotypes that correlate with cardiometabolic risk biomarkers: Comparison between normoweight, overweight-obesity and metabolic syndrome. AB - BACKGROUND & AIMS: Urolithins are microbial metabolites produced after consumption of ellagitannin-containing foods such as pomegranates and walnuts. Parallel to isoflavone-metabolizing phenotypes, ellagitannin-metabolizing phenotypes (urolithin metabotypes A, B and 0; UM-A, UM-B and UM-0, respectively) can vary among individuals depending on their body mass index (BMI), but correlations between urolithin metabotypes (UMs) and cardiometabolic risk (CMR) factors are unexplored. We investigated the association between UMs and CMR factors in individuals with different BMI and health status. METHODS: UM was identified using UPLC-ESI-qToF-MS in individuals consuming pomegranate or nuts. The associations between basal CMR factors and the urine urolithin metabolomic signature were explored in 20 healthy normoweight individuals consuming walnuts (30 g/d), 49 healthy overweight-obese individuals ingesting pomegranate extract (450 mg/d) and 25 metabolic syndrome (MetS) patients consuming nuts (15 g walnuts, 7.5 g-hazelnuts and 7.5 g-almonds/d). RESULTS: Correlations between CMR factors and urolithins were found in overweight-obese individuals. Urolithin-A (mostly present in UM-A) was positively correlated with apolipoprotein A-I (P <= 0.05) and intermediate-HDL-cholesterol (P <= 0.05) while urolithin-B and isourolithin-A (characteristic from UM-B) were positively correlated with total cholesterol, LDL-cholesterol (P <= 0.001), apolipoprotein B (P <= 0.01), VLDL cholesterol, IDL-cholesterol, oxidized-LDL and apolipoprotein B:apolipoprotein A I ratio (P <= 0.05). In MetS patients, urolithin-A only correlated inversely with glucose (P <= 0.05). Statin-treated MetS patients with UM-A showed a lipid profile similar to that of healthy normoweight individuals while a poor response to lipid-lowering therapy was observed in MB patients. CONCLUSIONS: UMs are potential CMR biomarkers. Overweight-obese individuals with UM-B are at increased risk of cardiometabolic disease, whereas urolithin-A production could protect against CMR factors. Further research is warranted to explore these associations in larger cohorts and whether the effect of lipid-lowering drugs or ellagitannin consumption on CMR biomarkers depends on individuals' UM. CLINICAL TRIAL REGISTRY NUMBERS AND WEBSITES: NCT01916239 (https://clinicaltrials.gov/ct2/show/NCT01916239) and ISRCTN36468613 (http://www.isrctn.com/ISRCTN36468613). PMID- 28347565 TI - Reply-Letter to the Editor-The lipid accumulation product is a powerful tool to predict metabolic syndrome in undiagnosed Brazilian adults. PMID- 28347566 TI - Hypercoagulable states: A role in ventricular assist device outcomes? PMID- 28347567 TI - Art and historical personages with probable Graves disease. PMID- 28347568 TI - How Can We Better Detect Unauthorized GMOs in Food and Feed Chains? AB - Current GMO detection systems have limited abilities to detect unauthorized genetically modified organisms (GMOs). Here, we propose a new workflow, based on next-generation sequencing (NGS) technology, to overcome this problem. In providing information about DNA sequences, this high-throughput workflow can distinguish authorized and unauthorized GMOs by strengthening the tools commonly used by enforcement laboratories with the help of NGS technology. In addition, thanks to its massive sequencing capacity, this workflow could be used to monitor GMOs present in the food and feed chain. In view of its potential implementation by enforcement laboratories, we discuss this innovative approach, its current limitations, and its sustainability of use over time. PMID- 28347569 TI - Predictors of 9-month hospitalization in patients with first-episode affective and non-affective psychosis. Results from the GET UP pragmatic cluster randomized controlled trial. PMID- 28347570 TI - Nonpharmacologic Strategies to Modulate Nuclear Factor Erythroid 2-related Factor 2 Pathway in Chronic Kidney Disease. AB - Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor with a high sensitivity to oxidative stress, which regulates the expression of detoxifying enzymes, besides that, can also control antioxidant and anti inflammatory cellular responses. Therefore, the modulation of this transcription factor can be a new therapeutic approach to reduce complications in chronic kidney disease (CKD) patients, like oxidative stress and inflammation, which leads to increased risk of developing cardiovascular disease, the major cause of death in these patients. Recent studies have shown that nutritional components and physical exercises can regulate the activation of Nrf2; however, very few studies were performed in CKD patients. This review provides an overview about some of the nonpharmacologic strategies that may promote the activation of Nrf2, which may have impact on the human health, particularly in CKD, by preventing oxidative stress and maintaining cellular redox homeostasis. PMID- 28347571 TI - Determination of therapeutic strategy for adhesive small bowel obstruction using water-soluble contrast agents: An audit of 776 cases in a single center. AB - BACKGROUND: Several studies have investigated the diagnostic and therapeutic role of water-soluble contrast agents in adhesive small bowel obstruction, but there is no clear diagnostic classification for the determination of therapeutic strategy. The aim of this study was to clarify the clinical value of classification using water-soluble contrast agents in patients with adhesive small bowel obstruction. METHODS: Between January 2009 and December 2015, 776 consecutive patients with adhesive small bowel obstruction were managed initially with water-soluble contrast agents and were included in the study. Abdominal x rays were taken 5 hours after administration of 100 mL water-soluble contrast agents and classified into 4 types. The medical records of the patients with adhesive small bowel obstruction were analyzed retrospectively and divided into 2 groups of patients with complete obstruction (ie, the absence of contrast agent in the colon) with (type I) or without (type II) a detectable point of obstruction and a group with an incomplete obstruction (ie, the presence of contrast agent in the colon) with (type IIIA) or without (type IIIB) dilated small intestine. RESULTS: Types I, II, IIIA, and IIIB were identified in 27, 90, 358, and 301 patients, respectively. The overall operative rate was 16.6%. In the patients treated conservatively (types IIIA and IIIB), 647 patients (98.2%) were treated successfully without operative intervention. The operative rate was 3.4% (n = 12/358) in type IIIA vs 0% (n = 0/301) in the type IIIB group (P = .001). Compared with type IIIA, type IIIB was associated with earlier initiation of oral intake (2.1 vs 2.6 days, P < .001) and a lesser hospital stays (9 vs 11 days, P < .001). CONCLUSION: This new classification using water-soluble contrast agents is a simple and useful diagnostic method for the determination of therapeutic strategy for adhesive small bowel obstruction. PMID- 28347572 TI - The effect of nefopam on lactation after caesarean section: a single-blind randomised trial. AB - BACKGROUND: Nefopam is a centrally acting analgesic which has a theoretical risk of stopping lactation due to its anticholinergic and dopaminergic effects. The aim of this study was to evaluate the effect of nefopam on lactation and to investigate potential adverse effects on newborns. METHODS: Seventy-two women, scheduled to undergo a caesarean delivery under spinal anaesthesia and wanting to breastfeed, were randomised to one of two groups: nefopam (20mg, six hourly) or paracetamol (1g, six hourly). In both groups, postoperative analgesia was supplemented with ketoprofen (50mg, six hourly) in conjunction with intrathecal morphine 0.1mg. The primary outcome was onset of lactation, estimated by weighing the newborns before and after feeding; by maternal perception of breast fullness and based on serum prolactin concentration 48hours postpartum. Secondary outcomes were neonatal adverse effects evaluated by neurobehavioural score at 12, 24, 48, and 72hours after birth. Statistical analyses were performed using Chi-squared, Fisher exact and Student t tests as appropriate. P<0.05 was considered statistically significant. RESULTS: The difference in the weight of the newborn before and after each feed, maternal perception of breast fullness and serum prolactin did not significantly differ between groups. The volume of artificial milk given to newborns of mothers in the nefopam group on days two and three was significantly greater than for the paracetamol group. Neurobehavioural scores were comparable at each time point. CONCLUSION: Nefopam does not appear to delay the onset of lactation or present any clear risk to the newborn. PMID- 28347573 TI - Recurrent respiratory papillomatosis in a parturient presenting for cesarean delivery. PMID- 28347574 TI - What's trending now? An analysis of trends in internet searches for labor epidurals. AB - BACKGROUND: The study aim was to investigate internet use for obtaining information about epidurals for labor and delivery. METHODS: Google Trends for US data was queried from 2004 to 2015 to find the most common searches and determine temporal trends. The Google Trends query used the term [epidural] and evaluated changes in search trends over time. Search comparisons were made for each year from 2004 to 2015, and three equal time epochs during the study period (2004-07, 2008-11, 2012-15) were compared. We also compared searches for epidurals with commonly searched birth-related terms. RESULTS: Internet searches are increasing; there were 726000 searches for [epidural] in 2015. Search terms with the most significant growth in the past 4years (2012-15) were "birth with epidural," "pain after epidural," "labor without epidural," "epidural birth video," and "epidural vs natural". Searches for epidural side effects, risks, and pain on insertion were among the most common and were increasing most rapidly. Searches related to epidurals were more common than searches related to "natural births", "home births", and "labor pain", but were less common than searches for "midwives" or "doulas". CONCLUSION: The findings provide an insight into internet use by those seeking information about labor analgesic options. Identifying the most common and rapidly increasing online search queries may guide physician-parturient interactions and online content creation, to address labor analgesic topics that most interest users. PMID- 28347575 TI - Validation of a basic neurosonology laboratory for detecting cervical carotid artery stenosis. AB - INTRODUCTION: Most of the cases of ischaemic stroke in our setting are of atherothrombotic origin. Detecting intracranial and cervical carotid artery stenosis in patients with ischaemic stroke is therefore essential. Ultrasonography has become the tool of choice for diagnosing carotid artery stenosis because it is both readily accessibility and reliable. However, use of this technique must be validated in each laboratory. The purpose of this study is to validate Doppler ultrasound in our laboratory as a means of detecting severe carotid artery stenosis. PATIENTS AND METHODS: We conducted an observational descriptive study to evaluate diagnostic tests. The results from transcranial and cervical carotid Doppler ultrasound scans conducted by neurologists were compared to those from carotid duplex scans performed by radiologists in patients diagnosed with stroke. Arteriography was considered the gold standard (MR angiography, CT angiography, or conventional arteriography). RESULTS: Our sample included 228 patients. Transcranial and cervical carotid Doppler ultrasound showed a sensitivity of 95% and specificity of 100% for detection of carotid artery stenosis > 70%, whereas carotid duplex displayed a sensitivity of 87% and a specificity of 94%. Transcranial carotid Doppler ultrasound achieved a sensitivity of 78% and a specificity of 98% for detection of intracranial stenosis. CONCLUSIONS: Doppler ultrasound in our neurosonology laboratory was found to be a useful diagnostic tool for detecting cervical carotid artery stenosis and demonstrated superiority to carotid duplex despite the lack of B mode. Furthermore, this technique was found to be useful for detecting intracranial stenosis. PMID- 28347576 TI - Familial classic trigeminal neuralgia. AB - INTRODUCTION: The classic form of trigeminal neuralgia is usually sporadic (no familial clustering). However, around 2% of all cases of trigeminal neuralgia may be familial. Describing this entity may be useful for diagnosing this process and may also be key to determining the underlying causes of sporadic classical trigeminal neuralgia. We report on cases in a series of 5 families with at least 2 members with classic trigeminal neuralgia, amounting to a total of 11 cases. MATERIAL AND METHODS: We recorded cases of familial classical trigeminal neuralgia between March 2014 and March 2015 by systematically interviewing all patients with a diagnosis of trigeminal neuralgia who visited the neurology department on an outpatient basis. RESULTS: In our sample, most patients with familial classic trigeminal neuralgia were women. Mean age at onset was 62.9+/ 13.93 years, decreasing in subsequent generations. V2 was the most frequently affected branch. Most of our patients responded well to medical treatment, and surgery was not effective in all cases. CONCLUSIONS: These family clusters support the hypothesis that classic trigeminal neuralgia may have a genetic origin. Several causes have been suggested, including inherited anatomical changes affecting the base of the skull which would promote compression of the trigeminal nerve by vascular structures, familial AHT (resulting in tortuous vessels that would compress the trigeminal nerve), and mutations in the gene coding for calcium channels leading to hyperexcitability. Classic trigeminal neuralgia may be an autosomal dominant disorder displaying genetic anticipation. PMID- 28347577 TI - Utility of ultrasound-guided injection of botulinum toxin type A for muscle imbalance in children with obstetric brachial plexus palsy: Description of the procedure and action protocol. AB - INTRODUCTION: Obstetric brachial plexus palsy (OBPP) usually has a favourable prognosis. However, nearly one third of all severe cases have permanent sequelae causing a high level of disability. In this study, we explore the effectiveness of ultrasound-guided injection of botulinum toxin A (BoNT-A) and describe the procedure. PATIENTS AND METHODS: We designed a prospective, descriptive study including patients with moderate to severe OBPP who were treated between January 2010 and December 2014. We gathered demographic data, type of OBPP, and progression. Treatment effectiveness was assessed with the Active Movement Scale (AMS), the Mallet classification, and video recordings. RESULTS: We gathered a total of 14 133 newborns, 15 of whom had OBPP (1.6 per 1000 live births). Forty percent of the cases had severe OBPP (0.4/1000), a dystocic delivery, and APGAR scores < 5; mean weight was 4038g. Mean age at treatment onset was 11.5 months. The muscles most frequently receiving BoNT-A injections were the pronator teres, subscapularis, teres major, latissimus dorsi, and pectoralis major. All the patients who completed the follow-up period (83%) experienced progressive improvements: up to 3 points on the AMS and a mean score of 19.5 points out of 25 on the Mallet classification at 2 years. Treatment improved muscle function and abnormal posture in all cases. Surgery was avoided in 3 patients and delayed in one. Adverse events were mild and self-limited. CONCLUSIONS: Due to its safety and effectiveness, BoNT-A may be used off-label as an adjuvant to physical therapy and/or surgery in moderate to severe OBPP. Ultrasound may increase effectiveness and reduce adverse effects. PMID- 28347578 TI - Editorial overview: Food biotechnology. PMID- 28347579 TI - Treatment Patterns and Differences in Survival of Non-Small Cell Lung Cancer Patients Between Academic and Non-Academic Hospitals in the Netherlands. AB - BACKGROUND: The aims of this study are to analyze differences in survival between academic and non-academic hospitals and to provide insight into treatment patterns for non-small cell lung cancer (NSCLC). Results show the state of NSCLC survival and care in the Netherlands. METHODS: The Netherlands Cancer Registry provided data on NSCLC survival for all Dutch hospitals. We used the Kaplan-Meier estimate to calculate median survival time by hospital type and a Cox proportional hazards model to estimate the relative risk of mortality (expressed as hazard ratios) for patients diagnosed in academic versus non-academic hospitals, with adjustment for age, gender, and tumor histology, and stratifying for disease stage. Data on treatment patterns in Dutch hospitals was obtained from 4 hospitals (2 academic, 2 non-academic). A random sample of patients diagnosed with NSCLC from January 2009 until January 2011 was identified through hospital databases. Data was obtained on patient characteristics, tumor characteristics, and treatments. RESULTS: The Cox proportional hazards model shows a significantly decreased hazard ratio of mortality for patients diagnosed in academic hospitals, as opposed to patients diagnosed in non-academic hospitals. This is specifically true for primary radiotherapy patients and patients who receive systemic treatment for non-metastasized NSCLC. CONCLUSION: Patients diagnosed in academic hospitals have better median overall survival than patients diagnosed in non-academic hospitals, especially for patients treated with radiotherapy, systemic treatment, or combinations. This difference may be caused by residual confounding since the estimates were not adjusted for performance status. A wide variety of surgical, radiotherapeutic, and systemic treatments is prescribed. PMID- 28347580 TI - Aorto-Right Atrial Fistula After Sutureless Valve Implantation. AB - Aortic valve replacement with sutureless valves has many potential applications including in redo surgery, minimally invasive scenarios, and heavily calcified aortic roots. Herein we report a case of the development of an aorto-right atrial fistula after replacement of a Medtronic Freestyle stentless subcoronary bioprosthesis (Medtronic Inc, Minneapolis, MN) with a Perceval sutureless valve (LivaNova PLC, London, UK). This eventually necessitated repair with repeat surgery and aortic valve replacement with a stented valve. For patients with failing stentless bioprostheses returning for reintervention, we suggest removal of only Freestyle leaflet tissue without supra-annular debridement to avoid weakening of the native root tissue. PMID- 28347581 TI - Validity of Commercial Activity Trackers in Children With Congenital Heart Disease. AB - BACKGROUND: Increasing physical activity levels is a high priority to optimize long-term health in children with congenital heart disease (CHD). Commercial activity trackers have been validated in adults and are increasingly used to measure and promote physical activity in pediatric populations, but they have not been validated in children. METHODS: In 30 children with CHD aged 10-18 years, we assessed the validity of physical activity form the wrist-based Fitbit Charge HR (Fitbit, San Francisco, CA) against hip-based ActiGraph (ActiGraph LLC, Pensacola, FL) accelerometers under free living conditions for 7 days. We assessed the association between devices using intraclass correlation coefficients (ICCs) and Bland-Altman plots. Receiver operating curves were used to identify Fitbit step cut points. RESULTS: There was a strong association between the 2 devices for daily steps across 138 analyzed person-days (ICC = 0.855; P < 0.001), but poorer agreement for time spent in physical activity intensities (ICCs < 0.7). Daily Fitbit steps of >= 12,500 identified meeting physical activity guidelines defined as >= 60 minutes of moderate-to-vigorous physical activity per day. Fitbit devices recorded more steps than accelerometers (-2242 steps per day, 95% limits of agreement of -7738 to 3253). Between-device differences were greater in boys vs girls. Fitbit devices were worn for longer than accelerometers (-36 minutes per day, 95% limits of agreement, -334 to 261), but overall differences in wear time explained little of the variance in step differences (7%, P = 0.048). CONCLUSIONS: Commercial activity trackers provide opportunities to remotely monitor physical activity in children with CHD, but absolute values might differ from accelerometers. These findings are important because of the increasing emphasis on physical activity promotion and monitoring in children with cardiovascular risk factors. PMID- 28347582 TI - Cost Analysis of Patients Referred for Inherited Heart Rhythm Disorder Evaluation. AB - BACKGROUND: Inherited heart rhythm disorders (IHRDs) are complex and uncommon arrhythmogenic conditions that can lead to sudden unexpected death in seemingly healthy individuals. Multidisciplinary programs can assist in the diagnostic testing of potentially affected individuals and their family members. METHODS: Patients evaluated in a specialized adult and pediatric IHRD clinic between April 2013 and February 2015 were characterized. The total costs per evaluation and diagnosis were calculated. Patients were divided according to referral indication (primary referral or family member). RESULTS: A total of 618 patients were evaluated (age 36 +/- 21 years; 52% male), of which 274 (44%) were primary referrals and 344 (56%) were family members referred for cascade screening. Overall, 47% had at least 1 follow-up visit. Patients had a median of 3 tests; primary referrals required more tests (4 vs 2; P < 0.01). The median cost per patient was $1340 CAD. Evaluation of the primary referrals was costlier than family members ($3096 vs $983; P < 0.01). A definite or probable diagnosis was determined in 464 patients (77%), with no difference according to patient type (P = 0.18). The total cost per diagnosis was $4021 in primary referrals compared with $1277 in family members (P < 0.01). CONCLUSIONS: Clinical evaluation of patients with suspected IHRD results in a high diagnostic yield and costs aligned with other complex disorders involving multidisciplinary clinics. Evaluation costs are expectedly higher in primary referrals compared with targeted family screening. PMID- 28347583 TI - Hypereosinophilic Syndrome as a Rare Cause of Reversible Biventricular Heart Failure. AB - Hypereosinophilic syndrome is a rare entity that can develop secondary to overproduction of eosinophilopoietic cytokines or as idiopathic disease. Cardiac involvement, which occurs often, is divided into 3 stages, the latter of which is nonreversible and leads to severe heart failure. Early detection and treatment of the syndrome is essential. For this reason, genetic testing for the FIP1L1-PDGFRA fusion gene has recently been added to the diagnostic algorithm. Patients with this mutation are at increased risk for the development of cardiac involvement and typically respond to treatment with the tyrosine kinase inhibitor imatinib mesylate. PMID- 28347584 TI - Acute Myocardial Infarction from Coronary Vasospasm Precipitated by Pseudoephedrine and Metoprolol Use. AB - Pseudoephedrine is a sympathomimetic alpha- and beta-adrenergic receptor agonist that causes vasoconstriction and reduction in edema throughout the nasal passages. Coronary vasospasm associated with pseudoephedrine has been reported in the literature. We discuss the case of a patient with new-onset atrial fibrillation receiving metoprolol for rate control on a background of pseudoephedrine use for allergic rhinitis leading to acute myocardial infarction from multivessel coronary vasospasm. This case illustrates the importance of understanding the pharmacology of potential drug-drug interactions when managing patients with acute cardiovascular syndromes. PMID- 28347585 TI - Characteristics and metal leachability of incinerated sewage sludge ash and air pollution control residues from Hong Kong evaluated by different methods. AB - The improper disposal of incinerated sewage sludge ash (ISSA) and air pollution control residues (APCR) from sewage sludge incinerators has become an environmental concern. The physicochemical, morphological and mineralogical characteristics of ISSA and APCR from Hong Kong, and the leachability and risk of heavy metals, are presented in this paper. The results showed that a low hydraulic and pozzolanic potential was associated with the ISSA and APCR due to the presence of low contents of SiO2, Al2O3 and CaO and high contents of P, S and Cl (especially for APCR). Although high concentrations of Zn and Cu (especially for ISSA) followed by Ni, Pb and As, Se were detected, a low leaching rate of these metals (especially at neutral and alkaline pH) rendered them classifiable as non-hazardous according to the U.S. EPA and Chinese national regulatory limits. The leached metals concentrations from ISSA and APCR were mainly pH dependent, and metals solubilization occurred mainly at low pH. Different leaching tests should be adopted based on the simulated different environmental conditions and exposure scenarios for assessing the leachability as contrasting results could be obtained due to the differences in complexing abilities and final pH of the leaching solutions. PMID- 28347586 TI - Recycling of indium from waste LCD: A promising non-crushing leaching with the aid of ultrasonic wave. AB - The tremendous amount of end-of-life liquid crystal displays (LCDs) has become one of the prominent sources of waste electrical and electronic equipment (WEEE) in recent years. Despite the necessity of safe treatment, recycling indium is also a focus of waste LCD treatment because of the scarcity of indium. Based on the analyses of the structure of Indium Tin Oxide (ITO) glass, crushing is demonstrated to be not required. In the present research, a complete non-crushing leaching method was firstly adopted to recycle indium from waste LCDs, and the ultrasonic waves was applied in the leaching process. The results demonstrated that indium can be leached efficiently with even a low concentration of chloride acid (HCl) without extra heating. About 96.80% can be recovered in 60mins, when the ITO glass was leached by 0.8MHCl with an enhancement of 300W ultrasonic waves. The indium leaching process is abridged free from crushing, and proves to be of higher efficiency. In addition, the ultrasonic wave influence on leaching process was also explained combing with micron-scale structure of ITO glass. PMID- 28347587 TI - Effect of hydrothermal pre-treatment (HTP) on poultry slaughterhouse waste (PSW) sludge for the enhancement of the solubilization, physical properties, and biogas production through anaerobic digestion. AB - This study is an assessment of the hydrothermal pre-treatment (HTP) of poultry slaughterhouse waste (PSW) sludge for the enhancement of the solubilization, physical properties, and biogas production through anaerobic digestion. This assessment was carried out to ascertain the optimal HTP temperature. The solubilization and physical properties efficacy was investigated by capillary suction time (CST), time to filter (TTF), and particle size. In addition, the anaerobic digestion was investigated through biochemical methane potential (BMP) tests and subsequent statistical analysis using the modified Gompertz model. HTP was found to have improved the solubilization of the PSW sludge with increasing HTP temperature. In addition, the results of the CST, TTF, and particle size decreased with increasing HTP temperature. These results of the assessment that was conducted in this study confirm that the HTP process indeed modifies the physical properties of PSWs to enhance the solubilization of organic solids. Nevertheless, the results of the BMP tests and the modified Gompertz model analysis show that the optimal HTP temperature of PSWs for anaerobic digestion is 190 degrees C. These findings show that to achieve high conversion efficiency, an accurately designed pre-treatment step must be included in the overall anaerobic digestion process for wastewater treatment. PMID- 28347588 TI - Reply to H. Ian Robins. PMID- 28347589 TI - The National Violent Death Reporting System: Use of the Restricted Access Database and Recommendations for the System's Improvement. PMID- 28347590 TI - Draft genome analysis of Dietzia sp. 111N12-1, isolated from the South China Sea with bioremediation activity. AB - Dietzia sp. 111N12-1, isolated from the seawater of South China Sea, shows strong petroleum hydrocarbons degradation activity. Here, we report the draft sequence of approximately 3.7-Mbp genome of this strain. To the best of our knowledge, this is the first genome sequence of Dietzia strain isolated from the sea. The genome sequence may provide fundamental molecular information on elucidating the metabolic pathway of hydrocarbons degradation in this strain. PMID- 28347591 TI - Variability of late and moderate preterm definitions. PMID- 28347592 TI - A review of the established and suspected causes of variations in human sex ratio at birth. AB - The human sex ratio (proportion male) at birth (SRB) varies with many variables. Some of this variation has an established proximate cause. For instance, low SRB (more females) at birth are associated with various forms of stressful events or circumstances during or prior to pregnancy. These low SRB are almost certainly mainly caused by maternal-stress-induced male foetal loss. Other types of SRB variation are thought to be caused by hormonal variation in either or both parents around the time of conception. One or other of these two types of proximate cause seems to be responsible for most of the established variation of SRB. This will be illustrated here in respect of some selected forms of SRB variation. It seems likely that a clarification of the hormonal causes of SRB variation will also help explain the striking (apparent) inconsistencies in the results of reported tests of the influential Trivers-Willard hypothesis. It is further proposed that an appreciation of the evidence that parental hormones influence SRB may enhance understanding of several important pathologies (hepatitis B, toxoplasmosis, testicular cancer, prostate cancer and autism). PMID- 28347593 TI - Development and validation of a fast SFC method for the analysis of flavonoids in plant extracts. AB - Flavonoids from plants always show a wide range of biological activities. In the present study, a rapid and highly efficient supercritical fluid chromatography (SFC) method was developed for the separation of 12 flavonoids. After careful optimization, the 12 flavonoids were baseline separated on a ZORBAX RX-SIL column using gradient elution. A 0.1% phosphoric acid solution in methanol was found to be the most suitable polar mobile phase component for the separation of flavonoids. From the viewpoint of retention and resolution, a backpressure of 200bar and a temperature of 40 degrees C were shown to give the best results. Compared with a previously developed reverse phase liquid chromatography method, the SFC method could provide flavonoid separations that were about three times faster, while maintaining good peak shape and comparable peak efficiency. This SFC method was validated and applied to the analysis of five flavonoids (kaempferol, luteolin, quercetin, luteoloside, buddleoside) present in Chrysanthemum morifolium Ramat. from different cultivars (Chuju, Gongju, Hangju, Boju). The results indicated a good repeatability and sensitivity for the quantification of the five analytes with RSDs for overall precision lower than 3%. The limits of detection ranged from 0.73 to 2.34MUg/mL, while the limits of quantification were between 2.19 and 5.86MUg/mL. The method showed that SFC could be employed as a useful tool for the quality assessment of Traditional Chinese medicines (TCMs) containing flavonoids as active components. PMID- 28347594 TI - The training of specialists in Family and Community Health Nursing according to the supervisors of the teaching units. AB - OBJECTIVE: To analyze the current situation of the training of specialists in family and community nursing from the perspective of nurses responsible for teaching units. METHODS: Exploratory analysis using nominal group technique of the contributions made by representatives of 19 multidisciplinary teaching units in family and community care from 11 Spanish autonomous communities. They categorized and weighted those contributions. RESULTS: The emerging categories on the strengths and difficulties encountered related to the tutors, the environment where the training took place, the structure of the teaching unit, the organization of the teaching and the official programme of the speciality, the external supports and the theoretical training. CONCLUSIONS: Training in Family and Community Nursing is an opportunity to improve primary health care to train in news and necessary but complex skills. Support is required for training to be effective and the specialty and training should be made known. Tutors are a key part of this process. PMID- 28347595 TI - Increased cortisol awakening response after completing the summer treatment program in children with ADHD. AB - OBJECTIVE: Little is known about the cortisol awakening response (CAR) in children with attention deficit hyperactivity disorder (ADHD). Here, we examined the CAR in children with ADHD and their mothers before, immediately after, and 4months after an intensive summer treatment program (STP). METHODS: Participants were 37 children aged 7-12years who completed the STP in 2009 and 2010, and their mothers. Daily saliva samples for cortisol measurement were collected twice daily at awakening and 30min afterwards at pre-STP, post-STP, and during a follow-up measurement period. ADHD symptom scores were evaluated by parents, and participants completed the Kid-KINDLR QOL questionnaire. RESULTS: CAR was low in children with ADHD before the STP, and increased to the control range 4months after STP. Maternal CAR also tended to increase after STP. Changes in the CAR in children tended to correlate with an improved ADHD inattention scores (p=0.091), physical health (p=0.070), and school life subscales scores in the Kid-KINDLR (p=0.079). CONCLUSION: We demonstrated that STP improved the behavior and QOL of children with ADHD. Our results indicate that STP could lead to improvements in HPA axis function, as reflected by increased CAR after STP. PMID- 28347596 TI - Left-sided endocarditis extending to the right chambers: Usefulness of three dimensional echocardiography in preoperative assessment. PMID- 28347597 TI - Does standing limb alignment after total knee arthroplasty predict dynamic alignment and knee loading during gait? AB - BACKGROUND: A principle of TKA is to achieve a neutral standing coronal alignment of the limb (HKA angle) to reduce risks of implant loosening, reduce polyethylene wear, and optimize patellar tracking. Several long-term studies have questioned this because the relationship between alignment and implant survivorship is weaker than previously reported. We hypothesize that standing HKA poorly predicts implant failure because it does not predict dynamic HKA, dynamic adduction moment, and loading of the knee during gait. Therefore, the aim of our study is to assess the relationship between the standing and the dynamic (gait activity) HKAs. METHODS: A prospective study on a cohort of 35 patients treated with a posterior-stabilized TKA for primary osteoarthritis. Three months after surgery each patient had a long-leg radiograph and the limb was classified as neutrally aligned (17 patients), varus aligned (nine patients), or valgus aligned (four patients). Patients then performed a gait analysis for level walking. RESULTS: Standing HKA has a moderate correlation with the peak dynamic varus (r=0.318, p=0.001) and the mean and peak adduction moments (r=0.31 and r=-0.352 respectively). No significant correlation between standing HKA and the mean dynamic coronal alignment (r=0.14, p=0.449). No differences were found for dynamic frontal parameters (dynamic HKA and adduction moment) between patients defined as neutrally or varus aligned. CONCLUSIONS: The standing HKA after TKA was of little value to predict dynamic behaviour of the limb during gait, this may explain why standing coronal alignment after TKA may have limited influence on long-term implant fixation and wear. PMID- 28347598 TI - Patellar tendon reconstruction using an extended gastrocnemius flap following cryogenic injury to the knee. AB - Cryogenic thermal necrosis after knee surgery is rare. We describe a patient who presented with an anterior knee soft tissue defect in conjunction with an extensor mechanism deficiency secondary to a cold thermal injury after an anterior cruciate ligament reconstruction. We treated the patient with a single stage surgical procedure combining patellar tendon reconstruction and soft tissue coverage utilizing the superficial portion of the patient's vascularized Achilles tendon attached to a medial gastrocnemius flap. The patient returned to unrestricted activities and has demonstrated this through a five year follow-up. PMID- 28347599 TI - The anti-dermatophyte activity of Zataria multiflora essential oils. AB - OBJECTIVE: Dermtophytes are a group of pathogenic fungi and the major cause of dermatophytosis in humans and animals. Fighting dermatophytes by natural essential oils is one important issue in new researches. MATERIALS AND METHODS: In this investigation, we evaluated the anti-dermatophyte activities of three samples of Z. multiflora essential oils against dermatophytes along with analysis of chemical compositions of the essential oils and their anti-elastase activities on elastase production in dermatophytes. RESULTS: Carvacrol (1.5-34.4%), thymol (25.8-41.2%), carvacrol methyl ether (1.9-28.3%) and p-cymene (2.3-8.3%) were the main components of Z. multiflora essential oils. Z. multiflora essential oils (100ppm) inhibited the mycelium growth of dermatophytes (6+/-1.7-47.0+/-1.4%) and had the minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) values of 0.03-0.25MUl/ml against dermatophytes. Essential oils inhibited elastase produced in dermatophytes and pure porcine elastase. CONCLUSION: Z. multiflora essential oils can be used as natural anti-dermatophyte agent for fighting dermatophytes in further preclinical and clinical studies. PMID- 28347600 TI - [Mycological profile of onychomycosis in Yaounde, Cameroon]. AB - BACKGROUND: The lack of data concerning the mycological spectrum of onychomycosis in Cameroon prompted us to conduct the present study, which aimed to determine the mycological profile of onychomycosis diagnosed during dermatologic consultations in Yaounde, Cameroon. METHODS: This was a cross-sectional study held from October 2014 to March 2015 in six hospitals of Yaounde. Patients suspected of onychomycosis were consecutively recruited during dermatologic consultations; anamnestic and clinical data were recorded and one or several nail fragments sampled for mycological examination (direct examination or culture). RESULTS: A total of 3457 patients were examined during the study period, 117 of whom were suspected of onychomycosis; 133 samplings were performed. The distolateral subungual form was the dominating one: 72/110; 65.5%. The diagnosis was confirmed with 110 of the 133 samples (82.7%), these collected among 96 patients, hence a prevalence of 2.8% (96/3457). We isolated 99 germs, among which two-co-infestations. Dermatophytes (52/99; 52.5%), especially Trichophyton rubrum (23/52; 44.2%) and Trichophyton verrucosum (11/52; 21.2%) were the main pathogens causing onychomycois of the toes whereas yeasts (43/99; 43.4%), Candida albicans (31/43; 72.1%) in majority, were the prevailing germs incriminated in onychomycosis of the fingers. There were few cases of molds infestation (4/99; 4%). CONCLUSION: Onychomycosis are common in dermatology consultations in Yaounde. Candida albicans, Trichophyton rubrum and Trichophyton verrucosum are the main pathogens in cause. PMID- 28347602 TI - Prognostic significance of extracapsular spread of lymph node metastasis from oral squamous cell carcinoma in the clinically negative neck. AB - The presence of extracapsular spread (ECS) in patients with oral squamous cell carcinoma (OSCC) indicates a poor prognosis and is associated with a higher risk of regional recurrence and distant metastasis. The aim of this study was to analyse this important feature of cervical lymph nodes in the clinically node negative setting. The study included 61 patients with clinically T1-T3N0 OSCC who underwent primary surgical treatment; 52 were male and nine were female, and their median age was 57 years. The 5-year disease-free survival, disease-specific survival, and overall survival rates were 30.6%, 28.3%, and 14.3%, respectively, in the ECS group compared to 61.9%, 61.9%, and 48.2%, respectively, in the pN+/ECS-negative group and 76.7%, 81.9%, and 47.0%, respectively, in the pN0 group. The differences between the survival curves were highly significant (P=0.023, P=0.003, and P=0.029, respectively). The incidence of local (50% vs. 14.9%, P=0.011) and regional (28.6% vs. 2.1%, P=0.008) recurrence was significantly greater in the ECS group compared to the other subgroups of patients. Furthermore, the time to recurrence was significantly shorter in the ECS subjects. The presence of ECS in patients with oral cancer indicates a poor prognosis. ECS is a frequent feature in clinically node-negative settings and may be more common in smaller lymph nodes than is generally appreciated. PMID- 28347601 TI - Scoliosis in Rett Syndrome: Progression, Comorbidities, and Predictors. AB - BACKGROUND: Scoliosis is prominent in Rett syndrome (RTT). Following the prior report from the US Natural History Study, the onset and progression of severe scoliosis (>=40 degrees Cobb angle) and surgery were examined regarding functional capabilities and specific genotypes, addressing the hypothesis that abnormal muscle tone, poor oral feeding, puberty, and delays or absence of sitting balance and ambulation may be responsible for greater risk in RTT. METHODS: The multicenter RTT Natural History Study gathered longitudinal data for classic RTT, including mutation type, scoliosis, muscle tone, sitting, ambulation, hand function, and feeding. Cox regression models were used to examine the association between scoliosis and functional characteristics. All analyses utilized SAS 9.4; two-sided P values of <0.05 were considered significant. RESULTS: A total of 913 females with classic RTT were included. Scoliosis frequency and severity increased with age. Severe scoliosis was found in 251 participants (27%), 113 of whom developed severe scoliosis during the follow-up assessments; 168 (18%) had surgical correction. Severe MECP2 mutations (R106W, R168X, R255X, R270X, and large deletions) showed a higher proportion of scoliosis. Individuals developing severe scoliosis or requiring surgery were less likely to sit, ambulate, or use their hands and were more likely to have begun puberty. Significant differences were absent for epilepsy rates, sleep problems, or constipation. DISCUSSION: Scoliosis requires vigilance regarding the risk factors noted, particularly specific mutations and the role of puberty and motor abilities. Bracing is recommended for moderate curves and surgery for severe curves in accordance with published guidelines for scoliosis management. PMID- 28347603 TI - Liver disease in cystic fibrosis presents as non-cirrhotic portal hypertension. PMID- 28347604 TI - The Prognostic Value of HER2-Positive Circulating Tumor Cells in Breast Cancer Patients: A Systematic Review and Meta-Analysis. AB - INTRODUCTION: A meta-analysis was conducted to determine the prognostic value of HER2-positive circulating tumor cells (CTCs) in patients with breast cancer. MATERIALS AND METHODS: MedLine, Central, and Embase databases were searched. Inclusion criteria were: (1) randomized controlled trials, 2-arm prospective studies, and retrospective studies; (2) patients with breast cancer; (3) HER2 positive CTCs were examined; and (4) hazard ratio (HR) of survival between patients with HER2-positive and HER2-negative CTCs was reported. RESULTS: Four studies with a total of 550 patients with stage I to IV breast cancer were included. HER2-positive CTCs were not associated with worse overall survival (OS; HR, 1.489, 95% confidence interval [CI], 0.873-2.540, P = .144) or progression free survival (PFS; HR, 1.543; 95% CI, 0.636-3.744; P = .338). In patients without metastasis, HER2-positive CTCs were associated with worse OS (HR, 2.273; 95% CI, 1.340-3.853; P = .002) and worse PFS (HR, 2.870; 95% CI, 1.298-6.343; P = .009). There was no significant relationship between HER2-positive CTCs and survival in subgroups of patients with metastasis. CONCLUSION: HER2-positive CTCs have prognostic value in patients with breast cancer and without distant metastasis. PMID- 28347605 TI - A single-center retrospective analysis of patency rates of intraluminal versus subintimal endovascular revascularization of long femoropopliteal occlusions. AB - OBJECTIVE: The evaluation of patency rates of intraluminal versus subintimal endovascular revascularization of long femoropopliteal (FP) lesions. BACKGROUND: Chronic total occlusions (CTO) of the FP artery in peripheral interventions are crossed either with a support catheter-guidewire based technique or subintimal dissection and re-entry device assisted approach. Both techniques have a high procedural success rate, but their long term patency is not well studied. There is also lack of comparative data addressing the patency of long non-CTO vs. CTO occlusions. METHODS: We performed a single center retrospective analysis, studying the patency rates in 215 patients (254 limbs) with TASC C and D FP lesions treated with stents. There were 3 patient groups: without CTO (non-CTO); CTO crossed using support catheter and guide-wire (CTO-SW) and CTO crossed with a re-entry device (CTO-RE). RESULTS: There were 155 limbs in CTO-SW group; 50 in CTO-RE group and 49 in non-CTO. Lesion length (mean+/-SD) was 251.81+/-7.48mm in CTO-SW group; 280+/-13.18mm in CTO-RE group and 248.77+/-13.31 in non-CTO group (p=non-significant). In-stent restenosis (ISR) at a mean follow-up of 19.26+/ 16.14months did not differ between groups occurring in 23 (47%) limbs in non-CTO; 66 (42%) in CTO-SW; and 24 (48%) in CTO-RE. Smoking and stent fracture were predictors of ISR by multivariate analysis. CONCLUSION: In patients with long FP lesions, ISR rates were similar between patients with and without CTO. In the CTO group mid-term vessel patency was not affected by the crossing technique utilized. PMID- 28347606 TI - New era of infant chest compression. PMID- 28347607 TI - Facebook: A last resort for patient contact. PMID- 28347608 TI - Sedation effects of intranasal dexmedetomidine delivered as sprays versus drops on pediatric response to venous cannulation. AB - OBJECTIVES: Mucosal atomization device (MAD) was designed to increase the bioavailability of intranasal medications by facilitating absorption, the present study aimed to evaluate and compare the sedation effects of intranasal dexmedetomidine delivered as drops versus sprays on pediatric responses to intravenous cannulation. METHODS: One hundred and six pediatric patients (aged from 2 to 5years) scheduled for elective ophthalmic surgery were intranasally received a dose of 2MUg/kg in 20MUl/kg of dexmedetomidine for sedation to reduce response to venous cannulation. The patients were randomized into syringe group and MAD group in which dexmedetomidine was delivered as drops or sprays via syringe or MAD respectively. The primary outcome was the response to peripheral vein cannulation assessed by the FLACC scores (faces, legs, activity, cry and consolability) 30min after intranasal administration of dexmedetomidine. The secondary outcomes included acceptance for intranasal medication, sedation onset time, and needle insertion times and any adverse event at the preoperative holding area. RESULTS: The FLACC scores in MAD group were significantly decreased than that treated by drops (P=0.021). The acceptance for intranasal administration between both groups was comparable (P>0.05), the onset time and the incidences in two and more times of needle insertion did not differ significantly between syringe and MAD groups (all P>0.05). None of patients were required to clinically intervene in heart rates reduction and none suffered respiratory depression after administrations of dexmedetomidine in either group. CONCLUSION: Intranasal dexmedetomidine by sprays offers better sedation effects to reduce responses to venous cannulation than drops. PMID- 28347609 TI - Rhupus and autoimmune hepatitis: A rare association. PMID- 28347610 TI - Abundance of antibiotics, antibiotic resistance genes and bacterial community composition in wastewater effluents from different Romanian hospitals. AB - Antimicrobial resistance represents a growing and significant public health threat, which requires a global response to develop effective strategies and mitigate the emergence and spread of this phenomenon in clinical and environmental settings. We investigated, therefore, the occurrence and abundance of several antibiotics and antibiotic resistance genes (ARGs), as well as bacterial community composition in wastewater effluents from different hospitals located in the Cluj County, Romania. Antibiotic concentrations ranged between 3.67 and 53.05 MUg L-1, and the most abundant antibiotic classes were beta lactams, glycopeptides, and trimethoprim. Among the ARGs detected, 14 genes confer resistance to beta-lactams, aminoglycosides, chloramphenicol, macrolide lincosamide-streptogramin B (MLSB) antibiotics, sulfonamides, and tetracyclines. Genes encoding quaternary ammonium resistance and a transposon-related element were also detected. The sulI and qacEDelta1 genes, which confer resistance to sulfonamides and quaternary ammonium, had the highest relative abundance with values ranging from 5.33 * 10-2 to 1.94 * 10-1 and 1.94 * 10-2 to 4.89 * 10-2 copies/16 rRNA gene copies, respectively. The dominant phyla detected in the hospital wastewater samples were Proteobacteria, Bacteroidetes, Firmicutes, and Actinobacteria. Among selected hospitals, one of them applied an activated sludge and chlorine disinfection process before releasing the effluent to the municipal collector. This conventional wastewater treatment showed moderate removal efficiency of the studied pollutants, with a 55-81% decrease in antibiotic concentrations, 1-3 order of magnitude lower relative abundance of ARGs, but with a slight increase of some potentially pathogenic bacteria. Given this, hospital wastewaters (raw or treated) may contribute to the spread of these emerging pollutants in the receiving environments. To the best of our knowledge, this study quantified for the first time the abundance of antibiotics and ARGs in wastewater effluents from different Romanian hospitals. PMID- 28347612 TI - Air ionization as a control technology for off-gas emissions of volatile organic compounds. AB - High energy electron-impact ionizers have found applications mainly in industry to reduce off-gas emissions from waste gas streams at low cost and high efficiency because of their ability to oxidize many airborne organic pollutants (e.g., volatile organic compounds (VOCs)) to CO2 and H2O. Applications of air ionizers in indoor air quality management are limited due to poor removal efficiency and production of noxious side products, e.g., ozone (O3). In this paper, we provide a critical evaluation of the pollutant removal performance of air ionizing system through comprehensive review of the literature. In particular, we focus on removal of VOCs and odorants. We also discuss the generation of unwanted air ionization byproducts such as O3, NOx, and VOC oxidation intermediates that limit the use of air-ionizers in indoor air quality management. PMID- 28347611 TI - Ambient particulate matter and carbon monoxide at an urban site of India: Influence of anthropogenic emissions and dust storms. AB - Continuous measurements of PM2.5, PM10 and CO were conducted at an urban site of Udaipur in India from April 2011 to March 2012. The annual mean concentrations of PM2.5, PM10 and CO were 42 +/- 17 MUg m-3, 114 +/- 31 MUg m-3 and 343 +/- 136 ppbv, respectively. Concentrations of both particulate and CO showed high values during winter/pre-monsoon (dry) period and lowest in the monsoon season (wet). Local anthropogenic emission and long-range transport from open biomass burning sources along with favourable synoptic meteorology led to elevated levels of pollutants in the dry season. However, higher values of PM10/PM2.5 ratio during pre-monsoon season were caused by the episodes of dust storm. In the monsoon season, flow of cleaner air, rainfall and negligible emissions from biomass burning resulted in the lowest levels of pollutants. The concentrations of PM2.5, PM10 and CO showed highest values during morning and evening rush hours, while lowest in the afternoon hours. In winter season, reductions of PM2.5, CO and PM10 during weekends were highest of 15%, 13% and 9%, respectively. In each season, the highest PM2.5/PM10 ratio coincided with the highest concentrations of pollutants (CO and NOX) indicating predominant emissions from anthropogenic sources. Exceptionally high concentrations of PM10 during the episode of dust storm were due to transport from the Arabian Peninsula and Thar Desert. Up to ~32% enhancements of PM10 were observed during strong dust storms. Relatively low levels of O3 and NOx during the storm periods indicate the role of heterogeneous removal. PMID- 28347613 TI - Theory of Animal Mind: Human Nature or Experimental Artefact? AB - Are animals capable of empathy, problem-solving, or even self-recognition? Much research is dedicated to answering these questions and yet few studies have considered how humans form beliefs about animal minds. Evidence suggests that our mentalising of animals is a natural consequence of Theory of Mind (ToM) capabilities. However, where beliefs regarding animal mind have been investigated, there has been slow progress in establishing the mechanism underpinning how this is achieved. Here, we consider what conclusions can be drawn regarding how people theorise about animal minds and the different conceptual and methodological issues that might limit the accuracy of conclusions currently drawn from this work. We suggest a new empirical framework for better capturing the human theory of animal mind, which in turn has significant political and social implications. PMID- 28347614 TI - Evolution and novel radiological changes of neurodegeneration associated with mutations in C19orf12. AB - INTRODUCTION: Neurodegeneration with brain iron accumulation (NBIA) comprises a heterogeneous group of disorders with accumulation of iron in the brain, mostly basal ganglia. NBIA subtype mitochondrial membrane protein-associated neurodegeneration (MPAN) is caused by recently discovered mutations in C19orf12, which encodes a protein localized in the mitochondrial membrane. METHODS: The present and past radiological features of 14 MPAN patients were analyzed. RESULTS: Clinical evaluation did not reveal novel findings: spastic para- and tetraparesis with muscle atrophy are typical for MPAN. Dysarthria, parkinsonism, and dystonia are very common but not present in all cases. Present brain imaging demonstrated increased iron levels in the globus pallidus (GP) and substantia nigra (SN) in all patients. In two cases first imaging didn't show typical hypointensity in GP and SN. A novel finding were white matter hyperintensities localized mainly in the periventricular region. CONCLUSIONS: WMH are observed in some MPAN patients, they are age dependent and localized periventricular. If they are due to altered brain and peripheral lipid metabolism remains unknown. PMID- 28347616 TI - The "Overdrive" Mode in the "Complete Vocal Technique": A Preliminary Study. AB - "Complete Vocal Technique," or CVT, is an internationally widespread method for teaching voice. It classifies voicing into four types, referred to as "vocal modes," one of which is called "Overdrive." The physiological correlates of these types are unclear. This study presents an attempt to analyze its voice source and formant frequency characteristics. A male and a female expert of CVT sang a set of "Overdrive" and falsetto tones on the syllable /pae/. The voice source could be analyzed by inverse filtering in the case of the male subject. Results showed that subglottal pressure, measured as the oral pressure during /p/ occlusion, was low in falsetto and high in "Overdrive", and it was strongly correlated with each of the voice source parameters. These correlations could be described in terms of equations. The deviations from these equations of the different voice source parameters for the various voice samples suggested that "Overdrive" phonation was produced with stronger vocal fold adduction than the falsetto tones. Further, the subject was also found to tune the first formant to the second partial in "Overdrive" tones. The results support the conclusion that the method used, to compensate for the influence of subglottal pressure on the voice source, seems promising to use for analyses of other CVT vocal modes and also for other types of phonation. PMID- 28347615 TI - The p.Thr11Met mutation in c19orf12 is frequent among adult Turkish patients with MPAN. AB - INTRODUCTION: Mutations in the C19orf12 gene cause mitochondrial membrane protein associated neurodegeneration (MPAN), an autosomal recessive form of neurodegeneration with brain iron accumulation (NBIA). A limited number of patients with C19orf12 mutations, particularly those with adult onset of symptoms, have been reported. METHODS: We sequenced the entire coding region of C19orf12 in 15 Turkish adult probands with idiopathic NBIA. We also performed haplotype analysis in families with a recurrent C19orf12 mutation. Clinical features were collected using a standardized form. RESULTS: Nine of our 15 probands (60%) carried the homozygous c.32C > T mutation in C19orf12 (predicted protein effect: p.Thr11Met). This homozygous mutation co-segregated with the disease in all affected relatives available for testing (16 homozygous subjects). Haplotypes across the C19orf12 locus were identical for a very small region, closest to the mutation, suggesting an old founder, or, two independent founders. The clinical phenotype was characterized by adult onset in most cases (mean 24.5 years, range 10-36), and broad spectrum, including prominent parkinsonism, pyramidal signs, psychiatric disturbances, cognitive decline, and motor axonal neuropathy, in various combinations. On T2- or susceptibility weighted-MRI images, all patients displayed bilateral hypointensities in globus pallidus and substantia nigra, without an eye-of-the-tiger sign; however, hyperintense streaking of the medial medullary lamina between the external and internal parts of globus pallidus was observed frequently. CONCLUSION: The C19orf12 p.Thr11Met mutation is frequent among adult Turkish patients with MPAN. These findings contribute to the characterization of this important NBIA form, and have direct implications for genetic testing of patients of Turkish origin. PMID- 28347617 TI - Sensorimotor Mismapping in Poor-pitch Singing. AB - OBJECTIVE: This study proposes that there are two types of sensorimotor mismapping in poor-pitch singing: erroneous mapping and no mapping. We created operational definitions for the two types of mismapping based on the precision of pitch-matching and predicted that in the two types of mismapping, phonation differs in terms of accuracy and the dependence on the articulation consistency between the target and the intended vocal action. The study aimed to test this hypothesis by examining the reliability and criterion-related validity of the operational definitions. STUDY DESIGN: A within-subject design was used in this study. METHODS: Thirty-two participants identified as poor-pitch singers were instructed to vocally imitate pure tones and to imitate their own vocal recordings with the same articulation as self-targets and with different articulation from self-targets. RESULTS: Definitions of the types of mismapping were demonstrated to be reliable with the split-half approach and to have good criterion-related validity with findings that pitch-matching with no mapping was less accurate and more dependent on the articulation consistency between the target and the intended vocal action than pitch-matching with erroneous mapping was. Furthermore, the precision of pitch-matching was positively associated with its accuracy and its dependence on articulation consistency when mismapping was analyzed on a continuum. Additionally, the data indicated that the self-imitation advantage was a function of articulation consistency. CONCLUSION: Types of sensorimotor mismapping lead to pitch-matching that differs in accuracy and its dependence on the articulation consistency between the target and the intended vocal action. Additionally, articulation consistency produces the self-advantage. PMID- 28347618 TI - Implementation of Hysterectomy Pathway: Impact on Complications. AB - OBJECTIVE: Hysterectomy is one of the most common surgical procedures in the United States. For women who need hysterectomy, it is important to ensure that minimally invasive hysterectomy procedures are used appropriately to reduce surgical complications and improve value of care. Although we previously demonstrated a reduction in total abdominal hysterectomy rates after the implementation of hysterectomy pathway treatment algorithm in 2012, this study focuses on exploring the effect of pathways implementation on surgical outcomes. METHODS: All retrospective medical records for hysterectomy surgeries performed for benign indications at University of Pittsburgh Medical Center hospitals between the fiscal years (FY) 2012 and 2014 were identified. We analyzed the health care outcomes by route of surgery and year using Chi2 test for categorical data, and non-parametric approaches for non-normal continuous variables. RESULTS: A total of 6,569 hysterectomies for benign indications were performed between FY 2012 and 2014. In FY 2012, 1,154 patients (59.15%) had a length of stay of 1 day or less, whereas in FY 2014 this number increased to 1,791 (74.53%; p < .0001). Within 3 years of implementing the pathway, surgical site infections had a reduction of 47%, with a considerable trend toward significance (p = .067). CONCLUSIONS: Implementation of hysterectomy pathway has been associated with reduction of surgical complications in benign hysterectomy settings. Implementation of clinical pathways offers an opportunity for improving patient outcomes that should be investigated in various health care settings and across procedures. PMID- 28347619 TI - Investigating the nitrification and denitrification kinetics under aerobic and anaerobic conditions by Paracoccus denitrificans ISTOD1. AB - Municipal wastewater contains multiple nitrogen contaminants such as ammonia, nitrate and nitrite. Two heterotrophic nitrifier and aerobic denitrifiers, bacterial isolates ISTOD1 and ISTVD1 were isolated from domestic wastewater. On the basis of removal efficiency of ammonia, nitrate and nitrite under both aerobic and anaerobic conditions, ISTOD1 was selected and identified as Paracoccus denitrificans. Aerobically, NH4+-N had maximum specific nitrogen removal rate (Rxi) of 7.6g/gDCW/h and anaerobically, NO3-N showed Rxi of 2.5*10 1g/g DCW/h. Monod equation described the bioprocess kinetic coefficients, umax and Ks, obtained by regression. Error functions were calculated to validate the Monod equation experimental data. Aerobic NO3-N showed the highest YW of 0.372mg DCW/mg NO3-N among the five conditions. ISTOD1 serves as a potential candidate for treating nitrogen rich wastewater using simultaneous nitrification and aerobic denitrification. It can be used in bioaugmentation studies under varied condition. PMID- 28347620 TI - Accumulation of phytoene, a colorless carotenoid by inhibition of phytoene desaturase (PDS) gene in Dunaliella salina V-101. AB - The aim of this work was to study the accumulation of phytoene in Dunaliella salina V-101 by down-regulating its phytoene desaturase (PDS) gene expression using RNA interference and Antisense technology. RNAi and antisense constructs were introduced into the Dunaliella cells by Agrobacterium-mediated transformation. Among thirty-two transformants, six showed positive down regulation of PDS expression with RNAi construct and five positive transformants were obtained using antisense construct. Characterization of PDS suppression was carried out using semi-quantitative RT-PCR and quantitative determination of phytoene as well as other carotenoids by HPLC. Both the RNAi and antisense lines showed a significant decrease in the expression levels of phytoene desaturase and carotenoid content compared to wild type cells. The RNAi line #5 showed maximum Phytoene content (108.34+/-22.34ug/100mg DCW) compared to other transgenic lines. These phytoene-accumulating phenotypes exhibited slower growth rates and were found to be sensitive to high light conditions. PMID- 28347621 TI - Effects of temperature and solvent on hydrothermal liquefaction of Sargassum tenerrimum algae. AB - The influence of various solvents (H2O, CH3OH, and C2H5OH) on product distribution and nature of products during hydrothermal liquefaction of sargassum tenerrimum algae has been examined. Hydrothermal liquefaction was performed using H2O (260, 280 and 300 degrees C) and organic solvents CH3OH and C2H5OH (280 degrees C) for 15min. The use of organic solvents significantly increased the yield of bio-oil. In the case of liquefaction with CH3OH and C2H5OH, the bio-oil yield was 22.8 and 23.8wt.% respectively whereas the bio-oil yield was 16.33wt.% with H2O. GC-MS analysis of the liquid products indicated the presence of various organic compounds including aromatics, nitrogenated and oxygenated compounds and higher selectivity amount of ester compounds were observed in the presence of alcoholic solvents. NMR and FT-IR showed that present of solvents have an effect on the decomposition of sargassum tenerrimum algae. PMID- 28347622 TI - An experimental approach aiming the production of a gas mixture composed of hydrogen and methane from biomass as natural gas substitute in industrial applications. AB - This work presents an experimental approach aiming the production of a gas mixture composed of H2 and CH4, which should serve as natural gas substitute in industrial applications. Therefore, a lab-scale process chain employing a water gas shift unit, scrubbing units, and a pressure swing adsorption unit was operated with tar-rich product gas extracted from a commercial dual fluidized bed biomass steam gasification plant. A gas mixture with a volumetric fraction of about 80% H2 and 19% CH4 and with minor fractions of CO and CO2 was produced by employing carbon molecular sieve as adsorbent. Moreover, the produced gas mixture had a lower heating value of about 15.5MJ.m-3 and a lower Wobbe index of about 43.4MJ.m-3, which is similar to the typical Wobbe index of natural gas. PMID- 28347623 TI - Assessment of pesticides removal using two-stage Integrated Aerobic Treatment Plant (IATP) by Bacillus sp. isolated from agricultural field. AB - The biodegradation of synthetic wastewater containing Atrazine, Malathion and Parathion was studied in two stage Integrated Aerobic Treatment Plant using Bacillus sp. (consortia) isolated from agricultural field. The influent stream containing these pesticides with initial COD of 1232mg/L were fed to first reactor and treated effluent of first reactor was fed to second reactor. The maximum removal of pesticides in IATP was found to be greater than 90%. The various process parameters such as pH, DO, Redox potential and BOD5/COD were monitored during the treatment. The degradation of pesticides and its metabolites in the treated effluent were confirmed by GC-MS. Kinetic parameters such as first order rate constant (Kobs), cell yield (YX/C) and decay coefficients (Kdp) were evaluated and found to be 0.00425 per hr, 0.696mg of COD/mg MLSS and 0.0010 per hr respectively. This integrated process was found more effective than physico chemical treatment of pesticides. PMID- 28347624 TI - Efficacy and safety of normal saline instillation and paediatric endotracheal suction: An integrative review. AB - OBJECTIVE: To synthesise research findings regarding the efficacy and safety of normal saline instillation (NSI) during endotracheal suction in the paediatric intensive care unit. DATA SOURCES: The Cochrane Library, PROSPERO, the National Health Service Centre for Reviews and Dissemination, PubMed and Cumulative Index to Nursing and Allied Health (CINAHL) databases were systematically searched. Subject headings included "suctioning, endotracheal", "suction", "sodium chloride", "normal saline" and "paediatrics". Additional references were sourced from hand searches of journal article reference lists and Google Scholar. METHOD: An integrative, systematic approach was used to qualitatively synthesise study results in the context of paediatric intensive care nursing practice. Data were extracted using a standardised data extraction form. Quality assessment was performed independently by two reviewers. RESULTS: Three studies met pre-defined inclusion criteria. Quality of all study methods was 75% on the Mixed Method Appraisal Tool, although reporting quality varied. Overall, there was a scarcity of high quality evidence examining NSI and paediatric endotracheal suction. Outcome measures included oxygen saturation (SpO2), serious adverse events (author/s defined) and ventilation parameters (author/s defined). Endotracheal suction with NSI was associated with a transient decrease in blood oxygen saturation; research protocols did not include interventions to mitigate alveolar derecruitment. Studies were not powered to detect differences in endotracheal tube (ETT) occlusion or ventilator associated pneumonia (VAP). CONCLUSION: NSI was associated with a transient decrease in oxygen saturation. In children with obstructive mucous, NSI may have a positive effect. Practices which maximise secretion removal and mitigate the negative physiological interactions of ETS have been poorly evaluated in the paediatric population. High quality, powered, clinical trials are needed to determine the safety and efficacy of normal saline instillation and to inform clinical practice. PMID- 28347625 TI - Combination of radiotherapy and double blockade HER2 with pertuzumab and trastuzumab for HER2-positive metastatic or locally recurrent unresectable and/or metastatic breast cancer: Assessment of early toxicity. AB - BACKGROUND AND PURPOSES: We evaluate the early toxicity of concurrent use of radiotherapy, pertuzumab and trastuzumab in patients with HER2-positive metastatic or locally recurrent unresectable breast cancer. PATIENTS AND METHODS: A retrospective study was performed in a population of 23 consecutive patients between 2013 and 2015. Radiotherapy was performed on the chest area or metastatic sites during maintenance with pertuzumab and trastuzumab after six cycles of pertuzumab, trastuzumab and docetaxel. Toxicity was assessed according to the National Cancer Institute Common Toxicity Criteria version 4. RESULTS: Irradiation volumes were whole breast (8 patients) and chest wall (9 patients) at 50Gy in 25 fractions, the supraclavicular nodes (16 patients), the axillary area (nine patients) and the internal mammary nodes (9 patients) at 46Gy in 23 fractions. For five patients, radiotherapy was palliative: bone irradiation (4 patients), whole brain radiotherapy (one patient). Median follow-up was 12.6 months (range: 6.1-21.6 months) since the start of pertuzumab and trastuzumab. One patient presented an asymptomatic decrease of left ventricular ejection fraction below 50%. No symptomatic cardiac events were reported. Two patients presented asymptomatic grade I radiation pneumonitis. Acute skin toxicity was grade III (one patient), grade II (6 patients), and grade I (5 patients). There were two grade II esophagitis. CONCLUSION: Combination of pertuzumab, trastuzumab and radiotherapy was well tolerated, which should be confirmed by the results of larger studies. PMID- 28347626 TI - Achieving equity in maternal health in China: more to be done. PMID- 28347627 TI - Simulation-guided navigation for vector control in pediatric mandibular distraction osteogenesis. AB - AIM: Navigation technology has given surgeons the capacity to know precisely where their instruments are during surgery, and simulation-guided navigation is a surgical method which is based on the use of navigation technology linked to 3D virtual surgery simulation. The aim of the present study was to evaluate the absolute accuracy of simulation-guided navigation as an aid to reproduce the planned position of the distraction device vector in pediatric mandibular distraction osteogenesis. MATERIALS AND METHODS: We retrospectively evaluated seven patients affected by unilateral (3 pts.) or bilateral (4 pts.) mandibular hypoplasia and treated with this method between 2012 and 2014 at the Maxillofacial Surgery Unit of the University of Bologna, Italy. All patients were enrolled for mandibular distraction using internal unidirectional devices (11 distraction devices implanted overall). Patients were studied through a complete three-dimensional workflow, which led to obtaining a virtual reconstruction of the facial bones and the simulation of the distraction device positioning using a specific experimental software. The surgical planning was loaded on the navigation system and the distraction device was placed following the virtual plan, which is displayed on the navigation system as a guide and tracked with the navigation instruments. RESULTS: We analyzed the outcome comparing the recorded three-dimensional coordinates of the achieved distractor position and the three dimensional coordinates of the planned distractor position. Among the eleven placed distractors, we found a mean angular error of 3.74 degrees +/- 3.30 degrees on the axial axis (yaw) and of 6.27 degrees +/- 5.32 degrees on the sagittal axis (pitch), while median angular errors are 3.72 degrees on the axial axis (yaw) and 4.08 degrees on the sagittal axis (pitch). CONCLUSION: Our preliminary experience seems to support that simulation-guided navigation for vector control in mandibular distraction osteogenesis could be a useful procedure for reproducing the virtually planned outcome. Nevertheless, our results cannot be considered completely satisfactory. There is a lot of room to improve accuracy and errors seem to depend mainly on the soft tissues interference during distractor placement. PMID- 28347628 TI - Factors affecting pain assessment scores in patients on mechanical ventilation. AB - OBJECTIVE: To determine how respiratory status and other aspects of the patients' condition affect pain assessments. METHODS: Pain was assessed in 20 patients aged >=20 years who underwent cardiovascular surgery, and required postoperative mechanical ventilation in an intensive care unit using the Behavioral Pain Scale (BPS). A BPS score of >=6 (pain) versus <6 (no pain) was the dependent variable for determining the effect on pain. RESULTS: Multiple logistic regression analysis showed that in 99 observations made at rest, pre- and post-turning and pre- and post-tracheal suctioning, the BPS score was significantly affected by gender, the Acute Physiology and Chronic Health Evaluation (APACHE) II score, Richmond Agitation-Sedation Scale score, PaCO2, and HCO3-. The associations between BPS scores and APACHE II scores and HCO3- demonstrated that pain results from biological responses to invasion. Increases in PaCO2 affecting only the total BPS score suggests that PaCO2 is associated with other pain responses, regardless of respiratory status. CONCLUSION: The BPS score was significantly associated with disease severity and ventilatory capacity, demonstrating a need to examine pain assessment methods tailored to the severity of underlying disease, degree of respiratory failure and other aspects of individual patient's condition for effective pain management. PMID- 28347629 TI - The effect of experience, simulator-training and biometric feedback on manual ventilation technique. AB - OBJECTIVE: To determine the frequency of provision and main providers (veterinary surgeons, nurses or trainees) of manual ventilation in UK veterinary practices. Furthermore, to determine the variation in peak inspiratory (inflation) pressure (PIP), applied to a lung model during manual ventilation, by three different groups of operators (inexperienced, experienced and specialist), before and after training. STUDY DESIGN: Questionnaire survey, lung model simulator development and prospective testing. METHODS: Postal questionnaires were sent to 100 randomly selected veterinary practices. The lung model simulator was manually ventilated in a staged process over 3 weeks, with and without real-time biometric feedback (PIP display), by three groups of volunteer operators: inexperienced, experienced and specialist. RESULTS: The questionnaires determined that veterinary nurses were responsible for providing the majority of manual ventilation in veterinary practices, mainly drawing on theoretical knowledge rather than any specific training. Thoracic surgery and apnoea were the main reasons for provision of manual ventilation. Specialists performed well when manually ventilating the lung model, regardless of feedback training. Both inexperienced and experienced operators showed significant improvement in technique when using the feedback training tool: variation in PIP decreased significantly until operators provided manual ventilation at PIPs within the defined optimum range. Preferences for different forms of feedback (graphical, numerical or scale display), revealed that the operators' choice was not always the method which gave least variation in PIP. CONCLUSIONS AND CLINICAL RELEVANCE: This study highlighted a need for training in manual ventilation at an early stage in veterinary and veterinary nursing careers and demonstrated how feedback is important in the process of experiential learning. A manometer device which can provide immediate feedback during training, or indeed in a real clinical setting, should improve patient safety. PMID- 28347630 TI - Tubulins and brain development - The origins of functional specification. AB - The development of the vertebrate central nervous system is reliant on a complex cascade of biological processes that include mitotic division, relocation of migrating neurons, and the extension of dendritic and axonal processes. Each of these cellular events requires the diverse functional repertoire of the microtubule cytoskeleton for the generation of forces, assembly of macromolecular complexes and transport of molecules and organelles. The tubulins are a multi gene family that encode for the constituents of microtubules, and have been implicated in a spectrum of neurological disorders. Evidence is building that different tubulins tune the functional properties of the microtubule cytoskeleton dependent on the cell type, developmental profile and subcellular localisation. Here we review of the origins of the functional specification of the tubulin gene family in the developing brain at a transcriptional, translational, and post transcriptional level. We remind the reader that tubulins are not just loading controls for your average Western blot. PMID- 28347631 TI - The first serological investigation of Chicken astrovirus infection in China. AB - Chicken astrovirus (CAstV) is associated with 'white chick' syndrome, which increases embryo mortality and reduces hatchability in chickens. In the present study, 1760 sera were collected from 21 provinces in China to detect antibodies directed against CAstV with an ELISA. The sera were from different varieties of chicken in 85 flocks and all the flocks produced positive reactions. The overall seroprevalence in the birds tested was 60.68%. The prevalence increased from 34.17% to 74.44% with the increase of age. The positivity rates in layer flocks, layer parent flocks, broiler flocks, broiler parent flocks, and domestic chicken flocks were 70.17%, 89.00%, 31.67%, 59.05%, and 45.79%, respectively. These data indicate that CAstV infections are very common in China. This is the first report of the seroprevalence of CAstV infections in China. PMID- 28347632 TI - Do spiroindolines have the potential to replace vesamicol as lead compound for the development of radioligands targeting the vesicular acetylcholine transporter? AB - The vesicular acetylcholine transporter (VAChT) is an important target for in vivo imaging of neurodegenerative processes using positron emission tomography (PET). So far the development of VAChT PET radioligands is based on the single known lead compound vesamicol. In this study we investigated a recently published spiroindoline based compound class (Sluder et al., 2012), which was suggested to have potential in the development of VAChT ligands. Therefore, we synthesized a small series of N,N-substituted spiro[indoline-3,4'-piperidine] derivatives and determined their in vitro binding affinities toward the VAChT. In order to investigate the selectivity, the off-target binding toward sigma1 and sigma2 receptors was determined. The compounds possessed VAChT affinities with Ki values in the range of 39-376nM. Binding affinities toward the sigma1 and sigma2 receptors are in a similar range indicating that the strong structural difference between the spiroindolines and vesamicol did not improve the selectivity. The observed potential to additionally bind to sigma receptors let us assume that the herein investigated spiroindolines are not suitable to replace vesamicol as lead compound for the development of VAChT ligands. PMID- 28347633 TI - Synthesis and carbonic anhydrase inhibition of a series of SLC-0111 analogs. AB - SLC-0111 is a sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor (CAI) in Phase I/II clinical trials for the treatment of advanced hypoxic tumors complicated with metastases. Its antitumor effects are due to inhibition of the enzymatic activity of CA IX, an isoform predominantly found in tumors/metastases, but it also reduces the cancer stem cells population. Here we report the synthesis of analogs of SLC-0111, both of the sulfanilamide and metanilamide series, which possess diverse substitution patterns at the terminal ureido-phenyl moiety, thus including one or more halogens, trifluoromethyl, perchloro /perfluorophenyl groups instead of the 4-fluorophenyl present in SLC-0111. Most of the sulfanilamide ureido derivatives were highly effective inhibitors of the tumor associated isoform and some showed selective CA IX/XII inhibitory profiles. Most of the sulfanilamide ureido derivatives were highly effective and in some cases selective CA IX/XII inhibitors, whereas the metanilamide ureido derivatives were less effective as transmembrane CA isoforms inhibitors. Structure activity relationship for this class of sulfonamides is discussed in detail. PMID- 28347634 TI - Ten-year outcomes of monomorphic ventricular tachycardia catheter ablation in repaired tetralogy of Fallot. AB - BACKGROUND: Monomorphic ventricular tachycardia (MVT) is common in adults with repaired tetralogy of Fallot (TOF), and is associated with sudden cardiac death. Management of MVT is not defined, and results of catheter ablation (CA) are limited. AIMS: To evaluate long-term outcomes of MVT CA in repaired TOF. METHODS: Thirty-four patients (mean age 32+/-10.3 years; 59% male) with repaired TOF underwent CA for symptomatic MVT between 1990 and 2012 in our centre; direct current ablation (DCA) was used in 6%, radiofrequency followed by DCA in 29% and radiofrequency alone in 65%. RESULTS: Right ventricular (RV) dysfunction was present in 35% and left ventricular (LV) dysfunction in 21%. Mean numbers of clinical and induced MVTs were 1 and 2, respectively. Mean VT rate was 225+/ 95bpm. Ablation targeted a single site (range 1-2), which was RV outflow tract in 85%. Primary success, defined as ventricular tachycardia (VT) termination during CA and final non-inducibility, was obtained in 82%. Seven patients (21%) required redo ablation in the first 3 months (before 2004; DCA). No death related to CA occurred. Mean follow-up time was 9.5+/-5.2 years. Antiarrhythmic therapy was discontinued in 71%. There were two cases of sudden cardiac death and four VT recurrences. Freedom from death and arrhythmia recurrence was 94% at 5 years, 81% at 10 years and 70% at 20 years. Global survival was 91% at 20 years. Baseline LV ejection fraction<60% was significantly associated with ventricular arrhythmia recurrence (hazard ratio 16.4, 95% confidence interval 1.8-147; P=0.01). CONCLUSIONS: CA can safely address macroreentrant MVT in repaired TOF patients with an acceptable long-term rate of recurrence in this high-risk population. Anatomical classification of isthmuses with electroanatomical mapping provides reproducible endpoints for CA. Attention should be given to LV systolic function in risk assessment and selection of candidates for implantable cardioverter defibrillator. PMID- 28347635 TI - Is it necessary to isolate the pulmonary veins in atrial fibrillation ablation? An analysis of the evolution of ablation approaches in major studies. PMID- 28347636 TI - Knowledge of hepatitis C and treatment willingness amongst people who inject drugs in an era of direct acting antivirals. AB - BACKGROUND: Knowledge of hepatitis C virus (HCV) is believed to be important in altering risk behaviour, improving engagement in care, and promoting willingness to initiate HCV treatment. We assessed factors associated with HCV knowledge and treatment willingness amongst people who inject drugs (PWID) in an era of direct acting antivirals. METHODS: Data were derived from three prospective cohort studies of PWID in Vancouver, Canada, between June 2014 and May 2015. HCV knowledge and treatment willingness were assessed using a Likert scale. Multivariable linear regression identified factors associated with higher HCV knowledge and treatment willingness. RESULTS: Amongst 630 participants, mean scores for HCV knowledge and treatment willingness were 25.41 (standard deviation [SD]: 2.52) out of 30, and 6.83 (SD: 1.83) out of 10, respectively. In multivariable analyses, Caucasian ancestry (adjusted linear regression model estimate [beta] 0.50; 95% confidence interval [CI] 0.17, 0.82), employment (beta 0.76; 95% CI: 0.38, 1.13), diagnosed mental health disorder (beta 0.44; 95% CI: 0.11, 0.78) and previous HCV treatment (beta 0.94; 95% CI: 0.46, 1.43) were independently associated with higher knowledge. Downtown Eastside (DTES) residence (i.e., epicenter of Vancouver's drug scene) was independently associated with lower knowledge (beta -0.48; 95% CI: -0.81, -0.15). Greater HCV knowledge (beta 0.12; 95% CI: 0.07, 0.17) was independently associated with higher HCV treatment willingness. DTES residence (beta -0.31; 95% CI: -0.56, 0.06) and daily crack cocaine smoking (beta -0.52; 95% CI: -0.92, -0.13) were independently associated with lower treatment willingness. CONCLUSION: Socioeconomic factors, such as neighborhood residence and employment, were associated with HCV knowledge. Higher HCV knowledge was associated with more HCV treatment willingness. Our findings suggest that increasing HCV knowledge amongst PWID may be an integral component of the HCV cascade of care and that efforts might be best targeted to individuals with greater socioeconomic disadvantage. PMID- 28347638 TI - [Congenital mesenteric band simulating a small-bowel volvulus in a mesenteric rotation anomaly]. AB - A congenital mesenteric band is a rare cause of intestinal obstruction. We describe a case of upper gastrointestinal obstruction on a jejunal congenital band in a 2-year-old child. The challenge is to make the diagnosis in a patient with no history of previous surgery. PMID- 28347637 TI - Transient neonatal diabetes mellitus and activating mutation in the KCNJ11 gene in two siblings. AB - Transient neonatal diabetes mellitus is a rare disease usually associated with chromosome 6 abnormalities. Mutations of the genes encoding the potassium channel are rarely associated with these transitional forms. Herein, we report the clinical features of two siblings with a heterozygous mutation C679 G>A in the KCNJ11 gene. PMID- 28347639 TI - Neurite outgrowth in cultured mouse pelvic ganglia - Effects of neurotrophins and bladder tissue. AB - Neurotrophic factors regulate survival and growth of neurons. The urinary bladder is innervated via both sympathetic and parasympathetic neurons located in the major pelvic ganglion. The aim of the present study was to characterize the effects of the neurotrophins nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3) on the sprouting rate of sympathetic and parasympathetic neurites from the female mouse ganglion. The pelvic ganglion was dissected out and attached to a petri dish and cultured in vitro. All three factors (BDNF, NT-3 and NGF) stimulated neurite outgrowth of both sympathetic and parasympathetic neurites although BDNF and NT-3 had a higher stimulatory effect on parasympathetic ganglion cells. The neurotrophin receptors TrkA, TrkB and TrkC were all expressed in neurons of the ganglia. Co-culture of ganglia with urinary bladder tissue, but not diaphragm tissue, increased the sprouting rate of neurites. Active forms of BDNF and NT-3 were detected in urinary bladder tissue using western blotting whereas tissue from the diaphragm expressed NGF. Neurite outgrowth from the pelvic ganglion was inhibited by a TrkB receptor antagonist. We therefore suggest that the urinary bladder releases trophic factors, including BDNF and NT-3, which regulate neurite outgrowth via activation of neuronal Trk-receptors. These findings could influence future strategies for developing pharmaceuticals to improve re-innervation due to bladder pathologies. PMID- 28347640 TI - A systematic review and meta-analysis of the utility of repeated versus single hepatic resection for colorectal cancer liver metastases. AB - BACKGROUND: Recurrence of colorectal liver metastases after a first hepatectomy is common (4-48% of patients). This review investigates the utility of repeated hepatic resection of colorectal liver metastases. METHODS: A systematic search of the literature was performed in the Cochrane Library, MEDLINE, EMBASE, and trial registers. All studies comparing repeated hepatic resection for colorectal liver metastases with patients who underwent only one hepatectomy were eligible. Outcome criteria were safety parameters and survival rates. Data were analyzed using the random-effects model. RESULTS: In eight observational clinical studies, 450 patients with repeated hepatic resection were compared with 2669 single hepatic resections. Morbidity such as hepatic insufficiency (OR [95% CI] 1.46 [0.69; 3.08], p = 0.32) and biliary leakage and fistula (OR [95% CI] 1.22 [0.80; 1.85], p = 0.35) was comparable between the two groups. Mortality (OR [95% CI] 1.13 [0.46; 2.74], p = 0.79) and overall survival (HR [95% CI] 1.00 [0.63; 1.60], p = 0.99) were not significantly different between the two groups. DISCUSSION: Repeated hepatic resection for colorectal liver metastases is safe in selected patients. A prospective, multicenter high-quality trial or register study of repeated hepatic resection will be required to clarify patient-oriented outcomes such as overall survival and quality of life. PMID- 28347641 TI - Differences in physical health, and health behaviors between family caregivers of children with and without disabilities. AB - BACKGROUND: Providing care for children with disabilities can negatively influence the physical health and health behaviors of family caregivers. OBJECTIVES/HYPOTHESIS: The study purposes were to compare the prevalence of chronic conditions and health risk behaviors of family caregivers of children with and without disabilities and to examine associations between disability status of children and family caregivers' chronic conditions and health risk behaviors. METHODS: This study compared chronic conditions and health risk behaviors across adult family caregivers of children with a disability (FCG-D) and family caregivers of children without a disability (FCG) living in a U.S. household using 2015 National Health Interview Survey data. Health risk behaviors were defined as heavy drinking, current smoking, physical inactivity, and unhealthy sleep. Multivariable logistic regression was conducted to compare chronic conditions and health risk behaviors between FCG-D and FCG with adjustments for demographic and healthcare coverage covariates. RESULTS: FCG-D showed significantly greater likelihoods of chronic conditions (e.g., asthma, back pain, chronic bronchitis, heart conditions, migraine, and obesity) than FCG. FCG-D also exhibited significantly more smoking and unhealthy sleep. CONCLUSIONS: Family caregivers of children with a disability reported significantly greater likelihoods of various chronic conditions and were more likely to engage in health risk behaviors (smoking and unhealthy sleep). Further study is needed to develop intervention programs for encouraging effective health-promoting behaviors among family caregivers of children with a disability as well as health policies for decreasing health disparities experienced by this population. PMID- 28347642 TI - The Need for Extracorporeal Support for Lung Transplantation: Why and What Does the Future Hold? PMID- 28347643 TI - Synchronous association of typical and transient mesenteric panniculitis with acute gastrointestinal attack of adult-onset Henoch-Schonlein purpura. PMID- 28347645 TI - Evolution of the vertebrate phototransduction cascade activation steps. AB - We examine the molecular phylogeny of the proteins underlying the activation steps of vertebrate phototransduction, for both agnathan and jawed vertebrate taxa. We expand the number of taxa analysed and we update the alignment and tree building methodology from a previous analysis. For each of the four primary components (the G-protein transducin alpha subunit, GalphaT, the cyclic GMP phosphodiesterase, PDE6, and the alpha and beta subunits of the cGMP-gated ion channel, CNGC), the phylogenies appear consistent with expansion from an ancestral proto-vertebrate cascade during two rounds of whole-genome duplication followed by divergence of the agnathan and jawed vertebrate lineages. In each case, we consider possible scenarios for the underlying gene duplications and losses, and we apply relevant constraints to the tree construction. From tests of the topology of the resulting trees, we obtain a scenario for the expansion of each component during 2R that accurately fits the observations. Similar analysis of the visual opsins indicates that the only expansion to have occurred during 2R was the formation of Rh1 and Rh2. Finally, we propose a hypothetical scenario for the conversion of an ancestral chordate cascade into the proto-vertebrate phototransduction cascade, prior to whole-genome duplication. Together, our models provide a plausible account for the origin and expansion of the vertebrate phototransduction cascade. PMID- 28347644 TI - Genomic determinants of epidermal appendage patterning and structure in domestic birds. AB - Variation in regional identity, patterning, and structure of epidermal appendages contributes to skin diversity among many vertebrate groups, and is perhaps most striking in birds. In pioneering work on epidermal appendage patterning, John Saunders and his contemporaries took advantage of epidermal appendage diversity within and among domestic chicken breeds to establish the importance of mesoderm ectoderm signaling in determining skin patterning. Diversity in chickens and other domestic birds, including pigeons, is driving a new wave of research to dissect the molecular genetic basis of epidermal appendage patterning. Domestic birds are not only outstanding models for embryonic manipulations, as Saunders recognized, but they are also ideal genetic models for discovering the specific genes that control normal development and the mutations that contribute to skin diversity. Here, we review recent genetic and genomic approaches to uncover the basis of epidermal macropatterning, micropatterning, and structural variation. We also present new results that confirm expression changes in two limb identity genes in feather-footed pigeons, a case of variation in appendage structure and identity. PMID- 28347646 TI - Allogeneic islet cells implant on poly-l-lactide matrix to reduce hyperglycaemia in streptozotocin-induced diabetic rat. AB - OBJECTIVE: To demonstrate the effects of allogeneic islet cell matrix implants for glycaemic control in rats with induced diabetes. METHOD: Sprague-Dawley rats were used as allogeneic donors of islet cells. Cells were seeded on three dimensional proprietary poly-(l-lactide) matrices. Animals were rendered diabetic and a week later a matrix seeded with islet cells (IMI group) or a control matrix (placebo group) was implanted in the small bowel mesentery. Blood glucose levels were measured weekly for 12 weeks. After sacrifice, implant sections were Gomori stained for beta-cells and immuno-stained for insulin 3, 4, 5, and 6 months post implantation. RESULTS: 82% of seeded islet cells attached to the matrices. In the IMI group blood glucose levels were significantly reduced after implantation compared with before implantation across several time points. In the IMI group beta-cells and insulin-positive cells were identified at the implant site. CONCLUSION: The islet cell matrix implant reduced the blood glucose levels although complete normo-glycaemia was not established. The islet cell matrix implant may serve as an additional option for islet cell transplantation using 3D scaffold platforms for better survival and function of the islet cells. PMID- 28347648 TI - Sarode honoured by American Society of Hematology. PMID- 28347647 TI - Laparoscopic sleeve gastrectomy after failed gastric banding: is it really effective? Six years of follow-up. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has become a valuable surgical option to rescue laparoscopic adjustable gastric banding (LAGB) failures. OBJECTIVES: The aim of this study was to determine whether conversion to LSG after failed LAGB (CLSG) is a well-tolerated and effective rescue procedure compared with primary LSG (PLSG) in the long term. SETTING: University hospital, France. METHODS: A retrospective review of data concerning consecutive patients receiving a LSG between February 2008 and December 2014 was conducted. Mortality, postoperative complications, and weight loss outcomes were analyzed. RESULTS: Of 701 LSG, 601 (85.7%) were PLSG and 100 (14.3%) were CLSG. The mortality rate was 0%. Overall morbidity was comparable between the primary and conversion group (10% versus 6%, P = .27). The mean percentage of excess weight loss at 3, 36, and 72 months was 34.9%, 72.1%, and 57.2% after PLSG and 22.6%, 51.2% and 29.8% after CLSG (P<.05). The failure rate (mean percentage of excess weight loss<50%) was higher in the CLSG group during the first 5 postoperative years (P < .001) with more than two thirds of the CLSG considered as having failed at 60 months. Patients who underwent band ablation as a result of insufficient weight loss or weight regain presented the worst results after conversion to LSG. CONCLUSION: In this study, the conversion of failed LAGB to LSG in 2 steps indicated a safety profile comparable to that of primary LSG but was significantly less effective from the early postoperative course (3 mo) up to 6 years postoperatively. CLSG may not be the best option because a third operation may be needed as a result of insufficient weight loss. PMID- 28347649 TI - The effect of intraarticular serum rich in growth factors (SRGF) on knee osteoarthritis in the rat model. AB - Osteoarthritis (OA) is a degenerative joint disease with high incidence in world. Various treatments have been used for decreasing pain and improving physical function without clearly beneficial evidences. Nowadays, platelet-rich therapy is used as a novel approach in field of regenerative medicine. The present study evaluated the effect of intraarticular serum rich in growth factors (SRGF) on the monosodium iodoacetate induced-osteoarthritis in rat model. SRGF was injected 3 times weekly. Femorotibial joints were examined 2 weeks after last injection. Histopathologic results showed remarkable articular regeneration in the SRGF treated rats. Our findings were less surface irregularities and articular clefts, proliferation of chondrocytes and increasing synthesis of matrix proteoglycan with toluidine blue staining. Destroyed articular cartilage was repaired by fibro hyaline cartilage in contrast to the OA rats that filled with fibrovascular tissues. The microscopic score had decreased in the treatment group. We concluded that SRGF, as a source of growth factors, have chondroinductive capacity with regard to enhancement of cartilage regeneration. PMID- 28347650 TI - Angiopoietin-like protein 8/betatrophin as a new determinant of type 2 diabetes remission after bariatric surgery. AB - This work aimed to explore the link between angiopoietin-like protein 8 (ANGPTL8) and weight loss after metabolic surgery. In the cross-sectional study (n = 100), circulating ANGPTL8 concentrations were significantly lower in morbidly obese than in lean subjects, and strikingly lower in morbidly obese patients with type 2 diabetes mellitus (T2DM). Conversely, ANGPTL8 expression in subcutaneous adipose tissue (SAT) was higher in morbidly obese patients, particularly in those with T2DM, whereas its expression in visceral adipose tissue was unchanged. The main predictors for circulating levels of ANGPTL8 were BMI and T2DM, whereas ANGPTL8 expression in SAT was determined by the presence of T2DM. The prospective cohort studies before and 1 year after bariatric surgery in morbidly obese patients with (n = 45) and without (n = 30) T2DM, revealed a significant increase of circulating ANGPTL8 levels 1 year after the bariatric surgery. Intriguingly, this increment, which was predicted by basal ANGPTL8 concentrations, appeared as a determinant of T2DM remission. In conclusion, circulating ANGPTL8 levels have an inverse relationship with SAT expression. Low basal levels of ANGPTL8 rebound after bariatric surgery. The increment in ANGPTL8 concentrations at 1 month of follow-up after weight loss emerged as a significant predictor of the T2DM remission at 1 year of follow-up. PMID- 28347651 TI - Selective Targeting of SH2 Domain-Phosphotyrosine Interactions of Src Family Tyrosine Kinases with Monobodies. AB - The binding of Src-homology 2 (SH2) domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the eight Src family kinases (SFKs). The high sequence conservation of the 120 human SH2 domains poses a significant challenge to selectively perturb the interactions of even the SFK SH2 family against the rest of the SH2 domains. We have developed synthetic binding proteins, termed monobodies, for six of the SFK SH2 domains with nanomolar affinity. Most of these monobodies competed with pY ligand binding and showed strong selectivity for either the SrcA (Yes, Src, Fyn, Fgr) or SrcB subgroup (Lck, Lyn, Blk, Hck). Interactome analysis of intracellularly expressed monobodies revealed that they bind SFKs but no other SH2-containing proteins. Three crystal structures of monobody-SH2 complexes unveiled different and only partly overlapping binding modes, which rationalized the observed selectivity and enabled structure-based mutagenesis to modulate inhibition mode and selectivity. In line with the critical roles of SFK SH2 domains in kinase autoinhibition and T cell receptor signaling, monobodies binding the Src and Hck SH2 domains selectively activated respective recombinant kinases, whereas an Lck SH2-binding monobody inhibited proximal signaling events downstream of the T-cell receptor complex. Our results show that SFK SH2 domains can be targeted with unprecedented potency and selectivity using monobodies. They are excellent tools for dissecting SFK functions in normal development and signaling and to interfere with aberrant SFK signaling networks in cancer cells. PMID- 28347652 TI - Reaction-diffusion waves of blood coagulation. AB - One of the main characteristics of blood coagulation is the speed of clot growth. In the current work we consider a mathematical model of the coagulation cascade and study existence, stability and speed of propagation of the reaction-diffusion waves of blood coagulation. We also develop a simplified one-equation model that reflects the main features of the thrombin wave propagation. For this equation we estimate the wave speed analytically. The resulting formulas provide a good approximation for the speed of wave propagation in a more complex model as well as for the experimental data. PMID- 28347653 TI - Cytochrome c oxidase subunit I haplotype diversity of Angiostrongylus cantonensis (Nematoda: Angiostrongylidae). AB - The rat lungworm Angiostrongylus cantonensis is a food-borne zoonotic parasite of public health importance worldwide. It is the primary etiologic agent of eosinophilic meningitis and eosinophilic meningoencephalitis in humans in many countries. It is highly endemic in Thailand especially in the northeast region. In this study, A. cantonensis adult worms recovered from the lungs of wild rats in different geographical regions/provinces in Thailand were used to determine their haplotype by means of the mitochondrial partial cytochrome c oxidase subunit I (COI) gene sequence. The results revealed three additional COI haplotypes of A. cantonensis. The geographical isolates of A. cantonensis from Thailand and other countries formed a monophyletic clade distinct from the closely related A. malaysiensis. In the present study, distinct haplotypes were identified in seven regions of Thailand - AC10 in Phitsanulok (northern region), AC11 in Nakhon Phanom (northeastern region), AC15 in Trat (eastern region), AC16 in Chantaburi (eastern region), AC4 in Samut Prakan (central region), AC14 in Kanchanaburi (western region), and AC13 in Ranong (southern region). Phylogenetic analysis revealed that these haplotypes formed distinct lineages. In general, the COI sequences did not differentiate the worldwide geographical isolates of A. cantonensis. This study has further confirmed the presence of COI haplotype diversity in various geographical isolates of A. cantonensis. The COI gene sequence will be a suitable marker for studying population structure, phylogeography and genetic diversity of the rat lungworm. PMID- 28347654 TI - Efficacy and safety of alirocumab in insulin-treated patients with type 1 or type 2 diabetes and high cardiovascular risk: Rationale and design of the ODYSSEY DM INSULIN trial. AB - AIMS: The coadministration of alirocumab, a PCSK9 inhibitor for treatment of hypercholesterolaemia, and insulin in diabetes mellitus (DM) requires further study. Described here is the rationale behind a phase-IIIb study designed to characterize the efficacy and safety of alirocumab in insulin-treated patients with type 1 (T1) or type 2 (T2) DM with hypercholesterolaemia and high cardiovascular (CV) risk. METHODS: ODYSSEY DM-INSULIN (NCT02585778) is a randomized, double-blind, placebo-controlled, multicentre study that planned to enrol around 400 T2 and up to 100 T1 insulin-treated DM patients. Participants had low-density lipoprotein cholesterol (LDL-C) levels at screening>=70mg/dL (1.81mmol/L) with stable maximum tolerated statin therapy or were statin intolerant, and taking (or not) other lipid-lowering therapy; they also had established CV disease or at least one additional CV risk factor. Eligible patients were randomized 2:1 to 24weeks of alirocumab 75mg every 2weeks (Q2W) or a placebo. Alirocumab-treated patients with LDL-C>=70mg/dL at week 8 underwent a blinded dose increase to 150mg Q2W at week 12. Primary endpoints were the difference between treatment arms in percentage change of calculated LDL-C from baseline to week 24, and alirocumab safety. RESULTS: This is an ongoing clinical trial, with 76 T1 and 441 T2 DM patients enrolled; results are expected in mid 2017. CONCLUSION: The ODYSSEY DM-INSULIN study will provide information on the efficacy and safety of alirocumab in insulin-treated individuals with T1 or T2 DM who are at high CV risk and have hypercholesterolaemia not adequately controlled by the maximum tolerated statin therapy. PMID- 28347655 TI - Long-term Clinical Outcome of Antibody Replacement Therapy in Humoral Immunodeficient Adults With Respiratory Tract Infections. AB - In severe humoral immunodeficiency the indication for antibody replacement therapy (ART) is clear, and supported by several large studies. However, for milder forms of humoral immunodeficiency, the indication for ART is less clear. This is a retrospective cohort study of 87 adults with recurrent respiratory tract infections who received ART. The patients had severe or mild humoral immunodeficiency, and were followed up for a median of 62months. Infection frequency, pharmacy-registered antibiotics use and hospital admissions significantly decreased under ART compared to the year prior to starting ART (median 5.50 (anamnestically)-0.82 (physician-confirmed) infections/year, p<0.001; median 4.00-2.05antibioticscourses/year, p<0.001; mean 0.75 0.44hospitaladmissions/year, p=0.009). These beneficial effects of ART were seen in both severe and mild immunodeficiency. Bronchiectasis was present in 27 patients when ART was started, but was not associated with clinical outcomes. An increase in hospital admissions under ART, observed in some patients, was significantly associated with pulmonary emphysema and current smoking. In conclusion, this study shows that ART is a long-term effective therapy in adults with recurrent respiratory tract infections with severe as well as with milder forms of humoral immunodeficiency. PMID- 28347657 TI - [Disseminated phytodermatitis: A nosological entity to know]. PMID- 28347656 TI - Telomeres and Cell Senescence - Size Matters Not. AB - Telomeres are protective structures present at the ends of linear chromosomes that are important in preventing genome instability. Telomeres shorten as a result of cellular replication, leading to a permanent cell cycle arrest, also known as replicative senescence. Senescent cells have been shown to accumulate in mammalian tissue with age and in a number of age-related diseases, suggesting that they might contribute to the loss of tissue function observed with age. In this review, we will first describe evidence suggesting a key role for senescence in the ageing process and elaborate on some of the mechanisms by which telomeres can induce cellular senescence. Furthermore, we will present multiple lines of evidence suggesting that telomeres can act as sensors of both intrinsic and extrinsic stress as well as recent data indicating that telomere-induced senescence may occur irrespectively of the length of telomeres. PMID- 28347658 TI - Galectin-9 as a prognostic and predictive biomarker in bladder urothelial carcinoma. AB - PURPOSE: Galectin-9, a member of the "tandem repeat" type galectins performing as animal lectins with an affinity for beta-galactosides, has been well documented to exert crucial functions in immunomodulation, survival, and growth of various tumors. This study aims to reveal the clinical significance of galectin-9 in urothelial carcinoma of the bladder (UCB) postoperatively. MATERIALS AND METHODS: We retrospectively included 202 patients with UCB who underwent radical cystectomy at a single institute from 2002 to 2014. Galectin-9 expression was assessed by immunohistochemistry on tissue microarrays. The Kaplan-Meier method was conducted to plot survival curves. Prognostic nomograms were constructed via integrating all the independent indicators from multivariate Cox analysis for recurrence-free survival (RFS) and cancer-specific survival (CSS). In addition, we evaluate whether patients with increased or decreased galectin-9 expression might benefit from adjuvant chemotherapy. RESULTS: Low galectin-9 expression was significantly correlated with lymphovascular invasion (P = 0.002), early recurrence (P = 0.010), and short CSS (P = 0.002). Furthermore, multivariate analysis identified galectin-9 expression as a potential independent indicator for RFS (hazard ratio = 0.62; 95% CI: 0.40-0.95; P = 0.030) and CSS (hazard ratio = 0.46; 95% CI: 0.26-0.81; P = 0.008). Moreover, the benefit associated with adjuvant chemotherapy was superior among galectin-9 low patients than among galectin-9 high patients (P = 0.014). CONCLUSIONS: Expression of galectin-9 is an independent prognostic factor for RFS and CSS in patients with UCB. Evaluation of galectin-9 expression may predict the benefit from adjuvant chemotherapy. PMID- 28347659 TI - Variant histology as a significant predictor of survival after radical nephroureterectomy in patients with upper urinary tract urothelial carcinoma. AB - OBJECTIVES: To investigate the effect of variant histology (VH) on survival after radical nephroureterectomy in patients with upper urinary tract urothelial carcinoma (UTUC) and the effect of adjuvant chemotherapy on the survival of patients with UTUC with VH. MATERIALS AND METHODS: A total of 452 patients who underwent radical nephroureterectomy for UTUC without neoadjuvant chemotherapy in our institution between 1991 and 2012 were retrospectively analyzed. We performed a comparative analysis between pure UTUC and UTUC with VH groups. The Kaplan Meier method was used to calculate survival estimates for cancer-specific survival (CSS) and overall survival (OS), and log-rank test was used to conduct comparisons between the groups. Univariate and multivariate Cox-proportional hazard regression analyses were performed to evaluate significant variables associated with CSS and OS. RESULTS: UTUC with VH was present in 41 (9.1%) patients. UTUC with VH showed aggressive clinicopathological features in comparison with pure UTUC. The Kaplan-Meier curves showed significantly decreased 5-year CSS and OS (both, P<0.001) in UTUC with VH group. Multivariate analysis revealed that VH was an independent predictor of CSS (P<0.001) and OS (P<0.002). The Kaplan-Meier curves also showed significantly decreased 5-year CSS and OS in UTUC with the VH group compared to the pure UTUC group in patients who received adjuvant chemotherapy. CONCLUSIONS: We found that UTUC with VH harbored aggressive biologic features, and VH was an independent prognostic factor for CSS and OS on both univariate and multivariate analyses. In addition, UTUC with VH group had poorer survival outcomes than pure UTUC group in patients who received adjuvant chemotherapy. Consequently, adjuvant treatment modalities other than adjuvant chemotherapy should be considered in this group. PMID- 28347660 TI - Effect of genetic polymorphism on the inhibition of dopamine formation from p tyramine catalyzed by brain cytochrome P450 2D6. AB - The inhibitory effects of steroid hormones, including glucocorticoids such as cortisol, and related compounds on dopamine formation from p-tyramine, catalyzed by cytochrome P450 (CYP) 2D6.2 (Arg296Cys, Ser486Thr) and CYP2D6.10 (Pro34Ser, Ser486Thr) were compared with the effects of those catalyzed by CYP2D6.1 (wild type), to investigate the effect of a CYP2D6 polymorphism on neuroactive amine metabolism in the brain. Inhibition constants (Ki) or 50% inhibitory concentrations of six steroid hormones (cortisol, cortisone, corticosterone, dehydroepiandrosterone, progesterone, and pregnenolone) and quinidine and quinine typical potent inhibitors of the human CYP2D6 and rat CYP2D subfamily, respectively-toward dopamine formation catalyzed by CYP2D6.1, CYP2D6.2, and CYP2D6.10 expressed in recombinant Escherichia coli were compared. Although most steroid hormones had no or minor inhibitory effects on the dopamine formation by all CYP2D6 variants, progesterone inhibited the metabolism and Ki value against CYP2D6.10 was approximately twice that for CYP2D6.1 and CYP2D6.2. Quinidine exhibited stronger inhibition than quinine; however, these two compounds inhibited the CYP2D6.10-mediated reaction more weakly than the CYP2D6.1 and CYP2D6.2 reactions. These results suggest that CYP2D6 polymorphism would affect drug interaction through dopamine formation in the brain. PMID- 28347661 TI - Functional characterization of a common CYP4F11 genetic variant and identification of functionally defective CYP4F11 variants in erythromycin metabolism and 20-HETE synthesis. AB - CYP4F11, together with CYP4F2, plays an important role in the synthesis of 20 hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid. We identified 21 variants by whole exome sequencing, including 4 non-synonymous variants in Korean subjects. The proteins of the wild-type CYP4F11 and the four coding variants (C276R, D315N, D374Y, and D446N) were expressed in Escherichia coli DH5alpha cells and purified to give cytochrome P450-specific carbon monoxide difference spectra. Wild-type CYP4F2 was also expressed and purified to compare its activity with the CYP4F11 wild-type. Wild-type CYP4F11 exhibited the highest maximal clearance for erythromycin N-demethylase activity followed by the variants D374Y, D446N, C276R, and D315N. In particular, the CYP4F11 D315N protein showed about 50% decrease in intrinsic clearance compared to the wild type. The ability of wild-type CYP4F11 and the variants to synthesize 20-HETE from arachidonic acid was similar; the CYP4F11 D315N variant, however, showed only 68% of wild-type activity. Furthermore, the ability of CYP4F2 to synthesize 20-HETE was 1.7-fold greater than that of CYP4F11. Overall, our results suggest that the metabolism of CYP4F11 substrates may be reduced in individuals carrying the CYP4F11 D315N genetic variant and individuals carrying the common D446N CYP4F11 variant likely exhibit comparable 20-HETE synthesis as individuals expressing wild-type CYP4F11. PMID- 28347662 TI - An Assessment of the Frequency of Palliative Procedures in Thoracic Surgery. AB - OBJECTIVES: Palliative care is a medical specialty focused on improving the quality of life of patients and their families with life threatening illness by preventing or relieving suffering. An assessment of a thoracic surgery service was performed to identify the scope and frequency of care that was considered palliative and any implications the findings might have on the current thoracic surgery residency curriculum. METHODS: A retrospective review of a prospectively collected database of general thoracic surgery procedures performed over a 5-year period at a single institution was performed. Procedures considered palliative were reviewed for demographics, diagnoses, palliative prognosis score, treatment, morbidity, operative mortality, and survival. Excluded were referrals from thoracic surgery to other specialties for palliative procedures. RESULTS: During the study period, 3842 procedures were performed of which 884 (23%) were palliative. Indications included pleural or pericardial effusion or both, dysphagia, hemoptysis, tracheobronchial obstruction, bronchopleural fistula, and tracheoesophageal fistula. The majority was related to a malignancy. Only 127 patients (14%) had a palliative care assessment before thoracic surgery consultation. Mean survival following thoracic surgery intervention was 110 days for patients with malignancy. CONCLUSIONS: This investigation found that thoracic surgeons commonly care for patients when the intention or indication or both is palliation. Most of these patients have an associated malignancy, a poor performance status and a projected significantly decreased survival compared with the general population. Thoracic surgeons should be familiar with the concepts of palliative care and consideration should be given to expanding exposure to the principles of palliative care in the cardiothoracic residency training curriculum. PMID- 28347663 TI - Prospective Trial of House Staff Time to Response and Intervention in a Surgical Intensive Care Unit: Pager vs. Smartphone. AB - OBJECTIVE: The objective of the study was to characterize house staff time to response and intervention when notified of a patient care issue by pager vs. smartphone. We hypothesized that smartphones would reduce house staff time to response and intervention. DESIGN: Prospective study of all electronic communications was conducted between nurses and house staff between September 2015 and October 2015. The 4-week study period was randomly divided into two 2 week study periods where all electronic communications between intensive care unit nurses and intensive care unit house staff were exclusively by smartphone or by pager, respectively. Time of communication initiation, time of house staff response, and time from response to clinical intervention for each communication were recorded. Outcomes are time from nurse contact to house staff response and intervention. SETTING: Single-center surgical intensive care unit of Cedars-Sinai Medical Center in Los Angeles, California, an academic tertiary care and level I trauma center. PARTICIPANTS: All electronic communications occurring between nurses and house staff in the study unit during the study period were considered. During the study period, 205 nurse-house staff electronic communications occurred, 100 in the phone group and 105 in the pager group. RESULTS: House staff response to communication time was significantly shorter in the phone group (0.5 [interquartile range = 1.7] vs. 2 [3]min, p < 0.001). Time to house staff intervention after response was also significantly more rapid in the phone group (0.8 [1.7] vs. 1 [2]min, p = 0.003). CONCLUSIONS: Dedicated clinical smartphones significantly decrease time to house staff response after electronic nursing communications compared with pagers. PMID- 28347664 TI - Venestatin, a Ca++-binding protein from the parasitic nematode Strongyloides venezuelensis, is involved in the larval migration process. AB - The secretory EF-hand Ca++-binding proteins act as calcium signaling molecules for control of cell functions, but those proteins from parasitic helminths are poorly understood. Here, we have identified and characterized an EF-hand Ca++ binding protein from the rodent nematode, Strongyloides venezuelensis, termed 'venestatin', which is highly conserved in Strongyloides spp. Canonical two EF hand domains and a signal peptide are present in venestatin. A gel mobility shift assay and Ruthenium red staining indicated that the recombinant venestatin possesses binding ability with Ca++ ions. Endogenous venestatin was seemingly localized in the hypodermis and gut of the worms and was found in the excretory secretory products. Quantitative reverse transcription-PCR data showed that venestatin-specific transcript was upregulated in the parasitic stages of S. venezuelensis, and the upregulation occurred promptly after larval invasion through the host's skin, but not in the case of in vitro incubation. Immunization of mice with recombinant venestatin caused a 55% reduction in larval migration to the lungs, and lung hemorrhaging was mild compared with non-immunized groups, suggesting that anti-venestatin sera may interfere with larval migration from skin to lung. Our results suggest that venestatin is secreted from the hypodermis and gut of S. venezuelensis, and has pivotal roles in larval migration. PMID- 28347665 TI - Discovery of small molecule inhibitors for the snake venom metalloprotease BaP1 using in silico and in vitro tests. AB - Snakebites represent an important public health problem, with a great number of victims with permanent sequelae or fatal outcomes, particularly in rural, agriculturally active areas. The snake venom metalloproteases (SVMPs) are the principal proteins responsible for some clinically-relevant effects, such as local and systemic hemorrhage, dermonecrosis, and myonecrosis. Because of the difficulties in neutralizing them rapidly and locally by antivenoms, the search and design of small molecules as inhibitors of SVMPs are proposed. The Bothrops asper metalloprotease P1 (BaP1) is hereby used as a target protein and by High Throughput Virtual Screening (HTVS) approach, the free access virtual libraries: ZINC, PubChem and ChEMBL, were searched for potent small molecule inhibitors. Results from the aforementioned approaches provided strong evidences on the structural requirements for the efficient BaP1 inhibition such as the presence of the pyrimidine-2,4,6-trione moiety. The two proposed compounds have also shown excellent results in performed in vitro interaction studies against BaP1. PMID- 28347666 TI - Discovery of a series of 8-(1-phenylpyrrolidin-2-yl)-6-carboxamide-2-morpholino 4H-chromen-4-one as PI3Kbeta/delta inhibitors for the treatment of PTEN-deficient tumours. AB - Attempts to lock the active conformation of compound 4, a PI3Kbeta/delta inhibitor (PI3Kbeta cell IC50 0.015MUM), led to the discovery of a series of 8-(1 phenylpyrrolidin-2-yl)-6-carboxamide-2-morpholino-4H-chromen-4-ones, which showed high levels of potency and selectivity as PI3Kbeta/delta inhibitors. Compound 10 proved exquisitely potent and selective: PI3Kbeta cell IC50 0.0011MUM in PTEN null MDA-MB-468 cell and PI3Kdelta cell IC50 0.014MUM in Jeko-1 B-cell, and exhibited suitable physical properties for oral administration. In vivo, compound 10 showed profound pharmacodynamic modulation of AKT phosphorylation in a mouse PTEN-null PC3 prostate tumour xenograft after a single oral dose and gave excellent tumour growth inhibition in the same model after chronic oral dosing. Based on these results, compound 10 was selected as one of our PI3Kbeta/delta preclinical candidates. PMID- 28347667 TI - Discovery of novel BRD4 inhibitors by high-throughput screening, crystallography, and cell-based assays. AB - As an epigenetic reader, BRD4 regulates the transcription of important downstream genes that are essential for the survival of tumor cells. Small molecular inhibitors targeting the first bromodomain of BRD4 (BRD4-BD1) have showed promising potentials in the therapies of BRD4-related cancers. Through AlphaScreen-based high-throughput screening assay, a novel small molecular inhibitor was identified, and named DCBD-005, which inhibited the binding between BRD4-BD1 and acetylated lysines with an IC50 value of 0.81+/-0.03MUM. The compound DCBD-005 effectively inhibited the viability, caused cell cycle arrest, and induced apoptosis in human leukemia MV4-11 cells. Moreover, the crystal structure of compound DCBD-005 with the BRD4-BD1 was determined at 1.72A resolution, which revealed the binding mechanism of the leading compound, and also provided solid basis for further structure-based optimization. These results indicated that this novel BRD4-BD1 inhibitor DCBD-005 is promising to be developed into a drug candidate in the treatment of BRD4-related diseases. PMID- 28347669 TI - Microbial Keratitis After Penetrating Keratoplasty. AB - PURPOSE: To report the incidence, microbiological profile, graft survival, and determining factors of microbial keratitis after penetrating keratoplasty (PK). DESIGN: Observational case series. METHODS: The study involved 51 patients (52 eyes) who were treated at a single tertiary referral center during a 10-year period. Retrospective chart review included medical records of all patients diagnosed with microbial keratitis after penetrating keratoplasty at the National Taiwan University Hospital between January 2000 and December 2009. The main outcome measures were incidence of graft infection, microbial profile, and graft survival status. RESULTS: There were 871 PKs performed and 67 episodes in 52 eyes of culture-positive microbial keratitis during the study period. There were 32 infectious episodes (47.8%) in the first year post-PK and 35 episodes (52.2%) after the first year post-PK. Forty-four gram-positive bacterial isolates (57.9%), 17 gram-negative bacterial isolates (22.4%), and 15 fungal isolates (19.7%) were found. Twenty-three (34.3%) grafts remained clear after the infection episode with a mean follow-up of 1127 days (range, 25-3962 days). There was no difference in graft survival rate regarding the original indication of PK or offending pathogen. Suture-related infection was associated with decreased risk of graft failure (P = .02), while the factor associated with increased risk of graft failure was usage of antiglaucoma agents (P = .01). CONCLUSION: Infectious keratitis after penetrating keratoplasty leads to a high graft failure rate. Such complications can occur before or after the first year post-PK. PMID- 28347668 TI - Corrigendum to "Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 2: Development of a [3.3.0]-based series and other piperidine bioisosteres" [Bioorg. Med. Chem. Lett. 24 (2014) 1062-1066]. PMID- 28347670 TI - Oral delivery of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, synthetic peptide leptin mimetics: Immunofluorescent localization in the mouse hypothalamus. AB - This study describes the localization of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, synthetic peptide leptin mimetics, in the hypothalamus of Swiss Webster and C57BL/6J wild-type mice, leptin-deficient ob/ob mice, and leptin-resistant diet induced obese (DIO) mice. The mice were given [D-Leu-4]-OB3 or MA-[D-Leu-4]-OB3 in 0.3% dodecyl maltoside by oral gavage. Once peak serum concentrations were reached, the mice received a lethal dose of pentobarbital and were subjected to intracardiac perfusion fixation. The brains were excised, post-fixed in paraformaldehyde, and cryo-protected in sucrose. Free-floating frozen coronal sections were cut at 25-um and processed for imaging by immunofluorescence microscopy. In all four strains of mice, dense staining was concentrated in the area of the median eminence, at the base and/or along the inner wall of the third ventricle, and in the brain parenchyma at the level of the arcuate nucleus. These results indicate that [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 cross the blood-brain barrier and concentrate in an area of the hypothalamus known to regulate energy balance and glucose homeostasis. Most noteworthy is the localization of [D-Leu-4] OB3 immunoreactivity within the hypothalamus of DIO mice via a conduit that is closed to leptin in this rodent model, and in most cases of human obesity. Together with our previous studies describing the effects of [D-Leu-4]-OB3 and MA [D-Leu-4]-OB3 on energy balance, glucose regulation, and signal transduction pathway activation, these findings are consistent with a central mechanism of action for these synthetic peptide leptin mimetics, and suggest their potential usefulness in the management of leptin-resistant obesity and type 2 diabetes in humans. PMID- 28347671 TI - Deletion of Numb/Numblike in glutamatergic neurons leads to anxiety-like behavior in mice. AB - Endocytic adaptor protein Numb is the first identified cell fate determinant in Drosophila melanogaster. It has been implicated in Notch signaling pathway and regulation of neural stem cells proliferation in the central nervous system. Numb is also expressed in postmitotic neurons, in vitro studies showed that Numb is involved in neuronal morphologic development, such as neurite growth, axonal growth and spine development. However, in vivo functions of Numb in the postmitotic neurons are largely unknown. Here we show that deletion of Numb/Numblike in glutamatergic neurons causes anxiety-like behavior in mouse. In this study, we conditionally deleted Numb and its homologous gene Numblike in the glutamatergic neurons in dorsal forebrain, and thoroughly characterized the behavioral phenotypes of mutant mice. On a battery of tests for anxiety-like behavior, the conditional double knockout mice showed increased anxiety-like behavior on light/dark exploration and novel open field tests, but not on elevated zero maze tests. The conditional double knockout mice also displayed novelty induced hyperactivity in novel open field test. Control measures of general health, motor functions, startle response, sensorimotor gating, depression-related behaviors did not show differences between genotypes. Our present findings provide new insight into the indispensable functions of Numb/Numblike in the brain and behavior, and suggest that Numb/Numblike may play a role in mediating neuronal functions that underlie behaviors related to anxiety. PMID- 28347672 TI - Structural and kinetic analysis of Schistosoma mansoni Adenylosuccinate Lyase (SmADSL). AB - Schistosoma mansoni is the parasite responsible for schistosomiasis, a disease that affects about 218 million people worldwide. Currently, both direct treatment and disease control initiatives rely on chemotherapy using a single drug, praziquantel. Concerns over the possibility of resistance developing to praziquantel, have stimulated efforts to develop new drugs for the treatment of schistosomiasis. Schistosomes do not have the de novo purine biosynthetic pathway, and instead depend entirely on the purine salvage pathway to supply its need for purines. The purine salvage pathway has been reported as a potential target for developing new drugs against schistosomiasis. Adenylosuccinate lyase (SmADSL) is an enzyme in this pathway, which cleaves adenylosuccinate (ADS) into adenosine 5'-monophosphate (AMP) and fumarate. SmADSL kinetic characterization was performed by isothermal titration calorimetry (ITC) using both ADS and SAICAR as substrates. Structures of SmADSL in Apo form and in complex with AMP were elucidated by x-ray crystallography revealing a highly conserved tetrameric structure required for their function since the active sites are formed from residues of three different subunits. The active sites are also highly conserved between species and it is difficult to identify a potent species-specific inhibitor for the development of new therapeutic agents. In contrast, several mutagenesis studies have demonstrated the importance of dimeric interface residues in the stability of the quaternary structure of the enzyme. The lower conservation of these residues between SmADSL and human ADSL could be used to lead the development of anti-schistosomiasis drugs based on disruption of subunit interfaces. These structures and kinetics data add another layer of information to Schistosoma mansoni purine salvage pathway. PMID- 28347673 TI - Move me, astonish me... delight my eyes and brain: The Vienna Integrated Model of top-down and bottom-up processes in Art Perception (VIMAP) and corresponding affective, evaluative, and neurophysiological correlates. AB - This paper has a rather audacious purpose: to present a comprehensive theory explaining, and further providing hypotheses for the empirical study of, the multiple ways by which people respond to art. Despite common agreement that interaction with art can be based on a compelling, and occasionally profound, psychological experience, the nature of these interactions is still under debate. We propose a model, The Vienna Integrated Model of Art Perception (VIMAP), with the goal of resolving the multifarious processes that can occur when we perceive and interact with visual art. Specifically, we focus on the need to integrate bottom-up, artwork-derived processes, which have formed the bulk of previous theoretical and empirical assessments, with top-down mechanisms which can describe how individuals adapt or change within their processing experience, and thus how individuals may come to particularly moving, disturbing, transformative, as well as mundane, results. This is achieved by combining several recent lines of theoretical research into a new integrated approach built around three processing checks, which we argue can be used to systematically delineate the possible outcomes in art experience. We also connect our model's processing stages to specific hypotheses for emotional, evaluative, and physiological factors, and address main topics in psychological aesthetics including provocative reactions-chills, awe, thrills, sublime-and difference between "aesthetic" and "everyday" emotional response. Finally, we take the needed step of connecting stages to functional regions in the brain, as well as broader core networks that may coincide with the proposed cognitive checks, and which taken together can serve as a basis for future empirical and theoretical art research. PMID- 28347674 TI - Serum thioredoxin and in-hospital major adverse events after traumatic brain injury. AB - BACKGROUND: In-hospital major adverse events (IMAEs), mainly including acute lung injury, acute traumatic coagulopathy, progressive hemorrhagic injury and posttraumatic cerebral infarction, are associated with poor prognosis after traumatic brain injury (TBI). Thioredoxin, a potent anti-oxidant, has been identified as an oxidative stress marker. This study was designed to explore the association of serum thioredoxin concentrations with IMAEs of patients with severe TBI. METHODS: This prospective, observational study recruited a total of 108 healthy controls and 108 patients with severe TBI. We investigated the possible relation of serum thioredoxin concentrations to IMAEs and trauma severity (reflected by Glasgow coma scale scores) following TBI using a multivariate analysis. RESULTS: Serum thioredoxin concentrations were higher in the patients than in the controls. Serum concentrations of thioredoxin significantly correlated with admission Glasgow coma scale scores. Thioredoxin in serum independently predicted any IMAEs. As compared to admission Glasgow coma scale scores, thioredoxin concentrations had similar areas under receiver operating characteristic curve for any IMAEs. CONCLUSION: Increased serum thioredoxin concentrations are highly associated with trauma severity and IMAEs, indicating thioredoxin might be a potential prognostic biomarker after TBI. PMID- 28347675 TI - Equal clinical performance of a novel point-of-care cardiac troponin I (cTnI) assay with a commonly used high-sensitivity cTnI assay. AB - BACKGROUND: Efficient rule-out of acute myocardial infarction (MI) facilitates early disposition of chest pain patients in emergency departments (ED). Point-of care (POC) cardiac troponin (cTn) may improve patient throughput. We compared the diagnostic accuracy of a novel cTnI test (Minicare cTnI, Philips), with current POC cTnI (I-Stat, Abbott) and high-sensitivity central laboratory cTnI (hs-cTnI; Architect, Abbott) assays. METHODS: The clinical performance of the assays were compared in samples from 450 patients from a previous clinical evaluation of Minicare cTnI. RESULTS: Minicare cTnI correlated with Architect hs-cTnI (r2=0.85, p<0.0001) and I-Stat cTnI (r2=0.93, p<0.0001). Areas under the receiver operating characteristics curves were 0.87-0.91 at admission (p=ns) and 0.96-0.97 3h after admission (p=ns). The negative predictive values (NPV) at admission were 95% ((92 97%, 95% CI) for Minicare cTnI and increased to 99% (97-100%) at 2-4h, and similar to Architect hs-cTnI (98%, 96-100%), but higher than I-Stat cTnI (95%, 92 97%; p<0.01). Negative likelihood ratios (LR-) after 2-4h were 0.06 (0.02-0.17, 95% CI) for Minicare cTnI, 0.11 (0.05-0.24) for Architect hs-cTnI (p=0.02) and 0.28 (0.18-0.43) for I-Stat cTnI (p<0.0001). The clinical concordances between Minicare cTnI and Architect hs-cTnI were 92% (admission) and 95% (2-4h), with lower concordances between Minicare cTnI and I-Stat cTnI (83% and 78%, respectively; p=0.007). CONCLUSIONS: The Minicare cTnI POC assay may become useful for prompt and safe ruling-out of AMI in ED patients with suspected AMI using a guideline supported 0/3h sampling protocol. PMID- 28347677 TI - Effect of pest management on asthma symptoms. PMID- 28347676 TI - Treating Multiple Myeloma Patients With Oral Therapies. AB - Recent advances have highlighted the importance of long-term, continuous treatment in multiple myeloma (MM) to improve survival. However, treatment burden continues to negatively impact the real-world duration of MM therapy, and strategies to limit the adverse impact of treatment on patient quality of life are therefore particularly important. Oral MM therapies include the immunomodulatory drugs lenalidomide, thalidomide, and pomalidomide; the alkylating agents melphalan and cyclophosphamide; the histone deacetylase inhibitor panobinostat; the corticosteroids prednisone and dexamethasone; and the proteasome inhibitor ixazomib. The most commonly reported adverse events with these treatments include hematologic events such as thrombocytopenia and neutropenia; the gastrointestinal events nausea, vomiting, and diarrhea; venous thrombotic events such as deep-vein thrombosis and pulmonary embolism; and events such as rash and peripheral neuropathy. It is important that patients receiving oral therapies at home report symptoms before they become difficult to manage. Appropriate management of these treatment-related adverse events, awareness of both food and drug interactions, and assisting patients with out-of-pocket costs are all important factors in providing efficacious, sustainable, and convenient MM therapy. We outline evidence-based recommendations to provide a practical guide for health care providers addressing the effective management of MM patients receiving oral therapy. PMID- 28347678 TI - One and a half syndrome following penetrating head injury: Case report. AB - The authors report a case of a 22-year-old otherwise healthy female who presented following a head injury during a bar altercation, with no associated loss of consciousness and an unknown mechanism of injury. Examination revealed an isolated 1cm laceration on the right upper eyelid, superior to her medial canthus. She experienced diplopia on right horizontal gaze due to a left internuclear ophthalmoplegia (INO) with an associated left conjugate horizontal gaze palsy, collectively described as a left one-and-a-half syndrome. CT and MRI demonstrated evidence of a deep penetrating injury above the right medial canthus, traversing the ethmoid and sphenoid sinuses, the dorsum sella, narrowly missing the basilar artery, penetrating the pons, and extending to the floor of the contralateral fourth ventricle. The patient was diagnosed with multiple sinus fractures, lesions in her left paramedian pontine reticular formation (PPRF) and medial longitudinal fasciculus (MLF), and progressive pneumocephalus. She underwent a transsphenoidal endoscopic repair via a vascularized mucosal flap without complication. Postoperatively, the patient's pneumocephalus resolved and her conjugate gaze markedly improved; however, minimal diplopia remained. This case demonstrates the importance of the clinical exam, and its benefit in localizing imaging findings and guiding treatment. PMID- 28347679 TI - Chronic Traumatic Encephalopathy: The cellular sequela to repetitive brain injury. AB - This review aims to integrate current literature on the pathogenic mechanisms of Chronic Traumatic Encephalopathy (CTE) to create a multifactorial understanding of the disease. CTE is a progressive neurodegenerative disease, classed as a tauopathy, although it appears the pathogenic mechanisms are more complex than this. It affects those with a history of repetitive mild traumatic brain injury. Currently, there are no treatments for CTE and the disease can only be affirmatively diagnosed in post mortem. Understanding the pathogenesis of the disease will provide an avenue to explore possible treatment and diagnostic modalities. The pathological hallmarks of CTE have been well characterised and have been linked to the pathophysiologic mechanisms in this review. Human studies are limited due to ethical implications of exposing subjects to head trauma. Phosphorylation of tau, microglial activation, TAR DNA-binding protein 43 and diffuse axonal injury have all been implicated in the pathogenesis of CTE. The neuronal loss and axonal dysfunction mediated by these pathognomonic mechanisms lead to the broad psycho-cognitive symptoms seen in CTE. PMID- 28347680 TI - Top 50 most cited articles on primary tumors of the spine. AB - Citation analysis was performed in order to identify the top 50 most cited articles pertaining to the field of primary spinal tumors. This collection of articles highlights important trends in the neurosurgical literature. We searched the Thomson Reuters Web of Knowledge in order to identify articles pertaining to primary tumors of the spine. Impertinent articles were removed. The top 50 most cited articles were identified. Thereafter, article characteristics were determined including article type, article topic, level of evidence, and citation rate. The selected articles were published between 1951 and 2008. The most productive year was 1997 with 6 publications. The top 50 articles were published in twenty-two different journals, most commonly in Neurosurgery (12), Journal of Neurosurgery (8), and Spine (6). The most frequently cited article was by Tomita et al. written in 1997 which described total en bloc spondylectomy as a novel surgical technique in management of primary tumors of the vertebral column. We identified the 50 most-cited articles in the field of primary spinal tumors. This collection of articles serves as a reference for recognizing impactful studies in the field. PMID- 28347682 TI - The importance of clinical competence in an age of the more diagnostic tests the better. PMID- 28347681 TI - Endovascular treatment of ruptured tiny (?3mm) intracranial aneurysms in the setting of subarachnoid hemorrhage: A case series of 20 patients and literature review. AB - Successful endovascular coiling of ruptured tiny saccular intracranial aneurysms (?3mm) is technically challenging and traditionally has been associated with technical failures, as well as morbidity related to thromboembolic events and high intraoperative rupture rates. This study analyzes the feasibility, technical efficacy, and clinical outcomes of coil embolization of ruptured tiny intracranial aneurysms using current coil and microcatheter technology and techniques. We performed a retrospective review of 20 patients with 20 ruptured tiny aneurysms treated with endovascular coil embolization from 2013 to 2016 at a single high-volume academic tertiary care practice. The mean aneurysm size was 2.4mm (median 2.5mm, 1-3). Complete occlusion was achieved in 12 of 20 patients (60%), the remaining 7 of 20 patients (35%) had a small neck remnant, and there was 1 failure (5%) converted to microsurgical clipping. Two patients had a failed attempted surgical clip reconstruction and were subsequently coiled. There was 1 intraprocedural rupture (5%) and 1 severe parent artery vasospasm (5%) during coiling. At discharge, 60% of patients were living independently. At follow-up three patients were deceased. Mean angiographic follow-up was 139days (SD 120). There were no aneurysm recurrences among occluded patients and there were no retreatments among those with neck remnants. Coiling of ruptured aneurysms ?3mm is feasible with high occlusion rates and low complication rates. The availability of softer coils with flexible detachment zones has led to safe and effective endovascular treatment of tiny ruptured aneurysms. PMID- 28347683 TI - Adult food borne botulism in Australia: The only 2 cases from the last 15years. PMID- 28347684 TI - Prognostic model for patients with traumatic brain injuries and abnormal computed tomography scans. AB - Traumatic brain injury (TBI) is an important cause of death and disability worldwide. The prognosis evaluation is a challenge when many variables are involved. The authors aimed to develop prognostic model for assessment of survival chances after TBI based on admission characteristics, including extracranial injuries, which would allow application of the model before in hospital therapeutic interventions. A cohort study evaluated 1275 patients with TBI and abnormal CT scans upon admission to the emergency unit of Hospital das Clinicas of University of Sao Paulo and analyzed the final outcome on mortality. A logistic regression analysis was undertaken to determine the adjusted weigh of each independent variable in the outcome. Four variables were found to be significant in the model: age (years), Glasgow Coma Scale (3-15), Marshall Scale (MS, stratified into 2,3 or 4,5,6; according to the best group positive predictive value) and anysochoria (yes/no). The following formula is in a logistic model (USP index to head injury) estimates the probability of death of patients according to characteristics that influence on mortality. We consider that our mathematical probability model (USP Index) may be applied to clinical prognosis in patients with abnormal CT scans after severe traumatic brain injury. PMID- 28347685 TI - Distinguishing age-related cognitive decline from dementias: A study based on machine learning algorithms. AB - BACKGROUND AND AIM: This study aims to examine the distinguishability of age related cognitive decline (ARCD) from dementias based on some neurocognitive tests using machine learning. MATERIALS AND METHODS: 106 subjects were divided into four groups: ARCD (n=30), probable Alzheimer's disease (AD) (n=20), vascular dementia (VD) (n=21) and amnestic mild cognitive impairment (MCI) (n=35). The following tests were applied to all subjects: The Wechsler memory scale-revised, a clock-drawing, the dual similarities, interpretation of proverbs, word fluency, the Stroop, the Boston naming (BNT), the Benton face recognition, a copying drawings and Oktem verbal memory processes (O-VMPT) tests. A multilayer perceptron, a support vector machine and a classification via regression with M5 model trees were employed for classification. RESULTS: The pairwise classification results show that ARCD is completely separable from AD with a success rate of 100% and highly separable from MCI and VD with success rates of 95.4% and 86.30%, respectively. The neurocognitive tests with the higher merit values were O-VMPT recognition (ARCD vs. AD), O-VMPT total learning (ARCD vs. MCI) and semantic fluency, proverbs, Stroop interference and naming BNT (ARCD vs. VD). CONCLUSION: The findings show that machine learning can be successfully utilized for distinguishing ARCD from dementias based on neurocognitive tests. PMID- 28347686 TI - A novel US-CAB protocol for ultrasonographic evaluation during cardiopulmonary resuscitation. PMID- 28347688 TI - Effects of diabetic retinopathy on the barrier functions of the retinal pigment epithelium. AB - Diabetic retinopathy is a debilitating microvascular complication of diabetes mellitus. A rich literature describes the breakdown of retinal endothelial cells and the inner blood-retinal barrier, but the effects of diabetes on the retinal pigment epithelium (RPE) has received much less attention. RPE lies between the choroid and neurosensory retina to form the outer blood-retinal barrier. RPE's specialized and dynamic barrier functions are crucial for maintaining retinal health. RPE barrier functions include a collection of interrelated structures and activities that regulate the transepithelial movement of solutes, including: diffusion through the paracellular spaces, facilitated diffusion through the cells, active transport, receptor-mediated and bulk phase transcytosis, and metabolic processing of solutes in transit. In the later stages of diabetic retinopathy, the tight junctions that regulate the paracellular space begin to disassemble, but there are earlier effects on the other aspects of RPE barrier function, particularly active transport and metabolic processing. With advanced understanding of RPE-specific barrier functions, and more in vivo-like culture models, the time is ripe for revisiting experiments in the literature to resolve controversies and extend our understanding of how diabetes affects the outer blood-retinal barrier. PMID- 28347689 TI - Intraneural ganglion cysts: A predictable method to their madness. PMID- 28347687 TI - Effects of chronic inhalation of electronic cigarettes containing nicotine on glial glutamate transporters and alpha-7 nicotinic acetylcholine receptor in female CD-1 mice. AB - Alteration in glutamate neurotransmission has been found to mediate the development of drug dependence, including nicotine. We and others, through using western blotting, have reported that exposure to drugs of abuse reduced the expression of glutamate transporter-1 (GLT-1) as well as cystine/glutamate antiporter (xCT), which consequently increased extracellular glutamate concentrations in the mesocorticolimbic area. However, our previous studies did not reveal any changes in glutamate/aspartate transporter (GLAST) following exposure to drugs of abuse. In the present study, for the first time, we investigated the effect of chronic exposure to electronic (e)-cigarette vapor containing nicotine, for one hour daily for six months, on GLT-1, xCT, and GLAST expression in frontal cortex (FC), striatum (STR), and hippocampus (HIP) in outbred female CD1 mice. In this study, we also investigated the expression of alpha-7 nicotinic acetylcholine receptor (alpha-7 nAChR), a major pre-synaptic nicotinic receptor in the glutamatergic neurons, which regulates glutamate release. We found that inhalation of e-cigarette vapor for six months increased alpha-7 nAChR expression in both FC and STR, but not in the HIP. In addition, chronic e-cigarette exposure reduced GLT-1 expression only in STR. Moreover, e cigarette vapor inhalation induced downregulation of xCT in both the STR and HIP. We did not find any significant changes in GLAST expression in any brain region. Finally, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques, we detected high concentrations of nicotine and cotinine, a major metabolite of nicotine, in the FC tissues of e-cigarette exposed mice. These data provide novel evidence about the effects of chronic nicotine inhalation on the expression of key glial glutamate transporters as well as alpha-7 nAChR. Our work may suggest that nicotine exposure via chronic inhalation of e-cigarette vapor may be mediated in part by alterations in the glutamatergic system. PMID- 28347690 TI - Nordic walking versus walking without poles for rehabilitation with cardiovascular disease: Randomized controlled trial. AB - BACKGROUND: With Nordic walking, or walking with poles, one can travel a greater distance and at a higher rate than with walking without poles, but whether the activity is beneficial for patients with cardiovascular disease is unknown. OBJECTIVE: This randomized controlled trial was undertaken to determine whether Nordic walking was more effective than walking without poles on walk distance to support rehabilitation training for patients with acute coronary syndrome (ACS) and peripheral arterial occlusive disease (PAOD). METHODS: Patients were recruited in a private specialized rehabilitation centre for cardiovascular diseases. The entire protocol, including patient recruitment, took place over 2 months, from September to October 2013. We divided patients into 2 groups: Nordic Walking Group (NWG, n=21) and Walking Group without poles (WG, n=21). All patients followed the same program over 4 weeks, except for the walk performed with or without poles. The main outcome was walk distance on the 6-min walk test. Secondary outcomes were maximum heart rate during exercise and walk distance and power output on a treadmill stress test. RESULTS: We included 42 patients (35 men; mean age 57.2+/-11 years and BMI 26.5+/-4.5kg/m2). At the end of the training period, both groups showed improved walk distance on the 6-min walk test and treatment stress test as well as power on the treadmill stress test (P<0.05). The NWG showed significantly greater walk distance than the WG (P<0.05). Both ACS and PAOD groups showed improvement, but improvement was significant for only PAOD patients. CONCLUSIONS: After a 4-week training period, Nordic walking training appeared more efficient than training without poles for increasing walk distance on the 6-min walk test for patients with ACS and PAOD. PMID- 28347691 TI - Workers' perspectives on return to work after total knee arthroplasty. AB - OBJECTIVES: Total knee arthroplasty is an effective intervention for people with osteoarthritis. However, 15 to 30% of patients do not return to work, and studies frequently fail to provide an explanation of what may lead to work disability from workers' perspectives of the biopsychosocial factors. This study aimed to document workers' representations or understanding of work disability after total knee arthroplasty. METHOD: We adopted a qualitative approach with a narrative inquiry method. A convenience sample of partially and fully disabled workers was interviewed 6 to 12months after surgery with use of a semi-structured interview guide and questionnaires on physical work demands and pain. Interviews were audiotaped, transcribed verbatim, and anonymized. Consensus was reached on coding, and multidisciplinary content analysis was performed. RESULTS: Among the 8 workers interviewed, all were formally employed before surgery, half were men, and the mean age was 55years. Half were not back at work when interviewed and felt they had received little support from their workplace, were struggling to adapt to their new condition, and had very few adaptive strategies for trying to get better (other than waiting), which did not make sense to them. By contrast, the other half felt they had experienced greater improvement after surgery and received concrete support from their workplace, which facilitated their return to work in their view. CONCLUSION: A work disability paradigm, based on a biopsychosocial approach, should be considered in rehabilitation when workers experience difficulty returning to work after total knee arthroplasty, because other factors besides the patient's condition may be involved. PMID- 28347692 TI - miR-21-5p/203a-3p promote ox-LDL-induced endothelial cell senescence through down regulation of mitochondrial fission protein Drp1. AB - This study aims to identify both endothelia-specific/enriched and senescence associated miRNAs as well as their functions. The rats were fed on high-fat diet to establish a hyperlipidemic model, which showed an increase in plasma lipids and acceleration in endothelial senescence and endothelial dysfunction, accompanied by alterations in 7 endothelia-specific/enriched and senescence associated miRNAs. Among the 7 selected miRNAs, miR-21-5p and miR-203a-3p were significantly up-regulated in a human umbilical vein endothelial cells (HUVECs) senescent model induced by ox-LDL, consistent with their changes in the hyperlipidemic rats. After performing the bioinformatic analysis, dynamin-related protein 1 (Drp1) was predicted to be a potential target for both miR-21-5p and miR-203a-3p. In ox-LDL-induced senescent HUVECs, Drp1 was significantly down regulated, concomitant with mitochondrial dysfunctions and the activation of AMPK p53/p16 pathway, while these phenomena were attenuated by miR-21-5p or miR-203a 3p inhibitor. Luciferase reporter gene assay confirmed a direct interaction between miR-21-5p and Drp1 but not between miR-203a-3p and Drp1. Based on these observations, we conclude that miR-21-5p/203a-3p promote ox-LDL-induced endothelial senescence through down-regulation of Drp1 in a direct or indirect way. Our findings highlight the plasma levels of miR-21-5p/203a-3p may serve as novel biomarkers to evaluate the degree of endothelial senescence in hyperlipidemia. PMID- 28347693 TI - CTT1 overexpression increases the replicative lifespan of MMS-sensitive Saccharomyces cerevisiae deficient in KSP1. AB - Ksplp is a nuclear-localized Ser/Thr kinase that is not essential for the vegetative growth of yeast. A global gene function analysis in yeast suggested that Ksplp was involved in the oxidative stress response; however, the underlying mechanism remains unclear. Here, we showed that KSP1-deficient yeast cells exhibit hypersensitivity to the DNA alkylating agent methyl methanesulphonate (MMS), and treatment of the KSP1-deficient strain with MMS could trigger abnormal mitochondrial membrane potential and up-regulate reactive oxygen species (ROS) production. In addition, the mRNA expression level of the catalase gene CTT1 (which encodes cytosolic catalase) and total catalase activity were strongly down regulated in the KSP1-deleted strain compared with those in wild-type cells. Moreover, the KSP1 deficiency also leads to a shortened replicative lifespan, which could be restored by the increased expression of CTT1. On the other hand, KSP1-overexpressed (KSP1OX) yeast cells exhibited increased resistance towards MMS, an effect that was, at least in part, CTT1 independent. Collectively, these findings highlight the involvement of Ksplp in the DNA damage response and implicate Ksplp as a modulator of the replicative lifespan. PMID- 28347694 TI - Agreement between automated and manual quantification of corneal nerve fiber length: Implications for diabetic neuropathy research. AB - AIMS: Quantification of corneal nerve fiber length (CNFL) by in vivo corneal confocal microscopy represents a promising diabetic neuropathy biomarker, but applicability is limited by resource-intensive image analysis. We aimed to evaluate, in cross-sectional analysis of non-diabetic controls and patients with type 1 and type 2 diabetes with and without neuropathy, the agreement between manual and automated analysis protocols. METHODS: Sixty-eight controls, 139 type 1 diabetes, and 249 type 2 diabetes participants underwent CNFL measurement (N=456). Neuropathy status was determined by clinical and electrophysiological criteria. CNFL was determined by manual (CNFLManual, reference standard) and automated (CNFLAuto) protocols, and results were compared for correlation and agreement using Spearman coefficients and the method of Bland and Altman (CNFLManual subtracted from CNFLAuto). RESULTS: Participants demonstrated broad variability in clinical characteristics associated with neuropathy. The mean age, diabetes duration, and HbA1c were 53+/-18years, 15.9+/-12.6years, and 7.4+/-1.7%, respectively, and 218 (56%) individuals with diabetes had neuropathy. Mean CNFLManual was 15.1+/-4.9mm/mm2, and mean CNFLAuto was 10.5+/-3.7mm/mm2 (CNFLAuto underestimation bias, -4.6+/-2.6mm/mm2 corresponding to -29+/-17%). Percent bias was similar across non-diabetic controls (-33+/-12%), type 1 (-30+/-20%), and type 2 diabetes (-28+/-16%) subgroups (ANOVA, p=0.068), and similarly in diabetes participants with and without neuropathy. Levels of CNFLAuto and CNFLManual were both inversely associated with neuropathy status. CONCLUSIONS: Although CNFLAuto substantially underestimated CNFLManual, its bias was non-differential between diverse patient groups and its relationship with neuropathy status was preserved. Determination of diagnostic thresholds specific to CNFLAuto should be pursued in diagnostic studies of diabetic neuropathy. PMID- 28347695 TI - Association of sarcopenia with both latent autoimmune diabetes in adults and type 2 diabetes: a cross-sectional study. AB - BACKGROUND: To investigate the association of both latent autoimmune diabetes in adults (LADA) and type 2 diabetes (T2DM) with muscle mass and function (sarcopenia). METHODS: Japanese patients with LADA (N=20), T2DM (N=208), and control subjects (N=41) were included in this cross-sectional study. The definition of LADA was based on age of onset (>=30), positive glutamic acid decarboxylase autoantibodies, and insulin requirement within the first 6months after diagnosis. Sarcopenia was diagnosed by the criteria for Asians, using skeletal muscle index (male <7.0 and female <5.4) and grip strength (male <26.0kg and female <18.0kg). The odds ratio (OR) with a 95% confidence interval (CI) was estimated using logistic regression. RESULTS: The prevalence of sarcopenia was higher in LADA (35.0%) than in either T2DM (13.3%) or control subjects (9.8%). LADA was significantly associated with an increased risk for sarcopenia in a multivariate model in which age and body mass index were incorporated (OR: 9.57, 95% CI: 1.86-49.27). In contrast, T2DM tended to be associated with an increased risk for sarcopenia (OR: 2.99, 95% CI: 0.83-10.80). CONCLUSIONS: This study provides evidence that patients with LADA are at a high risk for sarcopenia compared to those with T2DM or to control subjects. PMID- 28347697 TI - [Medication safety in nursing home residents with renal insufficiency - Results of a qualitative study]. AB - BACKGROUND: Nursing home residents often suffer from multimorbidity and polypharmacy. Impaired renal function and the lack of dose adjustments further increase the risk of adverse drug reactions (ADR). The aims of this qualitative study were to analyze the reasons for inadequate drug treatment and to identify possible intervention options to improve safety of drug treatment in nursing home residents with renal insufficiency. METHODS: Using a mixed-method approach a cross-sectional study and focus group discussions were performed in the project. Focus groups with general practitioners, nursing staff, nephrologists and pharmacists were held. Audiotapes were transcribed verbatim, qualitative content analysis of the transcripts according to Mayring was conducted using MAXQDA. RESULTS AND CONCLUSIONS: Focus groups discussed different aspects and possible interventions related to inadequate drug treatment in nursing home residents with renal insufficiency. The main topics identified were "health service situation", "reasons for ADR" and "interventions". Regarding the current health service situation "infrastructure", "role of polypharmacy", "assessment of renal function" and the "different role models" were identified as relevant aspects for improving the safety of drug treatment in nursing homes. According to the participants, there is a lack of evidence-based standards regarding laboratory monitoring and estimation of kidney function. PMID- 28347696 TI - Workplace mental health: An international review of guidelines. AB - The aim of this systematic review was to determine the quality and comprehensiveness of guidelines developed for employers to detect, prevent, and manage mental health problems in the workplace. An integrated approach that combined expertise from medicine, psychology, public health, management, and occupational health and safety was identified as a best practice framework to assess guideline comprehensiveness. An iterative search strategy of the grey literature was used plus consultation with experts in psychology, public health, and mental health promotion. Inclusion criteria were documents published in English and developed specifically for employers to detect, prevent, and manage mental health problems in the workplace. A total of 20 guidelines met these criteria and were reviewed. Development documents were included to inform quality assessment. This was performed using the AGREE II rating system. Our results indicated that low scores were often due to a lack of focus on prevention and rather a focus on the detection and treatment of mental health problems in the workplace. When prevention recommendations were included they were often individually focused and did not include practical tools or advice to implement. An inconsistency in language, lack of consultation with relevant population groups in the development process and a failure to outline and differentiate between the legal/minimum requirements of a region were also observed. The findings from this systematic review will inform translation of scientific evidence into practical recommendations to prevent mental health problems within the workplace. It will also direct employers, clinicians, and policy-makers towards examples of best-practice guidelines. PMID- 28347698 TI - Postzygotic Mutations in Beta-Actin Are Associated with Becker's Nevus and Becker's Nevus Syndrome. PMID- 28347699 TI - Effect of adipose-derived stem cells on acellular dermal matrix engraftment in a rabbit model of breast reconstruction. AB - Acellular dermal matrix (ADM) is frequently used in implant-based breast reconstruction. Although there are several advantages, ADM implantation also increases the risk of certain complications. Recently, ADM seeded with adipose derived stem cells (ADSCs) were shown to induce angiogenesis and improve wound healing. This study aimed to investigate the effects of ADSCs on ADM engraftment in a rabbit model of implant-based breast reconstruction. Silicone implants were inserted to submuscular pocket of 16 female New Zealand rabbits using ADM with or without seeding of fluorescent PKH26-labelled rabbit ADSCs. The marginal and central ADMs in each group were evaluated at 1 and 3 months after insertion. We performed a histological analysis including the number of CD31+ blood vessels, vimentin+ fibroblasts and lymphocytes; live/dead analysis; and gene expression analysis related to angiogenesis, inflammation and hypoxia. The implant was exposed in one rabbit with ADM without ADSCs during the study period. At 1 month, a histological analysis revealed more blood vessels and fibroblasts and reduced immune cell infiltration in marginal ADM with ADSCs. At 3 months, only angiogenesis was histologically different between groups. Conversely, cellularity was not significantly different in the central ADM between groups at month 1 or 3. ADSC supplementation increased the gene expression level associated with angiogenesis and inflammation, but not hypoxia. PKH26-labelled ADSCs were observed in both marginal and central ADMs at month 3. ADM seeded with ADSCs might be useful in promoting early incorporation with recipient tissue. This study supports the potential of ADM seeded with ADSCs as a reliable material for implant-based breast reconstruction. PMID- 28347700 TI - Connexins and Pannexins in cerebral ischemia. AB - A common cause of mortality and long-term adult disability, cerebral ischemia or brain ischemia imposes a significant health and financial burden on communities worldwide. Cerebral ischemia is a condition that arises from a sudden loss of blood flow and consequent failure to meet the high metabolic demands of the brain. The lack of blood flow initiates a sequelae of cell death mechanisms, including the activation of the inflammatory pathway, which can ultimately result in irreversible brain tissue damage. In particular, Connexins and Pannexins are non-selective channels with a large pore that have shown to play time-dependent roles in the perpetuation of ischaemic injury. This review highlights the roles of Connexin and Pannexin channels in cell death mechanisms as a promising therapeutic target in cerebral ischemia, and in particular connexin hemichannels which may contribute most of the ATP release as a result of ischemia as well as during reperfusion. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve. PMID- 28347701 TI - Long-term response in patient with recurrent oropharyngeal carcinoma treated with cetuximab, docetaxel and cisplatin (TPEx) as first-line treatment followed by cetuximab maintenance. AB - BACKGROUND: Cetuximab, an anti-EGFR monoclonal antibody in combination with platinum and 5FU is the standard of care in first-line treatment of patients with recurrent head and neck squamous cell carcinoma (HNSCC), with an expected median outcome of 10months. For this population, development of efficacious and safer therapies is still needed. CASE REPORT: A 62-year-old male with a first recurrence of human papillomavirus positive stage IVA (T3N2bM0) adenocarcinoma of the glossotonsillar sulcus not amenable to locoregional curative treatment was offered chemotherapy as part of the TPEx clinical trial. He was treated by cetuximab (loading dose 400mg/m2 on day 1 cycle 1, then 250mg/m2 weekly), and chemotherapy (cisplatin 75mg/m2 and docetaxel 75mg/m2, on day 1). Cycles were repeated every 21days for 4 cycles (TPEx regimen) with systematic granulocyte colony-stimulating factor support at each cycle. Bi-monthly maintenance cetuximab 500mg/m2 was then administered. The patient showed a clinical complete response according to RECIST 1.1 criteria after 5months maintenance, with progression-free survival of 25months. Relapses that followed were treated with stereotactic irradiation, radiofrequency ablation, cetuximab and paclitaxel. The patient is alive eleven years after cancer diagnosis and remains controlled for his disease, with a cumulative period of 59months of cetuximab administration (equivalence of 121 injections). CONCLUSION: This case report demonstrated that TPEx regimen, by synergistic interaction between taxanes and cetuximab, followed by bimonthly cetuximab maintenance may lead to patient complete remission within the first year of treatment. Furthermore, prolonged intermittent treatment with cetuximab seems to participate in the improved survival associated with preserved quality of life. Key favorable prognostic factors may be moderate tumor differentiation, oropharyngeal location, HPV p16 positive tumor status. PMID- 28347702 TI - Cytokine gene polymorphisms in populations from Parana, Southern Brazil. AB - In this study, were genotyped 22 single nucleotide polymorphisms (SNPs) in 13 genes that encode the pro-inflammatory (IL-1alpha, IL-1beta, IL-1R, IL-4Ralpha, IL-12, IFN-gamma, TNF-alpha, and IL-2) and anti-inflammatory (IL-1RA, TGF-beta, IL-4, IL-6 and IL-10) cytokines of 350 individuals by PCR-SSP (polymerase chain reaction - sequence specific primer). A total of 473 individuals were genotyped for IL17A and IL17F genes by PCR-RFLP (restriction fragment length polymorphism). The sample consisted of healthy and unrelated subjects from a mixed population from Parana state, in the South region of Brazil. The frequency analyses and genotype data are available in the Supplementary materials and are accessible at Allele Frequency Net Database (AFND). PMID- 28347703 TI - Afidopyropen: New and potent modulator of insect transient receptor potential channels. AB - The commercial insecticides pymetrozine and pyrifluquinazon control plant-sucking pests by disturbing their coordination and ability to feed. We have previously shown that these compounds act by overstimulating and eventually silencing vanilloid-type transient receptor potential (TRPV) channels, which consist of two proteins, Nanchung and Inactive, that are co-expressed exclusively in insect chordotonal stretch receptor neurons. Here we show that a new insecticidal compound, afidopyropen, modulates chordotonal organs of American grasshoppers (Schistocerca americana) in the same fashion. Afidopyropen stimulated heterologously expressed TRPV channels from two different insect species - fruit fly (Drosophila melanogaster) and pea aphid (Acyrthosiphon pisum) - but did not affect function of the mammalian TRPV channel TRPV4. Activation of the insect TRPVs required simultaneous expression of both Nanchung and Inactive proteins. Tritium-labeled afidopyropen bound fruit fly TRPVs with higher affinity than pymetrozine and competed with pymetrozine for binding. Nanchung protein formed the main binding interface for afidopyropen, whereas co-expression of Inactive dramatically increased binding affinity. Another modulator of chordotonal organs, flonicamid, did not activate insect TRPV channels, nor did it compete with afidopyropen for binding, indicating that it has a different target site. These results define afidopyropen as a new, potent and specific modulator of insect TRPV channels, and provide insight into the unique binding mode of these compounds. PMID- 28347704 TI - High glucose induced endothelial to mesenchymal transition in human umbilical vein endothelial cell. AB - BACKGROUND: Studies have shown that endothelial-to-mesenchymal transition (EndMT) could contribute to the progression of diabetic nephropathy, diabetic renal fibrosis, and cardiac fibrosis. The aim of this study was to investigate the influence of high glucose and related mechanism of MAPK inhibitor or specific antioxidant on the EndMT. METHODS: In vitro human umbilical vein endothelial cells (HUVEC) were cultured with 11mM, 30mM, 60mM and 120mM glucose for 0, 24, 48, 72 and 168h. Endothelial cell morphology was observed with microscope, and RT PCR was used to detect mRNA expression of endothelial markers VE-cadherin and CD31, mesenchymal markers alpha-SMA and collagen I, and transforming growth factor TGF-beta1. Immunofluorescence staining was performed to detect the expression of CD31 and alpha-SMA. The concentration of TGF-beta1 in the supernatant was detected by ELISA. ERK1/2 phosphorylation level was detected by Western blot analysis. RESULTS: High glucose induced EndMT and increased the TGF beta1 level in HUVEC cells. Cells in high glucose for 7 days showed a significant decrease in mRNA expression of CD31 and VE-cadherin, and a significant increase in that of alpha-SMA and collagen I, while lost CD31 staining and acquired alpha SMA staining. ERK signaling pathway blocker PD98059 significantly attenuated the high glucose-induced increase in the ERK1/2 phosphorylation level. PD98059 and NAC both inhibited high glucose-induced TGF-beta1 expression and attenuated EndMT marker protein synthesis. CONCLUSION: High glucose could induce HUVEC cells to undergo EndMT. NAC and ERK signaling pathway may play important role in the regulation of the TGF-beta1 biosynthesis during high glucose-induced EndMT. PMID- 28347705 TI - Impact of temperature on sea bass, Dicentrarchus labrax, retina: Fatty acid composition, expression of rhodopsin and enzymes of lipid and melatonin metabolism. AB - Teleost fish are ectothermic vertebrates. Their metabolism, physiology and behavior rely on the external temperature. This study, on the retina of the sea bass Dicentrarchus labrax, reports on the impact of temperature on the fatty acid composition and mRNA abundance of key enzymes of lipid metabolism: fatty acid desaturase-2 (FADS2), fatty acid elongase-5 (ELOVL5), sterol regulatory element binding protein-1 (SREBP-1), triglyceride lipase and phospholipase A2 (PLA2). We also report on the effects on the photopigment molecule rhodopsin and on enzymes of the melatonin synthesis pathway, namely arylalkylamine N-acetyltransferases 1a and 1b and acetylserotonin methyltransferase. Juvenile fish were placed for 30 days at 18, 23 or 28 degrees C. At 23 degrees C, the fatty acid composition of D. labrax retina showed, as generally reported for the retina of other fish species, particularly high amounts of docosahexaenoic (DHA), palmitic and oleic acids. The fatty acids composition was not significantly (P > 0.05) altered between 23 and 28 degrees C, but did increase at 18 degrees C compared to 23 and 28 degrees C. At 18 degrees C there were noticeable increases in total DHA, ecosapentaenoic, arachidonic, oleic, linoleic, palmitoleic and stearic acids. A negative correlation was found in the abundance of neutral (NL) vs. polar (PL) lipids: 18 degrees C induced an increase in NL and a decrease in PL, while 28 degrees C induced higher PL with decreased NL. In NL the changes affected mainly triglycerides. FADS2 and ELOVL5 mRNA abundance decreased from 18 degrees to 28 degrees C while SREBP-1 and triglyceride lipase mRNA remained stable. Conversely PLA2 mRNA was more abundant at 23 than at 18 and 28 degrees C. Temperature increased and decreased rhodopsin mRNA abundance, at 28 degrees C and 18 degrees C respectively, while there was no effect on mRNA from the melatonin synthesis enzymes. In conclusion the data indicate a temperature induced redistribution of fatty acids among the lipid classes that might affect the physical properties of the plasma membranes as well as functions associated with photoreception or generation of intracellular second messengers. In addition, the results suggest that temperature targets only the proteins and activities of retinal melatonin production. This study opens new lines of investigation related to the role temperature and fatty acids play in fish visual perception. They are relevant in the context of the global warming of seas affecting both the wild and the aquaculture species. PMID- 28347706 TI - Knowledge, attitudes and practice for Ebola virus disease in the national rapidly deployable isolation and treatment facility in Sierra Leone. PMID- 28347707 TI - The involvement of sirtuin 1 and heme oxygenase 1 in the hepatoprotective effects of quercetin against carbon tetrachloride-induced sub-chronic liver toxicity in rats. AB - The present study was designed to evaluate the therapeutic potential of quercetin in a sub-chronic model of hepatotoxicity. The roles of putative antioxidant enzymes, sirtuin 1 (SIRT1) and heme oxygenase 1 (HO-1), in hepatoprotection were also addressed. Sub-chronic liver injury was induced in rats by intraperitoneal administration of 0.5 ml/kg carbon tetrachloride (CTC), once every 3 days, for 2 weeks. Some CTC rats were concurrently treated with 100 mg/kg quercetin, intragastrically, once every day, for 2 weeks. The effects of these drugs in the liver were evaluated by biochemical, histological, immunohistochemical and molecular biological studies. CTC triggered oxidative damage to the liver as unanimously shown by altered biochemical parameters and liver morphology. Furthermore, CTC highly upregulated HO-1 and SIRT1 expression levels. Concomitant treatment of rats with quercetin downregulated SIRT1 expression and ameliorated the hepatotoxic effects of CTC. However, quercetin did not have any significant effect on HO-1 expression and bilirubin levels. Collectively, these results suggest that the antioxidant and cytoprotective effects of quercetin in CTC treated rats were SIRT1 mediated and less dependent on HO-1. Thus, pharmacologic modulation of SIRT1 could provide a logic therapeutic approach in sub-chronic hepatotoxicity. PMID- 28347709 TI - Reply to the comment of Daron et al. entitled "Occurrence of rheumatic symptoms in celiac disease: A meta-analysis". PMID- 28347708 TI - Analytical validation of a reverse transcriptase droplet digital PCR (RT-ddPCR) for quantitative detection of infectious hematopoietic necrosis virus. AB - Infectious hematopoietic necrosis virus (IHNV) is an important pathogen of salmonid fishes. A validated universal reverse transcriptase quantitative PCR (RT qPCR) assay that can quantify levels of IHNV in fish tissues has been previously reported. In the present study, we adapted the published set of IHNV primers and probe for use in a reverse-transcriptase droplet digital PCR (RT-ddPCR) assay for quantification of the virus in fish tissue samples. The RT-ddPCR and RT-qPCR assays detected 13 phylogenetically diverse IHNV strains, but neither assay produced detectable amplification when RNA from other fish viruses was used. The RT-ddPCR assay had a limit of detection (LOD) equating to 2.2 plaque forming units (PFU)/MUl while the LOD for the RT-qPCR was 0.2 PFU/MUl. Good agreement (69.4-100%) between assays was observed when used to detect IHNV RNA in cell culture supernatant and tissues from IHNV infected rainbow trout (Oncorhynchus mykiss) and arctic char (Salvelinus alpinus). Estimates of RNA copy number produced by the two assays were significantly correlated but the RT-qPCR consistently produced higher estimates than the RT-ddPCR. The analytical properties of the N gene RT-ddPCR test indicated that this method may be useful to assess IHNV RNA copy number for research and diagnostic purposes. Future work is needed to establish the within and between laboratory diagnostic performance of the RT-ddPCR assay. PMID- 28347710 TI - Prostanoids in the pathophysiology of human coronary artery. AB - Coronary artery disease is one of the leading causes of death in wordwide. There is growing evidence that prostanoids are involved in the physiology and pathophysiology of the human coronary artery by controlling vascular tone, remodelling of the vascular wall or angiogenesis. In this review, the production of prostanoids and the expression of prostanoid receptors in human coronary artery in health or disease are described. In addition, the interactions between sex hormones and prostanoids, their participations in the development of coronary artery diseases have been addressed. Globally, most of the studies performed in human coronary artery preparations have shown that prostacyclin (PGI2) has beneficial effects by inducing vasodilatation and promoting angiogenesis while reverse effects are confirmed by thromboxane A2 (TxA2). More studies are needed to determine the roles of the other prostanoids (PGE2, PGD2 and PGF2alpha) in vascular functions of the human coronary artery. Finally, in addition to the in vitro data about the human coronary artery, myocardial infarction induced by cyclooxygenase-2 (COX-2) inhibitor and the protective effects of aspirin after coronary artery bypass surgery suggest that prostanoids are key mediators in coronary homeostasis. PMID- 28347711 TI - Magnetic anchor-guided endoscopic submucosal dissection for colonic tumor. PMID- 28347712 TI - Novel endoscopic scissors for the treatment of Zenker's diverticulum. PMID- 28347713 TI - Fecal microbial transplantation. PMID- 28347714 TI - EUS-guided drainage for pancreatic walled-off necrosis by use of a novel large diameter metal stent. PMID- 28347715 TI - Preeclampsia: novel insights from global RNA profiling of trophoblast subpopulations. AB - BACKGROUND: The maternal signs of preeclampsia, which include the new onset of high blood pressure, can occur because of faulty placentation. We theorized that transcriptomic analyses of trophoblast subpopulations in situ would lend new insights into the role of these cells in preeclampsia pathogenesis. OBJECTIVE: Our goal was to enrich syncytiotrophoblasts, invasive cytotrophoblasts, or endovascular cytotrophoblasts from the placentas of severe preeclampsia cases. Total RNA was subjected to global transcriptional profiling to identify RNAs that were misexpressed compared with controls. STUDY DESIGN: This was a cross sectional analysis of placentas from women who had been diagnosed with severe preeclampsia. Gestational age-matched controls were placentas from women who had a preterm birth with no signs of infection. Laser microdissection enabled enrichment of syncytiotrophoblasts, invasive cytotrophoblasts, or endovascular cytotrophoblasts. After RNA isolation, a microarray approach was used for global transcriptional profiling. Immunolocalization identified changes in messenger RNA expression that carried over to the protein level. Differential expression of non protein-coding RNAs was confirmed by in situ hybridization. A 2-way analysis of variance of non-coding RNA expression identified particular classes that distinguished trophoblasts in cases vs controls. Cajal body foci were visualized by coilin immunolocalization. RESULTS: Comparison of the trophoblast subtype data within each group (severe preeclampsia or noninfected preterm birth) identified many highly differentially expressed genes. They included molecules that are known to be expressed by each subpopulation, which is evidence that the method worked. Genes that were expressed differentially between the 2 groups, in a cell type-specific manner, encoded a combination of molecules that previous studies associated with severe preeclampsia and those that were not known to be dysregulated in this pregnancy complication. Gene ontology analysis of the syncytiotrophoblast data highlighted the dysregulation of immune functions, morphogenesis, transport, and responses to vascular endothelial growth factor and progesterone. The invasive cytotrophoblast data provided evidence of alterations in cellular movement, which is consistent with the shallow invasion often associated with severe preeclampsia. Other dysregulated pathways included immune, lipid, oxygen, and transforming growth factor-beta responses. The data for endovascular cytotrophoblasts showed disordered metabolism, signaling, and vascular development. Additionally, the transcriptional data revealed the differential expression in severe preeclampsia of 2 classes of non-coding RNAs: long non-coding RNAs and small nucleolar RNAs. The long non-coding RNA, urothelial cancer associated 1, was the most highly up-regulated in this class. In situ hybridization confirmed severe preeclampsia-associated expression in syncytiotrophoblasts. The small nucleolar RNAs, which chemically modify RNA structure, also correlated with severe preeclampsia. Thus, we enumerated Cajal body foci, sites of small nucleolar RNA activity, in primary cytotrophoblasts that were isolated from control and severe preeclampsia placentas. In severe preeclampsia, cytotrophoblasts had approximately double the number of these foci as the control samples. CONCLUSION: A laser microdissection approach enabled the identification of novel messenger RNAs and non-coding RNAs that were misexpressed by various trophoblast subpopulations in severe preeclampsia. The results suggested new avenues of investigation, in particular, the roles of PRG2, Kell blood group determinants, and urothelial cancer associated 1 in syncytiotrophoblast diseases. Additionally, many of the newly identified dysregulated molecules might have clinical utility as biomarkers of severe preeclampsia. PMID- 28347717 TI - Long non-coding RNAs in brain development, synaptic biology, and Alzheimer's disease. AB - Long non-coding RNAs (lncRNAs), which are long transcripts without apparent protein-coding roles, interfere with gene expression and signaling events at various stages. Increasing evidence has suggested that lncRNAs function in the regulation of tissue homeostasis and under pathophysiologic conditions. In the nervous system, the expression of lncRNAs has been detected and characterized under normal physiologic conditions and in disease states. Some lncRNAs regulate brain development and synaptic plasticity. In Alzheimer's disease (AD), several lncRNAs have been demonstrated to regulate beta-amyloid production/generation, synaptic impairment, neurotrophin depletion, inflammation, mitochondrial dysfunction, and stress responses. This review summarizes data on lncRNA expression and focuses on neural lncRNAs that may function in AD. Although our understanding of lncRNAs remains in its infancy, this review provides insight into the contribution of lncRNAs to AD. PMID- 28347718 TI - Corrigendum to "Dry eye disease and uveitis: A closer look at immune mechanisms in animal models of two ocular autoimmune diseases" [AUTREV 15-12 (2016) 1181 1192]. PMID- 28347716 TI - Unique prediction of cannabis use severity and behaviors by delay discounting and behavioral economic demand. AB - Few studies have simultaneously evaluated delay discounting and behavioral economic demand to determine their unique contribution to drug use. A recent study in cannabis users found that monetary delay discounting uniquely predicted cannabis dependence symptoms, whereas cannabis demand uniquely predicted use frequency. This study sought to replicate and extend this research by evaluating delay discounting and behavioral economic demand measures for multiple commodities and including a use quantity measure. Amazon.com's Mechanical Turk was used to sample individuals reporting recent cannabis use (n=64) and controls (n=72). Participants completed measures of monetary delay discounting as well as alcohol and cannabis delay discounting and demand. Cannabis users and controls did not differ on monetary delay discounting or alcohol delay discounting and demand. Among cannabis users, regression analyses indicated that cannabis delay discounting uniquely predicted use severity, whereas cannabis demand uniquely predicted use frequency and quantity. These effects remained significant after controlling for other delay discounting and demand measures. This research replicates previous outcomes relating delay discounting and demand with cannabis use and extends them by accounting for the contribution of multiple commodities. This research also demonstrates the ability of online crowdsourcing methods to complement traditional human laboratory techniques. PMID- 28347719 TI - Controlling coaching and athlete thriving in elite adolescent netballers: The buffering effect of athletes' mental toughness. AB - OBJECTIVES: The purposes of this study were to examine the association between controlling coach behaviours and athlete experiences of thriving and test the buffering effect of mental toughness on this relation. DESIGN: A cross-sectional survey. METHODS: In total, 232 female netballers aged 11 to 17 years (14.97+1.52) with between 1 and 15 years of experience in their sport (7.50+2.28) completed measures of controlling coach interpersonal style, mental toughness and thriving. RESULTS: Latent moderated structural models indicated that (i) controlling coach behaviours were inversely related with experiences of vitality and learning; (ii) mental toughness was positively associated with psychological experiences of both dimensions of thriving; and (iii) mental toughness moderated the effect of coach's controlling interpersonal style on learning but not vitality experiences, such that the effect was weaker for individuals who reported higher levels of mental toughness. CONCLUSIONS: This study extends past work and theory to show that mental toughness may enable athletes to counteract the potentially deleterious effect of controlling coach interpersonal styles. PMID- 28347720 TI - Very-large-scale production of antibodies in plants: The biologization of manufacturing. AB - Gene technology has facilitated the biologization of manufacturing, i.e. the use and production of complex biological molecules and systems at an industrial scale. Monoclonal antibodies (mAbs) are currently the major class of biopharmaceutical products, but they are typically used to treat specific diseases which individually have comparably low incidences. The therapeutic potential of mAbs could also be used for more prevalent diseases, but this would require a massive increase in production capacity that could not be met by traditional fermenter systems. Here we outline the potential of plants to be used for the very-large-scale (VLS) production of biopharmaceutical proteins such as mAbs. We discuss the potential market sizes and their corresponding production capacities. We then consider available process technologies and scale-down models and how these can be used to develop VLS processes. Finally, we discuss which adaptations will likely be required for VLS production, lessons learned from existing cell culture-based processes and the food industry, and practical requirements for the implementation of a VLS process. PMID- 28347721 TI - Extra-analytical quality indicators and laboratory performances. AB - In the last few years much progress has been made in raising the awareness of laboratory medicine professionals about the effectiveness of quality indicators (QIs) in monitoring, and improving upon, performances in the extra-analytical phases of the Total Testing Process (TTP). An effective system for management of QIs includes the implementation of an internal assessment system and participation in inter-laboratory comparison. A well-designed internal assessment system allows the identification of critical activities and their systematic monitoring. Active participation in inter-laboratory comparison provides information on the performance level of one laboratory with respect to that of other participating laboratories. In order to guarantee the use of appropriate QIs and facilitate their implementation, many laboratories have adopted the Model of Quality Indicators (MQI) proposed by Working Group "Laboratory Errors and Patient Safety" (WG-LEPS) of IFCC, since 2008, which is the result of international consensus and continuous experimentation, and updating to meet new, constantly emerging needs. Data from participating laboratories are collected monthly and reports describing the statistical results and evaluating laboratory data, utilizing the Six Sigma metric, issued regularly. Although the results demonstrate that the processes need to be improved upon, overall the comparison with data collected in 2014 shows a general stability of quality levels and that an improvement has been achieved over time for some activities. The continuous monitoring of QI data allows identification all possible improvements, thus highlighting the value of participation in the inter-laboratory program proposed by WG-LEPS. The active participation of numerous laboratories will guarantee an ever more significant State-of-the-Art, promote the reduction of errors and improve quality of the TTP, thus guaranteeing patient safety. PMID- 28347722 TI - Testosterone, the progesterone/estradiol ratio, and female ratings of masculine facial fluctuating asymmetry for a long-term relationship. AB - Idiosyncratic variation within the normal range of androgens levels in women account for significant variations in personality and behavior. We studied if testosterone introduces significant biases in women's perception of fluctuating symmetry of male faces suitability for a long-term relationship. Participants were 145 female college students asked to rate in a two-choice forced paradigm the attractiveness, suitability as a long-term partner, and economic success, fatherliness and fidelity of an asymmetric and a symmetric male face. Since our sample consists of random women interested in participating, whether for personal reasons or because they were paid to participate, we controlled for menstrual phase. All participants provided salivary samples to determine testosterone (T), estradiol (E2) and progesterone (P4) levels. When the P4/E2 was low and T low-to normal, the symmetric face was rated as more attractive, and a desirable long term partner, but these preferences changed to the opposite when P4/E2 was high. In high T women, neither face was rated as more attractive, independently from the P4/E2 ratio, but the asymmetric face was preferred as a long-term partner when conception risk was high, changing to prefer the symmetric face as the P4/E2 increased. The overall perception of male faces was that the symmetric face was more economical successful but a poor parent and highly unfaithful compared to the asymmetric face. A significant interaction between T and P4/E2 for ratings success of the asymmetric face suggests that high levels of feminine T might be related to inter-sexual competition when conception risk is high. PMID- 28347723 TI - Hypothalamic insulin responsiveness is associated with pancreatic insulin secretion in humans. AB - CONTEXT: Activity of the hypothalamus - the major brain area controlling peripheral metabolism - is specifically modulated by insulin. Research in animals suggests that brain insulin action influences pancreatic insulin secretion. OBJECTIVE: We investigated the association between hypothalamic insulin sensitivity and pancreatic insulin secretion in humans. DESIGN AND SETTING: This was a clinical-experimental trial in an university hospital setting. PARTICIPANTS: 48 healthy volunteers (21 women and 27 men) were included. MAIN OUTCOME MEASURES: Insulin sensitivity of the hypothalamus was quantified by cerebral blood flow (CBF) using MRI in combination with intranasal insulin administration. On a different day, a 75g oral glucose tolerance test with glucose, insulin, and C-peptide levels measured at five time points was performed. Three established insulin secretion indices (insulinogenic index [IGI], corrected insulin response [CIR], and AUCC-peptide0-30/AUCglucose0-30) were then analyzed for correlations with hypothalamic insulin sensitivity independent of whole-body insulin sensitivity. RESULTS: Hypothalamic insulin sensitivity showed a significant association with all three investigated insulin secretion indices (IGI p=0.0043; CIR p=0.06; AUCCpep0-30/AUCgluc0-30 p=0.0179). Participants with a strong hypothalamic insulin effect (i.e. decreased CBF after intranasal insulin administration) had lower insulin secretion during the OGTT, whereas participants with hypothalamic insulin resistance had substantially higher insulin secretion. No correlations with the occipital cortex, a control region, were detected. CONCLUSIONS: Our data suggest that hypothalamic insulin resistance might contribute to pancreatic insulin hypersecretion. Alternatively, common pathogenetic mechanisms could introduce both brain insulin resistance and beta cell hypersecretion. PMID- 28347724 TI - Metabolic effects of intermittent access to caloric or non-caloric sweetened solutions in mice fed a high-caloric diet. AB - Human consumption of obesogenic diets and soft drinks, sweetened with different molecules, is increasing worldwide, and increases the risk of metabolic diseases. We hypothesized that the chronic consumption of caloric (sucrose, high-fructose corn syrup (HFCS), maltodextrin) and non-caloric (sucralose) solutions under 2 hour intermittent access, alongside the consumption of a high-fat high-sucrose diet, would result in differential obesity-associated metabolic abnormalities in mice. Male C57BL/6 mice had ad libitum access to an HFHS diet and to water (water control group). In addition, some mice had access, 2h/day, 5days/week (randomly chosen) for 12weeks, to different solutions: i) a sucrose solution (2.1kJ/ml), ii) an HFCS solution (2.1kJ/ml), iii) a maltodextrin solution (2.1kJ/ml) and a sucralose solution (60mM) (n=15/group). Despite no changes in total caloric intake, 2h-intermittent access to the sucrose, HFCS or maltodextrin solutions led to increased body weight and accumulation of lipids in the liver when compared to the group consuming water only. The HFCS and sucrose solutions induced a higher fat mass in various fat depots, glucose intolerance, increased glucose oxidation at the expense of lipid oxidation, and a lower hypothalamic expression of NPY in the fasted state. HFCS also reduced proopiomelanocortin expression in the hypothalamus. 2h-intermittent access to sucralose did not result in significant changes in body composition, but caused a stronger expression of CART in the hypothalamus. Finally, sucrose intake showed a trend to increase the expression of various receptors in the nucleus accumbens, linked to dopamine, opioid and endocannabinoid signaling. In conclusion, 2h-intermittent access to caloric solutions (especially those sweetened with sucrose and HFCS), but not sucralose, resulted in adverse metabolic consequences in high-fat high-sucrose-fed mice. PMID- 28347725 TI - Development of novel monoclonal antibodies directed against catechins for investigation of antibacterial mechanism of catechins. AB - Catechins are major polyphenolic compounds of green tea. To investigate mechanism for antibacterial action of catechins, 11 monoclonal antibodies (MAbs) were raised against a 3-succinyl-epicatechin (EC)-keyhole limpet hemocyanin (KLH) conjugate. Amino acid sequences of variable regions determined for MAbs b-1058, b 1565, and b-2106 confirmed their innovative character. MAb b-1058 strongly interacted with its target substances in the following order of magnitude: theaflavin-3,3'-di-O-gallate (TFDG)>theaflavin-3-O-gallate (TF3G)>=theaflavin-3' O-gallate (TF3'G)>gallocatechin gallate (GCg)>penta-O-galloyl-beta-d-glucose (PGG)>epigallocatechin gallate (EGCg), as determined using surface plasmon resonance (SPR) on MAb-immobilized sensor chips. The affinity profiles of MAbs b 1058 and b-2106 to the various polyphenols tested suggested that flavan skeletons with both carbonyl oxygen and hydroxyl groups are important for this interaction to take place. S. aureus cells treated with EGCg showed green fluorescence around the cells after incubation with FITC-labeled MAb b-1058. The fluorescence intensity increased with increasing concentrations of EGCg. These MAbs are effective to investigate antibacterial mechanism of catechins and theaflavins. PMID- 28347726 TI - Expanding the cardiac spectrum of Noonan syndrome with RIT1 variant: Left main coronary artery atresia causing sudden death. AB - Noonan syndrome is a well-known genetic condition associating congenital heart defects, short stature, and distinctive facial features. Pulmonary valve stenosis and hypertrophic cardiomyopathy are the most frequent cardiac abnormalities, the latter being associated with a higher mortality. Here we report for the first time, a case of congenital left main coronary artery atresia in a Noonan syndrome associated with RIT1 variant, leading to unrescued sudden death. This case-report supports the already-suspected severity of the RIT1-related Noonan syndrome compared to average Noonan syndrome, and should encourage clinicians to be very cautious with these patients. PMID- 28347727 TI - A novel method for examining corneal endothelial cell morphology in infants. AB - Previous studies have suggested that central corneal endothelial cell density (ECD) decreases from 6,100 cells/mm2 in neonates to 3,100 cells/mm2 in 10-year olds. Currently data on ECD in young children as well as the trend for ECD decrease during childhood is sparse because of the difficulty of examination using existing clinic-based specular microscopes. We developed a novel method of imaging young children intraoperatively with the goal of beginning to establish age-specific normative data for ECD and hexagonality of cells (%HEX). Children were imaged using our novel technique under general anesthesia or awake in clinic using a child-friendly technique. A total of 58 children were recruited (mean age, 5.50; range, 0.44-10.36). Our cohort displayed a significant linear decrease in ECD with age (r = -0.56, P < 0.001). No correlation was found between %HEX and age (r = -0.10, P = 0.48). PMID- 28347728 TI - The extended reciprocity: Strong belief outperforms persistence. AB - The existence of cooperation is a mysterious phenomenon and demands explanation, and direct reciprocity is one key potential explanation for the evolution of cooperation. Direct reciprocity allows cooperation to evolve for cooperators who switch their behavior on the basis of information about the opponent's behavior. Here, relevant to direct reciprocity is information deficiency. When the opponent's last move is unknown, how should players behave? One possibility is to choose cooperation with some default probability without using any further information. In fact, our previous paper (Kurokawa, 2016a) examined this strategy. However, there might be beneficial information other than the opponent's last move. A subsequent study of ours (Kurokawa, 2017) examined the strategy which uses the own last move when the opponent's last move is unknown, and revealed that referring to the own move and trying to imitate it when information is absent is beneficial. Is there any other beneficial information else? How about strong belief (i.e., have infinite memory and believe that the opponent's behavior is unchanged)? Here, we examine the evolution of strategies with strong belief. Analyzing the repeated prisoner's dilemma game and using evolutionarily stable strategy (ESS) analysis against an invasion by unconditional defectors, we find the strategy with strong belief is more likely to evolve than the strategy which does not use information other than the opponent player's last move and more likely to evolve than the strategy which uses not only the opponent player's last move but also the own last move. Strong belief produces the extended reciprocity and facilitates the evolution of cooperation. Additionally, we consider the two strategies game between strategies with strong belief and any strategy, and we consider the four strategies game in which unconditional cooperators, unconditional defectors, pessimistic reciprocators with strong belief, and optimistic reciprocators with strong belief are present. PMID- 28347730 TI - Crystal Structures and Vapor-Induced Crystalline Transformation of 7-Ethyl-10 Hydroxycamptothecin Pseudopolymorphs. AB - Solvent-induced 3 frameworks (the monohydrate, methanol solvate, and dimethyl formamide [DMF] solvate) of an anticancer drug, 7-ethyl-10-hydroxycamptothecin (SN38), were constructed. The crystal structures of the 3 pseudopolymorphs were characterized by single-crystal X-ray diffraction technique for the first time. Crystal structure analysis of all these polymorphs revealed that the monohydrate showed 3D frameworks linked by hydrogen bonds. In the methanol solvate, the 1D molecular chains were linked by the methanol molecules through intermolecular hydrogen bonds to form a 2D sheet. The DMF solvate exhibits the 1D hydrogen bonding-linked chains along b-axis. Vapor-induced transformation has been investigated for the monohydrate, the methanol solvate, and the DMF solvate. The conversion relationships among the 3 solid frameworks are illustrated. Insights regarding transformation mechanisms have been established from consideration of the crystal structures. PMID- 28347729 TI - Selenoprotein T is required for pathogenic bacteria avoidance in Caenorhabditis elegans. AB - Selenoprotein T (SELENOT) is an endoplasmatic reticulum (ER)-associated redoxin that contains the amino acid selenocysteine (Sec, U) within a CXXU motif within a thioredoxin-like fold. Its precise function in multicellular organisms is not completely understood although it has been shown in mammals to be involved in Ca2+ homeostasis, antioxidant and neuroendocrine functions. Here, we use the model organism C. elegans to address SELENOT function in a whole organism throughout its life cycle. C. elegans possess two genes encoding SELENOT protein orthologues (SELT-1.1 and SELT-1.2), which lack Sec and contain the CXXC redox motif instead. Our results show that a Sec->Cys replacement and a gene duplication were two major evolutionary events that occurred in the nematode lineage. We find that worm SELT-1.1 localizes to the ER and is expressed in different cell types, including the nervous system. In contrast, SELT-1.2 exclusively localizes in the cytoplasm of the AWB neurons. We find that selt-1.1 and selt-1.2 single mutants as well as the double mutant are viable, but the selt 1.1 mutant is compromised under rotenone-induced oxidative stress. We demonstrate that selt-1.1, but not selt-1.2, is required for avoidance to the bacterial pathogens Serratia marcescens and Pseudomonas aeruginosa. Aversion to the noxious signal 2-nonanone is also significantly impaired in selt-1.1, but not in selt-1.2 mutant animals. Our results suggest that selt-1.1 would be a redox transducer required for nociception and optimal organismal fitness. The results highlight C. elegans as a valuable model organism to study SELENOT-dependent processes. PMID- 28347731 TI - Three-Dimensional Printing of Medicinal Products and the Challenge of Personalized Therapy. AB - By 3-dimensional (3D) printing, solid objects of any shape are fabricated through layer-by-layer addition of materials based on a digital model. At present, such a technique is broadly exploited in many industrial fields because of major advantages in terms of reduced times and costs of development and production. In the biomedical and pharmaceutical domains, the interest in 3D printing is growing in step with the needs of personalized medicine. Printed scaffolds and prostheses have partly replaced medical devices produced by more established techniques, and more recently, 3D printing has been proposed for the manufacturing of drug products. Notably, the availability of patient-tailored pharmaceuticals would be of utmost importance for children, elderly subjects, poor and high metabolizers, and individuals undergoing multiple drug treatments. 3D printing encompasses a range of differing techniques, each involving advantages and open issues. Particularly, solidification of powder, extrusion, and stereolithography have been applied to the manufacturing of drug products. The main challenge to their exploitation for personalized pharmacologic therapy is likely to be related to the regulatory issues involved and to implementation of production models that may allow to efficiently turn the therapeutic needs of individual patients into small batches of appropriate drug products meeting preset quality requirements. PMID- 28347732 TI - Association between the p53 arginine/arginine homozygous genotype at codon 72 and human papillomavirus E6/E7 mRNA expression. AB - OBJECTIVE: To evaluate the association between p53 polymorphisms and human papillomavirus (HPV) E6/E7 mRNA expression. METHODS: We analyzed 175 cervical samples from women aged 16-69 years old who were tested for HPV E6/E7 mRNA expression (NucliSENS(r) EasyQ(r) HPV). The samples were divided into three groups: positive (n=75) those with positive HPV E6/E7 mRNA expression and positive high-risk HPV Hybrid Capture (HR-HC) test; negative (n=52) those with negative HPV E6/E7 mRNA expression and positive HR-HC; and control (n=48) those with negative HPV E6/E7 mRNA expression and negative HR-HC. The p53 polymorphisms at codons 11, 72, and 248 were evaluated through polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). RESULTS: The frequency of the arginine/arginine homozygous genotype at codon 72 was significantly higher in the positive (49.3%) than in the negative (32.7%) and control groups (20.8%, p=0.002*). The frequency of the arginine allele was also significantly higher in the positive (67.3%) than in the negative (53.8%) and control groups (38.5%, p<0.001*). The arginine/arginine homozygous genotype was significantly associated with positive HPV E6/E7 mRNA expression (positive group) compared with negative and control groups (odds ratio: 2.633; 95% CI, 1.399-4.954, p=0.003). The frequency of arginine/arginine homozygous genotype at codon 72 remained significantly more frequent in the positive group of women aged >=30 years than in the other two groups. CONCLUSION: The presence of the p53 arginine/arginine homozygous genotype at codon 72 was significantly associated with the positive HPV E6/E7 mRNA expression. PMID- 28347733 TI - Neonatal BCG vaccination has no effect on recurrent wheeze in the first year of life: A randomized clinical trial. AB - BACKGROUND: Recurrent wheeze (RW) is frequent in childhood. Studies have suggested that BCG vaccination can have nonspecific effects, reducing general nontuberculosis morbidity, including respiratory tract infections and atopic diseases. The mechanisms behind these nonspecific effects of BCG are not fully understood, but a shift from a TH2 to a TH1 response has been suggested as a possible explanation. OBJECTIVE: We hypothesized that BCG at birth would reduce the cumulative incidence of RW during the first year of life. METHODS: The Danish Calmette Study is a multicenter randomized trial conducted from 2012-2015 at 3 Danish hospitals. The 4262 newborns of 4184 included mothers were randomized 1:1 to BCG (SSI strain 1331) or to a no-intervention control group within 7 days of birth; siblings were randomized together as one randomization unit. Exclusion criteria were gestational age of less than 32 weeks, birth weight of less than 1000 g, known immunodeficiency, or no Danish-speaking parent. Information was collected through telephone interviews and clinical examinations at 3 and 13 months of age; data collectors were blind to randomization group. RW was defined in several ways, with the main definition being physician-diagnosed and medically treated RW up to 13 months of age. RESULTS: By 13 months, 211 (10.0%) of 2100 children in the BCG group and 195 (9.4%) of 2071 children in the control group had received a diagnosis of RW from a medical doctor and received antiasthma treatment (relative risk, 1.07; 95% CI, 0.89-1.28). Supplementary analyses were made, including an analysis of baseline risk factors for development of RW. CONCLUSION: Neonatal BCG had no effect on the development of RW before 13 months of age. PMID- 28347734 TI - Rhinovirus-induced first wheezing episode predicts atopic but not nonatopic asthma at school age. AB - BACKGROUND: Persistent childhood asthma is mainly atopy driven. However, limited data exist on the risk factors for childhood asthma phenotypes. OBJECTIVE: We sought to identify risk factors at the first severe wheezing episode for current asthma 7 years later and separately for atopic and nonatopic asthma. METHODS: One hundred twenty-seven steroid-naive children with the first severe wheezing episode (90% hospitalized/10% emergency department treated) were followed for 7 years. The primary outcome was current asthma at age 8 years, which was also analyzed separately as atopic and nonatopic asthma. Risk factors, including sensitization, viral cause, and other main asthma risk factors, were analyzed. RESULTS: At study entry, median age was 11 months (interquartile range, 6-16 months); 17% were sensitized, and 98% were virus positive. Current asthma (n = 37) at 8 years was divided into atopic (n = 19) and nonatopic (n = 18) asthma. The risk factors for current atopic asthma at study entry were sensitization (adjusted odds ratio [OR], 12; P < .001), eczema (adjusted OR, 4.8; P = .014), and wheezing with rhinovirus (adjusted OR, 5.0; P = .035). The risk factors for nonatopic asthma were the first severe respiratory syncytial virus/rhinovirus negative wheezing episode (adjusted OR, 8.0; P = .001), first wheezing episode at age less than 12 months (adjusted OR, 7.3; P = .007), and parental smoking (adjusted OR, 3.8; P = .028). CONCLUSIONS: The data suggest diverse asthma phenotypes and mechanisms that can be predicted by using simple clinical markers at the time of the first severe wheezing episode. These findings are important for designing early intervention strategies for secondary prevention of asthma. PMID- 28347735 TI - Sensitization trajectories in childhood revealed by using a cluster analysis. AB - BACKGROUND: Assessment of sensitization at a single time point during childhood provides limited clinical information. We hypothesized that sensitization develops as specific patterns with respect to age at debut, development over time, and involved allergens and that such patterns might be more biologically and clinically relevant. OBJECTIVE: We sought to explore latent patterns of sensitization during the first 6 years of life and investigate whether such patterns associate with the development of asthma, rhinitis, and eczema. METHODS: We investigated 398 children from the at-risk Copenhagen Prospective Studies on Asthma in Childhood 2000 (COPSAC2000) birth cohort with specific IgE against 13 common food and inhalant allergens at the ages of 1/2, 11/2, 4, and 6 years. An unsupervised cluster analysis for 3-dimensional data (nonnegative sparse parallel factor analysis) was used to extract latent patterns explicitly characterizing temporal development of sensitization while clustering allergens and children. Subsequently, these patterns were investigated in relation to asthma, rhinitis, and eczema. Verification was sought in an independent unselected birth cohort (BAMSE) constituting 3051 children with specific IgE against the same allergens at 4 and 8 years of age. RESULTS: The nonnegative sparse parallel factor analysis indicated a complex latent structure involving 7 age- and allergen-specific patterns in the COPSAC2000 birth cohort data: (1) dog/cat/horse, (2) timothy grass/birch, (3) molds, (4) house dust mites, (5) peanut/wheat flour/mugwort, (6) peanut/soybean, and (7) egg/milk/wheat flour. Asthma was solely associated with pattern 1 (odds ratio [OR], 3.3; 95% CI, 1.5-7.2), rhinitis with patterns 1 to 4 and 6 (OR, 2.2-4.3), and eczema with patterns 1 to 3 and 5 to 7 (OR, 1.6-2.5). All 7 patterns were verified in the independent BAMSE cohort (R2 > 0.89). CONCLUSION: This study suggests the presence of specific sensitization patterns in early childhood differentially associated with development of clinical outcomes. Using such patterns in future research might provide more robust and clinically relevant results. PMID- 28347736 TI - Impact of school peanut-free policies on epinephrine administration. AB - BACKGROUND: Children with food allergies spend a large proportion of time in school but characteristics of allergic reactions in schools are not well studied. Some schools self-designate as peanut-free or have peanut-free areas, but the impact of policies on clinical outcomes has not been evaluated. OBJECTIVE: We sought to determine the effect of peanut-free policies on rates of epinephrine administration for allergic reactions in Massachusetts public schools. METHODS: In this retrospective study, we analyzed (1) rates of epinephrine administration in all Massachusetts public schools and (2) Massachusetts public school nurse survey reports of school peanut-free policies from 2006 to 2011 and whether schools self-designated as "peanut-free" based on policies. Rates of epinephrine administration were compared for schools with or without peanut-restrictive policies. RESULTS: The percentage of schools with peanut-restrictive policies did not change significantly in the study time frame. There was variability in policies used by schools self-designated as peanut-free. No policy was associated with complete absence of allergic reactions. Both self-designated peanut-free schools and schools banning peanuts from being served in school or brought from home reported allergic reactions to nuts. Policies restricting peanuts from home, served in schools, or having peanut-free classrooms did not affect epinephrine administration rates. Schools with peanut-free tables, compared to without, had lower rates of epinephrine administration (incidence rate per 10,000 students 0.2 and 0.6, respectively, P = .009). CONCLUSIONS: These data provide a basis for evidence-based school policies for children with food allergies. Further studies are required before decisions can be made regarding peanut-free policies in schools. PMID- 28347738 TI - DNA damage-dependent mechanisms of ageing and disease in the macro- and microvasculature. AB - A decline in the function of the macro- and micro-vasculature occurs with ageing. DNA damage also accumulates with ageing, and thus DNA damage and repair have important roles in physiological ageing. Considerable evidence also supports a crucial role for DNA damage in the development and progression of macrovascular disease such as atherosclerosis. These findings support the concept that prolonged exposure to risk factors is a major stimulus for DNA damage within the vasculature, in part via the generation of reactive oxygen species. Genomic instability can directly affect vascular cellular function, leading to cell cycle arrest, apoptosis and premature vascular cell senescence. In contrast, the study of age-related impaired function and DNA damage mechanisms in the microvasculature is limited, although ageing is associated with microvessel endothelial dysfunction. This review examines current knowledge on the role of DNA damage and DNA repair systems in macrovascular disease such as atherosclerosis and microvascular disease. We also discuss the cellular responses to DNA damage to identify possible strategies for prevention and treatment. PMID- 28347737 TI - Sex differences in alcohol self-administration and relapse-like behavior in Long Evans rats. AB - Alcohol use disorders are a costly public health dilemma. Complicating this issue is the general lack of basic research assessing sex differences in many aspects of alcohol seeking and taking behaviors. The current experiments sought to decrease this gap in our understanding of sex differences in alcohol use disorders by assessing both male and female Long-Evans rats in parallel on alcohol self-administration, relapse-like behavior following abstinence and extinction, and motivation to respond for the standard alcohol solution and a quinine-adulterated alcohol solution. Here, we show that while males tend to have greater alcohol-reinforced responses throughout self-administration training, females show similar or greater alcohol intake (g/kg). Additionally, when tested for reinstatement of alcohol seeking and self-administration, following abstinence or extinction, males consistently showed greater reinstatement responding than females, which may be related to their training history. However, when assessed using the progressive ratio, there were no sex differences in motivation to respond for alcohol. Further, the consistent patterns of responding across months of self-administration training in both males and females, lend support for the feasibility of conducting these studies in male and female rats in parallel without concerns about daily variability. Our data also suggest that males and females should not be pooled as differences in alcohol lever responses and differences in reinstatement, as observed in the current experiments, could affect the overall outcome and possibly confound data interpretation. These studies demonstrate the importance of assessing males and females in parallel and advance the body of preclinical research on sex differences in alcohol self administration and relapse. PMID- 28347739 TI - Targeting white, brown and perivascular adipose tissue in atherosclerosis development. AB - Obesity is a well-established risk factor for atherosclerosis. However, the mechanistic link between accumulation of adipose tissue and development of atherosclerosis is not clear. Adipose tissue comprises various depots including white adipose tissue (WAT), brown adipose tissue (BAT) and thoracic and abdominal perivascular adipose tissue (PVAT). The phenotype of thoracic PVAT resembles BAT, whereas abdominal PVAT is more like WAT. Here, we review the distinct roles of the adipose tissue depots in the development of atherosclerosis with the ultimate aim to understand how these can be targeted to reduce atherosclerosis. In obesity, increased fatty acid release by WAT and decreased lipid combustion by BAT and thoracic PVAT lead to hyperlipidaemia, which contributes to atherosclerosis development. Besides, obese WAT and abdominal PVAT release pro inflammatory factors that further promote atherosclerosis. To discourage atherosclerosis development, strategies that reduce the release of pro inflammatory factors and fatty acids from WAT and abdominal PVAT, or increase combustion of fatty acids by activation of BAT and thoracic PVAT and beiging of WAT are probably most efficient. Possible therapies could include anti inflammatory compounds such as adiponectin and salicylates to lower inflammation, and beta3-adrenergic receptor activators to increase fatty acid combustion. Additional and more specific strategies to promote fatty acid combustion are currently subject of investigation. In conclusion, different adipose depots differentially affect atherosclerosis development, in which atherosclerosis is promoted by energy-storing adipose depots and attenuated by energy-combusting adipose tissue. In obesity, combining therapies that reduce inflammation and increase combustion of lipids are most conceivable to restrain atherogenesis. PMID- 28347740 TI - Selective cytotoxicity of the antibacterial peptide ABP-dHC-Cecropin A and its analog towards leukemia cells. AB - Some cationic antibacterial peptides, with typical amphiphilic alpha-helical conformations in a membrane-mimicking environment, exhibit anticancer properties as a result of a similar mechanism of action towards both bacteria and cancer cells. We previously reported the cDNA sequence of the antimicrobial peptide ABP dHC-Cecropin A precursor cloned from drury (Hyphantria cunea) (dHC). In the present study, we synthesized and structurally characterized ABP-dHC-Cecropin A and its analog, ABP-dHC-Cecropin A-K(24). Circular dichroism spectroscopy showed that ABP-dHC-Cecropin A and its analog adopt a well-defined alpha-helical structure in a 50% trifluorethanol solution. The cytotoxicity and cell selectivity of these peptides were further examined in three leukemia cell lines and two non-cancerous cell lines. The MTT assay indicated both of these peptides have a concentration-dependent cytotoxic effect in leukemia cells, although the observed cytotoxicity was greater with ABP-dHC-Cecropin A-K(24) treatment, whereas they were not cytotoxic towards the non-cancerous cell lines. Moreover, ABP-dHC-Cecropin A and its analog had a lower hemolytic effect in human red blood cells. Together, these results suggest the peptides are selectively cytotoxic towards leukemia cells. Confocal laser scanning microscopy determined that the peptides were concentrated at the surface of the leukemia cells, and changes in the cell membrane were determined with a permeability assay, which suggested that the anticancer activity of ABP-dHC-Cecropin A and its analog is a result of its presence at the leukemia cell membrane. ABP-dHC-Cecropin A and its analog may represent a novel anticancer agent for leukemia therapy, considering its cancer cell selectivity and relatively low cytotoxicity in normal cells. PMID- 28347742 TI - Corticosteroid responses of snakes to toxins from toads (bufadienolides) and plants (cardenolides) reflect differences in dietary specializations. AB - Toads are chemically defended by cardiotonic steroids known as bufadienolides. Resistance to the acute effects of bufadienolides in snakes that prey on toads is conferred by target-site insensitivity of the toxin's target enzyme, the Na+/K+ ATPase. Previous studies have focused largely on the molecular mechanisms of resistance but have not investigated the physiological mechanisms or consequences of exposure to the toxins. Adrenal enlargement in snakes often is associated with specialization on a diet of toads. These endocrine glands are partly composed of interrenal tissue, which produces the corticosteroids corticosterone and aldosterone. Corticosterone is the main hormone released in response to stress in reptiles, and aldosterone plays an important role in maintaining ion balance through upregulation of Na+/K+-ATPase. We tested the endocrine response of select species of snakes to acute cardiotonic steroid exposure by measuring circulating aldosterone and corticosterone concentrations. We found that Rhabdophis tigrinus, which specializes on a diet of toads, responds with lower corticosterone and higher aldosterone compared to other species that exhibit target-site resistance to the toxins but do not specialize on toads. We also found differences between sexes in R. tigrinus, with males generally responding with higher corticosterone and aldosterone than females. This study provides evidence of physiological adaptations, beyond target-site resistance, associated with tolerance of bufadienolides in a specialized toad-eating snake. PMID- 28347743 TI - Transcription of CYP19A1 is directly regulated by SF-1 in the theca cells of ovary follicles in chicken. AB - Many studies have suggested the important role of estrogen in ovarian differentiation and development of vertebrates including chicken. Cytochrome P450 aromatase, encoded by CYP19A1, is a key enzyme in estrogen synthesis, but the mechanism of CYP19A1 regulation in chicken remains unknown. Here, we found that CYP19A1 was only expressed in the theca cell layers of chicken ovary follicles. Steroidogenic factor 1 (SF-1, also named as nuclear receptor subfamily 5 group A member 1, NR5A1), a potential regulators, was expressed in both the theca cell layers and granulosa cell layers. Forkheadbox L2 (FOXL2), another potential regulator, was only expressed in the granulosa cell layers. Using luciferase assays in vitro, we found that SF-1 could activate the promoter of CYP19A1 by binding to the nuclear receptor half-site (5'-TCAAGGTCA-3') from -280 to -271 base pairs. FOXL2 did not activate the promoter of chicken CYP19A1 gene in either 293T or DF-1 cells. Overexpression of SF-1 in DF-1 cells upregulated aromatase expression, but FOXL2 could not. Taken together, our results indicated that SF-1 activates CYP19A1 mRNA expression via a conserved binding site in chicken ovary, but FOXL2 may not affect the expression of CYP19A1. PMID- 28347744 TI - The development of cellular immune defence in marine medaka Oryzias melastigma. AB - Environmentally induced alterations of the immune system during sensitive developmental stages may manifest as abnormalities in immune organ configuration and/or immune cell differentiation. These not only render the early life stages more vulnerable to pathogens, but may also affect the adult immune competence. Knowledge of these sensitive periods in fish would provide an important prognostic/diagnostic tool for aquatic risk assessment of immunotoxicants. The marine medaka Oryzias melastigma is an emerging seawater fish model for immunotoxicology. Here, the presence and onset of four potentially sensitive periods during the development of innate and adaptive cellular immune defence were revealed in O. melastigma: 1.) initiation of phagocyte differentiation, 2.) migration and expansion of lymphoid progenitor cells, 3.) colonization of immune organs through lymphocyte progenitors and 4.) establishment of immune competence in the thymus. By using an established bacterial resistance assay for O. melastigma, larval immune competence (from newly hatched 1dph to 14dph) was found concomitantly increased with advanced thymus development and the presence of mature T-lymphocytes. A comparison between the marine O. melastigma and the freshwater counterpart Oryzias latipes disclosed a disparity in the T-lymphocyte maturation pattern, resulting in differences in the length of T-lymphocyte maturation. The results shed light on a potential difference between seawater and freshwater medaka in their sensitivity to environmental immunotoxicants. Further, medaka immune system development was compared and contrasted to economically important fish. The present study has provided a strong scientific basis for advanced investigation of critical windows for immune system development in fish. PMID- 28347745 TI - Seasonal and ontogenetic changes modulate oxygen consumption and antioxidant defenses in the cutlassfish Trichiurus lepturus (Pisces, Trichiuridae). AB - Several oxidative stress markers and liver oxygen consumption were measured in different tissues of the marine fish Trichiurus lepturus in late summer and late winter, as well as in juveniles and adult females. Oxygen consumption in liver, superoxide dismutase (SOD) and catalase (CAT) activity in liver, red cells, lens and roe, vitamin E, ubiquinol10, beta-carotene in liver, red cells, and roe, as well as contents of reduced glutathione (GSH) and lipoperoxidation (TBARS) in red cells were evaluated. Regarding ontogeny, compared to adult fish, juveniles showed significant higher SOD activity in liver and lens, as well as higher liver contents of vitamin E. In contrast, adult females showed higher contents of vitamin E in roe, ubiquinol10 in liver and roe, and higher GSH levels in red cells, while the other markers remained unchanged. Regarding seasonal changes, no differences were detected in adult females for liver CAT and ubiquinol10, CAT in roe, vitamin E in roe and in red cells, liver and red cell ubiquinol10, and in GSH in red cells. However, and coinciding with the spawning period of late summer, liver oxygen consumption, SOD and CAT activity and ubiquinol10 contents in roe and SOD activity in red cells, and red cell TBARS contents were higher compared to late winter. These temporal antioxidant adjustments of Trichiurus lepturus seem to be parallel to the higher oxygen consumption typical of juvenile forms and also to the intense spawning and foraging activities of adult females in late summer. PMID- 28347746 TI - Matrix metalloproteinases - From the cleavage data to the prediction tools and beyond. AB - Understanding the physiological role of any protease requires identification of both its cleavage substrates and their relative cleavage efficacy as compared with other substrates and other proteinases. Our review manuscript is focused on the cleavage preferences of the individual matrix metalloproteinases (MMPs) and the cleavage similarity and distinction that exist in the human MMP family. The recent in-depth analysis of MMPs by us and many others greatly increased knowledge of the MMP biology and structural-functional relationships among this protease family members. A better knowledge of cleavage preferences of MMPs has led us to the development of the prediction tools that are now capable of the high throughput reliable prediction and ranking the MMP cleavage sites in the peptide sequences in silico. Our software unifies and consolidates volumes of the pre-existing data. Now this prediction-ranking in silico tool is ready to be used by others. The software we developed may facilitate both the identification of the novel proteolytic regulatory pathways and the discovery of the previously uncharacterized substrates of the individual MMPs. Because now the MMP research may be based on the mathematical probability parameters rather than on either random luck or common sense alone, the researchers armed with this novel in silico tool will be better equipped to fine-tune or, at least, to sharply focus their wet chemistry experiments. This article is part of a Special Issue entitled: Matrix Metalloproteinases edited by Rafael Fridman. PMID- 28347747 TI - Molecular characterization of human osteoblast-derived extracellular vesicle mRNA using next-generation sequencing. AB - Extracellular vesicles (EVs) are membrane-bound intercellular communication vehicles that transport proteins, lipids and nucleic acids with regulatory capacity between cells. RNA profiling using microarrays and sequencing technologies has revolutionized the discovery of EV-RNA content, which is crucial to understand the molecular mechanism of EV function. Recent studies have indicated that EVs are enriched with specific RNAs compared to the originating cells suggestive of an active sorting mechanism. Here, we present the comparative transcriptome analysis of human osteoblasts and their corresponding EVs using next-generation sequencing. We demonstrate that osteoblast-EVs are specifically depleted of cellular mRNAs that encode proteins involved in basic cellular activities, such as cytoskeletal functions, cell survival and apoptosis. In contrast, EVs are significantly enriched with 254 mRNAs that are associated with protein translation and RNA processing. Moreover, mRNAs enriched in EVs encode proteins important for communication with the neighboring cells, in particular with osteoclasts, adipocytes and hematopoietic stem cells. These findings provide the foundation for understanding the molecular mechanism and function of EV mediated interactions between osteoblasts and the surrounding bone microenvironment. PMID- 28347749 TI - Parents' educational level and second-hand tobacco smoke exposure at home in a sample of Portuguese children. AB - Second-hand tobacco smoke (SHS) exposure is a major and entirely avoidable health risk for children's health, well-being and development. The main objective of the current study was to investigate the association between parents' educational level and children's SHS home exposure. A self-administered questionnaire was conducted within a sample of 949 students in 4th grade (mean age 9.56+/-0.75, 53.4% male). The sample was randomly selected from all schools located at Lisbon District, Portugal. The current study confirmed that Portuguese children are exposed to unacceptable high levels of SHS at home, mainly by their parents' smoke. Prevalence of smokers was higher amongst parents with low educational level. Children of parents with low educational level were more likely to suffer SHS exposure at home. These results confirmed the social inequalities associated with smoking, support the relevance of more research on this subject and stress the need for more interventions to control this problem. Some interventions should be specifically aimed at less educated parents, particularly at less educated mothers. PMID- 28347748 TI - Local and hematological alterations induced by Philodryas olfersii snake venom in mice. AB - Envenomation by the South American opisthoglyphous snake Philodryas olfersii causes local pain, edema, erythema and ecchymosis; systemic envenomation is rare. In this work, we examined the inflammatory activity of P. olfersii venom (10, 30 and 60 MUg) in mouse gastrocnemius muscle 6 h after venom injection. Intramuscular injection of venom did not affect hematological parameters such as red cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration. The venom caused thrombocytopenia (at all three doses), leukopenia and lymphopenia (both at the two highest doses), as well as neutrophilia (30 MUg), monocytosis (30 MUg) and basophilia (10 MUg). Of the cytokines that were screened [IL-1beta, IL-6, IL-10, IL-13, IL-17, TNF-alpha, IFN-gamma, MIP-2 and KC] and IGF-1, only IGF-1 showed a significant increase in its circulating concentration, seen with 60 MUg of venom; there were no significant changes in the cytokines compared to control mice. Histological analysis revealed the presence of edema, an inflammatory infiltrate and progressive myonecrosis. Edema and myonecrosis were greatest with 60 MUg of venom, while the inflammatory infiltrate was greatest with 10 MUg of venom. All venom doses caused the migration of polymorphonuclear and mononuclear leukocytes into muscle, but with no significant dose-dependence in the response. These findings show that, at the doses tested, P. olfersii venom does not cause hematological alterations and has limited effect on circulating cytokine concentrations. These data also confirm that the principal effects of the venom in mice are local edema, inflammatory cell infiltration and myonecrosis. PMID- 28347750 TI - Glycoconjugates from extracellular vesicles: Structures, functions and emerging potential as cancer biomarkers. AB - Extracellular vesicles (EVs) are released by virtually all cells, carry cellular molecules to the extracellular environment, and may interact with other cells. They are found in body fluids, therefore, constituting useful target sources for the identification of disease biomarkers, for example, in cancer. EVs originate from the plasma membrane or from multivesicular endosomes. They have the same topology as the plasma membrane and are rich in glycoconjugates, displaying specific glycosignatures. Surface glycoconjugates play important roles in EVs biogenesis and in their interaction with other cells. Changes in glycosylation constitute a hallmark of different types of cancer, therefore, the study of glycoconjugates and glycosignatures of EVs appear as promising candidates to identify novel cancer biomarkers and to increase the specificity and sensitivity of the existing clinical biomarkers, many of which are glycosylated. PMID- 28347751 TI - The duality of macrophage function in chronic lymphocytic leukaemia. AB - Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia and, in some patients, is accompanied by resistance to both chemotherapeutics and immunotherapeutics. In this review we will discuss the role of tumour associated macrophages (TAMs) in promoting CLL cell survival and resistance to immunotherapeutics. In addition, we will discuss mechanisms by which TAMs suppress T-cell mediated antitumour responses. Thus, targeting macrophages could be used to i) reduce the leukaemic burden via the induction of T-cell-mediated antitumour responses, ii) to reduce pro-survival signalling and enhance response to conventional chemotherapeutics or iii) enhance the response to therapeutic antibodies in current clinical use. PMID- 28347752 TI - Expression, purification and characterization of active untagged recombinant human leukemia inhibitory factor from E.coli. AB - Leukemia inhibitory factor (LIF), a member of the IL-6 cytokine family, is considered to be a pleiotropic cytokine and functions in both cell proliferation and differentiation. It is widely used in the culture of mouse embryonic stem cells and is implicated in the implantation of mouse model and possibly in humans. Great efforts have been made on the efficient generation of LIF to meet the requirement of this cytokine in biomedical research. However, because of the low expression level in the eukaryotic system and poor purification yields, recombinant human LIF has usually been expressed either as inclusion body or as fusion protein in E. coli (Escherichia coli). Here we introduce a simple method to express hLIF in a soluble form in E. coli and a subsequent purification method. The expression of hLIF was induced at a low temperature (16 degrees C) and most of the expressed hLIF was observed to be in a soluble form. Then by using three steps of chromatography, which could be easily scaled-up for industrial purposes, active untagged hLIF was purified with similar bioactivity compared to that of the commercial product. The endotoxin level of purified hLIF protein in our method was determined to be lower than 1EU/MUg, which was also comparable to the commercial products. Furthermore, as hLIF was expressed in a soluble form, there was no need to develop the denaturation and renaturation methods. The yield of hLIF protein was evaluated to be approximately 0.7 mg hLIF from 1 g wet weight of E.coli in our method. PMID- 28347753 TI - Genetic and physicochemical analyses of a novel ferret hepatitis E virus, and clinical signs of infection after birth. AB - A novel cluster of five ferret hepatitis E virus (HEV) strains was detected from nine laboratory ferrets (Mustela putorius furo) imported from a ferret farm in the U.S. Our detection of ferret HEV RNA and anti-HEV antibodies, and alanine aminotransferase (ALT) value assessment indicated that all of the 9 ferrets were infected with ferret HEV, and that the infection exhibited three patterns: sub clinical infection (n=2), acute hepatitis (n=6) and persistent infection (n=1). Next-generation sequence analyses of the entire genome sequences of the five strains revealed that their nucleotide sequence identities ranged from 99.5% to 99.9%, indicating that genetically similar ferret HEVs had been circulating at this the U.S. ferret farm. In contrast, the strains shared 82% and 89% nucleotide sequence identities with other ferret HEV that isolated from the Netherlands (JN998607) and the U.S. (AB890374), suggesting that these strains form a novel cluster of ferret HEV with diverse genomes depending on the region where their host. Particles with a diameter of ~35nm at a density of 1.201g/cm3 were observed in the fecal specimens by electron microscopy. There was no evidence that the particles were associated with the cell membrane. The ferret HEV RNA was not constantly detected in urine, suggesting that the excretion of ferret HEV into urine is not a common feature of HEV infection. PMID- 28347754 TI - Cadmium disrupts autophagic flux by inhibiting cytosolic Ca2+-dependent autophagosome-lysosome fusion in primary rat proximal tubular cells. AB - Previous studies have shown that subcellular Ca2+ redistribution is involved in Cd-induced autophagy inhibition in primary rat proximal tubular (rPT) cells, but the mechanism remains unclear. In this study, the status of autophagic flux was monitored by the GFP and RFP tandemly tagged LC3 method. Pharmacological inhibition of cytosolic Ca2+ concentration ([Ca2+]c) with 2-APB or BAPTA-AM significantly alleviated Cd-elevated yellow puncta formation and restored Cd inhibited red puncta formation, while thapsigargin (TG) had the opposite regulatory effect, demonstrating that Cd-induced [Ca2+]c elevation inhibited the autophagic flux in rPT cells. Resultantly, Cd-induced autophagosomes accumulation was obviously modulated by 2-APB, BAPTA-AM and TG, respectively. Meanwhile, blockage of autophagosome-lysosome fusion and decreased recruitment of Rab7 to autophagosomes by Cd exposure was noticeably restored by 2-APB or BAPTA-AM, but co-treatment with Cd and TG further impaired Cd-induced autophagy arrest. Moreover, Cd-induced oxidative stress intimately correlated with cytosolic Ca2+ mobilization, and N-acetylcysteine (NAC) markedly rescued Cd-blocked autophagosome-lysosome fusion and recruitment of Rab7 to autophagosomes in rPT cells, implying that Cd-induced autophagy inhibition was due to [Ca2+]c elevation triggered oxidative stress. In summary, these results suggest that Cd-mediated autophagy inhibition in rPT cells is dependent on cytosolic Ca2+ overload. Elevation of [Ca2+]c inhibited the autophagosome-lysosome fusion to block the degradation of autophagosomes, which aggravated Cd-induced cytotoxicity in rPT cells. PMID- 28347756 TI - Gaussian modelling characteristics changes derived from finger photoplethysmographic pulses during exercise and recovery. AB - Gaussian modelling method has been reported as a useful method to analyze arterial pulse waveform changes. This study aimed to provide scientific evidence on Gaussian modelling characteristics changes derived from the finger photoplethysmographic (PPG) pulses during exercise and recovery. 65 healthy subjects (18 female and 47 male) were recruited. Finger PPG pulses were digitally recorded with 5 different exercise loads (0, 50, 75, 100, 125W) as well as during each of 4minute (min) recovery period. The PPG pulses were normalized in both width and amplitude for each recording, which were decomposed into three independent Gaussian waves with nine parameters determined, including the peak amplitude (H1, H2, H3), peak time position (N1, N2, N3) and half-width (W1, W2, W3) from each Gaussian wave, and four extended parameters determined, including the peak time interval (T1,2, T1,3) and amplitude ratio (R1,2, R1,3) between 1st Gaussian wave and 2nd, 3rd Gaussian waves. These derived parameters were finally compared between different exercise loads and recovery phases. With gradually increased exercise loads, the peak amplitude H2, peak time position N1, N2, N3, and half-width W1, W2 increased, peak amplitude H3 decreased significantly (all P<0.05). The peak time interval T1,2 and T1,3 increased significantly from 10.6+/ 1.2 and 36.0+/-4.4 at rest to 14.4+/-2.3 and 45.1+/-6.5 at 100W exercise load, respectively (both P<0.05). The amplitude ratio R1,2 also increased from 1.07+/ 0.2 at rest to 1.22+/-0.2 at 100W, and the amplitude ratio R1,3 decreased from 1.10+/-0.3 at rest to 0.42+/-0.2 at 125W (all P<0.05). An opposite changing trend of these parameters was observed during recovery phases. In conclusion, this study has quantitatively demonstrated significant changes of Gaussian modelling characteristics derived from finger PPG pulse with exercise and during recovery, providing scientific evidence for the physiological mechanism that exercise increases cardiac ejection and vasodilation, and reduces the total peripheral vascular resistance. PMID- 28347755 TI - Inhibition of inflammation induced shedding of the endothelial glycocalyx with low molecular weight heparin. AB - The endothelial surface layer (ESL) consists of the endothelial cell (EC) glycocalyx and adsorbed proteins, and forms a barrier between blood and the EC. Enzymatic shedding of the ESL in response to cytokines may expose receptors for leukocyte (WBC) adhesion and increase vascular permeability. Thus, intravital microscopy was used to explore stabilization of the ESL with low molecular weight heparin (LMWH) to mitigate structural changes with inflammation. Following bolus infusions (i.v.) of LMWH (0.12-1.6mg/kg), shedding of glycans in response to 10 7M fMLP was measured by loss of fluorescently labeled lectins bound to the EC and WBC-EC adhesion was monitored in post-capillary venules of rat mesentery. During a 30min exposure to fMLP, a 50% reduction in fluorescence (indicative of glycan shedding) occurred at the lowest dose of LMWH whereas a 50% increase occurred (indicative of ESL compaction) at the highest dose. Shedding was reduced by LMWH in a dose dependent manner with an EC50 of 0.6mg/kg. Concomitant WBC-EC adhesion increased over 3-fold for all doses of LMWH. However, at a dose of 1.6mg/kg, WBC EC adhesion did not rise significantly during the initial 10min exposure to fMLP. Correlation of WBC adhesion with intensity of the lectin stain for all measurements revealed a significant 40% reduction in adhesion as intensity increased 50%. This relationship was attributed to LMWH inhibition of heparanase and/or binding to components of the glycocalyx that resulted in mitigation of glycan shedding, compaction of the lectin stain and stabilization of the glycocalyx. PMID- 28347757 TI - TDS exposure project: How and when to consider seasonalityin a total diet study? AB - Seasonality is a key issue of total diet studies (TDS), as season may impact consumption patterns and concentrations of food chemicals, then exposure levels. This work aimed at analyzing the impact on dietary exposure of different options of seasonality management, to propose guidelines for TDS sampling. Dietary exposure to nine chemicals was assessed for adults and children from the second French Individual and National Food Consumption Survey: arsenic, copper, manganese, dioxins, furans, dioxin-like and non dioxin-like PCBs, deoxinivalenol and ochratoxin A. Seasonality was considered either in both consumption and concentration data, consumption data only, or concentration data only. Results showed significant differences between exposures during different seasons. For most chemicals, the difference between seasonal exposures may not be mainly driven by seasonality of consumption, but partly by seasonality of concentration. Results on risk assessment remained generally the same. If the main objective of the TDS is the risk assessment, considering season for sampling could be costly but with a low added value in terms of results. For exposure refinement, season has to be considered in the sampling design. More particularly, seasonal samples should be kept separately for chemicals with expected seasonal variation in concentrations, such as some metals or mycotoxins. PMID- 28347758 TI - Structure-activity relationships of flavonoids as natural inhibitors against E. coli beta-glucuronidase. AB - Bacterial beta-glucuronidases play key roles in the deconjugation of a variety of endogenous and drug glucuronides, thus have been recognized as important targets to modulate the enterohepatic circulation of various glucuronides. In this study, more than 30 natural flavonoids were collected and their inhibitory effects against E. coli beta-glucuronidase (EcGUS) were assayed. The results demonstrated that some flavonoids including scutellarein, luteolin, baicalein, quercetin and scutellarin displayed strong to moderate inhibitory effects against EcGUS, with the IC50 values ranging from 5.76 MUM to 29.64 MUM, while isoflavones and dihydroflavones displayed weak inhibitory effects against EcGUS. Further investigation on inhibition kinetics revealed that scutellarein and luteolin functioned as potent competitive inhibitors against EcGUS-mediated PNPG hydrolysis, with the Ki values less than 3.0 MUM. Molecular docking simulations demonstrated that scutellarein and luteolin could be well-docked into the catalytic site of EcGUS, while the binding areas of these two natural inhibitors on EcGUS were highly overlapped with that of PNPG on EcGUS. Additionally, the structure-inhibition relationships of natural flavonoids against EcGUS are also summarized, which will be very helpful for the medicinal chemists to design and develop more potent flavonoid-type inhibitors against EcGUS. PMID- 28347760 TI - Acute Atraumatic Splenic Hemorrhage: Babesiosis or Acute Infectious Mononucleosis. PMID- 28347759 TI - Second international symposium on phytochemicals in medicine and food (2-ISPMF). PMID- 28347761 TI - Humanizing the Electronic Medical Record with the Personal Fact. PMID- 28347762 TI - An in vitro approach for comparative interspecies metabolism of agrochemicals. AB - The metabolism and elimination of a xenobiotic has a direct bearing on its potential to cause toxicity in an organism. The confidence with which data from safety studies can be extrapolated to humans depends, among other factors, upon knowing whether humans are systemically exposed to the same chemical entities (i.e. a parent compound and its metabolites) as the laboratory animals used to study toxicity. Ideally, to understand a metabolite in terms of safety, both the chemical structure and the systemic exposure would need to be determined. However, as systemic exposure data (i.e. blood concentration/time data of test material or metabolites) in humans will not be available for agrochemicals, an in vitro approach must be taken. This paper outlines an in vitro experimental approach for evaluating interspecies metabolic comparisons between humans and animal species used in safety studies. The aim is to ensure, where possible, that all potential human metabolites are also present in the species used in the safety studies. If a metabolite is only observed in human in vitro samples and is not present in a metabolic pathway defined in the toxicological species already, the toxicological relevance of this metabolite must be evaluated. PMID- 28347763 TI - Risk assessment for pyrrolizidine alkaloids detected in (herbal) teas and plant food supplements. AB - Pyrrolizidine alkaloids (PAs) are plant metabolites present in some botanical preparations, with especially 1,2-unsaturated PAs being of concern because they are genotoxic carcinogens. This study presents an overview of tumour data on PAs and points of departure (PODs) derived from them, corroborating that the BMDL10 for lasiocarpine represents a conservative POD for risk assessment. A risk assessment using this BMDL10 and mean levels of PAs reported in literature for (herbal) teas, indicates that consumption of one cup of tea a day would result in MOE values lower than 10 000 for several types of (herbal) teas, indicating a priority for risk management for these products A refined risk assessment using interim relative potency (REP) factors showed that based on the mean PA levels, 7(54%) of 13 types of (herbal) teas and 1 (14%) of 7 types of plant food supplements (PFS) resulted in MOE values lower than 10 000, indicating a priority for risk management also for these products in particular. This includes both preparations containing PA-producing and non-PA-producing plants. Our study provides insight in the current state-of-the art and limitations in the risk assessment of PA-containing food products, especially (herbal) teas and PFS, indicating that PAs in food presents a field of interest for current and future risk management. PMID- 28347764 TI - BDNF is required for taste axon regeneration following unilateral chorda tympani nerve section. AB - Taste nerves readily regenerate to reinnervate denervated taste buds; however, factors required for regeneration have not yet been identified. When the chorda tympani nerve is sectioned, expression of brain-derived neurotrophic factor (BDNF) remains high in the geniculate ganglion and lingual epithelium, despite the loss of taste buds. These observations suggest that BDNF is present in the taste system after nerve section and may support taste nerve regeneration. To test this hypothesis, we inducibly deleted Bdnf during adulthood in mice. Shortly after Bdnf gene recombination, the chorda tympani nerve was unilaterally sectioned causing a loss of both taste buds and neurons, irrespective of BDNF levels. Eight weeks after nerve section, however, regeneration was differentially affected by Bdnf deletion. In control mice, there was regeneration of the chorda tympani nerve and taste buds reappeared with innervation. In contrast, few taste buds were reinnervated in mice lacking normal Bdnf expression such that taste bud number remained low. In all genotypes, taste buds that were reinnervated were normal-sized, but non-innervated taste buds remained small and atrophic. On the side of the tongue contralateral to the nerve section, taste buds for some genotypes became larger and all taste buds remained innervated. Our findings suggest that BDNF is required for nerve regeneration following gustatory nerve section. PMID- 28347765 TI - Spinal cord injury in hypertonic newborns after antenatal hypoxia-ischemia in a rabbit model of cerebral palsy. AB - While antenatal hypoxia-ischemia (H-I) is a well-established cause of brain injury, the effects of H-I on the spinal cord remain undefined. This study examined whether hypertonia in rabbits was accompanied by changes in spinal architecture. Rabbit dams underwent global fetal H-I at embryonic day 25 for 40min. High resolution diffusion tensor imaging was performed on fixed neonatal CNS. Fractional anisotropy (FA) and regional volumetric measurements were compared between kits with and without hypertonia after H-I and sham controls using Tract Based Spatial Statistics. Hypertonic kits showed evidence of damage from hypoxia not only in the brain, but in spinal cord as well. Hypertonic kits showed reduced FA and thickness in corticospinal tracts, external capsule, fimbria, and in white and gray matter of both cervical and lumbar spinal cord. Dorsal white matter of the spinal cord was the exception, where there was thickening and increased FA in hypertonic kits. Direct damage to the spinal cord was demonstrated in a subset of dams imaged during H-I with a 3T magnetic resonance scanner, where apparent diffusion coefficient in fetal spinal cords acutely decreased during hypoxia. Hypertonic kits showed subsequent decreases in lumbar motoneuron counts and extensive TUNEL- and Fluoro-Jade C-positive labeling was present in the spinal cord 48h after H-I, demonstrating spinal neurodegeneration. We speculate that global H-I causes significant loss of both spinal white and gray matter in hypertonic newborns due to direct H-I injury to the spinal cord as well as due to upstream brain injury and consequent loss of descending projections. PMID- 28347766 TI - Biosynthesis of an antiviral compound using a stabilized phosphopentomutase by multipoint covalent immobilization. AB - Ribavirin is a synthetic guanosine analogue with a broad-spectrum of antiviral activity. It is clinically effective against several viruses, such as respiratory syncytial virus, several hemorrhagic fever viruses and HCV when combined with pegylated interferon-alpha. Phosphopentomutase (PPM) catalyzes the transfer of intramolecular phosphate (from C1 to C5) on ribose, and is involved in pentose phosphate pathway and in purine metabolism. Reactions catalyzed by this enzyme are useful for nucleoside analogues production. However, out of its natural environment PPM is unstable and its stability is affected by parameters such as pH and temperature. Therefore, to irreversibly immobilize this enzyme, it needs to be stabilized. In this work, PPM from Escherichia coli ATCC 4157 was overexpressed, purified, stabilized at alkaline pH and immobilized on several supports. The activity of different additives as stabilizing agents was evaluated, and the best result was found using 10% (v/v) glycerol. Under this condition, PPM maintained 86% of its initial activity at pH 10 after 18h incubation, which allowed further covalent immobilization of this enzyme on glyoxyl-agarose with a high yield. This is the first time that PPM has been immobilized by multipoint covalent attachment on glyoxyl support, this derivative being able to biosynthesize ribavirin from alpha-d-ribose-5-phosphate. PMID- 28347767 TI - Characterization of a new UDP-sugar pyrophosphorylase from Hordeum vulgare (barley). AB - The broad substrate spectrum of UDP-sugar pyrophosphorylases from plant salvage pathways is of high interest for the synthesis of expensive nucleotide sugars by straightforward enzyme cascade reactions in combination with monosaccharide kinases. We here present a new UDP-sugar pyrophosphorylase from Hordeum vulgare with favorable biochemical properties like broad pH and temperature tolerances as well as a broad substrate spectrum and high synthesis stability. Enzyme properties were determined and reaction conditions were optimized by high-through put multiplexed capillary electrophoresis analysis. In combination with a galactokinase UDP-alpha-d-galactose (UDP-Gal) was efficiently synthesized with a space-time-yield of 17g/L*h for full conversion of 10mM substrate within 20min by 1.2U of each enzyme. PMID- 28347768 TI - Identification of a novel phospholipase D with high transphosphatidylation activity and its application in synthesis of phosphatidylserine and DHA phosphatidylserine. AB - Phosphatidylserine (PS) and docosahexaenoic acid-phosphatidylserine (DHA-PS) have significant nutritional and biological functions, which are extensively used in functional food industries. Phospholipase D (PLD)-mediated transphosphatidylation of phosphatidylcholine (PC) or DHA-PC with l-serine, is an effective method for PS and DHA-PS preparation. However, because of the hydrolysis activity of PLD, PC and DHA-PC would be converted to the undesirable byproduct, phosphatidic acid (PA) and DHA-PA. In this study, a novel phospholipase D (PLDa2) was firstly cloned from Acinetobacter radioresistens a2 with high transphosphatidylation activity and no hydrolysis activity. In the PLD-catalyzed synthesis process (12h), both the transphosphatidylation conversion rate and selectivity of PS and DHA-PS were about 100%, which is the only PLD enzyme reported with this superiority up till now. In comparison with the majority of other known PLDs, PLDa2 exerted the highest activity at neutral pH, and it was stable from pH 4.0 to pH 9.0. In addition, PLDa2 had excellent thermal stability, with an optimum reaction temperature of 40 degrees C and keeping more than 80% activity from 20 degrees C to 60 degrees C. The high catalytic selectivity mechanism of PLDa2 was explained by utilizing homology modeling, two-step docking, and binding energy and conformation analysis. PLDa2 ensured a stable supply of the biocatalyst with its most preponderant transphosphatidylation activity and PS selectivity, and had great potential in phospholipids industrial production. PMID- 28347769 TI - Probing the acetaldehyde-sensitivity of 2-deoxy-ribose-5-phosphate aldolase (DERA) leads to resistant variants. AB - The 2-deoxy-d-ribose-5-phosphate aldolase (DERA) is a synthetically attractive enzyme because of its ability to perform CC-couplings stereoselectively, the enzyme uses acetaldehyde as nucleophile and thus produces true aldols rather than ketols, and may add two acetaldehyde molecules onto one electrophile. However, DERA produces crotonaldehyde as side reaction from acetaldehyde which is then an irreversible inhibitor forming a covalent Michael-adduct within the active site in particular with cysteine 47 (Dick et al., 2016). This inhibition can be resolved by mutating C47 to non-nucleophile amino acids. Still, the inhibition is not an on-off-feature and the present mutagenesis study illustrates that there must be a C47-independent inactivation mechanism. As a practical result: The virtually fully resistant mutant C47L was found, which shows no loss in stereoselectivity, - this renders this variant as promising catalyst. PMID- 28347770 TI - Intermediate-Term Outcomes for Men with Very Low/Low and Intermediate/High Risk Prostate Cancer Managed by Active Surveillance. AB - PURPOSE: We compare intermediate term clinical outcomes among men with favorable risk and intermediate/high risk prostate cancer managed by active surveillance. MATERIALS AND METHODS: A total of 635 men with localized prostate cancer have been on active surveillance since 2002 at a high volume academic hospital in the United States. Median followup is 50.5 months (IQR 31.1-80.3). Time to event analysis was performed for our clinical end points. RESULTS: Of the cohort 117 men (18.4%) had intermediate/high risk disease. Overall 5 and 10-year all cause survival was 98% and 94%, respectively. Cumulative metastasis-free survival at 5 and 10 years was 99% and 98%, respectively. To date no cancer specific deaths had been observed. Overall freedom from intervention was 61% and 49% at 5 and 10 years, respectively. Overall cumulative freedom from failure of active surveillance, defined as metastasis or biochemical failure after local therapy with curative intent, was 97% and 91% at 5 and 10 years, respectively. Of the men 21 (9.9%) experienced biochemical failure after deferred treatment and the 5-year progression-free probability was 92%. Compared to men with favorable risk disease those with intermediate/high risk cancer experienced no difference in metastases, surveillance failure or curative intervention. However, patients at higher risk were at significantly increased risk for all cause mortality, likely reflecting patient selection factors. These conclusions may be limited by the small number of events and the duration of our study. CONCLUSIONS: Patients with localized prostate cancer who are on active surveillance demonstrated a low rate of active surveillance failure, prostate cancer specific mortality and metastases regardless of baseline risk. PMID- 28347771 TI - Comparison of Biochemical Recurrence-Free Survival after Radical Prostatectomy Triggered by Grade Reclassification during Active Surveillance and in Men Newly Diagnosed with Similar Grade Disease. AB - PURPOSE: We compared biochemical recurrence between men on active surveillance who underwent radical prostatectomy triggered by grade reclassification and men diagnosed with similar grade disease treated with immediate radical prostatectomy. MATERIALS AND METHODS: We retrospectively analyzed the records of men who underwent surgery from 1995 to 2015 at our institution. We identified 4 groups, including 94 and 56 men on active surveillance who underwent radical prostatectomy following reclassification to Gleason 7 (3 + 4) or greater (grade groups 2 or greater) and Gleason 7 (3 + 4) (grade group 2), and 3,504 and 1,979 in the immediate prostatectomy group diagnosed with grade group 2 or greater and 2, respectively. Biochemical recurrence was assessed by Kaplan-Meir analysis and a multivariable Cox model. RESULTS: Men on active surveillance had a lower incidence of biochemical recurrence than men in the immediate radical prostatectomy groups for biopsy grade groups 2 or greater and 2 (each p <0.05). One, 5 and 10-year biochemical recurrence-free survival for men in the active surveillance group vs the immediate radical prostatectomy group was 97.9% vs 85.5%, 76.6% vs 65.1% and 69.0% vs 54.2% in biopsy grade groups 2 or greater (p = 0.009) and 96.4% vs 91.2%, 89.6% vs 74.0% and 89.6% vs 63.9%, respectively, in biopsy grade group 2 (p = 0.071). For biopsy grade groups 2 or greater there was no significant difference in the risk of biochemical recurrence between the groups after adjusting for age, biopsy extent of cancer and prostate specific antigen density. CONCLUSIONS: Patients on active surveillance reclassified to grade groups 2 or greater are at no greater risk for treatment failure than men newly diagnosed with similar grades. PMID- 28347772 TI - Bifunctional opioid/nociceptin hybrid KGNOP1 effectively attenuates pain-related behaviour in a rat model of neuropathy. AB - A bifunctional peptide containing an opioid and nociceptin receptor-binding pharmacophore, H-Dmt-D-Arg-Aba-beta-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2 (KGNOP1), was tested for its analgesic properties when administered intrathecally in naive and chronic constriction injury (CCI)-exposed rats with neuropathy-like symptoms. KGNOP1 significantly increased the acute pain threshold, as measured by the tail flick test, and also increased the threshold of a painful reaction to mechanical and thermal stimuli in CCI-exposed rats. Both of the effects could be blocked by pre-administration of [Nphe1]-Nociceptin (1-13)-NH2 (NPhe) or naloxone, antagonists for nociceptin and opioid receptors, respectively. This led us to conclude that KGNOP1 acts as a dual opioid and nociceptin receptor agonist in vivo. The analgesic effect of KGNOP1 proved to be more powerful than clinical drugs such as morphine and buprenorphine. Repeated daily intrathecal injections of KGNOP1 led to the development of analgesic tolerance, with the antiallodynic action being completely abolished on day 6. Nevertheless, the development of tolerance to the antihyperalgesic effect was delayed in comparison to morphine, which lost its efficacy as measured by the cold plate test after 3days of daily intrathecal administration, whereas KGNOP1 was efficient up to day 6. A single intrathecal injection of morphine to KGNOP1-tolerant rats did not raise the pain threshold in any of the behavioural tests; in contrast, a single intrathecal dose of KGNOP1 significantly suppressed allodynia and hyperalgesia in morphine tolerant rats. PMID- 28347773 TI - Synthesis and biological evaluation of (R)-3,3,3-trifluoro-2-hydroxy-2 methylpropionamides as pyruvate dehydrogenase kinase 1 (PDK1) inhibitors to reduce the growth of cancer cells. AB - Most cancer cells exhibit a high rate of glycolysis and reduced capacity in mitochondrial oxidative phosphorylation. The expression of pyruvate dehydrogenase kinases (PDKs) was found to be increased in many cancer cells. Inhibition of PDKs increases the oxidative phosphorylation of glucose, which may disrupt the balance between the demand and supply of oxygen in cancer cell, thus leading to cell death. Several reports suggested that compounds containing (R)-3,3,3-trifluoro-2 hydroxy-2-methylpropionamide group could inhibit PDKs in pyruvate dehydrogenase primary enzymatic assay. However, none of them were capable of reducing the growth of cancer cells. Herein, we report the synthesis and biological evaluation of some novel PDK1 inhibitors containing the (R)-3,3,3-trifluoro-2-hydroxy-2 methylpropionamide warhead. Excitingly, these novel PDK1 inhibitors exhibited good potency to reduce the growth of cancer cells. We have demonstrated that these compounds could physically associate with PDK1 and activate pyruvate dehydrogenase in low micromolar levels. PMID- 28347774 TI - Polyanion based controlled release system for the GnRH-receptor antagonist degarelix. AB - The aim of this study was to investigate the interaction between the positively charged gonadotropin releasing hormone receptor antagonist degarelix and the two polyanions alginate and carboxymethyl cellulose (CMC). Light as well as transmission electron microscopy revealed that complexes formed by simple mixing of the peptide with one of the polymers had a nano-structure consisting of twisted fibers. The remarkable unique process of complex formation could be followed by isothermal titration calorimetry: We found that peptide self aggregates dissolved upon the addition of polyanion and peptide-polymer-complexes formed thereafter with the anionic polymer as a template. Peptide release from the complexes was tested in vitro and in vivo and compared to the dissolution of drug from self-aggregates. In vitro the release was monitored over a period of three months. We could find only slight differences in the release kinetics for the alginate and the CMC complexes compared to the pure drug. An in vivo study in Sprague Dawley rats showed similar degarelix plasma concentration levels for the complex formulations and an aqueous degarelix solution following subcutaneous injection. Overall, our findings suggest a competition between complex formation and peptide aggregation, which did not increase the availability of free drug. PMID- 28347775 TI - Thermo- and pH-responsive nano-in-micro particles for combinatorial drug delivery to cancer cells. AB - Drug combinatorial therapy has been gaining the scientific community attention as a suitable approach to increase treatments efficacy and promote cancer eradication. In this study, a new pH- and thermo- responsive carrier was developed by combining doxorubicin-loaded gold-core silica shell nanorods with salicylic acid loaded poly (lactic-co-glycolic acid) based microparticles (NIMPS). The obtained results showed that the drugs and nanorods release could be triggered by the near-infrared (NIR) laser irradiation or by the exposition to an acidic environment. The in vitro 2D cell studies showed that the NIMPS are biocompatible and easily uptaken by HeLa cells. In addition, 3D cell culture models revealed that the NIMPS administration, combined with the NIR laser irradiation, was capable of reducing the size of the HeLa spheroids up to 48%. Overall, the attained data support the application of the nano-in-micro spheres as a dual stimuli responsive drug carrier system for the local administration of combined therapies to cervical cancer cells. PMID- 28347776 TI - Identification of new SNPs associated with severe toxicity to capecitabine. AB - Predicting individual risk of chemotherapy-induced severe adverse reaction is a critical issue when selecting the best treatment for cancer patients. SNPs have been identified in genes involved in the pharmacodynamics of fluoropyrimidines, and guidelines even recommend genotyping some DPYD variants in order to estimate the risk of toxicity. However, the predictive value of this approach remains insufficient, thus limiting its clinical implementation. The aim of the present study was to identify new genetic variants by selecting a group of tag SNPs in genes associated with the pharmacodynamics of fluoropyrimidines (CDA, DPYD, ENOSF1, CES1, TYMS, SLC22A7, TYMP, and UMPS). For this purpose, 23 selected SNPs were genotyped on an OpenArrayTM platform in a cohort of 301 colorectal cancer patients receiving capecitabine-based chemotherapy. Univariate and multivariate statistical analysis by logistic regression revealed 10 SNPs associated with severe adverse reactions to capecitabine (P<0.05): rs1048977, rs12726436, and rs2072671 in CDA; rs12119882 in DPYD; rs2853741 in TYMS; rs699517 in TYMS/ENOSF1; rs2270860 and rs4149178 in SLC22A7; and rs2279199 and rs4678145 in UMPS. Except for rs2072671, no association had previously been reported between these SNPs and the risk of capecitabine-induced toxicity. The use of tag SNPs to find new polymorphisms related to adverse reactions to capecitabine was successful. These new variants could increase the predictive power of currently available tests and thus prevent severe adverse reactions to capecitabine. PMID- 28347777 TI - What makes dietary restraint problematic? Development and validation of the Inflexible Eating Questionnaire. AB - This study presents the Inflexible Eating Questionnaire (IEQ), which measures the inflexible adherence to subjective eating rules. The scale's structure and psychometric properties were examined in distinct samples from the general population comprising both men and women. IEQ presented an 11-item one dimensional structure, revealed high internal consistency, construct and temporal stability, and discriminated eating psychopathology cases from non-cases. The IEQ presented significant associations with dietary restraint, eating psychopathology, body image inflexibility, general psychopathology symptoms, and decreased intuitive eating. IEQ was a significant moderator on the association between dietary restraint and eating psychopathology symptoms. Findings suggested that the IEQ is a valid and useful instrument with potential implications for research on psychological inflexibility in disordered eating. PMID- 28347778 TI - Deconstructing family meals: Do family structure, gender and employment status influence the odds of having a family meal? AB - OBJECTIVES: We assessed the odds of having a family dinner by parental gender, family structure and parental employment. METHODS: This study used data from the American Time Use Survey (ATUS) (2006-2008). Multivariate analyses assessed the odds of two outcomes among parents: 1) eating at all with children and 2) having a family dinner. RESULTS: Single men had lower odds of eating at all with children and eating a family dinner in comparison to partnered/married males. Partnered/married women had increased odds of eating at all with children and eating a family dinner compared to their partnered/married male counterparts. While single women had increased odds of eating at all with children compared to partnered/married males, no difference was detected in the odds of having a family dinner. Among dual-headed households, women had lower odds of eating a family dinner when both parents were employed compared a dual-headed household with employed male/non-employed female. There were no differences among men regardless of their employment status or that of their partner/spouse. CONCLUSIONS: Family structure, parental gender and employment status all influence the odds of having a family dinner. Future research on family meals should consider all of these factors to better understand trends and disparities across household compositions. PMID- 28347779 TI - Consumption of food away from home in Bangladesh: Do rich households spend more? AB - While consumption of food away from home (FAFH) is an established phenomenon among households in the developed countries, FAFH is a growing phenomenon in many middle-income and rapidly growing developing countries. Although, studies are available on the factors affecting consumption of FAFH in developed countries, there is a paucity of such studies in developing countries. This study examines households' choice of and expenditures on FAFH. We used information from Bangladeshi households and applied a double-hurdle regression model estimation procedure. Findings show that, in general, rich households are spending proportionately less on FAFH and, over time, the trend is continuing. Although households with female members who work in the non-farm sector are more likely to consume FAFH, educated household heads and spouses, and particularly urban households are less likely to consume and spend on FAFH. As the problem of food adulteration by dishonest sellers is rampant in Bangladesh, perhaps it discourages rich, urban and households headed by educated heads and spouses to consume and spend more on FAFH. Based on the findings, some points of interventions are also prescribed in this study. PMID- 28347780 TI - Semaphorin4D promotes axon regrowth and swimming ability during recovery following zebrafish spinal cord injury. AB - Semaphorins comprise a family of proteins involved in axon guidance during development. Semaphorin4D (Sema4D) has both neuroregenerative and neurorepressive functions, being able to stimulate both axonal outgrowth and growth cone collapse during development, and therefore could play an important role in neurological recovery from traumatic injury. Here, we used a zebrafish spinal cord transection model to study the role of Sema4D in a system capable of neuroregeneration. Real time qPCR and in situ hybridization showed upregulated Sema4D expression in the acute response phase (within 3days post SCI), and downregulated levels in the chronic response phase (11-21days after SCI). Double-immunostaining for Sema4D and either Islet-1 (motoneuron marker) or Iba-1 (microglial marker) showed that microglia surrounded Sema4D-positive motoneurons along the central canal at 4h post injury (hpi) and 12hpi. Following administration of Sema4D morpholino (MO) to transected zebrafish, double-immunostaining showed that Sema4D-positive motoneurons surrounded by microglia decreased at 7days and 11days compared with standard control MO. Anterograde and retrograde tracing indicate that Sema4D participates in axon regeneration in the spinal cord following spinal cord injury (SCI) in the zebrafish. Swim tracking shows that MO-mediated inhibition of Sema4D retarded the recovery of swimming function when compared to standard control MO. The combined results indicate that Sema4D expression in motoneurons enhances locomotor recovery and axon regeneration, possibly by regulating microglia function, after SCI in adult zebrafish. PMID- 28347781 TI - Guillain-Barre syndrome during the Zika virus outbreak in Sucre, Colombia, 2016. PMID- 28347782 TI - Aggregation of t10,c12 conjugated linoleic Acid in presence of natural and modified cyclodextrins. A physicochemical, thermal and computational analysis. AB - In this work the aggregation behavior of t10,c12 Conjugated linoleic acid (t10,c12-CLA) is presented for first time. The results show a c.m.c. of 25MUM at pH 8 and 25 degrees C. The encapsulation process with cyclodextrins (CDs) presented a 1:1 stoichiometry in all cases studied but the complexation constants were strongly dependent on the type of CDs used, the pH and temperature. Hydroxypropyl-beta-Cyclodextrin (HPbetaCD) was the best CD studied for encapsulating t10,c12-CLA. The resulting t10,c12-CLA-HPbetaCD complex showed a very high dependency on pH, which explains why a pKa of 4.08 was found for first time, which was very close to the simulated value. Furthermore, the effect of temperature on the t10,c12-CLA-HPbetaCD was studied. The complexation constant (KF) showed an increase behavior with the temperature. In addition, molecular docking calculations provided further insights into how the different interactions influence the complexation constant. Finally, a comparative study with rumenic acid, an isomer, was carried out. PMID- 28347783 TI - Osteoarthritis after rotator cuff repair: A 10-year follow-up study. AB - BACKGROUND: Joint surgery is often complicated by gradual bone and cartilage deterioration that eventually leads to secondary osteoarthritis. The primary objective of this study was to identify preoperative risk factors for gleno humeral osteoarthritis after rotator cuff repair. The secondary objectives were to assess whether the risk of gleno-humeral osteoarthritis was influenced by the operative technique, occurrence of postoperative complications, cuff healing, and muscle degeneration and to determine whether gleno-humeral osteoarthritis affected the clinical outcome. HYPOTHESIS: The development of gleno-humeral osteoarthritis affects the postoperative clinical outcome. MATERIAL AND METHOD: A retrospective multicentre study of patients who underwent rotator cuff repair in 2003 and were re-evaluated at least 10 years later was conducted under the aegis of the Societe francaise de chirurgie orthopedique et traumatique (SOFCOT). Osteoarthritis severity was graded according to the Samilson-Prieto classification. RESULTS: Four hundred and one patients were included. At last follow-up, at least 10 years after surgery, the radiological Samilson-Prieto grades were distributed as follows: 0, n=181 (45%); 1, n=142 (n=35%); 2, n=57 (14%); 3, n=14 (4%); and 4, n=7 (2%). The mean Constant score was significantly higher in the patients without than with osteoarthritis at last follow-up (79/100 vs. 73/100, P<0.001). MRI assessment of cuff healing showed that the proportion of patients with osteoarthritis was significantly higher in the group with unhealed or re-torn cuffs (Sugaya type 4 or 5) than in the group with healed cuffs (Sugaya type 1, 2, or 3) (46% vs. 25%, P=0.012). DISCUSSION: Our study showed no associations linking the risk of gleno-humeral osteoarthritis to the patient activity profile, history of shoulder injury, or preoperative symptom duration. In contrast, statistically significant associations were identified between gleno-humeral osteoarthritis and age, male gender, initial tear severity, and the pain and mobility components of the preoperative Constant score. Decreased invasiveness of the operative technique probably diminishes the long term risk of osteoarthritis. An unhealed or re-torn cuff increases the risk of osteoarthritis. Osteoarthritis is associated with poorer final clinical outcomes. LEVEL OF EVIDENCE: IV, retrospective non-randomised study. PMID- 28347784 TI - A programmable smoke delivery device for PET imaging with cigarettes containing 11C-nicotine. AB - INTRODUCTION: PET imaging with 11C-nicotine-loaded cigarettes is a valuable tool to directly assess fast nicotine kinetics and its neuropharmacological role in tobacco dependence. To eliminate variations among puffs inhaled by subjects, this work aimed to develop a programmable smoke delivery device (SDD) to produce highly reproducible and adjustable puffs of cigarette smoke for PET experiments. NEW METHOD: The SDD was built around a programmable syringe pump as a smoking machine to draw a puff of smoke from a 11C-nicotine-loaded cigarette and make it available for a subject to take the smoke into the mouth and then inhale it during PET data acquisition. Brain nicotine time activity curves and total body absorbed 11C-nicotine doses (TAD) were measured in smokers who inhaled a single puff of smoke via the SDD from a 11C-nicotine-loaded cigarette. RESULTS: Nearly identical brain nicotine kinetics were observed between participants who inhaled a puff of smoke through the SDD and those who inhaled directly from a cigarette. COMPARISON WITH EXISTING METHODS: This new device minimizes puff variations that exist with earlier smoke delivery apparatuses which could introduce confounding factors. CONCLUSIONS: The SDD is effective in delivering 11C-nicotine from the study cigarettes. Despite a 2-s increase in aging of smoke delivered through the SDD versus smoke taken directly from a cigarette, the difference in brain nicotine kinetics after 11C-nicotine delivery with and without use of the SDD is negligible. This refined device may be useful for future research on the deposition and pharmacokinetics of nicotine inhaled with tobacco smoke. PMID- 28347785 TI - 3D chitinous scaffolds derived from cultivated marine demosponge Aplysina aerophoba for tissue engineering approaches based on human mesenchymal stromal cells. AB - The recently discovered chitin-based scaffolds derived from poriferans have the necessary prosperities for potential use in tissue engineering. Among the various demosponges of the Verongida order, Aplysina aerophoba is an attractive target for more in-depth investigations, as it is a renewable source of unique 3D microporous chitinous scaffolds. We found these chitinous scaffolds were cytocompatible and supported attachment, growth and proliferation of human mesenchymal stromal cells (hMSCs) in vitro. Cultivation of hMSCs on the scaffolds for 7days resulted in a two-fold increase in their metabolic activity, indicating increased cell numbers. Cells cultured onto chitin scaffolds in differentiation media were able to differentiate into the chondrogenic, adipogenic and osteogenic lineages, respectively. These results indicate A. aerophoba is a novel source of chitin scaffolds to futher hMSCs-based tissue engineering strategies. PMID- 28347786 TI - Consumption of guava may have beneficial effects in type 2 diabetes: A bioactive perspective. AB - The objectives of this study were to evaluate the anti-diabetic and anti hyperlipidemic effects and relative mechanisms of guava polysaccharides (GPs) in rats with type 2 diabetic mellitus (T2DM). The chemical characterization and monosaccharide compositions of GPs, named as GP-1, GP-2, GP-3, and GP-4, were determined by PMP-HPLC and FT-IR. The results revealed that all GPs had the typical saccharide absorptions, and all were heteropolysaccharides. In addition, GPs efficiently decreased levels of fasting blood glucose, glucosylated serum protein, serum insulin, homeostasis model assessment of insulin resistance, total cholesterol, triglyceride and serum alanine transaminase, improved oral glucose tolerance, and increased insulin sensitivity in rats with T2DM. Histopathological observations suggested that GP-1, GP-3, and GP-4 could alleviate injury in pancreatic islet cells, and Western blot analysis showed that these GPs upregulated gene expression of the insulin receptor, insulin receptor substrate 2, Akt, and glucose transporter type 4. Taken together, these data suggest that GPs may be beneficial in treating T2DM and reducing the risk of hyperlipidemia, vascular disease, and cirrhosis via the PI3K/Akt signaling pathway. PMID- 28347787 TI - Expression of chitinase gene in BL21 pET system and investigating the biocatalystic performance of chitinase-loaded AlgSep nanocomposite beads. AB - Chitin, a polysaccharide, is abundant in nature and this substrate can be easily hydrolyzed by chitinase. Pharmaceutical and industrial applications of chitinase are considerably noteworthy, therefore in this study, high scale production of Chit36 enzyme was targeted using the E. coli pET expression system. The purified Chit36 enzyme was immobilized in Ca2+-cross linked alginate/sepiolite (AlgSep) nanocomposite beads for improving the catalytic activity and stability of Chit36 enzyme during the biocatalytic process. Immobilized enzymes require optimal conditions different from soluble enzymes. The AlgSep nanocomposite can save spatial structure and activity of the enzyme which is critical for enzyme immobilization. The catalytic activity and specific activity of the Chit36 entrapped in alginate nanocomposite beads were evaluated. Results showed that the activity of immobilized Chit36 in Ca-Alginate sepiolite composites beads (3.10+/ 0.63U/g gel) was higher than that of immobilized Chit36 in Ca-alginate beads (3.95+/-0.40U/g gel). Also, the specific activity of Chit36 in AlgSep nanocomposite beads (22.9+/-1.521U/mg protein) was higher than the immobilized Chit36 in sepiolite-free alginate beads (8.52+/-0.758U/mg protein). The promising results obtained from this study would have beneficial pharmaceutical and industrial applications. PMID- 28347788 TI - Galactomannan from Schizolobium amazonicum seed and its sulfated derivatives impair metabolism in HepG2 cells. AB - This study evaluated the effects of native galactomannan from Schizolobium amazonicum seeds and its sulfated forms on certain metabolic parameters of HepG2 cells. Aqueous extraction from S. amazonicum seeds furnished galactomannan with 3.2:1 Man:Gal ratio (SAGM) and molar mass of 4.34*105g/mol. The SAGM fraction was subjected to sulfation using chlorosulfonic acid to obtain SAGMS1 and SAGMS2 with DS of 0.4 and 0.6, respectively. Cytotoxicity of SAGM, SAGMS1, and SAGMS2 was evaluated in human hepatocellular carcinoma cells (HepG2). After 72h, SAGM decreased the viability of HepG2 cells by 50% at 250MUg/mL, while SAGMS1 reduced it by 30% at the same concentration. SAGM, SAGMS1, and SAGMS2 promoted a reduction in oxygen consumption and an increase in lactate production in non permeabilized HepG2 cells after 72h of treatment. These results suggest that SAGM, SAGMS1, and SAGMS2 could be recognized by HepG2 cells and might trigger alterations that impair its survival. These effects could be implicated in the modification of the oxidative phosphorylation process in HepG2 cells and activation of the glycolytic pathway. PMID- 28347790 TI - Key considerations on nebulization of antimicrobial agents to mechanically ventilated patients. AB - Nebulized antibiotics have an established role in patients with cystic fibrosis or bronchiectasis. Their potential benefit to treat respiratory infections in mechanically ventilated patients is receiving increasing interest. In this consensus statement of the European Society of Clinical Microbiology and Infectious Diseases, the body of evidence of the therapeutic utility of aerosolized antibiotics in mechanically ventilated patients was reviewed and resulted in the following recommendations: Vibrating-mesh nebulizers should be preferred to jet or ultrasonic nebulizers. To decrease turbulence and limit circuit and tracheobronchial deposition, we recommend: (a) the use of specifically designed respiratory circuits avoiding sharp angles and characterized by smooth inner surfaces, (b) the use of specific ventilator settings during nebulization including use of a volume controlled mode using constant inspiratory flow, tidal volume 8 mL/kg, respiratory frequency 12 to 15 bpm, inspiratory:expiratory ratio 50%, inspiratory pause 20% and positive end expiratory pressure 5 to 10 cm H2O and (c) the administration of a short-acting sedative agent if coordination between the patient and the ventilator is not obtained, to avoid patient's flow triggering and episodes of peak decelerating inspiratory flow. A filter should be inserted on the expiratory limb to protect the ventilator flow device and changed between each nebulization to avoid expiratory flow obstruction. A heat and moisture exchanger and/or conventional heated humidifier should be stopped during the nebulization period to avoid a massive loss of aerosolized particles through trapping and condensation. If these technical requirements are not followed, there is a high risk of treatment failure and adverse events in mechanically ventilated patients receiving nebulized antibiotics for pneumonia. PMID- 28347789 TI - Induction of cell death in pancreatic ductal adenocarcinoma by indirubin 3'-oxime and 5-methoxyindirubin 3'-oxime in vitro and in vivo. AB - Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis. To identify potential effective therapeutic drugs for PDAC, we established a screening system based on spheroid formation using 170#3 mouse PDAC cells with or without fibroblasts. We found that indirubin 3'-oxime (Indox) and 5 methoxyindirubin 3'-oxime (5MeOIndox) inhibited PDAC cell proliferation. Furthermore, PDAC xenograft growth was also inhibited in BALB/c nu/nu mice after administration of Indox and 5MeOIndox. Both phosphorylated CDK1 and cyclin B1 levels in 170#3 cells were significantly reduced by treatment with Indox and 5MeOIndox in vitro and in vivo. Cell cycle analysis revealed that 5MeOIndox, but not Indox, induced G2/M arrest. Annexin V-propidium iodide double-staining analysis demonstrated that Indox induced abundant non-apoptotic cell death of 170#3 cells, while 5MeOIndox predominantly induced early apoptosis, indicating that the cytotoxicity of 5MeOIndox is lower than that of Indox. These results suggest that one mechanism of 5MeOIndox is to induce G2/M arrest of PDAC cells via inhibition of CDK1/cyclin B1 levels, thereby leading to apoptosis. Our findings suggest 5MeOIndox as a potential useful anticancer agent in PDAC. PMID- 28347791 TI - Cardiovascular training in 2017: Reshaping tradition to envision the future. PMID- 28347792 TI - PPARgamma agonist use and recurrence of atrial fibrillation after successful electrical cardioversion. AB - Inflammation is associated with atrial fibrillation (AF), and peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists have anti-inflammatory properties. We tested whether pioglitazone reduced AF recurrence after electrical cardioversion (EC) by modifying systemic inflammation. In this randomized and prospective trial, patients with persistent AF and type 2 diabetes mellitus were randomized into a pioglitazone group (n=48) or a control group (n=49) before EC. Treatment was continued for 3 months or until AF recurred. Serum inflammatory markers [high sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha)] were measured at baseline and follow up. During the 3-month follow-up, AF recurred in 22 (45.8%) patients of the pioglitazone-treated and 24 (49.0%) patients of the control group (P=0.756). However, the 3 inflammatory markers were significantly lowered with pioglitazone treatment during follow-up. Cox proportional hazards regression models showed that the predictors of recurrence included AF history (relative risk RR 1.002, 95% CI 1.003-1.061, P =0.037) and the left atrial diameter (RR 1.131, 95% CI 1.029-1.242, P = 0.010). In conclusion, while reducing some inflammatory markers, the PPARgamma agonist pioglitazone did not affect the recurrence of AF after EC. PMID- 28347793 TI - Reply by the Author. PMID- 28347794 TI - Re: Punjani et al.: Postoperative Urinary Retention and Urinary Tract Infections Predict Midurethral Sling Mesh Complications (Urology 2017;99:42-48). PMID- 28347795 TI - Clinical Experience With Penile Traction Therapy Among Men Undergoing Collagenase Clostridium histolyticum for Peyronie Disease. AB - OBJECTIVE: To evaluate the outcomes in men undergoing collagenase Clostridium histolyticum (CCH) with concurrent penile traction therapy (PTT) for the treatment of Peyronie disease (PD). MATERIALS AND METHODS: We identified patients treated with CCH between March 2014 and July 2016. Patients were recommended to perform modeling and PTT between injection series. A final curve assessment was performed after patients completed CCH. A prospective database was maintained, including patient-reported frequency and duration of PTT. Statistical analysis was performed to evaluate outcomes based on use and duration of PTT. RESULTS: A total of 51 patients completed CCH and had complete objective data available for analysis. Mean (standard deviation [SD]) baseline curvature was 66.7 (25.0) degrees, and mean (SD) improvement post CCH was 20.9 (17.3) degrees (P < .0001). Thirty-five (69%) men reported daily PTT for a mean (SD) of 9.8 (6.3) hours per week. No significant difference was identified in the degree of curve improvement based on frequency or duration of PTT (P = .40). Similarly, no associations between PTT and functional outcomes including intercourse restoration and surgery prevention were identified. Stretched penile length increased nonsignificantly by a mean (SD) of +0.4 (1.5) cm in the PTT group, compared with -0.35 (1.5) in the non-PTT group (P = .21). CONCLUSION: The current series represents a "true-to life" experience, wherein utilization patterns, attrition, and compliance issues are relevant factors impacting efficacy. PTT use with the Andropenis declined in both frequency and duration with subsequent injection series, and there was no significant difference in curve improvement or stretched penile length with a mean 10 hours of weekly concurrent PTT. PMID- 28347796 TI - Systematic Review of Self-Report Measures of Pain Intensity in 3- and 4-Year-Old Children: Bridging a Period of Rapid Cognitive Development. AB - : Claims are made for the validity of some self-report pain scales for 3- and 4 year-old children, but little is known about their ability to use such tools. This systematic review identified self-report pain intensity measures used with 3 and/or 4- year-old participants (3-4yo) and considered their reliability and validity within this age span. The search protocol identified research articles that included 3-4yo, reported use of any pain scale, and included self-reported pain intensity ratings. A total of 1,590 articles were screened and 617 articles met inclusion criteria. Of the included studies, 98% aggregated self-report data for 3-4yo with data for older children, leading to overestimates of the reliability and validity of self-report in the younger age group. In the 14 studies that provided nonaggregated data for 3-4yo, there was no evidence for 3 year-old and weak evidence for 4-year-old children being able to use published self-report pain intensity tools in a valid or reliable way. Preschool-age children have been reported to do better with fewer than the 6 response options offered on published faces scales. Simplified tools are being developed for young children; however, more research is needed before these are adopted. PERSPECTIVE: Some self-report pain scales have been promoted for use with 3- and 4-year-old children, but this is on the basis of studies that aggregated data for younger and older children, resulting in overestimates of reliability and validity for the preschool-age children. Scales with fewer response options show promise, at least for 4-year-old children. PMID- 28347797 TI - Twin Peaks? No Evidence of Bimodal Distribution of Outcomes in Clinical Trials of Nonsurgical Interventions for Spinal Pain: An Exploratory Analysis. AB - : The presence of bimodal outcome distributions has been used as a justification for conducting responder analyses, in addition to, or in place of analyses of the mean between-group difference, in clinical trials and systematic reviews of interventions for pain. The aim of this study was to investigate the distribution of participants' pain outcomes for evidence of bimodal distribution. We sourced data on participant outcomes from a convenience sample of 10 trials of nonsurgical interventions (exercise, manual therapy, medication) for spinal pain. We assessed normality using the Shapiro-Wilk test. When the Shapiro-Wilk test suggested non-normality we inspected distribution plots visually and attempted to classify them. To test whether responder analyses detected a meaningful number of additional patients experiencing substantial improvements we also calculated the risk difference and number needed to treat to benefit. We found no compelling evidence suggesting that outcomes were bimodally distributed for any of the intervention groups. Responder analysis would not meaningfully alter our interpretation of these data compared with the mean between group difference. Our findings suggest that bimodal distribution of outcomes should not be assumed in interventions for spinal pain and do not support the automatic prioritization of responder analysis over the between group difference in the evaluation of treatment effectiveness for pain. PERSPECTIVE: Secondary analysis of clinical trials of nonsurgical interventions for spinal pain found no evidence for bimodally distributed outcomes. The findings do not support the automatic prioritization of responder analyses over the average between group difference in the evaluation of treatment effectiveness for spinal pain. PMID- 28347798 TI - Predictors of Prescription Opioid Use 4 Months After Traumatic Musculoskeletal Injury and Corrective Surgery: A Prospective Study. AB - : The aim of the present study was to examine the incidence and predictors of persistent prescription opioid use 4 months after traumatic injury. Adults who sustained a traumatic musculoskeletal injury were recruited to participate in this observational prospective, longitudinal study within 14 days of injury (T1) and followed for 4 months (T2). Measures included questionnaires on pain, opioid consumption, pain disability, anxiety, depression, and posttraumatic stress symptoms as well as a chart review for injury related information. The sample consisted of 122 patients (66.4% male; mean age = 44.8 years, SD = 17.1), of whom 94.3% (n = 115) were using prescription opioids. At T2, 35.3% (n = 43) patients were using prescription opioids. After controlling for age, sex, injury severity, T1 pain severity, and T2 symptoms of depression, 2 factors emerged as significantly related to T2 prescription opioid use; namely, T2 pain severity (odds ratio = 1.248, 95% confidence interval, 1.071-1.742) and T2 pain self efficacy (odds ratio = .943, 95% confidence interval, .903-.984). These results suggest that opioid use after traumatic musculoskeletal injury is related to pain severity and how well patients cope specifically with their pain, over and above other psychological factors, such as depression and anxiety. PERSPECTIVE: This article identifies predictive factors for prescription opioid use after traumatic musculoskeletal injury, namely severe pain and a poor sense of control over the pain. These results highlight the importance of using prospective longitudinal study designs to understand why patients continue to use prescription opioids after major tissue-damaging events. PMID- 28347799 TI - Ursolic acid attenuates cigarette smoke-induced emphysema in rats by regulating PERK and Nrf2 pathways. AB - OBJECTIVE: Ursolic acid (UA) is widely distributed in natural plants to against oxidation, virus, inflammation, tumor, and has been widely used in the pharmaceutical and cosmetics. However, its effect on emphysema of chronic obstructive pulmonary disease (COPD) is unknown. Unfolded protein response is involved in pathogenesis of COPD through PERK pathway. Nuclear erythroid-related factor 2 (Nrf2) regulates antioxidant defensive mechanism in COPD. This study was to explore effect and mechanism of UA on cigarette smoke (CS)-induced rat emphysema. MATERIALS AND METHODS: 50 Wistar rats were divided into 5 groups (n = 10 each): rats were exposed to CS for 12 weeks in absence (CS group) or presence of UA at different doses. Control group was treated with UA vehicle only. Histopathology, apoptosis, key protein expression of PERK and Nrf2 pathway were determined in lung tissues. Oxidative stress levels in lung were represented by 8 OHdG, MDA and GSH levels. RESULTS: Emphysema-related pathology, based on inter alveolar wall distance and alveolar density, was less severe in UA groups than in CS group. Compared with CS group, UA treatment down-regulated PERK pathway protein expression, up-regulated expression of Bcl-2 and down-regulated expression of Bax, Cleaved-Caspase3 and Cleaved-Caspase12. Moreover, UA decreased number of apoptotic cells in rat lungs. UA also up-regulated protein expression of Nrf2/ARE pathway and GSH level, decreased expression of oxidant stress factor 8-OHdG and MDA. These improvements were in accordance with attenuation of severity of emphysema. CONCLUSIONS: UA attenuates CS-induced rat emphysema by down-regulating PERK pathway to alleviate CS-induced apoptosis in lung, and up regulating Nrf2 pathway to improve cigarette smoke-induced oxidant stress in rat lungs. PMID- 28347801 TI - Proposal of a novel MELD exception point system for hepatocellular carcinoma: Dynamics better than tumor characteristics? PMID- 28347800 TI - Reply to: "Proposal of a novel MELD exception point system for hepatocellular carcinoma: Dynamics better than tumor characteristics?" PMID- 28347802 TI - Adding embolization to TIPS implantation: A better therapy to control bleeding from ectopic varices? PMID- 28347803 TI - Reply to: "Adding embolization to TIPS implantation: A better therapy to control bleeding from ectopic varices?" PMID- 28347804 TI - O-GlcNAc transferase promotes fatty liver-associated liver cancer through inducing palmitic acid and activating endoplasmic reticulum stress. AB - BACKGROUND & AIMS: O-GlcNAc transferase (OGT) is a unique glycosyltransferase involved in metabolic reprogramming. We investigated the functional role of OGT in non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD HCC). METHODS: The biological function of OGT in NAFLD-HCC was determined by gain or loss- of OGT functional assays in vitro and in nude mice. OGT target factors and pathways were identified by liquid chromatography-tandem mass spectrometry (LC-MS), promoter luciferase assay, DNA binding activity assay and Western blot. RESULTS: OGT was upregulated in 12 out of 18 (66.7%) NAFLD-HCC tumor tissues by transcriptome sequencing, which was confirmed in additional NAFLD-HCC tumor tissues and cell lines. Biofunctional investigation demonstrated that OGT significantly increased cell growth (p<0.001), clonogenicity (p<0.01), migration and invasion (p<0.05) ability in vitro, and promoted xenograft tumor growth as well as lung metastasis in nude mice. The oncogenic effect of OGT was investigated, we found that OGT significantly induced palmitic acid production identified by LC-MS, which enhanced the protein expression of endoplasmic reticulum (ER) stress masters of glucose-regulated protein 78 and inositol requiring enzyme 1alpha. Consequently, OGT significantly activated JNK/c-jun/AP-1 cascade by increasing protein expression of p-JNK, p-c-Jun and activation of AP 1; and induced NF-kappaB pathway through enhancing the protein levels of p IKKalpha/ p-IKKbeta, p-p65, p-p50 and the NF-kappaB DNA binding activity. Notably, OGT inhibition by its antagonist (ST045849) suppressed cell proliferation in vitro (p<0.001) and in xenograft mice models (p<0.05). CONCLUSIONS: OGT plays an oncogenic role in NAFLD-associated HCC through regulating palmitic acid and inducing ER stress, consequently activating oncogenic JNK/c-jun/AP-1 and NF-kappaB cascades. LAY SUMMARY: OGT, a unique glycosyltransferase enzyme, was identified to be upregulated in non-alcoholic fatty liver disease-associated hepatocellular carcinoma tissues by transcriptome sequencing. Here, we found that OGT plays a role in cancer by promoting tumor growth and metastasis in both cell models and animal models. This effect is mediated by the induction of palmitic acid. PMID- 28347805 TI - beta2-glycoprotein I and its antibodies involve in the pathogenesis of the antiphospholipid syndrome. AB - The antiphospholipid syndrome (APS) is characterized by venous or arterial thrombosis, and associated with dysfunctions of endothelial cells and monocytes. beta2-glycoprotein I is a phospholipid-binding glycoprotein, and its antibodies have been reported to correlate strongly with thrombotic risk and play putative role in the pathogenesis of APS, whereas the biofunctions of anti-beta2 glycoprotein I antibodies remain largely uncertain. It is noted that beta2 glycoprotein I exhibits direct interaction with membrane Toll-like receptors, and through this interaction, the complex of beta2-glycoprotein I and its antibodies induces intracellular signals via Toll-like receptors, resulting in activation of endothelial cells and monocytes, and expression of proinflammatory cytokines. In this review, we further discussed the recent findings of beta2-glycoprotein I/antibody complex. Once activated by beta2-glycoprotein I/antibody and their signals, endothelial cells release microparticle/extracellular vesicles which can further stimulate the surrounding rest cells with procoagulant and pro inflammatory properties in a paracrine or/and autocrine manner. Novel evidence of beta2-glycoprotein I/antibody complex bioactivities may provide insight into the molecular mechanisms that the complex regulates cell function and involves in APS pathogenesis. PMID- 28347806 TI - Narratives of focal brain injured individuals: A macro-level analysis. AB - Focal brain injury can have detrimental effects on the pragmatics of communication. This study examined narrative production by unilateral brain damaged people (n=36) and healthy controls and focused on the complexity (content and coherence) and the evaluative aspect of their narratives to test the general hypothesis that the left hemisphere is biased to process microlinguistic information and the right hemisphere is biased to process macrolinguistic information. We found that people with left hemisphere damage's (LHD) narratives were less likely to maintain the overall theme of the story and produced fewer evaluative comments in their narratives. These deficits correlated with their performances on microlinguistic linguistic tasks. People with the right hemisphere damage (RHD) seemed to be preserved in expressing narrative complexity and evaluations as a group. Yet, single case analyses revealed that particular regions in the right hemisphere such as damage to the dorsolateral prefrontal cortex (DLPFC), the anterior and superior temporal gyrus, the middle temporal gyrus, and the supramarginal gyrus lead to problems in creating narratives. Our findings demonstrate that both hemispheres are necessary to produce competent narrative production. LHD people's poor production is related to their microlinguistic language problems whereas RHD people's impaired abilities can be associated with planning and working memory abilities required to relate events in a narrative. PMID- 28347807 TI - Retinal gene delivery enhancement by lycopene incorporation into cationic niosomes based on DOTMA and polysorbate 60. AB - The present study aimed to evaluate the incorporation of the natural lipid lycopene into niosome formulations based on cationic lipid DOTMA and polysorbate 60 non-ionic surfactant to analyze the potential application of this novel formulation to deliver genetic material into the rat retina. Both niosomes with and without lycopene were prepared by the reverse phase evaporation method and physicochemically characterized in terms of size, zeta potential, polydispersity index and capacity to condense, release and protect the DNA against enzymatic digestion. In vitro experiments were performed in ARPE-19 cells after complexion of niosomes with pCMS-EGFP plasmid at appropriate cationic lipid/DNA ratios. At 18/1 mass ratio, nioplexes containing lycopene had nanometric size, positive zeta potential, low polydispersity and were able to condense, release and protect DNA. Percentage of transfected cell was around 35% without compromising cell viability. The internalization pathways studies revealed a preference to caveolae mediated endocytosis and macropinocytosis, which could circumvent lysosomal degradation. Both subretinal and intravitreal administrations to the rat retina showed that nioplexes were able to transfect efficiently the outer segments of the retina, which offer reasonable hope for the treatment of many inherited retinal diseases by a safe non-viral vector formulation after the less invasive intravitreal administration. PMID- 28347808 TI - Optimizing CLEM protocols for plants cells: GMA embedding and cryosections as alternatives for preservation of GFP fluorescence in Arabidopsis roots. AB - Recently, a number of diverse correlative light and electron microscopy (CLEM) protocols have been developed for several model organisms. However, these CLEM methods have largely bypassed plant cell research, with most protocols having little application to plants. Using autophagosome identification as a biological background, we propose and compare two CLEM protocols that can be performed in most plant research laboratories, providing a good compromise that preserves fluorescent signals as well as ultrastructural features. These protocols are based on either the adaptation of a high pressure fixation/GMA acrylic resin embedding method, or on the Tokuyasu approach. Both protocols suitably preserved GFP fluorescence while allowing the observation of cell ultrastructure in plants. Finally, the advantages and disadvantages of these protocols are discussed in the context of multiscale imaging of plant cells. PMID- 28347809 TI - Developmental defects of enamel and dental caries in the primary dentition: A systematic review and meta-analysis. AB - OBJECTIVES: This systematic review and meta-analysis evaluated the association between developmental defects of enamel and dental caries in the primary dentition. SOURCES: Electronic searches were performed in PubMed, Web of Knowledge, Scopus and Scielo for the identification of relevant studies. STUDY SELECTION: Observational studies that examined the association between developmental defects of enamel and dental caries in the deciduous dentition were included. Additionally, meta-analysis, funnel plots and sensitivity analysis were employed to synthesize the available evidence. Multivariable meta-regression analysis was performed to explore heterogeneity among studies. DATA: A total of 318 articles were identified in the electronic searches. Of those, 16 studies were included in the meta-analysis. Pooled estimates revealed that children with developmental defects of enamel had higher odds of having dental caries (OR 3.32; 95%CI 2.41-4.57), with high heterogeneity between studies (I2 80%). Methodological characteristic of the studies, such as where it was conducted, the examined teeth and the quality of the study explained about 30% of the variability. Concerning type of defect, children with hypoplasia and diffuse opacities had higher odds of having dental caries (OR 4.28; 95%CI 2.24-8.15; OR1.42; 95%CI 1.15-1.76, respectively). CONCLUSIONS: This systematic review and meta-analysis demonstrates a clear association between developmental defects of enamel and dental caries in the primary dentition. PMID- 28347810 TI - Plasminogen activator inhibitor-1 4G/5G genotype and residual venous occlusion following acute unprovoked deep vein thrombosis of the lower limb: A prospective cohort study. AB - BACKGROUND: A recent study suggested that the plasminogen activator inhibitor (PAI)-1 4G/5G genotype may play a role in the resolution of deep vein thrombosis (DVT) after surgery. In the present study, we investigated the association between PAI-1 4G/5G genotype and the persistence of venous occlusion after acute idiopathic DVT of the lower limb. METHODS: The PAI-1 4G/5G genotype was determined by real-Time PCR in 43 patients with unprovoked DVT of the lower limb. Residual venous occlusion was assessed by duplex sonography 1, 3, 6, 12 and 24months after the acute event. The PAI-1 Activity was determined by ELISA. RESULTS: Ten patients (23%) were homozygous for 4G (4G/4G), 27 patients (63%) were heterozygous 4G/5G and 6 patients (14%) were homozygous for 5G (5G/5G). Residual venous occlusion (RVO) was found in 77%, 65%, 58%, 56% and 37% of the overall study population, at 1, 3, 6, 12 and 24months after acute DVT, respectively. The presence of residual venous occlusion at 1, 3, 6, 12 and 24months after acute unprovoked DVT did not differ significantly between genotypes, but age was associated with RVO. Plasma levels of PAI-1 activity correlated with body mass index but was not associated with genotypes in our study. CONCLUSION: The PAI-1 4G/5G genotype was not a relevant predictor of persistent residual venous occlusion after idiopathic DVT, which however was associated with age. PMID- 28347811 TI - Whole blood coagulation assays ROTEM and T-TAS to monitor dabigatran treatment. AB - BACKGROUND: A rapid and reliable assessment of the dabigatran effect is desirable in dabigatran treated patients with uncontrolled bleeding or before acute surgery. OBJECTIVE: To evaluate how the viscoelastic point-of-care test Rotational thromboelastometry (ROTEM) and Total Thrombus-formation system (T TAS), which studies thrombus formation under flowing conditions, correlate with dabigatran concentrations in patients with atrial fibrillation (AF). METHOD: ROTEM using the reagents In-tem, Ex-tem, Fib-tem or low tissue factor concentration (TF), and T-TAS with the AR-chip (shear rate 600s-1, representing flow in large arteries) were investigated in whole blood samples. Plasma concentrations were determined by mass spectrometry (LC-MS/MS) at trough and post dose in 30 patients on dabigatran 150mg BID. RESULTS: Median plasma dabigatran concentrations at trough were 86ng/mL (29-150) and post-dose (2.8h after ingestion) 175ng/mL (67-490). The ROTEM clotting time (CT) correlated strongly with dabigatran concentrations when activated with the reagents Ex-tem (r=0.92, p<0.01) and Fib-tem (r=0.93, p<0.01), while with In-tem and low TF the correlation was weaker (r=0.72 and r=0.36, p<0.01). There were significant but weaker correlations also between dabigatran concentrations and T-TAS variables (r values 0.39-0.41, p<0.01), aPTT (r=0.70, p<0.01) and PT-INR (r=0.43, p<0.01) respectively. CONCLUSIONS: ROTEM Ex-tem and Fib-tem CT shows a strong correlation with dabigatran concentrations in real-life AF-patients, and results are obtained within minutes. This could make ROTEM useful in acute situations. T-TAS detect differences in hemostasis caused by dabigatran, but the relationships to plasma concentrations of dabigatran are weaker than for ROTEM CT with the settings used in this study. PMID- 28347813 TI - Letter to the Editor Regarding Article, "Assembling a Functional Clitoris and Vulva from a Pseudo-Penis: A Surgical Technique for an Adult Woman with Congenital Adrenal Hyperplasia". PMID- 28347812 TI - Detection of antibodies against domain 1 of beta2-glycoprotein I is key in predicting thromboembolic complications in patients with systemic lupus erythematosus. PMID- 28347814 TI - The Blessings of Erectile Bodies. PMID- 28347815 TI - Sigma-2 ligands and PARP inhibitors synergistically trigger cell death in breast cancer cells. AB - The sigma-2 receptor is overexpressed in proliferating cells compared to quiescent cells and has been used as a target for imaging solid tumors by positron emission tomography. Recent work has suggested that the sigma-2 receptor may also be an effective therapeutic target for cancer therapy. Poly (ADP-ribose) polymerase (PARP) is a family of enzymes involved in DNA damage response. In this study, we looked for potential synergy of cytotoxicity between PARP inhibitors and sigma-2 receptor ligands in breast cancer cell lines. We showed that the PARP inhibitor, YUN3-6, sensitized mouse breast cancer cell line, EMT6, to sigma-2 receptor ligand (SV119, WC-26, and RHM-138) induced cell death determined by cell viability assay and colony forming assay. The PARP inhibitor, olaparib, sensitized tumor cells to a different sigma-2 receptor ligand SW43-induced apoptosis and cell death in human triple negative cell line, MDA-MB-231. Olaparib inhibited PARP activity and cell proliferation, and arrested cells in G2/M phase of the cell cycle in MDA-MB-231 cells. Subsequently cells became sensitized to SW43 induced cell death. In conclusion, the combination of sigma-2 receptor ligands and PARP inhibitors appears to hold promise for synergistically triggering cell death in certain types of breast cancer cells and merits further investigation. PMID- 28347816 TI - Evolutionary conservation of Notch signaling inhibition by TMEM131L overexpression. AB - Human KIAA0922/TMEM131L encodes a transmembrane protein, TMEM131L, that regulates the canonical Wnt/beta-catenin signaling pathway by eliciting the lysosome dependent degradation of phosphorylated LRP6 co-receptor. Here, we use a heterospecific Drosophila transgenic model to examine the potential evolutionary conservation of TMEM131L function. Analysis of TMEM131L transgenic flies shows that TMEM131L interference with the Wnt pathway results primarily from a Notch dependent decrease in Wingless production. Consistently, lentivirus-mediated overexpression of TMEM131L in human CD34+ hematopoietic progenitor cells leads to decreased susceptibility to Notch1 ligation and defective commitment toward the T lineage. These results show that TMEM131L corresponds to an evolutionary conserved regulator of the Notch signaling pathway. PMID- 28347817 TI - Activation of Wnt3alpha/beta-catenin signal pathway attenuates apoptosis of the cerebral microvascular endothelial cells induced by oxygen-glucose deprivation. AB - Brain microvascular endothelial cells (BMECs) play vital roles in cerebral ischemia, during which many signal pathways mediate BMECs apoptosis. In this study, we explored the potential role of Wnt3alpha/beta-catenin signal in BMECs apoptosis induced by ischemia. Here, we found that oxygen-glucose deprivation (OGD) could induce apoptosis of BMECs with Wnt3a mRNA expression decrease. Meanwhile, activation Wnt3a/beta-catenin signal with exogenous Wnt3alpha protein (100 ng/ml) or Lithium Chloride (LiCl, 4 mM) decreased significantly apoptosis of BMECs induced by OGD with increasing expression of Bcl-2 in the whole cell and beta-catenin in the nucleus. But, inhibition Wnt3a/beta-catenin signal with DKK1 (100 ng/ml) or 2.4-diamino quinazoline (DQ, 0.2 MUM) increased apoptosis of BMECs with decreasing expression of Bcl-2. These results suggest that activation Wnt3alpha/beta-catenin signal attenuate apoptosis of BMECs induced by ischemia. PMID- 28347818 TI - A xenograft model reveals that PU.1 functions as a tumor suppressor for multiple myeloma in vivo. AB - We previously demonstrated that PU.1 expression is down-regulated in the majority of myeloma cell lines and primary myeloma cells from patients. We introduced the tet-off system into the human myeloma cell lines U266 and KMS12PE that conditionally express PU.1 and demonstrated that PU.1 induces cell cycle arrest and apoptosis in myeloma cells in vitro. Here, we established a mouse xenograft model of myeloma using these cell lines to analyze the effects of PU.1 on the phenotype of myeloma cells in vivo. When doxycycline was added to the drinking water of mice engrafted with these myeloma cells, all mice had continuous growth of subcutaneous tumors and could not survived more than 65 days. In contrast, mice that were not exposed to doxycycline did not develop subcutaneous tumors and survived for at least 100 days. We next generated mice engrafted with subcutaneous tumors 5-10 mm in diameter that were induced by exposure to doxycycline. Half of the mice stopped taking doxycycline-containing water, whereas the other half kept taking the water. Although the tumors in the mice taking doxycycline continued to grow, tumor growth in the mice not taking doxycycline was significantly suppressed. The myeloma cells in the tumors of the mice not taking doxycycline expressed PU.1 and TRAIL and many of such cells were apoptotic. Moreover, the expression of a cell proliferation marker Ki67 was significantly decreased in tumors from the mice not taking doxycycline, compared with that of tumors from the mice continuously taking doxycycline. The present data strongly suggest that PU.1 functions as a tumor suppressor of myeloma cells in vivo. PMID- 28347819 TI - Deferiprone attenuates inflammation and myocardial fibrosis in diabetic cardiomyopathy rats. AB - We attempted to investigate the therapeutic effects of deferiprone on DC rats and explore the underlying mechanism. Total 24 6-week-old male Wistar rats (weighing from 180 g to 220 g) were subjected to DC model construction and then randomly divided to three groups (8 rats per group): DC group, DC + 50 mg, and DC + 100 mg deferiprone treatment group. The 8 normal rats were considered as controls. After deferiprone treatment for 20 weeks, the blood samples were collected for the biochemical parameters test, including fasting glucose, HOMA-IR (homeostasis model assessment of the insulin resistance), serum iron, ferritin and transferrin saturation (TS). The oxidative stress was assessed by detecting the level of malondialdehyde (MDA) and superoxide dismutase (SOD). Histopathologic changes were determined by Masson's trichrome staining and electron microscopy imaging. The expression levels of NF-kappaB (nuclear factor kappa B), COX2 (cytochrome c oxidase), tenascin C, collagen IV were measured by RT-PCR and western blotting. The expression of nitrotyrosine and MCP-1 (monocyte chemotactic protein 1) were determined by immunohistochemistry. Deferiprone treatment reduced iron deposition and IR in DC rats except for blood glucose. After deferiprone treatment, MDA level was significantly decreased and SOD level was increased significantly. The level of NF-kappaB, cyclooxygenase-2, tenascin C, collagen IV MCP-1 and nitrotyrosine were significantly reduced. There was no significant difference in the effect of deferiprone at 50 and 100 mg doses. Deferiprone showed therapeutic effects on DC by regulating the pro-inflammatory and pro-fibrotic factors. PMID- 28347820 TI - Functional characterization of the Arabidopsis universal stress protein AtUSP with an antifungal activity. AB - An antifungal protein, AtUSP protein (At3g53990), was isolated from Arabidopsis thaliana leaves by ion and size chromatography and sequenced by N-terminal sequencing. The AtUSP gene amplified from an Arabidopsis leaf cDNA library was transformed to Escherichia coli to express the AtUSP protein. The recombinant protein inhibited the cell growth of various pathogenic fungal strains. The levels of the AtUSP transcripts were increased by various stresses, including pathogenic infection and salt stress. These results suggest that Arabidopsis AtUSP plays a critical role in the plant tolerance to diverse pathogenic infections. The potent antifungal action, which is a new function of AtUSP, was attributed to fungal reactive oxygen species (ROS) generation and mitochondrial potential alteration. PMID- 28347821 TI - Pretreatment with light-emitting diode therapy reduces ischemic brain injury in mice through endothelial nitric oxide synthase-dependent mechanisms. AB - Photostimulation with low-level light emitting diode therapy (LED-T) modulates neurological and psychological functions. The purpose of this study was to evaluate the effects of LED-T pretreatment on the mouse brain after ischemia/reperfusion and to investigate the underlying mechanisms. Ischemia/reperfusion brain injury was induced by middle cerebral artery occlusion. The mice received LED-T twice a day for 2 days prior to cerebral ischemia. After reperfusion, the LED-T group showed significantly smaller infarct and edema volumes, fewer behavioral deficits compared to injured mice that did not receive LED-T and significantly higher cerebral blood flow compared to the vehicle group. We observed lower levels of endothelial nitric oxide synthase (eNOS) phosphorylation in the injured mouse brains, but significantly higher eNOS phosphorylation in LED-T-pretreated mice. The enhanced phospho-eNOS was inhibited by LY294002, indicating that the effects of LED-T on the ischemic brain could be attributed to the upregulation of eNOS phosphorylation through the phosphoinositide 3-kinase (PI3K)/Akt pathway. Moreover, no reductions in infarct or edema volume were observed in LED-T-pretreated eNOS-deficient (eNOS-/-) mice. Collectively, we found that pretreatment with LED-T reduced the amount of ischemia-induced brain damage. Importantly, we revealed that these effects were mediated by the stimulation of eNOS phosphorylation via the PI3K/Akt pathway. PMID- 28347822 TI - OsMYC2 mediates numerous defence-related transcriptional changes via jasmonic acid signalling in rice. AB - Jasmonic acid (JA) plays central roles in various events in plants, especially defence against pathogens and insects. The basic helix-loop-helix (bHLH) transcription factor MYC2 has attracted attention as a master regulator of JA signalling in dicotyledonous plants. However, how MYC2 functions in monocotyledonous plants, including agriculturally important crops such as cultivated rice, has been poorly understood. To elucidate the comprehensive effects of rice MYC2 (OsMYC2) on the JA-inducible transcriptional modifications, we performed RNA-sequencing by using OsMYC2-knockdown plants (osmyc2RNAi). In osmyc2RNAi, JA-inducible expression of many defence-related genes, for example chitinases and proteinase inhibitors, was compromised. Decrease in JA-dependent activation of the biosynthetic pathways of specialised metabolites, especially defence compounds, was also evident in the osmyc2RNAi line. Furthermore, a substantial change was noted in the expression of distinct types of transcription factors, such as MYB-type factors, likely depicting the importance of OsMYC2 in not only defence responses but also other morphogenetic events. Our findings provide fundamental information to understand the overall functions of MYC2 in JA signalling in monocotyledonous plants, which might yield agricultural benefits. PMID- 28347823 TI - Delay in diagnosis affects the clinical outcome in a cohort of cvid patients with marked reduction of iga serum levels. AB - Common variable immunodeficiency disorders (CVID) represent a collection of diseases leading to an absent or strongly impaired antibody production. CVID presents a wide range of immunological abnormalities and clinical manifestations, including infections, inflammatory and autoimmune diseases, and malignancies. The aim of this observational study was to analyze the epidemiological and clinical features of a cohort of 75 Italian CVID patients, and evaluate the correlation with comorbidity and mortality. Clinical data were retrospectively collected: the cohort was followed-up for a maximum of 30years (mean time of 10.24years, median of 9years). An higher age at the diagnosis of CVID and an higher age at onset of symptoms were significantly associated with a reduction of patients survival if stratified per median of IgA (less than or >8.00mg/dl). Thus IgA levels at diagnosis are correlated with patients survival contributing to identify a subset with a worse prognostic outcome. PMID- 28347824 TI - Participation of dorsal periaqueductal gray 5-HT1A receptors in the panicolytic like effect of the kappa-opioid receptor antagonist Nor-BNI. AB - Panic patients may have abnormalities in serotonergic and opioidergic neurotransmission. The dorsal periaqueductal gray (dPAG) plays an important role in organizing proximal defense, related to panic attacks. The 5-HT1A receptor (5 HT1A-R) is involved in regulating escape behavior that is organized in the dPAG. Activation of kappa-opioid receptor (KOR) in this region causes anxiogenic effects. In this study, we investigated the involvement of KOR in regulating escape behavior, using systemic and intra-dPAG injection of the KOR antagonist Nor-BNI. As panic models, we used the elevated T-maze (ETM) and the dPAG electrical stimulation test (EST). We also evaluated whether activation of the 5 HT1A-R or the MU-opioid receptor (MOR) in the dPAG contributes to the Nor-BNI effects. The results showed that systemic administration of Nor-BNI, either subcutaneously (2.0 and 4.0mg/kg) or intraperitoneally (2.0mg/kg), impaired escape in the EST, indicating a panicolytic-like effect. Intra-dPAG injection of this antagonist (6.8nmol) caused the same effect in the EST and in the ETM. Association of ineffective doses of Nor-BNI and the 5-HT1A-R agonist 8-OH-DPAT caused panicolytic-like effect in these two tests. Previous administration of the 5-HT1A-R antagonist WAY-100635, but not of the MOR antagonist CTOP, blocked the panicolytic-like effect of Nor-BNI. These results indicate that KOR enhances proximal defense in the dPAG through 5-HT1A-R modulation, independently of MOR. Because former results indicate that the 5-HT1A-R is involved in the antipanic action of antidepressants, KOR antagonists may be useful as adjunctive or alternative drug treatment of panic disorder. PMID- 28347826 TI - Changes in cerebral [18F]-FDG uptake induced by acute alcohol administration in a rat model of alcoholism. AB - Several [18F]-FDG positron emission tomography (PET) studies in alcoholics have consistently reported decreases in overall brain glucose metabolism at rest and following acute alcohol administration. However, changes in cerebral glucose utilization associated with the transition to addiction are not well understood and require longitudinal translational imaging studies in animal models of alcoholism. Here, we studied brain glucose uptake in alcohol drinking rats in order to provide convergent evidence to what has previously been reported in human studies. Brain glucose metabolism was measured by [18F]-FDG microPET imaging in different male Wistar rat groups: short-term drinking (three months), long-term drinking (twelve months) and alcohol-naive. Global and regional cerebral glucose uptake was measured at rest and following acute alcohol administration. We showed that alcohol significantly reduced the whole-brain glucose metabolism. This effect was most pronounced in the parietal cortex and cerebellum. Alcohol-induced decreases in brain [18F]-FDG uptake was most apparent in alcohol-naive rats, less intense in short-term drinkers and absent in long term drinkers. The latter finding indicates the occurrence of tolerance to the intoxicating effects of alcohol in long-term drinking individuals. In contrast, some regions, like the ventral striatum and entorhinal cortex, showed enhanced metabolic activity, an effect that did not undergo tolerance during long-term alcohol consumption. Our findings are comparable to those described in human studies using the same methodology. We conclude that [18F]-FDG PET studies in rat models of alcoholism provide good translation and can be used for future longitudinal studies investigating alterations in brain function during different stages of the addiction cycle. PMID- 28347825 TI - Brain monoamine levels and behaviour of young and adult chickens genetically selected on feather pecking. AB - Severe feather pecking (SFP) in chickens is a detrimental behaviour with possibly neurochemical deficits at its base. Recent neurological studies depicted conflicting results on the role of serotonin (5-hydroxytryptamine, 5-HT) and dopamine (DA) in the development and display of feather pecking. We studied brain monoamine levels and behaviour in domestic chickens divergently genetically selected on feather pecking behaviour, the Low Feather Pecking (LFP) and High Feather Pecking (HFP) lines, both at a young age and when adult, to elucidate the role of 5-HT and DA in feather pecking. Also pecking behaviour and the behavioural response to challenging test situations was determined. At 8 weeks of age, HFP had lower 5-HT and DA turnover in several brain areas than LFP, whereas these differences had disappeared or were even reversed at 25 weeks of age. Line differences in central monoamine activity were found both in emotion-regulating and motor-regulating areas. As expected from previous generations, HFP exceeded LFP in most types of pecking at other birds, including severe feather pecking. Furthermore, HFP responded more actively in most behavioural tests conducted, and seem more impulsive or (hyper)active in their way of coping with challenges. This paper shows different developmental trajectories of the neurochemical systems (5 HT and DA) for chickens divergently selected on feather pecking behaviour, and a remarkable reversion of differences in monoamine activity at a later stage of life. Whether this is a cause or consequence of SFP needs further investigation. PMID- 28347827 TI - Computational prediction of functional abortive RNA in E. coli. AB - Failure by RNA polymerase to break contacts with promoter DNA results in release of bound RNA and re-initiation of transcription. These abortive RNAs were assumed to be non-functional but have recently been shown to affect termination in bacteriophage T7. Little is known about the functional role of these RNA in other genetic models. Using a computational approach, we investigated whether abortive RNA could exert function in E. coli. Fragments generated from 3780 transcription units were used as query sequences within their respective transcription units to search for possible binding sites. Sites that fell within known regulatory features were then ranked based upon the free energy of hybridization to the abortive. We further hypothesize about mechanisms of regulatory action for a select number of likely matches. Future experimental validation of these putative abortive-mRNA pairs may confirm our findings and promote exploration of functional abortive RNAs (faRNAs) in natural and synthetic systems. PMID- 28347828 TI - Protective effects of Cinnamomum cassia (Lamaceae) against gout and septic responses via attenuation of inflammasome activation in experimental models. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cinnamomum cassia (C. cassia, Lauraceae family), commonly used for treating dyspepsia, gastritis, blood circulation, and inflammatory diseases is considered as one of the 50 fundamental herbs in traditional Chinese medicine. AIM OF THE STUDY: The anti-inflammatory action of an ethanol extract of C. cassia (CA), and its underlying mechanisms were explored in both in vitro cellular and in vivo murine models. MATERIALS AND METHODS: Bone marrow-derived macrophages (BMDMs) were used to study the regulatory effect of CA on inflammasome activation. A lipopolysaccharide (LPS)-induced sepsis mouse model and a monosodium urate (MSU)-induced gout model were employed to study the effect of CA on in vivo efficacy. RESULTS: CA improved the survival rate in the LPS induced septic shock mouse model and inhibited inflammasome activation including NLRP3, NLRC4, and AIM2, leading to suppression of interleukin-1beta secretion. Further, ASC oligomerization and its speck formation in cytosol were attenuated by CA treatment. Furthermore, CA improved both survival rate of LPS-induced septic shock and gout murine model. CONCLUSIONS: CA treatment significantly attenuated danger signals-induced inflammatory responses via regulation of inflammasome activation, substantiating the traditional claims of its use in the treatment of inflammation-related disorders. PMID- 28347829 TI - As vivid as a weed... Medicinal and cosmetic plant uses amongst the urban youth in French Guiana. AB - ETHNOPHARMACOLOGICAL RELEVANCE: French Guiana is a French overseas territory with a rich history of migration that has led to a highly intercultural society. Today, its population is one of the youngest in the French territory and is rapidly increasing. Despite a context of cultural revival seeking "tradition", a distanced baseline of local practices is still lacking. This work addresses some aspects of the cultural hybridizations in progress in urban areas. METHODS: Semi directed interviews were conducted with willing participants aged between 18 and 40. Interviews took place in French Guiana's two main urban centres: Cayenne and Saint Laurent du Maroni. People were interviewed about the last medicinal plant they used in the preceding year. Due to the high use of plant baths in French Guiana, a focus was made on baths. RESULTS AND DISCUSSION: Eighty-three people answered: 43 women and 40 men (mean age of 28.7 years old). In total, 226 remedies were counted in our study, 155 single plant remedies and 71 compound remedies leading to 316 use reports of plants from 16 cultural groups. A surprising number of 108 botanical species were recorded. Eighty-one recipes for baths were also collected. Despite this high citation rate, a rather low proportion of people declare a systematic and regular recourse upon local pharmacopoeia (46%; 38/83). Although many interviewees used plants, far from the majority used them on a regular basis. In practice, 50% of the species (54/108 spp.; 99/316 URs) are non-native but domesticated exotic species, imported from Asia, Europe, Africa or remote parts of America, either during colonization, the slave trade era, or more recently with the latest migrations. CONCLUSION: Although phytotherapy use is often thought to be related to countryside dwellers and older people, medicinal plants seem to play an important role in the lives of urban French Guianese youth. Research shows a large diversity of medicinal species used linked with the great cultural diversity of the Guianese cities. One characteristic of this population is the hybridization process leading to a perpetual renewal of practices, both in terms of species and practice. PMID- 28347830 TI - Inhibitory effect of Patrinia scabiosifolia Link on the development of atopic dermatitis-like lesions in human keratinocytes and NC/Nga mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Atopic dermatitis (AD) is a chronic pruritic and inflammatory disease occurring in skin. Patrinia scabiosifolia Link (PS), a member of the Patrinia genus (Caprifoliaceae family), has traditionally been used in folk medicines to treat various inflammatory diseases such as acute appendicitis, ulcerative colitis, and pelvic inflammation in Korea and other parts of East Asia. AIM OF THE STUDY: This study investigated the anti inflammatory effects of PS on AD in vitro and in vivo. MATERIALS AND METHODS: Whole PS plants were dried, powdered, and then underwent extraction with DMSO. Both ELISA and western blotting were performed to evaluate cytokine concentration and the expression and activation of filaggrin and signaling proteins. Five-week old female NC/Nga mice were used as an AD-like mouse model by treating them with 2,4-dinitrochlorobenzene (DNCB). RESULTS: In human keratinocytic HaCaT cells, PS extract inhibited the production of IL-8, and TARC, which had been increased by TNF-alpha and IFN-gamma. The TNF-alpha and IFN-gamma suppressed filaggrin expression was associated with phosphorylation of JNK1 and JNK2, and NF-kappaB translocation. PS recovered the inhibition of filaggrin expression induced by TNF alpha and IFN-gamma by blocking the activation of JNK1/2, and NF-kappaB by the IFN-gamma and TNF-alpha treatment. The in vivo experiment results showed that, compared to DNCB treatment PS administration reduced thickening of the epidermis and infiltration of inflammatory cells into the dermis. Moreover, the decrease of filaggrin expression due to DNCB treatment was recovered by PS administration. The serum IgE level was decreased by PS treatment. Additionally, secretions of IL 4, IL-5, IL-13, and eotaxin in splenocytes were lower in the PS-treated group than in the DNCB group. CONCLUSION: PS may attenuate the development of AD-like lesions by increasing filaggrin expression and lowering IgE and inflammatory cytokine levels. These results indicate the potential for development of a PS based drug treatment for AD. PMID- 28347831 TI - Rapid antidepressant effects of Yueju: A new look at the function and mechanism of an old herbal medicine. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Yueju is a traditional herbal medicine which consists of five herbs and formulated to treat depression-related syndromes 800 years ago. Yueju is still widely prescribed to treat conditions which include digestive dysfunction and depression. Recently, Yueju has been shown to promote a fast-onset antidepressant effect clinically and in preclinical studies. Because conventional antidepressants have a delayed onset in treating depression, the novelty of Yueju's rapid antidepressant effect and its underlying mechanism are of great significance both clinically and scientifically. AIM OF THE STUDY: To review the use of Yueju for treatment of mood-related syndromes, and particularly its use in depression. To evaluate recent evidence of Yueju rapid antidepressant actions, based on new findings at behavioral and molecular levels. To suggest direction for future studies to address further scientific issues. MATERIALS AND METHODS: Reports regarding to the history and current use of Yueju are summarized. Recent progress on rapid antidepressant effects of Yueju, the crucial constituent, Gardenia jasminoides J.Ellis (GJ) and other herbs, are reviewed. RESULTS: The medical need for rapid antidepressant actions, as well as breakthrough findings using ketamine and its limitations are introduced. Studies with Yueju using a number of acute, subacute and chronic behavioral paradigms are compared with ketamine. Findings from clinical reports also support the rapid action of Yueju. Studies examine the contribution of the constituent herb GJ, in rapid antidepressant effects. Importantly, research into the mechanism of Yueju or GJ's antidepressant response indicate the importance of up-regulation in the neural circuit responsible for antidepressant activity, and highlight common and specific molecular signaling by Yueju that may explain why this herb formula has unique antidepressant activity. CONCLUSION: Preclinical and clinical studies demonstrate that Yueju confers rapid antidepressant effects. The common mechanisms shared both for ketamine and Yueju, as well as the novel mechanism specific to Yueju are examined. Yueju and GJ may have great clinic applicability and further more detailed studies are warranted. PMID- 28347832 TI - The genus Achyranthes: A review on traditional uses, phytochemistry, and pharmacological activities. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Achyranthes L. (Amaranthaceae), also known as Chaff Flower and Niuxi/, mainly includes two famous medicinal species namely A. bidentata and A. aspera. A. bidentata has been widely used as blood-activating and stasis-resolving medicine for the treatment of various diseases including amenorrhea, dysmenorrhea, lumbago, gonalgia, paraplegia, edema, stranguria, headache, dizziness, odontalgia, oral ulcer, hematemesis, and epistaxis. A. aspera has been widely used to treat various diseases, including gynecological disorder, asthma, ophthalmia, odontalgia, haemorrhoids, and abdominal tumor, and has been applied to difficult labour, wound healing, insect and snake bites. AIM OF THIS REVIEW: This review aims to provide systematically reorganized information on distributions, botanical characteristics, ethnopharmacology, chemical constituents, qualitative and quantitative analysis, pharmacological activities, and toxicity of Achyranthes species to support their therapeutic potential. MATERIALS AND METHODS: The relevant information on Achyranthes species was gathered from worldwide accepted scientific databases via electronic search (Google Scholar, Web of Science, ScienceDirect, ACS Publications, PubMed, Wiley Online Library, SciFinder, CNKI). Information was also obtained from International Plant Names Index, Chinese Pharmacopoeia, Chinese herbal classic books, PhD and MSc dissertations, etc. RESULTS: A comprehensive analysis of literatures obtained through the above- mentioned sources confirms that the ethnomedicinal uses of Achyranthes species are mainly recorded in China, India, Korea, Pakistan, Ethiopia, Kenya, Sri Lanka, Bangladesh, Philippines, etc. Phytochemical investigations revealed that the major bioactive substances of Achyranthes plants are polysaccharides, polypeptides, triterpenoid saponins, and ketosteroids. Achyranthes plants have been shown to not only act on immune system, nervous system, bone metabolism, and reproduction, but also possess a wide range of biological activities, including blood-activating, anti-tumor, anti inflammation, anti-arthritis, anti-oxidation, anti-aging, wound healing, etc. Toxicity studies indicated that A. bidentata and A. aspera seem non-toxic at the common therapeutic doses. CONCLUSIONS: A. bidentata and A. aspera are very promising to be fully utilized in the development of nutraceutical and pharmaceutical products. There are, however, needs for further in-depth studies to confirm some ethnomedicinal uses of Achyranthes plants and to elucidate the scientific connotation of the widely documented property of conducting drug downward of A. bidentata. In addition, other widespread Achyranthes species like A. japonica and A. rubrofusca ought to be studied. Likewise, systematic comparative studies of the chemical constituents of medicinal Achyranthes plants resources with the same local name are also needed. Furthermore, not only should the investigations on the structure-activity relationship of the main bioactive compounds triterpenoid saponins and ketosteroids be carried out, but the pathways of absorption, distribution, metabolism, and excretion ought to be clarified. Last but not least, there is also a need to evaluate the long-term chronic toxicity and acute toxicity in vivo of the main bioactive compounds. PMID- 28347834 TI - Catheter ablation of para-Hisian atrial tachycardias: Is "earliest" still synonymous with "best"? PMID- 28347833 TI - Skin sympathetic nerve activity precedes the onset and termination of paroxysmal atrial tachycardia and fibrillation. AB - BACKGROUND: Skin sympathetic nerve activity (SKNA) is useful for estimating sympathetic tone in humans. OBJECTIVE: The purpose of this study was to test the hypotheses that (1) increased SKNA is associated with the onset and termination of paroxysmal atrial tachycardia (AT) and atrial fibrillation (AF) and (2) sinoatrial node response to SKNA is reduced in patients with more frequent AT or AF episodes. METHODS: SKNA and electrocardiogram were recorded in 11 patients (4 men and 7 women; average age 66 +/- 10 years), including 3 patients with AT (11 +/- 18 episodes per patient) and 8 patients with AF (24 +/- 26 episodes per patient). RESULTS: The average SKNA (aSKNA) 10 seconds before AT onset was 1.07 +/- 0.10 MUV and 10 seconds after termination was 1.27 +/- 0.10 MUV; both were significantly (P = .032 and P < .0001) higher than that during sinus rhythm (0.97 +/- 0.09 MUV). The aSKNA 10 seconds before AF onset was 1.34 +/- 0.07 MUV and 10 seconds after termination was 1.31 +/- 0.07 MUV; both were significantly (P < .0001) higher than that during sinus rhythm (1.04 +/- 0.07 MUV). The aSKNA before onset (P < .0001) and after termination (P = .0011) was higher in AF than in AT. The sinus rate correlated (P < .0001) with aSKNA in each patient (average r = 0.74; 95% confidence interval 0.65-0.84). The r value in each patient negatively correlated with the number of AT and AF episodes (r = -0.6493; 95% confidence interval -0.8990 to -0.08073; P = .0306). CONCLUSION: Increased SKNA was observed both at the onset and termination of AT and AF. Patients with more frequent AT and AF episodes had a weak correlation between sinus rate and aSKNA, suggesting sinoatrial node remodeling by tachycardia. PMID- 28347835 TI - Predictive value of device-derived activity level for short-term outcomes in MADIT-CRT. AB - BACKGROUND: There are limited data on the prognostic importance of declining activity level in patients with heart failure. OBJECTIVE: We aimed to assess the association of reduced activity level with adverse cardiovascular outcomes in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT). METHODS: Final device interrogations from patients enrolled in the MADIT-CRT with cardiac resynchronization devices capable of recording percent daily activity level were assessed. To determine temporal change, standardized activity levels (SALs) comparing each week to the monthly activity 3 months prior were obtained. Death, heart failure events (HFEs)/death, and ventricular tachyarrhythmias (VTAs)/death were the primary end points of this study. RESULTS: The average absolute activity level and SAL of the final week prior to death or end of study were significantly lower in patients who died compared with those in patients who did not. The total cohort (N = 1008) was further randomized into 2 subgroups to identify (group 1) and validate an optimal threshold (group 2). Patients with >40% reduced SAL had a significantly increased 77-day short-term cumulative incidence of death (P = .0006), HFE/death (P < .0001), or VTA/death (P = .0248). After adjustment for clinical covariates, these patients remained at an increased risk for death (hazard ratio [HR], 2.7; 95% confidence interval [CI], 1.5-4.9; P = .001), HFE/death (HR, 2.7; 95% CI, 1.8 3.9; P <= .001) and VTA/death (HR, 1.9; 95% CI, 1.31-2.6; P = .001). A decline in SAL following a nonfatal VTA and HFE was also associated with an increased probability of death. CONCLUSIONS: Decline in activity level is a short-term predictor for adverse cardiovascular events in patients with mild to moderate heart failure undergoing cardiac resynchronization. PMID- 28347837 TI - A novel therapeutic with two SNAP-25 inactivating proteases shows long-lasting anti-hyperalgesic activity in a rat model of neuropathic pain. AB - A pressing need exists for long-acting, non-addictive medicines to treat chronic pain, a major societal burden. Botulinum neurotoxin type A (BoNT/A) complex - a potent, specific and prolonged inhibitor of neuro-exocytosis - gives some relief in several pain disorders, but not for all patients. Our study objective was to modify BoNT/A to overcome its inability to block transmitter release elicited by high [Ca2+]i and increase its limited analgesic effects. This was achieved by fusing a BoNT/A gene to that for the light chain (LC) of type/E. The resultant purified protein, LC/E-BoNT/A, entered cultured sensory neurons and, unlike BoNT/A, inhibited release of calcitonin gene-related peptide evoked by capsaicin. Western blotting revealed that this improvement could be due to a more extensive truncation by LC/E of synaptosomal-associated protein of Mr = 25 k, essential for neuro-exocytosis. When tested in a rat spared nerve injury (SNI) model, a single intra-plantar (IPL) injection of LC/E-BoNT/A alleviated for ~2 weeks mechanical and cold hyper-sensitivities, in a dose-dependent manner. The highest non paralytic dose (75 U/Kg, IPL) proved significantly more efficacious than BoNT/A (15 U/Kg, IPL) or repeated systemic pregabalin (10 mg/Kg, intraperitoneal), a clinically-used pain modulator. Effects of repeated or delayed injections of this fusion protein highlighted its analgesic potential. Attenuation of mechanical hyperalgesia was extended by a second administration when the effect of the first had diminished. When injected 5 weeks after injury, LC/E-BoNT/A also reversed fully-established mechanical and cold hyper-sensitivity. Thus, combining advantageous features of BoNT/E and/A yields an efficacious, locally-applied and long-acting anti-hyperalgesic. PMID- 28347836 TI - Intranasal administration of recombinant Netrin-1 attenuates neuronal apoptosis by activating DCC/APPL-1/AKT signaling pathway after subarachnoid hemorrhage in rats. AB - Neuronal apoptosis is a crucial pathological process in early brain injury after subarachnoid hemorrhage (SAH). The effective therapeutic strategies to ameliorate neuronal apoptosis are still absent. We intended to determine whether intranasal administration of exogenous Netrin-1 (NTN-1) could attenuate neuronal apoptosis after experimental SAH, specifically via activating DCC-dependent APPL-1/AKT signaling cascade. Two hundred twenty-five male Sprague-Dawley rats were subjected to the endovascular perforation model of SAH. Recombinant human NTN-1 (rNTN-1) was administered intranasally. NTN-1 small interfering RNA (siRNA), APPL 1 siRNA, and AKT inhibitor MK2206 were administered through intracerebroventricular (i.c.v.) injection. SAH grade, neurological score, neuronal apoptosis assessed by cleaved caspase-3 (CC-3) expression and Fluoro Jade C (FJC) staining, double immunofluorescence staining, and Western blot were examined. Our results revealed that endogenous NTN-1 level was increased after SAH. Administration of rNTN-1 improved neurological outcomes at 24 h and 72 h after SAH, while knockdown of endogenous NTN-1 worsened neurological impairments. Furthermore, exogenous rNTN-1 treatment promoted APPL-1 activation, increased phosphorylated-AKT and Bcl-2 expression, as well as decreased apoptotic marker CC 3 expression and the number of FJC-positive neurons, thereby alleviated neuronal apoptosis. Conversely, APPL-1 siRNA and MK2206 abolished the anti-apoptotic effect of exogenous rNTN-1 at 24 h after SAH. Collectively, intranasal administration of exogenous rNTN-1 attenuated neuronal apoptosis and improved neurological function in SAH rats, at least in apart via activating DCC/APPL 1/AKT signaling pathway. PMID- 28347839 TI - Cellular response to star-shaped polyacids. Solution behavior and conjugation advantages. AB - The nanosized (~10nm in 0.01M PBS and 210nm in water) star-shaped polymethacrylates with various content of pendant carboxyl groups were characterized via basic physicochemical and biological properties toward their use as drug carriers for intravenous administration. The carboxyl groups in polymer were employed to conjugate fluorescein (FA) or doxorubicin (DOX) via amide bond formation. In case of DOX, the conjugation efficiency was higher (4.0 16.0%) than of FA conjugation (1.5-4.5%) for corresponding copolymers. The solubility of conjugates strongly depended on the type of attached compound, that is free carriers and their FA conjugates were water-soluble, whereas DOX conjugates were insoluble in water. Cytotoxicity tests performed on model fibroblast and epithelial cell lines showed that negatively charged copolymers (ZP ranged from -75 to -25mV) were slightly toxic for normal cells (NHDF) and non toxic for cancer cell lines (HCT-116 and MCF-7/R). The copolymer dose equal to 125MUg/mL resulted in cell viability 118% towards NHDF and 90% for HCT116 cells. The internalization of a representative polymer-fluorescein conjugate by HCT-116 and its accumulation in cytoplasm was proven via fluorescence microscopy. MMA/MAA stars showed no adverse effect on HCT-116 cells, hence fluorescein-tagged polymers might be applied as fluorescence probes for in vitro imaging, whereas doxorubicin-tagged polymers might be developed as a new polymeric drug carriers. PMID- 28347840 TI - Enhanced action tendencies in obsessive-compulsive disorder: An ERP study. AB - Obsessive-compulsive disorder (OCD) is characterized by repeated thoughts and behaviors. This study explored the stages of motor response preparation that precede action performance or inhibition: We investigated whether OCD is related to enhanced action tendencies in response to external stimuli. Response preparation processes were assessed using the event-related potential (ERP) component of the readiness potential (RP). ERPs were recorded while 15 participants with OCD and 16 healthy controls performed a variation of the go/no go task and the stop-signal task using schematic faces (angry and neutral). The OCD group presented with a greater RP slope gradient and amplitude over bilateral frontoparietal areas corresponding to the motor cortex. The amplitude effect was further enhanced under negative valence, compared to the neutral condition. Results support the hypothesis that stronger readiness for action might characterize OCD, especially in the presence of threatening stimuli. These findings - specifically correlated with OCD and not with anxiety and depression symptoms - may underlie habitual behavior and embodiment tendencies in OCD. This study suggests that early stages of motor preparation might be important to the etiology and maintenance of OCD. PMID- 28347838 TI - Studies using macaque monkeys to address excessive alcohol drinking and stress interactions. AB - The use of non-human primates (NHPs) in studies of volitional, oral self administration of alcohol can help address the complex interplay between stress and excessive alcohol consumption. There are aspects to brain, endocrine and behavior of NHPs, particularly macaques, that provide a critical translational link towards understanding the risks and consequences of alcohol use disorders (AUDs) in humans. These include wide individual differences in escalating daily alcohol intake, accurate measures of hypothalamic-pituitary-adrenal (HPA) axis hormonal interactions, neuroanatomical specificity of synaptic adaptations to chronic alcohol, genetic similarities to humans, and the ability to conduct in vivo brain imaging. When placed in a framework that alcohol addiction is a sequence of dysregulations in motivational circuitry associated with severity of AUD, the NHP can provide within-subject information on both risks for and consequences of repeatedly drinking to intoxication. Notably, long-term adaptations in neurocircuitry that mediate behavioral reinforcement, stress responses and executive functions are possible with NHPs. We review here the substantial progress made using NHPs to address the complex relationship between alcohol and stress as risk factors and consequences of daily drinking to intoxication. This review also highlights areas where future studies of brain and HPA axis adaptations are needed to better understand the mechanisms involved in stress leading to excessive alcohol consumption. This article is part of the Special Issue entitled "Alcoholism". PMID- 28347841 TI - Impaired memory updating associated with impaired recall of negative words in dysphoric rumination-Evidence for a removal deficit. AB - We present evidence that dysphoric rumination involves a working memory (WM) updating deficit. Sixty-one undergraduates-pre-screened with rumination and depression scales-completed a novel task providing a specific measure of WM updating. This task involved the substitution of emotionally-valenced words, and provided an online measure of the time taken to remove outdated items from WM. Results showed that dysphoric ruminators spent less time removing outdated words from WM when the new to-be-remembered word was negative. This effect was (1) associated with impaired subsequent recall of negative words, arguably caused by interference from the insufficiently removed outdated words; and (2) correlated with participants' rumination scores. This is the first study to use the novel removal task to investigate the nature of WM-updating impairments in rumination. The findings are consistent with a negative attentional bias in rumination, and provide preliminary evidence that rumination is associated with a valence-generic removal deficit during WM updating. Reducing the attentional bias could thus be an intervention target in the treatment of dysphoric rumination. PMID- 28347842 TI - Potential role of heme metabolism in the inducible expression of heme oxygenase 1. AB - BACKGROUND: The degradation of heme significantly contributes to cytoprotective effects against oxidative stress and inflammation. The enzyme heme oxygenase-1 (HO-1), involved in the degradation of heme, forms carbon monoxide (CO), ferrous iron, and bilirubin in conjunction with biliverdin reductase, and is induced by various stimuli including oxidative stress and heavy metals. We examined the involvement of heme metabolism in the induction of HO-1 by the inducers sulforaphane and sodium arsenite. METHODS: We examined the expression of HO-1 in sulforaphane-, sodium arsenite- and CORM3-treated HEK293T cells, by measuring the transcriptional activity and levels of mRNA and protein. RESULTS: The blockade of heme biosynthesis by succinylacetone and N-methyl protoporphyrin, which are inhibitors of heme biosynthesis, markedly decreased the induction of HO-1. The knockdown of the first enzyme in the biosynthesis of heme, 5-aminolevulinic acid synthase, also decreased the induction of HO-1. The cessation of HO-1 induction occurred at the transcriptional and translational levels, and was mediated by the activation of the heme-binding transcriptional repressor Bach1 and translational factor HRI. CO appeared to improve the expression of HO-1 at the transcriptional and translational levels. CONCLUSIONS: We demonstrated the importance of heme metabolism in the stress-inducible expression of HO-1, and also that heme and its degradation products are protective factors for self-defense responses. GENERAL SIGNIFICANCE: The key role of heme metabolism in the stress-inducible expression of HO-1 may promote further studies on heme and its degradation products as protective factors of cellular stresses and iron homeostasis in specialized cells, organs, and whole animal systems. PMID- 28347843 TI - Engineered N-acetylhexosamine-active enzymes in glycoscience. AB - BACKGROUND: In recent years, enzymes modifying N-acetylhexosamine substrates have emerged in numerous theoretical studies as well as practical applications from biology, biomedicine, and biotechnology. Advanced enzyme engineering techniques converted them into potent synthetic instruments affording a variety of valuable glycosides. SCOPE OF REVIEW: This review presents the diversity of engineered enzymes active with N-acetylhexosamine carbohydrates: from popular glycoside hydrolases and glycosyltransferases to less known oxidases, epimerases, kinases, sulfotransferases, and acetylases. Though hydrolases in natura, engineered chitinases, beta-N-acetylhexosaminidases, and endo-beta-N-acetylglucosaminidases were successfully employed in the synthesis of defined natural and derivatized chitooligomers and in the remodeling of N-glycosylation patterns of therapeutic antibodies. The genes of various N-acetylhexosaminyltransferases were cloned into metabolically engineered microorganisms for producing human milk oligosaccharides, Lewis X structures, and human-like glycoproteins. Moreover, mutant N-acetylhexosamine-active glycosyltransferases were applied, e.g., in the construction of glycomimetics and complex glycostructures, industrial production of low-lactose milk, and metabolic labeling of glycans. In the synthesis of biotechnologically important compounds, several innovative glycoengineered systems are presented for an efficient bioproduction of GlcNAc, UDP-GlcNAc, N acetylneuraminic acid, and of defined glycosaminoglycans. MAJOR CONCLUSIONS: The above examples demonstrate that engineering of N-acetylhexosamine-active enzymes was able to solve complex issues such as synthesis of tailored human-like glycoproteins or industrial-scale production of desired oligosaccharides. Due to the specific catalytic mechanism, mutagenesis of these catalysts was often realized through rational solutions. GENERAL SIGNIFICANCE: Specific N acetylhexosamine glycosylation is crucial in biological, biomedical and biotechnological applications and a good understanding of its details opens new possibilities in this fast developing area of glycoscience. PMID- 28347844 TI - Complex inhibition of autophagy by mitochondrial aldehyde dehydrogenase shortens lifespan and exacerbates cardiac aging. AB - Autophagy, a conservative degradation process for long-lived and damaged proteins, participates in a cascade of biological processes including aging. A number of autophagy regulators have been identified. Here we demonstrated that mitochondrial aldehyde dehydrogenase (ALDH2), an enzyme with the most common single point mutation in humans, governs cardiac aging through regulation of autophagy. Myocardial mechanical and autophagy properties were examined in young (4months) and old (26-28months) wild-type (WT) and global ALDH2 transgenic mice. ALDH2 overexpression shortened lifespan by 7.7% without affecting aging associated changes in plasma metabolic profiles. Myocardial function was compromised with aging associated with cardiac hypertrophy, the effects were accentuated by ALDH2. Aging overtly suppressed autophagy and compromised autophagy flux, the effects were exacerbated by ALDH2. Aging dampened phosphorylation of JNK, Bcl-2, IKKbeta, AMPK and TSC2 while promoting phosphorylation of mTOR, the effects of which were exaggerated by ALDH2. Co immunoprecipitation revealed increased dissociation between Bcl-2 and Beclin-1 (result of decreased Bcl-2 phosphorylation) in aging, the effect of which was exacerbated with ALDH2. Chronic treatment of the autophagy inducer rapamycin alleviated aging-induced cardiac dysfunction in both WT and ALDH2 mice. Moreover, activation of JNK and inhibition of either Bcl-2 or IKKbeta overtly attenuated ALDH2 activation-induced accentuation of cardiomyocyte aging. Examination of the otherwise elderly individuals revealed a positive correlation between cardiac function/geometry and ALDH2 gene mutation. Taken together, our data revealed that ALDH2 enzyme may suppress myocardial autophagy possibly through a complex JNK-Bcl 2 and IKKbeta-AMPK-dependent mechanism en route to accentuation of myocardial remodeling and contractile dysfunction in aging. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure - edited by Jun Ren & Megan Yingmei Zhang. PMID- 28347845 TI - Global assessment of oxidized free fatty acids in brain reveals an enzymatic predominance to oxidative signaling after trauma. AB - Traumatic brain injury (TBI) is a major health problem associated with significant morbidity and mortality. The pathophysiology of TBI is complex involving signaling through multiple cascades, including lipid peroxidation. Oxidized free fatty acids, a prominent product of lipid peroxidation, are potent cellular mediators involved in induction and resolution of inflammation and modulation of vasomotor tone. While previous studies have assessed lipid peroxidation after TBI, to our knowledge no studies have used a systematic approach to quantify the global oxidative changes in free fatty acids. In this study, we identified and quantified 244 free fatty acid oxidation products using a newly developed global liquid chromatography tandem-mass spectrometry (LC MS/MS) method. This methodology was used to follow the time course of these lipid species in the contusional cortex of our pediatric rat model of TBI. We show that oxidation peaked at 1h after controlled cortical impact and was progressively attenuated at 4 and 24h time points. While enzymatic and non-enzymatic pathways were activated at 1h post-TBI, enzymatic lipid peroxidation was the predominant mechanism with 15-lipoxygenase (LOX) contributing to the majority of total oxidized fatty acid content. Pro-inflammatory lipid mediators were significantly increased at 1 and 4h after TBI with return to basal levels by 24h. Anti inflammatory lipid mediators remained significantly increased across all three time points, indicating an elevated and sustained anti-inflammatory response following TBI. PMID- 28347847 TI - Dry powder inhaler performance of spray dried mannitol with tailored surface morphologies as carrier and salbutamol sulphate. AB - Nowadays, dry powder inhalation as applied in the therapy of pulmonary diseases is known as a very effective route of drug delivery to the lungs. Here, the system of coarse carrier and fine drug particles attached to the carrier surface has successfully been applied to overcome the cohesiveness of small drug particles. Particle properties of both carrier and drug are known to affect drug dispersion as has widely been discussed for lactose monohydrate and various drugs. This study utilises particle-engineered mannitol as an alternative carrier to discover the effect of mannitol carrier particle properties like particle shape, surface roughness, flowability or particle size on aerodynamic performance during inhalation. Spray drying as a technique to accurately control those properties was chosen for the generation of carrier sizes between 50 and 80 MUm and different morphologies and therefore various carrier flowabilities. A set of these carriers has then been blended with different spray dried and jet-milled qualities of salbutamol sulphate as model drug to examine the influence of carrier particle properties on aerodynamic behaviour and at the same time to cover the effect of drug particle properties on particle-particle interactions. This experimental setup allowed a general view on how drug and carrier properties affect the Fine Particle Fraction (FPF) as indicator for inhalation performance and gave the first study to distinguish between mannitol carrier particle shape and surface roughness. Further it was possible to relate carrier particle size and shape to drug accumulation and detachment mechanisms during inhalation as size and shape had the main influence on drug detachment. The addition of jet milled mannitol fines provided an initial insight into the improving effect of ternary powder blends as has been intensively studied for lactose monohydrate but not for mannitol yet. PMID- 28347846 TI - Supercritical anti-solvent technique assisted synthesis of thymoquinone liposomes for radioprotection: Formulation optimization, in-vitro and in-vivo studies. AB - The aim of this study was to develop Thymoquinone (TQ) loaded PEGylated liposomes using supercritical anti-solvent (SAS) process for enhanced blood circulation, and greater radioprotection. The SAS process of PEGylated liposomes synthesis was optimized by Box-Behnken design. Spherical liposomes with a particle size of 195.6+/-5.56nm and entrapment efficiency (%EE) of 89.4+/-3.69% were obtained. Optimized SAS process parameters; temperature, pressure and solution flow rate were 35 degrees C, 140bar and 0.18mL/min, respectively, while 7.5mmol phospholipid, 0.75mmol of cholesterol, and 1mmol TQ were optimized formulation ingredients. Incorporation of MPEG-2000-DSPE (5% w/w) provided the PEGylated liposomes (FV-17B; particle size=231.3+/-6.74nm, %EE=91.9+/-3.45%, maximum TQ release >70% in 24h). Pharmacokinetics of FV-17B in mice demonstrated distinctly superior systemic circulation time for TQ in plasma. Effectiveness of radioprotection by FV-17B in mice model was demonstrated by non-significant body weight change, normal vital blood components (WBCs, RBCs, and Platelets), micronuclei and spleen index and increased survival probability in post irradiation animal group as compared to controls (plain TQ and marketed formulation). Altogether, the results anticipated that the SAS process could serve as a single step environmental friendly technique for the development of stable long circulating TQ loaded liposomes for effective radioprotection. PMID- 28347848 TI - Comparison of the protective effect of self-emulsifying peptide drug delivery systems towards intestinal proteases and glutathione. AB - AIM: The aim of this study was to evaluate the protective effect of self emulsifying drug delivery systems (SEDDS) for therapeutic peptides towards intestinal proteases and reduced glutathione (GSH). METHODS: Sodium docusate was applied as anionic surfactant for hydrophobic ion pairing with leuprorelin (LEU), insulin (INS) and desmopressin (DES). The complexes were loaded into SEDDS that were characterized regarding droplet size distribution and zeta potential. The release profile of the peptides was examined by dialysis membrane method. Enzymatic digestion studies were performed by applying alpha-chymotrypsin, trypsin and elastase. Furthermore, the protective effect of SEDDS towards degradation through thiol-disulfide exchange reactions was examined by addition of GSH. RESULTS: SEDDS showed a mean droplet size of 0.27-3.9MUm and a zeta potential of -25 to -33mV. All formulations provided a sustained release of the peptides over 6h. Degradation of the model peptides by intestinal proteases and GSH could only be observed in the release medium. In the oily phase of SEDDS neither any of the proteases nor GSH was soluble (<=0.1%). Furthermore, no degradation of the model peptides by proteases and GSH took place in the oily phase of SEDDS. CONCLUSION: SEDDS can provide a 100% protective effect towards protease degradation and deactivation by GSH. According to this, SEDDS might be promising tools for oral delivery of peptide drugs. PMID- 28347849 TI - Prediction of solid fraction from powder mixtures based on single component compression analysis. AB - The aim of this study was to provide a systematic evaluation of various compression models (Percolation, Kawakita, Exponential model) in respect to predict tablets solid fraction for direct compression mixtures, based on single component compression analysis. Four mixtures were compressed over a wide pressure range at various fractions of microcrystalline cellulose (MCC) and pre agglomerated lactose monohydrate (LAC) to compare an adjusted Percolation, Kawakita and a simple Exponential model. Based on single compression analysis of the pure excipients and application of these models, it was possible to predict the solid fraction of all mixtures. The Kawakita model showed overall superior prediction accuracy, whereas the Percolation model resulted in the best fit for mixtures containing microcrystalline cellulose in a range of 72%-48%. Both models were in good agreement at residuals below 3%. PMID- 28347850 TI - Clinical features and treatment of patients with Vibrio vulnificus infection. AB - OBJECTIVES: Infections with Vibrio vulnificus are commonly fatal, and the speed and accuracy of diagnosis and treatment is directly linked to mortality. The main aims of this study were to investigate the clinical characteristics of six patients with V. vulnificus infections retrospectively and to determine the effect of treatment with tigecycline (TGC) alone compared with doxycycline plus ceftazidime (DOX/CAZ). METHODS: The medical records of patients were reviewed. The species-specific and pathogenic gene markers were detected by PCR, and multilocus sequence typing (MLST) was performed. Furthermore, the effects of TGC and of DOX/CAZ were determined using time-kill assays. RESULTS: MLST revealed six different sequence types and five of them were novel. The complete clinical pattern (vcg type C, CPS operon allele 1, 16S-rRNA type B) was found in one strain and the others had a mixed pattern. The lesion was mainly located at the distal end of the extremities and the most common clinical symptoms were fever, pain, erythema, and local swelling. The in vitro time-kill assay indicated that TGC monotherapy at a concentration of 0.1mg/l had a rapid bactericidal effect against the six tested V. vulnificus strains at 24h. CONCLUSIONS: TGC alone might be a better potential therapeutic option than the traditional combination of DOX/CAZ against V. vulnificus. PMID- 28347851 TI - Implementation of an antibiotic checklist increased appropriate antibiotic use in the hospital on Aruba. AB - OBJECTIVES: No interventions have yet been implemented to improve antibiotic use on Aruba. In the Netherlands, the introduction of an antibiotic checklist resulted in more appropriate antibiotic use in nine hospitals. The aim of this study was to introduce the antibiotic checklist on Aruba, test its effectiveness, and evaluate the possibility of implementing this checklist outside the Netherlands. METHODS: The antibiotic checklist includes seven quality indicators (QIs) that define appropriate antibiotic use. It applies to adult patients with a suspected bacterial infection, treated with intravenous antibiotics. The primary endpoint was the QI sum score, calculated by the patient's sum of performed checklist-items divided by the total number of QIs that applied to that specific patient. Outcomes before and after the introduction of the checklist were compared. RESULTS: The percentage of patients with a QI sum score >=50% increased significantly during the intervention (n=173) compared to baseline (n=150) (odds ratio 3.67, p<0.001). However, performance did not improve on each individual QI. The checklist was used in 63.3% of the eligible patients. CONCLUSIONS: The introduction of the antibiotic checklist increased appropriate antibiotic use on Aruba. Additional initiatives are necessary for further improvement per QI. These results suggest that the antibiotic checklist could be used internationally. PMID- 28347852 TI - First report of human parechovirus type 3 infection in a pregnant woman. AB - Human parechovirus type 3 (HPeV3) can cause serious conditions in neonates, such as sepsis and encephalitis, but data for adults are lacking. The case of a pregnant woman with HPeV3 infection is reported herein. A 28-year-old woman at 36 weeks of pregnancy was admitted because of myalgia and muscle weakness. Her grip strength was 6.0kg for her right hand and 2.5kg for her left hand. The patient's symptoms, probably due to fasciitis and not myositis, improved gradually with conservative treatment, however labor pains with genital bleeding developed unexpectedly 3 days after admission. An obstetric consultation was obtained and a cesarean section was performed, with no complications. A real-time PCR assay for the detection of viral genomic ribonucleic acid against HPeV showed positive results for pharyngeal swabs, feces, and blood, and negative results for the placenta, umbilical cord, umbilical cord blood, amniotic fluid, and breast milk. The HPeV3 was genotyped by sequencing of the VP1 region. The woman made a full recovery and was discharged with her infant in a stable condition. PMID- 28347853 TI - Exposure to traumatic events at work, posttraumatic symptoms and professional quality of life among midwives. AB - OBJECTIVE: in their line of duty, midwives are often exposed to traumatic births that may lead to symptoms of compassion fatigue (CF), which includes burnout (BO) and secondary traumatic stress (STS).Conversely, midwives derive pleasure and great satisfaction in seeing the positive effect they have on their clients. This experience is known as compassion satisfaction (CS). Together, CS and CF comprise the professional quality of life (ProQOL). The aim of this paper was to study midwives' professional quality of life and traumatic experiences. The highly stressful environment of midwives may also include primary exposure to traumatic experiences and therefore PTSD levels were also assessed. METHOD: the participants (N=93) were professional midwives from four medical centers in Israel. The participants answered selfreport questionnaires that assessed their ProQOL and PTSD symptoms. FINDINGS: results indicated relatively high levels of CS which may mitigate, at least to some degree, the negative aspects of CF. PTSD levels significantly and positively correlated with STS and BO. Sixteen per cent presented with PTSD symptoms of clinical significance. Also, seniority was significantly and positively correlated with BO and PTSD symptoms. CONCLUSIONS: high ProQOL was found amongst the participants, with more than 74% scoring on the high range of CS. Nevertheless, we recommend further research and implementing strategies to maintain or further enhance CS and decrease CF levels. Finally, a more comprehensive understanding of the development of PTSD amongst midwives is vital in order to minimize its occurrence in the future. PMID- 28347855 TI - Role of high resolution optical coherence tomography in diagnosing ocular surface squamous neoplasia with coexisting ocular surface diseases. AB - PURPOSE: Coexistence of an ocular surface disease can mask the typical features of ocular surface squamous neoplasia (OSSN). The purpose of this study was to evaluate high resolution optical coherence tomography (HR-OCT) as an adjunct in the detection and differentiation of OSSN within coexisting ocular surface pathologies. METHODS: Retrospective study of 16 patients with ocular surface disease and lesions suspicious for OSSN that were evaluated with HR-OCT. HR-OCT images of the lesions were taken to look for evidence of OSSN. Biopsies were performed in all cases, and the HR-OCT findings were compared to the histological results. RESULTS: Of the 16 patients with OSSN and a coexisting ocular surface disease, 12 were found to have OSSN by HR-OCT and all were subsequently confirmed by biopsy. Two patients had OSSN with rosacea, one with pingueculum, two within pterygia, one with Salzmann' nodular degeneration, six with limbal stem cell deficiency (LSCD)/scarring. In all 12 cases HR-OCT images revealed classical findings of hyper-reflective, thickened epithelium and an abrupt transition from normal to abnormal epithelium. OSSN was ruled out by HR-OCT in four cases (2 Salzmann's, 1 mucous membrane pemphigoid, and 1 LSCD). Negative findings were confirmed by biopsy. HR-OCT was used to follow resolution of the OSSN in positive cases, and it detected recurrence in 1 case. CONCLUSIONS: While histopathology is the gold standard in the diagnosis of OSSN, HR-OCT can be used to noninvasively detect the presence of OSSN in patients with coexisting ocular conditions. PMID- 28347857 TI - What do genetic studies tell us about the heritable basis of common epilepsy? Polygenic or complex epilepsy? AB - The search for genes associated with common epilepsy, including both focal and generalised epilepsies, has been intensive in the past few decades. Consequently, our understanding of the genetic background of common epilepsy has improved considerably, and current genetic studies have optimised their design accordingly, showing much promise for the future. Nevertheless, we can only explain a fraction of the heritability of common epilepsy with the currently known genetic factors. These factors have been identified with a range of different gene mapping techniques, including linkage analysis of epilepsy families, association studies, and recent large scale sequencing studies, which individually are optimal to detect a certain class of genetic variation. Here, we give a selected overview of the genetic studies that illustrate the evolution of epilepsy genetics and contribute to the evidence for a polygenic basis of common epilepsy that likely involves both rare and common disease variants. PMID- 28347856 TI - A multidisciplinary approach to designing and evaluating Electronic Medical Record portal messages that support patient self-care. AB - We describe a project intended to improve the use of Electronic Medical Record (EMR) patient portal information by older adults with diverse numeracy and literacy abilities, so that portals can better support patient-centered care. Patient portals are intended to bridge patients and providers by ensuring patients have continuous access to their health information and services. However, they are underutilized, especially by older adults with low health literacy, because they often function more as information repositories than as tools to engage patients. We outline an interdisciplinary approach to designing and evaluating portal-based messages that convey clinical test results so as to support patient-centered care. We first describe a theory-based framework for designing effective messages for patients. This involves analyzing shortcomings of the standard portal message format (presenting numerical test results with little context to guide comprehension) and developing verbally, graphically, video- and computer agent-based formats that enhance context. The framework encompasses theories from cognitive and behavioral science (health literacy, fuzzy trace memory, behavior change) as well as computational/engineering approaches (e.g., image and speech processing models). We then describe an approach to evaluating whether the formats improve comprehension of and responses to the messages about test results, focusing on our methods. The approach combines quantitative (e.g., response accuracy, Likert scale responses) and qualitative (interview) measures, as well as experimental and individual difference methods in order to investigate which formats are more effective, and whether some formats benefit some types of patients more than others. We also report the results of two pilot studies conducted as part of developing the message formats. PMID- 28347854 TI - Twenty years of the G protein-coupled estrogen receptor GPER: Historical and personal perspectives. AB - Estrogens play a critical role in many aspects of physiology, particularly female reproductive function, but also in pathophysiology, and are associated with protection from numerous diseases in premenopausal women. Steroids and the effects of estrogen have been known for ~90 years, with the first evidence for a receptor for estrogen presented ~50 years ago. The original ancestral steroid receptor, extending back into evolution more than 500 million years, was likely an estrogen receptor, whereas G protein-coupled receptors (GPCRs) trace their origins back into history more than one billion years. The classical estrogen receptors (ERalpha and ERbeta) are ligand-activated transcription factors that confer estrogen sensitivity upon many genes. It was soon apparent that these, or novel receptors may also be responsible for the "rapid"/"non-genomic" membrane associated effects of estrogen. The identification of an orphan GPCR (GPR30, published in 1996) opened a new field of research with the description in 2000 that GPR30 expression is required for rapid estrogen signaling. In 2005-2006, the field was greatly stimulated by two studies that described the binding of estrogen to GPR30-expressing cell membranes, followed by the identification of a GPR30-selective agonist (that lacked binding and activity towards ERalpha and ERbeta). Renamed GPER (G protein-coupled estrogen receptor) by IUPHAR in 2007, the total number of articles in PubMed related to this receptor recently surpassed 1000. In this article, the authors present personal perspectives on how they became involved in the discovery and/or advancement of GPER research. These areas include non-genomic effects on vascular tone, receptor cloning, molecular and cellular biology, signal transduction mechanisms and pharmacology of GPER, highlighting the roles of GPER and GPER-selective compounds in diseases such as obesity, diabetes, and cancer and the obligatory role of GPER in propagating cardiovascular aging, arterial hypertension and heart failure through the stimulation of Nox expression. PMID- 28347859 TI - The sensory arrays of the ant, Temnothorax rugatulus. AB - Individual differences in response thresholds to task-related stimuli may be one mechanism driving task allocation among social insect workers. These differences may arise at various stages in the nervous system. We investigate variability in the peripheral nervous system as a simple mechanism that can introduce inter individual differences in sensory information. In this study we describe size dependent variation of the compound eyes and the antennae in the ant Temnothorax rugatulus. Head width in T. rugatulus varies between 0.4 and 0.7 mm (2.6-3.8 mm body length). But despite this limited range of worker sizes we find sensory array variability. We find that the number of ommatidia and of some, but not all, antennal sensilla types vary with head width. The antennal array of T. rugatulus displays the full complement of sensillum types observed in other species of ants, although at much lower quantities than other, larger, studied species. In addition, we describe what we believe to be a new type of sensillum in hymenoptera that occurs on the antennae and on all body segments. T. rugatulus has apposition compound eyes with 45-76 facets per eye, depending on head width, with average lens diameters of 16.5 MUm, rhabdom diameters of 5.7 MUm and inter ommatidial angles of 16.8 degrees . The optical system of T. rugatulus ommatidia is severely under focussed, but the absolute sensitivity of the eyes is unusually high. We discuss the functional significance of these findings and the extent to which the variability of sensory arrays may correlate with task allocation. PMID- 28347858 TI - Higher interference susceptibility in reaction time task is accompanied by weakened functional dissociation between salience and default mode network. AB - BACKGROUND: The relationship between task-positive and task-negative components of brain networks has repeatedly been shown to be characterized by dissociated fluctuations of spontaneous brain activity. We tested whether the interaction between task-positive and task-negative brain areas during resting-state predicts higher interference susceptibility, i.e. increased reaction times (RTs), during an Attention Modulation by Salience Task (AMST). METHODS: 29 males underwent 3T resting-state Magnetic Resonance Imaging scanning. Subsequently, they performed the AMST, which measures RTs to early- and late-onset auditory stimuli while perceiving high- or low-salient visual distractors. We conducted seed-based resting-state functional connectivity (rsFC) analyses using global signal correction. We assessed general responsiveness and salience related interference in the AMST and set this into context of the resting-state functional connectivity (rsFC) between a key salience network region (dACC; task-positive region) and a key default mode network region (precuneus; task-negative region). RESULTS: With increasing RTs to high- but not low-salient pictures dACC shows significantly weakened functional dissociation to a cluster in precuneus. This cluster overlaps with a cluster that correlates in its dACC rsFC with subjects' interference, as measured of high-salient RTs relative to low-salient RTs. CONCLUSION: Our findings suggest that the interaction between salience network (SN) and default mode network (DMN) at rest predicts susceptibility to distraction. Subjects, that are more susceptible to high-salient stimuli - task irrelevant external information - showed increased dACC rsFC toward precuneus. This is consistent with prior work in individuals with impaired attentional focus. Future studies might help to conclude whether an increased rsFC between a SN region and DMN region may serve as a predictor for clinical syndromes characterized by attentional impairments, e.g. ADHD. This could lead to an alternative, objective diagnosis and treatment of such disorders by decreasing the rsFC of these regions. PMID- 28347860 TI - Ultrastructure of spermiogenesis and spermatozoa in Marchalina hellenica (Gennadius) (Hemiptera: Sternorrhyncha, Marchalinidae). AB - The spermiogenesis, the sperm structure and the sperm motility of Marchalina hellenica (Gennadius) were examined. In the early spermiogenesis a centriolar apparatus was identified, but this structure is not involved in the production of the sperm flagellum. As in other Coccoidea, the flagellar axoneme originates by the activity of the thickened tip of the numerous microtubules surrounding the nuclear anterior region close to the periphery of the cell. This region pushes against a narrow cytoplasmic layer, giving rise to a papilla. In this region a novel structure, consisting of a regular network of thin filaments, arranged orthogonally to the bundle of microtubules, is visible. The sperm flagellum consists of a series of about 260 microtubules, regularly arranged in rings around the axial nucleus. This latter extends in the middle part of the sperm length. As usual in scale insects, sperm form a bundle, which in M. hellenica is composed of 64 sperm cells, surrounded by somatic cyst cells. The sperm bundle has an helicoidal array, with a cap of dense material at its apex, lending the anterior and the posterior region of the sperm bundle with a different structural organization. This difference is responsible of the different speed gradient observed in the helical wave propagating along the sperm bundle. PMID- 28347862 TI - Cell sheet engineering using the stromal vascular fraction of adipose tissue as a vascularization strategy. AB - : Current vascularization strategies for Tissue Engineering constructs, in particular cell sheet-based, are limited by time-consuming and expensive endothelial cell isolation and/or by the complexity of using extrinsic growth factors. Herein, we propose an alternative strategy using angiogenic cell sheets (CS) obtained from the stromal vascular fraction (SVF) of adipose tissue that can be incorporated into more complex constructs. Cells from the SVF were cultured in normoxic and hypoxic conditions for up to 8days in the absence of extrinsic growth factors. Immunocytochemistry against CD31 and CD146 revealed spontaneous organization in capillary-like structures, more complex after hypoxic conditioning. Inhibition of HIF-1alpha pathway hindered capillary-like structure formation in SVF cells cultured in hypoxia, suggesting a role of HIF-1alpha. Moreover, hypoxic SVF cells showed a trend for increased secretion of angiogenic factors, which was reflected in increased network formation by endothelial cells cultured on matrigel using that conditioned medium. In vivo implantation of SVF CS in a mouse hind limb ischemia model revealed that hypoxia-conditioned CS led to improved restoration of blood flow. Both in vitro and in vivo data suggest that SVF CS can be used as simple and cost-efficient tools to promote functional vascularization of TE constructs. STATEMENT OF SIGNIFICANCE: Neovascularization after implantation is a major obstacle for producing clinically viable cell sheet based tissue engineered constructs. Strategies using endothelial cells and extrinsic angiogenic growth factors are expensive and time consuming and may raise concerns of tumorigenicity. In this manuscript, we describe a simplified approach using angiogenic cell sheets fabricated from the stromal vascular fraction of adipose tissue. The strong angiogenic behavior of these cell sheets, achieved without the use of external growth factors, was further stimulated by low oxygen culture. When implanted in an in vivo model of hind limb ischemia, the angiogenic cell sheets contributed to blood flux recovery. These cell sheets can therefore be used as a straightforward tool to increase the neovascularization of cell sheet-based thick constructs. PMID- 28347861 TI - Activatable bispecific liposomes bearing fibroblast activation protein directed single chain fragment/Trastuzumab deliver encapsulated cargo into the nuclei of tumor cells and the tumor microenvironment simultaneously. AB - : Molecular targeting plays a significant role in cancer diagnosis and therapy. However, the heterogeneity of tumors is a limiting obstacle for molecular targeting. Consequently, clinically approved drug delivery systems such as liposomes still rely on passive targeting to tumors, which does not address tumor heterogeneity. In this work, we therefore designed and elucidated the potentials of activatable bispecific targeted liposomes for simultaneous detection of fibroblast activation protein (FAP) and the human epidermal growth factor receptor 2 (HER2). The bispecific liposomes were encapsulated with fluorescence quenched concentrations of the near-infrared fluorescent dye, DY-676-COOH, making them detectable solely post processing within target cells. The liposomes were endowed with a combination of single chain antibody fragments specific for FAP and HER2 respectively, or with the FAP single chain antibody fragment in combination with Trastuzumab, which is specific for HER2. The Trastuzumab based bispecific formulation, termed Bi-FAP/Tras-IL revealed delivery of the encapsulated dye into the nuclei of HER2 expressing cancer cells and caused cell death at significantly higher rates than the free Trastuzumab. Furthermore, fluorescence imaging and live microscopy of tumor models in mice substantiated the delivery of the encapsulated cargo into the nuclei of target tumor cells and tumor stromal fibroblasts. Hence, they convey potentials to address tumor plasticity, to improve targeted cancer therapy and reduce Trastuzumab resistance in the future. STATEMENT OF SIGNIFICANCE: This work demonstrates the design of activatable bispecific liposomes aimed to target HER2, a poor prognosis tumor marker in many tumor types, and fibroblast activation protein (FAP), a universal tumor marker overexpressed on tumor fibroblasts and pericytes of almost all solid tumors. Encapsulating liposomes with a quenched concentration of a NIRF dye which only fluoresced after cellular degradation and activation enabled reliable visualization of the destination of the cargo in cells and animal studies. Conjugating single chain antibody fragments directed to FAP, together with Trastuzumab, a humanized monoclonal antibody for HER2 resulted in the activatable bispecific liposomes. In animal models of xenografted human breast tumors, the remarkable ability of the bispecific probes to simultaneously deliver the encapsulated dye into the nuclei of target tumor cells and tumor fibroblasts could be demonstrated. Hence, the bispecific probes represent model tools with high significance to address tumor heterogeneity and manage Trastuzumab resistance in the future. PMID- 28347863 TI - Common bean proteomics: Present status and future strategies. AB - : Common bean (Phaseolus vulgaris L.) is a legume of appreciable importance and usefulness worldwide to the human population providing food and feed. It is rich in high-quality protein, energy, fiber and micronutrients especially iron, zinc, and pro-vitamin A; and possesses potentially disease-preventing and health promoting compounds. The recently published genome sequence of common bean is an important landmark in common bean research, opening new avenues for understanding its genetics in depth. This legume crop is affected by diverse biotic and abiotic stresses severely limiting its productivity. Looking at the trend of increasing world population and the need for food crops best suited to the health of humankind, the legumes will be in great demand, including the common bean mostly for its nutritive values. Hence the need for new research in understanding the biology of this crop brings us to utilize and apply high-throughput omics approaches. In this mini-review our focus will be on the need for proteomics studies in common bean, potential of proteomics for understanding genetic regulation under abiotic and biotic stresses and how proteogenomics will lead to nutritional improvement. We will also discuss future proteomics-based strategies that must be adopted to mine new genomic resources by identifying molecular switches regulating various biological processes. SIGNIFICANCE: Common bean is regarded as "grain of hope" for the poor, being rich in high-quality protein, energy, fiber and micronutrients (iron, zinc, pro-vitamin A); and possesses potentially disease-preventing and health-promoting compounds. Increasing world population and the need for food crops best suited to the health of humankind, puts legumes into great demand, which includes the common bean mostly. An important landmark in common bean research was the recent publication of its genome sequence, opening new avenues for understanding its genetics in depth. This legume crop is affected by diverse biotic and abiotic stresses severely limiting its productivity. Therefore, the need for new research in understanding the biology of this crop brings us to utilize and apply high-throughput omics approaches. Proteomics can be used to track all the candidate proteins/genes responsible for a biological process under specific conditions in a particular tissue. The potential of proteomics will not only help in determining the functions of a large number of genes in a single experiment but will also be a useful tool to mine new genes that can provide solution to various problems (abiotic stress, biotic stress, nutritional improvement, etc). We believe that a combined approach including breeding along with omics tools will lead towards attaining sustainability in legumes, including common bean. PMID- 28347864 TI - iTRAQ-based quantitative proteomic analysis reveals proteomic changes in three fenoxaprop-P-ethyl-resistant Beckmannia syzigachne biotypes with differing ACCase mutations. AB - : American sloughgrass (Beckmannia syzigachne Steud.) is a weed widely distributed in wheat fields of China. In recent years, the evolution of herbicide (fenoxaprop-P-ethyl)-resistant populations has decreased the susceptibility of B. syzigachne. This study compared 4 B. syzigachne populations (3 resistant and 1 susceptible) using iTRAQ to characterize fenoxaprop-P-ethyl resistance in B. syzigachne at the proteomic level. Through searching the UniProt database, 3104 protein species were identified from 13,335 unique peptides. Approximately 2834 protein species were assigned to 23 functional classifications provided by the COG database. Among these, 2299 protein species were assigned to 125 predicted pathways. The resistant biotype contained 8 protein species that changed in abundance relative to the susceptible biotype; they were involved in photosynthesis, oxidative phosphorylation, and fatty acid biosynthesis pathways. In contrast to previous studies comparing only 1 resistant and 1 susceptible population, our use of 3 fenoxaprop-resistant B. syzigachne populations with different genetic backgrounds minimized irrelevant differential expression and eliminated false positives. Therefore, we could more confidently link the differentially expressed proteins to herbicide resistance. Proteomic analysis demonstrated that fenoxaprop-P-ethyl resistance is associated with photosynthetic capacity, a connection that might be related to the target-site mutations in resistant B. syzigachne. This is the first large-scale proteomics study examining herbicide stress responses in different B. syzigachne biotypes. BIOLOGICAL SIGNIFICANCE: This study has biological relevance because it is the first to employ proteomic analysis for understanding the mechanisms underlying Beckmannia syzigachne herbicide resistance. The plant is a major weed in China and negatively affects crop yield, but has developed considerable resistance to the most common herbicide, fenoxaprop-P-ethyl. Through comparisons of resistant and sensitive biotypes, our study identified multiple proteins (involved in photosynthesis, oxidative phosphorylation, and fatty acid biosynthesis) that are putatively linked to B. syzigachne herbicide response. This large-scale proteomics study, sorely lacking in weed science, contributes valuable data that can be applied to more fine-tuned analyses on the functions of specific proteins in herbicide resistance. PMID- 28347865 TI - Efficacy of periimplant mechanical curettage with and without adjunct antimicrobial photodynamic therapy in smokeless-tobacco product users. AB - OBJECTIVE: The aim was to investigate the effectiveness of antimicrobial photodynamic therapy (aPDT) as an adjuvant to mechanical curettage (MC) in the treatment of periimplant mucositis in smokeless tobacco (ST) product users. METHODS: Forty-eight ST product users with periimplant mucositis were randomly divided into 2 groups. In the test-group, participants underwent periimplant MC with adjunct aPDT; and in the control-group, the patients underwent MC alone. Periimplant plaque index (PI), bleeding on probing (BOP), and probing depth (PD) were measured at baseline and after 3-months of follow-up. Statistical analysis was performed using the Kruskal-Wallis test. Level of significance was set at P<0.05. RESULTS: At baseline, periimplant PI, BOP and PD were comparable among individuals in the test- and control groups. At 3-months follow-up, scores of periimplant PI (P<0.05), BOP (P<0.05) and PD (P<0.05) were statistically significantly higher among patients in the control-group compared with the test group. At 3-months follow-up, the percentages of sites of PI, BOP and PD were statistically significantly higher in the control-sites as compared to the test sites. CONCLUSION: Among patients with periimplant mucositis, MC with adjunct aPDT is more effective in reducing periimplant inflammation in ST product users as compared to MC alone; however, the present result should be interpreted with caution as they were based on a short-term follow-up. Further long-term studies are needed in this regard. PMID- 28347866 TI - Long-term changes in optic coherence tomography in a child with laser pointer maculopathy: A case report and mini review. AB - With a wide range of applications, laser pointers used as toys by children has become a major public safety problem worldwide. Here we present a long term followup of a ten-year-old boy retina injured patient who suffered from green light laser pointer. Retina injured patients caused by green light laser pointer were traditionally treated by steroid. We gave Lutein treatment prescription according to the wishes of the patient's parents. Over 12 months followup, the patient's visual acuity and retinal recovery outcomes were similar as in cases with steroid treatment. Primary school teacher and parents should pay more attention to children playing with laser pointer to prevent laser injury accident through school and family education. PMID- 28347867 TI - Microbiota differences between commercial breeders impacts the post-stroke immune response. AB - Experimental reproducibility between laboratories is a major translational obstacle worldwide, particularly in studies investigating immunomodulatory therapies in relation to brain disease. In recent years increasing attention has been drawn towards the gut microbiota as a key factor in immune cell polarization. Moreover, manipulation of the gut microbiota has been found effective in a diverse range of brain disorders. Within this study we aimed to test the impact of microbiota differences between mice from different sources on the post-stroke neuroinflammatory response. With this rationale, we have investigated the correlation between microbiota differences and the immune response in mice from three commercial breeders with the same genetic background (C57BL/6). While overall bacterial load was comparable, we detected substantial differences in species diversity and microbiota composition on lower taxonomic levels. Specifically, we investigated segmented filamentous bacteria (SFB)-which have been shown to promote T cell polarization-and found that they were absent in mice from one breeder but abundant in others. Our experiments revealed a breeder specific correlation between SFB presence and the ratio of Treg to Th17 cells. Moreover, recolonization of SFB-negative mice with SFB resulted in a T cell shift which mimicked the ratios found in SFB-positive mice. We then investigated the response to a known experimental immunotherapeutic approach, CD28 superagonist (CD28SA), which has been previously shown to expand the Treg population. CD28SA treatment had differing effects between mice from different breeders and was found to be ineffective at inducing Treg expansion in SFB-free mice. These changes directly corresponded to stroke outcome as mice lacking SFB had significantly larger brain infarcts. This study demonstrates the major impact of microbiota differences on T cell polarization in mice during ischemic stroke conditions, and following immunomodulatory therapies. PMID- 28347868 TI - Teneligliptin, a dipeptidyl peptidase-4 inhibitor, attenuated pro-inflammatory phenotype of perivascular adipose tissue and inhibited atherogenesis in normoglycemic apolipoprotein-E-deficient mice. AB - BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors have various cellular effects that are associated with vascular protection. Here, we examined whether teneligliptin alters the pro-inflammatory phenotype of perivascular adipose tissue (PVAT) and inhibits atherogenesis. METHODS AND RESULTS: Teneligliptin (60mg/kg/day) was administered orally to apolipoprotein-E-deficient (ApoE-/-) mice for 20weeks. Teneligliptin significantly inhibited the development of atherosclerosis in the aortic arch compared with vehicle (P<0.05), without alteration of blood glucose level or blood pressure. Histological analyses demonstrated that teneligliptin decreased lipid deposition and MCP-1 expression (P<0.05, respectively), and tended to decrease macrophage accumulation in atherosclerotic plaques. The results of quantitative RT-PCR analysis demonstrated that teneligliptin reduced the expression of inflammatory molecules such as TNF alpha and MCP-1 in the abdominal aorta. Furthermore, teneligliptin reduced the expression of a macrophage marker and Nox-4, a major NADPH oxidase subunit in adipocytes, in PVAT around the aortic arch. Administration of teneligliptin for 8weeks ameliorated endothelium-dependent vasodilation and reduced oxidative stress as determined by urinary 8-OHdG excretion (P<0.05) compared with vehicle. In vitro experiments demonstrated that exendin-4 (Ex-4), a GLP-1 analog, decreased the expression of inflammatory molecules in RAW264.7 cells. Also, Ex-4 decreased Nox4 expression in 3T3-L1 adipocytes. CONCLUSION: Teneligliptin inhibited atherogenesis with attenuation of the inflammatory phenotype in PVAT. A GLP-1 analog suppressed pro-inflammatory activation of macrophages and adipocytes. Suppression of the pro-inflammatory phenotype of PVAT might contribute, at least partially, to the cardioprotective effects of teneligliptin. PMID- 28347869 TI - Retrospective review of postoperative glycemic control in patients after distal pancreatectomy. AB - BACKGROUND: Distal pancreatectomy (DP) is carried out for resection of lesions in the body and tail of the pancreas. DP may lead to both insulin and glucagon deficiency, which may worsen diabetes mellitus and render patients more vulnerable to severe hypoglycemia. Maintaining glycemic control can be challenging after DP, and no guidelines have been established for clinicians. The objective of this study was to investigate postoperative glycemic control and insulin dose among patients after DP. METHODS: The medical records from 82 eligible adult patients after DP between 2013 and 2014 were reviewed retrospectively. RESULTS: Twenty-one (25.6%) patients had pre-existing diabetes. The average length of stay was 5.8 +/- 2.6 days. The average resected volume was 193 +/- 313 cm3. Of 2124 blood glucose (BG) values, only 0.3% were <70 mg/dL (3.9 mmol/L); 45% were 140-180 mg/dL (7.8-10.0 mmol/L); and 14% were >180 mg/dL. Postoperatively, insulin was the most common agent prescribed for glycemic control. Among those who received insulin, 86.8% used rapid-acting correction insulin, 4.4% prandial insulin, and 8.8% long-acting insulin. On postoperative day 1 through 6 and on the day before hospital discharge, <30% of patients received insulin, and a total daily dose (TDD) of <0.10 units/kg was frequently needed for glycemic control. At discharge, 35.3% of patients with pre-existing diabetes improved; 23.2% required diabetic medications, of whom 50% took insulin. Only 2 patients without pre-existing diabetes required medications. CONCLUSION: Postoperative BG levels were relatively well controlled. The majority of BG levels were in the optimal range, and the incidence of hypoglycemia or clinically significant hypoglycemia was minimal with our current regimen. Postoperative patients required small TDD of insulin for glycemic control. Our data suggested that 0.05-0.20 units/kg was an appropriate dose range for postoperative glycemic control among the vulnerable population. Our findings provide guidance for clinicians to dose insulin safely for postoperative patients with DP in a hospital setting. PMID- 28347870 TI - Mediator lipidomics by liquid chromatography-tandem mass spectrometry. AB - Comprehensive quantitative analysis of lipid mediators using liquid chromatography-tandem mass spectrometry is an effective strategy in the elucidation of disease mechanisms; but technically, it has been and is still a great challenge to achieve reliable datasets that cover variety of lipid metabolites contained at trace levels in complex biological matrices. In this opinion article, we introduce our experiences in developing lipid mediator profiling systems, and deliver some comments on limitations of current methodology. PMID- 28347871 TI - Acoustic emission source localization in thin metallic plates: A single-sensor approach based on multimodal edge reflections. AB - This paper presents a new acoustic emission (AE) source localization for isotropic plates with reflecting boundaries. This approach that has no blind spot leverages multimodal edge reflections to identify AE sources with only a single sensor. The implementation of the proposed approach involves three main steps. First, the continuous wavelet transform (CWT) and the dispersion curves of the fundamental Lamb wave modes are utilized to estimate the distance between an AE source and a sensor. This step uses a modal acoustic emission approach. Then, an analytical model is proposed that uses the estimated distances to simulate the edge-reflected waves. Finally, the correlation between the experimental and the simulated waveforms is used to estimate the location of AE sources. Hsu-Nielsen pencil lead break (PLB) tests were performed on an aluminum plate to validate this algorithm and promising results were achieved. Based on these results, the paper reports the statistics of the localization errors. PMID- 28347872 TI - Ultrasonic method for monitoring the clotting process during whole blood coagulation. AB - The purpose of this work was to develop a multichannel ultrasonic measurement method for monitoring a spatially non-uniform blood clotting process. This novel method is based on simultaneous multi-channel measurements of ultrasound propagation velocities in different horizontal cross-sections of clotting blood. The most common method used for determining blood-clotting time is the capillary tube method. For this purpose ultrasonic methods based on measurements of the velocities of ultrasound waves in clotting blood are also used. Measurement results essentially depend on the propagation path of the ultrasonic wave in a blood sample. The ultrasound velocity changes as fresh blood transforms into clot plus serum. The objective of this work was to develop a measurement method that allows one to measure ultrasound velocity and its evolution in time and space in an evolving clot while avoiding the influence of serum. To achieve this objective, a novel method has been proposed that is based on ultrasound propagation velocity measurements in different horizontal cross-sections of clotting blood using a pulse-echo mode. Such a technique enables researchers to monitor the clotting process and a clot's spatial structure, which are different in different layers due to the influence of gravity. The four-channel measurement chamber utilizing this method has been designed and manufactured. For the generation and reception of ultrasonic waves of high frequency, wide band (3 20MHz at -6dB) ultrasonic transducers were developed. To verify that the multi channel measurement system was operational, a special procedure based on monitoring of a polymerisation process in the acrylamide solution was proposed. Performance of the developed method was investigated by measuring clotting blood (sample volumes of less than 0.6ml) at the frequency of 12MHz. The results revealed that a clot structure indeed varies within a blood sample due to the influence of gravity; clotting times are different in different horizontal layers of the clot and range from 9 to 15min, defined by the standard capillary method. Clotting times are determined precisely from abrupt increases in ultrasound velocity. Uncertainty of the ultrasound velocity measurements was less than +/ 0.05m/s. The experiments were performed at 36.90+/-0.01 degrees C. The proposed method may be exploited for monitoring polymerisation reactions in the chemistry field, as well. PMID- 28347873 TI - The DRY motif and the four corners of the cubic ternary complex model. AB - Recent structural data on GPCRs using a variety of spectroscopic approaches suggest that GPCRs adopt a dynamic conformational landscape, with ligands stabilizing subsets of these states to activate one or more downstream signaling effectors. A key outstanding question posed by this emerging dynamic structural model of GPCRs is what states, active, inactive, or intermediate are captured by the numerous crystal structures of GPCRs complexed with a variety of agonists, partial agonists, and antagonists. In the early nineties the discovery of inverse agonists and constitutive activity led to the idea that the active receptor state (R*) is an intrinsic property of the receptor itself rather than of the RG complex, eventually leading to the formulation of the cubic ternary complex model (CTC). Here, by a careful analysis of a series of data obtained with a number of mutants of the highly conserved E/DRY motif, we show evidences for the existence of all the receptor states theorized by the CTC, four 'uncoupled (R, R* and HR and HR*), and, consequently four 'coupled' (RG, R*G, HRG and HR*G). The E/DRY motif located at the cytosolic end of transmembrane helix III of Class A GPCRs has been widely studied and analyzed because it forms a network of interactions believed to lock receptors in the inactive conformation (R), and, thus, to play a key role in receptor activation. Our conclusions are supported by recent crystal and NMR spectra, as well as by results obtained with two prototypical GPCRs using a new FRET technology that de-couples G protein binding to the receptor from signal transduction. Thus, despite its complexity and limitations, we propose that the CTC is a useful framework to reconcile pharmacological, biochemical and structural data. PMID- 28347874 TI - Nucleotide P2Y13-stimulated phosphorylation of CREB is required for ADP-induced proliferation of late developing retinal glial progenitors in culture. AB - Nucleotides stimulate phosphorylation of CREB to induce cell proliferation and survival in diverse cell types. We report here that ADP induces the phosphorylation of CREB in a time- and concentration-dependent manner in chick embryo retinal progenitors in culture. ADP-induced increase in phospho-CREB is mediated by P2 receptors as it is blocked by PPADS but not by the adenosine antagonists DPCPX or ZM241385. Incubation of the cultures with the CREB inhibitor KG-501 prevents ADP-induced incorporation of [3H]-thymidine, indicating that CREB is involved in retinal cell proliferation. No effect of this compound is observed on the viability of retinal progenitors. While no significant increase in CREB phosphorylation is observed with the P2Y1 receptor agonist MRS2365, ADP-induced phosphorylation of CREB is blocked by the P2Y13 receptor selective antagonist MRS2211, but not by MRS2179 or PSB0739, two antagonists of the P2Y1 and P2Y12 receptors, respectively, suggesting that ADP-induced CREB phosphorylation is mediated by P2Y13 receptors. ADP-induced increase in phospho-CREB is attenuated by the PI3K inhibitor LY294002 and completely prevented by the MEK inhibitor U0126, suggesting that at least ERK is involved in ADP-induced CREB phosphorylation. A pharmacological profile similar to the activation and inhibition of CREB phosphorylation is observed in the phosphorylation of ERK, suggesting that P2Y13 receptors mediate ADP induced ERK/CREB pathway in the cultures. While no increase in [3H]-thymidine incorporation is observed with the P2Y1 receptor agonist MRS2365, both MRS2179 and MRS2211 prevent ADP-mediated increase in [3H]-thymidine incorporation, but not progenitor's survival, suggesting that both P2Y1 and P2Y13 receptor subtypes are involved in ADP-induced cell proliferation. P2Y1 receptor-mediated increase in [Ca2+]i is observed in glial cells only when cultures maintained for 9days are used. In glia from cultures cultivated for only 2days, no increase in [Ca2+]i is detected with MRS2365 and no inhibition of ADP-mediated calcium response is observed with MRS2179. In contrast, MRS2211 attenuates ADP-mediated increase in [Ca2+]i in glial cells from cultures at both stages, suggesting the presence of P2Y13 receptors coupled to calcium mobilization in proliferating retinal glial progenitors in culture. PMID- 28347875 TI - Therapeutic implication of 'Iturin A' for targeting MD-2/TLR4 complex to overcome angiogenesis and invasion. AB - Tumor angiogenesis and invasion are deregulated biological processes that drive multistage transformation of tumors from a benign to a life-threatening malignant state activating multiple signaling pathways including MD-2/TLR4/NF-kappaB. Development of potential inhibitors of this signaling is emerging area for discovery of novel cancer therapeutics. In the current investigation, we identified Iturin A (A lipopeptide molecule from Bacillus megaterium) as a potent inhibitor of angiogenesis and cancer invasion by various in vitro and in vivo methods. Iturin A was found to suppress VEGF, a powerful inducer of angiogenesis and key player in tumor invasion, as confirmed by ELISA, western blot and real time PCR. Iturin A inhibited endothelial tube arrangement, blood capillary formation, endothelial sprouting and vascular growth inside the matrigel. In addition, Iturin A inhibited MMP-2/9 expression in MDA-MB-231 and HUVEC cells. Cancer invasion, migration and colony forming ability were significantly hampered by Iturin A. Expressions of MD-2/TLR4 and its downstream MyD88, IKK-alpha and NF kappaB were also reduced in treated MDA-MB-231 and HUVEC cells. Western blot and immunofluorescence study showed that nuclear accumulation of NF-kappaB was hampered by Iturin A. MD-2 siRNA or plasmid further confirmed the efficacy of Iturin A by suppressing MD-2/TLR4 signaling pathway. The in silico docking study showed that the Iturin A interacted well with the MD-2 in MD-2/TLR4 receptor complex. Conclusively, inhibition of MD-2/TLR4 complex with Iturin A offered strategic advancement in cancer therapy. PMID- 28347876 TI - Parietal lobe critically supports successful paired immediate and single-item delayed memory for targets. AB - The parietal lobe is important for successful recognition memory, but its role is not yet fully understood. We investigated the parietal lobes' contribution to immediate paired-associate memory and delayed item-recognition memory separately for hits (targets) and correct rejections (distractors). We compared the behavioral performance of 56 patients with known parietal and medial temporal lobe dysfunction (i.e. early Alzheimer's Disease) to 56 healthy control participants in an immediate paired and delayed single item object memory task. Additionally, we performed voxel-based morphometry analyses to investigate the functional-neuroanatomic relationships between performance and voxel-based estimates of atrophy in whole-brain analyses. Behaviorally, all participants performed better identifying targets than rejecting distractors. The voxel-based morphometry analyses associated atrophy in the right ventral parietal cortex with fewer correct responses to familiar items (i.e. hits) in the immediate and delayed conditions. Additionally, medial temporal lobe integrity correlated with better performance in rejecting distractors, but not in identifying targets, in the immediate paired-associate task. Our findings suggest that the parietal lobe critically supports successful immediate and delayed target recognition memory, and that the ventral aspect of the parietal cortex and the medial temporal lobe may have complementary preferences for identifying targets and rejecting distractors, respectively, during recognition memory. PMID- 28347877 TI - The role of GABAA in the expression of updated information through the reconsolidation process in humans. AB - Consolidated memory can be again destabilized by the presentation of a memory cue (reminder) of the previously acquired information. During this process of labilization/restabilization memory traces can be either impaired, strengthened or updated in content. Here, we study if a consolidated memory can be updated by linking one original cue to two different outcomes and whether this process was modulated by the GABAergic system. To aim that, we designed two experiments carried out in three consecutive days. All participants learned a list of non sense syllable pairs on day 1. On day 2 the new information was introduced after the reminder or no-reminder presentation. Participants were tested on day 3 for the updated or original list (Exp. 1). In Exp. 2 we tested whether this new information was incorporated by an inhibitory process mediated by the GABAergic system. For that, participants retrieved the original information before being taken Clonazepam 0.25mg (GABAA agonist) or Placebo pill. We found that the groups that received the reminder correctly recalled the old and new information. However, the no reminder groups only correctly recalled the original information. Furthermore, when testing occurred in the presence of Clonazepam, the group that received the reminder plus the new information showed an impaired original memory performance compared to the group that received only Clonazepam (without reminder) or the reminder plus Placebo pill. These results show that new information can be added to a reactivated declarative memory in humans by linking one cue to two different outcomes. Furthermore, we shed light on the mechanisms of memory updating being the GABAergic system involved in the modulation of the old and new information expression. PMID- 28347878 TI - Memory-guided drawing training increases Granger causal influences from the perirhinal cortex to V1 in the blind. AB - The perirhinal cortex (PRC) is a medial temporal lobe structure that has been implicated in not only visual memory in the sighted, but also tactile memory in the blind (Cacciamani & Likova, 2016). It has been proposed that, in the blind, the PRC may contribute to modulation of tactile memory responses that emerge in low-level "visual" area V1 as a result of training-induced cortical reorganization (Likova, 2012, 2015). While some studies in the sighted have indicated that the PRC is indeed structurally and functionally connected to the visual cortex (Clavagnier, Falchier, & Kennedy, 2004; Peterson, Cacciamani, Barense, & Scalf, 2012), the PRC's direct modulation of V1 is unknown particularly in those who lack the visual input that typically stimulates this region. In the present study, we tested Likova's PRC modulation hypothesis; specifically, we used fMRI to assess the PRC's Granger causal influence on V1 activation in the blind during a tactile memory task. To do so, we trained congenital and acquired blind participants on a unique memory-guided drawing technique previously shown to result in V1 reorganization towards tactile memory representations (Likova, 2012). The tasks (20s each) included: tactile exploration of raised line drawings of faces and objects, tactile memory retrieval via drawing, and a scribble motor/memory control. FMRI before and after a week of the Cognitive-Kinesthetic training on these tasks revealed a significant increase in PRC-to-V1 Granger causality from pre- to post-training during the memory drawing task, but not during the motor/memory control. This increase in causal connectivity indicates that the training strengthened the top down modulation of visual cortex from the PRC. This is the first study to demonstrate enhanced directed functional connectivity from the PRC to the visual cortex in the blind, implicating the PRC as a potential source of the reorganization towards tactile representations that occurs in V1 in the blind brain (Likova, 2012). PMID- 28347879 TI - Encountering the Accessory Polar Renal Artery during Laparoscopic Para-Aortic Lymphadenectomy. AB - A 60-year-old Korean woman underwent laparoscopic bilateral salpingo-oophorectomy and was confirmed to have high-grade serous carcinoma of both ovaries with a huge omental cake, extensive agglutinated intra-abdominal metastatic masses, extensive serosa invasion of the intestines, and mesenterial deposits. She underwent 3 cycles of neoadjuvant chemotherapy followed by laparoscopic interval debulking surgery, including hysterectomy, pelvic and para-aortic lymphadenectomy, appendectomy, partial peritonectomy, and omentectomy. We encountered the right accessory polar renal artery (APRA) during the surgery and carefully preserved the right APRA from the abdominal aorta to the right kidney (Fig. 1). Postoperative computed tomography angiography showed an intact right APRA and normal-appearing kidney (Fig. 2). The patient had adjuvant chemotherapy and is alive without disease recurrence. Because APRA is a functional end artery, it is important to preserve it during surgery to prevent ischemic damage and renal failure [1]. It is very important for the gynecologic-oncologist to have knowledge of the retroperitoneal vascular anatomy, experience in laparoscopic surgery, and an accurate surgical technique to avoid vascular injury during laparoscopic para-aortic lymphadenectomy. PMID- 28347881 TI - Can mindfulness influence weight management related eating behaviors? If so, how? AB - Mindfulness is increasingly being used for weight management. However, the strength of the evidence for such an approach is unclear; although mindfulness based weight management programs have had some success, it is difficult to conclude that the mindfulness components were responsible. Research in this area is further complicated by the fact that the term 'mindfulness' is used to refer to a range of different practices. Additionally, we have little understanding of the mechanisms by which mindfulness might exert its effects. This review addresses these issues by examining research that has looked at the independent effects of mindfulness and mindfulness-related strategies on weight loss and weight management related eating behaviors. As well as looking at evidence for effects, the review also considers whether effects may vary with different types of strategy, and the kinds of mechanisms that may be responsible for any change. It is concluded that there is some evidence to support the effects of (a) present moment awareness, when applied to the sensory properties of food, and (b) decentering. However, research in these areas has yet to be examined in a controlled manner in relation to weight management. PMID- 28347882 TI - Subsyndromal psychosomatic concepts and personality traits in community adults. AB - OBJECTIVE: To investigate the prevalence of features of the Diagnostic Criteria for Psychosomatic Research (DCPR) in the Taiwanese community and to explore their relationships with psychological states and personality traits. METHOD: The participants were 153 individuals without a DSM-5 psychiatric diagnosis who were grouped according to whether they had a DCPR diagnosis (at least one DCPR diagnosis, DCPR(+): n=66; no DCPR diagnosis, DCPR(-): n=87). The groups were compared with respect to psychological states (measured with Patient Health Questionnaire-15 [PHQ-15], Health Anxiety Questionnaire [HAQ], Beck Depression Inventory-II [BDI-II], Beck Anxiety Inventory [BAI)]) and personality (measured with Tridimensional Personality Questionnaire). Multiple logistic and linear regressions were used to examine associations among demographic, personality, DCPR, and psychological states. RESULTS: The DCPR(+) group had higher BDI-II, BAI, PHQ-15 and HAQ scores than the DCPR(-) group and also had a higher anticipatory worry. The most common DCPR diagnoses were health anxiety (42.42%) and alexithymia (37.88%). Anticipatory worry was the variable most closely associated with all the DCPR diagnoses. Health anxiety was related to anticipatory worry and age, whereas alexithymia was associated with dependence and fatiguability. PHQ-15, HAQ, and BDI-II scores were related to health anxiety but not alexithymia. CONCLUSION: DCPR has clinical utility in the community samples without DSM-5 diagnoses. DCPR may be a valid mediator between psychological trait and state. PMID- 28347880 TI - Impact of Surgical Route in Influencing the Risk of Lymphatic Complications After Ovarian Cancer Staging. AB - Lymphatic complications are a common occurrence after staging surgery for early stage ovarian cancer (eEOC). We investigated whether the introduction of minimally invasive surgery influences the risk of developing lymphoceles and lymphorrhea in patients undergoing staging for eEOC. For this purpose, data of consecutive patients affected by eEOC undergoing staging surgery between January 1980 and January 2016 were retrospectively reviewed, and a systematic review and meta-analysis was performed. This systematic review was registered in the International Prospective Register of Systematic Review. Among 341 patients included in the present study, 47 severe postoperative complications occurred (13.7%), including 40 lymphatic complications: 31 symptomatic lymphoceles (9%) and 9 cases of lymphorrhea (2.6%), respectively. Laparoscopic staging correlated with a lower risk of developing any severe lymphatic complications in comparison with open surgery (p = .02). In particular, the laparoscopic approach and para aortic node involvement were associated with a trend toward lower lymphoceles (odds ratio, .13; 95% confidence interval, .07-2.20; p = .05) and a trend toward higher risk of lymphorrhea developing (odds ratio, 4.02; 95% confidence interval, .93-17.3; p = .06), respectively. In conclusion, the implementation of a minimally invasive approach might result in a slight reduction of lymphatic complications after eEOC staging. PMID- 28347883 TI - Is it possible to produce a low-fat burger with a healthy n-6/n-3 PUFA ratio without affecting the technological and sensory properties? AB - Burgers subjected to lipid reformulation were made by replacing 50% of the fat component by microparticles containing chia (CO) and linseed (LO) oils obtained by external ionic gelation. The microparticles presented high n-3 PUFAs levels and were resistant to the pH and temperature conditions commonly used in burger processing. The lipid reformulation did not affect hardness and improved important technological properties, such as cooking loss and fat retention. In addition to reducing the fat content of burgers by up to 50%, the lipid reformulation led to healthier PUFA/SFA and n-6/n-3 ratios, and lower atherogenicity and thrombogenicity indices. The burgers with CO microparticles showed a higher lipid oxidation and a lower sensory quality compared to the other treatments. However, the substitution of pork back fat by LO microparticles did not impair the sensory quality of burgers. Therefore, the microencapsulation of n 3 PUFA-rich oils by external ionic gelation can be considered an effective strategy to produce healthier burgers. PMID- 28347884 TI - Porcine reproductive and respiratory syndrome virus (PRRSV) up-regulates IL-8 expression through TAK-1/JNK/AP-1 pathways. AB - The acute phase of respiratory distress caused by porcine reproductive and respiratory syndrome virus (PRRSV) is likely a consequence of the release of inflammatory cytokines in the lung. IL-8, the main chemokine and activator of neutrophils, might be related to the lung injury upon PRRSV infection. In this study, we showed that PRRSV induced IL-8 expression in vivo and in vitro. Subsequently, we demonstrated that JNK and NF-kappaB pathways were activated upon PRRSV infection and required for the enhancement of IL-8 expression. We further verified that PRRSV-activated TAK-1 was essential for the activation of JNK and NF-kappaB pathways and IL-8 expression. Moreover, we revealed an AP-1 binding motif in the cloned porcine IL-8 (pIL-8) promoter, and deletion of this motif abolished the pIL-8 promoter activity. Finally, we found that the JNK-activated AP-1 subunit c-Jun was critical for the up-regulation of IL-8 expression by PRRSV. These data suggest that PRRSV-induced IL-8 production is likely through the TAK-1/JNK/AP-1 pathways. PMID- 28347885 TI - Selective activation of a few limbic structures during paradoxical (REM) sleep by the claustrum and the supramammillary nucleus: evidence and function. AB - We review here classical and recent knowledge on the state of the cortex during paradoxical (REM) sleep (PS). Recent data indicate that only a few limbic cortical structures including the anterior cingulate, retrosplenial and medial entorhinal cortices and the dentate gyrus are strongly activated during PS. In contrast, most of the other cortices including the somatosensory ones are rather deactivated during PS. Further, recent results suggest that tonic activation of limbic cortical neurons during PS is due to projections from glutamate neurons of the claustrum and GABA/glutamate neurons of the supramammillary nucleus while their pacing with theta is induced by projections from GABAergic neurons of the medial septum. The limbic structures activated during PS have all been implicated in spatial memory and it is therefore likely that such activation is crucial for memory consolidation. PMID- 28347886 TI - Immunohistochemical expression of epithelial cell adhesion molecule (EpCAM) in mucoepidermoid carcinoma compared to normal salivary gland tissues. AB - OBJECTIVES: Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumor which displays biological, histological and clinical diversity thus representing a challenge for its diagnosis and management. Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein identified as a tumor specific antigen due to its frequent overexpression in the majority of epithelial carcinomas and its correlation with prognosis. It is considered to be a promising biomarker used as a therapeutic target already in ongoing clinical trials. The purpose of this study was to investigate the pattern, cellular characterization and level of EpCAM expression in MEC and demonstrate its correlation with histologic grading which may benefit future clinical trials using EpCAM targeted therapy. MATERIALS AND METHODS: 48 specimens (12 normal salivary gland tissue and 36 MEC) were collected and EpCAM membranous expression was evaluated by immunohistochemistry. Total immunoscore (TIS) was evaluated, the term 'EpCAM overexpression' was given for tissues showing a total immunoscore >4. RESULTS: A highly significant difference was observed between TIS percent values in control and different grades of MEC (p<0.001). High grade MEC (HG-MEC) was the highest EpCAM expressor. In addition, EpCAM expression pattern differed among the different grades. CONCLUSION: EpCAM expression was detected in MEC, and its overexpression correlated with increasing the histological grade. The diffuse membranous expression in HG-MEC could be of diagnostic value in relation to the patchy expression observed in both low grade and intermediate grade MEC. PMID- 28347887 TI - Using phylogenomics to understand the link between biogeographic origins and regional diversification in ratsnakes. AB - Globally distributed groups may show regionally distinct rates of diversification, where speciation is elevated given timing and sources of ecological opportunity. However, for most organisms, nearly complete sampling at genomic-data scales to reduce topological error in all regions is unattainable, thus hampering conclusions related to biogeographic origins and rates of diversification. We explore processes leading to the diversity of global ratsnakes and test several important hypotheses related to areas of origin and enhanced diversification upon colonizing new continents. We estimate species trees inferred from phylogenomic scale data (304 loci) while exploring several strategies that consider topological error from each individual gene tree. With a dated species tree, we examine taxonomy and test previous hypotheses that suggest the ratsnakes originated in the Old World (OW) and dispersed to New World (NW). Furthermore, we determine if dispersal to the NW represented a source of ecological opportunity, which should show elevated rates of species diversification. We show that ratsnakes originated in the OW during the mid Oligocene and subsequently dispersed to the NW by the mid-Miocene; diversification was also elevated in a subclade of NW taxa. Finally, the optimal biogeographic region-dependent speciation model shows that the uptick in ratsnake diversification was associated with colonization of the NW. We consider several alternative explanations that account for regionally distinct diversification rates. PMID- 28347888 TI - On the importance of geographic and taxonomic sampling in phylogeography: A reevaluation of diversification and species limits in a Neotropical thrush (Aves, Turdidae). AB - Phylogeographic studies seeking to describe biogeographic patterns, infer evolutionary processes, and revise species-level classification should properly characterize the distribution ranges of study species, and thoroughly sample genetic variation across taxa and geography. This is particularly necessary for widely distributed organisms occurring in complex landscapes, such as the Neotropical region. Here, we clarify the geographic range and revisit the phylogeography of the Black-billed Thrush (Turdus ignobilis), a common passerine bird from lowland tropical South America, whose evolutionary relationships and species limits were recently evaluated employing phylogeographic analyses based on partial knowledge of its distribution and incomplete sampling of populations. Our work employing mitochondrial and nuclear DNA sequences sampled all named subspecies and multiple populations across northern South America, and uncovered patterns not apparent in earlier work, including a biogeographic interplay between the Amazon and Orinoco basins and the occurrence of distinct lineages with seemingly different habitat affinities in regional sympatry in the Colombian Amazon. In addition, we found that previous inferences about the affinities and taxonomic status of Andean populations assumed to be allied to populations from the Pantepui region were incorrect, implying that inferred biogeographic and taxonomic scenarios need re-evaluation. We propose a new taxonomic treatment, which recognizes two distinct biological species in the group. Our findings illustrate the importance of sufficient taxon and geographic sampling to reconstruct evolutionary history and to evaluate species limits among Neotropical organisms. Considering the scope of the questions asked, advances in Neotropical phylogeography will often require substantial cross-country scientific collaboration. PMID- 28347889 TI - Genome-wide data delimits multiple climate-determined species ranges in a widespread Australian fish, the golden perch (Macquaria ambigua). AB - Species range limits often fluctuate in space and time in response to variation in environmental factors and to gradual niche evolution due to changes in adaptive traits. We used genome-wide data to investigate evolutionary divergence and species range limits in a generalist and highly dispersive fish species that shows an unusually wide distribution across arid and semi-arid regions of Australia. We generated ddRAD data (18,979 filtered SNPs and 1.725million bp of sequences) for samples from 27 localities spanning the native range of golden perch, Macquaria ambigua (Teleostei; Percichthyidae). Our analytical framework uses population genomics to assess connectivity and population structure using model-based and model-free approaches, phylogenetics to clarify evolutionary relationships, and a coalescent-based Bayesian species delimitation method to assess statistical support of inferred species boundaries. Addressing uncertainties regarding range limits and taxonomy is particularly relevant for this iconic Australian species because of the intensive stocking activities undertaken to support its recreational fishery and its predicted range shifts associated with ongoing climate change. Strong population genomic, phylogenetic, and coalescent species delimitation support was obtained for three separately evolving metapopulation lineages, each lineage should be considered a distinct cryptic species of golden perch. Their range limits match the climate-determined boundaries of main river basins, despite the ability of golden perch to cross drainage divides. We also identified cases suggestive of anthropogenic hybridization between lineages due to stocking of this recreationally important fish, as well as a potential hybrid zone with a temporally stable pattern of admixture. Our work informs on the consequences of aridification in the evolution of aquatic organisms, a topic poorly represented in the literature. It also shows that genome-scale data can substantially improve and rectify inferences about taxonomy, hybridization and conservation management previously proposed by detailed genetic studies. PMID- 28347890 TI - MicroRNA-328 is involved in wound repair process in human bronchial epithelial cells. AB - Our aim was to investigate the role of microRNA on epithelial wound repair by global microRNA silencing. We have also analysed the influence of five miRNAs (miR-328, miR-342, miR-411, miR-609, miR-888, previously identified) on wound repair in 16HBE14o-bronchial epithelial cell line. Cells were transfected with siRNAs against human DROSHA and DICER1 or miRNA mimics or inhibitors. Wounding assays were performed and the cells were observed using time-lapse microscopy. The area of damage was calculated at chosen time points, followed by data analysis. Cells with silenced global miRNA expression showed a significantly slower repair rate compared to the control cells (p=0.001). For miR-328, we observed significantly delayed repair in cells transfected with the inhibitor compared to control (p=0.02). Global microRNA silencing significantly decreased the repair rate of airway epithelial cells in vitro, indicating an important role of miRNA in the regulation of wound repair and that miR-328, possibly involved in actin pathway, may be a potent modifier of this process. PMID- 28347891 TI - Intracerebral Masson's Tumor-Slow-Filling Vascular Lesion Demonstrated by Indocyanine Green Video Angiography. AB - BACKGROUND: Intravascular papillary endothelial hyperplasia, or Masson's tumors, are benign vascular lesions that are rarely seen intracranially. The vascular characteristics of these lesions are also unknown. CASE DESCRIPTION: We report the case of a 24-year-old male patient with a 3-year history of headache and dizziness. Neuroradiologic imaging showed a slow-growing lesion consistent with a low-grade glioma. Intraoperative appearance was of a vascular lesion that was slow filling as demonstrated with indocyanine green video angiography. Histologic analysis following resection revealed intravascular papillary endothelial hyperplasia (Masson's tumor). CONCLUSION: Masson's tumors are slow-filling vascular lesions. The preoperative diagnosis of this lesion is difficult as it can mimic a neoplastic lesion. Conservative and surgical treatment options should therefore be carefully considered. Patients with subtotal resection must undergo long-term follow-up surveillance imaging as recurrence is a possibility. PMID- 28347892 TI - Transcranial Evacuation of Atypical Progressive Supradiaphragmatic Hematoma After Transsphenoidal Complete Resection of Pituitary Adenoma. AB - OBJECTIVE: Supradiaphragmatic hematoma is a type of hematoma that occurs after transsphenoidal (TS) resection of pituitary adenoma and requires special management. METHODS: Two patients had symptomatic supradiaphragmatic hematomas after total TS resection of pituitary adenomas in the absence of vascular anomalies. Both patients also had hydrocephalus at the time of diagnosis of the hematoma. The initial endoscopic endonasal inspection showed no subdiaphragmatic bleeding. The hematoma was evacuated via a frontolateral approach after insertion of an external ventricular drain (EVD). RESULTS: The supradiaphragmatic hematoma could be clinically and radiologically distinguished. It presented early with visual deterioration without headache. The patients developed hydrocephalus, which was associated with deterioration of level of consciousness. Radiologically, the hematoma filled the suprasellar space and was associated with the extension of bleeding in the basal cisterns. Recovery was good in both patients. There were no permanent neurologic deficits. The EVD was removed in both patients. One patient required a ventriculoperitoneal shunt because of delayed hydrocephalus. CONCLUSIONS: Supradiaphragmatic hematoma can be clinically and radiologically distinguished from other types of hematoma occurring after TS resection of pituitary adenoma. Transcranial surgery should be performed to manage supradiaphragmatic hematoma, when symptomatic. Insertion of an EVD at the time of evacuation is mandatory to relax the brain and to alleviate the hydrocephalus. PMID- 28347893 TI - Demographics and Short-Term Outcomes of Spontaneous Subarachnoid Hemorrhage in Young Adults. AB - OBJECTIVE: Spontaneous subarachnoid hemorrhage (SAH) is a catastrophic disease with a high mortality. Although it is associated with poor prognosis in older patients, the socioeconomic consequences in younger patients with stroke may be more severe. We aimed to focus on the demographics and short-term outcomes of SAH in a population younger than 50 years. METHODS: We retrospectively enrolled 1689 patients with a primary diagnosis of SAH from 1993 to 2010. We identified intergroup differences in clinical variables between the patients aged 18-49 years (n = 531) and those aged >=50 years (n = 1158). RESULTS: The patients with SAH included 688 men and 1001 women (an overall male/female ratio of 1:1.45), of whom 31.4% were aged 18-49 years. Men comprised 53.5% of the younger patients and 34.9% of the older patients (P < 0.01). The post-SAH sequela of hemiplegia was more common in the younger patients (P < 0.01), whereas the incidences of in hospital mortality in the younger and older groups were 25.4% and 32.4%, respectively (P < 0.01). CONCLUSIONS: Adults younger than 50 years account for a significant portion of the population with SAH. There is a male predominance in this age group, probably related to early and substantial risk exposure. Although younger age imparts a higher probability of survival, it is also accompanied by a greater incidence of resultant sequelae. A better understanding of the age related variability of SAH will assist in guidance for public health and adjustment of clinical management. PMID- 28347894 TI - Recurrent Malignant Gliomas: Treatment Options and Their Effect on Patient's Quality of Life. PMID- 28347895 TI - Metabolomic Changes in Rat Model of Cauda Equina Injury. AB - BACKGROUND: To show the differences of metabolomic changes in a rat model of cauda equina injury (CEI) and find potent metabolic biomarkers of CEI. METHODS: A total of 28 Sprague-Dawley rats were used in this study. After the rats were given anesthesia and fixed in a prone position, a piece of silicone block was placed into the epidural space below the lamina. Behavior tests including the Basso, Beattie, and Bresnahan open field locomotor scale and an inclined plane test were conducted 1 day and 2 days after surgery. The cauda equina tissue was collected 12 hours, 1 day, and 2 days after surgery. Ultraperformance liquid chromatography coupled with quadruple time-of-flight mass spectrometry was used for a quantitative analysis of cauda equine metabolic changes in rats from different groups. The differences between the metabolic profiles of the rats in 4 groups were analyzed using partial least squares discriminant analysis. RESULTS: In behavior tests and histologic analyses given 2 days after surgery, the animals showed remarkable organ dysfunction and pathologic damage. Metabolic profiles showed remarkable differences between the control and model groups. Thirty-four potential CEI metabolite biomarkers were identified between the control group and different time-point model groups. These potential biomarkers appeared in 15 metabolic pathways. CONCLUSIONS: Our results may improve the cause of CEI and provide a basis for clinical diagnosis and locating biomarkers in the early stages of the pathologic process of CEI. PMID- 28347896 TI - Medical Missions: Mission Accomplished or Mission Impossible? PMID- 28347897 TI - The Changing Health Care Landscape and Implications of Organizational Ethics on Modern Medical Practice. AB - INTRODUCTION: Medicine is rapidly changing, both in the level of collective medical knowledge and in how it is being delivered. The increased presence of administrators in hospitals helps to facilitate these changes and ease administrative workloads on physicians; however, tensions sometimes form between physicians and administrators. ANALYSIS: This situation is based on perceptions from both sides that physicians obstruct cost-saving measures and administrators put profits before patients. In reality, increasing patient populations and changes in health care are necessitating action by hospitals to prevent excessive spending as health care systems become larger and more difficult to manage. Recognizing the cause of changes in health care, which do not always originate with physicians and administrators, along with implementing changes in hospitals such as increased physician leadership, could help to ease tensions and promote a more collaborative atmosphere. Ethically, there is a need to preserve physician autonomy, which is a tenet of medical professionalism, and a need to rein in spending costs and ensure that patients receive the best possible care. CONCLUSION: Physicians and administrators both need to have a well-developed personal ethic to achieve these goals. Physicians need be allowed to retain relative autonomy over their practices as they support and participate in administrator-led efforts toward distributive justice. PMID- 28347899 TI - Measurement of the gamma-ray energy spectrum of the educational Kinki University Reactor (UTR-KINKI). AB - The gamma-ray energy spectrum of the Kinki University Reactor (UTR-KINKI) was estimated from Ge detector measurements combined with Monte Carlo N-particle transport criticality calculations. The gamma rays mainly originated from prompt fission components, although small amounts of gamma rays from (n,gamma) reactions, fission product gamma rays, and activation gamma rays were detected. The averaged gamma-ray tissue kerma rate in the irradiation port during UTR-KINKI operation at 1W was calculated as 10.5cGy/h based on the estimated gamma-ray energy spectrum. This value is consistent with a previous measurement with paired ionization chambers and a tissue equivalent gas proportional counter. This result demonstrates the reliability of the estimated gamma-ray energy spectrum. PMID- 28347898 TI - Stentriever Thrombectomy Failure: A Challenge in Stroke Management. AB - BACKGROUND AND OBJECTIVE: Stentriever thrombectomy failure in patients with acute ischemic stroke caused by anterior circulation large artery occlusion is not a rare event. The purpose of this study was to investigate whether other procedures (tirofiban, permanent stenting) are able to recanalize the occluded vessel and determine a better outcome without increasing mortality and intracranial hemorrhage rates. METHODS: Among 513 patients consecutively admitted with anterior circulation stroke, 109 underwent stentriever thrombectomy. Modified Thrombolysis in Cerebral Ischemia (mTICI) 2b-3 recanalization was achieved in 60 patients (55.0%, group 1). Only 3 of 19 patients (group 2) obtained additional recanalization with intra-arterial infusion of tirofiban. The remaining 46 either underwent permanent stenting (n = 23, group 3) or were left nonrecanalized (n = 23, group 4). The rate of mTICI 2b-3 and clinical outcomes were analyzed in the different groups. RESULTS: A successful recanalization (mTICI 2b-3) was achieved in 17 patients of group 3 (73.9%). A significantly better outcome was observed in group 3 (modified Rankin Scale [mRS] score, 0-2) than in group 4 at 3 months (56.5% vs. 17.4%). Symptomatic intracranial hemorrhage rates were not different between group 3 and group 4 (4.3% vs. 4.3%), whereas there was a significantly higher mortality in group 4 than in group 3 (39.1% vs. 4.3%). On multivariate analysis, permanent stenting was the only factor independently associated with favorable outcome and mortality. CONCLUSIONS: Permanent stenting might be a feasible solution in patients with acute large artery occlusion after stentriever thrombectomy failure. PMID- 28347900 TI - William M. Fowler, Jr, MD, 1926-2017. PMID- 28347901 TI - PAH emissions from old and new types of domestic hot water boilers. AB - Five different domestic heating boilers (automatic, over-fire, with down-draft combustion and gasification) and three types of fuel (lignite, wood and mixed fuel) were examined in 25 combustion tests and correlated with the emissions of particulate matter (PM), carbon monoxide (CO), total organic carbon (TOC) and 12 polycyclic aromatic hydrocarbons (PAHs with MW = 178-278 g/mol) focusing on particle phase. However, the distribution of 12 PAHs in gas phase was considered as well due to the presence mainly of lighter PAHs in gas phase. The PAHs, as well as the CO and TOC, are the indicators of incomplete combustion, and in this study PAH emission increased significantly with increasing emissions of CO and TOC. The PAHs were mainly detected on PM2.5, their contents were increasing linearly with increasing PM2.5 emissions. The highest emission factors of PAHs were measured for boilers of old construction, such as over-fire boiler (5.8-929 mg/kg) and boiler with down-draft combustion (3.1-54.1 mg/kg). Modern types of boilers produced much lower emissions of PAHs, in particular, automatic boiler (0.3-3.3 mg/kg) and gasification boilers (0.2-6.7 mg/kg). In general, the inefficient combustion at reduced output of boilers generated 1.4-17.7 times more emissions of PAHs than the combustion at nominal output of boilers. It is recommended to operate boilers at nominal output with sufficient air supply and to use the proper fuel to minimise PAHs emissions from domestic heating appliances. PMID- 28347902 TI - Rainbow trout (Oncorhynchus mykiss) detection, avoidance, and chemosensory effects of oil sands process-affected water. AB - Oil sands process-affected water (OSPW) - a byproduct of the oil sands industry in Northern Alberta, Canada - is currently stored in on-site tailings ponds. The goal of the present study was to investigate the interaction of OSPW with the olfactory system and olfactory-mediated behaviours of fish upon the first encounter with OSPW. The response of rainbow trout (Oncorhynchus mykiss) to different concentrations (0.1, 1, and 10%) of OSPW was studied using a choice maze and electro-olfactography (EOG), respectively. The results of the present study showed that rainbow trout are capable of detecting and avoiding OSPW at a concentration as low as 0.1%. Exposure to 1% OSPW impaired (i.e. reduced sensitivity) the olfactory response of rainbow trout to alarm and food cues within 5 min or less. The results of the present study demonstrated that fish could detect and avoid minute concentrations of OSPW. However, if fish were exposed to OSPW-contaminated water and unable to escape, their olfaction would be impaired. PMID- 28347903 TI - Detoxification of hexavalent chromate by growing Paecilomyces lilacinus XLA. AB - In the study, the capability of Paecilomyces lilacinus XLA (CCTCC: M2012135) to reduce Cr6+ and its main antagonistic mechanisms to Cr6+ were experimentally evaluated. Activated growing fungus XLA efficiently reduced over 90% Cr6+ in the media with Cr6+ concentration below 100 mg L-1 at pH 6 after 14 days. After 1-day exposure to 100 mg L-1 Cr6+, nearly 50% of Cr6+ was reduced. Moreover, SO42- stimulated Cr6+ reduction, whereas other interferential ions inhibited Cr6+ reduction. The interaction mechanisms between XLA and Cr6+ mainly involve biotransformation, biosorption, and bioaccumulation, as detected by electron microscopy and chemical methods. The lower concentrations of Cr6+ (5 and 50 mg L 1) stimulated the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) level in XLA, respectively, but the higher concentration of Cr6+ (150 mg L-1) decreased the enzymatic activities and GSH concentration. The results implied that SOD, CAT and GSH were defensive guards to the oxidant stress produced by Cr6+. All these extracellular/intracellular defense systems endowed XLA with the ability to resist and detoxify Cr6+ by transforming its valent species. The fungus XLA could efficiently reduce Cr6+ under different environmental conditions (pH, interferential ions, and concentration). Moreover, XLA could endure the high concentration of Cr6+ probably due to its high biotransformation capability of Cr6+ and intracellular antioxidant systems for the detoxification of ROS generated by external Cr6+. All these results suggested that the fungus XLA can be applied to remediation of Cr6+-contaminated environments. PMID- 28347904 TI - Bioaccumulation and biomagnification of ultraviolet absorbents in marine wildlife of the Pearl River Estuarine, South China Sea. AB - Bioaccumulation and trophic transfer in ecosystems is an important criterion for assessing environmental risks of contaminants. This study investigated bioaccumulation and biomagnification of 13 organic ultraviolet absorbents (UVAs) in marine wildlife organisms in the Pearl River Estuary, South China Sea. The UVAs could accumulate in the organisms with biota - sediment accumulation factors (BSAF) of 0.003-2.152. UV531 was the most abundant and showed the highest tendency to accumulate in the organisms with a median BSAF of 1.105. The UVAs demonstrated species - and compound-specific accumulation in the marine organism. Fishes showed significantly higher capability than the cephalopods and crustaceans in accumulation of the UVAs. Habitat did not demonstrate obvious impact on accumulation of the UVA. On the other hand, benzophenone-3, UV328, and UV234 showed significantly higher concentration in the detritus feeding fishes than carnivorous and planktivorous fishes, suggesting governing effect of dietary habits of the organisms on bioaccumulation of these UVAs. Direct uptake from growth media was a significant exposure pathway of the organisms to the UVAs. The estimated trophic magnification factors and biomagnification factors revealed that UV329, UV531, and octocrylene could potentially biomagnify in the marine food web. PMID- 28347905 TI - Detection of intermolecular homonuclear dipolar coupling in organic rich shale by transverse relaxation exchange. AB - The mechanism behind surface relaxivity within organic porosity in shales has been an unanswered question. Here, we present results that confirm the existence of intermolecular homonuclear dipolar coupling between solid and liquid phases in sedimentary organic matter. Transverse magnetization exchange measurements were performed on an organic-rich shale saturated with liquid hydrocarbon. Liquid and solid constituents were identified through both sample resaturation and through their T1/T2 ratios. Extensive cross peaks are observed in the T2-T2 exchange spectra between the solid and liquid constituents, indicating an exchange of magnetization between the two phases. This result cannot arise from physical molecular diffusion, and the dissolution energies are too high for chemical exchange, such that the magnetization exchange must arise from intermolecular homonuclear dipolar coupling. These results both confirm a possible source of surface relaxivity in organic matter and emphasize caution in the use of standard porous media interpretations of relaxation results in shales because of coupling between different magnetization environments. PMID- 28347906 TI - Coherent evolution of parahydrogen induced polarisation using laser pump, NMR probe spectroscopy: Theoretical framework and experimental observation. AB - We recently reported a pump-probe method that uses a single laser pulse to introduce parahydrogen (p-H2) into a metal dihydride complex and then follows the time-evolution of the p-H2-derived nuclear spin states by NMR. We present here a theoretical framework to describe the oscillatory behaviour of the resultant hyperpolarised NMR signals using a product operator formalism. We consider the cases where the p-H2-derived protons form part of an AX, AXY, AXYZ or AA'XX' spin system in the product molecule. We use this framework to predict the patterns for 2D pump-probe NMR spectra, where the indirect dimension represents the evolution during the pump-probe delay and the positions of the cross-peaks depend on the difference in chemical shift of the p-H2-derived protons and the difference in their couplings to other nuclei. The evolution of the NMR signals of the p-H2 derived protons, as well as the transfer of hyperpolarisation to other NMR-active nuclei in the product, is described. The theoretical framework is tested experimentally for a set of ruthenium dihydride complexes representing the different spin systems. Theoretical predictions and experimental results agree to within experimental error for all features of the hyperpolarised 1H and 31P pump probe NMR spectra. Thus we establish the laser pump, NMR probe approach as a robust way to directly observe and quantitatively analyse the coherent evolution of p-H2-derived spin order over micro-to-millisecond timescales. PMID- 28347907 TI - Through babies' eyes: Practical and theoretical considerations of using wearable technology to measure parent-infant behaviour from the mothers' and infants' view points. AB - AIMS: To explore the utility of first-person viewpoint cameras at home, for recording mother and infant behaviour, and for reducing problems associated with participant reactivity, which represent a fundamental bias in observational research. METHODS: We compared footage recording the same play interactions from a traditional third-person point of view (3rd PC) and using cameras worn on headbands (first-person cameras [1st PCs]) to record first-person points of view of mother and infant simultaneously. In addition, we left the dyads alone with the 1st PCs for a number of days to record natural mother-child behaviour at home. Fifteen mothers with infants (3-12 months of age) provided a total of 14h of footage at home alone with the 1st PCs. RESULTS: Codings of maternal behaviour from footage of the same scenario captured from 1st PCs and 3rd PCs showed high concordance (kappa >0.8). Footage captured by the 1st PCs also showed strong inter-rater reliability (kappa=0.9). Data from 1st PCs during sessions recorded alone at home captured more 'negative' maternal behaviours per min than observations using 1st PCs whilst a researcher was present (mean difference=0.90 (95% CI 0.5-1.2, p<0.001 representing 1.5 SDs). CONCLUSION: 1st PCs offer a number of practical advantages and can reliably record maternal and infant behaviour. This approach can also record a higher frequency of less socially desirable maternal behaviours. It is unclear whether this difference is due to lack of need of the presence of researcher or the increased duration of recordings. This finding is potentially important for research questions aiming to capture more ecologically valid behaviours and reduce demand characteristics. PMID- 28347908 TI - Decreased attention to object size information in scale errors performers. AB - Young children sometimes make serious attempts to perform impossible actions on miniature objects as if they were full-size objects. The existing explanations of these curious action errors assume (but never explicitly tested) children's decreased attention to object size information. This study investigated the attention to object size information in scale errors performers. Two groups of children aged 18-25 months (N=52) and 48-60 months (N=23) were tested in two consecutive tasks: an action task that replicated the original scale errors elicitation situation, and a looking task that involved watching on a computer screen actions performed with adequate to inadequate size object. Our key finding - that children performing scale errors in the action task subsequently pay less attention to size changes than non-scale errors performers in the looking task - suggests that the origins of scale errors in childhood operate already at the perceptual level, and not at the action level. PMID- 28347909 TI - Bone marrow perfusion measured with dynamic contrast enhanced magnetic resonance imaging is correlated to body mass index in adults. AB - Bone marrow metabolism is complex and far from being fully understood. Novel aspects, such as the roles of bone marrow adiposity and vascularisation in bone metabolism currently attract attention. There is also a growing interest in the influence obesity might have on bone metabolism. Our objective was to determine the effect of BMI on bone marrow perfusion parameters using dynamic contrast enhanced magnetic resonance imaging. This prospective monocentric study was approved by our local Ethics committee. Written consent was obtained. The right hip of 59 adults under 60years old (mean age 37.5) was imaged with a dynamic 3D T1 spoiled gradient echo magnetic resonance imaging sequence. Mean BMI was 24.8 (+/-4.4). Perfusion parameters were measured in the acetabulum and femoral neck, in the greater trochanter, in the femoral head epiphysis and in the subcutaneous adipose tissue. Associations between perfusion parameters and BMI were studied using a linear mixed model adjusted for age and sex effects. Our results showed that as the BMI increased, the exchanges between blood and bone marrow appeared more important (increased Ktrans and Kep values, p=0.018 and p=0.002 respectively) and the intramedullary blood flow appeared increased (lower time to peak values, p=0.0002). In the subcutaneous fat, as the BMI increased, the vascularization decreased (lower area under the curve and initial slope values, p=0.019 and p=0.013 respectively). These results suggest that there is a relation between bone marrow perfusion and BMI, and that subcutaneous fat and bone marrow fat have different microvascular behaviours. Researchers must be aware of the effect of BMI on bone marrow perfusion parameters when they build a MR research protocol and analyse their data. A better understanding of these findings may provide the basis for the management of obesity-related bone changes. PMID- 28347911 TI - A simultaneous stabilization and solidification of the top five most toxic heavy metals (Hg, Pb, As, Cr, and Cd). AB - A novel chemically bonded phosphate ceramic (CBPC) binder was developed for the simultaneous treatment of the top five most toxic heavy metals (Hg, Pb, As, Cr, and Cd). Various CBPC binders were synthesized and tested, and their toxicity characteristic leaching procedure (TCLP) values were obtained. A magnesium/calcium-potassium phosphate ceramic binder with FeCl2 (M/C-KP-FeCl2) simultaneously stabilized multiple heavy metals. The TCLP value of the final product for industrial waste (IW) treatment using the M/C-KP-FeCl2 technology was well below the Universal Treatment Standard (UTS). Additionally, the compressive strength of the final product was below the US Nuclear Regulatory Commission Standard. PMID- 28347910 TI - Acute lung injury complicating acute kidney injury: A model of endogenous alphaKlotho deficiency and distant organ dysfunction. AB - The lung interfaces with atmospheric oxygen via a large surface area and is perfused by the entire venous return bearing waste products collected from the whole body. It is logical that the lung is endowed with generous anti-oxidative capacity derived both locally and from the circulation. The single-pass pleiotropic alpha-Klotho (alphaKlotho) protein was discovered when its genetic disruption led to premature multi-organ degeneration and early death. The extracellular domain of alphaKlotho is cleaved by secretases and released into circulation as endocrine soluble alphaKlotho protein, exerting wide-ranging cytoprotective effects including anti-oxidation on distant organs including the lung, which exhibits high sensitivity to circulating alphaKlotho insufficiency. Because circulating alphaKlotho is derived mainly from the kidney, acute kidney injury (AKI) leads to systemic alphaKlotho deficiency that in turn increases the risks of pulmonary complications, i.e., edema and inflammation, culminating in the acute respiratory distress syndrome. Exogenous alphaKlotho increases endogenous anti-oxidative capacity partly via activation of the Nrf2 pathway to protect lungs against injury caused by direct hyperoxia exposure or AKI. This article reviews the current knowledge of alphaKlotho antioxidation in the lung in the setting of AKI as a model of circulating alphaKlotho deficiency, an under recognized condition that weakens innate cytoprotective defenses and contributes to the dysfunction in distant organs. PMID- 28347912 TI - On-site removal of antibiotics and antibiotic resistance genes from leachate by aged refuse bioreactor: Effects of microbial community and operational parameters. AB - The abuse of antibiotics has raised the prevalence of antibiotic resistance, which will pose potential risk to human health. Leachate, generated during the landfill treatment of municipal solid waste, is the important hotspot of the antibiotics and antibiotic resistance genes (ARGs), and no effective on-site treatment has been put forward for preventing ARGs dissemination. Herein, the aged refuse bioreactor was employed to remove antibiotics and ARGs from leachate, and the great removal performance was observed. For the detected antibiotics, the total removal efficiency was about 76.75%, and sulfanilamide and macrolide were removed with high efficiencies (>80%). Among the target ARGs, tetracycline and macrolide resistance genes (tetM, tetQ and ermB) were eliminated with 1.2-2.0 orders of magnitude. The occurrences of ARGs did not correlated with water quality parameters such as COD, total nitrogen, ammonia, nitrate and nitrite, but closely linked to the variations of the bacterial community structure. Redundancy analysis (RDA) indicated the significant correlations between four genera and the distribution of ARGs, which implied that these key genera (including potential pathogens) drove the ARGs removal. Furthermore, the hydraulic loading test confirmed that the aged refuse bioreactor was capable of achieving high removal efficiencies even under shock loading for the higher loading was negative for the proliferations of potential ARGs hosts. This study suggested that aged refuse bioreactor could be a promising way for antibiotics and ARGs on-site removal from leachate. PMID- 28347913 TI - Toxicity and sublethal effects of chlorantraniliprole on the development and fecundity of a non-specific predator, the multicolored Asian lady beetle, Harmonia axyridis (Pallas). AB - In order to further develop integrated pest management (IPM) approaches for controlling insect pests, it is important to estimate the effects of pesticides. In this study, the toxicity and sublethal effects of the insecticide chlorantraniliprole on a non-specific predator, the multicolored Asian lady beetle Harmonia axyridis, were evaluated and life table parameter data were analyzed statistically using the age-stage, two-sex life table procedure. The results of this study show that the development time of second and fourth instar larvae as well as pupa was significantly prolonged in populations treated with LC10 (2.42 mg (a.i.) L-1) and LC30 (12.06 mg (a.i.) L-1), while adult longevity and fecundity were both significantly reduced and the preoviposition period (POP) was significantly prolonged following treatment compared to the control. In addition, the net reproductive rate (R0), as well as the intrinsic (r) and finite rate of increase (lambda) were significantly decreased in groups treated with the insecticide. These results reveal that because sublethal concentrations of chlorantraniliprole impair the population growth of H. axyridis, more attention should be paid to the use of this chemical as a component of IPM strategies. PMID- 28347914 TI - Elemental analysis of tree leaves by total reflection X-ray fluorescence: New approaches for air quality monitoring. AB - This work shows that total reflection X-ray fluorescence (TXRF) is a fast, easy and successful tool to determine the presence of potentially toxic elements in atmospheric aerosols precipitations on tree leaves. Leaves are collected in eleven parks of different geographical areas of the Brescia city, Northern Italy, for environmental monitoring purposes. Two sample preparation procedures are considered: microwave acid digestion and the novel SMART STORE method for direct analysis. The latter consists in sandwiching a portion of the leaf between two organic foils, metals free, to save it from contamination and material loss. Mass composition of macro, micro and trace elements is calculated for digested samples, while relative elemental amount are obtained from direct analysis. Washed and unwashed leaves have a different composition in terms of trace elements. Differentiation occurs according to Fe, Pb and Cu contributions, considered as most representative of air depositions, and probably related to anthropogenic sources. Direct analysis is more representative of the composition of air precipitations. Advantages and drawbacks of the presented methods of sample preparation and TXRF analysis are discussed. Results demonstrate that TXRF allows to perform accurate and precise quantitative analysis of digested samples. In addition, direct analysis of leaves may be used as a fast and simple method for screening in the nanograms range. PMID- 28347915 TI - Chromium speciation, bioavailability, uptake, toxicity and detoxification in soil plant system: A review. AB - Chromium (Cr) is a potentially toxic heavy metal which does not have any essential metabolic function in plants. Various past and recent studies highlight the biogeochemistry of Cr in the soil-plant system. This review traces a plausible link among Cr speciation, bioavailability, phytouptake, phytotoxicity and detoxification based on available data, especially published from 2010 to 2016. Chromium occurs in different chemical forms (primarily as chromite (Cr(III)) and chromate (Cr(VI)) in soil which vary markedly in term of their biogeochemical behavior. Chromium behavior in soil, its soil-plant transfer and accumulation in different plant parts vary with its chemical form, plant type and soil physico-chemical properties. Soil microbial community plays a key role in governing Cr speciation and behavior in soil. Chromium does not have any specific transporter for its uptake by plants and it primarily enters the plants through specific and non-specific channels of essential ions. Chromium accumulates predominantly in plant root tissues with very limited translocation to shoots. Inside plants, Cr provokes numerous deleterious effects to several physiological, morphological, and biochemical processes. Chromium induces phytotoxicity by interfering plant growth, nutrient uptake and photosynthesis, inducing enhanced generation of reactive oxygen species, causing lipid peroxidation and altering the antioxidant activities. Plants tolerate Cr toxicity via various defense mechanisms such as complexation by organic ligands, compartmentation into the vacuole, and scavenging ROS via antioxidative enzymes. Consumption of Cr contaminated-food can cause human health risks by inducing severe clinical conditions. Therefore, there is a dire need to monitor biogeochemical behavior of Cr in soil-plant system. PMID- 28347916 TI - Cimicifugamide from Cimicifuga rhizomes functions as a nonselective beta-AR agonist for cardiac and sudorific effects. AB - Cimicifuga rhizomes (CR) are used in the treatment of respiratory and cardiovascular diseases in traditional Chinese medicine, but their key effective components and mechanism of action have not yet been reported. In this study, the cardiac, antipyretic and sudorific effects of CR were evaluated using the toad heart failure in vitro model and mice fever and sweating in vivo models. Moreover, the UPLC/Q-TOF-MS-integrated beta2-AR luciferase reporter gene assay system was used to screen the bioactive ingredients from CR extract, and the activity of this ingredient were verified using the above-mentioned in vitro and vivo models. Our results showed that CR had anti-heart failure, antipyretic and sweating effects, which could be antagonized by propranolol. On the other hand, cimicifugamide was screened as beta2-AR agonist from CR and cimicifugamide could activate beta1, 2-ARs more significantly than beta3-AR in beta-ARs selectivity assessment. The results not only revealed the key effective components and mechanism of CR in traditional use but also supplied a characteristic complementary ingredient for quality control of CR. PMID- 28347917 TI - Induction of apoptotic DNA fragmentation mediated by mitochondrial pathway with caspase-3-dependent BID cleavage in human gastric cancer cells by a new nitroxyl spin-labeled derivative of podophyllotoxin. AB - PURPOSE: 4-[4''-(2'', 2'', 6'', 6''-tetramethyl-l''-piperidinyloxy) amino]-4' demethyl-epipodophyllotoxin (GP7) is a new semi-synthesized nitroxyl spin-labeled derivative of podophyllotoxin with anti-leukemic and anti-osteosarcoma effects. The purpose of the present study is to investigate the anti-gastric cancer (GC) effects of GP7 and the possible involvement of caspase pathway in GP7-induced apoptotic DNA fragmentation in human GC cells. MATERIALS AND METHODS: Effects of GP7 on the proliferation of human GC cell lines MKN28, AGS, BGC-823 and HGC-27 in different degrees of differentiation and normal human gastric epithelial cell line GES-1 were studied by MTT assay and compared with the effects of etoposide. Effects of GP7 on cell viability and heat shock protein 90 expression of BGC-823 and HGC-27 cells were analyzed by trypan blue exclusion test and western blotting, respectively. Effects of GP7 on apoptotic DNA fragmentation and caspase pathway of BGC-823 and HGC-27 cells were detected by agarose gel electrophoresis, colorimetric assay and western blotting. Caspase-3 inhibitor was used to manipulate the activity of caspase-3. RESULTS: GP7 inhibited concentration- and time-dependently the proliferation of human GC cells, and the inhibitory effect of GP7 on the proliferation of BGC-823 or HGC-27 cells was 1.15- or 1.21-fold higher than that of etoposide. GP7 downregulated heat shock protein 90, improved the anti-GC effects of adriamycin, cisplatin, 5-fluorouracil and their combinations, induced apoptotic DNA fragmentation, activations of caspase-9 and 3 but not -8, cytochrome-c release and BID cleavage in BGC-823 and HGC-27 cells. Caspase-3 inhibitor abrogated GP7-induced BID cleavage, decreased cytochrome-c release, caspase-9 and -3 activities and apoptotic DNA fragmentation but increased cell viability in BGC-823 and HGC-27 cells. CONCLUSION: Our findings indicate that GP7 is a promising anti-GC derivative of podophyllotoxin, and GP7 induced apoptosis in human GC cells may be mediated by mitochondrial pathway with caspase-3-dependent BID cleavage. PMID- 28347918 TI - Response to letter entitled: Distinct metastatic patterns in colorectal cancer patients. PMID- 28347919 TI - Autophagy-related polymorphisms predict hypertension in patients with metastatic colorectal cancer treated with FOLFIRI and bevacizumab: Results from TRIBE and FIRE-3 trials. AB - PURPOSE: The most frequent bevacizumab-related side-effects are hypertension, proteinuria, bleeding and thromboembolism. To date, there is no biomarker that predicts anti-VEGF-associated toxicity. As autophagy inhibits angiogenesis, we hypothesised that single-nucleotide polymorphisms (SNPs) within autophagy-related genes may predict bevacizumab-mediated toxicity in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with mCRC treated with first-line FOLFIRI and bevacizumab in two phase III randomised trials, namely the TRIBE trial (n = 219, discovery cohort) and the FIRE-3 trial (n = 234, validation cohort) were included in this study. Patients receiving treatment with FOLFIRI and cetuximab (FIRE-3, n = 204) served as a negative control. 12 SNPs in eight autophagy-related genes (ATG3/5/8/13, beclin 1, FIP200, unc-51-like kinase 1, UVRAG) were analysed by PCR-based direct sequencing. RESULTS: The FIP200 rs1129660 variant showed significant associations with hypertension in the TRIBE cohort. Patients harbouring any G allele of the FIP200 rs1129660 SNP showed a significantly lower rate of grade 2-3 hypertension compared with the A/A genotype (3% versus 15%, odds ratio [OR] 0.17; 95% confidence interval [CI], 0.02-0.73; P = 0.009). Similarly, G allele carriers of the FIP200 rs1129660 SNP were less likely to develop grade 2-3 hypertension than patients with an A/A genotype in the FIRE-3 validation cohort (9% versus 20%, OR 0.43; 95% CI, 0.14-1.11; P = 0.077), whereas this association could not be observed in the control cohort (12% versus 9%, OR 1.40; 95% CI, 0.45-4.04; P = 0.60). CONCLUSION: This is the first report demonstrating that polymorphisms in the autophagy-related FIP200 gene may predict hypertension in patients with mCRC treated with FOLFIRI and bevacizumab. PMID- 28347921 TI - Experimental and DFT dimer modeling studies of the H-bond induced-vibration modes of l-beta-Homoserine. AB - The vibrational spectra for l-beta-Homoserine have been measured (IR absorption: 4000-400cm-1/Raman spectra: 4000-200cm-1). Characteristic vibrational modes of ammonium (-NH3+), carboxylate (-CO2-) and hydroxyl (-OH) groups across the 3700 1400cm-1 are all identified to have originated in inter-molecular hydrogen bonding involving these functional groups. DFT calculations at B3LYP/6-311++G(d, p) level have yielded a single neutral monomer in the gas phase. Since as a member of the amino acids which are known to possess zwitterionic structure in condensed phase, the neutral monomer of l-beta-Homoserine is optimized to a zwitterionic structure in a water medium. Consideration of two dimer structures, one dimer with -NH???O bond and another -OH???O bond, has given rise to vibrational modes that satisfactorily fit to all the observed absorption and Raman bands. It is found that the dimer with -OH???O bond (binding energy, 8.896kcal/mol) is more tightly bound than the dimer with -NH???O bond (8.363kcal/mol). PMID- 28347920 TI - MiR-200b and miR-155 as predictive biomarkers for the efficacy of chemoradiation in locally advanced head and neck squamous cell carcinoma. AB - BACKGROUND: The predictive value of microRNAs (miRNAs) in tumour cells and infiltrating immune cells for the efficacy of chemoradiation (CRTX) in locally advanced head and neck squamous cell carcinoma (HNSCC) was evaluated. METHODS: Formalin-fixed, paraffin-embedded tumour material was collected from patients with locally advanced HNSCC treated within the ARO-0401 phase III trial with radiotherapy in combination with either 5-fluorouracil/cisplatin (CDDP-CRTX) or 5 fluorouracil/mitomycin C (MMC-CRTX). MiRNA and immune profiles were established in a test cohort of 48 oropharyngeal carcinoma (OPSCC) cases by Affymetrix miRNA microarrays and the nanoString PanCancer Immune Panel, respectively. Expression of miRNA candidates was measured in 149 HNSCC patients by real-time PCR. Interference of miRNA profiles with CRTX efficacy was determined by Kaplan-Meier and Cox regression analysis. RESULTS: Expression levels of five miRNAs (miR-27b, 130b, -200b, -451 and -532-5p) were significantly associated with overall survival after MMC-CRTX. Six different miRNAs (miR-125b, -146a, -150, -155, -187 and -342-5p) were correlated with overall survival after CDDP-CRTX. Validation by real-time PCR confirmed the predictive value of miR-200b and miR-155 in OPSCC, which was absent in hypopharyngeal carcinomas. MiR-146a was revealed as a prognostic marker for both CRTX regimens. MiR-200b expression was mainly associated with distant metastasis, whereas miR-155 correlated with local recurrence. MiR-155 and miR-146a were identified as surrogate markers for tumour infiltrating lymphocytes. CONCLUSIONS: MiR-200b and miR-155 were established as potential markers for personalised treatment selection of two standard regimens of CRTX. The predictive role of miR-155 deserves further investigation, especially within the framework of clinical trials of CRTX/immune checkpoint inhibitor combinations. PMID- 28347922 TI - Cooperative effect on phenolic nuO-H frequencies in 1:1 hydrogen bonded complexes of o-fluorophenols with water: A matrix isolation infrared spectroscopic study. AB - Matrix isolation infrared spectra of 1:1 complexes of two ortho-fluorophenols, 2 fluorophenol (2-FPh) and 2,6-difluorophenol (2,6-DFPh), with water and benzene have been analyzed in combination with electronic structure calculations to investigate cooperative effect in O-H...O-H...F hydrogen bonded linkage, which manifests as large spectral shifts of the phenolic O-H stretching fundamental. Calculation predicts that a nearly planar cyclic geometry is preferred by the binary water complexes of the syn conformer of 2-FPh as well as 2,6-DFPh, and the observed spectral shifts are in good agreement with the predicted shifts for such conformers. On the other hand, for other possible isomeric structures, the molecular plane of water moiety is oriented perpendicular to that of the fluorophenols, and the observed as well as predicted shifts are smaller than those of the ortho substituted fluorophenols, although the total binding energies are predicted to be larger for the former. The observed spectral shifts are however consistent with local interaction energy parameters, like hyperconjugative charge transfer and accumulation of electron density (rho) along the O-H...O hydrogen bond path. For the binary O-H...pi hydrogen bonded benzene complexes of the fluorophenols, where cooperative interaction is not possible, the observed shifts are consistent with the conformers preferred according to total binding energies as well as local charge transfer effects of the complexes. PMID- 28347923 TI - Biocompatible 3D SERS substrate for trace detection of amino acids and melamine. AB - A novel, low-cost and biocompatible three-dimensional (3D) substrate for surface enhanced Raman spectroscopy (SERS) is fabricated using gold nanoparticles (AuNPs) loaded on cellulose paper for detection of amino acids and melamine. Dysosma pleiantha rhizome (Dp-Rhi) capped AuNPs (Dp-Rhi_AuNPs) were prepared by in situ using aqueous extract of Dp-Rhi and in situ functionalized Dp-Rhi on AuNPs surface was verified by Fourier transform infrared spectroscopy and zeta potentials analysis shows a negative (-18.4mV) surface charges, which confirm that presence of Dp-Rhi on AuNPs. The biocompatibility of Dp-Rhi_AuNPs is also examined by cell viability of FaDu cells using MTS assay and compared to control group. In conclusion, the SERS performance of AuNPs@cellulose paper substrates were systematically demonstrated and examined with different excitation wavelengths (i.e. 532, 632.8 and 785nm lasers) and the as-prepared 3D substrates provided an enhancement factor approaching 7 orders of magnitude compared with conventional Raman intensity using para-nitrothiophenol (p-NTP), para aminothiophenol (p-ATP) and para-mercaptobenzoic acid (p-MBA) as probe molecules. The strong electromagnetic effect was generated at the interface of AuNPs and pre treated roughened cellulose paper is also investigated by simulation in which the formation of possible Raman hot-spot zone in fiber-like microstructure of cellulose paper decorated with AuNPs. Notably, with optimized condition of as prepared 3D AuNPs@cellulose paper is highly sensitive in the SERS detection of aqueous tyrosine (10-10M) and melamine (10-9M). PMID- 28347924 TI - Cyclic cooperative intramolecular hydrogen bond in p-tert-butylcalix[6]arene according to FTIR spectroscopy and DFT studies. AB - This article describes a comparative research of IR spectra and H-bonds in the p tert-butylcalix[6]arene (TB6) and calix[6]arene (C6). IR spectra were computed for compressed cone conformation by DFT method. The assignment of the bands in the IR spectra of the TB6 and C6 was made. The effect of the bulky tert-butyl substituents on the structure and H-bonding in TB6 was established. Our research has shown that in TB6 and C6 the cyclic H-bond is realized, which ensures the existence of a compressed cone conformation. Introduction of tert-butyl substituents in TB6 leads to hardening of H-bonds. Examination of IR spectra showed that when heated TB6 remains in a compressed cone conformation. In a molecule of TB6 and C6 oxygen atoms are in a "boat" conformation. PMID- 28347925 TI - Life threatening presentation of thoracic duct injury post thyroid surgery; a case report. AB - BACKGROUND: Injury to thoracic duct is a rare potential complication of time honored conventional thyroidectomy. Nevertheless, it can be a cause of significant morbidity, and sometimes life-threatening. PATIENT FINDINGS: A 78 year-old female patient with a previous surgical history of thyroid lobectomy for nodular disease presented with primary hyperparathyroidism, and a nodule in the remaining thyroid lobe. The patient underwent completion thyroidectomy and parathyroidectomy. Less than 24h post operatively, the patient developed progressive shortness of breath and neck swelling requiring immediate intubation and re-exploration. A large amount of chyle was drained and an injured thoracic duct was identified and ligated. SUMMARY: In experienced hands thyroid surgery is safe. Nevertheless, factors such as the type of pathology and its extent, the level of surgery, and re-operative surgery increase the risk of postoperative complications. Immediate surgical exploration is necessary when patients present with neck swelling and respiratory distress. In our case, a high output chyle leak in a confined space was life threatening. CONCLUSION: Timely re-exploration following thyroid surgery and thorough knowledge of the anatomy of neck structures is crucial in sparing patients potential morbidity and/or mortality. PMID- 28347926 TI - Neglected dorsolateral dislocation of the first metatarsophalangeal joint: A case report. AB - INTRODUCTION: Although the first metatarsophalangeal (MTP) joint is frequently injured, Complete dislocation of the first MTP joint represents a relatively rare traumatic injury. PRESENTATION OF CASE: A 46-year-old gentleman presented with a traumatic first MTP joint dislocation resulting from an automobile accident. Due to coronavirus outbreak in the hospital at that time, patient was referred to another hospital. Six months later, reduction was achieved surgically and fixation of the MTP with K-wires was done. DISCUSSION: Only few case reports have described the injury, and the ideal treatment along with the long-term result of the injury has yet to be further studied because reports are rare in this regard. CONCLUSION: Functional range of motion may result even after 6 months of delayed treatment with ORIF and osteopenia may result. PMID- 28347927 TI - A systematic approach towards the development of quality indicators for postnatal care after discharge in Flanders, Belgium. AB - OBJECTIVE: to develop a set of quality indicators for postnatal care after discharge from the hospital, using a systematic approach. DESIGN: key elements of qualitative postnatal care were defined by performing a systematic review and the literature was searched for potential indicators (step 1). The potential indicators were evaluated by five criteria (validity, reliability, sensitivity, feasibility and acceptability) and by making use of the 'Appraisal of Guidelines for Research and Evaluation', the AIRE-instrument (step 2). In a modified Delphi survey, the quality indicators were presented to a panel of experts in the field of postnatal care using an online tool (step 3). The final results led to a Flemish model of postnatal care (step 4). SETTING: Flanders, Belgium PARTICIPANTS: health care professionals, representatives of health care organisations and policy makers with expertise in the field of postnatal care. FINDINGS: after analysis 57 research articles, 10 reviews, one book and eight other documents resulted in 150 potential quality indicators in seven critical care domains. Quality assessment of the indicators resulted in 58 concept quality indicators which were presented to an expert-panel of health care professionals. After two Delphi-rounds, 30 quality indicators (six structure, 17 process, and seven outcome indicators) were found appropriate to monitor and improve the quality of postnatal care after discharge from the hospital. KEY CONCLUSIONS AND IMPLICATIONS FOR CLINICAL PRACTICE: the quality indicators resulted in a Flemish model of qualitative postnatal care that was implemented by health authorities as a minimum standard in the context of shortened length of stay. Postnatal care should be adjusted to a flexible length of stay and start in pregnancy with an individualised care plan that follows mother and new-born throughout pregnancy, childbirth and postnatal period. Criteria for discharge and local protocols about the organisation and content of care are essential to facilitate continuity of care. PMID- 28347928 TI - Maintenance of membrane organization in the aging mouse brain as the determining factor for preventing receptor dysfunction and for improving response to anti Alzheimer treatments. AB - Although a major risk factor for Alzheimer's disease (AD), the "aging" parameter is not systematically considered in preclinical validation of anti-AD drugs. To explore how aging affects neuronal reactivity to anti-AD agents, the ciliary neurotrophic factor (CNTF)-associated pathway was chosen as a model. Comparison of the neuroprotective properties of CNTF in 6- and 18-month old mice revealed that CNTF resistance in the older animals is associated with the exclusion of the CNTF-receptor subunits from rafts and their subsequent dispersion to non-raft cortical membrane domains. This age-dependent membrane remodeling prevented both the formation of active CNTF-receptor complexes and the activation of prosurvival STAT3 and ERK1/2 pathways, demonstrating that age-altered membranes impaired the reactivity of potential therapeutic targets. CNTF-receptor distribution and CNTF signaling responses were improved in older mice receiving dietary docosahexaenoic acid, with CNTF-receptor functionality being similar to those of younger mice, pointing toward dietary intervention as a promising adjuvant strategy to maintain functional neuronal membranes, thus allowing the associated receptors to respond appropriately to anti-AD agents. PMID- 28347930 TI - Monetary cost of family caregiving for people with dementia in Singapore. AB - This study quantified the monetary cost of family caregiving for 51 patients with different severity of dementia. The mean annual informal cost of care was higher (M=SG$44,530.55, SD=SG$31,354.82) compared to the mean annual formal cost of care (M=SG$25,654.11, SD=SG$10,016.48). Costs were found to increase with severity of dementia (Severe: SG$47,251.30; Moderate: SG$38,607.84; Mild: SG$13,847.68). For each point increase in CMMSE scores, the informal cost lowered by SG$1,173.94. There was a significant negative correlation of cost and cognitive impairment but not functional impairment. The informal cost of care did not vary much with or without the use of day care centres, however the costs for those who did not have domestic helpers (DHs) was more than twice the costs for those with DHs. Results from this study show there were cost savings in care of people with dementia with DHs. PMID- 28347929 TI - Cerebral microbleeds and risk of incident dementia: the Framingham Heart Study. AB - Cerebral microbleeds (CMBs) are MRI markers attributed to the most common cerebral angiopathies in the elderly and in patients with dementia: hypertensive and cerebral amyloid angiopathy. CMB detection in asymptomatic persons may help identify those at risk for dementia and may influence preventive strategies and design of clinical trials testing treatments for dementia. We studied the association of CMB with risk of incident dementia in community dwelling individuals. A total of 1296 dementia-free Framingham Heart Study participants (mean age 72 years; 54% women) with available brain MRI and incident dementia data during a mean follow-up period of 6.7 years were included. Using Cox proportional hazards models, we related CMB presence to incident dementia. Multivariable models were adjusted for age, sex, APOE status, and education, with additional models adjusting for vascular risk factors and MRI markers of ischemic brain injury. CMBs were observed in 10.8% and incident dementia in 85 participants (6.6% over study period). Participants with any CMB had 1.74 times higher risk of dementia (hazard ratio [HR] 1.74, 95% confidence interval [CI] 1.00-3.01), whereas those with deep and mixed CMB had a three-fold increased risk (HR 2.99, 95% CI 1.52-5.90). The associations were independent of vascular risk factors, and for deep and mixed CMB also independent of MRI markers of ischemia (HR 2.44, 95% CI 1.22-4.88). Purely lobar CMBs were not associated with incident dementia. Our findings support a role for hypertensive vasculopathy and the interplay of hypertensive and cerebral amyloid angiopathy in risk of dementia and suggest that CMB presence can identify individuals at risk of dementia. PMID- 28347931 TI - Root branching plasticity: collective decision-making results from local and global signalling. AB - Cells within tissues can be regarded as autonomous entities that respond to their local environment and to signals from neighbours. Coordination between cells is particularly important in plants, as the architecture of the plant adapts to environmental cues. To explain the architectural plasticity of the root, we propose to view it as a swarm of coupled multi-cellular structures, rhizomers, rather than a large set of autonomous cells. Each rhizomer contains a primed site with the potential to develop a single lateral root. Rhizomers are spaced through oscillatory genetic events that occur at the basal root tip. The decision whether or not to develop a lateral root primordium results from the interplay between local interactions of the rhizomer with its immediate environment, such as local nutrient availability, long-range interactions between the rhizomers and global cues, such as overall nutrient uptake. It can halt lateral root progression through its developmental stages, resulting in the observed complex root architecture. PMID- 28347932 TI - The impact of child maltreatment on the risk of deliberate self-harm among adolescents: A population-wide cohort study using linked administrative records. AB - Adolescents exposed to maltreatment have an elevated risk of deliberate self-harm (DSH). The aim of this study was to investigate longitudinally the effects of the number, timing, and type of maltreatment allegations on adolescent risk of having a DSH-related hospital admission, using linked data in Western Australia. A total of 351,372 children born between 1986 and 2000 were followed from birth up to the year 2010. Cox regression models were utilized, while controlling for a range of psychosocial covariates. Compared to children without allegations of maltreatment, children with unsubstantiated allegations only (aHR=1.04, 95%CI: 1.00-1.08, p<.01) and children with a substantiated allegation (aHR=1.10, 95%CI: 1.06-1.15, p<.001) all had significantly increased risk of DSH in adolescence. Among children with a substantiated allegation of maltreatment, the greater the number of allegations, the longer the exposure to maltreatment, and the more types of maltreatment experienced by a child, the higher the child's risk of DSH. However, this dose-response pattern was not found among children with unsubstantiated allegations only. This study calls for the early identification of children who are vulnerable to maltreatment, the better identification of the duration and severity of maltreatment experiences, and the provision of continued care and support, to reduce the child's DSH risk in adolescence. PMID- 28347933 TI - Mechanical effects of traction on lumbar intervertebral discs: A magnetic resonance imaging study. AB - BACKGROUND: Although traction has long been used for treating patients with low back pain (LBP), its effects are still inconclusive mainly because of limited high-quality evidence. OBJECTIVE: To provide evidence of the mechanism of traction on lumbar intervertebral discs. DESIGN: A quantitative approach with a repeated measurement protocol. METHOD: Nine participants (mean age = 22.1 +/- 0.8 years) without any LBP history were recruited. Magnetic Resonance Images of the lumbar spine of each participant were recorded before and after 30 min of horizontal lying and directly after 30 min of horizontal traction of 42% body weight. The average, anterior, central, and posterior disc height and tilt angle of each lumbar disc and lumbar lordosis were measured. RESULTS: A significant increase in the average disc height for all lumbar discs, a significant reduction of lumbar lordosis and changes in tilt angle were observed after the application of 30 min of resting followed by 30 min of traction. A significant increase in the average disc height was observed only in lower lumbar discs after 30 min of traction. The increase in the posterior disc height was more apparent than that in the anterior disc height. CONCLUSIONS: Horizontal traction was evidently effective in increasing the disc height of lower lumbar levels, particularly in the posterior regions of the discs. Further evidence of the effects of traction of different modes, magnitudes, and durations on the change in disc height is required for proper control of traction applied to specific disc levels. PMID- 28347934 TI - Kinematic analysis of the shoulder complex after anatomic and reverse total shoulder arthroplasty: A cross-sectional study. AB - BACKGROUND: The movement of the arm relative to the trunk results from coordinated 3D glenohumeral and scapulothoracic movements. Changes in scapula kinematics may occur after total shoulder arthroplasty and could affect clinical and functional outcomes. OBJECTIVES: To assess the 3D movement of the scapula during arm elevation after anatomic and reverse total shoulder arthroplasty. DESIGN/METHODS: This was a single-centre, non-randomized, controlled cross sectional study. Patients with anatomic (n = 14) and reverse total shoulder arthroplasty (n = 9) were prospectively enrolled and were compared to age-matched asymptomatic controls (n = 23). 3D scapular kinematics were assessed by a non invasive, electromagnetic method during arm abduction and flexion. 3D scapular rotations and 3D linear displacements of the barycentre (geometrical centre) at rest and at 30 degrees , 60 degrees and 90 degrees arm elevation; as well as scapulohumeral rhythm were analysed. Participant groups were compared using one way ANOVA and Bonferroni post-hoc testing for normally distributed data, and Mann Whitney U test for non-normally distributed data. RESULTS/FINDINGS: Total range of scapular lateral rotation and barycentre displacement were increased, and scapulohumeral rhythm was reduced, in patients with anatomic and reverse total shoulder arthroplasty compared with age-matched controls; however, the global scapular kinematic pattern was preserved. CONCLUSION/INTERPRETATION: For patients after total shoulder arthroplasty, the increased contribution of the scapula to arm elevation is consistent with a compensatory mechanism for the reduced glenohumeral mobility. The stability of the global scapula kinematic pattern reflects its mechanical and neuromotor strength. PMID- 28347935 TI - Clinical characteristics and outcomes of treatment of the cervical spine in patients with persistent post-concussion symptoms: A retrospective analysis. AB - BACKGROUND: Concussion is typically defined as a mild brain injury, and yet the brain is unlikely to be the only source of persistent post-concussion symptoms. Concurrent injury to the cervical spine in particular is acknowledged as a potential source of common persistent symptoms such as headache, dizziness and neck pain. OBJECTIVES: To describe the cervical spine findings and outcomes of treatment in a series of patients with persistent post-concussion symptoms, and describe the clinical characteristics of a cervicogenic component when it is present. DESIGN: Retrospective chart review of a consecutive series of patients with concussion referred to a physiotherapist for cervical spine assessment. METHOD: Patient charts for all patients over a calendar year referred by a concussion service provider to a physiotherapist for cervical spine assessment were de-identified and transferred to the research team. Clinical data were independently extracted by two research assistants and analysed using descriptive statistics. RESULTS/FINDINGS: Data were analysed from 46 patient charts. Those with a cervicogenic component (n = 32) were distinguished from those without a cervicogenic component (n = 14) by physical examination findings, particularly pain on manual segmental examination. Physiotherapy treatment of the cervicogenic component (n = 21) achieved improvements in function (mean increase of 3.8 in the patient-specific functional scale), and pain (mean decrease of 4.6 in the numeric pain-rating scale). CONCLUSIONS: The clinical characteristics described give preliminary support to the idea that the cervical spine may contribute to persistent post-concussion symptoms, and highlight the value of physiotherapy assessment and treatment of the cervical spine following a concussive injury. PMID- 28347936 TI - Developmental differences in aversive conditioning, extinction, and reinstatement: A study with children, adolescents, and adults. AB - This study investigated developmental differences in aversive conditioning, extinction, and reinstatement (i.e., the recovery of conditioned aversive associations following reexposure to the unconditioned stimulus [US] post extinction). This study examined these mechanisms in children (Mage=8.8years), adolescents (Mage=16.1years), and adults (Mage=32.3years) using differential aversive conditioning with a geometric shape conditional stimulus (CS+) paired with an aversive sound US and another shape (CS-) presented alone. Following an extinction phase in which both CSs were presented alone, half of the participants in each age group received three US exposures (reinstatement condition) and the other half did not (control condition), followed by all participants completing an extinction retest phase on the same day. Findings indicated (a) significant differences in generalizing aversive expectancies to safe stimuli during conditioning and extinction that persisted during retest in children relative to adults and adolescents, (b) significantly less positive CS reevaluations during extinction that persisted during retest in adolescents relative to adults and children, and (c) reinstatement of US expectancies to the CS+ relative to the CS- in all age groups. Results suggest important differences in stimulus safety learning in children and stimulus valence reevaluation in adolescents relative to adults. PMID- 28347937 TI - Direct and indirect admission of ignorance by children. AB - Research has shown that children are able to admit their own ignorance directly (i.e., verbally) by 3years of age when they are totally ignorant about what is hidden in a box (total ignorance task) but fail to do so until 5 or 6years of age when having seen different objects without seeing which of them is being hidden (partial exposure task). This study investigated whether an earlier understanding of own ignorance in the partial exposure task is found when using an indirect measure-when children are allowed to either opt out from a risky decision (Experiment 1) or seek clarifying information by peeking inside (Experiment 2). No evidence for an earlier understanding was found in Experiment 1. In Experiment 2, however, 3- and 4-year-olds searched for clarifying information under partial exposure more often when being ignorant than when being knowledgeable. We argue that this discrepancy is related to whether spontaneous information seeking involves metacognitive processes or not. PMID- 28347938 TI - Varying cognitive targets and response rates to enhance the question-behaviour effect: An 8-arm Randomized Controlled Trial on influenza vaccination uptake. AB - RATIONALE: The question-behaviour effect (QBE) refers to the finding that survey questions about a behaviour can change that behaviour. However, little research has tested how the QBE can be maximized in behavioural medicine settings. The present research tested manipulations of cognitive targets (questions about anticipated regret or beneficence) and survey return rates (presence vs. absence of a sticky note requesting completion of the questionnaire) on the magnitude of the QBE for influenza vaccination in older adults. METHOD: Participants (N = 13,803) were recruited from general practice and randomly allocated to one of eight conditions: control 1 (no questionnaire); control 2 (demographics questionnaire); intention and attitude questionnaire (with or without a sticky note); intention and attitude plus anticipated regret questionnaire (with or without a sticky note); intention and attitude plus beneficence questionnaire (with or without a sticky note). Objective records of subsequent influenza vaccination from general practice records formed the dependent variable. RESULTS: Intention-to-treat analyses indicated that receiving an influenza vaccination questionnaire significantly increased vaccination rates compared to the no questionnaire, OR = 1.17, 95% CI = 1.01, 1.36 and combined control conditions, OR = 1.13, 95% CI = 1.01, 1.25. Including the sticky note significantly increased questionnaire return rates, OR = 1.25, 95% CI = 1.04, 1.50. However, there were no differences in vaccination rates between questionnaires containing different cognitive targets, a sticky note or not, and no interactions. There were no significant differences in the per-protocol analyses, i.e. among respondents who completed and returned the questionnaires. CONCLUSION: The QBE is a simple, low cost intervention to increase influenza vaccination rates. Increasing questionnaire return rates or asking anticipated regret or beneficence questions in addition to intention and attitude questions did not enhance the QBE. PMID- 28347939 TI - The more the heavier? Family size and childhood obesity in the U.S. AB - Childhood obesity remains a top public health concern and understanding its drivers is important for combating this epidemic. Contemporaneous trends in declining family size and increasing childhood obesity in the U.S. suggest that family size may be a potential contributor, but limited evidence exists. Using data from a national sample of children in the U.S. this study examines whether family size, measured by the number of siblings a child has, is associated with child BMI and obesity, and the possible mechanisms at work. The potential endogeneity of family size is addressed by using several complementary approaches including sequentially introducing of a rich set of controls, subgroup analyses, and estimating school fixed-effects and child fixed-effects models. Results suggest that having more siblings is associated with significantly lower BMI and lower likelihood of obesity. Children with siblings have healthier diets and watch less television. Family mealtimes, less eating out, reduced maternal work, and increased adult supervision of children are potential mechanisms through which family size is protective of childhood obesity. PMID- 28347940 TI - Does the media matter to suicide?: Examining the social dynamics surrounding media reporting on suicide in a suicide-prone community. AB - Despite the widespread acknowledgement by public health organizations that media reporting matters to suicide, this link has been much debated and the mechanisms undergirding it poorly understood. With this study, I combine a media analysis with ethnographic data collected during 2014-2016 (N = 91) to examine the social dynamics surrounding media reporting on suicide in a community (that I call Poplar Grove, USA) with an enduring adolescent suicide problem. I illustrate how the media crafted a particular story about why youth die by suicide that emphasized academic pressure over other plausible causes. In so doing, the media may have broadened ideas about when suicide is seen as an option. However, I also provide evidence that cautions against attributing too much causal power to the media. The media coverage in Poplar Grove reflected conditions that were already present in the community; it was already a high-pressure place for youth to live with widespread mental health stigma. These factors likely shaped media reporting, while also contributing independently to the suicide problem. Finally, I found that the suicide deaths that received media coverage were those that triggered significant cognitive dissonance and thus were much discussed among youth, independent of the media reporting. This generated ample opportunities for peer role modeling of suicide. Thus, while the media may have helped solidify a certain view of suicide in the community, it was not the only social force contributing to suicide in Poplar Grove. While the findings from this study do not negate the importance of responsible reporting on suicide, they do contextualize the role of the media in suicide and suggest that researchers must take a broader view of how suicide suggestion operates in the media and in social contexts. PMID- 28347941 TI - The role of metabolic states in development and disease. AB - During development, cells adopt distinct metabolic strategies to support growth, produce energy, and meet the demands of a mature tissue. Some of these metabolic states maintain a constrained program of nutrient utilization, while others providing metabolic flexibility as a means to couple developmental progression with nutrient availability. Here we discuss our understanding of metabolic programs, and how they support specific aspects of animal development. During phases of rapid proliferation a subset of metabolic programs provide the building blocks to support growth. During differentiation, metabolic programs shift to support the unique demands of each tissue. Finally, we discuss how a model system, such as Drosophila egg development, can provide a versatile platform to discover novel mechanisms controlling programmed shift in metabolism. PMID- 28347942 TI - Cross-kingdom comparison of the developmental hourglass. AB - The developmental hourglass model has its foundations in classic anatomical studies by von Baer and Haeckel. In this context, even the conservation of animal body plans has been explained by evolutionary constraints acting on mid embryogenic development. Recent studies have shown that developmental hourglass patterns also exist on the transcriptomic level, mirroring the corresponding morphological patterns. The identification of similar patterns in embryonic, post embryonic, and life cycle spanning transcriptomes in plant and fungus development, however, contradict the notion of a direct coupling between morphological and molecular patterns. To explain the existence of hourglass patterns across kingdoms and developmental processes, we propose the organizational checkpoint model that integrates the developmental hourglass model into a framework of transcriptome switches. PMID- 28347943 TI - The association between sodium fluctuations and mortality in surgical patients requiring intensive care. AB - PURPOSE: Serum sodium derangement is the most common electrolyte disturbance among patients admitted to intensive care. This study aims to validate the association between dysnatremia and serum sodium fluctuation with mortality in surgical intensive care patients. METHOD: We performed a retrospective analysis of the Medical Information Mart for Intensive Care II database. Dysnatremia was defined as a sodium concentration outside physiologic range (135-145mmol/L) and subjects were categorized by severity of dysnatremia and sodium fluctuation. Univariate and multivariable logistic regressions were used to test for associations between sodium fluctuations and mortality. RESULTS: We identified 8600 subjects, 39% of whom were female, with a median age of 66years for analysis. Subjects with dysnatremia were more likely to be dead at 28 days (17% vs 7%; P<.001). There was a significant association between sodium fluctuation and mortality at 28 days (adjusted odds ratio per 1mmol/L change, 1.10 [95% confidence interval, 1.08-1.12; P<.001]), even in patients who remained normotremic during their intensive care unit stay (1.12 [95% confidence interval, 1.09-1.16; P<.001]) CONCLUSIONS: This observational study validates previous findings of an association between serum sodium fluctuations and mortality in surgical intensive care patients. This association was also present in subjects who remained normonatremic throughout their intensive care unit admission. PMID- 28347944 TI - Regulating the gaps between folds on the surface of silk fibroin membranes via LBL deposition for improving their biomedical properties. AB - Silk fibroin (SF) has become a promising biomaterial in guided bone regeneration (GBR). In an attempt to modify the size of the gaps on the surface of SF barrier membrane and improve its antibacterial activity, biological and mechanical properties, positively charged Lysozyme (LY)-Collagen Type-I (COL) composites and negatively charged SF were introduced to the negatively charged surface of SF substrates utilizing the electrostatic layer-by-layer (LBL) self-assembly technique. The morphology, chemical structures and element content of the LBL structured membranes were investigated. The results suggested that LY and COL were successfully assembled and the gaps between the folds on the surface of the membranes became smaller gradually with the increase of coated film numbers. Besides, the content of beta-sheets of the membranes increased after deposition, which indicated the improvement of their mechanical properties. Moreover, the results of the measurement of immobilized LY and antibacterial assay not only revealed that the enzymatic catalysis and antibacterial activity of the samples enhanced with the increase of coated bilayer numbers but also implied that LBL modified membranes had better antibacterial activity when LY-COL was on the outermost layer. Furthermore, CCK-8 assay certified both SF membrane and LBL structured membranes could facilitate cell growth and proliferation, and the introduction of COL could further promote this ability. Finally, cell attachment and morphology examination provided intuitional evidence that SF membrane and LBL modified membranes have excellent biocompatibility. PMID- 28347945 TI - Structural effect of Fe3O4 nanoparticles on peroxidase-like activity for cancer therapy. AB - Ferromagnetic nanoparticles (Fe3O4 NPs) have been proven to have the intrinsic peroxidase-like activity. This property has been used for analyte detection, tumor tissue visualization, and cancer therapy, etc. However, the effect of particle structure and morphology on its peroxidase-like activity has been rarely reported. In this work, we fabricated Fe3O4 nanoparticles with different structures (nanoclusters, nanoflowers, and nanodiamonds) by facilely tuning the pH values in the hydrothermal reaction. Their in vitro peroxidase-like activity was evaluated via chromogenic reaction of 3,3',5,5'-tetramethylbenzidine (TMB) by the reduction of H2O2 to H2O. It was found the nanostructures had a great influence on their peroxidase-like activity, following the order of nanoclusters>nanoflowers>nanodiamonds. With this activity, the peroxidase-like activity of Fe3O4 NPs was used for cancer therapy with the addition of low concentration H2O2. The cancer cell-killing activity was due to the intracellular generated reactive oxygen species (ROS) after endocytosis of Fe3O4 NPs into the Hela cells. It was interesting that the cell killing ability of these three kinds of Fe3O4 NPs was not consistent with the in vitro enzyme-like activity. It was deduced that the cell endocytosis of the nanoparticles along with their enzyme like activity co-determined their cancer cell-killing performance. PMID- 28347946 TI - A two-component micelle with emergent pH responsiveness by mixing dilauroyl phosphocholine and deoxycholic acid and its delivery of proteins into the cytosol. AB - Providing appropriate pH responsiveness for drug delivery nanoparticles is one of the major issues in developing a new generation of delivery systems. This paper reports that, when phosphocholine and a bile acid were mixed, the resultant two component micelle gained pH responsiveness, while the individual components did not show any such responsiveness. The pH responsiveness was shown to be determined by the chemical structure, especially the positions and chirality of the OH groups, of the bile acid, and the sensitivity was determined by the alkyl chain length of the phosphocholine. The best combination for evading endocytosis was dilauroyl phosphocholine (DLPC) and deoxycholic acid (DA). Small-angle X-ray scattering revealed that the pH responsiveness was related to the change of surface hydrophobicity, namely, decreasing pH led to protonation of the carboxylic acid, resulting in aggregation of the preceding micelles. We assume that particles that become hydrophobic in this way can start interacting with the endocytotic bilayer, which eventually leads to rupture of the endocytotic vesicle. This mechanism is well supported by the finding that fluorescein conjugated ovalbumin proteins were transported into the cytosol when they were co administered with DLPC/DA. PMID- 28347947 TI - Thermosensitive hydrogel loaded with chitosan-carbon nanotubes for near infrared light triggered drug delivery. AB - Controlled drug release with on demand is an important challenge for drug delivery. Near-infrared (NIR) light triggered drug delivery reflected the development of a significant strategy to control drug release based on photothermal effects. Herein, a sustained and controlled drug delivery system was developed based on a PCL-PEG-PCL thermosensitive hydrogel combined with chitosan multiwalled carbon nanotubes for a near infrared light triggered drug delivery. Carbon nanotubes that incorporate hydrogel can enhance the sustained effect of drug delivery by a dual-stage release and allow drug delivery by controlling light irradiation. This in situ photothermal process was monitored by thermal imaging and the controlled drug delivery of doxorubicin was tracked in real-time by fluorescence imaging in vivo based on the fluorescence ability of the drug using nude mice as models. The results suggest that the photothermal effect of the carbon nanotubes can disrupt the structure of the hydrogel with a gel-sol transition, triggering the release of the drug from the sustained drug delivery system by NIR irradiation while responding on demand. The sustained and controlled drug delivery has the potential to implement the accurate administration of hydrogel-based drug delivery systems. PMID- 28347948 TI - Laser microfabrication of a microheater chip for cell culture outside a cell incubator. AB - Microfluidic chips have demonstrated their significant application potentials in microbiological processing and chemical reactions, with the goal of developing monolithic and compact chip-sized multifunctional systems. Heat generation and thermal control are critical in some of the biochemical processes. The paper presents a laser direct-write technique for rapid prototyping and manufacturing of microheater chips and its applicability for lab-on-a-chip cell culture outside a cell incubator. The aim of the microheater is to take the role of conventional incubators for cell culture for facilitating microscopic observation and/or other online monitoring activities during cell culture and provides portability of cell culture operation. Microheaters (5mm*5mm) have been successfully fabricated on soda-lime glass substrates covered with aluminium layer of thickness 120nm. Experimental results show that the microheaters exhibit good performance in temperature rise and decay characteristics, with localized heating at targeted spatial domains. These microheaters were suitable for a maximum long-term operation temperature of 120 degrees C and validated for operation at 37 degrees C for 48h. Results demonstrated that the microheaters are suitable for the culture of immortalised cell lines. The growth and viability of SW480 colon adenocarcinoma cells cultured the developed microheater chip were comparable to the results obtained in a conventional cell incubator. PMID- 28347949 TI - Perinatal and postnatal risk factors for disruptive mood dysregulation disorder at age 11: 2004 Pelotas Birth Cohort Study. AB - BACKGROUND: To date, there have been few studies of DMDD examining the risk factors during gestation and during the first years of life. We assessed the perinatal and postnatal risk factors associated with the occurrence of disruptive mood dysregulation disorder (DMDD) by 11 years of age. METHODS: Prospective longitudinal study. Mothers completed a standardized questionnaire shortly after childbirth. We used the Development and Well-Being Assessment, administered to the mothers or legal guardians, to identify DMDD among the 11-year-old subjects. We also employed logistic regression to perform bivariate and multivariate analyses, using a theoretical model of conceptual analysis. RESULTS: We evaluated data related to 3563 subjects at 11 years of age. The prevalence of DMDD was 2.5% (95% CI=2.0-3.0). After adjusting for potential confounders, we found that the early risk factors for the development of DMDD by 11 years of age were maternal mood symptoms during pregnancy, maternal depression during the first years after childbirth, and low maternal level of education. LIMITATIONS: We were unable to evaluate the genetic characteristics of the family at the birth of each subject, and there were no data available regarding the prenatal or postnatal mental health of the fathers. CONCLUSIONS: The prevalence of DMDD in early adolescence is low and its risk factors are related to potentially modifiable maternal characteristics. Scientific evidence indicates that DMDD is a major predictor of other psychiatric disorders, especially depression and anxiety. Effective prenatal and postnatal mental health care could prevent mental disorders in offspring. PMID- 28347950 TI - A mechanistic model for anaerobic phototrophs in domestic wastewater applications: Photo-anaerobic model (PAnM). AB - Purple phototrophic bacteria (PPB) have been recently proposed as a key potential mechanism for accumulative biotechnologies for wastewater treatment with total nutrient recovery, low greenhouse gas emissions, and a neutral to positive energy balance. Purple phototrophic bacteria have a complex metabolism which can be regulated for process control and optimization. Since microbial processes governing PPB metabolism differ from traditional processes used for wastewater treatment (e.g., aerobic and anaerobic functional groups in ASM and ADM1), a model basis has to be developed to be used as a framework for further detailed modelling under specific situations. This work presents a mixed population phototrophic model for domestic wastewater treatment in anaerobic conditions. The model includes photoheterotrophy, which is divided into acetate consumption and other organics consumption, chemoheterotrophy (including simplified fermentation and anaerobic oxidation) and photoautotrophy (using hydrogen as an electron donor), as microbial processes, as well as hydrolysis and biomass decay as biochemical processes, and is single-biomass based. The main processes have been evaluated through targeted batch experiments, and the key kinetic and stoichiometric parameters have been determined. The process was assessed by analyzing a continuous reactor simulation scenario within a long-term wastewater treatment system in a photo-anaerobic membrane bioreactor. PMID- 28347951 TI - Comment on "Thermodynamically enhancing propionic acid degradation by using sulfate as an external electron acceptor in a thermophilic anaerobic membrane reactor" by Qiao, W., Takayanagi, K., Li, Q., Shofie, M., Gao, F., Dong, R., Li, Y-Y. Water Res. (2016). PMID- 28347952 TI - Anaerobic biodegradation of (emerging) organic contaminants in the aquatic environment. AB - Although strictly anaerobic conditions prevail in several environmental compartments, up to now, biodegradation studies with emerging organic contaminants (EOCs), such as pharmaceuticals and personal care products, have mainly focused on aerobic conditions. One of the reasons probably is the assumption that the aerobic degradation is more energetically favorable than degradation under strictly anaerobic conditions. Certain aerobically recalcitrant contaminants, however, are biodegraded under strictly anaerobic conditions and little is known about the organisms and enzymatic processes involved in their degradation. This review provides a comprehensive survey of characteristic anaerobic biotransformation reactions for a variety of well-studied, structurally rather simple contaminants (SMOCs) bearing one or a few different functional groups/structural moieties. Furthermore it summarizes anaerobic degradation studies of more complex contaminants with several functional groups (CMCs), in soil, sediment and wastewater treatment. While strictly anaerobic conditions are able to promote the transformation of several aerobically persistent contaminants, the variety of observed reactions is limited, with reductive dehalogenations and the cleavage of ether bonds being the most prevalent. Thus, it becomes clear that the transferability of degradation mechanisms deduced from culture studies of SMOCs to predict the degradation of CMCs, such as EOCs, in environmental matrices is hampered due the more complex chemical structure bearing different functional groups, different environmental conditions (e.g. matrix, redox, pH), the microbial community (e.g. adaptation, competition) and the low concentrations typical for EOCs. PMID- 28347953 TI - Maximum specific growth rate of anammox bacteria revisited. AB - Anammox bacteria have long been considered to be slow-growing bacteria. However, it has recently been reported that they could grow much faster than previously thought when they were cultivated in a membrane bioreactor (MBR) with a step-wise decrease in the solid retention time (SRT). Here, we reevaluated the maximum specific growth rates (MUmax) of three phylogenetically distant anammox bacterial species (i.e. "Ca. Brocadia sinica", "Ca. Jettenia caeni" and "Ca. Scalindua sp.") by directly measuring 16S rRNA gene copy numbers using newly developed quantitative polymerase chain reaction (qPCR) assays. When free-living planktonic "Ca. B. sinica" and "Ca. J. caeni" cells were immobilized in polyvinyl alcohol (PVA) and sodium alginate (SA) gel beads and cultivated in an up-flow column reactor with high substrate loading rates at 37 degrees C, the MUmax were determined to be 0.33 +/- 0.02 d-1 and 0.18 d-1 (corresponding doubling time of 2.1 day and 3.9 day) from the exponential increases in 16S rRNA genes copy numbers, respectively. These values were faster than the fastest growth rates reported for these species so far. The cultivation of anammox bacteria in gel beads was achieved less than one month without special cultivation method and selection pressure, and the exponential increase in 16S rRNA gene numbers was directly measured by qPCR with high reproducibility; therefore, the resulting MUmax values were considered accurate. Taken together, the fast growth is, therefore, considered to be an intrinsic kinetic property of anammox bacteria. PMID- 28347954 TI - Interaction of IRF9 and STAT2 synergistically up-regulates IFN and PKR transcription in Ctenopharyngodon idella. AB - IRF9 is a key factor in the JAK-STAT pathway. Under the stimulation of type I IFN, IRF9 interacts with STAT1 and STAT2 to form the IFN-I-stimulated gene factor 3 (ISGF3) which activates the transcription of ISG. However, many studies also showed that the dimmer IRF9/STAT2 rather than the tripolymer IRF9/STAT1/STAT2 acts as the ISGF3 in cells in response to IFN signals. In the present study, the full-length cDNA sequence of IRF9 (termed CiIRF9, KT601055) and STAT2 (term CiSTAT2, KT781914) from grass carp were cloned and identified. A low level of constitutive expression of CiIRF9 was detected by RT-PCR in grass carp tissues, but it was significantly up-regulated by LPS and poly I:C stimulation. In vitro, a high-affinity interaction between CiIRF9 and the promoter of CiIFN or CiPKR was demonstrated by gel mobility shift assay. In vivo, the promoter activities of CiIFN and CiPKR were not only increased by transient transfection of CiIRF9, but also prominently increased by co-transfection of CiIRF9 and CiSTAT2. Moreover, the interaction of CiIRF9 and CiSTAT2 was further investigated by in vivo and in vitro protein interaction assays. Recombinant CiIRF9 and CiSTAT2, both tagged with FLAG (or HA), were expressed in HEK 293T cells by transient transfection experiment. Co-immunoprecipitation assays showed that CiIRF9 can interact with CiSTAT2 in vivo. Soluble GST-ST2-936 (containing the N-terminal and coiled-coil domain of CiSTAT2) was expressed and purified from E. coli. A GST pull-down assay suggested that GST-tagged ST2-936 efficiently bound to FLAG-tagged IRF9. The data indicated that interaction of IRF9 and STAT2 synergistically up-regulated the transcriptional level of IFN and ISG genes. PMID- 28347955 TI - A comparison of the material properties of natural and synthetic vascular walls. AB - Characterization of the mechanical properties of native and synthetic vascular grafts is an essential task in the process of designing novel vascular constructs. The aim in this study was to compare the mechanical behavior of ovine left Subclavian artery with that of POSS-PCU (a commercial biomaterial which is currently under clinical investigation. ClinicalTrials.gov Identifier: NCT02301312). We used Delfino's strain energy potential within the framework of quasilinear viscoelasticity theory to capture the viscoelastic response of the considered materials. The material parameters of the quasilinear viscoelastic constitutive equation were determined through a combination of experimental and computational method. First, a uniaxial tensile testing device was used to perform a series of stress relaxation tests on ring samples. Then, the derived quasilinear viscoelastic models were implemented into finite element system. With the aid of mechanical experimentation and finite element simulation, the material parameters were obtained, modified and used for comparison of the mechanical properties of vascular walls. The results showed that the stiffness and the long term viscoelastic parameters of POSS-PCU may lead to different stress responses of the vascular walls. These two factors can be improved by modifications in manufacturing parameters of the synthetic vessel. PMID- 28347956 TI - A foam model highlights the differences of the macro- and microrheology of respiratory horse mucus. AB - Native horse mucus is characterized with micro- and macrorheology and compared to hydroxyethylcellulose (HEC) gel as a model. Both systems show comparable viscoelastic properties on the microscale and for the HEC the macrorheology is in good agreement with the microrheology. For the mucus, the viscoelastic moduli on the macroscale are several orders of magnitude larger than on the microscale. Large amplitude oscillatory shear experiments show that the mucus responds nonlinearly at much smaller deformations than HEC. This behavior fosters the assumption that the mucus has a foam like structure on the microscale compared to the typical mesh like structure of the HEC, a model that is supported by cryogenic-scanning-electron-microscopy (CSEM) images. These images allow also to determine the relative amount of volume that is occupied by the pores and the scaffold. Consequently, we can estimate the elastic modulus of the scaffold. We conclude that this particular foam like microstructure should be considered as a key factor for the transport of particulate matter which plays a central role in mucus function with respect to particle penetration. PMID- 28347957 TI - Ventriculoatrial versus ventriculoperitoneal shunt complications in idiopathic normal pressure hydrocephalus. AB - BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a devastating condition that affects the elderly population. Although ventriculoatrial (VA) shunts can be used to manage iNPH, concerns for associated cardiopulmonary and renal complications have decreased their use. However, the rate of these complications is not well understood within this population of patients. PATIENTS AND METHODS: A retrospective review of the electronic medical records of patients diagnosed with iNPH by the senior author between 1993 and 2015 was performed. Demographic information and baseline symptoms were assessed. Complications including infection, shunt obstruction, overdrainage, cardiopulmonary events, renal dysfunction, and shunt revision were recorded. Complication rates were compared between VA and VP shunted patients. Statistical analysis using Chi square test, Fisher's exact test, logistic regression, Wald t-test, Poisson regression, ANOVA, and ANCOVA was performed. RESULTS: 496 Patients, including 150 receiving VA shunts and 346 receiving VP shunts, were included in the study. The median age was 74 and 73 for VA and VP shunted patients, respectively, with slight male predominance in both (58.0% and 58.4% for VA and VP groups, respectively). A total of 36.0% of VA shunted patients and 42.5% of VP shunted patients experienced at least one post-operative complication. Overdrainage was the most commonly experienced complication in both VA (27.4%) and VP patients (19.9%). Infection occurred in only 2.0% of patients, and renal complications occurred in 1.3%. No patients had cardiopulmonary complications. VA shunted patients were significantly less likely to experience shunt obstruction and require shunt revision compared to VP shunted patients (p=0.008 and <0.001, respectively). Only dizziness and gait disturbance at baseline were correlated with a shorter time to revision in VA shunted patients (p=0.002 for both). CONCLUSION: Although cardiopulmonary and renal complications are serious concerns associated with VA shunt placement, they were uncommon in patients with iNPH. VA shunted patients were less likely to experience shunt obstruction and require shunt revision compared to VP shunted patients. Therefore, VA shunts should be considered as an alternative primary treatment option in the iNPH population. PMID- 28347958 TI - Green synthesis of Ag nanoparticles using Tamarind fruit extract for the antibacterial studies. AB - In the present study, first time we report the microwave-assisted green synthesis of silver nanoparticles (AgNPs) using Tamarindus indica natural fruit extract. The plant extract plays a dual role of reducing and capping agent for the synthesis of AgNPs. The formation of spherical shape AgNPs is confirmed by XRD, HR-SEM, and HR-TEM. The presence of face-centered cubic (FCC) silver is confirmed by XRD studies and the average crystallite size of AgNPs is calculated to be around 6-8nm. The average particle diameter is found to be around 10nm, which is identified from HR-TEM images. The purity of AgNPs is confirmed by EDX analysis. The presence of sigmoid curve in UV-Visible absorption spectra suggests that the reaction has complicated kinetic features. To investigate the functional groups of the extract and their involvement in the reduction of AgNO3 to form AgNPs, FT IR studies are carried out. The redox peaks are observed in cyclic voltammetry in the potential range of -1.2 to +1.2V, due to the redox active components of the T. indica fruit extract. In photoluminescence spectroscopy, the excited and emission peaks were obtained at 432nm and 487nm, respectively. The as-prepared AgNPs showed good results towards antibacterial activities. Hence, the present approach is a facile, cost- effective, reproducible, eco-friendly, and green method. PMID- 28347959 TI - The impact of succinate trace on pWW0 and ortho-cleavage pathway transcription in Pseudomonas putida mt-2 during toluene biodegradation. AB - Toluene is a pollutant catabolised through the interconnected pWW0 (TOL) and ortho-cleavage pathways of Pseudomonas putida mt-2, while upon succinate and toluene mixtures introduction in batch cultures grown on M9 medium, succinate was previously reported as non-repressing. The effect of a 40 times lower succinate concentration, as compared to literature values, was explored through systematic real-time qPCR monitoring of transcriptional kinetics of the key TOL Pu, Pm and ortho-cleavage PbenR, PbenA promoters in mixed-substrate experiments. Even succinate trace inhibited transcription leading to bi-modal promoters expression. Potential carbon catabolite repression mechanisms and novel expression patterns of promoters were unfolded. Lag phase was shortened and biomass growth levels increased compared to sole toluene biodegradation suggesting enhanced pollutant removal efficiency. The study stressed the noticeable effect of a preferred compound's left-over on the main route of a bioprocess, revealing the beneficiary supply of low preferred substrates concentrations to design optimal bioremediation strategies. PMID- 28347960 TI - Pretreatment of eucalyptus with recycled ionic liquids for low-cost biorefinery. AB - It is urgent to develop recycled ionic liquids (ILs) as green solvents for sustainable biomass pretreatment. The goal of this study is to explore the availability and performance of reusing 1-allyl-3-methylimidazolium chloride ([amim]Cl) and 1-butyl-3-methylimidazolium acetate ([bmim]OAc) for pretreatment, structural evolution, and enzymatic hydrolysis of eucalyptus. Cellulose enzymatic digestibility slightly decreased with the increased number of pretreatment recycles. The hydrolysis efficiencies of eucalyptus pretreated via 4th recycled ILs were 54.3% for [amim]Cl and 72.8% for [bmim]OAc, which were 5.0 and 6.7-folds higher than that of untreated eucalyptus. Deteriorations of ILs were observed by the relatively lower sugar conversion and lignin removal from eucalyptus after 4th reuse. No appreciable changes in fundamental framework and thermal stability of [amim]Cl were observed even after successive pretreatments, whereas the anionic structure of [bmim]OAc was destroyed or replaced. This study suggested that the biomass pretreatment with recycled ILs was a potential alternative for low-cost biorefinery. PMID- 28347961 TI - A self-sustaining high-strength wastewater treatment system using solar-bio hybrid power generation. AB - This study focuses on system analysis of a self-sustaining high-strength wastewater treatment concept combining solar technologies, anaerobic digestion, and aerobic treatment to reclaim water. A solar bio-hybrid power generation unit was adopted to power the wastewater treatment. Concentrated solar power (CSP) and photovoltaics (PV) were combined with biogas energy from anaerobic digestion. Biogas is also used to store the extra energy generated by the hybrid power unit and ensure stable and continuous wastewater treatment. It was determined from the energy balance analysis that the PV-bio hybrid power unit is the preferred energy unit to realize the self-sustaining high-strength wastewater treatment. With short-term solar energy storage, the PV-bio-hybrid power unit in Phoenix, AZ requires solar collection area (4032m2) and biogas storage (35m3), while the same unit in Lansing, MI needs bigger solar collection area and biogas storage (5821m2 and 105m3, respectively) due to the cold climate. PMID- 28347962 TI - Effective depolymerization of concentrated acid hydrolysis lignin using a carbon supported ruthenium catalyst in ethanol/formic acid media. AB - Lignin isolated by two-step concentrated acid hydrolysis of empty fruit bunch (EFB) was effectively depolymerized into a high-quality bio-oil using formic acid (FA) as an in-situ hydrogen source and Ru/C as a catalyst in supercritical ethanol. A bio-oil yield of 66.3wt% with an average molecular weight of 822g/mol and an aromatic monomer content of 6.1wt% was achieved at 350 degrees C and a FA to-lignin mass ratio of 3 after a reaction time of 60min. The combination of Ru/C and FA also resulted in a significant reduction in the oxygen content of the bio oil by ~60% and a corresponding increase in the higher heating value (HHV) to 32.7MJ/kg due to the enhanced hydrodeoxygenation activity. An examination of the FA decomposition characteristics revealed that Ru/C provides a greater increase in the rate of hydrogen production from FA, explaining the efficient depolymerization of lignin in a combined system. PMID- 28347963 TI - Comparison of batch cultivation strategies for cost-effective biomass production of Micractinium inermum NLP-F014 using a blended wastewater medium. AB - Two competitive strategies, fed-batch and sequencing-batch cultivation, were compared in cost-effective biomass production of a high lipid microalgae, Micractinium inermum NLP-F014 using a blended wastewater medium. For fed-batch cultivations, additional nutrient was supplemented at day 2 (FB1) or consecutively added at day 2 and 4 (FB2). Through inoculum size test, 1.0g-DCWL-1 was selected for the sequencing-batch cultivation (SB) where about 65% of culture was replaced with fresh medium every 2days. Both fed-batch cultivations showed the maximum biomass productivity of 0.95g-DCWL-1d-1, while average biomass productivity in SB was slightly higher as 0.96+/-0.08g-DCWL-1d-1. Furthermore, remained concentrations of organics (426mg-CODL-1), total nitrogen (15.4mg-NL-1) and phosphorus (0.6mg-PL-1) in SB were much lower than those of fed-batch conditions. The results suggested that SB could be a promising strategy to cultivate M. inermum NLP-F014 with the blended wastewater medium. PMID- 28347964 TI - Effects of shearing on biogas production and microbial community structure during anaerobic digestion with recuperative thickening. AB - Recuperative thickening can intensify anaerobic digestion to produce more biogas and potentially reduce biosolids odour. This study elucidates the effects of sludge shearing during the thickening process on the microbial community structure and its effect on biogas production. Medium shearing resulted in approximately 15% increase in biogas production. By contrast, excessive or high shearing led to a marked decrease in biogas production, possibly due to sludge disintegration and cell lysis. Microbial analysis using 16S rRNA gene amplicon sequencing showed that medium shearing increased the evenness and diversity of the microbial community in the anaerobic digester, which is consistent with the observed improved biogas production. By contrast, microbial diversity decreased under either excessive shearing or high shearing condition. In good agreement with the observed decrease in biogas production, the abundance of Bacteroidales and Syntrophobaterales (which are responsible for hydrolysis and acetogenesis) decreased due to high shearing during recuperative thickening. PMID- 28347965 TI - Transport, fate, and long-term impacts of metal oxide nanoparticles on the stability of an anaerobic methanogenic system with anaerobic granular sludge. AB - The fate and long-term effect of different metal oxide (TiO2, CuO and ZnO) nanoparticles (NPs) on anaerobic granular sludge (AGS) was evaluated in an anaerobic methanogenic system. Operation stability and structural characteristics of the granules were compared, the metabolism changes in the microbial community were quantified, and NPs fate were investigated. CuO NPs had greatest toxic effect on AGS after extended exposure, whereas ZnO NPs benefited methanogenesis temporarily (no more than 5d). The inhibition on AGS caused by NPs varied due to the unique structure of AGS and different toxic mechanism. Structural changes of AGS provided new evidence that tested NPs have different toxicity. PMID- 28347966 TI - A novel aptasensor for lysozyme based on electrogenerated chemiluminescence resonance energy transfer between luminol and silicon quantum dots. AB - In the present work, electrogenerated chemiluminescence (ECL) of luminol was investigated in neutral condition at a gold electrode in the presence of silicon quantum dots (SiQDs). The results revealed that SiQDs can not only greatly enhance luminol ECL, but also act as energy acceptor to construct a novel ECL resonance energy transfer (ECL-RET) system with luminol. As a result, strong anodic ECL signal was obtained in neutral condition at the bare gold electrode, which is suitable for biosensing application. Lysozyme exhibited apparent inhibiting effect on the ECL-RET system, based on which an ECL aptasensor was fabricated for the sensitive detection of lysozyme. The proposed method showed high sensitivity, good selectivity, and wide linearity for the detection of lysozyme in the range of 5.0*10-14-5.0*10-9gmL-1 with a detection limit of 5.8*10 15gmL-1 (3sigma). The results suggested that as-proposed luminol/SiQDs ECL biosensor will be promising in the detection enzyme. PMID- 28347967 TI - A two-photon NIR-to-NIR fluorescent probe for imaging hydrogen peroxide in living cells. AB - Hydrogen peroxide (H2O2), one of the reactive oxygen species (ROS), plays vital roles in diverse physiological processes. Imbalance of the H2O2 is concerned with serious diseases such as cardiovascular disorders, neurodegenerative diseases, Alzheimer's disease and cancer. Therefore, it is critical to develop efficient methods for monitoring H2O2 in vivo. In this work, a two-photon excitation (860nm) NIR fluorescent turn-on probe TPNR-H2O2 for H2O2 based on Dicyanomethylene-4H-pyran fluorophore is reported, which can be used in solution detection with 13.2-fold NIR fluorescence enhancement, fast response (completed within 40min), excellent sensitivity (DL 72.48nM), and lower cellular auto fluorescence interference. Importantly, the perfect photostability of TPNR-H2O2 clearly demonstrated that the probe could be applied to imaging intracellular H2O2 for a long time without photobleaching. In addition, through two-photon imaging, this probe was cell permeable and used to monitor the level of endogenous and exogenous H2O2 with promising biological application. PMID- 28347968 TI - Assessing wildfire exposure in the Wildland-Urban Interface area of the mountains of central Argentina. AB - Wildfires are a major threat to people and property in Wildland Urban Interface (WUI) communities worldwide, but while the patterns of the WUI in North America, Europe and Oceania have been studied before, this is not the case in Latin America. Our goals were to a) map WUI areas in central Argentina, and b) assess wildfire exposure for WUI communities in relation to historic fires, with special emphasis on large fires and estimated burn probability based on an empirical model. We mapped the WUI in the mountains of central Argentina (810,000 ha), after digitizing the location of 276,700 buildings and deriving vegetation maps from satellite imagery. The areas where houses and wildland vegetation intermingle were classified as Intermix WUI (housing density > 6.17 hu/km2 and wildland vegetation cover > 50%), and the areas where wildland vegetation abuts settlements were classified as Interface WUI (housing density > 6.17 hu/km2, wildland vegetation cover < 50%, but within 600 m of a vegetated patch larger than 5 km2). We generated burn probability maps based on historical fire data from 1999 to 2011; as well as from an empirical model of fire frequency. WUI areas occupied 15% of our study area and contained 144,000 buildings (52%). Most WUI area was Intermix WUI, but most WUI buildings were in the Interface WUI. Our findings suggest that central Argentina has a WUI fire problem. WUI areas included most of the buildings exposed to wildfires and most of the buildings located in areas of higher burn probability. Our findings can help focus fire management activities in areas of higher risk, and ultimately provide support for landscape management and planning aimed at reducing wildfire risk in WUI communities. PMID- 28347969 TI - Effectiveness of management interventions on forest carbon stock in planted forests in Nepal. AB - Nepal has successfully established more than 370,000 ha of plantations, mostly with Pinus patula, in the last three and a half decades. However, intensive management of these planted forests is very limited. Despite the fact that the Kyoto Convention in 1997 recognized the role of plantations for forest-carbon sequestration, there is still limited knowledge on the effects of management practices and stand density on carbon-sequestration of popular plantation species (i.e. Pinus patula) in Nepal. We carried out case studies in four community forests planted between 1976 and 1990 to assess the impacts of management on forest carbon stocks. The study found that the average carbon stock in the pine plantations was 217 Mg C ha-1, and was lower in forests with intensively managed plantations (214.3 Mg C ha-1) than in traditionally managed plantations (219 Mg C ha-1). However, it was the reverse in case of soil carbon, which was higher (78.65 Mg C ha-1) in the forests with intensive management. Though stand density was positively correlated with carbon stock, the proportionate increment in carbon stock was lower with increasing stand density, as carbon stock increased by less than 25% with a doubling of stand density (300-600). The total carbon stock was higher in plantations aged between 25 and 30 years compared to those aged between 30 and 35 years. PMID- 28347970 TI - Sulfate removal from wastewater using ettringite precipitation: Magnesium ion inhibition and process optimization. AB - One of the main challenges in industrial wastewater treatment and recovery is the removal of sulfate, which usually coexists with Ca2+ and Mg2+. The effect of Mg2+ on sulfate removal by ettringite precipitation was investigated, and the process was optimized in the absence and presence of Mg2+. In the absence of Mg2+, the optimum conditions with sulfate removal of 99.7% were obtained at calcium-to sulfate ratio of 3.20, aluminum-to-sulfate ratio of 1.25 and pH of 11.3 using response surface methodology. In the presence of Mg2+, sulfate removal efficiency decreased with increasing Mg2+ concentration, and the inhibitory effect of Mg2+ matched the competitive inhibition Monod model with half maximum inhibition concentration of 57.4 mmol/L. X-ray diffraction and Fourier transform infrared spectroscopy analyses of precipitates revealed that ettringite was converted to hydrotalcite-type (HT) compound in the presence of Mg2+. The morphology of precipitates was transformed from prismatic crystals to stacked layered crystals, which confirmed that Mg2+ competes with Ca2+ for Al3+ to form HT compound. A two stage process was designed with Mg2+ removal before ettringite precipitation to eliminate the inhibitory effect, and is potential to realize sludge recovery at the same time of effective removal of sulfate and hardness. PMID- 28347971 TI - Projected impacts of urbanisation on hydrological resource flows: A case study within the uMngeni Catchment, South Africa. AB - Significant land use changes from natural/agricultural to urban land uses have been proposed within the Mpushini/Mkhondeni sub-catchments of the uMngeni Catchment in South Africa. A better understanding of the influences which such land use changes are likely to have on hydrological flows, is required, in order to make informed land use decisions for a sustainable future. As a point of departure, an overview of linkages between urbanisation and hydrological flow responses within this sub-humid study area is given. The urban characteristics of increased impervious areas and the potential return flows from transfers of potable water from outside the catchment were identified as being important in regard to hydrological flow responses. A methodology was developed to model urban response scenarios with urban characteristics as variables, using the daily time step process based ACRU model. This is a hydrological multi-process model and not an urban hydraulic model and it addresses the landscape as well as the channel components of a catchment, and in addition to runoff components includes evaporation and transpiration losses as outputs. For the study area strong links between proposed urbanisation and hydrological resource flow responses were found, with increases in stormflows, together with increased and more regulated baseflows, and with impacts varying markedly between dry or wet years and by season. The impacts will depend on the fractions of impervious areas, whether or not these are connected to permeable areas, the amount of imported water and water system leaks. Furthermore, the urban hydrological impacts were found to be relatively greater in more arid than humid areas because of changes in the rainfall to runoff conversion. Flow changes due to urbanisation are considered to have important environmental impacts, requiring mitigation. The methodology used in this paper could be used for other urbanising areas. PMID- 28347973 TI - A Software Framework for Remote Patient Monitoring by Using Multi-Agent Systems Support. AB - BACKGROUND: Although there have been significant advances in network, hardware, and software technologies, the health care environment has not taken advantage of these developments to solve many of its inherent problems. Research activities in these 3 areas make it possible to apply advanced technologies to address many of these issues such as real-time monitoring of a large number of patients, particularly where a timely response is critical. OBJECTIVE: The objective of this research was to design and develop innovative technological solutions to offer a more proactive and reliable medical care environment. The short-term and primary goal was to construct IoT4Health, a flexible software framework to generate a range of Internet of things (IoT) applications, containing components such as multi-agent systems that are designed to perform Remote Patient Monitoring (RPM) activities autonomously. An investigation into its full potential to conduct such patient monitoring activities in a more proactive way is an expected future step. METHODS: A framework methodology was selected to evaluate whether the RPM domain had the potential to generate customized applications that could achieve the stated goal of being responsive and flexible within the RPM domain. As a proof of concept of the software framework's flexibility, 3 applications were developed with different implementations for each framework hot spot to demonstrate potential. Agents4Health was selected to illustrate the instantiation process and IoT4Health's operation. To develop more concrete indicators of the responsiveness of the simulated care environment, an experiment was conducted while Agents4Health was operating, to measure the number of delays incurred in monitoring the tasks performed by agents. RESULTS: IoT4Health's construction can be highlighted as our contribution to the development of eHealth solutions. As a software framework, IoT4Health offers extensibility points for the generation of applications. Applications can extend the framework in the following ways: identification, collection, storage, recovery, visualization, monitoring, anomalies detection, resource notification, and dynamic reconfiguration. Based on other outcomes involving observation of the resulting applications, it was noted that its design contributed toward more proactive patient monitoring. Through these experimental systems, anomalies were detected in real time, with agents sending notifications instantly to the health providers. CONCLUSIONS: We conclude that the cost-benefit of the construction of a more generic and complex system instead of a custom-made software system demonstrated the worth of the approach, making it possible to generate applications in this domain in a more timely fashion. PMID- 28347972 TI - The Effect of Technology-Mediated Diabetes Prevention Interventions on Weight: A Meta-Analysis. AB - BACKGROUND: Lifestyle interventions targeting weight loss, such as those delivered through the Diabetes Prevention Program, reduce the risk of developing type 2 diabetes. Technology-mediated interventions may be an option to help overcome barriers to program delivery, and to disseminate diabetes prevention programs on a larger scale. OBJECTIVE: We conducted a meta-analysis to evaluate the effect of such technology-mediated interventions on weight loss. METHODS: In this meta-analysis, six databases were searched to identify studies reporting weight change that used technology to mediate diet and exercise interventions, and targeted individuals at high risk for developing type 2 diabetes. Studies published between January 1, 2002 and August 4, 2016 were included. RESULTS: The search identified 1196 citations. Of those, 15 studies met the inclusion criteria and evaluated 18 technology-mediated intervention arms delivered to a total of 2774 participants. Study duration ranged from 12 weeks to 2 years. A random effects meta-analysis showed a pooled weight loss effect of 3.76 kilograms (95% CI 2.8-4.7; P<.001) for the interventions. Several studies also reported improved glycemic control following the intervention. The small sample sizes and heterogeneity of the trials precluded an evaluation of which technology-mediated intervention method was most efficacious. CONCLUSIONS: Technology-mediated diabetes prevention programs can result in clinically significant amounts of weight loss, as well as improvements in glycaemia in patients with prediabetes. Due to their potential for large-scale implementation, these interventions will play an important role in the dissemination of diabetes prevention programs. PMID- 28347976 TI - Arthur "Sam" Davidson. PMID- 28347975 TI - Automated Adherence Reminders for High Risk Children With Asthma: A Research Protocol. AB - BACKGROUND: The use of inhaled corticosteroid (ICS) medications has been shown to improve asthma control and reduce asthma-related morbidity and mortality. Two recent randomized trials demonstrated dramatic improvements in ICS adherence by monitoring adherence with electronic sensors and providing automated reminders to participants to take their ICS medications. Given their lower levels of adherence and higher levels of asthma-related emergency department (ED) visits, hospitalizations, and death, urban minority populations could potentially benefit greatly from these types of interventions. OBJECTIVE: The principal objective of this study will be to evaluate the feasibility, acceptability, and limited efficacy of a text message (short message service, SMS) reminder intervention to enhance ICS adherence in an urban minority population of children with asthma. We will also assess trajectories of ICS adherence in the 2 months following asthma hospitalization. METHODS: Participants will include 40 children aged 2-13 years, who are currently admitted to the Children's Hospital of Philadelphia (CHOP) for asthma, and their parent or legal guardian. Participants will be assigned to intervention and control arms using a 1:1 randomization scheme. The intervention arm will receive daily text message reminders for a 30-day intervention phase following hospitalization. This will be followed by a 30-day follow-up phase, in which all participants may choose whether or not to receive the text messages. Feasibility will be assessed by measuring (1) retention of the participants through the study phases and (2) perceived usefulness, acceptability, and preferences regarding the intervention components. Limited efficacy outcomes will include percent adherence to prescribed ICS regimen measured using Propeller Health sensors and change in parent-reported asthma control. We will perform an exploratory analysis to assess for discrete trajectories of adherence using group based trajectory modeling (GBTM). RESULTS: Study enrollment began in December 2015 and the intervention and follow-up phases are ongoing. Results of the data analysis are expected to be available by December 2016. CONCLUSIONS: This study will add to the literature by providing foundational feasibility data on which elements of a mobile health text-message reminder intervention may need to be modified to suit the needs and constraints of high-risk urban minority populations. TRIAL REGISTRATION: Clinicaltrials.gov NCT02615743; https://www.clinicaltrials.gov/ct2/show/study/NCT02615743 (Archived with WebCite at http://www.webcitation.org/6ji59rAXN). PMID- 28347974 TI - Whiplash Syndrome Reloaded: Digital Echoes of Whiplash Syndrome in the European Internet Search Engine Context. AB - BACKGROUND: In many Western countries, after a motor vehicle collision, those involved seek health care for the assessment of injuries and for insurance documentation purposes. In contrast, in many less wealthy countries, there may be limited access to care and no insurance or compensation system. OBJECTIVE: The purpose of this infodemiology study was to investigate the global pattern of evolving Internet usage in countries with and without insurance and the corresponding compensation systems for whiplash injury. METHODS: We used the Internet search engine analytics via Google Trends to study the health information-seeking behavior concerning whiplash injury at national population levels in Europe. RESULTS: We found that the search for "whiplash" is strikingly and consistently often associated with the search for "compensation" in countries or cultures with a tort system. Frequent or traumatic painful injuries; diseases or disorders such as arthritis, headache, radius, and hip fracture; depressive disorders; and fibromyalgia were not associated similarly with searches on "compensation." CONCLUSIONS: In this study, we present evidence from the evolving viewpoint of naturalistic Internet search engine analytics that the expectations for receiving compensation may influence Internet search behavior in relation to whiplash injury. PMID- 28347977 TI - Whatever happened to the polypill? PMID- 28347979 TI - David Ruston Childs. PMID- 28347980 TI - Penny Taylor. PMID- 28347981 TI - US doctors' groups call for parties to work together on healthcare reform. PMID- 28347978 TI - Intra-articular implantation of collagen scaffold carriers is safe in both native and arthrofibrotic rabbit knee joints. AB - OBJECTIVES: Sustained intra-articular delivery of pharmacological agents is an attractive modality but requires use of a safe carrier that would not induce cartilage damage or fibrosis. Collagen scaffolds are widely available and could be used intra-articularly, but no investigation has looked at the safety of collagen scaffolds within synovial joints. The aim of this study was to determine the safety of collagen scaffold implantation in a validated in vivo animal model of knee arthrofibrosis. MATERIALS AND METHODS: A total of 96 rabbits were randomly and equally assigned to four different groups: arthrotomy alone; arthrotomy and collagen scaffold placement; contracture surgery; and contracture surgery and collagen scaffold placement. Animals were killed in equal numbers at 72 hours, two weeks, eight weeks, and 24 weeks. Joint contracture was measured, and cartilage and synovial samples underwent histological analysis. RESULTS: Animals that underwent arthrotomy had equivalent joint contractures regardless of scaffold implantation (-13.9 degrees versus -10.9 degrees , equivalence limit 15 degrees ). Animals that underwent surgery to induce contracture did not demonstrate equivalent joint contractures with (41.8 degrees ) or without (53.9 degrees ) collagen scaffold implantation. Chondral damage occurred in similar rates with (11 of 48) and without (nine of 48) scaffold implantation. No significant difference in synovitis was noted between groups. Absorption of the collagen scaffold occurred within eight weeks in all animals CONCLUSION: Our data suggest that intra-articular implantation of a collagen sponge does not induce synovitis or cartilage damage. Implantation in a native joint does not seem to induce contracture. Implantation of the collagen sponge in a rabbit knee model of contracture may decrease the severity of the contracture.Cite this article: J. A. Walker, T. J. Ewald, E. Lewallen, A. Van Wijnen, A. D. Hanssen, B. F. Morrey, M. E. Morrey, M. P. Abdel, J. Sanchez-Sotelo. Intra-articular implantation of collagen scaffold carriers is safe in both native and arthrofibrotic rabbit knee joints. Bone Joint Res 2016;6:162-171. DOI: 10.1302/2046-3758.63.BJR-2016-0193. PMID- 28347983 TI - Jorgen Kieler. PMID- 28347982 TI - Consultant who acted as loan shark must repay L525 000 or face jail term. PMID- 28347984 TI - Trends in the diagnosis and management of hypertension: repeated primary care survey in South West England. AB - BACKGROUND: Previous surveys identified a shift to nurse-led care in hypertension in 2010. In 2011 the National Institute for Health and Care Excellence (NICE) recommended ambulatory (ABPM) or home (HBPM) blood pressure (BP) monitoring for diagnosis of hypertension. AIM: To survey the organisation of hypertension care in 2016 to identify changes, and to assess uptake of NICE diagnostic guidelines. DESIGN AND SETTING: Questionnaires were distributed to all 305 general practices in South West England. METHOD: Responses were compared with previous rounds (2007 and 2010). Data from the 2015 Quality and Outcomes Framework (QOF) were used to compare responders with non-responders, and to explore associations of care organisation with QOF achievement. RESULTS: One-hundred-and-seventeen practices (38%) responded. Responders had larger list sizes and greater achievement of the QOF target BP <=150/90 mmHg. Healthcare assistants (HCAs) now monitor BP in 70% of practices, compared with 37% in 2010 and 19% in 2007 (P<0.001). Nurse prescribers alter BP medication in 26% of practices (11% in 2010, none in 2007; P<0.001). Of the practices, 89% have access to ABPM, but only 71% report confidence in interpreting results. Also, 87% offer HBPM, with 93% of these confident in interpreting results. CONCLUSION: In primary care BP monitoring has devolved from GPs and nurses to HCAs. One in 10 practices are not implementing NICE guidelines on ABPM and HBPM for diagnosis of hypertension. Most practices express confidence interpreting HBPM results but less so with ABPM. The need for education and quality assurance for allied health professionals is highlighted, and for training in ABPM interpretation for GPs. PMID- 28347985 TI - Clinical features of bowel disease in patients aged <50 years in primary care: a large case-control study. AB - BACKGROUND: Incidences of colorectal cancer (CRC) and inflammatory bowel disease (IBD) are increasing in those aged <50 years. AIM: To identify and quantify clinical features in primary care of CRC/IBD in those aged <50 years. This study considered the two conditions together and aimed to determine which younger patients, presenting in primary care with symptoms, would benefit from investigation for potentially serious colorectal disease. DESIGN AND SETTING: Matched case-control study using primary care records from the Clinical Practice Research Datalink, UK. METHOD: Incident cases (aged <50 years) of CRC (n = 1661) and IBD (n = 9578) diagnosed between 2000 and 2013 were each matched with up to three controls (n = 3979 CRC; n = 22 947 IBD). Odds ratios (OR) and positive predictive values (PPV) were estimated for features of CRC/IBD in the year before diagnosis. RESULTS: Ten features were independently associated with CRC/IBD (all P<0.001): rectal bleeding, change in bowel habit, diarrhoea, raised inflammatory markers, thrombocytosis, abdominal pain, low mean cell volume (MCV), low haemoglobin, raised white cell count, and raised hepatic enzymes. PPVs were >3% for rectal bleeding with diarrhoea, thrombocytosis, low MCV, low haemoglobin or raised inflammatory markers; for change in bowel habit with low MCV, thrombocytosis or low haemoglobin; and for diarrhoea with thrombocytosis. CONCLUSION: This study quantified the risk of serious bowel disease in symptomatic patients aged <50 years in primary care. Rectal bleeding and change in bowel habit are strongly predictive of CRC/IBD when combined with abnormal haematology. The present findings help prioritise patients for colonoscopy where the diagnosis is not immediately apparent. PMID- 28347986 TI - Evaluation of a complex intervention to improve primary care prescribing: a phase IV segmented regression interrupted time series analysis. AB - BACKGROUND: It is uncertain whether improvements in primary care high-risk prescribing seen in research trials can be realised in the real-world setting. AIM: To evaluate the impact of a 1-year system-wide phase IV prescribing safety improvement initiative, which included education, feedback, support to identify patients to review, and small financial incentives. DESIGN AND SETTING: An interrupted time series analysis of targeted high-risk prescribing in all 56 general practices in NHS Forth Valley, Scotland, was performed. In 2013-2014, this focused on high-risk non-steroidal anti-inflammatory drugs (NSAIDs) in older people and NSAIDs with oral anticoagulants; in 2014-2015, it focused on antipsychotics in older people. METHOD: The primary analysis used segmented regression analysis to estimate impact at the end of the intervention, and 12 months later. The secondary analysis used difference-in-difference methods to compare Forth Valley changes with those in NHS Greater Glasgow and Clyde (GGC). RESULTS: In the primary analysis, downward trends for all three NSAID measures that were existent before the intervention statistically significantly steepened following implementation of the intervention. At the end of the intervention period, 1221 fewer patients than expected were prescribed a high-risk NSAID. In contrast, antipsychotic prescribing in older people increased slowly over time, with no intervention-associated change. In the secondary analysis, reductions at the end of the intervention period in all three NSAID measures were statistically significantly greater in NHS Forth Valley than in NHS GGC, but only significantly greater for two of these measures 12 months after the intervention finished. CONCLUSION: There were substantial and sustained reductions in the high-risk prescribing of NSAIDs, although with some waning of effect 12 months after the intervention ceased. The same intervention had no effect on antipsychotic prescribing in older people. PMID- 28347988 TI - Basil C S Slater. PMID- 28347987 TI - Outcome prioritisation tool for medication review in older patients with multimorbidity: a pilot study in general practice. AB - BACKGROUND: Several methods have been developed to conduct and support medication reviews in older persons with multimorbidity. Assessing the patient's priorities for achieving specific health outcomes can guide the medication review process. Little is known about the impact of conducting such assessments. AIM: This pilot study aimed to determine proposed and observed medication changes when using an outcome prioritisation tool (OPT) during a medication review in general practice. DESIGN AND SETTING: Participants were older patients with multimorbidity (aged >=69 years) with polypharmacy (five or more chronic medications) from the practices of 14 GPs. METHOD: Patients were asked to prioritise four universal health outcomes - remaining alive, maintaining independence, reducing pain, and reducing other symptoms - using an OPT. GPs used this prioritisation to review the medication and to propose and discuss medication changes with the patient. The outcomes included the proposed medication change as documented by the GP, and the observed medication change in the electronic health record at follow-up. Descriptive analyses were conducted to determine medication changes according to the prioritised health outcomes. RESULTS: A total of 59 patients using 486 medications prioritised the four health outcomes. GPs proposed 34 changes of medication, mainly stopping, for 20 patients. At follow-up, 14 medication changes were observed for 10 patients. The stopping of medication (mostly preventive) was particularly observed in patients who prioritised 'reducing other symptoms' as most important. CONCLUSION: Using an OPT leads mainly to the stopping of medication. Medication changes appeared to be easiest for patients who prioritised 'reducing other symptoms' as most important. PMID- 28347989 TI - WRN conditioned media is sufficient for in vitro propagation of intestinal organoids from large farm and small companion animals. AB - Recent years have seen significant developments in the ability to continuously propagate organoids derived from intestinal crypts. These advancements have been applied to mouse and human samples providing models for gastrointestinal tissue development and disease. We adapt these methods for the propagation of intestinal organoids (enteroids) from various large farm and small companion (LF/SC) animals, including cat, dog, cow, horse, pig, sheep and chicken. We show that LF/SC enteroids propagate and expand in L-WRN conditioned media containing signaling factors Wnt3a, R-spondin-3, and Noggin (WRN). Multiple successful isolations were achieved for each species, and the growth of LF/SC enteroids was maintained to high passage number. LF/SC enteroids expressed crypt stem cell marker LGR5 and low levels of mesenchymal marker VIM. Labeling with EdU also showed distinct regions of cell proliferation within the enteroids marking crypt like regions. The ability to grow and maintain LF/SC enteroid cell lines provides additional models for the study of gastrointestinal developmental biology as well as platforms for the study of host-pathogen interactions between intestinal cells and zoonotic enteric pathogens of medical importance. PMID- 28347990 TI - Reduced beta-catenin expression affects patterning of bone primordia, but not bone maturation. AB - Wnt/beta-catenin signaling is involved in patterning of bone primordia, but also plays an important role in the differentiation of chondrocytes and osteoblasts. During these processes the level of beta-catenin must be tightly regulated. Excess beta-catenin leads to conditions with increased bone mass, whereas loss of beta-catenin is associated with osteoporosis or, in extreme cases, the absence of limbs. In this study, we examined skeletogenesis in mice, which retain only 25% of beta-catenin. These embryos showed severe morphological abnormalities of which the lack of hindlimbs and misshaped front paws were the most striking. Surprisingly however, calcification of bone primordia occurred normally. Moreover, the Wnt-dependent regulatory network of transcription factors driving the differentiation of cartilage and bone, as well as the expression of extracellular matrix components, were preserved. These findings show that 25% beta-catenin is insufficient for the correct patterning of bone primordia, but sufficient for their mineralization. Our approach helps to identify bone morphogenetic processes that can proceed normally even at low beta-catenin levels, in contrast to those that require high beta-catenin dosages. This information could be exploited to improve the treatment of bone diseases by fine tuning the individual beta-catenin dosage requirements. PMID- 28347992 TI - 2016 update of the EULAR recommendations for the management of rheumatoid arthritis: a utopia beyond patients in low/middle income countries? PMID- 28347991 TI - Patients with gout have short telomeres compared with healthy participants: association of telomere length with flare frequency and cardiovascular disease in gout. AB - AIM AND BACKGROUND: Chronic inflammation associates with increased senescence, which is a strong predictor for cardiovascular disease. We hypothesised that inflammation accelerates senescence and thereby enhances the risk of cardiovascular disease in gout. METHODS: We assessed replicative senescence by quantifying telomere length (TL) in a discovery cohort of 145 Dutch patients with gout and 273 healthy individuals and validated our results in 474 patients with gout and 293 healthy participants from New Zealand. Subsequently, we investigated the effect of cardiovascular disease on TL of all participants. Also, we measured TL of CD4+ and CD8+ T lymphocytes, B lymphocytes, monocytes, natural killer cells and plasmacytoid dendritic cells. Additionally, we assessed the potential temporal difference in TL and telomerase activity. RESULTS: TL in PBMCs of healthy donors decreased over time, reflecting normal ageing. Patients with gout demonstrated shorter telomeres (p=0.001, R2=0.01873). In fact, the extent of telomere erosion in patients with gout was higher at any age compared with healthy counterparts at any age (p<0.0001, R2=0.02847). Patients with gout with cardiovascular disease had the shortest telomeres and TL was an independent risk factor for cardiovascular disease in patients with gout (p=0.001). TL was inversely associated with the number of gouty flares (p=0.005). CONCLUSIONS: Patients with gout have shorter telomeres than healthy participants, reflecting increased cellular senescence. Telomere shortening was associated with the number of flares and with cardiovascular disease in people with gout. PMID- 28347993 TI - EULAR gout treatment guidelines by Richette et al.: uric acid and neurocognition. PMID- 28347994 TI - Longer-term quality of life following ACL injury and reconstruction. PMID- 28347995 TI - Evidence-based exercise prescription is facilitated by the Consensus on Exercise Reporting Template (CERT). PMID- 28347996 TI - Generic drugs have lost their profitability. PMID- 28347997 TI - Roop Mallik: From machines to molecular motors. AB - Roop Mallik studies how molecular motors and lipids interact to drive intracellular transport. PMID- 28347998 TI - Opioid rotation to alfentanil: comparative evaluation of conversion ratios. PMID- 28348000 TI - The impact of environment on abnormal behavior and mental disease: To alleviate the prevalence of mental disorders, we need to phenotype the environment for risk factors. PMID- 28347999 TI - Lipin-1 regulation of phospholipid synthesis maintains endoplasmic reticulum homeostasis and is critical for triple-negative breast cancer cell survival. AB - Cancer cells reprogram their metabolism to increase the synthesis of macromolecules for rapid proliferation. Compared to fatty acids, much less is known about the synthesis of phospholipids, which is essential for membrane biogenesis in cancer cells. We found that LPIN1, which encodes lipin-1, a phosphatidic acid phosphatase (PAP) controlling the rate-limiting step in the phospholipid synthesis pathway, is highly up-regulated in basal-like triple negative breast cancer (TNBC). Moreover, high LPIN1 expression correlates with the poor prognosis of these patients. Knockdown of LPIN1 increases apoptosis in basal-like TNBC cell lines, whereas it has minimal or less effect on normal human mammary gland epithelial cells (HMECs) and estrogen receptor-positive breast cancer cell lines. Fatty acid incorporation and lipidomics analyses showed that LPIN1 knockdown blocks phospholipid synthesis and changes membrane lipid compositions that ultimately induce the activation of 1 of the 3 branches of unfolded protein responses, the inositol-requiring enzyme-1alpha pathway. We also show for the first time, to our knowledge, that lipin-1 knockdown significantly inhibits tumor growth in vivo using an orthotopic xenograft breast mouse model. Our results suggest that lipin-1 is a potential target for cancer therapy.-He, J., Zhang, F., Tay, L. W. R., Boroda, S., Nian, W., Levental, K. R., Levental, I., Harris, T. E., Chang, J. T., Du, G. Lipin-1 regulation of phospholipid synthesis maintains endoplasmic reticulum homeostasis and is critical for triple negative breast cancer cell survival. PMID- 28348002 TI - Thyroid function in children and adolescents with Hashimoto's thyroiditis after l thyroxine discontinuation. AB - OBJECTIVE: Thyroid function may recover in patients with Hashimoto's thyroiditis (HT). DESIGN: To investigate thyroid function and the need to resume l-thyroxine treatment after its discontinuation. SETTING: Nine Italian pediatric endocrinology centers. PATIENTS: 148 children and adolescents (25 m and 123 f) with HT on treatment with l-thyroxine for at least one year. INTERVENTION AND MAIN OUTCOME MEASURE: Treatment was discontinued in all patients, and serum TSH and fT4 concentrations were measured at the time of treatment discontinuation and then after 2, 6, 12 and 24 months. Therapy with l-thyroxine was re-instituted when TSH rose >10 U/L and/or fT4 was below the normal range. The patients were followed up when TSH concentrations were between 5 and 10 U/L and fT4 was in the normal range. RESULTS: At baseline, TSH was in the normal range in 139 patients, and was between 5 and 10 U/L in 9 patients. Treatment was re-instituted after 2 months in 37 (25.5%) patients, after 6 months in 13 patients (6.99%), after 12 months in 12 patients (8.6%), and after 24 months in an additional 3 patients (3.1%). At 24 months, 34 patients (34.3%) still required no treatment. TSH concentration >10 U/L at the time of diagnosis was the only predictive factor for the deterioration of thyroid function after l-thyroxine discontinuation. CONCLUSIONS: This study confirms that not all children with HT need life-long therapy with l-thyroxine, and the discontinuation of treatment in patients with a TSH level <10 U/L at the time of diagnosis should be considered. PMID- 28348003 TI - The health of prisoners: summary of NICE guidance. PMID- 28348001 TI - Dissecting carboxypeptidase E: properties, functions and pathophysiological roles in disease. AB - Since discovery in 1982, carboxypeptidase E (CPE) has been shown to be involved in the biosynthesis of a wide range of neuropeptides and peptide hormones in endocrine tissues, and in the nervous system. This protein is produced from pro CPE and exists in soluble and membrane forms. Membrane CPE mediates the targeting of prohormones to the regulated secretory pathway, while soluble CPE acts as an exopeptidase and cleaves C-terminal basic residues from peptide intermediates to generate bioactive peptides. CPE also participates in protein internalization, vesicle transport and regulation of signaling pathways. Therefore, in two types of CPE mutant mice, Cpefat/Cpefat and Cpe knockout, loss of normal CPE leads to a lot of disorders, including diabetes, hyperproinsulinemia, low bone mineral density and deficits in learning and memory. In addition, the potential roles of CPE and DeltaN-CPE, an N-terminal truncated form, in tumorigenesis and diagnosis were also addressed. Herein, we focus on dissecting the pathophysiological roles of CPE in the endocrine and nervous systems, and related diseases. PMID- 28348004 TI - Peripheral fundus findings in X-linked retinoschisis. AB - BACKGROUND/AIMS: Vitreous haemorrhage (VH) and retinal detachment (RD) cause a precipitous decline in vision in a subset of patients with X-linked retinoschisis (XLRS), an otherwise a slowly progressive condition. This study aims to report the frequency of macular and peripheral retinal findings in a large cohort of patients with XLRS and to determine whether peripheral retinal findings are associated with VH and RD. METHODS: A retrospective observational case series was performed in 65 patients with XLRS with a pathogenic variant in retinoschisin 1. Chart review included examination notes, fundus photographs and optical coherence tomography (OCT). Fisher exact tests and univariable logistic regression analysis were used to determine the association between peripheral retinal findings (including retinoschisis, metallic sheen, vascular sheathing, pigmentary changes, white spiculations and vitreous veils) and complications (including VH and RD). RESULTS: Seven eyes (8%) showed normal macular structure on OCT. Peripheral retinoschisis was significantly associated with both VH and RD. Out of 10 eyes with complications, 9 (90%) had peripheral retinoschisis, compared with 33 out of 116 eyes (28%) without complications (p=0.0014). In addition, each additional peripheral finding increased the odds of RD by a factor of 4.06 (95% CI 1.58 to 10.39, p=0.028). There were no complications in the 28 eyes with a normal periphery (p=0.84) or in the 35 eyes with metallic sheen (p=0.42). CONCLUSION: The data suggest that patients with peripheral retinoschisis are at increased risk for VH and RD. Furthermore, patients with additional peripheral retinal findings together with peripheral schisis may carry additional risk for RD. PMID- 28348005 TI - Vascular basement membrane alterations and beta-amyloid accumulations in an animal model of cerebral small vessel disease. AB - Non-amyloid cerebral small vessel disease (CSVD) and cerebral amyloid angiopathy (CAA) may be interrelated through the damaged basement membranes (BMs) and extracellular matrix changes of small vessels, resulting in a failure of beta amyloid (Abeta) transport and degradation. We analyzed BM changes and the pattern of deposition of Abeta in the walls of blood vessels in spontaneously hypertensive stroke-prone rats (SHRSP), a non-transgenic CSVD model. In 45 SHRSP and 38 Wistar rats aged 18 to 32 weeks: (i) the percentage area immunostained for vascular collagen IV and laminin was quantified; (ii) the capillary BM thickness as well as endothelial and pericyte pathological changes were analysed using transmission electron microscopy (TEM); and (iii) the presence of vascular Abeta was assessed. Compared with controls, SHRSP exhibited a significantly higher percentage area immunostained with collagen IV in the striatum and thalamus. SHRSP also revealed an age-dependent increase of the capillary BM thickness and of endothelial vacuoles (caveolae) within subcortical regions. Endogenous Abeta deposits in the walls of small blood vessels were observed in the cortex (with the highest incidence found within fronto-parietal areas), striatum, thalamus and hippocampus. Vascular beta-amyloid accumulations were frequently detected at sites of small vessel wall damage. Our data demonstrate changes in the expression of collagen IV and of the ultrastructure of BMs in the small vessels of SHRSP. Alterations are accompanied by vascular deposits of endogenous Abeta. Impaired beta-amyloid clearance along perivascular and endothelial pathways and failure of extracellular Abeta degradation may be the key mechanisms connecting non-amyloid CSVD and CAA. PMID- 28348006 TI - GABAB receptor attenuation of GABAA currents in neurons of the mammalian central nervous system. AB - Ionotropic receptors are tightly regulated by second messenger systems and are often present along with their metabotropic counterparts on a neuron's plasma membrane. This leads to the hypothesis that the two receptor subtypes can interact, and indeed this has been observed in excitatory glutamate and inhibitory GABA receptors. In both systems the metabotropic pathway augments the ionotropic receptor response. However, we have found that the metabotropic GABAB receptor can suppress the ionotropic GABAA receptor current, in both the in vitro mouse retina and in human amygdala membrane fractions. Expression of amygdala membrane microdomains in Xenopus oocytes by microtransplantation produced functional ionotropic and metabotropic GABA receptors. Most GABAA receptors had properties of alpha-subunit containing receptors, with ~5% having rho-subunit properties. Only GABAA receptors with alpha-subunit-like properties were regulated by GABAB receptors. In mouse retinal ganglion cells, where only alpha subunit-containing GABAA receptors are expressed, GABAB receptors suppressed GABAA receptor currents. This suppression was blocked by GABAB receptor antagonists, G-protein inhibitors, and GABAB receptor antibodies. Based on the kinetic differences between metabotropic and ionotropic receptors, their interaction would suppress repeated, rapid GABAergic inhibition. PMID- 28348007 TI - Genome-Wide Analysis of DNA Methylation and Acute Coronary Syndrome. AB - RATIONALE: Acute coronary syndrome (ACS) is a leading cause of death worldwide. Immune functions play a vital role in ACS development; however, whether epigenetic modulation contributes to the regulation of blood immune cells in this disease has not been investigated. OBJECTIVE: We conducted an epigenome-wide analysis with circulating immune cells to identify differentially methylated genes in ACS. METHODS AND RESULTS: We examined genome-wide methylation of whole blood in 102 ACS patients and 101 controls using HumanMethylation450 array, and externally replicated significant discoveries in 100 patients and 102 controls. For the replicated loci, we further analyzed their association with ACS in 6 purified leukocyte subsets, their correlation with the expressions of annotated genes, and their association with cardiovascular traits/risk factors. We found novel and reproducible association of ACS with blood methylation at 47 cytosine phosphoguanine sites (discovery: false discovery rate <0.005; replication: Bonferroni corrected P<0.05). The association of methylation levels at these cytosine-phosphoguanine sites with ACS was further validated in at least 1 of the 6 leukocyte subsets, with predominant contributions from CD8+ T cells, CD4+ T cells, and B cells. Blood methylation of 26 replicated cytosine-phosphoguanine sites showed significant correlation with expressions of annotated genes (including IL6R, FASLG, and CCL18; P<5.9*10-4), and differential gene expression in case versus controls corroborated the observed differential methylation. The replicated loci suggested a role in ACS-relevant functions including chemotaxis, coronary thrombosis, and T-cell-mediated cytotoxicity. Functional analysis using the top ACS-associated methylation loci in purified T and B cells revealed vital pathways related to atherogenic signaling and adaptive immune response. Furthermore, we observed a significant enrichment of the replicated cytosine phosphoguanine sites associated with smoking and low-density lipoprotein cholesterol (Penrichment<=1*10-5). CONCLUSIONS: Our study identified novel blood methylation alterations associated with ACS and provided potential clinical biomarkers and therapeutic targets. Our results may suggest that immune signaling and cellular functions might be regulated at an epigenetic level in ACS. PMID- 28348008 TI - Impaired Hydrogen Sulfide-Mediated Vasodilation Contributes to Microvascular Endothelial Dysfunction in Hypertensive Adults. AB - Reductions in hydrogen sulfide (H2S) production have been implicated in the pathogenesis of vascular dysfunction in animal models of hypertension; however, no studies have examined a functional role for H2S in contributing to microvascular dysfunction in hypertensive (HTN) adults. We hypothesized that endogenous production of H2S would be reduced, impaired endothelium-dependent vasodilation would be mediated by reductions in H2S-dependent vasodilation, and vascular responsiveness to exogenous H2S (sodium sulfide) would be attenuated in HTN compared to normotensive adults. Fifteen normotensive (51+/-2 years; blood pressure, 116+/-3/76+/-3 mm Hg) and 14 HTN adults (57+/-2 years; blood pressure 140+/-3/89+/-2 mm Hg) participated. H2S biosynthetic enzyme expression (Western blot) and substrate-dependent H2S production (amperometric probe) were measured in cutaneous tissue homogenates. Red cell flux (laser Doppler flowmetry) was measured during graded perfusions of acetylcholine (ACh; 10-6-10-1 mol/L) and sodium sulfide (10-5-101 mol/L) using intradermal microdialysis; the functional role of H2S was determined using pharmacological inhibition with aminooxyacetic acid (0.5 mmol/L). H2S biosynthetic enzyme expression and substrate-dependent H2S production were reduced in HTN adults (all P<0.05). ACh-induced endothelium dependent vasodilation was blunted in HTN adults (P=0.012). Aminooxyacetic acid attenuated ACh-induced vasodilation in normotensive adults (ACh, 1.31+/-0.13 versus ACh+aminooxyacetic acid, 1.07+/-0.09 flux/mm Hg; P=0.025) but had no effect on vasodilation in HTN adults (ACh, 1.16+/-0.10 versus ACh+aminooxyacetic acid, 1.37+/-0.11 flux/mm Hg; P=0.47). Sodium sulfide-induced vasodilation was not different between groups. Collectively, these findings indicate that while the microvasculature maintains the ability to vasodilate in response to exogenous H2S, reductions in endogenous synthesis and H2S-dependent vasodilation contribute to endothelial dysfunction in human hypertension. PMID- 28348009 TI - Polymerization-Incompetent Uromodulin in the Pregnant Stroke-Prone Spontaneously Hypertensive Rat. AB - The kidney is centrally involved in blood pressure regulation and undergoes extensive changes during pregnancy. Hypertension during pregnancy may result in an altered urinary peptidome that could be used to indicate new targets of therapeutic or diagnostic interest. The stroke-prone spontaneously hypertensive rat (SHRSP) is a model of maternal chronic hypertension. Capillary electrophoresis-mass spectrometry was conducted to interrogate the urinary peptidome in SHRSP and the control Wistar-Kyoto strain at three time points: prepregnancy and gestational days 12 and 18. The comparison within and between the Wistar-Kyoto and SHRSP peptidome at all time points detected 123 differentially expressed peptides (fold change >1.5; P<0.05). Sequencing of these peptides identified fragments of collagen alpha-chains, albumin, prothrombin, actin, serpin A3K, proepidermal growth factor, and uromodulin. Uromodulin peptides showed a pregnancy-specific alteration in SHRSP with a 7.8-fold (P<0.01) and 8.8-fold (P<0.05) increase at gestational days 12 and 18, respectively, relative to the Wistar-Kyoto. Further investigation revealed that these peptides belonged to the polymerization-inhibitory region of uromodulin. Two forms of uromodulin (polymerization competent and polymerization incompetent) were found in urine from both Wistar-Kyoto and SHRSP, where the polymerization-incompetent form was increased in a pregnancy-specific manner in SHRSP. Nifedipine-treated pregnant SHRSP showed only polymerization-competent uromodulin, indicating that calcium may be mechanistically involved in uromodulin polymerization. This study highlights, for the first time, a potential role of uromodulin and its polymerization in hypertensive pregnancy. PMID- 28348011 TI - Office Blood Pressure and Cardiovascular Disease: Pathophysiologic Implications for Diagnosis and Treatment. PMID- 28348012 TI - Age at First Childbirth and Hypertension in Postmenopausal Women. AB - Whether age at first childbirth has an effect on hypertension incidence is unclear. The objectives of this study were to examine the relationship between age at first childbirth and hypertension and to examine whether degree of obesity, measured as body mass index, mediates age at first childbirth-related hypertension in postmenopausal women. This study analyzed 4779 postmenopausal women data from the Korea National Health and Nutrition Examination Survey 2010 to 2012. Logistic regression analyses were used to investigate relationship between age at first childbirth and hypertension. Mediation analysis was performed to examine the contribution of body mass index to age at first childbirth-related hypertension. Mean of participants' age at first childbirth and current age were 23.8 and 63.4 years, respectively. The prevalence of hypertension was 51.1%. Age at first childbirth was significantly associated with the prevalence of hypertension (odds ratio, 0.963; 95% confidence interval, 0.930 0.998; P=0.036). Women with age at first childbirth <=19 years had significantly higher risk of hypertension (odds ratio, 1.61; 95% confidence interval, 1.17 2.23; P=0.004) compared with those >19 years. Multivariable-adjusted prevalence of hypertension was significantly lower in women who delivered the first infant at 20 to 24 (45.5%), 25 to 29 (46.1%), and >=30 (39.9%) years compared with those at <=19 years (58.4%). Body mass index completely mediated age at first childbirth-hypertension relationship (indirect effect: odds ratio, 0.992; 95% confidence interval, 0.987-0.998; P=0.008). Age at first childbirth was significantly associated with hypertension in postmenopausal women. Body mass index mediated the effects of age at first childbirth on hypertension. PMID- 28348010 TI - Distinctive Risk Factors and Phenotype of Younger Patients With Resistant Hypertension: Age Is Relevant. AB - Resistant hypertension, defined as blood pressure >140/90 mm Hg despite using >=3 antihypertensive medications, is a well-recognized clinical entity. Patients with resistant hypertension are at an increased risk of cardiovascular disease compared with those with more easily controlled hypertension. Coronary heart disease mortality rates of younger adults are stagnating or on the rise. The purpose of our study was to characterize the phenotype and risk factors of younger patients with resistant hypertension, given the dearth of data on cardiovascular risk profile in this cohort. We conducted a cross-sectional analysis with predefined age groups of a large, ethnically diverse cohort of 2170 patients referred to the Hypertension Clinic at the University of Alabama at Birmingham. Patients (n=2068) met the inclusion criteria and were classified by age groups, that is, <=40 years (12.7% of total cohort), 41 to 55 years (32.1%), 56 to 70 years (36.1%), and >=71 years (19.1%). Patients aged <=40 years compared with those aged >=71 years had significantly earlier onset of hypertension (24.7+/-7.4 versus 55.0+/-14.1 years; P<0.0001), higher rates of obesity (53.4% versus 26.9%; P<0.0001), and significantly higher levels of plasma aldosterone (11.3+/-9.8 versus 8.9+/-7.4 ng/dL; P=0.005), plasma renin activity (4.9+/-10.2 versus 2.5+/-5.0 ng/mL per hour; P=0.001), 24-hour urinary aldosterone (13.4+/ 10.0 versus 8.2+/-6.2 ug/24 h; P<0.0001), and sodium excretion (195.9+/-92.0 versus 146.8+/-67.1 mEq/24 h; P<0.0001). Among patients with resistant hypertension, younger individuals have a distinct phenotype characterized by overlapping risk factors and comorbidities, including obesity, high aldosterone, and high dietary sodium intake compared with elderly. PMID- 28348013 TI - New Intermediate Phenotype of Resistant Hypertension. PMID- 28348014 TI - Hypoxia-Induced Mitogenic Factor Acts as a Nonclassical Ligand of Calcium-Sensing Receptor, Therapeutically Exploitable for Intermittent Hypoxia-Induced Pulmonary Hypertension. AB - Hypoxia-induced mitogenic factor (HIMF) is an inflammatory cytokine playing important role(s) in the development of hypoxic pulmonary hypertension. The molecular target mediating HIMF-stimulated downstream events remains unclear. The coimmunoprecipitation screen identified extracellular calcium-sensing receptor (CaSR) as the binding partner for HIMF in pulmonary artery smooth muscle cells. The yeast 2-hybrid assay then revealed the binding of HIMF to the intracellular, not the extracellular, domain of extracellular CaSR. The binding of HIMF enhanced the activity of extracellular CaSR and mediated hypoxia-evoked proliferation of pulmonary artery smooth cells and the development of pulmonary vascular remodeling and pulmonary hypertension, all of which was specifically attenuated by a synthesized membrane-permeable peptide flanking the core amino acids of the intracellular binding domain of extracellular CaSR. Thus, HIMF induces pulmonary hypertension as a nonclassical ligand of extracellular CaSR, and the binding motif of extracellular CaSR can be therapeutically exploitable. PMID- 28348015 TI - Sympathetic Nerve Activity in Monozygotic Twins: Identical at Rest but Not During Arousal. AB - Microneurographic recordings of human muscle sympathetic nerve activity responses to sudden sensory stimuli (ie, arousal) have revealed 2 intraindividually reproducible response profiles in healthy young males that predict different neural and blood pressure responses to more sustained stress. Approximately 50% of subjects inhibit muscle sympathetic nerve activity during arousal, whereas the remaining 50% do not, and the latter group displays a markedly greater blood pressure increase in response to arousal, as well as during and after 3 minutes of mental arithmetic. Studying a group of monozygotic twins (10 pairs, 2 excluded from analysis), the aim of the present study was to evaluate the degree of genetic determination of these sympathetic response profiles. Muscle sympathetic burst incidence at rest was similar in twins, with a within-pair burst incidence ratio of 0.87+/-0.02 (SEM) compared with 0.73+/-0.07 found in unrelated pairs (P=0.002), confirming a previous study from our laboratory. In contrast, the sympathetic responses to arousal showed large twin within-pair variance (arousal inhibition ratio 0.56+/-0.11), which did not significantly differ (P=0.939) from the variance in pairs of unrelated subjects (0.46+/-0.11). The finding that human muscle sympathetic nerve responses to arousal are less determined by genotype than the resting level of corresponding sympathetic nerve activity suggests that the arousal response pattern is more prone to be altered by environmental factors. This raises the possibility that these intraindividually reproducible sympathetic neural response profiles can be modified in a positive direction from a cardiovascular risk perspective. PMID- 28348016 TI - Dose-Response Association Between Physical Activity and Incident Hypertension: A Systematic Review and Meta-Analysis of Cohort Studies. AB - Despite the inverse association between physical activity (PA) and incident hypertension, a comprehensive assessment of the quantitative dose-response association between PA and hypertension has not been reported. We performed a meta-analysis, including dose-response analysis, to quantitatively evaluate this association. We searched PubMed and Embase databases for articles published up to November 1, 2016. Random effects generalized least squares regression models were used to assess the quantitative association between PA and hypertension risk across studies. Restricted cubic splines were used to model the dose-response association. We identified 22 articles (29 studies) investigating the risk of hypertension with leisure-time PA or total PA, including 330 222 individuals and 67 698 incident cases of hypertension. The risk of hypertension was reduced by 6% (relative risk, 0.94; 95% confidence interval, 0.92-0.96) with each 10 metabolic equivalent of task h/wk increment of leisure-time PA. We found no evidence of a nonlinear dose-response association of PA and hypertension (Pnonlinearity=0.094 for leisure-time PA and 0.771 for total PA). With the linear cubic spline model, when compared with inactive individuals, for those who met the guidelines recommended minimum level of moderate PA (10 metabolic equivalent of task h/wk), the risk of hypertension was reduced by 6% (relative risk, 0.94; 95% confidence interval, 0.92-0.97). This meta-analysis suggests that additional benefits for hypertension prevention occur as the amount of PA increases. PMID- 28348019 TI - Should research ethics committees police reporting bias? PMID- 28348020 TI - Simon J Newell. PMID- 28348017 TI - Long-Term Effects of Ambient PM2.5 on Hypertension and Blood Pressure and Attributable Risk Among Older Chinese Adults. AB - Long-term exposure to ambient fine particulate pollution (PM2.5) has been associated with cardiovascular diseases. Hypertension, a major risk factor for cardiovascular diseases, has also been hypothesized to be linked to PM2.5 However, epidemiological evidence has been mixed. We examined long-term association between ambient PM2.5 and hypertension and blood pressure. We interviewed 12 665 participants aged 50 years and older and measured their blood pressures. Annual average PM2.5 concentrations were estimated for each community using satellite data. We applied 2-level logistic regression models to examine the associations and estimated hypertension burden attributable to ambient PM2.5 For each 10 MUg/m3 increase in ambient PM2.5, the adjusted odds ratio of hypertension was 1.14 (95% confidence interval, 1.07-1.22). Stratified analyses found that overweight and obesity could enhance the association, and consumption of fruit was associated with lower risk. We further estimated that 11.75% (95% confidence interval, 5.82%-18.53%) of the hypertension cases (corresponding to 914, 95% confidence interval, 453-1442 cases) could be attributable to ambient PM2.5 in the study population. Findings suggest that long-term exposure to ambient PM2.5 might be an important risk factor of hypertension and is responsible for significant hypertension burden in adults in China. A higher consumption of fruit may mitigate, whereas overweight and obesity could enhance this effect. PMID- 28348018 TI - Synergistic Interaction of Hypertension and Diabetes in Promoting Kidney Injury and the Role of Endoplasmic Reticulum Stress. AB - Diabetes mellitus and hypertension are major risk factors for chronic kidney injury, together accounting for >70% of end-stage renal disease. In this study, we assessed interactions of hypertension and diabetes mellitus in causing kidney dysfunction and injury and the role of endoplasmic reticulum (ER) stress. Hypertension was induced by aorta constriction (AC) between the renal arteries in 6-month-old male Goto-Kakizaki (GK) type 2 diabetic and control Wistar rats. Fasting plasma glucose averaged 162+/-11 and 87+/-2 mg/dL in GK and Wistar rats, respectively. AC produced hypertension in the right kidney (above AC) and near normal blood pressure in the left kidney (below AC), with both kidneys exposed to the same levels of glucose, circulating hormones, and neural influences. After 8 weeks of AC, blood pressure above the AC (and in the right kidney) increased from 109+/-1 to 152+/-5 mm Hg in GK rats and from 106+/-4 to 141+/-5 mm Hg in Wistar rats. The diabetic-hypertensive right kidneys in GK-AC rats had much greater increases in albumin excretion and histological injury compared with left kidneys (diabetes mellitus only) of GK rats or right kidneys (hypertension only) of Wistar-AC rats. Marked increases in ER stress and oxidative stress indicators were observed in diabetic-hypertensive kidneys of GK-AC rats. Inhibition of ER stress with tauroursodeoxycholic acid for 6 weeks reduced blood pressure (135+/-4 versus 151+/-4 mm Hg), albumin excretion, ER and oxidative stress, and glomerular injury, while increasing glomerular filtration rate in hypertensive-diabetic kidneys. These results suggest that diabetes mellitus and hypertension interact synergistically to promote kidney dysfunction and injury via ER stress. PMID- 28348021 TI - HIV, sexual risk and ethnicity among gay and bisexual men in England: survey evidence for persisting health inequalities. AB - OBJECTIVES: To examine ethnic group differences in HIV testing and sexual behaviours among a large sample of gay and bisexual men (GBM), 13 years after similar observations were made, assess national HIV prevention responses and inform planning priorities. METHODS: Cross-sectional convenience self-completion online survey in summer 2014, designed and recruited in collaboration with community-based health promoters and gay internet services; comparison with earlier findings reporting on similarly designed survey in 2001. RESULTS: We recruited 15 388 GBM living in England who self-reported as follows: 18.5% from ethnic minorities; 9.0% tested HIV positive (cf. 17.0% and 5.4% in 2001). Compared with the white British, Asian men were no longer less likely to report diagnosed HIV but had an equal probability of doing so (2001 OR=0.32, 95% CI 0.13 to 0.79; 2014 OR=1.04, 95% CI 0.71 to 1.54); black men remained significantly more likely to report diagnosed HIV (2001 OR=2.06, 95% CI 1.56 to 3.29; 2014 OR=1.62, 95% CI 1.10 to 2.36) as did men in the other white group (2001 OR=1.54, 95% CI 1.23 to 1.93; 2014 OR=1.31, 95% CI 1.10 to 1.55). Overall annual incidence of reported HIV diagnoses in 2014 was 1.1%. Black men were significantly more likely to report diagnosis with HIV in the last 12 months than the white British (adjusted odds ratios (AOR) 2.57, 95% CI 1.22 to 5.39). No minority ethnic group was more or less likely to report condom unprotected anal intercourse (CUAI) in the last year but men in the Asian, black and all others groups were more likely than the white British to report CUAI with more than one non-steady partners. CONCLUSIONS: Among GBM in England, HIV prevalence continues to be higher among black men and other white men compared with the white British. The protective effect of being from an Asian background appears no longer to pertain. Sexual risk behaviours may account for some of these differences. PMID- 28348022 TI - Increase in thyroglobulin antibody and thyroid peroxidase antibody levels, but not preterm birth-rate, in pregnant Danish women upon iodine fortification. AB - OBJECTIVE: The presence of thyroid antibodies in pregnancy has been associated with preterm birth. In the non-pregnant population, the implementation of the Danish iodine fortification program has increased the prevalence of thyroid antibodies. This study investigated the prevalence of thyroid peroxidase antibodies (TPOAbs) and thyroglobulin antibodies (TgAbs) in pregnant Danish women before, during and after implementation of the iodine fortification program and association with preterm birth. DESIGN: Comparative cohort study of 1368 pregnancies from three cohorts gathered before (1996-1998), during (2000-2003) and after (2008-2009) the iodine fortification program. METHODS: In cohort 1 (n = 297), TPOAbs were measured (DYNOtest (BRAHMS)). In cohorts 2 (n = 148) and 3 (n = 923), both TPOAbs and TgAbs were measured (Kryptor immunofluorescent assay (BRAHMS)). The prevalence and effect of antibody positivity were explored using three cut-offs: TPOAbs and/or TgAbs >100 kU/L, TPOAbs and/or TgAbs >60 kU/L and TPOAbs >30 and/or TgAbs >20 kU/L. National preterm birth data were extracted from the National Birth Registry. RESULTS: In the three cohorts, TPOAb levels >60 kU/L were found in 5.4, 8.1 and 12.0% (chi2(2, n = 1367) = 11.7, P = 0.003) respectively, and TPOAbs and/or TgAbs >60 kU/L in 8.1 and 16.2% in cohorts 2 and 3 respectively (chi2(2, n = 1070) = 6.5, P = 0.01). TgAb levels (>20 kU/L) had increased plenty-fold from cohort 2 to 3 (chi2(1, n = 1071) = 136.5, P < 0.001). Preterm birth occurred in 4.1% of all pregnancies with no effect from antibody positivity (TPOAbs and/or TgAbs >60 kU/L, chi2(1, n = 1039) = 0.0, P = 0.98, aOR = 1.1, 95% CI (0.4-2.7)). The national preterm birth-rate showed no increase over the same period. CONCLUSIONS: Thyroid antibody positivity in Danish pregnant women has more than doubled upon the implementation of the iodine fortification program without an increase in preterm birth-rate. PMID- 28348023 TI - A homozygous mutation of GNRHR in a familial case diagnosed with polycystic ovary syndrome. AB - CONTEXT: PCOS is a heterogeneous condition characterized by hyperandrogenism and chronic anovulation and affects about 10% of women. Its etiology is poorly known, but a dysregulation of gonadotropin secretion is one of its hallmarks. OBJECTIVE: As the etiology of PCOS is unclear, we have performed a genome-wide analysis of a consanguineous family with three sisters diagnosed with PCOS. METHODS: Whole exome sequencing and Sanger sequencing confirmation. RESULTS: Whole-exome sequencing allowed the detection of the missense variant rs104893836 located in the first coding exon of the GNRHR gene and leading to the p.Gln106Arg (p.Q106R) substitution. Sanger sequencing of all available individuals of the family confirmed that the variant was homozygous in the three affected sisters and heterozygous in both parents. CONCLUSIONS: This is the first description of a GNRHR gene mutation in patients diagnosed with PCOS. Although we do not exclude a possible interaction of the identified variant with the genetic background and/or the environment, our result suggests that genetic alterations in the hypothalamo pituitary axis may play role in the pathogenesis of PCOS. PMID- 28348024 TI - Regulation of Sporangium Formation by BldD in the Rare Actinomycete Actinoplanes missouriensis. AB - The rare actinomycete Actinoplanes missouriensis forms sporangia, including hundreds of flagellated spores that start swimming as zoospores after their release. Under conditions suitable for vegetative growth, zoospores stop swimming and germinate. A comparative proteome analysis between zoospores and germinating cells identified 15 proteins that were produced in larger amounts in germinating cells. They include an orthologue of BldD (herein named AmBldD [BldD of A. missouriensis]), which is a transcriptional regulator involved in morphological development and secondary metabolism in Streptomyces AmBldD was detected in mycelia during vegetative growth but was barely detected in mycelia during the sporangium-forming phase, in spite of the constant transcription of AmbldD throughout growth. An AmbldD mutant started to form sporangia much earlier than the wild-type strain, and the resulting sporangia were morphologically abnormal. Recombinant AmBldD bound a palindromic sequence, the AmBldD box, located upstream from AmbldD 3',5'-Cyclic di-GMP significantly enhanced the in vitro DNA-binding ability of AmBldD. A chromatin immunoprecipitation-sequencing analysis and an in silico search for AmBldD boxes revealed that AmBldD bound 346 genomic loci that contained the 19-bp inverted repeat 5'-NN(G/A)TNACN(C/G)N(G/C)NGTNA(C/T)NN-3' as the consensus AmBldD-binding sequence. The transcriptional analysis of 27 selected AmBldD target gene candidates indicated that AmBldD should repress 12 of the 27 genes, including bldM, ssgB, whiD, ddbA, and wblA orthologues. These genes are involved in morphological development in Streptomyces coelicolor A3(2). Thus, AmBldD is a global transcriptional regulator that seems to repress the transcription of tens of genes during vegetative growth, some of which are likely to be required for sporangium formation.IMPORTANCE The rare actinomycete Actinoplanes missouriensis undergoes complex morphological differentiation, including sporangium formation. However, almost no molecular biological studies have been conducted on this bacterium. BldD is a key global regulator involved in the morphological development of streptomycetes. BldD orthologues are highly conserved among sporulating actinomycetes, but no BldD orthologues, except one in Saccharopolyspora erythraea, have been studied outside the streptomycetes. Here, it was revealed that the BldD orthologue AmBldD is essential for normal developmental processes in A. missouriensis The AmBldD regulon seems to be different from the BldD regulon in Streptomyces coelicolor A3(2), but they share four genes that are involved in morphological differentiation in S. coelicolor A3(2). PMID- 28348025 TI - Vibrio cholerae VciB Mediates Iron Reduction. AB - Vibrio cholerae is the causative agent of the severe diarrheal disease cholera. V. cholerae thrives within the human host, where it replicates to high numbers, but it also persists within the aquatic environments of ocean and brackish water. To survive within these nutritionally diverse environments, V. cholerae must encode the necessary tools to acquire the essential nutrient iron in all forms it may encounter. A prior study of systems involved in iron transport in V. cholerae revealed the existence of vciB, which, while unable to directly transport iron, stimulates the transport of iron through ferrous (Fe2+) iron transport systems. We demonstrate here a role for VciB in V. cholerae in which VciB stimulates the reduction of Fe3+ to Fe2+, which can be subsequently transported into the cell with the ferrous iron transporter Feo. Iron reduction is independent of functional iron transport but is associated with the electron transport chain. Comparative analysis of VciB orthologs suggests a similar role for other proteins in the VciB family. Our data indicate that VciB is a dimer located in the inner membrane with three transmembrane segments and a large periplasmic loop. Directed mutagenesis of the protein reveals two highly conserved histidine residues required for function. Taken together, our results support a model whereby VciB reduces ferric iron using energy from the electron transport chain.IMPORTANCEVibrio cholerae is a prolific human pathogen and environmental organism. The acquisition of essential nutrients such as iron is critical for replication, and V. cholerae encodes a number of mechanisms to use iron from diverse environments. Here, we describe the V. cholerae protein VciB that increases the reduction of oxidized ferric iron (Fe3+) to the ferrous form (Fe2+), thus promoting iron acquisition through ferrous iron transporters. Analysis of VciB orthologs in Burkholderia and Aeromonas spp. suggest that they have a similar activity, allowing a functional assignment for this previously uncharacterized protein family. This study builds upon our understanding of proteins known to mediate iron reduction in bacteria. PMID- 28348027 TI - Actinoplanes Swims into the Molecular Age. AB - The survival strategy of Actinoplanes is fascinating from an evolutionary perspective, combining a short motile phase in an otherwise nonmotile, filamentous life cycle and the somewhat paradoxical concept of spores-normally thought of as a resting stage-that swim. In the first paper to report a molecular genetic analysis of development in Actinoplanes, the authors identify a key regulator of the entry into development (Y. Mouri, K. Konishi, A. Fujita, T. Tezuka, Y. Ohnishi, J Bacteriol 199:e00840-16, 2017, https://doi.org/10.1128/JB.00840-16). PMID- 28348026 TI - Cooperative Metabolism in a Three-Partner Insect-Bacterial Symbiosis Revealed by Metabolic Modeling. AB - An important factor determining the impact of microbial symbionts on their animal hosts is the balance between the cost of nutrients consumed by the symbionts and the benefit of nutrients released back to the host, but the quantitative significance of nutrient exchange in symbioses involving multiple microbial partners has rarely been addressed. In this study on the association between two intracellular bacterial symbionts, "Candidatus Portiera aleyrodidarum" and "Candidatus Hamiltonella defensa," and their animal host, the whitefly Bemisia tabaci, we apply metabolic modeling to investigate host-symbiont nutrient exchange. Our in silico analysis revealed that >60% of the essential amino acids and related metabolites synthesized by "Candidatus Portiera aleyrodidarum" are utilized by the host, including a substantial contribution of nitrogen recycled from host nitrogenous waste, and that these interactions are required for host growth. In contrast, "Candidatus Hamiltonella defensa" retains most or all of the essential amino acids and B vitamins that it is capable of synthesizing. Furthermore, "Candidatus Hamiltonella defensa" suppresses host growth in silico by competition with "Candidatus Portiera aleyrodidarum" for multiple host nutrients, by suppressing "Candidatus Portiera aleyrodidarum" growth and metabolic function, and also by consumption of host nutrients that would otherwise be allocated to host growth. The interpretation from these modeling outputs that "Candidatus Hamiltonella defensa" is a nutritional parasite could not be inferred reliably from gene content alone but requires consideration of constraints imposed by the structure of the metabolic network. Furthermore, these quantitative models offer precise predictions for future experimental study and the opportunity to compare the functional organization of metabolic networks in different symbioses.IMPORTANCE The metabolic functions of unculturable intracellular bacteria with much reduced genomes are traditionally inferred from gene content without consideration of how the structure of the metabolic network may influence flux through metabolic reactions. The three-compartment model of metabolic flux between two bacterial symbionts and their insect host constructed in this study revealed that one symbiont is structured to overproduce essential amino acids for the benefit of the host, but the essential amino acid production in the second symbiont is quantitatively constrained by the structure of its network, rendering it "selfish" with respect to these nutrients. This study demonstrates the importance of quantitative flux data for elucidation of the metabolic function of symbionts. The in silico methodology can be applied to other symbioses with intracellular bacteria. PMID- 28348029 TI - Noninvasive Imaging of Bone Microarchitecture in Patients Receiving Renal Transplant: Can it Replace Histology? PMID- 28348028 TI - Examination of Enterococcus faecalis Toxin-Antitoxin System Toxin Fst Function Utilizing a Pheromone-Inducible Expression Vector with Tight Repression and Broad Dynamic Range. AB - Tools for regulated gene expression in Enterococcus faecalis are extremely limited. In this report, we describe the construction of an expression vector for E. faecalis, designated pCIE, utilizing the PQ pheromone-responsive promoter of plasmid pCF10. We demonstrate that this promoter is tightly repressed, responds to nanogram quantities of the peptide pheromone, and has a large dynamic range. To demonstrate its utility, the promoter was used to control expression of the toxic peptides of two par family toxin-antitoxin (TA) loci present in E. faecalis, parpAD1 of the pAD1 plasmid and parEF0409 located on the E. faecalis chromosome. The results demonstrated differences in the modes of regulation of toxin expression and in the effects of toxins of these two related systems. We anticipate that this vector will be useful for further investigation of par TA system function as well as the regulated expression of other genes in E. faecalisIMPORTANCEE. faecalis is an important nosocomial pathogen and a model organism for examination of the genetics and physiology of Gram-positive cocci. While numerous genetic tools have been generated for the manipulation of this organism, vectors for the regulated expression of cloned genes remain limited by high background expression and the use of inducers with undesirable effects on the cell. Here we demonstrate that the PQ pheromone-responsive promoter is repressed tightly enough to allow cloning of TA system toxins and evaluate their effects at very low induction levels. This tool will allow us to more fully examine TA system function in E. faecalis and to further elucidate its potential roles in cell physiology. PMID- 28348030 TI - Association between Monocyte Count and Risk of Incident CKD and Progression to ESRD. AB - BACKGROUND AND OBJECTIVES: Experimental evidence suggests a role for monocytes in the biology of kidney disease progression; however, whether monocyte count is associated with risk of incident CKD, CKD progression, and ESRD has not been examined in large epidemiologic studies. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: We built a longitudinal observational cohort of 1,594,700 United States veterans with at least one eGFR during fiscal year 2004 (date of last eGFR during this period designated time zero) and no prior history of ESRD, dialysis, or kidney transplant. Cohort participants were followed until September 30, 2013 or death. Monocyte count closest to and before time zero was categorized in quartiles: quartile 1, >0.00 to <=0.40 thousand cells per cubic millimeter (k/cmm); quartile 2, >0.40 to <=0.55 k/cmm; quartile 3, >0.55 to <=0.70 k/cmm; and quartile 4, >0.70 k/cmm. Survival models were built to examine the association between monocyte count and risk of incident eGFR<60 ml/min per 1.73 m2, risk of incident CKD, and risk of CKD progression defined as doubling of serum creatinine, eGFR decline >=30%, or the composite outcome of ESRD, dialysis, or renal transplantation. RESULTS: Over a median follow-up of 9.2 years (interquartile range, 8.3-9.4); in adjusted survival models, there was a graded association between monocyte counts and risk of renal outcomes. Compared with quartile 1, quartile 4 was associated with higher risk of incident eGFR<60 ml/min per 1.73 m2 (hazard ratio, 1.13; 95% confidence interval, 1.12 to 1.14) and risk of incident CKD (hazard ratio, 1.15; 95% confidence interval, 1.13 to 1.16). Quartile 4 was associated with higher risk of doubling of serum creatinine (hazard ratio, 1.22; 95% confidence interval, 1.20 to 1.24), >=30% eGFR decline (hazard ratio, 1.18; 95% confidence interval, 1.17 to 1.19), and the composite renal end point (hazard ratio, 1.19; 95% confidence interval, 1.16 to 1.22). Cubic spline analyses of the relationship between monocyte count levels and renal outcomes showed a linear relationship, in which risk was higher with higher monocyte count. Results were robust to changes in sensitivity analyses. CONCLUSIONS: Our results show a significant association between higher monocyte count and risks of incident CKD and CKD progression to ESRD. PMID- 28348034 TI - What Is the Predictive Value of Animal Models for Vaccine Efficacy in Humans? Rigorous Simian Immunodeficiency Virus Vaccine Trials Can Be Instructive. AB - Simian immunodeficiency virus (SIV) challenge of rhesus macaques provides an invaluable tool to evaluate the clinical prospects of HIV-1 vaccine concepts. However, as with any animal model of human disease, it is crucial to understand the advantages and limitations of this system to maximize the translational value of SIV vaccine studies. Here, we discuss the importance of assessing the efficacy of vaccine prototypes using stringent SIV challenge regimens that mimic HIV-1 transmission and pathogenesis. We also review some of the cautionary tales of HIV 1 vaccine research because they provide general lessons for the preclinical assessment of vaccine candidates. PMID- 28348033 TI - Minimal Cells-Real and Imagined. AB - A minimal cell is one whose genome only encodes the minimal set of genes necessary for the cell to survive. Scientific reductionism postulates the best way to learn the first principles of cellular biology would be to use a minimal cell in which the functions of all genes and components are understood. The genes in a minimal cell are, by definition, essential. In 2016, synthesis of a genome comprised of only the set of essential and quasi-essential genes encoded by the bacterium Mycoplasma mycoides created a near-minimal bacterial cell. This organism performs the cellular functions common to all organisms. It replicates DNA, transcribes RNA, translates proteins, undergoes cell division, and little else. In this review, we examine this organism and contrast it with other bacteria that have been used as surrogates for a minimal cell. PMID- 28348031 TI - Spine Trabecular Bone Score as an Indicator of Bone Microarchitecture at the Peripheral Skeleton in Kidney Transplant Recipients. AB - BACKGROUND AND OBJECTIVES: Studies using high-resolution peripheral quantitative computed tomography showed progressive abnormalities in cortical and trabecular microarchitecture and biomechanical competence over the first year after kidney transplantation. However, high-resolution peripheral computed tomography is a research tool lacking wide availability. In contrast, the trabecular bone score is a novel and widely available tool that uses gray-scale variograms of the spine image from dual-energy x-ray absorptiometry to assess trabecular quality. There are no studies assessing whether trabecular bone score characterizes bone quality in kidney transplant recipients. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: Between 2009 and 2010, we conducted a study to assess changes in peripheral skeletal microarchitecture, measured by high-resolution peripheral computed tomography, during the first year after transplantation in 47 patients managed with early corticosteroid-withdrawal immunosuppression. All adult first-time transplant candidates were eligible. Patients underwent imaging with high resolution peripheral computed tomography and dual-energy x-ray absorptiometry pretransplantation and 3, 6, and 12 months post-transplantation. We now test if, during the first year after transplantation, trabecular bone score assesses the evolution of bone microarchitecture and biomechanical competence as determined by high-resolution peripheral computed tomography. RESULTS: At baseline and follow up, among the 72% and 78%, respectively, of patients having normal bone mineral density by dual-energy x-ray absorptiometry, 53% and 50%, respectively, were classified by trabecular bone score as having high fracture risk. At baseline, trabecular bone score correlated with spine, hip, and ultradistal radius bone mineral density by dual-energy x-ray absorptiometry and cortical area, density, thickness, and porosity; trabecular density, thickness, separation, and heterogeneity; and stiffness and failure load by high-resolution peripheral computed tomography. Longitudinally, each percentage increase in trabecular bone score was associated with increases in trabecular number (0.35%+/-1.4%); decreases in trabecular thickness (-0.45%+/-0.15%), separation (-0.40%+/-0.15%), and network heterogeneity (-0.48%+/-0.20%); and increases in failure load (0.22%+/-0.09%) by high-resolution peripheral computed tomography (all P<0.05). CONCLUSIONS: Trabecular bone score may be a useful method to assess and monitor bone quality and strength and classify fracture risk in kidney transplant recipients. PMID- 28348035 TI - What Is the Predictive Value of Animal Models for Vaccine Efficacy in Humans? The Importance of Bridging Studies and Species-Independent Correlates of Protection. AB - Animal models have played a pivotal role in all stages of vaccine development. Their predictive value for vaccine effectiveness depends on the pathogen, the robustness of the animal challenge model, and the correlates of protection (if known). This article will cover key questions regarding bridging animal studies to efficacy trials in humans. Examples include human papillomavirus (HPV) vaccine in which animal protection after vaccination with heterologous prototype virus like particles (VLPs) predicted successful efficacy trials in humans, and a recent approval of anthrax vaccine in accordance with the "Animal Rule." The establishment of animal models predictive of vaccine effectiveness in humans has been fraught with difficulties with low success rate to date. Challenges facing the use of animal models for vaccine development against Ebola and HIV will be discussed. PMID- 28348036 TI - TGF-beta Signaling in Control of Cardiovascular Function. AB - Genetic studies in animals and humans indicate that gene mutations that functionally perturb transforming growth factor beta (TGF-beta) signaling are linked to specific hereditary vascular syndromes, including Osler-Rendu-Weber disease or hereditary hemorrhagic telangiectasia and Marfan syndrome. Disturbed TGF-beta signaling can also cause nonhereditary disorders like atherosclerosis and cardiac fibrosis. Accordingly, cell culture studies using endothelial cells or smooth muscle cells (SMCs), cultured alone or together in two- or three dimensional cell culture assays, on plastic or embedded in matrix, have shown that TGF-beta has a pivotal effect on endothelial and SMC proliferation, differentiation, migration, tube formation, and sprouting. Moreover, TGF-beta can stimulate endothelial-to-mesenchymal transition, a process shown to be of key importance in heart valve cushion formation and in various pathological vascular processes. Here, we discuss the roles of TGF-beta in vasculogenesis, angiogenesis, and lymphangiogenesis and the deregulation of TGF-beta signaling in cardiovascular diseases. PMID- 28348037 TI - What Is the Predictive Value of Animal Models for Vaccine Efficacy in Humans? Consideration of Strategies to Improve the Value of Animal Models. AB - Animal models are an essential feature of the vaccine design toolkit. Although animal models have been invaluable in delineating the mechanisms of immune function, their precision in predicting how well specific vaccines work in humans is often suboptimal. There are, of course, many obvious species differences that may limit animal models from predicting all details of how a vaccine works in humans. However, careful consideration of which animal models may have limitations should also allow more accurate interpretations of animal model data and more accurate predictions of what is to be expected in clinical trials. In this article, we examine some of the considerations that might be relevant to cross-species extrapolation of vaccine-related immune responses for the prediction of how vaccines will perform in humans. PMID- 28348038 TI - Bone Morphogenetic Proteins in Vascular Homeostasis and Disease. AB - It is well established that control of vascular morphogenesis and homeostasis is regulated by vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), Delta-like 4 (Dll4), angiopoietin, and ephrin signaling. It has become clear that signaling by bone morphogenetic proteins (BMPs), which have a long history of studies in bone and early heart development, are also essential for regulating vascular function. Indeed, mutations that cause deregulated BMP signaling are linked to two human vascular diseases, hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension. These observations are corroborated by data obtained with vascular cells in cell culture and in mouse models. BMPs are required for normal endothelial cell differentiation and for venous/arterial and lymphatic specification. In adult life, BMP signaling orchestrates neo-angiogenesis as well as vascular inflammation, remodeling, and calcification responses to shear and oxidative stress. This review emphasizes the pivotal role of BMPs in the vascular system, based on studies of mouse models and human vascular disorders. PMID- 28348039 TI - What Is the Predictive Value of Animal Models for Vaccine Efficacy in Humans? Reevaluating the Potential of Mouse Models for the Human Immune System. AB - Much of what we understand about immunology, including the response to vaccines, come from studies in mice because they provide many practical advantages compared with research in higher mammals and humans. Nevertheless, modalities for preventing or treating disease do not always translate from mouse to humans, which has led to increasing scrutiny of the continued merits of mouse research. Here, we summarize the pros and cons of current laboratory mouse models for immunology research and discuss whether overreliance on nonphysiological, ultra hygienic animal husbandry approaches has limited the ultimate translation potential of mouse-derived data to humans. Alternative approaches are discussed that may extend the use of the mouse model for preclinical studies. PMID- 28348040 TI - Escape path complexity and its context dependency in Pacific blue-eyes (Pseudomugil signifer). AB - The escape paths prey animals take following a predatory attack appear to be highly unpredictable - a property that has been described as 'protean behaviour'. Here, we present a method of quantifying the escape paths of individual animals using a path complexity approach. When individual fish (Pseudomugil signifer) were attacked, we found that a fish's movement path rapidly increased in complexity following the attack. This path complexity remained elevated (indicating a more unpredictable path) for a sustained period (at least 10 s) after the attack. The complexity of the path was context dependent: paths were more complex when attacks were made closer to the fish, suggesting that these responses are tailored to the perceived level of threat. We separated out the components of speed and turning rate changes to determine which of these components contributed to the overall increase in path complexity following an attack. We found that both speed and turning rate measures contributed similarly to an individual's path complexity in absolute terms. Overall, our work highlights the context-dependent escape responses that animals use to avoid predators, and also provides a method for quantifying the escape paths of animals. PMID- 28348041 TI - High-speed surface reconstruction of a flying bird using structured light. AB - Birds fly effectively and maneuver nimbly by dynamically changing the shape of their wings during each wingbeat. These shape changes have yet to be quantified automatically at high temporal and spatial resolution. Therefore, we developed a custom 3D surface reconstruction method, which uses a high-speed camera to identify spatially encoded binary striped patterns that are projected on a flying bird. This non-invasive structured-light method allows automated 3D reconstruction of each stand-alone frame and can be extended to multiple views. We demonstrate this new technique by automatically reconstructing the dorsal surface of a parrotlet wing at 3200 frames s-1 during flapping flight. From this shape we analyze key parameters such as wing twist and angle of attack distribution. While our binary 'single-shot' algorithm is demonstrated by quantifying dynamic shape changes of a flying bird, it is generally applicable to moving animals, plants and deforming objects. PMID- 28348042 TI - Hearing on the fly: the effects of wing position on noctuid moth hearing. AB - The ear of the noctuid moth has only two auditory neurons, A1 and A2, which function in detecting predatory bats. However, the noctuid's ears are located on the thorax behind the wings. Therefore, as these moths need to hear during flight, it was hypothesized that wing position may affect their hearing. The wing was fixed in three different positions: up, flat and down. An additional subset of animals was measured with freely moving wings. In order to negate any possible acoustic shadowing or diffractive effects, all wings were snipped, leaving the proximal-most portion and the wing hinge intact. Results revealed that wing position plays a factor in threshold sensitivity of the less sensitive auditory neuron A2, but not in the more sensitive neuron A1. Furthermore, when the wing was set in the down position, fewer A1 action potentials were generated prior to the initiation of A2 activity. Analyzing the motion of the tympanal membrane did not reveal differences in movement due to wing position. Therefore, these neural differences arising from wing position are proposed to be due to other factors within the animal such as different muscle tensions. PMID- 28348043 TI - Olfactory sensitivity of the marine flatfish Solea senegalensis to conspecific body fluids. AB - Chemical communication is better understood in freshwater fish than marine fish. The Senegalese sole (Solea senegalensis) is a marine flatfish wherein one of the problems in aquaculture is the poor reproductive performance of hatchery-bred males. Is chemical communication involved in the reproduction of this species? Urine, intestinal fluid and mucus samples were taken from adult fish (wild-caught and hatchery-bred) over the spawning season (March-May), and assessed for olfactory potency using the electro-olfactogram (EOG). The effect of stimulation of the olfactory system with adult female urine on circulating luteinizing hormone (LH) levels was also tested in males. Intestinal fluid and urine were potent olfactory stimuli for both juvenile and adult conspecifics, evoking large amplitude, concentration-dependent EOG responses, with thresholds of detection at approximately 1:106 However, the amplitude of the response to urine depended on the sex and state of maturity of both the donor and the receiver. Most olfactory activity could be extracted by C18 solid-phase cartridges. Urine from mature females evoked a slight, but significant, increase in circulating LH levels in mature males 30 min after exposure. Furthermore, the olfactory potency of urine differed between wild-caught and hatchery-bred fish; however, contrary to expectations, urine from wild-caught females was less potent than that from hatchery-bred females. Taken together, these results strongly suggest that faeces and urine-released odorants are involved in reproduction in the Senegalese sole, and establish a basis for further investigation into pheromonal communication in marine teleosts. PMID- 28348044 TI - Model-assisted measurements of suspension-feeding flow velocities. AB - Benthic marine suspension feeders provide an important link between benthic and pelagic ecosystems. The strength of this link is determined by suspension-feeding rates. Many studies have measured suspension-feeding rates using indirect clearance-rate methods, which are based on the depletion of suspended particles. Direct methods that measure the flow of water itself are less common, but they can be more broadly applied because, unlike indirect methods, direct methods are not affected by properties of the cleared particles. We present pumping rates for three species of suspension feeders, the clams Mya arenaria and Mercenaria mercenaria and the tunicate Ciona intestinalis, measured using a direct method based on particle image velocimetry (PIV). Past uses of PIV in suspension-feeding studies have been limited by strong laser reflections that interfere with velocity measurements proximate to the siphon. We used a new approach based on fitting PIV-based velocity profile measurements to theoretical profiles from computational fluid dynamic (CFD) models, which allowed us to calculate inhalant siphon Reynolds numbers (Re). We used these inhalant Re and measurements of siphon diameters to calculate exhalant Re, pumping rates, and mean inlet and outlet velocities. For the three species studied, inhalant Re ranged from 8 to 520, and exhalant Re ranged from 15 to 1073. Volumetric pumping rates ranged from 1.7 to 7.4 l h-1 for M. arenaria, 0.3 to 3.6 l h-1 for M. mercenaria and 0.07 to 0.97 l h-1 for C. intestinalis We also used CFD models based on measured pumping rates to calculate capture regions, which reveal the spatial extent of pumped water. Combining PIV data with CFD models may be a valuable approach for future suspension-feeding studies. PMID- 28348045 TI - Stratification of Pancreatic Ductal Adenocarcinoma: Combinatorial Genetic, Stromal, and Immunologic Markers. AB - Purpose: Pancreatic ductal adenocarcinoma (PDAC) is associated with an immunosuppressive milieu that supports immune system evasion and disease progression. Here, we interrogated genetic, stromal, and immunologic features of PDAC to delineate impact on prognosis and means to more effectively employ immunotherapy.Experimental Design: A cohort of 109 PDAC cases annotated for overall survival was utilized as a primary discovery cohort. Gene expression analysis defined immunologic subtypes of PDAC that were confirmed in the Cancer Genome Atlas dataset. Stromal and metabolic characteristics of PDAC cases were evaluated by histologic analysis and immunostaining. Enumeration of lymphocytes, as well as staining for CD8, FOXP3, CD68, CD163, PDL1, and CTLA4 characterized immune infiltrate. Neoantigens were determined by analysis of whole-exome sequencing data. Random-forest clustering was employed to define multimarker subtypes, with univariate and multivariate analyses interrogating prognostic significance.Results: PDAC cases exhibited distinct stromal phenotypes that were associated with prognosis, glycolytic and hypoxic biomarkers, and immune infiltrate composition. Immune infiltrate was diverse among PDAC cases and enrichment for M2 macrophages and select immune checkpoints regulators were specifically associated with survival. Composite analysis with neoantigen burden, immunologic, and stromal features defined novel subtypes of PDAC that could have bearing on sensitivity to immunologic therapy approaches. In addition, a subtype with low levels of neoantigens and minimal lymphocyte infiltrate was associated with improved overall survival.Conclusions: The mutational burden of PDAC is associated with distinct immunosuppressive mechanisms that are conditioned by the tumor stromal environment. The defined subtypes have significance for utilizing immunotherapy in the treatment of PDAC. Clin Cancer Res; 23(15); 4429-40. (c)2017 AACR. PMID- 28348049 TI - In children 7 years of age, prenatal antidepressant exposure is not associated with increased risk of poor behavioural outcomes after adjusting for maternal factors including antenatal mood. PMID- 28348048 TI - OSNA testing for lymph node staging in colorectal cancer. PMID- 28348046 TI - B-Cell Lymphoma Patient-Derived Xenograft Models Enable Drug Discovery and Are a Platform for Personalized Therapy. AB - Purpose: Patients with B-cell lymphomas often relapse after frontline therapy, and novel therapies are urgently needed to provide long-term remission. We established B-cell lymphoma patient-derived xenograft (PDX) models to assess their ability to mimic tumor biology and to identify B-cell lymphoma patient treatment options.Experimental Design: We established the PDX models from 16 patients with diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, or Burkitt lymphoma by inoculating the patient tumor cells into a human bone chip implanted into mice. We subjected the PDX models to histopathologic and phenotypical examination, sequencing, and drug efficacy analysis. Primary and acquired resistance to ibrutinib, an oral covalent inhibitor of Bruton tyrosine kinase, were investigated to elucidate the mechanisms underlying ibrutinib resistance and to identify drug treatments to overcome resistance.Results: The PDXs maintained the same biological, histopathologic, and immunophenotypical features, retained similar genetic mutations, and produced comparable drug responses with the original patient tumors. In the acquired ibrutinib-resistant PDXs, PLC-gamma2, p65, and Src were downregulated; however, a PI3K signaling pathway member was upregulated. Inactivation of the PI3K pathway with the inhibitor idelalisib in combination with ibrutinib significantly inhibited the growth of the ibrutinib-resistant tumors. Furthermore, we used a PDX model derived from a clinically ibrutinib relapsed patient to evaluate various therapeutic choices, ultimately eliminating the tumor cells in the patient's peripheral blood.Conclusions: Our results demonstrate that the B-cell lymphoma PDX model is an effective system to predict and personalize therapies and address therapeutic resistance in B-cell lymphoma patients. Clin Cancer Res; 23(15); 4212-23. (c)2017 AACR. PMID- 28348047 TI - Genome-Wide Association Study Meta-Analysis of Long-Term Average Blood Pressure in East Asians. AB - BACKGROUND: Genome-wide single marker and gene-based meta-analyses of long-term average (LTA) blood pressure (BP) phenotypes may reveal novel findings for BP. METHODS AND RESULTS: We conducted genome-wide analysis among 18 422 East Asian participants (stage 1) followed by replication study of <=46 629 participants of European ancestry (stage 2). Significant single-nucleotide polymorphisms and genes were determined by a P<5.0*10-8 and 2.5*10-6, respectively, in joint analyses of stage-1 and stage-2 data. We identified 1 novel ARL3 variant, rs4919669 at 10q24.32, influencing LTA systolic BP (stage-1 P=5.03*10-8, stage-2 P=8.64*10-3, joint P=2.63*10-8) and mean arterial pressure (stage-1 P=3.59*10-9, stage-2 P=2.35*10-2, joint P=2.64*10-8). Three previously reported BP loci (WBP1L, NT5C2, and ATP2B1) were also identified for all BP phenotypes. Gene-based analysis provided the first robust evidence for association of KCNJ11 with LTA systolic BP (stage-1 P=8.55*10-6, stage-2 P=1.62*10-5, joint P=3.28*10-9) and mean arterial pressure (stage-1 P=9.19*10-7, stage-2 P=9.69*10-5, joint P=2.15*10 9) phenotypes. Fourteen genes (TMEM180, ACTR1A, SUFU, ARL3, SFXN2, WBP1L, CYP17A1, C10orf32, C10orf32-ASMT, AS3MT, CNNM2, and NT5C2 at 10q24.32; ATP2B1 at 12q21.33; and NCR3LG1 at 11p15.1) implicated by previous genome-wide association study meta-analyses were also identified. Among the loci identified by the previous genome-wide association study meta-analysis of LTA BP, we transethnically replicated associations of the KCNK3 marker rs1275988 at 2p23.3 with LTA systolic BP and mean arterial pressure phenotypes (P=1.27*10-4 and 3.30*10-4, respectively). CONCLUSIONS: We identified 1 novel variant and 1 novel gene and present the first direct evidence of relevance of the KCNK3 locus for LTA BP among East Asians. PMID- 28348050 TI - Differential Gamma Interferon- and Tumor Necrosis Factor Alpha-Driven Cytokine Response Distinguishes Acute Infection of a Metatherian Host with Toxoplasma gondii and Neospora caninum. AB - Toxoplasma gondii and Neospora caninum (both Apicomplexa) are closely related cyst-forming coccidian parasites that differ significantly in their host ranges and ability to cause disease. Unlike eutherian mammals, Australian marsupials (metatherian mammals) have long been thought to be highly susceptible to toxoplasmosis and neosporosis because of their historical isolation from the parasites. In this study, the carnivorous fat-tailed dunnart (Sminthopsis crassicaudata) was used as a disease model to investigate the immune response and susceptibility to infection of an Australian marsupial to T. gondii and N. caninum The disease outcome was more severe in N. caninum-infected dunnarts than in T. gondii-infected dunnarts, as shown by the severity of clinical and histopathological features of disease and higher tissue parasite burdens in the tissues evaluated. Transcriptome sequencing (RNA-seq) of spleens from infected dunnarts and mitogen-stimulated dunnart splenocytes was used to define the cytokine repertoires. Changes in mRNA expression during the time course of infection were measured using quantitative reverse transcription-PCR (qRT-PCR) for key Th1 (gamma interferon [IFN-gamma] and tumor necrosis factor alpha [TNF alpha]), Th2 (interleukin 4 [IL-4] and IL-6), and Th17 (IL-17A) cytokines. The results show qualitative differences in cytokine responses by the fat-tailed dunnart to infection with N. caninum and T. gondii Dunnarts infected with T. gondii were capable of mounting a more effective Th1 immune response than those infected with N. caninum, indicating the role of the immune response in the outcome scenarios of parasite infection in this marsupial mammal. PMID- 28348051 TI - Iron Efflux by PmtA Is Critical for Oxidative Stress Resistance and Contributes Significantly to Group A Streptococcus Virulence. AB - Group A Streptococcus (GAS) is a human-only pathogen that causes a spectrum of disease conditions. Given its survival in inflamed lesions, the ability to sense and overcome oxidative stress is critical for GAS pathogenesis. PerR senses oxidative stress and coordinates the regulation of genes involved in GAS antioxidant defenses. In this study, we investigated the role of PerR-controlled metal transporter A (PmtA) in GAS pathogenesis. Previously, PmtA was implicated in GAS antioxidant defenses and suggested to protect against zinc toxicity. Here, we report that PmtA is a P1B4-type ATPase that functions as an Fe(II) exporter and aids GAS defenses against iron intoxication and oxidative stress. The expression of pmtA is specifically induced by excess iron, and this induction requires PerR. Furthermore, a pmtA mutant exhibited increased sensitivity to iron toxicity and oxidative stress due to an elevated intracellular accumulation of iron. RNA-sequencing analysis revealed that GAS undergoes significant alterations in gene expression to adapt to iron toxicity. Finally, using two mouse models of invasive infection, we demonstrated that iron efflux by PmtA is critical for bacterial survival during infection and GAS virulence. Together, these data demonstrate that PmtA is a key component of GAS antioxidant defenses and contributes significantly to GAS virulence. PMID- 28348053 TI - Acanthamoeba Activates Macrophages Predominantly through Toll-Like Receptor 4- and MyD88-Dependent Mechanisms To Induce Interleukin-12 (IL-12) and IL-6. AB - Acanthamoeba castellanii is a ubiquitous free-living amoeba with a worldwide distribution that can occasionally infect humans, causing particularly severe infections in immunocompromised individuals. Dissecting the immunology of Acanthamoeba infections has been considered problematic due to the very low incidence of disease, despite the high exposure rates. While macrophages are acknowledged as playing a significant role in Acanthamoeba infections, little is known about how this facultative parasite influences macrophage activity. Therefore, in this study we investigated the effects of Acanthamoeba on the activation of resting macrophages. Consequently, murine bone marrow-derived macrophages were cocultured with trophozoites of either the laboratory Neff strain or a clinical isolate of A. castellaniiIn vitro real-time imaging demonstrated that trophozoites of both strains often established evanescent contact with macrophages. Both Acanthamoeba strains induced a proinflammatory macrophage phenotype characterized by the significant production of interleukin 12 (IL-12) and IL-6. However, macrophages cocultured with the clinical isolate of Acanthamoeba produced significantly less IL-12 and IL-6 than the Neff strain. The utilization of macrophages derived from MyD88-, TRIF-, Toll-like receptor 2 (TLR2)-, TLR4-, and TLR2/4-deficient mice indicated that Acanthamoeba-induced proinflammatory cytokine production was through MyD88-dependent, TRIF independent, TLR4-induced events. This study shows for the first time the involvement of TLRs expressed on macrophages in the recognition of and response to Acanthamoeba trophozoites. PMID- 28348054 TI - The oppD Gene and Putative Peptidase Genes May Be Required for Virulence in Mycoplasma gallisepticum. AB - Relatively few virulence genes have been identified in pathogenic mycoplasmas, so we used signature-tagged mutagenesis to identify mutants of the avian pathogen Mycoplasma gallisepticum with a reduced capacity to persist in vivo and compared the levels of virulence of selected mutants in experimentally infected chickens. Four mutants had insertions in one of the two incomplete oppABCDF operons, and a further three had insertions in distinct hypothetical genes, two containing peptidase motifs and one containing a member of a gene family. The three hypothetical gene mutants and the two with insertions in oppD1 were used to infect chickens, and all five were shown to have a reduced capacity to induce respiratory tract lesions. One oppD1 mutant and the MGA_1102 and MGA_1079 mutants had a greatly reduced capacity to persist in the respiratory tract and to induce systemic antibody responses against M. gallisepticum The other oppD1 mutant and the MGA_0588 mutant had less capacity than the wild type to persist in the respiratory tract but did elicit systemic antibody responses. Although M. gallisepticum carries two incomplete opp operons, one of which has been acquired by horizontal gene transfer, our results suggest that one of the copies of oppD may be required for full expression of virulence. We have also shown that three hypothetical genes, two of which encode putative peptidases, may be required for full expression of virulence in M. gallisepticum. None of these genes has previously been shown to influence virulence in pathogenic mycoplasmas. PMID- 28348052 TI - Bile Acid Administration Elicits an Intestinal Antimicrobial Program and Reduces the Bacterial Burden in Two Mouse Models of Enteric Infection. AB - In addition to their chemical antimicrobial nature, bile acids are thought to have other functions in the homeostatic control of gastrointestinal immunity. However, those functions have remained largely undefined. In this work, we used ileal explants and mouse models of bile acid administration to investigate the role of bile acids in the regulation of the intestinal antimicrobial response. Mice fed on a diet supplemented with 0.1% chenodeoxycholic acid (CDCA) showed an upregulated expression of Paneth cell alpha-defensins as well as an increased synthesis of the type-C lectins Reg3b and Reg3g by the ileal epithelium. CDCA acted on several epithelial cell types, by a mechanism independent from farnesoid X receptor (FXR) and not involving STAT3 or beta-catenin activation. CDCA feeding did not change the relative abundance of major commensal bacterial groups of the ileum, as shown by 16S analyses. However, administration of CDCA increased the expression of ileal Muc2 and induced a change in the composition of the mucosal immune cell repertoire, decreasing the proportion of Ly6G+ and CD68+ cells, while increasing the relative amount of IgGkappa+ B cells. Oral administration of CDCA to mice attenuated infections with the bile-resistant pathogens Salmonella enterica serovar Typhimurium and Citrobacter rodentium, promoting lower systemic colonization and faster bacteria clearance, respectively. Our results demonstrate that bile acid signaling in the ileum triggers an antimicrobial program that can be potentially used as a therapeutic option against intestinal bacterial infections. PMID- 28348055 TI - The Enigmatic PE/PPE Multigene Family of Mycobacteria and Tuberculosis Vaccination. AB - The genome of Mycobacterium tuberculosis, the bacterium responsible for the disease tuberculosis, contains an unusual family of abundant antigens (PE/PPEs). To date, certain members of this multigene family occur only in mycobacteria that cause disease. It is possible that the numerous proteins encoded by these mycobacterial genes dictate the immune pathogenesis of this bacterial pathogen. There is also evidence that some of these antigens are present at the cell surface and that they affect the pathology and immunology of the organism in many ways. Also, they elicit both antibodies and T cells, they may be involved in antigenic variation, and they may be good candidates for vaccines and drugs. However, since they are plentiful and extremely homologous, these PE/PPEs are very challenging to study, and it is difficult to be certain what role(s) they have in the pathogenesis of tuberculosis. Consequently, how to develop treatments like vaccines using these antigens as candidates is complex. PMID- 28348058 TI - Edema and Nociception Induced by Philodryas patagoniensis Venom in Mice: A Pharmacological Evaluation with Implications for the Accident Treatment. AB - We have investigated the mechanisms involved in the genesis of edema and nociception induced by Philodryas patagoniensis venom (PpV) injected into the footpad of mice. PpV induced dose-related edema and nociceptive effects. Pretreatment of mice with cyclooxygenase inhibitor (indomethacin), but not with cyclooxygenase 2 inhibitor (celecoxib) markedly inhibited both effects. Pretreatments with H1 receptor antagonist (promethazine) or with dual histamine serotonin inhibitor (cyproheptadine) failed in inhibiting both effects. In groups pretreated with captopril (angiotensin-converting enzyme inhibitor) the edema was unaltered, but nociception was clearly increased, suggesting the participation of kinins in the pathophysiology of the nociception but not of the edema-forming effect of PpV. When PpV was treated with EDTA, the nociception was similar to the one induced by untreated venom, but edema was markedly reduced. We concluded that PpV-induced edema and nociception have cyclooxygenase eicosanoids as the main mediators and no participation of vasoactive amines. Kinins seem to participate in nociception but not in edema induced by PpV. The results also suggest that metalloproteinases are the main compounds responsible for the edema, but not for the nociception induced by this venom. PMID- 28348056 TI - Analysis of Shigella flexneri Resistance, Biofilm Formation, and Transcriptional Profile in Response to Bile Salts. AB - The Shigella species cause millions of cases of watery or bloody diarrhea each year, mostly in children in developing countries. While many aspects of Shigella colonic cell invasion are known, crucial gaps in knowledge regarding how the bacteria survive, transit, and regulate gene expression prior to infection remain. In this study, we define mechanisms of resistance to bile salts and build on previous research highlighting induced virulence in Shigella flexneri strain 2457T following exposure to bile salts. Typical growth patterns were observed within the physiological range of bile salts; however, growth was inhibited at higher concentrations. Interestingly, extended periods of exposure to bile salts led to biofilm formation, a conserved phenotype that we observed among members of the Enterobacteriaceae Characterization of S. flexneri 2457T biofilms determined that both bile salts and glucose were required for formation, dispersion was dependent upon bile salts depletion, and recovered bacteria displayed induced adherence to HT-29 cells. RNA-sequencing analysis verified an important bile salt transcriptional profile in S. flexneri 2457T, including induced drug resistance and virulence gene expression. Finally, functional mutagenesis identified the importance of the AcrAB efflux pump and lipopolysaccharide O-antigen synthesis for bile salt resistance. Our data demonstrate that S. flexneri 2457T employs multiple mechanisms to survive exposure to bile salts, which may have important implications for multidrug resistance. Furthermore, our work confirms that bile salts are important physiological signals to activate S. flexneri 2457T virulence. This work provides insights into how exposure to bile likely regulates Shigella survival and virulence during host transit and subsequent colonic infection. PMID- 28348059 TI - The Glycolytic Enzyme PFKFB3 Is Involved in Estrogen-Mediated Angiogenesis via GPER1. AB - The endogenous estrogen 17beta-estradiol (E2) is a key factor in promoting endothelial healing and angiogenesis. Recently, proangiogenic signals including vascular endothelial growth factor and others have been shown to converge in endothelial cell metabolism. Because inhibition of the glycolytic enzyme activator phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) reduces pathologic angiogenesis and estrogen receptor (ER) signaling stimulates glucose uptake and glycolysis by inducing PFKFB3 in breast cancer, we hypothesized that E2 triggers angiogenesis in endothelial cells via rapid ER signaling that requires PFKFB3 as a downstream effector. We report that treatment with the selective G protein-coupled estrogen receptor (GPER1) agonist G-1 (10-10 to 10-7 M) mimicked the chemotactic and proangiogenic effect of E2 as measured in a number of short-term angiogenesis assays in human umbilical vein endothelial cells (HUVECs); in addition, E2 treatment upregulated PFKFB3 expression in a time and concentration-dependent manner. Such an effect peaked at 3 hours and was also induced by G-1 and abolished by pretreatment with the GPER1 antagonist G-15 or GPER1 siRNA, consistent with engagement of membrane ER. Experiments with the PFKFB3 inhibitor 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one showed that PFKFB3 activity was required for estrogen-mediated HUVEC migration via GPER1. In conclusion, E2-induced angiogenesis was mediated at least in part by the membrane GPER1 and required upregulation of the glycolytic activator PFKFB3 in HUVECs. These findings unravel a previously unrecognized mechanism of estrogen-dependent endocrine-metabolic crosstalk in HUVECs and may have implications in angiogenesis occurring in ischemic or hypoxic tissues. PMID- 28348057 TI - Immune Recognition of the Epidemic Cystic Fibrosis Pathogen Burkholderia dolosa. AB - Burkholderia dolosa caused an outbreak in the cystic fibrosis (CF) clinic at Boston Children's Hospital from 1998 to 2005 and led to the infection of over 40 patients, many of whom died due to complications from infection by this organism. To assess whether B. dolosa significantly contributes to disease or is recognized by the host immune response, mice were infected with a sequenced outbreak B. dolosa strain, AU0158, and responses were compared to those to the well-studied CF pathogen Pseudomonas aeruginosa In parallel, mice were also infected with a polar flagellin mutant of B. dolosa to examine the role of flagella in B. dolosa lung colonization. The results showed a higher persistence in the host by B. dolosa strains, and yet, neutrophil recruitment and cytokine production were lower than those with P. aeruginosa The ability of host immune cells to recognize B. dolosa was then assessed, B. dolosa induced a robust cytokine response in cultured cells, and this effect was dependent on the flagella only when bacteria were dead. Together, these results suggest that B. dolosa can be recognized by host cells in vitro but may avoid or suppress the host immune response in vivo through unknown mechanisms. B. dolosa was then compared to other Burkholderia species and found to induce similar levels of cytokine production despite being internalized by macrophages more than Burkholderia cenocepacia strains. These data suggest that B. dolosa AU0158 may act differently with host cells and is recognized differently by immune systems than are other Burkholderia strains or species. PMID- 28348060 TI - GeneImp: Fast Imputation to Large Reference Panels Using Genotype Likelihoods from Ultralow Coverage Sequencing. AB - We address the task of genotype imputation to a dense reference panel given genotype likelihoods computed from ultralow coverage sequencing as inputs. In this setting, the data have a high-level of missingness or uncertainty, and are thus more amenable to a probabilistic representation. Most existing imputation algorithms are not well suited for this situation, as they rely on prephasing for computational efficiency, and, without definite genotype calls, the prephasing task becomes computationally expensive. We describe GeneImp, a program for genotype imputation that does not require prephasing and is computationally tractable for whole-genome imputation. GeneImp does not explicitly model recombination, instead it capitalizes on the existence of large reference panels comprising thousands of reference haplotypes-and assumes that the reference haplotypes can adequately represent the target haplotypes over short regions unaltered. We validate GeneImp based on data from ultralow coverage sequencing (0.5*), and compare its performance to the most recent version of BEAGLE that can perform this task. We show that GeneImp achieves imputation quality very close to that of BEAGLE, using one to two orders of magnitude less time, without an increase in memory complexity. Therefore, GeneImp is the first practical choice for whole-genome imputation to a dense reference panel when prephasing cannot be applied, for instance, in datasets produced via ultralow coverage sequencing. A related future application for GeneImp is whole-genome imputation based on the off-target reads from deep whole-exome sequencing. PMID- 28348061 TI - Alternative Polyadenylation Directs Tissue-Specific miRNA Targeting in Caenorhabditis elegans Somatic Tissues. AB - mRNA expression dynamics promote and maintain the identity of somatic tissues in living organisms; however, their impact in post-transcriptional gene regulation in these processes is not fully understood. Here, we applied the PAT-Seq approach to systematically isolate, sequence, and map tissue-specific mRNA from five highly studied Caenorhabditis elegans somatic tissues: GABAergic and NMDA neurons, arcade and intestinal valve cells, seam cells, and hypodermal tissues, and studied their mRNA expression dynamics. The integration of these datasets with previously profiled transcriptomes of intestine, pharynx, and body muscle tissues, precisely assigns tissue-specific expression dynamics for 60% of all annotated C. elegans protein-coding genes, providing an important resource for the scientific community. The mapping of 15,956 unique high-quality tissue specific polyA sites in all eight somatic tissues reveals extensive tissue specific 3'untranslated region (3'UTR) isoform switching through alternative polyadenylation (APA) . Almost all ubiquitously transcribed genes use APA and harbor miRNA targets in their 3'UTRs, which are commonly lost in a tissue specific manner, suggesting widespread usage of post-transcriptional gene regulation modulated through APA to fine tune tissue-specific protein expression. Within this pool, the human disease gene C. elegans orthologs rack-1 and tct-1 use APA to switch to shorter 3'UTR isoforms in order to evade miRNA regulation in the body muscle tissue, resulting in increased protein expression needed for proper body muscle function. Our results highlight a major positive regulatory role for APA, allowing genes to counteract miRNA regulation on a tissue-specific basis. PMID- 28348064 TI - Acidosis and Kidney Allograft Survival. PMID- 28348062 TI - Regulation of Hyphal Growth and N-Acetylglucosamine Catabolism by Two Transcription Factors in Candida albicans. AB - The amino sugar N-acetylglucosamine (GlcNAc) is increasingly recognized as an important signaling molecule in addition to its well-known structural roles at the cell surface. In the human fungal pathogen Candida albicans, GlcNAc stimulates several responses including the induction of the genes needed for its catabolism and a switch from budding to filamentous hyphal growth. We identified two genes needed for growth on GlcNAc (RON1 and NGS1) and found that mutants lacking these genes fail to induce the genes needed for GlcNAc catabolism. NGS1 was also important for growth on other sugars, such as maltose, but RON1 appeared to be specific for GlcNAc. Both mutants could grow on nonfermentable carbon sources indicating that they do not affect mitochondrial function, which we show is important for growth on GlcNAc but not for GlcNAc induction of hyphal morphogenesis. Interestingly, both the ron1Delta and ngs1Delta mutants were defective in forming hyphae in response to GlcNAc, even though GlcNAc catabolism is not required for induction of hyphal morphogenesis. The ron1Delta mutant showed a partial defect in forming hyphae, which was surprising since it displayed an elevated level of filamentous cells under noninducing conditions. The ron1Delta mutant also displayed an elevated basal level of expression of genes that are normally upregulated during hyphal growth. Consistent with this, Ron1 contains an Ndt80-like DNA-binding domain, indicating that it regulates gene expression. Thus, Ron1 is a key new component of the GlcNAc response pathway that acts as both an activator and a repressor of hyphal morphogenesis. PMID- 28348063 TI - Long-Term Endothelin-A Receptor Antagonism Provides Robust Renal Protection in Humanized Sickle Cell Disease Mice. AB - Sickle cell disease (SCD)-associated nephropathy is a major source of morbidity and mortality in patients because of the lack of efficacious treatments targeting renal manifestations of the disease. Here, we describe a long-term treatment strategy with the selective endothelin-A receptor (ETA) antagonist, ambrisentan, designed to interfere with the development of nephropathy in a humanized mouse model of SCD. Ambrisentan preserved GFR at the level of nondisease controls and prevented the development of proteinuria, albuminuria, and nephrinuria. Microscopy studies demonstrated prevention of podocyte loss and structural alterations, the absence of vascular congestion, and attenuation of glomerulosclerosis in treated mice. Studies in isolated glomeruli showed that treatment reduced inflammation and oxidative stress. At the level of renal tubules, ambrisentan treatment prevented the increased excretion of urinary tubular injury biomarkers. Additionally, the treatment strategy prevented tubular brush border loss, diminished tubular iron deposition, blocked the development of interstitial fibrosis, and prevented immune cell infiltration. Furthermore, the prevention of albuminuria in treated mice was associated with preservation of cortical megalin expression. In a separate series of identical experiments, combined ETA and ETB receptor antagonism provided only some of the protection observed with ambrisentan, highlighting the importance of exclusively targeting the ETA receptor in SCD. Our results demonstrate that ambrisentan treatment provides robust protection from diverse renal pathologies in SCD mice, and suggest that long-term ETA receptor antagonism may provide a strategy for the prevention of renal complications of SCD. PMID- 28348065 TI - Genomic Disorders and Neurocognitive Impairment in Pediatric CKD. AB - Children with CKD are at increased risk for neurocognitive impairment, but whether neurocognitive dysfunction is solely attributable to impaired renal function is unclear. Data from the CKD in Children Study Chronic Kidney Disease in Children (CKiD) Study indicate that a subset of children with CKD have unsuspected genomic disorders that predispose them to organ malformations and neurocognitive impairment. We therefore tested whether the CKiD Study participants with genomic disorders had impaired neurocognitive performance at enrollment. Compared with noncarriers (n=389), children with genomic disorders (n=31) scored significantly poorer on all measures of intelligence, anxiety/depressive symptoms, and executive function (differences of 0.6-0.7 SD; P=1.2*10-3-2.4*10-4). These differences persisted after controlling for known modifiers, including low birth weight, maternal education, seizure disorder, kidney disease duration, and genetically defined ancestry. The deleterious effect of genomic disorders on neurocognitive function was significantly attenuated in offspring of mothers with higher education, indicating the potential for modification by genetic and/or environmental factors. These data indicate that impaired neurocognitive function in some children with CKD may be attributable to genetic lesions that affect both kidney and neurocognitive development. Early identification of genomic disorders may provide opportunity for early diagnosis and personalized interventions to mitigate the effect on neurocognitive function. PMID- 28348068 TI - Focal Macroscopic Cortical Lesions in Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy. AB - BACKGROUND AND PURPOSE: Cortical microinfarcts and secondary cortical degeneration have been demonstrated in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a severe monogenic cerebral small vessel disease. The aim of this study was to determine whether focal macroscopic cortical lesions can be detected using a specific in vivo magnetic resonance imaging approach. METHODS: Three-dimensional T1 magnetic resonance imaging scans were obtained in 28 nondemented nondisabled CADASIL patients and 29 age- and sex-matched controls. The cortical mantle of patients and controls were extracted using Brainvisa by an experienced user and then evaluated during a dedicated reading session by a second reader after removing the white matter to stay blind to the clinical status. Thereafter, confirmed focal macroscopic cortical lesions were characterized using all available imaging data, including 7-T magnetic resonance imaging in some patients. RESULTS: Three focal macroscopic cortical lesions were confirmed in 3 of 28 patients (11%) but none in controls. All lesions were observed in the close vicinity of severe signal changes in the underlying white matter. CONCLUSIONS: Focal macroscopic cortical lesions can be detected using specific magnetic resonance imaging approaches in CADASIL patients long before the end stage of the disorder. The underlying mechanisms and precise clinical consequences of these cortical changes still need to be determined. PMID- 28348066 TI - Poplar MYB115 and MYB134 Transcription Factors Regulate Proanthocyanidin Synthesis and Structure. AB - The accumulation of proanthocyanidins is regulated by a complex of transcription factors composed of R2R3 MYB, basic helix-loop-helix, and WD40 proteins that activate the promoters of biosynthetic genes. In poplar (genus Populus), MYB134 is known to regulate proanthocyanidin biosynthesis by activating key flavonoid genes. Here, we characterize a second MYB regulator of proanthocyanidins, MYB115. Transgenic poplar overexpressing MYB115 showed a high-proanthocyanidin phenotype and reduced salicinoid accumulation, similar to the effects of MYB134 overexpression. Transcriptomic analysis of MYB115- and MYB134-overexpressing poplar plants identified a set of common up-regulated genes encoding proanthocyanidin biosynthetic enzymes and several novel uncharacterized MYB transcriptional repressors. Transient expression experiments demonstrated the capacity of both MYB134 and MYB115 to activate flavonoid promoters, but only in the presence of a basic helix-loop-helix cofactor. Yeast two-hybrid experiments confirmed the direct interaction of these transcription factors. The unexpected identification of dihydromyricetin in leaf extracts of both MYB115- and MYB134 overexpressing poplar led to the discovery of enhanced flavonoid B-ring hydroxylation and an increased proportion of prodelphinidins in proanthocyanidin of the transgenics. The dramatic hydroxylation phenotype of MYB115 overexpressors is likely due to the up-regulation of both flavonoid 3',5'-hydroxylases and cytochrome b5 Overall, this work provides new insight into the complexity of the gene regulatory network for proanthocyanidin synthesis in poplar. PMID- 28348067 TI - Proteomics and integrative omic approaches for understanding host-pathogen interactions and infectious diseases. AB - Organisms are constantly exposed to microbial pathogens in their environments. When a pathogen meets its host, a series of intricate intracellular interactions shape the outcome of the infection. The understanding of these host-pathogen interactions is crucial for the development of treatments and preventive measures against infectious diseases. Over the past decade, proteomic approaches have become prime contributors to the discovery and understanding of host-pathogen interactions that represent anti- and pro-pathogenic cellular responses. Here, we review these proteomic methods and their application to studying viral and bacterial intracellular pathogens. We examine approaches for defining spatial and temporal host-pathogen protein interactions upon infection of a host cell. Further expanding the understanding of proteome organization during an infection, we discuss methods that characterize the regulation of host and pathogen proteomes through alterations in protein abundance, localization, and post translational modifications. Finally, we highlight bioinformatic tools available for analyzing such proteomic datasets, as well as novel strategies for integrating proteomics with other omic tools, such as genomics, transcriptomics, and metabolomics, to obtain a systems-level understanding of infectious diseases. PMID- 28348070 TI - Syndecan 1 represses cell growth and FSH responsiveness in human granulosa cells. AB - Albeit devoid of intrinsic catalytic activity, the transmembrane heparan sulphate proteoglycan syndecan 1 plays critical roles in cellular processes such as extracellular matrix crosstalk, cytoskeletal organization, cell spreading, proliferation and differentiation. During the ovarian cycle, the expression of syndecan 1 in granulosa cells shows cyclic variation suggesting that it might fulfil specific roles in follicle development. To investigate its physiological roles on granulosa cells, syndecan 1 was overexpressed in human granulosa cell line KGN which retains features of granulosa cells from small antral follicle such as estradiol (E2) synthesis and low expression of functional FSH receptor (FSHR). We demonstrated that overexpression of syndecan 1 in immature granulosa cells (KGN-SDC1) induces a profound alteration in their intrinsic characteristics including enhanced spreading and attachment, both associated with a reduced growth rate. Flow cytometry analysis revealed that syndecan 1 overexpression increases the percentage of KGN cells in quiescent phase. This partial cell cycle exit is concordant with downregulated levels of CCND1 and CDK4 and upregulated expression of CDK inhibitor CDKN1A In parallel both unstimulated and FSH-induced E2 synthesis are reduced in KGN-SDC1 through both repression of CYP19A1 and FSHR mRNA associated with decreased levels of potential regulators NR5A1 and ESR2 Additionally, we provide evidence that transient cAMP accumulation reduction in cells overexpressing syndecan 1 is accompanied by an increase in cAMP-hydrolysing PDE activity. Our results demonstrated that syndecan 1 might regulate differentiation of granulosa cells and follicular development by means of various mechanisms involving morphological changes, control of signalling pathways and alterations in gene expressions.Free French abstract: A French translation of this abstract is freely available at http://www.reproduction online.org/content/153/6/797/suppl/DC1.Reproduction. PMID- 28348069 TI - Hypoxia-inducible factor-1alpha promotes endometrial stromal cells migration and invasion by upregulating autophagy in endometriosis. AB - Endometriosis is a benign gynecological disease that shares some characteristics with malignancy like migration and invasion. It has been reported that both hypoxia-inducible factor-1alpha (HIF-1alpha) and autophagy were upregulated in ectopic endometrium of patients with ovarian endometriosis. However, the crosstalk between HIF-1alpha and autophagy in the pathogenesis of endometriosis remains to be clarified. Accordingly, we investigated whether autophagy was regulated by HIF-1alpha, as well as whether the effect of HIF-1alpha on cell migration and invasion is mediated through autophagy upregulation. Here, we found that ectopic endometrium from patients with endometriosis highly expressed HIF 1alpha and autophagy-related protein LC3. In cultured human endometrial stromal cells (HESCs), autophagy was induced by hypoxia in a time-dependent manner and autophagy activation was dependent on HIF-1alpha. In addition, migration and invasion ability of HESCs were enhanced by hypoxia treatment, whereas knockdown of HIF-1alpha attenuated this effect. Furthermore, inhibiting autophagy with specific inhibitors and Beclin1 siRNA attenuated hypoxia triggered migration and invasion of HESCs. Taken together, these results suggest that HIF-1alpha promotes HESCs invasion and metastasis by upregulating autophagy. Thus, autophagy may be involved in the pathogenesis of endometriosis and inhibition of autophagy might be a novel therapeutic approach to the treatment of endometriosis. PMID- 28348071 TI - Acromegalic arthropathy in various stages of the disease: an MRI study. AB - BACKGROUND: Arthropathy is a prevalent and invalidating complication of acromegaly with a characteristic radiographic phenotype. We aimed to further characterize cartilage and bone abnormalities associated with acromegalic arthropathy using magnetic resonance imaging (MRI). METHODS: Twenty-six patients (23% women, mean age 56.8 +/- 13.4 years), with active (n = 10) and controlled acromegaly (n = 16) underwent a 3.0 T MRI of the right knee. Osteophytes, cartilage defects, bone marrow lesions and subchondral cysts were assessed by the Knee Osteoarthritis Scoring System (KOSS) method. Cartilage thickness and cartilage T2 relaxation times, in which higher values reflect increased water content and/or structural changes, were measured. Twenty-five controls (52% women, mean age: 59.6 +/- 8.0 years) with primary knee OA were included for comparison. RESULTS: Both in active and controlled acromegaly, structural OA defects were highly prevalent, with thickest cartilage and highest cartilage T2 relaxation times in the active patients. When compared to primary OA subjects, patients with acromegaly seem to have less cysts (12% vs 48%, P = 0.001) and bone marrow lesions (15% vs 80%, P = 0.006), but comparable prevalence of osteophytosis and cartilage defects. Patients with acromegaly had 31% thicker total joint cartilage (P < 0.001) with higher cartilage T2 relaxation times at all measured sites than primary OA subjects (P < 0.01). CONCLUSIONS: Patients with active acromegaly have a high prevalence of structural OA abnormalities in combination with thick joint cartilage. In addition, T2 relaxation times of cartilage are high in active patients, indicating unhealthy cartilage with increased water content, which is (partially) reversible by adequate treatment. Patients with acromegaly have a different distribution of structural OA abnormalities visualized by MRI than primary OA subjects, especially of cartilage defects. PMID- 28348072 TI - The follicle-stimulating hormone (FSH) and luteinizing hormone (LH) response to a gonadotropin-releasing hormone analogue test in healthy prepubertal girls aged 10 months to 6 years. AB - OBJECTIVE: Premature thelarche and precocious puberty are frequently diagnosed in girls even below 6 years of age and may be difficult to differentiate in the early stages. A GnRH test is often included in the diagnostic work-up, although interpretation of the GnRH test in girls below 6 years of age is challenging, as no reference interval exists for this age group. The objective is to determine the normal FSH and LH response to a GnRH test in healthy prepubertal girls below 6 years of age. DESIGN AND METHODS: A standardized GnRH test, baseline reproductive hormones, clinical evaluation and bone age were determined in all participants. Forty-eight healthy normal-weight girls aged 3.5 +/- 0.2 years (range: 0.8-5.9 years) were included. Serum concentrations of LH and FSH were measured before and 30 min after the gonadorelin injection. RESULTS: The 30-min LH responses (mean +/- 2 s.d.) were 5.2 +/- 4.0 and 2.9 +/- 2.5 IU/L and the FSH responses were 23.3 +/- 16.2 and 14.5 +/- 10.3 IU/L in girls aged 0.8-3.0 years and 3.0-5.9 years respectively. This corresponds to upper cut-off limits for LH of 9.2 IU/L (<3 years) and 5.3 IU/L (3-6 years). The stimulated LH/FSH ratio was 0.23 +/- 0.19 (range 0.06-0.43) and did not correlate with age. CONCLUSIONS: We found that LH increases up to 9.2 IU/L during GnRH test in healthy normal-weight girls below 3 years of age and that the stimulated LH/FSH ratio did not exceed 0.43. Our findings have important implications for appropriate diagnosis of central precocious puberty in girls below 6 years of age. PMID- 28348073 TI - From benign adrenal incidentaloma to adrenocortical carcinoma: an exceptional random event. AB - New European guidelines for the management of adrenal incidentalomas were recently released. One of the most novel recommendations is to stop following patients when they present a typical, small and non-secreting adenoma. We report here the case of a 71-year-old man with such an adenoma, who developed an adrenocortical carcinoma (ACC) fourteen years later, with subsequent metastases and death. Clinically, he had a normal blood pressure and no sign of hormonal hypersecretion. The hormonal work-up showed no hormone excess: urinary free cortisol level was normal, the diurnal cortisol rhythm was respected and urinary catecholamine metabolites levels were normal. Computed tomography (CT) scan showed a homogeneous lesion, with a low density. The lesion remained unchanged during the five years of follow-up. Eight years after the last CT, a large right heterogeneous adrenal mass was incidentally discovered during an ultrasound examination. On CT scan, it was a 6 cm heterogeneous tumor. On hormonal work-up, there was no secretion. The patient was operated of an adrenalectomy, and the histology described an ACC with a Weiss score at 8, with no benign contingent. To our knowledge, this is the first case of an ACC occurring in a patient with prior adrenal imaging showing a typical benign adenoma. PMID- 28348074 TI - Prognostic Value of Inflammatory and Cardiovascular Biomarkers for Prediction of 90-Day All-Cause Mortality after Acute Ischemic Stroke-Results from the Linz Stroke Unit Study. AB - BACKGROUND: Early outcome prediction after acute ischemic stroke is of great interest. The aim of our study was to evaluate the prognostic value of blood biomarkers in patients with acute ischemic stroke. METHODS: We measured interleukin-6 (IL-6), d-dimer, amino-terminal pro-B-type natriuretic peptide (NT proBNP), high-sensitivity cardiac troponin T, and soluble ST2 plasma concentrations within 24 h after admission to our stroke unit in 721 consecutive acute ischemic stroke patients. End point was 90-day all-cause mortality. RESULTS: During follow-up 81 patients died (11%). In univariate Cox proportional hazards regression analyses with the biochemical markers dichotomized according to median values, all baseline blood biomarkers were strong prognostic markers. However, in the multivariate analysis after adjustment for several clinical variables and the NIH Stroke Scale (NIHSS), only NIHSS >3 [risk ratio (RR) 7.87, 95% CI, 3.61-17.16; P < 0.001], IL-6 > 7 pg/mL (RR 4.09, 95% CI, 2.02-8.29; P < 0.001), and NT-proBNP >447 ng/L (RR 4.88, 95% CI, 2.41-9.88; P < 0.001) remained independent predictors. Using a simple multimarker approach combining these 3 complementary markers, we demonstrated that patients with increased NIHSS, IL-6, and NT-proBNP had the poorest outcome with a mortality rate of 38%, whereas no patient with negative readings for all 3 markers died during follow-up. CONCLUSIONS: In this large cohort of patients with acute ischemic stroke, IL-6 and NT-proBNP at admission were strong and independent prognostic markers for 90 day all-cause mortality, and provided complementary prognostic information to the routinely used stroke severity score NIHSS. PMID- 28348075 TI - Computational and structural evidence for neurotransmitter-mediated modulation of the oligomeric states of human insulin in storage granules. AB - Human insulin is a pivotal protein hormone controlling metabolism, growth, and aging and whose malfunctioning underlies diabetes, some cancers, and neurodegeneration. Despite its central position in human physiology, the in vivo oligomeric state and conformation of insulin in its storage granules in the pancreas are not known. In contrast, many in vitro structures of hexamers of this hormone are available and fall into three conformational states: T6, T3Rf3, and R6 As there is strong evidence for accumulation of neurotransmitters, such as serotonin and dopamine, in insulin storage granules in pancreatic beta-cells, we probed by molecular dynamics (MD) and protein crystallography (PC) if these endogenous ligands affect and stabilize insulin oligomers. Parallel studies independently converged on the observation that serotonin binds well within the insulin hexamer (site I), stabilizing it in the T3R3 conformation. Both methods indicated serotonin binding on the hexamer surface (site III) as well. MD, but not PC, indicated that dopamine was also a good site III ligand. Some of the PC studies also included arginine, which may be abundant in insulin granules upon processing of pro-insulin, and stable T3R3 hexamers loaded with both serotonin and arginine were obtained. The MD and PC results were supported further by in solution spectroscopic studies with R-state-specific chromophore. Our results indicate that the T3R3 oligomer is a plausible insulin pancreatic storage form, resulting from its complex interplay with neurotransmitters, and pro-insulin processing products. These findings may have implications for clinical insulin formulations. PMID- 28348076 TI - The crystal structure of a multidomain protease inhibitor (HAI-1) reveals the mechanism of its auto-inhibition. AB - Hepatocyte growth factor activator inhibitor 1 (HAI-1) is a membrane-bound multidomain protein essential to the integrity of the basement membrane during placental development and is also important in maintaining postnatal homeostasis in many tissues. HAI-1 is a Kunitz-type serine protease inhibitor, and soluble fragments of HAI-1 with variable lengths have been identified in vivo The full length extracellular portion of HAI-1 (sHAI-1) shows weaker inhibitory activity toward target proteases than the smaller fragments, suggesting auto-inhibition of HAI-1. However, this possible regulatory mechanism has not yet been evaluated. Here, we solved the crystal structure of sHAI-1 and determined the solution structure by small-angle X-ray scattering. These structural analyses revealed that, despite the presence of long linkers, sHAI-1 exists in a compact conformation in which sHAI-1 active sites in Kunitz domain 1 are sterically blocked by neighboring structural elements. We also found that in the presence of target proteases, sHAI-1 adopts an extended conformation that disables the auto inhibition effect. Our results also reveal the roles of non-inhibitory domains of this multidomain protein and explain the low activity of the full-length protein. The structural insights gained here improve our understanding of the regulation of HAI-1 inhibitory activities and point to new approaches for better controlling these activities. PMID- 28348077 TI - Structural and thermodynamic basis of a frontometaphyseal dysplasia mutation in filamin A. AB - Filamin-mediated linkages between transmembrane receptors (TR) and the actin cytoskeleton are crucial for regulating many cytoskeleton-dependent cellular processes such as cell shape change and migration. A major TR binding site in the immunoglobulin repeat 21 (Ig21) of filamin is masked by the adjacent repeat Ig20, resulting in autoinhibition. The TR binding to this site triggers the relief of Ig20 and protein kinase A (PKA)-mediated phosphorylation of Ser-2152, thereby dynamically regulating the TR-actin linkages. A P2204L mutation in Ig20 reportedly cause frontometaphyseal dysplasia, a skeletal disorder with unknown pathogenesis. We show here that the P2204L mutation impairs a hydrophobic core of Ig20, generating a conformationally fluctuating molten globule-like state. Consequently, unlike in WT filamin, where PKA-mediated Ser-2152 phosphorylation is ligand-dependent, the P2204L mutant is readily accessible to PKA, promoting ligand-independent phosphorylation on Ser-2152. Strong TR peptide ligands from platelet GP1balpha and G-protein-coupled receptor MAS effectively bound Ig21 by displacing Ig20 from autoinhibited WT filamin, but surprisingly, the capacity of these ligands to bind the P2204L mutant was much reduced despite the mutation induced destabilization of the Ig20 structure that supposedly weakens the autoinhibition. Thermodynamic analysis indicated that compared with WT filamin, the conformationally fluctuating state of the Ig20 mutant makes Ig21 enthalpically favorable to bind ligand but with substantial entropic penalty, resulting in total higher free energy and reduced ligand affinity. Overall, our results reveal an unusual structural and thermodynamic basis for the P2204L induced dysfunction of filamin and frontometaphyseal dysplasia disease. PMID- 28348078 TI - pH regulation in glycosomes of procyclic form Trypanosoma brucei. AB - Here we report the use of a fluorescein-tagged peroxisomal targeting sequence peptide (F-PTS1, acetyl-C{K(FITC)}GGAKL) for investigating pH regulation of glycosomes in live procyclic form Trypanosoma brucei When added to cells, this fluorescent peptide is internalized within vesicular structures, including glycosomes, and can be visualized after 30-60 min. Using F-PTS1 we are able to observe the pH conditions inside glycosomes in response to starvation conditions. Previous studies have shown that in the absence of glucose, the glycosome exhibits mild acidification from pH 7.4 +/- 0.2 to 6.8 +/- 0.2. Our results suggest that this response occurs under proline starvation as well. This pH regulation is found to be independent from cytosolic pH and requires a source of Na+ ions. Glycosomes were also observed to be more resistant to external pH changes than the cytosol; placement of cells in acidic buffers (pH 5) reduced the pH of the cytosol by 0.8 +/- 0.1 pH units, whereas glycosomal pH decreases by 0.5 +/- 0.1 pH units. This observation suggests that regulation of glycosomal pH is different and independent from cytosolic pH regulation. Furthermore, pH regulation is likely to work by an active process, because cells depleted of ATP with 2-deoxyglucose and sodium azide were unable to properly regulate pH. Finally, inhibitor studies with bafilomycin and EIPA suggest that both V-ATPases and Na+/H+ exchangers are required for glycosomal pH regulation. PMID- 28348079 TI - Structure of human promyeloperoxidase (proMPO) and the role of the propeptide in processing and maturation. AB - Myeloperoxidase (MPO) is synthesized by neutrophil and monocyte precursor cells and contributes to host defense by mediating microbial killing. Although several steps in MPO biosynthesis and processing have been elucidated, many questions remained, such as the structure-function relationship of monomeric unprocessed proMPO versus the mature dimeric MPO and the functional role of the propeptide. Here we have presented the first and high resolution (at 1.25 A) crystal structure of proMPO and its solution structure obtained by small-angle X-ray scattering. Promyeloperoxidase hosts five occupied glycosylation sites and six intrachain cystine bridges with Cys-158 of the very flexible N-terminal propeptide being covalently linked to Cys-319 and thereby hindering homodimerization. Furthermore, the structure revealed (i) the binding site of proMPO-processing proconvertase, (ii) the structural motif for subsequent cleavage to the heavy and light chains of mature MPO protomers, and (iii) three covalent bonds between heme and the protein. Studies of the mutants C158A, C319A, and C158A/C319A demonstrated significant differences from the wild-type protein, including diminished enzymatic activity and prevention of export to the Golgi due to prolonged association with the chaperone calnexin. These structural and functional findings provide novel insights into MPO biosynthesis and processing. PMID- 28348081 TI - The herpes simplex virus 1 UL36USP deubiquitinase suppresses DNA repair in host cells via deubiquitination of proliferating cell nuclear antigen. AB - Herpes simplex virus 1 (HSV-1) infection manipulates distinct host DNA-damage responses to facilitate virus proliferation, but the molecular mechanisms remain to be elucidated. One possible HSV-1 target might be DNA damage-tolerance mechanisms, such as the translesion synthesis (TLS) pathway. In TLS, proliferating cell nuclear antigen (PCNA) is monoubiquitinated in response to DNA damage-caused replication fork stalling. Ubiquitinated PCNA then facilitates the error-prone DNA polymerase eta (poleta)-mediated TLS, allowing the fork to bypass damaged sites. Because of the involvement of PCNA ubiquitination in DNA-damage repair, we hypothesized that the function of PCNA might be altered by HSV-1. Here we show that PCNA is a substrate of the HSV-1 deubiquitinase UL36USP, which has previously been shown to be involved mainly in virus uptake and maturation. In HSV-1-infected cells, viral infection-associated UL36USP consistently reduced PCNA ubiquitination. The deubiquitination of PCNA inhibited the formation of poleta foci and also increased cell sensitivity to DNA-damage agents. Moreover, the catalytically inactive mutant UL36C40A failed to deubiquitinate PCNA. Of note, the levels of virus marker genes increased strikingly in cells infected with wild-type HSV-1, but only moderately in UL36C40A mutant virus-infected cells, indicating that the UL36USP deubiquitinating activity supports HSV-1 virus replication during infection. These findings suggest a role of UL36USP in the DNA damage-response pathway. PMID- 28348080 TI - A positive feedback loop between Pim-1 kinase and HBP1 transcription factor contributes to hydrogen peroxide-induced premature senescence and apoptosis. AB - Oxidative stress can induce cell dysfunction and lead to a broad range of degenerative alterations, including carcinogenesis, aging, and other oxidative stress-related conditions. To avoid undergoing carcinogenesis in response to oxidative stress, cells trigger a succession of checkpoint responses, including premature senescence and apoptosis. Increasing evidence indicates that H2O2, an important cause of oxidative stress, functions as an important physiological regulator of intracellular signaling pathways that participate in regulation of cell premature senescence and apoptosis. However, the precise mechanisms underlying this process remain to be studied extensively. In this study, we describe the importance of Pim-1 kinase in this checkpoint response to oxidative stress. Pim-1 binds to and phosphorylates the transcription factor high mobility group box transcription factor 1 (HBP1), activating it. H2O2 enhances the interaction between Pim-1 and HBP1 and promotes HBP1 accumulation. In turn, HBP1 rapidly and selectively up-regulates Pim-1 expression in H2O2-stimulated cells, thereby creating a Pim-1-HBP1 positive feedback loop that regulates H2O2-induced premature senescence and apoptosis. Furthermore, the Pim-1-HBP1 positive feedback loop exerts its effect by regulating the senescence markers DNMT1 and p16 and the apoptosis marker Bax. The Pim-1-HBP1 axis thus constitutes a novel checkpoint pathway critical for the inhibition of tumorigenesis. PMID- 28348082 TI - Urate hydroperoxide oxidizes human peroxiredoxin 1 and peroxiredoxin 2. AB - Urate hydroperoxide is a product of the oxidation of uric acid by inflammatory heme peroxidases. The formation of urate hydroperoxide might be a key event in vascular inflammation, where there is large amount of uric acid and inflammatory peroxidases. Urate hydroperoxide oxidizes glutathione and sulfur-containing amino acids and is expected to react fast toward reactive thiols from peroxiredoxins (Prxs). The kinetics for the oxidation of the cytosolic 2-Cys Prx1 and Prx2 revealed that urate hydroperoxide oxidizes these enzymes at rates comparable with hydrogen peroxide. The second-order rate constants of these reactions were 4.9 * 105 and 2.3 * 106 m-1 s-1 for Prx1 and Prx2, respectively. Kinetic and simulation data suggest that the oxidation of Prx2 by urate hydroperoxide occurs by a three step mechanism, where the peroxide reversibly associates with the enzyme; then it oxidizes the peroxidatic cysteine, and finally, the rate-limiting disulfide bond is formed. Of relevance, the disulfide bond formation was much slower in Prx2 (k3 = 0.31 s-1) than Prx1 (k3 = 14.9 s-1). In addition, Prx2 was more sensitive than Prx1 to hyperoxidation caused by both urate hydroperoxide and hydrogen peroxide. Urate hydroperoxide oxidized Prx2 from intact erythrocytes to the same extent as hydrogen peroxide. Therefore, Prx1 and Prx2 are likely targets of urate hydroperoxide in cells. Oxidation of Prxs by urate hydroperoxide might affect cell function and be partially responsible for the pro-oxidant and pro inflammatory effects of uric acid. PMID- 28348083 TI - Mechanical forces regulate the reactivity of a thioester bond in a bacterial adhesin. AB - Bacteria must withstand large mechanical shear forces when adhering to and colonizing hosts. Recent structural studies on a class of Gram-positive bacterial adhesins have revealed an intramolecular Cys-Gln thioester bond that can react with surface-associated ligands to covalently anchor to host surfaces. Two other examples of such internal thioester bonds occur in certain anti-proteases and in the immune complement system, both of which react with the ligand only after the thioester bond is exposed by a proteolytic cleavage. We hypothesized that mechanical forces in bacterial adhesion could regulate thioester reactivity to ligand analogously to such proteolytic gating. Studying the pilus tip adhesin Spy0125 of Streptococcus pyogenes, we developed a single molecule assay to unambiguously resolve the state of the thioester bond. We found that when Spy0125 was in a folded state, its thioester bond could be cleaved with the small molecule nucleophiles methylamine and histamine, but when Spy0125 was mechanically unfolded and subjected to forces of 50-350 piconewtons, thioester cleavage was no longer observed. For folded Spy0125 without mechanical force exposure, thioester cleavage was in equilibrium with spontaneous thioester reformation, which occurred with a half-life of several minutes. Functionally, this equilibrium reactivity allows thioester-containing adhesins to sample potential substrates without irreversible cleavage and inactivation. We propose that such reversible thioester reactivity would circumvent potential soluble inhibitors, such as histamine released at sites of inflammation, and allow the bacterial adhesin to selectively associate with surface-bound ligands. PMID- 28348084 TI - Delineating distinct heme-scavenging and -binding functions of domains in MF6p/helminth defense molecule (HDM) proteins from parasitic flatworms. AB - MF6p/FhHDM-1 is a small protein secreted by the parasitic flatworm (trematode) Fasciola hepatica that belongs to a broad family of heme-binding proteins (MF6p/helminth defense molecules (HDMs)). MF6p/HDMs are of interest for understanding heme homeostasis in trematodes and as potential targets for the development of new flukicides. Moreover, interest in these molecules has also increased because of their immunomodulatory properties. Here we have extended our previous findings on the mechanism of MF6p/HDM-heme interactions and mapped the protein regions required for heme binding and for other biological functions. Our data revealed that MF6p/FhHDM-1 forms high-molecular-weight complexes when associated with heme and that these complexes are reorganized by a stacking procedure to form fibril-like and granular nanostructures. Furthermore, we showed that MF6p/FhHDM-1 is a transitory heme-binding protein as protein.heme complexes can be disrupted by contact with an apoprotein (e.g. apomyoglobin) with higher affinity for heme. We also demonstrated that (i) the heme-binding region is located in the MF6p/FhHDM-1 C-terminal moiety, which also inhibits the peroxidase like activity of heme, and (ii) MF6p/HDMs from other trematodes, such as Opisthorchis viverrini and Paragonimus westermani, also bind heme. Finally, we observed that the N-terminal, but not the C-terminal, moiety of MF6p/HDMs has a predicted structural analogy with cell-penetrating peptides and that both the entire protein and the peptide corresponding to the N-terminal moiety of MF6p/FhHDM-1 interact in vitro with cell membranes in hemin-preconditioned erythrocytes. Our findings suggest that MF6p/HDMs can transport heme in trematodes and thereby shield the parasite from the harmful effects of heme. PMID- 28348087 TI - Site Principal Investigators in Multicenter Clinical Trials: Appropriately Recognizing Key Contributors. PMID- 28348085 TI - The extent of the temperature-induced membrane remodeling in two closely related Bordetella species reflects their adaptation to diverse environmental niches. AB - Changes in environmental temperature represent one of the major stresses faced by microorganisms as they affect the function of the cytoplasmic membrane. In this study, we have analyzed the thermal adaptation in two closely related respiratory pathogens Bordetella pertussis and Bordetella bronchiseptica Although B. pertussis represents a pathogen strictly adapted to the human body temperature, B. bronchiseptica causes infection in a broad range of animals and survives also outside of the host. We applied GC-MS to determine the fatty acids of both Bordetella species grown at different temperatures and analyzed the membrane fluidity by fluorescence anisotropy measurement. In parallel, we also monitored the effect of growth temperature changes on the expression and production of several virulence factors. In response to low temperatures, B. pertussis adapted its fatty acid composition and membrane fluidity to a considerably lesser extent when compared with B. bronchiseptica Remarkably, B. pertussis maintained the production of virulence factors at 24 degrees C, whereas B. bronchiseptica cells resumed the production only upon temperature upshift to 37 degrees C. This growth temperature-associated differential modulation of virulence factor production was linked to the phosphorylation state of transcriptional regulator BvgA. The observed differences in low-temperature adaptation between B. pertussis and B. bronchiseptica may result from selective adaptation of B. pertussis to the human host. We propose that the reduced plasticity of the B. pertussis membranes ensures sustained production of virulence factors at suboptimal temperatures and may play an important role in the transmission of the disease. PMID- 28348088 TI - Public Health Urgency Created by the Success of Mechanical Thrombectomy Studies in Stroke. PMID- 28348086 TI - The DEAD-box RNA helicase DDX41 is a novel repressor of p21WAF1/CIP1 mRNA translation. AB - The cyclin-dependent kinase inhibitor p21 is an important player in stress pathways exhibiting both tumor-suppressive and oncogenic functions. Thus, expression of p21 has to be tightly controlled, which is achieved by numerous mechanisms at the transcriptional, translational, and posttranslational level. Performing immunoprecipitation of bromouridine-labeled p21 mRNAs that had been incubated before with cytoplasmic extracts of untreated HCT116 colon carcinoma cells, we identified the DEAD-box RNA helicase DDX41 as a novel regulator of p21 expression. DDX41 specifically precipitates with the 3'UTR, but not with the 5'UTR, of p21 mRNA. Knockdown of DDX41 increases basal and gamma irradiation induced p21 protein levels without affecting p21 mRNA expression. Conversely, overexpression of DDX41 strongly inhibits expression of a FLAG-p21 and a luciferase construct, but only in the presence of the p21 3'UTR. Together, these data suggest that this helicase regulates p21 expression at the translational level independent of the transcriptional activity of p53. However, knockdown of DDX41 completely fails to increase p21 protein levels in p53-deficient HCT116 cells. Moreover, posttranslational up-regulation of p21 achieved in both p53+/+ and p53-/- HCT116 cells in response to pharmaceutical inhibition of the proteasome (by MG-132) or p90 ribosomal S6 kinases (by BI-D1870) is further increased by knockdown of DDX41 only in p53-proficient but not in p53-deficient cells. Although our data demonstrate that DDX41 suppresses p21 translation without disturbing the function of p53 to directly induce p21 mRNA expression, this process indirectly requires p53, perhaps in the form of another p53 target gene or as a still undefined posttranscriptional function of p53. PMID- 28348089 TI - The Development of Cardiac Arrhythmia Ablation: A Conversation With Melvin A. Scheinman, MD. AB - Dr Melvin A. Scheinman is Professor of Medicine and holds the Walter H. Shorenstein Endowed Chair in Cardiology at the University of California, San Francisco. He has received awards including the Paul Dudley White Award for Excellence in Teaching by the American Heart Association and the Distinguished Science Award of the American College of Cardiology. He grew up in Brooklyn, New York, and took his undergraduate degree at Johns Hopkins University, where he graduated first in his class. Postgraduate medical education included the Albert Einstein College of Medicine, residency training at the University of North Carolina (Chapel Hill), and cardiology training at the University of California, San Francisco Medical Center. PMID- 28348090 TI - Increased Risk of Cerebrovascular Events in Young Cancer Survivors: The Downside of Surviving Cancer. PMID- 28348091 TI - Trends in Heart Failure Incidence in the Community: A Gathering Storm. PMID- 28348093 TI - Value-Based Payments Likely to Survive Affordable Care Act Repeal: Coverage, Patient Protections May Be at Risk. PMID- 28348092 TI - Highlights from the Circulation Family of Journals. PMID- 28348094 TI - Letter by Kalavrouziotis et al Regarding Article, "Temporal Trends in Predictors of Early and Late Mortality After Emergency Coronary Artery Bypass Grafting for Cardiogenic Shock Complicating Acute Myocardial Infarction". PMID- 28348095 TI - Response by Davierwala and Leontyev to Letter Regarding Article, "Temporal Trends in Predictors of Early and Late Mortality after Emergency Coronary Artery Bypass Grafting for Cardiogenic Shock Complicating Acute Myocardial Infarction". PMID- 28348096 TI - Letter by Koh Regarding Articles, "Predicting the 10-Year Risks of Atherosclerotic Cardiovascular Disease in Chinese Population: The China-PAR Project (Prediction for ASCVD Risk in China)" and "Distribution of Estimated 10 Year Risk of Recurrent Vascular Events and Residual Risk in a Secondary Prevention Population". PMID- 28348097 TI - Response by Kaasenbrood et al to Letter Regarding Article, "Distribution of Estimated 10-Year Risk of Recurrent Vascular Events and Residual Risk in a Secondary Prevention Population". PMID- 28348098 TI - Response by Yang and Gu to Letter Regarding Article, "Predicting the 10-Year Risks of Atherosclerotic Cardiovascular Disease in Chinese Population: The China PAR Project (Prediction for ASCVD Risk in China)". PMID- 28348099 TI - Correction to: Estimating Longitudinal Risks and Benefits From Cardiovascular Preventive Therapies Among Medicare Patients: The Million Hearts Longitudinal ASCVD Risk Assessment Tool: A Special Report From the American Heart Association and American College of Cardiology. PMID- 28348100 TI - Effects of Conversion to a Bicarbonate/Lactate-Buffered, Neutral-pH, Low-GDP PD Regimen in Prevalent PD: A 2-Year Randomized Clinical Trial. AB - ? BACKGROUND: The use of pH-neutral peritoneal dialysis (PD) fluids low in glucose degradation products (GDP) may better preserve the peritoneal membrane and have fewer systemic effects. The effects of conversion from conventional to neutral-pH, low-GDP PD fluids in prevalent patients are unclear. Few studies on the role of neutral-pH, low-GDP PD have studied residual renal function, ultrafiltration, peritonitis incidence and technique failure, transport characteristics, and local and systemic markers of inflammation in prevalent PD patients. ? METHODS: In a multi-center open-label randomized clinical trial (RCT), we randomly assigned 40 of 78 stable continuous ambulatory PD (CAPD) and automated PD (APD) patients to treatment with bicarbonate/lactate, neutral-pH, low-GDP PD fluid (Physioneal; Baxter Healthcare Corporation, Deerfield, IL, USA) and compared them with 38 patients continuing their current standard lactate buffered PD fluid (PDF) (Dianeal; Baxter Healthcare Corporation, Deerfield, IL, USA) during 2 years. Primary outcome was residual renal function (RRF) and ultrafiltration (UF) during peritoneal equilibration test (PET); peritonitis incidence was a secondary outcome. Furthermore, clinical parameters as well as several biomarkers in effluents and serum were measured. ? RESULTS: During follow up, RRF did not differ between the groups. In the Physioneal group ultrafiltration (UF) during PET remained more or less stable (-20 mL [confidence interval (CI): -163.5 - 123.5 mL]; p = 0.7 over 24 months), whereas it declined in the Dianeal group (-243 mL [CI: -376.6 to -109.4 mL]; p < 0.0001 over 24 months), resulting in a difference of 233.7 mL [95% CI 41.0 - 425.5 mL]; p = 0.017 between the groups at 24 months. The peritonitis rate was lower in the Physioneal group: adjusted odds ratio (OR) 0.38 (0.15 - 0.97) p = 0.043. No differences were observed between the 2 groups in peritoneal adequacy or transport characteristics nor effluent markers of local inflammation (cancer antigen [CA]125, hyaluronan [HA], vascular endothelial growth factor [VEGF], macrophage chemo-attractant protein [MCP]-1, HA and transforming growth factor [TGF]beta-1). ? CONCLUSION: In prevalent PD patients, our study did not find a difference in RRF after conversion from conventional to neutral-pH, low-GDP PD fluids, although there is a possibility that the study was underpowered to detect a difference. Decline in UF during standardized PET was lower after 2 years in the Physioneal group. PMID- 28348101 TI - In-Hospital Mortality in Cirrhotic Patients with End-Stage Renal Disease Treated with Hemodialysis Versus Peritoneal Dialysis: A Nationwide Study. AB - BACKGROUND: Cirrhotic patients often develop end-stage renal disease (ESRD) requiring renal replacement therapy in the form of hemodialysis (HD) or peritoneal dialysis (PD). Studies comparing the outcomes and difference in in hospital mortality between these 2 groups, particularly among those with ascites, are sparse. We set our objective to determine the dialysis modality with a better in-hospital survival rate among cirrhotic patients with ESRD (ESRD-cirrhosis). METHODS: Data was extracted from the 2005 to 2012 Nationwide Inpatient Sample (NIS). Using propensity score matching, ESRD-cirrhosis patients on PD were matched with patients on HD at a 1:1 ratio. Another subgroup analysis of ESRD cirrhosis patients with ascites was performed using the same matching algorithm. Analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC, USA). RESULTS: Among 26,135 cirrhotic patients with incident ESRD, 25,686 (98.3%) and 449 (1.7%) were initiated on HD and PD, respectively, during the hospitalization. There was a nonsignificant mortality difference between the ESRD-cirrhosis patients treated with PD and those treated with HD. In a subgroup analysis of these patients with ascites, 18 patients underwent PD while 1,878 patients required HD. Also, PD had a significantly lower in-hospital mortality compared with HD in this subgroup (0% vs 26.67%, p = 0.03). Mean length of stay for those who received HD was 8.34 days compared with 7.06 days for the PD group (p < 0.0001). Similarly, mean hospital charges were greater for those who had HD compared with PD ($74,501 vs $57,460; p < 0.001). CONCLUSION: Cirrhotic patients with ESRD and ascites who undergo PD have a significantly lower mortality than those who are started on HD. However PD is rarely initiated for ESRD in cirrhotic patients with ascites during hospitalization in the United States. Due to the potential advantages of PD, nephrologists should encourage PD when selecting dialysis modality in this subgroup of patients whenever possible. PMID- 28348102 TI - Acute Peritoneal Dialysis in Patients with Acute Kidney Injury. AB - BACKGROUND: The purpose of this study was to evaluate the efficacy, complications, and mortality rate associated with acute peritoneal dialysis (PD) in patients with acute kidney injury (AKI). METHODS: A total of 75 patients who were treated at Samsung Changwon Hospital between February 2005 and March 2016 were included in the study sample. The outcomes included in-hospital survival, renal recovery, metabolic and fluid control rates, and technical success rates. RESULTS: Refractory heart failure was the most frequent cause of acute PD (49.3%), followed by hepatic failure (20.0%), septic shock (14.7%), acute pancreatitis (9.3%), and unknown causes (6.7%). The hospital survival of patients in the acute PD was 48.0%. Etiologies of acute kidney injury (AKI) (refractory heart failure, acute pancreatitis compared with hepatic failure, septic shock or miscellaneous causes), use of inotropes, use of a ventilator, and simplified acute physiology score (SAPS) II were associated with survival differences. Maintenance dialysis required after survival was high (80.1% [29/36]) due to AKI etiologies (heart or hepatic failures). Metabolic and fluid control rates were 77.3%. The technical success rate for acute PD was 93.3%. CONCLUSION: Acute PD remains a suitable treatment modality for patients with AKI in the era of continuous renal replacement therapy (CRRT). Nearly all patients who require dialysis can be dialyzed with acute PD without mechanical difficulties. This is particularly true in patients with refractory heart failure and acute pancreatitis who had a weak requirement for inotropes. PMID- 28348103 TI - Risk Factors and Outcomes of Vancomycin-Resistant Enterococcus Colonization in Patients on Peritoneal Dialysis: A Single-Center Study in Hong Kong. AB - BACKGROUND: Vancomycin-resistant Enterococcus (VRE) colonization is common among patients with chronic kidney disease. However, data concerning VRE colonization among patients receiving peritoneal dialysis (PD) is lacking. The aim of this study is to evaluate the risk factors and various clinical outcomes for VRE colonization among PD patients. METHODS: This is a retrospective cohort study of 166 PD patients who were hospitalized between 1 August 2013 and 31 July 2014. They were screened for VRE colonization status during a major VRE outbreak in Hong Kong in 2013 and were then categorized into 2 groups: VRE-positive and VRE negative. The primary outcome was all-cause mortality while the secondary outcomes included VRE infection, PD-related peritonitis, and length of hospitalization. RESULTS: Twenty-eight patients (16.9%) belonged to the VRE positive group. Multivariate analysis showed that previous contact with VRE positive patients (odds ratio [OR]: 417.86; 95% confidence interval [CI]: 17.21 - 10,147.26, p < 0.01), vancomycin use in previous 3 months (OR: 130.32; 95% CI: 5.35 - 3,176.30, p < 0.01), and old age (OR: 1.13; 95% CI: 1.02 - 1.24, p = 0.02) were the independent risk factors for VRE colonization. Patients in the VRE positive group had significantly longer length of hospitalization, but there was no significant difference in all-cause mortality and peritonitis-free survival. CONCLUSION: Vancomycin-resistant Enterococcus colonization is important among hospitalized PD patients. Cautious use of antibiotics and infection control measures are necessary to prevent VRE spreading, especially in high-risk patients. PMID- 28348104 TI - Non-canonical activity of the podosomal formin FMNL1gamma supports immune cell migration. AB - Having previously located the formin FMNL1 in macrophage podosomes, we developed an in vivo model to assess the role of FMNL1 in the migration activities of primary macrophages. Deletion of FMNL1 in mice was genetically lethal; however, targeted deletion in macrophages was achieved by employing macrophage-specific Cre. Unchallenged FMNL1-deficient mice exhibited an unexpected reduction in tissue-resident macrophages despite normal blood monocyte numbers. Upon immune stimulus, the absence of FMNL1 resulted in reduced macrophage recruitment in vivo, decreased migration in two-dimensional in vitro culture and a decrease in the number of macrophages exhibiting podosomes. Of the three described isoforms of FMNL1 - alpha, beta and gamma - only FMNL1gamma rescued macrophage migration when expressed exogenously in depleted macrophages. Surprisingly, mutation of residues in the FH2 domain of FMNL1gamma that disrupt barbed-end actin binding did not limit rescue of macrophage migration and podosome numbers. These observations suggest that FMNL1 contributes to macrophage migration activity by stabilizing the lifespan of podosomes without interaction of fast-growing actin termini. PMID- 28348106 TI - Unphosphorylated STAT1 represses apoptosis in macrophages during Mycobacteriumtuberculosis infection. AB - In murine macrophages infected with Mycobacterium tuberculosis (Mtb), the level of phosphorylated STAT1 (P-STAT1), which drives the expression of many pro apoptosis genes, increases quickly but then declines over a period of hours. By contrast, infection induces a continued increase in the level of unphosphorylated STAT1 that persists for several days. Here, we found that the level of unphosphorylated STAT1 correlated with the intracellular bacterial burden during the later stages of infection. To investigate the significance of a high level of unphosphorylated STAT1, we increased its concentration exogenously, and found that the apoptosis rate induced by Mtb was sufficiently decreased. Further experiments confirmed that unphosphorylated STAT1 affects the expression of several immune-associated genes and lessens the sensitivity of macrophages to CD95 (FAS)-mediated apoptosis during Mtb infection. Furthermore, we characterized 149 proteins that interacted with unphosphorylated STAT1 and the interactome network. The cooperation between unphosphorylated STAT1 and STAT3 results in downregulation of CD95 expression. Additionally, we verified that unphosphorylated STAT1 and IFIT1 competed for binding to eEF1A. Taken together, our data show that the role of unphosphorylated STAT1 differs from that of P STAT1, and represses apoptosis in macrophages to promote immune evasion during Mtb infection. PMID- 28348105 TI - Nuclear alpha-catenin mediates the DNA damage response via beta-catenin and nuclear actin. AB - alpha-Catenin is an F-actin-binding protein widely recognized for its role in cell-cell adhesion. However, a growing body of literature indicates that alpha catenin is also a nuclear protein. In this study, we show that alpha-catenin is able to modulate the sensitivity of cells to DNA damage and toxicity. Furthermore, nuclear alpha-catenin is actively recruited to sites of DNA damage. This recruitment occurs in a beta-catenin-dependent manner and requires nuclear actin polymerization. These findings provide mechanistic insight into the WNT mediated regulation of the DNA damage response and suggest a novel role for the alpha-catenin-beta-catenin complex in the nucleus. PMID- 28348107 TI - MCSF orchestrates branching morphogenesis in developing submandibular gland tissue. AB - The importance of macrophages in tissue development and regeneration has been strongly emphasized. However, the specific roles of macrophage colony-stimulating factor (MCSF), the key regulator of macrophage differentiation, in glandular tissue development have been unexplored. Here, we disclose new macrophage independent roles of MCSF in tissue development. We initially found that MCSF is markedly upregulated at embryonic day (E)13.5, at a stage preceding the colonization of macrophages (at E15.5), in mouse submandibular gland (SMG) tissue. Surprisingly, MCSF-induced branching morphogenesis was based on a direct effect on epithelial cells, as well as indirectly, by modulating the expression of major growth factors of SMG growth, FGF7 and FGF10, via the phosphoinositide 3 kinase (PI3K) pathway. Additionally, given the importance of neurons in SMG organogenesis, we found that MCSF-induced SMG growth was associated with regulation of neurturin expression and neuronal network development during early SMG development in an in vitro organogenesis model as well as in vivo These results indicate that MCSF plays pleiotropic roles and is an important regulator of early SMG morphogenesis. PMID- 28348108 TI - Comprehensive somatic genome alterations of urachal carcinoma. AB - BACKGROUND: Urachal cancer is a rare cancer that develops in the urachus. Because of its rarity, standard treatment therapies for urachal cancer are not established, and chemotherapeutic regimens for bladder cancer have been unsuccessful for patients with urachal cancer. Hence, we aim to understand a systematic molecular characterisation of urachal cancer. METHODS: We identified somatic single-nucleotide variations (SNVs)/indels and somatic copy number aberrations (SCNAs) in the 17 patients by using whole-exome sequencing (WES) and OncoScan platform (Affymetrix) as follows: tumour-normal paired sequencing (WES, n=10), tumour-only sequencing (WES, n=1; targeted deep sequencing, n=16), and OncoScan (n=17). RESULTS: Our analyses identified 27 genes with somatic SNVs and indels, as well as six genes (APC, COL5A1, KIF26B, LRP1B, SMAD4 and TP53) that were recurrent in at least two patients. By analysing the SCNAs, we found that the extent of chromosomal amplification was highly associated with the patient's cancer stage. Interestingly, 35% (6/17) of the patients had focal DNA amplifications in fibroblast growth factor receptor family genes. The integration of somatic SNVs, indels and SCNAs revealed significant alterations in the mitogen activated protein kinase signalling pathways. CONCLUSIONS: Our genome-wide analysis of urachal cancer suggests that molecular characteristics may be important for the treatment of urachal cancer. PMID- 28348109 TI - Consultant productivity drops as result of poor workforce planning. PMID- 28348110 TI - Low intensity pulsed ultrasound for bone healing: systematic review of randomized controlled trials. AB - Objective To determine the efficacy of low intensity pulsed ultrasound (LIPUS) for healing of fracture or osteotomy.Design Systematic review and meta analysis.Data sources Medline, Embase, CINAHL, Cochrane Central Register of Controlled Trials, and trial registries up to November 2016.Study selection Randomized controlled trials of LIPUS compared with sham device or no device in patients with any kind of fracture or osteotomy.Review methods Two independent reviewers identified studies, extracted data, and assessed risk of bias. A parallel guideline committee (BMJ Rapid Recommendation) provided input on the design and interpretation of the systematic review, including selection of outcomes important to patients. The GRADE system was used to assess the quality of evidence.Results 26 randomized controlled trials with a median sample size of 30 (range 8-501) were included. The most trustworthy evidence came from four trials at low risk of bias that included patients with tibia or clavicle fractures. Compared with control, LIPUS did not reduce time to return to work (percentage difference: 2.7% later with LIPUS, 95% confidence interval 7.7% earlier to 14.3% later; moderate certainty) or the number of subsequent operations (risk ratio 0.80, 95% confidence interval 0.55 to 1.16; moderate certainty). For pain, days to weight bearing, and radiographic healing, effects varied substantially among studies. For all three outcomes, trials at low risk of bias failed to show a benefit with LIPUS, while trials at high risk of bias suggested a benefit (interaction P<0.001). When only trials at low risk of bias trials were considered, LIPUS did not reduce days to weight bearing (4.8% later, 4.0% earlier to 14.4% later; high certainty), pain at four to six weeks (mean difference on 0-100 visual analogue scale: 0.93 lower, 2.51 lower to 0.64 higher; high certainty), and days to radiographic healing (1.7% earlier, 11.2% earlier to 8.8% later; moderate certainty).Conclusions Based on moderate to high quality evidence from studies in patients with fresh fracture, LIPUS does not improve outcomes important to patients and probably has no effect on radiographic bone healing. The applicability to other types of fracture or osteotomy is open to debate.Systematic review registration PROSPERO CRD42016050965. PMID- 28348111 TI - GPs challenge claim that they fail to take women's health seriously. PMID- 28348112 TI - Hypophysectomy abolishes rhythms in rat thyroid hormones but not in the thyroid clock. AB - The endocrine body rhythms including the hypothalamic-pituitary-thyroid axis seem to be regulated by the circadian timing system, and daily rhythmicity of circulating thyroid-stimulating hormone (TSH) is well established. The circadian rhythms are generated by endogenous clocks in the central brain oscillator located in the hypothalamic suprachiasmatic nucleus (SCN) as well as multiple peripheral clocks, but information on the existence and function of a thyroid clock is limited. The molecular machinery in all clock cells is composed of a number of clock genes and their gene products are connected by autoregulatory feedback loops. Here, we provide evidence for a thyroid clock in the rat by demonstrating 24-h antiphase oscillations for the mRNA of the canonical clock genes Per1 and Bmal1, which was unaffected by hypophysectomy. By immunostaining, we supported the existence of a core oscillator in the individual thyroid cells by demonstrating a daily cytoplasmatic-nuclear shuttling of PER1 protein. In normal rats, we found a significant daily rhythmicity in the circulating thyroid hormones preceded by a peak in TSH. In hypophysectomised rats, although the thyroid clock was not affected, the oscillations in circulating thyroid hormones were abolished and the levels were markedly lowered. No daily oscillations in the expression of TSH receptor mRNA were observed in neither control rats nor hypophysectomised rats. Our findings indicate that the daily rhythm of thyroid hormone secretion is governed by SCN signalling via the rhythmic TSH secretion rather than by the local thyroid clock, which was still ticking after hypophysectomy. PMID- 28348113 TI - 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Nongenomic effects via the mineralocorticoid receptor. AB - The mineralocorticoid receptor (MR) belongs to the steroid hormone receptor family and classically functions as a ligand-dependent transcription factor. It is involved in water-electrolyte homeostasis and blood pressure regulation but independent from these effects also furthers inflammation, fibrosis, hypertrophy and remodeling in cardiovascular tissues. Next to genomic effects, aldosterone elicits very rapid actions within minutes that do not require transcription or translation and that occur not only in classical MR epithelial target organs like kidney and colon but also in nonepithelial tissues like heart, vasculature and adipose tissue. Most of these effects can be mediated by classical MR and its crosstalk with different signaling cascades. Near the plasma membrane, the MR seems to be associated with caveolin and striatin as well as with receptor tyrosine kinases like EGFR, PDGFR and IGF1R and G protein-coupled receptors like AT1 and GPER1, which then mediate nongenomic aldosterone effects. GPER1 has also been named a putative novel MR. There is a close interaction and functional synergism between the genomic and the nongenomic signaling so that nongenomic signaling can lead to long-term effects and support genomic actions. Therefore, understanding nongenomic aldosterone/MR effects is of potential relevance for modulating genomic aldosterone effects and may provide additional targets for intervention. PMID- 28348114 TI - 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor mutations. AB - Aldosterone and the mineralocorticoid receptor (MR) are key elements for maintaining fluid and electrolyte homeostasis as well as regulation of blood pressure. Loss-of-function mutations of the MR are responsible for renal pseudohypoaldosteronism type 1 (PHA1), a rare disease of mineralocorticoid resistance presenting in the newborn with weight loss, failure to thrive, vomiting and dehydration, associated with hyperkalemia and metabolic acidosis, despite extremely elevated levels of plasma renin and aldosterone. In contrast, a MR gain-of-function mutation has been associated with a familial form of inherited mineralocorticoid hypertension exacerbated by pregnancy. In addition to rare variants, frequent functional single nucleotide polymorphisms of the MR are associated with salt sensitivity, blood pressure, stress response and depression in the general population. This review will summarize our knowledge on MR mutations in PHA1, reporting our experience on the genetic diagnosis in a large number of patients performed in the last 10 years at a national reference center for the disease. We will also discuss the influence of rare MR variants on blood pressure and salt sensitivity as well as on stress and cognitive functions in the general population. PMID- 28348117 TI - Spotlight on the March 28 issue. PMID- 28348116 TI - Increased vimentin in human alpha- and beta-cells in type 2 diabetes. AB - Type 2 diabetes (T2DM) is associated with pancreatic islet dysfunction. Loss of beta-cell identity has been implicated via dedifferentiation or conversion to other pancreatic endocrine cell types. How these transitions contribute to the onset and progression of T2DM in vivo is unknown. The aims of this study were to determine the degree of epithelial-to-mesenchymal transition occurring in alpha and beta cells in vivo and to relate this to diabetes-associated (patho)physiological conditions. The proportion of islet cells expressing the mesenchymal marker vimentin was determined by immunohistochemistry and quantitative morphometry in specimens of pancreas from human donors with T2DM (n = 28) and without diabetes (ND, n = 38) and in non-human primates at different stages of the diabetic syndrome: normoglycaemic (ND, n = 4), obese, hyperinsulinaemic (HI, n = 4) and hyperglycaemic (DM, n = 8). Vimentin co localised more frequently with glucagon (alpha-cells) than with insulin (beta cells) in the human ND group (1.43% total alpha-cells, 0.98% total beta-cells, median; P < 0.05); these proportions were higher in T2DM than ND (median 4.53% alpha-, 2.53% beta-cells; P < 0.05). Vimentin-positive beta-cells were not apoptotic, had reduced expression of Nkx6.1 and Pdx1, and were not associated with islet amyloidosis or with bihormonal expression (insulin + glucagon). In non human primates, vimentin-positive beta-cell proportion was larger in the diabetic than the ND group (6.85 vs 0.50%, medians respectively, P < 0.05), but was similar in ND and HI groups. In conclusion, islet cell expression of vimentin indicates a degree of plasticity and dedifferentiation with potential loss of cellular identity in diabetes. This could contribute to alpha- and beta-cell dysfunction in T2DM. PMID- 28348115 TI - Decrease in Ins+Glut2LO beta-cells with advancing age in mouse and human pancreas. AB - The presence and location of resident pancreatic beta-cell progenitors is controversial. A subpopulation of insulin-expressing but glucose transporter-2 low (Ins+Glut2LO) cells may represent multipotent pancreatic progenitors in adult mouse and in human islets, and they are enriched in small, extra-islet beta-cell clusters (<5 beta cells) in mice. Here, we sought to identify and compare the ontogeny of these cells in mouse and human pancreata throughout life. Mouse pancreata were collected at postnatal days 7, 14, 21, 28, and at 3, 6, 12, and 18 months of age, and in the first 28 days after beta-cell mass depletion following streptozotocin (STZ) administration. Samples of human pancreas were examined during fetal life (22-30 weeks gestation), infancy (0-1 year), childhood (2-9), adolescence (10-17), and adulthood (18-80). Tissues were analyzed by immunohistochemistry for the expression and location of insulin, GLUT2 and Ki67. The proportion of beta cells within clusters relative to that in islets was higher in pancreas of human than of mouse at all ages examined, and decreased significantly at adolescence. In mice, the total number of Ins+Glut2LO cells decreased after 7 days concurrent with the proportion of clusters. These cells were more abundant in clusters than in islets in both species. A positive association existed between the appearance of new beta cells after the STZ treatment of young mice, particularly in clusters and smaller islets, and an increased proportional presence of Ins+Glut2LO cells during early beta-cell regeneration. These data suggest that Ins+Glut2LO cells are preferentially located within beta-cell clusters throughout life in pancreas of mouse and human, and may represent a source of beta-cell plasticity. PMID- 28348119 TI - Editors' Note. PMID- 28348118 TI - Spontaneous intracranial hypotension diagnosed as Chiari I malformation. PMID- 28348120 TI - Letter re: Zoonotic bacterial meningitis in human adults. PMID- 28348121 TI - Author response: Zoonotic bacterial meningitis in human adults. PMID- 28348122 TI - Letter re: A genome-wide association study in multiple system atrophy. PMID- 28348123 TI - Author response: A genome-wide association study in multiple system atrophy. PMID- 28348124 TI - Recovering. PMID- 28348125 TI - Clinical Reasoning: A 13-year-old boy with chronic ataxia and developmental delay. PMID- 28348126 TI - Emerging Subspecialties in Neurology: Headache medicine. PMID- 28348127 TI - Comment: Headache medicine as an emerging subspecialty-Irony and reality. PMID- 28348128 TI - Teaching Video NeuroImages: Hyperekplexia: A syndrome of pathologic startle responses. PMID- 28348129 TI - Migraine relief: Nonpainful stimulation for acute attacks. PMID- 28348132 TI - Correction to: Successful Reperfusion With Mechanical Thrombectomy Is Associated With Reduced Disability and Mortality in Patients With Pretreatment Diffusion Weighted Imaging-Alberta Stroke Program Early Computed Tomography Score <=6. PMID- 28348131 TI - Correction to: Early Trajectory of Stroke Severity Predicts Long-Term Functional Outcomes in Ischemic Stroke Subjects: Results From the ESCAPE Trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times). PMID- 28348133 TI - Correction to: Cerebral Aneurysm Morphology Before and After Rupture: Nationwide Case Series of 29 Aneurysms. PMID- 28348134 TI - BMA condemns failure to deliver rescue funding to GPs. PMID- 28348135 TI - BK Channels Mediate Synaptic Plasticity Underlying Habituation in Rats. AB - Habituation is a basic form of implicit learning and represents a sensory filter that is disrupted in autism, schizophrenia, and several other mental disorders. Despite extensive research in the past decades on habituation of startle and other escape responses, the underlying neural mechanisms are still not fully understood. There is evidence from previous studies indicating that BK channels might play a critical role in habituation. We here used a wide array of approaches to test this hypothesis. We show that BK channel activation and subsequent phosphorylation of these channels are essential for synaptic depression presumably underlying startle habituation in rats, using patch-clamp recordings and voltage-sensitive dye imaging in slices. Furthermore, positive modulation of BK channels in vivo can enhance short-term habituation. Although results using different approaches do not always perfectly align, together they provide convincing evidence for a crucial role of BK channel phosphorylation in synaptic depression underlying short-term habituation of startle. We also show that this mechanism can be targeted to enhance short-term habituation and therefore to potentially ameliorate sensory filtering deficits associated with psychiatric disorders.SIGNIFICANCE STATEMENT Short-term habituation is the most fundamental form of implicit learning. Habituation also represents a filter for inundating sensory information, which is disrupted in autism, schizophrenia, and other psychiatric disorders. Habituation has been studied in different organisms and behavioral models and is thought to be caused by synaptic depression in respective pathways. The underlying molecular mechanisms, however, are poorly understood. We here identify, for the first time, a BK channel-dependent molecular synaptic mechanism leading to synaptic depression that is crucial for habituation, and we discuss the significance of our findings for potential treatments enhancing habituation. PMID- 28348137 TI - Early Golgi Abnormalities and Neurodegeneration upon Loss of Presynaptic Proteins Munc18-1, Syntaxin-1, or SNAP-25. AB - The loss of presynaptic proteins Munc18-1, syntaxin-1, or SNAP-25 is known to produce cell death, but the underlying features have not been compared experimentally. Here, we investigated these features in cultured mouse CNS and DRG neurons. Side-by-side comparisons confirmed massive cell death, before synaptogenesis, within 1-4 DIV upon loss of t-SNAREs (syntaxin-1, SNAP-25) or Munc18-1, but not v-SNAREs (synaptobrevins/VAMP1/2/3 using tetanus neurotoxin (TeNT), also in TI-VAMP/VAMP7 knock-out (KO) neurons). A condensed cis-Golgi was the first abnormality observed upon Munc18-1 or SNAP-25 loss within 3 DIV. This phenotype was distinct from the Golgi fragmentation observed in apoptosis. Cell death was too rapid after syntaxin-1 loss to study Golgi abnormalities. Syntaxin 1 and Munc18-1 depend on each other for normal cellular levels. We observed that endogenous syntaxin-1 accumulates at the Golgi of Munc18-1 KO neurons. However, expression of a non-neuronal Munc18 isoform that does not bind syntaxin-1, Munc18 3, in Munc18-1 KO neurons prevented cell death and restored normal cis-Golgi morphology, but not synaptic transmission or syntaxin-1 targeting. Finally, we observed that DRG neurons are the only Munc18-1 KO neurons that do not degenerate in vivo or in vitro In these neurons, cis-Golgi abnormalities were less severe, with no changes in Golgi shape. Together, these data demonstrate that cell death upon Munc18-1, syntaxin-1, or SNAP-25 loss occurs via a degenerative pathway unrelated to the known synapse function of these proteins and involving early cis Golgi abnormalities, distinct from apoptosis.SIGNIFICANCE STATEMENT This study provides new insights in a neurodegeneration pathway triggered by the absence of specific proteins involved in synaptic transmission (syntaxin-1, Munc18-1, SNAP 25), whereas other proteins involved in the same molecular process (synaptobrevins, Munc13-1/2) do not cause degeneration. Massive cell death occurs in cultured neurons upon depleting syntaxin-1, Munc18-1, and/or SNAP-25, well before synapse formation. This study characterizes several relevant cellular phenotypes, especially early cis-Golgi abnormalities, distinct from abnormalities observed during apoptosis, and rules out several other phenotypes as causal (defects in syntaxin-1 targeting and synaptic transmission). As proteins, such as syntaxin-1, Munc18-1, or SNAP-25, modulate alpha-synuclein neuropathy and/or are dysregulated in Alzheimer's disease, understanding this type of neurodegeneration may provide new links between synaptic defects and neurodegeneration in humans. PMID- 28348138 TI - Dynamical Timescale Explains Marginal Stability in Excitability Dynamics. AB - Action potentials, taking place over milliseconds, are the basis of neural computation. However, the dynamics of excitability over longer, behaviorally relevant timescales remain underexplored. A recent experiment used long-term recordings from single neurons to reveal multiple timescale fluctuations in response to constant stimuli, along with more reliable responses to variable stimuli. Here, we demonstrate that this apparent paradox is resolved if neurons operate in a marginally stable dynamic regime, which we reveal using a novel inference method. Excitability in this regime is characterized by large fluctuations while retaining high sensitivity to external varying stimuli. A new model with a dynamic recovery timescale that interacts with excitability captures this dynamic regime and predicts the neurons' response with high accuracy. The model explains most experimental observations under several stimulus statistics. The compact structure of our model permits further exploration on the network level.SIGNIFICANCE STATEMENT Excitability is the basis for all neural computations and its long-term dynamics reveal a complex combination of many timescales. We discovered that neural excitability operates under a marginally stable regime in which the system is dominated by internal fluctuation while retaining high sensitivity to externally varying stimuli. We offer a novel approach to modeling excitability dynamics by assuming that the recovery timescale is itself a dynamic variable. Our model is able to capture a wide range of experimental phenomena using few parameters with significantly higher predictive power than previous models. PMID- 28348139 TI - Potential effect of centre size on continuity of care and healthcare performance. PMID- 28348136 TI - Driving Human Motor Cortical Oscillations Leads to Behaviorally Relevant Changes in Local GABAA Inhibition: A tACS-TMS Study. AB - Beta and gamma oscillations are the dominant oscillatory activity in the human motor cortex (M1). However, their physiological basis and precise functional significance remain poorly understood. Here, we used transcranial magnetic stimulation (TMS) to examine the physiological basis and behavioral relevance of driving beta and gamma oscillatory activity in the human M1 using transcranial alternating current stimulation (tACS). tACS was applied using a sham-controlled crossover design at individualized intensity for 20 min and TMS was performed at rest (before, during, and after tACS) and during movement preparation (before and after tACS). We demonstrated that driving gamma frequency oscillations using tACS led to a significant, duration-dependent decrease in local resting-state GABAA inhibition, as quantified by short interval intracortical inhibition. The magnitude of this effect was positively correlated with the magnitude of GABAA decrease during movement preparation, when gamma activity in motor circuitry is known to increase. In addition, gamma tACS-induced change in GABAA inhibition was closely related to performance in a motor learning task such that subjects who demonstrated a greater increase in GABAA inhibition also showed faster short-term learning. The findings presented here contribute to our understanding of the neurophysiological basis of motor rhythms and suggest that tACS may have similar physiological effects to endogenously driven local oscillatory activity. Moreover, the ability to modulate local interneuronal circuits by tACS in a behaviorally relevant manner provides a basis for tACS as a putative therapeutic intervention.SIGNIFICANCE STATEMENT Gamma oscillations have a vital role in motor control. Using a combined tACS-TMS approach, we demonstrate that driving gamma frequency oscillations modulates GABAA inhibition in the human motor cortex. Moreover, there is a clear relationship between the change in magnitude of GABAA inhibition induced by tACS and the magnitude of GABAA inhibition observed during task-related synchronization of oscillations in inhibitory interneuronal circuits, supporting the hypothesis that tACS engages endogenous oscillatory circuits. We also show that an individual's physiological response to tACS is closely related to their ability to learn a motor task. These findings contribute to our understanding of the neurophysiological basis of motor rhythms and their behavioral relevance and offer the possibility of developing tACS as a therapeutic tool. PMID- 28348141 TI - Venous lactate, pH and partial pressure of carbon dioxide levels as prognostic indicators in 110 premature calves with respiratory distress syndrome. AB - Hyperlactatemia, hypercapnia, low pH and low oxygen saturation (SatO2) are commonly observed in premature calves. These clinical indicators are associated with increased mortality in preterm human newborns with respiratory distress syndrome (RDS). The aim of this study was to investigate the prognostic importance of venous pH, partial pressure of carbon dioxide (pCO2) and lactate level and which parameters are related with mortality in premature calves with RDS. All premature calves (52 male/58 female) were admitted to clinic within 12 24 hours after birth and blood samples were also taken into heparinised plastic syringes from the jugular vein within 30 minutes following admission. Diagnosis of RDS was made by both clinical signs and blood gas results. For the evaluation of independent samples, t test was used to compare the venous blood gas indicators of surviving and non-surviving premature calves. Receiver operating characteristics curves were used to determine a cut-off value in terms of lactate and pCO2 measurements among non-surviving and surviving calves. Venous pH, pCO2, SatO2, base deficit, bicarbonate (HCO3) and lactate levels showed a significant variance between surviving and non-surviving calves. Mean venous pH, pCO2, SatO2, lactate levels in non-surviving premature calves was 7.05, 78.9 mm Hg, 16.1 per cent and 9.50 mmol/l, respectively. Mean pH, pCO2, SatO2 and lactate levels in surviving premature calves were 7.29, 56.3 mm Hg, 25.5 per cent and 5.1 mmol/l, respectively. The cut-off values for lactate and pCO2 were 7.5 mmol/l and 63.5 mm Hg, respectively. In conclusion, the results of the study show that venous blood lactate and pCO2 have prognostic importance in premature calves with RDS. PMID- 28348140 TI - A classification system for zebrafish adipose tissues. AB - The zebrafish model system offers significant utility for in vivo imaging of adipose tissue (AT) dynamics and for screening to identify chemical and genetic modifiers of adiposity. In particular, AT can be quantified accurately in live zebrafish using fluorescent lipophilic dyes. Although this methodology offers considerable promise, the comprehensive identification and classification of zebrafish ATs has not been performed. Here, we use fluorescent lipophilic dyes and in vivo imaging systematically to identify, classify and quantify the zebrafish AT pool. We identify 34 regionally distinct zebrafish ATs, including five visceral ATs and 22 subcutaneous ATs. For each of these ATs, we describe detailed morphological characteristics to aid their identification in future studies. Furthermore, we quantify the areas for each AT and construct regression models to allow prediction of expected AT size and variation across a range of developmental stages. Finally, we demonstrate the utility of this resource for identifying effects of strain variation and high-fat diet on AT growth. Altogether, this resource provides foundational information on the identity, dynamics and expected quantities of zebrafish ATs for use as a reference for future studies. PMID- 28348142 TI - Survey of susceptibility to marbofloxacin in bacteria isolated from diseased pigs in Europe. AB - A monitoring programme of marbofloxacin susceptibility of bacteria from Europe causing respiratory tract infection and meningitis in pigs has been active since 1994 and 2002, respectively. Monitoring digestive, metritis and urinary tract infection (UTI) in pigs has been active since 2005 and susceptibility results until 2013 are presented. Minimum inhibitory concentration (MIC) was determined by broth microdilution. For MIC interpretation, Vetoquinol-evaluated breakpoints were applied. For digestive pathogens, Escherichia coli and Salmonella species (1717 and 300 isolates, respectively) exhibited 7.5 per cent resistance in E coli and no resistance in Salmonella species. Similarly, E coli from metritis (369 isolates) had 7.0 per cent resistance to marbofloxacin. However, E coli from UTI (633 isolates) had higher resistance (10.4 per cent). For Streptococcus suis causing meningitis (585 isolates), marbofloxacin susceptibility was very high with only 0.5 per cent resistance and 0.4 per cent resistance was observed with S suis causing respiratory disease (729 isolates). Other respiratory pathogens were also highly susceptible to marbofloxacin with no resistance in Actinobacillus pleuropneumoniae (647 isolates) or Bordetella bronchiseptica (504 isolates), 0.1 per cent resistance in Pasteurella multocida (1373 isolates) and 1.4 per cent resistance in Haemophilus parasuis (145 isolates). There was no apparent change in marbofloxacin MIC over time for any bacterial pathogen based on MIC50/90 These data confirm previously published MIC results from porcine and other animal infections. PMID- 28348144 TI - John Vavasour Earle. PMID- 28348143 TI - Daily salivary cortisol levels in response to stress factors in captive common bottlenose dolphins (Tursiops truncatus): a potential welfare indicator. PMID- 28348145 TI - The Complete Guide to Fertility Awareness. PMID- 28348146 TI - Denying contraceptive choice to women with a previous ectopic pregnancy. PMID- 28348147 TI - How do messenger RNA splicing alterations drive myelodysplasia? AB - Mutations in RNA splicing factors are the single most common class of genetic alterations in myelodysplastic syndrome (MDS) patients. Although much has been learned about how these mutations affect splicing at a global- and transcript specific level, critical questions about the role of these mutations in MDS development and maintenance remain. Here we present the questions to be addressed in order to understand the unique enrichment of these mutations in MDS. PMID- 28348148 TI - Inhibition of WNT signaling in the bone marrow niche prevents the development of MDS in the Apcdel/+ MDS mouse model. AB - There is accumulating evidence that functional alteration(s) of the bone marrow (BM) microenvironment contribute to the development of some myeloid disorders, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In addition to a cell-intrinsic role of WNT activation in leukemia stem cells, WNT activation in the BM niche is also thought to contribute to the pathogenesis of MDS and AML. We previously showed that the Apc-haploinsufficient mice (Apcdel/+ ) model MDS induced by an aberrant BM microenvironment. We sought to determine whether Apc, a multifunctional protein and key negative regulator of the canonical beta-catenin (Ctnnb1)/WNT-signaling pathway, mediates this disease through modulating WNT signaling, and whether inhibition of WNT signaling prevents the development of MDS in Apcdel/+ mice. Here, we demonstrate that loss of 1 copy of Ctnnb1 is sufficient to prevent the development of MDS in Apcdel/+ mice and that altered canonical WNT signaling in the microenvironment is responsible for the disease. Furthermore, the US Food and Drug Administration (FDA)-approved drug pyrvinium delays and/or inhibits disease in Apcdel/+ mice, even when it is administered after the presentation of anemia. Other groups have observed increased nuclear CTNNB1 in stromal cells from a high frequency of MDS/AML patients, a finding that together with our results highlights a potential new strategy for treating some myeloid disorders. PMID- 28348149 TI - Pharmacokinetics and Placental Transfer of Elvitegravir, Dolutegravir, and Other Antiretrovirals during Pregnancy. AB - The integrase inhibitors elvitegravir (EVG) and dolutegravir (DTG) rapidly decrease the plasma HIV-1 viral load, a key factor in the prevention of maternal to-fetal transmission of HIV-1. No data have been reported on the concentrations of these drugs in cord blood, maternal peripheral blood mononuclear cells (PBMCs), or placental tissue in pregnant women. We present in vivo pharmacokinetic data on antiretrovirals (ARV) within maternal and cord blood and within placentae from HIV-1-infected pregnant women. Maternal blood and cord blood were obtained from women receiving EVG, cobicistat, tenofovir disoproxil fumarate, and emtricitabine as a single fixed-dose combination formulation or DTG as part of a combination regimen. Plasma and PBMCs from maternal and cord blood were obtained along with villous placental samples. Drug concentrations were simultaneously determined by liquid chromatography-tandem mass spectrometry (LC MS/MS). Utilizing medians and ranges to interpret our data, we compared the drug concentration ratios between different matrices (maternal and cord blood plasma, PBMCs, and placenta). All five agents transferred from maternal into fetal circulation via the placenta. Concentration ratios for EVG, cobicistat, tenofovir, and emtricitabine (n = 10) and DTG (n = 3) were determined between cord plasma and placenta, cord and maternal plasma, and cord PBMCs and maternal PBMCs. TFV moves from maternal plasma through the placenta to the cord blood and then into cord PBMCs, where it is phosphorylated into its active forms (TFV diphosphate). These five ARVs were detected in each of the compartments, highlighting transfer of these agents from the maternal into the fetal circulation. PMID- 28348151 TI - Effect of a Health Care System Respiratory Fluoroquinolone Restriction Program To Alter Utilization and Impact Rates of Clostridium difficile Infection. AB - Fluoroquinolones are one of the most commonly prescribed antibiotic classes in the United States despite their association with adverse consequences, including Clostridium difficile infection (CDI). We sought to evaluate the impact of a health care system antimicrobial stewardship-initiated respiratory fluoroquinolone restriction program on utilization, appropriateness of quinolone based therapy based on institutional guidelines, and CDI rates. After implementation, respiratory fluoroquinolone utilization decreased from a monthly mean and standard deviation (SD) of 41.0 (SD = 4.4) days of therapy (DOT) per 1,000 patient days (PD) preintervention to 21.5 (SD = 6.4) DOT/1,000 PD and 4.8 (SD = 3.6) DOT/1,000 PD posteducation and postrestriction, respectively. Using segmented regression analysis, both education (14.5 DOT/1,000 PD per month decrease; P = 0.023) and restriction (24.5 DOT/1,000 PD per month decrease; P < 0.0001) were associated with decreased utilization. In addition, the CDI rates decreased significantly (P = 0.044) from preintervention using education (3.43 cases/10,000 PD) and restriction (2.2 cases/10,000 PD). Mean monthly CDI cases/10,000 PD decreased from 4.0 (SD = 2.1) preintervention to 2.2 (SD = 1.35) postrestriction. A significant increase in appropriate respiratory fluoroquinolone use occurred postrestriction versus preintervention in patients administered at least one dose (74/130 [57%] versus 74/232 [32%]; P < 0.001), as well as in those receiving two or more doses (47/65 [72%] versus 67/191 [35%]; P < 0.001). A significant reduction in the annual acquisition cost of moxifloxacin, the formulary respiratory fluoroquinolone, was observed postrestriction compared to preintervention within the health care system ($123,882 versus $12,273; P = 0.002). Implementation of a stewardship-initiated respiratory fluoroquinolone restriction program can increase appropriate use while reducing overall utilization, acquisition cost, and CDI rates within a health care system. PMID- 28348150 TI - Efficient Hepatitis C Virus Genotype 1b Core-NS5A Recombinants Permit Efficacy Testing of Protease and NS5A Inhibitors. AB - Hepatitis C virus (HCV) strains belong to seven genotypes with numerous subtypes that respond differently to antiviral therapies. Genotype 1, and primarily subtype 1b, is the most prevalent genotype worldwide. The development of recombinant HCV infectious cell culture systems for different variants, permitted by the high replication capacity of strain JFH1 (genotype 2a), has advanced efficacy and resistance testing of antivirals. However, efficient infectious JFH1 based cell cultures of subtype 1b are limited and comprise only the 5' untranslated region (5'UTR)-NS2, NS4A, or NS5A regions. Importantly, it has not been possible to develop efficient 1b infectious systems expressing the NS3/4A protease, an important target of direct-acting antivirals. We developed efficient infectious JFH1-based cultures with genotype 1b core-NS5A sequences of strains DH1, Con1, and J4 by using previously identified HCV cell culture adaptive substitutions A1226G, R1496L, and Q1773H. These viruses spread efficiently in Huh7.5 cells by acquiring additional adaptive substitutions, and final recombinants yielded peak supernatant infectivity titers of 4 to 5 log10 focus forming units (FFU)/ml. We subsequently succeeded in adapting a JFH1-based 5'UTR NS5A DH1 recombinant to efficient growth in cell culture. We evaluated the efficacy of clinically relevant NS3/4A protease and NS5A inhibitors against the novel genotype 1b viruses, as well as against previously developed 1a viruses. The inhibitors were efficient against all tested genotype 1 viruses, with NS5A inhibitors showing half-maximal effective concentrations several orders of magnitude lower than NS3/4A protease inhibitors. In summary, the developed HCV genotype 1b culture systems represent valuable tools for assessing the efficacy of various classes of antivirals and for other virological studies requiring genotype 1b infectious viruses. PMID- 28348152 TI - Pharmacokinetics and Tolerance of the Phage Endolysin-Based Candidate Drug SAL200 after a Single Intravenous Administration among Healthy Volunteers. AB - This study was a phase 1, single-center, randomized, double-blind, placebo controlled, single-dosing, and dose-escalating study of intravenous SAL200. It is a new candidate drug for the treatment of antibiotic-resistant staphylococcal infections based on a recombinant form of the phage endolysin SAL-1. The study evaluated the pharmacokinetics, pharmacodynamics, and tolerance among healthy male volunteers after the intravenous infusion of single ascending doses of SAL200 (0.1, 0.3, 1, 3, and 10 mg/kg of body weight). SAL200 was well tolerated, and no serious adverse events (AEs) were observed in this clinical study. Most AEs were mild, self-limiting, and transient. The AEs reported in more than three participants were fatigue, rigors, headache, and myalgia. No clinically significant values with respect to the findings of clinical chemistry, hematology, and coagulation analyses, urinalysis, vital signs, and physical examinations were observed, and no notable trends in our electrocardiogram (ECG) results for any tested dose were noticed. A greater-than-dose-proportional increase with regard to systemic exposure and the maximum serum concentration was observed when the SAL200 dose was increased from 0.1 mg/kg to 10 mg/kg. This investigation constitutes the first-in-human phase 1 study of an intravenously administered, phage endolysin-based drug. (This study has been registered at ClinicalTrials.gov under identifier NCT01855048 and at the Clinical Research Information Service [https://cris.nih.go.kr/cris/] under identifier KCT0000968.). PMID- 28348153 TI - Clofazimine-Containing Regimen for the Treatment of Mycobacterium abscessus Lung Disease. AB - Patients with lung disease caused by Mycobacterium abscessus subsp. abscessus (here M. abscessus) typically have poor treatment outcomes. Although clofazimine (CFZ) has been increasingly used in the treatment of M. abscessus lung disease in clinical practice, there are no reported data on its effectiveness for this disease. This study sought to evaluate the clinical efficacy of a CFZ-containing regimen for the treatment of M. abscessus lung disease. We performed a retrospective review of the medical records of 42 patients with M. abscessus lung disease who were treated with CFZ-containing regimens between November 2013 and January 2015. CFZ was administered in combination with other antibiotics as an initial antibiotic regimen in 15 (36%) patients (initial treatment group), and it was added to an existing antibiotic regimen for refractory M. abscessus lung disease in 27 (64%) patients (salvage treatment group). Overall, there was an 81% treatment response rate based on symptoms and a 31% response rate based on radiographic findings. Conversion to culture-negative sputum samples was achieved in 10 (24%) patients after CFZ-containing antibiotic treatment, and during treatment, there were significant decreases in the positivity of semiquantitative sputum cultures for acid-fast bacilli in both the initial (P = 0.018) and salvage (P = 0.001) treatment groups. Our study suggests that CFZ-containing regimens may improve treatment outcomes in patients with M. abscessus lung disease and that a prospective evaluation of CFZ in M. abscessus lung disease is warranted. PMID- 28348154 TI - Mechanisms of Vesicular Stomatitis Virus Inactivation by Protoporphyrin IX, Zinc Protoporphyrin IX, and Mesoporphyrin IX. AB - Virus resistance to antiviral therapies is an increasing concern that makes the development of broad-spectrum antiviral drugs urgent. Targeting of the viral envelope, a component shared by a large number of viruses, emerges as a promising strategy to overcome this problem. Natural and synthetic porphyrins are good candidates for antiviral development due to their relative hydrophobicity and pro oxidant character. In the present work, we characterized the antiviral activities of protoprophyrin IX (PPIX), Zn-protoporphyrin IX (ZnPPIX), and mesoporphyrin IX (MPIX) against vesicular stomatitis virus (VSV) and evaluated the mechanisms involved in this activity. Treatment of VSV with PPIX, ZnPPIX, and MPIX promoted dose-dependent virus inactivation, which was potentiated by porphyrin photoactivation. All three porphyrins inserted into lipid vesicles and disturbed the viral membrane organization. In addition, the porphyrins also affected viral proteins, inducing VSV glycoprotein cross-linking, which was enhanced by porphyrin photoactivation. Virus incubation with sodium azide and alpha tocopherol partially protected VSV from inactivation by porphyrins, suggesting that singlet oxygen (1O2) was the main reactive oxygen species produced by photoactivation of these molecules. Furthermore, 1O2 was detected by 9,10 dimethylanthracene oxidation in photoactivated porphyrin samples, reinforcing this hypothesis. These results reveal the potential therapeutic application of PPIX, ZnPPIX, and MPIX as good models for broad antiviral drug design. PMID- 28348155 TI - Molecular beta-Lactamase Characterization of Aerobic Gram-Negative Pathogens Recovered from Patients Enrolled in the Ceftazidime-Avibactam Phase 3 Trials for Complicated Intra-abdominal Infections, with Efficacies Analyzed against Susceptible and Resistant Subsets. AB - The correlation of the clinical efficacy of ceftazidime-avibactam (plus metronidazole) with that of meropenem was evaluated in subjects infected with Gram-negative isolates having characterized beta-lactam resistance mechanisms from the complicated intra-abdominal infection (cIAI) phase 3 clinical trials. Enterobacteriaceae isolates displaying ceftriaxone and/or ceftazidime MIC values of >=2 MUg/ml and Pseudomonas aeruginosa isolates with ceftazidime MIC values of >=16 MUg/ml were characterized for extended-spectrum-beta-lactamase (ESBL) content. Enterobacteriaceae and P. aeruginosa isolates with imipenem and meropenem MIC values of >=2 and >=8 MUg/ml, respectively, were tested for carbapenemase genes. The primary efficacy endpoint was clinical cure at test of cure (TOC) among the members of the microbiologically modified intention-to-treat (mMITT) population. A total of 14.5% (56/387) and 18.8% (74/394) of patients in the ceftazidime-avibactam and meropenem arms had isolates that met the MIC screening criteria at the baseline visit, respectively. CTX-M variants alone (29.7%; 41/138) or in combination with OXA-1/30 (35.5%; 49/138), most commonly, blaCTX-M group 1 variants (79/90; 87.8%), represented the beta-lactamases most frequently observed among Enterobacteriaceae isolates. Among the patients infected with pathogens that did not meet the screening criteria, 82.2% showed clinical cure in the ceftazidime-avibactam group versus 85.9% in the meropenem group. Among patients infected with any pathogens that met the MIC screening criteria, clinical cure rates at TOC were 87.5% and 86.5% for the ceftazidime avibactam and meropenem groups, respectively. Ceftazidime-avibactam had clinical cure rates of 92.5% to 90.5% among patients infected with ESBL- and/or carbapenemase-producing Enterobacteriaceae strains at the baseline visit, while meropenem showed rates of 84.9% to 85.4%. The ceftazidime-avibactam and meropenem groups had cure rates of 75.0% and 86.7%, respectively, among patients having any pathogens producing AmpC enzymes. The efficacy of ceftazidime-avibactam was similar to that of meropenem for treatment of cIAI caused by ESBL-producing organisms. (This study has been registered at ClinicalTrials.gov under registration no. NCT01499290 and NCT01500239.). PMID- 28348156 TI - Bioluminescence Method for In Vitro Screening of Plasmodium Transmission-Blocking Compounds. AB - The sporogonic stage of the life cycle of Plasmodium spp., the causative agents of malaria, occurs inside the parasite's mosquito vector, where a process of fertilization, meiosis, and mitotic divisions culminates in the generation of large numbers of mammalian-infective sporozoites. Efforts to cultivate Plasmodium mosquito stages in vitro have proved challenging and yielded only moderate success. Here, we describe a methodology that simplifies the in vitro screening of much-needed transmission-blocking (TB) compounds employing a bioluminescence based method to monitor the in vitro development of sporogonic stages of the rodent malaria parasite Plasmodium berghei Our proof-of-principle assessment of the in vitro TB activity of several commonly used antimalarial compounds identified cycloheximide, thiostrepton, and atovaquone as the most active compounds against the parasite's sporogonic stages. The TB activity of these compounds was further confirmed by in vivo studies that validated our newly developed in vitro approach to TB compound screening. PMID- 28348158 TI - GES-14-Producing Acinetobacter baumannii Isolates in a Neonatal Intensive Care Unit in Tunisia Are Associated with a Typical Middle East Clone and a Transferable Plasmid. PMID- 28348157 TI - Exploring the Landscape of Diazabicyclooctane (DBO) Inhibition: Avibactam Inactivation of PER-2 beta-Lactamase. AB - PER beta-lactamases are an emerging family of extended-spectrum beta-lactamases (ESBL) found in Gram-negative bacteria. PER beta-lactamases are unique among class A enzymes as they possess an inverted omega (Omega) loop and extended B3 beta-strand. These singular structural features are hypothesized to contribute to their hydrolytic profile against oxyimino-cephalosporins (e.g., cefotaxime and ceftazidime). Here, we tested the ability of avibactam (AVI), a novel non-beta lactam beta-lactamase inhibitor to inactivate PER-2. Interestingly, the PER-2 inhibition constants (i.e., k2/K = 2 * 103 +/- 0.1 * 103 M-1 s-1, where k2 is the rate constant for acylation (carbamylation) and K is the equilibrium constant) that were obtained when AVI was tested were reminiscent of values observed testing the inhibition by AVI of class C and D beta-lactamases (i.e., k2/K range of ~103 M-1 s-1) and not class A beta-lactamases (i.e., k2/K range, 104 to 105 M 1 s-1). Once AVI was bound, a stable complex with PER-2 was observed via mass spectrometry (e.g., 31,389 +/- 3 atomic mass units [amu] -> 31,604 +/- 3 amu for 24 h). Molecular modeling of PER-2 with AVI showed that the carbonyl of AVI was located in the oxyanion hole of the beta-lactamase and that the sulfate of AVI formed interactions with the beta-lactam carboxylate binding site of the PER-2 beta-lactamase (R220 and T237). However, hydrophobic patches near the PER-2 active site (by Ser70 and B3-B4 beta-strands) were observed and may affect the binding of necessary catalytic water molecules, thus slowing acylation (k2/K) of AVI onto PER-2. Similar electrostatics and hydrophobicity of the active site were also observed between OXA-48 and PER-2, while CTX-M-15 was more hydrophilic. To demonstrate the ability of AVI to overcome the enhanced cephalosporinase activity of PER-2 beta-lactamase, we tested different beta-lactam-AVI combinations. By lowering MICs to <=2 mg/liter, the ceftaroline-AVI combination could represent a favorable therapeutic option against Enterobacteriaceae expressing blaPER-2 Our studies define the inactivation of the PER-2 ESBL by AVI and suggest that the biophysical properties of the active site contribute to determining the efficiency of inactivation. PMID- 28348159 TI - An Azole-Tolerant Endosomal Trafficking Mutant of Candida albicans Is Susceptible to Azole Treatment in a Mouse Model of Vaginal Candidiasis. AB - We recently reported that a Candida albicans endosomal trafficking mutant continues to grow after treatment with the azole antifungals. Herein, we report that the vps21Delta/Delta mutant does not have a survival advantage over wild type isolates after fluconazole treatment in a mouse model of vaginal candidiasis. Furthermore, loss of VPS21 does not synergize with established mechanisms of azole resistance, such as overexpression of efflux pumps or of Erg11p, the target enzyme of the azoles. In summary, although loss of VPS21 function enhances C. albicans survival after azole treatment in vitro, it does not seem to affect azole susceptibility in vivo. PMID- 28348162 TI - Why health services research needs bioethics. PMID- 28348161 TI - Loss of Methyltransferase Function and Increased Efflux Activity Leads to Doxycycline Resistance in Burkholderia pseudomallei. AB - The soil-dwelling bacterium Burkholderia pseudomallei is the causative agent of the potentially fatal disease melioidosis. The lack of a vaccine toward B. pseudomallei means that melioidosis treatment relies on prolonged antibiotic therapy, which can last up to 6 months in duration or longer. Due to intrinsic resistance, few antibiotics are effective against B. pseudomallei The lengthy treatment regimen required increases the likelihood of resistance development, with subsequent potentially fatal relapse. Doxycycline (DOX) has historically played an important role in the eradication phase of melioidosis treatment. Both primary and acquired DOX resistances have been documented in B. pseudomallei; however, the molecular mechanisms underpinning DOX resistance have remained elusive. Here, we identify and functionally characterize the molecular mechanisms conferring acquired DOX resistance in an isogenic B. pseudomallei pair. Two synergistic mechanisms were identified. The first mutation occurred in a putative S-adenosyl-l-methionine-dependent methyltransferase (encoded by BPSL3085), which we propose leads to altered ribosomal methylation, thereby decreasing DOX binding efficiency. The second mutation altered the function of the efflux pump repressor gene, amrR, resulting in increased expression of the resistance-nodulation division efflux pump, AmrAB-OprA. Our findings highlight the diverse mechanisms by which B. pseudomallei can become resistant to antibiotics used in melioidosis therapy and the need for resistance monitoring during treatment regimens, especially in patients with prolonged or recrudesced positive cultures for B. pseudomallei. PMID- 28348163 TI - Process factors facilitating and inhibiting medical ethics teaching in small groups. AB - PURPOSE: To examine process factors that either facilitate or inhibit learning medical ethics during case-based learning. METHODS: A qualitative research approach using microanalysis of transcribed videotaped discussions of three consecutive small-group learning (SGL) sessions on medical ethics teaching (MET) for three groups, each with 10 students. RESULTS: This research effort revealed 12 themes of learning strategies, divided into 6 coping and 6 evasive strategies. Cognitive-based strategies were found to relate to Kamin's model of critical thinking in medical education, thereby supporting our distinction between the themes of coping and evasive strategies. The findings also showed that cognitive efforts as well as emotional strategies are involved in discussions of ethical dilemmas. Based on Kamin's model and the constructivist learning theory, an examination of the different themes within the two learning strategies-coping and evasive-revealed that these strategies may be understood as corresponding to process factors either facilitating or inhibiting MET in SGL, respectively. CONCLUSIONS: Our classification offers a more nuanced observation, specifically geared to pinpointing the desired and less desired process factors in the learning involved in MET in the SGL environment. Two key advantages of this observation are: (1) it brings to the forefront process factors that may inhibit and not merely facilitate MET in SGL and (2) it acknowledges the existence of emotional and not just cognitive process factors. Further enhancement of MET in SGL may thus be achieved based on these observations. PMID- 28348160 TI - The Race To Find Antivirals for Zika Virus. AB - Zika virus (ZIKV), a flavivirus transmitted by mosquitoes, was an almost neglected pathogen until its introduction in the Americas in 2015 and its subsequent explosive spread throughout the continent, where it has infected millions of people. The virus has caused social and sanitary alarm, mainly due to its association with severe neurological disorders (Guillain-Barre syndrome and microcephaly in fetuses and newborns). Nowadays, no specific antiviral therapy against ZIKV is available. However, during the past months, a great effort has been made to search for antiviral candidates using different approaches and methodologies, ranging from testing specific compounds with known antiviral activity to the screening of libraries with hundreds of bioactive molecules. The identified antiviral candidates include drugs targeting viral components as well as cellular ones. Here, an updated review of what has been done in this line is presented. PMID- 28348164 TI - Undue inducement: a case study in CAPRISA 008. AB - : Participant safety and data integrity, critical in trials of new investigational drugs, are achieved through honest participant report and precision in the conduct of procedures. HIV prevention post-trial access studies in middle-income countries potentially offer participants many benefits including access to proven efficacious but unlicensed technologies, ancillary care that often exceeds local standards-of-care, financial reimbursement for participation and possibly unintended benefits if participants choose to share or sell investigational drugs. This case study examines the possibility that this combination of benefits may constitute an undue inducement for some participants in middle-income countries, where economic challenges are prevalent. A case study is presented of a single participant in a cohort of 382 participants who used concealment, fabrication and deception to ensure eligibility for a post-trial access study of an unlicensed HIV prevention technology at potential risk to her health and that of her fetus. A root cause analysis revealed her desire to access HIV prevention during an unplanned pregnancy with a partner whose faithfulness was in question. Researchers should consider implementation of systems to efficiently identify similar cases without inconveniencing the majority of participants TRIAL REGISTRATION NUMBER: NCT01691768. PMID- 28348165 TI - Combinatorial DNA methylation codes at repetitive elements. AB - DNA methylation is an essential epigenetic modification, present in both unique DNA sequences and repetitive elements, but its exact function in repetitive elements remains obscure. Here, we describe the genome-wide comparative analysis of the 5mC, 5hmC, 5fC, and 5caC profiles of repetitive elements in mouse embryonic fibroblasts and mouse embryonic stem cells. We provide evidence for distinct and highly specific DNA methylation/oxidation patterns of the repetitive elements in both cell types, which mainly affect CA repeats and evolutionarily conserved mouse-specific transposable elements including IAP-LTRs, SINEs B1m/B2m, and L1Md-LINEs. DNA methylation controls the expression of these retroelements, which are clustered at specific locations in the mouse genome. We show that TDG is implicated in the regulation of their unique DNA methylation/oxidation signatures and their dynamics. Our data suggest the existence of a novel epigenetic code for the most recently acquired evolutionarily conserved repeats that could play a major role in cell differentiation. PMID- 28348166 TI - Mfn2 is critical for brown adipose tissue thermogenic function. AB - Mitochondrial fusion and fission events, collectively known as mitochondrial dynamics, act as quality control mechanisms to ensure mitochondrial function and fine-tune cellular bioenergetics. Defective mitofusin 2 (Mfn2) expression and enhanced mitochondrial fission in skeletal muscle are hallmarks of insulin resistant states. Interestingly, Mfn2 is highly expressed in brown adipose tissue (BAT), yet its role remains unexplored. Using adipose-specific Mfn2 knockout (Mfn2-adKO) mice, we demonstrate that Mfn2, but not Mfn1, deficiency in BAT leads to a profound BAT dysfunction, associated with impaired respiratory capacity and a blunted response to adrenergic stimuli. Importantly, Mfn2 directly interacts with perilipin 1, facilitating the interaction between the mitochondria and the lipid droplet in response to adrenergic stimulation. Surprisingly, Mfn2-adKO mice were protected from high-fat diet-induced insulin resistance and hepatic steatosis. Altogether, these results demonstrate that Mfn2 is a mediator of mitochondria to lipid droplet interactions, influencing lipolytic processes and whole-body energy homeostasis. PMID- 28348167 TI - Wnt proteins contribute to neuromuscular junction formation through distinct signaling pathways. AB - Understanding the developmental steps that shape formation of the neuromuscular junction (NMJ) connecting motoneurons to skeletal muscle fibers is crucial. Wnt morphogens are key players in the formation of this specialized peripheral synapse, but their individual and collaborative functions and downstream pathways remain poorly understood at the NMJ. Here, we demonstrate through Wnt4 and Wnt11 gain-of-function studies in cell culture or in mice that Wnts enhance acetylcholine receptor (AChR) clustering and motor axon outgrowth. By contrast, loss of Wnt11 or Wnt-dependent signaling in vivo decreases AChR clustering and motor nerve terminal branching. Both Wnt4 and Wnt11 stimulate AChR mRNA levels and AChR clustering downstream of activation of the beta-catenin pathway. Strikingly, Wnt4 and Wnt11 co-immunoprecipitate with Vangl2, a core component of the planar cell polarity (PCP) pathway, which accumulates at embryonic NMJs. Moreover, mice bearing a Vangl2 loss-of-function mutation (loop-tail) exhibit fewer AChR clusters and overgrowth of motor axons bypassing AChR clusters. Together, our results provide genetic and biochemical evidence that Wnt4 and Wnt11 cooperatively contribute to mammalian NMJ formation through activation of both the canonical and Vangl2-dependent core PCP pathways. PMID- 28348168 TI - FGFR2 is required for airway basal cell self-renewal and terminal differentiation. AB - Airway stem cells slowly self-renew and produce differentiated progeny to maintain homeostasis throughout the lifespan of an individual. Mutations in the molecular regulators of these processes may drive cancer or degenerative disease, but are also potential therapeutic targets. Conditionally deleting one copy of FGF receptor 2 (FGFR2) in adult mouse airway basal cells results in self-renewal and differentiation phenotypes. We show that FGFR2 signalling correlates with maintenance of expression of a key transcription factor for basal cell self renewal and differentiation: SOX2. This heterozygous phenotype illustrates that subtle changes in receptor tyrosine kinase signalling can have significant effects, perhaps providing an explanation for the numerous changes seen in cancer. PMID- 28348169 TI - Developmental patterning of the sub-epidermal integument cell layer in Arabidopsis seeds. AB - Angiosperm seed development is a paradigm of tissue cross-talk. Proper seed formation requires spatial and temporal coordination of the fertilization products - embryo and endosperm - and the surrounding seed coat maternal tissue. In early Arabidopsis seed development, all seed integuments were thought to respond homogenously to endosperm growth. Here, we show that the sub-epidermal integument cell layer has a unique developmental program. We characterized the cell patterning of the sub-epidermal integument cell layer, which initiates a previously uncharacterized extra cell layer, and identified TRANSPARENT TESTA 16 and SEEDSTICK MADS box transcription factors as master regulators of its polar development and cell architecture. Our data indicate that the differentiation of the sub-epidermal integument cell layer is insensitive to endosperm growth alone and to the repressive mechanism established by FERTILIZATION INDEPENDENT ENDOSPERM and MULTICOPY SUPPRESSOR OF IRA1 Polycomb group proteins. This work demonstrates the different responses of epidermal and sub-epidermal integument cell layers to fertilization. PMID- 28348170 TI - Crystal structure of U2 snRNP SF3b components: Hsh49p in complex with Cus1p binding domain. AB - Spliceosomal proteins Hsh49p and Cus1p are components of SF3b, which together with SF3a, Msl1p/Lea1p, Sm proteins, and U2 snRNA, form U2 snRNP, which plays a crucial role in pre-mRNA splicing. Hsh49p, comprising two RRMs, forms a heterodimer with Cus1p. We determined the crystal structures of Saccharomyces cerevisiae full-length Hsh49p as well as its RRM1 in complex with a minimal binding region of Cus1p (residues 290-368). The structures show that the Cus1 fragment binds to the alpha-helical surface of Hsh49p RRM1, opposite the four stranded beta-sheet, leaving the canonical RNA-binding surface available to bind RNA. Hsh49p binds the 5' end region of U2 snRNA via RRM1. Its affinity is increased in complex with Cus1(290-368)p, partly because an extended RNA-binding surface forms across the protein-protein interface. The Hsh49p RRM1-Cus1(290 368)p structure fits well into cryo-EM density of the Bact spliceosome, corroborating the biological relevance of our crystal structure. PMID- 28348171 TI - The Identification of Macrophage-enriched Glycoproteins Using Glycoproteomics. AB - Prostate cancer is a leading cause of cancer-related deaths of men in the United States. Whereas the localized disease is highly treatable by surgical resection and radiation, cancer that has metastasized remains incurable. Immune cells that primarily scavenge debris and promote prostate cancer angiogenesis and wound repair are M2 macrophages. They are phenotypically similar to M2 tumor-associated macrophages (M2-TAMs) and have been reported to associate with solid tumors and aide in proliferation, metastasis, and resistance to therapy. As an invasive species within the tumor microenvironment, this makes M2-TAMs an ideal therapeutic target in prostate cancer. To identify novel surface glycoproteins expressed on M2 macrophages, we developed a novel method of creating homogeneous populations of human macrophages from human CD14+ monocytes in vitro These homogeneous M1 macrophages secrete pro-inflammatory cytokines, and our M2 macrophages secrete anti-inflammatory cytokines as well as vascular endothelial growth factor (VEGF). To identify enriched surface glycoproteins, we then performed solid-phase extraction of N-linked glycopeptides followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) on our homogeneous macrophage populations. We discovered five novel peptides that are enriched exclusively on human M2 macrophages relative to human M1 macrophages and human CD14+ monocytes. Finally, we determined whether these surface glycoproteins, found enriched on M2 macrophages, were also expressed in human metastatic castrate-resistant prostate cancer (mCRPC) tissues. Using mCRPC tissues from rapid autopsies, we were able to determine M2 macrophage infiltration by using immunohistochemistry and flow cytometry. These findings highlight the presence of macrophage infiltration in human mCRPC but also surface glycoproteins that could be used for prognosis of localized disease and for targeting strategies. PMID- 28348172 TI - Database-independent Protein Sequencing (DiPS) Enables Full-length de Novo Protein and Antibody Sequence Determination. AB - Traditional "bottom-up" proteomic approaches use proteolytic digestion, LC-MS/MS, and database searching to elucidate peptide identities and their parent proteins. Protein sequences absent from the database cannot be identified, and even if present in the database, complete sequence coverage is rarely achieved even for the most abundant proteins in the sample. Thus, sequencing of unknown proteins such as antibodies or constituents of metaproteomes remains a challenging problem. To date, there is no available method for full-length protein sequencing, independent of a reference database, in high throughput. Here, we present Database-independent Protein Sequencing, a method for unambiguous, rapid, database-independent, full-length protein sequencing. The method is a novel combination of non-enzymatic, semi-random cleavage of the protein, LC-MS/MS analysis, peptide de novo sequencing, extraction of peptide tags, and their assembly into a consensus sequence using an algorithm named "Peptide Tag Assembler." As proof-of-concept, the method was applied to samples of three known proteins representing three size classes and to a previously un-sequenced, clinically relevant monoclonal antibody. Excluding leucine/isoleucine and glutamic acid/deamidated glutamine ambiguities, end-to-end full-length de novo sequencing was achieved with 99-100% accuracy for all benchmarking proteins and the antibody light chain. Accuracy of the sequenced antibody heavy chain, including the entire variable region, was also 100%, but there was a 23-residue gap in the constant region sequence. PMID- 28348173 TI - Rate Coding and the Control of Muscle Force. AB - The force exerted by a muscle during a voluntary contraction depends on the number of motor units recruited for the action and the rates at which they discharge action potentials (rate coding). Over most of the operating range of a muscle, the nervous system controls muscle force by varying both motor unit recruitment and rate coding. Except at relatively low forces, however, the control of muscle force depends primarily on rate coding, especially during fast contractions. This review provides five examples of how the modulation of rate coding influences the force exerted by muscle during voluntary actions. The five examples comprise fast contractions, lengthening and shortening contractions, steady isometric contractions, fatiguing contractions, and contractions performed after a change in the daily level of physical activity. PMID- 28348175 TI - Omics and Exercise: Global Approaches for Mapping Exercise Biological Networks. AB - The application of global "-omics" technologies to exercise has introduced new opportunities to map the complexity and interconnectedness of biological networks underlying the tissue-specific responses and systemic health benefits of exercise. This review will introduce major research tracks and recent advancements in this emerging field, as well as critical gaps in understanding the orchestration of molecular exercise dynamics that will benefit from unbiased omics investigations. Furthermore, significant research hurdles that need to be overcome to effectively fill these gaps related to data collection, computation, interpretation, and integration across omics applications will be discussed. Collectively, a cross-disciplinary physiological and omics-based systems approach will lead to discovery of a wealth of novel exercise-regulated targets for future mechanistic validation. This frontier in exercise biology will aid the development of personalized therapeutic strategies to improve athletic performance and human health through precision exercise medicine. PMID- 28348174 TI - The Self-Assembling Process and Applications in Tissue Engineering. AB - Tissue engineering strives to create neotissues capable of restoring function. Scaffold-free technologies have emerged that can recapitulate native tissue function without the use of an exogenous scaffold. This review will survey, in particular, the self-assembling and self-organization processes as scaffold-free techniques. Characteristics and benefits of each process are described, and key examples of tissues created using these scaffold-free processes are examined to provide guidance for future tissue-engineering developments. We aim to explore the potential of self-assembly and self-organization scaffold-free approaches, detailing the recent progress in the in vitro tissue engineering of biomimetic tissues with these methods toward generating functional tissue replacements. PMID- 28348176 TI - Honing Cell and Tissue Culture Conditions for Bone and Cartilage Tissue Engineering. AB - An avenue of tremendous interest and need in health care encompasses the regeneration of bone and cartilage. Over the years, numerous tissue engineering strategies have contributed substantial progress toward the realization of clinically relevant therapies. Cell and tissue culture protocols, however, show many variations that make experimental results among different publications challenging to compare. This collection surveys prevalent cell sources, soluble factors, culture medium formulations, environmental factors, and genetic modification approaches in the literature. The intent of consolidating this information is to provide a starting resource for scientists considering how to optimize the parameters for cell differentiation and tissue culture procedures within the context of bone and cartilage tissue engineering. PMID- 28348177 TI - Historical Perspective and Future Direction of Blood Vessel Developments. AB - Over the past 40 years, remarkable advances have been made in our understanding of successful blood vessel regeneration, starting with the failures of early tissue-engineered vascular grafts designed using isolated components or molecules, such as collagen gels. The vascular tissue engineers are today better educated and have steered ongoing research developments toward clinical developments of more complete vascular grafts that replicate the multitude of specialized arterial aspects required for function. PMID- 28348178 TI - Craniofacial Tissue Engineering. AB - The craniofacial complex is composed of fundamental components such as blood vessels and nerves, and also a variety of specialized tissues such as craniofacial bones, cartilages, muscles, ligaments, and the highly specialized and unique organs, the teeth. Together, these structures provide many functions including speech, mastication, and aesthetics of the craniofacial complex. Craniofacial defects not only influence the structure and function of the jaws and face, but may also result in deleterious psychosocial issues, emphasizing the need for rapid and effective, precise, and aesthetic reconstruction of craniofacial tissues. In a broad sense, craniofacial tissue reconstructions share many of the same issues as noncraniofacial tissue reconstructions. Therefore, many concepts and therapies for general tissue engineering can and have been used for craniofacial tissue regeneration. Still, repair of craniofacial defects presents unique challenges, mainly because of their complex and unique 3D geometry. PMID- 28348179 TI - The BMJ Awards 2017: Anaesthesia. PMID- 28348180 TI - Experience of miscarriage: an interpretative phenomenological analysis. AB - OBJECTIVE: The objective of the study was to explore the experiences of those who have experienced miscarriage, focusing on men's and women's accounts of miscarriage. DESIGN: This was a qualitative study using a phenomenological framework. Following in-depth semistructured interviews, analysis was undertaken in order to identify superordinate themes relating to their experience of miscarriage. SETTING: A large tertiary-level maternity hospital in Ireland. PARTICIPANTS: A purposive sample of 16 participants, comprising 10 women and 6 men, was recruited. RESULTS: 6 superordinate themes in relation to the participant's experience of miscarriage were identified: (1) acknowledgement of miscarriage as a valid loss; (2) misperceptions of miscarriage; (3) the hospital environment, management of miscarriage; (4) support and coping; (5) reproductive history; and (6) implications for future pregnancies. CONCLUSIONS: One of the key findings illustrates a need for increased awareness in relation to miscarriage. The study also indicates that the experience of miscarriage has a considerable impact on men and women. This study highlights that a thorough investigation of the underlying causes of miscarriage and continuity of care in subsequent pregnancies are priorities for those who experience miscarriage. Consideration should be given to the manner in which women who have not experienced recurrent miscarriage but have other potential risk factors for miscarriage could be followed up in clinical practice. PMID- 28348181 TI - Trajectories of CKD-MBD biochemical parameters over a 2-year period following diagnosis of secondary hyperparathyroidism: a pharmacoepidemiological study. AB - OBJECTIVES: To define groups of patients according to the changes of biochemical parameters, that is, serum calcium, phosphate and parathyroid hormone (PTH), over a 2-year follow-up period using group-based multi-trajectory modeling (GBMM) among a cohort of dialysis patients with newly diagnosed secondary hyperparathyroidism (SHPT) (ie, PTH>=500 ng/L for the first time) and to compare their patient characteristics and treatments. DESIGN: Pharmacoepidemiological study. SETTING: In the 12 dialysis units located in the French region of Lorraine. PARTICIPANTS: A total of 269 dialysis patients with newly diagnosed SHPT were prospectively included from December 2009 to May 2012 and followed-up for 2 years. RESULTS: We identified four distinct trajectory groups: 'rapid PTH drop' experiencing a rapid and sharp decrease (over weeks) in PTH level associated with decreasing phosphate level within normal range (n=34; 12.7%), 'gradual PTH decrease' experiencing a gradual and continuous decrease (over months) in PTH level and maintaining phosphate at a middle level throughout the study (n=98; 36.4%), 'slow PTH decrease with high phosphate' experiencing a slow decrease in PTH level associated with a relatively high phosphate level (n=105; 39.0%) and 'uncontrolled SHPT' with high levels of PTH and phosphate throughout the study (n=32; 11.9%). Patients in the 'uncontrolled SHPT' group were significantly (p<0.00001) younger than patients in other groups. Kidney Disease Improving Global Outcomes (KDIGO) targets for PTH, phosphate and calcium were reached simultaneously for 14.9% of patients at baseline and 16.7% at the end of the study. Patients were given cinacalcet more frequently at months 3 and 6 in the 'rapid PTH drop' and at month 24 in the 'uncontrolled SHPT' groups. CONCLUSIONS: Over 2 years following a new SHPT diagnosis, a younger age and a higher rate of alkaline phosphatase were associated to a continuous uncontrolled SHPT. Patients with the lowest PTH at the end of the follow-up tended to receive more often cinacalcet. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number, NCT02888639, post results. PMID- 28348182 TI - Constraint choice in revision knee arthroplasty: study protocol of a randomised controlled trial assessing the effect of level of constraint on postoperative outcome. AB - INTRODUCTION: The proper management of total knee arthroplasty (TKA) in patients with severe deformities regarding the preferable prosthetic design and the required amount of constraint is a controversial subject. In the absence of any high-level clinical evidence, we designed a randomised clinical trial to investigate if rotating hinged (RTH) and constrained condylar knee (CCK) designs yield similar outcomes. METHODS AND ANALYSIS: This study is a multicentre, randomised clinical trial including two groups of 85 patients. Patients will be randomised to a CCK knee design group or an RTH knee design group. Patients will be followed for 2 years. The study will be designed as an equivalence trial. The primary study outcome will be the postoperative functional outcome as measured by the self-administered Knee Injury and Osteoarthritis Outcome Score. Secondary outcomes will be postoperative joint awareness during various activities of daily living as measured by the Forgotten Joint Score-12, the Knee Society Score, along with the incidence and location of radiolucent lines using the Knee Society TKA radiographic evaluation system. ETHICS AND DISSEMINATION: This study is approved by the ethics committee of the Landesarztekammer Brandenburg ((S 10(a)/2013) from 27.08.2013, amended on 25.04.2016) and will be conducted according to the principles of the World Medical Association Declaration of Helsinki and the ISO14155:2011. TRIAL REGISTRATION NUMBER: DRKS00010539. PMID- 28348184 TI - Comparison of the prognostic values of inflammation markers in patients with acute pancreatitis: a retrospective cohort study. AB - OBJECTIVES: Inflammation-based prognostic markers (neutrophil-lymphocyte ratio (NLR), prognostic nutritional index (PNI), red cell distribution width (RDW) and lymphocyte-monocyte ratio (LMR)) are associated with overall survival in some diseases. This study assessed their prognostic value in mortality and severity in acute pancreatitis (AP). DESIGN: A retrospective cohort study. SETTING: Patients with AP were recruited from the emergency department at our hospital. PARTICIPANTS: A total of 359 patients with AP (31 non-survivors) were enrolled. PRIMARY AND SECONDARY OUTCOME MEASURES: Mortality and severity of AP were the primary and secondary outcome measures, respectively. Biochemistry and haematology results of the first test after admission were collected. Independent relationships between severe AP (SAP) and markers were assessed using multivariate logistic regression models. Mortality prediction ability was evaluated using receiver operating characteristic (ROC) curves. Overall survival was evaluated using the Kaplan-Meier method, with differences compared using the log-rank test. Independent relationships between mortality and each predictor were estimated using the Cox proportional hazard models. RESULTS: Compared with survivors of AP, non-survivors had higher RDW (p<0.001), higher NLR (p<0.001), lower LMR (p<0.001) and lower PNI (p<0.001) at baseline. C reactive protein (CRP; OR=8.251, p<0.001), RDW (OR=2.533, p=0.003) and PNI (OR=7.753, p<0.001) were independently associated with the occurrence of SAP. For predicting mortality, NLR had the largest area under the ROC curve (0.804, p<0.001), with a 16.64 cut off value, 82.4% sensitivity and 75.6% specificity. RDW was a reliable marker for excluding death owing to its lowest negative likelihood ratio (0.11). NLR (HR=4.726, p=0.004), CRP (HR=3.503, p=0.003), RDW (HR=3.139, p=0.013) and PNI (HR=2.641, p=0.011) were independently associated with mortality of AP. CONCLUSIONS: NLR was the most powerful marker of overall survival in this patient series. PMID- 28348183 TI - Smartphone application for women with gestational diabetes mellitus: a study protocol for a multicentre randomised controlled trial. AB - INTRODUCTION: The promotion of a healthy diet, physical activity and measurement of blood glucose levels are essential components in the care for women with gestational diabetes mellitus (GDM). Smartphones offer a new way to promote health behaviour. The main aim is to investigate if the use of the Pregnant+ app, in addition to standard care, results in better blood glucose levels compared with current standard care only, for women with GDM. METHODS AND ANALYSIS: This randomised controlled trial will include 230 pregnant women with GDM followed up at 5 outpatient departments (OPD) in the greater Oslo Region. Women with a 2-hour oral glucose tolerance test (OGTT) >=9 mmol/L, who own a smartphone, understand Norwegian, Urdu or Somali and are <33 weeks pregnant, are invited. The intervention group receives the Pregnant+ app and standard care. The control group receives standard care only. Block randomisation is performed electronically. Data are collected using self-reported questionnaires and hospital records. Data will be analysed according to the intention-to-treat principle. Groups will be compared using linear regression for the main outcome and chi2 test for categorical data and Student's t-test or Mann-Whitney-Wilcoxon test for skewed distribution. The main outcome is the glucose level measured at the 2-hour OGTT 3 months postpartum. Secondary outcomes are a change in health behaviour and knowledge about GDM, quality of life, birth weight, mode of delivery and complications for mother and child. ETHICS AND DISSEMINATION: The study is exempt from regional ethics review due to its nature of quality improvement in patient care. Our study has been approved by the Norwegian Social Science Data Services and the patient privacy protections boards governing over the recruitment sites. Findings will be presented in peer-reviewed journals and at conferences. TRIAL REGISTRATION NUMBER: NCT02588729, Post-results. PMID- 28348186 TI - Biological rationale and potential clinical use of gabapentin and pregabalin in bipolar disorder, insomnia and anxiety: protocol for a systematic review and meta analysis. AB - INTRODUCTION: Gabapentin has been extensively prescribed off-label for psychiatric indications, with little established evidence of efficacy. Gabapentin and pregabalin, a very similar drug with the same mechanism of action, bind to a subunit of voltage-dependent calcium channels which are implicated in the aetiopathogenesis of bipolar disorder, anxiety and insomnia. This systematic review and meta-analysis aims to collect and critically appraise all the available evidence about the efficacy and tolerability of gabapentin and pregabalin in the treatment of bipolar disorder, insomnia and anxiety. METHODS AND ANALYSIS: We will include all randomised controlled trials (RCTs) reported as double-blind and comparing gabapentin or pregabalin with placebo or any other active pharmacological treatment (any preparation, dose, frequency, route of delivery or setting) in patients with bipolar disorder, anxiety or insomnia. For consideration of adverse effects (tolerability), single-blind or open-label RCTs and non-randomised evidence will also be summarised. The main outcomes will be efficacy (measured as dichotomous and continuous outcome) and acceptability (proportion of patients who dropped out of the allocated treatment). Published and unpublished studies will be sought through relevant database searches, trial registries and websites; all reference selection and data extraction will be conducted by at least 2 independent reviewers. We will conduct a random-effects meta-analysis to synthesise all evidence for each outcome. Heterogeneity between studies will be investigated by the I2 statistic. Data from included studies will be entered into a funnel plot for investigation of small-study effects. No subgroup analysis will be undertaken, but we will carry out sensitivity analyses about combination treatment, psychiatric comorbidity, use of rescue medications and fixed versus random-effects model. ETHICS AND DISSEMINATION: This review does not require ethical approval. This protocol has been registered on PROSPERO (CRD42016041802). The results of the systematic review will be disseminated via publication in a peer-reviewed journal. PMID- 28348187 TI - Protocol for systematic review of school-based interventions to prevent and control obesity in African learners. AB - INTRODUCTION: The increasing prevalence of obesity and overweight in childhood in developing countries is a public health concern to many governments. Schools play a significant role in the obesity epidemic as well as provide favourable environments for change in behaviours in childhood which can be carried on into adulthood. There is dearth of information on intervention studies in poor resource settings. This review will summarise the available evidence on school based interventions that focused on promoting healthy eating and physical activity among learners aged 6-15 years in Africa and to identify factors that lead to successful interventions or potential barriers to success of these programmes within the African context. METHODS AND ANALYSIS: This protocol is developed following the guidelines of PRIMSA-P 2015. Relevant search terms and keywords generated from the subject headings and the African search filter will be used to conduct a comprehensive search of MEDLINE (PubMed), MEDLINE (EbscoHost), CINAHL (EbscoHost), Register Academic Search Complete (EbscoHost) and ISI Web of Science (Science Citation Index) for published literature on school-based interventions to prevent and control obesity in learners in Africa. Grey literature will be also be obtained. The searches will cover 1 January 2000 to 30 June 2016. No language limitations will be applied. Full-text articles of eligible studies will be screened. Risk of bias and quality of reporting will be assessed. Data will be extracted, synthesised and presented by country and major regional groupings. Meta-analysis will be conducted for identical variables across studies, where data allow. This protocol is developed following the guidelines of PRISMA-P 2015. ETHICS AND DISSEMINATION: No primary data will be collected hence ethics is not a requirement. The findings will be submitted for publication in peer-reviewed journals, in conferences and in policy documents for decision-making, where needed. PMID- 28348185 TI - Surgery for Type B Ankle Fracture Treatment: a Combined Randomised and Observational Study (CROSSBAT). AB - BACKGROUND: Isolated type B ankle fractures with no injury to the medial side are the most common type of ankle fracture. OBJECTIVE: This study aimed to determine if surgery is superior to non-surgical management for the treatment of these fractures. METHODS: A pragmatic, multicentre, single-blinded, combined randomised controlled trial and observational study. Setting Participants between 18 and 65 years with a type B ankle fracture and minimal talar shift were recruited from 22 hospitals in Australia and New Zealand. Participants willing to be randomised were randomly allocated to undergo surgical fixation followed by mobilisation in a walking boot for 6 weeks. Those treated non-surgically were managed in a walking boot for 6 weeks. Participants not willing to be randomised formed the observational cohort. Randomisation stratified by site and using permuted variable blocks was administered centrally. Outcome assessors were blinded for the primary outcomes. Primary outcomes Patient-reported ankle function using the American Academy of Orthopaedic Surgeons Foot and Ankle Outcomes Questionnaire (FAOQ) and the physical component score (PCS) of the SF-12v2 General Health Survey at 12 months postinjury. Primary analysis was intention to treat; the randomised and observational cohorts were analysed separately. RESULTS: From August 2010 to October 2013, 160 people were randomised (80 surgical and 80 non surgical); 139 (71 surgical and 68 non-surgical) were analysed as intention to treat. 276 formed the observational cohort (19 surgical and 257 non-surgical); 220 (18 surgical and 202 non-surgical) were analysed. The randomised cohort demonstrated that surgery was not superior to non-surgery for the FAOQ (49.8 vs 53.0; mean difference 3.2 (95% CI 0.4 to 5.9), p=0.028), or the PCS (53.7 vs 53.2; mean difference 0.6 (-2.9 to 1.8), p=0.63). 23 (32%) and 10 (14%) participants had an adverse event in the surgical and non-surgical groups, respectively. Similar results were found in the observational cohort. CONCLUSIONS: Surgery is not superior to non-surgical management for 44-B1 ankle fractures in the short term, and is associated with increased adverse events. TRIAL REGISTRATION NUMBER: NCT01134094. PMID- 28348188 TI - Influencing factors on compliance of timely visits among patients with proliferative diabetic retinopathy in southern China: a qualitative study. AB - OBJECTIVE: To identify the reasons for low adherence among patients with diabetic retinopathy (DR) in southern China using a qualitative method. METHODS: Exploratory indepth interviews were conducted in 27 diabetic patients with proliferative diabetic retinopathy who required vitrectomy surgery at Zhongshan Ophthalmic Centre, Sun Yat-sen University, from March to August 2015. Qualitative data analysis and research software (ATLAS.ti7) was used for data processing and analysis. RESULTS: Factors influencing the occurrence of timely visits included lack of DR related knowledge, fear and worries about insulin, interactions between patients and society combined with the complexity of emotions and social culture, and the economic burden of treatment. CONCLUSIONS: Although the reasons for low adherence involved social, emotional, cultural and economic factors, the key issue was the lack of awareness and knowledge of DR. Our findings have several practical implications for health policymakers and programme planners in China. PMID- 28348189 TI - Global systematic review of Indigenous community-led legal interventions to control alcohol. AB - OBJECTIVES: The national and subnational governments of most developed nations have adopted cost-effective regulatory and legislative controls over alcohol supply and consumption with great success. However, there has been a lack of scrutiny of the effectiveness and appropriateness of these laws in shaping the health-related behaviours of Indigenous communities, who disproportionately experience alcohol-related harm. Further, such controls imposed unilaterally without Indigenous consultation have often been discriminatory and harmful in practice. SETTING, PARTICIPANTS AND OUTCOME MEASURES: In this systematic review of quantitative evaluations of Indigenous-led alcohol controls, we aim to investigate how regulatory responses have been developed and implemented by Indigenous communities worldwide, and evaluate their effectiveness in improving health and social outcomes. We included articles from electronic databases MEDLINE, EMBASE, CINAHL, PsycINFO and Web of Science from inception to December 2015. RESULTS: Our search yielded 1489 articles from which 18 met the inclusion criteria. Controls were implemented in rural and remote populations of high income nations. Communities employed a range of regulatory options including alcohol rationing, prohibition of sale, importation or possession, restrictions on liquor sold, times of sale or mode of sale, Indigenous-controlled liquor licensing, sin tax and traditional forms of control. 11 studies reported interventions that were effective in reducing crime, injury deaths, injury, hospitalisations or lowering per capita consumption. In six studies interventions were found to be ineffective or harmful. The results were inconclusive in one. CONCLUSIONS: Indigenous-led policies that are developed or implemented by communities can be effective in improving health and social outcomes. PMID- 28348190 TI - Improving swallowing outcomes in patients with head and neck cancer using a theory-based pretreatment swallowing intervention package: protocol for a randomised feasibility study. AB - INTRODUCTION: The incidence of head and neck cancer (HNC) in the UK is rising, with an average of 31 people diagnosed daily. Patients affected by HNC suffer significant short-term and long-term post-treatment morbidity as a result of dysphagia, which affects daily functioning and quality of life (QOL). Pretreatment swallowing exercises may provide additional benefit over standard rehabilitation in managing dysphagia after primary HNC treatments, but uncertainty about their effectiveness persists. This study was preceded by an intervention development phase to produce an optimised swallowing intervention package (SIP). The aim of the current study is to assess the feasibility of this new intervention and research processes within a National Health Service (NHS) setting. METHOD AND ANALYSIS: A two-arm non-blinded randomised controlled feasibility study will be carried out at one tertiary referral NHS centre providing specialist services in HNC. Patients newly diagnosed with stage III and IV disease undergoing planned surgery and/or chemoradiation treatments will be eligible. The SIP will be delivered pre treatment, and a range of swallowing related and QOL measures will be collected at baseline, 1, 3 and 6 months post treatment. Outcomes will test the feasibility of a future randomised controlled trial (RCT), detailing rate of recruitment and patient acceptance to participation and randomisation. Salient information relating to protocol implementation will be collated and study material such as the case report form will be tested. A range of candidate outcome measures will be examined for suitability in a larger RCT. ETHICS AND DISSEMINATION: Ethical approval was obtained from an NHS Research Ethics Committee. Findings will be published open access in a peer-reviewed journal, and presented at relevant conferences and research meetings. TRIAL REGISTRATION NUMBER: ISRCTN40215425; Pre-results. PMID- 28348191 TI - Elucidating challenges that electronic cigarettes pose to tobacco control in Asia: a population-based national survey in Taiwan. AB - OBJECTIVES: This study investigated the prevalence and correlates of electronic cigarettes (e-cigarettes) use in Taiwan. DESIGN AND SETTING: We studied a nationally representative random sample in the 2015 Taiwan Adult Smoking Behavior Survey. PARTICIPANTS: This study included 26 021 participants aged 15 years or older (51% women, 79% non-smokers, 16% aged 15-24 years), after excluding 31 persons (0.1%) who had missing information on e-cigarette use. PRIMARY OUTCOME MEASURES: The prevalence of ever having used e-cigarettes was calculated in the overall sample and by smoking status (current, former and never) or age (15-24, 25-44 and >=45 years). We performed multivariable log-binomial regression to assess correlates of ever having used e-cigarettes among all participants and separately for subgroups by smoking status and age. RESULTS: Approximately 3% of all participants had ever used e-cigarettes. The prevalence of ever having used e cigarettes was high in current smokers (14%) and people aged 18-24 years (7%). E cigarette use was particularly common in people aged 15-24 years who were current (49-52%) or former (22-39%) smokers. Ever having used e-cigarettes was positively associated with tobacco smoking (adjusted prevalence ratio (aPR): 21.5, 95% CI 15.4 to 29.8, current smokers; aPR: 8.3, 95% CI 15.2 to 13.1, former smokers), younger age and high socioeconomic status. Age remained a significant factor of ever having used e-cigarettes across smoking status groups. Among non-smokers, men had a 2.4-fold (95% CI 1.5 to 3.8) greater prevalence of e-cigarette use than women. CONCLUSIONS: E-cigarette use was uncommon in the general population in Taiwan, but prevalence was high among smokers and young people. This study highlights challenges that e-cigarettes pose to tobacco control, which warrant high priority action by policymakers and public health professionals. E-cigarette regulations should focus on young people. PMID- 28348192 TI - Surveillance Systems from Public Health Institutions and Scientific Societies for Antimicrobial Resistance and Healthcare-Associated Infections in Europe (SUSPIRE): protocol for a systematic review. AB - INTRODUCTION: The worldwide spread of antimicrobial resistance is now recognised as a global public health threat. Owing to the geographical heterogeneity, complexity and continuously evolving dynamics of resistant organisms and genes, surveillance is a key tool for understanding, measuring and informing actions in the fight against this problem. To date there is no harmonisation of key indicators or of methodologies used to obtain them. METHODS AND ANALYSIS: The main objective of this project is to systematically review and analyse the current publicly available surveillance activities on antimicrobial resistance and healthcare-associated infections in Europe. Eligible activities are those endorsed by regional, national or transnational health organisations and scientific societies providing data on a periodic basis. Grey and peer-reviewed literature will be searched with no language restrictions. Three independent reviewers will perform a two-step selection process using a previously piloted, tailored electronic data extraction form. Descriptive summaries and tables of all relevant findings will be performed and reported according to PRISMA guidelines. ETHICS AND DISSEMINATION: We did not seek ethical approval for this study because the data to be collected are not linked to individuals. Data will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: CRD42016033867. PMID- 28348193 TI - Determinants of second pregnancy among pregnant women: a hospital-based cross sectional survey in China. AB - OBJECTIVES: This study aimed to explore determinants of second pregnancy and underlying reasons among pregnant Chinese women. DESIGN: The study was a population-based cross-sectional survey. SETTING: 16 hospitals in 5 provinces of Mainland China were included. PARTICIPANTS: A total of 2345 pregnant women aged 18 years or above were surveyed face to face by investigators between June and August 2015. MAIN OUTCOME MEASURES: The pregnancy statuses (first or second pregnancy) and reasons for entering second pregnancy. RESULTS: A total of 1755 (74.8%) and 590 (25.2%) women in their respective first and second pregnancies were enrolled in this study. The most common self-reported reasons for entering second pregnancy among participants included the benefits to the first child (26.1%), love of children (25.8%), adoption of the 2-child policy (11.5%), concerns about losing the first child (7.5%) and suggestions from parents (7.5%). Pregnant women with low (prevalence ratio (PR) 1.96; 95% CI 1.62 to 2.36) and moderate education level (PR 1.97; 95% CI 1.65 to 2.36) were more likely to have a second pregnancy than their higher educated counterparts. Income was inversely associated with second pregnancy. However, unemployed participants (PR 0.79; 95% CI 0.66 to 0.95) were less likely to enter a second pregnancy than those employed. Women with moderate education were 3 times more likely to have a second child following the '2-child policy' than the low education level subgroup. CONCLUSIONS: 1 in every 4 pregnant women is undergoing a second pregnancy. The benefits of the firstborn or the love of children were the key drivers of a second pregnancy. Low socioeconomic status was positively associated with a second pregnancy as well. The new 2-child policy will have an influence on China's demographics. PMID- 28348194 TI - Cross-sectional observational assessment of quality of newborn care immediately after birth in health facilities across six sub-Saharan African countries. AB - OBJECTIVE: To present information on the quality of newborn care services and health facility readiness to provide newborn care in 6 African countries, and to advocate for the improvement of providers' essential newborn care knowledge and skills. DESIGN: Cross-sectional observational health facility assessment. SETTING: Ethiopia, Kenya, Madagascar, Mozambique, Rwanda and Tanzania. PARTICIPANTS: Health workers in 643 facilities. 1016 health workers were interviewed, and 2377 babies were observed in the facilities surveyed. MAIN OUTCOME MEASURES: Indicators of quality of newborn care included (1) provision of immediate essential newborn care: thermal care, hygienic cord care, and early and exclusive initiation of breast feeding; (2) actual and simulated resuscitation of asphyxiated newborn infants; and (3) knowledge of health workers on essential newborn care, including resuscitation. RESULTS: Sterile or clean cord cutting instruments, suction devices, and tables or firm surfaces for resuscitation were commonly available. 80% of newborns were immediately dried after birth and received clean cord care in most of the studied facilities. In all countries assessed, major deficiencies exist for essential newborn care supplies and equipment, as well as for health worker knowledge and performance of key routine newborn care practices, particularly for immediate skin-to-skin contact and breastfeeding initiation. Of newborns who did not cry at birth, 89% either recovered on their own or through active steps taken by the provider through resuscitation with initial stimulation and/or ventilation. 11% of newborns died. Assessment of simulated resuscitation using a NeoNatalie anatomic model showed that less than a third of providers were able to demonstrate ventilation skills correctly. CONCLUSIONS: The findings shared in this paper call attention to the critical need to improve health facility readiness to provide quality newborn care services and to ensure that service providers have the necessary equipment, supplies, knowledge and skills that are critical to save newborn lives. PMID- 28348197 TI - Neutrophils diminish T-cell immunity to foster gastric cancer progression: the role of GM-CSF/PD-L1/PD-1 signalling pathway. PMID- 28348198 TI - The changing role of the chief medical officer for England. PMID- 28348196 TI - Secondary prevention and cognitive function after stroke: a study protocol for a 5-year follow-up of the ASPIRE-S cohort. AB - INTRODUCTION: Cognitive impairment is common following stroke and can increase disability and levels of dependency of patients, potentially leading to greater burden on carers and the healthcare system. Effective cardiovascular risk factor control through secondary preventive medications may reduce the risk of cognitive decline. However, adherence to medications is often poor and can be adversely affected by cognitive deficits. Suboptimal medication adherence negatively impacts secondary prevention targets, increasing the risk of recurrent stroke and further cognitive decline. The aim of this study is to profile cognitive function and secondary prevention, including adherence to secondary preventive medications and healthcare usage, 5 years post-stroke. The prospective associations between cognition, cardiovascular risk factors, adherence to secondary preventive medications, and rates of recurrent stroke or other cardiovascular events will also be explored. METHODS AND ANALYSIS: This is a 5-year follow-up of a prospective study of the Action on Secondary Prevention Interventions and Rehabilitation in Stroke (ASPIRE-S) cohort of patients with stroke. This cohort will have a detailed assessment of cognitive function, adherence to secondary preventive medications and cardiovascular risk factor control. ETHICS AND DISSEMINATION: Ethical approval for this study was granted by the Research Ethics Committees at Beaumont Hospital, Dublin and Connolly Hospital, Dublin, Mater Misericordiae University Hospital, Dublin, and the Royal College of Surgeons in Ireland. Findings will be disseminated through presentations and peer-reviewed publications. PMID- 28348199 TI - Needs of Kinship Care Families and Pediatric Practice. AB - As many as 3% of children in the United States live in kinship care arrangements with caregivers who are relatives but not the biological parents of the child. A growing body of evidence suggests that children who cannot live with their biological parents fare better, overall, when living with extended family than with nonrelated foster parents. Acknowledging this, federal laws and public policies increasingly favor kinship care over nonrelative foster care when children are unable to live with their biological parents. Despite overall better outcomes, families providing kinship care experience many hardships, and the children experience many of the same adversities of children in traditional foster care. This policy statement reviews both the strengths and vulnerabilities of kinship families and suggests strategies for pediatricians to use to address the needs of individual patients and families. Strategies are also outlined for community, state, and federal advocacy on behalf of these children and their families. PMID- 28348195 TI - Impact of the Early Start Denver Model on the cognitive level of children with autism spectrum disorder: study protocol for a randomised controlled trial using a two-stage Zelen design. AB - INTRODUCTION: Early intervention for autism spectrum disorder (ASD) in the European French-speaking countries is heterogeneous and poorly evaluated to date. Early intervention units applying the Early Start Denver Model (ESDM) for toddlers and young children with ASD have been created in France and Belgium to improve this situation. It is essential to evaluate this intervention for the political decision-making process regarding ASD interventions in European French speaking countries. We will evaluate the effectiveness of 12 hours per week ESDM intervention on the cognitive level of children with ASD, over a 2-year period. METHODS AND ANALYSIS: The study will be a multicentre, randomised controlled trial, using a two-stage Zelen design. Children aged 15-36 months, diagnosed with ASD and with a developmental quotient (DQ) of 30 or above on the Mullen Scale of Early Learning (MSEL) will be included. We will use a stratified minimisation randomisation at a ratio 1:2 in favour of the control group. The sample size required is 180 children (120 in the control and 60 in the intervention group). The experimental group will receive 12 hours per week ESDM by trained therapists 10 hours per week in the centre and 2 hours in the toddlers' natural environment (alternatively by the therapist and the parent). The control group will receive care available in the community. The primary outcome will be the change in cognitive level measured with the DQ of the MSEL scored at 2 years. Secondary outcomes will include change in autism symptoms, behavioural adaptation, communicative and productive language level, sensory profile and parents' quality of life. The primary analysis will use the intention-to-treat principle. An economic evaluation will be performed. DISSEMINATION: Findings from the study will be disseminated through peer reviewed publications and meetings. TRIAL REGISTRATION NUMBER: NCT02608333 (clinicaltrials.gov); Pre-results. PMID- 28348200 TI - Breastfeeding, Cognitive and Noncognitive Development in Early Childhood: A Population Study. AB - BACKGROUND AND OBJECTIVES: There is mixed evidence from correlational studies that breastfeeding impacts children's development. Propensity score matching with large samples can be an effective tool to remove potential bias from observed confounders in correlational studies. The aim of this study was to investigate the impact of breastfeeding on children's cognitive and noncognitive development at 3 and 5 years of age. METHODS: Participants included ~8000 families from the Growing Up in Ireland longitudinal infant cohort, who were identified from the Child Benefit Register and randomly selected to participate. Parent and teacher reports and standardized assessments were used to collect information on children's problem behaviors, expressive vocabulary, and cognitive abilities at age 3 and 5 years. Breastfeeding information was collected via maternal report. Propensity score matching was used to compare the average treatment effects on those who were breastfed. RESULTS: Before matching, breastfeeding was associated with better development on almost every outcome. After matching and adjustment for multiple testing, only 1 of the 13 outcomes remained statistically significant: children's hyperactivity (difference score, -0.84; 95% confidence interval, -1.33 to -0.35) at age 3 years for children who were breastfed for at least 6 months. No statistically significant differences were observed postmatching on any outcome at age 5 years. CONCLUSIONS: Although 1 positive benefit of breastfeeding was found by using propensity score matching, the effect size was modest in practical terms. No support was found for statistically significant gains at age 5 years, suggesting that the earlier observed benefit from breastfeeding may not be maintained once children enter school. PMID- 28348201 TI - Tobacco Product Use Among Lesbian, Gay, and Bisexual Adolescents. AB - OBJECTIVES: Sexual minority youth face health disparities and a high risk of substance abuse. This study sought to fully characterize the disparity of tobacco use and risk factors in this high-risk subpopulation. METHODS: Using data from the 2015 Youth Risk Behavior Survey, the current use of various tobacco products (cigarettes, smokeless tobacco, cigars, and e-cigarettes) was compared according to sex and distinct sexual identities (lesbian, gay, bisexual, and unsure). Heterosexual/straight adolescents served as the control group. RESULTS: Of 14 703 respondents, 88.8% were heterosexual/straight, 2.0% were lesbian or gay, 6.0% were bisexual, and 3.2% were unsure about their sexual identity. Sexual minorities had a higher prevalence of tobacco product use than their heterosexual/straight counterparts. Sex had a significant effect on the disparities of tobacco use. Lesbian and bisexual girls had higher odds of reporting current use of any tobacco product, cigarettes, cigars, and e cigarettes than did straight girls, whereas sexual minority boys had similar smoking behaviors compared with straight boys. Substance use, including marijuana use, drinking, and binge drinking, was significantly associated with any tobacco use. CONCLUSIONS: Tobacco use differs among subgroups of sexual minority youth, with lesbians and bisexual girls having a higher prevalence of tobacco use than their straight peers. Heterogeneity of tobacco use across distinct sexual identity groups underscores the need to develop evidence-based tobacco control strategies for sexual minority youth. PMID- 28348203 TI - Breastfeeding: What Do We Know, and Where Do We Go From Here? PMID- 28348202 TI - Parent-Physician Partnership at the Edge of Viability. PMID- 28348204 TI - HIV: Persistence through division. AB - A long-lived latent reservoir for HIV-1 persists in CD4+ T cells despite antiretroviral therapy and is the major barrier to cure. In this issue of JEM, Hosmane et al. show that T cell proliferation could explain the long-term persistence of this reservoir. PMID- 28348205 TI - Association between socioeconomic position and the prevalence of type 2 diabetes in Ghanaians in different geographic locations: the RODAM study. AB - BACKGROUND: The prevalence of diabetes has been shown to be socially patterned but the direction of the association in low-income countries and among migrant populations in Europe has varied in the literature. This study examined the association between socioeconomic position (SEP) and diabetes in Ghanaians in Europe and in Ghana. METHODS: Data were derived from the multicentre Research on Obesity and Diabetes among African Migrants (RODAM) study of Ghanaian adults aged 25-70 years residing in Europe (Amsterdam, Berlin and London) and in urban and rural Ghana. Educational attainment (elementary, secondary or higher) and occupational class (low or high) were used as indicators of SEP. Age-standardised prevalence of diabetes and prevalence ratios were evaluated separately for men and women of different SEP in Ghana and Europe. RESULTS: A total of 5290 participants were included in the analyses. The prevalence of diabetes decreased with increasing level of education in Ghanaian men and women in Europe and in men in urban Ghana, whereas diabetes prevalence increased with increasing level of education in men and women in rural Ghana. The association between occupational class and the prevalence of diabetes followed a less consistent pattern in men and women in the different locations. CONCLUSIONS: The association of diabetes and SEP differed in rural Ghana compared with urban settings in Ghana and Europe and comparing men and women, highlighting the complex interaction of SEP and the development of diabetes. These findings have important implications for diabetes prevention strategies in Ghanaians in different locations. PMID- 28348206 TI - High-throughput identification of small molecules that affect human embryonic vascular development. AB - Birth defects, which are in part caused by exposure to environmental chemicals and pharmaceutical drugs, affect 1 in every 33 babies born in the United States each year. The current standard to screen drugs that affect embryonic development is based on prenatal animal testing; however, this approach yields low-throughput and limited mechanistic information regarding the biological pathways and potential adverse consequences in humans. To develop a screening platform for molecules that affect human embryonic development based on endothelial cells (ECs) derived from human pluripotent stem cells, we differentiated human pluripotent stem cells into embryonic ECs and induced their maturation under arterial flow conditions. These cells were then used to screen compounds that specifically affect embryonic vasculature. Using this platform, we have identified two compounds that have higher inhibitory effect in embryonic than postnatal ECs. One of them was fluphenazine (an antipsychotic), which inhibits calmodulin kinase II. The other compound was pyrrolopyrimidine (an antiinflammatory agent), which inhibits vascular endothelial growth factor receptor 2 (VEGFR2), decreases EC viability, induces an inflammatory response, and disrupts preformed vascular networks. The vascular effect of the pyrrolopyrimidine was further validated in prenatal vs. adult mouse ECs and in embryonic and adult zebrafish. We developed a platform based on human pluripotent stem cell-derived ECs for drug screening, which may open new avenues of research for the study and modulation of embryonic vasculature. PMID- 28348207 TI - Nurr1:RXRalpha heterodimer activation as monotherapy for Parkinson's disease. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra and the gradual depletion of dopamine (DA). Current treatments replenish the DA deficit and improve symptoms but induce dyskinesias over time, and neuroprotective therapies are nonexistent. Here we report that Nuclear receptor related 1 (Nurr1):Retinoid X receptor alpha (RXRalpha) activation has a double therapeutic potential for PD, offering both neuroprotective and symptomatic improvement. We designed BRF110, a unique in vivo active Nurr1:RXRalpha-selective lead molecule, which prevents DAergic neuron demise and striatal DAergic denervation in vivo against PD-causing toxins in a Nurr1-dependent manner. BRF110 also protects against PD-related genetic mutations in patient induced pluripotent stem cell (iPSC)-derived DAergic neurons and a genetic mouse PD model. Remarkably, besides neuroprotection, BRF110 up-regulates tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase (AADC), and GTP cyclohydrolase I (GCH1) transcription; increases striatal DA in vivo; and has symptomatic efficacy in two postneurodegeneration PD models, without inducing dyskinesias on chronic daily treatment. The combined neuroprotective and symptomatic effects of BRF110 identify Nurr1:RXRalpha activation as a potential monotherapeutic approach for PD. PMID- 28348208 TI - MYO6 is targeted by Salmonella virulence effectors to trigger PI3-kinase signaling and pathogen invasion into host cells. AB - To establish infections, Salmonella injects virulence effectors that hijack the host actin cytoskeleton and phosphoinositide signaling to drive pathogen invasion. How effectors reprogram the cytoskeleton network remains unclear. By reconstituting the activities of the Salmonella effector SopE, we recapitulated Rho GTPase-driven actin polymerization at model phospholipid membrane bilayers in cell-free extracts and identified the network of Rho-recruited cytoskeleton proteins. Knockdown of network components revealed a key role for myosin VI (MYO6) in Salmonella invasion. SopE triggered MYO6 localization to invasion foci, and SopE-mediated activation of PAK recruited MYO6 to actin-rich membranes. We show that the virulence effector SopB requires MYO6 to regulate the localization of PIP3 and PI(3)P phosphoinositides and Akt activation. SopE and SopB target MYO6 to coordinate phosphoinositide production at invasion foci, facilitating the recruitment of cytoskeleton adaptor proteins to mediate pathogen uptake. PMID- 28348209 TI - Strategic siting and regional grid interconnections key to low-carbon futures in African countries. AB - Recent forecasts suggest that African countries must triple their current electricity generation by 2030. Our multicriteria assessment of wind and solar potential for large regions of Africa shows how economically competitive and low environmental-impact renewable resources can significantly contribute to meeting this demand. We created the Multicriteria Analysis for Planning Renewable Energy (MapRE) framework to map and characterize solar and wind energy zones in 21 countries in the Southern African Power Pool (SAPP) and the Eastern Africa Power Pool (EAPP) and find that potential is several times greater than demand in many countries. Significant fractions of demand can be quickly served with "no regrets" options-or zones that are low-cost, low-environmental impact, and highly accessible. Because no-regrets options are spatially heterogeneous, international interconnections are necessary to help achieve low-carbon development for the region as a whole, and interconnections that support the best renewable options may differ from those planned for hydropower expansion. Additionally, interconnections and selecting wind sites to match demand reduce the need for SAPP-wide conventional generation capacity by 9.5% in a high-wind scenario, resulting in a 6-20% cost savings, depending on the avoided conventional technology. Strategic selection of low-impact and accessible zones is more cost effective with interconnections compared with solutions without interconnections. Overall results are robust to multiple load growth scenarios. Together, results show that multicriteria site selection and deliberate planning of interconnections may significantly increase the economic and environmental competitiveness of renewable alternatives relative to conventional generation. PMID- 28348211 TI - Evolution of the early Antarctic ice ages. AB - Understanding the stability of the early Antarctic ice cap in the geological past is of societal interest because present-day atmospheric CO2 concentrations have reached values comparable to those estimated for the Oligocene and the Early Miocene epochs. Here we analyze a new high-resolution deep-sea oxygen isotope (delta18O) record from the South Atlantic Ocean spanning an interval between 30.1 My and 17.1 My ago. The record displays major oscillations in deep-sea temperature and Antarctic ice volume in response to the ~110-ky eccentricity modulation of precession. Conservative minimum ice volume estimates show that waxing and waning of at least ~85 to 110% of the volume of the present East Antarctic Ice Sheet is required to explain many of the ~110-ky cycles. Antarctic ice sheets were typically largest during repeated glacial cycles of the mid Oligocene (~28.0 My to ~26.3 My ago) and across the Oligocene-Miocene Transition (~23.0 My ago). However, the high-amplitude glacial-interglacial cycles of the mid-Oligocene are highly symmetrical, indicating a more direct response to eccentricity modulation of precession than their Early Miocene counterparts, which are distinctly asymmetrical-indicative of prolonged ice buildup and delayed, but rapid, glacial terminations. We hypothesize that the long-term transition to a warmer climate state with sawtooth-shaped glacial cycles in the Early Miocene was brought about by subsidence and glacial erosion in West Antarctica during the Late Oligocene and/or a change in the variability of atmospheric CO2 levels on astronomical time scales that is not yet captured in existing proxy reconstructions. PMID- 28348210 TI - Myosin-1E interacts with FAK proline-rich region 1 to induce fibronectin-type matrix. AB - Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase involved in development and human disease, including cancer. It is currently thought that the four-point one, ezrin, radixin, moesin (FERM)-kinase domain linker, which contains autophosphorylation site tyrosine (Y) 397, is not required for in vivo FAK function until late midgestation. Here, we directly tested this hypothesis by generating mice with FAK Y397-to-phenylalanine (F) mutations in the germline. We found that Y397F embryos exhibited reduced mesodermal fibronectin (FN) and osteopontin expression and died during mesoderm development akin to FAK kinase dead mice. We identified myosin-1E (MYO1E), an actin-dependent molecular motor, to interact directly with the FAK FERM-kinase linker and induce FAK kinase activity and Y397 phosphorylation. Active FAK in turn accumulated in the nucleus where it led to the expression of osteopontin and other FN-type matrix in both mouse embryonic fibroblasts and human melanoma. Our data support a model in which FAK Y397 autophosphorylation is required for FAK function in vivo and is positively regulated by MYO1E. PMID- 28348213 TI - Correction for Lee et al., MicroRNA-10a is crucial for endothelial response to different flow patterns via interaction of retinoid acid receptors and histone deacetylases. PMID- 28348212 TI - Climate change both facilitates and inhibits invasive plant ranges in New England. AB - Forecasting ecological responses to climate change, invasion, and their interaction must rely on understanding underlying mechanisms. However, such forecasts require extrapolation into new locations and environments. We linked demography and environment using experimental biogeography to forecast invasive and native species' potential ranges under present and future climate in New England, United States to overcome issues of extrapolation in novel environments. We studied two potentially nonequilibrium invasive plants' distributions, Alliaria petiolata (garlic mustard) and Berberis thunbergii (Japanese barberry), each paired with their native ecological analogs to better understand demographic drivers of invasions. Our models predict that climate change will considerably reduce establishment of a currently prolific invader (A. petiolata) throughout New England driven by poor demographic performance in warmer climates. In contrast, invasion of B. thunbergii will be facilitated because of higher growth and germination in warmer climates, with higher likelihood to establish farther north and in closed canopy habitats in the south. Invasion success is in high fecundity for both invasive species and demographic compensation for Apetiolata relative to native analogs. For A. petiolata, simulations suggest that eradication efforts would require unrealistic efficiency; hence, management should focus on inhibiting spread into colder, currently unoccupied areas, understanding source-sink dynamics, and understanding community dynamics should A. petiolata (which is allelopathic) decline. Our results-based on considerable differences with correlative occurrence models typically used for such biogeographic forecasts-suggest the urgency of incorporating mechanism into range forecasting and invasion management to understand how climate change may alter current invasion patterns. PMID- 28348215 TI - PLP and GABA trigger GabR-mediated transcription regulation in Bacillus subtilis via external aldimine formation. AB - The Bacillus subtilis protein regulator of the gabTD operon and its own gene (GabR) is a transcriptional activator that regulates transcription of gamma aminobutyric acid aminotransferase (GABA-AT; GabT) upon interactions with pyridoxal-5'-phosphate (PLP) and GABA, and thereby promotes the biosynthesis of glutamate from GABA. We show here that the external aldimine formed between PLP and GABA is apparently responsible for triggering the GabR-mediated transcription activation. Details of the "active site" in the structure of the GabR effector binding/oligomerization (Eb/O) domain suggest that binding a monocarboxylic gamma amino acid such as GABA should be preferred over dicarboxylic acid ligands. A reactive GABA analog, (S)-4-amino-5-fluoropentanoic acid (AFPA), was used as a molecular probe to examine the reactivity of PLP in both GabR and a homologous aspartate aminotransferase (Asp-AT) from Escherichia coli as a control. A comparison between the structures of the Eb/O-PLP-AFPA complex and Asp-AT-PLP AFPA complex revealed that GabR is incapable of facilitating further steps of the transamination reaction after the formation of the external aldimine. Results of in vitro and in vivo assays using full-length GabR support the conclusion that AFPA is an agonistic ligand capable of triggering GabR-mediated transcription activation via formation of an external aldimine with PLP. PMID- 28348214 TI - Spemann organizer transcriptome induction by early beta-catenin, Wnt, Nodal, and Siamois signals in Xenopus laevis. AB - The earliest event in Xenopus development is the dorsal accumulation of nuclear beta-catenin under the influence of cytoplasmic determinants displaced by fertilization. In this study, a genome-wide approach was used to examine transcription of the 43,673 genes annotated in the Xenopus laevis genome under a variety of conditions that inhibit or promote formation of the Spemann organizer signaling center. Loss of function of beta-catenin with antisense morpholinos reproducibly reduced the expression of 247 mRNAs at gastrula stage. Interestingly, only 123 beta-catenin targets were enriched on the dorsal side and defined an early dorsal beta-catenin gene signature. These genes included several previously unrecognized Spemann organizer components. Surprisingly, only 3 of these 123 genes overlapped with the late Wnt signature recently defined by two other groups using inhibition by Dkk1 mRNA or Wnt8 morpholinos, which indicates that the effects of beta-catenin/Wnt signaling in early development are exquisitely regulated by stage-dependent mechanisms. We analyzed transcriptome responses to a number of treatments in a total of 46 RNA-seq libraries. These treatments included, in addition to beta-catenin depletion, regenerating dorsal and ventral half-embryos, lithium chloride treatment, and the overexpression of Wnt8, Siamois, and Cerberus mRNAs. Only some of the early dorsal beta-catenin signature genes were activated at blastula whereas others required the induction of endomesoderm, as indicated by their inhibition by Cerberus overexpression. These comprehensive data provide a rich resource for analyzing how the dorsal and ventral regions of the embryo communicate with each other in a self-organizing vertebrate model embryo. PMID- 28348216 TI - Splicing variation of Long-IRBIT determines the target selectivity of IRBIT family proteins. AB - IRBIT [inositol 1,4,5-trisphosphate receptor (IP3R) binding protein released with inositol 1,4,5-trisphosphate (IP3)] is a multifunctional protein that regulates several target molecules such as ion channels, transporters, polyadenylation complex, and kinases. Through its interaction with multiple targets, IRBIT contributes to calcium signaling, electrolyte transport, mRNA processing, cell cycle, and neuronal function. However, the regulatory mechanism of IRBIT binding to particular targets is poorly understood. Long-IRBIT is an IRBIT homolog with high homology to IRBIT, except for a unique N-terminal appendage. Long-IRBIT splice variants have different N-terminal sequences and a common C-terminal region, which is involved in multimerization of IRBIT and Long-IRBIT. In this study, we characterized IRBIT and Long-IRBIT splice variants (IRBIT family). We determined that the IRBIT family exhibits different mRNA expression patterns in various tissues. The IRBIT family formed homo- and heteromultimers. In addition, N-terminal splicing of Long-IRBIT changed the protein stability and selectivity to target molecules. These results suggest that N-terminal diversity of the IRBIT family and various combinations of multimer formation contribute to the functional diversity of the IRBIT family. PMID- 28348217 TI - In situ characterization of cofacial Co(IV) centers in Co4O4 cubane: Modeling the high-valent active site in oxygen-evolving catalysts. AB - The Co4O4 cubane is a representative structural model of oxidic cobalt oxygen evolving catalysts (Co-OECs). The Co-OECs are active when residing at two oxidation levels above an all-Co(III) resting state. This doubly oxidized Co(IV)2 state may be captured in a Co(III)2(IV)2 cubane. We demonstrate that the Co(III)2(IV)2 cubane may be electrochemically generated and the electronic properties of this unique high-valent state may be probed by in situ spectroscopy. Intervalence charge-transfer (IVCT) bands in the near-IR are observed for the Co(III)2(IV)2 cubane, and spectroscopic analysis together with electrochemical kinetics measurements reveal a larger reorganization energy and a smaller electron transfer rate constant for the doubly versus singly oxidized cubane. Spectroelectrochemical X-ray absorption data further reveal systematic spectral changes with successive oxidations from the cubane resting state. Electronic structure calculations correlated to experimental data suggest that this state is best represented as a localized, antiferromagnetically coupled Co(IV)2 dimer. The exchange coupling in the cofacial Co(IV)2 site allows for parallels to be drawn between the electronic structure of the Co4O4 cubane model system and the high-valent active site of the Co-OEC, with specific emphasis on the manifestation of a doubly oxidized Co(IV)2 center on O-O bond formation. PMID- 28348218 TI - Ancient palace complex (300-100 BC) discovered in the Valley of Oaxaca, Mexico. AB - Recently completed excavations at the site of El Palenque in Mexico's Valley of Oaxaca have recovered the well-preserved remains of a palace complex dated by associated radiocarbon samples and ceramics to the Late Formative period or Late Monte Alban I phase (300-100 BC), the period of archaic state emergence in the region. The El Palenque palace exhibits certain architectural and organizational features similar to the royal palaces of much later Mesoamerican states described by Colonial-period sources. The excavation data document a multifunctional palace complex covering a maximum estimated area of 2,790 m2 on the north side of the site's plaza and consisting of both governmental and residential components. The data indicate that the palace complex was designed and built as a single construction. The palace complex at El Palenque is the oldest multifunctional palace excavated thus far in the Valley of Oaxaca. PMID- 28348220 TI - Communicating the deadly consequences of global warming for human heat stress. AB - In December of 2015, the international community pledged to limit global warming to below 2 degrees C above preindustrial (PI) to prevent dangerous climate change. However, to what extent, and for whom, is danger avoided if this ambitious target is realized? We address these questions by scrutinizing heat stress, because the frequency of extremely hot weather is expected to continue to rise in the approach to the 2 degrees C limit. We use analogs and the extreme South Asian heat of 2015 as a focusing event to help interpret the increasing frequency of deadly heat under specified amounts of global warming. Using a large ensemble of climate models, our results confirm that global mean air temperature is nonlinearly related to heat stress, meaning that the same future warming as realized to date could trigger larger increases in societal impacts than historically experienced. This nonlinearity is higher for heat stress metrics that integrate the effect of rising humidity. We show that, even in a climate held to 2 degrees C above PI, Karachi (Pakistan) and Kolkata (India) could expect conditions equivalent to their deadly 2015 heatwaves every year. With only 1.5 degrees C of global warming, twice as many megacities (such as Lagos, Nigeria, and Shanghai, China) could become heat stressed, exposing more than 350 million more people to deadly heat by 2050 under a midrange population growth scenario. The results underscore that, even if the Paris targets are realized, there could still be a significant adaptation imperative for vulnerable urban populations. PMID- 28348219 TI - Mouse-adapted MERS coronavirus causes lethal lung disease in human DPP4 knockin mice. AB - The Middle East respiratory syndrome (MERS) emerged in Saudi Arabia in 2012, caused by a zoonotically transmitted coronavirus (CoV). Over 1,900 cases have been reported to date, with ~36% fatality rate. Lack of autopsies from MERS cases has hindered understanding of MERS-CoV pathogenesis. A small animal model that develops progressive pulmonary manifestations when infected with MERS-CoV would advance the field. As mice are restricted to infection at the level of DPP4, the MERS-CoV receptor, we generated mice with humanized exons 10-12 of the mouse Dpp4 locus. Upon inoculation with MERS-CoV, human DPP4 knockin (KI) mice supported virus replication in the lungs, but developed no illness. After 30 serial passages through the lungs of KI mice, a mouse-adapted virus emerged (MERSMA) that grew in lungs to over 100 times higher titers than the starting virus. A plaque-purified MERSMA clone caused weight loss and fatal infection. Virus antigen was observed in airway epithelia, pneumocytes, and macrophages. Pathologic findings included diffuse alveolar damage with pulmonary edema and hyaline membrane formation associated with accumulation of activated inflammatory monocyte-macrophages and neutrophils in the lungs. Relative to the parental MERS CoV, MERSMA viruses contained 13-22 mutations, including several within the spike (S) glycoprotein gene. S-protein mutations sensitized viruses to entry-activating serine proteases and conferred more rapid entry kinetics. Recombinant MERSMA bearing mutant S proteins were more virulent than the parental virus in hDPP4 KI mice. The hDPP4 KI mouse and the MERSMA provide tools to investigate disease causes and develop new therapies. PMID- 28348221 TI - Transfer of pathogenic and nonpathogenic cytosolic proteins between spinal cord motor neurons in vivo in chimeric mice. AB - Recent studies have reported spread of pathogenic proteins in the mammalian nervous system, but whether nonpathogenic ones spread is unknown. We initially investigated whether spread of a mutant amyotrophic lateral sclerosis-associated cytosolic superoxide dismutase 1 (SOD1) protein between motor neurons could be detected in intact chimeric mice. Eight-cell embryos from G85R SOD1YFP and G85R SOD1CFP mice were aggregated, and spinal cords of adult chimeric progeny were examined for motor neurons with cytosolic double fluorescence. By 3 mo of age, we observed extensive double fluorescence, including in amyotrophic lateral sclerosis-affected cranial nerve motor nuclei but not in the relatively spared extraocular nuclei. Chimeras of nonpathogenic wtSOD1YFP and G85R SOD1CFP also exhibited double fluorescence. In a third chimera, mitochondrial mCherry did not transfer to G85R SOD1YFP motor neurons, suggesting that neither RNA nor organelles transfer, but mito-mCherry neurons received G85R SOD1YFP. In a chimera of ChAT promoter-EGFP and mito-mCherry, EGFP efficiently transferred to mito mCherry+ cells. Thus, nonpathogenic cytosolic proteins appear capable of transfer. During study of both the SOD1FP and EGFP chimeras, we observed fluorescence also in small cells neighboring the motor neurons, identified as mature gray matter oligodendrocytes. Double fluorescence in the G85R SOD1FP chimera and observation of the temporal development of fluorescence first in motor neurons and then in these oligodendrocytes suggest that they may be mediators of transfer of cytosolic proteins between motor neurons. PMID- 28348222 TI - Form and function of topologically associating genomic domains in budding yeast. AB - The genome of metazoan cells is organized into topologically associating domains (TADs) that have similar histone modifications, transcription level, and DNA replication timing. Although similar structures appear to be conserved in fission yeast, computational modeling and analysis of high-throughput chromosome conformation capture (Hi-C) data have been used to argue that the small, highly constrained budding yeast chromosomes could not have these structures. In contrast, herein we analyze Hi-C data for budding yeast and identify 200-kb scale TADs, whose boundaries are enriched for transcriptional activity. Furthermore, these boundaries separate regions of similarly timed replication origins connecting the long-known effect of genomic context on replication timing to genome architecture. To investigate the molecular basis of TAD formation, we performed Hi-C experiments on cells depleted for the Forkhead transcription factors, Fkh1 and Fkh2, previously associated with replication timing. Forkhead factors do not regulate TAD formation, but do promote longer-range genomic interactions and control interactions between origins near the centromere. Thus, our work defines spatial organization within the budding yeast nucleus, demonstrates the conserved role of genome architecture in regulating DNA replication, and identifies a molecular mechanism specifically regulating interactions between pericentric origins. PMID- 28348224 TI - High-numerical-aperture cryogenic light microscopy for increased precision of superresolution reconstructions. AB - Superresolution microscopy has fundamentally altered our ability to resolve subcellular proteins, but improving on these techniques to study dense structures composed of single-molecule-sized elements has been a challenge. One possible approach to enhance superresolution precision is to use cryogenic fluorescent imaging, reported to reduce fluorescent protein bleaching rates, thereby increasing the precision of superresolution imaging. Here, we describe an approach to cryogenic photoactivated localization microscopy (cPALM) that permits the use of a room-temperature high-numerical-aperture objective lens to image frozen samples in their native state. We find that cPALM increases photon yields and show that this approach can be used to enhance the effective resolution of two photoactivatable/switchable fluorophore-labeled structures in the same frozen sample. This higher resolution, two-color extension of the cPALM technique will expand the accessibility of this approach to a range of laboratories interested in more precise reconstructions of complex subcellular targets. PMID- 28348223 TI - Quantification of circulating Mycobacterium tuberculosis antigen peptides allows rapid diagnosis of active disease and treatment monitoring. AB - Tuberculosis (TB) is a major global health threat, resulting in an urgent unmet need for a rapid, non-sputum-based quantitative test to detect active Mycobacterium tuberculosis (Mtb) infections in clinically diverse populations and quickly assess Mtb treatment responses for emerging drug-resistant strains. We have identified Mtb-specific peptide fragments and developed a method to rapidly quantify their serum concentrations, using antibody-labeled and energy-focusing porous discoidal silicon nanoparticles (nanodisks) and high-throughput mass spectrometry (MS) to enhance sensitivity and specificity. NanoDisk-MS diagnosed active Mtb cases with high sensitivity and specificity in a case-control study with cohorts reflecting the complexity of clinical practice. Similar robust sensitivities were obtained for cases of culture-positive pulmonary TB (PTB; 91.3%) and extrapulmonary TB (EPTB; 92.3%), and the sensitivities obtained for culture-negative PTB (82.4%) and EPTB (75.0%) in HIV-positive patients significantly outperformed those reported for other available assays. NanoDisk-MS also exhibited high specificity (87.1-100%) in both healthy and high-risk groups. Absolute quantification of serum Mtb antigen concentration was informative in assessing responses to antimycobacterial treatment. Thus, a NanoDisk-MS assay approach could significantly improve the diagnosis and management of active TB cases, and perhaps other infectious diseases as well. PMID- 28348225 TI - Origins of house mice in ecological niches created by settled hunter-gatherers in the Levant 15,000 y ago. AB - Reductions in hunter-gatherer mobility during the Late Pleistocene influenced settlement ecologies, altered human relations with animal communities, and played a pivotal role in domestication. The influence of variability in human mobility on selection dynamics and ecological interactions in human settlements has not been extensively explored, however. This study of mice in modern African villages and changing mice molar shapes in a 200,000-y-long sequence from the Levant demonstrates competitive advantages for commensal mice in long-term settlements. Mice from African pastoral households provide a referential model for habitat partitioning among mice taxa in settlements of varying durations. The data reveal the earliest known commensal niche for house mice in long-term forager settlements 15,000 y ago. Competitive dynamics and the presence and abundance of mice continued to fluctuate with human mobility through the terminal Pleistocene. At the Natufian site of Ain Mallaha, house mice displaced less commensal wild mice during periods of heavy occupational pressure but were outcompeted when mobility increased. Changing food webs and ecological dynamics in long-term settlements allowed house mice to establish durable commensal populations that expanded with human societies. This study demonstrates the changing magnitude of cultural niche construction with varying human mobility and the extent of environmental influence before the advent of farming. PMID- 28348227 TI - Statistical significance of seasonal warming/cooling trends. AB - The question whether a seasonal climate trend (e.g., the increase of summer temperatures in Antarctica in the last decades) is of anthropogenic or natural origin is of great importance for mitigation and adaption measures alike. The conventional significance analysis assumes that (i) the seasonal climate trends can be quantified by linear regression, (ii) the different seasonal records can be treated as independent records, and (iii) the persistence in each of these seasonal records can be characterized by short-term memory described by an autoregressive process of first order. Here we show that assumption ii is not valid, due to strong intraannual correlations by which different seasons are correlated. We also show that, even in the absence of correlations, for Gaussian white noise, the conventional analysis leads to a strong overestimation of the significance of the seasonal trends, because multiple testing has not been taken into account. In addition, when the data exhibit long-term memory (which is the case in most climate records), assumption iii leads to a further overestimation of the trend significance. Combining Monte Carlo simulations with the Holm Bonferroni method, we demonstrate how to obtain reliable estimates of the significance of the seasonal climate trends in long-term correlated records. For an illustration, we apply our method to representative temperature records from West Antarctica, which is one of the fastest-warming places on Earth and belongs to the crucial tipping elements in the Earth system. PMID- 28348226 TI - ERRalpha induces H3K9 demethylation by LSD1 to promote cell invasion. AB - Lysine Specific Demethylase 1 (LSD1) removes mono- and dimethyl groups from lysine 4 of histone H3 (H3K4) or H3K9, resulting in repressive or activating (respectively) transcriptional histone marks. The mechanisms that control the balance between these two antagonist activities are not understood. We here show that LSD1 and the orphan nuclear receptor estrogen-related receptor alpha (ERRalpha) display commonly activated genes. Transcriptional activation by LSD1 and ERRalpha involves H3K9 demethylation at the transcriptional start site (TSS). Strikingly, ERRalpha is sufficient to induce LSD1 to demethylate H3K9 in vitro. The relevance of this mechanism is highlighted by functional data. LSD1 and ERRalpha coregulate several target genes involved in cell migration, including the MMP1 matrix metallo-protease, also activated through H3K9 demethylation at the TSS. Depletion of LSD1 or ERRalpha reduces the cellular capacity to invade the extracellular matrix, a phenomenon that is rescued by MMP1 reexpression. Altogether our results identify a regulatory network involving a direct switch in the biochemical activities of a histone demethylase, leading to increased cell invasion. PMID- 28348228 TI - AMPA glutamate receptors are required for sensory-organ formation and morphogenesis in the basal chordate. AB - AMPA-type glutamate receptors (GluAs) mediate fast excitatory transmission in the vertebrate central nervous system (CNS), and their function has been extensively studied in the mature mammalian brain. However, GluA expression begins very early in developing embryos, suggesting that they may also have unidentified developmental roles. Here, we identify developmental roles for GluAs in the ascidian Ciona intestinalis Mammals express Ca2+-permeable GluAs (Ca-P GluAs) and Ca2+-impermeable GluAs (Ca-I GluAs) by combining subunits derived from four genes. In contrast, ascidians have a single gluA gene. Taking advantage of the simple genomic GluA organization in ascidians, we knocked down (KD) GluAs in Ciona and observed severe impairments in formation of the ocellus, a photoreceptive organ used during the swimming stage, and in resorption of the tail and body axis rotation during metamorphosis to the adult stage. These defects could be rescued by injection of KD-resistant GluAs. GluA KD phenotypes could also be reproduced by expressing a GluA mutant that dominantly inhibits glutamate-evoked currents. These results suggest that, in addition to their role in synaptic communication in mature animals, GluAs also have critical developmental functions. PMID- 28348229 TI - Structural basis of mitochondrial dysfunction in response to cytochrome c phosphorylation at tyrosine 48. AB - Regulation of mitochondrial activity allows cells to adapt to changing conditions and to control oxidative stress, and its dysfunction can lead to hypoxia dependent pathologies such as ischemia and cancer. Although cytochrome c phosphorylation-in particular, at tyrosine 48-is a key modulator of mitochondrial signaling, its action and molecular basis remain unknown. Here we mimic phosphorylation of cytochrome c by replacing tyrosine 48 with p-carboxy-methyl-l phenylalanine (pCMF). The NMR structure of the resulting mutant reveals significant conformational shifts and enhanced dynamics around pCMF that could explain changes observed in its functionality: The phosphomimetic mutation impairs cytochrome c diffusion between respiratory complexes, enhances hemeprotein peroxidase and reactive oxygen species scavenging activities, and hinders caspase-dependent apoptosis. Our findings provide a framework to further investigate the modulation of mitochondrial activity by phosphorylated cytochrome c and to develop novel therapeutic approaches based on its prosurvival effects. PMID- 28348230 TI - Deficiency of transcription factor RelB perturbs myeloid and DC development by hematopoietic-extrinsic mechanisms. AB - RelB is an NF-kappaB family transcription factor activated in the noncanonical pathway downstream of NF-kappaB-inducing kinase (NIK) and TNF receptor family members including lymphotoxin-beta receptor (LTbetaR) and CD40. Early analysis suggested that RelB is required for classical dendritic cell (cDC) development based on a severe reduction of cDCs in Relb-/- mice associated with profound myeloid expansion and perturbations in B and T cells. Subsequent analysis of radiation chimeras generated from wild-type and Relb-/- bone marrow showed that RelB exerts cell-extrinsic actions on some lineages, but it has remained unclear whether the impact of RelB on cDC development is cell-intrinsic or -extrinsic. Here, we reevaluated the role of RelB in cDC and myeloid development using a series of radiation chimeras. We found that there was no cell-intrinsic requirement for RelB for development of most cDC subsets, except for the Notch2- and LTbetaR-dependent subset of splenic CD4+ cDC2s. These results identify a relatively restricted role of RelB in DC development. Moreover, the myeloid expansion in Relb-/- mice resulted from hematopoietic-extrinsic actions of RelB. This result suggests that there is an unrecognized but critical role for RelB within the nonhematopoietic niche that controls normal myelopoiesis. PMID- 28348231 TI - Metabolic evolution and the self-organization of ecosystems. AB - Metabolism mediates the flow of matter and energy through the biosphere. We examined how metabolic evolution shapes ecosystems by reconstructing it in the globally abundant oceanic phytoplankter Prochlorococcus To understand what drove observed evolutionary patterns, we interpreted them in the context of its population dynamics, growth rate, and light adaptation, and the size and macromolecular and elemental composition of cells. This multilevel view suggests that, over the course of evolution, there was a steady increase in Prochlorococcus' metabolic rate and excretion of organic carbon. We derived a mathematical framework that suggests these adaptations lower the minimal subsistence nutrient concentration of cells, which results in a drawdown of nutrients in oceanic surface waters. This, in turn, increases total ecosystem biomass and promotes the coevolution of all cells in the ecosystem. Additional reconstructions suggest that Prochlorococcus and the dominant cooccurring heterotrophic bacterium SAR11 form a coevolved mutualism that maximizes their collective metabolic rate by recycling organic carbon through complementary excretion and uptake pathways. Moreover, the metabolic codependencies of Prochlorococcus and SAR11 are highly similar to those of chloroplasts and mitochondria within plant cells. These observations lead us to propose a general theory relating metabolic evolution to the self-amplification and self organization of the biosphere. We discuss the implications of this framework for the evolution of Earth's biogeochemical cycles and the rise of atmospheric oxygen. PMID- 28348232 TI - Symplastic communication spatially directs local auxin biosynthesis to maintain root stem cell niche in Arabidopsis. AB - Stem cells serve as the source of new cells for plant development. A group of stem cells form a stem cell niche (SCN) at the root tip and in the center of the SCN are slowly dividing cells called the quiescent center (QC). QC is thought to function as a signaling hub that inhibits differentiation of surrounding stem cells. Although it has been generally assumed that cell-to-cell communication provides positional information for QC and SCN maintenance, the tools for testing this hypothesis have long been lacking. Here we exploit a system that effectively blocks plasmodesmata (PD)-mediated signaling to explore how cell-to-cell communication functions in the SCN. We showed that the symplastic signaling between the QC and adjacent cells directs the formation of local auxin maxima and establishment of AP2-domain transcription factors, PLETHORA gradients. Interestingly we found symplastic signaling is essential for local auxin biosynthesis, which acts together with auxin polar transport to provide the guidance for local auxin enrichment. Therefore, we demonstrate the crucial role of cell-to-cell communication in the SCN maintenance and further uncover a mechanism by which symplastic signaling initiates and reinforces the positional information during stem cell maintenance via auxin regulation. PMID- 28348233 TI - Complement modulation in the retinal pigment epithelium rescues photoreceptor degeneration in a mouse model of Stargardt disease. AB - Recessive Stargardt macular degeneration (STGD1) is caused by mutations in the gene for the ABCA4 transporter in photoreceptor outer segments. STGD1 patients and Abca4-/- (STGD1) mice exhibit buildup of bisretinoid-containing lipofuscin pigments in the retinal pigment epithelium (RPE), increased oxidative stress, augmented complement activation and slow degeneration of photoreceptors. A reduction in complement negative regulatory proteins (CRPs), possibly owing to bisretinoid accumulation, may be responsible for the increased complement activation seen on the RPE of STGD1 mice. CRPs prevent attack on host cells by the complement system, and complement receptor 1-like protein y (CRRY) is an important CRP in mice. Here we attempted to rescue the phenotype in STGD1 mice by increasing expression of CRRY in the RPE using a gene therapy approach. We injected recombinant adeno-associated virus containing the CRRY coding sequence (AAV-CRRY) into the subretinal space of 4-wk-old Abca4-/- mice. This resulted in sustained, several-fold increased expression of CRRY in the RPE, which significantly reduced the complement factors C3/C3b in the RPE. Unexpectedly, AAV CRRY-treated STGD1 mice also showed reduced accumulation of bisretinoids compared with sham-injected STGD1 control mice. Furthermore, we observed slower photoreceptor degeneration and increased visual chromophore in 1-y-old AAV-CRRY treated STGD1 mice. Rescue of the STGD1 phenotype by AAV-CRRY gene therapy suggests that complement attack on the RPE is an important etiologic factor in STGD1. Modulation of the complement system by locally increasing CRP expression using targeted gene therapy represents a potential treatment strategy for STGD1 and other retinopathies associated with complement dysregulation. PMID- 28348234 TI - KETCH1 imports HYL1 to nucleus for miRNA biogenesis in Arabidopsis. AB - MicroRNA (miRNA) is processed from primary transcripts with hairpin structures (pri-miRNAs) by microprocessors in the nucleus. How cytoplasmic-borne microprocessor components are transported into the nucleus to fulfill their functions remains poorly understood. Here, we report KETCH1 (karyopherin enabling the transport of the cytoplasmic HYL1) as a partner of hyponastic leaves 1 (HYL1) protein, a core component of microprocessor in Arabidopsis and functional counterpart of DGCR8/Pasha in animals. Null mutation of ketch1 is embryonic lethal, whereas knockdown mutation of ketch1 caused morphological defects, reminiscent of mutants in the miRNA pathway. ketch1 knockdown mutation also substantially reduced miRNA accumulation, but did not alter nuclear-cytoplasmic shuttling of miRNAs. Rather, the mutation significantly reduced nuclear portion of HYL1 protein and correspondingly compromised the pri-miRNA processing in the nucleus. We propose that KETCH1 transports HYL1 from the cytoplasm to the nucleus to constitute functional microprocessor in Arabidopsis This study provides insight into the largely unknown nuclear-cytoplasmic trafficking process of miRNA biogenesis components through eukaryotes. PMID- 28348235 TI - Live imaging of root-bacteria interactions in a microfluidics setup. AB - Plant roots play a dominant role in shaping the rhizosphere, the environment in which interaction with diverse microorganisms occurs. Tracking the dynamics of root-microbe interactions at high spatial resolution is currently limited because of methodological intricacy. Here, we describe a microfluidics-based approach enabling direct imaging of root-bacteria interactions in real time. The microfluidic device, which we termed tracking root interactions system (TRIS), consists of nine independent chambers that can be monitored in parallel. The principal assay reported here monitors behavior of fluorescently labeled Bacillus subtilis as it colonizes the root of Arabidopsis thaliana within the TRIS device. Our results show a distinct chemotactic behavior of B. subtilis toward a particular root segment, which we identify as the root elongation zone, followed by rapid colonization of that same segment over the first 6 h of root-bacteria interaction. Using dual inoculation experiments, we further show active exclusion of Escherichia coli cells from the root surface after B. subtilis colonization, suggesting a possible protection mechanism against root pathogens. Furthermore, we assembled a double-channel TRIS device that allows simultaneous tracking of two root systems in one chamber and performed real-time monitoring of bacterial preference between WT and mutant root genotypes. Thus, the TRIS microfluidics device provides unique insights into the microscale microbial ecology of the complex root microenvironment and is, therefore, likely to enhance the current rate of discoveries in this momentous field of research. PMID- 28348237 TI - Correction for Tang et al., High-throughput screening of rare metabolically active tumor cells in pleural effusion and peripheral blood of lung cancer patients. PMID- 28348236 TI - Optical visualization and quantification of enzyme activity using dynamic droplet lenses. AB - In this paper, we describe an approach to measuring enzyme activity based on the reconfiguration of complex emulsions. Changes in the morphology of these complex emulsions, driven by enzyme-responsive surfactants, modulate the transmission of light through a sample. Through this method we demonstrate how simple photodetector measurements may be used to monitor enzyme kinetics. This approach is validated by quantitative measurements of enzyme activity for three different classes of enzymes (amylase, lipase, and sulfatase), relying on two distinct mechanisms for coupling droplet morphology to enzyme activity (host-guest interactions with uncaging and molecular cleavage). PMID- 28348238 TI - Evolving polycentric governance of the Great Barrier Reef. AB - A growing field of sustainability science examines how environments are transformed through polycentric governance. However, many studies are only snapshot analyses of the initial design or the emergent structure of polycentric regimes. There is less systematic analysis of the longitudinal robustness of polycentric regimes. The problem of robustness is approached by focusing not only on the structure of a regime but also on its context and effectiveness. These dimensions are examined through a longitudinal analysis of the Great Barrier Reef (GBR) governance regime, drawing on in-depth interviews and demographic, economic, and employment data, as well as organizational records and participant observation. Between 1975 and 2011, the GBR regime evolved into a robust polycentric structure as evident in an established set of multiactor, multilevel arrangements addressing marine, terrestrial, and global threats. However, from 2005 onward, multiscale drivers precipitated at least 10 types of regime change, ranging from contextual change that encouraged regime drift to deliberate changes that threatened regime conversion. More recently, regime realignment also has occurred in response to steering by international organizations and shocks such as the 2016 mass coral-bleaching event. The results show that structural density and stability in a governance regime can coexist with major changes in that regime's context and effectiveness. Clear analysis of the vulnerability of polycentric governance to both diminishing effectiveness and the masking effects of increasing complexity provides sustainability science and governance actors with a stronger basis to understand and respond to regime change. PMID- 28348239 TI - Why the US science and engineering workforce is aging rapidly. AB - The science and engineering workforce has aged rapidly in recent years, both in absolute terms and relative to the workforce as a whole. This is a potential concern if the large number of older scientists crowds out younger scientists, making it difficult for them to establish independent careers. In addition, scientists are believed to be most creative earlier in their careers, so the aging of the workforce may slow the pace of scientific progress. We develop and simulate a demographic model, which shows that a substantial majority of recent aging is a result of the aging of the large baby boom cohort of scientists. However, changes in behavior have also played a significant role, in particular, a decline in the retirement rate of older scientists, induced in part by the elimination of mandatory retirement in universities in 1994. Furthermore, the age distribution of the scientific workforce is still adjusting. Current retirement rates and other determinants of employment in science imply a steady-state mean age 2.3 y higher than the 2008 level of 48.6. PMID- 28348240 TI - Endothelial transcription factor KLF2 negatively regulates liver regeneration via induction of activin A. AB - Endothelial cells (ECs) not only are important for oxygen delivery but also act as a paracrine source for signals that determine the balance between tissue regeneration and fibrosis. Here we show that genetic inactivation of flow-induced transcription factor Kruppel-like factor 2 (KLF2) in ECs results in reduced liver damage and augmentation of hepatocyte proliferation after chronic liver injury by treatment with carbon tetrachloride (CCl4). Serum levels of GLDH3 and ALT were significantly reduced in CCl4-treated EC-specific KLF2-deficient mice. In contrast, transgenic overexpression of KLF2 in liver sinusoidal ECs reduced hepatocyte proliferation. KLF2 induced activin A expression and secretion from endothelial cells in vitro and in vivo, which inhibited hepatocyte proliferation. However, loss or gain of KLF2 expression did not change capillary density and liver fibrosis, but significantly affected hepatocyte proliferation. Taken together, the data demonstrate that KLF2 induces an antiproliferative secretome, including activin A, which attenuates liver regeneration. PMID- 28348241 TI - Structure of the MeCP2-TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders. AB - Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the methyl-CpG-binding protein 2 (MeCP2) gene. The majority of RTT missense mutations disrupt the interaction of the MeCP2 with DNA or the nuclear receptor corepressor (NCoR)/silencing mediator of retinoic acid and thyroid receptors (SMRT) corepressor complex. Here, we show that the "NCoR/SMRT interaction domain" (NID) of MeCP2 directly contacts transducin beta-like 1 (TBL1) and TBL1 related (TBLR1), two paralogs that are core components of NCoR/SMRT. We determine the cocrystal structure of the MeCP2 NID in complex with the WD40 domain of TBLR1 and confirm by in vitro and ex vivo assays that mutation of interacting residues of TBLR1 and TBL1 disrupts binding to MeCP2. Strikingly, the four MeCP2-NID residues mutated in RTT are those residues that make the most extensive contacts with TBLR1. Moreover, missense mutations in the gene for TBLR1 that are associated with intellectual disability also prevent MeCP2 binding. Our study therefore reveals the molecular basis of an interaction that is crucial for optimal brain function. PMID- 28348244 TI - Opinion: Let's march to stress the value of science for the public good, not to engage in partisan politics. PMID- 28348243 TI - Frequency and potential dependence of reversible electrocatalytic hydrogen interconversion by [FeFe]-hydrogenases. AB - The kinetics of hydrogen oxidation and evolution by [FeFe]-hydrogenases have been investigated by electrochemical impedance spectroscopy-resolving factors that determine the exceptional activity of these enzymes, and introducing an unusual and powerful way of analyzing their catalytic electron transport properties. Attached to an electrode, hydrogenases display reversible electrocatalytic behavior close to the 2H+/H2 potential, making them paradigms for efficiency: the electrocatalytic "exchange" rate (measured around zero driving force) is therefore an unusual parameter with theoretical and practical significance. Experiments were carried out on two [FeFe]-hydrogenases, CrHydA1 from the green alga Chlamydomonas reinhardtii, which contains only the active-site "H cluster," and CpI from the fermentative anaerobe Clostridium pasteurianum, which contains four low-potential FeS clusters that serve as an electron relay in addition to the H cluster. Data analysis yields catalytic exchange rates (at the formal 2H+/H2 potential, at 0 degrees C) of 157 electrons (78 molecules H2) per second for CpI and 25 electrons (12 molecules H2) per second for CrHydA1. The experiments show how the potential dependence of catalytic electron flow comprises frequency-dependent and frequency-independent terms that reflect the proficiencies of the catalytic site and the electron transfer pathway in each enzyme. The results highlight the "wire-like" behavior of the Fe-S electron relay in CpI and a low reorganization energy for electron transfer on/off the H cluster. PMID- 28348242 TI - Structures of closed and open states of a voltage-gated sodium channel. AB - Bacterial voltage-gated sodium channels (BacNavs) serve as models of their vertebrate counterparts. BacNavs contain conserved voltage-sensing and pore forming domains, but they are homotetramers of four identical subunits, rather than pseudotetramers of four homologous domains. Here, we present structures of two NaVAb mutants that capture tightly closed and open states at a resolution of 2.8-3.2 A. Introduction of two humanizing mutations in the S6 segment (NaVAb/FY: T206F and V213Y) generates a persistently closed form of the activation gate in which the intracellular ends of the four S6 segments are drawn tightly together to block ion permeation completely. This construct also revealed the complete structure of the four-helix bundle that forms the C-terminal domain. In contrast, truncation of the C-terminal 40 residues in NavAb/1-226 captures the activation gate in an open conformation, revealing the open state of a BacNav with intact voltage sensors. Comparing these structures illustrates the full range of motion of the activation gate, from closed with its orifice fully occluded to open with an orifice of ~10 A. Molecular dynamics and free-energy simulations confirm designation of NaVAb/1-226 as an open state that allows permeation of hydrated Na+, and these results also support a hydrophobic gating mechanism for control of ion permeation. These two structures allow completion of a closed-open inactivated conformational cycle in a single voltage-gated sodium channel and give insight into the structural basis for state-dependent binding of sodium channel-blocking drugs. PMID- 28348245 TI - Alpha-1 antitrypsin dysfunction and large artery stroke. PMID- 28348248 TI - Imaging morphogenesis. AB - The hostile environment of the microscope stage poses numerous challenges to successful imaging of morphogenesis in live tissues. This review aims to highlight some of the main practical considerations to take into account when embarking on a project to image cell behaviour in the context of cells' normal surroundings. Scrutiny of these activities is likely to be the most informative approach to understanding mechanical morphogenesis but is often confounded by the substantial technical difficulties involved in imaging samples over extended periods of time. Repeated observation of cells in live tissue requires that strategies be adopted to prioritize the stability of the sample, ensuring that it remains viable and develops normally while being held in a manner accessible to microscopic examination. Key considerations when creating reliable protocols for time-lapse imaging may be broken down into three main criteria; labelling, mounting and image acquisition. Choices and compromises made here, however, will directly influence image quality, and even small refinements can substantially improve what information may be extracted from images. Live imaging of tissue is difficult but paying close attention to the basics along with a little innovation is likely to be well rewarded.This article is part of the themed issue 'Systems morphodynamics: understanding the development of tissue hardware'. PMID- 28348247 TI - Entropy redistribution controls allostery in a metalloregulatory protein. AB - Allosteric communication between two ligand-binding sites in a protein is a central aspect of biological regulation that remains mechanistically unclear. Here we show that perturbations in equilibrium picosecond-nanosecond motions impact zinc (Zn)-induced allosteric inhibition of DNA binding by the Zn efflux repressor CzrA (chromosomal zinc-regulated repressor). DNA binding leads to an unanticipated increase in methyl side-chain flexibility and thus stabilizes the complex entropically; Zn binding redistributes these motions, inhibiting formation of the DNA complex by restricting coupled fast motions and concerted slower motions. Allosterically impaired CzrA mutants are characterized by distinct nonnative fast internal dynamics "fingerprints" upon Zn binding, and DNA binding is weakly regulated. We demonstrate the predictive power of the wild-type dynamics fingerprint to identify key residues in dynamics-driven allostery. We propose that driving forces arising from dynamics can be harnessed by nature to evolve new allosteric ligand specificities in a compact molecular scaffold. PMID- 28348246 TI - Mechanism of transcription initiation and promoter escape by E. coli RNA polymerase. AB - To investigate roles of the discriminator and open complex (OC) lifetime in transcription initiation by Escherichia coli RNA polymerase (RNAP; alpha2betabeta'omegasigma70), we compare productive and abortive initiation rates, short RNA distributions, and OC lifetime for the lambdaPR and T7A1 promoters and variants with exchanged discriminators, all with the same transcribed region. The discriminator determines the OC lifetime of these promoters. Permanganate reactivity of thymines reveals that strand backbones in open regions of long-lived lambdaPR-discriminator OCs are much more tightly held than for shorter-lived T7A1-discriminator OCs. Initiation from these OCs exhibits two kinetic phases and at least two subpopulations of ternary complexes. Long RNA synthesis (constrained to be single round) occurs only in the initial phase (<10 s), at similar rates for all promoters. Less than half of OCs synthesize a full length RNA; the majority stall after synthesizing a short RNA. Most abortive cycling occurs in the slower phase (>10 s), when stalled complexes release their short RNA and make another without escaping. In both kinetic phases, significant amounts of 8-nt and 10-nt transcripts are produced by longer-lived, lambdaPR discriminator OCs, whereas no RNA longer than 7 nt is produced by shorter-lived T7A1-discriminator OCs. These observations and the lack of abortive RNA in initiation from short-lived ribosomal promoter OCs are well described by a quantitative model in which ~1.0 kcal/mol of scrunching free energy is generated per translocation step of RNA synthesis to overcome OC stability and drive escape. The different length-distributions of abortive RNAs released from OCs with different lifetimes likely play regulatory roles. PMID- 28348249 TI - Deciphering tissue morphodynamics using bioimage informatics. AB - In recent years developmental biology has greatly benefited from the latest advances in fluorescence microscopy techniques. Consequently, quantitative and automated analysis of this data is becoming a vital first step in the quest for novel insights into the various aspects of development. Here we present an introductory overview of the various image analysis methods proposed for developmental biology images, with particular attention to openly available software packages. These tools, as well as others to come, are rapidly paving the way towards standardized and reproducible bioimaging studies at the whole-tissue level. Reflecting on these achievements, we discuss the remaining challenges and the future endeavours lying ahead in the post-image analysis era.This article is part of the themed issue 'Systems morphodynamics: understanding the development of tissue hardware'. PMID- 28348250 TI - Taking the strain: quantifying the contributions of all cell behaviours to changes in epithelial shape. AB - Computer-assisted tracking of the shapes of many cells over long periods of development has driven the exploration of novel ways to quantify the contributions of different cell behaviours to morphogenesis. A handful of similar methods have now been published that are used to calculate tissue deformations (strain rates) in epithelia. These methods are further used to quantify strain rates attributable to each of the cell behaviours in the tissue, such as cell shape change, cell rearrangement and cell division, that together sum to the tissue strain rates. In this review, aimed at developmental biologists, I will introduce the general approach, characterize differences in current approaches and highlight extensions of these methods that remain to be fully explored. The methods will make a major contribution to the emerging field of tissue mechanics. Precisely quantified strain rates are an essential first step towards exploring constitutive equations relating stress to strain via tissue mechanical properties.This article is part of the themed issue 'Systems morphodynamics: understanding the development of tissue hardware'. PMID- 28348251 TI - Complex structures from patterned cell sheets. AB - The formation of three-dimensional structures from patterned epithelial sheets plays a key role in tissue morphogenesis. An important class of morphogenetic mechanisms relies on the spatio-temporal control of apical cell contractility, which can result in the localized bending of cell sheets and in-plane cell rearrangements. We have recently proposed a modified vertex model that can be used to systematically explore the connection between the two-dimensional patterns of cell properties and the emerging three-dimensional structures. Here we review the proposed modelling framework and illustrate it through the computational analysis of the vertex model that captures the salient features of the formation of the dorsal appendages during Drosophila oogenesis.This article is part of the themed issue 'Systems morphodynamics: understanding the development of tissue hardware'. PMID- 28348252 TI - Mechanical design in embryos: mechanical signalling, robustness and developmental defects. AB - Embryos are shaped by the precise application of force against the resistant structures of multicellular tissues. Forces may be generated, guided and resisted by cells, extracellular matrix, interstitial fluids, and how they are organized and bound within the tissue's architecture. In this review, we summarize our current thoughts on the multiple roles of mechanics in direct shaping, mechanical signalling and robustness of development. Genetic programmes of development interact with environmental cues to direct the composition of the early embryo and endow cells with active force production. Biophysical advances now provide experimental tools to measure mechanical resistance and collective forces during morphogenesis and are allowing integration of this field with studies of signalling and patterning during development. We focus this review on concepts that highlight this integration, and how the unique contributions of mechanical cues and gradients might be tested side by side with conventional signalling systems. We conclude with speculation on the integration of large-scale programmes of development, and how mechanical responses may ensure robust development and serve as constraints on programmes of tissue self-assembly.This article is part of the themed issue 'Systems morphodynamics: understanding the development of tissue hardware'. PMID- 28348253 TI - Mechanocellular models of epithelial morphogenesis. AB - Embryonic epithelia achieve complex morphogenetic movements, including in-plane reshaping, bending and folding, through the coordinated action and rearrangement of individual cells. Technical advances in molecular and live-imaging studies of epithelial dynamics provide a very real opportunity to understand how cell-level processes facilitate these large-scale tissue rearrangements. However, the large datasets that we are now able to generate require careful interpretation. In combination with experimental approaches, computational modelling allows us to challenge and refine our current understanding of epithelial morphogenesis and to explore experimentally intractable questions. To this end, a variety of cell based modelling approaches have been developed to describe cell-cell mechanical interactions, ranging from vertex and 'finite-element' models that approximate each cell geometrically by a polygon representing the cell's membrane, to immersed boundary and subcellular element models that allow for more arbitrary cell shapes. Here, we review how these models have been used to provide insights into epithelial morphogenesis and describe how such models could help future efforts to decipher the forces and mechanical and biochemical feedbacks that guide cell and tissue-level behaviour. In addition, we discuss current challenges associated with using computational models of morphogenetic processes in a quantitative and predictive way.This article is part of the themed issue 'Systems morphodynamics: understanding the development of tissue hardware'. PMID- 28348254 TI - Vertex models: from cell mechanics to tissue morphogenesis. AB - Tissue morphogenesis requires the collective, coordinated motion and deformation of a large number of cells. Vertex model simulations for tissue mechanics have been developed to bridge the scales between force generation at the cellular level and tissue deformation and flows. We review here various formulations of vertex models that have been proposed for describing tissues in two and three dimensions. We discuss a generic formulation using a virtual work differential, and we review applications of vertex models to biological morphogenetic processes. We also highlight recent efforts to obtain continuum theories of tissue mechanics, which are effective, coarse-grained descriptions of vertex models.This article is part of the themed issue 'Systems morphodynamics: understanding the development of tissue hardware'. PMID- 28348255 TI - The temporal basis of angiogenesis. AB - The process of new blood vessel growth (angiogenesis) is highly dynamic, involving complex coordination of multiple cell types. Though the process must carefully unfold over time to generate functional, well-adapted branching networks, we seldom hear about the time-based properties of angiogenesis, despite timing being central to other areas of biology. Here, we present a novel, time based formulation of endothelial cell behaviour during angiogenesis and discuss a flurry of our recent, integrated in silico/in vivo studies, put in context to the wider literature, which demonstrate that tissue conditions can locally adapt the timing of collective cell behaviours/decisions to grow different vascular network architectures. A growing array of seemingly unrelated 'temporal regulators' have recently been uncovered, including tissue derived factors (e.g. semaphorins or the high levels of VEGF found in cancer) and cellular processes (e.g. asymmetric cell division or filopodia extension) that act to alter the speed of cellular decisions to migrate. We will argue that 'temporal adaptation' provides a novel account of organ/disease-specific vascular morphology and reveals 'timing' as a new target for therapeutics. We therefore propose and explain a conceptual shift towards a 'temporal adaptation' perspective in vascular biology, and indeed other areas of biology where timing remains elusive.This article is part of the themed issue 'Systems morphodynamics: understanding the development of tissue hardware'. PMID- 28348256 TI - Cellular systems for epithelial invagination. AB - Epithelial invagination is a fundamental module of morphogenesis that iteratively occurs to generate the architecture of many parts of a developing organism. By changing the physical properties such as the shape and/or position of a population of cells, invagination drives processes ranging from reconfiguring the entire body axis during gastrulation, to forming the primordia of the eyes, ears and multiple ducts and glands, during organogenesis. The epithelial bending required for invagination is achieved through a variety of mechanisms involving systems of cells. Here we provide an overview of the different mechanisms, some of which can work in combination, and outline the circumstances in which they apply.This article is part of the themed issue 'Systems morphodynamics: understanding the development of tissue hardware'. PMID- 28348258 TI - Flower development: from morphodynamics to morphomechanics. AB - The shoot apical meristem (SAM) is a small population of stem cells that continuously generates organs and tissues. We will discuss here flower formation at the SAM, which involves a complex network of regulatory genes and signalling molecules. A major downstream target of this network is the extracellular matrix or cell wall, which is a local determinant for both growth rates and growth directions. We will discuss here a number of recent studies aimed at analysing the link between cell wall structure and molecular regulation. This has involved multidisciplinary approaches including quantitative imaging, molecular genetics, computational biology and biophysics. A scenario emerges where molecular networks impact on both cell wall anisotropy and synthesis, thus causing the rapid outgrowth of organs at specific locations. More specifically, this involves two interdependent processes: the activation of wall remodelling enzymes and changes in microtubule dynamics.This article is part of the themed issue 'Systems morphodynamics: understanding the development of tissue hardware'. PMID- 28348259 TI - Inferring cellular forces from image stacks. AB - Although the importance of cellular forces to a wide range of embryogenesis and disease processes is widely recognized, measuring these forces is challenging, especially in three dimensions. Here, we introduce CellFIT-3D, a force inference technique that allows tension maps for three-dimensional cellular systems to be estimated from image stacks. Like its predecessors, video force microscopy and CellFIT, this cell mechanics technique assumes boundary-specific interfacial tensions to be the primary drivers, and it constructs force-balance equations based on triple junction (TJ) dihedral angles. The technique involves image processing, segmenting of cells, grouping of cell outlines, calculation of dihedral planes, averaging along three-dimensional TJs, and matrix equation assembly and solution. The equations tend to be strongly overdetermined, allowing indistinct TJs to be ignored and solution error estimates to be determined. Application to clean and noisy synthetic data generated using Surface Evolver gave tension errors of 1.6-7%, and analyses of eight-cell murine embryos gave estimated errors smaller than the 10% uncertainty of companion aspiration experiments. Other possible areas of application include morphogenesis, cancer metastasis and tissue engineering.This article is part of the themed issue 'Systems morphodynamics: understanding the development of tissue hardware'. PMID- 28348260 TI - Systems morphodynamics: understanding the development of tissue hardware. AB - Systems morphodynamics describes a multi-level analysis of mechanical morphogenesis that draws on new microscopy and computational technologies and embraces a systems biology-informed scope. We present a selection of articles that illustrate and explain this rapidly progressing field.This article is part of the themed issue 'Systems morphodynamics: understanding the development of tissue hardware'. PMID- 28348261 TI - Fungal malignant otitis externa. AB - An 89-year-old man presented to the outpatient clinic with a 2-month history of persistent unilateral left-sided otalgia, otorrhoea and reduced hearing despite oral and topical antibiotics. Treatment was protracted, requiring a 4-month hospital admission for intravenous antifungal medication as well as 3 further months of oral antifungal treatment. We describe the clinical presentation, complications and treatment of this potentially fatal condition in the context of an unusual, and easily missed, causative organism. PMID- 28348262 TI - Rare progression of cholangiocarcinoma: distal femoral metastasis. AB - Cholangiocarcinoma (CCA) is a rare cancer of the bile duct epithelial cells, with metastases to long bones rarely reported. We present the case of a woman aged 61 years, diagnosed with CCA 6 years previously. She presented with right thigh discomfort, rapidly progressing to immobility with severe pain. Radiological investigations revealed a lytic lesion in her right distal femur, most likely a metastatic deposit, at high risk of pathological fracture. This was managed with an en bloc resection and implantation of a distal femoral replacement. Pathology specimens from theatre confirmed metastatic CCA. Despite sustaining a subsequent fractured neck of femur on the operative side, she recovered well from surgery, with minimal pain and improved mobility on discharge. She restarted palliative chemotherapy. This case illustrates the option of definitive major surgery for the management of metastatic bone disease. As in this case, this can lead to improved symptom control and quality of remaining life. PMID- 28348257 TI - Building branched tissue structures: from single cell guidance to coordinated construction. AB - Branched networks are ubiquitous throughout nature, particularly found in tissues that require large surface area within a restricted volume. Many tissues with a branched architecture, such as the vasculature, kidney, mammary gland, lung and nervous system, function to exchange fluids, gases and information throughout the body of an organism. The generation of branched tissues requires regulation of branch site specification, initiation and elongation. Branching events often require the coordination of many cells to build a tissue network for material exchange. Recent evidence has emerged suggesting that cell cooperativity scales with the number of cells actively contributing to branching events. Here, we compare mechanisms that regulate branching, focusing on how cell cohorts behave in a coordinated manner to build branched tissues.This article is part of the themed issue 'Systems morphodynamics: understanding the development of tissue hardware'. PMID- 28348263 TI - Pure motor axonal neuropathy triggered by antituberculous therapy in an undiagnosed case of acute intermittent porphyria. AB - A man aged 22 years misdiagnosed as suffering from recurrent abdominal tuberculosis, in view of recurrent abdominal pain was treated for abdominal tuberculosis in the past. The patient was prescribed antituberculous therapy. 2 months after starting treatment, he developed progressive weakness of all 4 limbs. Electrodiagnostic examination revealed an acute severe motor axonal neuropathy. Further workup revealed elevated porphyrin precursors in urine. PMID- 28348264 TI - Unusual metallic penile foreign body. PMID- 28348265 TI - Group G Streptococcus dysgalactiae subspecies equisimilis, the clinical significance of a rare infection: endocarditis, polyarteritis, septic bursitis and pneumonia with complicated parapneumonic effusion. PMID- 28348266 TI - It's not what it looks like: atypical rash in cryoglobulinaemic vasculitis. AB - A 48-year-old man with a history of intravenous drug use and chronic, untreated hepatitis C presented to the emergency room with acute bilateral lower extremity swelling, erythema and maculopapular rash. Serum C4 levels were low, but dermatology felt the rash was due to venous stasis dermatitis. The patient was discharged with compression stockings, but returned to the hospital 5 days later with no improvement in his symptoms. A more extensive laboratory workup revealed hepatitis C viral load of 4 million, elevated serum cryoglobulins, and skin biopsy showing leucocytoclastic vasculitis. He was treated with oral prednisone, with complete resolution of his symptoms after 2 weeks. He was scheduled for follow-up in gastroenterology clinic for treatment of his hepatitis C for definitive cure of his mixed cryoglobulinaemia, but failed to get insurance authorisation to begin treatment with Harvoni. He presented to the hospital 4 months later with diffuse alveolar haemorrhage. PMID- 28348267 TI - Unilateral optic disc swelling associated with idiopathic hypertrophic pachymeningitis: a rare cause for a rare clinical finding. PMID- 28348268 TI - Cutting Edge: Class II-like Structural Features and Strong Receptor Binding of the Nonclassical HLA-G2 Isoform Homodimer. AB - HLA-G is a natural tolerogenic molecule and has the following unique features: seven isoforms (HLA-G1 to HLA-G7), formation of disulfide-linked homodimers, and beta2-microglobulin (beta2m)-free forms. Interestingly, individuals null for the major isoform, HLA-G1, are healthy and expressed the alpha2 domain-deleted isoform, HLA-G2, which presumably compensates for HLA-G1 function. However, the molecular characteristics of HLA-G2 are largely unknown. In this study, we unexpectedly found that HLA-G2 naturally forms a beta2m-free and nondisulfide linked homodimer, which is in contrast to the disulfide-bonded beta2m-associated HLA-G1 homodimer. Furthermore, single-particle analysis, using electron microscopy, revealed that the overall structure and domain organization of the HLA-G2 homodimer resemble those of the HLA class II heterodimer. The HLA-G2 homodimer binds to leukocyte Ig-like receptor B2 with slow dissociation and a significant avidity effect. These findings provide novel insights into leukocyte Ig-like receptor B2-mediated immune regulation by the HLA-G2 isoform, as well as the gene evolution of HLA classes. PMID- 28348270 TI - Characterization of the B Cell Receptor Repertoire in the Intestinal Mucosa and of Tumor-Infiltrating Lymphocytes in Colorectal Adenoma and Carcinoma. AB - The B cells inhabited in mucosa play a vital role in mediating homeostasis with autoantigens and external Ags. Tumor-infiltrating lymphocytes are potential prognostic markers and therapeutic agents for cancer. However, the spatial heterogeneity of the B cell repertoire in intestinal mucosa and the tumor infiltrating lymphocytes in colorectal cancer (CRC) remain poorly understood. In this study, we developed an unbiased method to amplify the IgH repertoire, as well as a bioinformatic pipeline to process these high-throughput sequencing data. With biopsies from seven intestinal mucosal segments, we uncovered their strong spatial homogeneity among the large intestine, where the clone overlap rate was up to 62.21%. The heterogeneity between terminal ileum and large intestine was also observed, including discrepant isotype distribution and low clone overlap rate. With tumor and adjacent normal mucosal tissues from CRC and colorectal advanced adenoma (AD) patients, we observed a similar IgH profile between tumor and adjacent normal mucosal tissues in AD, as well as a slight difference in CRC. Interestingly, we found distinct repertoire properties in the CRC tumor from AD and normal mucosa. Finally, we identified 1445 public clones for the normal mucosa, and 22 public clones for the CRC tumor with characteristic features. These data may be of potential use in clinical prognosis, diagnosis, and treatment of CRC. PMID- 28348271 TI - Identification of Novel STAT6-Regulated Proteins in Mouse B Cells by Comparative Transcriptome and Proteome Analysis. AB - The transcription factor STAT6 plays a key role in mediating signaling downstream of the receptors for IL-4 and IL-13. In B cells, STAT6 is required for class switch recombination to IgE and for germinal center formation during type 2 immune responses directed against allergens or helminths. In this study, we compared the transcriptomes and proteomes of primary mouse B cells from wild-type and STAT6-deficient mice cultured for 4 d in the presence or absence of IL-4. Microarray analysis revealed that 214 mRNAs were upregulated and 149 were downregulated >3-fold by IL-4 in a STAT6-dependent manner. Across all samples, ~5000 proteins were identified by label-free quantitative liquid chromatography/mass spectrometry. A total of 149 proteins was found to be differentially expressed >3-fold between IL-4-stimulated wild-type and STAT6-/- B cells (75 upregulated and 74 downregulated). Comparative analysis of the proteome and transcriptome revealed that expression of these proteins was mainly regulated at the transcriptional level, which argues against a major role for posttranscriptional mechanisms that modulate the STAT6-dependent proteome. Nine proteins were selected for confirmation by flow cytometry or Western blot. We show that CD30, CD79b, SLP-76, DEC205, IL-5Ralpha, STAT5, and Thy1 are induced by IL-4 in a STAT6-dependent manner. In contrast, Syk and Fc receptor-like 1 were downregulated. This dataset provides a framework for further functional analysis of newly identified IL-4-regulated proteins in B cells that may contribute to germinal center formation and IgE switching in type 2 immunity. PMID- 28348269 TI - Bonobos Maintain Immune System Diversity with Three Functional Types of MHC-B. AB - Fast-evolving MHC class I polymorphism serves to diversify NK cell and CD8 T cell responses in individuals, families, and populations. Because only chimpanzee and bonobo have strict orthologs of all HLA class I, their study gives unique perspectives on the human condition. We defined polymorphism of Papa-B, the bonobo ortholog of HLA-B, for six wild bonobo populations. Sequences for Papa-B exon 2 and 3 were determined from the genomic DNA in 255 fecal samples, minimally representing 110 individuals. Twenty-two Papa-B alleles were defined, each encoding a different Papa-B protein. No Papa-B is identical to any chimpanzee Patr-B, human HLA-B, or gorilla Gogo-B. Phylogenetic analysis identified a clade of MHC-B, defined by residues 45-74 of the alpha1 domain, which is broadly conserved among bonobo, chimpanzee, and gorilla. Bonobo populations have 3-14 Papa-B allotypes. Three Papa-B are in all populations, and they are each of a different functional type: allotypes having the Bw4 epitope recognized by killer cell Ig-like receptors of NK cells, allotypes having the C1 epitope also recognized by killer cell Ig-like receptors, and allotypes having neither epitope. For population Malebo, these three Papa-B are the only Papa-B allotypes. Although small in number, their sequence divergence is such that the nucleotide diversity (mean proportional distance) of Papa-B in Malebo is greater than in the other populations and is also greater than expected for random combinations of three Papa-B Overall, Papa-B has substantially less diversity than Patr-B in chimpanzee subspecies and HLA-B in indigenous human populations, consistent with bonobo having experienced narrower population bottlenecks. PMID- 28348272 TI - Cutting Edge: beta-Catenin-Interacting Tcf1 Isoforms Are Essential for Thymocyte Survival but Dispensable for Thymic Maturation Transitions. AB - T cell factor 1 (Tcf1) is essential for T cell development; however, it remains controversial whether beta-catenin, a known coactivator of Tcf1, has a role. Tcf1 is expressed in multiple isoforms in T lineage cells, with the long isoforms interacting with beta-catenin through an N-terminal domain. In this study, we specifically ablated Tcf1 long isoforms in mice (p45-/-mice) to abrogate beta catenin interaction. Although thymic cellularity was diminished in p45-/- mice, transition of thymocytes through the maturation stages was unaffected, with no overt signs of developmental blocks. p45-/- thymocytes showed increased apoptosis and alterations in transcriptome, but these changes were substantially more modest than in thymocytes lacking all Tcf1 isoforms. These data indicate that Tcf1-beta-catenin interaction is necessary for promoting thymocyte survival to maintain thymic output. Rather than being dominant-negative regulators, Tcf1 short isoforms are adequate in supporting developing thymocytes to traverse through maturation steps and in regulating the expression of most Tcf1 target genes. PMID- 28348273 TI - Cutting Edge: Loss of T Cell RIAM Precludes Conjugate Formation with APC and Prevents Immune-Mediated Diabetes. AB - Rap1-interacting adaptor molecule (RIAM) is a Rap1 effector that mediates the recruitment of talin to integrins, thereby supporting their activation. In this study, we investigated the role of RIAM in an adoptive transfer model for type I diabetes and report that RIAM expression in T cells is necessary for diabetes development. Loss of RIAM did not prevent lymphocyte recruitment to draining lymph nodes 24 h after transfer, but it was required for Ag-driven proliferation and cytotoxic killing. RIAM is recruited to immune synapses along with talin and LFA-1, and loss of RIAM profoundly suppresses Ag-dependent conjugate formation in primary naive and effector T cells. These data identify the requirement of RIAM for formation of immunological synapses and in resulting T cell functions in autoimmunity. Moreover, because RIAM-null mice are healthy, fertile, and display no bleeding abnormalities, our results identify RIAM and its regulators as potential targets for therapies of T cell-mediated autoimmunity. PMID- 28348275 TI - Strontium-doped calcium silicate bioceramic with enhanced in vitro osteogenic properties. AB - Gehlenite (GLN, Ca2SiAl2O7) is a bioceramic that has been recently shown to possess excellent mechanical strength and in vitro osteogenic properties for bone regeneration. Substitutional incorporation of strontium in place of calcium is an effective way to further enhance biological properties of calcium-based bioceramics and glasses. However, such strategy has the potential to affect other important physicochemical parameters such as strength and degradation due to differences in the ionic radius of strontium and calcium. This study is the first to investigate the effect of a range of concentrations of strontium substitution of calcium at 1, 2, 5, 10 mol% (S1-GLN, S2-GLN, S5-GLN and S10-GLN) on the physicochemical and biological properties of GLN. We showed that up to 2 mol% strontium ion substitution retains the monophasic GLN structure when sintered at 1450 degrees C, whereas higher concentrations resulted in presence of calcium silicate impurities. Increased strontium incorporation resulted in changes in grain morphology and reduced densification when the ceramics were sintered at 1450 degrees C. Porous GLN, S1-GLN and S2-GLN scaffolds (~80% porosity) showed compressive strengths of 2.05 +/- 0.46 MPa, 1.76 +/- 0.79 MPa and 1.57 +/- 0.52 MPa respectively. S1-GLN and S2-GLN immersed in simulated body fluid showed increased strontium ion release but reduced calcium and silicon ion release compared to GLN without affecting overall weight loss and pH over a 21 d period. The bioactivity of the S2-GLN ceramics was significantly improved as reflected in the significant upregulation of HOB proliferation and differentiation compared to GLN. Overall, these results suggest that increased incorporation of strontium presents a trade-off between bioactivity and mechanical strength for GLN bioceramics. This is an important consideration in the development of strontium doped bioceramics. PMID- 28348276 TI - Another Journal on Nanomaterials? AB - It is my great pleasure to welcome you to Nanomaterials, a new open access journal, which is dedicated to the fabrication, characterization, functionalization, modeling and application of nanomaterials. In answer to the title question, I would like to (mis)quote one of my favourite pieces of literature: I "[We] hold these truths to be self-evident, that all men ... are endowed ... with certain unalienable rights, that among these are ..." free access to information and education. The prime goal of Nanomaterials is to publish first-class, original research articles under an open access policy with minimal fees for the authors. The quality of the published articles will be assured by a fast yet rigorous peer-review process. [...]. PMID- 28348274 TI - Low Antigen Dose in Adjuvant-Based Vaccination Selectively Induces CD4 T Cells with Enhanced Functional Avidity and Protective Efficacy. AB - T cells with high functional avidity can sense and respond to low levels of cognate Ag, a characteristic that is associated with more potent responses against tumors and many infections, including HIV. Although an important determinant of T cell efficacy, it has proven difficult to selectively induce T cells of high functional avidity through vaccination. Attempts to induce high avidity T cells by low-dose in vivo vaccination failed because this strategy simply gave no response. Instead, selective induction of high-avidity T cells has required in vitro culturing of specific T cells with low Ag concentrations. In this study, we combined low vaccine Ag doses with a novel potent cationic liposomal adjuvant, cationic adjuvant formulation 09, consisting of dimethyldioctadecylammonium liposomes incorporating two immunomodulators (monomycolyl glycerol analog and polyinosinic-polycytidylic acid) that efficiently induces CD4 Th cells, as well as cross-primes CD8 CTL responses. We show that vaccination with low Ag dose selectively primes CD4 T cells of higher functional avidity, whereas CD8 T cell functional avidity was unrelated to vaccine dose in mice. Importantly, CD4 T cells of higher functional avidity induced by low-dose vaccinations showed higher cytokine release per cell and lower inhibitory receptor expression (PD-1, CTLA-4, and the apoptosis-inducing Fas death receptor) compared with their lower-avidity CD4 counterparts. Notably, increased functional CD4 T cell avidity improved antiviral efficacy of CD8 T cells. These data suggest that potent adjuvants, such as cationic adjuvant formulation 09, render low-dose vaccination a feasible and promising approach for generating high-avidity T cells through vaccination. PMID- 28348277 TI - Films, Buckypapers and Fibers from Clay, Chitosan and Carbon Nanotubes. AB - The mechanical and electrical characteristics of films, buckypapers and fiber materials from combinations of clay, carbon nanotubes (CNTs) and chitosan are described. The rheological time-dependent characteristics of clay are maintained in clay-carbon nanotube-chitosan composite dispersions. It is demonstrated that the addition of chitosan improves their mechanical characteristics, but decreases electrical conductivity by three-orders of magnitude compared to clay-CNT materials. We show that the electrical response upon exposure to humid atmosphere is influenced by clay-chitosan interactions, i.e., the resistance of clay-CNT materials decreases, whereas that of clay-CNT-chitosan increases. PMID- 28348278 TI - Metallic Nanoparticle Block Copoloymer Vesicles with Enhanced Optical Properties. AB - The fabrication and characterization of template silver nanoshell structures and the encapsulation of gold nanoparticles using biocompatible poly(oxyethylene) poly(butylene) diblock co-polymer vesicles is described in this work. These vesicles have a narrow diameter size distribution around 200 nm. Silver nanoparticles (O = 1-10 nm) functionalized with decanethiol were successfully entrapped in the hydrophobic membrane and non-functionalized gold nanoparticles (O = 3.0-5.5 nm) were encapsulated in the vesicle core. Transmission Electron Microscopy confirms the localisation of the particles; silver functionalized nanoparticles appear to thicken the vesicle membrane as shown with TEM image analysis. The enhancement of the optical properties is confirmed using transmission spectrophotometry; the 430 nm plasmon resonance peak of the silver nanoparticles was replaced by a broader extinction spectrum to beyond 700 nm (O.D. = 0.8). For a number density of 4.8 x 1012 mL-1 the scattering cross section was calculated to be 0.92 x 10-4 MUm2 with a scattering coefficient of 0.44 mm-1. The measurements indicate scattering cross section of 3.8 x 10-5 MUm2, attenuation coefficient of 0.18 mm-1 and extinction efficiency equal to 1.2 x 10 3. Stable and biocompatible block co-polymer vesicles can potentially be used as plasmon-resonant optical contrast agents for biomedical applications. PMID- 28348281 TI - Quantum Dot Sensitized Photoelectrodes. AB - Quantum Dots (QDs) are promising alternatives to organic dyes as sensitisers for photocatalytic electrodes. This review article provides an overview of the current state of the art in this area. More specifically, different types of QDs with a special focus on heavy-metal free QDs and the methods for preparation and adsorption onto metal oxide electrodes (especially titania and zinc oxide) are discussed. Eventually, the key areas of necessary improvements are identified and assessed. PMID- 28348280 TI - Fabrication of Size-Tunable Metallic Nanoparticles Using Plasmid DNA as a Biomolecular Reactor. AB - Plasmid DNA can be used as a template to yield gold, palladium, silver, and chromium nanoparticles of different sizes based on variations in incubation time at 70 degrees C with gold phosphine complexes, with the acetates of silver or palladium, or chromium acetylacetonate. The employment of mild synthetic conditions, minimal procedural steps, and aqueous solvents makes this method environmentally greener and ensures general feasibility. The use of plasmids exploits the capabilities of the biotechnology industry as a source of nanoreactor materials. PMID- 28348282 TI - Composite Electrolyte Membranes from Partially Fluorinated Polymer and Hyperbranched, Sulfonated Polysulfone. AB - Macromolecular modification of poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF) was done with various proportions of sulfonic acid terminated, hyperbranched polysulfone (HPSU) with a view to prepare ion conducting membranes. The PVDF-co-HFP was first chemically modified by dehydrofluorination and chlorosulfonation in order to make the membrane more hydrophilic as well as to introduce unsaturation, which would allow crosslinking of the PVDF-co-HFP matrix to improve the stability of the membrane. The modified samples were characterized for ion exchange capacity, morphology, and performance. The HPSU modified S-PVDF membrane shows good stability and ionic conductivity of 5.1 mS cm-1 at 80 degrees C and 100% RH for blends containing 20% HPSU, which is higher than the literature values for equivalent blend membranes using Nafion. SEM analysis of the blend membranes containing 15% or more HPSU shows the presence of spherical domains with a size range of 300-800 nm within the membranes, which are believed to be the HPSU-rich area. PMID- 28348279 TI - Functionalized Gold Nanoparticles and Their Biomedical Applications. AB - Metal nanoparticles are being extensively used in various biomedical applications due to their small size to volume ratio and extensive thermal stability. Gold nanoparticles (GNPs) are an obvious choice due to their amenability of synthesis and functionalization, less toxicity and ease of detection. The present review focuses on various methods of functionalization of GNPs and their applications in biomedical research. Functionalization facilitates targeted delivery of these nanoparticles to various cell types, bioimaging, gene delivery, drug delivery and other therapeutic and diagnostic applications. This review is an amalgamation of recent advances in the field of functionalization of gold nanoparticles and their potential applications in the field of medicine and biology. PMID- 28348284 TI - Effect of Low-Frequency AC Magnetic Susceptibility and Magnetic Properties of CoFeB/MgO/CoFeB Magnetic Tunnel Junctions. AB - In this investigation, the low-frequency alternate-current (AC) magnetic susceptibility (chiac) and hysteresis loop of various MgO thickness in CoFeB/MgO/CoFeB magnetic tunneling junction (MTJ) determined coercivity (Hc) and magnetization (Ms) and correlated that with chiac maxima. The multilayer films were sputtered onto glass substrates and the thickness of intermediate barrier MgO layer was varied from 6 to 15 A. An experiment was also performed to examine the variation of the highest chiac and maximum phase angle (thetamax) at the optimal resonance frequency (fres), at which the spin sensitivity is maximal. The results reveal that chiac falls as the frequency increases due to the relationship between magnetization and thickness of the barrier layer. The maximum chiac is at 10 Hz that is related to the maximal spin sensitivity and that this corresponds to a MgO layer of 11 A. This result also suggests that the spin sensitivity is related to both highest chiac and maximum phase angle. The corresponding maximum of chiac is related to high exchange coupling. High coercivity and saturation magnetization contribute to high exchange-coupling chiac strength. PMID- 28348283 TI - Multiple Exciton Generation in Colloidal Nanocrystals. AB - In a conventional solar cell, the energy of an absorbed photon in excess of the band gap is rapidly lost as heat, and this is one of the main reasons that the theoretical efficiency is limited to ~33%. However, an alternative process, multiple exciton generation (MEG), can occur in colloidal quantum dots. Here, some or all of the excess energy is instead used to promote one or more additional electrons to the conduction band, potentially increasing the photocurrent of a solar cell and thereby its output efficiency. This review will describe the development of this field over the decade since the first experimental demonstration of multiple exciton generation, including the controversies over experimental artefacts, comparison with similar effects in bulk materials, and the underlying mechanisms. We will also describe the current state-of-the-art and outline promising directions for further development. PMID- 28348285 TI - Enhanced Upconversion Luminescence in Yb3+/Tm3+-Codoped Fluoride Active Core/Active Shell/Inert Shell Nanoparticles through Directed Energy Migration. AB - The luminescence efficiency of lanthanide-doped upconversion nanoparticles is of particular importance for their embodiment in biophotonic and photonic applications. Here, we show that the upconversion luminescence of typically used NaYF4:Yb3+30%/Tm3+0.5% nanoparticles can be enhanced by ~240 times through a hierarchical active core/active shell/inert shell (NaYF4:Yb3+30%/Tm3+0.5%)/NaYbF4/NaYF4 design, which involves the use of directed energy migration in the second active shell layer. The resulting active core/active shell/inert shell nanoparticles are determined to be about 11 times brighter than that of well-investigated (NaYF4:Yb3+30%/Tm3+0.5%)/NaYF4 active core/inert shell nanoparticles when excited at ~980 nm. The strategy for enhanced upconversion in Yb3+/Tm3+-codoped NaYF4 nanoparticles through directed energy migration might have implications for other types of lanthanide-doped upconversion nanoparticles. PMID- 28348286 TI - One-Pot Solvothermal Synthesis of Highly Emissive, Sodium-Codoped, LaF3 and BaLaF5 Core-Shell Upconverting Nanocrystals. AB - We report a one-pot solvothermal synthesis of sub-10 nm, dominant ultraviolet (UV) emissive upconverting nanocrystals (UCNCs), based on sodium-codoped LaF3 and BaLaF5 (0.5%Tm; 20%Yb) and their corresponding core@shell derivatives. Elemental analysis shows a Na-codopant in these crystal systems of ~20% the total cation content; X-ray diffraction (XRD) data indicate a shift in unit cell dimensions consistent with these small codopant ions. Similarly, X-ray photoelectron spectroscopic (XPS) analysis reveals primarily substitution of Na+ for La3+ ions (97% of total Na+ codopant) in the crystal system, and interstitial Na+ (3% of detected Na+) and La3+ (3% of detected La3+) present in (Na)LaF3 and only direct substitution of Na+ for Ba2+ in Ba(Na)LaF5. In each case, XPS analysis of La 3d lines show a decrease in binding energy (0.08-0.25 eV) indicating a reduction in local crystal field symmetry surrounding rare earth (R.E.3+) ions, permitting otherwise disallowed R.E. UC transitions to be enhanced. Studies that examine the impact of laser excitation power upon luminescence intensity were conducted over 2.5-100 W/cm2 range to elucidate UC mechanisms that populate dominant UV emitting states. Low power saturation of Tm3+ 3F3 and 3H4 states was observed and noted as a key initial condition for effective population of the 1D2 and 1I6 UV emitting states, via Tm-Tm cross-relaxation. PMID- 28348287 TI - Numerical Modeling of Sub-Wavelength Anti-Reflective Structures for Solar Module Applications. AB - This paper reviews the current progress in mathematical modeling of anti reflective subwavelength structures. Methods covered include effective medium theory (EMT), finite-difference time-domain (FDTD), transfer matrix method (TMM), the Fourier modal method (FMM)/rigorous coupled-wave analysis (RCWA) and the finite element method (FEM). Time-based solutions to Maxwell's equations, such as FDTD, have the benefits of calculating reflectance for multiple wavelengths of light per simulation, but are computationally intensive. Space-discretized methods such as FDTD and FEM output field strength results over the whole geometry and are capable of modeling arbitrary shapes. Frequency-based solutions such as RCWA/FMM and FEM model one wavelength per simulation and are thus able to handle dispersion for regular geometries. Analytical approaches such as TMM are appropriate for very simple thin films. Initial disadvantages such as neglect of dispersion (FDTD), inaccuracy in TM polarization (RCWA), inability to model aperiodic gratings (RCWA), and inaccuracy with metallic materials (FDTD) have been overcome by most modern software. All rigorous numerical methods have accurately predicted the broadband reflection of ideal, graded-index anti reflective subwavelength structures; ideal structures are tapered nanostructures with periods smaller than the wavelengths of light of interest and lengths that are at least a large portion of the wavelengths considered. PMID- 28348290 TI - Percolation Diffusion into Self-Assembled Mesoporous Silica Microfibres. AB - Percolation diffusion into long (11.5 cm) self-assembled, ordered mesoporous microfibres is studied using optical transmission and laser ablation inductive coupled mass spectrometry (LA-ICP-MS). Optical transmission based diffusion studies reveal rapid penetration (<5 s, D > 80 MUm2?s-1) of Rhodamine B with very little percolation of larger molecules such as zinc tetraphenylporphyrin (ZnTPP) observed under similar loading conditions. The failure of ZnTPP to enter the microfibre was confirmed, in higher resolution, using LA-ICP-MS. In the latter case, LA-ICP-MS was used to determine the diffusion of zinc acetate dihydrate, D~3 * 10-4 nm2?s-1. The large differences between the molecules are accounted for by proposing ordered solvent and structure assisted accelerated diffusion of the Rhodamine B based on its hydrophilicity relative to the zinc compounds. The broader implications and applications for filtration, molecular sieves and a range of devices and uses are described. PMID- 28348288 TI - Recent Advance of Biological Molecular Imaging Based on Lanthanide-Doped Upconversion-Luminescent Nanomaterials. AB - Lanthanide-doped upconversion-luminescent nanoparticles (UCNPs), which can be excited by near-infrared (NIR) laser irradiation to emit multiplex light, have been proven to be very useful for in vitro and in vivo molecular imaging studies. In comparison with the conventionally used down-conversion fluorescence imaging strategies, the NIR light excited luminescence of UCNPs displays high photostability, low cytotoxicity, little background auto-fluorescence, which allows for deep tissue penetration, making them attractive as contrast agents for biomedical imaging applications. In this review, we will mainly focus on the latest development of a new type of lanthanide-doped UCNP material and its main applications for in vitro and in vivo molecular imaging and we will also discuss the challenges and future perspectives. PMID- 28348291 TI - Magnetite Nanoparticles Induce Genotoxicity in the Lungs of Mice via Inflammatory Response. AB - Nanomaterials are useful for their characteristic properties and are commonly used in various fields. Nanosized-magnetite (MGT) is widely utilized in medicinal and industrial fields, whereas their toxicological properties are not well documented. A safety assessment is thus urgently required for MGT, and genotoxicity is one of the most serious concerns. In the present study, we examined genotoxic effects of MGT using mice and revealed that DNA damage analyzed by a comet assay in the lungs of imprinting control region (ICR) mice intratracheally instilled with a single dose of 0.05 or 0.2 mg/animal of MGT was approximately two- to three-fold higher than that of vehicle-control animals. Furthermore, in gpt delta transgenic mice, gpt mutant frequency (MF) in the lungs of the group exposed to four consecutive doses of 0.2 mg MGT was significantly higher than in the control group. Mutation spectrum analysis showed that base substitutions were predominantly induced by MGT, among which G:C to A:T transition and G:C to T:A transversion were the most significant. To clarify the mechanism of mutation caused by MGT, we analyzed the formation of DNA adducts in the lungs of mice exposed to MGT. DNA was extracted from lungs of mice 3, 24, 72 and 168 h after intratracheal instillation of 0.2 mg/body of MGT, and digested enzymatically. 8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and lipid peroxide related DNA adducts were quantified by stable isotope dilution liquid chromatography-mass spectrometry (LC-MS/MS). Compared with vehicle control, these DNA adduct levels were significantly increased in the MGT-treated mice. In addition to oxidative stress- and inflammation related-DNA adduct formations, inflammatory cell infiltration and focal granulomatous formations were also observed in the lungs of MGT-treated mice. Based on these findings, it is suggested that inflammatory responses are probably involved in the genotoxicity induced by MGT in the lungs of mice. PMID- 28348292 TI - Mesoporous Silica Nanoparticles with Co-Condensed Gadolinium Chelates for Multimodal Imaging. AB - Several mesoporous silica nanoparticle (MSN) contrast agents have been synthesized using a co-condensation method to incorporate two different Gd3+ complexes at very high loadings (15.5-28.8 wt %). These MSN contrast agents, with an MCM-41 type pore structure, were characterized using a variety of methods including SEM and TEM, nitrogen adsorption measurements, thermogravimetric analysis (TGA), direct current plasma (DCP) spectroscopy, and powder X-ray diffraction (PXRD). The magnetic resonance (MR) relaxivities of these contrast agents were determined using a 3 T MR scanner. The r1 relaxivities of these nanoparticles range from 4.1 to 8.4 mM-1s-1 on a per Gd basis. Additionally, the MSN particles were functionalized with an organic fluorophore and cancer cell targeting peptide to allow for demonstration of both the optical and MR contrast enhancing capabilities in vitro. PMID- 28348293 TI - Accurate Size and Size-Distribution Determination of Polystyrene Latex Nanoparticles in Aqueous Medium Using Dynamic Light Scattering and Asymmetrical Flow Field Flow Fractionation with Multi-Angle Light Scattering. AB - Accurate determination of the intensity-average diameter of polystyrene latex (PS latex) by dynamic light scattering (DLS) was carried out through extrapolation of both the concentration of PS-latex and the observed scattering angle. Intensity average diameter and size distribution were reliably determined by asymmetric flow field flow fractionation (AFFFF) using multi-angle light scattering (MALS) with consideration of band broadening in AFFFF separation. The intensity-average diameter determined by DLS and AFFFF-MALS agreed well within the estimated uncertainties, although the size distribution of PS-latex determined by DLS was less reliable in comparison with that determined by AFFFF-MALS. PMID- 28348294 TI - Study of Alginate-Supported Ionic Liquid and Pd Catalysts. AB - New catalytic materials, based on palladium immobilized in ionic liquid supported on alginate, were elaborated. Alginate was associated with gelatin for the immobilization of ionic liquids (ILs) and the binding of palladium. These catalytic materials were designed in the form of highly porous monoliths (HPMs), in order to be used in a column reactor. The catalytic materials were tested for the hydrogenation of 4-nitroaniline (4-NA) in the presence of formic acid as hydrogen donor. The different parameters for the elaboration of the catalytic materials were studied and their impact analyzed in terms of microstructures, palladium sorption properties and catalytic performances. The characteristics of the biopolymer (proportion of beta-D-mannuronic acid (M) and alpha-L-guluronic acid (G) in the biopolymer defined by the M/G ratio), the concentration of the porogen agent, and the type of coagulating agent significantly influenced catalytic performances. The freezing temperature had a significant impact on structural properties, but hardly affected the catalytic rate. Cellulose fibers were incorporated as mechanical strengthener into the catalytic materials, and allowed to enhance mechanical properties and catalytic efficiency but required increasing the amount of hydrogen donor for catalysis. PMID- 28348295 TI - Synthesis and Size Dependent Reflectance Study of Water Soluble SnS Nanoparticles. AB - Near-monodispersed water soluble SnS nanoparticles in the diameter range of 3-6 nm are synthesized by a facile, solution based one-step approach using ethanolamine ligands. The optimal amount of triethanolamine is investigated. The effect of further heat treatment on the size of these SnS nanoparticles is discussed. Diffuse reflectance study of SnS nanoparticles agrees with predictions from quantum confinement model. PMID- 28348296 TI - Wettability of Y2O3: A Relative Analysis of Thermally Oxidized, Reactively Sputtered and Template Assisted Nanostructured Coatings. AB - The wettability of reactively sputtered Y2O3, thermally oxidized Y-Y2O3 and Cd CdO template assisted Y2O3 coatings has been studied. The wettability of as deposited Y2O3 coatings was determined by contact angle measurements. The water contact angles for reactively sputtered, thermally oxidized and template assisted Y2O3 nanostructured coatings were 99 degrees , 117 degrees and 155 degrees , respectively. The average surface roughness values of reactively sputtered, thermally oxidized and template assisted Y2O3 coatings were determined by using atomic force microscopy and the corresponding values were 3, 11 and 180 nm, respectively. The low contact angle of the sputter deposited Y2O3 and thermally oxidized Y-Y2O3 coatings is attributed to a densely packed nano-grain like microstructure without any void space, leading to low surface roughness. A water droplet on such surfaces is mostly in contact with a solid surface relative to a void space, leading to a hydrophobic surface (low contact angle). Surface roughness is a crucial factor for the fabrication of a superhydrophobic surface. For Y2O3 coatings, the surface roughness was improved by depositing a thin film of Y2O3 on the Cd-CdO template (average roughness = 178 nm), which resulted in a contact angle greater than 150 degrees . The work of adhesion of water was very high for the reactively sputtered Y2O3 (54 mJ/m2) and thermally oxidized Y-Y2O3 coatings (43 mJ/m2) compared to the Cd-CdO template assisted Y2O3 coating (7 mJ/m2). PMID- 28348297 TI - A New Method for Characterization of Natural Zeolites and Organic Nanostructure Using Atomic Force Microscopy. AB - In order to study and develop an economical solution to environmental pollution in water, a wide variety of materials have been investigated. Natural zeolites emerge from that research as the best in class of this category. Zeolites are natural materials which are relatively abundant and non biodegradable, economical and serve to perform processes of environmental remediation. This paper contains a full description of a new method to characterize the superficial properties of natural zeolites of exotic provenience (Caribbean Islets) with atomic force microscopy (AFM). AFM works with the simplicity of the optical microscope and the high resolution typical of a transmission electron microscope (TEM). If the sample is conductive, structural information of mesoporous material is obtained using scanning and transmission electron microscopy (SEM and TEM), otherwise the sample has to be processed through the grafitation technique, but this procedure induces errors of topography. Therefore, the existing AFM method, to observe zeolite powders, is made in a liquid cell-head scanner. This work confirms that it is possible to use an ambient air-head scanner to obtain a new kind of microtopography. Once optimized, this new method will allow investigation of organic micelles, a very soft nanostructure of cetyltriammonium bromide (CTAB), upon an inorganic surface such as natural zeolites. The data also demonstrated some correlation between SEM microphotographies and AFM 3D images. PMID- 28348299 TI - From Metal Thiobenzoates to Metal Sulfide Nanocrystals: An Experimental and Theoretical Investigation. AB - A simple preparation of metal sulfide nanoparticles via the decomposition of thiobenzoate precursors at room temperature is presented and discussed. Long chain alkylamines were found to mediate the breakdown of metal thiobenzoates, such as those containing Ag, Cu, In and Cd, to produce uniform Ag2S, Cu2-xS, In2S3 and CdS nanoparticles respectively. The long chain amines are assumed to play dual roles as the nucleophilic reagent and the capping agent. It was found that sizes of the nanoparticles can be controlled by changing the type of amine used, as well as the molar ratio between amine and the precursor. We performed DFT calculations on a proposed mechanism involving an initial nucleophilic addition of amine molecule onto the thiocarboxylates. The proposed reaction was also confirmed through the analysis of by-products via infrared spectroscopy. On the basis of this understanding, we propose to manipulate the stability of the precursors by coordination with suitable stabilizing groups, such that the reaction kinetics can be modified to generate different nanostructures of interest. PMID- 28348298 TI - Near-Infrared Fluorescent Nanoprobes for in Vivo Optical Imaging. AB - Near-infrared (NIR) fluorescent probes offer advantages of high photon penetration, reduced light scattering and minimal autofluorescence from living tissues, rendering them valuable for noninvasive mapping of molecular events, assessment of therapeutic efficacy, and monitoring of disease progression in animal models. This review provides an overview of the recent development of the design and optical property of the different classes of NIR fluorescent nanoprobes associated with in vivo imaging applications. PMID- 28348300 TI - Iron Oxide Nanocrystals for Magnetic Hyperthermia Applications. AB - Magnetic nanocrystals have been investigated extensively in the past several years for several potential applications, such as information technology, MRI contrast agents, and for drug conjugation and delivery. A specific property of interest in biomedicine is magnetic hyperthermia-an increase in temperature resulting from the thermal energy released by magnetic nanocrystals in an external alternating magnetic field. Iron oxide nanocrystals of various sizes and morphologies were synthesized and tested for specific losses (heating power) using frequencies of 111.1 kHz and 629.2 kHz, and corresponding magnetic field strengths of 9 and 25 mT. Polymorphous nanocrystals as well as spherical nanocrystals and nanowires in paramagnetic to ferromagnetic size range exhibited good heating power. A remarkable 30 degrees C temperature increase was observed in a nanowire sample at 111 kHz and magnetic field of 25 mT (19.6 kA/m), which is very close to the typical values of 100 kHz and 20 mT used in medical treatments. PMID- 28348301 TI - Al2O3 Nanoparticle Addition to Commercial Magnesium Alloys: Multiple Beneficial Effects. AB - The multiple beneficial effects of Al2O3 nanoparticle addition to cast magnesium based systems (followed by extrusion) were investigated, constituting either: (a) enhanced strength; or (b) simultaneously enhanced strength and ductility of the corresponding magnesium alloys. AZ31 and ZK60A nanocomposites containing Al2O3 nanoparticle reinforcement were each fabricated using solidification processing followed by hot extrusion. Compared to monolithic AZ31 (tension levels), the corresponding nanocomposite exhibited higher yield strength (0.2% tensile yield strength (TYS)), ultimate strength (UTS), failure strain and work of fracture (WOF) (+19%, +21%, +113% and +162%, respectively). Compared to monolithic AZ31 (compression levels), the corresponding nanocomposite exhibited higher yield strength (0.2% compressive yield strength (CYS)) and ultimate strength (UCS), lower failure strain and higher WOF (+5%, +5%, -4% and +11%, respectively). Compared to monolithic ZK60A (tension levels), the corresponding nanocomposite exhibited lower 0.2% TYS and higher UTS, failure strain and WOF (-4%, +13%, +170% and +200%, respectively). Compared to monolithic ZK60A (compression levels), the corresponding nanocomposite exhibited lower 0.2% CYS and higher UCS, failure strain and WOF (-10%, +7%, +15% and +26%, respectively). The capability of Al2O3 nanoparticles to enhance the properties of cast magnesium alloys in a way never seen before with micron length scale reinforcements is clearly demonstrated. PMID- 28348302 TI - Porous Copolymer Resins: Tuning Pore Structure and Surface Area with Non Reactive Porogens. AB - In this review, the preparation of porous copolymer resin (PCR) materials via suspension polymerization with variable properties are described by tuning the polymerization reaction, using solvents which act as porogens, to yield microporous, mesoporous, and macroporous materials. The porogenic properties of solvents are related to traditional solubility parameters which yield significant changes in the surface area, porosity, pore volume, and morphology of the polymeric materials. The mutual solubility characteristics of the solvents, monomer units, and the polymeric resins contribute to the formation of porous materials with tunable pore structures and surface areas. The importance of the initiator solubility, surface effects, the temporal variation of solvent composition during polymerization, and temperature effects contribute to the variable physicochemical properties of the PCR materials. An improved understanding of the factors governing the mechanism of formation for PCR materials will contribute to the development and design of versatile materials with tunable properties for a wide range of technical applications. PMID- 28348303 TI - Amino Acid and Peptide Immobilization on Oxidized Nanocellulose: Spectroscopic Characterization. AB - In this work, oxidized nanocellulose (ONC) was synthesized and chemically coupled with amino acids and peptides using a two step coupling method at room temperature. First, ONC was activated by N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide hydrochloride, forming a stable active ester in the presence of N hydroxysuccinimide. Second, the active ester was reacted with the amino group of the amino acid or peptide, forming an amide bond between ONC and the grafted molecule. Using this method, the intermolecular interaction of amino acids and peptides was avoided and uniform coupling of these molecules on ONC was achieved. The coupling reaction was very fast in mild conditions and without alteration of the polysaccharide. The coupling products (ONC-amino acids and ONC-peptides) were characterized by transmission electron microscopy and by the absorption, emission, Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) spectroscopic techniques. PMID- 28348304 TI - Preparation and Characteristics of SiOx Coated Carbon Nanotubes with High Surface Area. AB - An easy method to synthesize SiOx coated carbon nanotubes (SiOx-CNT) through thermal decomposition of polycarbomethylsilane adsorbed on the surface of CNTs is reported. Physical properties of SiOx-CNT samples depending on various Si contents and synthesis conditions are examined by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), nitrogen isotherm, scanning electron microscope (SEM), and transmission electron microscope (TEM). Morphology of the SiOx-CNT appears to be perfectly identical to that of the pristine CNT. It is confirmed that SiOx is formed in a thin layer of approximately 1 nm thickness over the surface of CNTs. The specific surface area is significantly increased by the coating, because thin layer of SiOx is highly porous. The surface properties such as porosity and thickness of SiOx layers are found to be controlled by SiOx contents and heat treatment conditions. The preparation method in this study is to provide useful nano-hybrid composite materials with multi-functional surface properties. PMID- 28348306 TI - Effects of Varied Cleaning Methods on Ni-5% W Substrate for Dip-Coating of Water based Buffer Layers: An X-ray Photoelectron Spectroscopy Study. AB - This work describes various combinations of cleaning methods involved in the preparation of Ni-5% W substrates for the deposition of buffer layers using water based solvents. The substrate has been studied for its surface properties using X ray photoelectron spectroscopy (XPS). The contaminants in the substrates have been quantified and the appropriate cleaning method was chosen in terms of contaminants level and showing good surface crystallinity to further consider them for depositing chemical solution-based buffer layers for Y1Ba2Cu3Oy (YBCO) coated conductors. PMID- 28348307 TI - All-Solid-State Textile Batteries Made from Nano-Emulsion Conducting Polymer Inks for Wearable Electronics. AB - A rollable and all-solid-state textile lithium battery based on fabric matrix and polymer electrolyte that allows flexibility and fast-charging capability is reported. When immerged into poly(3,4-ethylenedioxythiophene) (PEDOT) nano emulsion inks, an insulating fabric is converted into a conductive battery electrode for a fully solid state lithium battery with the highest specific energy capacity of 68 mAh/g. This is superior to most of the solid-state conducting polymer primary and/or secondary batteries reported. The bending radius of such a textile battery is less than 1.5 mm while lightening up an LED. This new material combination and inherent flexibility is well suited to provide an energy source for future wearable and woven electronics. PMID- 28348309 TI - Influence of High Shear Dispersion on the Production of Cellulose Nanofibers by Ultrasound-Assisted TEMPO-Oxidation of Kraft Pulp. AB - Cellulose nanofibers can be produced using a combination of TEMPO, sodium bromide (NaBr) and sodium hypochlorite, and mechanical dispersion. Recently, this process has been the subject of intensive investigation. However, studies on the aspects of mechanical treatment of this process remain marginal. The main objective of this study is to evaluate the high shear dispersion parameters (e.g., consistency, stator-rotor gap, recirculation rate and pH) and determine their influences on nanocellulose production using ultrasound-assisted TEMPO-oxidation of Kraft pulp. All nanofiber gels produced in this study exhibited rheological behaviors known as shear thinning. From all the dispersion parameters, the following conditions were identified as optimal: 0.042 mm stator-rotor gap, 200 mL/min recycle rate, dispersion pH of 7 and a feed consistency of 2%. High quality cellulose gel could be produced under these conditions. This finding is surely of great interest for the pulp and paper industry. PMID- 28348308 TI - Assembly of DNA Architectures in a Non-Aqueous Solution. AB - In the present work, the procedures for the creation of self-assembled DNA nanostructures in aqueous and non-aqueous media are described. DNA-Surfactant complex formation renders the DNA soluble in organic solvents offering an exciting way to bridge the transition of DNA origami materials electronics applications. The DNA retains its structural features, and these unique geometries provide an interesting candidate for future electronics and nanofabrication applications with potential for new properties. The DNA architectures were first assembled under aqueous conditions, and then characterized in solution (using circular dichroism (CD) spectroscopy) and on the surface (using atomic force microscopy (AFM)). Following aqueous assembly, the DNA nanostructures were transitioned to a non-aqueous environment, where butanol was chosen for optical compatibility and thermal properties. The retention of DNA hierarchical structure and thermal stability in non-aqueous conditions were confirmed via CD spectroscopy. The formation and characterization of these higher order DNA-surfactant complexes is described in this paper. PMID- 28348310 TI - Aqueous Chemical Solution Deposition of Novel, Thick and Dense Lattice-Matched Single Buffer Layers Suitable for YBCO Coated Conductors: Preparation and Characterization. AB - In this work we present the preparation and characterization of cerium doped lanthanum zirconate (LCZO) films and non-stoichiometric lanthanum zirconate (LZO) buffer layers on metallic Ni-5% W substrates using chemical solution deposition (CSD), starting from aqueous precursor solutions. La2Zr2O7 films doped with varying percentages of Ce at constant La concentration (La0.5CexZr1-xOy) were prepared as well as non-stoichiometric La0.5+xZr0.5-xOy buffer layers with different percentages of La and Zr ratios. The variation in the composition of these thin films enables the creation of novel buffer layers with tailored lattice parameters. This leads to different lattice mismatches with the YBa2Cu3O7 x (YBCO) superconducting layer on top and with the buffer layers or substrate underneath. This possibility of minimized lattice mismatch should allow the use of one single buffer layer instead of the current complicated buffer architectures such as Ni-(5% W)/LZO/LZO/CeO2. Here, single, crack-free LCZO and non-stoichiometric LZO layers with thicknesses of up to 140 nm could be obtained in one single CSD step. The crystallinity and microstructure of these layers were studied by XRD, and SEM and the effective buffer layer action was studied using XPS depth profiling. PMID- 28348305 TI - Rafts, Nanoparticles and Neural Disease. AB - This review examines the role of membrane rafts in neural disease as a rationale for drug targeting utilizing lipid-based nanoparticles. The article begins with an overview of methodological issues involving the existence, sizes, and lifetimes of rafts, and then examines raft function in the etiologies of three major neural diseases-epilepsy, Parkinson's disease, and Alzheimer's disease selected as promising candidates for raft-based therapeutics. Raft-targeting drug delivery systems involving liposomes and solid lipid nanoparticles are then examined in detail. PMID- 28348311 TI - Simultaneous Patterning of Independent Metal/Metal Oxide Multi-Layer Films Using Two-Tone Photo-Acid Generating Compound Systems. AB - (1) The photo-induced solubility and positive-tone direct photo-patterning of iron, copper and lanthanides chelated with 4-(2-nitrobenzyloxycarbonyl)catechol (NBOC) or 4-(6-nitroveratryloxycarbonyl)catechol (NVOC) was investigated. Photo patterning of iron, copper, cerium, samarium, europium, terbium, dysprosium, holmium, erbium and lutetium complexes was accomplished. Continuous films were formed by the pyrolysis of metal complex films at 500 °C. (2) Based on the difference in the photo-reaction excitation wavelength profile of NBOC and NVOC complexes, a short and simple method for simultaneous micro-patterning of two independent films on each side of a transparent glass substrate was developed. Using the developed procedure, indium tin oxide and/or titanium oxide films were formed on each side of a quartz substrate without use of resist or etching. PMID- 28348312 TI - Improved Dispersion of Carbon Nanotubes in Polymers at High Concentrations. AB - The polymer nanocomposite used in this work comprises elastomer poly(dimethylsiloxane) (PDMS) as a polymer matrix and multi-walled carbon nanotubes (MWCNTs) as a conductive nanofiller. To achieve uniform distribution of carbon nanotubes within the polymer, an optimized dispersion process was developed, featuring a strong organic solvent-chloroform, which dissolved PDMS base polymer easily and allowed high quality dispersion of MWCNTs. At concentrations as high as 9 wt.%, MWCNTs were dispersed uniformly through the polymer matrix, which presented a major improvement over prior techniques. The dispersion procedure was optimized via extended experimentation, which is discussed in detail. PMID- 28348314 TI - Evaluation of the Mechanism of the Gold Cluster Growth during Heating of the Composite Gold-Polytetrafluoroethylene Thin Film. AB - Nanocomposite films consisting of gold inclusions in the polytetrafluoroethylene (PTFE) matrix were obtained by thermal vacuum deposition. Annealing of the obtained films with different temperatures was used to measure varying of film morphologies. The dependence of optical properties of the films on their morphology was studied. It was established that absorption and profile of the nanocomposite film obtained by thermal vacuum deposition can be changed with annealing owing to the fact that different annealing temperatures lead to different average particle sizes. A method to calculate the optical properties of nanocomposite thin films with inclusions of different sizes was proposed. Thus, comparison of experimental optical spectra with the spectra obtained during the simulation enables estimating average sizes of inclusions. The calculations give the possibility of understanding morphological changes in the structures. PMID- 28348313 TI - Characterization of Hybrid Epoxy Nanocomposites. AB - This study focused on the effect of Multi Wall Carbon Nanotubes (MWCNT) content and its surface treatment on thermo-mechanical properties of epoxy nanocomposites. MWCNTs were surface treated and incorporated into two epoxy systems. MWCNT's surface treatments were based on: (a) Titania coating obtained by sol-gel process and (b) a nonionic surfactant. Thermo-mechanical properties improvement was obtained following incorporation of treated MWCNT. It was noticed that small amounts of titania coated MWCNT (0.05 wt %) led to an increase in the glass transition temperature and stiffness. The best performance was achieved adding 0.3 wt % titania coated MWCNT where an increase of 10 degrees C in the glass transition temperature and 30% in storage modulus were obtained. PMID- 28348315 TI - Recent Advances in Nanostructured Thermoelectric Half-Heusler Compounds. AB - Half-Heusler (HH) alloys have attracted considerable interest as promising thermoelectric (TE) materials in the temperature range around 700 K and above, which is close to the temperature range of most industrial waste heat sources. The past few years have seen nanostructuing play an important role in significantly enhancing the TE performance of several HH alloys. In this article, we briefly review the recent progress and advances in these HH nanocomposites. We begin by presenting the structure of HH alloys and the different strategies that have been utilized for improving the TE properties of HH alloys. Next, we review the details of HH nanocomposites as obtained by different techniques. Finally, the review closes by highlighting several promising strategies for further research directions in these very promising TE materials. PMID- 28348316 TI - Maghemite Intercalated Montmorillonite as New Nanofillers for Photopolymers. AB - In this work, maghemite intercalated montmorillonite (gammaFe2O3-MMT)/polymer nanocomposites loaded with 1 or 2 wt.% of nanofillers were obtained by photopolymerization of difunctional acrylate monomers. The gammaFe2O3-MMT nanofillers were prepared by a new method based on the in situ formation of maghemite in the interlayer space of Fe-MMT using a three step process. X-ray diffraction (XRD), chemical analysis, TG/DTA and transmission electron microscopy (TEM) characterization of these nanofillers indicated the efficiency of the synthesis. When following the kinetics of the photopolymerization of diacrylate gammaFe2O3-MMT nanocomposites using FTIR spectroscopy no significant inhibition effect of the nanofillers was observed at a loading up to 2 wt.%. These innovative nanocomposites exhibit improved mechanical properties compared to the crude polymer. PMID- 28348317 TI - Spontaneous Deposition of Prussian Blue on Multi-Walled Carbon Nanotubes and the Application in an Amperometric Biosensor. AB - A simple method has been developed for the spontaneous deposition of Prussian blue (PB) particles from a solution containing only ferricyanide ions onto conducting substrates such as indium tin oxide glass, glassy carbon disk and carbon nanotube (CNT) materials. Formation of PB deposits was confirmed by ultraviolet-visible absorption spectrometry and electrochemical techniques. The surface morphology of the PB particles deposited on the substrates was examined by atomic force microscopy and scanning electron microscopy. CNT/PB composite modified glassy carbon electrodes exhibited an electrocatalytic property for hydrogen peroxide reduction. These modified electrodes exhibited a high sensitivity for electrocatalytic reduction of hydrogen peroxide at -0.05 V (vs. Ag|AgCl), probably due to the synergistic effect of CNT with PB. Then, CNT/PB modified electrodes were further developed as amperometric glucose biosensors. These biosensors offered a linear response to glucose concentration from 0.1 to 0.9 mM with good selectivity, high sensitivity of 0.102 A M-1 cm-2 and short response time (within 2 s) at a negative operation potential of -0.05 V (vs. Ag|AgCl). The detection limit was estimated to be 0.01 mM at a signal-to-noise ratio of 3. PMID- 28348318 TI - Polyhedral Oligomeric Silsesquioxane (POSS)-Containing Polymer Nanocomposites. AB - Hybrid materials with superior structural and functional properties can be obtained by incorporating nanofillers into polymer matrices. Polyhedral oligomeric silsesquioxane (POSS) nanoparticles have attracted much attention recently due to their nanometer size, the ease of which these particles can be incorporated into polymeric materials and the unique capability to reinforce polymers. We review here the state of POSS-containing polymer nanocomposites. We discuss the influence of the incorporation of POSS into polymer matrices via chemical cross-linking or physical blending on the structure of nanocomposites, as affected by surface functional groups, and the POSS concentration. PMID- 28348319 TI - Empirical Equation Based Chirality (n, m) Assignment of Semiconducting Single Wall Carbon Nanotubes from Resonant Raman Scattering Data. AB - This work presents a technique for the chirality (n, m) assignment of semiconducting single wall carbon nanotubes by solving a set of empirical equations of the tight binding model parameters. The empirical equations of the nearest neighbor hopping parameters, relating the term (2n, m) with the first and second optical transition energies of the semiconducting single wall carbon nanotubes, are also proposed. They provide almost the same level of accuracy for lower and higher diameter nanotubes. An algorithm is presented to determine the chiral index (n, m) of any unknown semiconducting tube by solving these empirical equations using values of radial breathing mode frequency and the first or second optical transition energy from resonant Raman spectroscopy. In this paper, the chirality of 55 semiconducting nanotubes is assigned using the first and second optical transition energies. Unlike the existing methods of chirality assignment, this technique does not require graphical comparison or pattern recognition between existing experimental and theoretical Kataura plot. PMID- 28348321 TI - Hydrothermal Synthesis and Characterization of Ni-Al Montmorillonite-Like Phyllosilicates. AB - This work describes the first hydrothermal synthesis in fluoride medium of Ni-Al montmorillonite-like phyllosilicates, in which the only metallic elements in the octahedral sheet are Ni and Al. X-ray diffraction, chemical analysis, thermogravimetric and differential thermal analysis, scanning electron microscopy and transmission electron microscopy confirm that the synthesized samples are montmorillonite-like phyllosilicates having the expected chemical composition. The specific surface areas of the samples are relatively large (>100 m2 g-1) compared to naturally occurring montmorillonites. 29Si and 27Al nuclear magnetic resonance (NMR) indicate substitutions of Al for Si in the tetrahedral sheet. 19F NMR and Ni K-edge extended X-ray absorption fine structure (EXAFS) local probes highlight a clustering of the metal elements and of the vacancies in the octahedral sheet of the samples. These Ni-Al phyllosilicates exhibit a higher local order than in previously synthesized Zn-Al phyllosilicates. Unlike natural montmorillonites, where the distribution of transition metal cations ensures a charge equilibrium allowing a stability of the framework, synthetic montmorillonites entail clustering and instability of the lattice when the content of divalent element in the octahedral sheet exceeds ca. 20%. Synthesis of Ni-Al montmorillonite-like phyllosilicates, was successfully achieved for the first time. These new synthetic materials may find potential applications as catalysts or as materials with magnetic, optical or staining properties. PMID- 28348320 TI - Harnessing Sun's Energy with Quantum Dots Based Next Generation Solar Cell. AB - Our energy consumption relies heavily on the three components of fossil fuels (oil, natural gas and coal) and nearly 83% of our current energy is consumed from those sources. The use of fossil fuels, however, has been viewed as a major environmental threat because of their substantial contribution to greenhouse gases which are responsible for increasing the global average temperature. Last four decades, scientists have been searching for alternative sources of energy which need to be environmentally clean, efficient, cost-effective, renewable, and sustainable. One of the promising sustainable sources of energy can be achieved by harnessing sun energy through silicon wafer, organic polymer, inorganic dye, and quantum dots based solar cells. Among them, quantum dots have an exceptional property in that they can excite multiple electrons using only one photon. These dots can easily be synthesized, processed in solution, and incorporated into solar cell application. Interestingly, the quantum dots solar cells can exceed the Shockley-Queisser limit; however, it is a great challenge for other solar cell materials to exceed the limit. Theoretically, the quantum dots solar cell can boost the power conversion efficiency up to 66% and even higher to 80%. Moreover, in changing the size of the quantum dots one can utilize the Sun's broad spectrum of visible and infrared ranges. This review briefly overviews the present performance of different materials-based solar cells including silicon wafer, dye-sensitized, and organic solar cells. In addition, recent advances of the quantum dots based solar cells which utilize cadmium sulfide/selenide, lead sulfide/selenide, and new carbon dots as light harvesting materials has been reviewed. A future outlook is sketched as to how one could improve the efficiency up to 10% from the current highest efficiency of 6.6%. PMID- 28348322 TI - Influence of the Sonication Temperature on the Debundling Kinetics of Carbon Nanotubes in Propan-2-ol. AB - The effect of sonication temperature on the debundling of carbon nanotube (CNT) macro-bundles is reported and demonstrated by analysis with different particle sizing methods. The change of bundle size over time and after several comparatively gentle sonication cycles of suspensions at various temperatures is reported. A novel technique is presented that produces a more homogeneous nanotube dispersion by lowering the temperature during sonication. We produce evidence that temperature influences the suspension stability, and that low temperatures are preferable to obtain better dispersion without increasing damage to the CNT walls. PMID- 28348324 TI - Assembl y of Poly-3-Hexylthiophene Nano-Crystallites into Low Dimensional Structures Using Indandione Derivatives. AB - Conductive polymer poly-3-hexylthiophene (P3HT) needles were self-assembled using a second component (indandione derivatives) as a linking agent to enhance their long range alignment. The morphologies of the hybrid organic/organic materials were characterized by transmission electron microscopy (TEM). Both linear and branched structures could be produced, with the degree of branching depending upon the linker used. Incorporation of indandione derivatives broadened the UV absorbance band of P3HT without significant change to its photoluminescence. This hybrid material could open a promising avenue in photovoltaic applications due to its interesting morphologies and optical properties. PMID- 28348323 TI - Investigation of Sub-100 nm Gold Nanoparticles for Laser-Induced Thermotherapy of Cancer. AB - Specialized gold nanostructures are of interest for the development of alternative treatment methods in medicine. Photothermal therapy combined with gene therapy that supports hyperthermia is proposed as a novel multimodal treatment method for prostate cancer. In this work, photothermal therapy using small (<100 nm) gold nanoparticles and near-infrared (NIR) laser irradiation combined with gene therapy targeting heat shock protein (HSP) 27 was investigated. A series of nanoparticles: nanoshells, nanorods, core-corona nanoparticles and hollow nanoshells, were synthesized and examined to compare their properties and suitability as photothermal agents. In vitro cellular uptake studies of the nanoparticles into prostate cancer cell lines were performed using light scattering microscopy to provide three-dimensional (3D) imaging. Small gold nanoshells (40 nm) displayed the greatest cellular uptake of the nanoparticles studied and were used in photothermal studies. Photothermal treatment of the cancer cell lines with laser irradiation at 800 nm at 4 W on a spot size of 4 mm (FWHM) for 6 or 10 min resulted in an increase in temperature of ~12 degrees C and decrease in cell viability of up to 70%. However, in vitro studies combining photothermal therapy with gene therapy targeting HSP27 did not result in additional sensitization of the prostate cancer cells to hyperthermia. PMID- 28348325 TI - A Novel Fluoride Route for the Synthesis of Aluminosilicate Nanotubes. AB - In this work we present a novel method for synthesis of aluminosilicate nanotubes: the fluoride route. F-containing imogolite (F-IMO) exhibits an improved crystallization rate and improved yield. The structure of F-IMO was investigated and compared with F-free imogolite (IMO) by means of X-ray diffraction (XRD) and Fourier transformed infrared spectroscopy (FTIR) confirming imogolite structure. Solid state nuclear magnetic resonance (NMR) analyses show an increased crystallization rate for F-IMO and confirm the incorporation of fluorine ion in the structure. PMID- 28348326 TI - Kinetic and Surface Study of Single-Walled Aluminosilicate Nanotubes and Their Precursors. AB - The structural and surface changes undergone by the different precursors that are produced during the synthesis of imogolite are reported. The surface changes that occur during the synthesis of imogolite were determined by electrophoretic migration (EM) measurements, which enabled the identification of the time at which the critical precursor of the nanoparticles was generated. A critical parameter for understanding the evolution of these precursors is the isoelectric point (IEP), of which variation revealed that the precursors modify the number of active =Al-OH and =Si-OH sites during the formation of imogolite. We also found that the IEP is displaced to a higher pH level as a consequence of the surface differentiation that occurs during the synthesis. At the same time, we established that the pH of the reaction (pHrx) decreases with the evolution and condensation of the precursors during aging. Integration of all of the obtained results related to the structural and surface properties allows an overall understanding of the different processes that occur and the products that are formed during the synthesis of imogolite. PMID- 28348327 TI - Grafting of Polycaprolactone on Oxidized Nanocelluloses by Click Chemistry. AB - The main objective of this work is the grafting of polycaprolactone diol (PCL) on the surface of oxidized nanocelluloses (ONC) in order to enhance the compatibility between the hydrophilic cellulose nanofibres and the hydrophobic polymer matrix. This grafting was successfully realized with a new strategy known as click chemistry. In this context, the oxidized nanocelluloses bearing alkyl groups (ONC-PR) were prepared by reacting amino groups of propargylamine (PR) with carboxyl groups of ONC. In parallel, PCL was converted into azido polycaprolactone (PCL-N3) in two steps: (i) tosylation of polycaprolactone (PCL OTs) and (ii) conversion of PCL-OTs into PCL-N3 by nucleophilic displacement using sodium azide. Finally, ONC-PR was reacted with PCL-N3 in heterogeneous conditions through click chemistry in order to prepare polycaprolactone grafted oxidized nanocellulose (ONC-g-PCL), which could be suitable for improving the interfacial adhesion in the composite materials. The grafted samples were characterized by transmission electron microscopy and by Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS) and Carbon 13 nuclear magnetic resonance spectroscopy (13C-NMR) spectroscopic techniques. PMID- 28348328 TI - Surface Enhanced Raman Scattering (SERS) Studies of Gold and Silver Nanoparticles Prepared by Laser Ablation. AB - Gold and silver nanoparticles (NPs) were prepared in water, acetonitrile and isopropanol by laser ablation methodologies. The average characteristic (longer) size of the NPs obtained ranged from 3 to 70 nm. 4-Aminobenzebethiol (4-ABT) was chosen as the surface enhanced Raman scattering (SERS) probe molecule to determine the optimum irradiation time and the pH of aqueous synthesis of the laser ablation-based synthesis of metallic NPs. The synthesized NPs were used to evaluate their capacity as substrates for developing more analytical applications based on SERS measurements. A highly energetic material, TNT, was used as the target compound in the SERS experiments. The Raman spectra were measured with a Raman microspectrometer. The results demonstrate that gold and silver NP substrates fabricated by the methods developed show promising results for SERS based studies and could lead to the development of micro sensors. PMID- 28348329 TI - Liquid-State and Solid-State Properties of Nanotube/Polypropylene Nanocomposites Elaborated via a Simple Procedure. AB - Non-modified Multiwalled Carbon Nanotubes (MWCNT) and polypropylene (PP) in absence of compatibilizer have been chosen to elaborate MWCNT/PP nanocomposites using a simple melt-mixing dispersing method. Calorimetry results indicate little effect of MWCNTs on crystallinity of PP, revealing not much interaction between nanotubes and PP chains, which is compatible with the employed manufacturing procedure. In any case, a hindering of polymer chains motion by MWCNTs is observed in the molten state, using oscillatory flow experiments, and a rheological percolation threshold is determined. The percolation limit is not noticed by Pressure-Volume-Temperature (PVT) measurements in the melt, because this technique rather detects local motions. Keeping the nanocomposites in the molten state provokes an electrical conductivity increase of several orders of magnitude, but on ulterior crystallization, the conductivity decreases, probably due to a reduction of the ionic conductivity. For a concentration of 2% MWCNTs, in the limit of percolation, the conductivity decreases considerably more, because percolation network constituted in the molten state is unstable and is destroyed during crystallization. PMID- 28348330 TI - Controlling the Nanoscale Patterning of AuNPs on Silicon Surfaces. AB - This study evaluates the effectiveness of vapour-phase deposition for creating sub-monolayer coverage of aminopropyl triethoxysilane (APTES) on silicon in order to exert control over subsequent gold nanoparticle deposition. Surface coverage was evaluated indirectly by observing the extent to which gold nanoparticles (AuNPs) deposited onto the modified silicon surface. By varying the distance of the silicon wafer from the APTES source and concentration of APTES in the evaporating media, control over subsequent gold nanoparticle deposition was achievable to an extent. Fine control over AuNP deposition (AuNPs/MUm2) however, was best achieved by adjusting the ionic concentration of the AuNP-depositing solution. Furthermore it was demonstrated that although APTES was fully removed from the silicon surface following four hours incubation in water, the gold nanoparticle-amino surface complex was stable under the same conditions. Atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS) were used to study these affects. PMID- 28348331 TI - Effects of Microstructure on Electrode Properties of Nanosheet-Derived Hx(Ni1/3Co1/3Mn1/3)O2 for Electrochemical Capacitors. AB - Nanosheet-derived Hx(Ni1/3Co1/3Mn1/3)O2 was prepared by restacking (Ni1/3Co1/3Mn1/3)O2 nanosheets with large or small lateral sizes and their electrochemical properties in a 1 M KOH aqueous solution; microstructural factors were compared with those of bulk Hx(Ni1/3Co1/3Mn1/3)O2 (HNCM). The electrodes composed of small nanosheets exhibited very large capacitances of 1241 F.g-1 (395 mAh.g-1) at a current density of 50 mA.g-1, and 430 F.g-1 (100 mAh.g-1) at a large current density of 1000 mA.g-1. These large capacitances resulted from a heterogeneous layer structure with a large surface area and pore volume. The electrodes of large nanosheets, with a strongly interconnected microstructure and a surface area slightly larger than that of HNCM, exhibited good cycle stability and capacitances larger than that of HNCM. Microstructural control through the restacking of (Ni1/3Co1/3Mn1/3)O2 nanosheets improved the electrochemical properties of Hx(Ni, Co, Mn)O2. PMID- 28348332 TI - Separation of Short Single- and Double-Stranded DNA Based on Their Adsorption Kinetics Difference on Graphene Oxide. AB - Separation of short single- and double-stranded DNA typically requires gel electrophoresis followed by DNA extraction, which is a time consuming process. Graphene oxide adsorbs single-stranded DNA more quickly than double-stranded ones, allowing for selective removal of the former with a simple mixing and centrifugation operation. The effect of DNA length and salt on adsorption selectivity has been characterized and its application in DNA melting curve measurement has been demonstrated. PMID- 28348333 TI - A Thermal Model for Carbon Nanotube Interconnects. AB - In this work, we have studied Joule heating in carbon nanotube based very large scale integration (VLSI) interconnects and incorporated Joule heating influenced scattering in our previously developed current transport model. The theoretical model explains breakdown in carbon nanotube resistance which limits the current density. We have also studied scattering parameters of carbon nanotube (CNT) interconnects and compared with the earlier work. For 1 um length single-wall carbon nanotube, 3 dB frequency in S12 parameter reduces to ~120 GHz from 1 THz considering Joule heating. It has been found that bias voltage has little effect on scattering parameters, while length has very strong effect on scattering parameters. PMID- 28348335 TI - Electrophoretic Deposition of Carbon Nanotubes on 3-Amino-Propyl-Triethoxysilane (APTES) Surface Functionalized Silicon Substrates. AB - Fabrication of uniform thin coatings of multi-walled carbon nanotubes (MWCNTs) by electrophoretic deposition (EPD) on semiconductor (silicon) substrates with 3 aminopropyl-triethoxysilane (APTES) surface functionalization has been studied extensively in this report. The gradual deposition and eventual film formation of the carbon nanotubes (CNTs) is greatly assisted by the Coulombic force of attraction existing between the positively charged -NH2 surface groups of APTES and the acid treated, negatively charged nanotubes migrating towards the deposition surfaces. The remarkable deposition characteristics of the CNT coatings by EPD in comparison to the dip coating method and the influence of isopropyl (IPA)-based CNT suspension in the fabricated film quality has also been revealed in this study. The effect of varying APTES concentration (5%-100%) on the Raman spectroscopy and thickness of the deposited CNT film has been discussed in details, as well. The deposition approach has eliminated the need of metal deposition in the electrophoretic deposition approach and, therefore, establishes a cost-effective, fast and entirely room temperature-based fabrication strategy of CNT thin films for a wide range of next generation electronic applications. PMID- 28348334 TI - Nanostructured Biomaterials and Their Applications. AB - Some of the most important advances in the life sciences have come from transitioning to thinking of materials and their properties on the nanoscale rather than the macro or even microscale. Improvements in imaging technology have allowed us to see nanofeatures that directly impact chemical and mechanical properties of natural and man-made materials. Now that these can be imaged and quantified, substantial advances have been made in the fields of biomimetics, tissue engineering, and drug delivery. For the first time, scientists can determine the importance of nanograins and nanoasperities in nacre, direct the nucleation of apatite and the growth of cells on nanostructured scaffolds, and pass drugs tethered to nanoparticles through the blood-brain barrier. This review examines some of the most interesting materials whose nanostructure and hierarchical organization have been shown to correlate directly with favorable properties and their resulting applications. PMID- 28348336 TI - Desorption of 1,3,5-Trichlorobenzene from Multi-Walled Carbon Nanotubes: Impact of Solution Chemistry and Surface Chemistry. AB - The strong affinity of carbon nanotubes (CNTs) to environmental contaminants has raised serious concern that CNTs may function as a carrier of environmental pollutants and lead to contamination in places where the environmental pollutants are not expected. However, this concern will not be realized until the contaminants are desorbed from CNTs. It is well recognized that the desorption of environmental pollutants from pre-laden CNTs varies with the environmental conditions, such as the solution pH and ionic strength. However, comprehensive investigation on the influence of solution chemistry on the desorption process has not been carried out, even though numerous investigations have been conducted to investigate the impact of solution chemistry on the adsorption of environmental pollutants on CNTs. The main objective of this study was to determine the influence of solution chemistry (e.g., pH, ionic strength) and surface functionalization on the desorption of preloaded 1,3,5-trichlorobenzene (1,3,5-TCB) from multi-walled carbon nanotubes (MWNTs). The results suggested that higher pH, ionic strength and natural organic matter in solution generally led to higher desorption of 1,3,5-TCB from MWNTs. However, the extent of change varied at different values of the tested parameters (e.g., pH < 7 vs. pH > 7). In addition, the impact of these parameters varied with MWNTs possessing different surface functional groups, suggesting that surface functionalization could considerably alter the environmental behaviors and impact of MWNTs. PMID- 28348337 TI - Nano-Electrochemistry and Nano-Electrografting with an Original Combined AFM SECM. AB - This study demonstrates the advantages of the combination between atomic force microscopy and scanning electrochemical microscopy. The combined technique can perform nano-electrochemical measurements onto agarose surface and nano electrografting of non-conducting polymers onto conducting surfaces. This work was achieved by manufacturing an original Atomic Force Microscopy-Scanning ElectroChemical Microscopy (AFM-SECM) electrode. The capabilities of the AFM-SECM electrode were tested with the nano-electrografting of vinylic monomers initiated by aryl diazonium salts. Nano-electrochemical and technical processes were thoroughly described, so as to allow experiments reproducing. A plausible explanation of chemical and electrochemical mechanisms, leading to the nano grafting process, was reported. This combined technique represents the first step towards improved nano-processes for the nano-electrografting. PMID- 28348338 TI - A Strategy for Hydroxide Exclusion in Nanocrystalline Solid-State Metathesis Products. AB - We demonstrate a simple strategy to either prevent or enhance hydroxide incorporation in nanocrystalline solid-state metathesis reaction products prepared in ambient environments. As an example, we show that ZnCO3 (smithsonite) or Zn5(CO3)2(OH)6 (hydrozincite) forms extremely rapidly, in less than two minutes, to form crystalline domains of 11 +/- 2 nm and 6 +/- 2 nm, respectively. The phase selectivity between these nanocrystalline products is dominated by the alkalinity of the hydrated precursor salts, which may in turn affect the availability of carbon dioxide during the reaction. Thus, unlike traditional aqueous precipitation reactions, our solid-state method offers a way to produce hydroxide-free, nanocrystalline products without active pH control. PMID- 28348339 TI - Photoelectrochemical Properties of Graphene and Its Derivatives. AB - Graphene and its derivatives combine a numerous range of supreme properties that can be useful in many applications. The purpose of this review is to analyse the photoelectrochemical properties of pristine graphene, graphene oxide (GO) and reduced graphene oxide (rGO) and their impact on semiconductor catalysts/quantum dots. The mechanism that this group of materials follows to improve their performance will be cleared by explaining how those properties can be exploited in several applications such as photo-catalysts (degradation of pollutants) and photovoltaics (solar cells). PMID- 28348340 TI - CO and NO2 Selective Monitoring by ZnO-Based Sensors. AB - ZnO nanomaterials with different shapes were synthesized, characterized and tested in the selective monitoring of low concentration of CO and NO2 in air. ZnO nanoparticles (NPs) and nanofibers (NFs) were synthesized by a modified sol-gel method in supercritical conditions and electrospinning technique, respectively. CO and NO2 sensing tests have demonstrated that the annealing temperature and shape of zinc oxide nanomaterials are the key factors in modulating the electrical and sensing properties. Specifically, ZnO NPs annealed at high temperature (700 degrees C) have been found sensitive to CO, while they displayed negligible response to NO2. The opposite behavior has been registered for the one-dimensional ZnO NFs annealed at medium temperature (400 degrees C). Due to their adaptable sensitivity/selectivity characteristics, the developed sensors show promising applications in dual air quality control systems for closed ambient such as automotive cabin, parking garage and tunnels. PMID- 28348341 TI - Alkyl and Aromatic Amines as Digestive Ripening/Size Focusing Agents for Gold Nanoparticles. AB - Both long chain alkyl thiols and alkyl amines behave as size focusing agents for gold nanoparticles, a process that is under thermodynamic control. However, amines do not oxidize surface gold atoms while thiols do oxidize surface gold to gold(I) with evolution of hydrogen gas. Therefore, alkyl amines participate in digestive ripening by a different mechanism. The efficiency of alkyl amines for this process is described and compared, and ultimate gold particle size differences are discussed. Reported herein is a detailed investigation of alkyl chain lengths for alkyl amines, aromatic amines (aniline), and unusually reactive amines (2-phenylethyl amine). Also, two methods of preparation of the crude gold nanoparticles were employed: gold ion reduction/inverse micelle vs. metal vaporization (Solvated Metal Atom Dispersion-SMAD). PMID- 28348342 TI - Theory of Carbon Nanotube (CNT)-Based Electron Field Emitters. AB - Theoretical problems arising in connection with development and operation of electron field emitters on the basis of carbon nanotubes are reviewed. The physical aspects of electron field emission that underlie the unique emission properties of carbon nanotubes (CNTs) are considered. Physical effects and phenomena affecting the emission characteristics of CNT cathodes are analyzed. Effects given particular attention include: the electric field amplification near a CNT tip with taking into account the shape of the tip, the deviation from the vertical orientation of nanotubes and electrical field-induced alignment of those; electric field screening by neighboring nanotubes; statistical spread of the parameters of the individual CNTs comprising the cathode; the thermal effects resulting in degradation of nanotubes during emission. Simultaneous consideration of the above-listed effects permitted the development of the optimization procedure for CNT array in terms of the maximum reachable emission current density. In accordance with this procedure, the optimum inter-tube distance in the array depends on the region of the external voltage applied. The phenomenon of self-misalignment of nanotubes in an array has been predicted and analyzed in terms of the recent experiments performed. A mechanism of degradation of CNT based electron field emitters has been analyzed consisting of the bombardment of the emitters by ions formed as a result of electron impact ionization of the residual gas molecules. PMID- 28348343 TI - Synthesis of Microspherical LiFePO4-Carbon Composites for Lithium-Ion Batteries. AB - This paper reports an "all in one" procedure to produce mesoporous, micro spherical LiFePO4 composed of agglomerated crystalline nanoparticles. Each nanoparticle is individually coated with a thin glucose-derived carbon layer. The main advantage of the as-synthesized materials is their good performance at high charge-discharge rates. The nanoparticles and the mesoporosity guarantee a short bulk diffusion distance for both lithium ions and electrons, as well as additional active sites for the charge transfer reactions. At the same time, the thin interconnected carbon coating provides a conductive framework capable of delivering electrons to the nanostructured LiFePO4. PMID- 28348344 TI - Inkjet Printing of Carbon Nanotubes. AB - In an attempt to give a brief introduction to carbon nanotube inkjet printing, this review paper discusses the issues that come along with preparing and printing carbon nanotube ink. Carbon nanotube inkjet printing is relatively new, but it has great potential for broad applications in flexible and printable electronics, transparent electrodes, electronic sensors, and so on due to its low cost and the extraordinary properties of carbon nanotubes. In addition to the formulation of carbon nanotube ink and its printing technologies, recent progress and achievements of carbon nanotube inkjet printing are reviewed in detail with brief discussion on the future outlook of the technology. PMID- 28348345 TI - Nanostructure-Directed Chemical Sensing: The IHSAB Principle and the Effect of Nitrogen and Sulfur Functionalization on Metal Oxide Decorated Interface Response. AB - The response matrix, as metal oxide nanostructure decorated n-type semiconductor interfaces are modified in situ through direct amination and through treatment with organic sulfides and thiols, is demonstrated. Nanostructured TiO2, SnOx, NiO and CuxO (x = 1,2), in order of decreasing Lewis acidity, are deposited to a porous silicon interface to direct a dominant electron transduction process for reversible chemical sensing in the absence of significant chemical bond formation. The metal oxide sensing sites can be modified to decrease their Lewis acidity in a process appearing to substitute nitrogen or sulfur, providing a weak interaction to form the oxynitrides and oxysulfides. Treatment with triethylamine and diethyl sulfide decreases the Lewis acidity of the metal oxide sites. Treatment with acidic ethane thiol modifies the sensor response in an opposite sense, suggesting that there are thiol (SH) groups present on the surface that provide a Bronsted acidity to the surface. The in situ modification of the metal oxides deposited to the interface changes the reversible interaction with the analytes, NH3 and NO. The observed change for either the more basic oxynitrides or oxysulfides or the apparent Bronsted acid sites produced from the interaction of the thiols do not represent a simple increase in surface basicity or acidity, but appear to involve a change in molecular electronic structure, which is well explained using the recently developed inverse hard and soft acids and bases (IHSAB) model. PMID- 28348346 TI - Magnetism of Amorphous and Nano-Crystallized Dc-Sputter-Deposited MgO Thin Films. AB - We report a systematic study of room-temperature ferromagnetism (RTFM) in pristine MgO thin films in their amorphous and nano-crystalline states. The as deposited dc-sputtered films of pristine MgO on Si substrates using a metallic Mg target in an O2 containing working gas atmosphere of (N2 + O2) are found to be X ray amorphous. All these films obtained with oxygen partial pressure (PO2) ~10% to 80% while maintaining the same total pressure of the working gas are found to be ferromagnetic at room temperature. The room temperature saturation magnetization (MS) value of 2.68 emu/cm3 obtained for the MgO film deposited in PO2 of 10% increases to 9.62 emu/cm3 for film deposited at PO2 of 40%. However, the MS values decrease steadily for further increase of oxygen partial pressure during deposition. On thermal annealing at temperatures in the range 600 to 800 degrees C, the films become nanocrystalline and as the crystallite size grows with longer annealing times and higher temperature, MS decreases. Our study clearly points out that it is possible to tailor the magnetic properties of thin films of MgO. The room temperature ferromagnetism in MgO films is attributed to the presence of Mg cation vacancies. PMID- 28348349 TI - Influence of Nanoclay Dispersion Methods on the Mechanical Behavior of E Glass/Epoxy Nanocomposites. AB - Common dispersion methods such as ultrasonic sonication, planetary centrifugal mixing and magnetic dispersion have been used extensively to achieve moderate exfoliation of nanoparticles in polymer matrix. In this study, the effect of adding three roll milling to these three dispersion methods for nanoclay dispersion into epoxy matrix was investigated. A combination of each of these mixing methods with three roll milling showed varying results relative to the unmodified polymer laminate. A significant exfoliation of the nanoparticles in the polymer structure was obtained by dispersing the nanoclay combining three roll milling to magnetic and planetary centrifugal mixing methods. This exfoliation promoted a stronger interfacial bond between the matrix and the fiber, which increased the final properties of the E-glass/epoxy nanocomposite. However, a combination of ultrasound sonication and three roll milling on the other hand, resulted in poor clay exfoliation; the sonication process degraded the polymer network, which adversely affected the nanocomposite final properties relative to the unmodified E-glass/epoxy polymer. PMID- 28348347 TI - Conducting Polyaniline Nanowire and Its Applications in Chemiresistive Sensing. AB - One dimensional polyaniline nanowire is an electrically conducting polymer that can be used as an active layer for sensors whose conductivity change can be used to detect chemical or biological species. In this review, the basic properties of polyaniline nanowires including chemical structures, redox chemistry, and method of synthesis are discussed. A comprehensive literature survey on chemiresistive/conductometric sensors based on polyaniline nanowires is presented and recent developments in polyaniline nanowire-based sensors are summarized. Finally, the current limitations and the future prospect of polyaniline nanowires are discussed. PMID- 28348348 TI - Current Trends in Sensors Based on Conducting Polymer Nanomaterials. AB - Conducting polymers represent an important class of functional organic materials for next-generation electronic and optical devices. Advances in nanotechnology allow for the fabrication of various conducting polymer nanomaterials through synthesis methods such as solid-phase template synthesis, molecular template synthesis, and template-free synthesis. Nanostructured conducting polymers featuring high surface area, small dimensions, and unique physical properties have been widely used to build various sensor devices. Many remarkable examples have been reported over the past decade. The enhanced sensitivity of conducting polymer nanomaterials toward various chemical/biological species and external stimuli has made them ideal candidates for incorporation into the design of sensors. However, the selectivity and stability still leave room for improvement. PMID- 28348350 TI - Hydrothermal Synthesis of Nanoclusters of ZnS Comprised on Nanowires. AB - Cetyltrimethyl ammonium bromide cationic (CTAB) surfactant was used as template for the synthesis of nanoclusters of ZnS composed of nanowires, by hydrothermal method. The structural and morphological studies were performed by using X-ray diffraction (XRD), scanning electron microscopy (SEM) and high resolution transmission electron microscopy (HRTEM) techniques. The synthesized ZnS nanoclusters are composed of nanowires and high yield on the substrate was observed. The ZnS nanocrystalline consists of hexagonal phase and polycrystalline in nature. The chemical composition of ZnS nanoclusters composed of nanowires was studied by X-ray photo electron microscopy (XPS). This investigation has shown that the ZnS nanoclusters are composed of Zn and S atoms. PMID- 28348351 TI - Nanomaterials in Sensors. AB - This Special Issue of Nanomaterials is focused on the continuing implementation of nanomaterials and nanostructures in the development of more sensitive and more specific sensing devices. As a result, these new devices employ smaller sensing elements and provide more "real time" capability. Often, the inclusion of nanomaterials leads to sensing elements for targets that were previously inaccessible. [...]. PMID- 28348352 TI - Susceptibility of CoFeB/AlOx/Co Magnetic Tunnel Junctions to Low-Frequency Alternating Current. AB - This investigation studies CoFeB/AlOx/Co magnetic tunneling junction (MTJ) in the magnetic field of a low-frequency alternating current, for various thicknesses of the barrier layer AlOx. The low-frequency alternate-current magnetic susceptibility (chiac) and phase angle (theta) of the CoFeB/AlOx/Co MTJ are determined using an cac analyzer. The driving frequency ranges from 10 to 25,000 Hz. These multilayered MTJs are deposited on a silicon substrate using a DC and RF magnetron sputtering system. Barrier layer thicknesses are 22, 26, and 30 A. The X-ray diffraction patterns (XRD) include a main peak at 2theta = 44.7 degrees from hexagonal close-packed (HCP) Co with a highly (0002) textured structure, with AlOx and CoFeB as amorphous phases. The full width at half maximum (FWHM) of the Co(0002) peak, decreases as the AlOx thickness increases; revealing that the Co layer becomes more crystalline with increasing thickness. chiac result demonstrates that the optimal resonance frequency (fres) that maximizes the chiac value is 500 Hz. As the frequency increases to 1000 Hz, the susceptibility decreases rapidly. However, when the frequency increases over 1000 Hz, the susceptibility sharply declines, and almost closes to zero. The experimental results reveal that the mean optimal susceptibility is 1.87 at an AlOx barrier layer thickness of 30 A because the Co(0002) texture induces magneto-anisotropy, which improves the indirect CoFeB and Co spin exchange-coupling strength and the chiac value. The results concerning magnetism indicate that the magnetic characteristics are related to the crystallinity of Co. PMID- 28348353 TI - Tuning NaYF4 Nanoparticles through Alkaline Earth Doping. AB - Phase and size of lanthanide-doped nanoparticles are the most important characteristics that dictate optical properties of these nanoparticles and affect their technological applications. Herein, we present a systematic study to examine the effect of alkaline earth doping on the formation of NaYF4 upconversion nanoparticles. We show that alkaline earth doping has a dual function of tuning particle size of hexagonal phase NaYF4 nanoparticles and stabilizing cubic phase NaYF4 nanoparticles depending on composition and concentration of the dopant ions. The study described here represents a facile and general strategy to tuning the properties of NaYF4 upconversion nanoparticles. PMID- 28348354 TI - Formation of Gold Microparticles by Ablation with Surface Plasmons. AB - The formation of gold microparticles on a silicon substrate through the use of energetic surface plasmons is reported. A laser-assisted plasmonics system was assembled and tested to synthesize gold particles from gold thin film by electrical field enhancement mechanism. A mask containing an array of 200 nm diameter holes with a periodicity of 400 nm was prepared and placed on a silicon substrate. The mask was composed of 60 um thick porous alumina membrane sputter coated with 100 nm thin gold film. A Nd:YAG laser with 1064 nm wavelength and 230 us pulse width (free-running mode) was then passed through the mask at an energy fluence of 0.35 J/cm2. The extraordinary transmission of laser light through alumina/gold micro-hole optical antenna created both extended and localized surface plasmons that caused the gold film at the bottom of the mask to fragment into microparticles and deposit on the silicon substrate that is in direct contact with the mask. The surface plasmon method is simpler, quicker, more energy efficient, and environmentally safer than existing physical and chemical methods, as well as being contamination-free, and can be extended to all types of materials that will in turn allow for new possibilities in the formation of structured surfaces. PMID- 28348355 TI - Fabrication and Characterization of SnO2/Graphene Composites as High Capacity Anodes for Li-Ion Batteries. AB - Tin-oxide and graphene (TG) composites were fabricated using the Electrostatic Spray Deposition (ESD) technique, and tested as anode materials for Li-ion batteries. The electrochemical performance of the as-deposited TG composites were compared to heat-treated TG composites along with pure tin-oxide films. The heat treated composites exhibited superior specific capacity and energy density than both the as-deposited TG composites and tin oxide samples. At the 70th cycle, the specific capacities of the as-deposited and post heat-treated samples were 534 and 737 mA.h/g, respectively, and the corresponding energy densities of the as deposited and heat-treated composites were 1240 and 1760 W.h/kg, respectively. This improvement in the electrochemical performance of the TG composite anodes as compared to the pure tin oxide samples is attributed to the synergy between tin oxide and graphene, which increases the electrical conductivity of tin oxide and helps alleviate volumetric changes in tin-oxide during cycling. PMID- 28348356 TI - Molecularly Imprinted Nanomaterials for Sensor Applications. AB - Molecular imprinting is a well-established technology to mimic antibody-antigen interaction in a synthetic platform. Molecularly imprinted polymers and nanomaterials usually possess outstanding recognition capabilities. Imprinted nanostructured materials are characterized by their small sizes, large reactive surface area and, most importantly, with rapid and specific analysis of analytes due to the formation of template driven recognition cavities within the matrix. The excellent recognition and selectivity offered by this class of materials towards a target analyte have found applications in many areas, such as separation science, analysis of organic pollutants in water, environmental analysis of trace gases, chemical or biological sensors, biochemical assays, fabricating artificial receptors, nanotechnology, etc. We present here a concise overview and recent developments in nanostructured imprinted materials with respect to various sensor systems, e.g., electrochemical, optical and mass sensitive, etc. Finally, in light of recent studies, we conclude the article with future perspectives and foreseen applications of imprinted nanomaterials in chemical sensors. PMID- 28348358 TI - Effect of Nanotube Film Thickness on the Performance of Nanotube-Silicon Hybrid Solar Cells. AB - The results of measurements on solar cells made from randomly aligned thin films of single walled carbon nanotubes (SWCNTs) on n-type monocrystalline silicon are presented. The films are made by vacuum filtration from aqueous TritonX-100 suspensions of large diameter arc-discharge SWCNTs. The dependence of the solar cell performance on the thickness of the SWCNT film is shown in detail, as is the variation in performance due to doping of the SWCNT film with SOCl2. PMID- 28348357 TI - Study of the Effect of Grafting Method on Surface Polarity of Tempo-Oxidized Nanocellulose Using Polycaprolactone as the Modifying Compound: Esterification versus Click-Chemistry. AB - Esterification and click-chemistry were evaluated as surface modification treatments for TEMPO-oxidized nanocelluloses (TONC) using Polycaprolactone-diol (PCL) as modifying compound in order to improve the dispersion of nanofibers in organic media. These two grafting strategies were analyzed and compared. The first consists of grafting directly the PCL onto TONC, and was carried out by esterification between hydroxyl groups of PCL and carboxyl groups of TONC. The second strategy known as click-chemistry is based on the 1,3-dipolar cycloaddition reaction between azides and alkyne terminated moieties to form the triazole ring between PCL and TONC. The grafted samples were characterized by transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), and Thermogravimetry analysis (TGA). Further, the effects of the two treatments on the surface hydrophobization of TONC were investigated by contact angle measurements. The results show that both methods confirm the success of such a modification and the click reaction was significantly more effective than esterification. PMID- 28348359 TI - Dynamics of Fukuoka Criteria and Patient Management in Pancreatic Intraductal Papillary Mucinous Neoplasms (IPMNs) During Follow-Up. AB - BACKGROUND Pancreatic intraductal papillary mucinous neoplasms (IPMNs) present a clinical challenge. Evidence-based guidelines are lacking. The so-called "Fukuoka criteria" were developed to assess the risk of malignancy in IPMNs upon imaging. However, little is known about their diagnostic value and the natural course of IPMNs. Thus, the aim of this study was the assessment of Fukuoka criteria and patient management in pancreatic IPMNs -during follow-up. MATERIAL AND METHODS IPMNs were identified via retrospective survey of endoscopic ultrasound (EUS) examinations. Fukuoka criteria were assessed on EUS findings and additional imaging (CT, MRI, ultrasound). Patients' symptoms and comorbidities were recorded. Dynamics of Fukuoka criteria and patient management were compared at first presentation and during follow-up. RESULTS We screened 1324 EUS examinations. Sixty-five patients (male/female, 14/37; mean age, 68.8 years; range, 48-85 years) with IPMNs were identified (57 branch duct (BD-)IPMNs, 3 main duct (MD-) IPMNs, 5 mixed-type (MT)-IPMNs). Seven patients received surgical resection (4 BD-IPMNs, 2 MD-IPMNs, 1 MT-IPMN). Nine BD-IPMNs had neither surgery nor follow-up. Fifty-one patients (44 BD-IPMNs, 2 MD-IPMNs, 5 MT-IPMNs) underwent follow-up (mean duration, 18.7 months; range, 3-139 months). There were 15/51 patients who were initially Fukuoka-positive. One MD-IPMN, 4/5 MT-IPMNs, and 13/44 BD-IPMNs showed progressive changes but were not resected due to patients' refusal or comorbidities. Four BD-IPMNs converted to Fukuoka-positive. CONCLUSIONS Evidence-based guidelines for non-invasive dignity assessment of IPMNs are lacking. In our study, MD-IPMNs displayed greater dynamics than BD IPMNs and MT-IPMNs concerning Fukuoka criteria. Prospective long-term studies are needed to clarify prognostic significance of the single Fukuoka criteria and sensible duration of follow-up. PMID- 28348360 TI - An Uncommon Case of Lower Limb Deep Vein Thrombosis with Multiple Etiological Causes. AB - BACKGROUND Deep vein thrombosis (DVT) is a type of venous thromboembolism with diverse clinical and environmental risk factors. Very few cases of DVT with multiple high risk factors have been reported. Here, we report an uncommon DVT case with multiple etiological causes, including appendicitis/appendectomy, morbid obesity, immobilization, positive phosphatidylserine IgG, and heterozygous factor V Leiden mutation. CASE REPORT A 43-year-old female was brought to the emergency room because of 2-week history of pain and swelling and ultrasound revealing evidence of DVT in the right leg. One month ago, she underwent an exploratory laparotomy because of subacute appendicitis. After surgery, the patient stayed at home in bed with very limited activity. She did not have a cough, hemoptysis, chest pain, or shortness of breath. She was morbidly obese, and had a past medical history of diabetes, hypertension, and hyperlipidemia. A full coagulation workup was completed, including Protein C, Protein S, and antiphospholipid antibody, as well as factor V and prothrombin gene mutation screen. Her D-dimer was positive. Computed tomography (CT) angiography of the lungs ruled out major emboli but was unable to rule out minor emboli. A heterozygous factor V Leiden R506Q mutation was detected. Of interest was a significantly positive phosphatidylserine IgG with a value of over 42. She was started with enoxaparin (120 mg, twice a day), and warfarin was added on day 2 when pulmonary embolism was ruled out by CT angiography. The International Normalized Ratio (INR) was monitored daily to adjust warfarin dose. CONCLUSIONS Multiple etiological factors present in this patient may have contributed to her lower-limb DVT, including appendicitis/appendectomy, morbid obesity, immobilization, positive phosphatidylserine IgG, and factor V Leiden mutation. Therefore, it is important to follow the complete workup for hypercoagulable states. This can help with diagnosis and therapy, and also give insight into the pathogenicity, which can help with prevention of recurrence and severe complications of DVT. PMID- 28348361 TI - The Impact of Donor-Specific Anti-Human Leukocyte Antigen (HLA) Antibody Rebound on the Risk of Antibody Mediated Rejection in Sensitized Kidney Transplant Recipients. AB - BACKGROUND Donor-specific anti-HLA antibody (DSA) detected on Luminex-based single antigen assay (LSA) has become the subject of desensitization based upon the results of previous studies. We retrospectively investigated the impact of preoperative DSA on the incidence of antibody mediated rejection (AMR) in patients desensitized using a protocol based on rituximab and rabbit antithymocyte globulin (rATG). MATERIAL AND METHODS Nine patients (Group 1, 9/327, 2.8%) were complement dependent cytotoxicity crossmatch (CDC-XM) positive and underwent desensitization with rituximab (375 mg/m2), intravenous immunoglobulin (IVIG; 400 mg/kg), plasmapheresis, and rATG. Twenty-two patients (Group 2, 22/327, 6.7%) were CDC-XM negative but DSA positive on LSA and had received desensitization with rituximab and rATG, while 55 patients (Group 3, 55/327, 16.8%) were CDC-XM and DSA negative with a calculated panel reactive antibody (cPRA) >=50%. Another 241 patients (Group 4, 241/327, 73.7%) were CDC-XM and DSA negative with a cPRA <50%. RESULTS Recipients with DSA (Group 2) experienced more AMR than other groups (p<0.01). More de novo DSAs also developed in Group 2 (p<0.001). The mean fluorescence intensity (MFI) of DSA of patients with AMR tended to rebound (p=0.01). CONCLUSIONS Patients who were CDC-XM negative but DSA positive status were at a higher risk of developing AMR even though they had received desensitization with rATG and rituximab. A more intense desensitization protocol is needed for these recipients. Patients with MFI rebound of DSA should be carefully monitored for the risk of AMR. PMID- 28348362 TI - Interspecific differences in how habitat degradation affects escape response. AB - Degradation of habitats is widespread and a leading cause of extinctions. Our study determined whether the change in the chemical landscape associated with coral degradation affected the way three fish species use olfactory information to optimize their fast-start escape response. Water from degraded coral habitats affected the fast-start response of the three closely-related damselfishes, but its effect differed markedly among species. The Ward's damselfish (Pomacentrus wardi) was most affected by water from degraded coral, and displayed shorter distances covered in the fast-start and slower escape speeds compared to fish in water from healthy coral. In the presence of alarm odours, which indicate an imminent threat, the Ambon damsel (P. amboinensis) displayed enhanced fast-start performance in water from healthy coral, but not when in water from degraded coral. In contrast, while the white-tailed damsel (P. chrysurus) was similarly primed by its alarm odour, the elevation of fast start performance was not altered by water from degraded coral. These species-specific responses to the chemistry of degraded water and alarm odours suggest differences in the way alarm odours interact with the chemical landscape, and differences in the way species balance information about threats, with likely impacts on the survival of affected species in degraded habitats. PMID- 28348363 TI - High performance lithium-sulfur batteries for storing pulsed energy generated by triboelectric nanogenerators. AB - Storing pulsed energy harvested by triboelectric nanogenerators (TENGs) from ambient mechanical motion is an important technology for obtaining sustainable, low-cost, and green power. Here, we introduce high-energy-density Li-S batteries with excellent performance for storing pulsed output from TENGs. The sandwich structured sulfur composites with multi-walled carbon nanotubes and polypyrrole serve as cathode materials that suppress the shuttle effect of polysulfides and thus preserve the structural stability of the cathode during Li-ion insertion and extraction. The charging time and energy storage efficiency of the Li-S batteries are directly affected by the rotation rates of the TENGs. The average storage efficiency of the batteries for pulsed output from TENGs can exceed 80% and even reach 93% at low discharge currents. The Li-S batteries also show excellent rate performance for storing pulsed energy at a high discharge current rate of 5 C. The high storage efficiency and excellent rate capability and cyclability demonstrate the feasibility of storing and exploiting pulsed energy provided by TENGs and the potential of Li-S batteries with high energy storage efficiency for storing pulsed energy harvested by TENGs. PMID- 28348364 TI - Earthquake-Related Changes in Species Spatial Niche Overlaps in Spring Communities. AB - Species interactions between stygobites (obligate groundwater organisms) are poorly known, reflecting the difficulty in studying such organisms in their natural environments. Some insight can be gained from the study of the spatial variability in microcrustacean communities in groundwater-fed springs. Earthquakes can increase hydraulic conductivity in the recharge area of karstic aquifers and flow rates in discharge zones, thus dislodging stygobites from their original habitats to the spring outlets. Earthquakes are expected to alter species spatial niche overlap at the spring outlets, where stygobites coexist with non-stygobites living in benthic and subsurface habitats. We compared the abundance of stygobiotic and non-stygobiotic microcrustaceans in groundwater-fed springs before and after the 6.3-Mw earthquake that hit the karstic Gran Sasso Aquifer (Italy) in 2009. Pre-seismic (1997, 2005) overall niche overlaps were not different from null expectations, while post-seismic (2012) species mean niche overlaps were higher, following the redistribution of animals caused by the earthquake-triggered discharge. The reduced abundance of stygobites following their dislodgement from the aquifer and the concomitant displacement of non stygobites led to a higher post-seismic co-occurrence of stygobites and non stygobites. Changes in aquifer structure destroyed pre-seismic species segregation patterns by creating new or strengthening already existing interactions. PMID- 28348365 TI - EMU and 3'RR IgH enhancers show hierarchic unilateral dependence in mature B cells. AB - Enhancer and super-enhancers are master regulators of cell fate. While they act at long-distances on adjacent genes, it is unclear whether they also act on one another. The immunoglobulin heavy chain (IgH) locus is unique in carrying two super-enhancers at both ends of the constant gene cluster: the 5'EMU super enhancer promotes VDJ recombination during the earliest steps of B-cell ontogeny while the 3' regulatory region (3'RR) is essential for late differentiation. Since they carry functional synergies in mature B-cells and physically interact during IgH locus DNA looping, we investigated if they were independent engines of locus remodelling or if their function was more intimately intermingled, their optimal activation then requiring physical contact with each other. Analysis of chromatin marks, enhancer RNA transcription and accessibility in EMU- and 3'RR deficient mice show, in mature activated B-cells, an unilateral dependence of this pair of enhancers: while the 3'RR acts in autonomy, EMU in contrast likely falls under control of the 3'RR. PMID- 28348366 TI - A novel technique to determine the cell type specific response within an in vitro co-culture model via multi-colour flow cytometry. AB - Determination of the cell type specific response is essential towards understanding the cellular mechanisms associated with disease states as well as assessing cell-based targeting of effective therapeutic agents. Recently, there have been increased calls for advanced in vitro multi-cellular models that provide reliable and valuable tools correlative to in vivo. In this pursuit the ability to assess the cell type specific response is imperative. Herein, we report a novel approach towards resolving each specific cell type of a multi cellular model representing the human lung epithelial tissue barrier via multi colour flow cytometry (FACS). We proved via <= five-colour FACS that the manipulation of this in vitro model allowed each cell type to be resolved with no impact upon cell viability. Subsequently, four-colour FACS verified the ability to determine the biochemical effect (e.g. oxidative stress) of each specific cell type. This technique will be vital in gaining information upon cellular mechanics when using next-level, multi-cellular in vitro strategies. PMID- 28348367 TI - A Strategy to Delay the Development of Cisplatin Resistance by Maintaining a Certain Amount of Cisplatin-Sensitive Cells. AB - Cisplatin (ddp), which is commonly employed in the treatment of many advanced cancers, often results in initial therapeutic success; however, rapid progression of ddp-resistant cells remains the main reason for treatment failure. Facd with such a problem, we investigated the fitness differences between ddp-sensitive and ddp-resistant cell lines. We found that the growth of ddp-resistant cells was significantly slower than that of sensitive cells due to elevated ROS levels, which suggested that the ddp resistance mechanisms may have negative impacts on the growth of resistant cells. Furthermore, we observed that, when mixed with ddp sensitive cells, ddp-resistant cells failed to compete, and the growth of ddp resistant cells could therefore be suppressed by treatment in vivo. We propose a mathematical model parameterized based on in vivo experiments to describe the allometric growth of tumors consisting of two competing subclones. According to our model, a quantitative strategy with a variant drug-dosing interval is proposed to control tumor growth. Taking advantage of intratumoral competition, our strategy with appropriate dosing intervals could remarkably delay the development of ddp resistance and prolong overall survival. Maintaining a certain number of ddp-sensitive cells rather than eradicating the tumor with continuous treatment is feasible for future tumor treatment. PMID- 28348368 TI - Plasmonic photoluminescence for recovering native chemical information from surface-enhanced Raman scattering. AB - Surface-enhanced Raman scattering (SERS) spectroscopy has attracted tremendous interests as a highly sensitive label-free tool. The local field produced by the excitation of localized surface plasmon resonances (LSPRs) dominates the overall enhancement of SERS. Such an electromagnetic enhancement is unfortunately accompanied by a strong modification in the relative intensity of the original Raman spectra, which highly distorts spectral features providing chemical information. Here we propose a robust method to retrieve the fingerprint of intrinsic chemical information from the SERS spectra. The method is established based on the finding that the SERS background originates from the LSPR-modulated photoluminescence, which contains the local field information shared also by SERS. We validate this concept of retrieval of intrinsic fingerprint information in well controlled single metallic nanoantennas of varying aspect ratios. We further demonstrate its unambiguity and generality in more complicated systems of tip-enhanced Raman spectroscopy (TERS) and SERS of silver nanoaggregates. PMID- 28348369 TI - Novel molecular approach to define pest species status and tritrophic interactions from historical Bemisia specimens. AB - Museum specimens represent valuable genomic resources for understanding host endosymbiont/parasitoid evolutionary relationships, resolving species complexes and nomenclatural problems. However, museum collections suffer DNA degradation, making them challenging for molecular-based studies. Here, the mitogenomes of a single 1912 Sri Lankan Bemisia emiliae cotype puparium, and of a 1942 Japanese Bemisia puparium are characterised using a Next-Generation Sequencing approach. Whiteflies are small sap-sucking insects including B. tabaci pest species complex. Bemisia emiliae's draft mitogenome showed a high degree of homology with published B. tabaci mitogenomes, and exhibited 98-100% partial mitochondrial DNA Cytochrome Oxidase I (mtCOI) gene identity with the B. tabaci species known as Asia II-7. The partial mtCOI gene of the Japanese specimen shared 99% sequence identity with the Bemisia 'JpL' genetic group. Metagenomic analysis identified bacterial sequences in both Bemisia specimens, while hymenopteran sequences were also identified in the Japanese Bemisia puparium, including complete mtCOI and rRNA genes, and various partial mtDNA genes. At 88-90% mtCOI sequence identity to Aphelinidae wasps, we concluded that the 1942 Bemisia nymph was parasitized by an Eretmocerus parasitoid wasp. Our approach enables the characterisation of genomes and associated metagenomic communities of museum specimens using 1.5 ng gDNA, and to infer historical tritrophic relationships in Bemisia whiteflies. PMID- 28348371 TI - Dust outpaces bedrock in nutrient supply to montane forest ecosystems. AB - Dust provides ecosystem-sustaining nutrients to landscapes underlain by intensively weathered soils. Here we show that dust may also be crucial in montane forest ecosystems, dominating nutrient budgets despite continuous replacement of depleted soils with fresh bedrock via erosion. Strontium and neodymium isotopes in modern dust show that Asian sources contribute 18-45% of dust deposition across our Sierra Nevada, California study sites. The remaining dust originates regionally from the nearby Central Valley. Measured dust fluxes are greater than or equal to modern erosional outputs from hillslopes to channels, and account for 10-20% of estimated millennial-average inputs of bedrock P. Our results demonstrate that exogenic dust can drive the evolution of nutrient budgets in montane ecosystems, with implications for predicting forest response to changes in climate and land use. PMID- 28348370 TI - Non-classical monocytes are biased progenitors of wound healing macrophages during soft tissue injury. AB - Successful tissue repair requires the activities of myeloid cells such as monocytes and macrophages that guide the progression of inflammation and healing outcome. Immunoregenerative materials leverage the function of endogenous immune cells to orchestrate complex mechanisms of repair; however, a deeper understanding of innate immune cell function in inflamed tissues and their subsequent interactions with implanted materials is necessary to guide the design of these materials. Blood monocytes exist in two primary subpopulations, characterized as classical inflammatory or non-classical. While classical monocytes extravasate into inflamed tissue and give rise to macrophages or dendritic cells, the recruitment kinetics and functional role of non-classical monocytes remains unclear. Here, we demonstrate that circulating non-classical monocytes are directly recruited to polymer films within skin injuries, where they home to a perivascular niche and generate alternatively activated, wound healing macrophages. Selective labeling of blood monocyte subsets indicates that non-classical monocytes are biased progenitors of alternatively activated macrophages. On-site delivery of the immunomodulatory small molecule FTY720 recruits S1PR3-expressing non-classical monocytes that support vascular remodeling after injury. These results elucidate a previously unknown role for blood-derived non-classical monocytes as contributors to alternatively activated macrophages, highlighting them as key regulators of inflammatory response and regenerative outcome. PMID- 28348372 TI - Infrared broadband metasurface absorber for reducing the thermal mass of a microbolometer. AB - We demonstrate an infrared broadband metasurface absorber that is suitable for increasing the response speed of a microbolometer by reducing its thermal mass. A large fraction of holes are made in a periodic pattern on a thin lossy metal layer characterised with a non-dispersive effective surface impedance. This can be used as a non-resonant metasurface that can be integrated with a Salisbury screen absorber to construct an absorbing membrane for a microbolometer that can significantly reduce the thermal mass while maintaining high infrared broadband absorption in the long wavelength infrared (LWIR) band. The non-dispersive effective surface impedance can be matched to the free space by optimising the surface resistance of the thin lossy metal layer depending on the size of the patterned holes by using a dc approximation method. In experiments a high broadband absorption was maintained even when the fill factor of the absorbing area was reduced to 28% (hole area: 72%), and it was theoretically maintained even when the fill factor of the absorbing area was reduced to 19% (hole area: 81%). Therefore, a metasurface with a non-dispersive effective surface impedance is a promising solution for reducing the thermal mass of infrared microbolometer pixels. PMID- 28348373 TI - The role of rhizobial (NifV) and plant (FEN1) homocitrate synthases in Aeschynomene/photosynthetic Bradyrhizobium symbiosis. AB - In the most studied rhizobium-legume interactions, the host plant supplies the symbiont with homocitrate, an essential co-factor of the nitrogenase enzyme complex, via the expression of a nodule-specific homocitrate synthase FEN1. Photosynthetic bradyrhizobia interacting with Nod factor (NF) dependent and NF independent Aeschynomene legumes are able to synthesize homocitrate themselves as they contain a nifV gene encoding a homocitrate synthase. Here, we show that in the model strain ORS285, nifV is required for free-living and symbiotic dinitrogen fixation with NF-independent Aeschynomene species. In contrast, in symbiosis with NF-dependent Aeschynomene species, the nifV requirement for efficient nitrogen fixation was found to be host plant dependent. Interestingly, orthologs of FEN1 were found in both NF-dependent and NF-independent Aeschynomene species. However, a high nodule specific induction of FEN1 expression was only observed in A. afraspera, a host plant in which nifV is not required for symbiotic dinitrogen fixation. These data indicate that efficient symbiotic nitrogen fixation in many of the tested Aeschynomene species requires rhizobial homocitrate synthesis. Considering that more than 10% of the fully sequenced rhizobium strains do contain a nifV gene, the Aeschynomene/photosynthetic Bradyrhizobium interaction is likely not the only rhizobium/legume symbiosis where rhizobial nifV expression is required. PMID- 28348374 TI - One-step fabrication of crystalline metal nanostructures by direct nanoimprinting below melting temperatures. AB - Controlled fabrication of metallic nanostructures plays a central role in much of modern science and technology, because changing the dimensions of a nanocrystal enables tailoring of its mechanical, electronic, optical, catalytic and antibacterial properties. Here we show direct superplastic nanoimprinting (SPNI) of crystalline metals well below their melting temperatures, generating ordered nanowire arrays with aspect ratios up to ~2,000 and imprinting features as small as 8 nm. Surface-enhanced Raman scattering (SERS) spectra reveal strongly enhanced electromagnetic signals from the prepared nanorod arrays with sizes up to ~100 nm, which indicates that our technique can provide an ideal way to fabricate robust SERS substrates. SPNI, as a one-step, controlled and reproducible nanofabrication method, could facilitate the applications of metal nanostructures in bio-sensing, diagnostic imaging, catalysis, food industry and environmental conservation. PMID- 28348375 TI - A redox-mediated Kemp eliminase. AB - The acid/base-catalysed Kemp elimination of 5-nitro-benzisoxazole forming 2-cyano 4-nitrophenol has long served as a design platform of enzymes with non-natural reactions, providing new mechanistic insights in protein science. Here we describe an alternative concept based on redox catalysis by P450-BM3, leading to the same Kemp product via a fundamentally different mechanism. QM/MM computations show that it involves coordination of the substrate's N-atom to haem-Fe(II) with electron transfer and concomitant N-O heterolysis liberating an intermediate having a nitrogen radical moiety Fe(III)-N. and a phenoxyl anion. Product formation occurs by bond rotation and H-transfer. Two rationally chosen point mutations cause a notable increase in activity. The results shed light on the prevailing mechanistic uncertainties in human P450-catalysed metabolism of the immunomodulatory drug leflunomide, which likewise undergoes redox-mediated Kemp elimination by P450-BM3. Other isoxazole-based pharmaceuticals are probably also metabolized by a redox mechanism. Our work provides a basis for designing future artificial enzymes. PMID- 28348376 TI - A missense single nucleotide polymorphism in the ALDH2 gene, rs671, is associated with hip fracture. AB - Hip fracture is the most severe bone fragility fracture among osteoporotic injuries. Family history is a known risk factor for fracture and now included among criteria for osteoporosis diagnosis and treatment; however, genetic factors underlying family history favoring fracture remain to be elucidated. Here we demonstrate that a missense SNP in the ALDH2 gene, rs671 (ALDH2*2), is significantly associated with hip fracture (odds ratio = 2.48, 95% confidence interval: 1.20-5.10, p = 0.021). The rs671 SNP was also significantly associated with osteoporosis development (odds ratio = 2.04, 95% confidence interval: 1.07 3.88, p = 0.040). For analysis we enrolled 92 hip fracture patients plus 48 control subjects without bone fragility fractures with higher than -2.5 SD bone mineral density. We also recruited 156 osteoporosis patients diagnosed as below 2.5 SD in terms of bone mineral density but without hip fracture. Association of rs671 with hip fracture and osteoporosis was significant even after adjustment for age and body mass index. Our results provide new insight into the pathogenesis of hip fracture. PMID- 28348377 TI - Bilirubin augments Ca2+ load of developing bushy neurons by targeting specific subtype of voltage-gated calcium channels. AB - Neonatal brain is particularly vulnerable to pathological levels of bilirubin which elevates and overloads intracellular Ca2+, leading to neurotoxicity. However, how voltage-gated calcium channels (VGCCs) are functionally involved in excess calcium influx remains unknown. By performing voltage-clamp recordings from bushy cells in the ventral cochlear nucleus (VCN) in postnatal rat pups (P4 17), we found the total calcium current density was more than doubled over P4-17, but the relative weight of VGCC subtypes changed dramatically, being relatively equal among T, L, N, P/Q and R-type at P4-6 to predominantly L, N, R over T and P/Q at P15-17. Surprisingly, acute administration of bilirubin augmented the VGCC currents specifically mediated by high voltage-activated (HVA) P/Q-type calcium currents. This augment was attenuated by intracellular loading of Ca2+ buffer EGTA or calmodulin inhibitory peptide. Our findings indicate that acute exposure to bilirubin increases VGCC currents, primarily by targeting P/Q-type calcium channels via Ca2+ and calmodulin dependent mechanisms to overwhelm neurons with excessive Ca2+. Since P/Q-subtype calcium channels are more prominent in neonatal neurons (e.g. P4-6) than later stages, we suggest this subtype-specific enhancement of P/Q-type Ca2+ currents likely contributes to the early neuronal vulnerability to hyperbilirubinemia in auditory and other brain regions. PMID- 28348378 TI - Endocannabinoid signalling modulates susceptibility to traumatic stress exposure. AB - Stress is a ubiquitous risk factor for the exacerbation and development of affective disorders including major depression and posttraumatic stress disorder. Understanding the neurobiological mechanisms conferring resilience to the adverse consequences of stress could have broad implications for the treatment and prevention of mood and anxiety disorders. We utilize laboratory mice and their innate inter-individual differences in stress-susceptibility to demonstrate a critical role for the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) in stress-resilience. Specifically, systemic 2-AG augmentation is associated with a stress-resilient phenotype and enhances resilience in previously susceptible mice, while systemic 2-AG depletion or CB1 receptor blockade increases susceptibility in previously resilient mice. Moreover, stress-resilience is associated with increased phasic 2-AG-mediated synaptic suppression at ventral hippocampal-amygdala glutamatergic synapses and amygdala-specific 2-AG depletion impairs successful adaptation to repeated stress. These data indicate amygdala 2 AG signalling mechanisms promote resilience to adverse effects of acute traumatic stress and facilitate adaptation to repeated stress exposure. PMID- 28348380 TI - Preventing intrusive memories after trauma via a brief intervention involving Tetris computer game play in the emergency department: a proof-of-concept randomized controlled trial. AB - After psychological trauma, recurrent intrusive visual memories may be distressing and disruptive. Preventive interventions post trauma are lacking. Here we test a behavioural intervention after real-life trauma derived from cognitive neuroscience. We hypothesized that intrusive memories would be significantly reduced in number by an intervention involving a computer game with high visuospatial demands (Tetris), via disrupting consolidation of sensory elements of trauma memory. The Tetris-based intervention (trauma memory reminder cue plus c. 20 min game play) vs attention-placebo control (written activity log for same duration) were both delivered in an emergency department within 6 h of a motor vehicle accident. The randomized controlled trial compared the impact on the number of intrusive trauma memories in the subsequent week (primary outcome). Results vindicated the efficacy of the Tetris-based intervention compared with the control condition: there were fewer intrusive memories overall, and time series analyses showed that intrusion incidence declined more quickly. There were convergent findings on a measure of clinical post-trauma intrusion symptoms at 1 week, but not on other symptom clusters or at 1 month. Results of this proof-of concept study suggest that a larger trial, powered to detect differences at 1 month, is warranted. Participants found the intervention easy, helpful and minimally distressing. By translating emerging neuroscientific insights and experimental research into the real world, we offer a promising new low-intensity psychiatric intervention that could prevent debilitating intrusive memories following trauma. PMID- 28348379 TI - Genetic evidence for role of integration of fast and slow neurotransmission in schizophrenia. AB - The most recent genome-wide association studies (GWAS) of schizophrenia (SCZ) identified hundreds of risk variants potentially implicated in the disease. Further, novel statistical methodology designed for polygenic architecture revealed more potential risk variants. This can provide a link between individual genetic factors and the mechanistic underpinnings of SCZ. Intriguingly, a large number of genes coding for ionotropic and metabotropic receptors for various neurotransmitters-glutamate, gamma-aminobutyric acid (GABA), dopamine, serotonin, acetylcholine and opioids-and numerous ion channels were associated with SCZ. Here, we review these findings from the standpoint of classical neurobiological knowledge of neuronal synaptic transmission and regulation of electrical excitability. We show that a substantial proportion of the identified genes are involved in intracellular cascades known to integrate 'slow' (G-protein-coupled receptors) and 'fast' (ionotropic receptors) neurotransmission converging on the protein DARPP-32. Inspection of the Human Brain Transcriptome Project database confirms that that these genes are indeed expressed in the brain, with the expression profile following specific developmental trajectories, underscoring their relevance to brain organization and function. These findings extend the existing pathophysiology hypothesis by suggesting a unifying role of dysregulation in neuronal excitability and synaptic integration in SCZ. This emergent model supports the concept of SCZ as an 'associative' disorder-a breakdown in the communication across different slow and fast neurotransmitter systems through intracellular signaling pathways-and may unify a number of currently competing hypotheses of SCZ pathophysiology. PMID- 28348381 TI - Greater extracellular free-water in first-episode psychosis predicts better neurocognitive functioning. AB - Free Water Imaging is a novel diffusion magnetic resonance (MR) imaging method that is able to separate changes affecting the extracellular space from those that reflect changes in neuronal cells and processes. A previous Free Water Imaging study in schizophrenia identified significantly greater extracellular water volume in the early stages of the disorder; however, its clinical and functional sequelae have not yet been investigated. Here, we applied Free Water Imaging to a larger cohort of 63 first-episode patients with psychosis and 70 healthy matched controls to better understand the functional significance of greater extracellular water. We used diffusion MR imaging data and the Tract Based Spatial Statistics analytic pipeline to first analyze fractional anisotropy (FA), the most commonly employed metric for assessing white matter. This comparison was then followed by Free Water Imaging analysis, where two parameters, the fractional volume of extracellular free-water (FW) and cellular tissue FA (FA-t), were estimated and compared across the entire white matter skeleton between groups, and correlated with cognitive measures at baseline and following 12 weeks of antipsychotic treatment. Our results indicated lower FA across the whole brain in patients compared with healthy controls that overlap with significant increases in FW, with only limited decreases in FA-t. In addition, higher FW correlated with better neurocognitive functioning following 12 weeks of antipsychotic treatment. We believe this is the first study to suggest that an extracellular water increase during the first-episode of psychosis, which may be indicative of an acute neuroinflammatory process, and/or cerebral edema may predict better functional outcome. PMID- 28348382 TI - Delta-frequency stimulation of cerebellar projections can compensate for schizophrenia-related medial frontal dysfunction. AB - Schizophrenia involves abnormalities in the medial frontal cortex that lead to cognitive deficits. Here we investigate a novel strategy to normalize medial frontal brain activity by stimulating cerebellar projections. We used an interval timing task to study elementary cognitive processing that requires both frontal and cerebellar networks that are disrupted in patients with schizophrenia. We report three novel findings. First, patients with schizophrenia had dysfunctional delta rhythms between 1-4 Hz in the medial frontal cortex. We explored cerebellar frontal interactions in animal models and found that both frontal and cerebellar neurons were modulated during interval timing and had delta-frequency interactions. Finally, delta-frequency optogenetic stimulation of thalamic synaptic terminals of lateral cerebellar projection neurons rescued timing performance as well as medial frontal activity in a rodent model of schizophrenia related frontal dysfunction. These data provide insight into how the cerebellum influences medial frontal networks and the role of the cerebellum in cognitive processing. PMID- 28348383 TI - Prefrontal gray matter volume mediates genetic risks for obesity. AB - Genetic and neuroimaging research has identified neurobiological correlates of obesity. However, evidence for an integrated model of genetic risk and brain structural alterations in the pathophysiology of obesity is still absent. Here we investigated the relationship between polygenic risk for obesity, gray matter structure and body mass index (BMI) by the use of univariate and multivariate analyses in two large, independent cohorts (n=330 and n=347). Higher BMI and higher polygenic risk for obesity were significantly associated with medial prefrontal gray matter decrease, and prefrontal gray matter was further shown to significantly mediate the effect of polygenic risk for obesity on BMI in both samples. Building on this, the successful individualized prediction of BMI by means of multivariate pattern classification algorithms trained on whole-brain imaging data and external validations in the second cohort points to potential clinical applications of this imaging trait marker. PMID- 28348384 TI - Microglia and schizophrenia: where next? PMID- 28348385 TI - Depression, telomeres and mitochondrial DNA: between- and within-person associations from a 10-year longitudinal study. AB - Alterations in cellular aging, indexed by leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn), might partly account for the increased health risks in persons with depression. Although some studies indeed found cross sectional associations of depression with LTL and mtDNAcn, the longitudinal associations remain unclear. This 10-year longitudinal study examined between- and within-person associations of depressive symptoms with LTL and mtDNAcn in a large community sample. Data are from years 15, 20 and 25 follow-up evaluations in 977 subjects from the Coronary Artery Risk Development in Young Adults study. Depressive symptoms (years 15, 20, 25) were assessed with the Center for Epidemiologic Studies Depression (CES-D) scale; LTL (years 15, 20, 25) and mtDNAcn (years 15, 25) were measured in whole blood by quantitative PCR. With mixed-model analyses, we explored between- and within-person associations between CES-D scores and cellular aging markers. Results showed that high levels of depressive symptomatology throughout the 10-year time span was associated with shorter average LTL over 10 years (B=-4.2; P=0.014) after covarying for age, sex, race and education. However, no within-person association was found between depressive symptoms and LTL at each year (B=-0.8; P=0.548). Further, we found no between-person (B=-0.2; P=0.744) or within-person (B=0.4; P=0.497) associations between depressive symptomatology and mtDNAcn. Our results provide evidence for a long-term, between-person relationship of depressive symptoms with LTL, rather than a dynamic and direct within-person relationship. In this study, we found no evidence for an association between depressive symptoms and mtDNAcn. PMID- 28348387 TI - A synthetic small-molecule Isoxazole-9 protects against methamphetamine relapse. AB - Adult neurogenesis in the dentate gyrus (DG) is strongly influenced by drug taking behavior and may have a role in the etiology of drug-seeking behavior. However, mechanistic studies on the relationship of neurogenesis on drug seeking are limited. Outbred Wistar rats experienced extended access methamphetamine self administration and individual differences in drug taking defined animals with higher preferred and lower preferred levels of drug intake. Forced abstinence from higher preferred levels of drug taking enhanced neurogenesis and neuronal activation of granule cell neurons (GCNs) in the DG and produced compulsive-like drug reinstatement. Systemic treatment with the drug Isoxazole-9 (a synthetic small molecule known to modulate neurogenesis in the adult rodent brain) during abstinence blocked compulsive-like context-driven methamphetamine reinstatement. Isoxazole-9 modulated neurogenesis, neuronal activation and structural plasticity of GCNs, and expression of synaptic proteins associated with learning and memory in the DG. These findings identify a subset of newly born GCNs within the DG that could directly contribute to drug-seeking behavior. Taken together, these results support a direct role for the importance of adult neurogenesis during abstinence in compulsive-like drug reinstatement. PMID- 28348386 TI - Perinatal risk factors in Tourette's and chronic tic disorders: a total population sibling comparison study. AB - Adverse perinatal events may increase the risk of Tourette's and chronic tic disorders (TD/CTD), but previous studies have been unable to control for unmeasured environmental and genetic confounding. We aimed to prospectively investigate potential perinatal risk factors for TD/CTD, taking unmeasured factors shared between full siblings into account. A population-based birth cohort, consisting of all singletons born in Sweden in 1973-2003, was followed until December 2013. A total of 3 026 861 individuals were identified, 5597 of which had a registered TD/CTD diagnosis. We then studied differentially exposed full siblings from 947 942 families; of these, 3563 families included siblings that were discordant for TD/CTD. Perinatal data were collected from the Medical Birth Register and TD/CTD diagnoses were collected from the National Patient Register, using a previously validated algorithm. In the fully adjusted models, impaired fetal growth, preterm birth, breech presentation and cesarean section were associated with a higher risk of TD/CTD, largely independent from shared family confounders and measured covariates. Maternal smoking during pregnancy was associated with risk of TD/CTD in a dose-response manner but the association was no longer statistically significant in the sibling comparison models or after the exclusion of comorbid attention-deficit/hyperactivity disorder. A dose-response relationship between the number of adverse perinatal events and increased risk for TD/CTD was also observed, with hazard ratios ranging from 1.41 (95% confidence interval (CI): 1.33-1.50) for one event to 2.42 (95% CI: 1.65-3.53) for five or more events. These results pave the way for future gene by environment interaction and epigenetic studies in TD/CTD. PMID- 28348389 TI - Stable and solubilized active Au atom clusters for selective epoxidation of cis cyclooctene with molecular oxygen. AB - The ability of Au catalysts to effect the challenging task of utilizing molecular oxygen for the selective epoxidation of cyclooctene is fascinating. Although supported nanometre-size Au particles are poorly active, here we show that solubilized atomic Au clusters, present in ng ml-1 concentrations and stabilized by ligands derived from the oxidized hydrocarbon products, are active. They can be formed from various Au sources. They generate initiators and propagators to trigger the onset of the auto-oxidation reaction with an apparent turnover frequency of 440 s-1, and continue to generate additional initiators throughout the auto-oxidation cycle without direct participation in the cycle. Spectroscopic characterization suggests that 7-8 atom clusters are effective catalytically. Extension of work based on these understandings leads to the demonstration that these Au clusters are also effective in selective oxidation of cyclohexene, and that solubilized Pt clusters are also capable of generating initiators for cyclooctene epoxidation. PMID- 28348388 TI - Nano-silver-decorated microfibrous eggshell membrane: processing, cytotoxicity assessment and optimization, antibacterial activity and wound healing. AB - An ideal wound dressing can both promote wound healing and prevent bacterial infection. Here, we report a potential dressing prepared by incorporating an optimized concentration of silver nanoparticles (AgNPs) into the microfibers of a natural eggshell membrane (EM) using environmentally friendly and mussel-inspired dopamine. Briefly, acid-treated EM was used as a porous membrane for polydopamine reduced AgNPs synthesis. To obtain the optimal cytocompatible silver concentration, cellular attachment and MTT assay were performed with different concentrations of AgNPs. The morphology of the EM and AgNPs was confirmed by scanning electronic microscopy, scanning transmission electronic microscopy and Fourier transform infrared spectroscopy. The synthesized EM/AgNPs exhibited steady and safe AgNPs release, which was further tested for antibacterial activity against Escherichia coli and Staphylococcus aureus by disc diffusion method and bacterial suspension assay. Finally, in a murine full-thickness skin wound model, we found that EM/AgNPs could promote re-epithelialization, granulation tissue formation and wound healing via enhancing cell proliferation, as demonstrated by the expression of proliferating cell nuclear antigen (PCNA), and controlling inflammation response, as demonstrated by the expression of interleukin-1beta (IL-1beta). These findings suggest that EM/AgNPs may have a promising application in wound management. PMID- 28348390 TI - Donor cell leukemia: evidence for multiple preleukemic clones and parallel long term clonal evolution in donor and recipient. PMID- 28348392 TI - Augmented reality with image registration, vision correction and sunlight readability via liquid crystal devices. AB - Augmented reality (AR), which use computer-aided projected information to augment our sense, has important impact on human life, especially for the elder people. However, there are three major challenges regarding the optical system in the AR system, which are registration, vision correction, and readability under strong ambient light. Here, we solve three challenges simultaneously for the first time using two liquid crystal (LC) lenses and polarizer-free attenuator integrated in optical-see-through AR system. One of the LC lens is used to electrically adjust the position of the projected virtual image which is so-called registration. The other LC lens with larger aperture and polarization independent characteristic is in charge of vision correction, such as myopia and presbyopia. The linearity of lens powers of two LC lenses is also discussed. The readability of virtual images under strong ambient light is solved by electrically switchable transmittance of the LC attenuator originating from light scattering and light absorption. The concept demonstrated in this paper could be further extended to other electro optical devices as long as the devices exhibit the capability of phase modulations and amplitude modulations. PMID- 28348391 TI - Functional cis-regulatory modules encoded by mouse-specific endogenous retrovirus. AB - Cis-regulatory modules contain multiple transcription factor (TF)-binding sites and integrate the effects of each TF to control gene expression in specific cellular contexts. Transposable elements (TEs) are uniquely equipped to deposit their regulatory sequences across a genome, which could also contain cis regulatory modules that coordinate the control of multiple genes with the same regulatory logic. We provide the first evidence of mouse-specific TEs that encode a module of TF-binding sites in mouse embryonic stem cells (ESCs). The majority (77%) of the individual TEs tested exhibited enhancer activity in mouse ESCs. By mutating individual TF-binding sites within the TE, we identified a module of TF binding motifs that cooperatively enhanced gene expression. Interestingly, we also observed the same motif module in the in silico constructed ancestral TE that also acted cooperatively to enhance gene expression. Our results suggest that ancestral TE insertions might have brought in cis-regulatory modules into the mouse genome. PMID- 28348393 TI - Combination of volume and perfusion parameters reveals different types of grey matter changes in schizophrenia. AB - Diverse brain structural and functional changes have been reported in schizophrenia. Identifying different types of brain changes may help to understand the neural mechanisms and to develop reliable biomarkers in schizophrenia. We aimed to categorize different grey matter changes in schizophrenia based on grey matter volume (GMV) and cerebral blood flow (CBF). Structural and perfusion magnetic resonance imaging data were acquired in 100 schizophrenia patients and 95 healthy comparison subjects. Voxel-based GMV comparison was used to show structural changes, CBF analysis was used to demonstrate functional changes. We identified three types of grey matter changes in schizophrenia: structural and functional impairments in the anterior cingulate cortex and insular cortex, displaying reduction in both GMV and CBF; structural impairment with preserved function in the frontal and temporal cortices, demonstrating decreased GMV with normal CBF; pure functional abnormality in the anterior cingulate cortex and lateral prefrontal cortex and putamen, showing altered CBF with normal GMV. By combination of GMV and CBF, we identified three types of grey matter changes in schizophrenia. These findings may help to understand the complex manifestations and to develop reliable biomarkers in schizophrenia. PMID- 28348395 TI - The Role of Local Instabilities in Fluid Invasion into Permeable Media. AB - Wettability is an important factor which controls the displacement of immiscible fluids in permeable media, with far reaching implications for storage of CO2 in deep saline aquifers, fuel cells, oil recovery, and for the remediation of oil contaminated soils. Considering the paradigmatic case of random piles of spherical beads, fluid front morphologies emerging during slow immiscible displacement are investigated in real time by X-ray micro-tomography and quantitatively compared with model predictions. Controlled by the wettability of the bead matrix two distinct displacement patterns are found. A compact front morphology emerges if the invading fluid wets the beads while a fingered morphology is found for non-wetting invading fluids, causing the residual amount of defending fluid to differ by one order of magnitude. The corresponding crossover between these two regimes in terms of the advancing contact angle is governed by an interplay of wettability and pore geometry and can be predicted on the basis of a purely quasi-static consideration of local instabilities that control the progression of the invading interface. PMID- 28348394 TI - The G2A receptor (GPR132) contributes to oxaliplatin-induced mechanical pain hypersensitivity. AB - Chemotherapy-induced peripheral neuropathic pain (CIPN) is a common and severe debilitating side effect of many widely used cytostatics. However, there is no approved pharmacological treatment for CIPN available. Among other substances, oxaliplatin causes CIPN in up to 80% of treated patients. Here, we report the involvement of the G-protein coupled receptor G2A (GPR132) in oxaliplatin-induced neuropathic pain in mice. We found that mice deficient in the G2A-receptor show decreased mechanical hypersensitivity after oxaliplatin treatment. Lipid ligands of G2A were found in increased concentrations in the sciatic nerve and dorsal root ganglia of oxaliplatin treated mice. Calcium imaging and patch-clamp experiments show that G2A activation sensitizes the ligand-gated ion channel TRPV1 in sensory neurons via activation of PKC. Based on these findings, we conclude that targeting G2A may be a promising approach to reduce oxaliplatin induced TRPV1-sensitization and the hyperexcitability of sensory neurons and thereby to reduce pain in patients treated with this chemotherapeutic agent. PMID- 28348396 TI - Cooperation and competition shape ecological resistance during periodic spatial disturbance of engineered bacteria. AB - Cooperation is fundamental to the survival of many bacterial species. Previous studies have shown that spatial structure can both promote and suppress cooperation. Most environments where bacteria are found are periodically disturbed, which can affect the spatial structure of the population. Despite the important role that spatial disturbances play in maintaining ecological relationships, it remains unclear as to how periodic spatial disturbances affect bacteria dependent on cooperation for survival. Here, we use bacteria engineered with a strong Allee effect to investigate how the frequency of periodic spatial disturbances affects cooperation. We show that at intermediate frequencies of spatial disturbance, the ability of the bacterial population to cooperate is perturbed. A mathematical model demonstrates that periodic spatial disturbance leads to a tradeoff between accessing an autoinducer and accessing nutrients, which determines the ability of the bacteria to cooperate. Based on this relationship, we alter the ability of the bacteria to access an autoinducer. We show that increased access to an autoinducer can enhance cooperation, but can also reduce ecological resistance, defined as the ability of a population to resist changes due to disturbance. Our results may have implications in maintaining stability of microbial communities and in the treatment of infectious diseases. PMID- 28348397 TI - Nanostructure Introduces Artifacts in Quantitative Immunofluorescence by Influencing Fluorophore Intensity. AB - Quantitative analysis of fluorescence signals from cells reacted with fluorescently labeled probes is a widely-used method for assessing cell biology. This method has become especially powerful for screening novel nanostructured materials for their influence on cell behavior. However, the effect of nanostructured surface on fluorescence intensity has largely been ignored, which likely leads to erroneous conclusions about cell behavior. This paper investigates this possibility by using fibroblasts cultured on nanoporous gold (np-Au) as a model nanostructured material system. We found that fibroblasts stained for f-actin using phalloidin conjugated with common fluorophores display different levels of fluorescence on np-Au, planar gold, and glass, suggesting different levels of f-actin composition. However, direct quantification via western blots indicates that the actin expression is the same across all conditions. We further investigated whether the fluorescence intensity depended on np-Au feature size, complementing the findings with reflection dark field measurements from different np-Au surfaces. Overall, our experimental measurements in agreement with our electrodynamic simulations suggest that nanostructured surfaces alter the fluorescence intensity of fluorophores by modulating both the excitation and light emission processes. We conclude that comparison of fluorescence on materials with different nanostructures should be done with a quantification method decoupled from the nanostructure's influence. PMID- 28348398 TI - Depleting Mycobacterium tuberculosis of the transcription termination factor Rho causes pervasive transcription and rapid death. AB - Rifampicin, which inhibits bacterial RNA polymerase, provides one of the most effective treatments for tuberculosis. Inhibition of the transcription termination factor Rho is used to treat some bacterial infections, but its importance varies across bacteria. Here we show that Rho of Mycobacterium tuberculosis functions to both define the 3' ends of mRNAs and silence substantial fragments of the genome. Brief inactivation of Rho affects over 500 transcripts enriched for genes of foreign DNA elements and bacterial virulence factors. Prolonged inactivation of Rho causes extensive pervasive transcription, a genome-wide increase in antisense transcripts, and a rapid loss of viability of replicating and non-replicating M. tuberculosis in vitro and during acute and chronic infection in mice. Collectively, these data suggest that inhibition of Rho may provide an alternative strategy to treat tuberculosis with an efficacy similar to inhibition of RNA polymerase. PMID- 28348399 TI - Regioregular narrow-bandgap-conjugated polymers for plastic electronics. PMID- 28348400 TI - Faster phonological processing and right occipito-temporal coupling in deaf adults signal poor cochlear implant outcome. AB - The outcome of adult cochlear implantation is predicted positively by the involvement of visual cortex in speech processing, and negatively by the cross modal recruitment of the right temporal cortex during and after deafness. How these two neurofunctional predictors concur to modulate cochlear implant (CI) performance remains unclear. In this fMRI study, we explore the joint involvement of occipital and right hemisphere regions in a visual-based phonological task in post-lingual deafness. Intriguingly, we show that some deaf subjects perform faster than controls. This behavioural effect is associated with reorganized connectivity across bilateral visual, right temporal and left inferior frontal cortices, but with poor CI outcome. Conversely, preserved normal-range reaction times are associated with left-lateralized phonological processing and good CI outcome. These results suggest that following deafness, involvement of visual cortex in the context of reorganized right-lateralized phonological processing compromises its availability for audio-visual synergy during adaptation to CI. PMID- 28348401 TI - X-ray ptychographic and fluorescence microscopy of frozen-hydrated cells using continuous scanning. AB - X-ray microscopy can be used to image whole, unsectioned cells in their native hydrated state. It complements the higher resolution of electron microscopy for submicrometer thick specimens, and the molecule-specific imaging capabilites of fluorescence light microscopy. We describe here the first use of fast, continuous x-ray scanning of frozen hydrated cells for simultaneous sub-20 nm resolution ptychographic transmission imaging with high contrast, and sub-100 nm resolution deconvolved x-ray fluorescence imaging of diffusible and bound ions at native concentrations, without the need to add specific labels. By working with cells that have been rapidly frozen without the use of chemical fixatives, and imaging them under cryogenic conditions, we are able to obtain images with well preserved structural and chemical composition, and sufficient stability against radiation damage to allow for multiple images to be obtained with no observable change. PMID- 28348402 TI - Plasmonic hot electron transport drives nano-localized chemistry. AB - Nanoscale localization of electromagnetic fields near metallic nanostructures underpins the fundamentals and applications of plasmonics. The unavoidable energy loss from plasmon decay, initially seen as a detriment, has now expanded the scope of plasmonic applications to exploit the generated hot carriers. However, quantitative understanding of the spatial localization of these hot carriers, akin to electromagnetic near-field maps, has been elusive. Here we spatially map hot-electron-driven reduction chemistry with 15 nm resolution as a function of time and electromagnetic field polarization for different plasmonic nanostructures. We combine experiments employing a six-electron photo-recycling process that modify the terminal group of a self-assembled monolayer on plasmonic silver nanoantennas, with theoretical predictions from first-principles calculations of non-equilibrium hot-carrier transport in these systems. The resulting localization of reactive regions, determined by hot-carrier transport from high-field regions, paves the way for improving efficiency in hot-carrier extraction science and nanoscale regio-selective surface chemistry. PMID- 28348403 TI - Transcriptome and functional analysis reveals hybrid vigor for oil biosynthesis in oil palm. AB - Oil palm is the most productive oil crop in the world and composes 36% of the world production. However, the molecular mechanisms of hybrids vigor (or heterosis) between Dura, Pisifera and their hybrid progeny Tenera has not yet been well understood. Here we compared the temporal and spatial compositions of lipids and transcriptomes for two oil yielding organs mesocarp and endosperm from Dura, Pisifera and Tenera. Multiple lipid biosynthesis pathways are highly enriched in all non-additive expression pattern in endosperm, while cytokinine biosynthesis and cell cycle pathways are highly enriched both in endosperm and mesocarp. Compared with parental palms, the high oil content in Tenera was associated with much higher transcript levels of EgWRI1, homolog of Arabidopsis thaliana WRINKLED1. Among 338 identified genes in lipid synthesis, 207 (61%) has been identified to contain the WRI1 specific binding AW motif. We further functionally identified EgWRI1-1, one of three EgWRI1 orthologs, by genetic complementation of the Arabidopsis wri1 mutant. Ectopic expression of EgWRI1-1 in plant produced dramatically increased seed mass and oil content, with oil profile changed. Our findings provide an explanation for EgWRI1 as an important gene contributing hybrid vigor in lipid biosynthesis in oil palm. PMID- 28348405 TI - Isolation and Characterization of Encephalomyocarditis Virus from Dogs in China. AB - Encephalomyocarditis virus (EMCV) is as a potential zoonotic agent with a wide host range. Here, we describe an EMC virus isolate, identified as EMCV C15, which was successfully obtained from the serum of dogs from animal hospitals. Virus production in cell culture was confirmed by EMCV-specific real-time RT-PCR, indirect immunofluorescence assays and electron microscopy. In addition, the open reading frame sequence (ORF) of the EMCV C15 virus was determined. From sequence comparison and phylogenetic analysis among 24 reference EMCV strains, it appears that the EMCV C15 strain is closely genetically related to strain BEL2887A/91 (>99.0% nucleotide identity). In artificially challenged dogs, the heart and brain were important targets of EMCV C15. This study provides genetic and pathogenic characterization of the EMCV C15 strain isolated in Beijing and calls for sustained surveillance of EMCV infection in China to support better prevention and control of the disease. PMID- 28348406 TI - Cross shelf benthic biodiversity patterns in the Southern Red Sea. AB - The diversity of coral reef and soft sediment ecosystems in the Red Sea has to date received limited scientific attention. This study investigates changes in the community composition of both reef and macrobenthic communities along a cross shelf gradient. Coral reef assemblages differed significantly in species composition and structure with location and depth. Inner shelf reefs harbored less abundant and less diverse coral assemblages with higher percentage macroalgae cover. Nutrient availability and distance from the shoreline were significantly related to changes in coral composition and structure. This study also observed a clear inshore offshore pattern for soft sediment communities. In contrast to the coral reef patterns the highest diversity and abundance of soft sediment communities were recorded at the inshore sites, which were characterized by a higher number of opportunistic polychaete species and bivalves indicative of mild disturbance. Sediment grain size and nutrient enrichment were important variables explaining the variability. This study aims to contribute to our understanding of ecosystem processes and biodiversity in the Red Sea region in an area that also has the potential to provide insight into pressing topics, such as the capacity of reef systems and benthic macrofaunal organisms to adapt to global climate change. PMID- 28348404 TI - Proteogenomic integration reveals therapeutic targets in breast cancer xenografts. AB - Recent advances in mass spectrometry (MS) have enabled extensive analysis of cancer proteomes. Here, we employed quantitative proteomics to profile protein expression across 24 breast cancer patient-derived xenograft (PDX) models. Integrated proteogenomic analysis shows positive correlation between expression measurements from transcriptomic and proteomic analyses; further, gene expression based intrinsic subtypes are largely re-capitulated using non-stromal protein markers. Proteogenomic analysis also validates a number of predicted genomic targets in multiple receptor tyrosine kinases. However, several protein/phosphoprotein events such as overexpression of AKT proteins and ARAF, BRAF, HSP90AB1 phosphosites are not readily explainable by genomic analysis, suggesting that druggable translational and/or post-translational regulatory events may be uniquely diagnosed by MS. Drug treatment experiments targeting HER2 and components of the PI3K pathway supported proteogenomic response predictions in seven xenograft models. Our study demonstrates that MS-based proteomics can identify therapeutic targets and highlights the potential of PDX drug response evaluation to annotate MS-based pathway activities. PMID- 28348407 TI - Fabrication of nanotweezers and their remote actuation by magnetic fields. AB - A new kind of nanodevice that acts like tweezers through remote actuation by an external magnetic field is designed. Such device is meant to mechanically grab micrometric objects. The nanotweezers are built by using a top-down approach and are made of two parallelepipedic microelements, at least one of them being magnetic, bound by a flexible nanohinge. The presence of an external magnetic field induces a torque on the magnetic elements that competes with the elastic torque provided by the nanohinge. A model is established in order to evaluate the values of the balanced torques as a function of the tweezers opening angles. The results of the calculations are confronted to the expected values and validate the overall working principle of the magnetic nanotweezers. PMID- 28348408 TI - Feasible attack on detector-device-independent quantum key distribution. AB - Recently, to bridge the gap between security of Measurement-device-independent quantum key distribution (MDI-QKD) and a high key rate, a novel protocol, the so called detector-device-independent QKD (DDI-QKD), has been independently proposed by several groups and has attracted great interest. A higher key rate is obtained, since a single photon bell state measurement (BSM) setup is applied to DDI-QKD. Subsequently, Qi has proposed two attacks for this protocol. However, the first attack, in which Bob's BSM setup is assumed to be completely a "black box", is easily prevented by using some additional monitoring devices or by specifically characterizing the BSM. The second attack, which combines the blinding attack and the detector wavelength-dependent efficiency, is not explicitly discussed, and its feasibility is not experimentally confirmed. Here, we show that the second attack is not technically viable because of an intrinsically wavelength-dependent property of a realistic beam splitter, which is an essential component in DDI-QKD. Moreover, we propose a feasible attack that combines a well-known attack-detector blinding attack with intrinsic imperfections of single-photon detectors. The experimental measurement and proof of-principle test results confirm that our attack can allow Eve to get a copy of quantum keys without being detected and that it is feasible with current technology. PMID- 28348409 TI - Inhibiting the system xC-/glutathione axis selectively targets cancers with mutant-p53 accumulation. AB - TP53, a critical tumour suppressor gene, is mutated in over half of all cancers resulting in mutant-p53 protein accumulation and poor patient survival. Therapeutic strategies to target mutant-p53 cancers are urgently needed. We show that accumulated mutant-p53 protein suppresses the expression of SLC7A11, a component of the cystine/glutamate antiporter, system xC-, through binding to the master antioxidant transcription factor NRF2. This diminishes glutathione synthesis, rendering mutant-p53 tumours susceptible to oxidative damage. System xC- inhibitors specifically exploit this vulnerability to preferentially kill cancer cells with stabilized mutant-p53 protein. Moreover, we demonstrate that SLC7A11 expression is a novel and robust predictive biomarker for APR-246, a first-in-class mutant-p53 reactivator that also binds and depletes glutathione in tumours, triggering lipid peroxidative cell death. Importantly, system xC- antagonism strongly synergizes with APR-246 to induce apoptosis in mutant-p53 tumours. We propose a new paradigm for targeting cancers that accumulate mutant p53 protein by inhibiting the SLC7A11-glutathione axis. PMID- 28348410 TI - A Pseudomonas T6SS effector recruits PQS-containing outer membrane vesicles for iron acquisition. AB - Iron sequestration by host proteins contributes to the defence against bacterial pathogens, which need iron for their metabolism and virulence. A Pseudomonas aeruginosa mutant lacking all three known iron acquisition systems retains the ability to grow in media containing iron chelators, suggesting the presence of additional pathways involved in iron uptake. Here we screen P. aeruginosa mutants defective in growth in iron-depleted media and find that gene PA2374, proximal to the type VI secretion system H3 (H3-T6SS), functions synergistically with known iron acquisition systems. PA2374 (which we have renamed TseF) appears to be secreted by H3-T6SS and is incorporated into outer membrane vesicles (OMVs) by directly interacting with the iron-binding Pseudomonas quinolone signal (PQS), a cell-cell signalling compound. TseF facilitates the delivery of OMV-associated iron to bacterial cells by engaging the Fe(III)-pyochelin receptor FptA and the porin OprF. Our results reveal links between type VI secretion, cell-cell signalling and classic siderophore receptors for iron acquisition in P. aeruginosa. PMID- 28348413 TI - THE BLOODY AMPUTATION: A DISCUSSION OF A FIRST DREAM IN AN ANALYSIS. PMID- 28348412 TI - Pentameric ligand-gated ion channels exhibit distinct transmembrane domain archetypes for folding/expression and function. AB - Although transmembrane helix-helix interactions must be strong enough to drive folding, they must still permit the inter-helix movements associated with conformational change. Interactions between the outermost M4 and adjacent M1 and M3 alpha-helices of pentameric ligand-gated ion channels have been implicated in folding and function. Here, we evaluate the role of different physical interactions at this interface in the function of two prokaryotic homologs, GLIC and ELIC. Strikingly, disruption of most interactions in GLIC lead to either a reduction or a complete loss of expression and/or function, while analogous disruptions in ELIC often lead to gains in function. Structural comparisons suggest that GLIC and ELIC represent distinct transmembrane domain archetypes. One archetype, exemplified by GLIC, the glycine and GABA receptors and the glutamate activated chloride channel, has extensive aromatic contacts that govern M4-M1/M3 interactions and that are essential for expression and function. The other archetype, exemplified by ELIC and both the nicotinic acetylcholine and serotonin receptors, has relatively few aromatic contacts that are detrimental to function. These archetypes likely have evolved different mechanisms to balance the need for strong M4 "binding" to M1/M3 to promote folding/expression, and the need for weaker interactions that allow for greater conformational flexibility. PMID- 28348411 TI - Global site-specific N-glycosylation analysis of HIV envelope glycoprotein. AB - HIV-1 envelope glycoprotein (Env) is the sole target for broadly neutralizing antibodies (bnAbs) and the focus for design of an antibody-based HIV vaccine. The Env trimer is covered by ~90N-linked glycans, which shield the underlying protein from immune surveillance. bNAbs to HIV develop during infection, with many showing dependence on glycans for binding to Env. The ability to routinely assess the glycan type at each glycosylation site may facilitate design of improved vaccine candidates. Here we present a general mass spectrometry-based proteomics strategy that uses specific endoglycosidases to introduce mass signatures that distinguish peptide glycosites that are unoccupied or occupied by high mannose/hybrid or complex-type glycans. The method yields >95% sequence coverage for Env, provides semi-quantitative analysis of the glycosylation status at each glycosite. We find that most glycosites in recombinant Env trimers are fully occupied by glycans, varying in the proportion of high-mannose/hybrid and complex type glycans. PMID- 28348415 TI - Potential role of fecal microbiota from patients with slow transit constipation in the regulation of gastrointestinal motility. AB - The gut microbiota is involved in various physiological functions, and disturbances in the host-microbiome have been proven to contribute to the dysfunction of gut; however, whether microbiota participates in the pathogenesis of constipation remains unclear. In this study, we extracted and analyzed microbiota in feces from constipated donors who had undergone effective therapy with fecal microbiota transplantation, transplanted microbiota into pseudo-germ free mice, and measured gut motility. These mice presented with lower pellet frequency and water percentage, smaller pellet size, delayed gastrointestinal transit time, and weaker spontaneous contractions of colonic smooth muscle. To determine the mechanism underlying delayed gut motility, microbial metabolites were measured. Short chain fatty acids and secondary bile acids were decreased in mice receiving microbiota from constipated donors. Moreover, the compositional changes of gut microbiota in constipated patients were identified, including the operational taxonomic unit, and the species richness and alpha diversity were much greater than those in healthy volunteers. These findings suggest that alterations of the microbiome might affect gut motility via altered microbial derived metabolites in the development of constipation, and the restoration of disturbed microbiota might improve the clinical phenotype. This study indicates that regulating the intestinal environment may be a novel therapy strategy for constipation. PMID- 28348417 TI - Effects of cadmium on the glial architecture in lizard brain. AB - The glial cells are positioned to be the first cells of the brain parenchyma to face molecules crossing the blood-brain barrier with a relevant neuroprotective role from cytotoxic action of heavy metals on the nervous system. Cadmium is a highly toxic metal and its levels in the environment are increasing due to industrial activities. This element can pass the blood-brain barrier and have neurotoxic activity. For this reason we have studied the effects of cadmium on the glial architecture in the lizard Podarcis siculus, a significant bioindicator of chemical exposure due to its persistence in a variety of habitats. The study was performed on two groups of lizards. The first group of P. siculus was exposed to an acute treatment by a single i.p. injection (2 mg/kg-BW) of CdCl2 and sacrificed after 2, 7 and 16 days. The second one was used as control. The histology of the brain was studied by Hematoxylin/Eosin and Cresyl/Violet stains while the glial structures were analyzed by immunodetection of the glial fibrillary acidic protein (GFAP), the most widely accepted marker for astroglial cells. Evident morphological alterations of the brain were observed at 7 and 16 days from the injection, when we revealed also a decrease of the GFAP immunopositive structures in particular in the rhombencephalic ventricle, telencephalon and optic tectum. These results show that in the lizards an acute exposure to cadmium provokes morphological cellular alterations in the brain but also a decrement of the expression of GFAP marker with possible consequent damage of glial cells functions. PMID- 28348416 TI - Cannabinoid CB2 receptors are involved in the protection of RAW264.7 macrophages against the oxidative stress: an in vitro study. AB - Research in the last decades has widely investigated the anti-oxidant properties of natural products as a therapeutic approach for the prevention and the treatment of oxidative-stress related disorders. In this context, several studies were aimed to evaluate the therapeutic potential of phytocannabinoids, the bioactive compounds of Cannabis sativa. Here, we examined the anti-oxidant ability of Cannabigerol (CBG), a non-psychotropic cannabinoid, still little known, into counteracting the hydrogen peroxide (H2O2)-induced oxidative stress in murine RAW264.7 macrophages. In addition, we tested selective receptor antagonists for cannabinoid receptors and specifically CB1R (SR141716A) and CB2R (AM630) in order to investigate through which CBG may exert its action. Taken together, our in vitro results showed that CBG is able to counteract oxidative stress by activation of CB2 receptors. CB2 antagonist pre-treatment indeed blocked the protective effects of CBG in H2O2 stimulated macrophages, while CB1R was not involved. Specifically, CBG exhibited a potent action in inhibiting oxidative stress, by down-regulation of the main oxidative markers (iNOS, nitrotyrosine and PARP-1), by preventing IkappaB-alpha phosphorylation and translocation of the nuclear factor-kappaB (NF-kappaB) and also via the modulation of MAP kinases pathway. On the other hand, CBG was found to increase anti-oxidant defense of cells by modulating superoxide dismutase-1 (SOD-1) expression and thus inhibiting cell death (results focused on balance between Bax and Bcl-2). Based on its antioxidant activities, CBG may hold great promise as an anti-oxidant agent and therefore used in clinical practice as a new approach in oxidative-stress related disorders. PMID- 28348418 TI - Expression of CGRP, vasculogenesis and osteogenesis associated mRNAs in the developing mouse mandible and tibia. AB - The neuropeptide Calcitonin Gene-Related Peptide (CGRP) is a well-characterized neurotransmitter. However, little is known about the role of CGRP in osteogenesis and vascular genesis during the developmental formation of bone. In the present study, we assessed the abundance of CGRP mRNA and the mRNA of osteogenesis and vascular genesis markers in the foetal mouse mandible and leg bone (tibia). We also analysed the expression and localization of CGRP, osteopontin (OPN) and vascular endothelial growth factor (VEGF-A) using in situ hybridization and immunohistochemical localization in the mouse mandible and tibia at embryonic days 12.5 (E12.5), E14.5, E17.5, and postnatal day 1 (P1). CGRP was clearly detected in the mandible relative to the tibia at E14.5. Hybridization using an anti-sense probe for CGRP was not detected in the mandible at P1. Hybridization with an anti-sense probe for OPN was detected at E14.5, later in the mandible and at P1 in Meckel's cartilage. However, OPN was only detected in the tibia at E17.5 and later. The abundance of CGRP mRNA differed between the mandible and tibia. The level of vasculogenesis markers, such as VEGF-A, was similar to that of CGRP in the mandible. The levels of VEGF-A, cluster of differentiation 31 (CD31) and lymphatic vessel endothelial hyaluronan receptor 1 (LIVE-1) differed from that of OPN in the mandible. In contrast, the levels of VEGF-A, CD31, matrix metalloproteinase-2 (MMP-2), collagen I (Col I), collagen II (Col II) and OPN mRNA differed from E12.5 to P1 (P<0.001) in the tibia. The abundance of mRNA of CGRP and bone matrix markers (Col I, Col II, and OPN) was low at P5 in the tibia. These differences in CGRP and other mRNAs may induce a different manner of ossification between the mandible and tibia. Therefore, a time lag of ossification occurs between the mandible and tibia during foetal development. PMID- 28348419 TI - Functional topography of the fully grown human oocyte. AB - In vivo maturation (IVM) of human oocytes is a technique used to increase the number of usable oocytes for in vitro fertilization (IVF) and represents a necessity for women with different ovarian pathologies. During IVM the oocytes progress from the germinal vesicle stage (GV) through the metaphase II and during this journey both nuclear and cytoplasmic rearrangements must be obtained to increase the probability to get viable and healthy zygotes/embryos after IVF. As the successful clinical outcomes of this technique are a reality, we wanted to investigate the causes behind oocytes maturation arrest. For obvious ethical reasons, we were able to analyze only few human immature oocytes discarded and donated to research by transmission electron microscopy showing that, as in the mouse, they have different chromatin and cytoplasmic organizations both essential for further embryo development. PMID- 28348420 TI - Reelin expression in human liver of patients with chronic hepatitis C infection. AB - Reelin is a secreted extracellular glycoprotein that plays a critical role during brain development. Several studies have described Reelin expression in hepatic stellate cells of the human liver. In order to investigate the possible role of Reelin in the process of hepatic fibrogenesis, in this study we investigated Reelin expression in the liver tissue of patients infected with the Hepatitis C Virus (HCV). On this basis, Reelin expression was analysed by immunohistochemistry during liver biopsies of 81 patients with HCV-related chronic hepatitis. A Knodell score was used to stage liver fibrosis. Hepatic stellate cells/myofibroblast immunohistochemical markers (CRBP-1, alpha-SMA) were also evaluated. As further confirmed by co-localization experiments (Reelin +CRBP 1), Reelin protein was expressed by hepatic stellate cells/myofibroblasts, and a significant positive correlation was found between Reelin expression and the stage of liver fibrosis (P=0.002). Moreover, Reelin correlated with CRBP-1 positive cells (P=0.002), but not with alpha-SMA, suggesting that Reelin should not be regarded as a marker of hepatic stellate cells/myofibroblasts differentiation but rather as a functional protein expressed during some phases of liver fibrosis. Furthermore, Disabled-1 (Dab1), a Reelin adaptor protein, was expressed in cells of ductular reaction suggesting a paracrine role for Reelin with regards these elements. In conclusion, Reelin was expressed by human hepatic stellate cells/myofibroblasts and the number of these cells increased significantly in the lobule as the liver fibrosis progressed, suggesting a role for Reelin in the activation of hepatic stellate cells/myofibroblasts during liver injury. Reelin may potentially be incorporated into liver injury evaluations in combination with other histological data. PMID- 28348421 TI - The multifaceted role of podoplanin expression in hepatocellular carcinoma. AB - The role of podoplanin in hepatocellular carcinoma (HCC) is not clear yet. The aim of our study was to evaluate the expression of podoplanin in HCC and to determine its role in hepatocarcinogenesis. We performed immunohistochemistry with monoclonal D2-40 antibody, on paraffin-embedded tissue sections of 72 patients diagnosed with HCC. Lymphatic vessels density (LVD) was increased in patients who had vascular invasion at the time of diagnosis (P=0.018) and in those with associated cirrhosis (P=0.006). Tumor cells showing podoplanin expression were correlated with histological grade (P=0.040). Podoplanin expressing cancer associated fibroblasts (CAFs) were correlated with both LVD (P=0.019) and tumor cells (P=0.015). Our results sustain the dual role of podoplanin in HCC by its involvement in both HCC tumorigenesis, lymphatic neovascularization and tumor invasion invasiveness. A possible crosstalk between epithelial and stromal tumor cells in HCC tumor microenvironment may be mediated by podoplanin, but this hypothesis needs further studies to elucidate this interrelation. PMID- 28348422 TI - Lectin-like, oxidized low-density lipoprotein receptor-1-deficient mice show resistance to age-related knee osteoarthritis. AB - The lectin-like, oxidized low-density lipoprotein (ox-LDL) receptor-1 (LOX-1)/ox LDL system contributes to atherosclerosis and may be involved in cartilage degeneration. The purpose of this study was to determine whether the LOX-1/ox-LDL system contributes to age-related osteoarthritis (OA) in vivo, using LOX-1 knockout (LOX-1 KO) mice. Knee cartilage from 6, 12, and 18-month old (n = 10/group) C57Bl/6 wild-type (WT) and LOX-1 KO mice was evaluated by determining the Osteoarthritis Research Society International (OARSI) score of Safranin-O stained samples. The prevalence of knee OA in both mouse strains was also investigated. Expression levels of LOX-1, ox-LDL, runt-related transcription factor-2 (Runx2), type-X collagen (COL X), and matrix metalloproteinase-13 (MMP 13) in the articular chondrocytes were analyzed immunohistologically. No significant difference was observed in the mean scores of WT (2.00+/-0.61) and LOX-1 KO mice (2.00+/-0.49) at 6 months of age (P=1.00, n=10). At 12 and 18 months of age, the mean scores of LOX-1 KO mice (3.75+/-0.93 and 5.50+/-0.78) were significantly lower than those of WT mice (5.25+/-1.14 and 9.00+/-1.01; P<0.001 in both cases; n=10). The prevalence of OA in LOX-1 KO mice was lower than that in WT mice at 12 and 18 months of age (40 vs 70%, 70 vs 90%, respectively; n=10). The expression levels of Runx2, COL X, and MMP-13 in articular chondrocytes significantly decreased in LOX-1 KO, mice compared with those in WT mice. The study indicated that the LOX-1/ox-LDL system in chondrocytes plays a role in the pathogenesis of age-related knee OA, which is potentially a target for preventing OA progression. PMID- 28348423 TI - OTX1 and OTX2 as possible molecular markers of sinonasal carcinomas and olfactory neuroblastomas. AB - OTX Homeobox genes are involved in embryonic morphogenesis and in the development of olfactory epithelium in adult. Mutations occurring in the OTX genes are reported to be associated to tumorigenisis in human. No reports correlate the expression of OTX genes and neoplasms of the nasal cavity. Thus, through immunohistochemical and Real-time PCR analysis we investigated OTX1 and OTX2 expression in the more frequent types of nasal and sinonasal tumours. Variable expression of both genes were found in normal sinonasal mucosa and in tumours. Interestingly, no expression of both OTX genes were detected in sinonasal intestinal-type adenocarcinomas; only OTX1 was found in non-intestinal-type adenocarcinomas and OTX2 was selectively expressed in olfactory neuroblastomas. In conclusion, OTX1 and OTX2 genes might have a role in the pathogenesis of different types of sinonasal neoplasms. PMID- 28348425 TI - The Roles We Have as Hospital Pharmacists. PMID- 28348426 TI - ? PMID- 28348424 TI - Immunohistochemistry detected and localized cannabinoid receptor type 2 in bovine fetal pancreas at late gestation. AB - At present, data on the endocannabinoid system expression and distribution in the pancreatic gland appear scarce and controversial as descriptions are limited to humans and laboratory animals. Since the bovine pancreas is very similar to the human in endocrine portion development and control, studies on the fetal gland could prove to be very interesting, as an abnormal maternal condition during late pregnancy may be a predisposing trigger for adult metabolic disorders. The present investigation studied cannabinoid receptor type 2 presence and distribution in the bovine fetal pancreas towards the end of gestation. Histological analyses revealed numerous endocrinal cell clusters or islets which were distributed among exocrine adenomeri in connectival tissue. Immunohistochemistry showed that endocrine-islets contained some CB2-positive cells with a very peculiar localization that is a few primarily localized at the edges of islets and some of them also scattered in the center of the cluster. Characteristically, also the epithelium of the excretory ducts and the smooth muscle layers of the smaller arteries, in the interlobular glandular septa, tested positive for the CB2 endocannabinoid receptor. Conse - quently, the endocannabinoid system, via the cannabinoid receptor type 2, was hypothesized to play a major role in controlling pancreas function from normal fetal development to correct metabolic functioning in adulthood. PMID- 28348427 TI - Extended Stability of Sodium Phosphate Solutions in Polyvinyl Chloride Bags. AB - BACKGROUND: Sodium phosphate injection is used to treat moderate to severe hypophosphatemia. There have been no published reports documenting the physical compatibility or chemical stability of sodium phosphate injection in IV solutions. OBJECTIVE: To evaluate the physical compatibility and chemical stability of 30 and 150 mmol/L solutions of phosphate, prepared from sodium phosphate injection, in 5% dextrose in water (D5W) and in 0.9% sodium chloride (normal saline [NS]) and stored in polyvinyl chloride (PVC) bags at 23 degrees C or 4 degrees C over 63 days. METHODS: On study day 0, solutions of phosphate 30 and 150 mmol/L in D5W or NS were prepared in PVC bags and stored at 4 degrees C and 23 degrees C. On prespecified days during the 63-day study period, the concentrations of sodium and phosphate were determined, and admixture weight was checked to assess moisture loss during storage without a plastic overwrap. Chemical stability was calculated from the intersection of the lower 95% confidence limit of the degradation rate and the lower limit of acceptability (90%) for concentration remaining. RESULTS: The analytical methods for both sodium and phosphate were found to be precise (coefficient of variation averaging less than 1% for pre-study validation samples). Both sodium and phosphate retained more than 94% of the initial concentration over the 63-day study period. With 95% confidence, the time to achieve 90% of the initial concentration of both sodium and phosphate approached or exceeded the 63-day study period, regardless of temperature, concentration, or base solution. CONCLUSIONS: Sodium phosphate solutions at a phosphate concentration of 30 or 150 mmol/L in either NS or D5W retained more than 94% of the initial concentration of both sodium and phosphate over 63 days when stored at 23 degrees C or 4 degrees C. In compliance with United States Pharmacopeia General Chapter <797> recommendations, a beyond-use date of 14 days (with refrigeration) or 48 h (room temperature) may be applied. Extending the beyond-use date beyond these limits may be considered, if a validated sterility test is performed. PMID- 28348428 TI - Respiratory Syncytial Virus Infection Rates with Limited Use of Palivizumab for Infants Born at 29 to 31+6/7 Weeks Gestational Age. AB - BACKGROUND: Immunoprophylaxis with palivizumab can reduce respiratory syncytial virus (RSV) infections and hospitalizations. Criteria in British Columbia limit the use of palivizumab to infants born at 29 to 31+6/7 weeks gestational age, which differ from guidelines of the American Academy of Pediatrics (AAP) and the Canadian Paediatric Society (CPS). OBJECTIVE: To determine whether the limited use of palivizumab affected the frequency of hospital visits by RSV-positive infants (termed "RSV-positive hospital visits") who received approval for palivizumab and those who met the AAP/CPS criteria but did not receive approval for palivizumab. METHODS: Data sets were generated for the period May 1, 2008, to April 30, 2011, to identify infants with gestational age of 29 to 31+6/7 weeks who were born in or transferred to the Fraser Health authority, RSV-positive results for infants less than 12 months of age who had visited Fraser Health sites and BC Children's Hospital, and palivizumab approvals. Infants were matched across these 3 data sets through their personal health numbers. RESULTS: The study included 359 infants born at 29 to 31+6/7 weeks, of whom 297 met the AAP/CPS criteria. However, only 46 of these 297 received approval for palivizumab according to the BC criteria. Sixteen (4.5%) of the 359 infants had RSV-positive hospital visits during the RSV season (November through March). Of the 46 infants who received approval for palivizumab, 2 (4.3%) had RSV-positive hospital visits, and of the 251 who met the AAP/CPS criteria but did not receive palivizumab approval, 14 (5.6%) had RSV-positive hospital visits. Of the 359 infants, 6 (1.7%) had RSV-positive results while admitted to the neonatal intensive care unit, and 10 (2.8%) tested positive for RSV during a subsequent hospital visit. CONCLUSIONS: The frequency of RSV-positive hospital visits did not differ between infants who received and those who did not receive approval for palivizumab in the Fraser Health authority. Limited use of palivizumab for RSV prophylaxis led to reasonable rates of RSV-positive hospital visits in the study population. PMID- 28348429 TI - Implementation and Assessment of a Pharmacy Educational Program Concerning Laboratory Monitoring for Medications. AB - BACKGROUND: The pharmacist's role in monitoring medication therapy, including the ability to order laboratory tests as a delegated medical function, has increased dramatically over the past 20 years. OBJECTIVES: To implement and assess the impact of an intervention designed to educate pharmacists about appropriate medication-related laboratory monitoring and clinical interpretation of results. METHODS: This pilot project had a pretest-posttest study design. The intervention was an educational program comprising 8 self-directed learning modules, each with a corresponding seminar. Evaluation of the program included scoring of the appropriateness and significance of clinical interventions related to laboratory monitoring, pre- and post-program test scores, and participants' subjective assessments of their abilities to order and assess the results of medication related laboratory investigations. Descriptive statistics, the Wilcoxon signed rank test, the Student t-test, and the paired Student t-test were used where appropriate. Associations were assessed with the Pearson or Spearman rho correlation coefficient. All statistical tests were 2-tailed, and the p value for significance was established a priori at 0.05. RESULTS: There was no statistically significant difference with regard to the appropriateness (p = 0.70) or significance (p = 0.94) of clinical interventions undertaken before and after the educational program. Among the 21 pharmacists who completed the program, the average test score (+/- standard deviation) was 27.2 +/- 8.1 before the program, increasing to 39.2 +/- 8.7 after the program (p < 0.001). There was a statistically significant improvement in the perceived level of knowledge for each individual module (p < 0.05 for all). CONCLUSIONS: The establishment of an educational program led to improvements in both subjective and objective measures of knowledge and perceived abilities to order and assess the results of medication-related laboratory tests. PMID- 28348431 TI - Use of the 2008 Basel Consensus Statements to Assess, Realign, and Monitor Pharmacy Practice at a Tertiary Care Hospital in Northern Uganda: Illustrative Case Study, Part 2. PMID- 28348432 TI - Should Institutional Pharmacy Managers Maintain an Active Clinical Practice? PMID- 28348430 TI - Influenza Vaccination for Secondary Prevention of Cardiovascular Events: A Systematic Review. AB - BACKGROUND: Influenza is a common respiratory infection that may cause complications, including cardiovascular events. Influenza illness has been shown to double the risk of myocardial infarction, with the highest risk among patients with established cardiovascular disease. Vaccination against influenza has been associated with reductions in myocardial infarction, cerebrovascular disease, and death. OBJECTIVE: To evaluate the evidence for influenza vaccination as a strategy to reduce cardiovascular events specifically in patients with established cardiovascular disease. DATA SOURCES AND STUDY SELECTION: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched with the terms "influenza vaccine" and "cardiovascular disease". Included in this review were randomized controlled trials (RCTs), nonrandomized studies, and meta analyses that compared influenza vaccination against control in patients with established cardiovascular disease and that reported clinically meaningful cardiovascular outcomes (defined as cardiovascular death, myocardial infarction, and stroke). DATA EXTRACTION AND SYNTHESIS: The search yielded 10 studies (3 nonrandomized studies, 5 RCTs, and 2 meta-analyses). The nonrandomized studies and the RCTs had inconsistent results with respect to cardiovascular death and adverse cardiovascular events. The 2 meta-analyses, which included the same 4 RCTs involving patients with established cardiovascular disease, showed that the influenza vaccine reduced cardiovascular death by about 50% relative to control. Vaccination also reduced major cardiovascular events by about 43%; the reduction was greater (54%) in the subgroup of patients with recent (<= 1 year) acute coronary syndrome. However, these data are potentially confounded by small sample sizes, low event rates, and variable outcome reporting. There was also high clinical heterogeneity among the studies, which may not reflect contemporary practice. CONCLUSIONS: Given the limitations of these data, it is unclear whether the cardiovascular benefit with influenza vaccination in patients with cardiovascular disease is a true effect. Nevertheless, because of the potential benefit and the low risk of adverse events, the annual influenza vaccine should be recommended for all patients with established cardiovascular disease. PMID- 28348433 TI - Stability of Extemporaneously Compounded Tacrolimus in Glass Bottles and Plastic Syringes. PMID- 28348434 TI - "You Want To Go Where?" A Perspective on Skills and Competencies Developed through International Pharmacy Education Experiences. PMID- 28348435 TI - Tribute to the Reviewers of the Canadian Journal of Hospital Pharmacy. PMID- 28348436 TI - The Year of the Cat. PMID- 28348438 TI - ? PMID- 28348437 TI - ? PMID- 28348439 TI - The Pursuit of Professional Practice Excellence and the Achievement of Peer Recognition. PMID- 28348440 TI - Family Structure, Residential Mobility, and Environmental Inequality. AB - This study combines micro-level data on families with children from the Panel Study of Income Dynamics with neighborhood-level industrial hazard data from the Environmental Protection Agency and neighborhood-level U.S. census data to examine both the association between family structure and residential proximity to neighborhood pollution and the micro-level, residential mobility processes that contribute to differential pollution proximity across family types. Results indicate the existence of significant family structure differences in household proximity to industrial pollution in U.S. metropolitan areas between 1990 and 1999, with single-mother and single-father families experiencing neighborhood pollution levels that are on average 46% and 26% greater, respectively, than those experienced by two-parent families. Moreover, the pollution gap between single-mother and two-parent families persists with controls for household and neighborhood socioeconomic, sociodemographic, and race/ethnic characteristics. Examination of underlying migration patterns reveals that single-mother, single father, and two-parent families are equally likely to move in response to pollution. However, mobile single-parent families move into neighborhoods with significantly higher pollution levels than do mobile two-parent families. Thus, family structure differences in pollution proximity are maintained more by these destination neighborhood differences than by family structure variations in the likelihood of moving out of polluted neighborhoods. PMID- 28348441 TI - Educational Pathways and Change in Crime Between Adolescence and Early Adulthood. AB - OBJECTIVES: This article examines the relationship between intergenerational educational pathways and change in crime. Moreover, it examines the potential mediating roles of family and employment transitions, economic stressors, and social psychological factors. METHOD: Data from the National Longitudinal Study of Adolescent to Adult Health (N = 14,742) and negative binomial models are used to assess associations between educational pathways (i.e., upward, downward, and stable) and change in crime between adolescence and early adulthood. Selection effects are assessed with lagged dependent variables and controls for self control, grades, and the Add Health Picture Vocabulary Test. RESULTS: Intergenerational educational pathways are significantly associated with changes in crime. Downward educational pathways were predictive of increases in crime, whereas upward pathways were associated with decreases in crime. These associations were partly mediated by family transitions, and more strongly by economic stressors. These results were robust to controls for selection related variables. CONCLUSIONS: This study is among the first to examine the relationship between intergenerational educational pathways and crime in the United States. Both upward and downward changes in educational attainments were found to be significant for crime. These findings are notable given the continuing expansion of higher education as well as concerns regarding increasing stratification and downward mobility in the United States. PMID- 28348442 TI - Learning Additional Languages as Hierarchical Probabilistic Inference: Insights From First Language Processing. AB - We present a framework of second and additional language (L2/Ln) acquisition motivated by recent work on socio-indexical knowledge in first language (L1) processing. The distribution of linguistic categories covaries with socio indexical variables (e.g., talker identity, gender, dialects). We summarize evidence that implicit probabilistic knowledge of this covariance is critical to L1 processing, and propose that L2/Ln learning uses the same type of socio indexical information to probabilistically infer latent hierarchical structure over previously learned and new languages. This structure guides the acquisition of new languages based on their inferred place within that hierarchy, and is itself continuously revised based on new input from any language. This proposal unifies L1 processing and L2/Ln acquisition as probabilistic inference under uncertainty over socio-indexical structure. It also offers a new perspective on crosslinguistic influences during L2/Ln learning, accommodating gradient and continued transfer (both negative and positive) from previously learned to novel languages, and vice versa. PMID- 28348444 TI - Sirolimus on Gorham-Stout disease. Case report. AB - BACKGROUND: Gorham-Stout disease (GSD) is a rare disease of unknown etiology characterized by vascular proliferation that produces destruction of bone matrix. CASE DESCRIPTION: This case is about 43 year old woman who begins with pain in sternum, dyspnea, abdominal mass and, serous-hematic pleural effusion. Imaging tests were performed showing lesions on 6th and 10th left ribs archs. Later, a thoracotomy was performed observed absence of the end of the 6th and lung, pleural and costal biopsy was token. The histologic features described lymphatic vascular proliferation in bone tissue of chest wall. Other pathologies were excluded and in view of the findings, GSD diagnosis was made. TREATMENT AND OUTCOME: treatment was initiated with sirolimus achieving remission of the disease after the first month; however, because the presence of metrorrhagia the treatment was discontinued, reappearing symptoms afterwards. For that reason the treatment was restarted getting disappearance of the symptoms again, 4 weeks later. CLINICAL RELEVANCE: we present the first clinical cases of EGS with pleural effusion with response to sirolimus treatment that could be an alternative to the current therapy. PMID- 28348445 TI - Concurrent and longitudinal associations of peers' acceptance with emotion and effortful control in kindergarten. AB - The purpose of the study was to evaluate bidirectional associations between peer acceptance and both emotion and effortful control during kindergarten (N = 301). In both the fall and spring semesters, we obtained peer nominations of acceptance, measures of positive and negative emotion based on naturalistic observations in school (i.e., classroom, lunch/recess), and observers' reports of effortful control (i.e., inhibitory control, attention focusing) and emotions (i.e., positive, negative). In structural equation panel models, peer acceptance in fall predicted higher effortful control in spring. Effortful control in fall did not predict peer acceptance in spring. Negative emotion predicted lower peer acceptance across time for girls but not for boys. Peer acceptance did not predict negative or positive emotion over time. In addition, we tested interactions between positive or negative emotion and effortful control predicting peer acceptance. Positive emotion predicted higher peer acceptance for children low in effortful control. PMID- 28348443 TI - Role of Mechanical Factors in Applications of Stimuli-Responsive Polymer Gels - Status and Prospects. AB - Due to their unique characteristics such as multifold change of volume in response to minute change in the environment, resemblance of soft biological tissues, ability to operate in wet environments, and chemical tailorability, stimuli responsive gels represent a versatile and very promising class of materials for sensors, muscle-type actuators, biomedical applications, and autonomous intelligent structures. Success of these materials in practical applications largely depends on their ability to fulfill application-specific mechanical requirements. This article provides an overview of recent application driven development of covalent polymer gels with special emphasis on the relevant mechanical factors and properties. A short account of mechanisms of gel swelling and mechanical characteristics of importance to stimuli-responsive gels is presented. The review highlights major barriers for wider application of these materials and discusses latest advances and potential future directions toward overcoming these barriers, including interpenetrating networks, homogeneous networks, nanocomposites, and nanofilamentary gels. PMID- 28348447 TI - Fos Expression in the Olfactory Pathway of High- and Low-Sexually Performing Rams Exposed to Urine from Estrous or Ovariectomized Ewes. AB - Exposure to estrous ewe urine stimulates investigation and mounting activity in sexually active but not sexually inactive rams. It was hypothesized sexual indifference may result from an inability to detect olfactory cues or an interruption of the pathway from detection of the olfactory stimulus to the motor response. Sexually active (n=4) and inactive (n=3) rams were exposed to urine from estrous ewes. An additional group of sexually active rams (n=3) were exposed to urine from ovariectomized ewes. Rams were exsanguinated following 1 h of exposure to stimulus. Neural activity was determined in tissues of interest by the presence of fos and fos-related proteins detected by immunohistochemistry procedures. Sexually active rams exposed to urine from ovariectomized ewes had more (P <= 0.05) fos-positive cells in the olfactory bulb, but fewer (P = 0.03) fos-positive cells in the cortical amygdala compared to sexually active rams exposed to urine from estrous ewes. Sexually inactive rams had similar (P >= 0.13) numbers of fos positive neurons in the olfactory bulb and medial amygdala but fewer (P <= 0.04) in the central amygdala, bed nucleus of the stria terminalis and the medial preoptic area compared to sexually active rams exposed to urine from estrous ewes. Sexual inactivity was not associated with decreased hypothalamic function since fos activity was similar (P >= 0.14) among groups in the suprachiasmatic and ventral medial nucleus. Sexual inactivity is not likely due to an impaired ability to detect or process olfactory stimuli by the main olfactory bulb and medial-cortical amygdala. Sexually inactive rams may have reduced attentiveness to sexual stimuli and/or decreased responsiveness of regions in the brain which regulate reproductive behaviors. PMID- 28348448 TI - Parenting and Adolescent Self-Regulation Mediate between Family Socioeconomic Status and Adolescent Adjustment. AB - Using two waves of longitudinal data, we utilized the family stress model of economic hardship (Conger & Conger, 2002) to test whether family socioeconomic status is related to adolescent adjustment (substance use and academic achievement) through parental knowledge and adolescent self-regulation (behavioral self-control and delay discounting). Participants included 220 adolescent (55% male, mean age = 13 years at Wave 1, mean age = 15 years at Wave 2) and primary caregiver dyads. Results of Structural Equation Modeling revealed significant three-path mediation effects such that low family socioeconomic status at Wave 1 is associated with low parental knowledge at Wave 1, which in turn was related to low academic performance and high substance use at Wave 2 mediated through low adolescent behavioral self-control at Wave 2. The results illustrate how parental knowledge, influenced by family economic status, may play an important role in the development of adolescent behavioral self-control and adjustment. PMID- 28348450 TI - A Novel Panel of Serum Biomarkers for MPM Diagnosis. AB - Exposure to asbestos is the main cause of malignant pleural mesothelioma (MPM), a highly aggressive cancer of the pleura. Since the only tools for early detection are based on radiological tests, some authors focused on serum markers (i.e., mesothelin). The aim of this study was the evaluation of new serum biomarkers to be used individually or in combination, in order to improve the outcome of patients whose disease would be diagnosed at an earlier stage. Serum and plasma were available from 43 subjects previously exposed to asbestos and 27 MPM patients, all being epithelioid type. All the new markers found differentially expressed in MPM and healthy subjects, by proteomic and genomic approaches, have been validated in the serum by the use of specific ELISA. The combined approach, using tools of genomics and proteomics, is found to be highly innovative for this type of disease and led to the identification of new serum markers in the diagnosis of MPM. These results, if confirmed in a larger series, may have a strong impact in this area, because early detection of this cancer in people at high risk could significantly improve the course of the disease and the clinical approach to an individualized therapy. PMID- 28348449 TI - Combined Genetic Biomarkers Confer Susceptibility to Risk of Urothelial Bladder Carcinoma in a Saudi Population. AB - We evaluated the associations between seven single nucleotide polymorphisms and susceptibility to urothelial bladder carcinoma (UBC) in a Saudi population. Genomic DNA was taken from buccal cells of 52 patients with UBC and 104 controls for genotyping of GSTT1, GSTM1, rs4646903, rs1048943, TP53 rs1042522, rs1801133, and rs1801394 using PCR and TaqMan(r) assays. The rs1801133 and rs1801394 variants showed strong associations with UBC (OR = 2.3, P = 0.0002; OR = 2.6, P = 0.0001, resp.). Homozygosity of Pro72 conferred a significant double risk in cases compared with controls (30.8% versus 15.4%), but the homozygote Arg/Arg had no effect on risk. Genotypic combinations of GSTM1/GSTT1, rs4646903/rs1048943, and rs1801133/rs1801394 exhibited significant linkage with the disease (chi2 = 10.3, P = 0.006; chi2 = 13.9, P = 0.003; and chi2 = 20.4, P = 0.0004, resp.). The GSTM1 and rs1042522Arg and rs1801394G variant alleles were more frequent in current smokers with UBC (52.4%, 52.5%, and 64.3%, resp.) than were the corresponding wild-types. Despite some variants having only a slight effect on UBC risk, the interaction effect of combined genetic biomarkers-or even the presence of one copy of a variant allele-is potentially much greater. Perhaps more studies regarding next-generation genetic sequencing and its utility can add to the risk of UBC. PMID- 28348446 TI - Exploring the genomic diversity of black yeasts and relatives (Chaetothyriales, Ascomycota). AB - The order Chaetothyriales (Pezizomycotina, Ascomycetes) harbours obligatorily melanised fungi and includes numerous etiologic agents of chromoblastomycosis, phaeohyphomycosis and other diseases of vertebrate hosts. Diseases range from mild cutaneous to fatal cerebral or disseminated infections and affect humans and cold-blooded animals globally. In addition, Chaetothyriales comprise species with aquatic, rock-inhabiting, ant-associated, and mycoparasitic life-styles, as well as species that tolerate toxic compounds, suggesting a high degree of versatile extremotolerance. To understand their biology and divergent niche occupation, we sequenced and annotated a set of 23 genomes of main the human opportunists within the Chaetothyriales as well as related environmental species. Our analyses included fungi with diverse life-styles, namely opportunistic pathogens and closely related saprobes, to identify genomic adaptations related to pathogenesis. Furthermore, ecological preferences of Chaetothyriales were analysed, in conjuncture with the order-level phylogeny based on conserved ribosomal genes. General characteristics, phylogenomic relationships, transposable elements, sex-related genes, protein family evolution, genes related to protein degradation (MEROPS), carbohydrate-active enzymes (CAZymes), melanin synthesis and secondary metabolism were investigated and compared between species. Genome assemblies varied from 25.81 Mb (Capronia coronata) to 43.03 Mb (Cladophialophora immunda). The bantiana-clade contained the highest number of predicted genes (12 817 on average) as well as larger genomes. We found a low content of mobile elements, with DNA transposons from Tc1/Mariner superfamily being the most abundant across analysed species. Additionally, we identified a reduction of carbohydrate degrading enzymes, specifically many of the Glycosyl Hydrolase (GH) class, while most of the Pectin Lyase (PL) genes were lost in etiological agents of chromoblastomycosis and phaeohyphomycosis. An expansion was found in protein degrading peptidase enzyme families S12 (serine-type D-Ala-D-Ala carboxypeptidases) and M38 (isoaspartyl dipeptidases). Based on genomic information, a wide range of abilities of melanin biosynthesis was revealed; genes related to metabolically distinct DHN, DOPA and pyomelanin pathways were identified. The MAT (MAting Type) locus and other sex-related genes were recognized in all 23 black fungi. Members of the asexual genera Fonsecaea and Cladophialophora appear to be heterothallic with a single copy of either MAT-1-1 or MAT-1-2 in each individual. All Capronia species are homothallic as both MAT1 1 and MAT1-2 genes were found in each single genome. The genomic synteny of the MAT-locus flanking genes (SLA2-APN2-COX13) is not conserved in black fungi as is commonly observed in Eurotiomycetes, indicating a unique genomic context for MAT in those species. The heterokaryon (het) genes expansion associated with the low selective pressure at the MAT-locus suggests that a parasexual cycle may play an important role in generating diversity among those fungi. PMID- 28348451 TI - Serum HMGB1 as a Potential Biomarker for Patients with Asbestos-Related Diseases. AB - High-mobility group box 1 (HMGB1) functions as a proinflammatory cytokine and is one of the most intriguing molecules in inflammatory disorders and cancers. Notably, HMGB1 is a potential therapeutic target and novel biomarker in related diseases. However, the diagnostic value of HMGB1 for benign and malignant asbestos-related diseases (ARDs) remains unclear. In this work, we detected preoperative serum HMGB1 levels in Chinese asbestos-exposed (AE) and ARDs populations and further evaluated the diagnostic value of HMGB1 in patients with certain types of ARDs, including those with pleural plaques, asbestosis, or malignant mesothelioma (MM). The experimental data presented that the serum level of HMGB1 was significantly elevated in AE and ARDs subjects. Our findings indicated that serum HMGB1 is a sensitive and specific biomarker for discriminating asbestosis- and MM-affected individuals from healthy or AE individuals. In addition, serum matrix metalloproteinases 2 and 9 are not correlated with HMGB1 in ARDs. Thus, our study provides supporting evidence for HMGB1 as a potential biomarker either for the clinical diagnosis of high-risk AE cohorts or for evaluating ARDs. PMID- 28348452 TI - Hyperferritinemia as a Diagnostic Marker for Severe Fever with Thrombocytopenia Syndrome. AB - Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral disease in East Asia with high mortality. Few studies have examined markers that suggest SFTS in febrile patients. To determine useful biochemical markers for SFTS, patients aged 18 years or older with SFTS or microbiologically confirmed community-onset bacteremia with thrombocytopenia (BT) at presentation between June 2013 and December 2015 were included from two tertiary university hospitals in Republic of Korea retrospectively. Eleven patients with SFTS and 62 patients with bacteremia and thrombocytopenia were identified in the study period. Age and sex did not show significant difference among two groups. Fever was more commonly observed but comorbidities were less common in SFTS than in BT (P < 0.05, each). The areas under the curves of serum ferritin, C-reactive protein, white blood cell count, serum procalcitonin, and fibrinogen were above 0.9, indicating the discriminative power of these biomarkers (1.000, 0.991, 0.963, 0.931, and 0.934, resp., all P < 0.05). The optimal cutoff value of serum ferritin was 3,822 ng/mL in this study. These results suggest that hyperferritinemia is a typical laboratory feature of SFTS, and the serum ferritin level can be used as a marker for clinicians suspecting SFTS. PMID- 28348453 TI - Probability-scale residuals for continuous, discrete, and censored data. AB - We describe a new residual for general regression models, defined as pr(Y* < y) - pr(Y* > y), where y is the observed outcome and Y* is a random variable from the fitted distribution. This probability-scale residual can be written as E {sign(y, Y*)} whereas the popular observed-minus-expected residual can be thought of as E(y - Y*). Therefore, the probability-scale residual is useful in settings where differences are not meaningful or where the expectation of the fitted distribution cannot be calculated. We present several desirable properties of the probability-scale residual that make it useful for diagnostics and measuring residual correlation, especially across different outcome types. We demonstrate its utility for continuous, ordered discrete, and censored outcomes, including current status data, and with various models including Cox regression, quantile regression, and ordinal cumulative probability models, for which fully specified distributions are not desirable or needed, and in some cases suitable residuals are not available. The residual is illustrated with simulated data and real datasets from HIV-infected patients on therapy in the southeastern United States and Latin America. PMID- 28348454 TI - Division of Household and Childcare Labor and Relationship Conflict Among Low Income New Parents. AB - We examine the relationships among the division of housework and childcare labor, perceptions of its fairness for two types of family labor (housework and childcare), and parents' relationship conflict across the transition to parenthood. Perceived fairness is examined as a mediator of the relationships between change in the division of housework and childcare and relationship conflict. Working-class, dual-earner couples (n = 108) in the U.S Northeast were interviewed at five time points from the third trimester of pregnancy and across the first year of parenthood. Research questions addressed whether change in the division of housework and childcare across the transition to parenthood predicted mothers' and fathers' relationship conflict, with attention to the mediating role of perceived fairness of these chores. Findings for housework indicated that perceived fairness was related to relationship conflict for mothers and fathers, such that when spouses perceived the change in the division of household tasks to be unfair to either partner, they reported more conflict, However, fairness did not significantly mediate relations between changes in division of household tasks and later relationship conflict. For childcare, fairness mediated relations between mothers' violated expectations concerning the division of childcare and later conflict such that mothers reported less conflict when they perceived the division of childcare as less unfair to themselves; there was no relationship for fathers. Findings highlight the importance of considering both childcare and household tasks independently in our models and suggest that the division of housework and childcare holds different implications for mothers' and fathers' assessments of relationship conflict. PMID- 28348456 TI - Positively Biased Processing of Mother's Emotions Predicts Children's Social and Emotional Functioning. AB - Risk for internalizing problems and social skills deficits likely emerges in early childhood when emotion processing and social competencies are developing. Positively biased processing of social information is typical during early childhood and may be protective against poorer psychosocial outcomes. We tested the hypothesis that young children with relatively less positively biased attention to, interpretations of, and attributions for their mother's emotions would exhibit poorer prosocial skills and more internalizing problems. A sample of 4- to 6-year-old children (N=82) observed their mothers express happiness, sadness and anger during a simulated emotional phone conversation. Children's attention to their mother when she expressed each emotion was rated from video. Immediately following the phone conversation, children were asked questions about the conversation to assess their interpretations of the intensity of mother's emotions and misattributions of personal responsibility for her emotions. Children's prosocial skills and internalizing problems were assessed using mother report rating scales. Interpretations of mother's positive emotions as relatively less intense than her negative emotions, misattributions of personal responsibility for her negative emotions, and lack of misattributions of personal responsibility for her positive emotions were associated with poorer prosocial skills. Children who attended relatively less to mother's positive than her negative emotions had higher levels of internalizing problems. These findings suggest that children's attention to, interpretations of, and attributions for their mother's emotions may be important targets of early interventions for preventing prosocial skills deficits and internalizing problems. PMID- 28348455 TI - Reflection on Molecular Approaches Influencing State-of-the-Art Bioremediation Design: Culturing to Microbial Community Fingerprinting to Omics. AB - Bioremediation is generally viewed as a cost effective and sustainable technology because it relies on microbes to transform pollutants into benign compounds. Advances in molecular biological analyses allow unprecedented microbial detection and are increasingly incorporated into bioremediation. Throughout history, state of-the-art techniques have informed bioremediation strategies. However, the insights those techniques provided were not as in depth as those provided by recently developed omics tools. Advances in next generation sequencing (NGS) have now placed metagenomics and metatranscriptomics within reach of environmental engineers. As NGS costs decrease, metagenomics and metatranscriptomics have become increasingly feasible options to rapidly scan sites for specific degradative functions and identify microorganisms important in pollutant degradation. These omic techniques are capable of revolutionizing biological treatment in environmental engineering by allowing highly sensitive characterization of previously uncultured microorganisms. Omics enables the discovery of novel microorganisms for use in bioaugmentation and supports systematic optimization of biostimulation strategies. This review describes the omics journey from roots in biology and medicine to its current status in environmental engineering including potential future directions in commercial application. PMID- 28348457 TI - Validation of Dual-energy X-Ray Absorptiometry to Predict Body Composition of Channel Catfish, Ictalurus punctatus. AB - Dual-energy X-ray absorptiometry (DXA) provides a noninvasive way to determine lean tissue mass (LTM), fat mass (FM), bone mineral content (BMC), and bone mineral density (BMD) in humans and small mammals. Live channel catfish (n=74, 78g - 1200 g) were anesthetized and scanned in both a lateral position and a dorsa-ventral position. Six individual fish (300g - 600g) were scanned five times each to determine precision by the coefficient of variation. Precision was good for LTM (0.75-1.06%) and for BMC and BMD (2-2.6%). Precision for FM was not good (27-34%), which was due to the very low FM (0-1g) recorded by the DXA. However, using the predicted values, FM precision improved to 5-5.5%. DXA values for LTM, FM, and BMC were significantly different from chemical analysis (P< 0.001). DXA overestimated LTM and underestimated FM and BMC. However, all three compartments were strongly correlated with carcass values (P <0.0001). Using the prediction equations and the jackknife procedure, predicted values of LTM, FM, and BMC were not significantly different from the carcass values (P >0.05). DXA may also be a valuable tool for evaluating body condition longitudinally in commercial or in threatened or endangered fish species, where non-invasive procedures would be invaluable. PMID- 28348458 TI - Vascular Cognitive Impairment through the Looking Glass of Transcranial Magnetic Stimulation. AB - In the last years, there has been a significant growth in the literature exploiting transcranial magnetic stimulation (TMS) with the aim at gaining further insights into the electrophysiological and neurochemical basis underlying vascular cognitive impairment (VCI). Overall, TMS points at enhanced brain cortical excitability and synaptic plasticity in VCI, especially in patients with overt dementia, and neurophysiological changes seem to correlate with disease process and progress. These findings have been interpreted as part of a glutamate mediated compensatory effect in response to vascular lesions. Although a single TMS parameter owns low specificity, a panel of measures can support the VCI diagnosis, predict progression, and possibly identify early markers of "brain at risk" for future dementia, thus making VCI a potentially preventable cause of both vascular and degenerative dementia in late life. Moreover, TMS can be also exploited to select and evaluate the responders to specific drugs, as well as to become an innovative rehabilitative tool in the attempt to restore impaired neural plasticity. The present review provides a perspective of the different TMS techniques by further understanding the cortical electrophysiology and the role of distinctive neurotransmission pathways and networks involved in the pathogenesis and pathophysiology of VCI and its subtypes. PMID- 28348459 TI - Lysophosphatidic Acid Triggers Apoptosis in HeLa Cells through the Upregulation of Tumor Necrosis Factor Receptor Superfamily Member 21. AB - Lysophosphatidic acid (LPA), a naturally occurring bioactive phospholipid, activates G protein-coupled receptors (GPCRs), leading to regulation of diverse cellular events including cell survival and apoptosis. Despite extensive studies of the signaling pathways that mediate LPA-regulated cell growth and survival, the mechanisms underlying the apoptotic effect of LPA remain largely unclear. In this study, we investigated this issue in HeLa cells. Our data demonstrate that LPA induces apoptosis in HeLa cells at pathologic concentrations with a concomitant upregulation of the expression of TNFRSF21 (tumor necrosis factor receptor superfamily member 21), also known as death receptor number 6 (DR6) involved in inflammation. Moreover, treatment of cells with LPA receptor (LPAR) antagonist abolished the DR6 upregulation by LPA. LPA-induced DR6 expression was also abrogated by pertussis toxin (PTX), an inhibitor of GPCRs, and by inhibitors of PI3K, PKC, MEK, and ERK. Intriguingly, LPA-induced DR6 expression was specifically blocked by dominant-negative form of PKCdelta (PKCdelta-DN). LPA induced DR6 expression was also dramatically inhibited by knockdown of ERK or CREB. These results suggest that activation of the MEK/ERK pathway and the transcription factor CREB mediate LPA-induced DR6 expression. More interestingly, knockdown of DR6 using siRNA approach remarkably attenuated LPA-induced apoptosis. In conclusion, our results suggest that LPA-induced apoptosis in HeLa cells is mediated by the upregulation of DR6 expression. PMID- 28348460 TI - Epac1 Blocks NLRP3 Inflammasome to Reduce IL-1beta in Retinal Endothelial Cells and Mouse Retinal Vasculature. AB - Inflammation is an important component of diabetic retinal damage. We previously reported that a novel beta-adrenergic receptor agonist, Compound 49b, reduced Toll-like receptor 4 (TLR4) signaling in retinal endothelial cells (REC) grown in high glucose. Others reported that TLR4 activates high-mobility group box 1 (HMGB1), which has been associated with the NOD-like receptor 3 (NLRP3) inflammasome. Thus, we hypothesized that Epac1, a downstream mediator of beta adrenergic receptors, would block TLR4/HMGB1-mediated stimulation of the NLRP3 inflammasome, leading to reduced cleavage of caspase-1 and interleukin-1 beta (IL 1beta). We generated vascular specific conditional knockout mice for Epac1 and used REC grown in normal and high glucose treated with an Epac1 agonist and/or NLRP3 siRNA. Protein analyses were done for Epac1, TLR4, HMGB1, NLRP3, cleaved caspase-1, and IL-1beta. Loss of Epac1 in the mouse retinal vasculature significantly increased all of the inflammatory proteins. Epac1 effectively reduced high glucose-induced increases in TLR4, HMGB1, cleaved caspase-1, and IL 1beta in REC. Taken together, the data suggest that Epac1 reduces formation of the NLRP3 inflammasome to reduce inflammatory responses in the retinal vasculature. PMID- 28348462 TI - NLRP3 Deficiency Attenuates Renal Fibrosis and Ameliorates Mitochondrial Dysfunction in a Mouse Unilateral Ureteral Obstruction Model of Chronic Kidney Disease. AB - Background and Aims. The nucleotide-binding domain and leucine-rich repeat containing PYD-3 (NLRP3) inflammasome has been implicated in the pathogenesis of chronic kidney disease (CKD); however, its exact role in glomerular injury and tubulointerstitial fibrosis is still undefined. The present study was performed to identify the function of NLRP3 in modulating renal injury and fibrosis and the potential involvement of mitochondrial dysfunction in the murine unilateral ureteral obstruction (UUO) model of CKD. Methods. Employing wild-type (WT) and NLRP3-/- mice with or without UUO, we evaluated renal structure, tissue injury, and mitochondrial ultrastructure, as well as expression of some vital molecules involved in the progression of fibrosis, apoptosis, inflammation, and mitochondrial dysfunction. Results. The severe glomerular injury and tubulointerstitial fibrosis induced in WT mice by UUO was markedly attenuated in NLRP3-/- mice as evidenced by blockade of extracellular matrix deposition, decreased cell apoptosis, and phenotypic alterations. Moreover, NLRP3 deletion reversed UUO-induced impairment of mitochondrial morphology and function. Conclusions. NLRP3 deletion ameliorates mitochondrial dysfunction and alleviates renal fibrosis in a murine UUO model of CKD. PMID- 28348461 TI - AM966, an Antagonist of Lysophosphatidic Acid Receptor 1, Increases Lung Microvascular Endothelial Permeability through Activation of Rho Signaling Pathway and Phosphorylation of VE-Cadherin. AB - Maintenance of pulmonary endothelial barrier integrity is important for reducing severity of lung injury. Lysophosphatidic acid (LPA) regulates cell motility, cytoskeletal rearrangement, and cell growth. Knockdown of LPA receptor 1 (LPA1) has been shown to mitigate lung injury and pulmonary fibrosis. AM966, an LPA1 antagonist exhibiting an antifibrotic property, has been considered to be a future antifibrotic medicine. Here, we report an unexpected effect of AM966, which increases lung endothelial barrier permeability. An electric cell-substrate sensing (ECIS) system was used to measure permeability in human lung microvascular endothelial cells (HLMVECs). AM966 decreased the transendothelial electrical resistance (TEER) value immediately in a dose-dependent manner. VE cadherin and f-actin double immunostaining reveals that AM966 increases stress fibers and gap formation between endothelial cells. AM966 induced phosphorylation of myosin light chain (MLC) through activation of RhoA/Rho kinase pathway. Unlike LPA treatment, AM966 had no effect on phosphorylation of extracellular signal regulated kinases (Erk). Further, in LPA1 silencing cells, we observed that AM966 increased lung endothelial permeability as well as phosphorylation of VE-cadherin and focal adhesion kinase (FAK) were attenuated. This study reveals that AM966 induces lung endothelial barrier dysfunction, which is regulated by LPA1-mediated activation of RhoA/MLC and phosphorylation of VE-cadherin. PMID- 28348463 TI - Human beta-Defensin 3 Reduces TNF-alpha-Induced Inflammation and Monocyte Adhesion in Human Umbilical Vein Endothelial Cells. AB - The aim of this study was to investigate the role of human beta-defensin 3 (hBD3) in the initiation stage of atherosclerosis with human umbilical vein endothelial cells (HUVECs) triggered by tumor necrosis factor- (TNF-) alpha. The effects of hBD3 on TNF-alpha-induced endothelial injury and inflammatory response were evaluated. Our data revealed that first, hBD3 reduced the production of interleukin-6 (IL-6), IL-8, monocyte chemoattractant protein-1 (MCP-1), and macrophage migration inhibitory factor (MIF) in HUVECs in a dose-dependent manner. In addition, hBD3 significantly prevented intracellular reactive oxygen species (ROS) production by HUVECs. Second, western blot analysis demonstrated that hBD3 dose-dependently suppressed the protein levels of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in TNF-alpha-induced HUVECs. As a result, hBD3 inhibited monocyte adhesion to TNF alpha-treated endothelial cells. Additionally, hBD3 suppressed TNF-alpha-induced F-actin reorganization in HUVECs. Third, hBD3 markedly inhibited NF-kappaB activation by decreasing the phosphorylation of IKK-alpha/beta, IkappaB, and p65 subunit within 30 min. Moreover, the phosphorylation of p38 and c-Jun N-terminal protein kinase (JNK) in the mitogen-activated protein kinase (MAPK) pathway were also inhibited by hBD3 in HUVECs. In conclusion, hBD3 exerts anti-inflammatory and antioxidative effects in endothelial cells in response to TNF-alpha by inhibiting NF-kappaB and MAPK signaling. PMID- 28348465 TI - Impact of Hepatic and Extrahepatic Insults on the Outcome of Acute-on-Chronic Liver Failure. AB - BACKGROUND: To study the differences in outcome and predictors of mortality in acute-on-chronic liver failure (ACLF) precipitated by hepatic or extrahepatic insults. METHODS: Consecutive patients of cirrhosis with acute decompensation were prospectively included and followed up for 90 days from admission. ACLF was defined based on chronic liver failure (CLIF) acute-on-chronic liver failure in cirrhosis (CANONIC study) criteria. Acute worsening due to acute viral hepatitis A and E, hepatitis B flare, alcoholic hepatitis, autoimmune hepatitis flare, or drug-induced liver injury were categorized as hepatic ACLF and that due to bacterial infection, upper gastrointestinal bleed or surgery as extrahepatic ACLF. Patients with both hepatic and extrahepatic insults were included in combined insult group. RESULTS: Of 179 patients of acute decompensation, 122 had ACLF (hepatic insults 47 and extrahepatic insults 51). Alcohol (64.8%) was the most common etiology of cirrhosis while infection (36%) was the most common acute insult followed by alcoholic hepatitis (24.6%). Higher proportion of extrahepatic ACLF patients had history of prior decompensation than hepatic ACLF patients (62.7% vs. 27.7%, P < 0.001). There was no difference in mortality among hepatic and extrahepatic ACLF groups at 28 and 90 days (53.2% vs. 56.9%, P = 0.715 and 85% vs. 74.5%, P = 0.193, respectively). Area under receiver-operating curve (AUROC) for 28-day mortality in extrahepatic ACLF group was 0.788, 0.724, 0.718, 0.634, and 0.726 and in hepatic-ACLF group was 0.786, 0.625, 0.802, 0.761, and 0.648 for chronic liver failure-sequential organ failure assessment (CLIF-SOFA), model for end stage liver disease (MELD), integrated MELD score (iMELD), acute physiology and chronic health evaluation score (APACHE-II), and Child-Turcotte Pugh score scores, respectively. CONCLUSION: There is no difference in mortality among hepatic and extrahepatic ACLF groups at 28 and 90 days. iMELD and CLIF-SOFA have highest AUROC to predict 28-day mortality in hepatic and extrahepatic ACLF groups, respectively. PMID- 28348464 TI - Liver Function Tests Abnormalities and Hepatitis B Virus & Hepatitis C Virus Co infection in Human Immunodeficiency Virus (HIV)-infected Patients in India. AB - BACKGROUND: While highly active anti-retroviral therapy (HAART) has improved survival of HIV-infected patients, there is increasing liver disease and progressive Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) related liver disease. AIMS: To study the liver function tests (LFT) and HBV and HCV co infection in HIV-infected patients. MATERIAL AND METHODS: All HIV-positive patients presenting to a tertiary level hospital from April 2009 to April 2011 were evaluated. Baseline LFT, CD4/CD8 counts, ultrasound abdomen, HBsAg, IgG anti HBc, HBVDNA, Anti-HCV and HCVRNA were done in all patients. LFT was repeated monthly or more frequently with anti-tubercular therapy (ATT)/HAART. RESULTS: Abnormal LFT were seen in 143/320 (44.6%) HIV-infected patients (n = 320; M-282, F-38; mean age-35.4 +/- 7.3 years). Baseline LFT was abnormal in 48 (15%) [hepatotropic viruses-19, alcohol-24, NAFLD-1, disseminated TB-1, idiopathic-03). Subsequent LFT derangement developed in 95/272 (34.9%). In the majority, the LFT abnormality was mild (119/143-83.2%) and multi-factorial [HAART 132 (76.4%), alcohol 69 (48.2%), ATT 31 (21.7%), HBV 16 (11.2%), HCV 15 (10.4%)]. Using multivariate analysis, abnormal LFT were associated with HAART (OR, 5.92; 95%CI, 2.83-12.37), ATT (OR, 2.06; 95%CI, 1.06-3.99) or HCV infection (OR, 2.54; 95%CI, 1.03-6.26). Significant hepatotoxicity requiring drug modification was seen in only 7 cases. HBV, HCV and HBV + HCV co-infection were seen in 37 (11.6%), 28 (8.8%) and 2 (0.6%) respectively. Occult co-infections were rare [HBV-1 (0.3%); HCV-3 (0.9%)]. CONCLUSION: While LFT abnormalities in HIV are common, they are usually mild and multifactorial. HBV and HCV co-infections were seen in 11.6% and 8.8%, respectively. Occult HBV and HCV infections were rare. PMID- 28348466 TI - Handgrip Strength as an Important Bed Side Tool to Assess Malnutrition in Patient with Liver Disease. AB - BACKGROUND: Malnutrition is frequently present in patients with cirrhosis. Anthropometric measures such as body mass index (BMI), mid arm muscle circumference (MAMC), triceps skin fold thickness (TST) and subjective global assessment (SGA) have some limitations in assessment of malnutrition. This study aims to determine the prevalence of malnutrition in non-hospitalized cirrhotic and chronic hepatitis patients and to assess handgrip (HG) strength as a tool for identifying malnutrition. METHODS: Consecutive patients of cirrhosis (n = 352), chronic hepatitis (n = 189) and healthy controls (n = 159) were enrolled. All patients underwent MAMC, TST, HG and SGA assessment. Malnutrition was diagnosed on basis of SGA score. Values of MAMC, TST and HG below the 5th percentile or less than 60% of healthy controls were considered as abnormal. RESULTS: According to SGA (taken as standard) 24% patients with chronic hepatitis and 56% of patients with cirrhosis had malnutrition (P = 0.001). In patients with chronic hepatitis prevalence of malnutrition according to MAMC (12%), TST (31%) and HG (18%). In patients with cirrhosis prevalence of malnutrition according to MAMC (27%), TST (60%) and HG (42%). HG exercise strength had the highest area under curve 0.82 (95% confidence interval (CI) 0.78-0.86, P = 0.001) compared to MAMC 0.60 (95% CI 0.55-0.64, P = 0.001) and TST 0.65 (95% CI 0.61-0.69, P = 0.001) for assessing malnutrition. On comparison of HG, TST and MAMC, the sensitivity was 67%, 60% and 31%, respectively, Specificity was 95%, 71% and 89%, respectively, and diagnostic accuracy was 87%, 67% and 71%, respectively. CONCLUSION: HG strength is an excellent tool to assess at bed side the nutrition status in patients with cirrhosis and has the highest diagnostic accuracy compared to other anthropometric tests such as MAMC and TST. PMID- 28348467 TI - 2D Shear Wave Elastography of Liver in Patients with Primary Extrahepatic Portal Vein Obstruction. AB - AIMS: To evaluate liver stiffness (LS) in patients of primary extrahepatic portal vein obstruction (EHPVO) using 2D shear wave elastography (SWE) and compare it with healthy volunteers. METHODS: Fifty patients (mean age: 22.4 years) of EHPVO and 25 healthy volunteers were included in the study. Liver function tests and viral markers were done in both groups and endoscopy in EHPVO group, followed by ultrasonography and SWE of liver. Liver elastography was done with patients/volunteers in supine position through right intercostal space. The LS for right lobe of liver was recorded in kilopascals. Three such measurements were taken and the mean of both groups were compared. The variables were also correlated with mean LS using Pearson's correlation coefficient in EHPVO group. RESULTS: There was no significant difference in the mean LS in patients of EHPVO (5.96 kPa) and healthy volunteers (5.47 kPa) (P = 0.093). There was no significant correlation between LS with duration of symptoms, hematemesis, esophageal varices, total bilirubin, serum alkaline phosphatase and aspartate aminotranferase levels in EHPVO group. CONCLUSION: SWE of liver may be used as a simple additional tool in the diagnosis of patients of EHPVO who show LS values similar to normal liver. PMID- 28348468 TI - Early Acute Severe HCV Recurrence After Transplantation: From Universal Mortality to Cure. AB - Acute severe recurrence of hepatitis C virus (HCV) after solid organ transplant is associated with high mortality. Pegylated interferon and ribavirin are suboptimal in treatment of this severe form of recurrence. We report 4 cases of acute severe HCV recurrence (within 6 months after transplant), including 3 cases with fibrosing cholestatic hepatitis treated with sofosbuvir and ribavirin. All four patients achieved a rapid suppression of HCV RNA with a normalization of liver function tests within 4 weeks of starting therapy. All patients were HCV RNA negative at 12 weeks after stopping therapy. The combination was found to be safe as anemia was the only adverse effect, which developed in 2 patients (1 patient required blood transfusion, while another managed with erythropoietin). Sofosbuvir and ribavirin appear to be safe and efficacious in treatment of acute severe HCV recurrence after organ transplant. PMID- 28348469 TI - The Preliminary Study on Procurement Biliary Convergence from Donors with Complicated Bile Duct Variant in Emergency Right Lobe Living Donor Liver Transplantation. AB - BACKGROUND: The incidence of biliary complications after living donor adult liver transplantation (LDALT) is still high due to the bile duct variation and necessity reconstruction of multiple small bile ducts. The current surgical management of the biliary variants is unsatisfactory. We evaluated the role of a new surgical approach in a complicated hilar bile duct variant (Nakamura type IV and Nakamura type II) under emergent right lobe LDALT for high model for end stage liver disease score patients. METHODS: The common hepatic duct (CHD) and the left hepatic duct (LHD) of the donor were transected in a right-graft including short common trunks with right posterior and anterior bile ducts, whereas the LHD of the donor was anastomosed to the CHD and the common trunks of a right-graft bile duct and the recipient CHD was end-to-end anastomosed. RESULTS: Ten of 13 grafts (Nakamura types II, III, and IV) had two or more biliary orifices after right graft lobectomy; seven patients had biliary complications (53.8%). Later, the surgical innovation was carried out in five donors with variant bile duct (four Nakamura type IV and one type II), and, consequently, no biliary or other complications were observed in donors and recipients during 47-53 months of follow-up; significant differences (P < 0.05) were found when two stages were compared. CONCLUSION: Our initial experience suggests that, in the urgent condition of LDALT when an alternative live donor was unavailable, a surgical innovation of cutting part of the CHD trunks including variant right hepatic ducts in a complicated donor bile duct variant may facilitate biliary reconstruction and reduce long-term biliary complications. PMID- 28348472 TI - Portal Inflow in Extensive Portomesenteric Thrombosis: Using the Pericholedochal Varix in Living Donor Liver Transplantation. AB - Extensive portomesenteric thrombosis presents a technical challenge in liver transplantation. Establishing portal inflow in living donor liver transplantation (LDLT) is indispensable to ensure regeneration of the graft. The use of a pericholedochal varix for inflow has been described only in a few case reports. Described herein is one such instance in the setting of LDLT, highlighting the nuances of this procedure in the light of available literature. PMID- 28348471 TI - Role of Allopurinol in Optimizing Thiopurine Therapy in Patients with Autoimmune Hepatitis: A Review. AB - Autoimmune hepatitis (AIH) is a chronic immune mediated liver disease characterized by elevated transaminases, hyper gammaglobulinemia, presence of autoantibodies and interface hepatitis in the absence of a known etiology of liver disease. Thiopurines (azathioprine [AZA]/6-mercaptopurine [6MP]) and steroids remain the first line of treatment of AIH in both children and adults. However, a small proportion of AIH patients are either non-responders or develop side effects with AZA. The metabolism of AZA is complex and mediated by multiple enzymes. After absorption and getting converted to 6MP, it is converted to 6 thiouric acid, 6-methyl mercaptopurine (6MMP) and 6-thioguanine (6TG) by different enzymes. Elevated 6MMP levels are associated with hepatotoxicity and also poor efficacy due to simultaneous lower levels of 6TG, which is the active drug metabolite related to both efficacy and myelosuppression. Allopurinol, a xanthine oxidase inhibitor shifts the metabolism of AZA away from 6MMP toward 6TG. This combination of allopurinol with reduced dose of AZA is an alternative to more expensive and toxic second line therapy to induce remission in patients with AIH. This article discusses the mechanism of action of allopurinol in inducing response to AZA, reviews the published literature on this combination therapy and gives guidelines on the use of allopurinol in patients with AIH. PMID- 28348470 TI - Potential Liver Transplant Recipients with Hepatitis C: Should They Be Treated Before or After Transplantation? AB - Treatment of hepatitis C virus (HCV) with newer directly acting antivirals (DAAs) and lead to sustained viral response (SVR) in majority of patients and SVR has been documented to be associated with reversal of liver cirrhosis. The improved SVR rates and safety profiles of DAAs have led to the treatment of patients with decompensated cirrhosis awaiting liver transplantation (LT). Several clinical trials of DAAs in decompensated HCV patients have recently demonstrated SVR rates above 80%, which have been associated with significant improvements, in the Child Pugh-Turcotte scores/or model for end-stage liver disease scores in a proportion of patients. Moreover, it has been shown that HCV RNA becomes negative after 2-4 weeks of treatment, and those who are transplanted after becoming HCV RNA negative will be have very low the risk of HCV recurrence after transplantation. Some of the patients may have reached the "point of no return" and may proceed to worsening of decomposition over time. To avoid the risk of worsening, there is an additional option of treating these patients after LT should they develop recurrent HCV infection. Currently there are no guidelines as to select patients who would benefit from treatment prior to LT as opposed to those who will be better off being treated after the transplant surgery. The article discusses a possible approach for such selection. PMID- 28348473 TI - Acute Onset Significant Muscle Weakness in a Patient Awaiting Liver Transplantation: Look for Statins. AB - Statins are commonly used drugs in patients with liver and cardiac disease. Statin-induced severe myopathy is a very uncommon presentation and rhabdomyolysis may occur in extreme cases which leads to renal failure. Patients with comorbidities like diabetes, hypothyroidism, and liver disease have higher chances of development of statin-induced myopathy. We describe a case of Child's C cirrhosis wherein the patient had acute onset significant muscle weakness and improved on statin discontinuation. PMID- 28348474 TI - Malignant Hepatic Epithelioid Hemangioendothelioma with Villaret Syndrome. AB - Malignant hepatic epithelioid hemangioendothelioma is a rare, vascular tumor of the liver with peak incidence in the middle age with a female preponderance and of unknown etiology. Majority of the tumors are asymptomatic. The gold standard for diagnosis of the tumor is liver histology showing presence of epithelioid tumor cells on a background of a hyaline stroma. Immunohistochemical positivity for CD31, CD34, Factor VIII, and Podoplanin (D2-40) is confirmatory. The treatment of choice is liver transplantation. PMID- 28348475 TI - Giant Intrahepatic Portal Vein Aneurysm: Leave it or Treat it? AB - Portal vein aneurysm (PVA) is a rare vascular dilatation of the portal vein. It is a rare vascular anomaly representing less than 3% of all visceral aneurysms and is not well understood. Usually, PVA are incidental findings, are asymptomatic, and clinical symptoms are proportionally related to size. Patients present with nonspecific epigastric pain or gastrointestinal bleeding with underlying portal hypertension. PVA may be associated with various complications such as biliary tract compression, portal vein thrombosis/rupture, duodenal compression, gastrointestinal bleeding, and inferior vena cava obstruction. Differential diagnoses of portal vein aneurysms are solid, cystic, and hypervascular abdominal masses, and it is important that the radiologists be aware of their multi-modality appearance; hence, the aim of this article was to provide an overview of the available literature to better simplify various aspects of this rare entity and diagnostic appearance on different modality with available treatment options. In our case, a 55-year-old male patient came to the gastroenterology OPD for further management of pancreatitis with portal hypertension and biliary obstruction with plastic stents in CBD and PD for the same. In this article, we have reported a case of largest intrahepatic portal vein aneurysm and its management by endovascular technique. As per our knowledge, this is the largest intrahepatic portal vein aneurysm and first case where the endovascular technique was used for the treatment of the same. PMID- 28348476 TI - Unusual Presentation of Tubercular Liver Abscess in an Immune-Competent Adult. AB - Isolated hepatobiliary tuberculosis (TB) has been uncommonly described with or without biliary involvement and accounts for less than 1% of all tubercular infections. Isolated hepatic TB is even rare and poses a great diagnostic challenge. We report a case of isolated tubercular liver abscess with extension into the chest wall in an immune-competent adult, which was diagnosed and managed successfully with antitubercular treatment. PMID- 28348477 TI - Rapid Onset of Fatal Lactic Acidosis Complicating Tenofovir Therapy in a Diabetic Patient with Cirrhosis: A Cautionary Tale. PMID- 28348478 TI - Portal hypertension: Imaging of portosystemic collateral pathways and associated image-guided therapy. AB - Portal hypertension is a common clinical syndrome, defined by a pathologic increase in the portal venous pressure. Increased resistance to portal blood flow, the primary factor in the pathophysiology of portal hypertension, is in part due to morphological changes occurring in chronic liver diseases. This results in rerouting of blood flow away from the liver through collateral pathways to low-pressure systemic veins. Through a variety of computed tomographic, sonographic, magnetic resonance imaging and angiographic examples, this article discusses the appearances and prevalence of both common and less common portosystemic collateral channels in the thorax and abdomen. A brief overview of established interventional radiologic techniques for treatment of portal hypertension will also be provided. Awareness of the various imaging manifestations of portal hypertension can be helpful for assessing overall prognosis and planning proper management. PMID- 28348480 TI - Ghrelin and gastrointestinal stromal tumors. AB - Ghrelin, as a kind of multifunctional protein polypeptide, is mainly produced in the fundus of the stomach and can promote occurrence and development of many tumors, including gastrointestinal tumors, which has been proved by the relevant researches. Most gastrointestinal stromal tumors (GISTs, about 80%), as the most common mesenchymal tumor, also develop in the fundus. Scientific research has confirmed that ghrelin, its receptors and mRNA respectively can be found in GISTs, which demonstrated the existence of a ghrelin autocrine/paracrine loop in GIST tissues. However, no reports to date have specified the mechanism whether ghrelin can promote the occurrence and development of GISTs. Studies of pulmonary artery endothelial cells in a low-oxygen environment and cardiac muscle cells in an ischemic environment have shown that ghrelin can activate the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. Moreover, some studies of GISTs have confirmed that activation of the PI3K/AKT/mTOR pathway can indeed promote the growth and progression of GISTs. Whether ghrelin is involved in the development or progression of GISTs through certain pathways remains unknown. Can we find a new target for the treatment of GISTs? This review explores and summaries the relationship among ghrelin, the PI3K/AKT/mTOR pathway and the development of GISTs. PMID- 28348479 TI - Non-alcoholic fatty liver disease connections with fat-free tissues: A focus on bone and skeletal muscle. AB - The estimates of global incidence and prevalence of non-alcoholic fatty liver disease (NAFLD) are worrisome, due to the parallel burden of obesity and its metabolic complications. Indeed, excess adiposity and insulin resistance represent two of the major risk factors for NAFLD; interestingly, in the last years a growing body of evidence tended to support a novel mechanistic perspective, in which the liver is at the center of a complex interplay involving organs and systems, other than adipose tissue and glucose homeostasis. Bone and the skeletal muscle are fat- free tissues which appeared to be independently associated with NAFLD in several cross-sectional studies. The deterioration of bone mineral density and lean body mass, leading to osteoporosis and sarcopenia, respectively, are age-related processes. The prevalence of NAFLD also increases with age. Beyond physiological aging, the three conditions share some common underlying mechanisms, and their elucidations could be of paramount importance to design more effective treatment strategies for the management of NAFLD. In this review, we provide an overview on epidemiological data as well as on potential contributors to the connections of NAFLD with bone and skeletal muscle. PMID- 28348481 TI - Hyperplasia vs hypertrophy in tissue regeneration after extensive liver resection. AB - AIM: To address to what extent hypertrophy and hyperplasia contribute to liver mass restoration after major tissue loss. METHODS: The ability of the liver to regenerate is remarkable on both clinical and biological grounds. Basic mechanisms underlying this process have been intensively investigated. However, it is still debated to what extent hypertrophy and hyperplasia contribute to liver mass restoration after major tissue loss. We addressed this issue using a genetically tagged system. We were able to follow the fate of single transplanted hepatocytes during the regenerative response elicited by 2/3 partial surgical hepatectomy (PH) in rats. Clusters of transplanted cells were 3D reconstructed and their size distribution was evaluated over time after PH. RESULTS: Liver size and liver DNA content were largely recovered 10 d post-PH, as expected (e.g., total DNA/liver/100 g b.w. was 6.37 +/- 0.21 before PH and returned to 6.10 +/- 0.36 10 d after PH). Data indicated that about 2/3 of the original residual hepatocytes entered S-phase in response to PH. Analysis of cluster size distribution at 24, 48, 96 h and 10 d after PH revealed that about half of the remnant hepatocytes completed at least 2 cell cycles. Average size of hepatocytes increased at 24 h (248.50 MUm2 +/- 7.82 MUm2, P = 0.0015), but returned to control values throughout the regenerative process (up to 10 d post-PH, 197.9 MUm2 +/- 6.44 MUm2, P = 0.11). A sizeable fraction of the remnant hepatocyte population does not participate actively in tissue mass restoration. CONCLUSION: Hyperplasia stands as the major mechanism contributing to liver mass restoration after PH, with hypertrophy playing a transient role in the process. PMID- 28348482 TI - Catheterization of the gallbladder: A novel mouse model of severe acute cholangitis. AB - AIM: To establish a severe acute cholangitis (SAC) model in mice. METHODS: Cholecystic catheterization was performed under the condition of bile duct ligation (BDL). Trans-cholecystic injection of lipopolysaccharide (LPS) was defined as the SAC animal model. Sham operation group, intraperitoneal injection of LPS without BDL group, intraperitoneal injection of LPS with BDL group and trans-cholecystic injection of normal saline with BDL group were defined as control groups. The survival rates and tissue injuries in liver, lungs and kidney were evaluated. RESULTS: Mice in the SAC group showed a time-dependent mortality and much more severe tissue injuries in liver, lungs and kidney, compared with other groups. However, relieving biliary obstruction could effectively reduce mortality and attenuate liver injury in the SAC mouse model. CONCLUSION: Trans cholecystic injection of LPS under the condition of biliary obstruction could establish a repeatable and reversible mouse model of SAC. PMID- 28348483 TI - Clinicopathological significance of overexpression of interleukin-6 in colorectal cancer. AB - AIM: To compare the expression levels of interleukin (IL)-6 in colorectal cancer (CRC) tissues and adjacent non-cancerous tissues, and analyse the correlation of IL-6 expression with the clinicopathological parameters of CRC. METHODS: Fifty CRC tissue specimens and 50 matched adjacent mucosa specimens were collected. The expression of IL-6 in these clinical samples was examined by immunohistochemical staining. The correlation between IL-6 expression and clinicopathological parameters was assessed by statistical analysis. RESULTS: IL-6 expression was significantly elevated in CRC tissues compared with noncancerous tissues (P < 0.001). IL-6 expression was positively correlated with tumour TNM stage (P < 0.001), but a negative correlation was detected between IL-6 expression and tumor histological differentiation in CRC (P < 0.05). Furthermore, IL-6 expression was associated with invasion depth and lymph node metastasis in CRC. CONCLUSION: IL-6 might be a useful marker for predicting a poor prognosis in patients with CRC and might be used as a potential therapeutic target in CRC. PMID- 28348484 TI - Integrated analysis of microRNA and mRNA expression profiles in HBx-expressing hepatic cells. AB - AIM: To identify the miRNA-mRNA regulatory network in hepatitis B virus X (HBx) expressing hepatic cells. METHODS: A stable HBx-expressing human liver cell line L02 was established. The mRNA and miRNA expression profiles of L02/HBx and L02/pcDNA liver cells were identified by RNA-sequencing analysis. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was performed to investigate the function of candidate biomarkers, and the relationship between miRNA and mRNA was studied by network analysis. RESULTS: Compared with L02/pcDNA cells, 742 unregulated genes and 501 downregulated genes were determined as differentially expressed in L02/HBx cells. Gene ontology analysis suggested that the differentially expressed genes were relevant to different biological processes. Concurrently, 22 differential miRNAs were also determined in L02/HBx cells. Furthermore, integrated analysis of miRNA and mRNA expression profiles identified a core miRNA-mRNA regulatory network that is correlated with the carcinogenic role of HBx. CONCLUSION: Collectively, the miRNA-mRNA network-based analysis could be useful to elucidate the potential role of HBx in liver cell malignant transformation and shed light on the underlying molecular mechanism and novel therapy targets for hepatocellular carcinoma. PMID- 28348485 TI - ECRG2 enhances the anti-cancer effects of cisplatin in cisplatin-resistant esophageal cancer cells via upregulation of p53 and downregulation of PCNA. AB - AIM: To explore the anti-tumor effects of esophageal cancer-related gene 2 (ECRG2) in combination with cisplatin (DDP) in DDP-resistant esophageal cancer cells (EC9706/DDP). METHODS: A drug-resistant cell model was established, with EC9706/DDP cells being treated with ECRG2 and/or DDP. Cell viability was examined by MTT assay. The rate of cell apoptosis was determined by flow cytometry. The mRNA expression levels of proliferating cell nuclear antigen (PCNA), metallothionein (MT), and p53 were determined by RT-PCR and PCNA, while MT and p53 protein expression levels were determined by western blotting. RESULTS: The anti-proliferative effect of ECRG2 in combination with DDP was superior when compared to ECRG2 or DDP alone. The inhibition rate for the combination reached its peak (51.33%) at 96 h. The early apoptotic rates of the control, ECRG2 alone, DDP alone, and ECRG2 plus DDP groups were 5.71% +/- 0.27%, 12.68% +/- 0.61%, 14.15% +/- 0.87%, and 27.96% +/- 0.36%, respectively. Although all treatment groups were significantly different from the control group (P < 0.05), the combination treatment of ECRG2 plus DDP performed significantly better when compared to either ECRG2 or DDP alone (P < 0.05). The combination of ECRG2 and DDP significantly upregulated p53 mRNA and protein levels and downregulated PCNA mRNA and protein levels compared to ECRG2 or DDP alone (P < 0.05). However, no changes were seen in the expression of MT mRNA or protein. CONCLUSION: ECRG2 in combination with DDP can inhibit viability and induce apoptosis in esophageal cancer DDP-resistant cells, possibly via upregulation of p53 expression and downregulation of PCNA expression. These findings suggest that the combination of ECRG2 and DDP may be a promising strategy for the clinical treatment of esophageal cancers that are resistant to DDP. PMID- 28348486 TI - Therapeutic effect of curcumin on experimental colitis mediated by inhibiting CD8+CD11c+ cells. AB - AIM: To verify whether curcumin (Cur) can treat inflammatory bowel disease by regulating CD8+CD11c+ cells. METHODS: We evaluated the suppressive effect of Cur on CD8+CD11c+ cells in spleen and Peyer's patches (PPs) in colitis induced by trinitrobenzene sulfonic acid. Mice with colitis were treated by 200 mg/kg Cur for 7 d. On day 8, the therapeutic effect of Cur was evaluated by visual assessment and histological examination, while co-stimulatory molecules of CD8+CD11c+ cells in the spleen and PPs were measured by flow cytometry. The levels of interleukin (IL)-10, interferon (IFN)-gamma and transforming growth factor (TGF)-beta1 in spleen and colonic mucosa were determined by ELISA. RESULTS: The disease activity index, colon weight, weight index of colon and histological score of experimental colitis were obviously decreased after Cur treatment, while the body weight and colon length recovered. After treatment with Cur, CD8+CD11c+ cells were decreased in the spleen and PPs, and the expression of major histocompatibility complex II, CD205, CD40, CD40L and intercellular adhesion molecule-1 was inhibited. IL-10, IFN-gamma and TGF-beta1 levels were increased compared with those in mice with untreated colitis. CONCLUSION: Cur can effectively treat experimental colitis, which is realized by inhibiting CD8+CD11c+ cells. PMID- 28348487 TI - miR-34a mediates oxaliplatin resistance of colorectal cancer cells by inhibiting macroautophagy via transforming growth factor-beta/Smad4 pathway. AB - AIM: To investigate whether microRNA (miR)-34a mediates oxaliplatin (OXA) resistance of colorectal cancer (CRC) cells by inhibiting macroautophagy via the transforming growth factor (TGF)-beta/Smad4 pathway. METHODS: miR-34a expression levels were detected in CRC tissues and CRC cell lines by quantitative real-time polymerase chain reaction. Computational search, functional luciferase assay and western blotting were used to demonstrate the downstream target of miR-34a in CRC cells. Cell viability was measured with Cell Counting Kit-8. Apoptosis and macroautophagy of CRC cells were analyzed by flow cytometry and transmission electron microscopy, and expression of beclin I and LC3-II was detected by western blotting. RESULTS: Expression of miR-34a was significantly reduced while expression of TGF-beta and Smad4 was increased in CRC patients treated with OXA based chemotherapy. OXA treatment also resulted in decreased miR-34a levels and increased TGF-beta and Smad4 levels in both parental cells and the OXA-resistant CRC cells. Activation of macroautophagy contributed to OXA resistance in CRC cells. Expression levels of Smad4 and miR-34a in CRC patients had a significant inverse correlation and overexpressing miR-34a inhibited macroautophagy activation by directly targeting Smad4 through the TGF-beta/Smad4 pathway. OXA induced downregulation of miR-34a and increased drug resistance by activating macroautophagy in CRC cells. CONCLUSION: miR-34a mediates OXA resistance of CRC by inhibiting macroautophagy via the TGF-beta/Smad4 pathway. PMID- 28348488 TI - Experimental porcine model of complex fistula-in-ano. AB - AIM: To establish and evaluate an experimental porcine model of fistula-in-ano. METHODS: Twelve healthy pigs were randomly divided into two groups. Under general anesthesia, the experimental group underwent rubber band ligation surgery, and the control group underwent an artificial damage technique. Clinical magnetic resonance imaging (MRI) and histopathological evaluation were performed on the 38th d and 48th d after surgery in both groups, respectively. RESULTS: There were no significant differences between the experimental group and the control group in general characteristics such as body weight, gender, and the number of fistula (P > 0.05). In the experimental group, 15 fistulas were confirmed clinically, 13 complex fistulas were confirmed by MRI, and 11 complex fistulas were confirmed by histopathology. The success rate in the porcine complex fistula model establishment was 83.33%. Among the 18 fistulas in the control group, 5 fistulas were confirmed clinically, 4 complex fistulas were confirmed by MRI, and 3 fistulas were confirmed by histopathology. The success rate in the porcine fistula model establishment was 27.78%. Thus, the success rate of the rubber band ligation group was significantly higher than the control group (P < 0.05). CONCLUSION: Rubber band ligation is a stable and reliable method to establish complex fistula-in-ano models. Large animal models of complex anal fistulas can be used for the diagnosis and treatment of anal fistulas. PMID- 28348489 TI - Serum HER2 as a predictive biomarker for tissue HER2 status and prognosis in patients with gastric cancer. AB - AIM: To investigate the association between serum human epidermal growth factor receptor 2 (HER2) extracellular domain (ECD) and tissue HER2 status, and the prognostic value of serum HER2 ECD in patients with gastric cancer. METHODS: A total of 239 patients with gastric cancer were enrolled from December 2012 to June 2013. Serum HER2 ECD was determined by chemiluminescent assay, and tissue HER2 status was evaluated by immunohistochemistry and fluorescence in situ hybridization assay. A receiver operating characteristic (ROC) curve was plotted to identify the optimal cut-off value for serum HER2 ECD assay for predicting survival in gastric cancer patients. RESULTS: Serum HER2 ECD was significantly correlated with tissue HER2 status (P < 0.001), tumor size (P < 0.001), and intestinal type of gastric cancer (P = 0.021). Serum HER2 ECD levels differed significantly between patients with HER2-positive tissue expression and those with HER2-negative tissue expression. ROC analysis yielded an area under the curve value of 0.79 (95%CI: 0.71-0.87, P < 0.001), with a sensitivity and specificity of 0.54 (95%CI: 0.37-0.70) and 0.93 (95%CI: 0.88-0.96), respectively. With a cut-off value of 24.75 ng/mL, high serum HER2 ECD had a negative impact on overall survival of the patients (HR: 1.93, 95%CI: 1.32-4.38, P = 0.006). CONCLUSION: Serum HER2 ECD could be a highly specific surrogate biomarker for tissue HER2 status in gastric cancer. Optimal cut-off criteria for predicting survival should be established. PMID- 28348490 TI - Endoscopic submucosal tunnel dissection of upper gastrointestinal submucosal tumors: A comparative study of hook knife vs hybrid knife. AB - AIM: To compare the efficacy and safety of a hook knife (HO) with a hybrid knife (HK) during endoscopic submucosal tunnel dissection (ESTD) procedure. METHODS: Between August 2012 and December 2015, the ESTD procedure was performed for 83 upper GI submucosal lesions, which originated from the muscularis propria layer identified by upper endoscopy and endoscopic ultrasonography. Of these, 34 lesions were treated by a HO, whereas 49 lesions were treated by a HK. Data regarding age, gender, presenting symptoms, tumor location and size, procedure time, complications, en bloc resection rate and others were analyzed and compared between the two groups. RESULTS: There were no significant differences in the age, gender, presenting symptoms and tumor location between the two groups. ESTD was successfully completed in all the patients, and no case was converted to laparoscopy. The mean procedure time was significantly shorter in the HK group than in the HO group (41.3 +/- 20.3 min vs 57.2 +/- 28.0 min, P = 0.004). The mean frequency of device exchange was 1.4 +/- 0.6 in the HK group and significantly less than 3.3 +/- 0.6 in the HO group (P < 0.001). The differences in tumor size and histopathological diagnoses were not significant between the two groups (P = 0.813, P = 0.363, respectively). Both groups had an equal en bloc resection rate and complete resection rate. Additionally, the complication rate was similar between the two groups (P = 0.901). During the follow-up, no recurrence occurred in either group. CONCLUSION: We demonstrate for the first time that HO and HK do not differ in efficacy or safety, but HK reduces the frequency of device exchange and procedure time. PMID- 28348491 TI - Percutaneous intraductal radiofrequency ablation for treatment of biliary stent occlusion: A preliminary result. AB - AIM: To assess the feasibility and effectiveness of a novel application of percutaneous intraductal radiofrequency (RF) for the treatment of biliary stent obstruction. METHODS: We specifically report a retrospective study presenting the results of percutaneous intraductal RF in patients with biliary stent occlusion. A total of 43 cases involving biliary stent obstruction were treated by placing an EndoHPB catheter and percutaneous intraductal RF was performed to clean stents. The stent patency was evaluated by cholangiography and follow-up by contrast enhanced computed tomography or ultrasound after the removal of the drainage catheter. RESULTS: Following the procedures, of the 43 patients, 40 survived and 3 died with a median survival of 80.5 (range: 30-243) d. One patient was lost to follow-up. One patient had the stent patent at the time of last follow-up. Two patients with stent blockage at 35 d and 44 d after procedure underwent percutaneous transhepatic drain insertion only. The levels of bilirubin before and after the procedure were 128 +/- 65 MUmol/L and 63 +/- 29 MUmol/L, respectively. There were no related complications (haemorrhage, bile duct perforation, bile leak or pancreatitis) and all patients' stent patency was confirmed by cholangiography after the procedure, with a median patency time of 107 (range: 12-180) d. CONCLUSION: This preliminary clinical study demonstrated that percutaneous intraductal RF is safe and effective for the treatment of biliary stent obstruction, increasing the duration of stent patency, although randomized controlled trials are needed to confirm the effectiveness of this approach. PMID- 28348492 TI - Hospital resource intensity and cirrhosis mortality in United States. AB - AIM: To determine whether hospital characteristics predict cirrhosis mortality and how much variation in mortality is attributable to hospital differences. METHODS: We used data from the 2005-2011 Nationwide Inpatient Sample and the American Hospital Association Annual survey to identify hospitalizations for decompensated cirrhosis and corresponding facility characteristics. We created hospital-specific risk and reliability-adjusted odds ratios for cirrhosis mortality, and evaluated patient and facility differences based on hospital performance quintiles. We used hierarchical regression models to determine the effect of these factors on mortality. RESULTS: Seventy-two thousand seven hundred and thirty-three cirrhosis admissions were evaluated in 805 hospitals. Hospital mean cirrhosis annual case volume was 90.4 (range 25-828). Overall hospital cirrhosis mortality rate was 8.00%. Hospital-adjusted odds ratios (aOR) for mortality ranged from 0.48 to 1.89. Patient characteristics varied significantly by hospital aOR for mortality. Length of stay averaged 6.0 +/- 1.6 days, and varied significantly by hospital performance (P < 0.001). Facility level predictors of risk-adjusted mortality were higher Medicaid case-mix (OR = 1.00, P = 0.029) and LPN staffing (OR = 1.02, P = 0.015). Higher cirrhosis volume (OR = 0.99, P = 0.025) and liver transplant program status (OR = 0.83, P = 0.026) were significantly associated with survival. After adjusting for patient differences, era, and clustering effects, 15.3% of variation between hospitals was attributable to differences in facility characteristics. CONCLUSION: Hospital characteristics account for a significant proportion of variation in cirrhosis mortality. These findings have several implications for patients, providers, and health care delivery in liver disease care and inpatient health care design. PMID- 28348493 TI - Mortality associated with hepatitis C and hepatitis B virus infection: A nationwide study on multiple causes of death data. AB - AIM: To analyze mortality associated with hepatitis C virus (HCV) and hepatitis B virus (HBV) infection in Italy. METHODS: Death certificates mentioning either HBV or HCV infection were retrieved from the Italian National Cause of Death Register for the years 2011-2013. Mortality rates and proportional mortality (percentage of deaths with mention of HCV/HBV among all registered deaths) were computed by gender and age class. The geographical variability in HCV-related mortality rates was investigated by directly age-standardized rates (European standard population). Proportional mortality for HCV and HBV among subjects aged 20-59 years was assessed in the native population and in different immigrant groups. RESULTS: HCV infection was mentioned in 1.6% (n = 27730) and HBV infection in 0.2% (n = 3838) of all deaths among subjects aged >= 20 years. Mortality rates associated with HCV infection increased exponentially with age in both genders, with a male to female ratio close to unity among the elderly; a further peak was observed in the 50-54 year age group especially among male subjects. HCV-related mortality rates were higher in Southern Italy among elderly people (45/100000 in subjects aged 60-79 and 125/100000 in subjects aged >= 80 years), and in North Western Italy among middle-aged subjects (9/100000 in the 40-59 year age group). Proportional mortality was higher among Italian citizens and North African immigrants for HCV, and among Sub-Saharan African and Asian immigrants for HBV. CONCLUSION: Population ageing, immigration, and new therapeutic approaches are shaping the epidemiology of virus-related chronic liver disease. In spite of limits due to the incomplete reporting and misclassification of the etiology of liver disease, mortality data represent an additional source of information for surveillance. PMID- 28348494 TI - Prognostic value of site-specific metastases in pancreatic adenocarcinoma: A Surveillance Epidemiology and End Results database analysis. AB - AIM: To evaluate the prognostic value of site-specific metastases among patients with metastatic pancreatic carcinoma registered within the Surveillance, Epidemiology and End Results (SEER) database. METHODS: SEER database (2010-2013) has been queried through SEER*Stat program to determine the presentation, treatment outcomes and prognostic outcomes of metastatic pancreatic adenocarcinoma according to the site of metastasis. In this study, metastatic pancreatic adenocarcinoma patients were classified according to the site of metastases (liver, lung, bone, brain and distant lymph nodes). We utilized chi square test to compare the clinicopathological characteristics among different sites of metastases. We used Kaplan-Meier analysis and log-rank testing for survival comparisons. We employed Cox proportional model to perform multivariate analyses of the patient population; and accordingly hazard ratios with corresponding 95%CI were generated. Statistical significance was considered if a two-tailed P value < 0.05 was achieved. RESULTS: A total of 13233 patients with stage IV pancreatic cancer and known sites of distant metastases were identified in the period from 2010-2013 and they were included into the current analysis. Patients with isolated distant nodal involvement or lung metastases have better overall and pancreatic cancer-specific survival compared to patients with isolated liver metastases (for overall survival: lung vs liver metastases: P < 0.0001; distant nodal vs liver metastases: P < 0.0001) (for pancreatic cancer specific survival: lung vs liver metastases: P < 0.0001; distant nodal vs liver metastases: P < 0.0001). Multivariate analysis revealed that age < 65 years, white race, being married, female gender; surgery to the primary tumor and surgery to the metastatic disease were associated with better overall survival and pancreatic cancer-specific survival. CONCLUSION: Pancreatic adenocarcinoma patients with isolated liver metastases have worse outcomes compared to patients with isolated lung or distant nodal metastases. Further research is needed to identify the highly selected subset of patients who may benefit from local treatment of the primary tumor and/or metastatic disease. PMID- 28348495 TI - Role of illness perception and self-efficacy in lifestyle modification among non alcoholic fatty liver disease patients. AB - AIM: To describe the relationships between non-alcoholic fatty-liver disease (NAFLD) patient's disease consequences and treatment perceptions, self-efficacy, and healthy lifestyle maintenance. METHODS: A cross-sectional study among 146 ultrasound diagnosed NAFLD patients who visited the fatty liver clinic at the Tel Aviv Medical Center. Eighty-seven of these individuals, participated in a clinical trial of physical activity and underwent fasting blood tests, analyzed at the same lab. Exclusion criteria included positivity for serum HBsAg or anti HCV antibodies; fatty liver suspected to be secondary to hepatotoxic drugs; excessive alcohol consumption (>= 30 g/d in men or >= 20 g/d in women) and positive markers of genetic or immune-mediated liver diseases. Patients were asked to complete a self-report structured questionnaire, assembled by the Israeli Center for Disease Control. Nutrition habits were measured using six yes/no questions (0 = no, 1 = yes) adopted from the national survey questionnaire. Participants in the clinical trial completed a detailed semi quantitative food frequency questionnaire (FFQ) reporting their habitual nutritional intake during the past year. Self-efficacy was assessed by the Self Efficacy Scale questionnaire, emotional representation, degree of illness understanding, timeline perception, treatment perception and symptoms were measured by the Brief Illness Perception questionnaire. Illness consequences were measured by the Personal Models of Diabetes Interview questionnaire. A path analysis was performed to describe the interrelationships between the patients' illness perceptions, and assess the extent to which the data fit a prediction of nutritional habits. RESULTS: The study sample included 54.1% men, with a mean age of 47.76 +/- 11.68 years (range: 20-60) and mean body mass index of 31.56 +/- 4.6. The average perceived nutrition habits score was 4.73 +/- 1.45 on a scale between 0-6, where 6 represents the healthiest eating habits. Most of the study participants (57.2%) did not feel they fully understood what NAFLD is. Better nutritional habits were positively predicted by the degree of illness understanding (beta = 0.26; P = 0.002) and self-efficacy (beta = 0.25; P = 0.003). Perceptions of more severe illness consequences were related with higher emotional representation (beta = 0.55; P < 0.001), which was related with lower self-efficacy (beta = -0.17; P = 0.034). The perception of treatment effectiveness was positively related with self-efficacy (beta = 0.32; P < 0.001). In accordance with the correlation between self-efficacy and the perceived nutrition habits score, self-efficacy was also correlated with nutrient intake evaluated by the FFQ; negatively with saturated fat (percent of saturated fat calories from total calories) (r = -0.28, P = 0.010) and positively with fiber (r = 0.22, P = 0.047) and vitamin C intake (r = 0.34, P = 0.002). In a sub analysis of the clinical trial participants, objectively measured compliance to physical activity regimen was positively correlated with the self-efficacy level (r = 0.34, P = 0.046). CONCLUSION: Self-efficacy and illness understanding are major determinants of lifestyle-modification among NAFLD patients. This information can assist clinicians in improving compliance with lifestyle changes among these patients. PMID- 28348496 TI - Validation of the chinese version of the EORTC QLQ-CR29 in patients with colorectal cancer. AB - AIM: To assess the validity and reliability of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Colorectal Cancer 29 (EORTC QLQ-CR29) in Chinese patients with colorectal cancer (CRC). METHODS: From March 2014 to January 2015, 356 patients with CRC from four different hospitals in China were enrolled in the study, and all patients self-administered the EORTC QLQ-CR29 and the quality of life core questionnaire (EORTC QLQ-C30). Evaluation of the scores was based on the Karnofsky Performance Scale (KPS). The reliability and validity of the questionnaires were assessed by Cronbach's alpha coefficient, the Spearman correlation test and Wilcoxon rank sum test. RESULTS: The EORTC QLQ-CR29 showed satisfactory reliability (alpha > 0.7), although the urinary frequency and blood and mucus in stool dimensions had only moderate reliability (alpha = 0.608). The multitrait scaling analyses showed good convergent (r > 0.4) and discriminant validity. Significant differences were obtained for each item in the different KPS subgroups (KPS <= 80; KPS > 80). Body image and most single-item dimensions showed statistically significant differences in patients with a stoma compared with the rest of the patients. CONCLUSION: The EORTC QLQ-CR29 exhibits high validity and reliability in Chinese patients with CRC, and can therefore be recommended as a valuable tool for the assessment of quality of life in these patients. PMID- 28348497 TI - Microbiome and pancreatic cancer: A comprehensive topic review of literature. AB - AIM: To review microbiome alterations associated with pancreatic cancer, its potential utility in diagnostics, risk assessment, and influence on disease outcomes. METHODS: A comprehensive literature review was conducted by all inclusive topic review from PubMed, MEDLINE, and Web of Science. The last search was performed in October 2016. RESULTS: Diverse microbiome alterations exist among several body sites including oral, gut, and pancreatic tissue, in patients with pancreatic cancer compared to healthy populations. CONCLUSION: Pilot study successes in non-invasive screening strategies warrant further investigation for future translational application in early diagnostics and to learn modifiable risk factors relevant to disease prevention. Pre-clinical investigations exist in other tumor types that suggest microbiome manipulation provides opportunity to favorably transform cancer response to existing treatment protocols and improve survival. PMID- 28348500 TI - Regression Models For Multivariate Count Data. AB - Data with multivariate count responses frequently occur in modern applications. The commonly used multinomial-logit model is limiting due to its restrictive mean variance structure. For instance, analyzing count data from the recent RNA-seq technology by the multinomial-logit model leads to serious errors in hypothesis testing. The ubiquity of over-dispersion and complicated correlation structures among multivariate counts calls for more flexible regression models. In this article, we study some generalized linear models that incorporate various correlation structures among the counts. Current literature lacks a treatment of these models, partly due to the fact that they do not belong to the natural exponential family. We study the estimation, testing, and variable selection for these models in a unifying framework. The regression models are compared on both synthetic and real RNA-seq data. PMID- 28348499 TI - Supraclavicular lymph node metastases from malignant gastrointestinal stromal tumor of the jejunum: A case report with review of the literature. AB - Gastrointestinal stromal tumors (GISTs) represent the most common mesenchymal tumors of the alimentary tract. These tumors may have different clinical and biological behaviors. Malignant forms usually spread via a hematogenous route, and lymph node metastases rarely occur. Herein, we report a patient with a jejunal GIST who developed supraclavicular lymph node metastasis. We conclude that lymphatic diffusion via the mediastinal lymphatic station to the supraclavicular lymph nodes can be a potential metastatic route for GISTs. PMID- 28348498 TI - Markers of systemic inflammation and colorectal adenoma risk: Meta-analysis of observational studies. AB - AIM: To perform a meta-analysis of observational studies on inflammatory markers levels and occurrence of colorectal adenoma. METHODS: PubMed and EMBASE databases were searched until March 2016 for the articles reporting on the circulating levels of inflammatory markers, including: C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) and risk of colorectal adenoma. Random-effects models were used to calculate summary odds ratios (ORs) with 95%CIs for the highest vs lowest category of exposure. Heterogeneity was assessed by using the Q test and I2 statistic. Subgroup analyses were also performed to test for potential source of heterogeneity. RESULTS: A total of 14 case-control studies were included. Ten studies on CRP including a total of 3350 cases and 4168 controls showed non-significant summary (OR = 1.23, 95%CI: 0.98 1.54; I2 = 54%, Pheterogeneity = 0.01) in the general analysis, but significant increased odds when considering only advanced adenoma (OR = 1.59, 95%CI: 1.09 2.32; I2 = 44%, Pheterogeneity = 0.15). Subgroup and stratified analyses revealed a potential influence of smoking status and aspirin use on the association between CRP levels and colorectal adenoma. Five studies examined the association between circulating levels of TNF-alpha and colorectal adenoma risk, including a total of 1,568 cases and 2,832 controls. The summary OR for the highest vs the lowest category of exposure was 1.00 (95%CI: 0.77-1.29). The relationship between circulating IL-6 levels and colorectal adenoma risk was investigated in 7 studies including a total of 1936 cases and 3611 controls. The summary OR for the highest vs the lowest category of exposure was 1.19 (95%CI: 0.92-1.55). CONCLUSION: Summary of current evidence suggests a positive association of CRP levels and advanced colorectal adenoma risk. The role of potential confounding factors should be further evaluated. PMID- 28348501 TI - An Investigation into the Relation between the Technique of Movement and Overload in Step Aerobics. AB - The aim of this research was to determine the features of a step workout technique which may be related to motor system overloading in step aerobics. Subjects participating in the research were instructors (n = 15) and students (n = 15) without any prior experience in step aerobics. Kinematic and kinetic data was collected with the use of the BTS SMART system comprised of 6 calibrated video cameras and two Kistler force plates. The subjects' task was to perform basic steps. The following variables were analyzed: vertical, anteroposterior, and mediolateral ground reaction forces; foot flexion and abduction and adduction angles; knee joint flexion angle; and trunk flexion angle in the sagittal plane. The angle of a foot adduction recorded for the instructors was significantly smaller than that of the students. The knee joint angle while stepping up was significantly higher for the instructors compared to that for the students. Our research confirmed that foot dorsal flexion and adduction performed while stepping up increased load on the ankle joint. Both small and large angles of knee flexion while stepping up and down resulted in knee joint injuries. A small trunk flexion angle in the entire cycle of step workout shut down dorsal muscles, which stopped suppressing the load put on the spine. PMID- 28348502 TI - Nontuberculous Mycobacteria in Saudi Arabia and Gulf Countries: A Review. AB - Nontuberculous Mycobacteria (NTM) are causing growing health problems worldwide. This is indicated by an increasing amount of scientific reports showing not only well-identified species reemerging but also emergence of new species. The emergence and reemergence of NTM are particularly worrying in developing countries due to scarce published data and improper identification. Here we aimed to examine the main epidemiological aspects and diagnostic challenges associated with NTM in countries of the Gulf Cooperation Council (GCC) and compare these findings to the international arena findings. Data revealed that countries of the GCC are largely dominated by rapidly growing mycobacteria species such as M. fortuitum (29%) and M. abscessus (17%) with high rate of definitive respiratory diseases. On the other hand, most of the developed countries are dominated by slowly growing mycobacteria such as MAC, M. kansasii, and M. gordonae. More efforts are needed, however, to gain insights into NTM issues in countries of the GCC. PMID- 28348503 TI - Gabapentin Does Not Appear to Improve Postoperative Pain and Sleep Patterns in Patients Who Concomitantly Receive Regional Anesthesia for Lower Extremity Orthopedic Surgery: A Randomized Control Trial. AB - In recent years, gabapentin has gained popularity as an adjuvant therapy for the treatment of postoperative pain. Numerous studies have shown a decrease in pain score, even with immediate postoperative activity, which is significant for early post-op ambulation and regaining functionality sooner. However, studies have been in conclusive in patients undergoing lower extremity orthopedic surgery. For this reason, we hoped to study the effect of gabapentin on postoperative pain in patients undergoing total knee arthroplasty, total hip arthroplasty, or a hip fracture repair. This was done in the setting of ensuring adequate postoperative analgesia with regional blocks and opioid PCA, as is protocol at our institution. Given the sedative effects of gabapentin and the potential for improving postoperative sleep patterns, we also studied the drug's effect on this aspect of our patient's postoperative course. We utilized the Pittsburg Sleep Quality Index and Visual Analog Scale for pain to obtain a more objective standardized score amongst our study population. Our results indicate that gabapentin does not offer any additional relief in pain or improve sleep habits in patients who have received either a femoral or lumbar plexus block for lower extremity orthopedic surgery. This trial is registered with NCT01546857. PMID- 28348504 TI - Epidural Dexamethasone for Postoperative Analgesia in Patients Undergoing Unilateral Inguinal Herniorrhaphy: A Comparative Study. AB - Background. This study was designed to evaluate the effect of adding dexamethasone to epidural bupivacaine on postoperative analgesia in unilateral inguinal herniorrhaphy. Methods. Forty-four patients were enrolled in this double blind, clinical trial study. Patients were randomly allocated into dexamethasone or control group. In the dexamethasone group, patients received 18 ml of bupivacaine 0.5% and 2 ml (8 mg) of dexamethasone; in the control group, patients received 18 ml of bupivacaine 0.5% and 2 ml of normal saline. The onset of sensory block and its duration and incidence of nausea and vomiting were recorded. Results. The onset of epidural anesthesia was significantly more rapid in the dexamethasone group than in the control group (P < 0.001). Duration of analgesia was markedly prolonged in the dexamethasone group than in the control group (P < 0.001). Five patients (22.7%) in the control group had nausea in the first hour after the procedure (P = 0.048). None of the patients in the dexamethasone group had nausea. None of our patients had vomiting in the two groups. Conclusions. This study showed that adding dexamethasone to bupivacaine significantly prolongs the duration of postoperative analgesia. This trial is registered with Iranian Registry of Clinical Trials (IRCT) number IRCT2012062910137N1. PMID- 28348506 TI - Pain Catastrophizing and Its Relationship with Health Outcomes: Does Pain Intensity Matter? AB - Pain catastrophizing is known to contribute to physical and mental functioning, even when controlling for the effect of pain intensity. However, research has yet to explore whether the strength of the relationship between pain catastrophizing and pain-related outcomes varies across pain intensity levels (i.e., moderation). If this was the case, it would have important implications for existing models of pain and current interventions. The present investigation explored whether pain intensity moderates the relationship between pain catastrophizing and pain related outcomes. Participants were 254 patients (62% women) with heterogeneous chronic pain. Patients completed a measure of pain intensity, pain interference, pain catastrophizing, and physical and mental health. Pain intensity moderated the relationship between pain catastrophizing and pain interference and between pain catastrophizing and physical health status. Specifically, the strength of the correlation between pain catastrophizing and these outcomes decreased considerably as pain intensity increased. In contrast, pain intensity did not moderate the relationship between pain catastrophizing and mental health. Study findings provide a new insight into the role of pain intensity (i.e., moderator) in the relationship between pain catastrophizing and various pain-related outcomes, which might help develop existent models of pain. Clinical implications are discussed in the context of personalized therapy. PMID- 28348505 TI - Effects of a Pain Catastrophizing Induction on Sensory Testing in Women with Chronic Low Back Pain: A Pilot Study. AB - Pain catastrophizing, a pattern of negative cognitive-emotional responses to actual or anticipated pain, maintains chronic pain and undermines response to treatments. Currently, precisely how pain catastrophizing influences pain processing is not well understood. In experimental settings, pain catastrophizing has been associated with amplified pain processing. This study sought to clarify pain processing mechanisms via experimental induction of pain catastrophizing. Forty women with chronic low back pain were assigned in blocks to an experimental condition, either a psychologist-led 10-minute pain catastrophizing induction or a control (10-minute rest period). All participants underwent a baseline round of several quantitative sensory testing (QST) tasks, followed by the pain catastrophizing induction or the rest period, and then a second round of the same QST tasks. The catastrophizing induction appeared to increase state pain catastrophizing levels. Changes in QST pain were detected for two of the QST tasks administered, weighted pin pain and mechanical allodynia. Although there is a need to replicate our preliminary results with a larger sample, study findings suggest a potential relationship between induced pain catastrophizing and central sensitization of pain. Clarification of the mechanisms through which catastrophizing affects pain modulatory systems may yield useful clinical insights into the treatment of chronic pain. PMID- 28348507 TI - Variations of Surveillance Practice for Patients with Bone Sarcoma: A Survey of Australian Sarcoma Clinicians. AB - Introduction. After treatment, bone sarcoma patients carry a high chance of relapse and late effects from multimodal therapy. We hypothesize that significant variation in surveillance practice exists between pediatric medical oncology (PO) and nonpediatric medical oncology (NP) sarcoma disciplines. Methods. Australian sarcoma clinicians were approached to do a web based survey that assessed radiologic surveillance (RS) strategies, late toxicity assessment, and posttreatment psychosocial interventions. Results. In total, 51 clinicians responded. No differences were identified in local disease RS. In metastatic disease response assessment, 100% of POs (23/23) and 93% of NPs (24/26) conducted CT chest. However, this was more likely to occur for NPs in the context of a CT chest/abdomen/pelvis (NP: 10/26; PO: 1/23; p = 0.006). POs were more likely to use CXR for RS (p = 0.006). POs showed more prescriptive intensity in assessment of heart function (p = 0.001), hearing (p < 0.001), and fertility (p = 0.02). POs were more likely to deliver written information for health maintenance/treatment summary (p = 0.04). The majority of respondents described enquiring about psychosocial aspects of health (n = 33/37, 89%), but a routine formal psychosocial screen was only used by 23% (n = 6/26). Conclusion. There is high variability in bone sarcoma surveillance between PO and NP clinicians. Efforts to harmonize approaches would allow early and late effects recognition/intervention and facilitate improved patient care/transition and research. PMID- 28348508 TI - Construction of Expression Shuttle Vectors for the Haloarchaeon Natrinema sp. J7 Based on Its Chromosomal Origins of Replication. AB - Haloarchaeon Natrinema sp. J7, the first reported archaeon harboring both plasmid and chromosome-based temperate viruses, is a useful model for investigating archaeal virus-host and virus-virus interactions. However, the lack of genetic tools has limited such studies. On the basis of the automatically replicating sequences of the J7 chromosome and the pyrF marker, we constructed seven vectors, six of which were confirmed to possess replication ability in a pyrF-deletion derivative of J7 (J7-F). Among these vectors, pFJ1, pFJ4, and pFJ6 could be transformed into the host strain with relatively high efficiency (approximately 103 colony-forming units/MUg DNA) and were present at about one copy per chromosome. These three vectors could be stably maintained in J7-F without selection and were used for heterologous protein expression. Only pFJ6 was found to be present in the transformed cells in an exclusively episomal, nonintegrated state (one copy per chromosome). In contrast, some pFJ1 and pFJ4 DNA was probably integrated into the J7-F chromosome. In addition, pFJ6 was found to be compatible with pYCJ in J7 cells, suggesting that these two vectors could be used for further studies of virus-virus and virus-host interactions. PMID- 28348509 TI - Equilibrium, Kinetic, and Thermodynamic Studies on the Adsorption of Cadmium from Aqueous Solution by Modified Biomass Ash. AB - Natural biomass ash of agricultural residuals was collected from a power plant and modified with hexagonal mesoporous silica and functionalized with 3 aminopropyltriethoxysilane. The physicochemical and morphological properties of the biomass ash were analyzed by ICP-OES, SEM, TEM-EDS, FTIR, and BET analysis. The adsorption behavior of the modified product for Cd2+ in aqueous solution was studied as a function of pH, initial metal concentration, equilibrium time, and temperature. Results showed that the specific surface area of the modified product was 9 times that of the natural biomass ash. The modified biomass ash exhibited high affinity for Cd2+ and its adsorption capacity increased sharply with increasing pH from 4.0 to 6.0. The maximum adsorption capacity was 23.95 mg/g in a pH 5 solution with an initial metal concentration of 50 mg/L and a contact time of 90 min. The adsorption of Cd2+ onto the modified biomass ash was well fitted to the Langmuir model and it followed pseudo-second-order kinetics. Thermodynamic analysis results showed that the adsorption of Cd2+ was spontaneous and endothermic in nature. The results suggest that the modified biomass ash is promising for use as an inexpensive and effective adsorbent for Cd2+ removal from aqueous solution. PMID- 28348510 TI - Comprehensive Optimization of LC-MS Metabolomics Methods Using Design of Experiments (COLMeD). AB - INTRODUCTION: Both reverse-phase and HILIC chemistries are deployed for liquid chromatography mass spectrometry (LC-MS) metabolomics analyses, however HILIC methods lag behind reverse-phase methods in reproducibility and versatility. Comprehensive metabolomics analysis is additionally complicated by the physiochemical diversity of metabolites and array of tunable analytical parameters. OBJECTIVE: Our aim was to rationally and efficiently design complementary HILIC-based polar metabolomics methods on multiple instruments using Design of Experiments (DoE). METHODS: We iteratively tuned LC and MS conditions on ion-switching triple quadrupole (QqQ) and quadrupole-time-of-flight (qTOF) mass spectrometers through multiple rounds of a workflow we term COLMeD (Comprehensive optimization of LC-MS metabolomics methods using design of experiments). Multivariate statistical analysis guided our decision process in the method optimizations. RESULTS: LC-MS/MS tuning for the QqQ method on serum metabolites yielded a median response increase of 161.5% (p<0.0001) over initial conditions with a 13.3% increase in metabolite coverage. The COLMeD output was benchmarked against two widely used polar metabolomics methods, demonstrating total ion current increases of 105.8% and 57.3%, with median metabolite response increases of 106.1% and 10.3% (p<0.0001 and p<0.05 respectively). For our optimized qTOF method, 22 solvent systems were compared on a standard mix of physiochemically diverse metabolites, followed by COLMeD optimization, yielding a median 29.8% response increase (p<0.0001) over initial conditions. CONCLUSIONS: The COLMeD process elucidated response tradeoffs, facilitating improved chromatography and MS response without compromising separation of isobars. COLMeD is efficient, requiring no more than 20 injections in a given DoE round, and flexible, capable of class-specific optimization as demonstrated through acylcarnitine optimization within the QqQ method. PMID- 28348511 TI - Constraints and Adaptation of Closed-Loop Neuroprosthetics for Functional Restoration. AB - Closed-loop neuroprosthetics aim to compensate for lost function, e.g., by controlling external devices such as prostheses or wheelchairs. Such assistive approaches seek to maximize speed and classification accuracy for high dimensional control. More recent approaches use similar technology, but aim to restore lost motor function in the long term. To achieve this goal, restorative neuroprosthetics attempt to facilitate motor re-learning and to strengthen damaged and/or alternative neural connections on the basis of neurofeedback training within rehabilitative environments. Such a restorative approach requires reinforcement learning of self-modulated brain activity which is considered to be beneficial for functional rehabilitation, e.g., improvement of beta-power modulation over sensorimotor areas for post-stroke movement restoration. Patients with motor impairments, however, may also have a compromised ability for motor task-related regulation of the targeted brain activity. This would affect the estimation of feature weights and hence the classification accuracy of the feedback device. This, in turn, can frustrate the patients and compromise their motor learning. Furthermore, the feedback training may even become erroneous when unconstrained classifier adaptation-which is often used in assistive approaches is also applied in this rehabilitation context. In conclusion, the conceptual switch from assistance toward restoration necessitates a methodological paradigm shift from classification accuracy toward instructional efficiency. Furthermore, a constrained feature space, a priori regularized feature weights, and difficulty adaptation present key elements of restorative brain interfaces. These factors need, therefore, to be addressed within a therapeutic framework to facilitate reinforcement learning of brain self-regulation for restorative purposes. PMID- 28348512 TI - Using Dual Regression to Investigate Network Shape and Amplitude in Functional Connectivity Analyses. AB - Independent Component Analysis (ICA) is one of the most popular techniques for the analysis of resting state FMRI data because it has several advantageous properties when compared with other techniques. Most notably, in contrast to a conventional seed-based correlation analysis, it is model-free and multivariate, thus switching the focus from evaluating the functional connectivity of single brain regions identified a priori to evaluating brain connectivity in terms of all brain resting state networks (RSNs) that simultaneously engage in oscillatory activity. Furthermore, typical seed-based analysis characterizes RSNs in terms of spatially distributed patterns of correlation (typically by means of simple Pearson's coefficients) and thereby confounds together amplitude information of oscillatory activity and noise. ICA and other regression techniques, on the other hand, retain magnitude information and therefore can be sensitive to both changes in the spatially distributed nature of correlations (differences in the spatial pattern or "shape") as well as the amplitude of the network activity. Furthermore, motion can mimic amplitude effects so it is crucial to use a technique that retains such information to ensure that connectivity differences are accurately localized. In this work, we investigate the dual regression approach that is frequently applied with group ICA to assess group differences in resting state functional connectivity of brain networks. We show how ignoring amplitude effects and how excessive motion corrupts connectivity maps and results in spurious connectivity differences. We also show how to implement the dual regression to retain amplitude information and how to use dual regression outputs to identify potential motion effects. Two key findings are that using a technique that retains magnitude information, e.g., dual regression, and using strict motion criteria are crucial for controlling both network amplitude and motion related amplitude effects, respectively, in resting state connectivity analyses. We illustrate these concepts using realistic simulated resting state FMRI data and in vivo data acquired in healthy subjects and patients with bipolar disorder and schizophrenia. PMID- 28348513 TI - Commentary: Microstructure, length, and connection of limbic tracts in normal human brain development. PMID- 28348514 TI - Postnatal Dendritic Growth and Spinogenesis of Layer-V Pyramidal Cells Differ between Visual, Inferotemporal, and Prefrontal Cortex of the Macaque Monkey. AB - Pyramidal cells in the primate cerebral cortex, particularly those in layer III, exhibit regional variation in both the time course and magnitude of postnatal growth and pruning of dendrites and spines. Less is known about the development of pyramidal cell dendrites and spines in other cortical layers. Here we studied dendritic morphology of layer-V pyramidal cells in primary visual cortex (V1, sensory), cytoarchitectonic area TE in the inferotemporal cortex (sensory association), and granular prefrontal cortex (Walker's area 12, executive) of macaque monkeys at the ages of 2 days, 3 weeks, 3.5 months, and 4.5 years. We found that changes in the basal dendritic field area of pyramidal cells were different across the three areas. In V1, field size became smaller over time (largest at 2 days, half that size at 4.5 years), in TE it did not change, and in area 12 it became larger over time (smallest at 2 days, 1.5 times greater at 4.5 years). In V1 and TE, the total number of branch points in the basal dendritic trees was similar between 2 days and 4.5 years, while in area 12 the number was greater in the adult monkeys than in the younger ones. Spine density peaked at 3 weeks and declined in all areas by adulthood, with V1 exhibiting a faster decline than area TE or area 12. Estimates of the total number of spines in the dendritic trees revealed that following the onset of visual experience, pyramidal cells in V1 lose more spines than they grow, whereas those in TE and area 12 grow more spines than they lose during the same period. These data provide further evidence that the process of synaptic refinement in cortical pyramidal cells differs not only according to time, but also location within the cortex. Furthermore, given the previous finding that layer-III pyramidal cells in all these areas exhibit the highest density and total number of spines at 3.5 months, the current results indicate that pyramidal cells in layers III and V develop spines at different rates. PMID- 28348515 TI - Transcriptome Analysis of Hypothalamic Gene Expression during Daily Torpor in Djungarian Hamsters (Phodopus sungorus). AB - Animals living at high or temperate latitudes are challenged by extensive changes in environmental conditions over seasons. Djungarian hamsters (Phodopus sungorus) are able to cope with extremely cold ambient temperatures and food scarcity in winter by expressing spontaneous daily torpor. Daily torpor is a circadian controlled voluntary reduction of metabolism that can reduce energy expenditure by up to 65% when used frequently. In the past decades it has become more and more apparent, that the hypothalamus is likely to play a key role in regulating induction and maintenance of daily torpor, but the molecular signals, which lead to the initiation of daily torpor, are still unknown. Here we present the first transcriptomic study of hypothalamic gene expression patterns in Djungarian hamsters during torpor entrance. Based on Illumina sequencing we were able to identify a total number of 284 differentially expressed genes, whereby 181 genes were up- and 103 genes down regulated during torpor entrance. The 20 most up regulated group contained eight genes coding for structure proteins, including five collagen genes, dnha2 and myo15a, as well as the procoagulation factor vwf. In a proximate approach we investigated these genes by quantitative real-time PCR (qPCR) analysis over the circadian cycle in torpid and normothermic animals at times of torpor entrance, mid torpor, arousal and post-torpor. These qPCR data confirmed up regulation of dnah2, myo15a, and vwf during torpor entrance, but a decreased mRNA level for all other investigated time points. This suggests that gene expression of structure genes as well as the procoagulation factor are specifically initiated during the early state of torpor and provides evidence for protective molecular adaptions in the hypothalamus of Djungarian hamsters including changes in structure, transport of biomolecules and coagulation. PMID- 28348517 TI - Inhibition of H3K27me3 Histone Demethylase Activity Prevents the Proliferative Regeneration of Zebrafish Lateral Line Neuromasts. AB - The H3K27 demethylases are involved in a variety of biological processes, including cell differentiation, proliferation, and cell death by regulating transcriptional activity. However, the function of H3K27 demethylation in the field of hearing research is poorly understood. Here, we investigated the role of H3K27me3 histone demethylase activity in hair cell regeneration using an in vivo animal model. Our data showed that pharmacologic inhibition of H3K27 demethylase activity with the specific small-molecule inhibitor GSK-J4 decreased the number of regenerated hair cells in response to neomycin damage. Furthermore, inhibition of H3K27me3 histone demethylase activity dramatically suppressed cell proliferation and activated caspase-3 levels in the regenerating neuromasts of the zebrafish lateral line. GSK-J4 administration also increased the expression of p21 and p27 in neuromast cells and inhibited the ERK signaling pathway. Collectively, our findings indicate that H3K27me3 demethylation is a key epigenetic regulator in the process of hair cell regeneration in zebrafish and suggest that H3K27me3 histone demethylase activity might be a novel therapeutic target for the treatment of hearing loss. PMID- 28348516 TI - Molecular Mechanisms for the Coupling of Endocytosis to Exocytosis in Neurons. AB - Neuronal communication and brain function mainly depend on the fundamental biological events of neurotransmission, including the exocytosis of presynaptic vesicles (SVs) for neurotransmitter release and the subsequent endocytosis for SV retrieval. Neurotransmitters are released through the Ca2+- and SNARE-dependent fusion of SVs with the presynaptic plasma membrane. Following exocytosis, endocytosis occurs immediately to retrieve SV membrane and fusion machinery for local recycling and thus maintain the homeostasis of synaptic structure and sustained neurotransmission. Apart from the general endocytic machinery, recent studies have also revealed the involvement of SNARE proteins (synaptobrevin, SNAP25 and syntaxin), synaptophysin, Ca2+/calmodulin, and members of the synaptotagmin protein family (Syt1, Syt4, Syt7 and Syt11) in the balance and tight coupling of exo-endocytosis in neurons. Here, we provide an overview of recent progress in understanding how these neuron-specific adaptors coordinate to ensure precise and efficient endocytosis during neurotransmission. PMID- 28348518 TI - Combination of Endothelial-Monocyte-Activating Polypeptide-II with Temozolomide Suppress Malignant Biological Behaviors of Human Glioblastoma Stem Cells via miR 590-3p/MACC1 Inhibiting PI3K/AKT/mTOR Signal Pathway. AB - This study aims to investigate the effect of Endothelial-Monocyte-Activating Polypeptide-II (EMAP-II) combined with temozolomide (TMZ) upon glioblastoma stem cells (GSCs) and its possible molecular mechanisms. In this study, combination of EMAP-II with TMZ inhibited cell viability, migration and invasion in GSCs, and autophagy inhibitor 3-methyl adenine (3-MA) and chloroquine (CQ) partly reverse the anti-proliferative effect of the combination treatment. Autophagic vacuoles were formed in GSCs after the combination therapy, accompanied with the up regulation of LC3-II and Beclin-1 as well as the down-regulation of p62/SQSTM1. Further, miR-590-3p was up-regulated and Metastasis-associated in colon cancer 1 (MACC1) was down-regulated by the combination treatment in GSCs; MiR-590-3p overexpression and MACC1 knockdown up-regulated LC3-II and Beclin-1 as well as down-regulated p62/SQSTM1 in GSCs; MACC1 was identified as a direct target of miR 590-3p, mediating the effects of miR-590-3p in the combination treatment. Furthermore, the combination treatment and MACC1 knockdown decreased p-PI3K, p Akt, p-mTOR, p-S6 and p-4EBP in GSCs; PI3K/Akt agonist insulin-like growth factor 1(IGF-1) partly blocked the effect of the combination treatment. Moreover, in vivo xenograft models, the mice given stable overexpressed miR-590-3p cells and treated with EMAP-II and TMZ had the smallest tumor sizes, besides, miR-590-3p + EMAP-II + TMZ up-regulated the expression level of miR-590-3p, LC3-II and Beclin 1 as well as down-regulated p62/SQSTM1. In conclusion, these results elucidated anovel molecular mechanism of EMAP-II in combination with TMZ suppressed malignant biological behaviors of GSCs via miR-590-3p/MACC1 inhibiting PI3K/AKT/mTOR signaling pathway, and might provide potential therapeutic approaches for human GSCs. PMID- 28348519 TI - Strings on a Violin: Location Dependence of Frequency Tuning in Active Dendrites. AB - Strings on a violin are tuned to generate distinct sound frequencies in a manner that is firmly dependent on finger location along the fingerboard. Sound frequencies emerging from different violins could be very different based on their architecture, the nature of strings and their tuning. Analogously, active neuronal dendrites, dendrites endowed with active channel conductances, are tuned to distinct input frequencies in a manner that is dependent on the dendritic location of the synaptic inputs. Further, disparate channel expression profiles and differences in morphological characteristics could result in dendrites on different neurons of the same subtype tuned to distinct frequency ranges. Alternately, similar location-dependence along dendritic structures could be achieved through disparate combinations of channel profiles and morphological characteristics, leading to degeneracy in active dendritic spectral tuning. Akin to strings on a violin being tuned to different frequencies than those on a viola or a cello, different neuronal subtypes exhibit distinct channel profiles and disparate morphological characteristics endowing each neuronal subtype with unique location-dependent frequency selectivity. Finally, similar to the tunability of musical instruments to elicit distinct location-dependent sounds, neuronal frequency selectivity and its location-dependence are tunable through activity-dependent plasticity of ion channels and morphology. In this morceau, we explore the origins of neuronal frequency selectivity, and survey the literature on the mechanisms behind the emergence of location-dependence in distinct forms of frequency tuning. As a coda to this composition, we present some future directions for this exciting convergence of biophysical mechanisms that endow a neuron with frequency multiplexing capabilities. PMID- 28348520 TI - The Role of Serotonin beyond the Central Nervous System during Embryogenesis. AB - Serotonin, or 5-hydroxytryptamine (5-HT), is a well-known neurotransmitter that plays vital roles in neural activities and social behaviors. Clinically, deficiency of serotonin is linked with many psychiatric disorders. Interestingly, a large proportion of serotonin is also produced outside the central nervous system (CNS). There is increasing evidence demonstrating important roles of serotonin in the peripheral tissues. Here, we will describe the multiple biological functions of serotonin in hematopoietic system, such as development of hematopoietic stem and progenitor cells (HSPCs), differentiation of hematopoietic cells, maintenance of vascular system, and relationship with hematological diseases. The roles of serotonin in inflammatory responses mediated by hematopoietic cells as well as in liver regeneration are also discussed. Our recent understandings of the impact of serotonin on hematopoietic system, immune responses, and tissue regeneration support utilization of serotonin as a potential therapeutic target for the treatment of hematological diseases and organ repair in clinic. PMID- 28348521 TI - Intrinsic Brain Activity Responsible for Sex Differences in Shyness and Social Anxiety. AB - Male and female show significant differences in important behavioral features such as shyness, yet the neural substrates of these differences remain poorly understood. Previous neuroimaging studies have demonstrated that both shyness and social anxiety in healthy subjects are associated with increased activation in the fronto-limbic and cognitive control areas. However, it remains unknown whether these brain abnormalities would be shared by different genders. Therefore, in the current study, we used resting-state fMRI (r-fMRI) to investigate sex differences in intrinsic cerebral activity that may contribute to shyness and social anxiety. Sixty subjects (28 males, 32 females) participated in r-fMRI scans, and the amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF) were used to measure the spontaneous regional cerebral activity in all subjects. We first compared the differences between male and female both in the ALFF and fALFF and then we also examined the whole brain correlation between the ALFF/fALFF and the severity of shyness as well as social anxiety by genders. Referring to shyness measure, we found a significant positive correlation between shyness scores (CBSS) and ALFF/fALFF value in the frontoparietal control network and a negative correlation in the cingulo-insular network in female; while in male, there is no such correlation. For the social anxiety level, we found positive correlations between Leibowitz Social Anxiety Scale (LSAS) scores and spontaneous activity in the frontal-limbic network in male and negative correlation between the frontal-parietal network; however, such correlation was not prominent in female. This pattern suggests that shy female individuals engaged a proactive control process, driven by a positive association with activity in frontoparietal network and negative association in cingulo insular network, whereas social anxiety males relied more on a reactive control process, driven by a positive correlation of frontal-limbic network and negative correlation of frontoparietal network. Our results reveal that shyness or social anxiety is associated with disrupted spontaneous brain activity patterns and that these patterns are influenced by sex. PMID- 28348523 TI - A-Book: A Feedback-Based Adaptive System to Enhance Meta-Cognitive Skills during Reading. AB - In the digital era, tech devices (hardware and software) are increasingly within hand's reach. Yet, implementing information and communication technologies for educational contexts that have robust and long-lasting effects on student learning outcomes is still a challenge. We propose that any such system must a) be theoretically motivated and designed to tackle specific cognitive skills (e.g., inference making) supporting a given cognitive task (e.g., reading comprehension) and b) must be able to identify and adapt to the user's profile. In the present study, we implemented a feedback-based adaptive system called A book (assisted-reading book) and tested it in a sample of 4th, 5th, and 6th graders. To assess our hypotheses, we contrasted three experimental assisted reading conditions; one that supported meta-cognitive skills and adapted to the user profile (adaptive condition), one that supported meta-cognitive skills but did not adapt to the user profile (training condition) and a control condition. The results provide initial support for our proposal; participants in the adaptive condition improved their accuracy scores on inference making questions over time, outperforming both the training and control groups. There was no evidence, however, of significant improvements on other tested meta-cognitive skills (i.e., text structure knowledge, comprehension monitoring). We discussed the practical implications of using the A-book for the enhancement of meta cognitive skills in school contexts, as well as its current limitations and future developments that could improve the system. PMID- 28348522 TI - Lack of beta2-AR Increases Anxiety-Like Behaviors and Rewarding Properties of Cocaine. AB - It is well known that beta-adrenoceptors (beta-ARs) play a critical role in emotional arousal and stressful events, but the specific contributions of the beta2-AR subtype to the psychological disorders are largely unknown. To investigate whether beta2-AR are involved in anxiety-like behavior and reward to addictive drugs, we conducted a series of behavioral tests on beta2-AR knock-out (KO) mice. beta2-AR KO mice exhibited increased preference for the dark compartment and closed arm in tests of Light/Dark box and elevated plus maze, indicating that beta2-AR deletion elevates level of anxiety or innate fear. beta2 AR KO mice also showed decreased immobility in tail suspension test (TST), suggesting that beta2-AR deletion inhibits depression-like behavior. Interestingly, beta2-AR ablation did not change basal locomotion but significantly increased locomotor activity induced by acute cocaine administration. beta2-AR KO mice showed enhanced place preference for cocaine, which could be attenuated by beta1-selective AR antagonist betaxolol. Consistently, beta2-AR agonist suppressed cocaine-conditioned place preference (CPP). These data indicate that beta2-AR deletion enhances acute response and reward to cocaine. Our results suggest that beta2-AR regulates anxiety level, depression-like behavior and hedonic properties of cocaine, implicating that beta2-AR are the potential targets for the treatment of emotional disorders and cocaine addiction. PMID- 28348524 TI - Recovery of Sentence Production Processes Following Language Treatment in Aphasia: Evidence from Eyetracking. AB - Introduction: Sentence production impairments in aphasia often improve with treatment. However, little is known about how cognitive processes supporting sentence production, such as sentence planning, are impacted by treatment. Methods: The present study used eyetracking to examine changes in sentence production resulting from a 12-week language treatment program focused on passive sentences (Treatment of Underlying Forms (TUF); Thompson and Shapiro, 2005). In two pre-treatment and two post-treatment sessions, nine participants with mild-to moderate agrammatic aphasia performed a structural priming task, which involved repeating primed sentences (actives or passives) and then, using the same verb, producing sentences describing pictured events. Two individuals with aphasia performed the eyetracking task on the same schedule without intervening language treatment. Ten unimpaired older adults also performed the task to identify normal performance patterns. Sentence production accuracy and speech onset latencies were examined, and eye movements to the pictured Agent and Theme characters were analyzed in the first 400 ms after picture onset, reflecting early sentence planning, and in the regions preceding the production of the sentence subject and post-verbal noun, reflecting lexical encoding. Results: Unimpaired controls performed with high accuracy. Their early eye movements (first 400 ms) indicated equal fixations to the Agent and Theme, consistent with structural sentence planning (i.e., initial construction of an abstract structural frame). Subsequent eye movements occurring prior to speech onset were consistent with encoding of the correct sentence subject (i.e., the Agent in actives, Theme in passives), with encoding of the post-verbal noun beginning at speech onset. In participants with aphasia, accuracy improved significantly with treatment, and post-treatment (but not pre-treatment) eye movements were qualitatively similar to those of unimpaired controls, indicating correct encoding of the Agent and Theme nouns for both active and passive sentences. Analysis of early eye movements also showed a treatment-induced increase in structural planning. No changes in sentence production accuracy or eye movements were found in the aphasic participants who did not receive treatment. Conclusion: These findings indicate that treatment improves sentence production and results in the emergence of normal-like cognitive processes associated with successful sentence production, including structural planning. PMID- 28348525 TI - Heterogeneity in Autonomic Arousal Level in Perseverative Worry: The Role of Cognitive Control and Verbal Thought. AB - One puzzle in high worry and generalized anxiety disorder (GAD) is the heterogeneity in the level of autonomic arousal symptoms seen among affected individuals. While current models agree that worry persists, in part, because it fosters avoidance of unpleasant internal experiences, they disagree as to whether worry does so by suppressing activation of autonomic arousal or by fostering persistent autonomic hyperarousal. Our Cognitive Control Model predicts that which pattern of autonomic arousal occurs depends on whether or not a worrier has sufficient cognitive control capacity to worry primarily in a verbal versus imagery-based manner. Because this model has been supported by only one study to date, the present study sought to replicate and extend that study's findings. Results from an online survey in an unselected sample of over 900 college students provide further support for our model's central tenet and initial support for its prediction that higher effortful control is associated with a higher percentage of verbal thought during worry. Finally, we report tentative evidence that autonomic arousal symptoms in worry and GAD vary as a function of individual differences in cognitive control capacity because higher capacity is linked to a greater predominance of verbal thought during worry. PMID- 28348527 TI - Tuning Up the Old Brain with New Tricks: Attention Training via Neurofeedback. AB - Neurofeedback (NF) is a form of biofeedback that uses real-time (RT) modulation of brain activity to enhance brain function and behavioral performance. Recent advances in Brain-Computer Interfaces (BCI) and cognitive training (CT) have provided new tools and evidence that NF improves cognitive functions, such as attention and working memory (WM), beyond what is provided by traditional CT. More published studies have demonstrated the efficacy of NF, particularly for treating attention deficit hyperactivity disorder (ADHD) in children. In contrast, there have been fewer studies done in older adults with or without cognitive impairment, with some notable exceptions. The focus of this review is to summarize current success in RT NF training of older brains aiming to match those of younger brains during attention/WM tasks. We also outline potential future advances in RT brainwave-based NF for improving attention training in older populations. The rapid growth in wireless recording of brain activity, machine learning classification and brain network analysis provides new tools for combating cognitive decline and brain aging in older adults. We optimistically conclude that NF, combined with new neuro-markers (event-related potentials and connectivity) and traditional features, promises to provide new hope for brain and CT in the growing older population. PMID- 28348528 TI - Development of Near-Isogenic Lines in a Parthenogenetically Reproduced Thrips Species, Frankliniella occidentalis. AB - Although near-isogenic lines (NILs) can standardize genetic backgrounds among individuals, it has never been applied in parthenogenetically reproduced animals. Here, through multiple rounds of backcrossing and spinosad screening, we generated spinosad resistant NILs in the western flower thrips, Frankliniella occidentalis (Pergande) (Thysanoptera: Thripidae), with a haplo-diploid reproduction system. The resultant F. occidentalis NIL-R strain maintained a resistance ratio over 30,000-fold, which was comparable to its parental resistant strain, Spin-R. More importantly, F. occidentalis NIL-R shared 98.90% genetic similarity with its susceptible parental strain Ivf03. By developing this toolset, we are able to segregate individual resistance and facilitate the mechanistic study of insecticide resistances in phloem-feeding arthropods, a group of devastating pest species reproducing sexually as well as asexually. PMID- 28348526 TI - Exteroceptive and Interoceptive Body-Self Awareness in Fibromyalgia Patients. AB - Fibromyalgia is a widespread chronic pain disease characterized by generalized musculoskeletal pain and fatigue. It substantially affects patients' relationship with their bodies and quality of life, but few studies have investigated the relationship between pain and body awareness in fibromyalgia. We examined exteroceptive and interoceptive aspects of body awareness in 30 women with fibromyalgia and 29 control participants. Exteroceptive body awareness was assessed by a body-scaled action-anticipation task in which participants estimated whether they could pass through apertures of different widths. Interoceptive sensitivity (IS) was assessed by a heartbeat detection task where participants counted their heartbeats during different time intervals. Interoceptive awareness was assessed by the Multidimensional Assessment of Interoceptive Awareness (MAIA). The "passability ratio" (the aperture size for a 50% positive response rate, divided by shoulder width), assessed by the body scaled action-anticipation task, was higher for fibromyalgia participants, indicating disrupted exteroceptive awareness. Overestimating body size correlated positively with pain and its impact on functionality, but not with pain intensity. There was no difference in IS between groups. Fibromyalgia patients exhibited a higher tendency to note bodily sensations and decreased body confidence. In addition, the passability ratio and IS score correlated negatively across the whole sample, suggesting an inverse relationship between exteroceptive and interoceptive body awareness. There was a lower tendency to actively listen to the body for insight, with higher passability ratios across the whole sample. Based on our results and building on the fear-avoidance model, we outline a proposal that highlights possible interactions between exteroceptive and interoceptive body awareness and pain. Movement based contemplative practices that target sensory-motor integration and foster non-judgmental reconnection with bodily sensations are suggested to improve body confidence, functionality, and quality of life. PMID- 28348529 TI - Sport-Specific Capacity to Use Elastic Energy in the Patellar and Achilles Tendons of Elite Athletes. AB - Introduction: During running and jumping activities, elastic energy is utilized to enhance muscle mechanical output and efficiency. However, training-induced variations in tendon spring-like properties remain under-investigated. The present work extends earlier findings on sport-specific profiles of tendon stiffness and cross-sectional area to examine whether years of distinct loading patterns are reflected by tendons' ability to store and return energy. Methods:Ultrasound scans were performed to examine the morphological features of knee extensor and plantar flexor muscle-tendon units in elite ski jumpers, distance runners, water polo players, and sedentary controls. Tendon strain energy and hysteresis were measured with combined motion capture, ultrasonography, and dynamometry. Results: Apart from the fractional muscle-to tendon cross-sectional area ratio being lower in the knee extensors of ski jumpers (-31%) and runners (-33%) than in water polo players, no difference in the considered muscle-tendon unit morphological features was observed between groups. Similarly, no significant difference in tendon energy storage or energy return was detected between groups. In contrast, hysteresis was lower in the patellar tendon of ski jumpers (-33%) and runners (-30%) compared to controls, with a similar trend for the Achilles tendon (significant interaction effect and large effect sizes eta2 = 0.2). Normalized to body mass, the recovered strain energy of the patellar tendon was ~50% higher in ski jumpers than in water polo players and controls. For the Achilles tendon, recovered strain energy was ~40% higher in ski jumpers and runners than in controls. Discussion: Advantageous mechanical properties related to tendon spring-like function are observed in elite athletes whose sport require effective utilization of elastic energy. However, the mechanisms underpinning the better tendon capacity of some athletes to retain elastic energy could not be ascribed to intrinsic or morphological features of the lower limb muscle-tendon unit. PMID- 28348530 TI - Paradigm Shifts in Voluntary Force Control and Motor Unit Behaviors with the Manipulated Size of Visual Error Perception. AB - The detection of error information is an essential prerequisite of a feedback based movement. This study investigated the differential behavior and neurophysiological mechanisms of a cyclic force-tracking task using error reducing and error-enhancing feedback. The discharge patterns of a relatively large number of motor units (MUs) were assessed with custom-designed multi channel surface electromyography following mathematical decomposition of the experimentally-measured signals. Force characteristics, force-discharge relation, and phase-locking cortical activities in the contralateral motor cortex to individual MUs were contrasted among the low (LSF), normal (NSF), and high scaling factor (HSF) conditions, in which the sizes of online execution errors were displayed with various amplification ratios. Along with a spectral shift of the force output toward a lower band, force output with a more phase-lead became less irregular, and tracking accuracy was worse in the LSF condition than in the HSF condition. The coherent discharge of high phasic (HP) MUs with the target signal was greater, and inter-spike intervals were larger, in the LSF condition than in the HSF condition. Force-tracking in the LSF condition manifested with stronger phase-locked EEG activity in the contralateral motor cortex to discharge of the (HP) MUs (LSF > NSF, HSF). The coherent discharge of the (HP) MUs during the cyclic force-tracking predominated the force-discharge relation, which increased inversely to the error scaling factor. In conclusion, the size of visualized error gates motor unit discharge, force-discharge relation, and the relative influences of the feedback and feedforward processes on force control. A smaller visualized error size favors voluntary force control using a feedforward process, in relation to a selective central modulation that enhance the coherent discharge of (HP) MUs. PMID- 28348533 TI - Clinical Characteristics of Diabetes Mellitus and Suicide Risk. AB - BACKGROUND: Diabetes mellitus (DM) is a chronic illness with impaired health related quality of life and a high risk of psychiatric disorders. We carried out a systematic review analyzing the relationship between DM and suicide by providing a qualitative data synthesis of the studies. METHODS: We conducted, in accordance with Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines, a systematic search of the literature in PubMed, Scopus, ISI Web of Science, PsycINFO, Google Scholar, and ScienceDirect. Search terms were "suicid*" combined with the Boolean "AND" operator with "diabetes." RESULTS: The initial search identified 568 citations. A total of 17 research reports met the predefined inclusion criteria and were analyzed. DM was found to be significantly associated with a marked increase in suicidal behaviors and suicidal ideation (SI), especially in patients with depressive symptoms. Insulin therapy, DM of long duration, and unsatisfactory glycemic control were identified as risk factors for SI in Type 1 (T1DM) and Type 2 (T2DM). CONCLUSION: Health-care professionals need to be aware of the higher suicidal risk in patient subgroups based on the clinical characteristics of DM; thus, patients with these characteristics warrant special attention. In this regard, clinical management should include efforts to manage emotional distress in DM care. PMID- 28348532 TI - Ethical Implications of the Mild Encephalitis Hypothesis of Schizophrenia. AB - Schizophrenia is a serious mental disease with a high mortality rate and severe social consequences. Due to insufficient knowledge about its etiopathogenesis, curative treatments are not available. One of the most promising new research concepts is the mild encephalitis hypothesis of schizophrenia, developed mainly by Karl Bechter and Norbert Muller. According to this hypothesis, a significant subgroup of schizophrenia patients suffer from a mild, but chronic, form of encephalitis with markedly different etiologies ranging from viral infections, traumas to autoimmune diseases. This inflammatory process is thought to occur in the beginning or during the course of the disease. In this article, we investigate the consequences of the mild encephalitis hypothesis of schizophrenia for the scientific community, and evaluate these consequences ethically. The mild encephalitis hypothesis implies that schizophrenia would no longer be considered an incurable psychiatric disorder. Instead, it would be considered a chronic, but treatable, neurological disease. This paradigm shift would doubtlessly have significant consequences: (1) major reforms would be necessary in the theoretical conceptualization of schizophrenia, which would challenge the psychiatric diagnostic systems, Diagnostic and Statistical Manual of Mental Disorders version 5 and ICD-10. (2) Psychotic patients should be treated in interdisciplinary teams, optimally in neuropsychiatric units; additionally, specialists for endocrinology, diabetology, and cardiology should be consulted for the frequently occuring somatic comorbidities. (3) Current diagnostic procedures and (4) therapies would have to be modified significantly. (5) There might be repercussions for the pharmaceutical industry as well: first, because old drugs with expired patent protection could partly replace expensive drugs and, second, because there would be a demand for the development of new anti-inflammatory drugs. (6) Legal evaluation of compulsory treatment orders might have to be reconsidered in light of causal therapies; leading to increased legal approval and reduced need for compulsory treatment orders due to better patient compliance. (7) The social inclusion of patients might improve, if treatment became more effective regarding cognitive and social functioning. (8) The stigmatization of patients and their relatives might decrease. PMID- 28348534 TI - The "Emotional Side" of Entrepreneurship: A Meta-Analysis of the Relation between Positive and Negative Affect and Entrepreneurial Performance. AB - The experience of work in an entrepreneurial context is saturated with emotional experiences. While the literature on the relation between affect and entrepreneurial performance (EP) is growing, there was no quantitative integration of the results so far. This study addresses this gap and meta analytically integrates the results from 17 studies (N = 3810) in order to estimate the effect size for the relation between positive (PA) and negative affect (NA), on the one hand, and EP, on the other hand. The meta-analysis includes studies in English language, published until August 2016. The results indicate a significant positive relation between PA and EP, r = 0.18. The overall NA - EP relation was not significant, r = -0.12. Only state NA has a significant negative relation with EP (r = -0.16). The moderating role of several conceptual (i.e., emotion duration, integrality etc.), sample (i.e., gender, age, education) and methodological characteristics of the studies (i.e., type of measurements etc.) are explored and implications for future research are discussed. PMID- 28348531 TI - Mitochondrial Bioenergetics in the Metabolic Myopathy Accompanying Peripheral Artery Disease. AB - Peripheral artery disease (PAD) is a serious but relatively underdiagnosed and undertreated clinical condition associated with a marked reduction in functional capacity and a heightened risk of morbidity and mortality. The pathophysiology of lower extremity PAD is complex, and extends beyond the atherosclerotic arterial occlusion and subsequent mismatch between oxygen demand and delivery to skeletal muscle mitochondria. In this review, we evaluate and summarize the available evidence implicating mitochondria in the metabolic myopathy that accompanies PAD. Following a short discussion of the available in vivo and in vitro methodologies to quantitate indices of muscle mitochondrial function, we review the current evidence implicating skeletal muscle mitochondrial dysfunction in the pathophysiology of PAD myopathy, while attempting to highlight questions that remain unanswered. Given the rising prevalence of PAD, the detriment in quality of life for patients, and the associated significant healthcare resource utilization, new alternate therapies that ameliorate lower limb symptoms and the functional impairment associated with PAD are needed. A clear understanding of the role of mitochondria in the pathophysiology of PAD may contribute to the development of novel therapeutic interventions. PMID- 28348535 TI - Neurophysiological Correlates of Featural and Spacing Processing for Face and Non face Stimuli. AB - The peculiar ability of humans to recognize hundreds of faces at a glance has been attributed to face-specific perceptual mechanisms known as holistic processing. Holistic processing includes the ability to discriminate individual facial features (i.e., featural processing) and their spatial relationships (i.e., spacing processing). Here, we aimed to characterize the spatio-temporal dynamics of featural- and spacing-processing of faces and objects. Nineteen healthy volunteers completed a newly created perceptual discrimination task for faces and objects (i.e., the "University of East London Face Task") while their brain activity was recorded with a high-density (128 electrodes) electroencephalogram. Our results showed that early event related potentials at around 100 ms post-stimulus onset (i.e., P100) are sensitive to both facial features and spacing between the features. Spacing and features discriminability for objects occurred at circa 200 ms post-stimulus onset (P200). These findings indicate the existence of neurophysiological correlates of spacing vs. features processing in both face and objects, and demonstrate faster brain processing for faces. PMID- 28348536 TI - The Interaction between Central and Peripheral Processing in Chinese Handwritten Production: Evidence from the Effect of Lexicality and Radical Complexity. AB - The interaction between central and peripheral processing in written word production remains controversial. This study aims to investigate whether the effects of radical complexity and lexicality in central processing cascade into peripheral processing in Chinese written word production. The participants were asked to write characters and non-characters (lexicality) with different radical complexity (few- and many-strokes). The findings indicated that regardless of the lexicality, the writing latencies were longer for characters with higher complexity (the many-strokes condition) than for characters with lower complexity (the few-strokes condition). The participants slowed down their writing execution at the radicals' boundary strokes, which indicated a radical boundary effect in peripheral processing. Interestingly, the lexicality and the radical complexity affected the pattern of shift velocity and writing velocity during the execution of writing. Lexical processing cascades into peripheral processing but only at the beginning of Chinese characters. In contrast, the radical complexity influenced the execution of handwriting movement throughout the entire character, and the pattern of the effect interacted with the character frequency. These results suggest that the processes of the lexicality and the radical complexity function during the execution of handwritten word production, which suggests that central processing cascades over peripheral processing during Chinese characters handwriting. PMID- 28348537 TI - Graphemes Sharing Phonetic Features Tend to Induce Similar Synesthetic Colors. AB - Individuals with grapheme-color synesthesia experience idiosyncratic colors when viewing achromatic letters or digits. Despite large individual differences in grapheme-color association, synesthetes tend to associate graphemes sharing a perceptual feature with similar synesthetic colors. Sound has been suggested as one such feature. In the present study, we investigated whether graphemes of which representative phonemes have similar phonetic features tend to be associated with analogous synesthetic colors. We tested five Korean multilingual synesthetes on a color-matching task using graphemes from Korean, English, and Japanese orthography. We then compared the similarity of synesthetic colors induced by those characters sharing a phonetic feature. Results showed that graphemes associated with the same phonetic feature tend to induce synesthetic color in both within- and cross-script analyses. Moreover, this tendency was consistent for graphemes that are not transliterable into each other as well as graphemes that are. These results suggest that it is the perceptual-i.e., phonetic-properties associated with graphemes, not just conceptual associations such as transliteration, that determine synesthetic color. PMID- 28348538 TI - If You Don't Have Valence, Ask Your Neighbor: Evaluation of Neutral Words as a Function of Affective Semantic Associates. AB - How do humans perform difficult forced-choice evaluations, e.g., of words that have been previously rated as being neutral? Here we tested the hypothesis that in this case, the valence of semantic associates is of significant influence. From corpus based co-occurrence statistics as a measure of association strength we computed individual neighborhoods for single neutral words comprised of the 10 words with the largest association strength. We then selected neutral words according to the valence of the associated words included in the neighborhoods, which were either mostly positive, mostly negative, mostly neutral or mixed positive and negative, and tested them using a valence decision task (VDT). The data showed that the valence of semantic neighbors can predict valence judgments to neutral words. However, all but the positive neighborhood items revealed a high tendency to elicit negative responses. For the positive and negative neighborhood categories responses congruent with the neighborhood's valence were faster than incongruent responses. We interpret this effect as a semantic network process that supports the evaluation of neutral words by assessing the valence of the associative semantic neighborhood. In this perspective, valence is considered a semantic super-feature, at least partially represented in associative activation patterns of semantic networks. PMID- 28348540 TI - New Empirical Evidence on the Validity and the Reliability of the Early Life Stress Questionnaire in a Polish Sample. AB - Background: The Early Life Stress Questionnaire (ELSQ) is widely used to estimate the prevalence of negative events during childhood, including emotional, physical, verbal, sexual abuse, negligence, severe conflicts, separation, parental divorce, substance abuse, poverty, and so forth. Objective: This study presents the psychometric properties of the Polish adaptation of the ELSQ. It also verifies if early life stress (ELS) is a good predictor of psychopathology symptoms during adulthood. Materials and Methods: We analyzed data from two samples. Sample 1 was selected by random quota method from across the country and included 609 participants aged 18-50 years, 306 women (50.2%) and 303 men (49.8%). Sample 2 contained 503 young adults (253 women and 250 men) aged 18-25. Confirmatory and exploratory factor analyses were used to measure ELSQ internal consistency. The validity was based on the relation to psychopathological symptoms and substance misuse. Results: Results showed good internal consistency and validity. Exploratory factor analysis indicates a six-factor structure of the ELSQ. ELS was related to psychopathology in adulthood, including depressive, sociophobic, vegetative as well as pain symptoms. ELSQ score correlated also with alcohol use, but not nicotine dependence. Moreover, ELS was correlated with stress in adulthood. Conclusion: The findings indicate that the Polish version of the ELSQ is a valid and reliable instrument for assessing ELS in the Polish population and may be applied in both clinical and community samples. PMID- 28348539 TI - Autonomic Reactivity to Arousing Stimuli with Social and Non-social Relevance in Alexithymia. AB - Emotional difficulties in alexithymia and their social consequences have been linked to alterations in autonomic nervous system. However, most of previous studies did not take into account the distinction between the affective and the cognitive dimensions of the alexithymia, leading to inconsistent results. Aim: In this study, we compared the effects of both dimensions of alexithymia on the autonomic arousal to emotional and social visual stimulations. Methods: Skin conductance responses (SCRs) to items of the International Affective Pictures System characterized by emotional (unpleasant, neutral, and pleasant), social (with humans) or non-social (without humans) content were recorded in non alexithymic (NA), affective (AA) and cognitive alexithymic (CA) participants, selected on the basis of the Toronto Alexithymia Scale and the Bermond-Vorst Alexithymia Questionnaire. All participants responded to questionnaires of empathy, social phobia, depression, and anxiety before the experiment and evaluated the arousal of the pictures after it. Results: Cognitive alexithymic group showed lower amplitudes of SCRs to pictures with social than without social relevance whereas the opposite pattern was observed for the NA group. Arousal emotional effects of the pictures on SCRs did not differ among groups. In addition, CA participants showed lower scores than NA in the Personal Taking sub scale of the empathy questionnaire, while AA showed lower scores than NA in the fantasy sub-scale. The CA group showed higher social phobia, depression and anxiety scores, than the other two groups. Conclusion: This work has two original outcomes: first, affective alexithymics expressed lower empathic affective scores than other groups; second, alexithymia modulated the impact of the social relevance of the stimuli on the autonomic reactivity, this impact vanishing in affective alexithymics and reversing in cognitive alexithymics. Thus, though the groups could not be distinguished on the basis of emotional effect on SCRs, they clearly differed when the empathic characteristics and the autonomic impact of social relevance were considered. Finally, the described autonomic signature to social relevant information could contribute to elucidate the difficulty of alexithymics to deal with emotions during social transactions. PMID- 28348541 TI - Sensory and Emotional Perception of Wooden Surfaces through Fingertip Touch. AB - Previous studies on tactile experiences have investigated a wide range of material surfaces across various skin sites of the human body in self-touch or other touch modes. Here, we investigate whether the sensory and emotional aspects of touch are related when evaluating wooden surfaces using fingertips in the absence of other sensory modalities. Twenty participants evaluated eight different pine and oak wood surfaces, using sensory and emotional touch descriptors, through the lateral motion of active fingertip exploration. The data showed that natural and smooth wood surfaces were perceived more positively in emotional touch than coated surfaces. We highlight the importance of preserving the naturalness of the surface texture in the process of wood-surface treatment so as to improve positive touch experiences, as well as avoid negative ones. We argue that the results may offer possibilities in the design of wood-based interior products with a view to improving consumer touch experiences. PMID- 28348542 TI - The Efficacy of Short-term Gated Audiovisual Speech Training for Improving Auditory Sentence Identification in Noise in Elderly Hearing Aid Users. AB - : This study aimed to examine the efficacy and maintenance of short-term (one session) gated audiovisual speech training for improving auditory sentence identification in noise in experienced elderly hearing-aid users. Twenty-five hearing aid users (16 men and 9 women), with an average age of 70.8 years, were randomly divided into an experimental (audiovisual training, n = 14) and a control (auditory training, n = 11) group. Participants underwent gated speech identification tasks comprising Swedish consonants and words presented at 65 dB sound pressure level with a 0 dB signal-to-noise ratio (steady-state broadband noise), in audiovisual or auditory-only training conditions. The Hearing-in-Noise Test was employed to measure participants' auditory sentence identification in noise before the training (pre-test), promptly after training (post-test), and 1 month after training (one-month follow-up). The results showed that audiovisual training improved auditory sentence identification in noise promptly after the training (post-test vs. pre-test scores); furthermore, this improvement was maintained 1 month after the training (one-month follow-up vs. pre-test scores). Such improvement was not observed in the control group, neither promptly after the training nor at the one-month follow-up. However, no significant between groups difference nor an interaction between groups and session was observed. CONCLUSION: Audiovisual training may be considered in aural rehabilitation of hearing aid users to improve listening capabilities in noisy conditions. However, the lack of a significant between-groups effect (audiovisual vs. auditory) or an interaction between group and session calls for further research. PMID- 28348543 TI - The Predictive Validity of Four Intelligence Tests for School Grades: A Small Sample Longitudinal Study. AB - Intelligence is considered the strongest single predictor of scholastic achievement. However, little is known regarding the predictive validity of well established intelligence tests for school grades. We analyzed the predictive validity of four widely used intelligence tests in German-speaking countries: The Intelligence and Development Scales (IDS), the Reynolds Intellectual Assessment Scales (RIAS), the Snijders-Oomen Nonverbal Intelligence Test (SON-R 6-40), and the Wechsler Intelligence Scale for Children (WISC-IV), which were individually administered to 103 children (Mage = 9.17 years) enrolled in regular school. School grades were collected longitudinally after 3 years (averaged school grades, mathematics, and language) and were available for 54 children (Mage = 11.77 years). All four tests significantly predicted averaged school grades. Furthermore, the IDS and the RIAS predicted both mathematics and language, while the SON-R 6-40 predicted mathematics. The WISC-IV showed no significant association with longitudinal scholastic achievement when mathematics and language were analyzed separately. The results revealed the predictive validity of currently used intelligence tests for longitudinal scholastic achievement in German-speaking countries and support their use in psychological practice, in particular for predicting averaged school grades. However, this conclusion has to be considered as preliminary due to the small sample of children observed. PMID- 28348544 TI - Substance P/Neurokinin 1 and Trigeminal System: A Possible Link to the Pathogenesis in Sudden Perinatal Deaths. AB - Sudden demise of a healthy fetus or a neonate is a very tragic episode in the life of parents. These deaths have been a mystery since ages but still remain unexplained. This review proposes the involvement of trigeminal nerve, neurotransmitter substance P (SP), and its receptor neurokinin 1 (NK-1R) in regulation of cardiorespiratory control in fetuses and newborns. Anomalies and immaturity of neuroregulatory systems such as trigeminal system in medulla oblongata of brainstem may provide a possible mechanism of sudden perinatal deaths. Vulnerable infants are born with respiratory center immaturity which in combination with any stressor such as cold, hypoxia, and smoking may lead to cessation of breathing and ventilatory response. SP/NK-1R may be involved in regulating the ventilatory control in neonates while it is decreased in fetal and adult life in humans, and any alterations from these may lead to irreversible sleep apnea and fatal breathing, ultimately sudden death. This review summarizes the studies performed to highlight the expression of SP or NK-1R in sudden perinatal deaths and proposes the involvement of trigeminal ganglion along with its nerve and SP/NK-1R expression alteration as one of the possible pathophysiological underlying mechanism. However, further studies are required to explore the role of SP, NK-1R, and trigeminal system in the pathogenesis of sudden infant deaths, sudden intrauterine deaths, stillbirths, and sudden deaths later in human life. PMID- 28348545 TI - Extracerebral Tissue Damage in the Intraluminal Filament Mouse Model of Middle Cerebral Artery Occlusion. AB - Middle cerebral artery occlusion is the most common model of focal cerebral ischemia in the mouse. In the surgical procedure, the external carotid artery (ECA) is ligated; however, its effect on the tissue supplied by the vessel has not been described so far. C57BL/6 mice underwent 1 h of transient MCAO (tMCAO) or sham surgery. Multi-spectral optoacoustic tomography was employed at 30 min after surgery to assess oxygenation in the temporal muscles. Microstructural changes were assessed with magnetic resonance imaging and histological examination at 24 h and 48 h after surgery. Ligation of the ECA resulted in decreased oxygenation of the left temporal muscle in most sham-operated and tMCAO animals. Susceptible mice of both groups exhibited increased T2 relaxation times in the affected muscle with histological evidence of myofibre degeneration, interstitial edema, and neutrophil influx. Ligatures had induced an extensive neutrophil-dominated inflammatory response. ECA ligation leads to distinct hypoxic degenerative changes in the tissue of the ECA territory and to ligature induced inflammatory processes. An impact on outcome needs to be considered in this stroke model. PMID- 28348548 TI - Response of Human Immunodeficiency Virus-Associated Cerebral Angiitis to the Combined Antiretroviral Therapy. AB - When secondary causes are excluded, mechanisms underlying central nervous system angiitis (ACNS) in human immunodeficiency virus (HIV)-infected patients are still not understood and optimal treatment remains undefined. We report here a patient with an untreated HIV infection who presented multiple ischemic strokes probably due to HIV-ACNS. ACNS signs on vessel-wall imaging magnetic resonance monitoring retracted with combined antiretroviral therapy without adjunct immunosuppressive drugs. PMID- 28348547 TI - Altered Cervical Vestibular-Evoked Myogenic Potential in Children with Attention Deficit and Hyperactivity Disorder. AB - OBJECTIVE: Emerging evidence suggests that children with attention deficit and hyperactivity disorder (ADHD) present more difficulties in standing and walking balance than typically developing children. Most of previous studies have assessed these functions using postural and sensory organization tests showing differences in balance performance between control and ADHD children. However, to date, it is unknown whether these balance alterations are accompanied with vestibular dysfunction. The principal aim of this study is to evaluate vestibular otolith function in ADHD and matched control children. METHODS: We assessed vestibular otolith function in children with ADHD and controls using the subjective visual vertical (SVV) bucket test and cervical vestibular-evoked myogenic potentials (cVEMPs). In addition, gait and balance were evaluated using the dynamic gait index (DGI) and computerized posturography. RESULTS: Non significant differences between groups were obtained in SVV evaluation. DGI results show lower scores for overall test performance in children with ADHD (p < 0.001), while computerized postural recordings showed significant differences for the limit of stability between groups (p = 0.02). cVEMPs in response to 500 Hz tone bursts presented at 100 dB were absent or reduced in children with ADHD, as revealed by differences in P1 and N1 peak-to-peak amplitudes between groups (p < 0.01). CONCLUSION: These findings suggest that vestibular brainstem reflexes are altered in a subset of children with ADHD. We propose to include cVEMP reflexes in the clinical evaluation of ADHD patients. PMID- 28348549 TI - A Comparative Analysis of the Lyve-SET Phylogenomics Pipeline for Genomic Epidemiology of Foodborne Pathogens. AB - Modern epidemiology of foodborne bacterial pathogens in industrialized countries relies increasingly on whole genome sequencing (WGS) techniques. As opposed to profiling techniques such as pulsed-field gel electrophoresis, WGS requires a variety of computational methods. Since 2013, United States agencies responsible for food safety including the CDC, FDA, and USDA, have been performing whole genome sequencing (WGS) on all Listeria monocytogenes found in clinical, food, and environmental samples. Each year, more genomes of other foodborne pathogens such as Escherichia coli, Campylobacter jejuni, and Salmonella enterica are being sequenced. Comparing thousands of genomes across an entire species requires a fast method with coarse resolution; however, capturing the fine details of highly related isolates requires a computationally heavy and sophisticated algorithm. Most L. monocytogenes investigations employing WGS depend on being able to identify an outbreak clade whose inter-genomic distances are less than an empirically determined threshold. When the difference between a few single nucleotide polymorphisms (SNPs) can help distinguish between genomes that are likely outbreak-associated and those that are less likely to be associated, we require a fine-resolution method. To achieve this level of resolution, we have developed Lyve-SET, a high-quality SNP pipeline. We evaluated Lyve-SET by retrospectively investigating 12 outbreak data sets along with four other SNP pipelines that have been used in outbreak investigation or similar scenarios. To compare these pipelines, several distance and phylogeny-based comparison methods were applied, which collectively showed that multiple pipelines were able to identify most outbreak clusters and strains. Currently in the US PulseNet system, whole genome multi-locus sequence typing (wgMLST) is the preferred primary method for foodborne WGS cluster detection and outbreak investigation due to its ability to name standardized genomic profiles, its central database, and its ability to be run in a graphical user interface. However, creating a functional wgMLST scheme requires extended up-front development and subject-matter expertise. When a scheme does not exist or when the highest resolution is needed, SNP analysis is used. Using three Listeria outbreak data sets, we demonstrated the concordance between Lyve-SET SNP typing and wgMLST. Availability: Lyve-SET can be found at https://github.com/lskatz/Lyve-SET. PMID- 28348546 TI - Dementia with Lewy Bodies: Molecular Pathology in the Frontal Cortex in Typical and Rapidly Progressive Forms. AB - OBJECTIVES: The goal of this study was to assess mitochondrial function, energy, and purine metabolism, protein synthesis machinery from the nucleolus to the ribosome, inflammation, and expression of newly identified ectopic olfactory receptors (ORs) and taste receptors (TASRs) in the frontal cortex of typical cases of dementia with Lewy bodies (DLB) and cases with rapid clinical course (rpDLB: 2 years or less) compared with middle-aged non-affected individuals, in order to learn about the biochemical abnormalities underlying Lewy body pathology. METHODS: Real-time quantitative PCR, mitochondrial enzymatic assays, and analysis of beta-amyloid, tau, and synuclein species were used. RESULTS: The main alterations in DLB and rpDLB, which are more marked in the rapidly progressive forms, include (i) deregulated expression of several mRNAs and proteins of mitochondrial subunits, and reduced activity of complexes I, II, III, and IV of the mitochondrial respiratory chain; (ii) reduced expression of selected molecules involved in energy metabolism and increased expression of enzymes involved in purine metabolism; (iii) abnormal expression of nucleolar proteins, rRNA18S, genes encoding ribosomal proteins, and initiation factors of the transcription at the ribosome; (iv) discrete inflammation; and (v) marked deregulation of brain ORs and TASRs, respectively. Severe mitochondrial dysfunction involving activity of four complexes, minimal inflammatory responses, and dramatic altered expression of ORs and TASRs discriminate DLB from Alzheimer's disease. Altered solubility and aggregation of alpha-synuclein, increased beta-amyloid bound to membranes, and absence of soluble tau oligomers are common in DLB and rpDLB. Low levels of soluble beta-amyloid are found in DLB. However, increased soluble beta-amyloid 1-40 and beta-amyloid 1-42, and increased TNFalpha mRNA and protein expression, distinguish rpDLB. CONCLUSION: Molecular alterations in frontal cortex in DLB involve key biochemical pathways such as mitochondria and energy metabolism, protein synthesis, purine metabolism, among others and are accompanied by discrete innate inflammatory response. PMID- 28348551 TI - Evolutionary Constraints on the Norovirus Pandemic Variant GII.4_2006b over the Five-Year Persistence in Japan. AB - Norovirus GII.4 is a major cause of global outbreaks of viral gastroenteritis in humans, and has evolved by antigenic changes under the constantly changing human herd immunity. Major shift in the pandemic GII.4 strain periodically occurs concomitant with changes in the antigenic capsid protein VP1. However, how the newly emerged strain evolves after the onset of pandemic remains unclear. To address this issue, we examined molecular evolution of a pandemic lineage, termed the GII.4_2006b, by using the full-length viral genome and VP1 sequences (n = 317) from stools collected at 20 sites in Japan between 2006 and 2011. Phylogenetic tree showed a radial diversification of the genome sequences of GII.4_2006b, suggesting a rapid genetic diversification of the GII.4_2006b population from a few ancestral variants. Impressively, amino acid sequences of the variable VP1 in given seasons remained as homogeneous as those of viral enzymes under annual increase in the nucleotide diversity in the VP1 coding region. The Hamming distances between the earliest and subsequent variants indicate strong constraints on amino acid changes even for the highly variable P2 subdomain. These results show the presence of evolutionary constraints on the VP1 protein and viral enzymes, and suggest that these proteins gain near maximal levels of fitness benefits in humans around the onset of the outbreaks. These findings have implications for our understanding of molecular evolution, mechanisms of the periodic shifts in the pandemic NoV GII.4 strains, and control of the NoV GII.4 pandemic strain. PMID- 28348550 TI - An In vitro Study of Bio-Control and Plant Growth Promotion Potential of Salicaceae Endophytes. AB - Microbial communities in the endosphere of Salicaceae plants, poplar (Populus trichocarpa) and willow (Salix sitchensis), have been demonstrated to be important for plant growth promotion, protection from biotic and abiotic stresses, and degradation of toxic compounds. Our study aimed to investigate bio control activities of Salicaceae endophytes against various soil borne plant pathogens including Rhizoctonia solani AG-8, Fusarium culmorum, Gaeumannomyces graminis var. tritici, and Pythium ultimum. Additionally, different plant growth promoting traits such as biological nitrogen fixation (BNF), indole-3-acetic acid (IAA) biosynthesis, phosphate solubilization, and siderophore production were assessed in all bio-control positive strains. Burkholderia, Rahnella, Pseudomonas, and Curtobacterium were major endophyte genera that showed bio control activities in the in-vitro assays. The bio-control activities of Burkholderia strains were stronger across all tested plant pathogens as compared to other stains. Genomes of sequenced Burkholderia strains WP40 and WP42 were surveyed to identify the putative genes involved in the bio-control activities. The ocf and hcnABC gene clusters responsible for biosynthesis of the anti-fungal metabolites, occidiofungin and hydrogen cyanide, are present in the genomes of WP40 and WP42. Nearly all endophyte strains showing the bio-control activities produced IAA, solubilized tricalcium phosphate, and synthesized siderophores in the culture medium. Moreover, some strains reduced acetylene into ethylene in the acetylene reduction assay, a common assay used for BNF. Salicaceae endophytes could be useful for bio-control of various plant pathogens, and plant growth promotion possibly through the mechanisms of BNF, IAA production, and nutrient acquisition. PMID- 28348552 TI - FurIOS: A Web-Based Tool for Identification of Vibrionaceae Species Using the fur Gene. AB - Gene based methods for identification of species from the Vibrionaceae family have been developed during the last decades to address the limitations of the commonly used 16S rRNA gene phylogeny. Recently, we found that the ferric-uptake regulator gene (fur) can be used as a single identification marker providing species discrimination, consistent with multi-locus sequencing analyses and whole genome phylogenies. To allow for broader and easy use of this marker, we have developed an online prediction service that allows the identification of Vibrionaceae species based on their fur-sequence. The input is a DNA sequence that can be uploaded on the web service; the output is a table containing the strain identifier, e-value, and percentage of identity for each of the matches with rows colored in green for hits with high probability of being the same species. The service is available on the web at: http://www.cbs.dtu.dk/services/furIOS-1.0/. The fur-sequences can be derived either from genome sequences or from PCR-amplification of the genomic region encoding the fur gene. We have used 191 strains identified as Vibrionaceae based on 16S rRNA gene sequence to test the PCR method and the web service on a large dataset. We were able to classify 171 of 191 strains at the species level and 20 strains remained unclassified. Furthermore, the fur phylogenetics and subsequent in silico DNA-DNA hybridization demonstrated that two strains (ATCC 33789 and ZS 139) previously identified as Vibrio splendidus are more closely related to V. tasmaniensis and V. cyclitrophicus, respectively. FurIOS is an easy-to-use online service that allows the identification of bacteria from the Vibrionaceae family at the species level using the fur gene as a single marker. Its simplistic design and straightforward pipeline makes it suitable for any research environment, from academia to industry. PMID- 28348553 TI - Exploring the Antimicrobial and Antitumor Potentials of Streptomyces sp. AGM12-1 Isolated from Egyptian Soil. AB - The occurrence of extensive antibiotics resistant bacteria increased the demands for mining out new sources of antimicrobial agents. Actinomycetes, especially Streptomyces sp. have grasped considerable attention worldwide due to production of many useful bioactive metabolites. In the present study, a total of 52 actinomycetes were isolated from agricultural soil samples in Beni-Suef, Egypt. All isolates were characterized based on colony morphology, mycelium coloration, and pigment diffusion. They were screened for their capabilities to show antimicrobial activities against different indicator microorganisms, and only 20 isolates have shown significant antimicrobial activities against at least one of the tested indicator microorganisms. The isolate AGM12-1 was active against all tested microorganisms and showed a marked antitumor activity with IC50 3.3 and 1.1 MUg/ml against HCT-116 and HepG-2 cell lines respectively. It was genotypically characterized as Streptomyces sp. with the presence of PKS Pi biosynthetic gene cluster. Mannitol, ammonium sulfate, pH 7, 2% inoculum size and incubation for 11 days at 30 degrees C were the optimum conditions that used to maximize the production and hence allowed purification of one active antimicrobial compound to homogeneity using high performance liquid chromatography with a molecular mass of m/z 488.05. Nuclear magnetic resonance structural elucidation showed that this compound was a diketopiperazine derivative. PMID- 28348554 TI - Barriers to Radiation-Induced In Situ Tumor Vaccination. AB - The immunostimulatory properties of radiation therapy (RT) have recently generated widespread interest due to preclinical and clinical evidence that tumor localized RT can sometimes induce antitumor immune responses mediating regression of non-irradiated metastases (abscopal effect). The ability of RT to activate antitumor T cells explains the synergy of RT with immune checkpoint inhibitors, which has been well documented in mouse tumor models and is supported by observations of more frequent abscopal responses in patients refractory to immunotherapy who receive RT during immunotherapy. However, abscopal responses following RT remain relatively rare in the clinic, and antitumor immune responses are not effectively induced by RT against poorly immunogenic mouse tumors. This suggests that in order to improve the pro-immunogenic effects of RT, it is necessary to identify and overcome the barriers that pre-exist and/or are induced by RT in the tumor microenvironment. On the one hand, RT induces an immunogenic death of cancer cells associated with release of powerful danger signals that are essential to recruit and activate dendritic cells (DCs) and initiate antitumor immune responses. On the other hand, RT can promote the generation of immunosuppressive mediators that hinder DCs activation and impair the function of effector T cells. In this review, we discuss current evidence that several inhibitory pathways are induced and modulated in irradiated tumors. In particular, we will focus on factors that regulate and limit radiation-induced immunogenicity and emphasize current research on actionable targets that could increase the effectiveness of radiation-induced in situ tumor vaccination. PMID- 28348556 TI - T Cell Polarization toward TH2/TFH2 and TH17/TFH17 in Patients with IgG4-Related Disease. AB - IgG4-related disease (IgG4-RD) is a fibro-inflammatory disorder involving virtually every organ with a risk of organ dysfunction. Despite recent studies regarding B cell and T cell compartments, the disease's pathophysiology remains poorly understood. We examined and characterized subsets of circulating lymphocytes in untreated patients with active IgG4-RD. Twenty-eight consecutive patients with biopsy-proven IgG4-RD were included in a prospective, multicentric study. Lymphocytes' subsets were analyzed by flow cytometry, with analysis of TH1/TH2/TH17, TFH cells, and cytokine release by peripheral blood mononuclear cells. Results were compared to healthy controls and to patients with primary Sjogren's syndrome. Patients with IgG4-RD showed an increase of circulating T regulatory, TH2, TH17, and CD4+CXCR5+PD1+ TFH cell subsets. Accordingly, increased levels of IL-10 and IL-4 were measured in IgG-RD patients. TFH increase was characterized by the specific expansion of TFH2 (CCR6-CXCR3-), and to a lesser extent of TFH17 (CCR6+CXCR3-) cells. Interestingly, CD4+CXCR5+PD1+ TFH cells normalized under treatment. IgG4-RD is characterized by a shift of circulating T cells toward a TH2/TFH2 and TH17/TFH17 polarization. This immunological imbalance might be implicated in the disease's pathophysiology. Treatment regimens targeting such T cells warrant further evaluation. PMID- 28348557 TI - Dendritic Cell Response to HIV-1 Is Controlled by Differentiation Programs in the Cells and Strain-Specific Properties of the Virus. AB - Dendritic cells (DCs) are potent antigen-presenting cells that might play contradictory roles during HIV-1 infection, contributing not only to antiviral immunity but also to viral dissemination and immune evasion. Although DCs are characterized by enormous functional diversity, it has not been analyzed how differentially programmed DCs interact with HIV-1. We have previously described the reprogramming of DC development by endogenously produced lactic acid that accumulated in a cell culture density-dependent manner and provided a long lasting anti-inflammatory signal to the cells. By exploiting this mechanism, we generated immunostimulatory DCs characterized by the production of TH1 polarizing and inflammatory mediators or, alternatively, suppressed DCs that produce IL-10 upon activation, and we tested the interaction of these DC types with different HIV-1 strains. Cytokine patterns were monitored in HIV-1-exposed DC cultures. Our results showed that DCs receiving suppressive developmental program strongly upregulated their capacity to produce the TH1 polarizing cytokine IL-12 and the inflammatory chemokines CCL2 and CCL7 upon interaction with HIV-1 strains IIIB and SF162. On the contrary, HIV-1 abolished cytokine production in the more inflammatory DC types. Preincubation of the cells with the HIV-1 proteins gp120 and Nef could inhibit IL-12 production irrespectively of the tested DC types, whereas MyD88- and TRIF-dependent signals stimulated IL-12 production in the suppressed DC type only. Rewiring of DC cytokines did not require DC infections or ligation of the HIV-1 receptor CD209. A third HIV-1 strain, BaL, could not modulate DC cytokines in a similar manner indicating that individual HIV-1 strains can differ in their capacity to influence DCs. Our results demonstrated that HIV-1 could not induce definite and invariable modulatory programs in DCs. Instead, interaction with the virus triggered different responses in different DC types. Thus, the outcome of DC-HIV-1 interactions might be highly variable, shaped by endogenous features of the cells and diversity of the virus. PMID- 28348555 TI - A Systematic Review of Immunological Studies of Erythema Nodosum Leprosum. AB - Erythema nodosum leprosum (ENL) is a painful inflammatory complication of leprosy occurring in 50% of lepromatous leprosy patients and 5-10% of borderline lepromatous patients. It is a significant cause of economic hardship, morbidity and mortality in leprosy patients. Our understanding of the causes of ENL is limited. We performed a systematic review of the published literature and critically evaluated the evidence for the role of neutrophils, immune complexes (ICs), T-cells, cytokines, and other immunological factors that could contribute to the development of ENL. Searches of the literature were performed in PubMed. Studies, independent of published date, using samples from patients with ENL were included. The search revealed more than 20,000 articles of which 146 eligible studies were included in this systematic review. The studies demonstrate that ENL may be associated with a neutrophilic infiltrate, but it is not clear whether it is an IC-mediated process or that the presence of ICs is an epiphenomenon. Increased levels of tumor necrosis factor-alpha and other pro-inflammatory cytokines support the role of this cytokine in the inflammatory phase of ENL but not necessarily the initiation. T-cell subsets appear to be important in ENL since multiple studies report an increased CD4+/CD8+ ratio in both skin and peripheral blood of patients with ENL. Microarray data have identified new molecules and whole pathophysiological pathways associated with ENL and provides new insights into the pathogenesis of ENL. Studies of ENL are often difficult to compare due to a lack of case definitions, treatment status, and timing of sampling as well as the use of different laboratory techniques. A standardized approach to some of these issues would be useful. ENL appears to be a complex interaction of various aspects of the immune system. Rigorous clinical descriptions of well-defined cohorts of patients and a systems biology approach using available technologies such as genomics, epigenomics, transcriptomics, and proteomics could yield greater understanding of the condition. PMID- 28348559 TI - miR-31 Links Lipid Metabolism and Cell Apoptosis in Bacteria-Challenged Apostichopus japonicus via Targeting CTRP9. AB - The biological functions of microRNAs (miRNAs) have been studied in a number of eukaryotic species. Recent studies on vertebrate animals have demonstrated critical roles of miRNA in immune and metabolic activities. However, studies on the functions of miRNA in invertebrates are very limited. Here, we demonstrated that miR-31 from Apostichopus japonicus disrupts the balance of lipid metabolism, thus resulting in cell apoptosis by targeting complement C1q tumor necrosis factor-related protein 9 (AjCTRP9), a novel adipokine with pleiotropic functions in immunity and metabolism. Lipidomic analysis suggested that the intercellular lipid metabolites were markedly altered, and three ceramide (Cer) species synchronously increased in the AjCTRP9-silenced coelomocytes. Moreover, exogenous Cer exposure significantly induced apoptosis in the coelomocytes in vivo, in agreement with findings from miR-31 mimic- or AjCTRP9 small-interfering RNA transfected coelomocytes. Furthermore, we found that the imbalance in sphingolipid metabolism triggered by the overproduction of Cers ultimately resulted in the activation of the apoptosis initiator caspase-8 and executioner caspase-3. Our findings provide the first direct evidence that miR-31 negatively modulates the expression of AjCTRP9 and disturbance of Cer channels, thus leading to caspase-3- and caspase-8-dependent apoptosis, during the interactions between pathogens and host. PMID- 28348558 TI - Microbiota, Immune Subversion, and Chronic Inflammation. AB - Several host-adapted pathogens and commensals have evolved mechanisms to evade the host innate immune system inducing a state of low-grade inflammation. Epidemiological studies have also documented the association of a subset of these microorganisms with chronic inflammatory disorders. In this review, we summarize recent studies demonstrating the role of the microbiota in chronic inflammatory diseases and discuss how specific microorganisms subvert or inhibit protective signaling normally induced by toll-like receptors (TLRs). We highlight our work on the oral pathogen Porphyromonas gingivalis and discuss the role of microbial modulation of lipid A structures in evasion of TLR4 signaling and resulting systemic immunopathology associated with atherosclerosis. P. gingivalis intrinsically expresses underacylated lipid A moieties and can modify the phosphorylation of lipid A, leading to altered TLR4 signaling. Using P. gingivalis mutant strains expressing distinct lipid A moieties, we demonstrated that expression of antagonist lipid A was associated with P. gingivalis-mediated systemic inflammation and immunopathology, whereas strains expressing agonist lipid A exhibited modest systemic inflammation. Likewise, mice deficient in TLR4 were more susceptible to vascular inflammation after oral infection with P. gingivalis wild-type strain compared to mice possessing functional TLR4. Collectively, our studies support a role for P. gingivalis-mediated dysregulation of innate and adaptive responses resulting in immunopathology and systemic inflammation. We propose that anti-TLR4 interventions must be designed with caution, given the balance between the protective and destructive roles of TLR signaling in response to microbiota and associated immunopathologies. PMID- 28348560 TI - Specific Strains of Lactic Acid Bacteria Differentially Modulate the Profile of Adipokines In Vitro. AB - Obesity induces local/systemic inflammation accompanied by increases in macrophage infiltration into adipose tissue and production of inflammatory cytokines, chemokines, and hormones. Previous studies have shown that probiotics could improve the intestinal dysbiosis induced by metabolic diseases such as obesity, diabetes, and metabolic syndrome. Microorganisms could (directly or indirectly) affect adipokine levels due to their capacity to induce translocation of several intestinal microbial antigens into systemic circulation, which could lead to metabolic endotoxemia or produce immunomodulation in different organs. The aim of the present study was to select non-inflammatory lactic acid bacteria (LAB) strains with the capacity to modulate adipokine secretion by the adipose tissue. We wish to elucidate the role of potential probiotic strains in the regulation of the cross talking between immune cells such as macrophages and adipose cells. Mouse macrophage cell line RAW 264.7 was used for evaluating the ability of 14 LAB strains to induce cytokine production. The LAB strains were chosen based on their previously studied beneficial properties in health. Then, in murine adipocyte culture and macrophage-adipocyte coculture, we determined the ability of these strains to induce cytokines and leptin secretion. Tumor necrosis factor alpha, interleukin 6 (IL-6), IL-10, monocyte chemoattractant protein-1, and leptin levels were measured in cell supernatants. We also performed the detection and quantification of leptin receptor (Ob-Rb) expression in macrophage cell lines stimulated by these LAB strains. Differential secretion profile of cytokines in macrophage cells induced by LAB strains was observed. Also, the levels of Ob-Rb expression diverged among different LAB strains. In LAB stimulated coculture cells (adipocytes and macrophages), we observed differential production of leptin and cytokines. Furthermore, we detected lower production levels in single culture than cocultured cells. The principal component analysis showed an association between the four clusters of strains established according to their inflammatory profiles and leptin adipocyte production and leptin receptor expression in macrophages. We conclude that coculture is the most appropriate system for selecting strains with the ability to modulate adipokine secretion. The use of microorganisms with low and medium inflammatory properties and ability to modulate leptin levels could be a strategy for the treatment of some metabolic diseases associated with dysregulation of immune response. PMID- 28348561 TI - CIMAvax-EGF: A New Therapeutic Vaccine for Advanced Non-Small Cell Lung Cancer Patients. AB - Lung cancer is the common fatal illness with the highest incidence and mortality globally. Epidermal growth factor receptor overexpression by tumor cells is associated with uncontrolled proliferation, angiogenesis, anti-apoptotic signals, metastization, and invasiveness. CIMAvax-EGF vaccine consists of a chemical conjugate of the EGF with the P64 protein derived from the Meningitis B bacteria and Montanide ISA 51, as adjuvant. The vaccine is projected to induce antibodies against EGF that results in EGF withdrawal. CIMAvax-EGF demonstrated to be safe and immunogenic in advanced non-small cell lung cancer (NSCLC) patients. The efficacy study was an open-label, multicentric Phase III clinical trial, which enrolled 405 advanced NSCLC patients. Patients with proven stage IIIB/IV NSCLC, who had completed four to six cycles of chemotherapy (CTP) were randomized to receive CIMAvax-EGF or best supportive care. CIMAvax-EGF resulted in a significantly larger overall survival in patients receiving at least four doses. High EGF concentration at baseline was a good predictive biomarker of the vaccine activity and a poor prognostic biomarker for the non-treated population. The proportion of CD8+CD28- cells, CD4 cells, and the CD4/CD8 ratio after first-line CTP was also associated with CIMAvax-EGF clinical benefit. After completing the Phase III, a Phase IV trial was done where the vaccine was administered in primary care units. Administering the vaccine at primary care institutions granted better access and treatment compliance. Safety was confirmed. Several clinical trials are currently ongoing to validate EGF as a predictive biomarker of CIMAvax-EGF efficacy. PMID- 28348563 TI - Perturbations of Monocyte Subsets and Their Association with T Helper Cell Differentiation in Acute and Chronic HIV-1-Infected Patients. AB - Monocytes have been recently subdivided into three subsets: classical (CD14++CD16 ), intermediate (CD14++CD16+), and non-classical (CD14+CD16++) subsets, but phenotypic and functional abnormalities of the three monocyte subsets in HIV-1 infection have not been fully characterized, especially in acute HIV-1 infection (AHI). In the study, we explored the dynamic changes of monocyte subsets and their surface markers, and the association between monocyte subsets and the IFN gamma, interleukin (IL)-4, IL-17, and TNF-alpha producing CD4+ T cells in acute and chronic HIV-1-infected patients. We found that, in the acute HIV-1-infected individuals, the frequency of the intermediate CD14++CD16+ monocyte subsets, the CD163 density and HLA-DR density on intermediate CD14++CD16+ monocytes, and plasma soluble form of CD163 (sCD163) were significantly higher than that in healthy controls. Intermediate CD14++CD16+ monocyte subsets and their HLA-DR expression levels were inversely correlated with the CD4+ T cell counts, and the intermediate CD14++CD16+ monocytes were positively correlated with plasma sCD163. In contrast to the non-classical CD14+CD16++ and classical CD14++CD16- monocyte subsets, the frequency of the intermediate CD14++CD16+ monocytes was positively associated with the frequency of IFN-gamma and IL-4 producing CD4+ T cells in HIV 1-infected patients. Taken together, our observations provide new insight into the roles of the monocyte subsets in HIV pathogenesis, particularly during AHI, and our findings may be helpful for the treatment of HIV-related immune activation. PMID- 28348565 TI - A Novel Heterozygous Mutation in the STAT1 SH2 Domain Causes Chronic Mucocutaneous Candidiasis, Atypically Diverse Infections, Autoimmunity, and Impaired Cytokine Regulation. AB - Chronic mucocutaneous candidiasis (CMC) is a primary immunodeficiency characterized by persistent or recurrent skin and mucosal surface infections with Candida species. Different gene mutations leading to CMC have been identified. These include various heterozygous gain-of-function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) that are not only associated with infections but also with autoimmune manifestations. Recently, two STAT1 GOF mutations involving the Src homology 2 (SH2) domain have been reported, while so far, over 50 mutations have been described mainly in the coiled coil and the DNA binding domains. Here, we present two members of a Dutch family with a novel STAT1 mutation located in the SH2 domain. T lymphocytes of these patients revealed STAT1 hyperphosphorylation and higher expression of STAT1 target genes. The clinical picture of CMC in our patients could be explained by diminished production of interleukin (IL)-17 and IL-22, cytokines important in the protection against fungal infections. PMID- 28348562 TI - Impact of Metabolism on T-Cell Differentiation and Function and Cross Talk with Tumor Microenvironment. AB - The immune system and metabolism are highly integrated and multilevel interactions between metabolic system and T lymphocyte signaling and fate exist. Accumulating evidence indicates that the regulation of nutrient uptake and utilization in T cells is critically important for the control of their differentiation and manipulating metabolic pathways in these cells can shape their function and survival. This review will discuss some potential cell metabolism pathways involved in shaping T lymphocyte function and differentiation. It will also describe show subsets of T cells have specific metabolic requirements and signaling pathways that contribute to their respective function. Examples showing the apparent similarity between cancer cell metabolism and T cells during activation are illustrated and finally some mechanisms being used by tumor microenvironment to orchestrate T-cell metabolic dysregulation and the subsequent emergence of immune suppression are discussed. We believe that targeting T-cell metabolism may provide an additional opportunity to manipulate T cell function in the development of novel therapeutics. PMID- 28348564 TI - Lower Serum Vitamin D Metabolite Levels in Relation to Circulating Cytokines/Chemokines and Metabolic Hormones in Pregnant Women with Hypertensive Disorders. AB - The aim of this study was to investigate whether lower serum vitamin D metabolite levels were associated with altered cytokine/chemokine and metabolic hormone levels in three different hypertensive disorders in pregnancy (HDP). Healthy pregnancy (n = 30) and hypertensive disorders in pregnancy (HDP) (n = 30), i.e., gestational hypertension (GH), preeclampsia (PE), and eclampsia (EC) subjects were enrolled. Vitamin D metabolites were measured by UPLC/APCI/HRMS method. Circulatory 27 cytokines/chemokines and 10 metabolic hormones were measured. Significantly decreased 25(OH)D and 1,25(OH)2D levels were observed in HDP. The levels of 25(OH)D were significantly lower in PE and EC, whereas the serum levels of 1,25(OH)2D significantly decreased only in EC subjects. Serum 25(OH)D and 1,25(OH)2D levels were negatively correlated with systolic- and diastolic blood pressure, creatinine, and uric acid levels. Serum interleukin (IL)-6 and IL-13 decreased, and GIP levels were increased in gestational hypertensive subjects. Platelet-derived growth factor-BB and IL-8 levels were increased and macrophage inflammatory protein-1beta levels were decreased in EC subjects. IL-8 and IL-10 increased, and rantes and GIP levels decreased in the EC group as compared with the GH group. Multivariate logistic regression analysis showed that eotaxin, monocyte chemotactic protein-1, 25(OH)D, and 1,25(OH)2D were predictors of HDP. Our analyses suggest that lower vitamin D metabolites are associated with altered cytokines/chemokines and metabolic hormones in HDP. PMID- 28348567 TI - Natural Killers Are Made Not Born: How to Exploit NK Cells in Lung Malignancies. AB - In recent years, progress has been made in the characterization of natural killer (NK) cells in lung malignancies, and we have now gained a better understanding of the frequency, localization, phenotype, and functional status of NK cells infiltrating these tumors. NK cell subset recruited in lung cancer is mainly capable of producing relevant cytokines rather than exerting direct cancer cell killing. Thus, the relevance of NK cells in tumor microenvironment might also go beyond the killing of tumor cells, being NK cells endowed with regulatory functions toward an ample array of immune effectors. Nevertheless, boosting their cytotoxic functions and redirecting the migration of cytotoxic NK cell subset to the tumor site might open new therapeutic avenues for lung cancer. Also, we believe that a deeper investigation into the impact of both conventional (e.g., chemotherapy) or new therapies (e.g., anti-immune checkpoints mAbs) on NK cell homeostasis in lung cancer patients is now required. PMID- 28348569 TI - Combined Application of Biofertilizers and Inorganic Nutrients Improves Sweet Potato Yields. AB - Sweet potato [Ipomoea batatas (L) Lam] yields currently stand at 4.5 t ha-1 on smallholder farms in Uganda, despite the attainable yield (45-48 t ha-1) of NASPOT 11 cultivar comparable to the potential yield (45 t ha-1) in sub-Saharan Africa (SSA). On-farm field experiments were conducted for two seasons in the Mt Elgon High Farmlands and Lake Victoria Crescent agro-ecological zones in Uganda to determine the potential of biofertilizers, specifically arbuscular mycorrhizal fungi (AMF), to increase sweet potato yields (NASPOT 11 cultivar). Two kinds of biofertilizers were compared to different rates of phosphorus (P) fertilizer when applied with or without nitrogen (N) and potassium (K). The sweet potato response to treatments was variable across sites (soil types) and seasons, and significant tuber yield increase (p < 0.05) was promoted by biofertilizer and NPK treatments during the short-rain season in the Ferralsol. Tuber yields ranged from 12.8 to 20.1 t ha-1 in the Rhodic Nitisol (sandy-clay) compared to 7.6 to 14.9 t ha-1 in the Ferralsol (sandy-loam) during the same season. Root colonization was greater in the short-rain season compared to the long-rain season. Biofertilizers combined with N and K realized higher biomass and tuber yield than biofertilizers alone during the short-rain season indicating the need for starter nutrients for hyphal growth and root colonization of AMF. In this study, N0.25PK (34.6 t ha-1) and N0.5PK (32.9 t ha-1) resulted in the highest yield during the long and the short-rain season, respectively, but there was still a yield gap of 11.9 and 13.6 t ha-1 for the cultivar. Therefore, a combination of 90 kg N ha-1 and 100 kg K ha 1 with either 15 or 30 kg P ha-1 can increase sweet potato yield from 4.5 to >30 t ha-1. The results also show that to realize significance of AMF in nutrient depleted soils, starter nutrients should be included. PMID- 28348568 TI - A Bacterial Artificial Chromosome Reporter System for Expression of the Human FOXP3 Gene in Mouse Regulatory T-Cells. AB - The transcription factor FOXP3 plays key roles in the development and function of regulatory T cells (Treg) capable of preventing and correcting immunopathology. There has been much interest in exploiting Treg as adoptive cell therapy in man, but issues of lack of nominal antigen-specificity and stability of FoxP3 expression in the face of pro-inflammatory cytokines have been a concern. In order to enable fundamental studies of human FOXP3 (hFOXP3) gene regulation and to provide preclinical tools to guide the selection of drugs that might modulate hFOXP3 expression for therapeutic purposes, we generated hFOXP3/AmCyan bacterial artificial chromosome (BAC) transgenic mice and transfectants, wherein hFOXP3 expression was read out as AmCyan expression. Using the transgenic mice, one can now investigate hFOXP3 gene expression under defined experimental conditions used for mouse Foxp3 (mFoxp3) studies. Here, we demonstrate that hFOXP3 gene expression in BAC transgenic mice is solely restricted to CD4+ T-cells, as for mFoxp3 gene expression, showing that hFOXP3 expression in Treg cells depends on fundamentally similar processes to mFoxp3 expression in these cells. Similarly, hFOXP3 expression could be observed in mouse T-cells through TCR stimulation in the presence of TGF-beta. These data suggest that, at least in part, cell type specific human and mouse foxp3 gene expression is regulated by common regulatory regions which for the human, are located within the 110-kb human FOXP3 BAC DNA. To investigate hFOXP3 gene expression further and to screen potential therapeutics in modulating hFOXP3 gene expression in vitro, we also generated hFOXP3/AmCyan expression reporter cell lines. Using the reporter cells and transcription factor inhibitors, we showed that, just as for mFoxp3 expression, inhibitors of NF-kappaB, AP1, STAT5, Smad3, and NFAT also block hFOXP3 expression. hFOXP3 induction in the reporter cells was also TGF-beta dependent, and substantially enhanced by an mTOR inhibitor, Torin1. In both the reporter transgenic mice and cell lines, histone H4 molecules in the hFOXP3 promoter and enhancers located in human CNS1 and CNS2 regions were highly acetylated in natural Treg and TCR/TGF-beta-induced Treg, indicating hFOXP3 gene expression is regulated by mechanisms similar to those previously identified for the mFoxp3 gene. PMID- 28348570 TI - DNA Methylation Affects the Efficiency of Transcription Activator-Like Effector Nucleases-Mediated Genome Editing in Rice. AB - Genome editing in plants becomes popular since the advent of sequence-specific nucleases (SSNs) that are simple to set up and efficient in various plant species. Although transcription activator-like effector nucleases (TALENs) are one of the most prevalent SSNs and have a potential to provide higher target specificity by their dimeric property, TALENs are sensitive to methylated cytosines that are present not only in transposons but also in active genes in plants. In mammalian cells, the methylation sensitivity of TALENs could be overcome by using a base-recognition module (N*) that has a higher affinity to methylated cytosine. In contrast to mammals, plants carry DNA methylation at all cytosine contexts (CG, CHG, and CHH, where H represents A, C, or T) with various degrees and effectiveness of N* module in genome editing in plants has not been explored. In this study, we designed sets of TALENs with or without N* modules and examined their efficiency in genome editing of methylated regions in rice. Although improvement in genome editing efficiency was observed with N*-TALENs designed to a stably methylated target, another target carrying cytosines with various levels of methylation showed resistance to both normal and N*-TALENs. The results suggest that variability of cytosine methylation in target regions is an additional factor affecting the genome editing efficiency of TALENs. PMID- 28348571 TI - Population Structure and Phylogenetic Relationships in a Diverse Panel of Brassica rapa L. AB - The crop species Brassica rapa L. has significant economic importance around the world. However, the global distribution and complex evolutionary history of the species has made investigating its genetic population structure difficult. Crop domestication and improvement has resulted in extreme phenotypic diversity and subspecies that are used for oilseed, food for human consumption, and fodder for livestock. These subspecies include the oilseed morphotypes. oleifera (turnip rape), ssp. dichotoma (brown sarson/toria), ssp. trilocularis (yellow sarson); ssp. rapa (turnip); and Asian leafy vegetables ssp. pekinensis (Chinese cabbage), ssp. chinensis (bok choy), ssp. nipposinica (mizuna/mibuna), ssp. rapifera (rapini/broccoli rabe), ssp. narinosa (tatsoi), ssp parachinensis (choy sum), and ssp. perviridis (komatsuna). To date, studies have had insufficient sampling to determine the relationship of all morphotypes, especially oilseed morphotypes, and questions remain over the contribution of morphotype and geographic origin to population structure. We used genotyping-by-sequencing to score 18,272 single nucleotide polymorphism markers in a globally diverse panel of 333 B. rapa National Plant Germplasm System accessions that included 10 recognized subspecies. Our population genetic and phylogenetic analyses were broadly congruent and revealed five subpopulations that were largely reflective of morphotype and geography. These subpopulations were 1. European turnips/oilseed, 2. Asian turnips/oilseed, 3. yellow/brown sarson (ssp. trilocularis and ssp. dichotoma), 4. Chinese cabbage (ssp. pekinensis), and 5. bok choy, choy sum, and tatsoi (ssp. chinensis, ssp. parachinensis, ssp. narinosa). Additionally, we found evidence of polyphyly and/or paraphyly, particularly for oilseed morphotypes (ssp. oleifera and ssp. dichotoma) and turnips. The results of this study have provided improved resolution to the genetic and phylogenetic relationships of subspecies within the species B. rapa. Understanding of these relationships is key to the future genetic study and improvement of this globally important crop species. PMID- 28348572 TI - A Casein Kinase II Phosphorylation Site in AtYY1 Affects Its Activity, Stability, and Function in the ABA Response. AB - The phosphorylation and dephosphorylation of proteins are crucial in the regulation of protein activity and stability in various signaling pathways. In this study, we identified an ABA repressor, Arabidopsis Ying Yang 1 (AtYY1) as a potential target of casein kinase II (CKII). AtYY1 physically interacts with two regulatory subunits of CKII, CKB3, and CKB4. Moreover, AtYY1 can be phosphorylated by CKII in vitro, and the S284 site is the major CKII phosphorylation site. Further analyses indicated that S284 phosphorylation can enhance the transcriptional activity and protein stability of AtYY1 and hence strengthen the effect of AtYY1 as a negative regulator in the ABA response. Our study provides novel insights into the regulatory mechanism of AtYY1 mediated by CKII phosphorylation. PMID- 28348573 TI - Characterization of the FAD2 Gene Family in Soybean Reveals the Limitations of Gel-Based TILLING in Genes with High Copy Number. AB - Soybean seed oil typically contains 18-20% oleic acid. Increasing the content of oleic acid is beneficial for health and biodiesel production. Mutations in FAD2-1 genes have been reported to increase seed oleic acid content. A subset of 1,037 mutant families from a mutagenized soybean cultivar (cv.) Forrest population was screened using reverse genetics (TILLING) to identify mutations within FAD2 genes. Although no fad2 mutants were identified using gel-based TILLING, four fad2-1A and one fad2-1B mutants were identified to have high seed oleic acid content using forward genetic screening and subsequent target sequencing. TILLING has been successfully used as a non-transgenic reverse genetic approach to identify mutations in genes controlling important agronomic traits. However, this technique presents limitations in traits such as oil composition due to gene copy number and similarities within the soybean genome. In soybean, FAD2 are present as two copies, FAD2-1 and FAD2-2. Two FAD2-1 members: FAD2-1A and FAD2-1B; and three FAD2-2 members: FAD2-2A, FAD2-2B, and FAD2-2C have been reported. Syntenic, phylogenetic, and in silico analysis revealed two additional members constituting the FAD2 gene family: GmFAD2-2D and GmFAD2-2E, located on chromosomes 09 and 15, respectively. They are presumed to have diverged from other FAD2-2 members localized on chromosomes 19 (GmFAD2-2A and GmFAD2-2B) and 03 (GmFAD2-2C). This work discusses alternative solutions to the limitations of gel-based TILLING in functional genomics due to high copy number and multiple paralogs of the FAD2 gene family in soybean. PMID- 28348566 TI - Lifetime Modulation of the Pain System via Neuroimmune and Neuroendocrine Interactions. AB - Chronic pain is a debilitating condition that still is challenging both clinicians and researchers. Despite intense research, it is still not clear why some individuals develop chronic pain while others do not or how to heal this disease. In this review, we argue for a multisystem approach to understand chronic pain. Pain is not only to be viewed simply as a result of aberrant neuronal activity but also as a result of adverse early-life experiences that impact an individual's endocrine, immune, and nervous systems and changes which in turn program the pain system. First, we give an overview of the ontogeny of the central nervous system, endocrine, and immune systems and their windows of vulnerability. Thereafter, we summarize human and animal findings from our laboratories and others that point to an important role of the endocrine and immune systems in modulating pain sensitivity. Taking "early-life history" into account, together with the past and current immunological and endocrine status of chronic pain patients, is a necessary step to understand chronic pain pathophysiology and assist clinicians in tailoring the best therapeutic approach. PMID- 28348574 TI - Proteome Profiling of Wheat Shoots from Different Cultivars. AB - Wheat is a cereal grain and one of the world's major food crops. Recent advances in wheat genome sequencing are by now facilitating its genomic and proteomic analyses. However, little is known about possible differences in total protein levels of hexaploid versus tetraploid wheat cultivars, and also knowledge of phosphorylated wheat proteins is still limited. Here, we performed a detailed analysis of the proteome of seedling leaves from two hexaploid wheat cultivars (Triticum aestivum L. Pavon 76 and USU-Apogee) and one tetraploid wheat (T. turgidum ssp. durum cv. Senatore Cappelli). Our shotgun proteomics data revealed that, whereas we observed some significant differences, overall a high similarity between hexaploid and tetraploid varieties with respect to protein abundance was observed. In addition, already at the seedling stage, a small set of proteins was differential between the small (USU-Apogee) and larger hexaploid wheat cultivars (Pavon 76), which could potentially act as growth predictors. Finally, the phosphosites identified in this study can be retrieved from the in-house developed plant PTM-Viewer (bioinformatics.psb.ugent.be/webtools/ptm_viewer/), making this the first searchable repository for phosphorylated wheat proteins. This paves the way for further in depth, quantitative (phospho)proteome-wide differential analyses upon a specific trigger or environmental change. PMID- 28348575 TI - A Member of the 14-3-3 Gene Family in Brachypodium distachyon, BdGF14d, Confers Salt Tolerance in Transgenic Tobacco Plants. AB - Plant 14-3-3 proteins are involved in diverse biological processes, but for the model monocotyledonous species, Brachypodium distachyon, their roles in abiotic stress tolerance are not well understood. In this study, a total of eight Bd14-3 3 genes were identified from B. distachyon and these were designated respectively as BdGF14a-BdGF14g. The qRT-PCR analyses of 3-month-old plants of B. distachyon showed that these genes were all expressed in the stems, leaves, and spikelets. By contrast, most of the plants had relatively lower transcriptional levels in their roots, except for the BdGF14g gene. The different expression profiles of the Bd14-3-3s under various stress treatments, and the diverse interaction patterns between Bd14-3-3s and BdAREB/ABFs, suggested that these gene products probably had a range of functions in the stress responses. The NaCl-induced Bd14 3-3 gene, BdGF14d, was selected for overexpression in tobacco. BdGF14d was found to be localized throughout the cell and it conferred enhanced tolerance to salt in the transgenic plants. Lowered contents of malondialdehyde, H2O2, and Na+, and lower relative electronic conductance (Rec%), yet greater activities of catalase and peroxidase, were observed in the overexpressing plants. Higher photosynthetic rate, transpiration rate, stomatal conductance, and water use efficiency were measured in the transgenic lines. Following abscisic acid (ABA) or NaCl treatment, stomatal aperture in leaves of the BdGF14d-overexpression plants was significantly lower than in leaves of the wild type (WT) controls. The stress related marker genes involved in the ABA signaling pathway, the reactive oxygen species (ROS)-scavenging system, and the ion transporters were all up-regulated in the BdGF14d-overexpressing plants as compared with WT. Taken together, these results demonstrate that the Bd14-3-3 genes play important roles in abiotic stress tolerance. The ABA signaling pathway, the ROS-scavenging system, and ion transporters were all involved in enhancing the tolerance to salt stress in the BdGF14d-overexpression plants. PMID- 28348576 TI - Temporal Genetic Dynamics of an Experimental, Biparental Field Population of Phytophthora capsici. AB - Defining the contributions of dispersal, reproductive mode, and mating system to the population structure of a pathogenic organism is essential to estimating its evolutionary potential. After introduction of the devastating plant pathogen, Phytophthora capsici, into a grower's field, a lack of aerial spore dispersal restricts migration. Once established, coexistence of both mating types results in formation of overwintering recombinant oospores, engendering persistent pathogen populations. To mimic these conditions, in 2008, we inoculated a field with two P. capsici isolates of opposite mating type. We analyzed pathogenic isolates collected in 2009-2013 from this experimental population, using genome wide single-nucleotide polymorphism markers. By tracking heterozygosity across years, we show that the population underwent a generational shift; transitioning from exclusively F1 in 2009-2010, to multi-generational in 2011, and ultimately all inbred in 2012-2013. Survival of F1 oospores, characterized by heterozygosity excess, coupled with a low rate of selfing, delayed declines in heterozygosity due to inbreeding and attainment of equilibrium genotypic frequencies. Large allele and haplotype frequency changes in specific genomic regions accompanied the generational shift, representing putative signatures of selection. Finally, we identified an approximately 1.6 Mb region associated with mating type determination, constituting the first detailed genomic analysis of a mating type region (MTR) in Phytophthora. Segregation patterns in the MTR exhibited tropes of sex-linkage, where maintenance of allele frequency differences between isolates of opposite mating type was associated with elevated heterozygosity despite inbreeding. Characterizing the trajectory of this experimental system provides key insights into the processes driving persistent, sexual pathogen populations. PMID- 28348578 TI - Contrast-Enhanced Magnetic Resonance Cholangiography: Practical Tips and Clinical Indications for Biliary Disease Management. AB - Since its introduction, MRCP has been improved over the years due to the introduction of several technical advances and innovations. It consists of a noninvasive method for biliary tree representation, based on heavily T2-weighted images. Conventionally, its protocol includes two-dimensional single-shot fast spin-echo images, acquired with thin sections or with multiple thick slabs. In recent years, three-dimensional T2-weighted fast-recovery fast spin-echo images have been added to the conventional protocol, increasing the possibility of biliary anatomy demonstration and leading to a significant benefit over conventional 2D imaging. A significant innovation has been reached with the introduction of hepatobiliary contrasts, represented by gadoxetic acid and gadobenate dimeglumine: they are excreted into the bile canaliculi, allowing the opacification of the biliary tree. Recently, 3D interpolated T1-weighted spoiled gradient echo images have been proposed for the evaluation of the biliary tree, obtaining images after hepatobiliary contrast agent administration. Thus, the acquisition of these excretory phases improves the diagnostic capability of conventional MRCP-based on T2 acquisitions. In this paper, technical features of contrast-enhanced magnetic resonance cholangiography are briefly discussed; main diagnostic tips of hepatobiliary phase are showed, emphasizing the benefit of enhanced cholangiography in comparison with conventional MRCP. PMID- 28348579 TI - Risk Factors for an Iatrogenic Mallory-Weiss Tear Requiring Bleeding Control during a Screening Upper Endoscopy. AB - Background and Aim. In some cases of iatrogenic Mallory-Weiss tears (MWTs), hemostasis is needed due to severe mucosal tearing with bleeding. Therefore, we aimed to evaluate the risk factors for severe iatrogenic MWTs and the methods of endoscopic bleeding control. Materials and Methods. Between January 2008 and December 2012, 426,085 cases of screening upper endoscopy were performed at the Asan Medical Center. We retrospectively analyzed the risk factors for severe iatrogenic MWTs requiring an endoscopic procedure and the treatment modalities of bleeding control. Results. Iatrogenic MWTs occurred in 546 cases (0.13%) of screening upper endoscopy in 539 patients. Bleeding control due to severe bleeding was applied in 71 cases (13.0%), and rebleeding after initial bleeding control occurred in 1 case. Multivariate analysis showed that old age, a history of distal gastrectomy, and a less-experienced endoscopist (fewer than 2,237.5 endoscopic procedures at the time of the MWT) were associated with severe iatrogenic MWTs requiring an endoscopic procedure. Among 71 cases requiring bleeding control, a hemoclip was used in 81.7% (58 cases). Conclusions. Screening endoscopy procedures should be carefully performed when patients are in their old age and have a history of distal gastrectomy, particularly if the endoscopist is less experienced. PMID- 28348577 TI - Deciphering the Roles of Thiazolidinediones and PPARgamma in Bladder Cancer. AB - The use of thiazolidinedione (TZD) therapy in type II diabetic patients has proven useful in the lowering of blood glucose levels. However, recent investigations have shown that there may be potential health concerns associated, including the risk of developing bladder cancer as well as complications in the cardiovasculature. TZDs are ligands for the nuclear receptor PPARgamma, and activation causes lipid uptake and insulin sensitization, both of which are critical processes for diabetic patients whose bodies are unable to utilize insulin effectively. Several studies have shown that PPARgamma/TZDs decrease IGF 1 levels and, thus, reduce cancer growth in carcinomas such as the pancreas, colon, liver, and prostate. However, other studies have shed light on the potential of the receptor as a biomarker for uroepithelial carcinomas, particularly due to its stimulatory effect on migration of bladder cancer cells. Furthermore, PPARgamma may provide the tumor-promoting microenvironment by de novo synthesis of nutrients that are needed for bladder cancer development. In this review, we closely examine the TZD class of drugs and their effects on PPARgamma in patient studies along with additional molecular factors that are positive modulators, such as protein phosphatase 5 (PP5), which may have considerable implications for bladder cancer therapy. PMID- 28348580 TI - Outcome and Genetic Factors in IgG4-Associated Autoimmune Pancreatitis and Cholangitis: A Single Center Experience. AB - Introduction. Most investigations on autoimmune pancreatitis (AIP) were published on Asian cohorts while those on Caucasians are limited. However, there might be differences related to the origin. Patients and Methods. We analyzed 36 patients and compared type 1 (AIP1) with type 2 (AIP2). Results. The majority of patients suffered from AIP1 (55.6%). AIP1 patients were significantly older than AIP2 patients (54.4 versus 40.8 years). Moreover, 85.0% of AIP1 patients had concurrent autoimmune cholangitis (AIC) while 18.8% of AIP2 patients suffered from overlap to ulcerative colitis (UC). However, AIP1 patients revealed a cholestatic course and had significantly higher immunoglobulin G4 levels (IgG4). When compared to allele frequencies in healthy controls, in patients with AIP1 HLA-B8 reached statistical significance. Response to steroids was excellent in both groups, but we noticed high rates of relapse especially in AIP1 patients. Finally, 3 patients with AIP1 were diagnosed with cholangiocellular carcinoma (CCC). Conclusion. In contrast to Asian studies, we found an almost equal distribution of AIP1 and AIP2 patients in our German cohort. AIP2 patients were younger and mostly of female gender whereas AIP1 patients revealed higher IgG4 levels and involvement of the biliary tract in sense of IgG4-associated cholangitis. PMID- 28348581 TI - TFCP2 Genetic Polymorphism Is Associated with Predisposition to and Transplant Prognosis of Hepatocellular Carcinoma. AB - TFCP2 is an oncogene and plays crucial roles in the incidence and progression of hepatocellular carcinoma (HCC). However, no reports are available on the impact of TFCP2 genetic polymorphism on the susceptibility to and the transplant prognosis of HCC. Here, we genotyped 7 SNPs of TFCP2 in a case-control study of 119 patients with HCC and 200 patients with chronic liver disease. Of the 7 SNPs in TFCP2, rs7959378 distributed differentially between patients with versus patients without HCC. The patients with the CA (OR = 0.58, 95% CI = 0.35-0.96), the CC (OR = 0.39, 95% CI = 0.20-0.76), and the CA/CC (OR = 0.52, 95% CI = 0.32 0.83) genotypes had significantly decreased risk for HCC compared with those carrying the rs7959378 AA genotype. After adjusting for confounding factors, rs7959378 still conferred significant risk for HCC. Furthermore, the patients who carried rs7959378 AC/CC had a higher overall survival and lower relapse-free survival than those with the rs7959378 AA genotype. Similar results were found in the multivariate analysis adjusted by AFP, tumor size and tumor number, and differentiation. These findings indicate that rs7959378 is associated with the risk of HCC in patient with chronic liver disease and prognosis of HCC patients after liver transplantation. PMID- 28348582 TI - Genetic Background and Clinical Characters of Pediatric Chronic Pancreatitis: Data and Implications from the East. AB - Background. The clinical pattern and genetic background of juvenile idiopathic chronic pancreatitis (ICP) are yet unclear. Methods. A retrospective study of 73 Chinese juvenile ICP patients was performed, and genetic tests were carried out to detect relevant mutations using direct sequencing technique and high resolution melting technique. Subjects without pancreatitis served as controls. Results. The SPINK1 c.194+2T>C variant was present in 56.16% and 42.00% of juvenile and adult ICP patients, respectively (p = 0.020), but was not present in any of the control subjects. Thirty-four (46.58%) of the 73 juvenile ICP patients were male, and a significantly higher ratio of male patients in the adult group was identified (46.58% versus 64.00%, p = 0.022). Although most of the juvenile patients presented with abdominal pain (70/73, 95.89%), the patterns of pain attack are significantly different in patients with or without SPINK1 c.194+2T>C mutation. Patients carrying the mutation are more likely to present with recurrent acute pancreatitis (70.70%). Conclusions. The main symptom of pediatric ICP was abdominal pain. SPINK1 c.194+2T>C mutation had a higher occurrence in juvenile ICP patients than in adult group and typically presented with recurrent acute pancreatitis. There may be unidentified factors that lead to a greater incidence rate of ICP in adult male population. PMID- 28348583 TI - Distribution of Neuroendocrine Cells in the Transition Zone of the Prostate. AB - Objectives. To evaluate the distribution of neuroendocrine (NE) cells which may influence the development of benign prostatic hyperplasia (BPH) in the transition zone (TZ). Methods. We reviewed specimens from 80 patients who underwent radical prostatectomy in our institution and evaluated the density of NE cells in the TZ. They were histologically classified into 3 groups: those with no adenomatous nodule in the TZ (group A), those with small nodules with normal epithelium and stroma around them in the TZ (group B), and those with large nodules occupying the TZ (group C). In the patients of group B, intra-adenoma (adenomatous nodules) and extra-adenoma (normal tissue) NE cells in the TZ were separately counted. Results. There were 22, 23, and 35 patients in groups A, B, and C, respectively. The median density of NE cells in the TZ of group B patients, 2.80/mm2, was significantly higher than that of NE cells in group A, 1.43/mm2, and group C, 0.61/mm2 (p < 0.001). In group B, the median density of extra-adenoma NE cells was significantly higher than that of intra-adenoma. Conclusions. Many NE cells exist around small adenoma in the TZ. NE cells may influence the initial growth of BPH in a paracrine fashion. Trial Registration. This study approved by our institutional review board was retrospectively registered (#272-14). PMID- 28348584 TI - Age-Friendliness and Life Satisfaction of Young-Old and Old-Old in Hong Kong. AB - Age-friendliness, promoted by the World Health Organization (WHO), aims to enable and support individuals in different aspects of life for fostering life satisfaction and personal well-being as they age. We identified specific aspect(s) of age-friendliness associated with life satisfaction and examined similarities and differences in age-friendliness and life satisfaction in young old and old-old adults. Six hundred and eighty-two ageing adults were asked to complete a survey questionnaire consisting of the Age-friendly City Scale, Satisfaction with Life Scale, and sociodemographic variables. Multiple linear regression analysis was used to examine the effects of various domains of age friendliness on life satisfaction among the young-old adults (aged 65 to 74, n = 351) and the old-old adults (aged 75 to 97, n = 331). Common domains associated with life satisfaction in both young-old and old-old groups were transportation and social participation. Community and health services were associated with life satisfaction for the young-old group only. On the other hand, civic participation and employment was significantly associated with the old-old group only. Social participation is important for the young-old and the old-old. Ageing older adults can be a resource to the society. Implications for promoting and implementing age friendliness were discussed in the context of successful and productive ageing and the need for a more refined taxonomy of social activities. PMID- 28348585 TI - The Determinants of Leptin Levels in Diabetic and Nondiabetic Saudi Males. AB - Objective. This study aimed to identify the main determinants of serum leptin levels. Methods. A sample of 113 Saudi adult males (55 diabetic and 58 nondiabetic) was selected according to the inclusion and exclusion criteria identified below. Blood samples were taken from participants after fasting for 12 hours. For diabetic patients, the insulin dose was given 12 hours before. In general, the study instrument consisted of blood biochemical tests. Metabolic parameters, glycosylated hemoglobin (HbA1c), low-density lipoprotein (LDL), high density lipoprotein (HDL), cholesterol, and triglyceride (TG), and adipokines, leptin, adiponectin, visfatin, and resistin, were measured. Multivariate model was utilized to identify the relationship between leptin levels and the independent variables. Results. When adjusted for resistin in the diabetic group, the results demonstrated a significant relationship between visfatin, LDL and TG, and leptin levels (p < 0.05). However, when controlled for resistin, the effect of LDL and TG disappeared while that of visfatin stayed in the model. For the nondiabetic group, the results indicated a significant relationship between insulin, BMI, and leptin levels when adjusted for resistin (p < 0.05). However, the effect of insulin disappeared when the model was controlled for resistin. The study results found no relationship between leptin and adiponectin levels in either the diabetic or nondiabetic group and whether adjusted or controlled for resistin. Conclusion. This study provided better understanding of the metabolism of leptin and unveiled the major determinants of leptin levels in diabetic and nondiabetic males. In conclusion, these results show that the association between leptin and metabolic parameters decreases with the progress of disease. PMID- 28348586 TI - Inositol and In Vitro Fertilization with Embryo Transfer. AB - Recently, studies on inositol supplementation during in vitro fertilization program (IVF) have gained particular importance due to the effect of this molecule on reducing insulin resistance improving ovarian function, oocyte quality, and embryo and pregnancy rates and reducing gonadotropin amount during stimulation. Inositol and its isoforms, especially myoinositol (MYO), are often used as prestimulation therapy in infertile patients undergoing IVF cycle. Inositol supplementation started three months before ovarian stimulation, resulting in significant improvements in hormonal responses, reducing the amount of FSH necessary for optimal follicle development and serum levels of 17beta estradiol measured the day of hCG injection. As shown by growing number of trials, MYO supplementation improves oocyte quality by reducing the number of degenerated and immature oocytes, in this way increasing the quality of embryos produced. Inositol can also improve the quality of sperm parameters in those patients affected by oligoasthenoteratozoospermia. PMID- 28348588 TI - Thyroid Cancer in Saudi Arabia: A Histopathological and Outcome Study. AB - Most data on differentiated thyroid cancer (DTC) came from the Western world. We describe its salient characteristics and outcome from a Middle Eastern country. Patients and Methods. We studied all cases of TC seen during a 2-year period (2004-2005) seen at our institution. Results. A total of 600 consecutive cases of DTC with a median age at diagnosis of 39 years (5-85) and the female : male ratio of 459 : 141 (76.5% : 23.5%). The cases included classical papillary thyroid cancer (PTC) in 77%, follicular variant PTC in 13.3%, follicular thyroid cancer in 3.2%, and other rare subtypes 6.5%. Total or near-total thyroidectomy was performed in 93%, central and/or lateral neck dissection in 64.5% of cases, and radioactive iodine ablation in 82% of cases. Additional therapies were administered to 154 patients (25.7%). At a median follow-up period of 7.63 years (0.22-13.1), 318 patients (53.3%) were in excellent response, 147 (24.5%) having an indeterminate response, 55 (9.2%) biochemically incomplete, 33 (5.5%) structurally incomplete, and 27 (4.5%) unclassifiable. Twenty cases died secondary to DTC (disease-specific mortality 3.3%). Conclusions. In Saudi Arabia, DTC is common and occurs at young age and predominantly in females. Although remission is common, persistent disease is also common but disease-specific mortality is low. PMID- 28348587 TI - Metabolomic Signature of Coronary Artery Disease in Type 2 Diabetes Mellitus. AB - Coronary artery disease (CAD) is a common complication of type 2 diabetes mellitus (T2D). This case-control study was done to identify metabolites with different concentrations between T2D patients with and without CAD and to characterise implicated metabolic mechanisms relating to CAD. Fasting serum samples of 57 T2D subjects, 26 with (cases) and 31 without CAD (controls), were targeted for metabolite profiling of 163 metabolites. To assess the association between metabolite levels and CAD, partial least squares (PLS) analysis and multivariate logistic regression analysis with adjustment for CAD risk factors and medications were performed. We observed a separation of cases and controls with two classes of metabolites being significantly associated with CAD, including phosphatidylcholines, and serine. Four metabolites being independent from the common CAD risk factors displaying best separation between cases and controls were further selected. Addition of the metabolite concentrations to risk factor analysis raised the area under the receiver-operating-characteristic curve from 0.72 to 0.88 (p = 0.020), providing improved sensitivity and specificity for CAD classification. Serum phospholipid and serine levels independently discriminate T2D patients with and without CAD. Oxidative stress and reduced antioxidative capacity lead to lower metabolite concentrations probably due to changes in membrane composition and accelerated phospholipid degradation. PMID- 28348589 TI - Thyroid Imaging Reporting and Data System Score Combined with the New Italian Classification for Thyroid Cytology Improves the Clinical Management of Indeterminate Nodules. AB - The new Italian cytological classification (2014) of thyroid nodules replaced the TIR3 category of the old classification (2007) with two subclasses, TIR3A and TIR3B, with the aim of reducing the rate of surgery for benign diseases. Moreover, thyroid imaging reporting and data system (TI-RADS) score appears to ameliorate the stratification of the malignancy risk. We evaluated whether the new Italian classification has improved diagnostic accuracy and whether its association with TI-RADS score could improve malignancy prediction. We retrospectively analyzed 70 nodules from 70 patients classified as TIR3 according to the old Italian classification who underwent surgery for histological diagnosis. Of these, 51 were available for cytological revision according to the new Italian cytological classification. Risk of malignancy was determined for TIR3A and TIR3B, TI-RADS score, and their combination. A different rate of malignancy (p = 0.0286) between TIR3A (13.04%) and TIR3B (44.44%) was observed. Also TI-RADS score is significantly (p = 0.003) associated with malignancy. By combining cytology and TI-RADS score, patients could be divided into three groups with low (8.3%), intermediate (21.4%), and high (80%) risk of malignancy. In conclusion, the new Italian cytological classification has an improved diagnostic accuracy. Interestingly, the combination of cytology and TI-RADS score offers a better stratification of the malignancy risk. PMID- 28348590 TI - Patterns of Human Respiratory Viruses and Lack of MERS-Coronavirus in Patients with Acute Upper Respiratory Tract Infections in Southwestern Province of Saudi Arabia. AB - We undertook enhanced surveillance of those presenting with respiratory symptoms at five healthcare centers by testing all symptomatic outpatients between November 2013 and January 2014 (winter time). Nasal swabs were collected from 182 patients and screened for MERS-CoV as well as other respiratory viruses using RT PCR and multiplex microarray. A total of 75 (41.2%) of these patients had positive viral infection. MERS-CoV was not detected in any of the samples. Human rhinovirus (hRV) was the most detected pathogen (40.9%) followed by non-MERS-CoV human coronaviruses (19.3%), influenza (Flu) viruses (15.9%), and human respiratory syncytial virus (hRSV) (13.6%). Viruses differed markedly depending on age in which hRV, Flu A, and hCoV-OC43 were more prevalent in adults and RSV, hCoV-HKU1, and hCoV-NL63 were mostly restricted to children under the age of 15. Moreover, coinfection was not uncommon in this study, in which 17.3% of the infected patients had dual infections due to several combinations of viruses. Dual infections decreased with age and completely disappeared in people older than 45 years. Our study confirms that MERS-CoV is not common in the southwestern region of Saudi Arabia and shows high diversity and prevalence of other common respiratory viruses. This study also highlights the importance and contribution of enhanced surveillance systems for better infection control. PMID- 28348591 TI - Microbiological Sealing Analysis of a Tapered Connection and External Hexagon System. AB - Considering the variety of implant connection systems available in the market and the contrasting literature regarding tapered connection systems in terms of bacterial leakage, the aim of this in vitro study was to compare the effectiveness of the bacterial seal at the implant/abutment interface between an external hexagon and a tapered connection system. Twelve sets of indexed tapered connection components and twelve sets of external hexagon connection components were used for microbiological analysis. In addition, for each model, an implant with its respective prosthetic abutment was used as a negative control and another as a positive control of microbial contamination. Failure of the abutment/implant interface seal was observed via turbidity or presence of deposits in the culture. Descriptive analysis of the data and relative frequency (percentage) as well as Fisher's exact test were used at a significance level of 5%. Two of ten (20%) external hexagon specimens showed contamination against 0/10 (0%) tapered connection implants. In conclusion, both implant/abutment connections were able to prevent bacterial leakage in vitro. PMID- 28348592 TI - Polymorphisms of Il-10 (-1082) and RANKL (-438) Genes and the Failure of Dental Implants. AB - Background. Genetic polymorphisms in certain cytokines and chemokines have been investigated to understand why some individuals display implant flaws despite having few risk factors at the time of implant. Purpose. To investigate the association of genetic polymorphisms in interleukin- (IL-) 10 [-1082 region (A/G)] and RANKL [-438 region (A/G)] with the failure of dental implants. Materials and Methods. This study included 90 partially edentulous male and female patients who were rehabilitated with a total of 245 Straumann dental implants. An implant was considered a failure if any of the following occurred: mobility, persistent subjective complaint, recurrent peri-implant infection with suppuration, continuous radiolucency around the implant, probing depth >= 5 mm, and bleeding on probing. Buccal mucosal cells were collected for analysis of RANKL438 and IL-10. Results. The implant success rate in this population was 34.4%. The mutant allele (G) in RANKL had an incidence of 52.3% and mutant allele (A) in IL-10 was observed in 37.8%. No statistically significant difference was detected between the failure of the implant and the genotypes and allelic frequencies. Conclusion. No association was detected between the genetic polymorphisms of RANKL (-438) and IL-10 (-1082) and the failure of dental implants in the population studied. PMID- 28348593 TI - Dental Anxiety among Medical and Paramedical Undergraduate Students of Malaysia. AB - Aim. To assess the dental anxiety level among dental, medical, and pharmacy students of MAHSA University, Malaysia. Materials and Methods. A cross-sectional questionnaire study was conducted among 1500 undergraduate students of MAHSA University. The Modified Dental Anxiety Scale (MDAS) was used to measure dental anxiety among the study population. The responses were assessed by 5-point likert scale ranging from 1 to 5. The level of anxiety was categorized into lowly anxious (5-11), moderately anxious (12-18), and severely anxious >=19. Out of 1500 students enrolled, 1024 students (342 males and 682 females) completed and returned the questionnaire having response rate of 68.26%. Results. There was a statistically significant difference (P < 0.001) when the mean dental anxiety scores were compared among the three faculties and dental students had lowest mean score (11.95 +/- 4.21). The fifth year (senior) dental students scored significantly (P = 0.02) lower mean anxiety score as compared to the first dental students (junior). The students were anxious mostly about tooth drilling and local anesthetic injection. Conclusions. Dental students have a significantly low level of dental anxiety as compared with medical and pharmacy students. Incorporation of dental health education in preuniversity and other nondental university curriculums may reduce dental anxiety among the students. PMID- 28348594 TI - Randomized Clinical Trial of a Self-Adhering Flowable Composite for Class I Restorations: 2-Year Results. AB - Objectives. To compare the clinical performances of a self-adhering resin composite and a conventional flowable composite with a self-etch bonding system on permanent molars. The influence of using rubber dam versus cotton roll isolation was also investigated. Materials and Methods. Patients aged between 6 and 12 years and presenting at least two permanent molars in need of small class I restorations were selected. Thirty-four pairs of restorations were randomly placed by the same operator. Fifteen patients were treated under rubber dam and nineteen using cotton rolls isolation and saliva ejector. They were evaluated according to the modified USPHS criteria at baseline, 6 months, and 1 and 2 years by two independent evaluators. Results. All patients attended the two-year recall. For all measured variables, there was no significant difference between rubber dam and cotton after 2 years of restoration with Premise Flowable or Vertise Flow (p value > 0.05). The percentage of restorations scored alpha decreased significantly over time with Premise Flowable and Vertise Flow for marginal adaptation and surface texture as well as marginal discoloration while it did not vary significantly for color matching. After 2 years, Vertise Flow showed a similar behaviour to the Premise Flowable used with a self-adhesive resin system. PMID- 28348595 TI - In Vitro Comparative Evaluation of Different Types of Impression Trays and Impression Materials on the Accuracy of Open Tray Implant Impressions: A Pilot Study. AB - Purpose. For a precise fit of multiple implant framework, having an accurate definitive cast is imperative. The present study evaluated dimensional accuracy of master casts obtained using different impression trays and materials with open tray impression technique. Materials and Methods. A machined aluminum reference model with four parallel implant analogues was fabricated. Forty implant level impressions were made. Eight groups (n = 5) were tested using impression materials (polyether and vinylsiloxanether) and four types of impression trays, two being custom (self-cure acrylic and light cure acrylic) and two being stock (plastic and metal). The interimplant distances were measured on master casts using a coordinate measuring machine. The collected data was compared with a standard reference model and was statistically analyzed using two-way ANOVA. Results. Statistically significant difference (p < 0.05) was found between the two impression materials. However, the difference seen was small (36 MUm) irrespective of the tray type used. No significant difference (p > 0.05) was observed between varied stock and custom trays. Conclusions. The polyether impression material proved to be more accurate than vinylsiloxanether impression material. The rigid nonperforated stock trays, both plastic and metal, could be an alternative for custom trays for multi-implant impressions when used with medium viscosity impression materials. PMID- 28348597 TI - Prevalence of Bacteriuria and Antimicrobial Susceptibility Patterns among Diabetic and Nondiabetic Patients Attending at Debre Tabor Hospital, Northwest Ethiopia. AB - Background. Urinary tract infection is a major health problem especially in developing countries. Information about bacterial pathogens isolated from urinary tract infection in diabetic patients and their antimicrobial susceptibility patterns is limited in Ethiopia. Therefore, this study aimed at isolating bacterial pathogens and their antimicrobial susceptibility patterns. Methods. A hospital based comparative cross-sectional study was conducted at Debre Tabor. Urine sample was inoculated onto cysteine lysine electrolyte deficient (CLED) medium. Bacterial pathogens were identified using standard bacteriological methods. The data were cleaned and entered into SPSS version 20. P value less than 0.05 is considered statistically significant. Result. A total of 384 study participants were included in the study. Of them, 21 (10.9%) were from diabetics and 9 (4.7%) of them were from nondiabetics. Large proportion of gram positive bacteria at 18 (58.1%) were isolated compared to gram negatives at 13 (41.9%). Gram positive isolates were resistant to cotrimoxazole 10 (58.8%). Conclusion. The isolation rates of bacterial pathogens were higher in diabetic than nondiabetic patients. Bacteriuria was significantly associated with sex and type of diabetes. Multidrug resistance to two or more antibiotics was observed in 56.7% of bacterial isolates. Rational use of antimicrobial agent should be thought of to prevent the emergence of multidrug resistance. PMID- 28348596 TI - Genetic Association of MMP10, MMP14, and MMP16 with Dental Caries. AB - Matrix metalloproteinases (MMPs), which degrade extracellular proteins as part of a variety of physiological processes, and their inhibitors have been implicated in the dental caries process. Here we investigated 28 genetic variants spanning the MMP10, MMP14, and MMP16 genes to detect association with dental caries experience in 13 age- and race-stratified (n = 3,587) samples from 6 parent studies. Analyses were performed separately for each sample, and results were combined across samples by meta-analysis. Two SNPs (rs2046315 and rs10429371) upstream of MMP16 were significantly associated with caries in an individual sample of white adults and via meta-analysis across 8 adult samples after gene wise adjustment for multiple comparisons. Noteworthy is SNP rs2046315 (p = 8.14 * 10-8) association with caries in white adults. This SNP was originally nominated in a genome-wide-association study (GWAS) of dental caries in a sample of white adults and yielded associations in a subsequent GWAS of surface level caries in white adults as well. Therefore, in our study, we were able to recapture the association between rs2046315 and dental caries in white adults. Although we did not strengthen evidence that MMPs 10, 14, and 16 influence caries risk, MMP16 is still a likely candidate gene to pursue. PMID- 28348598 TI - Paratesticular Angiomyofibroblastoma-Like Tumor: Unusual Case of a Solidocystic Form. AB - The angiomyofibroblastoma-like tumor of the male genital tract is a rare benign tumor. A total of 34 cases have been reported in the literature. We herein report an exceptional case of solidocystic form in its paratesticular location, in a 79 year-old man. Clinical examination objectified a right testicular induration. Macroscopic examination of the orchidectomy objectified a paratesticular solidocystic tumor formation. Microscopically, the solid area was composed of vessels with small caliber and turgidity of endothelial cells. These vessels were surrounded by clusters of epithelioid cells, sometimes having the appearance of giant cells. They were associated with spindle cells. The cystic area was uncoated. Immunohistochemically, the fusiform cells expressed Desmin and Smooth Muscle Actin. Endothelial cells and clusters of cells surrounding large vessels expressed CD34. The expression of receptors for estrogen and progesterone was negative. To our knowledge, this is the second solidocystic case of angiomyofibroblastoma-like tumor of male genital tract. PMID- 28348599 TI - A Rare Case of Stroke Secondary to Iron Deficiency Anemia in a Young Female Patient. AB - Ischemic strokes occur when there is a sudden obstruction of an artery supplying blood flow to an area of the brain, leading to a focal neurological deficit. Strokes can be thrombotic or embolic in etiology and are associated with underlying conditions such as hypertension and atherosclerosis. Possible etiologies of strokes include cardioembolic disease, hematologic disorders, connective tissue disorders, and substance abuse or can be cryptogenic. Most stroke cases are seen in patients over 65 years of age. However, about one-fourth of strokes occur in young adults. Iron deficiency anemia (IDA) has been described as a known cause for strokes in children, but very few case reports describe this association in adults. We describe a 20-year-old female who presented with sudden onset left side weakness. Magnetic Resonance Imaging (MRI) of the brain demonstrated ischemic infarctions. Patient was also found to be severely anemic. Patient had a thorough work-up including Magnetic Resonance Angiography (MRA) of the brain, echocardiogram, and an extensive screen for thrombophilia disorders. This, however, did not demonstrate a clear etiology. As it has been suggested that IDA is a potential cause for stroke, it is possible the stroke in this young patient was attributable to severe IDA. PMID- 28348600 TI - Delivery of Bone Marrow-Derived Mesenchymal Stem Cells Improves Tear Production in a Mouse Model of Sjogren's Syndrome. AB - The purpose of the present study was to test the potential of mouse bone marrow derived mesenchymal stem cells (BD-MSCs) in improving tear production in a mouse model of Sjogren's syndrome dry eye and to investigate the underlying mechanisms involved. NOD mice (n = 20) were randomized to receive i.p. injection of sterile phosphate buffered saline (PBS, control) or murine BD-MSCs (1 * 106 cells). Tears production was measured at baseline and once a week after treatment using phenol red impregnated threads. Cathepsin S activity in the tears was measured at the end of treatment. After 4 weeks, animals were sacrificed and the lacrimal glands were excised and processed for histopathology, immunohistochemistry, and RNA analysis. Following BD-MSC injection, tears production increased over time when compared to both baseline and PBS injected mice. Although the number of lymphocytic foci in the lacrimal glands of treated animals did not change, the size of the foci decreased by 40.5% when compared to control animals. The mRNA level of the water channel aquaporin 5 was significantly increased following delivery of BD-MSCs. We conclude that treatment with BD-MSCs increases tear production in the NOD mouse model of Sjogren's syndrome. This is likely due to decreased inflammation and increased expression of aquaporin 5. PMID- 28348601 TI - Diversity of Leptospira spp. in Rats and Environment from Urban Areas of Sarawak, Malaysia. AB - Various prevalence studies on Leptospira in animals and humans, as well as environmental samples, had been conducted worldwide, including Malaysia. However, limited studies have been documented on the presence of pathogenic, intermediate, and saprophytic Leptospira in selected animals and environments. This study was therefore conducted to detect Leptospira spp. in rats, soil, and water from urban areas of Sarawak using the polymerase chain reaction (PCR) method. A total of 107 rats, 292 soil samples, and 324 water samples were collected from April 2014 to February 2015. Pathogenic Leptospira was present in 5.6% (6/107) of rats, 11.6% (34/292) of soil samples, and 1.9% (6/324) of water samples. Intermediate Leptospira was present in 2.7% (8/292) of soil samples and 1.9% (6/324) of water samples. Saprophytic Leptospira was present in 10.3% (11/107) of rats, 1.4% (4/292) of soil samples, and 0.3% (1/324) of water samples. From this study, 76 Leptospira spp. were isolated. Based on DNA sequencing, the dominant Leptospira spp. circulating in urban areas of Sarawak are pathogenic Leptospira noguchii, intermediate Leptospira wolffii serovar Khorat, and saprophytic Leptospira meyeri, respectively. Overall, this study provided important surveillance data on the prevalence of Leptospira spp. from rats and the environment, with dominant local serovars in urban areas of Sarawak. PMID- 28348602 TI - Incidence and Predictors of Antiretroviral Treatment Modification in HIV-Infected Adults: A Brazilian Historical Cohort from 2001 to 2010. AB - This study estimated the incidence of and time to first antiretroviral therapy (ART) modification. This longitudinal analysis comprised a sample of 236 patients from three HIV/AIDS referral centers in Belo Horizonte, Brazil-part of a major historical cohort. Inclusion criteria were as follows: having been treatment naive patient >=18 years old who initiated ART between 2001 and 2005 in these three referral centers. The main endpoint was time to first ART modification. Patients were followed up for five years, covering the period 2001-2010, during which time Pearson's chi-square test was performed to compare ART modification between groups. Kaplan-Meier inverse survival curves were employed to describe the probability of ART modification and Cox proportional hazard regression was used to estimate the adjusted hazard ratio (aHR) of ART modification. Among 247 patients from the major cohort, 236 were eligible. Median follow-up time was 37.2 months and the contribution in person-months was 7,615.4 months. A total of 108 (45.8%) patients had their ART regimen modified at least once (incidence rate: 1.42 per 100 person-months). Adverse drug reactions were the main reason for ART modification. Women (aHR = 1.62; p = 0.022) and patients on protease inhibitor- (PI-) based regimens (aHR = 2.70; p < 0.001) were at higher risk of ART modification. PMID- 28348603 TI - Prevalence and Associated Factors of Peer Victimization (Bullying) among Grades 7 and 8 Middle School Students in Kuwait. AB - Background. Peer victimization (bullying) is a universal phenomenon with detrimental effects. The aim of this study is to determine the prevalence and factors of bullying among grades 7 and 8 middle school students in Kuwait. Methods. The study is a cross-sectional study that includes a sample of 989 7th and 8th grade middle school students randomly selected from schools. The Revised Olweus Bully/Victim Questionnaire was used to measure different forms of bullying. After adjusting for confounding, logistic regression identified the significant associated factors related to bullying. Results. Prevalence of bullying was 30.2 with 95% CI 27.4 to 33.2% (3.5% bullies, 18.9% victims, 7.8% bully victims). Children with physical disabilities and one or both non-Kuwaiti parents or children with divorced/widowed parents were more prone to be victims. Most victims and bullies were found to be current smokers. Bullies were mostly in the fail/fair final school grade category, whereas victims performed better. The logistic regression showed that male gender (adjusted odds ration = 1.671, p = 0.004), grade 8 student (adjusted odds ratio = 1.650, p = 0.004), and student with physical disabilities (adjusted odds ratio = 1.675, p = 0.003), were independently associated with bullying behavior. Conclusions. There is a need for a school-wide professional intervention program and improvement in the students' adjustment to school environment to control bullying behavior. PMID- 28348604 TI - Urinary Lactate Dehydrogenase Activity and Its Isozyme Patterns in Kawasaki Disease. AB - Abnormal urinary findings, such as sterile pyuria, proteinuria, and microscopic hematuria, are often seen in the acute phase of Kawasaki disease (KD). We investigated the potential significance of urinary lactate dehydrogenase (U-LDH) activity and its isozyme patterns in KD. Total U-LDH activity and its isozymes (U LDH1-5) levels were compared among 120 patients with KD, 18 patients with viral infection (VI), and 43 patients with upper urinary tract infection (UTI) and additionally compared between intravenous immunoglobulin (IVIG) responders (n = 89) and nonresponders (n = 31) with KD. Total U-LDH activity was higher in KD (35.4 +/- 4.8 IU/L, P < 0.05) and UTI patients (66.0 +/- 8.0 IU/L, P < 0.01) than in VI patients (17.0 +/- 6.2 IU/L). In the isozyme pattern analysis, KD patients had high levels of U-LDH1 and U-LDH2, while UTI patients had high levels of U LDH3, U-LDH4, and U-LDH5. Furthermore, IVIG nonresponders of KD had significantly higher levels of total U-LDH activity (45.1 +/- 4.7 IU/L, P < 0.05), especially U LDH1 and U-LDH2 (P < 0.05), than IVIG responders (32.0 +/- 2.8 IU/L). KD patients have increased levels of total U-LDH activity, especially U-LDH-1 and U-LDH2, indicating a unique pattern of U-LDH isozymes different from that in UTI patients. PMID- 28348605 TI - Associations between Parental and Friend Social Support and Children's Physical Activity and Time Spent outside Playing. AB - The purpose of this study was to examine the structural validity of a parent and a child questionnaire that assessed parental and friends' influences on children's physical activity and investigate the associations between the derived factors, physical activity, and time spent outside. Children (N = 154, mean age = 11.7) and 144 of their parents completed questionnaires assessing parental and friends' influences on children's physical activity. Children wore a pedometer for six days. Exploratory factor analyses revealed four factors for the parental and five for the child's questionnaire that explained 66.71% and 63.85% of the variance, respectively. Five factors were significantly associated with physical activity and five significantly associated with time spent outside. Higher correlations were revealed between "general friend support," "friends' activity norms," and physical activity (r = 0.343 and 0.333 resp., p < 0.001) and between "general friend support" and time spent outside (r = 0.460, p < 0.001). Obtaining information relating to parental and friends' influences on physical activity from both parents and children may provide a more complete picture of influences. Parents and friends seem to influence children's physical activity behavior and time spent outside, but friends' influences may have a stronger impact on children's behaviors. PMID- 28348606 TI - A Simulation Study on Hypothetical Ebola Virus Transmission in India Using Spatiotemporal Epidemiological Modeler (STEM): A Way towards Precision Public Health. AB - Background. Precision public health is a state-of-the-art concept in public health research and its application in health care. Application of information technology in field of epidemiology paves the way to its transformation to digital epidemiology. A geospatial epidemiological model was simulated to estimate the spread of Ebola virus disease after a hypothetical outbreak in India. Methods. It was a simulation study based on SEIR (Susceptible-Exposed Infectious-Recovered) compartmental model. Simulation was done in Spatiotemporal Epidemiological Modeler (STEM). Epidemiological profile of Ebola virus, that transmitted throughout the Sierra Leon in 2014-2016, was fitted into the SEIR deterministic compartment model designed for India. Result. Spatiotemporal distribution of EVD exposed, infectious, and recovered population at 4-month interval represented by different figures. It is estimated that if no intervention is taken to stop the spread, within 2 years, almost half of the country will be effected by EVD and cumulative number of exposed individuals, infectious persons, and deaths will be 106947760, 30651674, and 18391005, respectively. Conclusion. Precision public health may play the key role to achieve the health related targets in the Sustainable Development Goals. Policy makers, public health specialists, and data scientists need to put their hands together to make precision public health a reality. PMID- 28348608 TI - Erratum to: Lukasz Maciej Czarnecki. Assessment of chest X-ray images in newborns with respiratory disorders. Kardiochirurgia i Torakochirurgia Polska 2015; 12 (1): 83-86. AB - [This corrects the article DOI: 10.5114/kitp.2015.50578.]. PMID- 28348609 TI - Erratum to: Cezary Danielecki. Implantation of mitral, aortic, and tricuspid bioprostheses due to infective endocarditis with necessary reimplantation of the bioprosthetic aortic valve. Kardiochirurgia i Torakochirurgia Polska 2016; 13 (3): 248-250. AB - [This corrects the article DOI: 10.5114/kitp.2016.62615.]. PMID- 28348607 TI - Epidemiology and Outcomes in Critically Ill Patients with Human Immunodeficiency Virus Infection in the Era of Combination Antiretroviral Therapy. AB - Purpose. The impact of critical illness on survival of HIV-infected patients in the era of antiretroviral therapy remains uncertain. We describe the epidemiology of critical illness in this population and identify predictors of mortality. Materials and Methods. Retrospective cohort of HIV-infected patients was admitted to intensive care from 2002 to 2014. Patient sociodemographics, comorbidities, case-mix, illness severity, and 30-day mortality were captured. Multivariable Cox regression analyses were performed to identify predictors of mortality. Results. Of 282 patients, mean age was 44 years (SD 10) and 169 (59%) were male. Median (IQR) CD4 count and plasma viral load (PVL) were 125 cells/mm3 (30-300) and 28,000 copies/mL (110-270,000). Fifty-five (20%) patients died within 30 days. Factors independently associated with mortality included APACHE II score (adjusted hazard ratio [aHR] 1.12; 95% CI 1.08-1.16; p < 0.001), cirrhosis (aHR 2.30; 95% CI 1.12-4.73; p = 0.024), coronary artery disease (aHR 6.98; 95% CI 2.20-22.13; p = 0.001), and duration of HIV infection (aHR 1.07 per year; 95% CI 1.02-1.13; p = 0.01). CD4 count and PVL were not associated with mortality. Conclusions. Mortality from an episode of critical illness in HIV-infected patients remains high but appears to be driven by acute illness severity and HIV unrelated comorbid disease rather than degree of immune suppression. PMID- 28348610 TI - Comparison of anti-inflammatory and analgesic effects of Ginger powder and Ibuprofen in postsurgical pain model: A randomized, double-blind, case-control clinical trial. AB - BACKGROUND: Ginger has been used as an herbal drug for a long time for the treatment of chronic inflammatory conditions. MATERIALS AND METHODS: This randomized, double-blind clinical trial was conducted on 67 healthy adults with at least one impacted lower third molar. Participants were randomly allocated into three groups: Ibuprofen, Ginger, and placebo. Evaluation of inflammation was done by measuring cheek swelling, mouth opening ability, serum C-reactive protein (CRP) levels, and visual analog scale (for pain scoring). The number and the time of using rescue medication were recorded too. RESULTS: Sixty patients completed the study. In all three groups, there was a significant increase in the mean cheek swelling measures, compared with the baseline, until day 5. The reduction in mouth opening ability was significant in all three groups, compared with the baseline, until day 5. There was no significant difference between ibuprofenand ginger groups in pain scores in all follow-up days. Number of required rescue medication on the day of surgery was significantly more in the placebo group. No significant or strong correlations were found between CRP levels and clinical findings. CONCLUSION: Within the limitations of this study, it can ban be concluded that gingerpowder is as effective as ibuprofenin the management of postsurgical sequelae. Furthermore, CRP levels alone are not suggested for the assessment of anti-inflammatory effects of drugs. PMID- 28348611 TI - Can tert-butylhydroquinone improve the healing of extracted tooth socket in rats? AB - BACKGROUND: Tooth extraction causes an open wound in the soft and hard tissues. During the inflammatory phase of the healing process, a large amount of free radicals are produced and cause oxidative stress, which leads to tissue damage and delayed wound healing. Thus, in this study, we evaluated the effect of tert butylhydroquinone (TBHQ), as an antioxidant, on the healing process of tooth sockets in rats. MATERIALS AND METHODS: To conduct this experimental study, male Wistar rats (n = 42) were divided into two groups. In each case, one upper second molar was extracted under general anesthesia. After the extraction, the tooth sockets of the experimental group were treated with a 0.02% TBHQ solution (0.1 ml) while the same volume of distilled water placed in the sockets of the control group. On days 3, 7, and 21 postoperatively, 7 rats from each group were euthanized, and histological slides were prepared from their tooth sockets. The prepared slides were examined histopathologically using a light microscope and compared using an independent two-sample t-test. The significance level was set at 0.05. RESULTS: In the experimental group, a statistically significant (P = 0.003) increase in granulation tissue was observed on day 3, in comparison to the control group. The extent of bony trabeculation was also significantly higher in the TBHQ-treated group than in the control group on day 21 (P < 0.001). CONCLUSION: Considering the limitations of an experimental study, it can be concluded that TBHQ may enhance the healing of the hard tissue in the tooth sockets. PMID- 28348612 TI - Diagnostic accuracy of salivary creatinine, urea, and potassium levels to assess dialysis need in renal failure patients. AB - BACKGROUND: The prevalence of chronic renal failure is increasing because of increase in chronic debilitating diseases and progressing age of population. These patients experience accumulation of metabolic byproducts and electrolyte imbalance, which has harmful effects on their health. Timely hemodialysis at regular intervals is a life-saving procedure for these patients. Salivary diagnostics is increasingly used as an alternative to the traditional methods. Thus, the aim of the present study was to determine the diagnostic efficacy of saliva in chronic renal failure patients. MATERIALS AND METHODS: This case control study included 82 individuals, of which 41 were chronic renal failure patients and 41 were age- and sex-matched controls. Blood and saliva were collected and centrifuged. Serum and supernatant saliva were used for biochemical analysis. Serum and salivary urea, creatinine, sodium, potassium, calcium, and phosphorus were evaluated and correlated in chronic renal failure patients using unpaired t-test, Pearson's correlation coefficient, diagnostic validity tests, and receiver operative curve. RESULTS: When compared to serum; salivary urea, creatinine, sodium, and potassium showed diagnostic accuracy of 93%, 91%, 73%, and 89%, respectively, based on the findings of study. CONCLUSION: It can be concluded that salivary investigation is a dependable, noninvasive, noninfectious, simple, and quick method for screening the mineral and metabolite values of high-risk patients and monitoring the renal failure patients. PMID- 28348613 TI - Histopathological changes in dental pulp of rats following radiotherapy. AB - BACKGROUND: Radiotherapy is one of the oral and pharyngeal cancer treatment methods that can cause damage to the tissues in the radiation area; the purpose of this study is to evaluate the effects of radiotherapy on dental pulp tissue in rats. MATERIALS AND METHODS: In this interventional, experimental double-blind study, 30 rats were studied in three groups (n = 10 each). The first group received 12 gray (Gy), the second group received 18 Gy in one session, and the third group was not exposed to radiation (control group). The 5 MUm sections of mandibular molar tooth were prepared and stained with hematoxylin and eosin. Samples were studied under optical microscope to evaluate and score inflammation, necrosis, hyalinization, and vascular congestion. The data were coded and analyzed by statistical tests of chi2 and Fisher's exact tests. The significant level of P = 0.05. RESULTS: In Group 1, necrosis in two cases, inflammation in one case, hyalinization in one case, and vascular congestion in four cases were observed. In Group 2, inflammation in four cases, hyalinization in two cases, and vascular congestion in five cases were observed. In Group 3, inflammation was observed only in one case. In comparison between the groups, no significant differences were observed in inflammation (P > 0.05), necrosis (P > 0.05), and hyalinization (P > 0.05). However, the difference was significant for vascular congestion (P < 0.05). CONCLUSION: Radiotherapy with doses of 12 and 18 Gy had no significant effect on inflammation, necrosis, and hyalinization in all groups; however, the difference was significant for vascular congestion. PMID- 28348614 TI - Influence of sodium chloride content in electrolyte solution on electrochemical impedance measurements of human dentin. AB - BACKGROUND: The aim of this study was to investigate the influence of sodium chloride (NaCl) content in electrolyte solution on electrochemical impedance measurements of human dentin by employing electrochemical impedance spectroscopy. MATERIALS AND METHODS: Dentin samples were prepared from extracted molars. Electrochemical impedance measurements were carried out over a wide frequency range (0.01Hz-10MHz). After measurements, samples were characterized using scanning electron microscopy. RESULTS: Electrochemical impedance measurements showed that the mean values of dentin electrical resistance were 4284, 2062, 1336, 53 and 48kOmega at different NaCl contents in electrolyte solution. One-way ANOVA test of mean values of dentin electrical resistance revealed a significant difference (P < 0.0001) as a function of NaCl content in electrolyte solution. Comparing electrical resistance values of dentin samples at 0.05% w/v and 0.9% w/v concentrations were found to be significantly different (P < 0.05 at 95% confidence level). Scanning electron microscopy revealed structure of dentin sample with intertubular dentin matrix and distribution of patent dentinal tubules. CONCLUSION: This in vitro study indicated, through electrochemical impedance spectroscopy measurements, that electrical resistance of dentin was affected by the concentration of NaCl in electrolyte solution. It is clear from the current study that NaCl concentration in electrolyte solution has a marked influence on dentin electrical resistance. Therefore, this baseline data need to be considered in any future study on dental samples. PMID- 28348615 TI - Assessment of digital panoramic radiography's diagnostic value in angular bony lesions with 5 mm or deeper pocket depth in mandibular molars. AB - BACKGROUND: Assessment of alveolar bone level in periodontitis is very important in determining prognosis and treatment plan. Panoramic radiography is a diagnostic tool used to screen patients. The aim of the present study was to assess the diagnostic value of digital panoramic radiography in angular bony defects with 5 mm or deeper pocket depth in mandibular molars. MATERIALS AND METHODS: In this cross-sectional study, ninety angular bony defects in mandibular molars teeth with 5 mm or deeper pocket depth were selected in sixty patients with the diagnosis of chronic periodontitis. Before surgery, bone probing was performed. During the surgery, the vertical distance from cementoenamel junction to the most apical part of bony defect was measured using a Williams probe and this measurements were employed as gold standard. This distance was measured on the panoramic radiographs by a Digital Calliper and Digital Ruler. All data were compare dusing independent samples t-test and Pearson's correlation coefficient. RESULTS: No significant difference was found between the results of bone probing and intra-surgical measurements (P = 0.377). The mean defect depth determined by Digital Caliper and Digital Ruler on panoramic radiographs was significantly less than surgical measurements (P < 0.001). The correlation between bone probing and surgical measurements in determining the defect depth was strong (r = 0.98, P < 0.001). Radiographic measurements made by Digital Ruler (r = 0.86), comparing to Digital Caliper (r = 0.79), showed a higher degree of correlation with surgical measurements. CONCLUSION: Based on this study, bone probing is a reliable method in vertical alveolar bone defect measurements. While the information obtained from digital panoramic radiographs should be used with caution and the ability of digital panoramic radiography in the determination of defect depth is limited. PMID- 28348616 TI - Correlation coefficients of three self-perceived orthodontic treatment need indices. AB - BACKGROUND: To determine patient orthodontic treatment need, appropriate self perceived indices are required. The aim of this study was to assess the sensitivity and specificity of esthetic component (AC) of the index of orthodontic treatment need (IOTN), oral esthetic subjective index scale (OASIS), and visual analog scale (VAS) through dental health component (DHC) IOTN as a normative index to determine the more appropriate self-perceived index among young adults. MATERIALS AND METHODS: In this cross-sectional study, a sample of 993 was randomly selected from freshman students of Isfahan University. Those with a history of orthodontic treatment or current treatment were excluded. DHC was evaluated by two inter- and intra-calibrated examiners. Data for AC, OASIS, and VAS were collected through a questionnaire completed by students. Descriptive statistics, Mann-Whitney U-test, and Spearman correlation test, were used for data analyses. Sensitivity, specificity, positive and negative predictive values of self-perceived indices were calculated through DHC. RESULTS: Sensitivity of AC, OASIS, and VAS for evaluating definite orthodontic treatment need was calculated at 15.4%, 22.3%, and 44.6%, respectively. Specificity of these indices for evaluating definite orthodontic treatment need was calculated at 92.7%, 90.5%, and 76.2% percent, respectively. All self-perceived indices had a significant correlation with together and with DHC (P < 0.01). Among demographic factors, there was weak but significant correlation only between mother's educational level and VAS (P < 0.01). CONCLUSION: Due to the sensitivity and specificity of the three self-perceived indices, these indices are not recommended for population screening and should be used as adjuncts to a normative index for decision-making in orthodontic treatment planning. PMID- 28348617 TI - Assessment of oral health-related quality of life in 9-15 year old children with visual impairment in Uttarakhand, India. AB - BACKGROUND: To assess the prevalence of dental diseases among 9-15-year-old visually impaired children and find out its impact on their daily activities using the Child-Oral Impact on Daily Performance (C-OIDP) questionnaire in districts of Uttarakhand, India. MATERIALS AND METHODS: A total of 423 visually impaired institutionalized children between the age group of 9-15 years were included in the study. Stratified random sampling technique was used to obtain the study population. Dental caries was recorded using dmft for primary dentition and DMFT for permanent dentition, traumatic dental injuries were assessed using traumatic dental injury index, and dentofacial anomalies were recorded using Angle's classification of malocclusion. The Hindi braille version of C-OIDP questionnaire was used to gather information regarding oral health-related quality of life (OHRQoL). RESULTS: There was a high dental caries prevalence of 57.7% in visually impaired children. The prevalence of traumatic dental injuries was 50.6%. Crowding (61.5%) was the most commonly seen dentofacial anomaly and the most commonly perceived oral health problem was toothache. There was less favorable OHRQoL in males as compared to females. CONCLUSION: There was a high prevalence of dental diseases in this group and higher C-OIDP scores suggestive of unfavorable OHRQoL. PMID- 28348619 TI - Comparative study of substance P and neurokinin A in gingival crevicular fluid of healthy and painful carious permanent teeth. AB - BACKGROUND: It is shown that neuropeptides can be transported from pulp chamber to periodontal ligament through apical foramen and accessory canals. Therefore, clinical pulpal pain leads to expression of preinflammatory neuropeptides such as substance P (SP) and neurokinin A (NKA) in gingival crevicular fluid (GCF). This study aimed to evaluate levels of SP and NKA in GCF of carious and healthy permanent teeth, comparatively. MATERIALS AND METHODS: This cross-sectional study was performed on twenty children referred to Department of Pediatric Dentistry, Tehran University of Medical Sciences, who had a painful permanent first molar. Sampling was done by sterile paper cone from GCF of the mentioned teeth and the intact tooth of the other side of the jaw in the same patient. Values of SP and NKA were measured by ELISA test. RESULTS: The mean concentration of SP in GCF of painful carious and healthy teeth was 2.65 +/- 0.56 and 1.83 +/- 0.65 pcgr/ml, respectively. This value was 2.29 +/- 0.29 and 1.61 +/- 0.35 pcgr/ml for NKA concentration in carious and healthy teeth as well. CONCLUSION: Significant higher levels of both SP and NKA in GCF of painful carious teeth were observed, which is in line with previous studies' findings. PMID- 28348618 TI - Toothbrushing frequency among 4-6-year-old Iranian children and associated maternal attitude and sociobehavioral factors. AB - BACKGROUND: Toothbrushing is an important aspect of children's oral health self care. This study aimed to explore toothbrushing frequency among 4-6-year-old Iranian children and associated maternal attitude and sociobehavioral factors. MATERIALS AND METHODS: This cross-sectional study was conducted on 407 mother child (aged 4-6 years) pairs through stratified random sampling in Tabriz, Iran. Data were collected using self-reported questionnaires including demographic characteristic, maternal attitude, and toothbrushing frequency of both mothers and children. Logistic regression was used to determine the predicators of children's toothbrushing. Statistical significance was set at P < 0.05 for all tests. RESULTS: The mean ages were 32.6 +/- 4.8 and 5.3 +/- 1.1 years for mothers and children respectively. Twice-daily toothbrushing was observed at a relative frequency of 12.8% in children and 18.4% in mothers. About 43.7% of children brushed their teeth once daily. Nearly 38.7% of children started toothbrushing behavior regularly at 4 years of age, and 41% had dental visits. Multiple logistic regression analysis indicated that children's toothbrushing (once daily or more) was associated with maternal brushing frequency (odds ratio [OR] =2.0, 95% confidence interval [CI] =1.53-2.86), maternal attitude toward oral health (OR = 1.15, CI = 1.08-1.22), and children's age (OR = 1.21, 95% CI = 1.02-1.77). CONCLUSION: The descriptive results indicated that maternal and children toothbrushing behaviors are unfavorable. Furthermore, maternal toothbrushing behavior is a strong predicator of children's brushing behavior. Health promotional activities seem necessary for mothers to enhance oral health behavior of their children. PMID- 28348620 TI - In vitro evaluation of the antibacterial activity of five sealers used in root canal therapy. AB - BACKGROUND: Antibacterial activity is one of the important characteristics of an ideal root canal sealer. The aim of this study was to investigate the antibacterial activity of five different sealers against Enterococcus faecalis using two different methods. MATERIALS AND METHODS: The mineral trioxide aggregate (MTA) Fillapex, Tg-sealer, Endomethasone, AH-26, and RoekoSeal sealers were placed into the brain heart infusion (BHI) culture medium containing E. faecalis (PTCC1393). The diameter of the bacterial zone of inhibition was measured. In the direct contact test, a suspension containing grinded set sealers and E. faecalis bacteria was cultured in BHI after 6, 15, and 60 min. The number of colonies in milliliter was calculated. Data were subjected to one-way ANOVA and Tukey's multiple comparisons test (P < 0.05). RESULTS: In the agar diffusion test, Endomethasone had the highest antibacterial activity against E. faecalis compared to other sealers (P < 0.001). In the direct test, the antibacterial effect of MTA Fillapex was significantly higher than that of all other sealers (P < 0.001). CONCLUSION: The technique and components of the tested sealers affect the antibacterial activity results. This study showed that all of sealers had antimicrobial effect. PMID- 28348621 TI - Synergic effect of salivary pH baselines and low pH intakes on the force relaxation of orthodontic latex elastics. AB - BACKGROUND: Latex elastics are still in common use due to their low cost and high flexibility to improve sagittal discrepancies or interdigitation of teeth. Mechanical properties of elastics are influenced by several environmental factors such as pH changes. This study evaluated similar latex elastics to define the influence of synergic effect of intermittent low pH and various baselines pH of saliva. MATERIALS AND METHODS: Four groups of latex elastics (3-M Unitek, 3/16 inch) were tested (n = 15 in each group). Two groups of elastics were immersed in two tanks of artificial saliva with different pH levels of 7 and 5, and two groups were immersed in two tanks of artificial saliva with intermittent drop of pH to 4. The force was measured when the elastics were stretched to 25 mm. These measurements were taken in 0, 4, 8, 12, 24, 36, and 48 h for each group. Repeated measures analysis of variance (RMANOVA) and post-hoc Tukey's test were used to assess the findings. The level of significance was 0.05%. RESULTS: The interaction between pH and time analyzed with RMANOVA showed no significant differences (P > 0.05) except in 36 h (P = 0.014). The Tukey's analysis showed that each comparison between any two groups did not indicate significant differences (P > 0.05) except between Groups 1 and 3 and between Groups 2 and 3 (P < 0.05). CONCLUSION: No significant correlation was seen between fluctuation of pH and force degradation in latex elastic band except in 36 h. PMID- 28348622 TI - Cervical lymphadenopathy: Unwinding the hidden truth. AB - Lymphadenopathy is a common clinical finding in a patient seeking oral health care. It may be in a localized, limited, or generalized form. Malignancies, infections, autoimmune disorders, iatrogenic, and other miscellaneous conditions are considered as the causes for cervical lymphadenopathy. Unexplained cervical lymphadenopathy is a cause of concern for physician and patient because sometimes it could be the manifestation of an underlying malignancy. However, a methodological approach to lymphadenopathy can disclose the accurate diagnosis causing minimal discomfort for the patient and in a short time. This paper reports the significance of cervical lymph node examination and ensuing investigations, which led to a diagnosis of non-Hodgkins lymphoma. PMID- 28348623 TI - Involvement of Normalized Glial Fibrillary Acidic Protein Expression in the Hippocampi in Antidepressant-Like Effects of Xiaoyaosan on Chronically Stressed Mice. AB - The research has only yielded a partial comprehension of MDD and the mechanisms underlying the antidepressant-like effects of XYS. Therefore, in this study, we aimed to explore the effects of XYS on chronic unpredictable mild stress- (CUMS-) induced changes in the neuronal and the astrocytic markers in the mouse hippocampus. The physical states and depressive-like behaviors in mice with CUMS were recorded. The serum contents of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) were measured. The protein and mRNA expressions and the immunoreactivities of glial fibrillary acidic protein (GFAP) and neuronal nuclei (NeuN) in mouse hippocampus were detected using a Western blot, qRT-PCR, and immunohistochemical staining, respectively. XYS treatment markedly improved the physical state and depressive-like behaviors in mice subjected to CUMS compared with the model group, and the serum contents of BDNF and GDNF were significantly upregulated. XYS treatment also elevated the protein and mRNA levels, as well as the immunoreactivity of GFAP in the hippocampus. However, CUMS did not influence NeuN expression. In conclusion, these results reveal that chronic administration of XYS elicits antidepressant like effects in a mouse model of depression and may normalize glial fibrillary acidic protein expression in the hippocampi of mice with CUMS. PMID- 28348624 TI - Antioxidative and Anti-Inflammatory Activities of Galloyl Derivatives and Antidiabetic Activities of Acer ginnala. AB - Chromatographic isolation of the 80% MeOH extract of Acer ginnala (AG) yielded seven galloyl derivatives: gallic acid (1), ginnalin B (2), acertannin (3), maplexin D (4), maplexin E (5), quercetin-3-O-(2''-galloyl)-alpha-L rhamnopyranoside (6), and kaempferol-3-O-(2''-galloyl)-alpha-L-rhamnopyranoside (7). This is the first study to report the isolation of compounds 4 and 5 from AG. Galloyl derivatives 3-7 exhibited potent radical scavenging activities, with 5 and 7 showing particularly strong inhibitory activities against nitric oxide production in lipopolysaccharides- (LPS-) stimulated RAW264.7 cells. In addition, oral administration of AG extract (500 mg/kg b.w.) improved symptoms of hyperglycemia and blunted the increases in serum GOT/GPT levels in a rat model of streptozotocin-induced diabetes. These results suggest that galloyl derivatives (1-7) are antioxidant and anti-inflammatory agents and that AG extract has potential as a functional material or novel herbal medicine for treating diabetes mellitus. PMID- 28348625 TI - Components of Goutengsan in Rat Plasma by Microdialysis Sampling and Its Protection on Abeta1-42-Induced PC12 Cells Injury. AB - Goutengsan, a Chinese herbal formula, potential protection on Alzheimer's disease (AD) has been less reported. In current study, we investigated the protection of Goutengsan on Abeta1-42-induced pheochromocytoma-derived cells (PC12). Furthermore, the components from Goutengsan in rat plasma were identified by microdialysis (MD) for in vivo sampling. Meanwhile, the protection of components identified was also verified. At last, we found that Goutengsan has a potential protective effect on Abeta1-42-induced PC12 cells via reducing cells damage and increasing cells vitality as well as six components (pachymic acid, liquiritin, rhynchophylline, isorhynchophylline, corynoxeine, and isocorynoxeine) which may be effective components. This study helps to understand the treatment of Goutengsan for AD and would facilitate the clinical and further studies for this formula. PMID- 28348626 TI - Amiodarone-Associated Optic Neuropathy: Clinical Review. AB - Amiodarone, an antiarrhythmic agent, has been associated with visual loss secondary to optic neuropathy. The reported mean duration of amiodarone use before visual loss is about 9 months. Patients receiving amiodarone have a 2-fold increased risk of developing optic neuropathy, especially in males and possibly in patients with longer duration of treatment. Amiodarone-associated optic neuropathy is characterised by an insidious onset, slow progression, bilateral simultaneous visual loss, and protracted disc swelling. After discontinuing amiodarone use, visual acuity and visual field deficits tend to improve or stabilise in most patients, with about 20% of the patients getting worse. PMID- 28348627 TI - Visual Field Losses in Patients with Migraine without Aura and Tension-Type Headache. AB - The aim of the study was to compare the visual fields during pain attacks in the patients with migraine without aura and tension-type headache using automated perimetry. In this study 25 patients with migraine and 25 patients with tension type headache were evaluated.The optic disc, macula and retina were assessed and patients with normal values were enrolled into the study. Intraocular pressure of all patients were measured. Furthermore, visual field test was applied to both groups using Humphrey field analyzer (Carl-Zeiss Meditec, model-745 i, Dublin, CA, USA). Both mean deviation and pattern standart deviation values of these two goups were not statistically significant. PMID- 28348628 TI - Risk Factors for Non-arteritic Anterior Ischaemic Optic Neuropathy in a Korean Population. AB - To determine the risk factors for non-arteritic anterior ischaemic optic neuropathy (NAION) in Korean patients, medical records from 45 Korean patients group and 45 healthy controls group were retrospectively reviewed. 10 NAION risk factors, including age, sex, associated systemic disease, past medical/social history, and fundus findings were analyzed. Significant risk factors for NAION in Korean patients were diabetes mellitus (odds ratio (OR) = 3.613, p = 0.020), hypercholesterolaemia (OR = 5.200, p = 0.001), smoking (OR = 3.58, p = 0.014), microaneurysm/haemorrhage (OR = 5.375, p = 0.024), and crowded small cup (OR = 17.200, p < 0.001). PMID- 28348630 TI - Intracanalicular Optic Nerve Swelling and Signal Change in Fulminant Untreated Idiopathic Intracranial Hypertension. AB - The role of the optic canal in the pathogenesis of papilloedema has been under scrutiny recently. Whether a larger canal precedes more severe papilloedema or is the result of bone remodelling from chronically raised pressure across a pressure gradient is not clear. The authors present the magnetic resonance imaging findings of a 29-year-old female with fulminant and untreated idiopathic intracranial hypertension. Imaging showed focal expansion and intrinsic signal changes of the intracanalicular optic nerve. The authors discuss the possibility of either fluid accumulation within the optic nerves from a water hammer effect across blocked optic canals resulting from the steep pressure gradient or opticomalacia (optic nerve softening) from chronic ischaemia. PMID- 28348629 TI - Optical Coherence Angiographic Demonstration of Retinal Changes From Chronic Optic Neuropathies. AB - Glaucoma causes a decrease in peripapillary perfused capillary density on optical coherence tomography (OCT) angiography. However, other chronic optic neuropathies have not been explored with OCT angiography to see if these changes were specific to glaucoma. The authors evaluated OCT angiography in 10 patients who suffered various kinds of chronic optic neuropathies, including optic neuritis and ischaemic optic neuropathy, and found that all optic neuropathies showed a decrease in peripapillary vessel density on OCT angiography, regardless of the aetiology of the optic neuropathy. The peripapillary vessel loss on OCT angiography correlated well with the areas of retinal nerve fibre layer thinning seen on OCT. PMID- 28348631 TI - Optic Neuropathy As the Initial Presenting Sign of N-methyl-d-aspartate (NMDA) Encephalitis. AB - A 52-year-old woman presented with painless vision loss for 3 months. She was in custody for allegedly robbing a bank and had recently been diagnosed with paranoid schizophrenia. She had 20/100 VA OD, a 2+RAPD, and optic atrophy. Extensive diagnostic workup including MRI, Fluorescein Angiography, Infectious Disease Panel, lumbar puncture, and leptomeningeal biopsy were unrevealing. Vision in her right eye declined to NLP and her left eye declined to 20/200 VA. Anti N-methyl-D-aspartate (NMDA) Autoimmune Encephalitis was diagnosed based on CSF serology and clinical suspicion. Her clinical course improved as she was treated with corticosteroids and rituximab. PMID- 28348632 TI - Primary Ocular Adnexal Extranodal Marginal Zone Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma Presenting as Orbital Apex Syndrome. AB - A 75-year-old female with a past medical history significant for prior stroke and atrial fibrillation presented with acute onset of orbital apex syndrome with chemosis and periorbital ecchymosis. Following initial treatment to relieve intraocular pressure, she began spontaneously haemorrhaging retro-orbitally. Preliminary investigation with neuroimaging demonstrated a left orbital mass with extension into the orbital apex. A provisional diagnosis of cavernous haemangioma was made. She was treated with transorbital resection of the orbital mass. Subsequent histopathology revealed a diagnosis of ocular adnexal non-Hodgkin lymphoma of histologic type extranodal marginal zone of mucosa-associated lymphoid tissue (MALT lymphoma). MALT lymphoma should be considered in cases of orbital apex syndrome. PMID- 28348633 TI - Differentiating Leber Hereditary Optic Neuropathy from Normal-Tension Glaucoma. AB - Glaucoma is a neurodegenerative disorder characterized by thinning of neuroretinal rim, enlarged cup-to-disc ratio (CDR) and visual field damage. Although raised intraocular pressure is main risk factor for development of glaucoma, it can occur with consistently normal measurements in the intraocular pressure as normal tension glaucoma (NTG). Enlargement of CDR is a classical sign of glaucoma, but it can also result from non-glaucomatous optic neuropathies such as Leber hereditary optic neuropathy (LHON). We describe a case of LHON with increased CDR, discuss its differential diagnosis with NTG and highlight the reasons for misdiagnoses between these two entities. PMID- 28348634 TI - Trans-synaptic Retrograde Degeneration Following Hemispherectomy in Childhood. AB - Trans-synaptic retrograde degeneration (TRD) in the human visual system has been established. However there are few studies demonstrating macular thinning of the Retinal Ganglion cell Layer and/or Inner Plexiform layer (RGCL-IPL), corresponding to an acquired homonymous hemianopia. We report a 17 year old with a homonymous hemianopia, secondary to a hemispherectomy for intractable epilepsy. Three years following hemispherectomy, Optical Coherence Tomography (OCT) revealed evidence of TRD, corresponding to his complete homonymous hemianopia. Macular maps of the RGCL-IPL thickness provides useful additional information to measurements of optic nerve Retinal Nerve Fibre Layer Thickness (RNFL) in identifying TRD in acquired homonymous hemianopia. PMID- 28348635 TI - Re: Unusual Cause of Horner Syndrome 13 Years After In Situ Ductal Carcinoma. PMID- 28348636 TI - HIV and reproductive healthcare in pregnant and postpartum HIV-infected women: adapting successful strategies. AB - Linkage and retention in care for many HIV-infected women in the postpartum period is suboptimal, which compromises long-term virologic suppression and the HIV Care Continuum. Efforts are needed to improve individual outcomes by addressing transitions in care. We summarize some successful strategies to engage and retain HIV-infected women in care during the postpartum period. PMID- 28348637 TI - Automated Classification of Severity in Cardiac Dyssynchrony Merging Clinical Data and Mechanical Descriptors. AB - Cardiac resynchronization therapy (CRT) improves functional classification among patients with left ventricle malfunction and ventricular electric conduction disorders. However, a high percentage of subjects under CRT (20%-30%) do not show any improvement. Nonetheless the presence of mechanical contraction dyssynchrony in ventricles has been proposed as an indicator of CRT response. This work proposes an automated classification model of severity in ventricular contraction dyssynchrony. The model includes clinical data such as left ventricular ejection fraction (LVEF), QRS and P-R intervals, and the 3 most significant factors extracted from the factor analysis of dynamic structures applied to a set of equilibrium radionuclide angiography images representing the mechanical behavior of cardiac contraction. A control group of 33 normal volunteers (28 +/- 5 years, LVEF of 59.7% +/- 5.8%) and a HF group of 42 subjects (53.12 +/- 15.05 years, LVEF < 35%) were studied. The proposed classifiers had hit rates of 90%, 50%, and 80% to distinguish between absent, mild, and moderate-severe interventricular dyssynchrony, respectively. For intraventricular dyssynchrony, hit rates of 100%, 50%, and 90% were observed distinguishing between absent, mild, and moderate severe, respectively. These results seem promising in using this automated method for clinical follow-up of patients undergoing CRT. PMID- 28348638 TI - Cardioprotection Effects of Sevoflurane by Regulating the Pathway of Neuroactive Ligand-Receptor Interaction in Patients Undergoing Coronary Artery Bypass Graft Surgery. AB - This study was designed to identify attractor modules and further reveal the potential biological processes involving in sevoflurane-induced anesthesia in patients treated with coronary artery bypass graft (CABG) surgery. Microarray profile data (ID: E-GEOD-4386) on atrial samples obtained from patients receiving anesthetic gas sevoflurane prior to and following CABG procedure were downloaded from EMBL-EBI database for further analysis. Protein-protein interaction (PPI) networks of baseline and sevoflurane groups were inferred and reweighted according to Spearman correlation coefficient (SCC), followed by systematic modules inference using clique-merging approach. Subsequently, attract method was utilized to explore attractor modules. Finally, pathway enrichment analyses for genes in the attractor modules were implemented to illuminate the biological processes in sevoflurane group. Using clique-merging approach, 27 and 36 modules were obtained from the PPI networks of baseline and sevoflurane-treated samples, respectively. By comparing with the baseline condition, 5 module pairs with the same gene composition were identified. Subsequently, 1 out of 5 modules was identified as an attractor based on attract method. Additionally, pathway analysis indicated that genes in the attractor module were associated with neuroactive ligand-receptor interaction. Accordingly, sevoflurane might exert important functions in cardioprotection in patients following CABG, partially through regulating the pathway of neuroactive ligand-receptor interaction. PMID- 28348639 TI - Brushed polyethylene glycol and phosphorylcholine for grafting nanoparticles against protein binding. AB - To provide a molecular insight for guiding polymer coating in surface science and nanotechnology, here we examined the structures of brushed polyethylene glycol(bPEG)- and phosphorylcholine(bPC)-grafted iron oxide nanoparticles and analyzed their protein avoiding properties. We show bPC as an advantageous biomimetic alternative to PEG in rendering stealth nanostructures. PMID- 28348640 TI - Exploration of small RNA-seq data for small non-coding RNAs in Human Colorectal Cancer. AB - Background: Improved healthcare and recent breakthroughs in technology have substantially reduced cancer mortality rates worldwide. Recent advancements in next-generation sequencing (NGS) have allowed genomic analysis of the human transcriptome. Now, using NGS we can further look into small non-coding regions of RNAs (sncRNAs) such as microRNAs (miRNAs), Piwi-interacting-RNAs (piRNAs), long non-coding RNAs (lncRNAs), and small nuclear/nucleolar RNAs (sn/snoRNAs) among others. Recent studies looking at sncRNAs indicate their role in important biological processes such as cancer progression and predict their role as biomarkers for disease diagnosis, prognosis, and therapy. Results: In the present study, we data mined publically available small RNA sequencing data from colorectal tissue samples of eight matched patients (benign, tumor, and metastasis) and remapped the data for various small RNA annotations. We identified aberrant expression of 13 miRNAs in tumor and metastasis specimens [tumor vs benign group (19 miRNAs) and metastasis vs benign group (38 miRNAs)] of which five were upregulated, and eight were downregulated, during disease progression. Pathway analysis of aberrantly expressed miRNAs showed that the majority of miRNAs involved in colon cancer were also involved in other cancers. Analysis of piRNAs revealed six to be over-expressed in the tumor vs benign cohort and 24 in the metastasis vs benign group. Only two piRNAs were shared between the two cohorts. Examining other types of small RNAs [sn/snoRNAs, mt_rRNA, miscRNA, nonsense mediated decay (NMD), and rRNAs] identified 15 sncRNAs in the tumor vs benign group and 104 in the metastasis vs benign group, with only four others being commonly expressed. Conclusion: In summary, our comprehensive analysis on publicly available small RNA-seq data identified multiple differentially expressed sncRNAs during colorectal cancer progression at different stages compared to normal colon tissue. We speculate that deciphering and validating the roles of sncRNAs may prove useful in colorectal cancer prognosis, diagnosis, and therapy. PMID- 28348641 TI - Complete genome sequence and functional study of the fibrinolytic enzyme producing bacterium Leuconostoc holzapfelii 5H4, a silage probiotic. AB - To process silage, rye is usually removed before the heading stage but the rye biomass increased up to 30% after the heading stage. However, after the heading stage, lignification rapidly accelerated and it resulted in a poor NDF digestibility problem. This has led to a demand for a strong fibrinolytic enzyme producing probiotic for rye silage. The Gram-positive Leuconostoc holzapfelii 5H4 was selected as a fibrinolytic enzyme-producing probiotic to overcome lignification of rye silage. The L. holzapfelii 5H4 has a relatively small circular chromosome (1,885,398 bp), but the strain has one cellulase, two xylanase, and five esterase in its genome sequence. All fibrinolytic enzyme genes were relatively highly expressed compared to housekeeping genes, and this was confirmed by qRT-PCR. In this study, we report the complete genome sequence of the bacterium so that fibrinolytic enzyme production and its fibrinolytic activity mechanism are better understood. PMID- 28348642 TI - Metagenomic Analysis of a Complex Community Present in Pond Sediment. AB - The metagenomic profiling of complex communities is gaining immense interest across the scientific community. A complex community present in the pond sediment of a water body located close to a hexachlorocyclohexane (HCH) production site of the Indian Pesticide Limited (IPL) (Chinhat, Lucknow) was selected in an attempt to identify and analyze the unique microbial diversity and functional profile of the site. In this study, we supplement the metagenomic study of pond sediment with a variety of binning approaches along with an in depth functional analysis. Our results improve the understanding of ecology, in terms of community dynamics. The findings are crucial with respect to the mechanisms such as those involving the lin group of genes that are known to be implicated in the HCH degradation pathway or the Type VI secretory system (T6SS) and its effector molecules. Metagenomic studies using the comparative genomics approach involving the isolates from adjacent HCH contaminated soils have contributed significantly towards improving our understanding of unexplored concepts, while simultaneously uncovering the novel mechanisms of microbial ecology. PMID- 28348643 TI - Whole-genome Sequencing of Vibrio sinaloensis T47, a Tropical Marine Isolate with Quorum Sensing Properties. AB - A large number of Vibrio sp. thrive in the marine environment and they are notable to cause food borne infection associated with undercooked seafood. In this study, we report the whole genome sequence of Vibrio sinaloensis T47 which was isolated from coastal marine water in Morib Beach, Hulu Selangor. The genome is made up of approximately 4.59 Mbp with 80 contigs and 46% G+C content. From the annotated genome, genes associated with quorum sensing (QS) were identified. This research provides a genetic basis for better understanding of QS pathway which contributes to the physiological traits of strain T47 to thrive in the marine environment. PMID- 28348644 TI - Navigation-synchronized multimodal control wheelchair from brain to alternative assistive technologies for persons with severe disabilities. AB - Currently, electric wheelchairs are commonly used to improve mobility in disabled people. In severe cases, the user is unable to control the wheelchair by themselves because his/her motor functions are disabled. To restore mobility function, a brain-controlled wheelchair (BCW) would be a promising system that would allow the patient to control the wheelchair by their thoughts. P300 is a reliable brain electrical signal, a component of visual event-related potentials (ERPs), that could be used for interpreting user commands. This research aimed to propose a prototype BCW to allowed severe motor disabled patients to practically control a wheelchair for use in their home environment. The users were able to select from 9 possible destination commands in the automatic mode and from 4 directional commands (forward, backward, turn left and right) in the shared control mode. These commands were selected via the designed P300 processing system. The wheelchair was steered to the desired location by the implemented navigation system. Safety of the user was ensured during wheelchair navigation due to the included obstacle detection and avoidance features. A combination of P300 and EOG was used as a hybrid BCW system. The user could fully operate the system such as enabling P300 detection system, mode shifting and stop/cancelation command by performing a different consecutive blinks to generate eye blinking patterns. The results revealed that the prototype BCW could be operated in either of the proposed modes. With the new design of the LED-based P300 stimulator, the average accuracies of the P300 detection algorithm in the shared-control and automatic modes were 95.31 and 83.42% with 3.09 and 3.79 bits/min, respectively. The P300 classification error was acceptable, as the user could cancel an incorrect command by blinking 2 times. Moreover, the proposed navigation system had a flexible design that could be interfaced with other assistive technologies. This research developed 3 alternative input modules: an eye tracker module and chin and hand controller modules. The user could select the most suitable assistive technology based on his/her level of disability. Other existing assistive technologies could also be connected to the proposed system in the future using the same protocol. PMID- 28348645 TI - The feeling of understanding: an exploration with neural models. AB - There exists a dynamic interaction between the world of information and the world of concepts, which is seen as a quintessential byproduct of the cultural evolution of individuals as well as of human communities. The feeling of understanding (FU) is that subjective experience that encompasses all the emotional and intellectual processes we undergo in the process of gathering evidence to achieve an understanding of an event. This experience is part of every person that has dedicated substantial efforts in scientific areas under constant research progress. The FU may have an initial growth followed by a quasi stable regime and a possible decay when accumulated data exceeds the capacity of an individual to integrate them into an appropriate conceptual scheme. We propose a neural representation of FU based on the postulate that all cognitive activities are mapped onto dynamic neural vectors. Two models are presented that incorporate the mutual interactions among data and concepts. The first one shows how in the short time scale, FU can rise, reach a temporary steady state and subsequently decline. The second model, operating over longer scales of time, shows how a reorganization and compactification of data into global categories initiated by conceptual syntheses can yield random cycles of growth, decline and recovery of FU. PMID- 28348646 TI - Complexity of resting-state EEG activity in the patients with early-stage Parkinson's disease. AB - To investigate the abnormal brain activities in the early stage of Parkinson's disease (PD), the electroencephalogram (EEG) signals were recorded with 20 channels from non-dementia PD patients (18 patients, 8 females) and age matched healthy controls (18 subjects, 8 females) during the resting state. Two methods based on the ordinal patterns of the recorded series, i.e., permutation entropy (PE) and order index (OI), were introduced to characterize the complexity of the cortical activities for two groups. It was observed that the resting-state EEG of PD patients showed lower PE and higher OI than healthy controls, which indicated that the early-stage PD caused the reduced complexity of EEG. We further applied two methods to determine the complexity of EEG rhythms in five sub-bands. The results showed that the gamma, beta and alpha rhythms of PD patients were characterized by lower PE and higher OI, i.e., reduced complexity, than healthy subjects. No significant differences were observed in theta or delta rhythms between two groups. The findings suggested that PE and OI were promising methods to detect the abnormal changes in the dynamics of EEG signals associated with early-stage PD. Further, such changes in EEG complexity may be the early markers of the cortical or subcortical dysfunction caused by PD. PMID- 28348647 TI - An EEG-based machine learning method to screen alcohol use disorder. AB - Screening alcohol use disorder (AUD) patients has been challenging due to the subjectivity involved in the process. Hence, robust and objective methods are needed to automate the screening of AUD patients. In this paper, a machine learning method is proposed that utilized resting-state electroencephalography (EEG)-derived features as input data to classify the AUD patients and healthy controls and to perform automatic screening of AUD patients. In this context, the EEG data were recorded during 5 min of eyes closed and 5 min of eyes open conditions. For this purpose, 30 AUD patients and 15 aged-matched healthy controls were recruited. After preprocessing the EEG data, EEG features such as inter-hemispheric coherences and spectral power for EEG delta, theta, alpha, beta and gamma bands were computed involving 19 scalp locations. The selection of most discriminant features was performed with a rank-based feature selection method assigning a weight value to each feature according to a criterion, i.e., receiver operating characteristics curve. For example, a feature with large weight was considered more relevant to the target labels than a feature with less weight. Therefore, a reduced set of most discriminant features was identified and further be utilized during classification of AUD patients and healthy controls. As results, the inter-hemispheric coherences between the brain regions were found significantly different between the study groups and provided high classification efficiency (Accuracy = 80.8, sensitivity = 82.5, and specificity = 80, F-Measure = 0.78). In addition, the power computed in different EEG bands were found significant and provided an overall classification efficiency as (Accuracy = 86.6, sensitivity = 95, specificity = 82.5, and F-Measure = 0.88). Further, the integration of these EEG feature resulted into even higher results (Accuracy = 89.3 %, sensitivity = 88.5 %, specificity = 91 %, and F-Measure = 0.90). Based on the results, it is concluded that the EEG data (integration of the theta, beta, and gamma power and inter-hemispheric coherence) could be utilized as objective markers to screen the AUD patients and healthy controls. PMID- 28348648 TI - Regularized common spatial patterns with subject-to-subject transfer of EEG signals. AB - In the context of brain-computer interface (BCI) system, the common spatial patterns (CSP) method has been used to extract discriminative spatial filters for the classification of electroencephalogram (EEG) signals. However, the classification performance of CSP typically deteriorates when a few training samples are collected from a new BCI user. In this paper, we propose an approach that maintains or improves the recognition accuracy of the system with only a small size of training data set. The proposed approach is formulated by regularizing the classical CSP technique with the strategy of transfer learning. Specifically, we incorporate into the CSP analysis inter-subject information involving the same task, by minimizing the difference between the inter-subject features. Experimental results on two data sets from BCI competitions show that the proposed approach greatly improves the classification performance over that of the conventional CSP method; the transformed variant proved to be successful in almost every case, based on a small number of available training samples. PMID- 28348649 TI - Down-regulated expression of aquaporin-4 in the cerebellum after status epilepticus. AB - Status epilepticus (SE) is a common neurological condition associated with high rates of mortality and permanent brain injury. SE usually leads to neuronal death which may be accompanied by edema, epileptogenesis and learning impairment. Aquaporin-4 (AQP4), is a transmembrane water channel protein in the neuropil of the central nervous system that has an important role in water transport in the brain; AQP4 expression is altered in many pathological conditions such as changes in the blood- brain barrier and/or astrocytic activation, including seizures. AQP4 was shown to be downregulated in the piriform cortex and the hippocampus after SE. Although it is normally expressed at a high level in the cerebellum, little is known about AQP4 levels in the cerebellum following SE. We addressed this in the present study in a mouse model of pilocarpine-induced SE. We found that AQP4 expression was reduced from 3 h to 3 days after SE, with the levels recovering on day 7. Moreover, mice in the acute post-SE stages exhibited impaired motor coordination and learning. These results indicate that cerebellar damage following SE involves changes in AQP4 expression. PMID- 28348650 TI - A basic bifurcation structure from bursting to spiking of injured nerve fibers in a two-dimensional parameter space. AB - Two different bifurcation scenarios of firing patterns with decreasing extracellular calcium concentrations were observed in identical sciatic nerve fibers of a chronic constriction injury (CCI) model when the extracellular 4 aminopyridine concentrations were fixed at two different levels. Both processes proceeded from period-1 bursting to period-1 spiking via complex or simple processes. Multiple typical experimental examples manifested dynamics closely matching those simulated in a recently proposed 4-dimensional model to describe the nonlinear dynamics of the CCI model, which included most cases of the bifurcation scenarios. As the extracellular 4-aminopyridine concentrations is increased, the structure of the bifurcation scenario becomes more complex. The results provide a basic framework for identifying the relationships between different neural firing patterns and different bifurcation scenarios and for revealing the complex nonlinear dynamics of neural firing patterns. The potential roles of the basic bifurcation structures in identifying the information process mechanism are discussed. PMID- 28348651 TI - Erratum to: Noise effects on robust synchronization of a small pacemaker neuronal ensemble via nonlinear controller: electronic circuit design. AB - [This corrects the article DOI: 10.1007/s11571-016-9393-1.]. PMID- 28348652 TI - Nasal Septal Deviation and Concha Bullosa - Do They Have an Impact on Maxillary Sinus Volumes and Prevalence of Maxillary Sinusitis? AB - BACKGROUND: The aim of the study was to assess if the presence of nasal septal deviation and concha bullosa is connected with the development of sinuses and the incidence of inflammation within them. MATERIAL/METHODS: We retrospectively analysed 214 patients who underwent paranasal sinus computed tomography. There were 125 females and 89 males, the mean age being 47.67+/-16.74 years (range 18 97). Exclusion criteria included: age under 18 years, prior sinonasal surgery and S-shaped septum. RESULTS: Mean volume of the right maxillary sinus was 17.794 cm3, while for the left one it was 17.713 cm3. Nasal septal deviation was found in 79.9% of computed tomography examinations and concha bullosa was observed in 42.1% of the patients' examinations. There was an association between the presence of unilateral or dominant concha bullosa and contralateral direction of septal deviation [right-sided (p=0.039), left-sided (p=0.003)]. There was higher incidence of bilateral maxillary sinusitis in patients with septal deviation (p=0.007). Bilateral concha bullosa did not influence the incidence of bilateral maxillary sinusitis (p=0.495). Neither septal deviation (right sided: p=0.962; left-sided: p=0.731), nor unilateral/dominant concha bullosa (right: p=0.512; left: p=0,430) affected the asymmetry in volumes of maxillary sinuses. Bilateral concha bullosa was connected with larger volume of maxillary sinuses (right sinus: p=0.005; left sinus: p=0.048). CONCLUSIONS: Nasal septal deviation, contrary to concha bullosa, has influence on the development of maxillary sinusitis. There is a connection between the presence of concha bullosa and direction of septal deviation. Only bilateral concha bullosa affects maxillary sinus volumes. PMID- 28348653 TI - Magnetic Resonance Imaging (MRI) Depiction of Robert's Uterus: A Rare Mullerian Duct Anomaly Presenting with Cyclical Pain in Young Menstruating Woman. AB - BACKGROUND: Robert's uterus is a very rare mullerian duct anomaly which is characterised by septate uterus with obstruction of a one-sided cavity and formation of hematometra. Therefore, patients present with cyclical abdominal pain during menstruation along with normal menstrual flow. CASE REPORT: We present magnetic resonance imaging (MRI) findings in a case of Robert's uterus in a young woman. CONCLUSIONS: Robert's uterus is a very rare anomaly which can be very well characterized by magnetic resonance imaging (MRI). MRI can also show any associated hematometra and endometriomas complicating this condition and aid in the institution of appropriate management in such cases. PMID- 28348654 TI - Underutilization of Implantable Cardioverter Defibrillator in Primary Prevention of Sudden Cardiac Arrest. AB - BACKGROUND: The aim of this study was to evaluate the overall use of implantable cardioverter defibrillators (ICD) for primary prevention of sudden cardiac arrest (SCA), among eligible patients from an outpatient cardiology clinic and to determine what factors might contribute to underutilization of ICDs. METHODS: This report was a retrospective chart review of patients with ischemic or non ischemic cardiomyopathy and left ventricular ejection fraction <= 35% from an outpatient cardiology practice from January 2005 to May 2008. These patients met the eligibility criteria for ICD implantation for primary prevention of SCA. A detailed review of medical records captured distribution of ICD implantation including future plans for ICD implant, patient preference against ICD use, presence of severe co-morbidities, and any other documented reasons/contraindications regarding ICD implantation. RESULTS: Of the 275 patients who were eligible for ICD for primary prevention of SCA, 119 (43%) had an ICD implantation. ICDs were used in 84 (48%) eligible men and 35 (35%) eligible women (P 0.02). Among 156 (57%) patients who did not receive ICD, 79 (28%) had severe co-morbidities precluding them from having ICD. Twenty-six patients (10%) refused to have ICD implanted. The remaining 51 (19%) patient charts did not include any documentation regarding ICD use (future plan or contraindication). CONCLUSIONS: ICDs are underutilized for primary prevention of SCA, with rates of use being lowest among eligible women. This underutilization exists even after accounting for patient preferences and presence of severe co morbid conditions that might make an otherwise eligible patient not a suitable candidate for ICD implantation. PMID- 28348655 TI - Closure of Interatrial Septal Communications: Adverse Events and Lessons Learned. AB - BACKGROUND: Percutaneous closure of interatrial septal communications (IASC) is generally being regarded as a safe and straightforward intervention. Reporting and classification of adverse events (AE) as is the case for percutaneous coronary intervention (PCI) is not standardized. Also, the focus of reported larger studies has not been primarily on AE and strategies to avoid them. METHODS: The data of all 112 consecutive patients undergoing IASC by a single operator were reviewed. In analogy to classification for PCI, an AE was considered to be major if any of the following occurred: death, major or minor stroke, myocardial infarction, the need for an originally unplanned additional surgery or intervention or blood transfusion. Every AE and how it may have been avoided is reviewed in detail. RESULTS: Major AE according to the suggested classification occurred in 2.7% of patients, including tamponade in 1 patient necessitating thoracotomy 7 months after IASC, percutaneous retrieval of an embolized device in 1 patient, and ambulatory same day surgical treatment of an arteriovenous fistula in 1 patient. CONCLUSIONS: The proposed new classification of AE provides a unified and comparable approach for IASC procedures. Retrospectively, two of the 3 major AE could have probably been avoided by more thoughtful patient and material selection. PMID- 28348656 TI - Mitral Annular Systolic Velocities Predict Left Ventricular Wall Motion Abnormality During Dobutamine Stress Echocardiography. AB - BACKGROUND: Longitudinal systolic left ventricular contraction is complementary to the radial performance and can be assessed using tissue Doppler imaging (TDI). This study was performed to evaluate the contribution of mitral annular systolic velocities using TDI after dobutamine stress echocardiography (DSE). METHODS AND RESULTS: Fifty subjects with suspected coronary artery disease and chest pain were examined, using DSE as usual, as well as TDI imaging of the mitral annulus at the septal, lateral, inferior, anterior, posterior regions and the proximal anteroseptal region from the apical views, before and immediately after DSE. In 24 subjects the study was normal, while wall motion abnormality was seen in 26, 9 of them only after DSE. Mitral annular systolic velocity at the 6 locations increased significantly after DSE both in normal subjects and in those with wall motion abnormality (WMA). After DSE mitral annular septal systolic velocity in normals, 19.2 +/- 3.8 cm/sec, was higher than in those with WMA, 14.6 +/- 2.5 cm/sec, P < 0.0003. Post-DSE mitral systolic velocity was senstive and accurate in predicting WMA. CONCLUSIONS: Systolic mitral TDI velocities increase after DSE, however to a lesser extent in those with wall motion abnormality, and can differentiate them from normal subjects. PMID- 28348657 TI - Ultra-Sensitive C-Reactive Protein (US-CRP) in Patients With Periodontal Disease and Risk of Acute Myocardial Infarction. AB - BACKGROUND: The purpose of this study was to determine if the US-CRP values associated with periodontal disease are risk markers for Acute Myocardial Infarction (AMI) and to determine if the US-CRP levels associated with recent AMI are higher in patients with Periodontal disease. METHODS: In order to meet the goal of the study, a case control study design was conducted. The analysis sample consisted of 401 adults (30 - 75 years old), living in Bogota D.C., Colombia, from the Hospital Universitario San Ignacio, the Faculty of Dentistry at the Pontificia Universidad Javeriana, and the Fundacion Cardio Infantil. Patients with current infections, antibiotic use in the last 3 months, periodontal treatment at least six months before the baseline of this study, mouth ulcerations caused by any type of prosthesis, candidiasis, stomatitis, or less than 7 teeth in mouth were excluded. Periodontal examination for the case group and the control group was conducted by three previously calibrated examiners. Periodontal disease was diagnosed by the presence of bleeding on probing and attachment loss. The Chronic Periodontitis diagnosis was confirmed with these clinical signs, according to the 1999 Armitage classification. The assessment of the US-CRP was performed using the IMMULITE method containing one monoclonal and one polyclonal anti-CRP antibody. This method provides a measurement range of 0.1 - 500 mg/L. Statistical analysis of variables was performed with OR and confidence intervals. A multivariate analysis was performed to determine the association between the US-CRP increase, periodontal disease and acute myocardial infarction, adjusting for smoking and other confounding factors identified in the analysis. RESULTS: The study population was constituted by 401 patients, 56.1% (225) males, with a mean age of 52.6. When groups were compared it was observed that, in those patients with AMI and chronic severe or moderate periodontitis, 24.2% had HDL-C values lower than 40 mg/dl, 78.8% had LDL-C values higher than 100 mg/dl, 55.2% had triglycerides over 150 mg/dl, and US-CRP over 2 mg/L in 53.3%. CONCLUSIONS: Periodontal disease (moderate, severe, and chronic periodontal disease) may increase the risk of Acute Myocardial Infarction (AMI) by increasing the US-CRP levels. PMID- 28348658 TI - Application of Mitral Annular Systolic Displacements and Velocities for the Evaluation of Left Ventricular Systolic Function and Reserve. AB - BACKGROUND: Mitral annular systolic displacement from M-mode echocardiography and velocity from tissue Doppler imaging reflect subendocardial longitudinal systolic LV performance and may precede radial abnormalities. The aim of this study is to evaluate the utility of mitral annular systolic displacement (D) and velocity (V) during dobutamine stress echocardiography (DSE) in detecting left ventricular (LV) functional reserve and wall motion abnormality (WMA). METHODS AND RESULTS: Fifty-nine subjects, 15 with resting WMA, underwent DSE and measurement of mitral systolic (D) and (V) before and immediately after DSE. Annular septal (D) was lower in those with WMA than in those without, at rest 10.5 +/- 4 cm versus 13.2 +/- 2 cm, p = 0.015, and after DSE, 11.7 +/- 3.8 cm versus 14 +/- 2.25 cm, p = 0.036, but without significant change after stress. Annular systolic (V) at rest with WMA was 9.7 +/- 1.8 cm/sec and similar to those without, 11.25 +/- 2.7 cm/sec. In both groups the velocity increased after DSE, 14.5 +/- 4.5 cm/sec, p = 0.025 with WMA and 17.8 +/- 3.2 cm/sec, p = 1.99 x 10-10 in those without WMA. Velocities after DSE were lower in those with WMA, p = 2.25 x 10-6. CONCLUSIONS: To evaluate LV systolic performance mitral annular systolic longitudinal displacement is valuable at rest, but for assessment of LV functional reserve after stress velocities are better. PMID- 28348659 TI - Acute ST Elevation Myocardial Infarction in Patients With Immune Thrombocytopenia Purpura: A Case Report. AB - Acute myocardial infarction (AMI) in patients with immune thrombocytopenic purpura (ITP) is rare. We describe a case of AMI in patient with ITP. An 81-year old woman presented with acute inferoposterior MI with low platelet count on admission (34,000/ul). Coronary angiography revealed significant mid right coronary artery (RCA) stenosis with thrombus, subsequently underwent successful percutaneous coronary intervention (PCI). In some patients with immune thrombocytopenia purpura and acute myocardial infarction, percutaneous coronary intervention is a therapeutic option. PMID- 28348660 TI - The Electrocardiogram of an ER Patient With Chest Pain. AB - The electrocardiogram (ECG) is an essential investigation in the evaluation of chest pain in the emergency room (ER). Correct interpretation of the ECG findings, determines the diagnosis and management strategy. This ECG spot diagnosis will improve the skills of the residents and physicians working in ER. PMID- 28348661 TI - Right Ventricle Failure in Sepsis: A Case Report. AB - Sepsis could produce myocardial depression and typically it affects the left ventricle (LV). Sepsis could also affect right ventricle (RV), in addition to the interdependence with LV. RV pressure may be elevated secondary to pulmonary vasoconstriction, leading to RV dysfunction. Unlike LV, RV is poorly prepared to compensate for acute overload. Aggressive volume replacement may be vital to maintain RV function, but excess hydration can cause RV dilation, decreased LV diastolic filling, and reduced cardiac output. In patients having signs of inadequate cardiac output even after initial volume resuscitation, RV function should be assessed with echocardiogram. If RV dysfunction is noted, then fluid therapy should be guided by CVP measurements. If cardiac output increases with increasing CVP, maintaining higher filling pressures on the right side is indicated. On the other hand, increasing CVP with worsening of the cardiac output could worsen the RV dysfunction. In addition to the fluid management, treatment of other reversible causes like acidosis and hypoxia is also a key. PMID- 28348662 TI - Use of Bioimpedance to Assess Changes in Hemodynamics During Acute Administration of CPAP. AB - BACKGROUND: Attempts to investigate the mechanisms by which continuous positive airway pressure (CPAP) therapy improves heart function in patients with obstructive sleep apnea (OSA) have been limited by the lack of non-invasive methods to assess cardiac performance. We used transthoracic electrical bioimpedance (TEB) to assess acute hemodynamic changes including heart rate (HR), stroke volume (SV), cardiac output (CO) and cardiac index (CI) during PAP titration in (1) post-operative cardiac surgery patients, (2) patients with severe OSA, and (3) normal healthy volunteers. METHODS: Post-operative cardiac surgery patients were studied via TEB and pulmonary artery catheter (PAC) during acute titration of positive end-expiratory pressure (PEEP) while mechanically ventilated. Patients with severe OSA were studied non-invasively by TEB during acute CPAP titration in supine stage 2 sleep, and normal subjects while awake and recumbent. RESULTS: In post-operative cardiac surgery patients (n = 3), increasing PEEP to 18 cmH2O significantly reduced SV and CI relative to baseline. There was no difference between TEB and PAC in terms of ability to assess variations in hemodynamic parameters. In patients with severe OSA (n = 3), CPAP titration to optimal pressure to alleviate obstructive apneas reduced HR, SV, CO and CI significantly compared to without CPAP. In three healthy subjects, maximal tolerated CPAP reduced SV and CO significantly compared to baseline. CONCLUSIONS: Acute administration of CPAP causes a decrease in CO and CI, apparently a consequence of a reduction in SV. TEB appears to be an accurate and reproducible non-invasive method of detecting changes in hemodynamics. PMID- 28348663 TI - The Acute Impact of Smoking One Cigarette on Cardiac Hemodynamic Parameters. AB - BACKGROUND: The acute impact of tobacco smoking on the cardiac hemodynamic parameters and its pathological implication in the process of arterial atherosclerosis need further exploration. This investigation was purposed to assess the acute impact of tobacco smoke on blood pressure and cardiac hemodynamic parameters. METHODS: Using an Ultrasonic Cardiac Output Monitor, and DINAMAP Pro 400 Series V2 blood pressure monitor, several cardiac hemodynamic parameters and the blood pressure were assessed in 14 smokers, 11 females and 3 males, at 2 time points, before and after smoking of one cigarette. Data, in terms of ratio of the means and 95% confidence interval were analyzed using ANOVA. RESULTS: Single-subject design in which the subject has served as his/her own control has been used. Tobacco smoking led to statistically significant acute increase in the means of all hemodynamic parameters, except for heart rate in female subjects, as compared to the means obtained before smoking. CONCLUSIONS: Cigarette smoking induces acute non-physiologic alteration in cardiac outflow forces, exposing the aortic valve and arch to mechanical injury that might be implicated in initiating and promoting the process of aortic arch atherosclerosis and associated pathological lesions. PMID- 28348664 TI - Upper Digestive Bleeding in Atrial Fibrillation: Evaluation of Gastroscopy Prior to Oral Anticoagulant Therapy (GOAT), Prospective, Randomized, Double Blind Study on a Community Population. AB - BACKGROUND: The aim of this study was to investigate the incidence of digestive hemorrhages in patients with non-valvular atrial fibrillation (NVAF), scheduled for oral anticoagulant therapy. METHODS: We conducted, over 24 months, a prospective, randomized, population-based observational study on consecutive patients with recurrent paroxysmal, persistent, or permanent NVAF, scheduled for oral anticoagulant therapy. The study initially included 268 patients with NVAF (162 males and 106 females) with a mean age of 74 years (range 42-86 years). Patients were split into two groups: those undergoing preventive Esophago-Gastro Duodenoscopy (EGD) (Group A) and those who did not (Group B). All patients positive by EGD underwent medical treatment and subsequent 30-day endoscopic controls showed complete healing. The primary outcome of the study was to determine if previous EGD in patients with NVAF resulted in a low risk of bleeding during oral anticoagulant therapy. The two groups were comparable for most variables. RESULTS: Significant differences were found between groups for the incidence of antiarrhythmic drugs and for early hemorrhage (P <0.001). The incidences of early hemorrhages were significantly different between the two groups with 12 in group B (12%) and 2 in group A (1.7%). CONCLUSIONS: Preventive EGD can identify hidden digestive diseases, which may increase the incidence of early hemorrhages. PMID- 28348665 TI - Alteration of Time Intervals in Patients With Hypertrophic Cardiomyopathy During an Exercise Echocardiography. AB - BACKGROUND: Hypertrophic cardiomyopathy (HCM) is often associated with diastolic dysfunction. Theoretically, a more marked alteration of diastolic function is revealed during exercise. METHODS AND RESULTS: We studied 84 persons: 1) 25 patients with HCM, 2) 25 patients with essential arterial hypertension (AH) and 3) 34 healthy controls. Each person performed a treadmill echocardiography. Before and after work, the following parameters were measured: the time interval between the QRS complex and the onset of mitral early diastolic filling velocity (TE), the interval between the QRS complex and the onset of peak early tissue mitral annular velocity (Te'), the isovolumetric relaxation time over the difference of TE and Te' ratio (IVRT/(TE-Te')), and changes of the time parameters during the stress test. In comparison with hypertensive and control groups, HCM patients at rest showed a significantly longer TE (448 +/- 55 vs. 423 +/- 33 vs. 417 +/- 24 ms, P < 0.04) and Te' (446 +/- 48 vs. 403 +/- 44 vs. 416 +/ 38 ms, P < 0.003). After stress the HCM group had a longer Te' (355 +/- 59 vs. 299 +/- 40 vs. 292 +/- 30 ms, P < 0.000004) and a higher IVRT/(TE-Te') ratio (3.1 +/- 1.5 vs. 0.9 +/- 2.4 vs. 1.7 +/- 1.2, P < 0.002). CONCLUSIONS: HCM patients show an alteration in the time parameters not only compared to healthy persons but to hypertensive patients as well. PMID- 28348666 TI - Does the Cardiologist Have a Key Role in Long-Term Management of Hypertension? AB - BACKGROUND: Hypertension is a widespread chronic condition which is usually treated with hypertensive drugs. However, 50% of hypertensive patients do not achieve control of their blood pressure below the standard target of 140/90 mmHg when treated with a single antihypertensive drug. Generally, hypertension specialists have a key role in managing hypertensive patients. METHODS: A retrospective case note review based on observations made in a cardiological outpatient clinic in Germany was carried out to assess whether the recommendation given by hypertension specialists were followed. The aim was to lower the blood pressure to < 130/85 mmHg over a period of six months by administering the new antihypertensive drug Zaneril(r) (lercanidipine/enalapril). Twenty-four hour blood pressure profiles were monitored a fortnight and six months later. RESULTS: Of the 130 patients, whose average blood pressure was 163/87 mmHg before receiving hypertensive treatment, only 44 (34%) were still on Zaneril(r) therapy six months later. Eighty-four patients (65%) did not turn up for follow-up examinations. The blood pressure of patients who were under Zaneril(r) therapy for the whole six months was better adjusted than that of patients who changed their treatment in the meantime (133/78 mmHg vs. 139/80 mmHg). CONCLUSIONS: Specialists have only little influence on the long-term therapy of hypertensive patients. PMID- 28348667 TI - Takotsubo Cardiomyopathy: A Cardiac Syndrome Mimicking Acute Myocardial Infarction in a Liver Transplant Recipient. AB - Takotsubo cardiomyopathy (TTC) is a rare clinical syndrome defined as a profound but reversible left ventricular dysfunction in the absence of coronary artery disease. We describe the clinical features and management of TC manifesting in the postoperative period in a patient undergoing liver transplantation. Two days after surgery, the patient developed clinical features of acute myocardial infarction. Ecochardiography revealed hypokinesis of the left ventricle. Coronary angiography revealed normal arteries without any stenosis or obstruction. The patient required vasopressor and inotropic support. The placement of intra-aortic balloon pump had a beneficial effect on the management of heart failure. The patient had a complete recovery of cardiac function 40 days after surgery. TC is a possible occurrence after liver transplant. Awareness of this condition is essential as early diagnosis and prompt management can save the patient's life. PMID- 28348668 TI - Prolonged Respiratory Failure Following Acute Myocardial Infarction: A Case Report. AB - We have recently treated a case of acute anterior wall myocardial infarction who developed prolonged respiratory failure. The clinical details and possible mechanism are discussed. PMID- 28348669 TI - Transesophageal Echocardiographic Diagnosis and Management of Circumflex Artery Injury Following Mitral Valve Repair. AB - A 16-year-old woman with severe mitral regurgitation as a result of rheumatic heart disease underwent mitral valve repair with posterior mitral annuloplasty. ST elevation was observed in leads II, III and aVF after weaning from cardiopulmonary bypass. On transesophageal echocardiography, the stenosis of the circumflex artery was suggested by a modified midesophageal long axis. Since the patient was hemodynamically unstable, an emergency coronary angiography could not be considered. An urgent cardiopulmonary bypass was re-instituted; the first two sutures in the P1 region of the posterior mitral annulus were translocated more superficially. Transesophageal echocardiography revealed good opening of the circumflex artery and improvement in regional wall motion abnormality following the corrected procedure. PMID- 28348670 TI - Incidental Finding of Cor Triatriatum Sinister in an Asymptomatic Woman With Ankylosing Spondylitis. AB - We present a 24-year-old woman with symptoms of backache, acute peripheral arthritis, joint swelling, and erythema, diagnosed with ankylosing spondylitis (AS) and determined to have cor triatriatum sinister (CTS) without cardiac symptoms. On physical examination, the patient had a rythmic S1 with a loud pulmonic component to her S2 and a grade 2/6 systolic murmur along the left sternal edge. Pulmonary examination was normal. Also her left knee and left metacarpophalangeal joints were swollen. Chest radiography revealed a slight prominence of the pulmonary arteries. Her echocardiogram showed a normal left ventricle and that the left atrium was divided into 2 distinct chambers by a membranous septum. In the left atrium, a moderately obstructive fibromuscular membrane was imaged, resulting in a transmembrane mean pressure gradient of 6 mm Hg. Pulmonary artery pressure was increased (peak systolic pulmonary pressure: 44 mm Hg). There was also mild mitral regurgitation and the atrial septum was intact. Cardiac MRI demonstrated CTS. Cardiovascular involvement is a common finding in patients with AS. Thus, careful cardiac evaluation appears to be mandatory in all cases of AS. Our case may be interesting in that to the best of our knowledge, AS with CTS has not been previously reported. Also a patient with CTS who has no cardiac symptoms is a very rare occurrence in the literature. PMID- 28348671 TI - Basic Concepts in Metastatic Cardiac Disease. AB - The involvement of the heart in metastatic cancer is a rare clinical diagnosis, as it may be asymptomatic or symptoms, when present, may be attributed to other causes. Issues regarding incidence, intracardiac location, clinical presentation, diagnosis and treatment of metastatic cardiac tumors will be discussed here. PMID- 28348672 TI - Percutaneous Closure of the Left Atrial Appendage in Atrial Fibrillation, Second Thoughts? AB - Life expectancy of the population is steadily increasing world wide. Consequently, the incidence and ultimately the prevalence of atrial fibrillation (AF) and it's sequelae will be rising proportionately. It is estimated that 3-5% of persons above 65 years of age have chronic AF, 30% of which will suffer at least one stroke. On the other hand, chronic AF is responsible for about 20% of all cerebrovascular accidents. Predictors of stroke in AF have been defined by the CHADS2 score, and in these patients, oral anticoagulation has been the cornerstone of thromboembolic disease prevention. Because elderly patients have an increased risk of bleeding complications even under the newer antagonists of Factor Xa and direct Thrombin inhibitors, percutaneous occlusion of the left atrial appendage (LAA) as the main thrombogenic source offers an attractive alternative to permanent anticoagulation. This promising new therapeutic approach is put into clinical real world perspective. PMID- 28348673 TI - Treating Refractory Cardiogenic Shock With the TandemHeart and Impella Devices: A Single Center Experience. AB - BACKGROUND: Patients with cardiogenic shock (CS) are routinely treated with intra aortic balloon pumps (IABPs). The utility of 2 new percutaneous left ventricular assist devices (PLVADs), the Impella and TandemHeart, is unknown. The objective of this study was to describe the use of PLVADs for patients with CS at our institution. METHODS: All cases involving PLVADs in patients with CS between between January 1, 2008 and June 30, 2010 at a private, tertiary referral hospital were reviewed retrospectively. RESULTS: All 76 cases were identified (50 IABP only, 7 Impella, 19 TandemHeart). Most Impella (5/7) and TandemHeart (10/19) patients were initially treated with an IABP before "upgrading" for increased hemodynamic support. All 76 devices (100%) were initiated successfully. Percutaneous revascularization was attempted in 63 patients with angiographic success in 57 (90%). The incidences of major complications were similar between groups, except bleeding occurred less frequently with the IABP. Mean ejection fraction on presentation was 30.4+/-16.5% and increased by a mean of 6.6+/-11.4% (P < 0.001). With the institutional approach of treating patients with CS initially with vasopressors and IABPs, then upgrading to an Impella or TandemHeart device for patients refractory to IABP therapy, the overall mortality rate was 40%. CONCLUSION: The Impella and TandemHeart devices can be initiated successfully in patients with CS, are associated with high rates of angiographic success during high risk percutaneous interventions and may benefit the myocardium during myocardial infarction. Randomized trials are warranted investigating use of the Impella and TandemHeart devices in patients with CS and in patients refractory to conventional IABP therapy. PMID- 28348674 TI - Clopidogrel Therapy Discontinuation Following Drug Eluting Stent Implantation in Real World Practice in Israel. AB - BACKGROUND: Incidence and predictors of clopidogrel discontinuation after drug eluting stent (DES) implantation, in real world practice, are poorly known. METHODS: Prospective study included all patients who underwent implantation of at least one DES between February 2006 and January 2007. Predictors of clopidogrel discontinuation were assessed by a multivariable analysis. RESULTS: In 269 patients, mean period for clopidogrel therapy was 13.2 +/- 7.2 month. Twenty eight patients (10.4%) discontinued clolopidogrel prematurely (< 3 months). Early clopidogrel discontinuation was a predictor of late stent thrombosis (P = 0.005) and urgent target vessel revascularization (P = 0.05). There was a trend for higher cardiac mortality among that group (P = 0.07). By 12 months, 173 patients (64.3%) have discontinued clopidogrel therapy. The most frequent circumstance to stop clopidogrel before 12 months was recommendation of family physician. Patients that were followed by cardiologist were more encouraged to longer clopidogrel therapy. In multivariable analysis being non Jew (OR 19.2, 95% CI 2.4 to 142, P = 0.005), not followed by cardiologist (OR 4.7, 95% CI 1 to 23.1, P = 0.05) and lack of information regarding the importance of clopidogrel maintenance at discharge from hospital (OR 10.8, 95% CI 2.7 to 42.9, P = 0.001) were independent predictors of early clopidogrel discontinuation. CONCLUSIONS: Clopidogrel discontinuation, in real world practice is not unusual and related to poor outcome. Education for general physicians, clear instructions about the importance of antiplatelet maintenance at discharge and follow up by an expert cardiologist are opportunities to improve adherence do antiplatelet therapy following DES implantation. PMID- 28348675 TI - Quality Assessment in Dobutamine Stress Echocardiography: What are the Clinical Predictors Associated With a Non-Diagnostic Test? AB - BACKGROUND: Non-diagnostic dobutamine stress echocardiography (ndDSE, failure to achieve 85% of maximal predicted heart rate (HR) without evidence of inducible ischemia) is an important limitation affecting quality of DSE testing. The objectives of this study were to identify the clinical variables associated with a non-diagnostic Dobutamine Stress Echocardiogram (ndDSE) and further evaluate the patterns of subsequent testing for myocardial ischemia. METHODS: Consecutive DSE's over a 17 month period (January 2008 to June 2009) were studied. Baseline demographics, medical history, and vital signs were collected. Subsequent testing was determined for up to 6 months after the initial DSE. Univariate and multivariate logistic regression analysis was performed to identify clinical factors associated with ndDSE. RESULTS: Of 467 total DSE, 314 (67%) were negative for ischemia, 69 (15%) were positive, and 84 (18%) were ndDSE. Of those recommended for further nuclear MPI testing 12 (14%) had an ndDSE compared to 16 (4%) patients with a diagnostic DSE (P = 0.001). Fifty percent of the ndDSE nuclear MPI tests were positive for ischemia. In the univariate analysis, Diabetes Mellitus (DM; P = 0.003), calcium channel antagonist (CCA) use (P = 0.047), Hypertension (HTN; P = 0.06), low baseline HR (P < 0.001), and younger age group (P = 0.02) were predictive of ndDSE. Of these, all except CCA use remained independent predictors of ndDSE in multivariate analysis. A 4 variable model for predicting ndDSE was developed from the multivariate logistic regression displayed in Table 1 (age and baseline HR were categorized and scored 0-2; DM and HTN were scored as 0 (absent) or 1 (present)). Figure 2 demonstrates how risk of ndDSE correlated with a higher score, with each increment having an odds ratio of 2.1 (P < 0.001). CONCLUSIONS: DM, HTN, younger age, and lower baseline HR affect the quality of DSE testing, resulting in non-diagnostic tests. A model combining these factors can identify patients most likely to have this outcome. Identification of this cohort may improve referral patterns and improve the quality of stress testing. PMID- 28348676 TI - The Effects of Lowering Uric Acid Levels Using Allopurinol on Components of Metabolic Syndrome. AB - BACKGROUND: Researchers have reported an independent direct relationship between lipid levels and hyperuricemia with MetS. The purpose of this study was to determine the relationship between serum uric acid levels and lipids among patients on allopurinol. METHODS: A retrospective secondary data analysis was conducted on 66 adult patients from a family health clinic in Central Texas. Medical records used were recorded during a nine year period (2002 - 2010) ascertaining the relationship between uric acid and lipids. RESULTS: Spearman correlations revealed a weak correlation between uric acid and total cholesterol, a weak correlation between uric acid and triglycerides and LDL-C. A weak inverse correlation was discovered between uric acid and HDL-C. A moderate correlation was discovered when all lipid variables combined were compared to uric acid. CONCLUSIONS: We discovered LDL-C and triglycerides to be significant predictors of uric acid with weak correlations. Additionally, weak correlations existed between uric acid and total cholesterol and HDL-C with an inverse relationship discovered with HDL-C. These findings support the literature suggesting that uric acid is more likely to be associated with total cholesterol and triglycerides. In addition, new discoveries serve as an indication that LDL-C may also be associated with uric acids levels. The mechanism by which uric acid may regulate lipids is elusive but suggestions have included suppression of lipid peroxidase and decreases in critical lipase activity. PMID- 28348677 TI - Smoking was a Possible Negative Predictor of Incident Hypertension After a Five Year Follow-up Among a General Japanese Population. AB - BACKGROUNDS: The association between cigarette smoking and hypertension is controversial. The aim of this study is to investigate the association between smoking and incident hypertension. METHODS: This is a post-hoc five-year follow up study in a general Japanese population. Logistic regressions were performed using incident hypertension as an outcome and smoking status as an independent predictor adjusting for sex, age, body mass index (BMI), total cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides, fasting plasma glucose (FPG), drinking status, and diabetes in 1,297 subjects without hypertension at baseline. RESULTS: The incidence of hypertension was 16.9% vs. 27.6% (smokers vs. nonsmokers, P = 0.01) in men and 0.0% vs. 16.9% (smokers vs. nonsmokers, P = 0.03) in women. The odds ratio (OR) (95% confidence interval (CI)) of incident hypertension was 0.38 (0.19 - 0.76) (P = 0.006) for smokers at baseline, 0.33 (0.16 - 0.68) (P = 0.003) for continuing smokers, and 2.11 (0.33 - 13.45) (P = 0.4) for ex-smokers. Age (OR = 1.52, P < 0.0001), BMI (OR = 1.46, P < 0.0001), and FPG (OR = 1.23, P = 0.007) were other independent predictors of incident hypertension. CONCLUSIONS: Smoking was a possible significant negative predictor of incident hypertension in a general Japanese population. PMID- 28348678 TI - A Type A Aortic Dissection Mimicking an Acute Myocardial Infarction. AB - We describe a case of a 54 years old man in whom an initial diagnosis of acute coronary syndrome (ACS) revealed to be finally an acute aortic dissection. This case report stresses the importance to maintain a high grade of suspicion of aortic dissection as a possible alternative in presence of eletrocardiographic myocardial ischemic signs. In many medical centers where thrombolitic therapy, antiplatelets receptor blockers, heparin or percutaneous coronary angioplasty is the first line therapy for ACS the outcome may be catastrophic in situation such as aortic dissection. PMID- 28348679 TI - Aliskiren in Patients Failing to Achieve Blood Pressure Targets With Angiotensin Converting Enzyme Inhibitors or Angiotensin Receptor Blockers. AB - BACKGROUND: To assess the efficacy of aliskiren in patients failing to reach blood pressure (BP) goals with angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). METHODS: A total of 107 patients who failed to reach BP goals on ACEI or ARB were switched to aliskiren. Changes in BP were determined during maximal ACEI, ARB, or aliskiren therapy. RESULTS: Mean reduction in sBP and dBP with ACEI was 8.5 +/- 6.3 mmHg and 6.0 +/- 4.7 mmHg, respectively. Mean reduction in sBP and dBP with ARB was 8.3 +/- 6.7 mmHg and 5.0 +/- 5.2 mmHg, respectively. Mean reduction in sBP and dBP with aliskiren 150 mg/d was 6.7 +/- 5.4 mmHg and 5.4 +/- 4.8 mmHg, respectively. Mean reduction in sBP and dBP with aliskiren 300 mg/d was 8.6 +/- 6.3 mmHg and 6.0 +/- 4.9 mmHg, respectively. BP reductions between ACEI, ARB, and aliskiren were not significantly different. CONCLUSIONS: Aliskiren is ineffective in patients failing ACEI or ARB therapy. Given the label changes restricting the use of aliskiren in combination with ACEI and ARB, excess cost compared to ACEI and ARB, and a paucity of outcome data, there is a limited role for aliskiren in practice. PMID- 28348680 TI - The Duration of Impella 2.5 Circulatory Support and Length of Hospital Stay of Patients Undergoing High-risk Percutaneous Coronary Interventions. AB - BACKGROUND: To evaluate the impact of duration of Impella 2.5 support (Abiomed, Danvers, MA) on hospitalization of patients after high-risk percutaneous coronary intervention (PCI). There has been a continuous increase in prevalence of coronary artery disease with more patients needing PCI during acute myocardial infarction. Some of these patients have to undergo high-risk revascularization with circulatory support like the Impella 2.5 device. METHODS: This study was a single center retrospective study of patients admitted to our hospital who required Impella circulatory support during percutaneous coronary intervention. Patients' medical records, cardiac catheterization laboratory and 2-D echocardiography reports were reviewed to ascertain left ventricular ejection fraction, duration of Impella support, Coronary Care Unit (CCU) days and the length of stay in the hospital. A P-value of <= 0.05 was considered statistically significant. RESULTS: Over a 15-month period, we had 25 patients with 19 males and 6 females. Mean age of the patient cohort was 68 +/- 10 years. Mean LVEF of the group was 32 +/- 16%. Mean length of hospital stay was 8 +/- 8 days and mean CCU stay was 4 +/- 4 days. The Impella was successfully inserted in all cases with a median duration of support of 70 minutes (range, 4 - 5760 minutes). Bleeding complication occurred in 8%. Spearman's rank correlation coefficient between the duration of Impella support and hospital stay was 0.49 (P = 0.023) while it was 0.71 (P = 0.001) between Impella support duration and CCU days. CONCLUSIONS: Our study suggests that there is a positive correlation between the duration of Impella 2.5 circulatory support and hospital stay and/or CCU days. The correlation seems to be stronger with CCU days. PMID- 28348681 TI - Adjunctive Pharmacotherapy for Elective Direct Current Cardioversion in Patients With Atrial Fibrillation. AB - BACKGROUND: Direct current cardioversion (DCCV) can restore sinus rhythm in patients with atrial fibrillation (AF), but the long term efficacy is poor. Pharmacological therapies may improve the initial success of the procedure, but whether long term maintenance of sinus rhythm can be improved is unclear. The aim of this study was to evaluate which pharmacotherapies, including antiarrhythmic and renin-angiotensin-aldosterone system (RAAS) inhibiting drugs, most successfully promotes sinus rhythm after elective DCCV in unselected patients with atrial fibrillation. METHODS: A retrospective cohort was to study of AF patients attending or DCCV between Jan 2010 and Feb 2012. The data were analysed using multivariate logistical regression models. Initial success of DCCV was the dependent variable in the first analysis. Maintenance of sinus rhythm at follow up was the dependent variable in the second analysis. RESULTS: One hundred and thirty patients were included in the first analysis, and 71 patients were included in the second analysis. The only association observed was a positive association between flecainide and an increased odds of maintaining sinus rhythm at follow up (OR 2.14, SE +/- 0.93, P = 0.02) .Other antiarrhythmic drugs and RAAS inhibiting drugs had no association with an increased odds of successful DCCV or maintenance of sinus rhythm thereafter. CONCLUSIONS: This is the first study to demonstrate an association between flecainide and a increased odds of maintaining sinus rhythm after DCCV in the long term. This warrants further research, and should be taken into account when choosing adjunctive antiarrhythmic therapy for elective DCCV for AF. PMID- 28348682 TI - Depressed Exercise Peak Ejection Rate Detected on Ambulatory Radionuclide Monitoring Reflects End-Stage Cardiac Inotropic Reserve and Predicts Mortality in Ischaemic Cardiomyopathy. AB - BACKGROUND: Fifteen patients with ischaemic cardiomyopathy and inducible ischaemia were studied to determine the mechanisms of mortality. Failure of the contractile reserve during daily life activities may reflect a prognostic index. METHODS: Single photon emission cardiac tomography and radionuclide ambulatory monitoring (Vest) data were analysed in all patients with a 7-year follow-up. RESULTS: At peak exercise on Vest, the 7 non-survivors (N-SURV) showed worse peak ejection rates (PERs) and ejection fractions (EFs) compared with the 8 survivors (SURV), (2 +/- 0.6 vs. 3.3 +/- 0.7; end-diastolic volumes (EDVs), P < 0.003), and (34 +/- 10% vs. 50 +/- 13%; P < 0.02), respectively. However, exercise peak filling rates (PFRs) (1.9 +/- 0.6 vs. 2.7 +/- 0.9; EDVs/s) and exercise heart rates (HRs), (97 +/- 17 vs. 106 +/- 10), did not differ between the two groups (P > 0.05). In SURV, exercise PERs, which represented rapid left ventricular (LV) emptying, were significantly correlated with exercise PFRs, representing rapid LV filling, (r = 0.71, P < 0.04) but not in N-SURV (r = 0.66, P > 0.05). Among SURV, the Frank-Starling mechanism was thus preserved but not in N-SURV. Upon Cox analysis, overall LV function parameters, exercise PER was the only predictive measure associated with mortality (b = - 0.018, relative hazard ratio = 0.98, P = 0.02). CONCLUSIONS: Exercise PER reduced values reflected failure of the Frank Starling mechanism, the incapacity of the heart to perform rapid contractile adaptations to daily life activities and a poor prognosis. PMID- 28348684 TI - Endothelial Function and Carotid Intimal Medial Thickness in Asymptomatic Subjects With and Without Cardiovascular Risk Factors. AB - BACKGROUND: The study was performed to assess endothelial function and carotid intimal-medial thickness (IMT) in asymptomatic patients, with and without risk factors for cardiovascular disease. METHODS: A cross sectional survey of asymptomatic patients, aged 21 - 60 years, with and without risk factors for cardiovascular disease was recruited from the outpatient department of Cardiology. Endothelial function was evaluated by flow mediated dilatation (FMD) of the brachial artery and carotid IMT was determined using a high resolution B mode ultrasonography system. RESULTS: A total of 104 patients were included in the study. The mean carotid IMT was 0.67 +/- 0.05 mm in the group without risk factors and 0.78 +/- 0.12 mm in the group with risk factors (P value < 0.05). Endothelial dysfunction (ED) and increased carotid IMT were more significant in the group with risk factors (P value < 0.001). Age, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, blood pressure, body mass index and HbA1c had a significant correlation with both IMT and FMD response. A higher proportion of subjects with diabetes mellitus (87%), metabolic syndrome (86%) and family history of premature coronary artery disease (78%) had ED. In subjects with normal coronary angiogram, 71% had abnormal FMD response and 36% had increased carotid IMT. CONCLUSION: In asymptomatic subjects, risk factors for cardiovascular disease are significantly associated with objective evidence of ED and increased carotid IMT. FMD response and carotid IMT values are likely to yield additional information beyond traditional risk factors for classifying patients in regard to the likelihood of cardiovascular event. Therapeutic measures with the aim of improving endothelial function and reducing carotid IMT may reduce the burden of cardiovascular disease. PMID- 28348683 TI - Assessment of Cardiovascular Risk Factors Among University Students: The Gender Factor. AB - BACKGROUND: Evidence indicates that the pathophysiological process of cardiovascular (CV) disease begins at early age, though the manifestations of the disease do not appear until middle age adulthood. Risk factors for CV disease, particularly lipoprotein profiles, are affected by physiological abnormalities, and lifestyle related issues. To evaluate prevalence of CV diseases risk factors among university students and to investigate relation between number of risk factors and body anthropometric, hematological and biochemical indices parameters. METHODS: In this cross sectional study, 348 students were randomly recruited. Blood glucose, cholesterol profile (total, HDL, and LDL cholesterol), and triglyceride were measured using standard protocols. Physical activity (PA) level was assessed using the short-form Arabic version of the International Physical Activity Questionnaires (IPAQ). RESULTS: The most commonly encountered CV disease risk factor was low levels of HDL-C, followed by physical inactivity, high levels TG, and obese BMI. When stratified by gender, females were less likely to have low HDL-C, and high TG, whereas, males were more likely to have overweight or obese BMI (P < 0.001). About 49% of the participants had at least one CV disease risk factor, where as the prevalence of having one, two and three or more CV disease risk factors were 35.7%, 9.3% and 4%, respectively. Additionally, the number of CV disease risk factors showed strong positive correlation with increases in body fat and bone percentages, glucose, total cholesterol, TG, LDL-C, BMI, and WHR (range of R2: 0.17 to 0.603). On the other hand, physical activity, percentages of body water and muscle, HDL-C showed inverse strong correlation with cardiovascular risk factors (range of R2: -0.239 to -0.412). CONCLUSIONS: Results indicate the high prevalence of CV disease risk factors among university students, and stress the need for early intervention programs to counteract these risks. PMID- 28348685 TI - Incidental Finding of Malpositioned Pacing Lead in the Left Ventricle in a Patient With Subacute Subdural Hematoma. AB - Malposition of the right ventricular lead into the left ventricle is an unusual complication of challenging management. We report a case of an elderly woman with a dual chamber permanent pacemaker implanted 2 months before admission because of high grade AV block, who presented to our institution with sub acute subdural hematoma along the left fronto-parietal area. Incidental ventricular pacemaker lead in the left ventricle was found on chest CT scan. The patient was not candidate for anticoagulation due to her recent subdural hematoma, hence a discussion about the risks of explantation of the pacemaker lead led to patient's lead extraction without any complication. PMID- 28348686 TI - Recent Toxoplasmosis Infection With Acute Myopericarditis and Persistent Troponin Elevation in an Immunocompetent Patient. AB - Although often considered as "begnin", acute infections in young healthy adults can lead to heart inflammation, including acute myocarditis. We report a rare case of myopericarditis in a young immunocompetent adult, in the context of recent toxoplasmosis infection. Clinical presentation was common acute pericarditis, but with risk biomarkers: high troponin I levels and multiple inflammation-compatible images on MR-scan. Diagnosis of myopericarditis was established. In spite of spontaneous favourable clinical evolution, troponin remained elevated. MR-scan is shown; acute myocarditis in the context of an acute toxoplasmosis infection is discussed. PMID- 28348688 TI - Seasonal Variations in Hospital Admissions for ST-Elevation Myocardial Infarction in New Zealand. AB - BACKGROUND: Increased numbers of ST Elevation Myocardial Infarction (STEMI) admissions have been observed during winter in many countries. Our aim was to assess if seasonal variation of STEMI was present in the Waikato region of New Zealand. METHODS: Case notes of patients admitted to Waikato hospital with STEMI between July 1998 and December 2007 were analysed. The incidence of STEMI during summer (December to February), autumn (March to May), winter (June to August) and spring (September to November) were calculated. The individuals were divided into 2 age groups of <= 70 and > 70 years of age. RESULTS: A total of 3,569 patients (mean age 66.9 +/- 14.1 years, 64% men) were included. STEMI presentation during winter was significantly higher compared with summer (35 +/- 13 versus 27.3 +/- 11.3 cases per month, P < 0.02) with 3 additional STEMI admissions per fortnight during winter months. The increase in STEMI in winter was more apparent in patients > 70 years of age, with an 8.5% increase in winter admissions compared to summer (P < 0.01). There was no significant difference in the incidence of STEMI between other seasons. CONCLUSION: There is a higher incidence of STEMI during winter in the Waikato region compared with summer. This increased incidence is particularly pronounced in patients over 70 years of age. Further investigations are necessary to elicit potential causes. PMID- 28348687 TI - Age- and Gender-Normalized Coronary Incidence and Mortality Risks in Primary and Secondary Prevention. AB - Epidemiologic differences in ischemic heart disease incidence between women and men remain largely unexplained. The reasons of women's "protection" against coronary artery disease (CAD) are not still clear. However, there are subsets more likely to die of a first myocardial infarction. The purpose of this review is to underline different treatment strategies between genders and describe the role of classical and novel factors defined to evaluate CAD risk and mortality, aimed at assessing applicability and relevance for primary and secondary prevention. Women and men present different age-related risk patterns: it should be important to understand whether standard factors may index CAD risk, including mortality, in different ways and/or whether specific factors might be targeted gender-wise. Take home messages include: HDL-cholesterol levels, higher in pre menopausal women than in men, are more strictly related to CAD. The same is true for high triglycerides and Lp(a). HDL-cholesterol levels are inversely related to incidence and mortality. In primary prevention the role of statins is not completely ascertained in women although in secondary prevention these agents are equally effective in both genders. Weight and glycemic control are effective to reduce cardiovascular disease (CVD) mortality in women from middle to older age. Blood pressure is strongly and directly related to CVD mortality, from middle to older age, particularly in diabetic and over weighted women. Kidney dysfunction, defined using UAE and eGFR predicts primary CVD incidence and risk in both genders. In secondary prediction, kidney dysfunction predicts sudden death in women in conjunction with left ventricular ejection fraction evaluation. Serum uric acid does not differentiate gender-related CVD incidences, although it increases with age. Age-related differences between genders have been related to loss of ovarian function traditionally and to lower iron stores more recently. QT interval, physiologically longer in women than men, may be an index of arrhythmic risk in patients with mitral valve prolapse and increased circulating levels of catecholamines. However, there are no large population-based studies to assess this. In conjunction with novel parameters, such as inflammatory markers and reproductive hormones, classical risk score in women may be implemented in the future. PMID- 28348689 TI - Clopidogrel Within Few Hours of Coronary Artery Bypass Grafting Does Significantly Increase the Risk of Bleeding. AB - BACKGROUND: Postoperative bleeding after coronary artery surgery is partly related to platelet dysfunction. The aim of this study was to evaluate the effects of a single loading dose of clopidogrel (300 mg) before coronary angiography on bleeding and use of blood and blood products after emergency coronary artery bypass surgery (CABG). METHODS: This is a nonrandomized observational prospective study between January, 2006 till December 2009, at a university hospital, we compare the results of a cohort of 65 patients who received 300 mg clopidogrel during coronary angiography that was followed by emergency CABG (group A or study group) to a cohort of 206 patients who underwent elective coronary artery bypass surgery during the same period by the same surgeons in whom clopidogrel was stopped 7 days before surgery (Group B or control group). Emergency surgery was done because of critical coronary anatomy or because of ongoing chest pain. All patients in the two groups were kept on 100 mg of aspirin until the day of surgery. Outcome data used to compare the two groups, Chest tube drainage in first 12 hours (12 h), need for re-exploration and use of blood and blood product transfusion were prospectively collected. RESULTS: Postoperative bleeding, reoperation rates for bleeding and use of blood products are significantly more in those who received a loading dose of clopedogril within few hours of CABG (group A) compared to those who stopped clopedogril for a week before CABG. CONCLUSIONS: Preoperative 300 mg of clopidogrel is associated with significant increase in post operative bleeding, need for surgical exploration and use of blood and blood product transfusion after CABG. PMID- 28348690 TI - Relationship Between Brachial Artery Flow-Mediated Dilation, Carotid Artery Intima-Media Thickness and Coronary Flow Reserve in Patients With Coronary Artery Disease. AB - BACKGROUND: The aim of this study was to assess the relationship between brachial artery flow mediated dilation (FMD), carotid artery intima-media thickness (IMT) and coronary flow reserve (CFR) in patients with coronary artery disease (CAD). METHODS: Fifty patients with coronary artery disease, except left anterior descending artery (LAD), who showed no cardiac symptoms and 45 control subjects underwent assessment of brachial artery FMD, carotid artery intima-media thickness by high-resolution ultrasound. In addition, transthoracic second harmonic Doppler echocardiography was used to measure CFR. RESULTS: All of the parameters were found to be correlated with each other. CFR correlated with brachial artery FMD (r = 0.232, P < 0.05) and with carotid IMT (r = -0.403, P < 0.001). Carotid IMT correlated with brachial artery FMD (r = -0.211, P < 0.05). CONCLUSION: Transthoracic CFR correlated with well-established noninvasive predictors of atherosclerosis and we suggest that it can be used as a surrogate for coronary atherosclerosis. PMID- 28348691 TI - Association Between High Serum Matrix Metalloproteinase-9 and MMP-9 (-1562C>T) Polymorphism in Patients With ST-Elevation Acute Myocardial Infarction. AB - BACKGROUND: Matrix metalloproteinase (MMP)-9 is excessively expressed in frail region of atherosclerotic plaque and released in circulation following plaque rupture. High MMP-9 level associated with severity of occluded thrombus and subsequent myocardial infarction. MMP-9 (-1562C>T) polymorphism associated with acute myocardial infarction, however conflicting data present regarding impact of MMP-9 (-1562C>T) polymorphism on circulating MMP-9 level in acute myocardial infarction with ST-elevation (STEMI), clinical entity represents totally occluded coronary thrombus. METHODS: We enrolled consecutively subjects with acute coronary syndrome treated in intensive coronary care unit. Acute coronary syndrome diagnosis were classified into STEMI and non-ST-elevation acute coronary syndrome (NSTEACS). Seventy consecutive subjects were enrolled for this study, 31 subjects with STEMI and 39 subjects with NSTEACS. RESULTS: On admission serum MMP 9 level, measured with sandwich enzyme immunoassay, were higher in STEMI as compared with NSTEACS (1,574.2 +/- 604.1 ng/mL vs. 1,104.4 +/- 591.5 ng/mL, P < 0.01). Proportion of subjects with MMP-9 (-1562C>T) polymorphism, analyzed with PCR-RFLP, were higher in STEMI as compared with NSTEACS (66.7% vs. 33.3%, P = 0.15). T allele frequency was almost twice in STEMI as compared to in NSTEACS. Almost all (83%) subjects with MMP-9 (-1562C>T) polymorphism had high serum MMP-9 level (> 1,334.5 ng/mL) during STEMI, whereas in NSTEACS all subjects had low level. CONCLUSION: MMP-9 (-1562C>T) polymorphism associated with high serum MMP-9 level in patients with STEMI. PMID- 28348692 TI - Externalized Conductor Cables in QuickSite Left Ventricular Pacing Lead and Riata Right Ventricular Lead in a Single Patient: A Common Problem With Silicone Insulation. AB - QuickSite (St Jude Medical, Sylmar, CA, USA) is a silicone and polyurethane insulated coronary sinus pacing lead. Riata lead (St Jude Medical, Sylmar, CA, USA) is a silicone insulated right ventricular shock lead. Recently, insulation breach of silicone based leads raised a huge concern. Fluoroscopic examination of these two leads in the same patient revealed externalization of these two leads. Same mechanism producing insulation breach of Riata lead may be involved in externalization of QuickSite LV lead as distal part of insulation is also made of silicone. PMID- 28348693 TI - A Case of Acute Myocardial Infarction due to Left Main Trunk Occlusion Complicated With Aortic Dissection as Diagnosed by Intravascular Ultrasound. AB - A 52-year-old man was transferred to our hospital with a sudden onset of severe chest pains. His electrocardiogram revealed ST-segment elevation suggestive of acute myocardial infarction. Emergency coronary angiography showed subtotal occlusion of left main trunk (LMT) with delayed coronary flow. Because intravascular ultrasound revealed a large intimal flap, we diagnosed aortic dissection involving the LMT. After stenting of the LMT, the patient underwent surgical repair of the aortic dissection. Although it is difficult to obtain a correct diagnosis of aortic dissection complicated with myocardial ischemia, we succeeded in diagnosing this rare condition by use of a intravascular ultrasound. PMID- 28348694 TI - Severe Hypokalemia Masquerading Myocardial Ischemia. AB - An advanced degree of body potassium deficit may produce striking changes in the electrocardiogram (ECG). These changes can result in incidental findings on the 12-lead ECG or precipitate potentially life-threatening dysrhythmias. Although usually readily recognized, at times these abnormalities may be confused with myocardial ischemia. The object was to report a case of severe hypokalemia mimicking myocardial ischemia. A 33-year-old, previously healthy man, presented to the Emergency Department (ED) with a progressive weakness and chest discomfort. The electrocardiogram showed a marked ST-segment depression in leads II, III, aVF, V1-V6. The initial diagnosis was non ST-elevation myocardial infarction. Echocardiography was normal and troponin levels were within normal limits. A more detailed history revealed that the patient had an episode of acute gastroenteritis with diarrhea and vomiting. Serum chemistries were notable for a potassium concentration of 1,8 mmol per liter. With aggressive electrolyte correction, the ECG abnormalities reverted as potassium levels normalized. Hypokalemia induced ST-segment depression may simulate myocardial ischemia. The differential diagnosis might be difficult, especially in the cases when ST changes are accompanied with chest discomfort. PMID- 28348695 TI - Complete Atrioventricular Block Presenting With Syncope Caused by Severe Hypothyroidism. AB - A 75-year-old man was admitted to our hospital with syncope. Electrocardiogram showed complete atrioventricular block and bradycardia with the minimum heart rate of 22 beats/ min. There was a possible indication for temporary cardiac pacemaker implantation. Laboratory data on admission revealed high TSH level with low free T4 level. To rule out functional atrioventricular block, we treated several days with thyroxine. A follow-up electrocardiogram showed improved heart rate without any atrioventricular block. We found that severe hypothyroidism caused a complete atrioventricular block with syncope, and thyroxine replacement completely improved these conditions. PMID- 28348697 TI - Carotid Artery Stenting 2013: Thumbs up. AB - It has been customary for interventional cardiologists involved in carotid artery stenting, to underline non-inferiority of the percutaneous technique versus surgical carotid endarterectomy. To that end, all cause morbidity and mortality figures of both methods are compared. Surgery has, in most large randomized studies, had an edge over stenting in terms of cerebrovascular adverse events. This may have partly been due to occasional indiscriminate indication for stenting in lesions and/or vessels with unfavourable characteristics (severe target vessel tortuosity and calcification, Type III aortic arch, and so on). On one hand, the author pleads for improvement of the excellent results of endarterectomy, by subjecting all patients planned for surgery to a thorough preoperative cardiological work up, including generous invasive investigation, thus reducing the incidence of perioperative myocardial infarction, heart failure and cardiac death. On the other hand, we are convinced that the results of carotid stenting should then be compared to best practice surgery. The rate of neurological adverse event rate after carotid endarterectomy at our institution lies under 0.7% at 30 days postoperatively. Specifically, the goal should be that carotid stenting underbids surgical endarterectomy, also and mainly, in terms of cerebral and cerebrovascular adverse events. Cardiac morbidity and mortality as well as laryngeal nerve palsy should no more be the main arguments for the percutaneous approach. This should easily be possible if patient selection for carotid revascularisation would be approached according to morphological criteria, in analogy with the "Syntax"-score used to optimise revascularisation strategies in coronary artery disease. PMID- 28348696 TI - Is There Still a Role for Glycoprotein IIb/IIIa Antagonists in Acute Coronary Syndromes? AB - The role played by glycoprotein (GP) IIb/IIIa inhibitors has continuously evolved from the initial introduction in mid 90 s until the most recent guidelines for treating acute coronary syndromes, and competed with a wider use of ADP inhibitors and novel anticoagulant drugs, to the extent that they stepped down from class I to class II recommendation in the routine setting of acute coronary syndromes. As a consequence, GP IIb/IIIa use was greatly narrowed. The purpose of this review is to define the roles that GP IIb/IIIa inhibitors may still have in acute ischemic settings by explaining why in high risk patients they might be preferable and/or whether they might be added to ADP inhibitors also emphasizing the underlying mechanistic actions. It is concluded that there might be a more extensive use of GP IIb/IIIa inhibitors in patients presenting with acute coronary syndromes, strictly based on the definition for a high risk procedure: complexity, angiographic characteristics and patient's risk profile, regardless whether STEMI or NSTEMI. The positive elements one should appreciate in GP IIb/IIIa inhibitors are: efficacy, rapid onset and reversibility of action, absence of pharmacogenomic variability, pharmacoeconomic considerations and the possibility of intracoronary administration. PMID- 28348698 TI - Using Novel Technology to Determine Mobility Among Hospitalized Heart Failure Patients: A Pilot Study. AB - BACKGROUND: Patients with heart failure (HF) experience frequent rehospitalizations and poor functional capacity. Early hospital mobility may prevent functional decline, but mobility patterns among hospitalized HF patients are not yet known. Accelerometers may provide a method to monitor and measure patient mobility objectively. Therefore, the purpose of this study was to describe mobility and function using accelerometers among hospitalized HF patients. METHODS: Wireless accelerometers were attached to the thigh and ankle of previously ambulatory hospitalized HF patients (n = 32) continuously for up to 5 days, beginning on the second day of hospitalization. The mean proportion of time spent lying, sitting, and standing or walking daily was measured. Ability to perform activities of daily living (ADLs) and physical function was measured using the Katz Index and Short Physical Performance Battery (SPPB). RESULTS: Patients' mean age was 58.2 +/- 13.6 and 78% (n = 25) were male. Mean New York Heart Association Class upon enrollment and at the end of the study period was 2.9 +/- 0.8 and 2.2 +/- 0.8 respectively. A mean Katz Index of 5.6 +/- 1.1 upon enrollment demonstrated minimal dependence on assistance for completion of ADLs (possible scores 0 - 6). However, mobility testing revealed low physical function, with mean SPPB scores of 6.4 +/- 3.1 (possible scores 0 - 12). During hospitalization, 70% of the measured hospital stay (16.8 hours/day) was spent lying in bed. The average time spent standing or walking was 4.1%, or 59 minutes per day and the range was 0-10% (0 - 150 minutes). CONCLUSIONS: Immobility was pervasive as HF patients spent almost all of their time sitting or lying in bed despite their baseline ambulatory status and improved NYHA class. PMID- 28348699 TI - Diastolic Function Evaluations by Tissue Doppler Imaging in Patients With Mitral Valve Prolapse. AB - BACKGROUND: Tissue Doppler imaging (TDI) is a new echocardiographic imaging technique that is believed to be superior to older conventional techniques in assessing abnormalities of cardiac function in many conditions affecting the heart. There are very limited data regarding the role of TDI in evaluating patients with mitral valve prolapse (MVP). Current study evaluates diastolic function in patients with MVP by this method. METHODS: From November 2009 to April 2011, one hundred and ten adults matched for age and sex and without structural heart disease were studied in two groups, with and without MVP, at Madani Heart Center, Tabriz, Iran. TDI was performed at the basal-lateral wall and S, E, E', A, and A' velocities, as well as the E/A and E'/A' ratios were measured. Mitral annular systolic velocity and early diastolic (E') velocities were measured lateral corner of mitral valve in apical 4-chamber view. RESULTS: Patients with MVP had higher left atrium volume (42.31 +/- 10.47 vs. 35.19 +/- 9.15 cm3; P < 0.001) and deceleration time (186.70 +/- 26.00 vs. 176.89 +/- 20.36 ms; P = 0.03). Diastolic dysfunction, although seemed more prevalent in MVP group (14.54%) than normal subjects (5.45%), the difference was not statistically significant between groups (P = 0.11). CONCLUSION: Left atrial volume and deceleration time of mitral valve inflow was significantly higher in MVP which could be indicative of early stages of diastolic dysfunction in patients with MVP. However, larger follow-up studies are required to evaluate clinical significance of our findings in these patients. PMID- 28348700 TI - Left Ventricle Hypertrophy, Dilatation and Ejection Fraction Changes Before and After Kidney Transplantation. AB - BACKGROUND: Patients with end stage renal disease (ESRD) are at risk of complications in different organs including cardiovascular system. Renal transplantation is the best choice in these patients which diminishes these complications. It is observed that after renal transplantation, cardiac parameters have appropriate improvement. Current study evaluates echocardiographic findings in renal transplant recipients before and after kidney transplantation. METHODS: In an analytic cross sectional study, 30 patients (50% male, mean age of 45.57 +/- 13.32 years) with ESRD who underwent renal transplantation were studied. All patients had echocardiographic studies after the last dialysis before and 6 months after transplantation. Echocardiographic study was done by Color Doppler two dimension methods and left ventricle ejection fraction was measured by Simpson method. All echocardiograms before and after transplantation were interpreted by the same cardiologist. RESULTS: Mean left ventricle ejection fraction before and after renal transplantation was 53.83+/ 10.14% and 57.33+/-4.49%, respectively (P = 0.09). Left ventricle hypertrophy, mitral regurgitation and tricuspid regurgitation existed in 46.7%, 76.7% and 33.3% respectively, which was improved in 30%, 50% and 33.3% after renal transplantation. CONCLUSION: According to the results of current study it is suggested that renal transplantation could improve left ventricle parameters in patients with end stage renal disease. PMID- 28348702 TI - Atrial Septal Defect in a Very Old Woman. AB - Atrial Septal Defect (ASD) is one of the most frequently congenital heart diseases in adults and it is often asymptomatic until adulthood. We report a case of a 90-year-old woman admitted to hospital with dyspnea and orthopnea insidiously progressing over the preceding 5 years and becoming severe with dyspnea on minimal activities, orthopnea and paroxysmal nocturnal dyspnea, in the last 2 weeks. The transthoracic echocardiogram revealed an atrial septal defect ostium secundum type, with left-to-right shunt, moderate to severe tricuspid insufficiency, severe pulmonary hypertension (72 mmHg) and preserved biventricular function. With diuretic therapy optimization the patient showed symptomatic improvement. This present case represents and unusual and very late presentation of an atrial septal defect ostium secundum type, which is usually diagnosed at the mild adult age. Our patient lived symptom-free for over 80 years. PMID- 28348701 TI - Potential for Infra-Nodal Heart Block and Cardiogenic Shock With Propofol Administration. AB - We report a case of infra-nodal complete heart block and cardiogenic shock in a previously healthy 64-year-old man after administration of 180 mg of intravenous Propofol. Although bradycardia, hypotension, and heart block are commonly seen with propofol administration, such findings are transient and respond quickly to administration of vagolytic or sympathomimetic agents suggesting an AV nodal mechanism of heart block. Sustained left ventricular systolic dysfunction and cardiogenic shock by an alternative, non-autonomic mechanism has also been described in the setting of Propofol administration. Our case is the first to note sustained complete infra-nodal heart block in this setting. Early recognition of such a complication, restoration of atrio-ventricular (A-V) synchrony with dual chamber pacing, and aggressive circulatory support is essential in bridging such patients to recovery. PMID- 28348703 TI - Telomeres and Estrogens: The Unholy Nexus in Pathogenesis of Atherosclerosis. AB - Atherosclerosis (AS) is a complex inflammatory process and is categorized as a multifactorial disease involving the interplay of genetic and environmental factors. There are many factors which play role in predisposition and development of AS. In this review we have tried to address the basic pathophysiology of AS lesions and the role played by two important factors - telomeres and estrogens in the development of this disease. PMID- 28348704 TI - A Culturally Appropriate Educational Intervention Can Improve Self-Care in Hispanic Patients With Heart Failure: A Pilot Randomized Controlled Trial. AB - BACKGROUND: Hispanics constitute the largest US ethnic group and have been shown to have more frequent heart failure (HF) hospitalizations than non-Hispanic whites. Disease management programs can reduce HF hospitalizations and mortality by increasing patient self-care, but most programs are limited to patients who speak English. Therefore, we hypothesize that Project Fluido, a culturally appropriate self-care education intervention, will improve self-care behaviors and knowledge in Hispanic patients with HF compared with usual care (UC). METHODS: Project Fluido (N = 42) was a randomized controlled pilot trial over 3 months. Patients in the experimental group (n = 22) received individualized education in Spanish using the "teach-back" method on the following: high salt foods, when to call the physician, when to report weight gain and the use of diuretics. They also received a nurse-initiated phone call every 2 weeks, a script for calling their physician with increased symptoms, a weight scale and a daily diary to complete. The UC group (n = 20) received a scale and written information. Self-care was measured using the self-care heart failure index and knowledge using teach-back scores. Four knowledge topics were included when using teach-back. RESULTS: Participants' mean age was 57 +/- 14 years, 57% (24) were male, 64% (27) had hypertension, 86% (36) were New York Heart Association Class I III and 65% (26) had HF with reduced ejection fraction. Participant health literacy scores showed poor health literacy in 31% (n = 13) and 67% (n = 28) spoke Spanish only. Household income was reported as < $20,000 in 93% (n = 39). Self-care and knowledge scores significantly improved (P < 0.04 and P < 0.02, respectively) in the intervention group compared to UC. CONCLUSION: The intervention utilized in Project Fluido was a remarkably effective method to improve self-care and HF knowledge in a group of Spanish-speaking HF patients. This improvement is in spite of low physical function, health literacy, acculturation and economic challenges. In addition, teach-back was an effective teaching strategy to improve HF knowledge. Future work is needed to investigate the relationship between increased self-care knowledge, readmissions, and mortality in Spanish-speaking patients with HF. PMID- 28348705 TI - Evaluation of a New Shirt-Based Electrocardiogram Device for Cardiac Screening in Soccer Players: Comparative Study With Treadmill Ergospirometry. AB - BACKGROUND: Prevention of cardiac events during competitive sports is fundamental. New technologies with remote monitoring systems integrated into clothing could facilitate the screening of heart disease. Our aim was to evaluate the feasibility of Nuubo system during a field stress test performed by soccer players, comparing results with treadmill ergospirometry as test reference. METHODS: Nineteen male professional soccer players (19.2 +/- 1.6 years) were studied. Wireless electrocardiographic monitoring during a Yo-Yo intermittent recovery test level 1 in soccer field and subsequent analysis of arrhythmias were firstly performed. Subsequently, in a period no longer than 4 weeks, each player underwent cardiopulmonary exercise testing in hospital. RESULTS: During Yo-Yo test, electrocardiogram (ECG) signal was interpretable in 16 players (84.2%). In the other three players, ECG artifacts did not allow a proper analysis. Estimation of maximum oxygen consumption was comparable between two exercise tests (VO2 max 53.3 +/- 2.4 vs. 53.7 +/- 3.0 mL/kg/min for Yo-Yo test and ergometry respectively; intra-class correlation coefficient 0.84 (0.63 - 0.93), P < 0.001). No arrhythmias were detected in any player during both tests. CONCLUSIONS: The use of Nuubo's technology allows an accurate single-lead electrocardiographic recording and estimation of reliable performance variables during exercise testing in field, and provides a new perspective to cardiac remote monitoring in collective sports. PMID- 28348706 TI - Acute Myocardial Infarction in Patient With Triple Negative Breast Cancer After Paclitaxel Infusion: A Case Report. AB - A 47-year-old woman with breast cancer suffered progressive chest pain and flushing within 5 minutes of her second exposure to paclitaxel. Her symptoms progressed and she became pulseless. Advanced cardiac life support (ACLS) was initiated, and after a series of chest compressions the cardiac monitor revealed ventricular fibrillation. With ongoing ACLS she was transferred to the emergency department where she regained a pulse. Review of electrocardiogram revealed prominent ST elevation in leads V1, V2 and V3 with reciprocal ST depression. She was transferred urgently to the catheterization laboratory. Angiography revealed a high-grade stenosis in the proximal left anterior descending artery (LAD), and drug-eluting stents were placed without complications. She was then transferred to the floor and shortly thereafter suffered pulseless electrical activity and died despite prolonged attempts at resuscitation. Herein, we describe the development of acute myocardial infarction after paclitaxel administration, discuss potential etiologies and review evidence for an allergic component. PMID- 28348707 TI - Paradoxical Thromboembolism/ST-Elevation Myocardial Infarction via a Patent Foramen Ovale in Sub-Massive Pulmonary Embolism Following an Upper Extremity Deep Venous Thrombosis: Is It Time for a Change in the Standard of Care? AB - The objective of this case study is to discuss a rare case of proven paradoxical thromboembolism captured in-transit. A 23-year-old female with a diagnosis of right internal jugular deep vein thrombus who developed acute onset chest pain, dyspnea and hypotension, was selected for the study. Sub-massive PE and STEMI were diagnosed. Transthoracic echocardiogram revealed a left ventricular (LV) mass moving across the aortic valve. Soon after, the patient developed numbness of right extremities with non-palpable pulses. A transesophageal echocardiogram revealed absent LV mass, PFO, left atrial mass entering through the PFO and emboli in bilateral pulmonary arteries. We report a case of sub-massive PE and paradoxical proven coronary and upper extremity embolism, captured in-transit, following destabilization of an UEDVT in a patient with PFO. PMID- 28348708 TI - Myocardial Scar Detection by Standard CT Coronary Angiography. AB - We have described a myocardial infarct scar identified by a standard dual source CT coronary angiography (CTCA). We were able to detect the scar during the routine coronary assessment without contrast late enhancement and without additional radiation exposure. It is therefore feasible to assess chronic scar using a standard CTCA technique. PMID- 28348709 TI - Evolution of Artificial Hearts: An Overview and History. AB - The heart is a muscular organ which pumps blood through blood vessels to different organs of the body. It is the most significant and vital organ in the human body. Without this organ, life is unimaginable. Doctors and scientists have been trying for a long time to create something similar or equivalent to the heart. The purpose is to develop a temporary machine or pump for a person who has a disease of the heart and their survival without transplant is impossible. These temporary devices can provide enough time for the patient until a donor heart is available. The purpose of this review is to provide an overview and history of how man has developed an artificial heart for survival. PMID- 28348711 TI - Takotsubo Cardiomyopathy: Typical and Atypical Variants, A Two-Year Retrospective Cohort Study. AB - BACKGROUND: Typical or classical takotsubo cardiomyopathy (TCM) is associated with the characteristic abnormality of a ballooned left ventricular apex with basal segmental hyperkinesis. TCM may not present with the "classical" wall motion abnormalities but can have a variety of segmental wall motion abnormalities. The aim of our work was to assess for any unique identifying factors that can help distinguish typical and atypical variants of TCM. METHODS: We studied 11 consecutive patients between 2010 and 2012 admitted with chest pain, electrocardiographic and cardiac biomarker changes consistent with acute coronary syndrome (ACS) who underwent left heart angiography and were clinically diagnosed to have TCM. RESULTS: Our study found no specific features distinguishing typical and atypical variants of TCM. In our study, all patients were female and all had excellent outcome. One patient was in fourth decade of life, three patients in fifth and sixth decade of life, while remaining were older. One patient had diabetes mellitus, five had hypertension, four had concurrent coronary artery disease, but no patient had any family history of TCM. Nine of 11 patients had immediate clear-cut stressors. Three patients had normal ECG, two with ST segment elevation, with nine patients having only modest troponin elevations. One patient had an anomalous RCA take-off from the right coronary cusp, otherwise remaining patients had normal anatomy. One patient had only apical involvement, remaining had multiple wall motion abnormalities, and all patients had involvement of the anterior wall. Four patients had apical sparing. No inverted TCM pattern with basal akinesis with normal wall motion in the midventricular and apical regions was found among our patients. CONCLUSIONS: We report that the classification of TCM as typical versus atypical is probably not clinically meaningful. The regional wall motion abnormalities are related to catecholamine excess and to the susceptibility of that particular region to excess catecholamine. We do not know why such differences in regional susceptibility exist, and agree with the other authors that sub-classification would only add to confusion, and a delay in understanding of the disease process. PMID- 28348710 TI - Reducing Heart Failure Hospital Readmissions: A Systematic Review of Disease Management Programs. AB - The recent enactment of the Patient Protection and Affordable Care Act which established the federal Hospital Readmissions Reduction Program (HRRP) has accelerated efforts to develop heart failure (HF) disease management programs (DMPs) that reduce readmissions in patients hospitalized for HF. This systematic review identified randomized controlled trials of HF DMPs which included home care, outpatient clinic interventions, structured telephone support, and non invasive and invasive telemonitoring. These different types of DMPs have been associated with conflicting results. No specific type of DMP has produced consistent benefit in reducing HF hospitalizations. Although probably effective at reducing readmissions, home visits and outpatient clinic interventions have substantial limitations including cost and accessibility. Telemanagement has the potential to reach a large number of patients at a reasonable cost. Structured telephone support follow-up has been shown to significantly reduce HF readmissions, but does not significantly reduce all-cause mortality or all-cause hospitalization. A meta-analysis of 11 non-invasive telemonitoring studies demonstrated significant reductions in all-cause mortality and HF hospitalizations. Invasive telemonitoring is a potentially effective means of reducing HF hospitalizations, but only one study using pulmonary artery pressure monitoring was able to demonstrate a reduction in HF hospitalizations. Other studies using invasive hemodynamic monitoring have failed to demonstrate changes in rates of readmission or mortality. The efficacy of HF DMPs is associated with inconsistent results. Our review should not be interpreted to indicate that HF DMPs are universally ineffective. Rather, our data suggest that one approach applied to a broad spectrum of different patient types may produce an erratic impact on readmissions and clinical outcomes. HF DMPs should include the flexibility to meet the individualized needs of specific patients. PMID- 28348712 TI - Azelnidipine, Not Amlodipine, Induces Secretion of Vascular Endothelial Growth Factor From Smooth Muscle Cells and Promotes Endothelial Tube Formation. AB - BACKGROUND: We previously reported that the calcium channel blocker (CCB) nifedipine-induced secretion of vascular endothelial growth factor (VEGF) from human coronary smooth muscle cells (HCSMCs) promoted human coronary endothelial cell (HCEC) tube formation. Therefore, we analyzed whether other CCBs, azelnidipine and amlodipine, also induced the secretion of VEGF and promoted HCEC tube formation, and the underlying molecular mechanisms. METHODS: To evaluate the tube formation, HCECs were grown on Matrigel for 18 hours in the supernatants from HCSMCs that had been treated with different kinds of reagents. Concentrations of VEGF in cultured HCSMCs were determined by specific enzyme immunoassays. Nuclear extracts from HCSMCs were prepared, and nuclear factor kappa B (NF-kappaB) activation was measured by EZ-DetectTM Transcription Factor Kits for NF-kappaB p50 or p65. RESULTS: Although azelnidipine dose-dependently stimulated the significant secretion of VEGF from HCSMCs and this stimulation was abolished by a protein kinase C inhibitor, amlodipine-induced secretion of VEGF was significantly lower than that induced by azelnidipine. The medium derived from azelnidipine (at up to 2 MUM)-treated HCSMCs led to HCEC tube formation, whereas that obtained with amlodipine did not. Azelnidipine-induced tube formation was blocked by an inhibitor of kinase insert domain-containing receptor/fetal liver kinase-1 tyrosine kinase. Azelnidipine at up to 2 MUM induced NF-kappaB activation. CONCLUSIONS: Azelnidipine, but not amlodipine, stimulated the secretion of VEGF from HCSMCs and induced HCEC tube formation. This secretion is mediated at least in part via the activation of NF-kappaB. Azelnidipine may have a novel beneficial effect in improving coronary microvascular blood flow in addition to its main effect of lowering blood pressure. PMID- 28348713 TI - The Relationship Between Blood Monocyte Count and Coronary Artery Ectasia. AB - BACKGROUND: The pathophysiology of coronary artery ectasia (CAE) has not been clearly identified, although multiple abnormalities including arteritis, endothelial dysfunction, and atherothrombosis have been reported. It is known that monocytes play an important role in inflammation, atherosclerosis and cardiovascular disease. We aimed to compare the numbers of monocyte counts of the CAE patients versus controls. METHOD: This study included 84 CAE patients (40 male, mean age 55.4 +/- 9.7 years) and 30 controls (10 male, mean age 57.86 +/- 11.6 years). Concurrent routine biochemical tests and neutrophil, lymphocyte, monocyte count and mean platelet volume (MPV) on whole blood count were performed for these participants. These parameters were compared between groups. RESULTS: Baseline characteristics of the study groups were comparable. CAE patients had a higher MPV value and monocyte count than controls (8.8 +/- 0.2 vs. 6.2 +/- 1.6 fL and 732 +/- 88 vs. 321 +/- 75 cell/MUL; both P < 0.001, respectively). CONCLUSION: As a result, our study revealed a relationship between monocyte count and MPV in patients with CAE. PMID- 28348714 TI - A One-Sided Affair: Unoriginal Origin of the Left Coronary Artery, a Case Report. AB - Coronary artery anomalies constitute a group of congenital malformations that have a multitude of clinical manifestations and highly variable pathophysiology. We report a 56-year-old male with angina due to an anomalous origin of the left main coronary artery; approach and management. PMID- 28348715 TI - 3-Methylglutaconyl-Coenzyme-A Hydratase Deficiency and the Development of Dilated Cardiomyopathy. AB - A 25-year-old Canadian male with a history of 3-methylglutaconyl-coenzyme-A hydratase deficiency, also known as 3-methylglutaconic aciduria type I, a very rare inborn error of metabolism, presented with respiratory distress, nausea, vomiting and signs of multisystem organ failure due to a suspected underlying infectious process. An electrocardiogram revealed bilateral atrial enlargement and an elevated brain natriuretic peptide on the initial laboratory studies, which prompted a more thorough cardiac workup. The transthoracic echocardiogram revealed a dilated cardiomyopathy with severe systolic dysfunction. The deficient enzyme present in this patient is involved in the pathway of leucine catabolism and is particularly important in various tissues for energy production and sterol synthesis. The dilated cardiomyopathy in this patient possibly had a variety of potential mechanisms including: a mitochondrial myopathy due to the deficiency of this enzyme leading to a defect in energy production inside cardiac myocytes; or a direct toxicity from 3-methylglutaconic acid (3-MGA) and its toxic metabolites; or a cardiac dysfunction due to a variety of other potential mechanisms. In conclusion, this patient's clinical presentation suggested that 3 methylglutaconyl-CoA hydratase deficiency could cause a severe dilated cardiomyopathy and heart failure. PMID- 28348716 TI - Understanding Protein Structure Deformation on the Surface of Gold Nanoparticles of Varying Size. AB - Gold nanoparticles (AuNPs) have been of recent interest due to their unique optical properties and their biocompatibility. Biomolecules spontaneously adsorb to their surface, a trait that could potentially be exploited for drug targeting. Currently, it is unclear whether protein-AuNP interactions at the nanoparticle surface are dependent on nanoparticle size. In this work, we investigate whether varying surface curvature can induce protein unfolding and multilayer binding in citrate-coated AuNPs of various sizes. A recently developed NMR-based approach was utilized to determine the adsorption capacity, and protein NMR spectra were compared to determine whether nanoparticle size influences protein interactions at the surface. In addition, transmission electron microscopy (TEM) and dynamic light scattering (DLS) were employed to corroborate the NMR studies. Over a broad range of AuNP sizes (14-86 nm), we show that adsorption capacity can be predicted by assuming that proteins are compact and globular on the nanoparticle surface. Additionally, roughly one layer of proteins is adsorbed regardless of AuNP size. Our results hold for two proteins of significantly different sizes, GB3 (6 kDa) and bovine carbonic anhydrase (BCA, 29 kDa). However, the unstable drkN SH3 domain (DeltaG0 ~ 0, 7 kDa) does not appear to follow the same trend seen for stable, globular proteins. This observation suggests that unstable proteins can deform significantly when bound to AuNP surfaces. Taken together, the results of this work can be used to improve our knowledge of the mechanism of protein-AuNP interactions to optimize their use in the biomedical field. PMID- 28348717 TI - Cephalomedullary nail versus sliding hip screw for fixation of AO 31 A1/2 intertrochanteric femoral fracture: a 12-year comparison of failure, complications, and mortality. AB - BACKGROUND: In the United States intertrochanteric and pertrochanteric fractures occur at a rate of more than 150,000 cases annually. Current standard of care for these fractures includes fixation with either a cephalomedullary nail (CMN) or a sliding hip screw (SHS). The purpose of this study was to compare failure and medical complications of intertrochanteric femoral fractures repaired by CMN or SHS. METHODS: This study is a retrospective cohort study that included 249 patients with AO/OTA 31 A1.1-3, 31 A2.1-3 nonpathological fractures of the femur, of which 137 received CMN and 112 received SHS. Analysis was stratified by fracture type as stable (AO 31A1.1-2.1) or unstable (AO 31A2.2-3). RESULTS: The tip-apex distance in stable fractures fixed with CMN was 17.3 +/- 5.9 compared to 26.2 +/- 7.9 in the stable SHS group (p<0.001) while it was 19.0 +/- 5.3 in the unstable CMN group compared to 24.0 +/- 6.7 in the unstable SHS patients (P = 0.004). Among patients with stable fracture patterns there was no difference in collapse, complications, failure, or mortality (all P > 0.05). Among patients with unstable fractures CMN had significantly less collapse (P < 0.001) and failure (P = 0.046) but no difference in complications (P = 0.126) or mortality (P = 0.586). CONCLUSIONS: There were no significant differences in failure or complication rates when comparing the CMN to the SHS in stable intertrochanteric fractures. CMN demonstrated significantly reduced failure and collapse rates in unstable intertrochanteric fractures when compared to SHS; however, this study had a relatively small sample size of unstable fractures and all results must be interpreted within this context. PMID- 28348718 TI - Intramyocardial Injection of Recombinant Adeno-Associated Viral Vector Coexpressing PR39/Adrenomedullin Enhances Angiogenesis and Reduces Apoptosis in a Rat Myocardial Infarction Model. AB - Cotransfer of angiogenic and antiapoptotic genes could be the basis of new gene therapy strategies for myocardial infarction. In this study, rAAV-PR39-ADM, coexpressing antimicrobial peptide (PR39) and adrenomedullin (ADM), was designed with the mediation of recombinant adeno-associated virus. In vitro, CRL-1730 cells were divided into four groups, namely, the sham group, the AAV-null group, the NS (normal saline) group, and the PR39-ADM group. Immunocytochemistry analysis, CCK-8 assays, Matrigel assays, and apoptotic analysis were performed; in vivo, myocardial infarction model was established through ligation of the left coronary artery on rats, and treatment groups corresponded to those used in vitro. Myocardial injury, cardiac performance, and the extent of myocardial apoptosis were assessed. Results suggested that rAAV-PR39-ADM administration after myocardial infarction improved cell viability and cardiac function, attenuated apoptosis and myocardial injury, and promoted angiogenesis. Subsequently, levels of 6*His, HIF-1alpha, VEGF, p-Akt, Akt, ADM, Bcl-2, and Bax were measured by western blot. rAAV-PR39-ADM increased p-Akt, HIF-1alpha, and VEGF levels and induced higher Bcl-2 expression and lower Bax expression. In conclusion, our results demonstrate that rAAV-PR39-ADM mitigates myocardial injury by promoting angiogenesis and reducing apoptosis. This study suggests a potential novel gene therapy-based method that could be used clinically for myocardial infarction. PMID- 28348719 TI - BAG5 Interacts with DJ-1 and Inhibits the Neuroprotective Effects of DJ-1 to Combat Mitochondrial Oxidative Damage. AB - Loss-of-function mutations in gene encoding DJ-1 contribute to the pathogenesis of autosomal recessive early-onset familial forms of Parkinson's disease (PD). DJ 1 is a multifunctional protein and plays a protective role against oxidative stress-induced mitochondrial damage and cell death, but the exact mechanism underlying this is not yet clearly understood. Here, using coimmunoprecipitation (Co-IP) and immunofluorescence methods, we prove that Bcl-2-associated athanogene 5 (BAG5), a BAG family member, interacts with DJ-1 in mammalian cells. Moreover, we show that BAG5 could decrease stability of DJ-1 and weaken its role in mitochondrial protection probably by influencing dimerization in stress condition. Our study reveals the relationship of BAG5 and DJ-1 suggesting a potential role for BAG5 in the pathogenesis of PD through its functional interactions with DJ-1. PMID- 28348720 TI - The OptiMUM-study: EMDR therapy in pregnant women with posttraumatic stress disorder after previous childbirth and pregnant women with fear of childbirth: design of a multicentre randomized controlled trial. AB - Background: Approximately 3% of women develop posttraumatic stress disorder (PTSD) after giving birth, and 7.5% of pregnant women show a pathological fear of childbirth (FoC). FoC or childbirth-related PTSD during (a subsequent) pregnancy can lead to a request for an elective caesarean section as well as adverse obstetrical and neonatal outcomes. For PTSD in general, and several subtypes of specific phobia, eye movement desensitization and reprocessing (EMDR) therapy has been proven effective, but little is known about the effects of applying EMDR during pregnancy. Objective: To describe the protocol of the OptiMUM-study. The main aim of the study is to determine whether EMDR therapy is an effective and safe treatment for pregnant women with childbirth-related PTSD or FoC. In addition, the cost-effectiveness of this approach will be analysed. Method: The single-blind OptiMUM-study consists of two two-armed randomized controlled trials (RCTs) with overlapping design. In several hospitals and community midwifery practices in Amsterdam, the Netherlands, all eligible pregnant women with a gestational age between eight and 20 weeks will be administered the Wijma delivery expectations questionnaire (WDEQ) to asses FoC. Multiparous women will also receive the PTSD checklist for DSM-5 (PCL-5) to screen for possible PTSD. The clinician administered PTSD scale (CAPS-5) will be used for assessing PTSD according to DSM-5 in women scoring above the PCL-5 cut-off value. Fifty women with childbirth-related PTSD and 120 women with FoC will be randomly allocated to either EMDR therapy carried out by a psychologist or care-as-usual. Women currently undergoing psychological treatment or women younger than 18 years will not be included. Primary outcome measures are severity of childbirth-related PTSD or FoC symptoms. Secondary outcomes are percentage of PTSD diagnoses, percentage caesarean sections, subjective childbirth experience, obstetrical and neonatal complications, and health care costs. Results: The results are meant to provide more insight about the safety and possible effectiveness of EMDR therapy during pregnancy for women with PTSD or FoC. Conclusion: This study is the first RCT studying efficacy and safety of EMDR in pregnant women with PTSD after childbirth or Fear of Childbirth. PMID- 28348721 TI - Geographical Disparities in the Health of Iranian Women: Health Outcomes, Behaviors, and Health-care Access Indicators. AB - BACKGROUND: Women's health is a key factor affecting the health of the whole population. Tackling inequality in determinants of health is recognized as the main path toward reducing the inequality in health outcomes. This study aimed to analyze the provincial inequality in determinants of women's health and health care in Iran. METHODS: Using the Moss's model (2002) as a comprehensive framework of determinants of women's health, including "geopolitical environment," "culture, norms, sanctions," "women's roles in reproduction and production," "health-related mediators," and "health outcome" categories, we chose 13 indicators. Afterward, using data sources including the Iranian Multiple Indicators of Demographics and Health Survey, the National Organization for Civil Registration, and Statistics Centre of Iran, we analyzed provincial inequality in these indicators in Iran (2011). Gini coefficient and Lorenz curve were used for measuring inequality. RESULTS: Gini coefficients calculated as follows; life satisfaction level (0.027), literate women (0.398), women with proper knowledge about HIV/AIDS prevention (0.483), unemployed women (0.380), women without an income (0.384), women who use at least one type of mass media (0.389), women who used computer or internet (0.467), women who had received pregnancy care from a skill birth attendant (SBA) (0.420), women who had delivered with the help of an SBA (0.426), women who currently smoke cigarettes (0.603), women who currently consume hookah (0.561), women with at least one chronic disease (0.438), and women's deaths in 2010 and 2011 (0.393 and 0.359, respectively). CONCLUSIONS: We found large provincial disparities in determinants of women's health in Iran. Determinants such as lifestyle, health behavior, health knowledge, and health care services availability should be considered by health policymakers in addressing the inequality in women's health at a provincial level. PMID- 28348722 TI - Prevalence and Risk Factors of Low Birth Weight in the Southeast of Iran. AB - BACKGROUND: The purpose of this study was to determine the prevalence and related factors of low birth weight (LBW) in the Southeast of Iran. METHODS: This cross sectional study was carried out in Kerman province. Data were collected from Iranian Maternal and Neonatal Network at public and private hospitals. All live births from March 2014 to March 2015 considered as the source population. The risk factors including maternal age, gravida, parity, abortion, pregnancy risk factors, maternal nationality, maternal education, maternity insurance, place of living, consanguinity, neonate sex, preterm labor, place of birth, delivery manager, and delivery type were compared between LBW and normal birth weight groups. RESULTS: The prevalence of LBW was 9.4% in the present study. Preterm labor (odds ratio [OR]: 22.06; P < 0.001), neonate female sex (OR: 1.41; P < 0.001), low parity (OR: 0.85; P < 0.001), pregnancy age <18 years (OR: 1.26; P = 0.012), pregnancy age >35 years (OR: 1.21; P = 0.001), delivery by cesarean section (OR: 1.17; P = 0.002), pregnancy risk factors (OR: 1.67; P < 0.001), maternal illiteracy (OR: 1.91; P < 0.001), living in the rural area (OR: 1.19; P < 0.001), consanguineous (OR: 1.08; P = 0.025), and delivery by obstetrician (OR: 1.12; P = 0.029) were identified as significant factors associated with LBW in this study. CONCLUSIONS: Prevention of preterm labor, consanguineous marriage, pregnancy age <18 and >35 years old, and maternal medical risk factors are some critical interventions to reduce its burden. Increasing the access to high quality health-care services in rural and deprived areas is another effective strategy for the prevention of LBW. PMID- 28348723 TI - Nurse Staffing Norm in Iran Hospitals: What Features Should be Included for Success? AB - BACKGROUND: Designing and implementing a model for estimation and distribution of required nurse is one of strategies to prevent unequal distribution of nurses within and between hospitals. The purpose of this research was to determine required features for hospital nursing staff estimation model. METHODS: We conducted a qualitative study using a Colaizzi analysis approach. We used semi structure and in-depth interviews by purposive, quota, and snowball sampling of 32 participants (10 informed experts in area of policy making in human resources in Ministry of Health, 10 decisions making in employment and distribution of human resources in treatment and administrative chancellors of medical universities, and 12 process owners in hospitals). The data were analyzed using ATLAS.ti software version 6.0.15. RESULTS: The ten following sub-themes emerged from data analysis: Skill mix and task shifting, work measurement, legal support, stakeholder involvement in designing a model, considering the ward activity, considering type and extent of care patients required, model development by experts predominate in nursing process, considering the nurses availability, considering the capabilities and professional merits of nurses, fitness with social, cultural, and belief of people. The main themes were occupation analysis, planning and policy making, real workload, acceptability, nurses' efficiency, and being a native. CONCLUSIONS: Given that standardization of nursing staff estimation is announced as one of the challenges in reaching Iran's 20-year vision plan. Hence, design and implementation of a nursing staff estimation model in regard to identified features could be part of priorities in Ministry of Health in Iran. PMID- 28348725 TI - Elimination of Maternal and Neonatal Tetanus in India: A Triumph Tale. PMID- 28348724 TI - The Persian Version of Orebro Musculoskeletal Pain Screening Questionnaire: Translation and Evaluation of its Psychometric Properties. AB - BACKGROUND: Screening of psychosocial risk factors for chronic low back pain (LBP) is essential. The Orebro Musculoskeletal Pain Screening Questionnaire (OMPSQ) is one of the most recognized and widely used instruments for this purpose. This study aimed to translate the OMPSQ into Persian, to adapt it for Iranian culture, and to investigate its psychometric properties. METHODS: Using a linguistic methodology, the OMPSQ was translated into Persian according to the World Health Organization guideline. A total of 106 patients with LBP participated in the study. Internal consistency and test-retest reliability were evaluated. Concurrent validity was estimated with Pearson's correlation between the OMPSQ and short form health survey (SF-12), Hospital Anxiety and Depression Scale (HADS), and visual analog scale (VAS). Factor analysis was used to evaluate dimensionality. RESULTS: The content validity index was 0.80. The instrument had a good test-retest reliability (intraclass correlation coefficient = 0.82) and internal consistency (Cronbach's alpha =0.82). Factor analysis indicates that factorial structure of Persian version was similar to original questionnaire. There was a significant correlation (r = 0.252-0.639, P < 0.01) between VAS score and all the OMPSQ domains. Physical component summary of SF-12 was positively correlated with miscellaneous domain (r = 384, P < 0.05) and negatively correlated with psychology domain of OMPSQ (r = -0.364, P < 0.05). A significant correlation between total score and anxiety component of HADS and psychology domain of OMPSQ was found (r = 0.49, P < 0.01 and r = 0.442, P < 0.05, respectively). Correlations between the OMPSQ and SF-12 and HADS and VAS indicate acceptable concurrent validity. CONCLUSIONS: The Persian version of OMPSQ was as a valid and reliable instrument and also a good cross-cultural equivalent for original English version. PMID- 28348726 TI - Targeting patients with asthma for omalizumab therapy: choosing the right patient to get the best value for money. AB - The asthma syndrome has many manifestations, termed phenotypes, that arise by specific cellular and molecular mechanisms, termed endotypes. Understanding an individual's asthma phenotype helps clinicians make rational therapeutic decisions while the understanding of endotypes has led to the development of specific precision medications. Allergic asthma is an example of an asthma phenotype and omalizumab, a monoclonal antibody that neutralizes serum immunoglobulin (Ig)E, is a specific targeted treatment which was developed as a result of an understanding of the endotype of allergic asthma. Omalizumab has been widely used in clinical practice in Europe for over a decade as an add-on therapy to treat patients who have severe refractory allergic asthma. Over this period, many centres have reported their experience with omalizumab as an add-on therapy in patients with severe asthma. These 'real world' clinical effectiveness studies have confirmed the benefits, cost-effectiveness and clinical utility of this medication. Combining the outcomes of both sources of research has yielded important insights that may benefit patients with severe asthma, clinicians who treat them, as well as the funding agencies that reimburse the cost of this medication. The purpose of this review is to describe how to identify and evaluate a patient with asthma for whom treatment with omalizumab may be of clinical and cost-effective benefit. The assessment and investigations used to confirm allergic asthma, the objective assessment of adherence to asthma therapy and the expected benefits of add-on omalizumab treatment are described. PMID- 28348728 TI - Citrate-based fluorescent materials for low-cost chloride sensing in the diagnosis of Cystic Fibrosis. AB - Chloride is an essential electrolyte that maintains homeostasis within the body, where abnormal chloride levels in biological fluids may indicate various diseases such as Cystic Fibrosis. However, current analytical solutions for chloride detection fail to meet the clinical needs of both high performance and low material or labor costs, hindering translation into clinical settings. Here we present a new class of fluorescence chloride sensors derived from a facile citrate -based synthesis platform that utilize dynamic quenching mechanisms. Based on this low-cost platform, we demonstrate for the first time a selective sensing strategy that uses a single fluorophore to detect multiple halides simultaneously, promising both selectivity and automation to improve performance and reduce labor costs. We also demonstrate the clinical utility of citrate-based sensors as a new sweat chloride test method for the diagnosis of Cystic Fibrosis by performing analytical validation with sweat controls and clinical validation with sweat from individuals with or without Cystic Fibrosis. Lastly, molecular modeling studies reveal the structural mechanism behind chloride sensing, serving to expand this class of fluorescence sensors with improved chloride sensitivities. Thus citrate-based fluorescent materials may enable low-cost, automated multi-analysis systems for simpler, yet accurate, point-of-care diagnostics that can be readily translated into clinical settings. More broadly, a wide range of medical, industrial, and environmental applications can be achieved with such a facile synthesis platform, demonstrated in our citrate-based biodegradable polymers with intrinsic fluorescence sensing. PMID- 28348727 TI - Steps forward in the treatment of pulmonary arterial hypertension: latest developments and clinical opportunities. AB - Pulmonary arterial hypertension (PAH) is a chronic disease that results in narrowing of the small pre-capillary pulmonary arteries leading to elevation of pulmonary artery pressure and pulmonary vascular resistance, subsequent right ventricular failure, and if unchecked, death. Advances in the treatment of PAH over the last two decades have markedly improved survival. These improvements reflect a combination of changes in treatments, improved patient care strategies, and varying disease phenotypes in the PAH population. Currently approved therapies for PAH are directed at the recognized abnormalities within the pulmonary vasculature and include endothelin receptor antagonists, phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators, and prostacyclin pathway agents. Most of these drugs have been approved on the basis of short-term trials that mainly demonstrated improvements in exercise capacity. More recently, long-term, event-driven trials of novel drugs have been performed, demonstrating new efficacy parameters. There have also been exciting advances in the understanding of right heart failure pathophysiology in PAH that have the potential to inspire the development of right ventricular targeted therapy and continued discoveries in the heterogeneity of disease and response to treatment has great potential for developing more 'personalized' therapeutic options. In this article, we review the current available data regarding the management of PAH, with an emphasis on the pharmacologic therapies and discussion of novel therapeutic directions for the treatment of this fatal disease. PMID- 28348729 TI - Copper-Catalyzed Click Reaction on/in Live Cells. AB - We demonstrated that copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction could be performed inside live mammalian cells without using a chelating azide. Under optimized conditions, the reaction was performed in human ovary cancer cell line OVCAR5 in which newly synthesized proteins were metabolically modified with homopropargylglycine (HPG). This model system allowed us to estimate the efficiency of the reaction on the cell membranes and in the cytosol using mass spectrometry. We found that the reaction was greatly promoted by a tris(triazolylmethyl)amine CuI ligand tethering a cell-penetrating peptide. Uptake of the ligand, copper, and a biotin-tagged azide in the cells was determined to be 69 +/- 2, 163 +/- 3 and 1.3 +/- 0.1 uM, respectively. After 10 minutes of reaction, the product yields on the membrane and cytosolic proteins were higher than 18% and 0.8%, respectively, while 75% cells remained viable. By reducing the biothiols in the system by scraping or treatment with N ethylmalemide, the reaction yield on the cytosolic proteins was greatly improved to ~9% and ~14%, respectively, while the yield on the membrane proteins remained unchanged. The results indicate that out of many possibilities, deactivation of the current copper catalysts by biothiols is the major reason for the low yield of CuAAC reaction in the cytosol. Overall, we have improved the efficiency for CuAAC reaction on live cells by 3-fold. Despite the low yielding inside live cells, the products that strongly bind to the intracellular targets can be detected by mass spectrometry. Hence, the in situ CuAAC reaction can be potentially used for screening of cell-specific enzyme inhibitors or biomarkers containing 1,4-substituted 1,2,3-triazoles. PMID- 28348730 TI - Prescribing pattern of clozapine and other antipsychotics for patients with first episode psychosis: a cross-sectional survey of early intervention teams. AB - OBJECTIVE: To describe the pattern of antipsychotic drug prescribing in patients with first episode psychosis, with more emphasis in the use of clozapine in this group of patients. METHOD: A cross-sectional survey involving six early intervention service (EIS) teams in the West Midlands was conducted. Data was extracted from case notes and electronic records by clinicians working in each participating team. The pattern of antipsychotic prescribing and the changes that took place after being accepted in EIS, including the use of clozapine, was established. Clinicians involved in the treatment of patients in each team rated the overall clinical response to treatment based on the presence or absence of positive psychotic symptoms. RESULT: 431 patients with FEP were included in the final analysis. Low antipsychotic discontinuation rate was observed, with the majority (88.2%) still being prescribed antipsychotics. Most (77.3%) were prescribed second-generation antipsychotic drugs, with olanzapine (21.8%) and aripiprazole (19.7%) being the most frequently prescribed antipsychotics. There was low rate use of antipsychotic combinations (7.4%), high dose antipsychotic regime (3.9%), low depot antipsychotic prescribing (9.3%), and clozapine use was low (9.7%). On average, three antipsychotics were tried before clozapine was initiated and it took on average 19.5 months from being accepted into EIS to clozapine being initiated. CONCLUSION: The majority of patients were prescribed antipsychotics within the guidelines. EIS was associated with an overall low antipsychotic discontinuation. There was also a short waiting time before clozapine was initiated following patients being accepted into EIS. PMID- 28348731 TI - Clonazepam improves dopamine supersensitivity in a schizophrenia patient: a case report. AB - Dopamine supersensitivity is an important consideration for assessing treatment resistant schizophrenia. The emergence of dopamine supersensitivity might be related to upregulation of dopamine D2 receptor, which engenders tolerance to antipsychotics, rebound psychosis, and tardive dyskinesia (TD). A 24-year-old man with a history of treatment-resistant schizophrenia was hospitalized for treatment of bone fracture sustained during a suicide attempt. After the operation, his clinical symptoms implied malignant catatonia. The patient discontinued antipsychotics without rebound psychosis under clonazepam treatment. His psychotic symptoms were controlled further with 24 mg/day aripiprazole without relapse or worsening. Clonazepam might be an effective option for the management of dopamine supersensitivity psychosis (DSP). PMID- 28348733 TI - Complications after implantation of subcutaneous central venous ports (PowerPortR). AB - BACKGROUND: The aim of our study was revised as follows: to clarify the postoperative complications of multifunctional central venous ports and the risk factors for such complications to promote the safe use of the PowerPort system in the hospital. METHODS: The study group comprised 132 patients in whom implantable central venous access ports (PowerPortR) were placed in our hospital from March 2014 through December 2015. The approach used for port placement was the subclavian vein in 43 patients (33%), the internal jugular vein in 87 patients (66%), and the femoral vein in 2 patients (1%). RESULTS: Postoperative complications occurred in 8 patients (6%). The catheter was removed because of infection in 4 patients and catheter kinking in 1 patient. Port extravasation occurred in 3 patients. No patient had catheter pinch-off. The mean operation time was 74 min (range, 32 to 171). No patients had intraoperative bleeding or pneumothorax. Benign disease was a risk factor for postoperative complications (p = 0.009). CONCLUSION: PowerPort is a multifunctional port. Benign disease was a risk factor for postoperative complications. Because many types of subcutaneously implanted ports are used in our hospital, we had to inform the hospital staff about the functions of PowerPort. PMID- 28348732 TI - Probuphine(r) (buprenorphine implant): a promising candidate in opioid dependence. AB - Opioid dependence leads to physical dependence and addiction which finally results in profound medical, psychological and social dysfunction. One of the useful medications for opioid dependence is buprenorphine, the partial opioid agonist, which is used alone or in combination with naloxone. However, buprenorphine is the victim of its own success due to its illicit use and accidental poisoning in children. Also, buprenorphine typically requires daily self-administration and its effectiveness heavily depends on patient adherence. So, poor treatment adherence results in ineffective treatment manifesting as craving and withdrawal symptoms. Short-term use of buprenorphine in opioid dependence is also often followed by relapse. Buprenorphine when used sublingually often results in inadequate or fluctuating blood concentrations and poorer treatment retention compared with methadone. All of these led to the development of Probuphine(r), a polymeric matrix composed of ethylene vinyl acetate and buprenorphine in the form of implants, that are implanted subdermally in office practice and deliver the active drug over 6 months. Buprenorphine release from such implant is fairly consistent, avoiding plasma peaks and troughs, and the implant is also reported to be safe. In this review article, we have highlighted these aspects of treatment of opioid addiction, stressing on the pharmacology of buprenorphine and Probuphine(r), and relevant clinical trials addressing the efficacy and safety of Probuphine(r). This sustained-release implantable formulation of buprenorphine has the potential to be a suitable alternative to daily or alternate day sublingual buprenorphine which can thereby eliminate the need for daily supervision, minimizing fluctuations in plasma concentrations, and allowing these patients to reduce clinic or pharmacy visits. PMID- 28348735 TI - A multimodal approach to improving human papillomavirus vaccination in a community pharmacy setting. AB - BACKGROUND: Community pharmacy has become a major access point for several types of vaccinations. Despite the success of vaccination programs like influenza, pneumococcal, and herpes zoster, the rates of human papillomavirus vaccination continue to lag. OBJECTIVES: The primary objective is to describe and report on the impact of a multimodal series of pharmacist-led educational interventions on human papillomavirus vaccination rates in a community pharmacy setting. The primary outcome of this study was change in pharmacist-delivered human papillomavirus vaccination throughout a corresponding 8-week period in 2014 and 2015. METHODS: A single-center, quasi-experimental interrupted time series mixed methods pilot study was used to investigate a pharmacist-led, multimodal educational intervention approach to improve human papillomavirus vaccination rates in the community. RESULTS: During the 2014 control period, there were no human papillomavirus vaccines dispensed or administered according to the internal prescription dispensing software. In 2015, a total of 10 patients indicated that they were vaccinated, with 9 patients receiving their first dose and 1 patient receiving his or her second dose at the pharmacy. Pharmacist recommendation was the most reported education method for increasing patient awareness of the human papillomavirus vaccine (n = 10). CONCLUSION: This study demonstrates pharmacist designed, educational interventions may impact human papillomavirus vaccination rates in the community. Further community-based research with larger sample sizes is warranted to verify these results. Due to the unique barriers to human papillomavirus vaccination, a multimodal and inter-professional approach such as the one presented here is warranted. PMID- 28348734 TI - A retrospective study on how primary care providers manage specialists' recommendations after an e-consultation. AB - INTRODUCTION: E-consultations are asynchronous text-based consultations between providers which can facilitate patient access to timely specialty care. In contrast to traditional face-to-face consults, conveying and completing recommendations of the specialist is the responsibility of the referring provider. This presents a new workflow for primary care providers who have multiple options (face-to-face, telephone, letter, secure message) to communicate the e-consultation recommendations. This study examines how primary care providers are managing this new workflow. METHODS: We performed a retrospective random sampling of e-consultations with individual medical record review and classified e-consultations by type of recommendation, how recommendations were communicated to patients, and whether recommendations were carried out. RESULTS: We randomly selected 220 e-consultations in 13 different specialties for review. In all, 85% of e-consultations contained recommendations for referring providers. Recommendations on medication(s) were most common (35%) followed by recommendations on ordering laboratory tests (29%). In all, 25% of the time e consultants gave multiple possible courses of action for referring providers to choose from. Patient notification of recommendations was found for 192 (87%) of e consultations with providers performing the notification 63% of the time and nursing staff performing the notification 37% of the time. The communication back to the patients included communication via nurse telephone calls (37%), provider telephone calls (23%), secure messages (24%), face-to-face visits (11%), and by written correspondence (5%). DISCUSSION: Managing recommendations from e consultations results in a new workflow for primary care providers. Healthcare institutions that utilize e-consults should be aware of this new workflow. Further study is needed to determine best practices for this task that is now increasing in primary care. PMID- 28348736 TI - Effect of high-intensity training on endothelial function in patients with cardiovascular and cerebrovascular disease: A systematic review. AB - OBJECTIVES: Exercise improves endothelial dysfunction, the key manifestation of cardiovascular and cerebrovascular disease, and is recommended in both cardiovascular and cerebrovascular rehabilitation. Disagreement remains, however, on the role of intensity of exercise. The purpose of this review was to gather current knowledge on the effects of high-intensity training versus moderate intensity continuous exercise on endothelial function in cardiovascular and cerebrovascular patients. METHODS: A systematic review was performed in PubMed database, Embase and Cochrane libraries and on PEDro using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies were restricted to cardiovascular and cerebrovascular patients, and healthy subjects as general reference. Interventions comprised of high-intensity training alone, high-intensity training compared to moderate-intensity continuous exercise, or no training, with endothelial function as outcome measure. Endothelial function was measured either physiologically by flow-mediated dilatation and/or by systemic biomarkers. Data were analyzed descriptively due to non-comparability for a meta analysis to be performed. RESULTS: A total of 20 studies were included in the review. Although there was great heterogenecity in design, population and exercise protocols, all studies found high-intensity training to be safe. High intensity training was equal to moderate-intensity continuous exercise through improvement in endothelial function in 15 of the 20 selected studies, as measured by flow-mediated dilatation, nitric oxide bioavailability and circulating biomarkers. Only a few studies examined high-intensity training in cerebrovascular patients, none with endothelial function as outcome. CONCLUSION: High-intensity training is promising as a time-efficient exercise strategy in cardiovascular rehabilitation, but data on endothelial effects in cerebrovascular rehabilitation are warranted. Agreement on a more uniform exercise protocol is essential to further investigate the optimal exercise mode for cerebrovascular rehabilitation. PMID- 28348737 TI - Performance of a cognitive load inventory during simulated handoffs: Evidence for validity. AB - BACKGROUND: Advancing patient safety during handoffs remains a public health priority. The application of cognitive load theory offers promise, but is currently limited by the inability to measure cognitive load types. OBJECTIVE: To develop and collect validity evidence for a revised self-report inventory that measures cognitive load types during a handoff. METHODS: Based on prior published work, input from experts in cognitive load theory and handoffs, and a think-aloud exercise with residents, a revised Cognitive Load Inventory for Handoffs was developed. The Cognitive Load Inventory for Handoffs has items for intrinsic, extraneous, and germane load. Students who were second- and sixth-year students recruited from a Dutch medical school participated in four simulated handoffs (two simple and two complex cases). At the end of each handoff, study participants completed the Cognitive Load Inventory for Handoffs, Paas' Cognitive Load Scale, and one global rating item for intrinsic load, extraneous load, and germane load, respectively. Factor and correlational analyses were performed to collect evidence for validity. RESULTS: Confirmatory factor analysis yielded a single factor that combined intrinsic and germane loads. The extraneous load items performed poorly and were removed from the model. The score from the combined intrinsic and germane load items associated, as predicted by cognitive load theory, with a commonly used measure of overall cognitive load (Pearson's r = 0.83, p < 0.001), case complexity (beta = 0.74, p < 0.001), level of experience (beta = -0.96, p < 0.001), and handoff accuracy (r = -0.34, p < 0.001). CONCLUSION: These results offer encouragement that intrinsic load during handoffs may be measured via a self-report measure. Additional work is required to develop an adequate measure of extraneous load. PMID- 28348738 TI - Use of selective-serotonin reuptake inhibitors and platelet aggregation inhibitors among individuals with co-occurring atherosclerotic cardiovascular disease and depression or anxiety. AB - OBJECTIVE: Medications commonly used to treat heart disease, anxiety, and depression can interact resulting in an increased risk of bleeding, warranting a cautious approach in medical decision making. This retrospective, descriptive study examined the prevalence and the factors associated with the use of both selective-serotonin reuptake inhibitor and platelet aggregation inhibitor among individuals with co-occurring atherosclerotic cardiovascular disease and anxiety or depression. METHODS: Respondents aged 22 years and older, alive throughout the study period, and diagnosed with co-occurring atherosclerotic cardiovascular disease and anxiety or depression (n = 1507) in years 2007 through 2013 of the Medical Expenditures Panel Survey were included. The use of treatment was grouped as follows: selective-serotonin reuptake inhibitor and platelet aggregation inhibitor, selective-serotonin reuptake inhibitor or platelet aggregation inhibitor, and neither selective-serotonin reuptake inhibitor nor platelet aggregation inhibitor. RESULTS: Overall, 16.5% used both selective-serotonin reuptake inhibitor and platelet aggregation inhibitor, 61.2% used selective serotonin reuptake inhibitor or platelet aggregation inhibitor, and 22.3% used neither selective-serotonin reuptake inhibitor nor platelet aggregation inhibitor. Respondents aged over 65 years (adjusted odds ratio = 1.93 (95% confidence interval = 1.08-3.45)) and having a diagnosis of diabetes (adjusted odds ratio = 1.63 (95% confidence interval = 1.15-2.31)) and hypertension (adjusted odds ratio = 1.84 (95% confidence interval = 1.04-3.27)) were more likely to be prescribed the combination. CONCLUSION: The drug interaction was prevalent in patients who are already at higher risk of health disparities and worse outcomes thus requiring vigilant evaluation. PMID- 28348739 TI - Effectiveness of an early mobilization program on functional capacity after coronary artery bypass surgery: A randomized controlled trial protocol. AB - BACKGROUND: Muscle atrophy and prolonged inactivity are associated with an increased sensation of fatigue and reduced functional capacity in the postoperative period in patients undergoing coronary artery bypass grafting. Cardiac rehabilitation after hospital discharge is highly recommended and contributes to improvement in functional capacity and quality of life. However, few studies have evaluated the effectiveness of early mobilization protocols during hospitalization on the patterns of physical activity and functional capacity after coronary artery bypass grafting. OBJECTIVE: To investigate the effectiveness of an early mobilization program on the functional capacity of patients undergoing coronary artery bypass grafting in the short and long term. METHODS: This is a prospective, randomized, controlled, single-blind trial protocol that will evaluate 66 consecutive patients undergoing coronary artery bypass grafting. Patients will be randomized into two training groups: the control group (N = 33), which will perform breathing exercises and the intervention group (N = 33), which will perform breathing exercises and aerobic exercises. The groups will receive treatment from first to the seventh postoperative day, twice daily. In the preoperative period, the following outcomes will be assessed: physical activity level (Baecke Questionnaire), Functional Independence Measure, and functional capacity (6-min walking test). Functional capacity will be reassessed after the 7th and 60th postoperative day. Pulmonary complications and length of hospital stay will also be evaluated. Statistical analysis will be calculated using linear mixed models and will be based on intention-to-treat. The level of significance will be set at alpha = 5%. PMID- 28348740 TI - Type 2 diabetes mellitus is associated with increased risk of pancreatic cancer: A veteran administration registry study. AB - BACKGROUND: The etiology of pancreatic cancer remains elusive. Several studies have suggested a role for diabetes mellitus, but the magnitude of its contribution remains controversial. OBJECTIVES: Utilizing a large administrative database, this retrospective cohort study was designed to investigate the relationship between type 2 diabetes mellitus and pancreatic cancer. PATIENTS AND DESIGN: Using the Veterans Integrated Services Network 16 database, 322,614 subjects were enrolled in the study, including 110,919 with type 2 diabetes mellitus and 211,695 diabetes-free controls matched by gender, year of birth and healthcare facility. RESULTS: A significantly higher incidence of pancreatic cancer was observed in patients with type 2 diabetes mellitus, with an adjusted hazard ratio (95% confidence interval) of 2.17 (1.70-2.77) for type 2 diabetes mellitus compared to controls (p < 10-9) after controlling for the matching factors. CONCLUSION: The association between type 2 diabetes mellitus and pancreatic cancer was statistically significant and may, in part, explain the rising incidence of pancreatic cancer. PMID- 28348741 TI - Fructose: Toxic effect on cardiorenal risk factors and redox state. AB - AIM: To investigate the effects of fructose consumption on the antioxidant capacity in heart and kidney, cardiovascular disease risk factors, and evaluation of these variables after its removal. METHODS: Male Wistar rats (n = 36) were divided into control group (n = 12): standard chow + water or F group: standard chow + fructose in drinking water (30%) for 15 weeks. After, F group was divided to continue receiving standard chow + fructose in drinking water (30%) (n = 12) or standard chow + water (Ex group, n = 12) for 9 weeks. Water, chow and caloric diaries intake, final body weight, adiposity index, plasma glucose and triacylglycerol, systolic blood pressure, and cardiac and renal hydrophilic antioxidant capacity were analyzed. RESULTS: Control and Ex groups consumed less chow and water compared to F group. Caloric intake was higher in control group. There was no difference in final body weight and adiposity index. Systolic blood pressure and cardiac and renal hydrophilic antioxidant capacity were worst in F group. CONCLUSION: Prolonged exposure to fructose induces oxidative stress, systolic blood pressure, and increase in triacylglycerol. When stopped fructose consumption, Ex group presented improvement in these variables, suggesting the toxicity effect of fructose when consumed in high amounts and prolonged exposure. PMID- 28348742 TI - Risk factors for Clostridium difficile infection in HIV-infected patients. AB - BACKGROUND: Clostridium difficile infection is a healthcare-associated infection resulting in significant morbidity. Although immunosuppression is associated with Clostridium difficile infection acquisition and adverse outcomes, the epidemiology of Clostridium difficile infection in HIV-infected patients has been little studied in the era of antiretroviral therapy. This study identifies the risk factors for acquisition of Clostridium difficile infection in HIV-infected patients. METHODS: A retrospective, propensity score-matched case-control study design was employed, with patients selected from our institution's outpatient HIV clinic. Clostridium difficile infection cases were defined as having positive stool testing plus an appropriate clinical presentation. The propensity score was generated via multiple logistic regression from year of HIV diagnosis, age at first contact, duration of follow-up, gender, and initial CD4 count. RESULTS: The 46 cases included were matched to a total of 180 controls. Prior antibiotic treatment was a significant predictor of Clostridium difficile infection (odds ratio: 13, 95% confidence interval: 3.49-48.8, p < .001) as was number of hospital admissions in the preceding year (odds ratio: 4.02, confidence interval: 1.81-8.94, p < .001). Having both proton pump inhibitor use and CD4 count <200 cells/uL significantly increased odds of Clostridium difficile infection in the multivariable model (odds ratio: 15.17, confidence interval: 1.31-175.9, p = .021). CONCLUSION: As in the general population, frequent hospitalizations and exposure to antimicrobials are independent predictors of Clostridium difficile infection acquisition in patients with HIV. Additionally, low CD4 count and proton pump inhibitor use are new potentially modifiable variables that can be targeted for prevention of Clostridium difficile infection in future interventional studies. PMID- 28348743 TI - Management of upper ureteral stones exceeding 15 mm in diameter: Shock wave lithotripsy versus semirigid ureteroscopy with holmium:yttrium-aluminum-garnet laser lithotripsy. AB - OBJECTIVES: We conducted a retrospective study to evaluate the efficacy and outcome of shock wave lithotripsy versus semirigid ureteroscopy in the management of the proximal ureteral stones of diameter exceeding 15 mm. METHODS: During the 2009-2014 study period, 147 patients presenting with the proximal ureteral stones exceeding 15 mm in diameter were treated. Both shock wave lithotripsy and ureteroscopy with laser lithotripsy were offered for our patients. A 6/8.9 Fr semirigid ureteroscope was used in conjunction with a holmium:yttrium-aluminum garnet laser. The stone-free rate was assessed at 2 weeks and 3 months post treatment. All patients were evaluated for stone-free status, operation time, hospital stay, perioperative complications, and auxiliary procedures. RESULTS: Of the 147 patients who took part in this study, 66 (45%) had undergone shock wave lithotripsy and 81 (55%) underwent ureteroscopy. At the 3-month follow-up, the overall stone-free rate in the shock wave lithotripsy group was 39/66 (59%) compared to 70/81 (86.4%) in the ureteroscopic laser lithotripsy group. Ureteroscopic laser lithotripsy achieved a highly significant stone-free rate (p = 0.0002), and the mean operative time, auxiliary procedures, and postoperative complication rates were comparable between the two groups. CONCLUSION: In terms of the management of proximal ureteral stones exceeding 15 mm in diameter, ureteroscopy achieved a greater stone-free rate and is considered the first-line of management. Shock wave lithotripsy achieved lower stone-free rate, and it could be used in selected cases. PMID- 28348744 TI - Urinary infection due to Balantioides coli: a rare accidental zoonotic disease in an addicted and diabetic young female in Iran. AB - BACKGROUND: Balantiosis, a rare zoonotic infection resulting in dysentery, is caused by the large ciliated protozoan parasite Balantioides coli. Humans acquire this organism via the faecal-oral route. Very rarely, extraintestinal infections can occur in the urinary tract system. There are very few case reports of urinary balantiosis in humans. CASE PRESENTATION: Here, an interesting case of urinary balantiosis in a 35-year-old addicted woman with multiple health problems including spontaneous abortion and diabetes is reported. Her midstream urine sample, collected while all sterile precautions were being taken, demonstrated B. coli along with Trichomonas vaginalis and bacteria. B. coli was identified by its characteristic morphology and rapid rotary motility in the urinary tract, which is an abnormal site for invasion by this parasite. CONCLUSION: To the best of our knowledge, this is only the eighth case described in literature in which B. coli was detected in urine sediment; it is reported for its rarity and for future reference. PMID- 28348745 TI - Use of a serotype-specific urine immunoassay to determine the course of a hospital outbreak of Streptococcus pneumoniae complicated by influenza A. AB - INTRODUCTION: An outbreak of Streptococcus pneumoniae (pneumococcal) infection complicated by concomitant influenza A on an elderly care ward was detected. CASE PRESENTATION: Thirteen patients with hospital-acquired respiratory infections were investigated during the course of the outbreak investigation. Six had a positive BinaxNOW S. pneumoniae urinary antigen test and two patients had culture confirmed pneumococcal bacteraemia and a positive urine antigen test. Five patients gave positive influenza A PCR results of which two were also positive for S. pneumoniae antigen. CONCLUSION: The concurrence of influenza and pneumococcal infections made tracking the course of the infection difficult. This case study shows how the use of a sensitive, S. pneumoniae serotype-specific urine antigen assay, in the absence of cultured isolates, helped determine whether patients were infected with the same pneumococcal serotype. This was particularly useful when additional respiratory symptoms were seen following the administration of chemoprophylaxis. PMID- 28348746 TI - An unusual presentation of leishmaniasis in a human immunodeficiency virus positive individual. AB - INTRODUCTION: Leishmaniasis is a neglected tropical disease caused by vector borne protozoa of the genus Leishmania. Cutaneous and mucocutaneous forms result in disfiguration or mutilation, whilst visceral leishmaniasis (VL) affects multiple organs and is fatal if untreated. Notably, Leishmania are capable of establishing a chronic infection, which may reactivate years after initial infection when the host becomes immune-suppressed. CASE PRESENTATION: A 24-year old human immunodeficiency virus (HIV)-positive male presented for excision of anal condylomas. At the time of his current condyloma excision, the patient had no additional symptoms or cutaneous findings, but was noted to have been only intermittently compliant with his antiretroviral therapy. Microscopic examination of the haematoxylin and eosin-stained anal condyloma tissue revealed koilocytic change, ulceration and brisk histiocytic inflammation containing numerous small intracellular bodies suggestive of Leishmania amastigotes. A bone marrow biopsy was performed and demonstrated similar intracellular forms. Anal condyloma tissue and bone marrow aspirate were sent to the Centers for Disease Control and Prevention's Parasitic Diseases Branch for confirmation of Leishmania and speciation. Specific immunohistochemical staining for Leishmania in the tissue section was positive and the species was confirmed as Leishmania donovani by PCR. Subsequently, the patient resumed highly active antiretroviral therapy and received anti-Leishmania therapy. CONCLUSION: Whilst the presentation of VL in HIV-positive patients is often similar to those without HIV, here we describe an unusual initial presentation of leishmaniasis in an HIV-positive patient where the parasite was found in an anal condyloma. VL is a critical diagnosis that should be considered and pursued when leishmaniasis is encountered in seemingly illogical clinical settings. PMID- 28348747 TI - Haemolytic differential identification of Arcanobacterium haemolyticum isolated from a patient with diabetic foot ulcers. AB - INTRODUCTION: Arcanobacterium haemolyticum (formerly known as Corynebacterium haemolyticum) is the causative agent of sore throat and also causes skin and soft tissue infections in diabetes patients. A. haemolyticum is a Gram-positive, catalase-negative, beta-haemolytic bacillus. A. haemolyticum poses a diagnostic challenge in the hospital laboratory because most coryneform bacilli are considered as normal flora or contaminants, and it is therefore difficult to differentiate from beta-haemolytic streptococci by colony characteristics. CASE PRESENTATION: A. haemolyticum was isolated from a diabetic patient with foot ulcers and the isolate was identified by using a VITEK-2 system, CAMP inhibition test, reverse CAMP test and a 23S rRNA gene sequence analysis. The isolated A. haemolyticum inhibited haemolysis of Staphylococcus aureus in the CAMP test and enhanced haemolysis of Streptococcus agalactiae in the reverse CAMP test. The diabetic patient was treated with teicoplanin and imipenem, and the ulcers healed within 2 weeks. CONCLUSION: The present study suggests that a haemolytic differential method using the CAMP inhibition and reverse CAMP tests can be useful for differentiating A. haemolyticum from beta-haemolytic streptococci. PMID- 28348749 TI - Aspergillus fumigatus native valve infective endocarditis in an otherwise healthy adult. AB - INTRODUCTION: Fungal endocarditis is a rare cause of infective endocarditis, and Aspergillus spp. account for up to 30 % of all cases. Risk factors include intravenous drug use, immunosuppression, malignancy and the presence of prosthetic valves. CASE PRESENTATION: We present a case of A. fumigatus endocarditis in a patient without any known or described risk factors. CONCLUSION: Diagnosis of Aspergillus endocarditis requires a high clinical index of suspicion, given the initial non-specific presentation, and treatment may require both medical and surgical therapies to ensure improved outcomes, but mortality rates still approach 80 %. Voriconazole remains the antifungal agent of choice. PMID- 28348748 TI - Paediatric meningococcaemia in northwestern Ontario, Canada: a case for publicly funded meningococcal B vaccination. AB - INTRODUCTION: Neisseria meningitidis serogroup B is an important infectious agent in developed countries, including Canada. Infants are particularly susceptible to infection with serogroup B because of immature immune systems, pathogen virulence factors and changing serogroup dynamics in the post-vaccination era. Currently, the Ontario provincial government does not include serogroup B in its routine publicly funded meningococcal vaccination program. CASE PRESENTATION: A formerly well 14-month-old male presented to a tertiary hospital emergency department with fever, minor respiratory problems, diffuse purpuric rash, distended abdomen, tachycardia, and history of one episode of vomiting and melena each. Meningococcaemia was immediately suspected, and he was treated with ceftriaxone, cefotaxime and vancomycin before transfer to a different acute care facility within 12 h. N. meningitidis serogroup B, sensitive to ceftriaxone and penicillin, was identified in his blood. The patient developed gangrene of the lower legs and underwent bilateral below-knee amputation 8 days post-admission. CONCLUSION: This instance of meningococcaemia with extensive sequelae is an example of the various serious outcomes of meningococcal infection. It provides persuasive reason for routine publicly funded vaccination against N. meningitidis serogroup B in Ontario. PMID- 28348750 TI - Comprehensive pathogen detection associated with four recurrent episodes of Kawasaki disease in a patient during a single year using next-generation sequencing. AB - INTRODUCTION: Kawasaki disease (KD) is the most common multisystem vasculitis in childhood. Pathogens can be associated with the onset of KD. However, a lack of consistency prevails among reports about this disease. CASE PRESENTATION: For this case of a 1-year-old boy with four recurrent episodes of KD within a year, we analysed profiles of pathogen reads in his serum and pharynx specimens using next-generation sequencing. Comparative analysis of the identified bacterial reads from serum samples found significant correlation of bacteria such as Streptococcus and Haemophilus spp. with the first and fourth episodes (R2 = 0.9506) before treatment. In the first convalescent phase, the number of Streptococcus spp. was reduced remarkably (P < 0.0001). From sequencing of the pharynx specimen from the fourth episode, a similar correlation was found with serum from the fourth episode (R2 = 0.6633). CONCLUSION: In this case, Streptococcus spp. may have been associated with onset of KD. Further studies must be undertaken to evaluate the putative association of micro-organism infection with KD pathogenesis. PMID- 28348751 TI - Enteroccocus pallens as a potential novel human pathogen: three cases of spontaneous bacterial peritonitis. AB - INTRODUCTION: Enterococcus pallens is one of the four yellow-pigmented members of the genus Enterococcus. To date, a single report of E. pallens isolated from a human sample has been published. CASE PRESENTATION: We report three cases of E. pallens spontaneous bacterial peritonitis in patients with liver cirrhosis that all occurred in Quebec, Canada. Ascitic fluid analysis revealed the presence of E. pallens in culture. Identification was made by classical biochemical testing and MALDI-TOF MS, as well as 16S rRNA and elongation factor (tuf) gene sequencing. Two of the three patients recovered after antimicrobial treatment. CONCLUSION: This report identifies E. pallens as a novel human pathogen that appears to possess particular but as-yet unidentified virulence factors that favour the development of peritoneal fluid infections, as previously reported for other Enterococcus species. Clinical microbiologist should be aware of this micro organism which can be identified by phenotypic and molecular methods. PMID- 28348752 TI - Rhodococcus fascians infection after haematopoietic cell transplantation: not just a plant pathogen? AB - INTRODUCTION: Rhodococcus spp. have been implicated in a variety of infections in immunocompromised and immunocompetent hosts. Rhodococcus equi is responsible for the majority of reported cases, but Rhodococcus erythropolis, Rhodococcusgordoniae and Rhodococcusruber infections have been described. There are no prior reports of human infection with Rhodococcus fascians. CASE PRESENTATION: We describe the unexpected finding of R. fascians in liver lesions incidentally noted at autopsy in an immunosuppressed patient status after bone marrow transplant for acute lymphoblastic leukaemia who died of unrelated causes (septic shock due to Clostridium difficile colitis). At autopsy, an otherwise unremarkable liver contained several dozen well-demarcated sclerotic-appearing lesions measuring 0.1-0.3 cm in size. The absence of other bacterial or fungal DNA in the setting of histologically visible organisms argues against its presence as a contaminant and raises the consideration that R. fascians represents a human pathogen for the immunocompromised. CONCLUSION: Whether it represents the sole infectious agent responsible for the miliary lesions or a partially treated co-infection is impossible to determine, but our finding continues to reinforce the importance of molecular techniques in associating organisms with sites of infection and optimizing treatment of infectious diseases. PMID- 28348753 TI - Delayed recognition of fatal invasive meningococcal disease in adults. AB - INTRODUCTION: Invasive meningococcal disease can be difficult to detect early in its course when patients may appear well and the severity of their illness is obscured by non-specific complaints. CASE PRESENTATION: We report five cases of meningococcal sepsis in adult patients who presented to an emergency department early in the course of their disease, but whose severity of illness was not recognized. CONCLUSION: Suspicion of meningococcal sepsis should be heightened in the setting of hypotension, tachycardia, elevated shock index, leukopaenia with left shift, thrombocytopaenia and hypokalaemia, prompting early sepsis care. PMID- 28348754 TI - Actinobacillus hominis osteomyelitis: First reported case in the English language medical literature. AB - INTRODUCTION: Actinobacillus hominis is currently a rarely reported pathogen. It has previously been associated with respiratory tract infections and bacteraemia in debilitated patients. However, under-reporting may occur due to misidentification by commonly used laboratory bacterial identification systems. This case is, to the best of our knowledge, the first reported case of A. hominis osteomyelitis in the English language medical literature. CASE PRESENTATION: A 37 year-old male presented with a painful foot. He had no previous foot problems, history of injury or animal contact. Osteomyelitis was confirmed by magnetic resonance imaging (MRI), and blood cultures were positive for Gram-variable bacilli. The organism was identified initially as Pasteurella pneumotropica by the local routine diagnostic laboratory and as a Pasteurella species by the UK National Reference Laboratory (Colindale, London, UK), using standard operating procedures at the time. It was finally identified as an A. hominis using 16S rRNA gene sequence analysis. Difficulties in the accurate identification of this organism remain current, as other biochemical identification systems have also resulted in misidentifications. The patient refused admission and intravenous antibiotics. He was successfully treated using an 8-week course of oral ciprofloxacin and amoxicillin based on antibiotic disc susceptibility testing resulting in clinical, serological and radiological resolution. CONCLUSION: Laboratories should maintain a high index of suspicion for A. hominis as several commonly used bacterial identification systems may not accurately identify the organism. Colonial morphology and absence of animal contact should prompt consideration of this organism in appropriate clinical situations. Oral ciprofloxacin and amoxicillin treatment was successful in this case. PMID- 28348755 TI - A Balamuthia survivor. AB - INTRODUCTION: This case report describes a human survivor of Balamuthia mandrillaris infection. This is a free-living amoeba that can cause infection with the devastating consequence of near universally fatal encephalitis. We report this case to demonstrate the possibility of recovery. CASE PRESENTATION: A 26-year-old Hispanic male, a landscape gardener, presented to the hospital in March 2010 with a two month history of headache, visual disturbances and new onset seizures. Brain imaging identified two enhancing central lesions and Balamuthia mandrillaris was later identified by brain biopsy. He received several months of various antimicrobials including miltefosine, a novel use of the drug in this disease at the time. Seven weeks into therapy, considerations were made to switch him to 'comfort care' because of worsening clinical status and seemingly lack of response to treatment. The patient finally demonstrated clinical and radiological improvement after eight weeks with modified therapy, despite experiencing some debilitating toxic effects likely to be related to antibiotics. Two years after his initial presentation he made a complete recovery. CONCLUSION: Balamuthia mandrillaris amoebic encephalitis is considered an almost universally fatal disease; this case demonstrates the possibility of recovery. This report outlines his treatment, drug toxicities and includes additional information regarding the therapeutic use of the drug miltefosine. Whether his survival is related to the specific antimicrobials used in this case is unknown and further investigation is warranted. PMID- 28348756 TI - Amoeboma in a Saudi resident: a case report. AB - INTRODUCTION: Amoebiasis is the third most frequent cause of mortality after malaria and schistosomiasis. In developed countries, amebiasis is also seen in migrants who have travelled to endemic areas. The factors responsible for its progression from intestinal amebiasis to an amebic liver abscess are not fully understood. CASE PRESENTATION: A 54-year-old man presented with abdominal pain, fever and diarrhoea. Laparotomy confirmed an inflammatory mass involving the right colon, and he underwent a right hemicolectomy. He later developed abdominal distenstion due to an amoebic liver abscess and died from secondary nosocomial bacterial infection and surgical complications. CONCLUSION: Amoeboma is an uncommon manifestation of amoebiasis, and can mimic both carcinoma and inflammatory bowel disease; so, distinguishing between these two conditions is the key to providing appropriate therapy. Hepatic amoebiasis is the most common extraintestinal disease of invasive amoebiasis. This clinical report presents a case of an uncommon parasitic disease in Saudi Arabia and discusses the difficulties encountered while attempting to establish the correct diagnosis. Hence, a high index of suspicion is crucial for diagnosing Entamoeba histolytica to avoid unnecessary surgery and further complications. PMID- 28348757 TI - Zika virus infection as an unexpected finding in a Leptospirosis patient. AB - INTRODUCTION: Areas where leptospirosis and arboviruses are endemic largely overlap in the tropics. However, the number of arbovirus infections is usually much higher. The initial clinical presentation can be highly confusing; therefore, laboratory confirmation is key to an accurate diagnosis. CASE PRESENTATION: A 19-year-old man presented to a peripheral health centre with an acute febrile illness. Dengue was initially suspected, but the patient deteriorated to a shock syndrome. Leptospirosis as well as a co-infection with Zika virus were both confirmed in the laboratory, the latter being clinically masked in this dual infection. CONCLUSION: This case highlights the importance of not only considering the differential diagnosis of acute febrile syndromes, but also to consider the possibility of dual infections in the context of global spread of arboviruses. The specific context of travellers returning from endemic areas and pregnant women is also highlighted and discussed. PMID- 28348758 TI - Recurrent sepsis and neuroinvasive disease in a neonate culture-positive for a Group B Streptococcus CPS III serotype, hvgA+ strain. AB - INTRODUCTION: Late-onset disease with Group B Streptococcus (GBS LOD) remains a significant problem in neonates. Unlike early-onset disease, rates of GBS LOD have not changed with prenatal testing. Effects of GBS LOD can be severe and thus identifying risk factors for severe GBS LOD, such as hypervirulence genes, may help in managing these infants. CASE PRESENTATION: We present a case of a neonate with capsular serotype III GBS sepsis without meningitis that recurred 6 days after a 10-day-treatment period with IV ampicillin. The second episode was characterized by sepsis, neuroinvasion, meningitis and subsequent profound encephalomalacia. The short duration between the two episodes suggested recrudescence rather than reinfection. The GBS isolate was ultimately found to be positive for hypervirulence gene hvgA+, which encodes for a protein known to mediate meningeal tropism and neuroinvasion. CONCLUSION: hvgA positivity may thus potentially serve as an important biomarker for severe and neuroinvasive GBS LOD that can influence treatment decisions. PMID- 28348759 TI - Positive blood cultures in a patient recovering from febrile neutropenia. PMID- 28348760 TI - Report of two paediatric cases of central line infections caused by species of the genus Kocuria. AB - INTRODUCTION: Species of the genus Kocuria are Gram-positive cocci of the family Micrococcacceae that are ubiquitous in the environment and part of the normal skin and oral flora in humans. A paucity of cases have been reported of Kocuria as human pathogens and there are currently no evidence-based guidelines for managing these uncommon infections. CASE PRESENTATION: We present two paediatric cases of central line infections with species of the genus Kocuria that required line removal despite antimicrobial therapy. CONCLUSION: Species of the genus Kocuria are uncommon human pathogens that have rarely been reported to cause opportunistic infections in both adult and paediatric populations. The cases presented here add to the growing body of literature documenting the pathogenicity of these organisms and the possible need for line removal to achieve clinical cure in central line-associated bacteraemia caused by species of the genus Kocuria. PMID- 28348761 TI - Fatal primary amoebic meningoencephalitis in a Norwegian tourist returning from Thailand. AB - INTRODUCTION: Primary amoebic meningoencephalitis (PAM) is a rare disease caused by the free-living amoeba Naegleria fowleri. Infection occurs by insufflation of water containing amoebae into the nasal cavity, and is usually associated with bathing in freshwater. Nasal irrigation is a more rarely reported route of infection. CASE PRESENTATION: A fatal case of PAM in a previously healthy Norwegian woman, acquired during a holiday trip to Thailand, is described. Clinical findings were consistent with rapidly progressing meningoencephalitis. The cause of infection was discovered by chance, owing to the unexpected detection of N. fowleri DNA by a PCR assay targeting fungi. A conclusive diagnosis was established based on sequencing of N. fowleri DNA from brain biopsies, supported by histopathological findings. Nasal irrigation using contaminated tap water is suspected as the source of infection. CONCLUSION: The clinical presentation of PAM is very similar to severe bacterial meningitis. This case is a reminder that when standard investigations fail to identify a cause of infection in severe meningoencephalitis, it is of crucial importance to continue a broad search for a conclusive diagnosis. PAM should be considered as a diagnosis in patients with symptoms of severe meningoencephalitis returning from endemic areas. PMID- 28348762 TI - A case of Ignatzschineria bacteraemia in an unconscious man from the Netherlands. AB - INTRODUCTION: Ignatzschineria species were previously known as Schineria species and are well known inhabitants of the larvae of the parasitic fly Wohlfahrtia magnifica. CASE PRESENTATION: We report a case of Ignatzschineria species bacteraemia in a Dutch patient with a wound infested with maggots. CONCLUSION: In the past, these bacteria have been isolated from Wohlfahrtia magnifica, a fly not indigenous to The Netherlands. Other fly larvae such as the blowfly larvae probably infested the wound and harboured this Ignatzschineria strain which subsequently caused this bacteraemia. A two-week course of amoxicillin/clavulanic acid was given with good clinical response. PMID- 28348763 TI - Granulicatella adiacens prosthetic hip joint infection after dental treatment. AB - INTRODUCTION: Granulicatella adiacens is a Gram-positive bacteria and a normal component of oral flora. It is also found in dental plaques, endodontic abscesses and can rarely cause more serious infections. CASE PRESENTATION: We describe a prosthetic hip joint infection in an 81-year-old fit and healthy man due to Granulicatella adiacens who underwent a prolonged dental intervention two days earlier without antibiotic prophylaxis. The infection was successfully treated with surgical intervention and a combination of antibiotics. The patient eventually succumbed to severe community-acquired pneumonia two months later. CONCLUSION: Current guidelines recommend avoidance of antibiotic prophylaxis prior to dental treatment in patients who have no co-morbidities and no prior operation on the index prosthetic joint. This case report indicates that infections of prosthetic joints may be associated with dental procedures even in fit and healthy patients without the recognized risk factors. PMID- 28348764 TI - First reported case of Campylobacter lanienae enteritis in a human. AB - INTRODUCTION: Campylobacters are the most frequently identified bacteria causing diarrhoea in humans worldwide. Campylobacter lanienae was isolated for the first time in 2000 from faecal samples of two asymptomatic abattoir workers in Switzerland during a routine hygiene screen, but has never been associated with human disease. CASE PRESENTATION: At hospital admission, the patient reported diarrhoea, lower abdominal cramps, nausea, one episode of bilious vomiting and low-grade fever of 38 degrees C. The patient was having 10 or more diarrheic stools per day as well as during the night, and had noticed blood mixed with the stools on several occasions. Stool cultures were negative for species of Salmonella and Shigella, Escherichia coli O157:H7 and Yersinia enterocolitica, but were positive for C. lanienae. Identification was made by classical biochemical testing, as well as 16S rRNA gene and cpn60 sequencing. The patient slowly improved without antibiotic treatment and was discharged nine days after admission with complete resolution of symptoms. CONCLUSION: On the whole it seems very likely that C. lanienae was the causative agent. Clinical microbiologists should be aware of this micro-organism which can be identified by phenotypic and molecular methods. The real burden of C. lanienae infection in humans might be underestimated and should be further investigated as a potential cause of human diarrhoea disease. PMID- 28348765 TI - Progressive disseminated histoplasmosis mimicking a flare of systemic lupus erythematosus: a European case report. AB - INTRODUCTION: Diagnosing progressive disseminated histoplasmosis (PDH) in patients with systemic lupus erythematosus (SLE) is diagnostically challenging. Since PDH is lethal when untreated, awareness of this infection in patients with SLE is of utmost importance. To the best of our knowledge, this is the first description of a case of PDH in a patient with SLE in Europe. CASE PRESENTATION: A 56-year-old woman of Surinamese descent with a history of SLE, presented with fever and polyarthritis. Although a flare of SLE was suspected initially, cultures of bone marrow and broncho-alveolar lavage fluid grew Histoplasma capsulatum. CONCLUSION: This case report highlights that physicians should be aware of progressive disseminated histoplasmosis in patients with SLE treated with immunosuppressive agents. The signs and symptoms can easily mimic a SLE flare, which would then be treated with more aggressive immunosuppression. Failure to recognize the infection will therefore invariably lead to death of the patient. Progressive disseminated histoplasmosis is usually not recognized by doctors in non-endemic areas such as Europe. However, globalisation and more frequent intercontinental traffic of immunocompromised patients currently increases the incidence of histoplasmosis in these areas. It is therefore of life saving importance that doctors are aware of the features of the infection in areas where H. capsulatum is not endemic. PMID- 28348766 TI - Can anaerobes be acid fast? A novel, clinically relevant acid fast anaerobe. AB - INTRODUCTION: Anaerobic acid fast bacilli (AFB) have not been previously reported in clinical microbiology. This is the second case report of a novel anaerobic AFB causing disease in humans. CASE PRESENTATION: An anaerobic AFB was isolated from an abdominal wall abscess in a 64-year-old Caucasian diabetic male, who underwent distal pancreatectomy and splenectomy for resection of a pancreatic neuroendocrine tumour. The isolated bacteria were gram-variable and acid-fast, consisting of small irregular rods. The 16S rRNA gene sequence analysis showed that the isolate is a novel organism described in the literature only once before. The organism was studied at the CDC (Centers for Disease Control and Prevention) by the same group that worked with the isolates from the previous report; their findings suggest that the strain belongs to the suborder Corynebacterineae. CONCLUSION: This is the fifth reported case of an anaerobic AFB involved in clinical disease; its microbiological features and 16S RNA sequence are identical to previously reported cases. Clinical disease with this organism seems to be associated with recent history of surgery and abscess formation in deep soft tissues. Acquisition from surgical material is uncertain but seems unlikely. PMID- 28348768 TI - Myocarditis in Mediterranean spotted fever: a case report and a review of the literature. AB - INTRODUCTION: Mediterranean spotted fever (MSF) is a tick-borne acute febrile disease caused by Rickettsia conorii. Most cases follow a benign course, with a case fatality rate of 3-7 % among hospitalized patients. Complications are described mainly in adult patients and include hepatic, renal, neurological and cardiac impairment. Among cardiac complications, pericarditis, myocarditis and heart rhythm disorders are uncommon complications in MSF and only a few cases have been reported in the literature. CASE PRESENTATION: We describe a new case of acute myocarditis complicating MSF in an immunocompetent adult patient without risk factors for severe MSF. CONCLUSION: Myocarditis is an uncommon but severe complication of MSF. Clinicians should be aware of a possible cardiac involvement in patients with MSF. Close monitoring and an aggressive approach are essential to reduce mortality rates of MSF. PMID- 28348767 TI - First case of mixed infection with Cryptococcus deuterogattii and Cryptococcus neoformans VNI in an Ivorian HIV-positive patient. AB - INTRODUCTION: Cryptococcal meningitis (CM) may be caused by several species of Cryptococcus. CASE PRESENTATION: We describe a fatal case of CM in a HIV-positive patient from Ivory Coast infected by Cryptococcus neoformans VNI and Cryptococcusdeuterogattii. Isolates were recovered from cerebrospinal fluid (CSF) prior to systemic antifungal treatment. Six isolates were studied (the entire culture plus five isolated colonies from it). Serotyping was performed via LAC 1 and CAP 64 gene amplification. Genotyping was performed using restriction fragment length polymorphism (RFLP) analysis of the URA5 gene, (GACA)4, (GTG)5 and M13 PCR fingerprinting. URA5-RFLP analysis identified the original culture with two different molecular type combinations. However, URA5-RFLP profiles of the five colonies isolated from the original sample revealed two different species. Four colonies were identified as C.deuterogattii and the last isolate as C.neoformans VNI. The in vitro susceptibility profile was determined using the standard method according to the CLSI M27-A3 protocol. The isolates were susceptible to the tested antifungals (fluconazole, flucytosine and amphotericin B). Treatment with fluconazole (1200 mg day-1) was initiated; however, the patient died 17 days after the onset of antifungal therapy. CONCLUSION: This is the first reported case of mixed infection with C. neoformans and C.deuterogattii in a HIV-positive patient. PMID- 28348769 TI - Clostridium baratii: a rare case of pneumonia associated with an Alzheimer patient in Rio de Janeiro, Brazil. AB - INTRODUCTION: Clostridium baratii is rarely associated with human diseases. Infection is usuallcaused by ingestion of contaminated food, and infant botulism is the most common clinical presentation. CASE REPORT: Here we report a case of pneumonia by a non-toxigenic strain of C. baratii in an Alzheimer 70-year-old male with sepsis in Rio de Janeiro, Brazil. The micro-organism was identified by phenotypical tests, mass spectrometry (MALDI-TOF), DNA amplification (PCR) and sequencing of the 16S rRNA gene. Testing for the presence of botulinum F toxin was made using multiplex PCR. Bioassay for a large number of colonies was performed in mice to evaluate the production of any lethal toxin, but the results were negative. CONCLUSION: To our knowledge, there are no cases of C. baratii infection reported in Brazil and we highlight the importance of anaerobic lab tests in the standard routine of diagnosis. PMID- 28348770 TI - Non-traumatic keratitis due to Colletotrichum truncatum. AB - INTRODUCTION: The fungal genus Colletotrichum is an uncommon cause of human infections. It has been implicated in cutaneous phaeohyphomycosis, artritis and keratitis secondary to traumatic implantation. CASE PRESENTATION: We report two cases of keratitis due Colletotrichum truncatum in middle-aged, immunocompetent persons without history of trauma. The aetiological agents were identified based on DNA sequencing. Azoles and echinocandins showed high minimal inhibitory concentrations while amphotericin B was <= 0.25 mg l-1. Both patients failed topical antifungal treatment and needed penetrating keratoplasty with a favourable outcome. CONCLUSION: C. truncatum caused keratomycosis which did not respond to topical antifungal agents. To the best of our knowledge these are the first reported cases of keratitis due to this fungus in Cuba and Latin-America and highlights the expanding spectrum of fungal agents causing eye infections. PMID- 28348771 TI - Angioinvasive mucormycosis and paradoxical stroke: a case report. AB - INTRODUCTION: Rhizopus typically results in acute, aggressive and angioinvasive infection, particularly in immunosuppressed individuals. Risk factors include immunosuppression in haematologic malignancy, uncontrolled hyperglycemia, iron overload states, and older chelator agents such as deferoxamine. CASE PRESENTATION: We describe a case of a 33-year-old female with transfusion dependent beta thalassemia who was started on intravenous deferiprone therapy and subsequently presented with a retropharyngeal abscess. Despite intravenous broad spectrum antibiotics, she continued to deteriorate and developed aphasia. A CT scan of her head showed multiple hypodensities. Blood cultures grew Rhizopus species and a subsequent transesophageal echocardiogram showed a mass in the right atrium with a patent foramen ovale. CONCLUSION: Although deferiprone, a newer iron chelator agent, has antifungal properties in vivo, this case illustrates that angioinvasive Rhizopus infections can occur in patients treated with deferiprone. PMID- 28348772 TI - Case series of Bartonella quintana blood culture-negative endocarditis in Washington, DC. AB - INTRODUCTION: Prior studies (predominantly from Europe) have demonstrated blood culture-negative endocarditis due to Bartonella. Our objective was to describe three cases of Bartonella quintana endocarditis identified within one year at a large hospital in Washington, DC, USA. CASE PRESENTATION: We constructed a descriptive case series from a retrospective review of medical records from April to December 2013 at an 800-bed urban hospital. All three patients (ages: 52, 55 and 57 years) were undomiciled/homeless men with a history of alcoholism. Although they had negative blood cultures, echocardiography demonstrated aortic/mitral valve perforation and regurgitation in one patient, aortic/mitral valve vegetation with mitral regurgitation in the second patient, and aortic valve vegetation with regurgitation in the third patient. The patients had positive Bartonella quintana serum immunoglobulin G (IgG) with negative immunoglobulin M (IgM). PCR on DNA extracted from cardiac valves was positive for Bartonella, and DNA sequencing of PCR amplicons identified Bartonella quintana. Patients received treatment with doxycycline/rifampin or doxycycline/gentamicin. CONCLUSION: Clinicians should consider Bartonella endocarditis as a differential diagnosis in patients who fit elements of the Duke Criteria, as well as having a history of homelessness and alcoholism. PMID- 28348773 TI - Pleural empyema due to Salmonella enterica serovar Enteritidis in an immunocompetent elderly patient: a case report. AB - INTRODUCTION: Pleural empyema as a focal infection due to Salmonella enterica serovar Enteritidis is rare and most commonly described among immunosuppressed patients or patients who suffer from sickle cell anaemia and lung malignancies. CASE PRESENTATION: Here, we present an 81-year-old immunocompetent Greek woman with bacteraemia and pleural empyema due to Salmonella Enteritidis without any gastrointestinal symptoms. CONCLUSION: In our case, we suggest that patient's pleural effusion secondary to heart failure was complicated by empyema and that focal intravascular infection was the cause of bacteraemia. PMID- 28348774 TI - Latent infection of human bocavirus accompanied by flare of chronic cough, fatigue and episodes of viral replication in an immunocompetent adult patient, Cologne, Germany. AB - INTRODUCTION: The human bocavirus (HBoV) is a parvovirus and is associated with mild to life-threatening acute or persisting respiratory infections, frequently accompanied by further pathogens. So far, there is limited knowledge on the mechanisms of persistence, and no reports on chronic infections or latency have been published so far. CASE PRESENTATION: An immunocompetent male patient suffers from a chronic HBoV1 infection, i.e. viral DNA was detected in both serum and bronchoalveolar lavage (BAL) for >5 months without co-infections and with respiratory symptoms resolved spontaneously while receiving symptomatic treatment with montelukast and corticosteroids. Following the symptomatic medication of a chronic infection with HBoV1 viraemia indicating active viral replication lasting over 5 months, the patient cleared the viraemia and no further viral DNA was detectable in the BAL. However, by fluorescence in situ hybridization analyses of mucosal biopsies, it was shown that the virus genome still persisted in the absence of viral shedding but in a more compact manner possibly representing a supercoiled episomal form of this otherwise linear single-stranded DNA genome. This indicated the entry into a latency phase. Moreover, the cytokine profile and the IP-10/TARC ratio, a marker for fibrotization, seem to have been altered by HBoV1 replication. Although specific IgG antibodies were detectable during the whole observation period, they showed an apparently insufficient neutralising activity. CONCLUSION: On the one hand, these findings suggest that the symptomatic medication may have led to clearance of the virus from blood and airways and, moreover, that the viral DNA persists in the tissue as an altered episomal form favoured by lacking neutralising antibodies. This appears to be important in order to reduce possible long-term effects such as lung fibrosis. PMID- 28348775 TI - Progressive multifocal leukoencephalopathy and black fungus in a patient with rheumatoid arthritis without severe lymphocytopenia. AB - INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating brain infection caused by JC polyomavirus (JCV), primarily seen in patients with severely compromised cellular immunity. Clinical presentation varies depending on the affected white matter. PML prognosis is variable and effective treatments are lacking. CASE PRESENTATION: A 75-year-old Chinese woman with type 2 diabetes mellitus, chronic kidney disease and rheumatoid arthritis, treated with low-dose methotrexate and prednisolone for 2.5 years, developed a Pleurostomophora richardsiae infection of her left arm. After 6 months of treating this rare black fungus infection with voriconazole, surgery and immunosuppression discontinuation, she presented with progressive afebrile encephalopathy with right-sided hemiparesis. There were no signs of inflammation or metabolic abnormalities. Brain magnetic resonance imaging revealed diffuse frontal white matter lesions and a cerebrospinal fluid PCR confirmed PML due to JC virus. Severe lymphopenia was never present, and at PML diagnosis, CD4 and CD8 T-cell counts were 454 mm-3 and 277 mm-3. CD8 T-cells were able to respond to JCV VP1 peptide stimulation with TNFalpha secretion. Peripheral B-cell count was only 8 mm-3. Mirtazapine and Maraviroc were started, but unfortunately, she rapidly deteriorated and died 5 weeks after PML diagnosis. CONCLUSION: Although peripheral lymphocyte counts were never low and CD4 T-cell count was close to normal, the persistent black fungus infection was a hallmark of severely compromised cellular immunity. The unexpected extremely low absolute B-cell count might suggest a protective role for B-cells. The paradoxical, clinical PML onset months after immunosuppressive discontinuation suggests that it was only discovered in the context of an immune reconstitution inflammatory syndrome. PMID- 28348776 TI - First case report of pulmonary nocardiosis caused by Nocardia mexicana. AB - INTRODUCTION: Nocardia species usually cause opportunistic infections, and the frequency of these infections is increasing owing to the growing population of immunocompromised hosts. However, Nocardia species may sometimes cause an infection disease in immunocompetent hosts. Nocardia mexicana infections are the least common and are very rare. CASE PRESENTATION: Herein, we report the first case of a pulmonary infection with N. mexicana in a 61-year-old Japanese woman with a history of hyperlipidaemia and bronchiectasis and a 6-month history of non productive hacking cough. A sample of bronchial lavage fluid obtained by bronchofiberscopy showed filamentous branching gram-positive rods and acid-fast filamentous branching rods, and a colony of suspected Nocardia was cultured. Based on 16S rRNA, gyrB,rpoB, secA1 and hsp65 gene sequence analyses and biochemical and physiological properties, the strain was identified as N. mexicana. The strain was resistant to the antimicrobial agents amoxicillin clavulanic acid, clarithromycin, minocycline, gentamycin, tobramycin, ciprofloxacin and trimethoprim-sulfamethoxazole. The patient was treated with biapenem followed by intravenous amikacin and oral linezolid. CONCLUSION: Despite its rarity, the species require attention owing to the existence of multidrug resistant strains. PMID- 28348777 TI - Fatal case of co-infection with dengue virus and Neisseria meningitidis during a dengue epidemic in the state of Rio de Janeiro, Brazil. AB - INTRODUCTION: Dengue and meningococcal disease are caused by two different agents: a flavivirus and a Gram-negative bacterium, respectively. The first symptoms of both diseases can be indistinct and a rapid and accurate diagnosis is crucial, considering that both diseases are associated with high morbidity and mortality, representing a major public-health problem in Brazil. CASE PRESENTATION: We report a fatal case of co-infection of dengue virus (DENV) and Neisseria meningitidis in a 54-year-old patient. The serum tested positive for DENV NS1 antigen, and N. meningitidis serogroup C was detected by nspA-PCR. Following the initial positive result for DENV infection, rRT-PCRwas performed and DENV-4 was confirmed. CONCLUSION: Our report highlights the importance of accurate differential diagnosis during periods of high circulation of DENV, in order to provide adequate management and an improved outcome. PMID- 28348778 TI - VEB-1 extended-spectrum beta-lactamase-producing multidrug-resistant Proteus mirabilis sepsis outbreak in a neonatal intensive care unit in India: clinical and diagnostic implications. AB - INTRODUCTION: Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, multidrug-resistant (MDR) pathogens, are increasingly implicated in nosocomial outbreaksworldwide, particularly in neonatal intensive care units (NICUs). Proteus mirabilis is an uncommon nosocomial pathogen causing sepsis in neonates. CASE PRESENTATION: We report an outbreak of ESBL-positive MDR P. mirabilis sepsis involving five babies within 10 days in a NICU, which was promptly detected and managed. The aim of this study was to characterize the molecular mechanism of resistance to third-generation cephalosporins (3GCs) in the bacteria. Surveillance cultures were collected from health-care personnel (hand swabs, urine) and the surrounding patient-care environment. Ribotyping was performed to determine the clonality of the strain. Thirteen P. mirabilis were recovered from the blood cultures of the five babies and surveillance cultures. Twelve isolates were positive for the VEB-1 ESBL type, and were susceptible only to ciprofloxacin and carbapenems. There was an unusual phenotypic synergy observed between the 3GCs and imipenem/cefoxitin. The source of infection was traced to a contaminated multidose vial. The outbreak was associated with a high mortality (80 %). A change of empirical antibiotic policy to ciprofloxacin, with strict infection control measures, brought the outbreak to an abrupt end. CONCLUSION: This is believed to be the first report of a nosocomial outbreak of VEB-1 ESBL-producing P. mirabilis sepsis in neonates from India. The present report of infection due to VEB-1-producing P. mirabilis, an uncommon pathogen for an epidemic in a neonatal unit, highlights the growing significance of such Gram negative bacteria as a cause of infections in newborns. Epidemic spread in a neonatal unit of an ESBL-producing Proteus species, which also had an intrinsically reduced susceptibility to imipenem, and resistance to colistin and tigecycline, can be a threatening situation and can result in high neonatal mortality unless recognized and controlled in a timely manner. PMID- 28348779 TI - Unusual case of pelvic hydatid cyst of broad ligament mimicking an ovarian tumour. AB - INTRODUCTION: The diagnosis of hydatid cyst in female genital tract is rare and difficult. A high degree of clinical suspicion is needed for pre-operative investigations to exclude hydatid cyst of female pelvis. The objective of this presentation is to highlight a pelvic hydatid cyst that presented as an ovarian tumour. CASE PRESENTATION: A 22-year-old female, presented with constipation and haematuria with acute urinary retention. On examination, a mass measuring 15*13 cm was palpable in the left iliac region reaching up to the umbilicus. It was smooth, movable and non-tender and a provisional diagnosis of ovarian teratoma was made pre-operatively. At laparotomy, a cystic mass was found attached to the broad ligament, excised, and a frozen section was sent for histopathology. Gross features were consistent with hydatid cyst; the cystic wall was white and there were multiple small thin-wall daughter cysts. Microscopic diagnosis with paraffin sections showed cystic lesions with laminated wall and scolices in the daughter cyst. Indirect haemagglutination test for specific antibodies was positive (128 IU). The patient responded well to surgical excision followed by albendazole administration. CONCLUSION: This case highlights the fact that a pelvic hydatid disease may resemble neoplastic ovarian cyst, clinically and radiologically. The possibility of pelvic hydatid disease should be included, in endemic areas where differential diagnosis of cystic ovarian lesions is needed, so that the patient can be managed accordingly. PMID- 28348780 TI - Pelvic abscess due to Mycoplasma hominis following caesarean section. AB - INTRODUCTION: Mycoplasma hominis is associated with genito-urinary tract infection and adverse pregnancy outcomes. However, whether the species is a true pathogen or part of the genito-urinary tracts natural flora remains unclear. CASE PRESENTATION: A 41-year-old pregnant woman was admitted to our hospital at 38 weeks and 5 days of gestation owing to premature rupture of the membranes. The patient delivered by caesarean section. Subsequently, the patient complained of lower abdominal pain and had persistent fever. Enhanced computed tomography revealed pelvic abscesses. Gram staining of pus from the abscess and vaginal secretions indicated presence of polymorphonuclear leucocytes but no pathogens. Cultures on blood agar showed growth of pinpoint-sized colonies in an anaerobic environment within 48 h. Although administration of carbapenem and metronidazole was ineffective and we could not fully drain the abscess, administration of clindamycin led to clinical improvement. The isolates 16S rRNA gene and yidC gene sequences exhibited identity with those of M. hominis. CONCLUSION: Physicians should consider M. hominis in cases of pelvic abscesses where Gram staining yields negative results, small colonies are isolated from the abscess and treatment with beta-lactam antibiotics is ineffective. PMID- 28348781 TI - Human Clostridium difficile infection caused by a livestock-associated PCR ribotype 237 strain in Western Australia. AB - INTRODUCTION: Clostridium difficile infection (CDI) is a significant gastrointestinal disease in the developed world and increasingly recognised as a zoonotic infection. In North America and Europe, the PCR ribotype (RT) 078 strain of C. difficile is commonly found in production animals and as a cause of disease in humans although proof of transmission from animals is lacking. This strain is absent in Australian livestock. We report a case of human CDI caused by a strain of C. difficile belonging to known Australian livestock-associated RT 237. CASE PRESENTATION: A young male was admitted for multiple trauma following a motor vehicle accident and placed on piperacillin/tazobactam for pneumonia. After 4 days of treatment, he developed symptoms of CDI, which was confirmed in the laboratory. His symptoms resolved after 6 days of intravenous metronidazole. The strain of C. difficile isolated was identified as RT 237, an unusual RT previously found in with several Western Australia piggeries. CONCLUSION: This case of CDI caused by an unusual livestock-associated C. difficile RT 237 supports the hypothesis of zoonotic transmission. The case highlights the potential of livestock to act as reservoir for C. difficile and the need for continued surveillance of CDI in both human and animal populations. PMID- 28348782 TI - An unusual case of seronegative, 16S PCR positive Brucella infection. AB - INTRODUCTION: Brucella is a zoonotic infection commonly diagnosed by isolation of the organism from blood culture or positive serological testing. It is an uncommon cause of a pyrexia of unknown origin in the United Kingdom. CASE PRESENTATION: We describe the case of a 14-year-old girl with no history of travel who presented with pyrexia, weight loss, arthralgia, multiple splenic abscesses and a subsequent pleural effusion, the latter of which isolated a Brucella species on 16S rRNA PCR. The patient responded well to initiation of treatment for brucellosis and on repeat imaging, after 3 months, the splenic abscesses had resolved. CONCLUSION: This unique case demonstrates uncommon complications of brucellosis and the challenges of diagnosing the organism, the latter of which can be alleviated by the utilization of molecularbased technologies. This patient had a negative serology result for brucellosis, which highlights the need to interpret serology results with caution in non-endemic regions for brucellosis. PMID- 28348783 TI - An unusual case of thoracic empyema caused by Granulicatella elegans (nutritionally variant streptococci) in a patient with pulmonary tuberculosis and human immunodeficiency virus infection. AB - INTRODUCTION: Nutritionally variant streptococci (NVS) are an infrequent cause of human infection with Granulicatella elegans being the least encountered species in clinical specimens. The most common infection caused by NVS is infective endocarditis. CASE PRESENTATION: We report an unusual case of thoracic empyema due to G. elegans in a patient with pulmonary tuberculosis (TB) and human immunodeficiency virus infection. The patient responded favourably to drainage and penicillin. CONCLUSION: This case illustrates that even though TB is responsible for the majority of pleural effusions in this setting, other rare opportunistic bacteria may cause infection in susceptible patients. Therefore, microbiological investigations should be performed in all patients presenting with pleural effusion. PMID- 28348784 TI - Identification of a novel sequence type of Escherichia coli as the causative agent of pyelonephritis and bloodstream infection. AB - INTRODUCTION: Globally, extra-intestinal pathogenic Escherichia coli are one of the predominant causative agents of bacteraemia. CASE PRESENTATION: This case report outlines a presentation of community-acquired pyelonephritis and secondary bloodstream infection in an 81-year-old man. Laboratory investigations revealed that the causative isolate was a multi-drug-resistant E. coli of a novel multi locus sequence type. This sequence type (ST) was designated ST-458 and was most closely related to the globally prevalent ST-131 lineage. CONCLUSION: This is the first report of a novel E. coli ST, ST-458, which caused pyelonephritis and bacteraemia. PMID- 28348785 TI - Retrospective PCR-based species identification of Leishmania in two patients with visceral leishmaniasis in Serbia. AB - INTRODUCTION: Retrospective molecular identification of Leishmania parasites in two patients with visceral leishmaniasis (VL) previously treated in Serbia was carried out. DNA was isolated from unstained bone marrow smears (BMSs) kept for 11 and 8 years. Genus-specific real-time PCR was combined with conventional PCR and sequencing for detection and species identification. CASE PRESENTATION: In 2003, a 40-year-old Serbian male was admitted to the Clinical Centre of Serbia (CCS) with fever, sweating, fatigue and splenomegaly, which developed over a period of 7 weeks. He had frequently travelled around Europe. VL was confirmed by microscopy of Giemsa-stained BMS. Treatment by pentavalent antimonials was successfully completed. Two years later, the patient developed post-kala-azar dermal leishmaniasis. Treatment resulted in symptom resolution. Later on, Leishmania infantum was identified as the causative agent of the VL by sequencing of the ITS (internal transcribed spacer) region; mixed Leishmania spp. infection could not be excluded. In 2006, a 33-year-old female from Vojvodina, Serbia, with pre-existing diabetes mellitus and chronic meningoencephalitis and a history of frequent visits to the Montenegrin seacoast, was admitted to the CCS with fever, pancytopenia and moderate hepatosplenomegaly. A stained BMS revealed abundant Leishmania amastigotes. Indirect haemagglutination analysis was positive with a titre of 1 : 2048, and a rapid dipstick rK39 test was also positive. Treatment by liposomal amphotericin B was successful; however, shortly after, the patient developed neural infection and pneumonia and died. The causative agent was identified as L. infantum. CONCLUSION: Molecular diagnosis of VL and species delineation using DNA from unstained BMSs stored for several years is possible. PMID- 28348786 TI - Haemophilus influenzae type a as a cause of paediatric septic arthritis. AB - INTRODUCTION: Incidence rates of invasive Haemophilus influenzae serotype b disease have decreased significantly since the introduction of the Hib vaccine; however, the rates in indigenous populations remain disproportionately high, specifically in the paediatric population. Additionally, with the decline of type b invasive infections, there has been a rebound in the incidence of invasive infections caused by other strains of H. influenzae, particularly serotype a. CASE PRESENTATION: We present a paediatric case of septic arthritis caused by H. influenzae type a in a toddler that was fully resolved following antibiotic therapy. This report adds to other reports of septic arthritis in indigenous populations as shown through a review of recently documented H. influenzae type a septic arthritis cases. CONCLUSION: Socio-economic risk factors for invasive H. influenzae type a disease, such as poverty, poor housing conditions, overcrowding, smoking and substance abuse during pregnancy, as well as the need for H. influenzae type a immunization of vulnerable populations, are discussed. PMID- 28348787 TI - Staphylococcus caprae native mitral valve infective endocarditis. AB - INTRODUCTION: Staphylococcus caprae is a rare cause of infective endocarditis. Here, we report a case involving the native mitral valve in the absence of an implantable cardiac electronic device. CASE PRESENTATION: A 76-year-old man presented with a 2 week history of confusion and pyrexia. His past medical history included an open reduction and internal fixation of a humeral fracture 17 years previously, which remained non-united despite further revision 4 years later. There was no history of immunocompromise or farm-animal contact. Two sets of blood culture bottles, more than 12 h apart, were positive for S. caprae. Trans-thoracic echocardiography revealed a 1*1.2 cm vegetation on the mitral valve, with moderate mitral regurgitation. Due to ongoing confusion, he had a magnetic resonance imaging brain scan, which showed a subacute small vessel infarct consistent with a thromboembolic source. A humeral SPECT-CT (single photon emission computerized tomography-computerized tomography) scan showed no clear evidence of acute osteomyelitis. Surgical vegetectomy and mitral-valve repair were considered to reduce the risk of further systemic embolism and progressive valve infection. However, the potential risks of surgery to this patient led to a decision to pursue a cure with antibiotic therapy alone. He remained well 3 months after discharge, with repeat echocardiography demonstrating a reduction in the size of the vegetation (0.9 cm). CONCLUSION: Management of this infection was challenging due to its rarity and its unclear progression, complicated by the dilemma surrounding surgical intervention in a patient with a complex medical background. PMID- 28348788 TI - Streptococcus suis serotype 2 strains isolated in Argentina (South America) are different from those recovered in North America and present a higher risk for humans. AB - INTRODUCTION: Streptococcus suis serotype 2 is an important swine pathogen and emerging zoonotic agent causing meningitis and septicemia/septic shock. Strains are usually virulent (Eurasia) or of intermediate/low virulence (North America). Very few data regarding human and swine isolates from South America are available. CASE PRESENTATION: Seventeen new human S. suis cases in Argentina (16 serotype 2 strains and a serotype 5 strain) are reported. Alongside, 14 isolates from pigs are analyzed: 12 from systemic disease, one from lungs and one from tonsils of a healthy animal. All human serotype 2 strains and most swine isolates are sequence type (ST) 1, as determined by multilocus sequence typing and present a mrp+/epf+/sly+ genotype typical of virulent Eurasian ST1 strains. The remaining two strains (recovered from swine lungs and tonsils) are ST28 and possess a mrp+/epf - /sly- genotype typical of low virulence North American strains. Representative human ST1 strains as well as one swine ST28 strain were analyzed by whole-genome sequencing and compared with genomes from GenBank. ST1 strains clustered together with three strains from Vietnam and this cluster is close to another one composed of 11 strains from the United Kingdom. CONCLUSION: Close contact with pigs/pork products, a good surveillance system, and the presence of potentially virulent Eurasian-like serotype 2 strains in Argentina may be an important factor contributing to the higher number of human cases observed. In fact, Argentina is now fifth among Western countries regarding the number of reported human cases after the Netherlands, France, the UK and Poland. PMID- 28348789 TI - Sternal wound infection caused by Gordonia bronchialis: identification by MALDI TOF MS. AB - INTRODUCTION: Gordonia spp. infections are uncommon. However, a few clinical cases have been reported in the literature, particularly those involving immunocompromised hosts. Advanced microbiology diagnosis techniques, such as matrix-assisted laser desorption ionization-time of flight MS (MALDI-TOF MS), have been recently introduced in clinical microbiology laboratories in order to improve microbial identification, resulting in better patient management. CASE PRESENTATION: Here, we present a new clinical case of persistent wound infection caused by Gordonia bronchialis in a 64-year-old woman after a mitral valve replacement, using two MALDI-TOF-based systems for identifying this micro organism. CONCLUSION: Both MALDI-TOF systems were able to identify Gordonia spp.; thus, providing a useful tool that overcomes the current limitations of phenotypic identification associated with this micro-organism. Although the technique validation deserves additional verification, our study provides guidance about MALDI-TOF as a fast and easy method for Gordonia spp. identification. PMID- 28348790 TI - Streptococcus pneumoniae bacteraemia due to parotitis in a patient with systemic sclerosis and secondary Sjogren's syndrome. AB - INTRODUCTION: Invasive pneumococcal disease is an uncommon and notifiable disease in Singapore. It is often associated with significant morbidity and mortality. We report a rare case of invasive pneumococcal bacteraemia due to parotitis in a patient with systemic sclerosis and secondary Sjogren's syndrome. We also present a retrospective review of Streptococcus pneumoniae bacteraemia cases in Singapore General Hospital from January 2011 to April 2016. CASE PRESENTATION: A 59-year old Malay lady with a history of systemic sclerosis with secondary Sjogren's syndrome presented with fever and left parotid gland swelling. Clinical examination revealed poor salivary pooling and left parotid swelling without fluctuance. Ultrasound of the left parotid gland confirmed acute parotitis without evidence of abscess or sialolithiasis. Blood cultures were positive for S. pneumoniae. She was diagnosed to have invasive pneumococcal bacteraemia secondary to acute parotitis, and treated with intravenous benzylpenicillin with clearance of bacteraemia after 3 days. Upon discharge, her antibiotics were changed to intravenous ceftriaxone to facilitate outpatient parenteral antibiotic therapy for another 2 weeks. She responded favourably to antibiotics at follow up, with no complications from the bacteraemia. A review of the microbiological records of the Singapore General Hospital revealed 116 cases of pneumococcal bacteraemia, most (80.3 %) of which were due to pneumonia. None were due to parotitis. CONCLUSION: S. pneumoniae parotitis and subsequent bacteraemia is rare. Prompt recognition of the disease and appropriate use of antibiotics are important. This case highlights that close communication between healthcare workers (microbiologist, rheumatologist and infectious disease specialist) is essential in ensuring good clinical outcomes in patients with a potentially fatal disease. PMID- 28348791 TI - Successful treatment of recurrent Helicobacter fennelliae bacteraemia by selective digestive decontamination with kanamycin in a lung cancer patient receiving chemotherapy. AB - INTRODUCTION: Helicobacter fennelliae is an enterohepatic Helicobacter species causing bacteraemia in immunocompromised hosts. Only a few cases of recurrent H. fennelliae bacteraemia have been reported in Japan and there are no guidelines regarding antimicrobial treatment for H. fennelliae infection. CASE PRESENTATION: H. fennelliae bacteraemia was observed in a patient receiving platinum-based chemotherapy for lung cancer. To prevent recurrence, the patient received antibiotic therapy with cefepime, amoxicillin and doxycycline for 6 weeks, which is similar to the therapy for Helicobactercinaedi bacteraemia. Bacteraemia recurred despite the long-term antibiotic therapy. We hypothesized that the H. fennelliae bacteraemia originated from endogenous infection in the intestinal tract due to the long-term damage of the enteric mucosa by platinum-based drugs and performed selective digestive decontamination (SDD) with kanamycin. Bacteraemia did not recur after SDD. CONCLUSION: Our observations indicate that clinicians should be aware of possible recurrent H. fennelliae bacteraemia, which could be effectively prevented by SDD with kanamycin. PMID- 28348792 TI - An unusual case of vaginal myiasis. AB - INTRODUCTION: Myiasis, a term used to describe the infestation of a live animal by fly larvae, is rarely reported in human subjects. The adult fly lays its eggs on living tissue that progresses to become larvae that feed on living tissue having gone through three developmental stages known as the first, second and third instar. The larvae become pupae before finally developing into adults. CASE PRESENTATION: We describe an unusual case of a 79-year-old female who collapsed in her garden and lay there for several days before presenting to her local hospital Accident and Emergency department with an infestation of larvae in her vagina labia, identified as those from the Protophormia species northern blowfly. After complete removal of the larvae using tweezers followed by cleansing of the affected area and a course of antibiotics, the patient's condition improved. A follow-up review by the local gynaecology team revealed no evidence of further infestation. CONCLUSION: It is our understanding that this is the first highly unusual case of a blowfly larvae infestation to be reported in a human within the UK. PMID- 28348793 TI - Understanding cutaneous tuberculosis: two clinical cases. AB - Tuberculosis (TB) is an ancient human disease and remains today one of the most important public health problems and the second most frequent cause of death from an infectious disease worldwide. While pulmonary TB is the most common form, extra-pulmonary TB is on the rise due to the increase in immunosuppressed subjects. Cutaneous TB manifestations are rare forms of extra-pulmonary TB due to systemic dissemination of bacilli or direct inoculation, involving skin or skin associated tissue, more common in immunocompromised subjects. Some risk factors and the features of the lesion may prompt the suspicion of cutaneous TB, but only microbiological assays can confirm the diagnosis. Our work summarizes cutaneous TB manifestations and differences from other skin mycobacterial infections, also describes two characteristic clinical cases. PMID- 28348794 TI - Zika and Chikungunya virus co-infection in a traveller returning from Colombia, 2016: virus isolation and genetic analysis. AB - INTRODUCTION: Zikavirus (ZIKV) and Chikungunyavirus (CHIKV) can share the same mosquito vector, and co-infections by these viruses can occur in humans. While infections with these viruses share commonalities, CHIKV is unique in causing arthritis and arthralgias that may persist for a year or more. These infections are commonly diagnosed by RT-PCR-based methods during the acute phase of infection. Even with the high specificity and sensitivity characteristic of PCR, false negatives can occur, highlighting the need for additional diagnostic methods for confirmation. CASE PRESENTATION: On her return to the USA, a traveller to Colombia, South America developed an illness consistent with Zika, Chikungunya and/or Dengue. RT-PCR of her samples was positive only for ZIKV. However, arthralgias persisted for months, raising concerns about co-infection with CHIKV or Mayaro viruses. Cell cultures inoculated with her original clinical samples demonstrated two types of cytopathic effects, and both ZIKV and CHIKV were identified in the supernatants. On phylogenetic analyses, both viruses were found to be related to strains found in Colombia. CONCLUSION: These findings highlight the need to consider CHIKV co-infection in patients with prolonged rheumatological symptoms after diagnosis with ZIKV, and the usefulness of cell culture as an amplification step for low-viremia blood and other samples. PMID- 28348795 TI - Complicated sea urchin-induced wound infection caused by Vibrioalginolyticus and Staphylococcus lugdunensis in a 14-year-old boy. AB - INTRODUCTION: Wound infections with Vibrio alginolyticus, a Gram-negative bacterium found in all temperate oceans, are rarely reported. However, a rising incidence of wound infections caused by V. alginolyticus requires better knowledge about this infectious agent. CASE PRESENTATION: We report the case of a 14-year-old boy suffering from a wound infection caused by V. alginolyticus and Staphylococcus lugdunensis after stepping on a sea urchin. Despite wound debridement and antibiotic therapy with cefaclor, the lesion did not heal over several weeks. After identification of the pathogens and antibiotic susceptibility testing, antibiotic therapy was switched to ciprofloxacin, followed by trimethoprim/sulfamethoxazole. Two months after the accident the wound was re-epithelialized. Follow up after 6 months revealed a painful scar. CONCLUSION: Non-cholera vibrios like V. alginolyticus should be considered as possible causative agents in seawater-contaminated wounds. S. lugdunensis is a relevant pathogen in mixed wound infections. Early microbiological diagnosis and antibiotic-susceptibility testing is crucial to prevent therapeutic failure. PMID- 28348796 TI - Diagnostic difficulty identifying Apophysomyces trapeziformis septic arthritis in a patient with multiple myeloma. AB - INTRODUCTION: Mucormycosis is a rare fungal infection, but can cause substantial morbidity and mortality in both immunocompromised and immunocompetent patients. Apophysomyces is a mucormycetes species ubiquitous in nature, particularly in soil, decaying wood and other organic matter. Apophysomyces is known to cause cutaneous fungal infections, particularly after penetrating trauma. Septic arthritis is a rare clinical manifestation. CASE PRESENTATION: We describe a case of Apophysomyces trapeziformis causing septic arthritis of the knee of a patient with multiple myeloma. He was treated multiple times for bacterial septic arthritis with minimal improvement. Surgical tissue specimens finally grew mucoraceous mould, and DNA sequencing and morphological assessment of spores identified the mould as A. trapeziformis. The patient was treated with amphotericin B and posaconazole, but ultimately required an above-the-knee amputation for definitive treatment. CONCLUSION: This case illustrates the need to evaluate for fungal infection in a persistent septic arthritis that is culture negative and refractory to empiric antibiotics, particularly in an immunocompromised individual. It also shows the importance of a thorough social history and adequate tissue specimens for culture. PMID- 28348799 TI - Community-acquired urinary tract infections caused by Burkholderiacepacia complex in patients with no underlying risk factor. AB - Introduction. Urinary tract infections (UTIs) remain common infections diagnosed in outpatients as well as hospitalized patients. Community-acquired UTIs are generally caused by Escherichia coli and other members of the family Enterobacteriaceae.Burkholderiacepacia is an opportunistic pathogen mainly affecting immunocompromised and hospitalized patients, particularly those who have received prior broad-spectrum antibacterial therapy. Case presentation. Urine samples were collected from 157 outpatients clinically diagnosed with UTI and from 100 healthy control subjects. Samples were cultured on differential media and non-motile lactose-non-fermentors were identified via the Remel RapID ONE system. The isolates were tested by the disc diffusion method against 17 antimicrobial agents. Burkholderia was isolated as a single organism from four patients having uncomplicated infections, and one from recurrent infection. None of these patients had an underlying risk factor for this pathogen. Identification of these isolates by the Remel-RapID ONE system was confirmed by recA gene amplification. The four isolates were resistant to lincomycin, nalidixic acid, oxacillin and penicillin G. These cases received monotherapy of oral co trimoxazole. Conclusions. Our findings alert urologists and diagnostic laboratories to the potential of B.cepacia complex infections in similar cases, and that this bacterium should not be ruled out. PMID- 28348798 TI - Primary pyogenic ventriculitis caused by Neisseria meningitidis: case report and review of the literature. AB - Background. Pyogenic ventriculitis is a well-known complication of meningitis, brain abscesses and intraventricular drains. Primary pyogenic ventriculitis is a rare entity and few cases have been described so far. We report the first case of primary pyogenic ventriculitis in an adult caused by Neisseria meningitidis and present an overview of all reported adult primary pyogenic ventriculitis cases in the English literature. Methods. A PubMed search was performed using the terms ependymitis, ventricular empyema, pyocephalus and ventriculitis. Filter was set for adults and English. Articles in which pyogenic ventriculitis was a complication of well-known risk factors were excluded. A total of five cases of primary pyogenic ventriculitis were identified. Results. There were seven adult patients. Only one patient showed signs of meningeal irritation. Four patients had positive blood cultures with Escherichia coli (one patient), methicillin resistant Staphylococcus aureus (one patient), one patient was bacteraemic with Enterococcus faecalis, Escherichia coli and Peptostreptococcus spp., and N. meningitidis (our patient). In four patients cerebrospinal fluid was sent for culture, which yielded methicillin-sensitive Staphylococcus aureus (one patient), Peptostreptococcus spp. (one patient), Streptococcus intermedius (one patient, identified via 16S PCR) and Listeria monocytogenes (one patient). Cerebrospinal fluid cell count was determined in four patients and showed pleocytosis in all four cases. Ventricular drainage was performed in four patients. Five patients survived. Discussion. We report the first case of pyogenic ventriculitis caused by N. meningitidis. Primary pyogenic ventriculitis is a rare entity with various clinical presentations caused by various bacterial species. Treatment consists of adequate antimicrobial therapy, and ventricular drainage may be necessary. PMID- 28348797 TI - Acute influenza virus-associated encephalitis and encephalopathy in adults: a challenging diagnosis. AB - Background: Acute influenza-associated encephalopathy/encephalitis (IAE) in adults is a rare but well-known complication of influenza virus infection. The diagnosis is difficult to make due to the absence of distinctive clinical symptoms and validated diagnostic criteria. We present an illustrative case and a case review on acute IAE in adults. Methods: We performed a Medline search of the English literature using the terms influenz*, encephal* and adult, and constructed a database of detailed descriptions of patients with influenza virus infection with influenza-like symptoms at the onset of neurological symptoms. Results: A total of 44 patients were included. Confusion and seizures were the most prevalent neurological symptoms, present in 12 (27 %) and 10 (23 %) patients, respectively. Magnetic resonance imaging (MRI) was performed in 21 patients and anomalies were found in 13 (62 %), with lesions located throughout the brain. Influenza virus RNA was detected in cerebrospinal fluid (CSF) in 5 (16 %) of 32 patients. Eight (18 %) of the forty-four patients died. The benefits of antiviral and immunomodulatory therapy have not been well studied. Discussion: Our results show that many different neurological symptoms can be present in patients with acute onset IAE. Therefore, the diagnosis should be considered in patients with fever and neurological symptoms, especially during the influenza season. Laboratory diagnosis consists of demonstration of influenza virus RNA in brain tissue, CSF or respiratory samples, and demonstration of intrathecal antibody production against influenza virus. The presence of brain lesions in MRI and influenza virus in CSF appear to be of prognostic value. PMID- 28348800 TI - Pasteurella multocida urinary tract infection in a patient with cervical cancer. AB - Introduction. Infections caused by Pasteurella species are commonly associated with contact with dogs and cats, typically involving bites and scratches, but casual contact with household pets can also be a risk factor. Urinary tract infection (UTI) caused by Pasteurella species is rare and a significant majority of cases have some known risk factor associated with an underlying chronic illness or structural and/or functional urological abnormality. Case presentation. Here, we present a case of a UTI due to Pasteurella multocida in a patient with squamous cell carcinoma of the cervix who also had a household cat. Conclusion. Providers and laboratorians should be aware of risk factors associated with UTIs caused by Pasteurella species. PMID- 28348801 TI - Chromobacterium violaceum infection in chronic granulomatous disease: a case report and review of the literature. AB - Introduction.Chromobacterium violaceum is an opportunistic human pathogen, associated with significant mortality, and has been reported in patients with chronic granulomatous disease (CGD), a genetic condition causing impaired phagocytosis. Case presentation. A 28-year-old man with a history of CGD presented with fever, pharyngitis, cervical lymphadenopathy and internal jugular vein thrombosis, following travel to the rural Solomon Islands. C. violaceum was recovered from his blood. The patient recovered after treatment with meropenem and trimethoprim/sulfamethoxazole. Conclusion. To the best of our knowledge, this is the first case report of internal jugular vein thrombophlebitis (Lemierre's syndrome) caused by C. violaceum in a patient with CGD. A review of the literature demonstrated that the diagnosis of C. violaceum preceded the diagnosis of CGD in the majority of cases. This case emphasizes the importance of this organism in patients with CGD who live in or visit tropical areas. PMID- 28348802 TI - Cat-bite-induced Francisella tularensis infection with a false-positive serological reaction for Bartonella quintana. AB - Introduction. Tularaemia is caused by infection with Francisella tularensistransmitted via direct contact with an infected hare carcass or indirectly through the bites of vectors, but may be cat-bite-associated as well. Medical history and reliable diagnostic analysis are important in order to differentiate it from other cat-associated infections, e.g. Bartonella spp. Casepresentation. A healthy 56-year-old man was examined because of a cat-bite associated ulceroglandular wound on his right thumb. Nineteen days after the cat bite occurred, a serology test was positive for anti-Bartonella quintana, but negative for anti-F. tularensis. Since Bartonella infections are rare in Sweden, another serology test was analysed 2 weeks later with a positive result for anti F. tularensis. The patient was treated with doxycycline for 14 days and recovered. The patient was re-sampled after 18 months to obtain a convalescent sample. The acute and the convalescent samples were both analysed at a reference centre, with negative results for anti-Bartonella spp. this time. Conclusion. This case is enlightening about the importance of extending the medical history and re-sampling the patient for antibody detection when the clinical suspicion of cat-bite-associated tularaemia is high. The false-positive result for anti-B. quintana antibodies may have been due to technical issues with the assay, cross reactivity or both. PMID- 28348803 TI - Non-O1/non-O139 Vibrio cholerae septicaemia in a Saudi man: a case report. AB - Background. The non-O1/non-O139 serogroups of Vibrio cholerae occur in diverse natural niches, and usually cause mild and self-limiting gastrointestinal illness. However, they have well-documented potential to cause invasive and extra intestinal infections among immunocompromised patients. Furthermore, their ability to grow in low-salinity surface water, and the existence of asymptomatic human carriers, suggest novel acquisition routes for this unusual infection, even in people without obvious risk factors. Case presentation. A 62-year-old man presented with epigastric pain, vomiting and fever. The patient had a history of diabetes and cholecystectomy, although our initial examination did not reveal any significant findings that might indicate V. cholerae infection. However, blood cultures subsequently revealed the presence of V. cholerae, which was positively identified using both conventional and modern non-conventional technologies. The identity of the V. cholerae isolate was confirmed using Vitek MS (matrix-assisted laser desorption ionization-time of flight MS) and the FilmArray system, in addition to its initial identification using the Vitek 2 system. The septicaemia was successfully treated using a 14 day course of ciprofloxacin. Conclusion. The present case highlights the need to remain highly suspicious of non-O1/non-O139 V. cholerae infections in patients with known risk factors, as well as in healthy individuals with epidemiological exposure and compatible clinical symptoms. Special care should be taken to avoid false-positive results from confirmatory laboratory tests, as the organism can grow in fresh water, and the results should be verified using multiple methods. PMID- 28348804 TI - Cytolethal distending toxin-producing Escherichia coli strains causing severe diarrhoea in young Mexican children. AB - Introduction. Cytolethal distending toxins (CDTs), encoded by cdt genes, have DNase activity leading to cellular and nuclear distension, resulting in irreversible cell cycle arrest and apoptosis of target cells. cdt-positive Escherichia coli strains have been isolated from children with diarrhoea. There is, however, scant information on the prevalence and clinical presentation of diarrhoeal disease caused by these strains. Furthermore, toxin production of cdt positive strains is rarely confirmed. We report five young children with diarrhoea caused by CDT-producing E. coli in whom stools were negative for other bacterial or enteric pathogens. Case presentation. On admission to hospital, all children presented watery diarrhoea with high stool output (range 7-20 stools/24 h); five had fever of 38 degrees C or more and four presented vomiting. Dehydration was present in four patients, one of whom had hypovolaemic shock; one child also presented hyponatraemia and hypokalaemia. In two children, cdt positive strains were classified as typical and atypical enteropathogenic E. coli, and the remaining three harboured cdt-positive strains that did not belong to any diarrhoeagenic pathogroup. One cdt-positive strain from each case was characterized by a CDT cytotoxic assay and a cdt type-specific PCR. All strains produced the characteristic cellular intoxication due to CDT. Two strains carried the cdt-I, one cdt-III, one cdt-IV, and one concurrently had cdt-I, cdt-II and cdt-III genes. Conclusion. Our results suggest that CDT-producing E. coli strains are an infrequent, albeit significant, cause of severe diarrhoeal illness in children. Future research should measure the true burden of cdt-positive E. coli diarrhoea among children. PMID- 28348806 TI - Aerococcus urinae, a cause of cystitis with malodorous urine in a child: clinical and microbiological challenges. AB - Introduction. An infection of the lower urinary tract associated with an extremely unpleasant odour due to Aerococcus urinae in an otherwise healthy 5 year-old boy is described herein. Case presentation. Interestingly, imaging examination revealed the presence of a bladder diverticulum. Routine microbiological examination based on Gram staining, colony morphology and catalase reactivity suggested that the responsible pathogen could belong either to staphylococci, alpha-haemolytic streptococci or enterococci, which are more common urine isolates. Of note is that the VITEK 2 automated system could not identify the micro-organism. Susceptibility testing showed full sensitivity to beta-lactam antibiotics and resistance to trimethoprim/sulfamethoxazole. The isolate was subjected to 16S rRNA gene sequence analysis because of its unusual characteristics. It was identified as A. urinae and the sequence was deposited in GenBank under the accession number KU207150. Conclusion.A. urinae should be considered as a causative agent of urinary-tract infection associated with malodorous urine. PMID- 28348805 TI - A cardiac implantable device infection by Raoultella planticola in an immunocompromized patient. AB - Introduction. Infection of cardiac implantable electronic devices is a severe condition associated with high mortality, particularly in patients who are dependent upon heart-pacing devices. Staphylococci are found in 70 % of reported cases. Case presentation. We report the case of a cardiac-pacemaker infection in a 79-year-old man, cumulating a history of rheumatoid arthritis treated by corticosteroids and methotrexate by a recently identified micro-organism: Raoultella planticola. He presented local signs of infection on his VVI pacemaker implantation site and underwent urgent pocket device replacement under cefamandole antibioprophylaxis. On incision thick pus oozed out. It was necessary to perform a complete hardware extraction comprising the pulse generator and the ancient lead. Pus was inoculated into aerobic and anaerobic culture vials and Gram staining unveiled Gram-negative rods. Microbiology analysis identified the organism as R. planticola. A new pacing device was inserted on the contrlateral pectoral region. Ciprofloxacin enabled full recovery. A literature review concerning this pathogen revealed that it is involved in severe infections such as bloodstream infections, peritonitis, cellulitis, pneumonia and lung abscesses, and urinary tract infections. In these case reports, underlying co-morbidities were identified such as solid active neoplasia, recent chemotherapy, corticosteroids, solid-organ-recipient patients and recent open surgery. Conclusion.R. planticola is a serious emerging pathogen and contributes to the burden of various infectious conditions. Its pathogenicity and occurrence should be known by clinicians and a high level of awareness is necessary to precisely identify it provide the correct antibiotic regimen. PMID- 28348807 TI - Successful treatment of Listeria monocytogenes prosthetic valve endocarditis using rifampicin and benzylpenicillin in combination with valve replacement. AB - Introduction.Listeria monocytogenes is an uncommon cause of prosthetic valve endocarditis (PVE). Recommended antimicrobial therapy typically includes intravenous beta-lactams with or without synergistic aminoglycosides. In vitro studies have previously identified antagonism when rifampicin has been used in combination with beta-lactams. However, in vivo data of rifampicin use are limited despite its enhanced anti-biofilm activity. Case presentation. A 63-year old male presented with fever and back pain. L. monocytogenes bacteraemia and bioprosthetic aortic valve endocarditis was confirmed, along with spinal discitis and osteomyelitis. He was successfully treated with benzylpenicillin and rifampicin, in conjunction with valve replacement. Conclusion. Rifampicin remains an alternate agent to use, when there are contraindications to traditional aminoglycoside therapy. Further data on rifampicin use in L. monocytogenes PVE are awaited. PMID- 28348808 TI - Meningitis due to Moraxella nonliquefaciens in a paediatric patient: a case report and review of the literature. AB - Introduction.Moraxella nonliquefaciens is an unusual organism to be isolated from cerebral spinal fluid (CSF) and there exists only one case report of M. nonliquefaciens meningitis from a neonate. Moraxella species normally exist as part of the human upper respiratory tract flora and rarely cause invasive human disease. There are only a handful of case reports implicating the organism as a cause of endocarditis, bacteraemia, septic arthritis and endophthalmitis. Identification to the species level based on routine laboratory techniques has been challenging, with final identification often made through 16S rRNA sequencing. With the use of a newer diagnostic tool, matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) MS, we were able to rapidly identify the organism and initiate appropriate treatment. Case presentation. We present a rare care of M. nonliquefaciens meningitis in a paediatric patient with an underlying cranial anatomical defect due to Crouzon syndrome. She had been admitted to hospital 3 months previously with Streptococcus pneumoniae meningitis and mastoiditis, and returned to the emergency department with meningismus. CSF culture grew M. nonliquefaciens. She was treated with ceftriaxone with rapid improvement and eventually was taken for endoscopic surgical repair of a right encephalocele defect. Conclusion. The use of MALDI-TOF MS allowed for the rapid identification of the organism. The patient recovered with appropriate antimicrobial therapy and eventual surgical correction. An underlying anatomical defect should be considered in all patients who present with meningitis due to this unusual organism. PMID- 28348809 TI - Expanded roles of leucine-responsive regulatory protein in transcription regulation of the Escherichia coli genome: Genomic SELEX screening of the regulation targets. AB - Leucine-responsive regulatory protein (Lrp) is a transcriptional regulator for the genes involved in transport, biosynthesis and catabolism of amino acids in Escherichia coli. In order to identify the whole set of genes under the direct control of Lrp, we performed Genomic SELEX screening and identified a total of 314 Lrp-binding sites on the E. coli genome. As a result, the regulation target of Lrp was predicted to expand from the hitherto identified genes for amino acid metabolism to a set of novel target genes for utilization of amino acids for protein synthesis, including tRNAs, aminoacyl-tRNA synthases and rRNAs. Northern blot analysis indicated alteration of mRNA levels for at least some novel targets, including the aminoacyl-tRNA synthetase genes. Phenotype MicroArray of the lrp mutant indicated significant alteration in utilization of amino acids and peptides, whilst metabolome analysis showed variations in the concentration of amino acids in the lrp mutant. From these two datasets we realized a reverse correlation between amino acid levels and cell growth rate: fast-growing cells contain low-level amino acids, whilst a high level of amino acids exists in slow growing cells. Taken together, we propose that Lrp is a global regulator of transcription of a large number of the genes involved in not only amino acid transport and metabolism, but also amino acid utilization. PMID- 28348810 TI - K-Pax2: Bayesian identification of cluster-defining amino acid positions in large sequence datasets. AB - The recent growth in publicly available sequence data has introduced new opportunities for studying microbial evolution and spread. Because the pace of sequence accumulation tends to exceed the pace of experimental studies of protein function and the roles of individual amino acids, statistical tools to identify meaningful patterns in protein diversity are essential. Large sequence alignments from fast-evolving micro-organisms are particularly challenging to dissect using standard tools from phylogenetics and multivariate statistics because biologically relevant functional signals are easily masked by neutral variation and noise. To meet this need, a novel computational method is introduced that is easily executed in parallel using a cluster environment and can handle thousands of sequences with minimal subjective input from the user. The usefulness of this kind of machine learning is demonstrated by applying it to nearly 5000 haemagglutinin sequences of influenza A/H3N2.Antigenic and 3D structural mapping of the results show that the method can recover the major jumps in antigenic phenotype that occurred between 1968 and 2013 and identify specific amino acids associated with these changes. The method is expected to provide a useful tool to uncover patterns of protein evolution. PMID- 28348811 TI - Large tandem chromosome expansions facilitate niche adaptation during persistent infection with drug-resistant Staphylococcus aureus. AB - We used genomics to study the evolution of meticillin-resistant Staphylococcus aureus (MRSA) during a complex, protracted clinical infection. Preparing closed MRSA genomes from days 0 and 115 allowed us to precisely reconstruct all genetic changes that occurred. Twenty-three MRSA blood cultures were also obtained during treatment, yielding 44 colony morphotypes that varied in size, haemolysis and antibiotic susceptibility. A subset of 15 isolates was sequenced and shown to harbour a total of 37 sequence polymorphisms. Eighty per cent of all mutations occurred from day 45 onwards, which coincided with the appearance of discrete chromosome expansions, and concluded in the day 115 isolate with a 98 kb tandem DNA duplication. In all heterogeneous vancomycin-intermediate Staphylococcus aureus isolates, the chromosomal amplification spanned at least a 20 kb region that notably included mprF, a gene involved in resistance to antimicrobial peptides, and parC, an essential DNA replication gene with an unusual V463 codon insertion. Restoration of the chromosome after serial passage under non-selective growth was accompanied by increased susceptibility to antimicrobial peptide killing and reduced vancomycin resistance, two signature phenotypes that help explain the clinical persistence of this strain. Elevated expression of the V463 parC was deleterious to the cell and reduced colony size, but did not alter ciprofloxacin susceptibility. In this study, we identified large DNA expansions as a clinically relevant mechanism of S. aureus resistance and persistence, demonstrating the extent to which bacterial chromosomes remodel in the face of antibiotic and host immune pressures. PMID- 28348812 TI - Region-specific diversification of the highly virulent serotype 1 Streptococcus pneumoniae. AB - Serotype 1 Streptococcus pneumoniae is a leading cause of invasive pneumococcal disease (IPD) worldwide, with the highest burden in developing countries. We report the whole-genome sequencing analysis of 448 serotype 1 isolates from 27 countries worldwide (including 11 in Africa). The global serotype 1 population shows a strong phylogeographic structure at the continental level, and within Africa there is further region-specific structure. Our results demonstrate that region-specific diversification within Africa has been driven by limited cross region transfer events, genetic recombination and antimicrobial selective pressure. Clonal replacement of the dominant serotype 1 clones circulating within regions is uncommon; however, here we report on the accessory gene content that has contributed to a rare clonal replacement event of ST3081 with ST618 as the dominant cause of IPD in the Gambia. PMID- 28348813 TI - Redefining the differences in gene content between Yersinia pestis and Yersinia pseudotuberculosis using large-scale comparative genomics. AB - Yersinia pestis, the causative agent of plague, is best known for historical pandemics, but still actively causes disease in many parts of the world. Y. pestis is a recently derived clone of the pathogenic species Yersinia pseudotuberculosis, but is more associated with human infection. Numerous studies have documented genomic changes since the two species differentiated, although all of these studies used a relatively small sample set for defining these differences. In this study, we compared the complete genomic content between a diverse set of Y. pestis and Y. pseudotuberculosis genomes, and identified unique loci that could serve as diagnostic markers or for better understanding the evolution and pathogenesis of each group. Comparative genomics analyses also identified subtle variations in gene content between individual monophyletic clades within these species, based on a core genome single nucleotide polymorphism phylogeny that would have been undetected in a less comprehensive genome dataset. We also screened loci that were identified in other published studies as unique to either species and generally found a non-uniform distribution, suggesting that the assignment of these unique genes to either species should be re-evaluated in the context of current sequencing efforts. Overall, this study provides a high-resolution view into the genomic differences between Y. pestis and Y. pseudotuberculosis, demonstrating fine-scale differentiation and unique gene composition in both species. PMID- 28348814 TI - Applying phylogenomics to understand the emergence of Shiga-toxin-producing Escherichia coli O157:H7 strains causing severe human disease in the UK. AB - Shiga-toxin-producing Escherichia coli (STEC) O157:H7 is a recently emerged zoonotic pathogen with considerable morbidity. Since the emergence of this serotype in the 1980s, research has focussed on unravelling the evolutionary events from the E. coli O55:H7 ancestor to the contemporaneous globally dispersed strains observed today. In this study, the genomes of over 1000 isolates from both human clinical cases and cattle, spanning the history of STEC O157:H7 in the UK, were sequenced. Phylogenetic analysis revealed the ancestry, key acquisition events and global context of the strains. Dated phylogenies estimated the time to evolution of the most recent common ancestor of the current circulating global clone to be 175 years ago. This event was followed by rapid diversification. We show the acquisition of specific virulence determinates has occurred relatively recently and coincides with its recent detection in the human population. We used clinical outcome data from 493 cases of STEC O157:H7 to assess the relative risk of severe disease including haemolytic uraemic syndrome from each of the defined clades in the population and show the dramatic effect Shiga toxin repertoire has on virulence. We describe two strain replacement events that have occurred in the cattle population in the UK over the last 30 years, one resulting in a highly virulent strain that has accounted for the majority of clinical cases in the UK over the last decade. There is a need to understand the selection pressures maintaining Shiga-toxin-encoding bacteriophages in the ruminant reservoir and the study affirms the requirement for close surveillance of this pathogen in both ruminant and human populations. PMID- 28348815 TI - Directional gene flow and ecological separation in Yersinia enterocolitica. AB - Yersinia enterocolitica is a common cause of food-borne gastroenteritis worldwide. Recent work defining the phylogeny of the genus Yersinia subdivided Y. enterocolitica into six distinct phylogroups. Here, we provide detailed analyses of the evolutionary processes leading to the emergence of these phylogroups. The dominant phylogroups isolated from human infections, PG3-5, show very little diversity at the sequence level, but do present marked patterns of gain and loss of functions, including those involved in pathogenicity and metabolism, including the acquisition of phylogroup-specific O-antigen loci. We tracked gene flow across the species in the core and accessory genome, and show that the non pathogenic PG1 strains act as a reservoir for diversity, frequently acting as donors in recombination events. Analysis of the core and accessory genome also suggested that the different Y. enterocolitica phylogroups may be ecologically separated, in contrast to the long-held belief of common shared ecological niches across the Y. enterocolitica species. PMID- 28348817 TI - EuPaGDT: a web tool tailored to design CRISPR guide RNAs for eukaryotic pathogens. AB - Recent development of CRISPR-Cas9 genome editing has enabled highly efficient and versatile manipulation of a variety of organisms and adaptation of the CRISPR Cas9 system to eukaryotic pathogens has opened new avenues for studying these otherwise hard to manipulate organisms. Here we describe a webtool, Eukaryotic Pathogen gRNA Design Tool (EuPaGDT; available at http://grna.ctegd.uga.edu), which identifies guide RNA (gRNA) in input gene(s) to guide users in arriving at well-informed and appropriate gRNA design for many eukaryotic pathogens. Flexibility in gRNA design, accommodating unique eukaryotic pathogen (gene and genome) attributes and high-throughput gRNA design are the main features that distinguish EuPaGDT from other gRNA design tools. In addition to employing an array of known principles to score and rank gRNAs, EuPaGDT implements an effective on-target search algorithm to identify gRNA targeting multi-gene families, which are highly represented in these pathogens and play important roles in host-pathogen interactions. EuPaGDT also identifies and scores microhomology sequences flanking each gRNA targeted cut-site; these sites are often essential for the microhomology-mediated end joining process used for double-stranded break repair in these organisms. EuPaGDT also assists users in designing single-stranded oligonucleotides for homology directed repair. In batch processing mode, EuPaGDT is able to process genome-scale sequences, enabling preparation of gRNA libraries for large-scale screening projects. PMID- 28348816 TI - Genome-wide analysis of the response to nitric oxide in uropathogenic Escherichia coli CFT073. AB - Uropathogenic Escherchia coli (UPEC) is the causative agent of urinary tract infections. Nitric oxide (NO) is a toxic water-soluble gas that is encountered by UPEC in the urinary tract. Therefore, UPEC probably requires mechanisms to detoxify NO in the host environment. Thus far, flavohaemoglobin (Hmp), an NO denitrosylase, is the only demonstrated NO detoxification system in UPEC. Here we show that, in E. coli strain CFT073, the NADH-dependent NO reductase flavorubredoxin (FlRd) also plays a major role in NO scavenging. We generated a mutant that lacks all known and candidate NO detoxification pathways (Hmp, FlRd and the respiratory nitrite reductase, NrfA). When grown and assayed anaerobically, this mutant expresses an NO-inducible NO scavenging activity, pointing to the existence of a novel detoxification mechanism. Expression of this activity is inducible by both NO and nitrate, and the enzyme is membrane associated. Genome-wide transcriptional profiling of UPEC grown under anaerobic conditions in the presence of nitrate (as a source of NO) highlighted various aspects of the response of the pathogen to nitrate and NO. Several virulence associated genes are upregulated, suggesting that host-derived NO is a potential regulator of UPEC virulence. Chromatin immunoprecipitation and sequencing was used to evaluate the NsrR regulon in CFT073. We identified 49 NsrR binding sites in promoter regions in the CFT073 genome, 29 of which were not previously identified in E. coli K-12. NsrR may regulate some CFT073 genes that do not have homologues in E. coli K-12. PMID- 28348818 TI - High-throughput DNA sequencing of the moose rumen from different geographical locations reveals a core ruminal methanogenic archaeal diversity and a differential ciliate protozoal diversity. AB - Moose rumen samples from Vermont, Alaska and Norway were investigated for methanogenic archaeal and protozoal density using real-time PCR, and diversity using high-throughput sequencing of the 16S and 18S rRNA genes. Vermont moose showed the highest protozoal and methanogen densities. Alaskan samples had the highest percentages of Methanobrevibacter smithii, followed by the Norwegian samples. One Norwegian sample contained 43 % Methanobrevibacter thaueri, whilst all other samples contained < 10 %. Vermont samples had large percentages of Methanobrevibacter ruminantium, as did two Norwegian samples. Methanosphaera stadtmanae represented one-third of sequences in three samples. Samples were heterogeneous based on gender, geographical location and weight class using analysis of molecular variance (AMOVA). Two Alaskan moose contained >70 % Polyplastron multivesiculatum and one contained >75 % Entodinium spp. Protozoa from Norwegian moose belonged predominantly (>50 %) to the genus Entodinium, especially Entodinium caudatum. Norwegian moose contained a large proportion of sequences (25-97 %) which could not be classified beyond family. Protozoa from Vermont samples were predominantly Eudiplodinium rostratum (>75 %), with up to 7 % Diploplastron affine. Four of the eight Vermont samples also contained 5-12 % Entodinium spp. Samples were heterogeneous based on AMOVA, principal coordinate analysis and UniFrac. This study gives the first insight into the methanogenic archaeal diversity in the moose rumen. The high percentage of rumen archaeal species associated with high starch diets found in Alaskan moose corresponds well to previous data suggesting that they feed on plants high in starch. Similarly, the higher percentage of species related to forage diets in Vermont moose also relates well to their higher intake of fibre. PMID- 28348820 TI - Shetti, a simple tool to parse, manipulate and search large datasets of sequences. AB - Parsing and manipulating long and/or multiple protein or gene sequences can be a challenging process for experimental biologists and microbiologists lacking prior knowledge of bioinformatics and programming. Here we present a simple, easy, user friendly and versatile tool to parse, manipulate and search within large datasets of long and multiple protein or gene sequences. The Shetti tool can be used to search for a sequence, species, protein/gene or pattern/motif. Moreover, it can also be used to construct a universal consensus or molecular signatures for proteins based on their physical characteristics. Shetti is an efficient and fast tool that can deal with large sets of long sequences efficiently. Shetti parses UniProt Knowledgebase and NCBI GenBank flat files and visualizes them as a table. PMID- 28348819 TI - Recombination-mediated remodelling of host-pathogen interactions during Staphylococcus aureus niche adaptation. AB - Large-scale recombination events have led to the emergence of epidemic clones of several major bacterial pathogens. However, the functional impact of the recombination on clonal success is not understood. Here, we identified a novel widespread hybrid clone (ST71) of livestock-associated Staphylococcus aureus that evolved from an ancestor belonging to the major bovine lineage CC97, through multiple large-scale recombination events with other S. aureus lineages occupying the same ruminant niche. The recombination events, affecting a 329 kb region of the chromosome spanning the origin of replication, resulted in allele replacement and loss or gain of an array of genes influencing host-pathogen interactions. Of note, molecular functional analyses revealed that the ST71 hybrid clone has acquired multiple novel pathogenic traits associated with acquired and innate immune evasion and bovine extracellular matrix adherence. These findings provide a paradigm for the impact of large-scale recombination events on the rapid evolution of bacterial pathogens within defined ecological niches. PMID- 28348822 TI - Recombination produces coherent bacterial species clusters in both core and accessory genomes. AB - BACKGROUND: Population samples show bacterial genomes can be divided into a core of ubiquitous genes and accessory genes that are present in a fraction of isolates. The ecological significance of this variation in gene content remains unclear. However, microbiologists agree that a bacterial species should be 'genomically coherent', even though there is no consensus on how this should be determined. RESULTS: We use a parsimonious model combining diversification in both the core and accessory genome, including mutation, homologous recombination (HR) and horizontal gene transfer (HGT) introducing new loci, to produce a population of interacting clusters of strains with varying genome content. New loci introduced by HGT may then be transferred on by HR. The model fits well to a systematic population sample of 616 pneumococcal genomes, capturing the major features of the population structure with parameter values that agree well with empirical estimates. CONCLUSIONS: The model does not include explicit selection on individual genes, suggesting that crude comparisons of gene content may be a poor predictor of ecological function. We identify a clearly divergent subpopulation of pneumococci that are inconsistent with the model and may be considered genomically incoherent with the rest of the population. These strains have a distinct disease tropism and may be rationally defined as a separate species. We also find deviations from the model that may be explained by recent population bottlenecks or spatial structure. PMID- 28348821 TI - Genome sequence comparisons of serial multi-drug-resistant Mycobacterium tuberculosis isolates over 21 years of infection in a single patient. AB - We report a case of chronic pulmonary multi-drug-resistant tuberculosis. Despite 14 years of treatment, Mycobacterium tuberculosis was persistently isolated from sputum. Following treatment cessation the patient remained well, although M. tuberculosis was isolated from sputum for a further 8 years. Genome sequencing of eight serial M. tuberculosis isolates cultured between 1991 and 2011 revealed 17 mutations (0.8 mutations per genome year- 1). Eight of these were persisting mutations and only two mutations were detected in the 7 years following cessation of treatment in 2004. In four isolates there were mixed alleles, suggesting the likely presence of bacterial subpopulations. The initial 1991 isolate demonstrated genotypic resistance to isoniazid (katG W91R), rifampicin (rpoB S531L), ethambutol (embB M306V), streptomycin (gidB L16R), quinolones (gyrA S95T) and P-aminosalicylic acid (thyA T202A). Subsequent resistance mutations developed for pyrazinamide (pncA I31F) and ethionamide (ethA frameshift). Such information might have been instructive when developing a treatment regimen. In retrospect and with the benefit of high-resolution genomic hindsight we were able to determine that the patient received only one or two active anti-tuberculous agents for most of their treatment. Additionally, mutations in bacA and Rv2326c were detected, which may have contributed to the persistent but mild disease course. BacA is likely to be associated with maintenance of chronic infection and Rv2326c with a decreased bacterial metabolic state. These results expand our understanding of M. tuberculosis evolution during human infection and underline the link between antibiotic resistance and clinical persistence. PMID- 28348823 TI - Whole-genome sequencing investigation of animal-skin-drum-associated UK anthrax cases reveals evidence of mixed populations and relatedness to a US case. AB - There have been two anthrax cases affecting people that played and/or made animal skin drums in the UK during the last 10 years, with single fatal occurrences in Scotland in 2006 and London in 2008. Investigations by the Health Protection Agency (now Public Health England) employing multi-locus-variable number tandem repeat analysis had previously linked the clinical cases to spores associated with animal skins and drums the patients had been in contact with. In this study, whole-genome sequencing of 23 Bacillus anthracis isolates harvested during the investigations was performed. High-quality draft assemblies of these genomes provided greater characterization of the B. anthracis strains present and placed them all upon a new branch of the global phylogeny. Although closely related, the clinical isolates from the two events, and another isolated from a drum-skin associated case in New York in 2006, were distinct from each other. Multiple distinct genotypes were found during both investigations, implying either multiple contamination events or a single heterogeneous contamination. One environmental isolate from the Scottish incident was more closely related to London isolates than to the other Scottish isolates. As B. anthracis of this subgroup was present at both geographically and temporally distinct events, it may be more widespread at the source of contamination. All isolates were distinct from currently characterized West African strains, despite this being the likely origin of the drums and hides, therefore adding to our knowledge of B. anthracis diversity in the region. PMID- 28348824 TI - 70th Anniversary Collection for the Microbiology Society: Microbial Genomics. AB - In the context of the Microbiology Society's 70th anniversary celebration, Microbial Genomics (MGen) is the new baby of the Society's publishing family. Born on 15 July 2015, it is still in its infancy but already showing promising signs, and we have great hopes and expectations for the future. The journal captures a new and expanding area of research, one which is already having a major impact on research in microbiology, and has and continues to accelerate discoveries in the field. PMID- 28348825 TI - Introduction and establishment of fluoroquinolone-resistant Shigella sonnei into Bhutan. AB - Shigella sonnei is a major contributor to the global burden of diarrhoeal disease, generally associated with dysenteric diarrhoea in developed countries but also emerging in developing countries. The reason for the recent success of S. sonnei is unknown, but is likely catalysed by its ability to acquire resistance against multiple antimicrobials. Between 2011 and 2013, S. sonnei exhibiting resistance to fluoroquinolones, the first-line treatment recommended for shigellosis, emerged in Bhutan. Aiming to reconstruct the introduction and establishment of fluoroquinolone-resistant S. sonnei populations in Bhutan, we performed whole-genome sequencing on 71 S. sonnei samples isolated in Bhutan between 2011 and 2013.We found that these strains represented an expansion of a clade within the previously described lineage III, found specifically in Central Asia. Temporal phylogenetic reconstruction demonstrated that all of the sequenced Bhutanese S. sonnei diverged from a single ancestor that was introduced into Bhutan around 2006. Our data additionally predicted that fluoroquinolone resistance, conferred by mutations in gyrA and parC, arose prior to the introduction of the founder strain into Bhutan. Once established in Bhutan, these S. sonnei had access to a broad gene pool, as indicated by the acquisition of extended-spectrum beta-lactamase-encoding plasmids and genes encoding type IV pili. The data presented here outline a model for the introduction and maintenance of fluoroquinolone-resistant S. sonnei in a new setting. Given the current circulation of fluoroquinolone-resistant S. sonnei in Asia, we speculate that this pattern of introduction is being recapitulated across the region and beyond. PMID- 28348826 TI - Comparative genomics of pyridoxal 5'-phosphate-dependent transcription factor regulons in Bacteria. AB - The MocR-subfamily transcription factors (MocR-TFs) characterized by the GntR family DNA-binding domain and aminotransferase-like sensory domain are broadly distributed among certain lineages of Bacteria. Characterized MocR-TFs bind pyridoxal 5'-phosphate (PLP) and control transcription of genes involved in PLP, gamma aminobutyric acid (GABA) and taurine metabolism via binding specific DNA operator sites. To identify putative target genes and DNA binding motifs of MocR TFs, we performed comparative genomics analysis of over 250 bacterial genomes. The reconstructed regulons for 825 MocR-TFs comprise structural genes from over 200 protein families involved in diverse biological processes. Using the genome context and metabolic subsystem analysis we tentatively assigned functional roles for 38 out of 86 orthologous groups of studied regulators. Most of these MocR-TF regulons are involved in PLP metabolism, as well as utilization of GABA, taurine and ectoine. The remaining studied MocR-TF regulators presumably control genes encoding enzymes involved in reduction/oxidation processes, various transporters and PLP-dependent enzymes, for example aminotransferases. Predicted DNA binding motifs of MocR-TFs are generally similar in each orthologous group and are characterized by two to four repeated sequences. Identified motifs were classified according to their structures. Motifs with direct and/or inverted repeat symmetry constitute the majority of inferred DNA motifs, suggesting preferable TF dimerization in head-to-tail or head-to-head configuration. The obtained genomic collection of in silico reconstructed MocR-TF motifs and regulons in Bacteria provides a basis for future experimental characterization of molecular mechanisms for various regulators in this family. PMID- 28348828 TI - The RegA regulon exhibits variability in response to altered growth conditions and differs markedly between Rhodobacter species. AB - The RegB/RegA two-component system from Rhodobacter capsulatus regulates global changes in gene expression in response to alterations in oxygen levels. Studies have shown that RegB/RegA controls many energy-generating and energy-utilizing systems such as photosynthesis, nitrogen fixation, carbon fixation, hydrogen utilization, respiration, electron transport and denitrification. In this report, we utilized RNA-seq and ChIP-seq to analyse the breadth of genes indirectly and directly regulated by RegA. A comparison of mRNA transcript levels in wild type cells relative to a RegA deletion strain shows that there are 257 differentially expressed genes under photosynthetic defined minimal growth medium conditions and 591 differentially expressed genes when grown photosynthetically in a complex rich medium. ChIP-seq analysis also identified 61 unique RegA binding sites with a well-conserved recognition sequence, 33 of which exhibit changes in neighbouring gene expression. These transcriptome results define new members of the RegA regulon including genes involved in iron transport and motility. These results also reveal that the set of genes that are regulated by RegA are growth medium specific. Similar analyses under dark aerobic conditions where RegA is thought not to be phosphorylated by RegB reveal 40 genes that are differentially expressed in minimal medium and 20 in rich medium. Finally, a comparison of the R. capsulatus RegA regulon with the orthologous PrrA regulon in Rhodobacter sphaeroides shows that the number of photosystem genes regulated by RegA and PrrA are similar but that the identity of genes regulated by RegA and PrrA beyond those involved in photosynthesis are quite distinct. PMID- 28348827 TI - Evolutionary interpretations of mycobacteriophage biodiversity and host-range through the analysis of codon usage bias. AB - In an genomics course sponsored by the Howard Hughes Medical Institute (HHMI), undergraduate students have isolated and sequenced the genomes of more than 1,150 mycobacteriophages, creating the largest database of sequenced bacteriophages able to infect a single host, Mycobacterium smegmatis, a soil bacterium. Genomic analysis indicates that these mycobacteriophages can be grouped into 26 clusters based on genetic similarity. These clusters span a continuum of genetic diversity, with extensive genomic mosaicism among phages in different clusters. However, little is known regarding the primary hosts of these mycobacteriophages in their natural habitats, nor of their broader host ranges. As such, it is possible that the primary host of many newly isolated mycobacteriophages is not M. smegmatis, but instead a range of closely related bacterial species. However, determining mycobacteriophage host range presents difficulties associated with mycobacterial cultivability, pathogenicity and growth. Another way to gain insight into mycobacteriophage host range and ecology is through bioinformatic analysis of their genomic sequences. To this end, we examined the correlations between the codon usage biases of 199 different mycobacteriophages and those of several fully sequenced mycobacterial species in order to gain insight into the natural host range of these mycobacteriophages. We find that UPGMA clustering tends to match, but not consistently, clustering by shared nucleotide sequence identify. In addition, analysis of GC content, tRNA usage and correlations between mycobacteriophage and mycobacterial codon usage bias suggests that the preferred host of many clustered mycobacteriophages is not M. smegmatis but other, as yet unknown, members of the mycobacteria complex or closely allied bacterial species. PMID- 28348829 TI - Monomorphic genotypes within a generalist lineage of Campylobacter jejuni show signs of global dispersion. AB - The decreased costs of genome sequencing have increased the capability to apply whole-genome sequencing to epidemiological surveillance of zoonotic Campylobacter jejuni. However, knowledge of the genetic diversity of this bacteria is vital for inferring relatedness between epidemiologically linked isolates and a necessary prerequisite for correct application of this methodology. To address this issue in C. jejuni we investigated the spatial and temporal signals in the genomes of a major clonal complex and generalist lineage, ST-45 CC, by analysing the population structure and genealogy as well as applying genome-wide association analysis of 340 isolates from across Europe collected over a wide time range. The occurrence and strength of the geographical signal varied between sublineages and followed the clonal frame when present, while no evidence of a temporal signal was found. Certain sublineages of ST-45 formed discrete and genetically isolated clades containing isolates with extremely similar genomes regardless of time and location of sampling. Based on a separate data set, these monomorphic genotypes represent successful C. jejuni clones, possibly spread around the globe by rapid animal (migrating birds), food or human movement. In addition, we observed an incongruence between the genealogy of the strains and multilocus sequence typing (MLST), challenging the existing clonal complex definition and the use of whole genome gene-by-gene hierarchical nomenclature schemes for C. jejuni. PMID- 28348830 TI - Population-genomic insights into emergence, crop adaptation and dissemination of Pseudomonas syringae pathogens. AB - Many bacterial pathogens are well characterized but, in some cases, little is known about the populations from which they emerged. This limits understanding of the molecular mechanisms underlying disease. The crop pathogen Pseudomonas syringae sensu lato has been widely isolated from the environment, including wild plants and components of the water cycle, and causes disease in several economically important crops. Here, we compared genome sequences of 45 P. syringae crop pathogen outbreak strains with 69 closely related environmental isolates. Phylogenetic reconstruction revealed that crop pathogens emerged many times independently from environmental populations. Unexpectedly, differences in gene content between environmental populations and outbreak strains were minimal with most virulence genes present in both. However, a genome-wide association study identified a small number of genes, including the type III effector genes hopQ1 and hopD1, to be associated with crop pathogens, but not with environmental populations, suggesting that this small group of genes may play an important role in crop disease emergence. Intriguingly, genome-wide analysis of homologous recombination revealed that the locus Psyr 0346, predicted to encode a protein that confers antibiotic resistance, has been frequently exchanged among lineages and thus may contribute to pathogen fitness. Finally, we found that isolates from diseased crops and from components of the water cycle, collected during the same crop disease epidemic, form a single population. This provides the strongest evidence yet that precipitation and irrigation water are an overlooked inoculum source for disease epidemics caused by P. syringae. PMID- 28348831 TI - Methionine-mediated gene expression and characterization of the CmhR regulon in Streptococcus pneumoniae. AB - This study investigated the transcriptomic response of Streptococcus pneumoniae D39 to methionine. Transcriptome comparison of the S. pneumoniae D39 wild-type grown in chemically defined medium with 0-10 mM methionine revealed the elevated expression of various genes/operons involved in methionine synthesis and transport (fhs, folD, gshT, metA, metB-csd, metEF, metQ, tcyB, spd-0150, spd-0431 and spd-0618). Furthermore, beta-galactosidase assays and quantitative RT-PCR studies demonstrated that the transcriptional regulator, CmhR (SPD-0588), acts as a transcriptional activator of the fhs, folD, metB-csd, metEF, metQ and spd-0431 genes. A putative regulatory site of CmhR was identified in the promoter region of CmhR-regulated genes and this CmhR site was further confirmed by promoter mutational experiments. PMID- 28348832 TI - Genomic analysis of Salmonella enterica serotype Paratyphi A during an outbreak in Cambodia, 2013-2015. AB - In 2013, an unusual increase in the number of Salmonella enterica serotype Paratyphi A (Salmonella Paratyphi A) infections was reported in patients in Phnom Penh, Cambodia, and in European, American and Japanese travellers returning from Cambodia. Epidemiological investigations did not identify a common source of exposure. To analyse the population structure and genetic diversity of these Salmonella Paratyphi A isolates, we used whole-genome sequencing on 65 isolates collected from 1999 to 2014: 55 from infections acquired in Cambodia and 10 from infections acquired in other countries in Asia, Africa and Europe. Short-read sequences from 80 published genomes from around the world and from 13 published genomes associated with an outbreak in China were also included. Pulsed-field gel electrophoresis (PFGE) was performed on a subset of isolates. Genomic analyses were found to provide much more accurate information for tracking the individual strains than PFGE. All but 2 of the 36 isolates acquired in Cambodia during 2013 2014 belonged to the same clade, C5, of lineage C. This clade has been isolated in Cambodia since at least 1999. The Chinese outbreak isolates belonged to a different clade (C4) and were resistant to nalidixic acid, whereas the Cambodian outbreak isolates displayed pan-susceptibility to antibiotics. Since 2014, the total number of cases has decreased, but there has been an increase in the frequency with which nalidixic acid-resistant C5 isolates are isolated. The frequency of these isolates should be monitored over time, because they display decreased susceptibility to ciprofloxacin, the first-choice antibiotic for treating paratyphoid fever. PMID- 28348833 TI - Microreact: visualizing and sharing data for genomic epidemiology and phylogeography. AB - Visualization is frequently used to aid our interpretation of complex datasets. Within microbial genomics, visualizing the relationships between multiple genomes as a tree provides a framework onto which associated data (geographical, temporal, phenotypic and epidemiological) are added to generate hypotheses and to explore the dynamics of the system under investigation. Selected static images are then used within publications to highlight the key findings to a wider audience. However, these images are a very inadequate way of exploring and interpreting the richness of the data. There is, therefore, a need for flexible, interactive software that presents the population genomic outputs and associated data in a user-friendly manner for a wide range of end users, from trained bioinformaticians to front-line epidemiologists and health workers. Here, we present Microreact, a web application for the easy visualization of datasets consisting of any combination of trees, geographical, temporal and associated metadata. Data files can be uploaded to Microreact directly via the web browser or by linking to their location (e.g. from Google Drive/Dropbox or via API), and an integrated visualization via trees, maps, timelines and tables provides interactive querying of the data. The visualization can be shared as a permanent web link among collaborators, or embedded within publications to enable readers to explore and download the data. Microreact can act as an end point for any tool or bioinformatic pipeline that ultimately generates a tree, and provides a simple, yet powerful, visualization method that will aid research and discovery and the open sharing of datasets. PMID- 28348834 TI - Genome-scale rates of evolutionary change in bacteria. AB - Estimating the rates at which bacterial genomes evolve is critical to understanding major evolutionary and ecological processes such as disease emergence, long-term host-pathogen associations and short-term transmission patterns. The surge in bacterial genomic data sets provides a new opportunity to estimate these rates and reveal the factors that shape bacterial evolutionary dynamics. For many organisms estimates of evolutionary rate display an inverse association with the time-scale over which the data are sampled. However, this relationship remains unexplored in bacteria due to the difficulty in estimating genome-wide evolutionary rates, which are impacted by the extent of temporal structure in the data and the prevalence of recombination. We collected 36 whole genome sequence data sets from 16 species of bacterial pathogens to systematically estimate and compare their evolutionary rates and assess the extent of temporal structure in the absence of recombination. The majority (28/36) of data sets possessed sufficient clock-like structure to robustly estimate evolutionary rates. However, in some species reliable estimates were not possible even with 'ancient DNA' data sampled over many centuries, suggesting that they evolve very slowly or that they display extensive rate variation among lineages. The robustly estimated evolutionary rates spanned several orders of magnitude, from approximately 10-5 to 10-8 nucleotide substitutions per site year 1. This variation was negatively associated with sampling time, with this relationship best described by an exponential decay curve. To avoid potential estimation biases, such time-dependency should be considered when inferring evolutionary time-scales in bacteria. PMID- 28348835 TI - Whole genome analysis of Yersinia ruckeri isolated over 27 years in Australia and New Zealand reveals geographical endemism over multiple lineages and recent evolution under host selection. AB - Yersinia ruckeri is a salmonid pathogen with widespread distribution in cool temperate waters including Australia and New Zealand, two isolated environments with recently developed salmonid farming industries. Phylogenetic comparison of 58 isolates from Australia, New Zealand, USA, Chile, Finland and China based on non-recombinant core genome SNPs revealed multiple deep-branching lineages, with a most recent common ancestor estimated at 18 500 years BP (12 355-24 757 95% HPD) and evidence of Australasian endemism. Evolution within the Tasmanian Atlantic salmon serotype O1b lineage has been slow, with 63 SNPs describing the variance over 27 years. Isolates from the prevailing lineage are poorly/non motile compared to a lineage pre-vaccination, introduced in 1997, which is highly motile but has not been isolated since from epizootics. A non-motile phenotype has arisen independently in Tasmania compared to Europe and USA through a frameshift in fliI, encoding the ATPase of the flagella cluster. We report for the first time lipopolysaccharide O-antigen serotype O2 isolates in Tasmania. This phenotype results from deletion of the O-antigen cluster and consequent loss of high-molecular-weight O-antigen. This phenomenon has occurred independently on three occasions on three continents (Australasia, North America and Asia) as O2 isolates from the USA, China and Tasmania share the O-antigen deletion but occupy distant lineages. Despite the European and North American origins of the Australasian salmonid stocks, the lineages of Y. ruckeri in Australia and New Zealand are distinct from those of the northern hemisphere, suggesting they are pre-existing ancient strains that have emerged and evolved with the introduction of susceptible hosts following European colonization. PMID- 28348836 TI - Evolution of a zoonotic pathogen: investigating prophage diversity in enterohaemorrhagic Escherichia coli O157 by long-read sequencing. AB - Enterohaemorrhagic Escherichia coli (EHEC) O157 is a zoonotic pathogen for which colonization of cattle and virulence in humans is associated with multiple horizontally acquired genes, the majority present in active or cryptic prophages. Our understanding of the evolution and phylogeny of EHEC O157 continues to develop primarily based on core genome analyses; however, such short-read sequences have limited value for the analysis of prophage content and its chromosomal location. In this study, we applied Single Molecule Real Time (SMRT) sequencing, using the Pacific Biosciences long-read sequencing platform, to isolates selected from the main sub-clusters of this clonal group. Prophage regions were extracted from these sequences and from published reference strains. Genome position and prophage diversity were analysed along with genetic content. Prophages could be assigned to clusters, with smaller prophages generally exhibiting less diversity and preferential loss of structural genes. Prophages encoding Shiga toxin (Stx) 2a and Stx1a were the most diverse, and more variable compared to prophages encoding Stx2c, further supporting the hypothesis that Stx2c-prophage integration was ancestral to acquisition of other Stx types. The concept that phage type (PT) 21/28 (Stx2a+, Stx2c+) strains evolved from PT32 (Stx2c+) was supported by analysis of strains with excised Stx-encoding prophages. Insertion sequence elements were over-represented in prophage sequences compared to the rest of the genome, showing integration in key genes such as stx and an excisionase, the latter potentially acting to capture the bacteriophage into the genome. Prophage profiling should allow more accurate prediction of the pathogenic potential of isolates. PMID- 28348837 TI - Whole genome sequencing to investigate a putative outbreak of the virulent community-associated methicillin-resistant Staphylococcus aureus ST93 clone in a remote Indigenous community. AB - We report two cases of severe pneumonia due to clone ST93 methicillin-resistant Staphylococcus aureus (MRSA) presenting from a remote Australian Indigenous community within a 2-week period, and the utilization of whole genome sequences to determine whether these were part of an outbreak. S. aureus was isolated from 12 of 92 nasal swabs collected from 25 community households (including the two index households); one isolate was ST93. Three of five skin lesion S. aureus isolates obtained at the community were ST93. Whole genome sequencing of the ST93 isolates from this study and a further 20 ST93 isolates from the same region suggested that recent transmission and progression to disease had not taken place. The proximity in time and space of the two severe pneumonia cases is probably a reflection of the high burden of disease due to ST93 MRSA in this population where skin infections and household crowding are common. PMID- 28348838 TI - Sequence-based analysis of the genus Ruminococcus resolves its phylogeny and reveals strong host association. AB - It has become increasingly clear that the composition of mammalian gut microbial communities is substantially diet driven. These microbiota form intricate mutualisms with their hosts, which have profound implications on overall health. For example, many gut microbes are involved in the conversion of host-ingested dietary polysaccharides into host-usable nutrients. One group of important gut microbial symbionts are bacteria in the genus Ruminococcus. Originally isolated from the bovine rumen, ruminococci have been found in numerous mammalian hosts, including other ruminants, and non-ruminants such as horses, pigs and humans. All ruminococci require fermentable carbohydrates for growth, and their substrate preferences appear to be based on the diet of their particular host. Most ruminococci that have been studied are those capable of degrading cellulose, much less is known about non-cellulolytic non-ruminant-associated species, and even less is known about the environmental distribution of ruminococci as a whole. Here, we capitalized on the wealth of publicly available 16S rRNA gene sequences, genomes and large-scale microbiota studies to both resolve the phylogenetic placement of described species in the genus Ruminococcus, and further demonstrate that this genus has largely unexplored diversity and a staggering host distribution. We present evidence that ruminococci are predominantly associated with herbivores and omnivores, and our data supports the hypothesis that very few ruminococci are found consistently in non-host-associated environments. This study not only helps to resolve the phylogeny of this important genus, but also provides a framework for understanding its distribution in natural systems. PMID- 28348839 TI - Long-range dispersal moved Francisella tularensis into Western Europe from the East. AB - For many infections transmitting to humans from reservoirs in nature, disease dispersal patterns over space and time are largely unknown. Here, a reversed genomics approach helped us understand disease dispersal and yielded insight into evolution and biological properties of Francisella tularensis, the bacterium causing tularemia. We whole-genome sequenced 67 strains and characterized by single-nucleotide polymorphism assays 138 strains, collected from individuals infected 1947-2012 across Western Europe. We used the data for phylogenetic, population genetic and geographical network analyses. All strains (n=205) belonged to a monophyletic population of recent ancestry not found outside Western Europe. Most strains (n=195) throughout the study area were assigned to a star-like phylogenetic pattern indicating that colonization of Western Europe occurred via clonal expansion. In the East of the study area, strains were more diverse, consistent with a founder population spreading from east to west. The relationship of genetic and geographic distance within the F. tularensis population was complex and indicated multiple long-distance dispersal events. Mutation rate estimates based on year of isolation indicated null rates; in outbreak hotspots only, there was a rate of 0.4 mutations/genome/year. Patterns of nucleotide substitution showed marked AT mutational bias suggestive of genetic drift. These results demonstrate that tularemia has moved from east to west in Europe and that F. tularensis has a biology characterized by long-range geographical dispersal events and mostly slow, but variable, replication rates. The results indicate that mutation-driven evolution, a resting survival phase, genetic drift and long-distance geographical dispersal events have interacted to generate genetic diversity within this species. PMID- 28348842 TI - Big data or bust: realizing the microbial genomics revolution. AB - Pathogen genomics has the potential to transform the clinical and public health management of infectious diseases through improved diagnosis, detection and tracking of antimicrobial resistance and outbreak control. However, the wide ranging benefits of this technology can only fully be realized through the timely collation, integration and sharing of genomic and clinical/epidemiological metadata by all those involved in the delivery of genomic-informed services. As part of our review on bringing pathogen genomics into 'health-service' practice, we undertook extensive stakeholder consultation to examine the factors integral to achieving effective data sharing and integration. Infrastructure tailored to the needs of clinical users, as well as practical support and policies to facilitate the timely and responsible sharing of data with relevant health authorities and beyond, are all essential. We propose a tiered data sharing and integration model to maximize the immediate and longer term utility of microbial genomics in healthcare. Realizing this model at the scale and sophistication necessary to support national and international infection management services is not uncomplicated. Yet the establishment of a clear data strategy is paramount if failures in containing disease spread due to inadequate knowledge sharing are to be averted, and substantial progress made in tackling the dangers posed by infectious diseases. PMID- 28348840 TI - Identification of Klebsiella capsule synthesis loci from whole genome data. AB - Klebsiella pneumoniae is a growing cause of healthcare-associated infections for which multi-drug resistance is a concern. Its polysaccharide capsule is a major virulence determinant and epidemiological marker. However, little is known about capsule epidemiology since serological typing is not widely accessible and many isolates are serologically non-typeable. Molecular typing techniques provide useful insights, but existing methods fail to take full advantage of the information in whole genome sequences. We investigated the diversity of the capsule synthesis loci (K-loci) among 2503 K. pneumoniae genomes. We incorporated analyses of full-length K-locus nucleotide sequences and also clustered protein encoding sequences to identify, annotate and compare K-locus structures. We propose a standardized nomenclature for K-loci and present a curated reference database. A total of 134 distinct K-loci were identified, including 31 novel types. Comparative analyses indicated 508 unique protein-encoding gene clusters that appear to reassort via homologous recombination. Extensive intra- and inter locus nucleotide diversity was detected among the wzi and wzc genes, indicating that current molecular typing schemes based on these genes are inadequate. As a solution, we introduce Kaptive, a novel software tool that automates the process of identifying K-loci based on full locus information extracted from whole genome sequences (https://github.com/katholt/Kaptive). This work highlights the extensive diversity of Klebsiella K-loci and the proteins that they encode. The nomenclature, reference database and novel typing method presented here will become essential resources for genomic surveillance and epidemiological investigations of this pathogen. PMID- 28348841 TI - Polysaccharide utilization loci and nutritional specialization in a dominant group of butyrate-producing human colonic Firmicutes. AB - Firmicutes and Bacteroidetes are the predominant bacterial phyla colonizing the healthy human large intestine. Whilst both ferment dietary fibre, genes responsible for this important activity have been analysed only in the Bacteroidetes, with very little known about the Firmicutes. This work investigates the carbohydrate-active enzymes (CAZymes) in a group of Firmicutes, Roseburia spp. and Eubacterium rectale, which play an important role in producing butyrate from dietary carbohydrates and in health maintenance. Genome sequences of 11 strains representing E. rectale and four Roseburia spp. were analysed for carbohydrate-active genes. Following assembly into a pan-genome, core, variable and unique genes were identified. The 1840 CAZyme genes identified in the pan genome were assigned to 538 orthologous groups, of which only 26 were present in all strains, indicating considerable inter-strain variability. This analysis was used to categorize the 11 strains into four carbohydrate utilization ecotypes (CUEs), which were shown to correspond to utilization of different carbohydrates for growth. Many glycoside hydrolase genes were found linked to genes encoding oligosaccharide transporters and regulatory elements in the genomes of Roseburia spp. and E. rectale, forming distinct polysaccharide utilization loci (PULs). Whilst PULs are also a common feature in Bacteroidetes, key differences were noted in these Firmicutes, including the absence of close homologues of Bacteroides polysaccharide utilization genes, hence we refer to Gram-positive PULs (gpPULs). Most CAZyme genes in the Roseburia/E. rectale group are organized into gpPULs. Variation in gpPULs can explain the high degree of nutritional specialization at the species level within this group. PMID- 28348843 TI - Identification of commonly expressed exoproteins and proteolytic cleavage events by proteomic mining of clinically relevant UK isolates of Staphylococcus aureus. AB - The range of exoproteins and core exoproteome of 14 Staphylococcus aureus isolates representing major lineages associated with asymptomatic carriage and clinical disease in the UK was identified by MS proteomics using a combined database incorporating sequences derived from 39 S. aureus genomes. In all, 632 different proteins were identified and, of these, only 52 (8 %) were found in all 14 isolates whereas 144 (23 %) were found in just a single isolate. Comparison of the observed mass of each protein (based on migration by SDS-PAGE) with its predicted mass (based on amino acid sequence) suggested that 95 % of the proteins identified were not subject to any major post-translational modification. Migration of 5 % of the proteins was not as expected: 1 % of the proteins migrated at a mass greater than predicted, while 4 % appeared to have undergone proteolytic cleavage; these included SsaA2, Aur, SspP, Ebh as well as BlaR1, MecR1, FsH, OatA and LtaS. Intriguingly, a truncated SasG was produced by a single CC8 USA300-like strain. The analysis provided evidence of the marked heterogeneity in protein expression by S. aureus in broth, while yielding a core but narrow common exoproteome. PMID- 28348844 TI - Five decades of genome evolution in the globally distributed, extensively antibiotic-resistant Acinetobacter baumannii global clone 1. AB - The majority of Acinetobacter baumannii isolates that are multiply, extensively and pan-antibiotic resistant belong to two globally disseminated clones, GC1 and GC2, that were first noticed in the 1970s. Here, we investigated microevolution and phylodynamics within GC1 via analysis of 45 whole-genome sequences, including 23 sequenced for this study. The most recent common ancestor of GC1 arose around 1960 and later diverged into two phylogenetically distinct lineages. In the 1970s, the main lineage acquired the AbaR resistance island, conferring resistance to older antibiotics, via a horizontal gene transfer event. We estimate a mutation rate of ~5 SNPs genome- 1 year- 1 and detected extensive recombination within GC1 genomes, introducing nucleotide diversity into the population at >20 times the substitution rate (the ratio of SNPs introduced by recombination compared with mutation was 22). The recombination events were non randomly distributed in the genome and created significant diversity within loci encoding outer surface molecules (including the capsular polysaccharide, the outer core lipooligosaccharide and the outer membrane protein CarO), and spread antimicrobial resistance-conferring mutations affecting the gyrA and parC genes and insertion sequence insertions activating the ampC gene. Both GC1 lineages accumulated resistance to newer antibiotics through various genetic mechanisms, including the acquisition of plasmids and transposons or mutations in chromosomal genes. Our data show that GC1 has diversified into multiple successful extensively antibiotic-resistant subclones that differ in their surface structures. This has important implications for all avenues of control, including epidemiological tracking, antimicrobial therapy and vaccination. PMID- 28348845 TI - Towards the complete small RNome of Acinetobacter baumannii. AB - In recent years, the Gram-negative bacterium Acinetobacter baumannii has garnered considerable attention for its unprecedented capacity to rapidly develop resistance to antibacterial therapeutics. This is coupled with the seemingly epidemic emergence of new hyper-virulent strains. Although strain-specific differences for A. baumannii isolates have been well described, these studies have primarily focused on proteinaceous factors. At present, only limited publications have investigated the presence and role of small regulatory RNA (sRNA) transcripts. Herein, we perform such an analysis, describing the RNA-seq based identification of 78 A. baumannii sRNAs in the AB5075 background. Together with six previously identified elements, we include each of these in a new genome annotation file, which will serve as a tool to investigate regulatory events in this organism. Our work reveals that the sRNAs display high expression, accounting for >50 % of the 20 most strongly expressed genes. Through conservation analysis we identified six classes of similar sRNAs, with one found to be particularly abundant and homologous to regulatory, C4 antisense RNAs found in bacteriophages. These elements appear to be processed from larger transcripts in an analogous manner to the phage C4 molecule and are putatively controlled by two further sRNAs that are strongly antisense to them. Collectively, this study offers a detailed view of the sRNA content of A. baumannii, exposing sequence and structural conservation amongst these elements, and provides novel insight into the potential evolution, and role, of these understudied regulatory molecules. PMID- 28348847 TI - Refined analyses suggest that recombination is a minor source of genomic diversity in Pseudomonas aeruginosa chronic cystic fibrosis infections. AB - Chronic bacterial airway infections in people with cystic fibrosis (CF) are often caused by Pseudomonas aeruginosa, typically showing high phenotypic diversity amongst co-isolates from the same sputum sample. Whilst adaptive evolution during chronic infections has been reported, the genetic mechanisms underlying the observed rapid within-population diversification are not well understood. Two recent conflicting reports described very high and low rates of homologous recombination in two closely related P. aeruginosa populations from the lungs of different chronically infected CF patients. To investigate the underlying cause of these contrasting observations, we combined the short read datasets from both studies and applied a new comparative analysis. We inferred low rates of recombination in both populations. The discrepancy in the findings of the two previous studies can be explained by differences in the application of variant calling techniques. Two novel algorithms were developed that filter false positive variants. The first algorithm filters variants on the basis of ambiguity within duplications in the reference genome. The second omits probable false positive variants at regions of non-homology between reference and sample caused by structural rearrangements. As gains and losses of prophage or genomic islands are frequent causes of chromosomal rearrangements within microbial populations, this filter has broad appeal for mitigating false-positive variant calls. Both algorithms are available in a Python package. PMID- 28348846 TI - Repeated local emergence of carbapenem-resistant Acinetobacter baumannii in a single hospital ward. AB - We recently reported a dramatic increase in the prevalence of carbapenem resistant Acinetobacter baumannii infections in the intensive care unit (ICU) of a Vietnamese hospital. This upsurge was associated with a specific oxa23-positive clone that was identified by multilocus VNTR analysis. Here, we used whole-genome sequence analysis to dissect the emergence of carbapenem-resistant A. baumannii causing ventilator-associated pneumonia (VAP) in the ICU during 2009-2012. To provide historical context and distinguish microevolution from strain introduction, we compared these genomes with those of A. baumannii asymptomatic carriage and VAP isolates from this same ICU collected during 2003-2007. We identified diverse lineages co-circulating over many years. Carbapenem resistance was associated with the presence of oxa23, oxa40, oxa58 and ndm1 genes in multiple lineages. The majority of resistant isolates were oxa23-positive global clone GC2; fine-scale phylogenomic analysis revealed five distinct GC2 sublineages within the ICU that had evolved locally via independent chromosomal insertions of oxa23 transposons. The increase in infections caused by carbapenem resistant A. baumannii was associated with transposon-mediated transmission of a carbapenemase gene, rather than clonal expansion or spread of a carbapenemase harbouring plasmid. Additionally, we found evidence of homologous recombination creating diversity within the local GC2 population, including several events resulting in replacement of the capsule locus. We identified likely donors of the imported capsule locus sequences amongst the A. baumannii isolated on the same ward, suggesting that diversification was largely facilitated via reassortment and sharing of genetic material within the localized A. baumannii population. PMID- 28348849 TI - Response to 'Refined analyses suggest that recombination is a minor source of genomic diversity in Pseudomonas aeruginosa chronic cystic fibrosis infections' by ). PMID- 28348848 TI - PhagePhisher: a pipeline for the discovery of covert viral sequences in complex genomic datasets. AB - Obtaining meaningful viral information from large sequencing datasets presents unique challenges distinct from prokaryotic and eukaryotic sequencing efforts. The difficulties surrounding this issue can be ascribed in part to the genomic plasticity of viruses themselves as well as the scarcity of existing information in genomic databases. The open-source software PhagePhisher (http://www.putonti lab.com/phagephisher) has been designed as a simple pipeline to extract relevant information from complex and mixed datasets, and will improve the examination of bacteriophages, viruses, and virally related sequences, in a range of environments. Key aspects of the software include speed and ease of use; PhagePhisher can be used with limited operator knowledge of bioinformatics on a standard workstation. As a proof-of-concept, PhagePhisher was successfully implemented with bacteria-virus mixed samples of varying complexity. Furthermore, viral signals within microbial metagenomic datasets were easily and quickly identified by PhagePhisher, including those from prophages as well as lysogenic phages, an important and often neglected aspect of examining phage populations in the environment. PhagePhisher resolves viral-related sequences which may be obscured by or imbedded in bacterial genomes. PMID- 28348850 TI - Identifying copy number variation of the dominant virulence factors msa and p22 within genomes of the fish pathogen Renibacterium salmoninarum. AB - Renibacterium salmoninarum is the causative agent of bacterial kidney disease, an important disease of farmed and wild salmonid fish worldwide. Despite the wide spatiotemporal distribution of this disease and habitat pressures ranging from the natural environment to aquaculture and rivers to marine environments, little variation has been observed in the R. salmoninarum genome. Here we use the coverage depth from genomic sequencing corroborated by real-time quantitative PCR to detect copy number variation (CNV) among the genes of R. salmoninarum. CNV was primarily limited to the known dominant virulence factors msa and p22. Among 68 isolates representing the UK, Norway and North America, the msa gene ranged from two to five identical copies and the p22 gene ranged from one to five copies. CNV for these two genes co-occurred, suggesting they may be functionally linked. Isolates carrying CNV were phylogenetically restricted and originated predominantly from sites in North America, rather than the UK or Norway. Although both phylogenetic relationship and geographical origin were found to correlate with CNV status, geographical origin was a much stronger predictor than phylogeny, suggesting a role for local selection pressures in the repeated emergence and maintenance of this trait. PMID- 28348851 TI - SNP-sites: rapid efficient extraction of SNPs from multi-FASTA alignments. AB - Rapidly decreasing genome sequencing costs have led to a proportionate increase in the number of samples used in prokaryotic population studies. Extracting single nucleotide polymorphisms (SNPs) from a large whole genome alignment is now a routine task, but existing tools have failed to scale efficiently with the increased size of studies. These tools are slow, memory inefficient and are installed through non-standard procedures. We present SNP-sites which can rapidly extract SNPs from a multi-FASTA alignment using modest resources and can output results in multiple formats for downstream analysis. SNPs can be extracted from a 8.3 GB alignment file (1842 taxa, 22 618 sites) in 267 seconds using 59 MB of RAM and 1 CPU core, making it feasible to run on modest computers. It is easy to install through the Debian and Homebrew package managers, and has been successfully tested on more than 20 operating systems. SNP-sites is implemented in C and is available under the open source license GNU GPL version 3. PMID- 28348853 TI - Declaring a tuberculosis outbreak over with genomic epidemiology. AB - We report an updated method for inferring the time at which an infectious disease was transmitted between persons from a time-labelled pathogen genome phylogeny. We applied the method to 48 Mycobacterium tuberculosis genomes as part of a real time public health outbreak investigation, demonstrating that although active tuberculosis (TB) cases were diagnosed through 2013, no transmission events took place beyond mid-2012. Subsequent cases were the result of progression from latent TB infection to active disease, and not recent transmission. This evolutionary genomic approach was used to declare the outbreak over in January 2015. PMID- 28348852 TI - Pan-genomic perspective on the evolution of the Staphylococcus aureus USA300 epidemic. AB - Staphylococcus aureus USA300 represents the dominant community-associated methicillin-resistant S. aureus lineage in the USA, where it is a major cause of skin and soft tissue infections. Previous comparative genomic studies have described the population structure and evolution of USA300 based on geographically restricted isolate collections. Here, we investigated the USA300 population by sequencing genomes of a geographically distributed panel of 191 clinical S. aureus isolates belonging to clonal complex 8 (CC8), derived from the Tigecycline Evaluation and Surveillance Trial program. Isolates were collected at 12 healthcare centres across nine USA states in 2004, 2009 or 2010. Reconstruction of evolutionary relationships revealed that CC8 was dominated by USA300 isolates (154/191, 81 %), which were heterogeneous and demonstrated limited phylogeographic clustering. Analysis of the USA300 core genomes revealed an increase in median pairwise SNP distance from 62 to 98 between 2004 and 2010, with a stable pattern of above average dN/dS ratios. The phylogeny of the USA300 population indicated that early diversification events led to the formation of nested clades, which arose through cumulative acquisition of predominantly non synonymous SNPs in various coding sequences. The accessory genome of USA300 was largely homogenous and consisted of elements previously associated with this lineage. We observed an emergence of SCCmec negative and ACME negative USA300 isolates amongst more recent samples, and an increase in the prevalence of phiSa5 prophage. Together, the analysed S. aureus USA300 collection revealed an evolving pan-genome through increased core genome heterogeneity and temporal variation in the frequency of certain accessory elements. PMID- 28348854 TI - Bayesian codon substitution modelling to identify sources of pathogen evolutionary rate variation. AB - Phylodynamic reconstructions rely on a measurable molecular footprint of epidemic processes in pathogen genomes. Identifying the factors that govern the tempo and mode by which these processes leave a footprint in pathogen genomes represents an important goal towards understanding infectious disease evolution. Discriminating between synonymous and non-synonymous substitution rates is crucial for testing hypotheses about the sources of evolutionary rate variation. Here, we implement a codon substitution model in a Bayesian statistical framework to estimate absolute rates of synonymous and non-synonymous substitution in unknown evolutionary histories. To demonstrate how this model can provide critical insights into pathogen evolutionary dynamics, we adopt hierarchical phylogenetic modelling with fixed effects and apply it to two viral examples. Using within-host HIV-1 data from patients with different host genetic background and different disease progression rates, we show that viral populations undergo faster absolute synonymous substitution rates in patients with faster disease progression, probably reflecting faster replication rates. We also re-analyse rabies data from different bat species in the Americas to demonstrate that climate predicts absolute synonymous substitution rates, which can be attributed to climate associated bat activity and viral transmission dynamics. In conclusion, our model to estimate absolute rates of synonymous and non-synonymous substitution can provide a powerful approach to investigate how host ecology can shape the tempo of pathogen evolution. PMID- 28348855 TI - Emergence of a novel lineage containing a prophage in emm/M3 group A Streptococcus associated with upsurge in invasive disease in the UK. AB - A sudden increase in invasive Group A Streptococcus (iGAS) infections associated with emm/M3 isolates during the winter of 2008/09 prompted the initiation of enhanced surveillance in England. In order to characterise the population of emm/M3 GAS within the UK and determine bacterial factors that might be responsible for this upsurge, 442 emm/M3 isolates from cases of invasive and non invasive infections during the period 2001-2013 were subjected to whole genome sequencing. MLST analysis differentiated emm/M3 isolates into three sequence types (STs): ST15, ST315 and ST406. Analysis of the whole genome SNP-based phylogeny showed that the majority of isolates from the 2008-2009 upsurge period belonged to a distinct lineage characterized by the presence of a prophage carrying the speC exotoxin and spd1 DNAase genes but loss of two other prophages considered typical of the emm/M3 lineage. This lineage was significantly associated with the upsurge in iGAS cases and we postulate that the upsurge could be attributed in part to expansion of this novel prophage-containing lineage within the population. The study underlines the importance of prompt genomic analysis of changes in the GAS population, providing an advanced public health warning system for newly emergent, pathogenic strains. PMID- 28348856 TI - Genomic characterization of Mycobacterium tuberculosis lineage 7 and a proposed name: 'Aethiops vetus'. AB - Lineage 7 of the Mycobacterium tuberculosis complex has recently been identified among strains originating from Ethiopia. Using different DNA typing techniques, this study provides additional information on the genetic heterogeneity of five lineage 7 strains collected in the Amhara Region of Ethiopia. It also confirms the phylogenetic positioning of these strains between the ancient lineage 1 and TbD1-deleted, modern lineages 2, 3 and 4 of Mycobacterium tuberculosis. Four newly identified large sequence polymorphisms characteristic of the Amhara Region lineage 7 strains are described. While lineage 7 strains have been previously identified in the Woldiya area, we show that lineage 7 strains circulate in other parts of the Amhara Region and also among foreign-born individuals from Eritrea and Somalia in The Netherlands. For ease of documenting future identification of these strains in other geographical locations and recognizing the place of origin, we propose to assign lineage 7 strains the lineage name 'Aethiops vetus'. PMID- 28348857 TI - Comparative genomics and evolution of transcriptional regulons in Proteobacteria. AB - Comparative genomics approaches are broadly used for analysis of transcriptional regulation in bacterial genomes. In this work, we identified binding sites and reconstructed regulons for 33 orthologous groups of transcription factors (TFs) in 196 reference genomes from 21 taxonomic groups of Proteobacteria. Overall, we predict over 10 600 TF binding sites and identified more than 15 600 target genes for 1896 TFs constituting the studied orthologous groups of regulators. These include a set of orthologues for 21 metabolism-associated TFs from Escherichia coli and/or Shewanella that are conserved in five or more taxonomic groups and several additional TFs that represent non-orthologous substitutions of the metabolic regulators in some lineages of Proteobacteria. By comparing gene contents of the reconstructed regulons, we identified the core, taxonomy-specific and genome-specific TF regulon members and classified them by their metabolic functions. Detailed analysis of ArgR, TyrR, TrpR, HutC, HypR and other amino-acid specific regulons demonstrated remarkable differences in regulatory strategies used by various lineages of Proteobacteria. The obtained genomic collection of in silico reconstructed TF regulons contains a large number of new regulatory interactions that await future experimental validation. The collection provides a framework for future evolutionary studies of transcriptional regulatory networks in Bacteria. It can be also used for functional annotation of putative metabolic transporters and enzymes that are abundant in the reconstructed regulons. PMID- 28348858 TI - Quantitative assessment of insertion sequence impact on bacterial genome architecture. AB - Insertion sequence (IS) elements are important mediators of genome plasticity and can lead to phenotypic changes with evolutionary significance. In multidrug resistant Acinetobacter baumannii and Klebsiella pneumoniae, IS elements have contributed significantly to the mobilization of genes that encode resistance to antimicrobial drugs. A systematic analysis of IS elements is needed for a more comprehensive understanding of their evolutionary impact. We developed a computational approach (ISseeker) to annotate IS elements in draft genome assemblies and applied the method to analysis of IS elements in all publicly available A. baumannii(>1000) and K. pneumoniae(>800) genome sequences, in a phylogenetic context. Most IS elements in A. baumanniigenomes are species specific ISAba elements, whereas K. pneumoniaegenomes contain significant numbers of both ISKpn elements and elements that are found throughout the Enterobacteriaceae. A. baumanniigenomes have a higher density of IS elements than K. pneumoniae, averaging ~33 vs ~27 copies per genome. In K. pneumoniae, several insertion sites are shared by most genomes in the ST258 clade, whereas in A. baumannii, different IS elements are abundant in different phylogenetic groups, even among closely related Global Clone 2 strains. IS elements differ in the distribution of insertion locations relative to genes, with some more likely to disrupt genes and others predominantly in intergenic regions. Several genes and intergenic regions had multiple independent insertion events, suggesting that those events may confer a selective advantage. Genome- and taxon-wide characterization of insertion locations revealed that IS elements have been active contributors to genome diversity in both species. PMID- 28348859 TI - In silico serotyping of E. coli from short read data identifies limited novel O loci but extensive diversity of O:H serotype combinations within and between pathogenic lineages. AB - The lipopolysaccharide (O) and flagellar (H) surface antigens of Escherichia coli are targets for serotyping that have traditionally been used to identify pathogenic lineages. These surface antigens are important for the survival of E. coli within mammalian hosts. However, traditional serotyping has several limitations, and public health reference laboratories are increasingly moving towards whole genome sequencing (WGS) to characterize bacterial isolates. Here we present a method to rapidly and accurately serotype E. coli isolates from raw, short read WGS data. Our approach bypasses the need for de novo genome assembly by directly screening WGS reads against a curated database of alleles linked to known and novel E. coli O-groups and H-types (the EcOH database) using the software package srst2. We validated the approach by comparing in silico results for 197 enteropathogenic E. coli isolates with those obtained by serological phenotyping in an independent laboratory. We then demonstrated the utility of our method to characterize isolates in public health and clinical settings, and to explore the genetic diversity of >1500 E. coli genomes from multiple sources. Importantly, we showed that transfer of O- and H-antigen loci between E. coli chromosomal backbones is common, with little evidence of constraints by host or pathotype, suggesting that E. coli 'strain space' may be virtually unlimited, even within specific pathotypes. Our findings show that serotyping is most useful when used in combination with strain genotyping to characterize microevolution events within an inferred population structure. PMID- 28348860 TI - Transcriptomic analysis of staphylococcal sRNAs: insights into species-specific adaption and the evolution of pathogenesis. AB - Next-generation sequencing technologies have dramatically increased the rate at which new genomes are sequenced. Accordingly, automated annotation programs have become adept at identifying and annotating protein coding regions, as well as common and conserved RNAs. Additionally, RNAseq techniques have advanced our ability to identify and annotate regulatory RNAs (sRNAs), which remain significantly understudied. Recently, our group catalogued and annotated all previously known and newly identified sRNAs in several Staphylococcus aureus strains. These complete annotation files now serve as tools to compare the sRNA content of S. aureus with other bacterial strains to investigate the conservation of their sRNomes. Accordingly, in this study we performed RNAseq on two staphylococcal species, Staphylococcus epidermidis and Staphylococcus carnosus, identifying 118 and 89 sRNAs in these organisms, respectively. The sRNA contents of all three species were then compared to elucidate their common and species specific sRNA content, identifying a core set of between 53 and 36 sRNAs encoded in each organism. In addition, we determined that S. aureus has the largest set of unique sRNAs (137) while S. epidermidishas the fewest (25). Finally, we identify a highly conserved sequence and structural motif differentially represented within, yet common to, both S. aureus and S. epidermidis. Collectively, in this study, we uncover the sRNome common to three staphylococcal species, shedding light on sRNAs that are likely to be involved in basic physiological processes common to the genus. More significantly, we have identified species-specific sRNAs that are likely to influence the individual lifestyle and behaviour of these diverse staphylococcal strains. PMID- 28348861 TI - First insight into the faecal microbiota of the high Arctic muskoxen (Ovibos moschatus). AB - The faecal microbiota of muskoxen (n=3) pasturing on Ryoya (69 degrees 33' N 18 degrees 43' E), Norway, in late September was characterized using high throughput sequencing of partial 16S rRNA gene regions. A total of 16 209 high quality sequence reads from bacterial domains and 19 462 from archaea were generated. Preliminary taxonomic classifications of 806 bacterial operational taxonomic units (OTUs) resulted in 53.7-59.3 % of the total sequences being without designations beyond the family level. Firmicutes (70.7-81.1 % of the total sequences) and Bacteroidetes (16.8-25.3 %) constituted the two major bacterial phyla, with uncharacterized members within the family Ruminococcaceae (28.9-40.9 %) as the major phylotype. Multiple-library comparisons between muskoxen and other ruminants indicated a higher similarity for muskoxen faeces and reindeer caecum (P>0.05) and some samples from cattle faeces. The archaeal sequences clustered into 37 OTUs, with dominating phylotypes affiliated to the methane-producing genus Methanobrevibacter (80-92 % of the total sequences). UniFrac analysis demonstrated heterogeneity between muskoxen archaeal libraries and those from reindeer and roe deer (P=1.0e-02, Bonferroni corrected), but not with foregut fermenters. The high proportion of cellulose-degrading Ruminococcus affiliated bacteria agrees with the ingestion of a highly fibrous diet. Further experiments are required to elucidate the role played by these novel bacteria in the digestion of this fibrous Artic diet eaten by muskoxen. PMID- 28348863 TI - Massive dispersal of Coxiella burnetii among cattle across the United States. AB - Q-fever is an underreported disease caused by the bacterium Coxiella burnetii, which is highly infectious and has the ability to disperse great distances. It is a completely clonal pathogen with low genetic diversity and requires whole-genome analysis to identify discriminating features among closely related isolates. C. burnetii, and in particular one genotype (ST20), is commonly found in cow's milk across the entire dairy industry of the USA. This single genotype dominance is suggestive of host-specific adaptation, rapid dispersal and persistence within cattle. We used a comparative genomic approach to identify SNPs for high resolution and high-throughput genotyping assays to better describe the dispersal of ST20 across the USA. We genotyped 507 ST20 cow milk samples and discovered three subgenotypes, all of which were present across the entire country and over the complete time period studied. Only one of these sub-genotypes was observed in a single dairy herd. The temporal and geographic distribution of these sub genotypes is consistent with a model of large-scale, rapid, frequent and continuous dissemination on a continental scale. The distribution of subgenotypes is not consistent with wind-based dispersal alone, and it is likely that animal husbandry and transportation practices, including pooling of milk from multiple herds, have also shaped the patterns. On the scale of an entire country, there appear to be few barriers to rapid, frequent and large-scale dissemination of the ST20 subgenotypes. PMID- 28348864 TI - DNA uptake sequences in Neisseria gonorrhoeae as intrinsic transcriptional terminators and markers of horizontal gene transfer. AB - DNA uptake sequences are widespread throughout the Neisseria gonorrhoeae genome. These short, conserved sequences facilitate the exchange of endogenous DNA between members of the genus Neisseria. Often the DNA uptake sequences are present as inverted repeats that are able to form hairpin structures. It has been suggested previously that DNA uptake sequence inverted repeats present 3' of genes play a role in rho-independent termination and attenuation. However, there is conflicting experimental evidence to support this role. The aim of this study was to determine the role of DNA uptake sequences in transcriptional termination. Both bioinformatics predictions, conducted using TransTermHP, and experimental evidence, from RNA-seq data, were used to determine which inverted repeat DNA uptake sequences are transcriptional terminators and in which direction. Here we show that DNA uptake sequences in the inverted repeat configuration occur in N. gonorrhoeae both where the DNA uptake sequence precedes the inverted version of the sequence and also, albeit less frequently, in reverse order. Due to their symmetrical configuration, inverted repeat DNA uptake sequences can potentially act as bi-directional terminators, therefore affecting transcription on both DNA strands. This work also provides evidence that gaps in DNA uptake sequence density in the gonococcal genome coincide with areas of DNA that are foreign in origin, such as prophage. This study differentiates for the first time, to our knowledge, between DNA uptake sequences that form intrinsic transcriptional terminators and those that do not, providing characteristic features within the flanking inverted repeat that can be identified. PMID- 28348862 TI - Whole-genome sequencing of a quarter-century melioidosis outbreak in temperate Australia uncovers a region of low-prevalence endemicity. AB - Melioidosis, caused by the highly recombinogenic bacterium Burkholderia pseudomallei, is a disease with high mortality. Tracing the origin of melioidosis outbreaks and understanding how the bacterium spreads and persists in the environment are essential to protecting public and veterinary health and reducing mortality associated with outbreaks. We used whole-genome sequencing to compare isolates from a historical quarter-century outbreak that occurred between 1966 and 1991 in the Avon Valley, Western Australia, a region far outside the known range of B. pseudomallei endemicity. All Avon Valley outbreak isolates shared the same multilocus sequence type (ST-284), which has not been identified outside this region. We found substantial genetic diversity among isolates based on a comparison of genome-wide variants, with no clear correlation between genotypes and temporal, geographical or source data. We observed little evidence of recombination in the outbreak strains, indicating that genetic diversity among these isolates has primarily accrued by mutation. Phylogenomic analysis demonstrated that the isolates confidently grouped within the Australian B. pseudomallei clade, thereby ruling out introduction from a melioidosis-endemic region outside Australia. Collectively, our results point to B. pseudomallei ST 284 being present in the Avon Valley for longer than previously recognized, with its persistence and genomic diversity suggesting long-term, low-prevalence endemicity in this temperate region. Our findings provide a concerning demonstration of the potential for environmental persistence of B. pseudomallei far outside the conventional endemic regions. An expected increase in extreme weather events may reactivate latent B. pseudomallei populations in this region. PMID- 28348865 TI - Phylogenetic structure of European Salmonella Enteritidis outbreak correlates with national and international egg distribution network. AB - Outbreaks of Salmonella Enteritidis have long been associated with contaminated poultry and eggs. In the summer of 2014 a large multi-national outbreak of Salmonella Enteritidis phage type 14b occurred with over 350 cases reported in the United Kingdom, Germany, Austria, France and Luxembourg. Egg supply network investigation and microbiological sampling identified the source to be a Bavarian egg producer. As part of the international investigation into the outbreak, over 400 isolates were sequenced including isolates from cases, implicated UK premises and eggs from the suspected source producer. We were able to show a clear statistical correlation between the topology of the UK egg distribution network and the phylogenetic network of outbreak isolates. This correlation can most plausibly be explained by different parts of the egg distribution network being supplied by eggs solely from independent premises of the Bavarian egg producer (Company X). Microbiological sampling from the source premises, traceback information and information on the interventions carried out at the egg production premises all supported this conclusion. The level of insight into the outbreak epidemiology provided by whole-genome sequencing (WGS) would not have been possible using traditional microbial typing methods. PMID- 28348866 TI - Integrated computational prediction and experimental validation identifies promiscuous T cell epitopes in the proteome of Mycobacterium bovis. AB - The discovery of novel antigens is an essential requirement in devising new diagnostics or vaccines for use in control programmes against human tuberculosis (TB) and bovine tuberculosis (bTB). Identification of potential epitopes recognised by CD4+ T cells requires prediction of peptide binding to MHC class II, an obligatory prerequisite for T cell recognition. To comprehensively prioritise potential MHC-II-binding epitopes from Mycobacterium bovis, the agent of bTB and zoonotic TB in humans, we integrated three binding prediction methods with the M. bovisproteome using a subset of human HLA alleles to approximate the binding of epitope-containing peptides to the bovine MHC class II molecule BoLA DRB3. Two parallel strategies were then applied to filter the resulting set of binders: identification of the top-scoring binders or clusters of binders. Our approach was tested experimentally by assessing the capacity of predicted promiscuous peptides to drive interferon-gamma secretion from T cells of M. bovis infected cattle. Thus, 376 20-mer peptides, were synthesised (270 predicted epitopes, 94 random peptides with low predictive scores and 12 positive controls of known epitopes). The results of this validation demonstrated significant enrichment (>24 %) of promiscuously recognised peptides predicted in our selection strategies, compared with randomly selected peptides with low prediction scores. Our strategy offers a general approach to the identification of promiscuous epitopes tailored to target populations where there is limited knowledge of MHC allelic diversity. PMID- 28348867 TI - The electrically conductive pili of Geobacter species are a recently evolved feature for extracellular electron transfer. AB - The electrically conductive pili (e-pili) of Geobactersulfurreducens have environmental and practical significance because they can facilitate electron transfer to insoluble Fe(III) oxides; to other microbial species; and through electrically conductive biofilms. E-pili conductivity has been attributed to the truncated PilA monomer, which permits tight packing of aromatic amino acids to form a conductive path along the length of e-pili. In order to better understand the evolution and distribution of e-pili in the microbial world, type IVa PilA proteins from various Gram-negative and Gram-positive bacteria were examined with a particular emphasis on Fe(III)-respiring bacteria. E-pilin genes are primarily restricted to a tight phylogenetic group in the order Desulfuromonadales. The downstream gene in all but one of the Desulfuromonadales that possess an e-pilin gene is a gene previously annotated as 'pilA-C' that has characteristics suggesting that it may encode an outer-membrane protein. Other genes associated with pilin function are clustered with e-pilin and 'pilA-C' genes in the Desulfuromonadales. In contrast, in the few bacteria outside the Desulfuromonadales that contain e-pilin genes, the other genes required for pilin function may have been acquired through horizontal gene transfer. Of the 95 known Fe(III)-reducing micro-organisms for which genomes are available, 80 % lack e pilin genes, suggesting that e-pili are just one of several mechanisms involved in extracellular electron transport. These studies provide insight into where and when e-pili are likely to contribute to extracellular electron transport processes that are biogeochemically important and involved in bioenergy conversions. PMID- 28348868 TI - The diversity of Klebsiella pneumoniae surface polysaccharides. AB - Klebsiella pneumoniae is considered an urgent health concern due to the emergence of multi-drug-resistant strains for which vaccination offers a potential remedy. Vaccines based on surface polysaccharides are highly promising but need to address the high diversity of surface-exposed polysaccharides, synthesized as O antigens (lipopolysaccharide, LPS) and K-antigens (capsule polysaccharide, CPS), present in K. pneumoniae. We present a comprehensive and clinically relevant study of the diversity of O- and K-antigen biosynthesis gene clusters across a global collection of over 500 K. pneumoniae whole-genome sequences and the seroepidemiology of human isolates from different infection types. Our study defines the genetic diversity of O- and K-antigen biosynthesis cluster sequences across this collection, identifying sequences for known serotypes as well as identifying novel LPS and CPS gene clusters found in circulating contemporary isolates. Serotypes O1, O2 and O3 were most prevalent in our sample set, accounting for approximately 80 % of all infections. In contrast, K serotypes showed an order of magnitude higher diversity and differ among infection types. In addition we investigated a potential association of O or K serotypes with phylogenetic lineage, infection type and the presence of known virulence genes. K1 and K2 serotypes, which are associated with hypervirulent K. pneumoniae, were associated with a higher abundance of virulence genes and more diverse O serotypes compared to other common K serotypes. PMID- 28348869 TI - NASP: an accurate, rapid method for the identification of SNPs in WGS datasets that supports flexible input and output formats. AB - Whole-genome sequencing (WGS) of bacterial isolates has become standard practice in many laboratories. Applications for WGS analysis include phylogeography and molecular epidemiology, using single nucleotide polymorphisms (SNPs) as the unit of evolution. NASP was developed as a reproducible method that scales well with the hundreds to thousands of WGS data typically used in comparative genomics applications. In this study, we demonstrate how NASP compares with other tools in the analysis of two real bacterial genomics datasets and one simulated dataset. Our results demonstrate that NASP produces similar, and often better, results in comparison with other pipelines, but is much more flexible in terms of data input types, job management systems, diversity of supported tools and output formats. We also demonstrate differences in results based on the choice of the reference genome and choice of inferring phylogenies from concatenated SNPs or alignments including monomorphic positions. NASP represents a source-available, version controlled, unit-tested method and can be obtained from tgennorth.github.io/NASP. PMID- 28348870 TI - Bayesian identification of bacterial strains from sequencing data. AB - Rapidly assaying the diversity of a bacterial species present in a sample obtained from a hospital patient or an environmental source has become possible after recent technological advances in DNA sequencing. For several applications it is important to accurately identify the presence and estimate relative abundances of the target organisms from short sequence reads obtained from a sample. This task is particularly challenging when the set of interest includes very closely related organisms, such as different strains of pathogenic bacteria, which can vary considerably in terms of virulence, resistance and spread. Using advanced Bayesian statistical modelling and computation techniques we introduce a novel pipeline for bacterial identification that is shown to outperform the currently leading pipeline for this purpose. Our approach enables fast and accurate sequence-based identification of bacterial strains while using only modest computational resources. Hence it provides a useful tool for a wide spectrum of applications, including rapid clinical diagnostics to distinguish among closely related strains causing nosocomial infections. The software implementation is available at https://github.com/PROBIC/BIB. PMID- 28348871 TI - NGMASTER:in silico multi-antigen sequence typing for Neisseria gonorrhoeae. AB - Whole-genome sequencing (WGS) provides the highest resolution analysis for comparison of bacterial isolates in public health microbiology. However, although increasingly being used routinely for some pathogens such as Listeria monocytogenes and Salmonella enterica, the use of WGS is still limited for other organisms, such as Neisseria gonorrhoeae. Multi-antigen sequence typing (NG-MAST) is the most widely performed typing method for epidemiological surveillance of gonorrhoea. Here, we present NGMASTER, a command-line software tool for performing in silico NG-MAST on assembled genome data. NGMASTER rapidly and accurately determined the NG-MAST of 630 assembled genomes, facilitating comparisons between WGS and previously published gonorrhoea epidemiological studies. The source code and user documentation are available at https://github.com/MDU-PHL/ngmaster. PMID- 28348872 TI - Phase variable DNA repeats in Neisseria gonorrhoeae influence transcription, translation, and protein sequence variation. AB - There are many types of repeated DNA sequences in the genomes of the species of the genus Neisseria, from homopolymeric tracts to tandem repeats of hundreds of bases. Some of these have roles in the phase-variable expression of genes. When a repeat mediates phase variation, reversible switching between tract lengths occurs, which in the species of the genus Neisseria most often causes the gene to switch between on and off states through frame shifting of the open reading frame. Changes in repeat tract lengths may also influence the strength of transcription from a promoter. For phenotypes that can be readily observed, such as expression of the surface-expressed Opa proteins or pili, verification that repeats are mediating phase variation is relatively straightforward. For other genes, particularly those where the function has not been identified, gathering evidence of repeat tract changes can be more difficult. Here we present analysis of the repetitive sequences that could mediate phase variation in the Neisseria gonorrhoeae strain NCCP11945 genome sequence and compare these results with other gonococcal genome sequences. Evidence is presented for an updated phase-variable gene repertoire in this species, including a class of phase variation that causes amino acid changes at the C-terminus of the protein, not previously described in N. gonorrhoeae. PMID- 28348873 TI - Molecular and biochemical characterization of the NS1 protein of non-cultured influenza B virus strains circulating in Singapore. AB - In this study we compared the NS1 protein of Influenza B/Lee/40 and several non cultured Influenza B virus clinical strains detected in Singapore. In B/Lee/40 virus-infected cells and in cells expressing the recombinant B/Lee/40 NS1 protein a full-length 35 kDa NS1 protein and a 23 kDa NS1 protein species (p23) were detected. Mutational analysis of the NS1 gene indicated that p23 was generated by a novel cleavage event within the linker domain between an aspartic acid and proline at amino acid residues at positions 92 and 93 respectively (DP92-93), and that p23 contained the first 92 amino acids of the NS1 protein. Sequence analysis of the Singapore strains indicated the presence of either DP92-93 or NP92-93 in the NS1 protein, but protein expression analysis showed that p23 was only detected in NS1 proteins with DP92-93.. An additional adjacent proline residue at position 94 (P94) was present in some strains and correlated with increased p23 levels, suggesting that P94 has a synergistic effect on the cleavage of the NS1 protein. The first 145 amino acids of the NS1 protein are required for inhibition of ISG15-mediated ubiquitination, and our analysis showed that Influenza B viruses circulating in Singapore with DP92-93 expressed truncated NS1 proteins and may differ in their capacity to inhibit ISG15 activity. Thus, DP92-93 in the NS1 protein may confer a disadvantage to Influenza B viruses circulating in the human population and interestingly the low frequency of DP92-93detection in the NS1 protein since 2004 is consistent with this suggestion. PMID- 28348874 TI - Robust high-throughput prokaryote de novo assembly and improvement pipeline for Illumina data. AB - The rapidly reducing cost of bacterial genome sequencing has lead to its routine use in large-scale microbial analysis. Though mapping approaches can be used to find differences relative to the reference, many bacteria are subject to constant evolutionary pressures resulting in events such as the loss and gain of mobile genetic elements, horizontal gene transfer through recombination and genomic rearrangements. De novo assembly is the reconstruction of the underlying genome sequence, an essential step to understanding bacterial genome diversity. Here we present a high-throughput bacterial assembly and improvement pipeline that has been used to generate nearly 20 000 annotated draft genome assemblies in public databases. We demonstrate its performance on a public data set of 9404 genomes. We find all the genes used in multi-locus sequence typing schema present in 99.6 % of assembled genomes. When tested on low-, neutral- and high-GC organisms, more than 94 % of genes were present and completely intact. The pipeline has been proven to be scalable and robust with a wide variety of datasets without requiring human intervention. All of the software is available on GitHub under the GNU GPL open source license. PMID- 28348876 TI - Comparison of bacterial genome assembly software for MinION data and their applicability to medical microbiology. AB - Translating the Oxford Nanopore MinION sequencing technology into medical microbiology requires on-going analysis that keeps pace with technological improvements to the instrument and release of associated analysis software. Here, we use a multidrug-resistant Enterobacter kobei isolate as a model organism to compare open source software for the assembly of genome data, and relate this to the time taken to generate actionable information. Three software tools (PBcR, Canu and miniasm) were used to assemble MinION data and a fourth (SPAdes) was used to combine MinION and Illumina data to produce a hybrid assembly. All four had a similar number of contigs and were more contiguous than the assembly using Illumina data alone, with SPAdes producing a single chromosomal contig. Evaluation of the four assemblies to represent the genome structure revealed a single large inversion in the SPAdes assembly, which also incorrectly integrated a plasmid into the chromosomal contig. Almost 50 %, 80 % and 90 % of MinION pass reads were generated in the first 6, 9 and 12 h, respectively. Using data from the first 6 h alone led to a less accurate, fragmented assembly, but data from the first 9 or 12 h generated similar assemblies to that from 48 h sequencing. Assemblies were generated in 2 h using Canu, indicating that going from isolate to assembled data is possible in less than 48 h. MinION data identified that genes responsible for resistance were carried by two plasmids encoding resistance to carbapenem and to sulphonamides, rifampicin and aminoglycosides, respectively. PMID- 28348875 TI - Short-term evolution of Shiga toxin-producing Escherichia coli O157:H7 between two food-borne outbreaks. AB - Shiga toxin-producing Escherichia coli (STEC) O157:H7 is a public health threat and outbreaks occur worldwide. Here, we investigate genomic differences between related STEC O157:H7 that caused two outbreaks, eight weeks apart, at the same restaurant. Short-read genome sequencing divided the outbreak strains into two sub-clusters separated by only three single-nucleotide polymorphisms in the core genome while traditional typing identified them as separate phage types, PT8 and PT54. Isolates did not cluster with local strains but with those associated with foreign travel to the Middle East/North Africa. Combined long-read sequencing approaches and optical mapping revealed that the two outbreak strains had undergone significant microevolution in the accessory genome with prophage gain, loss and recombination. In addition, the PT54 sub-type had acquired a 240 kbp multi-drug resistance (MDR) IncHI2 plasmid responsible for the phage type switch. A PT54 isolate had a general fitness advantage over a PT8 isolate in rich medium, including an increased capacity to use specific amino acids and dipeptides as a nitrogen source. The second outbreak was considerably larger and there were multiple secondary cases indicative of effective human-to-human transmission. We speculate that MDR plasmid acquisition and prophage changes have adapted the PT54 strain for human infection and transmission. Our study shows the added insights provided by combining whole-genome sequencing approaches for outbreak investigations. PMID- 28348878 TI - A phylogenomic framework for assessing the global emergence and evolution of clonal complex 398 methicillin-resistant Staphylococcus aureus. AB - Distinct clones of methicillin-resistant Staphylococcus aureus (MRSA) have emerged as important causes of infection in individuals who have exposure to livestock (livestock-associated MRSA; LA-MRSA). Clonal complex 398 (CC398) is the most prevalent LA-MRSA clone, and has been reported from several geographical settings, including Europe, the Americas and Asia. To understand the factors contributing to the global dissemination of this clone, we analysed CC398 MRSA isolates from New Zealand (NZ), a geographically isolated country with an economy strongly dependent on livestock farming. We supplemented the NZ CC398 MRSA collection with global datasets of CC398 MRSA and CC398 methicillin-susceptible S. aureus. Here, we demonstrate multiple sporadic incursions of CC398 MRSA into NZ, as well as recent importation and spread of a swine-associated clade related to the European LA-MRSA lineage. Within a larger global phylogenomic framework, Bayesian modelling suggested that this NZ clade emerged in the late 2000s, with a probable origin in swine from Western Europe. Elucidating the factors responsible for the incursion and spread of LA-MRSA in geographically distant regions, such as NZ, provides important insights into global pathways of S. aureus transmission, and will inform strategies to control importation and spread. PMID- 28348877 TI - Large scale genomic analysis shows no evidence for pathogen adaptation between the blood and cerebrospinal fluid niches during bacterial meningitis. AB - Recent studies have provided evidence for rapid pathogen genome diversification, some of which could potentially affect the course of disease. We have previously described such variation seen between isolates infecting the blood and cerebrospinal fluid (CSF) of a single patient during a case of bacterial meningitis. Here, we performed whole-genome sequencing of paired isolates from the blood and CSF of 869 meningitis patients to determine whether such variation frequently occurs between these two niches in cases of bacterial meningitis. Using a combination of reference-free variant calling approaches, we show that no genetic adaptation occurs in either invaded niche during bacterial meningitis for two major pathogen species, Streptococcus pneumoniae and Neisseria meningitidis. This study therefore shows that the bacteria capable of causing meningitis are already able to do this upon entering the blood, and no further sequence change is necessary to cross the blood-brain barrier. Our findings place the focus back on bacterial evolution between nasopharyngeal carriage and invasion, or diversity of the host, as likely mechanisms for determining invasiveness. PMID- 28348879 TI - Absence of genome reduction in diverse, facultative endohyphal bacteria. AB - Fungi interact closely with bacteria, both on the surfaces of the hyphae and within their living tissues (i.e. endohyphal bacteria, EHB). These EHB can be obligate or facultative symbionts and can mediate diverse phenotypic traits in their hosts. Although EHB have been observed in many lineages of fungi, it remains unclear how widespread and general these associations are, and whether there are unifying ecological and genomic features can be found across EHB strains as a whole. We cultured 11 bacterial strains after they emerged from the hyphae of diverse Ascomycota that were isolated as foliar endophytes of cupressaceous trees, and generated nearly complete genome sequences for all. Unlike the genomes of largely obligate EHB, the genomes of these facultative EHB resembled those of closely related strains isolated from environmental sources. Although all analysed genomes encoded structures that could be used to interact with eukaryotic hosts, pathways previously implicated in maintenance and establishment of EHB symbiosis were not universally present across all strains. Independent isolation of two nearly identical pairs of strains from different classes of fungi, coupled with recent experimental evidence, suggests horizontal transfer of EHB across endophytic hosts. Given the potential for EHB to influence fungal phenotypes, these genomes could shed light on the mechanisms of plant growth promotion or stress mitigation by fungal endophytes during the symbiotic phase, as well as degradation of plant material during the saprotrophic phase. As such, these findings contribute to the illumination of a new dimension of functional biodiversity in fungi. PMID- 28348880 TI - Modification of the Streptococcus mutans transcriptome by LrgAB and environmental stressors. AB - The Streptococcus mutans Cid/Lrg system is central to the physiology of this cariogenic organism, affecting oxidative stress resistance, biofilm formation and competence. Previous transcriptome analyses of lytS (responsible for the regulation of lrgAB expression) and cidB mutants have revealed pleiotropic effects on carbohydrate metabolism and stress resistance genes. In this study, it was found that an lrgAB mutant, previously shown to have diminished aerobic and oxidative stress growth, was also much more growth impaired in the presence of heat and vancomycin stresses, relative to wild-type, lrgA and lrgB mutants. To obtain a more holistic picture of LrgAB and its involvement in stress resistance, RNA sequencing and bioinformatics analyses were used to assess the transcriptional response of wild-type and isogenic lrgAB mutants under anaerobic (control) and stress-inducing culture conditions (aerobic, heat and vancomycin). Hierarchical clustering and principal components analyses of all differentially expressed genes revealed that the most distinct gene expression profiles between S. mutans UA159 and lrgAB mutant occurred during aerobic and high-temperature growth. Similar to previous studies of a cidB mutant, lrgAB stress transcriptomes were characterized by a variety of gene expression changes related to genomic islands, CRISPR-C as systems, ABC transporters, competence, bacteriocins, glucosyltransferases, protein translation, tricarboxylic acid cycle, carbohydrate metabolism/storage and transport. Notably, expression of lrgAB was upregulated in the wild-type strain under all three stress conditions. Collectively, these results demonstrate that mutation of lrgAB alters the transcriptional response to stress, and further support the idea that the Cid/Lrg system acts to promote cell homeostasis in the face of environmental stress. PMID- 28348881 TI - In Vitro Assessment of Anthelmintic Activities of Rauwolfia vomitoria (Apocynaceae) Stem Bark and Roots against Parasitic Stages of Schistosoma mansoni and Cytotoxic Study. AB - Schistosomiasis is a Neglected Tropical Diseases which can be prevented with mass deworming chemotherapy. The reliance on a single drug, praziquantel, is a motivation for the search of novel antischistosomal compounds. This study investigated the anthelmintic activity of the stem bark and roots of Rauwolfia vomitoria against two life stages of Schistosoma mansoni. Both plant parts were found to be active against cercariae and adult worms. Within 2 h of exposure all cercariae were killed at a concentration range of 62.5-1000 ug/mL and 250-1000 ug/mL of R. vomitoria stem bark and roots, respectively. The LC50 values determined for the stem bark after 1 and 2 h of exposure were 207.4 and 61.18 ug/mL, respectively. All adult worms exposed to the concentrations range of 250 1000 ug/mL for both plant parts died within 120 h of incubation. The cytotoxic effects against HepG2 and Chang liver cell assessed using MTT assay method indicated that both plant extracts which were inhibitory to the proliferation of cell lines with IC50 > 20 MUg/mL appear to be safe. This report provides the first evidence of in vitro schistosomicidal potency of R. vomitoria with the stem bark being moderately, but relatively, more active and selective against schistosome parasites. This suggests the presence of promising medicinal constituent(s). PMID- 28348882 TI - Combination of Anti-VEGF and Laser Photocoagulation for Diabetic Macular Edema: A Review. AB - Diabetic macular edema (DME) is the most common cause of vision loss in diabetic patients. Thirty years ago, the Early Treatment Diabetic Retinopathy Study (ETDRS) demonstrated that focal/grid laser photocoagulation reduces moderate vision loss from DME by 50% or more; thus, macular photocoagulation became the gold standard treatment for DME. However, with the development of anti-VEGF drugs (bevacizumab, ranibizumab, and aflibercept), better outcomes were obtained in terms of visual acuity gain and decrease in macular thickness in some studies when antiangiogenic drugs were administered in monotherapy. Macular laser therapy may still play an important role as an adjuvant treatment because it is able to improve macular thickness outcomes and reduce the number of injections needed. Here, we review some of the clinical trials that have assessed the efficacy of macular laser treatment, either as part of the treatment protocol or as rescue therapy. PMID- 28348883 TI - Familial Retinoblastoma: Raised Awareness Improves Early Diagnosis and Outcome. AB - Purpose. To study the impact of awareness of retinoblastoma in the affected families on the management and outcome of familial retinoblastoma patients. Methods and Materials. This is a retrospective, clinical case series of 44 patients with familial retinoblastoma. Collected data included patient's demographics, laterality, family history, age at diagnosis, presenting signs, treatment modalities, tumor stage, eye salvage rate, metastasis, and mortality. Results. Out of 200 retinoblastoma patients in our registry, 44 (22%) patients were familial, 18 were probands, and 26 were second, third, or fourth affected family members. There were 76 affected eyes: 31 eyes of probands and 45 eyes of the other affected family members. Among probands, all patients (100%) had at least one eye enucleated: 58% (18 eyes) of the affected eyes were enucleated and 32% (10 eyes) of the affected eyes were radiated. On the other hand, among the nonprobands, only 20% had one eye enucleated, and only 4 eyes (9%) received radiation. The eye salvage rate was significantly higher in the nonprobands than in the probands in this series (p = 0.00206). Patients diagnosed by screening (38%) had excellent visual outcome, and both eyes were salvaged. Conclusion. Awareness of families of the possibility of retinoblastoma and adequate screening led to a significantly higher rate of eye salvage in patients with familial retinoblastoma. PMID- 28348884 TI - XEN Glaucoma Implant with Mitomycin C 1-Year Follow-Up: Result and Complications. AB - Purpose. To evaluate gel microstent (XEN, Aquesys, Inc) for treatment of primary open angle glaucoma (POAG). Methods. In this prospective interventional study, 13 eyes with POAG underwent XEN implantation with subconjunctival mitomycin-C. Of those eyes, 3 were pseudophakic and 10 underwent simultaneous phacoemulsification and XEN. Patients had uncontrolled IOP, had intolerance to therapy, or had maximal therapy but undergoing cataract extraction. Follow-up visits included IOP, number of medications, vision, and complications and lasted for 1 year. Complete success was defined as IOP reduction >=20% from preoperative baseline at 1 year without any glaucoma medications while partial success as IOP reduction of >=20% at 1 year with medications. Results. IOP dropped from 16 +/- 4 mmHg pre-op to 9 +/- 5, 11 +/- 6, 12 +/- 5, 12 +/- 4, and 12 +/- 3 mmHg at 1 week, 1, 3, 6, and 12 months (p = 0.004, 0.026, 0.034, 0.01, and 0.01, Wilcoxon Signed Ranks) consecutively. BCVA (LogMAR) was 0.33 +/- 0.34 and improved to 0.13 +/- 0.11 at 1 year. Mean number of medications dropped from 1.9 +/- 1 preoperatively to 0.3 +/- 0.49 (p = 0.003) at 1 year. 42% of eyes achieved complete success and 66% qualified success. Complications included choroidal detachment in 2 eyes, and implant extrusion in 1 eye, and 2 eyes underwent trabeculectomy. Conclusion. XEN implant is an effective surgical treatment for POAG, with significant reduction in IOP and glaucoma medications at 1 year follow-up. PMID- 28348885 TI - Switch to Aflibercept in Diabetic Macular Edema Patients Unresponsive to Previous Anti-VEGF Therapy. AB - Purpose. The aim was to evaluate the efficacy of aflibercept in patients with diabetic macular edema (DME) unresponsive to prior anti-VEGF therapy. Methods. Retrospective review of DME unresponsive to previous anti-VEGF switched to aflibercept with 3 months of follow-up. Changes in best correct visual acuity (BCVA), central retinal thickness (CRT), and frequency of injections were analyzed. The percentage of subjects who had >=20/40 (logMAR equivalent 0.3) and <=20/200 (logMAR equivalent 1) was evaluated. Results. A total of 32 eyes from 26 patients were included. Mean age was 65 +/- 10 years old. The mean number of previous anti-VEGF injections was 5.34 +/- 2.38, and the mean number of aflibercept injections at the end of the study was 2.00 +/- 0.00. The CRT at baseline was 501.47 +/- 150.51 MUm and 367.97 +/- 124.61 MUm at 3 months of follow-up (P < 0.001). The logMAR BCVA at baseline was 0.71 +/- 0.36 and 0.65 +/- 0.33 at the end of the follow-up (P = 0.037). At baseline, 12.5% of patients had >=20/40 compared with 25% at the end of follow-up. At baseline, 28.13% of patients had 20/200 or inferior vision compared with 15.63% at the end of the follow-up. Conclusions. DME patients unresponsive to previous multiple ranibizumab injections demonstrate a significant anatomical and functional improvement with the switch to aflibercept. PMID- 28348886 TI - Values, Norms, and Peer Effects on Weight Status. AB - This study uses data from the European Social Survey in order to test the Prinstein-Dodge hypothesis that posits that peer effects may be larger in collectivistic than in individualistic societies. When defining individualism and collectivism at the country level, our results show that peer effects on obesity are indeed larger in collectivistic than in individualistic societies. However, when defining individualism and collectivism with individual values based on the Shalom Schwartz universal values theory, we find little support for this hypothesis. PMID- 28348887 TI - Factors Associated with Treatment Delay among Pulmonary Tuberculosis Patients in Public and Private Health Facilities in Addis Ababa, Ethiopia. AB - Background. Early detection and diagnosis of tuberculosis (TB) and the timely commencement of antituberculosis (anti-TB) treatment are the parts of efficient tuberculosis prevention and control program. Delay in the commencement of anti-TB treatment worsens the prognosis and increases the risk of death and the chance of transmission in the community and among health care workers. Objective. To assess tuberculosis treatment delay and associated factors among pulmonary TB patients in Addis Ababa, Ethiopia. Methods. A cross-sectional study was conducted in 10 public and 10 private health facilities that provide TB treatment. The data were collected from 425 newly registered pulmonary TB patients using pretested structured questionnaire from April to June 2012. Data were entered in EPI info version 3.5.1 and analyzed using SPSS version 16.0. Findings. The median durations of a patient, health care system, and total treatment delays were 17, 9, and 35 days, respectively. Overall 179 (42.1%), 233 (54.8%), and 262 (61.6%) of patients experienced patient delay, health care system delay, and total treatment delay, respectively. Distance more than 2.5 km from TB treatment health facility [AOR = 1.6, 95% CI (1.1-2.5)] and the presence of TB-associated stigma [AOR = 2.1, 95% CI (1.3, 3.4)] indicate higher odds of patient delay, whereas, being unemployed, patients with the hemoptysis symptom complain indicated lower odds of health care system delay [AOR = 0.41, 95% CI (0.24, 0.70)] and [AOR = 0.61 (0.39, 0.94)], respectively. Conclusions. A significant proportion of clients experienced patient and health care system delay. Thus, there is a need for designing and implementing appropriate strategies to decrease the delays. Efforts to reduce delays should give focus on integrating prevention programs such as active case detection and expanding access to TB care. PMID- 28348888 TI - The Influence of Oblique Angle Forced Exercise in Surgically Destabilized Stifle Joints Is Synergistic with Bone, but Antagonistic with Cartilage in an Ovine Model of Osteoarthritis. AB - Large animal models of osteoarthritis are a necessary testing ground for FDA approval of human medicine applications. Sheep models have advantages over other available large animals, but development and progression of osteoarthritis in sheep is exceedingly slow, which handicaps progress in development of potential treatments. We combined oblique angle forced exercise to increase stress on the stifle, with surgical destabilization to hasten the development of osteoarthritis in ewes. Methods for early detection of clinical signs included radiography, urine, and serum biomarker assays and gait analysis and ex vivo we used microcomputed tomography and macroscopic joint analysis. Our model was able to produce clinically detectable signs of osteoarthritis in a relatively short period (14 weeks). Changes in bone were highly correlated between microcomputed tomography and radiographic analysis and changes in cartilage correlated well between urinary glycosaminoglycan levels and serum aggrecanase analyses. Exercise improved the negative effects of destabilization in bone but exacerbated the negative effects of destabilization in cartilage. These observations suggest that we may need to consider treatments for bone and cartilage separately. These results represent an improved large animal model of osteoarthritis with rapid onset of disease and superior detection of bone and soft tissue changes. PMID- 28348889 TI - Cortical Thinning in Network-Associated Regions in Cognitively Normal and Below Normal Range Schizophrenia. AB - This study assessed whether cortical thickness across the brain and regionally in terms of the default mode, salience, and central executive networks differentiates schizophrenia patients and healthy controls with normal range or below-normal range cognitive performance. Cognitive normality was defined using the MATRICS Consensus Cognitive Battery (MCCB) composite score (T = 50 +/- 10) and structural magnetic resonance imaging was used to generate cortical thickness data. Whole brain analysis revealed that cognitively normal range controls (n = 39) had greater cortical thickness than both cognitively normal (n = 17) and below-normal range (n = 49) patients. Cognitively normal controls also demonstrated greater thickness than patients in regions associated with the default mode and salience, but not central executive networks. No differences on any thickness measure were found between cognitively normal range and below normal range controls (n = 24) or between cognitively normal and below-normal range patients. In addition, structural covariance between network regions was high and similar across subgroups. Positive and negative symptom severity did not correlate with thickness values. Cortical thinning across the brain and regionally in relation to the default and salience networks may index shared aspects of the psychotic psychopathology that defines schizophrenia with no relation to cognitive impairment. PMID- 28348890 TI - Forecasting the Incidence and Prevalence of Patients with End-Stage Renal Disease in Malaysia up to the Year 2040. AB - Background. The incidence of patients with end-stage renal disease (ESRD) requiring dialysis has been growing rapidly in Malaysia from 18 per million population (pmp) in 1993 to 231 pmp in 2013. Objective. To forecast the incidence and prevalence of ESRD patients who will require dialysis treatment in Malaysia until 2040. Methodology. Univariate forecasting models using the number of new and current dialysis patients, by the Malaysian Dialysis and Transplant Registry from 1993 to 2013 were used. Four forecasting models were evaluated, and the model with the smallest error was selected for the prediction. Result. ARIMA (0, 2, 1) modeling with the lowest error was selected to predict both the incidence (RMSE = 135.50, MAPE = 2.85, and MAE = 87.71) and the prevalence (RMSE = 158.79, MAPE = 1.29, and MAE = 117.21) of dialysis patients. The estimated incidences of new dialysis patients in 2020 and 2040 are 10,208 and 19,418 cases, respectively, while the estimated prevalence is 51,269 and 106,249 cases. Conclusion. The growth of ESRD patients on dialysis in Malaysia can be expected to continue at an alarming rate. Effective steps to address and curb further increase in new patients requiring dialysis are urgently needed, in order to mitigate the expected financial and health catastrophes associated with the projected increase of such patients. PMID- 28348891 TI - Surface Area of Patellar Facets: Inferential Statistics in the Iraqi Population. AB - Background. The patella is the largest sesamoid bone in the body; its three dimensional complexity necessitates biomechanical perfection. Numerous pathologies occur at the patellofemoral unit which may end in degenerative changes. This study aims to test the presence of statistical correlation between the surface areas of patellar facets and other patellar morphometric parameters. Materials and Methods. Forty dry human patellae were studied. The morphometry of each patella was measured using a digital Vernier Caliper, electronic balance, and image analyses software known as ImageJ. The patellar facetal surface area was correlated with patellar weight, height, width, and thickness. Results. Inferential statistics proved the existence of linear correlation of total facetal surface area and patellar weight, height, width, and thickness. The correlation was strongest for surface area versus patellar weight. The lateral facetal area was found persistently larger than the medial facetal area, the p value was found to be <0.001 (one-tailed t-test) for right patellae, and another significant p value of < 0.001 (one-tailed t-test) was found for left patellae. Conclusion. These data are vital for the restoration of the normal biomechanics of the patellofemoral unit; these are to be consulted during knee surgeries and implant designs and can be of an indispensable anthropometric, interethnic, and biometric value. PMID- 28348892 TI - Minimizing Stress Shielding and Cement Damage in Cemented Femoral Component of a Hip Prosthesis through Computational Design Optimization. AB - The average life expectancy of many people undergoing total hip replacement (THR) exceeds twenty-five years and the demand for implants that increase the load bearing capability of the bone without affecting the short- or long-term stability of the prosthesis is high. Mechanical failure owing to cement damage and stress shielding of the bone are the main factors affecting the long-term survival of cemented hip prostheses and implant design must realistically adjust to balance between these two conflicting effects. In the following analysis we introduce a novel methodology to achieve this objective, the numerical technique combines automatic and realistic modeling of the implant and embedding medium, and finite element analysis to assess the levels of stress shielding and cement damage and, finally, global optimization, using orthogonal arrays and probabilistic restarts, were used. Applications to implants, fabricated using a homogeneous material and a functionally graded material, were presented. PMID- 28348894 TI - Imaging Neural Plasticity following Brain Injury. PMID- 28348893 TI - Effect of Illumination on Ocular Status Modifications Induced by Short-Term 3D TV Viewing. AB - Objectives. This study aimed to compare changes in ocular status after 3D TV viewing under three modes of illumination and thereby identify optimal illumination for 3D TV viewing. Methods. The following measures of ocular status were assessed: the accommodative response, accommodative microfluctuation, accommodative facility, relative accommodation, gradient accommodative convergence/accommodation (AC/A) ratio, phoria, and fusional vergence. The observers watched 3D television for 90 minutes through 3D shutter glasses under three illumination modes: A, complete darkness; B, back illumination (50 lx); and C, front illumination (130 lx). The ocular status of the observers was assessed both before and after the viewing. Results. After 3D TV viewing, the accommodative response and accommodative microfluctuation were significantly changed under illumination Modes A and B. The near positive fusional vergence decreased significantly after the 90-minute 3D viewing session under each illumination mode, and this effect was not significantly different among the three modes. Conclusions. Short-term 3D viewing modified the ocular status of adults. The least amount of such change occurred with front illumination, suggesting that this type of illumination is an appropriate mode for 3D shutter TV viewing. PMID- 28348895 TI - In-Flight Hypoxemia in a Tracheostomy-Dependent Infant. AB - Millions of passengers board commercial flights every year. Healthcare providers are often called upon to treat other passengers during in-flight emergencies. The case presented involves an anesthesia resident treating a tracheostomy-dependent infant who developed hypoxemia on a domestic flight. The patient had an underlying congenital muscular disorder and was mechanically ventilated while at altitude. Although pressurized, cabin barometric pressure while at altitude is less than at sea level. Due to this environment patients with underlying pulmonary or cardiac pathology might not be able to tolerate commercial flight. The Federal Aviation Administration (FAA) has mandated a specific set of medical supplies be present on all domestic flights in addition to legislature protecting "Good Samaritan" providers. PMID- 28348896 TI - Effect of Arm Positioning on Entrapment of Infraclavicular Nerve Block Catheter. AB - Continuous brachial plexus nerve block catheters are commonly inserted for postoperative analgesia after upper extremity surgery. Modifications of the insertion technique have been described to improve the safety of placing an infraclavicular brachial plexus catheter. Rarely, these catheters may become damaged or entrapped, complicating their removal. We describe a case of infraclavicular brachial plexus catheter entrapment related to differences in arm positioning during catheter placement and removal. Written authorization to obtain, use, and disclose information and images was obtained from the patient. PMID- 28348897 TI - ACE Inhibitor-Induced Angioedema following Cervical Spine Surgery. AB - Angioedema is a well-known side effect of angiotensin converting enzyme inhibitors (ACEi). However, ACE inhibitors induced angioedema after cervical surgery is a rare condition. They result in increased levels of circulating bradykinins. Rare cases of angioedema following local trauma in patients using ACE inhibitors have been published. We present such a case. A 54-year-old Caucasian female with a history significant for hypertension, controlled with lisinopril, was admitted for routine cervical spine surgery. She has severe degenerative cervical disc disease and was admitted to the hospital for an elective cervical diskectomy. The patient failed weaning off the ventilator on multiple attempts postoperatively. There were no observed symptoms of an allergic reaction. A CT scan of the neck showed extensive soft tissue edema at the level of the arytenoids. Dexamethasone was given to reduce the edema without successful resolution. On review of her medications, it was found that the patient was resumed on lisinopril following the procedure. It was subsequently discontinued. By the following day the patient had a positive leak around the ET tube cuff and patient was successfully extubated. PMID- 28348898 TI - Conventional Coronary Angiography Induced Takotsubo Cardiomyopathy Complicated with Cardiac Tamponade. AB - Takotsubo cardiomyopathy (TCM) is a transient left ventricular dysfunction that typically occurs after emotional or physical stress. TCM has a benign prognosis and serious complications are uncommon. However, though very rarely reported, cardiac tamponade has occurred on some occasions. We hereby report the case of a 70-year-old woman who underwent coronary angiography with an ergonovine provocation test to evaluate recurrent chest pain and was readmitted 7 days later presenting with TCM, followed by left ventricular outflow tract obstruction and cardiac tamponade. PMID- 28348899 TI - Abnormal Breathing Patterns Predict Extubation Failure in Neurocritically Ill Patients. AB - In neurologically injured patients, predictors for extubation success are not well defined. Abnormal breathing patterns may result from the underlying neurological injury. We present three patients with abnormal breathing patterns highlighting failure of successful extubation as a result of these neurologically driven breathing patterns. Recognizing abnormal breathing patterns may be predictive of extubation failure and thus need to be considered as part of extubation readiness. PMID- 28348900 TI - Unusual Sites of Cutaneous Tuberculosis: A Report of Two Cases. AB - Cutaneous tuberculosis (CTB) is an uncommon small subset of extrapulmonary tuberculosis, comprising 1-1.5% of all extrapulmonary tuberculosis manifestations, which manifests only in 8.4-13.7% of all tuberculosis cases. Lupus vulgaris (LV) and tuberculosis verrucosa cutis (TBVC) are forms of reinfection tuberculosis and often occur in presensitized patients, by exogenous inoculation. We report two cases of cutaneous tuberculosis at unusual sites. A 35 year-old female having a forehead lesion for 2 years was diagnosed as having tuberculosis verrucosa cutis and another 16-year-old girl with lesion in left axilla for 10 years was proven to have lupus vulgaris. The delayed diagnosis was possibly due to lower clinical suspicion due to the presentation of CTB at unusual sites. This highlights the importance of keeping TB as an important differential as misdiagnosis or delayed diagnosis of this entity can lead to prolonged morbidity. PMID- 28348901 TI - Addison's Disease and Possible Cannabis Withdrawal Syndrome Presenting as an Eating Disorder in a Thirty-Year-Old Female. AB - A 30-year-old female with a history of anxiety, cannabis use, and Avoidant/Restrictive Food Intake Disorder presented for residential treatment of a Cannabis Use Disorder. Upon arrival, she had not eaten for two days and was found to be hypotensive with electrolyte disturbances. She was admitted to a nearby hospital, where the Internist diagnosed her with Addison's disease. She was treated with corticosteroid therapy, with rapid normalization of her electrolytes, eating, and anxiety. This is the first published case of undiagnosed Addison's disease presenting as an eating disorder, with cannabis use likely contributing to symptoms. This case elucidates the importance of ruling out other biologic and psychologic causes of clinical presentations before an eating disorder diagnosis can be made. PMID- 28348902 TI - Atypical Complications of Graves' Disease: A Case Report and Literature Review. AB - Graves' disease (GD) may display uncommon manifestations. We report a patient with rare complications of GD and present a comprehensive literature review. A 35 year-old woman presented with a two-week history of dyspnea, palpitations, and edema. She had a raised jugular venous pressure, goiter, and exophthalmos. Laboratory tests showed pancytopenia, a raised alkaline phosphatase level, hyperbilirubinemia (mainly direct bilirubin), and hyperthyroidism [TSH: <0.01 mIU/L (reference values: 0.45-4.5), fT4: 54.69 pmol/L (reference values: 9.0 20.0), and fT3: >46.08 pmol/L (reference values: 2.6-5.7)]. Her thyroid uptake scan indicated GD. Echocardiography showed a high right ventricular systolic pressure: 60.16 mmHg. Lugol's iodine, propranolol, cholestyramine, and dexamethasone were initiated. Hematologic investigations uncovered no reason for the pancytopenia; therefore, carbimazole was started. Workup for hepatic impairment and pulmonary hypertension (PH) was negative. The patient became euthyroid after 3 months. Leukocyte and platelet counts and bilirubin levels normalized, and her hemoglobin and alkaline phosphatase levels and right ventricular systolic pressure (52.64 mmHg) improved. This is the first reported single case of GD with the following three rare manifestations: pancytopenia, cholestatic liver injury, and PH with right-sided heart failure. With antithyroid drugs treatment, pancytopenia should resolve with euthyroidism, but PH and liver injury may take several months to resolve. PMID- 28348903 TI - Successful Treatment of Clostridium difficile Bacteremia with Aortic Mycotic Aneurysm in a Patient with Prior Endovascular Aortic Aneurysm Repair. AB - The clinical spectrum of Clostridium difficile infection can range from benign gastrointestinal colonization to mild diarrhea and life threatening conditions such as pseudomembranous colitis and toxic megacolon. Extraintestinal manifestations of C. difficile are rare. Here, we report a patient with a history of an endovascular aortic aneurysm repair (EVAR) presenting with an endovascular leak complicated by C. difficile bacteremia and a mycotic aneurysm. He was successfully treated with an explant of the EVAR, an aorto-left renal bypass, and aorto-bi-iliac bypass graft placement along with a six-week duration of intravenous vancomycin and oral metronidazole. PMID- 28348904 TI - Central Hyperthermia Treated with Bromocriptine. AB - Introduction. Central hyperthermia is common in patients with brain injury. It typically has a rapid onset with high temperatures and marked fluctuations and responds poorly to antibiotics and antipyretics. It is also associated with worse outcomes in the brain injured patient. Recognizing this, it is important to aggressively manage it. Case Report. We report a 34-year-old male with a right thalamic hemorrhage extending to the midbrain and into the ventricles. During his admission, he developed intractable fevers with core temperatures as high as 39.3 degrees C. Infectious workup was unremarkable. The fever persisted despite empiric antibiotics, antipyretics, and cooling wraps. Bromocriptine was started resulting in control of the central hyperthermia. The fever spikes were reduced to minor fluctuations that significantly worsened with any attempt to wean off the bromocriptine. Conclusion. Diagnosing and managing central hyperthermia can be challenging. The use of bromocriptine can be beneficial as we have reported. PMID- 28348905 TI - Treatment of Endometrial Cancer in Association with Pelvic Organ Prolapse. AB - Background. Uterine malignancy coexistent with pelvic organ prolapse (POP) is uncommon and standardized treatment is not established. The objective of this case study was to highlight the management of endometrial cancer in association with pelvic organ prolapse. Case Report. An 87-year-old woman presented with POP Stage IV combined with endometrioid adenocarcinoma of the uterus: clinical Stage IV B. She had multiple medical conditions including stroke, deep vein thrombosis, and pulmonary embolism. She was treated with radiotherapy and pessary was placed. Conclusion. Genital prolapse with abnormal uterine bleeding requires proper evaluation and management. Concurrent adenocarcinoma and POP can be a difficult clinical situation to treat, and optimum management is controversial. PMID- 28348906 TI - Rare Epithelioid Leiomyoma of the Vagina Exhibiting a Pelvic Mass. AB - Epithelioid leiomyoma of the vagina is extremely rare. Smooth muscle tumors of the vagina usually present with a submucosal growth pattern or a pedunculated growth pattern from the anterior vaginal wall into the vaginal cavity. Here we report a case of a 43-year-old woman with a solid epithelioid leiomyoma and a palpable mass in the pouch of Douglas. Transvaginal biopsy and angiography showed the epithelioid leiomyoma feeding from the vaginal artery behind the posterior vagina. An abdominal wide excision of the tumor with a partial vaginectomy was performed. Our use of ultrasound-guided needle biopsy and angiography was useful for preoperative diagnosis of a vaginal epithelioid leiomyoma exhibiting a pelvic mass. PMID- 28348907 TI - An OCT Study of Anterior Nodular Episcleritis and Scleritis. AB - Anterior scleritis and episcleritis are a well-known presentation in tuberculosis. The case of a female patient with presumed tuberculous anterior scleritis and episcleritis is discussed in this article. Anterior segment OCT was efficient in diagnosis and evaluation of the therapeutic outcome. Antituberculosis chemotherapy was sufficient to achieve clinical remission. PMID- 28348908 TI - Recurrent Intrathoracic Locking of the Scapula after Lung Cancer Resection and Combined Rib Resection. AB - We report a case of recurrent locking of the scapula in the thorax after combined lobectomy and thoracic wall resection for advanced lung cancer. The patient was a 52-year-old man with advanced spindle cell carcinoma in his right lung. He had undergone right lung lobectomy and thoracic wall excision (Th1-5). Intrathoracic repair had not been performed to address the defect in the thoracic wall. Two months after the operation he experienced sudden acute pain in the right shoulder. Three-dimensional computed tomography revealed locking of the scapula intrathoracically. The diagnosis was recurrent locking of the scapula in the thorax. He underwent conservative treatment. Because his symptoms were not alleviated and he continued to experience recurrent locking, we performed partial resection of the inferior part of the scapula. Although scapular locking diminished after this procedure, there were still some pain and "catching" between the scapula and the thoracic wall (T6) when he undertook certain movements. No further surgery could be performed, however, because the cancer from the primary lesion had recurred near the previously operated thoracic wall. A procedure for recurrent intrathoracic locking of the scapula was not successful in this case. PMID- 28348909 TI - Adenoid Cystic Carcinoma of the Uterine Cervix: A Report of 2 Cases. AB - Adenoid cystic carcinoma is malignant tumor that exceptionally occurs in the uterine cervix. It is mostly seen in postmenopausal women and has an aggressive clinical course. We report two cases of an adenoid cystic carcinoma associated with a high grade squamous intraepithelial lesion and invasive squamous cell carcinoma of the uterine cervix and discuss briefly its clinical and pathological characteristics. PMID- 28348910 TI - A Wandering Abdominal Mass in a Neonate: An Enteric Duplication Cyst Mimicking an Ovarian Cyst. AB - Enteric duplication cysts are rare congenital anomalies that are prenatally diagnosed through antenatal ultrasonography (US). In female patients, however, attention must be paid since these formations might be confused with ovarian cysts. Herein, we present a case of a low birth weight female infant with an enteric duplication cyst. A cystic lesion was detected in the right abdomen of the fetus on antenatal US and magnetic resonance imaging (MRI). Serial US and MRI examinations performed after birth showed a single cyst that wandered from side to side in the abdomen; the initial diagnosis was thought to be an ovarian cyst. During laparotomy, however, it was found to be an enteric duplication cyst with volvulus. To our knowledge, there has been no report of an enteric duplication cyst presenting as a wandering abdominal mass. Our experience indicates that early intervention is necessary for patients who have a wandering abdominal mass to avoid complications and urgent surgery, whether it is an ovarian cyst or an enteric duplication cyst. PMID- 28348911 TI - A Case of Persistent Generalized Retrograde Autobiographical Amnesia Subsequent to the Great East Japan Earthquake in 2011. AB - Functional retrograde autobiographical amnesia is often associated with physical and/or psychological trauma. On 11 March 2011, the largest earthquake on record in Japan took place, and subsequent huge tsunami devastated the Pacific coast of northern Japan. This case report describes a patient suffering from retrograde episodic-autobiographical amnesia for whole life, persisting for even more than five years after the disaster. A Japanese man, presumably in his 40s, got police protection in April 2016 but was unable to respond to question about his own name. He lost all information about his personal identity, and his memory was wholly lost until the disaster on 11 March 2011. He was able to recall his life after the disaster, and semantic memories and social abilities were largely preserved. A medical examination performed on 1 November 2016 verified that he was awake, alert, and oriented to time, place, and person (except for himself). General physical and neurological examinations revealed no pathological findings. He also experienced some symptoms associated with posttraumatic stress disorder (PTSD), such as intrusive thoughts, flashbacks, and nightmares. No abnormalities were detected by biochemical test and brain magnetic resonance imaging (MRI). Physicians and other professionals who take care of victims of disaster should be aware of dissociative spectrum disorders, such as psychogenic amnesia. PMID- 28348912 TI - Nocardia brasiliensis Infection Complicating Cryptogenic Organizing Pneumonia. AB - Pulmonary nocardiosis is a severe and uncommon opportunistic infection caused by Nocardia species. We present a patient with cryptogenic organizing pneumonia who was receiving long-term immunosuppressive therapy, whose treatment course was complicated by cutaneous and pulmonary nocardiosis. Tissue cultures confirmed Nocardia brasiliensis. Nocardiosis should be a diagnostic consideration for patients treated with long-term immunosuppression who have worsening pulmonary symptoms and relapsing pustular skin lesions. PMID- 28348913 TI - A Rare Case of Digital Ischemia and Gangrene in ANCA-Associated Vasculitis with Review of the Literature. AB - This paper describes one patient with Antineutrophil Cytoplasmic Antibody- (ANCA ) associated vasculitis who initially presented with multiple ischemic fingers and toes. On further evaluation, the patient was also found to have pulmonary renal involvement and episcleritis. The diagnosis was supported with a positive cANCA (anti-proteinase 3) and a bronchoscopy consistent with diffuse alveolar hemorrhage. Although the patient refused a tissue biopsy, clinical presentation including nasal ulceration, sinus congestion, and epistaxis and anti-proteinase 3 antibody were more consistent with Granulomatosis with Polyangiitis (GPA) rather than Microscopic Polyangiitis (MPA) or Eosinophilic Granulomatosis with Polyangiitis (EGPA) based on the recently presented ACR/EULAR Provisional 2017 Classification Criteria for GPA (Luqmani et al., 2016). The patient responded well to therapy including high dose steroids and cyclophosphamide, with improvement of all organs involved and had no further digital ischemia or gangrene on follow-up. We include a review of the English literature summarizing presentation, management, and outcome of 16 similar cases. PMID- 28348914 TI - Brincidofovir Use after Foscarnet Crystal Nephropathy in a Kidney Transplant Recipient with Multiresistant Cytomegalovirus Infection. AB - Background. Cytomegalovirus (CMV) antiviral drug resistance constitutes an increasing challenge in transplantation. Foscarnet is usually proposed when resistance for ganciclovir is suspected, but its use is limited by its nephrotoxicity. Case Presentation. We report a case of multiresistant CMV disease in a kidney transplant recipient. Foscarnet was prescribed after ganciclovir treatment failure in a patient with two mutations in the UL97 viral gene. Foscarnet induced biopsy-proven kidney crystal precipitation that resulted in severe acute transplant failure and nephrotic syndrome. Despite a large decrease in immunosuppression, CMV disease was not controlled and a salvage therapy with Brincidofovir (BCV), which is an oral lipid conjugate of cidofovir with limited nephrotoxicity, was attempted. Clinical and virological remission was observed after a 21-day course of BCV, despite mild and reversible liver toxicity. However, a new relapse could not be effectively cured by BCV due to a new mutation in the UL54 gene, which is known to confer resistance to cidofovir. A new course of foscarnet finally resulted in prolonged CMV remission. Herein, we present a review of foscarnet nephropathy cases in solid-organ transplanted patients. Conclusions. This unique case highlights the potential benefit of BCV use during resistant CMV infection, although mutations in the UL54 gene may limit its therapeutic efficacy. These findings need to be confirmed in clinical trials. PMID- 28348915 TI - Bradycardia during Transradial Cardiac Catheterization due to Catheter Manipulation: Resolved by Catheter Removal. AB - Purpose. To report the resolution of bradycardia encountered during transradial cardiac catheterization through the catheter pullback technique in two cases. Case Report. A 62-year-old male and an 81-year-old male underwent coronary angiogram to evaluate for coronary artery disease and as a result of positive stress test, respectively. Upon engagement of the FL 3.5 catheter into the ascending aorta through the transradial approach, the first case developed bradycardia with a heart rate of 39 beats per minute. The second case developed profound bradycardia with a heart rate of 25 beats per minute upon insertion of the 5 Fr FL 3.5 catheter near the right brachiocephalic trunk through the right radial access. Conclusion. Bradycardia can be subsided by removal of the catheter during catheter manipulation in patients undergoing transradial coronary angiogram if there is a suspicion of excessive stretching of aortic arch receptors and/or carotid sinus receptors. PMID- 28348916 TI - Aerobic Training Intensity for Improved Endothelial Function in Heart Failure Patients: A Systematic Review and Meta-Analysis. AB - Objective. Flow-mediated dilation (FMD) is widely utilised to assess endothelial function and aerobic exercise improves FMD in heart failure patients. The aim of this meta-analysis is to quantify the effect of aerobic training intensity on FMD in patients with heart failure. Background. A large number of studies now exist that examine endothelial function in patients with heart failure. We sought to add to the current literature by quantifying the effect of the aerobic training intensity on endothelial function. Methods. We conducted database searches (PubMed, Embase, ProQuest, and Cochrane Trials Register to June 30, 2016) for exercise based rehabilitation trials in heart failure, using search terms exercise training, endothelial function, and flow-mediated dilation (FMD). Results. The 13 included studies provided a total of 458 participants, 264 in intervention groups, and 194 in nonexercising control groups. Both vigorous and moderate intensity aerobic training significantly improved FMD. Conclusion. Overall both vigorous and moderate aerobic exercise training improved FMD in patients with heart failure. PMID- 28348917 TI - The Level of Knowledge of Parkinson's Disease among Nonprofessional Caregivers in a Movement Disorders Center in Turkey. AB - Introduction. Only a few studies have been conducted to determine the level of knowledge among caregivers about Parkinson's disease (PD). The aim of the current study was to determine the knowledge of PD among caregivers at a movement disorder clinic in Turkey. Methods. We conducted a questionnaire based interview with the subjects in a tertiary care neurology facility in Turkey. The questions were divided into two parts covering the symptomatology and treatment of PD. A questionnaire consisting of 10 questions was applied to the subjects who had to mark the correct option in a stipulated time. Results. Eighty caregivers were included in the study. The caregivers' mean age was 47.94 years (SD = 12.40). There were 47 female caregivers (58.8%). The most well-known question was that the number of drugs given to the patient may vary with time (76.3%), whereas "the benefit noted in the patient's treatment decreases over time" was the least known question (11.3%). Discussion. This study is the first in our country and shows the necessity to increase the knowledge of PD among caregivers and the public. Education programs may have a positive role in imparting knowledge to the caregivers of PD patients. PMID- 28348918 TI - Correlation of Visuospatial Ability and EEG Slowing in Patients with Parkinson's Disease. AB - Background. Visuospatial dysfunction is among the first cognitive symptoms in Parkinson's disease (PD) and is often predictive for PD-dementia. Furthermore, cognitive status in PD-patients correlates with quantitative EEG. This cross sectional study aimed to investigate the correlation between EEG slowing and visuospatial ability in nondemented PD-patients. Methods. Fifty-seven nondemented PD-patients (17 females/40 males) were evaluated with a comprehensive neuropsychological test battery and a high-resolution 256-channel EEG was recorded. A median split was performed for each cognitive test dividing the patients sample into either a normal or lower performance group. The electrodes were split into five areas: frontal, central, temporal, parietal, and occipital. A linear mixed effects model (LME) was used for correlational analyses and to control for confounding factors. Results. Subsequently, for the lower performance, LME analysis showed a significant positive correlation between ROCF score and parietal alpha/theta ratio (b = .59, p = .012) and occipital alpha/theta ratio (b = 0.50, p = .030). No correlations were found in the group of patients with normal visuospatial abilities. Conclusion. We conclude that a reduction of the parietal alpha/theta ratio is related to visuospatial impairments in PD-patients. These findings indicate that visuospatial impairment in PD-patients could be influenced by parietal dysfunction. PMID- 28348919 TI - Optimized Multiresidue Analysis of Organic Contaminants of Priority Concern in a Daily Consumed Fish (Grass Carp). AB - The organic contaminants, including polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyls (PCBs), are of priority concern because of their persistence, toxicity, and long-distance transportation in global environment. Their residues in a daily consumed fish (grass carp) pose potential threat to human health and aquatic ecosystems. The present study optimized an analytical protocol of microwave-assisted extraction (MAE), lip-removal by gel permeation chromatography (GPC), cleanup by solid phase cartridge (SC) or adsorption chromatography column (CC), and gas chromatography-mass spectrometry (GC/MS). Besides traditional statistical parameters, some indicators were calculated to judge the performances of extraction by various methods. The optimization experiment showed that n-hexane/acetone was the best MEA extraction solvent; an optimal fraction time of 10-39 min could simultaneously elute all the target chemicals in a single GPC run. Both CC and SC showed good recoveries. However, CC performed better than SC (p < 0.05) for OCPs, and SC performed better than CC for PBDEs (p < 0.05). We also emphasized the limitations and advantages of SC and CC and finally proposed SC as the promising cleanup method because of its low-cost materials, time-saving steps, being free of manual filling, and operation by automated SPE system. PMID- 28348920 TI - A New Kinetic Spectrophotometric Method for the Quantitation of Amorolfine. AB - Amorolfine (AOF) is a compound with fungicide activity based on the dual inhibition of growth of the fungal cell membrane, the biosynthesis and accumulation of sterols, and the reduction of ergosterol. In this work a sensitive kinetic and spectrophotometric method for the AOF quantitation based on the AOF oxidation by means of KMnO4 at 30 min (fixed time), pH alkaline, and ionic strength controlled was developed. Measurements of changes in absorbance at 610 nm were used as criterion of the oxidation progress. In order to maximize the sensitivity, different experimental reaction parameters were carefully studied via factorial screening and optimized by multivariate method. The linearity, intraday, and interday assay precision and accuracy were determined. The absorbance-concentration plot corresponding to tap water spiked samples was rectilinear, over the range of 7.56 * 10-6-3.22 * 10-5 mol L-1, with detection and quantitation limits of 2.49 * 10-6 mol L-1 and 7.56 * 10-6 mol L-1, respectively. The proposed method was successfully validated for the application of the determination of the drug in the spiked tap water samples and the percentage recoveries were 94.0-105.0%. The method is simple and does not require expensive instruments or complicated extraction steps of the reaction product. PMID- 28348921 TI - The Effect of Artificial Mowing on the Competition of Phragmites australis and Spartina alterniflora in the Yangtze Estuary. AB - Spartina alterniflora Loisel. is one of the most invasive species in the world. However, little is known about the role of artificial mowing in its invasiveness and competiveness. In this work, we studied the effect of mowing on its interspecific interactions with native species Phragmites australis (Cav.) Trin ex Steud of the Yangtze Estuary, China. We calculated their relative neighbor effect (RNE) index, effect of relative crowding (Dr ) index, and interaction strength (I) index. The results showed that the RNE of Phragmites australis and Spartina alterniflora was 0.354 and 0.619, respectively, and they have competitive interactions. The mowing treatments can significantly influence the RNE of Phragmites australis and Spartina alterniflora on each other. Concretely, the RNE of Spartina alterniflora in the removal treatments was significantly higher than the value in the controls. But the RNE of Phragmites australis in the removal treatments was significantly lower than the value in the controls. Meanwhile, Dr of the two species on the targets was higher in the removal treatments than that in the controls, and the opposite was for I. We concluded that artificial mowing could promote the invasion of Spartina alterniflora by increasing its competitive performance compared with native species. PMID- 28348922 TI - Simulation of the Effect of Artificial Water Transfer on Carbon Stock of Phragmites australis in the Baiyangdian Wetland, China. AB - How to explain the effect of seasonal water transfer on the carbon stocks of Baiyangdian wetland is studied. The ecological model of the relationship between the carbon stocks and water depth fluctuation of the reed was established by using STELLA software. For the first time the Michaelis-Menten equation (1) introduced the relation function between the water depth and reed environmental carrying capacity, (2) introduced the concept of suitable growth water depth, and (3) simulated the variation rules of water and reed carbon stocks of artificial adjustment. The model could be used to carry out the research on the optimization design of the ecological service function of the damaged wetland. PMID- 28348923 TI - Massive Urinary Protein Excretion Associated with Greater Neonatal Risk in Preeclampsia. AB - Objective The objective of this study was to compare clinical outcomes of preeclamptic pregnancies according to the proteinuria level. Study Design Secondary analysis of a multicenter prospective cohort study of women with preeclampsia (PE) symptomatology. Nonproteinuria, mild-proteinuria, and massive proteinuria PEs were defined as: < 165 mg in 12 hours or < 300 mg in 24 hours, 165 mg to 2.69 g in 12 hours or 300 mg to 4.99 g in 24 hours, and >= 2.7 g in 12 hours or >= 5.0 g in 24 hours, respectively. Individual and composite maternal, fetal, and neonatal outcomes were compared among the PE groups. Results Of the 406 analyzed pregnancies, 36 (8.8%) had massive-proteinuria PE, 268 (66.0%) mild proteinuria PE, and 102 (25.1%) nonproteinuria PE. Compared with the other groups, massive-proteinuria PE women had significantly higher blood pressures (p < 0.001), epigastric pain (p = 0.007), and uric acid serum levels (p < 0.001) prior to delivery. Composite maternal morbidity was similar across the groups. Delivery < 340/7 weeks occurred in 80.6, 49.3, and 22.5% of massive-proteinuria, mild-proteinuria, and nonproteinuria PE groups, respectively (p < 0.0001). Composite adverse neonatal outcomes were significantly higher in the massive proteinuria PE compared with the other groups (p = 0.001). Conclusion While potentially not important diagnostically, massive proteinuria is associated with more severe clinical manifestations of PE prompting earlier delivery. PMID- 28348925 TI - Neogene amphibians and reptiles (Caudata, Anura, Gekkota, Lacertilia, and Testudines) from the south of Western Siberia, Russia, and Northeastern Kazakhstan. AB - BACKGROUND: The present-day amphibian and reptile fauna of Western Siberia are the least diverse of the Palaearctic Realm, as a consequence of the unfavourable climatic conditions that predominate in this region. The origin and emergence of these herpetofaunal groups are poorly understood. Aside from the better-explored European Neogene localities yielding amphibian and reptile fossil remains, the Neogene herpetofauna of Western Asia is understudied. The few available data need critical reviews and new interpretations, taking into account the more recent records of the European herpetofauna. The comparison of this previous data with that of European fossil records would provide data on palaeobiogeographic affiliations of the region as well as on the origin and emergence of the present day fauna of Western Siberia. An overview of the earliest occurrences of certain amphibian lineages is still needed. In addition, studies that address such knowledge gaps can be useful for molecular biologists in their calibration of molecular clocks. METHODS AND RESULTS: In this study, we considered critically reviewed available data from amphibian and reptile fauna from over 40 Western Siberian, Russian and Northeastern Kazakhstan localities, ranging from the Middle Miocene to Early Pleistocene. Herein, we provided new interpretations that arose from our assessment of the previously published and new data. More than 50 amphibians and reptile taxa were identified belonging to families Hynobiidae, Cryptobranchidae, Salamandridae, Palaeobatrachidae, Bombinatoridae, Pelobatidae, Hylidae, Bufonidae, Ranidae, Gekkonidae, Lacertidae, and Emydidae. Palaeobiogeographic analyses were performed for these groups and palaeoprecipitation values were estimated for 12 localities, using the bioclimatic analysis of herpetofaunal assemblages. CONCLUSION: The Neogene assemblage of Western Siberia was found to be dominated by groups of European affinities, such as Palaeobatrachidae, Bombina, Hyla, Bufo bufo, and a small part of this assemblage included Eastern Palaearctic taxa (e.g. Salamandrella, Tylototriton, Bufotes viridis). For several taxa (e.g. Mioproteus, Hyla, Bombina, Rana temporaria), the Western Siberian occurrences represented their most eastern Eurasian records. The most diverse collection of fossil remains was found in the Middle Miocene. Less diversity has been registered towards the Early Pleistocene, potentially due to the progressive cooling of the climate in the Northern Hemisphere. The results of our study showed higher-amplitude changes of precipitation development in Western Siberia from the Early Miocene to the Pliocene, than previously assumed. PMID- 28348924 TI - Random sampling causes the low reproducibility of rare eukaryotic OTUs in Illumina COI metabarcoding. AB - DNA metabarcoding, the PCR-based profiling of natural communities, is becoming the method of choice for biodiversity monitoring because it circumvents some of the limitations inherent to traditional ecological surveys. However, potential sources of bias that can affect the reproducibility of this method remain to be quantified. The interpretation of differences in patterns of sequence abundance and the ecological relevance of rare sequences remain particularly uncertain. Here we used one artificial mock community to explore the significance of abundance patterns and disentangle the effects of two potential biases on data reproducibility: indexed PCR primers and random sampling during Illumina MiSeq sequencing. We amplified a short fragment of the mitochondrial Cytochrome c Oxidase Subunit I (COI) for a single mock sample containing equimolar amounts of total genomic DNA from 34 marine invertebrates belonging to six phyla. We used seven indexed broad-range primers and sequenced the resulting library on two consecutive Illumina MiSeq runs. The total number of Operational Taxonomic Units (OTUs) was ~4 times higher than expected based on the composition of the mock sample. Moreover, the total number of reads for the 34 components of the mock sample differed by up to three orders of magnitude. However, 79 out of 86 of the unexpected OTUs were represented by <10 sequences that did not appear consistently across replicates. Our data suggest that random sampling of rare OTUs (e.g., small associated fauna such as parasites) accounted for most of variation in OTU presence-absence, whereas biases associated with indexed PCRs accounted for a larger amount of variation in relative abundance patterns. These results suggest that random sampling during sequencing leads to the low reproducibility of rare OTUs. We suggest that the strategy for handling rare OTUs should depend on the objectives of the study. Systematic removal of rare OTUs may avoid inflating diversity based on common beta descriptors but will exclude positive records of taxa that are functionally important. Our results further reinforce the need for technical replicates (parallel PCR and sequencing from the same sample) in metabarcoding experimental designs. Data reproducibility should be determined empirically as it will depend upon the sequencing depth, the type of sample, the sequence analysis pipeline, and the number of replicates. Moreover, estimating relative biomasses or abundances based on read counts remains elusive at the OTU level. PMID- 28348926 TI - Climate change promotes hybridisation between deeply divergent species. AB - Rare hybridisations between deeply divergent animal species have been reported for decades in a wide range of taxa, but have often remained unexplained, mainly considered chance events and reported as anecdotal. Here, we combine field observations with long-term data concerning natural hybridisations, climate, land use, and field-validated species distribution models for two deeply divergent and naturally sympatric toad species in Europe (Bufo bufo and Bufotes viridis species groups). We show that climate warming and seasonal extreme temperatures are conspiring to set the scene for these maladaptive hybridisations, by differentially affecting life-history traits of both species. Our results identify and provide evidence of an ultimate cause for such events, and reveal that the potential influence of climate change on interspecific hybridisations goes far beyond closely related species. Furthermore, climate projections suggest that the chances for these events will steadily increase in the near future. PMID- 28348927 TI - Are floating algal mats a refuge from hypoxia for estuarine invertebrates? AB - Eutrophic aquatic habitats are characterized by the proliferation of vegetation leading to a large standing biomass that upon decomposition may create hypoxic (low-oxygen) conditions. This is indeed the case in nutrient impacted estuaries of Prince Edward Island, Canada, where macroalgae, from the genus Ulva, form submerged ephemeral mats. Hydrological forces and gases released from photosynthesis and decomposition lead to these mats occasionally floating to the water's surface, henceforth termed floating mats. Here, we explore the hypothesis that floating mats are refugia during periods of sustained hypoxia/anoxia and examine how the invertebrate community responds to it. Floating mats were not always present, so in the first year (2013) sampling was attempted monthly and limited to when both floating and submerged mats occurred. In the subsequent year sampling was weekly, but at only one estuary due to logistical constraints from increased sampling frequency, and was not limited to when both mat types occurred. Water temperature, salinity, and pH were monitored bi-weekly with dissolved oxygen concentration measured hourly. The floating and submerged assemblages shared many of the same taxa but were statistically distinct communities; submerged mats tended to have a greater proportion of benthic animals and floating mats had more mobile invertebrates and insects. In 2014, sampling happened to occur in the weeks before the onset of anoxia, during 113 consecutive hours of sustained anoxia, and for four weeks after normoxic conditions returned. The invertebrate community on floating mats appeared to be unaffected by anoxia, indicating that these mats may be refugia during times of oxygen stress. Conversely, there was a dramatic decrease in animal abundances that remained depressed on submerged mats for two weeks. Cluster analysis revealed that the submerged mat communities from before the onset of anoxia and four weeks after anoxia were highly similar to each other, indicating recovery. When mobile animals were considered alone, there was an exponential relationship between the percentage of animals on floating mats, relative to the total number on both mat types, and hypoxia. The occupation of floating mats by invertebrates at all times, and their dominance there during hypoxia/anoxia, provides support for the hypothesis that floating mats are refugia. PMID- 28348928 TI - Analysis of different vibration patterns to guide blind people. AB - The literature indicates the best vibration positions and frequencies on the human body where tactile information is transmitted. However, there is a lack of knowledge about how to combine tactile stimuli for navigation. The aim of this study is to compare different vibration patterns outputted to blind people and to determine the most intuitive vibration patterns to indicate direction for navigation purposes through a tactile belt. The vibration patterns that stimulate the front side of the waist are preferred for indicating direction. Vibration patterns applied on the back side of the waist could be suitable for sending messages such as stop. PMID- 28348929 TI - Curvature reduces bending strains in the quokka femur. AB - This study explores how curvature in the quokka femur may help to reduce bending strain during locomotion. The quokka is a small wallaby, but the curvature of the femur and the muscles active during stance phase are similar to most quadrupedal mammals. Our hypothesis is that the action of hip extensor and ankle plantarflexor muscles during stance phase place cranial bending strains that act to reduce the caudal curvature of the femur. Knee extensors and biarticular muscles that span the femur longitudinally create caudal bending strains in the caudally curved (concave caudal side) bone. These opposing strains can balance each other and result in less strain on the bone. We test this idea by comparing the performance of a normally curved finite element model of the quokka femur to a digitally straightened version of the same bone. The normally curved model is indeed less strained than the straightened version. To further examine the relationship between curvature and the strains in the femoral models, we also tested an extra-curved and a reverse-curved version with the same loads. There appears to be a linear relationship between the curvature and the strains experienced by the models. These results demonstrate that longitudinal curvature in bones may be a manipulable mechanism whereby bone can induce a strain gradient to oppose strains induced by habitual loading. PMID- 28348930 TI - Effects of various factors on Doppler flow ultrasonic radial and coccygeal artery systolic blood pressure measurements in privately-owned, conscious dogs. AB - OBJECTIVE: The purpose of this study was to assess the effects of age, body condition score (BCS) and muscle condition score (MCS) on indirect radial and coccygeal Doppler systolic arterial blood pressure (SAP) measurements in dogs. METHODS: Sixty-two privately-owned dogs were enrolled between June and July 2016. The BCS and MCS were determined by two investigators. Blood pressure was measured per published guidelines and using headphones, and the order of measurement site was randomized. Dogs were positioned in right lateral recumbency for radial measurements and sternal recumbency or standing for coccygeal measurements. Associations between SAP and other variables were assessed by correlation coefficients and analysis of covariance. RESULTS: Radial and coccygeal SAP measurements were moderately correlated (r = 0.45, P < 0.01). Radial SAP measurements were higher than coccygeal SAP measurements (mean difference 9 mmHg, P < 0.01), but discordance occurred in both directions. No difference was observed between the first measurement taken, the average of measurements 2-6, or the average of all 6 measurements for either the radial (128, 129, and 129 mmHg; P = 0.36) or coccygeal (121, 122, and 122 mmHg; P = 0.82) site. Associations were not found between SAP measurements for either site and age, weight, BCS, MCS, anxiety score, or cuff size. Heart rate decreased significantly from the start of acclimation to the end of the first data collection series regardless of site (P < 0.01). CONCLUSIONS AND CLINICAL RELEVANCE: Initial measurement site can be based on patient and operator preference given lack of associations with patient variables, but the same site should be used for serial SAP measurements given discordant results between sites. PMID- 28348932 TI - Seed germination in a southern Australian temperate seagrass. AB - In a series of experiments, seeds from a temperate seagrass species, Zostera nigricaulis collected in Port Phillip Bay, Victoria, Australia were exposed to a range of salinities (20 PSU pulse/no pulse, 25 PSU, 30 PSU, 35 PSU), temperatures (13 degrees C, 17 degrees C, 22 degrees C), burial depths (0 cm, 1 cm, 2 cm) and site specific sediment characteristics (fine, medium, coarse) to quantify their impacts on germination rate and maximum overall germination. In southern Australia the seagrass Z. nigricaulis is a common subtidal species; however, little is known about the factors that affect seed germination which is a potential limiting factor in meadow resilience to natural and anthropogenic disturbances. Overall seed germination was low (<20%) with germination decreasing to <10% when seeds were placed in the sediment. When germination of Z. nigricaulis seeds was observed, it was enhanced (greater overall germination and shorter time to germination) when seeds were exposed to a 20 PSU pulse for 24 h, maintained at salinity of 25 PSU, temperatures <13 degrees C, in sediments with fine or medium grain sand and buried at a depth of <1 cm. These results indicate that germination of Z. nigricaulis seeds under in situ conditions may be seasonally limited by temperatures in southern Australia. Seed germination may be further restricted by salinity as freshwater pulses reaching 20 PSU are typically only observed in Port Phillip Bay following large scale rainfall events. As a result, these populations may be particularly susceptible to disturbance with only a seasonally limited capacity for recovery. PMID- 28348931 TI - Basal tolerance to heat and cold exposure of the spotted wing drosophila, Drosophila suzukii. AB - The spotted wing Drosophila, Drosophila suzukii, is a new pest in Europe and America which causes severe damages, mostly to stone fruit crops. Temperature and humidity are among the most important abiotic factors governing insect development and fitness. In many situations, temperature can become stressful thus compromising survival. The ability to cope with thermal stress depends on basal level of thermal tolerance. Basic knowledge on temperature-dependent mortality of D. suzukii is essential to facilitate management of this pest. The objective of the present study was to investigate D. suzukii basal cold and heat tolerance. Adults and pupae were subjected to six low temperatures (-5-7.5 degrees C) and seven high temperatures (30-37 degrees C) for various durations, and survival-time-temperature relationships were investigated. Data showed that males were globally more cold tolerant than females. At temperature above 5 degrees C, adult cold mortality became minor even after prolonged exposures (e.g., only 20% mortality after one month at 7.5 degrees C). Heat tolerance of males was lower than that of females at the highest tested temperatures (34, 35 and 37 degrees C). Pupae appeared much less cold tolerant than adults at all temperatures (e.g., Lt50 at 5 degrees C: 4-5 d for adults vs. 21 h for pupae). Pupae were more heat tolerant than adults at the most extreme high temperatures (e.g., Lt50 at 37 degrees C: 30 min for adults vs. 4 h for pupae). The pupal thermal tolerance was further investigated under low vs. high humidity. Low relative humidity did not affect pupal cold survival, but it reduced survival under heat stress. Overall, this study shows that survival of D. suzukii under heat and cold conditions can vary with stress intensity, duration, humidity, sex and stage, and the methodological approach used here, which was based on thermal tolerance landscapes, provides a comprehensive description of D. suzukiithermal tolerance and limits. PMID- 28348933 TI - Effects of long-term elevated temperature on covering, sheltering and righting behaviors of the sea urchin Strongylocentrotus intermedius. AB - Increases in ocean temperature due to climate change are predicted to change the behaviors of marine invertebrates. Altered behaviors of keystone ecosystem engineers such as echinoderms will have consequences for the fitness of individuals, which are expected to flow on to the local ecosystem. Relatively few studies have investigated the behavioral responses of echinoderms to long-term elevated temperature. We investigated the effects of exposure to long-term (~31 weeks) elevated temperature (~3 degrees C above the ambient water temperature) on covering, sheltering and righting behaviors of the sea urchin Strongylocentrotus intermedius. Long-term elevated temperature showed different effects on the three behaviors. It significantly decreased covering behavior, including both covering behavior reaction (time to first covering) and ability (number of covered sea urchins and number of shells used for covering). Conversely, exposure to long-term elevated temperature significantly increased sheltering behavior. Righting response in S. intermedius was not significantly different between temperature treatments. The results provide new information into behavioral responses of echinoderms to ocean warming. PMID- 28348934 TI - Genetic insights into family group co-occurrence in Cryptocercus punctulatus, a sub-social woodroach from the southern Appalachian Mountains. AB - The wood-feeding cockroach Cryptocercus punctulatus Scudder (Blattodea: Cryptocercidae) is an important member of the dead wood (saproxylic) community in montane forests of the southeastern United States. However, its population biology remains poorly understood. Here, aspects of family group co-occurrence were characterized to provide basic information that can be extended by studies on the evolution and maintenance of sub-sociality. Broad sampling across the species' range was coupled with molecular data (mitochondrial DNA (mtDNA) sequences). The primary questions were: (1) what proportion of rotting logs contain two or more different mtDNA haplotypes and how often can this be attributed to multiple families inhabiting the same log, (2) are multi-family logs spatially clustered, and (3) what levels of genetic differentiation among haplotypes exist within a log, and how genetically similar are matrilines of co occurring family groups? Multi-family logs were identified on the premise that three different mtDNA haplotypes, or two different haplotypes among adult females, is inconsistent with a single family group founded by one male-female pair. Results showed that of the 88 rotting logs from which multiple adult C. punctulatus were sampled, 41 logs (47%) contained two or more mtDNA haplotypes, and at least 19 of these logs (22% overall) were inferred to be inhabited by multiple families. There was no strong evidence for spatial clustering of the latter class of logs. The frequency distribution of nucleotide differences between co-occurring haplotypes was strongly right-skewed, such that most haplotypes were only one or two mutations apart, but more substantial divergences (up to 18 mutations, or 1.6% uncorrected sequence divergence) do occasionally occur within logs. This work represents the first explicit investigation of family group co-occurrence in C. punctulatus, providing a valuable baseline for follow-up studies. PMID- 28348935 TI - Systematic drug repositioning through mining adverse event data in ClinicalTrials.gov. AB - Drug repositioning (i.e., drug repurposing) is the process of discovering new uses for marketed drugs. Historically, such discoveries were serendipitous. However, the rapid growth in electronic clinical data and text mining tools makes it feasible to systematically identify drugs with the potential to be repurposed. Described here is a novel method of drug repositioning by mining ClinicalTrials.gov. The text mining tools I2E (Linguamatics) and PolyAnalyst (Megaputer) were utilized. An I2E query extracts "Serious Adverse Events" (SAE) data from randomized trials in ClinicalTrials.gov. Through a statistical algorithm, a PolyAnalyst workflow ranks the drugs where the treatment arm has fewer predefined SAEs than the control arm, indicating that potentially the drug is reducing the level of SAE. Hypotheses could then be generated for the new use of these drugs based on the predefined SAE that is indicative of disease (for example, cancer). PMID- 28348936 TI - Ciprofloxacin-induced Hepatotoxicity in a Healthy Young Adult. AB - Ciprofloxacin is a broad-spectrum fluoroquinolone antibiotic that is widely used in the treatment of many common infections, including urinary tract infections (UTIs). Despite the increase in Escherichia coli resistance to ciprofloxacin, especially in the United States (US), clinicians continue to utilize the high bioavailability of this drug in urine to counter UTIs. A rare adverse effect following use of ciprofloxacin is drug-induced hepatitis. In this case report, we describe a young 29-year-old female with a previous medical history significant for pyelonephritis and ovarian cyst who presented to the emergency room with signs and symptoms suggestive of progressive liver injury for two weeks that started two days after a complete course of ciprofloxacin therapy for a UTI. An extensive workup failed to identify a particular cause for the hepatotoxicity. The associated onset of symptoms following ciprofloxacin use, the pattern of hepatic enzyme elevation coupled with abdominal pain suggestive of liver pathology, and the resolution of all symptoms following supportive therapy all pointed towards the possible diagnosis of ciprofloxacin-induced hepatotoxicity. The patient was treated with supportive therapy, and subsequently, her symptoms resolved over the next few days with the improvement of her liver enzyme levels. The patient was discharged with instructions to avoid ciprofloxacin and other fluoroquinolones in the future. Clinicians should maintain a high degree of suspicion when treating patients with ciprofloxacin who subsequently develop signs and/or symptoms of liver injury. PMID- 28348937 TI - Redefining Health: The Evolution of Health Ideas from Antiquity to the Era of Value-Based Care. AB - The current healthcare system in the United States (US) is characterized by high costs and poor patient outcomes. A value-based healthcare system, centered on providing the highest quality of care for the lowest cost, is the country's chosen solution for its healthcare crisis. As the US transitions to a value-based model, a new definition of health is necessary to clearly define what constitutes a healthy state. However, such a definition is impossible to develop without a proper understanding of what "health" actually means. To truly understand its meaning, one must have a thorough historical understanding of the changes in the concept of health and how it has evolved to reflect the beliefs and scientific understanding of each time period. Thus, this review summarizes the changes in the definition of health over time in order to provide a context for the definition needed today. We then propose a new definition of health that is specifically tailored to providers working in the era of value-based care. PMID- 28348938 TI - Giardia-filled Pancreatic Mass in a Patient With Recently Treated T-cell-rich B cell Lymphoma. AB - Giardia lamblia (G. lamblia)-filled pancreatic masses are a rarely reported entity. Furthermore, there are only a few case reports in literature on the association of these masses with cancer. We present a case of a G. lamblia-filled pancreatic cystic mass in a patient with a history of T-cell-rich B-cell lymphoma. The authors performed a PubMed search using (Medical Subject Headings) MeSH terms of pancreas, mass, Giardia, and lymphoma. A 53-year-old male with past medical and surgical history of T-cell-rich B-cell lymphoma, status post R CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab) therapy with positron emission tomography (PET) scan showing no residual disease, essential hypertension, and alcohol use disorder presented to the emergency department (ED) with epigastric pain and nausea for one week. Computed tomography (CT) scan of the abdomen showed a 2.3 cm hypodense pancreatic cystic mass. This was a new finding when compared to his prior abdominal imaging. Fine needle aspiration (FNA) biopsy of the mass showed lymphocytes, reactive atypical epithelial cells, and numerous organisms consistent with Giardia lamblia. He was treated with metronidazole 250 mg by mouth three times a day (TID) for five days. Follow-up magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP) showed complete resolution of the pancreatic mass. There are only a few case reports on G. lamblia in the pancreas. The pathologist indicated sheets of numerous Giardia in the sample, making small bowel contamination less likely and G. lamblia aspirate from the pancreas more probable as the source. The authors hypothesize that this patient may have had chronic G. lamblia infection as a potential cause for the T-cell-rich B-cell lymphoma manifestation. The patient reported travel to an area with possible exposure to G. lamblia one year prior to presentation with the lymphoma. During that time he had increasing abdominal pain, intermittent chronic diarrhea, and weight loss. G. lamblia's mechanism of action has been theorized to involve induction of pro-apoptotic factors, intestinal barrier dysfunction, up-regulation of cell-cycle genes, and crypt hyperplasia. The mechanism of action of pancreatic masses filled with G. lamblia and the association of G. lamblia and cancer is not completely understood. Further research is required to better understand these possible phenomena as it can help us better comprehend G. lamblia, its associations, and new cancer etiologies. PMID- 28348939 TI - Radiolucent Skull Clamps for Intra-Operative Imaging: A Technical Note. AB - Conventionally, surgery and procedural-based radiology are performed on different premises. With advances in imaging technology, the operating room is rapidly being transformed into an intraoperative imaging suite. Diagnostic imaging in conjunction with surgery has great utility and by all accounts has great future potential. During the last decade, cone beam computed tomography (CT) scanners have been introduced and have made intraoperative imaging more feasible because these scanners can be made less bulky. The current usefulness of intraoperative magnetic resonance imaging (MRI) or CT for neurosurgery, however, is impaired by the lack of completely radiolucent skull clamps, causing image artifacts. Metal artifacts are particularly problematic, given that they lead to a considerably higher image quality degradation factor for cone beam CT scanners than for conventional CT scanners. Here, we describe our experience with near-radiolucent skull clamps and their associated problems and discuss future improvements to facilitate high-quality image guidance in the field of neurosurgery. PMID- 28348940 TI - Minimally Invasive Robotic Laser Corpus Callosotomy: A Proof of Concept. AB - INTRODUCTION: We describe the feasibility of using minimally invasive robotic laser interstitial thermotherapy (LITT) for achieving an anterior two-thirds as well as a complete corpus callosotomy. METHODS: Ten probe trajectories were plotted on normal magentic resonance imaging (MRI) scans using the Brainlab Stereotactic Planning Software (Brainlab, Munich, Germany). The NeuroBlate(r) System (Monteris Medical, MN, USA) was used to conform the thermal burn to the corpus callosum along the trajectory of the probe. The distance of the ideal entry site from either the coronal suture and the torcula or nasion and the midline was calculated. The distance of the probe tip from the dorsal and ventral limits of the callosotomy in the sagittal plane were also calculated. RESULTS: Anterior two-thirds callosotomy was possible in all patients using a posterior parieto-occipital paramedian trajectory through the non-dominant lobe. The average entry point was 3.64 cm from the midline, 10.6 cm behind the coronal suture, and 9.2 cm above the torcula. The probe tip was an average of 1.4 cm from the anterior commissure. For a total callosotomy, an additional contralaterally placed frontal probe was used to target the posterior one-third of the corpus callosum. The average entry site was 3.3 cm from the midline and 9.1 cm above the nasion. The average distance of the probe tip from the base of the splenium was 0.94 cm. CONCLUSION: The directional thermoablation capability of the NeuroBlate(r) system allows for targeted lesioning of the corpus callosum, to achieve a two-thirds or complete corpus callosotomy. A laser distance of < 2 cm is sufficient to reach the entire corpus callosum through one trajectory for an anterior two-thirds callosotomy and two trajectories for a complete callosotomy. PMID- 28348941 TI - Cutting the Stone: Health Defined in the Era of Value-based Care. AB - The immune system contributes to the maintenance of health by preventing and limiting the clinical consequences of infections by pathogenic microorganisms. During the evolution of Homo sapiens, those with the fittest immune system survived. The immune system of Homo sapiens was further improved and adapted by admixture with Neanderthal genes. Nowadays, the human immune system provides adequate protection against the majority of infections. For some 20 infectious diseases, the immune system needs to be improved by vaccination. Vaccination is the number one value-based healthcare intervention and has resulted in global eradication of smallpox. Eradication of poliomyelitis and measles is within reach. A continuous effort will be required for recently emerged pathogens, such as Ebola and HIV, as well as the most difficult - malaria and tuberculosis. PMID- 28348942 TI - Biochemistry in Endeavor Adventure Racers Study (BEARS). AB - BACKGROUND: Adventure sports events consist of a combination of two or more endurance disciplines, such as orienteering, running, and rock climbing, that range from a day's to a week's duration. No studies have examined acute kidney injury (AKI) in adventure sports athletes. OBJECTIVES: To describe the prevalence of AKI in participants in the Endeavor Team Challenge, a 30-hour, 40-mile adventure race. METHODS: In this prospective observational study, body weights were recorded at race registration. At the finish line, blood sample results by point-of-care testing and weights were recorded. Changes in serum creatinine (Cr) from an estimated baseline value and severity of AKI were calculated, with "risk of injury" defined as 1.5 x baseline Cr, and "injury" defined as 2 x baseline Cr. These two categories of AKI were combined to calculate the total prevalence. Results: There were 88 enrolled study participants with complete data available on 46 (52%). The mean age of those enrolled in the study was 36.8 years (+/- 7.7), 90% were males, and body mass index (BMI) was 25.7 kg/m2 (+/- 2.4). Of the competitors who completed the study, 34 (73%) had some degree of AKI, with 27 (58%) found to be at "risk" and seven (15%) with "injury". There was a significant correlation between weight loss and elevated Cr (r = -0.29, p = 0.047), with a trend towards nonsteroidal anti-inflammatory drug (NSAID) use being correlated with AKI (p = 0.058). CONCLUSION: Acute kidney injury was observed in the majority of the Endeavor Team Challenge adventure racers, similar to what has been observed in multistage ultramarathons, and greater than after standard marathons and single-stage ultramarathons. PMID- 28348943 TI - Correlation of IVC Diameter and Collapsibility Index With Central Venous Pressure in the Assessment of Intravascular Volume in Critically Ill Patients. AB - OBJECTIVE: The objective of our study is to assess the correlation between inferior vena cava (IVC) diameters, central venous pressure (CVP) and the IVC collapsibility index for estimating the volume status in critically ill patients. METHODS: This cross-sectional study used the convenient sampling of 100 adult medical intensive care unit (ICU) patients for a period of three months. Patients >= 18 years of age with an intrathoracic central venous catheter terminating in the distal superior vena cava connected to the transducer to produce a CVP waveform were included in the study. A Mindray diagnostic ultrasound system model Z6 ultrasound machine (Mindray, NJ, USA) was used for all examinations. An Ultrasonic Transducer model 3C5P (Mindray, NJ, USA) for IVC imaging was utilized. A paired sampled t-test was used to compute the p-values. RESULTS: A total of 32/100 (32%) females and 68/100 (68%) males were included in the study with a mean age of 50.4 +/- 19.3 years. The mean central venous pressure maintained was 10.38 +/- 4.14 cmH2O with an inferior vena cava collapsibility index of 30.68 +/- 10.93. There was a statistically significant relation among the mean CVP pressure, the IVC collapsibility index, the mean maximum and minimum IVC between groups as determined by one-way analysis of variance (ANOVA) (p < 0.001). There was a strong negative correlation between CVP and IVC collapsibility index (%), which was statistically significant (r = -0.827, n = 100, p < 0.0005). A strong positive correlation between CVP and maximum IVC diameter (r = 0.371, n = 100, p < 0.0005) and minimum IVC diameter (r = 0.572, n = 100, p < 0.0005) was found. CONCLUSION: There is a positive relationship of CVP with minimum and maximum IVC diameters but an inverse relationship with the IVC collapsibility index. PMID- 28348944 TI - Tumoral Melanosis Associated with Pembrolizumab-Treated Metastatic Melanoma. AB - Tumoral melanosis is a form of completely regressed melanoma that usually presents as darkly pigmented lesions suspicious for malignant melanoma. Histology reveals dense dermal and subcutaneous infiltration of melanophages. Pembrolizumab is an antibody directed against programmed death receptor-1 (PD1) and is frontline treatment for advanced melanoma. An 81-year-old man with metastatic melanoma treated with pembrolizumab who developed tumoral melanosis at previous sites of metastases is described. The PubMed database was searched with the key words: antibody, immunotherapy, melanoma, melanosis, metastasis, pembrolizumab, and tumoral. The papers generated by the search and their references were reviewed. The patient was initially diagnosed with lentigo maligna melanoma on the left cheek three years earlier, and he was treated with wide local excision. The patient was subsequently diagnosed with epidermotropic metastatic malignant melanoma on the left parietal scalp 14 months later and was treated with wide local excision. Three months later, the patient was found to have metastatic melanoma in the same area of the scalp and was started on pembrolizumab immunotherapy. The patient was diagnosed with tumoral melanosis in the site of previous metastases nine months later. The patient remained free of disease 13 months after starting pembrolizumab. Tumoral melanosis may mimic malignant melanoma; hence a workup, including skin biopsy, should be undertaken. Extensive tumoral melanosis has been reported with ipilimumab, and we add a case following treatment with pembrolizumab. Additional cases of tumoral melanosis may present since immunotherapy has become frontline therapy for advanced melanoma. PMID- 28348945 TI - Infective Endocarditis in a Patient with Celiac Disease after Central Venous Catheter Insertion. AB - There is an increasing incidence of infective endocarditis secondary to central venous catheters, which is termed as 'healthcare-associated infective endocarditis'. There is an increased risk of getting infective endocarditis in conditions with malnutrition and also if the tip of the central venous catheter is deep in the right atrium close to the tricuspid valve. We present a case of 31 year-old female who had all these risk factors. She was admitted to the hospital for the work up of the weight loss and was diagnosed with celiac disease. Central venous access was obtained because of poor peripheral intravenous access via the peripherally inserted central catheter which was complicated by thrombosis and removed after three days of insertion, and she was started on anticoagulation. Two weeks after being discharged, she presented to the emergency department with fever, shortness of breath, and had signs of congestive heart failure. A computed tomography of the chest for pulmonary embolism was taken and showed small clot burden pulmonary embolism and two cavitary lesions in the right lung. A transthoracic echocardiogram was taken and showed vegetation on the tricuspid valve and blood cultures were positive for Staphylococcus aureus. Hence, a diagnosis of infective endocarditis was made, and she was treated with intravenous antibiotics for a total of six weeks after a long and complicated hospital stay. PMID- 28348946 TI - Relationship between children's physical activity, sedentary behavior, and childcare environments: A cross sectional study. AB - The purpose of this study was to investigate the relationship between the childcare environment and physical activity and sedentary behavior of toddlers and preschoolers. A total of 68 toddlers (1.0-2.9 years) and 233 preschoolers (3.0-5.9 years) were recruited from 11 childcare services in 2013 within the Illawarra and Shoalhaven region of NSW, Australia. For this study analysis was conducted in 2016. The childcare environment was assessed using the Environment and Policy Assessment Observation (EPAO) instrument, and childcare services categorized as low, medium, or high based on their scores. Time spent in physical activity and sitting was assessed over one week using activPAL accelerometers. Relationship between EPAO and children's physical activity and sedentary behavior was assessed using multilevel mixed-effects linear regression. Toddlers who attended high EPAO services sat more (8.73 min [- 10.26, 27.73]) and stood less ( 13.64 min [- 29.27, 2.00]) than those who attended low EPAO services. Preschoolers who attended high EPAO services sat less than those in low and medium services (mean [95%CI] = - 7.81 min [- 26.64, 11.02]). Sub-categories of the EPAO that were associated with less time sitting were: sedentary environments for toddlers and portable play equipment for preschoolers. This study extends previous research by identifying differences between toddlers and preschooler's physical activity and sedentary behaviors in relation to childcare environments. A greater understanding of how the childcare environment relates to sitting time for both toddlers and preschool aged children is needed. PMID- 28348947 TI - Legionella pneumonia associated with severe acute respiratory distress syndrome and diffuse alveolar hemorrhage - A rare association. AB - Legionella pneumophila is a common, usually underreported and undiagnosed cause of community acquired pneumonia which can lead to significant morbidity and mortality. Diffuse alveolar hemorrhage rarely have been associated with legionella infection. We present a 61-year-old man with hypertension, diabetes mellitus and obesity admitted with severe acute respiratory distress syndrome. He was found to have Legionella pneumonia with associated diffuse alveolar hemorrhage diagnosed with bronchoscopic sequential bronchoalveolar lavage. He was successfully managed with antibiotics, lung protective strategies and intravenous pulse dose steroids. This patient highlights the unusual association of Legionella infection and diffuse alveolar hemorrhage. Additionally, the case re enforces the need for early and aggressive evaluation and management of patients presenting with pneumonia and progressive hypoxia despite adequate treatment. PMID- 28348948 TI - Microscopic polyangiitis: Atypical presentation with extensive small bowel necrosis, diffuse alveolar hemorrhage, and renal failure. AB - Microscopic polyangiitis is an uncommon systemic vasculitis of varying severity that is associated with myeloperoxidase (MPO) and perinuclear antineutrophil cytoplasmic (p-ANCA) antibodies. The most commonly affected organs are the lungs and kidneys. We report on a very unusual case of microscopic polyangiitis presenting with severe mesenteric ischemia in addition to diffuse alveolar hemorrhage and acute renal failure. The patient was initially diagnosed with acute pancreatitis at an outside facility given his severe abdominal pain and elevated pancreatic enzymes. Further investigations after transfer to our facility determined that the patient was actually suffering from a severe exacerbation of previously diagnosed microscopic polyangiitis. He quickly developed diffuse alveolar hemorrhage (DAH) necessitating intubation and acute kidney injury (AKI) requiring dialysis. He subsequently developed mesenteric ischemia and bowel necrosis resulting in emergent laparotomy and extensive small bowel resection. Physicians need to be aware that microscopic polyangiitis can very rarely present with severe involvement of the abdominal viscera and mesenteric vessels. Severe disease necessitates the use of high dose IV steroids, rituximab or cyclophosphamide, and plasma exchange (PLEX). PMID- 28348949 TI - Impact of advanced medical therapy for the outcome of an adult patient with Eisenmenger syndrome. AB - Eisenmenger syndrome (ES) is the most severe form of pulmonary arterial hypertension (PAH) associated with congenital heart disease. It is an extremely devastating condition with a serious impact on patients' life. Classical therapy of ES remains directed to avoid complications, such as erythrocytosis, treatment of congestive heart failure, prevention of infection, and secondary haematological abnormalities such as iron deficiency and coagulation disorders. However, the only effective treatment is heart-lung transplantation; still, morbidity and mortality after transplantation remain substantially high. Furthermore, waiting lists for heart-lung transplantation are long. Recent studies examining the use of advanced medical treatment in patients with ES have shown that it may have beneficial effects in patients with ES; however, additional studies need to be done to confirm its efficacy and appropriate clinical use. A 41-year-old female admitted to the Hospital of Lithuanian University of Health Sciences due to progressive dyspnea on minimal effort, heart failure symptoms leading to NYHA functional class III-IV. After clinical and instrumental investigations, ES secondary to unrepaired patent ductus arteriosus with severe PAH was diagnosed. Treatment with sildenafil was initiated together with the standard pharmacological therapy, and the patient was added to the waiting list for the heart and lung transplantation. After 24 months of stable condition, her clinical status deteriorated, and combination therapy (sildenafil and ambrisentan) was initiated. Clinical symptoms and exercise capacity improved, and she has been stable for 4 years thereafter. Our experience of the management of an adult patient with ES showed the benefits of treatment with advanced therapy with pulmonary vasodilators that improved the patient's quality of life and delayed the need for heart and lung transplantation. PMID- 28348950 TI - A case of sulfhemoglobinemia in a child with chronic constipation. AB - Sulfhemoglobinemia is a rare condition in which a sulfur atom oxidizes the heme moiety in hemoglobin, making the hemoglobin incapable of carrying oxygen and leading to hypoxia and cyanosis. This condition has been described in patients taking sulfur medications or who have cultured hydrogen sulfide producing intestinal bacteria such as Morganella morganii. This case describes a pediatric patient who was found to have cyanosis on two occasions of urinary tract infection in the setting of chronic constipation, with confirmed sulfhemoglobinemia during the second admission. Sulfhemoglobinemia due to increases in sulfur producing intestinal bacteria led to cyanosis and low oxygen saturations. The patient had an incidental finding of a pulmonary arteriovenous malformation (AVM) but had a normal PAO2 so was not hypoxemic though she was cyanotic. Low oxygen saturations by pulse oximetry may be explained by dyshemoglobinemia as opposed to true arterial hypoxemia; the importance of measuring an arterial blood gas in cases of cyanosis is paramount. PMID- 28348951 TI - Spontaneous pneumomediastinum: A rare complication of methamphetamine use. AB - OBJECTIVE: To present an unusual case of spontaneous pneumomediastinum subsequent to recreational amphetamine use. CASE REPORT: A young African American adult male was admitted to internal medicine service for treatment of rhabdomyolysis secondary to methamphetamine use. On admission, he was complaining of chest pain in addition to nausea and generalized muscle aches. By his second hospital day, chest pain had resolved yet physical exam demonstrated crepitation of the anterior chest and left axilla. Portable chest x-ray revealed subcutaneous emphysema in addition to pneumomediastinum. CONCLUSION: Spontaneous pneumomediastinum is a rare complication of amphetamine use that is often associated with subcutaneous emphysema and can be diagnosed with chest x-ray. Management is conservative, with observation, pain control, and supplemental oxygen as needed. PMID- 28348952 TI - Radiation-induced abnormal cortical thickness in patients with nasopharyngeal carcinoma after radiotherapy. AB - Conventional MRI studies showed that radiation-induced brain necrosis in patients with nasopharyngeal carcinoma (NPC) in years after radiotherapy (RT) could involve brain gray matter (GM) and impair brain function. However, it is still unclear the radiation-induced brain morphological changes in NPC patients with normal-appearing GM in the early period after RT. In this study, we acquired high resolution brain structural MRI data from three groups of patients, 22 before radiotherapy (pre-RT) NPC patients with newly diagnosed but not yet medically treated, 22 NPC patients in the early-delayed stage after radiotherapy (post-RT ED), and 20 NPC patients in the late-delayed stage after radiotherapy (post-RT LD), and then analyzed the radiation-induced cortical thickness alteration in NPC patients after RT. Using a vertex-wise surface-based morphometry (SBM) approach, we detected significantly decreased cortical thickness in the precentral gyrus (PreCG) in the post-RT-ED group compared to the pre-RT group. And the post-RT-LD group showed significantly increased cortical thickness in widespread brain regions, including the bilateral inferior parietal, left isthmus of the cingulate, left bank of the superior temporal sulcus and left lateral occipital regions, compared to the pre-RT group, and in the bilateral PreCG compared to the post-RT-ED group. Similar analysis with ROI-wise SBM method also found the consistent results. These results indicated that radiation-induced brain injury mainly occurred in the post-RT-LD group and the cortical thickness alterations after RT were dynamic in different periods. Our findings may reflect the pathogenesis of radiation-induced brain injury in NPC patients with normal appearing GM and an early intervention is necessary for protecting GM during RT. PMID- 28348953 TI - Cerebello-thalamo-cortical networks predict positive symptom progression in individuals at ultra-high risk for psychosis. AB - Prospective longitudinal evaluation of adolescents at ultra-high-risk (UHR) for the development of psychosis enables an enriched neurodevelopmental perspective of disease progression in the absence of many of the factors that typically confound research with formally psychotic patients (antipsychotic medications, drug/alcohol dependence). The cerebellum has been linked to cognitive dysfunction and symptom severity in schizophrenia and recent work from our team suggests that it is a promising target for investigation in UHR individuals as well. However, the cerebellum and cerebello-thalamo-cortical networks have not been investigated developmentally or with respect to disease progression in this critical population. Further, to date, the types of longitudinal multimodal connectivity studies that would substantially inform our understanding of this area have not yet been conducted. In the present investigation 26 UHR and 24 healthy control adolescents were administered structured clinical interviews and scanned at baseline and then again at 12-month time points to investigate both functional and structural connectivity development of cerebello-thalamo-cortical networks in conjunction with symptom progression. Our results provide evidence of abnormal functional and structural cerebellar network development in the UHR group. Crucially, we also found that cerebello-thalamo-cortical network development and connectivity at baseline are associated with positive symptom course, suggesting that cerebellar networks may be a biomarker of disease progression. Together, these findings provide support for neurodevelopmental models of psychotic disorders and suggest that the cerebellum and respective networks with the cortex may be especially important for elucidating the pathophysiology of psychosis and highlighting novel treatment targets. PMID- 28348954 TI - Tractography in the clinics: Implementing a pipeline to characterize early brain development. AB - In imaging studies of neonates, particularly in the clinical setting, diffusion tensor imaging-based tractography is typically unreliable due to the use of fast acquisition protocols that yield low resolution and signal-to-noise ratio (SNR). These image acquisition protocols are implemented with the aim of reducing motion artifacts that may be produced by the movement of the neonate's head during the scanning session. Furthermore, axons are not yet fully myelinated in these subjects. As a result, the water molecules' movements are not as constrained as in older brains, making it even harder to define structure using diffusion profiles. Here, we introduce a post-processing method that overcomes the difficulties described above, allowing the determination of reliable tracts in newborns. We tested our method using neonatal data and successfully extracted some of the limbic, association and commissural fibers, all of which are typically difficult to obtain by direct tractography. Geometrical and diffusion based features of the tracts are then utilized to compare premature babies to term babies. Our results quantify the maturation of white matter fiber tracts in neonates. PMID- 28348955 TI - Role of corpus callosum integrity in arm function differs based on motor severity after stroke. AB - While the corpus callosum (CC) is important to normal sensorimotor function, its role in motor function after stroke is less well understood. This study examined the relationship between structural integrity of the motor and sensory sections of the CC, as reflected by fractional anisotropy (FA), and motor function in individuals with a range of motor impairment level due to stroke. Fifty-five individuals with chronic stroke (Fugl-Meyer motor score range 14 to 61) and 18 healthy controls underwent diffusion tensor imaging and a set of motor behavior tests. Mean FA from the motor and sensory regions of the CC and from corticospinal tract (CST) were extracted and relationships with behavioral measures evaluated. Across all participants, FA in both CC regions was significantly decreased after stroke (p < 0.001) and showed a significant, positive correlation with level of motor function. However, these relationships varied based on degree of motor impairment: in individuals with relatively less motor impairment (Fugl-Meyer motor score > 39), motor status correlated with FA in the CC but not the CST, while in individuals with relatively greater motor impairment (Fugl-Meyer motor score <= 39), motor status correlated with FA in the CST but not the CC. The role interhemispheric motor connections play in motor function after stroke may differ based on level of motor impairment. These findings emphasize the heterogeneity of stroke, and suggest that biomarkers and treatment approaches targeting separate subgroups may be warranted. PMID- 28348956 TI - High-dose antidepressants affect near-infrared spectroscopy signals: A retrospective study. AB - BACKGROUND: Recent studies have highlighted the clinical usefulness of near infrared spectroscopy (NIRS) in psychiatry. However, the potential effects of psychotropics on NIRS signals remain unknown. METHODS: We conducted a systematic chart review of 40 depressed patients who underwent NIRS scans during a verbal fluency task to clarify the relationships between psychotropic dosage and NIRS signals. The dosage of psychotropic medications was calculated using defined daily dose (DDD). We investigated the associations between the DDD of psychotropic medications and oxygenated hemoglobin (oxy-Hb) in single channel levels. LIMITATIONS: Retrospective study design and small sample size are the main limitations. RESULTS: Multiple regression analysis revealed that one channel in the right temporoparietal region had a significant association with antidepressant DDD controlling for age, sex, depression severity, and the DDD of antipsychotics and benzodiazepines. Moreover, high doses of antidepressants had significant effects on NIRS signals compared with low doses, in group comparisons. CONCLUSIONS: The dose-dependent impact of antidepressants on NIRS signals should be taken into account when interpreting NIRS data. PMID- 28348957 TI - Predicting behavioral variant frontotemporal dementia with pattern classification in multi-center structural MRI data. AB - PURPOSE: Frontotemporal lobar degeneration (FTLD) is a common cause of early onset dementia. Behavioral variant frontotemporal dementia (bvFTD), its most common subtype, is characterized by deep alterations in behavior and personality. In 2011, new diagnostic criteria were suggested that incorporate imaging criteria into diagnostic algorithms. The study aimed at validating the potential of imaging criteria to individually predict diagnosis with machine learning algorithms. MATERIALS & METHODS: Brain atrophy was measured with structural magnetic resonance imaging (MRI) at 3 Tesla in a multi-centric cohort of 52 bvFTD patients and 52 healthy control subjects from the German FTLD Consortium's Study. Beside group comparisons, diagnosis bvFTD vs. controls was individually predicted in each subject with support vector machine classification in MRI data across the whole brain or in frontotemporal, insular regions, and basal ganglia known to be mainly affected based on recent meta-analyses. Multi-center effects were controlled for with a new method, "leave one center out" conjunction analyses, i.e. repeatedly excluding subjects from each center from the analysis. RESULTS: Group comparisons revealed atrophy in, most consistently, the frontal lobe in bvFTD beside alterations in the insula, basal ganglia and temporal lobe. Most remarkably, support vector machine classification enabled predicting diagnosis in single patients with a high accuracy of up to 84.6%, where accuracy was highest in a region-of-interest approach focusing on frontotemporal, insular regions, and basal ganglia in comparison with the whole brain approach. CONCLUSION: Our study demonstrates that MRI, a widespread imaging technology, can individually identify bvFTD with high accuracy in multi-center imaging data, paving the road to personalized diagnostic approaches in the future. PMID- 28348959 TI - Apparent effect of chronic Plasmodium infections on disease severity caused by experimental infections with Mycoplasma gallisepticum in house finches. AB - An epidemic caused by a successful host jump of the bacterial pathogen Mycoplasma gallisepticum from poultry to house finches in the 1990s has by now spread across most of North America. M. gallisepticum causes severe conjunctivitis in house finches. We experimentally show that M. gallisepticum transmission to birds with or without chronic Plasmodium infection does not differ. However, once infected with M. gallisepticum house finches chronically infected with Plasmodium develop more severe clinical disease than birds without such infection. We speculate as to possible effects of coinfection. PMID- 28348960 TI - Delayed diagnosis of shunt overdrainage following functional hemispherotomy and ventriculoperitoneal shunt placement in a hemimegalencephaly patient. AB - Shunt overdrainage represents a nebulous condition of variable clinical and imaging presentations, where the diagnosis is primarily clinical. The condition presents a diagnostic challenge particularly in patients with cognitive impairment and developmental delays. Here we present a 3-year-old boy with drug resistant focal onset seizures due to hemimegalencephaly who previously underwent functional hemispherotomy followed by ventriculoperitoneal shunt placement for postoperative hydrocephalus. The subsequent clinical course was complicated by delayed diagnosis of shunt overdrainage in the absence of significant image findings. Maintaining a high index of suspicion for the possibility of shunt overdrainage is critical even in the face of unremarkable imaging findings. PMID- 28348961 TI - Preoperative visual field deficits in temporal lobe epilepsy. AB - Surgical resection and laser thermoablation have been used to treat medically refractory epilepsy with good results. However, they are not without risk. One of the most commonly reported complications of temporal lobe surgery is contralateral superior homonymous quadrantanopsia. We describe a patient with quadrantanopsia discovered as part of our recently modified protocol to workup patients prior to epilepsy surgery. This field cut was subtle and not detected on routine neurological examination. While we understand that this is a single case, we advocate for more judicious preoperative visual field examinations to truly characterize the incidence of postoperative visual field lesions. PMID- 28348958 TI - Diffusion imaging of reversible and irreversible microstructural changes within the corticospinal tract in idiopathic normal pressure hydrocephalus. AB - The symptoms of idiopathic normal pressure hydrocephalus (iNPH) can be improved by shunt surgery, but prediction of treatment outcome is not established. We investigated changes of the corticospinal tract (CST) in iNPH before and after shunt surgery by using diffusion microstructural imaging, which infers more specific tissue properties than conventional diffusion tensor imaging. Two biophysical models were used: neurite orientation dispersion and density imaging (NODDI) and white matter tract integrity (WMTI). In both methods, the orientational coherence within the CSTs was higher in patients than in controls, and some normalization occurred after the surgery in patients, indicating axon stretching and recovery. The estimated axon density was lower in patients than in controls but remained unchanged after the surgery, suggesting its potential as a marker for irreversible neuronal damage. In a Monte-Carlo simulation that represented model axons as undulating cylinders, both NODDI and WMTI separated the effects of axon density and undulation. Thus, diffusion MRI may distinguish between reversible and irreversible microstructural changes in iNPH. Our findings constitute a step towards a quantitative image biomarker that reflects pathological process and treatment outcomes of iNPH. PMID- 28348962 TI - Lamotrigine-related pseudolymphoma presenting as cervical lymphadenopathy. AB - Immune-mediated drug reactions are a potentially life-threatening complication of antiseizure medications. Drug hypersensitivity syndrome (DHS) is the best recognised of these, presenting with fever, eosinophilia, rash and internal organ involvement. Isolated lymphadenopathy is a less recognized immune-mediated reaction to antiseizure drugs such as lamotrigine. We describe the case of a 24 year-old woman who developed lamotrigine-related bilateral cervical lymphadenopathy (pseudolymphoma) fifteen months following therapy initiation. This is the second such case reported in the medical literature. PMID- 28348963 TI - Unilateral predominance of abnormal movements: A characteristic feature of the pediatric anti-NMDA receptor encephalitis? AB - Anti-NMDA receptor encephalitis is a treatable autoimmune disease characterized by cognitive, motor and psychiatric features that primarily affects young adults and children. We present a case of a 7-year-old boy with asymmetrical (mainly right hemibody) and abnormal polymorphic movements without concomitant scalpictal EEG changes but had background slowing predominating over the left hemisphere. This report illustrates previous descriptions of asymmetric presentation of abnormal movements in pediatric anti-NMDA receptor encephalitis and emphasizes the importance of video-EEG interpreted within the overall clinical context, to differentiate epileptic from non-epileptic abnormal movements in patients with autoimmune encephalitis. PMID- 28348964 TI - Gustav III's risk assessment on coffee consumption; A medical history report. PMID- 28348965 TI - In vitro and in vivo assessment of inhibitory effect of stevioside on pro inflammatory cytokines. AB - OBJECTIVE: Stevioside is a natural non-caloric sweetener which has been reported to have anti-inflammatory activity. The aim of the present study was to examine in vitro and in vivo effects of stevioside on rats plasma levels of tumor necrosis factor- alpha (TNF-alpha), interleukin-1beta (IL-1beta), TNF-alpha and IL-1beta release from lipopolysaccharide(LPS)-stimulated rat peripheral blood mononuclear cells (PBMCs). MATERIALS AND METHODS: Male wistar rats weighing between 170-220 g were given stevioside (0, 500 and 1000 mg/kg BW/day) for 6 weeks. Mononuclear cells were separated from peripheral blood samples. TNF-alpha and IL-1beta levels in plasma and the release of TNF-alpha and IL-1beta from PBMCs were determined using rat enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: Plasma levels of TNF-alpha and IL-1beta were found to be non-detectable in control and groups treated with 500 and 1000 mg/kg of stevioside. Regarding TNF-alpha release from LPS-stimulated PBMCs, rats that were orally fed with 500 and 1000 mg/kg of stevioside were significantly different (p<0.05) from those in LPS-treated control group (186.8+18.6 and 151.4 + 15.4 vs 248.6+21.4 pg/ml). Additionally, IL-1beta levels in rats treated with 500 and 1000 mg/kg of stevioside were significantly different (p<0.05) from those in LPS-treated control group (220.0+12.1 and 158.1 + 22.6 vs 294.4+16.1 pg/ml). CONCLUSION: Consumption of stevioside has an inhibitory effect on the release of TNF-alpha and IL-1beta from LPS-stimulated PBMCs in rats. PMID- 28348966 TI - Cassia fistula: A remedy from Traditional Persian Medicine for treatment of cutaneous lesions of pemphigus vulgaris. AB - OBJECTIVE: Pemphigus is a rare autoimmune disease that may be fatal without proper medical intervention. It is a blistering disease that involves both the skin and mucus membranes, in which the most important causes of death comprise superimposed opportunistic infections and complications of long-term high-dose corticosteroid therapy or prolonged consumption of immune suppressant drugs. Skin lesions are the most important sources of infection, and any local treatment decreasing the healing time of lesions and reducing the total dosage of drugs is favorable. MATERIALS AND METHODS: Here, we review the probable mechanism of action of a traditional formulary of Cassia fistula (C. fistula) fruit extract in almond oil as a new topical medication for reducing the duration of treatment of pemphigus vulgaris erosions. RESULTS: C. fistula fruit oil has lupeol, anthraquinone compounds as rhein and flavonoids. Previous in vitro and animal studies on C. fistula fruit have demonstrated wound healing, antioxidative, anti leukotrienes, anti-inflammatory, antibacterial and antifungal effects of this plant. CONCLUSION: It is hypothesized that C. fistula L. can be a botanical therapeutic choice for treatment of pemphigus erosions. PMID- 28348967 TI - Preventive effect of Coriandrum sativum on neuronal damages in pentylentetrazole induced seizure in rats. AB - OBJECTIVE: Coriandrum sativum (C. sativum) as a medicinal plant has been pointed to have analgesic, hypnotic and anti-oxidant effects. In the current study, a possible preventive effect of the hydro-alcoholic extract of the plant on neuronal damages was examined in pentylenetetrazole (PTZ) rat model of seizure. MATERIALS AND METHODS: Forty male rats were divided into five main groups and treated by (1) saline, (2) PTZ: 100 mg/kg PTZ (i.p) and (3-5) 50, 100 and 200 mg/kg of hydro-alcoholic extract of C. sativum during seven consecutive days before PTZ injection. After electrocorticography (ECoG), the brains were removed to use for histological examination. RESULTS: All doses of the extract reduced duration, frequency and amplitude of the burst discharges while prolonged the latency of the seizure attacks (p<0.05, p<0.01, and p<0.001). Administration of all 3 doses of the extract significantly prevented from production of dark neurons (p<0.01, and p<0.001) and apoptotic cells (p<0.05, p<0.01, and p<0.001) in different areas of the hippocampus compared to PTZ group. CONCLUSION: The results of this study allow us to conclude that C. sativum, because of its antioxidant properties, prevents from neuronal damages in PTZ rat model of seizure. PMID- 28348968 TI - A comparison of the efficacy of metronidazole vaginal gel and Myrtus (Myrtus communis) extract combination and metronidazole vaginal gel alone in the treatment of recurrent bacterial vaginosis. AB - OBJECTIVE: Due to the high incidence of bacterial vaginosis (BV) and its resistance to chemical medications and considering the anti-bacterial and anti fungal effects of Myrtus communis, the present study aimed to compare the therapeutic effects of the vaginal gel of M. communis 2% (in metronidazole base) with metronidazole vaginal gel 0.75% alone on BV. MATERIALS AND METHODS: This research was a randomized controlled clinical trial conducted on 80 women of 18 40 years old with BV. Patients were divided into two groups of 40 women. Diagnostic criteria were Amsel's criteria and Gram staining. The first group received vaginal gel of metronidazole plus M. communis 2% and the second group received metronidazole vaginal gel alone for five consecutive nights. Therapeutic effects and Amsel's criteria were assessed after one week. Finally, the data were analyzed by SPSS 16 using t-test and Chi square tests. RESULTS: There was a significant difference in the therapeutic response between the two groups. The results demonstrated that the combination of metronidazole and M. communis had a higher efficiency (p<0.05). The patients receiving M. communis in metronidazole gel base did not experience any recurrent BV, but 30% of patients taking metronidazole alone faced recurrent BV after three weeks of follow up. CONCLUSION: Findings of the study suggested that adding M. communis extract to metronidazole increases the efficiency of BV treatment. PMID- 28348969 TI - Kelussia odoratissima potentiates cytotoxic effects of radiation in HeLa cancer cell line. AB - OBJECTIVE: Cervical cancer is the second most common cause of death from cancer in women throughout the world. The aim of this study was to evaluate the cytotoxic activity of Kelussia odoratissima (K. odoratissima) extract associated with radiotherapy in cervical cancer cells (HeLa cell line). MATERIALS AND METHODS: Different concentration of the extract (25-500ug/ml) was tested in HeLa cell lines. Cell cytotoxicity of the extract and the effects of the extract on radiation (2Gy/min)-induced damages were assessed by MTT assay. Apoptosis was assessed using flow cytometric analysis. RESULT: K. odoratissima decreased cell viability in HeLa cell line in a concentration and time-dependent manner. When compared to the control, K. odoratissima induced a sub-G1 peak in the flow cytometry histogram of treated cells, indicating that apoptotic cell death is involved in K. odoratissima-induced toxicity. It was also shown that K. odoratissima sensitizes cells to radiation-induced toxicity. CONCLUSION: Our result showed the extract increased the radiation effect. This observation may be related to the presence of active compounds such as phthalides and ferulic acid. PMID- 28348970 TI - Anti-carcinogenic and anti-angiogenic properties of the extracts of Acorus calamus on gastric cancer cells. AB - OBJECTIVE: Acorus calamus (A. calamus) has been used as a medicinal plant in Asia for its effects on digestive system for the last 2000 years. To investigate the anti-cancer activity of rhizome of A. calamus, the ethanolic and methanolic extracts and essential oil of the rhizome were prepared and their effects were assessed on human gastric cancer cell line (AGS). MATERIALS AND METHODS: The viability of cells which were treated with the extracts and the essential oil was assessed by MTT assay. To evaluate the anti-angiogenic property of the extracts, in vitro tube formation assay was done. Cell cycle distribution and the expression of Oct4 and Nucleostemin, after treatments, were checked by flowcytometry and quantitative RT-PCR, respectively. Furthermore, analysis of essential oil from A.calamus was done by GC-MS. RESULTS: Our results showed that the growth of AGS cells was inhibited by the extracts and essential oil and the extracts inhibited the angiogenesis in HUVEC cells. Our data revealed that the extracts and essential oil of A. calamus caused G1 arrest in AGS cells and downregulation of Oct4 and NS after treatment. By GC-MS analysis, we found new compounds such as epiprezizaene, valencene and isocyclocitral in essential oil of A. CONCLUSION: All together, our results showed that the extracts of A. calamus have anti-proliferative and anti-angiogenic effects on cancer cells. PMID- 28348971 TI - Antioxidant, cytotoxic and DNA protective properties of Achillea eriophora DC. and Achillea biebersteinii Afan. extracts: A comparative study. AB - OBJECTIVE: Achillea is a traditional medicinal herb which contains different phenol and flavonoid compounds that are responsible for Achillea pharmacological effects. We aimed to determine phenol and flavonoid contents, besides antioxidant activities of different extracts from Achillea eriophoraa (A. eriophora) DC. and Achillea biebersteinii (A. biebersteinii) Afan. (endemic species in Iran) and to investigate their effects on human cells. MATERIALS AND METHODS: Achillea extracts, were prepared by maceration and shaking methods, from different parts (aerial parts, stem, leaves and inflorescence) of two species using methanol and ethanol as solvents. Total phenol and flavonoid contents were measured by spectrophotometry, and antioxidant activities of the extracts were determined by DPPH radical scavenging, BCB and TBARS assays. Cytotoxicity and antioxidant activities of the extracts were investigated in Human Foreskin Fibroblast (HFF3) cells using MTT, comet and H2O2 assays. RESULTS: Methanol extracts of A. biebersteinii prepared from leaves and inflorescence by maceration method exhibited maximum phenol (1657.58 +/- 36.45 mg GAE/100 g DW) and flavonoid (264.00 +/- 62.16 mg QUE/100 g DW) contents. Leaf methanol extract showed significantly higher antioxidant activity (0.0276 +/- 0.003, 0.16 +/- 0.016 and 13.96 +/- 0.26 mg/ml for DPPH, BCB and TBARS IC50s, respectively) than those of the other extracts. Leaf extract of A. biebersteinii was not cytotoxic even at the highest examined dose (512 ug/ml) and inhibited cell toxicity induced by H2O2 (98% viability for the cells pretreated with plant extract in the presence of H2O2). Comet assay also confirmed high DNA protective activity of leaf extracts. CONCLUSION: Achillea extracts possess remarkable antioxidant activity, and could be good natural alternatives to synthetic antioxidants in pharmaceutical and food industries. PMID- 28348972 TI - Antidiabetic, hypolipidemic and hepatoprotective effects of Arctium lappa root's hydro-alcoholic extract on nicotinamide-streptozotocin induced type 2 model of diabetes in male mice. AB - OBJECTIVE: Arctium lappa (burdock), (A. lappa) root has hypoglycemic and antioxidative effects, and has been used for treatment of diabetes in tradition medicine. This study was conducted to evaluate the antidiabetic and hypolipidemic properties of A. lappa root extract on nicotinamide-streptozotocin (NA-STZ) induced type2 diabetes in mice. MATERIALS AND METHODS: In this investigation, 70 adult male NMRI mice (30-35g) randomly divided into 7 groups (n=10) as follow: 1 control, 2-type 2 diabetic mice, 3-diabetic mice that received glibenclamide (0.25 mg/kg) as an anti-diabetic drug, 4, 5, 6 and 7- diabetic and normal animals that were pre-treated with 200 and 300 mg/kg A. lappa root extract, respectively, for 28 days. Diabetes has been induced by intraperitoneal injection of NA and STZ. Finally, the blood sample was taken and insulin, glucose, SGOT, SGPT, alkaline phosphatase, leptin and lipid levels was evaluated. RESULTS: Induction of diabetes decreased the level of insulin, leptin and high density lipoprotein (HDL) and increased the level of other lipids, glucose, and hepatic enzymes significantly (p<0.05). Administration of both doses of the extract significantly decreased the level of triglyceride, very low density lipoprotein, glucose and alkaline phosphatase in diabetic mice (p<0.05). Insulin levels increased in animals treated with 200 mg/kg (p<0.05) and HDL and leptin levels increased in animals treated with 300 mg/kg of the extract (p<0.01). CONCLUSION: The results showed that A. lappa root extract, at specific doses, has an anti-diabetic effect through its hypolipidemic and insulinotropic properties. Hence, this plant extract may be beneficial in the treatment of diabetes. PMID- 28348973 TI - Kidney stone formation and antioxidant effects of Cynodon dactylon decoction in male Wistar rats. AB - OBJECTIVES: The antioxidant capacity impairs in kidney and urinary bladder of animals with stone disease. Herbal medicine can improve the antioxidant condition of renal tissue. Cynodon dactylon (C. dactylon) is a medicinal plant with antioxidative and diuretic properties and different preparations of this plant have shown promising effects in stone disease. Assessment of the whole plant decoction to prevent kidney stone disease as well as its antioxidant effects was the aim of this paper. MATERIALS AND METHODS: Fifty male Wistar rats were randomly divided into 5 experimental groups (n=10). One group was left without treatment and four groups received ethylene glycol (1% v/v) in drinking water for 6 weeks. Three doses of Cynodon dactylon aqueous decoction (12.5, 50 and 200 mg/kg BW) were added to the drinking water of groups 3-5. Finally, water intake, 24-hour urine volume, MDA, total thiol concentration and FRAP value were measured in the serum and kidney tissues. The CaOx depositions were evaluated by hematoxylin and eosin staining. RESULTS: Compared to the ethylene glycol-treated group, 200 mg/kg C. dactylon, lowered stone incidents, decreased urine volume, increased FRAP/g Cr (43%) and thiol content (p<0.05) with no significant alteration of water intake, MDA decreased significantly compared to C. dactylon 12.5 (p<0.01). Kidney weight increased and body weight decreased in ethylene glycol-treated group compared to the control group (p<0.05). CONCLUSION: A minimum dose of 200 mg/kg C. dactylon reduced stone formation and simultaneously increased total antioxidant power of serum and preserved MDA content and water. PMID- 28348974 TI - Capparis spinosa L. aqueous extract evokes antidiabetic effect in streptozotocin induced diabetic mice. AB - OBJECTIVE: As the aqueous extract of Capparis spinosa (CS) possess antidiabetic effect, he present study aims to reveal the possible mechanism of action of CS in diabetic mice. MATERIALS AND METHODS: Both single and repeated oral administrations of aqueous extract of CS were performed in multi-low dose streptozotocin-induced (MLDS) diabetic mice. Euglycemic hyperinsulinemic clamp was used in association with the endogenous glucose production (perfusion rate of 3-3H glucose) to evaluate the effect of CS aqueous extract on insulin sensitivity. RESULTS: Our study showed that aqueous extract of CS possess a potent hypoglycaemic activity in MLDS diabetic mice. Furthermore, the analysis perfusion of 3-3H glucose demonstrated the parallel decrease of basal endogenous glucose production (EGP) with the hypoglycaemic activity. EGP was lower in CS Treated group when compared to the control group (p<0.001). The euglycemic hyperinsulinemic clamp technique demonstrated that CS treatment improves insulin sensitivity in peripheral tissues. CONCLUSION: We conclude that the antihyperglycemic effet CS is probably due to the inhibition of basal endogenous glucose production and the improvement of insulin sensitivity in MLDS diabetic mice. PMID- 28348975 TI - Commentary: Randomized Phase II Study of Duligotuzumab (MEHD7945A) vs. Cetuximab in Squamous Cell Carcinoma of the Head and Neck (MEHGAN Study). PMID- 28348976 TI - Combination of Photon and Carbon Ion Irradiation with Targeted Therapy Substances Temsirolimus and Gemcitabine in Hepatocellular Carcinoma Cell Lines. AB - BACKGROUND: This work investigates on putative cytotoxic effects in four different hepatocellular carcinoma (HCC) cell lines after irradiation with photons or carbon ions in combination with new targeted molecular therapy using either Temsirolimus (TEM) or Gemcitabine (GEM). METHODS AND MATERIALS: The HCC cell lines HepG2, Hep3B, HuH7, and PLC were cultured and irradiated with photons or carbon ions at the Heidelberg Ion Beam Therapy Center using the raster scanning method. For combination experiments, cell lines were first treated with Temsirolimus or GEM before irradiation. Cytotoxicity was measured by a clonogenic survival assay. The evaluation of the experiments and the obtained survival curves were based on the concept of additivity defined by Steel and Peckham. RESULTS: The results for the combination of carbon ions and both tested systemic substances TEM and GEM showed independent toxicities in all four cell lines. Supra-additive effects were observed in PLC cells for photon irradiation combined either with TEM or GEM and in HuH7 cells for the combination of photons with TEM. CONCLUSION: Addition of targeted therapy substances Temsirolimus and GEM to photon irradiation showed additive cytotoxicity in HCC cell lines, whereas independent toxicities where reached by the combination of carbon ions to these substances. It can be assumed that combining 12C with systemic substances only has independent effects because heavy ions cause direct damage because of their high-LET character resulting in complex and clustered double-strand breaks. Nonetheless, further investigations are warranted in order to determine whether addition of systemic therapy allows a reduction of radiation doses in combination therapy. This could possibly lead to better responses and tolerances in patients with HCC. PMID- 28348977 TI - Taming Tumor Glycolysis and Potential Implications for Immunotherapy. AB - Immune evasion and deregulation of energy metabolism play a pivotal role in cancer progression. Besides the coincidence in their historical documentation and concurrent recognition as hallmarks of cancer, both immune evasion and metabolic deregulation may be functionally linked as well. For example, the metabolic phenotype, particularly tumor glycolysis (aerobic glycolysis), impacts the tumor microenvironment (TME), which in turn acts as a major barrier for successful targeting of cancer by antitumor immune cells and other therapeutics. Similarly, in the light of recent research, it has been known that some of the immune sensitive antigens that are downregulated in cancer may also be restored or induced by cellular/metabolic stress. For instance, cancer cells downregulate the cell surface ligands such as MHC class I chain-related (MIC) protein-(A/B) that are normally upregulated in disease/pathological conditions. Noteworthy, the MHC class I chain-related protein A and B (MIC-A/B) are recognized by natural killer (NK) cells for immune elimination. Interestingly, MIC-A/B is stress inducible as demonstrated by oxidative stress and other cellular-stress factors. Consequently, stimulation of metabolic stress has also been shown to sensitize cancer cells to NK cell-mediated cytotoxicity. Taken together, data from recent reports imply that dysregulation of tumor glycolysis could facilitate induction of immune sensitive surface ligands leading to increased efficacy of antitumor immunotherapeutics. Nonetheless, dysregulated tumor glycolysis may also impact the TME and alter it from acidic, low pH into a therapeutically desirable TME that can enhance the effective infiltration of antitumor immune cells. In this mini-review, targeting tumor glycolysis has been discussed to evaluate its potential implications to enhance and/or facilitate anticancer immunity. PMID- 28348978 TI - mHealth and Application Technology Supporting Clinical Trials: Today's Limitations and Future Perspective of smartRCTs. AB - Nowadays, applications (apps) for smartphones and tablets have become indispensable especially for young generations. The estimated number of mobile devices will exceed 2.16 billion in 2016. Over 2.2 million apps are available in the Google Play store(r), and about 1.8 million apps are available in the Apple App Store(r). Google and Apple distribute nearly 70,000 apps each in the category Health and Fitness, and about 33,000 and 46,000 each in medical apps. It seems like the willingness to use mHealth apps is high and the intention to share data for health research is existing. This leads to one conclusion: the time for app accompanied clinical trials (smartRCTs) has come. In this perspective article, we would like to point out the stones put in the way while trying to implement apps in clinical research. Further, we try to offer a glimpse of what the future of smartRCT research may hold. PMID- 28348980 TI - Overexpression of the Endosomal Anion/Proton Exchanger ClC-5 Increases Cell Susceptibility toward Clostridium difficile Toxins TcdA and TcdB. AB - Virulent C. difficile toxins TcdA and TcdB invade host intestinal epithelia by endocytosis and use the acidic environment of intracellular vesicles for further processing and activation. We investigated the role of ClC-5, a chloride/proton exchanger expressed in the endosomes of gastrointestinal epithelial cells, in the activation and processing of C. difficile toxins. Enhanced intoxication by TcdA and TcdB was observed in cells expressing ClC-5 but not ClC-4, another chloride/proton exchanger with similar function but different localization. In accordance with the established physiological function of ClC-5, its expression lowered the endosomal pH in HEK293T cells by approximately 0.6 units and enhanced approximately 5-fold the internalization of TcdA. In colon HT29 cells, 34% of internalized TcdA localized to ClC-5-containing vesicles defined by colocalization with Rab5, Rab4a, and Rab7 as early and early-to-late of endosomes but not as Rab11-containing recycling endosomes. Impairing the cellular uptake of TcdA by deleting the toxin CROPs domain did not abolish the effects of ClC-5. In addition, the transport-incompetent mutant ClC-5 E268Q similarly enhanced both endosomal acidification and intoxication by TcdA but facilitated the internalization of the toxin to a lower extent. These data suggest that ClC-5 enhances the cytotoxic action of C. difficile toxins by accelerating the acidification and maturation of vesicles of the early and early-to-late endosomal system. The dispensable role of electrogenic ion transport suggests that the voltage-dependent nonlinear capacitances of mammalian CLC transporters serve important physiological functions. Our data shed light on the intersection between the endocytotic cascade of host epithelial cells and the internalization pathway of the large virulence C. difficile toxins. Identifying ClC-5 as a potential specific host ion transporter hijacked by toxins produced by pathogenic bacteria widens the horizon of possibilities for novel therapies of life threatening gastrointestinal infections. PMID- 28348983 TI - Future of profession. AB - Being a doctor in today's time is a tough experience in many parts of the world. Many young people motivated by the traditional image of profession and desire for service opted for this vocation without anticipating today's challenging environment. Bad press, violence against doctors, tough employment conditions, unemployment, and lack of societal respect have become common phenomenon across the world. It is indeed time to introspect. The institution of medical profession is rapidly transforming not necessarily only under the influence of rapidly changing technology. The presented viewpoint is an analysis on impact of changing global political scenario on the future of medical profession. PMID- 28348981 TI - PPE38 Protein of Mycobacterium tuberculosis Inhibits Macrophage MHC Class I Expression and Dampens CD8+ T Cell Responses. AB - Suppression of CD8+ T cell activation is a critical mechanism used by Mycobacterium tuberculosis (MTB) to escape protective host immune responses. PPE38 belongs to the unique PPE family of MTB and in our previous study, PPE38 protein was speculated to participate in manipulating macrophage MHC class I pathway. To test this hypothesis, the function of mycobacterial PPE38 protein was assessed here using macrophage and mouse infection models. Decreased amount of MHC class I was observed on the surface of macrophages infected with PPE38 expressing mycobacteria. The transcript of genes encoding MHC class I was also inhibited by PPE38. After infection of C57BL/6 mice with Mycobacterium smegmatis expressing PPE38 (Msmeg-PPE38), decreased number of CD8+ T cells was found in spleen, liver, and lungs through immunohistochemical analysis, comparing to the control strain harboring empty vector (Msmeg-V). Consistently, flow cytometry assay showed that fewer effector/memory CD8+ T cells (CD44highCD62Llow) were activated in spleen from Msmeg-PPE38 infected mice. Moreover, Msmeg-PPE38 confers a growth advantage over Msmeg-V in C57BL/6 mice, indicating an effect of PPE38 to favor mycobacterial persistence in vivo. Overall, this study shows a unique biological function of PPE38 protein to facilitate mycobacteria to escape host immunity, and provides hints for TB vaccine development. PMID- 28348982 TI - Tick-Pathogen Ensembles: Do Molecular Interactions Lead Ecological Innovation? PMID- 28348984 TI - Dental public health in India: An insight. AB - Oral diseases are a major public health problem, and their burden is on increase in many low- and middle-income countries. Dental public health (DPH) aims to improve the oral health of the population through preventive and curative services. However, its achievements in India are being questioned probably because of lack of proficiency and skill among DPH personnel. The literature search for the present study was conducted utilizing various search engines and electronic databases such as PubMed and MEDLINE. Documents related to the Central and State Governments of India were also considered. Finally, 26 articles were selected for the present study from which relevant information can be extracted. The present study focuses on some of the important aspects relating to DPH in India such as priority for oral health, DPH workforce and curriculum, utilization of DPH personnel in providing primary oral health care, role of mobile dental vans, and research in DPH. It was concluded that more attention should be given toward preventive oral health care by employing more number of public health dentists in public sector, strengthening DPH education and research, and combining oral health programs with general health-care programs. PMID- 28348986 TI - A cross-sectional study of migrant women with reference to their antenatal care services utilization and delivery practices in an urban slum of Mumbai. AB - INTRODUCTION: Migrant is a vulnerable population. They face several barriers in accessing health services. The immigration status presents various challenges for maternity services utilization. So this study was conducted (1) to estimate proportion of women utilizing full ANC package and to find out reasons for its nonutilization (2) to estimate the proportion of institutional deliveries and reasons for home deliveries. METHODS: A cross-sectional community based study was conducted among migrant women in reproductive age group in an urban slum. The sample size was 120. Multistage simple random sampling was done. RESULTS: Maximum numbers of migrants (71.7%) were from Uttar Pradesh. Sixty two percent married before the age of 18 years. Full ANC package was received by only 18% migrants. Proportion of home deliveries was 12%, and all were conducted by Untrained Dai. Lack of transport facility and availability of Dai (local birth attendant) were the reasons mentioned for home delivery. For nonutilization of full ANC package, far location of health center (30%); it is not necessary (25.8%); and family did not allow them to visit health center (21.8%) were the reasons mentioned. Religion and type of family were significantly associated with nonutilization of full ANC package. CONCLUSION: The present study revealed low utilization of ANC services and high proportion of home deliveries among the migrant women even after availability of health facilities for providing ANC care and to conduct deliveries in urban area. PMID- 28348987 TI - Factors associated with internet addiction among school-going adolescents in Vadodara. AB - INTRODUCTION: The internet is an important modern means of obtaining information and communicating with others which has converted the world into a global village. At the same time, increasing internet use among adolescents is also likely to pose a major public health concern that is internet addiction (IA). The aim was to assess the prevalence of IA among school-going adolescents and factors associated with IA. METHODS: A cross-sectional study was designed to survey adolescents studying in 8th to 11th standard of five schools of Vadodara. Information regarding sociodemography and various patterns of internet use were obtained using survey forms. IA test (IAT) was used to screen for IA. Descriptive analysis, univariate analysis, and logistic regression were done to analyze the data. RESULTS: Seven hundred and twenty-four participants that completed IAT were analyzed. Internet use prevalence was 98.9%. Prevalence of IA was 8.7%. Male gender, owning a personal device, hours of internet use/day, use of smartphones, permanent login status, use of internet for chatting, making online friends, shopping, watching movies, online gaming, searching information online and instant messaging were found to be associated significantly with IA in univariate analysis. Internet use for online friendships was found to be a significant predictor of IA (odds ratio [OR] =2.4), and internet use for searching information was found to be protective (OR = 0.20) against IA on logistic regression. CONCLUSIONS: IA is prevalent in the adolescent population and requires awareness and intervention. Characteristics of internet usage found to be associated with IA needs to be considered while developing strategies for interventions. PMID- 28348985 TI - Current concepts in the management of acute pancreatitis. AB - Guidelines for the management of acute pancreatitis (AP) are based on the Western experience, which may be difficult to extrapolate in India due to socioeconomic constraints. Hence, modifications based on the available resources and referral patterns should be introduced so as to ensure appropriate care. We reviewed the current literature on the management of AP available in English on Medline and proposed guidelines locally applicable. Patients of AP presenting with systemic inflammatory response syndrome are at risk of moderate-severe pancreatitis and hence, should be referred to a tertiary center early. The vast majority of patients with AP have mild disease and can be managed at smaller centers. Early aggressive fluid resuscitation with controlled fluid expansion, early enteral nutrition, and culture-directed antibiotics improve outcomes in AP. Infected pancreatic necrosis should be managed in a tertiary care hospital within a multidisciplinary setup. The "step up" approach involving antibiotics, percutaneous drainage, and minimally invasive necrosectomy instituted sequentially based on clinical response has improved the outcomes in this subgroup of patients. PMID- 28348988 TI - Acceptance rate, probability of follow-up, and expulsion of postpartum intrauterine contraceptive device offered at two primary health centers, North India. AB - INTRODUCTION: Acceptance rate of postpartum intrauterine contraceptive device (PPIUCD) offered through a public health approach is unknown. Our aim was to describe the acceptance rate, expulsion, and follow-up and factors associated with it when PPIUCD was offered to women delivering at two primary health centers (PHCs). METHODS: We analyzed routine health data of deliveries at two PHCs in district Faridabad, India between May and December 2014, having sociodemographic variables, obstetric history, and during the follow-up check-up at 6-weeks postpartum for in situ status of intrauterine contraceptive device, side effects, and complications. RESULTS: The overall acceptance rate among those eligible for PPIUCD was 39% (95% confidence interval [CI]: 35.1-42.9). Independent predictor of acceptance was a monthly family income of 25 years (O.R.: 2.21, 95% CI: 1.03-4.73), gravida >=4 (O.R.: 4.01, 95% CI: 1.28 12.56), and a living previous-child (O.R.: 1.51, 95% CI: 1.04-2.19). CONCLUSION: Acceptance rate of PPIUCD was higher than that reported in literature. Women from lower income family, having at least one living child, and having attended antenatal care clinic were more likely to accept PPIUCD. PMID- 28348990 TI - Prevalence of chronic insomnia in adult patients and its correlation with medical comorbidities. AB - INTRODUCTION: Insomnia is one of the common but neglected conditions seen in family practice with long term and serious effects on health of a patient. Family physicians have the responsibility of diagnosing and adequately treating this. This study was done to find the prevalence of chronic insomnia in adult patients visiting a family medicine outpatient department (OPD) in a hospital and to assess the risk factors and co morbidities associated with it. MATERIALS AND METHODS: A cross-sectional study was done in the family medicine OPD at St. Philomena's Hospital, Bengaluru. All adult patients attending the OPD from September 1 to October 30, 2015 were enrolled in the study after obtaining written consent. Athens Insomnia Scale was used to diagnose insomnia and information regarding medical co morbidities was collected. Data was analyzed for the prevalence of insomnia and its association with co morbidities. RESULTS: Chronic insomnia was seen in 33% of the adult population sampled. Increasing age and diabetes were significantly associated with insomnia, while other socioeconomic factors and co morbidities were not significantly associated. Twenty-seven percent of patients who had insomnia did not perceive the condition, which was statistically significant. CONCLUSION: Insomnia is a common sleep disorder which is many times missed by a primary care physician until/unless asked for. Since there is a higher incidence with increasing age and co morbidities such as diabetes, all patients, especially middle-aged and diabetics, should be screened for insomnia by the primary care physician with a self assessed questionnaire and counseled. PMID- 28348989 TI - Reporting measles case fatality due to complications from a tertiary care hospital of Kolkata, West Bengal 2011-2013. AB - INTRODUCTION: Measles is affecting millions of people in the developing countries particularly in India with significant morbidity and responsible for thousands of death in spite of having a safe, effective, and cheap vaccine. Pulmonary complications account for 90% measles-related death. The objectives of this study were to describe age distribution, clinical features, complications, and clinical outcomes of measles cases in a referral infectious disease hospital of West Bengal. METHODS: We conducted a retrospective descriptive study including 584 patients and collected information from record section on demographics, clinical features, complications, and clinical outcomes using data abstraction form. RESULTS: The mean age of 584 measles cases was 3.7 years (+/-1.2 years). The most common complication was pneumonia (149 cases) followed by diarrhea and encephalopathy. Very severe pneumonia occurred in 34 cases requiring intensive care out of which 13 patients died. The average duration of stay in the hospital was 5.7 days (+/-3.2 days). Surprisingly, 45 cases admitted to this hospital were <9 months of age with subsequent death in 5 cases. CONCLUSION: Substantial number of measles cases was seen in zero to <9 months of age group and fatality due to complication was more among them. PMID- 28348979 TI - Biology of Acinetobacter baumannii: Pathogenesis, Antibiotic Resistance Mechanisms, and Prospective Treatment Options. AB - Acinetobacter baumannii is undoubtedly one of the most successful pathogens responsible for hospital-acquired nosocomial infections in the modern healthcare system. Due to the prevalence of infections and outbreaks caused by multi-drug resistant A. baumannii, few antibiotics are effective for treating infections caused by this pathogen. To overcome this problem, knowledge of the pathogenesis and antibiotic resistance mechanisms of A. baumannii is important. In this review, we summarize current studies on the virulence factors that contribute to A. baumannii pathogenesis, including porins, capsular polysaccharides, lipopolysaccharides, phospholipases, outer membrane vesicles, metal acquisition systems, and protein secretion systems. Mechanisms of antibiotic resistance of this organism, including acquirement of beta-lactamases, up-regulation of multidrug efflux pumps, modification of aminoglycosides, permeability defects, and alteration of target sites, are also discussed. Lastly, novel prospective treatment options for infections caused by multi-drug resistant A. baumannii are summarized. PMID- 28348991 TI - Myths and misconceptions in general public toward ocular complications followed by the removal of upper teeth. AB - INTRODUCTION: The upper jaw forms the floor of the maxillary sinus and the upper teeth are continuous with the whole midface and cranium, therefore while treating these teeth, it is important for the practitioner to consider the possibility of ocular complications. Ocular disturbances such as blurring of vision, mydriasis, ptosis, diplopia, enophthalmos, miosis, and blindness are rare complications due to intraoral local anesthesia. So far at present, the general population is having myths and misconceptions regarding the extraction of teeth and vision loss; hence, we evaluated the same. METHODS: A cross-sectional prospective survey targeting the general public was conducted using a self-administered questionnaire. A total of 300 standardized self-administered questionnaires were given and the data were analyzed. RESULTS: Out of 300 patients, 148 were educated and 152 were uneducated. The study population was analyzed based on their age, sex, and literacy, i.e. the level of education. Seventy-six percent of uneducated and 48% of educated groups had false belief of ocular complications followed by the removal of upper teeth and among them uneducated females of older age group showed higher prevalence. CONCLUSION: The general public's knowledge about ocular complications due to tooth extraction in our study group is not adequate and needs improvement. Although the practice of informing by dentists is satisfactory, there is a need for creating awareness in the general public against such complications. PMID- 28348992 TI - Community level evaluation of adenoid hypertrophy on the basis of symptom scoring and its X-ray correlation. AB - INTRODUCTION: One of the major causes of pediatric morbidity today at the community level is infection involving the ear, nose, and throat. Maximum of these patients respond well initially on general regular medications, but then recurrent complaints are not very uncommon. One of the major causes for such recurrence is hypertrophy of adenoids, the evaluation of which requires a battery of sophisticated investigative tools and expertise which are lacking at the community level. The aim of the study is to evaluate various symptoms related to adenoid hypertrophy and its correlation to the size of the adenoid seen in the lateral view nasopharyngeal X-ray. The aim of the study was to assess various symptoms related to adenoid hypertrophy and its correlation with the size of adenoid radiologically. METHODS: A total of fifty cases of pediatric age with strong clinical suspicion of adenoid hypertrophy were included in the study. Through ENT examination was done. X-ray lateral view nasopharynx was obtained. RESULTS: Adenoid hypertrophy was graded according to symptoms score and lateral cephalometric/radiographs. Snoring was the most frequent symptom which had a linear relation with the size of the adenoid. CONCLUSION: There was good agreement between symptom and the X-ray findings. PMID- 28348994 TI - Evaluation of patient and doctor perception toward the use of telemedicine in Apollo Tele Health Services, India. AB - INTRODUCTION: Telemedicine incorporates electronic information and medical technology. It connects healthcare through vast distances which would benefit both patients and doctors. The aim of this questionnaire study was to evaluate the effects of telemedicine on patients and medical specialists. METHODS: A cross sectional study was conducted among 122 participants (71 patients and 51 doctors) on satisfaction in quality of service, cost-effectiveness, and problems encountered in healthcare provided by the telemedicine in Apollo Tele Health Services, Hyderabad, Telangana, India. The data for each group were calculated and compared. RESULTS: About 80% patients and all the doctors reported their satisfaction on the quality of treatment given through telemedicine. Approximately, 90% of the participants found telemedicine cost-effective and 61% of the doctors found an increase in patient's inflow apart for their regular practice. Problems encountered in telemedicine were 47% in technical issues and 39% in time scheduling by doctors and 31% of patients were uncomfortable to face the camera, and 24% had technical issues. CONCLUSIONS: The results of the present study showed that telemedicine in healthcare could prove to be useful to patients in distant regions and to rural doctors in India. In the near future, telemedicine can be considered as an alternate to face to face patient care. PMID- 28348993 TI - Profile of elderly attending a general practice clinic in a poor urban area: A cross-sectional study from South India. AB - INTRODUCTION: In India, the number of elderly is steadily increasing and is likely to reach 301 million by 2051. The increasing number and proportion of elderly will have a direct impact on the demand for health and pension services. As per the Demography of Indian Aging (Rajan et al.), information on morbidity profile of this population is essential to plan health-care facilities. METHODS: A descriptive cross-sectional study was designed to study the morbidity profile of 100 elderly persons reporting to the outpatient clinic of a family practice unit of a tertiary care center in South India between June 2008 and May 2010. This was done with a view to plan better services for the elderly in that area. RESULTS: In this study, 88% of the participants were on a follow-up while new ailment(s) were diagnosed in 11 participants. A majority of participants were illiterate (62%), unemployed (83%), and financially dependent (54%). Forty-four participants screened had depression that required intervention such as counseling and follow-up; in ten participants, the screening score was sufficient to warrant therapy. In nearly half of the participants, the musculoskeletal system was involved, and a significant number had the involvement of cardiorespiratory system and urinary incontinence. CONCLUSION: A large number of elderly are affected by a constellation of conditions including mental as well social issues. A family practice unit may be a good setup to provide the first contact care for the diagnosis and management of common problems in the elderly and help to improve their quality of life. PMID- 28348995 TI - A study on alcohol use and its related health and social problems in rural Puducherry, India. AB - INTRODUCTION: Harmful use of alcohol was the cause for 5.9% of all deaths and 5.1% of the global burden of disease and injury. India is the third largest market for alcoholic beverages in the world with estimated 62.5 million alcohol user in 2005. The objective of this study was to know the prevalence of alcohol consumption, pattern of drinking, and its effect on people's health and social consequences. METHODS: This cross-sectional study was conducted in 850 households selected from 19 villages of two Primary Health Centers. A total of 30 clusters were selected, and from each cluster, 28 houses were surveyed by random walk method. Information was collected on predesigned and pretested questionnaire forms and analyzed using Epi Info 3.4.3. Chi-square test was used for statistical significance. RESULTS: The overall prevalence of alcohol use among >=18 years of age was 9.7% and exclusively among males was 17.1%. The highest prevalence (17.1%) was among 46-55 years age groups and the residents of joint families (37.0%). One-third of the users began drinking before 20 years of age and half of them consumed for getting relief from pain/strain/tiredness. About half of the users had strained relations with their family members and neighbors both. The majority had alcohol dependence problems and about one-fifth had chronic health problems, diabetes mellitus, and hypertension. CONCLUSION: The prevalence of alcohol use in Puducherry was low and restricted to males only. The prevalence was high among low uneducated farmers and labors. About one-third of users had alcohol dependence problems and one-fifth had chronic health problems. PMID- 28348996 TI - Subclinical hypothyroidism and the risk of hypercholesterolemia. AB - INTRODUCTION: Subclinical hypothyroidism (SCH) is a condition wherein there are small elevations in thyroid stimulating hormone (TSH), yet normal circulating levels of free thyroid hormones (FT4). Alterations in thyroid function result in changes in composition and transport of lipoproteins. METHODS: The study was undertaken in the outpatient department of Lourdes hospital, Ernakulam. 110 patients between 40-69 years were studied, of which 60 were identified to have SCH based on cross-sectional survey, 50 patients were randomly selected to represent the EU group. Data based on interview, clinical examination, thyroid function, lipid profiles. Student's t, chi-square tests used for computation of p values. RESULTS: SCH were seen in females (66.66%) and in the age group of 40-49 years (61.66%). Mean cholesterol values were elevated in the subclinical hypothyroid group and in relation to age (60-69) and gender. Statistical analysis showed significant difference in total cholesterol(TC) (P<0.005) and triglycerides (P<0.05) in relation to age (40-49 yrs.) between two groups. Based on TSH, group A 5-7.49Mu/L and group B 7.5-10Mu/L were compared to the euthyroid group N<5Mu/L. Mean cholesterol values were raised in both subgroups. Statistically significant difference seen (P<0.0005) in cholesterol values between the subclinical hypothyroid group B and the euthyroid group N. CONCLUSIONS: SCH appears to be associated with increased mean cholesterol levels in females and of age > 60 years. The TC values were elevated in both subgroups of patients with SCH (A and B) based on TSH values. PMID- 28348997 TI - Proportion of beneficiaries and factors affecting Janani Suraksha Yojana direct cash transfer scheme in Puducherry, India. AB - INTRODUCTION: Janani Suraksha Yojana (JSY) direct benefit transfer scheme was launched in the year 2013 in India and there is a paucity of information affecting it. The study aimed to assess the proportion of eligible beneficiaries utilizing JSY direct cash benefit transfer in Puducherry and to identify its barriers and facilitating factors. METHODS: This cross sectional study was conducted from January to March 2015 among 152 eligible JSY beneficiaries residing in rural and urban field practice areas of a tertiary care institution in Puducherry, India. Data were collected using a pretested semi structured questionnaire and presented as proportion or percentages. RESULTS: About 144 beneficiaries participated in the study with a response rate of 94.7%. About 46% (66) of them availed cash transfer benefit. The mean time of receiving the benefit is 95.8 days (interquartile range 60-120 days). Among those who have not received (78), about 49 (62.8%) had not applied and 29 (37.18%) filled applications were rejected due to various reasons. About 77.1% (111) of beneficiaries were informed about JSY scheme through health workers. About 52.1% (75/144) still preferred direct bank transfer through the bank. The reasons for not availing benefits includes not having a bank account (24.3%), followed by not having Aadhaar number (9.7%), 11.8% had no ration card, and 13.8% stayed in their mother house. CONCLUSION: Majority of the beneficiaries did not receive direct cash transfer benefits in urban area than rural area and there is a need to simplify the procedures to improve the uptake of services to this group. PMID- 28348998 TI - Effect of female sex hormones on cardiorespiratory parameters. AB - INTRODUCTION: Female sex hormones, estrogen and progesterone regulate various phases of the menstrual cycle. Hormonal changes tend to affect various parameters of physical fitness. Maximum oxygen uptake (VO2 max) is a measure of aerobic power. This study was planned to assess effect of different phases of menstrual cycle on cardiorespiratory parameters like pulse rate, respiratory rate and VO2 max. METHODS: 100 female medical students in the age group of 17-22 years were studied for three consecutive menstrual cycles. Weight, resting pulse rate, respiratory rate and VO2 max were measured during premenstrual phase (20th-25th day) and postmenstrual phase (5th to 10th day). RESULTS: It was observed that there was a significant increase in body weight, pulse rate, and respiratory rate during premenstrual phase. There was a decrease in VO2 max during the premenstrual phase. CONCLUSION: This study indicates that there is decreased cardio-respiratory efficiency during premenstrual phase. PMID- 28348999 TI - Goiter prevalence in school-going children: A cross-sectional study in two border districts of sub-Himalayan Jammu and Kashmir. AB - INTRODUCTION: Iodine deficiency disorder remains one of the major public health problems, despite it being easily preventable. Initially thought as the disorder of Himalayan goiter belt, the disorder has been found to have a pan-India presence. The study was planned with the aim to assess the prevalence of goiter among 6-12 years school-going children and to identify levels of iodine in salt consumed at the household level in the study area. MATERIALS AND METHODS: The study was conducted among 3955 school-going (2162 children from Rajouri and 1793 children from Poonch) children age 6-12 years in Rajouri and Poonch districts of Jammu Province. The children were examined clinically to detect and grade the goiter. Salt samples were collected from subsample (n = 400) to estimate iodine content in the salt. RESULTS: The prevalence of goiter in the study population was found to be 18.87% and 9.70% in Rajouri and Poonch districts, respectively. Goiter prevalence was higher in 9-12 years age group as compared to 6-9 years age group and the difference in goiter prevalence in males of these two age groups was statistically significant (P = 0.02). Estimation of iodine content of the salt samples revealed that all of them (100%) had adequate iodine content. CONCLUSION: Despite the implementation of Universal Iodization Program and adequate content of iodine in salt consumed by the families, the goiter prevalence in both the districts is high. The future research should focus on identifying the reasons for this high prevalence. PMID- 28349000 TI - Oral health of preschool children in Dhanbad District, Jharkhand: A gander into the maternal behavior and practices. AB - INTRODUCTION: Mothers have an important role in taking decisions about their children's oral health. The study assessed the echelon of oral health behavior and practices of the mothers in relation to their preschool-aged children, which could possibly influence their oral health. METHODS: A cross-sectional study was carried out among 312 mothers, selected randomly from eight blocks of Dhanbad District, Jharkhand State, by administering a structured questionnaire on oral health behavior and practices regarding oral health. RESULTS: The overall data indicated that the practices of mothers about oral health of their preschool children increased as their age increased, which was however, not statistically significant (P > 0.47). The mothers who had less than higher secondary school education and belonging to lower socioeconomic groups had poorer oral health practices and was found to be statistically significant (P < 0.002). CONCLUSION: The mothers ought to inculcate positive practices and perceptions about preventive oral health for themselves first, to be good role models for their children. PMID- 28349002 TI - Family physicians' attitude and interest toward participation in urban family physician program and related factors. AB - INTRODUCTION: Every family physician has a key role in achieving the goals of the family physician program (FPP). Low satisfaction of physicians in certain areas of Iran and their low maintenance level in the program is quite challenging. The aims of the present study were; (1) to assess the attitude of rural/rural-urban family physicians about FPP and (2) to investigate their interest toward participation in urban FPP and (3) to explore the influencing factors. METHODS: This cross-sectional study was performed on 137 family physicians who were working in rural/rural-urban FPP in Mashhad University of Medical Sciences (Iran). A self-designed valid and reliable questionnaire including demographic data and thirty questions on the participants' attitudes toward the FPP in Likert scale were used. Data were analyzed by multiple logistic regression models using SPSS software. RESULTS: 49.3% of physicians were interested in continuing their cooperation in the urban-FPP. The mean total attitude score was 62.18 out of 100. The highest agreement and positive attitude of physicians were related to achievements of the program goals dimension. Multiple analyses showed that gender (odds ratio [OR] =5.5; male vs. female) and employment status (OR = 16.7 and 10.9 for permanent employment and by contract compared to legal obligation, respectively) were significantly associated with physicians' willingness toward participation in the urban-FPP. CONCLUSION: About half of the studied physicians were interested toward participation in the urban-FPP; Male physicians more than females and permanent employees more than others were willing and interested to participate in the urban-FPP. PMID- 28349001 TI - Environmental correlates of undernutrition among children of 3-6 years of age, Rajkot, Gujarat, India. AB - INTRODUCTION: There are lots of studies focusing on the role of reproductive and child health factors and dietary factors on the nutrition status of the child. The present study is an attempt to highlight the role of macro- and micro environmental factors in predicting the occurrence of undernutrition in children. METHODS: This was a cross-sectional study conducted in field practice area of Community Medicine Department, PDU Medical College, Rajkot. The nutrition status of children was assessed using the weight for age WHO reference standards, 2006. Children below two standard deviation of the reference median (weight for age) were considered as malnourished. Data were collected for sociodemographic factors, sanitation, hygiene, and attitude of mother toward her child, etc., Data were entered in MS excel, and logistic regression was used. RESULTS: Analysis of 495 selected children showed 24% prevalence of undernutrition. Employment status of mothers (adjusted odds ratio [AOR] 1.65), drinking water quality (AOR 1.53), and cleanliness of mother's hands and clothes (AOR 1.91) significantly affected the nutrition status of the child. Children classified in fair or poor category for Briscoe's sanitation scale had 1.34 and1.92 times higher odds of being undernourished (P > 0.05), respectively. Children classified in fair or poor category for Elizabeth's microenvironment scale had 2.05 and 2.41 times higher odds of being undernourished (P < 0.05), respectively. CONCLUSIONS: Water, sanitation, and hygiene-related factors, as well as microenvironmental factors, significantly affected the nutrition status of the children. PMID- 28349003 TI - Knowledge and self-care practices regarding diabetes among patients with Type 2 diabetes in Rural Sullia, Karnataka: A community-based, cross-sectional study. AB - INTRODUCTION: Diabetes is a lifestyle disease which requires a multipronged approach for its management, wherein patient has an important role to play in terms of self-care practices, which can be taught to them by educational programs. To develop such an educational program, a baseline assessment of knowledge and self-care practices of patients, needs to be made. The two objectives of the study were to estimate the knowledge of diabetic patients regarding the disease and its complications, and to estimate the knowledge and adherence to self-care practices concerned with Type 2 diabetes mellitus. METHODS: The study was conducted in rural Sullia, Karnataka, from January 2014 to May 2015. The sample size was calculated to be 400, and the sampling method was probability proportionate to sampling size. RESULT: Majority of them were married males of Hindu religion and belonged to upper middle class. Only 24.25% of them had good knowledge. Among the self-care practices, foot care was the most neglected area. CONCLUSION: Only one-fourth of the study population had a good knowledge toward diabetes. Adherence to some of the self-care practices was also poor. Government policies may help in creating guidelines on diabetes management, funding community programs for public awareness, availability of medicines, and diagnostic services to all sections of the community. Continuing education programs for health-care providers and utilization of mass media to the fullest potential may also help in creating awareness. PMID- 28349004 TI - Assessment of physical disability using Barthel index among elderly of rural areas of district Jhansi (U.P), India. AB - INTRODUCTION: The health of the elderly will be an important issue defining the health status of a population. With the rise in aged population, there is a greater need to look into their physical disability aspects, which is otherwise neglected. The rationale behind the study is to assess the physical disability of the elderly living in rural area of Jhansi. The aims of the study were to study the prevalence of physical disability among the elderly of rural area, and to find out the factors and association affecting the physical disability. METHODS: A community-based cross-sectional study was carried out in a Baragaon block of rural area of Jhansi, Uttar Pradesh, India, from July 2015 to October 2015. Multistage random sampling was performed. A total of 265 participants of age 60 years and above were selected. Physical disability was assessed using Barthel index. Appropriate data entry and statistical analysis were done in EpiInfo. Frequency tables were used to calculate the prevalence, and Chi-square test was used to find out the association. RESULTS: The overall prevalence of physical disability was 23.4%. 70% belongs to the age group from 60 to 69 years. Physical disability was significantly higher among age group >80 years. Similarly, women were more affected with physical disability than men. CONCLUSIONS: High prevalence of physical disability is the major area of concern. More extensive postdischarge health facilities to be provided to elderly. PMID- 28349005 TI - Multidrug-resistant Acinetobacter meningitis in children. AB - Acinetobacter species have emerged as one of the most troublesome pathogens for healthcare institutions globally. In more recent times, nosocomial infections involving the central nervous system, skin and soft tissue, and bone have emerged as highly problematic. Acinetobacter species infection is common in intensive care units; however, Acinetobacter baumannii meningitis is rarely reported. Here, we report two cases of Acinetobacter baumannii meningitis which was multidrug resistance and ultimately required the carbapenem group of drugs for the treatment. PMID- 28349006 TI - Immediate access to antiretroviral therapy is important in children living with HIV. AB - This article reviews a case of a child with perinatal HIV followed for 30 months during a prospective cohort study on pneumonia prevention in HIV-infected children. The point of this case report is to illustrate how delayed access to antiretroviral therapy (ART) in HIV-infected children impacts immunization response and growth. Given the WHO's early release guideline changes on ART recommendations and the expected full revised guidelines coming out this year, this article is a timely discussion on the need for access to ART for HIV infected Indian children regardless of CD4 count. PMID- 28349007 TI - Neonatal cholestasis due to primary sclerosing cholangitis. AB - Neonatal cholestasis is rarely caused due to primary sclerosing cholangitis, which is an inflammatory disease of the bile ducts, which results in obstructive fibrosis of the ducts. A 7-month-old male child presented with jaundice along with high-colored urine and clay-colored stools since birth. Liver biopsy showed mild bile duct proliferation with cholangioles showing bile and thrombi suggestive of primary sclerosing cholangitis. PMID- 28349008 TI - A case of hard palate perforation. AB - Tuberculosis (TB) is a major public health problem in developing countries. Lung is most common affected organ, however extra pulmonary tuberculosis (EPTB) is also not uncommon. The clinical manifestations of EPTB may be non-specific that mimics other diseases and is usually misdiagnosed. Therefore, high clinical suspicion of EPTB infection is important, especially in endemic areas. Here, we present a case of hard palate perforation that proved to be tuberculous in origin. The diagnosis was made by histo-pathological examination and positive TB Polymerase chain reaction (PCR). PMID- 28349009 TI - An atypical presentation of infiltrating ductal carcinoma. AB - A 64-year-old African-American female presented with nonbloody nipple discharge. Clinical and cytological examination of the discharge was normal. The mammography suggested pleomorphic calcification in the left breast. A stereotactic biopsy showed ductal carcinoma in situ and her estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2-neu receptor were negative. We removed the tumor tissue through lumpectomy and found that the mass was invasive ductal carcinoma. This case report highlights invasive ductal carcinoma, presenting with unilateral nipple discharge. PMID- 28349010 TI - Tuberculosis in a case of hyper immunoglobulin E syndrome. AB - Hyper immunoglobulin E syndrome (HIES) is a rare primary immunodeficiency disorder characterized by elevated serum IgE, dermatitis, and immunodeficiency that predisposes to multiple skin and lung infections. The most frequent pathogen responsible for infections in these patients is Staphylococcus aureus. Tuberculosis (TB) in patients with HIES is an uncommon finding, and there are only a few reports of mycobacterial infections in known cases of HIES. We present a case of abdominal TB that developed in a 15-year-old boy who also had HIES. PMID- 28349011 TI - Late onset hydrocephalus in children with tuberculous meningitis. AB - Hydrocephalus is a known complication of tuberculous meningitis (TBM). It is almost always present in patients who have had the disease for four to six weeks. However, hydrocephalus can also develop later in the disease course as seen in our 3 patients. All 3 patients had multi-drug resistant (MDR) tuberculosis (TB) and developed hydrocephalus after variable time after starting second line anti tuberculous therapy (ATT). A 7 years old girl had hydrocephalus at onset of TBM and was shunted but the hydrocephalus increased in size after 6 months of being on second line ATT in spite of a patent ventricular peritoneal (VP) shunt. Hydrocephalus responded to oral acetazolamide. Other 2 patients, a 2 years old girl and 31/2 years old boy developed hydrocephalus after being on treatment for 14 months. Both required insertion of VP shunt. Thus, in patients with MDR-TB, hydrocephalus may develop as late onset phenomenon and a neurological examination would be essential in each visit to the hospital. PMID- 28349012 TI - Low-dose methotrexate-induced acute interstitial pneumonitis: Report of two cases from South India and review of literature. AB - Methotrexate (MTX) is an antimetabolite used as a disease-modifying agent for various rheumatological conditions. We report two patients who were treated with daily low-dose MTX and developed acute interstitial pneumonitis requiring hospital admission. MTX-induced pneumonitis is a rare life-threatening side effect, high index of clinical suspicion is required, treatment is mainly withdrawal of MTX, supportive therapy, and adjunctive steroids, outcome is good if condition is recognized early, and appropriate treatment is given. PMID- 28349013 TI - An unusual case of sustained ventricular tachycardia following a wasp bite. AB - Sustained ventricular tachycardia (VT) is a life-threatening condition which requires immediate intervention. We report a case of unusual etiology of sustained VT in a 42-year-old male after a wasp bite in the absence of anaphylaxis. The patient was treated with amiodarone and improved within 48 h. Thus, wasp stings can lead to serious tachyarrhythmias which can be life threatening. Emergency care physicians should be aware of such arrhythmias in the setting of wasp bites which can be fatal. PMID- 28349014 TI - Sertraline induced mandibular dystonia and bruxism. AB - Specific serotonin reuptake inhibitors have been associated with the occurrence of drug-induced parkinsonism, dystonia, dyskinesia, and akathisia. Here, we describe a young female patient with a diagnosis of the moderate depressive episode who developed mandibular dystonia and bruxism with sertraline in the absence of concurrent prescription of medications, which have potential action on the dopaminergic system. PMID- 28349015 TI - Smoke on a white coat. PMID- 28349016 TI - Screening of tuberculosis patients for diabetes mellitus is feasible with the existing health system in India. PMID- 28349017 TI - Psychological symptoms predicted chest pain intensity and discomfort in cardiac rehabilitation patients. PMID- 28349018 TI - Bodybuilders pneumonia. PMID- 28349019 TI - Acute disseminated encephalomyelitis after mumps infection. PMID- 28349020 TI - Treatment Outcome of the Drug-resistant Zoonotic Cutaneous Leishmaniasis by Glucantime. AB - BACKGROUND: Resistance of Leishmania species to antimonial drugs has increased. Hence, in the present study Leishmania major isolates were collected from patients with resistance phenotype and the presence/absence of resistance to Glucantime was investigated. MATERIALS AND METHODS: Samples were taken from 10 cutaneous leishmaniasis (CL) patients who had not responded to chemotherapy with Glucantime. Nested polymerase chain reaction (PCR) was performed to identify the isolated species. Stationary phase promastigotes were added to the grown, adhesive J774 macrophages. Values obtained from standard strain were compared with the test cultures after exposure to the medicine. In vivo, the effects of Glucantime were assessed by comparing the sizes and the parasite burden of the lesions on mouse model. RESULTS: The results of amplified band on agarose gel demonstrated all samples were L. major. After exposure to medicine, a reduction of intracellular amastigotes to half was detected. In vivo, the parasite was eliminated in 90% of mice with lesions caused by both isolates of patients and standard L. major, and their lesions became smaller significantly. CONCLUSION: Pentavalent antimonial (SbV) salts are the main component of chemotherapy against leishmaniasis. However, the medicine has been found ineffective. In the present study, isolates from patients with no response to treatment had no significant difference from the standard L. major strain (as the sensitive strain). Therefore, in patients with resistance phenotype to Glucantime, the parasites did not actually have intrinsic resistance, i.e., environmental and host factors prevented the successful treatment of the disease. PMID- 28349022 TI - Evaluating Accuracy of Free-hand Pedicle Screw Insertion in Adolescent Idiopathic Scoliosis Using Postoperative Multi-Slice Computed Tomography Scan. AB - BACKGROUND: Pedicle screw instrumentation has many advantages for correction of adolescent idiopathic scoliosis (AIS) deformity including better correction and fewer late complications. On the other hand, screw insertion in AIS is challenging. Intraoperative fluoroscopy or navigation techniques are expensive, time-consuming, and exposed to high radiation. Free-hand technique relies on the surgeon's experience and locating the pedicle entry point with anatomical landmarks. There are few studies that evaluated pedicle screw position accuracy with postoperative multi-slice computed tomography scan. MATERIALS AND METHODS: We prospectively considered 38 consecutive AIS cases, who underwent corrective surgery with all pedicle screw technique. All the screws were inserted with free hand technique using anatomic landmarks as a guide for an entry site. We divided pedicle penetration in medial, lateral, inferior, superior, and anterior vertebral body as Grades 0-4, that Grade 0 is fully contained within the pedicle, Grade 1 (<2 mm), Grade 2 (2.1-4 mm), Grade 3 (4.1-6 mm), and Grade 4 (>6 mm). RESULTS: A total of 720 screws were inserted, of which 623 screws (86.5%) were perfect and 97 screws (13.5%) were misplaced. Of those which were misplaced, 39 screws (40.2%) were medial and 58 (59.8%) were lateral, which shows that the prevalence of lateral misplacement was more in comparison to medial misplacement. However, in all misplaced cases, the deviation of the screw was <2 mm (Grade 1). There was no misplacement in the inferior and superior. CONCLUSION: Pedicle screw insertion in AIS with the free-hand technique is a safe and reliable method. PMID- 28349021 TI - Evaluation of Diagnostic Values of Clinical Assessment in Determining the Maturation of Arteriovenous Fistulas for Satisfactory Hemodialysis. AB - BACKGROUND: Fistulas are the preferred permanent hemodialysis vascular access, but a significant obstacle to increasing their prevalence is the fistula's high "failure to mature" (FTM) rate. This study aimed to identify postoperative clinical characteristics that are predictive of fistula FTM. MATERIALS AND METHODS: This descriptive cross-sectional study was performed on 80 end-stage renal disease patients who referred to Al Zahra Hospital, Isfahan, for brachiocephalic fistula placement. After 4 weeks, the clinical criteria (trill, firmness, vein length, and venous engorgement) examined and the fistulas situation divided to favorable or unfavorable by each criterion, and the results comprised with dialysis possibility. Data were analyzed with SPSS version 21. Diagnostic index for CLINICAL examination was calculated. RESULTS: Among the 80 cases, 25 (31.2%) female and 55 (68.8%) male were studied with the mean age of 51.9 (standard deviation = 17) year ranged between 18 and 86 years old. Sixty-two (77.5%) cases had successful hemodialysis. All four clinical assessments were significantly more acceptable in patients with successful dialysis (P < 0.001). According to the results of our study, the accuracy of all physical assessments was above 70% and except vein length other criteria had a sensitivity and negative predictive value of 100%. In this study, firmness of vein has highest specificity and positive predictive value (83.9% and 64.3%, respectively). CONCLUSION: Results of our study showed that high sensitivity and relatively low specificity of the clinical criterion. It means that unfavorable results of each clinical criterion predict unfavorable dialysis. Clinical evaluation of a newly created fistula 4-6 weeks after surgery should be considered mandatory. PMID- 28349023 TI - Fractional Carbon Dioxide Laser and its Combination with Subcision in Improving Atrophic Acne Scars. AB - BACKGROUND: Acne is a very common skin disease in which scars are seen in 95% of the patients. Although numerous treatments have been recommended, researchers are still searching for a single modality to treat the complication due to its variety in shape and depth. We compared the effects of fractional carbon dioxide (CO2) laser alone and in combination with subcision in the treatment of atrophic acne scars. MATERIALS AND METHODS: This clinical trial study was performed in Skin Diseases and Leishmaniasis Research Center (Isfahan, Iran) during 2011-2012. Eligible patients with atrophic acne scars were treated with fractional CO2 laser alone (five sessions with 3-week interval) on the right side of the face and fractional CO2 laser plus subcision (one session using both with four sessions of fractional CO2 laser, with 3-week interval) on the left side. The subjects were visited 1, 2, and 6 months after the treatment. Patient satisfaction rate was analyzed using SPSS 20 software. RESULTS: The average of recovery rate was 54.7% using the combination method and 43.0% using laser alone (P < 0.001). The mean patient satisfaction was significantly higher with the combination method than laser alone (6.6 +/- 1.2 vs. 5.2 +/- 1.8; P < 0.001). Bruising was only seen with the combination method and lasted for 1 week in 57.0% and for 2 weeks in 43.0%. Erythema was seen in both methods. Postinflammatory pigmentation and hyperpigmentation were associated with combination method. No persistent side effects were seen after 6 months. CONCLUSION: Using a combination of subcision and laser had suitable results regarding scar recovery and satisfaction rate. PMID- 28349024 TI - The Mediating Role of Mental Health in the Relations between Dietary Behaviors and General Health: A Cross-sectional Study. AB - BACKGROUND: The aim of this study is to find a pathway to explaining the relations between dietary behaviors with mental health and psychological functioning. MATERIALS AND METHODS: This cross-sectional study contains 4763 participants from the employees of Isfahan University of Medical Sciences. In this study, four questionnaires were administered which were provided as follows: demographic characteristics, 21-item dietary behaviors questionnaire, Hospital Anxiety and Depression Scale questionnaire, and 12-item General Health Questionnaire (GHQ-12). We started the analysis with the structural equation modeling (SEM) model with 4 unobserved latent and 16 observed variables. RESULTS: The results show that the regression coefficient (standard error) of diet behavior on mental health and mental health on GHQ were - 1 (0.37) and 0.02 (0.01) with their P values as 0.007 and 0.01, respectively. For this model, the estimated root mean square error of approximation is 0.062 with 90% confidence interval of (0.060-0.065). In addition, the comparative fit indices (CFIs) were as 0.866 for incremental fit index and 0.866 for CFI. All these indices represent fairly good fit of the model to the data. CONCLUSION: We can conclude that "lower scores on diet behavior - higher scores on mental health problems" and "higher mean scores in depression and/or anxiety - higher scores in GHQ domains." The SEM results showed that dietary behaviors have significance related to depression and/or anxiety and general health status. PMID- 28349025 TI - Optimization of the Expression of DT386-BR2 Fusion Protein in Escherichia coli using Response Surface Methodology. AB - BACKGROUND: The aim of this study was to determine the best condition for the production of DT386-BR2 fusion protein, an immunotoxin consisting of catalytic and translocation domains of diphtheria toxin fused to BR2, a cancer specific cell penetrating peptide, for targeted eradication of cancer cells, in terms of the host, cultivation condition, and culture medium. MATERIALS AND METHODS: Recombinant pET28a vector containing the codons optimized for the expression of the DT386-BR2 gene was transformed to different strains of Escherichia coli (E. coli BL21 DE3, E. coli Rosetta DE3 and E. coli Rosetta-gami 2 DE3), followed by the induction of expression using 1 mM IPTG. Then, the strain with the highest ability to produce recombinant protein was selected and used to determine the best expression condition using response surface methodology (RSM). Finally, the best culture medium was selected. RESULTS: Densitometry analysis of sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the expressed fusion protein showed that E. coli Rosetta DE3 produced the highest amounts of the recombinant fusion protein when quantified by 1 mg/ml bovine serum albumin (178.07 MUg/ml). Results of RSM also showed the best condition for the production of the recombinant fusion protein was induction with 1 mM IPTG for 2 h at 37 degrees C. Finally, it was established that terrific broth could produce higher amounts of the fusion protein when compared to other culture media. CONCLUSION: In this study, we expressed the recombinant DT386-BR2 fusion protein in large amounts by optimizing the expression host, cultivation condition, and culture medium. This fusion protein will be subjected to purification and evaluation of its cytotoxic effects in future studies. PMID- 28349026 TI - Current and future of the Journal of Exercise Rehabilitation. PMID- 28349027 TI - Review of researches on smartphone applications for physical activity promotion in healthy adults. AB - Physical activity is known as a preventative method for preventing life-style related diseases. Smartphone applications for health and fitness intervention have released with rapid increase of innovative technology. Reviews of recent publications on mobile application have been conducted to observe feasibility and applicability for physical activity intervention. Bibliographic searches of PubMed and ScienceDirect were conducted with key terms, 'physical activity,' 'fitness,' 'smart-phone,' and 'health' between the years 2014 and 2017 to obtain 5,087 publications. Out of 5,087 articles, five articles on sensor-based applications and five articles on user entry-based applications were obtained through the inclusion and exclusion processes. Accuracy of the physical activity assessments were reported to be high in comparison to the conventional assessment tools. The overall subject rating on the app motivational ratings were positive with high correlation between physical activity and treats and cues. The adherence rates to the apps significantly dropped prior to 3 months. Publications that elucidate feasibility and accuracy of smartphone applications that motivates physical activity seem limited with adequately conducted study designs. Large scaled, control-compared, long-term randomized control trials should be conducted to elucidate the effects of the app interventions. PMID- 28349029 TI - Effect of square stepping exercise for older adults to prevent fall and injury related to fall: systematic review and meta-analysis of current evidences. AB - Falls and fall related injuries become an emerging health problem among older adults. As a result a review of the recent evidences is needed to design a prevention strategy. The aim of this review was to determine the effect of square stepping exercise (SSE) for fall down injury among older adults compared with walking training or other exercises. An electronic database search for relevant randomized control trials published in English from 2005 to 2016 was conducted. Articles with outcome measures of functional reach, perceived health status, fear of fall were included. Quality of the included articles was rated using Physiotherapy Evidence Database (PEDro) scale and the pooled effect of SSE was obtained by Review Manager (RevMan5) software. Significant effect of SSE was detected over walking or no treatment to improve balance as well to prevent fear of fall and improve perceived health status. The results of this systematic review proposed that SSE significantly better than walking or no treatment to prevent fall, prevent fear of fall and improve perceived health status. PMID- 28349028 TI - Therapeutic effectiveness of instrument-assisted soft tissue mobilization for soft tissue injury: mechanisms and practical application. AB - This article reviews the mechanism and effects of instrument-assisted soft tissue mobilization (IASTM), along with guidelines for its practical application. IASTM refers to a technique that uses instruments to remove scar tissues from injured soft tissues and facilitate healing process through formation of new extracellular matrix proteins such as collagen. Recently, frequent use of this instrument has increased in the fields of sports rehabilitation and athlete training. Some experimental studies and case reports have reported that IASTM can significantly improve soft tissue function and range of motion following sports injury, while also reducing pain. Based on the previous studies, it is thought that IASTM can help shorten the rehabilitation period and time to return to sports among athletes and ordinary people who have suffered sports injuries. However, few experimental studies of the mechanisms and effects of IASTM have examined, while case reports have accounted for the majority of articles. In the future, the scientific basis of IASTM and its reliability should be provided through well-designed experimental studies on humans. Moreover, IASTM studies that have mostly focused on tendons need to broaden their scope toward other soft tissues such as muscles and ligaments. PMID- 28349030 TI - Treadmill exercise alleviates nigrostriatal dopaminergic loss of neurons and fibers in rotenone-induced Parkinson rats. AB - Parkinson disease is one of the common brain diseases caused by dopaminergic neuronal loss in the substantia nigra and dopaminergic fiber loss in the striatum. In the present study, the effects of treadmill exercise on motor performance, dopaminergic loss of neurons and fibers, and alpha-synuclein expression in the nigrostriatum were evaluated using rotenone-induced Parkinson rats. For the induction of Parkinson rats, 3-mg/kg rotenone was injected, once a day for 14 consecutive days. Treadmill running was conducted for 30 min once a day during 14 consecutive days. Rota-rod test for motor balance and coordination and immunohistochemistry for tyrosine hydroxylase and alpha-synuclein in the nigrostriatum were performed. In the present study, motor balance and coordination was disturbed by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise alleviated motor dysfunction in the rotenone-induced Parkinson rats. Nigrostriatal dopaminergic loss of neurons and fibers was occurred by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise alleviated nigrostriatal dopaminergic loss of neurons and fibers in the rotenone-induced Parkinson rats. alpha-Synuclein expression in the nigrostriatum was enhanced by induction of rotenone-induced Parkinson disease, in contrast, treadmill exercise suppressed alpha-synuclein expression in the rotenone-induced Parkinson rats. Treadmill exercise improved motor function through preservation of nigrostriatal dopaminergic neurons and fibers and suppression of nigrostriatal formation of Lewy bodies in rotenone-induced Parkinson rats. PMID- 28349031 TI - Treadmill exercise improves depression-like symptoms by enhancing serotonergic function through upregulation of 5-HT1A expression in the olfactory bulbectomized rats. AB - The olfactory bulbectomy (OBX) is a well-known method inducing animal model of depression. Depression is associated with dysfunction of serotonin (5 hydroxytryptamine, 5-HT) system. In the present study, antidepressive effect of treadmill exercise was investigated using olfactory bulbectomized rats. After bilateral bulbectomy, the rats in the treadmill exercise groups were subjected to run on a treadmill for 30 min once a day during 28 days. Increased immobility time and decreased fast time in the forced swim test were observed in the olfactory bulbectomized rats. Sucrose preference in the sucrose preference test was decreased and activity in the open field test was also increased in the olfactory bulbectomized rats. Treadmill exercise decreased immobility time and activity and increased fast time and sucrose preference in the olfactory bulbectomized rats. Expressions of 5-HT and tryptophan hydroxylase (TPH) in the dorsal raphe of rats were suppressed by OBX and treadmill exercise increased the expressions of 5-HT and TPH in the olfactory bulbectomized rats. Serotonin receptor type 1A (5-HT1A) expression in the dorsal raphe was reduced by OBX and treadmill exercise increased 5-HT1A expression in the olfactory bulbectomized rats. In the present study, treadmill exercise ameliorated OBX-induced depressive symptoms. The antidepressive effect of treadmill exercise might be ascribed to the enhancement of serotonergic function through upregulation of 5-HT1A expression in the dorsal raphe. PMID- 28349032 TI - Experience of sport stacking in Korean older adults. AB - Today sedentary lifestyles are a major public health concern and there are many evidences related to physical inactivity. The well-documented evidence is that regular physical activity is an essential part for improving overall health with advancing aging and the most efficient means playing roles of rehabilitation and prehabilitation. However, there are few activity programs which could motivate older adults to continue and maintain their active lifestyles. The purpose of the current study was to describe experience of sport stacking which applied to Korean older adults in the first time. Eighteen older adults living in the community in Seoul which was the capital and largest metropolis of the Republic of Korea participated in the study. A qualitative interview and a survey were conducted and data were analyzed by interpretive content analysis. Individual, semistructured, face-to-face interviews were recorded, transcribed, condensed and coded to find themes. The main themes were identified regarding older adults' experience of sport stacking: enjoyment of sport stacking, attitudes toward sport stacking as a physical activity program, and benefits from sport stacking. In conclusions, Korean older adults had positive experience of sport stacking and it was necessary for developing strategies to spread it as the physical activity program for older persons in Korea to improve their health and quality of life. PMID- 28349033 TI - Effects of smartphone texting on the visual perception and dynamic walking stability. AB - Mobile phone use while walking can cause dual-task interference and increases safety risks by increasing attentional and cognitive demands. While the interference effect on cognitive function has been examined extensively, how perception of the environment and walking dynamics are affected by mobile phone use while walking is not well understood. The amount of visual information loss and its consequent impact on dynamic walking stability was examined in this study. Young adults (mean, 20.3 years) volunteered and walked on a treadmill while texting and attending to visual tasks simultaneously. Performance of visual task, field of regard loss, and margin of stability under dual-task conditions were compared with those of single-task conditions (i.e., visual task only). The results revealed that the size of visual field and visual acuity demand were varied across the visual task conditions. Approximately half of the visual cues provided during texting while walking were not perceived as compared to the visual task only condition. The field of regard loss also increased with increased dual-task cost of mobile phone use. Dynamic walking stability, however, showed no significant differences between the conditions. Taken together, the results demonstrate that the loss of situational awareness is unavoidable and occurs simultaneously with decrements in concurrent task performance. The study indicates the importance of considering the nature of attentional resources for the studies in dual-task paradigm and may provide practical information to improve the safe use of mobile phones while walking. PMID- 28349034 TI - Repeated sprint ability is not enhanced by caffeine, arginine, and branched-chain amino acids in moderately trained soccer players. AB - The aim was to investigate the effect of a dietary supplementation on the repeated sprint ability (RSA) performance in recreationally trained team sports athletes. Twelve young men underwent a RSA exercise protocol in five trials, in which participants ingested carbohydrates (CHO) plus caffeine (Caf), CHO plus arginine (Arg), CHO plus branched-chain amino acids (BCAA), CHO plus Caf, Arg, and BCAA (ALL), and CHO only. Heart rate, oxygen saturation, hematic lactate, ratings of perceived exertion, average sprint time, total time, best sprint time, peak power, and average power were taken. Data revealed no significant effects neither on physiological nor performance parameters with any of the supplements. PMID- 28349035 TI - Characteristics of upper extremity's muscle strength in Turkish national wheelchair basketball players team. AB - The objective of this study was to reveal characteristics of muscle strength of upper extremities of wheelchair (WC) basketball players and to ensure more specific training program preparation. Isokinetic muscle strength of 12 WC basketball players were assessed by ISOMED 2000 device. The assessment protocol was evaluated at 60 degrees /sec velocity with 5 times repeated force and at 240 degrees /sec with 15 times repeated force. This protocol was carried out individually for shoulder flexion-extension and wrist flexion-extension movements at the right and left extremities. The flexion/extension ratio was determined to be outside of the ratios accepted as normal for primarily shoulder joint and for wrist joint. The extension movement was stronger than flexion movement in the shoulders at both velocities and the flexion movement was stronger than ex tension movement in the wrist. The repeat times where the peak torque occurred were 2-3 repeats at 60 degrees /sec velocity during flexion and extension movements for the wrist and shoulders, and the peak torque occurred at an average of 5-6 repeats in the shoulders at 240 degrees /sec velocity and it occurred at 3 4 repeats in the wrist. The angles where the peak torque of the shoulder flexion and extension occurred varied between 80 degrees -115 degrees at both velocities, and it varied between 5 degrees -30 degrees angles for the wrist. As this study revealed, determination of muscle strength characteristics of WC athletes and especially using objective isokinetic devices will guide the planning of the appropriate training and exercise programs and preventing sports injuries in long term. PMID- 28349036 TI - Monitoring internal training load and salivary immune-endocrine responses during an annual judo training periodization. AB - The objective of this study was to examine the internal training load (TL), IgA, and salivary steroid hormone responses in elite youth judo athletes during an entire annual training periodization. Ten male judo athletes (18+/-2 years, 72.3+/-12.3 kg, and 175+/-6 cm) competing at a state/national level were examined for the TL and salivary imune-endocrine responses variations over an annual judo season, divided in three macrocyles composed by distinct periods denominated preparatory period (PP), competitive period (CP) and transition period (TP). At the end of PP and CP, saliva samples were collected to determine cortisol, testosterone and IgA concentrations. Throughout PP and CP the session-rating of perceived exertion and the total duration of each session were monitored, allowing the internal TL and weekly training strain (TS) calculation. During all macrocycles, significant decreases in TL and TS were observed during CP compared with PP (P<0.05), although no significant differences were observed for immune endocrine concentrations between PP and CP (P>0.05). Specific variations were observed comparing periods with similar characteristics throughout the macrocycles as higher TL and TS (PP1 to PP2 and PP3, P<0.05), increased testosterone (CP1 to CP3, P=0.024) and decreased testosterone-cortisol ratio (PP1 to PP2, P=0.005). The present findings suggest that the internal TL variations over an annual multipeak traditional periodization did not influence the resting mucosal immune-endocrinal responses in young judo athletes. PMID- 28349037 TI - Inpatient cardiac rehabilitation programs' exercise therapy for patients undergoing cardiac surgery: National Korean Questionnaire Survey. AB - Inpatient cardiac rehabilitation (ICR) has been commonly conducted after cardiac surgery in many countries, and has been reported a lots of results. However, until now, there is inadequacy of data on the status of ICR in Korea. This study described the current status of exercise therapy in ICR that is performed after cardiac surgery in Korean hospitals. Questionnaires modified by previous studies were sent to the departments of thoracic surgery of 10 hospitals in Korea. Nine replies (response rate 90%) were received. Eight nurses and one physiotherapist completed the questionnaire. Most of the education on wards after cardiac surgery was conducted by nurses. On postoperative day 1, four sites performed sitting on the edge of bed, sit to stand, up to chair, and walking in the ward. Only one site performed that exercise on postoperative day 2. One activity (stairs up and down) was performed on different days at only two sites. Patients received education preoperatively and predischarge for preventing complications and reducing muscle weakness through physical inactivity. The results of the study demonstrate that there are small variations in the general care provided by nurses after cardiac surgery. Based on the results of this research, we recommended that exercise therapy programs have to conduct by exercise specialists like exercise physiologists or physiotherapists for patients in hospitalization period. PMID- 28349038 TI - The effect of treadmill-based and track-based walking training on physical fitness in ankle-sprain experienced young people. AB - The purpose of this study was to evaluate the effects of 12-week treadmill-based (MT) and track-based (TT) walking program on maximal oxygen consumption (VO2max), muscular endurance, muscle strength, and ankle range of motion (ROM) in ankle sprain experienced young people. Twenty subjects (12 males, 8 females) volunteered to participate in this study and divided into two groups (MT and TT). All subjects completed MT and TT 4 times per week with each session of 60 min with 65% from maximum heart rate. Incremental test on treadmill and 20-m shuttle run test for endurance capacity (VO2max), 2-km walking test for muscular endurance, vertical jump for strength, and ankle ROM for flexibility were analyzed before and after the training intervention. We found significant increase in incremental, 2-km walking and 20-m shuttle run after both MT and TT. Just after TT were significant increased vertical jump and ankle ROM. In conclusion, TT seems to induce a more positive effect on muscle strength in lower extremity and ankle ROM than treadmill-based walking training in ankle sprain experienced young people. PMID- 28349039 TI - A community-based aquatic exercise program to improve endurance and mobility in adults with mild to moderate intellectual disability. AB - The purpose of this study was to investigate the impact of a community-based aquatic exercise program on physical performance among adults with mild to moderate intellectual disability (ID). Twenty-two community-dwelling adults with mild to moderate ID volunteered to participate in this study. Participants completed an 8-week aquatic exercise program (2 days/wk, 1 hr/session). Measures of physical performance, which were assessed prior to and following the completion of the aquatic exercise program, included the timed-up-and-go test, 6 min walk test, 30-sec chair stand test, 10-m timed walk test, hand grip strength, and the static plank test. When comparing participants' measures of physical performance prior to and following the 8-week aquatic exercise program, improvements were seen in all measures, but the change in scores for the 6-min walk test, 30-sec chair stand test, and the static plank test achieved statistical significance (P<0.05). An 8-week group aquatic exercise program for adults with ID may promote improvements in endurance and balance/mobility. PMID- 28349040 TI - The effect of resistance exercise on fitness, blood pressure, and blood lipid of hypertensive middle-aged men. AB - The purpose of this study is to investigate the effect of resistance exercise on fitness, blood pressure, and blood lipid of hypertensive middle-aged men. To achieve the goal of the study, a total of 23 subjects were selected. Among them, 14 subjects who exercised regularly were selected as the exercise group, while the remaining 9 subjects were selected as the control group. In terms of data processing, the IBM SPSS Statistics ver. 21.0 software was used to calculate the mean and standard deviation. Regarding the verification of difference on the change of means between the groups, analysis of covariance was used for statistical process. As a result, significant differences were found in cardiovascular endurance, muscle endurance, flexibility, and triglyceride. These results indicate that the resistance exercise only had slight effect on hypertensive middle-aged men. PMID- 28349041 TI - Influence of expectations plus mobilization with movement in patient with lateral epicondylalgia: a pilot randomized controlled trial. AB - The aim of this study was to determine the influence of expectations plus mobilization with movement (MWM) in kinesiophobia, perceived disability and sensorimotor variables in patients with lateral epicondylalgia. A pilot randomized controlled trial in 24 patients with lateral epicondylalgia was conducted. Perceived pain, pain-free grip strength, pressure pain detection threshold, kinesiophobia measured with the short version of Tampa Scale of Kinesiophobia, perceived disability of the upper limb measured with disability of the arm, hand and shoulder questionnaire, and perceived disability specifically for the elbow joint measured with patient-rating tennis elbow evaluation, and also satisfaction were assessed. Participants were randomized to receive written instructions in order to create positive expectations regarding the technique in one group (n=12) or neutral expectations in the other one (n=12). All patients were treated for three sessions with the MWM technique. Measures were recorded before and after treatment. The effect size was calculated by Rosenthal "r" for nonparametrical tests. There were no significant statistical differences (P>0.05) between groups after receiving the treatment for none of the physical analyzed variables. The Wilcoxon test showed statistically significant changes in kinesiophobia (Z=-2.278, r=0.47, P=0.023) and perceived disability (Z= -2.934, r=0.61, P=0.003) within positive expectations group. In conclusion this pilot study shows that a positive expectation almost given in a sealed envelope before treatment plus MWM produced changes in kinesiophobia and perceived disability in the immediate term, in patients with lateral epicondylalgia. PMID- 28349042 TI - Effects of strength and neuromuscular training on functional performance in athletes after partial medial meniscectomy. AB - The aims of this study were to determine an effective knee function rehabilitation program for athletes undergoing partial medial meniscectomy. Participants were randomly assigned to neuromuscular training (NT) or strength training (ST) group and subjected to functional assessments before surgery and again at 4, and 8 weeks post hoc. Functional knee assessment, such as Lysholm knee scoring, star excursion balance, and BTE PrimusRS isokinetic performance tests were evaluated in each group. All postoperational symptoms were significantly improved after 4 and 8 weeks of NT and ST. Both NT and ST programs showed effective knee function recovery seen as an increase in muscular strength and endurance. However, the NT program showed the most significant functional improvement of dynamic balance and coordination. PMID- 28349043 TI - Relationship among the variables of kinematic and tilt angle of whole body according to the foot trip during gait. AB - The aim of this study was to analyze the relation between incline angle of whole body and kinematic variables at tripping during gait. The participants consisted of healthy adult female (n=6). The three-dimensional (3D) motion analysis of posture restoring after inducing tripping of right foot at supporting phase of left foot was performed. As a result, supporting time elapsed of one stride and one foot at tripping showed longer than that of normal gait. The length of one stride showed longer at tripping than that of normal gait, and velocity of center of gravity (COG) showed faster at tripping than that of normal gait. Anteriorposterior incline angle of whole body showed more forwarded incline at tripping than that of normal gait. As a result of correlation among variables, one stride and supporting time elapsed showed positive relation r=0.973 (R2 =0.947, P<0.001), also r=0.920 (R2 =0.846, P<0.001) relative to velocity of COG, r=0.970 (R2 =0.941, P<0.001) of 1-stride time elapsed relative to velocity of COG and r=0.833 (R2 =0.613, P<0.05) of velocity of COG relative to anteriorposterior incline angle respectively. Therefore instantaneous stoppage of gait posture when tripped at supporting phase of one leg during gait may be impossible and rather may cause a recovery of gait pattern when secured the faster velocity of COG and the longer of supporting time elapsed of one leg. PMID- 28349045 TI - Safety Profile of Liver FibroScan in Patients with Cardiac Pacemakers or Implantable Cardioverter-Defibrillators. AB - Background. Emerging evidence suggests that nonalcoholic fatty liver disease (NAFLD) is associated with coronary artery diseases and arrhythmias. The FibroScan (Echosens, France), a widely available, noninvasive device, is able to detect liver fibrosis and steatosis within this patient population. However, the FibroScan is currently contraindicated in patients with cardiac pacemakers (PM) or implantable cardioverter-defibrillators (ICD). Objective. To determine the safety profile of FibroScan testing in patients with PM or ICD. Methods. Consecutive outpatients undergoing routine device interrogations at a tertiary level teaching hospital underwent simultaneous liver stiffness measurements. PM or ICD performance data, device types, patient demographics, medical history, and previous laboratory and conventional liver imaging results were collected. Results. Analysis of 107 subjects with 33 different types of implanted cardiac devices, from 5 different companies (Medtronic, Sorin, ELA Medical, Boston Scientific, and St. Jude), did not demonstrate any adverse events as defined by abnormal device sensing/pacing or ICD firing. This population included high risk subjects undergoing active pacing (n = 53) and with right pectoral PM placement (n = 1). None of the subjects had any clinical signs of decompensated congestive heart failure or cirrhosis during the exam. Conclusion. TE with FibroScan can be safely performed in patients with PM or ICD. PMID- 28349044 TI - Vonoprazan-Based Regimen Is More Useful than PPI-Based One as a First-Line Helicobacter pylori Eradication: A Randomized Controlled Trial. AB - Background. A new agent, potassium-competitive acid blocker vonoprazan (VPZ) has potent acid-inhibitory effects and may offer advantages over conventional H. pylori eradication therapies. We aimed to compare the eradication rate between VPZ-based treatment and PPI-based one. Methods. This randomized controlled trial was designed to assign 141 patients with H. pylori-positive gastritis to VPZ group (VPZ 20 mg, amoxicillin 750 mg, and clarithromycin 200 or 400 mg twice daily for 7 days) or PPI group (rabeprazole 20 mg or lansoprazole 30 mg, amoxicillin 750 mg, and clarithromycin 200 or 400 mg twice daily for 7 days). Primary endpoints were eradication rates and adverse events. Results. Seventy of 72 patients in VPZ group and 63 of 69 patients in PPI group completed the treatment after 7 days. The eradication rate was significantly higher in VPZ group than PPI group by intention-to-treat analysis (95.8% versus 69.6%, P = 0.00003, 95% confidence interval [CI] 88.3-99.1% versus 57.3-80.1%) and per protocol analysis (95.7% versus 71.4%, P = 0.0002, 95% CI 88.0-99.1% versus 58.7 82.1%). The incidence of adverse events was not different between the groups (26.3% in VPZ group versus 37.7% in PPI group, P = 0.15). Conclusion. VPZ-based regimen is more useful than that PPI-based regimen as a first-line H. pylori eradication therapy. PMID- 28349046 TI - Venous Thromboembolism in Critical Illness and Trauma: Pediatric Perspectives. AB - Critically ill children and those sustaining severe traumatic injuries are at higher risk for developing venous thromboembolism (VTE) than other hospitalized children. Multiple factors including the need for central venous catheters, immobility, surgical procedures, malignancy, and dysregulated inflammatory state confer this increased risk. As well as being at higher risk of VTE, this population is frequently at an increased risk of bleeding, making the decision of prophylactic anticoagulation even more nuanced. The use of pharmacologic and mechanical prophylaxis remains variable in this high-risk cohort. VTE pharmacologic prophylaxis is an accepted practice in adult trauma and intensive care to prevent VTE development and associated morbidity, but it is not standardized in critically ill or injured children. Given the lack of pediatric specific guidelines, prevention strategies are variably extrapolated from the successful use of mechanical and pharmacologic prophylaxis in adults, despite the differences in developmental hemostasis and thrombosis risk between children and adults. Whether the burden of VTE can be reduced in the pediatric critically ill or injured population is not known given the lack of robust data. There are no trials in children showing efficacy of mechanical compression devices or prophylactic anticoagulation in reducing the rate of VTE. Risk stratification using clinical factors has been shown to identify those at highest risk for VTE and allows targeted prophylaxis. It remains unproven if such a strategy will mitigate the risk of VTE and its potential sequelae. PMID- 28349047 TI - Up, Down, and All Around: Diagnosis and Treatment of Novel STAT3 Variant. AB - The number of identified monogenic causes of childhood-onset autoimmunity due to nodal and extranodal lymphoproliferation has increased. These pathogenic genetic variants provide the potential for pathway-specific treatment. Novel variants also require pathway-specific verification. In this report, we describe a 14-year old patient with a novel variant in STAT3. We report clinical and laboratory findings that support STAT3 p.G419R as a novel pathogenic STAT3 gain-of-function variant. PMID- 28349048 TI - Use of Natural Family Planning (NFP) and Its Effect on Couple Relationships and Sexual Satisfaction: A Multi-Country Survey of NFP Users from US and Europe. AB - PURPOSE: Birth control is a persistent global health concern. Natural family planning (NFP) comprises methods to achieve or avoid pregnancy independent of mechanical or pharmacological intervention. The sympto-thermal method (STM) of NFP employs daily observation of cervical fluids and measurement of basal body temperature. This multi-country study was undertaken to describe the characteristics of STM users, understand their perceptions of NFP, and its perceived impact on relationships. METHODS AND RESULTS: Questionnaires for women and men were developed in German and translated to English, Polish, Italian, Czech, and Slovak by native speakers. A total of 2,560 respondents completed the online questionnaire (37.4% response). Participants were married (89%) and well educated, and their self-perceived financial status was described as "good" or "very good" by 65% of the respondents. Forty-seven percent had previously used contraceptives. Ninety-five percent of women and 55% of men said using NFP has helped them to know their body better. Large majorities of men (74%) and women (64%) felt NFP helped to improve their relationship while <10% felt use of NFP had harmed their relationship. Most women (53%) and men (63%) felt using NFP improved their sex life while 32% of women and 24% of men felt it was unchanged from before they used NFP. Seventy-five percent of women and 73% of men said they are either "satisfied" or "very satisfied" with their frequency of sexual intercourse. CONCLUSION: This survey demonstrates STM of NFP is a well-accepted approach to family planning across several Western cultures. It is consistently viewed as being beneficial to couples' self-knowledge, their relationship, and satisfaction with frequency of sexual intercourse. PMID- 28349049 TI - Relationship between Human Immunodeficiency Virus (HIV) Knowledge, HIV-Related Stigma, and HIV Testing among Young Black Adults in a Southeastern City. AB - The southeast is identified as the epicenter of the nation's human immunodeficiency virus (HIV) epidemic, accounting for nearly 44% of all persons living with a HIV diagnosis in the United States. HIV stigma and knowledge have been cited as some of the complex factors increasing risk of acquiring HIV within African-American communities. We sought to understand how HIV knowledge and HIV related stigma impact HIV testing experience among young Black adults who completed a community-based participatory research survey in a Southeastern city. Survey measures were developed with active engagement among the research team and community members, with the goal of balancing community knowledge, interests and concerns with scientific considerations, and the realities of funding and the project timeline. A total of 508 of the 513 audio computer-assisted self interview questionnaires completed were analyzed. Eighty-one percent of participants had ever tested and had an intention-to-test for HIV in the next 12 months. Overall, analyses revealed low HIV-related stigma and relatively moderate to high HIV knowledge among young Black adults in the Southeastern city. Logistic regression indicated that having ever tested for HIV was positively correlated with HIV knowledge [odds ratio (OR): 1.50; 95% confidence interval (CI): 1.23 1.84, p < 0.001], but inversely correlated with low HIV-related stigma (OR: 0.08; 95% CI: 0.01-0.76, p < 0.03). However, there were no significant relationships between HIV-related stigma, HIV knowledge, and intention-to test for HIV in the future. These findings suggest that reducing HIV-related stigma and increasing HIV knowledge are not sufficient in promoting HIV testing (i.e., intention-to test) among young Black adults in this city, unless specific emphasis is placed on addressing internalized HIV-related stigma and misperceptions about HIV prevention and control. PMID- 28349050 TI - Primary Health Care in Nigeria: 24 Years after Olikoye Ransome-Kuti's Leadership. PMID- 28349051 TI - Implementation of a Novel Structured Social and Wellness Committee in a Surgical Residency Program: A Case Study. AB - This article provides a theoretical and practical rational for the implementation of an innovative and comprehensive social wellness program in a surgical residency program at a large safety net hospital on the East Coast of the United States. Using basic needs theory, we describe why it is particularly important for surgical residency programs to consider the residents sense of competence, autonomy, and belonging during residence. We describe how we have developed a comprehensive program to address our residents' (and residents' families) psychological needs for competence, autonomy, and belongingness. PMID- 28349052 TI - Hybrid Methods in Iron-Sulfur Cluster Biogenesis. AB - Hybrid methods, which combine and integrate several biochemical and biophysical techniques, have rapidly caught up in the last twenty years to provide a way to obtain a fuller description of proteins and molecular complexes with sizes and complexity otherwise not easily affordable. Here, we review the use of a robust hybrid methodology based on a mixture of NMR, SAXS, site directed mutagenesis and molecular docking which we have developed to determine the structure of weakly interacting molecular complexes. We applied this technique to gain insights into the structure of complexes formed amongst proteins involved in the molecular machine, which produces the essential iron-sulfur cluster prosthetic groups. Our results were validated both by X-ray structures and by other groups who adopted the same approach. We discuss the advantages and the limitations of our methodology and propose new avenues, which could improve it. PMID- 28349053 TI - Immunomodulatory Effects of Saccharomyces cerevisiae Fermentation Product Supplementation on Immune Gene Expression and Lymphocyte Distribution in Immune Organs in Broilers. AB - A study was conducted to evaluate the molecular and cellular immunomodulatory effects of a Saccharomyces cerevisiae fermentation product (Original XPC, Diamond V) in broilers. Our lab has previously demonstrated that broilers fed XPC generate faster and stronger antigen-specific humoral immune responses to Newcastle disease virus (NDV) vaccination. This study aims at investigating the mechanism behind this increased immunocompetence. One-day-old broilers were randomly assigned to one of two treatments: 1.25 kg/ton S. cerevisiae fermentation product (XPC treatment group) or control diet. Birds were vaccinated against NDV on day 1 (B1 strain) and day 21 (LaSota strain) post-hatch. Innate and adaptive immune-related gene expression profiles in central (thymus and bursa of Fabricius) and peripheral (spleen) immune organs were investigated at 14 and 28 days of age by qPCR array. Fold changes larger than 1.2 (P < 0.05) between treated and control were considered significant. Lymphocyte subpopulations in central and peripheral immune organs and blood leukocytes were analyzed by flow cytometry at 14, 21, 28, and 42 days of age. In the spleen, Th1 immune responses and antiviral genes, such as IFN-gamma, and its downstream genes signal transducer and activator of transcription (STAT4) and NFkappaB, were significantly upregulated in the treated group by 14 days of age. In the thymus, genes belonging to different functional groups were influenced at different time points. Cytokine genes associated with lymphocyte maturation, differentiation, and proliferation, such as IL-1R, IL-2, and IL-15 were significantly upregulated in the treated group by 28 days of age. Genes preferentially expressed in the medulla of the thymus and mature thymocytes, such as Myxovirus resistance gene 1, interferon regulatory factor-1, interferon regulatory factor-7, and STAT1, were upregulated in the birds supplemented with XPC. Birds supplemented with XPC had significantly higher percentages of CD3+, CD4+, and CD8+ T-cells in the thymus at day 28 of age, indicating production of more mature T-cells, which was consistent with gene expression results. Results suggest that XPC supplementation primes broilers to become more immunocompetent, without compromising growth performance. PMID- 28349055 TI - Antiurolithiasis Activity of Bioactivity Guided Fraction of Bergenia ligulata against Ethylene Glycol Induced Renal Calculi in Rat. AB - Dried rhizome of Bergenia ligulata (pashanbhed) is commonly used as a traditional herbal medicine with a wide range of therapeutic applications including urolithiasis. Aqueous extract of B. ligulata was prepared through maceration followed by decoction (mother extract, 35.9% w/w). Further, polarity based fractions were prepared successively from mother extract which yielded 3.4, 2.9, 5.4, 7.5, and 11.3% w/w of hexane, toluene, dichloromethane (DCM), n-butanol, and water fractions, respectively. The in vitro, ex vivo, and real-time antiurolithiasis activity of mother extract and fractions were carried out using aggregation assay in synthetic urine and in rat plasma. The study revealed that DCM fraction has significantly (p < 0.05) greater inhibitory potential than other fractions. Ethylene glycol in drinking water (0.75%, v/v) for 28 days was used for induction of urolithiasis and the curative effects of mother extract and DCM fraction were checked for the level of oxalate, calcium, creatinine, uric acid, and urea of both urine and serum. Treatment with mother extract and DCM fraction at a dose of 185 mg/kg and 7 mg/kg, respectively, in ethylene glycol induced rats resulted in a significant (p < 0.05) decrease in serum and urine markers. Histological study revealed lower number of calcium oxalate deposits with minimum damage in the kidneys of mother extract and DCM fraction treated rats. This result provides a scientific basis for its traditional claims. PMID- 28349054 TI - Impact of Different Analytic Approaches on the Analysis of the Breast Fibroglandular Tissue Using Diffusion Weighted Imaging. AB - Purpose. This study investigated the impact of the different region of interest (ROI) approaches on measurement of apparent diffusion coefficient (ADC) values in the breast firbroglandular tissue (FT). Methods. Breast MR images of 38 women diagnosed with unilateral breast cancer were studied. Percent density (PD) and ADC were measured from the contralateral normal breast. Four different ROIs were used for ADC measurement. The measured PD and ADC were correlated. Results. Among the four ROIs, the manually placed small ROI on FT gave the highest mean ADC (ADC = 1839 +/- 343 [*10-6 mm2/s]), while measurement from the whole breast gave the lowest mean ADC (ADC = 933 +/- 383 [*10-6 mm2/s]). The ADC measured from the whole breast was highly correlated with PD with r = 0.95. In slice-to-slice comparison, the central slices with more FT had higher ADC values than the peripheral slices did, presumably due to less partial volume effect from fat. Conclusions. Our results indicated that the measured ADC heavily depends on the composition of breast tissue contained in the ROI used for the ADC measurements. Women with low breast density showing lower ADC values were most likely due to the partial volume effect of fatty tissues. PMID- 28349056 TI - Maxillary Sinus Augmentation with Decellularized Bovine Compact Particles: A Radiological, Clinical, and Histologic Report of 4 Cases. AB - Background. One of the most problematic regions for endosseous implants is the posterior maxilla, not only having poor bone density, but also lacking adequate vertical height as a result of sinus pneumatization. The purpose of the present study was a radiologic, histological, and histomorphometrical evaluation, in humans, of specimens retrieved from sinuses augmented with decellularized bovine compact particles, after a healing period of 6 months. Methods. Four patients, with atrophic resorbed maxillas, underwent a sinus lift augmentation with decellularized bovine compact bone from bovine femur. The size of the particles used was 0.25-1 mm. A total of four grafts and 5 biopsies were retrieved and processed to obtain thin ground sections with the Precise 1 Automated System. Results. The mean volume after graft elevation calculated for each of the 4 patients was 2106 mm3 in the immediate postoperative period (5-7 days), ranging from 1408.8 to 2946.4 mm3. In the late postoperative period (6 months) it was 2053 mm3, ranging from 1339.9 to 2808.9 mm3. Histomorphometry showed that newly formed bone was 36 +/- 1.6% and marrow spaces were 34 +/- 1.6%, while the residual graft material was 35 +/- 1.4%. Conclusion. In conclusion, based on the outcome of the present study, Re-Bone(r) can be used with success in sinus augmentation procedures and 6 months are considered an adequate time for maturation before implant placement. PMID- 28349057 TI - Interleukin-9 Promotes Pancreatic Cancer Cells Proliferation and Migration via the miR-200a/Beta-Catenin Axis. AB - Background. Both IL-9 and miR-200a are involved in the pathogenesis of cancers; however, the role of IL-9 in pancreatic cancer and the possible underlying mechanisms remain unknown. The aim of this study was to investigate the effect of IL-9 on pancreatic cancer cells and its interaction with miR-200a. Methods. Pancreatic cancer cells (PANC-1 and AsPC-1) were treated with IL-9 and the expression of miR-200a and beta-catenin in pancreatic cancer cells was measured. beta-Catenin was examined as a target gene of miR-200a in pancreatic cancer cells. The interaction between IL-9 and miR-200a in pancreatic cancer cells was determined by infecting miR-200a mimics prior to IL-9 treatment and then measuring miR-200a and beta-catenin expression. Results. IL-9 significantly promoted the proliferation, invasion, and migration of pancreatic cancer cells; however, the effect on pancreatic cancer cell apoptosis was insignificant. beta Catenin was verified as a target gene of miR-200a in pancreatic cancer cells. Overexpression of miR-200a in pancreatic cancer cells significantly attenuated proliferation and metastasis and reduced beta-catenin expression. IL-9 treatment of pancreatic cancer cells decreased miR-200a expression and increased beta catenin expression. The effect of miR-200a on pancreatic cancer cells decreased following IL-9 treatment. Conclusions. IL-9 promotes proliferation and metastasis in pancreatic cancer cells; this effect may partly involve regulation of the miR 200a/beta-catenin axis. PMID- 28349058 TI - Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2) for the Treatment of Nonunion of the Femur in Children and Adolescents: A Retrospective Analysis. AB - Background. The aim of this study was to examine clinical and radiographic healing after rhBMP-2 application in children and adolescents presenting with nonunion of the femur and to investigate the safety of rhBMP-2 use in these cases. Materials and Methods. We reviewed the medical records of five patients with a mean age of 11 years (5.4 to 16.2) with nonunion of the femur who were treated with rhBMP-2 and internal fixation using a locking plate at a single institution. Particular attention was paid to identify all adverse events that may be due to rhBMP-2 use. Results. Union occurred in four of five patients at a mean of 12.1 months (7.9 to 18.9). The locking plates were removed after a mean of 16 months (11 to 23). One patient had nonunion due to deep infection. After a mean follow-up of 62.5 months (17 to 100), union was still evident in all four patients and they were fully weight-bearing without pain. Discussion. In this retrospective study, rhBMP-2 combined with a locking plate has been used successfully to treat children and adolescents with nonunion of the femur in four of five cases. One major complication was thought to be possibly related to its use. PMID- 28349059 TI - Psoralen Inhibited Apoptosis of Osteoporotic Osteoblasts by Modulating IRE1-ASK1 JNK Pathway. AB - Osteoporosis is a common disease causing fracture in older populations. Abnormal apoptosis of osteoblasts contributes to the genesis of osteoporosis. Inhibiting apoptosis of osteoblasts provides a promising strategy to prevent osteoporosis. The proliferation of osteoblasts isolated from osteoporotic patients or healthy subjects was determined by MTT assay. Apoptosis was determined by Annexin V/PI assay. Protein expression was measured by western blot. The proliferation of osteoblasts isolated from osteoporotic patients was inhibited and the apoptosis level of these cells was higher than the osteoblasts from healthy subjects. Incubation with psoralen or estradiol significantly enhanced the proliferation and decreased the apoptosis level of osteoporotic osteoblasts. Western blot demonstrated that psoralen or estradiol treatment downregulated the expression of IRE1, p-ASK, p-JNK, and Bax. Meanwhile, expression of Bcl-2 was upregulated. Pretreatment by IRE1 agonist tunicamycin or JNK agonist anisomycin attenuated the effect of psoralen on osteoporotic osteoblasts. Psoralen inhibited apoptosis of osteoporotic osteoblasts by regulating IRE1-ASK1-JNK pathway. PMID- 28349060 TI - Serum Cytokine Profile in Relation to the Severity of Coronary Artery Disease. AB - Objectives. To investigate the potential association of a set of serum cytokines with the severity of coronary artery disease (CAD). Methods. A total of 201 patients who underwent coronary angiography for chest discomfort were enrolled. The concentrations of serum IFN-gamma, TNF-alpha, IL-2, IL-4, IL-6, IL-10, IL-9, and IL-17 were determined by xMAP multiplex technology. The CAD severity was assessed by Gensini score (GS). Results. The serum levels of TNF-alpha, IL-6, IL 9, IL-10, and IL-17 were significantly higher in high GS group (GS >= 38.5) than those in low GS group (GS < 38.5). Positive correlations were also found between these cytokines and the severity of CAD. After adjustment for other associated factors, three serum cytokines (IL-6, IL-9, and IL-17) and two clinical risk factors (creatinine and LDL-C) were identified as the independent predictors of increased severity of CAD. ROC curve analysis revealed that the logistic regression risk prediction model had a good performance on predicting CAD severity. Conclusions. Combinatorial analysis of serum cytokines (IL-6, IL-9, and IL-17) with clinical risk factors (creatinine and LDL-C) may contribute to the evaluation of the severity of CAD and may help guide the risk stratification of angina patients, especially in primary health facilities and in the catheter lab resource-limited settings. PMID- 28349061 TI - Physicochemical and Biological Characterization of the Proposed Biosimilar Tocilizumab. AB - HS628 has been developed as a proposed biosimilar product of originator tocilizumab (Actemra(r)). An extensive physicochemical and biological characterization was conducted to assess similarity between HS628 and originator tocilizumab. The amino acid sequence was shown to be identical between HS628 and originator tocilizumab. The higher order structure was found to be indistinguishable from originator tocilizumab. Concerning purity and heterogeneity, HS628 was demonstrated to have similar posttranslational modifications, charge heterogeneity, size heterogeneity, and glycosylation to originator tocilizumab. Moreover, HS628 exhibited highly similar binding affinity and antiproliferative activity as well as capability of inhibiting STAT3 phosphorylation compared to originator tocilizumab. Taken together, HS628 can be considered as a highly similar molecule to originator tocilizumab in terms of physicochemical and biological properties. PMID- 28349063 TI - Thermography Improves Clinical Assessment in Patients with Systemic Sclerosis Treated with Ozone Therapy. AB - Objective. Treatment of scleroderma is challenging and limited. The aim of our study was to evaluate the usefulness of thermography in assessment of the clinical condition (joints movability and skin thickness) in clinically advanced patients with systemic sclerosis before and after ozone therapy. Method. The study included 42 patients aged 32 to 73 years with advanced systemic sclerosis hospitalized in the university clinic between 2003 and 2006. Thermography and clinical examinations were conducted at baseline and after two series of bath in water with ozone. Results. The comparison of results showed significant increase in skin temperature by 2.5 degrees C, significant increase in interphalangeal joints movability by 18 degrees, and significant decrease in skin score by 14.7 points. The skin temperature was correlated with skin score (r = -0.59) and joints movability (r = +0.8). Conclusions. Ozone therapy shows positive effect on clinical parameters and skin temperature as measured with thermography. The study indicated possibility of introducing ozonotherapy as an independent therapy in cases with low level of progression or during remission periods and as additional treatment in patients with advanced disease requiring immunosuppressive treatment. Thermography is useful in assessment of skin condition showing strong correlation between skin temperature and clinical parameters. PMID- 28349062 TI - Imaging of Myocardial Fibrosis in Patients with End-Stage Renal Disease: Current Limitations and Future Possibilities. AB - Cardiovascular disease in patients with end-stage renal disease (ESRD) is driven by a different set of processes than in the general population. These processes lead to pathological changes in cardiac structure and function that include the development of left ventricular hypertrophy and left ventricular dilatation and the development of myocardial fibrosis. Reduction in left ventricular hypertrophy has been the established goal of many interventional trials in patients with chronic kidney disease, but a recent systematic review has questioned whether reduction of left ventricular hypertrophy improves cardiovascular mortality as previously thought. The development of novel imaging biomarkers that link to cardiovascular outcomes and that are specific to the disease processes in ESRD is therefore required. Postmortem studies of patients with ESRD on hemodialysis have shown that the extent of myocardial fibrosis is strongly linked to cardiovascular death and accurate imaging of myocardial fibrosis would be an attractive target as an imaging biomarker. In this article we will discuss the current imaging methods available to measure myocardial fibrosis in patients with ESRD, the reliability of the techniques, specific challenges and important limitations in patients with ESRD, and how to further develop the techniques we have so they are sufficiently robust for use in future clinical trials. PMID- 28349064 TI - Reliability of Baropodometry on the Evaluation of Plantar Load Distribution: A Transversal Study. AB - Introduction. Baropodometry is used to measure the load distribution on feet during rest and walking. The aim of this study was to evaluate changes in plantar foot pressures distribution due to period of working and due to stretching exercises of the posterior muscular chain. Methods. In this transversal study, all participants were submitted to baropodometric evaluation at two different times: before and after the working period and before and after stretching the muscles of the posterior chain. Results. We analyzed a total of 54 feet of 27 participants. After the working period, there was an average increase in the forefoot pressure of 0.16 Kgf/cm2 and an average decrease in the hindfoot pressure of 0.17 Kgf/cm2. After stretching the posterior muscular chain, the average increase in the forefoot pressure was 0.56 Kgf/cm2 and the hindfoot average pressure decrease was 0.56 Kgf/cm2. These changes were not statistically significant. Discussion. It was reported that the strength of the Achilles tendon generates greater forefoot load transferred from the hindfoot. In our study, no significant variation in the distribution of plantar pressure was observed. It can be inferred that baropodometry was a reliable instrument to determine the plantar pressure, regardless of the tension of the posterior chain muscles. PMID- 28349065 TI - Banhasasim-Tang Treatment Reduces the Severity of Esophageal Mucosal Ulcer on Chronic Acid Reflux Esophagitis in Rats. AB - The present study was conducted to evaluate both antioxidant and anti inflammatory activity of Banhasasim-tang (BHSST) on chronic acid reflux esophagitis (CRE) model. Rat CRE model was established operatively and then treated with BHSST (1 g/kg body weight per day) for 15 days Esophageal pathological changes were analyzed using macroscopic examination and hematoxylin/eosin staining. The antioxidant and inflammatory protein levels were determined using Western blotting. The administration of BHSST significantly reduced both the overexpression of serum reactive oxygen species (ROS) and an excessive formation of thiobarbituric acid-reactive substances (TBARS) in esophagus tissue. Thus, the severity of esophageal ulcer was lower in BHSST treated rats than control rats on the gross and histological evaluation. Nuclear factor-erythroid 2-related factor 2 (Nrf2) led to the upregulation of antioxidant enzyme including SOD, GPx-1/2, and HO-1 by binding to antioxidant response element (ARE). Moreover, BHSST administration markedly reduced the expression of inflammatory proteins through mitogen-activated protein kinase- (MAPK-) related signaling pathways and decreased significantly the protein expressions of inflammatory mediators and cytokines by inhibition of nuclear factor-kappa B (NF kappaB) activation. Taken together, these results support the fact that BHSST administration can suppress the development of esophageal mucosal ulcer via regulating inflammation through the activation of the antioxidant pathway. PMID- 28349066 TI - Circulating MicroRNAs as Potential Biomarkers of Atrial Fibrillation. AB - Atrial fibrillation (AF) is the most common supraventricular arrhythmia in the population. MicroRNAs (small endogenous noncoding RNAs) are attractive candidates as biomarkers for AF, especially considering that miRNAs are stable and are detected within easily accessible biofluids such as blood. In this review, we selected twelve studies (2012 to 2016) that were classified according to the sample type. We aimed to provide an overview of the role of circulating miRNAs in AF and to discuss the variability of the results, seeking to improve the perspective of the use of miRNAs as potential noninvasive biomarkers for this heart disease. PMID- 28349067 TI - A Noninvasive Score Model for Prediction of NASH in Patients with Chronic Hepatitis B and Nonalcoholic Fatty Liver Disease. AB - Aims. To develop a noninvasive score model to predict NASH in patients with combined CHB and NAFLD. Objective and Methods. 65 CHB patients with NAFLD were divided into NASH group (34 patients) and non-NASH group (31 patients) according to the NAS score. Biochemical indexes, liver stiffness, and Controlled Attenuation Parameter (CAP) were determined. Data in the two groups were compared and subjected to multivariate analysis, to establish a score model for the prediction of NASH. Results. In the NASH group, ALT, TG, fasting blood glucose (FBG), M30 CK-18, CAP, and HBeAg positive ratio were significantly higher than in the non-NASH group (P < 0.05). Multivariate analysis showed that CK-18 M30, CAP, FBG, and HBVDNA level were independent predictors of NASH. Therefore, a new model combining CK18 M30, CAP, FBG, and HBVDNA level was established using logistic regression. The AUROC curve predicting NASH was 0.961 (95% CI: 0.920-1.00, cutoff value is 0.218), with a sensitivity of 100% and specificity of 80.6%. Conclusion. A noninvasive score model might be considered for the prediction of NASH in patients with CHB combined with NAFLD. PMID- 28349068 TI - Reducing Caloric Intake Prevents Ischemic Injury and Myocardial Dysfunction and Affects Anesthetic Cardioprotection in Type 2 Diabetic Rats. AB - Background. Type 2 diabetes mellitus (T2DM) increases the risk of myocardial ischemia, followed by increased perioperative risk of cardiovascular morbidity. We investigated whether reducing caloric intake reduces ischemic injury and myocardial dysfunction and affects the protective effects of the volatile anesthetic sevoflurane in diet-induced T2DM rats. Methods. Rats received a western (WD) or control diet (CD). Caloric intake was reduced by reversing WD-fed rats to CD. Myocardial function was determined with echocardiography. After 8 weeks of diet feeding, myocardial infarction was induced and the effect of sevoflurane was studied on myocardial function and ischemia/reperfusion injury. Results. WD-feeding resulted in a mild T2DM phenotype and myocardial dysfunction. Sevoflurane further impaired systolic function in WD-fed rats. Unexpectedly, WD feeding reduced infarct size compared to CD-feeding. Sevoflurane reduced infarct size in CD-fed rats; however it enlarged infarct size in WD-fed rats. Caloric reduction restored myocardial dysfunction and the protective effect of sevoflurane against ischemia compared to WD-fed rats, whereas the protective effects of WD-feeding persisted. Conclusion. Caloric reduction restored the T2DM phenotype and myocardial function, while the cardioprotective properties of WD feeding or sevoflurane persisted. Our data suggest that reducing caloric intake in T2DM might be a possible intervention to reduce perioperative risk of cardiovascular morbidity. PMID- 28349069 TI - Association between STK11 Gene Polymorphisms and Coronary Artery Disease in Type 2 Diabetes in Han Population in China. AB - Background. Recent studies indicated that the Serine threonine kinase 11 (STK11), which is a key regulator of the AMP-activated protein kinase (AMPK), plays a crucial role in cardiovascular system. This study aimed to investigate whether genetic variations in the STK11 gene affect the risk of coronary artery disease (CAD) in Chinese type 2 diabetics. Methods. 5 haplotype-tagging single nucleotide polymorphisms (SNPs) were selected, and 288 CAD-positive cases and 159 CAD negative controls with type 2 diabetes were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Results. The carriers of minor allele A at rs12977689 had a higher risk of CAD compared to the homozygotes of CC (OR = 1.572, 95% CI = 1.039-2.376, p = 0.035), and the difference was still significant after adjustment for the other known CAD risk factors (OR' = 1.184, 95% CI' = 1.036-1.353, p' = 0.013). Conclusion. Genetic variability at STK11 locus is associated with CAD risk in type 2 diabetes in the Chinese population. PMID- 28349070 TI - Diabetes Is Associated with Increased Autoreactivity of Mannan-Binding Lectin. AB - Mannan-binding lectin (MBL) has been reported to be involved in the pathophysiology of diabetic nephropathy. MBL is a pattern-recognition molecule of the innate immune system that initiates the lectin pathway of the complement system upon recognition of evolutionary conserved pathogen-associated molecular patterns or to altered self-tissue. Our group have previously shown direct effects of MBL on diabetes-induced kidney damage, and we hypothesized that MBL may cause autoactivation of the complement system via binding to neoepitopes induced by hyperglycemia. In the present study, we induced diabetes in MBL knockout mice and in wild type C57BL/6J mice by low-dose streptozotocin injection and measured blood glucose and urine albumin-to-creatinine ratio to monitor development of diabetes. After 24 weeks, fluorescently labelled recombinant MBL was injected intravenously in diabetic MBL knockout mice after which the distribution was investigated using in vivo fluorescence imaging. Mice were subjected to in vivo and ex vivo imaging 24 hours after injection. MBL was found to accumulate in the kidneys of diabetic mice as compared to healthy control mice (p < 0.0001). These findings support the hypothesis of a significant role of MBL and the complement system in the pathophysiology of diabetic nephropathy. PMID- 28349071 TI - Forkhead Protein FoxO1 Acts as a Repressor to Inhibit Cell Differentiation in Human Fetal Pancreatic Progenitor Cells. AB - Our colleagues have reported previously that human pancreatic progenitor cells can readily differentiate into insulin-containing cells. Particularly, transplantation of these cell clusters upon in vitro induction for 3-4 w partially restores hyperglycemia in diabetic nude mice. In this study, we used human fetal pancreatic progenitor cells to identify the forkhead protein FoxO1 as the key regulator for cell differentiation. Thus, induction of human fetal pancreatic progenitor cells for 1 week led to increase of the pancreatic beta cell markers such as Ngn3, but decrease of stem cell markers including Oct4, Nanog, and CK19. Of note, FoxO1 knockdown or FoxO1 inhibitor significantly upregulated Ngn3 and insulin as well as the markers such as Glut2, Kir6.2, SUR1, and VDCC, which are designated for mature beta cells. On the contrary, overexpression of FoxO1 suppressed the induction and reduced expression of these beta cell markers. Taken together, these results suggest that FoxO1 may act as a repressor to inhibit cell differentiation in human fetal pancreatic progenitor cells. PMID- 28349072 TI - Comparable Effects of Brief Resistance Exercise and Isotime Sprint Interval Exercise on Glucose Homeostasis in Men. AB - This study compared the effects of a single bout of resistance exercise (RES) on glycemic homeostasis to isotime sprint interval exercise (SIE) using a within subjects design. Nineteen nondiabetic males (age: 23.3 +/- 0.7 yrs; height: 173.1 +/- 1.2 cm; weight: 79.1 +/- 4.8 kg; % fat: 22.5 +/- 2.5%) were studied. RES involved nine exercises of 10 repetitions at 75% 1-RM using a 2 : 2 s tempo and was interspersed with a one-minute recovery; SIE involved four 30 s' all-out cycling effort interspersed with four minutes of active recovery. Plasma glucose and insulin in response to a 75 g oral glucose tolerance test were assessed 12 h after exercise. In comparison to a no exercise control trial (CON), the area under curve (AUC) of plasma glucose was reduced with both RES and SIE (P < 0.05), while insulin AUC was only reduced with RES. Cederholm, Gutt, Matsuda, and HOMA indices were improved (P < 0.05) following RES compared to CON. Corresponding changes following SIE were only found in Cederholm and Gutt indices (P < 0.05). No difference was found in plasma variables and indices between RES and SIE (P > 0.05). Such findings suggest that the RES may represent a potential alternative to the SIE in the development of time-efficient lifestyle intervention strategies for improving diabetes risk factors in healthy populations. PMID- 28349073 TI - DEPTOR-mTOR Signaling Is Critical for Lipid Metabolism and Inflammation Homeostasis of Lymphocytes in Human PBMC Culture. AB - Abnormal immune response of the body against substances and tissues causes autoimmune diseases, such as polymyositis, dermatomyositis, and rheumatoid arthritis. Irregular lipid metabolism and inflammation may be a significant cause of autoimmune diseases. Although much progress has been made, mechanisms of initiation and proceeding of metabolic and inflammatory regulation in autoimmune disease have not been well-defined. And novel markers for the detection and therapy of autoimmune disease are urgent. mTOR signaling is a central regulator of extracellular metabolic and inflammatory processes, while DEP domain containing mTOR-interacting protein (DEPTOR) is a natural inhibitor of mTOR. Here, we report that overexpression of DEPTOR reduces mTORC1 activity in lymphocytes of human peripheral blood mononuclear cells (PBMCs). Combination of DEPTOR overexpression and mTORC2/AKT inhibitors effectively inhibits lipogenesis and inflammation in lymphocytes of PBMC culture. Moreover, DEPTOR knockdown activates mTORC1 and increases lipogenesis and inflammations. Our findings provide a deep insight into the relationship between lipid metabolism and inflammations via DEPTOR-mTOR pathway and imply that DEPTOR-mTOR in lymphocytes of PBMC culture has the potential to be as biomarkers for the detection and therapies of autoimmune diseases. PMID- 28349075 TI - IgG4-related hypertrophic pachymeningitis coexpressing antineutrophil cytoplasmic antibodies. PMID- 28349074 TI - Dysregulation of MS risk genes and pathways at distinct stages of disease. AB - OBJECTIVE: To perform systematic transcriptomic analysis of multiple sclerosis (MS) risk genes in peripheral blood mononuclear cells (PBMCs) of subjects with distinct MS stages and describe the pathways characterized by dysregulated gene expressions. METHODS: We monitored gene expression levels in PBMCs from 3 independent cohorts for a total of 297 cases (including clinically isolated syndromes (CIS), relapsing-remitting MS, primary and secondary progressive MS) and 96 healthy controls by distinct microarray platforms and quantitative PCR. Differential expression and pathway analyses for distinct MS stages were defined and validated by literature mining. RESULTS: Genes located in the vicinity of MS risk variants displayed altered expression in peripheral blood at distinct stages of MS compared with the healthy population. The frequency of dysregulation was significantly higher than expected in CIS and progressive forms of MS. Pathway analysis for each MS stage-specific gene list showed that dysregulated genes contributed to pathogenic processes with scientific evidence in MS. CONCLUSIONS: Systematic gene expression analysis in PBMCs highlighted selective dysregulation of MS susceptibility genes playing a role in novel and well-known pathogenic pathways. PMID- 28349076 TI - How hot is it Down Under? PMID- 28349077 TI - Electric fan use in heat waves: Turn on or turn off? PMID- 28349078 TI - Imaging and menopausal hot flashes. PMID- 28349079 TI - Timing of activities of daily life is jaggy: How episodic ultradian changes in body and brain temperature are integrated into this process. AB - Charles Darwin noted that natural selection applies even to the hourly organization of daily life. Indeed, in many species, the day is segmented into active periods when the animal searches for food, and inactive periods when the animal digests and rests. This episodic temporal patterning is conventionally referred to as ultradian (<24 hours) rhythmicity. The average time between ultradian events is approximately 1-2 hours, but the interval is highly variable. The ultradian pattern is stochastic, jaggy rather than smooth, so that although the next event is likely to occur within 1-2 hours, it is not possible to predict the precise timing. When models of circadian timing are applied to the ultradian temporal pattern, the underlying assumption of true periodicity (stationarity) has distorted the analyses, so that the ultradian pattern is frequently averaged away and ignored. Each active ultradian episode commences with an increase in hippocampal theta rhythm, indicating the switch of attention to the external environment. During each active episode, behavioral and physiological processes, including changes in body and brain temperature, occur in an integrated temporal order, confirming organization by programs endogenous to the central nervous system. We describe methods for analyzing episodic ultradian events, including the use of wavelet mathematics to determine their timing and amplitude, and the use of fractal-based procedures to determine their complexity. PMID- 28349080 TI - Sago supplementation for exercise performed in a thermally stressful environment: Rationale, efficacy and opportunity. AB - Sago (Metroxylin sagu), a carbohydrate (CHO) based dietary staple of Southeast Asia is easily digestible and quickly absorbed, and thus has potential to be prescribed as an affordable pre-and post-exercise food in this part of the world. Compared to other CHO staples, research into the physiological response to sago ingestion is sparse, and only a few recent studies have investigated its value before, during, and after exercise. The purpose of this review is to describe the published literature pertaining to sago, particularly as a supplement in the peri exercise period, and suggest further avenues of research, principally in an environment/climate which would be experienced in Southeast Asia i.e. hot/humid. PMID- 28349081 TI - Occupational heat stress in Australian workplaces. AB - The aim of this review was to summarize the current state of knowledge on heat stress risk within typical Australian occupational settings. We assessed identified occupations (mining, agriculture, construction, emergency services) for heat production and heat loss potential, and resultant levels of physiological heat strain. A total of 29 reports were identified that assessed in situ work settings in Northern Territory, South Australia, Western Australia, Queensland, New South Wales and Victoria, that measured physiological responses and characterized the thermal environment. Despite workers across all industries being regularly exposed to high ambient temperatures (32-42 degrees C) often coupled with high absolute humidity (max: 33 hPa), physiological strain is generally low in terms of core temperature (<38 degrees C) and dehydration (<1 % reduction in mass) by virtue of the low energy demands of many tasks, and self regulated pacing of work possible in most jobs. Heat stress risk is higher in specific jobs in agriculture (e.g. sheep shearing), deep underground mining, and emergency services (e.g., search/rescue and bushfire fighting). Heat strain was greatest in military-related activities, particularly externally-paced marching with carried loads which resulted in core temperatures often exceeding 39.5 degrees C despite being carried out in cooler environments. The principal driver of core temperature elevations in most jobs is the rate of metabolic heat production. A standardized approach to evaluating the risk of occupational heat strain in Australian workplaces is recommended defining the individual parameters that alter human heat balance. Future research should also more closely examine female workers and occupational activities within the forestry and agriculture/horticulture sector. PMID- 28349083 TI - Periodizing heat acclimation in elite Laser sailors preparing for a world championship event in hot conditions. AB - Purpose : To examine the retention and re-acclimation responses during a periodized heat acclimation (HA) protocol in elite sailors preparing for the 2013 World Championships in Muscat, Oman (~27-30 degrees C, 40-60% RH). Methods : Two elite male Laser class sailors completed 5 consecutive days of HA (60 min per day in 35 degrees C, 60% RH). Heat response tests (HRT) were performed on day 1 and 5 of HA, then 1 (decay 1, D1) and 2 (D2) weeks following HA. Participants were then re-acclimated (RA) for 2 days, within the next week, before a final HRT ~72 h post-RA. Rectal temperature, plasma volume, heart rate, sweat rate, as well as thermal discomfort and rating of perceived exertion were measured during each HRT. Results : Rectal temperature decreased with HA (0.46 +/- 0.05 degrees C), while individual responses following D1, D2 and RA varied. Heart rate (14 +/- 7 bpm), thermal discomfort (0.6 +/- 0.1 AU) and rating of perceived exertion (1.8 +/- 0.6 AU) decreased across HA, and adaptations were retained by D2. Plasma volume steadily increased over the decay period (D2 = 8.0 +/- 1.3%) and after RA (15.5 +/- 1.1%) compared with baseline. RA resulted in further thermoregulatory improvements in each Athlete, although individual adjustments varied. Conclusion : Heat strain was reduced in elite Laser sailors following HA and most thermoregulatory adaptations were retained for 2 weeks afterwards. RA may 'top up' adaptations after 2 weeks of HA decay. PMID- 28349084 TI - Sago supplementation for recovery from cycling in a warm-humid environment and its influence on subsequent cycling physiology and performance. AB - This study determined whether sago porridge ingested immediately after exercise (Exercise 1) in warm-humid conditions (30 +/- 1 degrees C, 71 +/- 4 % RH; 20 km.h 1 frontal airflow) conferred more rapid recovery, as measured by repeat performance (Exercise 2), compared to a control condition. Eight well-trained, male cyclists/triathletes (34 +/- 9 y, VO2peak 70 +/- 10 ml.kg-1.min-1, peak aerobic power 413 +/- 75 W) completed two 15-min time-trials pre-loaded with 15 min warm-up cycling following >24h standardization of training and diet. Mean power output was not different between trials during Exercise 1 (286 +/- 67 vs. 281 +/- 59 W), however, was reduced during Exercise 2 for control (274 +/- 61 W) but not sago (283 +/- 60 W) that led to a significant performance decrement (vs. Exercise 1) of 3.9% for control and an improvement (vs. control) of 3.7% for sago during Exercise 2 (P < 0.05). Sago ingestion was also associated with higher blood glucose concentrations during recovery compared to control. These results indicate that feeding sago during recovery from exercise in a warm-humid environment improves recovery of performance during a subsequent exercise bout when compared to a water-only control. As these effects were larger than the test retest coefficient of variation for work completed during the 15-min time-trial (2.3%) it can be confidently concluded that the observed effects are real. PMID- 28349086 TI - Attenuated cold defense responses in orexin neuron-ablated rats. AB - Recent reports of the use of transgenic mice targeting orexin neurons show that the ablation of orexin neurons in the hypothalamus causes hypothermia during cold exposure. This suggests the importance of orexin neurons for cold-induced autonomic and physiological defense responses, including brown adipose tissue (BAT) thermogenesis and vasoconstriction in thermoregulatory cutaneous vascular bed. The present study investigated whether the ablation of orexin neurons attenuated cold-elicited BAT thermogenesis and cutaneous vasoconstriction. The study took advantage of our established conscious rat experimental model of direct measurement of BAT and body temperature and tail cutaneous blood flow. The study used transgenic orexin neurons-ablated (ORX-AB) rats and wild type (WT) rats. BAT temperature and tail artery blood flow with pre-implanted probes were measured, as well as behavioral locomotor activity under conscious free-moving condition. Gradually, the ambient temperature was decreased to below 5 degrees C. ORX-AB rats showed an attenuated cold-induced BAT thermogenesis and behavioral activity, and delayed tail vasoconstriction. An ambient temperature that initiated BAT thermogenesis and established full cutaneous vasoconstriction was 14.1 +/- 1.9 degrees C, which was significantly lower than 20.5 +/- 1.9 degrees C, the corresponding value in WT rats (n = 10, P < 0.01). The results from this study suggest that the integrity of orexin-synthesising neurons in thermoregulatory networks is important for full expression of the cold defense responses. PMID- 28349085 TI - The effects of a systematic increase in relative humidity on thermoregulatory and circulatory responses during prolonged running exercise in the heat. AB - This study examined the thermoregulatory and circulatory responses, and exercise performance of trained distance runners during exercise in the heat (31 degrees C) at varying relative humidity (RH). In a randomized order, 11 trained male distance runners performed 5 60 min steady-state runs at a speed eliciting 70% of VO2max in RH of 23, 43, 52, 61 and 71%. This was followed immediately with an incremental exercise test to volitional exhaustion. Core (Tre) and mean skin temperature (T-sk), cardiac output (Q), heart rate (HR), and stroke volume (SV) were recorded at regular intervals. A significant (P = 0.003) main effect was detected for RH on mean body temperature (Tb), with a significantly higher Tb detected during steady-state exercise in the 61 and 71% RH compared to that in the 23% RH. During the steady-state exercise, no differences were detected in whole body sweat loss (P = 0.183). However, a significant main effect of RH was observed for HR and SV (P = 0.001 and 0.006, respectively) but not Q (P = 0.156). The time to exhaustion of the incremental exercise test was significantly reduced at 61 and 71% RH compared with 23% RH (P = 0.045 and 0.005, respectively). Despite an increase in dry heat loss, a greater thermoregulatory and circulatory stress was evident during steady-state exercise at 61 and 71% RH. This ultimately limits the capacity to perform the subsequent incremental exercise to exhaustion. This study highlighted that in a warm environment, the range of the prescriptive zone progressively narrows as RH increases. PMID- 28349082 TI - Heat stress and dehydration in adapting for performance: Good, bad, both, or neither? AB - Physiological systems respond acutely to stress to minimize homeostatic disturbance, and typically adapt to chronic stress to enhance tolerance to that or a related stressor. It is legitimate to ask whether dehydration is a valuable stressor in stimulating adaptation per se. While hypoxia has had long-standing interest by athletes and researchers as an ergogenic aid, heat and nutritional stressors have had little interest until the past decade. Heat and dehydration are highly interlinked in their causation and the physiological strain they induce, so their individual roles in adaptation are difficult to delineate. The effectiveness of heat acclimation as an ergogenic aid remains unclear for team sport and endurance athletes despite several recent studies on this topic. Very few studies have examined the potential ergogenic (or ergolytic) adaptations to ecologically-valid dehydration as a stressor in its own right, despite longstanding evidence of relevant fluid-regulatory adaptations from short-term hypohydration. Transient and self-limiting dehydration (e.g., as constrained by thirst), as with most forms of stress, might have a time and a place in physiological or behavioral adaptations independently or by exacerbating other stressors (esp. heat); it cannot be dismissed without the appropriate evidence. The present review did not identify such evidence. Future research should identify how the magnitude and timing of dehydration might augment or interfere with the adaptive processes in behaviorally constrained versus unconstrained humans. PMID- 28349087 TI - How to keep cool in a hot desert: Torpor in two species of free-ranging bats in summer. AB - Small insectivorous tree-roosting bats are among the most taxonomically diverse group of mammals in Australia's desert, yet little is known about their thermal physiology, torpor patterns and roosting ecology, especially during summer. We used temperature-telemetry to quantify and compare thermal biology and roost selection by broad-nosed bats Scotorepens greyii (6.3 g; n = 11) and Scotorepens balstoni (9.9 g; n = 5) in Sturt National Park (NSW Australia) over 3 summers (2010-13). Both vespertilionids used torpor often and the total time bats spent torpid was ~7 h per day. Bats rewarmed using entirely passive rewarming on 44.8% (S. greyii) and 29.4% (S. balstoni) of all torpor arousals. Both bat species roosted in hollow, cracked dead trees relatively close to the ground (~3 m) in dense tree stands. Our study shows that torpor and passive rewarming are 2 common and likely crucial survival traits of S. greyii and S. balstoni. PMID- 28349089 TI - Thermoregulation as a non-unified system: A difficult to teach concept. PMID- 28349088 TI - Marsupials don't adjust their thermal energetics for life in an alpine environment. AB - Marsupials have relatively low body temperatures and metabolic rates, and are therefore considered to be maladapted for life in cold habitats such as alpine environments. We compared body temperature, energetics and water loss as a function of ambient temperature for 4 Antechinus species, 2 from alpine habitats and 2 from low altitude habitats. Our results show that body temperature, metabolic rate, evaporative water loss, thermal conductance and relative water economy are markedly influenced by ambient temperature for each species, as expected for endothermic mammals. However, despite some species and individual differences, habitat (alpine vs non-alpine) does not affect any of these physiological variables, which are consistent with those for other marsupials. Our study suggests that at least under the environmental conditions experienced on the Australian continent, life in an alpine habitat does not require major physiological adjustments by small marsupials and that they are physiologically equipped to deal with sub-zero temperatures and winter snow cover. PMID- 28349090 TI - The importance of body temperature: An anesthesiologist's perspective. PMID- 28349091 TI - UCP1 and T3: A key "(un)couple" in energy balance. PMID- 28349092 TI - The TRPM2 channel in temperature detection and thermoregulation. PMID- 28349093 TI - Regulation of thermoTRPs by lipids. AB - The family of Transient Receptor Potential (TRP) ion channels is constituted by 7 subfamilies among which are those that respond to temperature, the thermoTRPs. These channels are versatile molecules of a polymodal nature that have been shown to be modulated in various fashions by molecules of a lipidic nature. Some of these molecules interact directly with the channels on specific regions of their structures and some of these promote changes in membrane fluidity or modify their gating properties in response to their agonists. Here, we have discussed how some of these lipids regulate the activity of thermoTRPs and included some of the available evidence for the molecular mechanisms underlying their effects on these channels. PMID- 28349094 TI - Current concepts of active vasodilation in human skin. AB - In humans, an increase in internal core temperature elicits large increases in skin blood flow and sweating. The increase in skin blood flow serves to transfer heat via convection from the body core to the skin surface while sweating results in evaporative cooling of the skin. Cutaneous vasodilation and sudomotor activity are controlled by a sympathetic cholinergic active vasodilator system that is hypothesized to operate through a co-transmission mechanism. To date, mechanisms of cutaneous active vasodilation remain equivocal despite many years of research by several productive laboratory groups. The purpose of this review is to highlight recent advancements in the field of cutaneous active vasodilation framed in the context of some of the historical findings that laid the groundwork for our current understanding of cutaneous active vasodilation. PMID- 28349095 TI - Cooling interventions for athletes: An overview of effectiveness, physiological mechanisms, and practical considerations. AB - Exercise-induced increases in core body temperature could negative impact performance and may lead to development of heat-related illnesses. The use of cooling techniques prior (pre-cooling), during (per-cooling) or directly after (post-cooling) exercise may limit the increase in core body temperature and therefore improve exercise performance. The aim of the present review is to provide a comprehensive overview of current scientific knowledge in the field of pre-cooling, per-cooling and post-cooling. Based on existing studies, we will discuss 1) the effectiveness of cooling interventions, 2) the underlying physiological mechanisms and 3) practical considerations regarding the use of different cooling techniques. Furthermore, we tried to identify the optimal cooling technique and compared whether cooling-induced performance benefits are different between cool, moderate and hot ambient conditions. This article provides researchers, physicians, athletes and coaches with important information regarding the implementation of cooling techniques to maintain exercise performance and to successfully compete in thermally stressful conditions. PMID- 28349096 TI - Hyperthermia and cardiovascular strain during an extreme heat exposure in young versus older adults. AB - We examined whether older individuals experience greater levels of hyperthermia and cardiovascular strain during an extreme heat exposure compared to young adults. During a 3-hour extreme heat exposure (44 degrees C, 30% relative humidity), we compared body heat storage, core temperature (rectal, visceral) and cardiovascular (heart rate, cardiac output, mean arterial pressure, limb blood flow) responses of young adults (n = 30, 19-28 years) against those of older adults (n = 30, 55-73 years). Direct calorimetry measured whole-body evaporative and dry heat exchange. Body heat storage was calculated as the temporal summation of heat production (indirect calorimetry) and whole-body heat loss (direct calorimetry) over the exposure period. While both groups gained a similar amount of heat in the first hour, the older adults showed an attenuated increase in evaporative heat loss (p < 0.033) in the first 30-min. Thereafter, the older adults were unable to compensate for a greater rate of heat gain (11 +/- 1 ; p < 0.05) with a corresponding increase in evaporative heat loss. Older adults stored more heat (358 +/- 173 kJ) relative to their younger (202 +/- 92 kJ; p < 0.001) counterparts at the end of the exposure leading to greater elevations in rectal (p = 0.043) and visceral (p = 0.05) temperatures, albeit not clinically significant (rise < 0.5 degrees C). Older adults experienced a reduction in calf blood flow (p < 0.01) with heat stress, yet no differences in cardiac output, blood pressure or heart rate. We conclude, in healthy habitually active individuals, despite no clinically observable cardiovascular or temperature changes, older adults experience greater heat gain and decreased limb perfusion in response to 3-hour heat exposure. PMID- 28349097 TI - Vagal afferent activation decreases brown adipose tissue (BAT) sympathetic nerve activity and BAT thermogenesis. AB - In urethane/alpha-chloralose anesthetized rats, electrical stimulation of cervical vagal afferent fibers inhibited the increases in brown adipose tissue sympathetic nerve activity and brown adipose tissue thermogenesis evoked by cold exposure, by nanoinjection of the GABAA receptor antagonist, bicuculline, in the dorsomedial hypothalamus, and by nanoinjection of N-methyl-D-aspartate in the rostral raphe pallidus. Vagus nerve stimulation-evoked inhibition of brown adipose tissue sympathetic nerve activity was prevented by blockade of ionotropic glutamate receptors in the termination site of vagal afferents in the nucleus of the solitary tract, and by nanoinjection of GABAA receptor antagonists in the rostral raphe pallidus. In conclusion, the brown adipose tissue sympathoinhibitory effect of cervical afferent vagal nerve stimulation is mediated by glutamatergic activation of second-order sensory neurons in the nucleus of the solitary tract and by a GABAergic inhibition of brown adipose tissue sympathetic premotor neurons in the rostral raphe pallidus, but does not require GABAergic inhibition of the brown adipose tissue sympathoexcitatory neurons in the dorsomedial hypothalamus. PMID- 28349098 TI - Dataset on the importation of the exotic shrimp Penaeus vannamei broodstock (Boone, 1931) to India. AB - Penaeus vannamei is an exotic shrimp species that has gained high culture momentum, since its introduction to India [1]. Currently, the culture of the species in the Country is being done by the shrimp farmers by importation of Specific Pathogen Free (SPF) vannamei broodstock from approved suppliers, which are located overseas. The value of one brooder normally ranges from 50 to 61 US $, excluding the custom duty, processing fee and other charges for the transboundary shipment of the stock to India. The P. vannamei stock are permitted to be imported to the Country by the hatchery operators only through the single declared port of entry, i.e. Chennai in Tamil Nadu in the Country. The imported parent shrimps are then to be quarantined at the Aquatic Quarantine Facility before being transported to the vannamei hatcheries [2]. This article reports the data available on import of vannamei broodstock to India since its importation to India in 2009. The dataset presented here contains information on transit and quarantine mortality of the brooders following the shipment of the stock by the various broodstock suppliers from the overseas. PMID- 28349099 TI - Draft genome of the fungus-growing termite pathogenic fungus Ophiocordyceps bispora (Ophiocordycipitaceae, Hypocreales, Ascomycota). AB - This article documents the public availability of genome sequence data and assembled contigs representing the partial draft genome of Ophiocordyceps bispora. As one of the few known pathogens of fungus-farming termites, a draft genome of O. bispora represents the opportunity to further the understanding of disease and resistance in these complex termite societies. With the ongoing attempts to resolve the taxonomy of the Hypocralaean family, more genetic data will also help to shed light on the phylogenetic relationship between sexual and asexual life stages. Next generation sequence data is available from the European Nucleotide Archive (ENA) under accession PRJEB13655; run numbers: ERR1368522, ERR1368523, and ERR1368524. Genome assembly available from ENA under accession numbers: FKNF01000001-FKNF01000302. Gene prediction available as protein fasta, nucleotide fasta and GFF file from Mendeley Data with accession doi:10.17632/r99fd6g3s4.2 (http://dx.doi.org/10.17632/r99fd6g3s4.2). PMID- 28349100 TI - A dataset of housing market and self-attitudes towards housing location choices in Alexandria, Egypt. AB - A survey, of sample size 224, is designed to include the different related factors to housing location choice, such as; socioeconomic factors, housing characteristics, travel behavior, current self-selection factors, housing demand and future location preferences. It comprises 16 questions, categorized into three different sections; socioeconomic (5 Questions), current dwelling unit characteristics (7 Questions), and housing demand characteristics (4 Questions). The first part, socioeconomic, covers the basic information about the respondent, such as; age, gender, marital status, employment, and car ownership. While the second part, current dwelling unit characteristics, covers different aspect concerning the residential unit typology, financial aspects, and travel behavior of the respondent. It includes the tenure types of the residential unit, estimation of the unit price (in the case of ownership or renting), housing typologies, the main reason for choosing the unit, in case of working, the modes of travel to work, and time to reach it, residential mobility in the last decade, and the ownership of any other residential units. The last part, housing demand characteristics, covers the size of the demand for a residential unit, preference in living in a certain area and the reason to choose it, and the preference of residential unit's tenure. This survey is a representative sample for the population in Alexandria, Egypt. The data in this article is represented in: How do people select their residential locations in Egypt? The case of Alexandria; JCIT1757. PMID- 28349102 TI - A novel dataset on horizontal property rights in 126 jurisdictions. AB - The law and the economy are deeply influenced by horizontal property rights, which are the rules regulating legal direct and indirect takings between private parties. To foster research on the determinants and impact of these institutions, we illustrate here a novel data set partially employed in (Dari-Mattiacci, Giuseppe, Carmine Guerriero, 2015; Dari-Mattiacci, Giuseppe, Carmine Guerriero, Zhenxing Huang, 2016) [3], [4], and (Guerriero Carmine, 2016) [6] and describing the acquisition of ownership through adverse possession of personal and real property and the use of government takings to transfer real property from a private party to another private party in 126 jurisdictions. These data are based on the laws and judicial decisions prevailing in each jurisdiction between 1981 and 2011. PMID- 28349101 TI - Data of self-made Taq DNA polymerase prepared for screening purposes. AB - DNA analysis is a key procedure in genetic engineering. Nowadays the analysis is often done by PCR with Taq DNA polymerase. Although the last enzyme price is quite low, demand for numerous analyses results in much money expenditure which are not affordable for many laboratories. In a meanwhile, many screening tasks do not require the highly purified enzyme. Taking into account the enzyme unique properties it makes possible to marginally simplify its production without resorting to costly or lengthy techniques such as column chromatography and/or dialysis. Here the data of routine usage of Taq DNA polymerase prepared according to the protocol developed in our laboratory is presented. The protocol takes only several hours to realize and does not need qualified personnel or expensive equipment. Yet it gives the enzyme preparation suitable for most screening purposes. The isolated Taq DNA polymerase stock can be stored as ammonium sulfate suspension in a refrigerator for prolonged period, not less than 6 months. The working enzyme solution is prepared from the stock suspension on demand, not more than once in a month and can be stored also in a refrigerator. PMID- 28349103 TI - Data on chemical activation of Wnt/beta-catenin during axolotl limb regeneration. AB - Limb amputation in axolotls was performed to obtain data demonstrating that a chemical agonist of Wnt (int-related protein)/beta-catenin signalling can have a role in axolotl limb regeneration (Wischin et al., 2017) [1]. The data revealed that active beta-catenin protein was present during limb regeneration in some Leydig cells in the epithelium; after the chemical treatment, it was observed in more Leydig cells. In addition, the chemical agonist of Wnt generated distinct limb malformation. PMID- 28349104 TI - Calculation of statistic estimates of kinetic parameters from substrate uncompetitive inhibition equation using the median method. AB - We provide initial rate data from enzymatic reaction experiments and tis processing to estimate the kinetic parameters from the substrate uncompetitive inhibition equation using the median method published by Eisenthal and Cornish Bowden (Cornish-Bowden and Eisenthal, 1974; Eisenthal and Cornish-Bowden, 1974). The method was denominated the direct linear plot and consists in the calculation of the median from a dataset of kinetic parameters Vmax and Km from the Michaelis Menten equation. In this opportunity we present the procedure to applicate the direct linear plot to the substrate uncompetitive inhibition equation; a three parameter equation. The median method is characterized for its robustness and its insensibility to outlier. The calculations are presented in an Excel datasheet and a computational algorithm was developed in the free software Python. The kinetic parameters of the substrate uncompetitive inhibition equation Vmax , Km and Ks were calculated using three experimental points from the dataset formed by 13 experimental points. All the 286 combinations were calculated. The dataset of kinetic parameters resulting from this combinatorial was used to calculate the median which corresponds to the statistic estimator of the real kinetic parameters. A comparative statistical analyses between the median method and the least squares was published in Valencia et al. [3]. PMID- 28349105 TI - SRM dataset of the proteome of inactivated iron-sulfur cluster biogenesis regulator SufR in Synechocystis sp. PCC 6803. AB - This article contains SRM proteomics data related to the research article entitled"Inactivation of iron-sulfur cluster biogenesis regulator SufR in Synechocystis sp. PCC 6803 induces unique iron-dependent protein-level responses" (L. Vuorijoki, A. Tiwari, P. Kallio, E.M. Aro, 2017) [1]. The data described here provide comprehensive information on the applied SRM assays, together with the results of quantifying 94 Synechocystis sp. PCC 6803 proteins. The data has been deposited in Panorama public (https://panoramaweb.org/labkey/SufR) and in PASSEL under the PASS00765 identifier (http://www.peptideatlas.org/PASS/PASS00765). PMID- 28349106 TI - Viscoplastic properties of laponite-CMC mixes. AB - In this dataset, 15 samples of laponite-CMC mixes were realized and their viscoplastic properties are determined. Rheological parameters are then expressed as a function of age and components concentrations. PMID- 28349107 TI - Data on IL-10R neutralization-induced chronic colitis in Lipocalin 2 deficient mice on BALB/c background. AB - The data herein is related to the research article entitled "Microbiota-inducible Innate Immune, Siderophore Binding Protein Lipocalin 2 is Critical for Intestinal Homeostasis" (Singh et al., 2016) [1] where we have demonstrated that C57BL/6 Lipocalin 2 deficient mice (Lcn2KO) developed chronic colitis upon anti interleukin-10 receptor (alphaIL-10R) monoclonal antibody administration. In the present article, we evaluated the susceptibility of BALB/c Lcn2KO mice and their WT littermates to the alphaIL-10R neutralization-induced chronic colitis. Our data showed that alphaIL-10R mAb-treated BALB/c Lcn2KO mice exhibited severe chronic colitis (i.e., splenomegaly, colomegaly, colonic pathology, and incidence of rectal prolapse) when compared to WT mice. PMID- 28349108 TI - Power analysis dataset for QCA based multiplexer circuits. AB - Power consumption in irreversible QCA logic circuits is a vital and a major issue; however in the practical cases, this focus is mostly omitted.The complete power depletion dataset of different QCA multiplexers have been worked out in this paper. At -271.15 degrees C temperature, the depletion is evaluated under three separate tunneling energy levels. All the circuits are designed with QCADesigner, a broadly used simulation engine and QCAPro tool has been applied for estimating the power dissipation. PMID- 28349109 TI - Data on solar sunburning ultraviolet (UVB) radiation at an urban Mediterranean climate. AB - This article describes data on the intensity of ultraviolet B (UVB) radiation collected during field questionnaire-based surveys in Athens, Greece. The surveys were conducted over 11 days of July and October 2010 at three different urban, outdoor sites. A total of 1104 interviews were conducted. The participants were asked to report whether they felt they got a sunburn at the moment of the interview. Questions related to personal characteristics including skin type and exposure time (visit duration at the interview site) were also included in the questionnaire. PMID- 28349110 TI - Data on the weights, specific gravities and chemical compositions of potato (Solanum tuberosum) tubers for food processing from different areas of Hokkaido, Japan. AB - This data article provides the weights, specific gravities and chemical compositions (moisture, protein, fat, ash, and carbohydrate) of potato tubers, for food processing use, from the Tokachi, Kamikawa and Abashiri areas of Hokkaido, Japan. Potato tubers of four cultivars ('Toyoshiro', 'Kitahime', 'Snowden' and 'Poroshiri') were employed in the current study. The weights and specific gravities of potato tubers from each cultivar, harvested from three areas, were measured, and those of near average weight and specific gravity from each group were analyzed for their chemical composition. In this article, weight, specific gravity, and chemical composition data are provided in tables. PMID- 28349112 TI - Treatment of alopecia universalis with oral alitretinoin: A case report. PMID- 28349111 TI - Dataset of the human homologues and orthologues of lipid-metabolic genes identified as DAF-16 targets their roles in lipid and energy metabolism. AB - The data presented in this article are related to the review article entitled 'Unravelling the role of fatty acid metabolism in cancer through the FOXO3-FOXM1 axis' (Saavedra-Garcia et al., 2017) [24]. Here, we have matched the DAF-16/FOXO3 downstream genes with their respective human orthologues and reviewed the roles of these targeted genes in FA metabolism. The list of genes listed in this article are precisely selected from literature reviews based on their functions in mammalian FA metabolism. The nematode Caenorhabditis elegans gene orthologues of the genes are obtained from WormBase, the online biological database of C. elegans. This dataset has not been uploaded to a public repository yet. PMID- 28349113 TI - Expanding phenotype of hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis caused by FAM111B mutations: Report of an additional family raising the question of cancer predisposition and a short review of early-onset poikiloderma. PMID- 28349114 TI - Comprehensive genomic profiling (CGP) of ovarian clear cell carcinomas (OCCC) identifies clinically relevant genomic alterations (CRGA) and targeted therapy options. AB - *MTOR pathway genes are often mutated in ovarian clear cell carcinomas (OCCC).*11.2% of OCCC have targetable alterations only in the mTOR pathway.*MTOR pathway mutations in OCCC can underlie robust, lasting responses to everolimus. PMID- 28349115 TI - Posterior reversible encephalopathy syndrome (PRES) associated with ovarian cancer and voltage-gated potassium channel antibodies: A case report. AB - *We report a case of PRES in conjunction with high grade serous ovarian carcinoma*There is a documented association between chemotherapy agents and PRES*Paraneoplastic panel was positive for voltage-gated potassium channel antibodies*Paraneoplastic workup may be justified in cases with high suspicion of PRES. PMID- 28349116 TI - Poorly differentiated high-grade urothelial carcinoma presenting as Paget's disease of the vulva with no overt urinary tract neoplasm detected. AB - OBJECTIVE: There are few reported cases of secondary (non-cutaneous) vulvar Paget's disease related to urothelial carcinoma (UC), with only 7 of them presenting initially with Paget's disease and up to a 13-year lapse from detecting a urinary tract neoplasm after the onset of symptoms. This is a case of Paget's disease of urothelial origin with no urinary tract neoplasm detected on initial presentation. METHODS: This is a 59-year-old African-American female who presented with worsening eczematous lesions for two years. She had no symptoms suggestive of UC. Initial biopsies showed poorly differentiated high-grade UC with pagetoid changes. RESULTS: Stains showed immunoreactivity for CK7, uroplakin III, p16 and p63 with negative CK20 expression. This staining pattern is characteristic of pagetoid urothelial intraepithelial lesion, now listed as secondary Paget's disease. Biopsies showed GATTA3 positivity suggestive of urothelial origin. Both GCDFP-15 and CEA were negative, which are normally expressed by Paget cells of the primary (cutaneous) type. A follow-up cystoscopy was unremarkable. The patient underwent a partial radical vulvectomy with bilateral lymphadenectomy for extensive disease. Final pathology confirmed infiltrating high-grade UC with overlying epidermis displaying pagetoid in-situ tumor component. CONCLUSION: This is a rare case of secondary Paget's disease of urothelial origin where there was no concurrent UC nor did the patient present with symptoms suggestive of a urinary tract malignancy. In initial presentations of vulvar Paget's disease, it is important to be aware of the secondary classification because it warrants investigation of surrounding structures to rule out underlying malignancies that are or have not yet become clinically apparent. PMID- 28349117 TI - Anogenital lichen sclerosus: Change of tissue position as pathogenetic factor. AB - *Lichen sclerosus in females primarily involves the hairless anogenital skin.*Skin tissue outside this area is constitutionally not at risk for lichen sclerosus.*Transplantation into the vulvar field may turn skin susceptible to lichen sclerosus.*Tissue inherent positional information might affect lichen sclerosus susceptibility. PMID- 28349118 TI - Vulvar condylomatosis after sex reassignment surgery in a male-to-female transsexual: Complete response to imiquimod cream. AB - BACKGROUND: The number of patients seeking sex reassignment surgery is increasing. Approximately 1:30,000 adult males and 1: 100,000 adult females seek this procedure. Neovaginal-related disorders after sex reassignment surgery are increasingly more common. Vulvar condylomatosis is the clinical manifestation of HPV 6- and 11 infection in biological women. The same HPV-subtypes are associated with anogenital warts and penile intraepithelial neoplasia in biological men. We aim to present a case of vulvar condylomatosis after sex reassignment surgery in a male-to-female transsexual and its complete response to 5% imiquimod cream. CASE: We describe a case of a 19-year-old female transexual who presented one year after male to female sex reassignment surgery by inverted penile skin vaginoplasty with condyloma accuminata of the vulva. The patient had a complete response to imiquimod 5% cream 12 weeks after initiation of treatment. CONCLUSION: Gynecologists should be prepared to treat neovaginal-related disorders in male-to-female transsexuals. PMID- 28349120 TI - Variability in medication taking is associated with cognitive performance in nondemented older adults. AB - Interventions to slow cognitive decline typically can do little to reverse decline. Thus, early detection methods are critical. However, tools like cognitive testing are time consuming and require costly expertise. Changes in activities of daily living such as medication adherence may herald the onset of cognitive decline before clinical standards. Here, we determine the relationship between medication adherence and cognitive function in preclinical older adults. We objectively assessed medication adherence in 38 older adults (mean age 86.7 +/ 6.9 years). Our results demonstrate that individuals with lower cognitive function have more spread in the timing of taking their medications (P = .014) and increase the spread in the timing of taking their medications over time (P = .012). These results demonstrate that continuous monitoring of medication adherence may provide the opportunity to identify patients experiencing slow cognitive decline in the earliest stages when pharmacologic or behavioral interventions may be most effective. PMID- 28349119 TI - A multinational study distinguishing Alzheimer's and healthy patients using cerebrospinal fluid tau/Abeta42 cutoff with concordance to amyloid positron emission tomography imaging. AB - INTRODUCTION: Changes in cerebrospinal fluid (CSF) tau and amyloid beta (Abeta)42 accompany development of Alzheimer's brain pathology. Robust tau and Abeta42 immunoassays were developed to establish a tau/Abeta42 cutoff distinguishing mild to-moderate Alzheimer's disease (AD) subjects from healthy elderly control (HC) subjects. METHODS: A CSF tau/Abeta42 cutoff criteria was chosen, which distinguished the groups and maximized concordance with amyloid PET. Performance was assessed using an independent validation cohort. RESULTS: A tau/Abeta42 = 0.215 cutoff provided 94.8% sensitivity and 77.7% specificity. Concordance with PET visual reads was estimated at 86.9% in a ~50% PET positive population. In the validation cohort, the cutoff demonstrated 78.4% sensitivity and 84.9% specificity to distinguish the AD and HC populations. DISCUSSION: A tau/Abeta42 cutoff with acceptable sensitivity and specificity distinguished HC from mild-to moderate AD subjects and maximized concordance to brain amyloidosis. The defined cutoff demonstrated that CSF analysis may be useful as a surrogate to imaging assessment of AD pathology. PMID- 28349121 TI - Cloacael Carriage and Multidrug Resistance Escherichia coli O157:H7 from Poultry Farms, Eastern Ethiopia. AB - A cross-sectional study was carried out to determine antimicrobial drug resistance patterns of E. coli O157:H7 isolates and estimate the level of the pathogen. A total of 194 cloacae swab samples were collected randomly in two poultry farms. Standard cultural, biochemical, and serological (latex agglutination) methods were used to isolate E. coli O157:H7. The isolates were subjected to antimicrobial susceptibility testing using disc diffusion method. Out of 194 cloacae samples examined, 13.4% (n = 26) were found to be positive for E. coli O157:H7. The finding indicated differences in E. coli O157:H7 infection among the different risk factors. Chicken from Adele Poultry Farm showed higher E. coli O157:H7 infection (OR = 3.89) than Haramaya University poultry farm and young birds had more infection (OR = 4.62) than adult birds. Of the total 14 antimicrobials included in the panel of study, the susceptibility results were varied with 96.15% and 0% E. coli O157:H7 isolates expressing resistance to erythromycin, clindamycin, spectinomycin, and ciprofloxacin, respectively. Multidrug resistance to more than two antimicrobial agents was detected in 24 (92.30%) of the isolates. The study showed high presence of antimicrobial resistant isolates of E. coli O157:H7. Further study is required to better understand the ecology and evolution of bacterial resistance to antimicrobial agents. PMID- 28349122 TI - Prediction of Hepatocellular Preservation Injury Immediately Before Human Liver Transplantation by Controlled Oxygenated Rewarming. PMID- 28349123 TI - Outcomes of Kidney Transplant Recipients With Percutaneous Ureteral Interventions: A Single-Center Study. AB - BACKGROUND: Long-term outcomes of kidney transplantation recipients with percutaneous ureteral management of transplant ureteral complications are not well characterized. METHODS: Electronic records of 1753 recipients of kidney alone transplant between January 2000 and December 2008 were reviewed. One hundred thirty-one patients were identified to have undergone percutaneous ureteral management, with placement of percutaneous nephrostomy tube or additional intervention (nephroureteral stenting and/or balloon dilation). Indications for intervention included transplant ureteral stricture or ureteral leak. Kaplan-Meier survival curves and multivariable regression modeling were performed to determine survival outcomes. RESULTS: Kaplan- Meier graft survival (P = 0.04) was lower in patients with percutaneous ureteral intervention for transplant ureteral complication. Graft survival at 1, 5, and 10 years was 94.3% 78.3%, and 59.1% for no intervention and 97.2%, 72.1%, and 36.2% for intervention cohort. Patient survival (P = 0.69) was similar between cohorts. Multivariate analysis demonstrated no association with graft failure (hazard ratio, 1.21; 95% confidence interval, 0.67-2.19; P = 0.53) or patient death (hazard ratio, 0.56; 95% confidence interval, 0.22-1.41; P = 0.22) in intervention group. The major cause of graft failure was infection for percutaneous ureteral intervention group (20.4%) and chronic rejection for those without intervention (17.3%). CONCLUSIONS: Kidney transplant recipients with percutaneous ureteral interventions for ureteral complications do not have a significant difference in graft and patient survival outcomes. Therefore, aggressive nonoperative management can be confidently pursued in the appropriate clinical setting. PMID- 28349124 TI - Alemtuzumab Induction and Delayed Acute Rejection in Steroid-Free Simultaneous Pancreas-Kidney Transplant Recipients. AB - BACKGROUND: The optimal immunosuppressive regimen in simultaneous pancreas-kidney transplant (SPKT) recipients that prevents acute rejection episodes (AREs) and allows optimal outcome remains elusive. METHODS: This cohort study assessed incidence and time to AREs in 73 consecutive SPKT recipients receiving alemtuzumab induction and steroid-free maintenance with tacrolimus and mycophenolate mofetil. A cohort with single high-dose antithymocyte globulin (ATG; n = 85) and triple therapy served as controls. In addition, we provided mechanistic insights in AREs after alemtuzumab depletion, including composition and alloreactivity of lymphocytes (flow cytometry and mixed lymphocyte reaction) plasma alemtuzumab levels (enzyme-linked immunosorbent assay), and maintenance drug exposure. RESULTS: Overall number of AREs at 3 years was significantly lower with alemtuzumab versus ATG induction (26.0% vs 43.5%; adjusted hazard ratio, 0.38; P = 0.029). Most AREs (94.6%) with ATG occurred within the first month, whereas 84.2% of AREs with alemtuzumab occurred beyond 3 months. Patients with and without an ARE in the steroid-free alemtuzumab group showed no differences in composition of lymphocytes, or in alemtuzumab levels. Of note, more than two thirds of these AREs were preceded by empiric tacrolimus and/or mycophenolate mofetil dose adjustments due to viral infections, leukopenia, or gastrointestinal symptoms. CONCLUSIONS: Alemtuzumab induction resulted in a significant lower incidence of AREs. Empiric dose adjustments beyond 3 months in the absence of steroids carry a significant risk for subsequent rejection in SPKT recipients. PMID- 28349125 TI - Application of Operational Tolerance Signatures Are Limited by Variability and Type of Immunosuppression in Renal Transplant Recipients: A Cross-Sectional Study. AB - BACKGROUND: Renal transplant recipients (RTR) frequently develop complications relating to chronic immunosuppression. Identifying RTR who could safely reduce immunosuppression is therefore highly desirable. We hypothesized that "signatures" described in RTR who have stopped immunosuppression but maintained stable graft function ("operational tolerance") may enable identification of immunosuppressed RTR who are candidates for immunosuppression minimization. However, the effect of immunosuppression itself on these signatures and circulating B-cell populations is currently unknown. METHODS: We undertook a cross-sectional study of 117 RTR to assess the effect of immunosuppression upon circulating B cell populations, humoral alloresponse and 2 previously published "signatures" of operational tolerance. RESULTS: Immunosuppression associated with alterations in both published "signatures." Azathioprine associated with a decrease in transitional and naive B-cell numbers and calcineurin inhibition associated with an increase in the number of circulating plasmablasts. However, only azathioprine use associated with the presence of donor-specific anti-HLA IgG antibodies. Calcineurin inhibition associated with an increase in total serum IgM but not IgG. Data were corrected for age, time since last transplant, and other immunosuppression. CONCLUSIONS: Current signatures of operational tolerance may be significantly affected by immunosuppressive regimen, which may hinder use in their current form in clinical practice. Calcineurin inhibition may prevent the development of long-lasting humoral alloresponses, whereas azathioprine therapy may be associated with donor specific antibody development. PMID- 28349126 TI - Genetics of stroke in a UK African ancestry case-control study: South London Ethnicity and Stroke Study. AB - OBJECTIVE: Despite epidemiologic data showing an increased stroke incidence in African ancestry populations, genetic studies in this group have so far been limited, and there has been little characterization of the genetic contribution to stroke liability in this population, particularly for stroke subtypes. METHODS: We evaluated the evidence that genetic factors contribute to stroke and stroke subtypes in a population of 917 African and African Caribbean stroke cases and 868 matched controls from London, United Kingdom. We (1) estimated the heritability of stroke in this population using genomic-relatedness matrix restricted maximum likelihood approaches, (2) assessed loci associated with stroke in Europeans in our population, and (3) evaluated the influence of genetic factors underlying cardiovascular risk factors on stroke using polygenic risk scoring. RESULTS: Our results indicate a substantial genetic contribution to stroke risk in African ancestry populations (h2 = 0.35 [SE = 0.19], p = 0.043). Polygenic risk scores indicate that cardiovascular risk scores contribute to the genetic liability (odds ratio [OR] 1.09 [95% confidence interval (CI) 1.01-1.17], p = 0.029) and point to a strong influence of type 2 diabetes in large vessel stroke (OR 1.62 [95% CI 1.19-2.22], p = 0.0024). Single nucleotide polymorphisms associated with ischemic stroke in Europeans shared direction of effect in SLESS (p = 0.031), suggesting that disease mechanisms are shared across ancestries. CONCLUSIONS: Stroke in African ancestry populations is highly heritable and influenced by genetic determinants underlying cardiovascular risk factors. In addition, stroke loci identified in Europeans share direction of effect in African populations. Future genome-wide association studies must focus on incorporating African ancestry individuals. PMID- 28349128 TI - Towards better environmental performance of wastewater sludge treatment using endpoint approach in LCA methodology. AB - The aim of this study is to use the life cycle assessment method to measure the environmental performance of the sludge incineration process in a wastewater treatment plant and to propose an alternative that can reduce the environmental impact. To show the damages caused by the treatment processes, the study aimed to use an endpoint approach in evaluating impacts on human health, ecosystem quality, and resources due to the processes. A case study was taken at Bissell Point Wastewater Treatment Plant in Saint Louis, Missouri, U.S. The plant specific data along with literature data from technical publications were used to build an inventory, and then analyzed the environmental burdens from sludge handling unit in the year 2011. The impact assessment method chosen was ReCipe 2008. The existing scenario (dewatering-multiple hearth incineration-ash to landfill) was evaluated and three alternative scenarios (fluid bed incineration and anaerobic digestion with and without land application) with energy recovery from heat or biogas were proposed and analyzed to find the one with the least environmental impact. The existing scenario shows that the most significant impacts are related to depletion in resources and damage to human health. These impacts mainly came from the operation phase (electricity and fuel consumption and emissions related to combustion). Alternatives showed better performance than the existing scenario. Using ReCipe endpoint methodology, and among the three alternatives tested, the anaerobic digestion had the best overall environmental performance. It is recommended to convert to fluid bed incineration if the concerns were more about human health or to anaerobic digestion if the concerns were more about depletion in resources. The endpoint approach may simplify the outcomes of this study as follows: if the plant is converted to fluid bed incineration, it could prevent an average of 43.2 DALYs in human life, save 0.059 species in the area from extinction, and make a 62% reduction in the plant's current expenses needed by future generations to extract resources per year. At the same time it may prevent 36.1 DALYs in humans, save 0.157 species, and make a 101% reduction in current expenses on resources per year, if converting to anaerobic digestion. PMID- 28349127 TI - Polymeric nanoparticle-based delivery of TRAIL DNA for cancer-specific killing. AB - Lack of specificity in cancer therapeutics severely limits the efficacy of many existing treatment modalities. The use of Tumor Necrosis Factor-related Apoptosis Inducing Ligand (TRAIL) is of interest to the field due to this protein's ability to cause cell death specifically in cancer cells without harming the surrounding healthy tissue. Here, we report that polymeric nanoparticles, based on synthetic poly(beta-amino ester)s (PBAEs) and containing DNA, are able to selectively transfect cancer cells in vitro over healthy cells of the same tissue type. Moreover, PBAE-based nanoparticles containing TRAIL DNA are able to transfect several human cancer cell cultures in vitro and cause cell death. While certain cell types, including human glioblastoma (GBM), showed resistance to TRAIL, we found that the expression of TRAIL-binding surface proteins was predictive of each cell type's resistance to TRAIL therapy. We demonstrate a non-viral nanomedicine approach to cancer gene therapy that can improve cancer specificity via both biomaterial selection and through the use of cancer-targeting genetic cargo. PMID- 28349129 TI - Effect of Corexit 9500A on Mississippi Canyon crude oil weathering patterns using artificial and natural seawater. AB - During the 2010 Deepwater Horizon oil well blowout in the Northern Gulf of Mexico (GoM), the application of 6.97 million litres of chemical dispersants was used at the well-head and on the sea surface to promote oil degradation and weathering of the Mississippi Canyon 252 (MC252) crude oil. Chemical dispersants encourage microbial degradation by increasing the surface area of the spilled oil, which also increases its bioavailability. However, the net beneficial effects of using chemical dispersants on spilled oil and their effects on weathering are not completely elucidated in contemporary literature. The use of simulated environmental conditions in replicate laboratory microcosm weathering experiments were employed to study the weathering of oil and the effects of dispersants on oil weathering. Fresh MC252 oil was evaporatively weathered 40% by-weight to approximate the composition of oil seen in surface slicks during the 2010 spill. This surface oil was then well mixed with two types of seawater, autoclaved artificial seawater, the abiotic control, and Gulf of Mexico seawater, the biotic experiment. Four different weathering combinations were tested: 10 mg of oil mixed in 150 ml artificial seawater (OAS) or natural (i.e., GoM) seawater (ON) and 10 mg of oil with dispersant mixed with 150 ml of artificial seawater (OASD) or natural (i.e., GoM) seawater (OND). For the treatments with dispersant (OASD and OND), the dispersant-to-oil ratio (DoR) was 1:20. The experiment was carried out over 28 days with replicates that were sacrificed on Days 0, 0.5, 3, 7, 14, 21 and 28. For the OAS and OASD treatments, abiotic weathering (i.e., evaporation) dominated the weathering process. However, the ON and OND treatments showed a dramatic and rapid decrease in total concentrations of both alkanes and aromatics with biodegradation dominating the weathering process. Further, there were no identifiable differences in the observed weathering patterns between microcosms using oil or oil treated with dispersant. In the biotic weathering microcosms, the relative degree of individual polycyclic aromatic hydrocarbon (PAH) depletion decreases with an increase in rings and within a homolog series (increased alkylation). The n-C17/pristane and n-C18/phytane ratios rapidly decreased compared to the abiotic weathering experiments. The C2 dibenzothiophenes (DBT)/C2-phenanthrenes (D2/P2) and C3-DBTs/C3-phenanthrenes (D3/P3) ratios initially remained constant during the early stages of weathering and then increased with time showing preferential weathering of the sulfur containing compounds compared to similar sized PAH compounds. These ratios in the abiotic microcosms remained constant over 28 days. Additionally, twenty-four quantitative MC252 oil biomarker ratios were evaluated to determine if their usefulness as oil source-fingerprinting tools were compromised after significant weathering and dispersant augmentation. PMID- 28349131 TI - C-Phycocyanin as a tumour-associated macrophage-targeted photosensitiser and a vehicle of phthalocyanine for enhanced photodynamic therapy. AB - C-Phycocyanin (CPC) as a tumour-associated macrophage (TAM)-targeted photosensitiser has been first proved, and used as a vehicle of zinc phthalocyanine (ZnPc) to fabricate a ZnPc-CPC conjugate, which exhibits an efficient in vitro photodynamic activity, and selectively accumulates in tumour sites probably due to the affinity to TAM. PMID- 28349132 TI - N-Tosylhydrazones: versatile synthons in the construction of cyclic compounds. AB - N-Tosylhydrazones have recently emerged as useful synthons in a variety of transition-metal-catalyzed and transition-metal-free reactions, which affords novel methodologies for the formation of carbon-carbon and carbon-heteroatom bonds. In this context, it has been found that N-tosylhydrazones can be used as versatile building blocks in the construction of a range of cyclic compounds. In this review, cyclization reactions based on N-tosylhydrazones as substrates are discussed. A series of cyclic compounds, including aromatic and non-aromatic ring systems, are demonstrated to be easily constructed by cyclizations with N tosylhydrazones. PMID- 28349133 TI - Spontaneous phase transition of hexagonal wurtzite CoO: application to electrochemical and photoelectrochemical water splitting. AB - The addition of water initiates the phase transition of hexagonal CoO to Co(OH)2 nanocrystals. Inducing the phase transition of h-CoO on various substrates results in efficient chemical bonding between Co(OH)2 and the substrate. The efficient deposition of Co(OH)2 is widely applicable for electrochemical and photoelectrochemical water oxidation reactions. PMID- 28349134 TI - Sodium-ion batteries: present and future. AB - Energy production and storage technologies have attracted a great deal of attention for day-to-day applications. In recent decades, advances in lithium-ion battery (LIB) technology have improved living conditions around the globe. LIBs are used in most mobile electronic devices as well as in zero-emission electronic vehicles. However, there are increasing concerns regarding load leveling of renewable energy sources and the smart grid as well as the sustainability of lithium sources due to their limited availability and consequent expected price increase. Therefore, whether LIBs alone can satisfy the rising demand for small- and/or mid-to-large-format energy storage applications remains unclear. To mitigate these issues, recent research has focused on alternative energy storage systems. Sodium-ion batteries (SIBs) are considered as the best candidate power sources because sodium is widely available and exhibits similar chemistry to that of LIBs; therefore, SIBs are promising next-generation alternatives. Recently, sodiated layer transition metal oxides, phosphates and organic compounds have been introduced as cathode materials for SIBs. Simultaneously, recent developments have been facilitated by the use of select carbonaceous materials, transition metal oxides (or sulfides), and intermetallic and organic compounds as anodes for SIBs. Apart from electrode materials, suitable electrolytes, additives, and binders are equally important for the development of practical SIBs. Despite developments in electrode materials and other components, there remain several challenges, including cell design and electrode balancing, in the application of sodium ion cells. In this article, we summarize and discuss current research on materials and propose future directions for SIBs. This will provide important insights into scientific and practical issues in the development of SIBs. PMID- 28349130 TI - Design Strategies and Applications of Biomaterials and Devices for Hernia Repair. AB - Hernia repair is one of the most commonly performed surgical procedures worldwide, with a multi-billion dollar global market. Implant design remains a critical challenge for the successful repair and prevention of recurrent hernias, and despite significant progress, there is no ideal mesh for every surgery. This review summarizes the evolution of prostheses design toward successful hernia repair beginning with a description of the anatomy of the disease and the classifications of hernias. Next, the major milestones in implant design are discussed. Commonly encountered complications and strategies to minimize these adverse effects are described, followed by a thorough description of the implant characteristics necessary for successful repair. Finally, available implants are categorized and their advantages and limitations elucidated, including non absorbable and absorbable (synthetic and biologically derived) prostheses, composite prostheses, and coated prostheses. This review not only summarizes the state of the art in hernia repair, but also suggests future research directions toward improved hernia repair utilizing novel materials and fabrication methods. PMID- 28349135 TI - Synthesis of highly efficient azure-to-blue-emitting Zn-Cu-Ga-S quantum dots. AB - To realize blue emission-capable non-Cd I-III-VI quantum dots (QDs), we explore the synthesis of ternary Cu-Ga-S (CGS) QDs and subsequent quaternary Zn-Cu-Ga-S (ZCGS) via Zn alloying into a CGS host. The resulting ZCGS/ZnS core/shell QDs possess not only Zn content-dependent tunable emissions in the azure-to-blue range but also exceptional quantum yields of 78-83%. PMID- 28349137 TI - Insights into the pores of microwave-assisted metal-imidazolate frameworks showing enhanced gas sorption. AB - Microwave heating (MW)-assisted synthesis has been widely applied as an alternative method for the chemical synthesis of organic and inorganic materials. In this work, we report MW-assisted synthesis of three isostructural 3D frameworks with a flexible linker arm of the chelating linker 2-substituted imidazolate-4-amide-5-imidate, named IFP-7-MW (M = Zn, R = OMe), IFP-8-MW (M = Co; R = OMe) and IFP-10-MW (M = Co; R = OEt) (IFP = Imidazolate Framework Potsdam). These chelating ligands were generated in situ by partial hydrolysis of 2-substituted 4,5-dicyanoimidazoles under MW- and also conventional electrical heating (CE)-assisted conditions in DMF. The structure of these materials was determined by IR spectroscopy and powder X-ray diffraction (PXRD) and the identity of the materials synthesized under CE-conditions was established. Materials obtained from MW-heating show many fold enhancement of CO2 and H2 uptake capacities, compared to the analogous CE-heating method based materials. To understand the inner pore-sizes of IFP structures and variations of gas sorptions, we performed positron annihilation lifetime spectroscopy (PALS), which shows that MW-assisted materials have smaller pore sizes than materials synthesized under CE-conditions. The "kinetically controlled" MW-synthesized material has an inherent ability to trap extra linkers, thereby reducing the pore sizes of CE-materials to ultra/micropores. These ultramicropores are responsible for high gas sorption. PMID- 28349138 TI - Metal coordination of ferrocene-histidine conjugates. AB - This study presents a few bis(histidine) ligands working to build a small peptidic model system of zinc structural sites. Ferrocene-peptide conjugates Fc[CO-His(Trt)-His(Trt)-OMe]2 (3), Fc[CO-His(Trt)-Asp(OMe)-OMe]2 (4), and Fc[CO His(Trt)-Glu(OMe)-OMe]2 (5) were synthesized and characterized spectroscopically. 1H-NMR and IR spectroscopic studies reveal hydrogen bonding interactions and while more detailed circular dichroism studies show a 1,2'-P helical "Herrick conformation" for Fc-conjugates 4 and 5, we discovered M-helical chirality in Fc peptide 3. The half-wave potentials (E1/2) of ferrocene-peptides follow the sequence 3 < 5 < 4 which is rationalized by the capability of the peptide side chains to stabilize the oxidized ferrocene-peptide form. The diffusion coefficient (D) and electron transfer rate constant (ksh) values for all Fc conjugates were determined by their resultant cyclic voltammetry data. The interactions for all Fc-conjugates were probed with metal ions Zn2+, Cd2+, Ni2+, Cu2+, Mn2+, and Mg2+ which were detected to interact at 1 : 1 ratio between the ligand and metal ion verified by 1H-NMR and UV titration studies, electrochemical investigations, and ESI-MS experiments. Electrochemical studies for all Fc conjugates exhibit anodic potential shifts upon the addition of metal ions, which follow the order Cu2+ > Zn2+ > Ni2+ > Cd2+ > Mn2+ > Mg2+. NMR spectroscopic experiments show that the two nitrogen atoms present on each imidazole ring of His residues are the site of metal coordination. There is a strong indication that peptide conjugates 4 and 5 in the presence of Zn2+ enforce a coordination number of four as the CD spectra of Fc-conjugates 4 and 5 exhibited a red shift which corresponds to the third and fourth coordination sites occupied by neutral carbonyl oxygen donor atoms, in addition, carbonyl amide appears downward shifted in wavenumber upon metal addition. PMID- 28349140 TI - Microfluidic neural probes: in vivo tools for advancing neuroscience. AB - Microfluidic neural probes hold immense potential as in vivo tools for dissecting neural circuit function in complex nervous systems. Miniaturization, integration, and automation of drug delivery tools open up new opportunities for minimally invasive implants. These developments provide unprecedented spatiotemporal resolution in fluid delivery as well as multifunctional interrogation of neural activity using combined electrical and optical modalities. Capitalizing on these unique features, microfluidic technology will greatly advance in vivo pharmacology, electrophysiology, optogenetics, and optopharmacology. In this review, we discuss recent advances in microfluidic neural probe systems. In particular, we will highlight the materials and manufacturing processes of microfluidic probes, device configurations, peripheral devices for fluid handling and packaging, and wireless technologies that can be integrated for the control of these microfluidic probe systems. This article summarizes various microfluidic implants and discusses grand challenges and future directions for further developments. PMID- 28349141 TI - Synthesis of phenanthridine spiropyrans and studies of their effects on G quadruplex DNA. AB - G-quadruplex (G4) DNA structures are involved in many important biological processes and can be linked to several human diseases. Drug-like low molecular weight compounds that target G4 structures are therefore interesting not only for their potential therapeutic properties but also for their potential use as chemical research tools. We report here on the development of methods to synthesize spiropyrans using a condensation-cyclisation reaction of quaternary salts of alpha-methyl quinoline or phenanthridine with salicylaldehydes. Evaluation of the synthesized phenanthridine spiropyrans' interactions with G4 DNA was performed with a Thioflavin T displacement assay, circular dichroism, Taq DNA polymerase stop assay, and NMR. This revealed that the substitution pattern on the phenanthridine spiropyrans was very important for their ability to bind and stabilize G4 structures. Some of the synthesized low molecular weight spirocyclic compounds efficiently stabilized G4 structures without inducing structural changes by binding the first G-tetrad in the G4 structure. PMID- 28349142 TI - High performance multifunctional green Co3O4 spinel nanoparticles: photodegradation of textile dye effluents, catalytic hydrogenation of nitro aromatics and antibacterial potential. AB - Tricobalt tetraoxide (Co3O4), a spinel-structured nanoparticle which possesses mixed oxidation states, has been synthesized via a Punica granatum (P. granatum, pomegranate) seed extract-mediated green reaction and has been investigated for its superior catalytic activity in three applications, which include (i) photodegradation of textile dye effluents (TDE) collected from the dyeing industry, Tiruppur, Tamil Nadu, India, (ii) catalytic hydrogenation of nitro aromatic pollutants such as 4-nitrophenol and 4-nitroaniline, and (iii) antibacterial potential in biomedical applications. Prior to the application studies, the synthesized Co3O4 spinel nanoparticles (Co3O4-NPs) were characterized by well-known established techniques such as X-ray diffraction (XRD), high resolution transmission electron microscopy (HRTEM), energy dispersive X-ray analysis (EDX), diffuse reflectance spectroscopy (DRS), photoluminescence spectroscopy (PL), and Raman and FT-IR spectroscopies. We have also discussed the probable mechanism and kinetic studies of the catalytic activity of the Co3O4-NPs. Finally, we concluded that the design and development of novel, economic and green synthesis-mediated catalysts such as Co3O4-NPs can exhibit efficient catalytic activity in diverse fields, which is necessary for environmental remediation. PMID- 28349143 TI - Non-equilibrium supramolecular polymerization. AB - Supramolecular polymerization has been traditionally focused on the thermodynamic equilibrium state, where one-dimensional assemblies reside at the global minimum of the Gibbs free energy. The pathway and rate to reach the equilibrium state are irrelevant, and the resulting assemblies remain unchanged over time. In the past decade, the focus has shifted to kinetically trapped (non-dissipative non equilibrium) structures that heavily depend on the method of preparation (i.e., pathway complexity), and where the assembly rates are of key importance. Kinetic models have greatly improved our understanding of competing pathways, and shown how to steer supramolecular polymerization in the desired direction (i.e., pathway selection). The most recent innovation in the field relies on energy or mass input that is dissipated to keep the system away from the thermodynamic equilibrium (or from other non-dissipative states). This tutorial review aims to provide the reader with a set of tools to identify different types of self assembled states that have been explored so far. In particular, we aim to clarify the often unclear use of the term "non-equilibrium self-assembly" by subdividing systems into dissipative, and non-dissipative non-equilibrium states. Examples are given for each of the states, with a focus on non-dissipative non-equilibrium states found in one-dimensional supramolecular polymerization. PMID- 28349144 TI - The 2016 edition of the Art in Science of MicroTAS. PMID- 28349145 TI - An adaptive mutation simulated annealing based investigation of Coulombic explosion and identification of dissociation patterns in (CO2)n2+ clusters. AB - In this communication, we would like to discuss the advantages of adaptive mutation simulated annealing (AMSA) over standard simulated annealing (SA) in studying the Coulombic explosion of (CO2)n2+ clusters for n = 20-68, where 'n' is the size of the cluster. We have demonstrated how AMSA itself can overcome the predicaments which can arise in conventional SA and carry out the search for better results by adapting the parameters (only when needed) dynamically during the simulations so that the search process can come out of high energy basins and not go astray for better exploration and convergence, respectively. This technique also has in-built properties for getting more than one minimum in a single run. For a (CO2)n2+ cluster system we have found the critical limit to be n = 43, above which the attractive forces between individual units become greater in value than that of the large repulsive forces and the clusters stay intact as the energetically favoured isomers. This result is in good concurrence with earlier studies. Moreover, we have studied the fragmentation patterns for the entire size range and we have found fission type fragmentation as the favoured mechanism nearly for all sizes. PMID- 28349146 TI - Distinct activation of Cu-MOR for direct oxidation of methane to methanol. AB - N2O activation of Cu-MOR enhanced methanol production at elevated temperatures, to a greater extent than activation by O2 under optimal conditions. The increase in methanol production by N2O activation was attributed to the facile formation of an active copper center with no formation of inactive intermediate species. PMID- 28349148 TI - Self-assembly and redox induced phase transfer of gold nanoparticles at a water propylene carbonate interface. AB - Citrate-stabilized gold nanoparticles were found to spontaneously self-assemble into a lustrous film at a bare water-propylene carbonate interface after vigorous shaking, due to the extremely low interfacial tension. The presence of an electron donor, tetrathiafulvalene, in the oil phase, led to the extraction of particles into the organic phase. PMID- 28349149 TI - Pico-HPLC system integrating an equal inner diameter femtopipette into a 900 nm I.D. porous layer open tubular column. AB - A picoflow high performance liquid chromatography (pico-HPLC) system was developed, which could directly pipette femtoliter samples using a separation column tip driven by an electroosmotic pump. Amino acid enantiomers were separated in the 900 nm I.D. porous layer open tubular column at a flow rate of 13.50 pL min-1. PMID- 28349150 TI - The aromaticity of dicupra[10]annulenes. AB - An extensive theoretical investigation of the electronic structure of a tested fair model dicupra[10]annulene compound, based on the analysis of atom-pair delocalization indices, Bader's molecular graph, the inspection of the canonical molecular orbitals, the z components of their Nuclear Independent Chemical Shifts, NICS(0)zz, and the normalized Giambiagi multicenter delocalization indices, concludes that the perimeter aromaticity of the dicupra[10]annulene ring is consistent with both 10 and 14 pi-electron Huckel aromatic 10-membered rings. In either case, the 10-membered ring encloses two 6 pi-electron aromatic inner rings, hinged at the Cu-Cu bond. This work demonstrates that the aromaticity of dicupra[10]annulenes closely resembles that of naphthalene. Hence, they are best regarded as metalla-polyacenes, which could make the building blocks of extended structures such as metalated nanotubes. PMID- 28349151 TI - Correction: Vibrational dynamics and solvatochromism of the label SCN in various solvents and hemoglobin by time dependent IR and 2D-IR spectroscopy. AB - Correction for 'Vibrational dynamics and solvatochromism of the label SCN in various solvents and hemoglobin by time dependent IR and 2D-IR spectroscopy' by Luuk J. G. W. van Wilderen et al., Phys. Chem. Chem. Phys., 2014, 16, 19643 19653. PMID- 28349152 TI - A mitochondria-targeted fluorescent probe for imaging endogenous malondialdehyde in HeLa cells and onion tissues. AB - The mitochondria-targeted turn-on fluorescent probe (Mito-FMP) based on a benzoxadiazole platform was developed for detection of malondialdehyde (MDA). Mito-FMP performed with large enhancement of the optical signal (774-fold) in response to MDA in an aqueous system and has the capability of monitoring endogenous MDA in HeLa cells and onion tissues. PMID- 28349153 TI - Al-Doped CoP nanoarray: a durable water-splitting electrocatalyst with superhigh activity. AB - The scalable production of hydrogen fuel through electrochemical water reduction needs efficient Earth-abundant electrocatalysts to make the whole water-splitting process more energy efficient. In this Article, we report that an Al-doped CoP nanoarray on carbon cloth (Al-CoP/CC) behaves as a durable hydrogen evolution electrocatalyst with superhigh activity in 0.5 M H2SO4. It demands a pretty low overpotential of 23 mV to drive a geometrical catalytic current density of 10 mA cm-2, outperforming all reported non-precious metal catalysts. Density functional theory calculations reveal that Al-CoP has a more thermo-neutral hydrogen adsorption free energy than CoP. Notably, this Al-CoP/CC is also superior in activity and durability as a bifunctional catalyst for alkaline water electrolysis, and its two-electrode water electrolyser delivers 10 mA cm-2 water splitting current at a cell voltage of 1.56 V in 1.0 M KOH. This work offers us an attractive cost-effective catalyst electrode in water-splitting devices for large-scale production of hydrogen fuels. PMID- 28349155 TI - Modeling the electronic states and magnetic properties derived from the f1 configuration in lanthanocene and actinocene compounds. AB - The electronic structure and magnetic properties of a series of Kramers ions with f1 configuration in axial symmetry have been analyzed with a combination of theoretical methods: ab initio relativistic wavefunction methods as well as a crystal-field (CF) model with parameters extracted from the ab initio calculations. The molecules were treated in an idealized D8h and D7h symmetry and different combinations of active electrons and orbitals were used to describe correctly the nature of the ground and excited states. The spin Hamiltonian parameters for the Kramers doublet derived from the ground multiplet were determined and discussed on the basis of the crystal-field (CF) and spin-orbit interaction. The prime interests were the electron paramagnetic resonance g factors and their relation to the complex geometry, crystal-field (CF) and spin orbit coupling. The developed models agree well with the ab initio calculations and experimental reports. PMID- 28349157 TI - Schiff base thorium(iv) and uranium(iv) chloro complexes: synthesis, substitution and oxidation chemistry. AB - New tetradentate Schiff base chloro complexes of U(iv) and Th(iv) are prepared by salt metathesis approaches. These compounds undergo clean salt metathesis with NaN3 to generate stable pseudo-trans azide compounds. The uranium dichloro complex also undergoes 2 e- oxidation with excess NaNO2 to generate the uranyl derivative. All classes of complexes are characterized by single crystal X-ray diffraction and NMR spectroscopy. PMID- 28349158 TI - The assembly of "S3N"-ligands decorated with an azo-dye as potential sensors for heavy metal ions. AB - An "S3N-ligand azo-dye" conjugate has been synthesised with a view to the development of a sensor for heavy metal ions. Complexation of this system with Ag(i), Hg(ii) and Cu(ii) salts has been investigated and an X-ray structure has been obtained for a Hg(ii) complex. Complexation of the conjugated dye to these metals results in a bathochromic shift in the absorption maximum of the azo dye, an effect which is most pronounced for Cu(ii). PMID- 28349159 TI - Recent applications of the 1,2-carbon atom migration strategy in complex natural product total synthesis. AB - 1,2-Carbon atom rearrangement has been broadly applied as a guiding strategy in complex molecule assembly. As it entails the carbon-carbon or carbon-heteroatom bond migration between two vicinal atoms, this type of reaction is capable of generating structural complexity through a molecular skeletal reorganization. This review will focus on recent employment of this strategy in the total synthesis of natural products, highlighting the exceptional utility of such synthetic methodologies in the construction of intricate carbocycles, heterocycles or structurally complex motifs from synthetically more accessible precursors. PMID- 28349160 TI - Cyclic dipeptide based cell-penetrating peptidomimetics for effective DNA delivery. AB - An unnatural CDP-amino acid (kd) is used in the design and synthesis of novel cell penetrating peptidomimetic (Kkd-5). The balanced cationic nature and structural rigidity of Kkd-5 resulted in serum stability, non-toxicity to cells, and interaction with membrane and DNA, all of which facilitated efficient cellular uptake and DNA delivery. PMID- 28349161 TI - Combined reconstruction of the anterior cruciate ligament associated with anterolateral tenodesis effectively controls the acceleration of the tibia during the pivot shift. AB - PURPOSE: The pivot shift test is quantified subjectively during assessment of patients presenting with suspected Anterior Cruciate Ligament (ACL) tears and has a low interobserver reproducibility. The Kinematic Rapid Assessment (KiRA) is a triaxial accelerometer that makes it possible to non-invasively quantify tibial acceleration during the pivot shift test. Abolishing pivot shift is considered to be a key element in surgical reconstruction but is incomplete in 25-38% of patients. METHODS: Patients were included prospectively. Inclusion criteria were patients requiring ACL reconstruction associated with at least one of the following factors corresponding to the patient who have a high risk of rupture either by their sports activity, a failure case, or the notion of important rotational laxity: the patient practiced a competitive pivot-contact sport, revision ACL reconstruction (besides STG (semitendinosus-gracilis graft) repair), subjective explosive rotational laxity, Segond fracture, and TELOS value of >10 mm. Standardized pre- and postoperative pivot shift tests were immediately performed under anesthesia in both knees. RESULTS: Forty-three patients were included. Mean preoperative variations in tibial acceleration in the healthy and injured knees were 1.2 +/- 0.1 and 2.7 +/- 0.3 m/s2, respectively, p < 0.01. A statistically significant decrease in immediate postoperative mean variations in acceleration in the injured knee occurred: 1.5 +/- 0.3 m/s2, p < 0.01. There was no longer any statistical difference between postoperative contralateral healthy knees and operated knees (n.s). CONCLUSIONS: Combined ACL reconstruction associated with anterolateral tenodesis suppress acute pathologic tibial acceleration in the pivot shift. LEVEL OF EVIDENCE: III. PMID- 28349162 TI - Substrates of Peltigera Lichens as a Potential Source of Cyanobionts. AB - Photobiont availability is one of the main factors determining the success of the lichenization process. Although multiple sources of photobionts have been proposed, there is no substantial evidence confirming that the substrates on which lichens grow are one of them. In this work, we obtained cyanobacterial 16S ribosomal RNA gene sequences from the substrates underlying 186 terricolous Peltigera cyanolichens from localities in Southern Chile and maritime Antarctica and compared them with the sequences of the cyanobionts of these lichens, in order to determine if cyanobacteria potentially available for lichenization were present in the substrates. A phylogenetic analysis of the sequences showed that Nostoc phylotypes dominated the cyanobacterial communities of the substrates in all sites. Among them, an overlap was observed between the phylotypes of the lichen cyanobionts and those of the cyanobacteria present in their substrates, suggesting that they could be a possible source of lichen photobionts. Also, in most cases, higher Nostoc diversity was observed in the lichens than in the substrates from each site. A better understanding of cyanobacterial diversity in lichen substrates and their relatives in the lichens would bring insights into mycobiont selection and the distribution patterns of lichens, providing a background for hypothesis testing and theory development for future studies of the lichenization process. PMID- 28349163 TI - Engineering of the LysR family transcriptional regulator FkbR1 and its target gene to improve ascomycin production. AB - Ascomycin (FK520), a macrocyclic polyketide natural antibiotic, displays high anti-fungal and immunosuppressive activity. In this study, the LysR family transcriptional regulator FkbR1 was characterized, and its role in ascomycin biosynthesis was explored by gene deletion, complementation, and overexpression. Inactivation of fkbR1 led to 67.5% reduction of ascomycin production, which was restored by complementation of fkbR1. Overexpression of fkbR1 resulted in a 33.5% increase in ascomycin production compared with the parent strain FS35. These findings indicated that FkbR1 was a positive regulator for ascomycin production. Quantitative RT-PCR analysis revealed that the expressions of fkbE, fkbF, fkbS, and fkbU were downregulated in the fkbR1 deletion strain and upregulated in the fkbR1 overexpression strain. Electrophoretic mobility shift assays (EMSAs) in vitro and chromatin immunoprecipitation (ChIP)-qPCR assays in vivo indicated that FkbR1 bound to the intergenic region of fkbR1-fkbE. To investigate the roles of the target genes fkbE and fkbF in ascomycin production, the deletion and overexpressions of fkbE and fkbF were implemented, respectively. Overexpression of fkbE resulted in a 45.6% increase in ascomycin production, but little change was observed in fkbF overexpression strain. To further enhance ascomycin production, the fkbR1 and fkbE combinatorial overexpression strain OfkbRE was constructed with the ascomycin yield increased by 69.9% to 536.7 mg/L compared with that of the parent strain. Our research provided a helpful strategy to increase ascomycin production via engineering FkbR1 and its target gene. PMID- 28349164 TI - Lateral flow assay for rapid detection of white spot syndrome virus (WSSV) using a phage-displayed peptide as bio-recognition probe. AB - White spot disease caused by the white spot syndrome virus (WSSV) has a major socio-economic impact on shrimp farming in India. It has been realized that a field-usable diagnostic capable of rapid detection of WSSV can prevent huge economic losses in disease outbreaks. In this work, we explored the possibility of using a peptide as bio-recognition probe in a field-usable device for the detection of WSSV from infected shrimps and prawns. A commercially available random phage-display library was screened against rVP28 (a major structural protein of WSSV, expressed as a recombinant protein in Escherichia coli). A bacteriophage clone VP28-4L was obtained, and its binding to purified rVP28 protein as well as WSSV from infected shrimp Litopaeneus vannamei tissue was confirmed by ELISA and western blot. The apparent equilibrium dissociation constant (Kd,app) was calculated to be 810 nM. VP28-4L did not show cross reactivity with any other shrimp viruses. A 12-mer peptide (pep28, with the sequence 'TFQAFDLSPFPS') displayed on the VP28-4L was synthesized, and its diagnostic potential was evaluated in a lateral flow assay (LFA). Visual detection of WSSV could be achieved using biotinylated-pep28 and streptavidin conjugated gold nanoparticles. In LFA, 12.5 MUg/mL of the virus could be detected from L. vannamei gill tissue homogenate within 20 min. Pep28 thus becomes an attractive candidate in bio-recognition of WSSV in field-usable diagnostic platforms benefitting the aquaculture sector. PMID- 28349165 TI - Programmed death-ligand 1 and its soluble form are highly expressed in nasal natural killer/T-cell lymphoma: a potential rationale for immunotherapy. AB - Nasal natural killer/T-cell lymphoma (NNKTL) is an aggressive neoplasm with poor therapeutic responses and prognosis. The programmed death-1/programmed death ligand 1 (PD-1/PD-L1) pathway plays an important role in immune evasion of tumor cells through T-cell exhaustion. The aim of the present study was to examine the expression of PD-L1 and PD-1 molecules in NNKTL. We detected the expression of PD L1 in biopsy samples from all of the NNKTL patients studied. PD-L1 was found on both malignant cells and tumor-infiltrating macrophages, while PD-1-positive mononuclear cells infiltrated the tumor tissues in 36% of patients. Most significantly, soluble PD-L1 (sPD-L1) was present in sera of NNKTL patients at higher levels as compared to healthy individuals and the levels of serum sPD-L1 in patients positively correlated with the expression of PD-L1 in lymphoma cells of tumor tissues. In addition, the high-sPD-L1 group of patients showed significantly worse prognosis than the low-sPD-L1 group. Furthermore, we confirmed that membrane and soluble PD-L1 was expressed on the surface and in the culture supernatant, respectively, of NNKTL cell lines. The expression of PD-L1 was observed in tumor tissues and sera from a murine xenograft model inoculated with an NNKTL cell line. Our results suggest that sPD-L1 could be a prognostic predictor for NNKTL and open up the possibility of immunotherapy of this lymphoma using PD-1/PD-L1 axis inhibitors. PMID- 28349166 TI - Comparative plasma and tissue distribution of Sun Pharma's generic doxorubicin HCl liposome injection versus Caelyx(r) (doxorubicin HCl liposome injection) in syngeneic fibrosarcoma-bearing BALB/c mice and Sprague-Dawley rats. AB - PURPOSE: The liposomal formulation of doxorubicin [doxorubicin (DXR) hydrochloride (HCl) liposome injection, Caelyx(r)] alters the tissue distribution of DXR as compared with nonliposomal DXR, resulting in an improved benefit-risk profile. We conducted studies in murine models to compare the plasma and tissue distribution of a proposed generic DXR HCl liposome injection developed by Sun Pharmaceuticals Industries Limited (SPIL DXR HCl liposome injection) with Caelyx(r). METHODS: The plasma and tissue distributions of the SPIL and reference DXR HCl liposome injections were compared in syngeneic fibrosarcoma-bearing BALB/c mice and Sprague-Dawley rats. Different batches and different lots of the same batch of the reference product were also compared with each other. RESULTS: The SPIL and reference DXR HCl liposome injections exhibited generally comparable plasma and tissue distribution profiles in both models. While minor differences were observed between the two products in some tissues, different batches and lots of the reference product also showed some differences in the distribution of various analytes in some tissues. The ratios of estimated free to encapsulated DXR for plasma and tissue were generally comparable between the SPIL and reference DXR HCl liposome injections in both models, indicating similar extents of absorption into the tissues and similar rates of drug release from liposomes. CONCLUSIONS: The plasma and tissue distribution profiles of the SPIL and reference DXR HCl liposome injections were shown to be generally comparable. Inconsistencies between the products observed in some tissues were thought to be due to biological variation. PMID- 28349167 TI - Evaluation of the effect of the EGFR antibody-drug conjugate ABT-414 on QT interval prolongation in patients with advanced solid tumors likely to over express EGFR. AB - PURPOSE: ABT-414 is an antibody-drug conjugate (ADC) being developed for the treatment of tumors harboring amplification of the epidermal growth factor receptor (EGFR). This study evaluated the potential of ABT-414 to prolong the QT interval as part of the initial phase 1 study (NCT01741727). METHODS: Data from patients who received ABT-414 monotherapy at a dose of 1-4 mg/kg once every 3 weeks or 1 or 1.5 mg/kg weekly for 2 out of every 3 weeks (alternate schedule) by intravenous infusion were included in the analysis of triplicate 12-lead ECGs obtained before dosing and through 168 h after dosing. Data from time-matched pharmacokinetic samples and QT interval assessments were evaluated using linear mixed-effects modeling to determine the effects of ABT-414, total ABT-806, and cysteine-maleimidocaproyl monomethyl auristatin F (Cys-mcMMAF) on the QT interval corrected using Fridericia's formula (QTcF). RESULTS: Fifty-one patients were included in the analyses. ABT-414 had no clinically meaningful effect on QTcF. Using pooled data from doses >=2 mg/kg, the estimated mean ?QTcF reached a maximum of 4.30 ms after dosing, with a one-sided 95% upper confidence bound of 8.32 ms. The exposure-response analysis showed no statistically significant relationship between DeltaQTcF and the concentration of any analyte (P > 0.05). No patient had a QTcF value >480 ms or a ?QTcF value >30 ms. CONCLUSIONS: ABT-414 had no clinically meaningful effect on the QTcF interval at doses being evaluated for treatment of patients with solid tumors. PMID- 28349168 TI - Amplification-free detection of microRNAs via a rapid microarray-based sandwich assay. AB - The detection and profiling of microRNAs are of great interest in disease diagnosis and prognosis. In this paper, we present a method for the rapid amplification-free detection of microRNAs from total RNA samples. In a two-step sandwich assay approach, fluorescently labeled reporter probes were first hybridized with their corresponding target microRNAs. The reaction mix was then added to a microarray to enable their specific capture and detection. Reporter probes were Tm equalized, enabling specificity by adjusting the length of the capture probe while maintaining the stabilizing effect brought about by coaxial base stacking. The optimized assay can specifically detect microRNAs in spiked samples at concentrations as low as 1 pM and from as little as 100 ng of total RNA in 2 h. The detection signal was linear between 1 and 100 pM (R2 = 0.99). Our assay data correlated well with results generated by qPCR when we profiled a select number of breast cancer related microRNAs in a total RNA sample. PMID- 28349169 TI - Multispectroscopic methodology to study Libyan desert glass and its formation conditions. AB - Libyan desert glass (LDG) is a melt product whose origin is still a matter of controversy. With the purpose of adding new information about this enigma, the present paper analyzes the inner part of LDG specimens and compares them with the results of LDG surfaces. An integrated analytical methodology was used combining different techniques such as Raman spectroscopy, in point-by-point and imaging modes, scanning electron microscopy with X-ray microanalysis (SEM-EDS), energy dispersive micro X-ray fluorescence spectrometry (MU-EDXRF), electron probe micro analyzer (EPMA), and optical cathodoluminescence (Optical-CL). According to our results, flow structures of the melt and the amorphous nature of the matrix could be discerned. Moreover, the observed displacement of Raman bands, such as in the cases of quartz and zircon, and the identification of certain compounds such as coesite (the most clarifying phase of high pressures), alpha-cristobalite, gypsum, anhydrite, corundum, rutile, amorphous calcite, aragonite, and calcite allowed us to know that LDGs could be subjected to shock pressures between 6 and more than 30 GPa, and temperatures between 300 and 1470 degrees C. The differences of temperature and pressure would be provoked by different cooling processes during the impact. Besides, in most cases the minerals corresponding to high pressure and temperatures were located in the inner part of the LDGs, with some exceptions that could be explained because they were trapped subsequently to the impact; there was more than one impact or heterogeneous cooling.Furthermore, nitrogen and oxygen gases were identified inside bubbles, which could have been introduced from the terrestrial atmosphere during the meteorite impact.These data helped us to clarify some clues about the origin of these enigmatic samples. PMID- 28349170 TI - CT reconstruction and MRI fusion of 3D rotational angiography in the evaluation of pediatric cerebrovascular lesions. AB - PURPOSE: Complex neurovascular lesions in children require precise anatomic understanding for treatment planning. Although 3DRA is commonly employed for volumetric reformation in neurointerventional procedures, the ability to reconstruct this data into CT-like images (3DRA-CT) is not widely utilized. This study demonstrates the feasibility and usefulness of 3DRA-CT and subsequent MRI fusion for problem solving in pediatric neuroangiography. METHODS: This retrospective study includes 18 3DRA-CT studies in 16 children (age 9.6 +/- 3.8 years, range 2-16 years) over 1 year. After biplane 2D-digital subtraction angiography (DSA), 5-second 3DRA was performed with selective vessel injection either with or without subtraction. Images were reconstructed into CT sections which were post-processed to generate multiplanar reformation (MPR) and maximum intensity projection (MIP) images. Fusion was performed with 3D T1 MRI images to precisely demonstrate neurovascular relationships. Quantitative radiation metrics were extracted and compared against those for the entire examination and for corresponding biplane 2D-DSA acquisitions. RESULTS: In all 18 cases, the 3DRA procedure and MRI fusion were technically successful and provided clinically useful information relevant to management. The unsubtracted and subtracted 3DRA acquisitions were measured to deliver 5.9 and 132.2%, respectively, of the mean radiation dose of corresponding biplane 2D-DSA acquisitions and contributed 1.2 and 12.5%, respectively, to the total procedure dose. CONCLUSION: Lower radiation doses, high spatial resolution, and multiplanar reformatting capability make 3DRA CT a useful adjunct to evaluate neurovascular lesions in children. Fusing 3DRA-CT data with MRI is an additional capability that can further enhance diagnostic information. PMID- 28349172 TI - [Improving the visibility of rare diseases in health care systems by specific routine coding]. AB - The evaluation of healthcare providers' routine data is an important basis for the analysis, planning and evaluation of measures in public health. The representation of rare diseases in the classifications that are used to record health data is not adequate. Coding rare diseases in a specific way is a challenge all around the world. There is still no general international solution for the routine coding of rare diseases.The double coding of rare diseases with ICD-10 Codes and Orphacodes is a short-term and low-cost alternative solution. Furthermore, this double coding enables international comparability. The specific encoding of rare diseases through this double coding can improve their capturing for statistical analysis and thus their visibility in healthcare systems. Nevertheless, the provision of a new classification is not enough to gather valid data. Some measures have already been adopted in Germany (and at the European level) in order to support the implementation of this double coding. Subsequently it would be possible to adopt more specific public health measures, based on better data, in order to provide better care to the more than four million people in Germany affected by rare diseases. PMID- 28349171 TI - Intersections of poverty, race/ethnicity, and sex: alcohol consumption and adverse outcomes in the United States. AB - We examine whether intersectionality theory-which formalizes the notion that adverse health outcomes owing to having a marginalized social status, identity, or characteristic, may be magnified for individuals with an additional marginalized social status, identity, or characteristic-can be applied using quantitative methods to describe the differential effects of poverty on alcohol consumption across sex and race/ethnicity. Using the National Epidemiologic Survey on Alcohol and Related Conditions, we analyze longitudinal data from Black, Hispanic, and White drinkers (n = 21,140) to assess multiplicative interactions between poverty, as defined by the US Census Bureau, sex, and race/ethnicity, on adverse alcohol outcomes. Findings indicated that the effect of poverty on the past-year incidence of heavy episodic drinking was stronger among Black men and Black women in comparison to men and women of other racial/ethnic groups. Poverty reduction programs that are culturally informed may help reduce racial/ethnic disparities in the adverse outcomes of alcohol consumption. PMID- 28349173 TI - [Soft tissue techniques in hallux valgus surgery]. AB - The hallux valgus represents combined bony and soft tissue pathology. In addition to known bony surgical procedures, addressing the soft tissue with regard to the anatomical structures, the surgical technique and the extent of correction are discussed.The goal of the operation is the restoration of the physiological balance between the active and passive stabilizing factors of the MTP-I-joint. The joint capsule, the ligaments and the tendons of the first ray act directly as stabilizing structures, whereas the hind foot and the position of the upper ankle have an indirect influence on the MTP-I-joint.The present work gives an overview of the pathoanatomy of the MTP-I-joint in the hallux valgus pathology. The individual anatomical structures are presented with regard to their physiological and pathological influence and the possible therapeutic options. PMID- 28349174 TI - Effects of a long-term lifestyle modification programme on peripheral neuropathy in overweight or obese adults with type 2 diabetes: the Look AHEAD study. AB - AIMS/HYPOTHESIS: The aim of this study was to evaluate the effects on diabetic peripheral neuropathy (DPN) of a long-term intensive lifestyle intervention (ILI) programme designed to achieve and maintain weight loss. METHODS: Beginning in 2001, a total of 5145 overweight or obese people with type 2 diabetes, aged 45-76 years, participating in the multicentre Look AHEAD (Action for Health in Diabetes) study were randomised to ILI (n = 2570) or to a diabetes support and education (DSE) control group (n = 2575) using a web-based management system at the study coordinating centre at Wake Forest School of Medicine (Winston-Salem, NC, USA). Randomisation was stratified by clinical centre and was not revealed to the clinical staff responsible for obtaining data on study outcomes. Because of the nature of the study, patients and the local centre interventionists were not blinded to the study group assignments. In addition, the coordinating centre staff members responsible for data management and statistical analyses were not blinded to the study group assignments. The interventions were terminated in September 2012, 9-11 years after randomisation, but both groups continued to be followed for both primary and secondary outcomes. Neuropathy evaluations included the Michigan Neuropathy Screening Instrument (MNSI) questionnaire completed at baseline in 5145 participants (ILI n = 2570, DSE n = 2575) and repeated annually thereafter and the MNSI physical examination and light touch sensation testing conducted in 3775 participants (ILI n = 1905, DSE n = 1870) 1-2.3 years after discontinuation of the intervention. RESULTS: At baseline, the MNSI questionnaire scores were 1.9 +/- 0.04 and 1.8 +/- 0.04 in the ILI and DSE groups, respectively (difference not statistically significant). After 1 year, when weight loss was maximal in the ILI group (8.6 +/- 6.9%) compared with DSE (0.7 +/- 4.8%), the respective MNSI scores were 1.7 +/- 0.04 and 2.0 +/- 0.04 (p <= 0.001). Subsequently, the scores increased gradually in both groups, but remained significantly lower in the ILI group for the first 3 years and at the end of follow-up. In both groups, there was a significant association between changes in the MNSI scores and changes in body weight, HbA1c and serum lipids. There were no significant between-group differences in the proportions of participants with MNSI physical examination scores >=2.5, considered to be indicative of diabetic neuropathy. The light touch sensation measured separately in either the right or left big toes (halluces) did not differ between ILI and DSE, but when the data were combined for both toes, light touch was better preserved in the ILI group. CONCLUSIONS/INTERPRETATION: ILI resulted in a significant decrease in questionnaire-based DPN, which was associated with the magnitude of weight loss. In both the ILI and DSE groups, changes in the MNSI score were also related to changes in HbA1c and lipids. There were no significant effects of ILI on physical examination measures of DPN conducted 1-2.3 years after termination of the active intervention, except for light touch sensation, which was significantly better in the ILI group when measurements were combined for both toes. However, a potential limiting factor to the interpretation of the physical examination data is that no baseline studies are available for comparison. TRIAL REGISTRATION: ClinicalTrials.gov NCT00017953. FUNDING: This work was funded by the National Institutes of Health through cooperative agreements with the National Institute of Diabetes and Digestive and Kidney Diseases. PMID- 28349175 TI - Characterization of the temporal and spatial expression of wheat (Triticum aestivum L.) plant height at the QTL level and their influence on yield-related traits. AB - KEY MESSAGE: The temporal and spatial expression patterns of stable QTL for plant height and their influences on yield were characterized. Plant height (PH) is a complex trait in wheat (Triticum aestivum L.) that includes the spike length (SL) and the internode lengths from the first to the fifth internode, which are counted from the top and abbreviated as FIRITL, SECITL, THIITL, FOUITL, and FIFITL, respectively. This study identified eight putative additive quantitative trait loci (QTL) for PH. In addition, unconditional and conditional QTL mapping were used to analyze the temporal and spatial expression patterns of five stable QTL for PH. qPh-3A mainly regulated SL, FIRITL, and FIFITL to affect PH during the booting-heading stage (BS-HS); qPh-3D regulated all internode lengths to affect PH, especially during the BS-HS; before HS, qPh-4B mainly affected FIRITL, SECITL, THIITL, and FOUITL and qPh-5A.1 mainly affected SECITL, THIITL, and FOUITL to regulate PH; and qPh-6B mainly regulated FIRITL to affect the PH after the booting stage (BS). qPhdv-4B, a QTL for the response of PH to nitrogen stress, was stable and co-localized with qPh-4B. All five stable QTL, except for qPh-3A, were related to the 1000 kernel weight and yield per plant. Regions of qPh-3A, qPh-3D, qPh-4B, qPh-5A.1, and qPh-6B showed synteny to parts of rice chromosomes 1, 1, 3, 9, and 2, respectively. Based on comparative genomics analysis, Rht-B1b was cloned and mapped in the CI of qPh-4B. This report provides useful information for fine mapping of the stable QTL for PH and the genetic improvement of wheat plant type. PMID- 28349176 TI - QTL analysis of cotton fiber length in advanced backcross populations derived from a cross between Gossypium hirsutum and G. mustelinum. AB - KEY MESSAGE: QTLs for fiber length mapped in three generations of advanced backcross populations derived from crossing Gossypium hirsutum and Gossypium mustelinum showed opportunities to improve elite cottons by introgression from wild relatives. The molecular basis of cotton fiber length in crosses between Gossypium hirsutum and Gossypium mustelinum was dissected using 21 BC3F2 and 12 corresponding BC3F2:3 and BC3F2:4 families. Sixty-five quantitative trait loci (QTLs) were detected by one-way analysis of variance. The QTL numbers detected for upper-half mean length (UHM), fiber uniformity index (UI), and short fiber content (SFC) were 19, 20, and 26 respectively. Twenty-three of the 65 QTLs could be detected at least twice near adjacent markers in the same family or near the same markers across different families/generations, and 32 QTLs were detected in both one-way variance analyses and mixed model-based composite interval mapping. G. mustelinum alleles increased UHM and UI and decreased SFC for five, one, and one QTLs, respectively. In addition to the main-effect QTLs, 17 epistatic QTLs were detected which helped to elucidate the genetic basis of cotton fiber length. Significant among-family genotypic effects were detected at 18, 16, and 16 loci for UHM, UI, and SFC, respectively. Six, two, and two loci showed genotype * family interaction for UHM, UI and SFC, respectively, illustrating complexities that might be faced in introgression of exotic germplasm into cultivated cotton. Co-location of many QTLs for UHM, UI, and SFC accounted for correlations among these traits, and selection of these QTLs may improve the three traits simultaneously. The simple sequence repeat (SSR) markers associated with G. mustelinum QTLs will assist breeders in transferring and maintaining valuable traits from this exotic source during cultivar development. PMID- 28349177 TI - Understanding ethical decisions for patients on extracorporeal life support. PMID- 28349178 TI - How much excess fluid impairs outcome of sepsis? PMID- 28349180 TI - Impregnated central venous catheters in children: a systematic review of randomized controlled trials. PMID- 28349181 TI - Hip fusion takedown to a total hip arthroplasty-is it worth it? A systematic review. AB - INTRODUCTION: Patients with surgically or spontaneously fused hips are often dissatisfied with their overall function and the debilitating effect on adjacent joints. Therefore, in properly selected patients, hip fusion-takedown and conversion to total hip arthroplasty (THA) can result in improved function and decreased pain. We aimed to (1) evaluate the indications for conversion, (2) evaluate the clinical outcomes, (3) analyze the overall complications, and (4) identify the overall satisfaction following the procedure. METHODS: A systematic and comprehensive literature search was performed to analyze studies evaluating conversion of hip fusion to THA. After reviewing 3,882 studies, 27 total studies (1,104 hips) met our inclusion/exclusion criteria and were included in our final analysis. A weighted mean of rates was determined for each complication, including infection, instability, loosening, nerve-related, abductor-related, venous thrombotic event, and revision. RESULTS: The study population consisted of 53.2% male and 46.8% female subjects. The mean age at time of conversion was 52 years (range 36-65 years), the mean time until follow-up was 9.2 years (range 2.5 17.3), and the mean duration of arthrodesis was 27.7 years (range 11-40.2). As measured by Harris Hip Score, overall clinical outcomes improved from 58.1 points (range 42.4-70 points) pre-operatively to 80.0 (range 62-93.5) post-operatively. The specific complication rates were 5.3% (range 0-43.6%) for infection, 2.6% (range 0-15.4%) for instability, 6.2% (range 0-17.2%) for loosening, 4.7% (range 0-13%) for nerve-related complications, 13.1% (range 0-87%) for abductor-related complications, and 1.2% (range 0-13%) for venous thrombotic events. The revision rate was 12.0% (range 0-43.6%). CONCLUSION: Takedown of a fused-hip can be a challenging procedure. Although patients can benefit functionally, both patients and surgeons need to be aware of the complications and increased risk of further revision procedures, which should be an important part of the pre-operative discussion. PMID- 28349182 TI - Biomechanical comparison of anatomical plating systems for comminuted distal humeral fractures. AB - PURPOSE: Six different mono-axial and poly-axial distal humeral plating systems with an anatomical plate design were compared. The aim of the biomechanical tests was to examine differences regarding system stiffness, median fatigue limit, and failure mechanisms. METHODS: Different configurations of two double plate fixation systems by two manufacturers for the treatment of complex distal humeral fractures (AO/OTA type C2.3) were biomechanically tested in a physiologically relevant setup. RESULTS: The 180 degrees Stryker configuration presented itself as the system with the highest stiffness, being significantly stiffer (p < 0.001) than every system other than the poly-axial 180 degrees aap system (p = 0.378). For the median fatigue limit the 180 degrees Stryker and poly-axial aap systems were ranked first and second. The failure mechanism for all 90 degrees systems was a fatigue breakage of the posterolateral plate. The 180 degrees aap systems demonstrated breakage of the most distal screws of the lateral plate. The 180 degrees Stryker system demonstrated screw breakage on both the medial and lateral plates. DISCUSSION: Breakage of the posterolateral plate as a failure mechanism for the 90 degrees systems was expected. The 180 degrees systems demonstrated a higher stiffness compared to the 90 degrees constructs for the axial loading. In conclusion, both poly-axial anatomical plating systems provide sufficient stability in this scenario, and the 180 degrees configurations demonstrated superior stiffness. PMID- 28349183 TI - Resveratrol protects the loss of connexin 43 induced by ethanol exposure in neonatal mouse cardiomyocytes. AB - Excessive alcohol consumption provides risk to cardiomyopathy with unknown mechanisms. Resveratrol, a plant polyphenol, is widely reported for its cardiovascular benefits, while its effect on alcohol-induced impairments in cardiomyocytes largely remains unknown. Effects of resveratrol on the cardiomyocytes under ethanol insult were studied in vitro. Ethanol exposure in mouse neonatal cardiomyocytes increased cell death and induced a specific loss of tight junction protein, connexin 43. In spite of adverse effects at higher concentrations, resveratrol at 10 MUM improved cell viability of cardiomyocytes in the presence of a deleterious dose of ethanol. Importantly, the co-treatment of resveratrol with ethanol exhibited the restoration of connexin 43 protein. Further assays showed that these effects were likely associated with the antioxidative actions of resveratrol, and correlated with the alleviation of MAP kinase activation in cultured cardiomyocytes in response to ethanol. Our data suggests a novel mechanism of cardiomyocyte cell loss under ethanol exposure and provides new evidence of protective effects of resveratrol in the cardiomyocytes. PMID- 28349185 TI - [First-line therapy for locally advanced or metastatic urothelial carcinoma : A randomized, controlled phase III trial comparing pembrolizumab with or without platinum-based combination chemotherapy and chemotherapy only in patients with advanced or metastatic urothelial carcinoma (keynote 361-AB 54/16 of the AUO)]. PMID- 28349184 TI - The Reliability of a Semi-automated Algorithm for Detection of Cortical Interruptions in Finger Joints on High Resolution CT Compared to MicroCT. AB - We developed a semi-automated algorithm for the detection of cortical interruptions in finger joints using high-resolution peripheral quantitative computed tomography (HR-pQCT). Here, we tested its reliability compared to microCT (uCT) as gold standard. Nineteen joints of 10 female anatomic index fingers were imaged by HR-pQCT and uCT (82 and 18 um isotropic voxel sizes, respectively). The algorithm was applied for detection of cortical interruptions of different minimum diameters (range >0.16 to >0.50 mm). Reliability was tested at the joint level with intra-class correlation coefficient (ICC) for the number of interruptions and interruption surface, and at the level of a single interruption for matching between HR-pQCT and uCT with a fixed interruption diameter (>0.10 mm) on uCT. The positive predictive value (PPV0.10mm) and sensitivity0.10mm were evaluated. The mean number of interruptions per joint depended on the diameter cut-off and ranged from 3.4 to 53.5 on HR-pQCT and from 1.8 to 45.1 on uCT for interruptions >0.50 to >0.16 mm, respectively. Reliability at the joint level was almost perfect (ICC >=0.81) for both the number and surface of interruptions >0.16 and >0.33 mm. As expected, the PPV0.10mm increased with increasing interruption diameter from 84.9 to 100%, for interruptions >0.16 and >0.50 mm, respectively. However, the sensitivity0.10mm decreased with increasing interruption diameter from 62.4 to 4.7%. This semi-automated algorithm for HR-pQCT in finger joints performed best for the detection of cortical interruptions with a minimum diameter of >0.16 or >0.33 mm, showing almost perfect reliability at the joint level and interruptions matched with those on uCT. PMID- 28349179 TI - Current challenges in the management of sepsis in ICUs in resource-poor settings and suggestions for the future. AB - BACKGROUND: Sepsis is a major reason for intensive care unit (ICU) admission, also in resource-poor settings. ICUs in low- and middle-income countries (LMICs) face many challenges that could affect patient outcome. AIM: To describe differences between resource-poor and resource-rich settings regarding the epidemiology, pathophysiology, economics and research aspects of sepsis. We restricted this manuscript to the ICU setting even knowing that many sepsis patients in LMICs are treated outside an ICU. FINDINGS: Although many bacterial pathogens causing sepsis in LMICs are similar to those in high-income countries, resistance patterns to antimicrobial drugs can be very different; in addition, causes of sepsis in LMICs often include tropical diseases in which direct damaging effects of pathogens and their products can sometimes be more important than the response of the host. There are substantial and persisting differences in ICU capacities around the world; not surprisingly the lowest capacities are found in LMICs, but with important heterogeneity within individual LMICs. Although many aspects of sepsis management developed in rich countries are applicable in LMICs, implementation requires strong consideration of cost implications and the important differences in resources. CONCLUSIONS: Addressing both disease-specific and setting-specific factors is important to improve performance of ICUs in LMICs. Although critical care for severe sepsis is likely cost-effective in LMIC setting, more detailed evaluation at both at a macro- and micro-economy level is necessary. Sepsis management in resource-limited settings is a largely unexplored frontier with important opportunities for research, training, and other initiatives for improvement. PMID- 28349186 TI - [Surgery for metastatic prostate cancer]. PMID- 28349187 TI - [Primary prostatic sarcoma - a rare malignancy]. AB - Primary prostatic sarcomas are rare, reportedly comprising less than 1% of all prostate malignancies. Most patients present with lower urinary tract symptoms due to bladder outlet obstruction. Prostate-specific antigen (PSA) is typically normal. Histological confirmation and staging by a computed tomography (CT) or magnetic resonance imaging (MRI) scan of the pelvis and abdomen are essential for diagnosis and treatment planning. The differential diagnosis includes sarcomatoid prostate cancer or benign spindle cell tumors. Primary prostatic sarcomas are often aggressive and require multimodal treatment with surgery and (neo)adjuvant radiation and/or chemotherapy. The risk of local recurrence is high and the long term prognosis is poor. PMID- 28349188 TI - [Erectile dysfunction : Current diagnostics and treatment]. AB - Erectile dysfunction is a medical disease with extensive influence on the quality of life and well-being of patients and their female or male partners. Nowadays, most of the underlying pathological factors are well known. The general medical history with the question of possible risk factors and the specific sexual history play the most important roles in the guideline-based diagnostics. In addition, a thorough clinical examination and specific laboratory tests should be carried out. Phosphodiesterase 5 (PDE-5) inhibitors, vacuum devices, injection therapy and penile prostheses are the options for an evidence-based and individual treatment of affected patients. The success rates are high in most cases. Every urologist, andrologist and practitioner of sexual medicine should have detailed knowledge in this field. PMID- 28349189 TI - [Level IV inferior vena cava tumor thrombus : A rare diagnosis in patients with renal cell carcinoma]. AB - Renal cell carcinoma in combination with a supradiaphragmatic tumor thrombus is a rare tumor entity. Radical surgery including nephrectomy and thrombectomy is still considered standard treatment. The extent of the tumor thrombus should be preoperatively evaluated by MRI and TEE. An interdisciplinary team is important for surgery planning and realization. Despite the known risks of an operation, a longer overall survival is achieved. PMID- 28349190 TI - [When should the primary tumor of metastatic bladder or prostate cancer be treated using a nonsurgical regimen?] AB - BACKGROUND: Patients with metastatic and locally advanced bladder or prostate cancer may suffer from pelvic symptoms such as pain, obstruction, and hemorrhage. Local tumor growth is associated with significant morbidity and systemic therapy is often ineffective. Local therapies such as bladder irrigation, transurethral resection of the prostate, and fulguration of bleeding vessels provide relief but often require repeated treatments. OBJECTIVES: The aim of this work was to review the current status of palliative pelvic radiotherapy for metastatic bladder and prostate cancer. MATERIALS AND METHODS: The available literature was evaluated and treatment recommendations are proposed depending on different clinical scenarios. RESULTS: To date, no standard regimen exists for the delivery of palliative pelvic radiotherapy. Various radiotherapy schedules manage successful and long-term palliation of pelvic symptoms in most patients and result in acceptable toxicity. For bladder cancer, the most common dose and fractionation regimens range from 20 Gy in 5 fractions to 40 Gy in 20 fractions. Some retrospective studies evaluated 6 weekly fractions of 6 Gy to a total dose of 36 Gy. For prostate cancer, the most common dose and fractionation regimes range from 30 Gy in 10 fractions to 50 Gy in 25 fractions. The symptomatic response rate is between 70 and 95%. CONCLUSIONS: Pelvic radiotherapy for patients with metastatic and locally advanced bladder or prostate cancer provides effective and long-term palliation of a variety of symptoms such as pain, obstruction, and hemorrhage, with acceptable toxicity. Future studies should investigate the optimal target dose and fractionation schedule. PMID- 28349191 TI - A Risk-Based Ecohydrological Approach to Assessing Environmental Flow Regimes. AB - For several decades there has been recognition that water resource development alters river flow regimes and impacts ecosystem values. Determining strategies to protect or restore flow regimes to achieve ecological outcomes is a focus of water policy and legislation in many parts of the world. However, consideration of existing environmental flow assessment approaches for application in Queensland identified deficiencies precluding their adoption. Firstly, in managing flows and using ecosystem condition as an indicator of effectiveness, many approaches ignore the fact that river ecosystems are subjected to threatening processes other than flow regime alteration. Secondly, many focus on providing flows for responses without considering how often they are necessary to sustain ecological values in the long-term. Finally, few consider requirements at spatial-scales relevant to the desired outcomes, with frequent focus on individual places rather than the regions supporting sustainability. Consequently, we developed a risk-based ecohydrological approach that identifies ecosystem values linked to desired ecological outcomes, is sensitive to flow alteration and uses indicators of broader ecosystem requirements. Monitoring and research is undertaken to quantify flow-dependencies and ecological modelling is used to quantify flow-related ecological responses over an historical flow period. The relative risk from different flow management scenarios can be evaluated at relevant spatial-scales. This overcomes the deficiencies identified above and provides a robust and useful foundation upon which to build the information needed to support water planning decisions. Application of the risk assessment approach is illustrated here by two case studies. PMID- 28349192 TI - [Interstitial processes of the lungs in childhood]. AB - Interstitial processes in the lungs of children can be due to several underlying diseases. Knowledge of the child's age is important as genetic aberrations play a major role in diseases in the first 2 years, whereas immunological diseases are more common starting in kindergarden age. In general lung diseases are rare in children, which makes the diagnostics difficult and results in a delayed diagnosis. In addition, pediatric pulmonologists are often very reluctant to perform lung biopsies due to a lack of a specialized pathologist. In order to make a contribution to the diagnostics of pediatric pulmonary diseases, pathologists should be specialized in pulmonary pathology, have a good knowledge of genetic methods and fetal lung development, which includes the genetic factors involved in lung growth and differentiation. A close cooperation with the pediatric pulmonologist is necessary and each patient should be discussed jointly on an interstitial lung disease board to promote the quality of diagnostics. The pathologist should be aware that the developing lungs of children are not just a smaller form of adult lungs and often react very differently. In this article, we mainly focus on diffuse infiltration patterns, such as ground glass and reticulonodular infiltrations as described in high-resolution computed tomography (HRCT). Localized interstitial processes, which can sometimes be tumor-like and malformations are not dealt with; however, vascular malformations are included as these often manifest as diffuse interstitial infiltrations and must therefore be taken into consideration for the differential diagnostics. PMID- 28349193 TI - Time-matched analysis of DNA adduct formation and early gene expression as predictive tool for renal carcinogenesis in methylazoxymethanol acetate treated Eker rats. AB - Genotoxic carcinogens pose great hazard to human health. Uncertainty of current risk assessment strategies and long latency periods between first carcinogen exposure and diagnosis of tumors have raised interest in predictive biomarkers. Initial DNA adduct formation is a necessary step for genotoxin induced carcinogenesis. However, as DNA adducts not always translate into tumorigenesis, their predictive value is limited. Here we hypothesize that the combined analysis of pro-mutagenic DNA adducts along with time-matched gene expression changes could serve as a superior prediction tool for genotoxic carcinogenesis. Eker rats, heterozygous for the tuberous sclerosis (Tsc2) tumor suppressor gene and thus highly susceptible towards genotoxic renal carcinogens, were continuously treated with the DNA alkylating carcinogen methylazoxymethanol acetate (MAMAc). Two weeks of MAMAc treatment resulted in a time-dependent increase of O6 methylguanine and N7-methylguanine adducts in the kidney cortex, which was however not reflected by significant expression changes of cyto-protective genes involved in DNA repair, cell cycle arrest or apoptosis. Instead, we found a transcriptional regulation of genes involved in the tumor-related MAPK, FoxO and TGF-beta pathways. Continuous MAMAc treatment for up to 6 months resulted in a mild but significant increase of cancerous lesions. In summary, the combined analysis of DNA adducts and early gene expression changes could serve as a suitable predictive tool for genotoxicant-induced carcinogenesis. PMID- 28349195 TI - To block it, or not to block it? PMID- 28349197 TI - Performance of the 2015 American College of Rheumatology/European League Against Rheumatism gout classification criteria in Thai patients. AB - To evaluate the sensitivity and specificity of the 2015 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) gout classification criteria in Thai patients presenting with acute arthritis in a real-life setting. Data were analyzed on consecutive patients presenting with arthritis of less than 2 weeks duration. Sensitivity and specificity were calculated by using the presence of monosodium urate (MSU) crystals in the synovial fluid or tissue aspirate as gold standard for gout diagnosis. Subgroup analysis was performed in patients with early disease (<=2 years), established disease (>2 years), and those without tophus. Additional analysis also was performed in non-tophaceous gout patients, and patients with acute calcium pyrophosphate dihydrate crystal arthritis were used as controls. One hundred and nine gout and 74 non-gout patients participated in this study. Full ACR/EULAR classification criteria had sensitivity and specificity of 90.2 and 90.0%, respectively; and 90.2 and 85.0%, respectively, when synovial fluid microscopy was excluded. Clinical-only criteria yielded sensitivity and specificity of 79.8 and 87.8%, respectively. The criteria performed well among patients with early and non-tophaceous disease, but had lower specificity in patients with established disease. The variation of serum uric acid level was a major limitation of the classification criteria. The ACR/EULAR classification criteria had high sensitivity and specificity in Thai patients presenting with acute arthritis, even when clinical criteria alone were used. PMID- 28349196 TI - Decreased mRNA expression levels of DNA methyltransferases type 1 and 3A in systemic lupus erythematosus. AB - OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic relapsing autoimmune disease characterized by the presence of autoantibodies directed against nuclear antigens and by chronic inflammation. Although the etiology of SLE remains unclear, the influence of environment factors, which is largely reflected by the epigenetic mechanisms, with DNA methylation changes in particular, is generally considered as main players in the pathogenesis of SLE. We studied DNA methyltransferases' (DNMTs) type 1, 3A and 3B transcript levels in peripheral blood mononuclear cells from patients diagnosed with systemic lupus erythematosus and from the healthy control subjects. Furthermore, the association of DNMT1, DNMT3A, and DNMT3B mRNA levels with gender, age, and major clinical manifestations was analyzed. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 32 SLE patients and 40 healthy controls. Reverse transcription and real-time quantitative polymerase chain reaction (RT-qPCR) analyses were used to determine DNMT1, DNMT3A, and DNMT3B mRNA expression levels. RESULTS: Significantly lower DNMT1 (p = 0.015543) and DNMT3A (p = 0.003652) transcript levels in SLE patients were observed compared with healthy controls. Nevertheless, the DNMT3B mRNA expression levels were markedly lower compared with DNMT1 and DNMT3A, both in PBMCs from affected patients and those from control subjects. Furthermore, the DNMT1 transcript levels were positively correlated with SLE disease activity index (SLEDAI) (r s = 0.4087, p = 0.020224), while the DNMT3A transcript levels were negatively correlated with patients age (r s = 0.3765, p = 0.03369). CONCLUSIONS: Our analyses confirmed the importance of epigenetic alterations in SLE etiology. Moreover, our results suggest that the presence of some clinical manifestations, such as phototosensitivity and arthritis, might be associated with the dysregulation of DNA methyltransferases' mRNA expression levels. PMID- 28349198 TI - Benign neonatal deep hypothermia in rodents and its relations to hibernation. AB - The neonates of many rodent species survive deep hypothermia (T b = 0-8 degrees C). In key respects, this hypothermia is more akin to hibernation than was thought during much of the twentieth century, indicating that studies of neonatal hypothermia may usefully supplement studies of hibernation in understanding evolved tissue adaptations to near-freezing T b. To clarify evolutionary diversity in neonatal survival of deep hypothermia, neonates of six species or strains were subjected to a standardized procedure: exposure for 2.5 h to test T bs followed by autoresuscitation. Mus and Peromyscus differed dramatically, the lowest T b survived by all ages studied (3-10 days) being 7-8 degrees C in Mus and 0-1 degrees C in Peromyscus. There was, however, no evidence of intrageneric plasticity because feral and laboratory Mus were identical, and Peromyscus species with cold- and warm-climate distribution ranges were identical. When neonates survive deep hypothermia, a key question is whether the experience is benign, meaning neonates tolerate hypothermia. To test the benign nature of deep hypothermia, neonates of Peromyscus leucopus were exposed four times (3 h each) to T b = 1-2 degrees C when 3-10 days old; controls were same-sex siblings not hypothermia exposed. When 74 such sibling pairs were exposed after weaning to predation by screech owls, the hypothermia-treated and control siblings did not differ in which was caught first. Based on study of deaths in 253 sibling pairs prior to weaning while under parental care, parents cared for hypothermia-treated siblings as attentively as controls. The results indicate that the experience of multiple neonatal deep-hypothermic episodes is benign in P. leucopus. PMID- 28349194 TI - Arthritis models: usefulness and interpretation. AB - Animal models of arthritis are used to better understand pathophysiology of a disease or to seek potential therapeutic targets or strategies. Focusing on models currently used for studying rheumatoid arthritis, we show here in which extent models were invaluable to enlighten different mechanisms such as the role of innate immunity, T and B cells, vessels, or microbiota. Moreover, models were the starting point of in vivo application of cytokine-blocking strategies such as anti-TNF or anti-IL-6 treatments. The most popular models are the different types of collagen-induced arthritis and arthritis in KBN mice. As spontaneous arthritides, human TNF-alpha transgenic mice are a reliable model. It is mandatory to use animal models in the respect of ethical procedure, particularly regarding the number of animals and the control of pain. Moreover, design of experiments should be of the highest level, animal models of arthritis being dedicated to exploration of well-based novelties, and never used for confirmation or replication of already proven concepts. The best interpretations of data in animal models of arthritis suppose integrated research, including translational studies from animals to humans. PMID- 28349200 TI - Dispersal traits may reflect dispersal distances, but dispersers may not connect populations demographically. AB - Ecological traits that reflect movement potential are often used as proxies for measured dispersal distances. Whether such traits reflect actual dispersal is often untested. Such tests are important because maximum dispersal distances may not be achieved and many dispersal events may be unsuccessful (without reproduction). For insects, many habitat patches harbour 'resident' species that are present as larvae (sedentary) and adults (winged and dispersing), and 'itinerant' species present only as adults that have dispersed from elsewhere and fail to reproduce. We tested whether itinerancy patterns were temporally consistent, and whether itinerant and resident species differed in wing morphology, a strong correlate of flight capability. Over 3 years and at multiple locations in a 22 km stream length, we sampled larvae and adults of caddisflies in the genus Ecnomus to categorize species as residents or itinerants. Flight capacity was measured using wing size (length and area) and shape parameters (aspect ratio and the second moment of wing area). Three species of Ecnomus were residents and three species were itinerants, and patterns were consistent over 3 years. On average, itinerant species had larger wings, suggesting a greater capacity to fly long distances. Wing shape differed between species, but did not differ systematically between residents and itinerants. Wing morphology was associated with actual but not effective dispersal of some species of Ecnomus. Morphological traits may have weak explanatory power for hypotheses regarding the demographic connectedness of populations, unless accompanied by data demonstrating which dispersers contribute new individuals to populations. PMID- 28349201 TI - Airway spray efficacy of local anesthetic with fiberscope. PMID- 28349199 TI - Amyloid-beta accumulation in the CNS in human growth hormone recipients in the UK. AB - Human-to-human transmission of Creutzfeldt-Jakob disease (CJD) has occurred through medical procedures resulting in iatrogenic CJD (iCJD). One of the commonest causes of iCJD was the use of human pituitary-derived growth hormone (hGH) to treat primary or secondary growth hormone deficiency. As part of a comprehensive tissue-based analysis of the largest cohort yet collected (35 cases) of UK hGH-iCJD cases, we describe the clinicopathological phenotype of hGH iCJD in the UK. In the 33/35 hGH-iCJD cases with sufficient paraffin-embedded tissue for full pathological examination, we report the accumulation of the amyloid beta (Abeta) protein associated with Alzheimer's disease (AD) in the brains and cerebral blood vessels in 18/33 hGH-iCJD patients and for the first time in 5/12 hGH recipients who died from causes other than CJD. Abeta accumulation was markedly less prevalent in age-matched patients who died from sporadic CJD and variant CJD. These results are consistent with the hypothesis that Abeta, which can accumulate in the pituitary gland, was present in the inoculated hGH preparations and had a seeding effect in the brains of around 50% of all hGH recipients, producing an AD-like neuropathology and cerebral amyloid angiopathy (CAA), regardless of whether CJD neuropathology had occurred. These findings indicate that Abeta seeding can occur independently and in the absence of the abnormal prion protein in the human brain. Our findings provide further evidence for the prion-like seeding properties of Abeta and give insights into the possibility of iatrogenic transmission of AD and CAA. PMID- 28349202 TI - Prevention of chronic post-surgical pain: the importance of early identification of risk factors. AB - Chronic post-surgical pain (CPSP) is currently an inevitable surgical complication. Despite the advances in surgical techniques and the development of new modalities for pain management, CPSP can affect 15-60% of all surgical patients. The development of chronic pain represents a burden to both the patient and to the community. In order to have a meaningful impact on this debilitating condition it is essential to identify those at risk. Early identification of patients at risk will help to reduce the percentage of patients who go on to develop CPSP. Unfortunately, evidence about any effective actions to reduce this condition is limited. This review will focus on providing context to the challenging problem of CPSP. The possible role of both the surgeon and anesthesiologist in reducing the incidence of this problem will be explored. PMID- 28349203 TI - Can the descending aortic stroke volume be estimated by transesophageal descending aortic photoplethysmography? AB - PURPOSE: The aim of this study was to investigate the ability of transesophageal photoplethysmography detected from the descending aorta (dPPG) for predicting low descending aortic stroke volume (dSV) level in cardiac surgical patients. METHODS: Fifteen patients scheduled for elective cardiac surgery were enrolled in our study. A transesophageal echocardiography (TEE) probe with an attached oximetry sensor was placed into the esophagus for paired dPPG signal and descending aortic Doppler blood flow signal acquisition. Metrics, including alternating current (AC), direct current (DC), area under the curve (AUC) and width (W), were extracted from the dPPG signals. The TEE-measured dSV, which was defined as the blood flow through the descending aorta during a cardiac cycle, was chosen as the standard reference. A receiver operating characteristic (ROC) curve was built to evaluate the performance of dPPG metrics in predicting low dSV level, and dSV measuring agreement between TEE and dPPG was analyzed by the Bland Altman method. RESULTS: A total of 644 paired dPPG and Doppler signals of the descending aorta were acquired. Significant correlations were found between the dPPG metrics and TEE-measured dSV, and the correlation coefficients between TEE measured dSV and AUC or AC were 0.64 and 0.66, respectively. AUC and AC values obviously decreased with the reduction of dSV level among the three groups (<20 mL, from 20-40 mL, and >40 mL). The areas under the ROC curve for AUC and AC in predicting low dSV level (<20 mL) were 0.85 and 0.88, respectively. Bland-Altman plot showed a small bias (0.02 mL) but a wide limit of agreement (-18.62 to 18.66 mL) in dSV measurement between dPPG and Doppler technology. CONCLUSIONS: The AC and AUC extracted from the dPPG signal provided a sensitive and qualitative prediction for dSV level. The dSV value could not be accurately measured by dPPG metrics. TRIAL REGISTRATION: Chinese Clinical Trials Register Identifier: ChiCTR OCS-12002789. PMID- 28349205 TI - Prevalence and clinical features of sports-related lumbosacral stress injuries in the young. AB - BACKGROUND: Stress injuries (stress fractures and stress reactions) of the lumbosacral region are one of the causes of sports-related lower back pain in young individuals. These injuries can be detected by bone marrow edema lesion on MRI. However, little is known about the prevalence and clinical features of early stage lumbosacral stress injuries. This study aimed to evaluate the epidemiology of lumbosacral stress injuries. METHODS: A total of 312 patients (under 18 years of age) who complained of sports-related lower back pain that had lasted for >=7 days underwent magnetic resonance imaging (MRI) scans. We reviewed patients' records retrospectively. RESULTS: MRI showed that 33.0% of the patients had lumbar stress injuries and 1.6% had sacral stress injuries. Lumbar stress injuries were more common in males than in females and were found in 30% of 13- to 18-year-old patients. About 50% of the patients that participated in soccer or track and field were diagnosed with lumbar stress injuries. No clinical patterns in the frequencies of sacral stress injuries were detected due to the low number of patients that suffered this type of injury. Plain radiography is rarely able to detect the early stage lesions associated with lumbosacral stress injuries, but such lesions can be detected in the caudal-ventral region of the pars interarticularis on sagittal computed tomography scans. Thirty-three percent of young patients that complained of sports-related lower back pain for >=7 days had lumbar stress injuries, while 1.6% of them had sacral stress injuries. Clinicians should be aware of the existence of these injuries. MRI is useful for diagnosing lumbosacral stress injuries. PMID- 28349204 TI - Relationship between response to induction chemotherapy and disease control in patients with advanced laryngeal carcinoma included in an organ preservation protocol. AB - The aim of the study is to analyze the relationship between the degree of response to induction chemotherapy and the disease control in patients with locally advanced laryngeal carcinomas candidates to total laryngectomy. This retrospective study includes 389 patients with T3-T4 laryngeal tumors candidates to total laryngectomy, diagnosed between 1985 and 2013, treated with induction chemotherapy in an organ preservation protocol. Five-year local recurrence-free survival for patients receiving conservative treatment with radiotherapy after a complete response to induction chemotherapy was 75.4%; for patients with partial response greater than 50%, it was 62.0%; and for patients with the absence of response, it was 32.7%. There were significant differences in local recurrence free survival and laryngeal dysfunction-free survival according to the response to induction chemotherapy (P = 0.0001) at the expense of patients with absence of response to induction chemotherapy. Patients with partial response greater than 50% treated with radiotherapy had a tendency to have worse local recurrence-free survival and laryngeal dysfunction-free survival than patients with complete response, but the differences did not reach statistical significance. Patients with the absence of response after induction chemotherapy had significant differences in disease-specific survival according to the second treatment: for patients treated with surgery it was 70.2%, whereas for patients treated with radiotherapy, it was 28.2% (P = 0.0001). In patients with the absence of response to induction chemotherapy, conservative treatment with radiotherapy implies a significant decrease in survival. PMID- 28349206 TI - Impingement of the patellar component against the tibial post after posterior stabilized and constrained TKA: a pilot study. AB - INTRODUCTION: Patella-post impingement (PPI), contact of the patellar component with the tibial post, occurs during deep knee flexion after posterior stabilized total knee arthroplasty (TKA). PPI can cause anterior knee pain, increased patellar pressure, wear of the polyethylene patellar component and tibial post, and poor range of motion. There have been no reports on the relationship between PPI and tibial post design. The aim of this study was to compare different tibial post designs with regard to PPI incidence. MATERIALS AND METHODS: Five posterior stabilized total knee prostheses were implanted in full-length models of the femur and tibia (Sawbones) using a navigation system. The thickness of the tibial component was 10 mm in all prostheses. The patella was set on a transparent polypropylene sheet, which was fixed to the tibial tubercle. The distance between the lower edge of the patellar component and the cut surface of the tibia was defined as the tibial-patellar clearance (TPC), which represents the length of the patellar tendon. The TPC was varied from 18 to 40 mm and the knee was moved from full extension to deep flexion while the knee angle at which PPI occurred (PPI angle) was recorded. RESULTS: The PPI angle differed between tibial post designs (p < 0.05). Shorter TPCs resulted in smaller PPI angles and longer TPCs resulted in larger PPI angles (p < 0.05). CONCLUSIONS: This is the first study to analyze the relationship between PPI and the design of tibial post. Our results clearly show that tibial post design and TPC affect PPI. To avoid patellar component and tibial post impingement in deep flexion, appropriate TPC must be achieved during surgery. Improvements in tibial post design, especially in constrained prostheses, are also desirable. This study highlights the potential risk of PPI during deep flexion after TKA. PMID- 28349207 TI - Trends in National Institutes of Health-Funded Congenital Heart Disease Research from 2005 to 2015. AB - In an era of ongoing need for research to enable evidence-based care for the expanding population with congenital heart disease (CHD), economic fluctuations have impacted research funding. We characterize trends in NIH-funded CHD research from 2005 to 2015. We searched the NIH RePORTER database from 2005 to 2015 using the terms "congenital heart" and "cardiac morphogenesis". Projects were characterized by year, institute, mechanism, costs, type and topic, and funding trends were analyzed. From 2005 to 2015, NIH funded 633 CHD research projects with total costs of $991 million. The National Heart, Lung, and Blood Institute funded 83% of CHD projects (528, $857 million). The R01 mechanism was used for 45% of projects (288, $421 million). Projects were 70% basic/early translational research, 27% clinical research, and 3% both. Cardiac developmental biology was the most common topic (52%), followed by technology/therapy development (15%), and diagnosis/management (12%). The total number of CHD projects ranged from 153 to 221 per year (30-58 new projects/year), and costs per year ranged from $58 to $116 million. The number of projects and total costs increased until 2012, but decreased again thereafter. CHD research did not experience as much erosion as overall NIH purchasing power; in constant dollars, CHD research funding levels in 2015 were $12 million higher than those in 2005. The NIH supported a diverse portfolio of CHD projects from 2005 to 2015. Support of CHD research projects trended upward until 2012, but declined thereafter due to fiscal austerity measures. PMID- 28349208 TI - Periventricular White Matter Lesions as a Prognostic Factor of Swallowing Function in Older Patients with Mild Stroke. AB - Older patients with stroke have poor functional prognosis compared to younger patients. Patients with stroke who have severe white matter (WM) lesions have been reported to have poor functional prognosis such as cognitive dysfunction, increased propensity for falling, and gait and balance problems. The aim of this study was to determine whether WM lesions exert negative effects on swallowing function in older patients with mild stroke. We conducted a retrospective analysis of 63 patients aged >65 years who had a National Institutes of Health Stroke Scale score <=5 and who underwent videofluoroscopic swallowing examination after their first stroke. Linear regression analysis showed that oral transit time tended to increase as Fazekas grade increased (p = 0.003). In addition, inadequate mastication was related to the presence of lesions in the left hemisphere (p = 0.039). The presence of penetration could also be predicted by Fazekas grade (p = 0.015). Our findings suggest that WM lesions observed in brain magnetic resonance imaging scans can impact swallowing problems in older patients with mild stroke, regardless of initial stroke severity or other factors associated with lesion location. Accordingly, our data indicate that WM lesions are a predictive factor by which patients can be stratified into favorable or unfavorable outcomes with respect to dysphagia. PMID- 28349209 TI - Phenytoin: a step by step insight into its multiple mechanisms of action-80 years of mechanistic studies in neuropharmacology. PMID- 28349210 TI - Subacute parkinsonism as a complication of Lyme disease. PMID- 28349212 TI - Erratum to: Evaluating Mendelian nephrotic syndrome genes for evidence for risk alleles or oligogenicity that explain heritability. PMID- 28349211 TI - Shoulder hemiarthroplasty for proximal humeral fractures: analysis of clinical and radiographic outcomes at midterm follow-up: a series of 51 patients. AB - Shoulder hemiarthroplasty has historically been the gold standard treatment for proximal humeral fractures not suitable to open reduction and internal fixation. In the last decades, reverse shoulder arthroplasty has gained more and more importance. Aim of this study is to retrospectively analyze subjective and objective outcomes of a group of consecutive patients. Fifty-one patients were evaluated with a mean follow-up of 18 months (range 12-60). For all the cases, the same surgical technique was performed in all cases. Range of motion, Constant Murley score, ponderate Constant-Murley score, visual analog score and a patients' self-assessment scale were calculated. Anatomic tuberosities healing, stem positioning or mobilization were evaluated on postoperative X-rays and follow-up CT-scans. Statistical analysis was performed to calculate a correlation between subjective and objective results. Thirty-five patients (75%) declared to be satisfied of the operated shoulder. The mean CMS was 50 (17-91), the mean pCMS 72 (16-111). The mean forward flexion measured was 98 degrees (40 degrees -170 degrees ), the mean external rotation with adducted arm 22 degrees (0 degrees 60 degrees ), the mean internal rotation at sacrum (gluteus-T12). Four implants needed revision. Forty-seven stems were correctly positioned; 84.3% of tuberosities was anatomic or low positioned and consolidated in 74.5% of cases. Statistical analysis revealed significant correlation between CMS, pCMS, VAS and subjective satisfaction and between anatomic tuberosities healing and 3-part fractures. HA implant is a valid and reliable technique for the treatment of proximal humeral fracture. From our data, patients' satisfaction depends upon pain relief more than upon restore of function. PMID- 28349213 TI - Diabetes in a child on growth hormone therapy: Questions. PMID- 28349214 TI - Diabetes in a child on growth hormone therapy: Answers. PMID- 28349215 TI - Adherence in pediatric kidney transplant recipients: solutions for the system. AB - Non-adherence remains a significant problem among pediatric (and adult) renal transplant recipients. Non-adherence among solid organ transplant recipients results in US$15-100 million annual costs. Estimates of non-adherence range from 30 to 70% among pediatric patients. Research demonstrates that a 10% decrement in adherence is associated with 8% higher hazard of graft failure and mortality. Focus has begun to shift from patient factors that impact adherence to the contributing healthcare and systems factors. The purpose of this review is to describe problems within the systems implicated in non-adherence and potential solutions that may be related to positive adherence outcomes. Systems issues include insurance and legal regulations, provider and care team barriers to optimal care, and difficulties with transitioning to adult care. Potential solutions include recognition of how systems can work together to improve patient outcomes through improvements in insurance programs, a multi-disciplinary care team approach, evidence-based medical management, pharmacy-based applications and interventions to simplify medication regimens, improved transition protocols, and telehealth/technology-based multi-component interventions. However, there remains a significant lack of reliability in the application of these potential solutions to systems issues that impact patient adherence. Future efforts should accordingly focus on these efforts, likely by leveraging quality improvement and related principles, and on the investigation of the efficacy of these interventions to improve adherence and graft outcomes. PMID- 28349217 TI - Modulation of microglia in the retina: new insights into diabetic retinopathy. AB - During last decades, the diagnosis of diabetes has been associated with several chronic complications such as diabetic retinopathy (DR). Recent studies of DR have revealed an inflammatory component, which precedes the detection of alterations in the visual function. During DR, the inflammatory process presents two opposite roles depending on the polarization of resident immune cells of the retina triggering proinflammatory (M1) or antiinflammatory (M2) actions. In an early stage of DR, the M2 response concurs with the M1 and is able to ameliorate inflammation and delay the progression of the disease. However, during the progression of DR, the M1 response is maintained whereas the M2 declines and, in this scenario, the classical proinflammatory signaling pathways are chronically activated leading to retinal neurodegeneration and the loss of visual function. The M1/M2 responses are closely related to the activation and polarization of microglial cells. This review aims to offer an overview of the recent insights into the role of microglial cells during inflammation in DR. We have focused on the possibility of modulating microglia polarization as a new therapeutic strategy in DR treatments. PMID- 28349216 TI - Does warming by open-top chambers induce change in the root-associated fungal community of the arctic dwarf shrub Cassiope tetragona (Ericaceae)? AB - Climate change may alter mycorrhizal communities, which impact ecosystem characteristics such as carbon sequestration processes. These impacts occur at a greater magnitude in Arctic ecosystems, where the climate is warming faster than in lower latitudes. Cassiope tetragona (L.) D. Don is an Arctic plant species in the Ericaceae family with a circumpolar range. C. tetragona has been reported to form ericoid mycorrhizal (ErM) as well as ectomycorrhizal (ECM) symbioses. In this study, the fungal taxa present within roots of C. tetragona plants collected from Svalbard were investigated using DNA metabarcoding. In light of ongoing climate change in the Arctic, the effects of artificial warming by open-top chambers (OTCs) on the fungal root community of C. tetragona were evaluated. We detected only a weak effect of warming by OTCs on the root-associated fungal communities that was masked by the spatial variation between sampling sites. The root fungal community of C. tetragona was dominated by fungal groups in the Basidiomycota traditionally classified as either saprotrophic or ECM symbionts, including the orders Sebacinales and Agaricales and the genera Clavaria, Cortinarius, and Mycena. Only a minor proportion of the operational taxonomic units (OTUs) could be annotated as ErM-forming fungi. This indicates that C. tetragona may be forming mycorrhizal symbioses with typically ECM-forming fungi, although no characteristic ECM root tips were observed. Previous studies have indicated that some saprophytic fungi may also be involved in biotrophic associations, but whether the saprotrophic fungi in the roots of C. tetragona are involved in biotrophic associations remains unclear. The need for more experimental and microscopy-based studies to reveal the nature of the fungal associations in C. tetragona roots is emphasized. PMID- 28349218 TI - Association of Inflammatory Status and Maxillary Sinus Schneiderian Membrane Thickness. AB - OBJECTIVES: Certain Schneiderian membrane thicknesses (SMT) have shown to be more prone to tearing/perforation, and some pathologies might influence SMT. Henceforth, we aimed at studying the correlation of inflammatory status to SMT in human fresh cadaver heads. MATERIAL AND METHODS: A total of 14 fresh cadaver heads including 27 Schneiderian membrane specimens were histologically collected. A 10-item inflammatory score was determined in the entire sample and also in the thinner and thicker areas of each sample. Data was analyzed by using the Wilcoxon rank test and the Spearman's rank correlation. RESULTS: The mean measured SMT was 0.40 +/- 0.12 mm and the median was 0.33 +/- 0.12 mm. A weak positive correlation was found between the mean SMT and inflammation score without a statistical significance. (r = 0.385, p = 0.115). The Wilcoxon signed-rank test showed a statistical difference between the medians of the thinner and thicker areas (p < 0.001). The mean inflammation score of the thinner and thicker areas was 8.55 +/- 2.57 and 11.61 +/- 2.65, respectively. A moderate positive and statistically significant correlation was found between the inflammation score and the thickness of the thinner and thicker areas (r = 0.638, p = 0.000). CONCLUSION: A moderate association between the Schneiderian membrane thickness and the level of inflammation exists. PMID- 28349220 TI - Social Media Monitoring of Discrimination and HIV Testing in Brazil, 2014-2015. AB - Big data can be used to assess perceptions about public health issues. This study assessed social media data from Twitter to inform communication campaigns to promote HIV testing and reduce discrimination related to HIV/AIDS or towards key populations to the HIV epidemic, and its potential utility to evaluate such campaigns through HIV testing uptake. Tweets from Brazil were collected from January 2014 to March 2015 and filtered by four categories of keywords including discrimination, HIV prevention, HIV testing, and HIV campaigns. In total over 100,000 geo-located tweets were extracted and analyzed. A dynamic online dashboard updated daily allowed mapping trends, anomalies and influencers, and enabled its use for feedback to campaigns, including correcting misconceptions. These results encourage the use of social networking data for improved messaging in campaigns. Clinical HIV test data was collected monthly from the city of Curitiba and compared to the number of tweets mapped to the city showing a moderate positive correlation (r = 0.39). Results are limited due to the availability of the HIV testing data. The potential of social media as a proxy for HIV testing uptake needs further validation, which can only be done with higher frequency and higher spatial granularity of service delivery data, enabling comparisons with the social media data. Such timely information could empower early response immediate media messaging to support programmatic efforts, such as HIV prevention, testing, and treatment scale up. PMID- 28349219 TI - Bacterial colonization in the apical part of extracted human teeth following root end resection and filling: a confocal laser scanning microscopy study. AB - OBJECTIVES: The purpose of this study was to evaluate Enterococcus faecalis colonization at the apical part of root canals following root-end resection and filling using confocal laser scanning microscopy (CLSM). MATERIALS AND METHODS: The apical 3-mm root-ends of 55 extracted single rooted human teeth were resected, and 3-mm retrograde cavities were prepared and filled using either mineral trioxide aggregate (MTA), intermediate restorative material (IRM), or Biodentine (n = 10 each); 25 teeth served as controls. The roots were placed in an experimental model, sterilized, and coronally filled with E. faecalis bacterial suspension for 21 days. Then, the apical 3-mm segments were cut to get two slabs (coronal and apical). The slabs were stained using LIVE/DEAD BacLight Bacterial Viability Kit and evaluated using CLSM. RESULTS: The fluorescence stained areas were larger in the bucco-lingual directions compared with the mesio distal directions (p < 0.05). The mean and maximal depths of bacterial colonization into the dentinal tubules were 755 and 1643 MUm, respectively, with no differences between the root-end filling materials (p > 0.05). However, more live bacteria were found in the MTA group in comparison to IRM and Biodentine groups (p < 0.05). CONCLUSIONS: CLSM can be used to histologically demonstrate bacterial root-end colonization following root-end filling. This colonization at the filling-dentine interfaces and deeper into the dentinal tubules may be inhomogeneous, favoring the bucco-lingual aspects of the root. CLINICAL RELEVANCE: Following root-end resection and filling bacterial colonization may lead to inflammatory reactions at the periapical tissues; the viability of the colonized bacteria may be affected by the type of root-end filling material. PMID- 28349221 TI - Total artificial heart implantation for biventricular failure due to eosinophilic myocarditis. AB - Idiopathic hypereosinophilic syndrome is a condition of unknown etiology characterized by proliferation of eosinophils and their infiltration into tissues. Although cardiac involvement is rare, eosinophilic myocarditis can lead to life-threating fulminant congestive heart failure. Treatment of patients with eosinophilic myocarditis is challenging as heart failure can be caused by biventricular dysfunction. To our knowledge, this is the first case reported in the literature describing a patient with acute severe biventricular heart failure caused by eosinophilic myocarditis with mural left ventricular apical thrombus who was successfully treated with implantation of a total artificial heart as a bridge to heart transplant. PMID- 28349222 TI - Anticoagulation therapy for a LVAD patient with acquired warfarin resistance. AB - Anticoagulation therapy with warfarin is essential for postoperative management in patients with left ventricular assist device (LVAD). In this manuscript, we report the case of a patient who developed warfarin resistance after LVAD implantation. Although we administered a novel anticoagulant drug in addition to warfarin and aspirin therapy, the patient developed a major stroke. The patient needed continuous intravenous heparinization until heart transplantation for approximately 2 years. Meticulous management of anticoagulation therapy is essential for a LVAD with warfarin resistance. To our best knowledge, our case is the first case of warfarin resistance in a patient with LVAD. PMID- 28349224 TI - Society of Abdominal Radiology Disease-Focused Panel Program: rationale for its genesis and status report. PMID- 28349223 TI - The Orexin System and Hypertension. AB - In this review, we focus on the role of orexin signaling in blood pressure control and its potential link to hypertension by summarizing evidence from several experimental animal models of hypertension. Studies using the spontaneously hypertensive rat (SHR) animal model of human essential hypertension show that pharmacological blockade of orexin receptors reduces blood pressure in SHRs but not in Wistar-Kyoto rats. In addition, increased activity of the orexin system contributes to elevated blood pressure and sympathetic nerve activity (SNA) in dark-active period Schlager hypertensive (BPH/2J) mice, another genetic model of neurogenic hypertension. Similar to these two models, Sprague-Dawley rats with stress-induced hypertension display an overactive central orexin system. Furthermore, upregulation of the orexin receptor 1 increases firing of hypothalamic paraventricular nucleus neurons, augments SNA, and contributes to hypertension in the obese Zucker rat, an animal model of obesity-related hypertension. Finally, we propose a hypothesis for the implication of the orexin system in salt-sensitive hypertension. All of this evidence, coupled with the important role of elevated SNA in increasing blood pressure, strongly suggests that hyperactivity of the orexin system contributes to hypertension. PMID- 28349225 TI - Hepatobiliary phase MRI: impact on planning image-guided liver tumor ablations. AB - PURPOSE: To assess the impact of hepatobiliary phase images obtained during intravenous gadoxetate disodium-enhanced liver MRI in the planning of image guided liver tumor ablations. METHODS: This institutional review board-approved retrospective study included 34 patients (21 men, 13 women, ages 25-80) who underwent 36 liver MRI examinations with gadoxetate disodium within 12 weeks prior to image-guided thermal ablation of 62 liver tumors during 36 procedures. Visibility of bile ducts, subdivided by branch order, on hepatobiliary phase images was compared to standard MRI sequence images by an attending abdominal radiologist and fellow. Interventional decision making (whether or not to ablate and technical plan) using hepatobiliary phase images was compared with standard MRI sequences by the ablationists. The technical success and adverse events of ablation procedures were noted. RESULTS: Bile duct visibility was significantly increased by at least one branch order in 18/36 (50%) examinations (p < 0.0001). Interventional decisions were significantly impacted in 15 (41.7%) of 36 ablation procedures (p < 0.0001), including changes to the technical plan in six (16.7%) of these procedures (p = 0.005). Technical success was achieved for 60/62 (97%) of tumors. Mild (grade 1) adverse events occurred in 4/36 (11%) procedures; no biliary complications occurred. CONCLUSIONS: Use of hepatobiliary phase images obtained during gadoxetate disodium-enhanced liver MRI impacted both when and how to perform image-guided liver tumor ablations in our practice. PMID- 28349226 TI - Colonic diverticulosis is associated with abdominal wall hernia. AB - PURPOSE: Colonic diverticulosis and abdominal wall hernia are common pathologies. Studies have suggested that connective tissue alterations play a role in the formation of both diverticulosis and abdominal wall hernia. The aim of this cohort study was to evaluate the association between diverticulosis and abdominal wall hernia in a large cohort of patients undergoing colonoscopy. METHODS: All consecutive patients who underwent colonoscopy between 2001 and 2013 at Bispebjerg Hospital were eligible for inclusion. The endoscopists prospectively registered the findings of diverticulosis in a database. Data were merged with the Danish Hernia Database identifying patients who underwent groin and ventral hernia repair. Calculated odds ratios (ORs) were used to describe the extent of association and multivariable logistic regression models were utilized to adjust for age and gender. RESULTS: A total of 13,855 patients were included, 3685 (26.6%) of whom were diagnosed with diverticulosis. Diverticulosis was independently associated with direct inguinal, OR 1.33, 95% CI 1.00-1.76, P = 0.049, and umbilical/epigastric hernia repair, OR 1.74, 95% CI 1.16-2.63, P = 0.008. CONCLUSIONS: Colonic diverticulosis was associated with direct inguinal and umbilical/epigastric hernia repair suggesting that connective tissue alterations, herniosis, could be a common etiologic factor of colonic diverticulosis and these abdominal wall hernias. PMID- 28349227 TI - Effects of bilateral vestibular deafferentation in rat on hippocampal theta response to somatosensory stimulation, acetylcholine release, and cholinergic neurons in the pedunculopontine tegmental nucleus. AB - Vestibular dysfunction has been shown to cause spatial memory impairment. Neurophysiological studies indicate that bilateral vestibular loss (BVL), in particular, is associated with an impairment of the response of hippocampal place cells and theta rhythm. However, the specific neural pathways through which vestibular information reaches the hippocampus are yet to be fully elucidated. The aim of the present study was to further investigate the hypothesised 'theta generating pathway' from the brainstem vestibular nucleus to the hippocampus. BVL, and in some cases, unilateral vestibular loss (UVL), induced by intratympanic sodium arsanilate injections in rats, were used to investigate the effects of vestibular loss on somatosensory-induced type 2 theta rhythm, acetylcholine (ACh) release in the hippocampus, and the number of cholinergic neurons in the pedunculopontine tegmental nucleus (PPTg), an important part of the theta-generating pathway. Under urethane anaesthesia, BVL was found to cause a significant increase in the maximum power of the type 2 theta (3-6 Hz) frequency band compared to UVL and sham animals. Rats with BVL generally exhibited a lower basal level of ACh release than sham rats; however, this difference was not statistically significant. The PPTg of BVL rats exhibited significantly more choline-acetyltransferase (ChAT)-positive neurons than that of sham animals, as did the contralateral PPTg of UVL animals; however, the number of ChAT-positive neurons on the ipsilateral side of UVL animals was not significantly different from sham animals. The results of these studies indicate that parts of the theta-generating pathway undergo a significant reorganisation following vestibular loss, which suggests that this pathway is important for the interaction between the vestibular system and the hippocampus. PMID- 28349228 TI - Biofeedback Training in Crisis Managers: A Randomized Controlled Trial. AB - Working in crisis environments represents a major challenge, especially for executive personnel engaged in directing disaster operations, i.e. crisis managers. Crisis management involves operating under conditions of extreme stress resulting, for instance, from high-level decision-making, principal responsibility for personnel, multitasking or working under conditions of risk and time pressure. The present study aimed to investigate the efficacy of a newly developed biofeedback training procedure based on electrodermal activity, especially designed for the target group of crisis managers. The training comprised exercises promoting acquisition of control over sympathetic arousal under resting conditions and during exposure to visual, acoustic and cognitive stressors resembling situations related to crisis management. In a randomized controlled design, 36 crisis managers were assigned to either a biofeedback training group or waiting list control group. Subjective stress was assessed using the Perceived Stress Scale. In the training group, stress level markedly decreased; the decrease remained stable at follow-up 2 months after the training. The results indicate that biofeedback training in crisis management is an effective method for stress management that may help to reduce vulnerability to stress-related performance decline and stress-related disease. PMID- 28349229 TI - MPT0B002, a novel microtubule inhibitor, downregulates T315I mutant Bcr-Abl and induces apoptosis of imatinib-resistant chronic myeloid leukemia cells. AB - Chronic myeloid leukemia (CML) is a hematopoietic malignancy caused by the constitutive activation of Bcr-Abl tyrosine kinase. The Bcr-Abl inhibitor imatinib and other second-generation tyrosine kinase inhibitors such as dasatinib and nilotinib have remarkable efficacy in CML treatment. However, gene mutation mediated drug resistance remains a critical problem. Among point mutations, the Bcr-Abl T315I mutation confers resistance to these Bcr-Abl inhibitors. Previously, we have synthesized the compound (1-methyl-1H-indol-5-yl)-(3,4,5 trimethoxy-phenyl)-methanone (MPT0B002) as a novel microtubule inhibitor. In this study, we evaluated its effects on the proliferation, cell cycle, and apoptosis of K562 CML cells and BaF3 cells expressing either wild-type Bcr-Abl (BaF3/p210) or T315I-mutated Bcr-Abl (BaF3/T315I). MPT0B002 inhibited cell viability in a dose-dependent manner in these cells but did not affect the proliferation of human umbilical vein endothelial cells. It disrupted tubulin polymerization and arrested cell cycle at the G2/M phase. Treatment with MPT0B002 induced apoptosis, and this induction was associated with increased levels of cleaved caspase-3 and cleaved PARP. Furthermore, MPT0B002 can downregulate both Bcr-Abl and Bcr-Abl T315I mRNA expressions and protein levels and the downstream signaling pathways. Taken together, our findings suggest that MPT0B002 may be considered a promising compound to downregulate not only wild type Bcr-Abl but also the T315I mutant to overcome Bcr-Abl-T315I mutation-mediated resistance in CML cells. PMID- 28349230 TI - The Japanese Histologic Classification and T-score in the Oxford Classification system could predict renal outcome in Japanese IgA nephropathy patients. AB - BACKGROUND: The Oxford Classification is utilized globally, but has not been fully validated. In this study, we conducted a comparative analysis between the Oxford Classification and Japanese Histologic Classification (JHC) to predict renal outcome in Japanese patients with IgA nephropathy (IgAN). METHODS: A retrospective cohort study including 86 adult IgAN patients was conducted. The Oxford Classification and the JHC were evaluated by 7 independent specialists. The JHC, MEST score in the Oxford Classification, and crescents were analyzed in association with renal outcome, defined as a 50% increase in serum creatinine. RESULTS: In multivariate analysis without the JHC, only the T score was significantly associated with renal outcome. While, a significant association was revealed only in the JHC on multivariate analysis with JHC. CONCLUSIONS: The JHC and T score in the Oxford Classification were associated with renal outcome among Japanese patients with IgAN. Superiority of the JHC as a predictive index should be validated with larger study population and cohort studies in different ethnicities. PMID- 28349231 TI - Thyrotropin levels are associated with chronic kidney disease among healthy subjects in cross-sectional analysis of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - BACKGROUND: Few studies have evaluated a possible relationship between thyrotropin levels and glomerular filtration rate (GFR) and albumin/creatinine ratio in euthyroid subjects. We aimed to analyze this association using baseline data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). METHODS: Cross-sectionally, we included subjects with normal thyroid function and with subclinical hypothyroidism (SCH). We excluded individuals using medications that affect thyroid function. Linear and logistic regression models evaluated GFR estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) and albuminuria/creatinine ratio as dependent variables and thyrotropin quartiles in individuals with euthyroidism and SCH as independent variables, adjusted for demographical characteristics and diseases related to CKD. RESULTS: We included 13,193 subjects with a median age of 51 years [interquartile range, (IQR): 45 58], 6840 (51.8%) women, 12,416 (94.1%) euthyroid, and 777 (5.9%) with SCH. SCH subjects were characterized by higher age, triglycerides, frequency of white race, cardiovascular disease, CKD, and former smokers. In adjusted models, log transformed TSH in euthyroid subjects was inversely and strongly associated with CKD (beta = -2.181, 95% CI -2.714 to -1.648), P < 0.0001 for glomerular filtration rate and 4.528 (1.190-7.865) for albuminuria/creatinine ratio. Multivariate logistic models for euthyroid subjects showed an OR of 1.45 (95% CI 1.15-1.83) for GFR and of 1.95 (95% CI 1.08-3.54) for albuminuria/creatinine ratio in the fourth quartile of TSH using the first as the reference. CONCLUSIONS: Thyrotropin levels are independently associated with CKD in euthyroid subjects. PMID- 28349232 TI - Primary Care Physicians Could Play a Role in Improving Colonoscopy Quality Measures. PMID- 28349233 TI - Low-Dose Cannabidiol Is Safe but Not Effective in the Treatment for Crohn's Disease, a Randomized Controlled Trial. AB - BACKGROUND: Cannabidiol (CBD) is an anti-inflammatory cannabinoid shown to be beneficial in a mouse model of IBD. Lacking any central effect, cannabidiol is an attractive option for treating inflammatory diseases. AIM: To assess the effects of cannabidiol on Crohn's disease in a randomized placebo-controlled trial. PATIENTS AND METHODS: Twenty patients aged 18-75 years with a Crohn's disease activity index (CDAI) >200 were randomized to receive oral (10 mg) CBD or placebo twice daily. Patients did not respond to standard treatment with steroids (11 patients), thiopurines (14), or TNF antagonists (11). Disease activity and laboratory parameters were assessed during 8 weeks of treatment and 2 weeks thereafter. Other medical treatment remained unchanged. RESULTS: Of 20 patients recruited 19 completed the study. Their mean age was 39 +/- 15, and 11 were males. The average CDAI before cannabidiol consumption was 337 +/- 108 and 308 +/ 96 (p = NS) in the CBD and placebo groups, respectively. After 8 weeks of treatment, the index was 220 +/- 122 and 216 +/- 121 in the CBD and placebo groups, respectively (p = NS). Hemoglobin, albumin, and kidney and liver function tests remained unchanged. No side effects were observed. CONCLUSION: In this study of moderately active Crohn's disease, CBD was safe but had no beneficial effects. This could be due to lack of effect of CBD on Crohn's disease, but could also be due to the small dose of CBD, the small number of patients in the study, or the lack of the necessary synergism with other cannabinoids. Further investigation is warranted. CLINICALTRIALS.GOV: NCT01037322. PMID- 28349234 TI - Prostaglandin E2 Upregulated Trigeminal Ganglionic Sodium Channel 1.7 Involving Temporomandibular Joint Inflammatory Pain in Rats. AB - Prostaglandin E2 (PGE2) is a key proinflammatory mediator that contributes to inflammatory hyperalgesia. Voltage-gated sodium channel 1.7 (Nav1.7) plays an important role in inflammatory pain. However, the modulation of Nav1.7 in inflammatory pain remains poorly understood. We hypothesized that PGE2 might regulate Nav1.7 expression in inflammatory pain. We here showed that treatment of rat trigeminal ganglion (TG) explants with PGE2 significantly upregulated the mRNA and protein expressions of Nav1.7 through PGE2 receptor EP2. This finding was confirmed by studies on EP2-selective antagonist PF-04418948. We also demonstrated that Nav1.7 and COX-2 expressions, as well as PGE2 levels, were upregulated in the TG after induction of rats' temporomandibular joint (TMJ) inflammation. Correspondingly, hyperalgesia, as indicated by head withdrawal threshold, was observed. Moreover, TMJ inflammation-induced upregulation of Nav1.7 expression and PGE2 levels in the TG could be reversed by COX-2-selective inhibitor meloxicam given by oral gavage, and meanwhile, the hyperalgesia of inflamed TMJ was also mitigated. So we concluded that PGE2 upregulated trigeminal ganglionic Nav1.7 expression to contribute to TMJ inflammatory pain in rats. Our finding suggests that PGE2 was an important regulator of Nav1.7 in TMJ inflammatory pain, which may help increase understanding on the hyperalgesia of peripheral inflammation and develop a new strategy to address inflammatory pain. PMID- 28349235 TI - The Relationship Between Marijuana and Conventional Cigarette Smoking Behavior from Early Adolescence to Adulthood. AB - Longitudinal analyses investigated (a) the co-occurrence of marijuana use and conventional cigarette smoking within time and (b) bidirectional associations between marijuana and conventional cigarette use in three developmental periods: adolescence, young adulthood, and adulthood. A cross-lag model was used to examine the bidirectional model of marijuana and conventional cigarette smoking frequency from ages 13 to 33 years. The bidirectional model accounted for gender, school-age economic disadvantage, childhood attention problems, and race. Marijuana use and conventional cigarette smoking were associated within time in decreasing magnitude and increased cigarette smoking predicted increased marijuana use during adolescence. A reciprocal relationship was found in the transition from young adulthood to adulthood, such that increased conventional cigarette smoking at age 24 years uniquely predicted increased marijuana use at age 27 years, and increased marijuana use at age 24 years uniquely predicted more frequent conventional cigarette smoking at age 27 years, even after accounting for other factors. The association between marijuana and cigarette smoking was found to developmentally vary in the current study. Results suggest that conventional cigarette smoking prevention efforts in adolescence and young adulthood could potentially lower the public health impact of both conventional cigarette smoking and marijuana use. Findings point to the importance of universal conventional cigarette smoking prevention efforts among adolescents as a way to decrease later marijuana use and suggest that a prevention effort focused on young adults as they transition to adulthood would lower the use of both cigarette and marijuana use. PMID- 28349236 TI - Concurrent Trajectories of Female Drinking and Smoking Behaviors Throughout Transitions to Pregnancy and Early Parenthood. AB - The purpose of this longitudinal study was to investigate whether there are distinct etiological processes explaining dual usage of alcohol and conventional cigarettes by mothers from preconception through the early parenting years. Data on 8800 biological mothers were drawn from the Early Childhood Longitudinal Study Birth Cohort (ECLS-B), representative of US births in 2001. A general growth mixture model (GGMM) was used to empirically identify developmental trajectories of maternal smoking and drinking over the 5-6-year study period. Six classes defined by alcohol consumption and cigarette smoking were identified. These included a nonsmoking, low probability of drinking class (41%), and two drinking classes displaying no smoking with either moderate (26%) or escalating high (8%) probability drinking. Additionally, two predominantly smoking classes were identified, one displaying temporary reduction in smoking during pregnancy and low probability of drinking (11%) and one following a trajectory of persistent heavy smoking with a declining probability of drinking (9%). The sixth class was described by temporary reduction in smoking during pregnancy with high probability of drinking (6%). Covariates differentially predicted class membership, e.g., having a high school degree but not further education predicted concurrent drinking and smoking, and breastfeeding for more than 6 months is protective against concurrent use. Prior to conception, during prenatal care, and in post-natal clinical visits, whether for personal or pediatric care, screening women of reproductive age via characteristics that predict heterogeneity in smoking and drinking trajectories may help guide prevention and treatment options. PMID- 28349237 TI - Histopathologic features predict survival in diffuse pleural malignant mesothelioma on pleural biopsies. AB - Malignant pleural mesothelioma is a rare tumor with a poor prognosis. The only universally recognized pathological prognostic factor is histopathological subtype with a shorter survival in non-epithelioid subtypes. Recently, a grading of epithelioid mesothelioma on surgical resection has been proposed. The aim of our work is to assess the prognostic role of several histopathological factors on a retrospective cohort of 116 patients diagnosed as a pleural mesothelioma for more than 95% of patients on pleural biopsy. Our work shows that mitotic count <3/10 HPF (p < 0.0001), the lack of necrosis (p = 0.0379), mild nuclear atypia (p = 0.0054), the lack of atypical mitoses (p = 0.0265), a nucleoli size <3 MUm (p = 0.0139), and a nucleoli absent or visible at 200* or higher magnification (p = 0.0170) are significantly associated with a better median overall survival in epithelioid mesothelioma. The presence of atypical mitoses was found to be related to a worse median survival in non-epithelioid mesothelioma. Mitotic count, necrosis, nuclear atypia, and nucleoli size are not associated with overall survival in non-epithelioid mesothelioma. Our work highlights that histopathological prognostic factors can be assessed on pleural biopsies and can predict reliably median overall survival. This is of interest in order to define subgroups of patients who could benefit of different therapies and select patients who could benefit of surgical excision. PMID- 28349238 TI - Strong association of insulin-like growth factor 1 receptor expression with histologic grade, subtype, and HPV status in penile squamous cell carcinomas: a tissue microarray study of 112 cases. AB - Insulin-like growth factor-1 receptor (IGF1R) plays a key role in cell growth and transformation. It is overexpressed in several solid tumors. This study evaluates IGF1R immunoexpression in penile squamous cell carcinoma (SCC). Four tissue microarrays were built from formalin-fixed, paraffin-embedded blocks of 112 penile SCC from Paraguay. Membranous IGF1R expression was evaluated by immunohistochemistry using two different approaches. An H-score was calculated in each spot (stain intensity by extent), and a median score per tumor was obtained. The second approach consisted of a score similar to the scoring system that was used for evaluating HER2 immunoexpression. For each case, the highest category obtained at any spot was used for statistical analyses. IGF1R expression was compared by histologic subtype, grade, and human papillomavirus (HPV) status. Median H-score was 22.5. The distribution of IGF1R expression by HER2 approach was as follows: 0 in 33.0% cases, 1+ in 46.4%, 2+ in 14.3%, and 3+ in 6.2%. IGF1R H-scores were associated with basaloid and warty/basaloid subtypes (p = 0.0026) and higher grade (p = 0.00052). Although weaker when using the HER2 approach, the association of IGF1R expression with subtype (p = 0.015) and grade (p = 0.015) remained significant. Furthermore, there was an association between IGF1R expression by HER2 approach and HPV status (p = 0.012). IGF1R was expressed in about two thirds of penile SCC cases, showing a strong positive association with histologic grade, subtype, and HPV status. Considering that grade is a predictor of outcome IGF1R expression may have prognostic relevance and could point to a potential role for IGF1R inhibitors in treating penile SCC. PMID- 28349239 TI - Detecting past male-mediated expansions using the Y chromosome. AB - Males and females display biological differences that lead to a higher variance of offspring number in males, and this is frequently exacerbated in human societies by mating practices, and possibly by past socio-cultural circumstances. This implies that the genetic record might contain the imprint of past male mediated expansions, which can be investigated by analysing the male-specific region of the Y chromosome (MSY). Here, we review studies that have used MSY data to infer such expansions. Sets of short-tandem repeats define haplotypes of very low average frequencies, but in a few cases, high-frequency haplotypes are observed, forming the core of descent clusters. Estimates of the ages of such clusters, together with geographical information, have been used to propose powerful historical founders, including Genghis Khan, although without direct supporting evidence. Resequencing of multi-megabase segments of MSY has allowed the construction of detailed phylogenies in which branch lengths are proportional to time, leading to the identification of lineage expansions in the last few millennia as well as the more distant past. Comparisons with maternally-inherited mitochondrial DNA sequence data allow the male specificity of some of these expansions to be demonstrated. These include expansions in Europe in the last ~5000 years that may be associated with a cultural shift during the Bronze Age, as well as expansions elsewhere in the world for which explanations from archaeological evidence are not yet clear. PMID- 28349240 TI - The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. AB - The Human Gene Mutation Database (HGMD(r)) constitutes a comprehensive collection of published germline mutations in nuclear genes that underlie, or are closely associated with human inherited disease. At the time of writing (March 2017), the database contained in excess of 203,000 different gene lesions identified in over 8000 genes manually curated from over 2600 journals. With new mutation entries currently accumulating at a rate exceeding 17,000 per annum, HGMD represents de facto the central unified gene/disease-oriented repository of heritable mutations causing human genetic disease used worldwide by researchers, clinicians, diagnostic laboratories and genetic counsellors, and is an essential tool for the annotation of next-generation sequencing data. The public version of HGMD ( http://www.hgmd.org ) is freely available to registered users from academic institutions and non-profit organisations whilst the subscription version (HGMD Professional) is available to academic, clinical and commercial users under license via QIAGEN Inc. PMID- 28349241 TI - Quality-of-life: a many-splendored thing? Belgian population norms and 34 potential determinants explored by beta regression. AB - PURPOSE: To identify determinants of health-related quality-of-life in the Belgian population and to provide age-specific population norms of health-related quality-of-life. METHODS: Between September 2010 and February 2011, a representative sample of 1774 persons (age 0-99) was surveyed using the standard Euroqol questionnaire (EQ-5D-3L) with a Visual Analogue Scale (VAS). Significant determinants were identified using multivariate beta (VAS) and one-inflated beta (EQ-5D) regression, the latter modelling the probability to be in perfect health separately from the average EQ-5D score if not in perfect health. RESULTS: Health related quality-of-life depends largely on age and experience with severe disease. The probability to be in perfect health is highest for children. For 0-2 years children who are not in perfect health, proxies report EQ-5D and VAS scores as low as that of the elderly. Also smoking behaviour, educational attainment, pet ownership, working or having worked in health care, and potentially household size and 60+ living on their own (yes/no) are associated with health-related quality-of-life, whereas no association was found with gender, living in a single parent home, educational attainment of mothers, alcohol consumption of 60+, having (grand-) children and the frequency of seeing them. The same determinants are significant for VAS and the probability to be in perfect health, but not for the average EQ-5D score if not in perfect health. CONCLUSIONS: The population norms provided can be used directly as input in health economic evaluations. Estimating health-related quality-of-life in children and developing statistical tools capturing the particular features of health-related quality-of-life measures are important areas for future research. PMID- 28349244 TI - Parent-Adolescent Discrepancies Regarding Adolescents' Peer-Related Loneliness: Associations with Adolescent Adjustment. AB - Because loneliness is a subjective experience, it is often examined using self reports. Yet, researchers have started to use other-reports to examine loneliness. As previous research suggests that discrepancies between self- and other views might have important implications for adolescents' mental health, the current study examines discrepancies in multi-informant reports on adolescents' loneliness in relation with prosocial behavior, aggression, and adolescents' parent-related loneliness. The sample consisted of 374 mother-adolescent dyads and 318 father-adolescent dyads (41.80% male, M age = 15.67 years, SD = 1.25). Results indicated that informants used different reference points to assess adolescents' peer-related loneliness, but were otherwise comparable. Moreover, informant discrepancies were associated with greater adolescents' reported parent related loneliness. The current study did not provide evidence that discrepancies were related to prosocial or aggressive behavior. The current study adds to the notion that other-reports on loneliness show substantial convergence with self reports. In addition, this study indicates that the discrepancy between other- and self-reports on loneliness holds valuable information for adolescent socio emotional adjustment. PMID- 28349245 TI - Effect of miglitol on the suppression of nonalcoholic steatohepatitis development and improvement of the gut environment in a rodent model. AB - BACKGROUND: The gut environment has been considered to play a role in the development of nonalcoholic steatohepatitis (NASH). alpha-glucosidase inhibitors (alpha-GIs) delay carbohydrate absorption and may change the gut environment. We considered that the protective effect of alpha-GIs against NASH development is related to changes in the gut environment and thus investigated the effects of miglitol, an alpha-GI, on NASH development and the gut environment. METHODS: Mice were divided into three groups and fed a normal chow diet (NCD), a high-fat high sucrose diet (HFHSD), or HFHSD plus 0.04% miglitol (HFHSD plus M) for 12 weeks. RESULTS: Insulin resistance developed more in the HFHSD group than in the NCD group, whereas it was suppressed in the HFHSD plus M group. NASH was evaluated histologically, biochemically, and on the basis of messenger RNA expression levels. Miglitol treatment suppressed HFHSD-induced NASH development with the suppression of hepatic Toll-like receptor 4 expression, increased glucagon-like peptide 1 (GLP-1) concentration, and reduced lipopolysaccharide concentration in portal plasma. Regarding the gut environment, the intestinal transit time was shortened and colon inflammation was suppressed in the HFHSD plus M group compared with the HFHSD group. Regarding the gut microbiota, the abundances of Erysipelotrichaceae and Coriobacteriaceae were increased in the HFHSD group compared with the NCD group, whereas the increase was suppressed in the HFHSD plus M group. CONCLUSIONS: We demonstrated that miglitol has a protective effect against HFHSD-induced NASH development. The increased GLP-1 secretion and the suppression of endotoxemia, associated with the changes in the gut environment, including the gut microbiota, could contribute to the underlying mechanisms. PMID- 28349242 TI - Host-Virus Interaction of ZIKA Virus in Modulating Disease Pathogenesis. AB - The Zika virus (ZIKV) is a newly emerging pathogen that has resulted in a worldwide epidemic. It primarily spreads either through infected Aedes aegypti or Aedes albopictus mosquitos leading to severe neurological disorders such as microcephaly and Guillain-Barre syndrome in susceptible individuals. The mode of ZIKV entry into specific cell types such as: epidermal keratinocytes, fibroblasts, immature dendritic cells (iDCs), and stem-cell-derived human neural progenitors has been determined through its major surface envelope glycoprotein. It has been known that oligosaccharides that are covalently linked to viral envelope proteins are crucial in defining host-virus interactions. However, the role of sugars/glycans in exploiting host-immune mechanisms and aiding receptor mediated virus entry is not well defined. Therefore, this review focuses on host pathogen interactions to better understand ZIKV pathogenesis. PMID- 28349243 TI - Endocytic Trafficking of HIV gp120 is Mediated by Dynamin and Plays a Role in gp120 Neurotoxicity. AB - Neurons that endocytose the human immunodeficiency virus-1 (HIV) protein gp120 exhibit neurite retraction and activation of caspase-3, suggesting that the endocytic process may be crucial for gp120-mediated neuronal injury. The goal of this study is to demonstrate that internalization and accumulation of gp120 play a role in its neurotoxic effects. In mammalian cells, endocytosis is primarily a dynamin-dependent process. To establish whether gp120 is endocytosed in a dynamin dependent manner, we used fibroblasts in which deletion of dynamins was induced by tamoxifen. We observed a robust reduction of intracellular gp120 immunoreactivity in tamoxifen-treated cells. To examine whether endocytosis of gp120 is crucial for its neurotoxic effect, we blocked gp120 internalization into primary rat cortical neurons by dynasore, an inhibitor of the dynamin GTP-ase activity. We found that dynasore blocks both gp120 internalization and neurotoxicity. We then utilized gp120-loaded mesoporous silica nanoparticles to deliver gp120 intracellularly. We established that once internalized, gp120 is neurotoxic regardless of chemokine receptor activation. Our data suggest that dynamin-dependent endocytosis of gp120 is critical for its neurotoxicity. PMID- 28349246 TI - Suicide patterns in children and adolescents: a review from a pediatric institution in England. AB - Suicide is a catastrophic event to both families and communities yet it is potentially preventable. This study aims to determine incidence and patterns of suicide in children and young adolescents in our region, raise awareness of this entity as a potentially preventable cause of death in this age group, and identify its possible associated risk factors. We retrospectively reviewed suicide cases presenting as sudden unexpected death in children and adolescents that underwent coronial post-mortems at our institution. This is the largest pathological review of completed suicide in children and young adolescents within a single institution in the United Kingdom. We identified 23 suicide cases during a 12 year period from 2003 to 2015, in which 18 cases (78%) were male and 5 cases (22%) were female. The age range was from 8 to 16 years (mean age 12.82 +/- 2.52 SD). With the exception of one case, all of the victims were Caucasian. The majority, 19 cases (81%), were found dead inside their place of residence, 15 of whom were discovered in their own bedrooms. Twenty-one cases (91%) died from neck compression due to hanging; 6 cases (26%) had used the cord of a dressing gown and 5 (22%) opted to use a belt as the ligature. Two cases (9%) that died from multiple-drug toxicity were female. In 7 cases (30.5%) there was evidence of self harm and in 3 cases (13%) there was a history of previous suicide attempts. Petechial hemorrhages were found at autopsy in more than half of hanging victims and only three cases (14%) displayed dual distribution of post-mortem hypostasis (back and legs). Seven victims (30.5%) left some form of suicide message to family members and friends, 2 of which wrote the message on their arm. Parental separation, conflict with parents, and depression, were common amongst decedents prior to committing suicide. Substance abuse was uncommon in suicide within our cases. Valuable information is available from thorough review of suicide data in children and young adolescents from a single institution. Pathologists and clinicians can play crucial roles in identifying potential risk factors that may contribute to prevent future deaths. PMID- 28349248 TI - Cancer and autoimmunity. PMID- 28349247 TI - Benzodiazepine long-term administration is associated with impaired attention/working memory in schizophrenia: results from the national multicentre FACE-SZ data set. AB - OBJECTIVE: The effect of benzodiazepine long-term administration (BLTA) in cognitive functioning of subjects with schizophrenia (SZ) has been partially explored to date. The objective was to assess BLTA-associated cognitive impairment with a comprehensive cognitive battery in a non-selected multicentric/national community-dwelling sample of stabilized SZ subjects. METHOD: 407 community-dwelling stabilized SZ subjects were consecutively included in the FondaMental Academic Centers of Expertise for Schizophrenia Cohort (FACE SZ). Patients taking daily benzodiazepine were defined as BLTA+ as all patients examined by the Expert Center were clinically stabilized and under stable dose of treatment for at least 3 months. Each patient has been administered a 1-day long comprehensive cognitive battery (including The National Adult Reading Test, the Wechsler Adult Intelligence Scale, the Trail Making Test, the California Verbal Learning Test, the Doors test, and The Continuous Performance Test-Identical Pairs). RESULTS: In the multivariate analyses, results showed that BLTA was associated with impaired attention/working memory (OR 0.60, 95% confidence interval 0.42-0.86; p = 0.005) independently of socio-demographic variables and illness characteristics. Verbal and performance current IQ-[respectively, OR 0.98, 95% CI (0.96;0.99), p = 0.016 and 0.98, 95% CI(0.97;0.99), p = 0.034] but not premorbid IQ-(p > 0.05) have been associated with BLTA in a multivariate model including the same confounding variables. CONCLUSION: BLTA is associated with impaired attention/working memory in schizophrenia. The BLTA benefit/risk ratio should be regularly reevaluated. Alternative pharmacological and non pharmacological strategies for comorbid anxiety disorders and sleep disorders should be preferred when possible. It seems reasonable to withdraw BLTA before the start of cognitive remediation therapy, as soon as possible, to improve the effectiveness of this therapy. Limits: the delay between the last benzodiazepine intake and testing, as well as the specific class of benzodiazepines (long half life vs. short half-life), and the number of benzodiazepine daily intakes have not been recorded in the present study. The precise motive for BLTA prescription and sleep disturbances have not been reported, which is a limit for the interpretation of the present results. PMID- 28349249 TI - Lost in space: multisensory conflict yields adaptation in spatial representations across frames of reference. AB - According to embodied cognition, bodily interactions with our environment shape the perception and representation of our body and the surrounding space, that is, peripersonal space. To investigate the adaptive nature of these spatial representations, we introduced a multisensory conflict between vision and proprioception in an immersive virtual reality. During individual bimanual interaction trials, we gradually shifted the visual hand representation. As a result, participants unknowingly shifted their actual hands to compensate for the visual shift. We then measured the adaptation to the invoked multisensory conflict by means of a self-localization and an external localization task. While effects of the conflict were observed in both tasks, the effects systematically interacted with the type of localization task and the available visual information while performing the localization task (i.e., the visibility of the virtual hands). The results imply that the localization of one's own hands is based on a multisensory integration process, which is modulated by the saliency of the currently most relevant sensory modality and the involved frame of reference. Moreover, the results suggest that our brain strives for consistency between its body and spatial estimates, thereby adapting multiple, related frames of reference, and the spatial estimates within, due to a sensory conflict in one of them. PMID- 28349250 TI - Curcumin improves treatment outcome of Takayasu arteritis patients by reducing TNF-alpha: a randomized placebo-controlled double-blind clinical trial. AB - Tumor necrosis factor (TNF) inhibitors have been found to exhibit certain efficacy in treating refractory Takayasu arteritis (TA) in clinic despite severe adverse effects. The aim of this study is to investigate a natural anti-TNF compound, curcumin, its function, and its potential as treatment against TA. In total, 246 patients who were diagnosed of acute TA participated have completed this clinical trial. They were randomly assigned in either treatment group or control group, in which they were daily administered with curcumin or placebo accordingly for 4 weeks with weekly revisits for data collection. The treatment outcome consisted of a primary one defined using Birmingham Vascular Activity Score (BVAS) and a secondary one defined by laboratory results, e.g., C-reactive protein (CRP), TNF-alpha, and erythrocyte sedimentation rate (ESR). In this study, the primary and secondary treatment outcomes were found to be steadily attenuated in patients who received curcumin treatment, while showed no significant change in patients in placebo group. TNF-alpha was found to be significantly correlated with BVAS scores (gamma 2 = 0.81, p = 0.016), ESR (gamma 2 = 0.76, p = 0.037), and plasma levels of CRP (gamma 2 = 0.79, p = 0.041). The treatment outcome was greatly improved by curcumin administration probably due to its anti-TNF property. PMID- 28349251 TI - The effect of magnesium on early osseointegration in osteoporotic bone: a histological and gene expression investigation. AB - : Magnesium has a key role in osteoporosis and could enhance implant osseointegration in osteoporotic patients. Titanium implants impregnated with Mg ions were installed in the tibia of ovariectomized rats. The release of Mg induced a significant increase of bone formation and the expression of anabolic markers in the peri-implant bone. INTRODUCTION: The success of endosseous implants is highly predictable in patients possessing normal bone status, but it may be impaired in patients with osteoporosis. Thus, the application of strategies that adjuvate implant healing in compromized sites is of great interest. Magnesium has a key role in osteoporosis prevention and it is an interesting candidate for this purpose. In this study, the cellular and molecular effects of magnesium release from implants were investigated at the early healing stages of implant integration. METHODS: Osteoporosis was induced in 24 female rats by means of ovariectomy and low-calcium diet. Titanium mini-screws were coated with mesoporous titania films and were loaded with magnesium (test group) or left as native (control group). The implants were inserted in the tibia and femur of the rats. One, 2 and 7 days after implantation, the implants were retrieved and histologically examined. In addition, expression of genes was evaluated in the peri-implant bone tissue at day 7 by means of quantitative polymerase chain reactions with pathway-oriented arrays. RESULTS: The histological evaluation revealed that new bone formation started already during the first week of healing for both groups. However, around the test implants, new bone was significantly more abundant and spread along a larger surface of the implants. In addition, the release of magnesium induced a significantly higher expression of BMP6. CONCLUSIONS: These results provide evidence that the release of magnesium promoted rapid bone formation and the activation of osteogenic signals in the vicinity of implants placed in osteoporotic bone. PMID- 28349252 TI - Prevalence of childhood hypertension and hypertension phenotypes by weight status and waist circumference: the Healthy Growth Study. AB - PURPOSE: The aim of the present study was to report for the first time the prevalence of hypertension and its phenotypes in obese children and in children with central obesity in a large sample of Greek children. METHODS: A regionally representative sample of 2263 schoolchildren (50.3% boys) (9-13 years) having full data on blood pressure assessment, physical examination, anthropometric, and physical activity participated in a cross-sectional study in Greece. RESULTS: Prevalence of stage 1 and 2 hypertension, of isolated systolic hypertension (ISH) and of combined systolic or diastolic hypertension, was significantly higher for obese children and children on the 3rd tertile of waist circumference in the total sample, as well as in each gender separately. ISH was the most prevalent phenotype reaching 24.3% in obese children and 17.5% in children on the highest tertile of waist circumference. Obese children and children on the highest tertile of waist circumference had 6.31 times and 3.94 times, respectively, higher likelihood to have abnormal systolic or diastolic blood pressure (SBP or DBP) than their normal-weight counterparts. CONCLUSIONS: Prevalence of hypertension and especially ISH in obese children and in children with central obesity in Greece are among the highest reported in Europe. Future public health initiatives should aim to prevent or tackle several underlying factors related to childhood hypertension, focusing primarily on children with excess body weight. PMID- 28349253 TI - Mangiferin suppresses endoplasmic reticulum stress in perivascular adipose tissue and prevents insulin resistance in the endothelium. AB - PURPOSE: Mangiferin is a naturally occurring glucosylxanthone with beneficial effects on glucose and lipid homeostasis. This study investigates the potential therapeutic effect of Mangiferin in perivascular adipose tissue (PVAT) and whether it contributes to regulating insulin action in the endothelium. METHODS: Palmitate challenge evoked ROS-associated endoplasmic reticulum stress (ER stress) and NLRP3 inflammasome activation in PVAT. The conditioned medium from PA stimulated PVAT was prepared to induce endothelial insulin resistance, and improved endothelium-dependent vasodilation in response to insulin was detected in vitro and in vivo. RESULTS: Mangiferin treatment enhanced LKB1-dependent AMPK activity and suppressed ER stress with downregulation of TXNIP induction, leading to the inhibition of NLRP3 inflammasome activation evidenced by attenuated NLRP3 and cleaved caspase-1 expression as well as reduced IL-1beta secretion. Moreover, Mangiferin restored insulin-mediated Akt and eNOS phosphorylations with increased NO production, immunohistochemistry examination of adipocytes, and endothelial tissue in high-fat diet-fed mice also showed that oral administration of Mangiferin inhibited ER stress and NLRP3 induction in PVAT, and then effectively prevented insulin resistance in the vessel endothelium. CONCLUSIONS: Taken together, these results revealed that Mangiferin suppressed ER stress-associated NLRP3 inflammasome activation in PVAT through regulation of AMPK activity, which prevented endothelial insulin resistance. These findings suggested that the amelioration of PVAT dysfunction may be a therapeutic strategy for the prevention of endothelial insulin resistance. PMID- 28349255 TI - Alcohol and red wine consumption, but not fruit, vegetables, fish or dairy products, are associated with less endothelial dysfunction and less low-grade inflammation: the Hoorn Study. AB - PURPOSE: Endothelial dysfunction and low-grade inflammation are key phenomena in the pathobiology of cardiovascular disease (CVD). Their dietary modification might explain the observed reduction in CVD that has been associated with a healthy diet rich in fruit, vegetables and fish, low in dairy products and with moderate alcohol and red wine consumption. We investigated the associations between the above food groups and endothelial dysfunction and low-grade inflammation in a population-based cohort of Dutch elderly individuals. METHODS: Diet was measured by food frequency questionnaire (n = 801; women = 399; age 68.5 +/- 7.2 years). Endothelial dysfunction was determined (1) by combining von Willebrand factor, and soluble intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1, endothelial selectin and thrombomodulin, using Z-scores, into a biomarker score and (2) by flow-mediated vasodilation (FMD), and low-grade inflammation by combining C-reactive protein, serum amyloid A, interleukin 6, interleukin 8, tumour necrosis factor alpha and sICAM-1 into a biomarker score, with smaller FMD and higher scores representing more dysfunction and inflammation, respectively. We used linear regression analyses to adjust associations for sex, age, energy, glucose metabolism, body mass index, smoking, prior CVD, educational level, physical activity and each of the other food groups. RESULTS: Moderate [beta (95% CI) -0.13 (-0.33; 0.07)] and high [-0.22 ( 0.45; -0.003)] alcohol consumption, and red wine [-0.16 (-0.30; -0.01)] consumption, but none of the other food groups, were associated with a lower endothelial dysfunction biomarker score and a greater FMD. The associations for FMD were, however, not statistically significant. Only red wine consumption was associated with a lower low-grade inflammation biomarker score [-0.18 (-0.33; 0.04)]. CONCLUSIONS: Alcohol and red wine consumption may favourably influence processes involved in atherothrombosis. PMID- 28349254 TI - alpha-Lipoic acid prevents the intestinal epithelial monolayer damage under heat stress conditions: model experiments in Caco-2 cells. AB - PURPOSE: Under conditions of high ambient temperatures and/or strenuous exercise, humans and animals experience considerable heat stress (HS) leading among others to intestinal epithelial damage through induction of cellular oxidative stress. The aim of this study was to characterize the effects of alpha-Lipoic Acid (ALA) on HS-induced intestinal epithelial injury using an in vitro Caco-2 cell model. METHODS: A confluent monolayer of Caco-2 cells was pre-incubated with ALA (24 h) prior to control (37 degrees C) or HS conditions (42 degrees C) for 6 or 24 h and the expression of heat shock protein 70 (HSP70), heat shock factor-1 (HSF1), and the antioxidant Nrf2 were investigated. Intestinal integrity was determined by measuring transepithelial resistance, paracellular permeability, junctional complex reassembly, and E-cadherin expression and localization. Furthermore, cell proliferation was measured in an epithelial wound healing assay and the expression of the inflammatory markers cyclooxygenase-2 (COX-2) and transforming growth Factor-beta (TGF-beta) was evaluated. RESULTS: ALA pretreatment increased the HSP70 mRNA and protein expression under HS conditions, but did not significantly modulate the HS-induced activation of HSF1. The HS-induced increase in Nrf2 gene expression as well as the Nrf2 nuclear translocation was impeded by ALA. Moreover, ALA prevented the HS-induced impairment of intestinal integrity. Cell proliferation under HS conditions was improved by ALA supplementation as demonstrated in an epithelial wound healing assay and ALA was able to affect the HS-induced inflammatory response by decreasing the COX-2 and TGF-beta mRNA expression. CONCLUSIONS: ALA supplementation could prevent the disruption of intestinal epithelial integrity by enhancing epithelial cell proliferation, and reducing the inflammatory response under HS conditions in an in vitro Caco-2 cell model. PMID- 28349257 TI - Corn-based vaccines: current status and prospects. AB - MAIN CONCLUSION: Corn is an attractive host for vaccine production and oral delivery. The present review provides the current outlook and perspectives for this field. Among seed-crops, corn represents a key source of biomass for food, fuel production, and other applications. Since the beginning of the development of plant-based vaccines, corn was explored for the production and delivery of vaccines. About a dozen of pathogens have been studied under this technology with distinct degrees of development. A vaccine prototype against enterotoxigenic Escherichia coli was evaluated in a phase I clinical trial and several candidates targeting bacterial and viral diseases are under preclinical evaluation. The present review provides an updated outlook on this topic highlighting the employed expression strategies; perspectives for the field are also provided. PMID- 28349256 TI - Virus-induced gene silencing of the two squalene synthase isoforms of apple tree (Malus * domestica L.) negatively impacts phytosterol biosynthesis, plastid pigmentation and leaf growth. AB - MAIN CONCLUSION: The use of a VIGS approach to silence the newly characterized apple tree SQS isoforms points out the biological function of phytosterols in plastid pigmentation and leaf development. Triterpenoids are beneficial health compounds highly accumulated in apple; however, their metabolic regulation is poorly understood. Squalene synthase (SQS) is a key branch point enzyme involved in both phytosterol and triterpene biosynthesis. In this study, two SQS isoforms were identified in apple tree genome. Both isoforms are located at the endoplasmic reticulum surface and were demonstrated to be functional SQS enzymes using an in vitro activity assay. MdSQS1 and MdSQS2 display specificities in their expression profiles with respect to plant organs and environmental constraints. This indicates a possible preferential involvement of each isoform in phytosterol and/or triterpene metabolic pathways as further argued using RNAseq meta-transcriptomic analyses. Finally, a virus-induced gene silencing (VIGS) approach was used to silence MdSQS1 and MdSQS2. The concomitant down regulation of both MdSQS isoforms strongly affected phytosterol synthesis without alteration in triterpene accumulation, since triterpene-specific oxidosqualene synthases were found to be up-regulated to compensate metabolic flux reduction. Phytosterol deficiencies in silenced plants clearly disturbed chloroplast pigmentation and led to abnormal development impacting leaf division rather than elongation or differentiation. In conclusion, beyond the characterization of two SQS isoforms in apple tree, this work brings clues for a specific involvement of each isoform in phytosterol and triterpene pathways and emphasizes the biological function of phytosterols in development and chloroplast integrity. Our report also opens the door to metabolism studies in Malus domestica using the apple latent spherical virus-based VIGS method. PMID- 28349258 TI - Role of bone marrow-derived CD11c+ dendritic cells in systolic overload-induced left ventricular inflammation, fibrosis and hypertrophy. AB - Inflammatory responses play an important role in the development of left ventricular (LV) hypertrophy and dysfunction. Recent studies demonstrated that increased T-cell infiltration and T-cell activation contribute to LV hypertrophy and dysfunction. Dendritic cells (DCs) are professional antigen-presenting cells that orchestrate immune responses, especially by modulating T-cell function. In this study, we investigated the role of bone marrow-derived CD11c+ DCs in transverse aortic constriction (TAC)-induced LV fibrosis and hypertrophy in mice. We observed that TAC increased the number of CD11c+ cells and the percentage of CD11c+ MHCII+ (major histocompatibility complex class II molecule positive) DCs in the LV, spleen and peripheral blood in mice. Using bone marrow chimeras and an inducible CD11c+ DC ablation model, we found that depletion of bone marrow derived CD11c+ DCs significantly attenuated LV fibrosis and hypertrophy in mice exposed to 24 weeks of moderate TAC. CD11c+ DC ablation significantly reduced TAC induced myocardial inflammation as indicated by reduced myocardial CD45+ cells, CD11b+ cells, CD8+ T cells and activated effector CD8+CD44+ T cells in LV tissues. Moreover, pulsing of autologous DCs with LV homogenates from TAC mice promoted T-cell proliferation. These data indicate that bone marrow-derived CD11c+ DCs play a maladaptive role in hemodynamic overload-induced cardiac inflammation, hypertrophy and fibrosis through the presentation of cardiac self antigens to T cells. PMID- 28349259 TI - Effect of paroxetine on left ventricular remodeling in an in vivo rat model of myocardial infarction. AB - Left ventricular (LV) remodeling following a myocardial infarction (MI) involves formation of reactive oxygen species (ROS). Paroxetine, a selective serotonin reuptake inhibitor, has an antioxidant effect in the vascular wall. We investigated whether paroxetine reduces myocardial ROS formation and LV remodeling following a MI. In a total of 32 Wistar rats, MI was induced by a 30 min ligation of the left anterior descending artery followed by 7- or 28-day reperfusion. During the 28 days of reperfusion, LV remodeling was evaluated by magnetic resonance imaging (MRI) and echocardiography (n = 20). After 28 days of reperfusion, the susceptibility to ventricular tachycardia was evaluated prior to sacrifice and histological assessment of myocyte cross-sectional area, fibrosis, and presence of myofibroblasts. Myocardial ROS formation was measured with dihydroethidium after 7 days of reperfusion in separate groups (n = 12). Diastolic LV volume, evaluated by MRI (417 +/- 60 vs. 511 +/- 64 uL, p < 0.05), and echocardiography (515 +/- 80 vs. 596 +/- 83 uL, p < 0.05) as well as diastolic LV internal diameter evaluated with echocardiography (7.2 +/- 0.6 vs. 8.1 +/- 0.7 mm, p < 0.05) were lower in the paroxetine group than in controls. Furthermore, myocyte cross-sectional area was reduced in the paroxetine group compared with controls (277 +/- 26 vs. 354 +/- 23 mm3, p < 0.05) and ROS formation was reduced in the remote myocardium (0.415 +/- 0.19 normalized to controls, p < 0.05). However, no differences in the presence of fibrosis or myofibroblasts were observed. Finally, paroxetine reduced the susceptibility to ventricular tachycardia (induced in 2/11 vs. 6/8 rats, p < 0.05). Paroxetine treatment following MI decreases LV remodeling and susceptibility to arrhythmias, probably by reducing ROS formation. PMID- 28349260 TI - Recent developments in understanding the length dependence of contractile response of skeletal muscle. AB - Maximal active force of skeletal muscle contraction occurs at a sarcomere length where overlap of thick and thin filaments is optimal. However, the interaction of muscle length and active force is complicated. Active force, is the force generated by energy-requiring processes. To calculate active force, passive force provided by in-parallel structures must be subtracted from total force. Sarcomere length will change during a contraction with constant muscle-tendon length, due to tendon stretch. Passive force therefore changes during the contraction. Taking this into account, it has been demonstrated that there is less length dependence of fatigue than previously thought. The remaining difference may be associated with length dependence of activation, a property that is evident with submaximal activation. The sarcomere length at which peak contraction occurs is longer than the length that gives optimal overlap of the filaments and this shift of optimal length appears to be due to increased Ca2+ sensitivity. The increased Ca2+ sensitivity occurs because at longer lengths, the myofilaments are closer together allowing greater force than expected. However, the potential for length dependent activation has been challenged. Submaximal contractions obtained by recruitment of fewer motor units but with maximal stimulation across different muscle lengths still demonstrate length-dependent activation. In contrast, contractions with similar absolute electromyographic signal magnitude at different lengths do not demonstrate length-dependent activation. Recent work has improved our understanding of how sarcomere length impacts the force of contraction but also reveals inadequacies in our knowledge that need to be addressed by additional research. PMID- 28349261 TI - Inconsistent approach to evaluating studies and selective interpretation of data reveals lack of objectivity and undermines repeated attempts to discredit SPV. PMID- 28349263 TI - How to Decide on Modeling Details: Risk and Benefit Assessment. AB - Mathematical models based on thermodynamic, kinetic, heat, and mass transfer analysis are central to this chapter. Microbial growth, death, enzyme inactivation models, and the modeling of material properties, including those pertinent to conduction and convection heating, mass transfer, such as diffusion and convective mass transfer, and thermodynamic properties, such as specific heat, enthalpy, and Gibbs free energy of formation and specific chemical exergy are also needed in this task. The origins, simplifying assumptions, and uses of model equations are discussed in this chapter, together with their benefits. The simplified forms of these models are sometimes referred to as "laws," such as "the first law of thermodynamics" or "Fick's second law." Starting to modeling a study with such "laws" without considering the conditions under which they are valid runs the risk of ending up with erronous conclusions. On the other hand, models started with fundamental concepts and simplified with appropriate considerations may offer explanations for the phenomena which may not be obtained just with measurements or unprocessed experimental data. The discussion presented here is strengthened with case studies and references to the literature. PMID- 28349262 TI - beta-alanine supplementation improves in-vivo fresh and fatigued skeletal muscle relaxation speed. AB - PURPOSE: In fresh muscle, supplementation with the rate-limiting precursor of carnosine, beta-alanine (BA), results in a decline in muscle half-relaxation time (HRT) potentially via alterations to calcium (Ca2+) handling. Accumulation of hydrogen cation (H+) has been shown to impact Ca2+ signalling during muscular contraction, carnosine has the potential to serve as a cytoplasmic regulator of Ca2+ and H+ coupling, since it binds to both ions. The present study examined the effect of BA supplementation on intrinsic in-vivo isometric knee extensor force production and muscle contractility in both fresh and fatigued human skeletal muscle assessed during voluntary and electrically evoked (nerve and superficial muscle stimulation) contractions. METHODS: Twenty-three males completed two experimental sessions, pre- and post- 28 day supplementation with 6.4 g.day-1 of BA (n = 12) or placebo (PLA; n = 11). Isometric force was recorded during a series of voluntary and electrically evoked knee extensor contractions. RESULTS: BA supplementation had no effect on voluntary or electrically evoked isometric force production, or twitch electromechanical delay and time-to-peak tension. There was a significant decline in muscle HRT in fresh and fatigued muscle conditions during both resting (3 +/- 13%; 19 +/- 26%) and potentiated (1 +/- 15%; 2 +/- 20%) twitch contractions. CONCLUSIONS: The mechanism for reduced HRT in fresh and fatigued skeletal muscle following BA supplementation is unclear. Due to the importance of muscle relaxation on total energy consumption, especially during short, repeated contractions, BA supplementation may prove to be beneficial in minimising contractile slowing induced by fatigue. TRIAL REGISTRATION: The trial is registered with Clinicaltrials.gov, ID number NCT02819505. PMID- 28349266 TI - Listening as a path to psychological discovery: an introduction to the Listening Guide. PMID- 28349264 TI - Long-term outcome of patients with triphasic mitral flow with a mid-diastolic L wave: prognostic role of left atrial volume and N-terminal pro-brain natriuretic peptide. AB - A mid-diastolic L wave has been recognized as a marker of advanced left ventricular (LV) diastolic dysfunction. However, its prognostic implication is unclear. This study assessed long-term prognosis and independent predictors of adverse outcomes in patients with a mid-diastolic L wave. A total of 144 consecutive patients (mean age 63 +/- 12 years, 88 female) with a mid-diastolic L wave of >=0.2 m/s and in sinus rhythm were identified. Patients with significant valvular heart disease, low LV ejection fraction and arrhythmias were excluded. Subjects were followed up for cardiovascular (CV) mortality and hospitalization for heart failure (HF). During follow-up for a median of 44 months (1-76), CV deaths and hospitalization for HF occurred in 41 (28%) patients. In multivariate Cox analysis, age (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.02 1.11; p = 0.001), log N-terminal pro-brain natriuretic peptide (NT-proBNP)(HR 3.81; 95% CI 1.78-8.15; p = 0.001), and left atrial volume index (HR 1.02; 95% CI 1.01-1.04; p = 0.019) were independent predictors of adverse outcomes in patients with a mid-diastolic L wave. In a stepwise model, NT-proBNP showed an incremental prognostic value for prediction of adverse outcomes when added to the clinical and echocardiographic parameters (Chi square from 30.1 to 41.1, p < 0.001). Patients with a mid-diastolic L wave and clinical, biochemical, and echocardiographic evidence of advanced diastolic dysfunction showed poor long term clinical outcome. PMID- 28349267 TI - Editorial. PMID- 28349265 TI - Scholarly concentration programs and medical student research productivity: a systematic review. AB - INTRODUCTION: Scholarly concentration programs have become a common method to promote student inquiry and independent research in medical schools. Given the high resource requirements of scholarly concentration program implementation, it is important to examine program efficacy. This systematic review examined the impact of scholarly concentration programs on student research productivity. METHODS: The authors carried out a literature search to find articles related to scholarly concentration program research productivity outcomes. The inclusion criterion was a method of rigorously evaluating program scholarly productivity. Study rigour was evaluated with the Medical Education Research Study Quality Instrument. RESULTS: The initial search disclosed 2467 unique records: 78 were considered based on titles and abstracts; eight were considered by scanning references. Eleven papers met the inclusion criteria: all were descriptive; none had a priori hypotheses that examined predictors of medical student research productivity in scholarly concentration programs or prospectively evaluated program impact on student scholarly output. DISCUSSION: While few in number and often lacking in rigour, the studies included herein suggest that adequate administrative support, strong mentorship and tailored program characteristics are essential in facilitating student research productivity in scholarly concentration programs. Given the challenges inherent in medical education research, a conceptual framework based on United Way's approach may help program planners and educators address this gap in the evaluation of scholarly concentration programs. PMID- 28349268 TI - Segmental vs non-segmental thoracic pedicle screws constructs in adolescent idiopathic scoliosis: is there any implant alloy effect? AB - PURPOSE: The aim of this study is to understand how many anchor sites are necessary to obtain maximum posterior correction of idiopathic scoliotic curve and if the alloy of instrumentation, stainless steel or titanium, may have a role in the percent of scoliosis correction. METHODS: We reviewed 143 consecutive patients, affected by AIS (Lenke 1-2), who underwent a posterior spinal fusion with pedicle screw-only instrumentation between 2002 and 2005. According to the implant density and alloy used we divided the cohort in four groups. RESULTS: All 143 patients were reviewed at an average follow-up of 7, 2 years, the overall final main thoracic curve correction averaged 61.4%, whereas the implant density within the major curve averaged 71%. A significant correlation was observed between final% MT correction and preoperative MT flexibility and implant density. CONCLUSIONS: When stainless steel instrumentation is used non-segmental pedicle screw constructs seem to be equally effective as segmental instrumentations in obtaining satisfactory results in patients with main thoracic AIS. When the implant alloy used is titanium one, an implant density of >=60% should be guaranteed to achieve similar results. PMID- 28349269 TI - Successful outcomes following transforaminal epidural steroid injections for C4/5 cervical disc prolapse associated with profound neurological deficit. AB - PURPOSE: To show that with C5 radiculopathy and profound neurological deficit, good outcomes can be obtained with injection therapy. METHOD: We present two cases of cervical radiculopathy secondary to disc prolapse associated with profound neurological deficit. In both cases, cervical injection therapy was used as the primary management. RESULTS: The two cases presented were both male, 59 and 36 years, and were diagnosed on MRI imaging with C4/5 disc prolapses. They presented with severe motor deficit and were both treated with foraminal epidural steroid injections, one of the patients also had two previous injections elsewhere prior to the first review. In both patients, pain and neurological deficit improved in a timely manner resulting in full recovery. MRI taken after recovery showed complete resorption of the disc prolapse in both cases. CONCLUSION: In C5 radiculopathy, even with severe neurological deficit, cervical injection therapy should be considered. These cases illustrate that excellent results can be obtained without the need for open surgery with its inherent risks. PMID- 28349270 TI - Effect of thymidylate synthase (TYMS) gene polymorphisms with methotrexate treatment outcome in south Indian Tamil patients with rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease causing joint damage and significant functional impairment. Methotrexate (MTX) remains the mainstay for the treatment of RA. MTX inhibits several enzymes of the folate and nucleotide pathways. Thymidylate synthase (TYMS) is an important enzyme in the de novo pyrimidine pathway responsible for DNA replication. The two common gene polymorphisms analyzed in TYMS are 28-bp tandem repeat polymorphism and a 6-bp insertion/deletion polymorphism. The present study was carried out to find the role of these TYMS gene polymorphisms with clinical phenotype, treatment response, and MTX adverse events in 254 patients with RA of south Indian Tamil ethnicity. TYMS gene polymorphisms were analyzed by PCR. The allele frequencies of TYMS gene polymorphisms did not differ between good and non-responders. However, the TYMS 28-bp tandem repeat 3R allele was higher in non-responders than in patients undergoing remission [64 vs 51.11%, p = 0.06, OR 0.58, 95% CI (0.34 1.00)]. The TYMS 6-bp deletion allele was higher in non-responders than good responders [78.20 vs 64.92%, p = 0.06, OR 0.51 95% CI (0.27-0.98)]. TYMS 3R allele and TYMS 6-bp deletion allele may favor non-response to MTX in south Indian Tamils. TYMS gene polymorphisms did not influence MTX adverse events. PMID- 28349271 TI - Evaluation of the effect of Elaeagnus angustifolia alone and combined with Boswellia thurifera compared with ibuprofen in patients with knee osteoarthritis: a randomized double-blind controlled clinical trial. AB - Osteoarthritis (OA) is one of the most common articular disorders. Many patients do not respond to acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), the mainstay of pharmacotherapy for knee OA. The plants Elaeagnus angustifolia and Boswellia thurifera have anti-inflammatory and analgesic properties. This study aimed to evaluate the effect of E. angustifolia alone and in combination with B. thurifera compared with ibuprofen in patients with knee osteoarthritis. In a randomized double-blind controlled clinical trial, 75 patients with knee OA were randomly and equally assigned to one of three groups Elaeagnus (n = 23), Elaeagnus/Boswellia (n = 26), and ibuprofen (n = 26) to receive the capsules of Elaeagnus, Elaeagnus/Boswellia, and ibuprofen, respectively, three times daily with meals for 4 weeks. Pain severity based on VAS (visual analog scale, 0 to 10 scale) and the scores of LPFI (Lequesne Pain and Function Index) and PGA (patient global assessment) were determined pre- and post-intervention for all patients. All interventions had significant lowering effects on VAS, LPFI, and PGA scores (P < 0.001 for all parameters) with no significant difference between groups in terms of effects on all evaluated parameters. Consumption of E. angustifolia fruit extract either alone or in combination with Boswellia oleo-gum resin extract could decrease pain and improve function in patients with knee osteoarthritis comparable to ibuprofen. PMID- 28349272 TI - DeltaNp63 activates EGFR signaling to induce loss of adhesion in triple-negative basal-like breast cancer cells. AB - PURPOSE: The basal-A subtype of triple-negative breast cancer is characterized by high levels of DeltaNp63. Various functions have been proposed for p63 in breast cancer initiation and growth, and p63 mediates chemotherapeutic response in a subset of triple-negative breast cancers. We investigated the signaling pathways that are controlled by DeltaNp63 in basal-A triple-negative breast cancer. METHODS: Human basal-A triple-negative breast cancer cell lines with DeltaNp63alpha induction or inhibition were studied, along with primary human triple-negative breast cancer tissues. Proteomic, phospho-kinase array, mRNA measurements, and immunohistochemistry were employed. RESULTS: Global phosphoproteomics identified increased EGFR phosphorylation in MDA-MB-468 cells expressing DeltaNp63alpha. DeltaNp63alpha expression increased EGFR mRNA, total EGFR protein, and phospho-EGFR(Y1086), whereas silencing endogenous DeltaNp63 in HCC1806 cells reduced both total and phospho-EGFR levels and inhibited the ability of EGF to activate EGFR. EGFR pathway gene expression analysis indicated that DeltaNp63 alters EGFR-regulated genes involved in cell adhesion, migration, and angiogenesis. Addition of EGF or neutralizing EGFR antibodies demonstrated that EGFR activation is responsible for DeltaNp63-mediated loss of cellular adhesion. Finally, immunohistochemical staining showed that p63-positive triple negative breast cancers were more likely to express high levels of EGFR than p63 negative cancers, corroborated by in silico analysis of gene expression profiling data. CONCLUSIONS: These data identify EGFR as a major target for DeltaNp63 regulation that influences cancer cell adhesion in basal-like triple-negative breast cancer. PMID- 28349273 TI - Background parenchymal enhancement on breast MRI: association with recurrence free survival in patients with newly diagnosed invasive breast cancer. AB - PURPOSE: To determine whether BPE in preoperative breast MRI influences patients' recurrence-free survival (RFS). METHODS: Between February 2010 and December 2011, 804 consecutive women with invasive breast cancer who had undergone preoperative breast MRI and curative cancer surgery were identified. BPE was visually graded by two reviewers. We determined the correlation between BPE grade and other clinicopathological variables, including age, adjuvant therapy, menopausal status, histologic grade, T stage, N stage, lymphovascular invasion, molecular subtype, surgical margin status, and mammographic density. A Cox proportional hazards model was used to analyze the effects of clinicopathological variables and radiological findings (BPE grade, mammographic density) on RFS. RESULTS: High BPE was associated with premenopausal status (Ps < 0.0001), higher mammographic density (Ps < 0.0001), progesterone receptor positivity (Ps = 0.039, 0.007, respectively), presence of lymphovascular invasion (Ps = 0.008, 0.001, respectively), and close surgical margin (Ps < 0.0001). Recurrences were observed in 75 patients after a mean follow-up period of 61.8 months (range 4-81 months). Non-minimal BPE grade (RFS hazard ratio = 3.086, P = 0.003 for reader 1; RFS hazard ratio = 2.221, P = 0.075 for reader 2) and T3 stage were associated with worse outcomes in postmenopausal women. In premenopausal women, non-minimal BPE grade by readers 1 and 2 did not affect the patients' outcomes. CONCLUSIONS: Increased BPE on preoperative breast MRI in postmenopausal women has potential as a predictor of poor RFS. PMID- 28349274 TI - A Systematic Review of Add-on Pharmacologic Therapy in the Treatment of Resistant Hypertension. AB - INTRODUCTION: The objective of this systematic review was to evaluate the efficacy and safety of add-on pharmacologic therapies in the treatment of resistant hypertension (RH), defined as blood pressure (BP) above target despite three antihypertensive agents. METHODS: A systematic search was performed in MEDLINE, Embase, CENTRAL, CINAHL, ClinicalTrials.gov, and Google Scholar (inception to June 2016) to identify randomized controlled trials (RCTs) that compared any antihypertensive agent with control in patients with RH. Outcomes of interest included differences in BP, cardiovascular events, and serious adverse events. The Cochrane Collaboration's tool for assessing risk of bias in RCTs was used to evaluate the quality of the included trials. RESULTS: Six RCTs were identified, including 749 participants. Four RCTs compared spironolactone with placebo and two used an active comparator. Four of the six studies did not report sufficient information regarding methods. A quantitative meta-analysis was not performed because of clinical heterogeneity among the RCTs. Compared with placebo, spironolactone reduced mean office BP by ~10 to 20 mmHg/~3 to 9 mmHg and home BP by ~10/4 mmHg. Compared with doxazosin or bisoprolol, spironolactone reduced clinic and home systolic BP, but not diastolic BP. Hyperkalemia occurred in ~3% of patients receiving spironolactone. Cardiovascular events were not consistently reported. All trials were limited by low enrollment, short follow up, and inconsistent reporting of clinically meaningful outcomes and/or serious adverse events. CONCLUSIONS: Spironolactone has the best evidence as add-on pharmacologic therapy in patients with RH, but data are limited. PMID- 28349275 TI - The 100 Most Influential Papers in the Field of Thrombolytic Therapy: A Bibliometric Analysis. AB - BACKGROUND: Bibliometric analyses are used by researchers and research funding agencies to help determine areas of greatest interest, and consequently which topics and domains warrant increased research attention. Bibliometric analyses have similarly been published in a number of clinical subspecialties concerning areas of specific medical interest; however, a thorough literature search revealed that such a study has been absent in the field of thrombolytics to date. To bridge this gap, we conducted a citation analysis of the 100 most influential articles on thrombolytics. METHODS: Scopus was selected as the database of choice. Two independent researchers explored the database to extract relevant articles. The articles were ranked according to the number of citations, and a sequential list of the top 100 original articles was prepared in descending order. A detailed analysis was carried out to identify trends and uncover significant discriminators. A second list containing the top 10 review articles was also separately prepared. RESULTS: The 100 most-cited articles regarding thrombolytics were published between 1973 and 2015, with the most articles (n = 29) published in the 5-year period extending from 1996 to 2000. The total number of citations of these 100 most-cited articles ranged from a low of 389 to a high of 6971, with a median of 612.5 citations. These 100 most-cited articles originated from 26 different countries, with more than half from the USA (n = 54), followed by the next most popular countries of origin Germany (n = 20) and France (n = 15). The New England Journal of Medicine (n = 26) and The Lancet (n = 26) contributed the majority of the articles. CONCLUSION: Our analysis provides insight into the span of research activity and the nature of inquiry dealing with 'thrombolytic therapy,' with the hope that such analysis may help to effectively guide future research. Our analysis also yielded a list of the most highly cited and presumably most impactful guideline articles within this field, for distinct consideration. PMID- 28349277 TI - The purpose of heart rate variability measurements. PMID- 28349278 TI - Clinical classification of orthostatic hypotensions. PMID- 28349276 TI - Novel phenotypes of pyridox(am)ine-5'-phosphate oxidase deficiency and high prevalence of c.445_448del mutation in Chinese patients. AB - To analyze the clinical and genetic characteristics of Chinese patients with pyridox(am)ine-5'-phosphate oxidase (PNPO) deficiency. The clinical presentations and the responses to treatments were analyzed in 4 patients. Blood and urinary metabolic screenings, electroencephalogram (EEG), brain magnetic resonance imaging (MRI) and epilepsy-related genes detection were performed in all patients. Patient 1 and 2 were identical twin brothers, who were born at 35+5 w gestation with a sign of encephalopathy. Their seizures started within the first day and could not be controlled by pyridoxine or pyridoxal-5'-phosphate (PLP) completely. Patient 3 presented seizures at 5 months, responding well to pyridoxine. Seizures in patient 4 began at 40 days after birth and were controlled by valproic acid and topiramate. EEG showed atypical hypsarrhythmia or multifocal epileptiform discharges in 3 patients, and showed normality in patient 4. MRI showed nonspecific abnormality or normality. Blood metabolic screening showed multiple amino acids level abnormalities in all cases. Urinary metabolic screening showed vanillactic acid prominently elevated in 3 patients. Genetic analysis revealed 5 mutations of PNPO, three of which were novel. The mutation c.445_448del was carried by the twins and patient 3. Assessment of psychomotor development indicated severe delay in 3 patients and borderline to mild delay in patient 3. This is the first time to report patients with PNPO deficiency diagnosed by gene analysis in China. The novel clinical characteristics and novel mutations found here expanded the phenotypes and genotypes of this disease. Further, the frameshift mutation c.445_448del might be high prevalence in PNPO deficiency in Chinese patients. PMID- 28349279 TI - Percutaneous transluminal forceps biopsy in patients suspected of having malignant biliary obstruction: factors influencing the outcomes of 271 patients. AB - OBJECTIVES: To evaluate predictive factors for false-negative diagnosis of percutaneous forceps biopsies in patients suspected of having a malignant biliary obstruction METHODS: Two hundred seventy one consecutive patients with obstructive jaundice underwent percutaneous forceps biopsy. In each patient, three to five specimens (mean, 3.5 specimens) were collected from the lesion. The final diagnosis for each patient was confirmed with pathologic findings at surgery, additional histocytologic data, or clinical and radiologic follow-up. Univariate and multivariate logistic regression analysis was used to identify risk factors associated with false-negative diagnosis. RESULTS: One hundred ninety four of 271 biopsies resulted in correct diagnoses of malignancy, while 20 biopsy diagnoses were proved to be true-negative. There were 57 false-negative diagnoses and no false-positive diagnoses. The diagnostic performance of transluminal forceps biopsy in malignant biliary obstructions was as follows: sensitivity, 77.2%; specificity, 100%; and accuracy, 78.9%; positive predictive value, 100%, negative predictive value; 25.9%. Periampullary segment of common bile duct, intrahepatic bile duct and metastatic disease were the significant risk factors of false-negative diagnosis. CONCLUSIONS: Percutaneous forceps biopsy provides relatively high accuracy in the diagnosis of malignant biliary obstructions. The predictive factors of false-negative biopsy were determined to be biopsy site and origin of primary tumour. KEY POINTS: * Percutaneous forceps biopsy provides relatively high accuracy in diagnosis of malignant biliary obstructions. * The predictive factors of false-negative biopsy were biopsy site and origin of primary tumour. * The procedure-related complications were low. PMID- 28349280 TI - Quantification of temporal changes in calcium score in active atherosclerotic plaque in major vessels by 18F-sodium fluoride PET/CT. AB - PURPOSE: Our aim was to assess whether 18F-NaF PET/CT is able to predict progression of the CT calcium score. METHODS: Between August 2007 and November 2015, 34 patients (18 women, 16 men; age, mean +/- standard deviation, 57.5 +/- 13.9 years; age range 19-78 years) with malignancy or orthopaedic disease were enrolled in this study, with approximately 1-year follow-up data. Baseline and follow-up CT images were retrospectively evaluated for the presence of calcification sites in major vessel walls. The maximum and mean CT values (CTmax and CTmean, in Hounsfield units), calcification volumetric score (CVS, in cubic millimetres) and Agatston units score (AU) were evaluated for each site. Subsequent changes in CTmax, CTmean, CVS and AU were calculated and expressed as DeltaCTmax, DeltaCTmean, DeltaCVS and DeltaAU, respectively. We then evaluated the relationship between 18F-NaF uptake (using the maximum target-to-background ratio, TBRmax, and the maximum blood-subtracted 18F-NaF activity, bsNaFmax, which was obtained by subtracting the SUVmax of each calcified plaque lesion and NaF avid site from the SUVmean in the right atrium blood pool) and the change in calcified plaque volume and characteristics obtained after 1 year. RESULTS: We detected and analysed 182 calcified plaque sites and 96 hot spots on major vessel walls. 18F-NaF uptake showed very weak correlations with CTmax, CTmean, CVS, CVS after 1 year, AU and AU after 1 year on both baseline and follow-up PET/CT scans for each site. 18F-NaF uptake showed no correlation with DeltaCTmax or DeltaCTmean. However, there was a significant correlation between the intensity of 18F-NaF uptake and DeltaCVS and DeltaAU. CONCLUSION: 18F-NaF uptake has a strong correlation with calcium score progression which was a predictor of future cardiovascular disease risk. PET/CT using 18F-NaF may be able to predict calcium score progression which is known to be the major characteristic of atherosclerosis. PMID- 28349283 TI - Infectious Agents in Bovine Red Meat and Milk and Their Potential Role in Cancer and Other Chronic Diseases. AB - Red meat and dairy products have frequently been suggested to represent risk factors for certain cancers, chronic neurodegenerative diseases, and autoimmune and cardiovascular disorders. This review summarizes the evidence and investigates the possible involvement of infectious factors in these diseases. The isolation of small circular single-stranded DNA molecules from serum and dairy products of Eurasian Aurochs (Bos taurus)-derived cattle, obviously persisting as episomes in infected cells, provides the basis for further investigations. Gene expression of these agents in human cells has been demonstrated, and frequent infection of humans is implicated by the detection of antibodies in a high percentage of healthy individuals. Epidemiological observations suggest their relationship to the development multiple sclerosis, to heterophile antibodies, and to N-glycolylneuraminic acid (Neu5Gc) containing cell surface receptors. PMID- 28349284 TI - The Evolution of Tumor Formation in Humans and Mice with Inherited Mutations in the p53 Gene. AB - While tumors are very heterogeneous in their origins, mutations in the p53 gene and inactivation of p53 gene functions are the most common feature that predispose to the formation of cancers in humans. Inherited p53 mutations lead to different tumor types at very different frequencies and at very different ages than somatic p53 mutations. The reasons for this are explored. When the first mutation arises in a stem cell (a gatekeeper mutation) it selects for a specific subset of second mutations which in turn select for mutations in a third subset of genes. The nature of the first mutation in a tumor determines, by selection, the functional types of subsequent mutations. Inherited mutations occur at different developmental times and in different orders of mutational sequences than somatic mutations. The excess risk of developing a cancer with an inherited p53 mutation is two- to three-fold in endodermal derived tissues compared with 100- to 1000-fold for ectodermal and mesenchymal derived tissues. By contrast, endodermal derived tumors with somatic p53 mutations occur at very high frequencies (70-100%). These evolutionary restrictions upon the mutational path that tumor development may take could open up new avenues for therapy and prevention. PMID- 28349282 TI - Detailed electroretinographic findings in rd8 mice. AB - PURPOSE: Previous work has suggested that the retinal degeneration mutant rd8 mouse lacks an electroretinographic (ERG) phenotype until about 9 months of age. We evaluated the ERG phenotype of these mice by measuring both conventional ERG responses and scotopic threshold responses. METHODS: Groups of 4-month-old wild type (WT) and mutant (rd8) mice were anesthetized and tested for mass retinal responses (ERGs) to several types of visual stimuli. Scotopic threshold responses were accumulated with brief scotopic flashes at a series of very dim intensities. Dark-adapted (scotopic) and light-adapted (photopic) responses to brief flashes at a series of higher intensities were recorded, along with long flashes and random modulations of light levels under photopic conditions. RESULTS: Negative scotopic threshold responses (nSTRs) had lower amplitudes in rd8 mice compared to WTs. Positive scotopic threshold responses were similar in the two groups. With the more intense stimuli, a- and c-wave amplitudes were smaller in rd8 mice. Both scotopic and photopic b-wave amplitudes tended to be larger in rd8 mice, though generally not significantly. CONCLUSIONS: The striking decrease in nSTR amplitudes was surprising, given that the main retinal effects of the rd8 mutation occur in the outer retina, at the external limiting membrane. The primary source of nSTRs in mice is thought to be at the amacrine cell level in the inner retina. Investigation of how this mutation leads to inner retinal dysfunction might reveal unexpected aspects of retinal cell biology and circuitry. PMID- 28349285 TI - Mitochondria-Associated Membranes and ER Stress. AB - The endoplasmic reticulum (ER) is a crucial organelle for coordinating cellular Ca2+ signaling and protein synthesis and folding. Moreover, the dynamic and complex membranous structures constituting the ER allow the formation of contact sites with other organelles and structures, including among others the mitochondria and the plasma membrane (PM). The contact sites that the ER form with mitochondria is a hot topic in research, and the nature of the so-called mitochondria-associated membranes (MAMs) is continuously evolving. The MAMs consist of a proteinaceous tether that physically connects the ER with mitochondria. The MAMs harness the main functions of both organelles to form a specialized subcompartment at the interface of the ER and mitochondria. Under homeostatic conditions, MAMs are crucial for the efficient transfer of Ca2+ from the ER to mitochondria, and for proper mitochondria bioenergetics and lipid synthesis. MAMs are also believed to be the master regulators of mitochondrial shape and motility, and to form a crucial site for autophagosome assembly. Not surprisingly, MAMs have been shown to be a hot spot for the transfer of stress signals from the ER to mitochondria, most notably under the conditions of loss of ER proteostasis, by engaging the unfolded protein response (UPR). In this chapter after an introduction on ER biology and ER stress, we will review the emerging and key signaling roles of the MAMs, which have a root in cellular processes and signaling cascades coordinated by the ER. PMID- 28349281 TI - Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer. AB - Japanese mortality due to colorectal cancer is on the rise, surpassing 49,000 in 2015. Many new treatment methods have been developed during recent decades. The Japanese Society for Cancer of the Colon and Rectum Guidelines 2016 for the treatment of colorectal cancer (JSCCR Guidelines 2016) were prepared to show standard treatment strategies for colorectal cancer, to eliminate disparities among institutions in terms of treatment, to eliminate unnecessary treatment and insufficient treatment, and to deepen mutual understanding between health-care professionals and patients by making these Guidelines available to the general public. These Guidelines were prepared by consensus reached by the JSCCR Guideline Committee, based on a careful review of the evidence retrieved by literature searches, and in view of the medical health insurance system and actual clinical practice settings in Japan. Therefore, these Guidelines can be used as a tool for treating colorectal cancer in actual clinical practice settings. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. As a result of the discussions held by the Guideline Committee, controversial issues were selected as Clinical Questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here we present the English version of the JSCCR Guidelines 2016. PMID- 28349286 TI - Epipodial Tentacle Gene Expression and Predetermined Resilience to Summer Mortality in the Commercially Important Greenlip Abalone, Haliotis laevigata. AB - "Summer mortality" is a phenomenon that occurs during warm water temperature spikes that results in the mass mortality of many ecologically and economically important mollusks such as abalone. This study aimed to determine whether the baseline gene expression of abalone before a laboratory-induced summer mortality event was associated with resilience to summer mortality. Tentacle transcriptomes of 35 greenlip abalone (Haliotis laevigata) were sequenced prior to the animals being exposed to an increase in water temperature-simulating conditions which have previously resulted in summer mortality. Abalone derived from three source locations with different environmental conditions were categorized as susceptible or resistant to summer mortality depending on whether they died or survived after the water temperature was increased. We detected two genes showing significantly higher expression in resilient abalone relative to susceptible abalone prior to the laboratory-induced summer mortality event. One of these genes was annotated through the NCBI non-redundant protein database using BLASTX to an anemone (Exaiptasia pallida) Transposon Ty3-G Gag Pol polyprotein. Distinct gene expression signatures were also found between resilient and susceptible abalone depending on the population origin, which may suggest divergence in local adaptation mechanisms for resilience. Many of these genes have been suggested to be involved in antioxidant and immune-related functions. The identification of these genes and their functional roles have enhanced our understanding of processes that may contribute to summer mortality in abalone. Our study supports the hypothesis that prestress gene expression signatures are indicative of the likelihood of summer mortality. PMID- 28349287 TI - Growth modulation effects of CBM2a under the control of AtEXP4 and CaMV35S promoters in Arabidopsis thaliana, Nicotiana tabacum and Eucalyptus camaldulensis. AB - The expression of cell-wall-targeted Carbohydrate Binding Modules (CBMs) can alter cell wall properties and modulate growth and development in plants such as tobacco and potato. CBM2a identified in xylanase 10A from Cellulomonas fimi is of particular interest for its ability to bind crystalline cellulose. However, its potential for promoting plant growth has not been explored. In this work, we tested the ability of CBM2a to promote growth when expressed using both CaMV35S and a vascular tissue-specific promoter derived from Arabidopsis expansin4 (AtEXP4) in three plant species: Arabidopsis, Nicotiana tabacum and Eucalyptus camaldulensis. In Arabidopsis, the expression of AtEXP4pro:CBM2a showed trends for growth promoting effects including the increase of root and hypocotyl lengths and the enlargements of the vascular xylem area, fiber cells and vessel cells. However, in N. tabacum, the expression of CBM2a under the control of either CaMV35S or AtEXP4 promoter resulted in subtle changes in the plant growth, and the thickness of secondary xylem and vessel and fiber cell sizes were generally reduced in the transgenic lines with AtEXP4pro:CBM2a. In Eucalyptus, while transgenics expressing CaMV35S:CBM2a showed very subtle changes compared to wild type, those transgenics with AtEXP4pro:CBM2a showed increases in plant height, enlargement of xylem areas and xylem fiber and vessel cells. These data provide comparative effects of expressing CBM2a protein in different plant species, and this finding can be applied for plant biomass improvement. PMID- 28349288 TI - Genetic Counselors' Perception of the Effect on Practice of Laws Restricting Abortion. AB - In 2013, twenty-two states enacted seventy provisions restricting access to abortion. The legislation restricted access to abortions by instituting more regulations on providers and facilities, by prohibiting abortion prior to viability, by restricting funding available to patients and by requiring patients to wait a mandatory time period before having a procedure. Genetic counselors are trained to provide unbiased, comprehensive information in a non-directive style in order to allow patients to exercise their reproductive freedom. We developed a survey of 37 questions for genetic counselors to gauge the potential impact these provisions will have on their ability to be a patient advocate. A total of 286 individuals completed the survey; however, not all respondents answered all questions. Qualitative questions complemented quantitative survey entries, allowing respondents to input thoughts and examples. Results indicate genetic counselors in all regions share similar professional opinions about the provisions. More genetic counselors in the South and Midwest noticed changes impacting patients since the provisions have been enacted. These regional differences correlate with the location of states that have seem the greatest increase in antiabortion provisions. PMID- 28349289 TI - A new world for locomotor organs brought about by portable echography. PMID- 28349290 TI - Exponentiated Weibull regression for time-to-event data. AB - The Weibull, log-logistic and log-normal distributions are extensively used to model time-to-event data. The Weibull family accommodates only monotone hazard rates, whereas the log-logistic and log-normal are widely used to model unimodal hazard functions. The increasing availability of lifetime data with a wide range of characteristics motivate us to develop more flexible models that accommodate both monotone and nonmonotone hazard functions. One such model is the exponentiated Weibull distribution which not only accommodates monotone hazard functions but also allows for unimodal and bathtub shape hazard rates. This distribution has demonstrated considerable potential in univariate analysis of time-to-event data. However, the primary focus of many studies is rather on understanding the relationship between the time to the occurrence of an event and one or more covariates. This leads to a consideration of regression models that can be formulated in different ways in survival analysis. One such strategy involves formulating models for the accelerated failure time family of distributions. The most commonly used distributions serving this purpose are the Weibull, log-logistic and log-normal distributions. In this study, we show that the exponentiated Weibull distribution is closed under the accelerated failure time family. We then formulate a regression model based on the exponentiated Weibull distribution, and develop large sample theory for statistical inference. We also describe a Bayesian approach for inference. Two comparative studies based on real and simulated data sets reveal that the exponentiated Weibull regression can be valuable in adequately describing different types of time-to-event data. PMID- 28349291 TI - Preliminary PET/CT Imaging with Somatostatin Analogs [68Ga]DOTAGA-TATE and [68Ga]DOTAGA-TOC. AB - PURPOSE: Somatostatin receptor positron emission tomography/X-ray computed tomography (SSTR-PET/CT) is a well-established technique for staging and detection of neuroendocrine tumors (NETs). Ga-68-labeled DOTA-conjugated octreotide analogs are the privileged radiotracers for diagnosis and therapeutic monitoring of NETs. Hence, we were interested in assessing the influence of promising, newer variant DOTAGA on the hydrophilicity, pharmacokinetics, and lesion pick-up of somatostatin analogs. Herein, the potential of ([68Ga]DOTAGA, Tyr3, Thr8) octreotide ([68Ga]DOTAGA-TATE) and ([68Ga]DOTAGA, Tyr3) octreotide ([68Ga]DOTAGA-TOC) as NET imaging agents has been investigated. PROCEDURES: Amenability of [68Ga]DOTAGA-(TATE/TOC) to kit-type formulation has been demonstrated. Biodistribution studies were carried out in normal rats at 1 h post injection (p.i.). [68Ga]DOTAGA-(TATE/TOC) PET/CT scans were carried out in patients (70-170 MBq, 1 h p.i.) with histologically confirmed well-differentiated NETs. RESULTS: [68Ga]DOTAGA-TATE exhibited hydrophilicity similar to [68Ga]DOTA TATE (log P = -3.51 vs -3.69) whereas [68Ga]DOTAGA-TOC was more hydrophilic than [68Ga]DOTA-TOC (log P = -3.27 vs -2.93). [68Ga]DOTAGA-TATE and [68Ga]DOTA-TATE showed almost identical blood and kidney uptake in normal rats whereas significantly fast clearance (p < 0.05) of [68Ga]DOTAGA-TATE was observed from other non-specific organs (liver, lungs, spleen, intestine). [68Ga]DOTAGA-TOC also demonstrated rapid clearance from blood and kidneys (p < 0.05) in comparison to [68Ga]DOTA-TOC. The metastatic lesions in NET patients were well identified by [68Ga]DOTAGA-TATE and [68Ga]DOTAGA-TOC. CONCLUSION: The phenomenal analogy was observed between [68Ga]DOTAGA-TATE and [68Ga]DOTA-TATE as well as between [68Ga]DOTAGA-TOC and [68Ga]DOTA-TOC in biodistribution studies in rats. The good lesion detection ability of the two radiotracers indicates their potential as NET imaging radiotracers. PMID- 28349292 TI - In Vitro and In Vivo Comparison of Gemcitabine and the Gemcitabine Analog 1-(2' deoxy-2'-fluoroarabinofuranosyl) Cytosine (FAC) in Human Orthotopic and Genetically Modified Mouse Pancreatic Cancer Models. AB - PURPOSE: Although gemcitabine is a mainstay of pancreatic cancer therapy, it is only moderately effective, and it would be desirable to measure drug uptake in patients. 1-(2'-deoxy-2'-fluoroarabinofuranosyl) cytosine (FAC), is an analog of gemcitabine, and when labeled with F-18, it may be a potential surrogate PET tracer for the drug. PROCEDURES: [18F]FAC was synthesized to a radiochemical purity of >96 %. The human tumor lines AsPC1, BxPC3, Capan-1, Panc1, and MiaPaca2 were grown orthotopically in nude mice. KPC mice that conditionally express oncogenic K-ras and p53 mutations in pancreatic tissue were also used. The intra tumoral distributions of [14C]gemcitabine and [18F]FAC were mapped with autoradiography. The inter-tumor correlation between [14C]gemcitabine and [18F]FAC was established in the orthotopic tumors. Expression of the equilibrative and concentrative nucleoside transporters (ENT, CNT) in vitro was detected by western blotting. Drug uptake was characterized in vitro using [3H]gemcitabine and the effect of transporter inhibition on gemcitabine and FAC uptake was investigated. The relative affinity of cells for gemcitabine and FAC was tested in competition assays. The cell lines differed in sensitivity to transport inhibitors and in competition studies. There was a good in vivo correlation between the total uptake of [18F]FAC and [14C]gemcitabine, measured across all orthotopic tumors. Using the KPC and BxPC3 models, we found that [14C]gemcitabine and [18F]FAC were largely co-localized. CONCLUSIONS: In the lines examined here, [18F]FAC uptake correlates well with gemcitabine in vivo, supporting the notion that [18F]FAC can serve as a PET radiotracer surrogate to determine the uptake and distribution of gemcitabine within pancreatic tumors. PMID- 28349294 TI - Erratum to: Long-term Effect of Ileal Transposition on Adipokine Serum Level in Zucker (Orl)-Lepr fa Fatty Rats. PMID- 28349295 TI - Endoscopic Drainage of Intra-Abdominal Collection after Bariatric Surgery. AB - INTRODUCTION: Symptomatic intra-abdominal collection after bariatric surgery occurs in up to 5% of cases. Surgical, percutaneous, or endoscopic drainage are the feasible approaches. MATERIALS AND METHODS: In this video, we show the case report of a 50-year-old woman who underwent to gastric omega bypass on a previous sleeve gastrectomy. After 3 weeks, she presented a well-organized liquid collection just behind the longitudinal staple line of the gastric pouch. No passage of contrast from the gastrointestinal tract to the collection was highlighted. Endoscopic ultrasound drainage approach failed due to tightness of the gastric pouch. Therefore, direct endoscopic drainage was successfully performed using CT scan images as guidance and according to fluoroscopic visualization of the staple line. RESULTS: The patient fully recovered, and she was discharged 48 h after endoscopy with complete normalization of inflammatory markers (CRP and leukocytosis). Upper GI endoscopy has been scheduled in 3 months in order to plan the removal of the stents. CONCLUSIONS: We managed such surgical complication creating a fistula between the gastric remnant and the collection achieving an internal drainage of the intra-abdominal fluid collection. The concept of internally drain any fluid collection with endoscopically delivered double pigtails plastic stents is gaining momentum and has been demonstrated effective in the management of leak following bariatric and upper GI surgery too. PMID- 28349296 TI - Roux-En-Y Fistulojejunostomy: a New Therapeutic Option for Complicated Post Sleeve Gastric Fistulas, Video-Report. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has become during the last few years the most frequent procedure in bariatric surgery. However, complications related to the gastric staple line can be even more serious. The incidence of gastric fistula after LSG varies from 1 to 7%. Its management can be very challenging and long. In case of chronic fistula and failure of the previous treatment, total gastrectomy or Roux-en-Y fistulo-jejunostomy (RYFJ) might be considered. RYFJ has been described very rarely as a salvage procedure of gastric leaks after LSG. METHODS: Between January 2015 and December 2015, we have performed a RYFJ in two patients, with chronic and persisting gastric fistulas, one after LSG and one after duodenal switch, respectively. In the two patients, the RYFJ procedure was attempted laparoscopically but in one case (patient after duodenal switch), conversion into laparotomy was necessary because of severe intra-abdominal inflammatory adhesions. In our video, we are presenting the case of this particular patient treated laparoscopically with a late and persisting leak 1 year after LSG. RESULTS: In this multimedia high-definition video, we described the steps of our technique of laparoscopic RYFJ. There was neither mortality nor severe postoperative complications. The fistula control after a minimum of 6 months follow-up was 100% for both of patients. CONCLUSIONS: RYFJ in our particular case was efficient. However, larger series and longer follow-up are needed to confirm the efficiency of the RYFJ as a salvage procedure. PMID- 28349293 TI - Molecular Imaging in Nanotechnology and Theranostics. AB - The fields of biomedical nanotechnology and theranostics have enjoyed exponential growth in recent years. The "Molecular Imaging in Nanotechnology and Theranostics" (MINT) Interest Group of the World Molecular Imaging Society (WMIS) was created in order to provide a more organized and focused forum on these topics within the WMIS and at the World Molecular Imaging Conference (WMIC). The interest group was founded in 2015 and was officially inaugurated during the 2016 WMIC. The overarching goal of MINT is to bring together the many scientists who work on molecular imaging approaches using nanotechnology and those that work on theranostic agents. MINT therefore represents scientists, labs, and institutes that are very diverse in their scientific backgrounds and areas of expertise, reflecting the wide array of materials and approaches that drive these fields. In this short review, we attempt to provide a condensed overview over some of the key areas covered by MINT. Given the breadth of the fields and the given space constraints, we have limited the coverage to the realm of nanoconstructs, although theranostics is certainly not limited to this domain. We will also focus only on the most recent developments of the last 3-5 years, in order to provide the reader with an intuition of what is "in the pipeline" and has potential for clinical translation in the near future. PMID- 28349298 TI - The Role of Spirituality in Lifestyle Changing Among Patients with Chronic Cardiovascular Diseases: A Literature Review of Qualitative Studies. AB - Chronic cardiovascular diseases (CVD) are diseases with marked morbidity. Patients are often advised to change their lifestyle to prevent complications and impairment of their diseases. Compliance, however, is influenced by multiple factors. Initial studies show that spirituality is an important aspect in health behavior and lifestyle changing, but to health professionals like nurses this is unknown. The aim of this review is to investigate and synthesize evidence about the role of spirituality in lifestyle changing in patients with chronic CVD. A comprehensive search was conducted in electronic databases Academic Search Premier, E-journals, Medline and PubMed, published between the years 2000-2015. After selection based on pre-set inclusion criteria, studies were retrieved and evaluated on quality using the criteria of the QOREC. Twelve studies with a qualitative empirical design and mixed methods were included. This review shows that spirituality, is related to the self-management of patients with chronic diseases. For instance, lifestyle changes are experienced as a continuous inner battle. Religion gives strength, but is also experienced as a struggle. Feelings of guilt and becoming a victim influence patients' experience. For effectively advising patients with CVD on lifestyle changes, nurses cannot ignore this factor but further investigation is required. PMID- 28349297 TI - Molecular identification of differential expression genes associated with sex pheromone biosynthesis in Spodoptera exigua. AB - Species-specific sex pheromone is biosynthesized and released in most female moths as a chemical cue in mating communication. However, information on genes involved in this pathway is limited. The beet armyworm, Spodoptera exigua, is a cosmopolitan agricultural pest that causes severe economic losses to many crops. In China, the female sex pheromones in sex pheromone glands (PGs) of S. exigua have been measured which comprises (Z,E)-9,12-tetradecadienyl acetate, (Z)-9 tetradecen-l-ol, (Z)-9-tetradecenyl acetate, and (Z,E)-9,12-tetradecadien-1-ol in a ratio of 47:18:18:17. Fifty-nine putative genes related to sex pheromone biosynthesis were identified in the present study by sequencing and analyzing the sex pheromone gland (PG) transcriptome of S. exigua. Expression profiles revealed that two desaturase (SexiDes5 and SexiDes11) and three fatty acyl reductase (SexiFAR2, 3, and 9) genes had PG-specific expression, and phylogenetic analysis demonstrated that they clustered with genes known to be involved in pheromone synthesis in other moth species. Our results provide crucial background information that could facilitate the elucidation of sex pheromone biosynthesis pathway of S. exigua as well as other Spodoptera species and help identify potential targets for disrupting sexual communication in S. exigua for developing novel environment-friendly pesticides. PMID- 28349299 TI - Efficacy and prognostic factors of imatinib plus CALLG2008 protocol in adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. AB - A CALLG2008 protocol was developed by the Chinese Acute Lymphoblastic Leukemia Cooperative Group for adult acute lymphoblastic leukemia (ALL). We retrospectively analyzed 153 newly diagnosed adult patients with Philadelphia chromosome (Ph)-positive ALL enrolled into imatinib (400 mg/d) plus CALLG2008 regimen between 2009 and 2015. The median age was 40 years (range, 18-68 years), with 81 (52.3%) males. The overall hematologic complete remission (CR) rate was 96.7% after induction. With a median follow-up of 24.2 months, the estimated 3 year overall survival (OS) and event-free survival (EFS) rates were 49.5%(95%confidence interval (CI): 38.5%-59.5%) and 49.2% (95% CI: 38.3%-59.2%), respectively. Fifty-eight (36 with haploidentical donor) patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first CR. Among the patients in CR1 after induction, both the 3-year OS and EFS were significantly better in the allo-HSCT group than in the without allo-HSCT group (73.2%, 95% CI: 58.3%-83.5% vs. 22.2%, 95% CI: 8.7%-39.6% and 66.5%, 95% CI: 50.7%-78.2% vs. 16.1%, 95% CI: 5.1%-32.7%, respectively). Multivariate analysis showed that allo-HSCT and achievement of major molecular response were associated with favorable OS or EFS independently. Interestingly, in the allo-HSCT cohort, the donor type (haploidentical versus matched donors) had no significant impact on EFS or OS. All these results suggested that imatinib plus CALLG2008 was an effective protocol for Ph-positive ALL. Haploidentical donors can also be a reasonable alternative expedient donor pool. PMID- 28349301 TI - Effect of traditional Chinese medicine combined with Western therapy on primary hepatic carcinoma: a systematic review with meta-analysis. AB - Primary hepatic carcinoma (PHC) is a common malignant tumor in China. Cancer is comprehensively treated with various therapeutic regimes, including traditional Chinese medicine (TCM). TCM has been widely used to improve the quality of life, delay the time of cancer progression, and prolong the median survival time. This systematic review with meta-analysis aimed to assess the effect of TCM combined with Western therapy on primary hepatic carcinoma. A comprehensive literature search was conducted in six databases, including CNKI, VIP, Wan-Fang Database, CBM, PubMed, and Cochrane library. A total of 44 randomized controlled trials (RCTs) involving 3429 participants suffering from PHC were selected. Meta analysis results indicated that the overall effect of TCM and Western integrative treatment on PHC was higher than that of Western intervention alone, which can postpone tumor recurrence and metastasis and prolong the overall survival time of patients with PHC. Although the obtained evidence remained weak because of the poor methodological quality of the included studies, this review provided relevant data supporting the efficacy and safety of TCM combined with Western therapies. In future research, individual RCT studies should incorporate accepted standards for trial design and reporting, proper outcome indicators according to international standards, blinding in allocation concealment, and valid follow-up periods. PMID- 28349300 TI - Behavioral methods for the functional assessment of hair cells in zebrafish. AB - Zebrafish is an emerging animal model for studies on auditory system. This model presents high comparability with humans, good accessibility to the hearing organ, and high throughput capacity. To better utilize this animal model, methodologies need to be used to quantify the hearing function of the zebrafish. Zebrafish displays a series of innate and robust behavior related to its auditory function. Here, we reviewed the advantage of using zebrafish in auditory research and then introduced three behavioral tests, as follows: the startle response, the vestibular-ocular reflex, and rheotaxis. These tests are discussed in terms of their physiological characteristics, up-to-date technical development, and apparatus description. Test limitation and areas to improve are also introduced. Finally, we revealed the feasibility of these applications in zebrafish behavioral assessment and their potential in the high-throughput screening on hearing-related genes and drugs. PMID- 28349302 TI - A Mutant Sumo Facilitates Quick Plasmid Construction for Expressing Proteins with Native N-termini After Tag Removal. AB - Sumo is one of the fusion tags commonly used to enhance the expression and the solubility of recombinant proteins. One advantage of using sumo is that the removal of the sumo tag is highly specific because its recognition by a sumo protease is determined by its structural characteristics, instead of the sequence of a short peptide. Recently, it was reported that sumo could also be used as a protease recognition site to facilitate the removal of other fusion tags, such as MBP, when sumo itself is not suitable to enhance the solubility of a particular target protein. Using sumo as a recognition site is highly desirable when the target protein needs to have its native N terminus. However, constructing such a plasmid involves more than one cloning step because the N terminus of the target protein needs to be the next residue after the diglycine of sumo. Here, we report the construction of a new vector with a mutant sumo tag. The incorporation of a Pvu II site near the 3' end of tag coding sequence enables quick construction of plasmids for producing proteins with native termini. Its usage includes producing recombinant food allergens for studying conformational IgE epitopes. PMID- 28349303 TI - Mechanistic and therapeutic perspectives for cardiac arrhythmias: beyond ion channels. AB - Cardiac arrhythmias are among the most common causes of death in the world. Foundational studies established the critical role of ion channel disorders in arrhythmias, yet defects in ion channels themselves, such as mutations, may not account for all arrhythmias. Despite the progress made in recent decades, the antiarrhythmic drugs currently available have limited effectiveness, and the majority of these drugs can have proarrhythmic effects. This review describes novel knowledge on cellular mechanisms that cause cardiac arrhythmias, focuses on the dysfunction of subcellular organelles and intracellular logistics, and discusses potential strategies and challenges for developing novel, safe and effective treatments for arrhythmias. PMID- 28349305 TI - Profile of Yi-Han Chen. PMID- 28349304 TI - Rapid generation of genetic diversity by multiplex CRISPR/Cas9 genome editing in rice. AB - The clustered regularly interspaced short palindromic repeats (CRISPR)-associated endonuclease 9 (CRISPR/Cas9) system has emerged as a promising technology for specific genome editing in many species. Here we constructed one vector targeting eight agronomic genes in rice using the CRISPR/Cas9 multiplex genome editing system. By subsequent genetic transformation and DNA sequencing, we found that the eight target genes have high mutation efficiencies in the T0 generation. Both heterozygous and homozygous mutations of all editing genes were obtained in T0 plants. In addition, homozygous sextuple, septuple, and octuple mutants were identified. As the abundant genotypes in T0 transgenic plants, various phenotypes related to the editing genes were observed. The findings demonstrate the potential of the CRISPR/Cas9 system for rapid introduction of genetic diversity during crop breeding. PMID- 28349306 TI - Trajectories of Suicidal Ideation among Adolescents Following Psychiatric Hospitalization. AB - Suicidal ideation (SI) is a common presenting problem for psychiatric hospitalizations in adolescents and often persists following discharge. This study examines whether distinct trajectories of SI could be delineated following hospitalization and the risk factors most strongly related to these trajectories. Adolescents (N = 104; 76 females; 28 males) were followed for 6 months after discharge from inpatient or partial hospitalization. Semi-parametric group modeling identified SI trajectory group membership. In all, 33.7% of adolescents fell in a Subclinical SI group, 43.3% in a Declining SI group, and 23.1% in a Chronic SI group. Multinomial logistic regression was utilized to examine baseline predictors of group membership. Emotion dysregulation differentiated Chronic SI from Declining SI. In multivariate analyses, adolescents endorsing greater non-acceptance of emotional responses (OR =1.18) and more limited access to emotion regulation strategies (OR =1.12) were more likely to belong to the Chronic SI than Declining SI trajectory. Those in the Chronic SI group also had the greatest number of suicide attempts and hospitalizations in the 6 months post discharge. These results suggest that clinicians should closely monitor and address emotion dysregulation when assessing suicide risk. Greater dysregulation may require more intensive services in order to have an effect on chronic SI. PMID- 28349307 TI - Pancreatic Tail Neoplasm Masquerading as Recurrent Splenic Abscesses. PMID- 28349308 TI - Efficient dibutyltin (DBT) elimination by the microscopic fungus Metarhizium robertsii under conditions of intensive aeration and ascorbic acid supplementation. AB - Dibutyltin (DBT) is an environmental pollutant characterized by immunotoxic, neurotoxic, and pro-oxidant properties. In this study, an attempt was made to enhance DBT elimination by the Metarhizium robertsii strain. We observed enhanced fungal growth in the bioreactor (pO2 >= 20%) compared to flask cultures (MU max increased from 0.061 to 0.086 h-1). Moreover, under aerated conditions, M. robertsii mycelium with "hairy" morphology biodegraded DBT (20 mg l-1) 10-fold faster in the bioreactor than in the flask cultures. Monobutyltin (MBT) and a hydroxylated derivative of MBT (OHBuSnH2) were detected as by-products of dibutyltin debutylation. Simultaneous usage of glucose and butyltins indicates the comatabolic nature of monobutyltin and dibutyltin removal. In order to protect fungal cells from oxidative stress caused by DBT presence, vitamin C (20 mg l-1) was applied. Supplementation with ascorbic acid (AA) resulted in a 3-fold acceleration of MBT removal during the first 7 h of incubation. Using the HPLC MS/MS technique, a quantitative analysis of malondialdehyde (MDA), a marker of oxidative stress, was performed. In the AA presence, a decrease in the MDA amount (about 45%) was observed compared to the case with fungal cells exposed to DBT alone. PMID- 28349309 TI - Dissipation of chlorantraniliprole, chlorpyrifos-methyl and indoxacarb insecticides used to control codling moth (Cydia Pomonella L.) and leafrollers (Tortricidae) in apples for production of baby food. AB - Dissipations of three insecticides: chlorantraniliprole, chlorpyrifos-methyl and indoxacarb in apples were studied following their foliar application on apples intended for production of baby food. The apples were sprayed with formulations for control of codling moth (Cydia Pomonella L.) and leafrollers (Tortricidae). Six experiments were conducted; each insecticide was applied individually on dessert apples. A validated gas chromatography-based method with simultaneous electron capture and nitrogen-phosphorus detection (GC-ECD/NPD) was used for the residue analysis. The analytical performance of the method was satisfactory, with expanded uncertainties <=36% (a coverage factor, k = 2, and a confidence level of 95%). The dissipations of insecticides were studied in pseudo-first-order kinetic models (for which the coefficient of determination, R 2 , ranged between 0.9188 and 0.9897). Residues of studied insecticides were below their maximum residue limits of 0.5 mg/kg at an early stage of growth of the fruit. The half-lives of chlorantraniliprole, chlorpyrifos-methyl and indoxacarb were 16-17, 4-6 and 20-24 days, respectively. The initial residue levels declined gradually and reached the level of 0.01 mg/kg in 1 month for chlorpyrifos-methyl, 2 months for chlorantraniliprole and 2.5 months for indoxacarb. To obtain the insecticide residue levels below 0.01 mg/kg, which is the default MRL for food intended for infants and young children, the application of the studied insecticides should be carried out at recommended doses not later then: 1 month before harvest for chlorpyrifos-methyl, 2 months for chlorantraniliprole and 2.5 months for indoxacarb. PMID- 28349310 TI - Parameters determining the use of zeolite 5A as collector medium in passive flux samplers to estimate N2O emissions from livestock sources. AB - The present study analyzes the effect of parameters that determine the use of the zeolite 5A as collector medium in passive flux samplers (PFS) developed to estimate N2O emissions from livestock buildings. The study analyzes the mass of N2O collected on the zeolite 5A as a function of gas flow rate (40 and 130 ml/min), inlet mass of N2O to the PFS (from 7 to 84 MUg), adsorbent mass (4 and 13.6 g), length of the adsorbent bed (1.9 and 10.9 cm), and inlet N2O concentration (0.6 and 2 ppmv). The mass of N2O collected on the zeolite 5A ranged from 1.24 to 6.19 MUg of N2O/g of adsorbent, which was mainly affected by inlet N2O concentration and mass of adsorbent contained in the PFS. The mass of N2O collected presented a significant relationship with the inlet N2O concentration and the adsorbent bed. Tests were performed using PFS in a laboratory farm under semi-real conditions. It was found that at sampling time of 1.5 h, the accuracy and precision of PFS was appropriate. Under evaluated conditions, a maximum variation between PFS and direct detection of around 12% was estimated. PMID- 28349311 TI - Integrating ecosystem services in terrestrial conservation planning. AB - The purpose of this study is to estimate the benefits of ecosystem services for prioritization of land use conservation and to highlight the importance of ecosystem services by comparison between ecosystem service value and green GDP accounting. Based on land use pattern and benefit transfer method, this research estimated value of ecosystem services in Taiwan. Scientific information of land use and land cover change is accessed through multi-year satellite imagery moderate resolution imaging spectroradiometer (MODIS), and geographic information system (GIS) technology. Combined with benefit transfer method, this research estimated the ecosystem service valuation of forest, grassland, cropland, wetland, water, and urban for the period of 2000 to 2015 in Taiwan. It is found that forest made the greatest contribution and the significant increasing area of wetland has huge potential benefit for environmental conservation in Taiwan. We recommend placing maintaining wetland ecosystem in Taiwan with higher priority. This research also compared ecosystem service value with natural capital consumption which would essentially facilitate policy makers to understand the relationship between benefits gained from natural capital and the loss from human made capital. PMID- 28349312 TI - Assessing post-industrial land cover change at the Pine Point Mine, NWT, Canada using multi-temporal Landsat analysis and landscape metrics. AB - This study investigates land cover change near the abandoned Pine Point Mine in Canada's Northwest Territories. Industrial mineral development transforms local environments, and the effects of such disturbances are often long-lasting, particularly in subarctic, boreal environments where vegetation conversion can take decades. Located in the Boreal Plains Ecozone, the Pine Point Mine was an extensive open pit operation that underwent little reclamation when it shut down in 1988. We apply remote sensing and landscape ecology methods to quantify land cover change in the 20 years following the mine's closure. Using a time series of near-anniversary Landsat images, we performed a supervised classification to differentiate seven land cover classes. We used raster algebra and landscape metrics to track changes in land cover composition and configuration in the 20 years since the mine shut down. We compared our results with a site in Wood Buffalo National Park that was never subjected to extensive anthropogenic disturbance. This space-for-time substitution provided an analog for how the ecosystem in the Pine Point region might have developed in the absence of industrial mineral development. We found that the dense conifer class was dominant in the park and exhibited larger and more contiguous patches than at the mine site. Bare land at the mine site showed little conversion through time. While the combination of raster algebra and landscape metrics allowed us to track broad changes in land cover composition and configuration, improved access to affordable, high-resolution imagery is necessary to effectively monitor land cover dynamics at abandoned mines. PMID- 28349313 TI - Foliar nutrient and metal levels of crops in the Mount Cameroon area-reference values for plant nutrition and environmental monitoring. AB - The growing population number and traffic loads, increasing environmental pressures, agricultural intensification, and the establishment of Mount Cameroon National Park demand farsighted environmental management in the region and the definition of a favorable ecological status. Since plants grow in the interface between soils and the atmosphere they can be used as passive biomonitors for the environmental quality. At the same time, the accumulation of nutrients and pollutants in crops is linked to human health, so that foliar elemental levels can be used as an integrative measure for environmental pollution and impact assessment. In the present study, we collected leaf samples of plantain, cassava, cocoyam, and maize on 28 sites at the southern flanks of Mt. Cameroon and determined 20 chemical elements. Air pollution in the study area comes from biomass and waste burning mainly, but emissions from traffic and a large refinery were believed to also play a significant role. However, spatial patterns in foliar elemental concentrations reflected the geochemistry rather than specific sources of pollution. Significant differences in foliar metal and nutrient levels were observed between the four species, indicating a different demand and uptake of specific elements. The results were compared to published data on nutrient concentrations in the tested species and the so-called reference plant. The data can be used as a baseline for future studies in plant nutrition and the environmental monitoring in inner tropical regions where these crops are grown. PMID- 28349314 TI - Measurement of faculty anesthesiologists' quality of clinical supervision has greater reliability when controlling for the leniency of the rating anesthesia resident: a retrospective cohort study. AB - BACKGROUND: Our department monitors the quality of anesthesiologists' clinical supervision and provides each anesthesiologist with periodic feedback. We hypothesized that greater differentiation among anesthesiologists' supervision scores could be obtained by adjusting for leniency of the rating resident. METHODS: From July 1, 2013 to December 31, 2015, our department has utilized the de Oliveira Filho unidimensional nine-item supervision scale to assess the quality of clinical supervision provided by faculty as rated by residents. We examined all 13,664 ratings of the 97 anesthesiologists (ratees) by the 65 residents (raters). Testing for internal consistency among answers to questions (large Cronbach's alpha > 0.90) was performed to rule out that one or two questions accounted for leniency. Mixed-effects logistic regression was used to compare ratees while controlling for rater leniency vs using Student t tests without rater leniency. RESULTS: The mean supervision scale score was calculated for each combination of the 65 raters and nine questions. The Cronbach's alpha was very large (0.977). The mean score was calculated for each of the 3,421 observed combinations of resident and anesthesiologist. The logits of the percentage of scores equal to the maximum value of 4.00 were normally distributed (residents, P = 0.24; anesthesiologists, P = 0.50). There were 20/97 anesthesiologists identified as significant outliers (13 with below average supervision scores and seven with better than average) using the mixed-effects logistic regression with rater leniency entered as a fixed effect but not by Student's t test. In contrast, there were three of 97 anesthesiologists identified as outliers (all three above average) using Student's t tests but not by logistic regression with leniency. The 20 vs 3 was significant (P < 0.001). CONCLUSIONS: Use of logistic regression with leniency results in greater detection of anesthesiologists with significantly better (or worse) clinical supervision scores than use of Student's t tests (i.e., without adjustment for rater leniency). PMID- 28349315 TI - Recurrent non-epileptiform seizure-like phenomena secondary to propofol administration. PMID- 28349317 TI - Trends in Procedures at Major Trauma Centres in New South Wales, Australia: An Analysis of State-Wide Trauma Data. AB - OBJECTIVES: To describe the trend in major trauma surgical procedures and interventional radiology in major trauma patients in Australia over the past 6 years. METHODS: This was a retrospective review of adult major trauma (Injury Severity Score greater than 15) patients using the New South Wales Statewide Trauma Registry between 2009 and 2014. Major trauma surgical procedures were classified into abdominal, neurosurgery, cardiothoracic and interventional radiology. The proportion of patients undergoing such procedures per year was the outcome of interest. RESULTS: There were around ten thousand cases analysed. The proportion of cases undergoing interventional radiology procedures increased from 1% in 2009 to around 6% in 2014. Other major trauma surgical procedures remained stable. Only around 100 laparotomies were performed in 2014. The predictors of having an IR procedure performed were increasing from 2009 (OR 1.5 95% CI 1.4, 1.6 p < 0.001), hypotension (OR 1.5 95% CI 1.1, 2.1 n = 0.01), severe abdominal injury (OR 4.2 95% CI 3.2, 5.3 p < 0.001) and lower limb (including pelvic) injury (OR 3.8 95% CI 3.0, 4.7 p < 0.001). CONCLUSION: There has been a rapid increase in the use of interventional radiology over the past few years which will need to be addressed in future trauma service planning and models of care. PMID- 28349316 TI - Cannabis, Cannabinoids, and Sleep: a Review of the Literature. AB - PURPOSE OF REVIEW: The current review aims to summarize the state of research on cannabis and sleep up to 2014 and to review in detail the literature on cannabis and specific sleep disorders from 2014 to the time of publication. RECENT FINDINGS: Preliminary research into cannabis and insomnia suggests that cannabidiol (CBD) may have therapeutic potential for the treatment of insomnia. Delta-9 tetrahydrocannabinol (THC) may decrease sleep latency but could impair sleep quality long-term. Novel studies investigating cannabinoids and obstructive sleep apnea suggest that synthetic cannabinoids such as nabilone and dronabinol may have short-term benefit for sleep apnea due to their modulatory effects on serotonin-mediated apneas. CBD may hold promise for REM sleep behavior disorder and excessive daytime sleepiness, while nabilone may reduce nightmares associated with PTSD and may improve sleep among patients with chronic pain. Research on cannabis and sleep is in its infancy and has yielded mixed results. Additional controlled and longitudinal research is critical to advance our understanding of research and clinical implications. PMID- 28349319 TI - Trauma Care and Surveillance: International "eCapacity" Efforts and Honduras Experience. PMID- 28349318 TI - Laparoscopic Versus Open Resection for Gastric Gastrointestinal Stromal Tumors (GISTs): A Size-Location-Matched Case-Control Study. AB - BACKGROUND: Laparoscopic resection for gastric gastrointestinal stromal tumors (GISTs) is technically feasible, but the long-term effect remains uncertain. This study aims to compare the long-term oncologic outcomes of laparoscopic versus open resection of GISTs by larger cases based on tumor size-location-matched study. METHODS: Between 2006 and 2015, 63 consecutive patients with a primary gastric GIST undergoing laparoscopic resection were enrolled in and matched (1:1) to patients undergoing open resection by tumor size and location. Clinical and pathologic parameters and surgical outcomes associated with each surgical type were collected and compared. RESULTS: The operation time, intraoperative blood loss, return of bowel function and oral intake, nasogastric tube retention time and postoperative stay were all shorter/faster in laparoscopic group than those in open group (P < 0.001). Postoperative complications were comparable except for the higher incidence of abdominal/incision pain in open group (9.52 vs 27%, P = 0.01). There was no statistical difference in recurrence rate (9.52 vs 15.87%, P = 0.29) and long-term recurrence-free survival between the two groups (P = 0.39). CONCLUSIONS: The long-term oncologic outcome of laparoscopic resection of primary gastric GISTs is comparable to that of open procedure, but laparoscopic procedure has the advantage of minimal invasion and is superior in postoperative recovery. PMID- 28349321 TI - Recurrent Laryngeal Nerve Monitoring and Rocuronium: A Selective Sugammadex Reversal Protocol. AB - BACKGROUND: The use of neuromuscular blocking agents may affect intraoperative neuromonitoring during thyroid surgery. A selective neuromuscular recovery protocol was evaluated in a retrospective cohort study during human thyroid neural monitoring surgery. METHODS: One hundred and twenty-five consecutive patients undergoing thyroidectomy with intraoperative neuromonitoring followed a selective neuromuscular block recovery protocol-single intubating dose of rocuronium followed by sugammadex if needed at the first vagal stimulation (V1). RESULTS: Data from 120 of 125 patients could be analysed. Fifteen (12.5%) patients needed sugammadex reversal to obtain an EMG response at the first vagal stimulation (V1). In the remaining 105 patients, spontaneous recovery of rocuronium-induced neuromuscular block was sufficient for a successful first vagal stimulation (V1). CONCLUSIONS: In patients undergoing thyroid surgery, routine reversal of rocuronium block with sugammadex is not mandatory for reliable intraoperative neuromonitoring. A selective neuromuscular block recovery approach may be a valuable and more cost-efficient alternative to routine reversal. PMID- 28349320 TI - Burden of Burns in Brazil from 2000 to 2014: A Nationwide Hospital-Based Study. AB - BACKGROUND: Burns are a major public health concern, affecting mostly low- and middle-income countries. However, there is a lack of epidemiological studies on burns in these countries, particularly in Latin American countries. Our aim was to analyze nationwide demographic, epidemiological and economic characteristics of hospitalized burn patients in Brazil. METHODS: A retrospective study was conducted including inpatients admitted with a diagnosis of burns (ICD-10:T20 T31) from all hospitals in Brazil from 2000 to 2014. We calculated hospitalization and in-hospital mortality rates. Length of stay (LoS), charges and premature mortality were also assessed. RESULTS: A total of 412,541 burn hospitalizations were found, with a hospitalization rate of 14.56 hospitalizations/100,000 inhabitants/year. This rate is decreasing since 2003, mostly due to the reduction among children and elderly. Children below 5 years old accounted for 24% of all admissions. In-hospital mortality rate was 8.1% and median LoS was 5 days. Mean hospitalization charge was 856 international dollars. Substantial regional discrepancies were found in several indicators. CONCLUSION: In this first Latin American nationwide study of burn patients, a decreasing trend of hospitalization rate and a low charge contrasted with a high in-hospital mortality rate. This latter indicator, associated with a low LoS, may raise concerns regarding the quality of healthcare. Important discrepancies were found between regions, which may indicate important differences in regard to healthcare access and risk of burns. Targeting effective prevention, improving healthcare quality and providing more widespread and accurate burn registry are recommended. PMID- 28349322 TI - Cost-Effectiveness of Two Government District Hospitals in Sub-Saharan Africa. AB - BACKGROUND: District hospitals in sub-Saharan Africa are in need of investment if countries are going to progress towards universal health coverage, and meet the sustainable development goals and the Lancet Commission on Global Surgery time bound targets for 2030. Previous studies have suggested that government hospitals are likely to be highly cost-effective and therefore worthy of investment. METHODS: A retrospective analysis of the inpatient logbooks for two government district hospitals in two sub-Saharan African hospitals was performed. Data were extracted and DALYs were calculated based on the diagnosis and procedures undertaken. Estimated costs were obtained based on the patient receiving ideal treatment for their condition rather than actual treatment received. RESULTS: Total cost per DALY averted was 26 (range 17-66) for Thyolo District Hospital in Malawi and 363 (range 187-881) for Bo District Hospital in Sierra Leone. CONCLUSION: This is the first published paper to support the hypothesis that government district hospitals are very cost-effective. The results are within the same range of the US$32.78-223 per DALY averted published for non-governmental hospitals. PMID- 28349323 TI - Yttrium-90 Radioembolization for Hepatocellular Carcinoma Prior to Liver Transplantation. PMID- 28349324 TI - Partiality and distributive justice in African bioethics. AB - African ethical theories tend to hold that moral agents ought to be partial, in the sense that they should favour members of their family or close community. This is considered an advantage over the impartiality of many Western moral theories, which are regarded as having counterintuitive implications, such as the idea that it is unethical to save a family member before a stranger. The partiality of African ethics is thought to be particularly valuable in the context of bioethics. Thaddeus Metz, in particular, argues that his African derived theory best accounts for a number of plausible intuitions, such as the intuition that health care practitioners ought to be biased towards the patients for whom they are directly responsible. In this article, I claim that the plausible intuitions drawn on in favour of partiality can be satisfactorily explained on the basis of impartial moral theories. Moreover, I argue that blanket acceptance of partiality has problematic consequences for distributive justice in resource allocation in biomedical contexts. By contrast, impartial theories can justify plausible instances of partiality whilst avoiding the pitfalls of fully partial moral theories. Although this provides grounds for abandoning partiality in principle, I claim that this finding should not be seen as damaging to African medical ethics. Instead, it prompts investigation of underexplored possibilities of impartial African moral theories. To demonstrate the value of this direction, I sketch some novel and attractive conceptions that combine impartiality with elements of African ethics. PMID- 28349325 TI - Guyton's venous return curves should be taught at medical schools (complete English translation of Japanese version). AB - Guyton's most significant contributions are the exploration into the development of venous return and circulatory equilibrium. Recently, several physiologists challenged the validity of venous return as a function of venous pressure. Guyton's experiment in effect controlled venous pressure by changing cardiac output. Thus, critics claimed that cardiac output is the determinant of venous return. This claim is true, but in the presence of constant stressed volume, venous return and venous pressure have a fixed reciprocal relationship. Thus, it is meaningless to argue which one is the independent variable. We fully support Guyton's venous return and in particular circulatory equilibrium. Guyton's framework should be taught at medical schools worldwide. PMID- 28349326 TI - "What Goes Around Comes Around": Antecedents, Mediators, and Consequences of Controlling vs. Need-Supportive Motivational Strategies Used by Exercise Professionals. AB - BACKGROUND: Research into the factors associated with the use of different motivational strategies by exercise professionals is of empirical and practical utility. PURPOSE: Grounded in self-determination theory, this study sought to analyze putative antecedents, mediators, and work-related well- and ill-being consequences of two types of motivational strategies reported by exercise professionals. METHODS: Participants were 366 exercise professionals (193 males; experience = 7.7 +/- 5.8 years). Questionnaires assessing psychological need satisfaction frustration, self-determined work motivation, motivational strategies (need-supportive vs. controlling), emotional exhaustion, and personal accomplishment were completed online. Path analysis was used to test the hypothesized model. RESULTS: Model with good fit [chi 2 (5) = 9.174, p> .05; CFI = .984; TLI = .936; RMSEA = .048; SRMR = .022] showed need satisfaction as positively associated with supportive strategies and personal accomplishment (beta between .267 and .399) and negatively with emotional exhaustion (beta = .145). Need frustration was negatively associated with work motivation and personal accomplishment (beta = -.315; -.176), and positively with controlling strategies and emotional exhaustion (beta = .195; .226). Furthermore, supportive strategies and work motivation were positively associated with personal accomplishment (beta = .134; .184), whereas controlling strategies were positively associated with emotional exhaustion (beta = .178). CONCLUSIONS: Findings have theoretical implications, providing evidence of need satisfaction and frustration as being differently associated with work-related motivation, type of strategies used, and work-related emotional outcomes. Practical implications convey the importance of these variables in relation to the standard of motivational strategies provided and their role on work-related well- and ill being indicators. PMID- 28349327 TI - A Theoretical Study on Inhibition of Melanoma with Controlled and Targeted Delivery of siRNA via Skin Using SPACE-EGF. AB - Melanoma is a potentially lethal skin cancer with high mortality rate. Recently, the peptide-mediated transdermal delivery of small interference RNA (siRNA) emerges as a promising strategy to treat melanoma by inducing the apoptosis of tumor cells, but the related theoretical model describing the delivery of siRNA under the effect of SPACE-EGF, the growth inhibition of melanoma and the dynamic expanding of the bump on the skin due to the growth of melanoma has not been reported yet. In this article, a theoretical model is developed to describe the percutaneous siRNA delivery mediated by SPACE-EGF to melanoma and the growth inhibition of melanoma. The results present the spatial-temporal distribution of siRNA and the growth of melanoma under the inhibition of siRNA, which shows a good consistency with the experimental results. In addition, this model represents the uplift process of tumors on the skin surface. The model presented here is a useful tool to understand the whole process of the SPACE-EGF-mediated delivery of the siRNA to melanoma through skin, to predict the therapeutic effect, and to optimize the therapeutic strategy, providing valuable references for the treatment of melanoma. PMID- 28349328 TI - The Effect of Food on Doravirine Bioavailability: Results from Two Pharmacokinetic Studies in Healthy Subjects. AB - BACKGROUND AND OBJECTIVE: Doravirine is a novel non-nucleoside reverse transcriptase inhibitor being developed for the treatment of HIV-1. In two open label, single-dose, randomized, two-period, crossover trials, the bioavailability of doravirine administered alone or in a fixed-dose combination (FDC) was determined under fed and fasted conditions. METHODS: Doravirine 100 mg alone or with lamivudine and tenofovir disoproxil fumarate (each 300 mg) were administered to healthy subjects fasted or 30 min after a high-fat, high-calorie breakfast. Twenty-eight subjects, aged 26-55 years, enrolled (doravirine, n = 14; FDC, n = 14). The sequence of fed/fasted treatment was randomized (1:1). Pharmacokinetic data were analyzed as geometric mean ratios (GMRs) with 90% confidence intervals. RESULTS: Doravirine area under the plasma concentration-time curve (AUC) from time zero to infinity (fed/fasted GMRs: alone 1.16 [1.06-1.26]; FDC 1.10 [1.02 1.20]), AUC from time zero to the last measurement (GMRs: alone 1.18 [1.08-1.29]; FDC 1.10 [1.01-1.20]), and plasma concentration 24 h after administration (GMRs: alone 1.36 [1.19-1.55]; FDC 1.26 [1.13-1.41]) values increased in the fed versus fasted state when administered alone or as the FDC; the magnitude was not clinically meaningful. Doravirine maximum achieved concentration was similar after fed or fasted administration for both doravirine alone and FDC (GMRs: alone 1.03 [0.89-1.19]; FDC 0.95 [0.80-1.12]). The pharmacokinetics of tenofovir and lamivudine in the FDC were also slightly altered by administration with food; the changes were not clinically meaningful. CONCLUSIONS: All treatments were generally well tolerated. Food had no clinically meaningful effect on doravirine 100 mg alone or as part of an FDC. PMID- 28349329 TI - Efficacy of Ripasudil as a Second-line Medication in Addition to a Prostaglandin Analog in Patients with Exfoliation Glaucoma: A Pilot Study. AB - OBJECTIVE: This study aimed to assess the intraocular pressure (IOP)-lowering effects of ripasudil, a Rho kinase inhibitor, as a second-line medication in patients with exfoliation glaucoma. METHODS: This retrospective cohort study included patients with exfoliation glaucoma who received ripasudil as the second line drug in addition to prostaglandin analogs, and were followed-up for at least 5 months. Twenty-seven eyes of 16 patients were enrolled; the mean (+/-standard deviation) age was 76.1 +/- 7.2 years (range 63-91 years). Baseline IOPs were the averages of three IOP measurements performed before ripasudil treatment. Statistical analyses used the paired t test with the Bonferroni correction. Relevant background factors were analyzed via stepwise, multiple regression analysis. RESULTS: The mean (+/-standard deviation) IOP levels prior to commencement of ripasudil, 1-2 months later, and 5-6 months later were 16.2 +/- 2.1, 14.7 +/- 2.8, and 13.1 +/- 2.6 mmHg, respectively. These levels differed significantly (p = 0.00019 for 0 versus 1-2 months, 0.00087 for 1-2 vs. 5-6 months, and <0.00001 for 0 vs. 5-6 months). Stepwise multiple regression analysis on data from all 27 eyes showed that the change in IOP at 5-6 months was associated with the treatment time with prostaglandin analogs and age, but not with baseline IOP, the severity of the visual field defect, the timing of IOP measurement, or pseudophakic status. CONCLUSIONS: Ripasudil significantly lowered IOP in patients with exfoliation glaucoma, and the effect thereof increased over time within 5 months. PMID- 28349331 TI - Compared to 123I-MIBG SPECT/CT, 18F-DOPA PET/CT provides accurate tumor extent in patients with extra-adrenal paraganglioma. AB - AIM: The aim of this study was to compare the accuracy of 123I-MIBG SPECT/CT with that of 18F-DOPA PET/CT for staging extra-adrenal paragangliomas (PGLs) using both functional and anatomical images (i.e., combined cross-sectional imaging) as the reference standards. METHODS: Three men and seven women (age range 26-73 years) with anatomical and/or histologically proven disease were included in this study. Three patients had either metastatic head-and-neck paragangliomas (HNPGLs) or multifocal PGL, and seven patients had nonmetastatic disease. Comparative evaluation included morphological imaging with CT, functional imaging with 18F DOPA PET, and 123I-MIBG imaging including SPECT/CT. Imaging results were analyzed on a per-patient and per-lesion basis. RESULTS: On a per-patient basis, 18F-DOPA PET's detection rate for both nonmetastatic and metastatic/multifocal disease was 100%, whereas that of planar 123I-MIBG imaging alone was 10.0% and that of 123I MIBG SPECT/CT was 20.0%. Overall, on a per-lesion basis, 18F-DOPA PET showed a sensitivity of 69.2% (McNemar p < 0.001) compared with anatomical imaging. Sensitivity of planar 123I-MIBG scintigraphy was 5.6%, and that of SPECT/CT was 11.1% (McNemar p < 0.0001). Overall, 18F-DOPA PET identified 18 lesions, and anatomical imaging identified 26 lesions; planar 123IMIBG imaging identified only 1 lesion, and SPECT/CT, 2 lesions. CONCLUSION: 18F-DOPA PET is more sensitive than is 123I-MIBG imaging, including SPECT/CT, for staging HNPGL. Combined functional and anatomical imaging (PET/CT) is indicated to exclude metastatic disease in extra-adrenal PGL. PMID- 28349330 TI - Klotho Regulates Cigarette Smoke-Induced Autophagy: Implication in Pathogenesis of COPD. AB - INTRODUCTION: Chronic obstructive pulmonary disease is a progressive lung disease characterized by abnormal cellular responses to cigarette smoke, resulting in tissue destruction and airflow limitation. Autophagy is a fundamental cellular process that eliminates long-lived proteins and damaged organelles through lysosomal degradation pathway, though its role in human diseases remains unclear. We hypothesized that an anti-aging protein, Klotho plays an important role in regulating autophagy in response to cigarette smoke (CS). METHODS: Autophagy was measured by detecting LC3-I and LC3-II expressions. The regulation of autophagy expression by cigarette smoke extract (CSE) was studied in vitro, and small interfering RNA (siRNA) and recombinant Klotho were employed to investigate the role of Klotho on CSE-induced autophagy. Protein levels and phosphorylation were measured by Western blot assay. RESULTS: CS exposure resulted in induction of autophagy in alveolar macrophages. Pretreatment of cells with Klotho attenuated CS-induced autophagy whereas knockdown of Klotho augmented CS-induced autophagy. Klotho inhibited phosphorylation of ERK, Akt, and IGF-1 in CSE-stimulated cells. CONCLUSIONS: These data suggest that Klotho plays a critical role in the regulation of CS-induced autophagy and have important implications in understanding the mechanisms of CS-induced cell death and senescence. PMID- 28349332 TI - A Nomogram for Predicting Overall Survival of Gastric Cancer Patients with Insufficient Lymph Nodes Examined. AB - Insufficient number of examined lymph nodes (eLNs) was considered to increase significantly the risk of stage migration in gastric cancer patients. The aim of our study is to establish a nomogram predicting the overall survival (OS) for patients with an insufficient number of eLNs. A total of 872 gastric cancer patients with extended lymphadenectomies were assigned randomly (2:1) to the development cohort and the validation cohort. The nomogram was established based on the Cox regression model using the development cohort. The concordance index (C-index) was used to evaluate the discriminative ability. We also compared our model with two other staging systems. Using multivariate analysis, age, sex, tumor location, depth of invasion, macroscopic type, lymphovascular invasion, the number of eLNs, and metastatic lymph nodes were selected and incorporated into the nomogram. The C-index of the nomogram was 0.742 and 0.743 in development and validation cohorts, respectively, which were significantly superior to the C indices (range 0.705-0.712, all P < 0.001) of American Joint Committee on Cancer (AJCC) seventh edition and lymph node ratio staging systems in both cohorts. We established a nomogram which could predict accurately OS for gastric cancer patients with insufficient number of eLNs. PMID- 28349333 TI - Laparoscopic Repair of Post-cholecystectomy Bile Duct Injury: an Advance in Surgical Management. AB - Despite widespread advances in laparoscopic surgery, laparoscopic repair of post cholecystectomy bile duct injury (BDI) has rarely been reported related mainly to technical difficulty. We describe three cases of BDI treated laparoscopically with one illustrated by a video. With our gained experience in hepatic pedicle dissection during laparoscopic pancreaticoduodenectomy, we decided to perform laparoscopic repair of BDI in patients with an intact biliary confluence without vascular injury. Three patients were operated including two women: one was re operated by subcostal incision for peritonitis and two had undergone cholecystectomy without conversion. Surgical technique is detailed in the manuscript and the video. Laparoscopic repair was performed between 45 and 300 days after cholecystectomy. Surgery lasted between 250 and 270 min with no conversion and no transfusion. The postoperative course was uneventful with a hospital stay ranging from 7 to 9 days. After a mean follow-up of 9-33 months, patients were symptom free with normal liver function tests. The laparoscopic approach can be safely and effectively proposed to a subgroup of patients with BDI. This approach has the advantages of the laparoscopic approach and represents the main new surgical advancement in the management of this complication. PMID- 28349334 TI - Biological Therapy of Refractory Ulcerative Oral Lichen Planus with Plasma Rich in Growth Factors. PMID- 28349335 TI - Population Pharmacokinetics to Model the Time-Varying Clearance of the PEGylated Asparaginase Oncaspar(r) in Children with Acute Lymphoblastic Leukemia. AB - BACKGROUND AND OBJECTIVES: The pharmacokinetics of the polyethylene glycol (PEG) conjugated asparaginase Oncaspar(r) are characterized by an increase in elimination over time. The focus of our analysis is the better understanding of this time-dependency. METHODS: In paediatric acute lymphoblastic leukemia therapy (AIEOP-BFM ALL 2009), two administrations of Oncaspar(r) (2500 U/m2 intravenously) in induction phase (14-day interval) and one single administration in reinduction were followed by weekly monitoring of asparaginase activity. Non linear mixed-effects modeling techniques (NONMEM) were used. Samples indicating immunological inactivation were excluded to describe the pharmacokinetics under standard conditions. Models with time-constant or time-varying clearance (CL) as well as transit compartment models with an increase in CL over a chain of compartments were investigated. RESULTS: Models with time-constant elimination could not adequately describe 6107 asparaginase activities from 1342 patients. Implementing a time-varying CL improved the fit. Modeling an increase of CL over time after dose (Emax- and Weibull-functions) were superior to models with an increase of CL over time after the first administration. However, a transit compartment model came out to be the best structural model. CONCLUSION: The increase in elimination of PEGylated asparaginase appears to be driven by physicochemical processes that are drug-related. The observed hydrolytically in vitro instability of the drug leads to the hypothesis that this increase in CL might be due to an in vivo hydrolysis of the instable ester bond between PEG and the enzyme combined with an increased elimination of the partly de-PEGylated enzyme (Trial registered at www.clinicaltrials.gov , NCT0111744). PMID- 28349336 TI - Contralateral Lobe Volume Brings Us One Step Closer to the Prediction of Hypothyroidism Following Partial Thyroid Resection. PMID- 28349337 TI - Erratum to: Impact of an In-visit Decision Aid on Patient Knowledge about Contralateral Prophylactic Mastectomy: A Pilot Study. PMID- 28349338 TI - Clinical Impact of Preoperative Chemotherapy on Microscopic Cancer Spread Surrounding Colorectal Liver Metastases. AB - BACKGROUND: A potentially favorable effect of chemotherapy on the incidence of micrometastases has been reported in patients with colorectal liver metastases (CLMs); however, the actual influence of chemotherapy on the distribution of micrometastases and surgical curability remains unclear. METHOD: The clinical impact of preoperative chemotherapy on the incidence and distribution of micrometastases was assessed in 191 patients with 357 CLM nodules. Potential radiologic measures for predicting the extent of microscopic cancer spread and surgical curability were then sought among the size-based and non-size-based radiologic response criteria. RESULTS: Multivariate analysis estimated a reduced incidence of micrometastases in patients receiving preoperative chemotherapy (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.26-0.76, p = 0.003). Furthermore, the addition of biologic agents to the preoperative chemotherapy regimen was correlated with a reduced incidence of microscopic cancer spread beyond a width of 1 mm from the margin of the main tumor (OR 0.28, 95% CI 0.11 0.74, p = 0.010 for bevacizumab; and OR 0.29, 95% CI 0.09-0.99, p = 0.048 for anti-epidermal growth factor receptor antibody). Receiver operating characteristic analyses revealed that the computed tomography (CT) morphologic response showed a moderate predictive power for the distribution of micrometastases, with an area under the curve of 0.687, while size-based response criteria were not reliable for estimating the extent of microscopic cancer spread. CONCLUSION: Notwithstanding the potential selection of patients after preoperative chemotherapy, the incidence and distribution of micrometastases may be reduced by preoperative chemotherapy. CT morphologic response may be a reliable predictor of both the degree of microscopic cancer spread and the curability of surgery. PMID- 28349339 TI - An Analysis of Tumor- and Surgery-Related Factors that Contribute to Inadvertent Positive Margins Following Soft Tissue Sarcoma Resection. AB - BACKGROUND: The risk of local recurrence (LR) after soft tissue sarcoma (STS) resection is higher in the setting of inadvertent positive margins (IPMs). This study assessed whether both tumor- and surgery-related factors contribute to IPMs, and whether tumor- versus surgery-related IPMs differ in LR or overall survival (OS). METHODS: Retrospective review of a tertiary center database identified patients with IPMs following STS resection between 1989 and 2014. Of 2234 resected STSs, 309 (13%) had positive margins; 89 (4%) were IPMs. Mean follow-up was 52 months, mean tumor size was 9.2 cm, and 55% were high grade. Cases were categorized as surgery-related (67, 75%) or tumor-related (22, 25%). RESULTS: There was a significant difference in positive margin location, with the deep margin commonly involved in surgery-related IPMs (55% vs. 9%; p < 0.001). Tissue type also differed (p = 0.01), with surgery-related IPMs frequently in muscle (33%), while tumor-related IPMs favored subcutaneous tissues (41%). STSs with surgery-related IPMs were larger (p = 0.01). Histologic subtypes differed (p = 0.02), with myxofibrosarcoma and undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma predominating in tumor-related IPMs (82%). The cumulative probability of LR after IPMs, with death as a competing risk, was 28% (95% confidence interval [CI] 18-35) at 5 years and 37% (95% CI 24-45) at 10 years. Mortality was 28% (95% CI 18-38) at 5 years and 38% (26-50) at 10 years. There was no difference in LR (p = 0.91) or OS (p = 0.44) between surgery- and tumor related IPMS. CONCLUSIONS: IPMs after STS resection results in substantial LR risk. While demonstrating distinct surgery- and tumor-related contributions, there was no between-group difference in LR or OS. These results may aid in avoiding IPMs. LEVEL OF EVIDENCE: Therapeutic Level III, retrospective comparative study. PMID- 28349340 TI - Continuing Medical Education: A Cross Sectional Study on a Developing Country's Perspective. AB - To determine the attitude of general practitioners towards continuing medical education (CME) and reasons motivating or hindering them from attending CME procedures, we conducted a cross-sectional survey from November 2013 to April 2014 in Karachi. Three hundred general practitioners who possessed a medical license for practice in Pakistan filled a pre-designed questionnaire consisting of questions pertaining to attitudes towards CME. Data was entered and analyzed using SPSS v16.0. 70.3% (n = 211) of the participants were males. Mean age was 47.75 +/- 9.47 years. Only 67.33% knew about CME and only 52% had attended a CME session. Reasons for attending CME procedures reported were: need for updating knowledge, skills and competencies (67.30%), opportunity to meet colleagues (18.58%) and presenting scientific papers (8.97%). Mean Likert score was 1.67 (+/ 0.667) for those who thought CME is worthwhile and 1.44 (+/-0.686) for those who consider their clinical duties as the major hurdle in attending CME procedures. Most common cause for not attending CME was lack of knowledge (32.66%) followed by time constraint (24%). Most physicians were not sufficiently informed about the potential benefits of CME and had never attended a CME session. Most common reason for attending CME procedures reported was need for updating knowledge, skills and competencies while reasons hindering physicians from attending CME were lack of knowledge and time constraint. PMID- 28349342 TI - In silico screening of dicarboxylic acids for cocrystallization with phenylpiperazine derivatives based on both cocrystallization propensity and solubility advantage. AB - In silico screening was performed to search for binary solids in which a phenylpiperazine-derivative drug was cocrystallized with a dicarboxylic acid. The phenylpiperazine derivative could be any of 61 such drugs, while the dicarboxylic acid could be any of nine such acids. The uniqueness of this approach was that two criteria had to be fulfilled simultaneously, namely a high propensity for cocrystallization and a sufficient solubility advantage. Using the mixing enthalpies of selected pairs of crystal formers with high affinities for one another permitted the classification of candidates with a high probability of cocrystallization. Further modeling of the solubility advantage allowed the identification of many binary solids that potentially exhibit significantly enhanced solubility in water. Based on the computed values for the mixing enthalpies and solubility advantage factors, it was concluded that dicarboxylic acids are both excellent coformers for cocrystallization with phenylpiperazines and very good solubility enhancers; indeed, the use of dicarboxylic acids as coformers would allow the degree of dissolution to be tuned for many of the studied drugs. The observed similarities of the cocrystallization landscapes of the studied drugs and excipients were also explored. PMID- 28349341 TI - Knowledge and opinion of pharmacists on emergency contraceptive pills in Hungary. AB - Background Emergency contraceptive pills (ECPs) are used to prevent unintended pregnancy. There is a worldwide intention to improve access to ECPs; therefore, identifying potential barriers to introducing over-the counter (OTC) access is of utmost importance. As pharmacists are the key personnel to convey accurate drug information, their knowledge and attitude on ECPs is important. Objective We aimed to conduct a nationwide study to assess pharmacists' knowledge on ECPs and to survey their opinion on sales category change of ECPs (i.e. to introduce OTC access in pharmacies). Setting Registered pharmacists in Hungary. Method A prospective cross-sectional study was conducted with an anonymous, web-based questionnaire. Univariate analysis (Mann-Whitney U test and Fischer's exact test) was used to identify factors associated with supportive opinion toward OTC provision. Main outcome measure Knowledge level of pharmacists, proportion of pharmacists with supportive opinion on OTC access. Results 357 out of 2019 pharmacists completed the questionnaire, yielding a 17.7% response rate. Almost 30% of pharmacists (N = 99) agreed that ECPs should have an OTC availability in Hungary. More than 40% of pharmacists (N = 145) considered ECPs as contraceptives. On average, 55.18% (standard deviation: +/-12.40%) of the answers were correct, showing moderate knowledge of the pharmacists. Age and rating ECPs as contraceptives were significantly associated with supportive opinion toward OTC provision (p < 0.001). The effect of knowledge on the pharmacist's opinion was significant in young pharmacists (p = 0.02). Conclusion Pharmacists' knowledge and opinion on ECPs should be improved, especially that of the young ones. Currently the attitude of pharmacists does not favor sales category changes of ECPs in Hungary. PMID- 28349343 TI - Characterization and evaluation of a peptide-based siRNA delivery system in vitro. AB - Since its inception more than a decade ago, gene silencing mediated by double stranded small interfering RNA (siRNA) has been widely investigated as a potential therapeutic approach for a variety of diseases. However, the use of siRNA is hampered by its rapid degradation and poor cellular uptake in vitro and in vivo. Recently, peptide-based carriers have been applied to siRNA delivery, as an alternative to the traditional delivery systems. Here, a histidine-containing amphipathic amino acid pairing peptide, C6M3, which can form complexes with siRNA, was used as a new siRNA delivery system. This peptide exhibited a high affinity for siRNA and ability to efficiently deliver siRNA into the cells. The interaction of C6M3 with siRNA was investigated to determine the loading capacity of C6M3 at different peptide/siRNA molar ratios. At C6M3/siRNA molar ratio of 10/1, siRNA molecules were entirely associated with C6M3 as indicated by a gel electrophoretic assay and further confirmed by zeta potential analysis. The particle size distribution of the C6M3-siRNA complexes was studied using dynamic light scattering, which showed an intensity-based size distribution peaked approximately at 100 nm in RNase-free water and 220 nm in the Opti-MEM medium. C6M3 adopted a helical secondary structure in RNase-free water and became more so after forming complexes with siRNA. The interaction of siRNA with C6M3 is an entropy-driven spontaneous process, as determined by isothermal titration calorimetry (ITC) study. The efficiency of cellular uptake of the siRNA complexes at different C6M3/siRNA molar ratios was evaluated, and the results showed that C6M3 promoted efficient cellular uptake of siRNA into cells. Furthermore, a significant level of GAPDH gene silencing efficiency (69%) was achieved in CHO-K1 cells, with minimal cytotoxicity. PMID- 28349344 TI - Long-term abstinence and predictors of tobacco treatment uptake among hospitalized smokers with serious mental illness enrolled in a smoking cessation trial. AB - Hospital patients with serious mental illness (SMI) have high rates of smoking. There are few post-discharge treatment models available for this population and limited research on their treatment uptake following discharge. This study is a secondary analysis of an RCT that compared multi-session intensive telephone counseling versus referral to state quitline counseling at two safety net hospitals in New York City. For this analysis, we selected all trial participants with a history of schizophrenia, schizoaffective disorder or bipolar disorder (N = 384) and used multivariable logistic regression to compare groups on self reported 30-day abstinence at 6 months and to identify patient factors associated with use of tobacco treatment. Analyses found no significant group differences in abstinence 6 months (28% quitline vs. 29% intervention, p > 0.05), use of cessation medications (42% quitline vs. 47% intervention, p > 0.05) or receipt of at least one counseling call (47% quitline vs. 42% intervention, p > 0.05). Patients with hazardous drinking (p = 0.04) or perceived good health (p = 0.03) were less likely to use cessation medications. Homeless patients were less likely to use counseling (p = 0.02). Most patients did not use cessation treatment after discharge, and the intensive intervention did not improve abstinence rates over quitline referral. Interventions are needed to improve use of cessation treatment and long-term abstinence in patients with SMI. PMID- 28349347 TI - Cardiac tamponade due to pyopneumopericardium from malignant bronchopericardial fistula. PMID- 28349346 TI - Two pathways of photoproduction of organic hydroperoxides on the donor side of photosystem 2 in subchloroplast membrane fragments. AB - Earlier the catalase-insensitive formation of organic hydroperoxides (via the interaction of organic radicals produced due to redox activity of P680+. (or TyrZ.) with molecular oxygen) has been found in Mn-depleted PS2 preparations (apo WOC-PS2) by Khorobrykh et al. (Biochemistry 50:10658-10665, 2011). The present work describes a second pathway of the photoproduction of organic peroxides on the donor side of PS2. It was shown that illumination of CaCl2-treated PS2 membranes (deprived of the PS2 extrinsic proteins without removal of the Mn containing water-oxidizing complex) (CaCl2-PS2) led to the photoproduction of highly lipophilic organic hydroperoxides (LP-OOH) (in amount corresponding to 1.5 LP-OOH per one reaction center of PS2) which significantly increased upon the addition of exogenous electron acceptor potassium ferricyanide (to 4.2 LP-OOH per one reaction center). Addition of catalase (200 U/ml) before illumination inhibited ferricyanide-induced photoproduction of hydroperoxides while no effect was obtained by adding catalase after illumination or by adding inactivated catalase before illumination. The hydroperoxide photoproduction was inhibited by the addition of exogenous electron donor for PS2, diphenylcarbazide or diuron (inhibitor of the electron transfer in PS2). The addition of exogenous hydrogen peroxide to the CaCl2-PS2 led to the production of highly lipophilic organic hydroperoxides in the dark (3.2 LP-OOH per one reaction center). We suggest that the photoproduction of highly lipophilic organic hydroperoxides in CaCl2-PS2 preparations occurs via redox activity of H2O2 produced on the donor side of PS2. PMID- 28349345 TI - Photodynamic inactivation of Paracoccidioides brasiliensis helps the outcome of oral paracoccidiodomycosis. AB - The antifungal drug therapy often employed to treat paracoccidiodomycosis (PCM), an important neglected fungal systemic infection, leads to offensive adverse effects, besides being very long-lasting. In addition, PCM compromises the oral health of patients by leading to oral lesions that are very painful and disabling. In that way, photodynamic therapy (PDT) arises as a new promising adjuvant treatment for inactivating Paracoccidioides brasiliensis (Pb), the responsible fungus for PCM, and also for helping the patients to deal with such debilitating oral lesions. PDT has been linked to an improved microbial killing, also presenting the advantage of not inducing immediate microbial resistance such as drugs. For the present study, we investigated the generation of reactive oxygen species (ROS) by using the fluorescent probes hydroxyphenyl fluorescein (HPF) and aminophenyl fluorescein (APF) after toluidine blue (TBO-37.5 mg/L) mediated PDT (660 nm, 40 mW, and 0.04 cm2 spot area) and the action of TBO-PDT upon Pb cultures grown for 7 or 15 days in semisolid Fava Netto's culture medium; we also targeted oral PCM manifestations by reporting the first clinical cases (three patients) to receive topic PDT for such purpose. We were able to show a significant generation of hydroxyl radicals and hypochlorite after TBO-PDT with doses around 90 J/cm2; such ROS generation was particularly useful to attack and inactivate Pb colonies at 7 and 15 days. All three patients reported herein related an immediate relief when it came to pain, mouth opening, and also the ability to chew and swallow. As extracted from our clinical results, which are in fact based on in vitro outcomes, TBO-PDT is a very safe, inexpensive, and promising therapy for the oral manifestations of PCM. PMID- 28349348 TI - Study of the uses of Information and Communication Technologies by Pain Treatment Unit Physicians. AB - Adequate use of Information and Communication Technologies (ICTs) in health has been shown to save the patient and caregiver time, improve access to the health system, improve diagnosis and control of disease or treatment. All this results in cost savings, and more importantly, they help improve the quality of service and the lives of patients. The purpose of this study is to analyse the differences in the uses of this ICTs between those physicians that belong to Pain Treatment Units (PU) and other physicians that work in pain not linked to these PUs. An online survey, generated by Netquest online survey tool, was sent to both groups of professionals and the data collected was statistical analysed through a logistic regression methodology which is the Logit binomial model. Our results show that those physicians that belong to PUs use ICTs more frequently and consider it more relevant to their clinical practice. PMID- 28349349 TI - Acute Disseminated Talaromyces marneffei in An Immunocompetent Patient. AB - Talaromyces marneffei (also called Penicilliosis Marneffei or T. marneffei) is a rare fungal disease that is prevalent mainly in Southeast Asia and commonly seen in immunocompromised hosts. It was rarely observed in immunocompetent hosts. We report a case of acute disseminated T. marneffei in an immunocompetent patient in the non-prevalent region. This patient had never visited the endemic area. The patient experienced a persistent fever. Brain CT and magnetic resonance imaging (MRI) showed a mass in the right frontal with osteolytic damage. Excessive white blood cell (WBC) count and C-reactive protein content were observed. Antibiotics including meropenem and linezolid could not play an effect, and another two hard masses appeared in his right neck and front chest wall. The aspirates from the right frontal mass and bone marrow were cultured. The final diagnose of this infection was disseminated T. marneffei. After voriconazole treatment, all symptoms improved gradually. We present this case and aim to promote more clinicians and microbiologists in the non-endemic region to recognize this rare disease. PMID- 28349350 TI - Visual Snow: a Potential Cortical Hyperexcitability Syndrome. AB - OPINION STATEMENT: The purpose of this review is to provide an overview of visual snow (VS) and provide information regarding current treatment options for VS. Visual snow (VS) is a rare disorder manifesting with a persistent visual phenomenon of seeing numerous tiny snow-like dots throughout the visual field, and it can cause debilitating visual and psychological consequences. It is emerging as a disorder separate from, but associated with, migraine visual aura, and neuronal cortical hyperexcitability is being considered as a theoretical mechanism for the persistent-positive visual symptoms. There are few studies that have investigated the treatment of VS, but as our understanding of this entity begins to change, we expect that new treatment approaches and treatment trials will emerge in the next decade. Currently, our approach is to consider pharmacologic treatment for all patients with VS who report decreased quality of life as a result of VS. Resolution of the disorder is difficult to accomplish with treatment, but in our experience, even when symptom intensity is simply reduced, many patients find that there is an improvement in their quality of life that is beneficial. Our preferred treatment options include: (1) oral lamotrigine with a slow increase from 25 mg daily to a maintenance dose of 200-300 mg daily in divided doses as tolerated, and this is typically achieved by advancing the dose in increments of 25-50 mg weekly following the first 2 weeks of therapy; (2) oral acetazolamide with an initial dose of 250 mg daily followed by a slow increase over 1-2 weeks to a total of 1000 mg daily in divided doses, and higher doses can be tolerated by some without increasing the risk-benefit ratio; or (3) oral verapamil long-acting at 120-240 mg daily, and if side effects limit the dose the can be initiated, then lower doses with short-acting verapamil two or three times daily can be substituted until higher doses with the long-acting formula can be tolerated. By initiating drug treatments with low doses and slowly increasing over 1 to 4 weeks, tolerability and compliance improves and allows patients to realize the full benefits of treatment. The proposed mechanisms of microstructural cortical abnormalities and hyperexcitability as a cause of VS may lead to new treatment approaches in the future. Until such a time, medications reported to relieve persistent visual phenomena of migraine and visual aura of migraine are treatment options worth considering and these are reviewed for that purpose. Although clinical trials for the treatment of visual snow are lacking due to the rarity of the disorder, medications reviewed here should be considered for use in patients with VS who experience an impact on their quality of life. Theoretical mechanisms that lead to cortical hyperexcitability are being investigated and could lead to new treatment options. In the meantime, medications may provide benefits in this disabling condition. PMID- 28349351 TI - Advanced MRI Techniques in the Monitoring of Treatment of Gliomas. AB - OPINION STATEMENT: With advances in treatments and survival of patients with glioblastoma (GBM), it has become apparent that conventional imaging sequences have significant limitations both in terms of assessing response to treatment and monitoring disease progression. Both 'pseudoprogression' after chemoradiation for newly diagnosed GBM and 'pseudoresponse' after anti-angiogenesis treatment for relapsed GBM are well-recognised radiological entities. This in turn has led to revision of response criteria away from the standard MacDonald criteria, which depend on the two-dimensional measurement of contrast-enhancing tumour, and which have been the primary measure of radiological response for over three decades. A working party of experts published RANO (Response Assessment in Neuro-oncology Working Group) criteria in 2010 which take into account signal change on T2/FLAIR sequences as well as the contrast-enhancing component of the tumour. These have recently been modified for immune therapies, which are associated with specific issues related to the timing of radiological response. There has been increasing interest in quantification and validation of physiological and metabolic parameters in GBM over the last 10 years utilising the wide range of advanced imaging techniques available on standard MRI platforms. Previously, MRI would provide structural information only on the anatomical location of the tumour and the presence or absence of a disrupted blood-brain barrier. Advanced MRI sequences include proton magnetic resonance spectroscopy (MRS), vascular imaging (perfusion/permeability) and diffusion imaging (diffusion weighted imaging/diffusion tensor imaging) and are now routinely available. They provide biologically relevant functional, haemodynamic, cellular, metabolic and cytoarchitectural information and are being evaluated in clinical trials to determine whether they offer superior biomarkers of early treatment response than conventional imaging, when correlated with hard survival endpoints. Multiparametric imaging, incorporating different combinations of these modalities, improves accuracy over single imaging modalities but has not been widely adopted due to the amount of post-processing analysis required, lack of clinical trial data, lack of radiology training and wide variations in threshold values. New techniques including diffusion kurtosis and radiomics will offer a higher level of quantification but will require validation in clinical trial settings. Given all these considerations, it is clear that there is an urgent need to incorporate advanced techniques into clinical trial design to avoid the problems of under or over assessment of treatment response. PMID- 28349352 TI - The Clinical Importance of Periodic Leg Movements in Sleep. AB - OPINION STATEMENT: Periodic leg movements during sleep (PLMS) are commonly found in patients with restless leg syndrome (RLS), but they may occur in other sleep disorders and several medical conditions. Their prevalence increases with age, but they can also be observed in children. During the last decades, very active research has been devoted to determine and understand the pathophysiology, associated events, and clinical significance of PLMS. This chapter tries to sum up the most relevant PLMS-related findings, focusing on the relationship between PLMS and the cardiovascular system, in order to understand the clinical implication of this complex motor phenomenon. PLMS have been associated with sympathetic overactivity, namely surges in nocturnal blood pressure and heart rate, without modification in global autonomic balance. Also, PLMS have been related to inflammatory cellular pathways, with elevated level of inflammatory markers, which are associated with cardiovascular risk. The PLMS-related modulation of the autonomic system and of inflammation may increase cardiovascular and cerebrovascular risk in subjects with frequent PLMS. Moreover, also, comorbidities associated with PLMS may play a synergic role in worsening the cardiovascular risk and the consequent mortality and morbidity. Furthermore, little is known about pathophysiological correlates in children with PLMS and their chronic implication on the cardiovascular and cerebrovascular systems. A few studies have suggested that treating PLMS with dopaminergic drugs may reduce their associated sympathetic overactivity and modify disease progression. Definitely, further research is needed to assess the clinical impact of PLMS, associated or not with RLS, and above all the long-term impact of treating PLMS on cardiovascular risk, morbidity, and mortality. PMID- 28349353 TI - Management of Chronic Obstructive Pulmonary Disease in Patients with Cardiovascular Diseases. AB - Chronic obstructive pulmonary disease (COPD) and cardiovascular diseases often coexist. The mechanistic links between these two diseases are complex, multifactorial and not entirely understood, but they can influence the therapeutic approach. Therapy can be primarily directed towards treating the respiratory symptoms and reducing lung inflammation. Smoking cessation, bronchodilators and inhaled corticosteroids are central to this therapeutic approach. The underlying pathophysiological mechanisms that are responsible for the increased cardiovascular risk in COPD remain unclear, but might include arterial stiffness, inflammation and endothelial dysfunction as a consequence of systemic exposure to chemicals in cigarette smoke or airborne pollution. Therefore, it is plausible that treatment of cardiovascular co-morbidities might reduce morbidity and mortality in patients with COPD and, consequently, therapy of COPD should be shifted to the treatment of cardiovascular diseases and systemic inflammation. In support of this approach, early data suggest that patients with COPD treated with angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, statins, anti-platelet drugs or beta adrenoceptor blockers may have improved survival and reduced hospitalisation from acute exacerbations of COPD. In this review, the potential impact of traditional therapies for COPD that are centred on treating the lungs and newer strategies potentially able to affect and mitigate cardiovascular risks in patients with COPD are discussed. PMID- 28349355 TI - Polymerase spiral reaction (PSR): a novel, visual isothermal amplification method for detection of canine parvovirus 2 genomic DNA. AB - Canine parvovirus-2 (CPV-2), which is ubiquitously distributed worldwide, causes severe and often fatal gastroenteritis in dogs. Accurate, differential and rapid diagnosis of canine parvoviral enteritis remains a challenge for clinicians. A recently developed isothermal amplification technique, polymerase spiral reaction (PSR), was optimized for the first time for a viral pathogen with reference recombinant plasmid standards from different CPV-2 antigenic variants (CPV-2, CPV 2a, CPV-2b and CPV-2c) and subsequently validated using clinical samples. Addition of chromogenic substrate SYBR Green I after the completion of the reaction resulted in bright green fluorescence in positive samples, while negative samples and a no-template control remained orange. These results were further substantiated through visualization of a laddering pattern of the PSR amplified product in an agarose gel in positive cases and the absence of this pattern in no-template control and negative samples. The PSR assay was found to be highly specific, as it did not react with other putative canine pathogens (canine adenovirus 1 and canine distemper virus). The sensitivity of the newly developed PSR technique was compared with that of conventional PCR, real-time PCR and LAMP, using a serial tenfold dilution of canine parvovirus DNA. The detection limit of PSR was found to be at the femtogram level, which is comparable with that of real-time PCR and LAMP, which are ten times more sensitive than conventional PCR. The assay was validated using 90 clinical samples, of which 54 were found positive, while only 45 samples were positive in conventional PCR. This novel assay, which is fully compliant with the 'ASSURED' concept for disease diagnosis, provides a simple, rapid, specific, sensitive and cost-effective method for diagnosis of canine parvoviral enteritis in veterinary clinics. PMID- 28349354 TI - Novel avian leukosis viruses from domestic chicken breeds in mainland China. AB - Two novel avian leukosis viruses (ALVs) were isolated from 1380 whole blood samples taken from domestic chicken breeds in China. The two ALVs were uniquely different from the env (Envelope) genes of ALV A-J and carried an LTR (long terminal repeat) cluster from ALV-E. Large scale sequence analysis further showed that these ALVs (with different env and LTRs) were recently endemic in domestic chicken breeds in both China and Japan. The emergence of these novel ALVs is challenging the current ALV eradication program, and as such novel ALVs should be monitored in a timely and careful manner to stop their transmission and further recombination in the future. PMID- 28349356 TI - Emergence of a deviating genotype VI pigeon paramyxovirus type-1 isolated from India. AB - Pigeon paramyxovirus type 1 (PPMV-1) is an antigenic variant of avian paramyxovirus type 1 (APMV-1), which infects pigeons. The virus causes high morbidity and mortality, creating an alarming state for the poultry industry. The present work describes the molecular and pathogenic characterization of a PPMV-1 strain isolated from pigeon in Bhopal, India. Complete genome sequence analysis revealed a genome of 15,192 nucleotides encoding six genes organized in the order 3'-N-P-M-F-HN-L-5'. The fusion gene sequence analysis showed the presence of multiple basic amino acids 112R-R-Q-K-R-F117 at the cleavage site corresponding to pathogenic strains. The mean death time and intracerebral pathogenicity index values indicated a mesogenic nature for the PPMV-1 isolate. On phylogenetic analysis, the strain clustered with genotype VI viruses, including isolates from pigeon and dove. The Bhopal strain showed significant intra and inter-genotype evolutionary distance, suggesting the emergence of a new sub-genotype, VIj. PMID- 28349357 TI - Characterization of siRNAs derived from cucumber mosaic virus in infected tobacco plants. AB - This study characterized the viral small interfering RNAs (vsiRNAs) from Nicotiana tabacum cv. Samsun infected with a cucumber mosaic virus (CMV) 2b deficient mutant. Most vsiRNAs were 21 -22 nucleotides in length and the 5' terminal ends were dominated by A and U, respectively. The observed vsiRNAs were heterogeneously distributed throughout the CMV genome; however, most of the vsiRNAs were derived from sense strands, as opposed to antisense strands. These results demonstrate the conserved and specific function of Dicer-like (DCL), Argonaute (AGO) and RNA-dependent RNA polymerase (RDR) proteins in tobacco. Finally, it was revealed that vsiRNAs target abundant host genes, indicating complex roles for CMV vsiRNAs during the development of symptoms. PMID- 28349358 TI - CRISPR-Cas9 and CRISPR-Cpf1 mediated targeting of a stomatal developmental gene EPFL9 in rice. AB - KEY MESSAGE: CRISPR-Cas9/Cpf1 system with its unique gene targeting efficiency, could be an important tool for functional study of early developmental genes through the generation of successful knockout plants. The introduction and utilization of systems biology approaches have identified several genes that are involved in early development of a plant and with such knowledge a robust tool is required for the functional validation of putative candidate genes thus obtained. The development of the CRISPR-Cas9/Cpf1 genome editing system has provided a convenient tool for creating loss of function mutants for genes of interest. The present study utilized CRISPR/Cas9 and CRISPR-Cpf1 technology to knock out an early developmental gene EPFL9 (Epidermal Patterning Factor like-9, a positive regulator of stomatal development in Arabidopsis) orthologue in rice. Germ-line mutants that were generated showed edits that were carried forward into the T2 generation when Cas9-free homozygous mutants were obtained. The homozygous mutant plants showed more than an eightfold reduction in stomatal density on the abaxial leaf surface of the edited rice plants. Potential off-target analysis showed no significant off-target effects. This study also utilized the CRISPR-LbCpf1 (Lachnospiracae bacterium Cpf1) to target the same OsEPFL9 gene to test the activity of this class-2 CRISPR system in rice and found that Cpf1 is also capable of genome editing and edits get transmitted through generations with similar phenotypic changes seen with CRISPR-Cas9. This study demonstrates the application of CRISPR-Cas9/Cpf1 to precisely target genomic locations and develop transgene-free homozygous heritable gene edits and confirms that the loss of function analysis of the candidate genes emerging from different systems biology based approaches, could be performed, and therefore, this system adds value in the validation of gene function studies. PMID- 28349359 TI - Therapeutic Drug Monitoring of Lacosamide in Norway: Focus on Pharmacokinetic Variability, Efficacy and Tolerability. AB - Lacosamide (LCM) is a new antiepileptic drug (AED). Experience from therapeutic drug monitoring (TDM) in clinical practice is limited. The purpose of this study is to evaluate the pharmacokinetic variability of LCM in relation to efficacy and tolerability in patients with refractory epilepsy in a real-life setting. Variables included age, gender, daily doses and serum concentrations of LCM and other AEDs from the TDM-database at the National Center for Epilepsy in Norway. Clinical data regarding efficacy and tolerability were collected from medical records. The Norwegian Prescription Database (NorPD) was used to include population-based numbers of users. TDM-data from 344 patients were included. The median dose, serum concentration, and concentration/dose (C/D)-ratio of LCM was 350 (range 25-700) mg/day, 19.7 (range 8.1-56.2) umol/L, and 0.06 (0.02-0.82) umol/L/mg, respectively. Serum concentrations were reduced by 28% by concomitant use of enzyme inducers and increased by 30% in patients aged >65 years. Efficacy and tolerability were assessed in 227 patients: 29% had >50% seizure reduction (eight seizure free), 30% had no effect, and 44% reported adverse effects. In Norway, there were on average 500 patients per year using LCM in this period based on NorPD. The study demonstrated pharmacokinetic variability and use of TDM of LCM in Norway. Data were collected from multiple sources for improved pharmacovigilance. Serum concentrations were influenced by enzyme inducers and ageing, indicating the usefulness of TDM. Effect and tolerability were favorable within a suggested reference range of 10-40 umol/L given drug-fasting conditions. PMID- 28349360 TI - Decreased Glutamatergic Activity in the Frontal Cortex of Single Prolonged Stress Model: In vivo and Ex Vivo Proton MR Spectroscopy. AB - Single prolonged stress (SPS) is one of the preclinical models of posttraumatic stress disorder (PTSD) in humans. Not every traumatized person develops PTSD and the onset of the disease varies from months to many years after exposure to life threatening events. The pathogenetic neurometabolites in PTSD have not been investigated to date, and could provide a means for therapeutic interventions. Therefore the present study aimed to evaluate neurochemical changes in the frontal cortex in the SPS model during time-dependent sensitization using in vivo and ex vivo proton magnetic spectroscopy (1H-MRS). Twenty-one male Sprague-Dawley rats (200-220 g) were randomly assigned into two groups (Control, n = 10; SPS, n = 11). SPS consists of three consecutive stressors (restraint, forced swimming, and ether exposure) followed by 7 days without disturbance. In vivo 1H-MRS scans were conducted at baseline, immediately after SPS, and 3 and 7 days after SPS to quantify time-dependent alterations in the frontal cortex. On day 7, all animals were sacrificed and ex vivo 1H-MRS was performed. After SPS exposure, the SPS group showed signs of excitatory activities (glutamate) and cellular membrane turnover (choline and total choline) for 7 days. After the time-sensitization period, the SPS group showed lower glutamate and creatine levels and higher choline and lactate levels than the control group. These results indicate that SPS induces sustained adaptation of glutamatergic neuronal activity in the frontal cortex. Therefore, we conclude that SPS-induced stress reduces glutamatergic metabolism in the frontal cortex. PMID- 28349361 TI - Transient Cerebral Ischemia Alters GSK-3beta and p-GSK-3beta Immunoreactivity in Pyramidal Neurons and Induces p-GSK-3beta Expression in Astrocytes in the Gerbil Hippocampal CA1 Area. AB - Glycogen synthase kinase 3beta (GSK-3beta) is a key downstream protein in the PI3K/Akt pathway. Phosphorylation of serine 9 of GSK-3beta (GSK-3beta activity inhibition) promotes cell survival. In this study, we examined changes in expressions of GSK-3beta and phosphorylation of GSK-3beta (p-GSK-3beta) in the gerbil hippocampal CA1 area after 5 min of transient cerebral ischemia. GSK-3beta immunoreactivity in the CA1 area was increased in pyramidal cells at 6 h after ischemia-reperfusion. It was decreased in CA1 pyramidal cells from 12 h after ischemia-reperfusion, and hardly detected in the CA1 pyramidal cells at 5 days after ischemia-reperfusion. p-GSK-3beta immunoreactivity was slightly decreased in CA1 pyramidal cells at 6 and 12 h after ischemia-reperfusion. It was significantly increased in these cells at 1 and 2 days after ischemia reperfusion. Five days after ischemia-reperfusion, p-GSK-3beta immunoreactivity was hardly found in CA1 pyramidal cells. However, p-GSK-3beta immunoreactivity was strongly expressed in astrocytes primarily distributed in strata oriens and radiatum. In conclusion, GSK-3beta and p-GSK-3beta were significantly changed in pyramidal cells and/or astrocytes in the gerbil hippocampal CA1 area following 5 min of transient cerebral ischemia. This finding indicates that GSK-3beta and p GSK-3beta are closely related to delayed neuronal death. PMID- 28349362 TI - Androgenetic alopecia: a review. AB - PURPOSE: Androgenetic alopecia, commonly known as male pattern baldness, is the most common type of progressive hair loss disorder in men. The aim of this paper is to review recent advances in understanding the pathophysiology and molecular mechanism of androgenetic alopecia. METHODS: Using the PubMed database, we conducted a systematic review of the literature, selecting studies published from 1916 to 2016. RESULTS: The occurrence and development of androgenetic alopecia depends on the interaction of endocrine factors and genetic predisposition. Androgenetic alopecia is characterized by progressive hair follicular miniaturization, caused by the actions of androgens on the epithelial cells of genetically susceptible hair follicles in androgen-dependent areas. Although the exact pathogenesis of androgenetic alopecia remains to be clarified, research has shown that it is a polygenetic condition. Numerous studies have unequivocally identified two major genetic risk loci for androgenetic alopecia, on the X chromosome AR/EDA2R locus and the chromosome 20p11 locus. CONCLUSIONS: Candidate gene and genome-wide association studies have reported that single-nucleotide polymorphisms at different genomic loci are associated with androgenetic alopecia development. A number of genes determine the predisposition for androgenetic alopecia in a polygenic fashion. However, further studies are needed before the specific genetic factors of this polygenic condition can be fully explained. PMID- 28349363 TI - Social Attention, Joint Attention and Sustained Attention in Autism Spectrum Disorder and Williams Syndrome: Convergences and Divergences. AB - There is limited knowledge on shared and syndrome-specific attentional profiles in autism spectrum disorder (ASD) and Williams syndrome (WS). Using eye-tracking, we examined attentional profiles of 35 preschoolers with ASD, 22 preschoolers with WS and 20 typically developing children across social and non-social dimensions of attention. Children with ASD and those with WS presented with overlapping deficits in spontaneous visual engagement with the target of others' attention and in sustained attention. Children with ASD showed syndrome-specific abnormalities in monitoring and following a person's referential gaze, as well as a lack of preferential attention to social stimuli. Children with ASD and WS present with shared as well as syndrome-specific abnormalities across social and non-social dimensions of attention. PMID- 28349364 TI - Hierarchical Letters in ASD: High Stimulus Variability Under Different Attentional Modes. AB - Studies using hierarchical patterns to test global precedence and local-global interference in individuals with ASD have produced mixed results. The current study focused on stimulus variability and locational uncertainty, while using different attentional modes. Two groups of 44 children with and without ASD completed a divided attention task as well as a global and local selective attention task. The results revealed global-to-local and local-to-global interference in ASD, to the same extent as in the TD group. Both groups struggled with the same type of stimuli (i.e., ignoring the global level information) and performed similar in all three tasks. Future studies on (visual) information processing in ASD should pursue the impact of stimulus noise and trial-by-trial uncertainty further. PMID- 28349367 TI - Erratum to: Shame proneness and eating disorders: a comparison between clinical and non-clinical samples. PMID- 28349366 TI - The Inversion Effect for Chinese Characters is Modulated by Radical Organization. AB - In studies of visual object recognition, strong inversion effects accompany the acquisition of expertise and imply the involvement of configural processing. Chinese literacy results in sensitivity to the orthography of Chinese characters. While there is some evidence that this orthographic sensitivity results in an inversion effect, and thus involves configural processing, that processing might depend on exact orthographic properties. Chinese character recognition is believed to involve a hierarchical process, involving at least two lower levels of representation: strokes and radicals. Radicals are grouped into characters according to certain types of structure, i.e. left-right structure, top-bottom structure, or simple characters with only one radical by itself. These types of radical structures vary in both familiarity, and in hierarchical level (compound versus simple characters). In this study, we investigate whether the hierarchical level or familiarity of radical-structure has an impact on the magnitude of the inversion effect. Participants were asked to do a matching task on pairs of either upright or inverted characters with all the types of structure. Inversion effects were measured based on both reaction time and response sensitivity. While an inversion effect was observed in all 3 conditions, the magnitude of the inversion effect varied with radical structure, being significantly larger for the most familiar type of structure: characters consisting of 2 radicals organized from left to right. These findings indicate that character recognition involves extraction of configural structure as well as radical processing which play different roles in the processing of compound characters and simple characters. PMID- 28349365 TI - Psychometric Properties of the Autism-Spectrum Quotient for Assessing Low and High Levels of Autistic Traits in College Students. AB - The current study systematically investigated the effects of scoring and categorization methods on the psychometric properties of the Autism-Spectrum Quotient. Four hundred and three college students completed the Autism-Spectrum Quotient at least once. Total scores on the Autism-Spectrum Quotient had acceptable internal consistency and test-retest reliability using a binary or Likert scoring method, but the results were more varied for the subscales. Overall, Likert scoring yielded higher internal consistency and test-retest reliability than binary scoring. However, agreement in categorization of low and high autistic traits was poor over time (except for a median split on Likert scores). The results support using Likert scoring and administering the Autism Spectrum Quotient at the same time as the task of interest with neurotypical participants. PMID- 28349368 TI - Acculturation, out-group positivity and eating disorders symptoms among Emirati women. AB - Western acculturation has been implicated in the development of eating disorders among populations living outside Europe and North America. This study explored the relationship between Western acculturation, in-group/out-group evaluations and eating disorders symptoms among female citizens of the United Arab Emirates (UAE). Emirati college women (N = 209) completed an affective priming task, designed to implicitly assess in-group (Emirati) and out-group (American) evaluations. Participants also completed the Westernization Survey, a widely used self-report measure of acculturation, and the Eating Attitudes Test (EAT-26). Across the whole sample, out-group positivity was correlated with higher levels of eating disorder symptoms. Participants classified as at risk for eating disorders showed a clear out-group preference (out-group positivity greater than in-group positivity). Western acculturation was also positively correlated with eating disorder symptoms. Overall, these findings lend further support to the acculturation hypothesis of eating disorders in the context of Emirati college women. PMID- 28349370 TI - Solid Cell Nests and Cyst Heterogeneity in Thyroglosal Duct Cysts. PMID- 28349369 TI - Is snack consumption associated with meal skipping in children and adolescents? The CASPIAN-IV study. AB - PURPOSE: The present inquiry set to assess the relationship between snack consumption and meal skipping in Iranian children and adolescents. METHODS: Overall, 14,880 students, aged 6-18 years, were selected via multistage cluster sampling method from rural and urban areas of 30 provinces of Iran. A validated questionnaire of food behaviors including questions on snacks consumption and taking/skipping meals was completed. Consuming and skipping meals and their related factors were reported in both crude and adjusted models. RESULTS: Overall, 13,486 students with a mean age of 12.47 +/- 3.36 years completed the study (90.6% participation rate). Among them, 32.08, 8.89, and 10.90% skipped breakfast, lunch, and dinner, respectively. Compared to their counterpart groups, the frequency of meal skipping was higher in girls, urban inhabitants, and students in higher school grades (P < 0.05). Snack consumption was associated with an increased odds ratio of meal skipping in many types of snack groups. CONCLUSIONS: Meal skipping and snack consumption were frequent among Iranian children and adolescents. Evidence based interventions are proposed to improve the students' eating habits. PMID- 28349371 TI - Intraoral Salivary Duct Cyst: Clinical and Histopathologic Features of 177 Cases. AB - The salivary duct cyst (SDC) is a reactive ductal ectasia most frequently seen in major salivary glands, and likely caused by obstruction. The aim of this study is to define the clinical and histopathologic spectrum of intraoral SDCs. Cases were retrieved from the archives of Harvard School of Dental Medicine/StrataDx, Inc. from January 2012 to August 2014. There were 177 cases of which 103 (58.2%) occurred in females, with a median age of 56 (range 2-95). Approximately half of cases (45.8%) presented in the area of the buccal mucosa, lower lip mucosa, or mandibular vestibule, and 23.2% presented in the floor of mouth. SDCs were lined at least focally by 1-2 layers of cuboidal/columnar epithelium in 85.3% of cases and showed varying degrees of metaplasia (oncocytic, mucous cell, squamous, ciliated, apocrine-like) in 68.4% of cases. Intraluminal mucous stasis was present in 41.8% of SDCs, incipient calcification was present within 4.5% of SDCs, and chronic obstructive sialadenitis was seen in 90.2% of cases. No cysts showed adenomatous ductal proliferations or true papillary structures with fibrovascular cores, although 41.2% exhibited reactive undulation of cyst lining. Thirty-nine 'papillary oncocytic cystadenoma-like' SDCs (22.0%) demonstrated complete oncocytic metaplasia and marked undulation. An additional seven such cysts (4.0%) had a 'Warthin tumor-like' lymphoplasmacytic infiltrate. Intraoral SDCs occur most commonly in the sixth decade of life in locations distinct from extravasation mucoceles, likely secondary to intraluminal obstruction. SDCs show diverse histopathology and certain phenotypic variants may be mistaken for papillary oncocytic cystadenoma or Warthin tumor. PMID- 28349373 TI - A time-motion study of residents and medical students performing patient discharges from general internal medicine wards: a disjointed, interrupted process. AB - Patients are at high risk for adverse events after discharge from a hospital admission. As a critical and often time-consuming aspect of care for hospitalized patients, the purpose of this study was to describe the physician time, events and workflow in performing a patient discharge. On General Internal Medicine (GIM) wards at two academic medical centers in Toronto, a time-motion study was performed on 11 residents and 2 medical students performing 32 patient discharges. Using a paper data collection tool, a research associate aimed to capture the distribution of activities and the nature and frequency of workflow interruptions during patient discharges from the perspective of resident and medical student housestaff. Thirty-two GIM patient discharges by the 13 housestaff were observed over a period of 116 h. Discharges required 69.2 +/- 41.2 min of housestaff-dedicated time to complete, but spanned over a mean 3.7 h from start to finish. On average, 32.8 min (47.3%) of time spent on discharges was dedicated to documentation activities; 13.5 min (19.6%) to direct patient communication; 10.8 min (15.6%) to communication with other clinicians and providers; 6.5 min (9.4%) to arranging outpatient care; 5.7 min (8.2%) to time in transit and waiting. For each discharge, housestaff were interrupted a mean of 5.5 times and switched tasks 8.7 times. During the discharge process, housestaff mainly dedicated themselves to documentation activities and focused minimally on direct patient communication. Clinicians were also found to experience several workflow inefficiencies and interruptions. The present study can be used to identify opportunities to improve and further focus efforts in characterizing this dynamic process. PMID- 28349374 TI - Release of Polyphenols Is the Major Factor Influencing the Bioconversion of Rice Straw to Lactic Acid. AB - In this study, we found that p-coumaric acid (p-CA), ferulic acid (FA), and condensed tannins were released from rice straw during saccharification. The presence of polyphenols prolonged the lag phase and lowered the productivity of lactic acid. p-CA was identified as a key inhibitor. Tannins had a lower inhibitory effect than p-CA; FA had little inhibitory effect. Acid, alkaline, and ball milling pretreatments elicited different levels of polyphenol release from rice straw. Due to the different levels of polyphenol release in the pretreatment step, the enzymatic hydrolysates contained different concentrations of polyphenols. Compared with fermentation with a synthetic medium, fermentation with the hydrolysates of ball-milled rice straw provided much lower productivity and yield of lactic acid due to the presence of polyphenols. Removal of these compounds played an important role in lactic acid fermentation. When rice straw was alkaline pretreated, the hydrolysates contained few phenolic compounds, resulting in high productivity and yield of lactic acid (1.8 g/L/h and 26.7 g/100 g straw), which were comparable to those in a synthetic medium. This indicates that there is a correlation between removal of phenolic compounds and efficiency in lactic acid fermentation. PMID- 28349372 TI - NUT Midline Carcinoma of the Sublingual Gland: Clinical Presentation and Review. AB - NUT midline carcinoma (NMC) is a rare and aggressive disease encountered in the midline of the head and neck or mediastinum. Due to its sparse incidence and subtle pathologic features, we aim to increase knowledge and awareness for this pathologic entity. We present an exemplary case of a young, healthy male presenting with oral cavity pain and cervical lymphadenopathy. This patient was initially diagnosed with an unspecified, highly aggressive sublingual gland malignancy and underwent locoregional resection with free flap reconstruction however suffered a rapid local recurrence and widely extensive metastasis within just 1 month. After rigorous analysis, final pathologic diagnosis revealed a poorly differentiated carcinoma with evidence of squamous differentiation that eventually, post-mortem tested positive for NMC. Only one prior case of sublingual gland NMC has been previously reported as we discuss the literature regarding all sublingual gland malignancies as well as the pathologic features and treatment options for NMC. We recommend consideration of testing for the NUT proto-oncogene at the time of biopsy in the clinical setting of a poorly differentiated midline carcinoma, especially with squamous differentiation, of the head or neck in order to identify patients for clinical trial enrollment and appropriately counsel on the poor clinical prognosis. Improving clinician awareness is critical to increase diagnostic accuracy and need to study prospective treatment outcomes as the first step toward improving management of this difficult disease. PMID- 28349375 TI - Evaluation of Chitosan-Based Films Containing Gelatin, Chondroitin 4-Sulfate and ZnO for Wound Healing. AB - In this work, chitosan-based films containing gelatin and chondroitin-4-sulfate (C4S) with and without ZnO particles were produced and tested in vitro to investigate their potential wound healing properties. Chitosans were produced from shrimp-head processing waste by alkaline deacetylation of chitin to obtain chitosans differing in molecular weight and degree of deacetylation (80 +/- 0.5%). The film-forming solutions (chitosan, C4S and gelatin) and ZnO suspension showed no toxicity towards fibroblasts or keratinocytes. Chitosan was able to agglutinate red blood cells, and film-forming solutions induced no hemolysis. Film components were released into solution when incubated in PBS as demonstrated by protein and sugar determination. These data suggest that a stable, chitosan based film with low toxicity and an ability to release components would be able to establish a biocompatible microenvironment for cell growth. Chitosan-based films significantly increased the percentage of wound healing (wound contraction from 65 to 86%) in skin with full-thickness excision when compared with control (51%), after 6 days. Moreover, histological analysis showed increased granulation tissue in chitosan and chitosan/gelatin/C4S/ZnO films. Chitosan-based biopolymer composites could be used for improved biomedical applications such as wound dressings, giving them enhanced properties. PMID- 28349376 TI - Broadly Neutralizing Antibodies as Treatment: Effects on Virus and Immune System. AB - PURPOSE OF REVIEW: The purpose of this study is to summarize recent advances in the use of broadly neutralizing antibodies (bNAbs) as therapeutics in human clinical trials and in non-human primate (NHP) models. We seek to highlight lessons from these studies with an emphasis on consequences to the virus and immune system. RECENT FINDINGS: In the past 10 years, advances in HIV-1 trimer structure and B cell isolation methods have precipitated the identification of "new-generation" anti-HIV antibodies with broad and potent neutralization. In the past 2 years, the concept of using these bNAbs as therapeutic tools has moved from NHP models into human clinical trials. These trials have investigated the effects of bNAb infusions into patients chronically infected with HIV-1, while the NHP model has investigated treatment during acute infection. Through this work, the relationship between in vitro breadth and potency and in vivo clinical effect, although unresolved, is gradually being elucidated. These results emphasize the need for combination antibody therapy. PMID- 28349378 TI - Gastrointestinal Tract: a Promising Target for the Management of Hypertension. AB - The pathogenesis of hypertension remains elusive. Current treatments on hypertension have only achieved modest reductions. Facilitating theoretical research and looking for new therapeutic strategy are urgently needed. Besides food digestion and nutrients absorption, the gastrointestinal tract (GI) has been shown to influence the status of the central nervous system, immune system, metabolism, and cardiovascular homeostasis. Emerging findings demonstrate that endogenous factors derived from GI including gut hormones, autonomic nerve, and gut microbiota play important roles in the regulation of vascular function and/or blood pressure. Meanwhile, evidences from clinical practice and experimental study have found that intervention in GI through metabolic surgery, probiotics consumption, and dietary modification can efficiently ameliorate or even remit hypertension and related cardiometabolic diseases. Thus, we propose that GI might be an initiating organ of hypertension and a promising target for the management of hypertension. Further, illuminating this concept may aid to understand the pathogenesis and control of hypertension. PMID- 28349380 TI - A new assay based on terminal restriction fragment length polymorphism of homocitrate synthase gene fragments for Candida species identification. AB - Candida sp. have been responsible for an increasing number of infections, especially in patients with immunodeficiency. Species-specific differentiation of Candida sp. is difficult in routine diagnosis. This identification can have a highly significant association in therapy and prophylaxis. This work has shown a new application of the terminal restriction fragment length polymorphism (t-RFLP) method in the molecular identification of six species of Candida, which are the most common causes of fungal infections. Specific for fungi homocitrate synthase gene was chosen as a molecular target for amplification. The use of three restriction enzymes, DraI, RsaI, and BglII, for amplicon digestion can generate species-specific fluorescence labeled DNA fragment profiles, which can be used to determine the diagnostic algorithm. The designed method can be a cost-efficient high-throughput molecular technique for the identification of six clinically important Candida species. PMID- 28349379 TI - Ulva pertusa lectin 1 delivery through adenovirus vector affects multiple signaling pathways in cancer cells. AB - Ulva pertusa lectin 1 (UPL1) is a N-acetyl-D-glucosamine (GlcNAc) binding lectin in marine green alga Ulva pertusa. Exogenous UPL1 colocalized with protein arginine methyltransferase 5 (PRMT5), methylosome protein 50 (MEP50), beta-actin and beta-tubulin, indicating the interaction of UPL1 with the methylosome and cytoskeleton. UPL1 delivery through adenovirus vector (Ad-UPL1) dramatically induced extracellularly regulated protein kinases 1/2 (ERK1/2) phosphorylation in liver cancer cell lines BEL-7404 and Huh7. Signaling pathways including p38 mitogen-activated protein kinase (MAPK), and Akt were also affected by Ad-UPL1 in a cell type dependent manner. MEK1/2 inhibitor U0126, as well as to a lesser extent p38 MAPK inhibitor SB203580 and phosphoinositide 3-kinase (PI3K) inhibitor LY294002, completely eliminated a higher molecular weight isoform of beta-tubulin induced by Ad-UPL1, and significantly enhanced the cytotoxicity of Ad-UPL1 in Huh7 cells, suggesting that the inhibition of MEK1/2, p38 MAPK, and PI3K enhanced antiproliferative effect of Ad-UPL1 possibly through regulating the modification of beta-tubulin. Ad-UPL1 completely inhibited the expression of autophagy-related factor Beclin1, but induced LC3-II expression in Huh7 cells. In addition, Ad-UPL1 significantly enhanced starvation induced survival suppression in Huh7 cells. Our data elucidated intracellular signaling pathways affected by exogenous UPL1, and may provide insights into a novel way of UPL1 delivery through adenovirus vectors combined with survival signaling inhibitors for cancer treatment. PMID- 28349377 TI - Preferred Fourth-Line Pharmacotherapy for Resistant Hypertension: Are We There Yet? AB - Resistant hypertension (RH) is defined as blood pressure (BP) that remains above target levels despite adherence to at least three different antihypertensive medications, typically including a diuretic. Epidemiological studies estimate that RH is increasing in prevalence, and is associated with detrimental health outcomes. The pathophysiology underlying RH is complex, involving multiple, overlapping contributors including activation of the renin-angiotensin aldosterone system and the sympathetic nervous system, volume overload, endothelial dysfunction, behavioural and lifestyle factors. Hypertension guidelines currently recommend specific pharmacotherapy for 1st, 2nd and 3rd-line treatment, however no specific fourth-line pharmacotherapy is provided for those with RH. Rather, five different antihypertensive drug classes are generally suggested as possible alternatives, including: mineralocorticoid receptor antagonists, alpha1-adrenergic antagonists, alpha2-adrenergic agonists, beta blockers, and peripheral vasodilators. Each of these drug classes vary in their efficacy, tolerability and safety profile. This review summarises the available data on each of these drug classes as a potential fourth-line drug and reveals a lack of robust clinical evidence for preferred use of most of these classes in the setting of RH. Moreover, there is a lack of direct comparative trials that could assist in identifying a preferred fourth-line pharmacologic approach and in providing evidence for hypertensive guidelines for adequate treatment of RH. PMID- 28349381 TI - Improved long-term survival with subdural drains following evacuation of chronic subdural haematoma. AB - BACKGROUND: Chronic subdural haematoma (CSDH) is a common condition that is effectively managed by burrhole drainage but requires repeat surgery in a significant minority of patients. The Cambridge Chronic Subdural Haematoma Trial (CCSHT) was a randomised controlled study that showed placement of subdural drains for 48 h following burrhole evacuation significantly reduces the incidence of reoperation and improves survival at 6 months. The present study examined the long-term survival of the patients in the trial. METHODS: In the original trial patients at a single neurosurgical centre from 2004-2007 were randomly assigned to receive a drain (n = 108) or no drain (n = 107) following burrhole drainage of CSDH. We ascertained whether the trial patients were alive in February 2016-a minimum of 8 years following enrollment-via the UK NHS tracing service. Survival was compared between the trial groups and against expected survival for the UK general population matched for age and sex. RESULTS: At 5 years following surgery the drain group continued to have significantly better survival than the no drain patients (p = 0.027), but this was no longer apparent at 10 years. Survival of patients in the drain group did not differ significantly from that of the general population whereas patients who did not receive a drain had significantly lower survival than expected (p = 0.0006). CONCLUSION: Subdural drains following CSDH evacuation are associated with improved long-term survival, which appears similar to that expected for the general population of the same age and sex. All patients having burrhole CSDH evacuation should receive a drain as standard practice unless specifically contraindicated. PMID- 28349382 TI - Protective Effect of Selenium on Aflatoxin B1-Induced Testicular Toxicity in Mice. AB - Aflatoxins have been considered as one of the major risk factors of male infertility, and aflatoxin B1 (AFB1) is the most highly toxic and prevalent member of the aflatoxins family. Selenium (Se), an essential nutritional trace mineral for normal testicular development and male fertility, has received extensive intensive on protective effects of male reproductive system due to its potential antioxidant and activating testosterone synthesis. To investigate the protective effect of Se on AFB1-induced testicular toxicity, the mice were orally administered with AFB1 (0.75 mg/kg) and Se (0.2 mg/kg or 0.4 mg/kg) for 45 days. We found that that Se elevated testes index, sperm functional parameters (concentration, malformation, and motility), and the level of serum testosterone in AFB1-exposed mice. Moreover, our results showed that Se attenuated the AFB1 induced oxidative stress and the reduction of testicular testosterone synthesis enzyme protein expression such as steroidogenic acute regulatory protein (StAR), P450 side-chain cleavage (P450scc), and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) in AFB1-exposed mice. These results demonstrated that Se conferred protection against AFB1-induced testicular toxicity and can be attributed to its antioxidant and increased testosterone level by stimulating protein expression of StAR and testosterone synthetic enzymes. PMID- 28349383 TI - Right away: A late, right-lateralized category effect complements an early, left lateralized category effect in visual search. AB - According to the Sapir-Whorf hypothesis, learned semantic categories can influence early perceptual processes. A central finding in support of this view is the lateralized category effect-namely, the finding that categorically different colors (e.g., blue and green hues) can be discriminated faster than colors within the same color category (e.g., different hues of green), especially when they are presented in the right visual field. Because the right visual field projects to the left hemisphere, this finding has been popularly couched in terms of the left-lateralization of language. However, other studies have reported bilateral category effects, which has led some researchers to question the linguistic origins of the effect. Here we examined the time course of lateralized and bilateral category effects in the classical visual search paradigm by means of eyetracking and RT distribution analyses. Our results show a bilateral category effect in the manual responses, which is combined of an early, left lateralized category effect and a later, right-lateralized category effect. The newly discovered late, right-lateralized category effect occurred only when observers had difficulty locating the target, indicating a specialization of the right hemisphere to find categorically different targets after an initial error. The finding that early and late stages of visual search show different lateralized category effects can explain a wide range of previously discrepant findings. PMID- 28349384 TI - Extended surgery for T4 lung cancer: a 30 years' experience. AB - T4 non-small cell lung carcinomas (NSCLC) were deemed unresectable. Advances in surgery have challenged this dogma. We describe technical aspects and result on superior vena cava (SVC), carinal, thoracic inlet tumor surgeries, and resection under cardiopulmonary bypass (CPB). SVC reconstruction requires hemodynamic control to reverse SVC clamping cerebral effects and excellent cephalic venous bed patency. Among 50 SVC resections, including 25 carinal pneumonectomies, post operative mortality rate was 8%. In the N0-N1 group, 5- and 10-year survival rates were 46.6 and 37.7%, respectively. Right carinal pneumonectomy was performed through right thoracotomy. Sternotomy was favored for left carinal pneumonectomy or carinal resection alone. Among 138 carinal resections, including eight right upper lobectomies, 123 right pneumonectomies, four left pneumonectomies, and three isolated carinal resections, the post-operative mortality rate was 9.4%. In the N0-N1 patients, 5-year survival rate was 47%. 191 patients underwent resections of thoracic inlet tumors through a transclavicular cervicothoracic anterior approach combined in 63 patients with a posterior midline incision for limited spine invasion. In N0-N1 group, 5- and 10-year survival rates were 41.5 and 29.7%, respectively. CPB allowed resection of tumors invading the heart or great vessels in 13 patients. R0 resection and post operative mortality rate were 94.4 and 5.5%, respectively. In this series of 388 T4 NSCLC, the post-operative mortality rate was 4%. In the R0 and N0-N1 groups, the 5-year survival rates were 44 and 41%, respectively. Surgical resection of T4 locally advanced NSCLC is worth being performed in selected N0-N1 patients, provided that a radical resection is expected. PMID- 28349385 TI - Risk of Gonadoblastoma Development in Patients with Turner Syndrome with Cryptic Y Chromosome Material. AB - Current guidelines recommend that testing for Y chromosome material should be performed only in patients with Turner syndrome harboring a marker chromosome and exhibiting virilization in order to detect individuals who are at high risk of gonadoblastoma. However, cryptic Y chromosome material is suggested to be a risk factor for gonadoblastoma in patients with Turner syndrome. Here, we aimed to estimate the frequency of cryptic Y chromosome material in patients with Turner syndrome and determine whether Y chromosome material increased the risk for development of gonadoblastoma. A total of 124 patients who were diagnosed with Turner syndrome by conventional cytogenetic techniques underwent additional molecular analysis to detect cryptic Y chromosome material. In addition, patients with Turner syndrome harboring Y chromosome cell lines had their ovaries removed prophylactically. Finally, we assessed the occurrence of gonadoblastoma in patients with Turner syndrome. Molecular analysis demonstrated that 10 patients had Y chromosome material among 118 patients without overt Y chromosome (8.5%). Six patients with overt Y chromosome and four patients with cryptic Y chromosome material underwent oophorectomy. Histopathological analysis revealed that the occurrence of gonadoblastoma in the total group was 2.4%, and gonadoblastoma occurred in one of six patients with an overt Y chromosome (16.7%) and 2 of 10 patients with cryptic Y chromosome material (20.0%). The risk of developing gonadoblastoma in patients with cryptic Y chromosome material was similar to that in patients with overt Y chromosome. Therefore, molecular screening for Y chromosome material should be recommended for all patients with Turner syndrome to detect individuals at a high risk of gonadoblastoma and to facilitate proper management of the disease. PMID- 28349386 TI - Pharmacokinetics and Tolerability of a Single Dose of Semaglutide, a Human Glucagon-Like Peptide-1 Analog, in Subjects With and Without Renal Impairment. AB - BACKGROUND: The pharmacokinetics and tolerability of semaglutide, a once-weekly human glucagon-like peptide-1 analog in development for the treatment of type 2 diabetes mellitus, were investigated in subjects with/without renal impairment (RI). METHODS: Fifty-six subjects, categorized into renal function groups [normal, mild, moderate, severe, and end-stage renal disease (ESRD)], received a single subcutaneous dose of semaglutide 0.5 mg. Semaglutide plasma concentrations were assessed <=480 h post-dose; the primary endpoint was the area under the plasma concentration-time curve from time zero to infinity. RESULTS: Semaglutide exposure in subjects with mild/moderate RI and ESRD was similar to that in subjects with normal renal function. In subjects with severe RI, the mean exposure of semaglutide was 22% higher than in subjects with normal renal function, and the 95% confidence interval (1.02-1.47) for the ratio exceeded the pre-specified limits (0.70-1.43). When adjusted for differences in sex, age, and body weight between the groups, all comparisons were within the pre-specified clinically relevant limits. Across RI groups there was no relationship between creatinine clearance (CLCR) and semaglutide exposure, or between CLCR and semaglutide maximum plasma drug concentration (C max). Hemodialysis did not appear to affect the pharmacokinetics of semaglutide. No appreciable changes in safety parameters or vital signs and no serious adverse events were noted. One subject with severe RI reported two major hypoglycemic events. CONCLUSION: When adjusted for differences in sex, age, and body weight, semaglutide exposure was similar between subjects with RI and subjects with normal renal function. Semaglutide (0.5 mg) was well-tolerated. Dose adjustment may not be warranted for subjects with RI. CLINICALTRIALS. GOV IDENTIFIER: NCT00833716. PMID- 28349388 TI - Genetic Approaches to Study Meiosis and Meiosis-Specific Gene Expression in Saccharomyces cerevisiae. AB - The budding yeast Saccharomyces cerevisiae has a long history as a model organism for studies of meiosis and the cell cycle. The popularity of this yeast as a model is in large part due to the variety of genetic and cytological approaches that can be effectively performed with the cells. Cultures of the cells can be induced to synchronously progress through meiosis and sporulation allowing large scale gene expression and biochemical studies to be performed. Additionally, the spore tetrads resulting from meiosis make it possible to characterize the haploid products of meiosis allowing investigation of meiotic recombination and chromosome segregation. Here we describe genetic methods for analysis progression of S. cerevisiae through meiosis and sporulation with an emphasis on strategies for the genetic analysis of regulators of meiosis-specific genes. PMID- 28349387 TI - Effect of Semaglutide on the Pharmacokinetics of Metformin, Warfarin, Atorvastatin and Digoxin in Healthy Subjects. AB - BACKGROUND AND OBJECTIVE: Semaglutide is a glucagon-like peptide-1 analogue in development for the once-weekly treatment of type 2 diabetes mellitus. Its effect on the rate and extent of absorption of concomitant oral medications (metformin, warfarin, atorvastatin and digoxin) was evaluated in healthy subjects. METHODS: Subjects received metformin (500 mg twice daily for 3.5 days), warfarin (25 mg, single dose), atorvastatin (40 mg, single dose) or digoxin (0.5 mg, single dose) before and with subcutaneous semaglutide treatment at steady state (1.0 mg). Lack of drug-drug interaction was concluded if the 90% confidence intervals for the area under the plasma concentration-time curve ratio before and with semaglutide were within a pre-specified interval (0.80-1.25). RESULTS: Overall, metformin, warfarin, atorvastatin and digoxin pharmacokinetics were not affected to a clinically relevant degree with semaglutide co-administration. Estimated area under the plasma concentration-time curve ratios for all concomitant medications before and with semaglutide treatment were within the pre-specified interval. In addition, semaglutide did not affect maximum plasma concentration of concomitant medications to a relevant degree. Furthermore, no clinically relevant change in international normalised ratio response to warfarin was observed with semaglutide co-administration. Most adverse events with semaglutide treatment were mild or moderate. Adverse events with semaglutide and co-administered medication were comparable to those reported during treatment with semaglutide alone, and were mostly gastrointestinal related. CONCLUSIONS: No clinically significant pharmacokinetic or pharmacodynamic interactions were identified and no new safety issues observed with combined treatment with semaglutide. This suggests that no dose adjustments should be required when semaglutide is administered concomitantly with these medications. PMID- 28349389 TI - Quantitative Genome-Wide Measurements of Meiotic DNA Double-Strand Breaks and Protein Binding in S. pombe. AB - The fission yeast Schizosaccharomyces pombe is especially well suited for studying meiosis in molecular detail. Experiments with S. pombe strains that undergo a nearly synchronous meiosis-at variable temperatures-have elucidated the mechanisms of meiotic progression and the proteins that are involved. For example, studies focused on the initiation of meiotic recombination by programmed DNA double-strand breaks (DSBs) have proven exceptionally informative. In meiosis, some regions of DNA have more frequent DSBs than the surrounding regions. These DSB hotspots can be visualized by Southern blot hybridization of restriction fragments ranging from kilobases (kb) to megabases (Mb) in size. More recently, the benefits of genome-wide analysis to map the distribution and frequency of meiotic DSBs have been attained, with resolution down to the nucleotide level. Infrequent, non-hotspot DSBs previously not detectable have been observed, creating a better understanding of how recombination is regulated. Additional genome-wide analyses have shown proteins that bind specifically to DSB hotspots, providing insight into how the DSB initiation complex functions. We describe here detailed methods for achieving these results. PMID- 28349390 TI - Sequencing Spo11 Oligonucleotides for Mapping Meiotic DNA Double-Strand Breaks in Yeast. AB - Meiosis is a specialized form of cell division resulting in reproductive cells with a reduced, usually haploid, genome complement. A key step after premeiotic DNA replication is the occurrence of homologous recombination at multiple places throughout the genome, initiated with the formation of DNA double-strand breaks (DSBs) catalyzed by the topoisomerase-like protein Spo11. DSBs are distributed non-randomly in genomes, and understanding the mechanisms that shape this distribution is important for understanding how meiotic recombination influences heredity and genome evolution. Several methods exist for mapping where Spo11 acts. Of these, sequencing of Spo11-associated oligonucleotides (Spo11 oligos) is the most precise, specifying the locations of DNA breaks to the base pair. In this chapter we detail the steps involved in Spo11-oligo mapping in the SK1 strain of budding yeast Saccharomyces cerevisiae, from harvesting cells of highly synchronous meiotic cultures, through preparation of sequencing libraries, to the mapping pipeline used for processing the data. PMID- 28349392 TI - Selection of G1 Phase Yeast Cells for Synchronous Meiosis and Sporulation. AB - Centrifugal elutriation is a procedure that allows the fractionation of cell populations based upon their size and shape. This allows cells in distinct cell cycle stages can be captured from an asynchronous population. The technique is particularly helpful when performing an experiment to monitor the progression of cells through the cell cycle or meiosis. Yeast sporulation like gametogenesis in other eukaryotes initiates from the G1 phase of the cell cycle. Conveniently, S. cerevisiae arrest in G1 phase when starved for nutrients and so withdrawal of nitrogen and glucose allows cells to abandon vegetative growth in G1 phase before initiating the sporulation program. This simple starvation protocol yields a partial synchronization that has been used extensively in studies of progression through meiosis and sporulation. By using centrifugal elutriation it is possible to isolate a homogeneous population of G1 phase cells and induce them to sporulate synchronously, which is beneficial for investigating progression through meiosis and sporulation. An additionally benefit of this protocol is that cell populations can be isolated based upon size and both large and small cell populations can be tested for progression through meiosis and sporulation. Here we present a protocol for purification of G1 phase diploid cells for examining synchronous progression through meiosis and sporulation. PMID- 28349391 TI - Ribosome Profiling for the Analysis of Translation During Yeast Meiosis. AB - Ribosome profiling provides a genome-wide view of translation with unprecedented resolution. Application of this approach to fission and budding yeast revealed widespread regulation of translational efficiency, translation of short open reading frames on unannotated transcripts, and frequent translation of open reading frames in 5' leader sequences. We present here a detailed protocol for the application of ribosome profiling to meiotic fission yeast cells, although the approach should be easily adapted to budding yeast. PMID- 28349393 TI - Fluorescent Protein as a Tool for Investigating Meiotic Recombination in Neurospora. AB - We have built a series of Neurospora crassa strains containing alleles of green fluorescent protein (GFP) to provide a visual phenotype for investigating meiotic recombination. These strains provide a convenient means of screening the Neurospora knockout library for genes involved in genetic recombination. They permit rapid analysis of recombination outcomes by allowing visualization of segregation patterns in a large number of octads from crosses heterozygous for GFP. Using this system the effect of a knockout on gene conversion and/or on crossing over between the fluorescent marker and the centromere can be measured. PMID- 28349394 TI - High-Throughput Screening to Identify Regulators of Meiosis-Specific Gene Expression in Saccharomyces cerevisiae. AB - Meiosis and gamete formation are processes that are essential for sexual reproduction in all eukaryotic organisms. Multiple intracellular and extracellular signals feed into pathways that converge on transcription factors that induce the expression of meiosis-specific genes. Once triggered the meiosis specific gene expression program proceeds in a cascade that drives progress through the events of meiosis and gamete formation. Meiosis-specific gene expression is tightly controlled by a balance of positive and negative regulatory factors that respond to a plethora of signaling pathways. The budding yeast Saccharomyces cerevisiae has proven to be an outstanding model for the dissection of gametogenesis owing to the sophisticated genetic manipulations that can be performed with the cells. It is possible to use a variety selection and screening methods to identify genes and their functions. High-throughput screening technology has been developed to allow an array of all viable yeast gene deletion mutants to be screened for phenotypes and for regulators of gene expression. This chapter describes a protocol that has been used to screen a library of homozygous diploid yeast deletion strains to identify regulators of the meiosis-specific IME1 gene. PMID- 28349395 TI - Analysis of Meiotic Chromosome-Associated Protein Dynamics Using Conditional Expression in Budding Yeast. AB - The visualization of meiotic chromosomes and their associated protein structures in both wild-type and mutant cells adds valuable insight into the molecular pathways that underlie reproductive cell formation. Here we describe basic methodology for visualizing meiotic chromosomes in a long-standing model organism for investigating the molecular and cell biology of meiosis, the budding yeast, S. cerevisiae. This chapter furthermore highlights a variety of conditional expression regimes that can be used to understand the dynamics and/or developmental constraints of chromosomal protein structures; such dynamic aspects of the macromolecular structures that mediate meiotic chromosome biology are typically not obvious from standard protein visualization experiments. PMID- 28349396 TI - In Vivo Imaging of Budding Yeast Meiosis. AB - Tracking biological events in living cells provides kinetic information about biological processes that can be missed in more traditional methods using fixed samples at designated time intervals. Here we describe a methodology for in vivo fluorescence microscopy of yeast cells undergoing meiosis. This method allows tracking of individual cells over extended periods of time through every stage of the meiotic transformation while minimizing phototoxicity and sustaining conditions that support meiotic growth. PMID- 28349397 TI - Sequential Immunofluorescent Light Microscopy and Electron Microscopy of Recombination Nodules During Meiotic Prophase I. AB - Immunolocalization using either fluorescence for light microscopy (LM) or gold particles for electron microscopy (EM) has become a common tool to pinpoint proteins involved in recombination during meiotic prophase. Each method has its advantages and disadvantages. For example, LM immunofluorescence is comparatively easier and higher throughput compared to immunogold EM localization. In addition, immunofluorescence has the advantages that a faint signal can often be enhanced by longer exposure times and colocalization using two (or more) probes with different absorbance and emission spectra is straightforward. However, immunofluorescence is not useful if the object of interest does not label with an antibody probe and is below the resolution of the LM. In comparison, immunogold EM localization is higher resolution than immunofluorescent LM localization, and individual nuclear structures, such as recombination nodules, can be identified by EM regardless of whether they are labeled or not. However, immunogold localization has other disadvantages including comparatively low signal-to-noise ratios, more difficult colocalization using gold particles of different sizes, and the inability to evaluate labeling efficiency before examining the sample using EM (a more expensive and time-consuming technique than LM). Here we describe a method that takes advantage of the good points of both immunofluorescent LM and EM to analyze two classes of late recombination nodules (RNs), only one of which labels with antibodies to MLH1 protein, a marker of crossovers. The method can be used readily with other antibodies to analyze early recombination nodules or other prophase I structures. PMID- 28349398 TI - Flow Cytometry for the Isolation and Characterization of Rodent Meiocytes. AB - Molecular analyses in mammalian meiotic cells have been hindered by the difficulty in isolating stage-specific cell populations, and this is especially true for early meiotic prophase stages (leptotene and zygotene). Here, we describe a method for obtaining cells in different spermatogenic stages from rodents including lepto-zygotene meiocytes at very high purity levels. The procedure includes an approach for the mechanical disaggregation of the testicular tissue, staining with a vital, noncytotoxic dye that is excitable with a blue laser, isolation of the cell populations by flow sorting, and different alternative protocols for the collection of the sorted cells. PMID- 28349399 TI - Imaging of Chromosome Dynamics in Mouse Testis Tissue by Immuno-FISH. AB - The mouse (Mus musculus) represents the central mammalian genetic model system for biomedical and developmental research. Mutant mouse models have provided important insights into chromosome dynamics during the complex meiotic differentiation program that compensates for the genome doubling at fertilization. Homologous chromosomes (homologues) undergo dynamic pairing and recombine during first meiotic prophase before they become partitioned into four haploid sets by two consecutive meiotic divisions that lack an intervening S phase. Fluorescence in situ hybridization (FISH) has been instrumental in the visualization and imaging of the dynamic reshaping of chromosome territories and mobility during prophase I, in which meiotic telomeres were found to act as pacemakers for the chromosome pairing dance. FISH combined with immunofluorescence (IF) co-staining of nuclear proteins has been instrumental for the visualization and imaging of mammalian meiotic chromosome behavior. This chapter describes FISH and IF methods for the analysis of chromosome dynamics in nuclei of paraffin-embedded mouse testes. The techniques have proven useful for fresh and archived paraffin testis material of several mammalian species. PMID- 28349401 TI - Live Imaging of Meiosis I in Late-Stage Drosophila melanogaster Oocytes. AB - Drosophila melanogaster has been studied for a century as a genetic model to understand recombination, chromosome segregation, and the basic rules of inheritance. However, it has only been about 25 years since the events that occur during nuclear envelope breakdown, spindle assembly, and chromosome orientation during D. melanogaster female meiosis I were first visualized by fixed cytological methods (Theurkauf and Hawley, J Cell Biol 116:1167-1180, 1992). Although these fixed cytological studies revealed many important details about the events that occur during meiosis I, they failed to elucidate the timing or order of these events. The development of protocols for live imaging of meiotic events within the oocyte has enabled collection of real-time information on the kinetics and dynamics of spindle assembly, as well as the behavior of chromosomes during prometaphase I. Here, we describe a method to visualize spindle assembly and chromosome movement during meiosis I by injecting fluorescent dyes to label microtubules and DNA into stage 12-14 oocytes. This method enables the events during Drosophila female meiosis I, such as spindle assembly and chromosome movement, to be observed in vivo, regardless of genetic background, with exceptional spatial and temporal resolution. PMID- 28349400 TI - Imaging Chromosome Separation in Mouse Oocytes by Responsive 3D Confocal Timelapse Microscopy. AB - Accurate chromosome segregation is necessary so that genetic material is equally shared among daughter cells. However, maturing mammalian oocytes are particularly prone to chromosome segregation errors, making them a valuable tool for identifying the causes of mis-segregation. Factors such as aging, cohesion loss, DNA damage, and the roles of a plethora of kinetochore and cell cycle-related proteins are involved. To study chromosome segregation in oocytes in a live setting is an imaging challenge that requires advanced techniques. Here we describe a method for examining chromosomes in live oocytes in detail as they undergo maturation. Our method is based on tracking the "center of brightness" of fluorescently labeled chromosomes. Here we describe how to set up our software and run experiments on a Leica TCS SP8 confocal microscope, but the method would be transferable to other microscopes with computer-aided microscopy. PMID- 28349402 TI - Microscopy Methods for Analysis of Spindle Dynamics in Meiotic Drosophila Spermatocytes. AB - The spindle is a microtubule-based structure whose remodeling is required for partitioning the chromosomes and cytoplasm during meiosis. Characterizing microtubule behavior is fundamental to understanding how these tubulin polymers contribute to successful cell division. Here, a procedure is described for the imaging and analysis of spindle microtubule dynamics in cultures of living Drosophila melanogaster primary spermatocytes expressing tubulin tagged with enhanced green fluorescent protein. It employs time-lapse scanning confocal microscopy and the photobleaching of fiduciary marks onto fluorescently tagged microtubules. These labels are subsequently used to determine the sites and rates of kinetochore fiber growth and shrinkage during metaphase. This method can be readily applied to different microtubule populations, meiotic stages, and genetic backgrounds. PMID- 28349403 TI - Drosophila Male Meiosis. AB - In Drosophila males, there is no synaptonemal complex and recombination does not occur. Thus, Drosophila male meiosis is a good model system for the analysis of achiasmate chromosome segregation. In addition, due to their large size, the meiotic spindles of Drosophila males are an excellent system for mutational dissection of the mechanisms of spindle assembly. Here, we describe the main techniques for visualization of live Drosophila testes and for preparation of fixed meiotic chromosomes and spindles. PMID- 28349404 TI - Analysis of Chromatin Dynamics During Drosophila Spermatogenesis. AB - In the course of spermatogenesis, germ cells undergo dramatic morphological changes that affect almost all cellular components. Therefore, it is impossible to study the process of spermatogenesis in its entirety without detailed morphological analyses. Here, we describe a method to visualize chromatin dynamics in differentiating Drosophila male germ cells using immunofluorescence staining. In addition, we demonstrate how to treat Drosophila sperm before immunofluorescence staining to help reveal epitopes in the highly condensed sperm chromatin that otherwise may be inaccessible to antibodies. PMID- 28349405 TI - Quantitative Modeling and Automated Analysis of Meiotic Recombination. AB - Many morphological features, in both physical and biological systems, exhibit spatial patterns that are specifically characterized by a tendency to occur with even spacing (in one, two, or three dimensions). The positions of crossover (CO) recombination events along meiotic chromosomes provide an interesting biological example of such an effect. In general, mechanisms that explain such patterns may (a) be mechanically based, (b) occur by a reaction-diffusion mechanism in which macroscopic mechanical effects are irrelevant, or (c) involve a combination of both types of effects. We have proposed that meiotic CO patterns arise by a mechanical mechanism, have developed mathematical expressions for such a process based on a particular physical system with analogous properties (the so-called beam-film model), and have shown that the beam-film model can very accurately explain experimental CO patterns as a function of the values of specific defined parameters. Importantly, the mathematical expressions of the beam-film model can apply quite generally to any mechanism, whether it involves mechanical components or not, as long as its logic and component features correspond to those of the beam-film system. Furthermore, via its various parameters, the beam-film model discretizes the patterning process into specific components. Thus, the model can be used to explore the theoretically predicted effects of various types of changes in the patterning process. Such predictions can expand detailed understanding of the bases for various biological effects. We present here a new MATLAB program that implements the mathematical expressions of the beam-film model with increased robustness and accessibility as compared to programs presented previously. As in previous versions, the presented program permits both (1) simulation of predicted CO positions along chromosomes of a test population and (2) easy analysis of CO positions, both for experimental data sets and for data sets resulting from simulations. The goal of the current presentation is to make these approaches more readily accessible to a wider audience of researchers. Also, the program is easily modified, and we encourage interested users to make changes to suit their specific needs. A link to the program is available on the Kleckner laboratory website: http://projects.iq.harvard.edu/kleckner_lab . PMID- 28349406 TI - A Computational Approach to Study Gene Expression Networks. AB - We describe a simple computational approach that can be used for the study and simulation of regulatory networks. The advantage of this approach is that it requires neither computational background nor exact quantitative data about the biological system under study. Moreover, it is suitable for examining alternative hypotheses about the structure of a biological network. We used a tool called BioNSi (Biological Network Simulator) that is based on a simple computational model, which can be easily integrated as part of the lab routine, in parallel to experimental work. One benefit of this approach is that it enables the identification of regulatory proteins, which are missing from the experimental work. We describe the general methodology for modeling a network's dynamics in the tool, and then give a point by point example for a specific known network, entry into meiosis in budding yeast. PMID- 28349407 TI - Permanence and Stability of a Kill the Winner Model in Marine Ecology. AB - We focus on the long-term dynamics of "killing the winner" Lotka-Volterra models of marine communities consisting of bacteria, virus, and zooplankton. Under suitable conditions, it is shown that there is a unique equilibrium with all populations present which is stable, the system is permanent, and the limiting behavior of its solutions is strongly constrained. PMID- 28349410 TI - Disseminated Sporotrichosis with Osteolytic Bone Involvement. PMID- 28349408 TI - Cancer of the Peripheral Nerve in Neurofibromatosis Type 1. AB - The RASopathy neurofibromatosis 1 is an autosomal dominant hereditary cancer syndrome that represents a major risk for the development of malignancies, particularly malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are unique sarcomas that originate from the peripheral nerve and represent the only primary cancer of the peripheral nervous system. To date, surgery is the only treatment modality proven to have survival benefit for MPNSTs and even when maximal surgery is feasible, these tumors are rarely curable, despite the use of chemotherapy and radiation. In this review, we discuss the current state-of-the-art treatments for MPNSTs, latest therapeutic developments, and critical aspects of the underlying molecular and pathophysiology that appear promising for therapeutic developments in the future. In particular, we discuss the specific elements of cancer in the peripheral nerve and how that may impel development of unique therapies for this form of sarcoma. PMID- 28349409 TI - Engaging Stakeholders to Inform Clinical Practice Guidelines That Address Multiple Chronic Conditions. AB - BACKGROUND: Having more than one chronic condition is common and is associated with greater health care utilization, higher medication burden and complexity of treatment. However, clinical practice guidelines (CPGs) do not routinely address the balance between harms and benefits of treatments for people with multiple chronic conditions (MCCs). OBJECTIVE: To partner with the Kaiser Permanente Integrated Cardiovascular Health (ICVH) program to engage multiple stakeholders in a mixed-methods approach in order to: 1) identify two high-priority clinical questions related to MCCs, and 2) understand patients' and family caregivers' perceptions of meaningful outcomes to inform benefit/harm assessments for these two high-priority questions. These clinical questions and outcomes will be used to inform CPG recommendations for people with MCCs. DESIGN AND PARTICIPANTS: The ICVH program provided 130 topics rank-ordered by the potential for finding evidence that would change clinical recommendations regarding the topic. We used a modified Delphi method to identify and reword topics into questions relevant to people with MCCs. We used two sets of focus groups (n = 27) to elicit patient and caregiver perspectives on two important research questions and relevant patient important outcomes on benefit/harm balance for people with MCCs. KEY RESULTS: Co investigators, patients and caregivers identified "optimal blood pressure goals" and "diabetes medication management" as important clinical topics for CPGs related to people with MCCs. Stakeholders identified a list of relevant outcomes to be addressed in future CPG development including 1) physical function and energy, 2) emotional health and well-being, 3) avoidance of treatment burden, side effects and risks, 4) interaction with providers and health care system, and 5) prevention of adverse long-term health outcomes. CONCLUSIONS: Through the application of a mixed-methods process, we identified the questions regarding optimal blood pressure goals and diabetes medication management, along with related patient-centered outcomes, to inform novel evidence syntheses for those with MCCs. This study provides the lessons learned and a generalizable process for CPG developers to engage patient and caregivers in priority-setting for the translation of evidence into future CPGs. Ultimately, engaging patient and stakeholders around MCCs could improve the relevance of CPGs for the care of people with MCCs. PMID- 28349411 TI - What's the Opposite of Burnout? PMID- 28349413 TI - Erratum to: Diacerein: Benefits, Risks and Place in the Management of Osteoarthritis. An Opinion-Based Report from the ESCEO. PMID- 28349412 TI - Evaluating Outcomes for Older Patients with Parkinson's Disease or Dementia with Lewy Bodies who have been Hospitalised for Hip Fracture Surgery: Potential Impact of Drug Administration. AB - INTRODUCTION: People with Parkinson's disease (PD) are at risk of falling and have an increased risk of complications and prolonged recovery during hospitalisation. OBJECTIVE: The aim of this study was to investigate the rate of complications and recovery related to a hip fracture in patients with PD. METHODS: All patients with PD or dementia with Lewy bodies (DLB) and a hip fracture who were admitted from January 2013 through June 2014 (18 months) to the Department of Orthopaedics, Copenhagen University Hospital, Herlev, Denmark were evaluated. Data regarding duration of admission, complications, timing of administration of anti-PD medication, and level of mobility at discharge were obtained from files of patients with PD or DLB and compared with data from a comparable group of patients who were admitted with a hip fracture and chronic obstructive pulmonary disease (COPD). RESULTS: A total of 31 patients with PD or DLB (PD/DLB group) and 45 patients with COPD (COPD group) were registered during the timeframe investigated. The patients in the PD/DLB group were significantly (p < 0.05) younger than those in the COPD group (77.7 vs. 80.7 years, respectively) and had lower co-morbidity scores (0.9 vs 2.6, respectively). There were no significant differences in length of stay, delirium, or number of infections between the groups. Two thirds of patients with PD were not able to walk unassisted at discharge. Less than 50% of anti-PD medication was given within +/-1 h of the scheduled time. CONCLUSIONS: Although patients with PD/DLB are significantly younger and have significantly lower degrees of co-morbidity than patients with COPD, their course and recovery after surgery are equivalent to those of patients with COPD. Patients with PD/DLB are at high risk of developing complications during hospital admission for hip fracture. PMID- 28349414 TI - Erratum to: Can We Identify Patients with High Risk of Osteoarthritis Progression Who Will Respond to Treatment? A Focus on Epidemiology and Phenotype of Osteoarthritis. PMID- 28349416 TI - The effect of the colostral cells on gene expression of cytokines in cord blood cells. AB - Beneficial effect of maternal milk is acknowledged, but there is still question whether maternal milk from allergic mother is as good as from healthy one. In our study, we have assayed the effect of cells from colostrum of healthy and allergic mothers on gene expression of cytokines in cord blood cells of newborns of healthy and allergic mothers. Cytokines typical for Th1 (IL-2, IFN-gamma), Th2 (IL-4, IL-13), Tregs (IL-10, TGF-beta), and IL-8 were followed. We were not able to detect significant influence of colostral cells on gene expression of cytokines in cord blood after 2-day coculture using Transwell system. There was no difference in gene expression of cytokines in nonstimulated cord blood cells of newborns of healthy and allergic mothers, but generally increased gene expression of cytokines except IL-10 and TGF-beta after polyclonal stimulation was detected in cord blood cells of children of allergic mothers. There was no difference in IL-10 expression in stimulated cord blood cells of children of healthy and allergic mothers. Gene expression of TGF-beta was even decreased in stimulated cord blood cells of children of allergic mothers in comparison to healthy ones. We have not observed difference in the capacity of colostral cells of healthy and allergic mothers to influence gene expression of cytokines in cord blood cells, but we have described difference in the reactivity of cord blood cells between children of allergic and healthy mothers. PMID- 28349417 TI - Midterm angiographic outcomes with sirolimus- and everolimus-eluting stents for small vessels in diabetic patients: propensity-score-matched comparisons in three different vessel diameters. AB - We conducted propensity-score-matched comparisons of midterm angiographic follow up outcomes of sirolimus- versus everolimus-eluting stents (SES, EES) after elective placements for de novo coronary stenosis in small vessels (SV) in patients with diabetes mellitus (DM), because the angiographic efficacy of EES over SES for those cohorts remained unclear. The study was a non-randomized, retrospective, lesion-based, multicenter study, examining lesions followed up angiographically within 550 days, extracted from the unified database of 6 institutes. The endpoint (binary restenosis) was defined as the percentage of subjects having >50% diameter stenosis at follow-up. Propensity-score-matched analyses were conducted in 3 different vessel-size cohorts, defined by a preprocedural reference diameter (RD) <2.10, <2.35, and <2.60 mm, yielding group sizes of n = 107, 183, and 312 baseline-adjusted lesions in each of the 2 stent arms. The frequency of binary restenosis decreased significantly with increasing vessel size, at 16.8, 12.6, and 12.2%, in the SES group. However, it remained almost the same across vessel-size groups in the EES group (8.0, 6.0, and 7.5%). The p values for the significance of the differences in binary restenosis between EES and SES in each vessel size increased with the decrease in vessel size [p = 0.002, 0.040, and 0.063 (the last still nearly significant)]. Thus, in patients with DM, EES showed increasingly superior efficacy over SES for SV stenosis as the vessel size became smaller, i.e., the risk for binary restenosis became greater. PMID- 28349418 TI - Comparing the effects of different dietary organic acids on the growth, intestinal short-chain fatty acids, and liver histopathology of red hybrid tilapia (Oreochromis sp.) and potential use of these as preservatives. AB - Dietary organic acids are increasingly being investigated as a potential means of improving growth and nutrient utilization in aquatic animals. A 9-week study was performed to compare equal amounts (2%) of different organic acids (sodium butyrate, acetate, propionate, or formate) on the growth, muscle proximate composition, fatty acid composition, cholesterol and lipid peroxidation, differential cell counts, plasma biochemistry, intestinal short-chain fatty acid (SCFA) level, and liver histopathology to red hybrid tilapia (Oreochromis sp.) (initial mean weight of 2.87 g). A second experiment was performed to determine their effects on lipid peroxidation and trimethylamine (TMA) when added at 1% to tilapia meat and left out for 24 h. The results of the first experiment showed no treatment effect to growth, feeding efficiencies, or muscle fatty acid composition, but all dietary organic acids significantly decreased intestinal SCFA. Dietary butyrate and propionate significantly decreased muscle lipid peroxidation compared to the control group, but the dietary formate treatment had the lowest lipid peroxidation compared to all treatments. Muscle crude protein and lipid in tilapia fed the formate diet were significantly lower and higher, respectively, and showed evidence of stress based on the differential cell counts, significantly higher plasma glucose and liver glycogen, as well as inflammatory responses in the liver. Although a potential benefit of dietary organic acids was a reduction to lipid peroxidation, this could be accomplished post-harvest by direct additions to the meat. In addition, inclusions of butyrate and propionate to tilapia meat significantly decreased TMA, which might be a more cost-effective option to improve the shelf life of tilapia products. PMID- 28349419 TI - ChIP-seq for the Identification of Functional Elements in the Human Genome. AB - Functional elements in the genome express their function through physical association with particular proteins: transcription factors, components of the transcription machinery, specific histone modifications, and others. The genome wide characterization of the protein-DNA interaction landscape of these proteins is thus a key approach toward the identification of candidate genomic regulatory regions. ChIP-seq (Chromatin Immunoprecipitation coupled with high-throughput sequencing) has emerged as the primary experimental methods for carrying out this task. Here, the ChIP-seq protocol is described together with some of the most important considerations for applying it in practice. PMID- 28349420 TI - Identification of Candidate Functional Elements in the Genome from ChIP-seq Data. AB - ChIP-seq datasets provide a wealth of information for the identification of candidate regulatory elements in the genome. For this potential to be fully realized, methods for evaluating data quality and for distinguishing reproducible signal from technical and biological noise are necessary. Here, the computational methods for addressing these challenges developed by the ENCODE Consortium are described and the key considerations for analyzing and interpreting ChIP-seq data are discussed. PMID- 28349421 TI - GRO-seq, A Tool for Identification of Transcripts Regulating Gene Expression. AB - The advent of next-generation sequencing (NGS) technologies has revolutionized the way we do research on gene expression. High-throughput transcriptomics became possible with the development of microarray technology, but its widespread application only occurred after the emergence of massive parallel sequencing. Especially, RNA sequencing (RNA-seq) has greatly increased our knowledge about the genome and led to the identification and annotation of novel classes of RNAs in different species. However, RNA-seq measures the steady-state level of a given RNA, which is the equilibrium between transcription, processing, and degradation. In recent years, a number of dedicated RNA-seq technologies were developed to measure specifically transcription events. Global run-on sequencing (GRO-seq) is the most widely used method to measure nascent RNA, and in recent years, it has been applied successfully to study the function and mechanism of action of noncoding RNAs. Here, we describe a detailed protocol of GRO-seq that can be readily applied to investigate different aspects of RNA biology in human cells. PMID- 28349423 TI - Deep Cap Analysis of Gene Expression (CAGE): Genome-Wide Identification of Promoters, Quantification of Their Activity, and Transcriptional Network Inference. AB - Among the most significant findings of the post-genomic era, the discovery of pervasive transcription of mammalian genomes has tremendously modified our understanding of the genome output seen as RNA molecules. The increased focus on non-protein-coding genomic regions together with concomitant technological innovations has led to rapid discovery of numerous noncoding transcripts (ncRNAs). Biological relevance and functional roles of the vast majority of these ncRNAs remain largely unknown.The cap analysis of gene expression (CAGE) technology allows accurate transcript detection and quantification without relying on preexisting transcript models. In combination with complementary data sets, generated using other technologies, it has been shown as an efficient approach for exploring transcriptome complexity.Here, we describe the use of CAGE for the identification of novel noncoding transcripts in mammalian cells providing detailed information for basic data processing and advanced bioinformatics analyses. PMID- 28349422 TI - NanoCAGE: A Method for the Analysis of Coding and Noncoding 5'-Capped Transcriptomes. AB - Transcripts in all eukaryotes are characterized by the 5'-end specific cap structure in mRNAs. Cap Analysis Gene Expression or CAGE makes use of these caps to specifically obtain cDNA fragments from the 5'-end of RNA and sequences those at high throughput for transcript identification and genome-wide mapping of transcription start sites for coding and noncoding genes. Here, we provide an improved version of our nanoCAGE protocol that has been developed for preparing CAGE libraries from as little as 50 ng of total RNA within three standard working days. Key steps in library preparation have been improved over our previously published protocol to obtain libraries having a good 5'-end selection and a more equal size distribution for higher sequencing efficiency on Illumina MiSeq and HiSeq sequencers. We recommend nanoCAGE as the method of choice for transcriptome profiling projects even from limited amounts of RNA, and as the best approach for genome-wide mapping of transcription start sites within promoter regions. PMID- 28349415 TI - Pharmacotherapeutic Management of Pancreatic Ductal Adenocarcinoma: Current and Emerging Concepts. AB - Pancreatic ductal adenocarcinoma is a devastating malignancy, which is the result of late diagnosis, aggressive disease, and a lack of effective treatment options. Thus, pancreatic ductal adenocarcinoma is projected to become the second leading cause of cancer-related death by 2030. This review summarizes recent developments of oncological therapy in the palliative setting of metastatic pancreatic ductal adenocarcinoma. It further compiles novel targets and therapeutic approaches as well as promising treatment combinations, which are presently in preclinical evaluation, covering several aspects of the hallmarks of cancer. Finally, challenges to the implementation of an individualized therapy approach in the context of precision medicine are discussed. PMID- 28349424 TI - Deep-RACE: Comprehensive Search for Novel ncRNAs Associated to a Specific Locus. AB - Deep-RACE (or RACEseq) is a recently described method (Olivarius et al. BioTechniques 46(2):130-132, 2009) that applies next-generation sequencing to the Rapid Amplification of cDNA End (RACE) protocol to define the 5' and 3' ends of RNA transcripts. Conventional mapping of 5' and 3' ends is achieved by manually cloning the PCR product of RACE followed by Sanger sequencing; this process can become costly and time-consuming when investigating multiple transcripts. High throughput sequencing of the RACE products streamlines this process by eliminating the need to manually cut bands from an agarose gel and to clone each product individually. Importantly, in addition to these advantages, next generation sequencing can detect low abundance fragments that would be difficult to extract from gel and clone for Sanger sequencing. For these reasons, Deep-RACE is an ideal protocol for the comprehensive study of noncoding transcripts from both intergenic regions of the genome and from within the loci of protein coding genes. PMID- 28349425 TI - In Silico Prediction of RNA Secondary Structure. AB - The secondary structure of an RNA molecule represents the base-pairing interactions within the molecule and fundamentally determines its overall structure. In this chapter, we overview the main approaches and existing tools for predicting RNA secondary structures, as well as methods for identifying noncoding RNAs from genomic sequences or RNA sequencing data. We then focus on the identification of a well-known class of small noncoding RNAs, namely microRNAs, which play very important roles in many biological processes through regulating post-transcriptionally the expression of genes and which dysregulation has been shown to be involved in several human diseases. PMID- 28349426 TI - Computational Prediction of RNA-Protein Interactions. AB - Experimental methods for identifying protein(s) bound by a specific promoter associated RNA (paRNA) of interest can be expensive, difficult, and time consuming. This chapter describes a general computational framework for identifying potential binding partners in RNA-protein complexes or RNA-protein interaction networks. Protocols for using three web-based tools to predict RNA protein interaction partners are outlined. Also, tables listing additional webservers and software tools for predicting RNA-protein interactions, as well as databases that contain valuable information about known RNA-protein complexes and recognition sites for RNA-binding proteins, are provided. Although only one of the tools described, lncPro, was designed expressly to identify proteins that bind long noncoding RNAs (including paRNAs), all three approaches can be applied to predict potential binding partners for both coding and noncoding RNAs (ncRNAs). PMID- 28349427 TI - Isolation of Nuclear RNA-Associated Protein Complexes. AB - Noncoding RNAs, being at the center stage of the organismal development and homeostasis, warrant a detailed analysis to utilize their full therapeutic potential. They form complexes with various proteins that enable the noncoding RNAs to acquire specific cellular functions such as the transcriptional outcomes that are controlled in a spatio-temporal manner. In this protocol, we describe a method to isolate such known (and unknown) protein complexes bound to a nuclear noncoding RNA. PMID- 28349428 TI - Identification of Long Noncoding RNAs Associated to Human Disease Susceptibility. AB - Transcriptomic as well as in vivo studies have revealed the importance of several lncRNAs in many complex diseases including cancer, cardiovascular, and neurological disorders. In this protocol, we describe how to perform RNAseq data analysis to identify lncRNAs associated with disease states utilizing the open source software CANEapp (application for Comprehensive automated Analysis of Next generation sequencing Experiments). PMID- 28349429 TI - Targeting Promoter-Associated RNAs by siRNAs. AB - Promoter-associated RNAs (paRNA) are long noncoding RNAs transcribed in sense or antisense direction in correspondence of promoters of other genes. Their expression influences promoter activity by means of specific regulatory function. PaRNA can act as a scaffold for proteins involved in processes regulating gene expression, as chromatin remodeling or transcription. RNA-induced transcriptional silencing (RITS) is the mechanism of transcriptional interference achieved by siRNA directed against chromatin-associated RNAs, as paRNAs. In this chapter, it is described how to detect interaction between siRNA and paRNA in cell nuclei and investigate siRNA capability to destabilize paRNA-protein complex. PMID- 28349430 TI - RNA-FISH to Study Regulatory RNA at the Site of Transcription. AB - The increasing role of all types of regulatory RNAs in the orchestration of cellular programs has enhanced the development of a variety of techniques that allow its precise detection, quantification, and functional scrutiny. Recent advances in imaging and fluoresecent in situ hybridization (FISH) methods have enabled the utilization of user-friendly protocols that provide highly sensitive and accurate detection of ribonucleic acid molecules at both the single cell and subcellular levels. We herein describe the approach originally developed by Stellaris(r), in which the target RNA molecule is fluoresecently labeled with multiple tiled complementary probes each carrying a fluorophore, thus improving sensitivity and reducing the chance of false positives. We have applied this method to the detection of nascent RNAs that partake of special regulatory structures called R loops. Their growing role in active gene expression regulation (Aguilera and Garcia-Muse, Mol Cell 46:115-124, 2012; Ginno et al., Mol Cell 45:814-825, 2012; Sun et al., Science 340:619-621, 2013; Bhatia et al., Nature 511:362-365, 2014) imposes the use of a combination of in vivo and in vitro techniques for the detailed analysis of the transcripts involved. Therefore, their study is a good example to illustrate how RNA FISH, combined with transcriptional arrest and/or cell synchronization, permits localization and temporal characterization of potentially regulatory RNA sequences. PMID- 28349431 TI - Detection and Characterization of R Loop Structures. AB - R loops are special three stranded nucleic acid structures that comprise a nascent RNA hybridized with the DNA template strand, leaving a non-template DNA single-stranded. More specifically, R loops form in vivo as G-rich RNA transcripts invade the DNA duplex and anneal to the template strand to generate an RNA:DNA hybrid, leaving the non-template, G-rich DNA strand in a largely single-stranded conformation (Aguilera and Garcia-Muse, Mol Cell 46:115-124, 2012).DNA-RNA hybrids are a natural occurrence within eukaryotic cells, with levels of these hybrids increasing at sites with high transcriptional activity, such as during transcription initiation, repression, and elongation. RNA-DNA hybrids influence genomic instability, and growing evidence points to an important role for R loops in active gene expression regulation (Ginno et al., Mol Cell 45, 814-825, 2012; Sun et al., Science 340: 619-621, 2013; Bhatia et al., Nature 511, 362-365, 2014). Analysis of the occurrence of such structures is therefore of increasing relevance and herein we describe methods for the in vivo and in vitro identification and characterization of R loops in mammalian systems.R loops (DNA:RNA hybrids and the associated single-stranded DNA) have been traditionally associated with threats to genome integrity, making some regions of the genome more prone to DNA-damaging and mutagenic agents. Initially considered to be rare byproducts of transcription, over the last decade accumulating evidence has pointed to a new view in which R loops form more frequently than previously thought. The R loop field has become an increasingly expanded area of research, placing these structures as a major threat to genome stability but also as potential regulators of gene expression. Special interest has arisen as they have also been linked to a variety of diseases, including neurological disorders and cancer, positioning them as potential therapeutic targets [5]. PMID- 28349432 TI - Induction of Transcriptional Gene Silencing by Expression of shRNA Directed to c Myc P2 Promoter in Hepatocellular Carcinoma by Tissue-Specific Virosomal Delivery. AB - Double-stranded RNA-mediated transcriptional gene silencing (TGS) has shown promising results over posttranscriptional gene silencing (PTGS) due to its long term and heritable nature. Various research groups have shed light on different mechanisms by which TGS operate. Some of these include histone modification, DNA methylation, or restriction of RNA polymerase binding onto the target gene's promoter. This serves as an added advantage since permanent c-Myc inactivation is critical for suppressing hepatocellular carcinoma (HCC). Inability to target cancer cells specifically, without affecting the normal cells, has been one of the biggest drawbacks of an effective cancer therapy. Therefore, we aimed to overcome this barrier by first generating tumor-specific transcriptional units expressing TGS inducing shRNAs against c-Myc's P2 promoter only in neoplastic liver cells. Secondly, we coupled this TGS inducing system with Sendai fusion virosomes for liver-specific delivery to minimize nonspecific side effects in vitro. PMID- 28349433 TI - Targeting Promoter-Associated Noncoding RNA In Vivo. AB - There are many classes of noncoding RNAs (ncRNAs), with wide-ranging functionalities (e.g., RNA editing, mediation of mRNA splicing, ribosomal function). MicroRNAs (miRNAs) and long ncRNAs (lncRNAs) are implicated in a wide variety of cellular processes, including the regulation of gene expression. Incorrect expression or mutation of lncRNAs has been reported to be associated with several disease conditions, such a malignant transformation in humans. Importantly, pivotal players in tumorigenesis and cancer progression, such as c Myc, may be regulated by lncRNA at promoter level. The function of lncRNA can be reduced with antisense oligonucleotides that sequester or degrade mature lncRNAs. In alternative, lncRNA transcription can be blocked by small interference RNA (RNAi), which had acquired, recently, broad interested in clinical applications. In vivo-jetPEITM is a linear polyethylenimine mediating nucleic acid (DNA, shRNA, siRNA, oligonucelotides) delivery with high efficiency. Different in vivo delivery routes have been validated: intravenous (IV), intraperitoneal (IP), intratumoral, subcutaneous, topical, and intrathecal. High levels of nucleic acid delivery are achieved into a broad range of tissues, such as lung, salivary glands, heart, spleen, liver, and prostate upon systemic administration. In addition, in vivo-jetPEITM is also an efficient carrier for local gene and siRNA delivery such as intratumoral or topical application on the skin. After systemic injection, siRNA can be detected and the levels can be validated in target tissues by qRT-PCR. Targeting promoter-associated lncRNAs with siRNAs (small interfering RNAs) in vivo is becoming an exciting breakthrough for the treatment of human disease. PMID- 28349434 TI - Manipulation of Promoter-Associated Noncoding RNAs in Mouse Early Embryos for Controlling Sequence-Specific Epigenetic Status. AB - In mammals, transcription in the zygote begins after fertilization. This transcriptional wave is called zygotic gene activation (ZGA). During ZGA, epigenetic modifications, such as DNA methylation and histone modifications, are dynamically and drastically reconstructed in a sequence-specific manner. However, how such orchestrated gene upregulation is regulated remains unknown. Recently, using microinjection techniques, we have revealed that a class of long noncoding RNAs, named promoter-associated noncoding RNAs (pancRNAs), mediates specific gene upregulation through promoter DNA demethylation during ZGA. Here, we describe the experimental methods available to control the expression levels of pancRNAs and to evaluate epigenetic status after pancRNA manipulation. PMID- 28349435 TI - Comparison of grayscale and color-scale renderings of digital medical images for diagnostic interpretation. AB - Medical images are increasingly being rendered as digital images that are displayed on a monitor to provide diagnoses. However, these images are often rendered in grayscale. In this context, we compare the detectability of low contrast signals between digital grayscale images and color-scale images. Low contrast phantom images were rendered with the use of five color tables (gray, blue, red, yellow, and green). The 32 acquired images sorted in random order were evaluated by nine observers, and their observations were subjected to receiver operating characteristic analysis. In addition, the evaluators' preferred color and their eye fatigue upon image observation were compared. The low-contrast resolutions of yellow and green color scales were superior to that of grayscale. The use of yellow resulted in the least eye fatigue, and importantly our results indicate that the interpretation of digital medical images can be improved when these images are rendered in a "yellow scale" rather than grayscale. PMID- 28349436 TI - Quantum Chemical Mass Spectrometry: Verification and Extension of the Mobile Proton Model for Histidine. AB - The quantum chemical mass spectrometry for materials science (QCMS2) method is used to verify the proposed mechanism for proton transfer - the Mobile Proton Model (MPM) - by histidine for ten XHS tripeptides, based on quantum chemical calculations at the DFT/B3LYP/6-311+G* level of theory. The fragmentations of the different intermediate structures in the MPM mechanism are studied within the QCMS2 framework, and the energetics of the proposed mechanism itself and those of the fragmentations of the intermediate structures are compared, leading to the computational confirmation of the MPM. In addition, the calculations suggest that the mechanism should be extended from considering only the formation of five membered ring intermediates to include larger-ring intermediates. Graphical Abstract ?. PMID- 28349437 TI - Sulfur Pentafluoride is a Preferred Reagent Cation for Negative Electron Transfer Dissociation. AB - Negative mode proteome analysis offers access to unique portions of the proteome and several acidic post-translational modifications; however, traditional collision-based fragmentation methods fail to reliably provide sequence information for peptide anions. Negative electron transfer dissociation (NETD), on the other hand, can sequence precursor anions in a high-throughput manner. Similar to other ion-ion methods, NETD is most efficient with peptides of higher charge state because of the increased electrostatic interaction between reacting molecules. Here we demonstrate that NETD performance for lower charge state precursors can be improved by altering the reagent cation. Specifically, the recombination energy of the NETD reaction-largely dictated by the ionization energy (IE) of the reagent cation-can affect the extent of fragmentation. We compare the NETD reagent cations of C16H10?+ (IE = 7.9 eV) and SF5?+ (IE = 9.6 eV) on a set of standard peptides, concluding that SF5?+ yields greater sequence ion generation. Subsequent proteome-scale nLC-MS/MS experiments comparing C16H10?+ and SF5?+ further supported this outcome: analyses using SF5?+ yielded 4637 peptide spectral matches (PSMs) and 2900 unique peptides, whereas C16H10?+ produced 3563 PSMs and 2231 peptides. The substantive gain in identification power with SF5?+ was largely driven by improved identification of doubly deprotonated precursors, indicating that increased NETD recombination energy can increase product ion yield for low charge density precursors. This work demonstrates that SF5?+ is a viable, if not favorable, reagent cation for NETD, and provides improved fragmentation over the commonly used fluoranthene reagent. Graphical Abstract ?. PMID- 28349438 TI - Combinatorial Labeling Method for Improving Peptide Fragmentation in Mass Spectrometry. AB - Annotation of peptide sequence from tandem mass spectra constitutes the central step of mass spectrometry-based proteomics. Peptide mass spectra are obtained upon gas-phase fragmentation. Identification of the protein from a set of experimental peptide spectral matches is usually referred as protein inference. Occurrence and intensity of these fragment ions in the MS/MS spectra are dependent on many factors such as amino acid composition, peptide basicity, activation mode, protease, etc. Particularly, chemical derivatizations of peptides were known to alter their fragmentation. In this study, the influence of acetylation, guanidinylation, and their combination on peptide fragmentation was assessed initially on a lipase (LipA) from Bacillus subtilis followed by a bovine six protein mix digest. The dual modification resulted in improved fragment ion occurrence and intensity changes, and this resulted in the equivalent representation of b- and y-type fragment ions in an ion trap MS/MS spectrum. The improved representation has allowed us to accurately annotate the peptide sequences de novo. Dual labeling has significantly reduced the false positive protein identifications in standard bovine six peptide digest. Our study suggests that the combinatorial labeling of peptides is a useful method to validate protein identifications for high confidence protein inference. Graphical Abstract ?. PMID- 28349439 TI - EGFR gene regulation in colorectal cancer cells by garlic phytocompounds with special emphasis on S-Allyl-L-Cysteine Sulfoxide. AB - Colorectal cancer is one among the most common cancers in the world and a major cause of cancer related deaths. Similar to other cancers, colorectal carcinogenesis is often associated with over expression of genes related to cell growth and proliferation, especially Epidermal Growth Factor Receptor (EGFR). There is an increasing attention towards the plant derived compounds in prevention of colorectal carcinogenesis by downregulating EGFR. Among plants, garlic (Allium sativum L.) is emerging with anticancer properties by virtue of its organosulfur compounds. The present study was aimed to analyze the interaction ability of garlic compounds in the active region of EGFR gene by in silico molecular docking studies and in vitro validation. This was conducted using the Discovery studio software version 4.0. Among the tested compounds, s allyl-l-cysteine-sulfoxide (SACS)/alliin showed higher affinity towards EGFR. Furthermore, wet lab analysis using cell viability test and EGFR expression analysis in colorectal cancer cells confirmed its efficacy as a potent anticancer agent. PMID- 28349440 TI - Patterns and reasons for switching classes of hormonal therapy among women with early-stage breast cancer. AB - PURPOSE: Breast cancer patients can switch hormonal therapy (HT) regimens due to treatment side effects or menopausal status change. We describe HT class switching from aromatase inhibitor (AI) to tamoxifen (TAM), and vice versa. METHODS: In a cohort of 3,265 women diagnosed with hormone-receptor-positive breast cancer at Kaiser Permanente Northern California from 2005 to 2013, we analyzed prescription records, switching reasons, and treatment adherence post switch by chart review, through 31 December 2014. RESULTS: There were 290 women who switched from AI to TAM (AI switchers), including 130 (45%) switchers during the first year of treatment; and 446 women who switched from TAM to AI (TAM switchers), including 120 (27%) switchers within the first year. After the switch, 136 (47%) AI switchers and 260 (58%) TAM switchers finished or remained on the planned therapy; 69 (24%) AI switchers and 99 (22%) TAM switchers discontinued therapy. AI side effects (73%), specifically joint pain/arthralgia and bone health issues, were the most common reasons for switching from AI to TAM, whereas from TAM to AI, it was menopausal status change (42%). CONCLUSIONS: Study findings highlight the need for better ways to control patient symptoms from HT to prevent discontinuation, and thus ensure best prognosis. PMID- 28349442 TI - Adding Prandial Insulin to Basal Insulin Plus Oral Antidiabetic Drugs in Chinese Patients with Poorly Controlled Type 2 Diabetes Mellitus: An Open-Label, Single Arm Study. AB - INTRODUCTION: There is relatively little data from China on the efficacy and safety of adding prandial insulin to basal insulin plus oral antidiabetic drugs (OADs) in people with poorly controlled type 2 diabetes mellitus (T2DM). This study assessed the efficacy and safety of basal insulin dose optimization followed by the addition of prandial insulin in Chinese people with T2DM achieving suboptimal glycemic control with basal insulin and OADs. METHODS: In this open-label, single-arm study, adults with T2DM receiving basal insulin plus OADs underwent insulin dose optimization for 12 weeks. At week 12, subjects who achieved fasting blood glucose (FBG) <=6.5 mmol/L but not HbA1c <=7% added one injection of prandial insulin at the main meal for an additional 24 weeks. Endpoints included mean HbA1c, the achievement rate of HbA1c <=7%, hypoglycemia, and other adverse events (AEs). RESULTS: A total of 120 subjects underwent basal insulin optimization; At week 12, 110 study subjects achieved FBG <=6.5 mmol/L, of whom 66 did not achieve HbA1c <=7% and therefore initiated prandial insulin. Three patients discontinued prandial insulin due to dissatisfaction with treatment outcome (n = 1), accidental injury (n = 1), or personal reasons (n = 1). After 24 weeks of basal-plus treatment, mean HbA1c significantly decreased (8.06% to 7.17%; p < 0.001), 65.1% of subjects achieved HbA1c <=7%, there was no change in FBG (6.23-6.20 mmol/L; p = 0.118), and mean post-prandial blood glucose decreased (13.17-10.14 mmol/L; p < 0.001). During basal-plus treatment, three individuals experienced hypoglycemia, and no significant change in the mean subject weight was observed (73.2 vs. 73.3 kg; p = 0.379). CONCLUSIONS: In people with T2DM who are achieving suboptimal glycemic control with basal insulin plus OADs, basal insulin dose optimization followed by the addition of prandial insulin improves glycemic control, is well tolerated, and is associated with a low incidence of hypoglycemia. PMID- 28349441 TI - Current Pharmacological Therapies in Heart Failure Patients. AB - Heart failure (HF) is a major problem of public health. More than 23 million patients worldwide are affected by heart failure. Despite incidence and prevalence of heart failure may vary according to real world or randomized trials database, advancing age is a major determinant of heart failure. Heart failure is also characterized by an elevated rate of morbidity and mortality and represents one of the leading causes of hospitalization. A major consequence of heart failure is the frequent hospital admissions and related costs. Guidelines have clearly indicated evidence-based treatments in patients with heart failure, and the adherence to these indications has translated in an improvement of patient's prognosis. Nevertheless, the use of recommended treatments at the recommended dosages is still lower than expected. In the last year in Europe new guidelines on the diagnosis and treatment of heart failure and in USA an update on pharmacological treatment of heart failure were published, pointing the attention on the use of new available pharmacological and non-pharmacological treatments. HF syndrome reflects the interaction between hemodynamic dysregulation (alterations in myocardial preload, afterload, and contractility and a neurohormonal disarray those results in the development of symptoms and in the progression of the disease. Current treatment approaches target both hemodynamic alterations and the neurohumoral elements to slow disease progression as well as to improve symptoms and outcomes. PMID- 28349443 TI - Cost-Effectiveness of Liraglutide Versus Dapagliflozin for the Treatment of Patients with Type 2 Diabetes Mellitus in the UK. AB - INTRODUCTION: To date there is a lack of economic analysis comparing glucagon like peptide-1 receptor agonists (GLP-1RAs) to sodium-glucose co-transporter 2 inhibitors (SGLT-2i) for the treatment of type 2 diabetes mellitus (T2DM). Liraglutide and dapagliflozin are the most commonly prescribed GLP-1RA and SGLT 2i in the UK. This analysis investigated the cost-effectiveness of liraglutide 1.2 and 1.8 mg/day compared to dapagliflozin 10 mg/day for the treatment of T2DM in the UK in patients on dual and triple antidiabetic therapy. METHODS: Cost effectiveness analysis was conducted in the QuintilesIMS CORE Diabetes Model (CDM). The model estimated expected costs and outcomes over a lifetime horizon using the UK national payer perspective. Liraglutide efficacy estimates and patient characteristics were sourced from a trial in patients on prior metformin monotherapy, and from a trial in patients on prior combination therapy. Comparative efficacy data for the other interventions were derived from a network meta-analysis. Utility inputs were extracted from a systematic literature review. Costs are presented in Great British Pound (GBP), 2016 values. RESULTS: In dual and triple therapy, liraglutide 1.2 mg was less costly and more effective compared with dapagliflozin 10 mg, providing a QALY gain of 0.04 and cost savings of GBP 11 per patient in dual therapy, and a QALY gain of 0.06 and cost savings of GBP 71 per patient in triple therapy. For liraglutide 1.8 mg, increased efficacy and costs compared with dapagliflozin 10 mg were observed in both dual and triple therapy. In dual therapy, a QALY gain of 0.07 and additional costs of GBP 888 per patient yielded an ICER of GBP 13,227, whereas in triple therapy a QALY gain of 0.07 and additional cost of GBP 791 per patient gave an ICER of 11,857. CONCLUSION: This long-term modelling analysis found that both dosages of liraglutide may be cost-effective treatment alternatives as part of a dual or a triple antidiabetic therapy in patients for whom an SGLT-2i therapy is considered. FUNDING: Novo Nordisk. PMID- 28349444 TI - IDegLira Versus Insulin Glargine U100: A Long-term Cost-effectiveness Analysis in the US Setting. AB - INTRODUCTION: Treatment with IDegLira has the potential to improve glycemic control in patients with type 2 diabetes mellitus (T2DM) without the weight gain and with a lower risk of hypoglycemia than with other therapies. The aim of the present analysis was to evaluate the long-term cost-effectiveness of IDegLira versus insulin glargine U100 with re-education and up-titration of the dose for treatment of patients with T2DM failing to achieve glycemic control on basal insulin in the US setting. METHODS: Data were obtained from the DUAL V randomized controlled trial in which adults with T2DM failing to achieve glycemic targets with insulin glargine U100 were randomly allocated to receive either IDegLira or insulin glargine U100. Long-term projections of clinical outcomes and direct costs were made using the IMS CORE Diabetes Model. Costs were accounted from a healthcare payer perspective. Future costs and clinical benefits were discounted at 3% annually. RESULTS: IDegLira was associated with improved discounted life expectancy (13.99 [standard deviation 0.19] versus 13.82 [standard deviation 0.20] years) and quality-adjusted life expectancy (9.14 [standard deviation 0.12] versus 8.87 [standard deviation 0.13] quality-adjusted life years [QALYs]) compared to insulin glargine U100. IDegLira was associated with increased direct costs of $16,970, yielding an incremental cost-effectiveness ratio (ICER) of $63,678 per QALY gained versus insulin glargine U100. Sensitivity analyses identified that the key driver of cost-effectiveness was the greater reduction in glycated hemoglobin with IDegLira compared with insulin glargine U100. CONCLUSIONS: Based on head-to-head clinical trial data, the present analysis suggests that IDegLira is likely to improve long-term clinical outcomes for patients with T2DM not achieving glycemic control on basal insulin compared to re education and up-titration of the dose of insulin glargine U100, with these improvements coming at an increased cost from a healthcare payer perspective. An ICER within the range described as high care value was calculated, suggesting IDegLira is a cost-effective treatment option in the US. FUNDING: Novo Nordisk A/S and Novo Nordisk Inc. PMID- 28349445 TI - Prophylactic use of octreotide for asparaginase-induced acute pancreatitis. AB - In the present study, we sought to evaluate the prophylactic use of octreotide for asparaginase-induced acute pancreatitis. We reviewed the medical records of seven patients in two institutions who received prophylactic octreotide for re administration of asparaginase after asparaginase-induced acute pancreatitis. Three patients completed asparaginase treatment without developing pancreatitis, and four experienced recurrence of pancreatitis. A literature search using PubMed identified four additional patients in whom asparaginase was successfully re administered with octreotide. Prophylactic use of octreotide may, thus, be warranted for patients who would benefit from re-administration of asparaginase for cancer treatment; however, careful observation is needed to monitor for breakthrough recurrence of pancreatitis. PMID- 28349448 TI - Neonatal-Onset Hereditary Coproporphyria: A New Variant of Hereditary Coproporphyria. AB - Genetic mutation of the coproporphyrinogen oxidase (CPOX) gene causes either hereditary coproporphyria (HCP) or harderoporphyria. HCP, a rare hepatic porphyria, causes acute attacks after puberty and rarely accompanies cutaneous symptoms. In contrast, harderoporphyria is an erythropoietic porphyria that represents photosensitivity and hemolytic anemia from the neonatal period. In patients with harderoporphyria, the p.Lys404Glu mutation is found in the homozygous or compound heterozygous state with another mutation, and a marked increase in harderoporphyrin is observed. This report describes a neonate with symptoms of erythropoietic harderoporphyria (photosensitivity of the skin, hemolytic anemia, and jaundice). However, the pattern of porphyrin metabolites of feces was consistent with that of typical HCP, not of harderoporphyria. We found a heterozygous, novel, four-base pair deletion in exon 7 of the CPOX gene, although other mutations including the p.Lys404Glu mutation in CPOX were not found. By unknown etiology, our patient had accompanying adrenocortical insufficiency and 46, XY disorders of sex development. Based on genetic mutation of the CPOX gene and information from a previous similar case report, we consider that neonatal-onset HCP is a variant of HCP. PMID- 28349446 TI - Hydroxychloroquine alleviates persistent proteinuria in IgA nephropathy. AB - PURPOSE: Dendritic cells, Toll-like receptor (TLR), interleukin-6 (IFN-alpha), interferon-alpha (IFN-alpha) and tumor necrosis factor-alpha (TNF-alpha) play an important role in the pathogenesis of IgA nephropathy (IgAN). Hydroxychloroquine (HCQ) is an antimalarial agent and had a notable impact on immune activation by the reduction of circulating activated immune cells that including decreased TLR expressing cells, reduced IFN-secreting DCs, reduced production of cytokines including IFN-alpha,IL-6 and TNF-alpha. We evaluated the efficacy of HCQ in reducing proteinuria in patients with IgAN. METHODS: Twenty-eight IgAN patients with persistent proteinuria (0.5-2.0 g/24 h) despite treatment with losartan for 3 months were matched to receive HCQ and losartan (group 1) or continue losartan therapy (group 2) for 24 weeks. The primary end point of this prospective, paired case-control study was reduction of proteinuria by 50% or more over entry level. RESULTS: Six patients (42.9%) in group one versus two patients (14.3%) in group 2 reach the primary end point (P = 0.004). By 24 weeks, the mean urinary protein excretion was 65.9 +/- 25.5% (P = 0.002) and 95.3 +/- 30.0% (P = 0.791) that of the corresponding baseline value in group 1 and group 2, respectively. Baseline proteinuria and histologic grades, blood pressure control and changes in serum creatinine and eGFR were not different between the two groups. CONCLUSIONS: In selected patients with IgAN, HCQ is effective in ameliorating proteinuria. PMID- 28349447 TI - Overexpression of placenta specific 8 is associated with malignant progression and poor prognosis of clear cell renal cell carcinoma. AB - BACKGROUND: Placenta specific 8 (PLAC8) plays an important role in many different cellular processes and human diseases, including multiple types of cancer. However, the functional role of PLAC8 in clear cell renal cell carcinoma (ccRCC) has never been elucidated. METHODS: PLAC8 mRNA expression was investigated in 31 pairs of fresh ccRCC tumor tissues and matched adjacent non-tumor tissues by RT qPCR and confirmed by analyzing the TCGA KRCC dataset which contains RNA-seq data of 534 ccRCC and 72 solid normal tissues. Protein level of PLAC8 expression was also investigated using immunohistochemistry in 129 ccRCC samples. Correlations with clinicopathological factors and overall survival were analyzed. To examine its effect on the biological activity, PLAC8 siRNAs were transfected into ccRCC cells. Cell proliferation was assessed by CCK8 cell viability assays, clone formation assays, and EdU incorporation assays. Cell invasion was examined using transwell assays. RNA sequencing was then performed to further elucidate the mechanisms by which PLAC8 regulates the cancer. RESULTS: PLAC8 expression was positively correlated with tumor size, metastasis, and clinical stage of ccRCC. Additionally, high PLAC8 expression was closely associated with a shorter overall survival time. Knockdown of PLAC8 with siRNAs significantly reduced the proliferation and invasion of RCC cells and increased the sensitivity of RCC cells to cisplatin. RNA-seq analysis revealed that knockdown of PLAC8 down regulated the expression of a panel of inflammatory mediators, which suggested that PLAC8 is associated with the ccRCC inflammatory microenvironment. Patients with high expression of PLAC8 had a significantly higher number of infiltrative lymphocytes than patients with low expression of PLAC8. CONCLUSION: Our findings suggest that PLAC8 may be a potential prognostic indicator and therapeutic target for ccRCC. PMID- 28349450 TI - LC-MS Analysis of Methylated RNA. AB - The detection and quantification of methylated RNA can be beneficial to understand certain cellular regulation processes such as transcriptional modulation of gene expression, immune response, or epigenetic alterations. Therefore, it is necessary to have methods available, which are extremely sensitive and accurate, for instance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Here, we describe the preparation of RNA samples by enzymatic hydrolysis and the subsequent analysis of ribonucleosides by LC-MS/MS via NLS (Neutral loss scan) and DMRM (Dynamic multiple reaction monitoring). Also, we provide variations of these methods including chromatographic techniques and different kinds of quantification. PMID- 28349451 TI - Comparative Analysis of Ribonucleic Acid Digests (CARD) by Mass Spectrometry. AB - We describe the comparative analysis of ribonucleic acid digests (CARD) approach for RNA modification analysis. This approach employs isotope labeling during RNase digestion, which allows the direct comparison of a tRNA of unknown modification status against a reference tRNA, whose sequence or modification status is known. The reference sample is labeled with 18O during RNase digestion while the candidate (unknown) sample is labeled with 16O. These RNase digestion products are combined and analyzed by mass spectrometry. Identical RNase digestion products will appear in the mass spectrum as characteristic doublets, separated by 2 Da due to the 16O/18O mass difference. Singlets arise in the mass spectrum when the sequence or modification status of a particular RNase digestion product from the reference is not matched in the candidate (unknown) sample. This CARD approach for RNA modification analysis simplifies the determination of differences between reference and candidate samples, providing a route for higher throughput screening of samples for modification profiles, including determination of tRNA methylation patterns. PMID- 28349449 TI - A Social Identity Approach to Understanding and Promoting Physical Activity. AB - Against the backdrop of a global physical inactivity crisis, attempts to both understand and positively influence physical activity behaviours are characterized by a focus on individual-level factors (e.g. cognitions, attitudes, motivation). We outline a new perspective, drawn from an emerging body of work exploring the applicability of social identity and self-categorization theories to domains of sport and health, from which to understand and address this pervasive problem. This social identity approach suggests that the groups to which people belong can be, and often are, incorporated into their sense of self and, through this, are powerful determinants of physical activity-related behaviour. We start by reviewing the current state of physical activity research and highlighting the potential for the social identity approach to help understand how social factors influence these behaviours. Next, we outline the theoretical underpinnings of the social identity approach and provide three key examples that speak to the analytical and practical value of the social identity approach in physical activity settings. Specifically, we argue that social identity (1) can be harnessed to promote engagement in physical activity, (2) underpins exercise group behaviour, and (3) underpins effective leadership in exercise settings. We conclude by identifying prospects for a range of theory informed research developments. PMID- 28349452 TI - Liquid Chromatography-Mass Spectrometry for Analysis of RNA Adenosine Methylation. AB - Dynamic RNA modifications recently were considered to constitute another realm for biological regulation in the form of "RNA epigenetics". N 6-methyladenosine (m6A), one of the most important modifications on RNA, plays a fundamental role in epigenetic regulation of the mammalian transcriptome. We recently established various liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI MS/MS)-based methods for the sensitive and accurate determination of modified nucleosides in both DNA and RNA. Here, we describe a protocol to analyze m6A in RNA by LC-ESI-MS/MS. And this protocol also can be extended to the analysis of other modified nucleosides in both DNA and RNA. PMID- 28349453 TI - Genome-Wide Location Analyses of N6-Methyladenosine Modifications (m6A-Seq). AB - N6-methyladenosine-sequencing (m6A-seq) is a critical tool to obtain an unbiased genome-wide picture of m6A sites of modification at high resolution. It allows the study of the impact of various perturbations on m6A modification distribution and the study of m6A functions. Herein, we describe the m6A-seq protocol, which entails RNA immunoprecipitation (RIP) performed on fragmented poly(A) RNA utilizing anti-m6A antibodies. The captured/enriched m6A positive RNA fragments are subsequently sequenced by RNA-seq in parallel with background control non immunoprecipitated input RNA fragments. Analyses reveal peaks of m6A enrichment containing sites of modifications analogous to chromatin modification immunoprecipitation experiments. PMID- 28349454 TI - Mapping m6A at Individual-Nucleotide Resolution Using Crosslinking and Immunoprecipitation (miCLIP). AB - N 6 -methyladenosine (m6A) is the most abundant modified base in eukaryotic mRNA and has been linked to diverse effects on mRNA fate. Current m6A mapping approaches localize m6A residues to 100-200 nt-long regions of transcripts. The precise position of m6A in mRNAs cannot be identified on a transcriptome-wide level because there are no chemical methods to distinguish between m6A and adenosine. Here, we describe a method for using anti-m6A antibodies to induce specific mutational signatures at m6A residues after ultraviolet light-induced antibody-RNA crosslinking and reverse transcription. Then, we describe how to use these mutational signatures to map m6A residues at nucleotide resolution. Taken together, our protocol allows for high-throughput detection of individual m6A residues throughout the transcriptome. PMID- 28349455 TI - Detection and Quantification of N 6-Methyladenosine in Messenger RNA by TLC. AB - The base-modified nucleotide, N 6-methyladenosine, is a relatively abundant modification found in the mRNA of most higher eukaryotes. Methylation levels can change dependent upon environmental conditions, cell differentiation state, or following knockdown of members of the methylase complex, and it is often useful to directly measure and compare N 6-methyladenosine levels between samples. Two dimensional chromatography of radiolabeled nucleotides, following specific nuclease treatments, provides a robust, sensitive, and reproducible assay for this modification. PMID- 28349457 TI - Detection of 5-Methylcytosine in Specific Poly(A) RNAs by Bisulfite Sequencing. AB - RNA bisulfite sequencing (RNA-BS-seq) represents a method for the detection of methylated cytosines in RNA. Developed originally for the analysis of DNA methylation, a modified version of this method can be used for the analysis of methylated cytosine in RNA. Treatment of nucleic acids with HSO3-ions under acidic conditions results in deamination of cytosine (C) to uracil, while 5 methylcytosine (m5C) or 5-hydroxymethylcytosine (hm5C) exhibit low reactivity in this reaction and remain unchanged. Subsequent PCR amplification and sequencing of specific targets allows for the assessment of the methylation status of single Cs in their native sequence context at nucleotide resolution. Here, we describe the application of this method for the analysis of cytosine methylation in low abundance poly(A)RNA using a combination of commercially available kits and standard lab methods to ensure reproducible results. Furthermore, useful information on optimizing the method, suitable controls for almost all steps, and general troubleshooting guides are provided. PMID- 28349456 TI - Illustrating the Epitranscriptome at Nucleotide Resolution Using Methylation iCLIP (miCLIP). AB - Next-generation sequencing technologies have enabled the transcriptome to be profiled at a previously unprecedented speed and depth. This yielded insights into fundamental transcriptomic processes such as gene transcription, RNA processing, and mRNA splicing. Immunoprecipitation-based transcriptomic methods such as individual nucleotide resolution crosslinking immunoprecipitation (iCLIP) have also allowed high-resolution analysis of the RNA interactions of a protein of interest, thus revealing new regulatory mechanisms. We and others have recently modified this method to profile RNA methylation, and we refer to this customized technique as methylation-iCLIP (miCLIP). Variants of miCLIP have been used to map the methyl-5-cytosine (m5C) or methyl-6-adenosine (m6A) modification at nucleotide resolution in the human transcriptome. Here we describe the m5C miCLIP protocol, discuss how it yields the nucleotide-resolution RNA modification maps, and comment on how these have contributed to the new field of molecular genetics research coined "epitranscriptomics." PMID- 28349458 TI - Transcriptome-Wide Detection of 5-Methylcytosine by Bisulfite Sequencing. AB - While low-throughput RNA bisulfite sequencing is the method of choice to assess the methylation status of specific cytosines in candidate RNAs, the combination of bisulfite treatment of RNA with today's high-throughput sequencing techniques opens the door to methylation studies at nucleotide resolution on a transcriptome wide scale. Below we describe a protocol for the transcriptome-wide analysis of total or fractionated poly(A)RNA in cells and tissues. Although the nature of the bisulfite sequencing protocol makes it comparably easy to translate from a low to a high-throughput approach, several critical points require attention before starting such a project. We describe a step-by-step protocol for planning and performing the experiment and analyzing the data. PMID- 28349459 TI - Analysis of High-Throughput RNA Bisulfite Sequencing Data. AB - Methylation of the 5-cytosine (m5C) is a common but not well-understood RNA modification, which can be detected by sequencing of bisulfite-treated transcripts (RNA-BSseq). In this Chapter, we discuss computational RNA-BSseq data analysis methods for transcriptome-wide identification and quantification of m5C. PMID- 28349460 TI - Statistical Methods for Transcriptome-Wide Analysis of RNA Methylation by Bisulfite Sequencing. AB - For the transcriptome-wide detection and quantification of the 5-methylcytosine (m5C) methylation modification of RNA, one experimental approach is via bisulfite conversion. In this chapter we discuss statistical methods, and a corresponding computational pipeline, to perform transcriptome-wide differential m5C methylation analysis between RNA samples, specialized for this assay. PMID- 28349461 TI - High-Throughput Mapping of 2'-O-Me Residues in RNA Using Next-Generation Sequencing (Illumina RiboMethSeq Protocol). AB - Detection of RNA modifications in native RNAs is a tedious and laborious task, since the global level of these residues is low and most of the suitable physico chemical methods require purification of the RNA of interest almost to homogeneity. To overcome these limitations, methods based on RT-driven primer extension have been developed and successfully used, sometimes in combination with a specific chemical treatment. Nowadays, some of these approaches have been coupled to high-throughput sequencing technologies, allowing the access to transcriptome-wide data. RNA 2'-O-methylation is one of the ubiquitous nucleotide modifications found in many RNA types from bacteria, archaea, and eukarya. Here, we describe a reliable and optimized protocol based on alkaline fragmentation of total RNA coupled to a commonly used ligation approach followed by Illumina sequencing. We describe the methodology for detection and relative quantification of 2'-O-methylations with a high sensitivity and reproducibility even with a limited amount of starting material (1 ng of total RNA). Altogether this technique unlocks a technological barrier since it will be applicable for routine parallel treatment of biological and clinical samples to decipher the functions of 2'-O-methylations in pathologies. PMID- 28349462 TI - RiboMeth-seq: Profiling of 2'-O-Me in RNA. AB - RiboMeth-seq is a sequencing-based method for mapping and quantitation of one of the most abundant RNA modifications, ribose methylation. It is based on a simple chemical principle, namely the several orders of magnitude difference in nucleophilicity of a 2'-OH and a 2'-O-Me. Thus, the method combines alkaline fragmentation and a specialized library construction protocol based on 5'-OH and 2',3' cyclic phosphate ends to prepare RNA for sequencing. The read-ends of library fragments are used for mapping with nucleotide resolution and calculation of the fraction of molecules methylated at the 2'-O-Me sites. PMID- 28349463 TI - In Silico Identification of RNA Modifications from High-Throughput Sequencing Data Using HAMR. AB - RNA molecules are often altered post-transcriptionally by the covalent modification of their nucleotides. These modifications are known to modulate the structure, function, and activity of RNAs. When reverse transcribed into cDNA during RNA sequencing library preparation, atypical (modified) ribonucleotides that affect Watson-Crick base pairing will interfere with reverse transcriptase (RT), resulting in cDNA products with mis-incorporated bases or prematurely terminated RNA products. These interactions with RT can therefore be inferred from mismatch patterns in the sequencing reads, and are distinguishable from simple base-calling errors, single-nucleotide polymorphisms (SNPs), or RNA editing sites. Here, we describe a computational protocol for the in silico identification of modified ribonucleotides from RT-based RNA-seq read-out using the High-throughput Analysis of Modified Ribonucleotides (HAMR) software. HAMR can identify these modifications transcriptome-wide with single nucleotide resolution, and also differentiate between different types of modifications to predict modification identity. Researchers can use HAMR to identify and characterize RNA modifications using RNA-seq data from a variety of common RT based sequencing protocols such as Poly(A), total RNA-seq, and small RNA-seq. PMID- 28349464 TI - High-Throughput Small RNA Sequencing Enhanced by AlkB-Facilitated RNA de Methylation (ARM-Seq). AB - N 1-methyladenosine (m1A), N 3-methylcytidine (m3C), and N 1-methylguanosine (m1G) are common in transfer RNA (tRNA) and tRNA-derived fragments. These modifications alter Watson-Crick base-pairing, and cause pauses or stops during reverse transcription required for most high-throughput RNA sequencing protocols, resulting in inefficient detection of methyl-modified RNAs. Here, we describe a procedure to demethylate RNAs containing m1A, m3C, or m1G using the Escherichia coli dealkylating enzyme AlkB, along with instructions for subsequent processing with widely used protocols for small RNA sequencing. PMID- 28349465 TI - Transcriptome-Wide Mapping of N 1-Methyladenosine Methylome. AB - N 1-Methyladenosine (m1A) is a prevalent posttranscriptional RNA modification and commonly found in tRNA and rRNA. Very recent works have also demonstrated the prevalence of m1A in mammalian mRNA. Hence, high-throughput methods that allow transcriptome-wide mapping of m1A will be important for further functional investigations. Here, we describe a technique called "m1A-ID-Seq", which is based on m1A immunoprecipitation and the inherent ability of m1A to stall reverse transcription, to map m1A in the transcriptome. Utilizing this technique, highly confident m1A peaks can be obtained on a transcriptome-wide level. PMID- 28349466 TI - In Vitro Assays for RNA Methyltransferase Activity. AB - RNA methyltransferases (MTases) are responsible for co- and posttranscriptional methylation of nucleotides in a wide variety of RNA substrates. Examination of the target specificity, catalytic activity, and function of these enzymes requires in vitro methylation assays. Here, we provide a detailed protocol for the methylation of in vitro transcripts, synthetic RNAs, and total cellular RNA using recombinant RNA methyltransferases and S-adenosylmethionine (SAM) as a methyl group donor. We describe how this method can be coupled to fluorographic detection of RNA methylation if 3H-labeled SAM is used, and discuss alternative chromatography-based methods for the detection of methylated nucleotides, focusing on reversed-phase high-performance liquid chromatography (RP-HPLC). In both cases, mutagenesis of the methyltransferase or the RNA substrate can be employed to elucidate the catalytic mechanisms and target specificity of the enzymes. Together these approaches provide valuable insight into the action of RNA methyltransferases on the molecular level and serve as a basis for further functional characterization of RNA methyltransferases in vivo. PMID- 28349467 TI - Crosslinking Methods to Identify RNA Methyltransferase Targets In Vivo. AB - Several crosslinking methods have been developed to identify interacting RNAs for proteins of interest. Here, we describe variants of the UV crosslinking and analysis of cDNA (CRAC) method that allow target identification of RNA methyltransferases on a genome-wide scale. We present a detailed protocol for the application of CRAC in human cells that stably express the protein of interest fused to a tandem affinity tag. After the introduction of a covalent link between the protein and its target RNAs, protein-RNA complexes are purified and bound RNAs trimmed, ligated to adapters, reverse transcribed, and amplified. Sequences obtained from next-generation sequencing are then mapped onto the human genome allowing the identification of possible substrates. For some RNA methyltransferases, e.g., m5C MTases, their catalytic mechanism can be exploited for chemical crosslinking approaches instead of UV based crosslinking. PMID- 28349468 TI - Methylated mRNA Nucleotides as Regulators for Ribosomal Translation. AB - Methylated RNA nucleotides were recently discovered to be highly abundant in RNAs. The effects of these methylations were mainly attributed to altered mRNA stabilities, protein-binding affinities, or RNA structures. The direct impact of RNA modifications on the performance of the ribosome has not been investigated so far. In this chapter, we describe an approach that allows introducing RNA modifications site-specifically into coding sequences of mRNAs and determining their effect on the translation machinery in a well-defined bacterial in vitro system. PMID- 28349469 TI - Automated Chemical Solid-Phase Synthesis and Deprotection of 5 Hydroxymethylcytosine-Containing RNA. AB - 5-Hydroxymethylcytosine is an epigenetic base modification that is part of the demethylation pathway of 5-methylcytosine in DNA. 5-Methylcytosine is iteratively oxidized to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxycytosine by enzymes of the TET protein family. Since the discovery of 5-hydroxymethylcytosine also in RNA its role in regulatory processes and metabolism remains elusive. To gain more insight into the function of RNA containing 5-hydroxymethylcytidine, innovative and interdisciplinary approaches are required. In this context, synthetic oligoribonucleotides containing 5-hyroxymethylcytidine are an inevitable tool. Therefore, in this chapter, we present the efficient synthesis of RNA oligonucleotides containing 5-hydroxymethylcytosine by solid-phase synthesis. The incorporation of the modified cytosine derivative into RNA is compatible with standard phosphoramidite-based synthesis procedures of oligoribonucleotides. PMID- 28349471 TI - Introduction to Homeostatic Migration. AB - Immune cell development and function occur in specialized immunological tissues, the function of which requires active cell migration and interactions between hematopoietic cells and underlying networks of stromal cells. These cells provide a scaffold on which immune cell migrate, provide microenvironments for efficient antigen presentation, and provide signals required for immune cell recruitment and survival. Technical advances in imaging technologies including multiphoton microscopy and 3D tissue reconstructions are being combined with computational approaches to provide new insights into the process of cell migration and function in immunological tissues. PMID- 28349470 TI - Pre-fracture hospitalization is associated with worse functional outcome and higher mortality in geriatric hip fracture patients. AB - : Hip fractures are common in elderly people. Despite great progress in surgical care, the outcomes of these patients remain disappointing. This study determined pre-fracture hospital admission as a prognostic variable for inferior functional outcomes and increased mortality rates in the perioperative phase and in the first postoperative year. PURPOSE: The influence of a pre-fracture hospitalization on outcomes in hip fracture patients has not yet been investigated. METHODS: Four hundred two patients who were surgically treated for hip fracture were prospectively enrolled. Patients with a hospital stay within the last 3 months prior to a hip fracture were compared to patients without a pre fracture hospitalization. Postoperative functional outcomes and mortality rates were compared between groups at the time of hospital discharge and additionally at the six- and twelve-month follow-up appointments. A multivariate regression analysis was performed. RESULTS: A pre-fracture hospitalization was reported by 67 patients (17%). In 63% of cases, patients were admitted due to non-surgical, general medical conditions. In 37% of cases, patients were treated due to a condition related to a surgical subject. In the multivariate analysis, pre fracture hospitalization was an independent risk factor for reduced values on the Barthel Index at 6 months after surgery (B, -9.918; 95%CI of B, -19.001--0.835; p = 0.032) and on the Tinetti Test at 6 months (B, -2.914; 95%CI of B, -1.992- 0.047; p = 0.047) and 12 months after surgery (B, -4.680; 95%CI of B, -8.042- 1.319; p = 0.007). Pre-fracture hospitalization was additionally associated with increased mortality rates at 6 months (OR 1.971; 95%CI 1.052-3.693; p = 0.034) and 12 months after surgery (OR 1.888; 95%CI 1.010-9.529; p = 0.046). CONCLUSIONS: Hip fracture patients with a recent pre-fracture hospital admission are at a substantial risk for inferior functional outcomes and increased mortality rates not only in the perioperative phase but also in the first postoperative year. As a simple dichotomous variable, pre-fracture hospitalization might be a suitable tool for future geriatric hip fracture screening instruments. PMID- 28349472 TI - Analysis of Thymocyte Migration, Cellular Interactions, and Activation by Multiphoton Fluorescence Microscopy of Live Thymic Slices. AB - Thymocytes migrate through discrete compartments within the thymus, engaging in cellular interactions essential for their differentiation into functional and self-tolerant T cells. Thus, understanding the temporal and spatial behavior of thymocytes within an intact thymic microenvironment is critical for elucidating processes governing T cell development. Towards this end, we describe methods for preparing thymic explant slices, in which the migration of thymocytes through three-dimensional space can be probed using time-lapse, multiphoton fluorescence microscopy. Thymocytes, enriched for developmental subsets of interest, are labeled with cytoplasmic fluorescent dyes, and seeded onto live thymic slices that express an endogenous, stromal cell-specific fluorescent reporter. In response to chemotactic cues produced by thymic stromal cells, the labeled thymocytes migrate withinthymic microenvironments and engage in cellular interactions that recapitulate a physiological system, whichcan be readily imaged. Here we describe specimen preparation that maintains the integrity of thymic structures. We also describe imaging protocols for acquiring multiple fluorochrome channels to enable detection of thymocyte:stromal cell interactions and quantification of relative intracellular calcium levels to monitor T cell receptor activation. Parameters for quantifying motility and interaction behaviors during data analysis are also briefly described. The thymic slice is a versatile tool for probing live cell behaviors and developing novel hypotheses not readily apparent by static experimental methods. PMID- 28349473 TI - Visualizing and Tracking T Cell Motility In Vivo. AB - Advanced cellular tracking and imaging techniques allow the dynamic nature of immune responses to be studied in detail and in a physiological context. Here we describe two methods applying multiphoton laser scanning microscopy to the visualization and tracking of fluorescently labeled CD4+ T cells and dendritic cells (DCs) within the complex lymph node (LN) environment. Ex vivo imaging of LNs allows the study of cell populations without the need for skilled surgical techniques while providing comparable data. While more technically demanding, intravital imaging of the popliteal LN allows aspects of T cell/DC responses to be studied in the context of an intact lymph and blood supply. We also describe methods to aid the acquisition of time series data suitable for cellular tracking, providing a quantitative approach to real-time analysis of DC and T cell LN responses. PMID- 28349474 TI - Graph Theory-Based Analysis of the Lymph Node Fibroblastic Reticular Cell Network. AB - Secondary lymphoid organs have developed segregated niches that are able to initiate and maintain effective immune responses. Such global organization requires tight control of diverse cellular components, specifically those that regulate lymphocyte trafficking. Fibroblastic reticular cells (FRCs) form a densely interconnected network in lymph nodes and provide key factors necessary for T cell migration and retention, and foster subsequent interactions between T cells and dendritic cells. Development of integrative systems biology approaches has made it possible to elucidate this multilevel complexity of the immune system. Here, we present a graph theory-based analysis of the FRC network in murine lymph nodes, where generation of the network topology is performed using high-resolution confocal microscopy and 3D reconstruction. This approach facilitates the analysis of physical cell-to-cell connectivity, and estimation of topological robustness and global behavior of the network when it is subjected to perturbation in silico. PMID- 28349475 TI - Visualizing Endogenous Effector T Cell Egress from the Lymph Nodes. AB - Local anatomy of lymphoid tissues during infection has emerged as a critical regulator of immunity; thus, studying the cellular choreography in the context of an intact tissue environment in situ is crucial. Following an infection, the local pathogen-specific T cell migration and the subsequent egress of effector T cells from the draining lymph nodes are important and complex biological processes. The mechanisms that regulate this complex process can now be investigated by directly visualizing T cell dynamics in vivo using intravital two photon (2P) microscopy. In addition, static whole-mount imaging technique can provide us with a comprehensive assessment of global changes in the distribution of cellular populations within an intact tissue. Thus, in this chapter, we detail methods to visualize the migration and egress of endogenous antigen-specific CD8 T cells following viral infection using two methods-intravital 2P microscopy and multicolor whole-mount in situ tetramer staining. PMID- 28349476 TI - Introduction: T Cell Trafficking in Inflammation and Immunity. AB - T cell migration across vascular endothelium is essential for T cell responses, as through the expression of specific tissue-homing receptors, these cells then access peripheral tissues, with the goal of eliminating invading pathogens and/or tumor cells. However, aberrant trafficking of T cells to peripheral tissues contributes to the development of most chronic inflammatory diseases. Very little is known about the mechanisms by which T cell trafficking is regulated during inflammation, and it is thus difficult to target this aspect of pathology for the development of new therapies. It is therefore important to understand the pathways involved in regulating the recruitment of immune cells. PMID- 28349477 TI - Leukocyte Adhesion Under Hemodynamic Flow Conditions. AB - Vascular endothelial cells (ECs) line the luminal side of all blood vessels and act as a selective barrier between blood and tissue. ECs are constantly exposed to biochemical and biomechanical stimuli from the blood and underlying tissue. Fluid shear stress acts in parallel to the vessel wall, resulting from friction of blood against EC. Despite the importance of flow on normal EC function, much of the information regarding EC function and dysfunction has been derived from cells harvested, grown, and studied in static culture.In order to study the effects of shear stress on EC function a number of in vitro models have been developed. This manuscript provides methodology for use of a system which enables recirculation of leukocytes and cell culture medium over the endothelium for a period of several minutes to days and enables investigation of the effects of prolonged leukocyte coculture on both the endothelial and leukocyte populations. PMID- 28349478 TI - Endocrine Regulation of Lymphocyte Trafficking In Vitro. AB - Lymphocyte recruitment in inflammation can be influenced by many molecules including cytokines, chemokines, and adipokines. In our lab, we have examined the effects of the adipokines leptin and adiponectin on lymphocyte migration, and observed modulation of this process. Lymphocyte behavior can be assessed in the lab under static conditions, or can be studied under flow, simulating in vivo conditions. In this chapter, in vitro methods for analyzing adhesion and migration of lymphocytes isolated from blood are described in detail. In static adhesion and migration assays, lymphocytes are allowed to settle on top of endothelial cell monolayers cultured in plates for a desired period of time. In the flow-based assay, lymphocytes are perfused over the endothelium at a continuous rate through microchannels which are commercially available. Depending on the choice of method employed, the efficiency of lymphocytes to adhere to and migrate across the endothelial cell monolayer under different conditions can be evaluated. Static assays are less complex and are of higher throughput. However, these assays provide less detailed information regarding lymphocyte behaviors. On the other hand, the flow-based assays are more difficult to perform, but are more physiologically relevant due to the presence of flow and yield more detailed information about lymphocyte activities such as capture, immobilization, and migration in real-time. PMID- 28349479 TI - Mesenchymal Stromal Cells as Active Regulators of Lymphocyte Recruitment to Blood Vascular Endothelial Cells. AB - Methods are described for analyzing adhesion and migration of isolated lymphocytes on endothelial cell monolayers which have been cocultured with different mesenchymal stromal cells, with or without additional cytokine treatment. The different cells types are grown on opposite sides of 3.0 or 0.4 MUm pore filters, depending on whether migration through the whole construct is to be analyzed, or adhesion to the endothelial cells alone. Migration away from the sub-endothelial space and through the stromal layer can also be assessed by culturing mesenchymal stromal cells within a 3-D collagen gel overlaid with endothelial cells. Assays may be "static" or the filter-based constructs can be incorporated into flow chambers so that cell behavior can be directly observed under conditions simulating those in vivo. In general, by choice of method, one can evaluate efficiency of attachment, and ability of cells to migrate across the endothelial monolayer, through the filter and through the stromal cell layer in 2 D or 3-D. Fluorescence microscopic examination of fixed filters can be used, e.g., to ascertain whether lymphocytes are retained by stromal cells. In general, static assays have the higher throughput and greatest ease of use, while the flow based assays are more physiologically relevant and allow detailed recording of cell behavior in real time. PMID- 28349480 TI - Monitoring RhoGTPase Activity in Leukocytes Using Classic "Pull-Down" Assays. AB - Inflammation is a complex process involving the contribution of leukocytes and blood vessels, which collectively aim to restore homeostasis following injury to the body. Leukocytes are essential front-line responders to infectious or noninfectious injury and can be deployed within minutes of sensing damage. A typical inflammatory response leads to the exit of circulating leukocytes into the surrounding extravascular space, which follows a series of increasingly adhesive events - collectively termed the "multistep adhesion cascade." The Ras homology (Rho) family of small GTPases (RhoGTPases) are intracellular proteins involved in translating extracellular signals into cellular behavior, such as adhesion and migration. This chapter focuses on how to prepare, perform, and monitor RhoGTPase activation assays using classic pull-down assays. Although this chapter focuses on RhoGTPase signaling downstream of L-selectin clustering, the methods outlined here can be applied to analyzing RhoGTPase activity in response to stimulating other surface receptors. PMID- 28349481 TI - Utilizing Lentiviral Gene Transfer in Primary Endothelial Cells to Assess Lymphocyte-Endothelial Interactions. AB - A major impediment when studying primary human endothelial cell function is the resistance of these cells to gene transfer. Here we describe methods for transferring genes into primary endothelial cells prior to incorporation into a static adhesion assay to analyze the adhesion and migration of isolated lymphocytes. Human embryonic kidney (HEK)-293T (HEK-293 cells expressing the large T-antigen of simian virus 40) cells are initially transfected with plasmids containing the lentiviral packaging and envelope genes and the target sequence, such as a gene of interest or short hairpin loop RNA (shRNA). These cells produce lentivirus packaged with this target sequence and are used to transduce primary human umbilical vein endothelial cells (HUVECs). Human peripheral blood lymphocytes (PBLs) isolated from venous blood are co-incubated with lentivirally transduced cytokine-stimulated endothelial cells to assess lymphocyte adhesion in a static adhesion assay. Direct observations of lymphocyte adhesion and migration over a time course can also be made. In general, lentiviral transduction of primary endothelial cells provides an invaluable system to manipulate gene expression levels when studying the cellular adhesion dynamics that regulate leukocyte adhesion and extravasation. PMID- 28349482 TI - Introduction to Lymphocyte Trafficking in Disease. AB - Lymphocytes are the key effector cells of the adaptive immune response but are also implicated in the development of chronic inflammatory diseases such as type 2 diabetes, cardiovascular disease, inflammatory bowel disease, and allergy. In order to understand the mechanisms responsible for the global increase in such debilitating conditions it is vital to appreciate the complexity of immune cell trafficking into tissue under normal and inflamed conditions. In this chapter we introduce the mechanisms of immune cell recruitment into tissue and highlight how these processes have been targeted by new therapeutic entities based on blocking integrin or chemokine function. PMID- 28349483 TI - Using Ex Vivo Liver Organ Cultures to Measure Lymphocyte Trafficking. AB - Lymphocyte recruitment to different organs, and even alternate anatomical regions within the same organ, is differentially regulated. Key combinations of adhesion molecules and chemokines govern compartmentalization, and these can change depending upon the nature and duration of tissue injury. We are interested in understanding lymphocyte recruitment to the liver during human disease, and thus need models of the liver inflammatory milieu that are as representative as possible. Here we describe the use of precision cut liver slices as models of disease. PMID- 28349484 TI - In Vitro and Ex Vivo Models to Study T Cell Migration Through the Human Liver Parenchyma. AB - The liver is the largest internal organ and filters around 3 pints of blood per minute. This continuous flux of blood should not be confused with rapid egress of lymphocytes through the liver; this organ has intricate corridors of specialized sinusoidal spaces, ensuring that immune cells decelerate to shear flow rates, and providing ample opportunities to interact with parenchymal cells. Migration has been intricately linked to T cell function; it is therefore important to study liver T cell biology into context within the liver microenvironment. Here we discuss the highly organized architecture of liver-resident cells (sinusoidal endothelia, Kupffer cells, stellate cells/myofibroblasts, and biliary and hepatic epithelia) and showcase basic, multicellular, and complex systems to model T cell migration through the human liver microenvironment in vitro and ex vivo. PMID- 28349485 TI - Monitoring Migration of Activated T Cells to Antigen-Rich Non-lymphoid Tissue. AB - Effective immunity requires appropriate recirculation of naive T cells through secondary lymphoid organs and migration of antigen-specific T cells to sites of inflammation. Leukocyte migration is a highly regulated process requiring specific interactions between leukocytes and endothelial cells (EC) termed collectively as the leukocyte adhesion cascade. Recruitment and retention of activated T cells to antigen-rich sites of inflammation is a key event in the immune response, which relies in part on local antigen presentation particularly by EC of inflamed vessels. Here we describe methods to assess the contributions of different molecules on antigen-dependent T cell migration, by utilizing IFN gamma to upregulate MHC molecules on EC and local antigen presentation, both in vitro and in vivo. PMID- 28349486 TI - Tissue Digestion for Stromal Cell and Leukocyte Isolation. AB - Tissue mechanical disruption is often not sufficient to disrupt cell-to-cell interactions; this is particularly relevant for stromal cells that are embedded within the extracellular matrix. For this reason, different enzyme combinations have been described to enable the isolation of single-cell populations, particularly stromal cells. This chapter aims to describe different methods used for enzymatic digestion of stromal cell and leukocyte populations from secondary and tertiary lymphoid organs. Collagenase D and P and collagenase D and dispase protocols provide a good yield of stromal cells, while a collagenase dispase-only protocol should be used if the main aim of the technique is to retrieve leukocyte populations. However, for isolation of both stroma and leukocyte populations the collagenase D and P protocol would provide the best results. Protocols for these techniques and illustrative results from flow cytometry analysis can be found in this chapter. PMID- 28349487 TI - T Cell Response in the Lung Following Influenza Virus Infection. AB - Methods that enable the identification of virus-specific CD4 and CD8 T cells are key to our understanding of how the adaptive immune response controls viral infection. Here we describe two distinct methods to evaluate the T cell response to influenza A virus (IAV). The number and phenotype of T cells that respond to natural IAV epitopes can be assessed by flow cytometry using MHC class I and class II tetramers. Using this system, IAV-specific T cells can be tracked in various organs within the same animal, or, in different cohorts, the response can be evaluated at several time points following infection. While providing clear quantitative data, flow cytometry cannot provide any information about T cell location within the lung or interactions between responding T cells and other cell types. Here we also describe a method to examine activated CD4 T cells in the lungs of living animals using multiphoton intravital microscopy, thus providing real-time analysis of T cell behavior during an infection. PMID- 28349491 TI - Low incidence of the immune reconstitution inflammatory syndrome among HIV infected patients starting antiretroviral therapy in Gabon: a prospective cohort study. AB - There is a paucity of data on the immune reconstitution inflammatory syndrome (IRIS) in the Central African region. We followed ART-naive HIV-infected patients initiating antiretroviral therapy in an HIV clinic in Gabon, for 6 months. Among 101 patients, IRIS was diagnosed in five. All IRIS cases were mucocutaneous manifestations. There were no cases of tuberculosis (TB) IRIS, but active TB (n = 20) was associated with developing other forms of IRIS (p = 0.02). Six patients died. The incidence of IRIS is low in Gabon, with mild, mucocutaneous manifestations. PMID- 28349493 TI - Effect of Nigella sativa seed administration on prevention of febrile neutropenia during chemotherapy among children with brain tumors. AB - PURPOSE: Seeds of Nigella sativa (NS) are used to combat various disease conditions through their antibacterial effects. To evaluate the seeds' potential, we studied their effect on the prevention of febrile neutropenia (FN) in children with brain tumors. METHODS: A randomized pretest-post-test control group study including 80 children (2-18 years) with brain tumors undergoing chemotherapy were equally allocated into two groups. Intervention group received 5 g of NS seeds daily throughout treatment while controls received nothing. CBC with differentials, incidence of FN, and LOS were noted on each follow-up. RESULTS: The majority of children 38/40 (95%), of the intervention group, took the seeds for 3-9 consecutive months. Eight out of 372 (2.2%) FN episodes were experienced by children of intervention group compared to controls 63/327 (19.3%) (p = 0.001) and a shorter LOS (median = 2.5 days) vs 5 days in the control group (p = 0.006). Children in both groups belonged to almost same geographical area with similar socio-economic background. Weights of children were almost equal at diagnosis. CONCLUSION: NS seeds showed a decrease in incidence of FN in children with brain tumors with shortening of subsequent LOS which may improve their outcome and thereby quality of life. Larger scale studies are needed to further evaluate the seeds' potential. PMID- 28349492 TI - Risk Analysis and Occurrence of Hepatitis E Virus (HEV) in Domestic Swine in Northeast Brazil. AB - Anti-HEV antibodies were detected in animals from abattoir and in farms from northeast Brazil. Our results suggest that HEV is highly disseminated in the swine population and might present a great risk to animal handlers and for consumption of raw or undercooked meat and meat products in northeast Brazil. PMID- 28349495 TI - A novel report on the use of an oncology zygomatic implant-retained maxillary obturator in a paediatric patient. AB - This report details the use of zygomatic oncology osseointegrated implants to support and retain a maxillary obturator in a 13-year-old male patient who underwent a right-sided hemi-maxillectomy (Brown Class 2b) (Brown and Shaw, Lancet Oncol 11:1001-8, 2010) for a myxoid spindle cell carcinoma. At the time of maxillary resection, two zygomatic oncology implants were inserted into the right zygomatic body and subsequently utilised to provide in-defect support and retention for a bar-retained maxillary acrylic obturator prosthesis, which restored the patient's aesthetics and function to a very high level. Close follow up over 2 years demonstrated ongoing excellent function and disease control with no deleterious effects on facial or dento-alveolar growth clinically. This is the first clinical report of its kind in the published literature detailing the use of a zygomatic implant-retained obturator in a paediatric patient. PMID- 28349494 TI - A solitary osteochondroma of the cervical spine: a case report and review of literature. AB - INTRODUCTION: Osteochondromas are usually found in the extremities and are rarely seen in the spine. They are most commonly found in the posterior elements of the spine, and intraspinal extension is uncommon. Compressive myelopathy as a presentation of vertebral osteochondroma in a child is a rare entity. METHODS: We report a case of vertebral osteochondroma arising from the lamina of C3 vertebra, presenting with features of compressive myelopathyin a 15 year old boy.Total excision of the tumor was carried out along with lamina of C3 vertebra.Patient recovered significantly. CONCLUSION: Spinal osteochondromas must be considered as rare etiology of spinal cord or root compression in the pediatric age group and utmost care should be taken while excising these benign lesions. PMID- 28349496 TI - A phase II randomized double-blind placebo-controlled study of 6-gingerol as an anti-emetic in solid tumor patients receiving moderately to highly emetogenic chemotherapy. AB - 6-Gingerol is a natural compound extracted from ginger. Preclinical studies demonstrated that 6-gingerol has an anti-emetic activity by inhibiting neurokinin 1, serotonin, and dopamine receptors. Several clinical trials examined crude ginger powder for preventing chemotherapy-induced nausea and vomiting (CINV), but none of them was conducted with a standardized bioactive compound. Patients who received moderately to highly emetogenic adjuvant chemotherapy were randomized to receive 6-gingerol 10 mg or placebo orally twice daily for 12 weeks. Ondansetron, metoclopramide, and dexamethasone were given to all patients. The primary endpoint was complete response (CR) rate defined as no emesis or rescue treatment at any time. Eighty-eight patients were randomized to receive 6-gingerol (N = 42) or placebo (N = 46). Most patients received highly emetogenic chemotherapy (93%). Overall CR rate was significantly higher in 6-gingerol group as compared with that of the placebo (77 vs. 32%; P < 0.001). The difference in means of appetite score was significant (P = 0.001) and more noticeable over time. Mean FACT-G score indicating quality of life was significantly higher (86.21) in 6-gingerol group at 64 days as compared with that of placebo group (72.36) (P < 0.001). No toxicity related to 6-gingerol was observed. Patients treated with 6-gingerol reported significantly less grade 3 fatigue (2 vs. 20%; P = 0.020). 6-Gingerol significantly improved overall CR rate in CINV, appetite and quality of life in cancer patients receiving adjuvant chemotherapy. A phase III randomized study of 6-gingerol is warranted to confirm these results. PMID- 28349499 TI - A Cost-Effectiveness Model for Frail Older Persons: Development and Application to a Physiotherapy-Based Intervention. AB - INTRODUCTION: The clinical importance of frailty is increasing. Existing economic evaluations of interventions to manage frailty have limited time horizons, but even in older populations there may be important longer-term differences in costs and outcomes. This paper reports on the development of a cost-effectiveness model to predict publicly funded health and aged care costs and quality-adjusted life years (QALYs) over the remaining lifetime of frail Australians and a model-based cost-utility analysis of a physiotherapy-based intervention for frail individuals. METHODS: A cohort-based state transition (Markov) model was developed to predict costs and QALYs over the remaining lifetime of a frail population. Frailty is defined using the phenotypic definition of frailty, and the model comprises health states that describe frailty status, residential status, the experience of bone fractures and depression, and death. Model input parameters were estimated and calibrated using the Dynamic Analyses to Optimise Ageing dataset, supplemented with data from the published literature. RESULTS: The cost-effectiveness model was subject to a range of validation approaches, which did not negate the validity of the model. The evaluated physiotherapy-based frailty intervention has an expected incremental cost per QALY gained of Australian $8129 compared to usual care, but there is a probability of 0.3 that usual care is more effective and less costly than the intervention. DISCUSSION: Frailty reduces quality of life, is costly to manage and it's prevalence is increasing, but new approaches to managing frailty need to demonstrate value for money. The value of the reported cost-effectiveness model is illustrated through the estimation of all important costs and effects of a physiotherapy-based frailty intervention, which facilitates comparisons with funding decisions for other new technologies in Australia. PMID- 28349498 TI - Halophilic mechanism of the enzymatic function of a moderately halophilic dihydrofolate reductase from Haloarcula japonica strain TR-1. AB - Dihydrofolate (DHF) reductase coded by a plasmid of the extremely halophilic archaeon Haloarcula japonica strain TR-1 (HjDHFR P1) shows moderate halophilicity on enzymatic activity at pH 6.0, although there is no significant effect of NaCl on its secondary structure. To elucidate the salt-activation and -inactivation mechanisms of this enzyme, we investigated the effects of pH and salt concentration, deuterium isotope effect, steady-state kinetics, and rapid-phase ligand-binding kinetics. Enzyme activity was increased eightfold by the addition of 500 mM NaCl at pH 6.0, fourfold by 250 mM at pH 8.0, and became independent of salt concentration at pH 10.0. Full isotope effects observed at pH 10.0 under 0 1000 mM NaCl indicated that the rate of hydride transfer, which was the rate determining step at the basic pH region, was independent of salt concentration. Conversely, rapid-phase ligand-binding experiments showed that the amplitude of the DHF-binding reaction increased and the tetrahydrofolate (THF)-releasing rate decreased with increasing NaCl concentration. These results suggested that the salt-activation mechanism of HjDHFR P1 is via the population change of the anion unbound and anion-bound conformers, which are binding-incompetent and -competent conformations for DHF, respectively, while that of salt inactivation is via deceleration of the THF-releasing rate, which is the rate-determining step at the neutral pH region. PMID- 28349497 TI - Alternative Chk1-independent S/M checkpoint in somatic cells that prevents premature mitotic entry. AB - Genomic instability is the hallmark of cancer. Checkpoint kinase-1 (Chk1) is required for cell cycle delay after DNA damage or blocked DNA replication. Chk1 depleted tumor cells undergo premature mitosis and apoptosis. Here we analyzed the depletion of Chk1 in normal somatic cells in the absence of DNA damage in order to investigate alternative cell cycle checkpoint mechanism(s). By means of adenoviruses, flow cytometry, immunofluorescence and Western blotting, Chk1 depleted mouse embryonic fibroblasts (MEFs) were investigated. Chk1-/- MEFs arrested at the S/G2 boundary of the cell cycle with decreased protein levels of many cell cycle key players. Cyclin B1 was predominantly cytoplasmic. Interestingly, overexpression of nuclear dominant Cyclin B1 leads to nuclear translocation and premature mitosis. Chk1-/- MEFs exhibited the absence of double strand breaks, yet cells showed delayed DNA damage recovery with pan-nuclear immunostaining pattern of Histone H2AX. Activation of this checkpoint would elicit a senescent-like phenotype. Taken together, our elaborated data revealed the existence of an additional S/M checkpoint functioning via gammaH2AX signaling and cytoplasmic retention of Cyclin B1 in somatic cells. PMID- 28349500 TI - The "polymorphous" history of a polymorphous skull bone: the sphenoid. AB - For a long time, because of its location at the skull base level, the sphenoid bone was rather mysterious as it was too difficult for anatomists to reach and to elucidate its true configuration. The configuration of the sphenoid bone led to confusion regarding its sutures with the other skull bones, its shape, its detailed anatomy, and the vascular and nervous structures that cross it. This article takes the reader on a journey through time and space, charting the evolution of anatomists' comprehension of sphenoid bone morphology from antiquity to its conception as a bone structure in the eighteenth century, and ranging from ancient Greece to modern Italy and France. The journey illustrates that many anatomists have attempted to name and to best describe the structural elements of this polymorphous bone. PMID- 28349501 TI - A Placebo-Controlled Trial of Riboflavin for Enhancement of Ultramarathon Recovery. AB - BACKGROUND: Riboflavin is known to protect tissue from oxidative damage but, to our knowledge, has not been explored as a means to control exercise-related muscle soreness. This study investigated whether acute ingestion of riboflavin reduces muscle pain and soreness during and after completion of a 161-km ultramarathon and improves functional recovery after the event. METHODS: In this double-blind, placebo-controlled trial, participants of the 2016 161-km Western States Endurance Run were assigned to receive a riboflavin or placebo capsule shortly before the race start and when reaching 90 km. Capsules contained either 100 mg of riboflavin or 95 mg of maltodextrin and 5 mg of 10% beta-carotene. Subjects provided muscle pain and soreness ratings before, during, and immediately after the race and for the 10 subsequent days. Subjects also completed 400-m runs at maximum speed on days 3, 5, and 10 after the race. RESULTS: For the 32 (18 in the riboflavin group, 14 in the placebo group) race finishers completing the study, muscle pain and soreness ratings during and immediately after the race were found to be significantly lower (p = .043) for the riboflavin group. Analysis of the 400-m run times also showed significantly faster (p < .05) times for the riboflavin group than the placebo group at post race days 3 and 5. Both groups showed that muscle pain and soreness had returned to pre-race levels by 5 days after the race and that 400-m run times had returned to pre-race performance levels by 10 days after the race. CONCLUSIONS: This preliminary work suggests that riboflavin supplementation before and during prolonged running might reduce muscle pain and soreness during and at the completion of the exercise and may enhance early functional recovery after the exercise. PMID- 28349502 TI - Measuring Sphingosine-1-Phosphate/Protein Interactions with the Kinetic Exclusion Assay. AB - By directly detecting the ligand-free binding sites in a sample, the kinetic exclusion assay (KinExA(r)) provides a compelling alternative to SPR-based techniques for determining equilibrium dissociation constants of protein-ligand interactions. It is especially useful for observing protein-lipid interactions, as binding of native lipids occurs entirely in solution, and monoclonal antibodies can be used to directly compete with a protein of interest for lipid binding. By measuring the antigen-free binding sites on the antibody and using competition affinity analysis, the K d for the lipid binding the protein and the antibody can be determined simultaneously. Herein, we describe this label-free approach for determining the K d for S1P-binding serum albumin, which chaperones ~30% of the S1P in human plasma. PMID- 28349503 TI - Comparison of visual and refractive results after transepithelial and mechanical photorefractive keratectomy in myopia. AB - PURPOSE: To compare postoperative visual outcomes and higher-order aberrations (HOAs) following transepithelial photorefractive keratectomy (t-PRK) and mechanical photorefractive keratectomy (m-PRK). METHODS: The medical records of patients who underwent photorefractive keratectomy (PRK) were retrospectively evaluated. Forty-five patients were treated with m-PRK, and 45 were treated with t-PRK. Visual acuity, subjective manifest refraction, and corneal topography were analyzed before surgery and 12 months after surgery for both groups. Total HOAs, spherical, coma, and trefoil aberrations were derived from topography data over the 6-mm corneal zone. RESULTS: In the m-PRK group, the mean preoperative spherical equivalence (SE) changed from -3.15 +/- 0.70 D preoperatively to -0.24 +/- 0.70 D 1 year postoperatively. Likewise, SE decreased from -3.36 +/- 0.63 to 0.25 +/- 0.63 D in the t-PRK group 1 year after the surgery. The number of eyes within +/- 0.50 D of the target refraction was 89% for m-PRK and 87% for t-PRK groups (p = 0.20). Eighty-four percentage of eyes in the t-PRK group and 80% of eyes in the m-PRK group showed an uncorrected distance visual acuity of 20/25 or better (p = 0.24). Total HOAs, spherical aberration, coma, and trefoil aberrations increased in both groups after surgery, but no statistically significant differences were detected postoperatively among the corneal aberrations. CONCLUSIONS: t-PRK and m-PRK result in comparable refractive results for the correction of low and moderate myopia. Corneal aberrations induced by t PRK and m-PRK were similar. Epithelial removal techniques do not affect visual, refractive results, or HOAs in PRK. PMID- 28349504 TI - Intravitreal bevacizumab alone or combined with 1 mg triamcinolone in diabetic macular edema: a randomized clinical trial. AB - PURPOSE: To compare the results of intravitreal bevacizumab (IVB) injection alone or in combination with intravitreal 1 mg triamcinolone acetonide (IVT) in center involved diabetic macular edema. METHODS: In this randomized clinical trial study, ninety-two eyes of 46 patients with bilateral center-involved diabetic macular edema and no previous treatment were included in the study. One eye of each patient was randomly assigned to 1.25 mg of IVB injection or combination of 1.25 IVB and 1 mg IVT. Evaluation of best-corrected visual acuity (BCVA), central macular thickness (CMT), intraocular pressure (IOP) and grading of lens opacity was conducted at baseline, and weeks 2, 4, 6, 8, 12 and 24 after treatment. Retreatment was performed at a 6-week interval whenever indicated based on CMT. RESULTS: Between the groups, BCVA changes were not statistically different until 24-week follow-up (P > 0.05), but at 24 weeks after treatment, BCVA improvement was significantly better in IVB group (P = 0.049). Significant CMT reduction was observed in each group along the follow-up period (P = 0.001). The mean CMT reduction was more significant in combination (IVB + IVT) group at 2 weeks of follow-up (P < 0.001), but CMT changes were not significant between the groups at weeks 12th and 24th after injection. Overall, retreatment was applied for 59 eyes up to 24 weeks (33 in the IVB group, 26 in the IVB + IVT group). Among patients with 2 or more injections, number of injections was significantly lower in IVB + IVT group (P = 0.043). Three eyes within IVB + IVT group developed IOP rise beyond 21 mmHg, which were controlled with topical anti-glaucoma medications within 1 week. Changes in lens opacity were not significant between two groups. CONCLUSION: Eyes treated with IVB plus 1 mg IVT injections had more significant reduction in CMT in early post-injection, but this effect was transient. Although after 24 weeks visual acuity improvement was better in IVB group, combination therapy may decrease the number of injections. Combining 1 mg of intravitreal triamcinolone with bevacizumab was not accompanied with significant side effects. PMID- 28349505 TI - Fast approximation for joint optimization of segmentation, shape, and location priors, and its application in gallbladder segmentation. AB - PURPOSE: This paper addresses joint optimization for segmentation and shape priors, including translation, to overcome inter-subject variability in the location of an organ. Because a simple extension of the previous exact optimization method is too computationally complex, we propose a fast approximation for optimization. The effectiveness of the proposed approximation is validated in the context of gallbladder segmentation from a non-contrast computed tomography (CT) volume. METHODS: After spatial standardization and estimation of the posterior probability of the target organ, simultaneous optimization of the segmentation, shape, and location priors is performed using a branch-and-bound method. Fast approximation is achieved by combining sampling in the eigenshape space to reduce the number of shape priors and an efficient computational technique for evaluating the lower bound. RESULTS: Performance was evaluated using threefold cross-validation of 27 CT volumes. Optimization in terms of translation of the shape prior significantly improved segmentation performance. The proposed method achieved a result of 0.623 on the Jaccard index in gallbladder segmentation, which is comparable to that of state-of-the-art methods. The computational efficiency of the algorithm is confirmed to be good enough to allow execution on a personal computer. CONCLUSIONS: Joint optimization of the segmentation, shape, and location priors was proposed, and it proved to be effective in gallbladder segmentation with high computational efficiency. PMID- 28349506 TI - Robust and automatic diagnosis of the intraventricular mechanical dyssynchrony for the left ventricle in cardiac magnetic resonance images. AB - PURPOSE: Robust and automatic diagnosis of the mechanical dyssynchrony for the left ventricle is essential for the cardiac resynchronization therapy. However, no existing method could meet the desired accuracy yet. In this paper, a new approach is proposed for auto-diagnosis of the intraventricular mechanical dyssynchrony of the left ventricle based on a series of image processing and signal processing techniques. METHODS: Firstly, the boundary of the left ventricle is identified automatically by the segmentation method. Secondly, the correspondence trajectories are computed based on the tangent field to make sure that they are perpendicular to all the intercepted boundaries. Thirdly, the intercepted points are smoothed by the proposed Fourier shape filter to eliminate noise and increase the diagnosis accuracy. Fourthly, the mechanical dyssynchrony is defined as the lag times between the periodic change of the sampled boundary points and the periodic change of the area of the left ventricle. It is calculated by cross-correlation. RESULTS: The segmentation method is trained with 10 cases, the proposed approach is evaluated with other 40 tested cases (20 normal cases and 20 patient cases), and the diagnosis accuracy is 100%. CONCLUSIONS: Experimental results showed that the proposed approach can accurately diagnose whether the left ventricle has mechanical dyssynchrony or not from the computed lag times. The proposed approach is robust in auto-diagnosis of the mechanical dyssynchrony for the left ventricle in cardiac magnetic resonance images. PMID- 28349507 TI - Transfer learning from RF to B-mode temporal enhanced ultrasound features for prostate cancer detection. AB - PURPOSE: We present a method for prostate cancer (PCa) detection using temporal enhanced ultrasound (TeUS) data obtained either from radiofrequency (RF) ultrasound signals or B-mode images. METHODS: For the first time, we demonstrate that by applying domain adaptation and transfer learning methods, a tissue classification model trained on TeUS RF data (source domain) can be deployed for classification using TeUS B-mode data alone (target domain), where both data are obtained on the same ultrasound scanner. This is a critical step for clinical translation of tissue classification techniques that primarily rely on accessing RF data, since this imaging modality is not readily available on all commercial scanners in clinics. Proof of concept is provided for in vivo characterization of PCa using TeUS B-mode data, where different nonlinear processing filters in the pipeline of the RF to B-mode conversion result in a distribution shift between the two domains. RESULTS: Our in vivo study includes data obtained in MRI-guided targeted procedure for prostate biopsy. We achieve comparable area under the curve using TeUS RF and B-mode data for medium to large cancer tumor sizes in biopsy cores (>4 mm). CONCLUSION: Our result suggests that the proposed adaptation technique is successful in reducing the divergence between TeUS RF and B-mode data. PMID- 28349509 TI - A new emerging oral infection: Raoultella planticola in a boy with haematological malignancy. AB - BACKGROUND: Oral mucositis is a common complication in pediatric cancer patients, affecting up to 80% of children. Due to neutropenia and disruption of the mucosal barrier, chemotherapy-induced oral mucositis is often complicated by super infections. CASE REPORT: A 16-years old male with stage 3 Burkitt's lymphoma developed chemotherapy induced oral mucositis grade 3 (according to WHO scale). Ulcers were quickly growing (reaching a maximum diameter of 3 cm) and became greyish in colour, resulting in dysphagia and pain. A swab of the lesions was taken and microbiological tests were performed. The sample grew for Raoultella planticola, an encapsulated Gram-negative bacterium whose full pathogenic potential still needs to be defined. TREATMENT: The patient received antibiotic combination therapy with Amikacin and Ceftazidime for 8 days. Complete healing of the lesions and resolution of the symptoms were reached and he completed his antineoplastic therapy without further complications. FOLLOW-UP: Twelve months after the infection, he is alive and well, with no oral complaints. CONCLUSION: This is the first report of a Raoultella planticola infection in a patient with chemotherapy induced oral mucositis. This type of infection must be added to the list of organisms to be considered when caring for these patients. PMID- 28349508 TI - Targeting Schlemm's Canal in the Medical Therapy of Glaucoma: Current and Future Considerations. AB - Schlemm's canal (SC) is a unique, complex vascular structure responsible for maintaining fluid homeostasis within the anterior segment of the eye by draining the excess of aqueous humour. In glaucoma, a heterogeneous group of eye disorders afflicting approximately 60 million individuals worldwide, the normal outflow of aqueous humour into SC is progressively hindered, leading to a gradual increase in outflow resistance, which gradually results in elevated intraocular pressure (IOP). By and large available antiglaucoma therapies do not target the site of the pathology (SC), but rather aim to decrease IOP by other mechanisms, either reducing aqueous production or by diverting aqueous flow through the unconventional outflow system. The present review first outlines our current understanding on the functional anatomy of SC. It then summarizes existing research on SC cell properties; first in the context of their role in glaucoma development/progression and then as a target of novel and emerging antiglaucoma therapies. Evidence from ongoing research efforts to develop effective antiglaucoma therapies targeting SC suggests that this could become a promising site of future therapeutic interventions. PMID- 28349510 TI - Fresh versus frozen embryo transfers in assisted reproduction. AB - BACKGROUND: In general, in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) implies a single fresh and one or more frozen-thawed embryo transfers. Alternatively, the 'freeze-all' strategy implies transfer of frozen thawed embryos only, with no fresh embryo transfers. In practice, both strategies can vary technically including differences in freezing techniques and timing of transfer of cryopreservation, that is vitrification versus slow freezing, freezing of two pro-nucleate (2pn) versus cleavage-stage embryos versus blastocysts, and transfer of cleavage-stage embryos versus blastocysts.In the freeze-all strategy, embryo transfers are disengaged from ovarian stimulation in the initial treatment cycle. This could avoid a negative effect of ovarian hyperstimulation on the endometrium and thereby improve embryo implantation. It could also reduce the risk of ovarian hyperstimulation syndrome (OHSS) in the ovarian stimulation cycle by avoiding a pregnancy.We compared the benefits and risks of the two treatment strategies. OBJECTIVES: To evaluate the effectiveness and safety of the freeze-all strategy compared to the conventional IVF/ICSI strategy in women undergoing assisted reproductive technology. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Trials Register, the Cochrane Central Register of Studies (CRSO), MEDLINE, Embase, PsycINFO, CINAHL, and two registers of ongoing trials in November 2016 together with reference checking and contact with study authors and experts in the field to identify additional studies. SELECTION CRITERIA: We included randomised clinical trials comparing a freeze-all strategy with a conventional IVF/ICSI strategy which includes fresh transfer of embryos in women undergoing IVF or ICSI treatment. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary review outcomes were cumulative live birth and OHSS. Secondary outcomes included other adverse effects (miscarriage rate). MAIN RESULTS: We included four randomised clinical trials analysing a total of 1892 women comparing a freeze-all strategy with a conventional IVF/ICSI strategy. The evidence was of moderate to low quality due to serious risk of bias and (for some outcomes) serious imprecision. Risk of bias was associated with unclear blinding of investigators for preliminary outcomes of the study, unit of analysis error, and absence of adequate study termination rules.There was no clear evidence of a difference in cumulative live birth rate between the freeze-all strategy and the conventional IVF/ICSI strategy (odds ratio (OR) 1.09, 95% confidence interval (CI) 0.91 to 1.31; 4 trials; 1892 women; I2 = 0%; moderate quality evidence). This suggests that if the cumulative live birth rate is 58% following a conventional IVF/ICSI strategy, the rate following a freeze-all strategy would be between 56% and 65%.The prevalence of OHSS was lower after the freeze-all strategy compared to the conventional IVF/ICSI strategy (OR 0.24, 95% CI 0.15 to 0.38; 2 trials; 1633 women; I2 = 0%; low-quality evidence). This suggests that if the OHSS rate is 7% following a conventional IVF/ICSI strategy, the rate following a freeze-all strategy would be between 1% and 3%.The freeze all strategy was associated with fewer miscarriages (OR 0.67, 95% CI 0.52 to 0.86; 4 trials; 1892 women; I2 = 0%; low-quality evidence) and a higher rate of pregnancy complications (OR 1.44, 95% CI 1.08 to 1.92; 2 trials; 1633 women; low quality evidence). There was no difference in multiple pregnancies per woman after the first transfer (OR 1.11, 95% CI 0.85 to 1.44; 2 trials; 1630 women; low quality evidence), and no data were reported for time to pregnancy. AUTHORS' CONCLUSIONS: We found moderate-quality evidence showing that one strategy is not superior to the other in terms of cumulative live birth rates. Time to pregnancy was not reported, but it can be assumed to be shorter using a conventional IVF/ICSI strategy in the case of similar cumulative live birth rates, as embryo transfer is delayed in a freeze-all strategy. Low-quality evidence suggests that not performing a fresh transfer lowers the OHSS risk for women at risk of OHSS. PMID- 28349511 TI - Risk of endometrial cancer in women treated with ovary-stimulating drugs for subfertility. AB - BACKGROUND: Medical treatment for subfertility principally involves the use of ovary-stimulating agents, including selective oestrogen receptor modulators (SERMs), such as clomiphene citrate, gonadotropins, gonadotropin-releasing hormone (GnRH) agonists and antagonists, as well as human chorionic gonadotropin. Ovary-stimulating drugs may act directly or indirectly upon the endometrium (lining of the womb). Nulliparity and some causes of subfertility are recognized as risk factors for endometrial cancer. OBJECTIVES: To evaluate the association between the use of ovary-stimulating drugs for the treatment of subfertility and the risk of endometrial cancer. SEARCH METHODS: A search was performed in CENTRAL, MEDLINE (Ovid) and Embase (Ovid) databases up to July 2016, using a predefined search algorithm. A search in OpenGrey, ProQuest, ClinicalTrials.gov, ZETOC and reports of major conferences was also performed. We did not impose language and publication status restrictions. SELECTION CRITERIA: Cohort and case control studies reporting on the association between endometrial cancer and exposure to ovary-stimulating drugs for subfertility in adult women were deemed eligible. DATA COLLECTION AND ANALYSIS: Study characteristics and findings were extracted by review authors independently working in pairs. Inconsistency between studies was quantified by estimating I2. Random-effects (RE) models were used to calculate pooled effect estimates. Separate analyses were performed, comparing treated subfertile women versus general population and/or unexposed subfertile women, to address the superimposition of subfertility as an independent risk factor for endometrial cancer. MAIN RESULTS: Nineteen studies were eligible for inclusion (1,937,880 participants). Overall, the quality of evidence was very low, due to serious risk of bias and indirectness (non-randomised studies (NRS), which was reflected on the GRADE assessment.Six eligible studies, including subfertile women, without a general population control group, found that exposure to any ovary-stimulating drug was not associated with an increased risk of endometrial cancer (RR 0.96, 95% CI 0.67 to 1.37; 156,774 participants; very low quality evidence). Fifteen eligible studies, using a general population as the control group, found an increased risk after exposure to any ovary-stimulating drug (RR 1.75, 95% CI 1.18 to 2.61; 1,762,829 participants; very low quality evidence).Five eligible studies, confined to subfertile women (92,849 participants), reported on exposure to clomiphene citrate; the pooled studies indicated a positive association ( RR 1.32; 95% CI 1.01 to 1.71; 88,618 participants; very low quality evidence), although only at high dosage (RR 1.69, 95% CI 1.07 to 2.68; two studies; 12,073 participants) and at a high number of cycles (RR 1.69, 95% CI 1.16 to 2.47; three studies; 13,757 participants). Four studies found an increased risk of endometrial cancer in subfertile women who required clomiphene citrate compared to a general population control group (RR 1.87, 95% CI 1.00 to 3.48; four studies, 19,614 participants; very low quality evidence). These data do not tell us whether the association is due to the underlying conditions requiring clomiphene or the treatment itself.Using unexposed subfertile women as controls, exposure to gonadotropins was associated with an increased risk of endometrial cancer (RR 1.55, 95% CI 1.03 to 2.34; four studies; 17,769 participants; very low quality evidence). The respective analysis of two studies (1595 participants) versus the general population found no difference in risk (RR 2.12, 95% CI 0.79 to 5.64: very low quality evidence).Exposure to a combination of clomiphene citrate and gonadotropins, compared to unexposed subfertile women, produced no difference in risk of endometrial cancer (RR 1.18, 95% CI 0.57 to 2.44; two studies; 6345 participants; very low quality evidence). However, when compared to the general population, an increased risk was found , suggesting that the key factor might be subfertility, rather than treatment (RR 2.99, 95% CI 1.53 to 5.86; three studies; 7789 participants; very low quality evidence). AUTHORS' CONCLUSIONS: The synthesis of the currently available evidence does not allow us to draw robust conclusions, due to the very low quality of evidence. It seems that exposure to clomiphene citrate as an ovary-stimulating drug in subfertile women is associated with increased risk of endometrial cancer, especially at doses greater than 2000 mg and high (more than 7) number of cycles. This may largely be due to underlying risk factors in women who need treatment with clomiphene citrate, such as polycystic ovary syndrome, rather than exposure to the drug itself. The evidence regarding exposure to gonadotropins was inconclusive. PMID- 28349512 TI - Chlorpromazine versus metiapine for schizophrenia. AB - BACKGROUND: Chlorpromazine, a widely available and inexpensive antipsychotic drug, is considered the benchmark treatment for schizophrenia worldwide. Metiapine, a dibenzothiazepine derivative, has been reported to have potent antipsychotic characteristics. However, no evidence currently exists on the effectiveness of chlorpromazine in treatment of people with schizophrenia compared to metiapine, a newer antipsychotic. OBJECTIVES: To compare the effect of chlorpromazine versus metiapine for the treatment of people with schizophrenia SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials in November 2015 and 2016. SELECTION CRITERIA: All randomised controlled trials (RCTs) focusing on chlorpromazine versus metiapine for adults with schizophrenia. We included trials meeting our selection criteria and reporting useable data. DATA COLLECTION AND ANALYSIS: We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated the mean difference between groups and its 95% CI. We employed a random effects model for analyses. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE. MAIN RESULTS: We included three studies randomising 161 people with schizophrenia. Data were available for only two of our seven prestated main outcomes. Clinically important improvement in global state was measured using the Clinical Global Impression (CGI). There was no clear difference between chlorpromazine and metiapine groups (2 RCTs, n = 120, RR 1.11, 95% CI 0.84 to 1.47, very low quality evidence) and numbers of participants with parkinsonism at eight weeks were similar (2 RCTs, n = 70, RR 0.97, 95% CI 0.46 to 2.03, very low quality evidence). There were no useable data available for the other key outcomes of clinically important improvement in mental state, readmission due to relapse, satisfaction with treatment, aggressive or violent behaviour, or cost of care. AUTHORS' CONCLUSIONS: Chlorpromazine has been the mainstay treatment for schizophrenia for decades, yet available evidence comparing this drug to metiapine fails to provide high-quality trial based data. However, the need to determine whether metiapine is more or less effective than chlorpromazine seems to be lacking in clinical relevance and future research on this comparison seems unlikely. PMID- 28349513 TI - Endometriosis education in schools: A New Zealand model examining the impact of an education program in schools on early recognition of symptoms suggesting endometriosis. AB - BACKGROUND: Menstrual morbidity plays a significant role in adolescent females' lives. There are no studies to date reporting such data from menstrual health education programs in schools. AIMS: The aim of our study was to report results from an audit of a menstrual health and endometriosis education program in secondary schools and observe age patterns of young women presenting for menstrual morbidity care. MATERIALS AND METHODS: Audit data from education in secondary schools and audit data of patients from an Endometriosis and Pelvic Pain Coaching clinic operating in a private endometriosis specialised centre are reported. RESULTS: In a region of consistent delivery of the education program, student awareness of endometriosis was 32% in 2015. Overall in 2015, 13% of students experienced distressing menstrual symptoms and 27% of students sometimes or always missed school due to menstrual symptoms. Further, in one region of consistent delivery of the menstrual health education program, data show an increase in younger patients attending for specialised endometriosis care. CONCLUSIONS: There is strong suggestive evidence that consistent delivery of a menstrual health education program in schools increases adolescent student awareness of endometriosis. In addition, there is suggestive evidence that in a geographical area of consistent delivery of the program, a shift in earlier presentation of young women to a specialised health service is observed. PMID- 28349514 TI - L-carnitine for cognitive enhancement in people without cognitive impairment. AB - BACKGROUND: Safe interventions to enhance cognitive function in cognitively healthy people would be very valuable for several reasons, including a better quality of life and professional success. While L-carnitine has been reported to enhance cognitive function in some conditions, its efficacy is disputed. The evidence of its efficacy for cognitively healthy people has not previously been systematically reviewed. OBJECTIVES: To assess the efficacy and safety of L carnitine for the enhancement of cognitive function in people without cognitive impairment. SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's Specialized Register, on 4 November 2016. We used the search terms 'L-carnitine' or 'acetyl-L-carnitine' or 'propionyl-L-carnitine' or 'ALC' or 'PLC' or 'ALCAR' or 'ALPAR'. We ran additional separate searches in several other sources to ensure that we retrieved the most up-to-date results. We also reviewed the bibliographies of the randomised controlled trials identified and contacted the authors and known experts in the field and pharmaceutical companies to identify additional published or unpublished data. SELECTION CRITERIA: Eligible trials were randomised controlled trials (RCTs) or quasi-RCTs, parallel-group or cross-over, that compared L-carnitine or its derivatives, acetyl-L-carnitine or propionyl-L-carnitine, at any dose and for any length of treatment, with placebo or no treatment in cognitively healthy people of any age and either gender. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors independently selected trials and evaluated the methodological quality, then extracted and analysed data from the included trials. MAIN RESULTS: Only two RCTs were eligible. One was a cross over trial with 18 participants. The other randomised 400 participants to one of four treatments, of which two (L-carnitine and placebo) were relevant to this review, but the exact numbers of participants in these two treatment groups was not reported. All participants were young adults. Methodological details were poorly reported, and we considered the risk of bias in both studies to be unclear. The trials assessed different cognitive outcomes. We could extract cognitive data on approximately 200 participants from one trial. We found no evidence that L-carnitine has any effect on reaction time, vigilance, immediate memory, or delayed recall after three days of treatment. This trial report stated that there was a small number of adverse effects, none of which were serious. The small cross-over trial also reported no effect of L-carnitine on cognition, but did not provide data; no information was provided on adverse effects. We considered the available evidence to be of very low quality for all reported outcomes. AUTHORS' CONCLUSIONS: Due to the limited number of included trials, short-term treatment, and inadequate reporting, we were unable to draw any conclusions about the efficacy or safety of L-carnitine for cognitive enhancement in healthy adults. Well-designed, randomised, placebo-controlled trials of L carnitine for cognition enhancement in cognitively healthy people, with large samples and relatively long-term follow-up, are still needed. PMID- 28349515 TI - Propofol-induced irreversible hair depigmentation: a case report. PMID- 28349516 TI - Outcomes and predictive tests from a dedicated specialist clinic for women at high risk of preterm labour: A ten year audit. AB - BACKGROUND: Preterm birth continues to be a major cause of infant morbidity and mortality worldwide, but advances have recently been made in its prediction and prevention. A short cervix (<25 mm) in the second trimester on transvaginal ultrasound scan and fetal fibronectin are important predictive tests. For over ten years, the Preterm Labour Clinic at the Royal Women's Hospital, Melbourne, Australia has provided care for women at high risk of preterm birth, including those with a previous preterm birth, previous cervical surgery, uterine malformation or incidental finding of short cervix at routine ultrasound. The purpose of this study was to review this clinic's outcomes for the first decade. METHODS: This was a retrospective cohort study of all referrals to the Preterm Labour Clinic during the period 2004-2013 inclusive. Seven hundred and fifty-six cases met the study inclusion criteria of appropriate risk factor, singleton pregnancy, surveillance undertaken and outcome data available. RESULTS: The preterm birth rate (<37 weeks) was 21.4%. The rate of preterm birth by year decreased significantly when adjusted for risk (P = 0.002). A short cervix was diagnosed in 32% of the sample, and positively correlated with lower gestational age at delivery. Fetal fibronectin and serum alkaline phosphatase were independent predictors of preterm birth <34 weeks and <37 weeks. CONCLUSION: The adjusted preterm birth rate at the Royal Women's Hospital's Preterm Labour Clinic has decreased significantly over the decade studied. Positive fetal fibronectin at 26 weeks and elevated serum alkaline phosphatase are independent predictors of preterm birth. PMID- 28349518 TI - Erratum. PMID- 28349517 TI - Oral nonsteroidal anti-inflammatory drugs for fibromyalgia in adults. AB - BACKGROUND: Oral nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain in fibromyalgia, despite being considered not to be effective. OBJECTIVES: To assess the analgesic efficacy, tolerability (drop-out due to adverse events), and safety (serious adverse events) of oral nonsteroidal anti-inflammatory drugs for fibromyalgia in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase for randomised controlled trials from inception to January 2017. We also searched the reference lists of retrieved studies and reviews, and online clinical trial registries. SELECTION CRITERIA: We included randomised, double-blind trials of two weeks' duration or longer, comparing any oral NSAID with placebo or another active treatment for relief of pain in fibromyalgia, with subjective pain assessment by the participant. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with substantial pain relief (at least 50% pain relief over baseline or very much improved on Patient Global Impression of Change scale (PGIC)) or moderate pain relief (at least 30% pain relief over baseline or much or very much improved on PGIC), serious adverse events, and withdrawals due to adverse events; secondary outcomes were adverse events, withdrawals due to lack of efficacy, and outcomes relating to sleep, fatigue, and quality of life. Where pooled analysis was possible, we used dichotomous data to calculate risk difference (RD) and number needed to treat for an additional beneficial outcome (NNT), using standard methods. We assessed the quality of the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: Our searches identified six randomised, double blind studies involving 292 participants in suitably characterised fibromyalgia. The mean age of participants was between 39 and 50 years, and 89% to 100% were women. The initial pain intensity was around 7/10 on a 0 to 10 pain scale, indicating severe pain. NSAIDs tested were etoricoxib 90 mg daily, ibuprofen 2400 mg daily, naproxen 1000 mg daily, and tenoxicam 20 mg daily; 146 participants received NSAID and 146 placebo. The duration of treatment in the double-blind phase varied between three and eight weeks.Not all studies reported all the outcomes of interest. Analyses consistently showed no significant difference between NSAID and placebo: substantial benefit (at least 50% pain intensity reduction) (risk difference (RD) -0.07 (95% confidence interval (CI) -0.18 to 0.04) 2 studies, 146 participants; moderate benefit (at least 30% pain intensity reduction) (RD -0.04 (95% CI -0.16 to 0.08) 3 studies, 192 participants; withdrawals due to adverse events (RD 0.04 (95% CI -0.02 to 0.09) 4 studies, 230 participants; participants experiencing any adverse event (RD 0.08 (95% CI -0.03 to 0.19) 4 studies, 230 participants; all-cause withdrawals (RD 0.03 (95% CI 0.07 to 0.14) 3 studies, 192 participants. There were no serious adverse events or deaths. Although most studies had some measures of health-related quality of life, fibromyalgia impact, or other outcomes, none reported the outcomes beyond saying that there was no or little difference between the treatment groups.We downgraded evidence on all outcomes to very low quality, meaning that this research does not provide a reliable indication of the likely effect. The likelihood that the effect could be substantially different is very high. This is based on the small numbers of studies, participants, and events, as well as other deficiencies of reporting study quality allowing possible risks of bias. AUTHORS' CONCLUSIONS: There is only a modest amount of very low-quality evidence about the use of NSAIDs in fibromyalgia, and that comes from small, largely inadequate studies with potential risk of bias. That bias would normally be to increase the apparent benefits of NSAIDs, but no such benefits were seen. Consequently, NSAIDs cannot be regarded as useful for treating fibromyalgia. PMID- 28349519 TI - Erratum. PMID- 28349520 TI - A retrospective review of the dermatologic manifestations of chronic arsenic poisoning in the Philippines. AB - BACKGROUND: The Section of Dermatology of the University of the Philippines, Philippine General Hospital, reported a case of chronic arsenic poisoning from a community in Luzon island to the Department of Health resulting in the conduct of two health and environmental assessment missions in December 2014. OBJECTIVE: To describe the demographic profile and cutaneous manifestations of chronic arsenic poisoning among affected residents in Luzon, Philippines. METHODS: A review of the medical records of 116 residents screened during the health assessment missions in December 2014 was conducted. RESULTS: Among the 116 residents screened, 81 (70%) had clinically confirmed arsenic keratoses and hyperpigmentation. Among them, 52 were males and 29 were females with age range of 4-82 years. Two cases of squamous cell carcinoma in situ were detected through skin biopsy. High levels of arsenic in the tap water and topsoil supported the occurrence of an epidemic of chronic arsenic poisoning. CONCLUSION: Specific dermatologic findings of arsenic keratoses and pigmentation were common among the residents screened. Significantly higher occurrence of arsenic keratoses was seen in adults. PMID- 28349521 TI - Erratum. PMID- 28349523 TI - Corrigendum. PMID- 28349524 TI - Corrigendum. PMID- 28349525 TI - Glucocorticoid supplementation during ovarian stimulation for IVF or ICSI. AB - BACKGROUND: Ovarian response to stimulation during in-vitro fertilisation (IVF) and intra-cytoplasmic sperm injection (ICSI) plays an important role in determining live birth rates. Adjuvant treatments during ovarian stimulation that have different modes of action have been used to improve ovarian response to stimulation and outcome of IVF. Glucocorticoids (GCs) are a class of steroid hormones that have been used either alone or in combination with other stimulatory regimens in order to improve folliculogenesis and pregnancy rates. However, considerable uncertainty remains over whether administration of glucocorticoid during ovarian stimulation until oocyte recovery is superior to no glucocorticoid in improving live birth rates in women undergoing IVF/ICSI. OBJECTIVES: To determine the safety and effectiveness of systemic glucocorticoids during ovarian stimulation for IVF and ICSI cycles. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register, the Cochrane Central Register of Studies Online (CRSO), MEDLINE, Embase, CINAHL and PsycINFO from inception to 10 October 2016. We handsearched reference lists of articles, trial registers and relevant conference proceedings and contacted researchers in the field. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing adjuvant treatment with systemic glucocorticoids during ovarian stimulation for IVF or ICSI cycles versus no adjuvant treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias and extracted the data. Our primary outcome was live birth. Secondary outcomes included clinical pregnancy, multiple pregnancy, miscarriage, ovarian hyperstimulation syndrome (OHSS) and side-effects. We calculated odds ratios (ORs) with 95% confidence intervals (CIs) and pooled the data using a fixed effect model. The quality of the evidence was assessed using GRADE methods. MAIN RESULTS: Four RCTs were included in the review (416 women). The trials compared glucocorticoid supplementation during IVF stimulation versus placebo. Two of the studies had data in a form that we could not enter into analysis, so results include data from only two trials (310) women. For the outcome of live birth, data were available for only 212 women, as the larger study had data available from only one study centre.One of the studies gave inadequate description of randomisation methods, but the other was at low risk of bias in all domains. The evidence was rated as low or very low quality for all outcomes, mainly due to imprecision, with low sample sizes and few events.There was insufficient evidence to determine whether there was any difference between the groups in live birth rate (OR 1.08, 95% CI 0.45 to 2.58; 2 RCTs, n = 212, I2 = 0%, low-quality evidence). Our findings suggest that if the chance of live birth with placebo is assumed to be 15%, the chance following supplementation would be between 7% and 31%. There was no conclusive evidence of a difference in the clinical pregnancy rate (OR 1.69, 95% CI 0.98 to 2.90; 2 RCTs, n = 310, I2 = 0%, low-quality evidence).The evidence suggests that if the chance of clinical pregnancy with placebo is assumed to be 24%, the chance following treatment with glucocorticoid supplementation would be between 23% and 47%. There was also insufficient evidence to determine whether there was any difference between the groups in multiple-pregnancy rate (OR 3.32 , 95% CI 0.12 to 91.60; 1 RCT , n = 20, very low quality evidence) or miscarriage rate (OR 1.00, 95% CI 0.05 to 18.57; 1 RCT, n = 20, very low-quality evidence). Neither of the studies reported OHSS or side effects. AUTHORS' CONCLUSIONS: The safety and effectiveness of glucocorticoid administration in women undergoing controlled ovarian hyperstimulation for IVF/ICSI cycles (until the day of oocyte retrieval) is unclear due to the small number of studies and low event rates. Whilst glucocorticoids possible increase the clinical pregnancy rate, there may be little or no impact on live birth rate. More research is needed. PMID- 28349526 TI - Pushing/bearing down methods for the second stage of labour. AB - BACKGROUND: Maternal pushing during the second stage of labour is an important and indispensable contributor to the involuntary expulsive force developed by uterine contraction. There is no consensus on an ideal strategy to facilitate these expulsive efforts and there are contradictory results about the influence on the mother and fetus. OBJECTIVES: To evaluate the benefits and possible disadvantages of different kinds of techniques regarding maternal pushing/breathing during the expulsive stage of labour on maternal and fetal outcomes. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (19 September 2016) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs assessing the effects of pushing/bearing down techniques (type and/or timing) performed during the second stage of labour on maternal and neonatal outcomes. Cluster-RCTs were eligible for inclusion, but none were identified. Studies using a cross-over design and those published in abstract form only were not eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, extracted data and assessed risk of bias. Data were checked for accuracy. MAIN RESULTS: In this updated review, we included 21 studies in total, eight (884 women) comparing spontaneous pushing versus directed pushing, with or without epidural analgesia and 13 (2879 women) comparing delayed pushing versus immediate pushing with epidural analgesia. Our GRADE assessments of evidence ranged from moderate to very low quality; the main reasons for downgrading were study design limitations and imprecision of effect estimates. Overall, the included studies varied in their risk of bias; most were judged to be at unclear risk of bias. Comparison 1: types of pushing: spontaneous pushing versus directed pushingThere was no clear difference in the duration of the second stage of labour (mean difference (MD) 10.26 minutes; 95% confidence interval (CI) -1.12 to 21.64 minutes, six studies, 667 women, random-effects, I2 = 81%) (very low-quality evidence). There was no clear difference in 3rd or 4th degree perineal laceration (risk ratio (RR) 0.87; 95% CI 0.45 to 1.66, one study, 320 women) (low-quality evidence), episiotomy (average RR 1.05; 95% CI 0.60 to 1.85, two studies, 420 women, random-effects, I2 = 81%), duration of pushing (MD 9.76 minutes, 95% CI -19.54 to 0.02; two studies; 169 women; I2 = 88%) (very low quality evidence), or rate of spontaneous vaginal delivery (RR 1.01, 95% CI 0.97 to 1.05; five studies; 688 women; I2 = 2%) (moderate-quality evidence). For primary neonatal outcomes such as five-minute Apgar score less than seven, there was no clear difference between groups (RR 0.35; 95% CI 0.01 to 8.43, one study, 320 infants) (very low-quality evidence), and the number of admissions to neonatal intensive care (RR 1.08; 95% CI 0.30 to 3.79, two studies, 393 infants) (very low-quality evidence) also showed no clear difference between spontaneous and directed pushing. No data were available on hypoxic ischaemic encephalopathy. Comparison 2: timing of pushing: delayed pushing versus immediate pushing (all women with epidural)For the primary maternal outcomes, delayed pushing was associated with an increase of 56 minutes in the duration of the second stage of labour (MD 56.40, 95% CI 42.05 to 70.76; 11 studies; 3049 women; I2 = 91%) (very low-quality evidence), but no clear difference in third or 4th degree perineal laceration (RR 0.94; 95% CI 0.78 to 1.14, seven studies. 2775 women) (moderate quality evidence) or episiotomy (RR 0.95; 95% CI 0.87 to 1.04, five studies, 2320 women). Delayed pushing was also associated with a 19-minute decrease in the duration of pushing (MD -19.05, 95% CI -32.27 to -5.83; 11 studies; 2932 women; I2 = 95%) (very low-quality evidence) and an increase in spontaneous vaginal delivery (RR 1.07; 95% CI 1.02 to 1.11, 12 studies, 3114 women) (moderate-quality evidence).For the primary neonatal outcomes, there was no clear difference between groups in admission to neonatal intensive care (RR 0.98; 95% CI 0.67 to 1.41, three studies, n = 2197) (low-quality evidence) and five-minute Apgar score less than seven (RR 0.15; 95% CI 0.01 to 3.00; three studies; 413 infants) (very low-quality evidence). There were no data on hypoxic ischaemic encephalopathy. Delayed pushing was associated with a greater incidence of low umbilical cord blood pH (RR 2.24; 95% CI 1.37 to 3.68, 4 studies, 2145 infants) and increased the cost of intrapartum care by CDN$ 68.22 (MD 68.22, 95% CI 55.37, 81.07, one study, 1862 women). AUTHORS' CONCLUSIONS: This updated review is based on 21 included studies of moderate to very low quality of evidence (with evidence mainly downgraded due to study design limitations and imprecision of effect estimates).Timing of pushing with epidural is consistent in that delayed pushing leads to a shortening of the actual time pushing and increase of spontaneous vaginal delivery at the expense of an overall longer duration of the second stage of labour and an increased risk of a low umbilical cord pH (based only on one study). Nevertheless, there was no clear difference in serious perineal laceration and episiotomy, and in other neonatal outcomes (admission to neonatal intensive care, five-minute Apgar score less than seven and delivery room resuscitation) between delayed and immediate pushing.Therefore, for the type of pushing, with or without epidural, there is no conclusive evidence to support or refute any specific style as part of routine clinical practice, and in the absence of strong evidence supporting a specific method or timing of pushing, the woman's preference and comfort and clinical context should guide decisions.Further properly well-designed RCTs, addressing clinically important maternal and neonatal outcomes are required to add evidence-based information to the current knowledge. Such trials will provide more complete data to be incorporated into a future update of this review. PMID- 28349527 TI - Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis. AB - BACKGROUND: People with cystic fibrosis, who are chronically colonised with the organism Pseudomonas aeruginosa, often require multiple courses of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations. The properties of aminoglycosides suggest that they could be given in higher doses less often. This is an update of a previously published review. OBJECTIVES: To assess the effectiveness and safety of once-daily versus multiple-daily dosing of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations in cystic fibrosis. SEARCH METHODS: We searched the Cystic Fibrosis Specialist Register held at the Cochrane Cystic Fibrosis and Genetic Disorders Group's editorial base, comprising references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings.Date of the most recent search: 24 June 2016. SELECTION CRITERIA: All randomised controlled trials, whether published or unpublished, in which once-daily dosing of aminoglycosides has been compared with multiple-daily dosing in terms of efficacy or toxicity or both, in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: The two authors independently selected the studies to be included in the review and assessed the risk of bias of each study; authors also assessed the quality of the evidence using the GRADE criteria. Data were independently extracted by each author. Authors of the included studies were contacted for further information. As yet unpublished data were obtained for one of the included studies. MAIN RESULTS: Fifteen studies were identified for possible inclusion in the review. Four studies reporting results from a total of 328 participants (aged 5 to 50 years) were included in this review. All studies compared once-daily dosing with thrice-daily dosing. One study had a low risk of bias for all criteria assessed; the remaining three included studies had a high risk of bias from blinding, but for other criteria were judged to have either an unclear or a low risk of bias.There was no significant difference between treatment groups in: forced expiratory volume in one second, mean difference 0.33 (95% confidence interval -2.81 to 3.48, moderate quality evidence); forced vital capacity, mean difference 0.29 (95% confidence interval -6.58 to 7.16, low quality evidence); % weight for height, mean difference -0.82 (95% confidence interval -3.77 to 2.13, low quality evidence); body mass index, mean difference 0.00 (95% confidence interval -0.42 to 0.42, low quality evidence); or in the incidence of ototoxicity, relative risk 0.56 (95% confidence interval 0.04 to 7.96, moderate quality evidence). The percentage change in creatinine significantly favoured once-daily treatment in children, mean difference -8.20 (95% confidence interval -15.32 to -1.08, moderate quality evidence), but showed no difference in adults, mean difference 3.25 (95% confidence interval -1.82 to 8.33, moderate quality evidence). The included trials did not report antibiotic resistance patterns or quality of life. AUTHORS' CONCLUSIONS: Once- and three-times daily aminoglycoside antibiotics appear to be equally effective in the treatment of pulmonary exacerbations of cystic fibrosis. There is evidence of less nephrotoxicity in children. PMID- 28349528 TI - The role of preschool teacher-child interactions in academic adjustment: An intervention study with Playing-2-gether. AB - BACKGROUND: Social relationships can serve as important risk or protective factors for child development in general, and academic adjustment in particular. AIMS: This study investigated the role of teacher-child interactions in academic adjustment among preschool boys at risk of externalizing behaviour, using a randomized controlled trial study with Playing-2-gether (P2G), a 12-week indicated two-component intervention aimed at improving the affective quality of the teacher-child relationship and teacher behaviour management. SAMPLE: In a sample of 175 preschool boys showing signs of externalizing behaviour (Mage = 4 years, 9 months, SDage = 7 months) and their teachers, we investigated P2G effects on academic engagement as well as on language achievement. METHODS: Academic engagement was rated by teachers at three occasions within one school year (T1 = pretest, T3 = post-test, and T2 = in-between intervention components). Language achievement was assessed by researchers at pre- and post-test, using a standardized test. RESULTS: Cross-lagged path analyses revealed a direct intervention effect of P2G on academic engagement at Time 2. In addition, a significant indirect intervention effect was found on academic engagement at Time 3 through academic engagement at Time 2. Finally, academic engagement at Time 2 was found to predict language achievement at post-test. A marginally significant indirect intervention effect was found on language achievement at Time 3, through academic engagement at Time 2. CONCLUSIONS: This intervention study suggests that teacher-child interactions predict academic engagement over time, which in turn improves language achievement among preschool boys at risk of externalizing behaviour. PMID- 28349529 TI - Continuous chest compression versus interrupted chest compression for cardiopulmonary resuscitation of non-asphyxial out-of-hospital cardiac arrest. AB - BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a major cause of death worldwide. Cardiac arrest can be subdivided into asphyxial and non asphyxial etiologies. An asphyxia arrest is caused by lack of oxygen in the blood and occurs in drowning and choking victims and in other circumstances. A non asphyxial arrest is usually a loss of functioning cardiac electrical activity. Cardiopulmonary resuscitation (CPR) is a well-established treatment for cardiac arrest. Conventional CPR includes both chest compressions and 'rescue breathing' such as mouth-to-mouth breathing. Rescue breathing is delivered between chest compressions using a fixed ratio, such as two breaths to 30 compressions or can be delivered asynchronously without interrupting chest compression. Studies show that applying continuous chest compressions is critical for survival and interrupting them for rescue breathing might increase risk of death. Continuous chest compression CPR may be performed with or without rescue breathing. OBJECTIVES: To assess the effects of continuous chest compression CPR (with or without rescue breathing) versus conventional CPR plus rescue breathing (interrupted chest compression with pauses for breaths) of non-asphyxial OHCA. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 1 2017); MEDLINE (Ovid) (from 1985 to February 2017); Embase (1985 to February 2017); Web of Science (1985 to February 2017). We searched ongoing trials databases including controlledtrials.com and clinicaltrials.gov. We did not impose any language or publication restrictions. SELECTION CRITERIA: We included randomized and quasi-randomized studies in adults and children suffering non-asphyxial OHCA due to any cause. Studies compared the effects of continuous chest compression CPR (with or without rescue breathing) with interrupted CPR plus rescue breathing provided by rescuers (bystanders or professional CPR providers). DATA COLLECTION AND ANALYSIS: Two authors extracted the data and summarized the effects as risk ratios (RRs), adjusted risk differences (ARDs) or mean differences (MDs). We assessed the quality of evidence using GRADE. MAIN RESULTS: We included three randomized controlled trials (RCTs) and one cluster-RCT (with a total of 26,742 participants analysed). We identified one ongoing study. While predominantly adult patients, one study included children. Untrained bystander-administered CPRThree studies assessed CPR provided by untrained bystanders in urban areas of the USA, Sweden and the UK. Bystanders administered CPR under telephone instruction from emergency services. There was an unclear risk of selection bias in two trials and low risk of detection, attrition, and reporting bias in all three trials. Survival outcomes were unlikely to be affected by the unblinded design of the studies.We found high quality evidence that continuous chest compression CPR without rescue breathing improved participants' survival to hospital discharge compared with interrupted chest compression with pauses for rescue breathing (ratio 15:2) by 2.4% (14% versus 11.6%; RR 1.21, 95% confidence interval (CI) 1.01 to 1.46; 3 studies, 3031 participants).One trial reported survival to hospital admission, but the number of participants was too low to be certain about the effects of the different treatment strategies on survival to admission(RR 1.18, 95% CI 0.94 to 1.48; 1 study, 520 participants; moderate-quality evidence).There were no data available for survival at one year, quality of life, return of spontaneous circulation or adverse effects.There was insufficient evidence to determine the effect of the different strategies on neurological outcomes at hospital discharge (RR 1.25, 95% CI 0.94 to 1.66; 1 study, 1286 participants; moderate-quality evidence). The proportion of participants categorized as having good or moderate cerebral performance was 11% following treatment with interrupted chest compression plus rescue breathing compared with 10% to 18% for those treated with continuous chest compression CPR without rescue breathing. CPR administered by a trained professional In one trial that assessed OHCA CPR administered by emergency medical service professionals (EMS) 23,711 participants received either continuous chest compression CPR (100/minute) with asynchronous rescue breathing (10/minute) or interrupted chest compression with pauses for rescue breathing (ratio 30:2). The study was at low risk of bias overall.After OHCA, risk of survival to hospital discharge is probably slightly lower for continuous chest compression CPR with asynchronous rescue breathing compared with interrupted chest compression plus rescue breathing (9.0% versus 9.7%) with an adjusted risk difference (ARD) of -0.7%; 95% CI (-1.5% to 0.1%); moderate-quality evidence.There is high-quality evidence that survival to hospital admission is 1.3% lower with continuous chest compression CPR with asynchronous rescue breathing compared with interrupted chest compression plus rescue breathing (24.6% versus 25.9%; ARD -1.3% 95% CI (-2.4% to -0.2%)).Survival at one year and quality of life were not reported.Return of spontaneous circulation is likely to be slightly lower in people treated with continuous chest compression CPR plus asynchronous rescue breathing (24.2% versus 25.3%; -1.1% (95% CI -2.4 to 0.1)), high-quality evidence.There is high-quality evidence of little or no difference in neurological outcome at discharge between these two interventions (7.0% versus 7.7%; ARD -0.6% (95% CI -1.4 to 0.1).Rates of adverse events were 54.4% in those treated with continuous chest compressions plus asynchronous rescue breathing versus 55.4% in people treated with interrupted chest compression plus rescue breathing compared with the ARD being -1% (-2.3 to 0.4), moderate-quality evidence). AUTHORS' CONCLUSIONS: Following OHCA, we have found that bystander administered chest compression-only CPR, supported by telephone instruction, increases the proportion of people who survive to hospital discharge compared with conventional interrupted chest compression CPR plus rescue breathing. Some uncertainty remains about how well neurological function is preserved in this population and there is no information available regarding adverse effects.When CPR was performed by EMS providers, continuous chest compressions plus asynchronous rescue breathing did not result in higher rates for survival to hospital discharge compared to interrupted chest compression plus rescue breathing. The results indicate slightly lower rates of survival to admission or discharge, favourable neurological outcome and return of spontaneous circulation observed following continuous chest compression. Adverse effects are probably slightly lower with continuous chest compression.Increased availability of automated external defibrillators (AEDs), and AED use in CPR need to be examined, and also whether continuous chest compression CPR is appropriate for paediatric cardiac arrest. PMID- 28349530 TI - The antiproliferative and apoptotic effects of apigenin on glioblastoma cells. AB - OBJECTIVES: Glioblastoma (GBM) is highly proliferative, infiltrative, malignant and the most deadly form of brain tumour. The epidermal growth factor receptor (EGFR) is overexpressed, amplified and mutated in GBM and has been shown to play key and important roles in the proliferation, growth and survival of this tumour. The goal of our study was to investigate the antiproliferative, apoptotic and molecular effects of apigenin in GBM. METHODS: Proliferation and viability tests were carried out using the trypan blue exclusion, MTT and lactate dehydrogenase (LDH) assays. Flow cytometry was used to examine the effects of apigenin on the cell cycle check-points. In addition, we determined the effects of apigenin on EGFR-mediated signalling pathways by Western blot analyses. KEY FINDINGS: Our results showed that apigenin reduced cell viability and proliferation in a dose- and time-dependent manner while increasing cytotoxicity in GBM cells. Treatment with apigenin-induced is poly ADP-ribose polymerase (PARP) cleavage and caused cell cycle arrest at the G2M checkpoint. Furthermore, our data revealed that apigenin inhibited EGFR-mediated phosphorylation of mitogen-activated protein kinase (MAPK), AKT and mammalian target of rapamycin (mTOR) signalling pathways and attenuated the expression of Bcl-xL. CONCLUSION: Our results demonstrated that apigenin has potent inhibitory effects on pathways involved in GBM proliferation and survival and could potentially be used as a therapeutic agent for GBM. PMID- 28349531 TI - Characterization of sea cucumber (stichopus japonicus) ovum hydrolysates: calcium chelation, solubility and absorption into intestinal epithelial cells. AB - BACKGROUND: Sea cucumber (Stichopus japonicus) ovum hydrolysates (SCOHs) chelated with calcium were produced to investigate the characteristics of calcium binding and solubility, as well as to study any effects on calcium absorption by human intestinal epithelial cells. RESULTS: The results of the present study show that the calcium-binding capacity of SCOHs depended greatly on the type of proteases. The maximum level of Ca binding (0.38 mmol L-1 ) occurred when trypsin was used, with a peptide yield of 85.7%. Investigation of the possible chelating modes between SCOHs and calcium ions indicated that calcium ions bound to SCOHs primarily via interactions with carboxyl oxygen and amino nitrogen atoms of Glu and Asp and also that the phosphoserine residues might be also responsible for SCOH-calcium chelation. Moreover, SCOH-calcium complexes maintained the solubility of calcium under simulated gastrointestinal digestion, regardless of the presence of dietary components such as oxalate. Furthermore, SCOH-Ca led to higher peak intracellular [Ca2+ ]i in both Caco-2 cells (338.3 nmol L-1 versus 269.6 nmol L-1 ) and HT-29 cells (373.9 nmol L-1 versus 271.7 nmol L-1 ) than casein phosphopeptide-Ca. CONCLUSION: Carboxyl oxygen and amino nitrogen atoms in the SCOHs could bind calcium ions, forming SCOH-calcium complexes. These complexes improved calcium solubility under simulated gastrointestinal digestion and also promoted calcium absorption in Caco-2 and HT-29 cells. (c) 2017 Society of Chemical Industry. PMID- 28349532 TI - Determining the effect of malondialdehyde on the IgE-binding capacity of shrimp tropomyosin upon in vitro digestion. AB - BACKGROUND: Stability in simulated gastric fluids is considered an important parameter for the estimation of food allergenicity. Moreover, proteins in food are highly susceptible to lipid oxidation during processing and preservation. In this study, the change in the IgE-binding capacity of malondialdehyde (MDA) treated shrimp tropomyosin (TM) following in vitro digestion was investigated by SDS-PAGE and western blot. RESULTS: Shrimp TM treated with different concentrations of MDA was slightly degraded and became increasingly resistant to pepsin digestion over time. While untreated TM was rapidly degraded, MDA-treated TM showed some resistance and was degraded by trypsin only after increasing the digestion time. Results of immunoblotting studies on IgE using sera from patients allergic to shrimp indicated that the IgE-binding capacity of TM and MDA (50 mmol L-1 )-treated TM decreased slightly after pepsin digestion and significantly decreased after trypsin digestion. CONCLUSION: The study indicated that the resistance of TM to degradation increased after oxidation. The treatment with proteases, especially trypsin, is quite effective in decreasing the IgG/IgE binding capacity of shrimp TM. (c) 2017 Society of Chemical Industry. PMID- 28349533 TI - Subtotal petrosectomy: Surgical technique, indications, outcomes, and comprehensive review of literature. AB - OBJECTIVES/HYPOTHESIS: To describe the technique of subtotal petrosectomy (STP), to analyze the outcomes, and to review the literature STUDY DESIGN: A retrospective review. METHODS: Four hundred sixty cases of STP performed for various indications were included in the study, which was conducted at a quaternary referral center for otology and skull base surgery. Surgical and audiological parameters, and complications were evaluated. Our results were compared with the existing literature on the subject. RESULTS: Two hundred ninety seven (64.6%) patients had been subjected to multiple surgeries before an STP was performed. The most common indication for STP was recurrent chronic otitis with or without cholesteatoma, with 165 (35.9%) patients. Difficult cases of cochlear implantation, temporal bone fractures, and class B3 tympanomastoid paragangliomas were the next most common indications, with 91 (19.8%), 43 (9.4%), and 38 (8.3%) cases, respectively. The median follow-up of the patient pool was 36 +/- 19 months. Recidivism and postauricular wound fistula were the most common complications, seen in five (1.1%) patients each. This series of STP is the largest reported in the literature CONCLUSIONS: STP is a very useful and safe surgical tool in the management of a variety of problematic situations in otology, as it offers the possibility of a definitive cure by offering radical clearance. This procedure can be combined safely with hearing implantation procedures. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2833-2842, 2017. PMID- 28349534 TI - Hearing loss and speech perception in noise difficulties in Fanconi anemia. AB - OBJECTIVES/HYPOTHESIS: Fanconi anemia is a hereditary chromosomal instability disorder. Hearing loss and ear abnormalities are among the many manifestations reported in this disorder. In addition, Fanconi anemia patients often complain about hearing difficulties in situations with background noise (speech perception in noise difficulties). Our study aimed to describe the prevalence of hearing loss and speech perception in noise difficulties in Dutch Fanconi anemia patients. STUDY DESIGN: Retrospective chart review. METHODS: A retrospective chart review was conducted at a Dutch tertiary care center. All patients with Fanconi anemia at clinical follow-up in our hospital were included. Medical files were reviewed to collect data on hearing loss and speech perception in noise difficulties. RESULTS: In total, 49 Fanconi anemia patients were included. Audiograms were available in 29 patients and showed hearing loss in 16 patients (55%). Conductive hearing loss was present in 24.1%, sensorineural in 20.7%, and mixed in 10.3%. A speech in noise test was performed in 17 patients; speech perception in noise was subnormal in nine patients (52.9%) and abnormal in two patients (11.7%). CONCLUSIONS: Hearing loss and speech perception in noise abnormalities are common in Fanconi anemia. Therefore, pure tone audiograms and speech in noise tests should be performed, preferably already at a young age, because hearing aids or assistive listening devices could be very valuable in developing language and communication skills. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2358-2361, 2017. PMID- 28349535 TI - Sternohyoid muscles for reconstruction after thyroid cartilage anterior partial resection. PMID- 28349536 TI - Effect of dietary plant extract on meat quality and sensory parameters of meat from Equidae. AB - BACKGROUND: Plant extracts as Lippia spp. have been proven antioxidant properties. Recent studies have been shown that dietary supplementation with plant extracts is able to enhance meat quality parameters. Studies regarding meat quality in Equidae are limited. RESULTS: The effect of dietary plant extract (PE), containing verbascoside, on meat quality, oxidative stability and sensory parameters of Longissimus Lumborum (LL) muscle in Equidae was studied. Dietary treatment did not affect (P > 0.05) pH, colour indices and chemical parameters of muscle in both donkey and horse. Dietary PE improved (P < 0.01) oxidative stability in donkey muscle during refrigerated storage. Sensory characteristics of LL muscle were positively affected (P < 0.05) by dietary PE in both donkey and horse. In particular, colour, taste and texture were enhanced in LL muscle from animals fed PE. Oxidative stability was lower (P < 0.05) in LL muscle of horse than that of donkey. CONCLUSION: Dietary plant extract, containing verbascoside, can be considered as a natural source of antioxidants, and is also able to improve oxidative stability of donkey meat and to affect the sensory attributes of Equidae meat. (c) 2017 Society of Chemical Industry. PMID- 28349537 TI - The state of academic sleep surgery: A survey of United States residency and fellowship programs. AB - OBJECTIVES/HYPOTHESIS: Our objectives were to describe otolaryngology residency programs' experience in and attitudes toward sleep surgery, and describe current otolaryngology sleep fellowships and their impact on future academic practice. STUDY DESIGN: E-mail survey. METHODS: A survey was e-mailed to program directors of 106 Accreditation Council for Graduate Medical Education-accredited otolaryngology residencies assessing resident sleep medicine experience, program satisfaction, and impact of sleep faculty. A separate survey was sent to directors of the seven sleep medicine otolaryngology fellowships. Frequency of graduates pursuing academic careers was examined. RESULTS: Forty-six (43.4%) residency programs responded. Thirty-one (67.4%) have a faculty member with any time spent practicing sleep medicine or surgery. Nineteen (41.3%) have a faculty member with >50% dedicated sleep practice and/or who is board certified in sleep medicine. These programs were significantly more likely to respond "extremely" or "very" satisfied with resident sleep exposure than those without (P < .001). Most programs (69.6%) "strongly agreed" or "agreed" their program would benefit from a dedicated sleep surgeon; there was no significant difference in response rates between programs already with and those without dedicated sleep faculty. All fellowship directors responded. In the past 5 years these programs have trained 11 total fellows. Ten (90.9%) have remained in academic practice. CONCLUSIONS: There is significantly increased satisfaction in resident sleep education at otolaryngology programs with dedicated sleep providers. Concurrently, there is strong program interest in sleep surgeons' involvement in resident training. Sleep fellowships are producing surgeons who pursue academic careers. This study provides support to training fellowship-specialized sleep surgeons and encouraging otolaryngology sleep faculty. LEVEL OF EVIDENCE: NA Laryngoscope, 127:2423-2428, 2017. PMID- 28349538 TI - Assessment of frozen section margin analysis during olfactory neuroblastoma surgery. AB - OBJECTIVES: 1) assess the performance of the intraoperative frozen section procedure to correctly classify biopsies obtained during olfactory neuroblastoma (ONB) surgery; 2) define the relationship between posttest probabilities and pretest probabilities from frozen section analysis; and 3) review incorrectly classified specimens. STUDY DESIGN: Study of diagnostic accuracy. METHODS: We searched our institution's pathology database for patients who had ONB surgery between January 1, 2000 and November 16, 2012. We only included patients who had a definitive diagnosis of ONB prior to surgery and frozen sections obtained during surgery. All frozen sections in this study had corresponding permanent sections available to serve as a gold standard. This database was analyzed to obtain classification statistics. The confidence intervals for classification performance were obtained using the bootstrap sampling method. Confidence intervals for posttest probability curves were derived using the Taylor series expansion. Finally, we obtained and reviewed the slides from ambiguous or incorrect reads. RESULTS: A total of 459 specimens from 33 patients were analyzed. We found the following performance characteristics: sensitivity: 0.89 (0.81, 0.94); specificity: 0.96 (0.94, 0.98); accuracy: 0.95 (0.92, 0.96); likelihood ratio positive: 24.4 (14.5, 44.1); prevalence: 0.20 (0.17, 0.25); positive predictive value: 0.86 (0.78, 0.92); and negative predictive value: 0.97 (0.95, 0.99). Histopathologic review revealed that crush artifacts and inadequate specimen size were major sources of incorrect reads. CONCLUSION: We found frozen section assessment of ONB specimens to be an excellent tool for the assessment of intraoperative margins. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:1735-1741, 2017. PMID- 28349539 TI - Fermentation of sarshir (kaymak) by lactic acid bacteria: antibacterial activity, antioxidant properties, lipid and protein oxidation and fatty acid profile. AB - BACKGROUND: The antioxidant and antibacterial activities of fermented sarshir (traditional dairy food), with three probiotic Lactobacillus plantarum strains (LP3, AF1, and LU5), were investigated. The oxidative stability and the lipid profile of non-fermented and fermented sarshir were compared, in addition to radical scavenging activity, as well as peroxide, anisidine and carbonyl values (PV, AnV and CV, respectively). RESULTS: The strong antibacterial activity of fermented sarshir against common pathogenic bacteria, including Gram-negative Escherichia coli O157: H7 ATCC 35150 and Pseudomonas aeruginosa ATCC 27853, as well as Gram-positive Bacillus cereus ATCC 10876 and Staphylococcus aureus ATCC 25923, was established. Among the strains examined, L. plantarum LP3 exhibited the highest radical scavenging activity (53.1 +/- 1.8%) and lowest PV (3.0 meq kg 1 ), AnV (1.31 +/- 0.06) and CV (1.4 +/- 0.08). The pH of sarshir decreased from 6.2 +/- 0 to 3.5 +/- 0.1 during 14 h of fermentation. Incorporated bacterial cells exhibited notable viability during 10 days of cold storage (4 degrees C). CONCLUSION: The fermentation of sarshir by L. plantarum strains, especially LP3, resulted in beneficial changes in radical scavenging activity, as well as PV, AnV and carbonyl values, in addition to a broad spectrum of inhibitory activity against strains of P. aeruginosa, E. coli O157:H7, B. cereus and S. aureus. (c) 2017 Society of Chemical Industry. PMID- 28349540 TI - Sublethal effects of angling and release on golden perch Macquaria ambigua: implications for reproduction and fish health. AB - The present study tested the hypothesis of no delayed sublethal effects of mild angling and release on the feeding, growth, somatic condition and gonadal development of golden perch Macquaria ambigua during gametogenesis. Subsamples of adult M. ambigua (n = 17-21 of 207), originally captured from the wild and stocked into ten 0.1 ha earthen ponds, were angled and released during early and late gametogenesis. Wild samples that were concurrently collected throughout the experiment underwent rapid and synchronous gonadal development and many spawned. While no spawning occurred in the ponds, most M. ambigua underwent normal gonadal development to maturity, including the angled fish. Angled fish also fed, maintained condition and actually grew faster than non-angled captive controls. Although females that were angled during late gametogenesis more readily ingested and retained baited hooks, neither their subsequent condition nor gonadal development was significantly affected. The predominance of null results was attributed to the combined effects of the flexible reproductive strategy of M. ambigua, the benignness of mouth hooking and immediate release, and possible methodological issues arising from differential hooking success of more aggressive and resilient individuals. The findings support earlier catch-and release research, but contrast with reports of acute reproductive effects following capture and handling for aquaculture broodstock. This discrepancy highlights the need for research to specifically address welfare questions relevant to recreational fisheries across various species and angling scenarios. PMID- 28349541 TI - Effect of the type and level of hydration of alcoholic solvents on the simultaneous extraction of oil and chlorogenic acids from sunflower seed press cake. AB - BACKGROUND: The present study aimed to evaluate the replacement of hexane by alcoholic solvents in oil extraction from sunflower seed press cake. The use of ethanol and isopropanol has important advantages, including low toxicity and good operational safety. Thus, in the present study, solid-liquid extractions were performed in a single stage from 60 to 90 degrees C and in consecutive extractions in three stages at 90 degrees C. RESULTS: Solvent hydration negatively affected the extraction of oil but favored the extraction of chlorogenic acids (CAs), especially when ethanol was used. Regarding oxidative stability, the oils extracted using ethanol presented long induction times, which could be related to the high levels of not only CAs and tocopherols, but also phospholipids. CONCLUSION: Alcoholic solvents can be used for extraction to produce sunflower seed oil containing minor compounds that give it greater oxidative stability. In addition, the results obtained using hydrous ethanol showed that this solvent can yield defatted sunflower seed meal with a low content of CAs, enabling future use of the protein fraction. (c) 2017 Society of Chemical Industry. PMID- 28349542 TI - Onset of bell's palsy in late pregnancy and early puerperium is associated with worse long-term outcomes. AB - INTRODUCTION: The incidence of Bell's palsy (BP) is elevated in the late phases of pregnancy. Controversy exists as to whether pregnancy is a risk factor for worse outcomes in BP, and whether such outcomes are the result of factors intrinsic to pregnancy or the tendency to withhold medical therapy in this cohort. METHODS: Long-term facial function outcomes in cases of pregnancy associated BP (PABP) were compared against outcomes in cases affecting nonpregnant adult women of child-bearing age by a blinded expert using the electronic clinician-graded facial function scale (eFACE) facial grading system. RESULTS: Fifty-one pregnancy-associated cases and 58 nonpregnancy-associated cases were included. Among patients who received early corticosteroid therapy, significantly worse static, synkinesis, and composite facial function eFACE scores were demonstrated among cases of PABP compared to nonpregnancy-associated cases (static median = 86 vs. 92.5, P = 0.005; synkinesis median = 79 vs. 86, P = 0.007; composite median = 78 vs. 84, P = 0.023). Among those not treated with corticosteroids, significantly worse dynamic and composite facial function eFACE scores were demonstrated in cases of PABP compared to those for nonpregnancy associated cases (dynamic median = 74 vs. 92.5, P = 0.038; composite median = 73 vs. 86.5, P = 0.038). A trend toward improved outcomes was demonstrated within both groups for those treated with corticosteroids compared to those who were not. CONCLUSION: In comparison to cases unrelated to pregnancy, late-term PABP is associated with worse long-term outcomes to a degree that cannot solely be explained by differences in medical therapy. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2854-2859, 2017. PMID- 28349543 TI - Corrigendum. PMID- 28349544 TI - Retracted: Corrigendum. PMID- 28349545 TI - Blanchability and sensory quality of large runner peanuts blanched in a radiant wall oven using infrared radiation. AB - BACKGROUND: The main factors behind the growing popularity of infrared radiation heating in food processing include its energy efficiency, food quality retention and process speed, as well as the simplicity of equipment. Infrared radiation was employed as an alternative heat treatment to the conventional hot air method used in peanut blanching. The present study aimed to investigate the application of infrared heating for blanching peanuts and determine their blanchability and sensory quality under various processing conditions. RESULTS: The total blanchabilities (expressed as a percentage of total blanched) of the infrared radiation trials (radiant wall oven) at 343 degrees C for 1.5 min, 316 degrees C for 1.5 min, 288 degrees C for 1.5 min and 343 degrees C for 1 min did not differ significantly compared to the hot air control trials (impingement oven) at 100 degrees C for 30 and 20 min. All infrared trials had significantly lower (P < 0.05) numbers of split kernels compared to those of the conventional trials and all blanched peanuts in the experiment remained raw. A descriptive sensory shelf life study with one control and three infrared samples demonstrated the possible initiation of oxidation for the conventionally blanched sample at 18 weeks of storage at 24 degrees C (room temperature), with no indication of oxidation in the infrared samples stored at the same temperature. CONCLUSION: Infrared radiation peanut blanching is a viable alternative to conventional hot air blanching because of the shorter process time and longer shelf-life, as evident from the sensory storage study. (c) 2017 Society of Chemical Industry. PMID- 28349546 TI - Enhanced growth of halophyte plants in biochar-amended coastal soil: roles of nutrient availability and rhizosphere microbial modulation. AB - Soil health is essential and irreplaceable for plant growth and global food production, which has been threatened by climate change and soil degradation. Degraded coastal soils are urgently required to reclaim using new sustainable technologies. Interest in applying biochar to improve soil health and promote crop yield has rapidly increased because of its multiple benefits. However, effects of biochar addition on the saline-sodic coastal soil health and halophyte growth were poorly understood. Response of two halophytes, Sesbania (Sesbania cannabina) and Seashore mallow (Kosteletzkya virginica), to the individual or co application of biochar and inorganic fertilizer into a coastal soil was investigated using a 52 d pot experiment. The biochar alone or co-application stimulated the plant growth (germination, root development, and biomass), primarily attributed to the enhanced nutrient availability from the biochar improved soil health. Additionally, the promoted microbial activities and bacterial community shift towards the beneficial taxa (e.g. Pseudomonas and Bacillus) in the rhizosphere also contributed to the enhanced plant growth and biomass. Our findings showed the promising significance because biochar added at an optimal level (<=5%) could be a feasible option to reclaim the degraded coastal soil, enhance plant growth and production, and increase soil health and food security. PMID- 28349548 TI - Multifocal but non-disseminated phaeohyphomycosis in a healthy man via a unique mechanism: Ejection from motor vehicle accident into a vegetable field in Afghanistan resulting in multiple contaminated skin wounds. AB - A 20-year-old male presented with multiple subcutaneous nodules on the head, neck, chest and oral cavity. FNA and biopsy showed pigmented fungal hyphae diagnostic of multifocal phaeohyphomycosis, found to be Exophiala spinifera by molecular diagnostics. The presentation initially raised concern for disseminated disease and occult immunosuppression. However, the patient appeared to be immunocompetent and otherwise healthy. Upon further inquiry, the patient was in a motor vehicle accident 4 years before presentation; he was ejected into a vegetable field resulting in multiple open wounds. Multifocal phaeohyphomycosis usually indicates disseminated systemic disease from immunosuppression and carries a grave prognosis. PMID- 28349547 TI - Larger men have larger prostates: Detection bias in epidemiologic studies of obesity and prostate cancer risk. AB - BACKGROUND: Obesity is associated with risk of aggressive prostate cancer (PCa), but not with over-all PCa risk. However, obese men have larger prostates which may lower biopsy accuracy and cause a systematic bias toward the null in epidemiologic studies of over-all risk. METHODS: Within a cohort of 6692 men followed-up after a biopsy or transurethral resection of the prostate (TURP) with benign findings, a nested case-control study was conducted of 495 prostate cancer cases and controls matched on age, race, follow-up duration, biopsy versus TURP, and procedure date. Data on body mass index and prostate volume at the time of the initial procedure were abstracted from medical records. RESULTS: Prior to consideration of differences in prostate volume, overweight (OR = 1.41; 95%CI 1.01, 1.97), and obese status (OR = 1.59; 95%CI 1.09, 2.33) at the time of the original benign biopsy or TURP were associated with PCa incidence during follow up. Prostate volume did not significantly moderate the association between body size and PCa, however it did act as an inverse confounder; adjustment for prostate volume increased the effect size for overweight by 22% (adjusted OR = 1.52; 95%CI 1.08, 2.14) and for obese status by 23% (adjusted OR = 1.77; 95%CI 1.20, 2.62). Larger prostate volume at the time of the original benign biopsy or TURP was inversely associated with PCa incidence during follow-up (OR = 0.92 per 10 cc difference in volume; 95%CI 0.88, 0.97). In analyses that stratified case control pairs by tumor aggressiveness of the case, prostate volume acted as an inverse confounder in analyses of non-aggressive PCa but not in analyses of aggressive PCa. CONCLUSIONS: In studies of obesity and PCa, differences in prostate volume cause a bias toward the null, particularly in analyses of non aggressive PCa. A pervasive underestimation of the association between obesity and overall PCa risk may exist in the literature. PMID- 28349550 TI - Photo absorption of p-coumaric acid in aqueous solution: RISM-SCF-SEDD theory approach. AB - Photo absorption properties of p-coumaric acid, the chromophore of photoactive yellow protein, in aqueous solution were investigated by means of reference interaction site model self-consistent field with spatial electron density distribution (RISM-SCF-SEDD) method. RISM-SCF-SEDD is a combination methodology of electronic structure theory and statistical mechanics for molecular liquids. Here, time-dependent density functional theory was coupled with RISM equation to study the electronic structure of p-coumaric acid in aqueous system. Excitation energies of the chromophore in its neutral, two monoanionic and dianionic forms were computed to elucidate the effect of the deprotonation and solvation on the spectroscopic properties. We found that solvation strongly affects the excitation character of the chromophore, especially for phenolate anion and dianion. The free energy difference among the four protonation states is also discussed. (c) 2017 Wiley Periodicals, Inc. PMID- 28349549 TI - Multiple narrow complex tachycardias: What are the mechanisms? PMID- 28349551 TI - What additional treatment is indicated for oral cavity cancer with isolated perineural invasion? PMID- 28349552 TI - Phage-like packing structures with mean field sequence dependence. AB - Packing of double-stranded DNA in phages must overcome both electrostatic repulsions and the problem of persistence length. We consider coarse-grained models with the ability to kink and with randomly generated disorder. We show that the introduction of kinking into configurations of the DNA polymer packaged within spherical confinement results in significant reductions of the overall energies and pressures. We use a kink model which has the ability to deform every 24 bp, close to the average length predicted from phage sequence. The introduction of such persistence length defects even with highly random packing models increases the local nematic ordering of the packed DNA polymer segments. Such local ordering allowed by kinking not only reduces the total bending energy of confined DNA due to nonlinear elasticity but also reduces the electrostatic component of the energy and pressure. We show that a broad ensemble of polymer configurations is consistent with the structural data. (c) 2016 Wiley Periodicals, Inc. PMID- 28349553 TI - Unilateral ovarian absence in a Black-headed Squirrel Monkey (Saimiri vanzolinii Ayres, 1985), a threatened neotropical primate species. AB - Ovarian agenesis is an unusual anomaly with traumatic or congenital origin. In the present case report, we describe our findings in a senile S. vanzolinii female. As this neotropical primate species is listed as vulnerable, with limited geographic distribution in the Brazilian Amazonia, ovarian agenesis may be an important finding to be reported. PMID- 28349554 TI - Regularized regression analysis of digitized molecular structures in organic reactions for quantification of steric effects. AB - In organic chemistry, Comparative Molecular Field Analysis (CoMFA) can be defined as a regression analysis between reaction outcomes and molecular fields, wherein we can extract and visualize important structural information from the coefficients of the constructed regression models. In CoMFA, partial least squares (PLS) regression, which determines all coefficients in the model, is used for fitting the regression models. However, in organic reactions, steric effects are observed only near the reactive site, indicating that a large number of regression coefficients in the CoMFA of organic reactions should be assigned as 0. The regularized regression method, LASSO/Elastic Net, allows us to fit the regression model while assigning 0 values to unimportant coefficients. Although LASSO/Elastic Net should be suitable for CoMFA, there is no example of its use for organic reaction analysis. Herein, we examine the performance of LASSO/Elastic Net for the quantification of steric effects in CoMFA. We employ digitized molecular structures (the indicator field) as molecular fields that represent steric effects. LASSO/Elastic Net regressions provide highly interpretable models that include less noise than those from PLS regression. (c) 2017 Wiley Periodicals, Inc. PMID- 28349555 TI - Phytosterols on growth performance, antioxidant enzymes and intestinal morphology in weaned piglets. AB - BACKGROUND: Plant extracts have been used widely to improve growth, lower cholesterol, and exert antioxidative defense and antimicrobial activities in animal production. The present study aimed to investigate the effects of dietary phytosterols (PS) on growth performance, antioxidant enzymes and intestinal morphology in weaned piglets. RESULTS: A total of 120 crossbred piglets, weighing 9.58 +/- 0.26 kg, were randomly allocated to three treatments: control, PS (0.2 g kg-1 ) and polymyxin E (0.04 g kg-1 , antibiotic control). Compared to the control, PS or polymyxin E supplementation decreased diarrhea rate, serum cholesterol and malondialdehyde (MDA) of the piglets (P < 0.05). Liver MDA was significantly decreased in PS-fed piglets compared to the control (P < 0.05), although there was no difference between the control and polymyxin E-fed piglets. PS increased the villous height/crypt depth ratio of the duodenum and jejunum compared to the control (P < 0.05). Polymyxin E supplementation in piglets did not alter the villous height/crypt depth ratio but raised the villous height and crypt depth of the duodenum compared to the control (P < 0.05). CONCLUSION: The results of the present study indicated that PS could decrease diarrhea rate, lower serum cholesterol, reduce lipid peroxidation and ameliorate intestinal morphology in weaned piglets. In addition, PS exerted better amelioration on intestinal morphology than polymyxin E in piglets. (c) 2017 Society of Chemical Industry. PMID- 28349556 TI - Cerebral oxygenation as measured by near-infrared spectroscopy in neonatal intensive care: correlation with arterial oxygenation. AB - AIM: To assess correlation between cerebral oxygenation (rScO2 ), as measured by near-infrared spectroscopy (NIRS), and arterial oxygenation (PaO2 ), as measured by arterial blood gases, in preterm neonates. METHODS: Preterm neonates <37 weeks gestation with an indwelling arterial vascular catheter were recruited between April and August 2015 from the neonatal intensive care unit of the Royal Hospital for Women, Randwick NSW, Australia. The NIRS sensor was placed on the frontolateral aspect of the head prior to arterial gas sampling. NIRS, blood gas and clinical observation data were analysed using mixed linear modelling. RESULTS: Twenty-two neonates between 24 and 31 weeks gestation (mean 27.6 weeks) were recruited, and 75 readings obtained. No significant correlation was identified between cerebral oxygenation (rScO2 ) and arterial oxygenation (PaO2 ) (p = 0.37). There was also no significant correlation between rScO2 and clinically relevant parameters of SaO2 (p = 0.06), SpO2 (p = 0.44) and PaCO2 (p = 0.79). CONCLUSION: This study did not demonstrate any correlation between NIRS values and arterial oxygenation in clinically stable preterm infants. These results highlight some of the difficulties in clinical interpretation of NIRS values in neonatal intensive care, and further evaluation is needed to determine the applicability of NIRS to management of preterm infants. PMID- 28349557 TI - Unusual cause of dysphagia: Superior thyroid cornu syndrome. PMID- 28349558 TI - Population-based study showed that necrotising enterocolitis occurred in space time clusters with a decreasing secular trend in Sweden. AB - AIM: This study investigated space-time clustering of neonatal necrotising enterocolitis over three decades. METHODS: Space-time clustering analyses objects that are grouped by a specific place and time. The Knox test and Kulldorff's scan statistic were used to analyse space-time clusters in 808 children diagnosed with necrotising enterocolitis in a national cohort of 2 389 681 children born between 1987 and 2009 in Sweden. The municipality the mother lived in and the delivery hospital defined closeness in space and the time between when the cases were born - seven, 14 and 21 days - defined closeness in time. RESULTS: The Knox test showed no indication of space-time clustering at the residential level, but clear indications at the hospital level in all the time windows: seven days (p = 0.026), 14 days (p = 0.010) and 21 days (p = 0.004). Significant clustering at the hospital level was found during 1987-1997, but not during 1998-2009. Kulldorff's scan statistic found seven significant clusters at the hospital level. CONCLUSION: Space-time clustering was found at the hospital but not residential level, suggesting a contagious environmental effect after delivery, but not in the prenatal period. The decrease in clustering over time may reflect improved routines to minimise the risk of contagion between patients receiving neonatal care. PMID- 28349559 TI - Health and Taxes and the Values at Stake in the ACA Debate. PMID- 28349560 TI - Evaluation of the chiral recognition properties and the column performances of three chiral stationary phases based on cellulose for the enantioseparation of six dihydropyridines by high-performance liquid chromatography. AB - Separations of six dihydropyridine enantiomers on three commercially available cellulose-based chiral stationary phases (Chiralcel OD-RH, Chiralpak IB, and Chiralpak IC) were evaluated with high-performance liquid chromatography (HPLC). The best enantioseparation of the six chiral drugs was obtained with a Chiralpak IC (250 * 4.6 mm i.d., 5 MUm) column. Then the influence of the mobile phase including an alcohol-modifying agent and alkaline additive on the enantioseparation were investigated and optimized. The optimal mobile phase conditions and maximum resolution for every analyte were as follows respectively: n-hexane/isopropanol (85:15, v/v) for nimodipine (R = 5.80) and cinildilpine (R = 5.65); n-hexane/isopropanol (92:8, v/v) for nicardipine (R = 1.76) and nisoldipine (R = 1.92); and n-hexane/isopropanol/ethanol (97:2:1, v/v/v) for felodipine (R = 1.84) and lercanidipine (R = 1.47). Relative separation mechanisms are discussed based on the separation results, and indicate that the achiral parts in the analytes' structure showed an important influence on the separation of the chiral column. PMID- 28349561 TI - Helical screw sense bias in chiral polyfluorene stimulated by solvent. AB - Conjugated homopolymer poly(9,9-bis(3-((S)-2-methylbutylpropanoate))fluorene) (PSF) with chiral pendants was synthesized and characterized. Dissolution experiments show that PSF is well dissolved in racemic limonene at high temperature and begins aggregating upon sequential cooling treatment. The corresponding assemblies were transferred to quartz plate by the spin-coating method. Comparably, film casting from chloroform solution was also prepared. Upon annealing thermal treatments, these PSF films exhibited perfect mirror circular dichroism (CD) Cotton effects and dissymmetry ratios. Optical absorption spectroscopy (UV-vis), CD, and fluorescence spectroscopy results reveal that chiral side chains successfully induced M- and P-helical structures in aggregates and films, and this significant difference was ascribed to their differential supramolecular conformations. PMID- 28349562 TI - Palbociclib has antitumour effects on Pten-deficient endometrial neoplasias. AB - PTEN is one of the most frequently mutated genes in human cancers. The frequency of PTEN alterations is particularly high in endometrial carcinomas. Loss of PTEN leads to dysregulation of cell division, and promotes the accumulation of cell cycle complexes such as cyclin D1-CDK4/6, which is an important feature of the tumour phenotype. Cell cycle proteins have been presented as key targets in the treatment of the pathogenesis of cancer, and several CDK inhibitors have been developed as a strategy to generate new anticancer drugs. Palbociclib (PD-332991) specifically inhibits CDK4/6, and it has been approved for use in metastatic breast cancer in combination with letrazole. Here, we used a tamoxifen-inducible Pten knockout mouse model to assess the antitumour effects of cyclin D1 knockout and CDK4/6 inhibition by palbociclib on endometrial tumours. Interestingly, both cyclin D1 deficiency and palbociclib treatment triggered shrinkage of endometrial neoplasias. In addition, palbociclib treatment significantly increased the survival of Pten-deficient mice, and, as expected, had a general effect in reducing tumour cell proliferation. To further analyse the effects of palbociclib on endometrial carcinoma, we established subcutaneous tumours with human endometrial cancer cell lines and primary endometrial cancer xenografts, which allowed us to provide more translational and predictive data. To date, this is the first preclinical study evaluating the response to CDK4/6 inhibition in endometrial malignancies driven by PTEN deficiency, and it reveals an important role of cyclin D-CDK4/6 activity in their development. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28349564 TI - Emerging roles for the amyloid precursor protein and derived peptides in the regulation of cellular and systemic metabolism. AB - The amyloid precursor protein (APP) is a transmembrane protein that can be cleaved by proteases through two different pathways to yield a number of small peptides, each with distinct physiological properties and functions. It has been extensively studied in the context of Alzheimer's disease, with the APP-derived amyloid beta (Abeta) peptide being a major constituent of the amyloid plaques observed in this disease. It has been known for some time that APP can regulate neuronal metabolism; however, the present review examines the evidence indicating that APP and its peptides can also regulate key metabolic processes such as insulin action, lipid synthesis and storage and mitochondrial function in peripheral tissues. This review presents the hypothesis that amyloidogenic processing of APP in peripheral tissues plays a key role in the response to nutrient excess and that this could contribute to the pathogenesis of metabolic diseases such as obesity and type 2 diabetes (T2D). PMID- 28349563 TI - Defining surgical criteria for empty nose syndrome: Validation of the office based cotton test and clinical interpretability of the validated Empty Nose Syndrome 6-Item Questionnaire. AB - OBJECTIVES/HYPOTHESIS: The validated Empty Nose Syndrome 6-Item Questionnaire (ENS6Q) identifies empty nose syndrome (ENS) patients. The unvalidated cotton test assesses improvement in ENS-related symptoms. By first validating the cotton test using the ENS6Q, we define the minimal clinically important difference (MCID) score for the ENS6Q. STUDY DESIGN: Individual case-control study. METHODS: Fifteen patients diagnosed with ENS and 18 controls with non-ENS sinonasal conditions underwent office cotton placement. Both groups completed ENS6Q testing in three conditions-precotton, cotton in situ, and postcotton-to measure the reproducibility of ENS6Q scoring. Participants also completed a five-item transition scale ranging from "much better" to "much worse" to rate subjective changes in nasal breathing with and without cotton placement. Mean changes for each transition point, and the ENS6Q MCID, were then calculated. RESULTS: In the precotton condition, significant differences (P < .001) in all ENS6Q questions between ENS and controls were noted. With cotton in situ, nearly all prior ENS6Q differences normalized between ENS and control patients. For ENS patients, the changes in the mean differences between the precotton and cotton in situ conditions compared to postcotton versus cotton in situ conditions were insignificant among individuals. Including all 33 participants, the mean change in the ENS6Q between the parameters "a little better" and "about the same" was 4.25 (standard deviation [SD] = 5.79) and -2.00 (SD = 3.70), giving an MCID of 6.25. CONCLUSIONS: Cotton testing is a validated office test to assess for ENS patients. Cotton testing also helped to determine the MCID of the ENS6Q, which is a 7-point change from the baseline ENS6Q score. LEVEL OF EVIDENCE: 3b. Laryngoscope, 127:1746-1752, 2017. PMID- 28349566 TI - Correction note. AB - Correction note for Sanders, M., Calam, R., Durand, M., Liversidge, T. and Carmont, S. A. (2008), Does self-directed and web-based support for parents enhance the effects of viewing a reality television series based on the Triple P Positive Parenting Programme?. Journal of Child Psychology and Psychiatry, 49: 924-932. doi: 10.1111/j.1469-7610.2008.01901.x. PMID- 28349565 TI - The effect on sleep of being on-call: an experimental field study. AB - The aim of this study was to: (i) gain more insight into the relationship between being on-call and sleep and (ii) investigate the role of stress in this relationship. Data were collected by means of an experimental field study with a within-subject design (two conditions, random order). Ninety-six students participated during two consecutive nights: a reference night and a simulated on call night without an actual call. Participants were told they could be called at any time during the on-call night. In the case of a call, participants had to perform online tasks for approximately 30 min. Self-reported sleep quality and the extent to which participants experienced stress during the on-call period were assessed by means of short questionnaires. Actigraphy was used to obtain objective sleep measures. Results for actigraphy data revealed no significant within-person differences between conditions. However, participants reported longer sleep onset latencies, more awakenings and more wake after sleep onset during the on-call night than during the reference night. They also reported more sleep problems and a lower overall sleep quality, and felt less recuperated after the on-call night. Perceived stress moderated the relationship between being on call, on one hand, and the number of awakenings, wake after sleep onset, sleep problems and overall sleep quality, on the other hand. Results show that, even in the absence of an actual call, sleep during on-call nights is of lower quality and has less restorative value - especially when being on-call is experienced as stressful. PMID- 28349567 TI - Laryngoscopic and stroboscopic signs in the diagnosis of vocal fold paresis. AB - OBJECTIVES/HYPOTHESIS: To identify strobolaryngoscopic findings significant in the diagnosis of paresis. STUDY DESIGN: Retrospective cohort study. METHODS: Fellowship-trained laryngologists reviewed 34 videostroboscopic examinations (24 with paresis, eight without paresis, two repeat). They indicated presence or absence of paresis, including side and type, degree of confidence in diagnosis, and ranked clinical findings that influenced diagnosis by order of importance. Fleiss's kappa was used to assess inter-rater agreement for paresis presence, side, and type. Clinical findings compelling in diagnosis were tabulated and described. Confidence levels for side and type were compared by analysis of variance/Kruskal-Wallis tests and post hoc pairwise comparisons. RESULTS: Thirty one laryngologists completed the review. Inter-rater agreement on presence or absence of paresis was fair at 0.334 (Fleiss's kappa). Fourteen examinations were diagnosed with paresis by >70% of raters and considered strong paresis-candidate exams. Diagnosis of paresis side and type were inconsistent, although with statistically significant differences in confidence ratings (unilateral vs. bilateral, recurrent laryngeal nerve [RLN] vs. superior laryngeal nerve [SLN], RLN vs. mixed RLN/SLN). Laryngoscopic and stroboscopic findings with the strongest association with paresis were vocal fold motion anomalies, vocal fold degeneration, glottic insufficiency, and mucosal wave anomalies. CONCLUSIONS: Most laryngologists use strobolaryngoscopy for diagnosis of paresis. Although certain clinical findings were found to be associated with diagnosis, most commonly vocal fold motion anomalies, these varied among raters, especially when determining sidedness and nerve involvement. Future studies should expand the discussion and consideration of strobolaryngoscopic factors and adjunct functional and objective measures to develop a heuristic algorithm for diagnosis of paresis. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2100-2105, 2017. PMID- 28349568 TI - Audiovestibular symptoms as predictors of prolonged sports-related concussion among NCAA athletes. AB - OBJECTIVE: We looked to determine the rates of audiovestibular symptoms following sports-related concussions among collegiate athletes. Further, we assessed the correlation between these symptoms and the time to return to participation in athletic activity. STUDY DESIGN: Retrospective analysis of the National Collegiate Athletic Association Injury Surveillance System (NCAA-ISS). METHODS: The NCAA-ISS was queried from 2009 through 2014 for seven men's sports and eight women's sports across divisions 1, 2, and 3. Injuries resulting in concussions were analyzed for audiovestibular symptoms, duration of symptoms, and return to participation times. RESULTS: From 2009 to 2014, there were 1,647 recorded sports related concussions, with athletes reporting dizziness (68.2%), imbalance (35.8%), disorientation (31.4%), noise sensitivity (29.9%), and tinnitus (8.5%). Concussion symptoms resolved within 1 day (17.1%), within 2 to 7 days (50.0%), within 8 to 30 days (25.9%), or persisted over 1 month (7.0%). Return to participation occurred within 1 week (38.3%), within 1 month (53.0%), or over 1 month (8.7%). Using Mann-Whitney U testing, overall symptom duration and return to competition time were significantly increased when any of these symptoms were present (P < 0.05). Duration of concussion symptom correlated with dizziness (P = 0.043) and noise sensitivity (P = 0.000), whereas return to participation times correlated with imbalance (P = 0.011) and noise sensitivity (P = 0.000). Dizziness and imbalance (odds ratio: 4.15, confidence interval: 3.20-5.38, P < 0.001) were the two symptoms with the strongest association. CONCLUSION: Audiovestibular symptoms are common complaints among collegiate athletes sustaining concussions. Dizziness and noise sensitivity correlated with the duration of concussive symptoms, whereas imbalance and noise sensitivity was correlated with prolonged return to competition time. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2850-2853, 2017. PMID- 28349569 TI - Erratum. PMID- 28349570 TI - Erratum. PMID- 28349571 TI - Idiopathic intracranial hypertension: Contemporary review and implications for the otolaryngologist. AB - OBJECTIVES: 1) Review controversies pertaining to the pathophysiology, diagnosis, and treatment of idiopathic intracranial hypertension. 2) Discuss the evolving role of otolaryngologists in managing this disease and related disorders. DATA SOURCES: Primary literature review, Centers for Disease Control and Prevention website, International Classification of Headache Disorders, Second Edition. METHODS: A comprehensive review of the primary literature was performed from 1990 to 2016 utilizing keywords idiopathic intracranial hypertension, pseudotumor cerebri, benign intracranial hypertension, spontaneous cerebrospinal fluid leak, and encephalocele. Articles were included at the discretion of the authors based on novel and/or historical contributions to the literature. RESULTS: The incidence of idiopathic intracranial hypertension is increasing along with the obesity epidemic. Undiagnosed patients may present to otolaryngologists with pulsatile tinnitus, dizziness, sleep apnea, and spontaneous cerebrospinal fluid leaks. Although diagnosis is predicated upon imaging findings and lumbar puncture, radiographic signs including empty sella, optic nerve dilation, and globe flattening may suggest the diagnosis. The most effective intervention is weight loss combined with acetazolamide. Surgery is reserved for severe or refractory symptoms and can be highly morbid. Otolaryngologists are increasingly responsible for managing a number of secondary disorders including cerebrospinal fluid rhinorrhea and otorrhea. Failure to manage intracranial hypertension may lead to adverse surgical outcomes. CONCLUSIONS: The knowledge base for idiopathic intracranial hypertension has greatly expanded over the past 25 years. This disease is associated with a number of conditions directly relevant to otolaryngologists. A keen understanding of this disorder and its management may optimize outcomes in a growing number of patients. Laryngoscope, 128:248-256, 2018. PMID- 28349572 TI - Nerve transection repair using laser-activated chitosan in a rat model. AB - OBJECTIVES/HYPOTHESIS: Cranial nerve transection during head and neck surgery is conventionally repaired with microsuture. Previous studies have demonstrated recovery with laser nerve welding (LNW), a novel alternative to microsuture. LNW has been reported to have poorer tensile strength, however. Laser-activated chitosan, an adhesive biopolymer, may promote nerve recovery while enhancing the tensile strength of the repair. Using a rat posterior tibial nerve injury model, we compared four different methods of nerve repair in this pilot study. STUDY DESIGN: Animal study. DESIGN: Animals underwent unilateral posterior tibial nerve transection. The injury was repaired by potassium titanyl phosphate (KTP) laser alone (n = 20), KTP + chitosan (n = 12), microsuture + chitosan (n = 12), and chitosan alone (n = 14). Weekly walking tracks were conducted to measure functional recovery (FR). Tensile strength (TS) was measured at 6 weeks. RESULTS: At 6 weeks, KTP laser alone had the best recovery (FR = 93.4% +/- 8.3%). Microsuture + chitosan, KTP + chitosan, and chitosan alone all showed good FR (87.4% +/- 13.5%, 84.6% +/- 13.0%, and 84.1% +/- 10.0%, respectively). One-way analysis of variance was performed (F(3,56) = 2.6, P = .061). A TS threshold of 3.8 N was selected as a control mean recovery. Three groups-KTP alone, KTP + chitosan, and microsuture + chitosan-were found to meet threshold 60% (95% confidence interval [CI]: 23.1%-88.3%), 75% (95% CI: 46.8%-91.1%), and 100% (95% CI: 75.8%-100.0%), respectively. CONCLUSIONS: In the posterior tibial nerve model, all repair methods promoted nerve recovery. Laser-activated chitosan as a biopolymer anchor provided good TS and appears to be a novel alternative to microsuture. This repair method may have surgical utility following cranial nerve injury during head and neck surgery. LEVEL OF EVIDENCE: NA Laryngoscope, 127:E253 E257, 2017. PMID- 28349573 TI - Where is the Dialectic in the Community-Diversity Dialectic? AB - Agent-based modeling has provided some interesting investigations of the hypothesis that there is a dialectical relationship between sense of community and diversity. A close look at those models strongly suggests that only models in which the attributes of agents are fixed completely support that hypothesis. Models which acknowledge that diversity is contextually defined, and thus changeable, suggest that there is no inherent dialectical relationship between the two values. Rather, it is the context of the setting, the way in which the setting is socially constructed, that determines whether a strong sense of community can exist in highly diverse settings. PMID- 28349574 TI - Antecedents of patients' trust in pharmacists: empirical investigation in the United Arab Emirates. AB - OBJECTIVES: To empirically identify the antecedents that influence patients trust in pharmacists. METHODS: A survey was conducted among 500 patients who visited community pharmacies in Al Ain City, United Arab Emirates. The questionnaire included the measures for constructs such as patients' perception of pharmacist communication, pharmacists' technical competence, medication self-efficacy, satisfaction with pharmacy and trust in pharmacists. KEY FINDINGS: The data were analysed using partial least-squares structural equation modelling approach to check the validity and reliability of the measures and to validate the proposed hypotheses of the study. Pharmacist communication, pharmacists' technical competence, satisfaction with pharmacy and patients' medication self-efficacy were found to significantly influence patients' trust in pharmacists. CONCLUSION: This study is the first one that has empirically identified the antecedents of trust in pharmacists. The study has established that patients' perception of pharmacist communication and pharmacists' technical competence positively influence trust in pharmacists as antecedents but not constitute trust itself as had been found in the previous research. Apart from enhancing pharmacists' technical competence and communication, the pharmacy organizations and policymakers should improve patients' satisfaction with pharmacy and patients' medication self-efficacy to enhance patients' trust in pharmacists. PMID- 28349575 TI - Low-Dose Naloxone for Prophylaxis of Postoperative Nausea and Vomiting: A Systematic Review and Meta-analysis. AB - STUDY OBJECTIVE: To determine whether postoperative administration of low-dose intravenous naloxone decreases the incidence of postoperative nausea and vomiting (PONV) and its impact on postoperative opioid requirements and pain scores. DESIGN: Meta-analysis of nine randomized controlled trials. PATIENTS: A total of 946 adult and pediatric patients who received low-dose intravenous naloxone for 24 hours after various surgeries. MEASUREMENTS AND MAIN RESULTS: Systemic literature searches of the Cochrane Central Register of Controlled Trials, Evidence-Based Medicine Reviews, PubMed, and Ovid MEDLINE databases were conducted. Among the relevant studies, data extraction and bias assessment determined the trials for inclusion in this meta-analysis. Nine randomized controlled trials met inclusion criteria. Naloxone demonstrated a reduced risk of postoperative nausea (risk ratio [RR] 0.80, 95% confidence interval [CI] 0.67 0.95, p=0.01) in a pooled analysis of eight of the nine studies. However, naloxone did not decrease the risk of postoperative vomiting in a collective assessment of all nine trials (RR 0.83, 95% CI 0.63-1.09, p=0.18). Subgroup analysis of continuous-infusion naloxone found further reductions in nausea and vomiting, but these findings were limited to 186 of the 946 patients. Three studies recorded antiemetic doses and found an overall dose reduction (RR 0.64, 95% CI 0.42-0.96, p=0.03). Compared with controls, naloxone prophylaxis of PONV did not significantly change cumulative postoperative opioid needs (mean difference 0.29 mg, 95% CI -3.55 to 4.13 mg, p=0.88) among five trials, nor visual analog scale pain scores (mean difference -0.11, 95% CI -0.26 to 0.05, p=0.18) in six studies. CONCLUSION: This pooled analysis of data suggests that low-dose naloxone plays no role in preventing PONV, while exhibiting no significant effects on postoperative opioid needs and pain scores. The reduction demonstrated in postoperative nausea did not translate into decreases in postoperative vomiting. PMID- 28349576 TI - Transfer of care - a randomised control trial investigating the effect of sending the details of patients' discharge medication to their community pharmacist on discharge from hospital. AB - OBJECTIVE: There is substantial evidence demonstrating that transferring patients between care providers is a high-risk area for medicines management. This study aimed to investigate the effect of sending patients' hospital discharge letters to their nominated community pharmacists on the number of discrepancies between the patient's general practitioner (GP) records and the discharge letter and between the patient's self-described medication regime and the discharge letter. METHODS: In a randomised, controlled trial, 33 participants in two groups, control and intervention, had their discharge letter sent to either their GP only or their GP and nominated community pharmacy after hospital discharge. At least 3 weeks after hospital discharge, the participant's current GP's medication record and their self-described medication regime was obtained. Discrepancies between their GP medication record and their discharge letter and between the participant's self-described medication regime and their discharge letter were counted. The number of discrepancies (relative to the number of drugs prescribed) in the intervention group was compared with the control group for each of the above two categories, using the chi-squared test to determine the statistical significance of any differences between the two groups. RESULTS: The intervention group had statistically fewer discrepancies than the control group for both data sets: GP records compared with the discharge letters (P < 0.0005); participants' self-described medication regimes compared with the discharge letters (P < 0.00005). CONCLUSIONS: Sending a copy of patients' discharge letters to their community pharmacists could be beneficial in reducing post-discharge prescribing discrepancies and improving patient understanding of the changes made to their medicines. PMID- 28349577 TI - Critical appraisal of clinical practice guidelines for adult cancer patients with febrile neutropenia. AB - OBJECTIVES: To critically appraise published international clinical practice guidelines (CPGs) for management of febrile neutropenia in adult patients with cancer and to determine opportunities for improved development and reporting. METHODS: A literature search identified CPGs for adult cancer patients with febrile neutropenia. Four independent assessors evaluated each included CPG according to the Appraisal of Guidelines for Research and Evaluation II instrument. Standardized scores were calculated for each guideline and polled collectively. Reliability of assessment was determined using a two-way random model intraclass correlation coefficients. KEY FINDINGS: Eight CPGs were independently evaluated by four assessors. Collectively, the highest scoring domain was editorial independence (83.3), followed by clarity of presentation (55.4), scope and purpose (53.4), stakeholder involvement (53.1), rigour of development (52.7) and applicability (47.8). Overall assessments ranged from 28.6 to 96.4 of 100 possible points. Three (37.5%) guidelines were recommended for use without alterations, two (25%) guidelines were recommended with alterations, and three (37.5%) guidelines were not recommended for implementation into practice. Reliability varied between guidelines with intraclass correlation coefficients ranging from 0.41 to 0.82. CONCLUSIONS: Clinical practice guidelines for febrile neutropenia in adult patients with cancer were moderately rated with a 37.5% of guidelines being recommended for use in practice. Guideline developers should focus on improving CPG applicability and rigour in the development and reporting processes. Critical appraisal of guidelines should become a standard practice prior to implementation into clinical settings. PMID- 28349578 TI - A randomised control trial to evaluate the clinical pharmacist's role in managing iron deficiency anaemia patients. AB - OBJECTIVE: To investigate the role of clinical pharmacists in managing iron deficiency anaemia patients. METHODS: A prospective parallel randomised controlled trial conducted in an outpatient clinic enrolled adult iron deficiency anaemia patients. Patients were randomised into either an intervention or a control group. Patients in the intervention group were followed closely by a clinical pharmacist who offered pharmaceutical care services and worked closely with physicians to manage iron deficiency anaemia. Patients in the control group received the usual medical care. KEY FINDINGS: One hundred and four patients were enrolled in the study. Eighty-two patients completed the 4-6 week study, with 43 patients in the intervention group and 39 patients in the control group. By the end of the study, 86% of intervention group patients and 59% of control group patients reached their haemoglobin goal values, with statistically significant improvement in intervention group patients versus control group patients (P value = 0.006). Most of the clinical pharmacist's recommendations were adopted by physicians (83.9%). CONCLUSION: Clinical pharmacist interventions improved iron deficiency anaemia patients' outcomes. PMID- 28349579 TI - Periodic olfactory assessment in patients undergoing skull base surgery with preservation of the olfactory strip. AB - OBJECTIVES/HYPOTHESIS: Others have reported olfactory disturbances following endoscopic approaches to the skull base. However, there is a lack of consensus on the extent and duration of dysfunction. This study aimed to compare our results with previously published work and to validate the olfactory strip-sparing approach. STUDY DESIGN: Prospective study to assess olfaction in 50 patients scheduled to undergo resection of skull base tumors via extended endoscopic approaches. METHODS: Patients were divided into two groups. Group I had a nasoseptal flap (NSF), and group II included patients in whom rescue flaps were performed bilaterally. Olfactory outcomes were assessed using repeated University of Pennsylvania Smell Identification Test at baseline, 6 weeks, 3 months, and 6 months following surgery. RESULTS: Ultimately, 42 patients (seven group I and 35 group II) were available for assessment. Scores for group I were lower than at baseline at 6 weeks postoperatively (30.71 +/- 5.5 vs. 24.5 +/- 5.4; P = .05). However, by the third postoperative month the scores had improved to a level that was not significantly different from baseline (29.0 +/- 3.7; P = .5). At 6 months, the score was 30.0 +/- 3.9. Patients in group II showed no difference between their baseline and 6-week scores (31.5 +/- 5.3 vs. 29.7 +/- 5.9; P = .16). Six months postoperatively, the score was significantly higher (33.78 +/- 3.6; P = .04). CONCLUSIONS: Expanded endoscopic approaches to skull base tumors involving reconstruction with an NSF are associated with a short-term negative impact on olfaction. Olfaction does not seem to be affected by the surgical resection of pituitary adenomas associated with rescue flaps. Identification of the olfactory epithelium and meticulous harvesting of the NSF are critical to preserve olfaction. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:1970-1975, 2017. PMID- 28349580 TI - Vicarious pain responders and emotion: Evidence for distress rather than mimicry. AB - Up to a third of the population experiences pain when seeing another in pain. The mechanisms underlying such vicarious sensory experiences are thought to reflect hyperactive mirror systems (threshold theory) or dysfunctional processing and representation of oneself versus others (self/other theory). This study investigated whether the tendency to experience vicarious pain corresponds to disinhibited physiological reactivity toward other's emotions, and/or greater empathic mimicry of other's physiological state (respiratory behavior) during fear, pain, and positive emotion. Fifty healthy individuals aged 18-55 years (23 vicarious pain responders) completed empathy- and anxiety-related questionnaires, and a film task. Respiration was measured noninvasively with piezoelectric respiration belts while participants viewed emotional film clips depicting three emotions (fear/pain/positive) interspersed with neutral clips. The emotional stimuli depicted scenes in which the characters showed increases or decreases in respiration. The results suggest that vicarious pain responders do not mimic emotional respiratory behavior. Rather, vicarious pain responders had a significantly slower respiration rate for all emotional stimuli (MDiff = 1.40 respiratory cycles, SE = .68), compared to nonresponders. However, this was associated with heightened trait anxiety. The findings suggest vicarious pain is associated with acute distress, rather than empathic mimicry of the emotional states of another. PMID- 28349581 TI - TCF1 deficiency ameliorates autoimmune lymphoproliferative syndrome (ALPS)-like phenotypes of lpr/lpr mice. AB - Autoimmune lymphoproliferative syndrome (ALPS) is an incurable disease, which is characterized by non-malignant autoimmune lymphoproliferation. TCF1 is a key effector in the canonical Wnt/beta-catenin pathway, regulating the development, activation and function of T cells. In this study, we aimed to explore the potential role of TCF1 in the development of ALPS-like phenotypes of lpr/lpr mice. We acquired TCF1-/- lpr/lpr double mutant mice by crossing TCF1 deficiency mice with lpr/lpr mice. Splenocyte compositions, serum cytokines levels, antidsDNA antibody production and kidney pathology were examined in the TCF1-/- lpr/lpr mice. With these examinations, we revealed that TCF1 deficiency relieved most manifestations of ALPS-like phenotype, which were caused by Fas mutation in TCF1-/- lpr/lpr mice. Splenocyte total numbers and compositions were downregulated to the similar levels with wildtype mice. TE and TEM cells were decreased in TCF1-/- lpr/lpr compared with lpr/lpr mice. The levels of autoantibodies and proinflammatory factors in serum, and the histopathology changes and the relative mRNA levels of proinflammatory factors in kidney all displayed parallel tendency in TCF1-/- lpr/lpr mice. Our study demonstrated that TCF1 deficiency ameliorated the ALPS-like phenotypes of TCF1-/- lpr/lpr mice, which might indicate a potential therapeutic direction for ALPS. PMID- 28349582 TI - ERP evidence for conflict in contingency learning. AB - The proportion congruency effect refers to the observation that the magnitude of the Stroop effect increases as the proportion of congruent trials in a block increases. Contemporary work shows that proportion effects can be driven by both context and individual items, and are referred to as context-specific proportion congruency (CSPC) and item-specific proportion congruency (ISPC) effects, respectively. The conflict-modulated Hebbian learning account posits that these effects manifest from the same mechanism, while the parallel episodic processing model posits that the ISPC can occur by simple associative learning. Our prior work showed that the neural correlates of the CSPC is an N2 over frontocentral electrode sites approximately 300 ms after stimulus onset that predicts behavioral performance. There is strong consensus in the field that this N2 signal is associated with conflict detection in the medial frontal cortex. The experiment reported here assesses whether the same qualitative electrophysiological pattern of results holds for the ISPC. We find that the spatial topography of the N2 is similar but slightly delayed with a peak onset of approximately 300 ms after stimulus onset. We argue that this provides strong evidence that a single common mechanism-conflict-modulated Hebbian learning drives both the ISPC and CSPC. PMID- 28349584 TI - Trypanoxyuris (Trypanoxyuris) minutus (Schneider, 1866) among Alouatta guariba clamitans (Cabrera, 1940) in the state of Rio de Janeiro, Brazil. AB - This study reports on infection by Trypanoxyuris (Trypanoxyuris) minutus among Alouatta guariba clamitans through biometry on adults and eggs. A total of 58 adult helminths were recovered from the small segment of the animal's large intestine. This study is the first report of this parasite among A. guariba clamitans in Rio de Janeiro. PMID- 28349583 TI - A general framework for the regression analysis of pooled biomarker assessments. AB - As a cost-efficient data collection mechanism, the process of assaying pooled biospecimens is becoming increasingly common in epidemiological research; for example, pooling has been proposed for the purpose of evaluating the diagnostic efficacy of biological markers (biomarkers). To this end, several authors have proposed techniques that allow for the analysis of continuous pooled biomarker assessments. Regretfully, most of these techniques proceed under restrictive assumptions, are unable to account for the effects of measurement error, and fail to control for confounding variables. These limitations are understandably attributable to the complex structure that is inherent to measurements taken on pooled specimens. Consequently, in order to provide practitioners with the tools necessary to accurately and efficiently analyze pooled biomarker assessments, herein, a general Monte Carlo maximum likelihood-based procedure is presented. The proposed approach allows for the regression analysis of pooled data under practically all parametric models and can be used to directly account for the effects of measurement error. Through simulation, it is shown that the proposed approach can accurately and efficiently estimate all unknown parameters and is more computational efficient than existing techniques. This new methodology is further illustrated using monocyte chemotactic protein-1 data collected by the Collaborative Perinatal Project in an effort to assess the relationship between this chemokine and the risk of miscarriage. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28349585 TI - Real-time continuous image-guided surgery: Preclinical investigation in glossectomy. AB - OBJECTIVES/HYPOTHESIS: To develop, validate, and study the efficacy of an intraoperative real-time continuous image-guided surgery (RTC-IGS) system for glossectomy. STUDY DESIGN: Prospective study. METHODS: We created a RTC-IGS system and surgical simulator for glossectomy, enabling definition of a surgical target preoperatively, real-time cautery tracking, and display of a surgical plan intraoperatively. System performance was evaluated by a group of otolaryngology residents, fellows, medical students, and staff under a reproducible setting by using realistic tongue phantoms. Evaluators were grouped into a senior and a junior group based on surgical experience, and guided and unguided tumor resections were performed. National Aeronautics and Space Administration Task Load Index (NASA-TLX) scores and a Likert scale were used to measure workloads and impressions of the system, respectively. Efficacy was studied by comparing surgical accuracy, time, collateral damage, and workload between RTC-IGS and non navigated resections. RESULTS: The senior group performed more accurately (80.9% +/- 3.7% vs. 75.2% +/- 5.5%, P = .28), required less time (5.0 +/- 1.3 minutes vs. 7.3 +/- 1.2 minutes, P = .17), and experienced lower workload (43 +/- 2.0 vs. 64.4 +/- 1.3 NASA-TLX score, P = .08), suggesting a trend of construct validity. Impressions were favorable, with participants reporting the system is a valuable practice tool (4.0/5 +/- 0.3) and increases confidence (3.9/5 +/- 0.4). Use of RTC-IGS improved both groups' accuracy, with the junior group improving from 64.4% +/- 5.4% to 75.2% +/- 5.5% (P = .01) and the senior group improving from 76.1% +/- 4.5% to 80.9% +/- 3.7% (P = .16). CONCLUSIONS: We created an RTC-IGS system and surgical simulator and demonstrated a trend of construct validity. Our navigated simulator allows junior trainees to practice glossectomies outside the operating room. In all evaluators, navigation assistance resulted in increased surgical accuracy. LEVEL OF EVIDENCE: NA Laryngoscope, 127:E347-E353, 2017. PMID- 28349586 TI - Transfemoral access when superior venous approach is not feasible equals overall success of permanent pacemaker implantation. Ten-year series. AB - BACKGROUND: When permanent pacemaker implantation is not possible or advisable via superior venous access (i.e., axillary or subclavian veins), safe and feasible surgical alternatives are required. The femoral approach is relatively unknown and seldom studied. This single-center study analyzed 10-year outcomes of a femoral implantation approach. METHODS: Data about the implantation procedure (indication, approach, lead and pacemaker models, complications), patient characteristics (age, sex, medications, comorbidities), and follow-up were analyzed for all permanent pacemaker implantations using the femoral approach between June 2001 and June 2011. RESULTS: A permanent pacemaker was implanted with the femoral approach in 50 patients (mean age, 76 years [range: 45-96], 31 [61%] men). The most frequent indication was atrioventricular block, associated with sinus rhythm in 30 patients and with atrial fibrillation in eight patients. Overall, 20 patients (40%) were treated with oral anticoagulants postimplantation. Mean implantation time was 64 minutes (range: 20-210) and mean fluoroscopy time was 6.7 minutes (range: 0.2-50). Minimum follow-up window was 1 year (June 2012), with a mean of 50 months [range: 1-113]). No deaths, septic episodes, or severe complications were associated with the procedure, acute or long-term. Follow-up data were available for 46 patients, of who 21 (46%) died during follow-up (mean age, 87 years [range: 73-101]). No cause of death was associated with the femoral technique. CONCLUSION: Permanent pacemaker implantation through femoral access is not difficult for an experienced implant surgeon. Outcomes were comparable to systems implanted by superior venous approach, and no severe complications were observed at 10-year follow-up. PMID- 28349587 TI - Lycium barbarum polysaccharide extracts preserve retinal function and attenuate inner retinal neuronal damage in a mouse model of transient retinal ischaemia. AB - BACKGROUND: Retinal ischaemia is a common feature shared by numerous eye diseases. Ischaemic insult leads to retinal dysfunction and neuronal death. Lycium barbarum polysaccharides are well known for eyesight preservation. We have previously reported the effect of Lycium barbarum polysaccharides on cell death, blood ocular barrier and oxidative stress within 24 h retinal ischaemia. This study focuses on retinal function and looks for ultrastructural and cellular correlates after a relatively long period of reperfusion for 7 days. METHODS: Two hour ischaemia was induced by intraluminal occlusion of the internal carotid artery. Either Lycium barbarum polysaccharides or phosphate-buffered saline was orally pre-administered daily for 7 days before ischaemia and continued for 1, 3 and 7 days after reperfusion. Electroretinogram was performed to evaluate visual function. Paraffin-embedded retinal sections were prepared 7 days after reperfusion and utilized for histological and immunohistochemical analyses. RESULTS: Ischaemia led to sustained inhibition of b-wave amplitude and oscillatory potentials. Lycium barbarum polysaccharide-treated mice exhibited greater b-wave and oscillatory potential responses from days 1 to 7 after reperfusion. In addition, increased number of viable cells and calretinin positive cells, as well as enhanced immunoreactivity of protein kinase C alpha and attenuated glial fibrillary acidic protein expression, was noted in Lycium barbarum polysaccharide-treated retina. CONCLUSIONS: Daily consumption of Lycium barbarum polysaccharides effectively alleviated ischaemia-induced retinal dysfunction as well as reduced correlated neuronal death and glial activation. This prolonged effect could last at least 7 days. It suggested that Lycium barbarum polysaccharides might serve as a neuroprotective agent in ischaemic retinopathies. PMID- 28349589 TI - A general framework for effectiveness concepts in mutualisms. AB - A core interest in studies of mutualistic interactions is the 'effectiveness' of mutualists in providing benefits to their partners. In plant-animal mutualisms it is widely accepted that the total effect of a mutualist on its partner is estimated as (1) a 'quantity' component multiplied by (2) a 'quality' component, although the meanings of 'effectiveness,' 'quantity,' and 'quality' and which terms are applied to these metrics vary greatly across studies. In addition, a similar quantity * quality = total effect approach has not been applied to other types of mutualisms, although it could be informative. Lastly, when a total effect approach has been applied, it has invariably been from a phytocentric perspective, focussing on the effects of animal mutualists on their plant partner. This lack of a common framework of 'effectiveness' of mutualistic interactions limits generalisation and the development of a broader understanding of the ecology and evolution of mutualisms. In this paper, we propose a general framework and demonstrate its utility by applying it to both partners in five different types of mutualisms: pollination, seed dispersal, plant protection, rhizobial, and mycorrhizal mutualisms. We then briefly discuss the flexibility of the framework, potential limitations, and relationship to other approaches. PMID- 28349588 TI - ADH1B: From alcoholism, natural selection, and cancer to the human phenome. AB - The ADH1B (Alcohol Dehydrogenase 1B (class I), Beta Polypeptide) gene and its best-known functional alleles, Arg48His (rs1229984, ADH1B*2) and Arg370Cys (rs2066702, ADH1B*3), have been investigated in relation to many phenotypic traits; most frequently including alcohol metabolism and alcohol drinking behaviors, but also human evolution, liver function, cancer, and, recently, the comprehensive human phenome. To understand ADH1B functions and consequences, we provide here a bioinformatic analysis of its gene regulation and molecular functions, literature review of studies focused on this gene, and a discussion regarding future research perspectives. Certain ADH1B alleles have large effects on alcohol metabolism, and this relationship particularly encourages further investigations in relation to alcoholism and alcohol-associated cancer to understand better the mechanisms by which alcohol metabolism contributes to alcohol abuse and carcinogenesis. We also observed that ADH1B has complex mechanisms that regulate its expression across multiple human tissues, and these may be involved in cardiac and metabolic traits. Evolutionary data strongly suggest that the selection signatures at the ADH1B locus are primarily related to effects other than those on alcohol metabolism. This is also supported by the involvement of ADH1B in multiple molecular pathways and by the findings of our recent phenome-wide association study. Accordingly, future studies should also investigate other functions of ADH1B potentially relevant for the human phenome. (c) 2017 Wiley Periodicals, Inc. PMID- 28349591 TI - Consolidating Molecular Logic with New Solid-Bound YES and PASS 1 Gates and Their Combinations. AB - Proton-driven YES and PASS 1 molecular logic tags based on anthracene and 4 aminonaphthalimide fluorophores, emitting blue and green, respectively, are employed on amino-terminated polyethylene glycol-polystyrene and aminopropyl silica particles. The (YES+PASS 1) logic combination is also a distinguishable tag in both colours. The scope of such tags is delineated. PMID- 28349590 TI - Benzalkonium Chloride: A Bronchoconstricting Preservative in Continuous Albuterol Nebulizer Solutions. AB - For convenience, many pediatric hospitals are preparing solutions for continuous nebulized albuterol using the 0.5% 20-ml multidose albuterol dropper bottle. This product contains benzalkonium chloride (BAC) that, by itself, produces bronchospasm that is dose dependent and cumulative. The bronchoconstrictive effects of BAC are greater in patients with more severe airway obstruction and increased airway responsiveness. Use of BAC-containing albuterol during severe acute asthma exacerbations may antagonize the bronchodilator response to albuterol, prolong treatment, and increase the risk of albuterol-related systemic adverse effects. Such a deleterious effect of BAC is difficult to detect because some patients improve slowly or may even worsen during treatment. We recommend that only preservative-free albuterol products be used. PMID- 28349592 TI - Clinical impact of surveillance colonoscopy using magnification without diminutive polyp removal. AB - BACKGROUND AND AIM: In Western countries, endoscopic removal of all adenomas during colonoscopy is recommended. The present study evaluates the usefulness of magnifying colonoscopy without removal of diminutive (<=5 mm) colorectal polyps. METHODS: Patients with diminutive polyps who were observed for over 5 years using magnification at Hiroshima University Hospital were selected retrospectively. Lesions >=6 mm in size, depressed lesions, and lesions with type V pit pattern were indications for endoscopic resection. We investigated the characteristics of lesions indicated for endoscopic resection detected on surveillance colonoscopy and the risk factors for the incidence of lesions indicated for endoscopic resection. RESULTS: A total of 706 consecutive patients were enrolled. Sixty eight lesions indicated for endoscopic resection were detected, averaging 9.0 +/- 4.8 mm, and 33 (49%) lesions were located in the right colon. Pathological diagnoses were adenoma, Tis carcinoma, and T1 carcinoma in 58 (85%), eight (12%), and two (3%) lesions, respectively. Five lesions were considered to grow from previously detected diminutive polyps. Relative risks for the incidence of a lesion indicated for endoscopic resection were 1.76 (95% confidence interval [CI], 1.004-3.23) for males compared with females, 3.76 (95% CI, 2.03-7.50) for more than three polyps at initial colonoscopy compared with one polyp, and 2.84 (95% CI, 1.43-5.24) for patients with carcinoma at initial colonoscopy compared with patients with no lesion indicated for endoscopic resection. Nine carcinomas were resected endoscopically. CONCLUSION: Diminutive low-grade adenomas detected by using magnifying colonoscopy may not necessarily require removal. PMID- 28349593 TI - Critical role of environmental factors in the pathogenesis of psoriasis. AB - Psoriasis is a common cutaneous disease with multifactorial etiology including genetic and non-genetic factors, such as drugs, smoking, drinking, diet, infection and mental stress. Now, the role of the interaction between environmental factors and genetics are considered to be a main factor in the pathogenesis of psoriasis. However, it is a challenge to explore the mechanisms how the environmental factors break the body balance to affect the onset and development of psoriasis. In this article, we review the pathogenesis of psoriasis and summarize numerous clinical data to reveal the association between environmental factors and psoriasis. In addition, we focus on the mechanisms of environmental risk factors impact on psoriasis and provide a series of potential treatments against environmental risk factors. PMID- 28349594 TI - Perceived swallowing problems and mortality risk in very elderly people >=85 years old: Results of the Tokyo Oldest Old Survey on Total Health study. AB - OBJECTIVE: The aim of this study was to clarify whether perceived swallowing problems affect the life expectancy of very elderly individuals. BACKGROUND: In an ageing society, oral function affects health status. In particular, a decline in swallowing function may increase the risk of various diseases, morbidity and malnutrition. MATERIALS AND METHODS: We evaluated 526 elderly individuals aged >=85 years. All participants completed a questionnaire and underwent oral, physical and mental health examinations. The comprehensive oral health assessment comprised a face-to-face interview that included a questionnaire on swallowing function. We estimated hazard ratios and 95% confidence intervals using the Cox proportional hazards model, adjusting for potential confounders between perceived swallowing problems and all-cause mortality over a 3-year period. RESULTS: Over a 3-year follow-up period, 88 of 526 participants died and 68 participants complained of perceived swallowing problems. Perceived swallowing problems had statistically significant associations with physical status and function and nutrition. In the univariate analysis, perceived swallowing problems had statistically significant associations with an approximately 1.9-fold higher risk of all-cause mortality during the 3-year period (HR: 1.89, 95% CI: 1.14-3.14). In the multivariate analysis, the statistically significant association between perceived swallowing problems and all-cause mortality remained after adjusting for various confounding factors (HR: 1.73, 95% CI: 1.03-2.92). CONCLUSION: Perceived swallowing disorders should be verified by a clinical examination, as they are associated with other health outcomes and increased all-cause mortality. PMID- 28349595 TI - Spatiotemporal modulation of abscisic acid and gibberellin metabolism and signalling mediates the effects of suboptimal and supraoptimal temperatures on seed germination in wheat (Triticum aestivum L.). AB - Seed germination is a complex process regulated by intrinsic hormonal cues such as abscisic acid (ABA) and gibberellin (GA), and environmental signals including temperature. Using pharmacological, molecular and metabolomics approaches, we show that supraoptimal temperature delays wheat seed germination through maintaining elevated embryonic ABA level via increased expression of ABA biosynthetic genes (TaNCED1 and TaNCED2), increasing embryo ABA sensitivity through upregulation of genes regulating ABA signalling positively (TaPYL5, TaSnRK2, ABI3 and ABI5) and decreasing embryo GA sensitivity via induction of TaRHT1 that regulates GA signalling negatively. Endospermic ABA and GA appeared to have minimal roles in regulating germination at supraoptimal temperature. Germination inhibition by suboptimal temperature is associated with elevated ABA level in the embryo and endosperm tissues, mediated by induction of TaNCEDs and decreased expression of endospermic ABA catabolic genes (TaCYP707As), and increased ABA sensitivity in both tissues via upregulation of TaPYL5, TaSnRK2, ABI3 and ABI5 in the embryo and TaSnRK2 and ABI5 in the endosperm. Furthermore, suboptimal temperature suppresses GA synthesis in both tissues and GA sensitivity in the embryo via repressing GA biosynthetic genes (TaGA20ox and TaGA3ox2) and inducing TaRHT1, respectively. These results highlight that spatiotemporal modulation of ABA and GA metabolism and signalling in wheat seeds underlies germination response to temperature. PMID- 28349596 TI - B1 -sensitivity analysis of quantitative magnetization transfer imaging. AB - PURPOSE: To evaluate the sensitivity of quantitative magnetization transfer (qMT) fitted parameters to B1 inaccuracies, focusing on the difference between two categories of T1 mapping techniques: B1 -independent and B1 -dependent. METHODS: The B1 -sensitivity of qMT was investigated and compared using two T1 measurement methods: inversion recovery (IR) (B1 -independent) and variable flip angle (VFA), B1 -dependent). The study was separated into four stages: 1) numerical simulations, 2) sensitivity analysis of the Z-spectra, 3) healthy subjects at 3T, and 4) comparison using three different B1 imaging techniques. RESULTS: For typical B1 variations in the brain at 3T (+/-30%), the simulations resulted in errors of the pool-size ratio (F) ranging from -3% to 7% for VFA, and -40% to > 100% for IR, agreeing with the Z-spectra sensitivity analysis. In healthy subjects, pooled whole-brain Pearson correlation coefficients for F (comparing measured double angle and nominal flip angle B1 maps) were rho = 0.97/0.81 for VFA/IR. CONCLUSION: This work describes the B1 -sensitivity characteristics of qMT, demonstrating that it varies substantially on the B1 -dependency of the T1 mapping method. Particularly, the pool-size ratio is more robust against B1 inaccuracies if VFA T1 mapping is used, so much so that B1 mapping could be omitted without substantially biasing F. Magn Reson Med 79:276-285, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28349597 TI - A brief pictorial and historical introduction to guaiacum - from a putative cure for syphilis to an actual screening method for colorectal cancer. PMID- 28349598 TI - Ultra-light extensometer for the assessment of the mechanical properties of the human skin in vivo. AB - BACKGROUND/PURPOSE: This paper aims to present an ultra-light extensometer device dedicated to the mechanical characterization of the human skin in vivo. METHODS: The device developed was conceived to be non-invasive, to work without any stand and to perform various uniaxial tensile tests with either effort or displacement control. We also use specific guarding tabs to make in vivo extension tests analogous to traction tests. RESULTS: Force-displacement curves are derived from the data provided by the device's sensors. The latter are converted into stress strain curves thanks to complementary measurements of the skin thickness. We present typical experimental data and results that demonstrate the device ability to built stress-strain curves characteristic of the human skin behavior. An additional imaging unit records a sequence of images of the solicited skin area for further calculations of the displacement fields by digital image correlation. CONCLUSION: The analysis of the displacement and deformation fields validates the guarding tab efficiency and the capacity of the device to characterize the mechanical behavior of the human skin in vivo. PMID- 28349599 TI - Evaluation of the restricted virtual space approximation in the algebraic diagrammatic construction scheme for the polarization propagator to speed-up excited-state calculations. AB - The applicability and limitations of the restricted virtual space (RVS) approximation within the algebraic-diagrammatic construction (ADC) scheme for the polarization propagator up to third order is evaluated. In RVS-ADC, not only the core but also a substantial amount of energetically high-lying virtual orbitals is restricted in excitation energy calculations of low-lying excited electronic states. Using octatetraene, indole, and pyridine as representative examples and different standard basis sets of triple-zeta quality, RVS-ADC(2) turns out to be highly useful and to have negligible effects on pipi* excited states. However, for npi* or pisigma* states, the RVS approximation is generally less reliable but better at third-order than second-order ADC level. In addition, a unified, basis set independent, thus normalized virtual orbital threshold (value) is introduced, making the RVS approximation more controllable and a priori applicable. (c) 2017 Wiley Periodicals, Inc. PMID- 28349600 TI - Importance of Inherent Substrate Reactivity in Enzyme-Promoted Carbocation Cyclization/Rearrangements. AB - The importance of inherent substrate reactivity for terpene synthase enzymes is discussed, with a focus on recent experimental tests of predictions derived from computations on gas-phase reactivity of carbocations. PMID- 28349601 TI - Guided bone regeneration of non-contained mandibular buccal bone defects using deproteinized bovine bone mineral and a collagen membrane: an experimental in vivo investigation. AB - AIM: The aim of this pre-clinical in vivo study was to analyse different stages of wound healing after guided bone regeneration in non-contained mandibular buccal bone defects. MATERIALS AND METHODS: Eighteen female beagle dogs, between 1.5 and 2 years old, were used. Buccal bone defects were created in the mandible following extraction of the mesial roots of M1, P4, the distal root of P3 and booth roots of P2. Augmentation procedures of the healed defects were performed 3 months later using a bone replacement graft (T1), an absorbable collagen membrane (T2) or a combination of both procedures (T3). Using a randomized block study design, four stages of healing in two groups of dogs were examined (4 days, 2, 6 weeks and 3 months). The animals were euthanized, and biopsies obtained at the end of each of the study periods were prepared for histological examination. RESULTS: The different reconstructive procedures resulted in regenerated tissue compartments of varying size that contained newly formed bone, non-mineralized tissue and bone augmentation biomaterial when a bone replacement graft was used. While the proportions of mineralized tissue increased and non-mineralized tissue decreased over time in the three groups, the changes in proportions of the DBBM material were small. Initial defect depth, healing time and treatment group significantly influenced the percentage of mineralized tissue obtained. The multivariate multilevel analysis showed that significantly larger area proportions of mineralized tissue were obtained when the T2 sites were compared with T1 and T3 sites, what highlights the importance of the barrier membrane effect for attaining new bone formation. Only in the larger size defects (M1) total ROI at T3 and T1 sites was significantly larger than at T2, what highlights the importance of using a bone replacement graft as a space maintenance scaffold. CONCLUSION: It is suggested that healing following augmentation of non-contained buccal bone defects was characterized by a gradual shift in the relative proportions of non-mineralized and mineralized tissue components. PMID- 28349602 TI - Development of an improved online comprehensive hydrophilic interaction chromatography * reversed-phase ultra-high-pressure liquid chromatography platform for complex multiclass polyphenolic sample analysis. AB - In this study, an improved online comprehensive two-dimensional liquid chromatography platform coupled to tandem mass spectrometry was developed for the analysis of complex polyphenolic samples. A narrowbore hydrophilic interaction chromatography column (150 * 2.0 mm, 3.0 MUm, cross-linked diol) was employed in the first dimension, while a reversed-phase column based on monodisperse sub-2 MUm fully porous particles (50 * 3.0 mm, 1.9 MUm d.p.) with high surface area (410 m2 /g) was employed in the second dimension. The combination of a trapping column modulation interface with the high retentive fully porous monodisperse reversed-phase column in the second dimension resulted in higher peak capacity values (1146 versus 867), increased sensitivity, sharper and more symmetrical peaks in comparison with a conventional loop-based method, with the same analysis time (70 min). The system was challenged against a complex polyphenolic extract of a typical Italian apple cultivar, enabling the simultaneous separation of multiple polyphenolic classes, including oligomeric procyanidins, up to degree of polymerization of 10. Hyphenation with an ion trap time-of-flight mass spectrometer led to the tentative identification of 121 analytes, showing how this platform could be a powerful analytical tool for the accurate profiling of complex polyphenolic samples. PMID- 28349603 TI - Ultrasound is an effective and noninvasive method of evaluating renal swelling in infants with their first urinary tract infection. AB - AIM: This study evaluated renal swelling in infants with a first urinary tract infection (UTI) by correlating renal length and volume with C-reactive protein (CRP) and body temperature. METHODS: Ultrasounds were carried out on 104 infants at The Queen Silvia Children's Hospital, Gothenburg, Sweden - 58 boys (mean age 3.3 months) and 46 girls (mean age 4.8 months) - during the acute phase of their UTI. A second scan was performed on 94 of them 4 weeks later. Renal length and volume were computed to standard deviation scores (SDS). RESULTS: The mean renal length and volume at the first ultrasound were 1.90 SDS (+/-1.54) and 1.67 SDS (+/-1.13) for the larger kidney and 0.86 SDS (+/-1.01) and 0.84 SDS (+/-0.90) for the smaller kidney. There was a significant decrease in renal length and volume between the two ultrasounds, with a mean difference of 0.96 SDS (+/-1.24) and 1.07 SDS (+/-1.10) for the larger kidney (p < 0.0001). The length and volume of the larger kidney correlated with CRP (p < 0.001), but only the renal length correlated with fever (p < 0.001). CONCLUSION: Early ultrasound determined renal swelling in infants with a UTI and may be a valuable noninvasive way of identifying infants with renal parenchymal involvement. PMID- 28349604 TI - Depression Treatment by Non-Mental-Health Providers: Incremental Evidence for the Effectiveness of Listening Visits. AB - Maternal depression is a prevalent public health problem, particularly for low income mothers of young children. Intervention development efforts, which often focus on surmounting instrumental barriers to care, have not successfully engaged and retained women in treatment. Task-sharing approaches like Listening Visits (LV) could overcome key instrumental and psychological barriers by leveraging the access of trusted, community caregivers to deliver treatment. A recent randomized controlled trial (RCT) demonstrated the efficacy of LV delivered by non-mental health providers as compared to usual care. The present report presents results from a follow-up phase of that RCT during which participants who had completed LV were followed for an additional 8 weeks and completed measures of depression and quality of life. In addition, participants who were initially randomized to the wait-list control group received LV and were assessed. Treatment gains previously observed in participants completing LV were enhanced during the 8-week follow-up period. Participants receiving LV during the follow-up period experienced significant improvement in depressive symptoms. Results demonstrate the sustainability of LV delivered by non-mental-health providers, and provide preliminary evidence for the replicability of this approach in a sample of predominately low-income pregnant women and mothers of young children. PMID- 28349605 TI - Predictors of Premature Match Closure in Youth Mentoring Relationships. AB - Although mentoring is a popular and effective means of intervention with youth, the positive effects of mentoring can be diminished by premature match closure of relationships. Program, mentor, and mentee characteristics were examined as predictors of premature match closure. Secondary data analyses were conducted on a large national database of mentoring programs consisting of match and youth risk information from 170 mentoring programs and 6468 matches from across the U.S. Premature closure was associated with mentee age at match inception and 19 individual mentee characteristics. The set of mentee characteristics were examined as part of a cumulative risk index encompassing seven conceptually combined categories including family background characteristics, school functioning problems, engagement in risky health behaviors, self-regulation difficulties, engagement in illegal or criminal activities, and internalizing and externalizing behavior problems. Both the age of mentees when matched and the cumulative risk index score significantly predicted premature closure. Results are discussed in terms of directions for future research and suggestions for enhancing mentoring program practices. PMID- 28349606 TI - From Moment to Movement: Empowerment and Resilience as a Framework for Collective Action in Hong Kong. AB - The Transconceptual Model of Empowerment and Resilience (American Journal of Community Psychology, 52, 2013, 333) suggests that a set of resilience and empowerment resources fuel both initial and sustained participation in collective action. Using the case study of a prodemocracy movement in Hong Kong, the present study focused on the subset of those resources that are relevant in ongoing collective action: efficacy, skills, and maintenance. As individuals possess varying combinations of these resources, the present study utilized latent profile analysis to test how patterns of empowerment and resilience resources influence initial and long-term collective action. Five groups were identified: (a) Uncommitted/Uninspired; (b) Committed to Status Quo; (c) Mainstream Populist; (d) Empowered; and (e) Ambivalent. ANOVA and ANCOVA analyses found that there are significant group differences in initial and long-term participation. Groups with higher level of resources reported greater levels of initial participation than their counterparts; however, high resource groups did not uniformly report greater levels of intention to participate in future collective action. Of the maintenance processes tested, collective identity emerged as a particularly important predictor differentiating initial and sustained participation. Findings from the present study raise questions about how individuals with multiple identities can come together and participate in collective action. PMID- 28349607 TI - Predicting the Emergence of Community Psychology and Community Development in 91 Countries with Brief Case Studies of Chile and Ghana. AB - Using a mixed-method analysis, we propose and test a framework for predicting the international development of community psychology (CP) and community development (CD) as two examples of applied community-based research (CBR) disciplines aiming to link local knowledge generation with social change. Multiple regressions on an international sample of 91 countries were used to determine the relative influences of preexisting grassroots activism, population size, social and economic development, and civil liberties on estimates of the current strength of CP and CD based on Internet search and review of training courses and programs, published articles and journals, and professional organizations and conferences in these countries. Our results provide support for the proposed model and suggest that grassroots activism positively accounts for the development of CP and CD, above and beyond the influences of the other predictors. Brief qualitative case-study analyses of Chile (high CP, low CD) and Ghana (high CD, low CP) explore the limitations of our quantitative model and the importance of considering other historical, sociopolitical, cultural, and geographic factors for explaining the development of CP, CD, and other applied community studies. PMID- 28349609 TI - Correction. PMID- 28349608 TI - Organic Microporous Nanofillers with Unique Alcohol Affinity for Superior Ethanol Recovery toward Sustainable Biofuels. AB - To minimize energy consumption and carbon footprints, pervaporation membranes are fast becoming the preferred technology for alcohol recovery. However, this approach is confined to small-scale operations, as the flux of standard rubbery polymer membranes remain insufficient to process large solvent volumes, whereas membrane separations that use glassy polymer membranes are prone to physical aging. This study concerns how the alcohol affinity and intrinsic porosity of networked, organic, microporous polymers can simultaneously reduce physical aging and drastically enhance both flux and selectivity of a super glassy polymer, poly [1-(trimethylsilyl)propyne] (PTMSP). Slight loss in alcohol transportation channels in PTMSP is compensated by the alcohol affinity of the microporous polymers. Even after continuous exposure to aqueous solutions of alcohols, PTMSP pervaporation membranes loaded with the microporous polymers outperform the state of-the-art and commercial pervaporation membranes. PMID- 28349610 TI - One Versatile Route to Three-Dimensional Graphene Wrapped Metal Cyanide Aerogels for Enhanced Sodium Ion Storage. AB - Facile and controllable integration of metal cyanides (MCs) into three dimensional graphene (3DG) with advantageous structures is of fundamental importance for the development of superior MC-based electrode materials for electrochemical energy storage and catalysis. Here a facile and versatile spatially-confined Ostwald ripening strategy was developed to synthesize a series of 3DG wrapped MC aerogels with different compositions, size, and structure based on the chemical instability of MC in the reaction system. Remarkably, the integration of Prussian blue (PB) into 3DG, with such unique architecture, largely improves the rate performance and long-term cycling stability of PB as a cathode material for sodium ion batteries. PMID- 28349611 TI - Ion cum molecularly dual imprinted polymer for simultaneous removal of cadmium and salicylic acid. AB - Ion cum molecularly dual imprinted polymer (DMIP) was synthesized for the simultaneous removal of salicylic acid (SA) and cadmium (Cd) by suspension polymerization method using chitosan (CTS) as functional polymer, epichlorohydrin as cross-linker, and 4-hydroxy benzoic acid (4HBA) as well as Cd as organic and inorganic templates, respectively. Use of the dummy template 4HBA during the synthesis of DMIP had the advantage of creating imprinted cavities in DMIP, which depicted good uptake for SA. Scanning electron microscopy and Fourier transform infrared spectroscopy indicated successful preparation of DMIP. Particle size analysis confirmed polydispersity, and thermal and swelling studies indicated the mechanical stability in DMIP. The rebinding capacities of the DMIP for Cd and SA were found to be 38.46 and 23.81 mgg-1 , respectively, under the optimize condition of the time, dose, and concentration. Adsorption isotherm results fitted into Langmuir adsorption isotherm model with the R2 values of 0.994 and 0.995 for Cd and SA, respectively. The presence of intramolecular hydrogen bonding in SA, stability of the template-monomer complexes (CTS-SA and CTS-4HBA), and the involvement of the hydroxyl groups on DMIP for the uptake of SA has been supported by molecular modeling studies using Gaussian 03 software. The electron doublet of the amino groups of DMIP was involved for the uptake of Cd. Lower binding efficiency of DMIP for SA as compared to Cd may be due to the partial participation of hydroxyl group in cross-linking with epichlorohydrin during the synthesis of DMIP. PMID- 28349612 TI - Efficacy of hyperbaric oxygen therapy in patients with radiation-induced rectal ulcers: Report of five cases. AB - For decades, hyperbaric oxygen therapy has been considered a treatment option in patients with chronic radiation-induced proctitis after pelvic radiation therapy. Refractory cases of chronic radiation-induced proctitis include ulceration, stenosis, and intestinal fistulas with perforation. Appropriate treatment needs to be given. In the present study, we assessed the efficacy of hyperbaric oxygen therapy in five patients with radiation-induced rectal ulcers. Significant improvement and complete ulcer resolution were observed in all treated patients; no side-effects were reported. Hyperbaric oxygen therapy has a low toxicity profile and appears to be highly effective in patients with radiation-induced rectal ulcers. However, hyperbaric oxygen therapy alone failed to improve telangiectasia and easy bleeding in four of the five patients; these patients were further treated with argon plasma coagulation (APC). Although hyperbaric oxygen therapy may be effective in healing patients with ulcers, it seems inadequate in cases with easy bleeding. Altogether, these data suggest that combination therapy with hyperbaric oxygen therapy and APC may be an effective and safe treatment strategy in patients with radiation-induced rectal ulcers. PMID- 28349613 TI - Prospective evaluation of digital single-operator cholangioscope for diagnostic and therapeutic procedures (with videos). AB - BACKGROUND AND AIM: Recently, the digital single-operator cholangioscope (SPY-DS) has become available. This system may allow diagnosis by direct visualization and allow performance of various therapeutic procedures. The aim of the present study was to prospectively evaluate the clinical utility of DSOCS for diagnostic and therapeutic procedures for biliary disease. METHODS: Technical success was defined as successful visualization of target lesions in the biliary tract and carrying out forceps biopsy as a diagnostic procedure, and successfully carrying out treatment such as guidewire insertion for the area of interest, electrohydraulic lithotripsy (EHL), or migrated stent removal. Also, the present study aimed at investigating diagnostic yield of the cholangioscopic findings and biopsy specimens. RESULTS: A total of 55 consecutive patients were prospectively enrolled in this study; a diagnostic procedure was done in 33 patients, and a therapeutic procedure was done in 22 patients. Overall accuracy of visual findings was 93%, with a sensitivity of 83%, a specificity of 89%, positive predictive value (PPV) of 83%, and negative predictive value (NPV) of 100%. However, the overall accuracy of forceps biopsy was 89%, with a sensitivity, specificity, and PPV of 100%, and NPV of 90%. Overall technical success rate of therapeutic procedures such as selective guidewire insertion, EHL or migrated stent removal was 91% (20/22). Finally, adverse events were seen in two cases in the diagnostic group, but were not seen in the therapeutic group. CONCLUSION: Although additional cases and a randomized, controlled study with another cholangioscope are needed, diagnostic and therapeutic procedures using SPY-DS appear to be feasible and safe. PMID- 28349614 TI - Progressive histoplasmosis with hemophagocytic lymphohistiocytosis and epithelioid cell granulomatosis: A case report and review of the literature. AB - Histoplasmosis in central Europe is a rare fungal disease with diverse clinical presentations. Apart from acute pulmonary histoplasmosis and involvement of the central nervous system, the most serious clinical presentation is progressive disseminated histoplasmosis which is generally associated with severe immunodeficiency and, in particular, advanced human immunodeficiency virus infection. Here, we report on an immunocompetent female residing in a non-endemic area, presenting with progressive disseminated histoplasmosis after a remote travel history to Thailand and Costa Rica. Diagnosis was delayed by several months due to misinterpretation of epithelioid cell granulomatosis of the intestine as Crohn's disease and of similar lung lesions as acute sarcoidosis. Prompted by clinical deterioration with signs and symptoms consistent with hemophagocytic lymphohistiocytosis, a bone marrow aspiration was performed that documented hemophagocytosis and intracellular organisms interpreted as Leishmania sp., but later identified by molecular methods as Histoplasma capsulatum. Treatment with liposomal amphotericin B followed by posaconazole led to prompt clinical improvement and ultimately cure. PMID- 28349615 TI - Development and perceived effects of an educational programme on quality and safety in medication handling in residential facilities. AB - OBJECTIVES: To develop and test an educational programme on quality and safety in medication handling for staff in residential facilities for the disabled. METHODS: The continuing pharmacy education instructional design model was used to develop the programme with 22 learning objectives on disease and medicines, quality and safety, communication and coordination. The programme was a flexible, modular seven + two days' course addressing quality and safety in medication handling, disease and medicines, and medication supervision and reconciliation. The programme was tested in five Danish municipalities. Municipalities were selected based on their application for participation; each independently selected a facility for residents with mental and intellectual disabilities, and a facility for residents with severe mental illnesses. Perceived effects were measured based on a questionnaire completed by participants before and after the programme. Effects on motivation and confidence as well as perceived effects on knowledge, skills and competences related to medication handling, patient empowerment, communication, role clarification and safety culture were analysed conducting bivariate, stratified analyses and test for independence. KEY FINDINGS: Of the 114 participants completing the programme, 75 participants returned both questionnaires (response rate = 66%). Motivation and confidence regarding quality and safety in medication handling significantly improved, as did perceived knowledge, skills and competences on 20 learning objectives on role clarification, safety culture, medication handling, patient empowerment and communication. CONCLUSIONS: The programme improved staffs' motivation and confidence and their perceived ability to handle residents' medication safely through improved role clarification, safety culture, medication handling and patient empowerment and communication skills. PMID- 28349616 TI - Antibiotic resistance in Staphylococcus sp. isolated from the vaginal environment of squirrel monkeys (Saimiri spp.) bred ex situ. AB - BACKGROUND: Squirrel monkeys (Saimiri spp.) have been widely used as animal models; however, the occurrence of Staphylococcus sp in their vaginal microbiota remains to be described. METHODS: Samples were collected from 175 adult squirrel monkeys to isolate Staphylococcus sp and to test for susceptibility to a panel of nine antimicrobial agents. RESULTS: Isolates with characteristics of the genus Staphylococcus were detected in 95 of 175 samples. Coagulase-negative staphylococci (CoNS) were the most common (95.8%, 91/95) isolates. Resistance to antibiotics was observed in 47.3% (45/95) of isolates. Resistance to tetracycline was observed in 28.5% (26/91), chloramphenicol in 15.4% (14/91), and methicillin in 13.2% (12/91) of CoNS. Coagulase-positive staphylococci were resistant to tetracycline, erythromycin, and methicillin. CONCLUSIONS: The presence of Staphylococcus sp in vaginal samples obtained from squirrel monkeys suggests that these animals were in a carrier state. Furthermore, isolating strains resistant to methicillin reinforces the biosafety care of a colony. PMID- 28349617 TI - Exploring synthetic heroin: Accounts of acetyl fentanyl use from a sample of dually diagnosed drug offenders. AB - INTRODUCTION AND AIMS: Acetyl fentanyl, a fentanyl analogue emerging onto the recreational drug scene, has been responsible for numerous recent fatal overdoses in the USA, Europe and Russia. Studies reporting acetyl fentanyl use are presently limited to case studies and mortality reports. This study explores the nature of acetyl fentanyl use through the collection of first-hand qualitative data from users to inform public health and drug control policy responses. DESIGN AND METHODS: A series of focus group interviews within a correctional setting Delaware County (Ohio) Jail, USA. Participants were 102 individuals in one of two US Bureau of Justice Assistance Second Chance Act substance use treatment initiatives participating in at least one focus group session. Five of these individuals reported acetyl fentanyl use. Semi-structured qualitative focus group sessions queried subjects' drugs of choice and nature of drug use. Responses were explored through follow-up organic discourse. RESULTS: Acetyl fentanyl users were generally unaware that they had administered the substance until after use (initially believing that they were administering heroin). They described the effects of acetyl fentanyl as stronger and qualitatively different from heroin. These individuals showed no interest in using acetyl fentanyl again describing it as unpleasant and more risky, both because of potency and the threat of a 'bad batch'. DISCUSSION AND CONCLUSIONS: Acetyl fentanyl is reaching heroin users, some of which administer it unknowingly. Regulation of acetyl fentanyl is recommended in all countries as is increasing public awareness that the substance is distinct from and being sold as heroin. [Miller JM, Stogner JM, Miller BL, Blough S. Exploring synthetic heroin: Accounts of acetyl fentanyl use from a sample of dually diagnosed drug offenders. Drug Alcohol Rev 2018;37:121-127]. PMID- 28349618 TI - Parameter estimation using weighted total least squares in the two-compartment exchange model. AB - PURPOSE: The linear least squares (LLS) estimator provides a fast approach to parameter estimation in the linearized two-compartment exchange model. However, the LLS method may introduce a bias through correlated noise in the system matrix of the model. The purpose of this work is to present a new estimator for the linearized two-compartment exchange model that takes this noise into account. METHOD: To account for the noise in the system matrix, we developed an estimator based on the weighted total least squares (WTLS) method. Using simulations, the proposed WTLS estimator was compared, in terms of accuracy and precision, to an LLS estimator and a nonlinear least squares (NLLS) estimator. RESULTS: The WTLS method improved the accuracy compared to the LLS method to levels comparable to the NLLS method. This improvement was at the expense of increased computational time; however, the WTLS was still faster than the NLLS method. At high signal-to noise ratio all methods provided similar precisions while inconclusive results were observed at low signal-to-noise ratio. CONCLUSION: The proposed method provides improvements in accuracy compared to the LLS method, however, at an increased computational cost. Magn Reson Med 79:561-567, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28349619 TI - Bridging the discursive gap between lay and medical discourse in care coordination. AB - For older people with multiple chronic co-morbidities, strategies to coordinate care depend heavily on information exchange. We analyse the information-sharing difficulties arising from differences between patients' oral narratives and medical sense-making; and whether a modified form of 'narrative medicine' might mitigate them. We systematically compared 66 general practice patients' own narratives of their health problems and care with the contents of their clinical records. Data were collected in England during 2012-13. Patients' narratives differed from the accounts in their medical record, especially the summary, regarding mobility, falls, mental health, physical frailty and its consequences for accessing care. Parts of patients' viewpoints were never formally encoded, parts were lost when clinicians de-coded it, parts supplemented, and sometimes the whole narrative was re-framed. These discrepancies appeared to restrict the patient record's utility even for GPs for the purposes of risk stratification, case management, knowing what other care-givers were doing, and coordinating care. The findings suggest combining the encoding/decoding theory of communication with inter-subjectivity and intentionality theories as sequential, complementary elements of an explanation of how patients communicate with clinicians. A revised form of narrative medicine might mitigate the discursive gap and its consequences for care coordination. PMID- 28349620 TI - Connectivity patterns during music listening: Evidence for action-based processing in musicians. AB - Musical expertise is visible both in the morphology and functionality of the brain. Recent research indicates that functional integration between multi sensory, somato-motor, default-mode (DMN), and salience (SN) networks of the brain differentiates musicians from non-musicians during resting state. Here, we aimed at determining whether brain networks differentially exchange information in musicians as opposed to non-musicians during naturalistic music listening. Whole-brain graph-theory analyses were performed on participants' fMRI responses. Group-level differences revealed that musicians' primary hubs comprised cerebral and cerebellar sensorimotor regions whereas non-musicians' dominant hubs encompassed DMN-related regions. Community structure analyses of the key hubs revealed greater integration of motor and somatosensory homunculi representing the upper limbs and torso in musicians. Furthermore, musicians who started training at an earlier age exhibited greater centrality in the auditory cortex, and areas related to top-down processes, attention, emotion, somatosensory processing, and non-verbal processing of speech. We here reveal how brain networks organize themselves in a naturalistic music listening situation wherein musicians automatically engage neural networks that are action-based while non musicians use those that are perception-based to process an incoming auditory stream. Hum Brain Mapp 38:2955-2970, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28349621 TI - 'It feels sometimes like my house has burnt down, but I can see the sky': A qualitative study exploring patients' views of cognitive behavioural therapy for chronic fatigue syndrome. AB - OBJECTIVES: Cognitive behavioural therapy (CBT) is currently a first-line treatment for chronic fatigue syndrome (CFS). Even though the results from trials are promising, there is variability in patient outcomes. The aim of this study was to explore the experiences of patients with CFS who undertook CBT at a specialist service for CFS. DESIGN: This was a qualitative study. METHODS: Thirteen patients with CFS, approaching the end of CBT, participated in semi structured interviews. In addition, participants were asked to rate their satisfaction with CBT and perceived level of improvement. The data were analysed using inductive thematic analysis. RESULTS: The majority of participants were satisfied with treatment and reported marked improvements. This was evident from the ratings and corroborated by the qualitative data, yet recovery was in general incomplete. Participants often disclosed mixed feelings towards CBT prior to its start. Behavioural aspects of treatment were found useful, while participants were more ambivalent towards the cognitive aspects of treatment. The tailored nature of CBT and therapist contact were important components of treatment, which provided participants with support and validation. Engagement and motivation were crucial for participants to benefit from CBT, as well as the acceptance of a bio psychosocial model of CFS. Illness beliefs around CFS were also discussed throughout the interviews, possibly impeding engagement with therapy. CONCLUSIONS: The results suggest that various factors may moderate the effectiveness of CBT, and a greater understanding of these factors may help to maximize benefits gained from CBT. Statement of contribution What is already known on this subject? CBT is effective in reducing CFS symptoms, but not all patients report marked improvements following treatment. Predictors of outcome have been explored in the literature. Few studies have looked at the experience of adult patients with CFS who have had CBT. What does this study add? Findings provide insights as to why variability in CBT-related improvements exists. Beliefs about CFS and CBT may shape engagement and consequently contribute to post-treatment outcomes. Flexibility and sensitivity are necessary from therapists throughout treatment to ensure full engagement. PMID- 28349623 TI - Managing workplace stress in community pharmacy organisations: lessons from a review of the wider stress management and prevention literature. AB - BACKGROUND: Workplace stress in community pharmacy is increasing internationally due, in part, to pharmacists' expanding roles and escalating workloads. Whilst the business case for preventing and managing workplace stress by employers is strong, there is little evidence for the effectiveness of organisational stress management interventions in community pharmacy settings. AIM: To identify and synthesise existing evidence for the effectiveness of organisational solutions to workplace stress from the wider organisational literature which may be adaptable to community pharmacies. METHOD: A secondary synthesis of existing reviews. Publications were identified through keyword searches of electronic databases and the internet; inclusion and exclusion criteria were applied; data about setting, intervention, method of evaluation, effectiveness and conclusions (including factors for success) were extracted and synthesised. FINDINGS: Eighteen reviews of the stress management and prevention literature were identified. A comprehensive list of organisational interventions to prevent or manage workplace stress, ordered by prevalence of evidence of effectiveness, was produced, together with an ordered list of the benefits both to the individual and employing organisation. An evidence-based model of best practice was derived specifying eight factors for success: top management support, context-specific interventions, combined organisational and individual interventions, a participative approach, clearly delineated tasks and responsibilities, buy-in from middle management, change agents as facilitators and change in organisational culture. CONCLUSIONS: This literature review provides community pharmacy organisations with evidence from which to develop effective and successful stress management strategies to support pharmacists and pharmacy staff. Well-designed trials of stress management interventions in community pharmacy organisations are still required. PMID- 28349622 TI - Actigraphic sleep measures and diet quality in the Hispanic Community Health Study/Study of Latinos Sueno ancillary study. AB - Using a cross-sectional probability sample with actigraphy data and two 24-h dietary recalls, we quantified the association between sleep duration, continuity, variability and timing with the Alternative Healthy Eating Index-2010 diet quality score and its components in 2140 Hispanic Community Health Study/Study of Latinos participants. The Alternative Healthy Eating Index diet quality-2010 score ranges from 0 to 110, with higher scores indicating greater adherence to the dietary guidelines and lower risk from major chronic disease. None of the sleep measures was associated with total caloric intake as assessed using dietary recalls. However, both an increase in sleep duration and sleep efficiency were associated with healthier diet quality. Each standard deviation increase in sleep duration (1.05 h) and sleep efficiency (4.99%) was associated with a 0.30 point increase and 0.28 point increase, respectively, in the total Alternative Healthy Eating Index-2010 score. The component of Alternative Healthy Eating Index-2010 most strongly associated with longer sleep duration was increased nuts and legumes intake. The components of Alternative Healthy Eating Index-2010 most strongly associated with higher sleep efficiency were increased whole fruit intake and decreased sodium intake. Both longer sleep duration and higher sleep efficiency were significantly associated with better diet quality among US Hispanic/Latino adults. The dietary components most strongly associated with sleep duration and sleep efficiency differed, suggesting potentially independent mechanisms by which each aspect of sleep impacts dietary choices. Longitudinal research is needed to understand the directionality of these identified relationships and the generalizability of these data across other ethnic groups. PMID- 28349624 TI - Partitioning within-species variance in behaviour to within- and between population components for understanding evolution. AB - Phenotypes vary at multiple hierarchical levels, of which the interspecific variance is the primary focus of phylogenetic comparative studies. However, the evolutionary role of particular within-species variance components (between population, between- or within-individual variances) remains neglected. Here, we partition the variance in an anti-predator behaviour, flight initiation distance (FID), and assess how its within- and between-population variance are related to life history, distribution, dispersal and habitat ecology. Although the composition of within-species variance in FID depended on the phylogeny, most variance occurred within populations. When accounting for allometry, density dependence, uncertainty in the phylogenetic hypothesis and heterogeneity in data quality, within-population variance was significantly associated with habitat diversity and population size. Between-population variance was a significant predictor of natal dispersal, senescence and habitat diversity. Accordingly, not only species-specific mean values of a behavioural trait, but also its variance within and among populations can shape the evolutionary ecology of species. PMID- 28349625 TI - Effects of melatonin on maturation, histone acetylation, autophagy of porcine oocytes and subsequent embryonic development. AB - Melatonin (MLT) is an endogenous hormone with roles in animal germ cell development. However, the effect of MLT on porcine oocyte maturation and its underlying mechanisms remain largely unknown. Here, we investigated the effects of exogenous MLT on oocyte maturation, histone acetylation, autophagy and subsequent embryonic development. We found that 1 nmol/L MLT supplemented in maturation medium was the optimal concentration to promote porcine oocyte maturation and subsequent developmental competence and quality of parthenogenetic embryos. Interestingly, the beneficial effects of 1 nmol/L MLT treatment on porcine oocyte maturation and embryo development were mainly attributed to the first half period of in vitro maturation. Simultaneously, MLT treatment could also improve maturation of small follicle-derived oocytes, morphologically poor (cumulus cell layer <=1) and even artificially denuded oocytes and their subsequent embryo development. Furthermore, MLT treatment not only could decrease the levels of H3K27ac and H4K16ac in metaphase II (MII) oocytes, but also could increase the expression abundances of genes associated with cumulus cell expansion, meiotic maturation, histone acetylation and autophagy in cumulus cells or MII oocytes. These results indicate that MLT treatment can facilitate porcine oocyte maturation and subsequent embryonic development probably, through improvements in histone acetylation and autophagy in oocytes. PMID- 28349627 TI - Rigid catheters reduced duration of less invasive surfactant therapy procedures in manikins. AB - AIM: Different catheters can be used for less invasive surfactant therapy (LIST): feeding tubes inserted with or without Magill forceps, different angiocatheters and centre specific devices, such as umbilical catheters affixed to a stylet. This study compared the effectiveness of LIST devices and endotracheal tubes (ETT). METHODS: Video recordings of 20 neonatologists simulating different LIST techniques on two manikin heads were analysed. Procedural effectiveness was evaluated by the duration of procedures and failure rates. Ease of use was scored. RESULTS: The median procedure time for the Neonatal Intubation Trainer was significantly longer with feeding tubes without Magill forceps. For the more difficult ALS Baby Trainer, successful procedures lasted a median of 24 (17-32) seconds with ETT, 24 (15-36) seconds with stylet-guided catheters and 34 (27-46) seconds and 37 (29-42) seconds with 13-cm and 30-cm angiocatheters, respectively. Both methods using feeding tubes were statistically slower than ETT intubation, lasting 32 (25-44) seconds and 39 (27-95) seconds with or without Magill forceps. Failure rates (7-20%) were no different between the LIST methods. Techniques using feeding tubes were rated as more difficult. CONCLUSION: Only rigid or stylet-guided catheters required tracheal catheterisation times similar to those of endotracheal intubation and neonatologists found them easier. PMID- 28349626 TI - Study of N-vinylpyrrolidone-N-vinylformamide copolymers labelled with indium 113m. AB - The procedure of the directed synthesis of N-vinylpyrrolidone-N-vinylformamide (VP-VFA) copolymers with grafted iminodiacetate (IDA) chelating units is presented. The methods for labelling resulting conjugates with indium-113m were developed. The metal-copolymer conjugates were characterized by different physicochemical methods, including IR and NMR, viscometry, light scattering, and exclusion high-performance liquid chromatography. Parameters of radiochemical synthesis of the conjugates labelled with indium-113m were optimized. It was shown that the VP-VFA-IDA copolymer firmly binds indium-113m both in the acid and alkaline solutions, with pH of the reaction mixture having almost no effect on the complexation. VP-VFA-IDA-In conjugates were found to be unstable in histidine challenge reaction. PMID- 28349628 TI - Ferritin, cellular iron storage and regulation. AB - Ferritin is considered the major iron storage protein which maintains a large iron core in its cavity and has ferroxidase activity. There are many types of ferritin particularly in prokaryotes that include the canonical 24-mer FTN molecules, the heme-containing BFR, the smaller 12-mer DPS and the newly recognized EncFtn of encapsulin that forms a very large iron storage compartment. Recent studies show that ferritin function is more dynamic than previous depicted and new mechanisms of ferritin iron recycling are emerging. They participate to the regulation of cellular iron homeostasis as those of ferritin biosynthesis, cooperating also with the iron-dependent mechanism of cellular iron secretion. Some of these basic processes are in common between unicellular and animal cells, and this review aims at discussing the findings on the connections between iron storage, cellular iron regulation and ferritin iron recycling that have been explored in unicellular organisms and in animals. (c) 2017 IUBMB Life, 69(6):414 422, 2017. PMID- 28349629 TI - The risk of healing complications in primary teeth with extrusive or lateral luxation-A retrospective cohort study. AB - BACKGROUND/AIM: Traumatic dental injuries (TDI) in the primary dentition occur frequently. Long-term complications may potentially cause damage to the permanent successor. The aim of this study was to report the risk of pulp necrosis (PN), pulp canal obliteration (PCO), infection-related resorption (IRR), ankylosis related resorption (ARR) and premature tooth loss (PTL) in primary teeth following extrusion or lateral luxation and to identify risk factors for PN and PTL. MATERIAL AND METHODS: This was a retrospective study of 24 patients with 26 extruded primary teeth and 242 patients with 331 primary teeth with lateral luxation. Laterally luxated teeth were left without treatment. Extruded teeth were repositioned. Follow up included examination after 4 weeks, 8 weeks, 6 months, 1 year and when the patients were 6 years old. The minimum follow up was 1 year or until tooth loss. Kaplan-Meier and Aahlen-Johansson tests were used along with Cox regression analysis. The level of significance was 5%. RESULTS: Risk estimated after 3 years-Extrusion: PCO 39.8% (95% CI: NA), PN 15.6% (95% CI: 1.5-29.7), IRR 3.8% (95% CI: 0-11.2) and PTL 43.3% (95% CI: 25.5-61.2). All cases of PN and PTL occurred within the first year. Lateral luxation: PCO 41.3% (CI: 95% 35.7-46.9), PN 19.8% CI: 95% (15.3-24.2), IRR 7.0% (95% CI: 4.1-9.8), ARR 1.4% (95% CI: 0-3.3) and PTL 24.8% (95% CI: 18.8-30.8). Risk factors for PN: concomitant crown fracture and patient aged 4 years or more. Nearly all teeth (95%) realigned spontaneously within the first year. Nearly all cases of PN and PTL (95.7%) occurred within the first year. CONCLUSION: The healing potential for laterally luxated teeth was high and more than half of the extruded teeth, which were repositioned after injury, showed long-term survival. PMID- 28349631 TI - ? PMID- 28349632 TI - ? PMID- 28349633 TI - ? PMID- 28349630 TI - Optimization of intra-voxel incoherent motion measurement in diffusion-weighted imaging of breast cancer. AB - PURPOSE: The purpose of this study was to optimize intra-voxel incoherent motion (IVIM) measurement in diffusion-weighted imaging (DWI) of breast cancer by separating perfusion and diffusion effects through the determination of an optimal threshold b-value, thus benign and cancerous breast tissues can be accurately differentiated using IVIM-derived diffusion and perfusion parameters. MATERIALS AND METHODS: Twenty-eight patients, with biopsy-confirmed breast cancers, were studied with a 3T MRI scanner, using T1-weighted dynamic contrast enhanced MRI images, and diffusion-weighted images with nine b-values, ranging from 0 to 1000 s/mm2. IVIM-derived parameter maps for tissue diffusion coefficients D, perfusion fraction f, and pseudo-diffusion coefficients D* were computed using the segmented fitting method with optimized threshold b-value, and the sum of squared residuals (SSR) were calculated for IVIM-derived parameters in different breast lesions. RESULTS: The IVIM analysis method developed in this work can separate perfusion and diffusion effects with the optimal threshold b value of 300 s/mm2, and the results of diffusion and perfusion parameters from IVIM analysis can be used to differentiate pathological changes in breast tissues. It was found that the averages and standard deviations of the diffusion and perfusion parameters, D, f, D*, are the following, for malignant, benign and normal breast tissues respectively: D (0.813 +/- 0.225 * 10-3 mm2 /s, 1.437 +/- 0.538 * 10-3 mm2 /s, 1.838 +/- 0.213 * 10-3 mm2 /s), f (10.73 +/- 3.44%, 7.86 +/- 3.70%, 8.92 +/- 3.72%), D* (15.23 +/- 12.17*10-3 mm2/s, 12.02 +/- 3.19 * 10-3 mm2 /s, 12.03 +/- 7.21 * 10-3 mm2 /s). CONCLUSION: IVIM-derived diffusion and perfusion parameter maps depend highly on the choice of threshold b-value. Using the methodology developed in this work, and with the optimized threshold b-value, the diffusion and perfusion parameters of breast tissues can be accurately assessed, making IVIM MRI a technique of choice for differential diagnosis of breast cancer. PMID- 28349634 TI - ? PMID- 28349635 TI - ? PMID- 28349636 TI - ? PMID- 28349637 TI - ? PMID- 28349638 TI - ? PMID- 28349639 TI - Metabolic mediators of the impact of general and central adiposity measures on cardiovascular disease and mortality risks in older adults: Tehran Lipid and Glucose Study. AB - AIMS: To investigate the relationship between body mass index, waist circumference, waist-to-hip ratio and waist-to-height ratio, as well as the mediating factors through which they might exert their risk for cardiovascular disease/coronary heart disease and mortality events in the older Iranian population during a median follow up of 9.5 years. METHODS: The study population included participants, aged >=65 years, free of cardiovascular disease at baseline. The confounder-adjusted hazard ratio was calculated for a 1-SD change in each anthropometric measure with and without adjustment for hypercholesterolemia, diabetes and hypertension. RESULTS: During the study follow up, 193 participants developed their first cardiovascular disease event and 183 deaths occurred. No association was found between cardiovascular disease/coronary heart disease and body mass index, even in the confounder-adjusted models. Central adiposity measures showed a significant risk for cardiovascular disease events in the confounder-adjusted model ranging from hazard ratio 1.16 (95% confidence interval 1.02-1.33) for waist-to-hip ratio to 1.21 (95% confidence interval 1.03-1.42) for waist-to-height ratio. Adjustment for hypertension alone or in combination with other metabolic mediators attenuated the hazard ratio to null. Although hypercholesterolemia did not show any mediating effect of central adiposity measures for cardiovascular disease/coronary heart disease, hypertension was the most powerful mediator, accounting for 30-45% of the excess risk. CONCLUSIONS: Central rather than general adiposity showed a significant role in determining cardiovascular disease/coronary heart disease risk. The harmful effect of central adiposity was completely attributable to mediators, especially hypertension. Clinical interventions for control of mediators focusing on hypertension should be emphasized. Geriatr Gerontol Int 2017; 17: 2017-2024. PMID- 28349640 TI - Developmental trajectories for young children with 16p11.2 copy number variation. AB - Copy number variation at 16p11.2 is associated with diverse phenotypes but little is known about the early developmental trajectories and emergence of the phenotype. This longitudinal study followed 56 children with the 16p11.2 BP4-BP5 deletion or duplication between the ages of 6 months and 8 years with diagnostic characterization and dimensional assessment across cognitive, adaptive, and behavioral domains. Linear mixed modeling revealed distinct developmental trajectories with deletions showing VIQ gains but declines in motor and social abilities while duplications showed VIQ gains and steady development across other domains. Nonparametric analyses suggest distinct trajectories and early cognitive abilities for deletion carriers who are ultimately diagnosed with intellectual disability and developmental coordination disorder as well as distinct trajectories and early social communication and cognitive abilities for duplication carriers diagnosed with ASD and intellectual disability. Findings provide predictions for patient developmental trajectories, insight into mean functioning of individuals with 16p11.2 at early ages, and highlight the need for ongoing monitoring of social and motor functioning and behavioral symptomatology to improve treatment planning. (c) 2017 Wiley Periodicals, Inc. PMID- 28349641 TI - Type 2 diabetes remission rates 1-year post-Roux-en-Y gastric bypass and validation of the DiaRem score: the Ontario Bariatric Network experience. AB - Roux-en-Y gastric bypass (RYGB) is associated with the remission of type 2 diabetes mellitus (DM). There are a number of scoring systems available that help predict type 2 diabetes remission rates after bariatric surgery; however, relatively few have been validated externally. The DiaRem score, comprised of four preoperative variables (age, haemoglobin A1c [HbA1c], sulfonylurea and insulin-sensitizing agent use and insulin use), allows for the identification of patients who are most likely to have DM remission following RYGB. Our primary objective was to determine the variables predictive of DM remission 1 year post RYGB, determine how well the DiaRem score predicts DM remission 1 year post-RYGB and identify the optimal cut-off DiaRem score. The study is based on results of RYGB performed across multiple centres in Ontario, Canada, overseen by the Centre for Surgical Invention and Innovation in Hamilton, with direction from the Ontario Bariatric Network. Regression analysis was used to determine the predictive value of demographic and clinical variables and that of the DiaRem score. The optimal DiaRem cut-off score was determined using sensitivity and specificity analysis. Of 3874 patients in the Ontario Bariatric Registry between January 2010 and February 2015, 915 had complete 1-year follow-up data. Among these, 15 were not classified as having DM at baseline and were excluded. Of the remaining 900 patients with type 2 diabetes and who underwent RYGB surgery, 333 (37.0%) had DM remission at 1-year follow-up. Three of four DiaRem variables (age, HbA1c, insulin use), in addition to use of any hypoglycaemic agent, were associated with DM remission. DiaRem score had moderate predictive value. A DiaRem score cut-off of <5 had a sensitivity of 71.8% and specificity of 71.3%. This study provides guidance to clinicians in using the DiaRem score to inform the selection and prioritization of patients to ensure timely access to bariatric surgery for those who are likely to benefit the most. PMID- 28349642 TI - Understanding the science that supports population-wide salt reduction programs. PMID- 28349643 TI - Causes of death in Japanese patients with diabetes based on the results of a survey of 45,708 cases during 2001-2010: Report of the Committee on Causes of Death in Diabetes Mellitus. AB - The principal causes of death among 45,708 patients with diabetes (29,801 men and 15,907 women) who died in 241 hospitals throughout Japan during 2001-2010 were determined based on a survey of the hospital records. Autopsy had been conducted in 978 of the 45,708 cases. The most frequent cause of death was malignant neoplasia (38.3%), followed by, in order of descending frequency: infections (17.0%); and then vascular diseases (14.9%), including renal failure (3.5%), ischemic heart diseases (4.8%) and cerebrovascular diseases (6.6%). Diabetic coma associated with hyperglycemia with or without ketoacidosis accounted for only 0.6% of the deaths. In regard to the relationship between the age and cause of death in patients with diabetes, the incidence of death due to vascular diseases was higher in patients over the age of 30 or 40 years, and the 97.0% of the total death due to vascular diseases was observed in patients over the age of 50 years. The incidence of death due to infectious diseases, especially pneumonia, increased in an age-dependent fashion, and the 80.7% of the total death due to pneumonia was observed in patients over the age of 70 years. 'Poorer' glycemic control was associated with the reduced lifespan of patients with diabetes, especially of those with nephropathy. The average age at death in the survey population was 72.6 years. The lifespan was 1.6 years shorter in patients with 'poorer' glycemic control than in those with 'better' glycemic control. In patients with diabetes of less than 10 years' duration, the incidence of death due to macroangiopathy was higher than that due to nephropathy. Of the 45,708 patients with diabetes, 33.9% were on oral medication, 41.9% received insulin therapy and 18.8% were treated by diet alone. Among the patients in whom the cause of death was diabetic nephropathy, a high percentage, 53.7%, was on insulin therapy. The average age at death of the 45,708 patients with diabetes was 71.4 years in men and 75.1 years in women. However, the report of the Ministry of Health and Welfare of Japan in 2010 set the average lifespan of the Japanese at 79.6 years for men and 86.3 years for women. Thus, the average lifespan of patients with diabetes still appears to be shorter than that of the general population in Japan. However, the differences in lifespan between patients with diabetes and the general population were shorter than those in the former surveys. PMID- 28349646 TI - Quality improvement of community pharmacy services: a prioritisation exercise. AB - OBJECTIVES: Effective strategies are needed to translate knowledge (evidence) into practice to improve the quality of community pharmacy services. We report the first step of a novel knowledge translation process which involved the systematic identification and prioritisation of community pharmacy services in Scotland which were perceived to require improvement and/or guideline development. METHODS: This process involved three stages and a stakeholder group comprising community pharmacists, policy makers, lay and pharmacy organisation representatives. A modified nominal group technique (NGT) was used for topic generation (August 2013) followed by an electronic Delphi survey (eDelphi), October-December 2013) and topic rationalisation (December 2013) based on feasibility, acceptability, and potential impact for practice improvement. KEY FINDINGS: In total, 63 items were identified during the modified NGT which were categorised into 20 topics to form the starting point of the eDelphi. In total, 74 individuals (mostly community pharmacists) indicated an interest in the eDelphi, which achieved response rates of 63.5%, 67.6%, and 70.3%, respectively in Rounds 1, 2, and 3. Consensus was achieved with six topics: promoting the appropriate sale and supply of over-the-counter medicines; patient counselling for prescribed medication; pharmaceutical care to promote medication adherence; promotion and delivery of a Minor Ailment Scheme; pharmaceutical care of vulnerable patients; and effective use of community pharmacy workforce. Of these, the priority topic selected for the next stage of the programme was promoting the appropriate sale and supply of over-the-counter medicines. CONCLUSIONS: This study adopted a systematic, inclusive, and rapid approach to identify priorities for community pharmacy practice improvement in Scotland. PMID- 28349647 TI - Finite element modeling, validation, and parametric investigations of a retinal reattachment stent. AB - A new retinal reattachment surgical procedure is based on a stent that is deployed to press the retina back in place. An eye-stent finite element model studied the strain induced by the stent on retina. Finite element model simulations were performed for several stent geometric configurations (number of loops, wire diameter, and intraocular pressure). The finite element model was validated against experiment. Parametric studies demonstrated that stents could be successfully designed so that the maximum strain would be below permanent damage strain threshold of 2%. PMID- 28349648 TI - Minimally invasive surgery for esophageal cancer after esophageal perforation. AB - Both esophageal rupture and esophageal cancer are life-threatening diseases. We report a case of esophageal cancer that occurred after esophageal rupture was treated with thoracoscopic and laparoscopic surgery. A 76-year-old man presented with vomiting followed by epigastric pain and was diagnosed with spontaneous esophageal rupture. Laparoscopic and thoracoscopic surgery were performed. Primary closure was completed with a fundic patch, and thoracic lavage was performed. Ten months later, his condition was diagnosed as squamous cell carcinoma of the abdominal esophagus. He underwent thoracoscopic esophageal resection in the prone position, and a gastric conduit was created laparoscopically. The pathological finding was superficial esophageal carcinoma without lymph node metastasis. The patient's postoperative course was uneventful, and there was no recurrence at 21 months of follow-up. PMID- 28349644 TI - Changes to cholesterol trafficking in macrophages by Leishmania parasites infection. AB - Leishmania spp. are protozoan parasites that are transmitted by sandfly vectors during blood sucking to vertebrate hosts and cause a spectrum of diseases called leishmaniases. It has been demonstrated that host cholesterol plays an important role during Leishmania infection. Nevertheless, little is known about the intracellular distribution of this lipid early after internalization of the parasite. Here, pulse-chase experiments with radiolabeled cholesteryl esterified to fatty acids bound to low-density lipoproteins indicated that retention of this source of cholesterol is increased in parasite-containing subcellular fractions, while uptake is unaffected. This is correlated with a reduction or absence of detectable NPC1 (Niemann-Pick disease, type C1), a protein responsible for cholesterol efflux from endocytic compartments, in the Leishmania mexicana habitat and infected cells. Filipin staining revealed a halo around parasites within parasitophorous vacuoles (PV) likely representing free cholesterol accumulation. Labeling of host cell membranous cholesterol by fluorescent cholesterol species before infection revealed that this pool is also trafficked to the PV but becomes incorporated into the parasites' membranes and seems not to contribute to the halo detected by filipin. This cholesterol sequestration happened early after infection and was functionally significant as it correlated with the upregulation of mRNA-encoding proteins required for cholesterol biosynthesis. Thus, sequestration of cholesterol by Leishmania amastigotes early after infection provides a basis to understand perturbation of cholesterol dependent processes in macrophages that were shown previously by others to be necessary for their proper function in innate and adaptive immune responses. PMID- 28349649 TI - Sewing needles in the abdominal cavity assumed to have been ingested and to have penetrated the GI tract 40 years ago: A case report. AB - A 60-year old woman had been hospitalized in a psychiatric hospital for 40 years for schizophrenia. An X-ray was performed when she fell, which showed needles in the abdominal field. After additional examinations and questioning, the patient was diagnosed with needles in the abdominal cavity, which were assumed to have been ingested and to have perforated the GI tract 40 years ago. They were removed by laparoscopic surgery. The needles were found in the omentum and near the left ovary. There were no inflammatory reactions around them. There have been previous reports about the removal of intra-abdominal foreign bodies, but foreign body reaction occurred in most of the reports. Our case had the longest period from ingestion of the foreign bodies to their removal. Laparoscopy and intraoperative fluoroscopy are useful for removing intra-abdominal foreign bodies because of their ability to help discriminate between structures and to navigate in real time. PMID- 28349650 TI - Efficient Aerobic Oxidation of Glucose to Gluconic Acid over Activated Carbon Supported Gold Clusters. AB - The catalytic performance of the atomically precise gold cluster-Au38 (PET)24 (PET=2-phenylethanethiolate), immobilized on activated carbon (AC), was investigated for the aerobic oxidation of glucose to gluconic acid. The Au38 (PET)24 /AC-120 catalysts, annealed at 120 degrees C in air, exhibited high catalytic activity and significantly better performance than the corresponding catalysts Au38 /AC-150 and Au38 /AC-300 (treated at 150 and 300 degrees C to remove the protecting thiolate ligands). The high activity of the robust Au cluster was a result of the partial ligand removal, providing catalytically active sites, which were evidenced by TEM, X-ray photoelectron spectroscopy, thermogravimetric analysis, and Fourier-transform IR spectroscopy. Au38 (PET)24 /AC-120 also showed excellent recyclability (up to seven cycles). The turnover frequency for the Au38 (PET)24 /AC-120 catalyst was 5440 h-1 , which is higher than for the Pd/AC, Pd-Bi/AC, and Au/AC under identical reaction conditions. This new ultra-small gold nanomaterial is expected to find wide application in other catalytic oxidations. PMID- 28349651 TI - Dermasence refining gel modulates pathogenetic factors of rosacea in vitro. AB - BACKGROUND: Over the counter cosmetics sold for local treatment of slight to moderate rosacea often state the claim of actively modulating rosacea pathogenesis. Factors involved in the pathogenesis of this common yet complex skin disorder include kallikrein-related peptidase 5 (KLK5), LL-37, as well as protease-activated receptor 2 (PAR2) and vascular endothelial growth factor (VEGF). OBJECTIVE: The objective was to prove the modulating effect of the cosmetic skin care agent Dermasence Refining Gel (DRG) on factors involved in rosacea pathogenesis. METHODS: We analyzed the effect of DRG on the expression of KLK5, LL-37, PAR2, and VEGF in an in vitro skin model of human reconstituted epidermis. RESULTS: The expression of CAMP (LL-37 gene, fold change -4.19 [+/ 0.11]), VEGFA (fold change -2.55 [+/-0.12]) and PAR2 (-1.33 [+/-0.12]) was reduced, KLK5 expression increased (fold change 2.06 (+/-0.08)) after 18 h of treatment with DRG in comparison to treatment with the matrix gel only. The reduction in CAMP expression was significant (P<.01). The protein expression of all four inflammatory markers was markedly reduced after 18 hours of DRG treatment in comparison to baseline (0 hour), by measure of fluorescence intensity. CONCLUSION: We show evidence explaining the anti-inflammatory effect of Dermasence Refining Gel in rosacea pathogenesis in vitro. The adjunctive use of DRG in mild to moderate rosacea as a topical cosmetic seems medically reasonable. PMID- 28349653 TI - The risk of healing complications in primary teeth with intrusive luxation: A retrospective cohort study. AB - BACKGROUND/AIMS: Intrusive luxation is a frequent injury in the primary dentition. Complications such as ankylosis or pulp necrosis (PN) and infection with periapical inflammation may affect the developing permanent tooth if not diagnosed and treated in time. The aim of this study was to report the risk of PN, pulp canal obliteration (PCO), infection-related resorption (IRR), ankylosis related resorption (ARR) and premature tooth loss (PTL) in primary teeth following intrusive luxation, and to identify possible risk factors for PN and PTL. MATERIALS AND METHOD: A retrospective analysis of a cohort comprising 149 patients 194 intruded primary incisors. No treatment was performed. The follow-up programme included examination after 4 weeks, 8 weeks, 6 months, 1 year, and at 6 years of age. The minimum follow-up period was 1 year or until time of tooth loss. STATISTICS: The Kaplan-Meier and Aalen-Johansen methods were employed along with Cox regression analysis. The level of significance was 5%. RESULTS: Risks estimated after 3 years: PCO 38.9% (95% CI: 31.8-46.0), PN 24.2% (95% CI: 17.7 30.6), IRR 8.8% (95% CI: 4.5-13.1), ARR 3.6% (95% CI: 1.0-6.2) and PTL 39.4% (95% CI: 31.2-47.5). Most teeth (83.7%) spontaneously re-erupted within the first year. Most complications were diagnosed within the first year. The risk of PN was lowest in patients less than 2 years of age. The degree of intrusion or a concomitant crown fracture did not affect the risk of PN or PTL. CONCLUSIONS: Over 80% of the intruded primary teeth re-erupted spontaneously. However, nearly one-third of the teeth showed complications such as pulp infection/periapical inflammation or ankylosis, which could potentially affect the development of the permanent incisor. Therefore, patients should be monitored regularly, especially during the first year after injury, to diagnose and treat complications in time. PMID- 28349652 TI - Normal IQ is possible in Smith-Lemli-Opitz syndrome. AB - Children with Smith-Lemli-Opitz syndrome (SLOS) are typically reported to have moderate to severe intellectual disability. This study aims to determine whether normal cognitive function is possible in this population and to describe clinical, biochemical and molecular characteristics of children with SLOS and normal intelligent quotient (IQ). The study included children with SLOS who underwent cognitive testing in four centers. All children with at least one IQ composite score above 80 were included in the study. Six girls, three boys with SLOS were found to have normal or low-normal IQ in a cohort of 145 children with SLOS. Major/multiple organ anomalies and low serum cholesterol levels were uncommon. No correlation with IQ and genotype was evident and no specific developmental profile were observed. Thus, normal or low-normal cognitive function is possible in SLOS. Further studies are needed to elucidate factors contributing to normal or low-normal cognitive function in children with SLOS. PMID- 28349655 TI - Review in peeling complications. AB - Chemical peeling, a procedure wherein a chemical agent is applied to the skin to cause controlled destruction followed by regeneration and remodeling, is a dynamic tool for the treatment of acne, pigmentation issues, and photoaging [Journal of cutaneous and aesthetic surgery vol. 5 (2012) 254-260]. The results and complications are related to the depth of the procedure, with deeper peels producing more marked results and higher rates of complications. Complications are more likely with darker skin types, certain peeling agents, and sun exposure after treatment [Journal of cutaneous and aesthetic surgery vol. 5 (2012) 254 260]. They can range from minor irritations and uneven pigmentation to permanent scarring. In extremely uncommon cases, the complications can be life-threatening. This knowledge is essential to prevent, reduce, and eliminate the occurrence of complications [Cirurgia dermatologica em consultorio. Sao Paulo: Atheneu; 2009]. Swelling, pain, persistent erythema, pruritus, allergic reactions, folliculitis/acne, infection, herpes recurrence, hypopigmentation and hyperpigmentation, demarcation lines, and scarring are some of the complications that will be discussed in this article. The first step in preventing complications is to identify the patients at risk. By doing so, complications can be anticipated, prevented, and, if they still occur, treated as early as possible. PMID- 28349654 TI - Piperolein B and piperchabamide D isolated from black pepper (Piper nigrum L.) as larvicidal compounds against the diamondback moth (Plutella xylostella). AB - BACKGROUND: There is growing demand for the development of alternative pest control agents that are effective as well as non-toxic to human health and the environment. Plant protection products derived from plant extracts are an eco friendly alternative to synthetic pesticides. The aim of this study was to identify larvicidal compounds isolated from a natural source against Plutella xylostella L. In a larvicidal activity assay, several solvent fractions from the methanol extract of Piper nigrum L. fruit showed larvicidal effects against P. xylostella. RESULTS: Screening results indicated that chloroform extract was the most effective against P. xylostella larvae. Two compounds with insecticidal activity in the chloroform fraction were identified as piperolein B and piperchabamide D by spectroscopic analyses, including mass spectrometry and NMR, and by comparison to published data. At applications of 0.1 mg mL-1 concentration, piperolein B and piperchabamide D, respectively, induced 96.7 +/- 5.8% and 79.2 +/- 16.6% mortality rates of P. xylostella larvae 4 days post application. CONCLUSION: Our results demonstrate that piperolein B and piperchabamide D isolated from P. nigrum are the major constituents of the extract demonstrating insecticidal properties for the control of P. xylostella larvae. These plant-derived compounds should become useful alternatives to synthetic chemicals after studying their insecticidal mechanisms. (c) 2017 Society of Chemical Industry. PMID- 28349656 TI - Equine performance genes and the future of doping in horseracing. AB - A horse's success on the racetrack is determined by genetics, training and nutrition, and their translation into physical traits such as speed, endurance and muscle strength. Advances in genetic technologies are slowly explaining the roles of specific genes in equine performance, and offering new insights into the development of novel therapies for diseases and musculoskeletal injuries that cause early retirement of many racehorses. Gene therapy approaches may also soon provide new means to artificially enhance the physical performance of racehorses. Gene doping, the misuse of gene therapies for performance enhancement, is predicted to be the next phase of doping faced by horseracing. The risk of gene doping to human sports has been recognised for almost 15 years, and the introduction of the first gene doping detection tests for doping control in human athletes is imminent. Gene doping is also a threat to horseracing, but there are currently no methods to detect it. Efficient and accurate detection methods need to be developed to deter those looking to use gene doping in horses and to maintain the integrity of the sport. Methods developed for human athletes could offer an avenue for detection in racehorses. Development of an equine equivalent test will first require identification of equine genes that will likely be targeted by gene doping attempts. This review focuses on genes that have been linked to athletic performance in horses and, therefore, could be targeted for genetic manipulation. The risks associated with gene doping and approaches to detect gene doping are also discussed. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28349657 TI - Program Schedule from the 42nd American Society of Andrology Annual Meeting, 21 - 25 April, 2017, Miami, Florida. PMID- 28349658 TI - Revision and reannotation of the Halomonas elongata DSM 2581T genome. AB - The genome of the Halomonas elongata type strain DSM 2581, an industrial producer, was reevaluated using the Illumina HiSeq2500 technology. To resolve duplication-associated ambiguities, PCR products were generated and sequenced. Outside of duplications, 72 sequence corrections were required, of which 24 were point mutations and 48 were indels of one or few bases. Most of these were associated with polynucleotide stretches (poly-T stretch overestimated in 19 cases, poly-C underestimated in 15 cases). These problems may be attributed to using 454 technology for original genome sequencing. On average, the original genome sequence had only one error in 56 kb. There were 23 frameshift error corrections in the 29 protein-coding genes affected by sequence revision. The genome has been subjected to major reannotation in order to substantially increase the annotation quality. PMID- 28349659 TI - Endoscopic management of tissue-engineered tracheal graft stenosis in an ovine model. AB - OBJECTIVE: To evaluate the safety and efficacy of bronchoscopic interventions in the management of tissue-engineered tracheal graft (TETG) stenosis. STUDY DESIGN: Animal research study. METHODS: TETGs were constructed with seeded autologous bone marrow-derived mononuclear cells on a bioartificial graft. Eight sheep underwent tracheal resection and orthotopic implantation of this construct. Animals were monitored by bronchoscopy and fluoroscopy at 3 weeks, 6 weeks, 3 months, and 4 months. Bronchoscopic interventions, including dilation and stenting, were performed to manage graft stenosis. Postdilation measurements were obtained endoscopically and fluoroscopically. RESULTS: Seven dilations were performed in six animals. At the point of maximal stenosis, the lumen measured 44.6 +/- 8.4 mm2 predilation and 50.7 +/- 14.1 postdilation by bronchoscopy (P = 0.3517). By fluoroscopic imaging, the airway was 55.9 +/- 12.9 mm2 predilation and 65.9 +/- 22.4 mm2 postdilation (P = 0.1303). Stents were placed 17 times in six animals. Pre- and poststenting lumen sizes were 62.8 +/- 38.8 mm2 and 80.1 +/ 54.5 mm2 by bronchoscopy (P = 0.6169) and 77.1 +/- 38.9 mm2 and 104 +/- 60.7 mm2 by fluoroscopy (P = 0.0825). Mortality after intervention was 67% with dilation and 0% with stenting (P = 0.0004). The average days between bronchoscopy were 8 +/- 2 for the dilation group and 26 +/- 17 in the stenting group (P = 0.05). One hundred percent of dilations and 29% of stent placements required urgent follow up bronchoscopy (P = 0.05). CONCLUSION: Dilation has limited efficacy for managing TETG stenosis, whereas stenting has a more lasting clinical effect. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:2219-2224, 2017. PMID- 28349662 TI - Redefining obesity: Beyond the numbers. PMID- 28349660 TI - Intra-prelimbic cortical inhibition of striatal-enriched tyrosine phosphatase suppresses cocaine seeking in rats. AB - Cocaine self-administration in rats results in dysfunctional neuroadaptations in the prelimbic (PrL) cortex during early abstinence. Central to these adaptations is decreased phospho-extracellular signal-regulated kinase (p-ERK), which plays a key role in cocaine seeking. Normalizing ERK phosphorylation in the PrL cortex immediately after cocaine self-administration decreases subsequent cocaine seeking. The disturbance in ERK phosphorylation is accompanied by decreased phosphorylation of striatal-enriched protein tyrosine phosphatase (STEP), indicating increased STEP activity. STEP is a well-recognized ERK phosphatase but whether STEP activation during early abstinence mediates the decrease in p-ERK and is involved in relapse is unknown. Here, we show that a single intra-PrL cortical microinfusion of the selective STEP inhibitor, TC-2153, immediately after self-administration suppressed post-abstinence context-induced relapse under extinction conditions and cue-induced reinstatement, but not cocaine prime induced drug seeking or sucrose seeking. Moreover, an intra-PrL cortical TC-2153 microinfusion immediately after self-administration prevented the cocaine-induced decrease in p-ERK within the PrL cortex during early abstinence. Interestingly, a systemic TC-2153 injection at the same timepoint failed to suppress post abstinence context-induced relapse or cue-induced reinstatement, but did suppress cocaine prime-induced reinstatement. These data indicate that the STEP-induced ERK dephosphorylation in the PrL cortex during early abstinence is a critical neuroadaptation that promotes relapse to cocaine seeking and that systemic versus intra-PrL cortical inhibition of STEP during early abstinence differentially suppresses cocaine seeking. PMID- 28349661 TI - Body mass index trajectories of Indigenous Australian children and relation to screen time, diet, and demographic factors. AB - OBJECTIVE: Limited cross-sectional data indicate elevated overweight/obesity prevalence among Indigenous versus non-Indigenous Australian children. This study aims to quantify body mass index (BMI) trajectories among Indigenous Australian children aged 3-6 and 6-9 years and to identify factors associated with the development of overweight/obesity. METHODS: Three-year BMI change was examined in up to 1,157 children in the national Longitudinal Study of Indigenous Children. BMI trajectories among children with normal baseline BMI (n = 907/1,157) were quantified using growth curve models. RESULTS: Baseline prevalences of overweight/obesity were 12.1% and 25.4% among children of mean age 3 and 6 years, respectively. Of children with normal baseline BMI, 31.9% had overweight/obesity 3 years later; BMI increased more rapidly for younger versus older (difference: 0.59 kg/m2 /year; 95% CI: 0.50-0.69), female versus male (difference: 0.15 kg/m2 /year; 95% CI: 0.07-0.23), and Torres Strait Islander versus Aboriginal (difference: 0.36 kg/m2 /year; 95% CI: 0.17-0.55) children. Results were consistent with less rapid rates of BMI increase for children with lower sugar sweetened beverage (including fruit juice) and high-fat food consumption. Children's BMI was lower in more disadvantaged areas. CONCLUSIONS: Overweight/obesity is common, and increases rapidly, in early childhood. Interventions are required to reduce the overweight/obesity prevalence among Indigenous Australian children in the first 3 years of life and to slow the rapid overweight/obesity onset from age 3 to 9 years. PMID- 28349663 TI - Keeping the baby and throwing out the bathwater. PMID- 28349664 TI - Erratum: Genetic variants in LEP, LEPR, and MC4R explain 30% of severe obesity in children from a consanguineous population. PMID- 28349666 TI - Progressive nature of obesity and diabetes in nonhuman primates. PMID- 28349665 TI - Steeper change in body mass across four decades predicts poorer cardiometabolic outcomes at midlife. AB - OBJECTIVE: This study examined patterns of change in adiposity across four decades starting in young adulthood as well as associations between change and midlife cardiometabolic outcomes. METHODS: BMI was assessed at ages 20, 40, 56, and 62 years in 977 male veterans from the Vietnam Era Twin Study of Aging. Age 62 (range 56-66) cardiometabolic outcomes included hypertension, diabetes, dyslipidemia, inflammation, and ischemic heart disease. Analyses included latent growth modeling (LGM), latent class growth modeling (LCGM), and logistic regression models. RESULTS: Linear BMI slope was associated with all outcomes. Accelerated (quadratic) BMI slope was significantly associated with greater risk for hypertension, diabetes, dyslipidemia, and inflammation; odds ratios ranged from 1.93 (diabetes) to 3.15 (dyslipidemia). Initial BMI did not predict later outcomes. Linear slope contributed significant unique variance for diabetes and dyslipidemia even controlling for age 62 BMI. LCGM revealed three trajectories. Men with the relatively stable, lower BMI trajectory had significantly better outcomes than those with trajectories with accelerated increases, especially those including obesity. CONCLUSIONS: How individuals reach late-midlife BMI is important. Steepness of BMI change across 40 years from young adulthood to late midlife, in addition to late-midlife BMI itself, was robustly associated with greater risk for poor cardiometabolic outcomes. PMID- 28349667 TI - Exercise training-induced improvement in skeletal muscle PGC-1alpha-mediated fat metabolism is independent of dietary glycemic index. AB - OBJECTIVE: This study hypothesized that a low-glycemic diet combined with exercise would increase expression of nuclear regulators of fat transport and oxidation in insulin-resistant skeletal muscle. METHOD: Nineteen subjects (64 +/- 1 y; 34 +/- 1 kg/m2 ) were randomized to receive isocaloric high-glycemic-index (HiGIX; 80 +/- 0.6 units, n = 10) or low-glycemic-index (LoGIX; 40 +/- 0.3 units, n = 9) diets combined with supervised exercise (1 h/d, 5 d/wk at ~85% HRmax ) for 12 weeks. Insulin sensitivity was determined by hyperinsulinemic-euglycemic clamp. Skeletal muscle biopsies were obtained before and after the intervention to assess fasting gene and protein expression. RESULTS: Weight loss was similar for both groups (9.5 +/- 1.3 kg). Likewise, improvements in insulin sensitivity (P < 0.002) and PPARgamma (P < 0.002), PGC-1alpha (P = 0.003), CD36 (P = 0.003), FABP3 (mRNA, P = 0.01 and protein, P = 0.02), and CPT1B (mRNA, P = 0.03 and protein, P = 0.008) expression were similar for both interventions. Increased insulin sensitivity correlated with increased PGC-1alpha expression (P = 0.04), and increased fasting fat oxidation correlated with increased FABP3 (P = 0.04) and CPT1B (P = 0.05) expression. CONCLUSIONS: An exercise/diet program resulting in 8% to 10% weight loss improved insulin sensitivity and key molecular mechanisms in skeletal muscle that are controlled by PGC-1alpha. These effects were independent of the glycemic index of the diets. PMID- 28349669 TI - Polymorphism in emergence of deciduous dentition: A cross-sectional study of Indian children. AB - AIM: The aim of the present study was to evaluate the timing and sequence of the eruption of deciduous teeth in Indian children. METHOD: This cross-sectional study focused on children aged 5-36 months. One hospital was randomly selected from four geographic zones of the city. A total of 400 children from each hospital, fulfilling the inclusion criteria, constituted the sample. The examination was carried out by a single, trained examiner. The tooth was recorded as "present" or "absent" on the day of examination. The mean age of emergence was calculated using a probit model. Independent sample t-test was used to assess the statistical significance of differences in the mean age of tooth emergence. RESULTS: The deciduous mandibular central incisor was the first tooth to erupt in the oral cavity (8.15+/-1.69 months). Girls showed delayed eruption compared to boys; however, no interarch variation was observed in the mean age of tooth eruption. There was also no difference in the sequence of eruption of deciduous teeth, as reported in other studies. CONCLUSIONS: The present study establishes a chronological table for the eruption of deciduous teeth in Indian children. There was delayed eruption of deciduous teeth when compared to the reference ranges of Western populations. PMID- 28349668 TI - Stress, cortisol, and other appetite-related hormones: Prospective prediction of 6-month changes in food cravings and weight. AB - OBJECTIVE: To examine whether baseline chronic stress, morning cortisol, and other appetite-related hormones (leptin, ghrelin, and insulin) predict future weight gain and food cravings in a naturalistic, longitudinal, 6-month follow-up study. METHODS: A prospective community cohort of 339 adults (age 29.1 +/- 9.0 years; BMI = 26.7 +/- 5.4 kg/m2 ; 56.9% female; 70.2% white) completed assessments at baseline and 6-month follow-up. Fasting blood draws were used to assess cortisol and other appetite-related hormone levels at baseline. At baseline and follow-up, body weight was measured, and the Cumulative Adversity Interview and Food Craving Inventory were administered. Data were analyzed using linear mixed models adjusting for demographic and clinical covariates. RESULTS: Over the 6-month period, 49.9% of the sample gained weight. Food cravings and chronic stress decreased over 6 months (Ps < 0.05). However, after adjusting for covariates, individuals with higher baseline total ghrelin had significantly higher food cravings at 6 months (P = 0.04). Furthermore, higher cortisol, insulin, and chronic stress were each predictive of greater future weight gain (Ps < 0.05). CONCLUSIONS: These results suggest that ghrelin plays a role in increased food cravings and reward-driven eating behaviors. Studies are needed that examine the utility of stress reduction methods for normalizing disrupted cortisol responses and preventing future weight gain. PMID- 28349670 TI - Metabolic engineering to expand the substrate spectrum of Pseudomonas putida toward sucrose. AB - Sucrose is an important disaccharide used as a substrate in many industrial applications. It is a major component of molasses, a cheap by-product of the sugar industry. Unfortunately, not all industrially relevant organisms, among them Pseudomonas putida, are capable of metabolizing sucrose. We chose a metabolic engineering approach to circumvent this blockage and equip P. putida with the activities necessary to consume sucrose. Therefore, we constructed a pair of broad-host range mini-transposons (pSST - sucrose splitting transposon), carrying either cscA, encoding an invertase able to split sucrose into glucose and fructose, or additionally cscB, encoding a sucrose permease. Introduction of cscA was sufficient to convey sucrose consumption and the additional presence of cscB had no further effect, though the sucrose permease was built and localized to the membrane. Sucrose was split extracellularly by the activity of the invertase CscA leaking out of the cell. The transposons were also used to confer sucrose consumption to Cupriavidus necator. Interestingly, in this strain, CscB acted as a glucose transporter, such that C. necator also gained the ability to grow on glucose. Thus, the pSST transposons are functional tools to extend the substrate spectrum of Gram-negative bacterial strains toward sucrose. PMID- 28349671 TI - In vitro algicidal effect of guanidine on Prototheca zopfii genotype 2 strains isolated from clinical and subclinical bovine mastitis. AB - : Prototheca species have increasingly been reported to be opportunistic pathogens that cause mastitis in dairy herds, and it poses an emergent problem because at present, there are no effective therapies for the treatment of protothecal mastitis. This study investigated the in vitro algicidal effect of guanidine on 75 Prototheca zopfii genotype 2 strains isolated from 75 cases of clinical and subclinical bovine mastitis. All strains were susceptible to guanidine in vitro with minimal algaecide concentrations ranging from 0.001 to 0.035%. Guanidine is known to have a high microbicidal effect and is considered to be a new generation microbicidal compound. It is not toxic to human mucous membranes and conjunctivas at low concentrations and has been used as a disinfectant in swimming pools and as an antiseptic for human wounds. The algicidal action of guanidine at low concentrations indicates that it could be an alternative disinfectant or antiseptic for cleaning of the dairy environment and milking equipment, in pre- and postdipping solutions, in the chemical dry therapy of bovine teats and even in the intramammary therapy of P. zopfii infections. This is the first report of the in vitro algicidal effect of guanidine on P. zopfii strains of animal origin. SIGNIFICANCE AND IMPACT OF THE STUDY: Prototheca zopfii genotype 2 is an opportunistic pathogen of bovine mastitis. To date, no effective therapies against protothecal mastitis have been developed. The in vitro algicidal effect of guanidine on 75 P. zopfii genotype 2 strains isolated from cows revealed that all of the isolates were susceptible to the compound at low concentrations, which indicates that guanidine may be used as an antiseptic/disinfectant for dairy milking equipment, in pre- and postdipping solutions, and as a chemical dry therapy or an intramammary therapy. This study describes the in vitro algicidal effect of guanidine on P. zopfii for the first time. PMID- 28349672 TI - Design, synthesis, antiviral bioactivity and three-dimensional quantitative structure-activity relationship study of novel ferulic acid ester derivatives containing quinazoline moiety. AB - BACKGROUND: Ferulic acid and quinazoline derivatives possess good antiviral activities. In order to develop novel compounds with high antiviral activities, a series of ferulic acid ester derivatives containing quinazoline were synthesized and evaluated for their antiviral activities. RESULTS: Bioassays indicated that some of the compounds exhibited good antiviral activities in vivo against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV). One of the compounds demonstrated significant curative and protective activities against TMV and CMV, with EC50 values of 162.14, 114.61 and 255.49, 138.81 mg L-1 , respectively, better than those of ningnanmycin (324.51, 168.84 and 373.88, 272.70 mg L-1 ). The values of q2 and r2 for comparative molecular field analysis and comparative molecular similarity index analysis in the TMV (0.508, 0.663 and 0.992, 0.930) and CMV (0.530, 0.626 and 0.997, 0.981) models presented good predictive abilities. CONCLUSION: Some of the title compounds demonstrated good antiviral activities. Three-dimensional quantitative structure-activity relationship models revealed that the antiviral activities depend on steric and electrostatic properties. These results could provide significant structural insights for the design of highly active ferulic acid derivatives. (c) 2017 Society of Chemical Industry. PMID- 28349675 TI - Corrigendum. PMID- 28349673 TI - Involvement of oxidative stress in protocatechuic acid-mediated bacterial lethality. AB - The involvement of oxidative stress in protocatechuic acid-mediated bacterial lethality was investigated. Minimum inhibitory concentrations (MIC) and minimum bactericidal concentration (MBC) of protocatechuic acid against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus are 600 and 700 MUg/ml, 600 and 800 MUg/ml, and 600 and 800 MUg/ml, respectively. The optical densities and colony-forming units of protocatechuic acid-treated bacteria decreased in time dependent manner. Protocatechuic acid (4* MIC) significantly increased the superoxide anion content of E. coli, P. aeruginosa, and S. aureus compared to dimethyl sulfoxide (DMSO). Superoxide dismutase, catalase, and NAD+ /NADH in protocatechuic acid-treated E. coli, P. aeruginosa, and S. aureus increased significantly when compared to DMSO. Conversely, level of reduced glutathione decreased in protocatechuic acid-treated E. coli, P. aeruginosa, and S. aureus, while glutathione disulfide increased when compared to DMSO. Furthermore, malondialdehyde and fragmented DNA increased significantly following exposure to protocatechuic acid. Protocatechuic acid inhibited the activity of complexes I and II. From the above findings, protocatechuic acid enhanced the generation of reactive oxygen species (superoxide anion radical and hydroxyl radical) in E. coli, P. aeruginosa, and S. aureus, possibly by autoxidation, fenton chemistry, and inhibiting electron transport chain resulting in lipid peroxidation and DNA fragmentation and consequentially bacterial cell death. PMID- 28349674 TI - Association between specific periodontal pathogens, Toll-like receptor-4, and nuclear factor-kappaB expression in placental tissues of pre-eclamptic women with periodontitis. AB - AIM: The aim of the present study was to determine the association between the presence of specific periodontal pathogens, Toll-like receptor-4 (TLR-4), and nuclear factor-kappaB (NF-kappaB) expression in the placental tissues of pre eclamptic women. METHODS: Antenatal periodontal screening was performed in 25 normotensive pregnant women and 25 pre-eclamptic women. Subgingival plaque and placental tissue samples were collected from both groups and screened for the presence of Porphyromonas gingivalis (P. gingivalis), Tannerella forsythia, Aggregatibacter actinomycetemcomitans, and Prevotella intermedia (P. intermedia) using real-time polymerase chain reaction. The placental samples were also analyzed to quantify TLR-4 and NF-kappaB expression. RESULTS: The subgingival plaque samples of pre-eclamptic women showed significantly higher frequencies of P. intermedia. In the placental samples, P. gingivalis, P. intermedia, and the expression of TLR-4 and NF-kappaB were found to be at significantly higher levels compared to normotensive pregnant women. Using linear regression analysis, the expression of TLR-4 was significantly influenced by the presence of P. gingivalis (coefficient=3.176, 95% confidence interval [CI]: 367-5.986) and P. intermedia (coefficient=2.886, 95% CI: 0.77-5.696), whereas NF-kappaB expression was influenced only by the presence of P. intermedia (coefficient=2.220, 95% CI: 0.051-4.388) in the placental tissues of pre-eclamptic women. CONCLUSION: An association exists between P. gingivalis and P. intermedia with increased TLR-4 and NF-kappaB expression in the placenta of pre-eclamptic women with periodontitis. PMID- 28349676 TI - Flourodeoxyglucose positron emission tomography scan may be helpful in the case of ductal variant prostate cancer when prostate specific membrane antigen ligand positron emission tomography scan is negative. AB - Gallium-68 prostate specific membrane antigen ligand (Ga-68 PSMA) positron emission tomography/computed tomography (PET/CT) scanning is emerging as a useful imaging modality for the staging of suspected and known recurrent or metastatic prostate cancer and in staging of newly diagnosed higher grade prostate cancer. However, we have observed at our institution that in some cases of the more aggressive ductal variant, Ga-68 PSMA uptake has sometimes been poor compared with prominent 18-flourodeoxyglucose (F-18 FDG) avidity seen in F-18 FDG PET/CT, which would suggest that FDG PET/CT scans are important in staging of ductal pattern prostate cancer. PMID- 28349677 TI - Aggressive tumor recurrence after radiofrequency ablation for hepatocellular carcinoma. AB - Image-guided radiofrequency ablation (RFA) is an evolving and growing treatment option for patients with hepatocellular carcinoma (HCC) and hepatic metastasis. RFA offers significant advantages as it is less invasive than surgery and carries a low risk of major complications. However, serious complications, including aggressive tumor recurrence, may be observed during follow-up, and recently, mechanical or thermal damage during RFA has been proposed to be one of the causes of this kind of recurrence. Although the exact mechanism of this still remains unclear, physicians should be familiar with the imaging features of aggressive tumor recurrence after RFA for HCC and its risk factors. In addition, in order to prevent or minimize this newly recognized tumor recurrence, a modified RFA technique, combined RFA treatments with transarterial chemoembolization, and cryoablation can be used as alternative treatments. Ultimately, combining an understanding of this potential complication of RFA with an understanding of the possible risk factors for aggressive tumor recurrence and choosing alternative treatments are crucial to optimize clinical outcomes in each patient with HCC. PMID- 28349678 TI - A lexicon for hepatocellular carcinoma surveillance ultrasonography: benign versus malignant lesions. AB - BACKGROUND/AIMS: To suggest a lexicon for liver ultrasonography and to identify radiologic features indicative of benign or malignant lesions on surveillance ultrasonography. METHODS: This retrospective study included 188 nodules (benign, 101; malignant, 87) from 175 at-risk patients identified during surveillance ultrasonography for hepatocellular carcinoma. We created a lexicon for liver ultrasonography by reviewing relevant literature regarding the ultrasonographic features of hepatic lesions. Using this lexicon, two abdominal radiologists determined the presence or absence of each ultrasonographic feature for the included hepatic lesions. Independent factors associated with malignancy and interobserver agreement were determined by logistic regression analysis and kappa statistics, respectively. RESULTS: Larger tumor size (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.06-1.183; P<0.001), multinodular confluent morphology (OR, 7.712; 95% CI, 1.053-56.465; P=0.044), thick hypoechoic rim (OR, 5.878; 95% CI, 2.681-12.888; P<0.001), and posterior acoustic enhancement (OR, 3.077; 95% CI, 1.237-7.655; P=0.016) were independently associated with malignant lesions. In a subgroup analysis of lesions <2 cm, none of the ultrasonographic features were significantly associated with malignancy or benignity. Interobserver agreement for morphology was fair (kappa=0.36), while those for rim (kappa=0.427), echogenicity (kappa=0.549), and posterior acoustic enhancement (kappa=0.543) were moderate. CONCLUSIONS: For hepatic lesions larger than 2 cm, some ultrasonography (US) features might be suggestive of malignancy. We propose a lexicon that may be useful for surveillance US. PMID- 28349679 TI - Transient elastography can be integrated into routine clinical practice for the evaluation of portal hypertension? PMID- 28349680 TI - Expression and Purification of ZASP Subdomains and Clinically Important Isoforms: High-Affinity Binding to G-Actin. AB - Z-disc-associated, alternatively spliced, PDZ motif-containing protein (ZASP) is a principal component of the sarcomere. The three prevalent isoforms of ZASP in skeletal muscle are generated by alternative splicing of exons 9 and 10. The long isoforms, either having (ZASP-L) or lacking exon 10 (ZASP-LDeltaex10), include an N-terminal PDZ domain, an actin-binding region (ABR) with a conserved motif (ZM), and three C-terminal LIM domains. The short isoform (ZASP-S) lacks the LIM domains. Mutations, A147T and A165V, within the ZM of ZASP-LDeltaex10 cause myofibrillar myopathy, but the mechanism is unknown. We have prepared these proteins, their ABR, and the respective mutant variants in recombinant form, characterized them biophysically, and analyzed their actin-binding properties by surface plasmon resonance and electron microscopy. All the proteins were physically homogeneous and monomeric and had circular dichroic spectra consistent with partially folded conformations. Comparison of the NMR HSQC spectra of ZASP-S and the PDZ domain showed that the ABR is unstructured. ZASP-S and its mutant variants and ZASP-LDeltaex10 all bound to immobilized G-actin with high affinity (Kd ~ 10-8 to 10-9 M). Constructs of the isolated actin-binding region missing exon 10 (ABRDelta10) bound with lower affinity (Kd ~ 10-7 M), but those retaining exon 10 (ABR+10) did so only weakly (Kd ~ 10-5 M). ZASP-S, and the ABRDelta10, also induced F-actin and array formation, even in conditions of low ionic strength and in the absence of KCl and Mg2+ ions. Interestingly, the ZM mutations A147T and A165V did not affect any of the results described above. PMID- 28349682 TI - Reaction Mechanism of Iodine-Catalyzed Michael Additions. AB - Molecular iodine, an easy to handle solid, has been successfully employed as a catalyst in different organic transformations for more than 100 years. Despite being active even in very small amounts, the origin of this remarkable catalytic effect is still unknown. Both a halogen bond mechanism as well as hidden Bronsted acid catalysis are frequently discussed as possible explanations. Our kinetic analyses reveal a reaction order of 1 in iodine, indicating that higher iodine species are not involved in the rate-limiting transition state. Our experimental investigations rule out hidden Bronsted acid catalysis by partial decomposition of I2 to HI and suggest a halogen bond activation instead. Finally, molecular iodine turned out to be a similar if not superior catalyst for Michael additions compared with typical Lewis acids. PMID- 28349681 TI - In Situ Investigation of Electrochemically Mediated Surface-Initiated Atom Transfer Radical Polymerization by Electrochemical Surface Plasmon Resonance. AB - Electrochemically mediated atom transfer radical polymerization (eATRP) initiates/controls the controlled/living ATRP chain propagation process by electrochemically generating (regenerating) the activator (lower-oxidation-state metal complex) from deactivator (higher-oxidation-state metal complex). Despite successful demonstrations in both of the homogeneous polymerization and heterogeneous systems (namely, surface-initiated ATRP, SI-ATRP), the eATRP process itself has never been in situ investigated, and important information regarding this process remains unrevealed. In this work, we report the first investigation of the electrochemically mediated SI-ATRP (eSI-ATRP) by rationally combining the electrochemical technique with real-time surface plasmon resonance (SPR). In the experiment, the potential of a SPR gold chip modified by the self assembled monolayer of the ATRP initiator was controlled to electrochemically reduce the deactivator to activator to initiate the SI-ATRP, and the whole process was simultaneously monitored by SPR with a high time resolution of 0.1 s. It is found that it is feasible to electrochemically trigger/control the SI-ATRP and the polymerization rate is correlated to the potential applied to the gold chip. This work reveals important kinetic information for eSI-ATRP and offers a powerful platform for in situ investigation of such complicated processes. PMID- 28349683 TI - Highly Flexible and Conductive Cellulose-Mediated PEDOT:PSS/MWCNT Composite Films for Supercapacitor Electrodes. AB - Recent improvements in flexible electronics have increased the need to develop flexible and lightweight power sources. However, current flexible electrodes are limited by low capacitance, poor mechanical properties, and lack of cycling stability. In this article, we describe an ionic liquid-processed supramolecular assembly of cellulose and 3,4-ethylenedioxythiophene for the formation of a flexible and conductive cellulose/poly(3,4-ethylenedioxythiophene) PEDOT:poly(styrene sulfonate) (PSS) composite matrix. On this base, multiwalled carbon nanotubes (MWCNTs) were incorporated into the matrix to fabricate an MWCNT reinforced cellulose/PEDOT:PSS film (MCPP), which exhibited favorable flexibility and conductivity. The MCPP-based electrode displayed comprehensively excellent electrochemical properties, such as a low resistance of 0.45 Omega, a high specific capacitance of 485 F g-1 at 1 A g-1, and good cycling stability, with a capacity retention of 95% after 2000 cycles at 2 A g-1. An MCPP-based symmetric solid-state supercapacitor with Ni foam as the current collector and PVA/KOH gel as the electrolyte exhibited a specific capacitance of 380 F g-1 at 0.25 A g-1 and achieved a maximum energy density of 13.2 Wh kg-1 (0.25 A g-1) with a power density of 0.126 kW kg-1 or an energy density of 4.86 Wh kg-1 at 10 A g-1, corresponding to a high power density of 4.99 kW kg-1. Another kind of MCPP-based solid-state supercapacitor without the Ni foam showed excellent flexibility and a high volumetric capacitance of 50.4 F cm-3 at 0.05 A cm-3. Both the electrodes and the supercapacitors were environmentally stable and could be operated under remarkable deformation or high temperature without damage to their structural integrity or a significant decrease in capacitive performance. Overall, this work provides a strategy for the fabrication of flexible and conductive energy-storage films with ionic liquid-processed cellulose as a medium. PMID- 28349684 TI - Asymmetric [3 + 2] Cycloaddition of 3-Amino Oxindole-Based Azomethine Ylides and alpha,beta-Enones with Divergent Diastereocontrol on the Spiro[pyrrolidine oxindoles]. AB - A general and practical organocatalytic asymmetric 1,3-dipolar cycloaddition of 3 amino oxindole-based azomethine ylides and alpha,beta-enones has been developed. This reaction delivered spiro[pyrrolidine-2,3'-oxindole] products in high yields with excellent regio- and enantioselectivities (up to 99% yield, >20:1 rr, 99% ee). In addition, an array of spiro[dihydropyrrole-2,3'-oxindoles] were readily accessed by oxidative dehydrogenation. Notably, the inversion of the diastereoselectivity of the spiro[pyrrolidine-oxindole] product could be easily achieved through a facile oxidation-reduction process. PMID- 28349686 TI - Synthesis of Functionalized beta-Keto Arylthioethers by the Aryne Induced [2,3] Stevens Rearrangement of Allylthioethers. AB - A mild and transition-metal-free synthesis of beta-keto arylthioethers has been developed by the aryne triggered [2,3] Stevens rearrangement of allylthioethers. The key sulfur ylide intermediate for the rearrangement was formed by the S arylation of allylthioethers with arynes generated from 2-(trimethylsilyl)aryl triflates using CsF. Later, the reaction products are converted into valuable heterocycles in two steps. PMID- 28349685 TI - PTMOracle: A Cytoscape App for Covisualizing and Coanalyzing Post-Translational Modifications in Protein Interaction Networks. AB - Post-translational modifications of proteins (PTMs) act as key regulators of protein activity and of protein-protein interactions (PPIs). To date, it has been difficult to comprehensively explore functional links between PTMs and PPIs. To address this, we developed PTMOracle, a Cytoscape app for coanalyzing PTMs within PPI networks. PTMOracle also allows extensive data to be integrated and coanalyzed with PPI networks, allowing the role of domains, motifs, and disordered regions to be considered. For proteins of interest, or a whole proteome, PTMOracle can generate network visualizations to reveal complex PTM associated relationships. This is assisted by OraclePainter for coloring proteins by modifications, OracleTools for network analytics, and OracleResults for exploring tabulated findings. To illustrate the use of PTMOracle, we investigate PTM-associated relationships and their role in PPIs in four case studies. In the yeast interactome and its rich set of PTMs, we construct and explore histone associated and domain-domain interaction networks and show how integrative approaches can predict kinases involved in phosphodegrons. In the human interactome, a phosphotyrosine-associated network is analyzed but highlights the sparse nature of human PPI networks and lack of PTM-associated data. PTMOracle is open source and available at the Cytoscape app store: http://apps.cytoscape.org/apps/ptmoracle . PMID- 28349688 TI - Portable and Reliable Surface-Enhanced Raman Scattering Silicon Chip for Signal On Detection of Trace Trinitrotoluene Explosive in Real Systems. AB - There is an increasing interest in the development of surface-enhanced Raman scattering (SERS) sensors for rapid and accurate on-site detection of hidden explosives. However, portable SERS methods for trace explosive detection in real systems remain scarce, mainly due to their relatively poor reliability and portability. Herein, we present the first demonstration of a portable silicon based SERS analytical platform for signal-on detection of trace trinitrotoluene (TNT) explosives, which is made of silver nanoparticle (AgNP)-decorated silicon wafer chip (0.5 cm * 0.5 cm). In principle, under 514 nm excitation, the Raman signals of p-aminobenzenethiol (PABT) modified on the AgNP surface could be largely lit up due to the formation of electronic resonance-active TNT-PABT complex. In addition, the surface of AgNPs and silicon substrate-induced plasmon resonances also contribute the total SERS enhancement. For quantitative evaluation, the as-prepared chip features ultrahigh sensitivity [limit of detection is down to ~1 pM (~45.4 fg/cm2)] and adaptable reproducibility (relative standard deviation is less than 15%) in the detection of TNT standard solutions. More importantly, the developed chip can couple well with a hand-held Raman spectroscopic device using 785 nm excitation, suitable for qualitative analysis of trace TNT even at ~10-8 M level from environmental samples including lake water, soil, envelope, and liquor with a short data acquisition time (~1 min). Furthermore, TNT vapors diffusing from TNT residues (~10-6 M) can be detected by using such a portable device, indicating its feasibility in determination of hidden samples. PMID- 28349687 TI - Aerobic C-H Oxidation of Arenes Using a Recyclable, Heterogeneous Rhodium Catalyst. AB - A novel, practical protocol for the aerobic direct C-H acetoxylation of arenes, employing a recyclable heterogeneous rhodium catalyst, is reported herein. The trifluoroacetoxylation of 2-amido-substituted anthracenes proceeded at the 9 position with exclusive regioselectivity. The oxidation of variously substituted anthracenes and other polycyclic aromatics with molecular oxygen as a terminal oxidant proceeded under mild conditions, providing products in good to excellent yields. PMID- 28349689 TI - Stability of Clay Particle-Coated Microbubbles in Alkanes against Dissolution Induced by Heating. AB - We investigated the dissolution and morphological dynamics of air bubbles in alkanes stabilized by fluorinated colloidal clay particles when subjected to temperature changes. A model for bubble dissolution with time-dependent temperature reveals that increasing the temperature enhances the bubble dissolution rate in alkanes, opposite to the behavior in water, because of the differing trends in gas solubility. Experimental results for uncoated air bubbles in decane and hexadecane confirm this prediction. Clay-coated bubbles in decane and hexadecane are shown to be stable in air-saturated oil at constant temperature, where dissolution is driven mainly by the Laplace pressure. When the temperature increases from ambient, the particle-coated bubbles are prone to dissolution as the oil phase becomes undersaturated. The interfacial layer of particles is observed to undergo buckling and crumpling, without shedding of clay particles. Increasing the concentration of particles is shown to enhance the bubble stability by providing a higher resistance to dissolution. When subjected to complex temperature cycles, for which the effect of time-dependent temperature is dominant, the clay-coated bubbles can resist long-term dissolution in conditions under which uncoated bubbles dissolve completely. These results underpin the design of ultrastable oil foams stabilized by solid particles with improved shelf life under changing environmental conditions. PMID- 28349690 TI - Stratification Dynamics in Drying Colloidal Mixtures. AB - Stratification in binary colloidal mixtures was investigated using implicit solvent molecular dynamics simulations. For large particle size ratios and film Peclet numbers greater than unity, smaller colloids migrated to the top of the film, while big colloids were pushed to the bottom, creating an "inverted" stratification. This peculiar behavior was observed in recent simulations and experiments conducted by Fortini et al. [ Phys. Rev. Lett. 2016 , 116 , 118301 ]. To rationalize this behavior, particle size ratios and drying rates spanning qualitatively different Peclet number regimes were systematically studied, and the dynamics of the inverted stratification were quantified in detail. The stratified layer of small colloids was found to grow faster and to larger thicknesses for larger size ratios. Interestingly, inverted stratification was observed even at moderate drying rates where the film Peclet numbers were comparable to unity, but the thickness of the stratified layer decreased. A model based on dynamical density functional theory is proposed to explain the observed phenomena. PMID- 28349691 TI - Synergetic SERS Enhancement in a Metal-Like/Metal Double-Shell Structure for Sensitive and Stable Application. AB - Because of either thermal/chemical instability or high optical loss in noble metal nanostructures, searching for alternative plasmonic materials is becoming more and more urgent, considering the practical biosensing applications under various extreme conditions. In this work, titanium nitride (TiN), a low-loss metal-like material with both excellent thermal and excellent chemical stabilities, was proposed to composite with Ag hollow nanosphere (HNS) nanostructures as an effective surface-enhanced Raman scattering (SERS) substrate to realize both highly sensitive and highly stable molecular detection. Because of the multiple-mode local surface plasmon resonance around the spherical composite nanospheres and the "gap effect" derived from the ultrasmall nanogaps within the precisely controlled plasmonic arrays, an intensively enhanced local field was successfully induced on this SERS substrate. Combined with the unique charge transferring process between Ag and TiN, a synergistically enhanced SERS sensitivity involving both physical and chemical mechanisms was achieved. Especially, with the isolation of TiN, a time-durable Raman detection on these TiN-Ag HNS arrays was accomplished, showing great potential for practical applications. PMID- 28349692 TI - Correction to Fragment-Linking Approach Using 19F NMR Spectroscopy To Obtain Highly Potent and Selective Inhibitors of beta-Secretase. PMID- 28349693 TI - Thermal Stability of Platinum-Cobalt Bimetallic Nanoparticles: Chemically Disordered Alloys, Ordered Intermetallics, and Core-Shell Structures. AB - Pt-Co bimetallic nanoparticles are promising candidates for Pt-based nanocatalysts and magnetic-storage materials. By using molecular dynamics simulations, we here present a detailed examination on the thermal stabilities of Pt-Co bimetallic nanoparticles with three configurations including chemically disordered alloy, ordered intermetallics, and core-shell structures. It has been revealed that ordered intermetallic nanoparticles possess better structural and thermal stability than disordered alloyed ones for both Pt3Co and PtCo systems, and Pt3Co-Pt core-shell nanoparticles exhibit the highest melting points and the best thermal stability among Pt-Co bimetallic nanoparticles, although their meltings all initiate at the surface and evolve inward with increasing temperatures. In contrast, Co-Pt core-shell nanoparticles display the worst thermal stability compared with the aforementioned nanoparticles. Furthermore, their melting initiates in the core and extends outward surface, showing a typical two-stage melting mode. The solid-solid phase transition is discovered in Co core before its melting. This work demonstrates the importance of composition distribution to tuning the properties of binary nanoparticles. PMID- 28349695 TI - Catalyst-Free Synthesis of Pyrrolo[1,2-a]quinolines via Dehydration/[3 + 2] Cycloaddition Directly from 2-Methylquinolines, Aldehydes, and Alkynoates. AB - A simple and efficient catalyst-free synthesis of pyrrolo[1,2-a]quinoline derivatives from 2-methylquinolines, aldehydes, and alkynoates via dehydration/[3 + 2] cycloaddition has been developed. The reaction conditions are tolerant to air, and H2O is the only byproduct of this transformation, thus offering an environmentally benign process with a wide range of potential applications in organic synthesis and medicinal chemistry. PMID- 28349694 TI - Assemblies of Colloidal CdSe Tetrapod Nanocrystals with Lengthy Arms for Flexible Thin-Film Transistors. AB - Herein, we report unique features of the assemblies of tetrapod-shaped colloidal nanocrystals (TpNCs) with lengthy arms applicable to flexible thin-film transistors. Due to the extended nature of tetrapod geometry, films made of the TpNC assemblies require reduced numbers of inter-NC hopping for the transport of charge carriers along a given channel length; thus, enhanced conductivity can be achieved compared to those made of typical spherical NCs without arms. Moreover, electrical conduction through the assemblies is tolerant against mechanical bending because interconnections between TpNCs can be well-preserved under bending. Interestingly, both the conductivity of the assemblies and their mechanical tolerance against bending are improved with an increase in the length of tetrapod arms. The arm length-dependency was demonstrated in a series of CdSe TpNC assemblies with different arm lengths (l = 0-90 nm), whose electrical conduction was modulated through electrolyte gating. From the TpNCs with the longest arm length included in the study (l = 90 nm), the film conductivity as high as 20 S/cm was attained at 3 V of gate voltage, corresponding to electron mobility of >10 cm2/(V s) even when evaluated conservatively. The high channel conductivity was retained (~90% of the value obtained from the flat geometry) even under high bending (bending radius = 5 mm). The results of the present study provide new insights and guidelines for the use of colloidal nanocrystals in solution-processed flexible electronic device applications. PMID- 28349696 TI - Peptide Receptor-Targeted Fluorescent Probe: Visualization and Discrimination between Chronic and Acute Ulcerative Colitis. AB - The inflammatory activity of ulcerative colitis plays an important role in the medical treatment. However, accurate and real-time monitoring of the colitis activity with noninvasive bioimaging method is still challenging, especially in distinguishing between chronic and acute colitis. As a good receptor, the oligopeptide transporter (PepT1) is overexpressed in the colonic epithelial cells of chronic ulcerative colitis, which can deliver tripeptide KPV (Lys-Pro-Val, the C-terminal sequence of alpha-MSH) into cytosol in the intestine. Herein, we report a PepT1 peptide receptor-targeted fluorescent probe, dicyanomethylene-4H pyran (DCM)-KPV, with the strategy of conjugating the KPV into the DCM chromophore. The diagnostic fluorescent probe bestows a specific receptor targeted interaction with PepT1 through the KPV moiety, possessing several beneficial characteristics, such as efficient long emission, low photobleaching, negligible cytotoxicity, and high cytocompatibility in living cells. We build the overexpressed PepT1 on the cytomembrane of ulcerative colitis model Caco-2 cell as the efficient receptor to accumulate the targeted tripeptide KPV in the cytoplasm and nucleus. With the co-localization of DCM-KPV and the DNA-specific fluorophore, DAPI, the specifically long emission from chromophore DCM and efficient receptor-targeted peptide KPV, the fluorescent probe of DCM-KPV makes a breakthrough to the direct noninvasive observation of the accumulation in colon inflammation regions via intestinal mucosa, even successfully distinguishing the chronic, acute ulcerative colitis and normal groups. Compared with the traditional unenhanced magnetic resonance imaging and hematoxylin and eosin (H&E) staining, we make full use of exploiting the specific target-receptor interaction between the tripeptide unit, KPV, and the oligopeptide transporter, PepT1, for sensing selectivity. The desirable diagnostic ability of DCM-KPV can guarantee the real-time tracking and visualization of the role of intracellular KPV on ulcerative colitis, which provides an alternative to replace the time-consuming and tissue sampling-invasive H&E staining diagnosis. PMID- 28349697 TI - Chained Iron Microparticles for Directionally Controlled Actuation of Soft Robots. AB - Magnetic field-directed self-assembly of magnetic particles in chains is useful for developing directionally responsive materials for applications in soft robotics. Using materials with greater complexity allows advanced functions, while still using simple device architectures. Elastomer films containing chained magnetic microparticles were prepared through solvent casting and formed into magnetically actuated lifters, accordions, valves, and pumps. Chaining both enhances actuation and imparts a directional response. Cantilevers used as lifters were able to lift up to 50 times the mass of the polymer film. We introduce the "specific torque", the torque per field per mass of magnetic particles, as a figure of merit for assessing and comparing the performance of lifters and related devices. Devices in this work generated specific torques of 68 Nm/kgT, which is significantly higher than in previously reported actuators. Applying magnetic fields to folded accordion structures caused extension and compression, depending on the accordion's orientation. In peristaltic pumps comprised of composite tubes containing embedded chains, magnetic fields caused a section of the tube to pinch closed where the field was applied. These results will facilitate both the further development of soft robots based on chained magnetic particles and efforts to engineer materials with higher specific torque. PMID- 28349698 TI - Enantioselective Synthesis of (-)-Acetylapoaranotin. AB - The first enantioselective total synthesis of the epipolythiodiketopiperazine (ETP) natural product (-)-acetylapoaranotin (3) is reported. The concise synthesis was enabled by an eight-step synthesis of a key cyclohexadienol containing amino ester building block. The absolute stereochemistry of both amino ester building blocks used in the synthesis is set through catalytic asymmetric (1,3)-dipolar cycloaddition reactions. The formal syntheses of (-)-emethallicin E and (-)-haemotocin are also achieved through the preparation of a symmetric cyclohexadienol-containing diketopiperazine. PMID- 28349699 TI - Limiting the Hydrolysis and Oxidation of Maleimide-Peptide Adducts Improves Detection of Protein Thiol Oxidation. AB - Oxidative stress, caused by reactive oxygen and nitrogen species (RONS), is important in the pathophysiology of many diseases. A key target of RONS is the thiol group of protein cysteine residues. Because thiol oxidation can affect protein function, mechanistic information about how oxidative stress affects tissue function can be ascertained by identifying oxidized proteins. The probes used must be specific and sensitive, such as maleimides for the alkylation of reduced cysteine thiols. However, we find that maleimide-alkylated peptides (MAPs) are oxidized and hydrolyzed under sample preparation conditions common for proteomic studies. This can result in up to 90% of the MAP signal being converted to oxidized or hydrolyzed MAPs, decreasing the sensitivity of the analysis. A substantial portion of these modifications were accounted for by Coomassie "blue silver" staining (~14%) of gels and proteolytic digestion buffers (~20%). More than 40% of the MAP signal can be retained with the use of thioglycolic acid during gel electrophoresis, trichloroethanol-UV protein visualization in gels, and proteolytic digestion buffer of pH 7.0 TRIS. This work demonstrates that it is possible to decrease modifications to MAPs through changes to the sample preparation workflow, enhancing the potential usefulness of maleimide in identifying oxidized peptides. PMID- 28349701 TI - Phytochemical study of Bituminaria basaltica aerial parts, an Italian endemism. AB - The first phytochemical investigation of the aerial parts of Bituminaria basaltica, an endemic species from the Aeolian Islands, led to the isolation and identification of eight compounds including plicatin B (3), two furanocoumarins: angelicin (1), psoralen (2), three pterocarpans: erybraedin C (4), 3,9-dihydroxy 4-isoprenyl-pterocarpan (5), bitucarpin A (8) and two flavonoid glycosides: isoorientin (6), daidzin (7). Their structures were elucidated by spectroscospic techniques and compared with data reported in the literature. Sesquiterpenes characterised the essential oil composition of the title plant where beta caryophyllene and germacrene D were the main constituents. PMID- 28349700 TI - Fast corroding, thin magnesium coating displays antibacterial effects and low cytotoxicity. AB - Bacterial colonisation and biofilm formation are characteristics of implant associated infections. In search of candidates for improved prosthetic materials, fast corroding Mg-based coatings on titanium surfaces were examined for their cytotoxic and antimicrobial properties. Human osteoblasts and Staphylococcus epidermidis were each cultured on cylindrical Ti samples coated with a thin layer of Mg/Mg45Zn5Ca, applied via magnetron sputtering. Uncoated titanium samples served as controls. S. epidermidis was quantified by counting colony forming units. The biofilm-bound fraction was isolated via ultrasonic treatment, and the planktonic fraction via centrifugation. Biofilm-bound S. epidermidis was significantly decreased by approximately four to five orders of magnitude in both Mg- and Mg45Zn5Ca-coated samples after seven days compared to the control. The osteoblast viability was within the tolerance threshold of 70% stated in DIN EN ISO 10993-5:2009-10 for Mg (~80%) but not for Mg45Zn5Ca (~25%). Accordingly, Mg coated titanium was identified as a promising candidate for an implant material with antibacterial properties and low cytotoxicity levels. The approach of exploiting fast corrosion contrasts with existing methods, which have generally focused on reducing corrosion. PMID- 28349702 TI - Biotransformation of ginsenosides F4 and Rg6 in zebrafish. AB - Ginsenosides F4 and Rg6 (GF4 and GRg6), two main active components of steamed notoginseng or red ginseng, are dehydrated disaccharide saponins. In this work, biotransformation of ginsenosides F4 and Rg6 in zebrafish was investigated by qualitatively identifying their metabolites and then proposing their possible metabolic pathways. The prediction of possible metabolism of ginsenosides F4 and Rg6 using zebrafish model which can effectively simulate existing mammals model was early and quickly performed. Metabolites of ginsenosides F4 and Rg6 after exposing to zebrafish for 24 h were identified by Ultraperformance Liquid Chromatography/Quadrupole-Time-of-Flight Mass Spectrometry. A total of 8 and 6 metabolites of ginsenosides F4 and Rg6 were identified in zebrafish, respectively. Of these, 7 and 5, including M1, M3-M5, M7-M9 and N1 (N5), N2, N4 (N9), N7-N8 were reported for the first time as far as we know. The mechanisms of their biotransformation involved were further deduced to be desugarization, glucuronidation, sulfation, dehydroxylation, loss of C-17 and/or C-23 residue pathways. It was concluded that loss of rhamnose at position C-6 and glucuronidation at position C-3 in zebrafish were considered as the main physiologic and metabolic processes of ginsenosides F4 and ginsenosides Rg6, respectively. PMID- 28349703 TI - Comparative effectiveness of botulinum toxin versus non-surgical treatments for treating lateral epicondylitis: a systematic review and meta-analysis. AB - OBJECTIVES: To explore the effectiveness of botulinum toxin compared with non surgical treatments in patients with lateral epicondylitis. METHODS: Data sources including PubMed, Scopus, Embase and Airity Library from the earliest record to February 2017 were searched. Study design, patients' characteristics, dosage/brand of botulinum toxin, injection techniques, and measurements of pain and hand grip strength were retrieved. The standardized mean differences (SMDs) in pain relief and grip strength reduction were calculated at the following time points: 2-4, 8-12, and 16 weeks or more after injection. RESULTS: Six randomized controlled trials (321 participants) comparing botulinum toxin with placebo or corticosteroid injections were included. Compared with placebo, botulinum toxin injection significantly reduced pain at all three time points (SMD, -0.729, 95% confidence interval [CI], -1.286 to -0.171; SMD, -0.446, 95% CI, -0.740 to 0.152; SMD, -0.543, 95% CI, -0.978 to -0.107, respectively). Botulinum toxin was less effective than corticosteroid at 2-4 weeks (SMD, 1.153; 95% CI, 0.568-1.737) and both treatments appeared similar in efficacy after 8 weeks. Different injection sites and dosage/brand did not affect effectiveness. Botulinum toxin decreased grip strength 2-4 weeks after injection, and high equivalent dose could extend its paralytic effects to 8-12 weeks. CONCLUSIONS: When treating lateral epicondylitis, botulinum toxin was superior to placebo and could last for 16 weeks. Corticosteroid and botulinum toxin injections were largely equivalent, except the corticosteroid injections were better at pain relief in the early stages and were associated with less weakness in grip in the first 12 weeks. PMID- 28349704 TI - LC-ESI-MS/MS profiling of phenolics in the leaves of Eleutherococcus senticosus cultivated in the West Europe and anti-hyaluronidase and anti acetylcholinestarase activities. AB - Neither secondary metabolites of the spring leaves nor the autumn leaves of Eleutherococcus senticosus species cultivated in Poland, or the bioactivity are known. The richest in polyphenols was the autumn leaves (171.1 mg/g DE), while in flavonoids the spring leaves (107.9 mg/g DE). Using LC-ESI-MS/MS, protocatechuic acid has been identified as the most abundant compound in the spring and autumn leaves (200 and 70 MUg/g DE, respectively). Amongst flavonoids, naringenin 7-O glucoside occurred in the largest amount (20 and 10 mg/g DE in the spring and autumn leaves, respectively). The autumn leaves inhibited Hyal the strongest (74.3%), comparing to the spring leaves (33%). A weak inhibition was found towards AChE (0.64 and 5.8% for the autumn and spring leaves, respectively). To our best knowledge, no information was available on the phytochemical composition and activity of the leaves of E. senticosus cultivated in Poland. PMID- 28349705 TI - Implementing system-wide risk stratification approaches: A review of critical success and failure factors. AB - Risk stratification has become a widely used tool for linking people identified at risk of health deterioration to the most appropriate evidence-based care. This article systematically reviews recent literature to determine key factors that have been identified as critical enablers and/or barriers to successful implementation of risk stratification tools at a system level. A systematic search found 23 articles and four promising protocols for inclusion in the review, covering the use to 20 different risk stratification tools. These articles reported on only a small fraction of the risk stratification tools used in health systems; suggesting that while the development and statistical validation of risk stratification algorithms is widely reported, there has been little published evaluation of how they are implemented in real-world settings. Controlled studies provided some evidence that the use of risk stratification tools in combination with a care management plan offer patient benefits and that the use of a risk stratification tool to determine components of a care management plan may contribute to reductions in hospital readmissions, patient satisfaction and improved patient outcomes. Studies with the strongest focus on implementation used qualitative and case study methods. Among these, the literature converged on four key areas of implementation that were found to be critical for overcoming barriers to success: the engagement of clinicians and safeguarding equity, both of which address barriers of acceptance; the health system context to address administrative, political and system design barriers; and data management and integration to address logistical barriers. PMID- 28349706 TI - Unintentional mass sodium nitrite poisoning with a fatality. PMID- 28349707 TI - Elimination half-life of diphenhydramine in overdose. PMID- 28349709 TI - Meeting Report: The Fourth Artificial Pancreas Workshop: Testing and Adoption of Current and Emerging Technologies. AB - On July 6 and 7, 2016 the Fourth Artificial Pancreas Workshop: Testing and Adoption of Current and Emerging Technologies was held on the National Institutes of Health (NIH) Campus at the Lister Hill Auditorium. The meeting was sponsored by a group of governmental organizations and NGOs, listed in Appendix A. This was a very timely meeting as the artificial pancreas appears to be growing from academic studies to commercial projects. The first artificial pancreas may be marketed within 12 months and a few may be approved within 24 months. The NIH, the FDA, the JDRF, Helmsley Trust, Diabetes Technology Society, and other agencies, funders, and organizations have been strongly supportive of advancing artificial pancreas technology and usability, and thus the proceedings from this conference should be of exceptional interest to the diabetes technology community. PMID- 28349708 TI - Use of Sitagliptin With Closed-Loop Technology to Decrease Postprandial Blood Glucose in Type 1 Diabetes. AB - BACKGROUND: Postprandial hyperglycemia poses a challenge to closed-loop systems. Dipeptidyl peptidase-4 (DPP-4) inhibitors, like sitagliptin, reduce postprandial glucose concentrations in patients with type 2 diabetes. The objective of this study was to assess sitagliptin's role in type 1 diabetes (T1DM) as an adjunct therapy in reducing postprandial blood glucose with an insulin-only closed-loop system. METHODS: This was a randomized, double-blinded, placebo controlled, crossover design trial. The participants were18-35 years old, had T1DM, and an HbA1c of <= 8.5%. A dose determination study included eight subjects with T1DM. There were three study visits. Four hours after receiving study drug (placebo, sitagliptin 50 mg, sitagliptin 100 mg), subjects underwent a mixed meal tolerance test with assessment of hormone concentrations. In a second study, 15 subjects underwent two visits receiving either placebo or 100 mg of sitagliptin plus an insulin only closed-loop system for 25 hours with timed meals. Blood glucose and other hormone concentrations were analyzed using repeated measures ANOVA. RESULTS: For the dose determination study, sitagliptin 100 mg resulted in reduced postprandial blood glucose ( P = .006). For the closed-loop study, glucose concentrations were lower in the treatment group, most prominently during the first two study meals ( P = .03). There was no difference in glucagon concentrations, but insulin concentrations and insulin delivery were lower in the treatment group. CONCLUSIONS: Sitagliptin may be considered as an adjunct therapy in a closed-loop setting. Larger studies are needed to determine the role of oral agents like sitagliptin to lower postprandial hyperglycemia with closed loop. PMID- 28349711 TI - A case for imaging in high-risk psychosis: insular pathology in first episode psychosis. PMID- 28349710 TI - Endovascular Devices and Revascularization Techniques for Limb-Threatening Ischemia in Individuals With Diabetes. AB - Diabetes mellitus (DM) is a rapidly worsening global epidemic over the last thirty-five years. The increased prevalence of DM has changed the phenotypic expression of atherosclerotic limb threatening ischemia (LTI), resulting in an increase in lesions in the tibial vessels. These patients are also afflicted with peripheral neuropathy, foot deformities, and medial calcification of the vasculature. In response to the evolving phenotype of atherosclerosis, newer minimally invasive tools and techniques have been developed to improve the blood supply in LTI. Arterial access, traditionally obtained from the contralateral common femoral artery (CFA) in a retrograde fashion, is now also frequently being obtained in the ipsilateral limb in an antegrade fashion. Retrograde access of the tibial, pedal, tarsal, or calf collateral vessels is also being utilized to provide a route through which wires, catheters, balloons and stents may be placed. Wires have evolved to have a variety of diameters, materials and coatings providing interventionalists with a wide variety of choices when attempting to traverse blockages in the arteries. When catheters and wires fail to traverse the lesion, newer chronic total occlusion (CTO) devices have been developed to aid in the placement of a wire across the offending lesions. Due to medial calcification associated with DM, atherectomy devices have been developed to debulk the atherosclerotic plaque within the vessel. High pressure balloon angioplasty with or without stents remain the mainstay of intervention, with drug-coated balloons (DCBs) and drug-eluting stents (DESs) now being frequently used to prevent reocclusions of atherosclerotic lesions. PMID- 28349712 TI - Escitalopram induced thrombocytopenia reversed after shifting to bupropion in a depressive patient. PMID- 28349713 TI - Senobtusin, a novel alkaloid with amidine moiety from Senecio obtusatus Wall. ex DC. AB - Phytochemical investigation of Senecio obtusatus Wall. ex DC led to the isolation of a novel alkaloid, senobtusin (1). Compound 1 possesses an atypical amidine moiety, and the structure was determined on the basis of extensive NMR analysis and HR-ESI-MS technique. This is the first report of this class of natural products obtained from family Asteraceae, and the systematic importance was also discussed. PMID- 28349714 TI - Intoxications involving acrylfentanyl and other novel designer fentanyls - results from the Swedish STRIDA project. AB - BACKGROUND: The number of new psychoactive substances (NPS) introduced through the online recreational drugs market increases continuously. This report from the Swedish STRIDA project describes analytically confirmed intoxications involving the novel fentanyl analogs acrylfentanyl, 4-chloroisobutyrfentanyl (4Cl-iBF), 4 fluoroisobutyrfentanyl (4F-iBF), and tetrahydrofuranfentanyl (THF-F), and cyclopentylfentanyl in a drug product. METHODS: Patients with suspected NPS exposure presenting in emergency departments (ED) or intensive care units (ICU) in Sweden and requiring hospital care are invited to the STRIDA project. NPS analysis of serum and urine samples was performed by multi-component liquid chromatography-mass spectrometry. Data on clinical features were retrieved from telephone consultations with the Swedish Poisons Information Centre and from medical records. RESULTS: Between April and October 2016, eleven intoxications involving acrylfentanyl (8 cases), acrylfentanyl together with 4Cl-iBF (1), 4F iBF (1), and THF-F (1) were analytically confirmed. Patients were aged 19-51 (median 28) years and 91% were men. Six (55%) were monitored at the ED, and five admitted to the ICU. Typical clinical features were decreased consciousness, respiratory depression, and miosis. In 8 cases, the antidote naloxone was administered to counter the opioid effects. The 4F-iBF positive patient eventually died of brain edema. The serum acrylfentanyl concentration (n = 8) ranged 0.5-2.1 (median 0.9) ng/mL, and in urine (n = 9) 0.2-10.5 (mean 4.6, median 5.2) MUg/mmol creatinine. For 4Cl-iBF, 4F-iBF, and THF-F (n = 1 each), higher serum (5-45 ng/mL) and urine (11-136 MUg/mmol creatinine) concentrations were found. Other NPS (e.g., flunitrazolam) and/or classical drugs were detected in five cases. In early 2016, nasal sprays with a claimed content of acrylfentanyl brought to hospital by patients or obtained by test purchase were demonstrated to instead contain fentanyl. CONCLUSIONS: Potentially life threatening opioid toxicity was seen in 11 acute intoxications involving the fentanyl analogs acrylfentanyl, 4Cl-iBF, 4F-iBF, and THF-F, which are available through open Internet trading. All patients were supported with acute and intensive hospital care, and naloxone was effective to reverse the opioid symptoms. One patient died of brain edema. PMID- 28349715 TI - A review of existing and emerging digital technologies to combat the global trade in fake medicines. AB - INTRODUCTION: The globalization of the pharmaceutical supply chain has introduced new challenges, chief among them, fighting the international criminal trade in fake medicines. As the manufacture, supply, and distribution of drugs becomes more complex, so does the need for innovative technology-based solutions to protect patients globally. Areas covered: We conducted a multidisciplinary review of the science/health, information technology, computer science, and general academic literature with the aim of identifying cutting-edge existing and emerging 'digital' solutions to combat fake medicines. Our review identified five distinct categories of technology including mobile, radio frequency identification, advanced computational methods, online verification, and blockchain technology. Expert opinion: Digital fake medicine solutions are unifying platforms that integrate different types of anti-counterfeiting technologies as complementary solutions, improve information sharing and data collection, and are designed to overcome existing barriers of adoption and implementation. Investment in this next generation technology is essential to ensure the future security and integrity of the global drug supply chain. PMID- 28349716 TI - Fixed-ratio combination therapy with GLP-1 receptor agonist liraglutide and insulin degludec in people with type 2 diabetes. AB - INTRODUCTION: A fixed combination of basal insulin degludec and glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide (IDegLira; 50 units degludec/1.8 mg liraglutide) has been developed as a once daily injection for the treatment of type 2 diabetes (T2D). In the phase 3a trial programme 'Dual action of liraglutide and insulin degludec in type 2 diabetes' (DUALTM), five trials of 26 weeks duration and one trial of 32 weeks duration have evaluated the efficacy and safety of IDegLira compared with administration of insulin degludec, insulin glargine, liraglutide alone or placebo. Areas covered: Combination therapy with IDegLira reduces HbA1c more than monotherapy with a GLP-1RA (liraglutide) or insulin (degludec or glargine). Combination therapy leads also to weight loss, or a stable body weight, with no increase in hypoglycaemia. Rates of adverse events did not differ between treatment groups; however, gastrointestinal side effects were fewer with IDegLira compared with liraglutide treatment alone. A limitation of the DUALTM development programme is that patients receiving basal insulin doses in excess of 50 units were excluded from the studies. Expert commentary: In conclusion, IDegLira combines the clinical advantages of basal insulin and GLP 1RA treatment, and is a treatment strategy that could improve the management of patients with T2D. PMID- 28349717 TI - HDL and macrophages: explaining the clinical failures and advancing HDL-based therapeutics in cardiovascular diseases? PMID- 28349718 TI - Overview of different available chemotherapy regimens combined with radiotherapy for the neoadjuvant and definitive treatment of esophageal cancer. AB - INTRODUCTION: Neoadjuvant chemoradiotherapy (CTRT) is the current standard of care for treatment of locally advanced cancer of the esophagus or gastroesophageal junction. Many efforts have been made over the last years to identify the best chemotherapy and radiotherapy combination regimen, but specific randomized trials addressing this issue are still lacking. Areas covered: A systematic review of the literature was performed searching in PubMed all published studies of combinations CTRT regimens for operable or unresectable esophageal cancer to describe activity and toxicity. Studies considered were prospective series or clinical phase II-III trials including at least 40 patients and published in English language. Expert commentary: Long-term results of CROSS trial have established RT combined with carboplatin plus paclitaxel chemotherapy as the preferred neoadjuvant treatment option for both squamous and adenocarcinoma of the esophagus. More effective multimodal treatment strategies integrating novel biological agents including immunotherapy and based on an extensive molecular tumor characterization are eagerly awaited. PMID- 28349719 TI - Evaluation of the influence of family and friends, and the Internet on patient perceptions of long-term topical corticosteroid use. AB - BACKGROUND: Topical corticosteroids (TCS) are key to managing chronic inflammatory dermatoses (CID). Parents/patients cite TCS phobia as an impediment to treatment adherence. Family/friends and the Internet are a source of misinformation on TCS which can negatively impact perceptions of TCS safety. PURPOSE: To assess information from family/friends and the Internet, as related to and reported by patients/parents using long-term TCS. METHODS: A multicenter cross-sectional survey of patients (aged >18 years) and parents of patients (aged <18 years) with a history of CID requiring long-term (>=1 month) TCS use assessing messages about TCS received from family/friends and the Internet. RESULTS: A total of 123 patients and 78 parents completed the survey (n = 201). Parents/patients were more likely to be informed by the Internet "[having] my [child's] skin condition means that [I/he/she] will need to use topical corticosteroids" (p < .001) and that "inflamed skin conditions will improve with the topical corticosteroids" (p = .007). Family/friends were more likely to recommend parents/patients "try non-prescription creams/ointments before resorting to the use of prescription topical corticosteroids" (p = .014). CONCLUSIONS: High rates of messages about TCS "risk" from family/friends and the Internet may affect patient/parent understanding about TCS safety. This may contribute to treatment non-adherence. PMID- 28349720 TI - Daily dosing of gentamicin using ideal body weight for the treatment of intrapartum chorioamnionitis: a pilot study. AB - PURPOSE: This study aimed to determine whether daily dosing of gentamicin using ideal body weight in the treatment of chorioamnionitis is effective. MATERIALS AND METHODS: We conducted a prospective observational study and followed all women receiving treatment for chorioamnionitis which included gentamicin daily dosing calculated using 5 mg/kg ideal body weight. Patients were excluded if pathological analysis of placenta did not confirm chorioamnionitis. Our primary outcome was resolution of infection following delivery without the development of maternal endometritis and/or neonatal sepsis. Ninety-five percent confidence intervals for proportions were calculated using exact binomial tests. These patients were retrospectively compared to patients who received treatment for chorioamnionitis which included traditional gentamicin every 8 h. RESULTS: The study included 160 patients. Of the patients receiving daily dosing (n = 80) compared to traditional dosing (n = 80), 96% (95% CI 95.7-97.6%) achieved the primary outcome versus 91% (88.9-93.1%), 2.5% (95% CI 1.2-3.8%) developed endometritis versus 6.3% (4.2-8.4%), 1.3% (95% CI 0.4-2.2%) delivered neonates with sepsis versus 2.5% (1.2-3.8%), and 39% required cesarean delivery (95% CI 46.2-53.8) versus 37% (33.2-40.8%). CONCLUSION: Daily dosing of gentamicin using ideal body weight is effective in successful treatment of chorioamnionitis without development endometritis and/or neonatal sepsis across different ethnicities. PMID- 28349721 TI - Immunohistochemical evaluation of the activation of hepatic progenitor cells and their niche in feline lymphocytic cholangitis. AB - Objectives The aim of the study was to compare the hepatic progenitor cell niche in healthy feline livers and the liver tissue of cats with lymphocytic cholangitis. Methods Immunohistochemical stainings for vimentin, laminin, beta (beta)-catenin and Notch1 intracellular domain (NICD) were used on formalin-fixed liver biopsies from affected (n = 12) and unaffected cats (n = 2). Results All immunohistochemical markers used were expressed in more cells, or more intensely, in the liver tissue of cats with lymphocytic cholangitis than in the liver tissue of unaffected cats. Conclusions and relevance Enhanced expression of vimentin, laminin, cytoplasmic/nuclear beta-catenin and NICD in liver biopsies from cats with lymphocytic cholangitis indicates that the hepatic progenitor cell (HPC) niche is remodelled and activated. HPCs might provide insights into new regenerative treatment options for lymphocytic cholangitis in cats in the future. PMID- 28349722 TI - Comparison of the Poisoning Severity Score and National Poison Data System schemes for the severity assessment of animal poisonings: a pilot study. AB - CONTEXT: To date, there are no publicly available schemes designed and evaluated specifically for severity assessment of animal poisonings. This poses challenges for the evaluation and comparison of animal poisoning exposure data. OBJECTIVE: Our objective for this pilot study was to evaluate agreement between raters using the Poisoning Severity Score (PSS) and National Poison Data System (NPDS) medical outcome scheme for severity assessment of canine exposures reported to a multistate poison center (PC) and to identify issues regarding their use for severity assessment of animal poisonings. Agreement between both schemes was also assessed. METHODS: The first 196 canine exposures reported to a multistate PC between 1 January and 31 August 2016 were selected and initial inquiry data from exposures was scored by four independent raters. Interrater agreement and agreement between the severity systems was calculated using weighted kappa (Kappa) (Light's kappa). Reported clinical effects were also described. RESULTS: Interrater agreement for both the PSS (Kappa 0.31; 95% CI 0.19, 0.43) and NPDS schemes (Kappa 0.34; 95% CI 0.22, 0.44) was low. Agreement between the schemes was slight (Kappa 0.05; 95% CI -0.08, 0.16) for pooled results from all four raters. For the PSS, 71.7% (n = 281) of ratings were minor, 23.0% (n = 90) moderate, and 5.4% (n = 21) severe. For the NPDS, 69.6% (n = 273) of ratings were minor, 27.0% (n = 106) moderate, and 3.3% (n = 13) severe. The top three reported clinical effects included vomiting (n = 86, 29.9%) drowsiness/lethargy (n = 38, 13.2%), and diarrhea (n = 24, 8.3%). DISCUSSION AND CONCLUSIONS: This study shows considerable variability between raters using either the PSS or NPDS schemes for canine exposures severity assessment. The subjective nature of the schemes, the influence of intra- and interrater variation, and predominance of minor cases on the study findings should be taken into account when interpreting this data. Further evaluation of these schemes is warranted and could help inform their future use for animal poisoning severity assessment. PMID- 28349723 TI - Targeted therapy in the treatment of chronic lymphocytic leukemia: facts, shortcomings and hopes for the future. AB - INTRODUCTION: The therapy for chronic lymphocytic leukemia (CLL) is undergoing a major transformation. However, the seminal progresses realized to date with the use of novel agents, leave many practical questions unanswered. Areas covered: This review focuses on the recent data of the literature of small-kinase inhibitor (KI) molecules and how results of KI clinical trials may translate into current clinical practice. Several questions such as the advantage of combining small-KI molecules with anti-CD20 monoclonal antibodies or with chemo immunotherapy in comparison to targeted agents alone are discussed. Expert commentary: Nowadays the challenge is to apply the principles of chemotherapy to combine different targeted agents with nonoverlapping toxicities. This approach is not likely to immediately change the standard of care, however, it raises relevant questions concerning the optimal strategy for incorporating novel agents in the treatment of CLL. Given the increasing number of patients who have access to treatment with small-KI molecules, generally administered over an extended duration, more sustainable pricing for such therapies is needed. PMID- 28349724 TI - Loperamide metabolite-induced cardiomyopathy and QTc prolongation. AB - Loperamide is an over-the-counter, peripherally acting, MU-opioid receptor agonist used for the treatment of diarrhea. In recent times users have found that at higher doses, loperamide crosses the blood-brain barrier and reaches central MU-receptors in the brain, leading to central opiate effects including euphoria and respiratory depression. We report a case of a 37-year-old female who attempted suicide with over 200 loperamide tablets. During her overdose, her QTc was significantly prolonged at >600 ms. Our case aims to add to the growing body of literature describing life-threatening ventricular arrhythmias associated with loperamide toxicity and further suggests that a metabolite of loperamide, desmethylloperamide, may play a role in the pathogenesis. PMID- 28349725 TI - [Formula: see text]The effect of stereotype threat on older people's clinical cognitive outcomes: investigating the moderating role of dementia worry. AB - OBJECTIVE: Numerous studies have shown that stereotype threat (ST) reduces older people's cognitive performance, but few have studied its impact on clinical cognitive outcomes. Our study was designed to further examine the impact of ST on the clinical assessment of older subjects' cognitive functioning, as well as the moderating role of fear of Alzheimer's Disease (AD) (or 'dementia worry'). METHOD: Seventy-two neurologically normal (MMSE > 26) participants aged between 59 and 70 completed a set of neuropsychological tasks in either an ST or a positive condition (condition in which negative stereotypes were invalidated). RESULTS: Regression-based path analyses showed that only participants who expressed moderate or high fear of AD underperformed on executive tasks in the ST condition compared to their counterparts in the positive condition. Moreover, in the ST condition, participants' performance on executive tasks was more impaired (relative to normative data) than in the positive condition. However, ST had no effect on memory and attention performance. DISCUSSION: Our results showed that ST can cause older people to perform at pathological levels on executive tasks. Results highlight the need for clinicians to be cautious when conducting neuropsychological assessments of older people who express high levels of dementia worry. PMID- 28349726 TI - A new alpha-pyrone from the deep-sea actinomycete Nocardiopsis dassonvillei subsp. dassonvillei DSM 43111(T). AB - A new alpha-pyrone, nocapyrone S (1), together with five known compounds (2-6), were isolated from the deep-sea actinomycete Nocardiopsis dassonvillei subsp. dassonvillei DSM 43111(T). Their structures were determined by spectroscopic analyses. The absolute configuration of 1 was established by quantum approaches. Cytotoxic activity of 1 was evaluated against K562, MCF-7, SGC7901, A375, Hela, and HepG2 cell lines. PMID- 28349727 TI - Six weeks of beta-alanine supplementation did not enhance repeated-sprint ability or technical performances in young elite basketball players. AB - Supplementation with beta-alanine plays an important role as a precursor of carnosine, the most effective intramuscular buffer, and has been seen as a potential ergogenic aid, especially for high-intensity modalities such as basketball. Thus, the aim of the present study was to investigate the effects of 6 weeks of beta-alanine supplementation on repeated sprint ability (RSA) and technical performances in young elite Brazilian basketball players. In total, 27 young basketball players (17+/-1 years) were randomized into a beta-alanine group (Gbeta - 6.4 g day-1 of beta-alanine) and a placebo group (GP - 6.4 g day-1 of dextrose). Before and after the supplementation period the athletes performed a RSA test composed of ten 30 m sprints with two 180 degrees changes of direction interspaced by 30 s of recovery. During the recovery period (i.e., after the sprints) the athletes performed a countermovement jump (CMJ) and a set of three free throws. After 48 h they performed a Yo-Yo intermittent recovery test level 1 (Yo-Yo IR1). Both groups increased the distance covered in the Yo-Yo IR1 after the supplementation period ( p = 0.001). On the other hand, both groups presented impairment in RSA time-performance (total time, best time, and mean time, p <= 0.04), while no significant changes were observed for technical task performances (i.e., CMJ and free throws) ( p >= 0.07). No between-group interactions were observed for any variable measured ( p >= 0.31). Thus, 6 weeks of beta-alanine supplementation did not improve RSA or technical performances in young elite basketball players. PMID- 28349728 TI - Schizoaffective disorder, catatonia and white matter changes - Revisiting the microglial hypothesis. PMID- 28349729 TI - Evidence-Based Design and Research-Informed Design: What's the Difference? Conceptual Definitions and Comparative Analysis. AB - OBJECTIVE: This article provides critical examination and comparison of the conceptual meaning and underlying assumptions of the concepts evidence-based design (EBD) and research-informed design (RID) in order to facilitate practical use and theoretical development. BACKGROUND: In recent years, EBD has experienced broad adoption, yet it has been simultaneously critiqued for rigidity and misapplication. Many practitioners are gravitating to the term RID to describe their method of integrating knowledge into the design process. However, the term RID lacks a clear definition and the blurring of terms has the potential to weaken advances made integrating research into practice. METHOD: Concept analysis methods from Walker and Avant were used to define the concepts for comparison. RESULTS: Conceptual definitions, process descriptions, examples (i.e., model cases), and methods of evaluation are offered for EBD and RID. Although EBD and RID share similarities in meaning, the two terms are distinct. When comparing evidence based (EB) and research informed, EB is a broad base of information types (evidence) that are narrowly applied (based), while the latter references a narrow slice of information (research) that is broadly applied (informed) to create an end product of design. CONCLUSIONS: Much of the confusion between the use of the concepts EBD and RID arises out of differing perspectives between the way practitioners and academics understand the underlying terms. The authors hope this article serves to generate thoughtful dialogue, which is essential to the development of a discipline, and look forward to the contribution of the readership. PMID- 28349730 TI - Effect of carbohydrate ingestion during cycling exercise on affective valence and activation in recreational exercisers. AB - Carbohydrate (CHO) ingestion enhances "feel-good" responses during acute exercise but no study has examined the effect of regular ingestion of CHO on affective valence. We investigated the effect of CHO ingestion on perceptual responses and perceived work intensity of individual exercise sessions throughout a 10-week cycling ("spin") exercise intervention. We also assessed whether any changes in affect and/or perceived work intensity would influence health and fitness parameters. Twelve recreational exercisers (46 +/- 9 years; nine females and three males) were randomly allocated to either CHO (7.5% CHO; 5 mL . kg-1 per exercise session; n = 6; CHO) or placebo (0% CHO, taste- and volume-matched solution; n = 6; PLA) groups. Participants exercised 2 * 45-min per week, over a 10-week intervention period. Perceptual measures of exertion (RPE), affect (feeling scale, FS) and activation (felt arousal scale, FAS) were assessed after each exercise session. The FAS ratings increased over time in CHO but decreased throughout the intervention in PLA (P = 0.03). There were no differences in heart rate (P = 0.70), RPE (P = 0.05) and FS (P = 0.84) between trials. Furthermore, no changes in health and fitness parameters were observed over time or between groups. CHO ingestion enhanced ratings of activation in recreational exercisers throughout a 10-week cycling intervention. PMID- 28349731 TI - Serum neuron-specific enolase as an early predictor of delayed neuropsychiatric sequelae in patients with acute carbon monoxide poisoning. AB - Delayed onset of neuropsychiatric symptoms after apparent recovery from acute carbon monoxide (CO) poisoning has been described as delayed neuropsychiatric sequelae (DNS). To date, there have been no studies on the utility of serum neuron-specific enolase (NSE), a marker of neuronal cell damage, as a predictive marker of DNS in acute CO poisoning. This retrospective observational study was performed on adult patients with acute CO poisoning consecutively treated over a 9-month period. Serum NSE was measured after emergency department arrival, and patients were divided into two groups. The DNS group comprised patients with delayed sequelae, while the non-DNS group included patients with none of these sequelae. A total of 98 patients with acute CO poisoning were enrolled in this study. DNS developed in eight patients. The median NSE value was significantly higher in the DNS group than in the non-DNS group. There was a statistical difference between the non-DNS group and the DNS group in terms of CO exposure time, Glasgow Coma Scale (GCS), loss of consciousness, creatinine kinase, and troponin I. GCS and NSE were the early predictors of development of DNS. The area under the curve according to the receiver operating characteristic curves of GCS, serum NSE, and GCS combined with serum NSE were 0.922, 0.836, and 0.969, respectively. In conclusion, initial GCS and NSE served as early predictors of development of DNS. Also, NSE might be a useful additional parameter that could improve the prediction accuracy of initial GCS. PMID- 28349732 TI - Body perception and meal type across age and gender on a Mediterranean island (Sardinia). AB - Our aim was to describe the differences in consumption of types of meal (complete/incomplete) eaten at lunch and dinner by gender in people of different age groups (children, young adults and seniors). In particular, we wanted to investigate the differences in choice of meal based on perceived weight. The study involved 516 participants, of which 156 were children (8-12y), 187 were young adults (19-30y) and 173 were elderly (65-90y). A cross-sectional analysis was carried out into the choice of meal type based on the different age groups and genders, on the three Body Mass Index categories (under, normal, overweight), on the three levels of self-perception (slim, normal and heavy) and on the degrees of perception of one's body weight (underestimation, accurate estimation, overestimation). The food eaten was grouped into three types of daily meal: (a) incomplete, (b) complete lunch or dinner, (c) always complete. Differences emerged in the type of meal eaten according to age, gender and perceived weight. The results show gender differences in associations with meal type according to the way in which body mass is measured or perceived. The choice of complete/incomplete meal type changes according to whether real weight or perceived weight is considered. PMID- 28349733 TI - Transgender Phonosurgery: A Systematic Review and Meta-analysis. AB - Objectives Different surgical techniques have been described in the literature to increase vocal pitch. The purpose of this study is to systematically review these surgeries and perform a meta-analysis to determine which technique increases pitch the most. Data Sources CINAHL, Cochrane, Embase, Medline, PubMed, and Science Direct. Review Methods A systematic review and meta-analysis of the literature was performed using the CINAHL, Cochrane, Embase, Medline, PubMed, and Science Direct databases. Studies were eligible for inclusion if they evaluated pitch-elevating phonosurgical techniques in live humans and performed pre- and postoperative acoustic analysis. Data were gathered regarding surgical technique, pre- and postoperative fundamental frequencies, perioperative care measures, and complications. Results Twenty-nine studies were identified. After applying inclusion and exclusion criteria, a total of 13 studies were included in the meta analysis. Mechanisms of pitch elevation included increasing vocal cord tension (cricothyroid approximation), shortening the vocal cord length (cold knife glottoplasty, laser-shortening glottoplasty), and decreasing mass (laser reduction glottoplasty). The most common interventions were shortening techniques and cricothyroid approximation (6 studies each). The largest increase in fundamental frequency was seen with techniques that shortened the vocal cords. Preoperative speech therapy, postoperative voice rest, and reporting of patient satisfaction were inconsistent. Many of the studies were limited by low power and short length of follow-up. Conclusions Multiple techniques for elevation of vocal pitch exist, but vocal cord shortening procedures appear to result in the largest increase in fundamental frequency. PMID- 28349734 TI - Impact of health education based intervention on community's awareness of dengue and its prevention in Delhi, India. AB - Dengue is endemic in India. The capital, Delhi, continues to witness a higher number of cases due to urbanization-related factors. This study is intended to implement health education towards prevention of dengue, and to assess its impact on people's knowledge and practices related to causes and prevention of dengue among urban poor in Delhi. Pre- ( n = 484) and post- ( n = 496) intervention surveys from 15 sub-clusters from five slums/slum-like settlements in Delhi were carried out. Health education based intervention was carried out through partnership with the municipal bodies and non-governmental organizations. Socio demographic characteristics of participants were similar in both surveys. Intervention resulted in significant increase in knowledge on cause, symptom perception and mosquito behaviour in terms of breeding and biting habits. Practice of personal protection measures increased significantly. The participation of people increased during intervention compared to the routine programme. Health education based interventions are instrumental in improving people's knowledge and behaviour. Hence, routine health educational activities as a supportive strategy in the health system need to be strengthened. New integrated approaches such as eco-bio-social approaches with community participation are to be developed and tested in endemic settings like Delhi. PMID- 28349735 TI - Analysis of the Relationship between the Location of the Anterior Ethmoid Artery and Keros Classification. AB - Objective We sought to identify a relationship between skull base height and anterior ethmoid artery (AEA) anatomy. Study Design Retrospective radiologic chart review. Setting University of Arkansas for Medical Sciences. Subjects Patients seen in a tertiary rhinology clinic between September 2014 and October 2015. Methods Review of 101 maxillofacial computed tomography scans with institutional review board approval. Skull base height and AEA locations were measured on each side. Prevalence of the AEA outside of the skull base and distance of the AEA from skull base were calculated and compared with Keros classification using chi2 testing. Comparisons of skull base height between sexes and age and distance between skull base and the AEA among Keros 2 and Keros 3 patients were made using an unpaired, 2-tailed t test. Results The AEA was located below the skull base in 25.7% of cases and more often in Keros type 3 (55%) than in Keros type 2 (29.5%) or Keros type 1 (0%) ( P < .05). Male patients were significantly more likely to have a greater average skull base height (5.25 vs 4.28 mm) and to have AEAs below the skull base (38.4% vs 14.8%). In addition, the distance of the AEA from the skull base was significantly higher in Keros type 3 patients compared with Keros type 2 patients (4.55 vs 3.42 mm, P = .001). Conclusions Variations in the AEA pathway occur more in male patients and those with higher Keros classifications. The distance between the variant AEA and the skull base increases with higher Keros classification. Keros classification can yield insight to the location of the AEA. PMID- 28349736 TI - The role of fear in predicting sexually transmitted infection screening. AB - OBJECTIVE: This study assessed the extent to which social-cognitive factors (attitude, subjective norm and perceived control) and the fear of a positive test result predict sexually transmitted infection (STI) screening intentions and subsequent behaviour. DESIGN: Study 1 (N = 85) used a longitudinal design to assess the factors that predict STI screening intention and future screening behaviour measured one month later at Time 2. Study 2 (N = 102) used an experimental design to determine whether the relationship between fear and screening varied depending on whether STI or HIV screening was being assessed both before and after controlling for social-cognitive factors. MAIN OUTCOME MEASURES: Across the studies the outcome measures were sexual health screening. RESULTS: In both studies, the fear of having an STI positively predicted STI screening intention. In Study 1, fear, but not the social-cognitive factors, also predicted subsequent STI screening behaviour. In Study 2, the fear of having HIV did not predict HIV screening intention, but attitude negatively and response efficacy positively predicted screening intention. CONCLUSION: This study highlights the importance of considering the nature of the health condition when assessing the role of fear on health promotion. PMID- 28349737 TI - Pediatric Acute Otitis Media in the Era of Pneumococcal Vaccination. AB - Objectives (1) Describe longitudinal trends in annual prevalence of hospital admission for pediatric acute otitis media (AOM) and complications of AOM (CAOM) since introduction of pneumococcal vaccination in 2000 and (2) describe the longitudinal trend of prevalence of hospital admission for pneumococcal meningitis in children with AOM-related diagnoses in the postvaccination era. Study Design Retrospective analysis of Kids' Inpatient Database from 2000 to 2012. Setting Community, nonrehabilitation hospitals. Subjects and Methods To determine annual prevalence of admission for AOM/CAOM, nationally weighted frequencies of children aged <21 years with acute suppurative otitis media, acute mastoiditis, suppurative labyrinthitis, and/or acute petrositis were collected. The frequency of coexisting pneumococcal meningitis diagnoses among these patients was also collected. Trend analysis of prevalences of admission for AOM/CAOM and for pneumococcal meningitis occurring in the setting of AOM/CAOM from 2000 to 2012 was performed. Results Between 2000 and 2012, annual prevalence of admission for AOM/CAOM decreased from 3.956 to 2.618 per 100,000 persons ( P < .0001) (relative risk reduction 34%). Declines in admission prevalence were most pronounced in children <1 year of age (from 22.647 to 8.715 per 100,000 persons between 2000 and 2012, P < .0001) and 1 to 2 years of age (from 13.652 to 5.554 per 100,000 persons between 2000 and 2012, P < .0001). For all ages, the admission prevalence for pneumococcal meningitis and concomitant AOM/CAOM decreased (from 1.760 to 0.717 per 1,000,000 persons, P < .0001) over the study period. Conclusions The prevalence of hospital admission for pediatric AOM/CAOM has declined since the advent of pneumococcal vaccination. Admission rates for pneumococcal meningitis with AOM/CAOM have similarly declined. PMID- 28349738 TI - Evaluation of pesticide residue dynamics in Chinese cabbage, head cabbage and cauliflower. AB - Pesticide residues from the time of application until harvest were analysed for 20, 17 and 18 active insecticidal and fungicidal substances in Chinese cabbage, head cabbage and cauliflower, respectively. In total, 40 mathematical models of residue degradation were developed using a first-order kinetic equation, and from these models it was possible to forecast the action pre-harvest interval for a given action threshold for low-residue production in Brassica vegetables as a percentage of the maximum residue level. Additionally, it was possible to establish an action pre-harvest interval based on an action threshold of 0.01 mg kg-1 for the production of Brassica vegetables for baby food. Among the evaluated commodities, the speed of residue degradation was highest in head cabbage, medium in Chinese cabbage and lowest in cauliflower. The half-lives of pesticide in various vegetables were also determined: they ranged from 1.55 to 5.25 days in Chinese cabbage, from 0.47 to 6.54 days in head cabbage and from 1.88 to 7.22 days in cauliflower. PMID- 28349739 TI - Improving Otolaryngology Residency Selection Using Principles from Personnel Psychology. AB - There has been a heightened focus on improving the resident selection process, particularly within highly competitive specialties. Previous research, however, has generally lacked a theoretical background, leading to inconsistent and biased results. Our recently published systematic review examining applicant characteristics and performance in residency can provide historical insight into the predictors (ie, constructs) and outcomes (ie, criteria) previously deemed pertinent by the otolaryngology community. Personnel psychology uses evidence based practices to identify the most qualified candidates for employment using a variety of selection methods. Extensive research in this discipline has shown that integrity tests, structured interviews, work samples, and conscientiousness offer the greatest increase in validity when combined with general cognitive ability. Blending past research knowledge with the principles of personnel selection can provide the necessary foundation with which to engage in theory driven, longitudinal studies on otolaryngology resident selection moving forward. PMID- 28349740 TI - Immunotherapy for gastric cancers: emerging role and future perspectives. AB - INTRODUCTION: The broad use of immunotherapy is revolutionizing the treatment paradigms of many solid tumors. Although chemotherapy remains the treatment backbone for advanced gastric cancer, improvements in its molecular characterization and progresses in understanding its underpinning biology have supported clinical development of novel immunotherapies. However, the results of recent trials testing these new agents raise the question on how to identify the patients that could greatly benefit. Areas covered: This article summarizes the current understanding on the biology and the mechanisms underlying different clinical features of gastric cancers. Particularly, after a comprehensive literature search, we speculate whether specific molecular subsets of patients could derive more benefit from immunotherapy. Expert commentary: Most cancers may evade the immune response, which is normally regulated by a delicate balance between activating and inhibitory signals. For example, both CTLA-4 and PD-1, once linked to PD-L1/2, may inhibit T-cell signaling. The use of agent to harness the power of the immune system appears to be the ultimate frontier in gastric cancer treatment. While anti-CTLA-4 antibodies are minimally active, there is growing evidence for the efficacy of PD1/-L1 inhibitors. The search of predictive factors for immunotherapy will provide key hints towards the optimal use of these agents. PMID- 28349741 TI - Organochlorine Pesticides (OCPs) in raft mussels coming from Galician rias. AB - This survey gives an overview of the range of organochlorine pesticides (OCPs) alpha and gamma-HCH (lindane), HCB, pp'-DDE, pp'-DDD, op'-DDT, pp'-DDT, aldrin, dieldrin, endrin, isodrin and trans-nonachlor in raft mussels cultivated in several polygons of the Galician Rias (Ares-Betanzos, Muros-Noia, Arousa, Pontevedra and Vigo) during the period 1998-2014. A significant number of OCPs were detected, but the levels found were generally low, mainly in the recent samplings (2010-2014). The levels of ?DDs (sum of DDTs and its metabolites, pp' DDE and pp'-DDD) ranged between 0.22 ng/g dry weight (dw) in samples from the Ria of Pontevedra and 46.4 ng/g dw in mussels from the Ria of Arousa. Both aldrin and endrin were not detected or were below the analytical limits of detection. With regard to other pesticides, dieldrin is the major compound, followed by gamma HCH, isodrin, alpha-HCH and transnonachlor. Significant ANOVA regressions indicated variations in levels of some OCPs with the biological parameters (lipid, condition index and shell length). Univariate and multivariate analysis of OCP levels revealed no significant differences between Rias. Temporal trends showed an important decline of OCPs in the studied samples during the period 1998 2014. PMID- 28349742 TI - Two new phenolic constituents from the root bark of Morus alba L. and their cardioprotective activity. AB - A new biphenyl-furocoumarin, named morescoumarin A (1), and a new prenylated flavanone, named morflavanone A (2) were isolated from the root bark of Morus alba L., together with four known compounds (3-6). Their structures were determined by extensive spectroscopic analyses and comparison with literature data. The cardioprotective effects of these compounds against doxorubicin-induced cell death were evaluated by MTT method. PMID- 28349743 TI - A patient presented with dark brown urine after mothballs powder ingestion. AB - We report a case who presented with dark brown urine and malaise after mothballs powder ingestion. PMID- 28349745 TI - Exposure assessment of epoxy fatty acids through consumption of specific foods available in Belgium. AB - Epoxy fatty acids (EFAs) are secondary oxidation products formed from unsaturated fatty acid hydroperoxides. Seventeen food categories were analysed for C18 monoEFAs of food products available on the Belgian market. A quantitative exposure assessment was performed based on deterministic and probabilistic approaches combining these concentration data with consumption data obtained from the Belgian National Food Consumption Survey of 2004. A preliminary evaluation of any potential risk related to the intake of the studied EFAs through the studied foods was performed by applying the threshold of toxicological concern (TTC) concept. Three food categories out of 17 foods, mayonnaise, butter-margarine and ready-to-eat meals were found to contribute most to the intake of EFAs. According to probabilistic determination, these foods had P50 intakes of 0.4085, 0.3328 and 0.2997 mg kg-1 bw day-1 respectively. They had P99.5 intakes of 3.7183, 2.7921 and 38.6068 mg kg-1 bw day-1 respectively. The intake below the TTC was from the consumption of cooked meat, smoked salmon and raw cured ham, with P50 intakes of 0.0006, 0.0007 and 0.0011 mg kg-1 bw day-1 respectively, and the other foods were above the TTC. Based on the TTC concept, a risk to human health could be identified related to the consumption of cheese, snacks foods, plant oils, French fries, dry nuts, chips, cured minced raw meat, cookies, fresh and frozen salmon and bacon. PMID- 28349746 TI - The Role of the Away Rotation in Otolaryngology Residency. AB - Objective To determine the availability and purpose of away rotations during otolaryngology residency. Study Design Cross-sectional survey. Setting Otolaryngology residency programs. Subjects and Methods An anonymous web-based survey was sent to 98 allopathic otolaryngology training program directors, of which 38 programs responded. Fisher exact tests and nonparametric correlations were used to determine statistically significant differences among various strata of programs. A P value of <.05 was considered statistically significant. Results Thirty-nine percent (n = 38) of queried programs responded. Mandatory away rotations and elective away rotations were both present in 6 of 38 programs (16%). Neither number of faculty ( P = .119) nor residents ( P = .88) was predictive of away rotation. Away rotations were typically >151 miles from the home institution and typically used to address deficiencies in clinical exposure (67%) or case volume (50%). Participants of mandatory away rotations were universally provided housing, with other consideration such as stipend (33%), relocation allowance (33%), or food allowance (16%) sometimes offered. In contrast to mandatory rotations, half of elective rotations were to obtain a unique international mission trip experience. Nearly one-third of surveyed program directors (29%) would consider adding an away rotation to their curriculum in the next 3 years. Conclusions Mandatory and elective away rotations play a role in a small, but not insignificant, number of training programs. The rationale for these rotations is variable. Given that nearly one-third of program directors would consider adding an away rotation in the near future, further research into components of a meaningful away rotation and how to optimize the away rotation experience is warranted. PMID- 28349744 TI - Treatment of Obesity Among Youth With Intellectual and Developmental Disabilities: An Emerging Role for Telenursing. AB - Childhood obesity is a serious health issue, associated with medical comorbidity and psychosocial impairment that can persist into adulthood. In the United States, youth with intellectual and developmental disabilities are more likely to be obese than youth without disabilities. A large body of evidence supports the efficacy of family-based treatment of childhood obesity, including diet, physical activity, and behavior modification, but few interventions have been developed and evaluated specifically for this population. We highlight studies on treatment of obesity among youth with intellectual and developmental disabilities, including both residential/educational settings as well as outpatient/hospital settings. All interventions were delivered in-person, and further development of promising approaches and delivery via telenursing may increase access by youth and families. Nursing scientists can assume an important role in overcoming barriers to care for this vulnerable and underserved population. PMID- 28349748 TI - Rash and pyrexia after succimer (dimercaptosuccinic acid; DMSA). PMID- 28349747 TI - Assessment of azole fungicides as a tool to control growth of Aspergillus flavus and aflatoxin B1 and B2 production in maize. AB - Aspergillus flavus is a highly aflatoxin (AF)-producing species infecting maize and other crops. It is dominant in tropical regions, but it is also considered an emerging problem associated with climate change in Europe. The aim of this study was to assess the efficacy of azole fungicides (prochloraz, tebuconazole and a 2:1 (w/w) mixture of prochloraz plus tebuconazole) to control the growth of A. flavus and AF production in yeast-extract-sucrose (YES) agar and in maize kernels under different water activities (aw) and temperatures. Aflatoxins B1 and B2 were determined by LC with fluorescence detection and post-column derivatisation of AFB1. In YES medium and maize grains inoculated with conidia of A. flavus, the growth rate (GR) of the fungus and AFB1 and AFB2 production were significantly influenced by temperature and treatment. In YES medium and maize kernels, optimal temperatures for GR and AF production were 37 and 25 degrees C, respectively. In maize kernels, spore germination was not detected at the combination 37oC/0.95 aw; however, under these conditions germination was found in YES medium. All fungicides were more effective at 0.99 than 0.95 aw, and at 37 than 25oC. Fungicides effectiveness was prochloraz > prochloraz plus tebuconazole (2:1) > tebuconazole. AFs were not detected in cultures containing the highest fungicide doses, and only very low AF levels were found in cultures containing 0.1 mg l-1 prochloraz or 5.0 mg l-1 tebuconazole. Azoles proved to be highly efficient in reducing A. flavus growth and AF production, although stimulation of AF production was found under particular conditions and low-dosage treatments. Maize kernels were a more favourable substrate for AF biosynthesis than YES medium. This paper is the first comparative study on the effects of different azole formulations against A. flavus and AF production in a semi-synthetic medium and in maize grain under different environmental conditions. PMID- 28349750 TI - Necrotising fasciitis after laparoscopic rectal cancer surgery. AB - Necrotising fasciitis is a rare, serious infection of the deep fascia leading to subcutaneous tissue necrosis. It is extremely important for this condition to be identified and treated promptly as it bears significant mortality. We describe a case of necrotising fasciitis after laparoscopic rectal cancer surgery. To our knowledge, this is the first case reported after the specific procedure. This case report aims to encourage surgeons to have a low threshold in recognising necrotising fasciitis postoperatively, especially for patients with possible risk factors. PMID- 28349751 TI - Bilateral peroneal artery aneurysms. AB - True aneurysm of the tibial arteries is a rare clinical condition. We report the case of a 67-year-old man who presented with a gradual onset of right calf swelling and pain. Imaging revealed large aneurysms arising from the proximal peroneal arteries bilaterally, measuring 7.4cm and 4cm on the right and left respectively. A detailed medical history, clinical examination and laboratory investigations did not identify evidence of an underlying cause. A surgical reconstruction with an interposition vein graft was successfully performed. To our knowledge, this is the first reported case of primary aneurysm of the peroneal artery in the English literature. We undertook a systematic literature review to identify all reported cases of primary aneurysms of the tibial arteries. The clinical presentation, modes of investigation and interventional treatments are discussed. PMID- 28349752 TI - Endoscopic cystic duct stent as primary treatment for intrahepatic gallbladder perforation with abscess formation. AB - Intrahepatic gallbladder perforation with abscess formation is an uncommon presentation of biliary disease. There is no consensus on how to treat this condition, with strategies varying from percutaneous drainage to open cholecystectomy and washout. We present a case of a novel, minimally invasive treatment, using endoscopic retrograde cholangiopancreatography to place a transcystic drain as a bridge to laparoscopic cholecystectomy. PMID- 28349753 TI - A novel technique to ensure accurate placement of synthetic bone graft. PMID- 28349754 TI - Useful alternative technique for tying a knot with one hand. PMID- 28349755 TI - Radical prostatectomy for locally advanced and metastatic prostate cancer. AB - The management of advanced prostate cancer remains challenging. Traditionally, radical prostatectomy was discouraged in patients with locally advanced or node positive disease owing to the increased complication rate and treatment related morbidity. However, technical advances and refinements in surgical techniques have enabled the outcomes for patients with high risk prostate cancer to be improved. More recently, the concept of cytoreductive prostatectomy has been described where surgery (often Combined with an extended lymph node dissection) is performed in the setting of metastatic disease. Indirect evidence suggests an advantage using the cytoreductive approach. Hypothetical explanations for this observed benefit include decreased tumour burden, immune modulation, improved response to secondary treatment and avoidance of secondary complications attributable to local tumour growth. Nevertheless, prospective trials are required to investigate this further. PMID- 28349756 TI - Extruded talus treated with reimplantation and primary tibiotalocalcaneal arthrodesis. AB - Extruded talus is a rare serious result from a high-energy injury to a supinated and plantar flexed foot. Treatment remains controversial with a lack of congruent evidence for talar reimplantation. A 34-year-old woman was involved in a road traffic accident at 40 mph. Imaging revealed a left talus extruded anterolaterally with a talar neck fracture. Additional injuries included right acetabular fracture, transverse process fractures and rib fractures, which were treated conservatively. The talus was reimplanted and the talar neck fixed with a cortical screw. A hindfoot nail was used to fuse the calcaneus, talus and tibia. Follow-up at two years showed solid tibiotalocalcaneal fusion, with no evidence of avascular development, and the patient was fully weight bearing without pain. We believe this is the first published case of successful primary tibiotalocalcaneal fusion for extruded talus injuries. PMID- 28349757 TI - DNACPR ('do not attempt cardiopulmonary resuscitation') orders in patients with a fractured neck of femur who lack capacity. AB - Nationally, half of all deaths occur in hospital, with 94% having a 'do not attempt cardiopulmonary resuscitation' (DNACPR) notice in place at the time of death. Recent court rulings have raised the profile of practices surrounding DNACPR orders where patients lack capacity. Failure to consult with those close to the patient in relation to DNACPR decisions is a breach of the right to respect for private and family life under article 8 of the Human Rights Act. A report from 2016 found that those close to the patient were not consulted before one out of every five DNACPR orders are placed. We advocate addressing the issue of resuscitation in patients with a fractured neck of femur who are approaching the end of their lives. Where the patient lacks capacity, there is a legal duty to consult with those close to the patient where it is practicable and appropriate to do so. There must be a convincing and well evidenced reason to proceed without consultation, and the orthopaedic surgeon should exercise extreme caution before doing so. PMID- 28349758 TI - Use of natural user interfaces for image navigation during laparoscopic surgery: initial experience. AB - BACKGROUND: Surgical environments require special aseptic conditions for direct interaction with the preoperative images. We aim to test the feasibility of using a set of gesture control sensors combined with voice control to interact in a sterile manner with preoperative information and an integrated operating room (OR) during laparoscopic surgery. MATERIAL AND METHODS: Two hepatectomies and two partial nephrectomies were performed by three experienced surgeons in a porcine model. The Kinect, Leap Motion, and MYO armband in combination with voice control were used as natural user interfaces (NUIs). After surgery, surgeons completed a questionnaire about their experience. RESULTS: Surgeons required <10 min training with each NUI. They stated that NUIs improved the access to preoperative patient information and kept them more focused on the surgical site. The Kinect system was reported as the most physically demanding NUI and the MYO armband in combination with voice commands as the most intuitive and accurate. The need to release one of the laparoscopic instruments in order to use the NUIs was identified as the main limitation. CONCLUSIONS: The presented NUIs are feasible to directly interact in a more intuitive and sterile manner with the preoperative images and the integrated OR functionalities during laparoscopic surgery. PMID- 28349759 TI - Capillary Hemangioma of the Tympanic Membrane. PMID- 28349760 TI - Effects of Ramadan on physical capacities of North African boys fasting for the first time. AB - Introduction Most of the literature related to the effects of Ramadan fasting on physical performance has focused on adults, and only three studies have examined its impact on children's physical performance. Aims To examine the effects of Ramadan fasting on first-time fasting boys' performance in short-term explosive exercises [vertical and horizontal jump tests (VJT and HJT), 20-m and 30-m sprints and medicine-ball throw (MBT)], as well as in sub-maximal endurance [6 min walking distance (6MWD) measured during the 6-min walk test (6MWT)]. Methods Eighteen Tunisian boys [mean+/-standard deviation (SD) of age and body mass (BM): 11.9+/-0.8 y and 55.4+/-18.2 kg, respectively] were included. The experimental design comprised four testing phases: 2-weeks before Ramadan (BR), the end of the second week (R2) and the fourth week (R4) of Ramadan, and 10-12 days after the end of Ramadan (AR). At each phase, boys performed two test sessions in the afternoon (15:00-17:00 h) interrupted by 48 h of recovery (first test session: BM, VJT, HJT, and 20-m and 30-m sprint tests; second session: MBT and 6MWT). The study was conducted during the summer of 2012 from July 5 to August 29. Results 6MWDs (m) were significantly shorter during R2 (652+/-101) and R4 (595+/-123) compared to BR (697+/-86) and came back to baseline values AR. BM (kg) mean+/-SD did not significantly change during R2 (52+/-15) and during R4 (53+/-15) compared to BR (55+/-17), and short-term explosive performances were unchanged throughout the study. Conclusion In non-athletic children, first-ever Ramadan fasting impairs sub-maximal aerobic capacity but has no effect on BM or short-term explosive performance. PMID- 28349761 TI - Roots and routes to resilience and its role in psychotherapy: a selective, attachment-informed review. AB - Developmental research on resilience is summarised and illustrated with a case example. Self-reflection, positive relationships, and agency foster resilience in the face of adversity. Attachment and resilience are related categories. The different patterns of attachment - secure, insecure-organised and insecure disorganised - are manifest in different patterns of resilience, depending on prevailing environmental conditions. However, the greater the environmental adversity, the less will the resilience factors emerge. Clients tend to present for psychotherapy when resilience strategies have failed. The therapeutic relationship has neurochemical and relational characteristic mirroring the secure mother-infant bond. These foster mentalising, stress innoculation, affect co regulation, self-esteem, and agency, forming the basis for enduring and more flexible resilience strategies. PMID- 28349762 TI - Segmental resection of anterior uterine wall in cases with placenta percreta: a modified technique for fertility preserving approach. AB - AIM: The aim of this study was to introduce a modified form of fertility preserving approach in cases with placenta percreta. METHODS: Eleven pregnant women with anterior placenta previa and suspected to have placenta percreta underwent cesarean section between 2015 and 2016 in Zeynep Kamil Women and Children's Health Training and Research Hospital. In all cases, following confirmation of placenta percreta diagnosis, a modified minimal invasive form of uterine preserving surgery was performed. RESULTS: During the present study period, 11 pregnant women who were confirmed to have placenta previa and placenta percreta underwent modified form of segmental resection. In all cases, modified form of segmental resection was successful except for the two cases. There were significant statistical differences between pre-postoperative hemoglobin and hematocrit levels (p = .003). There was a significant correlation between the volume of resected segment and number of transfusions (r = .760, p = .047). Postoperative blood transfusion was not needed in 4 cases. No maternal mortality or other postoperative complication was observed in any case. CONCLUSION: A modified minimal invasive form of uterine preserving surgery seems to be safe and result in more cosmetic results with minimal blood loss. PMID- 28349763 TI - Radiographic Evidence of Occult Intracranial Hypertension in Patients with Meniere's Disease. AB - Objectives (1) Describe the prevalence of radiographic signs of intracranial hypertension (ICH) in Meniere's disease (MD) and (2) compare the prevalence of radiographic signs of ICH in MD patients managed medically to those managed surgically. Study Design Case-control study. Setting Academic neurotologic practice. Subjects and Methods Adult MD patients (aged >=17 years) treated from 2011 to 2015 were reviewed. Inclusion required magnetic resonance imaging (MRI) of the head and follow-up >6 months. Patients with intracranial tumors, mass effect, trauma, previous intracranial surgery, and glaucoma were excluded. MD patients were separated by administered treatment into medical and surgical subgroups. Cochlear implant (CI) recipients served as radiographic controls. Eighty-four MD patients (46 surgical, 38 medical) and 37 CI controls were assessed. MRI measurements assessed for empty/partial sella (ES/PS), dilated/tortuous optic nerve sheath (ONS), and posterior globe flattening (PGF). Results Mean age was 53.8 +/- 1.3 years and median body mass index (BMI) was 28.2 kg/m2. Of the patients, 64% were female and 92% were white. MRI findings in the MD cohort were as follows: ES/PS, 46.4%; ONS change, 42.8%; and PGF, 8.3%. The prevalence of ONS change was higher in MD patients than in controls (42.8% vs 13.5%, P = .003). The surgical MD group had higher prevalence of ONS change (52%) compared with the medical group (31.5%, P = .05) and controls (13.5%, P = .0004). The surgical group had a higher prevalence of >=2 simultaneous MRI findings compared with medical MD patients (39% vs 10%, P = .01) and controls (14%, P = .01). Conclusion MD patients demonstrate a high prevalence of radiographic signs of ICH. MD patients who required surgery had a greater prevalence of radiographic signs of ICH compared with non-MD patients and medically managed MD patients. PMID- 28349764 TI - Computational fluid dynamics study of common stent models inside idealised curved coronary arteries. AB - The haemodynamic behaviour of blood inside a coronary artery after stenting is greatly affected by individual stent features as well as complex geometrical properties of the artery including tortuosity and curvature. Regions at higher risk of restenosis, as measured by low wall shear stress (WSS < 0.5 Pa), have not yet been studied in detail in curved stented arteries. In this study, three dimensional computational modelling and computational fluid dynamics methodologies were used to analyse the haemodynamic characteristics in curved stented arteries using several common stent models. Results in this study showed that stent strut thickness was one major factor influencing the distribution of WSS in curved arteries. Regions of low WSS were found behind struts, particularly those oriented at a large angle relative to the streamwise flow direction. These findings were similar to those obtained in studies of straight arteries. An uneven distribution of WSS at the inner and outer bends of curved arteries was observed where the WSS was lower at the inner bend. In this study, it was also shown that stents with a helical configuration generated an extra swirling component of the flow based on the helical direction; however, this extra swirl in the flow field did not cause significant changes on the distribution of WSS under the current setup. PMID- 28349765 TI - New three-dimensional model based on finite element method of bone nanostructure: single TC molecule scale level. AB - At the macroscopic scale, the bone mechanical behavior (fracture, elastic) depends mainly on its components' nature at the nanoscopic scale (collagen, mineral). Thus, an understanding of the mechanical behavior of the elementary components is demanded to understand the phenomena that can be observed at the macroscopic scale. In this article, a new numerical model based on finite element method is proposed in order to describe the mechanical behavior of a single Tropocollagen molecule. Furthermore, a parametric study with different geometric properties covering the molecular composition and the rate hydration influence is presented. The proposed model has been tested under tensile loading. While focusing on the entropic response, the geometric parameter variation effect on the mechanical behavior of Tropocollagen molecule has been revealed using the model. Using numerical and experimental testing, the obtained numerical simulation results seem to be acceptable, showing a good agreement with those found in literature. PMID- 28349766 TI - Bioimpedancemetry for the assessment of periodontal tissue inflammation: a numerical feasibility study. AB - In dentistry possible inflammatory episodes of oral cavity can be very frequent (periodontitis, mucositis, peri-implantitis) and they can have serious consequences. Indeed, peri-implantitis is still the principal cause of implant failure. Impedance values of biological tissues are related to the physiological/pathological state of the tissue itself. In fact, an inflamed site exhibits an impedance value lower than that of the corresponding healthy tissue. Based on these observations, the aim of this work is to determine if impedancemetric measurements are able to provide information about the inflammatory state of tissues. A numerical 3D model has been realized to simulate the measurement conditions present in the event of inflammation around a dental implant. The aim is to understand if it is possible to determine the presence of an inflamed tissue and to locate its site, so that the treatment could be specifically focused in that specific area. A simplified geometry reproducing the implant has been realized in order to validate the numerical model by means of experimental measurements. The obtained results are satisfactorily accurate, so the model can be considered reliable. Therefore, multiple simulations have been run on the original model to carry out a parametric study in terms of different conductivity values, different volumes of inflamed tissues and different measurement frequencies. The advantages and limits of such a method have been shown to properly define the main constraints for the system design. PMID- 28349767 TI - Finite element analyses for improved design of peripheral stents. AB - Due to the recent increase in the number of stent insertion procedures, the number of studies to evaluate the mechanical behaviors of stents, such as the stress and deformation states, using finite element analysis is also increasing. However, it is still not easy to design stents that are uniformly expanded and show enough radial strength and flexibility. Therefore, in this study, the Taguchi method and finite element analysis were used to determine a set of optimal design variables for unit patterns of stents, and a new design approach was developed to realize uniform expansion, enough radial strength and good flexibility. The stent designed using the new design approach was verified by experiments. PMID- 28349768 TI - Effect of body weight support variation on muscle activities during robot assisted gait: a dynamic simulation study. AB - BACKGROUND AND OBJECTIVES: While body weight support (BWS) intonation is vital during conventional gait training of neurologically challenged subjects, it is important to evaluate its effect during robot assisted gait training. In the present research we have studied the effect of BWS intonation on muscle activities during robotic gait training using dynamic simulations. METHODS: Two dimensional (2-D) musculoskeletal model of human gait was developed conjointly with another 2-D model of a robotic orthosis capable of actuating hip, knee and ankle joints simultaneously. The musculoskeletal model consists of eight major muscle groups namely; soleus (SOL), gastrocnemius (GAS), tibialis anterior (TA), hamstrings (HAM), vasti (VAS), gluteus maximus (GLU), uniarticular hip flexors (iliopsoas, IP), and Rectus Femoris (RF). BWS was provided at levels of 0, 20, 40 and 60% during the simulations. In order to obtain a feasible set of muscle activities during subsequent gait cycles, an inverse dynamics algorithm along with a quadratic minimization algorithm was implemented. RESULTS: The dynamic parameters of the robot assisted human gait such as joint angle trajectories, ground contact force (GCF), human limb joint torques and robot induced torques at different levels of BWS were derived. The patterns of muscle activities at variable BWS were derived and analysed. For most part of the gait cycle (GC) the muscle activation patterns are quite similar for all levels of BWS as is apparent from the mean of muscle activities for the complete GC. CONCLUSIONS: Effect of BWS variation during robot assisted gait on muscle activities was studied by developing dynamic simulation. It is expected that the proposed dynamic simulation approach will provide important inferences and information about the muscle function variations consequent upon a change in BWS during robot assisted gait. This information shall be quite important while investigating the influence of BWS intonation on neuromuscular parameters of interest during robotic gait training. PMID- 28349769 TI - Finite element analysis of implant-supported prosthesis with pontic and cantilever in the posterior maxilla. AB - The aim of this study was to evaluate the influence of pontic and cantilever designs (mesial and distal) on 3-unit implant-retained prosthesis at maxillary posterior region verifying stress and strain distributions on bone tissue (cortical and trabecular bones) and stress distribution in abutments, implants and fixation screws, under axial and oblique loadings, by 3D finite element analysis. Each model was composed of a bone block presenting right first premolar to the first molar, with three or two external hexagon implants (4.0 * 10 mm), supporting a 3-unit splinted dental fixed dental prosthesis with the variations: M1 - three implants supporting splinted crowns; M2 - two implants supporting prosthesis with central pontic; M3 - two implants supporting prosthesis with mesial cantilever; M4 - two implants supporting prosthesis with distal cantilever. The applied forces were 400 N axial and 200 N oblique. The von Mises criteria was used to evaluate abutments, implants and fixation screws and maximum principal stress and microstrain criteria were used to evaluate the bone tissue. The decrease of the number of implants caused an unfavorable biomechanical behavior for all structures (M2, M3, M4). For two implant-supported prostheses, the use of the central pontic (M2) showed stress and strain distributions more favorable in the analyzed structures. The use of cantilever showed unfavorable biomechanical behavior (M3 and M4), mainly for distal cantilever (M4). The use of three implants presented lower values of stress and strain on the analyzed structures. Among two implant-supported prostheses, prostheses with cantilever showed unfavorable biomechanical behavior in the analyzed structures, especially for distal cantilever. PMID- 28349770 TI - The Role of Tonsillectomy in Adults with Tonsillar Hypertrophy and Obstructive Sleep Apnea. AB - Objective To determine if tonsillectomy alone is an effective treatment in improving obstructive sleep apnea in adult subjects with tonsillar hypertrophy and to evaluate the effect of tonsillectomy on patient-reported quality-of-life indices. Study Design Case series with planned data collection. Setting Academic hospital. Subjects and Methods Thirty-four subjects completed enrollment and intervention from January 2011 to January 2016. Subjects completed pre- and postoperative quality-of-life questionnaires, including the Insomnia Severity Index, Epworth Sleepiness Scale, and the Functional Outcomes of Sleep Questionnaire-10. Surgical response to treatment was defined by a >50% decrease in the Apnea-Hypopnea Index and a decrease in the overall Apnea-Hypopnea Index to <20. Wilcoxon matched-pairs signed-rank tests were used to test each variable to assess for a change from pre- to postintervention. Subjects were then split into 3 BMI subgroups, with results also evaluated by Wilcoxon matched-pairs signed rank tests. Results There was a significant difference discovered between the mean preoperative Apnea-Hypopnea Index of 31.57 and the mean postoperative value of 8.12 ( P < .001). All patient-reported outcomes improved significantly following tonsillectomy. After stratifying all outcome variables (Apnea-Hypopnea Index, Epworth Sleepiness Scale, Insomnia Severity Index, and Functional Outcomes of Sleep Questionnaire-10) by sex, race, and tonsil size, no statistically significant difference was noted among any of these subgroups. There was a 78% surgical response to treatment. Conclusion Tonsillectomy appears to be an effective treatment for obstructive sleep apnea in a select population of adults with tonsillar hypertrophy. PMID- 28349771 TI - Antivenom for European Vipera species envenoming. AB - BACKGROUND: European viper bite is relatively uncommon but can cause serious envenoming, particularly swelling and hemorrhage spreading from limb to trunk that can cause long term disability. Systemic features are relatively mild compared to many other venomous species. Moderate-to-severe envenoming requires antivenom, which is given many hundreds of times each year across the continent. Several Vipera spp antivenoms are produced in Europe, but there is little comparative information available for the antivenoms and none is licensed with the European Medicines Agency. We aimed to collect descriptive data on European viper antivenoms and assess their relative effectiveness. METHODS: A systematic review of articles relating to antivenom in Europe was performed using the Medline medical database. The following keywords "Europ*" or the individual names of each European country and "antiven*" or "immun*" or "envenom*" and "snake" or "viper*" or "adder" were used. Articles published between 1 January 1996 and 11 March 2016 pertaining to clinical outcome, including case reports, were selected. Referenced articles in the indexed articles were explored for suitability and included if they met any of the criteria: specific antivenom used, route of antivenom administration, adverse reactions to antivenom therapy and length of hospital admission. All accepted abstracts from EAPCCT conferences since 2000 were searched and abstracts relating to Vipera spp envenoming were assessed for suitability. We extracted data on study type, safety and effectiveness. We sought information on antivenoms from manufacturers and individual patient data from authors of publications. Since individual patient data were only rarely available, we compared median length of stay between case series reporting each antivenom. We identified 40 papers and six published abstracts, and one unpublished paper that reported clinical cases and case series of envenomed patients treated with antivenom. No publication reported randomized controlled trials comparing any European Vipera antivenom with either placebo or another antivenom. 25 reports were of retrospective hospital- (n = 13) or poison center based (n = 12) case series including five or more patients; a further 12 reports were either case reports or case series with less than five patients and one paper was a limited literature review. An additional nine papers reported prospective data; seven collected data remotely through poison service telephone communication with the attending physicians. Antivenoms available in Europe: Eight antivenoms are available for European Vipera spp envenoming; a material safety data sheet providing information on manufacture was available for seven. Six are raised against V. berus or V. ammodytes venom; the seventh is raised against a mixture of V. ammodytes, V. aspis and V. berus venom and the eighth is raised against V. ammodytes, Macrovipera lebetina and Montivipera xanthina venom. Six manufacturers recommended intramuscular administration while two recommended intravenous administration. No randomized control trials comparing the effectiveness of antivenoms were identified. Pre-clinical data: We found two papers presenting comparative preclinical data. Clinical data: Clinical studies were predominantly retrospective and contained clinical data on antivenom used in 2602 patients; where the antivenom was identified (n = 2174), 2061 (94.8%) received Zagreb, ViperFAV or ViperaTAb antivenoms. There were few published data on the other antivenoms. Repeated use of antivenom: Repeat doses were reported in 230/1491 of cases (15.4%) where this information was recorded. Outcome and length of hospital stay: Intravenous administration of antivenom was associated with shorter length of hospital stay (median length of hospital stay in studies of intravenous ViperFAV or ViperaTAb ranged from 1 to 4.8 days versus 2 to 18 days for intramuscular Bulbio or Zagreb antivenoms). Antivenom versus no antivenom: Some small studies demonstrated no difference in the length of hospital stay in patients with equivalent envenomation grading who either did or did not receive antivenom. Adverse events: Adverse reactions were reported in 37 of 2408 cases (1.5%) including seven cases of anaphylaxis. CONCLUSIONS: There are very limited pre-clinical comparative data and no randomised controlled trials assessing effectiveness of the antivenoms against different Vipera species. Most descriptive data suggest the efficacy of Zagreb, ViperFAV and ViperaTAb antivenoms by the intravenous route but not intramuscular route, although this is level D evidence. Reported adverse reactions were rare, suggesting that the modern intravenous antivenoms are of good quality. Better and more systematic data, including perhaps randomized controlled trials comparing different antivenoms, are required for the many hundreds of antivenom administrations that occur annually across Europe. PMID- 28349772 TI - Stress, coping, executive function, and brain activation in adolescent offspring of depressed and nondepressed mothers. AB - This study examined the associations among chronic stress, activation in the prefrontal cortex (PFC), executive function, and coping with stress in at-risk and a comparison sample of adolescents. Adolescents (N = 16; age 12-15) of mothers with (n = 8) and without (n = 8) a history of depression completed questionnaires, neurocognitive testing, and functional neuroimaging in response to a working memory task (N-back). Children of depressed mothers demonstrated less activation in the anterior PFC (APFC) and both greater and less activation than controls in distinct areas within the dorsal anterior cingulate cortex (dACC) in response to the N-back task. Across both groups, activation of the dorsolateral PFC (DLPFC; Brodmann area [BA9]) and APFC (BA10) was positively correlated with greater exposure to stress and negatively correlated with secondary control coping. Similarly, activation of the dACC (BA32) was negatively correlated with secondary control coping. Regression analyses revealed that DLPFC, dACC, and APFC activation were significant predictors of adolescents' reports of their use of secondary control coping and accounted for the effects of stress exposure on adolescents' coping. This study provides evidence that chronic stress may impact coping through its effects on the brain regions responsible for executive functions foundational to adaptive coping skills. PMID- 28349773 TI - Epileptic Encephalopathies: Clinical Aspects, Molecular Features and Pathogenesis, Therapeutic Targets and Translational Opportunities, and Future Research Directions. AB - Epileptic encephalopathies encompass a heterogeneous group of epilepsy syndromes that manifest with cognitive, behavioral, and neurologic deficits, seizures that are often intractable and multiform, aggressive electroencephalographic paroxysmal activity, and sometimes early death. As more is learned about the etiologies and manifestations of epileptic encephalopathies, progress has been made toward better treatment options. However, there is still a great need for further randomized controlled trials and research to help create clinically effective therapies. The 2015 Neurobiology of Disease in Children symposium, held in conjunction with the 44th annual meeting of the Child Neurology Society, aimed to (1) describe the clinical concerns involving diagnosis and treatment, (2) review the current status of understanding in the pathogenesis of epileptic encephalopathy, (3) discuss clinical management and therapies for epileptic encephalopathy, and (4) define future directions of research. This article summarizes the presentations and includes an edited transcript of question-and answer sessions. PMID- 28349774 TI - Increasing Ketamine Use for Refractory Status Epilepticus in US Pediatric Hospitals. AB - Ketamine is an emerging therapy for pediatric refractory status epilepticus. The circumstances of its use, however, are understudied. The authors described pediatric refractory status epilepticus treated with ketamine from 2010 to 2014 at 45 centers using the Pediatric Hospital Inpatient System database. For comparison, they described children treated with pentobarbital. The authors estimated that 48 children received ketamine and pentobarbital for refractory status epilepticus, and 630 pentobarbital without ketamine. Those receiving only pentobarbital were median age 3 [interquartile range 0-10], and spent 30 [18-52] days in-hospital, including 17 [9-28] intensive care unit (ICU) days; 17% died. Median cost was $148 000 [81 000-241 000]. The pentobarbital-ketamine group was older (7 [2-11]) with longer hospital stays (51 [30-93]) and more ICU days (29 [20-56]); 29% died. Median cost was $298 000 [176 000-607 000]. For 71%, ketamine was given >=1 day after pentobarbital. Ketamine cases per half-year increased from 2 to 9 ( P < .05). Ketamine is increasingly used for severe pediatric refractory status epilepticus, typically after pentobarbital. Research on its effectiveness is indicated. PMID- 28349775 TI - A Patient as Art: Andrew Wyeth's Portrayal of Christina Olson's Neurologic Disorder in Christina's World. AB - In Christina's World, one of the most beloved works of American art, Andrew Wyeth painted Christina Olson crawling crablike across the field below her house, raised on emaciated arms, with a swollen knob for an elbow, and hands clenched and gnarled. The significance of these physical abnormalities, and the message Wyeth endeavored to convey via the portrait, are considered here in light of Christina's medical history and the disorder it most likely signifies. PMID- 28349776 TI - Associations between Otolaryngology Applicant Characteristics and Future Performance in Residency or Practice: A Systematic Review. AB - Objective This systematic review aims to evaluate which applicant characteristics available to an otolaryngology selection committee are associated with future performance in residency or practice. Data Sources PubMed, Scopus, ERIC, Health Business, Psychology and Behavioral Sciences Collection, and SocINDEX. Review Methods Study eligibility was performed by 2 independent investigators in accordance with the PRISMA protocol (Preferred Reporting Items for Systematic Reviews and Meta-analyses). Data obtained from each article included research questions, study design, predictors, outcomes, statistical analysis, and results/findings. Study bias was assessed with the Quality in Prognosis Studies tool. Results The initial search identified 439 abstracts. Six articles fulfilled all inclusion and exclusion criteria. All studies were retrospective cohort studies (level 4). Overall, the studies yielded relatively few criteria that correlated with residency success, with generally conflicting results. Most studies were found to have a high risk of bias. Conclusion Previous resident selection research has lacked a theoretical background, thus predisposing this work to inconsistent results and high risk of bias. The included studies provide historical insight into the predictors and criteria (eg, outcomes) previously deemed pertinent by the otolaryngology field. Additional research is needed, possibly integrating aspects of personnel selection, to engage in an evidence based approach to identify highly qualified candidates who will succeed as future otolaryngologists. PMID- 28349777 TI - Aortic Curvature Is a Predictor of Late Type Ia Endoleak and Migration After Endovascular Aneurysm Repair. AB - PURPOSE: To evaluate the association between aortic curvature and other preoperative anatomical characteristics and late (>1 year) type Ia endoleak and endograft migration in endovascular aneurysm repair (EVAR) patients. METHODS: Eight high-volume EVAR centers contributed 116 EVAR patients (mean age 81+/-7 years; 103 men) to the study: 36 patients (mean age 82+/-7 years; 31 men) with endograft migration and/or type Ia endoleak diagnosed >1 year after the initial EVAR and 80 controls without early or late complications. Aortic curvature was calculated from the preoperative computed tomography scan as the maximum and average curvature over 5 predefined aortic segments: the entire infrarenal aortic neck, aneurysm sac, and the suprarenal, juxtarenal, and infrarenal aorta. Other morphological characteristics included neck length, neck diameter, mural neck calcification and thrombus, suprarenal and infrarenal angulation, and largest aneurysm sac diameter. Independent risk factors were identified using backward stepwise logistic regression. Relevant cutoff values for each of the variables in the final regression model were determined with the receiver operator characteristic curve. RESULTS: Logistic regression identified maximum curvature over the length of the aneurysm sac (>47 m-1; p=0.023), largest aneurysm sac diameter (>56 mm; p=0.028), and mural neck thrombus (>11 degrees circumference; p<0.001) as independent predictors of late migration and type Ia endoleak. CONCLUSION: Aortic curvature is a predictor for late type Ia endoleak and endograft migration after EVAR. These findings suggest that aortic curvature is a better parameter than angulation to predict post-EVAR failure and should be included as a hostile neck parameter. PMID- 28349778 TI - Neuropsychological measurement of inhibitory control in posttraumatic stress disorder: An exploratory antisaccade paradigm. AB - OBJECTIVE: The aim of the study was to uncover inhibitory control dynamics and assess antisaccade eye-tracking tasks for relevance in a veteran posttraumatic stress disorder (PTSD) population. METHOD: Participants were 36 veterans enrolled at the Washington DC Veterans Affairs Medical Center. The groups (PTSD diagnosed vs. controls) did not vary between age and sex. Participants completed a testing battery of clinical neuropsychological measures and two different eye-tracking conditions, one that utilized face stimuli and one with standard shape stimuli, which test pro- (PS) and antisaccade (AS) eye movements. RESULTS: Veterans with PTSD, t(33) = 2.2, p = .04, took longer to respond than controls in the standard condition AS. In the face condition, a group by task interaction was seen with increased latency for PTSD veterans in the AS versus PS task, F(3, 33) = 3.99, p = .05, with a large overall effect (Hedges' g = 1.18, p < .001) compared to controls. After controlling for depression, analyses suggested that only the face condition AS task significantly predicted dimensions of PTSD symptomology measured by the Clinician Administered PTSD Scale (CAPS) for veterans with PTSD. CONCLUSIONS: This is the first study to extend AS findings to PTSD and suggests a specific capability to measure inhibitory control using eye-tracking technology. We discuss the notion that reduced capacity to regulate facial-related processing affects cognitive and attentional control networks of PTSD patients, potentially representing a core cognitive deficit. PMID- 28349779 TI - Leadership Training in Otolaryngology Residency. AB - Although residency training offers numerous leadership opportunities, most residents are not exposed to scripted leadership instruction. To explore one program's attitudes about leadership training, a group of otolaryngology faculty (n = 14) and residents (n = 17) was polled about their attitudes. In terms of self-perception, more faculty (10 of 14, 71.4%) than residents (9 of 17, 52.9%; P = .461) considered themselves good leaders. The majority of faculty and residents (27 of 31) thought that adults could be taught leadership ability. Given attitudes about leadership ability and the potential for improvement through instruction, consideration should be given to including such training in otolaryngology residency. PMID- 28349780 TI - Ganoderic acid targeting nuclear factor erythroid 2-related factor 2 in lung cancer. AB - Lung cancer causes huge mortality worldwide, and targeting new pathway may provide an alternative in modulating signaling in cancer. Nuclear factor erythroid 2-related factor 2 is the major regulator of endogenous and exogenous stress by activating numerous antioxidant genes critical in cancer, Alzheimer's, Parkinson's, and inflammatory bowel diseases. Ganoderic acid is a triterpene from basiodiomycetes fungus Ganoderma lucidum with numerous therapeutic effects. In this study, ganoderic acid and its 50 isomers and natural activators were docked by receptor-based molecular docking using Maestro 9.6 (Schrodinger Inc.) in the Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 signaling pathway. The receptor-based molecular docking reveals the best binding interaction of nuclear factor erythroid 2-related factor 2 and ganoderic acid A with GScore (-9.69) (kcal/mol), Lipophilic EvdW (-1.83), Electro (-0.72), Glide emodel (-73.369), H bond (-1.1), molecular mechanics/generalized Born surface area (-75.541) with Leu 718, Asp 800, Cys 797 residues involved in hydrogen bonding. The calculated docking energy highlights the lipophilic, hydrogen bonding, pi-pi stacking interactions, and non-covalent bonding. Analysis showed the involvement of cysteine and serine residues which were crucial in the activation and translocation from cytoplasm to the nucleus in the nuclear factor erythroid 2-related factor 2 signaling process. The molecular docking tool QikProp analyzed the absorption, distribution, metabolism, excretion, and toxicity but needs some modifications in their structure to satisfy Lipinski's rule. Ganoderic acid A is a best docked isoform which inhibits the cell proliferation, viability, migration, and reactive oxygen species and messenger RNA expression of nuclear factor erythroid 2-related factor 2 in H460 cells. PMID- 28349781 TI - Evaluation of sorafenib in Chinese unresectable hepatocellular carcinoma patients with prior surgery and portal vein tumor thrombosis: A subset analysis of GIDEON study data. AB - The purpose of this study was to examine the safety and efficacy of sorafenib in Chinese patients with unresectable hepatocellular carcinoma. Data of 338 Chinese patients from the Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib study database were included. Patients were divided into those who received and did not receive sorafenib prior to surgical resection and those with and without portal vein tumor thrombosis. In the non-surgery group, the median survival was 302 days (95% confidence interval: 244-371), and the median time from diagnosis to death was 428 days (95% confidence interval: 352-556); in the surgery group, half of the patients survived for 345 days and the median time from diagnosis to death was 1000 days (95% confidence interval: 750-2816). Median progression-free survival and median time to progression were not different between the two groups. Median overall survival was 360 days (95% confidence interval: 309-435) in the non-portal vein tumor thrombosis group and 240 days (95% confidence interval: 181-296) in the portal vein tumor thrombosis group; median time between hepatocellular carcinoma diagnosis and death was 750 days (95% confidence interval: 472-1000) and 420 days (95% confidence interval: 252-567), respectively, in the two groups. Median progression-free survival was 209 days (95% confidence interval: 166-264) for patients without portal vein tumor thrombosis and 154 days (95% confidence interval: 112-202) for patients with portal vein tumor thrombosis; median time to progression was 295 days (95% confidence interval: 209-463) and 221 days, respectively. Adverse events were generally comparable regardless of prior surgery and portal vein tumor thrombosis status. We thus conclude that earlier administration of sorafenib may result in improved outcomes in patients with unresectable hepatocellular carcinoma and portal vein tumor thrombosis. PMID- 28349782 TI - HR+HER2- breast cancers with growth factor receptor-mediated EMT have a poor prognosis and lapatinib downregulates EMT in MCF-7 cells. AB - Despite an overall good prognosis, a significant proportion of patients with hormone receptor positive human epidermal growth factor receptor 2 negative breast cancers develop distant metastases. The metastatic potential of epithelial cells is known to be regulated by tumor-stromal interaction and mediated by epithelial-to-mesenchymal transition. Hormone receptor positive human epidermal growth factor receptor 2 negative tumors were used to estimate markers of epithelial-to-mesenchymal transition, and the luminal breast cancer cell line MCF 7 was used to examine the interactions between integrins and growth factor receptors in causation of epithelial-to-mesenchymal transition. A total of 140 primary tumors were sub-divided into groups enriched for the markers of epithelial-to-mesenchymal transition (snail family transcriptional repressor 2 and integrin beta6) versus those with low levels. Within the epithelial-to mesenchymal transition+ tumors, there was a positive correlation between the transcripts of integrin beta6 and growth factor receptors-human epidermal growth factor receptor 2 and epidermal growth factor receptor. In tumors enriched for epithelial-to-mesenchymal transition markers, patients with tumors with the highest quartile of growth factor receptor transcripts had a shorter disease-free survival compared to patients with low growth factor receptor expression by Kaplan-Meier analysis (log rank, p = 0.03). Epithelial-to-mesenchymal transition was induced in MCF-7 cells by treatment with transforming growth factor beta 1 and confirmed by upregulation of SNAI1 and SNAI2 transcripts, increase of vimentin and integrin beta6 protein, and repression of E-cadherin. Treatment of these cells with the dual-specificity tyrosine-kinase inhibitor lapatinib led to downregulation of epithelial-to-mesenchymal transition as indicated by lower levels of SNAI1 and SNAI2 transcripts, integrin alphavbeta6, and matrix metalloproteinase 9 protein. The results suggest that synergistic interactions between growth factor receptors and integrin beta6 could mediate epithelial-to mesenchymal transition and migration in a subset of luminal breast cancers and lapatinib might be effective in disrupting this interaction. PMID- 28349783 TI - Toxicity from fluoropolymer-containing grout, tile and stone floor sealants reported to the UK National Poisons Information Service 2009-2015. AB - CONTEXT: Grout, tile and floor stone sealants contain a solvent, a water repelling agent and in the case of aerosols a propellant. The water-repelling agent used is typically a fluoropolymer resin, a silicon-based resin, or a combination of both. OBJECTIVE: To report the clinical course in patients exposed to fluoropolymer-containing sealants referred to the United Kingdom National Poisons Information Service. METHODS: A retrospective analysis was performed of telephone enquiries received between 2009 and 2015. RESULTS: 101 enquiries involving 96 exposures were received. The majority of the exposures (n = 88) occurred when the sealant was delivered from an aerosol. Twelve patients were exposed occupationally and the remainder were exposed while using the product at home. Eighty-nine exposures were as a result of inhalation alone, two followed ingestion, three skin contact and one eye contact; one involved inhalation and eye contact. All 90 patients exposed by inhalation developed clinical features: 31 had a World Health Organisation/International Programme on Chemical Safety/European Commission/European Association of Poison Centres and Clinical Toxicologists Poisoning Severity Score of 1 (minor toxicity), 51 patients had features of moderate toxicity (PSS 2) and eight were graded PSS 3 (severe poisoning). The most common features were dyspnea (n = 52; 57.8%; 95% CI = 47.0 68.5), chest pain/tightness (n = 34; 37.8%; 95% CI = 27.2-48.4), coughing (n = 27; 30.0%; 95% CI = 20.0-40.0) and sinus tachycardia (n = 11; 12.2%; 95% CI = 4.1 18.2); hypoxemia was present in 20 (22.2%; 95% CI = 13.1-31.4). At the time of the enquiry a chest X-ray had been performed on 15 patients: in eight patients (all of whom were PSS 3) the X-ray was reported as being abnormal and showed bilateral shadowing. CONCLUSIONS: This study demonstrates that if fluoropolymer containing sealants are inhaled then clinical features may occur and in a small proportion (9%) these features may be severe. PMID- 28349786 TI - The Use of Frozen Section in the Early Diagnosis of Acute Invasive Fungal Sinusitis. AB - Objectives Acute invasive fungal sinusitis (AIFS) remains a significant cause of morbidity and mortality in the immunocompromised patient population. Early diagnosis is key to improving patient outcomes. Frozen section biopsies have been shown to decrease time to diagnosis when compared with permanent pathology. However, its accuracy has not been adequately described in the literature, specifically in regard to AIFS. The aim of this study is to evaluate the statistical diagnostic accuracy of frozen sections and to review the etiology, clinical presentation, and current diagnostic protocols in management of AIFS. Study Design Case series with chart review. Setting Tertiary referral center. Subjects and Methods Retrospective review included 67 pathologic records in Co Path, with search criteria including invasive fungal, clinical history, frozen section, and final diagnosis between the dates of 2006 and 2015. Results Sixty seven cases were reviewed per the search criteria in Co-Path. Of these, 31 met further criteria of having had frozen section analysis. Variables such as sensitivity, specificity, positive predictive value, and negative predictive value were assessed. All 21 positive frozen sections correlated with positive permanent pathology, giving a positive predictive value of 100%. Frozen section biopsies were 87.5% sensitive and 100% specific. Conclusion Early diagnosis of AIFS has been shown to decrease morbidity and mortality. Frozen section biopsies remain key in obtaining an early diagnosis among patients with a high clinical suspicion for invasive fungal sinusitis. Frozen section biopsies positive for invasive fungal pathology were universally consistent with definitive diagnosis. PMID- 28349787 TI - Giant cystic schwannoma of the middle mediastinum with cervical extension. AB - Schwannomas (neurilemmomas) are benign tumors arising from the Schwann cells of the neural sheath. They are typically, well-encapsulated lesions which rarely adhere to the adjacent structures. In the chest, schwannomas are often seen within the posterior mediastinum and commonly originating along intercostal nerves. Several operative approaches have previously been described for the resection of these tumors, including thoracoscopic techniques and posterolateral thoracotomy. We report in this case a giant cystic mediastinal schwannoma of the left recurrent laryngeal nerve with cervical extension, unresectable by the usual described approaches, which was completely removed through a cervical approach. PMID- 28349784 TI - Fibroblasts in Hypoxic Conditions Mimic Laryngotracheal Stenosis. AB - Objective To elucidate the role of hypoxia and inflammatory pathways in the pathogenesis of iatrogenic laryngotracheal stenosis (iLTS). Study Design (1) Examination of mucosal surface gene expression in human iLTS. (2) In vitro comparison of normal and scar laryngotracheal fibroblasts under normoxic and hypoxic conditions. Setting Tertiary care hospital in a research university (2012 2016). Subjects and Methods Brush biopsies were obtained from normal laryngotracheal tissue and scar in iLTS patients; gene expression was compared. Fibroblasts were isolated from normal and scarred trachea and grown in vitro in either a 1% O2 or normoxic environment. Cell growth and gene and protein expression were compared. Statistical analysis utilized a multilevel mixed effects model. Results Expression of IL-6 (fold change = 2.8, P < .01), myofibroblast marker alphaSMA (fold change = 3.0, P = .01), and MMP13 (fold change = 5.4, P = .02) was significantly increased in scar biopsy samples as compared to normal. Under hypoxic conditions in vitro, normal laryngotracheal fibroblasts proliferated significantly faster (n = 8, P < .01 each day). Expression of IL-6 (n = 8, fold change = 2.6, P < .01) increased significantly after 12 hours under hypoxia. Expression of alphaSMA (n = 8, fold change= 2.0, P = .03), COL1 (n = 8, fold change = 1.1, P = .03), and MMP13 (n = 8, fold change = 1.6, P = .01) increased significantly after 48 hours under hypoxia. Scar fibroblasts also proliferated significantly faster under hypoxic conditions but did not display the same expression profile. Conclusion Human iLTS scar has a myofibroblast phenotype. Under hypoxic conditions in vitro, normal laryngotracheal fibroblasts can transdifferentiate into a similar phenotype. These changes may be mediated by IL-6, a fibrosis-related cytokine. PMID- 28349785 TI - Inflammatory Cell Findings in the Female Rabbit Heart and Stress-associated Exacerbation with Handling and Procedures Used in Nonclinical Studies. AB - Despite the use of rabbits in biomedical research, including regulatory toxicology and cardiovascular studies, little data exist on heart findings in this species. This study was designed to document myocardial findings in female rabbits and the impact of study-related procedures typical for vaccine toxicology studies. One hundred and forty 6- to 8-month-old female New Zealand White rabbits were divided equally into 2 groups, high and low study procedure groups (group 1 and group 2, respectively). All animals received intramuscular (IM) injections of sterile saline every 2 weeks for 5 times and were necropsied 2 days after the final IM injection. Clinical chemistry, hematology, and urinalysis were evaluated. Blood for stress biomarkers (norepinephrine, epinephrine, cortisol, and corticosterone), C-reactive protein, cardiac troponin I, and creatine kinase were collected at time 0 (just before dose administration) and then at 4, 24, and 48 hr after dose administration in group 1 only. Hearts were assessed histologically. Focal to multifocal minimal inflammatory cell infiltrates were common (~80%), particularly in the left ventricle and interventricular septum, and were similar to the types of infiltrates identified in other laboratory animal species. Additionally, study-related procedures elevated serum stress biomarkers and exacerbated the frequency and severity of myocardial inflammatory cell infiltrates. PMID- 28349788 TI - Critical analysis of the published literature about the effects of narghile use on oral health. PMID- 28349790 TI - Experimental evaluation of anti-inflammatory, antinociceptive and antipyretic activities of clove oil in mice. AB - Background Clove oil of Eugenia caryophyllata (Myrtaceae) is a light yellowish fluid obtained from dried flower buds. Clove oil is used traditionally to relieve toothache. Aim The aim of the present work was to study the anti-inflammatory, antinociceptive and antipyretic potential of clove oil in mice. Methods Analgesic activity was examined using acetic-acid-induced abdominal constrictions and the hot plate test. Carrageenan-induced paw edema and brewer's-yeast-induced pyrexia were used to investigate the anti-inflammatory activity and the antipyretic effects, respectively. The oil was administered intraperitoneally (i.p.) at a dose of 33 mg/kg body weight and the effects were compared with reference drugs. Results In the antinociceptive test, mice treated with clove oil exhibited significantly decreased acetic-acid-induced writhing movements by a maximum of 87.7% (p<0.01) compared with a decrease of 77.7% (p<0.01) in response to aspirin injection (100 mg/kg, intraperitoneal, i.p.). Similarly, in the hot plate test, clove oil significantly increased the reaction latency to pain after 60 min by 82.3% (p<0.05) compared with morphine value of 91.7% (p<0.01). In addition, clove oil and indomethacin produced anti-inflammatory effects, as demonstrated by respectively 50.6% (p<0.05) and 70.4% (p<0.01) inhibition of mouse paw edema induced by carrageenan. Furthermore, clove oil significantly attenuated the hyperthermia induced by yeast at DeltaT-max by 2.7 degrees C (p<0.001), and time of peak effects was 30-180 min compared with a paracetamol value DeltaT-max of 3.2 degrees C (p<0.001). The estimated i.p. LD50 of clove oil was 161.9 mg/kg. Phytochemical screening of the oil showed the presence of eugenol. Conclusion The present findings demonstrate the potential pharmacological properties of clove oil and provide further a support for its reported use in folk medicine. PMID- 28349789 TI - Dexmedetomidine protects from post-myocardial ischaemia reperfusion lung damage in diabetic rats. AB - Objective Diabetic complications and lipid peroxidation are known to have a close association. Lipid peroxidation commonly occurs at sites exposed to ischaemia, but distant organs and tissues also get damaged during ischaemia/reperfusion (I/R). Some of these targets are vital organs, such as the lung, liver, and kidney; the lung is the most frequently affected. The aim of our study was to investigate the effects of dexmedetomidine on I/R damage in lung tissue and on the oxidant/anti-oxidant system in diabetic rats. Material and methods Diabetes was induced with streptozotocin (55 mg/kg) in 18 Wistar Albino rats, which were then randomly divided into three groups (diabetes control (DC), diabetes plus ischaemia-reperfusion (DIR), and diabetes plus dexmedetomidine ischaemia/reperfusion (DIRD)) after the effects of diabetes were clearly evident. The rats underwent a left thoracotomy and then ischaemia was produced in the myocardium muscle by a left anterior descending artery ligation for 30 min in the DIR and DIRD groups. I/R was performed for 120 min. The DIRD group received a single intraperitoneal dose of dexmedetomidine (100 ug/kg); the DIR group received no dexmedetomidine. Group DC was evaluated as the diabetic control group and also included six rats (C group) in which diabetes was not induced. These mice underwent only left thoracotomy and were closed without undergoing myocardial ischaemia. Histopathological changes, activities of catalase (CAT) and glutathione-S-transferase anti-oxidant enzymes, and malondialdehyde (MDA) levels were evaluated in the lung tissues of all rats. Results Neutrophil infiltration/aggregation was higher in the DIR group than in the C, DC, and DIRD groups (p=0.001, p=0.013, and p=0.042, respectively). The lung injury score was significantly higher in the DIR group than in the C and DC groups (p<0.0001 and p=0.024, respectively). The levels of MDA were significantly higher in the DIR group than in the C and DIRD groups. CAT activity was significantly higher in the DIR group than in the DIRD and C groups. Conclusion Our results confirm that dexmedetomidine has protective effects against the lung damage resulting from I/R in diabetic rats. Future studies conducted to evaluate the effects of the use of dexmedetomidine on damage to various organs following different I/R durations may help understanding possible protective effects of dexmedetomidine and underlying mechanisms in tissue damage related to I/R injury. PMID- 28349791 TI - Illness perceptions of Libyans with T2DM and their influence on medication adherence: a study in a diabetes center in Tripoli. AB - Background The surrounding environment influences the constitution of illness perceptions. Therefore, local research is needed to examine how Libyan diabetes patients perceive diabetes and how their perceptions influence their medication adherence. Methods A cross-sectional study was conducted at the National Centre for Diabetes and Endocrinology in Tripoli, Libya, between October and December 2013. A total of 523 patients with type 2 diabetes participated in this study. A self-administered questionnaire was used for data collection; this included the Revised Illness Perception Questionnaire and the eight-item Morisky Medication Adherence Scale. Results The respondents showed moderately high personal control and treatment control perceptions and a moderate consequences perception. They reported a high perception of diabetes timeline as chronic and a moderate perception of the diabetes course as unstable. The most commonly perceived cause of diabetes was Allah's will. The prevalence of low medication adherence was 36.1%. The identified significant predictors of low medication adherence were the low treatment control perception (p=0.044), high diabetes identity perception (p=0.008), being male (p=0.026), and employed (p=0.008). Conclusion Diabetes illness perceptions of type 2 diabetic Libyans play a role in guiding the medication adherence and could be considered in the development of medication adherence promotion plans. PMID- 28349792 TI - Perceived competency towards preventive dentistry among dental graduates: the need for curriculum change. AB - Background A previous study has shown that dental practitioners in Benghazi believed that the less prevention-oriented education system is one of the barriers to applying preventive dentistry. Objective To assess attitudes and perceived competence of the dental graduates in Benghazi towards prevention and early management of dental caries. Methods A cross-sectional, questionnaire-based survey was conducted among internship students attending the Department of Community and Preventive Dentistry in Faculty of Dentistry, Benghazi, Libya. The participants were asked to provide demographic information, to respond to statements about their attitudes towards preventive dentistry, and to answer questions regarding their perceived competence in applying preventive dentistry procedures. Results Data from 108 Libyan dental graduates were analysed for this study, of which 64% of them were females and 42.1% of them passed their final year with grade: acceptable. The most acknowledged aspects of preventive dentistry were being useful and essential to the community (95.4 and 90.8%, respectively). The percentage of participants expressing a proficiency in providing oral hygiene instructions was the highest (95.4%). There were differences between study subgroups in their perceived competence of preventive dental practices by gender and academic performance (p<=0.05). Conclusion This study highlighted that the currently implemented undergraduate education programme in Benghazi dental school does not provide dentists with the required attitude and skills to fulfil their role in providing preventive-oriented health services. PMID- 28349793 TI - Polymorphisms of the thiopurine S-methyltransferase gene among the Libyan population. AB - Background Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme that catalyses the S-methylation of 6-mercaptopurine and azathioprine. Low activity phenotypes are correlated with polymorphism in the TPMT gene. Patients with low or undetectable TMPT activity could develop severe myelosuppression when they are treated with standard doses of thiopurine drugs. Since ethnic differences in the TPMT gene polymorphism have been demonstrated worldwide, assessing it in the Libyan population is worthwhile. Methods We investigated TPMT gene polymorphism in a total of 246 Libyan healthy adult blood donors from three different Libyan regions (Tripoli, Yefren, and Tawargha) and 50 children with acute lymphoblastic leukaemia (ALL). We used polymerase chain reaction restriction length polymorphism (PCR-RFLP) and allele-specific PCR-based assays to analyse the TPMT gene for the variants *2 c.238 G>C, 3A (c.460 G>A and c.719 A>G), *3B (c.460 G>A), and *3C (c.719 A>G). Results Our results show that the TPMT variants associated with low enzymatic activity were detected in 3.25% (8 in 246) of adult Libyan individuals and the frequency of total mutant alleles was 1.63%. Heterozygous genotypes were TPMT*3A in three subjects (0.61%) and TPMT*3C in five subjects (1.02%). No TPMT*2 and TPMT*3B allelic variants and no homozygous or compound heterozygous mutant alleles were detected. The normal allele (wild-type) was found in 98.4% of the adult individuals studied. No mutant alleles were detected among the 50 children who had ALL. Conclusions We report on the presence of the TPMT*3C and *3A mutant alleles in the Libyan population. Therefore, monitoring the patients to be treated with doses of thiopurine drugs for TPMT variants is worthwhile to avoid the development of severe myelosuppression. PMID- 28349794 TI - Lung function profiles and aerobic capacity of adult cigarette and hookah smokers after 12 weeks intermittent training. AB - Introduction Pulmonary function is compromised in most smokers. Yet it is unknown whether exercise training improves pulmonary function and aerobic capacity in cigarette and hookah smokers and whether these smokers respond in a similar way as do non-smokers. Aim To evaluate the effects of an interval exercise training program on pulmonary function and aerobic capacity in cigarette and hookah smokers. Methods Twelve cigarette smokers, 10 hookah smokers, and 11 non-smokers participated in our exercise program. All subjects performed 30 min of interval exercise (2 min of work followed by 1 min of rest) three times a week for 12 weeks at an intensity estimated at 70% of the subject's maximum aerobic capacity ([Formula: see text]). Pulmonary function was measured using spirometry, and maximum aerobic capacity was assessed by maximal exercise testing on a treadmill before the beginning and at the end of the exercise training program. Results As expected, prior to the exercise intervention, the cigarette and hookah smokers had significantly lower pulmonary function than the non-smokers. The 12-week exercise training program did not significantly affect lung function as assessed by spirometry in the non-smoker group. However, it significantly increased both forced expiratory volume in 1 second and peak expiratory flow (PEF) in the cigarette smoker group, and PEF in the hookah smoker group. Our training program had its most notable impact on the cardiopulmonary system of smokers. In the non smoker and cigarette smoker groups, the training program significantly improved [Formula: see text] (4.4 and 4.7%, respectively), v [Formula: see text] (6.7 and 5.6%, respectively), and the recovery index (7.9 and 10.5%, respectively). Conclusions After 12 weeks of interval training program, the increase of [Formula: see text] and the decrease of recovery index and resting heart rate in the smoking subjects indicated better exercise tolerance. Although the intermittent training program altered pulmonary function only partially, both aerobic capacity and life quality were improved. Intermittent training should be advised in the clinical setting for subjects with adverse health behaviors. PMID- 28349795 TI - Effect of active warm-up duration on morning short-term maximal performance during Ramadan. AB - Purpose To examine the effect of active warm-up duration on short-term maximal performance assessed during Ramadan in the morning. Methods Twelve healthy active men performed four Wingate tests for measurement of peak power and mean power before and during Ramadan at 09:00 a.m. The tests were performed on separate days, after either a 5-min or a 15-min warm-up. The warm-up consisted in pedaling at 50% of the power output obtained at the last stage of a submaximal multistage cycling test. Oral temperature was measured at rest and after warming-up. Furthermore, ratings of perceived exertion were obtained immediately after the Wingate test. Results Oral temperature was higher after the 15-min warm-up than the 5-min warm-up throughout the study. Moreover, peak power and mean power were higher after the 15-min warm-up than the 5-min warm-up before Ramadan. However, during Ramadan, there was no significant difference between the two warm-up durations. In addition, ratings of perceived exertion were higher after the 15 min warm-up than the 5-min warm-up only during Ramadan. Conclusions There is no need to prolong the warm-up period before short-term maximal exercise performed during Ramadan in the morning. PMID- 28349796 TI - Defining obstructive ventilatory defect in 2015. AB - Introduction There is no clear consensus as to what constitutes an obstructive ventilatory defect (OVD): Is it FEV1/FVC=45 years, n=2,654), smokers (n=1,208), and non-smokers (n=3,522) groups. Results For the total sample, the younger and older groups [mean+/-SD of age (years), respectively, 46.7+/-14.1; 33.9+/-7.4, and 56.8+/-9.1], the 'physiological definition' detected, respectively, 13.46, 43.22, and 5.09% more OVD than the 'operational one' (p<0.05). In addition, the operational definition, compared with the physiological one, overdiagnosed OVD in 2.33 and 0.44% of smokers and non-smokers, respectively, and underdiagnosed it in 4.46% and 29.72% of smokers and non-smokers, respectively (p<0.05). Compared with the group 'physio (-), operat (+)', the 'physio (+), operat (-)' one was younger (74.2+/ 4.7 years vs. 40.9+/-10.3 years) and had significantly higher FEV1 (62+/-13% vs. 78+/-17%) and FVC (71+/-15% vs. 93+/-19%). Conclusion The frequency of OVD much depends on the criteria used for its definition. PMID- 28349797 TI - Cardiac autonomic control in the obstructive sleep apnea. AB - Introduction The sympathetic activation is considered to be the main mechanism involved in the development of cardiovascular diseases in obstructive sleep apnea (OSA). The heart rate variability (HRV) analysis represents a non-invasive tool allowing the study of the autonomic nervous system. The impairment of HRV parameters in OSA has been documented. However, only a few studies tackled the dynamics of the autonomic nervous system during sleep in patients having OSA. Aims To analyze the HRV over sleep stages and across sleep periods in order to clarify the impact of OSA on cardiac autonomic modulation. The second objective is to examine the nocturnal HRV of OSA patients to find out which HRV parameter is the best to reflect the symptoms severity. Methods The study was retrospective. We have included 30 patients undergoing overnight polysomnography. Subjects were categorized into two groups according to apnea-hypopnea index (AHI): mild-to-moderate OSAS group (AHI: 5-30) and severe OSAS group (AHI>30). The HRV measures for participants with low apnea-hypopnea indices were compared to those of patients with high rates of apnea-hypopnea across the sleep period and sleep stages. Results HRV measures during sleep stages for the group with low rates of apnea-hypopnea have indicated a parasympathetic activation during non rapid eye movement (NREM) sleep. However, no significant difference has been observed in the high AHI group except for the mean of RR intervals (mean RR). The parasympathetic activity tended to increase across the night but without a statistical difference. After control of age and body mass index, the most significant correlation found was for the mean RR (p=0.0001, r=-0.248). Conclusion OSA affects sympathovagal modulation during sleep, and this impact has been correlated to the severity of the disease. The mean RR seemed to be a better index allowing the sympathovagal balance appreciation during the night in OSA. PMID- 28349798 TI - Prevalence and risk factors of low back pain among undergraduate students of a sports and physical education institute in Tunisia. AB - Introduction For obvious reasons, athletes are at greater risk of sustaining a lumber (lower) spine injury due to physical activity. To our knowledge, no previous studies have examined the prevalence of low back pain (LBP) in a Tunisian sports and physical education institute. Aim To assess the prevalence of LBP in different sports among students studying in a sports and physical education institute in Tunisia, to determine the causes of the injuries, and to propose solutions. Methods A total of 3,379 boys and 2,579 girls were studied. A retrospective cross-sectional survey was conducted on a group of students aged 18.5-24.5 years at the Higher Institute of Sport and Physical Education of Sfax to estimate the prevalence of LBP and its relation to the type of sports. Data on age, weight, height, smoking, and the sport in which the student was injured in the low back were collected from the institute health service records from 2005 until 2013. Results LBP was reported by 879 of the 5,958 study participants (14.8%). The prevalence of LBP was significantly higher (p<0.001) in females (17.6%) than in males (12.5%). LBP prevalence did not differ by body mass index or smoking habit (p>0.05). The sports associated with the higher rates of LBP were gymnastics, judo, handball, and volleyball, followed by basketball and athletics. Conclusion LBP is frequent among undergraduate students of a sports and physical education institute in Tunisia. It is strongly associated with fatigue after the long periods of training in different sports. Gymnastics, judo, handball, and volleyball were identified as high-risk sports for causing LBP. PMID- 28349799 TI - Mucocutaneous leishmaniasis in an 11-year-old girl with ataxia telangectasia - case report. PMID- 28349800 TI - Argument for the need of investigation of the relationship between body fatness and experimental pain sensitivity. AB - In this communication, we argue about the need for an extensive investigation of the relationship between body fatness and fat distribution and experimental pain to explore the factors that might contribute to the increased prevalence of pain conditions in obese individuals. PMID- 28349801 TI - Comparison of physical quality assurance between Scanora 3D and 3D Accuitomo 80 dental CT scanners. AB - Background The use of cone beam computed tomography (CBCT) in dentistry has proven to be useful in the diagnosis and treatment planning of several oral and maxillofacial diseases. The quality of the resulting image is dictated by many factors related to the patient, unit, and operator. Materials and methods In this work, two dental CBCT units, namely Scanora 3D and 3D Accuitomo 80, were assessed and compared in terms of quantitative effective dose delivered to specific locations in a dosimetry phantom. Resolution and contrast were evaluated in only 3D Accuitomo 80 using special quality assurance phantoms. Results Scanora 3D, with less radiation time, showed less dosing values compared to 3D Accuitomo 80 (mean 0.33 mSv, SD+/-0.16 vs. 0.18 mSv, SD+/-0.1). Using paired t-test, no significant difference was found in Accuitomo two scan sessions (p>0.05), while it was highly significant in Scanora (p>0.05). The modulation transfer function value (at 2 lp/mm), in both measurements, was found to be 4.4%. The contrast assessment of 3D Accuitomo 80 in the two measurements showed few differences, for example, the grayscale values were the same (SD=0) while the noise level was slightly different (SD=0 and 0.67, respectively). Conclusions The radiation dose values in these two CBCT units are significantly less than those encountered in systemic CT scans. However, the dose seems to be affected more by changing the field of view rather than the voltage or amperage. The low doses were at the expense of the image quality produced, which was still acceptable. Although the spatial resolution and contrast were inferior to the medical images produced in systemic CT units, the present results recommend adopting CBCTs in maxillofacial imaging because of low radiation dose and adequate image quality. PMID- 28349802 TI - Impact of corpulence parameters and haemoglobin A1c on metabolic control in type 2 diabetic patients: comparison of apolipoprotein B/A-I ratio with fasting and postprandial conventional lipid ratios. AB - Background and objective The incidence of diabetes co-morbidities could probably be better assessed by studying its associations with major corpulence parameters and glycaemic control indicators. We assessed the utility of body mass index (BMI), waist circumference (WC), and glycosylated haemoglobin (HbA1c) levels in metabolic control for type 2 diabetic patients. Methods Fasting and postprandial blood samples were collected from 238 type 2 diabetic patients aged 57.4+/-11.9 years. The sera were analysed for glucose, HbA1c, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and apolipoproteins (apoA-I and apoB). Ratios of lipids and apolipoproteins were calculated and their associations with BMI, WC, and HbA1c levels were analysed. Results Our investigation showed increases in most fasting and postprandial lipid parameters according to BMI and WC. In men, postprandial HDL-c and TG levels were significantly higher (p<0.05) in overweight and obese patients, respectively, as well as in patients with abdominal obesity. Contrariwise, postprandial TC levels were significantly higher (p<0.01) in overweight and abdominal obese women. However, elevations of apoA-I and apoB levels were according to BMI and WC in both genders. There was a strong influence of BMI, WC, and HbA1c levels on the apoB/apoA-I ratio compared to traditional fasting and postprandial lipid ratios in both men and women. The apoB/apoA-I ratio was more correlated with postprandial TC/HDL and LDL-c/HDL-c ratios in men and with postprandial TG/HDL-c in women. Conclusion The apoB/apoA-I ratio is helpful in assessing metabolic risk caused by overall obesity, abdominal obesity and impaired glycaemia in type 2 diabetic patients. PMID- 28349803 TI - Clinical audit as a framework for the consultation on the future of Libyan Health Services. PMID- 28349804 TI - Association between vitamin D receptor gene polymorphisms and chronic periodontitis among Libyans. AB - Background Chronic periodontitis (CP) is a common oral disease characterized by inflammation in the supporting tissue of the teeth 'the periodontium', periodontal attachment loss, and alveolar bone loss. The disease has a microbial etiology; however, recent findings suggest that the genetic factors, such as vitamin D receptor (VDR) gene polymorphisms, have also been included. Aim Investigation of the relationship between VDR gene polymorphisms and CP among Libyans. Materials and methods In this study, we examined 196 unrelated Libyans between the ages of 25 and 65 years, including 99 patients and 97 controls. An oral examination based on Ramfjord Index was performed at different dental clinics in Tripoli and information were collected using a self-reported questionnaire. DNA was extracted from buccal swabs; the VDR ApaI, BsmI, and FokI polymorphisms were genotyped using polymerase chain reaction and were sequenced using Sanger Method. Results A significant difference in the newly detected ApaI SNP C/T rs#731236 was found (p=0.022), whereas no significant differences were found in ApaI SNP G/T rs#7975232, BsmI SNP A/G rs#1544410, and FokI SNP A/G rs#2228570 between patients and controls (p=0.939, 0.466, 0.239), respectively. Conclusion VDR ApaI SNP C/T rs#731236 may be related to the risk of CP in the Libyan population. PMID- 28349805 TI - An oncolytic parasite to treat polycythemia vera. PMID- 28349806 TI - Quality of systematic reviews: an example of studies comparing artificial disc replacement with fusion in the cervical spine. AB - Cervical artificial disc replacement (C-ADR) is now an alternative to anterior cervical discectomy and fusion (ACDF). Many studies have evaluated the efficacy of C-ADR compared with ACDF. This led to a series of systematic reviews and meta analyses to evaluate the evidence of the superiority of one intervention against the other. The aim of the study presented here was to evaluate the quality of these reviews and meta-analyses. Medline via Ovid, Embase, and Cochrane Library were searched using the keywords: (total disk replacement, prosthesis, implantation, discectomy, and arthroplasty) AND (cervical vertebrae, cervical spine, and spine) AND (systematic reviews, reviews, and meta-analysis). Screening and data extraction were conducted by two reviewers independently. Two reviewers then assessed the quality of the selected reviews and meta-analysis using 11-item AMSTAR score which is a validated measurement tool to assess the methodological quality of systematic reviews. Screening of full reports of 46 relevant abstracts resulted in the selection of 15 systematic reviews and/or meta-analyses as eligible for this study. The two reviewers' inter-rater agreement level was high as indicated by kappa of >0.72. The AMSTAR score of the reviews ranged from 3 to 11. Only one study (a Cochrane review) scored 100% (AMSTAR 11). Five studies scored below (AMSTAR 5) indicating low-quality reviews. The most significant drawbacks of reviews of a score below 5 were not using an extensive search strategy, failure to use the scientific quality of the included studies appropriately in formulating a conclusion, not assessing publication bias, and not reporting the excluded studies. With a significant exception of a Cochrane review, the methodological quality of systematic reviews evaluating the evidence of C-ADR versus ACDF has to be improved. PMID- 28349808 TI - LJM Acknowledges its Reviewers. PMID- 28349807 TI - Multidrug resistance and extended-spectrum beta-lactamases genes among Escherichia coli from patients with urinary tract infections in Northwestern Libya. AB - Introduction Multidrug resistance (MDR) and emergence of extended-spectrum beta lactamases (ESBLs) that mediate resistance to beta-lactam drugs among Escherichia coli and other uropathogens have been reported worldwide. However, there is little information on the detection of ESBLs genes in E. coli from patients with urinary tract infections (UTIs) in the Arab countries using polymerase chain reaction (PCR), and in Libya such information is lacking. Methods All patients attending Zawiya Teaching Hospital in Zawiya city between November 2012 and June 2013 suspected of having UTIs and from whom midstream urine samples were taken as part of the clinical workup were included in this prospective study. Samples were examined for uropathogens by standard bacteriological procedures. VITEK-2 automated microbiology system was used to identify the isolated uropathogens and determine the susceptibility of E. coli and Klebsiella spp. isolates to antimicrobials. In addition, phenotypically ESBLs-positive E. coli isolates were tested for ESBLs genes by PCR. Results The present study enrolled 1,790 patients with UTIs. Uropathogens were found in 371 (20.7%) urine specimens examined. Mixed pathogens were detected in two specimens with 373 total pathogens isolated. E. coli and Klebsiella spp. were the predominant uropathogens at 55.8% (208/373) and 18.5% (69/373), respectively. Other pathogens were detected in 25.7% (96/373) of urine samples. Of the E. coli and Klebsiella spp. tested, 69.2 and 100% were resistant to ampicillin, 6.7 and 33.3% to ceftriaxone, and 23.1 and 17.4% to ciprofloxacin, respectively. MDR (resistance to >=3 antimicrobial groups) was found in 69 (33.2%) of E. coli and in 29 (42%) of Klebsiella spp. isolates. ESBLs were detected phenotypically in 14 (6.7%) of E. coli and in 15 (21.7%) of Klebsiella spp. isolates. Thirteen out of the 14 phenotypically ESBL-positive E. coli were positive for ESBL genes by PCR. blaTEM gene was detected in seven isolates, blaOXA gene in 10 isolates and blaCTX-M gene in six isolates. blaSHV gene was not detected in the present study. Conclusion The isolation of MDR ESBL producing uropathogens undoubtedly will limit the choices clinicians have to treat their patients with UTIs. Therefore, there is an urgent need for surveillance studies on antimicrobial resistance and prevalence of ESBLs among uropathogens to guide the clinical treatment of UTIs in Libya in the future. PMID- 28349809 TI - New Delhi metallo-beta-lactamase and OXA-48 carbapenemases in Gram-negative bacilli isolates in Libya. PMID- 28349810 TI - Interventricular septum hydatid cyst presenting with acute lower limb ischemia: a case report. AB - Cardiac hydatid cysts are rarely seen. The presentation of an acute lower limb ischemia secondary to embolization from an interventricular hydatic cyst is also rare. We describe a case of a 30-year-old-man who presented with acute lower limb ischemia revealing hydatid cyst of the interventricular septum and septal defect, and who was operated on successfully. PMID- 28349811 TI - Molecular basis of arsenite (As+3)-induced acute cytotoxicity in human cervical epithelial carcinoma cells. AB - Background Rapid industrialization is discharging toxic heavy metals into the environment, disturbing human health in many ways and causing various neurologic, cardiovascular, and dermatologic abnormalities and certain types of cancer. The presence of arsenic in drinking water from different urban and rural areas of the major cities of Pakistan, for example, Lahore, Faisalabad, and Kasur, was found to be beyond the permissible limit of 10 parts per billion set by the World Health Organization. Therefore the present study was initiated to examine the effects of arsenite (As+3) on DNA biosynthesis and cell death. Methods After performing cytotoxic assays on a human epithelial carcinoma cell line, expression analysis was done by quantitative polymerase chain reaction, western blotting, and flow cytometry. Results We show that As+3 ions have a dose- and time dependent cytotoxic effect through the activation of the caspase-dependent apoptotic pathway. In contrast to previous research, the present study was designed to explore the early cytotoxic effects produced in human cells during exposure to heavy dosage of As+3 (7.5 ug/ml). Even treatment for 1 h significantly increased the mRNA levels of p21 and p27 and caspases 3, 7, and 9. It was interesting that there was no change in the expression levels of p53, which plays an important role in G2/M phase cell cycle arrest. Conclusion Our results indicate that sudden exposure of cells to arsenite (As+3) resulted in cytotoxicity and mitochondrial-mediated apoptosis resulting from up-regulation of caspases. PMID- 28349812 TI - Impact of the 2011 Libyan conflict on road traffic injuries in Benghazi, Libya. AB - Background Road traffic injuries (RTIs) are a major public health concern in Libya. In the light of the armed conflict in Libya that broke out on February 2011 and the subsequent instability, the rate and pattern of RTIs was studied. Methods RTI patient data were gathered from Al-Jalaa hospital, the main trauma center in Benghazi, from 2010 to 2011. Various parameters [i.e. age, gender, nationality, method of entry, receiving department, intensive care unit (ICU) admission, duration of stay, method of discharge, and fatalities] were compared with data from the previous year (2010), and statistical analyses were performed (t-test, chi-square, and Poisson regression). Results During the conflict period, 15.8% (n=2,221) of hospital admissions were RTIs, that is, a rate of 6.08 RTI cases per day, levels not seen for 5 years (t=-5.719, p<0.001). The presence of armed conflict was found to have caused a significant 28% decrease in the trend of RTIs over the previous 10 years (B=-0.327, CI=-0.38--0.28, p<0.001). February and March, the peak period of active combat in Benghazi, witnessed the lowest number of RTIs during the conflict period. The average age of an RTI decreased to 28.35+/-16.3 years (t=-7.257, p<0.001) with significantly more males (84.1%, n=1,755) being affected (chi2=4.595, p=0.032, df=1). There was an increase in the proportion of younger aged patients (from 0 to 29 years) (chi2=29.874, p<0.001, df=8). More patients required admission to the ICU (chi2=36.808, p<0.001, df=8), and the mortality of an RTI increased to 5.2% (n=116) (chi2=48.882, p<0.001, df=6). Conclusion There were fewer RTIs during the conflict period; however, those that occurred had higher morbidity and mortality. The profile of an RTI victims also changed to an increased prominence of young males and motorcyclists. Further research is required to propose and analyze possible interventions. PMID- 28349813 TI - Methodological problems in the article comparing lung function profiles and aerobic capacity of adult cigarette and hookah smokers after 12 weeks intermittent training. PMID- 28349814 TI - Accelerated bone ingrowth by local delivery of Zinc from bioactive glass: oxidative stress status, mechanical property, and microarchitectural characterization in an ovariectomized rat model. AB - Background Synthetic bone graft substitutes such as bioactive glass (BG) material are developed in order to achieve successful bone regeneration. Zn plays an important role in the proper bone growth, development, and maintenance of healthy bones. Aims This study aims to evaluate in vivo the performance therapy of zinc doped bioactive glass (BG-Zn) and its applications in biomedicine. Methods Female Wistar rats were ovariectomized. BG and BG-Zn were implanted in the femoral condyles of Wistar rats and compared to that of control group. Grafted bone tissues were carefully removed to evaluate the oxidative stress status, histomorphometric profile, mechanical property, and mineral bone distribution by using inductively coupled plasma optical emission spectrometry. Results A significant decrease of thiobarbituric acid-reactive substances was observed after BG-Zn implantation. Superoxide dismutase, catalase (CAT), and glutathione peroxidase (GPx) activities significantly increased in ovariectomized group implanted with Zinc-doped bioactive glass (OVX-BG-Zn) as compared to ovariectomized group implanted with bioactive glass (OVX-BG). An improved mechanical property was noticed in contact of OVX-BG-Zn (39+/-6 HV) when compared with that of OVX-BG group (26+/-9 HV). After 90 days of implantation, the histomorphometric analysis showed that trabecular thickness (Tb.Th) and trabecular number (Tb.N) were significantly increased with 28 and 24%, respectively, in treated rats of OVX-BG-Zn group as compared to those of OVX-BG groups. Trabecular separation (Tb.Sp) and trabecular bone pattern factor (TBPf) were significantly decreased in OVX-BG-Zn group with 29.5 and 54% when compared with those of OVX-BG rat groups. On the other hand, a rise in Ca and P ion concentrations in the implanted microenvironment was shown and lead to the formation/deposition of Ca-P phases. The ratio of pyridinoline [Pyr] to dihydroxylysinonorleucine [DHLNL] cross-links was normalized to the control level. Conclusion Our findings suggested that BG-Zn might have promising potential applications for osteoporosis therapy. PMID- 28349815 TI - Critical analysis of the published literature about the effects of Ramadan intermittent fasting on healthy children's physical capacities. PMID- 28349816 TI - Highlights on immune checkpoint inhibitors in non-small cell lung cancer. AB - The treatment of advanced or refractory non-small cell lung cancer has been historically difficult owing to the lack of studies on effective systemic cure. The progress in lung cancer treatment has plateaued, necessitating new options for additional benefits. Immune checkpoint proteins are co-inhibitory factors that can diminish the antigen-specific immune responses by attenuating the regulatory role of cytotoxic T-lymphocyte-associated protein 4, programmed cell death-1, lymphocyte-activation gene 3, and T-cell immunoglobulin mucin-3. The therapeutic strategies targeting immune checkpoints mainly focus on the monoclonal antibody of these regulatory factors, which may facilitate clinical decision making. An enhanced understanding of the drug-resistance mechanisms and the therapeutic efficacy regulation will provide opportunities to improve the clinical outcomes of non-small cell lung cancer patients. Preclinical and clinical trials on these key immune-regulatory agents, which has heralded a new era in immuno-oncology in non-small cell lung cancer treatment, are currently in development. PMID- 28349817 TI - Salinomycin: A new paradigm in cancer therapy. AB - The primary hurdle in the treatment of cancer is acquisition of resistance by the tumor cells toward multiple drugs and selectively targeting the cancer stem cells. This problem was overcome by the chemotherapeutic property of recently discovered drug salinomycin. Exact mechanism of action of salinomycin is not yet known, but there are multiple pathways by which salinomycin inhibits tumor growth. Salinomycin decreases the expression of adenosine triphosphate-binding cassette transporter in multidrug resistance cells and interferes with Akt signaling pathway, Wnt/beta-catenin, Hedgehog, and Notch pathways of cancer progression. Salinomycin selectively targets cancer stem cells. The potential of salinomycin to eliminate both cancer stem cells and therapy-resistant cancer cells may characterize the compound as a novel and an efficient chemotherapeutic drug. PMID- 28349818 TI - The distribution and potential prognostic value of SMAD protein expression in chronic lymphocytic leukemia. AB - The SMAD proteins are responsible for transducing signals from activated transforming growth factor-beta. This is the first study assessing the expression of SMAD-1/8, SMAD-2/3, SMAD-4, and SMAD-7 in chronic lymphocytic leukemia cells with regard to their clinical significance and potential prognostic value. Overexpression of SMAD-1/8 was observed in 160 chronic lymphocytic leukemia patients compared to 42 healthy volunteers (p = 0.023) and was associated with a more progressive course of the disease (p = 0.016). Moreover, the high expression of SMAD-1/8 correlated with other, well-established prognostic factors, including clinical stage (p = 0.010) and lymphocyte doubling time (p = 0.021). The expression of SMAD-4 was lower in chronic lymphocytic leukemia patients compared with the control group (p = 0.003). Importantly, lower SMAD-4 levels correlated with longer progression-free survival (p = 0.009), progressive course of the disease (p = 0.002), advanced clinical stage (p = 0.0004), elevated beta-2 microglobulin and lactate dehydrogenase levels (p < 0.05), shorter lymphocyte doubling time (p = 0.009), and CD38 antigen expression (p = 0.039). In addition, lower SMAD-4 expression correlated with lower apoptotic index (p = 0.0007) and lower expression of receptors for vascular endothelial growth factors VEGFR-1 and VEGFR-2. A significant association was found between the low expression of inhibitory protein SMAD-7 and both zeta-chain-associated protein kinase 70 negative cells (p = 0.04) and lower apoptotic index (p = 0.004). No differences were observed in SMAD-2/3 expression. In conclusion, our results demonstrate a significant correlation between greater SMAD-1/8 and lower SMAD-4 expression in chronic lymphocytic leukemia cells, as well as more progressive outcome and poor prognosis. These data provide supporting evidence that the expression of SMAD proteins plays an important role in disease development and may be considered as a novel, biologic prognostic factor in this disease. PMID- 28349819 TI - ADAM-17/FHL2 colocalisation suggests interaction and role of these proteins in colorectal cancer. AB - FHL2 is a multifunctional scaffolding protein; its expression is associated with poor prognosis in colorectal cancer. ADAM-17 is a metalloprotease implicated in ectodomain shedding. FHL2 regulates ADAM-17 plasma membrane localisation, and FHL2 deficiency leads to decreased activity of ADAM-17 in mouse macrophages. Presence and relationship of the ADAM-17/FHL2 complex with colorectal cancer progression is unknown. We studied FHL2 and ADAM-17 expression in several colon cancer cell lines by immunocytochemistry and western blot. To highlight the interaction between both molecules, we used the Duolink(r) kit for proximity ligation assay on SW480 cells. We also performed proximity ligation assay on biopsies and surgical specimens of colorectal adenocarcinoma and on matched normal mucosa. Furthermore, biopsies of colorectal adenoma with matched normal mucosa were selected. For quantification, pictures of the malignant, adenomatous and normal tissues were taken. Proximity ligation assay signals were quantified. Mean numbers of proximity ligation assay signals and of proximity ligation assay signals/nucleus were calculated. All cell lines showed FHL2 immunoreactivity; strongest positivity was observed in SW480 cells. ADAM-17 was expressed in all cell lines. Proximity ligation assay signals were present in SW480 cells. Quantitative analysis revealed that the interaction between FHL2 and ADAM-17 is more frequent in malignant than in normal tissue (p = 0.005). The mean number of ADAM-17/FHL2 proximity ligation assay signals was higher in colorectal adenocarcinoma than in adenoma with low-grade dysplasia (p = 0.0004). FHL2 interacts with ADAM-17 in normal, dysplastic and malignant colon epithelial cells. Colocalisation of these proteins is more frequent in malignant than in normal and dysplastic cells, suggesting a role for ADAM-17/FHL2 complex in the development of colorectal cancer. PMID- 28349821 TI - LAMP3 expression correlated with poor clinical outcome in human ovarian cancer. AB - Lysosome-associated membrane protein 3 belongs to the lysosome-associated membrane glycoprotein family, which is associated with lymph node, metastasis, poor overall survival, and resistance to chemotherapy and radiotherapy. Epithelial ovarian cancer is one of the most deadly global female gynecologic malignant tumors. Its clinical outcome is poor and most epithelial ovarian cancer patients tend to relapse because of drug resistance. However, lysosome-associated membrane protein 3 expression in epithelial ovarian cancer and its relationship between clinicopathologic factors remain poorly understood. To clarify the prognostic implications of lysosome-associated membrane protein 3 in epithelial ovarian cancer, we analyzed both messenger RNA and protein levels of lysosome associated membrane protein 3 in ovarian carcinomas. Polymerase chain reaction results showed higher expression of lysosome-associated membrane protein 3 messenger RNA in epithelial ovarian cancer than in noncancerous tissues. Immunohistochemical results showed that high lysosome-associated membrane protein 3 cytoplasmic expression was significantly related to tumor grade ( p = 0.038), lymph node metastasis ( p = 0.049), metastasis ( p < 0.001), level of CA125 ( p = 0.030), and International Federation of Gynecology and Obstetrics (FIGO) ( p < 0.001). High lysosome-associated membrane protein 3 nuclear expression was significantly associated with tumor grade ( p = 0.046), tumor single or double (representative whether the tumor involving one or both ovaries) ( p = 0.016), metastasis ( p < 0.001), and FIGO stage ( p < 0.001). Survival analysis indicated that high lysosome-associated membrane protein 3 cytoplasmic expression (hazard ratio: 4.632, 95% confidence interval: 2.421-8.864; p < 0.001), patients' age (hazard ratio: 1.729, 95% confidence interval: 1.027-2.911; p = 0.039), and FIGO stage (hazard ratio: 2.049, 95% confidence interval: 1.113-3.774; p = 0.021) were significantly correlated with poor survival outcome of epithelial ovarian cancer patients. PMID- 28349820 TI - Efficient killing of radioresistant breast cancer cells by cytokine-induced killer cells. AB - Recurrence of breast cancer after radiotherapy may be partly explained by the presence of radioresistant cells. Thus, it would be desirable to develop an effective therapy against radioresistant cells. In this study, we demonstrated the intense antitumor activity of cytokine-induced killer cells against MCF-7 and radioresistant MCF-7 cells, as revealed by cytokine-induced killer-mediated cytotoxicity, tumor cell proliferation, and tumor invasion. Radioresistant MCF-7 cells were more susceptible to cytokine-induced killer cell killing. The stronger cytotoxicity of cytokine-induced killer cells against radioresistant MCF-7 cells was dependent on the expression of major histocompatibility complex class I polypeptide-related sequence A/B on radioresistant MCF-7 cells after exposure of cytokine-induced killer cells to sensitized targets. In addition, we demonstrated that cytokine-induced killer cell treatment sensitized breast cancer cells to chemotherapy via the downregulation of TK1, TYMS, and MDR1. These results indicate that cytokine-induced killer cell treatment in combination with radiotherapy and/or chemotherapy may induce synergistic antitumor activities and represent a novel strategy for breast cancer. PMID- 28349822 TI - SLCO1B3 screening in colorectal cancer patients using High-Resolution Melting Analysis method and immunohistochemistry. AB - Personalized medicine has made some major advances in colorectal cancer, but new biomarkers still remain a hot issue as an emerging tool with potential prognostic and therapeutic potential. We investigated for SLCO1B3 gene alterations and protein expression in colorectal cancer, using the novel high-resolution melting analysis technique and immunohistochemistry. Formalin-fixed paraffin-embedded tumor samples from 30 colorectal cancer patients were used. The screening for gene alterations was done by high-resolution melting analysis for all exons of SLCO1B3 gene. Organic anion-transporting polypeptide 1B3 protein expression was assessed by immunohistochemistry using the monoclonal mouse MDQ antibody. High level of polymorphism was observed in the SLCO1B3 gene. We identified three previously reported polymorphisms in exons 7, 12, and 14, 699G>A, 1557A>G, and 1833G>A, respectively. In the exon 5, one variant seems to correspond to an as yet unknown SLCO family member. The immunohistochemical study revealed that organic anion-transporting polypeptide 1B3 was expressed in 27/30 samples. Of great interest, the three samples, which were immunohistochemically negative, all appeared to accommodate mutations which lead to either early stop codons or other conformations of the tertiary protein structures affecting the antibody-epitope binding. The results of this study are of much interest as high-resolution melting analysis proved to be a reliable and rapid genotyping/scanning method for mutation detection of SLCO1B3 gene. PMID- 28349823 TI - Upregulation of long noncoding RNA zinc finger antisense 1 enhances epithelial mesenchymal transition in vitro and predicts poor prognosis in glioma. AB - Increasing evidence indicates that long noncoding RNAs play important roles in development and progression of various cancers. Zinc finger antisense 1 is a novel long noncoding RNA whose clinical significance, biological function, and underlying mechanism are still undetermined in glioma. In this study, we reported that zinc finger antisense 1 expression was markedly upregulated in glioma and tightly correlated with clinical stage. Moreover, patients with high zinc finger antisense 1 expression had shorter survival. Multivariate Cox regression analysis provided a clue that, probably, zinc finger antisense 1 level could serve as an independent prognostic factor for glioma. Functionally, zinc finger antisense 1 acted as an oncogene in glioma because its knockdown could promote apoptosis and significantly inhibit cell proliferation, migration, and invasion. Furthermore, zinc finger antisense 1 silencing could result in cell cycle arrest at the G0/G1 phase and correspondingly decrease the percentage of S phase cells in both U87 and U251 cell lines. Moreover, it was found that silenced zinc finger antisense 1 could impair migration and invasion by inhibiting the epithelial-mesenchymal transition through reducing the expression of MMP2, MMP9, N-cadherin, Integrin beta1, ZEB1, Twist, and Snail as well as increasing E-cadherin level in glioma. Taken together, our data identified that zinc finger antisense 1 might act as a valuable prognostic biomarker and potential therapeutic target for glioma. PMID- 28349824 TI - Increased efficacy of a dendritic cell-based therapeutic cancer vaccine with adenosine receptor antagonist and CD73 inhibitor. AB - Dendritic cells are important in initiating immune responses; therefore, a range of dendritic cell-based approaches have been established to induce immune response against cancer cells. However, the presence of immunosuppressive mediators such as adenosine in the tumor microenvironment reduces the efficacy of dendritic cell-based cancer immunotherapy. In this study, we investigated whether blockade of the A2A adenosine receptor with a selective antagonist and a CD73 inhibitor may increase the efficacy of a dendritic cell-based cancer vaccine. According to the findings, this therapeutic combination reduced tumor growth, prolonged survival of tumor-bearing mice, and enhanced specific antitumor immune responses. Thus, we suggest that targeting cancer-derived adenosine improves the outcomes of dendritic cell-based cancer immunotherapy. PMID- 28349825 TI - Methylomics of breast cancer: Seeking epimarkers in peripheral blood of young subjects. AB - Critical roles of epigenomic alterations in the pathogenesis of breast cancer have recently seized great attentions toward finding epimarkers in either non invasive or semi-non-invasive samples as well as peripheral blood. In this way, methylated DNA immunoprecipitation microarray (MeDIP-chip) was performed on DNA samples isolated from white blood cells of 30 breast cancer patients compared to 30 healthy controls. A total of 1799 differentially methylated regions were identified including SLC6A3, Rab40C, ZNF584, and FOXD3 whose significant methylation differences were confirmed in breast cancer patients through quantitative real-time polymerase chain reaction. Hypermethylation of APC, HDAC1, and GSK1 genes has been previously reported in more than one study on tissue samples of breast cancer. Methylation of those aforementioned genes in white blood cells of our young patients not only relies on their importance in breast cancer pathogenesis but also may highlight their potential as early epimarkers that makes further assessments necessary in large cohort studies. PMID- 28349826 TI - Mortalin overexpression predicts poor prognosis in early stage of non-small cell lung cancer. AB - Mortalin is a member of the heat shock protein 70 family, which is involved in multiple cellular processes and may play key roles in promoting carcinogenesis. This study attempted to identify the clinical consequences of Mortalin overexpression and its roles in the prognostic evaluation of non-small cell lung cancer. A total of 120 non-small cell lung cancer samples paired with the adjacent non-tumor tissue samples and 10 normal lung tissues were selected for immunohistochemical staining for Mortalin. The localization of Mortalin was detected in A549 non-small cell lung cancer cells using immunofluorescence staining. The correlations between Mortalin overexpression and the clinical features of non-small cell lung cancers were evaluated using the chi-square test. The survival analysis was calculated via the Kaplan-Meier method and the Cox proportional hazard models. Our studies suggested that Mortalin exhibited a primarily cytoplasmic staining pattern in the non-small cell lung cancers. The rate of strongly positive Mortalin expression was higher in the non-small cell lung cancer samples than in the adjacent non-tumor samples or in normal lung tissues. Mortalin overexpression was significantly correlated with high histological grades, advanced stages, lymph node metastases, and lower disease free survival and overall survival rates of the patients with non-small cell lung cancer. The survival analysis demonstrated that Mortalin overexpression was a significant independent prognostic factor in non-small cell lung cancer, especially for patients with early stage of non-small cell lung cancer. In conclusion, Mortalin is up-regulated in non-small cell lung cancer, and it may be a potential biomarker of prognostic evaluation and a molecular therapeutic target for patients with early stage of non-small cell lung cancer. PMID- 28349827 TI - Staurosporine suppresses survival of HepG2 cancer cells through Omi/HtrA2 mediated inhibition of PI3K/Akt signaling pathway. AB - Staurosporine, which is an inhibitor of a broad spectrum of protein kinases, has shown cytotoxicity on several human cancer cells. However, the underlying mechanism is not well understood. In this study, we examined whether and how this compound has an inhibitory action on phosphatidylinositol 3-kinase (PI3K)/Akt pathway in vitro using HepG2 human hepatocellular carcinoma cell line. Cell viability and apoptosis were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay and terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) assay, respectively. Glutathione S-transferase (GST) pull-down assay and co immunoprecipitation were performed to detect protein-protein interactions. Small interfering RNA (siRNA) was used to silence the expression of targeted protein. We found that staurosporine significantly decreased cell viability and increased cell apoptosis in a concentration- and time-dependent manner in HepG2 cancer cells, along with the decreased expressions of PDK1 protein and Akt phosphorylation. Staurosporine was also found to enhance Omi/HtrA2 release from mitochondria. Furthermore, Omi/HtrA2 directly bound to PDK1. Pharmacological and genetic inhibition of Omi/HtrA2 restored protein levels of PDK1 and protected HepG2 cancer cells from staurosporine-induced cell death. In addition, staurosporine was found to activate autophagy. However, inhibition of autophagy exacerbated cell death under concomitant treatment with staurosporine. Taken together, our results indicate that staurosporine induced cytotoxicity response by inhibiting PI3K/Akt signaling pathway through Omi/HtrA2-mediated PDK1 degradation, and the process provides a novel mechanism by which staurosporine produces its therapeutic effects. PMID- 28349828 TI - Silencing of bach1 gene by small interfering RNA-mediation regulates invasive and expression level of miR-203, miR-145, matrix metalloproteinase-9, and CXCR4 receptor in MDA-MB-468 breast cancer cells. AB - BACKGROUND: Recently experimental validation of the networks revealed bach1, a basic leucine zipper transcription factor, as the common regulator of several functional invasive genes. The expression of bach1 and its target genes was linked to the higher risk of breast cancer recurrence in patients. The aim of this study was to investigate the effect of specific bach1 small interfering RNAs, on the invasive and expression level of miR-203, miR-145, matrix metalloproteinase-9, and CXCR4 receptor which play a role in cancer metastasis, in MDA-MB-468 cell lines. METHODS: Small interfering RNA transfection was performed with transfection regent. The survival effects of small interfering RNA were determined using trypan blue assay cells. The expression level of messenger RNA and matrix metalloproteinase-9 to assess cell invasion and the expression level of miR-203, miR-145, and CXCR4 receptor were measured by quantitative real time polymerase chain reaction analysis on the MDA-MB-468 cell lines. RESULTS: Transfection with small interfering RNA significantly suppressed the expression of bach1 gene in dose-dependent manner after 48 h ( p < 0.0001). A significant reduction in cell invasion and CXCR4 receptor, matrix metalloproteinase-9 expression were observed ( p < 0.0001). It was also a dramatic increase in the expression level of miR-203 and miR-145 ( p < 0.0001). CONCLUSIONS: Our results suggest that the bach1-specific small interfering RNA effectively decrease CXCR4 receptor, matrix metalloproteinase-9 expression and breast adenocarcinoma cells invasive, also increased the expression of tumor-suppressive microRNA-203 and miR 145. Thus, these microRNAs may play a role in invasive/metastasis of carcinogenic breast cancer cells. Therefore, bach1 knockdown can be considered as a potent adjuvant in breast cancer therapy. PMID- 28349829 TI - MiR-590-3p suppresses hepatocellular carcinoma growth by targeting TEAD1. AB - MicroRNA signature is altered in different disease states including cancer, and some microRNAs act as oncogenes or tumor suppressors. MiR-590-3p has been shown to be involved in human cancer progression. However, its role in hepatocellular carcinoma remains unknown. In this study, miR-590-3p level was measured, and clinicopathological features were determined in hepatocellular carcinoma tissues. The function of miR-590-3p was examined in vitro and in vivo. Real-time reverse transcription polymerase chain reaction analysis demonstrated downregulation of miR-590-3p in hepatocellular carcinoma tissues, and its downregulation was associated with a poor overall survival of hepatocellular carcinoma patients. Ectopic expression of miR-590-3p promoted growth of hepatocellular carcinoma cells, whereas its depletion inhibited cell growth. Transcriptional enhancer activator domain 1 was identified as a validated miR-590-3p target. Upregulation of transcriptional enhancer activator domain 1 was found in hepatocellular carcinoma tissues and inversely correlated with miR-590-3p. Our results indicate a tumor suppressor role of miR-590-3p in hepatocellular carcinoma through targeting transcriptional enhancer activator domain 1 and suggest its use in the diagnosis and prognosis of liver cancer. PMID- 28349830 TI - Aberrant AML1 gene expression in the diagnosis of childhood leukemias not characterized by AML1-involved cytogenetic abnormalities. AB - The AML1 ( acute myeloid leukemia 1) gene, a necessary prerequisite of embryonic hematopoiesis and a critical regulator of normal hematopoietic development, is one of the most frequently mutated genes in human leukemia, involving over 50 chromosome translocations and over 20 partner genes. In the few existing studies investigating AML1 gene expression in childhood leukemias, aberrant upregulation seems to specifically associate with AML1 translocations and amplifications. The aim of this study was to determine whether overexpression also extends to other leukemic subtypes than the ones karyotypically involving AML1. We use quantitative real-time polymerase chain reaction methodology to investigate gene expression in 100 children with acute leukemias and compare them to those of healthy controls. We show that in childhood acute lymphoblastic leukemia, AML1 gene overexpression is associated with a variety of leukemic subtypes, both immunophenotypically and cytogenetically. Statistically significantly higher transcripts of the gene were detected in the acute lymphoblastic leukemia group as compared to the acute myeloid leukemia group, where AML1 overexpression appeared to associate with cytogenetic abnormalities additional to those that engage the AML1 gene, or that are reported as showing a "normal" karyotype. Collectively, our study shows that AML1 gene overexpression characterizes a broader range of leukemic subtypes than previously thought, including various maturation stages of B-cell acute lymphoblastic leukemia and cytogenetic types additional to those involving the AML1 gene. PMID- 28349831 TI - Cell division cycle 20 overexpression predicts poor prognosis for patients with lung adenocarcinoma. AB - The cell division cycle 20, a key component of spindle assembly checkpoint, is an essential activator of the anaphase-promoting complex. Aberrant expression of cell division cycle 20 has been detected in various human cancers. However, its clinical significance has never been deeply investigated in non-small-cell lung cancer. By analyzing The Cancer Genome Atlas database and using some certain online databases, we validated overexpression of cell division cycle 20 in both messenger RNA and protein levels, explored its clinical significance, and evaluated the prognostic role of cell division cycle 20 in non-small-cell lung cancer. Cell division cycle 20 expression was significantly correlated with sex (p = 0.003), histological classification (p < 0.0001), and tumor size (p = 0.0116) in non-small-cell lung cancer patients. In lung adenocarcinoma patients, overexpression of cell division cycle 20 was significantly associated with bigger primary tumor size (p = 0.0023), higher MKI67 level (r = 0.7618, p < 0.0001), higher DNA ploidy level (p < 0.0001), and poor prognosis (hazard ratio = 2.39, confidence interval: 1.87-3.05, p < 0.0001). However, in lung squamous cell carcinoma patients, no significant association of cell division cycle 20 expression was observed with any clinical parameter or prognosis. Overexpression of cell division cycle 20 is associated with poor prognosis in lung adenocarcinoma patients, and its overexpression can also be used to identify high risk groups. In conclusion, cell division cycle 20 might serve as a potential biomarker for lung adenocarcinoma patients. PMID- 28349832 TI - Differential expression of ten-eleven translocation genes in endometrial cancers. AB - Ten-eleven translocation proteins are alpha-ketoglutarate-dependent dioxygenases involved in the conversion of 5-methylcytosines (5-mC) to 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine, and 5-carboxylcytosine that play a significant role in DNA demethylation. Deregulation of TET genes expression and changes in the level of 5-hmC are thought to be associated with the onset and progression of several types of cancer, but there are no such data related to endometrial cancer. The aim of the work was to investigate the messenger RNA expression levels of TET1, TET2, and TET3 in relation to clinicopathological characteristics of endometrial cancer as well as the correlation between expression of TET genes and the level of 5-hmC/5-mC. The prognostic significance of TETs expression for overall survival was established. We found that TET1 and TET2 messenger RNA expression was lower and TET3 was higher in cancers compared to normal tissues. Positive correlation between 5-hmC and the relative expression of TET1 and TET2 was found, but no correlation was observed in the case of TET3. Decreased expression of TET1 and TET2 was significantly associated with increased lymph node metastasis and International Federation of Gynecology and Obstetrics stage. Kaplan-Meier analysis indicated that low TET1 expression predicted poor overall survival (p = 0.038). Multivariate analysis identified the TET1 expression in endometrial cancer as an independent prognostic factor. Our results suggest that decreased expression of TET1 correlates with tumor progression and may serve as a potential prognostic biomarker in endometrial cancer. PMID- 28349833 TI - Strong association of interleukin-6 -174G/C promoter single nucleotide polymorphism with a decreased risk of colorectal cancer in ethnic Kashmiri population: A case control study. AB - Chronic inflammation increases the risk of development of various cancers, including colorectal cancer. Interleukin-6 has been described as a key regulator of colorectal cancer development and is important in the process of colorectal tumorigenesis largely through the regulation of tumor-promoting inflammation. Several studies have reported the association of various polymorphisms in human interleukin-6 gene including IL-6 -174G/C single nucleotide polymorphism with various cancers, including colorectal cancer, but the results are mixed and inconclusive. The aim of this study was to analyze the association of IL-6 174G/C promoter single nucleotide polymorphism with colorectal cancer risk and also to evaluate the modifying effects of possible IL-6 -174G/C single nucleotide polymorphism genotypes on different risk factors of colorectal cancer or the reciprocal effect in ethnic Kashmiri population through a case control setup. The genotype frequencies of IL-6 -174G/C promoter single nucleotide polymorphism were compared between 142 colorectal cancer patients and 184 individually matched healthy controls by using polymerase chain reaction-restriction fragment length polymorphism method. The association between the IL-6 -174G/C single nucleotide polymorphism and colorectal cancer risk was examined through conditional logistic regression models adjusted for multiple possible confounding (third) variables. The possible effect measure modification of the association between the relevant single nucleotide polymorphism genotypes and colorectal cancer risk by various colorectal cancer risk factors including age, gender, and smoking status was also evaluated. Furthermore, the associations between these single nucleotide polymorphisms and various clinicopathological parameters, demographic variables, and environmental factors within the case group subjects with regard to colorectal cancer risk were also analyzed. The overall association between the IL 6 -174G/C single nucleotide polymorphism and the modulation of colorectal cancer risk was found to be highly significant (p = 0.001). The variant genotype (CC) was significantly associated with a decreased risk of colorectal cancer (odds ratio, 0.15 (95% confidence interval, 0.04-0.54); p = 0.004). Furthermore, the less common IL-6-174C allele was associated with a decreased risk of colorectal cancer (odds ratio, 0.49 (95% confidence interval, 0.33-0.73); p = 0.0006). The combined variant genotype (GC + CC) was also significantly associated with a decreased risk of colorectal cancer (odds ratio, 0.54 (95% confidence interval, 0.33-0.89); p = 0.015). This study demonstrates that there is a strong and highly significant association between the IL-6 -174G/C promoter single nucleotide polymorphism and a decreased risk of colorectal cancer in ethnic Kashmiri population. However, in order to substantiate our findings, this study needs to be replicated with larger sample size and with other ethnically defined populations with comparable colorectal cancer incidence. PMID- 28349834 TI - Downregulation of transcription factor GATA4 sensitizes human hepatoblastoma cells to doxorubicin-induced apoptosis. AB - Hepatoblastoma, the most common type of pediatric liver cancer, is treated with a combination of surgery and chemotherapy. An essential drug in the treatment of hepatoblastoma is doxorubicin, which in high doses is cardiotoxic. This adverse effect is due to downregulation of cardiac expression of transcription factor GATA4, leading in turn to diminished levels of anti-apoptotic BCL2 (B-cell lymphoma 2) protein family members. GATA4 is also expressed in early fetal liver, but absent from normal postnatal hepatocytes. However, GATA4 is highly expressed in hepatoblastoma tissue. In this study, we assessed the role of GATA4 in doxorubicin-induced apoptosis of hepatoblastoma cells. Herein, we demonstrate that doxorubicin decreases GATA4 expression and alters the expression pattern of BCL2 family members, most profoundly that of BCL2 and BAK, in the HUH6 hepatoblastoma cell line. Silencing of GATA4 by siRNA prior to doxorubicin treatment sensitizes HUH6 cells to the apoptotic effect of this drug by further shifting the balance of BCL2 family members to the pro-apoptotic direction. Specifically, expression levels of anti-apoptotic BCL2 were decreased and pro apoptotic BID were increased after GATA4 silencing. On the whole, our results indicate that since high endogenous levels of transcription factor GATA4 likely protect hepatoblastoma cells from doxorubicin-induced apoptosis, these cells can be rendered more sensitive to the drug by downregulation of GATA4. PMID- 28349835 TI - The role of epithelial cell adhesion molecule N-glycosylation on apoptosis in breast cancer cells. AB - Glycosylation of cell surface proteins plays an important role in the regulation of apoptosis. It has been demonstrated that knockdown of epithelial cell adhesion molecule promoted apoptosis, inhibited cell proliferation, and caused cell-cycle arrest. In this study, we investigated whether and how N-glycosylation of epithelial cell adhesion molecule influenced the apoptosis in breast cancer cells. We applied the N-glycosylation mutation epithelial cell adhesion molecule plasmid to express deglycosylation of epithelial cell adhesion molecule and then to study its function. Our results showed that deglycosylation of epithelial cell adhesion molecule promoted apoptosis and inhibited cell proliferation. Deglycosylation of epithelial cell adhesion molecule enhanced the cytotoxic effect of 5-fluorouracil, promoting apoptosis by downregulating the expression of the anti-apoptotic protein Bcl-2 and upregulating the expression of the pro apoptotic proteins Bax and Caspase 3 via the extracellular-signal-regulated kinase 1/2 and c-Jun N-terminal kinase mitogen-activated protein kinase signaling pathways in MCF-7 and MDA-MB-231 cells. These findings are important for a better understanding of epithelial cell adhesion molecule apoptosis regulation and suggest epithelial cell adhesion molecule as a potential target for the treatment of breast cancer. PMID- 28349836 TI - Identification of differentially expressed circular RNAs in human colorectal cancer. AB - Circular RNA, a class of non-coding RNA, is a new group of RNAs and is related to tumorigenesis. Circular RNAs are suggested to be ideal candidate biomarkers with potential diagnostic and therapeutic implications. However, little is known about their expression in human colorectal cancer. In our study, differentially expressed circular RNAs were detected using circular RNA array in paired tumor and adjacent non-tumorous tissues from six colorectal cancer patients. Expression levels of selected circular RNAs (hsa_circRNA_103809 and hsa_circRNA_104700) were measured by real-time polymerase chain reaction in 170 paired colorectal cancer samples for validation. Statistical analyses were conducted to investigate the association between hsa_circRNA_103809 and hsa_circRNA_104700 expression levels and respective patient clinicopathological features. Receiver operating characteristic curve was constructed to evaluate the diagnostic values. Our results indicated that there were 125 downregulated and 76 upregulated circular RNAs in colorectal cancer tissues compared with normal tissues. We also first demonstrated that the expression levels of hsa_circRNA_103809 ( p < 0.0001) and hsa_circRNA_104700 ( p = 0.0003) were significantly lower in colorectal cancer than in normal tissues. The expression level of hsa_circRNA_103809 was significantly correlated with lymph node metastasis ( p = 0.021) and tumor-node metastasis stage ( p = 0.011), and the expression level of hsa_circRNA_104700 was significantly correlated with distal metastasis ( p = 0.036). The area under receiver operating characteristic curves of hsa_circRNA_103809 and hsa_circRNA_104700 were 0.699 ( p < 0.0001) and 0.616 ( p < 0.0001), respectively. In conclusion, these results suggest that hsa_circRNA_103809 and hsa_circRNA_104700 may be potentially involved in the development of colorectal cancer and serve as potential biomarkers for the diagnosis of colorectal cancer. PMID- 28349837 TI - Apoptosis mediated chemosensitization of tumor cells to 5-fluorouracil on supplementation of fish oil in experimental colon carcinoma. AB - 5-Fluorouracil has been considered as a cornerstone therapy for colorectal cancer; however, it suffers from low therapeutic response rate and severe side effects. Therefore, there is an urgent need to increase the clinical efficacy of 5-fluorouracil. Recently, fish oil rich in n-3 polyunsaturated fatty acids has been reported to chemosensitize tumor cells to anti-cancer drugs. This study is designed to understand the underlying mechanisms of synergistic effect of fish oil and 5-fluorouracil by evaluation of tumor cell-associated markers such as apoptosis and DNA damage. The colon cancer was developed by administration of N,N dimethylhydrazine dihydrochloride and dextran sulfate sodium salt. Further these animals were treated with 5-fluorouracil, fish oil, or a combination of both. In carcinogen-treated animals, a decrease in DNA damage and apoptotic index was observed. There was also a decrease in the expression of Fas, FasL, caspase 8, and Bax, and an increase in Bcl-2. In contrast, administration of 5-fluorouracil and fish oil as an adjuvant increased both DNA damage and apoptotic index by activation of both extrinsic and intrinsic apoptotic pathways as compared to the other groups. The increased pro-apoptotic effect by synergism of 5-fluorouracil and fish oil may be attributed to the incorporation of n-3 polyunsaturated fatty acids in membrane, which alters membrane fluidity in cancer cells. In conclusion, this study highlights that the induction of apoptotic pathway by fish oil may increase the susceptibility of tumors to chemotherapeutic regimens. PMID- 28349838 TI - Glycaemic control status among type 2 diabetic patients and the role of their diabetes coping behaviours: a clinic-based study in Tripoli, Libya. AB - Background Achieving good glycaemic control is important in diabetes management. However, poor glycaemic control is widely reported. This article assessed the prevalence of uncontrolled and poor glycaemic control among Libyans with type 2 diabetes and examined the relative contribution of diabetes coping behaviours to their glycaemic control status. Methods A cross-sectional study was undertaken in 2013 in a large diabetes centre in Tripoli. The study included 523 respondents. Diabetes coping behaviours were measured using the revised version of the Summary of Diabetes Self-Care Activities measure (SDSCA) and the eight-item Morisky Medication Adherence Scale (MMAS-8(c)), while glycaemic control status was based on the HbA1c level. Results Mean HbA1c was 8.9 (+/-2.1), and of the 523 patients, only 114 (21.8%) attained the glycaemic control target of HbAc1 of less than 7.0%. Females (OR=1.74, 95% CI=1.03-2.91), patients on insulin and oral hypoglycaemic agents (OR=1.92, 95% CI=1.05-3.54), patients on insulin (OR=3.14, 95% CI=1.66-6.03), and low-medication adherents (OR=2.25, 95% CI=1.36-3.73) were more likely to have uncontrolled and poor glycaemic control, while exercise contributed to glycaemic control status as a protective factor (OR=0.85, 95% CI=0.77-0.94). Conclusion The findings from this study showed the considerable burden of uncontrolled and poor glycaemic control in one of the largest diabetes care settings in Libya. Medication adherence as well as exercise promotion programs would help in reducing the magnitude of poor glycaemic control. PMID- 28349839 TI - Prevalence of Entamoeba histolytica, Giardia lamblia, and Cryptosporidium spp. in Libya: 2000-2015. AB - Introduction The intestinal protozoa Entamoeba histolytica, Giardia lamblia, and Cryptosporidium spp. are the causative agents of giardiasis, amebiasis, and cryptosporidiosis, respectively. Adequate knowledge of the geographical distribution of parasites and the demographic variables that influence their prevalence is important for effective control of infection in at-risk populations. Methods The data were obtained by an English language literature search of Medline and PubMed for papers using the search terms 'intestinal parasites and Libya, G. lamblia and Libya, E. histolytica and Libya and Cryptosporidium and Libya' for the period 2000-2015. Results The data obtained for the period 2000-2015 showed prevalence rates of 0.8-36.6% (mean 19.9%) for E. histolytica/dispar, 1.2-18.2% (mean 4.6%) for G. lamblia and 0.9-13% (mean 3.4%) for Cryptosporidium spp. among individuals in Libya with gastroenteritis (GE). On the other hand, prevalence rates of 0.8-16.3% (mean 8.3%), 1.8-28.8% (mean 4.8%), and 1.0-2.5% (mean=2.4), respectively, were observed for individuals without GE. The mean prevalence rate of E. histolytica/dispar was significantly higher among individuals with GE compared with those without GE (p<0.0000001, OR=2.74). No significant difference in prevalence rate of the three organisms was found according to gender, but most of infections were observed in children aged 10 years or younger. Conclusion The reviewed data suggest that E. histolytica, G. lamblia, and Cryptosporidium spp. may play a minor role in GE in Libya. The observed high prevalence rates of E. histolytica/dispar reported from Libya could be due mainly to the non-pathogenic E. dispar and E. moshkovskii. However, more studies are needed in the future using E. histolytica-specific enzyme immunoassays and/or molecular methods to confirm this observation. PMID- 28349840 TI - Seroprevalence of IgM antibodies to hepatitis A virus in at-risk group in Benin City, Nigeria. PMID- 28349841 TI - Why should you choose to publish in the Libyan Journal of Medicine? PMID- 28349842 TI - Email communication in a developing country: different family physician and patient perspectives. AB - Background Email communication between physicians and patients could improve access to and delivery of health care. Most of the literature studies about email communication between physicians and patients have been conducted in developing countries. Therefore, this study aims to analyze the practices, attitudes, and barriers of both physicians' and patients' use of email within the same health care setting of a developing country. Methods A cross-sectional paper-based survey was conducted among 39 physicians and 500 patients at the Family Medicine clinics of the American University of Beirut, a tertiary academic medical center. Results Most of the surveyed patients and physicians reported that they would like to communicate through email and agreed that it is useful. However, only 19% of the patients have ever communicated with their physicians via email, and only 5.1% of physicians have often communicated with their patients via email. Almost half of the patients surveyed were unaware of the possibility of this form of communication, and only 17% reported that their physician offered them his or her email address. In addition, physicians and patients did not agree on the services to be provided by email communication. For instance, almost half of the patients indicated consultation for an urgent medical matter as suitable for email communication. Conclusion The use of email communication in health care is still scarce. Patients and physicians have different perspectives of its use and importance. Further rigorous research is needed to clarify the advantages and disadvantages of this form of communication, especially in the developing world. Interested physicians are encouraged to establish appropriate personal policies for email communication with adequate announcement and patient education plans. PMID- 28349843 TI - Thymoquinone ameliorates lead-induced suppression of the antioxidant system in rat kidneys. AB - Objective Alteration of the antioxidant status in the kidneys may be related to lead (Pb) intoxication. The present study aimed to investigate the possible beneficial effect of thymoquinone (TQ), the major active ingredient of the volatile oil of Nigella sativa seeds, on Pb-induced renal antioxidant defense system impairment. Methods A total of thirty two healthy adult male Wistar rats were randomly divided into four equal groups as follows: a control group, which received no treatment; a Pb group, which was exposed to 2,000 ppm of Pb acetate in drinking water; a Pb-TQ group, which was cotreated with Pb plus TQ (5 mg/kg/day, per os); and a TQ group receiving only TQ. All treatments were applied for five weeks. Results TQ alone did not induce any significant changes in the antioxidant defense system. By contrast, Pb exposure significantly decreased reduced glutathione level and superoxide dismutase, glutathione peroxidase, catalase, and glutathione reductase activities in the renal tissue. Interestingly, supplementation with TQ significantly improved the affected antioxidant parameters. Conclusion Our data are the first to provide evidence on the protective effect of TQ against Pb-induced renal antioxidant capacity impairment and suggest that this component might be a clinically promising alternative in Pb nephrotoxicity. PMID- 28349844 TI - Periodontal bone height of exclusive narghile smokers compared with exclusive cigarette smokers. AB - Objective To compare the periodontal bone height (PBH) of exclusive narghile smokers (ENS) with that of exclusive cigarette smokers (ECS). Methods Tunisian males aged 20-35 years who have been ENS for more than five narghile-years or ECS for more than five pack-years were recruited to participate in this comparative cross-sectional study. Information about oral health habits and tobacco consumption were gathered using a predetermined questionnaire. Plaque levels were recorded in four sites using the plaque index of Loe and Silness. The PBH was measured mesially and distally from digital panoramic radiographs of each tooth and expressed as a percentage of the root length. A PBH level <=0.70 was applied as a cutoff reference value signifying bone loss. Student t-test and Chi2 test were used to compare quantitative and qualitative data of both groups. Results There were no significant differences between the ENS (n=60) and ECS (n=60) groups regarding age and the consumed quantities of tobacco (28+/-4 vs. 27+/-5 years, 7+/-3 narghile-years vs. 8+/-3 pack-years, respectively). Compared with the ECS group, the ENS group had a significantly higher plaque index (mean+/-SD values were 1.54+/-0.70 vs. 1.84+/-0.73, respectively). However, the two groups had similar means of PBH (0.85+/-0.03 vs. 0.86+/-0.04) and tooth brushing frequencies (1.1+/-0.8 vs. 0.9+/-0.6 a day, respectively) and had similar bone loss frequencies (15% vs. 12%, respectively). Conclusions Both ENS and ECS exhibited the same PBH reduction, which means that both types of tobacco smoking are associated with periodontal bone loss. PMID- 28349845 TI - Cross-cultural adaptation and psychometric properties of an Arabic language version of the Brief Illness Perception Questionnaire in Lebanon. AB - Background Patients' positive illness perceptions (IPs) significantly contribute to treatment success. The Brief Illness Perception Questionnaire (Brief IPQ) is widely used in various diseases for assessing IPs. It was developed in English speaking countries and studies on it in Arab countries are scarce. Objectives, Setting and design This observational cross-sectional study aimed to cross culturally adapt the Brief IPQ English version into a modern Arabic language version and determine its psychometric properties in a sample of Lebanese cardiac disease patients. This study was approved by the Institutional Review Board of Saint Joseph University of Beirut, Lebanon. Participants A convenience sample of 30 patients with cardiac disease were recruited during routine visits to cardiologists' offices in Beirut, Lebanon. Inclusion criteria were at least one cardiac disease for at least 6 months with no acute episode or exacerbation of the disease during the 6 preceding months, age>=18 years, and the ability to read and comprehend Arabic. The pre-final version of the Brief IPQ Arabic version was tested for face and content validity. The meaning, comprehensibility, and acceptability were studied by individual interviews. For discriminant validity and internal consistency of the Brief IPQ Arabic version (Brief IPQ-Ar), 100 patients were recruited in a similar manner using the same inclusion criteria. To assess reproducibility, 30 patients, selected randomly from the 100 patients, filled the questionnaire a second time, 3-4 weeks after its first administration and under the same conditions. Main outcome measures Psychometric properties of the Brief IPQ-Ar among Lebanese patients suffering from cardiac diseases. Results Semantic equivalence between the Brief IPQ-Ar questions and patients' descriptions was 100%. Cronbach's alpha was 0.717, which shows good internal consistency. Reproducibility was satisfactory (ICC values>0.776). Moreover, the Brief IPQ-Ar discriminated participants according to the type of cardiac disease and treatment-related characteristics. Conclusions We confirm that the Brief IPQ Ar is appropriate for exploring IPs in cardiac disease patients whose first language is Arabic. Further research should be conducted to test this Arabic version in other types of diseases. PMID- 28349847 TI - How does serum brain natriuretic peptide level change under nasal continuous positive airway pressure in obstructive sleep apnea-hypopnea syndrome? AB - Background Obstructive sleep apnea-hypopnea syndrome (OSAHS) is associated with cardiovascular morbidity and mortality, which can be improved by using continuous positive airway pressure (CPAP) therapy. However, the pathophysiological links between the two kinds of disease and the mechanism of the CPAP effect remain incompletely understood. We aimed to inquire into the myocardial involvement in this relationship. We suggested that serum brain natriuretic peptide (BNP) is sensitive enough to detect myocardial stress caused by OSAHS. Design and methods Sixty-four subjects without cardiovascular disease (21 controls, 24 normotensive OSAHS patients, and 19 hypertensive OSAHS patients) were analyzed for serum BNP at baseline and serially over 6 months. CPAP was applied to 23 patients with severe OSAHS. Results At baseline, the serum BNP levels were significantly higher (p=0.0001) in the OSAHS group (22.3+/-14.79 pg/ml) than in the control group (9.2+/-6.75 pg/ml). Increased serum BNP levels were significantly associated with mean transcutaneous oxygen saturation (SpO2) (p<0.0001), minimal SpO2 (p=0.002), oxygen desaturation index (p=0.001), and total sleep time spent with SpO2 lower than 90% (p=0.002). All patients with elevated BNP levels (>=37 pg/ml) had moderate or severe OSAHS (11/43 OSAHS patients). The more severe the OSAHS, the higher the BNP levels were. However, only the difference between severe and mild OSAHS was statistically significant (p=0.029). Hypertensive OSAHS patients had the highest baseline BNP levels (27.7+/-16.74 pg/ml). They were significantly higher (p=0.001) than in normotensive OSAHS patients (18+/-11.72 pg/ml) (p=0.039) and the controls (9.2+/-6.75 pg/ml). As compared with baseline, treatment with CPAP significantly decreased BNP levels in both hypertensive and normotensive OSAHS patients (respectively, from 36+/-16.10 to 29.7+/-14.29 pg/ml, p<0.001, and from 20+/-10.09 to 16+/-8.98 pg/ml, p<0.001). In contrast, the BNP levels slightly increased in the controls (from 9.2+/-6.75 to 9.5+/-7.02 pg/ml, p=0.029), but there was no statistically significant difference in comparison with the baseline value. The effect of CPAP on BNP levels was more marked in patients with higher baseline BNP levels and those with the most prolonged nocturnal desaturation (p=0.001, r=0.65). It was also more marked in hypertensive OSHAS patients (p=0.015, r=0.72) in comparison with normotensive OSAHS patients (p=0.03, r=0.62). Conclusion BNP seems to be sensitive enough to detect myocardial stress caused by OSAHS. As such, it is a potential marker for screening of preclinical cardiovascular damage in patients with untreated OSAHS. Application of CPAP decreases levels significantly in normotensive and particularly in hypertensive OSAHS. These findings are consistent with previous results suggesting the potential benefits of CPAP on cardiovascular outcome in OSAHS patients. PMID- 28349846 TI - Irritable bowel syndrome among nurses working in King Abdulaziz University Hospital, Jeddah, Saudi Arabia. AB - Background Irritable bowel syndrome (IBS) is a highly prevalent gastrointestinal disorder that can cause disability and economic burden. Nurses are a vital part of the medical team and their well-being is an important issue. Yet, few studies have been done concerning IBS among nurses. Objectives To determine the prevalence, severity, and predictors of IBS among nurses working at King Abdulaziz University Hospital, Jeddah, Saudi Arabia. Materials and methods A cross-sectional study was conducted among 229 nurses who fulfilled the eligibility criteria. They were selected by stratified random sampling during 2014-2015. A validated, confidential, self-administered data collection sheet was used for collection of personal and sociodemographic data. Rome III Criteria, IBS Severity Scoring System (IBS-SSS), Hospital Anxiety and Depression Scale (HADS), and Pittsburgh Sleep Quality Index (PSQI) were included. Both descriptive and inferential statistics were done. A multiple logistic regression analysis was done to determine the predictors of IBS. Results The prevalence of IBS among nurses was 14.4%, and IBS-Mixed type was the commonest variety (54.5%). Positive family history of IBS, working in outpatient clinics, having day shift, poor sleep quality, and high anxiety and depression scale scores were significantly associated with IBS. After controlling for confounding factors in regression analysis, the predictors of IBS were food hypersensitivity (aOR=4.52; 95% CI: 1.80-11.33), morbid anxiety (aOR=4.34; 95% CI: 1.49-12.67), and positive family history of IBS (aOR=3.38; 95% CI: 1.12-13.23). Conclusion The prevalence of IBS was 14.4%. Food hypersensitivity, morbid anxiety, and family history were the predictors of IBS. Screening and management of IBS, food hypersensitivity, and psychological problems among nurses are recommended. PMID- 28349848 TI - Vitamin D inadequacy is widespread in Tunisian active boys and is related to diet but not to adiposity or insulin resistance. AB - Background Vitamin D inadequacy is widespread in children and adolescents worldwide. The present study was undertaken to assess the vitamin D status in active children living in a sunny climate and to identify the main determinants of the serum concentration of 25-hydroxyvitamin D (25-OHD). Methods This cross sectional study included 225 children aged 7-15 years practicing sports in a football academy. Anthropometric measures were performed to calculate body mass index (BMI), fat mass, and maturity status. A nutritional enquiry was performed including 3-day food records and food frequency questionnaire. Plasma 25-OHD and insulin were assessed by immunoenzymatic methods ensuring categorization of vitamin D status and calculation of insulin sensitivity/resistance indexes. A logistic regression model was applied to identify predictors for vitamin D inadequacy. Results Vitamin D deficiency (25-OHD<12 ug/L) was observed in 40.9% of children and insufficiency (12<25-OHD<20 ug/L) was observed in 44% of children. In a multivariate analysis, vitamin D deficiency and insufficiency were associated with a lower dietary intake of vitamin D, proteins, milk, red meat, fish, and eggs. However, no significant relationship was observed with maturation status, adiposity, or insulin resistance. Conclusions Tunisian children and adolescents are exposed to a high risk of vitamin D inadequacy despite living in a sunny climate. Circulating 25-OHD concentrations are related to the intake of vitamin D food sources but not to maturation status or body composition. Ensuring sufficient and safe sun exposure and adequate vitamin D intake may prevent vitamin D inadequacy in children from sunny environments. PMID- 28349849 TI - The establishment of ethical guidelines for biomedical research in Libya. PMID- 28349851 TI - First report of neurotoxic effect of the cyanobacterium Cylindrospermopsis raciborskii on the motility of trematode metacercariae. AB - Cylindrospermopsis raciborskii (Woloszynska) is a photosynthetic cyanobacterium that can produce cytotoxic (cylindrospermopsin) and neurotoxic cyanotoxins (saxitoxins). In Brazil the strains of C. raciborskii are reported to produce only saxitoxins (STX) and their effect on fish parasites has not been tested to date. The fish Poecilia vivipara Bloch and Schneider is a common host for the trematode Pygidiopsis macrostomum Travassos off the coast of Rio de Janeiro, and this fish-parasite interaction is a model for behavioural and ecotoxicological studies. The aim of this work was to evaluate the motility of metacercariae of P. macrostomum from P. vivipara exposed to 40 mg l-1 and 400 mg l-1 of crude lyophilized extract of the cyanobacterium C. raciborskii (CYRF-01) for 48 h. The fish were separated into groups of ten individuals and, after exposure, five fish from each group were dissected for counting and checking the motility of metacercariae. The other five fish were dissected after 48 h in clean water. The detection and quantification of STX in the solutions of cyanobacteria, and the gills and guts of fish, were performed by an enzyme-linked immunosorbent assay. The crude extract of C. raciborskii caused temporary paralysis in metacercariae of P. macrostomum after exposure of fish to both concentrations, and the motility recovered after the fish were kept for 48 h in clean water. STX was detected in the guts and gills of all fish analysed, suggesting that this toxin is involved in the paralysis of metacercariae. This is the first report on the action of neurotoxins in metacercariae of fish. PMID- 28349850 TI - Development and validation of a food photography manual, as a tool for estimation of food portion size in epidemiological dietary surveys in Tunisia. AB - Background Estimation of food portion sizes has always been a challenge in dietary studies on free-living individuals. The aim of this work was to develop and validate a food photography manual to improve the accuracy of the estimated size of consumed food portions. Methods A manual was compiled from digital photos of foods commonly consumed by the Tunisian population. The food was cooked and weighed before taking digital photographs of three portion sizes. The manual was validated by comparing the method of 24-hour recall (using photos) to the reference method [food weighing (FW)]. In both the methods, the comparison focused on food intake amounts as well as nutritional issues. Validity was assessed by Bland-Altman limits of agreement. In total, 31 male and female volunteers aged 9-89 participated in the study. Results We focused on eight food categories and compared their estimated amounts (using the 24-hour recall method) to those actually consumed (using FW). Animal products and sweets were underestimated, whereas pasta, bread, vegetables, fruits, and dairy products were overestimated. However, the difference between the two methods is not statistically significant except for pasta (p<0.05) and dairy products (p<0.05). The coefficient of correlation between the two methods is highly significant, ranging from 0.876 for pasta to 0.989 for dairy products. Nutrient intake calculated for both methods showed insignificant differences except for fat (p<0.001) and dietary fiber (p<0.05). A highly significant correlation was observed between the two methods for all micronutrients. The test agreement highlights the lack of difference between the two methods. Conclusion The difference between the 24-hour recall method using digital photos and the weighing method is acceptable. Our findings indicate that the food photography manual can be a useful tool for quantifying food portion sizes in epidemiological dietary surveys. PMID- 28349852 TI - Impact of the degree of urbanization on composition and structure of helminth communities in the Mongolian racerunner (Eremias argus) Peters, 1869. AB - The effects of the degree of urbanization on the composition and mean abundance of helminth species and the structure of helminth communities in the Mongolian racerunner were investigated along a rural-urban gradient in the region of Ulan Ude city (the Republic of Buryatia, Russia) and neighbouring rural districts. Racerunners were obtained from key areas and categorized into three grades based on the degree of urbanization. In this study, a total of 208 lizards were examined. The helminth communities in the Mongolian racerunner were studied at the infracommunity and component community levels. The nematode Spauligodon pseudoeremiasi was a sensitive bioindicator of the degree of urbanization in our study. All parameters of helminth infracommunities in the Mongolian racerunner were significantly reduced with increasing degree of urbanization of the key areas. Two parameters of helminth component communities (the proportion of hosts infected with parasites and the Shannon index) were significantly reduced with increasing degree of urbanization. The decline recorded in parameters of helminth infracommunities and component communities in the Mongolian racerunner were probably connected with the attenuation of the relationships between helminths, having a complex life cycle with intermediate hosts along the rural-urban gradient. PMID- 28349853 TI - Molecular identification of cryptic cysticercosis: Taenia ovis krabbei in wild intermediate and domestic definitive hosts. AB - The complex life cycle of taeniids represents an ideal model of a multi-host system. The complexity of these parasites can therefore cover the epidemiological issues of the interface between wild and domestic animals, especially once spatial overlap between wild and domestic definitive and intermediate hosts occurs. Here we use the occurrence of Taenia ovis krabbei in two model areas as an example of this epidemiological complexity. In two contiguous areas in the Italian northern Apennines, two hunted roe deer (Capreolus capreolus) showed numerous cysticerci in the muscles of their whole body and an adult tapeworm was recorded in a semi-stray dog (Canis lupus familiaris). Through molecular typing of the mitochondrial cytochrome c oxidase I (cox1) gene, cysticerci and the adult tapeworm of T. krabbei were identified. Taenia krabbei cysticercosis was recorded for the first time in Italy. Although the role of dogs in the parasite's life cycle emerges, the overlap between wild and domestic definitive hosts and the increase of wild population densities raise concerns about the temporal (old or new) introduction and the spread of this parasite by one of these canid species (wolf (Canis lupus) or dog). Although T. krabbei is not a public health issue, economic concerns emerged for hunters and meat producers, related to the damage of carcasses by cysticerci. Therefore, there is a need to evaluate the spread of T. krabbei in the intermediate and definitive host populations, and to ensure the relevant sanitary education for hunters in order to avoid practices that could favour the spread and maintenance of its life cycle. PMID- 28349854 TI - An economic analysis of a community-based model for dementia care in Ireland: a balance of care approach. AB - BACKGROUND: This study examined resource utilization, cost of care, and balance of care relationships for people with dementia on the boundary of community and residential care in Ireland. METHODS: A balance of care approach was used to examine how investment in personalized community care impacted on measured formal and informal costs, care relationships, and potential admission to long-stay care facilities for people with dementia over a three year period. RESULTS: 181 people with dementia on the boundary of community and residential care received additional personalized care supports to help them remain living at home in the community. The estimated average weekly cost of community care for these people, including usual formal care provision, new personalized supports, consumption, and housing, was ?418 per week, less than half the cost of potential residential care. However, when informal care is valued using an opportunity cost methodology, the social cost of community-based care increased threefold, rising above the cost of alternative residential care. CONCLUSION: Investment in personalized supports can support family carers to continue caring for longer, thus postponing expensive admission into long-stay care facilities. However, family-care costs remain high, irrespective of the additional supports received. PMID- 28349855 TI - Reliability of the NEO Five Factor Inventory short form for assessing personality after stroke. AB - BACKGROUND: It is well recognized that an individual's personality characteristics influence their psychological adjustment after stroke. However, there is a lack of research on the reliability of personality inventories for stroke. This study primarily aimed to evaluate the reliability of the Neuroticism, Extroversion, Openness to Experience (NEO)-Five Factor Inventory (NEO-FFI) for assessing pre-morbid personality and personality changes after stroke. Further aims were to investigate changes in personality during the hospital-to-home transition period and examine associations between personality and mood. METHODS: Forty participants with stroke (52.5% male, M age=65.55 years) were recruited at time of hospital discharge and completed the NEO-FFI, Centre for Epidemiologic Studies - Depression and Geriatric Anxiety Inventory. Significant others completed an informant version of the NEO-FFI. Stroke participants were re-assessed on the NEO-FFI at 1-month and 4-months post discharge. Forty matched controls also completed the NEO-FFI. RESULTS: Internal consistency was adequate for the NEO-FFI (alpha=0.57-0.86), although low for agreeableness. There was fair to excellent concordance between self-rated and informant versions of the NEO-FFI (ICC=0.58-0.78). Significant positive associations were found between neuroticism and mood (r=0.50-0.68), and significant negative associations were found between extraversion and mood (r= 0.33-0.36) and agreeableness and anxiety (r=-0.43). Self-ratings of stroke participants on the NEO-FFI at discharge did not significantly differ from matched controls. Extraversion levels significantly decreased, and agreeableness levels significantly increased between discharge and 1- and 4-months post discharge. CONCLUSIONS: Overall, the results support the reliability of the NEO FFI for assessing personality characteristics in the context of stroke. PMID- 28349857 TI - Fitting milk production curves through nonlinear mixed models. AB - The aim of this work was to fit and compare three non-linear models (Wood, Milkbot and diphasic) to model lactation curves from two approaches: with and without cow random effect. Knowing the behaviour of lactation curves is critical for decision-making in a dairy farm. Knowledge of the model of milk production progress along each lactation is necessary not only at the mean population level (dairy farm), but also at individual level (cow-lactation). The fits were made in a group of high production and reproduction dairy farms; in first and third lactations in cool seasons. A total of 2167 complete lactations were involved, of which 984 were first-lactations and the remaining ones, third lactations (19 382 milk yield tests). PROC NLMIXED in SAS was used to make the fits and estimate the model parameters. The diphasic model resulted to be computationally complex and barely practical. Regarding the classical Wood and MilkBot models, although the information criteria suggest the selection of MilkBot, the differences in the estimation of production indicators did not show a significant improvement. The Wood model was found to be a good option for fitting the expected value of lactation curves. Furthermore, the three models fitted better when the subject (cow) random effect was considered, which is related to magnitude of production. The random effect improved the predictive potential of the models, but it did not have a significant effect on the production indicators derived from the lactation curves, such as milk yield and days in milk to peak. PMID- 28349856 TI - Older Adult Spouses with Multiple Chronic Conditions: Challenges, Rewards, and Coping Strategies. AB - There is a paucity of research exploring how spouses to older adults with multiple chronic conditions make meaning of their caregiving experience. For this study, we asked: What is the experience of spousal caregivers to persons with multiple chronic conditions? We applied Thorne's interpretive description approach, interviewing 18 spouses who provided a rich description of their caregiving experience; interviews were transcribed verbatim and thematically analysed. Themes were categorized according to challenges encountered, rewards gleaned, and sustaining strategies employed by participants in caregiving to their spouse with multiple chronic conditions. Unique findings relate to the challenges inherent in decision-making within the context of multiple chronic conditions. This article begins to address the gap in the literature regarding the caregiving experience within the context of multiple chronic conditions. PMID- 28349858 TI - Potentially preventable hospitalizations in dementia: family caregiver experiences. AB - BACKGROUND: Health crises in persons living with dementia challenge their caregivers to make pivotal decisions, often under pressure, and to act in new ways on behalf of their care recipient. Disruption of everyday routines and heightened stress are familiar consequences of these events. Hospitalization for acute illness or injury is a familiar health crisis in dementia. The focus of this study is to describe the lived experience of dementia family caregivers whose care recipients had a recent unplanned admission, and to identify potential opportunities for developing preventive interventions. METHODS: Family caregivers (n = 20) of people with dementia who experienced a recent hospitalization due to an ambulatory care sensitive condition or fall-related injury completed phone interviews. Interviews used semi-structured protocols to elicit caregivers' reactions to the hospitalization and recollections of the events leading up to it. RESULTS: Analysis of interview data identified four major themes: (1) caregiver is uncertain how to interpret and act on the change; (2) caregiver is unable to provide necessary care; (3) caregiver experiences a personal crisis in response to the patient's health event; (4) mitigating factors may prevent caregiver crises. CONCLUSIONS: This study identifies a need for clinicians and family caregivers to work together to avoid health crises of both caregivers and people with dementia and to enable caregivers to manage the health of their care recipients without sacrificing their own health and wellness. PMID- 28349859 TI - Mental Health Experiences of Older Adults Living with HIV: Uncertainty, Stigma, and Approaches to Resilience. AB - This study describes the mental health experiences of older adults living with HIV in Ottawa. Eleven participants aged 52 to 67 completed in-depth personal interviews. Mental health concerns pervaded the lives of these older adults. We identified three central themes common to the participants' stories: uncertainty, stigma, and resilience. For some of these participants, uncertainty impacting mental health centred on unexpected survival; interpretation of one's symptoms; and medical uncertainty. Participants' experiences of stigma included discrimination in health care interactions; misinformation; feeling stigmatized due to aspects of their physical appearance; compounded stigma; and anticipated stigma. Participants reported using several coping strategies, which we frame as individual approaches to resilience. These strategies include reducing the space that HIV takes up in one's life; making lifestyle changes to accommodate one's illness; and engaging with social support. These findings inform understandings of services for people aging with HIV who may experience mental health concerns. PMID- 28349860 TI - Predictors for repeat self-harm and suicide among older people within 12 months of a self-harm presentation. AB - BACKGROUND: A past history of self-harm is a significant risk factor for suicide in older people. The aims of this study are to (i) characterize older people who present with self-harm to emergency departments (EDs); and (ii) determine the predictors for repeat self-harm and suicide. METHODS: Demographic and clinical data were retrospectively collected on older people (age 65+ years), who presented to seven EDs in New Zealand following an episode of self-harm between 1st July 2010 and 30th June 2013. In addition, 12-month follow-up information on repeat self-harm and suicide was collected. RESULTS: The sample included 339 older people (55.2% female) with an age range of 65-96 years (mean age = 75.0; SD = 7.6). Overdose (68.7%) was the most common method of self-harm. 76.4% of the self-harm cases were classified as suicide attempts. Perceived physical illness (47.8%) and family discord (34.5%) were the most common stressors. 12.7% of older people repeated self-harm and 2.1% died by suicide within 12 months. Older people who had a positive blood alcohol reading (OR = 3.87, 95% Cl = 1.35-11.12, p = 0.012) and were already with mental health services at the index self-harm (OR = 2.73, 95% Cl = 1.20-6.25, p = 0.047) were more likely to repeat self-harm/suicide within 12 months. CONCLUSION: Older people who self-harm are at very high risk of repeat self-harm and suicide. Screening and assessment for alcohol use disorders should be routinely performed following a self-harm presentation, along with providing structured psychological treatment as an adjunct to pharmacological treatment for depression and interventions to improve the person's resilience resources. PMID- 28349863 TI - Structural perspective of cooperative transcription factor binding. AB - In prokaryotes, individual transcription factors (TFs) can recognize long DNA motifs that are alone sufficient to define the genes that they induce or repress. In contrast, in higher organisms that have larger genomes, TFs recognize sequences that are too short to define unique genomic positions. In addition, development of multicellular organisms requires molecular systems that are capable of executing combinatorial logical operations. Co-operative recognition of DNA by multiple TFs allows both definition of unique genomic positions in large genomes, and complex information processing at the level of individual regulatory elements. The TFs can co-operate in multiple different ways, and the precise mechanism used for co-operation determines important features of the regulatory interactions. Here, we present an overview of the structural basis of the different mechanisms by which TFs can cooperate, focusing on insight from recent functional studies and structural analyses of specific TF-TF-DNA complexes. PMID- 28349862 TI - Dopamine signaling tunes spatial pattern selectivity in C. elegans. AB - Animals with complex brains can discriminate the spatial arrangement of physical features in the environment. It is unknown whether such sensitivity to spatial patterns can be accomplished in simpler nervous systems that lack long-range sensory modalities such as vision and hearing. Here we show that the nematode Caenorhabditis elegans can discriminate spatial patterns in its surroundings, despite having a nervous system of only 302 neurons. This spatial pattern selectivity requires touch-dependent dopamine signaling, including the mechanosensory TRP-4 channel in dopaminergic neurons and the D2-like dopamine receptor DOP-3. We find that spatial pattern selectivity varies significantly among C. elegans wild isolates. Electrophysiological recordings show that natural variations in TRP-4 reduce the mechanosensitivity of dopaminergic neurons. Polymorphic substitutions in either TRP-4 or DOP-3 alter the selectivity of spatial patterns. Together, these results demonstrate an ancestral role for dopamine signaling in tuning spatial pattern preferences in a simple nervous system. PMID- 28349864 TI - Why does the health of Mexican immigrants deteriorate? New evidence from linked birth records. AB - This study uses a unique dataset linking the birth records of two generations of children born in California and Florida (1970-2009) to analyze the mechanisms behind the generational decline observed in birth outcomes of children of Mexican origin. Calibrating a simple model of intergenerational transmission of birth weight, I show that modest positive selection on health at the time of migration can account for the initial advantage in birth outcomes of second-generation Mexicans. Moreover, accounting for the socioeconomic differences between second generation Mexicans and white natives and the observed intergenerational correlation in birth weight, the model predicts a greater deterioration than that observed in the data. Using a subset of siblings and holding constant grandmother quasi-fixed effects, I show that the persistence of healthier behaviors among second-generation Mexican mothers can explain more than half of the difference between the model prediction and the observed birth outcomes of third-generation Mexicans. PMID- 28349865 TI - Bans on electronic cigarette sales to minors and smoking among high school students. AB - Many states have banned electronic cigarette sales to minors under the rationale that using e-cigarettes leads to smoking traditional combustion cigarettes. Such sales bans would be counterproductive, however, if e-cigarettes and traditional cigarettes are substitutes, as bans might push teenagers back to smoking the more dangerous combustion cigarettes. We provide evidence that these sales bans reduce the incidence of smoking conventional cigarettes among high school seniors. Moreover, we provide evidence suggesting that sales bans reduced e-cigarette usage as well. This evidence suggests that not only are e-cigarettes and smoking regular cigarettes positively related and not substitutes for young people, banning retail sales to minors is an effective policy tool in reducing tobacco use. PMID- 28349867 TI - Evaluation of dredged sediment co-composted with green waste as plant growing media assessed by eco-toxicological tests, plant growth and microbial community structure. AB - Dredged sediments have currently no broad reuse options as compared to other wastes due to their peculiar physico-chemical properties, posing problems for the management of the large volumes of sediments dredged worldwide. In this study we evaluated the performance of sediment (S) co-composted with green waste (GW) as growing medium for ornamental plants. Analysis of the microbial community structure, eco-toxicological tests, were conducted on sediments at 1:1 and 3:1S:GW composting ratios. Sediment-based growing media were then reused to growth the ornamental plant Photina x fraseri in a pilot-scale experiment and plants' physiological and chemical parameters were measured. The results showed that co-composting with green waste increased the diversity of bacteria, fungi and archaea as compared to the untreated sediments, and that both the 1:1 and 3:1 S:GW composted sediments had no substantial eco-toxicological impacts, allowing an excellent plant growth. We concluded that co-composted of sediment with green waste produce a growing medium with suitable properties for growing ornamental plants, and represent a sustainable option for beneficial use of dredged sediments. PMID- 28349866 TI - Bolstering cholesteryl ester hydrolysis in liver: A hepatocyte-targeting gene delivery strategy for potential alleviation of atherosclerosis. AB - Current atherosclerosis treatment strategies primarily focus on limiting further cholesteryl esters (CE) accumulation by reducing endogenous synthesis of cholesterol in the liver. No therapy is currently available to enhance the removal of CE, a crucial step to reduce the burden of the existing disease. Given the central role of hepatic cholesteryl ester hydrolase (CEH) in the intrahepatic hydrolysis of CE and subsequent removal of the resulting free cholesterol (FC), in this work, we applied galactose-functionalized polyamidoamine (PAMAM) dendrimer generation 5 (Gal-G5) for hepatocyte-specific delivery of CEH expression vector. The data presented herein show the increased specific uptake of Gal-G5/CEH expression vector complexes (simply Gal-G5/CEH) by hepatocytes in vitro and in vivo. Furthermore, the upregulated CEH expression in the hepatocytes significantly enhanced the intracellular hydrolysis of high density lipoprotein associated CE (HDL-CE) and subsequent conversion/secretion of hydrolyzed FC as bile acids (BA). The increased CEH expression in the liver significantly increased the flux of HDL-CE to biliary as well as fecal FC and BA. Meanwhile, Gal-G5 did not induce hepatic or renal toxicity. It was also not immunotoxic. Because of these encouraging pre-clinical testing results, using this safe and highly efficient hepatocyte-specific gene delivery platform to enhance the hepatic processes involved in cholesterol elimination is a promising strategy for the alleviation of atherosclerosis. PMID- 28349868 TI - Ultimate biodegradability and ecotoxicity of orally administered antidiabetic drugs. AB - Hypoglycaemic pharmaceuticals are recently more and more frequently detected in the environment. In our previous study, we have shown that even though many of them undergo significant primary degradation some are transformed to stable products or undergo such transformation that a large part of the structure is still preserved. One of the main routes of elimination from wastewaters or surface waters is biodegradation and a lack thereof leads to accumulation in the environment. Within this work we tested the ultimate biodegradability of six oral antidiabetics: metformin and its main metabolite guanylurea, acarbose, glibenclamide, gliclazide, glimepiride and repaglinide. We also compared the experimental results obtained in this and accompanying work with models designed to predict biodegradability and showed that these models are only moderately successful. Additionally, we examined these compounds in acute Daphnia magna test to check if they might pose an ecotoxicological threat. Combining the results of biodegradability and toxicity tests allows a preliminary assessment of their potential environmental impact. PMID- 28349869 TI - Modulation of regulatory T cells by intranasal allergen immunotherapy in an experimental rat model of airway allergy. AB - Allergic airway diseases such as asthma and allergic rhinitis are increasing in prevalence worldwide. The theory of an altered Th1/Th2 balance in allergic diathesis has recently been termed a "procrustean paradigm" as it failed to explain many preclinical findings. Regulatory T cells (Treg) have now been shown to be critical in T-cell homeostasis and in the maintenance of peripheral tolerance to allergens. Allergen specific immunotherapy (SIT) has been shown to induce regulatory T cells in allergic patients. Among various types of SIT, intranasal immunotherapy had not been studied in detail for the treatment of allergic airway diseases. So, there was a need to study the contribution of regulatory T cells and their mechanistic pathways following intranasal immunotherapy in-vivo. It had been previously shown that intranasal allergen immunotherapy using Alstonia scholaris pollen extract abrogates allergic airway inflammation with decline in IgE and Th2 cytokine levels. The present study for the first time offers a multi-targeted approach towards attenuation of airway allergy by the generation of CD4+CD25+Foxp3+T cells and other subsets of Treg cells like Tr1 cells, Th3 cells, CTLA4+Treg cells, and also modulation of various Treg cell surface molecules like GITR, OX40, CD39 and CD73 by intranasal immunotherapy in the same animal model. This animal experiment will thus help to chart out newer molecular targets for treating allergic asthma or rhinitis. PMID- 28349870 TI - Improvement of cyanobacterial-killing biologically derived substances (BDSs) using an ecologically safe and cost-effective naphthoquinone derivative. AB - In previous studies, naphthoquinone (NQ) compounds have been shown to be effective, selective, and ecologically safe algicides for controlling harmful algal blooming species (HABs) or winter bloom species, such as Stephanodiscus hantzschii. However, there are no reports on NQ-based algicides for use with cyanobacterial blooming species. In this study, we developed 31 NQ compounds to investigate algicides for mitigating cyanobacterial blooms. In addition, to better apply these compounds in the field, we reduced the number of production steps to develop a cost-effective algicide. In preliminary testing, we screened NQ compounds that showed the best algicidal activity on target cyanobacteria, including Aphanizomenon, Dolichospermum, Microcystis, Oscillatoria, and Nostoc species. The compound NQ 2-0 showed the highest algicidal activity (90%) at a low concentration (>=1MUM) on target algae. These were very limiting algicidal effects of 1uM NQ 2-0 observed against non-target algae, such as diatoms (Stephanodiscus hantzschii, Cyclotella meneghiniana, Synedra acus, and Aulacoseira granulata) or green algae (Cosmarium bioculatum and Scenedesmus quadricauda), and the effect did not exceed 15-25% (except against S. quadricauda). NQ 2-0 (1MUM) showed no eco-toxicity, as represented by the survival rates of Pseudokirchneriella subcapitata (100%), Daphnia magna (100%), and Danio rerio (100%). Additionally, a chronic eco-toxicity assessment showed no toxicity toward the survival, growth or reproduction of D. magna. Moreover, NQ 2 0 quickly dissipated from field water samples and had a half-life of approximately 3.2 days. These results suggest that NQ 2-0 could be a selective and ecologically safe algicide to mitigate harmful cyanobacterial blooms. PMID- 28349871 TI - Development of methods for avian oil toxicity studies using the double crested cormorant (Phalacrocorax auritus). AB - Oral and external dosing methods replicating field exposure were developed using the double crested cormorant (DCCO) to test the toxicity of artificially weathered Deepwater Horizon Mississippi Canyon 252 oil. The majority of previous oil dosing studies conducted on wild-caught birds used gavage methods to dose birds with oil and determine toxicity. However, rapid gut transit time of gavaged oil likely reduces oil absorption. In the present studies, dosing relied on injection of oil into live feeder fish for oral dosing of these piscivorous birds, or applying oil to body contour feathers resulting in transdermal oil exposure and oral exposure through preening. Both oral and external oil dosing studies identified oil-related toxicity endpoints associated with oxidative stress such as hemolytic anemia, liver and kidney damage, and immuno-modulation or compromise. External oil application allowed for controlled study of thermoregulatory stress as well. Infrared thermal images indicated significantly greater surface temperatures and heat loss in treated birds following external oil applications; however, measurements collected by coelomically implanted temperature transmitters showed that internal body temperatures were stable over the course of the study period. Birds exposed to oil externally consumed more fish than control birds, indicating metabolic compensation for thermal stress. Conversely, birds orally dosed with oil experienced hypothermia and consumed less fish compared to control birds. PMID- 28349872 TI - Responses of gonadal transcriptome and physiological analysis following exposure to 17alpha-ethynylestradiol in adult rare minnow Gobiocypris rarus. AB - 17alpha-ethynylestradiol (EE2), a synthetic estrogen commonly used in the oral contraceptive pills, disrupts the sexual differentiation, gonadal development and reproduction in aquatic species. Nowadays aquatic species and even humans still have the potential risks of exposure to EE2. However, the mechanism of EE2 endocrine disruption is still unclear. Aiming to elucidate molecular mechanisms, we analyzed transcriptome profiling of gonads, gonadal histology and the sex steroid hormones in response to EE2 in G. rarus. Through this study, we obtained eight RNA-Seq libraries upon EE2 exposure, and found some key genes and pathways in correlation with the disruption effects of EE2. We found EE2 could disrupt oocyte development and spermatogenesis in adult G. rarus, and EE2 has more obvious disruption effects on male G. rarus than females. Interestingly, EE2 was indicated to be an exogenous DPC-inducing agent and ppp2r3b was suggested to be a spermatogenesis candidate gene in rare minnow. The differential gene expressions of rps30, samp9, ppp2r3b and spartan upon EE2 exposure suggest EE2's disruption effects on gonads could attribute to altered pathways of translation, ribosome biogenesis and cell division. PMID- 28349873 TI - Cadmium spiked soil modulates root organic acids exudation and ionic contents of two differentially Cd tolerant maize (Zea mays L.) cultivars. AB - Our earlier work described that the roots of two maize cultivars, grown hydroponically, differentially responded to cadmium (Cd) stress by initiating changes in medium pH depending on their Cd tolerance. The current study investigated the root exudation, elemental contents and antioxidant behavior of the same maize cultivars [cv. 3062 (Cd-tolerant) and cv. 31P41 (Cd-sensitive)] under Cd stress. Plants were maintained in a rhizobox-like system carrying soil spiked with Cd concentrations of 0, 10, 20, 30, 40 and 50 MUmol/kg soil. The root and shoot Cd contents increased, while Mg, Ca and Fe contents mainly decreased at higher Cd levels, and preferentially in the sensitive cultivar. Interestingly, the K contents increased in roots of cv. 3062 at low Cd treatments. The Cd stress caused acidosis of the maize root exudates predominantly in cv. 3062. The concentration of various organic acids was significantly increased in the root exudates of cv. 3062 with applied Cd levels. This effect was diminished in cv. 31P41 at higher Cd levels. Cd exposure increased the relative membrane permeability, anthocyanin (only in cv. 3062), proline contents and the activities of peroxidases (POD) and superoxide dismutase (SOD). The only exception was the catalase activity, which was diminished in both cultivars. Root Cd contents were positively correlated with the secretion of acetic acid, oxalic acid, glutamic acid, citric acid, and succinic acid. The antioxidants like POD and SOD exhibited a positive correlation with the organic acids under Cd stress. It is likly that a high exudation of dicarboxylic organic acids improves nutrient uptake and activities of antioxidants, which enables the tolerant cultivar to acclimatize in Cd polluted environment. PMID- 28349875 TI - Intact non-word repetition and similar error patterns in language-matched children with autism spectrum disorders: A pilot study. AB - PURPOSE: We investigated whether enhanced auditory short-term memory may contribute to the learning of novel word forms in children with Autism Spectrum Disorder. We also evaluated whether delayed but qualitatively normal, versus atypical, cognitive processes underlie non-word repetition in this population via a detailed error analysis. METHOD: English-speaking children with Autism Spectrum Disorder (who had significant language delay) and typically-developing children matched pairwise on language ability were compared on the Syllable Repetition Task (Shriberg et al., 2009). RESULTS: All children exhibited better performance on stimuli of shorter vs. longer syllable length. In addition there was a significant interaction whereby children with Autism Spectrum Disorder performed better than typically-developing children at the longest syllable length. Repetition accuracy was significantly correlated with language level in both groups. In contrast, the relationship between Repetition accuracy and age was only marginally significant in the Autism Spectrum Disorder group and did not reach significance in the typically-developing group. This underscores the importance of language level to non-word repetition performance, and supports the practice of matching on language rather than age alone. An error analysis (Shriberg et al., 2012) showed many similarities between groups in terms of number of consonants deleted, encoding accuracy, and transcoding accuracy components of the task. However the Autism Spectrum Disorder group tended to display better auditory short-term memory with a medium effect size, though this did not reach significance given the small sample size. CONCLUSION: These findings extend evidence of delayed but qualitatively normal non-word repetition previously described in preadolescents with Autism Spectrum Disorder (Williams et al., 2013) to younger kindergarten-age children with Autism Spectrum Disorder and language delay, indicating that non-word repetition is not an area of specific difficulty for this population. With respect to enhanced auditory short-term memory, we found preliminary evidence of better memory for longer nonwords in children with Autism Spectrum Disorder compared to younger typically developing children who were matched on language. PMID- 28349874 TI - Equilibrium isotherms, kinetics, and thermodynamics studies for congo red adsorption using calcium alginate beads impregnated with nano-goethite. AB - The present study is concerned with the batch adsorption of congo red (CR) from an aqueous solution using calcium alginate beads impregnated with nano-goethite (CABI nano-goethite) as an adsorbent. The optimum conditions for CR removal were determined by studying operational variables viz. pH, adsorbent dose, contact time, initial dye ion concentration and temperature. The CABI nano-goethite was characterized by Fourier transform infrared spectroscopy (FTIR), X- ray diffraction (XRD) and Scanning electron microscopy/energy dispersive spectroscopy (SEM/EDS) analysis. The CR sorption data onto CABI nano-goethite were described using Langmuir, Freundlich, Dubinin-Radushkevich and Temkin isotherm models. The results show that the best fit was achieved with the Langmuir isotherm model. The maximum adsorption capacity (181.1mg/g) of CR was occurred at pH 3.0. Kinetic studies showed that the adsorption followed a pseudo-second-order model. Desorption experiments were carried out to explore the feasibility of regenerating the adsorbent and the adsorbed CR from CABI nano-goethite. The best desorbing agent was 0.1M NaOH with an efficiency of 94% recovery. The thermodynamic parameters DeltaG degrees , DeltaH degrees , and DeltaS degrees for the CR adsorption were determined by using adsorption capacities at five different temperatures (293, 303, 313, 323 and 303K). Results show that the adsorption process was endothermic and favoured at high temperature. PMID- 28349876 TI - Location versus task relevance: The impact of differing internal focus of attention instructions on motor performance. AB - Impaired performance while executing a motor task is attributed to a disruption of normal automatic processes when an internal focus of attention is used. What remains unclear is whether the specificity of internally focused task instructions may impact task performance. The present study assessed the implications of changing the attentional focus of novice and skilled golfers by measuring behavioural, neurophysiological and kinematic changes during a golf putting task. Over six blocks of ten putting trials each, attention was directed either externally (towards the target) or internally in one of two ways: 1) proximal (keeping the elbows extended and the hands gripping the putter); or 2) distal (keeping the weight evenly distributed between both legs) to the critical elements of the task. Results provided evidence that when novice participants use an internal focus of attention more closely associated with task performance that their: 1) execution; 2) accuracy; 3) variability of surface electromyography (sEMG) activity; and 4) kinematics of the putter movement are all adversely affected. Skilled golfers are much more resilient to changes in attentional focus, while all participants interpret a distal internal focus of attention similar to an external focus. All participants produced decreased activity in the muscle (tibialis anterior) associated with the distal (less task relevant) focus of attention even when the "internal" focus was on the lower extremity. Our results provide evidence that the skill level of the participant and the distance of the internal focus of attention from the key elements of a motor skill directly impact the execution, muscle activity, and movement kinematics associated with skilled motor task performance. PMID- 28349877 TI - Monitoring of the energy levels by heteroatom substitution to hexacene and controlling over singlet fission and photo-oxidative resistance. AB - The singlet fission is a spin allowed and extremely fast internal conversion process involved in solar cell by which a photo-excited singlet exciton is splitted into two triplet ones. For effective singlet fission and to increase the efficiency of solar cell, designing of new molecules is an interesting area of research and our current interest. The silicon substituted oligocenes, commonly known as silaoligocenes, are found to be the efficient singlet fission material due to their special characteristics. We have shown the SF energy criteria satisfied by the singlet and triplet states of various silahexacene derivatives, and theoretically predicted whether such molecules exhibit fission properties or not. The fluorine atoms have been substituted to various positions of different silahexacenes to manipulate their singlet and triplet energy levels. As fluorine being the most electro-negative substituent, it is capable of lowering frontier molecular orbital energies effectively. Thus, the material can easily match SF energy criteria to compute the SF driving force or triplet-triplet annihilation possibility. The geometries, electronic structures, frontier molecular orbital energies, optimization of excited state and calculation of energies associated with fission process of the substituted hexacene are investigated with well known quantum mechanical methods. PMID- 28349878 TI - Adsorption behavior of acetone solvent at the HMX crystal faces: A molecular dynamics study. AB - Molecular dynamics simulations have been performed to understand the adsorption behavior of acetone (AC) solvent at the three surfaces of 1,3,5,7-tetranitro 1,3,5,7-tetraazacyclooctan (HMX) crystal, i.e. (011), (110), and (020) faces. The simulation results show that the structural features and electrostatic potentials of crystal faces are determined by the HMX molecular packing, inducing distinct mass density distribution, dipole orientation, and diffusion of solvent molecules in the interfacial regions. The solvent adsorption is mainly governed by the van der Waals forces, and the crystal-solvent interaction energies among three systems are ranked as (020)~(110)>(011). The adsorption sites for solvent incorporation at the crystal surface were found and visualized with the aid of occupancy analysis. A uniform arrangement of adsorption sites is observed at the rough (020) surface as a result of ordered adsorption motif. PMID- 28349879 TI - Docking, molecular dynamics and free energy studies on aspartoacylase mutations involved in Canavan disease. AB - The disruption of aspartoacylase enzyme's catalytic activity causes fatal neurodegenerative Canavan disease. By molecular dynamics and docking methods, here we studied two deleterious mutations that have been identified in the Canavan patients' genotype E285A, F295S, and revealed the possible cause for the enzyme inhibition due to the drastic changes in active site dynamics, loss of interactions among Arg 71, Arg 168 and the substrate and pKa value of critical Glu178 residue. In addition to changes in the enzyme dynamics, free energy calculations show that the binding energy of substrate decreases dramatically up on mutations. PMID- 28349880 TI - Anti-inflammatory and antithrombotic effects of nicotine exposure in oral contraceptive-induced insulin resistance are glucocorticoid-independent. AB - BACKGROUND: Reports showed that estrogen-progestin oral contraceptive (COC) or tobacco smoking causes increased risk of cardiovascular diseases (CVD) in premenopausal women. Studies also suggest that nicotine, a major tobacco alkaloid, may worsen or improve atherothrombotic CVD. Altered hemorheology, prothrombotic and pro-inflammatory biomarkers, have been implicated in the development of atherothrombotic CVD events. However, the effect of non-smoking nicotine exposure on these biomarkers during COC treatment is not yet established. We therefore sought to determine the effects of nicotine exposure during COC treatment on these biomarkers, and also tested the hypothesis that the nicotine effects would be glucocorticoid-dependent. METHODS: Female Sprague Dawley rats aged 10 weeks were given (po) vehicle, low-dose nicotine (0.1mg/kg) or high-dose nicotine (1.0mg/kg) with or without COC steroids (5.0MUg/kg ethinylestradiol and 25.0MUg/kg levonorgestrel) daily for 6 weeks. RESULTS: COC treatment or nicotine exposure led to increased insulin resistance (IR), hemorheological (blood viscosity, hematocrit and plasma viscosity), prothrombotic (plasminogen activator inhibitor-1), pro-inflammatory (uric acid, C-reactive protein, neutrophil/lymphocyte and platelet/lymphocyte ratios) biomarkers and corticosterone. However, these effects except that on corticosterone were abrogated by nicotine exposure during COC treatment. CONCLUSIONS: Our study indicates that nicotine- or COC-induced IR may be mediated via inflammatory/thrombotic pathway. The results imply that nicotine exposure could impact negatively on atherothrombotic biomarkers in COC non-users, whereas the impact in COC users could be positive. The results also suggest that the anti inflammatory, antithrombotic and blood viscosity-lowering effects of nicotine exposure during COC use is circulating glucocorticoid-independent. PMID- 28349881 TI - PM2.5 exposure in highly polluted cities: A case study from New Delhi, India. AB - Personal exposure (PE) to air pollutants is driven by a combination of pollutant concentrations in indoor and outdoor environments, and time-activity pattern of individuals. The objectives of this study were to estimate personal exposure to PM2.5 and black carbon (BC), and assess the representability of ambient air quality monitoring stations to serve as surrogates for PE in New Delhi. Personal exposure to air pollutants (PM2.5-PE and BCPE) was measured using portable, battery-operated instruments (PM2.5- pDR1500 and BC- microAethalometer AE51) in a small cohort of healthy adults (n=12 in summer, n=6 in winter) with no occupational exposure. Average PM2.5-PE and BCPE (ug/m3) were 53.9+/-136 and 3.71+/-4.29 respectively, in summer and 489.2+/-209.2 and 23.3+/-14.9 respectively, in winter. Activities associated with highest exposure levels were cooking and indoor cleaning for PM2.5, and commuting for BC. Within transport microenvironments, autorickshaws were found to be the most polluted, and lowest BC exposure was registered in public buses. Comparison of fixed-site ambient monitoring data showed a higher correlation with personal exposure dataset in winter compared to summer (r2 of 0.51 (winter) and 0.21 (summer); 51% (winter) and 20% (summer)). This study highlights the need for detailed assessment of PE to air pollutants in Indian cities, and calls for a denser network of monitoring stations for better exposure assessment. PMID- 28349883 TI - Functionalization of super-aligned carbon nanotube film using hydrogen peroxide solution and its application in copper electrodeposition. AB - In order to make super-aligned carbon nanotubes (SACNT) homogeneously spread in electrolytes, a swift and effective method was devised for surface functionalization of SACNT film by ohmic heating using hydrogen peroxide solution. Controllable generation of defects and notable graft of oxygen functional groups on the sidewall of SACNTs were induced as proven by X-ray photoelectron spectroscopy and Raman spectroscopy. Differently from the harsh wet chemical oxidation, the super-aligned morphology and structural integrity of carbon nanotubes in the SACNT film were found to be well preserved by electron microscopy analysis. The functionalized treatment can remove extraneous material contaminating SACNT film and improve its conductivity. The grafting of polar ionizable groups has been proved to effectively eliminate the agglomeration of SACNTs. When the oxidized SACNT film was used as host material for electrodeposition of copper, the composite film of well-bonded SACNTs and Cu was successfully prepared. PMID- 28349882 TI - Association of prenatal exposure to perfluoroalkyl substances with cord blood adipokines and birth size: The Hokkaido Study on environment and children's health. AB - Perfluoroalkyl substances (PFASs) are synthetic chemicals that persist in the environment and in humans. There is a possible association between prenatal PFASs exposure and both neonate adipokines and birth size, yet epidemiological studies are very limited. The objective of this study was to examine associations of prenatal exposure to PFASs with cord blood adipokines and birth size. We conducted birth cohort study, the Hokkaido Study. In this study, 168 mother-child pairs were included. Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) in maternal blood were determined by liquid chromatography tandem mass spectrometry. Cord blood adiponectin and leptin levels were measured by ELISA and RIA, respectively. Birth weight and ponderal index (PI) were obtained from birth record. The median maternal PFOS and PFOA were 5.1 and 1.4ng/mL, respectively. The median total adiponectin and leptin levels were 19.4MUg/mL and 6.2ng/mL, respectively. Adjusted linear regression analyses found that PFOS level was positively associated with total adiponectin levels (beta=0.12, 95% CI:0.01, 0.22), contrary was negatively associated with PI (beta=-2.25, 95% CI: -4.01, 0.50). PFOA level was negatively associated with birth weight (beta=-197, 95% CI: -391, -3). Leptin levels were not associated with PFASs levels. PFOS and adiponectin levels showed marginal dose-response relationship and both PFOS and PFOA and birth size showed significant dose-response relationships. Results from this study suggested that prenatal PFASs exposure may alter cord blood adiponectin levels and may decrease birth size. PMID- 28349884 TI - Surface modification of SiO2 coated ZnO nanoparticles for multifunctional cotton fabrics. AB - A simple chemical synthetic route was designed to prepare zinc oxide nanoparticles (ZnO-NPs) by using sodium alginate as anti-agglomeration agent in the presence of sodium hydroxide as alkali. Next, surface modification of ZnO-NPs with SiO2 nanoparticles was achieved as per to sol-gel process. Further enhancing of the multifunctional properties of SiO2@ZnO-NPs was conducted successfully thanks to (aminopropyl)triethoxysilan (APTES) and vinyltriethoxysilan (VTES) which, in turns, increase the affinity of the SiO2@ZnO-NPs nanocomposite towards glycosidic chains of cotton fabrics. Thorough characterizations of synthesized ZnO-NPs, SiO2@ZnO-NPs, SiO2@ZnO-NPs/APTES and SiO2@ZnO-NPs/VTES were conducted by the making use of well advanced techniques such as FT-IR, XRD, TEM, DLS and SEM EDX. The data obtained clarified the formation of an interfacial chemical bond between ZnO and SiO2 as affirmed by FT-IR and XRD analysis. In addition, the results revealed by TEM, zeta sizer and SEM-EDX techniques, declared that the amorphous layers of SiO2, APTES or VTES evenly coated the surface of ZnO-NPs. For these nanocomposites, the work was extended to render cotton fabrics multifunctional properties such as antibacterial and UV protection with high durability even after 20 washing cycles using pad dry cure method. Taking the advantages of the silane compounds terminated by active groups such as OH, NH2, etc., open the door for further functionalization of the cotton fabrics' surfaces by durable multifunctional agents applied in various applications. PMID- 28349885 TI - Enhanced photocatalytic degradation of dyes over graphene/Pd/TiO2 nanocomposites: TiO2 nanowires versus TiO2 nanoparticles. AB - In this study, at first, TiO2 nanowire was prepared by an alkaline hydrothermal process. In the following, Gr/Pd/TiO2-NPs and Gr/Pd/TiO2-NWs were synthesized by a combination of hydrothermal and photodeposition methods. The properties of as prepared products were characterized using XRD, FT-IR, SEM, DRS, TEM, ICP-OES, EDS and TGA analysis. SEM results confirmed nanodimension structure for all samples. Also the band gap values obtained using DRS technique suggests that all the samples have semiconductor behavior. Using TGA analysis, the amount of graphene loaded onto the powders was confirmed. Photocatalytic degradation of rhodamine B by TiO2-NWs, Gr/Pd/TiO2-NPs and Gr/Pd/TiO2-NWs nanocomposites was compared under ultraviolet light irradiation. Results confirmed that the Gr/Pd/TiO2-NWs composite show the highest photocatalytic activity due to much higher available surface area of TiO2 substrate in nanowire structure. It is expected that the synthesis of the high surface area TiO2 nanowires, facile photodeposition of palladium into its texture, and simple conversion of GO to graphene during hydrothermal process without using strong reducing agents, could be a suitable rote for preparing different types of carbon based TiO2 nanocomposite photocatalysts. PMID- 28349886 TI - Efficient removal of arsenic using graphene-zeolite based composites. AB - Removing heavy metals from water can be considered an important problem of global magnitude due to their toxic and carcinogenic properties. The main aim of this presentation was to synthesize different composites of graphene (graphene oxide (GO) or reduced graphene oxide (RGO is referred to reduced graphene oxide, which was obtained using solvothermal method)) with Cu-exchanged zeolite A (Cu-ZEA) and nanoparticles of magnetite (Fe3O4) (including Fe3O4/RGO/, GO/Cu-ZEA, Fe3O4/RGO/Cu ZEA and Fe3O4/GO/Cu-ZEA) for improving the properties of the individual components of mentioned composite and eventually investigate the composites' efficiency in arsenic adsorption. Among prepared composites, Fe3O4/RGO/Cu-ZEA composite had the highest efficiency in removing arsenic according to atomic absorption spectroscopy (AAS) results due to the high specific surface area, which was provided by the presence of Cu-ZEA and Fe3O4 in the structure of composite. Moreover, the adsorption kinetic investigation revealed that the adsorption of arsenate from aqueous suspension of Fe3O4/RGO/Cu-ZEA and Fe3O4/RGO composites followed a pseudo-second-order kinetic model. PMID- 28349887 TI - Atherosclerotic plaque metabolism in high cardiovascular risk subjects - A subclinical atherosclerosis imaging study with 18F-NaF PET-CT. AB - BACKGROUND AND AIMS: Atherosclerotic plaque molecular imaging with 18F-sodium fluoride (NaF) in positron emission tomography with computed tomography (PET-CT) provides potential discrimination between active unstable microcalcification and established dormant calcification. We aimed to study 18F-NaF atherosclerotic plaque uptake in high cardiovascular (CV) risk participants and its associations with CV risk factors, coronary calcium score and thoracic fat volume. METHODS: High CV risk hypertensive individuals from a single centre were prospectively scanned with 18F-NaF-PET-CT in the coronary, aortic and carotideal arteries. Atherosclerotic plaque 18F-NaF uptake was expressed as Corrected Uptake per Lesion (CUL): maximum standard uptake value in each vascular territory subtracted by mean blood pool activity. RESULTS: Mean age was 64 years, 56% male and 96% Caucasian (n = 25). Ninety six per cent of the subjects showed 18F-NaF uptake in the aorta (CUL 0.9 +/- 0.3), 40% in the carotid arteries (median CUL 0.0, IQR 0.0 0.7) and 64% in the coronary arteries (0.4, IQR 0.0-0.6). Individuals with >= five risk factors (60%) had increased overall 18F-NaF uptake (1.1 +/- 0.3 vs. 0.7 +/- 0.3, p < 0.01), which was positively correlated with predicted fatal CV risk SCORE (r = 0.49, p = 0.01). There was no correlation between 18F-NaF uptake in the coronary arteries and calcium score (p = 0.87). Thoracic fat was moderately correlated with overall CUL (r = 0.41, p = 0.04). CONCLUSIONS: In a high CV risk group, 18F-NaF atherosclerotic plaque uptake was related to the burden of CV risk factors and thoracic fat volume, but there was no association between coronary uptake and calcium score. PMID- 28349888 TI - Screening for familial hypercholesterolaemia in childhood: Avon Longitudinal Study of Parents and Children (ALSPAC). AB - BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is an autosomal-dominant disease with frequency of 1/500 to 1/250 that leads to premature coronary heart disease. New approaches to identify FH mutation-carriers early are needed to prevent premature cardiac deaths. In a cross-sectional study of the Avon Longitudinal Study of Parents and Children (ALSPAC), we evaluated the biochemical thresholds for FH screening in childhood, and modelled a two-stage biochemical and sequencing screening strategy for FH detection. METHODS: From 5083 ALSPAC children with cholesterol measurement at age nine years, FH genetic diagnosis was performed in 1512 individuals, using whole-genome or targeted sequencing of known FH-causing genes. Detection rate (DR) and false-positive rate (FPR) for proposed screening thresholds (total-cholesterol > 1.53, or LDL-C > 1.84 multiples of the median (MoM)) were assessed. RESULTS: Six of 1512 sequenced individuals had an FH causing mutation of whom five had LDL-C > 1.84 MoM, giving a verification-bias corrected DR of 62.5% (95% CI: 25-92), with a FPR of 0.2% (95% CI: 0.1-0.4). The DR for the TC cut-point of 1.53 MoM was 25% (95% CI: 3.2-65.1) with a FPR of 0.4% (95% CI: 0.2-0.6). We estimated 13 of an expected 20 FH mutation carriers (and 13 of the 20 parental carriers) could be detected for every 10,000 children screened, with false-positives reliably excluded by addition of a next generation sequencing step in biochemical screen-positive samples. CONCLUSIONS: Proposed cholesterol thresholds for childhood FH screening were less accurate than previously estimated. A sequential strategy of biochemical screening followed by targeted sequencing of FH genes in screen-positive children may help mitigate the higher than previously estimated FPR and reduce wasted screening of unaffected parents. PMID- 28349889 TI - Association between cumulative exposure to ideal cardiovascular health and arterial stiffness. AB - BACKGROUND AND AIMS: Ideal cardiovascular health (CVH) is associated with reduced risk of cardiac and cerebral events. Arterial stiffness plays an important role in the progress of cardiac and cerebral events, but it is unclear whether ideal CVH, in particular, cumulative exposure to ideal CVH (cumCVH), is associated with reduced risk of arterial stiffness. We examined the association between cumCVH and arterial stiffness using data from the Kailuan Study. METHODS: The study cohort consisted of 20,355 participants from the Kailuan community-based cohort, whose mean follow-up period was 3.36 years since baseline (visit 3). CumCVH was calculated as the summed average ideal CVH score between two consecutive visits, multiplied by the time between the two consecutive visits in years. Multivariable linear regression model analysis was used to evaluate the relationship between cumCVH and brachial ankle pulse wave velocity (baPWV).Variance inflation factor (VIF) was calculated to diagnose co-linearity between multiple variables. We also used logistic regression to evaluate the association between cumCVH and arterial stiffness by calculating the crude odds ratio (OR) and adjusted OR, with 95% confidence interval (CI). Sensitivity analysis was performed to test the robustness of our findings. RESULTS: The participants were classified into 5 groups according to the quintile of cumCVH exposure levels. Multivariate linear regression analysis showed that cumCVH had a significant inverse linear relationship with baPWV (B = -3.35, p < 0.001). The result of logistic regression demonstrated that compared with Q1 group,Q3, Q4, Q5 were associated with a 15%, 24%, 36% significantly lower incidence of arterial stiffness, after adjusting for confounders.What is more, the results of sensitivity analysis had no influence on our results. CONCLUSIONS: Exposure to higher cumCVH can prevent the increase in baPWV and reduce the incidence of arterial stiffness. PMID- 28349890 TI - Placental maternal and fetal vascular circulation in healthy non-obese and metabolically healthy obese pregnant women. AB - BACKGROUND AND AIMS: We investigated placental histopathology for lesions that are associated with maternal and fetal circulation abnormalities in obese pregnant women with and without metabolic alterations. METHODS: 332 pregnant women were divided into three groups: Group 1 included 163 non-obese metabolically healthy (NOMH), Group 2 106 obese metabolically healthy (OMH), and Group 3 63 obese metabolically abnormal (OMA) subjects, respectively. RESULTS: Fetal vascular supply (FVS) abnormalities and Willous maturation defect (WMD) rate were higher in obese subjects without metabolic abnormalities, compared to NOMH subjects (p < 0.021 and p < 0.018, respectively). In the logistic regression analysis, obesity emerged as a significant independent predictor of FVS abnormalities (OR 1.54, 95% CI 1.193-1.992, p = 0.001) and WMD (OR 2.004, 95% CI 1.173-3.422, p = 0.011). Although maternal vascular supply (MVS) abnormalities differed significantly across groups (31%, 38% and 54% respectively, p < 0.005), in the logistic regression analysis, obesity was not significantly associated with MVS abnormalities. CONCLUSIONS: We demonstrated that obesity, per se, is associated with an increased rate of placental vascular supply abnormalities and has a more adverse effect on fetal vascular circulation than on maternal vascular supply. PMID- 28349891 TI - The effectiveness of intrauterine insemination: A matched cohort study. AB - OBJECTIVE: To study the effectiveness of an intrauterine insemination (IUI) program compared to no treatment in subfertile couples with unexplained subfertility and a poor prognosis on natural conception. STUDY DESIGN: A retrospective matched cohort study in which ongoing pregnancy rates in 72 couples who voluntarily dropped out of treatment with IUI were compared to ongoing pregnancy rates in 144 couples who continued treatment with IUI. Couples with unexplained subfertility, mild male subfertility or cervical factor subfertility who started treatment with IUI between January 2000 and December 2008 were included. Couples were matched on hospital, age, duration of subfertility, primary or secondary subfertility and diagnosis. Primary outcome was cumulative ongoing pregnancy rate after three years. Time to pregnancy was censored at the moment couples were lost to follow up or when their child wish ended and, for the no-treatment group, when couples re-started treatment. RESULTS: After three years, there were 18 pregnancies in the stopped treatment group (25%) versus 41 pregnancies in the IUI group (28%) (RR 1.1 (0.59-2.2)(p=0.4)). The cumulative pregnancy rate after three years was 40% in both groups, showing no difference in time to ongoing pregnancy (shared frailty model p=0.86). CONCLUSIONS: In couples with unexplained subfertility and a poor prognosis for natural conception, treatment with IUI does not to add to expectant management. There is need for a randomized clinical trial comparing IUI with expectant management in these couples. PMID- 28349892 TI - Impact of antepartum diagnostic amnioinfusion on targeted ultrasound imaging of pregnancies presenting with severe oligo- and anhydramnios: An analysis of 61 cases. AB - OBJECTIVES: The primary objective our study was to assess the role of diagnostic antepartum amnioinfusion on the yield from targeted ultrasounds performed in pregnancies with severe oligo- and anhydramnios. STUDY DESIGN: This was a retrospective and descriptive study, conducted in the fetal medicine units of two private tertiary care referral centers in south India. The details of all the cases of diagnostic amnioinfusion performed at these two centers from January 2009 to June 2016 were collected and analyzed. Inclusion criteria were pregnancies between 17 and 26 weeks of gestational age with severe oligo- or anhydramnios. Pregnancies with obvious preterm premature rupture of membranes (PPROM) were excluded. The primary outcome measure was the improvement in diagnostic information pertaining to cause of severe oligo- and anhydramnios, and the nature of such anomalies. RESULTS: A total of 61 cases of were identified. The median gestational age at performance of the procedure was 22 weeks [IQR, 19.5-23]. The mean volume of normal saline infused was 314+/-54ml. A significant increase in the single vertical pocket (SVP) was observed following the procedure (pre-procedure SVP=0.6+/-0.9cm, post procedure SVP=3.4+/-1.7; paired t test, p<0.001). In 37 cases (37/61, 60.7%), there were no pre-procedure ultrasound findings. There was significant overall detection of abnormalities post procedure (mean pre-procedure findings=0.39+/-0.49, mean post procedure findings=1.59+/ 1.24; paired t test, p<0.001). The most frequent group of anomalies/abnormalities were renal (36/61, 59%), followed by PPROM (13/61, 21.3%) and finally fetal growth restriction (11/61, 18%). CONCLUSION(S): Antepartum amnioinfusion is a valuable ancillary technique in prenatal diagnosis as it increases the diagnostic yield from pregnancies presenting with severe oligo- and anhydramnios. PMID- 28349893 TI - Expression of miRNA-21, miRNA-107, miRNA-137 and miRNA-29b in meningioma. AB - OBJECTIVE: Meningiomas are among the most common intracranial tumors, accounting for 30% of all tumors of the central nervous system. Recent studies analyzing microRNA (miRNA) profiles and functions in cancer have provided valuable information about the molecular pathogenesis of several tumor types, including glioblastoma multiforme (GBM), hepatocellular carcinoma, and breast, lung, colon, and prostate cancer. miRNAs are a family of small, endogenous, noncoding RNAs of 18-25 nucleotides. In this study, we carried out a genome-wide array screen comparing miRNA-21, miRNA-107, miRNA-137 and miRNA-29b expression in meningiomas. PATIENTS AND METHODS: A total of 50 meningioma patients (16 men and 34 women) aged between 32 and 80 years were included. The study was conducted at Istanbul Research and Training Hospital Neurosurgery Clinic. RESULTS: Our results have shown a significant increase in miRNA-21 expression with increasing histopathologic grade, while there was a significant reduction in miRNA-107 expression with the increasing histopathological grade. miRNA-137 and miRNA-29b expression did not differ significantly according to histopathologic grade. CONCLUSION: The subject of our study, i.e. the association between miRNA expression and meningioma, is continuously gaining more importance in the wider context of the recent developments in genetic treatments. PMID- 28349894 TI - Application value of diffusional kurtosis imaging (DKI) in evaluating microstructural changes in the spinal cord of patients with early cervical spondylotic myelopathy. AB - OBJECTIVE: To investigate the application value of diffusional kurtosis imaging (DKI) in evaluating microstructural changes in the spinal cord of patients with early cervical spondylotic myelopathy (CSM). PATIENTS AND METHODS: Twenty-five patients with early clinical stage CSM and twenty-five healthy controls underwent 3.0T MR scans with conventional MRI sequences and DKI with echo-planar imaging (EPI) sequence. DKI metrics such as fractional anisotropy (FA), mean diffusivity (MD), and mean diffusional kurtosis (MK) values were calculated separately for white matter (WM) and gray matter (GM). RESULTS: MK of the WM and GM were significantly higher in patients with early CSM than in healthy controls (P<0.005). CONCLUSIONS: MK can reflect microstructural changes of white matter and gray matter of spinal cord in patients with early CSM and has the potential to provide new information prior to conventional diffusion metrics such as MD and FA. PMID- 28349895 TI - Low temperature magnetic structure of CeRhIn5 by neutron diffraction on absorption-optimized samples. AB - Two aspects of the ambient pressure magnetic structure of heavy fermion material CeRhIn5 have remained under some debate since its discovery: whether the structure is indeed an incommensurate helix or a spin density wave, and what is the precise magnitude of the ordered magnetic moment. By using a single crystal sample optimized for hot neutrons to minimize neutron absorption by Rh and In, here we report an ordered moment of [Formula: see text]. In addition, by using spherical neutron polarimetry measurements on a similar single crystal sample, we have confirmed the helical nature of the magnetic structure, and identified a single chiral domain. PMID- 28349896 TI - Reliable underwater dipole source characterization in 3D space by an optimally designed artificial lateral line system. AB - Inspired by the lateral line of aquatic vertebrates, an artificial lateral line (ALL) system can localize and track an underwater moving object by analyzing the ambient flow caused by its motion. There are several studies on object detection, localization and tracking by ALL systems, but only a few have investigated the optimal design of the ALL system, the one that on average provides the highest characterization accuracy. Design optimization is particularly important because the uncertainties in the employed flow model and in sensor measurements deteriorate the reliability of sensing. This study investigates the optimal design of the ALL system in three-dimensional (3D) space for dipole source characterization. It highlights some challenges specific to the 3D setting and demonstrates the shortcomings of the designs in which all sensors and their sensing directions are in the same plane. As an alternative, it proposes two design concepts, called 'Offset Strategy' and 'Angle Strategy' to overcome these shortcomings. It investigates potentials of having a swarm of cooperative ALLs as well. It performs design optimization in the presence of sensor and model uncertainties and analyzes the trade-off between the number of sensors and characterization accuracy. The obtained solutions are analyzed to reveal their strategies in solving the problem efficiently. The dependency of the optimized solutions on the uncertainties is also demonstrated. PMID- 28349897 TI - 3D printing scaffold coupled with low level light therapy for neural tissue regeneration. AB - 3D printing has shown promise for neural regeneration by providing customized nerve scaffolds to structurally support and bridge the defect gap as well as deliver cells or various bioactive substances. Low-level light therapy (LLLT) exhibits positive effects on rehabiliation of degenerative nerves and neural disorders. With this in mind, we postulate that 3D printed neural scaffold coupling with LLLT will generate a new strategy to repair neural degeneration. To achieve this goal, we applied red laser light to stimualte neural stem cells on 3D printed scaffolds and investigated the subsequent cell response with respect to cell proliferation and differentiation. Here we show that cell prolifeartion rate and intracellular reactive oxgen species synthesis were significantly increased after 15 s laser stimulation follwed by 1 d culture. Over culturing time of 14 d in vitro, the laser stimulation promoted neuronal differentiation of neural stem cells, while the glial differentiation was suppressed based on results of both immunocytochemistry studies and real-time quantitative reverse transcription polymerase chain reaction testing. These findings suggest that integration of 3D printing and LLLT might provide a powerful methodology for neural tissue engineering. PMID- 28349898 TI - Microscopic theory of the Coulomb based exchange coupling in magnetic tunnel junctions. AB - We study interlayer exchange coupling based on the many-body Coulomb interaction between conduction electrons in magnetic tunnel junction. This mechanism complements the known interaction between magnetic layers based on virtual electron hopping (or spin currents). We find that these two mechanisms have different behavior on system parameters. The Coulomb based coupling may exceed the hopping based exchange. We show that the Coulomb based exchange interaction, in contrast to the hopping based coupling, depends strongly on the dielectric constant of the insulating layer. The dependence of the interlayer exchange interaction on the dielectric properties of the insulating layer in magnetic tunnel junction is similar to magneto-electric effect where electric and magnetic degrees of freedom are coupled. We calculate the interlayer coupling as a function of temperature and electric field for magnetic tunnel junction with ferroelectric layer and show that the exchange interaction between magnetic leads has a sharp decrease in the vicinity of the ferroelectric phase transition and varies strongly with external electric field. PMID- 28349899 TI - Analysis of the time-resolved magneto-optical Kerr effect for ultrafast magnetization dynamics in ferromagnetic thin films. AB - We discuss fundamental aspects of laser-induced ultrafast demagnetization probed by the time-resolved magneto-optical Kerr effect (MOKE). Studying thin Fe films on MgO substrate in the absence of electronic transport, we demonstrate how to disentangle pump-induced variations of magnetization and magneto-optical coefficients. We provide a mathematical formalism for retrieving genuine laser induced magnetization dynamics and discuss its applicability in real experimental situations. We further stress the importance of temporal resolution achieved in the experiments and argue that measurements of both time-resolved MOKE rotation and ellipticity are needed for the correct assessment of magnetization dynamics on sub-picosecond timescales. The framework developed here sheds light onto the details of the time-resolved MOKE technique and contributes to the understanding of the interplay between ultrafast laser-induced optical and magnetic effects. PMID- 28349900 TI - Structural monitoring and modeling of the mechanical deformation of three dimensional printed poly(epsilon-caprolactone) scaffolds. AB - Three-dimensional (3D) printed poly(epsilon-caprolactone) (PCL) based scaffolds have being proposed for different tissue engineering applications. This study addresses the design and fabrication of 3D PCL constructs with different struts alignments at 90 degrees , 45 degrees and 90 degrees with offset. The morphology and the mechanical behavior under uniaxial compressive load were assessed at different strain percentages. The combination of a new compressionCT device and micro computed tomography (micro-CT) allowed understanding the influence of pore geometry under controlled compressive strain in the mechanical and structural behavior of PCL constructs. Finite element analysis (FEA) was applied using the micro-CT data to modulate the mechanical response and compare with the conventional uniaxial compression tests. Scanning electron microscopic analysis showed a very high level of reproducibility and a low error comparing with the theoretical values, confirming that the alignment and the dimensional features of the printed struts are reliable. The mechanical tests showed that the 90 degrees architecture presented the highest stiffness. With the compressionCT device was observed that the 90 degrees and 90 degrees with offset architectures presented similar values of porosity at same strain and similar pore size, contrary to the 45 degrees architecture. Thus, pore geometric configurations affected significantly the deformability of the all PCL scaffolds under compression. The prediction of the FEA showed a good agreement to the conventional mechanical tests revealing the areas more affected under compression load. The methodology proposed in this study using 3D printed scaffolds with compressionCT device and FEA is a framework that offers great potential in understanding the mechanical and structural behavior of soft systems for different applications, including for the biomedical engineering field. PMID- 28349901 TI - Etiologic Association between Epstein-Barr Virus and Oral Squamous Cell Carcinoma: A Brief Evidence-based Discussion. AB - Epstein-Barr virus (EBV), also known as human herpes virus-4, belongs to the gamma-subfamily of herpes viruses.1 Nearly 90 to 95% of the world's adult population is an asymptomatic carrier of EBV.1-3. PMID- 28349902 TI - Ozone Gas Effect on Mineral Content of Dentin exposed to Streptococcus mutans Biofilm: An Energy-dispersive X-ray Evaluation. AB - AIM: This study aims to assess the effect of ozone gas on dentin exposed to Streptococcus mutans biofilm by evaluation of mineral content [log calcium-to phosphorus (Ca/P)] using energy-dispersive X-ray (EDX) spectroscopy. MATERIALS AND METHODS: Five human third molars were sectioned into four slices of dentin and distributed in four groups: I - control (no treatment); II - ozone therapy; III - biofilm development; IV - ozone therapy followed by biofilm development. Mineral content (log Ca/P) was evaluated by EDX. Data were analyzed by analysis of variance and Tukey's test (p < 0.05). RESULTS: Results showed that the mineral content of control group (I) was similar to ozone group (II), and was statistically higher than biofilm (III) and ozone + biofilm (IV). The lowest log Ca/P was determined in biofilm group (III). CONCLUSION: It can be concluded that ozone gas did not grant preventive effects of demineralization by S. mutans biofilm on dentin surface. CLINICAL SIGNIFICANCE: Ozone gas therapy may be an alternative noninvasive treatment aiming to reduce the levels of caries associated microorganisms. This therapy may, thereby, be an alternative and/or complementary treatment strategy in preventive dentistry. PMID- 28349903 TI - Presence of Metallic Microfragments on Dentinal Walls and Instrument Defects following Root Canal Preparation. AB - AIM: To determine the presence of metallic microfragments and their elemental composition in the dentinal walls of root canals following preparation using different endodontic instruments and to assess the active cutting edges of instruments with regard to structural defects. MATERIALS AND METHODS: A total of 108 molar teeth were selected and prepared using different endodontic instruments. Teeth were randomly divided into nine groups of 12 teeth each, according to the instruments employed: Manual systems -K-FlexoFile, K-File, and Hedstroem; rotary systems - ProTaper Next, Mtwo, BioRaCe; and reciprocating systems - Reciproc, Unicone, and WaveOne. Both root canals and instruments were assessed using scanning electron microscopy, and the elemental composition of metallic microfragments was determined using energy-dispersive X-ray spectroscopy. RESULTS: Metallic microfragments were found in the groups prepared with both manual and reciprocating instruments, with no statistically significant differences between groups, thirds, or presence of metallic microfragments (p >= 0.05). Moreover, all groups presented structural defects in both new and used instruments; however, rotary instruments (ProTaper Next, Mtwo 702, BioRaCe) were the ones with the lowest number of defects, at statistically significant differences in comparison with other instruments (p < 0.05). CONCLUSION: The presence of metallic microfragments on dentinal walls following root canal preparation was associated with manual and reciprocating instrumentation. Furthermore, rotary instruments were the ones with the lowest number of defects. Considering the outcomes measured in this study, rotary instruments performed better than the other two groups, as they were associated with the lowest number of metallic microfragments and structural defects. CLINICAL SIGNIFICANCE: During root canal preparation, operative procedures may induce changes to the root canal shape, as well as the release of metallic fragments resulting from the action of instruments on dentinal walls. Therefore, it is important to determine, among the different techniques used for this purpose, which ones are least susceptible to this occurrence. PMID- 28349904 TI - Relation between Dental Caries and Body Mass Index-for-age among Schoolchildren of Jazan City, Kingdom of Saudi Arabia. AB - OBJECTIVE: To analyze and report the type of relation present between dental caries and body mass index (BMI)-for-age among schoolchildren in Jazan region of Kingdom of Saudi Arabia. MATERIALS AND METHODS: A cross-sectional study with multi-staged random sampling technique was designed to recruit the sample of schoolchildren. Caries was examined using the World Health Organization recommended "decayed and filled teeth"/"decayed missing and filled teeth (dft/DMFT)" method. The BMI-for-age was calculated using the value obtained from body weight and height (kg/m2) of each child. The obtained results were plotted on age- and gender-specific percentile curves by the Centers for Disease Control and Prevention and categorized accordingly. Chi-squared test was conducted to analyze the relation between BMI-for-age and dental caries. Logistic regression was performed to judge the predictor variables. The p-value < 0.05 was considered as significant. RESULTS: A total of 360 children were part of this study with equal recruitment from both genders. The mean dft/DMFT value for girls (2.52) was more than that for boys (1.88); and the (p = 0.00) calculated value was statistically significant. Most of the children had normal BMI-for-age (60.6%) and very few were obese (4.7%). Dental caries, fast food, and snacks between meals were significant independent predictor variables for BMI (p < 0.05). Dental caries was a strong predictor, and the analysis showed that children with untreated caries had 81% (odds ratio = 0.19; confidence interval = 0.65, 0.58) higher chance of suffering from low BMI. CONCLUSION: To conclude, this is the first study attempted to see the relationship between BMI-for-age and dental caries among schoolchildren in Jazan city of Kingdom of Saudi Arabia. Negative relation between dental caries and BMI should warrant health promoters about dental caries as a reason for low BMI in a subset of children. CLINICAL SIGNIFICANCE: High and alarming percentage of untreated dental caries demonstrates the oral health needs among the schoolgoing children in Jazan region. Public health dentists should develop and implement prevention programs so that the oral health issues among schoolchildren are addressed. PMID- 28349905 TI - Influence of Mechanical and Chemical Degradation in the Surface Roughness, Gloss, and Color of Microhybrid Composites. AB - AIM: The aim of this study was to investigate the association of different degradations on the roughness, gloss, and color changes of microhybrid composites. MATERIALS AND METHODS: Ten specimens were prepared for Charisma, Amelogen Plus, Point 4, and Opallis resins. Surfaces were polished and baseline measurements of roughness, gloss, and color were recorded. Specimens were then submitted to chemical and mechanical challenges, and the specimens were reevaluated. Roughness and gloss were analyzed by Kruskal -Wallis and Dunn's test (p < 0.05). Color change (DeltaE) was analyzed by one-way analysis of variance and Tukey's tests (p < 0.05). The initial and final data were compared using the Wilcoxon test (p < 0.05). Spearman test checked the correlation between the roughness and gloss (p < 0.05). RESULTS: Regarding surface roughness and gloss, there was no difference between composites before challenges. However, all composites showed a significant increase of roughness after challenges, with highest values for Charisma. The gloss was influenced by challenges, evidencing the best gloss for Point 4. Charisma showed the highest value of color change. There was no correlation between surface roughness and gloss for the initial analysis, and after the challenges. CONCLUSION: Composites were influenced by association of challenges, and Charisma showed the highest changes for roughness, gloss, and color. CLINICAL SIGNIFICANCE: The type of composite resin influenced the properties of materials, which are surface roughness, gloss, and color change. The dentist should be aware of the performance of different brands, to choose the correct required composite resin for each type of patient or region to be restored. PMID- 28349907 TI - Wire Roughness Assessment of 0.016'' * 0.022'' the Technique Lingual Orthodontics. AB - OBJECTIVE: To evaluate the difference in surface roughness of stainless steel archwires of different commercial brands used in lingual orthodontics. MATERIALS AND METHODS: Precontoured arches measuring 0.016'' * 0.022'' were selected of the following brands: Tecnident, Adenta, G&H, Highland Metals Inc., Ormco, Incognito, and Ebraces. Quantitative evaluation of the surface roughness of archwires was performed by means of an atomic force microscope in contact mode. Three surface readouts were taken of each sample, analyzing areas of 20 * 20 MUm. Each scan of the samples produced a readout of 512 lines, generating three-dimensional images of the wires. The analysis of variance statistical test was applied to prove significant variables (p > 0.05), with H0 being rejected and H1 accepted. RESULTS: The Incognito brand showed the lowest surface roughness. The archwires of brands Adenta, Tecnident, Highland, and Ormco showed similar values among them, and all close to these obtained by the Incognito brand. The archwires of the Ebraces brand showed the highest surface roughness, with values being close to those of the G&H Brand. CONCLUSION: There was a statistical difference in surface roughness of orthodontic archwires among the brands studied. CLINICAL SIGNIFICANCE: Companies should pay attention to the quality control of their materials, as these may directly affect the quality of orthodontic treatment. PMID- 28349906 TI - Effect of Sodium Hypochlorite on Push-out Bond Strength of Four Calcium Silicate based Endodontic Materials when used for repairing Perforations on Human Dentin: An in vitro Evaluation. AB - AIM: This study aimed to evaluate the push-out bond strength of NeoMTA Plus (NMTA), EndoSequence root repair material fast set putty (ERRMF), biodentine (BD), and ProRoot white mineral trioxide aggregate (PMTA) when used as perforation repair materials after exposure to 2.5% sodium hypochlorite (NaOCl) during the early setting phase. MATERIALS AND METHODS: Horizontal midroot sections were prepared from single-rooted human teeth. Sections (n = 144) were randomly divided into four groups: PMTA, BD, NMTA, and ERRMF. Materials were condensed and allowed to set for 10 minutes. The groups were further divided into two subgroups. The NaOCl group included specimens that were immersed in 2.5% NaOCl for 30 minutes, and the control group included specimens on which a wet cotton pellet was placed over the test material. After 48 hours, the highest force applied to the materials at the time of dislodgement was recorded. Slices were then examined under a digital microscope to evaluate the nature of the bond failure. The surfaces of two specimens from each subgroup were observed by scanning electron microscopy. Data were statistically analyzed with two-way and one-way analysis of variances, independent t-tests, and chi-square tests. The statistical significance was set at 0.05. RESULTS: In NaOCl-treated groups, PMTA showed a significantly higher push-out bond strength than the other three materials (p = 0.00). In the control groups, the bond strength of BD was significantly higher than that of PMTA, ERRMF, and NMTA (p < 0.05). Compared with the control group, NaOCl treatment significantly increased the push-out bond strength of PMTA (p = 0.00) and ERRMF (p = 0.00) and significantly reduced the bond strength of BD (p = 0.00) and NMTA (p = 0.03). None of the specimens showed an adhesive type of failure. The majority of the samples exhibited a cohesive failure type. Morphological observations revealed that the surfaces exhibited cubic crystals. In ERRMF, the crystals were few in number. Sodium hypochlorite enhanced the crystallization of NMTA. CONCLUSION: The push-out bond strengths of PMTA and ERRMF were significantly increased after exposure to 2.5% NaOCl in the early setting phase, and those of BD and NMTA were significantly decreased. CLINICAL SIGNIFICANCE: The results of the present study suggest that early exposure of NaOCl increase the push-out bond strength of PMTA and ERRMF. PMTA had the highest push-out values. Therefore, it would be a potentially useful perforation repair material for single visit endodontic treatment. PMID- 28349908 TI - Comparison of Fluoridated Miswak and Toothbrushing with Fluoridated Toothpaste on Plaque Removal and Fluoride Release. AB - INTRODUCTION: Dental caries and periodontal diseases are all induced by oral biofilm (dental plaque). This study was conducted to evaluate if fluoride impregnated miswak is as effective in plaque removal and fluoride release as toothbrushing with fluoride toothpaste. MATERIALS AND METHODS: This single-blind, randomized, crossover study was conducted at the Department of Cariology, University of Gothenburg, Gothenburg, Sweden, from February 2010 to January 2011. Fifteen healthy subjects participated in this study. The participants were instructed to use the following: (1) 0.5% NaF-impregnated miswak, (2) nonfluoridated miswak, (3) toothbrush with nonfluoride toothpaste, and (4) toothbrush with 1450 ppm fluoride toothpaste. Each method was used twice a day for 1 week after which plaque amount and fluoride concentration in resting saliva were measured. There was a 1-week washout period between each method. RESULTS: No significant difference between miswak and tooth-brushing was found regarding plaque removal on buccal and lingual surfaces. A somewhat higher fluoride concentration in resting saliva was found after using impregnated miswak when compared with toothbrushing with fluoride toothpaste (p < 0.05). CONCLUSION: Miswak and toothbrushing showed the same plaque removing effect on buccal and lingual surfaces. Miswak impregnated with 0.5% NaF resulted in a higher concentration of fluoride in saliva than brushing with 1450 ppm fluoride toothpaste. CLINICAL SIGNIFICANCE: Miswak impregnated with 0.5% NaF and toothbrushing results in comparable plaque removal and about the same fluoride concentration in saliva even it was somewhat higher for impregnated miswak. PMID- 28349909 TI - Cariogenic Potential of the commonly Prescribed Pediatric Liquid Medicaments in Kingdom of Saudi Arabia: An in vitro Study. AB - AIM: The aim of this study was to assess the cariogenic potential of the commonly prescribed pediatric liquid medicaments (PLMs) for dental disease in Jazan region, Kingdom of Saudi Arabia. MATERIALS AND METHODS: Seven most commonly prescribed PLMs were selected by prior questioning the pediatric dentists as well as general dentists in Jazan region. The endogenous pH and sucrose concentrations of the liquid medicaments were assessed. The endogenous pH was assessed by Hanna pH meter instrument. The sucrose concentration was assessed by anthrone reagent method. RESULTS: All the PLM were acidic. The pH of the PLM ranged from 4.22 to 6.10. All the PLM contained sucrose and its concentration ranged from 5.38 to 11.41 gm% in the samples. CONCLUSION: In this study, all the PLM were acidic and contained sucrose. Hence, they have cariogenic potential. CLINICAL SIGNIFICANCE: Parents and dentists are unaware of the hidden sugars and cariogenicity of these medications. Strict oral hygiene instructions are mandatory for the children taking these medications. The use of PLM should also be minimized and parents should seek early dental treatment to restore child's oral health. PMID- 28349910 TI - Good Bugs vs Bad Bugs: Evaluation of Inhibitory Effect of Selected Probiotics against Enterococcus faecalis. AB - INTRODUCTION: The main goal of endodontics is the prevention of apical periodontitis. This is due to the presence of persistent pathogenic microorganisms, such as Enterococcus faecalis, and its ability to directly cause acute and chronic inflammation in the periapical tissues. Lactobacillus has been shown to promote health in the intestines as well as to inhibit the growth of certain problematic oral bacteria. This study explores shifting the established paradigm of endodontic treatment, which has focused on eliminating all bacteria from the canal system and on elimination of the problematic bacteria through introducing probiotics. A preliminary work was performed to evaluate the possible effectiveness of probiotics in preventing the growth of E. faecalis. MATERIALS AND METHODS: Two probiotic cultures Lactobacillus plantarum ATCC 8041 and Lactobacillus rhamnosus ATCC 7408 were selected to check their antimicrobial activity against E. faecalis ATCC 29212 by two methods: agar cup/well diffusion method and deferred antagonism test. Agar cup method: A total of 0.5 mL of requisite test pathogen culture was inoculated into 20 mL of molten sterile Mueller and Hinton agar and cooled to 45 +/- 2 degrees C. Circular wells of diameter 10 mm were punched in each of the poured plates. Appropriately diluted test samples were added to the above-punched wells. The plates were incubated upright position at 37 degrees C for 24 hours in aerobic conditions. Postincubation, zone of inhibition was measured. The cell-free supernatant of Lactobacillus species was also evaluated for antimicrobial activity. Deferred antagonism test: The test probiotic strain was standardized to 0.1 optical density (OD) at 600 nm and inoculated in a 1 cm wide diametric streak across the surface of trypticase soy agar + yeast extract + calcium carbonate (TSYCa) agar using a sterile cotton swab. Then, the plate agar containing the test strain was incubated at 37 degrees C for 24 hours under aero-philic condition and then standardized to 0.1 OD at 600 nm for overnight (18 hours, 37 degrees C). A purified culture of indicator strain (pathogen) was streaked at right angles to the line of original producer growth. Postincubation plates were observed for the inhibition zone width of the indicator strain. RESULTS: Under the conditions of this study, Lactobacilli had an inhibitory effect on the growth of E. faecalis by agar cup method but not by deferred antagonism test. CONCLUSION: This pilot study demonstrated that probiotics show a potential in root canal therapy. CLINICAL SIGNIFICANCE: If probioitcs are effective against end-odontic pathogens, they can be potentially used as intracanal medicaments. This will be a novel concept of introducing bac-teriotherapy in endodontics and replacing pathogenic bacteria by healthy bacteria, normal flora. PMID- 28349911 TI - Evaluation of Soft Tissue Landmark Reliability between Manual and Computerized Plotting Methods. AB - AIM: The aim of the study is to evaluate the reliability of soft tissue landmark identification between manual and digital plot-tings in both X and Y axes. MATERIALS AND METHODS: A total of 50 pretreatment lateral cephalograms were selected from patients who reported for orthodontic treatment. The digital images of each cephalogram were imported directly into Dolphin software for onscreen digi-talization, while for manual tracing, images were printed using a compatible X-ray printer. After the images were standardized, and 10 commonly used soft tissue landmarks were plotted on each cephalogram by six different professional observers, the values obtained were plotted in X and Y axes. Intraclass correlation coefficient was used to determine the intrarater reliability for repeated landmark plotting obtained by both the methods. RESULTS: The evaluation for reliability of soft tissue landmark plottings in both manual and digital methods after subjecting it to interclass correlation showed a good reliability, which was nearing complete homogeneity in both X and Y axes, except for Y axis of throat point in manual plotting, which showed moderate reliability as a cephalometric variable. Intraclass correlation of soft tissue nasion had a moderate reliability along X axis. Soft tissue pogonion shows moderate reliability in Y axis. Throat point exhibited moderate reliability in X axis. CONCLUSION: The interclass correlation in X and Y axes shows high reliability in both hard tissue and soft tissue except for throat point in Y axis, when plotted manually. The intraclass correlation is more consistent and highly reliable for soft tissue landmarks and the hard tissue landmark identification is also consistent. CLINICAL SIGNIFICANCE: The results obtained for manual and digital methods were almost similar, but the digital landmark plotting has an added advantage in archiving, retrieval, transmission, and can be enhanced during plotting of lateral cephalograms. Hence, the digital method of landmark plotting could be preferred for both daily use and research because of the advantages. PMID- 28349912 TI - Correlation of Orthodontic Treatment by Fixed or Myofunctional Appliances and Periodontitis: A Retrospective Study. AB - INTRODUCTION: Malocclusion plays an important role in the development of periodontitis. Thus, by treating malocclusion, a good gingival health can be achieved. This study was conducted to establish the correlation between orthodontic tooth movement and periodontitis. MATERIALS AND METHODS: This is a retrospective study conducted on 220 patients who underwent orthodontic treatment for malocclusion. They were divided into two groups: Group I patients were treated with fixed orthodontics, while group II patients received myofunctional appliances. RESULTS: The value for plaque, gingival recession, and tooth mobility significantly increased in group I patients. However, the difference was statistically nonsignificant in group II patients. CONCLUSION: The authors concluded that there is correlation between malocclusion and periodontitis. Malocclusion leads to periodontitis. CLINICAL SIGNIFICANCE: Malocclusion is the main reason for the development of poor periodontal health. Combined effort has to be played by both periodontist and orthodontist for the treatment of various orthodontic-periodontal problems. PMID- 28349913 TI - Establishing Apical Patency: To be or not to be? AB - INTRODUCTION: The apical portion of the root canal is very complex and challenging during endodontic treatment. Root canal preparation and obturation to the apical constriction may provide the best prognosis. Incomplete debridement, foramen transportation, and inadequate seal in the apical portion are considered to be responsible for treatment failure. The technique "apical patency" is considered as a way for maintaining the apical part the free of the debris by recapitulation, using a small K-file through the area of the apical foramen. This term was firstly proposed by Buchanan. In this technique, the smallest diameter file is set 1 mm longer than working length and recapitulated after each instrument to prevent packing of debris in the apical part. Apical patency has been found to be effective in achieving an apical seal with gutta-percha. Teeth prepared with a step back method and with maintained apical patency may show less leakage when obturated with cold lateral condensation technique. Data regarding the effect of apical patency on the healing of periapical tissue are very scarce, and it has been shown that the patency file has detrimental effect on the healing of periapical tissues in animal studies. However, using patency file in endodontic treatment is controversial and further studies are needed. The purpose of this article is to review the effect of using a patency file on the extrusion of root canal contents, the apical seal, postoperative pain, and healing of periapical tissues. Furthermore, the effect of establishing patency on reaching irrigation solutions to the apical portion of the canal and prognosis of root canal treatment are discussed. CLINICAL SIGNIFICANCE: Keywords: Apical patency, Apical seal, Apical transportation, Postoperative pain, Prognosis. PMID- 28349914 TI - Outcome of Single- vs Multiple-visit Endodontic Therapy of Nonvital Teeth: A Meta analysis. AB - INTRODUCTION: Endodontic therapy is a specialized procedure more demanded by patients within public oral health care in the country. Then, single-visit endodontic therapy may offer advantages to the health care services, to the professionals, and to the patients by reducing access barriers. MATERIALS AND METHODS: A meta-analysis was done and the variables evaluated were periapical repair, microbiological control, and postobturation pain in randomized clinical trials (RCTs) involving endodontic treatment of nonvital teeth at single- or multiple visits. RESULTS: About 17 RCTs were included. There were no differences found in periapical repair or microbiological control in single- and multiple visit therapy. Single-visit endodontic therapy resulted in 21% less postobturation pain (relative risks = 0.79; 95%, confidence interval: 0.66-0.94). CONCLUSION: There was less postobturation pain in the single-visit endodontic therapy group. In the public dental care, this analysis favors the adoption of this one therapy because it will be possible to increase the patient access and the supply of this therapy. CLINICAL SIGNIFICANCE: It is possible to get a better cost-effectiveness for the patients and the health care service. This is very important because the reduction of the cost to the patient allows it to become a complete treatment. The health service, in turn, is able to be better used, with a greater supply of this service. PMID- 28349916 TI - Twelve Impacted Supernumerary Teeth in a Nonsyndromic Patient: A Rare Case Report. AB - Teeth in excess number than the normal count are called supernumerary teeth. They can be either unilateral or bilateral and single or multiple, found at any place in the dental arch, but most commonly found in the anterior maxillary region. Supernumerary teeth are commonly associated with syndromes when present in more numbers, but can be idiopathic. The present study shows a case report of a 16 year-old female patient who reported with overretained deciduous teeth. A panoramic radiograph showed multiple impacted supernumerary teeth. Based on clinical features and radiographic examination, a diagnosis of idiopathic hyperdontia was given. In such types of patients, management must be planned by a multidisciplinary approach. PMID- 28349915 TI - Use of Mini-anchors and Rehabilitation with 0 degrees Cusp Angle Teeth Complete Denture in Recurrent Condylar Dislocation: Technical Adequacy and Procedure. AB - AIM: To report a case of association between the surgical treatment of temporomandibular dysfunction and rehabilitation with denture total prosthesis (TP) using nonanatomic teeth (cusp 0 degrees ) in patients with anterior recurrent dislocation of the temporo-mandibular joint (TMJ) and persistent uncontrolled mandibular movement, showing a technical adaptation and conduct. INTRODUCTION: There are several treatment approaches available for dislocation of the TMJ. The use of condylar mini-anchors for recurrent TMJ dislocation is a valid option and should be considered since it does not alter the joint anatomy. In edentulous patients undergoing TMJ surgical procedures, prosthetic rehabilitation can be seen as a means of treatment preservation. CASE REPORT: A 73-year-old female patient attended the oral and maxillofacial surgery clinic presenting with joint instability, ligament laxity, and chronic recurrent TMJ dislocations. She had already been through three previous unsuccessful surgical procedures. A treatment plan was done based on the installation of a mini-anchor in the patient's TMJ through the preauricular surgical access. Dislocations were then resolved, but the lack of mandibular control even to a lesser extent after surgery precluded the use of prosthetics even at rest. Thus, it was planned to manufacture two conventional TPs with 0 degrees cusp angle teeth, a clinical protocol shortened to three sessions in an attempt to improve the stability of the prosthesis. CONCLUSION: The use of an individual mini-anchor is simple and effective, and the use of artificial teeth is well suited to the case. CLINICAL SIGNIFICANCE: A multidisciplinary intervention (surgery/ prosthesis) is of utmost importance for the resolution and preservation of the treatment of these complex cases. PMID- 28349917 TI - Emperipolesis: An Unreported Novel Phenomenon in Oral Squamous Cell Carcinoma. AB - Emperipolesis is a phenomenon characterized by engulfment of hematopoietic cells by megakaryocytes, monocytes, fibroblasts, and malignant cells within their cytoplasm. This phenomenon has been reported in various physiological and pathological conditions including malignancies. However, emperipolesis has never been reported in oral squamous cell carcinoma (OSCC) till date. We have analyzed histopathological slides of 56 cases of OSCC to see lymphocyte engulfment by tumor cells. Five cases showing features of this phenomenon were observed. Lymphocytes were typically identified as small round cells with oval nuclei and scanty cytoplasm. Both partial and complete engulfment of lymphocytes by tumor cells was appreciated. Nuclei of the host tumor cells were crescent shaped and illustrated small concave indentation, so as to accommodate the internalized lymphocyte. The intercellular bridges were not seen between the internalized cell and the host cell. There were no signs of degeneration appreciable in either cell, thus ruling out the possibility of cannibalism phenomenon. Although emperipolesis is a well-known phenomenon in pathology, this is the first report showing its evidence in OSCC. PMID- 28349918 TI - Land-use types and soil chemical properties influence soil microbial communities in the semiarid Loess Plateau region in China. AB - Similar land-use types usually have similar soil properties, and, most likely, similar microbial communities. Here, we assessed whether land-use types or soil chemical properties are the primary drivers of soil microbial community composition, and how changes in one part of the ecosystem affect another. We applied Ion Torrent sequencing to the bacterial and fungal communities of five different land-use (vegetation) types in the Loess Plateau of China. We found that the overall trend of soil quality was natural forest > plantation > bare land. Dominant bacterial phyla consisted of Proteobacteria (42.35%), Actinobacteria (15.61%), Acidobacteria (13.32%), Bacteroidetes (8.43%), and Gemmatimonadetes (6.0%). The dominant fungi phyla were Ascomycota (40.39%), Basidiomycota (38.01%), and Zygomycota (16.86%). The results of Canonical Correspondence Analysis (CCA) and Redundancy Analysis (RDA) based on land-use types displayed groups according to the land-use types. Furthermore, the bacterial communities were mainly organized by soil organic carbon (SOC). The fungal communities were mainly related to available phosphorus (P). The results suggested that the changes of land use type generated changes in soil chemical properties, controlling the composition of microbial community in the semiarid Loess Plateau region. The microbial community could be an indicator for soil quality with respect to ecological restoration. PMID- 28349919 TI - Checking behavior in rhesus monkeys is related to anxiety and frontal activity. AB - When facing doubt, humans can go back over a performed action in order to optimize subsequent performance. The present study aimed to establish and characterize physiological doubt and checking behavior in non-human primates (NHP). We trained two rhesus monkeys (Macaca mulatta) in a newly designed "Check or-Go" task that allows the animal to repeatedly check and change the availability of a reward before making the final decision towards obtaining that reward. By manipulating the ambiguity of a visual cue in which the reward status is embedded, we successfully modulated animal certainty and created doubt that led the animals to check. This voluntary checking behavior was further characterized by making EEG recordings and measuring correlated changes in salivary cortisol. Our data show that monkeys have the metacognitive ability to express voluntary checking behavior similar to that observed in humans, which depends on uncertainty monitoring, relates to anxiety and involves brain frontal areas. PMID- 28349920 TI - Profiling the MAPK/ERK dependent and independent activity regulated transcriptional programs in the murine hippocampus in vivo. AB - Activity-dependent alteration of the transcriptional program is central for shaping neuronal connectivity. Constitutively expressed transcription factors orchestrate the initial response to neuronal stimulation and serve as substrates for second messenger-regulated kinase signalling cascades. The mitogen-activated protein kinase ERK conveys signalling from the synapse to the nucleus but its genetic signature following neuronal activity has not been revealed. The goal of the present study was to identify ERK dependent and independent activity regulated transcriptional programs in the murine hippocampus. We used generalized seizures combined with the pharmacological intervention of MEK activation as an in vivo model to determine the complete transcriptional program initiated by ERK after neuronal activity. Our survey demonstrates that the induction of a large number of activity-regulated genes, including Arc/Arg3.1, Arl5b, Gadd45b, Homer1, Inhba and Zwint, is indeed dependent on ERK phosphorylation. In contrast, expression of a small group of genes, including Npas4, Arl4d, Errfi1, and Rgs2, is only partially dependent or completely independent (Ppp1r15a) of this signalling pathway. Among the identified transcripts are long non-coding (lnc) RNAs and induction of LincPint and splice variants of NEAT1 are ERK dependent. Our survey provides a comprehensive analysis of the transcriptomic response conveyed by ERK signalling in the hippocampus. PMID- 28349923 TI - Quantifying edge significance on maintaining global connectivity. AB - Global connectivity is a quite important issue for networks. The failures of some key edges may lead to breakdown of the whole system. How to find them will provide a better understanding on system robustness. Based on topological information, we propose an approach named LE (link entropy) to quantify the edge significance on maintaining global connectivity. Then we compare the LE with the other six acknowledged indices on the edge significance: the edge betweenness centrality, degree product, bridgeness, diffusion importance, topological overlap and k-path edge centrality. Experimental results show that the LE approach outperforms in quantifying edge significance on maintaining global connectivity. PMID- 28349921 TI - Efficient affinity maturation of antibody variable domains requires co-selection of compensatory mutations to maintain thermodynamic stability. AB - The ability of antibodies to accumulate affinity-enhancing mutations in their complementarity-determining regions (CDRs) without compromising thermodynamic stability is critical to their natural function. However, it is unclear if affinity mutations in the hypervariable CDRs generally impact antibody stability and to what extent additional compensatory mutations are required to maintain stability during affinity maturation. Here we have experimentally and computationally evaluated the functional contributions of mutations acquired by a human variable (VH) domain that was evolved using strong selections for enhanced stability and affinity for the Alzheimer's Abeta42 peptide. Interestingly, half of the key affinity mutations in the CDRs were destabilizing. Moreover, the destabilizing effects of these mutations were compensated for by a subset of the affinity mutations that were also stabilizing. Our findings demonstrate that the accumulation of both affinity and stability mutations is necessary to maintain thermodynamic stability during extensive mutagenesis and affinity maturation in vitro, which is similar to findings for natural antibodies that are subjected to somatic hypermutation in vivo. These findings for diverse antibodies and antibody fragments specific for unrelated antigens suggest that the formation of the antigen-binding site is generally a destabilizing process and that co-enrichment for compensatory mutations is critical for maintaining thermodynamic stability. PMID- 28349922 TI - Coumarin-chalcone hybrid instigates DNA damage by minor groove binding and stabilizes p53 through post translational modifications. AB - S009-131, a coumarin-chalcone hybrid, had been shown to possess anti proliferative and anti-tumour effect by triggering apoptosis. In this report, we investigated role of DNA damage signalling pathway in S009-131 induced cancer cell death. Here we show that S009-131 causes DNA damage by potential binding to the minor groove which led to the phosphorylation and activation of ATM and DNA PK, but not ATR, at earlier time points in order to initiate repair process. S009 131 induced DNA damage response triggered activation of p53 through phosphorylation at its key residues. Pharmacological inhibition of PIKKs abrogated S009-131 induced phosphorylation of p53 at Ser 15. DNA damage induced phosphorylation resulted in reduced proteasomal degradation of p53 by disrupting p53-MDM2 interaction. Additionally, our docking studies revealed that S009-131 might also contribute to increased cellular p53 level by occupying p53 binding pocket of MDM2. Posttranslational modifications of p53 upon S009-131 treatment led to enhanced affinity of p53 towards responsive elements (p53-RE) in the promoter regions of target genes and increased transcriptional efficiency. Together, the results suggest that S009-131 cleaves DNA through minor groove binding and eventually activates PIKKs associated DNA damage response signalling to promote stabilization and enhanced transcriptional activity of p53 through posttranslational modifications at key residues. PMID- 28349924 TI - Structural Basis for pH-mediated Regulation of F-actin Severing by Gelsolin Domain 1. AB - Six-domain gelsolin regulates actin structural dynamics through its abilities to sever, cap and uncap F-actin. These activities are modulated by various cellular parameters like Ca2+ and pH. Until now, only the molecular activation mechanism of gelsolin by Ca2+ has been understood relatively well. The fragment comprising the first domain and six residues from the linker region into the second domain has been shown to be similar to the full-length protein in F-actin severing activity in the absence of Ca2+ at pH 5. To understand how this gelsolin fragment is activated for F-actin severing by lowering pH, we solved its NMR structures at both pH 7.3 and 5 in the absence of Ca2+ and measured the pKa values of acidic amino acid residues and histidine residues. The overall structure and dynamics of the fragment are not affected significantly by pH. Nevertheless, local structural changes caused by protonation of His29 and Asp109 result in the activation on lowering the pH, and protonation of His151 directly effects filament binding since it resides in the gelsolin/actin interface. Mutagenesis studies support that His29, Asp109 and His151 play important roles in the pH-dependent severing activity of the gelsolin fragment. PMID- 28349926 TI - Contemporary crustal movement of southeastern Tibet: Constraints from dense GPS measurements. AB - The ongoing collision between the Indian plate and the Eurasian plate brings up N S crustal shortening and thickening of the Tibet Plateau, but its dynamic mechanisms remain controversial yet. As one of the most tectonically active regions of the world, South-Eastern Tibet (SET) has been greatly paid attention to by many geoscientists. Here we present the latest three-dimensional GPS velocity field to constrain the present-day tectonic process of SET, which may highlight the complex vertical crustal deformation. Improved data processing strategies are adopted to enhance the strain patterns throughout SET. The crustal uplifting and subsidence are dominated by regional deep tectonic dynamic processes. Results show that the Gongga Shan is uplifting with 1-1.5 mm/yr. Nevertheless, an anomalous crustal uplifting of ~8.7 mm/yr and negative horizontal dilation rates of 40-50 nstrain/yr throughout the Longmenshan structure reveal that this structure is caused by the intracontinental subduction of the Yangtze Craton. The Xianshuihe-Xiaojiang fault is a major active sinistral strike-slip fault which strikes essentially and consistently with the maximum shear strain rates. These observations suggest that the upper crustal deformation is closely related with the regulation and coupling of deep material. PMID- 28349927 TI - Quantitative strain analysis of InAs/GaAs quantum dot materials. AB - Geometric phase analysis has been applied to high resolution aberration corrected (scanning) transmission electron microscopy images of InAs/GaAs quantum dot (QD) materials. We show quantitatively how the lattice mismatch induced strain varies on the atomic scale and tetragonally distorts the lattice in a wide region that extends several nm into the GaAs spacer layer below and above the QDs. Finally, we show how V-shaped dislocations originating at the QD/GaAs interface efficiently remove most of the lattice mismatch induced tetragonal distortions in and around the QD. PMID- 28349928 TI - Corrugated Textile based Triboelectric Generator for Wearable Energy Harvesting. AB - Triboelectric energy harvesting has been applied to various fields, from large scale power generation to small electronics. Triboelectric energy is generated when certain materials come into frictional contact, e.g., static electricity from rubbing a shoe on a carpet. In particular, textile-based triboelectric energy-harvesting technologies are one of the most promising approaches because they are not only flexible, light, and comfortable but also wearable. Most previous textile-based triboelectric generators (TEGs) generate energy by vertically pressing and rubbing something. However, we propose a corrugated textile-based triboelectric generator (CT-TEG) that can generate energy by stretching. Moreover, the CT-TEG is sewn into a corrugated structure that contains an effective air gap without additional spacers. The resulting CT-TEG can generate considerable energy from various deformations, not only by pressing and rubbing but also by stretching. The maximum output performances of the CT-TEG can reach up to 28.13 V and 2.71 MUA with stretching and releasing motions. Additionally, we demonstrate the generation of sufficient energy from various activities of a human body to power about 54 LEDs. These results demonstrate the potential application of CT-TEGs for self-powered systems. PMID- 28349925 TI - Paroxetine alleviates T lymphocyte activation and infiltration to joints of collagen-induced arthritis. AB - T cell infiltration to synovial tissue is an early pathogenic mechanism of rheumatoid arthritis (RA). In the present work, we reveal that G protein coupled receptor kinase 2 (GRK2) is abundantly expressed in T cells of collagen-induced arthritis (CIA). A GRK2 inhibitor, paroxetine protects the joints from inflammation and destruction, primarily through inhibition of both CD4+ helper T (Th) cell and CD8+ cytotoxic T (Tc) cell migration to synovial tissue. Meanwhile, paroxetine restores the balance of Th/Tc, effector Th (Theff)/ naive Th (Thnaive) and effector Tc (Tceff)/ naive Tc (Tcnaive) to equilibrium by elevating the frequency of Thnaive, Tcnaive and regulatory Th cells; reducing the increased Theff, activated Th and Tceff, having a similar effect as methotrexate (MTX). In addition, both serum and synovial IL-1beta, TNF-alpha and CX3CL1 expression was effectively inhibited in treated rats. In vitro assay confirmed that paroxetine inhibits CX3CL1-induced T cell migration through blocking the activity of GRK2. Among three MAPK families, paroxetine was found to be able to decrease the phosphorylation of ERK. This study elucidates that paroxetine attenuates the symptoms of CIA rats due to its inhibitory effect on T cell activation and infiltration to synovial tissue via suppression of ERK pathway. PMID- 28349929 TI - Dynamics of volcanic ash remobilisation by wind through the Patagonian steppe after the eruption of Cordon Caulle, 2011. AB - Wind erosion of freshly-deposited volcanic ash causes persistent storms, strongly affecting ecosystems and human activity. Wind erosion of the volcanic ash was measured up to 17 months after the ash deposition, at 7 sites located within the ash-deposition area. The mass flux was measured up to 1.5 m above ground level. Mass transport rates were over 125 times the soil wind-erosion rates observed before the ash deposition, reaching up to 6.3 kg m-1 day-1. Total mass transport of ash during the 17 months ranged between 113.6 and 969.9 kg m-1 depending on topographic location and wind exposure. The vertical distribution of the mass flux at sites with higher vegetation cover was generally inverted as compared to sites with lower vegetation cover. This situation lasted 7 months and then a shift towards a more uniform vertical distribution was observed, in coincidence with the beginning of the decline of the mass transport rates. Decay rates differed between sites. Despite changes over time, an inverse linear correlation between the mass transports and the mass-flux gradients was found. Both the mass flux gradients and the average mass-transport rates were not linked with shear stress partition parameters, but with the ratio: ash-fall thickness to total vegetation cover. PMID- 28349932 TI - Microbial communities rock. PMID- 28349931 TI - Adipokines (Leptin, Adiponectin, Resistin) Differentially Regulate All Hormonal Cell Types in Primary Anterior Pituitary Cell Cultures from Two Primate Species. AB - Adipose-tissue (AT) is an endocrine organ that dynamically secretes multiple hormones, the adipokines, which regulate key physiological processes. However, adipokines and their receptors are also expressed and regulated in other tissues, including the pituitary, suggesting that locally- and AT-produced adipokines might comprise a regulatory circuit that relevantly modulate pituitary cell function. Here, we used primary pituitary cell-cultures from two normal nonhuman primate species [Papio-anubis/Macaca-fascicularis] to determine the impact of different adipokines on the functioning of all anterior-pituitary cell-types. Leptin and resistin stimulated GH-release, a response that was blocked by somatostatin. Conversely, adiponectin decreased GH-release, and inhibited GHRH-, but not ghrelin-stimulated GH-secretion. Furthermore: 1) Leptin stimulated PRL/ACTH/FSH- but not LH/TSH-release; 2) adiponectin stimulated PRL-, inhibited ACTH- and did not alter LH/FSH/TSH-release; and 3) resistin increased ACTH release and did not alter PRL/LH/FSH/TSH-secretion. These effects were mediated through the activation of common (AC/PKA) and distinct (PLC/PKC, intra-/extra cellular calcium, PI3K/MAPK/mTOR) signaling-pathways, and by the gene-expression regulation of key receptors/transcriptional-factors involved in the functioning of these pituitary cell-types (e.g. GHRH/ghrelin/somatostatin/insulin/IGF-I receptors/Pit-1). Finally, we found that primate pituitaries expressed leptin/adiponectin/resistin. Altogether, these and previous data suggest that local-production of adipokines/receptors, in conjunction with circulating adipokine-levels, might comprise a relevant regulatory circuit that contribute to the fine-regulation of pituitary functions. PMID- 28349930 TI - Pharmacogenetics of posttransplant diabetes mellitus. AB - Many factors (physiological, pathological, environmental or genetic) are associated with variability in drug effect. Most patients respond to a standard treatment but the drug may be ineffective or toxic. In this review, we focused on genetic markers of posttransplant diabetes mellitus (PTDM) after renal transplantation, a frequent complication of immunosuppressive therapy and important risk factor of graft loss and mortality. An initial literature search identified 100 publications and among them 32 association studies were retrieved under 'Pharmacogenetics and PTDM'. Thirty-five variants in 25 genes with an impact on insulin secretion, disposition or effect were significantly associated with PTDM. The population studied, immunosuppressive regimen, follow-up, PTDM diagnostic and genetic variations tested were highly variable between studies. Although pharmacogenetic biomarkers are key tools of great promise for preventing toxicities and improving event-free survival rates, replication studies are required to select validated biomarkers linked to the occurrence of PTDM and select appropriate immusuppressive treatment to improve renal graft and patient outcome. PMID- 28349933 TI - The VPS4 component of the ESCRT machinery plays an essential role in HPV infectious entry and capsid disassembly. AB - Human Papillomavirus (HPV) infection involves multiple steps, from cell attachment, through endocytic trafficking towards the trans-Golgi network, and, ultimately, the entry into the nucleus during mitosis. An essential viral protein in infectious entry is the minor capsid protein L2, which engages different components of the endocytic sorting machinery during this process. The ESCRT machinery is one such component that seems to play an important role in the early stages of infection. Here we have analysed the role of specific ESCRT components in HPV infection, and we find an essential role for VPS4. Loss of VPS4 blocks infection with multiple PV types, suggesting an evolutionarily conserved critical step in infectious entry. Intriguingly, both L1 and L2 can interact with VPS4, and appear to be in complex with VPS4 during the early stages of virus infection. By using cell lines stably expressing a dominant-negative mutant form of VPS4, we also show that loss of VPS4 ATPase activity results in a marked delay in capsid uncoating, resulting in a defect in the endocytic transport of incoming PsVs. These results demonstrate that the ESCRT machinery, and in particular VPS4, plays a critical role in the early stages of PV infection. PMID- 28349934 TI - Atmospheric impacts of the strongest known solar particle storm of 775 AD. AB - Sporadic solar energetic particle (SEP) events affect the Earth's atmosphere and environment, in particular leading to depletion of the protective ozone layer in the Earth's atmosphere, and pose potential technological and even life hazards. The greatest SEP storm known for the last 11 millennia (the Holocene) occurred in 774-775 AD, serving as a likely worst-case scenario being 40-50 times stronger than any directly observed one. Here we present a systematic analysis of the impact such an extreme event can have on the Earth's atmosphere. Using state-of the-art cosmic ray cascade and chemistry-climate models, we successfully reproduce the observed variability of cosmogenic isotope 10Be, around 775 AD, in four ice cores from Greenland and Antarctica, thereby validating the models in the assessment of this event. We add to prior conclusions that any nitrate deposition signal from SEP events remains too weak to be detected in ice cores by showing that, even for such an extreme solar storm and sub-annual data resolution, the nitrate deposition signal is indistinguishable from the seasonal cycle. We show that such a severe event is able to perturb the polar stratosphere for at least one year, leading to regional changes in the surface temperature during northern hemisphere winters. PMID- 28349936 TI - Bacterial pathogenesis: Pathogenic bacteria attack RHIM. PMID- 28349935 TI - Demographic associations for autoantibodies in disease-free individuals of a European population. AB - The presence of autoantibodies usually precedes autoimmune disease, but is sometimes considered an incidental finding with no clinical relevance. The prevalence of immune-mediated diseases was studied in a group of individuals from the Estonian Genome Project (n = 51,862), and 6 clinically significant autoantibodies were detected in a subgroup of 994 (auto)immune-mediated disease free individuals. The overall prevalence of individuals with immune-mediated diseases in the primary cohort was 30.1%. Similarly, 23.6% of the participants in the disease-free subgroup were seropositive for at least one autoantibody. Several phenotypic parameters were associated with autoantibodies. The results suggest that (i) immune-mediated diseases are diagnosed in nearly one-third of a random European population, (ii) 6 common autoantibodies are detectable in almost one-third of individuals without diagnosed autoimmune diseases, (iii) tissue non specific autoantibodies, especially at high levels, may reflect preclinical disease in symptom-free individuals, and (iv) the incidental positivity of anti TPO in men with positive familial anamnesis of maternal autoimmune disease deserves further medical attention. These results encourage physicians to evaluate autoantibodies in addition to treating a variety of patient health complaints to detect autoimmune-mediated disease early. PMID- 28349938 TI - SERS detection of the biomarker hydrogen cyanide from Pseudomonas aeruginosa cultures isolated from cystic fibrosis patients. AB - Pseudomonas aeruginosa is the primary cause of chronic airway infections in cystic fibrosis (CF) patients. Persistent infections are seen from the first P. aeruginosa culture in about 75% of young CF patients, and it is important to discover new ways to detect P. aeruginosa at an earlier stage. The P. aeruginosa biomarker hydrogen cyanide (HCN) contains a triple bond, which is utilized in this study because of the resulting characteristic C=N peak at 2135 cm-1 in a Raman spectrum. The Raman signal was enhanced by surface-enhanced Raman spectroscopy (SERS) on a Au-coated SERS substrate. After long-term infection, a mutation in the patho-adaptive lasR gene can alter the expression of HCN, which is why it is sometimes not possible to detect HCN in the breath of chronically infected patients. Four P. aeruginosa reference strains and 12 clinical P. aeruginosa strains isolated from CF children were evaluated, and HCN was clearly detected from overnight cultures of all wild type-like isolates and half of the later isolates from the same patients. The clinical impact could be that P. aeruginosa infections could be detected at an earlier stage, because daily breath sampling with an immediate output could be possible with a point-of-care SERS device. PMID- 28349937 TI - Biodegradable Polymeric Nanocapsules Prevent Cardiotoxicity of Anti-Trypanosomal Lychnopholide. AB - Chagas disease is a neglected parasitic disease caused by the protozoan Trypanosoma cruzi. New antitrypanosomal options are desirable to prevent complications, including a high rate of cardiomyopathy. Recently, a natural substance, lychnopholide, has shown therapeutic potential, especially when encapsulated in biodegradable polymeric nanocapsules. However, little is known regarding possible adverse effects of lychnopholide. Here we show that repeated dose intravenous administration of free lychnopholide (2.0 mg/kg/day) for 20 days caused cardiopathy and mortality in healthy C57BL/6 mice. Echocardiography revealed concentric left ventricular hypertrophy with preserved ejection fraction, diastolic dysfunction and chamber dilatation at end-stage. Single cardiomyocytes presented altered contractility and Ca2+ handling, with spontaneous Ca2+ waves in diastole. Acute in vitro lychnopholide application on cardiomyocytes from healthy mice also induced Ca2+ handling alterations with abnormal RyR2-mediated diastolic Ca2+ release. Strikingly, the encapsulation of lychnopholide prevented the cardiac alterations induced in vivo by the free form repeated doses. Nanocapsules alone had no adverse cardiac effects. Altogether, our data establish lychnopholide presented in nanocapsule form more firmly as a promising new drug candidate to cure Chagas disease with minimal cardiotoxicity. Our study also highlights the potential of nanotechnology not only to improve the efficacy of a drug but also to protect against its adverse effects. PMID- 28349939 TI - Phase-transfer induced room temperature ferromagnetic behavior in 1T@2H-MoSe2 nanosheets. AB - Manipulating electronic and magnetic properties of two-dimensional transitional metal dichalcogenides has raised a lot of attention recently. Herein we report the synthesis and ferromagnetic properties of phase-transfer induced room temperature ferromagnetic behavior in 1 T@2H-MoSe2 nanosheets. Experimental results indicate the saturated magnetization of the 1 T@2H-MoSe2 compound increases first and then decreases as the increasing of 1 T-MoSe2 phase, where 65.58% 1 T-MoSe2 phase incorporation in 2H-MoSe2 could enhance the saturated magnetization from 0.32 memu/g to 8.36 memu/g. Besides, obvious magnetoresistance behaviors are observed in these samples, revealing their potential applications in future spintronics. PMID- 28349940 TI - Adventitial lymphatic capillary expansion impacts on plaque T cell accumulation in atherosclerosis. AB - During plaque progression, inflammatory cells progressively accumulate in the adventitia, paralleled by an increased presence of leaky vasa vasorum. We here show that next to vasa vasorum, also the adventitial lymphatic capillary bed is expanding during plaque development in humans and mouse models of atherosclerosis. Furthermore, we investigated the role of lymphatics in atherosclerosis progression. Dissection of plaque draining lymph node and lymphatic vessel in atherosclerotic ApoE-/- mice aggravated plaque formation, which was accompanied by increased intimal and adventitial CD3+ T cell numbers. Likewise, inhibition of VEGF-C/D dependent lymphangiogenesis by AAV aided gene transfer of hVEGFR3-Ig fusion protein resulted in CD3+ T cell enrichment in plaque intima and adventitia. hVEGFR3-Ig gene transfer did not compromise adventitial lymphatic density, pointing to VEGF-C/D independent lymphangiogenesis. We were able to identify the CXCL12/CXCR4 axis, which has previously been shown to indirectly activate VEGFR3, as a likely pathway, in that its focal silencing attenuated lymphangiogenesis and augmented T cell presence. Taken together, our study not only shows profound, partly CXCL12/CXCR4 mediated, expansion of lymph capillaries in the adventitia of atherosclerotic plaque in humans and mice, but also is the first to attribute an important role of lymphatics in plaque T cell accumulation and development. PMID- 28349942 TI - Frugivore-Mediated Selection in A Habitat Transformation Scenario. AB - Plant-animal interactions are strong drivers of phenotypic evolution. However, the extent to which anthropogenic habitat transformation creates new selective scenarios for plant-animal interactions is a little explored subject. We examined the effects of native forest replacement by exotic Eucalyptus trees on the frugivore-mediated phenotypic selection coefficients imposed by the relict marsupial Dromiciops gliroides upon traits involved in frugivore attraction and germination success of the mistletoe Tristerix corymbosus (Loranthaceae). We found significant gradients for seed weight and sugar content along the native - transformed habitat gradient. While selection for larger seed weight was more relevant in native habitats, fruits with intermediate sugar content were promoted in transformed habitats. The spatial habitat structure and microclimate features such as the degree of sunlight received influenced the natural selection processes, as they correlated with the phenotypic traits analysed. The response of this plant-frugivore interaction to human disturbance seemed to be context dependent, in which extremely transformed habitats would offer new opportunities for natural selection on dispersal-related traits. Even in recent transformation events like this, human disturbance acts as a strong contemporary evolution driver. PMID- 28349941 TI - Milk Fat Globule Membrane Supplementation in Formula Modulates the Neonatal Gut Microbiome and Normalizes Intestinal Development. AB - Breast milk has many beneficial properties and unusual characteristics including a unique fat component, termed milk fat globule membrane (MFGM). While breast milk yields important developmental benefits, there are situations where it is unavailable resulting in a need for formula feeding. Most formulas do not contain MFGM, but derive their lipids from vegetable sources, which differ greatly in size and composition. Here we tested the effects of MFGM supplementation on intestinal development and the microbiome as well as its potential to protect against Clostridium difficile induced colitis. The pup-in-a-cup model was used to deliver either control or MFGM supplemented formula to rats from 5 to 15 days of age; with mother's milk (MM) reared animals used as controls. While CTL formula yielded significant deficits in intestinal development as compared to MM littermates, addition of MFGM to formula restored intestinal growth, Paneth and goblet cell numbers, and tight junction protein patterns to that of MM pups. Moreover, the gut microbiota of MFGM and MM pups displayed greater similarities than CTL, and proved protective against C. difficile toxin induced inflammation. Our study thus demonstrates that addition of MFGM to formula promotes development of the intestinal epithelium and microbiome and protects against inflammation. PMID- 28349943 TI - TTF-1- and/or CD56-positive Circulating Tumor Cells in patients with small cell lung cancer (SCLC). AB - The aim of the study was to evaluate the phenotypic CTCs heterogeneity (TTF-1+ and/or CD56+) in SCLC patients and correlate it with the CellSearch. Peripheral blood was obtained from 108 consecutive patients. CTCs were detected by CellSearch and double-immunofluorescence using anti-CD45, anti-TTF-1 and anti CD56 antibodies. Before chemotherapy TTF-1+/CD45-, CD56+/CD45- and TTF-1+/CD56+ CTCs were detected in 66(61.1%), 55(50.9%) and 46(42.6%) patients, respectively; 60.2% of patients were CellSearch+. Among the 22 patients with 0 CTCs/7.5 ml on CellSearch, TTF-1+/CD45-, CD56+/CD45- and TTF-1+/CD56+ CTCs were detected in 8(36.4%), 6(27.3) and 6(27.3%) patients, respectively; no CK+/EpCAM+ or TTF1+/EpCAM+ CTCs were detected in these patients. One-chemotherapy cycle decreased both the number of positive patients (p < 0.001) and their CTC number (p < 0.001), irrespectively of their phenotype and the detection method. The incidence and number of the different CTC subpopulations on PD, was significantly increased at their baseline levels. Multivariate analysis revealed that the increased number of CTCs at baseline and on PD were significantly associated with decreased PFS (p = 0.048) and OS (p = 0.041), respectively. There is an important CTC heterogeneity in such patients according to the expression of TTF-1 and CD56 which could detect EpCAM- CTC subpopulations and, thus, undetectable by CellSearch. These CTC subpopulations are dynamically correlated with treatment efficacy and disease-progression. PMID- 28349946 TI - Gut metagenomic analysis reveals prominent roles of Lactobacillus and cecal microbiota in chicken feed efficiency. AB - Interactions between the host and gut microbiota can affect gut metabolism. In this study, the individual performances of 252 hens were recorded to evaluate feed efficiency. Hens with contrasting feed efficiencies (14 birds per group) were selected to investigate their duodenal, cecal and fecal microbial composition by sequencing the 16S rRNA gene V4 region. The results showed that the microbial community in the cecum was quite different from those in the duodenum and feces. The highest biodiversity and all differentially abundant taxa between the different efficiency groups were observed in the cecal microbial community with false discovery rate (FDR) <0.05. Of these differentially abundant cecal microbes, Lactobacillus accounted for a greater proportion than the others. The abundances of Lactobacillus and Akkermansia were significantly higher while that of Faecalibacterium was lower (FDR < 0.05) in the better feed efficiency (BFE) group. Phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) analysis revealed that the functions relating to glycometabolism and amino acid metabolism were enriched in the cecal microbiota of the BFE group. These results indicated the prominent role of cecal microbiota in the feed efficiency of chickens and suggested plausible uses of Lactobacillus to improve the feed efficiency of host. PMID- 28349944 TI - Discrimination of Stem Cell Status after Subjecting Cynomolgus Monkey Pluripotent Stem Cells to Naive Conversion. AB - Experimental animal models have played an indispensable role in the development of human induced pluripotent stem cell (iPSC) research. The derivation of high quality (so-called "true naive state") iPSCs of non-human primates enhances their application and safety for human regenerative medicine. Although several attempts have been made to convert human and non-human primate PSCs into a truly naive state, it is unclear which evaluation methods can discriminate them as being truly naive. Here we attempted to derive naive cynomolgus monkey (Cm) (Macaca fascicularis) embryonic stem cells (ESCs) and iPSCs. Several characteristics of naive Cm ESCs including colony morphology, appearance of naive-related mRNAs and proteins, leukaemia inhibitory factor dependency, and mitochondrial respiration were confirmed. Next, we generated Cm iPSCs and converted them to a naive state. Transcriptomic comparison of PSCs with early Cm embryos elucidated the partial achievement (termed naive-like) of their conversion. When these were subjected to in vitro neural differentiation, enhanced differentiating capacities were observed after naive-like conversion, but some lines exhibited heterogeneity. The difficulty of achieving contribution to chimeric mouse embryos was also demonstrated. These results suggest that Cm PSCs could ameliorate their in vitro neural differentiation potential even though they could not display true naive characteristics. PMID- 28349945 TI - Touch and Hearing Mediate Osseoperception. AB - Osseoperception is the sensation arising from the mechanical stimulation of a bone-anchored prosthesis. Here we show that not only touch, but also hearing is involved in this phenomenon. Using mechanical vibrations ranging from 0.1 to 6 kHz, we performed four psychophysical measures (perception threshold, sensation discrimination, frequency discrimination and reaction time) on 12 upper and lower limb amputees and found that subjects: consistently reported perceiving a sound when the stimulus was delivered at frequencies equal to or above 400 Hz; were able to discriminate frequency differences between stimuli delivered at high stimulation frequencies (~1500 Hz); improved their reaction time for bimodal stimuli (i.e. when both vibration and sound were perceived). Our results demonstrate that osseoperception is a multisensory perception, which can explain the improved environment perception of bone-anchored prosthesis users. This phenomenon might be exploited in novel prosthetic devices to enhance their control, thus ultimately improving the amputees' quality of life. PMID- 28349947 TI - Patterns of correlation of facial shape with physiological measurements are more integrated than patterns of correlation with ratings. AB - This article exploits a method recently incorporated in the geometric morphometric toolkit that complements previous approaches to quantifying the facial features associated with specific body characteristics and trait attribution during social perception. The new method differentiates more globally encoded from more locally encoded information by a summary scaling dimension that is estimated by fitting a line to the plot of log bending energy against log variance explained, partial warp by partial warp, for some sample of varying shapes. In the present context these variances come from the regressions of shape on some exogenous cause or effect of form. We work an example involving data from male faces. Here the regression slopes are steepest, and the sums of explained variances over the uniform component, partial warp 1 and partial warp 2 are greatest, for the conventional body mass index, followed by cortisol and, lastly, perceived health. This suggests that physiological characteristics may be represented at larger scale (global patterns), whereas cues in perception are of smaller scale (local patterns). Such a polarity within psychomorphospace, the global versus the focal, now has a metric by which patterns of morphology can be modeled in both biological and psychological studies. PMID- 28349949 TI - Modeling out-of-plane actuation in thin-film nematic polymer networks: From chiral ribbons to auto-origami boxes via twist and topology. AB - Various experimental and theoretical studies demonstrate that complex stimulus responsive out-of-plane distortions such as twist of different chirality, emergence of cones, simple and anticlastic bending can be engineered and pre programmed in a liquid crystalline rubbery material given a well-controlled director microstructure. Via 3-d finite element simulation studies, we demonstrate director-encoded chiral shape actuation in thin-film nematic polymer networks under external stimulus. Furthermore, we design two complex director fields with twisted nematic domains and nematic disclinations that encode a pattern of folds for an auto-origami box. This actuator will be flat at a reference nematic state and form four well-controlled bend distortions as orientational order changes. Device fabrication is applicable via current experimental techniques. These results are in qualitative agreement with theoretical predictions, provide insight into experimental observations, and demonstrate the value of finite element methods at the continuum level for designing and engineering liquid crystal polymeric devices. PMID- 28349951 TI - Parasite pathogenesis: The dynamics of chronic malaria. PMID- 28349950 TI - Soil classification predicts differences in prokaryotic communities across a range of geographically distant soils once pH is accounted for. AB - Agricultural land is typically managed based on visible plant life at the expense of the belowground majority. However, microorganisms mediate processes sustaining plant life and the soil environment. To understand the role of microbes we first must understand what controls soil microbial community assembly. We assessed the distribution and composition of prokaryotic communities from soils representing four geographic regions on the South Island of New Zealand. These soils are under three different uses (dairy, sheep and beef, and high country farming) and are representative of major soil classification groups (brown, pallic, gley and recent). We hypothesized that pH would account for major community patterns based on 16S profiles, but that land use and location would be secondary modifiers. Community diversity and structure was linked to pH, coinciding with land use. Soil classification correlated with microbial community structure and evenness, but not richness in high country and sheep and beef communities. The impact of land use and pH remained significant at the regional scale, but soil classification provided support for community variability not explained by either of those factors. These results suggest that several edaphic properties must be examined at multiple spatial scales to robustly examine soil prokaryotic communities. PMID- 28349948 TI - Discriminating cognitive status in Parkinson's disease through functional connectomics and machine learning. AB - There is growing interest in the potential of neuroimaging to help develop non invasive biomarkers in neurodegenerative diseases. In this study, connection-wise patterns of functional connectivity were used to distinguish Parkinson's disease patients according to cognitive status using machine learning. Two independent subject samples were assessed with resting-state fMRI. The first (training) sample comprised 38 healthy controls and 70 Parkinson's disease patients (27 with mild cognitive impairment). The second (validation) sample included 25 patients (8 with mild cognitive impairment). The Brainnetome atlas was used to reconstruct the functional connectomes. Using a support vector machine trained on features selected through randomized logistic regression with leave-one-out cross validation, a mean accuracy of 82.6% (p < 0.002) was achieved in separating patients with mild cognitive impairment from those without it in the training sample. The model trained on the whole training sample achieved an accuracy of 80.0% when used to classify the validation sample (p = 0.006). Correlation analyses showed that the connectivity level in the edges most consistently selected as features was associated with memory and executive function performance in the patient group. Our results demonstrate that connection-wise patterns of functional connectivity may be useful for discriminating Parkinson's disease patients according to the presence of cognitive deficits. PMID- 28349952 TI - Nerve regeneration by human corneal stromal keratocytes and stromal fibroblasts. AB - Laser refractive surgeries reshape corneal stroma to correct refractive errors, but unavoidably affect corneal nerves. Slow nerve regeneration and atypical neurite morphology cause desensitization and neuro-epitheliopathy. Following injury, surviving corneal stromal keratocytes (CSKs) are activated to stromal fibroblasts (SFs). How these two different cell types influence nerve regeneration is elusive. Our study evaluated the neuro-regulatory effects of human SFs versus CSKs derived from the same corneal stroma using an in vitro chick dorsal root ganglion model. The neurite growth was assessed by a validated concentric circle intersection count method. Serum-free conditioned media (CM) from SFs promoted neurite growth dose-dependently, compared to that from CSKs. We detected neurotrophic and pro-inflammatory factors (interleukin-8, interleukin 15, monocyte chemoattractant protein-1, eotaxin, RANTES) in SFCM by Bio-Plex Human Cytokine assay. More than 130 proteins in SFCM and 49 in CSKCM were identified by nanoLC-MS/MS. Proteins uniquely present in SFCM had reported neuro regulatory activities and were predicted to regulate neurogenesis, focal adhesion and wound healing. Conclusively, this was the first study showing a physiological relationship between nerve growth and the metabolically active SFs versus quiescent CSKs from the same cornea source. The dose-dependent effect on neurite growth indicated that nerve regeneration could be influenced by SF density. PMID- 28349953 TI - Observation of low-loss broadband supermode propagation in coupled acoustic waveguide complex. AB - We investigate analytically, numerically, and experimentally the low-loss supermode propagation in a coupled acoustic waveguide complex within a broadband. The waveguide complex is implemented with air channels coupled via an ultrathin metafluid layer. We analytically derive the field distribution of incident sound needed for producing acoustic supermodes, and verify the periodically revival propagation in coupled waveguide systems numerically and experimentally. We find out that the supermode wavelength becomes longer for higher mode order or lower frequency. We have also demonstrated the robust propagation of supermodes in broadband. Our scheme can in principle be extended to three dimensions and the ultrasound regime with simplicity and may promote applications of high-fidelity signal transfer in complicated acoustic networks. PMID- 28349954 TI - Two-photon dual imaging platform for in vivo monitoring cellular oxidative stress in liver injury. AB - Oxidative stress reflects an imbalance between reactive oxygen species (ROS) and antioxidants, which has been reported as an early unifying event in the development and progression of various diseases and as a direct and mechanistic indicator of treatment response. However, highly reactive and short-lived nature of ROS and antioxidant limited conventional detection agents, which are influenced by many interfering factors. Here, we present a two-photon sensing platform for in vivo dual imaging of oxidative stress at the single cell-level resolution. This sensing platform consists of three probes, which combine the turn-on fluorescent transition-metal complex with different specific responsive groups for glutathione (GSH), hydrogen peroxide (H2O2) and hypochlorous acid (HOCl). By combining fluorescence intensity imaging and fluorescence lifetime imaging, these probes totally remove any possibility of crosstalk from in vivo environmental or instrumental factors, and enable accurate localization and measurement of the changes in ROS and GSH within the liver. This precedes changes in conventional biochemical and histological assessments in two distinct experimental murine models of liver injury. The ability to monitor real-time cellular oxidative stress with dual-modality imaging has significant implications for high-accurate, spatially configured and quantitative assessment of metabolic status and drug response. PMID- 28349955 TI - A canine model of tracheal stenosis induced by cuffed endotracheal intubation. AB - Postintubation tracheal stenosis is a complication of endotracheal intubation. The pathological mechanism and risk factors for endotracheal intubation-induced tracheal stenosis remain not fully understood. We aimed to establish an animal model and to investigate risk factors for postintubation tracheal stenosis. Beagles were intubated with 4 sized tubes (internal diameter 6.5 to 8.0 mm) and cuff pressures of 100 to 200 mmHg for 24 hr. The status of tracheal wall was evaluated by bronchoscopic and histological examinations. The model was successfully established by cuffed endotracheal intubation using an 8.0 mm tube and an intra-cuff pressure of 200 mmHg for 24 hr. When the intra-cuff pressures were kept constant, a larger sized tube would induce a larger tracheal wall pressure and more severe injury to the tracheal wall. The degree of tracheal stenosis ranged from 78% to 91% at 2 weeks postextubation. Histological examination demonstrated submucosal infiltration of inflammatory cells, hyperplasia of granulation tissue and collapse of tracheal cartilage. In summary, a novel animal model of tracheal stenosis was established by cuffed endotracheal intubation, whose histopathological feathers are similar to those of clinical cases of postintubation tracheal stenosis. Excessive cuff pressure and over-sized tube are the risk factors for postintubation tracheal stenosis. PMID- 28349956 TI - Facile synthesis of silicon nitride nanowires with flexible mechanical properties and with diameters controlled by flow rate. AB - Ultralong Si3N4 nanowires (NWs) were successfully synthesized with size controlled in N2 gas by using an efficient method. The diameters of the Si3N4 NWs increased when the flow rate of N2 gas increased, with average diameters of 290 nm from flow rates of 100 ml/min, 343 nm from flow rates of 200 ml/min and 425 nm from flow rates of 400 ml/min. Young's modulus was found to rely strongly on the diameters of the Si3N4 NWs, decreasing from approximately 526.0 GPa to 321.9 GPa; as the diameters increased from 360 nm to 960 nm. These findings provide a promising method for tailoring these mechanical properties of the NWs in a controlled manner over a wide range of Young's modulus values. Vapour-liquid solid (VLS) mechanisms were used to model the growth of Si3N4 NWs on the inner wall of an alumina crucible and on the surface of the powder mixture. Alumina may be an effective mediator of NW growth that plays an important role in controlling the concentrations of Si-containing reactants to support the growth of NWs on the inner wall of the alumina crucible. This approach offers a valuable means for preparing ultralong Si3N4 NWs doped with Al with unique properties. PMID- 28349957 TI - Stability of R2* and quantitative susceptibility mapping of the brain tissue in a large scale multi-center study. AB - Multi-center studies are advantageous for enrolling participants of varying pathological and demographical conditions, and especially in neurological studies. Hence stability of the obtained quantitative R2* and susceptibility in multicenter studies is a key issue for their widespread applications. In this work, the stabilities of simultaneously obtained R2* and susceptibility are investigated and compared across 10 sites that are equipped with the same scanner and receiver coil, the same post-processing process was used to achieve consistent experiment setup. Two healthy adult volunteers (one male and female) participated in this study. High intraclass correlation coefficient was obtained for both susceptibility (0.94) and R2* (0.96). The coefficients of variance for all measurements obtained were smaller than 0.1, the largest variations of measurements in all the chosen ROIs fall within +/-20% from the median value. Higher level of stability was obtained in R2* as compared to susceptibility at 1 mm resolution (P < 0.05) and at 1.5 mm (P < 0.01). PMID- 28349958 TI - Gene expression-based biomarkers for discriminating early and late stage of clear cell renal cancer. AB - In this study, an attempt has been made to identify expression-based gene biomarkers that can discriminate early and late stage of clear cell renal cell carcinoma (ccRCC) patients. We have analyzed the gene expression of 523 samples to identify genes that are differentially expressed in the early and late stage of ccRCC. First, a threshold-based method has been developed, which attained a maximum accuracy of 71.12% with ROC 0.67 using single gene NR3C2. To improve the performance of threshold-based method, we combined two or more genes and achieved maximum accuracy of 70.19% with ROC of 0.74 using eight genes on the validation dataset. These eight genes include four underexpressed (NR3C2, ENAM, DNASE1L3, FRMPD2) and four overexpressed (PLEKHA9, MAP6D1, SMPD4, C11orf73) genes in the late stage of ccRCC. Second, models were developed using state-of-art techniques and achieved maximum accuracy of 72.64% and 0.81 ROC using 64 genes on validation dataset. Similar accuracy was obtained on 38 genes selected from subset of genes, involved in cancer hallmark biological processes. Our analysis further implied a need to develop gender-specific models for stage classification. A web server, CancerCSP, has been developed to predict stage of ccRCC using gene expression data derived from RNAseq experiments. PMID- 28349959 TI - Organization of prefrontal network activity by respiration-related oscillations. AB - The medial prefrontal cortex (mPFC) integrates information from cortical and sub cortical areas and contributes to the planning and initiation of behaviour. A potential mechanism for signal integration in the mPFC lies in the synchronization of neuronal discharges by theta (6-12 Hz) activity patterns. Here we show, using in vivo local field potential (LFP) and single-unit recordings from awake mice, that prominent oscillations in the sub-theta frequency band (1-5 Hz) emerge during awake immobility in the mPFC. These oscillation patterns are distinct from but phase-locked to hippocampal theta activity and occur synchronized with nasal respiration (hence termed prefrontal respiration rhythm [PRR]). PRR activity modulates the amplitude of prefrontal gamma rhythms with greater efficacy than theta oscillations. Furthermore, single-unit discharges of putative pyramidal cells and GABAergic interneurons are entrained by prefrontal PRR and nasal respiration. Our data thus suggest that PRR activity contributes to information processing in the prefrontal neuronal network. PMID- 28349960 TI - Photonic transistor and router using a single quantum-dot-confined spin in a single-sided optical microcavity. AB - The future Internet is very likely the mixture of all-optical Internet with low power consumption and quantum Internet with absolute security guaranteed by the laws of quantum mechanics. Photons would be used for processing, routing and com munication of data, and photonic transistor using a weak light to control a strong light is the core component as an optical analogue to the electronic transistor that forms the basis of modern electronics. In sharp contrast to previous all-optical tran-sistors which are all based on optical nonlinearities, here I introduce a novel design for a high-gain and high-speed (up to terahertz) photonic transistor and its counterpart in the quantum limit, i.e., single-photon transistor based on a linear optical effect: giant Faraday rotation induced by a single electronic spin in a single-sided optical microcavity. A single-photon or classical optical pulse as the gate sets the spin state via projective measurement and controls the polarization of a strong light to open/block the photonic channel. Due to the duality as quantum gate for quantum information processing and transistor for optical information processing, this versatile spin cavity quantum transistor provides a solid-state platform ideal for all-optical networks and quantum networks. PMID- 28349961 TI - E3 Ubiquitin Ligase Nedd4 Promotes Japanese Encephalitis Virus Replication by Suppressing Autophagy in Human Neuroblastoma Cells. AB - Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus that causes the most prevalent viral encephalitis in Asia. Since JEV is a neurotropic virus, it is important to identify key molecules that mediate JEV infection in neuronal cells and to investigate their underlying mechanisms. In this study, the critical role of Nedd4, an E3 ubiquitin ligase that is highly expressed in the central nervous system, was examined in JEV propagation. In SK-N-SH neuroblastoma cells, Nedd4 was up-regulated in response to JEV infection. Moreover, down-regulation of Nedd4 resulted in a significant decrease in JEV replication without alterations in virus attachment and internalization or in JEV pseudotyped virus infection, suggesting that Nedd4 participates in the replication but not in the entry stage of JEV infection. Further functional analysis showed that Nedd4 attenuated JEV induced autophagy, which negatively regulates virus replication during infection. These results suggest that Nedd4 facilitates the replication of JEV by suppressing virus-induced autophagy. Taken together, our results indicate that Nedd4 plays a crucial role in JEV infection of neuronal cells, which provides a potential target for the development of novel treatment to combat JEV infection. PMID- 28349962 TI - Preparation and characterization of (-)-Epigallocatechin-3-gallate (EGCG)-loaded nanoparticles and their inhibitory effects on Human breast cancer MCF-7 cells. AB - We were employing nanotechnology to improve the targeting ability of (-) Epigallocatechin-3-gallate (EGCG) towards MCF-7 cells, and two kinds of EGCG nanoparticles (FA-NPS-PEG and FA-PEG-NPS) were obtained, besides, their characteristics and effects on MCF-7 cells were studied. The results indicated that (i) both FA-NPS-PEG and FA-PEG-NPS have high stabilities; (ii) their particles sizes were 185.0 +/- 13.5 nm and 142.7 +/- 7.2 nm, respectively; (iii) their encapsulation efficiencies of EGCG were 90.36 +/- 2.20% and 39.79 +/- 7.54%, respectively. (iv) there was no cytotoxicity observed in EGCG, FA-NPS-PEG and FA-PEG-NPS toward MCF-7 cells over all concentrations (0~400 MUg/mL) tested; (v) EGCG, FA-NPS-PEG and FA-PEG-NPS inhibited MCF-7 cells proliferation in dose dependent manners, with the average IC50 of 470.5 +/- 33.0, 65.9 +/- 0.4 and 66.6 +/- 0.6 MUg/mL; (vi) EGCG, FA-NPS-PEG and FA-PEG-NPS could modulated the expressions of several key regulatory proteins in PI3K-Akt pathway such as up regulation of PTEN, p21 and Bax, and down-regulation of p-PDK1, p-AKT, CyclinD1 and Bcl-2, which gave an illustration about the mechanism by which EGCG nanoparticles inhibited MCF-7 cells proliferation. In this study, EGCG nanoparticles can significantly enhance the targeting ability and efficacy of EGCG, which is considered to an experimental foundation for further research on its activity, targeting ability and metabolism in vivo. PMID- 28349963 TI - A platform for high-throughput bioenergy production phenotype characterization in single cells. AB - Driven by an increasing number of studies demonstrating its relevance to a broad variety of disease states, the bioenergy production phenotype has been widely characterized at the bulk sample level. Its cell-to-cell variability, a key player associated with cancer cell survival and recurrence, however, remains poorly understood due to ensemble averaging of the current approaches. We present a technology platform for performing oxygen consumption and extracellular acidification measurements of several hundreds to 1,000 individual cells per assay, while offering simultaneous analysis of cellular communication effects on the energy production phenotype. The platform comprises two major components: a tandem optical sensor for combined oxygen and pH detection, and a microwell device for isolation and analysis of single and few cells in hermetically sealed sub-nanoliter chambers. Our approach revealed subpopulations of cells with aberrant energy production profiles and enables determination of cellular response variability to electron transfer chain inhibitors and ion uncouplers. PMID- 28349966 TI - On the wrong side of history. PMID- 28349965 TI - The nicotinic acetylcholine receptor alpha7 subunit is an essential negative regulator of bone mass. AB - The nicotinic receptor alpha7nAchR reportedly regulates vagal nerve targets in brain and cardiac tissue. Here we show that nAchR7-/- mice exhibit increased bone mass due to decreased osteoclast formation, accompanied by elevated osteoprotegerin/RANKL ratios in serum. Vagotomy in wild-type mice also significantly increased the serum osteoprotegerin/RANKL ratio, and elevated bone mass seen in nAchR7-/- mice was reversed in alpha7nAchR/osteoprotegerin-doubly deficient mice. alpha7nAchR loss significantly increased TNFalpha expression in Mac1-positive macrophages, and TNFalpha increased the osteoprotegerin/RANKL ratio in osteoblasts. Targeting TNFalpha in nAchR7-/- mice normalized both serum osteoprotegerin/RANKL ratios and bone mass. Administration of nicotine, an alpha7nAchR ligand, to wild-type mice increased serum RANKL levels. Thus, vagal nerve stimulation of macrophages via alpha7nAchR regulates bone mass by modulating osteoclast formation. PMID- 28349964 TI - Probiotics may delay the progression of nonalcoholic fatty liver disease by restoring the gut microbiota structure and improving intestinal endotoxemia. AB - Gut-derived bacterial lipopolysaccharide (LPS) and subsequent hepatic toll-like receptor 4 (TLR4) activation have been recognized to be involved in the onset of diet-induced nonalcoholic fatty liver disease (NAFLD), but little is known about the variation of LPS and TLR4 during the progression of NAFLD. Probiotics were able to inhibit proliferation of harmful bacteria and improve gastrointestinal barrier function. However, it's unclear whether LPS/TLR4 is involved in the protection effect of probiotics on NAFLD. In this study, we described characteristic of gut microbiota structure in the progression of NAFLD, and we also analyzed the relationship between gut microbiota and LPS/TLR4 in this process. Furthermore, we applied probiotics intervention to investigate the effect of probiotics on gut flora structure, intestinal integrity, serum LPS, liver TLR4 and liver pathology. Our results showed that serum LPS and liver TLR4 were highly increased during progression of NAFLD, with gut flora diversity and gut mircobiological colonization resistance (B/E) declining. Furthermore, probiotics could improve gut microbiota structure and liver pathology. Probiotics could also downregulate serum LPS and liver TLR4. Our results suggested that both gut flora alteration and endotoxemia may be involved in the progression of NAFLD. Probiotics may delay the progression of NAFLD via LPS/TLR4 signaling. PMID- 28349967 TI - Development of a multiplex loop-mediated isothermal amplification method for the simultaneous detection of Salmonella spp. and Vibrio parahaemolyticus. AB - Rapid detection of food-borne pathogens is important in the food industry, to monitor and prevent the spread of these pathogens through contaminated food products. We therefore established a multiplex real-time loop-mediated isothermal amplification (LAMP) assay to simultaneously detect and distinguish Salmonella spp. and Vibrio parahaemolyticus DNA in a single reaction. Two target sequences, one specific for Salmonella and the other specific for Vibrio parahaemolyticus, were amplified by specific LAMP primers in the same reaction tube. After amplification at 65 degrees C for 60 min, the amplified products were subjected to melting curve analysis and thus could be distinguished based on the different melting temperatures (Tm values) of the two specifically amplified products. The specificity of the multiplex LAMP assay was evaluated using 19 known bacterial strains, including one V. parahaemolyticus and seven Salmonella spp. strains. The multiplex LAMP showed 100% inclusivity and exclusivity, and a detection limit similar to that of multiplex PCR. In addition, we observed and corrected preferential amplification induced by what we call LAMP selection in the multiplex LAMP reaction. In conclusion, our assay was rapid, specific, and quantitative, making it a useful tool for the food industry. PMID- 28349968 TI - Neural Crest Cells Contribute an Astrocyte-like Glial Population to the Spleen. AB - Neural crest cells (NCC) are multi-potent cells of ectodermal origin that colonize diverse organs, including the gastrointestinal tract to form the enteric nervous system (ENS) and hematopoietic organs (bone marrow, thymus) where they participate in lymphocyte trafficking. Recent studies have implicated the spleen as an anatomic site for integration of inflammatory signals from the intestine with efferent neural inputs. We have previously observed alterations in splenic lymphocyte subsets in animals with defective migration of NCC that model Hirschsprung's disease, leading us to hypothesize that there may be a direct cellular contribution of NCC to the spleen. Here, we demonstrate that NCC colonize the spleen during embryogenesis and persist into adulthood. Splenic NCC display markers indicating a glial lineage and are arranged anatomically adjacent to blood vessels, pericytes and nerves, suggesting an astrocyte-like phenotype. Finally, we identify similar neural-crest derived cells in both the avian and non human primate spleen, showing evolutionary conservation of these cells. PMID- 28349969 TI - Minoxidil is a potential neuroprotective drug for paclitaxel-induced peripheral neuropathy. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment. No medication has been shown to be effective in the treatment of CIPN. This study aims to integrate the image-based high-content screening, mouse behavior models and mechanistic cell-based assays to discover potential neuroprotective drugs. Among screened compounds, minoxidil showed the most potent neuroprotective effect against paclitaxel, with regard to neurite outgrowth of dorsal root ganglia (DRG). Minoxidil protected mice from thermal insensitivity and alleviated mechanical allodynia in paclitaxel-treated mice. The ultrastructure and quantified G-ratio of myelin integrity of sciatic nerve tissues supported the observations in mouse behavioral tests. The mechanistic study on DRG neurons suggested that minoxidil suppressed neuroinflammation and remodeled the dysregulation of intracellular calcium homeostasis provoked by paclitaxel. Importantly, minoxidil showed a synergistic anti-tumor effect with paclitaxel both in tumor xenograft models of cervical and breast cancer. Interestingly, the quantitative assays on hair length and hair growth both exhibited that minoxidil significantly improved the hair quality after chemotherapy. Since minoxidil is a drug approved by the Food and Drug Administration (FDA), the safety and biocompatibility are well documented. The immediate next step is to launch an early-stage clinical trial intending to prevent CIPN by minoxidil. PMID- 28349970 TI - Effect of Size and Surface Charge of Gold Nanoparticles on their Skin Permeability: A Molecular Dynamics Study. AB - Molecular level understanding of permeation of nanoparticles through human skin establishes the basis for development of novel transdermal drug delivery systems and design and formulation of cosmetics. Recent experiments suggest that surface coated nano-sized gold nanoparticles (AuNPs) can penetrate the rat and human skin. However, the mechanisms by which these AuNPs penetrate are not well understood. In this study, we have carried out coarse grained molecular dynamics simulations to explore the permeation of dodecanethiol coated neutral hydrophobic AuNPs of different sizes (2-5 nm) and surface charges (cationic and anionic) through the model skin lipid membrane. The results indicate that the neutral hydrophobic AuNPs disrupted the bilayer and entered in it with in ~200 ns, while charged AuNPs were adsorbed on the bilayer headgroup. The permeation free energy calculation revealed that at the head group of the bilayer, a very small barrier existed for neutral hydrophobic AuNP while a free energy minimum was observed for charged AuNPs. The permeability was maximum for neutral 2 nm gold nanoparticle (AuNP) and minimum for 3 nm cationic AuNP. The obtained results are aligned with recent experimental findings. This study would be helpful in designing customized nanoparticles for cosmetic and transdermal drug delivery application. PMID- 28349971 TI - Nine phenylethanoid glycosides from Magnolia officinalis var. biloba fruits and their protective effects against free radical-induced oxidative damage. AB - To systematically study the chemical constituents in Magnolia officinalis var. biloba fruits, nine phenylethanoid glycosides were isolated by solvent extraction, silica gel, and preparative high-performance liquid chromatography (HPLC). Their structures were elucidated by 1D and 2D NMR analyses, including COSY, HMQC and HMBC correlations, and HPLC analysis of sugar residue. Nine phenylethanoid glycosides, namely, magnoloside Ia (1), magnoloside Ic (2), crassifolioside (3), magnoloside Ib (4), magnoloside IIIa (5), magnoloside IVa (6), magnoloside IIa (7), magnoloside IIb (8) and magnoloside Va (9), were first isolated from the n-butanol fraction of Magnolia officinalis var. biloba fruits alcohol extract. Free radical scavenging activities of the nine phenylethanoid glycosides were assessed using the DPPH, ABTS, and superoxide anion radical scavenging assays. Simultaneously, protective effects of all compounds against free radical-induced oxidative damage were evaluated by two different kinds of mitochondrial damage model. The protective effects were assessed by mitochondrial swelling, the formations of malondialdehyde (MDA) and lipid hydroperoxide (LOOH), the activities of catalase (CAT), glutathione reductase (GR) and superoxide dismutase (SOD). All phenylethanoid glycosides showed significant protective effects. PMID- 28349972 TI - Enteric glial cells counteract Clostridium difficile Toxin B through a NADPH oxidase/ROS/JNK/caspase-3 axis, without involving mitochondrial pathways. AB - Enteric glial cells (EGCs) are components of the intestinal epithelial barrier essential for regulating the enteric nervous system. Clostridium difficile is the most common cause of antibiotic-associated colitis, toxin B (TcdB) being the major virulence factor, due to its ability to breach the intestinal epithelial barrier and to act on other cell types. Here we investigated TcdB effects on EGCs and the activated molecular mechanisms. Already at 2 hours, TcdB triggered ROS formation originating from NADPH-oxidase, as demonstrated by their reduction in the presence of the NADPH-oxidase inhibitor ML171. Although EGCs mitochondria support almost completely the cellular ATP need, TcdB exerted weak effects on EGCs in terms of ATP and mitochondrial functionality, mitochondrial ROS production occurring as a late event. ROS activated the JNK signalling and overexpression of the proapoptotic Bim not followed by cytochrome c or AIF release to activate the downstream apoptotic cascade. EGCs underwent DNA fragmentation through activation of the ROS/JNK/caspase-3 axis, evidenced by the ability of ML171, N-acetylcysteine, and the JNK inhibitor SP600125 to inhibit caspase-3 or to contrast apoptosis. Therefore, TcdB aggressiveness towards EGCs is mainly restricted to the cytosolic compartment, which represents a peculiar feature, since TcdB primarily influences mitochondria in other cellular types. PMID- 28349973 TI - Strain-specific estimation of epidemic success provides insights into the transmission dynamics of tuberculosis. AB - The transmission dynamics of tuberculosis involves complex interactions of socio economic and, possibly, microbiological factors. We describe an analytical framework to infer factors of epidemic success based on the joint analysis of epidemiological, clinical and pathogen genetic data. We derive isolate-specific, genetic distance-based estimates of epidemic success, and we represent success related time-dependent concepts, namely epidemicity and endemicity, by restricting analysis to specific time scales. The method is applied to analyze a surveillance-based cohort of 1,641 tuberculosis patients with minisatellite-based isolate genotypes. Known predictors of isolate endemicity (older age, native status) and epidemicity (younger age, sputum smear positivity) were identified with high confidence (P < 0.001). Long-term epidemic success also correlated with the ability of Euro-American and Beijing MTBC lineages to cause active pulmonary infection, independent of patient age and country of origin. Our results demonstrate how important insights into the transmission dynamics of tuberculosis can be gained from active surveillance data. PMID- 28349976 TI - Geomicrobiology of the built environment. PMID- 28349974 TI - Sex-related alterations of gut microbiota composition in the BTBR mouse model of autism spectrum disorder. AB - Alterations of microbiota-gut-brain axis have been invoked in the pathogenesis of autism spectrum disorders (ASD). Mouse models could represent an excellent tool to understand how gut dysbiosis and related alterations may contribute to autistic phenotype. In this study we paralleled gut microbiota (GM) profiles, behavioral characteristics, intestinal integrity and immunological features of colon tissues in BTBR T + tf/J (BTBR) inbred mice, a well established animal model of ASD. Sex differences, up to date poorly investigated in animal models, were specifically addressed. Results showed that BTBR mice of both sexes presented a marked intestinal dysbiosis, alterations of behavior, gut permeability and immunological state with respect to prosocial C57BL/6j (C57) strain. Noticeably, sex-related differences were clearly detected. We identified Bacteroides, Parabacteroides, Sutterella, Dehalobacterium and Oscillospira genera as key drivers of sex-specific gut microbiota profiles associated with selected pathological traits. Taken together, our findings indicate that alteration of GM in BTBR mice shows relevant sex-associated differences and supports the use of BTBR mouse model to dissect autism associated microbiota-gut-brain axis alteration. PMID- 28349975 TI - Mechanism of functional interaction between potassium channel Kv1.3 and sodium channel NavBeta1 subunit. AB - The voltage-gated potassium channel subfamily A member 3 (Kv1.3) dominantly expresses on T cells and neurons. Recently, the interaction between Kv1.3 and NavBeta1 subunits has been explored through ionic current measurements, but the molecular mechanism has not been elucidated yet. We explored the functional interaction between Kv1.3 and NavBeta1 through gating current measurements using the Cut-open Oocyte Voltage Clamp (COVC) technique. We showed that the N-terminal 1-52 sequence of hKv1.3 disrupts the channel expression on the Xenopus oocyte membrane, suggesting a potential role as regulator of hKv1.3 expression in neurons and lymphocytes. Our gating currents measurements showed that NavBeta1 interacts with the voltage sensing domain (VSD) of Kv1.3 through W172 in the transmembrane segment and modifies the gating operation. The comparison between G V and Q-V with/without NavBeta1 indicates that NavBeta1 may strengthen the coupling between hKv1.3-VSD movement and pore opening, inducing the modification of kinetics in ionic activation and deactivation. PMID- 28349977 TI - Photoactive layer based on T-shaped benzimidazole dyes used for solar cell: from photoelectric properties to molecular design. AB - Three benzimidazole-based organic dyes, possessing the same triphenylamine donors and cyanoacrylic acid acceptors with the bithiophene pi-bridges combined in different nuclear positions of benzimidazole, were investigated in the utility of dye-sensitizer solar cells. The structure, molecular orbital and energy, absorption spectra and some important parameters (such as light harvesting efficiency (LHE), electron injection driving force, the electron injection time, chemical reactivity parameters, vertical dipole moment as well as interaction models of dye-I2) were obtained according to Newns-Anderson model and DFT calculation. The process and strength of charge transfer and separation were visualized with charge different density and index of spatial extent (S, D and Deltaq). Current work paid attention to the new T-shaped dyes to reveal the relation between the structure and photoelectric performance. Furthermore, nine dyes (substitution of alkyl chains and pi-bridges) have been designed and characterized to screen promising sensitizer candidates with excellent photo electronic properties. PMID- 28349978 TI - Patient selection for prostate focal therapy in the era of active surveillance: an International Delphi Consensus Project. AB - BACKGROUND: Whole-gland extirpation or irradiation is considered the gold standard for curative oncological treatment for localized prostate cancer, but is often associated with sexual and urinary impairment that adversely affects quality of life. This has led to increased interest in developing therapies with effective cancer control but less morbidity. We aimed to provide details of physician consensus on patient selection for prostate focal therapy (FT) in the era of contemporary prostate cancer management. METHODS: We undertook a four stage Delphi consensus project among a panel of 47 international experts in prostate FT. Data on three main domains (role of biopsy/imaging, disease and patient factors) were collected in three iterative rounds of online questionnaires and feedback. Consensus was defined as agreement in ?80% of physicians. Finally, an in-person meeting was attended by a core group of 16 experts to review the data and formulate the consensus statement. RESULTS: Consensus was obtained in 16 of 18 subdomains. Multiparametric magnetic resonance imaging (mpMRI) is a standard imaging tool for patient selection for FT. In the presence of an mpMRI-suspicious lesion, histological confirmation is necessary prior to FT. In addition, systematic biopsy remains necessary to assess mpMRI negative areas. However, adequate criteria for systematic biopsy remains indeterminate. FT can be recommended in D'Amico low-/intermediate-risk cancer including Gleason 4+3. Gleason 3+4 cancer, where localized, discrete and of favorable size represents the ideal case for FT. Tumor foci <1.5 ml on mpMRI or <20% of the prostate are suitable for FT, or up to 3 ml or 25% if localized to one hemi-gland. Gleason 3+3 at one core 1mm is acceptable in the untreated area. Preservation of sexual function is an important goal, but lack of erectile function should not exclude a patient from FT. CONCLUSIONS: This consensus provides a contemporary insight into expert opinion of patient selection for FT of clinically localized prostate cancer. PMID- 28349979 TI - Androgen deprivation therapy for prostate cancer and dementia risk: a systematic review and meta-analysis. AB - BACKGROUND: Androgen deprivation therapy (ADT) to treat prostate cancer may be associated with an increased risk of dementia, but existing studies have shown conflicting results. Here we synthesize the literature on the association of ADT for the treatment of prostate cancer with dementia risk. METHODS: We conducted a systematic review of articles reporting the outcome of dementia among individuals with prostate cancer in those exposed to ADT versus a lesser-exposed comparison group (for example, ADT versus no-ADT; continuous versus intermittent ADT) using PubMed (1966-present), Web of Science (1945-present), Embase (1966-present) and PsycINFO (1806-present). The search was undertaken on 4 December 2016 by two authors. We meta-analyzed studies reporting an effect estimate and controlling for confounding. Random- or fixed-effects meta-analytic models were used in the presence or absence of heterogeneity per the I2 statistic, respectively. Small study effects were evaluated using Egger and Begg's tests. RESULTS: Nine studies were included in the systematic review. Seven studies reported an adjusted effect estimate for dementia risk. A random-effects meta-analysis of studies reporting any dementia outcome, which included 50 541 individuals, showed an increased risk of dementia among ADT users (hazard ratio (HR), 1.47; 95% confidence interval (CI), 1.08-2.00; P=0.02). We separately meta-analyzed studies reporting all-cause dementia (HR, 1.46; 95% CI, 1.05-2.02; P<0.001) and Alzheimer's disease (HR, 1.25; 95% CI, 0.99-1.57; P=0.06). There was no evidence of bias from small study effects (Egger, P=0.19; Begg, P=1.00). CONCLUSION: The currently available combined evidence suggests that ADT in the treatment of prostate cancer may be associated with an increased dementia risk. The potential for neurocognitive deficits secondary to ADT should be discussed with patients and evaluated prospectively. PMID- 28349980 TI - Celastrol, an active constituent of the TCM plant Tripterygium wilfordii Hook.f., inhibits prostate cancer bone metastasis. PMID- 28349981 TI - Impact of urologists' ownership of radiation equipment in the treatment of prostate cancer. AB - BACKGROUND: Physician practices that offer ancillary medical services may refer their patients for such services, a process known as self-referral. We wanted to evaluate how utilization and cost of care differ for men diagnosed with prostate cancer in a self-referral practice (SRP) compared to a traditional urologic practice. METHODS: A total of 17 982 men aged 66 years and older diagnosed with localized prostate cancer from 2006 to 2009 were identified from the Texas Cancer Registry. A total of 13 SRPs in the state of Texas were evaluated. We used multilevel logistic regression models that evaluated the odds of receiving a specific type of treatment. RESULTS: Men diagnosed in SRPs were more likely to receive upfront treatment (vs watchful waiting/active surveillance) than men diagnosed by traditional practices (92.7% vs 89%; adjusted odds ratio (AOR) 1.61, 95% confidence interval (CI) 1.30-2.00; P<0.001) and were more likely to be treated with external beam radiation (47.4% vs 34.1%; AOR 1.59, 95% CI 1.37-1.84; P<0.001). This persisted for both favorable and unfavorable risk cancer. Median annual prostate cancer care cost was $2460 (95% CI $1663-$3368) higher for men diagnosed by SRPs. Limitations include data limited to men aged 65 years or older and geographic concentration of SRPs in Texas may not depict nationwide patterns. CONCLUSIONS: Older men diagnosed with prostate cancer in SRPs are more likely to undergo upfront treatment and to receive radiation treatment. This may increase appropriate treatment of unfavorable disease but contribute to overtreatment of favorable disease. PMID- 28349982 TI - DNA-Mediated Patterning of Single Quantum Dot Nanoarrays: A Reusable Platform for Single-Molecule Control. AB - We present a facile strategy of general applicability for the assembly of individual nanoscale moieties in array configurations with single-molecule control. Combining the programming ability of DNA as a scaffolding material with a one-step lithographic process, we demonstrate the patterning of single quantum dots (QDs) at predefined locations on silicon and transparent glass surfaces: as proof of concept, clusters of either one, two, or three QDs were assembled in highly uniform arrays with a 60 nm interdot spacing within each cluster. Notably, the platform developed is reusable after a simple cleaning process and can be designed to exhibit different geometrical arrangements. PMID- 28349983 TI - Molecular dynamics simulations for mechanical properties of borophene: parameterization of valence force field model and Stillinger-Weber potential. AB - While most existing theoretical studies on the borophene are based on first principles calculations, the present work presents molecular dynamics simulations for the lattice dynamical and mechanical properties in borophene. The obtained mechanical quantities are in good agreement with previous first-principles calculations. The key ingredients for these molecular dynamics simulations are the two efficient empirical potentials developed in the present work for the interaction of borophene with low-energy triangular structure. The first one is the valence force field model, which is developed with the assistance of the phonon dispersion of borophene. The valence force field model is a linear potential, so it is rather efficient for the calculation of linear quantities in borophene. The second one is the Stillinger-Weber potential, whose parameters are derived based on the valence force field model. The Stillinger-Weber potential is applicable in molecular dynamics simulations of nonlinear physical or mechanical quantities in borophene. PMID- 28349985 TI - Origin of high oxygen reduction reaction activity of Pt12 and strategy to obtain better catalyst using sub-nanosized Pt-alloy clusters. AB - In the present study, methods to enhance the oxygen reduction reaction (ORR) activity of sub-nanosized Pt clusters were investigated in a theoretical manner. Using ab initio molecular dynamics and Monte Carlo simulations based on density functional theory, we have succeeded in determining the origin of the superior ORR activity of Pt12 compared to that of Pt13. That is, it was clarified that the electronic structure of Pt12 fluctuates to a greater extent compared to that of Pt13, which leads to stronger resistance against catalyst poisoning by O/OH. Based on this conclusion, a set of sub-nanosized Pt-alloy clusters was also explored to find catalysts with better ORR activities and lower financial costs. It was suggested that Ga4Pt8, Ge4Pt8, and Sn4Pt8 would be good candidates for ORR catalysts. PMID- 28349984 TI - Evidence for salicylic acid signalling and histological changes in the defence response of Eucalyptus grandis to Chrysoporthe austroafricana. AB - Eucalyptus species are cultivated for forestry and are of economic importance. The fungal stem canker pathogen Chrysoporthe austroafricana causes disease of varying severity on E. grandis. The Eucalyptus grandis-Chrysoporthe austroafricana interaction has been established as a model system for studying Eucalyptus antifungal defence. Previous studies revealed that the phytohormone salicylic acid (SA) affects the levels of resistance in highly susceptible (ZG14) and moderately resistant (TAG5) clones. The aims of this study were to examine histochemical changes in response to wounding and inoculation as well as host responses at the protein level. The anatomy and histochemical changes induced by wounding and inoculation were similar between the clones, suggesting that anatomical differences do not underlie their different levels of resistance. Tyloses and gum-like substances were present after inoculation and wounding, but cell death occurred only after inoculation. Hyphae of C. austroafricana were observed inside dead and living cells, suggesting that the possibility of a hemibiotrophic interaction requires further investigation. Proteomics analysis revealed the possible involvement of proteins associated with cell death, SA signalling and systemic resistance. In combination with previous information, this study forms a basis for future functional characterisation of candidate genes involved in resistance of E. grandis to C. austroafricana. PMID- 28349986 TI - Spatial transcriptome analysis provides insights of key gene(s) involved in steroidal saponin biosynthesis in medicinally important herb Trillium govanianum. AB - Trillium govanianum, an endangered medicinal herb native to the Himalaya, is less studied at the molecular level due to the non-availability of genomic resources. To facilitate the basic understanding of the key genes and regulatory mechanism of pharmaceutically important biosynthesis pathways, first spatial transcriptome sequencing of T. govanianum was performed. 151,622,376 (~11.5 Gb) high quality reads obtained using paired-end Illumina sequencing were de novo assembled into 69,174 transcripts. Functional annotation with multiple public databases identified array of genes involved in steroidal saponin biosynthesis and other secondary metabolite pathways including brassinosteroid, carotenoid, diterpenoid, flavonoid, phenylpropanoid, steroid and terpenoid backbone biosynthesis, and important TF families (bHLH, MYB related, NAC, FAR1, bZIP, B3 and WRKY). Differentially expressed large number of transcripts, together with CYPs and UGTs suggests involvement of these candidates in tissue specific expression. Combined transcriptome and expression analysis revealed that leaf and fruit tissues are the main site of steroidal saponin biosynthesis. In conclusion, comprehensive genomic dataset created in the current study will serve as a resource for identification of potential candidates for genetic manipulation of targeted bioactive metabolites and also contribute for development of functionally relevant molecular marker resource to expedite molecular breeding and conservation efforts in T. govanianum. PMID- 28349987 TI - Conditional Deletion of the Phd2 Gene in Articular Chondrocytes Accelerates Differentiation and Reduces Articular Cartilage Thickness. AB - Based on our findings that PHD2 is a negative regulator of chondrocyte differentiation and that hypoxia signaling is implicated in the pathogenesis of osteoarthritis, we investigated the consequence of disruption of the Phd2 gene in chondrocytes on the articular cartilage phenotype in mice. Immunohistochemistry detected high expression of PHD2 in the superficial zone (SZ), while PHD3 and HIF 1alpha (target of PHD2) are mainly expressed in the middle-deep zone (MDZ). Conditional deletion of the Phd2 gene (cKO) in chondrocytes accelerated the transition of progenitors to hypertrophic (differentiating) chondrocytes as revealed by reduced SZ thickness, and increased MDZ thickness, as well as increased chondrocyte hypertrophy. Immunohistochemistry further revealed decreased levels of progenitor markers but increased levels of hypertrophy markers in the articular cartilage of the cKO mice. Treatment of primary articular chondrocytes, in vitro, with IOX2, a specific inhibitor of PHD2, promoted articular chondrocyte differentiation. Knockdown of Hif-1alpha expression in primary articular chondrocytes using lentiviral vectors containing Hif-1alpha shRNA resulted in reduced expression levels of Vegf, Glut1, Pgk1, and Col10 compared to control shRNA. We conclude that Phd2 is a key regulator of articular cartilage development that acts by inhibiting the differentiation of articular cartilage progenitors via modulating HIF-1alpha signaling. PMID- 28349988 TI - Efficient collective influence maximization in cascading processes with first order transitions. AB - In many social and biological networks, the collective dynamics of the entire system can be shaped by a small set of influential units through a global cascading process, manifested by an abrupt first-order transition in dynamical behaviors. Despite its importance in applications, efficient identification of multiple influential spreaders in cascading processes still remains a challenging task for large-scale networks. Here we address this issue by exploring the collective influence in general threshold models of cascading process. Our analysis reveals that the importance of spreaders is fixed by the subcritical paths along which cascades propagate: the number of subcritical paths attached to each spreader determines its contribution to global cascades. The concept of subcritical path allows us to introduce a scalable algorithm for massively large scale networks. Results in both synthetic random graphs and real networks show that the proposed method can achieve larger collective influence given the same number of seeds compared with other scalable heuristic approaches. PMID- 28349989 TI - Distribution pattern of left-ventricular myocardial strain analyzed by a cine MRI based deformation registration algorithm in healthy Chinese volunteers. AB - The cine magnetic resonance imaging based technique feature tracking-cardiac magnetic resonance (FT-CMR) is emerging as a novel, simple and robust method to evaluate myocardial strain. We investigated the distribution characteristics of left-ventricular myocardial strain using a novel cine MRI based deformation registration algorithm (DRA) in a cohort of healthy Chinese subjects. A total of 130 healthy Chinese subjects were enrolled. Three components of orthogonal strain (radial, circumferential, longitudinal) of the left ventricle were analyzed using DRA on steady-state free precession cine sequence images. A distinct transmural circumferential strain gradient was observed in the left ventricle that showed universal increment from the epicardial to endocardial myocardial wall (epiwall: 15.4 +/- 1.9%; midwall: -18.8 +/- 2.0%; endowall: -22.3 +/- 2.3%, P < 0.001). Longitudinal strain showed a similar trend from epicardial to endocardial layers (epiwall: -16.0 +/- 2.9%; midwall: -15.6 +/- 2.7%; endowall: -14.8 +/- 2.4%, P < 0.001), but radial strain had a very heterogeneous distribution and variation. In the longitudinal direction from the base to the apex of the left ventricle, there was a trend of decreasing peak systolic longitudinal strain (basal: -23.3 +/- 4.6%; mid: -13.7 +/- 7.3%; apical: -13.2 +/- 5.5%; P < 0.001). In conclusion, there are distinct distribution patterns of circumferential and longitudinal strain within the left ventricle in healthy Chinese subjects. These distribution patterns of strain may provide unique profiles for further study in different types of myocardial disease. PMID- 28349990 TI - Silver Nanowires Modified with PEDOT: PSS and Graphene for Organic Light-Emitting Diodes Anode. AB - Silver nanowires (AgNWs) networks are promising candidates for the replacement of indium tin oxide (ITO). However, the surface roughness of the AgNWs network is still too high for its application in optoelectronic devices. In this work, we have reduced the surface roughness of the AgNWs networks to 6.4 nm, compared to 33.9 nm of the as-deposited AgNWs network through the hot-pressing process, treatment with poly (3,4ethylenedioxythiophene)-poly (styrenesulfanate), and covered with graphene films. Using this method, we are able to produce AgNWs/PEDOT: PSS/SLG composite films with the transmittance and sheet resistance of 88.29% and 30 Omega/?, respectively. The OLEDs based on the AgNWs/PEDOT: PSS/SLG anodes are comparable to those based on ITO anodes. PMID- 28349992 TI - Central Neuromodulators for Treating Functional GI Disorders: A Primer. AB - Patients with functional GI disorders (FGIDs) are commonplace in the gastroenterologist's practice. A number of these patients may be refractory to peripherally acting agents, yet respond to central neuromodulators. There are benefits and potential adverse effects to using TCAs, SSRIs, SNRIs, atypical antipsychotics, and miscellaneous central neuromodulators in these patients. These agents can benefit mood, pain, diarrhea, constipation, nausea, sleep, and depression. The mechanisms by which they work, the differences between classes and individual agents, and the various adverse effects are outlined. Dosing, augmentation strategies, and treatment scenarios specifically for painful FGIDs, FD with PDS, and chronic nausea and vomiting syndrome are outlined. PMID- 28349991 TI - Antiproliferative effects of ruthenium-based nucleolipidic nanoaggregates in human models of breast cancer in vitro: insights into their mode of action. AB - Looking for new metal-based anticancer treatments, in recent years many ruthenium complexes have been proposed as effective and safe potential drugs. In this context we have recently developed a novel approach for the in vivo delivery of Ru(III) complexes, preparing stable ruthenium-based nucleolipidic nanoaggregates endowed with significant antiproliferative activity. Herein we describe the cellular response to our ruthenium-containing formulations in selected models of human breast cancer. By in vitro bioscreens in the context of preclinical studies, we have focused on their ability to inhibit breast cancer cell proliferation by the activation of the intrinsic apoptotic pathway, possibly via mitochondrial perturbations involving Bcl-2 family members and predisposing to programmed cell death. In addition, the most efficient ruthenium-containing cationic nanoaggregates we have hitherto developed are able to elicit both extrinsic and intrinsic apoptosis, as well as autophagy. To limit chemoresistance and counteract uncontrolled proliferation, multiple cell death pathways activation by metal-based chemotherapeutics is a challenging, yet very promising strategy for targeted therapy development in aggressive cancer diseases, such as triple-negative breast cancer with limited treatment options. These outcomes provide valuable, original knowledge on ruthenium-based candidate drugs and new insights for future optimized cancer treatment protocols. PMID- 28349993 TI - Cannabinoid Receptor Type 1 and mu-Opioid Receptor Polymorphisms Are Associated With Cyclic Vomiting Syndrome. AB - OBJECTIVES: Cyclic vomiting syndrome (CVS) is a disorder defined by recurrent, unexplained episodes of severe nausea and vomiting. Our aim was to investigate whether CVS and pathophysiological mechanisms underlying this condition are associated with selected variations in genes encoding the components of the endogenous cannabinoid and opioid systems. METHODS: This case-control study included 65 patients with CVS-16 male and 49 female, and 1,092 healthy controls 525 male and 567 female from the 1000 Genomes Project. CVS subjects filled out study-specific questionnaires. Single-nucleotide polymorphisms (SNPs) in genes encoding cannabinoid receptors (CNR1 and CNR2), fatty acid amide hydrolase (FAAH) and mu-opioid receptor (OPRM1) were analyzed using the TaqMan SNP genotyping assay. Correlations between SNP's and clinical characteristics of CVS were ascertained. RESULTS: Our study disclosed an increased risk of CVS among individuals with AG and GG genotypes of CNR1 rs806380 (P<0.01), whereas the CC genotype of CNR1 rs806368 and AG and GG genotypes of OPRM1 rs1799971 were associated with a decreased risk of CVS (P<0.05). In addition, AG and GG genotypes of OPRM1 rs1799971 were correlated with migraine episodes, AG and GG of OPRM1 rs1799971, and CT and CC of CNR1 rs806368 with a family history of migraines (second degree relatives), and CT and CC of CNR1 rs2023239 with a positive response to therapy. CONCLUSIONS: Our results show for the first time that the variations in CNR1 and OPRM1 genes are associated with CVS and that different genotypes may contribute to the risk of CVS. PMID- 28349994 TI - Recommendations on Surveillance and Management of Biallelic Mismatch Repair Deficiency (BMMRD) Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. AB - The US Multi-Society Task Force on Colorectal Cancer, with invited experts, developed a consensus statement and recommendations to assist health care providers with appropriate management of patients with biallelic mismatch repair deficiency (BMMRD) syndrome, also called constitutional mismatch repair deficiency syndrome. This position paper outlines what is known about BMMRD, the unique genetic and clinical aspects of the disease, and reviews the current management approaches to this disorder. This article represents a starting point from which diagnostic and management decisions can undergo rigorous testing for efficacy. There is a lack of strong evidence and a requirement for further research. Nevertheless, providers need direction on how to recognize and care for BMMRD patients today. In addition to identifying areas of research, this article provides guidance for surveillance and management. The major challenge is that BMMRD is rare, limiting the ability to accumulate unbiased data and develop controlled prospective trials. The formation of effective international consortia that collaborate and share data is proposed to accelerate our understanding of this disease. PMID- 28349995 TI - Formation mechanism of fivefold deformation twins in a face-centered cubic alloy. AB - The formation mechanism considers fivefold deformation twins originating from the grain boundaries in a nanocrystalline material, resulting in that fivefold deformation twins derived from a single crystal have not been reported by molecular dynamics simulations. In this study, fivefold deformation twins are observed in a single crystal of face-centered cubic (fcc) alloy. A new formation mechanism is proposed for fivefold deformation twins in a single crystal. A partial dislocation is emitted from the incoherent twin boundaries (ITBs) with high energy, generating a stacking fault along {111} plane, and resulting in the nucleating and growing of a twin by the successive emission of partials. A node is fixed at the intersecting center of the four different slip {111} planes. With increasing stress under the indentation, ITBs come into being close to the node, leading to the emission of a partial from the node. This generates a stacking fault along a {111} plane, nucleating and growing a twin by the continuous emission of the partials. This process repeats until the formation of fivefold deformation twins. PMID- 28349997 TI - Applying Taguchi design and large-scale strategy for mycosynthesis of nano-silver from endophytic Trichoderma harzianum SYA.F4 and its application against phytopathogens. AB - Development of reliable and low-cost requirement for large-scale eco-friendly biogenic synthesis of metallic nanoparticles is an important step for industrial applications of bionanotechnology. In the present study, the mycosynthesis of spherical nano-Ag (12.7 +/- 0.8 nm) from extracellular filtrate of local endophytic T. harzianum SYA.F4 strain which have interested mixed bioactive metabolites (alkaloids, flavonoids, tannins, phenols, nitrate reductase (320 nmol/hr/ml), carbohydrate (25 MUg/MUl) and total protein concentration (2.5 g/l) was reported. Industrial mycosynthesis of nano-Ag can be induced with different characters depending on the fungal cultivation and physical conditions. Taguchi design was applied to improve the physicochemical conditions for nano-Ag production, and the optimum conditions which increased its mass weight 3 times larger than a basal condition were as follows: AgNO3 (0.01 M), diluted reductant (10 v/v, pH 5) and incubated at 30 degrees C, 200 rpm for 24 hr. Kinetic conversion rates in submerged batch cultivation in 7 L stirred tank bioreactor on using semi-defined cultivation medium was as follows: the maximum biomass production (Xmax) and maximum nano-Ag mass weight (Pmax) calculated (60.5 g/l and 78.4 g/l respectively). The best nano-Ag concentration that formed large inhibition zones was 100 MUg/ml which showed against A.alternate (43 mm) followed by Helminthosporium sp. (35 mm), Botrytis sp. (32 mm) and P. arenaria (28 mm). PMID- 28349998 TI - A new fluorescent probe for colorimetric and ratiometric detection of sulfur dioxide derivatives in liver cancer cells. AB - A new ratiometric fluorescent probe was constructed with hemicyanine and 7 nitrobenzofurazan for detection of sulfur dioxide derivatives (HSO3-/SO32-). The ratiometric response mode could be attributed to the efficient FRET (Forster resonance energy transfer) platform. The probe exbihited some desirable properties including fast response (within 2 minutes), good selectivity and high sensitivity. Moreover, the probe could detect endogenous HSO3- in liver cancer cells rather than normal liver cells, implying the diagnosal potential of the probe. PMID- 28349996 TI - Proteome dynamics during postnatal mouse corpus callosum development. AB - Formation of cortical connections requires the precise coordination of numerous discrete phases. This is particularly significant with regard to the corpus callosum, whose development undergoes several dynamic stages including the crossing of axon projections, elimination of exuberant projections, and myelination of established tracts. To comprehensively characterize the molecular events in this dynamic process, we set to determine the distinct temporal expression of proteins regulating the formation of the corpus callosum and their respective developmental functions. Mass spectrometry-based proteomic profiling was performed on early postnatal mouse corpus callosi, for which limited evidence has been obtained previously, using stable isotope of labeled amino acids in mammals (SILAM). The analyzed corpus callosi had distinct proteomic profiles depending on age, indicating rapid progression of specific molecular events during this period. The proteomic profiles were then segregated into five separate clusters, each with distinct trajectories relevant to their intended developmental functions. Our analysis both confirms many previously-identified proteins in aspects of corpus callosum development, and identifies new candidates in understudied areas of development including callosal axon refinement. We present a valuable resource for identifying new proteins integral to corpus callosum development that will provide new insights into the development and diseases afflicting this structure. PMID- 28349999 TI - Potential of MALDI-TOF MS as an alternative approach for capsular typing Streptococcus pneumoniae isolates. AB - Streptococcus pneumoniae can be classified in more than 90 capsular types, as traditionally determined by serological methods and more recently by PCR-based techniques. Such methods, however, can be expensive, laborious or unable to accurately discriminate among certain serotypes. Therefore, determination of capsular types, although extremely important for epidemiological purposes and for estimating the impact of pneumococcal conjugate vaccines, is mainly restricted to research laboratories, being rarely performed in the clinical setting. In the present study, MALDI-TOF MS was evaluated as an alternative tool to characterize 416 pneumococcal isolates belonging to serotypes 6A, 6B, 6C, 9N, 9V or 14. For MALDI-TOF MS analysis, each isolate was submitted to an extraction protocol using formic acid and acetonitrile. Measurements were performed with a Bruker Microflex LT mass spectrometer using default parameters and generating spectra in the range of 2,000-20,000 m/z. Spectra were analyzed with the BioNumerics software v7.6. Isolates were mainly distributed according to the capsular type in a Neighbor Joining tree and serotypes investigated were successfully discriminated by the presence/absence of 14 selected biomarkers. The results suggest that MALDI-TOF MS is a promising alternative for typing pneumococcal strains, highlighting its usefulness for rapid and cost-effective routine application in clinical laboratories. PMID- 28350000 TI - Engineering Structurally Interacting RNA (sxRNA). AB - RNA-based three-way junctions (3WJs) are naturally occurring structures found in many functional RNA molecules including rRNA, tRNA, snRNA and ribozymes. 3WJs are typically characterized as resulting from an RNA molecule folding back on itself in cis but could also form in trans when one RNA, for instance a microRNA binds to a second structured RNA, such as a mRNA. Trans-3WJs can influence the final shape of one or both of the RNA molecules and can thus provide a means for modulating the availability of regulatory motifs including potential protein or microRNA binding sites. Regulatory 3WJs generated in trans represent a newly identified regulatory category that we call structurally interacting RNA or sxRNA for convenience. Here we show that they can be rationally designed using familiar cis-3WJ examples as a guide. We demonstrate that an sxRNA "bait" sequence can be designed to interact with a specific microRNA "trigger" sequence, creating a regulatable RNA-binding protein motif that retains its functional activity. Further, we show that when placed downstream of a coding sequence, sxRNA can be used to switch "ON" translation of that sequence in the presence of the trigger microRNA and the amount of translation corresponded with the amount of microRNA present. PMID- 28350002 TI - Why prokaryotes have pangenomes. PMID- 28350001 TI - A new molecular prognostic score for predicting the risk of distant metastasis in patients with HR+/HER2- early breast cancer. AB - To make an optimal treatment decision for early stage breast cancer, it is important to identify risk of recurrence. Here, we developed and validated a new prognostic model for predicting the risk of distant metastasis in patients with pN0-N1, hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer treated with hormone therapy alone. RNA was extracted from formalin-fixed, paraffin-embedded tumor tissues and gene expression was measured by quantitative real-time reverse transcription-PCR. The relative expression of six novel prognostic genes was combined with two clinical variables (nodal status and tumor size) to calculate a risk score (BCT score). In the validation cohort treated with hormone therapy alone, the 10 year rate of distant metastasis in the high risk group (26.3%) according to BCT score was significantly higher than that in the low-risk group (3.8%) (P < 0.001). Multivariate analysis adjusted for clinical variables revealed that BCT score is an independent predictor of distant metastasis. Moreover, the C-index estimate revealed that BCT score has a prognostic power superior to that of prognostic models based on clinicopathological parameters. The BCT score outperforms prognostic models based on traditional clinicopathological factors and predicts the risk of distant metastasis in patients with HR+/HER2- early breast cancer. PMID- 28350003 TI - Room temperature three-photon pumped CH3NH3PbBr3 perovskite microlasers. AB - Hybrid lead halide perovskites have made great strides in next-generation light harvesting and light emitting devices. Recently, they have also shown great potentials in nonlinear optical materials. Two-photon absorption and two-photon light emission have been thoroughly studied in past two years. However, the three photon processes are rarely explored, especially for the laser emissions. Here we synthesized high quality CH3NH3PbBr3 perovskite microstructures with solution processed precipitation method and studied their optical properties. When the microstructures are pumped with intense 1240 nm lasers, we have observed clear optical limit effect and the band-to-band photoluminescence at 540 nm. By increasing the pumping density, whispering-gallery-mode based microlasers have been achieved from CH3NH3PbBr3 perovskite microplate and microrod for the first time. This work demonstrates the potentials of hybrid lead halide perovskites in nonlinear photonic devices. PMID- 28350006 TI - Reconstructing the Geomagnetic Field in West Africa: First Absolute Intensity Results from Burkina Faso. AB - We present absolute geomagnetic intensities from iron smelting furnaces discovered at the metallurgical site of Korsimoro, Burkina Faso. Up to now, archaeologists recognized four different types of furnaces based on different construction methods, which were related to four subsequent time periods. Additionally, radiocarbon ages obtained from charcoal confine the studied furnaces to ages ranging from 700-1700 AD, in good agreement with the archaeologically determined time periods for each type of furnace. Archaeointensity results reveal three main groups of Arai diagrams. The first two groups contain specimens with either linear Arai diagrams, or slightly curved diagrams or two phases of magnetization. The third group encompasses specimens with strong zigzag or curvature in their Arai diagrams. Specimens of the first two groups were accepted after applying selection criteria to guarantee the high quality of the results. Our data compared to palaeosecular variation curves show a similar decreasing trend between 900-1500 AD. However, they reveal larger amplitudes at around 800 AD and 1650 AD than the reference curves and geomagnetic field models. Furthermore, they agree well with archaeomagnetic data from Mali and Senegal around 800 AD and with volcanic data around 1700 AD. PMID- 28350005 TI - Chloro-benquinone Modified on Graphene Oxide as Metal-free Catalyst: Strong Promotion of Hydroxyl Radical and Generation of Ultra-Small Graphene Oxide. AB - Carbon-based metal-free catalyst has attracted more and more attention. It is a big challenge to improve catalytic activity of metal-free catalyst for decomposition of H2O2 to produce hydroxyl radical (HO*). Here, we report chloro benquinone (TCBQ) modified on graphene oxide (GO) as metal-free catalyst for strong promotion of HO*. By the incorporation of GO, the HO* production by H2O2 and TCBQ is significantly promoted. Based on density functional theory, TCBQ modified GO (GO-TCBQ) is more prone to be nucleophilic attacked by H2O2 to yield HO* via electron transfer acceleration. Furthermore, the generated HO* can cut GO nanosheets into uniform ultra-small graphene oxide (USGO) through the cleavage of epoxy and C-C bonds. Interestingly, the damaged GO and in situ formed GO fragments can further enhance decomposition of H2O2 to produce HO*. Different from other catalytic processes, the GO-TCBQ metal-free catalysis process can be enhanced by GO itself, producing more HO*, and uniform USGO also can be generated. Thus, the metal free catalysis will be considered a fabrication method for uniform USGO, and may be extended to other fields including detoxifying organic pollutants and the application as disinfectants. PMID- 28350004 TI - Mitochondrial DNA and trade data support multiple origins of Helicoverpa armigera (Lepidoptera, Noctuidae) in Brazil. AB - The Old World bollworm Helicoverpa armigera is now established in Brazil but efforts to identify incursion origin(s) and pathway(s) have met with limited success due to the patchiness of available data. Using international agricultural/horticultural commodity trade data and mitochondrial DNA (mtDNA) cytochrome oxidase I (COI) and cytochrome b (Cyt b) gene markers, we inferred the origins and incursion pathways into Brazil. We detected 20 mtDNA haplotypes from six Brazilian states, eight of which were new to our 97 global COI-Cyt b haplotype database. Direct sequence matches indicated five Brazilian haplotypes had Asian, African, and European origins. We identified 45 parsimoniously informative sites and multiple substitutions per site within the concatenated (945 bp) nucleotide dataset, implying that probabilistic phylogenetic analysis methods are needed. High diversity and signatures of uniquely shared haplotypes with diverse localities combined with the trade data suggested multiple incursions and introduction origins in Brazil. Increasing agricultural/horticultural trade activities between the Old and New Worlds represents a significant biosecurity risk factor. Identifying pest origins will enable resistance profiling that reflects countries of origin to be included when developing a resistance management strategy, while identifying incursion pathways will improve biosecurity protocols and risk analysis at biosecurity hotspots including national ports. PMID- 28350007 TI - Laser beam melting 3D printing of Ti6Al4V based porous structured dental implants: fabrication, biocompatibility analysis and photoelastic study. AB - Fabricating Ti alloy based dental implants with defined porous scaffold structure is a promising strategy for improving the osteoinduction of implants. In this study, we use Laser Beam Melting (LBM) 3D printing technique to fabricate porous Ti6Al4V dental implant prototypes with three controlled pore sizes (200, 350 and 500 MUm). The mechanical stress distribution in the surrounding bone tissue is characterized by photoelastography and associated finite element simulation. For in-vitro studies, experiments on implants' biocompatibility and osteogenic capability are conducted to evaluate the cellular response correlated to the porous structure. As the preliminary results, porous structured implants show a lower stress-shielding to the surrounding bone at the implant neck and a more densed distribution at the bottom site compared to the reference implant. From the cell proliferation tests and the immunofluorescence images, 350 and 500 MUm pore sized implants demonstrate a better biocompatibility in terms of cell growth, migration and adhesion. Osteogenic genes expression of the 350 MUm group is significantly increased alone with the ALP activity test. All these suggest that a pore size of 350 MUm provides an optimal provides an optimal potential for improving the mechanical shielding to the surrounding bones and osteoinduction of the implant itself. PMID- 28350009 TI - Activation of ERK1/2 Causes Pazopanib Resistance via Downregulation of DUSP6 in Synovial Sarcoma Cells. AB - Synovial sarcoma (SS) is a rare high-grade malignant mesenchymal tumour with a relatively poor prognosis despite intensive multimodal therapy. Although pazopanib, a multi-kinase inhibitor, is often used for advanced SS, most cases eventually become resistant to pazopanib. In the present study, we investigated the mechanisms of acquired pazopanib resistance in SS. To examine acquired pazopanib resistance, two SS cell lines, SYO-1 and HS-SY-II, were isolated after multiple selection steps with increasing concentrations of pazopanib. SYO-1 was also used in vivo. Then, pazopanib-resistant clones were investigated to assess potential mechanisms of acquired pazopanib resistance. Stable pazopanib-resistant clones were established and exhibited enhanced cell cycle progression, cell growth with increased ERK1/2 phosphorylation, and higher sensitivity than parental cells to a MEK-inhibitor, trametinib, both in vitro and in vivo. Furthermore, addition of low-dose trametinib partially reversed the pazopanib resistance. In the pazopanib-resistant clones, dual specificity phosphatase 6 (DUSP6) was downregulated. Inhibition of DUSP6 expression in parental HS-SY-II cells partially recapitulated acquired pazopanib resistance. Acquired pazopanib resistance in SS was associated with activation of ERK1/2 through downregulation of DUSP6 expression. Simultaneous treatment with pazopanib and a MEK inhibitor could be a promising strategy to overcome pazopanib resistance in SS. PMID- 28350008 TI - STAT3 and NF-kappaB are Simultaneously Suppressed in Dendritic Cells in Lung Cancer. AB - Tumour-induced dendritic cell (DC) dysfunction plays an important role in cancer immune escape. However, the underlying mechanisms are not yet fully understood, reflecting the lack of appropriate experimental models both in vivo and in vitro. In the present study, an in vitro study model for tumour-induced DC dysfunction was established by culturing DCs with pooled sera from multiple non-small cell lung cancer (NSCLC) patients. The results demonstrated that tumour-induced human monocyte-derived DCs exhibited systematic functional deficiencies. Transcriptomics analysis revealed that the expression of major functional cluster genes, including the MHC class II family, cytokines, chemokines, and co stimulatory molecules, was significantly altered in tumour-induced DCs compared to that in control cells. Further examination confirmed that both NF-kappaB and STAT3 signalling pathways were simultaneously repressed by cancer sera, suggesting that the attenuated NF-kappaB and STAT3 signalling could be the leading cause of DC dysfunction in cancer. Furthermore, reversing the deactivated NF-kappaB and STAT3 signalling could be a strategy for cancer immunotherapy. PMID- 28350010 TI - Albino T-DNA tomato mutant reveals a key function of 1-deoxy-D-xylulose-5 phosphate synthase (DXS1) in plant development and survival. AB - Photosynthetic activity is indispensable for plant growth and survival and it depends on the synthesis of plastidial isoprenoids as chlorophylls and carotenoids. In the non-mevalonate pathway (MEP), the 1-deoxy-D-xylulose-5 phosphate synthase 1 (DXS1) enzyme has been postulated to catalyze the rate limiting step in the formation of plastidial isoprenoids. In tomato, the function of DXS1 has only been studied in fruits, and hence its functional relevance during plant development remains unknown. Here we report the characterization of the wls-2297 tomato mutant, whose severe deficiency in chlorophylls and carotenoids promotes an albino phenotype. Additionally, growth of mutant seedlings was arrested without developing vegetative organs, which resulted in premature lethality. Gene cloning and silencing experiments revealed that the phenotype of wls-2297 mutant was caused by 38.6 kb-deletion promoted by a single T-DNA insertion affecting the DXS1 gene. This was corroborated by in vivo and molecular complementation assays, which allowed the rescue of mutant phenotype. Further characterization of tomato plants overexpressing DXS1 and comparative expression analysis indicate that DXS1 may play other important roles besides to that proposed during fruit carotenoid biosynthesis. Taken together, these results demonstrate that DXS1 is essentially required for the development and survival of tomato plants. PMID- 28350012 TI - Investigation on the plasmon Talbot effect of finite-sized periodic arrays of metallic nanoapertures. AB - We present an in-depth and systematical investigation on the plasmon Talbot effect of finite-sized two-dimensional (2D) periodic metallic nanoaperture arrays. The nanoaperture shapes, fill factor, lattice distribution, array size, film thickness, material property and polarization state of the incident light are considered, and the inherent influencing rules are summarized via the three dimensional (3D) finite-difference time-domain (FDTD) numerical simulations. The nanoaperture shapes, fill factor or array size seems to express a tiny influence on Talbot effect, which shows a good agreement with our previously reported experimental results. Besides, square lattice brings out a much more uniform Talbot pattern than the triangular distribution, and the smaller array period should be taken to estimate the Talbot distance when it comes to a rectangular distribution. Furthermore, the thickness of Au film is suggested to within the range of 50~100 nm, which gives a broadest Talbot contour. It is also found out that the elliptical shape of hotspots is closely related to the linearly polarization state of the light source, showing an asymmetric electromagnetic field. The research contributes to a better understanding of the optical transmission features through periodic metallic nanoaperture arrays, which provides opportunities for the potential applications such as nanofabrication, optoelectronics, and imaging. PMID- 28350013 TI - Inelastic electron injection in a water chain. AB - Irradiation of biological matter triggers a cascade of secondary particles that interact with their surroundings, resulting in damage. Low-energy electrons are one of the main secondary species and electron-phonon interaction plays a fundamental role in their dynamics. We have developed a method to capture the electron-phonon inelastic energy exchange in real time and have used it to inject electrons into a simple system that models a biological environment, a water chain. We simulated both an incoming electron pulse and a steady stream of electrons and found that electrons with energies just outside bands of excited molecular states can enter the chain through phonon emission or absorption. Furthermore, this phonon-assisted dynamical behaviour shows great sensitivity to the vibrational temperature, highlighting a crucial controlling factor for the injection and propagation of electrons in water. PMID- 28350011 TI - Characterisation of male breast cancer: a descriptive biomarker study from a large patient series. AB - Male breast cancer (MBC) is rare. We assembled 446 MBCs on tissue microarrays and assessed clinicopathological information, together with data from 15 published studies, totalling 1984 cases. By immunohistochemistry we investigated 14 biomarkers (ERalpha, ERbeta1, ERbeta2, ERbeta5, PR, AR, Bcl-2, HER2, p53, E cadherin, Ki67, survivin, prolactin, FOXA1) for survival impact. The main histological subtype in our cohort and combined analyses was ductal (81%, 83%), grade 2; (40%, 44%), respectively. Cases were predominantly ERalpha (84%, 82%) and PR positive (74%, 71%), respectively, with HER2 expression being infrequent (2%, 10%), respectively. In our cohort, advanced age (>67) was the strongest predictor of overall (OS) and disease free survival (DFS) (p = 0.00001; p = 0.01, respectively). Node positivity negatively impacted DFS (p = 0.04). FOXA1 p = 0.005) and AR p = 0.009) were both positively prognostic for DFS, remaining upon multivariate analysis. Network analysis showed ERalpha, AR and FOXA1 significantly correlated. In summary, the principle phenotype of MBC was luminal A, ductal, grade 2. In ERalpha+ MBC, only AR had prognostic significance, suggesting AR blockade could be employed therapeutically. PMID- 28350014 TI - Extremely high-performance visible light photodetector in the Sb2SeTe2 nanoflake. AB - The photocurrent was performed in the Sb2SeTe2 topological insulator at a wavelength of 532 nm. It exhibits extremely high performance that the responsivity and the photoconductive gain reach 2293 AW-1 and 5344 at 1 V. This high photoresponse is orders of magnitude higher than most reported values in topological insulators and two-dimensional transitional metal dichalcogenides. This finding suggests that the Sb2SeTe2 nanoflake has great potential for future optoelectronic device applications. PMID- 28350016 TI - Neointima development in externally stented saphenous vein grafts. External stents are bad for the patient: why not use an undamaged saphenous vein for coronary artery bypass graft? PMID- 28350017 TI - Highly selective synthesis of substituted (E)-alkenylsilatranes via catalytic trans-silylation and mechanistic implications. AB - A new route for the synthesis of functionalized alkenylsilatranes has been developed based on ruthenium-catalyzed trans-silylation with olefins. This transformation allowed for the synthesis of new (E)-alkenylsilatranes in good yields and excellent selectivity. Experimental studies concerning the reaction mechanism were carried out and the intermediate ruthenium-silatranyl complex was isolated and characterized. Moreover, detailed DFT calculations regarding the mechanism of the silylative coupling catalytic cycle of silatranes catalyzed by [Ru]-H complexes were also performed. PMID- 28350018 TI - Frequency tuning allows flow direction control in microfluidic networks with passive features. AB - Frequency tuning has emerged as an attractive alternative to conventional pumping techniques in microfluidics. Oscillating (AC) flow driven through a passive valve can be rectified to create steady (DC) flow, and tuning the excitation frequency to the characteristic (resonance) frequency of the underlying microfluidic network allows control of flow magnitude using simple hardware, such as an on chip piezo buzzer. In this paper, we report that frequency tuning can also be used to control the direction (forward or backward) of the rectified DC flow in a single device. Initially, we observed that certain devices provided DC flow in the "forward" direction expected from previous work with a similar valve geometry, and the maximum DC flow occurred at the same frequency as a prominent peak in the AC flow magnitude, as expected. However, devices of a slightly different geometry provided the DC flow in the opposite direction and at a frequency well below the peak AC flow. Using an equivalent electrical circuit model, we found that the "forward" DC flow occurred at the series resonance frequency (with large AC flow peak), while the "backward" DC flow occurred at a less obvious parallel resonance (a valley in AC flow magnitude). We also observed that the DC flow occurred only when there was a measurable differential in the AC flow magnitude across the valve, and the DC flow direction was from the channel with large AC flow magnitude to that with small AC flow magnitude. Using these observations and the AC flow predictions from the equivalent circuit model, we designed a device with an AC flowrate frequency profile that was expected to allow the DC flow in opposite directions at two distinct frequencies. The fabricated device showed the expected flow reversal at the expected frequencies. This approach expands the flow control toolkit to include both magnitude and direction control in frequency-tuned microfluidic pumps. The work also raises interesting questions about the origin of flow reversal behavior that may be addressed by the further study of the circuit model behavior or dynamic modeling of the fluid-solid mechanics of the valve under the AC flow. PMID- 28350015 TI - Calcium regulation of the human mitochondrial ATP-Mg/Pi carrier SLC25A24 uses a locking pin mechanism. AB - Mitochondrial ATP-Mg/Pi carriers import adenine nucleotides into the mitochondrial matrix and export phosphate to the cytosol. They are calcium regulated to control the size of the matrix adenine nucleotide pool in response to cellular energetic demands. They consist of three domains: an N-terminal regulatory domain containing four calcium-binding EF-hands, a linker loop domain with an amphipathic alpha-helix and a C-terminal mitochondrial carrier domain for the transport of substrates. Here, we use thermostability assays to demonstrate that the carrier is regulated by calcium via a locking pin mechanism involving the amphipathic alpha-helix. When calcium levels in the intermembrane space are high, the N-terminus of the amphipathic alpha-helix is bound to a cleft in the regulatory domain, leading to substrate transport by the carrier domain. When calcium levels drop, the cleft closes, and the amphipathic alpha-helix is released to bind to the carrier domain via its C-terminus, locking the carrier in an inhibited state. PMID- 28350021 TI - New insights into the photocatalytic activity of 3-D core-shell P25@silica nanocomposites: impact of mesoporous coating. AB - In this report, a three-dimensional (3-D) network of core-shell TiO2 (P25) mesoporous SiO2 (P25@mSiO2) nanocomposites was prepared via a controllable surfactant-assisted sol-gel method. The nanocomposites were investigated for photocatalytic reactions of organic dye degradation, water splitting, and CO2 reduction to understand the roles of the mSiO2 shell in these photocatalytic reactions. It was found that the mSiO2 shell accelerates the photodegradation of the organic dye, but dramatically reduces the photocatalytic activity of P25 in water splitting and CO2 reduction. The roles played by the mSiO2 shell in the photocatalytic reactions are summarized as: (1) effective prevention of agglomeration of P25 nanoparticles, (2) facilitating the transfer of uncharged photo-generated OH radicals via the abundant -OH groups on the mesoporous surface, (3) provision of increased reaction sites between OH radicals and dye molecules by its mesoporous nanostructure and large surface area, and (4) prevention of diffusion of the photo-generated charge carriers (photoelectrons and photoholes) because of its insulating nature. PMID- 28350022 TI - Complexes of Eu(iii)(hfa)3 with a planar chiral P(iii) ligand (Phanephos): solvent-sensitive sign inversion of circularly polarised luminescence. AB - Complexes of Eu(iii)(hfa)3 with a C2-symmetric planar P(iii) ligand exhibited intense circularly polarised luminescence (CPL) due to 5D0 -> 7F1 and 5D0 -> 7F2 transitions, with the signs and shapes of CPL signals depending on the choice of solvent (acetone or chloroform). PMID- 28350023 TI - Topochemical synthesis and photocatalytic activity of 3D hierarchical BaTiO3 microspheres constructed from crystal-axis-oriented nanosheets. AB - Novel BaTiO3 hierarchical porous microspheres were achieved by using H2Ti2O5.H2O (HTO) hierarchical microspheres as a precursor template via a facile solvothermal method. Interestingly, the BaTiO3 microspheres were constructed with two dimensional (2D) nanosheets, which were composed of many order nanocrystals with crystal-axis-orientation. The special hierarchical structure, which is both macroporous and mesoporous, exhibits a large specific surface area and a high total pore volume. The photocatalytic performance of BaTiO3 hierarchical microspheres for degradation of methyl orange (MO) under UV-light irradiation was tested, its apparent rate being up to 0.10183 min-1, almost 23 times higher than that for nanoscale BaTiO3 particles. The attractive photocatalytic properties are considered to benefit from the effective features of hierarchical BaTiO3 microspheres, such as the ultrathin thickness of nanosheets and their ordered interconnected macro-mesoporous structure and intrinsic photocatalytic activity. This study offers an in situ topochemical conversion route to synthesis of other titanium-based perovskite hierarchical nanostructures, and thus opening the door for the synthesis of other titanium-based functional materials and expanding their potential application. PMID- 28350024 TI - Generalization of the Tolman electronic parameter: the metal-ligand electronic parameter and the intrinsic strength of the metal-ligand bond. AB - The catalytic activity of transition metal complexes (R)nM-L can be predicted utilizing the metal-ligand electronic parameter (MLEP) that is based on the local stretching force constant of the M-L bond. Vibrational spectroscopy is an excellent tool to accurately determine vibrational mode properties such as stretching frequencies. These correspond, because of mode-mode coupling, to delocalized vibrational modes, which have to be first converted into local vibrational modes, and their properties. Each bond of a molecule can be uniquely characterized by the local stretching force constant and frequency. The former is ideally suited to set up a scale of bond strength orders, which identifies weak M L bonds with promising catalytic activity. It is shown how the MLEP replaces the TEP (Tolman Electronic Parameter), which is based on the CO stretching frequencies of a (CO)nM-L complex and which is now exclusively used in hundreds of investigations. However, the TEP is at best a qualitative parameter that suffers from relatively large mode-mode coupling errors and the basic deficiency of most indirect descriptors: They cannot correctly describe the intrinsic M-L bond strength via the CO stretching frequencies. PMID- 28350025 TI - Tuning the overpotential of electrocatalytically active cyclopentadienylnickel complexes containing 1,4-diaza-1,3-butadienes (DAB) for proton reduction. AB - The complexes [CpNi(DAB)]BF4, Cp = cyclopentadienyl, DAB = substituted 1,4-diaza 1,3-butadienes, undergo two reduction processes. EPR spectroscopically active Ni(i) intermediates were observed despite the potential redox activity of the DAB ligands and these reduced species catalyse the conversion of electrons and protons (from acetic acid) into dihydrogen. PMID- 28350027 TI - Are lutein, lycopene, and beta-carotene lost through the digestive process? AB - The bioavailability of many carotenoids has been assessed, but little attention has been given to the metabolism of these antioxidant compounds during digestion. The isomerization and loss of lutein, lycopene, and beta-carotene incorporated into a lipid-rich liquid meal was determined in vitro through the gastric, duodenal, and jejunal phases in the presence and absence of digestive enzymes, and in the presence and absence of known oxidizing agents often found in mixed meals (metmyoglobin in red meat and ferrous sulfate in supplemental iron). Carotenoids were quantitated using HPLC-PDA. In the absence of enzymes, lutein and lycopene were lost during earlier phases of the digestive process. In the presence of enzymes, lutein and lycopene were robust through the gastric and duodenal phases, with statistically significant losses of 40% and 20%, respectively, observed only during the jejunal phase. Regardless of the presence or absence of enzymes, an initial 25% of beta-carotene was lost during the gastric phase, but no further loss was observed. Ferrous sulfate had no significant impact on any carotenoid level. Metmyoglobin had no impact on lutein, but significantly reduced lycopene and beta-carotene levels by 30% and 80%, respectively, by the end of the jejunal phase. No significant isomerization was observed between the initial and jejunal phases for any of the carotenoids. PMID- 28350028 TI - Bis-cyclometalated iridium complexes with electronically modified aryl isocyanide ancillary ligands. AB - In this work we report a study on the effect of systematic ancillary ligand modifications on electrochemical and photophysical properties of cationic biscyclometalated bis(arylisocyanide)iridium(iii) complexes. Nine new Ir(iii) complexes were synthesized using three different cyclometalating (C^N) ligands (2,4-difluorophenylpyridine (F2ppy), 2-benzothienylpyridine (btp), and 2 phenylbenzothiazole (bt)) with three aryl isocyanide ancillary ligands (2,4 dimethoxyphenyl isocyanide (CNArOMe), 3,5-bis(trifluoromethyl)phenyl isocyanide (CNArCF3) and 4-nitrophenyl isocyanide (CNArNO2)). Systematic modifications of ancillary ligands with electron-donating or electron-withdrawing groups have a very minor influence on the positions of the absorption and emission bands, suggesting that aryl isocyanide ancillary ligands minimally perturb the primarily ligand-centered emissive states, but still can control the dynamics of the excited state. Replacing electron-donating groups with electron-withdrawing group influences kr and/or knr, resulting in changes in the lifetimes and quantum yields. In addition, we reveal that electronic structures can be substantially altered by incorporating electron-donating or electron-withdrawing groups on the aryl isocyanide ancillary ligand, with different magnitudes of the perturbation depending on the cyclometalating C^N ligand. Particularly, the formally IrIV/IrIII oxidation couple can be perturbed by over 200 mV when electron donating substituents are replaced with electron-withdrawing groups. PMID- 28350029 TI - Synthesis of (NHC)Pd(salicylaldimine)Cl complexes through template-directed ortho aromatic metaloxylation of NHC-palladacycles derived from arylimines. AB - Reactions of imidazoliums with palladacycles afforded NHC-palladacycle complexes. The reactivity of the NHC-palladacycles was explored and the results demonstrated that they could be template-directed ortho-aromatic metaloxylated in the presence of tert-butyl hydroperoxide (TBHP), affording (NHC)Pd(salicylaldimine)Cl complexes. Furthermore, the NHC-palladacycles showed efficient catalytic activities toward the ortho-aromatic hydroxylation of arylimines. PMID- 28350032 TI - Outstanding Reviewers for Molecular BioSystems in 2016. PMID- 28350034 TI - Spectrophotometric analysis at the single-cell level: elucidating dispersity within melanic immortalized cell populations. AB - It is widely held that the melanosome is an exemplar of the absorption features of melanin-containing cells, which are assumed to be uniform in both size and optical characteristics. In recent years, however, it has become increasingly apparent that this is a strikingly poor assumption. Indeed, melanin extracted from natural sources and synthetic melanin both show wide variability in their degree of polymerization (molecular weight) and spectroscopic characteristics. In the current study, imaging spectrophotometry performed on individual cells of immortalized melanin-producing cell lines revealed broad distributions in their sizes: 9.5-36.2 MUm for Hs936 human melanoma cells, 10.9-20.8 MUm for T47D human breast cancer cells, 5.3-43.5 MUm for B16F1 mouse melanoma cells, and 6.4-54.2 MUm for B16F10 mouse melanoma cells. The color appearance (from translucent to yellow to nearly black), absorption spectrum, and absorption (extinction) coefficient at 532 nm (28.73 to 364.75, 0.01 to 40.17, 5.88 to 977.19, and 0.01 to 1120 cm-1 for Hs936, T47D, B16F1, and B16F10 cells, respectively) of an individual cell also vary widely and cannot be adequately described by a 'typical' value. In comparison, human red blood cells are much more uniform in size (6.0-8.1 MUm diameter; 1.9-3.2 MUm thickness), although they too show a broad range of absorptivities, with extinction coefficients in the range of 65 to 370 cm-1 when measured at 532 nm. To further evaluate the impact of these findings on photoacoustic bioanalysis, we performed simulations of the generation of photoacoustic signals expected from these cell types. These simulations revealed that their variation in optical features exerts a pronounced effect on the amplitude and shape of the photoacoustic signals generated from these cell types. Finally, we compared the photoacoustic signal generated from these cells under ideal conditions (i.e., a single cell in isolation) versus a heterogeneous real-world sample, demonstrating that when a single or few cancer cells are present within a blood droplet, the photoacoustic signal is indistinguishable from that measured from blood alone. These outcomes have important ramifications for the early photoacoustic detection of cancer cells and circulating tumor emboli, while pointing to the potential of single-cell imaging spectrophotometry to assess heterogeneity within cell populations in more quantitative terms. PMID- 28350035 TI - Novel p-n heterojunction BiOI/CeO2 photocatalyst for wider spectrum visible-light photocatalytic degradation of refractory pollutants. AB - Recently, visible-light-driven photocatalysts have been widely used in environmental pollutant remediation. In the present study, BiOI/CeO2 p-n junction photocatalysts were successfully fabricated using a facile in situ chemical bath method. The BiOI/CeO2 p-n junction photocatalysts exhibited excellent photoactivity for the decomposition of the refractory pollutant bisphenol A (BPA) and methylene orange (MO) under visible light illumination. The sample with a 1 : 1 mole ratio of BiOI : CeO2 possessed the highest photocatalytic performance out of all of the as-obtained catalysts. Mott-Schottky plots indicated that p-n junctions were successfully constructed between BiOI and CeO2. The optical and electrical properties of the materials demonstrate that the introduction of BiOI can broaden the visible-light absorption region of CeO2, and the transfer rate of the electron-hole pairs dramatically improves through forming a p-n junction. Furthermore, the BPA degradation efficiency exhibited excellent photostability after four consecutive cycles. These features show that the BiOI/CeO2 p-n junction has great application potential for refractory pollutant removal from wastewater. PMID- 28350037 TI - Isolation and characterization of a promoter responsive to salt, osmotic and dehydration stresses in soybean. AB - Drought stress is the main limiting factor of soybean yield. Currently, genetic engineering has been one important tool in the development of drought-tolerant cultivars. A widely used strategy is the fusion of genes that confer tolerance under the control of the CaMV35S constitutive promoter; however, stress responsive promoters would constitute the best alternative to the generation of drought-tolerant crops. We characterized the promoter of alpha-galactosidase soybean (GlymaGAL) gene that was previously identified as highly up-regulated by drought stress. The beta-glucuronidase (GUS) activity of Arabidopsis transgenic plants bearing 1000- and 2000-bp fragments of the GlymaGAL promoter fused to the uidA gene was evaluated under air-dried, polyethylene glycol (PEG) and salt stress treatments. After 24 h of air-dried and PEG treatments, the pGAL-2kb led to an increase in GUS expression in leaf and root samples when compared to the control samples. These results were corroborated by qPCR expression analysis of the uidA gene. The pGAL-1kb showed no difference in GUS activity between control and treated samples. The pGAL-2kb promoter was evaluated in transgenic soybean roots, leading to an increase in EGFP expression under air-dried treatment. Our data indicates that pGAL-2kb could be a useful tool in developing drought tolerant cultivars by driving gene expression. PMID- 28350039 TI - Involved and Uninvolved Psoriatic Keratinocytes Display a Resistance to Apoptosis that may Contribute to Epidermal Thickness. AB - Psoriasis is a common autoimmune skin disease. The aim of this study was to investigate whether the apoptotic process is disturbed in psoriatic keratinocytes. In vitro culture of keratinocytes derived from both involved and uninvolved psoriatic skin, revealed higher viability and resistance to apoptosis following exposure to ultraviolet B, compared with cells from healthy controls. The position of apoptotic dysregulation was found to be upstream of cytochrome c release in the mitochondrial apoptotic pathway. Microarray transcriptome analysis revealed that 87 genes were differentially expressed in both involved and uninvolved psoriatic keratinocytes compared with controls. Among these, a general upregulation of anti-apoptotic genes and downregulation of pro-apoptotic genes were identified. This distinct apoptosis-resistant phenotype, unrelated to the inflammatory component of the disease, implies that intrinsic abnormalities in keratinocytes may contribute to the pathogenesis of psoriasis. PMID- 28350040 TI - Ulcerative Plaques and Nodules on the Lower Extremity: A Quiz. PMID- 28350038 TI - Regulation of Na+ and K+ homeostasis in plants: towards improved salt stress tolerance in crop plants. AB - Soil salinity is a major abiotic stress that results in considerable crop yield losses worldwide. However, some plant genotypes show a high tolerance to soil salinity, as they manage to maintain a high K+/Na+ ratio in the cytosol, in contrast to salt stress susceptible genotypes. Although, different plant genotypes show different salt tolerance mechanisms, they all rely on the regulation and function of K+ and Na+ transporters and H+ pumps, which generate the driving force for K+ and Na+ transport. In this review we will introduce salt stress responses in plants and summarize the current knowledge about the most important ion transporters that facilitate intra- and intercellular K+ and Na+ homeostasis in these organisms. We will describe and discuss the regulation and function of the H+-ATPases, H+-PPases, SOS1, HKTs, and NHXs, including the specific tissues where they work and their response to salt stress. PMID- 28350041 TI - Debunking the Myth of Wool Allergy: Reviewing the Evidence for Immune and Non immune Cutaneous Reactions. AB - Although wool is commonly believed to cause irritant (non-immune) and hypersensitivity (immune) cutaneous reactions, the evidence basis for this belief and its validity for modern garments have not been critically examined. Publications from the last 100 years, using MEDLINE and Google Scholar, were analysed for evidence that wool causes cutaneous reactions, both immune-mediated (atopic dermatitis exacerbation, contact urticaria, allergic contact dermatitis) and non-immune-mediated (irritant contact dermatitis, itch). Secondary aims of this paper were to examine evidence that lanolin and textile-processing additives (formaldehyde, chromium) cause cutaneous reactions in the context of modern wool processing techniques. Current evidence does not suggest that wool-fibre is a cutaneous allergen. Furthermore, contact allergy from lanolin, chromium and formaldehyde is highly unlikely with modern wool garments. Cutaneous irritation from wool relates to high fibre diameters (>= 30-32 um). Superfine and ultrafine Merino wool do not activate sufficient c-fibres to cause itch, are well tolerated and may benefit eczema management. PMID- 28350042 TI - Parent-of-origin Effect in Alopecia Areata: A Large-scale Pedigree Study. PMID- 28350046 TI - [Corrigendum] Promoter methylation of RASSF1A modulates the effect of the microtubule-targeting agent docetaxel in breast cancer. AB - Following the publication of this article, an interested reader drew to our attention that there were possible anomalies in the presentation of Fig. 5B in the above article. After having examined the figure, we recognized that several errors had indeed occurred during the process of compiling the figure. A corrected version of Fig. 5 is shown below, containing new data for Fig. 5B, after our having re-performed the western blot experiment according to the identical procedure detailed in the paper. We obtained broadly similar results to those featured originally in the article; therefore, the revision of this figure does not affect the conclusions reported in the study. We thank the reader of our article who drew this matter to our attention. [the original article was published in the International Journal of Oncology 41: 611-620, 2012; DOI: 10.3892/ijo.2012.1470]. PMID- 28350047 TI - Expression and prognostic value of the cell polarity PAR complex members in thyroid cancer. AB - Establishment and maintenance of the apical-basal cell polarity, required for proper replication, migration, specialized functions and tissue morphogenesis, relies on three evolutionary conserved complexes: PAR, CRUMBS and SCRIBBLE. Loss of cell polarity/cohesiveness (LOP/C) is implicated in cancer progression, and members of the polarity complex have been described as either oncogenes or oncosuppressors. However, no information on their role in thyroid cancer (TC) progression is available. In the present study, we evaluated the gene expression of the PAR complex members aPKCiota, PARD3alpha/beta and PARD6alpha/beta/gamma in 95 papillary TC (PTC), compared to their normal matched tissues and in 12 anaplastic TC (ATC). The mRNA and protein levels of investigated genes were altered in the majority of PTC and ATC tissues. In PTC, univariate analysis showed that reduced expression of aPKCiota, PARD3beta and PARD6gamma mRNAs is associated with increased tumor size, and the reduced expression of PARD3beta mRNA is associated also with recurrences. Multivariate analysis demonstrated that the presence of lymph node metastasis at diagnosis and the reduced expression of PARD3beta are independent risk factors for recurrences, with hazard ratio, respectively, of 8.21 (p=0.006) and 3.04 (p=0.029). The latter result was confirmed by the Kaplan-Meier analysis, which evidenced the association between decreased PARD3beta mRNA levels and shorter disease-free interval. In conclusion, we demonstrated that the expression of PAR complex components is deregulated in the majority of PTC and there is a general trend towards their reduction in ATC tissues. Moreover, a prognostic value for the PARD3beta gene in PTCs is suggested. PMID- 28350048 TI - Silybin attenuates LPS-induced lung injury in mice by inhibiting NF-kappaB signaling and NLRP3 activation. AB - Silybin is one of the main flavonoids produced by milk thistle, which has been used in the treatment of liver diseases. In this study, we examined the protective effects and possible mechanisms of action of silybin in lipopolysaccharide (LPS)-induced lung injury and inflammation. Pre-treatment of mice with silybin significantly inhibited LPS-induced airway inflammatory cell recruitment, including macrophages, T cells and neutrophils. The production of cytokines, such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) in bronchoalveolar fluid and serum was also decreased following treatment with silybin. Elevated cytokine mRNA levels induced by LPS in lung tissue were all suppressed by silybin and lung histological alterations were also improved. In addition, experiments using cells indicated that silybin significantly decreased the mRNA levels and secretion of IL-1beta and TNF-alpha in THP-1 cells. Moreover, the mechanisms responsible for these effects were attributed to the inhibitory effect of silybin on nuclear factor-kappaB (NF kappaB) signaling and NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. The data form our study thus support the utility of silybin as a potential medicine for the treatment of acute lung injury-associated inflammation and pathological changes. Silybin exerts protective effects against lung injury by regulating NF-kappaB signaling and the NLRP3 inflammasome activation. PMID- 28350050 TI - Role of autophagy in advanced atherosclerosis (Review). AB - Atherosclerosis (AS) remains the leading cause for global cardiovascular disease morbidity and mortality, and a major cause of cardiopathy, myocardial infarction and peripheral vascular diseases. Macrophages serve a critical role in atherosclerotic plaque stabilization and rupture, and the selective removal of macrophages may be beneficial in improving plaque stability. Autophagy is a process of self-feeding, during which cytoplasmic proteins or organelles are packaged into vesicles and fused with the lysosome to form an autophagosome. The newly formed autophagosome can degrade internalized proteins, and this process may be used to serve the metabolic and self-renewal requirements of the cell. Autophagy serves an important role in maintaining cell homeostasis and promoting cell survival, and therefore an imbalance in autophagy is closely associated with multiple diseases. PMID- 28350051 TI - B(a)P adduct levels and fertility: A cross-sectional study in a Sicilian population. AB - Benzo(a)pyrene (BaP) is a carcinogenic polycyclic aromatic hydrocarbon for human tissues. Still today it is not fully investigated if BaP can affect negatively the male fertility through the BaP-DNA adducts production. In the present study, BaP Tetrol I-1 (TI-1) and BaP Tetrol II-2 (TII-2) BaP-DNA adducts were investigated in spermatozoa of a Sicilian male population. Semen samples from 86 volunteers in two eastern Sicilian cities (Regalbuto and Melilli) were collected. The quality of semen was evaluated in all samples according to the World Health Organization (WHO) guidelines. We analyzed BaP-DNA adducts in extracted sperm cell DNA using the modified high-performance liquid chromatography-fluorescence method to detects both Tetrols. Differences between Tetrol levels were assessed by the Wilcoxon signed-rank test and the Mann-Whitney U test, as appropriate. Correlation between semen quality parameters and Tetrol concentrations were analyzed using the Spearman's correlation coefficient. Sigma(TI-1+TII-2) were significantly higher in spermatozoa of volunteers from Regalbuto. Furthermore, a greater dispersion of the levels of adducts was observed in these specimens. TI-1 adducts were higher than TII-2 in Melilli samples (95% CI) and TII-2 were higher than TI-1 in Regalbuto semen samples (95% CI). A significant inverse correlation between sperm progressive motility and both TI-1 and TII-2 adducts was observed. The present study showed that BaP negatively affects male fertility by TI-1 and TII-2 DNA-adduct production. These results suggest that DNA adducts could be used as biomarker to assess BaP exposure by air pollution. Further studies are needed to confirm if these findings could affect male fertility because of the growing impairment of this function observed in recent years. PMID- 28350060 TI - Silencing of FANCD2 enhances the radiosensitivity of metastatic cervical lymph node-derived head and neck squamous cell carcinoma HSC-4 cells. AB - Fanconi anemia complementation group D2 (FANCD2) is involved in the key steps of the Fanconi anemia (FA) pathway, which plays a role in the repair of DNA crosslink damage. However, the role of FANCD2 during radiotherapy for head and neck squamous cell carcinoma (HNSCC) is unclear. In this study, the HNSCC cell line HSC-4 was used. Western blotting was used to evaluate the expression of the FANCD2 in HSC-4 cells. We investigated the impact of FANCD2 on the radiosensitivity of HSC-4 cells in vitro and in vivo. TUNEL, western blotting and immunohistochemistry were used to analyze the apoptosis and proteins involved in apoptosis-related pathways after radiotherapy to investigate the relevant mechanism. The present study showed that shRNA interference could effectively and stably silence FANCD2 expression in HSC-4 cells. In vitro, the silencing of FANCD2 inhibited cell proliferation, decreased the survival rate, increased apoptosis and induced S phase arrest in HSC-4 cells after radiotherapy. In vivo, the silencing of FANCD2 could prolong the tumor-forming time and slow tumor growth. In addition, the tumor volume was significantly reduced, the weight was deceased, and the tumor inhibition rate was increased after radiotherapy. TUNEL showed that the silencing of FANCD2 significantly increased apoptosis in HSC-4 cells induced by radiotherapy. Both in vitro and in vivo esperiments revealed that the expression of the Bax and p-p38 proteins in HSC-4 cells, in which FANCD2 had been silenced, was increased after radiotherapy, whereas the expression of the p38 and Bcl2 proteins was decreased. Our results suggested that the silencing of FANCD2 enhanced the radiosensitivity of HSC-4 cells, and its mechanism involves the activation of the p38 MAPK signaling pathway and the regulation of the expression of Bax and Bcl2 proteins. This study provides a novel candidate target for HNSCC therapy. PMID- 28350049 TI - Activation of the CRABPII/RAR pathway by curcumin induces retinoic acid mediated apoptosis in retinoic acid resistant breast cancer cells. AB - Due to the anti-proliferative and anti-apoptotic effects of retinoic acid (RA), this hormone has emerged as a target for several diseases, including cancer. However, development of retinoid resistance is a critical issue and efforts to understand the retinoid signaling pathway may identify useful biomarkers for future clinical trials. Apoptotic responses of RA are exhibited through the cellular RA-binding protein II (CRABPII)/retinoic acid receptor (RAR) signaling cascade. Delivery of RA to RAR by CRABPII enhances the transcriptional activity of genes involved in cell death and cell cycle arrest. The purpose of this study was to investigate the role of curcumin in sensitizing RA-resistant triple negative breast cancer (TNBC) cells to RA-mediated apoptosis. We provide evidence that curcumin upregulates the expression of CRABPII, RARbeta and RARgamma in two different TNBC cell lines. Co-treatment of the cells with curcumin and RA results in increased apoptosis as demonstrated by elevated cleavage of poly(ADP-ribose) polymerase and cleaved caspase-9. Additionally, silencing CRABPII reverses curcumin sensitization of TNBC cells to the apoptotic inducing effects of RA. These findings provide mechanistic insights into sensitizing TNBC cells to RA mediated cell death by curcumin-induced upregulation of the CRABPII/RAR pathway. PMID- 28350062 TI - HCRP1 inhibits TGF-beta induced epithelial-mesenchymal transition in hepatocellular carcinoma. AB - Hepatocellular carcinoma-related protein 1 (HCRP1), also known as human vacuolar protein sorting 37 homologue A (hVps37A), has not been detected or is significantly downregulated in hepatocellular carcinoma (HCC) tissues. However, information on the regulatory mechanisms of HCRP1 in HCC remains unclear. Here we found that the downregulation of HCRP1 in HepG2 cells (with low invasion capacity) significantly enhanced migration and invasion, whereas HCRP1 upregulation in SMMC-7721 cells (with high invasion capacity) generated the opposite result. Interestingly, the morphology of HepG2 cells significantly changed from an epithelial to mesenchymal phenotype after HCRP1 knockdown. Moreover, we observed a decrease in the expression of epithelial cell markers E cadherin and beta-catenin, and an increase in the expression of mesenchymal cell markers N-cadherin and vimentin. We also observed that the downregulation of HCRP1 induced epithelial-mesenchymal transition (EMT) through the transforming growth factor-beta pathway. Together, our findings define a novel function for HCRP1 from the perspective of EMT, which is closely associated with the migration and invasion of HCC cells. PMID- 28350061 TI - Kif4 regulates the expression of VEGFR1 through the PI3K/Akt signaling pathway in RAW264.7 monocytes/macrophages. AB - Kinesin superfamily protein 4 (Kif4), a microtubule-based motor protein, has been shown to participate in a number of critical cellular processes, such as cell division, the intracellular transport of membranous vesicles and signal transduction. However, whether KIF4 regulates vascular endothelial growth factor (VEGF) receptor 1 (VEGFR1) expression remains unknown. Thus, in this study, in order to examine the effects of Kif4 on the expression of VEGFR1 in RAW264.7 monocytes/macrophages, Kif4 was silenced using siRNA. RT-qPCR, western blot analysis and ELISA were used to assess the expression of Kif4 and VEGFR1 up- and downstream signaling molecules, including VEGF-A, VEGFR1, soluble form of VEGFR1 (sVEGFR1), phosphorylated (p-)Akt and Akt. The silencing Kif4 inhibited the mRNA expression of VEGF (P<0.01) and p-Akt (P<0.05); however, the level of VEGF-A was increased (P<0.05) compared with the negative control siRNA-transfected group. The silencing of Kif4 decreased the VEGFR1 mRNA (P<0.05), VEGFR1 protein and sVEGFR1 levels in the cell supernatant (P<0.01). Following the application of insulin-like growth factor-1 (100 ng/ml), the specific agonist of PI3K/Akt in the Kif4 siRNA-transfected group, the VEGFR1 mRNA levels (P<0.001), the VEGFR1 protein levels and the sVEGFR1 (P<0.01) levels significantly increased; however, the levels of VEGF in the cell supernatant were decreased (P<0.05). Taken together, these findings suggest that Kif4 regulates the expression of VEGFR1 in RAW264.7 cells and that the PI3K/Akt pathway is involved in this process. PMID- 28350064 TI - SF-KDM2A binds to ribosomal RNA gene promoter, reduces H4K20me3 level, and elevates ribosomal RNA transcription in breast cancer cells. AB - Regulation of rRNA transcription is an important factor for control of cell proliferation. We previously found that the JmjC domain-containing demethylase KDM2A reduces H3K36me2 in the rRNA gene promoter and rRNA transcription under starvation, which results in suppression of cell proliferation. The KDM2A gene also produces another protein product, SF-KDM2A, which lacks a JmjC domain and has no demethylase activity. As yet, the function of SF-KDM2A is not clear. Recently, it was reported that KDM2A was frequently amplified and that elevated expression of KDM2A was significantly associated with short survival of breast cancer patients. SF-KDM2A was more abundant than full-length KDM2A in a subset of breast cancers. In the present study, we report that SF-KDM2A localized in nucleoli and bound to the rRNA gene promoter in breast cancer cells. Overexpression of SF-KDM2A stimulated the transcription of rRNA. While the zf CXXC domain was required for SF-KDM2A binding to the rRNA gene promoter, SF-KDM2A with mutations in the zf-CXXC domain lost the binding to the rRNA gene promoter and did not stimulate rRNA transcription. Knockdown of SF-KDM2A reduced rRNA transcription and cell proliferation. When SF-KDM2A was overexpressed, a transcriptionally repressive mark, H4K20me3, in the rRNA gene promoter was specifically reduced in a zf-CXXC domain-dependent manner, and knockdown of SF KDM2A increased the H4K20me3 level. Taken together, these results demonstrate that SF-KDM2A binds to the rRNA gene promoter, reduces the H4K20me3 level, and activates rRNA transcription, suggesting that the stimulation of rRNA transcription by SF-KDM2A may contribute to tumorigenesis in breast cancer. PMID- 28350065 TI - High stathmin 1 expression is associated with poor prognosis and chemoradiation resistance in esophageal squamous cell carcinoma. AB - Stathmin 1 (STMN1) is a major cytosolic phosphoprotein regulating microtubule dynamics, thereby playing an important role in cancer progression and resistance to microtubule-binding anticancer agents. We assessed the prognostic significance of STMN1 expression and STMN1-associated resistance to docetaxel and radiation in esophageal squamous cell carcinoma (ESCC) patients. STMN1 expression was evaluated by immunohistochemistry in 172 surgical specimens. The association of STMN1 expression with chemoradiation resistance using docetaxel was examined by comparing expression in 15 biopsy specimens obtained before neoadjuvant therapy to histological grades of post-therapy surgically resected tumors. We also evaluated the effects of STMN1 on sensitivity to docetaxel and radiation in ESCC cell lines. High STMN1 immunoexpression was significantly associated with tumor depth, lymph node metastasis, lymphatic invasion and venous invasion. Survival rates were significantly lower in ESCC patients with high STMN1 expression than in those with low STMN1 expression. Multivariable analysis showed that high STMN1 expression was an independent factor for poor survival. High STMN1 expression was also associated with poor response to neoadjuvant chemoradiotherapy using docetaxel. Knockdown of STMN1 expression enhanced ESCC cell line sensitivity to docetaxel and radiation. STMN1 appears critical for ESCC invasiveness and predicts an unfavorable prognosis in ESCC. PMID- 28350071 TI - Protective effects of oleanolic acid on oxidative stress and the expression of cytokines and collagen by the AKT/NF-kappaB pathway in silicotic rats. AB - Oleanolic acid (OA), a natural pentacyclic triterpenoid, has been reported to have several benefits and medicinal properties. However, its protective effects against silica-induced lung injury and fibrosis remain to be elucidated. The aim of the present study was to investigate the effects of OA on oxidative stress, and the expression of cytokines and collagen in silicotic rats. Male rats were induced by intratracheal instillation of silicosis (250 mg/kg), with the exception of the control group (NS). The rats in the OA group were intragastrically administered with OA (60 mg/kg/d). The rats in the solvent control group were gavaged daily with 0.6% sodium carboxymethyl cellulose (10 ml/kg) solution for 56 consecutive days. The data showed that OA significantly attenuated the extent of silicosis fibrosis by histopathologic analysis of the lung tissues. In addition, oxidative stress activated by silica exposure, as evidenced by increasing of malondialdehyde content, and activities of superoxide dismutase and glutathione peroxidase in the lung, was regulated by treatment with OA. Furthermore, enzyme-linked immunosorbent assay analysis showed that OA significantly decreased the levels of tumor necrosis factor-alpha and transforming growth factor-beta1. Immunohistochemistry analysis showed that OA significantly decreased collagen types I and III. In investigating the mechanisms underlying the action of OA, it was found that OA decreased the level of phosphorylated AKT1, which in turn inactivated the transcriptional of nuclear factor (NF)-kappaB in the development and progress of silicosis. In conclusion, these results suggested that the protective effects of OA were due, at least in part, to its anti-oxidant activity and its ability to decrease the expression of cytokines and collagen by modulating the AKT/NF-kappaB pathway. PMID- 28350068 TI - Concurrence of chromosome 3 and 4 aberrations in human uveal melanoma. AB - Uveal melanoma (UM) is the most common primary intraocular malignancy with a very poor prognosis. The most frequent chromosome aberration in UM is the monosomy of chromosome 3. Previously, we demonstrated that ~50% of UMs express type-I receptor for luteinizing hormone-releasing hormone (LH-RH-R). The gene encoding LH-RH-R is located in chromosome 4 (location: 4q21.2); however, the occurrence of numerical aberrations of chromosome 4 have never been studied in UM. In the present study, we investigated the abnormalities of chromosome 3 and 4, and the possible correlation between them, as well as with LH-RH-R expression. Forty-six specimens of UM were obtained after enucleation. Numerical aberrations of chromosome 3 and 4 were studied by fluorescence in situ hybridization (FISH). Chromosome 4 was detected in normal biparental disomy only in 14 (30%) samples; however, 32 cases (70%) showed more than 2 signals/nucleus. Monosomy of chromosome 3 could be found in 16 (35%) samples. In 6 specimens (13%), more than 2 copies of chromosome 3 were found, while normal biparental disomy was detected in 24 (52%) samples. Statistical analysis indicated a statistically significant (p<0.05) correlation between the copy number of chromosome 3 and 4. Moreover, moderate difference was revealed in the survival rate of the UM patients with various pathological profiles. No correlation was found between chromosome aberrations and LH-RH-R expression. Our results clearly demonstrate abnormalities in chromosome 3 and 4 and the incidence of the monosomy of chromosome 3 in human UM. In summary, our results provide new incite concerning the genetic background of this tumor. Our findings could contribute to a more precise determination of the prognosis of human UM and to the development of new therapeutic approaches to this malignancy. PMID- 28350072 TI - The role of miR-370 in fibrosis after myocardial infarction. AB - In the present study, we investigated the expression of miR-370 in the border area of infarction after myocardial infarction and its role in the process of post-infarction fibrosis. A myocardial infarction model in Sprague-Dawley rats was established. After two weeks, the mRNA levels of transforming growth factor beta1 (TGFbeta1), TGFbetaRII, ColIa1, ColIIIa1 and miR-370 and the expression of TGFbeta1, TGFbetaRII and alpha-smooth muscle actin (alpha-SMA) proteins in the border area of infarction were detected by real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) and western blot analysis. Cardiac fibroblasts in neonatal rat were isolated and cultured, and the changes in the above indicators were detected after AngII and miR-370 intervention. Luciferase reporter gene assay was conducted to verify whether TGFbetaRII was a target gene of miR-370. In the border area after myocardial infarction, the expression of miR 370 decreased, while mRNA levels of TGFbeta1, TGFbetaRII, ColIa1 and ColIIIa1 and levels of TGFbeta1, TGFbetaRII and alpha-SMA proteins were all increased. Luciferase reporter gene assay confirmed that TGFbetaRII was the target gene of miR-370. miR-370 reduced the expression of TGFbetaRII and inhibited the increased expression of TGFbetaRII and collagen protein caused by AngII. As well, its inhibited the differentiation effect of muscle fibroblasts while it did not inhibit the expression of TGFbeta1. miR-370 inhibited the expression of TGFbetaRII protein by combining with TGFbetaRII mRNA. miR-370 also partially blocked TGFbeta1-TGFbetaRII and induced the downstream signal transduction pathways, thus exerting anti-fibrotic effects. PMID- 28350074 TI - N-terminal polypeptide derived from vMIP-II exerts its antitumor activity by inhibiting the CXCR4 pathway in human glioma. AB - Emerging evidence demonstrates that the stromal derived factor-1 (SDF 1alpha)/CXCR4 axis is associated with tumor aggressiveness and metastasis, including glioma, the most common brain cancer. In the present study, we demonstrated that a novel designed peptide NT21MP of viral macrophage inflammatory protein II, targeting CXCR4 inhibits SDF-1alpha-induced activation in glioma. The effects of NT21MP on CXCR4 expression, cell survival and migration were assessed on the human glioma cell line U251 and SHG-44 exposed to SDF 1alpha, by western blotting, MTT assay, flow cytometry and transwell migration assay. Our results illustrated that NT21MP inhibited SDF-1alpha induced proliferation, migration and invasion by upregulated pro-apoptotic genes (Bak1 and caspase-3) and downregulated Bcl-2/Bax as well as cell cycle regulators (cyclin D1 and CDK4) to arrest cell cycle in G0/G1 phase and promote apoptosis. By RT-qPCR and immunofluorescence we found that CXCR4 was highly expressed in SHG 44 cells. Our results from wound healing and transwell invasion assays indicated silencing of CXCR4 significantly inhibited the SDF-1alpha-induced migration and invasion; similarly, flow cytometry showed that treatment with si-CXCR4 affected cell cycle and induced cell apoptosis in SHG-44. However, these effects were significantly weakened by NT21MP. In conclusion, the present study indicates that NT21MP plays a regulatory role in the SDF-1alpha/CXCR4 axis and further manages the invasion, migration, apoptosis and cell cycle of glioma cells. Thus, NT21MP might represent a novel therapeutic approach against glioma. PMID- 28350075 TI - Co-treatment of breast cancer cells with pharmacologic doses of 2-deoxy-D-glucose and metformin: Starving tumors. AB - A characteristic of tumor cells is the increased aerobic glycolysis for energy production. Thus, inhibition of glycolysis represents a selective therapeutic option. It has been shown that glycolysis inhibitor 2-deoxy-D-glucose (2DG) induces apoptotic cell death in different tumor entities. In addition, the antitumor activity of the anti-diabetic drug metformin has been demonstrated. In the present study, we aimed to ascertain whether the combination of pharmacologic doses of 2DG with metformin increases the antitumor efficacy. Cell viability of MDA-MB-231 and HCC1806 triple-negative breast cancer (TNBC) cells treated without or with 2DG or with metformin alone or with the combination of both agents was measured using Alamar Blue assay. Induction of apoptosis was quantified by measurement of the loss of mitochondrial membrane potential and cleavage of PARP. Treatment of breast cancer cells with glycolysis inhibitor 2DG or with the anti diabetic drug metformin resulted in a significant decrease in cell viability and an increase in apoptosis. Treatment with 2DG in combination with metformin resulted in significantly reduced viability compared with the single agent treatments. The observed reduction in viability was due to induction of apoptosis. In addition, in regards to apoptosis induction a stronger effect in the case of co-treatment compared with single agent treatments was observed. The glycolytic phenotype of human breast cancer cells can be targeted for therapeutic intervention. Co-treatment with doses of the glycolysis inhibitor 2DG and anti diabetic drug metformin is tolerable in humans and may be a suitable therapy for human breast cancers. PMID- 28350076 TI - Osthole enhances TRAIL-mediated apoptosis through downregulation of c-FLIP expression in renal carcinoma Caki cells. AB - Osthole, an active constituent isolated from the fruit of Cnidium monnieri (L.) Cusson, has been shown to induce various beneficial biochemical effects such as anti-inflammatory and antitumor. In the present study, we examined whether osthole could sensitize TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human renal carcinoma Caki cells. We found that osthole and TRAIL alone, had no effect on apoptosis, but combined treatment with osthole and TRAIL markedly induced apoptosis in Caki (renal carcinoma), U251MG (glioma) and MDA-MB 231 (breast carcinoma) cells. In contrast, combined treatment with osthole and TRAIL did not induce apoptosis in normal human skin fibroblast cells. Osthole induced downregulation of cellular FLICE-like inhibitory protein (c-FLIP) expression, and overexpression of c-FLIP markedly blocked apoptosis induced by the combined treatment with osthole and TRAIL. In addition, osthole markedly reduced mitochondrial membrane potential levels, and increased cytosolic cytochrome c release in combined treatment with osthole and TRAIL. Therefore, these data suggest that osthole may be an efficient TRAIL sensitizer. PMID- 28350078 TI - miR-28-5p promotes the development and progression of ovarian cancer through inhibition of N4BP1. AB - MicroRNAs (miRNAs) play important roles in transcriptional regulation by targeting the 3'-UTR of target genes which participate in various biological processes. We aimed to investigate the potential role of miR-28-5p in the process of ovarian cancer development through regulating N4BP1. We found that the mRNA expression level of miR-28-5p was significantly increased in ovarian cancer tissues in comparison with adjacent ovarian tissues by qRT-PCR (P<0.0001). We established that miR-28-5p promoted the progression of ovarian cancer cell proliferation using colony forming assay and MTT assay. Wound healing assay and the migration and invasion assay showed that miR-28-5p accelerated the migration and invasion abilities of ovarian cancer cells. Simultaneously, we showed that miR-28-5p promoted ovarian cancer cell cycle, and inhibited apoptosis by flow cytometry in vitro. Furthermore, the results showed that miR-28-5p promoted the growth of ovarian tumor by tumor formation assay in vivo. The results of western blot analysis indicated that miR-28-5p promoted the protein expression level of F actin. Western blot analysis also demonstrated that miR-28-5p promoted the progress of epithelial-mesenchymal transition (EMT) in ovarian carcinoma cells. In addition, we found that miR-28-5p downregulated N4BP1 mRNA and protein expression by qRT-PCR and western blot analysis in human ovarian cancer. Therefore, our study indicated that miR-28-5p promoted the progression of ovarian cancer cell cycle, proliferation, migration and invasion, inhibited apoptosis, and induced the process of EMT through inhibition of N4BP1 in vitro. Moreover, miR-28-5p promoted the growth of ovarian tumor in vivo. PMID- 28350077 TI - Advanced glycation end products promote the proliferation and migration of primary rat vascular smooth muscle cells via the upregulation of BAG3. AB - The present study was aimed to investigate the role of reactive oxygen species (ROS) on advanced glycation end product (AGE)-induced proliferation and migration of vascular smooth muscle cells (VSMCs) and whether Bcl-2-associated athanogene 3 (BAG3) is involved in the process. Primary rat VSMCs were extracted and cultured in vitro. Cell viability was detected by MTT assay and cell proliferation was detected by EdU incorporation assay. Cell migration was detected by wound healing and Transwell assays. BAG3 was detected using qPCR and western blot analysis. Transcriptional and translational inhibitors (actinomycin D and cycloheximide, respectively) were used to study the effect of AGEs on the expression of BAG3 in VSMCs. Lentiviral plasmids containing short hairpin RNA (shRNA) against rat BAG3 or control shRNA were transduced into VSMCs. Cellular ROS were detected by 2',7' dichlorofluorescein diacetate (DCFH-DA) staining. Mitochondrial membrane potential was detected by tetramethylrhodamine methyl ester (TMRE) staining. AGEs significantly increased the expression of BAG3 in a dose-and time-dependent manner. Furthermore, AGEs mainly increased the expression of BAG3 mRNA by increasing the RNA synthesis rather than inhibiting the RNA translation. BAG3 knockdown reduced the proliferation and migration of VSMCs induced by AGEs. BAG3 knockdown reduced the generation of ROS and sustained the mitochondrial membrane potential of VSMCs. Reduction of ROS production by N-acetylcysteine (NAC), a potent antioxidant, also reduced the proliferation and migration of VSMCs. On the whole, the present study demonstrated for the first time that AGEs could increase ROS production and promote the proliferation and migration of VSMCs by upregulating BAG3 expression. This study indicated that BAG3 should be considered as a potential target for the prevention and/or treatment of vascular complications of diabetes. PMID- 28350079 TI - Effects of irradiation on human leukocyte antigen class I expression in human papillomavirus positive and negative base of tongue and mobile tongue squamous cell carcinoma cell lines. AB - Human papillomavirus (HPV) infection is a risk factor for oropharyngeal cancer, besides smoking and alcohol. Patients with HPV-positive tumors have a better prognosis than those with HPV-negative tumors. Furthermore, patients with HPV positive tumors, with high CD8+ tumor infiltrating lymphocyte counts or absent/low human leukocyte antigen (HLA) class I expression have the best outcome. The latter is paradoxical, since HLA class I expression is important for tumor recognition. Below, the hypothesis that radiation therapy increases HLA class I expression was tested. HPV16 positive head and neck cancer cell lines UPCI-SCC-154, UPCI-SCC-090 and UM-SCC-47, and the HPV-negative cancer cell line UT-SCC-14, were treated with 2-10 Gray (Gy) and tested for HLA class I expression, cell cycle changes and apoptosis by flow cytometry. HPV16 E5, E7 and HLA-A mRNA expression was tested by quantitative PCR. A dose of 10 Gy resulted in a tendency of increased HLA class I cell surface expression for all cell lines and reached statistical significance for UPCI-SCC-154 and UPCI-SCC-090. There were, however, no significant changes in HLA-A mRNA expression in any of the cell lines, or HPV16 E5, or E7 mRNA expression for UPCI-SCC-47 and UPCI-SCC-154, while for UPCI-SCC-090 HPV16 E5 mRNA decreased. In all cell lines there was a shift towards G2/M phase and increased apoptosis after irradiation with 10 Gy. To conclude, irradiation with 10 Gy increased HLA class I expression in the HPV positive cell lines UPCI-SCC-154 and UPCI-SCC-090. A similar tendency was observed for HPV-positive UM-SCC-47 and HPV-negative UT-SCC-14. PMID- 28350082 TI - HOTAIR upregulates an 18-gene cell cycle-related mRNA network in glioma. AB - HOTAIR is a tumor promoting long non-coding RNA (lncRNA) with roles in multiple cancers. However, the role of HOTAIR in glioma has not been well charaterized. Genes that positively correlated with HOTAIR were identified from the Chinese Glioma Genome Atlas and constructed into an interacting network. In total, 18 genes with P-values <0.01 were further extracted and constructed into a subnetwork. Real-time PCR, western blot and immunofluorescence analyses were employed to examine the expression of the genes after HOTAIR overexpression or knockdown. Intracranial glioblastoma multiform (GBM) models were used to test the potential of HOTAIR as a glioma therapy target. It was discovered that the 18 genes that most significantly correlated with HOTAIR expression formed a cell cycle-related mRNA network, which is positively regulated by HOTAIR. Furthermore, HOTAIR knockdown inhibited mouse intracranial GBM model formation. HOTAIR positively regulates a cell cycle-related mRNA network in glioma, and could be a potential therapeutic target for treating glioma. PMID- 28350083 TI - Deep vein thrombosis related to environment (Review). AB - The first-time venous thromboembolism (VTE) is less frequent than other thrombotic events, however, both the pulmonary embolism (PE) and the deep vein thrombosis (DVT) show a frequent morbidity. Many factors play as risk situations in determining VTE, and the air exposure to the fine and ultrafine particulate matter (PM) as PM10, PM2.5, PM0.1 is considered. Epidemiological studies have supported this association although both the effective burden of the association and the mechanisms are to date unclear. The PM concentrations and the exposure time are notable as emerging factors. Interestingly, the seasonal climate variations resulted as effective risk factor for appearance of VTE or DVT. There is a need to ameliorate the environment by reducing the air pollution at global scale. PMID- 28350084 TI - TP53 and RET may serve as biomarkers of prognostic evaluation and targeted therapy in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the most common malignancy of the liver. Genomic analysis is conducted to identify genetic alterations in driver genes which are all druggable targets for cancer therapy. In the present study, we performed an exome sequencing of 45 driver genes in 100 paired samples from HCC patients including tumors and matched adjacent normal tissues using Illumina HiSeq 2000 platform. Non-synonymous mutations were ascertained using the iPLEX MassARRAY system and Sanger sequencing. Clinicopathological relevance with genetic variations was assessed using SPSS software. The prognostic analyses of patients with gene mutation status were summarized using Kaplan-Meier curves. Sixty-one non-synonymous somatic mutations were identified in 43% of the HCC patients. The most frequent mutations were: TP53 (20%), RET (6%), PLCE1 (5%), PTEN (4%) and VEGFR2 (3%). Patients with mutations in TP53 had a lower overall survival (OS) (P=0.002) than those without mutations. Recurrent mutations in the Ret proto-oncogene (RET) were associated with poor outcomes for both disease-free survival (DFS) (P=0.028) and OS (P=0.001) in HCC patients. The mutational status of sorafenib-targeted genes were associated with decreased DFS (P=0.039), and decreased OS (P=0.15) without statistical significance. Mutual exclusion of TP53 and RET mutations were observed in the present study. In conclusion, patients with TP53 mutations, RET mutations and sorafenib-targeted gene mutations were demonstrated to be associated with poor HCC prognosis, which suggests that both TP53 and RET may serve as biomarkers of prognostic evaluation and targeted therapy in HCC. PMID- 28350086 TI - Imazamethabenz inhibits human breast cancer cell proliferation, migration and invasion via combination with Pin1. AB - Overexpression of peptidyl-prolyl cis/trans isomerase, NIMA interacting-1 (Pin1) is a significant marker of the occurrence and development of tumors. In the present study, the imidazoline ketone herbicide imazamethabenz was investigated as a potential antitumor drug by inhibiting Pin1. Molecular docking and enzyme activity tests verified, for the first time, that the imidazoline ketone compound imazamethabenz effectively inhibited Pin1 in vitro. MTT assays, western blotting, wound healing assay and Matrigel invasion assays revealed that imazamethabenz induced apoptosis and inhibited migration and invasion of the breast cancer cell line MCF-7, which overexpresses Pin1, by inhibiting the Pin1-mediated signaling pathway involving vascular endothelial growth factor and matrix metalloproteinase 9. These findings indicated that imazamethabenz offers potential applications for the treatment of tumors as a Pin1 inhibitor. PMID- 28350087 TI - Paclitaxel induces apoptosis of esophageal squamous cell carcinoma cells by downregulating STAT3 phosphorylation at Ser727. AB - Paclitaxel induces apoptosis in a variety of cancer cells. However, the mechanism of paclitaxel inducing apoptosis in human esophageal squamous cell carcinoma (ESCC) remains to be defined. In this study, we found that paclitaxel-induced apoptosis by increasing the relevant apoptosis protein expression and the release of cytochrome c via downregulation of signal transducer and activator of transcription 3 (STAT3) and phospho-STAT3 (Ser727). In addition, paclitaxel treatment of ESCC cells EC-1 and Eca-109 led to marked mitochondrial membrane potential depolarization and significantly increasing of reactive oxygen species. Moreover, paclitaxel treatment resulted in the inhibition of mitochondrial respiration. In conclusion, our findings reveal that paclitaxel induced apoptosis in both EC-1 and Eca-109 cells through the reduction of STAT3 and phospho-STAT3 (Ser727) level, and suggest that paclitaxel may be of therapeutic potential in the treatment of ESCC through the induction of mitochondrial apoptosis in ESCC cells. PMID- 28350089 TI - miR-150 inhibits proliferation and tumorigenicity via retarding G1/S phase transition in nasopharyngeal carcinoma. AB - Cancer cells are characterized by a pathological manifestation of uncontrolled proliferation, which results in tumor formation. Therefore, it is necessary to improve understanding of the underlying mechanism of cell cycle control. Here, we report that miR-150 is downregulated in nasopharyngeal carcinoma tissues and cells. Upregulation of miR-150 suppresses nasopharyngeal carcinoma (NPC) cell proliferation and induces G1/S arrest in vitro, and inhibits tumorigenesis in vivo. Conversely, silencing miR-150 yields the opposite effect. Our results further demonstrate that miR-150 retards nasopharyngeal carcinoma cell proliferation and G1/S transition via targeting multiple cell cycle-related genes, including CCND1, CCND2, CDK2 and CCNE2. Therefore, our results uncover a novel mechanistic understanding of miR-150-mediated tumor suppression in NPC, which will facilitate the development of effective cancer therapies against nasopharyngeal carcinoma. PMID- 28350090 TI - Anti-hepatoma activities of ethyl acetate extract from Ampelopsis sinica root. AB - Ampelopsis sinica root (ASR) is a known hepatoprotective folk traditional Chinese medicine. The anti-hepatoma activity of ethyl acetate extract from A. sinica root (ASRE) in vitro and in vivo and its possible mechanism were explored. This study was designed to investigate cytotoxicity by MTT assay, induction of apoptosis via Hoechst 33258 staining, scanning electron microscopy and bivariate flow cytometric analysis (Annexin V-FITC/PI), inflammation and apoptosis related genes expression by RT-PCR and p53 protein expression by immunofluorescence assay in HepG2 cells. Then, the antitumor activity in vivo was detected by hepatoma H22 xenograft tumor in mice. The results showed that ASRE had powerful anti-hepatoma activity in vitro without obvious toxicity on normal cells and could induce HepG2 cell apoptosis. The mechanism may be associated with downregulation of inflammatory cytokines including cyclooxygenase-2, 5-lipoxygenase and FLAP, increase of the ratio of bax/bcl-2, activation caspase-3 and inhibition of survivin, and increased expression of p53 protein. Furthermore, the HPLC assay showed the main compounds of ASRE were gallic acid, catechin and gallic acid ethyl ester. In animal experiments, ASR ethanol extract decreased the tumor weights of hepatoma H22 tumor-bearing mice. Therefore, ASR may be a potential therapeutic agent in the treatment of hepatocellular carcinoma. PMID- 28350091 TI - Clinical implication of Frizzled 2 expression and its association with epithelial to-mesenchymal transition in hepatocellular carcinoma. AB - The epithelial-to-mesenchymal transition (EMT) is an initial, critical step in hepatocellular carcinoma (HCC) tumor invasion and metastasis. Frizzled 2 (Fzd2) expression might drive EMT through the non-canonical Wnt pathway, one of the various EMT signaling pathways. The expression of epithelial (E-cadherin) and mesenchymal (vimentin) markers, as well as that of Wnt5b, Stat3, IL-6, Jak2 and Fzd2, were measured in 15 HCC cell lines. The EMT status (vimentin to E-cadherin mRNA expression ratio), Fzd2 mRNA expression, and pSTAT3 protein expression were assessed by immunostaining in 100 HCC patients, and correlations of their expression with clinicopathological factors and prognosis were analyzed. Cell proliferation, migration, and invasiveness were assessed after Fzd2 knockdown. Fzd2 expression was significantly correlated with a mesenchymal phenotype in the HCC cell lines. Treatment of the cell lines with Fzd2 siRNA resulted in significantly reduced migration and invasiveness but did not affect proliferation. A significant correlation was detected between the EMT status and Fzd2 expression in the HCC patients. Multivariate analysis revealed that Fzd2 expression was an independent predictor of recurrence (P=0.034). Patients with high Fzd2 expression had significantly poorer recurrence-free survival than those with low expression (P=0.03). Finally, pSTAT3 expression was significantly correlated with the EMT and Fzd2 status (P=0.0028, and P=0.0066, respectively). Fzd2 expression induced EMT and enhanced cell migration and invasiveness, and it might be a novel predictor of HCC recurrence. Furthermore, Stat3 might be controlled by both the Wnt5/Fzd2 and IL-6/Jak2 signaling pathways and play an important role in EMT. PMID- 28350092 TI - Deubiquitinating enzyme USP20 is a positive regulator of Claspin and suppresses the malignant characteristics of gastric cancer cells. AB - The aim of the present study was to investigate the clinical significance, the biological function and the mechanisms of USP20 in gastric cancer. The expression of USP20 in 89 pairs of primary gastric cancer and peritumoral gastric tissues specimens were measured by immunohistochemistry. The correlation of USP20 expression with the survival and the clinicopathological characteristics of patients were analyzed. Moreover, the underlying mechanisms of ectopic USP20 expression and its impact on GC cells were also investigated. We found that the expression of USP20 is relatively low in GC tissues and negatively correlated with tumor size, tumor invasion and TNM staging. High expression of USP20 in GC predicted longer survival. Experimentally, small interfering RNA-mediated knockdown of USP20 expression significantly promoted cell proliferation, accelerated G1-S phase transition and attenuated the autophagy activity. Overexpression of USP20 led to the inhibition of proliferation, G1-S cell cycle transition delay and autophagy activation. Mechanistically, we confirmed that silencing the expression of USP20 in GC cells could reduce Claspin protein levels without altering Claspin mRNA levels, which is involved in the antitumor activity of USP20. Furthermore, the expression level of Claspin was relatively higher in peritumoral tissue than that of GC tissues and higher expression of Claspin in GC was also correlated with good prognosis of patients. Given its pivotal role in gastric tumorigenesis and progression, USP20 functioned as the tumor suppressor in GC and possessed promising value to be a therapeutic target for GC. PMID- 28350093 TI - Inhibitory effect of Angelica gigas on cold-induced RhoA activation in vascular cells. AB - The herbal extract Angelica gigas (AG) has been applied as a vasodilating agent for patients suffering from vascular diseases for many years; however, the underlying mechanism has not been fully elucidated. The present study hypothesized that the anti-vasoconstrictive effect of AG may be effective in the treatment of abnormal cold-mediated vasospasms that occur in Raynaud's phenomenon (RP). The effect of AG on the activity of ras homolog gene family member A (RhoA) was investigated in cold-exposed vascular cells. Vascular cells were pretreated to AG, followed by a warm (37C) or cold (25C) incubation for 30 min and investigated with western blotting, ELISA and confocal microscopy. Cold treatment induced the activation of RhoA in pericytes and vascular endothelial cells, however this was reduced by treatment with AG. Furthermore, AG treatment reduced the endothelin-1 (ET-1)-mediated RhoA activation in pericytes; however, cold induced ET-1 production by vascular endothelial cells was not affected by treatment with AG. In addition, AG treatment suppressed the formation of stress fibers and focal adhesion complexes, and the cold-induced phosphorylation of focal adhesion kinase, proto-oncogene tyrosine-protein kinase Src and extracellular signal-related kinase. Therefore, AG treatment demonstrated an ability to reduce cold-induced RhoA activation in pericytes and vascular endothelial cells, and attenuated ET-1-mediated RhoA activation in pericytes. In conclusion, the present study indicated that AG may be useful for the treatment of RP. PMID- 28350094 TI - Routine genetic testing of lung cancer specimens derived from surgery, bronchoscopy and fluid aspiration by next generation sequencing. AB - After the development of EGFR tyrosine kinase inhibitors (TKIs), genetic testing of EGFR became required for effective treatment of lung cancer. Initially, the testing was conducted separately for each mutated region. However, many EGFR mutations have since been identified that determine the efficacy of EGFR-TKIs. Therefore, genetic testing of EGFR by next generation sequencing (NGS) may be a suitable strategy for lung cancer. Here we examined the applicability of the NGS method in regard to sensitivity, time and cost. A total of 939 specimens were obtained from 686 lung cancer patients at our hospital. DNA and RNA were simultaneously extracted from specimens derived from surgery, bronchoscopy, and fluid aspiration. Specimens included cerebrospinal fluid, pleural effusion, abdominal fluid, and pericardial effusion. From RNA, target regions (EGFR, KRAS, ALK fusion and RET fusion) were enriched by RT-PCR and sequenced with MiSeq. From DNA, PCR or PCR-RFLP conventional methods were performed. NGS and conventional methods were carried out routinely per week. Among the total 939 specimens, 38 specimens could not be examined with NGS. Among these, 34 specimens were analyzed by conventional testing with simultaneously extracted DNA. The remaining four specimens could not be tested with either method. Compared with the conventional method, the concordance rate of mutations was 99% (892/901), excluding specimens with NGS failure. The time period required from processing of specimens to results was 4 days, and the cost per sample was sufficiently low. In conclusion, the genetic testing with NGS method was useful for lung cancer treatment. The cost, sensitivity and time were able to tolerate routine examinations. PMID- 28350096 TI - CIRH1A augments the proliferation of RKO colorectal cancer cells. AB - Accumulating evidence suggests that ribosomal proteins may have extraribosomal functions in various physiological and pathological processes, including cancer. We analyzed the expression of the CIRH1A ribosomal protein in colorectal carcinoma and para-carcinoma samples by bioinformatics analyses of data extracted from The Cancer Genome Atlas and in colorectal cancer cell lines in vitro by qPCR. CIRH1A was highly expressed in carcinoma samples and colorectal cancer cells. We also transduced the RKO colorectal cancer (CRC) cell line with lentivirus-mediated small interfering RNAs (siRNAs) and studied the impact that this knockdown of CIRH1A expression had on cell growth. RNA interference (RNAi) mediated inhibition of CIRH1A expression significantly suppressed proliferation and increased apoptosis of transduced cells, and tended to arrest them in G1 phase. Our data suggest that CIRH1A plays a critical role in the proliferation, cell cycle distribution, and apoptosis of human malignant colorectal cells, and might therefore be a potential target for therapeutic strategies. PMID- 28350095 TI - Clinical significance of sCD163 and its possible role in asthma (Review). AB - Macrophages exert important functions in the balance and efficiency of immune responses, and participate in innate and adaptive immunity. The proinflammatory actions of macrophages are implicated in autoimmune diseases. Unlike classically activated M1 macrophages, the alternatively activated cluster of differentiation (CD)163+ and CD206+ M2 macrophages are involved in tissue repair and wound healing, and use oxidative metabolism to support their long-term functions. CD163 is a member of the scavenger receptor superfamily, categorized into class B, and its soluble(s) form, sCD163, is a marker of activated M2 macrophages. CD163 is selectively expressed in cells of the monocyte and macrophage lineages; however, its biological role has yet to be elucidated. The expression of sCD163 is markedly induced by anti-inflammatory mediators, such as glucocorticoids and interleukin-10, whereas it is inhibited by proinflammatory mediators, such as interferon-gamma. These findings suggest that CD163 may serve as a potential target for the therapeutic modulation of inflammatory responses. The concentration of sCD163 in blood is associated with acute and chronic inflammatory processes in autoimmune disorders of connective tissue, fat metabolism and cardiovascular diseases, and it can be used for the assessment of cancer prognosis. A role for sCD163 in the pathogenesis of asthma has also been proposed. The present review serves to present the available knowledge concerning the implication of sCD163 in the pathophysiological mechanisms of asthma, and evaluate its potential as a biomarker and possible therapeutic target for asthma. PMID- 28350097 TI - Identification of novel cancer fusion genes using chromosome breakpoint screening. AB - Gene fusion due to rearrangement or translocation of chromosomes is a powerful mutational mechanism during tumorigenesis. Several new high-resolution technologies have recently been developed to evaluate large numbers of small aberrations as candidate loci for fusion gene screening. In our previous whole genome screening study using 500K SNP arrays, we identified more than 700 homozygous deletions (HDs) and amplicons in 23 cancer cell lines. To explore novel fusion genes in cancer, we established stringent criteria for defining HD and amplicon breakpoints. Then genomic PCR and sequencing analyses identified a fusion gene, FNDC3B-PRKCI, that resulted from chromosome intra-rearrangement. Western blotting and 3'-RACE analyses revealed that the chimeric transcript was an in-frame fusion between FNDC3B and PRKCI. Finally, cell migration and colony formation assays suggested that FNDC3B-PRKCI is a potential oncogene. PMID- 28350098 TI - SLC3A2 is upregulated in human osteosarcoma and promotes tumor growth through the PI3K/Akt signaling pathway. AB - Growing evidence indicates that SLC3A2 (solute carrier family 3 member 2) is upregulated and correlates with tumor growth in multiple types of cancers, while the role of SLC3A2 in human osteosarcoma (OS) is rarely discussed. Thus, the aim of the present study was to demonstrate the expression of SLC3A2 in human osteosarcoma and reveal its biological function and the underlying mechanisms. RT PCR, western blot analysis and immunohistochemistry (IHC) were used to assess the expression of SLC3A2 in OS samples and cell lines. Cell cycle, Cell Counting Kit 8 (CCK-8) and colony formation assays were used to test the cell survival capacity. To investigate the potential mechanism by which SLC3A2 regulates OS growth, we used a slide-based antibody array. We demonstrated that SLC3A2 was upregulated in OS cell lines as well as OS tissues. High expression of SLC3A2 was correlated with clinical stage and tumor size in OS. Reduced expression of SLC3A2 inhibited OS cell proliferation through G2/M phase arrest. Most importantly, we found that SLC3A2 may regulate OS growth through the PI3K/Akt signaling pathway. In conclusion, SLC3A2 is upregulated in OS and plays a crucial role in tumor growth. Targeting SLC3A2 may provide a new therapeutic strategy for OS. PMID- 28350100 TI - Overexpression of miR-203 increases the sensitivity of NSCLC A549/H460 cell lines to cisplatin by targeting Dickkopf-1. AB - The number of new lung cancer cases diagnosed yearly is high, and the mortality rate has not substantially declined. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and adenocarcinoma accounts for the largest proportion of NSCLC. Currently, platinum-based combined chemotherapy, particularly cisplatin (DDP) is still the main form of treatment for advanced NSCLC. However, cisplatin resistance often occurs in patients who receive chemotherapy. Previous studies offer various explanations for how miRNAs affect cisplatin resistance, but the underlying mechanism remains largely unknown. The present study was designed to focus on miR-203 and Dickkopf-1 (DKK1), investigating the potential mechanisms involved in cisplatin resistance in tissues of lung adenocarcinoma and A549/H460 cell lines. In DDP-sensitive NSCLC samples, miR-203 was expressed at a higher level when compared with this level in DDP-insensitive samples, while DKK1 mRNA was expressed at a relatively low level as indicated by qRT-PCR. Dual luciferase reporter assay revealed that DKK1 is a target gene of miR-203 in A549 and H460 cells. Upregulation of miR-203 reduced the IC50 value of cisplatin in the A549 and H460 cells by inhibiting cell growth and promoting cell apoptosis. Similar effects of tumor inhibition and cisplatin sensitization were verified in vivo. Further research showed that both overexpression of miR-203 and knockdown of DKK1 increased the sensitization to DDP with a lower IC50 value. Upon DKK1 knockdown, overexpression of miR-203 had no added effects on the sensitivity of the cells. In addition, miR-203 was unable to sensitize cells with DKK1 that lacked the 3' untranslated region (3'UTR). We conclude that miR-203 targets the 3'UTR of DKK1, and increases cisplatin sensitivity in A549/H460 cell lines. PMID- 28350105 TI - Inflammatory role of high salt level in tumor microenvironment (Review). AB - Chronic inflammation is known to play a critical role in cancer development and progression. High salt is known to mediate several chronic inflammatory diseases including hypertension, myocardial infarction, neurological ischemic attack, autoimmune diseases and cancers. High salt level is shown to induce angiogenesis and immune-dysfunction, both of which play a direct role in cancer proliferation. Furthermore, salt has been suggested to enhance Warburg-like metabolic phenotype in cancer cells and at the same time also induce pro-tumor MPhi2-macrophage phenotype. Recent studies have identified several molecular targets such as tonicity specific transcript factor NFAT5/TonEBP, sodium ion channel gammaENaC, and vascular endothelial growth factor, VEGF, which are upregulated under high salt external environment. These molecular targets offer futuristic therapeutic application in precision medicine. In this review, we discuss the current understanding of the salt mediated metabolic and immune dysfunctions playing a potential role in cancerous changes. PMID- 28350106 TI - miR-940 upregulation contributes to human cervical cancer progression through p27 and PTEN inhibition. AB - Cervical cancer is considered as a gynecological malignancy accompanied with high rates of mortality across the world. Effective diagnostic, prognostic markers as well as therapeutic targets are necessary to be explored. The p27 and PTEN are known to modulate tumor cell growth and proliferation. However, the molecular mechanisms modulating these genes have not completely been elucidated. In our study, real-time (RT) quantitative PCR indicated that miR-940 levels were upregulated in human cervical cancer tissue samples and cell lines. Overexpression of miR-940 could reduce overall survival in patients. Ectopic miR 940 accelerated cervical cancer cell growth, proliferation and cell cycle arrest in vitro as well as tumor formation in vivo. p27 and PTEN were evidenced as direct targets for miR-940 and inhibition of p27 and PTEN recovered the suppressive function of miR-940-silenced cell towards to proliferation and tumorigenicity in cervical cancer cells. In addition, miR-940 expression was inversely associated with p27 and PTEN expression levels and actively with cyclin D1 in cervical cancer specimens. The results from our study demonstrated that miR 940 regulated p27 and PTEN post-transcriptionally and might play a significant role in cervical cancer development and progression. Thus, miR-940 might provide a potential value as therapeutic target for cervical cancer treatment in future. PMID- 28350104 TI - Induction of galectin-1 by TLR-dependent PI3K activation enhances epithelial mesenchymal transition of metastatic ovarian cancer cells. AB - The expression of different toll-like receptors (TLRs) on tumor cells has been associated with disease aggressiveness, treatment resistance, and poor prognosis. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is considered critical for cancer cell survival and proliferation. Thus, we investigated the effect of TLR stimulated PI3K activation on the epithelial-to-mesenchymal transition (EMT) of primary (Caov-3) and metastatic (SK-OV-3) epithelial ovarian cancer cell lines in this study. TLR engagement with various ligands promoted the expression of class IA PI3K (p110alpha, p110beta, and p110delta) and increased the expression of mesenchymal markers (N-cadherin, Slug, Vimentin, Snail, alpha-SMA, and TCF) in SK OV-3 cells. The migratory activity and secretion of EMT-related cytokines of SK OV-3 were significantly higher compared to those of Caov-3 after activation with TLR agonist. Although the invasive capacity and production of EMT-related cytokines of LPS-stimulated SK-OV-3 cells were significantly suppressed by all pharmacological inhibitors of the p110 isoform, the Syk/Src-dependent p110beta isoform prominently attenuated migration activity. In contrast, the production of IL-10 and galectin-1 was mainly affected by the p110delta isoform. Gene silencing of TLR4 and galectin-1 with siRNA decreased the expression of matrix metalloproteinase-2 (MMP2) and MMP9 and reduced mesenchymal markers in LPS treated SK-OV-3 cells. This study demonstrated that TLR-mediated PI3K activation modulated the invasion and metastasis of ovarian cancer through the production of galectin-1, suggesting that inhibition of the p110 isoform is a promising therapeutic approach against metastatic ovarian cancer. PMID- 28350107 TI - A liquid biopsy-based method for the detection and quantification of circulating tumor cells in surgical osteosarcoma patients. AB - A method for the enumeration and quantification of osteosarcoma (OS) circulating tumor cells (CTCs) is currently not available. A correlation between the number of CTCs and progression-free survival (PFS) has been established for other cancers, but not for OS CTCs. A method was therefore developed for CTC quantification in OS and validated in a prospective cohort of surgical patients with primary and recurrent/metastatic OS (N=23). Human OS cells, acting as CTCs, were enumerated from spiked human peripheral blood (PB) following erythrocyte and leukocyte depletion. The OS cells were quantified microscopically based on aneuploidy and a CK18-/CD45- phenotype. Aneuploidy was assayed by fluorescence in situ hybridization (FISH) using fluorescence-labeled alpha-satellite probes for the centromeres of chromosome (CEP 8). CK18 and CD45 phenotyping was performed with immunocytochemistry. HOS cells in spiked PB could be effectively retrieved with the FISH-based enumeration method, which was subsequently employed in an OS patient cohort. PB of recurrent/metastatic OS patients contained more CTCs than the PB of primary OS patients. OS patients with >=2 CTCs per 7.5 ml of PB had worse PFS than patients whose PB contained <2 CTCs. In 2 cases, CTCs were present in PB of OS patients with negative X-ray and chest CT scans. In conclusion, our method was able to quantitate CTCs in liquid biopsies of OS patients. The number of CTCs has diagnostic and prognostic value. PMID- 28350110 TI - Glutamate-mediated effects of caffeine and interferon-gamma on mercury-induced toxicity. AB - The molecular mechanisms mediating mercury-induced neurotoxicity are not yet completely understood. Thus, the aim of this study was to investigate whether the severity of MeHg- and HgCl2-mediated cytotoxicity to SH-SY5Y human dopaminergic neurons can be attenuated by regulating glutamate-mediated signal-transmission through caffeine and interferon-gamma (IFN-gamma). The SH-SY5Y cells were exposed to 1, 2 and 5 uM of either MeHgCl2 or HgCl2 in the presence or absence of L glutamine. To examine the effect of adenosine receptor antagonist, the cells were treated with 10 and 20 uM caffeine. The total mitochondrial metabolic activity and oxidative stress intensity coefficient were determined in the 1 ng/ml IFN gamma- and glutamate-stimulated SH-SY5Y cells. Following exposure to mercury, the concentration-dependent decrease in mitochondrial metabolic activity inversely correlated with oxidative stress intensity. MeHg was more toxic than HgCl2. Mercury-induced neuronal death was dependent on glutamate-mediated excitotoxicity. Caffeine reduced the mercury-induced oxidative stress in glutamine-containing medium. IFN-gamma treatment decreased cell viability and increased oxidative stress in glutamine-free medium, despite caffeine supplementation. Although caffeine exerted a protective effect against MeHg induced toxicity with glutamate transmission, under co-stimulation with glutamine and IFN-gamma, caffeine decreased the MeHg-induced average oxidative stress only by half. Thereby, our data indicate that the IFN-gamma stimulation of mercury exposed dopaminergic neurons in neuroinflammatory diseases may diminish the neuroprotective effects of caffeine. PMID- 28350112 TI - Contribution of caspase-independent pathway to apoptosis in malignant glioma induced by carbon ion beams. AB - High linear energy transfer (LET) carbon ion beam (CIB) is becoming the best tool for external radiotherapy of inoperable tumors because of its greater cell killing than conventional low LET gamma or X-rays. In the present study, whether the caspase-independent pathway exerts the important contribution in CIB-induced cell apoptosis was explored. Herein we showed, despite the absence of caspase activity using a pan caspase inhibitor Z-VAD-FMK, that apoptosis induced by high LET CIB were clearly observed in the glioma cells. Simultaneously, the increased 8-OHdG level, PARP-1 activity and AIF translocation occurred in response to CIB irradiation. Moreover, it was distinctly higher in the nuclear translocation frequency along with PARP-1 activation when the caspase protease cascade was suppressed in the irradiated glioma cells. Nuclear colocalization between PARP-1 and AIF as well as a positive association of the PARP-1 mRNA expression with AIF translocation frequency indicated that PARP-1 activation controlled the translocation of AIF to the nucleus. Our findings strongly demonstrated that caspase-independent cell apoptosis provided a prominent compensation in the glioma cell death involving the PARP-1/AIF signaling pathway at 24 h after CIB exposure, and likely triggered by oxidative damage to DNA. The knowledge on the molecular mechanism of AIF-mediated cell death may be very useful for the improvement of the therapeutic efficacy of malignant gliomas with heavy charged particles. PMID- 28350113 TI - Bone marrow mesenchymal stem cells accelerate the hyperglycemic refractory wound healing by inhibiting an excessive inflammatory response. AB - The aim of the present study was to evaluate the healing effect of bone marrow derived mesenchymal stem cells administered to hyperglycemia model mice with skin wounds, and to explore the underlying mechanism contributing to their effects in promoting refractory wound healing. A full-thickness skin wound mouse model was established, and refers to a wound of the skin and subcutaneous tissue. The mice were randomly divided into three groups: Blank control group, hyperglycemic group and a hyperglycemic group treated with stem cells. Wound healing was monitored and the wound-healing rate was determined at 3, 6, 9, and 12 days following trauma. The structure of the organization of new skin tissue was observed by hematoxylin and eosin staining, and expression levels of the inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha were determined from 1 to 6 days following trauma. The wound healing of the hyperglycemic group was slower than that of the blank group, and the hyperglycemic mice treated with stem cells presented faster healing than the hyperglycemia group. The horny layer and granular layer of the skin were thinner and incomplete in the new skin tissue of the hyperglycemic group, whereas the new skin wound tissue basal layer was flat and demonstrated better fusion with the wound edge in the other two groups. The expression of inflammatory cytokines (IL 6 and TNF-alpha) was significantly increased in all three groups, with continuously higher expression in the hyperglycemic group and decreased expression in the other two groups over time. Hyperglycemia refractory wounds are likely related to the excessive expression of inflammatory cytokines surrounding the wound area. Stem cells may be able to alleviate the excessive inflammatory reaction in the wound tissue of hyperglycemic mice, so as to promote wound healing. PMID- 28350114 TI - Runx2 downregulation, migration and proliferation inhibition in melanoma cells treated with BEL beta-trefoil. AB - Malignant melanoma is a lethal form of skin cancer and highly metastatic tumor with poor prognosis; BEL beta-trefoil, a lectin, obtained by our group, possesses the ability to act specifically on malignant cells. Therefore, the aim of our study was to investigate the effects of BEL beta-trefoil in melanoma cells in an attempt to evaluate its potential usage as anticancer agent. BEL beta-trefoil was purified by chromatography and A375 and MeWo melanoma cells were treated. Viability and proliferation were evaluated as well as apoptosis, RUNX2 gene expression and migration ability. The treated tumor cells decreased viability as well as proliferative ability. Flow cytometry analysis showed a lessen effect of the treatment on apoptosis. The gene expression analysis showed a reduction of RUNX2 expression in a dose-dependent manner and migration ability was reduced significantly in both treated cell lines. Our findings suggest that BEL beta trefoil can be considered a useful tool against malignancy due to its effect based on the simultaneous proliferation ability reduction as well as the inhibition of migration capacity on melanoma tumor cells. PMID- 28350115 TI - Transition and heavy metals compared to oxidative parameter balance in patients with deep vein thrombosis: A case-control study. AB - Our study compared copper (Cu), zinc (Zn) and manganese (Mn), crucial for human normal physio-logy maintenance, and lead (Pb) levels as environmental pollutant, in subjects suffering of deep vein thrombosis of lower limbs (DVTs) vs. healthy subjects. Furthermore, we evaluated oxidative stress parameters, the thiobarbituric acid reactive substances (TBARS) as the sum of malondialdehyde or 1,1,3,3-tetraethoxypropane (MDA) and 4-hydroxynonenal 4-HNE) and cytosolic superoxide dismutase (Cu/Zn-SOD) concentrations in both groups. We recruited 24 DVT cases and 46 healthy subjects as controls. Questionnaire with socio demographic, habits and lifestyle were collected. Hair concentrations of Zn, Mn, Cu and Pb were measured by ICP-MS, plasma concentrations of MDA and 4-HNE were measured by HPLC and SOD plasma concentrations were detected by ELISA test. A quantitative and qualitative variables comparison between cases and controls group was made by Mann-Whitney U test and Pearson's Chi-square test, respectively. We found low concentrations of Zn, Mn and Cu vs. high Pb concentrations in DVTs subjects. TBARS were found higher in the cases group, conversely, SOD concentrations were found lower in cases with respect to controls. Furthermore, we found the diet of pathological subjects significantly deficient in vegetables. These results are indicative of a lower enzymatic activity in patients, related to low transition metal levels in the DVTs and high levels of Pb, coupled with an unbalanced diet. PMID- 28350116 TI - Selective FGFR inhibitor BGJ398 inhibits phosphorylation of AKT and STAT3 and induces cytotoxicity in sphere-cultured ovarian cancer cells. AB - Epithelial ovarian cancer is the most aggressive and lethal among the gynecological malignancies, which is often found disseminated to peritoneal cavity at the time of diagnosis. There is accumulating evidence on the existence of genetic alteration and amplification of fibroblast growth factor receptor (FGFR) in various cancers. Also the aberrated FGFR/FGF signaling has been implicated in cancer development and tumor microenvironment. However, the antitumor activity of BGJ398, a selective inhibitor of FGFR 1/2/3 against ovarian cancer still remains unknown. The aim of the present study is to evaluate the antitumoral activity of BGJ398 on ovarian cancer cell line SKOV3ip1 using 3 dimensional (3D) sphere culture system which has been accepted as a better mimic in vivo microenvironment than conventional 2-dimensional (2D) monolayer culture system. We examined the differential expression features of key signaling molecules which have a role in cell survival and proliferation between sphere cultured SKOV3ip1 cells and monolayer-cultured SKOV3ip1 cells. The phosphorylation of AKT and signal transducer and activator of transcription 3 (STAT3) known as survival signaling molecules were upregulated in sphere-cultured SKOV3ip1 cells compared to in monolayer-cultured SKOV3ip1 cells. Next, we evaluated the antitumor activity of BGJ398 in monolayer-cultured SKOV3ip1 cells or sphere-cultured SKOV3ip1 cells. Treatment of BGJ398 did not affect the SKOV3ip1 cell viability in monolayer culture system, but, the cell viability of sphere-cultured SKOV3ip1 cells was markedly reduced by BGJ398. The phosphorylation of AKT and STAT3 was downregulated by BGJ398 in sphere-cultured SKOV3ip1 cells, but not in monolayer cultured-SKOV3ip1 cells. Moreover, combination treatment with BGJ398 and paclitaxel in sphere-cultured SKOV3ip1 showed synergistic inhibitory effect on cell viability. Collectively, our report reveals the BGJ398 is a potent antitumor agent against ovarian cancer and FGFR is a promising therapeutic target to anticancer therapy considering ovarian cancer metastatic microenvironment. PMID- 28350117 TI - Reduced expression of miR-205-5p promotes apoptosis and inhibits proliferation and invasion in lung cancer A549 cells by upregulation of ZEB2 and downregulation of erbB3. AB - Previous studies have demonstrated that microRNA (miR)-205-5p expression is significantly increased in non-small cell lung cancer tissues and is associated with tumor differentiation grade. The aim of the present study was to explore the effects of miR-205-5p on viability, apoptosis and invasion of lung cancer A549 cells. The hsa-miR-205-5p small interfering RNA (siRNA) inhibitor was transfected into A549 cells and expression of miR-205-5p was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell viability, apoptosis and invasion were assayed by Cell Counting kit-8, Annexin V/propidium iodide double staining and Transwell assay, respectively. Target genes of miR-205 5p were predicted using bioinformatics analysis. Expression of mRNA and protein levels of candidate target genes following miR-205-5p inhibition were detected using RT-qPCR and western blot analysis respectively. The results demonstrated that relative survival rates of A549 cells were significantly inhibited in miR 205-5p siRNA-transfected cells at 24 and 48 h compared with control cells. Apoptosis was markedly increased in the miR-205-5p siRNA cells compared with control cells. The number of invaded cells following miR-205-5p siRNA silencing was significantly decreased compared with control cells. Bioinformatics analysis revealed that erb-B2 receptor kinase 3 (erbB3), zinc finger E-box binding homeobox 2 (ZEB2), clathrin heavy chain (CLTC) and mediator complex subunit 1 (MED1) may be potential target genes of miR-205-5p. Reduced expression of miR-205 5p significantly increased the expression of ZEB2 mRNA and protein, inhibited the expression of erbB3 protein, but had no significant effect on the expression levels of CLTC and MED1. In summary, reduced expression of miR-205-5p promoted apoptosis and inhibited proliferation and invasion in lung cancer A549 cells through upregulation of ZEB2 and downregulation of erbB3. The present results suggested that the increased miR-205-5p expression observed in non-small cell lung cancer tissues may contribute to increased proliferation and invasion of lung cancer cells and thus to cancer progression. PMID- 28350119 TI - Molecular mechanism of C-reaction protein in promoting migration and invasion of hepatocellular carcinoma cells in vitro. AB - Hepatocellular carcinoma (HCC) is one of most common malignant cancers and is the second leading cause of cancer related deaths. The prognosis and survival of patients are closely related to the degree of tumor metastasis. The mechanism of HCC metastasis is still unclear. In the present study, we investigated the molecular mechanism of C-reaction protein in promoting migration and invasion of hepatocellular carcinoma cells in vitro. We estimated that CRP is overexpressed in liver cancer tissues and that it promotes invasion and metastasis of HCC in vitro. In the present study, we employed iTRAQ-based mass spectrometry to analyze the HepG2 secretory proteins of CRP siRNA-treated cells and negative control siRNA-treated cells. We identified 109 differentially expressed proteins after silencing CRP, of which 45 were upregulated and 64 were downregulated. Some of the differentially expressed proteins were confirmed by western blot analysis and real-time quantitative PCR. Furthermore, we found that knockdown of CRP substantially abrogates HIF-1alpha expression levels, the luciferase activity of HIF-1alpha and ERK and Akt phosphorylation in HepG2 cells. The present study provides a novel mechanism by which CRP promotes the proliferation, migration, invasion and metastasis of hepatocellular carcinoma cells. Inhibition of CRP suppressed migration, invasion and healing of hepatoma carcinoma cells by decreasing HIF-1alpha activity and CTSD. PMID- 28350120 TI - Cross-validation of genes potentially associated with overall survival and drug resistance in ovarian cancer. AB - Ovarian cancer is the leading cause of death among malignancies of the female reproductive system. The 5-year survival rates of ovarian cancer (OC) patients are very poor as a result of recurrent disease and emergence of drug resistance; thus, studies to find predictive markers and factors for drug resistance are ongoing. In the present study, based on the microarrays from The Cancer Genome Atlas (TCGA), and the Gene Expression Omnibus (GEO) profiles covering 1648 OC patients, 11 out of 136 genes that were found to be significantly dysregulated in OC were associated with overall survival (OS) in 489 OC patients of the TCGA cohort. Of these genes, CRISP3, LYVE1, OVGP1 and BCHE were identified as independent prognostic factors, with decreased expression of the first three genes predicting shorter OS, and decreased BCHE predicting longer OS. OVGP1, BCHE and further two genes, CKAP2 and CLDN10, were consistently and remarkably associated with OS when the number of patients increased from 489 to 1583, with increased CKAP2 and decreased CLDN10 predicted shorter OS; combining the four genes provided better predictions. Associations among the four genes with OS in subgroups of OC were further verified. Downregulation of OVGP1 was significantly associated with shorter OS in all subgroups of OC patients, including subgroups of 752 patients treated with chemotherapy regimens containing taxol, 763 with both platin and taxol, 1364 with platin, 371 patients with grade 1-2 disease, 968 with grade 3 disease, 1148 with stage III-IV disease, and 439 with TP53 mutations. In addition, CKAP2 expression was significantly associated with shorter OS in 515 OC patients who had low CA125 levels. Furthermore, comprehensive analyses that including RT-qPCR, bioinformatics analysis and clinical data revealed an association of CKAP2, BCHE, CLDN10 and OVGP1 with drug resistance in OC. The genes identified in the present study might be prognostic factors as well as potential therapeutic targets in the treatment of OC. PMID- 28350121 TI - Stanniocalcin 1 promotes cell proliferation via cyclin E1/cyclin-dependent kinase 2 in human prostate carcinoma. AB - Stanniocalcin 1 (STC1) is a glycoprotein hormone that is involved in calcium/phosphate homeostasis. Increasing evidence suggests that STC1 is involved in carcinogenesis; however, few studies have defined the mechanisms and functional roles of STC1 activity in prostate carcinogenesis. In the present study, MTT, flow cytometry and colony formation assays, and small interfering RNA (siRNA) and overexpression in multiple cell lines were used to investigate the function of STC1 in prostate carcinoma in vivo and in vivo. Knockdown of endogenous STC1 using a siRNA decreased the proliferation of DU145 and LNCaP2 cells. These results were consistent with the changes in the protein levels of cyclin E1 and cyclin-dependent kinase 2. By contrast, increased expression of STC1 in RWPE-1 cells led to increased cell proliferation, suggesting that STC1 promotes prostate carcinoma cell proliferation. In summary, the present study investigated the impact of STC1 on the proliferation and growth of prostate cancer in an effort to evaluate STC1 as a predictive biomarker and as a potential target for therapy. PMID- 28350122 TI - Berberine sensitizes nasopharyngeal carcinoma cells to radiation through inhibition of Sp1 and EMT. AB - Nasopharyngeal carcinoma (NPC) is a tumor of epithelial origin with radiotherapy as its standard treatment. However, radioresistance remains a critical issue in the treatment of NPC. This study aimed to investigate the effect of berberine on the proliferation, cell cycle regulation, apoptosis, radioresistance of NPC cells and whether specificity protein 1 (Sp1) is a functional target of berberine. Our results showed that treatment with berberine reduced the proliferation and viability of CNE-2 cells in a dose- and time-dependent manner. Berberine induced cell cycle arrest in the G0/G1 phase and apoptosis. In CNE-2 cells exposed to gamma-ray irradiation, berberine reduced cell viability at various concentrations (25, 50, 75 and 100 umol/l). Berberine significantly decreased mRNA and protein expression of Sp1 in the CNE-2 cells. Mithramycin A, a selective Sp1 inhibitor, enhanced the radiosensitivity and the rate of apoptosis in the CNE-2 cells. Berberine inhibited transforming growth factor-beta (TGF-beta)-induced tumor invasion and suppressed epithelial-to-mesenchymal transition (EMT) process, as evidenced by increased E-cadherin and decreased vimentin proteins. Sp1 may be required for the TGF-beta1-induced invasion and EMT by berberine. In conclusion, berberine demonstrated the ability to suppress proliferation, induce cell cycle arrest and apoptosis, and enhance radiosensitivity of the CNE-2 NPC cells. Sp1 may be a target of berberine which is decreased during the radiosensitization of berberine. PMID- 28350123 TI - Design, synthesis and pharmaco-toxicological assessment of 5-mercapto-1,2,4 triazole derivatives with antibacterial and antiproliferative activity. AB - The extensive biochemical research of multiple types of cancer has revealed important enzymatic signaling pathways responsible for tumor occurrence and progression, thus compelling the need for the discovery of new means with which to block these signaling cascades. The phosphoinositide 3-kinase/ protein kinase B (PI3K/AKT) pathway, which plays an important role in maintaining relevant cellular functions, exhibits various alterations in common human cancers, thus representing a suitable target in cancer treatment. Molecules bearing the 1,2,4 triazole moiety are known to possess multiple biological activities, including anticancer activity. The current study used molecular docking in the design of 5 mercapto-1,2,4-triazole derivatives with antiproliferative activity targeting the PI3K/AKT pathway. Three structures emerged as the result of this method, which indicated for these a highly favorable accommodation within the active binding site of PI3K protein, thus acting as potential PI3K inhibitors, and hence interfering with the above-mentioned pathway. The molecules were synthesized and their chemical structure was confirmed. The antiproliferative activity of these compounds was tested on 4 cancer cell lines (A375, B164A5, MDA-MB-231 and A549) and on normal human keratinocytes (HaCaT) by in vitro alamarBlue assay. The 3 compounds revealed antitumor activity against the breast cancer cell line (MDA-MB 231) and reduced toxicity on the normal cell line. The antibacterial activity of the compounds was also tested in vitro on Gram-positive and Gram-negative bacterial strains, revealing moderate activity. PMID- 28350126 TI - G protein subunit alpha q regulates gastric cancer growth via the p53/p21 and MEK/ERK pathways. AB - Genetic alterations in G protein subunit alpha q (GNAQ) have been reported in numerous types of human cancer. However, the role of GNAQ in human gastric cancer (GC) has not been explored. In the present study, we found that GNAQ was highly expressed in GC patient samples and GNAQ expression was related to patient age, GC differentiation status and adjuvant therapy, as determined by immunohistochemical assay. Lentivirus delivery of short hairpin RNA (shRNA) targeting GNAQ was used to explore the function of GNAQ in GC cells. Silencing of GNAQ markedly suppressed proliferation and colony formation in GC cells, and arrested the cell cycle at the S phase. Mechanistic analysis revealed that knockdown of GNAQ significantly increased the expression of p53 and p21, and decreased cyclin A and p-CDK2 protein expression. Moreover, the phosphorylation of ERK and MEK was also decreased after knockdown of GNAQ as determined by western blotting assay. Overall, our results suggest that GNAQ plays a critical role in regulating GC cell growth and survival via canonical oncogenic signaling pathways including MAPK and p53, and therefore serves as a promising new therapeutic target in GC. PMID- 28350128 TI - Overexpression of miRNA-221 promotes cell proliferation by targeting the apoptotic protease activating factor-1 and indicates a poor prognosis in ovarian cancer. AB - MicroRNAs are a class of small non-coding, endogenous RNAs involved in cancer development and progression. MicroRNA-221 (mir-221) has been reported to have both an oncogenic and tumor-suppressive role in human tumors, but the role of miR 221 in ovarian cancer is poorly understood. In the present study, the expression levels of miR-221 and the apoptosis protease activating factor 1 (APAF1) protein in 63 samples of ovarian cancer tissues and the cell lines, IOSE25, A2780, OVCAR3, SKOV3 and 3AO were detected by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blot analysis, respectively. Cell proliferation was measured using cell counting kit-8 (CCK-8); cell migration and invasion were detected using a transwell assay; cell apoptosis was evaluated by flow cytometry and hoechst staining, and a luciferase assay was performed to verify a putative target site of miR-221 in the 3'-UTR of APAF1 mRNA. Expression of miR-221 was upregulated in ovarian cancer tissues. Patients with increased miR 221 expression levels had a reduced disease-free survival (P=0.0014) and overall survival (P=0.0058) compared with those with low miR-221 expression. Transfection of SKOV3 and A2780 cell lines with miR-221 inhibitor induced APAF1 protein expression, suppressed cell proliferation and migration and promoted tumor cell apoptosis. In conclusion, the APAF1 gene was confirmed as a direct target of miR 221 and overexpression of APAF1 suppressed ovarian cancer cell proliferation and induced cell apoptosis in vitro. These findings indicate that miR-221-APAF1 should be studied further as a potential new diagnostic or prognostic biomarker for ovarian cancer. PMID- 28350129 TI - Apoptosis is augmented in high-grade serous ovarian cancer by the combined inhibition of Bcl-2/Bcl-xL and PARP. AB - The aim of our study was to evaluate possible synergistic cytotoxic effects of the combination treatment with the BH3-mimetic ABT-263 and the PARP inhibitor BMN 673 in high-grade serous ovarian cancer (HGSOC) cells using clinically achievable concentrations of each drug. In vitro cytotoxic effects of ABT-263 and BMN 673 were assessed by XTT assay in three HGSOC cell lines: OVCAR3, OVCAR8, and OV90 cells. Combination index values and synergy/antagonism volumes were used to determine synergy. The drug effects on DNA damage accumulation, cell cycle progression, apoptosis induction, and expression levels of Bcl-2 family proteins were examined to dissect molecular mechanisms. The combination treatment synergistically decreased cell viability in a concentration- and time-dependent manner in all cell lines; combination index values were <0.9 and synergy/antagonism volumes were >100 after 72 h of treatment. Clinically achievable concentrations of ABT-263 2 uM and BMN 673 25 nM were used to investigate mechanisms. No increase in gamma-H2AX foci formation was observed with addition of ABT-263 to BMN 673 treatment. The combination treatment increased the sub-G1 and Annexin V-positive cell populations after 48 h compared with the control and each monotherapy. It also induced greater caspase-3/7 activity and PARP cleavage. ABT-263 alone and in combination with BMN 673 induced expression levels of Bim, a pro-apoptotic protein. In conclusion, the ABT-263 and BMN 673 combination resulted in synergistic cytotoxic effects against HGSOC cells through greater induction of apoptosis. This may be a novel therapeutic strategy for HGSOC. PMID- 28350132 TI - A new facet of NDRG1 in pancreatic ductal adenocarcinoma: Suppression of glycolytic metabolism. AB - N-myc downstream-regulated gene 1 (NDRG1) is known as tumor/metastasis suppressor in a variety of cancers including pancreas, being involved in angiogenesis, cancer growth and metastasis. However, the precise molecular mechanism how NDRG1 exerts its inhibitory function in pancreatic cancer remains unclear. In this investigation, we demonstrated that K-Ras plays a vital role in modulating NDRG1 protein level in PDAC cancer cells in vitro, which is mediated through ERK signaling. Noteworthy, K-Ras downstream Akt/mTOR signaling is inhibited upon NDRG1 overexpression, resulting in decease of HIF1alpha level. Moreover, NDRG1 has a unique role in modulating cancer metabolism of pancreatic ductal adenocarcinoma (PDAC). The mechanism accounting for NDRG1 in modulating aerobic glycolysis, at least partly, relied on its regulation of glycolysis genes including GLUT1, HK2, LDHA and PDK1. Additionally, NDRG1 is shown to suppress the activity of HIF1alpha, which is responsible for regulation of glycolysis enzymes. The current study is the first to elucidate a unique facet of the potent tumor/metastasis suppressor NDRG1 in the regulation of PDAC glycolysis, leading to important insights into the mechanism by which NDRG1 exert inhibitory function in PDAC. PMID- 28350133 TI - Low shear stress-induced autophagy alleviates cell apoptosis in HUVECs. AB - Low shear stress (LSS) is a well-established risk factor resulting in endothelial apoptosis and atherosclerosis. Autophagy has been reported to be involved in the development of atherosclerosis. However, whether autophagy participates in LSS induced atherosclerosis remains unclear. The effect of autophagy and its association with apoptosis, in the development of atherosclerosis, remains controversial. Therefore, in the present study, the level and role of autophagy in human umbilical vein endothelial cells (HUVECs) exposed to LSS was examined. The results revealed that LSS increased the formation of autophagosomes and MAP1 light chain 3-like protein (LC3) puncta (as demonstrated by transmission electron microscopy and immunofluorescence), and the protein levels of Beclin-1 and LC3II decreased the expression of p62 [as revealed by western blot analysis (WB)]. Furthermore, the level of p62 decreased when autophagy was induced by rapamycin, and increased when autophagy was inhibited by chloroquine (CQ), which indicated that LSS may serve an important role in inducing autophagy flux. In addition, it was observed that HUVECs treated with LSS underwent apoptotic death, by monitoring the rate of apoptosis and the expression of apoptosis regulator BAX (Bax) and apoptosis regulator Bcl-2 (Bcl-2) (by flow cytometry and WB) and the LSS-induced apoptosis in HUVECs, that was significantly alleviated by pretreatment with rapamycin, partially via a decrease in the level of Bax and an increase in the level of Bcl-2. Pretreatment of HUVECs with CQ markedly increased LSS-induced apoptosis, which was associated with an increased expression of Bax and a decreased expression of Bcl-2. In conclusion, the results of the present study indicate that LSS increases the level of autophagy, which may be through a Bcl-2/Beclin-1-dependent mechanism, which serves a protective role against LSS induced apoptosis. PMID- 28350134 TI - MicroRNA-455-3p functions as a tumor suppressor by targeting eIF4E in prostate cancer. AB - MicroRNAs (miRNAs) are strongly implicated in various cancers, including prostate cancer. Recently, microRNA-455-3p (miR-455-3p) has been shown to be aberrantly expressed in many tumor tissues, but its functions in tumorigenesis remain unknown. In this study, we investigated the role of miR-455-3p in prostate cancer. We found that miR-455-3p is markedly downregulated in prostate cancer cell lines and clinical tumor specimens. Gain-of-function and loss-of-function studies showed that miR-455-3p promotes prostate cancer cell growth both in vitro and in vivo. Bioinformatics analysis and Luciferase reporter assays demonstrated that miR-455-3p directly targets and suppresses eIF4E, the rate-limiting factor for cap-dependent translation, which plays important roles in the initiation and progression of prostate cancers. Further studies demonstrated that miR-455-3p inhibits cap-dependent translation and the proliferation of prostate cancer cells through targeting eIF4E. Taken together, our findings suggest that miR-455-3p functions as a tumor suppressor by directly targeting eIF4E in prostate carcinogenesis and may be used as a potential target for therapeutic intervention in prostate cancer. PMID- 28350136 TI - All-trans retinoic acid restored the osteogenic ability of BMP9 in osteosarcoma through the p38 MAPK pathway. AB - Osteosarcoma (OS) is the most common malignant bone tumour and is considered to be a disease caused by a dysfunction in differentiation. Bone morphogenetic protein 9 (BMP9) is the most potent osteogenic factor in mesenchymal stem cells, but it cannot induce osteogenic differentiation in OS cells; this might be one of the determinants in the pathogenesis of OS. All-trans retinoic acid (ATRA) can induce osteogenic differentiation of OS cells and potentiate BMP9-induced osteogenesis in preadipocytes. However, the concomitant effect of ATRA and BMP9 in OS cells is unclear; therefore, in the present study, we focused on this topic. The results showed that BMP9 significantly promoted the proliferation of human OS 143B cells and did not induce osteogenic differentiation of cells in vitro (p<0.01). ATRA inhibited proliferation and induced osteogenesis in 143B cells; these effects could be enhanced by BMP9 overexpression (p<0.05). ATRA could significantly increase the level of phosphorylated p38 MAPK (p-p38) in 143B cells, while BMP9 did not have any significant effect. Notably, BMP9 overexpression enhanced the ability of ATRA to increase the levels of p-p38. Both the osteogenic differentiation and the anti-proliferative activity of BMP9 in the presence of ATRA decreased upon treatment with a specific inhibitor of p38 MAPK (SB203580) (p<0.01). This study indicates that the osteogenic differentiation ability of BMP9 in 143B cells can be restored by ATRA, and the combination of BMP9 and ATRA generated a stronger anti-proliferative effect on 143B cells than ATRA alone. This result may be due to the activation of the p38 MAPK pathway. PMID- 28350135 TI - A systematic review of arterial stiffness, wave reflection and air pollution. AB - Arterial stiffening is associated with increased cardiovascular risk. Whether exposure to relatively high levels of air pollution is associated with arterial stiffening is unclear. We aimed to assess the association between exposure to major air pollutants and arterial stiffening. PubMed, SCOPUS and Web of Science databases (through 31 January 2017) were searched using a combination of terms related to exposure to gaseous [nitrogen dioxide (NO2), nitrogen oxides (NOx) and sulphur dioxide (SO2)] or particulate matter pollutants (PM2.5, PM10 and PM10 2.5), arterial stiffness (pulse wave velocity) and reflected waves (augmentation index, augmentation pressure). Pertinent information were extracted from selected studies. In this systematic review were included 8 studies with available data on air pollution and arterial stiffness/reflected waves parameters (8 studies explored the effects of exposure to particulate matter pollutants, 3 studies the effects of exposure to gaseous pollutants); seven of them reported increased arterial stiffness/reflected waves after exposure to air pollution (6 of 8 studies after particulate matter pollutants; 2 of 3 studies after gaseous pollutants). Arterial stiffness and reflected waves were increased in the majority of the studies after both short- and long-term exposure to air pollutants. In conclusion, available evidence supports an association of main air pollutants with increased arterial stiffness and reflected waves. This finding may have implications for population-based strategies for the reduction of arterial stiffness, a vascular biomarker and an intermediate endpoint for cardiovascular disease. PMID- 28350137 TI - Current status and future perspectives on treatment of liver metastasis in colorectal cancer (Review). AB - Liver metastasis is the most common site of colorectal cancer (CRC) metastasis. Approximately half of all colorectal cancer patients will develop liver metastases. Although radical surgery is the standard treatment modality, only 10 20% of patients are deemed eligible for resection. Despite advances in survival with chemotherapy, surgical resection is still considered the only curative option for patients with liver metastases. Much effort has been expended to address patients with metastatic liver disease. The majority of evidence stated a significant survival benefit with surgical resection to reach an overall 5-year survival rate of 35-55% after hepatic resection. However, still majority of patients will experience disease recurrence even after a successful resection. In this review, we describe current status and controversies related to treatment options for CRC liver metastases and its potential for enhancing oncologic outcomes and improving quality of life. PMID- 28350138 TI - miR-15b inhibits cancer-initiating cell phenotypes and chemoresistance of cisplatin by targeting TRIM14 in oral tongue squamous cell cancer. AB - Oral tongue squamous cell carcinoma (TSCC) is one of the most lethal cancers within the oral cavity and its prognosis remains dismal due to the paucity of effective therapeutic targets. The formation of cancer-initiating cells (CICs) and epithelial-mesenchymal transition (EMT) are pivotal events involved in the dismal prognosis. They have been shown to be related to the resistance to cisplatin treatment. In the present study, we showed that TRIM14 induced formation of cancer-initiating cells and EMT in TSCC SCC25 cells. Its overexpression promoted cisplatin resistance in the SCC25 cells. We found that overexpression of miR-15b suppressed TRIM14 and inhibited CIC phenotypes in the SCC25 cells. Moreover, overexpression of miR-15b promoted mesenchymal-epithelial transition (MET) in the SCC25 cells and sensitized cisplatin-resistant SCC25 (SCC25-res) cells to cisplatin. Thus, we conclude that miR-15b inhibited cancer stem cell phenotypes and its restoration reversed the chemoresistance of cisplatin by targeting TRIM14 in TSCC. Elucidating the molecular mechanism of EMT and cancer stem cells in TSCC may further aid in the understanding of the pathogenesis and progression of the disease, and offer novel targets for the discovery of new drugs. PMID- 28350139 TI - Upregulation of miR-137 reverses sorafenib resistance and cancer-initiating cell phenotypes by degrading ANT2 in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. More than 80% of patients with HCC are not good candidates for curative surgical resection due to advanced liver cirrhosis caused by underlying chronic hepatitis virus (B or C) infection. Sorafenib, an oral multikinase inhibitor, is the only approved agent for the treatment of advanced HCC. Although, sorafenib currently sets the new standard for advanced HCC treatment, tumor response rates are usually quite low. An understanding of the underlying mechanisms for sorafenib resistance is critical. In the present study, we found that adenine nucleotide translocator 2 (ANT2) was upregulated in sorafenib-resistant HCC Huh7 cells (Huh7 R) and its overexpression promoted sorafenib resistance. ANT2 induced the formation of cancer-initiating cell (CIC) phenotypes and promoted metastasis associated traits in the Huh7 cells. Silencing of miR-137 upregulated ANT2 protein expression in the Huh7 cells. miR-137 was downregulated in the Huh7-R cells, compared with that in the Huh7 cells and its restoration reversed sorafenib resistance in the Huh7-R cells. Restoration of miR-137 inhibited formation of CIC traits and attenuated the abilities of migration and invasion in the Huh7-R cells. Moreover, we demonstrated that high-intensity focused ultrasound (HIFU) in unresectable HCC upregulated serum miR-137. Combining HIFU and sorafenib may be a wise option for advanced and unresectable HCC. PMID- 28350140 TI - [Radicalisation, terrorism and psychiatry: an alternative truth?] PMID- 28350141 TI - [Suicidal behaviour and attempted suicide occurring during assessment by the outreach psychiatric emergency service]. AB - BACKGROUND: The outreach emergency psychiatric service plays an important role in recognising, arranging interventions and preventing suicide and suicidal behaviour. However, little is known about the assessments that members of the emergency team make when faced with patients showing suicidal behaviour.
AIM: To describe the relationships that are revealed between patient characteristics, suicidal thoughts and attempted suicide during assessments made by the emergency psychiatric service in The Hague.
METHOD: The emergency service kept a detailed record of 14,705 consultations. We compared the characteristics of patients who had suicidal thoughts with those of patients who had no such thoughts and we also compared the characteristics of patients who had attempted to commit suicide with those of patients who had not. We drew these comparisons by using logistic regression models, adjusting for clustering.
RESULTS: 32.2% of the patients showed signs of suicidal behaviour and 9.2 % appeared likely to attempt suicide. Suicidal behaviour occurred most often in patients with depression. Suicidal patients were more often admitted to hospital than were non-suicidal patients and they were more likely to have been referred by a general practitioner or a general hospital. Medication was the most frequent means employed in attempts to commit suicide.
CONCLUSION: In about one third of the consultations of the outreach emergency psychiatric service, the patient showed suicidal behaviour. The actions and the policy of the emergency psychiatric service with regard to suicidal behaviour were diverse and dependent on factors that could change over the course of time. PMID- 28350142 TI - [Comorbidity on axis I and treatment outcome]. AB - BACKGROUND: Clinical practice shows that patients with complicated psychopathology are more difficult to treat than those with simple psychopathology. Comorbidity may be the complicating factor involved here. The prognostic value that comorbidity on axis I has on treatment outcome may be relevant for establishing the treatment plan for a patient and may also be relevant for the evaluation of aggregated treatment outcomes achieved by clinicians, treatment teams or institutes.
AIM: To investigate whether comorbidity on axis I can explain disappointing results and whether we should correct for comorbidity when comparing the aggregated treatment results achieved by clinicians, treatment teams or institutes.
METHOD: Our observational study involved a large group of patients (n = 25,651). Outcome data for a subgroup of patients (n = 7754) were available. Comorbidity in this subgroup was established by means of a structured diagnostic interview (MINI-Plus) performed by trained research nurses.
RESULTS: Comorbidity appeared to have some association with the treatment outcome, but the severity of symptoms seemed to be a much more powerful predictor of treatment outcome.
CONCLUSION: After correcting for baseline severity, we found that comorbidity had very little prognostic value as far as the treatment outcome was concerned. PMID- 28350143 TI - [Assessment of guideline adherence and quality of care with routine outcome monitoring data]. AB - BACKGROUND: Treatment guidelines are widely used nowadays but it is not really clear whether or to what extent patients in routine care benefit from these guidelines.
AIM: To achieve a twofold objective: to measure in a routine clinical setting, the overall level of adherence to clinical guidelines by using a set of process indicators that are independent of the disorder under study, and to measure the clinical and psychosocial correlates of adherence among outpatients suffering from mood, anxiety and somatoform disorders.
METHOD: We developed a set of quality indicators and tested the set over a period of three years in a randomly selected sample of 300 outpatients who were about to receive treatment for a mood, anxiety and somatoform disorder. We used routine outcome monitoring (ROM) data to determine risk factors for non-adherence and to identify patients whose treatment outcomes were likely poor.
RESULTS: A high percentage of indicators were positive, indicating that many elements of treatment in this routine clinical practice had been carried out according to the guidelines. We observed that the combined treatment group showed significantly lower adherence than the two other treatment groups. Low-adherence was predicted independently by a low score on the vitality subscale of the SF-36. No significant differences relating to the degree of adherence were found in socio demographic variables, comorbidity and the scores on the BSI subscales. Predictor indicators for poor treatment outcome included higher age, a comorbid axis I diagnosis, a number of dysfunctional personality traits and a (reported) poor general health status.
CONCLUSION: It is possible to assess guideline adherence by means of our set of process indicators that were independent of all type of disorder involved. Most factors hampering adherence could be identified. An understanding of the factors that affect treatment adherence to treatment guidelines may help to prevent non-adherence and can contribute to both the quality and the cost-effectiveness of care. PMID- 28350145 TI - [Clotiapine in the treatment of acutely agitated patients: hardly any evidence]. AB - BACKGROUND: In Flemish emergency psychiatry, clotiapine is still one of the options available for the treatment of agitation. However, there is a lack of evidence concerning the efficacy of this practice.
AIM: To find out whether there is sufficient evidence to justify the continued use of clotiapine in the treatment of agitation.
METHOD: On searching the literature systematically, we identified controlled trials of clotiapine.
RESULTS: The efficacy and safety of clotiapine were studied in two randomised controlled trials. Clotiapine (administered intramuscularly) was compared with zuclopenthixol acetate and lorazepam. Clotiapine was found to be just as efficient as the control treatments, causing fewer anticholinergic side-effects than zuclopenthixol but more extrapyramidal side-effects than lorazepam. The study population comprised only 102 patients, 51 of whom were treated with clotiapine. Because the quality of the reported data was low, straightforward conclusions were difficult to draw.
CONCLUSION: Scientific evidence to support the use of clotiapine in the treatment of agitation ranges from meagre to practically non-existent. Since alternative treatment options are available, the contained use of clotiapine should be questioned. PMID- 28350144 TI - [Clinical staging and early intervention for borderline personality disorder]. AB - BACKGROUND: Within the accumulating evidence for a life span perspective on borderline personality disorder (BPD), the key factor is a developmental perspective.
AIM: To demonstrate that the lessons learnt from early intervention in somatic medicine and psychosis should be used to improve the diagnosis and treatment of BPD.
METHOD: We describe the rationale for early detection and intervention and present a staging model which can serve as a guideline for the development and selection of interventions for BPD.
RESULTS: There is increasing evidence that BPD first manifests itself in adolescence and that BPD symptoms can already be distinguished from normative adolescent development. BPD tends to develop gradually and to have a progressive, social and professional impact. Inadequate treatment can lead to iatrogenic damage, whereas adequate treatment shows promising results in adolescents with emerging BPD. These findings may underpin an early intervention paradigm for BPD.
CONCLUSION: Early intervention and clinical staging can improve the assessment and treatment of severe forms of psychopathology, such as BPD. This has implications for research, mental health care policy and society. PMID- 28350147 TI - [Reaction on 'Hypernatremia caused by treatment with GHB obtained via a doctor's prescription']. PMID- 28350146 TI - [A girl with self-harm treated with N-acetylcysteine (NAC)]. AB - Deliberate and recurrent self-harm could be regarded as addictive behaviour that can be treated with medication. In addiction, the dopaminergic mesolimbic reward system is activated. Pain caused by cutting stimulates the reward system through the opioid system. Glutamatergic neurotransmission follows the same pathway and plays a role in addiction as well. In this case-study a 17-year-old girl was successfully treated with N-acetylcysteine (nac) in order to reduce the frequency of self-cutting. In addition, in this case nac reduced the symptoms of attention deficit/hyperactivity disorder and depression. nac modulates the glutamatergic neurotransmission. This article provides possible explanations for the effect of nac in this case. PMID- 28350148 TI - [Assisted suicide/euthanasia: a thorn in the eye of the APA?] PMID- 28350150 TI - [Burn-out, commitment, personality and experiences during work and training; survey among psychiatry residents]. AB - BACKGROUND: In the last few years international studies have reported on increase in burn-out and depressive symptoms among psychiatry residents. In the field of research, however, commitment and dedication are now being mentioned more frequently as positive factors that counterbalance burn-out. AIM: To find out how a group of Dutch psychiatry residents feel about their work, to discover their degree of burn-out and commitment and to clarify the various factors involved. METHOD: 59 psychiatry residents from four teaching hospitals were asked to complete questionnaires concerning burn-out (U-BOS-C), commitment (UWES-15) and personality (BFI-NL). Respondents were also asked to describe how they felt about their experiences during their work and to give their views on the instruction and training they were receiving. RESULTS: In the U-BOS-C section only four trainees (almost 7%) met the criteria for burn-out. In the BFI-NL section the psychiatry residents obtained significantly lower scores on neuroticism and higher scores on empathy than did a comparable norm group of a similar age. The scores of the psychiatry residents indicated that the term 'being proud of your work' was significantly related to a feeling of commitment and particularly to all subscales that reflected commitment. CONCLUSION: In our study the percentage of psychiatry residents with burn-out is significantly lower than the percentage reported elsewhere in the literature. In fact, our results demonstrate that the psychiatry residents who were the subject of our study regarded themselves as being emotionally stable, friendly and committed to their work. PMID- 28350149 TI - [The bidirectional relationship between physical activity and sleep in depressed versus non-depressed individuals]. AB - BACKGROUND: Sleep and physical activity are related, but the direction of this relationship is unclear and it is not known whether the direction differs in depressed and non-depressed persons. AIM: To study the bidirectional relationship between physical activity and sleep in daily life by making repeated measurements in depressed and non-depressed people. METHOD: Every day for 30 consecutive days each depressed (N = 27) and non-depressed (N = 27) participant in our study had to complete an electronic questionnaire relating to subjective sleep quality and sleep duration and were required to wear an accelerometer that recorded physical activity. RESULTS: Multi-level analysis showed that an increase in subjective sleep duration resulted in a decrease in physical activity. The differences between individuals with regard to the direction and strength of this relationship were significant. Changes in physical activity did not predict changes in sleep quality or sleep duration. We did not find any differences in the relationships for depressed and non-depressed participants. CONCLUSION: Change in sleep duration predicts change in physical activity, although there was significant heterogeneity in the results for individuals. Our findings underline the importance of further research and of the development of interventions that are tailored to the precise needs of the individual patient. PMID- 28350151 TI - [The relationship between posttraumatic stress disorder and metabolic syndrome: an overview]. AB - BACKGROUND: In this article we discuss the relationship between posttraumatic stress disorder (PTSD) and metabolic syndrome (MbS). AIM: To assess the prevalence of MbS in patients with PTSD, establish which factors are involved and to consider what the implications are for clinical practice. METHOD: We performed a systematic search of the literature, using Medline, Embase Psychiatry and PsycINFO covering the period January 1990 up to and including October 2014. RESULTS: We found 12 studies including one meta-analysis which showed large variations in the prevalence of MbS in patients with PTSD; these variations ranged between 7.7% to 73.0%. The PTSD and its severity as well as the comorbid depression and the use of antipsychotics all played a role in the wide discrepancies of the results. Furthermore, the reported results seem to indicate that many methodologies were used in these studies. The reasons for the large differences found in the prevalence of MbS in PTSD patients are complex: the variations are probably due mainly to the different methodologies that were used. The prevalence of MbS which stood out in a positive sense varied between 31.9% and 47.8%. CONCLUSION: To obtain greater clarity, more quantitative and descriptive studies are needed, in which the screening is performed on a PTSD subgroup with severe PTSD, a severe comorbid depression and/or antipsychotic use. The studies should use method control for diagnoses of PTSD, depression, severity of both and of MbS. PMID- 28350152 TI - [An ethical reflection on outreaching mental health care]. AB - BACKGROUND: Care providers have a conflicting societal role: on the one hand they must respect the autonomy of individuals with psychiatric problems, but on the other hand they often feel the need to offer these individuals outreaching care. AIM: To compile an ethical reflection on some of the ways in which outreaching mental health care interventions can be provided in a responsible manner. METHOD: This ethical reflection is based on an ethical advice by the Ethics committee for Mental Health Care of the Brothers of Charity in Flanders. The method combines ethical discussion and a study of the relevant literature. RESULTS: A good starting point is a relational view of the human being that emphasises connectedness and involvement. Consequently, the care provider begins to intervene in the care programme by building a trusting relationship with the person with psychiatric problems. This is how these persons, their close family and friends and care providers exercise their responsibility. There is a gradation of responsibility that extends in a continuous line: personal responsibility develops into shared responsibility which can then become vicarious responsibility. On that basis there is also a gradation in the nature of outreaching care; the care providers first make themselves available and give information, then provide advice, negotiate, persuade, increase pressure, and finally take over and force the person with psychiatric problems. CONCLUSION: The care providers choose in dialogue and in a considered and consistent way for the appropriate form of outreaching care, in line with the degree of responsibility that the person with psychiatric problems can assume. PMID- 28350153 TI - [Smoking policy in mental health care]. AB - BACKGROUND: People with mental illnesses tend to smoke more often and more heavily than other members of the public and their addiction to tobacco also has harmful effects on their physical health. So far, however, limited priority was given to smoking cessation in mental health care settings. AIM: To provide insight into the formal and informal smoking policies of Dutch mental health care organisations and into the nature and extent of the smoking cessation support they offer, and, additionally, to look at the opportunities for improvement in clinical settings. METHOD: Document research on formal policies of 61 mental health care facilities, interviews with workers directly involved (n = 10), and a survey on policy implementation among staff members of treatment facilities (n = 600). RESULTS: One-third of the facilities did not have a formalised smoking policy document, and there was a marked difference between the smoking policies at the rest of the facilities. Treatment provision was limited, strongly dependent on the individual staff member, and was often not the most effective form of care (like medication). CONCLUSION: Many mental health patients really do want to give up smoking and often respond well to treatment. Psychiatrists play a key role in integrating and implementing an anti-smoking policy which will benefit their patients. PMID- 28350154 TI - [Wernicke encephalopathy and dry beriberi; late complications after bariatric surgery performed on a patient with a psychiatric history]. AB - A 38-year-old woman was admitted in a psychiatric hospital because of memory disorders. Dry beriberi and Korsakoff's syndrome, as a late neuropsychiatric manifestation of Wernicke's encephalopathy, were established. The beriberi symptoms decreased slowly, but the patient's memory impairments persisted. These clinical features were caused by a thiamine deficiency. Gastric bypass surgery is associated with an increased risk of thiamine deficiency. Excessive alcohol consumption and poor compliance with vitamin deficiency treatment both contributed to the rapid onset of these disorders. The case we describe demonstrates how important it is that patients who have undergone bariatric surgery are prescribed the correct vitamin supplements and that the treatment is continued for an appropriate period of time; this treatment is particularly important in the case of patients who are also suffering from an comorbid alcohol related disorder. PMID- 28350156 TI - One-Pot Sintering Strategy for Efficient Fabrication of High-Performance and Multifunctional Graphene Foams. AB - Macroscopic three-dimensional (3D) graphene foams (GFs) were fabricated efficiently by immediately sintering low-temperature exfoliated graphene powder under inert atmosphere at the temperature over 500 degrees C. The one-pot sintering process not only integrated two-dimensional (2D) graphene sheets into 3D GF, but also accelerated the structural integrity of graphene by inducing its deoxygenation and repairing the defects. More importantly, the whole process could be finished within hours, usually less than 12 h, and the resultant GFs with interconnected graphene framework as well as meso- and macroporous structure exhibited exceptional attenuating performance for high-frequency electromagnetic interference and adsorption capacities for organic pollutants. In comparison with conventional hydro/solvothermal, sol-gel chemistry, sol-freezing, and templating methods, our sintering strategy possesses more advantages in maneuverability, efficiency, and repeatability, benefiting for the mass production of high performance and multifunctional GFs. PMID- 28350157 TI - Luminescent Lanthanide-Based Organic/Inorganic Hybrid Materials for Discrimination of Glutathione in Solution and within Hydrogels. AB - Glutathione (GSH) as a biothiol is an essential peptide related to various diseases. Although multiple strategies for biothiols detection have been developed, there is increasing demand for sensors that can differentiate GSH from cysteine (Cys) and homocysteine (Hcy), owing to the similar structures and thiol groups in these amino acids. Herein, we report a novel Eu3+/LAPONITE (Lap)-based organic/inorganic hybrid material for selective detection of GSH via an "off-on" process. The fluorescence of Eu(DPA)3@Lap-Tris can be quenched by Cu2+ through photoinduced electron transfer (PET). The addition of GSH into the Eu(DPA)3@Lap Tris/Cu2+ system induces the removal of Cu2+ from Eu(DPA)3@Lap-Tris and blocks PET, resulting in the recovery of fluorescence. This proposed assay demonstrates higher selectivity toward GSH than Cys and Hcy, and showed a detection limit of 162 nM within a linear range of 0.5-30 MUM. Unlike other GSH selective sensors, this platform could be formed into a hydrogel while its sensitivity was maintained. The sensitive response to GSH in serum samples makes this platform an efficient tool for biological applications because of its ease of preparation, high selectivity, good biocompatibility, and low toxicity. PMID- 28350158 TI - Oral Nanomedicine Based on Multicomponent Microemulsions for Drug-Resistant Breast Cancer Treatment. AB - The aim of this study is to demonstrate the enhanced therapeutic efficacy of anticancer drugs on drug-resistant breast cancer using multicomponent microemulsions (ECG-MEs) as an oral delivery system. The etoposide-loaded ECG-MEs were composed of coix seed oil and ginsenoside Rh2 (G-Rh2), both of which possess not only the synergistic antitumor effect with etoposide, but also have excipient like properties. Orally administrated ECG-MEs were demonstrated to be able to accumulate at the tumor site following crossing the intestines as intact vehicles into the blood circulation. The spatiotemporal controlled release characteristics of ECG-MEs brought about the efficient P-gp inhibition by the initially released G-Rh2 and the increased intracellular accumulation of the sequentially released etoposide. The combination antitumor activity of etoposide, G-Rh2 and coix seed oil using ECG-MEs was verified on the xenograft drug-resistant breast tumor mouse models. In addition, the safety evaluation studies indicated that treatment with ECG-MEs did not cause any significant toxicity in vivo. These findings suggest that ECG-MEs as an oral formulation may offer a promising strategy to treat the drug-resistant breast cancer. PMID- 28350159 TI - In Situ Control of Oxygen Vacancies in TaOx Thin Films via Plasma-Enhanced Atomic Layer Deposition for Resistive Switching Memory Applications. AB - The plasma-enhanced atomic layer deposition (PEALD) process using Ta(OC2H5)5 as a Ta precursor and plasma-activated hydrogen as a reactant for the deposition of TaOx films with a controllable concentration of oxygen vacancies (VO) is reported herein. The VO concentration control was achieved by varying the hydrogen volume fraction of the hydrogen-argon mixture in the plasma, allowing the control of the leakage current density in the tantalum oxide films within the range of 5 orders of magnitude compared with the Ta2O5 film grown via thermal ALD using the identical Ta precursor and H2O. Temperature-dependent current-voltage measurements combined with Poole-Frenkel emission modeling demonstrated that the bulk trap depth decreases with the increasing hydrogen volume fraction, which could be attributed to the increase of the VO concentration. The possible chemical change in the PEALD TaOx films grown under different hydrogen volume fractions was confirmed by the in situ X-ray photoelectron spectroscopy (XPS) measurements of the Ta 4f core and valence band spectra. The comparison of the XPS-measured nonstoichiometry and the secondary ion mass spectrometry analysis of the hydrogen content allowed this study to conclude that the nonstoichiometry is largely related to the formation of Ta-VO sites rather than of Ta-H sites. Such oxygen-deficient TaOx layers were studied for application as an oxygen-deficient layer in a resistance switching random access memory stack (Ta2O5/TaOx) where the actual switching occurred within the stoichiometric Ta2O5 layer. The bilayer memory stack showed reliable resistance switching up to ~106 switching cycles, whereas the single-layer Ta2O5 memory showed only several hundred switching cycles. PMID- 28350160 TI - Resource Competition Shapes the Response of Genetic Circuits. AB - A common approach to design genetic circuits is to compose gene expression cassettes together. While appealing, this modular approach is challenged by the fact that expression of each gene depends on the availability of transcriptional/translational resources, which is in turn determined by the presence of other genes in the circuit. This raises the question of how competition for resources by different genes affects a circuit's behavior. Here, we create a library of genetic activation cascades in E. coli bacteria, where we explicitly tune the resource demand by each gene. We develop a general Hill function-based model that incorporates resource competition effects through resource demand coefficients. These coefficients lead to nonregulatory interactions among genes that reshape the circuit's behavior. For the activation cascade, such interactions result in surprising biphasic or monotonically decreasing responses. Finally, we use resource demand coefficients to guide the choice of ribosome binding site and DNA copy number to restore the cascade's intended monotonically increasing response. Our results demonstrate how unintended circuit's behavior arises from resource competition and provide a model-guided methodology to minimize the resulting effects. PMID- 28350161 TI - Multiparametric Atomic Force Microscopy Imaging of Biomolecular and Cellular Systems. AB - There is a need in biochemical research for new tools that can image and manipulate biomolecular and cellular systems at the nanoscale. During the past decades, there has been tremendous progress in developing atomic force microscopy (AFM) techniques to analyze biosystems, down to the single-molecule level. Force distance (FD) curve-based AFM in particular has enabled researchers to map and quantify biophysical properties and biomolecular interactions on a wide variety of specimens. Despite its great potential, this AFM method has long been limited by its low spatial and temporal resolutions. Recently, novel FD-based multiparametric imaging modalities have been developed, allowing us to simultaneously image the structure, elasticity and interactions of biological samples at high spatiotemporal resolution. By oscillating the AFM tip, spatially resolved FD curves are obtained at much higher frequency than before, and as a result, samples are mapped at a speed similar to that of conventional topographic imaging. In this Account, we discuss the general principle of multiparametric AFM imaging and we provide a snapshot of recent studies showing how this new technology has been applied to biological specimens, from soluble proteins to membranes and cells. We emphasize novel methodologies that we recently developed, in which multiparametric imaging is combined with probes functionalized with chemical groups, ligands, or even live cells, in order to image and quantify receptor interaction forces and free-energy landscapes in a way not possible before. Key breakthroughs include observing the mechanical and chemical properties of single proteins in purple membranes, measuring the electrostatic potential of transmembrane pore forming proteins, structurally localizing chemical groups of water-soluble proteins, mapping and nanomechanical analysis of single sensors on yeast cells, imaging the sites of assembly and extrusion of single filamentous bacteriophages in living bacteria, unravelling the adhesive properties of biofilm-forming microbial pathogens, mapping the ligand-binding free energy landscape of human membrane receptors in proteoliposomes, and finally, the nanomechanical mapping of the first binding events of viruses to animal cells. In the coming years, it is anticipated that multiparametric AFM imaging will be increasingly used by chemists from broad horizons, enabling them to shed light into the sophisticated functions of biomolecular and cellular systems. PMID- 28350162 TI - In Vivo Recognition of Human Vascular Endothelial Growth Factor by Molecularly Imprinted Polymers. AB - One of the mechanisms responsible for cancer-induced increased blood supply in malignant neoplasms is the overexpression of vascular endothelial growth factor (VEGF). Several antibodies for VEGF targeting have been produced for both imaging and therapy. Molecularly imprinted polymer nanoparticles, nanoMIPs, however, offer significant advantages over antibodies, in particular in relation to improved stability, speed of design, cost and control over functionalization. In the present study, the successful production of nanoMIPs against human VEGF is reported for the first time. NanoMIPs were coupled with quantum dots (QDs) for cancer imaging. The composite nanoparticles exhibited specific homing toward human melanoma cell xenografts, overexpressing hVEGF, in zebrafish embryos. No evidence of this accumulation was observed in control organisms. These results indicate that nanoMIPs are promising materials which can be considered for advancing molecular oncological research, in particular when antibodies are less desirable due to their immunogenicity or long production time. PMID- 28350163 TI - Temperature-Dependent Partitioning of Coumarin 152 in Phosphatidylcholine Lipid Bilayers. AB - Partitioning of coumarin 152 (C152) in phosphatidylcholine vesicles was quantified using time-resolved fluorescence emission. Phospholipid vesicles were comprised of 1,2-dilauroyl-sn-glycero-3-phosphocholine (12:0 DLPC), 1,2 dimyristoyl-sn-glycero-3-phosphocholine (14:0 DMPC), and 1,2-dipalmitoyl-sn glycero-3-phosphocholine (16:0 DPPC). C152 fluorescence emission decays were fit to three lifetimes, corresponding to C152 solvated by the aqueous buffer, embedded in polar lipid headgroups, and surrounded by the nonpolar lipid membrane core. Partitioning was measured as a function of sample temperature and vesicle composition. C152 in all three lipid systems showed qualitatively similar partitioning behavior. Partitioning into a gel phase membrane was thermoneutral and slightly entropically favored. Partitioning of C152 near the lipid membrane headgroups was entropically driven and endothermic. Well above the melting temperature, exsolvation of C152 from the membrane back into the aqueous buffer was enthalpically driven but entropically unfavorable. Regardless of solution temperature, relatively little (<15%) C152 partitions into the hydrophobic core of the membrane. The magnitudes of the forces driving C152 partitioning systematically increased with alkyl chain length (DLPC < DMPC < DPPC). Differences in partitioning between the three vesicle systems are attributed to differences in surface area per lipid as membrane phase changes from the gel to liquid-crystalline state. PMID- 28350164 TI - Ring-Puckering Potential Energy Functions for Trimethylene Sulfide and Its Monovalent Cation. AB - The spectra and ring-puckering potential energy function for trimethylene sulfide cation (TMS+) from vacuum ultraviolet mass-analyzed threshold ionization spectra have recently been reported. To provide an in-depth comparison of the potential function with that of trimethylene sulfide (TMS) itself, we have used ab initio MP2/cc-pVTZ calculations and DFT B3LYP/cc-pVTZ calculations to predict the structures of both TMS and TMS+ and then used these to calculate coordinate dependent ring-puckering kinetic energy functions for both species. These kinetic energy functions allowed us to calculate refined potential energy functions of the puckering for both molecules based on the previously published spectra. TMS has an experimental barrier of 271 cm-1 and energy minima at ring-puckering angles of +/-29 degrees . For TMS+ the barrier is 60 cm-1 and the energy minima correspond to ring-puckering angles of +/-21 degrees . The lower barrier for the cation reflects the smaller amount of angle strain in the ring angles for TMS+. PMID- 28350165 TI - Determining Key Local Vibrations in the Relaxation of Molecular Spin Qubits and Single-Molecule Magnets. AB - To design molecular spin qubits and nanomagnets operating at high temperatures, there is an urgent need to understand the relationship between vibrations and spin relaxation processes. Herein we develop a simple first-principles methodology to determine the modulation that vibrations exert on spin energy levels. This methodology is applied to [Cu(mnt)2]2- (mnt2- = 1,2-dicyanoethylene 1,2-dithiolate), a highly coherent complex. By theoretically identifying the most relevant vibrational modes, we are able to offer general strategies to chemically design more resilient magnetic molecules, where the energy of the spin states is not coupled to vibrations. PMID- 28350166 TI - IPPP-CLOPPA Analysis of the Influence of the Methylation on the Potential Energy and the Molecular Polarizability of the Hydrogen Bonds in the Cytosine-Guanine Base Pair. AB - The IPPP-CLOPPA method is applied to investigate the influence of a methyl group on the energy of the hydrogen bonds and the potential energy curve of the bridge protons in model compounds, which mimic the methylated and unmethylated cytosine guanine base pairs. On the same grounds, this influence on the polarizability of the intermolecular hydrogen bonds of these compounds is also addressed, in order to determine whether this linear response property provides a significant proof of the electronic mechanisms that affect the stabilization of the hydrogen bonds. Results obtained show that the methyl electronic system delocalizes on the hydrogen bond region, and changes of these intermolecular hydrogen bonds are due to this effect of delocalization. PMID- 28350167 TI - Accurate Classical Polarization Solution with No Self-Consistent Field Iterations. AB - We present a new solution for classical polarization that does not require any self-consistent field iterations, the aspect of classical polarization that makes it computationally expensive. The new method builds upon our iEL/SCF Lagrangian scheme that defines a set of auxiliary induced dipoles whose original purpose was to serve as a time-reversible initial guess to the SCF solution of the set of real induced dipoles. In the new iEL/0-SCF approach the auxiliary dipoles now drive the time evolution of the real induced dipoles such that they stay close to the Born-Oppenheimer surface in order to achieve a truly SCF-less method. We show that the iEL/0-SCF exhibits no loss of simulation accuracy when analyzed across bulk water, low to high concentration salt solutions, and small solutes to large proteins in water. In addition, iEL/0-SCF offers significant computational savings over more expensive SCF calculations based on traditional 1 fs time step integration using symplectic integrators and is as fast as reversible reference system propagator algorithms with an outer 2 fs time step. PMID- 28350168 TI - (+)-Thalianatriene and (-)-Retigeranin B Catalyzed by Sesterterpene Synthases from Arabidopsis thaliana. AB - Two GFPPS linked (+)-thalianatriene (1) and (-)-retigeranin B (2) sesterterpene synthase genes were identified from the genome of Arabidopsis thaliana. 1 possesses an unprecedented 11-6-5 tricyclic ring system, while 2 contains a characteristic 5-5-5-6-5 pentacyclic ring system. Their structures were determined by extensive NMR spectroscopy, chemical derivatization, and X-ray crystallography. The variable-temp NMR measurement of 3, a diepoxy-bearing derivative of 1, enables us to completely assign the NMR signals of the two conformers as 3a (67%, UUU) and 3b (33%, UUD). A plausible biosynthesis mechanism of 1 was proposed. PMID- 28350170 TI - Relating Silica Scaling in Reverse Osmosis to Membrane Surface Properties. AB - We investigated the relationship between membrane surface properties and silica scaling in reverse osmosis (RO). The effects of membrane hydrophilicity, free energy for heterogeneous nucleation, and surface charge on silica scaling were examined by comparing thin-film composite polyamide membranes grafted with a variety of polymers. Results show that the rate of silica scaling was independent of both membrane hydrophilicity and free energy for heterogeneous nucleation. In contrast, membrane surface charge demonstrated a strong correlation with the extent of silica scaling (R2 > 0.95, p < 0.001). Positively charged membranes significantly facilitated silica scaling, whereas a more negative membrane surface charge led to reduced scaling. This observation suggests that deposition of negatively charged silica species on the membrane surface plays a critical role in silica scale formation. Our findings provide fundamental insights into the mechanisms governing silica scaling in reverse osmosis and highlight the potential of membrane surface modification as a strategy to reduce silica scaling. PMID- 28350169 TI - Simple, Direct Routes to Polymer Brush Traps and Nanostructures for Studies of Diffusional Transport in Supported Lipid Bilayers. AB - Patterned poly(oligo ethylene glycol) methyl ether methacrylate (POEGMEMA) brush structures may be formed by using a combination of atom-transfer radical polymerization (ATRP) and UV photopatterning. UV photolysis is used to selectively dechlorinate films of 4-(chloromethyl)phenyltrichlorosilane (CMPTS) adsorbed on silica surfaces, by exposure either through a mask or using a two beam interferometer. Exposure through a mask yields patterns of carboxylic acid terminated adsorbates. POEGMEMA may be grown from intact Cl initiators that were masked during exposure. Corrals, traps, and other structures formed in this way enable the patterning of proteins, vesicles, and, following vesicle rupture, supported lipid bilayers (SLBs). Bilayers adsorbed on the carboxylic acid terminated surfaces formed by C-Cl bond photolysis in CMPTS exhibit high mobility. SLBs do not form on POEGMEMA. Using traps consisting of carboxylic acid functionalized regions enclosed by POEGMEMA structures, electrophoresis may be observed in lipid bilayers containing a small amount of a fluorescent dye. Segregation of dye at one end of the traps was measured by fluorescence microscopy. The increase in the fluorescence intensity was found to be proportional to the trap length, while the time taken to reach the maximum value was inversely proportional to the trap length, indicating uniform, rapid diffusion in all of the traps. Nanostructured materials were formed using interferometric lithography. Channels were defined by exposure of CMPTS films to maxima in the interferogram, and POEGMEMA walls were formed by ATRP. As for the micrometer-scale patterns, bilayers did not form on the POEGMEMA structures, and high lipid mobilities were measured in the polymer-free regions of the channels. PMID- 28350172 TI - Benchmark Study of the Structural and Thermochemical Properties of a Dihydroazulene/Vinylheptafulvene Photoswitch. AB - We investigate the performance of four different density functional theory (DFT) functionals (M06-2X, omegaB97X-D, PBE0, and B3LYP-D3BJ) for calculating the structural and thermochemical properties of the dihydroazulene/vinylheptafulvene photoswitch (DHA/VHF). We find that all the tested DFT functionals yield equilibrium geometries in good agreement with higher level CCSD/cc-pVDZ calculations and that the basis set had little influence on the geometries of the photoswitch. We found a negligible difference in the thermal contribution to the Gibbs free energy between the tested functionals, indicating that the largest source of error when calculating storage free energies originates from errors in the calculated single point energies. It was found that omegaB97X-D and M06-2X performed decently for predicting storage energies. While B3LYP-D3BJ and PBE0 generally underestimated the storage energy compared to CCSD(T)-F12a/VDZ-F12 results. Therefore, we tested if domain based local pair natural orbital coupled cluster (DLPNO-CCSD(T)) provided an improvement over density functional theory methods for the single point energies. We observed that the DLPNO-CCSD(T) storage energies were in better agreement with CCSD(T)-F12a/VDZ-F12 results than the DFT results. The DLPNO-CCSD(T) results already converged at cc-pVTZ quality basis set, making it possible to perform accurate estimates of the thermochemical properties in a time frame that makes the DLPNO-CCSD(T) method feasible for routine calculations on the photoswitch. Using DLPNO-CCSD(T)/cc-pVTZ, we calculate accurate storage energies for currently synthesized derivatives of the DHA/VHF photoswitch. PMID- 28350171 TI - Stereochemistry of Endogenous Palmitic Acid Ester of 9-Hydroxystearic Acid and Relevance of Absolute Configuration to Regulation. AB - Lipids have fundamental roles in the structure, energetics, and signaling of cells and organisms. The recent discovery of fatty acid esters of hydroxy fatty acids (FAHFAs), lipids with potent antidiabetic and anti-inflammatory activities, indicates that our understanding of the composition of lipidome and the function of lipids is incomplete. The ability to synthesize and test FAHFAs was critical in elucidating the roles of these lipids, but these studies were performed with racemic mixtures, and the role of stereochemistry remains unexplored. Here, we synthesized the R- and S- palmitic acid ester of 9-hydroxystearic acid (R-9 PAHSA, S-9-PAHSA). Access to highly enantioenriched PAHSAs enabled the development of a liquid chromatography-mass spectrometry (LC-MS) method to separate and quantify R- and S-9-PAHSA, and this approach identified R-9-PAHSA as the predominant stereoisomer that accumulates in adipose tissues from transgenic mice where FAHFAs were first discovered. Furthermore, biochemical analysis of 9 PAHSA biosynthesis and degradation indicate that the enzymes and pathways for PAHSA production are stereospecific, with cell lines favoring the production of R 9-PAHSA and carboxyl ester lipase (CEL), a PAHSA degradative enzyme, selectively hydrolyzing S-9-PAHSA. These studies highlight the role of stereochemistry in the production and degradation of PAHSAs and define the endogenous stereochemistry of 9-PAHSA in adipose tissue. This information will be useful in the identification and characterization of the pathway responsible for PAHSA biosynthesis, and access to enantiopure PAHSAs will elucidate the role of stereochemistry in PAHSA activity and metabolism in vivo. PMID- 28350173 TI - Bovine Serum Albumin Adsorption at a Silica Surface Explored by Simulation and Experiment. AB - Molecular details of BSA adsorption on a silica surface are revealed by fully atomistic molecular dynamics (MD) simulations (with a 0.5 MUs trajectory), supported by dynamic light scattering (DLS), zeta potential, multiparametric surface plasmon resonance (MP-SPR), and contact angle experiments. The experimental and theoretical methods complement one another and lead to a wider understanding of the mechanism of BSA adsorption across a range of pH 3-9. The MD results show how the negatively charged BSA at pH7 adsorbs to the negatively charged silica surface, and reveal a unique orientation with preserved secondary and tertiary structure. The experiments then show that the protein forms complete monolayers at ~ pH6, just above the protein's isoelectric point (pH5.1). The surface contact angle is maximum when it is completely coated with protein, and the hydrophobicity of the surface is understood in terms of the simulated protein conformation. The adsorption behavior at higher pH > 6 is also consistently interpreted using the MD picture; both the contact angle and the adsorbed protein mass density decrease with increasing pH, in line with the increasing magnitude of negative charge on both the protein and the surface. At lower pH < 5 the protein starts to unfold, and the adsorbed mass dramatically decreases. The comprehensive picture that emerges for the formation of oriented protein films with preserved native conformation will help guide efforts to create functional films for new technologies. PMID- 28350174 TI - Complexation of Polyelectrolytes with Hydrophobic Drug Molecules in Salt-Free Solution: Theory and Simulations. AB - The delivery and dissolution of poorly soluble drugs is challenging in the pharmaceutical industry. One way to significantly improve the delivery efficiency is to incorporate these hydrophobic small molecules into a colloidal polyelectrolyes(PE)-drug complex in their ionized states. Despite its huge application value, the general mechanism of PE collapse and complex formation in this system has not been well understood. In this work, by combining a mean-field theory with extensive molecular simulations, we unveil the phase behaviors of the system under dilute and salt-free conditions. We find that the complexation is a first-order-like phase transition triggered by the hydrophobic attraction between the drug molecules. Importantly, the valence ratio between the drug molecule and PE monomer plays a crucial role in determining the stability and morphology of the complex. Moreover, the sign of the zeta potential and the net charge of the complex are found to be inverted as the hydrophobicity of the drug molecules increases. Both theory and simulation indicate that the complexation point and complex morphology and the electrostatic properties of the complex have a weak dependence on chain length. Finally, the dynamics aspect of PE-drug complexation is also explored, and it is found that the complex can be trapped into a nonequilibrium glasslike state when the hydropobicity of the drug molecule is too strong. Our work gives a clear physical picture behind the PE-drug complexation phenomenon and provides guidelines to fabricate the colloidal PE-drug complex with the desired physical characteristics. PMID- 28350175 TI - "The safety of sodium reduction in the food supply: A cross-discipline balancing act"-Workshop proceedings. AB - This workshop, jointly presented by the ILSI North America Technical Committees on Food Microbiology and Sodium, aimed to provide greater knowledge and appreciation of the opportunities and challenges facing the food industry in answering the public health community's call to reduce sodium levels in the food supply. One major challenge is finding effective substitutes for the various antimicrobial and functional roles that sodium plays across different food categories. Sodium plays a critical role in retarding the growth of pathogens and food spoilage bacteria. Moreover, taste is an important factor for consumers when they choose food products, and the flavor changes that occur when salt is reduced or replaced must be considered and ingredients and processes adjusted accordingly. The workshop provided a platform for a multidisciplinary discussion among the microbiology, food science, nutrition, and public health communities to share progress and propose solutions, including the formation of public-private partnerships, to develop coordinated and comprehensive strategies. This paper provides an overview of the issues raised, rather than a specific summary of workshop discussions. The Food and Drug Administration's Draft Guidance for Industry on voluntary sodium reduction and the 2015 US Dietary Guidelines for Americans were released subsequent to the workshop and are also discussed. PMID- 28350176 TI - Facial emotion recognition in patients with focal and diffuse axonal injury. AB - OBJECTIVE: Facial emotion recognition impairment has been well documented in patients with traumatic brain injury. Studies exploring the neural substrates involved in such deficits have implicated specific grey matter structures (e.g. orbitofrontal regions), as well as diffuse white matter damage. Our study aims to clarify whether different types of injuries (i.e. focal vs. diffuse) will lead to different types of impairments on facial emotion recognition tasks, as no study has directly compared these patients. METHODS: The present study examined performance and response patterns on a facial emotion recognition task in 14 participants with diffuse axonal injury (DAI), 14 with focal injury (FI) and 22 healthy controls. RESULTS: We found that, overall, participants with FI and DAI performed more poorly than controls on the facial emotion recognition task. Further, we observed comparable emotion recognition performance in participants with FI and DAI, despite differences in the nature and distribution of their lesions. However, the rating response pattern between the patient groups was different. CONCLUSION: This is the first study to show that pure DAI, without gross focal lesions, can independently lead to facial emotion recognition deficits and that rating patterns differ depending on the type and location of trauma. PMID- 28350177 TI - 'We have different routes for different reasons': Exploring the purpose of walks for carers of people with dementia. AB - This paper explores the purpose of walks for co-residing carers of people with dementia, using a social citizenship lens. The findings are based on the first phase of a study examining the everyday experiences of place, space, and neighbourhood of dementia carers. Using three forms of data collection - social network mapping, walking interviews, and participant-driven photography - the study brings forth information about why carers go on walks either alone or with the person with dementia. Carers explained that walks facilitate their connections with themselves, the person with dementia, their social environment, and their natural and built environment. In sum, walks provide a way of practicing and sustaining social citizenship. Carers' discourse about walks highlights their personal, everyday practices and strategies, as well as the larger tensions and contradictions of dementia care. The findings reinforce the need to bring into dialogue, from a carer perspective, a social citizenship model of dementia with the growing interest in dementia-friendly communities. PMID- 28350178 TI - Young adults' concerns and coping strategies related to their interactions with their grandparents and great-grandparents with dementia. AB - Young adults' concerns and coping strategies related to their face-to-face interactions with their grandparents/great-grandparents with dementia were explored through the lens of a solidarity-conflict conceptual framework. Participants indicated concerns about their inability to maintain the relational connection, not knowing what to say or how to behave, their lack of perspective taking skills and emotion-regulation strategies, interacting with an ever changing other, as well as concerns about other co-participants in the interaction. Participants' coping strategies were driven by two interaction motives: maintaining solidarity (e.g., desire to maintain and improve the interaction with the grandparent by seeking the other's company, loving the other, and maintaining the other's personhood) and dealing with conflict (e.g., dealing with self-focused concerns about lack of skills and knowledge by engaging in substitute avenues for communication and down-regulating negative affect). Implications for improving interactions between young adults and their grandparents/great-grandparents with dementia are discussed. PMID- 28350179 TI - Safe and inclusive research practices for qualitative research involving people with dementia: A review of key issues and strategies. AB - Aim Developing strategies to ensure the safe participation of people with dementia in research is critical to support their wider inclusion in research and to advance knowledge in the areas of dementia policy and practice. Objectives This literature review synthesizes and critically appraises different approaches to promote the safe participation of people with dementia in qualitative research. Methods Two databases were searched for articles that discuss the methodological or ethical aspects of qualitative research involving people with dementia. We did not focus on informed consent or ethical review processes as these have been reviewed elsewhere. Findings Key issues that impact participant safety include: language, gatekeepers, the research relationship, communication, dealing with distress, knowledge dissemination, and researcher skills. Conclusion By synthesizing different approaches to safety and highlighting areas of debate, we hope to advance discussion and to contribute to the development of inclusive research methods. PMID- 28350181 TI - Effects of hemoglobin level on the early postsurgical cerebral metabolism in patients with severe traumatic brain injury. AB - OBJECTIVE: The study aims to explore the effects of different levels of haemoglobin (Hb) on early cerebral metabolism in patients with postoperative severe traumatic brain injury (TBI) . METHOD: Fifty-nine patients were randomly divided into catheter oxygen group and ventilator-assisted respiratory group. Each group was subsequently divided into three subgroups basing on different Hb level: Hb <= 70 g/L subgroup, 71 g/L <= Hb<=90 g/L subgroup and Hb >= 91 g/L subgroup. The blood samples from the femoral artery and the affected side internal jugular vein were, respectively, taken at the same time from the patient after postoperative 3 days. RESULTS: The incidence of anaemia after severe TBI operation was 88.14%. The VADL and cerebral glucose uptake (CMRglu) in both Hb <= 70 g/L and 71 g/L <= Hb<=90 g/L patients of oxygen catheter group were less than that in Hb >= 91 g/L patients. In the ventilator-assisted breathing group, the VADL and CMRglu of 71 g/L <= Hb<=90 g/L patients and Hb >= 91 g/L patients were lower than those in Hb <= 70 g/L patients. The result from comparing the two 71 g/L <= Hb <= 90 g/L subgroups showed that the brain metabolic indexs in the ventilator-assisted breathing group were better than those in the catheter oxygen group. CONCLUSIONS: In severe TBI postoperative patients, Hb<=90 g/L induced decrease in aerobic oxidation in brain tissue. Moreover, for the same Hb level of 71 g/L <= Hb<=90 g/L, ventilator-assisted breathing significantly improved cerebral metabolism. PMID- 28350180 TI - Systematic literature review of efficacy, safety and tolerability outcomes of chemotherapy regimens in patients with metastatic Merkel cell carcinoma. AB - AIM: Merkel cell carcinoma (MCC) is a rare neuroendocrine, cutaneous malignancy with poor prognosis once metastasized. The aim of this study was to conduct a systematic literature review to assess clinical outcomes associated with chemotherapy regimens in metastatic MCC. MATERIALS & METHODS: Embase(r), MEDLINE(r), MEDLINE(r)-In-Process and CENTRAL were searched for studies published in January 2016. RESULTS & CONCLUSION: Overall, the literature on chemotherapy in patients with metastatic MCC is sparse, with most studies being case series/reports. Across all studies, response rates ranged from 20 to 61%, with higher response rates in first-line setting (53-61%) versus second-line setting (23-45%). Among responders, duration of response was short (<=8 months) in both first- and second-line settings. There is a need for novel agents that can induce durable responses in metastatic MCC. PMID- 28350182 TI - Towards Communicative Justice in Health. AB - This article approaches care from a different angle by looking ethnographically at how it is shaped by structural differences in the power to control the circulation of knowledge. I focus on an investigation conducted by people classified as "indigenous", of an epidemic that killed 38 children and young adults in a Venezuelan rainforest. I trace how health/communicative inequities structured clinical interactions, documents, epidemiological investigations, news stories, and dialogues with healers, thwarting the identification of the epidemic, clinically identified as rabies. Although the Bolivarian socialist government provided access to care, professionals denigrated parents' contributions to care and communication and reduced complex, unequal relations between languages to practical problems of translation. Pointing to parallels with US social movements, I suggest that responding to demands for communicative justice in health requires seeing how health inequities are entangled with health/communicative inequities. The typographical slash points to importance of challenging the subdisciplinary boundary-work that relegates their study to non overlapping conversations in medical and linguistic anthropology. PMID- 28350183 TI - Prevalence and Antimicrobial Susceptibility of Enterobacteriaceae Isolated from Retail Pepper in Vietnam. AB - To investigate the microbial quality of retail pepper in Vietnam, the enumeration and detection of Enterobacteriaceae and the screening of cefotaxime (CTX) resistant coliforms were performed by using 84 commercial samples. Although Enterobacteriaceae were isolated from 78 samples, the number of Enterobacteriaceae was lower than 1.0 log CFU/g in 46 samples. For the detection of Enterobacteriaceae with the International Organization for Standardization methods, Salmonella spp., Escherichia coli , Klebsiella pneumoniae , Cronobacter sakazakii , and Enterobacter cloacae complex were isolated from 5, 12, 36, 19, and 30 samples, respectively. During screening of CTX-resistant coliforms, K. pneumoniae , C. sakazakii , and E. cloacae complex were isolated from 8, 1, and 21 samples, respectively. Seven K. pneumoniae and seven E. cloacae complex isolates obtained in the screening of CTX-resistant coliforms were resistant to at least one of the three third-generation cephalosporins (CTX, ceftazidime, and cefpodoxime). Moreover, one E. cloacae complex cluster IV and all K. pneumoniae isolates were positive for extended-spectrum beta-lactamase genes or plasmid mediated AmpC beta-lactamase genes or both. Additionally, two extended-spectrum beta-lactamase-producing K. pneumoniae isolates and one AmpC beta-lactamase producing E. cloacae complex cluster IV isolate were positive for the plasmid mediated quinolone resistance determinants and also had amino acid alterations in the quinolone resistance-determining regions of GyrA and ParC. Furthermore, 10 E. cloacae complex isolates were positive for the plasmid-mediated fosfomycin resistance gene fosA. As pepper is often consumed without a heating process, the possible spread to humans of foodborne, opportunistic, and nosocomial infection pathogens or resistance genes from foods prepared or seasoned with pepper cannot be excluded. Therefore, it is necessary to handle pepper by using hygienic conditions during the cultivation, harvesting and processing steps. PMID- 28350184 TI - Risk Assessment or Assessment of Risk? Developing an Evidence-Based Approach for Primary Producers of Leafy Vegetables To Assess and Manage Microbial Risks. AB - Over the last 10 years, some high-profile foodborne illness outbreaks have been linked to the consumption of leafy greens. Growers are required to complete microbiological risk assessments (RAs) for the production of leafy crops supplied either to retail or for further processing. These RAs are based primarily on qualitative judgements of hazard and risks at various stages in the production process but lack many of the steps defined for quantitative microbiological RAs by the Codex Alimentarius Commission. This article is based on the discussions of an industry expert group and proposes a grower RA approach based on a structured qualitative assessment, which requires all decisions to be based on evidence and a framework for describing the decision process that can be challenged and defended within the supply chain. In addition, this article highlights the need for evidence to be more easily available and accessible to primary producers and identifies the need to develop hygiene criteria to aid validation of proposed interventions. PMID- 28350185 TI - Brain contusion as the main risk factor of memory or emotional complaints in chronic complicated mild traumatic brain injury. AB - OBJECTIVE: To investigate the risk factors for memory or emotional complaints in patients with complicated mild traumatic brain injury (mTBI). METHODS: Retrospective analysis of medical records was conducted by physicians in a teaching hospital in Southern Taiwan, and complicated mTBI had been identified by means of computed tomography. Psychological complaints, including problems with memory and emotions, were collected by structured telephone interviews, 10-15 minutes long, and were held with subjects who agreed to participate in our study. Among 327 patients who were injured for more than two years, 190 agreed to join this study (mean age: 41.6 years; male: 60.5%; stably employed: 50.0%). We used demographic data and neurological factors to predict memory or emotional complaints without muscle power or response speed (MEMR) complaints. RESULTS: Only the presence or absence of cerebral contusions predicted memory or emotional complaints without MEMR complaints in different employed status, and the odds ratio was 4.82-13.50 times higher for those with cerebral contusions than for those without. CONCLUSIONS: Cerebral contusions were the primary risk factor for MEMR complaints in chronic complicated mTBI. Early preventive psychological intervention might be necessary for patients with complicated mTBI and cerebral contusions. PMID- 28350186 TI - IT-based wellness tools for older adults: Design concepts and feedback. AB - OBJECTIVE: To explore older adults' preferences regarding e-health applications through use of generated concepts that inform wellness tool design. METHODS: The 6-8-5 method and affinity mapping were used to create e-health design ideas that were translated into storyboards and scenarios. Focus groups were conducted to obtain feedback on the prototypes and included participant sketching. A qualitative analysis of the focus groups for emerging themes was conducted, and sketches were analyzed. RESULTS: Forty-three older adults participated in six focus group sessions. The majority of participants found the wellness tools useful. Preferences included features that supported participants in areas of unmet needs, such as ability to find reliable health information, cognitive training, or maintaining social ties. Participants favored features such as use of voice navigation, but were concerned over cost and the need for technology skills and access. Sketches reinforced these wants, including portability, convenience, and simplicity. CONCLUSIONS: Several factors were found to increase the desirability of such devices including convenient access to their health and health information, a simple, accessible interface, and support for memory issues. Researchers and designers should incorporate the feedback of older adults regarding wellness tools, so that future designs meet the needs of older adults. PMID- 28350187 TI - Epigenetic Status of H19-Igf2 Imprinted Genes and Loss of 5-Hydroxymethylcytosine in the Brain of Cloned Goats. AB - In mammals, the imprinted genes play vital roles in development and are generally controlled by DNA methylation at imprinting control regions (ICRs). Recently, it was discovered that 5-hydroxymethylcytosine (5-hmC) is a stable epigenetic modification; however, its functions in cloned animal genomes have not yet been fully elucidated. In this study, we interrogated and quantified the 5-hmC levels in the brain of cloned goats and discovered upregulation of Uhrf1 (p < 0.001), Dnmt1 (p < 0.05), Dnmt3a (p < 0.05), Igf2 (p < 0.01), and H19 (p < 0.05) and downregulation of Dnmt3b (p < 0.001), Tet1 (p < 0.001), Tet2 (p < 0.05), Tet3 (p < 0.001), Mecp2 (p < 0.05), and Igf2r (p < 0.05) in deceased cloned goat tissues compared with the normal controls. We demonstrated that DNA methylation was increased at H19 ICR (51.33% +/- 2.03% vs. 93.07% +/- 3.06%; p < 0.01) and that DNA was hypomethylated at Igf2 ICR (4.57% +/- 1.48% vs. 7.63% +/- 1.83%; p > 0.05) in the brain of deceased cloned goats. Finally, we showed that within the cloned goat brain genome, the amount of genome-wide 5-hmC was significantly decreased (0.083% +/- 0.026% vs. 0.024% +/- 0.007%; p < 0.05), whereas the 5-hmC levels within H19 and Igf2 CCGG sites were not significantly altered (0.17% +/- 0.09% vs. 0.03% +/- 0.01%; p > 0.05) in the brain of deceased cloned goats. Our data bring further experimental evidence regarding the abnormalities in 5-hmC and advance our current understanding of the role of 5-hmC in cloned animals. PMID- 28350188 TI - Formations of Femininity: Science and Aesthetics in Facial Feminization Surgery. AB - Facial feminization surgery (FFS) is a set of bone and soft tissue reconstructive surgical procedures intended to feminize the faces of trans- women in order to make their identities as women recognizable to others. In this article, I explore how the identification of facial femininity was negotiated in two FFS surgeons' practices. One committed to the metrics of normal skeletal form and the other to aspirational aesthetics of individual optimization; I argue that surgeons' competing clinical approaches illustrate a constitutive tension in the proliferating therapeutic logics of trans- medicine. The growing popularity of surgical practices like FFS demonstrates a shift in American trans- therapeutics away from a singular focus on the genitalia as the location of bodily sex and toward understandings of sex as a product of social recognition. PMID- 28350189 TI - The laboratory and the asylum: Francis Walker Mott and the pathological laboratory at London County Council Lunatic Asylum, Claybury, Essex (1895-1916). AB - London County Council's pathological laboratory in the LCC asylum at Claybury, Essex, was established in 1895 to study the pathology of mental illness. Historians of psychiatry have understood the Claybury laboratory as a predecessor of the Maudsley Hospital in London: not only was this laboratory closed when the Maudsley was opened in 1916, but its director, Frederick Walker Mott, a champion of the 'German' model in psychiatry, was instrumental in the establishment of this institution. Yet, as I argue in this essay, for all the continuities with the Maudsley, the Claybury laboratory should not be seen solely as its predecessor - or as a British answer to continental laboratories such as Theodor Meynert's in Vienna. Rather, as I show using the examples of general paralysis of the insane and 'asylum colitis', the Claybury laboratory is best understood as an attempt to prevent mental illness using a microbiological model. PMID- 28350190 TI - Additive effects of sequential excitatory and inhibitory theta burst stimulation in improving cortical excitability following ischaemic stroke. AB - PURPOSE: To study the effects of sequential excitatory and inhibitory theta burst stimulation (TBS) on cortical excitability in patients with subacute ischaemic stroke. METHODS: Fifteen patients with first-ever middle cerebral artery ischaemic stroke within last three months were subjected to intermittent TBS over the hand area (M1) of the stroke hemisphere (iTBSSH) followed by continuous TBS over the intact hemisphere M1 (cTBSIH). The study measured motor evoked potential (MEP) amplitude, resting motor threshold (RMT) and contralateral cortical silent period (cCSP) at baseline and after 7 minutes of each TBS session. RESULTS: The mean age of the patients was 62.4 +/- 8.0 years. The absolute changes in baseline motor physiological parameters were significantly greater after cTBSIH than after iTBSSH (p = 0.001). Following iTBSSH, there was a significant decrease in mean RMT (7.4%; p < 0.001). Following cTBSIH, there was further 18.3% increase in mean MEP amplitude and decrease in mean RMT (4.7%; p < 0.001) and cCSP (5.6%; p < 0.001) of the stroke hemisphere. Similar changes of smaller magnitude were noted in 12 age-matched controls. CONCLUSIONS: The results indicate that combining iTBSSH and cTBSIH can have additive effect in increasing cortical excitability in subacute ischaemic patients with stroke. PMID- 28350191 TI - Persons with brain injury and employment supports: Long-term employment outcomes and use of community-based services. AB - OBJECTIVES: To understand how employment services (ES) are provided to persons with brain injuries (PWBIs) in Ontario, Canada, and the impact service delivery has on competitive-employment outcomes. DESIGN AND METHODS: A mixed-method case study of one community-based agency that provides specialized services to PWBIs. Relationships between demographic, service-related variables and employment outcomes (2009-2014) were analysed using chi-squares and analyses of variance. In addition, 14 interviews were conducted and analysed using thematic analysis. RESULTS: PWBIs accessed services on average of 16 years post injury; 64% secured at least one competitive-employment job, which was how employment success was defined in this study. Average job tenure was 368 days, and average job intensity was 3.8 hours/day. Employment success was significantly associated (p < 0.05) with use of job development, job coaching, case management and job retention services. Interviews revealed that PWBIs were provided five services: job goal(s) identification, assessment of work-related abilities/skills, job development, on the-job supports and job retention assistance. Challenges to ES delivery included lack of suitable jobs and hiring incentives, and difficulties in establishing natural supports at the workplace. CONCLUSIONS: PWBIs' employment outcomes may be supported through provision of ES to assist with: the development of realistic job goals and job-finding skills, securing work, on-the-job coaching and advocacy with employers. PMID- 28350192 TI - A real world evaluation of a treatment for infant colic based on the experience and perceptions of 4004 parents. AB - Infant colic (IC) is a common condition in young babies seen by primary care health professionals, especially health visitors. Nevertheless, the diagnostic criteria for IC are vague, which has resulted in a lack of clarity in published guidance on its causes and treatment. Credence has been given to alternative therapies, while health professionals are sceptical about the efficacy of over the-counter treatments. Some 4004 parents of babies considered to have IC participated in this retrospective real world evidence study on the efficacy of a simeticone suspension in the treatment of IC. They were recruited via social media sources and were eligible for inclusion if their baby had received at least one dose of the simeticone suspension. Data were collected via an online questionnaire. The results showed that crying and discomfort-associated behaviour reduced and the babies' sleeping patterns improved following use of the suspension. More than two-thirds (69.7%) of respondents, who either used the suspension on its own or alongside another treatment, reported improvements in the signs of IC within one day. Almost all (93.2%) considered that its use was associated with either complete resolution of IC or had some effect on symptoms. PMID- 28350194 TI - Modafinil Treatment of Cocaine Dependence: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Currently, there is none FDA-approved medication to treat cocaine dependency. Studies conducted with various medications, including antipsychotics, antidepressants, anticonvulsants, and others, revealed inconsistent results. OBJECTIVES: To meta-analytically investigate the efficacy and safety of modafinil in the treatment of cocaine-dependent patients. METHODS: Randomized controlled trials with >=20 subjects comparing the numerical therapeutic outcomes of modafinil with placebo were identified in databases, such as PUBMED, psycINFO, EMBASE, and Clinicaltrials.gov. Relevant data on efficacy and safety were extracted. Relative risk (RR) and standardized mean difference were applied for reporting dichotomous and continuous outcomes respectively. Random effects, subgroup, and meta-regression analyses were conducted to further explore the results and evaluate for any moderators. RESULTS: In total, 11 studies (participants = 896, duration = 6.7 +/- 1.9 weeks) comparing modafinil with placebo were systematically analyzed, which indicated that modafinil was not superior to placebo in improving the treatment retention rate (studies = 11, participants = 891, RR = 1.030, 95% CI = 0.918-1.156, p = .613). Similarly, data from 7/11 studies did not evidence superiority of modafinil in achieving cocaine abstinence (participants = 696, RR = 1.259, 95% CI = 0.813-1.949, p = .302). However, subgroup analysis of six studies conducted in the United States demonstrated superiority of modafinil in cocaine abstinence rate (studies = 6, participants = 669, 95% CI = 1.027-2.020, p = 0.035). In addition, no evidence suggested modafinil-related discontinuation or specific adverse events than placebo. CONCLUSIONS: Overall, there is no evidence to conclude superiority of modafinil in increasing cocaine abstinence and treatment retention rate. However, promising result in subgroup analysis of cocaine abstinence, secondary outcomes, and good safety profile urged the need of larger studies to derive more conclusive results. PMID- 28350193 TI - Reconstitution of HuR-Inhibited CUGBP1 Expression Protects Cardiomyocytes from Acute Myocardial Infarction-Induced Injury. AB - AIM: Myocardial infarction (MI) is one of the leading causes of death in elderly people. Expanding the knowledge of the molecular mechanisms underlying MI is of profound importance to developing a cure for MI. The CUGBP- and ETR-3-like factor (CELF) proteins, a family of RNA-binding proteins, play key roles in RNA metabolism. To determine the functions and molecular mechanisms of CELF proteins in MI, an animal model of acute myocardial infarction (AMI) was used in our study. RESULTS: We found that the CUG triplet repeat RNA-binding protein 1 (CUGBP1)/CELF1 expression levels were decreased in AMI-injured hearts, and further studies showed that two highly conserved adenylate-uridylate-rich (AU rich) elements in the 3'UTR of CUGBP1 were responsible for the decreased CUGBP1 expression. Upon AMI, human antigen R (HuR) was relocated to the cytoplasm from the nucleus and interacted with these AU-rich elements to affect the expression of CUGBP1. Reintroduction of CUGBP1 via gene delivery by recombinant adenovirus improved cardiac function in AMI mice. Our studies also indicated that CUGBP1 protected cardiomyocytes from ischemia-induced injury through the promotion of angiogenesis and inhibition of apoptosis by regulating the vascular endothelial growth factor-A gene. Innovation and Conclusion: Our studies indicate a role for CUGBP1 in cardiac disease and reveal a novel MI post-transcriptional gene regulatory mechanism. The reconstitution of CUGBP1 could be developed as a potential therapeutic option for the management of MI. Antioxid. Redox Signal. 27, 1013-1026. PMID- 28350196 TI - Geriatric-HIV medicine: A science in its infancy. PMID- 28350197 TI - Correspondence. PMID- 28350195 TI - Standard-sampling microdialysis and spreading depolarizations in patients with malignant hemispheric stroke. AB - Spreading depolarizations (SD) occur in high frequency in patients with malignant hemispheric stroke (MHS). Experimentally, SDs cause marked increases in glutamate and lactate, whereas glucose decreases. Here, we studied extracellular brain glutamate, glucose, lactate, pyruvate and the lactate/pyruvate ratio in relationship to SDs after MHS. We inserted two microdialysis probes in peri infarct tissue at 5 and 15 mm to the infarct in close proximity to a subdural electrode strip. During 2356.6 monitoring hours, electrocorticography (ECoG) revealed 697 SDs in 16 of 18 patients. Ninety-nine SDs in electrically active tissue (spreading depressions, SDd) were single (SDds) and 485 clustered (SDdc), whereas 10 SDs with at least one electrode in electrically inactive tissue (isoelectric SDs, SDi) were single (SDis) and 103 clustered (SDic). More SDs and a significant number of clustered SDs occurred during the first 36 h post-surgery when glutamate was significantly elevated (> 100 uM). In a grouped analysis, we observed minor glutamate elevations with more than two SDs per hour. Glucose slightly decreased during SDic at 5 mm from the infarct. Directions of SD-related metabolic changes correspond to the experimental setting but the long sampling time of standard microdialysis precludes a more adequate account of the dynamics revealed by ECoG. PMID- 28350200 TI - Does the Level of Transection of the Biliary Remnant Affect Outcome After Laparoscopic Kasai Portoenterostomy for Biliary Atresia? AB - BACKGROUND: We assessed postoperative outcome in relation to the level of transection of the biliary remnant at the time of laparoscopic Kasai portoenterostomy (LKP) in biliary atresia (BA) patients. METHODS: The subjects for this study were 12 consecutive nonsyndromic type III BA patients who had LKP at our institute between 2009 and 2014. All LKPs were video recorded. Four board certified pediatric surgeons assessed the level of transection of the biliary remnant and suturing during the anastomosis in each video blindly. A standard protocol was used for postoperative management. RESULTS: The level of transection was assessed as being shallow and suturing techniques as being identical in all. Although all cases achieved jaundice disappearance, 4 required liver transplantation (NNL group) for relapse of jaundice and 8 remain anicteric with native livers after mean follow-up of 4.6 years (NL group). Demographic data (birth weight, weight and age at LKP, duration from onset of symptoms to LKP, size of microbile ducts, and preoperative biochemical markers) were similar for both groups. CONCLUSIONS: The level of transection of the biliary remnant and suturing techniques would appear to not directly influence the outcome of LKP. PMID- 28350198 TI - Subarachnoid hemorrhage - Induced block of cerebrospinal fluid flow: Role of brain coagulation factor III (tissue factor). AB - Subarachnoid hemorrhage (SAH) in 95% of cases results in long-term disabilities due to brain damage, pathogenesis of which remains uncertain. Hindrance of cerebrospinal fluid (CSF) circulation along glymphatic pathways is a possible mechanism interrupting drainage of damaging substances from subarachnoid space and parenchyma. We explored changes in CSF circulation at different time following SAH and possible role of brain tissue factor (TF). Fluorescent solute and fluorescent microspheres injected into cisterna magna were used to track CSF flow in mice. SAH induced by perforation of circle of Willis interrupted CSF flow for up to 30 days. Block of CSF flow did not correlate with the size of hemorrhage. Following SAH, fibrin deposits were observed on the brain surface including areas without visible blood. Block of astroglia-associated TF by intracerebroventricular administration of specific antibodies increased size of hemorrhage, decreased fibrin deposition and facilitated spread of fluorophores in sham/naive animals. We conclude that brain TF plays an important role in localization of hemorrhage and also regulates CSF flow under normal conditions. Targeting of the TF system will allow developing of new therapeutic approaches to the treatment of SAH and pathologies related to CSF flow such as hydrocephalus. PMID- 28350199 TI - A novel autophagy modulator 6-Bio ameliorates SNCA/alpha-synuclein toxicity. AB - Parkinson disease (PD) is a life-threatening neurodegenerative movement disorder with unmet therapeutic intervention. We have identified a small molecule autophagy modulator, 6-Bio that shows clearance of toxic SNCA/alpha-synuclein (a protein implicated in synucleopathies) aggregates in yeast and mammalian cell lines. 6-Bio induces autophagy and dramatically enhances autolysosome formation resulting in SNCA degradation. Importantly, neuroprotective function of 6-Bio as envisaged by immunohistology and behavior analyses in a preclinical model of PD where it induces autophagy in dopaminergic (DAergic) neurons of mice midbrain to clear toxic protein aggregates suggesting that it could be a potential therapeutic candidate for protein conformational disorders. PMID- 28350201 TI - A role for sex and a common HFE gene variant in brain iron uptake. AB - HFE (high iron) is an essential protein for regulating iron transport into cells. Mutations of the HFE gene result in loss of this regulation causing accumulation of iron within the cell. The mutated protein has been found increasingly in numerous neurodegenerative disorders in which increased levels of iron in the brain are reported. Additionally, evidence that these mutations are associated with elevated brain iron challenges the paradigm that the brain is protected by the blood-brain barrier. While much has been studied regarding the role of HFE in cellular iron uptake, it has remained unclear what role the protein plays in the transport of iron into the brain. We investigated regulation of iron transport into the brain using a mouse model with a mutation in the HFE gene. We demonstrated that the rate of radiolabeled iron (59Fe) uptake was similar between the two genotypes despite higher brain iron concentrations in the mutant. However, there were significant differences in iron uptake between males and females regardless of genotype. These data indicate that brain iron status is consistently maintained and tightly regulated at the level of the blood-brain barrier. PMID- 28350202 TI - Outcomes of Laparoscopic Cholecystectomy for Biliary Dyskinesia in Children. AB - PURPOSE: To determine the outcomes of laparoscopic cholecystectomy as a treatment for biliary dyskinesia in children. METHODS: With ethics approval, a retrospective chart review was performed on children (<21 years) at a single center diagnosed with biliary dyskinesia (defined as gallbladder ejection fraction [EF] <35% and/or pain with cholecystokinin [CCK] on cholescintigraphy, in the absence of gallstones or cholecystitis on ultrasound) and treated with laparoscopic cholecystectomy between March 2010 and February 2016. Demographic, medical history, diagnostic imaging, pathology, and outcome data were collected and analyzed based on degree of symptom resolution. RESULTS: Laparoscopic cholecystectomy was performed in 215 children with biliary dyskinesia (156/215 [72.6%] female, age 13.8 +/- 3.4 years, body mass index [BMI] 22.3 +/- 6.3 kg/m2). 181/206 (87.9%) had EF <35%. CCK reproduced symptoms in 149/177 (84.2%). 34/215 (15.8%) were lost to follow-up. Median follow-up time was 2.7 weeks. Pain improved in 162/181 (89.5%). Chronic cholecystitis was found in 183/213 (85.9%) and unexpected cholelithiasis in 4/213 (1.9%) on pathology. Postoperatively, 6/181 (3.3%) had wound infections and 8/181 (4.4%) required common bile duct stents for the following indications: 6 sphincter of Oddi dysfunction, 1 choledocholithiasis, and 1 stricture. Virgin abdomen (odds ratio [OR] 4.03, confidence interval [95% CI] 1.12-14.53, P = .0460) and follow-up <6 months (OR 7.35, 95% CI 2.68-20.21, P = .0002) were associated with better outcomes. CONCLUSIONS: Laparoscopic cholecystectomy is safe and effective in symptom resolution for biliary dyskinesia in children. Virgin abdomen and follow-up <6 months were associated with better outcomes. Prospective long-term studies comparing surgical and nonoperative management of biliary dyskinesia are required to determine the utility of cholecystectomy. PMID- 28350203 TI - Revision after shoulder replacement for acute fracture of the proximal humerus. AB - Background and purpose - For more than half a century, stemmed hemiarthroplasty (SHA) has been used in the treatment of comminuted and displaced fractures of the proximal humerus. Reverse shoulder arthroplasty (RSA) has been increasingly popular in cases where it is difficult to obtain satisfactory fixation of the tuberosities. We report revision rates and reasons for revision after shoulder arthroplasty for acute fractures of the proximal humerus. Patients and methods - This study was based on a common dataset from the Nordic Arthroplasty Register Association (NARA), which includes data reported to the national shoulder arthroplasty registries in Denmark, Sweden, and Norway. We included 6,756 shoulder arthroplasties performed for acute fractures between 2004 and 2013. Results - There were 6,112 SHAs (90%) and 565 RSAs (8.4%). The cumulative arthroplasty survival rate after 5 years was 0.96 for both SHA and RSA. The relative risk of revision of RSA was 1.4 (95% CI: 0.9-2.2) with SHA as reference. For both types of arthroplasty, the most common reason for revision was infection (SHA 0.8%, RSA 2.1%). The relative risk of revision due to infection was 3.1 (95% CI: 1.6-5.9) for RSA with SHA as reference. The relative risk of revision for patients who were less than 75 years of age was 2.8 (95% CI: 2.0-3.8) compared to older patients. Interpretation - Revision after shoulder arthroplasty for acute fractures was rare. Survival rates were similar between SHA and RSA, but RSA had a statistically significant and clinically relevant higher risk of revision because of infection. PMID- 28350204 TI - Carbon dioxide-modified polyethylenimine as a novel gene delivery vector and its in vitro validation. AB - In this work, the CO2-modified polyethylenimine, as a novel delivery vector, has been validated by combining with the plasmid DNA to form plasmid DNA/CO2-modified polyethylenimine complexes. We have modified polyethylenimine using CO2 to partially convert amine groups to carbamic acid groups. The buffering capacity and the plasmid DNA binding ability of the CO2-modified polyethylenimine and PEI 25 (polyethylenimine with Mw = 25 kDa) were characterized by acid-base titration and agarose gel electrophoresis, respectively. The particle size and zeta potential of the complexes were determined using a Zetasizer Nano ZS. Resistance to nuclease digestion was determined via DNase I protection assay. The cytotoxicity was measured by the MTT assay. The transfection efficiency of the complexes has been evaluated by flow cytometry. It is observed that the condensation capacity of CO2-modified polyethylenimine is still comparable to polyethylenimine and the CO2-modified polyethylenimine can protect plasmid DNA from degradation by DNase I. The diameter of the plasmid DNA/CO2-modified polyethylenimine complex is around 140 nm and the zeta potential decreases. MTT assays confirm that the cytotoxicity is much lower for plasmid DNA/CO2-modified polyethylenimine than for plasmid DNA/PEI-25. The flow cytometry found that in serum-free medium the transfection efficiency can reach a value of ~60% for plasmid DNA/CO2-modified polyethylenimine, and in 10% fetal bovine serum medium, the transfection efficiency is still as high as ~40%, which is much higher than that of plasmid DNA/PEI-25. CO2-modified polyethylenimine could be a novel and promising nonviral gene vector for gene therapy. PMID- 28350205 TI - A targeted drug delivery system based on folic acid-functionalized upconversion luminescent nanoparticles. AB - In this paper, multifunctional upconversion luminescent NaYF4:Yb,Er nanoparticles with excellent hollow mesoporous structure were first fabricated. The effects of various reaction conditions on the morphology and size of the as-prepared samples were investigated in detail and Ostwald ripening effect was adapted to explain the formation mechanism of the HMUCNPs. Then, folic acid, a well-known ligand for the selective targeting of drugs into tumor cells, was conjugated to the surface of the hollow mesoporous structured upconversion luminescent nanoparticles (HMUCNPs) via amide reaction for targeted delivery of anticancer drugs so as to enhance the therapeutic efficacy. The properties were extensively studied, which indicated the obtained samples showed a typical hollow mesoporous structure and excellent upconversion luminescence that were useful for cell imaging and drug delivery. Drug storage/release properties were demonstrated to be pH responsive, in which the drug release might be beneficial at the reduced pH in certain cancerous tissues for targeted release and controlled therapy at the pathological sites. Meanwhile, DOX-NaYF4:Yb,Er-FA HMUCNPs exhibited greater cytotoxicity than free doxorubicin hydrochloride because folic acid-conjugated HMUCNPs can be specifically taken up by FR-positive KB cells via a receptor-mediated endocytosis. Therefore, the folic acid-functionalized nanoparticles combining upconversion luminescent property and hollow mesoporous structure have potential for simultaneous targeted anticancer drug delivery and cell imaging. PMID- 28350206 TI - Normative data for the lower extremity functional scale (LEFS). AB - Background and purpose - The lower extremity functional scale (LEFS) is a well known and validated instrument for measurement of lower extremity function. The LEFS was developed in a group of patients with various musculoskeletal disorders, and no reference data for the healthy population are available. Here we provide normative data for the LEFS. Methods - Healthy visitors and staff at 4 hospitals were requested to participate. A minimum of 250 volunteers had to be included at each hospital. Participants were excluded if they had undergone lower extremity surgery within 1 year of filling out the questionnaire, or were scheduled for lower extremity surgery. Normative values for the LEFS for the population as a whole were calculated. Furthermore, the influence of sex, age, type of employment, socioeconomic status, and history of lower extremity surgery on the LEFS were investigated. Results - 1,014 individuals fulfilled the inclusion criteria and were included in the study. The median score for the LEFS for the whole population was 77 (out of a maximum of 80). Men and women had similar median scores (78 and 76, respectively), and younger individuals had better scores. Participants who were unfit for work had worse scores. There were no statistically significant correlations between socioeconomic status and type of employment on the one hand and LEFS score on the other. A history of lower extremity surgery was associated with a lower LEFS score. Interpretation - High scores were observed for the LEFS throughout the whole population, although they did decrease with age. Men had a slightly higher score than women. There was no statistically significant correlation between socioeconomic status and LEFS score, but people who were unfit for work had a significantly worse LEFS score. PMID- 28350208 TI - Polarity establishment by Cdc42: Key roles for positive feedback and differential mobility. AB - Cell polarity is fundamental to the function of most cells. The evolutionarily conserved molecular machinery that controls cell polarity is centered on a family of GTPases related to Cdc42. Cdc42 becomes activated and concentrated at polarity sites, but studies in yeast model systems led to controversy on the mechanisms of polarization. Here we review recent studies that have clarified how Cdc42 becomes polarized in yeast. On one hand, findings that appeared to support a key role for the actin cytoskeleton and vesicle traffic in polarity establishment now appear to reflect the action of stress response pathways induced by cytoskeletal perturbations. On the other hand, new findings strongly support hypotheses on the polarization mechanism whose origins date back to the mathematician Alan Turing. The key features of the polarity establishment mechanism in yeasts include a positive feedback pathway in which active Cdc42 recruits a Cdc42 activator to polarity sites, and differential mobility of polarity "activators" and "substrates." PMID- 28350207 TI - Can metabolic function and physical fitness improve without weight loss for inactive, obese, Hispanic adolescents? A feasibility study. AB - INTRODUCTION: A case series that examines the effects of a 12-week combined resistance and aerobic training program for four sedentary obese, Hispanic adolescents without weight loss. SUBJECTS/METHODS: Baseline and post-intervention anthropometric, metabolic and physical fitness measures were obtained. Body composition, hepatic, visceral, and intramuscular fat contents were analyzed via imaging. Fasting levels of alanine transaminase (ALT), insulin, glucose, free fatty acids, triglycerides, high- and low-density lipoproteins (LDL), and C reactive protein were obtained via blood samples. RESULTS: Two subjects decreased their glucose levels by 1.86% and 4.06%. Subjects 1, 3, and 4 increased their lean body mass by 4.12%, 9.70%, and 5.48%. ALT was reduced 13.0%, 16.0%, and 35.7% for subjects 2, 3, and 4, respectively. LDLs were reduced by 37.7%, 4.5%, and 7.5% for subjects 1, 2, and 3. Triglycerides were reduced by 25.4%, 37.8%, and 4.6% for subjects 1, 2, and 3. Visceral fat reductions by 16.5%, 14.2%, and 13.0% occurred for subjects 1, 2, and 3. C-reactive protein was reduced for subjects 1, 2, and 3 by 19.4%, 16.3%, and 32.0%. CONCLUSION: Expected directions of change were made for most indicators of metabolic function and body composition, but measures of physical fitness improved for all four subjects. PMID- 28350209 TI - B-cell non-Hodgkin lymphoma: Selective vulnerability to PIKFYVE inhibition. AB - We identified the PIKFYVE inhibitor apilimod as a potent and selective cytotoxic agent against B-cell non-Hodgkin lymphoma (B-NHL). Our data robustly establish PIKFYVE as the target through which apilimod kills B-NHL cells and show that apilimod-induced death in B-NHL is mediated by broad disruption of lysosome homeostasis characterized by lysosomal swelling, TFEB nuclear translocation, impaired maturation of lysosomal enzymes and incomplete autophagosome clearance. Furthermore, through genome-wide CRISPR knockout screening, we identified specific lysosomal genes (TFEB, CLCN7, OSTM1 and SNX10) as critical determinants of apilimod-induced cytotoxicity. Together these data highlight disruption of lysosome homeostasis through PIKFYVE inhibition as a novel anticancer mechanism in B-NHL and potentially other cancers. PMID- 28350210 TI - Transcutaneous electrical nerve stimulation effect on postoperative complications. AB - Objectives Transcutaneous electrical nerve stimulation has been used to control post-thoracotomy pain, with conflicting results. We aimed to assess its efficacy on post-thoracotomy pain and early complications. Methods Between January 2012 and December 2014, 87 patients underwent a standard posterolateral thoracotomy and were randomized in 2 groups: group T was 43 patients who had transcutaneous electrical nerve stimulation and group C was 44 patients who had placebo stimulation with an inoperative device. Pain score was measured using a visual analogue scale ranging from 0 to 10. The frequency of the device was set at 100 Hz and pulse width at 100 ms. Results There were no statistically significant differences in the demographic characteristics of the 2 groups, and there was no difference in the duration of hospitalization (4.74 +/- 1.6 vs. 5.23 +/- 1.5 days; p = 0.06). Postoperative pain scores of the two groups showed that on postoperative day 0, 1, and 2, the mean pain scores of group T were significantly lower ( p = 0.001, p < 0.001, and p = 0.003). There were no significant differences in early complications or surgical technique. Conclusion We concluded that electrical stimulation is a safe and effective adjunctive therapy for acute post-thoracotomy pain control. However, it does not affect the duration of hospitalization or early pulmonary complications. PMID- 28350211 TI - Popliteal artery pseudoaneurysm due to femur exostosis. AB - Vascular complications of femur exostoses are rare, with popliteal pseudoaneurysm being the most common. After establishing the diagnosis, surgical treatment is mandatory. A 35-year-old woman presented with a painful pulsatile swelling in the lower medial aspect of the left thigh. Investigations revealed a pseudoaneurysm arising from the left popliteal artery adjacent to femur exostoses. Skeletal survey revealed multiple exostoses involving the upper and lower limbs. Surgical excision of the pseudoaneurysm was followed by ePTFE patch repair of the defect and excision of the exostoses. The patient was discharged after 5 days and followed up for 6 months with excellent results. PMID- 28350212 TI - Gamma secretase inhibitors: a patent review (2013 - 2015). AB - INTRODUCTION: Gamma secretase (GS) is an intricate and multi-subunits complex, and it can cut various transmembrane proteins. Now it is a therapeutic target for a number of diseases. However, due to some side effects, the clinical development of GSI is not successful. Therefore, searching for effective GSIs has become a key point in drug discovery. Areas covered: This review discusses the structure and function of GS and various types of GSIs. And this article seeks to give an overview of the patents or applications published from 2013 to 2015 in which novel chemical classes are claimed to inhibit the GS. Expert opinion: Firstly, further understanding the structure and function of GS to elucidate the disease mechanism and develop AD therapies is urgent. Secondly, if the bioequivalence, pharmacokinetics and selectivity can be improved greatly, some failed clinical inhibitors still can become the promising compounds for clinical trials. Thirdly, some weaknesses are exposed during the development of GSI, especially the insufficient potency, low brain penetration and poor selectivity. Finally, to find potent and selective GSI is the major direction in future. Moreover, to find new indications and dosing regimens in a trial of GSIs also can be seen as new ways. PMID- 28350213 TI - True morels (Morchella)-nutritional and phytochemical composition, health benefits and flavor: A review. AB - Morels are edible mushrooms appreciated worldwide for their savory flavor. Morels have been in use in traditional medicine for centuries, due to their health related benefits, and current research demonstrated their anti-oxidative and anti inflammatory bioactivities, in addition to immunostimulatory and anti-tumor properties. In spite of the high demand for morels and their increasing economic importance, their cultivation is limited, and they are either used as wild harvested or fermented in culture, for consumption as a functional food and for food-flavoring. Morel's health benefits were attributed mainly to polysaccharides as the active compounds, and to various phytochemicals, mainly phenolic compounds, tocopherols, ascorbic acid and vitamin D. Morel's nutritional composition was reported, including sugar, amino acid, fatty and organic acid and mineral profile. Information regarding Morel's flavor is limited, and while some of their taste attributes have been described, including the role of umami taste, details about their volatile aroma profile are scarce, and it was reported to include eight carbon volatiles, the main aroma volatiles typical to most mushrooms. To the best of our knowledge, this is the first review presenting morels' nutritional and phytochemical composition, health benefits and flavor, and we will review the available information in current literature regarding these aspects in light of morels phenotypic plasticity. PMID- 28350214 TI - Outbreak of Campylobacteriosis Following a Dairy Farm Visit: Confirmation by Genotyping. AB - In April-May 2014, an outbreak of campylobacteriosis occurred after a preschool visit to a dairy farm in the South Western part of Sweden. During the visit, a meal, including unpasteurized milk, was served. A retrospective cohort study using a web-based questionnaire was performed among the participants (n = 30) of the farm visit. A total of 24 of the 30 (80%) cohort members completed the questionnaire. Eleven cases were identified, and Campylobacter jejuni was isolated from eight of them. Seven of the cases were 2- to 7-year-old children. We found the highest attack rates among those who usually drink milk (45%) and those who consumed unpasteurized milk during the farm visit (42%). No cases were unexposed (risk ratio incalculable). As result of the farm investigation, Campylobacter was isolated from cattle on the farm. Genotyping with pulsed-field gel electrophoresis and whole genome sequencing confirmed that human and cattle isolates of C. jejuni belonged to one cluster. Thus, cattle on the farm are considered the source of infection, and the most likely vehicle of transmission was contaminated unpasteurized milk. We recommend consumption of heat-treated milk only and increased awareness of the risk of consuming unpasteurized milk. PMID- 28350215 TI - Transumbilical Single-Site Multiport Laparoscopic Pyeloplasty for Children with Ureteropelvic Junction Obstruction in China: A Multicenter Study. AB - BACKGROUND: Transumbilical single-site multiport laparoscopic pyeloplasty (TSMLP) for children with ureteropelvic junction obstruction (UPJO) has become feasible and popular recently. The purpose of this study was to evaluate the safety and efficacy of TSMLP for pediatric UPJO in a large multicenter series. MATERIALS AND METHODS: Medical records of consecutive patients who underwent TSMLP for pediatric UPJO in six academic institutions between June 2010 and May 2015 were retrospectively analyzed. The data of ultrasound, magnetic resonance urography, and diuretic renogram using 99Tc-diethylene triamine pentaacetic acid scan were collected during preoperative and postoperative periods. RESULTS: A total of 704 patients (750 kidneys) with UPJO who underwent TSMLP were recruited for this study. Of these patients, there were no significant differences in demographics and clinical presentation of the patients among the six centers. The operative time of all patients decreased significantly with time. The earlier the beginning of the operation, such as cohort A, B, and C, the longer the learning curve has been. Of these 704 patients, there were 60 (8.11%) postoperative minor complications during the postoperative hospitalization period, and all minor postoperative complications were cured by observation or drugs. There were 14 (1.99%) major postoperative complications, and all major complications were cured by minimally invasive surgery. No additional complications were encountered during the follow-up of 2.1 years (mean, ranged 1 year to 4 years). Success rate of TSMLP are more than 95% among six centers. CONCLUSIONS: We reported a multi institutional series of TSMLP in children with UPJO. Our findings suggest that TSMLP represents a feasible treatment option for UPJO by offering reliable outcomes, low postoperative complications and high success rates. PMID- 28350216 TI - AtSLP2 is an intronless protein phosphatase that co-expresses with intronless mitochondrial pentatricopeptide repeat (PPR) and tetratricopeptide (TPR) protein encoding genes. AB - Shewanella-like PPP family phosphatases (SLPs) are a unique lineage of eukaryote PPP-family phosphatases of bacterial origin which are not found in metazoans. 1,2 Their absence in metazoans is marked by their ancient bacterial origins and presence in plants. 1 Recently, we found that the SLP2 phosphatase ortholog of Arabidopsis thaliana localized to the mitochondrial intermembrane space (IMS) where it was determined to be activated by mitochondrial intermembrane space protein 40 (MIA40) to regulate seed germination. 3 Through examination of atslp2 knockout (accelerated germination) and 35S::AtSLP2 over-expressing (delayed germination) plants it was found that AtSLP2 influences Arabidopsis thaliana germination rates via gibberellic acid (GA) biosynthesis. 3 However, the exact mechanism by which this occurs remains unresolved. To identify potential partners of AtSLP2 in regulating germination through GA, we undertook a gene co-expression network analysis using RNA-sequencing data available through Genevestigator ( https://genevestigator.com/gv/ ). PMID- 28350217 TI - Patient non-adherence: an interpretative phenomenological analysis. AB - Purpose While interpretative phenomenological analysis (IPA) has been used in health psychology research, it has so far not been applied to seek deeper insights into the patients' experiences about treatment. The purpose of this paper is to address this gap by using IPA to understand patient non-adherence. Design/methodology/approach In total, 18 patients with chronic conditions seeking healthcare services in Goa and Karnataka, India, were selected by using the snowball sampling method. In-depth interviews were conducted face to face. A semi structured questionnaire developed by the researchers was used to collect the data. IPA was used to explore the themes to predict patient non-adherence. Findings The study results indicate that economic factors, health system related factors, social factors and psychological factors impact patient non-adherence. Patient non-adherence includes medication non-adherence and lifestyle modification non-adherence. Research limitations/implications Being cross sectional in design, the results may not be as appropriate as the results derived from a longitudinal study given that non-adherence occurs over time. Practical implications Patient non-adherence is a global health issue. Multidisciplinary approach to enhance patient adherence to treatment should form part of public healthcare policy. Social implications Exploring the factors influencing patient non-adherence will help the health-care industry stakeholders to reduce healthcare cost and improve patient's quality of life. Originality/value Although there is extensive quantitative research on the prevalence of non-adherence, qualitative research is limited. This paper addresses this gap by using IPA to understand patient non-adherence and its factors and dimensions. PMID- 28350218 TI - Editorial. PMID- 28350219 TI - Improving throughput in a youth mental health service. AB - Purpose The discrepancy between increasing demand and limited resources in public mental health is putting pressure on services to continuously review their practices and develop innovative models of care that redress this discrepancy. To ensure the service models continue to meet the needs of all stakeholders, children and young people's mental health (CYPMH) conducts regular reviews of its service models. Accordingly, the youth mental health (YMH) model at CYPMH has evolved significantly over time in response to the needs of young people and service demand. The purpose of this paper is to outline the findings of a recent review of the YMH service, and the subsequent changes to the service model. Design/methodology/approach Informed by a participatory action philosophy, feedback was sought from staff on the service model through a range of methods including a questionnaire, staff consultations through a working party and interviews. This feedback was used to redesign the model, which was then evaluated again. Findings Staff identified a number of challenges with the service model and a range of service improvement solutions. The key issues included exceedingly high caseloads, workplace tensions, and fragmentation of the client journey. This paper outlines the primary solution to these key concerns, namely, the introduction of brief intervention (BI) as the entry point to the service. Originality/value BI approaches provide a solution to overly high caseloads as the direct and focussed approach of BI generally reduces the number of sessions people need. BI is an important addition to other treatment options and should be seen as a valid component of the continuum of mental healthcare. PMID- 28350220 TI - Embedding learning from adverse incidents: a UK case study. AB - Purpose This paper reports on a regionally based UK study uncovering what has worked well in learning from adverse incidents in hospitals. The purpose of this paper is to review the incident investigation methodology used in identifying strengths or weaknesses and explore the use of a database as a tool to embed learning. Design/methodology/approach Documentary examination was conducted of all adverse incidents reported between 1 June 2011 and 30 June 2012 by three UK National Health Service hospitals. One root cause analysis report per adverse incident for each individual hospital was sent to an advisory group for a review. Using terms of reference supplied, the advisory group feedback was analysed using an inductive thematic approach. The emergent themes led to the generation of questions which informed seven in-depth semi-structured interviews. Findings "Time" and "work pressures" were identified as barriers to using adverse incident investigations as tools for quality enhancement. Methodologically, a weakness in approach was that no criteria influenced the techniques which were used in investigating adverse incidents. Regarding the sharing of learning, the use of a database as a tool to embed learning across the region was not supported. Practical implications Softer intelligence from adverse incident investigations could be usefully shared between hospitals through a regional forum. Originality/value The use of a database as a tool to facilitate the sharing of learning from adverse incidents across the health economy is not supported. PMID- 28350221 TI - The NICE alcohol misuse standard - evaluating its impact. AB - Purpose The purpose of this paper is to explore factors affecting implementing the National Institute for Health and Care Excellence (NICE) quality standard on alcohol misuse (QS11) and barriers and facilitators to its implementation. Design/methodology/approach Qualitative interview study analysed using directed and conventional content analyses. Participants were 38 individuals with experience of commissioning, delivering or using alcohol healthcare services in Southwark, Lambeth and Lewisham. Findings QS11 implementation ranged from no implementation to full implementation across the 13 statements. Implementation quality was also reported to vary widely across different settings. The analyses also uncovered numerous barriers and facilitators to implementing each statement. Overarching barriers to implementation included: inherent differences between specialist vs generalist settings; poor communication between healthcare settings; generic barriers to implementation; and poor governance structures and leadership. Research limitations/implications QS11 was created to summarise alcohol-related NICE guidance. The aim was to simplify guidance and enhance local implementation. However, in practice the standard requires complex actions by professionals. There was considerable variation in local alcohol commissioning models, which was associated with variation in implementation. These models warrant further evaluation to identify best practice. Originality/value Little evidence exists on the implementing quality standards, as distinct from clinical practice guidelines. The authors present direct evidence on quality standard implementation, identify implementation shortcomings and make recommendations for future research and practice. PMID- 28350222 TI - Nurse staffing levels and outcomes - mining the UK national data sets for insight. AB - Purpose Despite the generation of mass data by the nursing workforce, determining the impact of the contribution to patient safety remains challenging. Several cross-sectional studies have indicated a relationship between staffing and safety. The purpose of this paper is to uncover possible associations and explore if a deeper understanding of relationships between staffing and other factors such as safety could be revealed within routinely collected national data sets. Design/methodology/approach Two longitudinal routinely collected data sets consisting of 30 years of UK nurse staffing data and seven years of National Health Service (NHS) benchmark data such as survey results, safety and other indicators were used. A correlation matrix was built and a linear correlation operation was applied (Pearson product-moment correlation coefficient). Findings A number of associations were revealed within both the UK staffing data set and the NHS benchmarking data set. However, the challenges of using these data sets soon became apparent. Practical implications Staff time and effort are required to collect these data. The limitations of these data sets include inconsistent data collection and quality. The mode of data collection and the itemset collected should be reviewed to generate a data set with robust clinical application. Originality/value This paper revealed that relationships are likely to be complex and non-linear; however, the main contribution of the paper is the identification of the limitations of routinely collected data. Much time and effort is expended in collecting this data; however, its validity, usefulness and method of routine national data collection appear to require re-examination. PMID- 28350223 TI - Potential facilitators and barriers to adopting standard treatment guidelines in clinical practice. AB - Purpose The purpose of this paper is to assess medicines information sources accessed by clinicians, if sources differed in theory and practice and to find out the barriers and facilitators to effective guideline adoption. Design/methodology/approach In all, 183 doctors were surveyed. Barriers and facilitators were classified as: communication; potential adopters; innovation; organization characteristics and environmental/social/economic context. Findings Most of the clinicians accessed multiple information sources including standard treatment guidelines, but also consulted seniors/colleagues in practice. The top three factors influencing clinical practice guideline adoption were innovation characteristics, environmental context and individual characteristics. The respondents differed in the following areas: concerns about flexibility offered by the guideline; denying patients' individuality; professional autonomy; insights into gaps in current practice and evidence-based practice; changing practices with little or no benefit. Barriers included negative staff attitudes/beliefs, guideline integration into organizational structures/processes, time/resource constraints. Fearing third parties (government and insurance companies) restricting medicines reimbursement and poor liability protection offered by the guidelines emerged as the barriers. Facilitators include aligning organizational structures/processes with the innovation; providing leadership support to guide diffusion; increasing awareness and enabling early innovation during pre/in-service training, with regular feedback on outcomes and use. Practical implications Guideline adoption in clinical practice is partly within doctors' control. There are other key prevailing factors in the local context such as environmental, social context, professional and organizational culture affecting its adoption. Organizational policy and accreditation standards necessitating adherence can serve as a driver. Originality/value This survey among clinicians, despite limitations, gives helpful insights. While favourable attitudes may be helpful, clinical adoption could be improved more effectively by targeting barriers. PMID- 28350224 TI - Failure mode and effect analysis: improving intensive care unit risk management processes. AB - Purpose Failure modes and effects analysis (FMEA) is a practical tool to evaluate risks, discover failures in a proactive manner and propose corrective actions to reduce or eliminate potential risks. The purpose of this paper is to apply FMEA technique to examine the hazards associated with the process of service delivery in intensive care unit (ICU) of a tertiary hospital in Yazd, Iran. Design/methodology/approach This was a before-after study conducted between March 2013 and December 2014. By forming a FMEA team, all potential hazards associated with ICU services - their frequency and severity - were identified. Then risk priority number was calculated for each activity as an indicator representing high priority areas that need special attention and resource allocation. Findings Eight failure modes with highest priority scores including endotracheal tube defect, wrong placement of endotracheal tube, EVD interface, aspiration failure during suctioning, chest tube failure, tissue injury and deep vein thrombosis were selected for improvement. Findings affirmed that improvement strategies were generally satisfying and significantly decreased total failures. Practical implications Application of FMEA in ICUs proved to be effective in proactively decreasing the risk of failures and corrected the control measures up to acceptable levels in all eight areas of function. Originality/value Using a prospective risk assessment approach, such as FMEA, could be beneficial in dealing with potential failures through proposing preventive actions in a proactive manner. The method could be used as a tool for healthcare continuous quality improvement so that the method identifies both systemic and human errors, and offers practical advice to deal effectively with them. PMID- 28350225 TI - Healthcare seeking behaviour among Chinese elderly. AB - Purpose The Chinese population is rapidly ageing before they are rich. The purpose of this paper is to describe healthcare seeking behaviour and the critical factors associated with healthcare seeking behaviour. Design/methodology/approach Using a purposive sampling method, the authors recruited 44 adults aged 60 years or older from three provinces, representing the developed (Shanghai), undeveloped (Ningxia) regions and the regions in between (Hubei). From July to September 2008, using a semi-structured guide, the authors interviewed participants in focus group discussions. Findings The healthcare needs for chronic and catastrophic diseases were high; however, the healthcare demands were low and healthcare utilizations were even lower owing to the limited accessibility to healthcare services, particularly, in underdeveloped rural areas. "Too expensive to see a doctor" was a prime complaint, explaining substantial discrepancies between healthcare needs, demands and use. Care seeking behaviour varied depending on insurance availability, perceived performance, particularly hospital services, and prescription medications. Participants consistently rated increasing healthcare accessibility as a high priority, including offering financial aid, and improving service convenience. Improving social security fairness was the first on the elderly's wish list. Originality/value Healthcare demand and use were lower than needs, and were influenced by multiple factors, primarily, service affordability and efficiency, perceived performance and hospital service quality. PMID- 28350227 TI - The Impact of Segmental Trunk Support on Posture and Reaching While Sitting in Healthy Adults. AB - The authors investigated postural and arm control in seated reaches while providing trunk support at midribs and pelvic levels in adults. Kinematics and electromyography of the arm and ipsiliateral and contralateral paraspinal muscles were examined before and during reaching. Kinematics remained constant across conditions, but changes were observed in neuromuscular control. With midribs support, the ipsilateral cervical muscle showed either increased anticipatory activity or earlier compensatory muscle responses, suggesting its major role in head stabilization. The baseline activity of bilateral lumbar muscles was enhanced with midribs support, whereas with pelvic support, the activation frequency of paraspinal muscles increased during reaching. The results suggest that segmental trunk support in healthy adults modulates ipsilateral or contralateral paraspinal activity while overall kinematic outputs remain invariant. PMID- 28350226 TI - Integration of Care in the Implementation of the Affordable Care Act: Changes in Treatment Services in a National Sample of Centers Treating Substance Use Disorders. AB - This study examined patterns of medicalization in substance use disorder (SUD) that are aligned with the goals of the Affordable Care Act (ACA). Using a nationally representative sample of SUD treatment programs, we examined changes in several treatment domains. While observed changes were modest, they were in directions that support the thrust of the ACA. Specifically, we found an increase in the percentage of treatment referrals from other health care providers. We found an increase in the number of physicians for programs that did have a physician on staff, and an increase in counselors certified in treating alcohol and drug addiction. There was significant growth in the availability of oral and injectable naltrexone but not of other pharmacotherapies. There was a decrease in support for the 12-step model and an increase on the emphasis of a medicalized treatment model. Finally, we found a shift away from federal block grants and other public funding, consistent with the expectations of the ACA. These data indicate that, while progress is slow, the environment of the recent past has been supportive of the goal of SUD treatment's integration into mainstream medical care. PMID- 28350228 TI - Intercultural gerontology curriculum: Principles and practice. AB - The internationalization of universities and the aging of the global population are two current issues that converge and challenge undergraduate gerontology curriculum development in Canada. One response to this challenge is to envision an intercultural gerontology curriculum. What might this curriculum encompass? How might it be taught? An exploratory study was undertaken to address these two questions. This paper presents findings from this study based primarily on interviews with university-based stakeholders from Canada, the United States, and Europe. Thematic analysis of the interviews resulted in five themes: multiple perspectives on cultural diversity; the dynamic nature of cultural diversity and aging; flow of an intercultural curriculum; institutional culture and intercultural curricula; and principles and practice for intercultural gerontology. Framed by principles of gerontology theory and educational approaches, this paper focuses on the principles and practice suggested by study participants. Scaffolding learning, active learning strategies, experiential learning opportunities, teacher modelling, and internet-based learning are discussed as key to intercultural learning. An appendix includes a list of resources that may be useful to developing an intercultural gerontology curriculum. PMID- 28350230 TI - Predicting in vivo behavior of injectable, in situ-forming drug-delivery systems. PMID- 28350229 TI - Commercial Health Plan Coverage of Selected Treatments for Opioid Use Disorders from 2003 to 2014. AB - Opioid use disorders (OUDs) are receiving significant attention in the U.S. as a public health crisis. Access to treatment for OUDs is essential and was expected to improve following implementation of the federal parity law and the Affordable Care Act. This study examines changes in coverage and management of treatments for OUDs (opioid treatment programs (OTPs) as a covered service benefit, buprenorphine as a pharmacy benefit) before, during, and after parity and ACA implementation. Data are from three rounds of a nationally representative survey conducted with commercial health plans regarding behavioral health services in benefit years 2003, 2010, and 2014. Data were weighted to be representative of health plans' commercial products in the continental United States (2003 weighted N = 7,469, 83% response rate; 2010 N = 8,431, 89% response rate; and 2014 N = 6,974, 80% response rate). Results showed treatment for OUDs was covered by nearly all health plan products in each year of the survey, but the types and patterns varied by year. Prior authorization requirements for OTPs have decreased over time. Despite the promise of expanded access to OUD treatment suggested by parity and the ACA, improved health plan coverage for treatment of OUDs, while essential, is not sufficient to address the opioid crisis. PMID- 28350231 TI - Object-Tool-Actor Interaction: Object Information Drives Intended Action. AB - Tool use is typically explored via actor-tool interactions. However, the target object (that which is being acted on) may influence perceived action possibilities and thereby guide action. Three different tool-target-object pairings were tested (Experiment 1). The hammering action demonstrated the greatest sensitivity and therefore subsequently used to further investigate target-object pairings. The hammer was removed as an option and instructions were provided using pictorial (Experiment 2), written (Experiment 3), and both pictorial and written formats (Experiment 4). The designed tool is chosen when available (Experiment 1) and when removed as a choice (i.e., the hammer), participants perform the same action associated with the designed tool (i.e., hammering) regardless of instruction method (Experiments 2, 3, and 4). PMID- 28350233 TI - Does slow motion impact on the perception of foul play in football? AB - OBJECTIVES: Slow-motion replays of foul play situations are now used in the education and training of sports officials. We investigated the impact of video speed on the decision-making process of association football referees and how this interacted with expertise. METHODS: Three different groups of referees, varying in level of expertise, assessed video clips from an in-game perspective. Video clips represented corner kick and open play situations in which a foul occurred or not. For these foul/no foul situations, the referees had to make a technical (no foul; indirect free kick; direct free kick; or penalty kick) and a disciplinary decision (no card; yellow card; or red card), under both slow-motion and real-time viewing conditions. Accuracy scores were determined by comparing participant's responses with the decisions of an expert panel. RESULTS: Significant differences were observed across groups for foul/no foul situations, suggesting that the experts were able to process the available information more effectively than their less expert colleagues. The accuracy scores for the technical decision were higher in slow motion (67%) compared to a real-time viewing condition (56%), particularly for corner kick situations. No differences were found between real time and slow motion for the disciplinary decision. CONCLUSIONS: Slow-motion footage results in higher accuracy scores for complex technical decisions. These findings have implications for the use of slow-motion replays in the decision-making process of referees. PMID- 28350232 TI - Massachusetts Substance Use Disorder Treatment Organizations' Perspectives on the Affordable Care Act: Changes in Payment, Services, and System Design. AB - The Affordable Care Act (ACA) expanded insurance benefits and coverage for substance use disorder (SUD) treatment and encouraged delivery and payment reforms. Massachusetts passed a similar reform in 2006. This study aims to assess Massachusetts SUD treatment organizations' responses to the ACA. Organizational interviews addressing challenges of and responses to the ACA were conducted in person June-December 2014 with 31 leaders at 12 treatment organizations across Massachusetts. Many organizations were affiliated with medical or social services and offered a range of SUD services. Sampling was based on services offered (detoxification only, detoxification and outpatient, outpatient only). Framework analysis was used. Challenges identified were considered similar to ongoing challenges, not unique to the ACA. Organizations experienced insurance expansions in 2006 and faced new challenges, including insurance coverage, payment arrangements, expansion of services, and system design. System design efforts included care coordination/integration, workforce development, and health information technology. Differences in responses related to connections with medical and social service organizations. Many organizations engaged in efforts to respond to changing policies by expanding capacity and services. Offering a range of SUD treatment (e.g., detoxification and outpatient) and affiliating with a medical organization could enable organizations to respond to new insurance, delivery, and payment reforms. PMID- 28350234 TI - Inclined Weight-Loaded Walking at Different Speeds: Pelvis-Shoulder Coordination, Trunk Movements and Cost of Transport. AB - Although studied at level surface, the trunk kinematics and pelvis-shoulder coordination of incline walking are unknown. The aim of this study was to evaluate the speed effects on pelvis-shoulder coordination and trunk movement and the cost of transport (C) during unloaded and loaded (25% of body mass) 15% incline walking. We collected 3-dimensional kinematic and oxygen consumption data from 10 physically active young men. The movements were analyzed in the sagittal plane (inclination and range of trunk motion) and the transverse plane (range of shoulder and pelvic girdle motion and phase difference). The rotational amplitude of the shoulder girdle decreased with load at all speeds, and it was lower at the highest speeds. The rotational amplitude of the pelvic girdle did not change with the different speeds. The phase difference was greater at optimal speed (3 km.hr 1, at the lowest C) in the loaded and the unloaded conditions. The trunk inclination was greater with load and increased with speed, whereas the range of trunk motion was lower in the loaded condition and decreased with increasing speed. In conclusion, the load decreased the range of girdles and trunk motion, and the pelvis-shoulder coordination seemed to be critical for the incline walking performance. PMID- 28350235 TI - Why non-inferiority is more challenging than superiority? AB - Demonstrating non-inferiority in clinical trials is usually more challenging than showing superiority. In multiple sclerosis (MS), non-inferiority trials are rarely designed since they would require prohibitive sample sizes. In this brief report, the reasons why non-inferiority trials are usually larger than superiority trials is explored. PMID- 28350236 TI - Improving a health information system for real-time data entries: An action research project using socio-technical systems theory. AB - BACKGROUND/PURPOSE: This paper presents the findings of an action research (AR) project to improve a health information system (HIS) at the Operating Theater Department (OTD) of a National Health Service (NHS) hospital in South East England, the UK. METHODS: Informed by socio-technical systems (STS) theory, AR was used to design an intervention to enhance an existing patient administration system (PAS) to enable data entries in real time while contributing to the literature. The study analyzed qualitative data collected through interviews, participant observations, and document reviews. RESULTS: The study found that the design of the PAS was unsuitable to the work of the three units of the OTD. Based on the diagnoses and STS theory, the project developed and implemented a successful intervention to enhance the legacy system for data entries in real time. CONCLUSIONS: The study demonstrates the value of AR from a socio-technical perspective for improving existing systems in healthcare settings. The steps adopted in this study could be applied to improve similar systems. A follow-up study will be essential to assess the sustainability of the improved system. PMID- 28350237 TI - * Hierarchically Structured Electrospun Scaffolds with Chemically Conjugated Growth Factor for Ligament Tissue Engineering. AB - The anterior cruciate ligament (ACL) of the knee is vital for proper joint function and is commonly ruptured during sports injuries or car accidents. Due to a lack of intrinsic healing capacity and drawbacks with allografts and autografts, there is a need for a tissue-engineered ACL replacement. Our group has previously used aligned sheets of electrospun polycaprolactone nanofibers to develop solid cylindrical bundles of longitudinally aligned nanofibers. We have shown that these nanofiber bundles support cell proliferation and elongation and the hierarchical structure and material properties are similar to the native human ACL. It is possible to combine multiple nanofiber bundles to create a scaffold that attempts to mimic the macroscale structure of the ACL. The goal of this work was to develop a hierarchical bioactive scaffold for ligament tissue engineering using connective tissue growth factor (CTGF)-conjugated nanofiber bundles and evaluate the behavior of mesenchymal stem cells (MSCs) on these scaffolds in vitro and in vivo. CTGF was immobilized onto the surface of individual nanofiber bundles or scaffolds consisting of multiple nanofiber bundles. The conjugation efficiency and the release of conjugated CTGF were assessed using X-ray photoelectron spectroscopy, assays, and immunofluorescence staining. Scaffolds were seeded with MSCs and maintained in vitro for 7 days (individual nanofiber bundles), in vitro for 21 days (scaled-up scaffolds of 20 nanofiber bundles), or in vivo for 6 weeks (small scaffolds of 4 nanofiber bundles), and ligament-specific tissue formation was assessed in comparison to non-CTGF-conjugated control scaffolds. Results showed that CTGF conjugation encouraged cell proliferation and ligament-specific tissue formation in vitro and in vivo. The results suggest that hierarchical electrospun nanofiber bundles conjugated with CTGF are a scalable and bioactive scaffold for ACL tissue engineering. PMID- 28350238 TI - Safety and Effectiveness of Robot-Assisted Versus Open Radical Cystectomy for Bladder Cancer: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: To evaluate the safety and effectiveness of robot-assisted radical cystectomy (RARC) compared with open radical cystectomy (ORC) in bladder cancer. METHODS: A literature search for the systematic review was conducted using international databases as well as domestic databases up to April 2015. Outcomes of interest included baseline characteristics, complication rates, perioperative, and oncologic outcomes. RESULTS: Twenty-four articles were finally selected for inclusion in the meta-analysis. Complication rates of RARC were similar to those of ORC, except for 90-day overall complication rate, wound dehiscence, abscess, pneumonia, respiratory failure, and sepsis, which was lower after RARC. RARC was also associated with a smaller amount of estimated blood loss, lower transfusion rate, shorter length of hospital stay, shorter time to flatus, and more lymph node yield, whereas ORC was associated with a shorter operation time and lower rate of stricture. Considering oncologic outcomes, there were no differences between RARC and ORC. CONCLUSIONS: RARC seems to be associated with equivalent complication rates, a smaller amount of estimated blood loss, lower transfusion rate, shorter length of hospital stay, shorter time to flatus, and more lymph node yield. Randomized controlled trials with a large sample size and comparative studies with long-term follow-up data are warranted to assess our findings and the oncologic effectiveness of RARC. PMID- 28350239 TI - Speak Up!! PMID- 28350240 TI - The Effects of Task Type on Time to Task Failure During Fatigue: A Modified Sorensen Test. AB - Understanding mechanisms of fatigue of the trunk extensors is important because fatigue is a major factor in predicting incidence of low back pain, but few studies have examined trunk extensor fatigue muscles using differing load types and measured the amplitude and frequency domain of the electromyographic signal to explain these differences. Sixteen healthy participants performed position- and force-matching fatigue tasks in a modified Sorensen test position. Time to task failure was significantly longer during the position-matching task compared to force-matching task (58.3 +/- 6.6 min vs. 36.1 +/- 5.4 min). This finding is the opposite of that commonly reported for the appendicular muscle, but the mean power frequency shifts and muscle activation patterns of the trunk and hip extensors did not explain this difference. The mean power frequency shifts and muscle activation patterns of the trunk and hip extensors did not explain this difference. The greater time to task failure during the position-matching task may reflect adaptation of the trunk extensor muscles to optimize maintaining specific joint angles more so than specific loads. PMID- 28350241 TI - Comparative effectiveness of delayed-release dimethyl fumarate versus glatiramer acetate in multiple sclerosis patients: results of a matching-adjusted indirect comparison. AB - AIM: Using matching-adjusted indirect comparison, we compared efficacy outcomes in patients with relapsing-remitting multiple sclerosis treated with delayed release dimethyl fumarate (DMF) or glatiramer acetate (GA). MATERIALS & METHODS: An indirect comparison of DMF (patient-level data) and GA (aggregate data) was conducted, with average baseline characteristics of DMF patients weighted to match those for GA patients. Direct comparison of DMF and GA was conducted in CONFIRM. Final results pooled the indirect and direct comparisons using meta analysis. RESULTS: After matching, baseline characteristics were balanced between DMF and GA patients. Compared with GA, efficacy was significantly in favor of DMF as measured by annualized relapse rate (rate ratio: 0.76; 95% CI: 0.57-1.00; p = 0.0474) and 12-week confirmed disability progression (risk ratio: 0.59; 95% CI: 0.46-0.76; p < 0.0001). CONCLUSION: DMF demonstrated superior clinical efficacy versus GA. PMID- 28350242 TI - Comparison of Psychopathological Symptoms in Adolescents Who Experienced Sexual Violence as a Victim and/or as a Perpetrator. AB - Research on sexual violence victims and perpetrators indicates that victims in general are found to report higher levels of psychopathological symptoms, especially internalizing behavior, whereas perpetrators often show externalizing behavior. Little is known, however, about the psychopathology of perpetrators of sexual violence who have also experienced sexual victimization (victim perpetrators). Thus, the aim of the current study was to examine this group within a sample of adolescents living in residential care or federal boarding schools. Participants reported their lifetime experience with sexual violence (both as victim and perpetrator) and completed the Youth Self Report. Results indicate that all three groups of adolescents with sexual violence experience report higher total problem scores than adolescents without this experience. Victim-perpetrators show results more similar to those of perpetrators only than those of victims only. The discussion deals with the implications of our findings for the treatment of victims of sexual violence. PMID- 28350243 TI - Fitts' Theorem and Movement Time Dissociation for Amplitude and Width Manipulations: Replying to Hoffmann. AB - The commentary by Errol Hoffmann asserts that previous work by our group provides the spurious conclusion that amplitude and width manipulations to a movement environment elicit dissociable relations between movement time (MT) and P. M. Fitts' (1954) index of difficulty (ID). Hoffmann concludes that any such dissociation is the result of actions evoked entirely as ballistic. In this reply, we demonstrate that Hoffmann's commentary is a clear misrepresentation of the study goals and conclusions stated by our group. Additionally, we provide kinematic evidence that actions involving online trajectory amendments are associated with dissociable MT-ID relations for amplitude versus width manipulations. Finally, we contend that the kinematic analyses of movement trajectories, and Hoffmann's failure to acknowledge its importance, is an important step in further understanding speed-accuracy relations in human movement. PMID- 28350244 TI - Training social work students to recognize later-life depression: Is standardized patient simulation effective? AB - Professional social workers are the largest provider of mental health services in the nation, yet they receive little coursework or clinical training in late-life depression unless they are in a gerontology specialization. Simulation training offers academic experiences that evoke conditions of the real world in a practical way. One hundred and four graduate social work students consented and completed the Standardized Patient Simulation course consisting of a human simulator interview, pre- and postdebriefing on late life depression, and self and faculty ratings of outcome measures. Results from pre-post testing of measures and the debriefing evaluation demonstrated that students gained in knowledge and achieved clinical skill competency. Students reported that the patient simulator was convincing, the environment was realistic, and they were satisfied with the training. The educational methodology tests students in challenging situations and offers immediate educational feedback to integrate and improve practice behaviors towards achieving clinical competency. PMID- 28350245 TI - Influence of Background Noise Produced in University Facilities on the Brain Waves Associated With Attention of Students and Employees. AB - As a consequence of noise exposure, lack of attention badly affects directly the academic and work performance. The study of the brain and the waves that it produces is the most objective way to evaluate this process. Attentional improvement is associated with increases of the amplitude in both beta and theta bands. The objective of this work is to study the influence of background noise produced inside university facilities on changes in the cerebral waves related to attention processes (beta 13-30 Hz and theta 4-7 Hz). Volunteers were asked to perform a specific task in which attention was involved. This task was performed in both silent and noisy conditions. To evaluate the cerebral activity of volunteers during the development of the test, measurement of spontaneous activity (electroencephalogram) was developed. The results show significant decreases in both beta and theta frequency bands under background noise exposure. Since attentional improvement is related to an increment on amplitude of both beta and theta bands, it is suggested that decreases on amplitude of these frequency bands could directly be related to a lack of attention caused by the exposure to background noise. PMID- 28350246 TI - Frequency, presentation, and outcome of Takayasu arteritis in Western Australia. AB - OBJECTIVES: Takayasu arteritis (TAK) is large-vessel vasculitis that predominantly affects young women. There is worldwide variation in the frequency of TAK depending on genetic and/or environmental factors. With Australian data lacking, we describe the epidemiology, clinical features and outcomes of TAK in Western Australia (WA). METHODS: Retrospective case cohort study of incident TAK cases between 1 January 2000 and 30 June 2015 in WA identified from multiple sources. Data on disease presentation and outcome were extracted from medical records. RESULTS: Eighteen patients received a clinical diagnosis with thirteen cases meeting 1990 ACR criteria for TAK (all female, 77% Caucasian, age at diagnosis 39 years) included in this analysis. Per million inhabitants the annual incidence and prevalence (2015) was 0.3 and 3.2 for Caucasians and 1.1 and 15 for Asians. Limb claudication and bruit were commonest symptoms; ESR or CRP was raised in 61% at diagnosis while aortic involvement Hata type IIb most prevalent (30%). Despite general combination therapy with corticosteroids and immunosuppressant drugs, four patients suffered a stroke, two patients developed myocardial infarction, and five patients required vascular intervention. Three Caucasian patients died during the study period. CONCLUSION: TAK is much more prevalent in the Asian than Caucasian population of WA and associates with significant long-term morbidity and mortality despite standard therapy. PMID- 28350247 TI - The Transgenic Zebrafish Display Fluorescence Reflecting the Expressional Dynamics of Dihydrofolate Reductase. AB - Dihydrofolate reductase (DHFR) reduces folic acid and recycles dihydrofolate generated during dTMP biosynthesis to tetrahydrofolate. DHFR is upregulated in rapidly proliferating cells and hence a favored target of antifolate drug against cancers, autoimmune diseases, and microbial infections. However, increased expression of dhfr contributed to the often emerging drug resistance and impeded the therapeutic efficacy of antifolate drugs. Therefore, comprehensive knowledge on the expressional control of dhfr becomes crucial. We generated two zebrafish transgenic lines, Tg(zdhfr+91:EGFP) and Tg(zdhfr+79:EGFP), which express green fluorescent protein driven by two zebrafish dhfr promoter fragments separately. The fluorescence intensity displayed in these transgenic embryos recapitulated the expressional dynamics of endogenous dhfr and reflected changes in dhfr mRNA and protein levels. The fluorescence intensity of these transgenic embryos was responsive to both genetic and environmental factors potentially modulating dhfr promoter activity. Sequence analyses revealed partial conservation on the landscape of transcription factor arrangement between zebrafish and human dhfr promoters. A noncanonical and inhibitory Sp1 site was identified 170 base-pair upstream to the conserved Sp1 site in close proximity to the translation initiation codon. Our results supported the potential use of these transgenic embryos for studying the expressional dynamics of dhfr and preliminary screening for dhfr promoter modulators. PMID- 28350248 TI - Impact of life stories on college students' positive and negative attitudes toward older adults. AB - Gerontological educators are increasingly interested in reducing college students' negative, and promoting their positive, attitudes toward older adults. Over the course of a semester, students from six 4-year institutions viewed three life story videos (documentaries) of older adults and completed pre- and posttest surveys that assessed their positive (Allophilia Scale) and negative (Fraboni Scale of Ageism) attitudes. The authors assessed changes in attitudinal scales between treatment (with videos, n = 80) and control (no video, n = 40) groups. Change score analysis with 95% bias-corrected bootstrap confidence intervals estimated the effects of the documentaries on students' attitudes. The treatment group showed significant increases in kinship, engagement, and enthusiasm, and decreases in antilocution and avoidance (all ps <.05). There was no significant change in affect, comfort, or discrimination. This study demonstrated how video stories impact students' attitudes about older adults. PMID- 28350249 TI - Defining doctoral gerontologists: Who are they and how are they contributing to the field of gerontology? AB - More than 300 individuals have earned doctoral degrees in gerontology since 1993, yet little is known about their training, professional placement, and contributions to the field. Given this lack of information, the authors sought to define the emerging mass of doctoral gerontologists. In this study, the authors analyzed results from the 2014 Gerontology Education Longitudinal Study survey sample of 84 individuals who earned a doctoral degree in gerontology between 1993 and 2013. Results revealed doctoral gerontologists completed training requirements that were consistent across eight programs offering doctorates in gerontology. The authors also found doctoral gerontologists have been successful in securing jobs in academic and nonacademic organizations, creating gerontological knowledge, and translating their work into other fields. The authors concluded by considering how the successful integration of doctoral gerontologists might continue, and they propose directions for future research. PMID- 28350250 TI - Proactive outreach smoking cessation program for Chinese employees in China. AB - We evaluated the first workplace intervention to help smokers quit in Hong Kong. Smoking employees (N = 642) received a 26-page self-help booklet and 15 fix SMS within 3 months and chose to receive cognitive behavioral workshop (N = 76), or face-to-face counseling (N = 11), or group health talk (N = 516), or telephone counseling (N = 39). Twenty participants were interviewed individually for their opinions about the interventions. By intention-to-treat, the overall self reported past 7-day point prevalence quit rate was 31.0% and 32.9%, and reduction rate was 15.0% and 13.2% at 6 and 12-months, respectively. More than 20% of the unmotivated smokers at baseline (N = 399) quit in this program. Proactive outreach workplace smoking cessation programs with diverse intensity but without medications, chosen by smokers and supported by employers without further incentives, were feasible in busy working environment in Hong Kong. PMID- 28350252 TI - Long-term cognitive and neuroanatomical stability in patients with anoxic amnesia: A Case Report. AB - BACKGROUND: Anoxia can result in selective hippocampal damage with associated impairments in declarative memory. Whilst memory impairments and brain structures are thought to be stable, there are little data regarding the effects of ageing or change over time in patients with amnesia from anoxic brain injury. METHODS: To assess change over time, we compared structural magnetic resonance imaging (MRI) with data obtained over ten years previously in two well-characterized patients with amnesia (JRW and RS) who experienced an anoxic brain injury. Six healthy, age-matched control participants were recruited to compare brain volumes with the patients at Time 2. Wechsler adult intelligence scale-revised and Wechsler memory scale-revised scores were compared to scores on the same tests administered 13 and 19 years prior. RESULTS: Patients with amnesia had significantly smaller hippocampal volumes than controls, but comparable medial temporal lobe and ventricular volumes. Memory, intellectual function and brain volumes were stable over time. CONCLUSION: Patients with an amnesia due to anoxia have memory impairments and smaller hippocampal volumes compared to controls; however, memory, intelligence and structural volumes remain stable over time. At ages 50 and 57, they do not appear to have early age-associated cognitive decline that is sometimes observed in patients with traumatic brain injury. PMID- 28350251 TI - Impact of CYP2D6 genotype on amitriptyline efficacy for the treatment of diabetic peripheral neuropathy: a pilot study. AB - AIM: Therapy with low-dose amitriptyline is commonly used to treat painful diabetic peripheral neuropathy. There is a knowledge gap, however, regarding the role of variable CYP2D6-mediated drug metabolism and side effects (SEs). We aimed to generate pilot data to demonstrate that SEs are more frequent in patients with variant CYP2D6 alleles. METHOD: To that end, 31 randomly recruited participants were treated with low-dose amitriptyline for painful diabetic peripheral neuropathy and their CYP2D6 gene sequenced. RESULTS: Patients with predicted normal or ultra-rapid metabolizer phenotypes presented with less SEs compared with individuals with decreased CYP2D6 activity. CONCLUSION: Hence, CYP2D6 genotype contributes to treatment outcome and may be useful for guiding drug therapy. Future investigations in a larger patient population are planned to support these preliminary findings. PMID- 28350254 TI - Career dreams among health care students: I want to make a difference. AB - There is a continuous increase in demand for health services in most countries because people who are older are living longer. Health care for people who are older is not, generally, an attractive career option for undergraduate health professionals. This study investigated career dreams among undergraduates studying a variety of health care subjects to understand what motivates them. Eighteen focus groups were conducted with 90 students, and template analysis was performed within a sociological framework. Four themes emerged from the analysis: no plans to work with people who are older, dreaming of making a difference, seeking variety, and the impact of clinical placements on stimulating or reducing interest in working with people who are older. Geriatrics and gerontology do not offer the opportunities that students are looking for in their future careers. There is a need to change the way we talk about adults who are older everywhere, not just in health care training. However, health care educators should also help students to understand the value of care provided to adults who are older. PMID- 28350255 TI - Diagnostic performance of breast ultrasonography and MRI in the prediction of lymph node status after neoadjuvant chemotherapy for breast cancer. AB - Background Neoadjuvant chemotherapy (NAC) is widely used to treat breast cancer. Sentinel lymph node biopsy has replaced axillary lymph node dissection in patients who convert to node-negative status after NAC. However, few studies have evaluated the diagnostic performance of ultrasonography and magnetic resonance imaging (MRI) in determining axillary lymph node status after NAC. Purpose To evaluate the diagnostic performance of breast ultrasonography and MRI in determining residual metastatic axillary lymph node status after NAC for breast cancer and to identify histopathological factors affecting radiological performance. Material and Methods This study included 157 patients who underwent initial and follow-up preoperative breast ultrasonography and MRI before NAC between January and December 2010. The sensitivity, specificity, negative and positive predictive values, and accuracy of ultrasonography, MRI, and their combinations were evaluated. Results The sensitivity of ultrasonography, MRI, and their combination in post-NAC axillary imaging was 60.00%, 57.33%, and 65.33%, respectively; the specificity was 60.47%, 72.09%, and 60.47%, respectively. The positive predictive value was highest with MRI (78.18%). On univariate analysis, positive estrogen receptor status was associated with misdiagnosis by ultrasonography ( P = 0.002), MRI ( P = 0.002), and their combination ( P = 0.001). When residual metastatic lymph nodes were present, lymph nodes with macrometastasis (>2.0 mm) were associated with correct ultrasonography-based diagnosis ( P = 0.0027). Conclusion Imaging assists in predicting axillary lymph node status in patients undergoing NAC; however, is imprudent to omit sentinel lymph node biopsy or axillary lymph node dissection for staging in women determined to be node-positive. PMID- 28350253 TI - 3D visualization and quantification of microvessels in the whole ischemic mouse brain using solvent-based clearing and light sheet microscopy. AB - The visualization of cerebral microvessels is essential for understanding brain remodeling after stroke. Injection of dyes allows for the evaluation of perfused vessels, but has limitations related either to incomplete microvascular filling or leakage. In conventional histochemistry, the analysis of microvessels is limited to 2D structures, with apparent limitations regarding the interpretation of vascular circuits. Herein, we developed a straight-forward technique to visualize microvessels in the whole ischemic mouse brain, combining the injection of a fluorescent-labeled low viscosity hydrogel conjugate with 3D solvent clearing followed by automated light sheet microscopy. We performed transient middle cerebral artery occlusion in C57Bl/6j mice and acquired detailed 3D vasculature images from whole brains. Subsequent image processing, rendering and fitting of blood vessels to a filament model was employed to calculate vessel length density, resulting in 0.922 +/- 0.176 m/mm3 in healthy tissue and 0.329 +/ 0.131 m/mm3 in ischemic tissue. This analysis showed a marked loss of capillaries with a diameter <= 10 um and a more moderate loss of microvessels in the range > 10 and <= 20 um, whereas vessels > 20 um were unaffected by focal cerebral ischemia. We propose that this protocol is highly suitable for studying microvascular injury and remodeling post-stroke. PMID- 28350256 TI - Separation of two sub-groups with different DNA content after treatment of T-47D breast cancer cells with low dose-rate irradiation and intermittent hypoxia. AB - Background Previous studies have shown that combined treatment with internal ultra-low dose-rate irradiation selectively inactivated hypoxic T-47D breast cancer cells after three to five weeks of treatment. However, 2-3% of the hypoxic cells were found to survive and restart proliferation upon re-oxygenation. Purpose To investigate the metastatic potential and characteristics of radiosensitivity of these surviving cells, named T - 47 DS. Material and Methods The T - 47 DS cells were grown in ambient air without irradiation. A cloning experiment identified two sub-groups with different DNA content ([Formula: see text] and [Formula: see text]). Furthermore, radiosensitivity and presence of hyper-radiosensitivity (HRS) was measured by Co-60 challenge irradiation and relative migration was determined by scratch assays. Results The two subpopulations of T - 47 DS had different DNA content; one had abnormally high DNA content ([Formula: see text]) and one had DNA content similar to wild-type T 47D cells ([Formula: see text]). HRS was surprisingly present in cells of the cloned population [Formula: see text], but was absent in cells of both [Formula: see text] and T - 47 DS. The radio response of T - 47 DS, [Formula: see text] at higher radiation doses were similar to that of T-47D cells, and neither subpopulation showed increased migration compared with wild-type T-47D. Conclusion No increase in the risk of metastasis was found and only slight changes in radiosensitivity in response to conventional clinical doses was observed. Thus, the data suggest that if ultra-low dose-rate irradiation is used for targeting the hypoxic tumor fraction, conventional high dose-rate irradiation can be used to eradicate eventual surviving cells as well as cells in the well oxygenated areas of the tumor. PMID- 28350257 TI - Intrahepatic mass-forming cholangiocarcinoma and solitary hypovascular liver metastases: is the differential diagnosis using diffusion-weighted MRI possible? AB - Background Intrahepatic mass-forming cholangiocellular carcinoma (IMC) is the second most common primary liver tumor. The differentiation between IMC and solitary hypovascular liver metastases (SHLM) represents a diagnostic challenge due to many overlapping magnetic resonance imaging (MRI) features. Purpose To determine the value of diffusion-weighted imaging (DWI) in addition to conventional MRI for the distinction between intrahepatic mass-forming cholangiocarcinoma and solitary hypovascular liver metastases. Material and Methods Fifty-three patients with pathologically proven IMC (n = 31) and SHLM (n = 22) who had undergone MRI and DWI before surgery or percutaneous biopsy were enrolled in this study. The following MRI features were analyzed: the size and shape of the lesion, presence of capsular retraction and segmental biliary dilatation, T2-weighted (T2W) signal intensity, the presence of target sign on DWI and enhancement pattern. Apparent diffusion coefficient (ADC) values were calculated for each lesion ( b = 800 s/mm2). Univariate and multivariate logistic regression analyses were used to identify significant differentiating features between IMCs and SHLMs. Results Univariate analysis revealed that following parameters favor diagnosis of IMCs over SHLMs: lobulating shape, heterogeneous T2W signal intensity, capsular retraction, segmental biliary dilatation, target sign on DWI and rim-like enhancement on arterial phase followed by progressive enhancement in delayed phases. ADC values measured in the periphery of the lesion were significantly lower in IMCs in comparison to SHLMs. Multivariate analysis revealed that target sign on DWI was the most significant predictor of IMCs. Conclusion Qualitative DWI analysis with target sign significantly improves diagnostic accuracy for differentiation among IMC and SHLM lesions. PMID- 28350258 TI - The Difficult Gallbladder: A Safe Approach to a Dangerous Problem. AB - Laparoscopic cholecystectomy is a common surgical procedure, and remains the gold standard for the management of benign gallbladder and biliary disease. While this procedure can be technically straightforward, it can also represent one of the most challenging operations facing surgeons. This dichotomy of a routine operation performed so commonly that poses such a hidden risk of severe complications, such as bile duct injury, must keep surgeons steadfast in the pursuit of safety. The "difficult gallbladder" requires strict adherence to the Culture of Safety in Cholecystectomy, which promotes safety first and assists surgeons in managing or avoiding difficult operative situations. This review will discuss the management of the difficult gallbladder and propose the use of subtotal fenestrating cholecystectomy as a definitive option during this dangerous situation. PMID- 28350259 TI - Obstacles to Help-Seeking for Sexual Offenders: Implications for Prevention of Sexual Abuse. AB - Persons with potentially harmful sexual interests such as attraction to minors are unlikely to seek or receive treatment before a sexual offense has been committed. The current study explored barriers to help-seeking in a sample of 372 individuals in treatment for sexual offending. Results revealed that the shame and secrecy resulting from stigma associated with pedophilic interests often prevented our respondents from seeking professional counseling, and only about 20% tried to talk to anyone about their sexual interests prior to their arrest. Barriers to seeking and receiving psychological services included concerns about confidentiality, fears of social and legal consequences, personal shame or confusion about the problem, affordability, and challenges finding competent therapists who were adequately equipped to help them. Understanding and ultimately reducing obstacles to help-seeking can improve the quality of life for people with harmful sexual interests and potentially prevent sexual abuse of children or other vulnerable individuals. PMID- 28350261 TI - Common Beliefs About Child Sexual Abuse and Disclosure: A College Sample. AB - Adults' common beliefs about child sexual abuse and disclosure were explored. Participants (N = 670) were questioned about key areas of child sexual abuse that could affect decision-making processes of jurors evaluating child sexual abuse cases. These areas included victim and perpetrator characteristics, medical and behavioral indicators of child sexual abuse, memories for the event, and disclosure of the event. The scientific literature pertaining to these same areas are reviewed. While individual beliefs were consistent with some areas of the scientific literature (e.g., victim and perpetrator characteristics), they strongly contrasted the literature in other important areas (e.g., memories for the event, indicators of child sexual abuse, and the likelihood of denial and recantation). Implications, including the option of providing expert testimony to reduce discrepancies, are discussed. PMID- 28350260 TI - Posttraumatic Stress Disorder and Suicidal Ideation Among Sexually Abused Adolescent Girls: The Mediating Role of Shame. AB - Sexual abuse is associated with a host of negative repercussions in adolescence. Yet the possible mechanisms linking sexual abuse and negative outcomes are understudied. The purpose of this study was to investigate the relationships among self-blame, shame, coping strategies, posttraumatic stress disorder, depressive symptoms, and suicidal ideation. The sample included 147 sexually abused adolescent girls between 14 and 18 years of age. A total of 66% of girls reached clinical score for posttraumatic stress disorder, and 53% reached clinical score for depressive symptoms. Close to half (46%) reported suicidal thoughts in the past 3 months. Shame was found to partially mediate the relationship between self-blame and posttraumatic stress disorder. Shame and depressive symptoms were also found to partially mediate the relationship between self-blame and suicidal ideation. Results suggest that shame is a crucial target in interventions designed for sexually abused adolescent girls. PMID- 28350262 TI - The Effect of Gender on Perceptions of Credibility in Child Sexual Assault Cases: A Systematic Review. AB - Child sexual assault cases have one of the highest attrition rates throughout the justice system, with jurors' perceptions of the credibility of the child playing a critical role in the judicial process and resulting outcomes. One of the most prominent influences on credibility is gender, specifically victim and perceiver gender. This article reports the findings of a systematic search of the literature exploring the impact of these factors on perceptions of victim credibility. Results suggest that overall females tend to rate victim credibility higher than do males; however, this gender effect is minimized when the alleged perpetrator is not the biological parent of the victim. There is little support for a victim gender effect, such that potential jurors' ratings of victim credibility does not appear to be influenced by the gender of the victim. The review highlights the lack of consistent and comprehensive measurement of credibility. Legal implications are discussed. PMID- 28350263 TI - Child Sexual Behaviors in School Context: Age and Gender Differences. AB - The main purpose of the study was to explore the child sexual behaviors that Italian teachers have observed in the school context. A representative sample of 227 children, from 5 to 10 years old, was rated by their teachers through the Child Sexual Behavior Inventory. Frequencies of sexual behaviors among children aged 5 to 6, 7 to 8, and 9 to 10 are presented. Younger children showed a broader range of sexual behaviors that decrease with the growing age, such as males in comparison to females. Moreover, findings showed that child sexual behavior is not only related to age and gender but also to family characteristics. These results suggested that child sexual behaviors reported by teachers through the Child Sexual Behavior Inventory may provide useful information about the development of children's sexuality. The knowledge of age appropriate sexual behaviors can help teachers discern normal sexual behaviors from problematic sexual behaviors. PMID- 28350264 TI - Some Epidemiological Characteristics of Perpetrators and Victims of Incest in Contemporary Ghana: Analysis of Media Reports. AB - In Ghana, incest is considered sinful, taboo, and illegal. However, recent media reports show that incest has become a daily reality in Ghana. This study is a situational analysis of the pattern of incest in Ghana as reported in the media from January 2008 through July 2015. Qualitative content analysis was conducted on 48 incest news reports in Ghana. The findings showed that father-daughter incest was most frequent across the study period. Forty-seven females aged 3 to 25 years and a male aged 3 years were identified as victims. Generally, the incest lasted between 1 day and 13 years before disclosure. Perpetrators employed psychological and/or physical methods to coerce their victims. Marital difficulties, diabolical control, and seduction by victim featured prominently as alleged motives behind the abuse. The study observes that the recent increase in father-daughter incest warrants an immediate shift of research attention onto men's mental health in Ghana. PMID- 28350265 TI - Persistent Complications of Child Sexual Abuse: Sexually Compulsive Behaviors, Attachment, and Emotions. AB - Child sexual abuse has the potential to cause distress for the victim across the lifespan. Romantic relationships may be particularly difficult for victims of child sexual abuse. This retrospective study examined differences in adult romantic attachment, sexually compulsive behaviors, and emotion regulation by history of child sexual abuse in a large, nonclinical sample. Those with a history of child sexual abuse reported more attachment anxiety in romantic relationships and engaged in more sexually compulsive behaviors. Overall, males displayed more sexually compulsive behaviors than females regardless of history of sexual abuse. Males with a history of sexual abuse displayed the greatest number of sexually compulsive behaviors. Surprisingly, no differences were observed in emotion regulation or attachment avoidant behaviors by history of child sexual abuse. Future research should seek to replicate current findings and examine emotion regulation difficulties experienced as a result of trauma. PMID- 28350266 TI - Pedophiles in the Ultra-Orthodox Haredi Sector in Israel: Thought Processes Regarding their Actions. AB - This study explores thought patterns of Jewish Ashkenazi Ultra-Orthodox pedophiles in Israel and how they resolve the contradiction between their commitment to Jewish Law and having committed sexual offenses against minors. Ten adult men participated in this study. Using open semistructured interviews, their cognitive distortions before, during, and after the abuse were examined. Content analysis revealed that participants used cognitive distortions based on their own world of Jewish Law and social-cultural values. The insular nature of Ultra Orthodox society and its many prohibitions, especially regarding sexuality, tempted offenders to test boundaries. When sexual drive was high, internal control mechanisms were ineffective even in presence of external control mechanisms. Some participants recognized the contradiction between their behaviors and being Ultra-Orthodox Jews, and others did not. Based on the findings, a flow chart was devised describing the cognitive processes of Jewish Ultra-Orthodox pedophiles. Theoretical and practical implications of the results were examined. PMID- 28350267 TI - Corrigendum. PMID- 28350268 TI - Molecular and biopharmaceutical investigation of alginate-inulin synbiotic coencapsulation of probiotic to target the colon. AB - Colon targeting, as a site-specific delivery for oral formulation, remains a major challenge, especially for sensitive bioactive components such as therapeutic forms of phages, live attenuated virus and prebiotics-probiotics association. Synbiotics could be used to protect encapsulated probiotics during the gastrointestinal tract and control their release in the colon. To achieve these goals, effective prebiotics, such as inulin, could be combined with alginate - the most exploited polymer used for probiotic encapsulation - in the form of beads. This work aimed to study the biopharmaceutical behaviour of alginate beads (A) and inulin-alginate beads of different inulin concentrations (5 or 20%) in 2% alginate (AI5, AI20). Beads were loaded with three probiotic strains (Pediococcus acidilactici Ul5, Lactobacillus reuteri and Lactobacillus salivarius). Dissolution of beads was studied by USP4 under conditions simulating the gastrointestinal condition. The survival rates of the bacterial strains were measured by a specific qPCR bacterial count. Mucoadhesiveness of beads was studied by an ex vivo method using intestinal mucosa. To understand the behaviour of each formulation, the ultrastructure of the polymeric network was studied using scanning electron microscopy (SEM). Molecular interactions between alginate and inulin were studied by Fourier transform infra-red spectroscopy (FTIR). Dissolution results suggested that the presence of inulin in beads provided more protection for the tested bacterial strains against the acidic pH. AI5 was the most effective formulation to deliver probiotics to the colon simulation conditions. FTIR and SEM investigations explained the differences in behaviour of each formula. The developed symbiotic form provided a promising matrix for the development of colonic controlled release systems. PMID- 28350270 TI - 2016 Research Forum Poster Session and Competition: Finalists and Posters. PMID- 28350269 TI - Review of a single surgeon's stapedotomy cases performed with a nickel titanium prosthesis over a 14-year period. AB - CONCLUSION: Stapes surgery with a nickel titanium prosthesis is a safe and well tolerated procedure that leads to a significant improvement in hearing outcomes. OBJECTIVE: To identify the efficacy and safety of stapedotomy procedures performed with a nickel titanium prosthesis for patients with otosclerosis. METHODS: A review of 431 unique stapedotomies performed over 14 years by a single surgeon at an academic tertiary care center yielded 312 cases with nickel titanium prosthesis that met inclusion criteria of otosclerosis diagnosis, initial surgery in operative ear, and presence of pre-operative and post operative audiograms. Pure-tone averages (PTA) at baseline and 8 weeks after surgery were calculated over four frequencies; 0.5, 1, 2, and 4 kHz. Average air bone gaps (ABG) were calculated from pre-operative and post-operative audiograms. RESULTS: Average pre-operative baseline PTA was 56.7 dB in the affected ear. Post operative PTA was 30.1 dB, a 26.6 dB improvement. Initial average ABG was 29.7 dB, while post-operative ABG averaged 5.4 dB, a 24.2 dB improvement. Surgical success (closure of ABG within 10 dB) was achieved in 263 (84%) patients. Rate of surgical success was not correlated with age, gender, race, or affected ear. Complications included recurrent conductive hearing loss (14), progressive SNHL (4), and post-operative BPPV (3). PMID- 28350271 TI - Human tooth-derived biomaterial as a graft substitute for hard tissue regeneration. AB - AIM: The present study was conducted to evaluate the efficacy of human dentine grafts for new bone augmentation. MATERIALS & METHODS: Dentine grafts (demineralized dentine matrix [DDM] and mineralized dentine matrix [MDM]) were prepared and implanted in rats. Tetracycline was administered twice. Paraffin and resin sections were prepared from the harvested grafts and stained respectively with hematoxylin and eosin (in addition to tartrate acid phosphatase for osteoclasts) and Villanueva. The new bone formation (bone thickness, mineral apposition rate and the bone formation rate) was analyzed in tetracycline-labeled resin sections. RESULTS & CONCLUSION: DDM grafts implanted in bone were better able to augment the bone compared to MDM grafts. However, both MDM and DDM failed to induce new bone in ectopic site, they could be considered as alternative autograft substitutes after protocol optimization. PMID- 28350273 TI - A randomized comparative trial of OTSC and Padlock for upper GI hemostasis in a standardized experimental setting. AB - INTRODUCTION: Upper gastrointestinal bleeding (UGIB) is the key emergency situation in clinical endoscopy and is traditionally treated with injection, thermal or through the scope clipping therapy. Mortality rates are in the range of 8-10% and demand new treatment approaches. The Over-The-Scope Clip (OTSC(r)) has been described as a very effective hemostatic device in UGIB. We compared OTSC with the PadlockTM device in an established pre-clinical setting. MATERIAL AND METHODS: Our test-bed consisted of the biohybrid EASIE model using soft silicone tubes, tunneled into the gastric wall and surfacing at a mucosa defect, representing the bleeding site. After successful deployment of the OTSC and Padlock devices on the spurting ulcer bleed (Forrest Ia) the vessel tubes were pressurized with a manometer to 120 mmHg. Tight closure at this pressure was defined as successful hemostasis (primary endpoint). N = 11 procedures were done with each device. Statistical testing was done using Fisher's exact test. Sample size was adjusted to an assumed alpha-error of 5% (two-sided test) and a power of 80%. RESULTS: Technically correct placement of the respective hemostatic device was achieved in all procedures. A statistically significant difference was found in the primary endpoint. In OTSC the success proportion was 100%; 11/11 (95% KI 74.1% to 100%); in Padlock it was 0%; 0/11 (95% KI 0%-25.8%). This means that no bleeding was stopped by Padlock. The mean value of perfusion pressure resistance was 300 mmHg (cut-off) for OTSC and 9.2 +/- 8.4 mmHg for Padlock. DISCUSSION: Our data on hemostatic function of OTSC coincide with the clinical literature and earlier pre-clinical studies in the EASIE model, which is widely accepted as a realistic and effective simulation system for clinical conditions. The inability of Padlock to stop hemorrhage may be due to design differences and, thus, its limitation in providing tight sealing of the clipped tissue. CONCLUSION: Different types of endoscope-tip mounted clips have different performances. OTSC consistently stops simulated spurting bleeding, Padlock fails to do so. These differences are statistically significant. PMID- 28350272 TI - Cadmium, lead, tin, total mercury, and methylmercury in canned tuna commercialised in Sao Paulo, Brazil. AB - The objective of this work was to determine levels of inorganic contaminants in 30 samples of five commercial brands of canned tuna, acquired on the local market in Campinas, Sao Paulo, Brazil, in the year of 2015. Total mercury and methylmercury (MeHg+) were determined by atomic absorption with thermal decomposition and amalgamation; and cadmium, lead, and tin were determined by inductively coupled plasma optical emission spectrometry. Results indicated that 20% of the tuna samples surpassed limits determined by the Brazilian and European Commission legislation for cadmium; for lead, the maximum value found was 59 ug kg-1 and tin was not detected in any samples. The maximum values found for total Hg and MeHg+ were 261 and 258 ug kg-1, respectively. As from the results obtained, it was estimated that the consumption of four cans per week (540 g) of tuna canned in water could surpass the provisional tolerable monthly intake for MeHg+ by 100%. PMID- 28350274 TI - Visual elements in direct-to-consumer advertising: Messages communicated to patients with arthritis. AB - Direct-to-consumer (DTC) advertising saturates popular health magazines, communicating persuasive messages to readers that may influence attitudes and behaviors. This research used a two-prong approach to investigate the visual elements used in DTC advertising and their influence on consumers' understanding of a disease and its treatment options. An analysis was conducted of DTC advertisements (N = 62) from a population sample of Arthritis Today magazine, 2000-2010. Three panels of people with arthritis were used to validate the findings and discuss implications for health literacy. Pharmaceutical companies have an opportunity to communicate tailored messages to readers of niche publications and improve disease management. PMID- 28350275 TI - Hospital branding in Italy: A pilot study based on the case method. AB - The article investigates if, and in affirmative case how, Italian hospitals are managing corporate brand communication. Thanks to results of qualitative research, this article offers insights on Italian hospital branding. The pilot study based in the case method is to be considered a starting point for wider investigations on this topic, and it is useful for managers and practitioners who want to understand the role of corporate brand in hospital communication management and to connect health care professionals with the audience in a meaningful way in those countries in which the health care system is a mix of both public and private institutions. PMID- 28350276 TI - An exploratory investigation of hospice marketing: How are palliative care providers marketing their services? AB - Hospice and palliative care is a recent, but fast growing, industry in healthcare. Demographics suggest that hospice care will only increase. The purpose of this article is to examine strategic marketing initiatives hospice organizations currently employ. Data were collected at a hospice regional conference, capturing opinions from hospice organizations located in North and South Carolina. The results show that many hospice organizations do not have a dedicated marketing staff person, have a limited marketing budget, do not fully utilize all strategic planning tools, and have yet to differentiate themselves via branding. Implications of these findings for hospice providers are discussed. PMID- 28350277 TI - An empirical examination of subjective age in older adults. AB - It has been observed that subjective age (SA) often trails chronological age, especially in older adults. In a previously published article, we argued that differences in individual's SA is a function of their level of activity on biological, mental, and social dimensions. This article empirically tests this proposition using a newly created Subjective Aging Index (SAI). The SAI is related to SA above the effect of age with differences existing across age groups and sex. The findings contribute to the literature on successful aging strategies with important implications for health care practitioners, marketers, and individuals heading towards older adult years. PMID- 28350279 TI - Erratum. PMID- 28350280 TI - No benefits of hypothermia in patients treated with hemicraniectomy for large ischemic stroke. AB - Background Space-occupying middle cerebral artery brain infarcts are associated with the development of brain edema, which may lead to cerebral herniation and death despite early hemicraniectomy. Aims To evaluate the benefit of therapeutic hypothermia in patients with space-occupying cerebral infarction treated with hemicraniectomy within 48 h of stroke onset. Methods Patients aged 18-60 years with space-occupying cerebral infarction treated with hemicraniectomy within 48 h and hypothermia (33-34 degrees C) were selected from a single university hospital between 2001 and 2010 (n = 53). Patients treated with hemicraniectomy alone served as comparison group (n = 58), originating from three randomized controlled trials evaluating the effects of early decompressive surgery (DECIMAL, DESTINY, HAMLET). Primary outcome was the score on the modified Rankin scale at 12 months dichotomized between modified Rankin scale 0-3 and modified Rankin scale 4-6. Secondary outcome measures were modified Rankin scale score 0-4 and survival. Risk ratios were adjusted with Poisson regression. Results Mean patient age was 48 years. Median time from stroke onset to hemicraniectomy was 23.5 h in both treatment groups. Treatment with hypothermia had no effect on the primary outcome (modified Rankin scale 0-3 versus 4-6 (13/53 (25%) versus 24/58 (41%)); adjusted risk ratio 0.66, 95% confidence interval 0.38-1.13). Fewer patients treated with hypothermia had a modified Rankin scale score of 0-4 (21/53 (40%) versus 42/58 (72%); adjusted risk ratio 0.53, 95% confidence interval 0.37-0.76) and fewer patients survived (26/53 (49%) versus 46/58 (79%); adjusted risk ratio 0.60, 95% confidence interval 0.44-0.82). Conclusions In patients with space-occupying cerebral infarction, treatment with hypothermia had no additional benefit on functional outcome compared with treatment with hemicraniectomy alone. PMID- 28350278 TI - Stroke doctors: Who are we? A World Stroke Organization survey. AB - Background Specialist training provides skilled workforce for service delivery. Stroke medicine has evolved rapidly in the past years. No prior information exists on background or training of stroke doctors globally. Aims To describe the specialties that represent stroke doctors, their training requirements, and the scientific organizations ensuring continuous medical education. Methods The World Stroke Organization conducted an expert survey between June and November 2014 using e-mailed questionnaires. All Organization for Economic Co-operation and Development countries with >1 million population and other countries with >50 million population were included ( n = 49, total 5.6 billion inhabitants, 85% of global strokes). Two stroke experts from each selected country were surveyed, discrepancies resolved, and further information on identified stroke-specific curricula sought. Results We received responses from 48 (98%) countries. Of ischemic stroke patients, 64% were reportedly treated by neurologists, ranging from 5% in Ireland to 95% in the Netherlands. Per thousand annual strokes there were average six neurologists, ranging from 0.3 in Ethiopia to 33 in Israel. Of intracerebral hemorrhage patients, 29% were reportedly treated by neurosurgeons, ranging from 5% in Sweden to 79% in Japan, with three neurosurgeons per thousand strokes, ranging from 0.1 in Ethiopia to 24 in South Korea. Most countries had a stroke society (86%) while only 10 (21%) had a degree or subspecialty for stroke medicine. Conclusions Stroke doctor numbers, background specialties, and opportunities to specialize in stroke vary across the globe. Most countries have a scientific society to pursue advancement of stroke medicine, but few have stroke curricula. PMID- 28350281 TI - A systematic review of satisfaction with teledermatology. AB - Background The two most commonly used modalities of teledermatology (TD) are store-and-forward (SF) and live-interactive (LI) TD. Existing studies have not compared these tools with respect to patient and provider satisfaction. Objective To systematically review all published studies of patient and provider satisfaction with SF and LI TD. Methods PubMed, EMBASE, and Cochrane databases were systematically searched for studies on provider or patient satisfaction with SF or LI TD between January 2000 and June 2016. Results Forty eligible studies were identified: 32 with SF TD, 10 with LI TD, and 2 evaluating both. With SF TD, 96% of studies assessing patient satisfaction and 82% of studies assessing provider satisfaction demonstrated satisfaction ( n = 24 and 17, respectively). With LI TD, 89% of studies assessing patient satisfaction and all studies assessing provider satisfaction revealed satisfaction (n = 9 and 6, respectively). Conclusion Patients and providers are satisfied with both SF and LI TD. Studies assessing satisfaction with LI have not been conducted in recent years, and have only been conducted in limited geographic patient populations. Further research assessing satisfaction with TD will help address any dissatisfaction with its uses and allow for increased support and funding of future programmes. PMID- 28350283 TI - Testing fine motor coordination via telehealth: Effects of video characteristics on reliability and validity. AB - Background There is limited research about the effects of video quality on the accuracy of assessments of physical function. Methods A repeated measures study design was used to assess reliability and validity of the finger-nose test (FNT) and the finger-tapping test (FTT) carried out with 50 veterans who had impairment in gross and/or fine motor coordination. Videos were scored by expert raters under eight differing conditions, including in-person, high definition video with slow motion review and standard speed videos with varying bit rates and frame rates. Results FTT inter-rater reliability was excellent with slow motion video (ICC 0.98-0.99) and good (ICC 0.59) under the normal speed conditions. Inter rater reliability for FNT 'attempts' was excellent (ICC 0.97-0.99) for all viewing conditions; for FNT 'misses' it was good to excellent (ICC 0.89) with slow motion review but substantially worse (ICC 0.44) on the normal speed videos. FTT criterion validity (i.e. compared to slow motion review) was excellent (beta = 0.94) for the in-person rater and good ( beta = 0.77) on normal speed videos. Criterion validity for FNT 'attempts' was excellent under all conditions ( r >= 0.97) and for FNT 'misses' it was good to excellent under all conditions ( beta = 0.61-0.81). Conclusions In general, the inter-rater reliability and validity of the FNT and FTT assessed via video technology is similar to standard clinical practices, but is enhanced with slow motion review and/or higher bit rate. PMID- 28350282 TI - An m-Health system for education and motivation in cardiac rehabilitation: the experience of HeartCycle guided exercise. AB - Introduction Home-based programmes for cardiac rehabilitation play a key role in the recovery of patients with coronary artery disease. However, their necessary educational and motivational components have been rarely implemented with the help of modern mobile technologies. We developed a mobile health system designed for motivating patients to adhere to their rehabilitation programme by providing exercise monitoring, guidance, motivational feedback, and educational content. Methods Our multi-disciplinary approach is based on mapping "desired behaviours" into specific system's specifications, borrowing concepts from Fogg's Persuasive Systems Design principles. A randomised controlled trial was conducted to compare mobile-based rehabilitation (55 patients) versus standard care (63 patients). Results Some technical issues related to connectivity, usability and exercise sessions interrupted by safety algorithms affected the trial. For those who completed the rehabilitation (19 of 55), results show high levels of both user acceptance and perceived usefulness. Adherence in terms of started exercise sessions was high, but not in terms of total time of performed exercise or drop outs. Educational level about heart-related health improved more in the intervention group than the control. Exercise habits at 6 months follow-up also improved, although without statistical significance. Discussion Results indicate that the adopted design methodology is promising for creating applications that help improve education and foster better exercise habits, but further studies would be needed to confirm these indications. PMID- 28350284 TI - Molecular Characterization of the Kamese Virus, an Unassigned Rhabdovirus, Isolated from Culex pruina in the Central African Republic. AB - Rhabdoviridae is one of the most diversified families of RNA viruses whose members infect a wide range of plants, animals, and arthropods. The members of this family are classified into 13 genera and >150 unassigned viruses. Here, we sequenced the complete genome of a rhabdovirus belonging to the Hart Park serogroup, the Kamese virus (KAMV), isolated in 1977 from Culex pruina in the Central African Republic. The genomic sequence showed an organization typical of rhabdoviruses with additional genes in the P-M and G-L intergenic regions, as already reported for the Hart Park serogroup. Our Kamese strain (ArB9074) had 98% and 78.8% nucleotide sequence similarity with the prototypes of the KAMV and Mossuril virus isolated in Uganda and Mozambique in two different Culex species, respectively. Moreover, the protein sequences had 98-100% amino acid similarity with the prototype of the KAMV, except for an additional gene (U3) that showed a divergence of 6%. These molecular data show that our strain of the KAMV is genetically close to the Culex annuliorus strain that was circulating in Uganda in 1967. However, this study suggests the need to improve our knowledge of the KAMV to better understand its behavior, its life cycle, and its potential reservoirs. PMID- 28350286 TI - Head and Trunk Control While Walking in Older Adults with Diabetes: Effects of Balance Confidence. AB - Investigations of gait in older adults with diabetes mellitus (DM) have been primarily focused on lower limb biomechanical parameters. Yet, the upper body accounts for two thirds of the body's mass, and head and trunk control are critical for balance. The authors examined head and trunk control during self selected comfortable, fast, and dual-task walking and the relationship between balance confidence and potential head-trunk stiffening strategies in older adults with DM without diagnosed diabetic peripheral neuropathy (DPN). Twelve older adults with DM without diagnosed DPN (DM group) and 12 without DM (no-DM group) were recruited. Walking speed, peak-to-peak head and trunk roll displacement, head and trunk roll velocity, and head-trunk correlation were measured while walking at a self-selected comfortable or fastest possible speed with or without a secondary cognitive task. The Activities-specific Balance Confidence scale measured balance confidence. Subtle group differences in axial segmental control (lower trunk roll velocity; higher head-trunk correlation) were apparent in older adults with DM even in the absence of DPN. Balance confidence was 19% lower in the DM group than in the no-DM group, and partially explained (34%) the group difference in head-trunk stiffening. These results emphasize the need for proactive monitoring of postural control and balance confidence before the onset of DPN. PMID- 28350285 TI - 2-18F-fluoro-2-deoxyglucose positron emission tomography in delirium. AB - Delirium is a common, serious, yet poorly understood syndrome. Growing evidence suggests cerebral metabolism is fundamentally disturbed; however, it has not been investigated using 2-18F-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) in delirium. This prospective study thus explored FDG PET patterns of cerebral glucose metabolism in older inpatients with delirium. A particular emphasis was on the posterior cingulate cortex (PCC), a key region for attention, which is a central feature of delirium. Delirium scans were compared with post delirium scans using visual analysis and semi-quantitative analysis with NeuroQ; 13 participants (8 female, median 84 y) were scanned during delirium, and 6 scanned again after resolution. On visual analysis, cortical hypometabolism was evident in all participants during delirium (13/13), and improved with delirium resolution (6/6). Using NeuroQ, glucose metabolism was higher post-delirium in the whole brain and bilateral PCC compared to during delirium ( p < 0.05). Greater metabolism in both PCCs correlated with better performance on a neuropsychological test of attention, the WAIS-IV Digit Span Test forwards, and with shorter delirium duration. This research found widespread, reversible cortical hypometabolism during delirium and PCC hypometabolism was associated with inattention during delirium. PMID- 28350287 TI - A Previously Unknown Path to Corpuscularism in the Seventeenth Century: Santorio's Marginalia to the Commentaria in Primam Fen Primi Libri Canonis Avicennae (1625). AB - This paper presents some of Santorio's marginalia to his Commentaria in primam fen primi libri Canonis Avicennae (Venice, 1625), which I identified in the Sloane Collection of the British Library in 2016, as well as the evidence for their authorship. The name of the Venetian physician Santorio Santori (1561-1636) is linked with the introduction of quantification in medicine and with the invention of precision instruments that, displayed for the first time in this work, laid down the foundations for what we today understand as evidence-based medicine. But Santorio's monumentale opus also contains evidence of many quantified experiments and displays his ideas on mixtures, structure of matter and corpuscles, which are in many cases clarified and completed by the new marginalia. These ideas testify to an early interest in chemistry within the Medical School of Padua which predates both Galileo and Sennert and which has hitherto been unknown. PMID- 28350288 TI - Prevalence and Treatment of Neuropathic Pain in Kidney and Liver Transplant Recipients. AB - OBJECTIVES: Neurologic complications are common after kidney and liver transplant. Neurologic complications affect mortality and morbidity in transplant recipients, and neuropathic pain is an important symptom affecting a patient's quality of life. The aim of the present study was to provide readers with our experience regarding causes and treatment of neuropathic pain in patients undergoing kidney and liver transplant at our transplantation center. MATERIALS AND METHODS: The medical data of 553 kidney transplant recipients and 258 liver transplant recipients who received transplant procedures at the Baskent University Transplantation Center between 2008 and May 2016 were retrospectively reviewed. Fifty-one patients who were examined by an expert neurologist and diagnosed with neuropathic pain on the basis of clinical, neurologic examination, and laboratory findings were included for analyses. RESULTS: Among 811 transplant recipients, 51 patients (6.2%) were diagnosed with neuropathic pain. Of these, 22 were female and 38 were male patients, and 42 were kidney transplant recipients and 9 were liver transplant recipients. Causes of neuropathic pain included uremia, diabetes mellitus, ischemic peripheral arterial disease, inflammatory neuropathy, vasculitis, discopathy, postherpetic neuralgia, carpal tunnel syndrome, and multiple myeloma. Patients with symptoms too mild to affect daily life activities were treated conservatively. Plasmapheresis, gabapentin, pregabalin, alpha-lipoic acid, and duloxetine were administered as treatment modalities and medications. CONCLUSIONS: Neuropathic pain was lower in our transplant recipients than in the general population. Treatment medications were effective for transplant recipients at lower doses for the management of neuropathic pain impairing quality of life than doses for the general population. PMID- 28350290 TI - HLA Genotypes in Turkish Hematopoietic Cell Recipients and Likelihood of Finding a Matched Donor Through Family Searches. AB - OBJECTIVES: Allogeneic hematopoietic stem cell transplant is a life-saving treatment, but donor numbers in Turkey do not meet the increasing demand for this procedure. Here, our objectives were (1) to assess the frequency of HLA-matched related donors in the Turkish population and (2) to identify the HLA antigens and haplotypes that are most frequent in Turkey. MATERIALS AND METHODS: The HLA genotypes of 841 consecutive recipients and 3071 family members were retrospectively reviewed. RESULTS: Matched related donors were identified for 368/841 recipients (44%). Extended family donor searches were performed for 111/181 pediatric recipients (61%), with nonsibling matched related donors found for 23 patients (21%). Matched related donors were found for a significantly higher proportion of pediatric patients (52%) than adult patients (41%) (odds ratio of 2.5; 95% confidence interval, 1.9-4.1; P = .02). The percentage of pediatric versus adult patients with 3 or more siblings was 13% versus 46% (odds ratio of 5.6; 95% confidence interval, 3.6-8.5; P = .001). The most frequent HLA class I antigens at each locus were HLA-A*02 (20.2%), HLA-B*35 (19.5%), and HLA C*07 (19.8%). The most frequent HLA class II antigens at each locus were HLA DRB1*11 (21.6%) and HLA-DQB1*03 (40.2%). The most common 3-locus haplotypes were HLA-A*24 B*35 DRB1*11 (F:0.020) and HLA-A*01 B*08 DRB1*03 (F:0.015). When adult and pediatric groups were combined, the most common locus haplotypes were found in 43/345 sibling donors (12%) and in 7/23 nonsibling pediatric donors (30%) (odds ratio of 2.7; 95% confidence interval, 1.2-6.4; P = .02). CONCLUSIONS: The results indicate that, in Turkey, it can be beneficial to revise donor search algorithms to include an extended family donor search before an unrelated donor search. This type of search can be effective because of the HLA haplotype diversity in Turkey, the frequency of consanguinity, and the country's limited donor pool. PMID- 28350289 TI - Rectal Carcinoid Tumor With Liver Metastases Treated by Local Excision and Orthotopic Liver Transplant With Long-term Follow-up. AB - In patients affected by unresectable liver metastases from neuroendocrine tumor, liver transplant represents currently the only realistic chance for cure. The first attempt to establish selection criteria for liver transplant in patients affected by neuroendocrine tumor liver metastases was made by Mazzaferro and associates in 2007. We report the case of a 46-year-old man who came to our institution in 2006 with right upper quadrant abdominal pain. Diagnosis of rectal neuroendocrine tumor with bilobar liver nodules was made; the patient underwent transanal local resection. A liver biopsy confirmed the metastatic nature of the hepatic lesion, showing a low-grade neuroendocrine tumor (G1, proliferation index Ki-67 <2%). The patient underwent 2 sessions of transarterial chemoembolization that resulted in stable disease. Afterward, the patient underwent a liver transplant, using the piggyback technique without a venous-venous bypass. His postoperative course was uneventful. The patient has been disease-free for 3 years. Posttransplant treatment has played a key role in increasing the overall survival of the patient and assuring him a good quality of life. He died 9 years (102 mo) after liver transplant. PMID- 28350291 TI - A Rare Clinical Entity: Staphylococcus-Related Glomerulonephritis. AB - Staphylococcus aureus is a rare cause of postinfectious glomerulonephritis, and Staphylococcus-related glomerulonephritis primarily occurs in middle-aged or elderly patients. Patients with Staphylococcus-related glomerulonephritis also present with hematuria, proteinuria of varying degrees, rising serum creatinine levels, and/or edema. The severity of renal insufficiency is proportional to the degree of proliferation and crescent formation. Here, we present a diabetic patient admitted with a history of 1 week of left elbow pain. Laboratory results revealed that erythrocyte sedimentation rate was 110 mm/hour, serum creatinine level was 1 mg/dL, C-reactive protein level was 150 mg/L, and magnetic resonance imaging showed signal changes in favor of osteomyelitis at the olecranon level, with diffuse edematous appearance in the elbow skin tissue and increased intra articular effusion. After diagnosis of osteomyelitis, ampicillin/sulbactam and teicoplanin were administered. After day 7 of admission, the patient developed acute kidney injury requiring hemodialysis under antibiotic treatment. Kidney biopsy was performed to determine the underlying cause, which showed Staphylococcus-related glomerulonephritis. Recovery of renal functions was observed after antibiotic and supportive treatment. PMID- 28350292 TI - Rescue Arterial Revascularization Using Cryopreserved Iliac Artery Allograft in Liver Transplant Patients. AB - OBJECTIVES: Management of hepatic arterial complications after liver transplant remains challenging. The aim of our study was to assess the efficacy of rescue arterial revascularization using cryopreserved iliac artery allografts in this setting. MATERIALS AND METHODS: Medical records of patients with liver transplants who underwent rescue arterial revascularization using cryopreserved iliac artery allografts at a single institution were reviewed. RESULTS: From 1992 to 2015, 7 patients underwent rescue arterial revascularization using cryopreserved iliac artery allografts for hepatic artery pseudoaneurysm (3 patients), thrombosis (2 patients), aneurysm (1 patient), or stenosis (1 patient). Two patients developed severe complications, comprising one biliary leakage treated percutaneously, and one acute necrotizing pancreatitis causing death on postoperative day 29. After a median follow-up of 75 months (range, 1 269 mo), 2 patients had an uneventful long-term course, whereas 4 patients developed graft thrombosis after a median period of 120 days (range, 2-488 d). Among the 4 patients who developed graft thrombosis, 1 patient developed ischemic cholangitis, 1 developed acute ischemic hepatic necrosis and was retransplanted, and 2 patients did not develop any further complications. CONCLUSIONS: Despite a high rate of allograft thrombosis, rescue arterial revascularization using cryopreserved iliac artery allografts after liver transplant is an effective and readily available approach, with a limited risk of infection and satisfactory long-term graft and patient survival. PMID- 28350293 TI - Transcranial electric stimulation seen from within the brain. AB - Computer models can make transcranial electric stimulation a better tool for research and therapy. PMID- 28350294 TI - Mechanotransduction current is essential for stability of the transducing stereocilia in mammalian auditory hair cells. AB - Mechanotransducer channels at the tips of sensory stereocilia of inner ear hair cells are gated by the tension of 'tip links' interconnecting stereocilia. To ensure maximal sensitivity, tip links are tensioned at rest, resulting in a continuous influx of Ca2+ into the cell. Here, we show that this constitutive Ca2+ influx, usually considered as potentially deleterious for hair cells, is in fact essential for stereocilia stability. In the auditory hair cells of young postnatal mice and rats, a reduction in mechanotransducer current, via pharmacological channel blockers or disruption of tip links, leads to stereocilia shape changes and shortening. These effects occur only in stereocilia that harbor mechanotransducer channels, recover upon blocker washout or tip link regeneration and can be replicated by manipulations of extracellular Ca2+ or intracellular Ca2+ buffering. Thus, our data provide the first experimental evidence for the dynamic control of stereocilia morphology by the mechanotransduction current. PMID- 28350296 TI - A developmental insurance policy. AB - Why does a totipotent state linger within the inner cell mass of mouse embryos? PMID- 28350295 TI - Lotka-Volterra pairwise modeling fails to capture diverse pairwise microbial interactions. AB - Pairwise models are commonly used to describe many-species communities. In these models, an individual receives additive fitness effects from pairwise interactions with each species in the community ('additivity assumption'). All pairwise interactions are typically represented by a single equation where parameters reflect signs and strengths of fitness effects ('universality assumption'). Here, we show that a single equation fails to qualitatively capture diverse pairwise microbial interactions. We build mechanistic reference models for two microbial species engaging in commonly-found chemical-mediated interactions, and attempt to derive pairwise models. Different equations are appropriate depending on whether a mediator is consumable or reusable, whether an interaction is mediated by one or more mediators, and sometimes even on quantitative details of the community (e.g. relative fitness of the two species, initial conditions). Our results, combined with potential violation of the additivity assumption in many-species communities, suggest that pairwise modeling will often fail to predict microbial dynamics. PMID- 28350297 TI - A mutant with bilateral whisker to barrel inputs unveils somatosensory mapping rules in the cerebral cortex. AB - In mammals, tactile information is mapped topographically onto the contralateral side of the brain in the primary somatosensory cortex (S1). In this study, we describe Robo3 mouse mutants in which a sizeable fraction of the trigemino thalamic inputs project ipsilaterally rather than contralaterally. The resulting mixture of crossed and uncrossed sensory inputs creates bilateral whisker maps in the thalamus and cortex. Surprisingly, these maps are segregated resulting in duplication of whisker representations and doubling of the number of barrels without changes in the size of S1. Sensory deprivation shows competitive interactions between the ipsi/contralateral whisker maps. This study reveals that the somatosensory system can form a somatotopic map to integrate bilateral sensory inputs, but organizes the maps in a different way from that in the visual or auditory systems. Therefore, while molecular pre-patterning constrains their orientation and position, preservation of the continuity of inputs defines the layout of the somatosensory maps. PMID- 28350300 TI - Impact of CCR5, integrase and protease inhibitors on human endothelial cell function, stress, inflammation and senescence. AB - BACKGROUND: Ageing HIV-infected patients present an increased incidence of cardiovascular diseases, endothelial dysfunction being an early alteration. Some protease inhibitors (PIs) have been shown to increase the risk of cardiovascular disease. We evaluated here the effects of CCR5 or integrase inhibitors as compared to PIs on endothelial functions in vitro. METHODS: Human coronary artery endothelial cells (HCAEC) from adult and old non-HIV-infected donors were treated for 15 days with the CCR5 inhibitor maraviroc, the integrase inhibitors dolutegravir or raltegravir or the ritonavir-boosted PIs, darunavir (DRV/r) or atazanavir (ATV/r), all at Cmax concentrations. We evaluated endothelial function, secretion of adhesion molecules and cytokines, inflammation, oxidative stress and senescence. RESULTS: In endothelial cells from adult donors, we confirmed that ATV/r and DRV/r adversely affected all assessed endothelial functions and enhanced senescence, these effects being mild for DRV/r. Raltegravir had no effect and maraviroc a mild anti-inflammatory effect. Dolutegravir decreased inflammation, by inhibiting the NFkappaB pathway, and senescence, by repressing the p21 pathway. Moreover, HCAEC from an old donor presented, constitutively, a high level of senescence. Raltegravir mildly affected inflammation and senescence while maraviroc and dolutegravir decreased oxidative stress, inflammation and senescence and improved endothelial dysfunction. CONCLUSIONS: We report here that the integrase inhibitor dolutegravir and the CCR5 inhibitor maraviroc reduced inflammation of human adult endothelial cells to different extents while raltegravir was neutral. Dolutegravir also reduced senescence, while PI/r increased inflammation and senescence. It is important to address the clinical relevance of these results. PMID- 28350298 TI - Oncogenic BRAF disrupts thyroid morphogenesis and function via twist expression. AB - Thyroid cancer is common, yet the sequence of alterations that promote tumor formation are incompletely understood. Here, we describe a novel model of thyroid carcinoma in zebrafish that reveals temporal changes due to BRAFV600E. Through the use of real-time in vivo imaging, we observe disruption in thyroid follicle structure that occurs early in thyroid development. Combinatorial treatment using BRAF and MEK inhibitors reversed the developmental effects induced by BRAFV600E. Adult zebrafish expressing BRAFV600E in thyrocytes developed invasive carcinoma. We identified a gene expression signature from zebrafish thyroid cancer that is predictive of disease-free survival in patients with papillary thyroid cancer. Gene expression studies nominated TWIST2 as a key effector downstream of BRAF. Using CRISPR/Cas9 to genetically inactivate a TWIST2 orthologue, we suppressed the effects of BRAFV600E and restored thyroid morphology and hormone synthesis. These data suggest that expression of TWIST2 plays a role in an early step of BRAFV600E-mediated transformation. PMID- 28350301 TI - Sub-cellular mRNA localization modulates the regulation of gene expression by small RNAs in bacteria. AB - Small non-coding RNAs can exert significant regulatory activity on gene expression in bacteria. In recent years, substantial progress has been made in understanding bacterial gene expression by sRNAs. However, recent findings that demonstrate that families of mRNAs show non-trivial sub-cellular distributions raise the question of how localization may affect the regulatory activity of sRNAs. Here we address this question within a simple mathematical model. We show that the non-uniform spatial distributions of mRNA can alter the threshold-linear response that characterizes sRNAs that act stoichiometrically, and modulate the hierarchy among targets co-regulated by the same sRNA. We also identify conditions where the sub-cellular organization of cofactors in the sRNA pathway can induce spatial heterogeneity on sRNA targets. Our results suggest that under certain conditions, interpretation and modeling of natural and synthetic gene regulatory circuits need to take into account the spatial organization of the transcripts of participating genes. PMID- 28350299 TI - Dual role for Jumu in the control of hematopoietic progenitors in the Drosophila lymph gland. AB - The Drosophila lymph gland is a hematopoietic organ in which the maintenance of hematopoietic progenitor cell fate relies on intrinsic factors and extensive interaction with cells within a microenvironment. The posterior signaling center (PSC) is required for maintaining the balance between progenitors and their differentiation into mature hemocytes. Moreover, some factors from the progenitors cell-autonomously control blood cell differentiation. Here, we show that Jumeau (Jumu), a member of the forkhead (Fkh) transcription factor family, controls hemocyte differentiation of lymph gland through multiple regulatory mechanisms. Jumu maintains the proper differentiation of prohemocytes by cell autonomously regulating the expression of Col in medullary zone and by non-cell autonomously preventing the generation of expanded PSC cells. Jumu can also cell autonomously control the proliferation of PSC cells through positive regulation of dMyc expression. We also show that a deficiency of jumu throughout the lymph gland can induce the differentiation of lamellocytes via activating Toll signaling. PMID- 28350302 TI - Data-Driven Program Planning, Personalized Approaches to Continuing Professional Development, and Expanding Use of Digital and Social Technologies. PMID- 28350303 TI - Applying Advanced Analytical Approaches to Characterize the Impact of Specific Clinical Gaps and Profiles on the Management of Rheumatoid Arthritis. AB - INTRODUCTION: The goal of this study was to add a predictive modeling approach to the meta-analysis of continuing medical education curricula to determine whether this technique can be used to better understand clinical decision making. Using the education of rheumatologists on rheumatoid arthritis management as a model, this study demonstrates how the combined methodology has the ability to not only characterize learning gaps but also identify those proficiency areas that have the greatest impact on clinical behavior. METHODS: The meta-analysis included seven curricula with 25 activities. Learners who identified as rheumatologists were evaluated across multiple learning domains, using a uniform methodology to characterize learning gains and gaps. A performance composite variable (called the treatment individualization and optimization score) was then established as a target upon which predictive analytics were conducted. RESULTS: Significant predictors of the target included items related to the knowledge of rheumatologists and confidence concerning 1) treatment guidelines and 2) tests that measure disease activity. In addition, a striking demographic predictor related to geographic practice setting was also identified. DISCUSSION: The results demonstrate the power of advanced analytics to identify key predictors that influence clinical behaviors. Furthermore, the ability to provide an expected magnitude of change if these predictors are addressed has the potential to substantially refine educational priorities to those drivers that, if targeted, will most effectively overcome clinical barriers and lead to the greatest success in achieving treatment goals. PMID- 28350304 TI - Transfer of Mindfulness Training to the Work Setting: A Qualitative Study in a Health Care System. AB - INTRODUCTION: Mindfulness training is now commonly offered as professional development for health care practitioners. Understanding how health care practitioners adopt mindfulness practices is limited, which poses a hurdle to the development of effective mindfulness training programs. To explore how health professionals use and perceive mindfulness practices at work, we conducted an exploratory qualitative study at a large multicomponent inner-city health system. METHODS: All participants were self-selected health professionals who attended at least one mindfulness training. Training content was derived from the Tergar Meditation Community's nonsectarian Joy of Living program and focused on calming the mind using a flexible and broadly applicable approach. Transcribed interview data were examined using thematic analysis. RESULTS: Individuals receiving mindfulness training varied substantially in their subsequent adoption and utilization of these practices. Interviewees' experiences overall suggest that the workplace presents a relatively challenging but nonetheless viable environment for being mindful. Health care workers relied on more informal practice models than on formal meditation practice routines while at work. Factors reported by some individuals to inhibit effective mindfulness practice supported mindfulness for others, and overall displayed equivocal effects. DISCUSSION: Adoption and integration of mindfulness practices within the workplace are feasible yet vary significantly by practice type, situation, and the individual. Greater understanding of how individuals adopt workplace mindfulness training could improve future intervention research while clarifying optimal mindfulness training approaches. PMID- 28350305 TI - User-Centered Design and Printed Educational Materials: A Focus Group Study of Primary Care Physician Preferences. AB - INTRODUCTION: It is challenging for primary care physicians (PCPs) to review and apply the growing amount of clinical evidence available. Printed educational materials (PEMs), which synthesize evidence, are often ineffective at improving knowledge, possibly due to poor design and limited uptake. In this study, we collected PCP preferences for the design and content of physician-oriented PEMs and determined key attributes that may increase their usability and uptake. METHODS: We held 90-minute focus groups with PCPs in Toronto, ON, Canada. Focus groups included discussion about whether and how participants use PEMs, feedback on three examples of PEMs, and a discussion on general format and design preferences in PEMs. We analyzed focus group transcripts using a thematic analysis and summarized results in a list of user preferences. RESULTS: Four focus groups were held with 13 PCPs. We found that participants only read PEMs relevant to their patients and prefer short, concise documents, with links to sources that can provide more detailed information. Simplicity of materials was important, with many participants preferring PEMs without lengthy backgrounds or scientific explanations. Most participants wanted to see key messages highlighted to easily assess the relevance of the materials to their practice. Some participants shared physician-oriented PEMs with patients. DISCUSSION: This study shows that PCPs may prefer shorter, simpler, and more concise documents that have less scientific detail but provide references to further information sources. It is important to understand end user preferences for the design and content of these materials to enhance their uptake. PMID- 28350306 TI - Flipping the Continuing Medical Education Classroom: Validating a Measure of Attendees' Perceptions. AB - INTRODUCTION: New teaching approaches for CME are needed. In flipped classrooms, coursework is completed beforehand and applied during class time. Studies of flipped classrooms and their potential benefits in CME have not been published. We sought to develop and validate an instrument measuring flipped classroom perceptions, identify whether participation changed perceptions, and determine which flipped classroom components were perceived as most effective. METHODS: In this cross-sectional validation study, 167 participants in the Mayo Clinic's 2015 Internal Medicine Board Review course received surveys. Online modules were developed to deliver content before flipped classroom courses on acid-base disorders and electrolyte disorders. A flipped classroom perception instrument (FCPI) was developed and validated. The FCPI, with eight items structured on 5 point Likert scales, was given to participants before and after their flipped classroom experiences. RESULTS: Of the 167 participants, 111 returned surveys. Flipped classroom perceptions improved, with mean (SD) FCPI scores increasing from 3.74 (0.75) to 3.94 (0.76) (P < .001). The percentage of participants who preferred flipped classrooms increased from 38% before the course to 53% after (P = .002). Positive changes in FCPI scores were unrelated to module completion. Most participants thought knowledge was enhanced by in-class sessions and online modules equally. DISCUSSION: The FCPI, the first validated measure of participants' perceptions of a CME flipped classroom, has strong validity evidence. Participants' perceptions of and preference for the flipped classroom improved after experiencing the flipped CME classroom. These findings support the need to further explore flipped classroom models in CME. PMID- 28350307 TI - A Novel Measure of "Good" Mentoring: Testing Its Reliability and Validity in Four Academic Health Centers. AB - INTRODUCTION: Despite the well-recognized benefits of mentoring in academic medicine, there is a lack of clarity regarding what constitutes effective mentoring. We developed a tool to assess mentoring activities experienced by faculty and evaluated evidence for its validity. METHODS: The National Initiative on Gender, Culture, and Leadership in Medicine-"C-Change"-previously developed the C-Change Faculty Survey to assess the culture of academic medicine. After intensive review, we added six items representing six components of mentoring to the survey-receiving help with career and personal goals, learning skills, sponsorship, and resources. We tested the items in four academic health centers during 2013 to 2014. We estimated reliability of the new items and tested the correlation of the new items with a mentoring composite variable representing faculty mentoring experiences as positive, neutral, or inadequate and with other C-Change dimensions of culture. RESULTS: Among the 1520 responding faculty (response rate 61-63%), there was a positive association between each of the six mentoring activities and satisfaction with both the amount and quality of mentoring received. There was no difference by sex. Cronbach alpha coefficients ranged from 0.89 to 0.95 across subgroups of faculty (by sex, race, and principal roles). The mentoring responses were associated most closely with dimensions of Institutional Support (r = 0.58, P < .001), Institutional Change Efforts for Faculty Support (r = 0.52, P < .001), Values Alignment (r = 0.58, P < .001), Self efficacy (r = 0.43; P < .001), and Relationships/Inclusion/Trust (r = 0.41; P < .001). DISCUSSION: Data demonstrated that the Mentoring scale is a valid instrument to assess mentoring. Survey results could facilitate mentoring program development and evaluation. PMID- 28350308 TI - An Innovative Program to Support Internationally Educated Health Professionals and Their Instructors: Role of the Clinical Practice Facilitator. AB - INTRODUCTION: Internationally educated health professionals immigrating to other countries may experience difficulty in clinical practice, due to linguistic and cultural factors. An important element of bridging is the opportunity for internationally educated health professionals to practice in a clinical environment. To support these health professionals and their clinical instructors, a Clinical Practice Facilitator (CPF) role was created. This study aimed to examine the CPF from internationally educated health professionals and clinical instructors' perspective. METHODS: A quantitative survey was conducted with two cohorts (2013 and 2015) of internationally educated physical therapists and clinical instructors who were asked about the nature of interaction with CPFs, mentor, and education roles and the benefits and challenges of the role. RESULTS: Thirty-five internationally educated physical therapists and 37 clinical instructors participated and were satisfied with the interaction with CPFs via face-to-face or e-mail communication. There was strong agreement (>80%) that the CPF educator role was to facilitate learner's reflection on clinical practice while the mentor role (>70%) was to answer questions, provide feedback, and investigate clinical concerns and conflicts. There was insufficient time for access to CPFs and resolution of learners' learning needs. There were differences (P = 0.04) in perspective on the benefit of the CPF in assisting with cultural differences. DISCUSSION: An innovative CPF role provided support encouragement, clinical, and professional advice. There were discordant views regarding the benefits of the CPF role in addressing cultural issues, which requires further examination. PMID- 28350309 TI - Assessing Clinical Faculty Understanding of Statistical Terms Used to Measure Treatment Effects and Their Application to Teaching. AB - INTRODUCTION: Understanding of statistical terms used to measure treatment effect is important for evidence-informed medical teaching and practice. We explored knowledge of these terms among clinical faculty who instruct and mentor a continuum of medical learners to inform medical faculty learning needs. METHODS: This was a mixed methods study that used a questionnaire to measure a health professional's understanding of measures of treatment effect and a focus group to explore perspectives on learning, applying, and teaching these terms. We analyzed questionnaire data using descriptive statistics and focus group data using thematic analysis. RESULTS: We analyzed responses from clinical faculty who were physicians and completed all sections of the questionnaire (n = 137). Overall, approximately 55% were highly confident in their understanding of statistical terms; self-reported understanding was highest for number needed to treat (77%). Only 26% of respondents correctly responded to all comprehension questions; however, 80% correctly responded to at least one of these questions. There was a significant association among self-reported understanding and ability to correctly calculate terms. A focus group with clinical/medical faculty (n = 4) revealed themes of mentorship, support and resources, and beliefs about the value of statistical literacy. DISCUSSION: We found that half of clinical faculty members are highly confident in their understanding of relative and absolute terms. Despite the limitations of self-assessment data, our study provides some evidence that self-assessment can be reliable. Recognizing that faculty development is not mandatory for clinical faculty in many centers, and the notion that faculty may benefit from mentorship in critical appraisal topics, it may be appropriate to first engage and support influential clinical faculty rather than using a broad strategy to achieve universal statistical literacy. Second, senior leadership in medical education should support continuous learning by providing paid, protected time for faculty to incorporate evidence in their teaching. PMID- 28350310 TI - Exploratory Study of Rural Physicians' Self-Directed Learning Experiences in a Digital Age. AB - INTRODUCTION: The nature and characteristics of self-directed learning (SDL) by physicians has been transformed with the growth in digital, social, and mobile technologies (DSMTs). Although these technologies present opportunities for greater "just-in-time" information seeking, there are issues for ensuring effective and efficient usage to compliment one's repertoire for continuous learning. The purpose of this study was to explore the SDL experiences of rural physicians and the potential of DSMTs for supporting their continuing professional development (CPD). METHODS: Semistructured interviews were conducted with a purposive sample of rural physicians. Interview data were transcribed verbatim and analyzed using NVivo analytical software and thematic analysis. RESULTS: Fourteen (N = 14) interviews were conducted and key thematic categories that emerged included key triggers, methods of undertaking SDL, barriers, and supports. Methods and resources for undertaking SDL have evolved considerably, and rural physicians report greater usage of mobile phones, tablets, and laptop computers for updating their knowledge and skills and in responding to patient questions/problems. Mobile technologies, and some social media, can serve as "triggers" in instigating SDL and a greater usage of DSMTs, particularly at "point of care," may result in higher levels of SDL. Social media is met with some scrutiny and ambivalence, mainly because of the "credibility" of information and risks associated with digital professionalism. DISCUSSION: DSMTs are growing in popularity as a key resource to support SDL for rural physicians. Mobile technologies are enabling greater "point-of-care" learning and more efficient information seeking. Effective use of DSMTs for SDL has implications for enhancing just-in-time learning and quality of care. Increasing use of DSMTs and their new effect on SDL raises the need for reflection on conceptualizations of the SDL process. The "digital age" has implications for our CPD credit systems and the roles of CPD providers in supporting SDL using DSMTs. PMID- 28350311 TI - A Theory-Based Study of Factors Explaining General Practitioners' Intention to Use and Participation in Electronic Continuing Medical Education. AB - INTRODUCTION: Electronic modes of continuing medical education (eCME) can provide an appropriate and scalable way of updating the knowledge and skills of general practitioners (GPs). To optimize the adoption of eCME and develop efficient and cost-effective eCME programs, factors explaining GPs' intention to use eCME must first be elucidated. METHODS: Using the Theory of Planned Behavior as a framework, we developed a questionnaire and administered it to GPs in seven CME seminars in Isfahan, Iran, in 2014. Three domains of GPs' intention to use eCME were measured: attitudes, perceived behavioral control, and subjective norms. We used linear and logistic regression to identify the main predictors of intention and behavior. RESULTS: GPs who had high score in perceived behavioral control and a more positive attitude toward e-learning had a higher intention to adopt it for CME. In contrast, subjective norms (eg, social pressures to use eCME) were not a predictor. Attitude toward usefulness of eCME was the main predictor of being an actual eCME user. DISCUSSION: Perceived behavioral control and attitude constitute the main predictors of the intention to use eCME. Establishing discussions forums and strengthening organizational support for eCME through an increased awareness among clinical superiors and CME managers would be expected to increase GPs' intention to use eCME. PMID- 28350312 TI - Miller's Pyramid and Core Competency Assessment: A Study in Relationship Construct Validity. AB - INTRODUCTION: Continuous professional development relies on the link between performance and an educational process aimed at improving knowledge and skill. One of the most broadly used frameworks for assessing skills is Miller's Pyramid. This Pyramid has a series of levels of achievement beginning with knowledge (at the base) and ending with routine application in the clinical setting. METHODS: The purpose of this study was to determine the degree of convergence of two measurement methods, one based on Miller's framework, the second using the Accreditation Council for Graduate Medical Education/American Board of Medical Specialties (ACGME/ABMS) Core Competency framework. The data were gathered from the faculty of a large, Midwestern regional health care provider and hospital system. Data from 264 respondents were studied. The 360 degrees data were from raters of physicians holding supervisory roles in the organization. The scale items were taken from an instrument that has been validated for both structure and known group prediction. RESULTS: The Miller scale was purposely built for this application. The questions were designed to describe each level of the model. The Miller scale was reduced to a single dimension. This result was then regressed on the items from the 360 degrees item ratings. Results of a multivariate analysis of variance isolated a significant relationship between the Miller's Pyramid score and the competency items (P < 0.001). DISCUSSION: These findings demonstrate a relationship between measures based on Miller's framework and behavioral measures based on the ABMS/ACGME core competencies. Equally important is the finding that while they are related they are not identical. These findings have implications for continuous professional development programing design. PMID- 28350313 TI - Improving the Reach of the National Diabetes Prevention Program Within a Health Disparities Population: A Bronx New York Pilot Project Crossing Health- and Community-Based Sectors. AB - INTRODUCTION: Diabetes affects upward of 30% of South Bronx residents. The Centers for Disease Control and Prevention's National Diabetes Prevention Program (NDPP) reduces risk of progression to diabetes, yet implementation has been elusive within health disparities populations. METHODS: This community-based, collaborative project piloted the NDPP in the South Bronx and evaluated implementation challenges and enablers. The New York State training group prepared community peer lifestyle coaches recruited by a community organization. A professional society trained academic detailers from local faculty. An interview process evaluated community needs and public health officials' beliefs. A portal managed by the New York State training group collected demographic and biometric data from the community participants and facilitated online registration. Data from interviews and observations were coded systematically using a thematic analysis framework. RESULTS: We were successful at recruiting and training 14 lifestyle coaches and 7 academic detailers, as well as recruiting members of the health disparities population in the South Bronx into the program. Fifty-two individuals completed the first 6 months of the yearlong program, attending an average of 12.7 of 16 sessions. By week 16, weight loss averaged 7.4 lbs and many had doubled their minutes of physical activity. Local electronic referral and feedback systems were developed. DISCUSSION: Health professionals, their teams, public health centers, and communities can work together to prevent diabetes by enhancing the reach of the NDPP to health disparities populations. Peer education using lifestyle coaches can provide a trustworthy process for crossing the boundaries between health teams and community support groups. PMID- 28350314 TI - Integrating Quality Improvement and Continuing Professional Development at an Academic Medical Center: A Partnership Between Practice Plan, Hospital, and Medical School. AB - INTRODUCTION: While quality improvement (QI) initiatives can be a highly effective means for improving health care delivery in academic medical centers (AMCs), many health care professionals are not formally trained in basic QI methodology, engaging clinicians in QI activities can be challenging, and there is often a lack of integration and coordination among QI functions (eg, Departments of Quality and Safety, Continuing Professional Development). In our AMC, we undertook a collaborative approach to achieve better vertical and horizontal integration of our QI education efforts. This article provides a case example describing our organizational context, what was done, and with what effect and makes our example and lessons learned available to others. METHODS: We developed a new educational QI program that was jointly planned and implemented by a group comprising major QI stakeholders. This project was intended to create horizontal organizational linkages between continuing professional development, clinicians, the hospital, and QI department and produce QI activities that aligned with the strategic objectives of senior management. RESULTS: The group developed and implemented a curriculum based on Lean methodology and concepts from the Institute for Health Care Improvement Model for Improvement. Two cohorts (27 teams) completed the training and planned and implemented QI projects. All projects were aligned with organizational quality, safety, and patient experience goals. The majority of projects met their aim statements. DISCUSSION: This case description provides an example of successful horizontal integration of an AMCs' QI functions to disseminate knowledge and implement meaningful QI aligned with strategic objectives (vertical integration). PMID- 28350315 TI - Death During Simulation: A Literature Review. AB - INTRODUCTION: One of the goals of simulation is to teach subjects critical skills and knowledge applicable to live encounters, without the risk of harming actual patients. Although simulation education has surged in medical training over the last two decades, several ethically challenging educational methods have arisen. Simulated death has arisen as one of these challenging issues and currently there is no consensus regarding how to best manage this controversial topic in the simulated environment. The goal of this review is to analyze how simulated mortality has been used and discover whether or not this tool is beneficial to learners. METHODS: In May 2016, the authors performed a literature search on both Pubmed and the Cochrane database using multiple variations of keywords; they then searched bibliographies and related articles. RESULTS: There were 901 articles acquired in the initial search. The authors eliminated articles that were not relevant to the subject matter. After adding articles from bibliographies and related articles, the authors included the 43 articles cited in this article. DISCUSSION: As a result, the authors of this article believe that death, when used appropriately in simulation, can be an effective teaching tool and can be used in a responsible manner. PMID- 28350319 TI - Letter to the Editor: "Ion Channels in Brain Metastasis"-Ion Channels in Cancer Set up and Metastatic Progression. AB - The review by Klumpp, L. et al. entitled Ion Channels in Brain Metastasis [1] discusses the role of ion channels in breast cancer, lung cancer and melanoma in metastatic tropism to the brain [...]. PMID- 28350318 TI - Overexpression of Exosomal Cardioprotective miRNAs Mitigates Hypoxia-Induced H9c2 Cells Apoptosis. AB - Recent evidence suggests that hypoxia caused by acute myocardial infarction can induce cardiomyocyte apoptosis. Exosomes are signalling mediators that contribute to intercellular communication by transporting cytosolic components including miRNAs, mRNAs, and proteins. However, the systemic regulation and function of exosomal miRNAs in hypoxic cardiomyocytes are currently not well understood. Here, we used small RNA sequencing to investigate the effects of hypoxia stress on miRNAome of rat cardiomyoblast cells (H9c2) and corresponding exosomes. We identified 92 and 62 miRNAs in cells and exosomes, respectively, that were differentially expressed between hypoxia and normoxia. Hypoxia strongly modulated expression of hypoxia-associated miRNAs in H9c2 cells, and altered the miRNAome of H9c2 cells-derived exosomes. Functional enrichment analysis revealed extensive roles of differentially expressed exosomal miRNAs in the HIF-1 signalling pathway and in apoptosis-related pathways including the TNF, MAPK, and mTOR pathways. Furthermore, gain- and loss-of-function analysis demonstrated potential anti apoptotic effects of the hypoxia-induced exosomal miRNAs, including miR-21-5p, miR-378-3p, miR-152-3p, and let-7i-5p; luciferase reporter assay confirmed that Atg12 and Faslg are targets of miR-152-3p and let-7i-5p, respectively. To summarize, this study revealed that hypoxia-induced exosomes derived from H9c2 cells loaded cardioprotective miRNAs, which mitigate hypoxia-induced H9c2 cells apoptosis. PMID- 28350317 TI - Recent Advances in Nanoparticle-Mediated Delivery of Anti-Inflammatory Phytocompounds. AB - Phytocompounds have been used in medicine for decades owing to their potential in anti-inflammatory applications. However, major difficulties in achieving sustained delivery of phyto-based drugs are related to their low solubility and cell penetration, and high instability. To overcome these disadvantages, nanosized delivery technologies are currently in use for sustained and enhanced delivery of phyto-derived bioactive compounds in the pharmaceutical sector. This review focuses on the recent advances in nanocarrier-mediated drug delivery of bioactive molecules of plant origin in the field of anti-inflammatory research. In particular, special attention is paid to the relationship between structure and properties of the nanocarrier and phytodrug release behavior. PMID- 28350320 TI - Performance of Hybrid Photocatalytic-Ceramic Membrane System for the Treatment of Secondary Effluent. AB - Evaluation of an advanced wastewater treatment system that combines photocatalysis with ceramic membrane filtration for the treatment of secondary effluent was undertaken. The results showed that, after photocatalysis and ceramic membrane filtration, the removal of dissolved organic carbon and UV254 was 60% and 54%, respectively, at a concentration of 4 g/L of TiO2. Dissolved organic matter (DOM) present in the secondary effluent was characterised with a liquid chromatography-organic carbon detector (LC-OCD) technique. The results showed low removal of humics, building blocks, the other oxidation by-products and no removal of biopolymers after TiO2/UV photocatalytic treatment. This suggested that the radical non-selective oxidation mechanisms of TiO2/UV process resulted in secondary effluent in which all of the DOM fractions were present. However, the hybrid system was effective for removing biopolymers with the exception of low molecular weight (LMW) compounds acids, which accumulated from the beginning of the reaction. In addition, monitoring of the DOM fractions with LC-OCD analysis demonstrated that the reduction of the effluent aromaticity was not firmly correlated with the removal of humic substances for the combined processes. PMID- 28350321 TI - Factor VII Deficiency: Clinical Phenotype, Genotype and Therapy. AB - Factor VII deficiency is the most common among rare inherited autosomal recessive bleeding disorders, and is a chameleon disease due to the lack of a direct correlation between plasma levels of coagulation Factor VII and bleeding manifestations. Clinical phenotypes range from asymptomatic condition-even in homozygous subjects-to severe life-threatening bleedings (central nervous system, gastrointestinal bleeding). Prediction of bleeding risk is thus based on multiple parameters that challenge disease management. Spontaneous or surgical bleedings require accurate treatment schedules, and patients at high risk of severe hemorrhages may need prophylaxis from childhood onwards. The aim of the current review is to depict an updated summary of clinical phenotype, laboratory diagnosis, and treatment of inherited Factor VII deficiency. PMID- 28350322 TI - Outcome of Clinical Trials with New Extended Half-Life FVIII/IX Concentrates. AB - The development of a new generation of coagulation factors with improved pharmacokinetic profile will change the paradigm of treatment of persons with hemophilia (PWH). The standard treatment in PWH is represented by regular long term prophylaxis that, given intravenously twice or thrice weekly, is associated with a not-negligible burden on patients' quality of life. The availability of drugs with improved pharmacokinetic profile may improve prophylaxis feasibility and protection against bleeding episodes. This article summarizes the main results obtained from clinical trials with modified factor VIII (FVIII) and factor IX (FIX) molecules. Published literature on new molecules for replacement treatment in hemophilia A and B was retrieved using PubMed search, and all ongoing clinical trials have been researched via www.clinicaltrials.gov. Such new molecules are usually engineered to have a longer plasma half-life than that which has been obtained by chemical modification (i.e., conjugation with polyethylene glycol, PEG) or by creating recombinant fusion proteins. Results from phase I/III studies in previously treated adults and children are now available for the vast majority of new products, including the results of their use in a surgical setting. On the contrary, trials involving previously untreated patients are still ongoing for all and results not yet available. PMID- 28350323 TI - Extracellular Vesicles as Therapeutic Agents in Systemic Lupus Erythematosus. AB - Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease that affects multiple organs. Currently, therapeutic molecules present adverse side effects and are only effective in some SLE patient subgroups. Extracellular vesicles (EV), including exosomes, microvesicles and apoptotic bodies, are released by most cell types, carry nucleic acids, proteins and lipids and play a crucial role in cell-to-cell communication. EVs can stimulate or suppress the immune responses depending on the context. In SLE, EVs can work as autoadjuvants, enhance immune complex formation and maintaining inflammation state. Over the last years, EVs derived from mesenchymal stem cells and antigen presenting cells have emerged as cell-free therapeutic agents to treat autoimmune and inflammatory diseases. In this review, we summarize the current therapeutic applications of extracellular vesicles to regulate immune responses and to ameliorate disease activity in SLE and other autoimmune disorders. PMID- 28350324 TI - Investigation on Inter-Limb Coordination and Motion Stability, Intensity and Complexity of Trunk and Limbs during Hands-Knees Crawling in Human Adults. AB - This study aimed to investigate the inter-limb coordination pattern and the stability, intensity, and complexity of the trunk and limbs motions in human crawling under different speeds. Thirty healthy human adults finished hands-knees crawling trials on a treadmill at six different speeds (from 1 km/h to 2.5 km/h). A home-made multi-channel acquisition system consisting of five 3-axis accelerometers (ACC) and four force sensors was used for the data collection. Ipsilateral phase lag was used to represent inter-limb coordination pattern during crawling and power, harmonic ratio, and sample entropy of acceleration signals were adopted to depict the motion intensity, stability, and complexity of trunk and limbs respectively. Our results revealed some relationships between inter-limb coordination patterns and the stability and complexity of trunk movement. Trot-like crawling pattern was found to be the most stable and regular one at low speed in the view of trunk movement, and no-limb-pairing pattern showed the lowest stability and the greatest complexity at high speed. These relationships could be used to explain why subjects tended to avoid no-limb pairing pattern when speed was over 2 km/h no matter which coordination type they used at low speeds. This also provided the evidence that the central nervous system (CNS) chose a stable inter-limb coordination pattern to keep the body safe and avoid tumbling. Although considerable progress has been made in the study of four-limb locomotion, much less is known about the reasons for the variety of inter-limb coordination. The research results of the exploration on the inter limb coordination pattern choice during crawling from the standpoint of the motion stability, intensity, and complexity of trunk and limbs sheds light on the underlying motor control strategy of the human CNS and has important significance in the fields of clinical diagnosis, rehabilitation engineering, and kinematics research. PMID- 28350326 TI - Reply to the Letter to the Editor by D. D'Arcangelo et al.: "Ion Channels in Brain Metastasis"-Ion Channels in Cancer Set up and Metastatic Progression Ion Channels in Brain Metastasis. PMID- 28350325 TI - Endogenously Expressed IL-4Ralpha Promotes the Malignant Phenotype of Human Pancreatic Cancer In Vitro and In Vivo. AB - Exogenous interleukin-4 (IL-4) has been demonstrated to affect the growth of different human malignancies including pancreatic cancer cells. The aim of our study was to determine the role of endogenously expressed IL-4-receptor-alpha chain (IL-4Ralpha) in pancreatic cancer cells. IL-4Ralpha-suppression was achieved by generating Capan-1 cells stably expressing shRNA targeting IL 4Ralpha. The malignant phenotype was characterized by assessing growth properties, directional and non-directional cell movement in vitro and tumor growth in vivo. Signaling pathways were analyzed upon IL-4 and IL-13 stimulation of wildtype (WT) and control-transfected cells compared to IL-4Ralpha-knockdown cells. Silencing of IL-4Ralpha resulted in reduced anchorage-dependent cell growth (p < 0.05) and reduced anchorage-independent colony size (p < 0.001) in vitro. Moreover, cell movement and migration was inhibited. IL-4 and IL-13 stimulation of Capan-1-WT cells induced activation of similar pathways like stimulation with Insulin-like growth factor (IGF)-I. This activation was reduced after IL-4Ralpha downregulation while IGF-I signaling seemed to be enhanced in knockdown-clones. Importantly, IL-4Ralpha silencing also significantly suppressed tumor growth in vivo. The present study indicates that endogenously expressed IL 4 and IL-4Ralpha contribute to the malignant phenotype of pancreatic cancer cells by activating diverse pro-oncogenic signaling pathways. Addressing these pathways may contribute to the treatment of the disease. PMID- 28350327 TI - The Envelope Gene of Hepatitis B Virus Is Implicated in Both Differential Virion Secretion and Genome Replication Capacities between Genotype B and Genotype C Isolates. AB - Chronic infection by hepatitis B virus (HBV) genotype C is associated with a prolonged replicative phase and an increased risk of liver cancer, compared with genotype B infection. We previously found lower replication capacity but more efficient virion secretion by genotype C than genotype B isolates. Virion secretion requires interaction between core particles and ENVELOPE proteins. In the present study, chimeric constructs between genotype B and genotype C clones were generated to identify the structural basis for differential virion secretion. In addition to dimeric constructs, we also employed 1.1mer constructs, where the cytomegalovirus (CMV) promoter drove pregenomic RNA transcription. Through transient transfection experiments in Huh7 cells, we found that exchanging the entire envelope gene or just its S region could enhance virion secretion by genotype B clones while diminishing virion secretion by genotype C. Site-directed mutagenesis established the contribution of genotype-specific divergence at codons 108 and 115 in the preS1 region, as well as codon 126 in the S region, to differential virion secretion. Surprisingly, exchanging the envelope gene or just its S region, but not the core gene or 3' S region, could markedly increase intracellular replicative DNA for genotype C clones but diminish that for genotype B, although the underlying mechanism remains to be clarified. PMID- 28350328 TI - Vitamin D Decreases Serum VEGF Correlating with Clinical Improvement in Vitamin D Deficient Women with PCOS: A Randomized Placebo-Controlled Trial. AB - Vascular endothelial growth factor (VEGF) has been suggested to play a role in the pathophysiology of polycystic ovary syndrome (PCOS) and may contribute to increased risk of ovarian hyperstimulation syndrome (OHSS) in affected individuals. Vitamin D (VitD) supplementation improves multiple clinical parameters in VitD-deficient women with PCOS and decreases VEGF levels in several other pathologic conditions. Unveiling the basic mechanisms underlying the beneficial effects of vitamin D on PCOS may enhance our understanding of the pathophysiology of this syndrome. It may also suggest a new treatment for PCOS that can improve it through the same mechanism as vitamin D and can be given regardless of vitamin D levels. Therefore, we aimed to explore the effect of VitD supplementation on serum VEGF levels and assess whether changes in VEGF correlate with an improvement in characteristic clinical abnormalities of PCOS. This is a randomized placebo-controlled trial conducted between October 2013 and March 2015. Sixty-eight VitD-deficient women with PCOS were recruited. Women received either 50,000 IU of oral VitD3 or placebo once weekly for 8 weeks. There was a significant decrease in serum VEGF levels (1106.4 +/- 36.5 to 965.3 +/- 42.7 pg.mL-1; p < 0.001) in the VitD group. Previously reported findings of this trial demonstrated a significant decrease in the intermenstrual intervals, Ferriman Gallwey hirsutism score, and triglycerides following VitD supplementation. Interestingly, ?VEGF was positively correlated with ?triglycerides (R2 = 0.22; p = 0.02) following VitD supplementation. In conclusion, VitD replacement significantly decreases serum VEGF levels correlating with a decrease in triglycerides in women with PCOS. This is a novel molecular explanation for the beneficial effects of VitD treatment. It also suggests the need to investigate a potential role of VitD treatment in reducing the incidence or severity of OHSS in VitD-deficient women with PCOS. PMID- 28350331 TI - Novel Sulfamethoxazole Ureas and Oxalamide as Potential Antimycobacterial Agents. AB - Infections caused by Mycobacterium tuberculosis (Mtb.) and nontuberculous mycobacteria (NTM) are considered to be a global health problem; current therapeutic options are limited. Sulfonamides have exhibited a wide range of biological activities including those against mycobacteria. Based on the activity of 4-(3-heptylureido)-N-(5-methylisoxazol-3-yl)benzenesulfonamide against NTM, we designed a series of homologous sulfamethoxazole-based n-alkyl ureas (C1-C12), as well as several related ureas and an oxalamide. Fifteen ureas and one oxalamide were synthesized by five synthetic procedures and characterized. They were screened for their activity against Mtb. and three NTM strains (M. avium, M. kansasii). All of them share antimycobacterial properties with minimum inhibitory concentration (MIC) values starting from 2 uM. The highest activity showed 4,4' [carbonylbis(azanediyl)]bis[N-(5-methylisoxazol-3-yl)benzenesulfonamide] with MIC of 2-62.5 uM (i.e., 1.07-33.28 ug/mL). Among n-alkyl ureas, methyl group is optimal for the inhibition of both Mtb. and NTM. Generally, longer alkyls led to increased MIC values, heptyl being an exception for NTM. Some of the novel derivatives are superior to parent sulfamethoxazole. Several urea and oxalamide derivatives are promising antimycobacterial agents with low micromolar MIC values. PMID- 28350329 TI - Harnessing Solute Carrier Transporters for Precision Oncology. AB - Solute Carrier (SLC) transporters are a large superfamily of transmembrane carriers involved in the regulated transport of metabolites, nutrients, ions and drugs across cellular membranes. A subset of these solute carriers play a significant role in the cellular uptake of many cancer therapeutics, ranging from chemotherapeutics such as antimetabolites, topoisomerase inhibitors, platinum based drugs and taxanes to targeted therapies such as tyrosine kinase inhibitors. SLC transporters are co-expressed in groups and patterns across normal tissues, suggesting they may comprise a coordinated regulatory circuit serving to mediate normal tissue functions. In cancer however, there are dramatic changes in expression patterns of SLC transporters. This frequently serves to feed the increased metabolic demands of the tumor cell for amino acids, nucleotides and other metabolites, but also presents a therapeutic opportunity, as increased transporter expression may serve to increase intracellular concentrations of substrate drugs. In this review, we examine the regulation of drug transporters in cancer and how this impacts therapy response, and discuss novel approaches to targeting therapies to specific cancers via tumor-specific aberrations in transporter expression. We propose that among the oncogenic changes in SLC transporter expression there exist emergent vulnerabilities that can be exploited therapeutically, extending the application of precision medicine from tumor specific drug targets to tumor-specific determinants of drug uptake. PMID- 28350332 TI - The Mechanism of Room-Temperature Ionic-Liquid-Based Electrochemical CO2 Reduction: A Review. AB - Electrochemical CO2 conversion technology is becoming indispensable in the development of a sustainable carbon-based economy. While various types of electrocatalytic systems have been designed, those based on room-temperature ionic liquids (RTILs) have attracted considerable attention because of their high efficiencies and selectivities. Furthermore, it should be possible to develop more advanced electrocatalytic systems for commercial use because target-specific characteristics can be fine-tuned using various combinations of RTIL ions. To achieve this goal, we require a systematic understanding of the role of the RTIL components in electrocatalytic systems, however, their role has not yet been clarified by experiment or theory. Thus, the purpose of this short review is to summarize recent experimental and theoretical mechanistic studies to provide insight into and to develop guidelines for the successful development of new CO2 conversion systems. The results discussed here can be summarized as follows. Complex physical and chemical interactions between the RTIL components and the reaction intermediates, in particular at the electrode surface, are critical for determining the activity and selectivity of the electrocatalytic system, although no single factor dominates. Therefore, more fundamental research is required to understand the physical, chemical, and thermodynamic characteristics of complex RTIL-based electrocatalytic systems. PMID- 28350330 TI - It Is Imperative to Establish a Pellucid Definition of Chimeric RNA and to Clear Up a Lot of Confusion in the Relevant Research. AB - There have been tens of thousands of RNAs deposited in different databases that contain sequences of two genes and are coined chimeric RNAs, or chimeras. However, "chimeric RNA" has never been lucidly defined, partly because "gene" itself is still ill-defined and because the means of production for many RNAs is unclear. Since the number of putative chimeras is soaring, it is imperative to establish a pellucid definition for it, in order to differentiate chimeras from regular RNAs. Otherwise, not only will chimeric RNA studies be misled but also characterization of fusion genes and unannotated genes will be hindered. We propose that only those RNAs that are formed by joining two RNA transcripts together without a fusion gene as a genomic basis should be regarded as authentic chimeras, whereas those RNAs transcribed as, and cis-spliced from, single transcripts should not be deemed as chimeras. Many RNAs containing sequences of two neighboring genes may be transcribed via a readthrough mechanism, and thus are actually RNAs of unannotated genes or RNA variants of known genes, but not chimeras. In today's chimeric RNA research, there are still several key flaws, technical constraints and understudied tasks, which are also described in this perspective essay. PMID- 28350333 TI - Molecular Imprinting Applications in Forensic Science. AB - Producing molecular imprinting-based materials has received increasing attention due to recognition selectivity, stability, cast effectiveness, and ease of production in various forms for a wide range of applications. The molecular imprinting technique has a variety of applications in the areas of the food industry, environmental monitoring, and medicine for diverse purposes like sample pretreatment, sensing, and separation/purification. A versatile usage, stability and recognition capabilities also make them perfect candidates for use in forensic sciences. Forensic science is a demanding area and there is a growing interest in molecularly imprinted polymers (MIPs) in this field. In this review, recent molecular imprinting applications in the related areas of forensic sciences are discussed while considering the literature of last two decades. Not only direct forensic applications but also studies of possible forensic value were taken into account like illicit drugs, banned sport drugs, effective toxins and chemical warfare agents in a review of over 100 articles. The literature was classified according to targets, material shapes, production strategies, detection method, and instrumentation. We aimed to summarize the current applications of MIPs in forensic science and put forth a projection of their potential uses as promising alternatives for benchmark competitors. PMID- 28350336 TI - Sensor Fault and Delay Tolerant Control for Networked Control Systems Subject to External Disturbances. AB - In this paper, the problem of sensor fault and delay tolerant control problem for a class of networked control systems under external disturbances is investigated. More precisely, the dynamic characteristics of the external disturbance and sensor fault are described as the output of exogenous systems first. The original sensor fault and delay tolerant control problem is reformulated as an equivalence problem with designed available system output and reformed performance index. The feedforward and feedback sensor fault tolerant controller (FFSFTC) can be obtained by utilizing the solutions of Riccati matrix equation and Stein matrix equation. Based on the designed fault diagnoser, the proposed FFSFTC is further reconstructed to compensate for the sensor fault and delayed measurement effects. Finally, numerical examples are provided to illustrate the effectiveness of our proposed FFSFTC with different cases with various types of sensor faults, measurement delays and external disturbances. PMID- 28350334 TI - Conceptions of Contraceptive Use in Rural KwaZulu-Natal, South Africa: Lessons for Programming. AB - Community family planning programmes in South Africa arose from the controversial apartheid history of controlling the African population while encouraging the growth of European migrant population. Post-apartheid population policies shifted away from population control to aligning policies to the global agenda that placed emphasis on the link between population and development. The focus on population and development polices in post-apartheid South Africa is on social equality, justice and peace rather than controlling sections of the population. Given the shift, this paper interrogates the conceptions of contraceptive use among rural communities in KwaZulu-Natal. Our primary objective is to understand the dynamics surrounding access to and use of family planning services in peri urban and rural areas of KwaZulu-Natal. Using focus group data, the findings of the study suggest that different social categories interact with the family planning programmes differently. How teenagers and married women perceive the value of family planning differs. Gender differences regarding the use of condoms are also evident. The paper attempts to grapple with the non-use of condoms despite the knowledge that these prevent pregnancy and provide protection from sexually-transmitted diseases. The contribution of this paper lies in its identification of socio-cultural factors and the political economy underlying the different attitudes towards contraceptive use in rural KwaZulu-Natal. PMID- 28350335 TI - Synthesis and Antitumor Activity of New Group 3 Metallocene Complexes. AB - The quest for alternative drugs with respect to the well-known cis-platin and its derivatives, which are still used in more than 50% of the treatment regimens for patients suffering from cancer, is highly needed. In this context, organometallic compounds, which are defined as metal complexes containing at least one direct covalent metal-carbon bond, have recently been found to be promising anticancer drug candidates. A series of new metallocene complexes with scandium, yttrium, and neodymium have been prepared and characterized. Some of these compounds show a very interesting anti-proliferative activity in triple negative breast cancer cell line (MDA.MB231) and the non-hormone sensitive prostate cancer cell line (DU145). Moreover, the interaction of some of them with biological membranes, evaluated using liposomes as bio-membrane mimetic model systems, seems to be relevant. The biological activity of these compounds, particularly those based on yttrium, already effective at low concentrations on both cancer cell lines, should be taken into account with regard to new therapeutic approaches in anticancer therapy. PMID- 28350338 TI - Prioritizing Seafloor Mapping for Washington's Pacific Coast. AB - Remote sensing systems are critical tools used for characterizing the geological and ecological composition of the seafloor. However, creating comprehensive and detailed maps of ocean and coastal environments has been hindered by the high cost of operating ship- and aircraft-based sensors. While a number of groups (e.g., academic research, government resource management, and private sector) are engaged in or would benefit from the collection of additional seafloor mapping data, disparate priorities, dauntingly large data gaps, and insufficient funding have confounded strategic planning efforts. In this study, we addressed these challenges by implementing a quantitative, spatial process to facilitate prioritizing seafloor mapping needs in Washington State. The Washington State Prioritization Tool (WASP), a custom web-based mapping tool, was developed to solicit and analyze mapping priorities from each participating group. The process resulted in the identification of several discrete, high priority mapping hotspots. As a result, several of the areas have been or will be subsequently mapped. Furthermore, information captured during the process about the intended application of the mapping data was paramount for identifying the optimum remote sensing sensors and acquisition parameters to use during subsequent mapping surveys. PMID- 28350337 TI - 3,4-Dihydroxybenzalactone Suppresses Human Non-Small Cell Lung Carcinoma Cells Metastasis via Suppression of Epithelial to Mesenchymal Transition, ROS-Mediated PI3K/AKT/MAPK/MMP and NFkappaB Signaling Pathways. AB - 3,4-Dihydroxybenzalactone (DBL) was isolated from Phellinus linteus (PL), which is a folk medicine possessing various physiological effects. In this study, we used highly metastatic A549 cells to investigate efficacy of DBL inhibition of cancer metastasis and possible mechanisms. The results revealed DBL inhibited migratory and invasive abilities of cancer cells at noncytotoxic concentrations. We found DBL suppressed enzymatic activities, protein expression, and RNA levels of matrix metalloproteinase (MMP)-2 and MMP-9. Western blot results showed DBL decreased phosphoinositide 3-kinase (PI3K)/AKT, phosphorylation status of mitogen activated protein kinases (MAPKs), and focal adhesion kinase (FAK)/paxillin, which correlated with cell migratory ability. DBL also affected epithelial to mesenchymal transition (EMT)-related biomarkers. In addition, DBL enhanced cytoprotective effects through elevated antioxidant enzymes including heme oxygenase 1 (HO-1), catalase, glutathione peroxidase (GPx), and superoxide dismutase (SOD). Moreover, DBL influenced the nuclear translocation of nuclear factor kappaB (NFkappaB), nuclear factor erythroid 2-related factor 2 (Nrf2), Snail, and Slug in A549 cells. Taken together, these results suggested that treatment with DBL may act as a potential candidate to inhibit lung cancer metastasis by inhibiting MMP-2 and -9 via affecting PI3K/AKT, MAPKs, FAK/paxillin, EMT/Snail and Slug, Nrf2/antioxidant enzymes, and NFkappaB signaling pathways. PMID- 28350339 TI - Underdetermined DOA Estimation of Quasi-Stationary Signals Using a Partly Calibrated Array. AB - Quasi-stationary signals have been widely found in practical applications, which have time-varying second-order statistics while staying static within local time frames. In this paper, we develop a robust direction-of-arrival (DOA) estimation algorithm for quasi-stationary signals based on the Khatri-Rao (KR) subspace approach. A partly-calibrated array is considered, in which some of the sensors have an inaccurate knowledge of the gain and phase. In detail, we first develop a closed-form solution to estimate the unknown sensor gains and phases. The array is then calibrated using the estimated sensor gains and phases which enables the improved DOA estimation. To reduce the computational complexity, we also proposed a reduced-dimensional method for DOA estimation. The exploitation of the KR subspace approach enables the proposed method to achieve a larger number of degrees-of-freedom, i.e., more sources than sensors can be estimated. The unique identification condition for the proposed method is also derived. Simulation results demonstrate the effectiveness of the proposed underdetermined DOA estimation algorithm for quasi-stationary signals. PMID- 28350341 TI - New Particle Filter Based on GA for Equipment Remaining Useful Life Prediction. AB - Remaining useful life (RUL) prediction of equipment has important significance for guaranteeing production efficiency, reducing maintenance cost, and improving plant safety. This paper proposes a novel method based on an new particle filter (PF) for predicting equipment RUL. Genetic algorithm (GA) is employed to improve the particle leanness problem that arises in traditional PF algorithms, and a time-varying auto regressive (TVAR) model and Akaike Information Criterion (AIC) are integrated to establish the dynamic model for PF. Moreover, starting prediction time (SPT) detection method based on hypothesis testing theory is presented, by which SPT of equipment RUL can be adaptively detected. In order to verify the effectiveness of the methods proposed in this study, a simulation test and the accelerating fatigue test of a rolling element bearing are designed for RUL prediction. The test results show the methods proposed in this study can accurately predict the RUL of the rolling element bearing, and it performs better than the traditional PF algorithm and support vector machine (SVM) in the RUL prediction. PMID- 28350340 TI - Function and Clinical Implications of Long Non-Coding RNAs in Melanoma. AB - Metastatic melanoma is the most deadly type of skin cancer. Despite the success of immunotherapy and targeted agents, the majority of patients experience disease recurrence upon treatment and die due to their disease. Long non-coding RNAs (lncRNAs) are a new subclass of non-protein coding RNAs involved in (epigenetic) regulation of cell growth, invasion, and other important cellular functions. Consequently, recent research activities focused on the discovery of these lncRNAs in a broad spectrum of human diseases, especially cancer. Additional efforts have been undertaken to dissect the underlying molecular mechanisms employed by lncRNAs. In this review, we will summarize the growing evidence of deregulated lncRNA expression in melanoma, which is linked to tumor growth and progression. Moreover, we will highlight specific molecular pathways and modes of action for some well-studied lncRNAs and discuss their potential clinical implications. PMID- 28350343 TI - On Multi-Hop Decode-and-Forward Cooperative Relaying for Industrial Wireless Sensor Networks. AB - Wireless sensor networks (WSNs) will play a fundamental role in the realization of Internet of Things and Industry 4.0. Arising from the presence of spatially distributed sensor nodes in a sensor network, cooperative diversity can be achieved by using the sensor nodes between a given source-destination pair as intermediate relay stations. In this paper, we investigate the end-to-end average bit error rate (BER) and the channel capacity of a multi-hop relay network in the presence of impulsive noise modeled by the well-known Middleton's class-A model. Specifically, we consider a multi-hop decode-and-forward (DF) relay network over Nakagami-m fading channel due to its generality, but also due to the absence of reported works in this area. Closed-form analytical expressions for the end-to end average BER and the statistical properties of the end-to-end channel capacity are obtained. The impacts of the channel parameters on these performance quantities are evaluated and discussed. PMID- 28350344 TI - Improving Observability of an Inertial System by Rotary Motions of an IMU. AB - It has been identified that the inertial system is not a completely observable system in the absence of maneuvers. Although the velocity errors and the accelerometer bias in the vertical direction can be solely observable, other error states, including the attitude errors, the accelerometer biases in the east and north directions, and the gyro biases, are just jointly observable states with velocity measurements, which degrades the estimation accuracy of these error states. This paper proposes an innovative method to improve the system observability for a Micro-Electro-Mechanical-System (MEMS)-based Inertial Navigation System (INS) in the absence of maneuvers by rotary motions of the Inertial Measurement Unit (IMU). Three IMU rotation schemes, namely IMU continuous rotation about the X, Y and Z axes are employed. The observability is analyzed for the rotating system with a control-theoretic approach, and tests are also conducted based on a turntable to verify the improvements on the system observability by IMU rotations. Both theoretical analysis and the results indicate that the system observability is improved by proposed IMU rotations, the roll and pitch errors, the accelerometer biases in the east and north directions, the gyro biases become observable states in the absence of vehicle maneuvers. Although the azimuth error is still unobservable, the enhanced estimability of the gyro bias in the vertical direction can effectively mitigate the azimuth error accumulation. PMID- 28350342 TI - The Role of PI3K Isoforms in Regulating Bone Marrow Microenvironment Signaling Focusing on Acute Myeloid Leukemia and Multiple Myeloma. AB - Despite the development of novel treatments in the past 15 years, many blood cancers still remain ultimately fatal and difficult to treat, particularly acute myeloid leukaemia (AML) and multiple myeloma (MM). While significant progress has been made characterising small-scale genetic mutations and larger-scale chromosomal translocations that contribute to the development of various blood cancers, less is understood about the complex microenvironment of the bone marrow (BM), which is known to be a key player in the pathogenesis of chronic lymphocytic leukaemia (CLL), AML and MM. This niche acts as a sanctuary for the cancerous cells, protecting them from chemotherapeutics and encouraging clonal cell survival. It does this by upregulating a plethora of signalling cascades within the malignant cell, with the phosphatidylinositol-3-kinase (PI3K) pathway taking a critical role. This review will focus on how the PI3K pathway influences disease progression and the individualised role of the PI3K subunits. We will also summarise the current clinical trials for PI3K inhibitors and how these trials impact the treatment of blood cancers. PMID- 28350347 TI - Trust Model of Wireless Sensor Networks and Its Application in Data Fusion. AB - In order to ensure the reliability and credibility of the data in wireless sensor networks (WSNs), this paper proposes a trust evaluation model and data fusion mechanism based on trust. First of all, it gives the model structure. Then, the calculation rules of trust are given. In the trust evaluation model, comprehensive trust consists of three parts: behavior trust, data trust, and historical trust. Data trust can be calculated by processing the sensor data. Based on the behavior of nodes in sensing and forwarding, the behavior trust is obtained. The initial value of historical trust is set to the maximum and updated with comprehensive trust. Comprehensive trust can be obtained by weighted calculation, and then the model is used to construct the trust list and guide the process of data fusion. Using the trust model, simulation results indicate that energy consumption can be reduced by an average of 15%. The detection rate of abnormal nodes is at least 10% higher than that of the lightweight and dependable trust system (LDTS) model. Therefore, this model has good performance in ensuring the reliability and credibility of the data. Moreover, the energy consumption of transmitting was greatly reduced. PMID- 28350346 TI - Bioactive Constituents Obtained from the Seeds of Lepidium apetalum Willd. AB - Three new compounds, apetalumosides C1 (1), D (2), and 1-thio--d-glucopyranosyl(1 >1)-1-thio-alpha-d-glucopyranoside (3), together with twenty-two known ones (4 25) were obtained from the seeds of Lepidium apetalum Willd. Among the known isolates, 5-8, 10-13, 16-20, and 25 were obtained from the genus for the first time; 4, 14, 15, and 21-24 were isolated from the species for the first time. Meanwhile, the NMR data of 16 was first reported here. Their structures were determined by means of chemical and spectroscopic methods. On the other hand, their inhibitory effects on sodium oleate-induced triglyceride (TG) overloading in HepG2 cells were evaluated. As a result, two new compounds (1 and 2), together with known isolates 7-11, 13, 14, 16-18, 20, 21, and 25 possessed significant inhibitory effects in the cells. PMID- 28350345 TI - Time Trends and Patterns of Reported Egg Consumption in the U.S. by Sociodemographic Characteristics. AB - Eggs have the potential to contribute essential nutrients to nutritionally vulnerable populations on limited food budgets. Further research is needed to better understand patterns of egg consumption across diverse sociodemographic groups in order to inform clinical practice to improve nutrient adequacy. Data on demographics and egg intake of 29,694 U.S. adults were obtained from the National Health and Nutrition Examination Survey, 2001-2012. The National Cancer Institute's usual intake methodology was used to estimate the distribution of egg intake. Linear and logistic regression models were used to test for time trends in egg consumption and for differences between sociodemographic groups. The proportion of the U.S. population, overall (21%-22%; p = 0.311) and by sociodemographic group (p > 0.05 for all groups), that reported consuming eggs remained unchanged from 2001 to 2012. Mean egg consumption increased overall from 23.0 (95% CI, 20.8-25.2) g/day in 2001-2002 to 25.5 (22.7-28.4) g/day in 2011 2012 (p = 0.012), but not among food insecure individuals (p = 0.816) and Supplemental Nutrition Assistance Program (SNAP) participants (p = 0.399). No differences in the odds of egg consumption were observed by income level, food security status, or SNAP participation status (p > 0.05 for all groups). Given the nutritional benefits of eggs, as well as their low cost and culinary versatility, the results presented here have important implications for reducing disparities in health outcomes and diet quality, in particular among food insecure individuals and SNAP participants. Further research is needed to examine factors that influence egg consumption and associated nutrient intake, and to identify potential barriers to increasing egg consumption, such as egg price changes, across diverse sociodemographic groups. PMID- 28350348 TI - Variation Quality and Kinetic Parameter of Commercial n-3 PUFA-Rich Oil during Oxidation via Rancimat. AB - Different biological sources of n-3 polyunsaturated fatty acids (n-3 PUFA) in mainstream commercial products include algae and fish. Lipid oxidation in n-3 PUFA-rich oil is the most important cause of its deterioration. We investigated the kinetic parameters of n-3 PUFA-rich oil during oxidation via Rancimat (at a temperature range of 70~100 degrees C). This was done on the basis of the Arrhenius equation, which indicates that the activation energies (Ea) for oxidative stability are 82.84-96.98 KJ/mol. The chemical substrates of different oxidative levels resulting from oxidation via Rancimat at 80 degrees C were evaluated. At the initiation of oxidation, the tocopherols in the oil degraded very quickly, resulting in diminished protection against further oxidation. Then, the degradation of the fatty acids with n-3 PUFA-rich oil was evident because of decreased levels of PUFA along with increased levels of saturated fatty acids (SFA). The quality deterioration from n-3 PUFA-rich oil at the various oxidative levels was analyzed chemometrically. The anisidine value (p-AV, r: 0.92) and total oxidation value (TOTOX, r: 0.91) exhibited a good linear relationship in a principal component analysis (PCA), while oxidative change and a significant quality change to the induction period (IP) were detected through an agglomerative hierarchical cluster (AHC) analysis. PMID- 28350349 TI - Identification of Conditions for Successful Aphid Control by Ladybirds in Greenhouses. AB - As part of my research on the mass production and augmentative release of ladybirds, I reviewed the primary research literature to test the prediction that ladybirds are effective aphid predators in greenhouses. Aphid population reduction exceeded 50% in most studies and ladybird release rates usually did not correlate with aphid reduction. The ratio of aphid reduction/release rate was slightly less for larvae than adults in some studies, suggesting that larvae were less effective (than adults) in suppressing aphids. Some adult releases were inside cages, thereby limiting adult dispersion from plants. Overall, the ratio of aphid reduction/release rate was greatest for ladybird adults of the normal strain (several species combined), but least for adults of a flightless Harmonia axyridis strain. The combined action of ladybirds and hymenopteran parasitoids could have a net positive effect on aphid population suppression and, consequently, on host (crop) plants. However, ladybird encounters with aphid tending or foraging ants must be reduced. Deploying ladybirds to help manage aphids in greenhouses and similar protective structures is encouraged. PMID- 28350352 TI - Discovering the Giant Nest Architecture of Grass-Cutting Ants, Atta capiguara (Hymenoptera, Formicidae). AB - Atta capiguara is a grass-cutting ant species frequently found in Cerrado biome. However, little is known about the giant nest architecture of this ant. In this study, we investigated the architecture of three A. capiguara nests from a fragment of Cerrado in Botucatu, Sao Paulo, Brazil. Casts were made of the nests by filling them with cement to permit better visualization of internal structures such as chambers and tunnels. After excavation, the depth and dimensions (length, width, and height) of the chambers were measured. The results showed the shape of Atta capiguara nests consisting of mounds of loose soil with unique features resembling a conic section. The fungus chambers were found distant from the mound of loose soil and were spaced apart and distributed laterally at the soil profile. The waste chambers were located beneath the largest mound of loose soil. Both the fungus and waste chambers were separated and distant. Our study contributes to a better understanding of the so far unknown nest architecture of the grass-cutting ant A. capiguara. PMID- 28350351 TI - Assembly of Iron Oxide Nanocubes for Enhanced Cancer Hyperthermia and Magnetic Resonance Imaging. AB - Multiple formulations of iron oxide nanoparticles (IONPs) have been proposed for enhancing contrast in magnetic resonance imaging (MRI) and for increasing efficacy in thermal ablation therapies. However, insufficient accumulation at the disease site and low magnetic performance hamper the clinical application of IONPs. Here, 20 nm iron oxide nanocubes were assembled into larger nanoconstructs externally stabilized by a serum albumin coating. The resulting assemblies of nanocubes (ANCs) had an average diameter of 100 nm and exhibited transverse relaxivity (r2 = 678.9 +/- 29.0 mM-1.s-1 at 1.41 T) and heating efficiency (specific absorption rate of 109.8 +/- 12.8 W.g-1 at 512 kHz and 10 kA.m-1). In mice bearing glioblastoma multiforme tumors, Cy5.5-labeled ANCs allowed visualization of malignant masses via both near infrared fluorescent and magnetic resonance imaging. Also, upon systemic administration of ANCs (5 mgFe.kg-1), 30 min of daily exposure to alternating magnetic fields for three consecutive days was sufficient to halt tumor progression. This study demonstrates that intravascular administration of ANCs can effectively visualize and treat neoplastic masses. PMID- 28350350 TI - Differential Proteome Analysis of a Flor Yeast Strain under Biofilm Formation. AB - Several Saccharomyces cerevisiae strains (flor yeasts) form a biofilm (flor velum) on the surface of Sherry wines after fermentation, when glucose is depleted. This flor velum is fundamental to biological aging of these particular wines. In this study, we identify abundant proteins in the formation of the biofilm of an industrial flor yeast strain. A database search to enrich flor yeast "biological process" and "cellular component" according to Gene Ontology Terminology (GO Terms) and, "pathways" was carried out. The most abundant proteins detected were largely involved in respiration, translation, stress damage prevention and repair, amino acid metabolism (glycine, isoleucine, leucine and arginine), glycolysis/gluconeogenesis and biosynthesis of vitamin B9 (folate). These proteins were located in cellular components as in the peroxisome, mitochondria, vacuole, cell wall and extracellular region; being these two last directly related with the flor formation. Proteins like Bgl2p, Gcv3p, Hyp2p, Mdh1p, Suc2p and Ygp1p were quantified in very high levels. This study reveals some expected processes and provides new and important information for the design of conditions and genetic constructions of flor yeasts for improving the cellular survival and, thus, to optimize biological aging of Sherry wine production. PMID- 28350353 TI - Insect Artifacts Are More than Just Altered Bloodstains. AB - The bases for forensic entomology are that insects and their arthropod relatives can serve as evidence in criminal, medical and civil legal matters. However, some of the very same species that provide utility to legal investigations can also complicate crime scenes by distorting existing body fluid evidence (e.g., bloodstains, semen, saliva) and/or depositing artifacts derived from the insect alimentary canal at primary or secondary crime scenes. The insect contaminants are referred to as insect stains, artifacts, specks or spots, and are most commonly associated with human bloodstains. This review will discuss the different types of insect artifacts that have been described from crime scenes and laboratory experiments, as well as examine insect contaminates (non-blood based artifacts, transfer patterns, meconium, and larval fluids) that have received little research or case attention. Methods currently used for distinguishing insect stains from human body fluids will also be discussed and compared to presumptive tests used for identification of human body fluids. Since all available methods have severe limitations, areas of new research will be identified for the purpose of development of diagnostic techniques for detection of insect artifacts. PMID- 28350354 TI - Proteomic Profiling Comparing the Effects of Different Heat Treatments on Camel (Camelus dromedarius) Milk Whey Proteins. AB - Camel milk is consumed in the Middle East because of its high nutritional value. Traditional heating methods and the duration of heating affect the protein content and nutritional quality of the milk. We examined the denaturation of whey proteins in camel milk by assessing the effects of temperature on the whey protein profile at room temperature (RT), moderate heating at 63 degrees C, and at 98 degrees C, for 1 h. The qualitative and quantitative variations in the whey proteins before and after heat treatments were determined using quantitative 2D-difference in gel electrophoresis (DIGE)-mass spectrometry. Qualitative gel image analysis revealed a similar spot distribution between samples at RT and those heated at 63 degrees C, while the spot distribution between RT and samples heated at 98 degrees C differed. One hundred sixteen protein spots were determined to be significantly different (p < 0.05 and a fold change of >=1.2) between the non-heated and heated milk samples. Eighty protein spots were decreased in common in both the heat-treated samples and an additional 25 spots were further decreased in the 98 degrees C sample. The proteins with decreased abundance included serum albumin, lactadherin, fibrinogen beta and gamma chain, lactotransferrin, active receptor type-2A, arginase-1, glutathione peroxidase-1 and, thiopurine S, etc. Eight protein spots were increased in common to both the samples when compared to RT and included alpha-lactalbumin, a glycosylation dependent cell adhesion molecule. Whey proteins present in camel milk were less affected by heating at 63 degrees C than at 98 degrees C. This experimental study showed that denaturation increased significantly as the temperature increased from 63 to 98 degrees C. PMID- 28350355 TI - Frequency-Switchable Microfluidic CSRR-Loaded QMSIW Band-Pass Filter Using a Liquid Metal Alloy. AB - In this paper, we have proposed a frequency-switchable complementary split-ring resonator (CSRR)-loaded quarter-mode substrate-integrated-waveguide (QMSIW) band pass filter. For frequency switching, a microfluidic channel and liquid metal are used. The liquid metal used is eutectic gallium-indium (EGaIn), consisting of 24.5% indium and 75.5% gallium. The microfluidic channels are built using the elastomer polydimethylsiloxane (PDMS) and three-dimensional-printed microfluidic channel frames. The CSRR-loaded QMSIW band-pass filter is designed to have two states. Before the injection of the liquid metal, the measured center frequency and fractional bandwidths are 2.205 GHz and 6.80%, respectively. After injection, the center frequency shifts from 2.205 GHz to 2.56 GHz. Although the coupling coefficient is practically unchanged, the fractional bandwidth changes from 6.8% to 9.38%, as the CSRR shape changes and the external quality factor decreases. After the removal of the liquid metal, the measured values are similar to the values recorded before the liquid metal was injected. The repeatability of the frequency-switchable mechanism is, therefore, verified. PMID- 28350356 TI - An IoT Reader for Wireless Passive Electromagnetic Sensors. AB - In the last years, many passive electromagnetic sensors have been reported. Some of these sensors are used for measuring harmful substances. Moreover, the response of these sensors is usually obtained with laboratory equipment. This approach highly increases the total cost and complexity of the sensing system. In this work, a novel low-cost and portable Internet-of-Things (IoT) reader for passive wireless electromagnetic sensors is proposed. The reader is used to interrogate the sensors within a short-range wireless link avoiding the direct contact with the substances under test. The IoT functionalities of the reader allows remote sensing from computers and handheld devices. For that purpose, the proposed design is based on four functional layers: the radiating layer, the RF interface, the IoT mini-computer and the power unit. In this paper a demonstrator of the proposed reader is designed and manufactured. The demonstrator shows, through the remote measurement of different substances, that the proposed system can estimate the dielectric permittivity. It has been demonstrated that a linear approximation with a small error can be extracted from the reader measurements. It is remarkable that the proposed reader can be used with other type of electromagnetic sensors, which transduce the magnitude variations in the frequency domain. PMID- 28350357 TI - A Smartphone Camera-Based Indoor Positioning Algorithm of Crowded Scenarios with the Assistance of Deep CNN. AB - Considering the installation cost and coverage, the received signal strength indicator (RSSI)-based indoor positioning system is widely used across the world. However, the indoor positioning performance, due to the interference of wireless signals that are caused by the complex indoor environment that includes a crowded population, cannot achieve the demands of indoor location-based services. In this paper, we focus on increasing the signal strength estimation accuracy considering the population density, which is different to the other RSSI-based indoor positioning methods. Therefore, we propose a new wireless signal compensation model considering the population density, distance, and frequency. First of all, the number of individuals in an indoor crowded scenario can be calculated by our convolutional neural network (CNN)-based human detection approach. Then, the relationship between the population density and the signal attenuation is described in our model. Finally, we use the trilateral positioning principle to realize the pedestrian location. According to the simulation and tests in the crowded scenarios, the proposed model increases the accuracy of the signal strength estimation by 1.53 times compared to that without considering the human body. Therefore, the localization accuracy is less than 1.37 m, which indicates that our algorithm can improve the indoor positioning performance and is superior to other RSSI models. PMID- 28350358 TI - Automated Software Acceleration in Programmable Logic for an Efficient NFFT Algorithm Implementation: A Case Study. AB - Non-equispaced Fast Fourier transform (NFFT) is a very important algorithm in several technological and scientific areas such as synthetic aperture radar, computational photography, medical imaging, telecommunications, seismic analysis and so on. However, its computation complexity is high. In this paper, we describe an efficient NFFT implementation with a hardware coprocessor using an All-Programmable System-on-Chip (APSoC). This is a hybrid device that employs an Advanced RISC Machine (ARM) as Processing System with Programmable Logic for high performance digital signal processing through parallelism and pipeline techniques. The algorithm has been coded in C language with pragma directives to optimize the architecture of the system. We have used the very novel Software Develop System-on-Chip (SDSoC) evelopment tool that simplifies the interface and partitioning between hardware and software. This provides shorter development cycles and iterative improvements by exploring several architectures of the global system. The computational results shows that hardware acceleration significantly outperformed the software based implementation. PMID- 28350360 TI - Identification of Key Candidate Genes and Pathways in Colorectal Cancer by Integrated Bioinformatical Analysis. AB - Colorectal cancer (CRC) is one of the most common malignant diseases worldwide, but the involved signaling pathways and driven-genes are largely unclear. This study integrated four cohorts profile datasets to elucidate the potential key candidate genes and pathways in CRC. Expression profiles GSE28000, GSE21815, GSE44076 and GSE75970, including 319 CRC and 103 normal mucosa, were integrated and deeply analyzed. Differentially expressed genes (DEGs) were sorted and candidate genes and pathways enrichment were analyzed. DEGs-associated protein protein interaction network (PPI) was performed. Firstly, 292 shared DEGs (165 up regulated and 127 down-regulated) were identified from the four GSE datasets. Secondly, the DEGs were clustered based on functions and signaling pathways with significant enrichment analysis. Thirdly, 180 nodes/DEGs were identified from DEGs PPI network complex. Lastly, the most significant 2 modules were filtered from PPI, 31 central node genes were identified and most of the corresponding genes are involved in cell cycle process, chemokines and G protein-coupled receptor signaling pathways. Taken above, using integrated bioinformatical analysis, we have identified DEGs candidate genes and pathways in CRC, which could improve our understanding of the cause and underlying molecular events, and these candidate genes and pathways could be therapeutic targets for CRC. PMID- 28350361 TI - Thiazine-2-thiones as Masked 1-Azadienes in Cascade Dimerization Reactions). AB - We report the unexpected formation of a 1-azadiene dimer from 4,6-diphenyl-3,6 dihydro-2H-1,3-thiazine-2-thiones under prolonged microwave irradiation. In this manner, thiazine-2-thiones act as "masked" 1-azadiene equivalents, which makes them useful synthetic tools to access complex heterocyclic frameworks. We compare this dimerization with earlier approaches and elaborate on the observed diastereoselectivity. PMID- 28350359 TI - NF-kappaB Signaling in Gastric Cancer. AB - Gastric cancer is a leading cause of cancer death worldwide. Diet, obesity, smoking and chronic infections, especially with Helicobacter pylori, contribute to stomach cancer development. H. pylori possesses a variety of virulence factors including encoded factors from the cytotoxin-associated gene pathogenicity island (cagPAI) or vacuolating cytotoxin A (VacA). Most of the cagPAI-encoded products form a type 4 secretion system (T4SS), a pilus-like macromolecular transporter, which translocates CagA into the cytoplasm of the host cell. Only H. pylori strains carrying the cagPAI induce the transcription factor NF-kappaB, but CagA and VacA are dispensable for direct NF-kappaB activation. NF-kappaB-driven gene products include cytokines/chemokines, growth factors, anti-apoptotic factors, angiogenesis regulators and metalloproteinases. Many of the genes transcribed by NF-kappaB promote gastric carcinogenesis. Since it has been shown that chemotherapy-caused cellular stress could elicit activation of the survival factor NF-kappaB, which leads to acquisition of chemoresistance, the NF-kappaB system is recommended for therapeutic targeting. Research is motivated for further search of predisposing conditions, diagnostic markers and efficient drugs to improve significantly the overall survival of patients. In this review, we provide an overview about mechanisms and consequences of NF-kappaB activation in gastric mucosa in order to understand the role of NF-kappaB in gastric carcinogenesis. PMID- 28350362 TI - Ergot Alkaloids in Fattening Chickens (Broilers): Toxic Effects and Carry over Depending on Dietary Fat Proportion and Supplementation with Non-Starch Polysaccharide (NSP) Hydrolyzing Enzymes. AB - Ergot alkaloids (EA) are mycotoxins produced by Claviceps purpurea. EA-toxicity is poorly characterized for fattening chickens. Therefore, a dose-response study was performed to identify the lowest, and no observed adverse effect levels (LOAEL and NOAEL, respectively) based on several endpoints. Non-starch polysaccharide (NSP) cleaving enzyme addition and dietary fat content were additionally considered as factors potentially influencing EA-toxicity. Feed intake was proven to respond most sensitively to the EA presence in the diets. This sensitivity appeared to be time-dependent. While LOAEL corresponded to a total dietary EA content of 5.7 mg/kg until Day 14 of age, it decreased to 2.03 mg/kg when birds were exposed for a period of 35 days. Consequently, NOAEL corresponded to an EA content of 2.49 mg/kg diet until Day 14 of age, while 1.94 mg/kg diet applied until Day 35 of age. Liver lesions indicating enzyme activities in serum were increased after 14 days of exposure. Dietary fat content and NSP-enzyme supplementation modified EA toxicity in an interactive manner. The EA residues in serum, bile, liver and breast meat were <5 ng/g suggesting a negligible carry over of intact EA. PMID- 28350364 TI - Are Brief Alcohol Interventions Adequately Embedded in UK Primary Care? A Qualitative Study Utilising Normalisation Process Theory. AB - Despite substantial evidence for their effectiveness, the adoption of alcohol screening and brief interventions (ASBI) in routine primary care remains inconsistent. Financial incentive schemes were introduced in England between 2008 and 2015 to encourage their delivery. We used Normalisation Process Theory informed interviews to understand the barriers and facilitators experienced by 14 general practitioners (GPs) as they implemented ASBI during this period. We found multiple factors shaped provision. GPs were broadly cognisant and supportive of preventative alcohol interventions (coherence) but this did not necessarily translate into personal investment in their delivery (cognitive participation). This lack of investment shaped how GPs operationalised such "work" in day-to-day practice (collective action), with ASBI mostly delegated to nurses, and GPs reverting to "business as usual" in their management and treatment of problem drinking (reflexive monitoring). We conclude there has been limited progress towards the goal of an effectively embedded preventative alcohol care pathway in English primary care. Future policy should consider screening strategies that prioritise patients with conditions with a recognised link with excessive alcohol consumption, and which promote more efficient identification of the most problematic drinkers. Improved GP training to build skills and awareness of evidence-based ASBI tools could also help embed best practice over time. PMID- 28350363 TI - Determination of Vancomycin in Human Serum by Cyclodextrin-Micellar Electrokinetic Capillary Chromatography (CD-MEKC) and Application for PDAP Patients. AB - A simple and sensitive cyclodextrin-micellar electrokinetic capillary chromatography (CD-MEKC) method with UV detection was developed and validated for the determination of vancomycin (VCM) in serum. The separation was achieved in 14 min at 25 degrees C with a fused-silica capillary column of 40.2 cm * 50 mm i.d. (effective length 30.2 cm) and a run buffer containing 25 mM borate buffer with 50 mM sodium dodecylsulfonate (SDS) (pH 9.5) and 2% sulfobutyl-beta-cyclodextrin (sulfobutyl-beta-CD). Under optimal conditions for biological samples, good separations with high efficiency and short analysis time were achieved. Several parameters affecting the drug separation from biological matrices were studied, including buffer types, concentrations, and pHs. The methods were validated over the range of 0.9998-99.98 ug/mL. Calibration curves of VCM also showed good linearity (r2 > 0.999). Intra- and interday precisions (relative standard deviation, RSD) were less than 5.80% and 7.38%, and lower limit of quantification (LLOQ) were lower than 1.0 MUg/mL. The mean recoveries ranged between 84.03% and 91.69%. The method was successfully applied for monitoring VCM concentrations in serum of patients with peritoneal dialysis-associated peritonitis (PDAP). The assay should be applicable to pharmacokinetic studies and routine therapeutic drug monitoring of this drug in serum. PMID- 28350366 TI - Modeling the Relationship between Safety Climate and Safety Performance in a Developing Construction Industry: A Cross-Cultural Validation Study. AB - This study attempts to validate a safety performance (SP) measurement model in the cross-cultural setting of a developing country. In addition, it highlights the variations in investigating the relationship between safety climate (SC) factors and SP indicators. The data were collected from forty under-construction multi-storey building projects in Pakistan. Based on the results of exploratory factor analysis, a SP measurement model was hypothesized. It was tested and validated by conducting confirmatory factor analysis on calibration and validation sub-samples respectively. The study confirmed the significant positive impact of SC on safety compliance and safety participation, and negative impact on number of self-reported accidents/injuries. However, number of near-misses could not be retained in the final SP model because it attained a lower standardized path coefficient value. Moreover, instead of safety participation, safety compliance established a stronger impact on SP. The study uncovered safety enforcement and promotion as a novel SC factor, whereas safety rules and work practices was identified as the most neglected factor. The study contributed to the body of knowledge by unveiling the deviations in existing dimensions of SC and SP. The refined model is expected to concisely measure the SP in the Pakistani construction industry, however, caution must be exercised while generalizing the study results to other developing countries. PMID- 28350365 TI - Anatomy of Mammalian Replication Domains. AB - Genetic information is faithfully copied by DNA replication through many rounds of cell division. In mammals, DNA is replicated in Mb-sized chromosomal units called "replication domains." While genome-wide maps in multiple cell types and disease states have uncovered both dynamic and static properties of replication domains, we are still in the process of understanding the mechanisms that give rise to these properties. A better understanding of the molecular basis of replication domain regulation will bring new insights into chromosome structure and function. PMID- 28350367 TI - Improving Suicide Prevention in Dutch Regions by Creating Local Suicide Prevention Action Networks (SUPRANET): A Study Protocol. AB - The European Alliance against Depression (EAAD) program is to be introduced in The Netherlands from 2017 onwards. This program to combat suicide consists of interventions on four levels: (1) increasing the awareness of suicide by local media campaigns; (2) training local gatekeepers, such as teachers or police officers; (3) targeting high-risk persons in the community; and (4) training and support of professionals in primary care settings. The implementation starts in seven Dutch pilot regions. Each region is designated as a Suicide Prevention Action NETwork (SUPRANET). This paper describes the SUPRANET program components and the evaluation of its feasibility and impact. The findings will be used to facilitate the national implementation of EAAD in The Netherlands and to add new findings to the existing literature on EAAD. PMID- 28350368 TI - Pathways to Suicide in Australian Farmers: A Life Chart Analysis. AB - Farmers have been found to be at increased risk of suicide in Australia. The Interpersonal-Psychological Theory of Suicidal Behaviour suggests that the proximal factors leading to the suicidal desire or ideation include an individual's experiences of both perceived burdensomeness and thwarted belongingness. Suicidal desire with acquired capability to engage in lethal self injury is predictive of suicidal behaviour. This study investigates the pathways to suicide of 18 Australian male farmers in order to understand the suicidal process and antecedents to suicide in Australian male farmers. The psychological autopsy (PA) method was used to generate life charts. Two pathways with distinct suicidal processes were identified: acute situational (romantic relationship problems and financial concerns/pending retirement) and protracted (long-term psychiatric disorder). Long working hours, interpersonal conflicts, physical illnesses and pain, alcohol abuse, access to firearms, and exposure to drought were additional common factors identified. An understanding of the interrelatedness of diverse distal and proximal risk factors on suicidal pathways in the wider environmental context for male farmers is required when developing and implementing rural suicide prevention activities. PMID- 28350369 TI - A Novel Ultrasonic Method for Liquid Level Measurement Based on the Balance of Echo Energy. AB - This study presents a novel method for determining the liquid level from the outside of a sealed container, which is based on the balance of echo energy received by two receiving sensors. The proposed method uses one transmitting transducer and two receiving sensors that are encapsulated in a coupling plane and arranged by certain rules. The calculation and comparison of echo energy are grounded on the difference ultrasonic impedance between gas and liquid media. First, by analyzing the propagation and attenuation characteristics of ultrasonic waves in a solid, an acoustic model for calculating the echo energy is established and simulated in MATLAB. Second, the proposed method is evaluated through a series of experiments. The difference and ratio of echo energy received by two receiving sensors are calculated and compared under two different coupling conditions. Two kinds of the sensors that are arranged by different rules are selected for measuring the liquid level, and the measurement are analyzed and discussed in detail. Finally, the experimental results indicate that the proposed method can meet the proposed accuracy requirements and can effectively solve the problems caused by some poor coupling conditions. PMID- 28350370 TI - Feasibility Study of Extended-Gate-Type Silicon Nanowire Field-Effect Transistors for Neural Recording. AB - In this research, a high performance silicon nanowire field-effect transistor (transconductance as high as 34 uS and sensitivity as 84 nS/mV) is extensively studied and directly compared with planar passive microelectrode arrays for neural recording application. Electrical and electrochemical characteristics are carefully characterized in a very well-controlled manner. We especially focused on the signal amplification capability and intrinsic noise of the transistors. A neural recording system using both silicon nanowire field-effect transistor-based active-type microelectrode array and platinum black microelectrode-based passive type microelectrode array are implemented and compared. An artificial neural spike signal is supplied as input to both arrays through a buffer solution and recorded simultaneously. Recorded signal intensity by the silicon nanowire transistor was precisely determined by an electrical characteristic of the transistor, transconductance. Signal-to-noise ratio was found to be strongly dependent upon the intrinsic 1/f noise of the silicon nanowire transistor. We found how signal strength is determined and how intrinsic noise of the transistor determines signal-to-noise ratio of the recorded neural signals. This study provides in-depth understanding of the overall neural recording mechanism using silicon nanowire transistors and solid design guideline for further improvement and development. PMID- 28350372 TI - Genome-Wide Analysis of the Sucrose Synthase Gene Family in Grape (Vitis vinifera): Structure, Evolution, and Expression Profiles. AB - Sucrose synthase (SS) is widely considered as the key enzyme involved in the plant sugar metabolism that is critical to plant growth and development, especially quality of the fruit. The members of SS gene family have been identified and characterized in multiple plant genomes. However, detailed information about this gene family is lacking in grapevine (Vitis vinifera L.). In this study, we performed a systematic analysis of the grape (V. vinifera) genome and reported that there are five SS genes (VvSS1-5) in the grape genome. Comparison of the structures of grape SS genes showed high structural conservation of grape SS genes, resulting from the selection pressures during the evolutionary process. The segmental duplication of grape SS genes contributed to this gene family expansion. The syntenic analyses between grape and soybean (Glycine max) demonstrated that these genes located in corresponding syntenic blocks arose before the divergence of grape and soybean. Phylogenetic analysis revealed distinct evolutionary paths for the grape SS genes. VvSS1/VvSS5, VvSS2/VvSS3 and VvSS4 originated from three ancient SS genes, which were generated by duplication events before the split of monocots and eudicots. Bioinformatics analysis of publicly available microarray data, which was validated by quantitative real-time reverse transcription PCR (qRT-PCR), revealed distinct temporal and spatial expression patterns of VvSS genes in various tissues, organs and developmental stages, as well as in response to biotic and abiotic stresses. Taken together, our results will be beneficial for further investigations into the functions of SS gene in the processes of grape resistance to environmental stresses. PMID- 28350374 TI - Energy Efficiency of D2D Multi-User Cooperation. AB - The Device-to-Device (D2D) communication system is an important part of heterogeneous networks. It has great potential to improve spectrum efficiency, throughput and energy efficiency cooperation of multiple D2D users with the advantage of direct communication. When cooperating, D2D users expend extraordinary energy to relay data to other D2D users. Hence, the remaining energy of D2D users determines the life of the system. This paper proposes a cooperation scheme for multiple D2D users who reuse the orthogonal spectrum and are interested in the same data by aiming to solve the energy problem of D2D users. Considering both energy availability and the Signal to Noise Ratio (SNR) of each D2D user, the Kuhn-Munkres algorithm is introduced in the cooperation scheme to solve relay selection problems. Thus, the cooperation issue is transformed into a maximum weighted matching (MWM) problem. In order to enhance energy efficiency without the deterioration of Quality of Service (QoS), the link outage probability is derived according to the Shannon Equation by considering the data rate and delay. The simulation studies the relationships among the number of cooperative users, the length of shared data, the number of data packets and energy efficiency. PMID- 28350375 TI - Corrigendum: Two novel mutations in PRPF3 causing autosomal dominant retinitis pigmentosa. PMID- 28350377 TI - Erratum: Hybrid acoustic metamaterial as super absorber for broadband low frequency sound. PMID- 28350376 TI - Event-related potential data from a guess the number brain-computer interface experiment on school children. AB - Guess the number is a simple P300-based brain-computer interface experiment. Its aim is to ask the measured participant to pick a number between 1 and 9. Then, he or she is exposed to corresponding visual stimuli and experimenters try to guess the number thought while they are observing event-related potential waveforms on line. 250 school-age children participated in the experiments that were carried out in elementary and secondary schools in the Czech Republic. Electroencephalographic data from three EEG channels (Fz, Cz, Pz) and stimuli markers were stored. Additional metadata about the participants were collected (gender, age, laterality, the number thought by the participant, the guess of the experimenters, and various interesting additional information). Consequently, we offer the largest publicly available odd-ball paradigm collection of datasets to neuroscientific and brain-computer interface community. PMID- 28350373 TI - DNA Replication Origins and Fork Progression at Mammalian Telomeres. AB - Telomeres are essential chromosomal regions that prevent critical shortening of linear chromosomes and genomic instability in eukaryotic cells. The bulk of telomeric DNA is replicated by semi-conservative DNA replication in the same way as the rest of the genome. However, recent findings revealed that replication of telomeric repeats is a potential cause of chromosomal instability, because DNA replication through telomeres is challenged by the repetitive telomeric sequences and specific structures that hamper the replication fork. In this review, we summarize current understanding of the mechanisms by which telomeres are faithfully and safely replicated in mammalian cells. Various telomere-associated proteins ensure efficient telomere replication at different steps, such as licensing of replication origins, passage of replication forks, proper fork restart after replication stress, and dissolution of post-replicative structures. In particular, shelterin proteins have central roles in the control of telomere replication. Through physical interactions, accessory proteins are recruited to maintain telomere integrity during DNA replication. Dormant replication origins and/or homology-directed repair may rescue inappropriate fork stalling or collapse that can cause defects in telomere structure and functions. PMID- 28350378 TI - Developing a dataset to track aid for reproductive, maternal, newborn and child health, 2003-2013. AB - We created a dataset to generate estimates of donor-reported 'official development assistance' and private grants (ODA+) to reproductive, maternal, newborn and child health (RMNCH) by donor, recipient country and activity type over the period 2003-2013. We collected disbursement information from the Organisation for Economic Co-operation and Development Creditor Reporting System (CRS) in January 2015. All 2.1 million records across all sectors were coded based on donor name, project title, short and long descriptions, and CRS code describing the purpose of the disbursement. We classified records according to the degree to which they would promote attainment of Millennium Development Goals 4 and 5 (reproductive and sexual health, maternal and newborn health, and child health). We also classified records according to whether they supported prenatal and neonatal health (PNH). The dataset includes project funding as well as allocating shares of general budget support, health sector support and basket funding. The data can be used to analyse resource flows to RMNCH or to other purposes or beneficiaries of ODA+. PMID- 28350379 TI - Corrigendum: Doxorubicin-loaded platelets as a smart drug delivery system: An improved therapy for lymphoma. PMID- 28350371 TI - A Neurophysiological Perspective on a Preventive Treatment against Schizophrenia Using Transcranial Electric Stimulation of the Corticothalamic Pathway. AB - Schizophrenia patients are waiting for a treatment free of detrimental effects. Psychotic disorders are devastating mental illnesses associated with dysfunctional brain networks. Ongoing brain network gamma frequency (30-80 Hz) oscillations, naturally implicated in integrative function, are excessively amplified during hallucinations, in at-risk mental states for psychosis and first episode psychosis. So, gamma oscillations represent a bioelectrical marker for cerebral network disorders with prognostic and therapeutic potential. They accompany sensorimotor and cognitive deficits already present in prodromal schizophrenia. Abnormally amplified gamma oscillations are reproduced in the corticothalamic systems of healthy humans and rodents after a single systemic administration, at a psychotomimetic dose, of the glutamate N-methyl-d-aspartate receptor antagonist ketamine. These translational ketamine models of prodromal schizophrenia are thus promising to work out a preventive noninvasive treatment against first-episode psychosis and chronic schizophrenia. In the present essay, transcranial electric stimulation (TES) is considered an appropriate preventive therapeutic modality because it can influence cognitive performance and neural oscillations. Here, I highlight clinical and experimental findings showing that, together, the corticothalamic pathway, the thalamus, and the glutamatergic synaptic transmission form an etiopathophysiological backbone for schizophrenia and represent a potential therapeutic target for preventive TES of dysfunctional brain networks in at-risk mental state patients against psychotic disorders. PMID- 28350380 TI - Transcriptomic profiling of 39 commonly-used neuroblastoma cell lines. AB - Neuroblastoma cell lines are an important and cost-effective model used to study oncogenic drivers of the disease. While many of these cell lines have been previously characterized with SNP, methylation, and/or mRNA expression microarrays, there has not been an effort to comprehensively sequence these cell lines. Here, we present raw whole transcriptome data generated by RNA sequencing of 39 commonly-used neuroblastoma cell lines. These data can be used to perform differential expression analysis based on a genetic aberration or phenotype in neuroblastoma (e.g., MYCN amplification status, ALK mutation status, chromosome arm 1p, 11q and/or 17q status, sensitivity to pharmacologic perturbation). Additionally, we designed this experiment to enable structural variant and/or long-noncoding RNA analysis across these cell lines. Finally, as more DNase/ATAC and histone/transcription factor ChIP sequencing is performed in these cell lines, our RNA-Seq data will be an important complement to inform transcriptional targets as well as regulatory (enhancer or repressor) elements in neuroblastoma. PMID- 28350381 TI - Metagenome sequencing and 98 microbial genomes from Juan de Fuca Ridge flank subsurface fluids. AB - The global deep subsurface biosphere is one of the largest reservoirs for microbial life on our planet. This study takes advantage of new sampling technologies and couples them with improvements to DNA sequencing and associated informatics tools to reconstruct the genomes of uncultivated Bacteria and Archaea from fluids collected deep within the Juan de Fuca Ridge subseafloor. Here, we generated two metagenomes from borehole observatories located 311 meters apart and, using binning tools, retrieved 98 genomes from metagenomes (GFMs). Of the GFMs, 31 were estimated to be >90% complete, while an additional 17 were >70% complete. Phylogenomic analysis revealed 53 bacterial and 45 archaeal GFMs, of which nearly all were distantly related to known cultivated isolates. In the GFMs, abundant Bacteria included Chloroflexi, Nitrospirae, Acetothermia (OP1), EM3, Aminicenantes (OP8), Gammaproteobacteria, and Deltaproteobacteria, while abundant Archaea included Archaeoglobi, Bathyarchaeota (MCG), and Marine Benthic Group E (MBG-E). These data are the first GFMs reconstructed from the deep basaltic subseafloor biosphere, and provide a dataset available for further interrogation. PMID- 28350382 TI - A dataset of stereoscopic images and ground-truth disparity mimicking human fixations in peripersonal space. AB - Binocular stereopsis is the ability of a visual system, belonging to a live being or a machine, to interpret the different visual information deriving from two eyes/cameras for depth perception. From this perspective, the ground-truth information about three-dimensional visual space, which is hardly available, is an ideal tool both for evaluating human performance and for benchmarking machine vision algorithms. In the present work, we implemented a rendering methodology in which the camera pose mimics realistic eye pose for a fixating observer, thus including convergent eye geometry and cyclotorsion. The virtual environment we developed relies on highly accurate 3D virtual models, and its full controllability allows us to obtain the stereoscopic pairs together with the ground-truth depth and camera pose information. We thus created a stereoscopic dataset: GENUA PESTO-GENoa hUman Active fixation database: PEripersonal space STereoscopic images and grOund truth disparity. The dataset aims to provide a unified framework useful for a number of problems relevant to human and computer vision, from scene exploration and eye movement studies to 3D scene reconstruction. PMID- 28350384 TI - Corrigendum: Human behaviour can trigger large carnivore attacks in developed countries. PMID- 28350383 TI - A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle. AB - The endocrine system dynamically controls tissue differentiation and homeostasis, but has not been studied using dynamic tissue culture paradigms. Here we show that a microfluidic system supports murine ovarian follicles to produce the human 28-day menstrual cycle hormone profile, which controls human female reproductive tract and peripheral tissue dynamics in single, dual and multiple unit microfluidic platforms (Solo-MFP, Duet-MFP and Quintet-MPF, respectively). These systems simulate the in vivo female reproductive tract and the endocrine loops between organ modules for the ovary, fallopian tube, uterus, cervix and liver, with a sustained circulating flow between all tissues. The reproductive tract tissues and peripheral organs integrated into a microfluidic platform, termed EVATAR, represents a powerful new in vitro tool that allows organ-organ integration of hormonal signalling as a phenocopy of menstrual cycle and pregnancy-like endocrine loops and has great potential to be used in drug discovery and toxicology studies. PMID- 28350386 TI - Corrigendum: Motivational, proteostatic and transcriptional deficits precede synapse loss, gliosis and neurodegeneration in the B6.HttQ111/+ model of Huntington's disease. PMID- 28350385 TI - Molecular, phenotypic, and sample-associated data to describe pluripotent stem cell lines and derivatives. AB - The use of induced pluripotent stem cells (iPSC) derived from independent patients and sources holds considerable promise to improve the understanding of development and disease. However, optimized use of iPSC depends on our ability to develop methods to efficiently qualify cell lines and protocols, monitor genetic stability, and evaluate self-renewal and differentiation potential. To accomplish these goals, 57 stem cell lines from 10 laboratories were differentiated to 7 different states, resulting in 248 analyzed samples. Cell lines were differentiated and characterized at a central laboratory using standardized cell culture methodologies, protocols, and metadata descriptors. Stem cell and derived differentiated lines were characterized using RNA-seq, miRNA-seq, copy number arrays, DNA methylation arrays, flow cytometry, and molecular histology. All materials, including raw data, metadata, analysis and processing code, and methodological and provenance documentation are publicly available for re-use and interactive exploration at https://www.synapse.org/pcbc. The goal is to provide data that can improve our ability to robustly and reproducibly use human pluripotent stem cells to understand development and disease. PMID- 28350387 TI - The global avian invasions atlas, a database of alien bird distributions worldwide. AB - The introduction of species to locations where they do not naturally occur (termed aliens) can have far-reaching and unpredictable environmental and economic consequences. Therefore there is a strong incentive to stem the tide of alien species introduction and spread. In order to identify broad patterns and processes of alien invasions, a spatially referenced, global dataset on the historical introductions and alien distributions of a complete taxonomic group is required. Here we present the Global Avian Invasions Atlas (GAVIA)-a new spatial and temporal dataset comprising 27,723 distribution records for 971 alien bird species introduced to 230 countries and administrative areas spanning the period 6000BCE-AD2014. GAVIA was initiated to provide a unified database of records on alien bird introductions, incorporating records from all stages of invasion, including introductions that have failed as well as those that have succeeded. GAVIA represents the most comprehensive resource on the global distribution of alien species in any major taxon, allowing the spatial and temporal dynamics of alien bird distributions to be examined. PMID- 28350388 TI - Corrigendum: The formation of multivesicular bodies in activated blastocysts is influenced by autophagy and FGF signaling in mice. PMID- 28350391 TI - Structural and genomic variation in preterm birth. PMID- 28350389 TI - Erratum: Targeted RNA-Seq profiling of splicing pattern in the DMD gene: exons are mostly constitutively spliced in human skeletal muscle. PMID- 28350392 TI - Animal-like prostaglandins in marine microalgae. AB - Diatoms are among the most successful primary producers in ocean and freshwater environments. Deriving from a secondary endosymbiotic event, diatoms have a mixed genome containing bacterial, animal and plant genes encoding for metabolic pathways that may account for their evolutionary success. Studying the transcriptomes of two strains of the diatom Skeletonema marinoi, we report, for the first time in microalgae, an active animal-like prostaglandin pathway that is differentially expressed in the two strains. Prostaglandins are hormone-like mediators in many physiological and pathological processes in mammals, playing a pivotal role in inflammatory responses. They are also present in macroalgae and invertebrates, where they act as defense and communication mediators. The occurrence of animal-like prostaglandins in unicellular photosynthetic eukaryotes opens up new intriguing perspectives on the evolution and role of these molecules in the marine environment as possible mediators in cell-to-cell signaling, eventually influencing population dynamics in the plankton. PMID- 28350394 TI - Long-term growth data of Escherichia coli at a single-cell level. AB - Long-term, single-cell measurement of bacterial growth is extremely valuable information, particularly in the study of homeostatic aspects such as cell-size and growth rate control. Such measurement has recently become possible due to the development of microfluidic technology. Here we present data from single-cell measurements of Escherichia coli growth over 70 generations obtained for three different growth conditions. The data were recorded every minute, and contain time course data of cell length and fluorescent intensity of constitutively expressed yellow fluorescent protein. PMID- 28350395 TI - Corrigendum: Antigen distribution of TMUV and GPV are coincident with the expression profiles of CD8alpha-positive cells and goose IFNgamma. PMID- 28350393 TI - Potential for microbial H2 and metal transformations associated with novel bacteria and archaea in deep terrestrial subsurface sediments. AB - Geological sequestration in deep underground repositories is the prevailing proposed route for radioactive waste disposal. After the disposal of radioactive waste in the subsurface, H2 may be produced by corrosion of steel and, ultimately, radionuclides will be exposed to the surrounding environment. To evaluate the potential for microbial activities to impact disposal systems, we explored the microbial community structure and metabolic functions of a sediment hosted ecosystem at the Horonobe Underground Research Laboratory, Hokkaido, Japan. Overall, we found that the ecosystem hosted organisms from diverse lineages, including many from the phyla that lack isolated representatives. The majority of organisms can metabolize H2, often via oxidative [NiFe] hydrogenases or electron-bifurcating [FeFe] hydrogenases that enable ferredoxin-based pathways, including the ion motive Rnf complex. Many organisms implicated in H2 metabolism are also predicted to catalyze carbon, nitrogen, iron and sulfur transformations. Notably, iron-based metabolism is predicted in a novel lineage of Actinobacteria and in a putative methane-oxidizing ANME-2d archaeon. We infer an ecological model that links microorganisms to sediment-derived resources and predict potential impacts of microbial activity on H2 consumption and retardation of radionuclide migration. PMID- 28350399 TI - Repeated administration of an acetylcholinesterase inhibitor attenuates nicotine taking in rats and smoking behavior in human smokers. PMID- 28350397 TI - Diagnosis and body mass index effects on hippocampal volumes and neurochemistry in bipolar disorder. AB - We previously reported that higher body mass index (BMI) was associated with greater hippocampal glutamate+glutamine in people with bipolar disorder (BD), but not in non-BD healthy comparator subjects (HSs). In the current report, we extend these findings by examining the impact of BD diagnosis and BMI on hippocampal volumes and the concentrations of several additional neurochemicals in 57 early stage BD patients and 31 HSs. Using 3-T magnetic resonance imaging and magnetic resonance spectroscopy, we measured bilateral hippocampal volumes and the hippocampal concentrations of four neurochemicals relevant to BD: N acetylaspartate+N-acteylaspartylglutamate (tNAA), creatine+phosphocreatine (Cre), myoinositol (Ins) and glycerophosphocholine+phosphatidylcholine (Cho). We used multivariate factorial analysis of covariance to investigate the impact of diagnosis (patient vs HS) and BMI category (normal weight vs overweight/obese) on these variables. We found a main effect of diagnosis on hippocampal volumes, with patients having smaller hippocampi than HSs. There was no association between BMI and hippocampal volumes. We found diagnosis and BMI effects on hippocampal neurochemistry, with patients having lower Cre, Ins and Cho, and overweight/obese subjects having higher levels of these chemicals. In patient-only models that controlled for clinical and treatment variables, we detected an additional association between higher BMI and lower tNAA that was absent in HSs. To our knowledge, this was the first study to investigate the relative contributions of BD diagnosis and BMI to hippocampal volumes, and only the second to investigate their contributions to hippocampal chemistry. It provides further evidence that diagnosis and elevated BMI both impact limbic brain areas relevant to BD. PMID- 28350398 TI - Electroconvulsive therapy modulates plasma pigment epithelium-derived factor in depression: a proteomics study. AB - Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, yet its mechanism of action is not fully understood. Peripheral blood proteomic analyses may offer insights into the molecular mechanisms of ECT. Patients with a major depressive episode were recruited as part of the EFFECT-Dep trial (enhancing the effectiveness of electroconvulsive therapy in severe depression; ISRCTN23577151) along with healthy controls. As a discovery-phase study, patient plasma pre-/post-ECT (n=30) was analyzed using 2-dimensional difference in gel electrophoresis and mass spectrometry. Identified proteins were selected for confirmation studies using immunodetection methods. Samples from a separate group of patients (pre-/post-ECT; n=57) and matched healthy controls (n=43) were then used to validate confirmed changes. Target protein mRNA levels were also assessed in rat brain and blood following electroconvulsive stimulation (ECS), the animal model of ECT. We found that ECT significantly altered 121 protein spots with 36 proteins identified by mass spectrometry. Confirmation studies identified a post-ECT increase (P<0.01) in the antiangiogenic and neuroprotective mediator pigment epithelium-derived factor (PEDF). Validation work showed an increase (P<0.001) in plasma PEDF in depressed patients compared with the controls that was further increased post-ECT (P=0.03). PEDF levels were not associated with mood scores. Chronic, but not acute, ECS increased PEDF mRNA in rat hippocampus (P=0.02) and dentate gyrus (P=0.03). This study identified alterations in blood levels of PEDF in depressed patients and further alterations following ECT, as well as in an animal model of ECT. These findings implicate PEDF in the biological response to ECT for depression. PMID- 28350396 TI - Genetic effects influencing risk for major depressive disorder in China and Europe. AB - Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor=8.08) but failed to replicate in an independent European sample (P=0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies. PMID- 28350400 TI - Immune involvement in the pathogenesis of schizophrenia: a meta-analysis on postmortem brain studies. AB - Although the precise pathogenesis of schizophrenia is unknown, genetic, biomarker and imaging studies suggest involvement of the immune system. In this study, we performed a systematic review and meta-analysis of studies investigating factors related to the immune system in postmortem brains of schizophrenia patients and healthy controls. Forty-one studies were included, reporting on 783 patients and 762 controls. We divided these studies into those investigating histological alterations of cellular composition and those assessing molecular parameters; meta-analyses were performed on both categories. Our pooled estimate on cellular level showed a significant increase in the density of microglia (P=0.0028) in the brains of schizophrenia patients compared with controls, albeit with substantial heterogeneity between studies. Meta-regression on brain regions demonstrated this increase was most consistently observed in the temporal cortex. Densities of macroglia (astrocytes and oligodendrocytes) did not differ significantly between schizophrenia patients and healthy controls. The results of postmortem histology are paralleled on the molecular level, where we observed an overall increase in expression of proinflammatory genes on transcript and protein level (P=0.0052) in patients, while anti-inflammatory gene expression levels were not different between schizophrenia and controls. The results of this meta-analysis strengthen the hypothesis that components of the immune system are involved in the pathogenesis of schizophrenia. PMID- 28350402 TI - Metabolomics approach for multibiomarkers determination to investigate dengue virus infection in human patients. AB - BACKGROUND: Dengue is one of the major public health problems in the world, affecting more than fifty million cases in tropical and subtropical region every year. The metabolome, as pathophysiological end-points, provide significant understanding of the mechanism and progression of dengue pathogenesis via changes in the metabolite profile of infected patients. Recent developments in diagnostic technologies provide metabolomics for the early detection of infectious diseases. METHODS: The mid-stream urine was collected from 96 patients diagnosed with dengue fever at Penang General Hospital (PGH) and 50 healthy volunteers. Urine samples were analyzed with proton nuclear magnetic resonance (1H NMR) spectroscopy, followed by chemometric multivariate analysis. NMR signals highlighted in the orthogonal partial least square-discriminant analysis (OPLS DA) S-plots were selected and identified using Human Metabolome Database (HMDB) and Chenomx Profiler. A highly predictive model was constructed from urine profile of dengue infected patients versus healthy individuals with the total R2Y (cum) value 0.935, and the total Q2Y (cum) value 0.832. RESULTS: Data showed that dengue infection is related to amino acid metabolism, tricarboxylic acid intermediates cycle and beta-oxidation of fatty acids. Distinct variations in certain metabolites were recorded in infected patients including amino acids, various organic acids, betaine, valerylglycine, myo-inositol and glycine. CONCLUSION: Metabolomics approach provides essential insight into host metabolic disturbances following dengue infection. PMID- 28350403 TI - Age-dependent systemic DNA damage in early Type 2 Diabetes mellitus. AB - Oxidative stress, capable of eliciting damage to various biomolecules including DNA, is a recognized component of diabetes mellitus and its complications. Metabolic syndrome (MetS) is associated with the development of type 2 diabetes mellitus (T2DM), as well as other unfavorable outcomes. The aim of this study was to elucidate the role of oxidative stress in the development of T2DM, by investigating association of oxidative DNA damage with metabolic parameters in subjects with MetS and early T2DM. Selected anthropometric and biochemical parameters of MetS, inflammation and oxidative DNA damage: body mass index (BMI), fatty liver index (FLI), waist circumference (WC), total cholesterol, HDL and LDL cholesterol, gamma-glutamyl transpeptidase (GGT), uric acid, C-reactive protein (CRP), total leukocyte/neutrophil count, and urinary 8-hidroxy-deoxyguanosine (u 8-OHdG) were assessed in male subjects with MetS and both younger (<=55 years) and older (>55 years) subjects with T2DM of short duration without complications. BMI, FLI, WC, total and LDL-cholesterol and uric acid were higher, while the u-8 OHdG was lower in MetS group, when compared to older T2DM subjects. None of these parameters were different neither between MetS and younger T2DM, nor between two sub-groups of subjects with T2DM. Values of CRP, HDL-cholesterol, triglycerides, GGT, leukocytes and neutrophils were not different between all examined groups of subjects. Higher 8-OHdG in older subjects with T2DM suggests that both aging process and diabetes could contribute to the development of DNA damage. Oxidative DNA damage cannot serve as an universal early marker of T2DM. PMID- 28350406 TI - Power-free, digital and programmable dispensing of picoliter droplets using a Digit Chip. AB - There is a growing need for power-free methods to manipulate small volumes of liquids and thereby enable use of diagnostic assays in resource-limited settings. Most existing self-powered devices provide analog manipulation of fluids using paper, capillary or pressure-driven pumps. These strategies are well-suited to manipulating larger micro- and milliliter-scale volumes at constant flow rates; however, they fail to enable the manipulation of nanoliter and picoliter volumes required in assays using droplets, capillary sampling (e.g. finger prick), or expensive reagents. Here we report a device, termed the Digit Chip, that provides programmable and power-free digital manipulation of sub-nanoliter volumes. The device consists of a user-friendly button interface and a series of chambers connected by capillary valves that serve as digitization elements. Via a button press, the user dispenses and actuates ultra-small, quantitatively-programmed volumes. The device geometry is optimized using design models and experiments and precisely dispenses volumes as low as 21 pL with 97% accuracy. The volume dispensed can be tuned in 10 discrete steps across one order-of-magnitude with 98% accuracy. As a proof-of-principle that nanoliter-scale reagents can be precisely actuated and combined on-chip, we deploy the device to construct a precise concentration gradient with 10 discrete concentrations. Additionally, we apply this device alongside an inexpensive smartphone-based fluorescence imaging platform to perform a titration of E. coli with ampicillin. We observe the onset of bacterial death at a concentration of 5 MUg mL-1, increasing to a maximum at 50 MUg mL-1. These results establish the utility of the Digit Chip for diagnostic applications in low-resource environments. PMID- 28350408 TI - Well-ordered mesoporous Fe2O3/C composites as high performance anode materials for sodium-ion batteries. AB - Sodium-ion batteries have attracted considerable attention in recent years. In order to promote the practical application of sodium-ion batteries, the electrochemical performances, such as specific capacity, reversibility, and rate capability of the anode materials, should be further improved. In this work, a Fe2O3/C composite with a well-ordered mesoporous structure is prepared via a facile co-impregnation method by using mesoporous silica SBA-15 as a hard template. When used as an anode material for sodium-ion batteries, the well ordered mesoporous structure ensures fast mass transport kinetics. The presence of nano-sized Fe2O3 particles confined within the carbon walls significantly enhances the specific capacity of the composite. The carbon walls in the composite act not only as an active material contributing to the specific capacity, but also as a conductive matrix improving the cycling stability of Fe2O3 nanoparticles. As a result, the well-ordered mesoporous Fe2O3/C composite exhibits high specific capacity, excellent cycleability, and high rate capability. It is proposed that this simple co-impregnation method is applicable for the preparation of well-ordered mesoporous transition oxide/carbon composite electrode materials for high performance sodium-ion and lithium-ion batteries. PMID- 28350401 TI - Systemic inflammation enhances stimulant-induced striatal dopamine elevation. AB - Changes in the mesolimbic dopamine (DA) system are implicated in a range of neuropsychiatric conditions including addiction, depression and schizophrenia. Dysfunction of the neuroimmune system is often comorbid with such conditions and affects similar areas of the brain. The goal of this study was to use positron emission tomography with the dopamine D2 antagonist tracer, 11C-raclopride, to explore the effect of acute immune activation on striatal DA levels. DA transmission was modulated by an oral methylphenidate (MP) challenge in order to reliably elicit DA elevation. Elevation in DA concentration due to MP was estimated via change in 11C-raclopride binding potential from the baseline scan. Prior to the post-MP scan, subjects were pre-treated with either the immune activator lipopolysaccharide (LPS) or placebo (PBO) in a cross-over design. Immune activation was confirmed by measuring tumor necrosis factor alpha (TNFalpha), interleukin (IL)-6 and IL-8 concentration in plasma. Eight healthy subjects were scanned four times each to determine the MP-induced DA elevation under both LPS and PBO pre-treatment conditions. MP-induced DA elevation in the striatum was significantly greater (P<0.01) after LPS pre-treatment compared to PBO pre-treatment. Seven of eight subjects responded similarly. This effect was observed in the caudate and putamen (P<0.02), but was not present in ventral striatum. DA elevation induced by MP was significantly greater when subjects were pre-treated with LPS compared to PBO. The amplification of stimulant-induced DA signaling in the presence of systemic inflammation may have important implications for our understanding of addiction and other diseases of DA dysfunction. PMID- 28350409 TI - Magnetically recoverable Fe3O4@Au-coated nanoscale catalysts for the A3-coupling reaction. AB - The utility of novel Fe3O4@Au nanoparticles as magnetically separable and recyclable heterogeneous catalysts for the A3-coupling reaction of aldehydes, amines and terminal alkynes to yield the corresponding propargylamines is demonstrated. Herein we present a comprehensive analysis of the experimentally observed trends in the conversions with computational analysis using LUMO density on molecular isosurfaces and the electrostatic potential (ESP) effects estimated using DFT calculations. PMID- 28350410 TI - A Ni-Mg-Al layered triple hydroxide-supported Pd catalyst for heterogeneous acceptorless dehydrogenative aromatization. AB - In the presence of a Ni-Mg-Al layered triple hydroxide-supported Pd catalyst, the acceptorless dehydrogenative aromatization of a wide range of cyclohexanols/cyclohexanones and cyclohexylamines efficiently proceeded to give the corresponding phenols and anilines, respectively, in moderate to high yields with the liberation of molecular hydrogen. PMID- 28350411 TI - Employees' drug purchases before and after organizational downsizing: a natural experiment on the Norwegian working population (2004-2012). AB - Objectives This study investigated the association between organizational downsizing and purchases of prescribed drugs by private sector employees in Norway. Methods A natural experiment was constructed using individual-level employer and employee data linked to the national prescription database for the period 2004-2012. The study population comprised 144 089 employees who had been exposed to major downsizing in the same period. Random effects logistic regression models were used to investigate relative changes in drug purchases (antidepressants, hypnotics/sedatives, anxiolytics, and anti-psychotics, as well as anti-obesity, anti-diabetic, cardiovascular, and thyroid drugs, anti inflammatory drugs, opioids, and analgesics/antipyretics) in the five-year-period before and after exposure to downsizing. Results Compared with the situation three years before exposure, the odds ratios (OR) of purchasing psychotropic drugs one year after exposure increased for antidepressants (OR 1.44, 95% CI 1.34 1.55), hypnotics/sedatives (OR 1.39, 95% CI 1.29-1.49), anxiolytics (OR 1.32, 95% CI 1.22-1.43), and antipsychotics (OR 1.34, 95% CI 1.19-1.52). Similar associations were found for cardiovascular, anti-diabetic, and thyroid drugs. Stratified analyses showed that the odds of purchasing psychotropic, anti diabetic, and cardiovascular drugs in the years around downsizing was more pronounced in men compared with women. Elevated odds were also found for employees in the oldest age group and those with less than tertiary education. Conclusions Exposure to organizational downsizing increased the odds of purchasing prescribed psychotropic, cardiovascular, anti-diabetic, and thyroid drugs. The clinical implications of these results might be systematic involvement from medical personnel and occupational health services in workforce reduction processes. PMID- 28350412 TI - Effectiveness of a structured sexual rehabilitation programme following stroke: A randomized controlled trial. AB - BACKGROUND: Sexual activity is an integral part of life; it is important to address sexual health after stroke, but this is often poorly done. OBJECTIVE: To assess the effectiveness of a structured sexual rehabilitation programme compared with written information alone regarding sexual and psychological functioning (anxiety, depression, stress), functional independence and quality of life in an Australian stroke cohort. METHODS: A total of 68 participants were randomized to a structured sexual rehabilitation programme (treatment group; n = 35) or to written information alone (control group; n = 33). Outcome measures included: Sexual Functioning Questionnaire Short Form; Depression, Anxiety Stress Scale; Functional Independence Measure, and Stroke and Aphasia Quality of Life Scale-39 Generic. Assessments were performed at baseline, 6 weeks and 6 months after the intervention. Participant's preferences regarding how they would like to receive information, who from, and how frequently, were collected at baseline. RESULTS: There was no difference between groups for any outcome measures. Half of the participants (51%) wished to receive information and were divided equally into preferring written information vs face-to-face counselling, with the majority (54%) preferring information after discharge from an inpatient setting. CONCLUSION: Provision of written information alone appears to be as effective as a 30-min individualized sexual rehabilitation programme in an inpatient setting. Further research is needed regarding longer term outcomes and outpatient settings. PMID- 28350413 TI - Risk of Myocardial Infarction in Patients with Psoriasis and Psoriatic Arthritis: A Nationwide Cohort Study. AB - Psoriasis has been associated with increased risk of myocardial infarction (MI) in some, but not all, studies. This study investigated the risk of MI in patients with psoriasis and psoriatic arthritis in Denmark. All residents aged >=18 years from 1 January 2008 through 31 December 2012 were included. Adjusted hazard ratios (HRs) did not show an increased risk of MI in patients with mild psoriasis (HR 1.02; 95% confidence interval (95% CI) 0.96-1.09), whereas the risk was slightly increased in patients with severe psoriasis (HR 1.21; 1.07-1.37). Stratified by age, there was no increased risk of MI in any specific age group, regardless of severity. Limited to first-time MI, the risk was increased only in patients with severe psoriasis aged <50 years (HR 1.52; 1.03-2.25). The same applied to patients without psoriatic arthritis (severe psoriasis aged <50 years; HR 1.74; 1.11-2.72). In analyses restricted to patients with psoriatic arthritis, age-specific strata did not show any association between psoriatic arthritis and MI risk. PMID- 28350414 TI - Visual dysfunction is underestimated in patients with acquired brain injury. AB - OBJECTIVES: More than 50% of human cerebral activity is related to vision. Visual impairments are therefore common after acquired brain injury, although they are often overlooked. In order to evaluate the prevalence of visual deficits in our Out-patient Brain Injury Program, a structured screening questionnaire, the Visual Interview, was administered. METHODS: A total of 170 patients with acquired brain injury, mean age 47 years, who were enrolled in the programme during 2010-12, underwent the Visual Interview. The interview consists of 18 questions concerning visual impairment and was performed on admission. The different types of visual impairment were compared with regard to sex and diagnosis. RESULTS: Fifty-four percent of the patients reported visual changes, mainly reading difficulties, photosensitivity, blurred vision and disorders of the visual field. Sixteen patients who did not experience visual changes also reported visual symptoms in 4-9 questions. Only slight differences were noted in the occurrence of visual symptoms when correlated with sex or diagnosis. CONCLUSION: Visual impairments are common after acquired brain injury, but some patients do not define their problems as vision-related. A structured questionnaire, covering the most common visual symptoms, is helpful for the rehabilitation team to facilitate assessment of visual changes. PMID- 28350415 TI - Anaerobic exercise testing in rehabilitation: A systematic review of available tests and protocols. AB - OBJECTIVE: Anaerobic capacity assessment in rehabilitation has received increasing scientific attention in recent years. However, anaerobic capacity is not tested consistently in clinical rehabilitation practice. This study reviews tests and protocols for anaerobic capacity in adults with various disabilities (spinal cord injury, cerebral palsy, cerebral vascular accident, lower-limb amputation(s)) and (able-bodied) wheelchair users. DATA SOURCES: PubMed, CINAHL and Web of Science. STUDY SELECTION: Papers were screened by 2 independent assessors, and were included when anaerobic exercise tests were performed on the above-selected subject groups. DATA EXTRACTION: Included articles were checked for methodological quality. DATA SYNTHESIS: A total of 57 papers was included. Upper-body testing [56 protocols] was conducted with arm crank [16] and wheelchair tests [40]. With a few [2] exceptions, modified Wingate (Wingate) protocols and wheelchair sprint tests dominated upper-body anaerobic testing. In lower-body anaerobic work [11], bicycle [3] and recumbent [1], and overground tests [7] were used, in which Wingate, sprint or jump protocols were employed. CONCLUSION: When equipment is available a Wingate protocol is advised for assessment of anaerobic capacity in rehabilitation. When equipment is not avail able a 20-45 s sprint test is a good alternative. Future research should focus on standardized tests and protocols specific to different disability groups. PMID- 28350416 TI - [Iatrogenic cerebral arterial gas embolism after lung biopsy]. PMID- 28350417 TI - [Cardiac implantable electronic devices (CIED) not an absolute contraindication to MRI]. AB - Cardiac implantable electronic devices (CIED) not an absolute contraindication to MRI Conventional cardiac implantable electronic devices (CIED) are presently not an absolute contraindication to magnetic resonance imaging (MRI), which thus is accessible for device patients depending on risk/benefit assessments. While current literature suggests that MRI can be performed without risk if precautions are taken, adverse events have been reported. The number of MR conditional CIEDs is rapidly increasing, and depending on device and electrode combinations, patients can now undergo advanced MRI at 3.0 T without risk, possibly with restriction, e.g. anatomy coverage. This article describes published guidelines, recommendations and complications that may appear during MRI and precautions to avoid and manage them. The recommendations made are based on a thorough literature review and our own experiences reported with the aim to increase the awareness of healthcare professionals so that device patients no longer are excluded from the advantages of MRI as a diagnostic tool. PMID- 28350418 TI - [Imperforate hymen - an often missed diagnosis]. AB - Imperforate hymen - an often missed diagnosis Imperforate hymen is the most common congenital malformation in the female reproduction system that give rise to obstructive symptoms. If the diagnosis is not made in the newborn girl, symptoms often first arise at menarche. The diagnosis is easy to make but has to be suspected. This case reports describes the typical clinical picture of a late diagnosed imperforate hymen. As shown in this case and from a review of the literature, these girls often have symptoms for a long time before the diagnosis is made. Further, they are often initially misdiagnosed, and a thorough history and examination is seldom performed despite repeated contacts with the primary care. PMID- 28350419 TI - [Patient participation for safer health care - interviews with physicians and nurses]. AB - Patient participation for safer health care - interviews with physicians and nurses Patient participation to achieve safer care is an area of growing policy, research and health care management and practice interest. Patients are uniquely placed to observe their treatment, care and physical environment throughout their journey in the health care system. However, very few studies have investigated health care providers' attitudes and beliefs concerning patient participation for improved patient safety. This study explored factors that acted as facilitators and/or barriers to patient participation for safer care, as perceived by physicians and nurses in Swedish health care. Interviews were conducted with 13 physicians and 11 nurses, using a purposeful sampling strategy to achieve a heterogeneous sample of providers. We identified nine categories of factors, many of which functioned as barriers to patient participation to achieve safer care. PMID- 28350420 TI - [Time to fill the knowledge gaps about the use of antibiotics in practice]. PMID- 28350421 TI - [Patient that was pronounced dead lived - 40 years later]. PMID- 28350423 TI - [Create a registry for management development]. PMID- 28350422 TI - [COPD not only found amongst smokers: a quarter have never smoked]. AB - COPD not only found amongst smokers: a quarter have never smoked Chronic obstructive pulmonary disease (COPD) is characterized by irreversible expiratory airflow limitation. Symptoms and exacerbations are now the most important factors for making treatment decisions. Recent data suggest that accelerated loss of lung function is not necessary for developing COPD. A lower lung function at the time when the lungs are fully developed, i.e. at the age of 20, and a normal loss in adulthood will increase the likelihood of developing chronic airflow limitation later. The proportion of neversmokers is estimated to 20-25% of the COPD population. Other risk factors than cigarette smoking, such as events in the neonatal period/childhood and air pollutants, have therefore been highlighted. PMID- 28350424 TI - ? PMID- 28350425 TI - ? PMID- 28350427 TI - Expression of Cytokines Interleukin-2, Interleukin-4, Interleukin-10 and Transforming Growth Factor beta in Gastric Adenocarcinoma Biopsies Obtained from Mexican Patients AB - Objective: In this study, expression of Interleukin-2, Interleukin-4, Interleukin 10 and transforming growth factorbeta in diffuse and intestinal type gastric cancers from Mexican patients was assessed for use as markers of malignancy.Methods: A total of 30 biopsies from gastric adenocarcinomas, 60% diffuse, 20% intestinal and 20% mixed in type, werestudied by immunohistochemistry. Results: Regarding expression of cytokines, 23% were positive for IL-2, 26.7% forIL-4, 16.6% for IL-10 and none for TGF-beta. There were found Significant statistically stage differences were noted.Forexample, for stages I-II 100% were IL-2 positive (p = 0.009), 87.5% were IL-4 positive (p = 0.005) and 100.0% IL-10positive (p = 0.009). Young women were more likely to suffer gastric adenocarcinoma. In biopsies of male patientswith gastric cancer, there was an increased expression of IL-2 and in biopsies from female patients in IL4. There wassignificantly greater detection of IL-4 and IL-10 expression in stages I and II than in stages III and IV. It was also foundthat IL-4, IL-10 had a higher positive expression in patients biopsies with low-level differentiations than patients withwell differentiated gastric cancer in which cases were undetected. Conclusions: These results suggest that positiveexpression of IL-4 and IL-10 may be useful as a molecular marker to distinguish stage I and II diffuse gastric cancerswhich can be more readily controlled. PMID- 28350430 TI - Insurance Coverage, Access to Care, and Medical Debt Since the ACA: a Look at California, Florida, New York, and Texas. AB - ISSUE: The Affordable Care Act has significantly increased health insurance coverage and access to care among U.S. adults nationwide. However, the law gives states flexibility in implementing certain provisions, leading to wide variations between states in consumers' experiences. GOAL: To examine the differences in insurance coverage, access to care, and medical bill problems in the four largest states-California, Florida, New York, and Texas-all of which have made different choices in implementing the law. METHODS: Analysis of the Commonwealth Fund Biennial Health Insurance Survey, 2016. FINDINGS AND CONCLUSIONS: In 2016, uninsured rates among adults ages 19 to 64 across the four states varied from 7 percent in New York and 10 percent in California to 16 percent in Florida and 25 percent in Texas. This variation was also apparent in the proportions of residents reporting problems getting needed care because of the cost significantly lower in California and New York than in Florida and Texas. Lower percentages of Californians and New Yorkers reported having a medical bill problem in the past 12 months or having accrued medical debt compared to Floridians and Texans. These variations might be explained by several factors: whether the state expanded Medicaid eligibility; whether it ran its own health insurance marketplace; what the uninsured rate was prior to the Affordable Care Act; differences in the cost protections provided by private health plans; and demographic differences. PMID- 28350431 TI - Cellulose Nanofibers from Softwood, Hardwood, and Tunicate: Preparation-Structure Film Performance Interrelation. AB - This work reveals the structural variations of cellulose nanofibers (CNF) prepared from different cellulose sources, including softwood (Picea abies), hardwood (Eucalyptus grandis * E. urophylla), and tunicate (Ciona intestinalis), using different preparation processes and their correlations to the formation and performance of the films prepared from the CNF. Here, the CNF are prepared from wood chemical pulps and tunicate isolated cellulose by an identical homogenization treatment subsequent to either an enzymatic hydrolysis or a 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO)-mediated oxidation. They show a large structural diversity in terms of chemical, morphological, and crystalline structure. Among others, the tunicate CNF consist of purer cellulose and have a degree of polymerization higher than that of wood CNF. Introduction of surface charges via the TEMPO-mediated oxidation is found to have significant impacts on the structure, morphology, optical, mechanical, thermal, and hydrophobic properties of the prepared films. For example, the film density is closely related to the charge density of the used CNF, and the tensile stress of the films is correlated to the crystallinity index of the CNF. In turn, the CNF structure is determined by the cellulose sources and the preparation processes. This study provides useful information and knowledge for understanding the importance of the raw material for the quality of CNF for various types of applications. PMID- 28350426 TI - Pharmacological interventions for primary biliary cholangitis: an attempted network meta-analysis. AB - BACKGROUND: Primary biliary cholangitis (previously primary biliary cirrhosis) is a chronic liver disease caused by the destruction of small intra-hepatic bile ducts resulting in stasis of bile (cholestasis), liver fibrosis, and liver cirrhosis. The optimal pharmacological treatment of primary biliary cholangitis remains uncertain. OBJECTIVES: To assess the comparative benefits and harms of different pharmacological interventions in the treatment of primary biliary cholangitis through a network meta-analysis and to generate rankings of the available pharmacological interventions according to their safety and efficacy. However, it was not possible to assess whether the potential effect modifiers were similar across different comparisons. Therefore, we did not perform the network meta-analysis, and instead, assessed the comparative benefits and harms of different interventions using standard Cochrane methodology. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and randomised controlled trials registers to February 2017 to identify randomised clinical trials on pharmacological interventions for primary biliary cholangitis. SELECTION CRITERIA: We included only randomised clinical trials (irrespective of language, blinding, or publication status) in participants with primary biliary cholangitis. We excluded trials which included participants who had previously undergone liver transplantation. We considered any of the various pharmacological interventions compared with each other or with placebo or no intervention. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager 5. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE. MAIN RESULTS: We identified 74 trials including 5902 participants that met the inclusion criteria of this review. A total of 46 trials (4274 participants) provided information for one or more outcomes. All the trials were at high risk of bias in one or more domains. Overall, all the evidence was low or very low quality. The proportion of participants with symptoms varied from 19.9% to 100% in the trials that reported this information. The proportion of participants who were antimitochondrial antibody (AMA) positive ranged from 80.8% to 100% in the trials that reported this information. It appeared that most trials included participants who had not received previous treatments or included participants regardless of the previous treatments received. The follow-up in the trials ranged from 1 to 96 months.The proportion of people with mortality (maximal follow-up) was higher in the methotrexate group versus the no intervention group (OR 8.83, 95% CI 1.01 to 76.96; 60 participants; 1 trial; low quality evidence). The proportion of people with mortality (maximal follow-up) was lower in the azathioprine group versus the no intervention group (OR 0.56, 95% CI 0.32 to 0.98; 224 participants; 2 trials; I2 = 0%; low quality evidence). However, it has to be noted that a large proportion of participants (25%) was excluded from the trial that contributed most participants to this analysis and the results were not reliable. There was no evidence of a difference in any of the remaining comparisons. The proportion of people with serious adverse events was higher in the D-penicillamine versus no intervention group (OR 28.77, 95% CI 1.57 to 526.67; 52 participants; 1 trial; low quality evidence). The proportion of people with serious adverse events was higher in the obeticholic acid plus ursodeoxycholic acid (UDCA) group versus the UDCA group (OR 3.58, 95% CI 1.02 to 12.51; 216 participants; 1 trial; low quality evidence). There was no evidence of a difference in any of the remaining comparisons for serious adverse events (proportion) or serious adverse events (number of events). None of the trials reported health-related quality of life at any time point. FUNDING: nine trials had no special funding or were funded by hospital or charities; 31 trials were funded by pharmaceutical companies; and 34 trials provided no information on source of funding. AUTHORS' CONCLUSIONS: Based on very low quality evidence, there is currently no evidence that any intervention is beneficial for primary biliary cholangitis. However, the follow up periods in the trials were short and there is significant uncertainty in this issue. Further well-designed randomised clinical trials are necessary. Future randomised clinical trials ought to be adequately powered; performed in people who are generally seen in the clinic rather than in highly selected participants; employ blinding; avoid post-randomisation dropouts or planned cross-overs; should have sufficient follow-up period (e.g. five or 10 years or more); and use clinically important outcomes such as mortality, health-related quality of life, cirrhosis, decompensated cirrhosis, and liver transplantation. Alternatively, very large groups of participants should be randomised to facilitate shorter trial duration. PMID- 28350432 TI - Functionalized Porous Aromatic Framework for Efficient Uranium Adsorption from Aqueous Solutions. AB - We demonstrate the successful functionalization of a porous aromatic framework for uranium extraction from water as exemplified by grafting PAF-1 with the uranyl chelating amidoxime group. The resultant amidoxime-functionalized PAF-1 (PAF-1-CH2AO) exhibits a high uranium uptake capacity of over 300 mg g-1 and effectively reduces the uranyl concentration from 4.1 ppm to less than 1.0 ppb in aqueous solutions within 90 min, well below the acceptable limit of 30 ppb set by the US Environmental Protection Agency. The local coordination environment of uranium in PAF-1-CH2AO is revealed by X-ray absorption fine structure spectroscopic studies, which suggest the cooperative binding between UO22+ and adjacent amidoxime species. PMID- 28350433 TI - Scalable Fabrication of Photochemically Reduced Graphene-Based Monolithic Micro Supercapacitors with Superior Energy and Power Densities. AB - Micro-supercapacitors (MSCs) hold great promise as highly competitive miniaturized power sources satisfying the increased demand of smart integrated electronics. However, single-step scalable fabrication of MSCs with both high energy and power densities is still challenging. Here we demonstrate the scalable fabrication of graphene-based monolithic MSCs with diverse planar geometries and capable of superior integration by photochemical reduction of graphene oxide/TiO2 nanoparticle hybrid films. The resulting MSCs exhibit high volumetric capacitance of 233.0 F cm-3, exceptional flexibility, and remarkable capacity of modular serial and parallel integration in aqueous gel electrolyte. Furthermore, by precisely engineering the interface of electrode with electrolyte, these monolithic MSCs can operate well in a hydrophobic electrolyte of ionic liquid (3.0 V) at a high scan rate of 200 V s-1, two orders of magnitude higher than those of conventional supercapacitors. More notably, the MSCs show landmark volumetric power density of 312 W cm-3 and energy density of 7.7 mWh cm-3, both of which are among the highest values attained for carbon-based MSCs. Therefore, such monolithic MSC devices based on photochemically reduced, compact graphene films possess enormous potential for numerous miniaturized, flexible electronic applications. PMID- 28350434 TI - Stepwise Synthesis of Metal-Organic Frameworks. AB - Metal-organic frameworks (MOFs) are a category of porous materials that offer unparalleled control over their surface areas (demonstrated as higher than for any other material), pore characteristics, and functionalization. This allows them to be customized for exceptional performance in a wide variety of applications, most commonly including gas storage and separation, drug delivery, luminescence, or heterogeneous catalysis. In order to optimize biomimicry, controlled separations and storage of small molecules, and detailed testing of structure-property relationships, one major goal of MOF research is "rational design" or "pore engineering", or precise control of the placement of multiple functional groups in pores of chosen sizes and shapes. MOF crystal growth can be controlled through judicious design of stepwise synthetic routes, which can also allow functionalization of MOFs in ways that were previously synthetically inaccessible. Organic chemists have developed a library of powerful techniques over the last century, allowing the total synthesis and detailed customization of complex molecules. Our hypothesis is that total synthesis is also possible for customized porous materials, through the development of similar multistep techniques. This will enable the rational design of MOFs, which is a major goal of many researchers in the field. We have begun developing a library of stepwise synthetic techniques for MOFs, allowing the synthesis of ultrastable MOFs with multiple crystallographically ordered and customizable functional groups at controlled locations within the pores. In order to design MOFs with precise control over pore size and shape, stability, and the placement of multiple different functional groups within the pores at tunable distances from one another, we have concentrated on methods which allow us to circumvent the lack of control inherent to one-pot MOF crystallization. Kinetically tuned dimensional augmentation (KTDA) is an approach using preformed metal clusters as starting materials and monotopic carboxylates as equilibrium shifting agents to make single crystals of ultrastable MOFs. Postsynthetic metathesis and oxidation (PSMO) takes advantage of the fast ligand exchange rate of a metal ion at the low oxidation state as well as the kinetic inertness of the same metal at high oxidation state to make ultrastable and highly crystalline MOFs. Multiple similar strategies have been successful for the metathesis of Fe-based MOFs to Cr3+. Several highly crystalline Ti-MOFs have also been prepared. Kinetically controlled linker installation and cluster metalation methods utilize a stable MOF with inherent coordinatively unsaturated sites as matrix and postsynthetically install linkers or grow clusters on the matrix, so that a robust MOF with precisely placed functionalities is realized. This method has diverse applications especially when specific functional groups or metals having synergistic effects are desired in the proper proximity. Exceptional porosity and stability are required for many potential applications. We have demonstrated several of these, including entrapment of nanoscaled functional moieties such as enzymes. We have developed a series of metal-organic frameworks (PCN-333) with rationally designed ultralarge mesoporous cages as single-molecule traps for enzyme encapsulation. We successfully incorporated metalloporphyrins, well-known biofunctional moieties, into robust MOFs for biomimetic catalytic applications. By rationally tuning the synthetic conditions, we obtained several different porphyrinic Zr-, Fe-, and Ti-MOFs with distinct pore size and concentrated acid or base stability, which offer eligible candidates for different applications. These and other stepwise kinetic tuning and catalyst incorporation methods are small steps toward achieving the grand challenge of detailed control of the placement of matter on an atomic and molecular level. PMID- 28350435 TI - Insight into a Fast-Phototuning Azobenzene Switch for Sustainably Tailoring the Foam Stability. AB - A photoresponsive surfactant of 4-octoxy-4'-[(trimethylamino)ethoxy]azobenzene (OTAEAzo) has been synthesized for developing a fast-phototuning foam switch based on its high sensitivity, reversibility, and fatigue resistance of the photoisomerization capability. Ultraviolet (UV)-light irradiation for 1 s enabled conversion from the trans isomer to the cis configuration, while exposure to visible (Vis)-light for 3 min induced a cis-to-trans transformation, which maintains an excellent cycling stability for 20 cycles of photoisomerization. The photoisomerization speed depended on the concentration of OTAEAzo, and a lower concentration facilitated a faster photoisomerization process. Because of the low critical micelle concentration (CMC), OTAEAzo with a small dosage of 0.2 g.L-1 showed foamability, which accelerated the photoisomerization speed, enabling it to become a highly efficient switch. The surface activities of trans-OTAEAzo presented distinct differences from those of cis-OTAEAzo, resulting in the foam stabilization effects of trans-OTAEAzo (t1/2 = 2.58 min) and the destabilization effects of cis-OTAEAzo (t1/2 = 0.38 min). Moreover, the foam properties varied slightly in the phototuning cycles. OTAEAzo with low CMC presents high sensitivity and reversible photoisomerization capability, providing an environmental and sustainable approach for tailoring the foam stability. PMID- 28350436 TI - Potential Fluctuations at Low Temperatures in Mesoscopic-Scale SmTiO3/SrTiO3/SmTiO3 Quantum Well Structures. AB - Heterointerfaces of SrTiO3 with other transition metal oxides make up an intriguing family of systems with a bounty of coexisting and competing physical orders. Some examples, such as LaAlO3/SrTiO3, support a high carrier density electron gas at the interface whose electronic properties are determined by a combination of lattice distortions, spin-orbit coupling, defects, and various regimes of magnetic and charge ordering. Here, we study electronic transport in mesoscale devices made with heterostructures of SrTiO3 sandwiched between layers of SmTiO3, in which the transport properties can be tuned from a regime of Fermi liquid like resistivity (rho ? T2) to a non-Fermi liquid (rho ? T5/3) by controlling the SrTiO3 thickness. In mesoscale devices at low temperatures, we find unexpected voltage fluctuations that grow in magnitude as T is decreased below 20 K, are suppressed with increasing contact electrode size, and are independent of the drive current and contact spacing distance. Magnetoresistance fluctuations are also observed, which are reminiscent of universal conductance fluctuations but not entirely consistent with their conventional properties. Candidate explanations are considered, and a mechanism is suggested based on mesoscopic temporal fluctuations of the Seebeck coefficient. An improved understanding of charge transport in these model systems, especially their quantum coherent properties, may lead to insights into the nature of transport in strongly correlated materials that deviate from Fermi liquid theory. PMID- 28350437 TI - Bacteria-Activated Theranostic Nanoprobes against Methicillin-Resistant Staphylococcus aureus Infection. AB - Despite numerous advanced imaging and sterilization techniques available nowadays, the sensitive in vivo diagnosis and complete elimination of drug resistant bacterial infections remain big challenges. Here we report a strategy to design activatable theranostic nanoprobes against methicillin-resistant Staphylococcus aureus (MRSA) infections. This probe is based on silica nanoparticles coated with vancomycin-modified polyelectrolyte-cypate complexes (SiO2-Cy-Van), which is activated by an interesting phenomenon of bacteria responsive dissociation of the polyelectrolyte from silica nanoparticles. Due to the aggregation of hydrophobic cypate fluorophores on silica nanoparticles to induce ground-state quenching, the SiO2-Cy-Van nanoprobes are nonfluorescent in aqueous environments. We demonstrate that MRSA can effectively pull out the vancomycin-modified polyelectrolyte-cypate complexes from silica nanoparticles and draw them onto their own surface, changing the state of cypate from off (aggregation) to on (disaggregation) and leading to in vitro MRSA-activated near infrared fluorescence (NIRF) and photothermal elimination involving bacterial cell wall and membrane disruption. In vivo experiments show that this de novo designed nanoprobe can selectively enable rapid (4 h postinjection) NIRF imaging with high sensitivity (105 colony-forming units) and efficient photothermal therapy (PTT) of MRSA infections in mice. Remarkably, the SiO2-Cy-Van nanoprobes can also afford a long-term tracking (16 days) of the development of MRSA infections, allowing real-time estimation of bacterial load in infected tissues and further providing a possible way to monitor the efficacy of antimicrobial treatment. The strategy of bacteria-activated polyelectrolyte dissociation from nanoparticles proposed in this work could also be used as a general method for the design and fabrication of bacteria-responsive functional nanomaterials that offer possibilities to combat drug-resistant bacterial infections. PMID- 28350438 TI - An Acyl-Linked Dimer of Daptomycin Is Strongly Inhibited by the Bacterial Cell Wall. AB - The lipopeptide antibiotic daptomycin is active against Gram-positive pathogens. It permeabilizes bacterial cell membranes, which involves the formation of membrane-associated oligomers. We here studied a dimer of daptomycin whose two subunits were linked through a bivalent aliphatic acyl chain. Unexpectedly, the dimer had very low activity on vegetative Staphylococcus aureus and Bacillus subtilis cells. However, activity resembled that of monomeric daptomycin on liposomes and on B. subtilis L-forms. These findings underscore the importance of the bacterial cell wall in daptomycin resistance. PMID- 28350439 TI - Correction to Trends in Adhesion Energies of Metal Nanoparticles on Oxide Surfaces: Understanding Support Effects in Catalysis and Nanotechnology. PMID- 28350441 TI - Chemical Probes Unravel an Antimicrobial Defense Response Triggered by Binding of the Human Opioid Dynorphin to a Bacterial Sensor Kinase. AB - Host-microbe communication via small molecule signals is important for both symbiotic and pathogenic relationships, but is often poorly understood at the molecular level. Under conditions of host stress, levels of the human opioid peptide dynorphin are elevated, triggering virulence in the opportunistic pathogenic bacterium Pseudomonas aeruginosa via an unknown pathway. Here we apply a multilayered chemical biology strategy to unravel the mode of action of this putative interkingdom signal. We designed and applied dynorphin-inspired photoaffinity probes to reveal the protein targets of the peptide in live bacteria via chemical proteomics. ParS, a largely uncharacterized membrane sensor of a two-component system, was identified as the most promising hit. Subsequent full proteome studies revealed that dynorphin(1-13) induces an antimicrobial peptide-like response in Pseudomonas, with specific upregulation of membrane defense mechanisms. No such response was observed in a parS mutant, which was more susceptible to dynorphin-induced toxicity. Thus, P. aeruginosa exploits the ParS sensing machinery to defend itself against the host in response to dynorphin as a signal. This study highlights interkingdom communication as a potential essential strategy not only for induction of P. aeruginosa virulence but also for maintaining viability in the hostile environment of the host. PMID- 28350442 TI - Engineered Polymer-Transferrin Conjugates as Self-Assembling Targeted Drug Delivery Systems. AB - Polymer-protein conjugates can be engineered to self-assemble into discrete and well-defined drug delivery systems, which combine the advantages of receptor targeting and controlled drug release. We designed specific conjugates of the iron-binding and transport protein, transferrin (Tf), to combine the advantages of this serum-stable protein as a targeting agent for cancer cells with self assembling polymers to act as carriers of cytotoxic drugs. Tf variants were expressed with cysteine residues at sites spanning different regions of the protein surface, and the polymer conjugates grown from these variants were compared with polymer conjugates grown from nonselectively derivatized sites on native Tf. The resulting synthetic biopolymer hybrids were evaluated for self assembly properties, size and topology, ability to carry an anticancer drug (paclitaxel), and cytotoxicity with and without a drug payload in a representative human colon cancer cell line. The results demonstrated that the engineered Tf variant polymer conjugates formed better-defined self-assembled nanoparticles than the nonselectively derivatized conjugates and showed greater efficacy in paclitaxel delivery. A polymer conjugate grown from a specific Tf variant, S415C was found to be taken up rapidly into cancer cells expressing the Tf-receptor, and, while tolerated well by cells in the absence of drugs, was as cytotoxic as free paclitaxel, when loaded with the drug. Importantly, the S415C conjugate polymer was not the most active variant in Tf-receptor binding, suggesting that the nanoscale self-assembly of the polymer-protein hybrid is also a key factor in delivery efficacy. The data overall suggest new design rules for polymer-biopolymer hybrids and therapeutic delivery systems, which include engineering specific residues for conjugation that mediate nanoscale assembly as well as control of ligand-receptor interactions to target specific cell types. PMID- 28350440 TI - Identification of Trypanosoma brucei AdoMetDC Inhibitors Using a High-Throughput Mass Spectrometry-Based Assay. AB - Human African trypanosomiasis (HAT) is a fatal infectious disease caused by the eukaryotic pathogen Trypanosoma brucei (Tb). Available treatments are difficult to administer and have significant safety issues. S-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the parasite polyamine biosynthetic pathway. Previous attempts to develop TbAdoMetDC inhibitors into anti-HAT therapies failed due to poor brain exposure. Here, we describe a large screening campaign of two small-molecule libraries (~400,000 compounds) employing a new high-throughput (~7 s per sample) mass spectrometry-based assay for AdoMetDC activity. As a result of primary screening, followed by hit confirmation and validation, we identified 13 new classes of reversible TbAdoMetDC inhibitors with low-micromolar potency (IC50) against both TbAdoMetDC and T. brucei parasite cells. The majority of these compounds were >10-fold selective against the human enzyme. Importantly, compounds from four classes demonstrated high propensity to cross the blood-brain barrier in a cell monolayer assay. Biochemical analysis demonstrated that compounds from eight classes inhibited intracellular TbAdoMetDC in the parasite, although evidence for a secondary off-target component was also present. The discovery of several new TbAdoMetDC inhibitor chemotypes provides new hits for lead optimization programs aimed to deliver a novel treatment for HAT. PMID- 28350443 TI - Monitoring the Disassembly of Virus-like Particles by 19F-NMR. AB - Virus-like particles (VLPs) are stable protein cages derived from virus coats. They have been used extensively as biomolecular platforms, e.g., nanocarriers or vaccines, but a convenient in situ technique is lacking for tracking functional status. Here, we present a simple way to monitor disassembly of 19F-labeled VLPs derived from bacteriophage Qbeta by 19F NMR. Analysis of resonances, under a range of conditions, allowed determination not only of the particle as fully assembled but also as disassembled, as well as detection of a degraded state upon digestion by cells. This in turn allowed mutational redesign of disassembly and testing in both bacterial and mammalian systems as a strategy for the creation of putative, targeted-VLP delivery systems. PMID- 28350444 TI - Bottom-Up Elucidation of Glycosidic Bond Stereochemistry. AB - The lack of robust, high-throughput, and sensitive analytical strategies that can conclusively map the structure of glycans has significantly hampered progress in fundamental and applied aspects of glycoscience. Resolution of the anomeric alpha/beta glycan linkage within oligosaccharides remains a particular challenge. Here, we show that "memory" of anomeric configuration is retained following gas phase glycosidic bond fragmentation during tandem mass spectrometry (MS2). These findings allow for integration of MS2 with ion mobility spectrometry (IM-MS2) and lead to a strategy to distinguish alpha- and beta-linkages within natural underivatized carbohydrates. We have applied this fragment-based hyphenated MS technology to oligosaccharide standards and to de novo sequencing of purified plant metabolite glycoconjugates, showing that the anomeric signature is also observable in fragments derived from larger glycans. The discovery of the unexpected anomeric memory effect is further supported by IR-MS action spectroscopy and ab initio calculations. Quantum mechanical calculations provide candidate geometries for the distinct anomeric fragment ions, in turn shedding light on gas-phase dissociation mechanisms of glycosidic linkages. PMID- 28350446 TI - Temporal Shifts in Poly- and Perfluoroalkyl Substances (PFASs) in North Atlantic Pilot Whales Indicate Large Contribution of Atmospheric Precursors. AB - Poly- and perfluoroalkyl substances (PFASs) are persistent, bioaccumulative anthropogenic compounds associated with adverse health impacts on humans and wildlife. PFAS production changed in North America and Europe around the year 2000, but impacts on wildlife appear to vary across species and location. Unlike other mammal species, cetaceans lack the enzyme for transforming an important intermediate precursor (perfluorooctane sulfonamide: FOSA), into a prevalent compound in most wildlife (perfluorooctanesulfonate: PFOS). Thus, their tissue burden differentiates these two compounds while other mammals contain PFOS from both direct exposure and precursor degradation. Here we report temporal trends in 15 PFASs measured in muscle from juvenile male North Atlantic pilot whales (Globicephala melas) harvested between 1986 and 2013. FOSA accounted for a peak of 84% of the 15 PFASs around 2000 but declined to 34% in recent years. PFOS and long-chained PFCAs (C9-C13) increased significantly over the whole period (2.8% yr-1 to 8.3% yr-1), but FOSA declined by 13% yr-1 after 2006. Results from FOSA partitioning and bioaccumulation modeling forced by changes in atmospheric inputs reasonably capture magnitudes and temporal patterns in FOSA concentrations measured in pilot whales. Rapid changes in atmospheric FOSA in polar and subpolar regions around 2000 helps to explain large declines in PFOS exposure for species that metabolize FOSA, including seafood consuming human populations. This work reinforces the importance of accounting for biological exposures to PFAS precursors. PMID- 28350447 TI - Self-Functionalization Behind a Solution-Processed NiOx Film Used As Hole Transporting Layer for Efficient Perovskite Solar Cells. AB - Fabrication of solution-processed perovskite solar cells (PSCs) requires the deposition of high quality films from precursor inks. Frequently, buffer layers of PSCs are formed from dispersions of metal oxide nanoparticles (NPs). Therefore, the development of trustable methods for the preparation of stable colloidal NPs dispersions is crucial. In this work, a novel approach to form very compact semiconducting buffer layers with suitable optoelectronic properties is presented through a self-functionalization process of the nanocrystalline particles by their own amorphous phase and without adding any other inorganic or organic functionalization component or surfactant. Such interconnecting amorphous phase composed by residual nitrate, hydroxide, and sodium ions, proved to be fundamental to reach stable colloidal dispersions and contribute to assemble the separate crystalline nickel oxide NPs in the final film, resulting in a very homogeneous and compact layer. A proposed mechanism behind the great stabilization of the nanoparticles is exposed. At the end, the self functionalized nickel oxide layer exhibited high optoelectronic properties enabling perovskite p-i-n solar cells as efficient as 16.6% demonstrating the pertinence of the presented strategy to obtain high quality buffer layers processed in solution at room temperature. PMID- 28350445 TI - Structural Changes in an Anion Channelrhodopsin: Formation of the K and L Intermediates at 80 K. AB - A recently discovered natural family of light-gated anion channelrhodopsins (ACRs) from cryptophyte algae provides an effective means of optogenetically silencing neurons. The most extensively studied ACR is from Guillardia theta (GtACR1). Earlier studies of GtACR1 have established a correlation between formation of a blue-shifted L-like intermediate and the anion channel "open" state. To study structural changes of GtACR1 in the K and L intermediates of the photocycle, a combination of low-temperature Fourier transform infrared (FTIR) and ultraviolet-visible absorption difference spectroscopy was used along with stable-isotope retinal labeling and site-directed mutagenesis. In contrast to bacteriorhodopsin (BR) and other microbial rhodopsins, which form only a stable red-shifted K intermediate at 80 K, GtACR1 forms both stable K and L-like intermediates. Evidence includes the appearance of positive ethylenic and fingerprint vibrational bands characteristic of the L intermediate as well as a positive visible absorption band near 485 nm. FTIR difference bands in the carboxylic acid C?O stretching region indicate that several Asp/Glu residues undergo hydrogen bonding changes at 80 K. The Glu68 -> Gln and Ser97 -> Glu substitutions, residues located close to the retinylidene Schiff base, altered the K:L ratio and several of the FTIR bands in the carboxylic acid region. In the case of the Ser97 -> Glu substitution, a significant red-shift of the absorption wavelength of the K and L intermediates occurs. Sequence comparisons suggest that L formation in GtACR1 at 80 K is due in part to the substitution of the highly conserved Leu or Ile at position 93 in helix 3 (BR sequence) with the homologous Met105 in GtACR1. PMID- 28350448 TI - Mechanism Exploration of Ion Transport in Nanocomposite Cation Exchange Membranes. AB - The origin of property enhancement of nanocomposite ion exchange membranes (IEMs) is far from being fully understood. By combining experimental work and computational modeling analysis, we could determine the influence of nanomaterials on the ion transport properties of nanocomposite cation exchange membranes (CEMs). We synthesized and characterized a series of nanocomposite CEMs by using SPPO as polymer materials and silica nanoparticles (NPs) (unsulfonated or sulfonated) as nanomaterials. We found that with the increase of NP loading, measured CEM permselectivity and swelling degree first increased and then decreased. We also found the ion exchange capacity (IEC) and ionic resistance of nanocomposite CEMs tend to be the same, regardless what type of NPs are incorporated into the membrane. Modeling analysis suggests that the change of membrane properties is related to the change in membrane microstructure. With the addition of silica NPs, membrane porosity (volume fraction of intergel phase) increases so that membranes can absorb more water. Also, volume fraction of sulfonated polymer segments increases, which can allow membranes to retain more counterions, causing membrane IEC to increase. By calculating the effective ion diffusion coefficients and membrane tortuosity factors of all the silica-NP-based CEMs synthesized in this study, along with nanocomposite CEMs from previous studies, we conclude that membrane ion transport efficiency tends to increase with the incorporation of nanomaterials. In addition, this paper presents a simulation model, which explains how the membrane property changes upon nanomaterial aggregation; the simulation results are in good agreement with the experimental data. Simulation results indicate that membrane properties are related to nanomaterial number concentration in the membrane matrices; thus, a plateau is reached for membrane ion diffusion coefficients due to the severe influence of aggregation on the increase of nanomaterial real number concentration. The results of this study can provide insight into membrane structure-property relation and contribute to the value of future designs of new nanocomposite IEMs. PMID- 28350449 TI - Long-Chain 4-Aminoquinolines as Quorum Sensing Inhibitors in Serratia marcescens and Pseudomonas aeruginosa. AB - Antibiotic resistance has become a serious global threat to public health; therefore, improved strategies and structurally novel antimicrobials are urgently needed to combat infectious diseases. Here we report a new type of highly potent 4-aminoquinoline derivatives as quorum sensing inhibitors in Serratia marcescens and Pseudomonas aeruginosa, exhibiting weak bactericidal activities (minimum inhibitory concentration (MIC) > 400 MUM). Through detailed structure-activity study, we have identified 7-Cl and 7-CF3 substituted N-dodecylamino-4 aminoquinolines (5 and 10) as biofilm formation inhibitors with 50% biofilm inhibition at 69 MUM and 63 MUM in S. marcescens and P. aeruginosa, respectively. These two compounds, 5 and 10, are the first quinoline derivatives with anti biofilm formation activity reported in S. marcescens. Quantitative structure activity relationship (QSAR) analysis identified structural descriptors such as Wiener indices, hyper-distance-path index (HDPI), mean topological charge (MTC), topological charge index (TCI), and log D(o/w)exp as the most influential in biofilm inhibition in this bacterial species. Derivative 10 is one of the most potent quinoline type inhibitors of pyocyanin production described so far (IC50 = 2.5 MUM). While we have demonstrated that 5 and 10 act as Pseudomonas quinolone system (PQS) antagonists, the mechanism of inhibition of S. marcescens biofilm formation with these compounds remains open since signaling similar to P. aeruginosa PQS system has not yet been described in Serratia and activity of these compounds on acylhomoserine lactone (AHL) signaling has not been detected. Our data show that 7-Cl and 7-CF3 substituted N-dodecylamino-4-aminoquinolines present the promising scaffolds for developing antivirulence and anti-biofilm formation agents against multidrug-resistant bacterial species. PMID- 28350450 TI - Evolution of the Spin Magnetic Moments and Atomic Valence of Vanadium in VCux+, VAgx+, and VAux+ Clusters (x = 3-14). AB - The atomic structures, bonding characteristics, spin magnetic moments, and stability of VCux+, VAgx+, and VAux+ (x = 3-14) clusters were examined using density functional theory. Our studies indicate that the effective valence of vanadium is size-dependent and that at small sizes some of the valence electrons of vanadium are localized on vanadium, while at larger sizes the 3d orbitals of the vanadium participate in metallic bonding eventually quenching the spin magnetic moment. The electronic stability of the clusters may be understood through a split-shell model that partitions the valence electrons in either a delocalized shell or localized on the vanadium atom. A molecular orbital analysis reveals that in planar clusters the delocalization of the 3d orbital of vanadium is enhanced when surrounded by gold due to enhanced 6s-5d hybridization. Once the clusters become three-dimensional, this hybridization is reduced, and copper most readily delocalizes the vanadium's valence electrons. By understanding these unique features, greater insight is offered into the role of a host material's electronic structure in determining the bonding characteristics and stability of localized spin magnetic moments in quantum confined systems. PMID- 28350451 TI - ROS-Switchable Polymeric Nanoplatform with Stimuli-Responsive Release for Active Targeted Drug Delivery to Breast Cancer. AB - Tumor microenvironment plays a vital role in the process of tumor development, proliferation, invasion, and metastasis. It is well acknowledged that reduction in pH, reactive oxygen species (ROS), and increased level of glucose transporter 1 (GLUT1) have become featured intracellular and extracellular biochemical markers of cancer owing to oncogenic transformation and abnormal metabolism. To establish a distinctive drug delivery system directed against the tumor microenvironment features, we develop a newly engineered polymeric nanoplatform for efficient doxorubicin (DOX) delivery with reduced systemic toxicity and high antitumor efficiency. A thioketal cross-linker is used to improve the formulation's stability during circulation and to foster quick intracellular drug release in response to tumor's ROS potential. Furthermore, the low drug loading efficiency of conventional micelles is ameliorated in this polymeric nanoplatform via a drug-conjugation strategy with an acid-labile chemical bond. The optimized formulation, MPLs-sB-DOX micelles, possesses a high drug-loading efficiency (31%) within nanosize diameter (37.8 nm). In addition, this formulation shows significant improvement in the pharmacokinetics and biodistribution profiles with a 2.69-fold increase of tumor accumulation, while with largely reduced systemic toxicity in comparison with free DOX. With advantages of efficient cellular uptake, preferential tumor accumulation, and controlled release behaviors, MPLs sB-DOX micelles demonstrate good tumor-targeting ability with reduced systemic toxicity, proving to be a promising formulation for breast cancer therapy. PMID- 28350452 TI - Velcro-Inspired SiC Fuzzy Fibers for Aerospace Applications. AB - The most recent and innovative silicon carbide (SiC) fiber ceramic matrix composites, used for lightweight high-heat engine parts in aerospace applications, are woven, layered, and then surrounded by a SiC ceramic matrix composite (CMC). To further improve both the mechanical properties and thermal and oxidative resistance abilities of this material, SiC nanotubes and nanowires (SiCNT/NWs) are grown on the surface of the SiC fiber via carbon nanotube conversion. This conversion utilizes the shape memory synthesis (SMS) method, starting with carbon nanotube (CNT) growth on the SiC fiber surface, to capitalize on the ease of dense surface morphology optimization and the ability to effectively engineer the CNT-SiC fiber interface to create a secure nanotube fiber attachment. Then, by converting the CNTs to SiCNT/NWs, the relative morphology, advantageous mechanical properties, and secure connection of the initial CNT-SiC fiber architecture are retained, with the addition of high temperature and oxidation resistance. The resultant SiCNT/NW-SiC fiber can be used inside the SiC ceramic matrix composite for a high-heat turbo engine part with longer fatigue life and higher temperature resistance. The differing sides of the woven SiCNT/NWs act as the "hook and loop" mechanism of Velcro but in much smaller scale. PMID- 28350453 TI - Diazaphenoxazines and Diazaphenothiazines: Synthesis of the "Correct" Isomers Reveals They Are Highly Reactive Radical-Trapping Antioxidants. AB - The preparation of 2,4-diazaphenothiazines and 2,4-diazaphenoxazines via a copper catalyzed intramolecular amination is described. Literature approaches which utilize easily accessed (2'-aminophenyl) 4-pyri(mi)dyl sulfides undergo a Smiles rearrangement that gives rise to the 1,3-diaza derivatives instead, confirmed by X-ray crystallography. Inversion of the polarity of the cyclization avoids the rearrangement and affords the desired products. Preliminary kinetic studies suggest that 2,4-diazaphenothiazines and diazaphenoxazines, but not the 1,3-diaza isomers, are remarkably potent radical-trapping antioxidants. PMID- 28350454 TI - Structural Optimizations of Thieno[3,2-b]pyrrole Derivatives for the Development of Metabolically Stable Inhibitors of Chikungunya Virus. AB - Chikungunya virus (CHIKV) is a re-emerging vector-borne alphavirus, and there is no approved effective antiviral treatment currently available for CHIKV. We previously reported the discovery of thieno[3,2-b]pyrrole 1b that displayed good antiviral activity against CHIKV infection in vitro. However, it has a short half life in the presence of human liver microsomes (HLMs) (T1/2 = 2.91 min). Herein, we report further optimization studies in which potential metabolically labile sites on compound 1b were removed or modified, resulting in the identification of thieno[3,2-b]pyrrole 20 and pyrrolo[2,3-d]thiazole 23c possessing up to 17-fold increase in metabolic half-lives in HLMs and good in vivo pharmacokinetic properties. Compound 20 not only attenuated viral RNA production and displayed broad-spectrum antiviral activity against other alphaviruses and CHIKV isolates but also exhibited limited cytotoxic liability (CC50 > 100 MUM). These studies have identified two compounds that have the potential for further development as antiviral drugs against CHIKV infection. PMID- 28350455 TI - Model-Based Classification for Digital PCR: Your Umbrella for Rain. AB - Standard data analysis pipelines for digital PCR estimate the concentration of a target nucleic acid by digitizing the end-point fluorescence of the parallel micro-PCR reactions, using an automated hard threshold. While it is known that misclassification has a major impact on the concentration estimate and substantially reduces accuracy, the uncertainty of this classification is typically ignored. We introduce a model-based clustering method to estimate the probability that the target is present (absent) in a partition conditional on its observed fluorescence and the distributional shape in no-template control samples. This methodology acknowledges the inherent uncertainty of the classification and provides a natural measure of precision, both at individual partition level and at the level of the global concentration. We illustrate our method on genetically modified organism, inhibition, dynamic range, and mutation detection experiments. We show that our method provides concentration estimates of similar accuracy or better than the current standard, along with a more realistic measure of precision. The individual partition probabilities and diagnostic density plots further allow for some quality control. An R implementation of our method, called Umbrella, is available, providing a more objective and automated data analysis procedure for absolute dPCR quantification. PMID- 28350456 TI - Starch-Derived Nanographene Oxide Paves the Way for Electrospinnable and Bioactive Starch Scaffolds for Bone Tissue Engineering. AB - A straightforward process that enabled electrospinning of bioactive starch-based nanofiber scaffolds was developed by utilizing starch derived nano graphene oxide (nGO) as a property enhancer and formic acid as a solvent and esterification reagent. The reaction mechanism and process were followed by detailed spectroscopic investigation. Furthermore, the incorporation of nGO as a "green bioactive additive" endorsed starch nanofibrous scaffolds several advantageous functionalities including improved electrospinnability and thermal stability, good cytocompatibility, osteo-bioactivity, and retained biodegradability. The biodegradable starch/nGO nanofibers underwent simultaneous degradation and mineralization process during 1 week of cell culture and mineralization test, thus, mimicking the structure and function of extracellular matrices (ECMs) and indicating promise for bone tissue engineering applications. PMID- 28350457 TI - Role of Thiolate Ligand in Spin State and Redox Switching in the Cytochrome P450 Catalytic Cycle. AB - The catalytic cycle of cytochrome P450 involves a change from the resting-state, water-bound, six-coordinated form (1, low-spin state) to a five-coordinated form (2, high-spin state) upon binding of a hydrophobic substrate. Here, we used a heme-thiolate model complex (SR complex) with THF as a model of nonionic H2O to address the question of whether or not coordination of nonionic water is sufficient to induce the low-spin state. Measurements of electronic absorption spectra and magnetic properties confirmed that five-coordinated SR complex has a high-spin state, and THF-bound, six-coordinated SR has a low-spin state in dichloromethane at ambient temperature. The redox potential E1/2 (FeII/FeIII) of THF-bound SR was 80-90 mV more negative than that of five-coordinated SR. These properties indicate SR is a good model of P450. Our results suggest that thiolate coordination plays a key role in setting the low energy barrier between the high spin and low-spin states. PMID- 28350458 TI - Immobilization to Positively Charged Cellulose Nanocrystals Enhances the Antibacterial Activity and Stability of Hen Egg White and T4 Lysozyme. AB - Antibacterial bionanostructures were produced from cellulose nanocrystals (CNC) with immobilized lysozyme from hen egg white (HEW) and T4 bacteriophage, respectively. The nanocrystals were prepared from microcrystalline cellulose by ammonium persulfate oxidation with a yield of 68% and having an average size of 250 nm and low polydispersity index. HEW lysozyme (HEWL) and T4 lysozyme (T4L) were immobilized to CNC by different mechanisms including adsorption and covalent coupling to carbodiimide-activated carboxylate groups and to glutaraldehyde activated aminated CNC (Am-CNC), respectively. The effect of immobilization on the enzymatic activity (both lytic and hydrolytic) and antibacterial activity of the lysozymes was studied using different methods. Am-CNC-lysozyme conjugates retained the highest lytic activity, 86.3% and 78.3% for HEWL and T4L, respectively. They also showed enhanced bactericidal activity with high potency against Gram-positive as well as Gram-negative bacteria in a relatively shorter time as compared to the free enzymes and resulted in extensive cellular damage, as shown by transmission electron microscopy. The enhanced antibacterial activity was correlated with the increase in zeta potential of Am-CNC-lysozyme conjugates. The immobilized lysozyme preparations further exhibited enhanced storage stability at 4 and 22 degrees C. PMID- 28350459 TI - STAT3 Inhibitory Activity of Structurally Simplified Withaferin A Analogues. AB - Signal transducer and activator of transcription 3 (STAT3) is a component of the JAK/STAT pathway. Therapeutic inhibition of STAT3 has been of high interest, as its aberrant activation has been linked to cancer, inflammation, and other human diseases. The withanolide family natural product withaferin A (1) inhibits STAT3 activation. We designed, synthesized, and evaluated simplified withanolide analogues SLW1 (3) and SLW2 (4), and found that SLW1 retained the STAT3 inhibitory activity of withaferin A. PMID- 28350460 TI - Time-Dependent Model for Fluid Flow in Porous Materials with Multiple Pore Sizes. AB - An understanding of fluid transport through porous materials is critical for the development of lateral flow assays and analytical devices based on paper microfluidics. Models of fluid transport within porous materials often assume a single capillary pressure and permeability value for the material, implying that the material comprises a single pore size and that the porous material is fully saturated behind the visible wetted front. As a result, current models can lead to inaccuracies when modeling transport over long distances and/or times. A new transport model is presented that incorporates a range of pore sizes to more accurately predict the capillary transport of fluid in porous materials. The model effectively predicts the time-dependent saturation of rectangular strips of Whatman filter no. 1 paper using the manufacturer's data, published pore-size distribution measurements, and the fluid's properties. PMID- 28350461 TI - Asymmetric Cascade Assembly of 1,2-Diaza-1,3-dienes and alpha,beta-Unsaturated Aldehydes via Dienamine Activation. AB - A cascade vinylogous 1,6-Michael addition/1,4-proton shift/aza-Michael addition/hemiaminal formation sequence of 1,2-diaza-1,3-dienes and beta substituted 2-butenals has been developed under the influence of dienamine activation of a chiral secondary amine. This method exhibits high regio- and chemoselectivity and provides an efficient and straightforward approach to bicyclic l,8-diazabicyclo[3.3.0]octane skeletons with a tetrasubstituted stereogenic center with fair to excellent enantioselectivity. PMID- 28350462 TI - Automated Design Framework for Synthetic Biology Exploiting Pareto Optimality. AB - In this work we consider Pareto optimality for automated design in synthetic biology. We present a generalized framework based on a mixed-integer dynamic optimization formulation that, given design specifications, allows the computation of Pareto optimal sets of designs, that is, the set of best trade offs for the metrics of interest. We show how this framework can be used for (i) forward design, that is, finding the Pareto optimal set of synthetic designs for implementation, and (ii) reverse design, that is, analyzing and inferring motifs and/or design principles of gene regulatory networks from the Pareto set of optimal circuits. Finally, we illustrate the capabilities and performance of this framework considering four case studies. In the first problem we consider the forward design of an oscillator. In the remaining problems, we illustrate how to apply the reverse design approach to find motifs for stripe formation, rapid adaption, and fold-change detection, respectively. PMID- 28350463 TI - Is Single-Molecule Fluorescence Spectroscopy Ready To Join the Organic Chemistry Toolkit? A Test Case Involving Click Chemistry. AB - Single molecule spectroscopy (SMS) has matured to a point where it can be used as a convenient tool to guide organic synthesis and drug discovery, particularly applicable to catalytic systems where questions related to homogeneous vs heterogeneous pathways are important. SMS can look at intimate mechanistic details that can inspire major improvements of the catalyst performance, its recovery, and reuse. Here, we use the click reaction between alkynes and azides as an example where improvements at the bench have been inspired and validated using single-molecule fluorescence spectroscopy. PMID- 28350464 TI - Fluorescence Determination of Omethoate Based on a Dual Strategy for Improving Sensitivity. AB - Omethoate is a frequently used organophosphorus pesticide, and the establishment of a sensitive, selective, and simple method to determine omethoate is very important for food safety. In this paper, a dual strategy was applied to improve the detection sensitivity of omethoate. In the first strategy, graphene quantum dots (GQDs) were doped with nitrogen to increase the fluorescence quantum yield to 30%. By coupling N-GQDs with omethoate aptamer, an N-GQDs-aptamer probe was synthesized. The fluorescence of the N-GQDs-aptamer probe was turned off by graphene oxide (GO), but recovered by omethoate. Based on this principle, the fluorescence method for detecting omethoate was established with a detection limit of 0.041 nM. To further improve the detection sensitivity, the fluorescence polarization analysis method was applied as another strategy based on the polarization signal of GQDs. The detection limit was decreased to 0.029 pM by using the fluorescence polarization method. The detection limits in this paper were lower than those in other reports. The imaging of omethoate on plant leaves showed that the probe could be used for visual semiquantitative determination of omethoate. PMID- 28350465 TI - 3,5-Diarylimidazo[1,2-a]pyridines as Color-Tunable Fluorophores. AB - A new protocol for the synthesis of color-tunable fluorescent 3,5 diarylimidazo[1,2-a]pyridines has been achieved via palladium-catalyzed C-H amination of pyridinium zwitterions. Based on experimental results and computational analysis, we extracted a high correlation of photophysical properties with the theoretical concept and predicted emission wavelengths of 3,5 diarylimidazo[1,2-a]pyridines. The emission wavelengths of imidazo[1,2 a]pyridines increase as a function of the electron-withdrawing nature of the substituent on the C5-aryl group of imidazo[1,2-a]pyridine as a result of inductive effects on the LUMO levels. Varying the substituent on the C3-aryl group imidazo[1,2-a]pyridine changes the HOMO levels. Combining these two sites, the HOMO and LUMO levels can be tuned fairly decoupled from each other. This conceptual trend is demonstrated across a series where the C3 and C5 positions were functionalized independently and then utilizes a combination strategy where both sites are used to prepare fluorophores with a large window of emission wavelengths. In view of the biological properties of imidazo[1,2-a]pyridines, the developed method provides an efficient approach for understanding and preparing strongly fluorescent bioprobes. PMID- 28350466 TI - Wrapping Aligned Carbon Nanotube Composite Sheets around Vanadium Nitride Nanowire Arrays for Asymmetric Coaxial Fiber-Shaped Supercapacitors with Ultrahigh Energy Density. AB - The emergence of fiber-shaped supercapacitors (FSSs) has led to a revolution in portable and wearable electronic devices. However, obtaining high energy density FSSs for practical applications is still a key challenge. This article exhibits a facile and effective approach to directly grow well-aligned three-dimensional vanadium nitride (VN) nanowire arrays (NWAs) on carbon nanotube (CNT) fiber with an ultrahigh specific capacitance of 715 mF/cm2 in a three-electrode system. Benefiting from their intriguing structural features, we successfully fabricated a prototype asymmetric coaxial FSS (ACFSS) with a maximum operating voltage of 1.8 V. From core to shell, this ACFSS consists of a CNT fiber core coated with VN@C NWAs as the negative electrode, Na2SO4 poly(vinyl alcohol) (PVA) as the solid electrolyte, and MnO2/conducting polymer/CNT sheets as the positive electrode. The novel coaxial architecture not only fully enables utilization of the effective surface area and decreases the contact resistance between the two electrodes but also, more importantly, provides a short pathway for the ultrafast transport of axial electrons and ions. The electrochemical results show that the optimized ACFSS exhibits a remarkable specific capacitance of 213.5 mF/cm2 and an exceptional energy density of 96.07 MUWh/cm2, the highest areal capacitance and areal energy density yet reported in FSSs. Furthermore, the device possesses excellent flexibility in that its capacitance retention reaches 96.8% after bending 5000 times, which further allows it to be woven into flexible electronic clothes with conventional weaving techniques. Therefore, the asymmetric coaxial architectural design allows new opportunities to fabricate high-performance flexible FSSs for future portable and wearable electronic devices. PMID- 28350467 TI - Relating Chromophoric and Structural Disorder in Conjugated Polymers. AB - The optoelectronic properties of amorphous conjugated polymers are sensitive to the details of the conformational disorder, and spectroscopy provides the means for structural characterization of the fragments of the chain that interact with light-"chromophores". A faithful interpretation of spectroscopic conformational signatures, however, presents a theoretical challenge. Here we investigate the relationship between the ground-state optical gaps, the properties of the excited states, and the structural features of chromophores of a single molecule poly(3 hexyl)-thiophene (P3HT) using quantum-classical atomistic simulations. Our results demonstrate that chromophoric disorder arises through the interplay between excited-state delocalization and electron-hole polarization, controlled by the torsional disorder introduced by side chains. Within this conceptual framework, we predict and explain the counterintuitive spectral behavior of P3HT, a red-shifted absorption, despite shortening of chromophores, with increasing temperature. This discussion introduces the concept of disorder-induced separation of charges in amorphous conjugated polymers. PMID- 28350468 TI - Three-Dimensional Proton Beam Writing of Optically Active Coherent Vacancy Spins in Silicon Carbide. AB - Constructing quantum devices comprises various challenging tasks, especially when concerning their nanoscale geometry. For quantum color centers, the traditional approach is to fabricate the device structure after the nondeterministic placement of the centers. Reversing this approach, we present the controlled generation of quantum centers in silicon carbide (SiC) by focused proton beam in a noncomplex manner without need for pre- or postirradiation treatment. The generation depth and resolution can be predicted by matching the proton energy to the material's stopping power, and the amount of quantum centers at one specific sample volume is tunable from ensembles of millions to discernible single photon emitters. We identify the generated centers as silicon vacancies through their characteristic magnetic resonance signatures and demonstrate that they possess a long spin-echo coherence time of 42 +/- 20 MUs at room temperature. Our approach hence enables the fabrication of quantum hybrid nanodevices based on SiC platform, where spin centers are integrated into p-i-n diodes, photonic cavities, and mechanical resonators. PMID- 28350469 TI - Synthesis of Sugar-Boronic Acid Derivatives: A Class of Potential Agents for Boron Neutron Capture Therapy. AB - To date, sugar analogues that contain boronic acids as substitutes for hydroxyl groups are a class of compounds nearly unknown in the literature. The challenging synthesis of two sugar-boronic acid analogues is described, and data are retrieved on their solution behavior, stability, and toxicity. As these compounds were expected to mimic the behavior of carbohydrates, they were tested in regards to their future development as potential boron neutron capture therapy agents. PMID- 28350470 TI - Aluminum-Catalyzed Cross-Coupling of Silylalkynes with Aliphatic C-F Bonds. AB - We report the generation of aliphatic and benzylic acetylenes via reaction of primary, secondary, and tertiary aliphatic fluorides with various trimethylsilyl acetylides. These reactions are catalyzed by Al and B Lewis acids, most effectively by the extremely fluorophilic tris(pentafluorophenyl)alane, representing the first example of catalytic incorporation of alkynes into aliphatic C-F positions. The fluorophilicity of the catalysts gives rise to fluorine selectivity over other halogens, allowing orthogonal reactivity pathways. PMID- 28350471 TI - Functionalized Molybdenum Disulfide Nanosheets for 0D-2D Hybrid Nanostructures: Photoinduced Charge Transfer and Enhanced Photoresponse. AB - The high-concentration stable dispersion of free-standing mono- or few-layer transition metal dichalcogenide (TMD) nanosheets (NSs) remains a significant barrier for their application in solution-processed optoelectronic devices. Here, we report oleylamine (OLA)- and dodecanethiol (DDT)-assisted exfoliation of MoS2 NSs in nonpolar organic solvent 1,2-dichlorobenzene (DCB), which enables high concentration stable dispersion of free-standing mono- or few-layer NSs. The functionalized MoS2 NSs were further utilized for the fabrication of solution processed 0D-2D hybrids of CuInS2 quantum dots (CIS QDs) and MoS2 NSs. The strong photoluminescence (PL) quenching and decreased PL lifetimes of CIS QDs attached to MoS2 NSs indicates efficient charge transfer from photoexcited CIS to MoS2 NSs. The photocurrent of CIS/MoS2 hybrid devices is dramatically enhanced compared to that of pure CIS and pristine MoS2-based devices, confirming that efficient charge separation and transfer occur from CIS QDs to MoS2 NSs. PMID- 28350472 TI - Development of a CHO-Based Cell-Free Platform for Synthesis of Active Monoclonal Antibodies. AB - Chinese Hamster Ovary (CHO) cells are routinely optimized to stably express monoclonal antibodies (mAbs) at high titers. At the early stages of lead isolation and optimization, hundreds of sequences for the target protein of interest are screened. Typically, cell-based transient expression technology platforms are used for expression screening, but these can be time- and resource intensive. Here, we have developed a cell-free protein synthesis (CFPS) platform utilizing a commercially available CHO extract for the rapid in vitro synthesis of active, aglycosylated mAbs. Specifically, we optimized reaction conditions to maximize protein yields, established an oxidizing environment to enable disulfide bond formation, and demonstrated the importance of temporal addition of heavy chain and light chain plasmids for intact mAb production. Using our optimized platform, we demonstrate for the first time to our knowledge the cell-free synthesis of biologically active, intact mAb at >100 mg/L using a eukaryotic based extract. We then explored the utility of our system as a tool for ranking yields of candidate antibodies. Unlike stable or transient transfection-based screening, which requires a minimum of 7 days for setup and execution, results using our CHO-based CFPS platform are attained within 2 days and it is well suited for automation. Further development would provide a tool for rapid, high throughput prediction of mAb expression ranking to accelerate design-build-test cycles required for antibody expression and engineering. Looking forward, the CHO based CFPS platform could facilitate the synthesis of toxic proteins as well. PMID- 28350473 TI - Visible-Light-Induced Synthesis of Carbazoles by in Situ Formation of Photosensitizing Intermediate. AB - A visible-light-induced synthesis of N-H carbazoles from easily accessible 2,2' diaminobiaryls in the absence of any external photosensitizer is reported. The process only requires tBuONO and natural resources, visible light, and molecular oxygen for the synthesis of N-H carbazoles. Experimental and computational studies support that the in situ formation of a visible-light-absorbing photosensitizing intermediate, benzocinnoline N-imide, is responsible for the activation of triplet molecular oxygen to singlet oxygen that, in turn, promotes the synthesis of carbazole. PMID- 28350474 TI - Detachment of Membrane Bound Virions by Competitive Ligand Binding Induced Receptor Depletion. AB - Multivalent receptor-mediated interactions between virions and a lipid membrane can be weakened using competitive nonpathogenic ligand binding. In particular, the subsequent binding of such ligands can induce detachment of bound virions, a phenomenon of crucial relevance for the development of new antiviral drugs. Focusing on the simian virus 40 (SV40) and recombinant cholera toxin B subunit (rCTB), and using (monosialotetrahexosyl)ganglioside (GM1) as their common receptor in a supported lipid bilayer (SLB), we present the first detailed investigation of this phenomenon by employing the quartz crystal microbalance with dissipation (QCM-D) and total internal reflection fluorescence (TIRF) microscopy assisted 2D single particle tracking (SPT) techniques. Analysis of the QCM-D-measured release kinetics made it possible to determine the binding strength of a single SV40-GM1 pair. The release dynamics of SV40, monitored by SPT, revealed that a notable fraction of SV40 becomes mobile just before the release, allowing to estimate the distribution of SV40-bound GM1 receptors just prior to release. PMID- 28350477 TI - Individual and Dynamic: Western Views of a Good Death. PMID- 28350475 TI - Occupational Radiation Exposure and Deaths From Malignant Intracranial Neoplasms of the Brain and CNS in U.S. Radiologic Technologists, 1983-2012. AB - OBJECTIVE: Childhood exposure to acute, high-dose radiation has consistently been associated with risk of benign and malignant intracranial tumors of the brain and CNS, but data on risks of adulthood exposure to protracted, low-to-moderate doses of radiation are limited. In a large cohort of radiologic technologists, we quantified the association between protracted, low-to-moderate doses of radiation and malignant intracranial tumor mortality. MATERIALS AND METHODS: The study population included 83,655 female and 26,642 male U.S. radiologic technologists who were certified for at least 2 years as of 1982. The cohort was followed from the completion date of the first or second survey (1983-1989 or 1994-1998) to the date of death, loss to follow-up, or December 31, 2012, whichever was earliest. Occupational brain doses through 1997 were based on work history, historical data, and, for most years after the mid 1970s, individual film badge measurements. Radiation-related excess relative risks (ERRs) and 95% CIs were estimated from Poisson regression models adjusted for attained age and sex. RESULTS: Cumulative mean absorbed brain dose was 12 mGy (range, 0-290 mGy). During follow-up (median, 26.7 years), 193 technologists died of a malignant intracranial neoplasm. Based on models incorporating a 5-year lagged cumulative brain dose, cumulative brain dose was not associated with malignant intracranial tumor mortality (overall ERR per 100 mGy, 0.1; 95% CI, < -0.3 to 1.5). No effect modification was observed by sex or birth cohort. CONCLUSION: In this nationwide cohort of radiologic technologists, cumulative occupational radiation exposure to the brain was not associated with malignant intracranial tumor mortality. PMID- 28350476 TI - Initial Experience with "Honoring Choices Wisconsin": Implementation of an Advance Care Planning Pilot in a Tertiary Care Setting. AB - BACKGROUND: Although previous research on advance care planning (ACP) has associated ACP with improved quality of care at the end of life, the appropriate use of ACP remains limited. OBJECTIVE: To evaluate the impact of a pilot program using the "Honoring Choices Wisconsin" (HCW) model for ACP in a tertiary care setting, and to understand barriers to system-wide implementation. DESIGN: Retrospective review of prospectively collected data. SETTING/SUBJECTS: Patients who received medical or surgical oncology care at Froedtert and the Medical College of Wisconsin. MEASUREMENTS: Patient demographics, disease characteristics, patient satisfaction, and clinical outcomes. RESULTS: Data from 69 patients who died following the implementation of the HCW program were reviewed; 24 patients were enrolled in the HCW program while 45 were not. Patients enrolled in HCW were proportionally less likely to be admitted to the ICU (12.5% vs. 17.8%) and were more likely to be "do not resuscitate" (87.5% vs. 80.0%), as well as have a completed ACP (83.3% vs. 79.1%). Furthermore, admission to a hospice was also higher among patients who were enrolled in the HCW program (79.2% vs. 25.6%), with patients enrolled in HCW more likely to die in hospice (70.8% vs. 53.3%). The HCW program was favorably viewed by patients, patient caregivers, and healthcare providers. CONCLUSIONS: Implementation of a facilitator-based ACP care model was associated with fewer ICU admissions, and a higher use of hospice care. System-level changes are required to overcome barriers to ACP that limit patients from receiving end-of-life care in accordance with their preferences. PMID- 28350478 TI - Importance of Chemical Communication in Ecology. PMID- 28350479 TI - Treating Sexual Side Effects from Oral Contraceptive Pills. PMID- 28350481 TI - A Qualitative Study of a Maintenance Support Program for Women at Risk of Homelessness: Part 2: Situational Factors. AB - People who are homeless tend to have a number of complex needs. A housing maintenance support program (MSP) for women from the perspectives of clients, case managers and health professionals within the program was explored in this qualitative descriptive study. Interviews were conducted, and data were analysed using thematic analysis. The overarching theme that emerged from the data was "A life-changing event: I have the power to change." This theme was supported by three sub-themes: personal, situational and societal dimensions. In this article, the sub-theme - situational factors, is presented and refers to poverty, resources and services, as well as social support systems. These aspects all impinged on the client's ability to face life changes with optimism towards a better future. Their experiences of disconnection with the community changed for the clients after being part of the MSP. The MSP enabled the clients to feel part of society again, and empowered them to participate in the world around them. Key aspects of inclusion in the world are relationships based on acceptance, connecting with others, being involved and creating a sense of home/community. PMID- 28350480 TI - Lung Cancer in Never-Smoking Women: A Sub-Analysis of the Spanish Female-Specific Database WORLD07. AB - The WORLD07 study characterizes lung cancer in Spanish women. This analysis investigated lung cancer features in never-smoking women. Of 2072 women recruited, 2035 were analyzed. Patient characteristics and demographics were similar for current/former smokers and never smokers. Among never smokers, 38.3% were exposed to passive smoking. Non-small-cell lung cancer was the most common type (78.8% of current/former smokers and 96.1% of never smokers) and adenocarcinoma the most common histology (69.1% and 83.4% respectively). There was a high incidence of lung cancer in Spanish never-smoking women and a high proportion (about 50%) had mutant epidermal growth factor receptor. PMID- 28350482 TI - Analysis of the Revision Process by American Journal of Roentgenology Reviewers and Section Editors: Metrics of Rejected Manuscripts and Their Final Disposition. AB - OBJECTIVE: The objective of this study was to evaluate metrics related to manuscripts rejected by AJR with and without review during 2014 and to determine their final disposition: no record of eventual publication, eventually published, published with modified authors and title, published with the same title but modified authors, and published with modified title but the same authors. MATERIALS AND METHODS: A total of 1245 unsolicited manuscripts submitted from January to December 2014 were included in this retrospective analysis. Data were extracted from the AJR's manuscript submission system. Standard statistical analysis was used to assess the fate of a sample of 200 rejected manuscripts. RESULTS: Of the 200 manuscripts studied, 117 (59%) were published in other scientific journals (61 with revision, 56 without revision; Chi2 = 0.329, p = 0.566). Thirty-two of the 61 manuscripts (52%) rejected after peer review were later published in other journals without changes in their titles or authors, 16 (26%) with changes only in authors, 10 (16%) with changes only in their titles, and three (5%) with changes in authors and titles. Twenty-six of the 56 manuscripts (46%) rejected without peer review were published without changes in their titles or authors, 17 (30%) with changes in authors, 11 (20%) with changes only in their titles, and two (4%) with changes in both authors and titles (p = 0.686). Ten articles were published in open access journals. Of the remaining articles, those that had been reviewed were published in journals with a mean impact factor +/- SD of 2.37 +/- 1.30, and those that had not been reviewed were published in journals with a mean impact factor of 2.04 +/- 1.06. Analysis of the 25th and 75th percentiles revealed that values were also higher for the group rejected with review (Wilcoxon rank sum test: W = 1679, p = 0.1127). Out of 61 articles rejected for publication with review, 52.5% were published with changes to their abstracts, whereas the remaining 47.5% were unchanged. CONCLUSION: This analysis found that manuscripts submitted to AJR that were rejected after review were published in journals with higher impact factors than those rejected without review. The commentaries provided by AJR reviewers and section editors appear to improve the quality of rejected manuscripts and thus contribute to the scientific community. PMID- 28350483 TI - A Qualitative Study of a Maintenance Support Program for Women at Risk of Homelessness: Part 1: Personal Factors. AB - In this article, a qualitative study of homeless women and their experiences attending a Maintenance Support Programme (MSP) is discussed. The overarching theme that emerged from the study of women in the MSP was 'A life-changing event: I have the power to change'. The article focuses on the first of the sub-themes: personal factors including: (a) health status, (b) beliefs and attitudes, (c) knowledge, and (d) life and interpersonal skills. Findings demonstrate the influence that these factors have on the capacity of homeless women to change their lives. The MSP was instrumental in supporting these women to manage personal issues, by assisting with accessing health and social services, and developing life skills and achieving life goals. Understanding the homeless women's experiences may inform the development of future programmes and services in order to support and empower them to break the cycle of homelessness and help them to lead meaningful lives within society. PMID- 28350484 TI - Variability in Radiation Dose From Repeat Identical CT Examinations: Longitudinal Analysis of 2851 Patients Undergoing 12,635 Thoracoabdominal CT Scans in an Academic Health System. AB - OBJECTIVE: The purpose of this study was to conduct longitudinal analyses of radiation dose data from adult patients undergoing clinically indicated, repeat identical thoracoabdominal CT examinations. MATERIALS AND METHODS: Radiation dose data were electronically collected from 2851 subjects undergoing 12,635 repeat identical CT scans (mean number of scans per patient, 4.8; range, 2-33) in one health system. Included CT protocols were chest-abdomen-pelvis with contrast administration (n = 4621 CT studies of 1064 patients), abdomen-pelvis with contrast administration (n = 876 CT studies of 261 patients), renal stone (n = 1053 CT studies of 380 patients), and chest (n = 6085 CT studies of 1146 patients) without contrast administration. A radiation-tracking software infrastructure was adopted to extract data from DICOM headers in PACS. Size specific dose estimate (SSDE) was calculated. RESULTS: A trend was observed toward global reduction in SSDE values with all protocols investigated (chest abdomen-pelvis slope, -1.78; abdomen-pelvis slope, -0.82; renal stone slope, 0.83; chest slope, -0.47; p < 0.001 for all comparisons). The intraindividual analyses of radiation dose distribution showed widespread variability in SSDE values across the four protocols investigated (chest-abdomen-pelvis mean coefficient of variance, 14.02 mGy; abdomen-pelvis mean coefficient of variance, 10.26 mGy; renal stone mean coefficient of variance, 34.18 mGy; chest mean coefficient of variance, 6.74 mGy). CONCLUSION: Although there is a trend toward global reduction in radiation doses, this study showed widespread variability in the radiation dose that each patient undergoing identical repeat thoracoabdominal CT protocols absorbs. These data may provide a foundation for the future development of best-practice guidelines for patient-specific radiation dose monitoring. PMID- 28350485 TI - CT Findings, Radiologic-Pathologic Correlation, and Imaging Predictors of Survival for Patients With Interstitial Pneumonia With Autoimmune Features. AB - OBJECTIVE: The objective of this study is to determine the CT findings and patterns of interstitial pneumonia with autoimmune features (IPAF) and to assess whether imaging can predict survival for patients with IPAF. MATERIALS AND METHODS: The study included 136 subjects who met the criteria for IPAF and had diagnostic-quality chest CT scans obtained from 2006 to 2015; a total of 74 of these subjects had pathologic samples available for review within 1 year of chest CT examination. CT findings and the presence of an usual interstitial pneumonitis (UIP) pattern of disease were assessed, as was the UIP pattern noted on pathologic analysis. Analysis of chest CT findings associated with survival was performed using standard univariate and multivariate Cox proportional hazards methods as well as the unadjusted log-rank test. Survival data were visually presented using the Kaplan-Meier survival curve estimator. RESULTS: Most subjects with IPAF (57.4%; 78/136) had a high-confidence diagnosis of a UIP pattern on CT. Substantially fewer subjects (28.7%; 39/136) had a pattern that was inconsistent with UIP noted on CT. The presence of a UIP pattern on CT was associated with smoking (p < 0.01), male sex (p < 0.01), and older age (p < 0.001). Approximately one-fourth of the subjects had a nonspecific interstitial pneumonitis pattern on CT. Of interest, nearly one-tenth of the subjects had a CT pattern that was most consistent with hypersensitivity pneumonitis rather than the customary CT patterns ascribed to lung disease resulting from connective tissue disease. Most subjects with a possible UIP pattern on CT (83.3%) had UIP diagnosed on the basis of pathologic findings. Focused multivariate analysis showed that honeycombing on CT (hazard ratio, 2.17; 95% CI, 1.05-4.47) and pulmonary artery enlargement on CT (hazard ratio, 2.08; 95% CI, 1.02-4.20) were independent predictors of survival. CONCLUSION: IPAF most often presents with a UIP pattern on CT and is associated with worse survival when concomitant honeycombing or pulmonary artery enlargement is present. PMID- 28350486 TI - Predictive Clinicopathologic and Dynamic Contrast-Enhanced MRI Findings for Tumor Response to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer. AB - OBJECTIVE: The purpose of this study is to investigate whether clinicopathologic factors and dynamic contrast-enhanced MRI (DCE-MRI) features are associated with pathologic tumor response to neoadjuvant chemotherapy (NAC) in patients with triple-negative breast cancer (TNBC). MATERIALS AND METHODS: Seventy-three patients with TNBC who underwent pre-NAC MRI, completed NAC, and underwent surgery between January 2009 and December 2010 were included in the study. MRI features and clinicopathologic factors for predicting pathologic responses were analyzed, and residual tumor sizes, as measured using MRI and surgical specimens, were evaluated. RESULTS: Of 73 study patients, 20 (27%) had a pathologic complete response (pCR). Homogeneous enhancement on pre-NAC MRI (odds ratio from multivariate analysis, 14.66) and a concentric shrinkage pattern of tumor volume reduction on post-NAC MRI (odds ratio, 8.63) were independently associated with pCR. Residual tumor sizes, as measured using MRI and surgical specimens, showed a strong correlation (r = 0.652, p < 0.001). The correlation for residual tumor sizes was stronger for patients with pCR (r = 0.600, p < 0.001) and those with a concentric shrinkage pattern (r = 0.818, p < 0.001) than for patients with a response other than near pCR or pCR (i.e., the non-pCR group) (r = -0.128, p = 0.590) and patients with a dendritic shrinkage pattern of tumor volume reduction (r = 0.270, p = 0.182). CONCLUSION: Homogeneous enhancement of tumors on pre-NAC MRI and the presence of a concentric shrinkage pattern after NAC are associated with pCR in patients with TNBC. Residual tumor sizes on MRI and surgical specimens tended to show a stronger correlation in the pCR group or the concentric shrinkage group than in the non-pCR group or the dendritic shrinkage group. PMID- 28350487 TI - Epidemiology and Outcomes of Lisfranc Injuries Identified at the National Football League Scouting Combine. AB - BACKGROUND: Lisfranc injuries are challenging to treat and may have a detrimental effect on athletic performance. PURPOSE: (1) Determine the epidemiological characteristics of Lisfranc injuries at the annual National Football League (NFL) Scouting Combine, (2) define player positions at risk for these injuries, and (3) evaluate the impact that these injuries and radiographic findings have on NFL draft position and performance. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: All players who sustained a Lisfranc injury prior to Combine evaluation between 2009 and 2015 were evaluated. The epidemiological characteristics, player positions affected, treatment methods, and number of missed collegiate games were recorded. Radiographic outcomes were analyzed via Combine radiograph findings, while NFL performance outcomes were assessed for all Lisfranc injuries (2009 2013) compared with matched controls in the first 2 years of play. RESULTS: A total of 41 of 2162 (1.8%) Combine participants were identified with Lisfranc injuries, of whom 26 of 41 (63.4%) were managed operatively. Players who underwent surgery were more likely to go undrafted compared with players managed nonoperatively (38.5% vs 13.3%, operative vs nonoperative management, respectively; P = .04) and featured a worse NFL draft pick position (155.6 vs 109; P = .03). Lisfranc-injured players when compared with controls were noted to have worse outcomes in terms of NFL draft position (142 vs 111.3, Lisfranc injured players vs controls, respectively; P = .04), NFL career length 2 years or longer (62.5% vs 69.6%; P = .23), and number of games played (16.9 vs 23.3; P = .001) and started (6.8 vs 10.5; P = .08) within the first 2 years of their NFL career. Radiographs demonstrated that 17 of 41 (41.5%) athletes had residual Lisfranc joint displacement greater than 2 mm compared with the contralateral foot. Lisfranc-injured athletes with greater than 2 mm residual displacement, when compared with matched controls, had worse draft position (156.9 vs 111.2 for Lisfranc-injured players vs controls, respectively; P = .009) and fewer games played (14.4 vs 23.3; P = .001) and started (3.1 vs 10.5; P = .03). Moreover, athletes with greater than 2 mm residual displacement featured worse outcomes across all assessed NFL variables versus athletes with residual displacement of 2 mm or less. CONCLUSION: Lisfranc injuries identified at the NFL Combine have an adverse effect on an NFL athlete's draft status, draft position, and overall play during initial NFL seasons. In particular, residual displacement of the Lisfranc joint has a detrimental effect on the first 2 seasons of NFL play and may lead to long-lasting negative effects on the athlete's career. PMID- 28350488 TI - Effect of Supplemental Trace Minerals on Hsp-70 mRNA Expression in Commercial Broiler Chicken. AB - The effects of supplementing the organic forms of selenium (Se), chromium (Cr), and zinc (Zn) on Hsp-70 mRNA expression and body weight in broiler chickens were evaluated. 200 chicks were equally distributed into stainless steel battery brooders at the rate of 5 birds per pen and reared under heat stress condition up to 42nd day. The chicks were fed with three experimental diets supplemented with organic forms of Se (0.30 mg/kg), Cr (2 mg/kg), and Zn (40 mg/kg) during the starter and finisher phases and a control diet without any supplementation. On the 21st and 42nd day, 20 birds from each period were sacrificed and samples were collected for analysis. Organic Se, Cr, and Zn supplementation significantly (P < 0.05) reduced the expression of Hsp-70 mRNA levels. The Hsp-70 mRNA expression levels were significantly (P < 0.05) different between the tissues studied with spleen having the lowest expression level. Hsp-70 mRNA expression level was not affected by age of the birds. The study concluded that organic trace mineral (oTM) supplementation resulted in low Hsp-70 mRNA expression, indicating reduced heat stress in broilers. PMID- 28350489 TI - Redescription and Molecular Assessment of Relationships Among Three Species of Echeneibothrium (Rhinebothriidea: Echeneibothriidae) Parasitizing the Yellownose Skate, Dipturus chilensis, in Chile. AB - Much progress has recently been made in revising the taxonomic assignments of genera originally classified in the polyphyletic "Tetraphyllidea." Many of these genera, including Echeneibothrium, were accommodated in the order Rhinebothriidea. However, beyond this larger taxonomic action, little work has been conducted on this genus over the past 50 yr. Consequently, the criteria used for characterizing species of Echeneibothrium have lagged behind those typically used in more modern descriptions of elasmobranch-hosted cestode taxa. A series of collecting trips to Chile to obtain cestodes from the yellownose skate, Dipturus chilensis , provided a unique opportunity to apply modern morphological and molecular methods to investigate the 3 species of Echeneibothrium reported parasitizing this skate, specifically Echeneibothrium megalosoma, Echeneibothrium multiloculatum, and Echeneibothrium williamsi. In addition to redescribing all 3 species, using morphological data from light and scanning electron microscopy, maximum likelihood and bayesian inference phylogenetic analyses of the D1-D3 regions of the 28S rDNA gene were conducted to assess their relationships among other echeneibothriids for which comparable data are available. Sequencing of 59 specimens representing these 3 species of Echeneibothrium allowed us to assess the intra- and interspecific variation in the 28S rDNA gene. The redescriptions use standardized terminology for scolex morphology, proglottid anatomy, and microthrix forms and pattern; they also expand on the original descriptions to include data on scolex size, ovary size, vas deferens and vaginal configurations, testes arrangement, and genital pore position. Our morphological work led to a major reinterpretation of the scolex morphology with the recognition that all 3 species bear an apical bothridial sucker, rather than an apical loculus, prompting emendation of the diagnosis for the family Echeneibothriidae. The presence of a band of spinitriches at the apex of the apical modification of the scolex proper seems to represent an important feature for distinguishing the 2 portions of the myzorhynchus across species. Intraspecific variation ranged from 0 to 7 bp across species and interspecific variation ranged from a low of 39-46 bp between E. williamsi and E. multiloculatum to a high of 61-66 bp between E. multiloculatum and E. megalosoma. Phylogenetic analyses indicate that the 3 species of Echeneibothrium hosted by the yellownose skate are not each other's closest relatives, suggesting multiple colonization events of D. chilensis have occurred. Further phylogenetic investigation is also likely to confirm the status of the genus Pseudanthobothrium as a synonym of Echeneibothrium because its species generally group among members of Echeneibothrium. PMID- 28350490 TI - Single Center Experience on Anatomy-and Histopathology-Based Gastric Cancer Molecular Classification. AB - We analyzed the clinical utility of molecular classification based on anatomical and histological background. The study was conducted on 457 patients treated for gastric cancer with additional information about microsatellite instability status. We divided the patients in three groups of molecular classification based on anatomical and histological background: proximal non-diffused, diffused, and distal non-diffused groups. These groups varied in terms of clinical and pathological factors as well as survival rates. The molecular classification based on anatomical and histological data seems to be a useful tool in a simple classification of gastric cancer. PMID- 28350491 TI - Liver-Directed Therapy for Hepatocellular Carcinoma: An Overview of Techniques, Outcomes, and Posttreatment Imaging Findings. AB - OBJECTIVE: The purposes of this article are to describe the indications, techniques, and results of arterially directed therapies and ablation and to review the imaging assessment of response and complications. CONCLUSION: Most patients with hepatocellular carcinoma are not eligible for surgery, and systemic treatments are suboptimal. Therefore, locoregional therapy plays a large role in this disease. Locoregional therapies include arterially directed therapies, ablation, and radiation therapy. PMID- 28350492 TI - Addressing Stillbirth in India Must Include Men. AB - BACKGROUND: Millennium Development Goal 4, to reduce child mortality, can only be achieved by reducing stillbirths globally. A confluence of medical and sociocultural factors contribute to the high stillbirth rates in India. The psychosocial aftermath of stillbirth is a well-documented public health problem, though less is known of the experience for men, particularly outside of the Western context. Therefore, men's perceptions and knowledge regarding reproductive health, as well as maternal-child health are important. METHODS: Key informant interviews (n = 5) were analyzed and 28 structured interviews were conducted using a survey based on qualitative themes. RESULTS: Qualitative themes included men's dual burden and right to medical and reproductive decision making power. Wives were discouraged from expressing grief and pushed to conceive again. If not successful, particularly if a son was not conceived, a second wife was considered a solution. Quantitative data revealed that men with a history of stillbirths had greater anxiety and depression, perceived less social support, but had more egalitarian views towards women than men without stillbirth experience. At the same time fathers of stillbirths were more likely to be emotionally or physically abusive. Predictors of mental health, attitudes towards women, and perceived support are discussed. CONCLUSIONS: Patriarchal societal values, son preference, deficient women's autonomy, and sex-selective abortion perpetuate the risk for future poor infant outcomes, including stillbirth, and compounds the already higher risk of stillbirth for males. Grief interventions should explore and take into account men's perceptions, attitudes, and behaviors towards reproductive decision making. PMID- 28350493 TI - Fitness Consequences of Boldness in Juvenile and Adult Largemouth Bass. AB - To date, most studies investigating the relationship between personality traits and fitness have focused on a single measure of fitness (such as survival) at a specific life stage. However, many personality traits likely have multiple effects on fitness, potentially operating across different functional contexts and stages of development. Here, we address the fitness consequences of boldness, under seminatural conditions, across life stages and functional contexts in largemouth bass (Micropterus salmoides). Specifically, we report the effect of boldness on (1) juvenile survivorship in an outdoor pond containing natural prey and predators and (2) adult reproductive success in three outdoor ponds across three reproductive seasons (years). Juvenile survival was negatively affected by boldness, with bolder juveniles having a lower probability of survival than shyer juveniles. In contrast, bolder adult male bass had greater reproductive success than their shyer male counterparts. Female reproductive success was not affected by boldness. These findings demonstrate that boldness can affect fitness differently across life stages. Further, boldness was highly consistent across years and significantly heritable, which suggests that boldness has a genetic component. Thus, our results support theory suggesting that fitness trade-offs across life stages may contribute to the maintenance of personality variation within populations. PMID- 28350494 TI - Expanding the Link between Out-Group Threats and In-Group Behavior: (A Reply to Kavaliers and Choleris). AB - In social species, groups and their members face a variety of threats from conspecific outsiders. Such out-group conflict is predicted to influence within group behavior, with empirical work demonstrating this link in humans, primates, and birds. In our note "Out-Group Threat Promotes Within-Group Affiliation in a Cooperative Fish," appearing in The American Naturalist in February 2016, we provided experimental evidence that simulated territorial intrusions result in subsequent increases in affiliation among groupmates in a cichlid fish (Neolamprologus pulcher). Martin Kavaliers and Elena Choleris, in their comment "Out-Group Threat Responses, In-Group Bias, and Nonapeptide Involvement Are Conserved Across Vertebrates," appearing in this issue, commented on our cichlid fish article; they consider the conserved nature of the link between out-group threat and in-group behavior and bias in vertebrates, the influence of pathogens in the process, and the potential underpinning hormonal mechanisms. Here, we provide clarification and expansion of some of the core points that are discussed in the comment by Kavaliers and Choleris. PMID- 28350495 TI - Out-Group Threat Responses, In-Group Bias, and Nonapeptide Involvement Are Conserved across Vertebrates: (A Comment on Bruintjes et al., "Out-Group Threat Promotes Within-Group Affiliation in a Cooperative Fish"). AB - The challenges and threats posed by out-groups have major effects on human social behavior and how individuals interact with one another. We briefly review evidence here that out-group threat similarly affects nonhuman animal behavior. Actual and potential threats posed by out-group individuals (unfamiliar and genetically nonrelated individuals of the same species) affect social behavior promoting "out-group" avoidance and "in-group" bias and enhancing in-group (familiar and/or genetically related individuals) affiliation and interactions. Individuals from out-groups present risks of pathogen exposure as well as being threats to resources, territory, and offspring. All of these threats function to promote in-group bias in humans and nonhumans. There are also striking similarities in the underlying neurobiological mechanisms mediating the responses to out-group threat and the expression of in-group bias. In particular, the evolutionarily conserved, hormone-regulated nonapeptide systems (oxytocin, arginine-vasopressin, and homologous neuropeptides and their receptors) are involved in the mediation of the detection and avoidance of out-groups and response to in-groups and facilitation of in-group responses across multiple vertebrate species. Consequently, comparative investigations of both the behavioral expression of and the mechanism underlying out-group avoidance and in group bias are necessary for a full understanding of the evolution of social behavior and responses to in- and out-groups. PMID- 28350496 TI - Fundamental Theorems of Evolution. AB - Evolutionary biology is undergirded by an extensive and impressive set of mathematical models. Yet only one result, Fisher's theorem about selection and fitness, is generally accorded the status of a fundamental theorem. I argue that although its fundamental status is justified by its simplicity and scope, there are additional results that seem similarly fundamental. I suggest that the most fundamental theorem of evolution is the Price equation, both because of its simplicity and broad scope and because it can be used to derive four other familiar results that are similarly fundamental: Fisher's average-excess equation, Robertson's secondary theorem of natural selection, the breeder's equation, and Fisher's fundamental theorem. These derivations clarify both the relationships behind these results and their assumptions. Slightly less fundamental results include those for multivariate evolution and social selection. A key feature of fundamental theorems is that they have great simplicity and scope, which are often achieved by sacrificing perfect accuracy. Quantitative genetics has been more productive of fundamental theorems than population genetics, probably because its empirical focus on unknown genotypes freed it from the tyranny of detail and allowed it to focus on general issues. PMID- 28350497 TI - Clines Arc through Multivariate Morphospace. AB - Evolutionary biologists typically represent clines as spatial gradients in a univariate character (or a principal-component axis) whose mean changes as a function of location along a transect spanning an environmental gradient or ecotone. This univariate approach may obscure the multivariate nature of phenotypic evolution across a landscape. Clines might instead be plotted as a series of vectors in multidimensional morphospace, connecting sequential geographic sites. We present a model showing that clines may trace nonlinear paths that arc through morphospace rather than elongating along a single major trajectory. Arcing clines arise because different characters diverge at different rates or locations along a geographic transect. We empirically confirm that some clines arc through morphospace, using morphological data from threespine stickleback sampled along eight independent transects from lakes down their respective outlet streams. In all eight clines, successive vectors of lake-stream divergence fluctuate in direction and magnitude in trait space, rather than pointing along a single phenotypic axis. Most clines exhibit surprisingly irregular directions of divergence as one moves downstream, although a few clines exhibit more directional arcs through morphospace. Our results highlight the multivariate complexity of clines that cannot be captured with the traditional graphical framework. We discuss hypotheses regarding the causes, and implications, of such arcing multivariate clines. PMID- 28350498 TI - Evolutionary Assembly of Communities in Butterfly Mimicry Rings. AB - Species co-occurrence in ecological communities is thought to be influenced by multiple ecological and evolutionary processes, especially colonization and competition. However, effects of other interspecific interactions and evolutionary relationships are less explored. We examined evolutionary histories of community members and roles of mutualistic and parasitic interactions (Mullerian and Batesian mimicry, respectively) in the assembly of mimetic butterfly communities called mimicry rings in tropical forests of the Western Ghats, India. We found that Mullerian mimics were phylogenetically clustered, sharing aposematic signals due to common ancestry. On the other hand, Batesian mimics joined mimicry rings through convergent evolution and random phylogenetic assembly. Since the Western Ghats are a habitat island, we compared species diversity and composition in its mimicry rings with those of habitat mainland to test effects of biogeographic connectivity. The Western Ghats consisted of fewer mimicry rings and an overall smaller number of aposematic species and mimics compared to habitat mainland. The depauperate mimicry rings in the Western Ghats could have resulted from stochastic processes, reflecting their long temporal and spatial isolation and trickling colonization by the mimetic butterfly communities. These results highlight how evolutionary history, biogeographic isolation, and stochastic colonization influence the evolutionary assembly and diversity of ecological communities. PMID- 28350499 TI - Determining Selection across Heterogeneous Landscapes: A Perturbation-Based Method and Its Application to Modeling Evolution in Space. AB - Spatial structure can decisively influence the way evolutionary processes unfold. To date, several methods have been used to study evolution in spatial systems, including population genetics, quantitative genetics, moment-closure approximations, and individual-based models. Here we extend the study of spatial evolutionary dynamics to eco-evolutionary models based on reaction-diffusion equations and adaptive dynamics. Specifically, we derive expressions for the strength of directional and stabilizing/disruptive selection that apply both in continuous space and to metacommunities with symmetrical dispersal between patches. For directional selection on a quantitative trait, this yields a way to integrate local directional selection across space and determine whether the trait value will increase or decrease. The robustness of this prediction is validated against quantitative genetics. For stabilizing/disruptive selection, we show that spatial heterogeneity always contributes to disruptive selection and hence always promotes evolutionary branching. The expression for directional selection is numerically very efficient and hence lends itself to simulation studies of evolutionary community assembly. We illustrate the application and utility of the expressions for this purpose with two examples of the evolution of resource utilization. Finally, we outline the domain of applicability of reaction diffusion equations as a modeling framework and discuss their limitations. PMID- 28350500 TI - Local Adaptation Interacts with Expansion Load during Range Expansion: Maladaptation Reduces Expansion Load. AB - The biotic and abiotic factors that facilitate or hinder species range expansions are many and complex. We examine the impact of two genetic processes and their interaction on fitness at expanding range edges: local maladaptation resulting from the presence of an environmental gradient and expansion load resulting from increased genetic drift at the range edge. Results from spatially explicit simulations indicate that the presence of an environmental gradient during range expansion reduces expansion load; conversely, increasing expansion load allows only locally adapted populations to persist at the range edge. Increased maladaptation reduces the speed of range expansion, resulting in less genetic drift at the expanding front and more immigration from the range center, therefore reducing expansion load at the range edge. These results may have ramifications for species being forced to shift their ranges because of climate change or other anthropogenic changes. If rapidly changing climate leads to faster expansion as populations track their shifting climatic optima, populations may suffer increased expansion load beyond previous expectations. PMID- 28350501 TI - Trophic Strategies of Unicellular Plankton. AB - Unicellular plankton employ trophic strategies ranging from pure photoautotrophs over mixotrophy to obligate heterotrophs (phagotrophs), with cell sizes from 10-8 to 1 MUg C. A full understanding of how trophic strategy and cell size depend on resource environment and predation is lacking. To this end, we develop and calibrate a trait-based model for unicellular planktonic organisms characterized by four traits: cell size and investments in phototrophy, nutrient uptake, and phagotrophy. We use the model to predict how optimal trophic strategies depend on cell size under various environmental conditions, including seasonal succession. We identify two mixotrophic strategies: generalist mixotrophs investing in all three investment traits and obligate mixotrophs investing only in phototrophy and phagotrophy. We formulate two conjectures: (1) most cells are limited by organic carbon; however, small unicellulars are colimited by organic carbon and nutrients, and only large photoautotrophs and smaller mixotrophs are nutrient limited; (2) trophic strategy is bottom-up selected by the environment, while optimal size is top-down selected by predation. The focus on cell size and trophic strategies facilitates general insights into the strategies of a broad class of organisms in the size range from micrometers to millimeters that dominate the primary and secondary production of the world's oceans. PMID- 28350502 TI - Complex Relationships between Competing Guilds along Large-Scale Environmental Gradients. AB - Despite much research over the past 30 years, there is still little general understanding of how the outcomes of interactions vary along environmental gradients, particularly at large geographic scales. A simple expectation is that decreasing environmental quality should reduce densities of competitors and hence the effects of competition should weaken in poorer environments. A counterintuitive consequence is that associations between densities of competitors might change from negative to positive as environments decrease in quality. Here we test these predictions in a set of vascular plant communities where perennial species share space and resources with less competitive annuals. We surveyed nine gray dune communities annually for 5 years along a cross European latitudinal gradient of habitat quality. We find that densities of annual and perennial species are negatively correlated at the high-quality end of the gradient, while at the low-quality end, guild densities are uncorrelated or positively correlated, consistent with a weakening of competition linked to increasing environmental limitations. Our results suggest that even simple interactions can give rise to nonobvious changes in species associations along environmental gradients. They highlight that understanding the outcome of species interactions may require explicit characterization of their changing intensity with environmental quality and that the factors limiting species' codistribution can vary along environmental gradients. PMID- 28350504 TI - Royal Darwinian Demons: Enforced Changes in Reproductive Efforts Do Not Affect the Life Expectancy of Ant Queens. AB - One of the central tenets of life-history theory is that organisms cannot simultaneously maximize all fitness components. This results in the fundamental trade-off between reproduction and life span known from numerous animals, including humans. Social insects are a well-known exception to this rule: reproductive queens outlive nonreproductive workers. Here, we take a step forward and show that under identical social and environmental conditions the fecundity longevity trade-off is absent also within the queen caste. A change in reproduction did not alter life expectancy, and even a strong enforced increase in reproductive efforts did not reduce residual life span. Generally, egg-laying rate and life span were positively correlated. Queens of perennial social insects thus seem to maximize at the same time two fitness parameters that are normally negatively correlated. Even though they are not immortal, they best approach a hypothetical "Darwinian demon" in the animal kingdom. PMID- 28350503 TI - A Novel, Enigmatic Basal Leafflower Moth Lineage Pollinating a Derived Leafflower Host Illustrates the Dynamics of Host Shifts, Partner Replacement, and Apparent Coadaptation in Intimate Mutualisms. AB - Leafflower plant/leafflower moth brood pollination mutualisms are widespread in the Paleotropics. Leafflower moths pollinate leafflower plants, but their larvae consume a subset of the hosts' seeds. These interactions are highly phylogenetically constrained: six clades of leafflower plants are each associated with a unique clade of leafflower moths (Epicephala). Here, we report a previously unrecognized basal seventh pollinating Epicephala lineage-associated with the highly derived leafflower clade Glochidion-in Asia. Epicephala lanceolaria is a pollinator and seed predator of Glochidion lanceolarium. Phylogenetic inference indicates that the ancestor of E. lanceolaria most likely shifted onto the ancestor of G. lanceolarium and displaced the ancestral allospecific Epicephala pollinator in at least some host populations. The unusual and apparently coadapted aspects of the G. lanceolarium/E. lanceolaria reproductive cycles suggest that plant-pollinator coevolution may have played a role in this displacement and provide insights into the dynamics of host shifts and trait coevolution in this specialized mutualism. PMID- 28350506 TI - Honorary Lifetime Membership Award: Johanna Schmitt. PMID- 28350505 TI - Maladaptation to Acute Metal Exposure in Resurrected Daphnia ambigua Clones after Decades of Increasing Contamination. AB - Human environmental impacts have driven some of the strongest and fastest phenotypic changes recorded in wild animal populations. Across populations, this variation is often adaptive, because populations evolve fitness advantages in response to human-modified environments. Yet some populations fail to adapt to changing environments. Evidenced by declines in relative fitness, such seemingly maladaptive outcomes are less common but may be more likely in human-modified contexts. Further, our ability to investigate the dynamics of these adaptive and maladaptive responses over time is typically limited in natural systems. I combined resurrection ecology and paleolimnology approaches to examine evolutionary responses of the freshwater zooplankter Daphnia to exposure to heavy metal contamination over the past 50-75 years, using animals hatched from diapausing egg banks. In contrast to the predicted trend of adaptation to metal exposure over time, I observed an increase in sensitivity to both copper and cadmium exposure associated with increasing historic contamination. This potentially maladaptive trend occurred in Daphnia populations in three lakes. Given that the release of toxicants such as heavy metals is widespread and that other researchers have observed local maladaptation to toxicant exposure, it is important to understand the drivers and implications of this pattern. PMID- 28350507 TI - Portrait of an optimist. PMID- 28350508 TI - Role of Nutrition Support in Inflammatory Conditions [Formula: see text]. AB - This review intends to summarize recent development on the potential nutrition implications of acute inflammation encountered during critical illness. Different aspects of the inflammatory response and their impact on nutrition management during critical illness will be discussed: the timing of the postinjury metabolic response, the integration of regulatory mechanisms involved in the metabolic response to stress, the oxidative stress, the metabolic and clinical consequences in terms of energy expenditure, use of energy, changes in body composition, and behavior. PMID- 28350510 TI - A Qualitative Study of a Maintenance Support Program for Women at Risk of Homelessness: Part 3: Societal Factors. AB - Homelessness is a collective societal problem, and people who are homeless are often treated as society's underclass, stigmatised and excluded. These issues are often exacerbated among homeless people from countries other than the one in which they are currently living. In this article we report findings from a qualitative study of homeless women, case managers and health professionals from a Maintenance Support Program and their personal accounts and insights into their experiences of the program. This article presents the third and last sub-theme "societal factors" of the study where the overarching theme was "A life-changing event: I have the power to change." This sub-theme is supported by three categories including gender, race and ethnicity, and environment. The findings highlight the impact of the societal factors that linked women's experiences with domestic violence and abuse. Further cultural views regarding the role of women in society hinder their capacity to recognise that they should not be treated differently and that they should be supported to access health and social services to improve their lives in a safe and supportive environment. PMID- 28350509 TI - Epstein-Barr virus and its association with Fascin expression in colorectal cancers in the Syrian population: A tissue microarray study. AB - Colorectal cancer (CRC) is the third most common malignancy in both men and women worldwide. Colorectal carcinogenesis is a complex, multistep process involving environmental and lifestyle features as well as sequential genetic changes in addition to bacterial and viral infections. Viral infection has a proven role in the incidence of approximately 20% of human cancers including gastric malignancies. Accordingly, Epstein-Barr virus (EBV) has been recently shown to be present in human gastric cancers, which could play an important role in the initiation and progression of these cancers. Therefore, this work explores the prevalence of EBV in 102 CRC tissues from the Syrian population using polymerase chain reaction (PCR) and tissue microarray (TMA) analysis. We found that EBV is present in 37 (36.27%) of CRC samples. Additionally, the expression of LMP1 onco protein of EBV was found to be correlated with Fascin expression/overexpression in the majority of CRC tissue samples, which are intermediate/high grade invasive carcinomas. Our data indicate that EBV is present in CRC and its presence is associated with more aggressive cancer phenotype. Consequently, future investigations are needed to expose the role of EBV in CRC initiation and progression. PMID- 28350511 TI - Design, construction, and evaluation of "sensor lock": an electromechanical stance control knee joint. AB - BACKGROUND AND AIM: Most currently-available stance control knee ankle foot orthoses (SCKAFOs) still need full knee extension to lock the knee joint, and they are still noisy, bulky, and heavy. Therefore, the aim of this study was to design, construct, and evaluate an original electromechanical SCKAFO knee joint that could feasibly solve these problems, and thus address the problems of current stance control knee joints with regards to their structure, function, cosmesis, and cost. METHOD: Ten able-bodied (AB) participants and two (knee ankle foot orthosis) KAFO users were recruited to participate in the study. A custom SCKAFO with the same set of components was constructed for each participant. Lower limb kinematics were captured using a 6-camera, video-based motion analysis system. RESULTS: For AB participants, significant differences were found between normal walking and walking with the SCKAFO for temporal-spatial parameters and between orthoses with two modes of knee joints in the healthy subjects. Walking with stance control mode produced greater walking speed and step length, greater knee flexion during swing, and less pelvic obliquity than walking with a locked knee, for both AB and KAFO users. CONCLUSIONS: The feasibility of this new knee joint with AB people was demonstrated. Implications for rehabilitation Stance control knee ankle foot orthoses (SCKAFOs) are designed to stop knee flexion in stance phase and provide free knee movement during swing phase of walking. Due to their high cost, size, excessive weight, and poor performance, few SCKAFO were optimal clinically and commercially. The feasibility of the new knee joint with able-bodied people and poliomyelitis subjects was demonstrated. PMID- 28350512 TI - High prevalence of prion protein genotype associated with resistance to chronic wasting disease in one Alberta woodland caribou population. AB - Chronic wasting disease (CWD) is a prion disease found in deer, elk and moose in North America and since recently, wild reindeer in Norway. Caribou are at-risk to encounter CWD in areas such as Alberta, Canada, where the disease spreads toward caribou habitats. CWD susceptibility is modulated by species-specific polymorphisms in the prion protein gene (Prnp). We sequenced Prnp of woodland caribou from 9 Albertan populations. In one population (Chinchaga) a significantly higher frequency of the 138N allele linked to reduced CWD susceptibility was observed. These data are relevant for developing CWD management strategies including conservation of threatened caribou populations. PMID- 28350514 TI - Brachytherapy for Patients With Prostate Cancer: American Society of Clinical Oncology/Cancer Care Ontario Joint Guideline Update Summary. PMID- 28350513 TI - Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline Summary From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. PMID- 28350515 TI - International Association for Hospice and Palliative Care Response Regarding Voluntary Cessation of Food and Water. PMID- 28350516 TI - Relationship Between Preoperative Extrusion of the Medial Meniscus and Surgical Outcomes After Partial Meniscectomy. AB - BACKGROUND: No previous study has examined arthritic change after meniscectomy with regard to extrusion of the medial meniscus. PURPOSE: (1) To determine the factors related to preoperative meniscal extrusion; (2) to investigate the relationship between medial meniscal extrusion and postoperative outcomes of partial meniscectomy, and to identify a cutoff point of meniscal extrusion that contributes to arthritic change after partial meniscectomy in nonosteoarthritic knees. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 208 patients who underwent partial meniscectomy of the medial meniscus between January 2000 and September 2006 were retrospectively reviewed. The extent of extrusion and severity of degeneration of the medial meniscus as shown on preoperative MRI were evaluated. The minimum follow-up duration was 7 years. Clinical function was assessed with the Lysholm knee scoring scale, the International Knee Documentation Committee (IKDC) subjective knee evaluation form, and the Tapper and Hoover grading system. Radiological evaluation was conducted by use of the IKDC radiographic assessment scale. Regression analysis was performed to identify factors affecting preoperative extrusion of the medial meniscus and factors influencing follow-up results after partial meniscectomy. Receiver operating characteristic curve was used to identify a cutoff point for the extent of meniscal extrusion that was associated with arthritic change. RESULTS: The mean +/- SD preoperative Lysholm knee score was 65.0 +/- 6.3 and the mean IKDC subjective score was 60.1 +/- 7.5. The mean follow-up functional scores were 93.2 +/- 5.1 ( P < .001) for the Lysholm knee score and 89.0 +/- 6.2 for the IKDC subjective score ( P < .001). Preoperative extent of meniscal degeneration ( P < .001) and preoperative pattern of meniscal tear ( P < .001) were related to preoperative meniscal extrusion. Preoperative extrusion of the meniscus showed a tendency to increase as the extent of intrameniscal degeneration increased, and the medial meniscus was extruded more in patients with horizontal, horizontal flap, and complex tears. The preoperative extent of meniscal extrusion had a statistically significant correlation with follow-up Lysholm knee score (coefficient = -0.10, P = .002), IKDC subjective score (coefficient = -0.09, P = .007), Tapper and Hoover grade (odds ratio = 1.05, P < .001), and IKDC radiographic grade (odds ratio = 1.13, P < .001) at the mean follow-up period of 88.6 months. The cutoff point for the relative value of preoperative meniscal extrusion associated with arthritic change was 34.6% (sensitivity = 69.3%; specificity = 82.7%; accuracy = 77.9%). CONCLUSION: The preoperative extent of intrameniscal degeneration and the preoperative patterns of meniscal tear including horizontal, horizontal flap, and complex tears were associated with preoperative extrusion of the medial meniscus. The preoperative extrusion of the medial meniscus was negatively correlated with outcomes of partial meniscectomy. The preoperative extent of meniscal extrusion can be used as a predictive factor for osteoarthritis in partial meniscectomy. PMID- 28350517 TI - Anti-Inflammatory Diet in Clinical Practice: A Review. AB - Recently, there has been an increase in the research regarding the impact of acute and chronic inflammation on health and disease. Specific foods are now known to exert strong effects on inflammatory pathways within the body. Carefully selecting foods that are anti-inflammatory in nature while avoiding foods that are proinflammatory is central to an anti-inflammatory diet plan. Ultimately, the plan models a pattern of eating that (1) focuses on eating whole, plant-based foods that are rich in healthy fats and phytonutrients and (2) maintains a stable glycemic response. PMID- 28350518 TI - Reproductive Patterns Among Childhood and Adolescent Cancer Survivors in Sweden: A Population-Based Matched-Cohort Study. AB - Purpose To compare the probability of a first live birth, age at time of birth, and time between diagnosis/referent date and birth between childhood and adolescent cancer survivors and an age-matched comparison group. Materials and Methods A total of 1,206 survivors was included in the study, together with 2,412 age-matched individuals from the general population. A Cox proportional hazards model was used to investigate first live birth after diagnosis/referent date. Data were stratified by sex, age at diagnosis, and diagnostic era (ie, diagnosis before 1988 v in 1988 or later). Results Overall, the probability of having a first live birth (hazard ratio [HR]) was significantly lower; men had lower HRs than women (HR, 0.65 v 0.79). There were no significant differences in the probability of having a first live birth among women diagnosed during adolescence (HR, 0.89), but the HR was lower among women with childhood cancers (HR, 0.47). Among male survivors, the situation was the opposite; men diagnosed during adolescence had lower HRs than survivors of childhood cancer (HR, 0.56 v 0.70). Examination of the data from the two diagnostic eras (before 1988 and 1988 or later) shows that the HR increased among female survivors after 1988 (HR, 0.71 v 0.90) and decreased among male survivors (HR, 0.72 v 0.59). A shorter time had elapsed between diagnosis/referent date and the birth of a first child among both male and female survivors compared with controls. In addition, female survivors were younger at time of birth. Conclusion The study demonstrates reduced probability of having a first live birth among cancer survivors diagnosed during childhood or adolescence; men were particularly vulnerable. PMID- 28350520 TI - Genomic Classifier Augments the Role of Pathological Features in Identifying Optimal Candidates for Adjuvant Radiation Therapy in Patients With Prostate Cancer: Development and Internal Validation of a Multivariable Prognostic Model. AB - Purpose Despite documented oncologic benefit, use of postoperative adjuvant radiotherapy (aRT) in patients with prostate cancer is still limited in the United States. We aimed to develop and internally validate a risk-stratification tool incorporating the Decipher score, along with routinely available clinicopathologic features, to identify patients who would benefit the most from aRT. Patient and Methods Our cohort included 512 patients with prostate cancer treated with radical prostatectomy at one of four US academic centers between 1990 and 2010. All patients had >= pT3a disease, positive surgical margins, and/or pathologic lymph node invasion. Multivariable Cox regression analysis tested the relationship between available predictors (including Decipher score) and clinical recurrence (CR), which were then used to develop a novel risk stratification tool. Our study adhered to the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis guidelines for development of prognostic models. Results Overall, 21.9% of patients received aRT. Median follow-up in censored patients was 8.3 years. The 10-year CR rate was 4.9% vs. 17.4% in patients treated with aRT versus initial observation ( P < .001). Pathologic T3b/T4 stage, Gleason score 8-10, lymph node invasion, and Decipher score > 0.6 were independent predictors of CR (all P < .01). The cumulative number of risk factors was 0, 1, 2, and 3 to 4 in 46.5%, 28.9%, 17.2%, and 7.4% of patients, respectively. aRT was associated with decreased CR rate in patients with two or more risk factors (10-year CR rate 10.1% in aRT v 42.1% in initial observation; P = .012), but not in those with fewer than two risk factors ( P = .18). Conclusion Using the new model to indicate aRT might reduce overtreatment, decrease unnecessary adverse effects, and reduce risk of CR in the subset of patients (approximately 25% of all patients with aggressive pathologic disease in our cohort) who benefit from this therapy. PMID- 28350519 TI - Outcome of Lower-Risk Patients With Myelodysplastic Syndromes Without 5q Deletion After Failure of Erythropoiesis-Stimulating Agents. AB - Purpose Most anemic patients with non-deleted 5q lower-risk myelodysplastic syndromes (MDS) are treated with erythropoiesis-stimulating agents (ESAs), with a response rate of approximately 50%. Second-line treatments, including hypomethylating agents (HMAs), lenalidomide (LEN), and investigational drugs, may be used after ESA failure in some countries, but their effect on disease progression and overall survival (OS) is unknown. Here, we analyzed outcome after ESA failure and the effect of second-line treatments. Patients and Methods We examined an international retrospective cohort of 1,698 patients with non-del(5q) lower-risk MDS treated with ESAs. Results Erythroid response to ESAs was 61.5%, and median response duration was 17 months. Of 1,147 patients experiencing ESA failure, 653 experienced primary failure and 494 experienced relapse after a response. Primary failure of ESAs was associated with a higher risk of acute myeloid leukemia (AML) progression, which did not translate into an OS difference. Of 450 patients (39%) who received second-line treatment, 194 received HMAs, 148 received LEN, and 108 received other treatments (MISC), whereas 697 received RBC transfusions only. Five-year AML cumulative incidence was 20.3%, 20.3%, and 11.3% for those receiving HMAs, LEN, and MISC, respectively ( P = .05). Five-year OS for patients receiving HMA, LEN, and MISC was 36.5%, 41.7%, and 51%, respectively ( P = .21). In a multivariable analysis adjusted for age, sex, revised International Prognostic Scoring System score, and progression at ESA failure, there was no significant OS difference among the three groups. Conclusion In this large, multicenter, retrospective cohort of patients with non del(5q) lower-risk MDS treated with ESAs, none of the most commonly used second line treatments (HMA and LEN) significantly improved OS. Early failure of ESAs was associated with a higher risk of AML progression. PMID- 28350522 TI - The influences of SLCO1B1 and ABCB1 genotypes on the pharmacokinetics of simvastatin, in relation to CYP3A4 inhibition. AB - AIM: To investigate the combined effects of SLCO1B1 and ABCB1 genotypes on the pharmacokinetics of simvastatin and its active metabolite simvastatin acid, in relation to CYP3A4 inhibition. METHODS: We conducted a single-dose pharmacokinetic study of simvastatin in 26 healthy volunteers screened for their SLCO1B1 c.521T>C and ABCB1 c.1236C>T-2677G>T-3435C>T genotypes, with and without amlodipine pretreatment. The genetic effects and drug-interaction effect on simvastatin pharmacokinetic parameters were analyzed using a linear-mixed model. RESULTS: The SLCO1B1 c.521T>C variant significantly increased exposure to simvastatin acid by around 40% (p < 0.05), similar to that caused by the amlodipine pretreatment. The ABCB1 gene showed no influence on exposure to simvastatin or simvastatin acid. CONCLUSION: Only SLCO1B1, not ABCB1 genotype, is likely to be associated with simvastatin-induced myopathy. SLCO1B1 genotyping may be particularly beneficial in simvastatin users who are co-administered CYP3A4 inhibitors. PMID- 28350521 TI - Clinical Activity of the gamma-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis). AB - Purpose Desmoid tumors (aggressive fibromatosis) arise from connective tissue cells or fibroblasts. In general, they are slow growing and do not metastasize; however, locally aggressive desmoid tumors can cause severe morbidity and loss of function. Disease recurrence after surgery and/or radiation and diagnosis of multifocal desmoid tumors highlight the need to develop effective systemic treatments for this disease. In this study, we evaluate objective response rate after therapy with the gamma-secretase inhibitor PF-03084014 in patients with recurrent, refractory, progressive desmoid tumors. Patients and Methods Seventeen patients with desmoid tumors received PF-03084014 150 mg orally twice a day in 3 week cycles. Response to treatment was evaluated at cycle 1 and every six cycles, that is, 18 weeks, by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. Patient-reported outcomes were measured at baseline and at every restaging visit by using the MD Anderson Symptoms Inventory. Archival tumor and blood samples were genotyped for somatic and germline mutations in APC and CTNNB1. Results Of 17 patients accrued to the study, 15 had mutations in APC or CTNNB1 genes. Sixteen patients (94%) were evaluable for response; five (29%) experienced a confirmed partial response and have been on study for more than 2 years. Another five patients with prolonged stable disease as their best response remain on study. Patient-reported outcomes confirmed clinician reporting that the investigational agent was well tolerated and, in subgroup analyses, participants who demonstrated partial response also experienced clinically meaningful and statistically significant improvements in symptom burden. Conclusion PF-03084014 was well tolerated and demonstrated promising clinical benefit in patients with refractory, progressive desmoid tumors who receive long-term treatment. PMID- 28350523 TI - Comparison of micro-CT and cone beam CT on the feasibility of assessing trabecular structures in mandibular condyle. AB - OBJECTIVES: To evaluate the accuracy of CBCT in assessing trabecular structures. METHODS: Two human mandibles were scanned by micro-CT (Skyscan 1173 high-energy spiral scan micro-CT; Skyscan NV, Kontich, Belgium) and CBCT (3D Accuitomo 170; Morita, Japan). The CBCT images were reconstructed with 0.5 and 1 mm thicknesses. The condylar images were selected for registration. A parallel algorithm for histogram computation was introduced to perform the registration. A mutual information (MI) value was used to evaluate the match between the images obtained from micro-CT and CBCT. RESULTS: In comparison with the micro-CT image for the two samples, the CBCT image with 0.5 mm thickness has a MI value of 0.873 and 0.903 while that with 1.0 mm thickness has a MI value of 0.741 and 0.752. The CBCT images with 0.5 mm thickness were better matched with micro-CT images. CONCLUSIONS: CBCT shows comparable accuracy with high-resolution micro-CT in assessing trabecular structures. CBCT can be a feasible tool to evaluate osseous changes of jaw bones. PMID- 28350525 TI - Hang Height of Enteral Nutrition Influences the Delivery of Enteral Nutrition. AB - PURPOSE: Adequate enteral nutrition (EN) delivery to critically ill patients is difficult to achieve. Given the large number of unpreventable influences affecting adequate caloric intake, further research on preventable influences of adequate EN administration is warranted. The purpose of this study was to evaluate whether hang height of EN formula, formula viscosity, or flow rate influences pump accuracy and formula delivery. METHODS: Formulas of varying viscosities (1.0, 1.5, and 2.0 kcal/mL) were infused at different hang heights (0, 6, 12, and 18 inches) and rates (20, 40, and 80 mL/h). The mean percent difference and the bias between the programmed volume, volume reported, and volume delivered were calculated for the different hang heights, formula compositions, and infusion rates studied. RESULTS: For all prespecified hang heights and infusion rates, the volume delivered was less than the programmed volume and volume reported; the mean percent difference increased as the hang height decreased. The volume was overestimated for both the programmed volume (14.4% +/- 5.5%) and volume reported (12.9% +/- 6.7%) compared with volume delivered. The overestimation bias was significantly influenced by differences in hang height as well as type of formula ( P < .0001, each) but not by rate of delivery ( P = .4633 for programmed volume and .8411 for volume reported). CONCLUSIONS: Measures should be taken in clinical practice to ensure adequate hang height of EN. Appropriate hang height of EN may result in more accurate delivery of nutrition provisions to the critically ill patient and subsequently reduce complications related to underfeeding. PMID- 28350524 TI - An ATF4-ATG5 signaling in hypothalamic POMC neurons regulates obesity. AB - ATF4 (activating transcription factor 4) is an important transcription factor that has many biological functions, while its role in hypothalamic POMC (pro opiomelanocortin-alpha) neurons in the regulation of energy homeostasis has not been explored. We recently discovered that mice with an Atf4 deletion specific to POMC neurons (PAKO mice) are lean and have higher energy expenditure. Furthermore, these mice are resistant to high-fat diet (HFD)-induced obesity and obesity-related metabolic disorders. Mechanistically, we found the expression of ATG5 (autophagy-related 5) is upregulated in POMC neurons of PAKO mice, and ATF4 regulates ATG5 expression by binding directly to its promoter. Mice with Atf4 and Atg5 double knockout in POMC neurons have reduced energy expenditure and gain more fat mass compared with PAKO mice under a HFD. Finally, the effect of Atf4 knockout in POMC neurons is possibly mediated by enhanced ATG5-dependent macroautophagy/autophagy and alpha-melanocyte-stimulating hormone (alpha-MSH) production in the hypothalamus. Together, this work not only identifies a beneficial role for ATF4 in hypothalamic POMC neurons in the regulation of obesity, but also provides a new potential therapeutic target for obesity and obesity-related metabolic diseases. PMID- 28350526 TI - Exploring types of play in an adapted robotics program for children with disabilities. AB - PURPOSE: Play is an important occupation in a child's development. Children with disabilities often have fewer opportunities to engage in meaningful play than typically developing children. The purpose of this study was to explore the types of play (i.e., solitary, parallel and co-operative) within an adapted robotics program for children with disabilities aged 6-8 years. METHOD: This study draws on detailed observations of each of the six robotics workshops and interviews with 53 participants (21 children, 21 parents and 11 programme staff). RESULTS: Our findings showed that four children engaged in solitary play, where all but one showed signs of moving towards parallel play. Six children demonstrated parallel play during all workshops. The remainder of the children had mixed play types play (solitary, parallel and/or co-operative) throughout the robotics workshops. We observed more parallel and co-operative, and less solitary play as the programme progressed. Ten different children displayed co-operative behaviours throughout the workshops. The interviews highlighted how staff supported children's engagement in the programme. Meanwhile, parents reported on their child's development of play skills. CONCLUSIONS: An adapted LEGO(r) robotics program has potential to develop the play skills of children with disabilities in moving from solitary towards more parallel and co-operative play. Implications for rehabilitation Educators and clinicians working with children who have disabilities should consider the potential of LEGO(r) robotics programs for developing their play skills. Clinicians should consider how the extent of their involvement in prompting and facilitating children's engagement and play within a robotics program may influence their ability to interact with their peers. Educators and clinicians should incorporate both structured and unstructured free-play elements within a robotics program to facilitate children's social development. PMID- 28350527 TI - Seasonal and Annual Variation in Trematode Infection of Stream Snail Elimia proxima in the Southern Appalachian Mountains of Virginia. AB - Understanding temporal variation of host-pathogen dynamics can be important for predicting disease risks and anticipating how disease systems may change in response to natural or human disturbances. Seasonal changes in weather, especially those associated with changes in temperature or precipitation, are often a key component of temporal changes in infection risk and can have important impacts on disease systems. However, these patterns can be difficult to track due to interannual variation and the need for longer term, multi-year surveillance efforts. We assessed seasonal and annual changes in the trematode component community of first-intermediate host stream snail Elimia (= Oxytrema = Goniobasis) proxima across 5 streams in the southern Appalachian Mountains. Over 3 yr, we found no evidence of consistent seasonal peaks of trematode infection in E. proxima. There was some across-site consistency in infection prevalence over 4 yr, because high prevalence sites tended to maintain higher prevalence from year to year, relative to lower prevalence sites. In addition, we examined the relationship between prevalence of first-intermediate host infection, weather variables, and site-level factors, including snail density and water quality metrics. Trematode prevalence was negatively related to total precipitation, which may have been due to the movement of infectious parasite stages and hosts downstream during high flows. We found no strong relationships between trematode prevalence and snail density or any of the water quality metrics examined in this study, indicating that snail infection may be driven primarily by definitive host activity. PMID- 28350528 TI - Pulmonary hypertension complicating systemic sclerosis: A successful pregnancy outcome. PMID- 28350529 TI - Risk of caesarean delivery after induction of labour stratified by foetal sex. AB - This study describes a retrospective analysis of all women admitted for induction of labour (IoL), carrying a viable singleton foetus, after 34 + 0 weeks of gestation. We aimed to evaluate if foetal sex has an impact on the rate of caesarean delivery following labour induction. Our results demonstrate that among the 1062 women who met the inclusion criteria, 49% (521/1062) were carrying a male foetus. Other than a lower rate of Oxytocin use for the female sex pregnancies, there were no significant differences in pre-labour and labour characteristics between male or female sex pregnancies. There was no difference in caesarean delivery rate between groups (14.4% vs. 14.2%, male vs. female, respectively, p = .505). We concluded conclude that foetal sex does not impact the caesarean delivery rate among women undergoing IoL, regardless of the indication for induction and the indication for the caesarean delivery. Impact statement Male sex foetuses are at increased risk for adverse perinatal outcomes including, among others, an increased risk for caesarean delivery. The possible contribution of male sex to caesarean delivery after labour induction has not been specifically explored. Following induction of labour, there is no difference in failed induction or caesarean delivery rate between male and female sex pregnancies. Induction of labour may be safely employed for both male and female foetuses. PMID- 28350531 TI - Phytophthora infestans Effectors IPI-O1 and IPI-O4 Each Contribute to Pathogen Virulence. AB - Potato late blight, caused by the oomycete pathogen Phytophthora infestans, is one of the most destructive plant diseases. Despite decades of intensive breeding efforts, it remains a threat to potato production worldwide, because newly evolved pathogen strains have overcome major resistance genes quickly. The RB protein, from the diploid wild potato species Solanum bulbocastanum, confers partial resistance to most P. infestans strains through its recognition of members of the corresponding pathogen effector protein family IPI-O. IPI-O comprises a multigene family and while some variants are recognized by RB to elicit host resistance (e.g., IPI-O1 and IPI-O2), others are able to elude detection (e.g., IPI-O4). IPI-O1 is almost ubiquitous in global P. infestans strains while IPI-O4 is more rare. No direct experimental evidence has been shown to demonstrate the effect of IPI-O on pathogen virulence in the P. infestans potato pathosystem. Here, our work has demonstrated that in planta expression of both IPI-O1 and IPI-O4 increases P. infestans aggressiveness resulting in enlarged lesions in potato leaflets. We have previously shown that IPI-O4 has gained the ability to suppress the hypersensitive response induced by IPI-O1 in the presence of RB. In this study, our work has shown that this gain-of-function of IPI-O4 does not compromise its virulence effect, as IPI-O4 overexpression results in larger lesions than IPI-O1. We have also found that higher expression of IPI-O effectors correlates with enlarged lesions, indicating that IPI-O can contribute to virulence quantitatively. In summary, this study has provided accurate and valuable information on IPI-O's virulence effect on the potato host. PMID- 28350532 TI - Urethral proteomic analysis in ovariectomized mice administered 17beta-oestradiol replacement therapy. AB - The molecular mechanism by which 17beta-oestradiol (E2) increases urethral tone is unclear. As human tissue is limited in availability, we explored changes in the urethras of ovariectomized (OVX) mice. Twenty-four virgin female mice were randomised into three groups: mice with a sham operation only (control), OVX mice without E2 replacement (OVX), and OVX mice with E2 replacement (OVX + E2). Two weeks after the ovariectomy, mice received either E2 or placebo for 4 weeks. Leak point pressure (LPP) and maximum urethral closure pressure (MUCP) were assessed in these mice at 6 weeks after OVX, under anaesthesia. After measurements were recorded, the animals were sacrificed and the urethras were removed for proteomic and further analyses. LPP and MUCP values were significantly higher in OVX + E2 group than in OVX group. Fourteen differentially expressed proteins within the urethras of mice from OVX and OVX + E2 groups were identified; six proteins were upregulated and eight proteins were down-regulated. Most E2-induced proteins are involved in proteolysis, development, neurophysiological processes, transcription, and the cell cycle. Expression of survival motor neuron (SMN) protein in the urethra was significantly increased in OVX + E2 group compared to OVX group. OVX can impair urethral tone in female mice. E2 supplementation in OVX mice rescued urethral tone. E2-mediated increase in urethral tone in OVX mice involves overexpression of SMN, decreased proteolysis and promotion of development, neurophysiological processes, and transcription in the urethra. The urethra actively undergoes multiple biological processes in response to OVX and OVX with E2 stimuli. Impact statement Estrogens are known to modulate lower urinary tract trophicity. Although treatments with 17beta-oestradiol (E2) result in an increase in urethral tone, the mechanism by which E2 increases urethral tone is still not completely understood. Ovariectomy can impair urethral tone in female mice. E2 supplementation in ovariectomized mice rescued urethral tone. E2 mediated increase in urethral tone in ovariectomized mice involves overexpression of survival motor neuron, decreased proteolysis and promotion of development, neurophysiological processes, and transcription in the urethra. This information will offer clues about pathogenesis of stress urinary incontinence after menopause and will open additional avenues for novel research and potential therapies. PMID- 28350534 TI - Evaluation of a POCT device for C-reactive protein, hematocrit and leukocyte differential. PMID- 28350535 TI - Relationship between polymorphisms in the CRP, LEP and LEPR genes and high sensitivity C-reactive protein levels in Spanish children. AB - BACKGROUND: We investigated the association of single nucleotide polymorphisms (SNPs) in the C-reactive protein (CRP), leptin (LEP) and leptin receptor (LEPR) genes with high sensitivity CRP (hs-CRP) levels in two independent cohorts of healthy Spanish children. METHODS: We measured hs-CRP levels in 646 6-8-year-old and 707 12-16-year-old children using a high-sensitivity C-Reactive Protein ELISA kit. Four SNPs in the CRP gene (rs1205, rs1130864, rs2794521 and rs1800947), one SNP in the LEP gene (rs7799039) and two SNPs in the LEPR (rs1137100 and rs1137101) gene were determined by TaqMan(r) allelic discrimination assays. RESULTS: The four CRP SNPs studied were significantly (p<0.05) associated with hs CRP levels in both cohorts. Furthermore, two common CRP haplotypes (constructed using the SNPs in order: rs1205, rs1130864, rs1800947, rs2794521) ACGA and GCGG were associated with significantly lower CRP levels (p<0.05) at both ages. The LEPR SNPs rs1137100 (K109R) and rs1137101 (Q223R), and LEP SNP rs7799039 (G2548A) were also associated to hs-CRP levels (p<0.05) in both cohorts. CONCLUSIONS: hs CRP levels in healthy Spanish children, besides being associated to common polymorphisms in the CRP gene, are associated to polymorphisms in the LEP and LEPR genes, which suggests that other loci, in addition the CRP gene, may have a role determining CRP levels in children. PMID- 28350536 TI - Anti-inflammatory effects and anti-oxidant capacity of Myrathius arboreus (Cecropiaceae) in experimental models. AB - BACKGROUND: Inflammation is involved in various diseases; search for safe treatments is warranted. Anti-inflammatory effects of ethanol extract of Myrathius arboreus (EEMa) were studied in carrageenan-induced model, formaldehyde sub-acute-induced model, and in 48 h lipopolysaccharide-induced air pouch model of inflammation. EEMa membrane-stabilizing activities and anti-oxidant capacity were determined in vitro. METHODS: In the carrageenan model EEMa (125, 250, or 500 mg/kg), indomethacin (5 mg/kg), or vehicle 3 mL/kg was administered orally in rats (n=5). After 1 h, 0.1 mL of 1% carrageenan was injected into the right hind paw of rats. Change in edema sizes was measured for 3 h with plethysmometer. One tenth milliliter (0.1 mL) of 2.5% formaldehyde was injected into the rat paw on the first day and the third day to induce sub-acute inflammation; changes in the edema sizes were determined, and percentages of inhibitions were calculated. Anti inflammatory effects of EEMa were further examined in lipopolysaccharide (LPS) induced air-pouch based on leukocytes count, volume of exudates, levels of malondialdehyde, glutathione, superoxide dismutase, nitric oxides, and tumor necrosis factor released into the inflammatory fluids. EEMa-free radicals scavenging activities were studied in DPPH and reducing power tests. Membrane stabilizing activities of EEMa were evaluated in the red blood cell lysis induced by thermal and hypotonic solution. RESULTS: EEMa (250, 500 mg/kg) produced significant (p<0.001; p<0.05) inhibition of inflammation when compared with vehicle. Also, EEMa (250, 500, or 1000 MUg/mL) significantly stabilized membrane and produced free radical scavenging activities. CONCLUSIONS: M. arboreus possesses anti-inflammatory and the anti-oxidant properties that might benefit translational medicine. PMID- 28350538 TI - Possible effects of neonatal vitamin B12 status on TSH-screening program: a cross sectional study from Turkey. AB - BACKGROUND: In this study we evaluated whether vitamin B12 deficiency affects neonatal screening (NS) for congenital hypothyroidism (CH). METHODS: A cross sectional study conducted from 2010 to 2011. A total of 10,740 infants were born in our hospital in this period. Thyroid-stimulating hormone (TSH) was tested for NS and neonates with abnormal screening results (TSH>20 mIU/L) were re-examined. Two hundred and twenty-nine re-called subjects (re-call rate 2.3%) were compared to 77 randomly selected newborns with normal TSH screening among these term newborns in terms of serum TSH, free T4, vitamin B12 and homocysteine status. RESULTS: Of the 229 re-called subjects, 11 infants with CH and 21 infants with transient TSH elevation were detected. In the normal TSH screening group, only two infants were diagnosed with transient TSH elevation. Mean serum B12 levels were 126.4+/-48.7 pg/mL and 211.9+/-127.9 pg/mL in the positive TSH-screening group and the control group, respectively. There was a significant difference between positive and normal TSH-screening groups in regard to serum TSH, free T4, serum B12 and homocysteine levels. CONCLUSIONS: We found a significant vitamin B12 deficiency in positive TSH-screening infants. Beside the crucial role of vitamin B12 in newborns, deficiency seems to increase the recall rates of infants in an NS program for CH. PMID- 28350537 TI - Comparison of structured and unstructured physical activity training on predicted VO2max and heart rate variability in adolescents - a randomized control trial. AB - BACKGROUND: Physical inactivity contributes to many health issues. The WHO recommended physical activity for adolescents encompasses aerobic, resistance, and bone strengthening exercises aimed at achieving health-related physical fitness. Heart rate variability (HRV) and maximal aerobic capacity (VO2max) are considered as noninvasive measures of cardiovascular health. The objective of this study is to compare the effect of structured and unstructured physical training on maximal aerobic capacity and HRV among adolescents. METHODS: We designed a single blinded, parallel, randomized active-controlled trial (Registration No. CTRI/2013/08/003897) to compare the physiological effects of 6 months of globally recommended structured physical activity (SPA), with that of unstructured physical activity (USPA) in healthy school-going adolescents. We recruited 439 healthy student volunteers (boys: 250, girls: 189) in the age group of 12-17 years. Randomization across the groups was done using age and gender stratified randomization method, and the participants were divided into two groups: SPA (n=219, boys: 117, girls: 102) and USPA (n=220, boys: 119, girls: 101). Depending on their training status and gender the participants in both SPA and USPA groups were further subdivided into the following four sub-groups: SPA athlete boys (n=22) and girls (n=17), SPA nonathlete boys (n=95) and girls (n=85), USPA athlete boys (n=23) and girls (n=17), and USPA nonathlete boys (n=96) and girls (n=84). RESULTS: We recorded HRV, body fat%, and VO2 max using Rockport Walk Fitness test before and after the intervention. Maximum aerobic capacity and heart rate variability increased significantly while heart rate, systolic blood pressure, diastolic blood pressure, and body fat percentage decreased significantly after both SPA and USPA intervention. However, the improvement was more in SPA as compared to USPA. CONCLUSIONS: SPA is more beneficial for improving cardiorespiratory fitness, HRV, and reducing body fat percentage in terms of magnitude than USPA in adolescent individuals irrespective of their gender and sports activities. PMID- 28350539 TI - Personalized precision medicine in extreme preterm infants with transient neonatal diabetes mellitus. AB - Although hyperglycemia is common in neonates, especially preterm infants, a diagnosis of neonatal diabetes mellitus (NDM) is rarely made. NDM can be permanent (45%), transient (45%) or syndromic (10%). Of the 95% of identifiable mutations for NDM, methylation defects in 6q24, KCNJ11, ABCC8, and INS account for the majority. Two cases of transient NDM in extremely preterm, 24 weeks' gestational age (GA) triplets, due to a missense mutation c.685G>A in the KCNJ11 gene are presented. Both patients were successfully transitioned from insulin to Glyburide (Glibenclamide) at 2 months of age. Comprehensive genetic testing with targeted next-generation sequencing and 6q24 methylation analysis helps identify monogenic diabetes early, thereby improving metabolic and glycemic control when patients with potassium channel mutations are started on sulfonylurea (SU) treatment. PMID- 28350540 TI - Construction of a biomechanical head and neck motion model as a guide to evaluation of deformable image registration. AB - The use of deformable image registration methods in the context of adaptive radiotherapy leads to uncertainties in the simulation of the administered dose distributions during the treatment course. Evaluation of these methods is a prerequisite to decide if a plan adaptation will improve the individual treatment. Current approaches using manual references limit the validity of evaluation, especially for low-contrast regions. In particular, for the head and neck region, the highly flexible anatomy and low soft tissue contrast in control images pose a challenge to image registration and its evaluation. Biomechanical models promise to overcome this issue by providing anthropomorphic motion modelling of the patient. We introduce a novel biomechanical motion model for the generation and sampling of different postures of the head and neck anatomy. Motion propagation behaviour of the individual bones is defined by an underlying kinematic model. This model interconnects the bones by joints and thus is capable of providing a wide range of motion. Triggered by the motion of the individual bones, soft tissue deformation is described by an extended heterogeneous tissue model based on the chainmail approach. This extension, for the first time, allows the propagation of decaying rotations within soft tissue without the necessity for explicit tissue segmentation. Overall motion simulation and sampling of deformed CT scans including a basic noise model is achieved within 30 s. The proposed biomechanical motion model for the head and neck site generates displacement vector fields on a voxel basis, approximating arbitrary anthropomorphic postures of the patient. It was developed with the intention of providing input data for the evaluation of deformable image registration. PMID- 28350541 TI - Computational hybrid anthropometric paediatric phantom library for internal radiation dosimetry. AB - Hybrid computational phantoms combine voxel-based and simplified equation-based modelling approaches to provide unique advantages and more realism for the construction of anthropomorphic models. In this work, a methodology and C++ code are developed to generate hybrid computational phantoms covering statistical distributions of body morphometry in the paediatric population. The paediatric phantoms of the Virtual Population Series (IT'IS Foundation, Switzerland) were modified to match target anthropometric parameters, including body mass, body length, standing height and sitting height/stature ratio, determined from reference databases of the National Centre for Health Statistics and the National Health and Nutrition Examination Survey. The phantoms were selected as representative anchor phantoms for the newborn, 1, 2, 5, 10 and 15 years-old children, and were subsequently remodelled to create 1100 female and male phantoms with 10th, 25th, 50th, 75th and 90th body morphometries. Evaluation was performed qualitatively using 3D visualization and quantitatively by analysing internal organ masses. Overall, the newly generated phantoms appear very reasonable and representative of the main characteristics of the paediatric population at various ages and for different genders, body sizes and sitting stature ratios. The mass of internal organs increases with height and body mass. The comparison of organ masses of the heart, kidney, liver, lung and spleen with published autopsy and ICRP reference data for children demonstrated that they follow the same trend when correlated with age. The constructed hybrid computational phantom library opens up the prospect of comprehensive radiation dosimetry calculations and risk assessment for the paediatric population of different age groups and diverse anthropometric parameters. PMID- 28350542 TI - Intermediate stages of surface state formation and collapse of topological protection to transport in Bi2Se3. AB - Surface states consisting of helical Dirac fermions have been extensively studied in three-dimensional topological insulators. Yet, experiments to date have only investigated fully formed topological surface states (TSS) and it is not known whether preformed or partially formed surface states can exist or what properties they could potentially host. Here, by decorating thin films of Bi2Se3 with nanosized islands of the same material, we show for the first time that not only can surface states exist in various intermediate stages of formation but they exhibit unique properties not accessible in fully formed TSS. These include tunability of the Dirac cone mass, vertical migration of the surface state wave function and the appearance of mid-gap Rashba-like states as exemplified by our theoretical model for decorated TIs. Our experiments show that an interplay of Rashba and Dirac fermions on the surface leads to an intriguing multi-channel weak anti-localization effect concomitant with an unprecedented tuning of the topological protection to transport. Our work offers a new route to engineer topological surface states involving Dirac-Rashba coupling by nano-scale decoration of TI thin films, at the same time shedding light on the real-space mechanism of surface state formation in general. PMID- 28350543 TI - MONDO: a neutron tracker for particle therapy secondary emission characterisation. AB - Tumour control is performed in particle therapy using particles and ions, whose high irradiation precision enhances the effectiveness of the treatment, while sparing the healthy tissue surrounding the target volume. Dose range monitoring devices using photons and charged particles produced by the beam interacting with the patient's body have already been proposed, but no attempt has been made yet to exploit the detection of the abundant neutron component. Since neutrons can release a significant dose far away from the tumour region, precise measurements of their flux, production energy and angle distributions are eagerly sought in order to improve the treatment planning system (TPS) software. It will thus be possible to predict not only the normal tissue toxicity in the target region, but also the risk of late complications in the whole body. The aforementioned issues underline the importance of an experimental effort devoted to the precise characterisation of neutron production, aimed at the measurement of their abundance, emission point and production energy. The technical challenges posed by a neutron detector aimed at high detection efficiency and good backtracking precision are addressed within the MONDO (monitor for neutron dose in hadrontherapy) project, whose main goal is to develop a tracking detector that can target fast and ultrafast neutrons. A full reconstruction of two consecutive elastic scattering interactions undergone by the neutrons inside the detector material will be used to measure their energy and direction. The preliminary results of an MC simulation performed using the FLUKA software are presented here, together with the DSiPM (digital SiPM) readout implementation. New detector readout implementations specifically tailored to the MONDO tracker are also discussed, and the neutron detection efficiency attainable with the proposed neutron tracking strategy are reported. PMID- 28350544 TI - Efimov physics: a review. AB - This article reviews theoretical and experimental advances in Efimov physics, an array of quantum few-body and many-body phenomena arising for particles interacting via short-range resonant interactions, that is based on the appearance of a scale-invariant three-body attraction theoretically discovered by Vitaly Efimov in 1970. This three-body effect was originally proposed to explain the binding of nuclei such as the triton and the Hoyle state of carbon-12, and later considered as a simple explanation for the existence of some halo nuclei. It was subsequently evidenced in trapped ultra-cold atomic clouds and in diffracted molecular beams of gaseous helium. These experiments revealed that the previously undetermined three-body parameter introduced in the Efimov theory to stabilise the three-body attraction typically scales with the range of atomic interactions. The few- and many-body consequences of the Efimov attraction have been since investigated theoretically, and are expected to be observed in a broader spectrum of physical systems. PMID- 28350545 TI - Reliability of dose volume constraint inference from clinical data. AB - Dose volume histogram points (DVHPs) frequently serve as dose constraints in radiotherapy treatment planning. An experiment was designed to investigate the reliability of DVHP inference from clinical data for multiple cohort sizes and complication incidence rates. The experimental background was radiation pneumonitis in non-small cell lung cancer and the DVHP inference method was based on logistic regression. From 102 NSCLC real-life dose distributions and a postulated DVHP model, an 'ideal' cohort was generated where the most predictive model was equal to the postulated model. A bootstrap and a Cohort Replication Monte Carlo (CoRepMC) approach were applied to create 1000 equally sized populations each. The cohorts were then analyzed to establish inference frequency distributions. This was applied to nine scenarios for cohort sizes of 102 (1), 500 (2) to 2000 (3) patients (by sampling with replacement) and three postulated DVHP models. The Bootstrap was repeated for a 'non-ideal' cohort, where the most predictive model did not coincide with the postulated model. The Bootstrap produced chaotic results for all models of cohort size 1 for both the ideal and non-ideal cohorts. For cohort size 2 and 3, the distributions for all populations were more concentrated around the postulated DVHP. For the CoRepMC, the inference frequency increased with cohort size and incidence rate. Correct inference rates >[Formula: see text] were only achieved by cohorts with more than 500 patients. Both Bootstrap and CoRepMC indicate that inference of the correct or approximate DVHP for typical cohort sizes is highly uncertain. CoRepMC results were less spurious than Bootstrap results, demonstrating the large influence that randomness in dose-response has on the statistical analysis. PMID- 28350546 TI - Comparing stochastic proton interactions simulated using TOPAS-nBio to experimental data from fluorescent nuclear track detectors. AB - Whilst Monte Carlo (MC) simulations of proton energy deposition have been well validated at the macroscopic level, their microscopic validation remains lacking. Equally, no gold-standard yet exists for experimental metrology of individual proton tracks. In this work we compare the distributions of stochastic proton interactions simulated using the TOPAS-nBio MC platform against confocal microscope data for Al2O3:C,Mg fluorescent nuclear track detectors (FNTDs). We irradiated [Formula: see text] mm3 FNTD chips inside a water phantom, positioned at seven positions along a pristine proton Bragg peak with a range in water of 12 cm. MC simulations were implemented in two stages: (1) using TOPAS to model the beam properties within a water phantom and (2) using TOPAS-nBio with Geant4-DNA physics to score particle interactions through a water surrogate of Al2O3:C,Mg. The measured median track integrated brightness (IB) was observed to be strongly correlated to both (i) voxelized track-averaged linear energy transfer (LET) and (ii) frequency mean microdosimetric lineal energy, [Formula: see text], both simulated in pure water. Histograms of FNTD track IB were compared against TOPAS nBio histograms of the number of terminal electrons per proton, scored in water with mass-density scaled to mimic Al2O3:C,Mg. Trends between exposure depths observed in TOPAS-nBio simulations were experimentally replicated in the study of FNTD track IB. Our results represent an important first step towards the experimental validation of MC simulations on the sub-cellular scale and suggest that FNTDs can enable experimental study of the microdosimetric properties of individual proton tracks. PMID- 28350547 TI - Assessment of vectorial total variation penalties on realistic dual-energy CT data. AB - Vectorial extensions of total variation have recently been developed for regularizing the reconstruction and denoising of multi-channel images, such as those arising in spectral computed tomography. Early studies have focused mainly on simulated, piecewise-constant images whose structure may favor total-variation penalties. In the current manuscript, we apply vectorial total variation to real dual-energy CT data of a whole turkey in order to determine if the same benefits can be observed in more complex images with anatomically realistic textures. We consider the total nuclear variation ([Formula: see text]) as well as another vectorial total variation based on the Frobenius norm ([Formula: see text]) and standard channel-by-channel total variation ([Formula: see text]). We performed a series of 3D TV denoising experiments comparing the three TV variants across a wide range of smoothness parameter settings, optimizing each regularizer according to a very-high-dose 'ground truth' image. Consistent with the simulation studies, we find that both vectorial TV variants achieve a lower error than the channel-by-channel TV and are better able to suppress noise while preserving actual image features. In this real data study, the advantages are subtler than in the previous simulation study, although the [Formula: see text] penalty is found to have clear advantages over either [Formula: see text] or [Formula: see text] when comparing material images formed from linear combinations of the denoised energy images. PMID- 28350549 TI - Loss of E-cadherin as Part of a Migratory Phenotype in Melanoma Is Associated With Ulceration. AB - It has been suggested that embryogenic properties of migratory cells are reactivated during wound healing and metastasis in adults. This might explain the association between wound-induced inflammation and poor survival in patients with ulcerated melanoma. Linking inflammation with a migratory phenotype, we characterize the infiltration of innate inflammatory cells, loss of cell-to-cell adhesion (E-cadherin), factors associated with extracellular matrix degradation [matrix metalloproteinase-9 (MMP-9), and neutrophil elastase (NE)], and spindle shaped cell morphology, between ulcerated (n = 179) and nonulcerated (n = 206) melanoma. In addition, the presence of "extravascular migratory metastasis" (angiotropism) and tumor-vessel density were evaluated as important factors for tumor cell dispersal in ulcerated melanoma. We showed a correlation between expression of the granulocyte marker cd66b+ and the expression of NE and MMP-9, reflecting activated neutrophils. Ulcerated melanoma correlated with a low global E-cadherin score (P = 0.041) and weak-spot score (P = 0.0004). Thus, 28% of the nonulcerated, 42% of the minimally/moderately ulcerated melanoma, and 53% of the excessively ulcerated melanoma presented low scores as opposed to a high E cadherin score. In addition, the presence of ulceration was correlated with angiotropism (P < 0.0001) and spindle-shaped morphology (P = 0.021). There were no differences in MMP-9 expression or intratumoral vessel density between the ulcerated and nonulcerated group. In conclusion, expression of migratory cell properties showed a highly heterogeneous pattern, which was associated with ulcerated areas and inflammatory cells, in general and with neutrophils in particular. We, therefore, suggest that wound-associated inflammation may be involved in the induction of migratory cell transition and tumor cell dispersal in ulcerated melanoma. PMID- 28350548 TI - Pelvic Discontinuity Associated With Total Hip Arthroplasty: Evaluation and Management. AB - Pelvic discontinuity is a challenging complication encountered during revision total hip arthroplasty. Pelvic discontinuity is defined as a separation of the ilium superiorly from the ischiopubic segment inferiorly and is typically a chronic condition in failed total hip arthroplasties in the setting of bone loss. After a history and a physical examination have been completed and infection has been ruled out, appropriate imaging must be obtained, including plain hip radiographs, oblique Judet radiographs, and often a CT scan. The main management options are a hemispheric acetabular component with posterior column plating, a cup-cage construct, pelvic distraction, and a custom triflange construct. The techniques have unique pros and cons, but the goals are to obtain stable and durable acetabular component fixation and a healed or unitized pelvis while minimizing complications. PMID- 28350550 TI - Erythematous Bullous Patch in a Patient With Myelodysplastic Syndrome: Answer. PMID- 28350551 TI - The Impact of a Violent Physical Assault on a Registered Nurse: Her Healing Journey and Return to Work. AB - Healthcare practitioners are at an increased risk for workplace violence. What happens to a practitioner after a devastating physical assault from a patient in the workplace? This case report describes the impact of a violent assault on a registered nurse and her healing journey and return to the workplace. The Department of Veteran Affairs/Department of Defense "Clinical Practice Guidelines for Posttraumatic Stress Disorder" outline three categories of risk factors that are associated with the development of posttraumatic stress disorder: pretraumatic factors, peritraumatic or trauma-related factors, and posttraumatic factors. Each of these risk factors can contribute to the likelihood of an individual developing posttraumatic stress disorder after a traumatic incident and will be used to frame the discussion of this case. The registered nurse gave her full and informed consent for the author to tell her story. PMID- 28350552 TI - Characteristics of Forensic Patients in California With Dementia/Alzheimer's Disease. AB - Criminal defendants found incompetent to stand trial (IST) are sent to state hospitals for treatment to be restored to competency. IST patients diagnosed with dementia and related disorders present a particular challenge to clinicians, because they must be restored successfully within a statutorily mandated time frame (e.g., 3 years in California for defendants charged with a felony offense). This study examined a comprehensive data set that included all forensic patients served by California's Department of State Hospitals from September 2003 to February 2016. The findings revealed that, although most IST patients with a dementia diagnosis were restored to competency within the statutory time frames, they spent, on average, over twice as long confined than IST patients without a dementia diagnosis and were less likely than the latter group to be successfully restored. One implication of these findings is that forensic clinicians ought to assess whether IST patients diagnosed with dementia are likely to be restored or not as early as possible in the evaluation and triage process and report to the court any IST patients with a dementia diagnosis who are unlikely to be restored successfully. This would both prevent such patients from gratuitous confinement as well as free up treatment resources for other patients. PMID- 28350553 TI - Impact of Allogeneic Hematopoietic Stem Cell Transplantation on the HIV Reservoir and Immune Response in 3 HIV-Infected Individuals. AB - BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) can lead to significant changes to the HIV reservoir and HIV immune responses, indicating that further characterization of HIV-infected patients undergoing HSCT is warranted. METHODS: We studied 3 patients who underwent HSCT after either reduced intensity conditioning or myeloablative conditioning regimen. We measured HIV antigens and antibodies (Ag/Ab), HIV-specific CD4 T-cell responses, HIV RNA, and DNA in plasma, peripheral blood mononuclear cells, isolated CD4 T cells from peripheral blood, and lymph node cells. The patients remained on antiretroviral therapy throughout the follow-up period. RESULTS: All patients have been in continued remission for 4-6 years post-HSCT. Analyses of HIV RNA and DNA levels showed substantial reductions in HIV reservoir-related measurements in all 3 patients, changes in immune response varied with pronounced reductions in 2 patients and a less dramatic reduction in 1 patient. One patient experienced unexpected viral rebound 4 years after HSCT. CONCLUSIONS: These 3 cases highlight the substantial changes to the HIV reservoir and the HIV immune response in patients undergoing allogeneic HSCT. The viral rebound observed in 1 patient indicates that replication competent HIV can re-emerge several years after HSCT despite these marked changes. PMID- 28350554 TI - Brief Report: High Sensitivity and Specificity of the Cepheid Xpert HIV-1 Qualitative Point-of-Care Test Among Newborns in Botswana. AB - BACKGROUND: HIV point-of-care (POC) testing allows for early infant HIV diagnosis and treatment, but POC accuracy at birth and in the setting of antiretroviral prophylaxis for the prevention of mother-to-child HIV transmission is unknown. METHODS: We evaluated the Cepheid Xpert HIV-1 Qual POC test against the Roche Taqman HIV-1 DNA polymerase chain reaction (PCR) platform using dried blood spots from 15 HIV-infected and 75 HIV-exposed uninfected newborns. These infants were screened for HIV at <96 hours of life at 5 hospital maternity wards in Botswana; all infants received postexposure antiretroviral prophylaxis with single-dose nevirapine and zidovudine, and most mothers received 3-drug antiretroviral therapy in pregnancy and at delivery. RESULTS: Fourteen of the 15 PCR positive samples tested positive by Cepheid POC, yielding a sensitivity of 93.3% (95% confidence interval: 68.1 to 99.8). Baseline viral load among positive infants ranged from <40 to >10,000,000 copies/mL, with a median of 2403 copies/mL. The HIV RNA for the infant with false-negative POC testing was 1661 copies/mL. Of note, 2 infants with low HIV RNA (<40 and 272 copies/mL) were correctly identified as HIV positive by Cepheid POC. All the 75 PCR-negative samples tested negative by Cepheid POC, yielding a specificity of 100% (95% confidence interval: 96.1 to 100). DISCUSSION: Our study demonstrates high sensitivity and specificity for the Cepheid POC assay in the first week of life despite early infection and antiretroviral prophylaxis. This platform may be a useful approach for adding early infant HIV diagnosis to current testing programs. PMID- 28350555 TI - Apheresis in food allergies. AB - PURPOSE OF REVIEW: The prevalence of IgE-mediated food allergy and anaphylaxis has risen rapidly in developed countries, and countries with rapid industrialization may follow. Therapies include elimination diets, Oral ImmunoTherapy, and the administration of biologics, but high serum IgE levels may preclude their use. Consequently, decreasing IgE becomes a rational approach and could be obtained by immunoapheresis. The aim of this review is to evaluate the rationale and advantages of immunoapheresis. RECENT FINDINGS: The majority of the available adsorbers remove aspecifically all classes of immunoglobulins. Recently, IgE-specific adsorbers have been approved. Data on immunoapheresis for the treatment of allergic diseases with pathologically elevated IgE levels are emerging. In atopic dermatitis, this therapy alone seems to be beneficial. IgE selective apheresis appears to be sufficient to reduce the risk of anaphylaxis in multiple food allergy (MFA) and, when IgE titers are high, to open the way to treatment with Omalizumab. SUMMARY: Prospective studies, with well designed protocols, are needed to assess the efficacy, tolerability, and cost effectiveness of immunoapheresis in the field of food allergy. PMID- 28350557 TI - Double Versus Single Tendon Transfers to Improve Shoulder Function in Brachial Plexus Birth Palsy. AB - BACKGROUND: In children with brachial plexus birth palsy (BPBP) undergoing tendon transfers to augment shoulder external rotation, it is unclear whether transfer of the latissimus dorsi with its combined latissimus dorsi and teres major (cLT) versus isolated teres major (iTM) tendon transfer yield different outcomes. METHODS: Records of patients with BPBP who underwent shoulder tendon transfers to augment external rotation were retrospectively reviewed. Transfer type (cLT or iTM) was considered indiscriminate by virtue of surgeon preference. Modified Mallet Scale (mMS) and Active Movement Scale scores were recorded. Patients with <12 months' follow-up, C7 or lower palsy, humeral osteotomy, shoulder procedure(s) within 8 months, microsurgery within 1 year, or recurrent glenohumeral subluxation confirmed by postoperative imaging were excluded. Matched cohorts were identified within each tendon transfer group to yield similar preoperative shoulder function and glenohumeral alignment status. Outcomes for all tendon transfers as well as differences between cLT and iTM cohorts were analyzed. RESULTS: Among 121 cLT and 34 iTM transfers, 49 cLT and 14 iTM met the inclusion criteria. Subsequent matching of cohorts yielded 28 patients (14 cLT and 14 iTM). Average age at time of transfer was 3.0+/-1.4 years. Follow-up averaged 4.1+/-3.1 years. There were no statistically significant preoperative differences between cohorts, thus matching criteria were validated. Regardless of tendon(s) transferred, mMS external rotation improved (2.2 to 3.5, P<0.001), whereas mMS internal rotation decreased (3.8 to 3.2, P<0.001). When comparing matched cohorts, cLT transfer produced a greater mMS external rotation improvement than iTM (2.1 vs. 1.5, respectively; P=0.025). Loss of midline function (defined as mMS external rotation <3) occurred in 5 (35.7%) cLT and 2 (14.3%) iTM patients. CONCLUSIONS: Both cLT or iTM transfer are effective at augmenting shoulder external rotation in children with C5-C6 BPBP. Furthermore, cLT transfers may yield a larger improvement in external rotation in certain patients. However, both techniques slightly decrease shoulder internal rotation. Given that more total cLT patients lost midline function among matched cohorts, iTM transfer may still be considered when limited midline function is a concern. LEVEL OF EVIDENCE: Level III. PMID- 28350556 TI - Resorbable Plates Prevent Regression in Pediatric Mandibular Distraction Osteogenesis. AB - BACKGROUND: Mandibular distraction osteogenesis is an important technique to correct the pediatric hypoplastic mandible. Regression of the mandible after distraction continues to be a challenge, with some studies reporting up to 22% to 56% decrease toward predistraction length in the first year. We hypothesize that a resorbable plate placed after removal of the distractor will provide additional stability to newly formed bone, allowing further time for consolidation and minimizing regression. METHODS: This is a retrospective review of neonatal and pediatric patients between 2010 and 2015 who had mandibular distraction osteogenesis performed by the senior author (D.J.). Five patients, including 1 control and 4 intervention subjects, who had preoperative, postdistraction, and follow-up imaging were evaluated. Mandibular distraction was performed via internal devices (KLS Martin, Jacksonville, Fla) and followed by a consolidation period of 6 to 8 weeks. At the second operation when the distractors were removed, the intervention group had a SonicWeld Resorbx (KLS Martin) resorbable plate placed across the bone regenerate. A digital imaging and communications in medicine viewer was used to create a 3-dimensional reconstruction of each of the computed tomography scans and measurements of the mandible were made in the lateral cephalometric view. We then determined distraction distance, regression distance and percent regression. RESULTS: The average mandible distraction distance was 8.2 mm for the control group, and 9.9 mm for the intervention group (range, 6.7-12 mm). The average distance that the mandible regressed after distraction (regression distance) was 2.7 mm for the control group, and 0.5 mm for the intervention group (range, 0.2-0.9 mm). The average percent regression was 32.9% for the control group, and 5.1% for the intervention group (range 1.8 to 7.5%). CONCLUSIONS: The results of this study suggest that resorbable plate placement after removal of distractors helps prevent regression in pediatric mandibular distraction osteogenesis. The improvement was readily apparent both radiographically and clinically. PMID- 28350558 TI - Updates on hepatitis C virus therapy in the direct-acting antiviral era. AB - PURPOSE OF REVIEW: Hepatitis C virus (HCV) is a major cause of clinical burden in the United States and worldwide, as a percentage of patients can develop complications such as cirrhosis and hepatocellular carcinoma. RECENT FINDINGS: Therapy for chronic HCV infection was previously interferon-based, but with the advent of direct-acting antivirals (DAAs), there has been a dramatic improvement in eradicating the virus with favourable side effect profiles. SUMMARY: Emerging data are demonstrating new successful agents in difficult-to-manage populations. This review is aimed to provide a brief overview of currently accepted therapy, as well providing new information on upcoming therapeutic agents available for practioners going forward. PMID- 28350559 TI - Interventional Spine Considerations for Dural Ectasia in a Patient With Marfan Syndrome. AB - For patients with Marfan syndrome who present with radicular low back pain, interventional spine providers should be familiar with dural ectasia with variable diffuse thinning of the posterior wall of the lumbar spine and sacrum. Providers should carefully weigh the risks and benefits of offering elective procedures because altered anatomy may put these patients at higher risk of dural puncture. Patient selection is essential because hydrostatic pressures and/or neural tension should also be considered as potential pain generators that may not be relieved by steroid injections. Careful evaluation of recent magnetic resonance images and vigilant procedural technique is highly recommended. PMID- 28350562 TI - Role of Personality Functioning in the Quality of Life of Patients with Depression. AB - Depression is associated with reduced quality of life (QoL), and personality pathology is associated with higher impairment and poorer treatment outcomes in patients with depression. This study aims to analyze the effects of personality functioning on the QoL of patients with depression. Severity of depressive symptoms (Beck Depression Inventory), level of personality functioning (Operationalized Psychodynamic Diagnosis Structure Questionnaire), and QoL (Medical Outcome Study 36-item Short-Form) were assessed in a sample of 84 depressive outpatients. Personality functioning showed main effects on both the mental and physical components of QoL. A moderating effect of personality functioning on the relationship between depressive symptoms and QoL was tested but not confirmed. Severity of depressive symptoms was found to mediate the effect of personality functioning on the mental component of QoL. These results suggest that the effect of personality functioning on the QoL of patients with depression may be related to the higher severity of depressive symptoms found in patients with lower levels of personality functioning. PMID- 28350563 TI - Predicting the Mental Health and Functioning of Torture Survivors. AB - The psychological effects of war represent a growing public health concern as more refugees and asylum seekers migrate across borders. This study investigates whether sociodemographic, premigration and postmigration, and psychosocial factors predict adverse psychiatric symptoms in refugees and asylum seekers exposed to torture (N = 278). Hierarchical linear regressions revealed that female sex, older age, and unstable housing predicted greater severity of anxiety, posttraumatic stress disorder (PTSD), and depression. Cumulative exposure to multiple torture types predicted anxiety and PTSD, while mental health, basic resources (access to food, shelter, medical care), and external risks (risk of being victimized at home, community, work, school) were the strongest psychosocial predictors of anxiety, PTSD, and depression. Also, time spent in the United States before presenting for services significantly predicted anxiety, PTSD, and depression. Consequently, public-sector services should seek to engage this high-risk population immediately upon resettlement into the host country using a mental health stepped care approach. PMID- 28350561 TI - Reducing Pediatric Sternal Wound Infections: A Quality Improvement Project. AB - OBJECTIVES: To evaluate whether a quality improvement intervention reduces sternal wound infection rates in children after cardiac surgery. DESIGN: This is a pre- and postintervention quality improvement study. SETTING: A 16-bed cardiac ICU in a university-affiliated pediatric tertiary care children's hospital. PATIENTS: All patients undergoing cardiac surgery via median sternotomy from January 2010 to December 2014 are included. The sternal wound infection rates for primary closure and delayed sternal closure are reported per 100 sternotomies. The hospital-acquired infection records were used to identify preintervention cases, while postintervention cases were collected prospectively. INTERVENTION: Implementation of a sternal wound prevention bundle during the preoperative, intraoperative, and postoperative periods for cardiac surgical cases. MEASUREMENTS AND MAIN RESULTS: During the preintervention period, 32 patients (3.8%) developed sternal wound infection, whereas only 19 (2.1%) developed sternal wound infection during the postintervention period (p = 0.04). The rates of sternal wound infection following primary closure were not significantly different pre- and postintervention (2.4% vs 1.6%; p = 0.35). However, patients with delayed sternal closure had significantly lower postintervention infection rates (10.6% vs 3.9%; p = 0.02). CONCLUSIONS: Implementation of a sternal wound prevention bundle during the perioperative period was associated with lower sternal wound infection rates in surgeries with delayed sternal closure. PMID- 28350564 TI - OpTrust: Validity of a Tool Assessing Intraoperative Entrustment Behaviors. AB - OBJECTIVE: The aim of this study is to establish evidence to support the validity of a novel faculty-resident intraoperative assessment tool for entrustment known as OpTrust. BACKGROUND: Recently, the landscape of surgical training has been altered, in part, because of resident work-hour changes and increased supervision requirements. To address these concerns, a new model for assessment of teaching and learning in surgical residencies must be anchored on progression through milestones and entrustment. METHODS: OpTrust was designed to assess the faculty resident dyad in the operating room and measure the entrustment exhibited during intraoperative interactions across 5 domains: (i) types of questions asked, (ii) operative plan, (iii) instruction, (iv) problem solving, and (v) leadership by the surgical resident. After initial pilot testing and refinement of OpTrust, 5 individual raters underwent rater training sessions; 49 individual operating room observations were completed based on 28 cases. RESULTS: OpTrust, as a tool for assessing intraoperative entrustment, is supported by strong validity evidence. In part, it demonstrates strong interrater reliability across all faculty domains as measured by intraclass correlation 1 (ICC1) (0.81-0.93). For resident domains the results were similar with ICC1 (0.84-0.94). Cronbach alpha was 0.89 and 0.87 for faculty and resident entrustment respectively, signifying the 5 domains could be combined into a single construct of entrustment. A high correlation existed between faculty and resident scores (Pearson r = 0.94, P < 0.001) indicating a strong positive linear relationship between faculty and resident mean entrustment scores across all scale domains. CONCLUSIONS: OpTrust successfully assesses behaviors associated with entrustment during intraoperative faculty-resident interactions, and has the potential to be adopted across other procedural-based specialties to promote autonomous training progression. PMID- 28350565 TI - Impact of Surgical Approach on Long-term Survival in Esophageal Adenocarcinoma Patients With or Without Neoadjuvant Chemoradiotherapy. AB - OBJECTIVE: To compare overall survival in patients with esophageal adenocarcinoma who underwent transhiatal esophagectomy (THE) with limited lymphadenectomy or transthoracic esophagectomy (TTE) with extended lymphadenectomy with or without neoadjuvant chemoradiotherapy (nCRT). BACKGROUND: The application of neoadjuvant therapy might change the association between the extent of lymphadenectomy and survival in patients with esophageal adenocarcinoma. This may influence the choice of surgical approach in patients treated with nCRT. METHODS: Patients with potentially curable subcarinal esophageal adenocarcinoma treated with surgery alone or nCRT followed by surgery in 7 centers were included. The effect of surgical approach on overall survival, differentiated by the addition or omission of nCRT, was analyzed using a multivariable Cox regression model that included well-known prognostic factors and factors that might have influenced the choice of surgical approach. RESULTS: In total, 701 patients were included, of whom 318 had TTE with extended lymphadenectomy and 383 had THE with limited lymphadenectomy. TTE had differential effects on survival (P for interaction = 0.02), with a more favorable prognostic effect in patients who were treated with surgery alone [hazard ratio (HR) = 0.77, 95% confidence interval (CI) 0.58-1.03]. This association was statistically significant in a subgroup of patients with 1 to 8 positive lymph nodes in the resection specimen (HR = 0.62, 95% CI 0.43 0.90). The favorable prognostic effect of TTE over THE was absent in the nCRT and surgery group (HR = 1.16, 95% CI 0.80-1.66) and in the subgroup of nCRT patients with 1 to 8 positive lymph nodes in the resection specimen (HR = 1.00, 95% CI 0.61-1.68). CONCLUSIONS: Compared to surgery alone, the addition of nCRT may reduce the need for TTE with extended lymphadenectomy to improve long-term survival in patients with esophageal adenocarcinoma. PMID- 28350560 TI - Outcomes Related to the Use of Frozen Plasma or Pooled Solvent/Detergent-Treated Plasma in Critically Ill Children. AB - OBJECTIVE: To determine if the use of fresh frozen plasma/frozen plasma 24 hours compared to solvent detergent plasma is associated with international normalized ratio reduction or ICU mortality in critically ill children. DESIGN: This is an a priori secondary analysis of a prospective, observational study. Study groups were defined as those transfused with either fresh frozen plasma/frozen plasma 24 hours or solvent detergent plasma. Outcomes were international normalized ratio reduction and ICU mortality. Multivariable logistic regression was used to determine independent associations. SETTING: One hundred one PICUs in 21 countries. PATIENTS: All critically ill children admitted to a participating unit were included if they received at least one plasma unit during six predefined 1 week (Monday to Friday) periods. All children were exclusively transfused with either fresh frozen plasma/frozen plasma 24 hours or solvent detergent plasma. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 443 patients enrolled in the study. Twenty-four patients (5%) were excluded because no plasma type was recorded; the remaining 419 patients were analyzed. Fresh frozen plasma/frozen plasma 24 hours group included 357 patients, and the solvent detergent plasma group included 62 patients. The median (interquartile range) age and weight were 1 year (0.2-6.4) and 9.4 kg (4.0-21.1), respectively. There was no difference in reason for admission, severity of illness score, pretransfusion international normalized ratio, or lactate values; however, there was a difference in primary indication for plasma transfusion (p < 0.001). There was no difference in median (interquartile range) international normalized ratio reduction, between fresh frozen plasma/frozen plasma 24 hours and solvent detergent plasma study groups, -0.2 (-0.4 to 0) and -0.2 (-0.3 to 0), respectively (p = 0.80). ICU mortality was lower in the solvent detergent plasma versus fresh frozen plasma/frozen plasma 24 hours groups, 14.5% versus 29.1%%, respectively (p = 0.02). Upon adjusted analysis, solvent detergent plasma transfusion was independently associated with reduced ICU mortality (odds ratio, 0.40; 95% CI, 0.16-0.99; p = 0.05). CONCLUSIONS: Solvent detergent plasma use in critically ill children may be associated with improved survival. This hypothesis generating data support a randomized controlled trial comparing solvent detergent plasma to fresh frozen plasma/frozen plasma 24 hours. PMID- 28350566 TI - Blinding in Surgical Randomized Clinical Trials in 2015. AB - : Lack of blinding in randomized clinical trials can bias the effect estimates of the observed intervention. In trials assessing nonpharmacological interventions (eg, surgical randomized clinical trials) blinding is usually more difficult. In this mini-review the blinding and reporting of blinding was assessed from surgical randomized clinical trials that were published in leading medical and surgical journals in 2015. Conducting a systematic search on PubMed, a total of 99 studies were deemed as relevant and blinding status assessed. Blinding was explicitly stated for practitioners, patients, and outcome observers in 3%, 37%, and 52%, respectively. The blinding status was not clearly stated in a large proportion of studies or had sometimes a misleading classification. Hence, authors and journals publishing randomized controlled trials should pay attention that status of blinding is unambiguously reported. PMID- 28350568 TI - Reducing Length of Stay Using a Robotic-assisted Approach for Retromuscular Ventral Hernia Repair: A Comparative Analysis From the Americas Hernia Society Quality Collaborative. AB - OBJECTIVE: The aim of this study was to compare length of stay (LOS) after robotic-assisted and open retromuscular ventral hernia repair (RVHR). BACKGROUND: RVHR has traditionally been performed by open techniques. Robotic-assisted surgery enables surgeons to perform minimally invasive RVHR, but with unknown benefit. Using real-world evidence, this study compared LOS after open (o-RVHR) and robotic-assisted (r-RVHR) approach. METHODS: Multi-institutional data from patients undergoing elective RVHR in the Americas Hernia Society Quality Collaborative between 2013 and 2016 were analyzed. Propensity score matching was used to compare median LOS between o-RVHR and r-RVHR groups. This work was supported by an unrestricted grant from Intuitive Surgical, and all clinical authors have declared direct or indirect relationships with Intuitive Surgical. RESULTS: In all, 333 patients met inclusion criteria for a 2:1 match performed on 111 r-RVHR patients using propensity scores, with 222 o-RVHR patients having similar characteristics as the robotic-assisted group. Median LOS [interquartile range (IQR)] was significantly decreased for r-RVHR patients [2 days (IQR 2)] compared with o-RVHR patients [3 days (IQR 3), P < 0.001]. No differences in 30 day readmissions or surgical site infections were observed. Higher surgical site occurrences were noted with r-RVHR, consisting mostly of seromas not requiring intervention. CONCLUSIONS: Using real-world evidence, a robotic-assisted approach to RVHR offers the clinical benefit of reduced postoperative LOS. Ongoing monitoring of this technique should be employed through continuous quality improvement to determine the long-term effect on hernia recurrence, complications, patient satisfaction, and overall cost. PMID- 28350567 TI - Watchful Waiting Versus Surgery of Mildly Symptomatic or Asymptomatic Inguinal Hernia in Men Aged 50 Years and Older: A Randomized Controlled Trial. AB - OBJECTIVE: To compare if watchful waiting is noninferior to elective repair in men aged 50 years and older with mildly symptomatic or asymptomatic inguinal hernia. BACKGROUND: The role of watchful waiting in older male patients with mildly symptomatic or asymptomatic inguinal hernia is still not well-established. METHODS: In this noninferiority trial, we randomly assigned men aged 50 years and older with mildly symptomatic or asymptomatic inguinal hernia to either elective inguinal hernia repair or watchful waiting. Primary endpoint was the mean difference in a 4-point pain/discomfort score at 24 months of follow-up. Using a 0.20-point difference as a clinically relevant margin, it was hypothesized that watchful waiting was noninferior to elective repair. Secondary endpoints included quality of life, event-free survival, and crossover rates. RESULTS: Between January 2006 and August 2012, 528 patients were enrolled, of whom 496 met the inclusion criteria: 234 were assigned to elective repair and 262 to watchful waiting. The mean pain/discomfort score at 24 months was 0.35 [95% confidence interval (CI) 0.28-0.41)] in the elective repair group and 0.58 (95% CI 0.52 0.64) in the watchful waiting group. The difference of these means (MD) was -0.23 (95% CI -0.32 to -0.14). In the watchful waiting group, 93 patients (35.4%) eventually underwent elective surgery and 6 patients (2.3%) received emergent surgery for strangulation/incarceration. Postoperative complication rates and recurrence rates in these 99 operated individuals were comparable with individuals originally assigned to the elective repair group (8.1% vs 15.0%; P = 0.106, 7.1% vs 8.9%; P = 0.668, respectively). CONCLUSIONS: Our data could not rule out a relevant difference in favor of elective repair with regard to the primary endpoint. Nevertheless, in view of all other findings, we feel that our results justify watchful waiting as a reasonable alternative compared with surgery in men aged 50 years and older. PMID- 28350569 TI - Overall Splenectomy Rates Stable Despite Increasing Usage of Angiography in the Management of High-grade Blunt Splenic Injury. AB - OBJECTIVE: The purpose of this study was to understand the contemporary trends of splenectomy in blunt splenic injury (BSI) and to determine if angiography and embolization (ANGIO) may be impacting the splenectomy rate. BACKGROUND: The approach to BSI has shifted to increasing use of nonoperative management, with a greater reliance on ANGIO. However, the impact ANGIO has on splenic salvage remains unclear with little contemporary data. METHODS: The National Trauma Data Bank was used to identify patients 18 years and older with high-grade BSI (Abbreviated Injury Scale >II) treated at Level I or II trauma centers between 2008 and 2014. Primary outcomes included yearly rates of splenectomy, which was defined as early if performed within 6 hours of ED admission and delayed if greater than 6 hours, ANGIO, and mortality. Trends were studied over time with hierarchical regression models. RESULTS: There were 53,689 patients who had high grade BSI over the study period. There was no significant difference in the adjusted rate of overall splenectomy over time (24.3% in 2008, 24.3% in 2014, P value = 0.20). The use of ANGIO rapidly increased from 5.3% in 2008 to 13.5% in 2014 (P value < 0.001). Mortality was similar overtime (8.7% in 2008, 9.0% in 2014, P value = 0.33). CONCLUSION: Over the last 7 years, the rate of angiography has been steadily rising while the overall rate of splenectomy has been stable. The lack of improved overall splenic salvage, despite increased ANGIO, calls into question the role of ANGIO in splenic salvage on high-grade BSI at a national level. PMID- 28350570 TI - Low-Density Lipoprotein Receptor-Related Protein 4-Positive Myasthenia Gravis in a Double-Seronegative, Electromyography-Negative Patient. AB - We describe a patient with ocular myasthenia gravis, where single-fiber electromyography and testing for acetylcholine receptor and muscle-specific kinase antibodies were negative. However, antibodies to low-density lipoprotein receptor-related protein 4 (LRP4) were positive, and this prompted appropriate management. We recommend that testing for LRP4 antibodies be considered when the clinical suspicion for myasthenia gravis is high despite negative conventional diagnostic tests. PMID- 28350571 TI - Vertebrobasilar Dolichoectasia Causing An Optic Tract Syndrome. AB - Vertebrobasilar dolichoectasia (VBD) is characterized by significant dilation, elongation, and tortuosity of the vertebrobasilar system. We present a unique case of VBD, confirmed by neuroimaging studies, showing vascular compression of the right optic tract and lower cranial nerves leading to an incongruous left homonymous inferior quadrantanopia and glossopharyngeal neuralgia. PMID- 28350572 TI - Aripiprazole Lauroxil: Pharmacokinetic Profile of This Long-Acting Injectable Antipsychotic in Persons With Schizophrenia. AB - BACKGROUND: Aripiprazole lauroxil is an extended-release prodrug of aripiprazole for intramuscular injection, approved for schizophrenia treatment. We developed a population pharmacokinetic (PopPK) model to characterize aripiprazole lauroxil PK and evaluate dosing scenarios likely to be encountered in clinical practice. METHODS: Data from 616 patients with schizophrenia, collected from 5 clinical studies, were used to construct the PopPK model. The model was subsequently used to evaluate various dose levels and frequency and the impact of dosing delay on aripiprazole concentrations. FINDINGS: The results of the model indicate that aripiprazole is released into the systemic circulation after 5 to 6 days, and release continues for an additional 36 days. The slow increase in aripiprazole concentration after injection necessitates the coadministration of oral aripiprazole for 21 days with the first injection. Based on the PopPK model simulations, a dosing interval of 882 mg every 6 weeks results in aripiprazole concentrations that fall within the concentration range associated with the efficacious aripiprazole lauroxil dose range (441-882 mg dosed monthly). A 662-mg monthly dose also resulted in aripiprazole concentrations within the efficacious dose range. Aripiprazole lauroxil administration results in prolonged exposure, such that dose delays of 2 to 4 weeks, depending on the dose regimen, do not require oral aripiprazole supplementation upon resumption of dosing. CONCLUSIONS: This PopPK model and model-based simulations were effective means for evaluating aripiprazole lauroxil dosing regimens and management of missed doses. Such analyses play an important role in determining the use of this long-acting antipsychotic in clinical practice. PMID- 28350574 TI - Recurrent Hyperammonemia Associated With Olanzapine. PMID- 28350573 TI - Possible Clozapine Overdose-Associated Thromboembolic Event. PMID- 28350575 TI - Influence of carotid atherosclerotic plaques on pulse wave assessment with arterial tonometry. AB - OBJECTIVE: Aortic stiffness and central pressure measurements have become increasingly important for the overall estimation of cardiovascular risk. The aim of this study is to verify whether the presence of stenosis in the carotid arteries due to atherosclerotic plaques may induce a bias in the measurement of carotid-femoral pulse wave velocity (PWV) and in the analysis of central pulse waveform variables assessed by carotid tonometry. METHODS: Eighty-four patients (age: 67.1 +/- 12.4 years) undergoing screening for carotid atherosclerosis were enrolled, divided into three groups according to carotid ultrasound findings (NASCET criteria): 28 patients without significant stenosis, 30 patients with bilateral plaques, and 26 patients with right or left monolateral stenosis. PWV and other variables derived from the central pulse waveform analysis (central blood pressure, augmentation index and forward and backward waves) were measured at both right and left carotid arteries by a validated PulsePen tonometer. A repeatability study was performed in 28 young healthy patients (age: 25.4 +/- 2.9 years). RESULTS: A high degree of correlation was found between bilateral measurements in all groups, and particularly in groups with monolateral carotid stenosis, with no significant difference attributable to lateralized stenosis. Right-left differences in asymmetric groups were 0.35 +/- 5.12 mmHg (R = 0.960) for central blood pressure, -2.12 +/- 7.39% (R = 0.743) for augmentation index, 0.64 +/- 1.56 m/s (R = 0.947) for PWV, 0.08 +/- 8.48 mmHg for forward wave (R = 0.742) and 0.35 +/- 2.35 mmHg for backward wave (R = 0.907). CONCLUSION: Measurement of PWV and of variables derived from the central pulse waveform analysis by carotid tonometry is not biased by the presence of local atherosclerotic plaques. PMID- 28350576 TI - Absence of resting cardiovascular dysfunction in middle-aged endurance-trained athletes with exaggerated exercise blood pressure responses. AB - OBJECTIVE: Untrained individuals with exaggerated blood pressure (EBP) responses to graded exercise testing are characterized as having resting dysfunction of the sympathetic and cardiovascular systems. The purpose of this study was to determine the resting cardiovascular state of endurance-trained individuals with EBP through a comparison of normotensive athletes with and without EBP. METHODS: EBP was defined as a maximal systolic blood pressure (SBP) at least 190 mmHg and at least 210 mmHg for women and men respectively, in response to a graded exercise test. Twenty-two life-long endurance-trained athletes (56 +/- 5 years, 16 men) with EBP (EBP+) and 11 age and sex-matched athletes (55 +/- 5 years, eight men) without EBP (EBP-) participated in the study. Sympathetic reactivity was assessed using BP responses to a cold pressor test, isometric handgrip exercise, and postexercise muscle ischemia. Resting left ventricular structure and function was assessed using two-dimensional echocardiography, whereas central arterial stiffness was assessed using carotid-to-femoral pulse wave velocity. Calf vascular conductance was measured at rest and peak postexercise using strain gauge plethysmography. RESULTS: All sympathetic reactivity, left ventricular, and arterial stiffness indices were similar between groups. There was no between group difference in resting vascular conductance, whereas peak vascular conductance was higher in EBP+ relative to EBP- (1.81 +/- 0.65 vs. 1.45 +/- 0.32 ml/100 ml/min/mmHg, P < 0.05). CONCLUSION: Findings from this study suggest that athletes with EBP do not display the resting cardiovascular state typically observed in untrained individuals with EBP. This response in athletes, therefore, is likely a compensatory mechanism to satisfy peripheral blood-flow demands rather than indicative of latent dysfunction. PMID- 28350577 TI - Reliability of heart rate as neuroadrenergic marker in the metabolic syndrome. AB - BACKGROUND: Metabolic syndrome is characterized by a pronounced sympathetic overactivity as documented by the marked increase in muscle sympathetic nerve traffic (MSNA) as well as in plasma norepinephrine values reported in this condition. Whether and to what extent heart rate (HR) reflects the abovementioned adrenergic alterations in metabolic syndrome remains largely undefined. It is also undefined the validity of the abovementioned adrenergic markers in reflecting the main features of the metabolic syndrome. METHODS: In 65 metabolic syndrome patients, aged 56.5 +/- 1.3 years (mean +/- SEM), we measured over a 30 min resting period blood pressure, HR (ECG), venous plasma norepinephrine (HPLC) and MSNA (microneurography). We also evaluated anthropometric and metabolic variables including HOMA index, correlating them with the adrenergic markers. The same measurements were also made in 48 age-matched healthy controls. RESULTS: HR was significantly greater in the metabolic syndrome patients than in controls (74.6 +/- 1.5 versus 67.5 +/- 1.5 bpm, P < 0.001) and significantly and directly correlated with the elevated norepinephrine and MSNA values (r = 0.25 and 0.33, P < 0.05 and 0.01, respectively). MSNA was significantly and directly related to blood pressure (r = 0.27 and 0.31 SBP and DBP, respectively, P < 0.05 for both), BMI (r = 0.36, P < 0.01), waist circumference (r = 0.34, P < 0.01), waist-to-hip ratio (r = 0.49, P < 0.01) and plasma insulin (r = 0.57, P < 0.01). In contrast, no significant correlation was detectable between HR or norepinephrine and the abovementioned anthropometric and metabolic variables. CONCLUSION: Our data show that in the metabolic syndrome not only peripheral but also cardiac sympathetic drive is markedly potentiated and HR can be regarded as a marker of adrenergic overdrive characterizing this clinical condition. The reliability of HR (and of plasma norepinephrine) as sympathetic marker appears to be limited, however, this variable being unable to reflect, at variance from MSNA, the main metabolic and anthropometric abnormalities characterizing the metabolic syndrome. PMID- 28350579 TI - Cervical screening: toward an equal risk/equal management approach, irrespective of HIV status. PMID- 28350578 TI - Increasing voluntary medical male circumcision uptake among adult men in Tanzania. AB - OBJECTIVE: We evaluated a demand-creation intervention to increase voluntary medical male circumcision (VMMC) uptake among men aged 20-34 years in Tanzania, to maximise short-term impact on HIV incidence. METHODS: A cluster randomized controlled trial stratified by region was conducted in 20 outreach sites in Njombe and Tabora regions. The sites were randomized 1 : 1 to receive either a demand-creation intervention package in addition to standard VMMC outreach, or standard VMMC outreach alone. The intervention package included enhanced public address messages, peer promotion by recently circumcised men, facility setup to increase privacy, and engagement of female partners in demand creation. The primary outcome was the proportion of VMMC clients aged 20-34 years. FINDINGS: Overall, 6251 and 3968 VMMC clients were enrolled in intervention and control clusters, respectively. The proportion of clients aged 20-34 years was slightly greater in the intervention than control arm [17.7 vs. 13.0%; prevalence ratio = 1.36; 95% confidence intervals (CI):0.9-2.0]. In Njombe region, the proportion of clients aged 20-34 years was similar between arms but a significant two-fold difference was seen in Tabora region (P value for effect modification = 0.006). The mean number of men aged 20-34 years (mean difference per cluster = 97; 95% CI:40-154), and of all ages (mean difference per cluster = 227, 95% CI:33-420) were greater in the intervention than control arm. CONCLUSION: The intervention was associated with a significant increase in the proportion of clients aged 20 34 years in Tabora but not in Njombe. The intervention may be sensitive to regional factors in VMMC programme scale-up, including saturation. PMID- 28350580 TI - Alemtuzumab induction therapy in HIV-positive renal transplant recipients. PMID- 28350581 TI - Transient HIV-specific T cells increase and inflammation in an HIV-infected patient treated with nivolumab. PMID- 28350582 TI - HIV cure strategies: response to ignore the central nervous system at your patients' peril. PMID- 28350583 TI - Dolutegravir plasma levels after gastric bypass surgery. PMID- 28350585 TI - Effect of Anchor Length on the Pullout Strength of Palatal Mini Implants. AB - PURPOSE: The aim of this study was to evaluate the pullout strength of 3 different orthodontic mini implants. MATERIALS AND METHODS: Twenty-seven mini implants (diameter: 2 mm, length: 7 mm) were implanted into artificial bone (Sawbones; Pacific Research Laboratories Inc.) at depths of 3, 4, and 5 mm. The insertion torque (IT), resonance frequency (RF), pullout strength (PS), and anchor length (AL) were measured. One-way analysis of variance with Tukey honest significant difference (HSD) postcomparison were used to detect intergroup differences. The null hypothesis was that IT, RF, and PS would significantly correlate in the same brand. RESULTS: In the implantation depths (ID) (5 and 4 mm), IT of Types C (16.67 and 14.33 N.cm) and Type B (14 and 13.33 N.cm) were significantly higher than Type A (10.33 and 9.33 N.cm). Type A had a largest AL and PS at the IDs (5 and 4 mm). In the IDs (3 mm), PS was no different. Type C had no correlation among the RF, IT, and PS. Therefore, null hypothesis was rejected. CONCLUSION: AL exerted crucial effects on the PS of the mini implants. PMID- 28350587 TI - What Can We Learn From the Letters of Students and Residents About Improving the Medical Curriculum? PMID- 28350586 TI - Predictors of Outcome in Conservative and Minimally Invasive Surgical Management of Pain Originating From the Sacroiliac Joint: A Pooled Analysis. AB - STUDY DESIGN: A pooled patient-level analysis of two multicenter randomized controlled trials and one multicenter single-arm prospective trial. OBJECTIVE: The aim of this study was to identify predictors of outcome of conservative and minimally invasive surgical management of pain originating from the sacroiliac joint (SIJ). SUMMARY OF BACKGROUND DATA: Three recently published prospective trials have shown that minimally invasive SIJ fusion (SIJF) using triangular titanium implants produces better outcomes than conservative management for patients with pain originating from the SIJ. Due to limitations in individual trial sample size, analyses of predictors of treatment outcome were not conducted. METHODS: We pooled individual patient data from the three trials and used random effects models with multivariate regression analysis to identify predictors for treatment outcome separately for conservative and minimally invasive surgical treatment. Outcome was measured using visual analogue scale (VAS), Oswestry Disability Index (ODI), and EuroQOL-5D (EQ-5D). RESULTS: We included 423 patients assigned to either nonsurgical management (NSM, n = 97) or SIJF (n = 326) between 2013 and 2015. The reduction in SIJ pain was 37.9 points larger [95% confidence interval (95% CI) 32.5-43.4, P < 0.0001] in the SIJF group than in the NSM group. Similarly, the improvement in ODI was 18.3 points larger (95% CI 14.3-22.4), P < 0.0001). In NSM, we found no predictors of outcome. In SIJF, a reduced improvement in outcome was predicted by smoking (P = 0.030), opioid use (P = 0.017), lower patient age (P = 0.008), and lower duration of SIJ pain (P = 0.028). CONCLUSIONS: Our results support the view that SIJF leads to better treatment outcome than conservative management of SIJ pain and that a higher margin of improvement can be predicted in nonsmokers, nonopioid users, and patients of increased age and with longer pain duration. LEVEL OF EVIDENCE: 1. PMID- 28350588 TI - Assessing for Learner Shame Should Be a Routine Part of Remediation for Unprofessional Behavior. PMID- 28350589 TI - In Reply to Bynum. PMID- 28350590 TI - Beyond the Controversy About Advocacy. PMID- 28350591 TI - In Reply to Reardon et al. PMID- 28350592 TI - Clinical Reasoning and Threshold Concepts. PMID- 28350593 TI - In Reply to Ma et al. PMID- 28350594 TI - To Take Care of Patients Well, Physicians Must Take Care of Themselves. PMID- 28350595 TI - Applying Design Thinking to Curriculum Reform. PMID- 28350596 TI - Do Students Really Have an Inability to Concentrate During Lectures? PMID- 28350597 TI - Choosing the Right Words in the Curriculum and Beyond. PMID- 28350598 TI - Are the Didactic Years an Artifact of Ancestral Medicine? Updating the Curriculum to Meet Modern Needs. PMID- 28350600 TI - Build or Buy? Curricular Design and External Basic Sciences Learning Resources. PMID- 28350599 TI - The Role of E-Learning in Medical Education. PMID- 28350601 TI - Effective Collaboration on Skin Disease Starts With Medical Education. PMID- 28350602 TI - Student Research in the Medical Curriculum: Experiences From Norway. PMID- 28350603 TI - Quality Improvement in Medical Education: Implications for Curriculum Change. PMID- 28350604 TI - LGBTQ Health Education: Where Are We Now? PMID- 28350605 TI - Teaching Physicians to Teach: The Underappreciated Path to Improving Patient Outcomes. PMID- 28350606 TI - Improving Medical Education by Improving Its Instructors. PMID- 28350607 TI - Reflection Fatigue Among Medical Students. PMID- 28350608 TI - A Grassroots Student-Faculty Coalition on Curriculum Change. PMID- 28350609 TI - The Illness of Present Histories. PMID- 28350610 TI - Stroke Education Is Underrepresented in U.S. Undergraduate Clinical Curricula. PMID- 28350611 TI - Health Systems Education: A Call for National Medical Curriculum Reform. PMID- 28350612 TI - Case-Based Suffering. PMID- 28350613 TI - Artist's Statement: Learning to Float. PMID- 28350614 TI - Prozac Diary: [Excerpt]. PMID- 28350615 TI - Commentary on an Excerpt From Prozac Diary. PMID- 28350617 TI - Working together for better blood pressure control and cardiovascular disease reduction. PMID- 28350616 TI - Her Story of Present Illness. PMID- 28350618 TI - Association between serum uric acid and cardiovascular mortality and all-cause mortality: a cohort study. AB - OBJECTIVE: Previous studies have reported the association among serum uric acid (SUA) levels and cardiovascular and all-cause mortality; however, the results have been inconsistent. The aim of this study was to investigate whether SUA is independently associated with cardiovascular and all-cause mortality in relatively healthy Korean adults. METHODS: A total of 396 951 individuals were enrolled for the study between 2002 and 2012. About 39 991 participants were excluded for various reasons. All-cause and cardiovascular mortality data were collected. Cox proportional hazards models were used to estimate adjusted hazard ratios and 95% confidence intervals for all-cause and cardiovascular mortality according to baseline uric acid quintiles, and the third, middle SUA quintile was the reference group. RESULTS: A total of 356 960 participants were considered to be eligible for the analysis, and median follow-up duration was 5.88 years. The lowest and highest quintiles of SUA were less than 5.2 and more than 7.1 mg/dl in men, and less than 3.5 and more than 5.0 mg/dl in women, respectively. A total of 2082 deaths (312 from cardiovascular disease and 1770 from other causes) occurred during follow-up. In the highest SUA group, adjusted hazard ratios for all-cause mortality were 1.24 (1.01, 1.51) in men and 1.04 (0.76, 1.42) in women, and for cardiovascular mortality were 1.15 (0.72, 1.83) in men and 1.69 (0.70, 4.04) in women after adjustment for various possible confounding factors. CONCLUSION: In the current large relatively healthy population-based observational study, SUA showed no significant association with all-cause and cardiovascular mortality. PMID- 28350619 TI - Genetic determinants of essential hypertension in the population of Tatars from Russia. AB - OBJECTIVE: Systemic inflammation and impaired function of endothelium play an important role in the development of hypertension. Our study aimed to analyze an association between essential hypertension and polymorphic markers in candidate genes in the group of 530 Tatars from the Republic of Bashkortostan, Russia. METHODS: The study group consisted of 216 male patients with essential hypertension (mean age 48.92 +/- 8.8 years) and 314 healthy individuals of corresponding sex and age without history of cardiovascular disease. Association between studied polymorphisms and essential hypertension was analyzed using PLINK. RESULTS: We detected an association between EDNRB rs5351, VEGFA 2549(18)I/D, and ADRB2 rs1042713 polymorphisms and essential hypertension in men of Tatar ethnic origin. EDNRB, VEGFA, and VCAM1 single-nucleotide polymorphisms were associated with SBP and DBP. However, only EDNRB rs5351 remained associated with hypertension after Bonferroni correction for multiple testing. A Markov chain Monte Carlo-based approach implemented in the APSampler program was used to analyze association of genotype and/or allele combinations with disease. The most influential in conferring risk of hypertension was EDNRBG/G+ADRB2A+VCAM1A combination (odds ratio = 4.15, PBonf = 5.43 * 10). CONCLUSION: Our results suggest that rs5351 single-nucleotide polymorphism is a strong independent predictor of essential hypertension in men of Tatar ethnic origin. PMID- 28350621 TI - Visit-to-visit SBP variability and cardiovascular disease in a multiethnic primary care setting: 10-year retrospective cohort study. AB - OBJECTIVES: The current study aims to determine the relationship of long-term visit-to-visit variability of SBP to cardiovascular disease (CVD) in a multiethnic primary care setting. METHOD: This is a retrospective study of a cohort of 807 hypertensive patients over a period of 10 years. Three-monthly clinic blood pressure readings were used to derive blood pressure variability (BPV), and CVD events were captured from patient records. RESULTS: Mean age at baseline was 57.2 +/- 9.8 years with 63.3% being women. The BPV and mean SBP over 10 years were 14.7 +/- 3.5 and 142 +/- 8 mmHg, respectively. Prevalence of cardiovascular event was 13%. In multivariate logistic regression analysis, BPV was the predictor of CVD events, whereas the mean SBP was not independently associated with cardiovascular events in this population. Those with lower SBP and lower BPV had fewer cardiovascular events than those with the same low mean SBP but higher BPV (10.5 versus 12.8%). Similarly those with higher mean SBP but lower BPV also had fewer cardiovascular events than those with the same high mean and higher BPV (11.6 versus 16.7%). Other variables like being men, diabetes and Indian compared with Chinese are more likely to be associated with cardiovascular events. CONCLUSION: BPV is associated with an increase in CVD events even in those who have achieved lower mean SBP. Thus, we should prioritize not only control of SBP levels but also BPV to reduce CVD events further. PMID- 28350620 TI - Treatment of uncomplicated hypertension is associated with a reduction in cardiovascular mortality: a Korean national cohort study. AB - BACKGROUND: Although the benefit of hypertension treatment is well established in high-risk patients, there is a paucity of evidence regarding the benefit of treatment in patients with uncomplicated hypertension. METHODS: Hypertensive adult patients were selected from the Korea National Health Insurance Sample Cohort in 2002 and were followed until 2013. Patients with a diagnosis of heart failure, coronary artery disease, stroke, malignancy, diabetes, or chronic kidney disease were excluded. Ultimately, 40 496 patients were divided into three groups: never-treated (N = 6756), treated-from-baseline (N = 28 443), and treated during-follow-up (N = 5297). Five first-line antihypertensive agents were categorized into four classes: renin-angiotensin system blocker (RASB), beta blocker, calcium channel blocker (CCB), and diuretics. All-cause mortality, cardiovascular mortality, and hazard ratio were determined. RESULTS: All-cause and cardiovascular mortality rates were significantly lower in both treatment groups than in the never-treated group (all log-rank P < 0.001). Treatment from baseline (hazard ratio = 0.49 for all-cause mortality and hazard ratio = 0.62 for cardiovascular mortality) and treatment started during follow-up (hazard ratio = 0.41 for all-cause mortality and hazard ratio = 0.44 for cardiovascular mortality) were independently associated with lower mortality on multivariable Cox analyses. Although RASB, beta-blocker, and CCB significantly reduced all cause mortality, multivariable Cox analyses showed that RASB and CCB were closely associated with lower all-cause mortality. In terms of cardiovascular mortality, only CCB was associated with lower cardiovascular mortality on multivariable Cox analyses. CONCLUSION: Treatment of hypertension significantly reduces mortality in patients with uncomplicated hypertension. PMID- 28350622 TI - Keratitis Due to Achromobacter xylosoxidans in a Contact Lens User. AB - OBJECTIVES: Ocular infections due to Achromobacter xylosoxidans are extremely uncommon; their diagnosis is a challenge and the optimal treatment remains controversial. We present a case of A. xylosoxidans in a contact lens user and a review of the literature to facilitate diagnostic suspicion and empirical therapeutic management. METHODS: Review of the literature in PubMed and MEDLINE. We also document a case diagnosed in our department in January 2016. SETTING: Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain. RESULTS: According to the literature, clinical manifestations and antibiotic sensitivity of A. xylosoxidans varied greatly. Our patient with no history of keratopathy presented three risk factors that made the diagnosis suspicious. The infection was resolved with topical moxifloxacin and fluorometholone. CONCLUSIONS: A. xylosoxidans is an uncommon cause of infection, but must be suspected in atypical keratitis, reported contact with warm or still waters, use of contact lenses, or previous corneal damage. In these cases, microbiological studies and antibiotic sensitivity testing are particularly important. PMID- 28350623 TI - Ocular Surface Squamous Neoplasia in Papillon-Lefevre Syndrome: Outcome at Long Term Follow-Up of 12 Years. AB - PURPOSE: To discuss the association between ocular surface squamous neoplasia (OSSN) and Papillon-Lefevre syndrome (PLS) and present the long-term outcome in a patient with these diseases. METHODS: Case report. RESULTS: A 14-year-old boy presented with a raised pigmented mass lesion at the limbus in the right eye, which was clinically suggestive of OSSN. He also had palmoplantar hyperkeratosis and periodontosis suggestive of PLS. Excision biopsy of the lesion confirmed the diagnosis of OSSN. He was free of tumor recurrence for 2 years and was lost to follow-up thereafter. Seven years later, the patient presented with diffuse tumor recurrence with orbital extension in the right eye, regional lymph node metastasis, and ipsilateral parotid gland infiltration. The patient underwent exenteration of the right orbital contents, right parotidectomy, and radical neck dissection followed by concomitant external beam radiotherapy and systemic chemotherapy. Eleven years from initial presentation, the patient was detected to have OSSN in the contralateral eye and was managed by wide excision biopsy and adjuvant cryotherapy. One year after detection of OSSN in the left eye, the patient was found to have systemic metastases to the lungs and brain. The patient died of the disease within 3 months of detection of systemic metastasis. CONCLUSIONS: OSSN in PLS is associated with poor prognosis. PMID- 28350624 TI - Application of Scanning Electron Microscopy With Energy-Dispersive X-Ray Spectroscopy for Analyzing Ocular Surface Particles on Schirmer Strips. AB - PURPOSE: To demonstrate the application of scanning electron microscopy with energy-dispersive x-ray spectroscopy (SEM/EDS) for analyzing Schirmer strips for particle concentration, size, morphology, and type distribution. METHODS: A cross sectional design was used. Patients were prospectively recruited from the Miami Veterans Affairs (VA) Healthcare System eye clinic, and they underwent a complete ocular surface examination. The size, type, and chemical composition of particulate matter on Schirmer strips (from the left eye) were analyzed using SEM/EDS. RESULTS: Schirmer strips from all 6 patients showed particle loading, ranging from 1 to 33 particles, whereas the blank Schirmer strip that served as a control showed no particle loading. Most particles were coarse, with an average size of 19.7 MUm (95% confidence interval 15-24.4 MUm). All samples contained organic particles (eg, pollen and mold), and 5 of the 6 samples contained nonorganic particles. The nonorganic particles were composed of silicon, minerals, and metals, including gold and titanium. The size of aluminum and iron particles was >=62 MUm, whereas the size of 2 other metals, zinc and gold, was smaller, that is, <20 MUm. Most metal particles were elongated compared with the organic particles, which were round. CONCLUSIONS: Although SEM/EDS has been extensively used in biomedical research, its novel application to assess the size, morphology, and chemical composition of the ocular surface particles offers an unprecedented opportunity to tease out the role of particulate matter exposure in ocular surface disease and disorders. PMID- 28350625 TI - Outcome and Histopathology of Secondary Penetrating Keratoplasty Graft Failure Managed by Descemet Membrane Endothelial Keratoplasty. AB - PURPOSE: To describe the clinical outcome and histopathology of Descemet membrane endothelial keratoplasty (DMEK) performed for secondary graft failure after penetrating keratoplasty (PK). METHODS: A total of 11 eyes from 10 patients who underwent DMEK for secondary PK graft failure at a tertiary referral center were included in this retrospective study. Best-corrected visual acuity, endothelial cell density, and central pachymetry were evaluated before and at regular time intervals up to 36 months after DMEK and complications were recorded; 1 post mortem cornea was available for light microscopy. RESULTS: At their last follow up visit (on average, 16 months after DMEK), 7 of 11 transplanted corneas were clear. In the 7 eyes with clear grafts, 5 had a best-corrected visual acuity of >=20/25 (>=0.8), central pachymetry averaged 535 (+/-70) MUm, and endothelial cell density averaged 1045 (+/-500) cells/mm. Of the 11 eyes, 4 required rebubbling in the early postoperative phase; 1 eye was left with a small (<1/3) detachment. Light microscopy of the pathology specimen showed complete attachment of the DMEK graft onto the preexisting PK posterior stroma, with interface scarring over DMEK graft folds and underneath the graft area that had initially been detached. CONCLUSIONS: DMEK may be a viable option to manage secondary PK graft failure with acceptable outcomes in many cases. Rebubbling for graft detachment may be anticipated, especially because of preexisting glaucoma conditions (severe decompensation, hypotony, and tubes from glaucoma-draining devices). Graft reattachment may occur through interface scarring. PMID- 28350626 TI - Applying Clinical and Public Health Research to Prevent Sexually Transmitted Infections. PMID- 28350627 TI - Data, Staff, and Money: Leadership Reflections on the Future of Public Health Informatics. AB - CONTEXT: Health informatics can play a critical role in supporting local health departments' (LHDs') delivery of certain essential public health services and improving evidence base for decision support. However, LHDs' informatics capacities are below an optimum level. Efforts to build such capacities face ongoing challenges. Moreover, little is known about LHD leaders' desires for the future of public health informatics. OBJECTIVES: Conduct a qualitative analysis of LHDs' future informatics plans, perceived barriers to accomplishing those plans, and potential impact of future advances in public health informatics on the work of the public health enterprise. METHODS: This research presents findings from 49 in-depth key informant interviews with public health leaders and informatics professionals from LHDs, representing insights from across the United States. Interviewees were selected on the basis of the size of the population their LHD serves, as well as level of informatics capacity. Interviews were transcribed, verified, and double coded. RESULTS: Major barriers to doing more with informatics included staff capacity and training, financial constraints, dependency on state health agency, and small LHD size/lack of regionalization. When asked about the role of leadership in expanding informatics, interviewees said that leaders could make it a priority through (1) learning more about informatics and (2) creating appropriate budgets for integrated information systems. Local health department leaders said that they desired data that were timely and geographically specific. In addition, LHD leaders said that they desired greater access to clinical data, especially around chronic disease indicators. CONCLUSIONS: Local health department leadership desires to have timely or even real-time data. Local health departments have a great potential to benefit from informatics, particularly electronic health records in advancing their administrative practices and service delivery, but financial and human capital represents the largest barrier. Interoperability of public health systems is highly desirable but hardly achievable in the presence of such barriers. PMID- 28350628 TI - Developing an Informatics-Savvy Health Department: From Discrete Projects to a Coordinating Program. Part I: Assessment and Governance. PMID- 28350629 TI - Wanted: Academic Health Departments to Foster Evidence-Based Practice and Practice-Based Evidence. PMID- 28350630 TI - PH 3.0: Supporting Local Health Departments in the New Paradigm to Improve Population Health. PMID- 28350632 TI - 30-Day Readmission After Spine Surgery: An Analysis of 1400 Consecutive Spine Surgery Patients. AB - STUDY DESIGN: Retrospective cohort review. OBJECTIVE: To identify the rates, causes, and risk factors for 30-day unplanned readmissions in after elective spine surgery at our institution. SUMMARY OF BACKGROUND DATA: Early readmission after spine surgery is being used as a proxy for quality of care. One-fifth of patients are rehospitalized within 30 days after spine surgery. Nearly 60% of these readmissions are unplanned, which translates into billions of dollars in healthcare costs. METHODS: A total of 1400 patients undergoing elective spine surgery at Duke University Hospital between 2008 and 2010 were included in the study. We identified all unplanned readmissions within 30 days of discharge. Unplanned readmissions were defined to have occurred as a result of either a surgical or a nonsurgical complication. Patient records were reviewed to determine the cause of readmission and the length of hospital stay. RESULTS: A total of 132 (9.4%) unplanned early readmissions were identified. The mean +/- SD age was 58.6 +/- 15.1 years. Lumbar decompression and fusion was the most common procedure The most common causes for readmission were infection or a concern for infection (34.8%) and pain (19.7%), and 26.5% of readmissions required a return to the operating room. The majority of patients that were readmitted presented to the emergency department from home (58.0%) whereas 25.2% were readmitted from a skilled nursing facility. The mean +/- SD number of days from discharge to readmission was 9.8 +/- 7.9 days and the average length of hospital stay for the readmissions was 7.5 days. CONCLUSION: This study suggests that infection and refractory pain were the most common primary reasons for unplanned readmission. Efforts at reducing unplanned early readmission after elective spine surgery should be focused on more effective post discharge care. PMID- 28350634 TI - Documenting Community Health Worker Roles in Primary Care: Contributions to Evidence-Based Integration Into Health Care Teams, 2015. AB - The Patient Protection and Affordable Care Act provided community health workers (CHWs) with new opportunities, and current efforts develop evidence-based guidelines for CHW integration into clinical teams. This qualitative study documents CHW roles and activities in 3 federally qualified health care centers in southern Arizona. Community health worker clinical roles, activities, and integration varied by health center and were in flux. Integration included complementary roles, scheduled and everyday communications with team members, and documentation in the electronic health records. These findings contribute to evidence-based guidelines for CHW integration into clinical teams that are critical to maximizing CHW contributions to patient health improvements. PMID- 28350633 TI - Patient and Physician Race and the Allocation of Time and Patient Engagement Efforts to Mental Health Discussions in Primary Care: An Observational Study of Audiorecorded Periodic Health Examinations. AB - This study investigated racial differences in patient-physician communication around mental health versus biomedical issues. Data were collected from audiorecorded periodic health examinations of adults with mental health needs in the Detroit area (2007-2009). Patients and their primary care physicians conversed for twice as long, and physicians demonstrated greater empathy during mental health topics than during biomedical topics. This increase varied by patient and physician race. Patient race predicted physician empathy, but physician race predicted talk time. Interventions to improve mental health communication could be matched to specific populations based on the separate contributions of patient and physician race. PMID- 28350635 TI - Evidence on the Validity of a Comprehensive Health Risk Index and Implications for Ambulatory Care and Population Health Management. AB - A novel, comprehensive health risk index for adults has been validated and is now ready for use to improve the health of individuals and populations. This health risk index provides an estimate of the avoidable risk of death for adults 30 years or older. It includes 12 evidence-based clinical and behavioral risk factors and was validated on discrimination and calibration using the NHANES (National Health and Nutrition Examination Survey) and Framingham Heart Study cohorts. The results from both cohorts were consistent and similar. Discrimination was good, and calibration was acceptable but tended to overpredict mortality risk for females in the higher-risk deciles. PMID- 28350636 TI - The Impact of Hospital Health Network Affiliation on Discharge Communication Preferences of Primary Care Providers. AB - Primary care physicians (PCPs) experience differential postdischarge access to electronic health records, depending upon affiliation with the discharging hospital's health network. To better understand whether this affiliation impacts discharge communication preferences, we surveyed a convenience sample of PCPs in and out of our hospital's health network. We also surveyed hospitalists and compared PCPs' and hospitalists' responses. We found that PCP discharge communication preferences differed by hospital health network affiliation. In addition, PCPs and hospitalists reported different expectations of responsibility for pending laboratory test follow-up. More inclusive communication strategies and standardization of responsibility for pending laboratory results may improve discharge communication quality. PMID- 28350637 TI - Physician Perception of the Role of the Patient Portal in Pediatric Health. AB - The patient portal, increasingly available to patients, allows secure electronic communication with physicians. Although physician attitude toward the portal plays a crucial role in patient adoption, little information regarding physician opinion of the portal is available, with almost no information gathered in the pediatric environment. Using a mixed-methods approach, physicians in a large pediatric medical facility and integrated delivery network were surveyed using an online quantitative questionnaire and structured interviews. Physicians reported the portal's role in more communication efficiency for patients, parents, and providers. The portal's acceptance also introduces new challenges such as frequent questions from some parents and medical visit avoidance. PMID- 28350638 TI - Short-term Impact of Meaningful Use Stage 1 Implementation: A Comparison of Health Outcomes in 2 Primary Care Clinics. AB - We studied a primary care clinic transitioning to Meaningful Use stage 1 and a comparison clinic within the same health system. In the 6 months following implementation, after adjusting for confounders, mean systolic blood pressure worsened (+3.3 mm Hg; P = .004) in the intervention clinic compared with the comparison clinic. We did not see a change in the mean or proportion of patients meeting target goals for diabetes (hemoglobin A1c) or obesity (body mass index). Our findings suggest that the worsening of systolic blood pressure associated with Meaningful Use implementation is likely due to distractions of system changes negatively impacting health outcomes. PMID- 28350639 TI - Measuring the Cost of the Patient-Centered Medical Home: A Cost-Accounting Approach. AB - To explore the cost for individual practices to become more patient-centered, we inventoried and calculated the cost of costly activities involved in implementing the Patient-Centered Medical Home (PCMH) as defined by the National Committee for Quality Assurance. There were 3 key findings. The cost of each PCMH-related clinical activity can be classified in 1 of 3 major categories. Cost offsets can be used to defray part of the cost recognition. The cost of PCMH transformation varied by practice with no clear level or pattern of costs. Our study suggests that small- and medium-sized practices may experience difficulty with the financial burden of PCMH recognition. PMID- 28350640 TI - In-class Active Video Game Supplementation and Adherence to Cardiac Rehabilitation. AB - PURPOSE: The application of active video games (AVGs) during cardiac rehabilitation (CR) sessions could potentially facilitate patient adherence. The feasibility, safety, and efficacy of in-class AVG supplementation as an alternative to conventional phase 2 programs were investigated. METHODS: A pilot, evaluator-blinded, intention-to-treat, randomized controlled trial recruited 32 low-moderate risk CR participants and allocated them to conventional or AVG supplemented exercise. Both groups experienced equal exercise loads for 6 weeks. Patients were assessed at baseline, end of the program, and after an 8-week followup. Adherence and safety-related outcomes were the primary endpoints. Secondary outcomes included change in exercise capacity, daily physical activity (PA), energy expenditure (EE), and psychometric profiling. RESULTS: Patients (males 81%; 60 +/- 10 years) presented with typical cardiovascular risk factors and similar baseline characteristics. Participants did not perceive an increased risk of injury and were more interactive. At the end of the program, there was a lower tendency for dropping out (6% vs 19%, P > .05), a significant improvement in PA (322 vs 247 arbitrary acceleration units/min, P = .047) and related EE per body weight (13 vs 11 kcal/kg/d, P = .04) among AVG participants compared with controls. No significant differences between groups for adverse medical events, exercise capacity, affect toward exercise, anxiety, depression, or quality-of life changes were reported. CONCLUSIONS: The additional use of AVGs during CR sessions is feasible, safe, and significantly improved daily PA and EE. A dropout reduction trend among its users, which needs to be confirmed in a larger trial, raises awareness to AVG supplementation as a promising strategy to increase CR adherence. PMID- 28350641 TI - Exercise Training in a Patient With a Left Ventricular Assist Device and Large Aortic Valve Thrombus. AB - DETAILS OF THE CLINICAL CASE: An aortic valve thrombus (AVT) is a rare complication after HeartMate II implantation. In a 44-year-old man, a large AVT was discovered 6 weeks after implantation of a HeartMate II for severe dilated cardiomyopathy. The aortic valve was permanently closed. DISCUSSION: After a followup of 3 months without embolic events, the patient started a cardiac rehabilitation (CR) program involving aerobic exercise, resistance exercises, group gymnastics, and relaxation exercise, and completed the program without any complications, resulting in a significant functional benefit. SUMMARY: CR might not be systematically contraindicated in patients with HeartMate II and an AVT, in particular, if there is no opening of the aortic valve at rest. PMID- 28350642 TI - Increased Early Systemic Inflammation in ICU-Acquired Weakness; A Prospective Observational Cohort Study. AB - OBJECTIVES: To investigate whether patients who develop ICU-acquired weakness have a different pattern of systemic inflammatory markers compared with critically ill patients who do not develop ICU-acquired weakness. DESIGN: Prospective observational cohort study. SETTING: Mixed medical-surgical ICU of a tertiary care hospital in the Netherlands. PATIENTS: Newly admitted critically ill patients, greater than or equal to 48 hours on mechanical ventilation with a nonneurologic ICU admission diagnosis, were included. INTERVENTIONS: A panel of systemic inflammatory markers and soluble vascular adhesion molecules were measured in plasma samples of day 0, 2, and 4 after ICU admission. ICU-acquired weakness was diagnosed by manual muscle strength testing as soon as patients were awake and attentive. MEASUREMENTS AND MAIN RESULTS: Ninety-nine of 204 included patients developed ICU-acquired weakness. Principal component regression analysis, adjusted for confounders, showed that principal component 1, mainly loaded with interleukin-6, interleukin-8, interleukin-10, and fractalkine, was significantly higher in patients who developed ICU-acquired weakness (odds ratio, 1.35 [95% CI, 1.18-1.55]). Partial least squares-discriminant analysis also showed that these markers were the most important discriminative markers. Mixed effects models of these markers showed that ICU-acquired weakness was associated with an independent 1.5- to two-fold increase in these markers. CONCLUSIONS: Systemic inflammation is increased in patients who develop ICU-acquired weakness compared with patients who do not develop ICU-acquired weakness in the first 4 days after ICU admission. This finding is consistent when adjusted for confounders, like disease severity. A group consisting of interleukin-6, interleukin-8, interleukin-10, and fractalkine was identified to be the most important. PMID- 28350643 TI - Delayed Referral Results in Missed Opportunities for Organ Donation After Circulatory Death. AB - OBJECTIVES: Rates of organ donation and transplantation have steadily increased in the United States and Canada over the past decade, largely attributable to a notable increase in donation after circulatory death. However, the number of patients awaiting solid organ transplantation continues to remain much higher than the number of organs transplanted each year. The objective of this study was to determine the potential to increase donation rates further by identifying gaps in the well-established donation after circulatory death process in Ontario. DESIGN: Retrospective cohort study. SETTING: Provincial organ procurement organization. PATIENTS: Patients who died in designated donation hospitals within the province of Ontario, Canada between April 1, 2013, and March 31, 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 1,407 patient deaths following planned withdrawal of life-sustaining therapy, 54.0% (n = 760) were medically suitable for donation after circulatory death. In 438 cases where next of kin was approached, consent rates reached 47.5%. A total of 119 patients became actual organ donors. Only 66.2% (n = 503) of suitable patients were appropriately referred, resulting in 251 missed potential donors whose next of kin could not be approached regarding organ donation because referral occurred after initiation of withdrawal of life-sustaining therapy or not at all. CONCLUSIONS: The number of medically suitable patients who die within 2 hours of planned withdrawal of life-sustaining therapy is nearly six times higher than the number of actual organ donors, with the greatest loss of potential due to delayed referral until at the time of or after planned withdrawal of life-sustaining therapy. Intensive care teams are not meeting their ethical responsibility to recognize impending death and appropriately refer potential organ donors to the local organ procurement organization. In cases where patients had previously registered their consent decision, they were denied a healthcare right. PMID- 28350644 TI - Disassociating Lung Mechanics and Oxygenation in Pediatric Acute Respiratory Distress Syndrome. AB - OBJECTIVES: Both oxygenation and peak inspiratory pressure are associated with mortality in pediatric acute respiratory distress syndrome. Since oxygenation and respiratory mechanics are linked, it is difficult to identify which variables, pressure or oxygenation, are independently associated with outcome. We aimed to determine whether respiratory mechanics (peak inspiratory pressure, positive end expiratory pressure, DeltaP [PIP minus PEEP], tidal volume, dynamic compliance [Cdyn]) or oxygenation (PaO2/FIO2) was associated with mortality. DESIGN: Prospective, observational, cohort study. SETTING: University affiliated PICU. PATIENTS: Mechanically ventilated children with acute respiratory distress syndrome (Berlin). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Peak inspiratory pressure, positive end-expiratory pressure, DeltaP, tidal volume, Cdyn, and PaO2/FIO2 were collected at acute respiratory distress syndrome onset and at 24 hours in 352 children between 2011 and 2016. At acute respiratory distress syndrome onset, neither mechanical variables nor PaO2/FIO2 were associated with mortality. At 24 hours, peak inspiratory pressure, positive end expiratory pressure, DeltaP were higher, and Cdyn and PaO2/FIO2 lower, in nonsurvivors. In multivariable logistic regression, PaO2/FIO2 at 24 hours and DeltaPaO2/FIO2 (change in PaO2/FIO2 over the first 24 hr) were associated with mortality, whereas pressure variables were not. Both oxygenation and pressure variables were associated with duration of ventilation in multivariable competing risk regression. CONCLUSIONS: Improvements in oxygenation, but not in respiratory mechanics, were associated with lower mortality in pediatric acute respiratory distress syndrome. Future trials of mechanical ventilation in children should focus on oxygenation (higher PaO2/FIO2) rather than lower peak inspiratory pressure or DeltaP, as oxygenation was more consistently associated with outcome. PMID- 28350645 TI - The Use of Bowel Protocols in Critically Ill Adult Patients: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: Constipation is common among critically ill patients and has been associated with adverse patient outcomes. Many ICUs have developed bowel protocols to treat constipation; however, their effect on clinical outcomes remains uncertain. We conducted a systematic review to determine the impact of bowel protocols in critically ill adults. DATA SOURCES: We searched MEDLINE, Embase, CINAHL, CENTRAL, ISRCTN, ClinicalTrials.gov, and conference abstracts until January 2016. STUDY SELECTION: Two authors independently screened titles and abstracts for randomized controlled trials comparing bowel protocols to control (placebo, no protocol, or usual care) in critically ill adults. DATA EXTRACTION: Two authors independently, and in duplicate, extracted study characteristics, outcomes, assessed risk of bias, and appraised the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. DATA SYNTHESIS: We retrieved 4,520 individual articles, and excluded 4,332 articles during title and abstract screening and 181 articles during full-text screening. Four trials, including 534 patients, were eligible for analysis. The use of a bowel protocol was associated with a trend toward a reduction in constipation (risk ratio, 0.50 [95% CI, 0.25-1.01]; p = 0.05; low quality evidence); no reduction in tolerance of enteral feeds (risk ratio, 0.94 [95% CI, 0.62-1.42]; p = 0.77; low-quality evidence), and no change in the duration of mechanical ventilation (mean difference, 0.01 d [95% CI, -2.67 to 2.69 d]; low-quality evidence). CONCLUSIONS: Large, rigorous, randomized control trials are needed to determine whether bowel protocols impact patient-important outcomes in critically ill adults. PMID- 28350647 TI - Discussion: Reconstruction of the Irradiated Breast: A National Claims-Based Assessment of Postoperative Morbidity. PMID- 28350646 TI - Association Between Hospital Case Volume of Sepsis, Adherence to Evidence-Based Processes of Care and Patient Outcomes. AB - OBJECTIVES: We sought to explore potential mechanisms underlying hospital sepsis case volume-mortality associations by investigating implementation of evidence based processes of care. DESIGN: Retrospective cohort study. We determined associations of sepsis case volume with three evidence-based processes of care (lactate measurement during first hospital day, norepinephrine as first vasopressor, and avoidance of starch-based colloids) and assessed their role in mediation of case volume-mortality associations. SETTING: Enhanced administrative data (Premier, Charlotte, NC) from 534 U.S. hospitals. SUBJECTS: A total of 287,914 adult patients with sepsis present at admission between July 2010 and December 2012 of whom 58,045 received a vasopressor for septic shock during the first 2 days of hospitalization. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among patients with sepsis, 1.9% received starch, and among patients with septic shock, 68.3% had lactate measured and 64% received norepinephrine as initial vasopressor. Patients at hospitals with the highest case volume were more likely to have lactate measured (adjusted odds ratio quartile 4 vs quartile 1, 2.8; 95% CI, 2.1-3.7) and receive norepinephrine as initial vasopressor (adjusted odds ratio quartile 4 vs quartile 1, 2.1; 95% CI, 1.6-2.7). Case volume was not associated with avoidance of starch products (adjusted odds ratio quartile 4 vs quartile 1, 0.73; 95% CI, 0.45-1.2). Adherence to evidence-based care was associated with lower hospital mortality (adjusted odds ratio, 0.81; 95% CI, 0.70 0.94) but did not strongly mediate case volume-mortality associations (point estimate change <= 2%). CONCLUSIONS: In a large cohort of U.S. patients with sepsis, select evidence-based processes of care were more likely implemented at high-volume hospitals but did not strongly mediate case volume-mortality associations. Considering processes and case volume when regionalizing sepsis care may maximize patient outcomes. PMID- 28350648 TI - Differences in the Reporting of Racial and Socioeconomic Disparities among Three Large National Databases for Breast Reconstruction. AB - BACKGROUND: Research derived from large-volume databases plays an increasing role in the development of clinical guidelines and health policy. In breast cancer research, the Surveillance, Epidemiology and End Results, National Surgical Quality Improvement Program, and Nationwide Inpatient Sample databases are widely used. This study aims to compare the trends in immediate breast reconstruction and identify the drawbacks and benefits of each database. METHODS: Patients with invasive breast cancer and ductal carcinoma in situ were identified from each database (2005-2012). Trends of immediate breast reconstruction over time were evaluated. Patient demographics and comorbidities were compared. Subgroup analysis of immediate breast reconstruction use per race was conducted. RESULTS: Within the three databases, 1.2 million patients were studied. Immediate breast reconstruction in invasive breast cancer patients increased significantly over time in all databases. A similar significant upward trend was seen in ductal carcinoma in situ patients. Significant differences in immediate breast reconstruction rates were seen among races; and the disparity differed among the three databases. Rates of comorbidities were similar among the three databases. CONCLUSIONS: There has been a significant increase in immediate breast reconstruction; however, the extent of the reporting of overall immediate breast reconstruction rates and of racial disparities differs significantly among databases. The Nationwide Inpatient Sample and the National Surgical Quality Improvement Program report similar findings, with the Surveillance, Epidemiology and End Results database reporting results significantly lower in several categories. These findings suggest that use of the Surveillance, Epidemiology and End Results database may not be universally generalizable to the entire U.S. POPULATION: PMID- 28350649 TI - Oncoplastic Breast Reduction Technique and Outcomes: An Evolution over 20 Years. AB - BACKGROUND: Reduction mammaplasty at the time of lumpectomy is a good option in women with breast cancer and macromastia. We critically evaluated refinements and outcomes of this technique. METHODS: A prospectively maintained database was reviewed of all women with breast cancer who received lumpectomy and reduction mammaplasty at our institution from 1994 to 2015. Patients' demographics were reviewed. Preoperative and postoperative patient satisfaction (BREAST-Q) was determined. Comparisons were made between early and recent cases. RESULTS: There were 353 patients included. Average age was 54 (range, 21 to 80 years), with the largest number having stage I disease [n = 107 of 246 (43.5 percent)]. Average lumpectomy specimen was 207 g (range, 11.6 to 1954 g) and total reduction weight averaged 545 g (range, 21 to 4102 g). Tumor size averaged 2.02 cm (range, 0.00 to 15.60 cm). The positive margin rate was 6.2 percent (n = 22). Completion mastectomy rate was 9.9 percent (n = 35). Overall complication rate was 16 percent. The recurrence rate was 5.2 percent (n = 10 of 192) at a mean follow-up of 2 years (range, 2 months to 15 years). Resection weights greater than 1000 g were associated with having a positive margin (16.7 percent versus 5.0 percent; p = 0.016), and tended to be associated with having a completion mastectomy (p = 0.069). Positive margin and completion mastectomy rates have been lower in the past 10 years. Over 1 year postoperatively, women reported increased self confidence (p = 0.020), feelings of attractiveness (p = 0.085), emotional health (p = 0.037), and satisfaction with sex life (p = 0.092). CONCLUSIONS: The oncoplastic reduction technique is effective and results in improved patient reported outcomes. Resections over 1000 g are associated with a higher incidence of positive margins and may increase the risk for completion mastectomy. Outcomes have improved with experience and refinement in technique. PMID- 28350650 TI - Direct-to-Implant Breast Reconstruction without the Use of an Acellular Dermal Matrix Is Cost Effective and Oncologically Safe. AB - BACKGROUND: Direct-to-implant breast reconstruction is a predictable, reliable, and cost-effective reconstruction. Most units performing direct-to-implant reconstructions recommend the use of an acellular dermal matrix or a mesh to reinforce the lower pole of the breast reconstruction. METHODS: Two hundred seventy-two consecutive patients with 488 immediate direct-to-implant breast reconstructions performed in a 34-month period are included in this group. Mean follow-up of this group is 35 months. RESULTS: Four hundred eight reconstructions were performed through a lazy-S mastectomy, and 80 were performed through a Wise pattern mastectomy. Two local recurrences occurred. Minor complications accounted for 5.5 percent (n = 27): seromas, 3.4 percent (n = 17); wound healing problems, 0.6 percent (n = 3); and grade 2 capsular contracture, 1.4 percent (n = 7). Major complications accounted for 4.3 percent (n = 21): infection, 0.8 percent (n = 4); prosthetic loss, 0.4 percent (n = 2); hematoma, 0.4 percent (n = 2); and wounds requiring debridement, 2 percent (n = 10). The additional cost of acellular dermal matrix is dependent on manufacturer and size, but increases the cost of the procedure by 35.5 to 47.7 percent. CONCLUSIONS: This reconstruction method compares very favorably with published data from other units as far as early and late complications and cosmetic outcome are concerned. It has a complication rate similar to that of reconstructions using an acellular dermal matrix and is more cost effective. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28350651 TI - Application of Posterior Thigh Three-Dimensional Profunda Artery Perforator Perforasomes in Refining Next-Generation Flap Designs: Transverse, Vertical, and S-Shaped Profunda Artery Perforator Flaps. AB - BACKGROUND: This study aimed to delineate and compare the hot spots and three dimensional vascular territories of dominant profunda artery perforators in the posterior thigh region, and modifications in flap design are discussed. METHODS: Twenty-nine posterior thigh flaps were raised in fresh cadaveric specimens, and profunda artery perforators were documented. Dominant perforators were injected with iodinated contrast to assess perforasomes using computed tomographic angiography. Analysis with three-dimensional rendering and volume calculations of perfusion patterns was performed. RESULTS: In total, 316 perforators were mapped and 33 perforators were injected for analysis. The hot spot for dominant perforators was the proximal medial quadrant, 5 to 10 cm from the inferior gluteal crease, with two smaller hot spots in the upper lateral and distal posterior midline. Although 69 percent were musculocutaneous, distal perforators were predominantly septocutaneous in the posterior midline, 5 to 8 cm from the popliteal crease. Proximal perforators were classified into first (most proximal) and second perforators, and their median perforasome was 233 and 286.4 cm, respectively (p = 0.86). There were no significant differences between proximal and distal perforators in perforasome surface areas, percentage areas perfused, and perforasome volumes. Large linking vessel networks were attributed to a broader perforasome and greater overlap between adjacent or distal perforators. CONCLUSIONS: Dominant linking vessels and recurrent flow through the subdermal plexus contribute to the robust vascular supply of profunda artery perforator flaps. Posterior thigh region perforator hot spots and their perfusion characteristics can inform the potential limits, orientation, and modifications of flap or skin paddle designs. PMID- 28350652 TI - Role of Mitomycin C in Preventing Capsular Contracture in Implant-Based Reconstructive Breast Surgery: A Randomized Controlled Trial. AB - BACKGROUND: Capsular contracture represents the most frequent complication after implant-based breast reconstruction. An experimental study on mice demonstrated that capsule formation around breast implants is considerably diminished after topical application of mitomycin C. The authors conducted a randomized controlled clinical trial investigating the efficacy of mitomycin C in reducing capsular contracture rates following implant-based breast reconstruction after mastectomy for breast cancer. METHODS: The authors randomized all women older than 18 years scheduled for the second stage of an implant-based breast reconstruction after mastectomy for breast cancer at the National Cancer Institute in Milan from October of 2005 to February of 2010 to receive or not receive the topical application of mitomycin C during surgery. The authors assessed capsular contracture, major postoperative complications, and aesthetic outcome. RESULTS: The authors randomized 322 patients to receive mitomycin C or not at the second stage of implant-based breast reconstruction. One hundred sixty-two patients were allocated to the mitomycin C group and 160 patients were allocated to the control group. The relative risk of capsular contracture in the mitomycin C group was 0.92 (95 percent CI, 0.60 to 1.41). Major complications leading to reintervention, oncologic outcomes, and aesthetic outcomes were comparable between the two groups. CONCLUSIONS: This is the first trial reporting data about the use of mitomycin C in breast reconstructive surgery in a clinical setting. Mitomycin C seems not to significantly affect capsular contracture rate and severity following implant-based reconstructive breast surgery at the tested doses. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I. PMID- 28350653 TI - Understanding the Health Burden of Macromastia: Normative Data for the BREAST-Q Reduction Module. AB - BACKGROUND: The BREAST-Q Reduction module evaluates outcomes in reduction mammaplasty. However, there are currently no published normative scores, limiting the interpretation of BREAST-Q data. METHODS: The BREAST-Q Reduction module was administered via the Army of Women, an online community of women (with and without breast cancer) engaged in breast-cancer related research. Normative data were generated from women aged 18 years and older, without a history of breast cancer or breast surgery. Data analysis was performed using descriptive statistics and a linear multivariate regression. Generated normative data were compared to published BREAST-Q Reduction findings. RESULTS: The preoperative version of the BREAST-Q Reduction module was completed by 1206 women. Participant mean age was 55 +/- 13 years, mean body mass index was 27 +/- 6 kg/m, and 40 percent (n = 481) had a bra cup size >= D. Mean normative scores were as follows: Satisfaction with Breasts, 57 +/- 16; Psychosocial Well-being, 68 +/- 19; Sexual Well-being, 55 +/- 19; and Physical Well-being, 76 +/- 11. Normative scores were lower in women with body mass index >= 30 and bra cup size >= D. In comparison to normative Army of Women scores, published BREAST-Q scores for women undergoing reduction mammaplasty were lower (worse) for preoperative patients and higher (better) for postoperative patients. CONCLUSION: These new Army of Women normative data provide insights into breast-related satisfaction and well-being in women not pursuing breast reduction, giving new clinical context to better understand the health burden of macromastia, and to demonstrate the value of reduction mammaplasty in certain patients. PMID- 28350654 TI - A Prospective Randomized Trial of the Efficacy of Fibrin Glue, Triamcinolone Acetonide, and Quilting Sutures in Seroma Prevention after Latissimus Dorsi Breast Reconstruction. AB - BACKGROUND: Donor-site seroma is the most common complication following latissimus dorsi flap breast reconstruction. Various agents and techniques have attempted to minimize seroma formation. The purpose of this study was to compare the efficacy of different products and quilting sutures at seroma prevention. METHODS: This is a single-center, double-blinded, randomized, controlled trial of a consecutive series of breast cancer patients (n = 96) undergoing latissimus dorsi flap reconstruction performed by a single surgeon. Patients were randomized to receive (1) fibrin glue (Tisseel) (n = 23), (2) triamcinolone acetonide (n = 26), or (3) normal saline (control) (n = 27) sprayed into the donor site. The fourth arm included donor-site quilting sutures (n = 20). Outcomes included seroma, drain output, and days to last drain removal. Drain removal was standardized at less than 30 cc/day. RESULTS: All groups were matched evenly without differences in risk, procedures, or complications. The overall seroma rate was 31.3 percent (n = 30). The quilting group had significantly less drainage for weeks 1 (p = 0.006) and 2 (p = 0.050) postoperatively. Quilting statistically reduced the incidence of seromas to 5.0 percent (n = 1; p = 0.038) compared with other groups (control, 34.5 percent; fibrin, 27.6 percent; and triamcinolone, 37.6 percent). Drains were removed 10 days earlier with quilting (control, 35.5 days; fibrin, 39.5 days; triamcinolone, 37.4 days; and quilting, 25.8 days; p = 0.001). The incidence of all other complications was similar between groups. CONCLUSION: The use of quilting donor sites significantly decreases the incidence of donor-site seromas and leads to earlier drain removal following latissimus dorsi flap reconstruction and maintains a low complication profile. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 28350655 TI - High-Resolution Magnetic Resonance Imaging of Aging Upper Face Fat Compartments. AB - BACKGROUND: Age-related changes in fat compartments have yet to be fully characterized. Uncertainty remains in terms of volume gains/losses or shape fluctuations over time. The authors' aim was to determine the evolution of subcutaneous fat in the aging upper face, focusing on shifts in volume and dimension. METHODS: Over the course of 4.5 years, 100 faces of living female Caucasian patients were prospectively studied using high-resolution magnetic resonance imaging. Subjects were stratified by age as follows: group 1, 18 to 30 years; group 2, 30 to 60 years; and group 3, older than 60 years. Superficial temporal and central forehead compartments were delimited, analyzing respective volumes and dimensions by group. RESULTS: In 85 patients studied, superficial temporal fat (mean volume, 5.14 cm) increased 35.48 percent in total volume between youth and old age (p = 0.046). Overall height and magnitude of the lower one-third also increased with aging. Central forehead fat (mean volume, 2.56 cm), studied in 83 patients, showed a 209.75 percent volume gain in group 2 (versus group 1) and a 17.59 percent volume loss in group 3 (versus group 2) (p = 0.001). CONCLUSION: Subcutaneous facial fat fluctuates with aging, increasing in the upper face and promoting ptosis through basal compartmental expansion. PMID- 28350656 TI - An Update on the Anatomy of the Forehead Compartments. AB - BACKGROUND: The forehead is one of the most frequent locations for neuromodulator and soft tissue filler applications; however, the underlying anatomy is still poorly understood. Thus far, the presence of deep forehead compartments has not been confirmed. METHODS: Twenty Caucasian cephalic specimens, 15 fresh frozen (six female and nine male) and five with formalin-phenol embalmment (three female and two male) were investigated using contrast-enhanced computed tomographic scans, dye injections, and anatomical dissections. RESULTS: Three superficial (one central and two lateral) and three deep (one central and two lateral) forehead compartments were identified. The superficial fat compartments were found within the subcutaneous fat tissue (layer 2) and measured 2.1 * 4.6 mm for the superficial central forehead compartments and the right superficial lateral forehead compartments and 2.6 * 3.2 cm for the left superficial lateral forehead compartments, with a mean volume of 2.5, 3.1, and 3.4 cc, respectively. The deep fat compartments were identified deep to the frontalis muscle but superficial to the periosteum with an extent of 6.4 * 5.9 cm for the deep central forehead compartments, 2.6 * 5.8 cm for the right deep lateral forehead compartments, and 2.7 * 5.8 cm for the left deep lateral forehead compartments, and a mean volume of 9.1, 1.6, and 1.4 cc, respectively. CONCLUSIONS: The results presented in this study increase the understanding of the forehead anatomy. Understanding the presence of the superficial and the deep forehead compartments allows one to change the signs of frontal aging. The deep forehead compartments are in general avascular planes and permit blunt dissection for access to the supraorbital region. PMID- 28350657 TI - Normative Data for Interpreting the BREAST-Q: Augmentation. AB - BACKGROUND: The BREAST-Q is a rigorously developed, well-validated, patient reported outcome instrument with a module designed for evaluating breast augmentation outcomes. However, there are no published normative BREAST-Q scores, limiting interpretation. METHODS: Normative data were generated for the BREAST-Q Augmentation module by means of the Army of Women, an online community of women (with and without breast cancer) engaged in breast-cancer related research. Members were recruited by means of e-mail; women aged 18 years or older without a history of breast cancer or breast surgery were invited to participate. Descriptive statistics and a linear multivariate regression were performed. A separate analysis compared normative scores to findings from previously published BREAST-Q augmentation studies. RESULTS: The preoperative BREAST-Q Augmentation module was completed by 1211 women. Mean age was 54 +/- 24 years, the mean body mass index was 27 +/- 6 kg/m, and 39 percent (n = 467) had a bra cup size of D or greater. Mean scores were as follows: Satisfaction with Breasts, 54 +/- 19; Psychosocial Well-being, 66 +/- 20; Sexual Well-being, 49 +/- 20; and Physical Well-being, 86 +/- 15. Women with a body mass index of 30 kg/m or greater and bra cup size of D or greater had lower scores. In comparison with Army of Women scores, published BREAST-Q augmentation scores were lower before and higher after surgery for all scales except Physical Well-being. CONCLUSIONS: The Army of Women normative data represent breast-related satisfaction and well-being in women not actively seeking breast augmentation. These data may be used as normative comparison values for those seeking and undergoing surgery as we did, demonstrating the value of breast augmentation in this patient population. PMID- 28350658 TI - Top Surgery in Transgender Men: How Far Can You Push the Envelope? AB - BACKGROUND: The authors present their grading scale and the outcomes of the largest cohort of top surgery published to date. Application of this grading system can help determine which patients will benefit from a subcutaneous mastectomy with free nipple graft versus a circumareolar technique, with the primary endpoint being need for aesthetic revisions. METHODS: The authors reviewed their database of transgender males who underwent bilateral mastectomy between 2006 and 2015. Data collected included age, body mass index, American Society of Anesthesiologists class, smoking, diabetes, testosterone use, months of social transition, technique used, postoperative complications, and need for revision. Two techniques were used, circumareolar incision and free nipple graft technique. RESULTS: Between 2006 and 2015, 1686 consecutive mastectomies were performed on 843 patients. Of those, 548 patients were excluded because of inadequate follow-up. Of the 295 included, 109 were treated using a circumareolar incision and 186 were treated using a free nipple graft technique. There was no statistically significant difference in complications between the two groups; however, there was a statistically significant difference in the rate of aesthetic revisions in the grade 2B circumareolar incision group (34 percent versus 8.8 percent). CONCLUSIONS: The authors' outcomes are comparable to the literature, and demonstrate that these procedures can safely be performed in an outpatient setting. The authors' grading scale classifies patients and helps the surgeon select a surgical technique. The authors show a statistical difference in rates of aesthetic revisions in Fischer grade 2B patients when a circumareolar incision is selected over a free nipple graft technique. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28350659 TI - First Female-to-Male Facial Confirmation Surgery with Description of a New Procedure for Masculinization of the Thyroid Cartilage (Adam's Apple). AB - : Although male-to-female transgender patients commonly seek facial feminization surgery, facial masculinization surgery in the female-to-male transgender population is unreported in the literature. This report documents the first known female-to-male facial masculinization surgery, including a new technique for creating an "Adam's apple" to enhance the facial masculine appearance of a natal female. The authors "reversed" the methods typically used to feminize male facial features, and modified the forehead, nose, and chin to masculinize the patient's natal female facial features. The authors devised a novel technique to augment the thyroid cartilage using autologous rib cartilage to create a visible Adam's apple. Initially, masculinization of the chin was accomplished with a multisegment chin osteotomy with grafts to vertically expand and widen the chin along with correcting pronounced microgenia. Subsequently, a second facial masculinization procedure was performed to masculinize the forehead, nose, and thyroid cartilage. Rib cartilage was harvested and carved into an appropriately shaped thyroid cartilage onlay graft and then attached and integrated with the native thyroid cartilage, creating a fully mobile cartilage that translocates up and down with swallowing and a visible Adam's apple. Previously described techniques to masculinize the facial features of natal male patients were adapted to masculinize the female-to-male patient. Those procedures were combined with the novel technique to create a visually perceptible and naturally mobile Adam's apple in the female-to-male transsexual patient. Collectively, these described procedures can now provide most female-to-male transsexual patients with a satisfying transformation of their facial features. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 28350660 TI - Why Women Request Labiaplasty. AB - BACKGROUND: In recent years, labiaplasty has jumped in popularity, despite opposition to the procedure. In 2007, the American College of Obstetricians and Gynecologists declared the recommendation of cosmetic vaginal procedures to be "untenable," although in 2016 they allowed consideration of labiaplasty in adolescents if symptoms persist. The reasons for labiaplasty requests are not yet fully understood, and physician opposition limits patient access to surgical relief. METHODS: In this prospective study, 50 consecutive patients consulting about labiaplasty were given a questionnaire assessing 11 physical and appearance related symptoms associated with elongated labia. RESULTS: The mean patient age was 33.5 years (range, 17 to 51 years). Fifty-eight percent of women had given birth, 52 percent noticed that their labia had become elongated as they got older, and 93 percent had bilateral elongation. When asked about physical symptoms, over half of patients experienced tugging during intercourse, found tight pants uncomfortable, experienced twisting of the labia, and noted labia visibility in yoga pants. Nearly half experienced pain during intercourse, and 40 percent said their labia could become exposed in bathing suits. Regarding appearance, almost all patients were self-conscious and over half felt less attractive to their partner, experienced restricted clothing choice, and noted a negative impact on self-esteem and intimacy. Nearly all patients experienced at least four symptoms. CONCLUSIONS: Most patients requesting labiaplasty experience both physical and appearance-related symptoms. Understanding this patient perspective is crucial in assessing surgical outcomes. Furthermore, the better all physicians understand labia symptomatology, the better supported patients will be in seeking surgical relief. PMID- 28350661 TI - Discussion: Why Women Request Labiaplasty. PMID- 28350662 TI - Neck Rejuvenation through the Lateral Platysma Window: A Key Component of Face Lift Surgery. AB - Rejuvenating an aged face relies on maintaining facial harmony to provide optimal aesthetic results. Restoration of more youthful facial contours is dependent on blending the aesthetic facial topographic units. Many authors continue to debate the best approach for neck rejuvenation through a medial approach, a lateral approach, or a combination of the two. The authors present their approach to neck rejuvenation through medial platysma plication, inferior release, and lateral platysma window. PMID- 28350663 TI - The Combination of Tissue Dissection and External Volume Expansion Generates Large Volumes of Adipose Tissue. AB - BACKGROUND: Noninvasive external volume expansion device has been applied to stimulate nonsurgical breast enlargement in clinical settings. Although previous results demonstrate the capacity of external volume expansion to increase the number of adipocytes, this strategy alone is insufficient to reconstruct soft tissue defects or increase breast mass. The authors combined a minimally invasive tissue dissection method with external volume expansion to generate large volumes of adipose tissue. METHOD: In vitro, various densities of adipose-derived stem cells were prepared to evaluate relations between cell contacts and cell proliferation. In vivo, dorsal adipose tissue of rabbits was thoroughly dissected and the external volume expansion device was applied to maintain the released state. External volume expansion without tissue dissection served as the control. RESULTS: In the dissection group, the generated adipose tissue volume was much larger than that in the control group at all time points. A larger number of proliferating cells appeared in the dissection samples than in the control samples at the early stage after tissue dissection. At low cell density, adipose derived stem cells displayed an increasing proliferation rate compared to high cell density. Protein expression analysis revealed that cell proliferation was mediated by a similar mechanism both in vivo and in vitro, involving the release of cell contact inhibition and Hippo/Yes-associated protein pathway activation. CONCLUSIONS: Adipose tissue dissection releases cell-to-cell contacts and induces adipose-derived stem cell proliferation. Preexpanded adipose-derived stem cells undergo adipogenesis under the adipogenic environment created by external volume expansion, leading to better adipose regeneration compared with the control. PMID- 28350665 TI - Moderate-Intensity Intermittent External Volume Expansion Optimizes the Soft Tissue Response in a Murine Model. AB - BACKGROUND: Intermittent external volume expansion using suction enhances the vascular network of soft tissues, possibly increasing fat graft survival. However, the optimal kinetics of application have not been determined. Based on their previous experience, the authors hypothesized that moderate-intensity intermittent external volume expansion application may further enhance both the angiogenic and adipogenic potential. METHODS: Fifty 12-week-old wild-type mice were assigned to five experimental groups (n = 10 per group) and underwent five different intermittent applications of external volume expansion (i.e., single application control, low-intensity, moderate-intensity, and two groups of high intensity). Five days after the final stimulation, skin biopsy specimens were obtained from stimulated and contralateral nonstimulated areas. Microscopic sections were analyzed for angiogenesis, skin remodeling, and adipogenesis. RESULTS: Moderate-intensity intermittent stimulation (0.5 hour, 6 times/day for 5 days at -25 mmHg suction) almost doubled cutaneous vascular density (1.9-fold increase), induced skin thickening (1.9-fold increase), and expanded the subcutaneous tissue (2.3-fold increase) compared with control. External volume expansion kinetics did not affect tissue inflammation at 5 days after treatment. High-intensity intermittent stimulations also increased the density of blood vessels (1.6-fold increase compared with controls) but caused tissue damage, whereas low-intensity external volume expansion did not induce significant changes. CONCLUSION: Application of moderate-intensity intermittent external volume expansion optimizes induction of angiogenesis and adipogenesis in soft tissues without tissue damage, holding potential for time-effective recipient site preconditioning before fat grafting. PMID- 28350664 TI - Human Adipose-Derived Stem Cells Labeled with Plasmonic Gold Nanostars for Cellular Tracking and Photothermal Cancer Cell Ablation. AB - BACKGROUND: Gold nanostars are unique nanoplatforms that can be imaged in real time and transform light energy into heat to ablate cells. Adipose-derived stem cells migrate toward tumor niches in response to chemokines. The ability of adipose-derived stem cells to migrate and integrate into tumors makes them ideal vehicles for the targeted delivery of cancer nanotherapeutics. METHODS: To test the labeling efficiency of gold nanostars, undifferentiated adipose-derived stem cells were incubated with gold nanostars and a commercially available nanoparticle (Qtracker), then imaged using two-photon photoluminescence microscopy. The effects of gold nanostars on cell phenotype, proliferation, and viability were assessed with flow cytometry, 3-(4,5-dimethylthiazolyl-2)-2,5 diphenyltetrazolium bromide metabolic assay, and trypan blue, respectively. Trilineage differentiation of gold nanostar-labeled adipose-derived stem cells was induced with the appropriate media. Photothermolysis was performed on adipose derived stem cells cultured alone or in co-culture with SKBR3 cancer cells. RESULTS: Efficient uptake of gold nanostars occurred in adipose-derived stem cells, with persistence of the luminescent signal over 4 days. Labeling efficiency and signal quality were greater than with Qtracker. Gold nanostars did not affect cell phenotype, viability, or proliferation, and exhibited stronger luminescence than Qtracker throughout differentiation. Zones of complete ablation surrounding the gold nanostar-labeled adipose-derived stem cells were observed following photothermolysis in both monoculture and co-culture models. CONCLUSIONS: Gold nanostars effectively label adipose-derived stem cells without altering cell phenotype. Once labeled, photoactivation of gold nanostar-labeled adipose-derived stem cells ablates neighboring cancer cells, demonstrating the potential of adipose-derived stem cells as a vehicle for the delivery of site specific cancer therapy. PMID- 28350666 TI - Long-Term Comparison between Human Normal Conchal and Microtia Chondrocytes Regenerated by Tissue Engineering on Nanofiber Polyglycolic Acid Scaffolds. AB - BACKGROUND: Previous regeneration studies of auricle-shaped cartilage by tissue engineering leave unresolved whether the chondrocyte phenotype from human auricular chondrocytes seeded onto polymeric scaffolds is retained over the long term and whether microtia remnants may be a viable cell source for auricular reconstruction. METHODS: Chondrocytes were isolated from human ears, either normal conchal ear or microtia cartilage remnants, expanded in vitro, and seeded onto nanoscale-diameter polyglycolic acid sheets. These tissue-engineered constructs were implanted into athymic mice for up to 40 weeks. At harvest times of 5, 10, 20, and 40 weeks, samples were documented by gross morphology, histology, and reverse transcription-quantitative polymerase chain reaction analysis. RESULTS: Neocartilages generated from the two types of surgical tissues were similar in appearance of their extracellular matrices and positive staining for elastin and proteoglycans. In the 5- to 40-week time interval, there was an increasing trend in gene expression for type II collagen, elastin, and sex determining region Y box 5, important to normal cartilage phenotype, and a decreasing trend in gene expression for type III collagen, a fibroblast and dedifferentiation marker. Over 40 weeks of implantation, the original nanoscale diameter polyglycolic acid scaffold dimensions (1 cm * 1 cm * 80 um) were generally maintained in tissue-engineered cartilage length and width, and thickness was statistically significantly increased. CONCLUSIONS: Auricular cartilage can be regenerated over the long term (40 weeks) from surgical remnants by tissue-engineering techniques incorporating nanoscale-diameter polyglycolic acid scaffolds. Based on the present assays, microtia neocartilage very closely resembles tissue-engineered cartilage regenerated from chondrocytes isolated from normal conchal cartilage. PMID- 28350667 TI - Acellular Hypothermic Extracorporeal Perfusion Extends Allowable Ischemia Time in a Porcine Whole Limb Replantation Model. AB - BACKGROUND: One of the major challenges in traumatic amputation is the need to keep ischemia time brief (4 to 6 hours) to avoid ischemic damage and enable successful replantation. The current inability to meet this challenge often leads to traumatic limb loss, which has a considerable detrimental impact on the quality of life of patients. METHODS: The authors' team built a portable extracorporeal membrane oxygenator device for the perfusion of amputated extremities with oxygenated acellular solution under controlled parameters. The authors amputated forelimbs of Yorkshire pigs, perfused them ex vivo with acellular Perfadex solution for 12 hours at 10 degrees C in their device, and subsequently replanted them into the host animal. The authors used limbs stored on ice slurry for 4 hours before replantation as their control group. RESULTS: Clinical observation and histopathologic evaluation both demonstrated that there was less morbidity and less tissue damage to the cells during preservation and after replantation in the perfusion group compared with the standard of care. Significant differences in blood markers of muscle damage and tissue cytokine levels underscored these findings. CONCLUSIONS: The authors demonstrated the feasibility and superiority of ex vivo hypothermic oxygenated machine perfusion for preservation of amputated limbs over conventional static cold storage and herewith a substantial extension of the allowable ischemia time for replantation after traumatic amputation. This approach could also be applied to the field of transplantation, expanding the potential pool of viable donor vascularized composite allografts. PMID- 28350668 TI - Regeneration of Vascularized Corticocancellous Bone and Diploic Space Using Muscle-Derived Stem Cells: A Translational Biologic Alternative for Healing Critical Bone Defects. AB - BACKGROUND: Regeneration of functional bone substrate remains a priority in reconstructive surgery especially for patients suffering from complex skeletal defects. Efforts to develop implantable osteoinductive constructs and novel osteoconductive materials remain at the forefront of industry forces and product line development. Despite advancement in clinical practice and bone biology, cancellous autograft remains the gold standard for procedures requiring osteogenic mechanisms of healing. This study investigates the utility of muscle derived stem cells as a cellular therapy for definitive bone regeneration through a form of neo-osteogenesis. METHODS: Adipose-derived stem cell, bone marrow derived mesenchymal stem cell, and muscle-derived stem cell populations were isolated separately from C57BL/6 murine tissues and supplemented with collagen scaffolding with or without bone morphogenetic protein-2 to compare relative osteogenic potency and ultrastructure organization in both two- and three dimensional systems. Parallel populations were bound to a deployable collagen implant within a syngeneic murine cranial defect model. RESULTS: Although all populations provided and maintained mesenchymal stem cell multilineage capacity, adipose-derived stem cell- and bone marrow-derived mesenchymal stem cell-enriched constructs were capable of forming small bone aggregates. Defects receiving muscle-derived stem cells self-assembled a form of organized corticocancellous structures within two- and three-dimensional in vitro systems and within the in vivo model. Muscle-derived stem cells also augmented healing, implant angiogenesis, and diploic space formation. CONCLUSION: Muscle-derived stem cell enriched implants appear to provide an autologous response to current industry derived products and an attractive alternative to mesenchymal stem cells for the regeneration of corticocancellous bone and a vascularized diploic space. PMID- 28350669 TI - Discussion: Regeneration of Vascularized Corticocancellous Bone and Diploic Space Using Muscle-Derived Stem Cells: A Translational Biologic Alternative for Healing Critical Bone Defects. PMID- 28350670 TI - Discussion: Regeneration of Vascularized Corticocancellous Bone and Diploic Space Using Muscle-Derived Stem Cells: A Translational Biologic Alternative for Healing Critical Bone Defects. PMID- 28350671 TI - Enhanced Calvarial Bone Healing in CD11c-TLR4-/- and MyD88-/- Mice. AB - BACKGROUND: Inflammation is integral to the injury response. The inflammatory response is essential to the host defense against infection and also to tissue regeneration and repair. Toll-like receptors (TLRs) are critical activators of the innate immune response and present attractive therapeutic targets for inflammation-modulated tissue regeneration. The authors' previous study showed that depletion of TLR4 resulted in accelerated skull bone healing concurrent with increased expression of osteoclastogenic genes. As such, in the present study, the authors used various knockout mouse models for TLR4 and its associated signaling mediators as tools to further understand the role of Toll-like receptor mediated inflammation in calvarial bone healing. METHODS: Calvarial defects (1.8 mm diameter) were created in wild-type, TLR4 knockout (TLR4), TLR2, MyD88, TRIF, TLR4 knockout in myeloid cell (Lyz-TLR4), and TLR4 knockout in dendritic-lineage cell (CD11c-TLR4) mice. Bone healing was examined using micro-computed tomographic, histologic, and histomorphometric analyses. RESULTS: Micro-computed tomographic and histomorphometric analyses revealed that TLR4-deficient mice (TLR4, Lyz-TLR4, and CD11c-TLR4) exhibited a faster intramembraneous healing response at postoperative day 7, whereas MyD88 and CD11c-TLR4 mice showed enhanced bone healing at day 28. CONCLUSIONS: The authors' data suggest a detrimental role for TLR4 in CD11c cells, mediated by Myd88 signaling, during calvarial bone healing. The authors have demonstrated that Toll-like receptor signaling components affect calvarial bone healing, establishing a link between the skeletal and immune systems during craniofacial bone healing. Toll-like receptor signaling components might be used to initiate enhanced healing in bone defects to improve clinical outcomes. PMID- 28350672 TI - Purified Adipose-Derived Stromal Cells Provide Superior Fat Graft Retention Compared with Unenriched Stromal Vascular Fraction. AB - Cell-assisted lipotransfer has shown much promise as a technique to improve fat graft retention in both mouse and human studies. However, the literature varies as to whether fresh stromal vascular fraction or culture-expanded adipose-derived stromal cells are used to augment volume retention. The authors' study sought to determine whether there was a significant advantage to using adipose-derived stromal cells over unpurified stromal vascular fraction cells in a mouse model of cell-assisted lipotransfer. PMID- 28350673 TI - The Effect of Workers' Compensation on Outcome Measurement Methods after Upper Extremity Surgery: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Patients who receive workers' compensation often display worse surgical results, such as prolonged pain or reduced functional ability. The outcomes of surgery can be assessed using a variety of surveys, assessments, and measurements. It is unknown whether the confounding effect differs based on how results are measured. The aim of this study was to determine whether these variations exist. METHODS: A search of full-length articles published between January 1, 1995, and December 31, 2015, was conducted using 3 online databases. The authors performed a systematic review and meta-analysis using unique inclusion criteria for each. RESULTS: A total of 101 articles were included in the systematic review; 62 of them were retained for the meta-analysis. In the systematic review, 70 percent of studies found that patients receiving workers' compensation had significantly worse postoperative results than uncompensated patients, whereas only 42 percent of studies that measured preoperative versus postoperative improvement were influenced by workers' compensation. The meta analysis found that uncompensated patients were more likely to experience improvement after surgery than patients receiving workers' compensation (summary OR, 3.17; 95 percent CI, 2.47 to 4.08). A subgroup analysis demonstrated that functional measures, such as grip strength or nonunion, were least affected by workers' compensation, compared with other outcome measures such as patient reported outcomes questionnaires or time off work. CONCLUSION: Potential bias introduced by workers' compensation can be mitigated by evaluating surgical treatment of work-related upper extremity disorders using preoperative versus postoperative improvement or functional measures. PMID- 28350674 TI - A New Microtia Reconstruction Method Using Delayed Postauricular Skin Flap. AB - BACKGROUND: This article presents a new microtia reconstruction method using a delayed postauricular skin flap. METHODS: The surgery is scheduled in three stages, the first of which delays the postauricular skin flap and deals with the remnant auricle. Three weeks later, the second stage is carried out. An erect, three-dimensional ear framework fabricated from autogenous rib cartilage is inserted between two flaps. The anterior auricular surface of the framework is draped with the delayed skin flap, and the postauricular surface is draped with postauricular fascia and overlying grafted skin. Six months later, the third stage reconstructs the tragus and shapes a hollow mimicking the external auditory meatus, and locally improves the reconstructed auricle. RESULTS: Ninety-six cases of microtia were reconstructed using the delayed skin flap. All ear reconstructions were successful, with good locations, sizes, and shapes, with few complications. CONCLUSIONS: The authors' method enables an adequately large, thin skin flap with sufficient blood supply, and also appropriately manages the remnant auricle. A delayed postauricular skin flap with a three-dimensional autologous costal cartilage framework represents a promising approach to microtia reconstruction. PMID- 28350675 TI - Early Distraction for Mild to Moderate Unilateral Craniofacial Microsomia: Long Term Follow-Up, Outcomes, and Recommendations. AB - BACKGROUND: There is controversy regarding the treatment of young patients with unilateral craniofacial microsomia and moderate dysmorphism. The relative indication for mandibular distraction in such patients poses several questions: Is it deleterious in the context of craniofacial growth and appearance? This study was designed to address these questions. METHODS: A retrospective review of patients undergoing mandibular distraction by a single surgeon between 1989 and 2010 was conducted. Patients with "moderate" unilateral craniofacial microsomia (as defined by Pruzansky type I or IIa mandibles) and follow-up until craniofacial skeletal maturity were included for analysis. Patients were divided into two cohorts: satisfactory and unsatisfactory results based on photographic aesthetic evaluation by independent blinded observers at the initial presentation and at the age of skeletal maturity. Clinical variables were analyzed to detect predictors for satisfactory distraction. RESULTS: Nineteen patients were included for analysis. The average age at distraction was 68.2 months and the average age at follow-up was 19.55 years. Thirteen patients (68.4 percent) had Pruzansky type IIA and six patients (31.6 percent) had Pruzansky type I mandibles. Twelve patients (63.2 percent) had satisfactory outcomes, whereas seven patients (36.8 percent) had unsatisfactory outcomes. Comparing the two cohorts, patients with satisfactory outcomes had distraction at an earlier age (56.4 months versus 89.8 months; p = 0.07) and a greater percentage overcorrection from craniofacial midline (41.7 percent versus 1.8 percent; p = 0.003). CONCLUSION: Mandibular distraction is successful in patients with mild to moderate dysmorphism, provided that there is a comprehensive clinical program emphasizing adequate mandibular bone stock, proper vector selection, planned overcorrection, and comprehensive orthodontic management. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28350676 TI - Comparison of the Outcomes of Complex Orbital Fracture Repair with and without a Surgical Navigation System: A Prospective Cohort Study with Historical Controls. AB - BACKGROUND: In severe orbital fractures, restoration of orbital shape and volume is required to avoid diplopia and posttraumatic enophthalmos. The purpose of this study was to compare outcomes between navigation-aided and conventional techniques for complex unilateral orbital fractures using titanium mesh. METHODS: The outcomes and the computed tomography-measured orbital volume of two groups of orbital complex unilateral reconstruction cases were compared. The study group consisted of a consecutive cohort of unilateral severe orbital fracture that underwent surgery with the aid of a Brainlab navigation system. A historical control group was composed of consecutive operations performed immediately before the beginning of navigation system use. A total of 55 operations were then identified and studied for patient characteristics, diplopia and globe position, preoperative and postoperative orbital volumes, complications, need for revision surgery, and the surgeon's performance. RESULTS: Postoperative diplopia severity was lower in the study group than in the control group. Orbital volume analysis showed that reconstructed orbital volume in the study group was closer to unaffected orbital volume compared with the control group. Significant orbital volume reduction in the reconstructed orbit could be achieved in the study group, and there was no significant reduction in the control group compared with the unaffected side. The globe projection was higher compared with the preoperative situation in the study group than in the control group. The navigational platform could also contribute to reduce the learning curve. CONCLUSION: This study demonstrated that computer-assisted techniques improve outcomes compared with conventional techniques. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28350677 TI - Insight into the Pathophysiologic Mechanisms behind Cognitive Dysfunction in Trigonocephaly. AB - BACKGROUND: The relationship between trigonocephaly and cognitive problems might be explained by: secondary mechanical factors related to growth restriction of the skull, and primary structural defects caused by a shared mechanism related to brain developmental disorder(s) and skull malformation. However, because the exact pathophysiology remains unknown, we examined the pathophysiologic mechanisms behind cognitive dysfunction in patients with trigonocephaly, with an aim of providing a model for cognitive dysfunction based on routinely available variables. METHODS: Included were 72 patients with trigonocephaly who were operated on. Postoperatively, intelligence was assessed prospectively. The two independent variables, secondary mechanical and primary brain developmental mechanisms, were evaluated retrospectively. Computed tomographic imaging was used to assess skull volume and severity of the frontal stenosis (secondary mechanical factors), width of the central part of the lateral ventricles, and other structural brain anomalies (primary brain developmental factors). Extracranial congenital anomalies were also taken into account. RESULTS: No association was found between secondary mechanical factors and postoperative IQ score. Width of the central part of the lateral ventricles, and an interaction effect between this width and additional extracranial anomalies, showed a significant negative association with postoperative IQ. CONCLUSIONS: Primary brain developmental disorders seem to play an important role in the development of cognitive problems in trigonocephaly. Assessment of width of the central part of the lateral ventricle scores and additional extracranial congenital anomalies for the early prediction of cognitive problems in patients with trigonocephaly could be clinically valuable and can be performed using routinely available tools. PMID- 28350678 TI - Ocular Morbidity in the Correction of Orbital Hypertelorism and Dystopia: A 15 Year Experience. AB - BACKGROUND: Complex surgery for appearance change is controversial. Correction of orbital hypertelorism risks diplopia and loss of stereopsis for aesthetic gain. The risk-to-benefit ratio remains ill-defined. The aim of this study was to define specific ocular morbidity following orbital translocation. METHODS: The authors compared stable preoperative and postoperative orthoptic indices (i.e., angle of strabismus, ocular motility, and acuity) for 23 consecutive patients who underwent orbital translocation between 2000 and 2015 and noted the requirement for corrective surgery. RESULTS: Eighteen patients underwent 33 box osteotomies (15 bilateral and three unilateral). Five patients underwent facial bipartition. Diagnosis was craniofrontonasal dysplasia in 11, frontonasal dysplasia in six, facial cleft in four, and Saethre-Chotzen syndrome in two cases. Median grade of orbital hypertelorism was III. Median age at surgery was 13 years (range, 5 to 17 years). Nontransient change (favorable or unfavorable) in angle of strabismus was noted in 14 patients. Ocular motility was altered in 12. Six patients had stereopsis preoperatively that was disrupted in two cases because of changes in ocular alignment and/or motility. There was one perioperative ophthalmic emergency (superior orbital fissure syndrome) and three acute reexplorations for external ocular muscle entrapment. Corrective surgery for strabismus was performed for four patients. Three required secondary canthopexy and three required surgery for blepharoptosis. CONCLUSIONS: Orbital translocation is associated with ocular risks including changes to angle of strabismus, ocular motility, and (when present) loss of stereopsis. Secondary surgery to correct strabismus or eyelid malposition is common. Orbital translocation is an operative process, not a single procedure. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28350679 TI - Frontal Sinus Volume and Frontal Bar Position Are Associated in Unicoronal Craniosynostosis. AB - BACKGROUND: Frontal sinus pneumatization plays an important role in brow protrusion, and absence of frontal sinus development may be associated with brow retrusion. Using unicoronal craniosynostosis as a model, the authors studied the relationship among frontal sinus volume, supraorbital retrusion, and brow position. METHODS: The authors conducted a retrospective review of unicoronal craniosynostosis patients with head computed tomographic scans and photographs taken from ages 5 to 18 years. Frontal sinus volume and supraorbital retrusion were calculated using three-dimensional computed tomographic reconstructions. A "brow score" from 0 to 3 was assigned to each patient's photographs by a consensus of two craniofacial surgeons; sinus morphology and brow scores were compared. RESULTS: The study included 20 unicoronal craniosynostosis patients. The affected side demonstrated increased retrusion (7.1 +/- 3.7 mm versus 3.0 +/- 3.1 mm; p < 0.001) and decreased frontal sinus volume (0.8 +/- 0.9 cc versus 2.6 +/- 1.8 cc; p < 0.001). Qualitative brow retrusion scores differed between affected and unaffected sides (score of 0, 17 percent affected versus 78 percent unaffected; score of 1, 28 percent versus 22 percent; score of 2, 39 percent versus 0 percent; and score of 3, 17 percent versus 0 percent; p < 0.001). Brow scores trended with retrusion measurements (score of 0, 2.7 +/- 2.9 mm retrusion; score of 1, 6.1 +/- 3.5 mm; score of 2, 8.9 +/- 3.2 mm; and score of 3, 9.7 +/- 2.8 mm; p < 0.001). Subjects with brow scores of 0 or 1 had larger frontal sinus volumes than subjects with brow scores of 2 or 3 (p = 0.018). CONCLUSIONS: Qualitative brow retrusion correlates strongly with both quantitative supraorbital retrusion and frontal sinus volume. Although this retrospective study cannot prove causality, which is likely multifactorial, its strong correlation with frontal sinus pneumatization highlights the importance of the frontal sinus in brow position in unicoronal craniosynostosis. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28350680 TI - Airway and Feeding Outcomes of Mandibular Distraction, Tongue-Lip Adhesion, and Conservative Management in Pierre Robin Sequence: A Prospective Study. AB - BACKGROUND: Pierre Robin sequence is characterized by mandibular retrognathia and glossoptosis resulting in airway obstruction and feeding difficulties. When conservative management fails, mandibular distraction osteogenesis or tongue-lip adhesion may be required to avoid tracheostomy. The authors' goal was to prospectively evaluate the airway and feeding outcomes of their comprehensive approach to Pierre Robin sequence, which includes conservative management, mandibular distraction osteogenesis, and tongue-lip adhesion. METHODS: A longitudinal study of newborns with Pierre Robin sequence treated at a pediatric academic medical center between 2010 and 2015 was performed. Baseline feeding and respiratory data were collected. Patients underwent conservative management if they demonstrated sustainable weight gain without tube feeds, and if their airway was stable with positioning alone. Patients who required surgery underwent tongue lip adhesion or mandibular distraction osteogenesis based on family and surgeon preference. Postoperative airway and feeding data were collected. RESULTS: Twenty eight patients with Pierre Robin sequence were followed prospectively. Thirty-two percent had a syndrome. Ten underwent mandibular distraction osteogenesis, eight underwent tongue-lip adhesion, and 10 were treated conservatively. There were no differences in days to extubation or discharge, change in weight percentile, requirement for gastrostomy tube, or residual obstructive sleep apnea between the three groups. No patients required tracheostomy. The greatest reduction in apnea hypopnea index occurred with mandibular distraction osteogenesis, followed by tongue-lip adhesion and conservative management. CONCLUSIONS: Careful selection of which patients with Pierre Robin sequence need surgery, and of the most appropriate surgical procedure for each patient, can minimize the need for postprocedure tracheostomy. A comprehensive approach to Pierre Robin sequence that includes conservative management, mandibular distraction osteogenesis, and tongue-lip adhesion can result in excellent airway and feeding outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 28350681 TI - Evolution of a Surgical Philosophy in Orthognathic Surgery. AB - A surgical philosophy of orthognathic surgery is presented. It has evolved over an entire surgical career as orthognathic surgical goals have evolved to become primarily aesthetic. In this context, the occlusal result serves as a means of achieving the aesthetic ends. It relies on the physical examination, using qualitative concepts of facial appearance, to be the most important determinant of treatment plans. It makes a distinction between a quantitatively normal face and one that is visually well proportioned and emphasizes the attributes of the soft tissue. The emotional expression of the patient is also considered in treatment planning. By using surgical tactics that provide control of facial projection and height, this philosophy affords the surgeon an opportunity to manipulate the skeletal elements to the extent that one can simultaneously achieve a well-proportioned face and favorably influence the appearance of the soft tissues and facial countenance. PMID- 28350682 TI - Vasculature of a Medial Femoral Condyle Free Flap in Intact and Osteotomized Flaps. AB - BACKGROUND: A small size and difficulties with shaping a medial femoral condyle corticocancellous bone flap are factors limiting its use. The goal of this study was to evaluate range of vascular supply to a medial femoral condyle corticocancellous bone flap to determine whether harvesting of larger flaps and performing a flap osteotomy would compromise the vasculature of a flap's bone. METHODS: Twenty-four limbs were dissected and medial femoral condyle corticocancellous bone flaps were harvested with skin paddles. Thirteen of 24 flaps had subperiosteal osteotomies simulating shaping a bone for reconstruction. A pedicle artery was perfused with red latex. Medial femoral condyle corticocancellous bone flap vascularization was evaluated by cutting the bone into 1-cm blocks and assessing the number of Haversian canals filled with red latex. RESULTS: Length of harvested flaps was 7 to 13 cm, thickness was 0.5 to 3 cm, and width was 1 to 3 cm. Pedicle length was between 3.5 and 9 cm (mean +/- SD, 6.6 +/- 1.6 cm). Red latex filled bone vessels at a distance of 6 to 11.5 cm from the distal end of a flap (8.2 +/- 1.4 cm). Skin paddles were filled with latex in all cases. CONCLUSION: A medial femoral condyle corticocancellous bone flap had sufficient blood supply, allowing for harvesting flaps up to 11 cm long, and subperiosteal osteotomy did not compromise the vasculature of the flap's bone. PMID- 28350683 TI - The Relationship of Superficial Cutaneous Nerves and Interperforator Connections in the Leg: A Cadaveric Anatomical Study. AB - BACKGROUND: The lower limb is a source of many flaps both for closure of local defects and for free transfer. Fasciocutaneous flap techniques have been progressively refined, although the vascular basis for their success needs clarification. METHODS: Archival studies of 48 lower limbs were reviewed and combined with 20 studies of lower limbs from fresh cadavers, making a total of 68 investigations. Lower limbs were injected with a dilute lead oxide solution; the integument was removed and radiographed; and the cutaneous nerves were dissected, tagged with wire, radiographed again, and their paths traced on the original images. RESULTS: The major cutaneous nerves in the leg are paralleled by a longitudinal vascular axis often comprising long branches with large-caliber true anastomotic connections between perforators. The most highly developed vascular axes followed the medial sural cutaneous and saphenous nerves, together with their accompanying veins, immediately superficial to the deep fascia. The intervening areas were characterized by shorter branches usually connected by small-caliber choke anastomotic connections. CONCLUSIONS: These findings provide the anatomical basis for the observed reliability of longitudinal flaps in the leg. The superficial cutaneous nerves of the leg, especially the saphenous and medial sural cutaneous nerves, are paralleled by a vascular axis on or beside the nerve comprising long perforator branches connected usually but not always by large-caliber true anastomotic connections. This emphasizes the importance of understanding the characteristics of interperforator anastomoses when designing and raising flaps. PMID- 28350684 TI - Current Concepts in the Surgical Management of Lymphedema. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Discuss the key points in diagnosing lymphedema. 2. Understand the imaging modalities that facilitate diagnosis and surgical planning. 3. Appreciate the indications for both physiologic and ablative procedures. 4. Recognize the potential role of lymphaticovenular anastomosis and vascularized lymph node transfer in the treatment of patients with lymphedema. SUMMARY: Lymphedema is an incurable disease caused by insufficient lymphatic drainage leading to abnormal accumulation of interstitial fluid within the soft tissues. Although this condition may result from a primary structural defect of the lymphatic system, most cases in developed countries are secondary to iatrogenic causes. The diagnosis of lymphedema can be made readily by performing a clinical history and physical examination and may be confirmed by imaging studies such as lymphoscintigraphy, magnetic resonance lymphangiography, or indocyanine green lymphangiography. Nonsurgical treatment continues to be the mainstay of lymphedema management. However, advances in microsurgical techniques have revolutionized surgical options for treating lymphedema, and emerging evidence suggests that reconstructive methods may be performed to restore lymphatic flow. Procedures such as lymphaticovenular anastomosis and vascularized lymph node transfer can potentially offer a more permanent solution to chronic lymphedema, and initial studies have demonstrated promising results. PMID- 28350685 TI - Inadequate Enoxaparin Dosing Predicts 90-Day Venous Thromboembolism Risk among Plastic Surgery Inpatients: An Examination of Enoxaparin Pharmacodynamics. AB - BACKGROUND: Evidence-based plastic surgery guidelines support the effectiveness of once-daily enoxaparin prophylaxis. Despite prophylaxis, one in 25 highest risk patients has a venous thromboembolism event. The authors examined the pharmacodynamics of standard enoxaparin doses in plastic surgery patients to examine whether patient-level factors predict enoxaparin metabolism, whether inadequate enoxaparin dose predicts downstream venous thromboembolism events, and whether a pharmacist-driven dose-adjustment protocol was effective. METHODS: The authors recruited adult plastic surgery patients who received postoperative enoxaparin at 40 mg/day. Steady-state peak anti-factor Xa levels, a marker of enoxaparin effectiveness and safety, were determined. Patients with out-of-range anti-factor Xa levels had real-time dose adjustment based on a written protocol. Patients were followed for 90-day venous thromboembolism events. RESULTS: Ninety four patients were recruited, and 44 percent had in-range peak anti-factor Xa levels in response to standard enoxaparin dosing. Patient-level factors including extent of surgical injury and gross weight were independent predictors of enoxaparin metabolism. Patients with low anti-factor Xa levels were significantly more likely to have 90-day venous thromboembolism (10.2 percent versus 0 percent; p = 0.041). Real-time dose adjustment allowed a significantly increased proportion of patients to have in-range levels (67.1 percent versus 44.3 percent; p = 0.002). CONCLUSIONS: Based on pharmacodynamic data, the majority of plastic surgery patients receive inadequate enoxaparin prophylaxis using fixed dosing. Patient-level factors can predict how patients will metabolize enoxaparin, and patients who receive inadequate enoxaparin prophylaxis are significantly more likely to have downstream venous thromboembolism events. Individualization of enoxaparin prophylaxis may minimize perioperative venous thromboembolism risk and further improve patient safety after plastic and reconstructive surgery procedures. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 28350686 TI - So, Do You Want to Be Facebook Friends? How Social Media Have Changed Plastic Surgery and Medicine Forever. PMID- 28350687 TI - Reply: Acellular Dermal Matrix-Assisted Direct-to-Implant Breast Reconstruction and Capsular Contracture: A 13-Year Experience. PMID- 28350688 TI - Evaluation of the Upper Limb Lymphatic System: A Prospective Lymphoscintigraphic Study in Melanoma Patients and Healthy Controls. PMID- 28350689 TI - Spheno-Orbital Meningiomas: An Analysis Based on World Health Organization Classification and Ki-67 Proliferative Index. AB - PURPOSE: To evaluate the clinical behavior of spheno-orbital meningiomas with regard to World Health Organization (WHO) tumor grade and Ki-67, a cellular marker of proliferation. METHODS: A retrospective review over a 16-year period of the demographic, clinical, radiographic, and surgical data of all patients with spheno-orbital meningioma who underwent surgical resection. Tumor specimens were examined histologically using the current WHO 2016 classification and immunohistochemically using Ki-67/MIB-1 monoclonal antibody. RESULTS: Thirty eight patients met all inclusion criteria: 78.9% of tumors were WHO grade I with a mean Ki-67 of 3.76, and 93% of patients were clinically stable at last follow up; 10.5% of lesions were WHO grade II (atypical) with a mean Ki-67 of 14.93, and 10.5% of lesions were WHO grade III (anaplastic) with a mean Ki-67 of 58.3. All grade II and III meningiomas exhibited an aggressive clinical course. There were statistically significant correlations between disease clinical progression and WHO tumor grade (p < 0.001), between disease clinical progression and Ki-67 (p < 0.001), and between increasing Ki-67 index and higher WHO grade (p < 0.001). For WHO grade I lesions, a Ki-67 of >=3.3 correlated with recurrence (p = 0.0256). Overall, disease-specific mortality occurred in 5 (13%) patients. CONCLUSIONS: Ki 67 index is a valuable marker to use in conjunction with WHO grade to predict meningioma behavior, particularly in histologically borderline lesions, and possibly to identify a subset of WHO grade I tumors at risk of recurrence. This combination of methods can aid in tailoring treatment and surveillance strategies. PMID- 28350690 TI - Programmed Death-1 Pathway in Orbital Invasion of Cutaneous Carcinomas. AB - PURPOSE: The programmed death-1 pathway negatively regulates the immune system. Previous reports have indicated worse tumor-related outcomes with increased expression of the ligand for this pathway. This study was undertaken to assess the role of the PD pathway in cutaneous malignancies that invade the orbit. METHODS: Immunohistochemical staining for the programmed death-1 receptor and ligand was performed on exenteration specimens of invasive cutaneous orbital malignancies (n = 12) and nodular basal cell carcinoma (n = 10). The numbers of positively-staining cells/40* field were counted across 5 consecutive fields, and statistical analyses were performed to compare the differences between the 2 groups. RESULTS: Programmed death-1 receptor positivity was seen in means of 30.9 cells/40* field and 62.4 cells/40* field for nodular basal cell carcinomas and invasive malignancies, respectively (p = 0.0046). A mean of 4.54 cells/40* field stained positively for the programmed death-1 ligand in nodular basal cell carcinoma, whereas a mean of 46.4 cells/40* field stained positively for programmed cell death ligand-1 in orbital invasive cutaneous carcinomas (p = 0.0015). Both of these differences were statistically significant. CONCLUSIONS: Both the programmed death-1 receptor and its ligand are enriched in invasive cutaneous malignancies. This finding indicates that negative regulation of the immune system likely prohibits tumor surveillance, and facilitates increasing aggressiveness and invasion of cutaneous malignancies. PMID- 28350691 TI - Conjunctival Inclusion Cyst Containing a Scleral Buckle. PMID- 28350692 TI - Enhanced Fasanella-Servat Procedure for the Graded Repair of Blepharoptosis. AB - PURPOSE: To describe in detail a technique for a modified Fasanella-Servat procedure that provides a simplified method for graded Mueller muscle excision with minimal and controlled tarsal excision. METHODS: A retrospective study of 71 patients (102 eyelids) who underwent the modified Fasanella-Servat procedure is reported. Measurements include the preoperative, post-phenylephrine, and postoperative margin-to-reflex distance-1, and postoperative upper eyelid height symmetry as determined by the absolute difference between right- and left-sided margin-to-reflex distance-1. Postoperative complications are reported. RESULTS: The average increase in margin-to-reflex distance-1 was 2.4 mm with an average postoperative upper eyelid height symmetry of 0.4 mm. Postoperative asymmetry was 1.5 mm or less in 68 patients, a success rate of 96%. Four patients (6%) exhibited overcorrection, 2 of which required additional surgery. No lagophthalmos or notable eyelid contour abnormalities were seen. CONCLUSIONS: The modified Fasanella-Servat technique offers a simple method to isolate and resect Mueller muscle and a minimal segment of tarsus in a quantitative fashion, allowing for a graded repair of blepharoptosis and thereby decreasing the risk of postoperative overcorrection, lagophthalmos, and eyelid contour asymmetry whilst preserving the bulk of tarsus. PMID- 28350693 TI - Prognostic Value of the Staging System for Eyelid Tumors in the 7th Edition of the American Joint Committee on Cancer Staging Manual. AB - PURPOSE: To determine the prognostic value of the staging criteria for eyelid tumors in the 7th edition of the American Joint Committee on Cancer (AJCC) staging manual and to determine, for each type of eyelid tumor, which AJCC T categories are associated with increased risk of nodal metastasis and thus potential usefulness of sentinel lymph node biopsy. METHODS: Systematic review and analysis of articles found by searching PubMed and Google Scholar using the search terms "AJCC," "eyelid," "carcinoma," and "melanoma." RESULTS: Rates of local recurrence, regional nodal metastasis, and distant metastasis were approximately 7% to 10%, 1% to 9%, and 0% to 0.8%, respectively, for eyelid squamous cell carcinoma; 5% to 6%, 8% to 23%, and 2% and 14%, respectively, for eyelid sebaceous carcinoma; 10%, 10% to 22%, and 19% to 22%, respectively, for eyelid Merkel cell carcinoma (when staged according to the criteria for eyelid carcinoma as opposed to Merkel cell carcinoma), 14%, 5%, and 0%, respectively, for eyelid sweat gland carcinoma; and 2%, 9%, and 6%, respectively, for eyelid melanoma. Overall, the risks of local recurrence and regional nodal and distant metastasis appeared to increase with increasing AJCC T category, although not statistically significant in all studies. Clinical T2b or greater T category was significantly associated with increased risk of nodal metastasis for eyelid squamous cell carcinomas, sebaceous carcinomas, Merkel cell carcinomas (staged with eyelid carcinoma criteria), sweat gland carcinomas, and melanomas. Clinical T3 or greater T category was significantly associated with distant metastasis for eyelid carcinomas and melanomas. CONCLUSION: For eyelid carcinomas and eyelid melanomas, AJCC 7th edition T category correlates with the risks of nodal and distant metastasis, with T2b and larger tumors associated with highest risk of nodal metastasis. Patients with T2b or larger tumors may be candidates for sentinel lymph node biopsy or close nodal surveillance. PMID- 28350695 TI - ICRP 67 Biokinetic Models for AM-241 Applied to Nonhuman Primates. AB - Between 1960 and 1985, Patricia Durbin and colleagues performed studies on the distribution of intravenously and intramuscularly injected Am citrate with dosages ranging from 16 to 32 kBq kg in 30 male and female non-human primates (NHP). Dr. Durbin died unexpectedly in March of 2009, leaving much of the extensive serial blood, bioassay, and autopsy data from these NHP studies unanalyzed. As part of the experimental design, serial blood samples were taken, and urine and feces samples were collected separately for the duration of the study. The measurements of urine, fecal excretion, blood samples, and organ burden data obtained from the animals were used to evaluate the transfer rates of the ICRP 67 biokinetic model for Am. Seven cases, in which the primates were administered Am citrate by intravenous injection, were evaluated using the ICRP 67 systemic model. There were differences ranging from 51.4% underestimated to 102.7% overestimated activity between the predicted intake, which was calculated using IMBA Professional Plus software and based upon the urine bioassay data and the actual activity. The difference between the predicted activity at the time of death in the liver and skeleton using IMBA professional software and the value of the measured activity at the time of death were also compared. Generally, the ratios of predicted activity in the liver and skeleton at the time of death to the measured activity were consistently more than 1. However, the ratios were less than 1 in the skeleton for animals that were sacrificed 2,199 and 973 d post injection. The posterior probability distributions for model parameters derived using WeLMoS method were inconsistent with the ICRP 67 default parameters. The prediction made based on the posterior probability distributions for model parameters derived using WeLMoS gave the best fit to these data; however, the modified parameters overestimated the activity in almost all cases. The difference between the predicted Am activity and the value of the measured activity may be due to the physiological age-related characteristics relative to the age of the animal at the time of the injection and early and long scarified time. PMID- 28350696 TI - Monte Carlo Simulations Comparing the Response of a Novel Hemispherical Tepc to Existing Spherical and Cylindrical Tepcs for Neutron Monitoring and Dosimetry. AB - Neutron dosimetry in reactor fields is currently mainly conducted with unwieldy flux monitors. Tissue Equivalent Proportional Counters (TEPCs) have been shown to have the potential to improve the accuracy of neutron dosimetry in these fields, and Multi-Element Tissue Equivalent Proportional Counters (METEPCs) could reduce the size of instrumentation required to do so. Complexity of current METEPC designs has inhibited their use beyond research. This work proposes a novel hemispherical counter with a wireless anode ball in place of the traditional anode wire as a possible solution for simplifying manufacturing. The hemispherical METEPC element was analyzed as a single TEPC to first demonstrate the potential of this new design by evaluating its performance relative to the reference spherical TEPC design and a single element from a cylindrical METEPC. Energy deposition simulations were conducted using the Monte Carlo code PHITS for both monoenergetic 2.5 MeV neutrons and the neutron energy spectrum of Cf-D2O moderated. In these neutron fields, the hemispherical counter appears to be a good alternative to the reference spherical geometry, performing slightly better than the cylindrical counter, which tends to underrespond to H*(10) for the lower neutron energies of the Cf-D2O moderated field. These computational results are promising, and if follow-up experimental work demonstrates the hemispherical counter works as anticipated, it will be ready to be incorporated into an METEPC design. PMID- 28350697 TI - Tritium ( 3 H) Retention In Mice: Administered As HTO, DTO or as 3 H-Labeled Amino-Acids. AB - The objective of this study was to compare the biokinetics of injected H-labeled light (HTO) and heavy (DTO) water in CBA/CaJ mice and to compare the organ distribution and/or body content of H administered by chronic ingestion for 1 mo to C57Bl/6J mice, as either H-labeled water or H-labeled amino acids (glycine, alanine and proline). HTO and DTO were administered to CBA/CaJ mice by single intraperitoneal injection and body retention was determined for up to 384 h post injection. Tritium-labeled water or H-labeled amino acids were given to C57Bl/6J mice ad libitum for 30 d in drinking water. Body content and organ distribution of H during the period of administration and subsequent to administration was determined by liquid scintillation counting. No differences were found between the biokinetics of HTO and DTO, indicating that data generated using HTO can be used to help assess the consequences of H releases from heavy water reactors. The results for H-water showed that the concentration of radionuclide in the mice reached a peak after about 10 d and dropped rapidly after the cessation of H administration. The maximum concentration reached was only 50% of that in the water consumed, indicating that mice receive a significant fraction of their water from respiration. Contrary to the findings of others, the pattern of H retention following the administration of a cocktail of the labeled amino acids was very little different from that found for the water. This is consistent with the suggestion that most of the ingested amino acids were rapidly metabolized, releasing water and carbon dioxide. PMID- 28350698 TI - Gamma-Ray Dose From an Overhead Plume. AB - Standard plume models can underestimate the gamma-ray dose when most of the radioactive material is above the heads of the receptors. Typically, a model is used to calculate the air concentration at the height of the receptor, and the dose is calculated by multiplying the air concentration by a concentration-to dose conversion factor. Models indicate that if the plume is emitted from a stack during stable atmospheric conditions, the lower edges of the plume may not reach the ground, in which case both the ground-level concentration and the dose are usually reported as zero. However, in such cases, the dose from overhead gamma emitting radionuclides may be substantial. Such underestimates could impact decision making in emergency situations. The Monte Carlo N-Particle code, MCNP, was used to calculate the overhead shine dose and to compare with standard plume models. At long distances and during unstable atmospheric conditions, the MCNP results agree with the standard models. At short distances, where many models calculate zero, the true dose (as modeled by MCNP) can be estimated with simple equations. PMID- 28350699 TI - Rapid Analysis of 239,238Pu, 241Am, and 90Sr for Nasal Smear Samples in Radiation Emergency and Evaluation of Intake Retention Fraction. AB - The efficiency of the nasal smear method was reviewed to perform a method of sample collection, analysis and initial dose estimation. The screening method of alpha-emitting radionuclides using chemical separation and alpha spectrometry was also studied. To rapidly conduct the appropriate response to victims, special monitoring for Pu, Am, and Sr using sequential analysis was established, and the method was successfully validated through participation in an international inter comparison program. The duration of the analysis method was evaluated with regard to application in emergency situations because of its relatively rapid treatment and counting time. The intake retention fraction was calculated and evaluated to review the characteristics of each radionuclide in the anterior nasal passage of the extra-thoracic region. No large difference was observed among the four radionuclides. However, the values of the intake retention fraction were affected by age groups because of the different respiratory rates. The effects of the Y ingrowth and particle size were also discussed. PMID- 28350700 TI - Effects of Medical Diagnostic Low-dose X Rays on Human Lymphocytes: Mitochondrial Membrane Potential, Apoptosis and Cell Cycle. AB - Low-dose radiation is widely used across the world for the diagnosis of many diseases by means of a variety of imaging technologies. However, the harmful effects of exposure to low-dose radiation during medical examination remain controversial. The authors studied the effects of medical diagnostic low-dose x rays (i.e., 0.03, 0.05, or 0.1 mGy) after an in vitro exposure of human lymphocytes. Cells with no irradiation served as the non-irradiated control group. Three biological indicators were used to determine the effects of medical diagnostic low-dose x rays at 4, 8, 24, 48, and 72 h post-irradiation. These biological endpoints were mitochondrial membrane potential (DeltaPsim), cell cycle, and apoptosis. Results indicated no changes in the DeltaPsim, number of apoptotic cells, and cell cycle in lymphocytes exposed to these low doses of radiation, as compared to the corresponding non-irradiated lymphocytes at all harvest time-points. These results suggested that there were no harmful effects of the diagnostic low-dose x rays when human lymphocytes were exposed in an in vitro condition. PMID- 28350701 TI - Interpretation of Nasal Swab Measurements Following Suspected Releases of Actinide Aerosols. AB - For radionuclides such as plutonium and americium, detection of removable activity in the nose (i.e., nasal swab measurements) are frequently used to determine whether follow-up bioassay measurements are warranted following a potential intake. For this paper, the authors analyzed 429 nasal swab measurements taken following incidents or suspicious circumstances (such as an air monitor alarming) at Los Alamos National Laboratory (LANL) for which the dose was later evaluated using in vitro bioassay. Nasal swab measurements were found to be very poor predictors of dose and should not be used as such in the field. However, nasal swab measurements can be indicative of whether a reliably detectable committed effective dose (CED) occurred. About 14% of nasal swab measurements between 1.25 and 16.7 Bq corresponded to CEDs greater than 1 mSv, so in general, positive nasal swabs always indicate that follow-up bioassay should be performed (positive nasal swabs less than 1.25 Bq are considered separately). This probability increased significantly for nasal swabs greater than 16.7 Bq. Only about 3% of nasal swabs with no detectable activity (NDA) corresponded to reliably detectable CEDs. A nasal swab with NDA is therefore necessary, but not sufficient, to negate the need for a follow-up bioassay if it was collected following other workplace indicators of a potential intake. PMID- 28350702 TI - Dose Conversion Coefficients Based on Taiwanese Reference Phantoms and Monte Carlo Simulations for Use in External Radiation Protection. AB - Reference phantoms are widely applied to evaluate the radiation dose for external exposure. However, the frequently used reference phantoms are based on Caucasians. Dose estimation for Asians using a Caucasian phantom can result in significant errors. This study recruited 40 volunteers whose body sizes are close to the average Taiwanese population. Magnetic resonance imaging was performed to obtain the organ volume for construction of the Taiwanese reference man (TRM) and Taiwanese reference woman (TRW). The dose conversion coefficients (DCC) resulting from photo beams in anterior-posterior, posterior-anterior, right-lateral, left lateral, and isotropic irradiation geometries were estimated. In the anterior posterior geometry, the mean DCC differences among organs between the TRM and ORNL phantom at 0.1, 1, and 10 MeV were 7.3%, 5.8%, and 5.2%, respectively. For the TRW, the mean differences from the ORNL phantom at the three energies were 10.6%, 7.4%, and 8.3%. The DCCs of the Taiwanese reference phantoms and the ORNL phantom presented similar trends in other geometries. The torso size of the phantom and the mass and geometric location of the organ have a significant influence on the DCC. The Taiwanese reference phantoms can be used to establish dose guidelines and regulations for radiation protection from external exposure. PMID- 28350703 TI - RF Safety Analysis of a Novel Ultra-wideband Fetal Monitoring System. AB - The LifeWave Ultra-Wideband RF sensor (LWUWBS) is a monitoring solution for a variety of physiologic assessment applications, including maternal fetal monitoring in both the antepartum and intrapartum periods. The system uses extremely low power radio frequency (RF) ultra-wide band (UWB) signals to provide continuous fetal heart rate and contractions monitoring during labor and delivery. Even with the incorporation of three very conservative assumptions, (1) concentration of the RF energy in 1 cm, (2) minimal (2.5 cm) maternal tissue attenuation of fetal exposure, and (3) absence of normal thermoregulatory compensation, the maternal whole body spatial-averaged specific absorption rate (WBSAR) would be 34,000 times below the FCC public exposure limit of 0.08 W kg and, at 8 wk or more gestation, the peak spatial-averaged specific absorption rate (PSSAR) in the fetus would be more than 160 times below the localized exposure limit of 1.6 mW g. Even when using very conservative assumptions, an analysis of the LWUWBS's impact on tissue heating is a factor of 7 lower than what is allowed for fetal ultrasound and at least a factor of 650 compared to fetal MRI. The actual transmitted power levels of the LWUWBS are well below all Federal safety standards, and the potential for tissue heating is substantially lower than associated with current ultrasonic fetal monitors and MRI. PMID- 28350704 TI - Change. PMID- 28350705 TI - RSO Interview with Miguel de la Guardia. PMID- 28350706 TI - A Posting Peculiarity. AB - The definitions of "radiation area," "high radiation area," and "very high radiation area," provided by the U.S. Department of Energy in 10 CFR Part 835.2, and by the Nuclear Regulatory Commission in 10 CFR Part 20.1003, appear to require redundant posting. This is counterintuitive and would be confusing if the regulations were followed as currently written. We suspect that this is unintentional. However, until the relevant regulations are revised, it is recommended that licensees request written clarification from the regulators to ensure that they are able to demonstrate regulatory compliance. PMID- 28350707 TI - A Useful Gadget to Reduce the Radiation Dose of Interventionist's Hands. AB - Increased demand for interventional radiology techniques has interventionists performing a large number of these procedures. Measurements and calculations have shown that the radiation doses received by these specialists can exceed the threshold of radiation-induced deterministic effects unless radiation protection procedures and devices are used. Proper usage of radiation protection devices can protect them from radiation-induced effects, even with a high workload. Occupational radiation protection entails proper training of interventionists to increase their awareness about available appropriate protection tools and equipment, and devices that can be used to minimize exposure, such as needle holders, tubing extensions, and injectors. This study introduces a device that can be used to fix the catheter to prevent the physician from holding the catheter by hand. The authors, also, discuss the importance of radiation protection training along with the training on new medical equipment, which can be applied to reduce the radiation dose. PMID- 28350710 TI - Physical Chemistry of Bile: Detailed Pathogenesis of Cholelithiasis. AB - Despite the overwhelming prevalence of cholelithiasis, many health care professionals are not familiar with the basic pathophysiology of gallstone formation. This article provides an overview of the biochemical pathways related to bile, with a focus on the physical chemistry of bile. We describe the important factors in bile synthesis and secretion that affect the composition of bile and consequently its liquid state. Within this biochemical background lies the foundation for understanding the clinical and sonographic manifestation of cholelithiasis, including the pathophysiology of cholesterol crystallization, gallbladder sludge, and gallstones. There is a brief discussion of the clinical manifestations of inflammatory and obstructive cholestasis and the impact on bile metabolism and subsequently on liver function tests. Despite being the key modality in diagnosing cholelithiasis, ultrasound has a limited role in the characterization of stone composition. PMID- 28350712 TI - Effect of Knee Joint Angle and Contraction Intensity on Hamstrings Coactivation. AB - PURPOSE: This study investigated the effect of knee joint angle and contraction intensity on the coactivation of the hamstring muscles (when acting as antagonists to the quadriceps) in young and older individuals of both sexes. METHODS: A total of 25 young (24 +/- 2.6 yr) and 26 older (70 +/- 2.5 yr) healthy men and women participated. Maximal voluntary isometric contraction of the knee extensors and flexors was assessed at two knee joint angles (90 degrees and 60 degrees , 0 degrees = full extension). At each angle, participants performed submaximal contractions of the knee extensors (20%, 50%, and 80% maximal voluntary isometric contraction), whereas surface EMG was simultaneously acquired from the vastus lateralis and biceps femoris muscles to assess the level (EMG root-mean-square) of agonist activation and antagonist coactivation. Subcutaneous adipose tissue in the areas corresponding to surface EMG electrode placements was measured via ultrasonography. RESULTS: The contractions performed at 90 degrees knee flexion demonstrated higher levels of antagonist coactivation (all P < 0.01) and agonist activation (all P < 0.01) as a function of contraction intensity compared with the 60 degrees knee flexion. Furthermore, after controlling for subcutaneous adipose tissue, older participants exhibited a higher level of antagonist coactivation at 60 degrees knee flexion compared with young participants (P < 0.05). CONCLUSIONS: The results of the present study suggest that 1) the antagonist coactivation is dependent on knee joint angle and contraction intensity and 2) subcutaneous adipose tissue may affect the measured coactivation level likely because of a cross-talk effect. Antagonist coactivation may play a protective role in stabilizing the knee joint and maintaining constant motor output. PMID- 28350711 TI - Physical Activity and Lifetime Risk of Cardiovascular Disease and Cancer. AB - PURPOSE: Although the World Health Organization has recommended moderate- to vigorous-intensity physical activity (MVPA) to prevent cardiovascular disease (CVD) and some cancers, there are no estimates of lifetime risk of these noncommunicable diseases according to PA levels. We aimed to estimate the lifetime risk of CVD and cancers according to PA levels. METHODS: We followed 5807 men and 7252 women in the United States, 45-64 yr old, initially free of CVD and cancer from 1987 through 2012, and used a life table approach to estimate lifetime risks of CVD (coronary heart disease, heart failure, and stroke) and total cancer according to PA levels: poor (0 min.wk of MVPA), intermediate (1-74 min.wk of VPA or 1-149 min.wk of MVPA), or recommended (>=75 min.wk of VPA or >=150 min.wk of MVPA). RESULTS: During the 246,886 person-years of follow-up, we documented 4065 CVD and 3509 cancer events and 2062 non-CVD and 2326 noncancer deaths. In men, the lifetime risks of CVD from 45 through 85 yr were 52.7% (95% confidence interval = 49.4-55.5) for poor PA and 45.7% (42.7-48.3) for recommended PA. In women, the respective lifetime risks of CVD were 42.4% (39.5 44.9) and 30.5% (27.5-33.1). Lifetime risks of total cancer were 40.1% (36.9 42.7) for poor PA and 42.6% (39.7-45.2) for recommended activity in men and 31.4% (28.7-33.8) and 30.4% (27.7-32.9), respectively, in women. CONCLUSIONS: Compared with a poor PA level, the PA recommended by the World Health Organization was associated with lower lifetime risk of CVD, but not total cancer, in both men and women. PMID- 28350714 TI - Multiple-Transportable Carbohydrate Effect on Long-Distance Triathlon Performance. AB - : The ingestion of multiple (2:1 glucose-fructose) transportable carbohydrate in beverages at high rates (>78 g.h) during endurance exercise enhances exogenous carbohydrate oxidation, fluid absorption, gut comfort, and performance relative to glucose alone. However, during long-distance endurance competition, athletes prefer a solid-gel-drink format, and the effect size of multiple-transportable carbohydrate is unknown. PURPOSE: This study aimed to determine the effect of multiple-transportable carbohydrate on triathlon competition performance when ingested within bars, gels, and drinks. METHODS: A double-blind randomized controlled trial was conducted within two national-body sanctioned half-ironman triathlon races held 3 wk apart in 74 well-trained male triathletes (18-60 yr; >2 yr competition experience). Carbohydrate comprising glucose/maltodextrin-fructose (2:1 ratio) or standard isocaloric carbohydrate (glucose/maltodextrin only) was ingested before (94 g) and during the cycle (2.5 g.km) and run (7.8 g.km) sections, averaging 78.6 +/- 6.6 g.h, partitioned to bars (25%), gels (35%), and drink (40%). Postrace, 0- to 10-unit Likert-type scales were completed to assess gut comfort and energy. RESULTS: The trial returned low dropout rate (9%), high compliance, and sensitivity (typical error 2.2%). The effect of multiple transportable carbohydrate on performance time was -0.53% (95% confidence interval = -1.30% to 0.24%; small benefit threshold = -0.54%), with likelihood based risk analysis supporting adoption (benefit-harm ratio = 48.9%:0.3%; odds ratio = 285:1). Covariate adjustments for preexercise body weight and heat stress had negligible impact performance. Multiple-transportable carbohydrate possibly lowered nausea during the swim and bike; otherwise, effects on gut comfort and perceived energy were negligible. CONCLUSIONS: Multiple-transportable (2:1 maltodextrin/glucose-fructose) compared with single-transportable carbohydrate ingested in differing format provided a small benefit to long-distance triathlon performance, inferred as adoption worthy. Large sample in-competition randomized trials offer ecological validity, high participant throughput, compliance, and sensitivity for evaluation of health and performance interventions in athletes. PMID- 28350716 TI - Movement Strategies among Groups of Chronic Ankle Instability, Coper, and Control. AB - INTRODUCTION: Comprehensive evaluation of movement strategies during functional movement is a difficult undertaking. Because of this challenge, studied movements have been oversimplified. Furthermore, evaluating movement strategies at only a discrete time point(s) provide limited insight into how movement strategies may change or adapt in chronic ankle instability (CAI) patients. This study aimed to identify abnormal movement strategies in individuals with a history of ankle sprain injury during a sports maneuver compared with healthy controls. METHODS: Sixty-six participants, consisting of 22 CAI patients, 22 ankle sprain copers, and 22 healthy controls, participated in this study. Functional profiles of lower extremity kinematics, kinetics, and EMG activation from initial contact (0% of stance) to toe-off (100% of stance) were collected and analyzed during a jump landing/cutting task using a functional data analysis approach. RESULTS: Compared with copers, CAI patients displayed landing positions of less plantarflexion, less inversion, more knee flexion, more hip flexion, and less hip abduction during the first 25% of stance. However, restricted dorsiflexion angle was observed in both CAI patients and copers relative to controls during the midlanding to mid-side-cutting phase when the ankle and knee reached its peak range of motion (e.g., dorsiflexion and knee flexion). Reduced EMG activation of tibialis anterior, peroneus longus, medial gastrocnemius, and gluteus medius may be due to altered kinematics that reduce muscular demands on the involved muscles. CONCLUSIONS: CAI patients displayed altered movement strategies, perhaps in an attempt to avoid perceived positions of risk. Although sagittal joint positions seemed to increase the external torque on the knee and hip extensors, frontal joint positions appeared to reduce the muscular demands on evertor and hip abductor muscles. PMID- 28350717 TI - Missed Fractures in Infants Presenting to the Emergency Department With Fussiness. AB - OBJECTIVES: The aim of this study was to evaluate incidence of prior fussy emergency visits in infants with subsequently diagnosed fractures suggestive of abuse. METHODS: This was a retrospective chart review of infants younger than 6 months who presented to the pediatric emergency department (ED) between January 1, 2006, and December 31, 2011. Inclusion criteria included age 0 to 6 months, discharge diagnosis including "fracture," "broken" (or break), or "trauma" or any child abuse diagnosis or chief complaint of "fussy" or "crying" as documented in the electronic medical record by the triage nurse. RESULTS: Three thousand seven hundred thirty-two charts were reviewed, and 279 infants with fractures were identified. Eighteen (6.5%) of 279 infants had a prior ED visit for fussiness without an obvious source. Of these, 2 had a witnessed event causing their fracture, and therefore the fracture was not considered concerning for abuse. The remaining 16 had fractures concerning for abuse. Mean age was 2.5 (SD, 1.2) months. Fifteen (83%) of 18 infants were 3 months or younger at the time of the fussy visit. The mean interval between the first and second ED visits was 27 days (median, 20 days). Thirty-nine percent were evaluated by a pediatric emergency medicine-trained physician during their initial fussy visit, whereas 78% were evaluated by pediatric emergency medicine-trained physician during their subsequent visit. Most common injuries were multiple types of fractures followed by extremity and rib fractures. CONCLUSIONS: Fractures concerning for child abuse are an important cause of unexplained fussiness in infants presenting to the pediatric ED. A high index of suspicion is essential for prompt diagnosis and likely prevention of other abuse. PMID- 28350718 TI - Serotonin Syndrome in a Pediatric Patient After Vilazodone Ingestion. AB - Serotonin syndrome (SS) is a serious toxicity that manifests with symptoms such as tremor, hyperthermia, agitation, and altered mental status that may lead to seizures, coma, or death. Selective serotonin reuptake inhibitors may precipitate SS, particularly in combination with other drugs that possess serotonergic activity. We present a case of SS in a 14-month-old after an ingestion of the selective serotonin reuptake inhibitor vilazodone. PMID- 28350719 TI - Previous Emergency Medical Services Use by Victims of Child Homicide. AB - INTRODUCTION: The medical diagnoses and frequency of emergency department visits made by children who are later given a diagnosis of maltreatment do not differ much from those of nonabused children. However, the type of medical complaints and frequency of emergency medical services (EMS) use by child homicide victims before their death are not known. We compared EMS use between child homicide victims and children who died from natural causes before their death. METHODS: This was a retrospective case-control study of children 0 to 5 years old who died in Houston, Texas, from 2005 to 2010. Cases were child homicide victims. Controls were children who died from natural causes. We reviewed death data and EMS and child protective services (CPS) encounter information before the victim's death. The association between death type (natural vs homicide) and EMS use was assessed using Poisson regression with EMS count adjusted for exposure time. RESULTS: There were 89 child homicides and 183 natural deaths. Age at death was significantly higher for homicides than natural deaths (1.1 vs 0.2 y, P < 0.001). Homicide victims used EMS services (39% vs 14%, P < 0.001) and had previous CPS investigations (55% vs 7%, P < 0.001) significantly more often than children who died from natural causes. Poisson regression, after adjustment for age, revealed that the homicide group had more EMS calls than the natural death group (beta = 0.55; 95% confidence interval, 0.04-1.07; P = 0.03). However, the EMS use frequency and working assessments were not helpful in identifying maltreatment victims. CONCLUSIONS: Child homicide victims use EMS more often and have a higher number of CPS investigations before their death than children who die from natural causes. However, the frequency and nature of EMS medical complaints are not helpful in identifying maltreatment. PMID- 28350720 TI - Pulmonary Embolism Mimicking Infectious Pleuritis. AB - The diagnosis of pulmonary thromboembolism (PE) is often delayed because it is usually misdiagnosed as pneumonia or deep vein thrombosis. We report an unusual case of PE misdiagnosed as viral pleuritis on the first arrival at the emergency department (ED) in our hospital. A 14-year-old girl with no previous significant medical history was referred to the ED with pleuritic and chest pain with low grade fever 4 days before admission. Echography showed a small amount of left pleural effusion. A 12-lead electrocardiogram was normal. She received a diagnosis of viral pleuritis. Two days before admission, she revisited ED with dyspnea and exacerbated pain. Echography showed slight increase in left pleural effusion. She had the same diagnosis. The chest pain remained at the same level. On the day of admission, she presented to ED with vomiting, watery diarrhea, abdominal pain, chest pain, and respiratory distress. Laboratory findings showed hypoalbuminemia and proteinuria. Echography showed a moderate amount of pleural effusion on both sides and no dilatation of the right cardiac ventricle. Contrast enhanced chest computed tomography was performed to search the cause of the respiratory distress, which showed filling defects with contrast material in pulmonary arteries. A 12-lead electrocardiogram showed an S1Q3T3 pattern. She received a diagnosis of PE caused by nephrotic syndrome. Pulmonary thromboembolism can mimic infectious pleuritis and lead to misdiagnosis and/or delayed diagnosis. Thus, risk factors of PE should be considered in pediatric patients presenting with symptoms suggesting infectious pleuritis. PMID- 28350721 TI - A Rare Case of Cor Triatriatum Leading to Respiratory Failure and Shock in an 8 Month-Old. AB - An 8-month-old boy presents with 1 week of gradually worsening respiratory distress. After chest radiograph shows bilateral airspace opacities, he is treated for pneumonia with antibiotics and intravenous fluids. Shortly after this, he decompensates requiring intubation, followed by cardiopulmonary support with pressors and eventually extracorporeal membrane oxygenation. Bedside ultrasound then shows an additional congenital membrane in the left atrium obstructing pulmonary venous return and thought to have caused his original presentation and subsequent decompensation. After surgical correction, he is decannulated from extracorporeal membrane oxygenation, makes a quick recovery, and is discharged from the hospital in good condition within 2 weeks. This rare case of cor triatriatum highlights the importance of considering congenital heart disease even with common presentations in the pediatric population. PMID- 28350722 TI - Buccal Midazolam Compared With Rectal Diazepam Reduces Seizure Duration in Children in the Outpatient Setting. AB - BACKGROUND: Seizures are very common in children. They frequently happen in outpatient settings, in the presence of caregivers who are not always trained in their management. First-line rescue therapy is based on benzodiazepine, historically diazepam. Recent studies have investigated the use of other benzodiazepines in the treatment of acute seizures. OBJECTIVES: The aims of this study were to evaluate the management of pediatric seizures carried out by parents or caregivers in an outpatient setting and to evaluate the differences in terms of immediate management and subsequent outcome when comparing the use of rectal diazepam versus buccal midazolam. METHODS: In this retrospective study, medical records of children consulting for seizures at the Robert Debre Pediatric Emergency Department of Paris, France, over 18 months were analyzed to evaluate seizure characteristics, management by caregivers, received treatments, and the admission rate. RESULTS: Five hundred ninety-four patients resulted eligible for the study. The interview was completed for 135 children who presented a further episode of seizure after inclusion. In the subgroup of children receiving buccal midazolam, compared with the subgroup receiving intrarectal diazepam, seizure duration was significantly shorter (10.3 vs 48.4 minutes, P = 0.0004), and the risk of a status epilepticus decreased (1 vs 11, P = 0.0008). The admission rate was not different between the 2 subgroups. CONCLUSIONS: Based on our results, buccal midazolam seems to have some advantages compared with rectal diazepam in terms of feasibility in an outpatient setting and in terms of reduced seizure duration. PMID- 28350723 TI - Reasons for Interfacility Emergency Department Transfer and Care at the Receiving Facility. AB - OBJECTIVES: The aims of this study were to (1) assess the reasons for pediatric interfacility transfers as identified by transferring providers and review the emergency medical care delivered at the receiving facilities and (2) investigate the emergency department (ED) care among the subpopulation of patients discharged from the receiving facility. METHODS: We performed a multicenter, cross-sectional survey of ED medical providers transferring patients younger than 18 years to 1 of 4 US tertiary care pediatric hospitals with a subsequent medical record review at the receiving facility. Referring providers completed surveys detailing reasons for transfer. RESULTS: Eight hundred thirty-nine surveys were completed by 641 providers for 25 months. The median patient age was 5.7 years. Sixty-two percent of the patients required admission. The most common reasons for transfer as cited by referring providers were subspecialist consultation (62%) and admission to a pediatric inpatient (17%) or intensive care (6%) unit. For discharged patients, plain radiography (26%) and ultrasonography (12%) were the most common radiologic studies. Procedural sedation (16%) was the most common ED procedure for discharged patients, and 55% had a subspecialist consult at the receiving facility. Ten percent of interfacility transfers did not require subspecialty consult, ED procedure, radiologic study, or admission. CONCLUSIONS: Approximately 4 of 10 interfacility transfers are discharged by the receiving facility, suggesting an opportunity to provide more comprehensive care at referring facilities. On the basis of the care provided at the receiving facility, potential interventions might include increased subspecialty access and developing both ultrasound and sedation capabilities. PMID- 28350724 TI - Prevalence and predictors of unsatisfactory anal cytology tests in a cohort of gay and bisexual men in Sydney, Australia: baseline findings from the Study of the Prevention of Anal Cancer (SPANC). AB - Anal cytology has been suggested as a screening test for the anal cancer precursor high-grade squamous intraepithelial lesion (HSIL). We aimed to assess the prevalence and predictors of initial unsatisfactory anal cytology tests ('unsats'). The Study of the Prevention of Anal Cancer is a natural history study of anal human papillomavirus (HPV) and precancerous lesions among gay and bisexual men (GBM) of at least 35 years in Sydney, Australia. At each study visit, an anal swab is collected for cytological testing. Unsats are defined as slides with fewer than 2000 nucleated squamous cells and no abnormal cells. Among 617 GBM enrolled, the median age was 49 (range: 35-79) years and 220 (35.7%) were HIV positive. Initial unsats occurred in 61 (9.9%, 95% confidence interval: 7.6 12.5%), and 29 (4.7%, 95% confidence interval: 3.2-6.7%) remained unsatisfactory on repeat cytology. Initial unsats were associated with fewer lifetime anal receptive partners with a condom (P=0.007); fewer recent anal-receptive sexual partners without a condom (P=0.005); never having had anal chlamydia (P=0.023) or gonorrhea (P=0.003); HIV-negative status (P=0.002); fewer total (P=0.002), low risk (P=0.005), and high-risk (P=0.015) HPV types detected; lack of anal HPV18 detection (P=0.001); never having anally douched (P<0.001); and douching with soapy water (P=0.009) among those who douched. Unsats were less common among those with histologic HSIL (P=0.008) and nonsignificantly less common among those with fewer anal canal octants affected by HSIL (P=0.080), but were more common among those who felt more nervous (P=0.020) during the examination. Our findings suggest that unsats are more common among GBM with less receptive anal sexual experience. Avoiding douching with soapy water and strategies to aid patient relaxation during sampling may reduce the unsat rate. PMID- 28350725 TI - Distance dependency of childhood leukaemia risk near the Mol-Dessel site. PMID- 28350727 TI - An adolescent with chest pain and cardiac hemangioma. AB - Less than 5% of chest pain in children is cardiac in origin, yet this complaint still represents one of the top reasons children are referred to pediatric cardiologists. This article describes a patient whose cardiac tumor illustrates the challenges of evaluating pediatric chest pain and the Standardized Clinical Assessment and Management Plan algorithm that can help. PMID- 28350728 TI - An unusual case of right upper quadrant pain in a pregnant woman. AB - Uterine fibroids occur in up to 30% of women of reproductive age and can cause complications during pregnancy that can harm mother and fetus, such as prematurity and increased risk of miscarriage. This article describes a pregnant woman whose abdominal pain was diagnosed as degenerating uterine fibroids. PMID- 28350729 TI - Real-time ultrasound-guided thoracentesis. AB - Clinicians commonly see patients with pleural effusions requiring thoracentesis. The latest evidence-based guidelines for thoracentesis recommend real-time ultrasound guidance for the safest outcomes from this procedure. This article reviews real-time ultrasound guidance for thoracentesis to help referring clinicians understand the technique and the guidelines for the performance of thoracentesis. PMID- 28350730 TI - PAs in orthopedics in the VHA's community-based outpatient clinics. AB - In the Veterans Health Administration (VHA) system, most orthopedic care takes place in the VA medical centers (VAMCs). Because most patients receiving orthopedic care were referred by adult medicine providers, more widely deploying physician assistants (PAs) in orthopedic medicine might help offset this workload. An orthopedic medicine demonstration project recruited, trained, and positioned PAs in community-based outpatient clinics (CBOCs) to improve access to care. The project involved surgeons at the Houston VAMC instructing five newly employed PAs in a wide range of orthopedic evaluation and management strategies before their assignment to a CBOC. An administrative assessment compared encounter data pre- and postproject (2012 and 2014) to determine if this strategy modified orthopedic workload and improved patient access to care. By 2014, orthopedic patient visit volume had increased 31%-10% at the VAMC and 21% at the five CBOCs. Overall, the five deployed PAs managed 28% of all orthopedic encounters spread over 1 year and only 3.2% of visits required VAMC referral for further evaluation or treatment. During the project, the total volume of patient visits increased throughout the Houston VAMC region but access to care for this specialty service also increased, with more veteran musculoskeletal care being met at the five CBOCs, off-loading visit demand centrally. The adaptability and flexibility of new roles has been identified as one of the defining characteristics of PAs. That the VHA can take advantage of this role malleability suggests that employing PAs is useful in meeting medical service needs of veterans. PMID- 28350731 TI - New Jersey PA regulation and the march on Trenton. AB - New Jersey was the next to the last state to recognize physician assistants (PAs) and pass legislation allowing them to practice. This first-person account supported by interviews with those who were there details the trail to NJ licensure, including the development of a state society, the growth of support from strong leaders in the medical and academic communities, and the grassroots efforts of many PAs aspiring to work in their home state. PMID- 28350732 TI - Esophageal motility disorders. PMID- 28350733 TI - Using PAs in prehospital environments to reduce ED and EMS overuse. AB - Emergency medical services (EMS) and EDs in large cities are burdened with a significant number of patients with chronic disease who have limited options for receiving proper care. Despite their relatively small numbers, these "superusers" can have a significant effect on EMS, particularly in large cities. Additionally, EDs are not designed to provide chronic and continuous healthcare. This article describes how several organizations use physician assistants to manage these patients. PMID- 28350734 TI - A young woman with ptosis. PMID- 28350736 TI - Beyond inclusion. PMID- 28350735 TI - Under the radar. PMID- 28350737 TI - Updated guidelines on digital media use by children. AB - Given the speed at which mobile media has grown recently, the updated American Academy of Pediatrics guidelines for digital technology use by children are a welcome addition to the toolbox of pediatric healthcare providers. This article discusses the changes to the guidelines as well as other useful current research not specifically included in those guidelines. PMID- 28350738 TI - Development of the United Kingdom physician associate profession. AB - The world of healthcare is changing, and patient needs are changing with it. Traditional doctor-driven models of workforce planning are no longer sustainable in the United Kingdom (UK) healthcare economy, and newer models are needed. In the multiprofessional, multiskilled clinical workforce of the future, the physician associate (PA) has a fundamental role to play as an integrated, frontline, generalist clinician. As of 2016, about 350 PAs were practicing in the UK, with 550 PAs in training and plans to expand rapidly. This report describes the development of the PA profession in the UK from 2002, with projections through 2020, and includes governance, training, and the path to regulation. With rising demands on the healthcare workforce, the PA profession is predicted to positively influence clinical workforce challenges across the UK healthcare economy. PMID- 28350740 TI - Prevalence of hepatitis B and C and factors for infection and nonimmune in inflammatory bowel disease patients in China. AB - OBJECTIVE: The aims of this study were to investigate the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in inflammatory bowel disease (IBD) patients and the risk factors related to the infection and nonimmune status. METHODS: A retrospective study was carried out at two clinical centers. The prevalence of viral markers and risk factors related to HBV and HCV infection and nonimmune status were analyzed in IBD patients. Age-matched and sex-matched healthy individuals were recruited as the controls. RESULTS: A total of 980 IBD patients were included in this study. Present and past HBV infection was detected in 41.21% of the IBD group, which was higher than that in the general population (P=0.003). Age older than 30 years (P=0.000), ulcerative colitis (P=0.002), and previous surgery (P=0.039) were found to be significant risk factors for HBV infection in the multivariate analysis. 36.43% of the patients in the IBD group had nonimmune status against HBV, and age less than 40 years (P=0.011) and Crohn's disease (P=0.002) were identified as independent risk factors in the multivariate analysis. The prevalence of HCV infection was low and similar to that of the general population. CONCLUSION: The prevalence of HBV infection in IBD patients in China was higher than that in Europe, USA, and the general population in China, but the prevalence of HCV infection in IBD patients was similar to that in the general population in this study. The frequency of nonimmune status against HBV was high, especially in young Crohn's disease patients, and HBV vaccination should be intensified and have a targeted coverage. PMID- 28350741 TI - Short article: Noninvasive assessment of portal hypertension and detection of esophageal varices in cirrhosis: state-of-the-art. AB - Portal hypertension (PHT) is a major consequence of any chronic liver disease and it is the main cause of complications in patients with cirrhosis. Measurement of hepatic vein pressure gradient is considered the gold standard for PHT assessment, together with its diagnosis and prognosis relevance. Even though hepatic vein pressure gradient measurement is a safe procedure, it is still considered an invasive technique and not widely available. There is thus a need for noninvasive methods that can predict the progression of PHT as well as the presence and the risk of complications related to esophageal varices. This review aimed to discuss the noninvasive markers used in the assessment of PHT and detection of high-risk esophageal varices in patients with liver cirrhosis. We focus on the main biomarkers, particularly those used in the routine assessment of chronic liver disease, and the physical methods that use tissue elastography as a diagnosis tool. PMID- 28350742 TI - Short article: Impact of genetic variation in the vasopressin 1a receptor on the development of organ failure in patients admitted for acute decompensation of liver cirrhosis. AB - BACKGROUND: Vasopressin receptor-mediated vasoconstriction is considered to be involved in the pathogenesis of organ failure in acute-on-chronic liver failure (ACLF). PATIENTS AND METHODS: We studied the association between six single nucleotide polymorphisms (SNPs) of the vasopressin 1a receptor gene and the development of organ failure in 826 patients admitted for acute decompensation of liver cirrhosis (n=641) or ACLF (n=185). RESULTS: No associations were found for SNPs with the presence of circulatory or renal failure. A C>T mutation in SNP rs7308855 and a T>A mutation in SNP rs7298346 showed an association with the presence of coagulation failure in the entire population (n=61, P=0.024 and 0.060, respectively) and in the subgroup of patients with ACLF (n=44, P=0.081 and 0.056, respectively). CONCLUSION: Genetic variation in the vasopressin 1a receptor was found not to be associated with circulatory or renal failure, but with the presence of coagulation failure in patients with acute decompensation of liver cirrhosis and ACLF. PMID- 28350743 TI - Home-based drainage of refractory ascites by a permanent-tunneled peritoneal catheter can safely replace large-volume paracentesis. AB - BACKGROUND AND AIM: Refractory ascites has a poor prognosis. Recurrent large volume paracentesis is the current standard of care; however, it results in circulatory dysfunction and renal dysfunction, and hospitalization is commonly required. Transjugular intrahepatic portosystemic shunt placement is not an option in a substantial number of patients because of contraindications. The placement of a tunneled peritoneal drainage catheter has been shown to be effective in patients with malignant ascites. However, data in patients with nonmalignant refractory ascites are rare. PATIENTS AND METHODS: We followed 24 consecutive patients in whom tunneled peritoneal drainage catheters were placed in the Endoscopy Unit at Hannover Medical School between June 2013 and December 2014. RESULTS: Catheters were placed in 24 patients with refractory ascites in end-stage liver disease and with a contraindication to transjugular intrahepatic portosystemic shunt placement. Placement was technically successful in all patients. The dosage of diuretics could be reduced significantly. The number of paracentesis decreased from 2.2+/-1 to 0 per week, although the volume of daily ascites removal remained stable (2 l). Despite frequent drainage of ascites, kidney function, serum sodium, and serum albumin remained stable. Seven adverse events occurred in six (25%) patients. Five patients listed for liver transplantation underwent successful transplantation without a negative impact. CONCLUSION: The tunneled peritoneal drainage catheter placement is a viable and effective treatment alternative in patients with refractory ascites because of end-stage liver disease, reducing diuretic intake and the need for paracentesis. The procedure avoids hyponatremia, worsening kidney function, and albumin infusions without an increased risk of spontaneous bacterial peritonitis. PMID- 28350744 TI - Usefulness of the Glasgow-Blatchford score to predict 1-week mortality in patients with esophageal variceal bleeding. AB - OBJECTIVES: Esophageal variceal bleeding is one of the most severe complications of liver cirrhosis, with high mortality. However, there is no established scoring system for short-term mortality in patients with esophageal variceal bleeding. The aim of this study was to evaluate the usefulness of the Glasgow-Blatchford score (GBS), the Model for End-Stage Liver Disease (MELD) score, and the Child Pugh score for predicting short-term and hospital mortality in patients with esophageal variceal bleeding. METHODS: A total of 47 patients with esophageal variceal bleeding were studied between September 2009 and March 2015. The GBS, the MELD score, and the Child-Pugh score were assessed for their ability to predict 1- and 6-week mortality rates using a receiver operating characteristic curve. RESULTS: The 1- and 6-week mortality rates were 17.0 and 31.9%, respectively. The median GBS, MELD, and Child-Pugh scores were 13 (range: 4-19), 10 (range: 0-34), and 9 (range: 5-13), respectively. The GBS was superior to both the MELD and the Child-Pugh scores for prediction of 1-week mortality [area under the curve=0.82 (95% confidence interval: 0.66-0.98) vs. 0.71 (0.47-0.96) and 0.72 (0.53-0.91)]. The MELD score was superior to both the Child-Pugh score and the GBS for prediction of 6-week mortality [area under the curve=0.83 (95% confidence interval: 0.69-0.97) vs. 0.69 (0.52-0.85) and 0.67 (0.50-0.83)]. CONCLUSION: For 1-week mortality, the GBS was superior to the Child-Pugh and the MELD scores in patients with esophageal variceal bleeding. However, for 6-week mortality, the MELD score was superior in patients with esophageal variceal bleeding. PMID- 28350745 TI - The Irish Helicobacter pylori Working Group consensus for the diagnosis and treatment of H. pylori infection in adult patients in Ireland. AB - BACKGROUND: Irish eradication rates for Helicobacter pylori are decreasing and there is an increase in the prevalence of antibiotic-resistant bacteria. These trends call into question current management strategies. OBJECTIVE: To establish an Irish Helicobacter pylori Working Group (IHPWG) to assess, revise and tailor current available recommendations. METHODS: Experts in the areas of gastroenterology and microbiology were invited to join the IHPWG. Questions of relevance to diagnosis, first-line and rescue therapy were developed using the PICO system. A literature search was performed. The 'Grading of Recommendations Assessment, Development and Evaluation' approach was then used to rate the quality of available evidence and grade the resulting recommendations. RESULTS: Key resultant IHPWG statements (S), the strength of recommendation and quality of evidence include S8: standard triple therapy for 7 days' duration can no longer be recommended (strong and moderate). S9: 14 days of clarithromycin-based triple therapy with a high-dose proton pump inhibitor (PPI) is recommended as first-line therapy. Bismuth quadruple therapy for 14 days is an alternative if available (strong and moderate). S12: second-line therapy depends on the first-line treatment and should not be the same treatment. The options are (a) 14 days of levofloxacin-based therapy with high-dose PPI, (b) 14 days of clarithromycin based triple therapy with high-dose PPI or (c) bismuth quadruple therapy for 14 days (strong and moderate). S13: culture and antimicrobial susceptibility testing should be performed following two treatment failures (weak and low/very low). CONCLUSION: These recommendations are intended to provide the most relevant current best-practice guidelines for the management of H. pylori infection in adults in Ireland. PMID- 28350746 TI - Perceived stress as a risk factor for dyspepsia: a register-based cohort study. AB - OBJECTIVE: Dyspepsia is a common condition and has a huge impact on quality of life and working capacity, but its causes are not well understood. An association between stress and dyspepsia has been debated for decades, but the issue has not been resolved. We examined the 3-year risk of redeeming a proton-pump inhibitor or an H2-receptor antagonist as a proxy of dyspepsia according to the level of perceived stress. PARTICIPANTS AND METHODS: Perceived stress was measured in a general health survey of 16 124 Danes aged older than 16 years of age in 2010 using Cohen's Perceived Stress Scale. Data were linked individually to national registries, including the Danish National Prescription Registry. The risk of redeeming a proton-pump inhibitor or an H2-receptor antagonist for quintiles of stress level was estimated using Cox proportional hazard regression. RESULTS: In total, 2703 redeemed one of these drugs during the 33 months of follow-up. The cumulative incidence proportion of dyspepsia increased gradually, from 11.6 to 24.9%, with quintiles of stress. After full model adjustment, the four highest stress quintiles had a statistically significantly increased risk of redeeming a drug compared with the lowest stress quintile. The hazard ratios were 1.16 [95% confidence interval (CI): 1.00-1.34] for the second quintile, 1.21 (95% CI: 1.06 1.39) for the third quintile, 1.20 (95% CI: 1.05-1.38) for the fourth quintile, and 1.30 (95% CI: 1.12-1.50) for the fifth quintile. CONCLUSION: Higher levels of self-reported perceived everyday life stress increased the risk of redeeming a drug for dyspepsia significantly during 33 months of follow-up. PMID- 28350747 TI - Short article: Small intestinal mucosal injury in patients taking chemotherapeutic agents for solid cancers. AB - OBJECTIVE: Chemotherapy for cancer is a systemic treatment often associated with side effects than can be debilitating and, in some cases, life-threatening. Few data are available on intestinal enterotoxicity. Wireless video capsule endoscopy (VCE) is a noninvasive method of imaging the small intestine. This study presents the results of VCE in patients with solid tumors undergoing antineoplastic regimens with agents, notably for toxicity for the gastrointestinal mucosa (i.e. carboplatin, cyclophosphamide, 5-fluorouracil, methotrexate, and cisplatin). MATERIALS AND METHODS: The capsule endoscopy procedure was performed 4-13 days after the end of the antineoplastic course. Each patient received a polyethylene glycol solution (1000 mg*2 in 2 l of water) for bowel preparation and fasted for 10 h before ingestion of the capsule. Videos were evaluated by one operator, supervised by a second operator, and conclusions were drawn by an expert reader. RESULTS: Twenty (age range: 38-77 years) patients were evaluated. The cecum was reached in 70% before exhaustion of the battery. The video capsule showed small widespread intestinal ulcerations in 25% and erosions in only one patient. The villus architecture appeared normal in all. VCE detected metastases in one patient with a melanoma. Few patients had more than one lesion. All capsules were passed in the stool. CONCLUSION: Our results suggest that chemotherapy in patients with solid cancers is associated with minimal visual small bowel injury. Factors other than damage of the intestinal mucosa causing loss of epithelium are likely involved in gastrointestinal toxicity and related symptoms. PMID- 28350748 TI - Short article: Mortality and differential diagnoses of villous atrophy without coeliac antibodies. AB - OBJECTIVE: Villous atrophy (VA) of the small bowel is mainly related to coeliac disease (CD), whose diagnosis is made on the basis of positive endomysial/tissue transglutaminase antibodies while on a gluten-containing diet in the vast majority of patients. However, VA can also occur in other conditions whose epidemiology is little known. Our aim was to study the epidemiology and clinical features of these rare enteropathies. PATIENTS AND METHODS: Clinical and laboratory data of all the patients with VA directly diagnosed in our centre in the last 15 years were collected and statistically analysed. RESULTS: Between September 1999 and June 2015, 274 patients were diagnosed with VA. A total of 260 patients were also positive to coeliac antibodies; the other 14 had VA, but no IgA endomysial antibodies: five had common variable immunodeficiency, three had dermatitis herpetiformis, two had IgA deficiency associated with CD, one had abdominal lymphoma, one had unclassified sprue, one had olmesartan-associated enteropathy and one had seronegative CD. Mortality was 6.0 deaths per 100 person years (95% confidence interval: 2.2-16) in patients with VA but negative coeliac antibodies, whereas only 0.2 deaths per 100 person years (95% confidence interval: 0.1-0.6) occurred in coeliac patients. CONCLUSION: Patients with VA and negative endomysial antibodies are rare. However, these forms of VA identify specific causes that can be diagnosed. These patients are affected by a very high mortality. PMID- 28350749 TI - Effect of threatening life experiences and adverse family relations in ulcerative colitis: analysis using structural equation modeling and comparison with Crohn's disease. AB - BACKGROUND AND AIMS: We published that threatening life experiences and adverse family relations impact Crohn's disease (CD) adversely. In this study, we examine the influence of these stressors in ulcerative colitis (UC). PATIENTS AND METHODS: Patients completed demography, economic status (ES), the Patient-Simple Clinical Colitis Activity Index (P-SCCAI), the Short Inflammatory Bowel Disease Questionnaire (SIBDQ), the Short-Form Health Survey (SF-36), the Brief Symptom Inventory (BSI), the Family Assessment Device (FAD), and the List of Threatening Life Experiences (LTE). Analysis included multiple linear and quantile regressions and structural equation modeling, comparing CD. RESULTS: UC patients (N=148, age 47.55+/-16.04 years, 50.6% women) had scores [median (interquartile range)] as follows: SCAAI, 2 (0.3-4.8); FAD, 1.8 (1.3-2.2); LTE, 1.0 (0-2.0); SF 36 Physical Health, 49.4 (36.8-55.1); SF-36 Mental Health, 45 (33.6-54.5); Brief Symptom Inventory-Global Severity Index (GSI), 0.5 (0.2-1.0). SIBDQ was 49.76+/ 14.91. There were significant positive associations for LTE and SCAAI (25, 50, 75% quantiles), FAD and SF-36 Mental Health, FAD and LTE with GSI (50, 75, 90% quantiles), and ES with SF-36 and SIBDQ. The negative associations were as follows: LTE with SF-36 Physical/Mental Health, SIBDQ with FAD and LTE, ES with GSI (all quantiles), and P-SCCAI (75, 90% quantiles). In structural equation modeling analysis, LTE impacted ES negatively and ES impacted GSI negatively; LTE impacted GSI positively and GSI impacted P-SCCAI positively. In a split model, ES had a greater effect on GSI in UC than CD, whereas other path magnitudes were similar. CONCLUSION: Threatening life experiences, adverse family relations, and poor ES make UC patients less healthy both physically and mentally. The impact of ES is worse in UC than CD. PMID- 28350750 TI - Family history, comorbidity, smoking and other risk factors in microscopic colitis: a case-control study. AB - OBJECTIVES: Data on heredity, risk factors and comorbidity in microscopic colitis, encompassing collagenous colitis (CC) and lymphocytic colitis (LC), are limited. AIM: The aim was to carry out a case-control study of family history, childhood circumstances, educational level, marital status, smoking and comorbidity in microscopic colitis. METHODS: A postal questionnaire was sent in 2008-2009 to microscopic colitis patients resident in Sweden and three population based controls per patient, matched for age, sex and municipality. RESULTS: Some 212 patients and 627 controls participated in the study. There was an association with a family history of microscopic colitis in both CC [odds ratio (OR): 10.3; 95% confidence interval (CI): 2.1-50.4, P=0.004] and LC (OR not estimated, P=0.008). Current smoking was associated with CC [OR: 4.7; 95% CI: 2.4-9.2, P<0.001) and LC (OR: 3.2; 95% CI: 1.6-6.7, P=0.002). The median age at diagnosis was around 10 years earlier in ever-smokers compared with never-smokers.CC was associated with a history of ulcerative colitis (UC) (OR: 8.7, 95% CI: 2.2-33.7, P=0.002), thyroid disease (OR: 2.3; 95% CI: 1.1-4.5, P=0.02), coeliac disease (OR: 13.1; 95% CI: 2.7-62.7, P=0.001), rheumatic disease (OR 1.9; 95% CI: 1.0 3.5, P=0.042) and previous appendicectomy (OR: 2.2; 95% CI: 1.3-3.8, P=0.003), and LC with UC (OR: 6.8; 95% CI: 1.7-28.0, P=0.008), thyroid disease (OR: 2.4; 95% CI: 1.1-5.4, P=0.037) and coeliac disease (OR: 8.7; 95% CI: 2.8-26.7, P<0.001). CONCLUSION: Association with a family history of microscopic colitis indicates that familial factors may be important. The association with a history of UC should be studied further as it may present new insights into the pathogenesis of microscopic colitis and UC. PMID- 28350751 TI - Time trends in the epidemiology and outcome of perianal fistulizing Crohn's disease in a population-based cohort. AB - OBJECTIVE: Perianal disease is a debilitating condition that frequently occurs in Crohn's disease (CD) patients. It is currently unknown whether its incidence has changed in the era of frequent immunomodulator use and biological availability. We studied the incidence and outcome of perianal and rectovaginal fistulas over the past two decades in our population-based Inflammatory Bowel Disease South Limburg cohort. PATIENTS AND METHODS: All 1162 CD patients registered in the Inflammatory Bowel Disease South-Limburg registry were included. The cumulative probabilities of developing a perianal and rectovaginal fistula were compared between three eras distinguished by the year of CD diagnosis: 1991-1998, 1999 2005 and 2006-2011. Second, clinical risk factors and the risk of fistula recurrence were determined. RESULTS: The cumulative 5-year perianal fistula rate was 14.1% in the 1991-1998 era, 10.4% in the 1999-2005 era and 10.3% in the 2006 2011 era, P=0.70. Colonic disease was associated with an increased risk of developing perianal disease, whereas older age was associated with a decreased risk (both P<0.01). Over time, more patients were exposed to immunomodulators or biologicals before fistula diagnosis (18.5 vs. 32.1 vs. 52.1%, respectively, P=0.02) and started biological therapy thereafter (18.6 vs. 34.1 vs. 54.0%, respectively, P<0.01). The cumulative 5-year perianal fistula recurrence rate was not significantly different between eras (19.5 vs. 25.5 vs. 33.1%, P=0.28). In contrast, the cumulative 5-year rectovaginal rate attenuated from 5.7% (the 1991 2005 era) to 1.7% (the 2006-2011 era), P=0.01. CONCLUSION: Over the past two decades, the risk of developing a perianal fistula was stable, as well as its recurrence rate, underlining the lasting need for improving treatment strategies for this invalidating condition. PMID- 28350752 TI - The yield of endoscopic investigation for unintentional weight loss. AB - AIM: The aim of this study was to assess the yield of endoscopic evaluation in isolated unintentional weight loss (UWL) patients compared with patients with weight loss and additional symptoms or signs. PATIENTS AND METHODS: A retrospective review of all patients who underwent an endoscopic evaluation for the investigation of UWL at Soroka University Medical Center between 2006 and 2012. Data on clinical indication, endoscopic, and laboratory finding were retrieved. Severe inflammation, ulcers, achalasia, and neoplasias were considered clinically significant endoscopic findings (CSEF) that could explain weight loss. Detection rates of CSEF were compared between endoscopic studies for which UWL was the sole indication (group 1) and those performed for UWL and at least one other indication (group 2). RESULTS: During the study period, 1843 patients with UWL were evaluated with 2098 endoscopic procedures. Of these, 1540 underwent esophagogastroduodenoscopy (EGD) and 558 underwent colonoscopy. EGD was performed in 229 (14.8%) patients in group 1 (mean age: 60.9+/-16.4, 43.3% men), and in 1311 (85.2%) patients in group 2 (mean age: 60.5+/-18.5, 45% men). Pathological endoscopic findings were identified in 712 (46%) EGDs. Of these, 155 (10%) studies detected significant outcomes: six (3.9%) in group 1 and 149 (96.1%) in group 2. Of the 558 colonoscopies performed, 105 (18.8%) were performed in group 1 (mean age: 61.7+/-17.5, 43% men) and 453 (82.2%) in group 2 patients (mean age: 62.9+/-14.6, 49% men). Abnormal findings were found in 190 (33.8%) of the procedures. CSEF were found in 34 (6%) patients: two in group 1 and 32 in group 2. CONCLUSION: The diagnostic yield of endoscopy for investigation of patients with UWL is non-negligible, and should be considered as part of its baseline evaluation, especially in older individuals and those who present with other gastrointestinal manifestations. PMID- 28350754 TI - Letter to the Editor. PMID- 28350753 TI - What to eat and drink in the festive season: a pan-European, observational, cross sectional study. AB - BACKGROUND: Digestive discomfort after meals is common in the community, especially during the festive season. It is uncertain whether this is related to intake of either high-calorie or high-fat foods or, alternatively, intake of specific foods. This prospective, cross-sectional study tested the hypothesis that the risk of reflux or dyspepsia is associated with the fat content of the meal independent of caloric load in a 'real-life' setting. MATERIALS AND METHODS: Four festive meals were served to delegates attending a conference on four consecutive days. Test meals had the same volume, but varied in calorie and fat content. Study procedures and symptoms were monitored using a mobile application (SymTrack). The effect of alcoholic compared with nonalcoholic drinks was also assessed. Primary outcome was the occurrence of reflux or dyspeptic symptoms. Fullness was documented by a visual analogue scale. RESULTS: A total of 84/120 (70%) delegates aged 22-69 years consented to participate. At screening, 22 (31%) participants reported at least mild symptoms on the Leuven Dyspepsia Questionnaire. Specific ingredients did not appear to impact on postprandial symptoms. All high-calorie dinners [British, German, Italian (with alcohol)] induced more symptoms than the low-fat, low-calorie Czech dinner [odds ratio: 2.6, 95% confidence interval (CI): 0.97-6.9 (P=0.058), 1.5 (0.3-3.8), and 2.8 (0.7-10.5), respectively]. Self-reported fullness after the high-fat, high calorie British dinner was higher by 23/100 (95% CI: 4-42, P=0.016) with respect to low-fat, low-calorie Czech and German dinners. CONCLUSION: Study participants tolerated a range of food and drink well. Reflux or dyspeptic symptoms were least likely after the low-fat, low-calorie meal. Fullness was increased after the high fat, high-calorie dinner, but not low-fat meals. These results will help the public to make evidence-based dietary choices during the carnival season! PMID- 28350755 TI - Reply to Hjorthoj et al. PMID- 28350757 TI - Acupuncture for menopausal hot flashes: clinical evidence update and its relevance to decision making. AB - OBJECTIVE: There is conflicting evidence on the efficacy and effectiveness of acupuncture for menopausal hot flashes. This article synthesizes the best available evidence for when women are considering whether acupuncture might be useful for menopausal hot flashes. METHODS: We searched electronic databases to identify randomized controlled trials and systematic reviews of acupuncture for menopausal hot flushes. RESULTS: The overall evidence demonstrates that acupuncture is effective when compared with no treatment, but not efficacious compared with sham. Methodological challenges such as the complex nature of acupuncture treatment, the physiological effects from sham, and the significant efficacy of placebo therapy generally in treating hot flashes all impact on these considerations. CONCLUSIONS: Acupuncture improves menopausal hot flashes compared with no treatment; however, not compared with sham acupuncture. This is also consistent with the evidence that a range of placebo interventions improve menopausal symptoms. As clinicians play a vital role in assisting evidence informed decisions, we need to ensure women understand the evidence and can integrate it with personal preferences. Some women may choose acupuncture for hot flashes, a potentially disabling condition without long-term adverse health consequences. Yet, women should do so understanding the evidence, and its strengths and weaknesses, around both effective medical therapies and acupuncture. Likewise, cost to the individual and the health system needs to be considered in the context of value-based health care. PMID- 28350758 TI - Effects of ultralow topical estriol dose on vaginal health and quality of life in postmenopausal women who underwent surgical treatment for pelvic organ prolapse. AB - OBJECTIVE: To evaluate the efficacy of low concentrations of vaginal estriol gel in postmenopausal women with pelvic static disorders before and after vaginal surgical treatment, assessing vaginal health, sexual function, and quality of life (QoL). METHODS: Women affected by genital prolapse were enrolled. Vaginal health, QoL, and sexual function were investigated at baseline (T0), before surgery (T1), and 13 weeks after surgery (T2). At baseline, participants were randomized 1:1. Women in group A (38 women) were treated daily with vaginal gel containing 50 MUg estriol for 12 weeks and women in group B (37 women) did not receive any estrogen treatment. After this period and before surgery, a first examination was carried out (T1). One week after surgical treatment, group A underwent randomization 1:1 to group A1 repeating estriol vaginal gel for 12 weeks, and group A2 discontinuing the estrogen treatment. The second follow-up examination (T2) was performed at the 13th week after surgery. RESULTS: All aspects of vaginal health improved in group A on estriol before surgery with respect to baseline (P < 0.001). After surgery, 17 participants of group A1, 16 of group A2, and 30 of group B completed the study. Group A1 (on estriol plus surgery) further improved with respect to the presurgery estriol treatment (P < 0.01). Moreover, group A2 (T2) experienced a worsening of vaginal health versus intragroup presurgery estriol treatment (P < 0.01), and versus intergroup surgical estriol treatment (P < 0.05). QoL improved in women only after surgery, with (P < 0.01) or without (P < 0.05) estriol treatment. Finally, the sexual function of participants on estriol before surgery did not change. On the contrary, it improved after surgery in both participants on estriol (P < 0.001) and without estriol (P < 0.01). Moreover, surgical estriol participants had a better score than surgical no-estriol participants (P < 0.05). CONCLUSIONS: Estriol vaginal gel (0.005%) administration significantly improved the vaginal health of natural postmenopausal women before and after vaginal surgery. Both sexual health and QoL also significantly improved after surgery. PMID- 28350759 TI - Resveratrol supplementation reduces pain experience by postmenopausal women. AB - OBJECTIVE: Pain is a common complaint among postmenopausal women. It has been postulated that vascular dysfunction caused by estrogen decline at menopause plays a key role in the initiation and progression of degradative joint disease, namely age-related osteoarthritis. We evaluated whether supplementation with resveratrol, a phytoestrogen, could improve aspects of well-being such as chronic pain that is commonly experienced by postmenopausal women. METHODS: A 14-week randomized, double-blind, placebo-controlled intervention with trans-resveratrol (75 mg, twice daily) was conducted in 80 healthy postmenopausal women. Aspects of well-being, including pain, menopausal symptoms, sleep quality, depressive symptoms, mood states, and quality of life were assessed by Short form-36 at baseline and at the end of treatment. Rating scales were averaged to provide a composite score representing overall well-being. Cerebral vasodilator responsiveness to hypercapnia was also assessed as a surrogate marker for cerebrovascular function. RESULTS: Compared with placebo treatment, there was a significant reduction in pain and an improvement in total well-being after resveratrol supplementation. Both benefits, including measures of quality of life, correlated with improvements in cerebrovascular function. CONCLUSIONS: Our preliminary findings indicate potential for resveratrol treatment to reduce chronic pain in age-related osteoarthritis. Resveratrol consumption may also boost perceptions of well-being in postmenopausal women. Further investigation to elucidate underlying mechanisms is warranted. PMID- 28350761 TI - Polycystic ovarian syndrome and the risk of subsequent primary ovarian insufficiency: a nationwide population-based study. AB - OBJECTIVE: To evaluate the risk of subsequent primary ovarian insufficiency (POI) amongst patients with a history of polycystic ovarian syndrome (PCOS). METHODS: This nationwide, population-based study is an inspection and review of data from the 1998 to 2012 Taiwan National Health Insurance Research Database. In a sample of 1,000,000 randomly sampled individuals, women with PCOS (exposure group; n = 7,049) and women without PCOS (contrast group; n = 70,490) were compared. Women initially diagnosed with PCOS at less than 15 or more than 35 years of age were excluded. Each woman with PCOS was age-matched to 10 women without PCOS. The diagnoses of PCOS and POI (coded using International Classification of Diseases, 9th Revision, Clinical Modification) were further confirmed with blood test results and ultrasonographic findings to ensure the accuracy of the diagnoses. RESULTS: POI occurred more among women with PCOS compared with women without PCOS (3.73% vs 0.44%; P < 0.001). Using Kaplan-Meier survival analysis, the POI-free survival rates were significantly different between the exposure and contrast groups (P < 0.001). During 10 years of follow-up, Cox proportional-hazard analysis revealed that the risk for POI was significantly higher in the exposure than in the contrast group (hazard ratio [HR] 8.64, 95% confidence interval [CI] 7.33-10.18) and remained similar after adjustment for covariates (adjusted HR 8.31, 95% CI 7.05-9.81). Compared with that of women without PCOS, the risk of POI was even higher for women with PCOS who did not receive metformin treatment (adjusted HR 9.93, 95% CI 8.28-11.90). However, the risk for POI was significantly reduced for women with PCOS who received metformin treatment (adjusted HR 5.66, 95% CI 4.36-7.35). CONCLUSIONS: As a possible precursor stage, prior PCOS is a significant and independent risk factor for development of POI. The use of metformin reduces the risk of POI. PMID- 28350760 TI - Involvement of HSP70 and HO-1 in the protective effects of raloxifene on multiple organ dysfunction syndrome by endotoxemia in ovariectomized rats. AB - OBJECTIVE: Accumulating evidence demonstrates that raloxifene, a selective estrogen receptor modulator, possesses anti-inflammatory action. This study evaluates the preventive effects of long-term treatment of raloxifene on acute inflammation and multiple organ dysfunction syndrome (MODS) in ovariectomized (OVX) rats with endotoxemia and its underlying mechanism of action. METHODS: Adult female rats were OVX bilaterally to induce estrogen insufficiency. OVX rats were administered with raloxifene (1 mg/kg, gavage, once daily) for 8 weeks, beginning 1 week after surgery, followed by induction of sepsis via intravenous infusion of lipopolysaccharides (LPS; 30 mg/kg) for 4 hours. LPS-activated RAW 264.7 cells were used to investigate the mechanism of raloxifene. RESULTS: Ovariectomy amplified the endotoxemia-induced hypotensive effect, MODS, and superoxide anion production in the myocardium. The levels of inducible nitric oxide synthase, high mobility group box 1, and nuclear factor-kappaB p65 protein increased in OVX rats 6 hours after LPS initiation. Raloxifene mitigated MODS, together with reduced inducible nitric oxide synthase induction and fewer superoxide anions in organs. Raloxifene induced high levels of heat shock protein 70 (HSP70) and heme oxygenase 1 (HO-1), which are associated with an increase in the transcription factor heat shock factor-1 and Nrf-2, respectively. Pretreatment with quercetin, an inhibitor of HSP70, or SnPP, an inhibitor of HO 1, reversed the protective effects of raloxifene in septic OVX rats and LPS activated macrophages. CONCLUSIONS: Long-term treatment with raloxifene reduces the severity of sepsis in OVX rats, attributed from up-regulation of HSP70 and HO 1 to exert the antioxidant and anti-inflammatory capacities. These findings provide new insights into bacterial infection during menopause and the molecular mechanism of raloxifene. PMID- 28350762 TI - Let Your Voice Be Heard. PMID- 28350763 TI - Commentary on "Autogenic Drainage in Children With Cystic Fibrosis". PMID- 28350764 TI - Handgrip Strength: A Population-Based Study of Norms and Age Trajectories for 3- to 17-Year-Olds. AB - PURPOSE: To provide normative values and equations for grip strength obtained from a population-based sample of individuals 3 to 17 years of age. METHODS: This cross-sectional study used grip strength data from 2706 participants (49.2% males, 91% right-hand dominant) in the normative phase of the National Institutes of Health Toolbox project. RESULTS: Analyses showed greater strength in the dominant hand in boys and with each yearly increase in age. Normative data are presented separately for each side, sex, and age. Separate regression equations using age and weight as explanatory variables of grip strength are provided for each side by sex. CONCLUSIONS: The normative data can serve as a guide for interpreting grip strength measurements. The trajectories can be used to investigate the effect of various pathologies and conditions on grip strength during physical maturation. PMID- 28350765 TI - Commentary on "Handgrip Strength: A Population-Based Study of Norms and Age Trajectories for 3- to 17-Year-Olds". PMID- 28350766 TI - Cardiac Autonomic System Response to Submaximal Test in Children With Cerebral Palsy. AB - AIM: To describe the heart rate (HR) and heart rate variability at rest, during a submaximal treadmill test and at rest posttreadmill in children with cerebral palsy (CP). METHODS: Twenty children (6-11 years) with CP participated, who had Gross Motor Function Classification System levels I to III. The HR was monitored for 5 minutes seated, during a submaximal treadmill test, and after 5 minutes rest posttreadmill. Outcome variables were HR and the square root of the mean squared differences of successive differences between adjacent heart beats (RMSSD). RESULTS: HR increased during the last stage of the treadmill test compared with rest. RMSSD was reduced during the last 2 minutes of the treadmill test compared with rest. The HR and RMSSD mean value at the second minute posttest were not significantly different from the pretreadmill rest value. INTERPRETATION: The cardiac system in children with CP responded to the submaximal testing. PMID- 28350767 TI - Commentary on "Cardiac Autonomic System Response to Submaximal Test in Children With Cerebral Palsy". PMID- 28350768 TI - Commentary on "Position Between Trunk and Pelvis During Gait Depending on the Gross Motor Function Classification System". PMID- 28350769 TI - Gait Training With Visual Feedback and Proprioceptive Input to Reduce Gait Asymmetry in Adults With Cerebral Palsy: A Case Series. AB - PURPOSE: The purpose of this case series was to investigate the feasibility of using visual feedback on gait asymmetry during gait retraining and whether this leads to reduced asymmetry, improvement in gait speed, cost of walking, and dynamic balance in ambulant adults with cerebral palsy (CP). METHODS: Five adults with CP, who were ambulatory and had step length or stance time asymmetry, trained for 18 sessions on a split-belt treadmill with concurrent visual feedback from a virtual environment. Training also included overground gait training to encourage transfer of learning. RESULTS: All participants reduced gait asymmetry and improved on outcomes at posttest and follow-up. CONCLUSIONS: Outcome measures and training protocols were feasible in this sample of convenience of adults with CP who were ambulatory and who did not have visual impairment. The adults with CP in this study demonstrated individual improvements in gait and balance following training. PMID- 28350770 TI - Commentary on "Gait Training With Visual Feedback and Proprioceptive Input to Reduce Gait Asymmetry in Adults With Cerebral Palsy: A Case Series". PMID- 28350771 TI - Concurrent Validity Between Live and Home Video Observations Using the Alberta Infant Motor Scale. AB - PURPOSE: Serial assessment of gross motor development of infants at risk is an established procedure in neonatal follow-up clinics. Assessments based on home video recordings could be a relevant addition. METHODS: In 48 infants (1.5-19 months), the concurrent validity of 2 applications was examined using the Alberta Infant Motor Scale: (1) a home video made by parents and (2) simultaneous observation on-site by a pediatric physical therapist. Parents' experiences were explored using a questionnaire. RESULTS: The intraclass correlation coefficient agreement between live and home video assessment was 0.99, with a standard error of measurement of 1.41 items. Intra- and interrater reliability: intraclass correlation coefficients were more than 0.99. According to 94% of the parents, recording their infant's movement repertoire was easy to perform. CONCLUSION: Assessing the Alberta Infant Motor Scale based on home video recordings is comparable to assessment by live observation. The video method is a promising application that can be used with low burden for parents and infants. PMID- 28350772 TI - Commentary on "Concurrent Validity Between Live and Home Video Observations Using the Alberta Infant Motor Scale". PMID- 28350773 TI - Validity of an Accelerometer Used to Measure Step Count in Children With Idiopathic Toe Walking. AB - PURPOSE: To assess the validity of accelerometer use in children with idiopathic toe walking (ITW). METHODS: Seventy-five children, 2 to 13 years old, with ITW were videotaped ambulating 50 ft wearing a NL-1000 accelerometer. Because of concerns for accelerometer accuracy in young children, 2 groups were created: 5 years or younger (n = 45) and 6 years or older (n = 30). Step counts recorded via accelerometer and video were compared and correlated. RESULTS: There was a significant difference in accelerometer and video step counts for 2- to 5-year olds (W = 72.00, P < .001). No significant difference was found for 6- to 13-year olds (W = 65.00, P = .24). Spearman rho values were 0.78 and 0.92 for the 5 years or younger and 6 years or older groups, respectively. CONCLUSION: Accelerometers accurately count steps in 6- to 13-year-olds with ITW but are inaccurate in 2- to 5-year-olds. PMID- 28350774 TI - Commentary on "Validity of an Accelerometer Used to Measure Step Count in Children With Idiopathic Toe Walking". PMID- 28350775 TI - Postsurgical Physical Therapy Management of Congenital Muscular Torticollis. AB - PURPOSE: To present 2 cases with severe congenital muscular torticollis and describe postsurgical physical therapy management. DESCRIPTION: Two children diagnosed with severe congenital muscular torticollis underwent surgical release of the involved sternocleidomastoid muscle with subsequent physical therapy. Presurgical examination findings, surgical technique, and postsurgical rehabilitation guidelines are described. RESULTS: Both cases achieved full range of motion and symmetrical muscle strength. Functionally, they were able to maintain consistent midline posture, perform transitions with symmetrical head righting, and demonstrate age-appropriate motor skills. CLINICAL IMPLICATIONS: Children with surgical management of congenital muscular torticollis tend to have more severe involvement of the sternocleidomastoid. Prolonged experience in atypical postures may result in potential asymmetrical development of visual, vestibular, and proprioceptive systems. Perception of midline was reestablished through integration of visual, vestibular, and proprioceptive stimuli. VIDEO ABSTRACT: For more insights from the authors, access Supplemental Digital Content 1, at http://links.lww.com/PPT/A141. PMID- 28350776 TI - School-Based Work Capacity Evaluation in Young People With Intellectual Disabilities: 2 Case Reports. AB - PURPOSE: These case reports examine the application of a work capacity/work hardening model to increase work capacity in young people with disabilities. KEY POINTS: Examination, evaluation, interventions, and outcomes are described for 2 teenagers with intellectual disability. This approach is novel in that it uses functional capacity evaluation concepts used in ergonomic/occupational health contexts and applies them to youth with disabilities in educational settings. CONCLUSION: These concepts expand the scope of practice for physical therapists in school settings and potentially increase work opportunities for youth with disabilities. PMID- 28350778 TI - Pediatric Rehabilitation Services for Children With Cerebral Palsy: What Can Existing Data Sources Tell Us? AB - Knowledge about associated service utilization patterns and positive outcomes in children with cerebral palsy (CP) of varying levels of severity is a national priority. Families, clinicians, program directors, and policy makers need this information for clinical decision-making and service planning. Existing data sources in the United States that contain information about children with CP, their health, function, well being, and utilization of health services may add to our existing knowledge. We provide a summary of fourteen national, state, and local sources' data: where the data come from, challenges and/or specific considerations when using or accessing information, and specific data elements included. Currently available sources of data can provide meaningful information for policy, practice, and program development. We propose questions for future inquiry and suggest elements that may be useful for when developing data sources specific to physical therapy and individuals with CP. A physical therapy specific registry is warranted. PMID- 28350777 TI - Understanding Brain Reorganization in Infants With Perinatal Stroke Through Neuroexcitability and Neuroimaging. AB - PURPOSE: The primary aim of this proposed study is to evaluate brain reorganization patterns in infants with perinatal stroke between 3 and 5 months of age using transcranial magnetic stimulation and magnetic resonance imaging, with the addition of the General Movements Assessment. A secondary aim is to demonstrate feasibility and safety of infant-appropriate brain assessment protocols. METHODS: Ten infants with perinatal stroke will be enrolled. In this exploratory study, infants will first receive magnetic resonance imaging scanning during natural sleep to examine their corticospinal tract integrity. Infants will then receive transcranial magnetic stimulation to assess their corticomotor excitability. A General Movements Assessment video of at least 5 minutes will also be recorded. DISCUSSION: Study results will enhance our understanding of brain reorganization in infants with perinatal stroke. We expect these results will also guide the development of early interventions designed to mitigate maladaptive neuroplastic changes and improve long-term motor outcomes. PMID- 28350780 TI - Johns Hopkins Psychiatry at 100 Years. PMID- 28350779 TI - Response to "Developing a Clinical Protocol for Habitual Physical Activity Monitoring in Youth With Cerebral Palsy". PMID- 28350781 TI - Introduction to 100 Years of Psychiatry at Johns Hopkins. PMID- 28350782 TI - Acknowledging the Risk for Traumatic Brain Injury in Women Veterans. AB - Since the Iraq and Afghanistan wars began, an unprecedented number of women have been engaging in combat operations. Likewise, the number of women using Department of Veterans Affairs (VA) services has doubled since 2001. Military service, and deployment to combat in particular, poses certain risks for traumatic brain injury (TBI)-for all service members. However, women may have additional military and nondeployment risk factors such as intimate partner violence (IPV). We briefly review the definition and classification issues related to TBI, as well as common acute and chronic health symptoms after TBI. Specific sex differences in prognosis after TBI, in particular the neurobehavioral symptoms, are also reviewed. We then focus on the emerging literature regarding TBI in women veterans including the etiologies, outcomes, and unique challenges this population faces. The article concludes with suggestions for enhanced screening by VA and non-VA providers alike, as well as directions for future research and clinical inquiry. PMID- 28350783 TI - Helping Alliance and Unmet Needs in Routine Care of People With Severe Mental Illness Across Europe: A Prospective Longitudinal Multicenter Study. AB - The helping alliance (HA) refers to the collaborative bond between patient and therapist, including shared goals and tasks. People with severe mental illness have a complex mixture of clinical and social needs. Using mixed-effects regression, this study examined in 588 people with severe mental illness whether an increase in the HA is associated with fewer unmet needs over time, and whether change in the HA precedes change in unmet needs. It was found that a reduction in unmet needs was slower in patients with higher HA (B = 0.04, p < 0.0001) only for patient-rated measures. Improvement in both patient-rated and staff-rated HA over time was associated with fewer subsequent patient-rated (B = -0.10, p < 0.0001) and staff-rated (B = -0.08, p = 0.0175) unmet needs. With positive changes in the HA preceding fewer unmet needs, findings provide further evidence for a causal relationship between alliance and outcome in the treatment of people with severe mental illness. PMID- 28350784 TI - Targeting Smoothened Sensitizes Gastric Cancer to Chemotherapy in Experimental Models. AB - BACKGROUND The Hedgehog pathway receptor smoothened (SMO) has critical roles in tumor progression. However, whether SMO is a key factor regulating gastric cancer chemotherapy resistance is unknown. MATERIAL AND METHODS We investigated the potential functions of SMO in inducing gastric cancer paclitaxel resistance in clinical samples, gastric cancer cell lines (424GC and AGS), and subcutaneous syngeneic mouse models. RESULTS We found high SMO expression in paclitaxel resistant gastric cancer clinical samples. Paclitaxel gastric cancer cells had higher SMO expression than in drug-sensitive cells. Upregulating SMO expression induced paclitaxel resistance in gastric cells lines via enhancing cell proliferation and inhibiting apoptosis. The combination of IPI-926, an inhibitor of SMO, with paclitaxel decreased cell viability of paclitaxel-resistant gastric cancer cells in vitro and controlled tumor growth in animal models. CONCLUSIONS The Hedgehog pathway receptor SMO is an important regulator of gastric cancer paclitaxel resistance and could be a target for sensitizing paclitaxel-resistant tumors. PMID- 28350785 TI - The PICTURE study: diagnostic accuracy of multiparametric MRI in men requiring a repeat prostate biopsy. AB - BACKGROUND: Transrectal prostate biopsy has limited diagnostic accuracy. Prostate Imaging Compared to Transperineal Ultrasound-guided biopsy for significant prostate cancer Risk Evaluation (PICTURE) was a paired-cohort confirmatory study designed to assess diagnostic accuracy of multiparametric magnetic resonance imaging (mpMRI) in men requiring a repeat biopsy. METHODS: All underwent 3 T mpMRI and transperineal template prostate mapping biopsies (TTPM biopsies). Multiparametric MRI was reported using Likert scores and radiologists were blinded to initial biopsies. Men were blinded to mpMRI results. Clinically significant prostate cancer was defined as Gleason ?4+3 and/or cancer core length ?6 mm. RESULTS: Two hundred and forty-nine had both tests with mean (s.d.) age was 62 (7) years, median (IQR) PSA 6.8 ng ml (4.98-9.50), median (IQR) number of previous biopsies 1 (1-2) and mean (s.d.) gland size 37 ml (15.5). On TTPM biopsies, 103 (41%) had clinically significant prostate cancer. Two hundred and fourteen (86%) had a positive prostate mpMRI using Likert score ?3; sensitivity was 97.1% (95% confidence interval (CI): 92-99), specificity 21.9% (15.5-29.5), negative predictive value (NPV) 91.4% (76.9-98.1) and positive predictive value (PPV) 46.7% (35.2-47.8). One hundred and twenty-nine (51.8%) had a positive mpMRI using Likert score ?4; sensitivity was 80.6% (71.6-87.7), specificity 68.5% (60.3 75.9), NPV 83.3% (75.4-89.5) and PPV 64.3% (55.4-72.6). CONCLUSIONS: In men advised to have a repeat prostate biopsy, prostate mpMRI could be used to safely avoid a repeat biopsy with high sensitivity for clinically significant cancers. However, such a strategy can miss some significant cancers and overdiagnose insignificant cancers depending on the mpMRI score threshold used to define which men should be biopsied. PMID- 28350786 TI - Methylation of MYLK3 gene promoter region: a biomarker to stratify surgical care in ovarian cancer in a multicentre study. AB - BACKGROUND: Survival benefit from surgical debulking of ovarian cancer (OC) is well established, but some women, despite total macroscopic clearance of disease, still have poor prognosis. We aimed to identify biomarkers to predict benefit from conventional surgery. METHODS: Clinical data from women debulked for high stage OC were analysed (Hammersmith Hospital, London, UK; 2001-2014). Infinium's HumanMethylation27 array interrogated tumour DNA for differentially methylated CpG sites, correlated to survival, in patients with the least residual disease (RD; Hammersmith Array). Validation was performed using bisulphite pyrosequencing (Charite Hospital, Berlin, Germany cohort) and The Cancer Genome Atlas' (TCGA) methylation data set. Kaplan-Meier curves and Cox models tested survival. RESULTS: Altogether 803 women with serous OC were studied. No RD was associated with significantly improved overall survival (OS; hazard ratio (HR) 1.25, 95% CI 1.06-1.47; P=0.0076) and progression-free survival (PFS; HR 1.23, 95% CI 1.05 1.43; P=0.012; Hammersmith database n=430). Differentially methylated loci within FGF4, FGF21, MYLK2, MYLK3, MYL7, and ITGAE associated with survival. Patients with the least RD had significantly better OS with higher methylation of MYLK3 (Hammersmith (HR 0.51, 95% CI 0.31-0.84; P=0.01), Charite (HR 0.46, 95% CI 0.21 1.01; P=0.05), and TCGA (HR 0.64, 95% CI 0.44-0.93; P=0.02)). CONCLUSIONS: MYLK3 methylation is associated with improved OS in patients with the least RD, which could potentially be used to determine response to surgery. PMID- 28350787 TI - Quality-adjusted survival with combination nal-IRI+5-FU/LV vs 5-FU/LV alone in metastatic pancreatic cancer patients previously treated with gemcitabine-based therapy: a Q-TWiST analysis. AB - BACKGROUND: In the NAPOLI-1 Phase 3 trial, nal-IRI+5-fluorouracil and leucovorin (5-FU/LV) significantly improved median overall survival (6.1 vs 4.2 months, P=0.012) and progression-free survival (3.1 vs 1.5 months, P=0.0001) vs 5-FU/LV alone in metastatic pancreatic adenocarcinoma patients previously treated with gemcitabine-based therapy. This analysis evaluated between treatment differences in quality-adjusted time without symptoms of disease progression or toxicity (Q TWiST). METHODS: Overall survival was partitioned into time with grade ?3 toxicity (TOX), disease progression (REL), and time without disease progression symptoms or grade ?3 toxicity (TWiST). Mean Q-TWiST was calculated by weighting time spent by a utility of 1.0 for TWiST and 0.5 for TOX and REL. In threshold analyses, utility for TOX and REL were varied from 0.0 to 1.0. RESULTS: Patients in nal-IRI+5-FU/LV (n=117) vs 5-FU/LV (n=119) had significantly more mean time in TWiST (3.4 vs 2.4 months) and TOX (1.0 vs 0.3 months) but similar REL (2.5 vs 2.7 months). In the base case, nal-IRI+5-FU/LV patients had 1.3 months (95% CI, 0.4 2.1; 5.1 vs 3.9) greater Q-TWiST (threshold analyses range: 0.9-1.6 months). CONCLUSIONS: Within NAPOLI-1, nal-IRI+5-FU/LV resulted in statistically significant and clinically meaningful gains in quality-adjusted survival vs 5 FU/LV alone. PMID- 28350788 TI - LDL cholesterol counteracts the antitumour effect of tyrosine kinase inhibitors against renal cell carcinoma. AB - BACKGROUND: Treatment with tyrosine kinase inhibitors (TKIs) significantly improves survival of patients with renal cell carcinoma (RCC). However, about one quarter of the RCC patients are primarily refractory to treatment with TKIs. METHODS: We examined viability of RCC and endothelial cells treated with low density lipoprotein (LDL) and/or TKIs. Next, we validated the potential role of PI3K/AKT signalling in LDL-mediated TKI resistance. Finally, we examined the effect of a high-fat/high-cholesterol diet on the response of RCC xenograft tumours to sunitinib. RESULTS: The addition of LDL cholesterol increases activation of PI3K/AKT signalling and compromises the antitumour efficacy of TKIs against RCC and endothelial cells. Furthermore, RCC xenograft tumours resist TKIs in mice fed a high-fat/high-cholesterol diet. CONCLUSIONS: The ability of renal tumours to maintain their cholesterol homoeostasis may be a critical component of TKI resistance in RCC patients. PMID- 28350789 TI - Dependence of cancer risk from environmental exposures on underlying genetic susceptibility: an illustration with polycyclic aromatic hydrocarbons and breast cancer. AB - BACKGROUND: Most studies of environmental risk factors and breast cancer are conducted using average risk cohorts. METHODS: We examined the association between polycyclic aromatic hydrocarbon (PAH)-albumin adducts in bloods from baseline and breast cancer risk in a prospective nested case-control study (New York site of the BCFR, 80 cases and 156 controls). We estimated the 10-year absolute breast cancer risk by a risk model that uses pedigree information (BOADICEA) and evaluated whether the increased risk from PAH differed by absolute risk. RESULTS: Women with detectable levels of PAH had a twofold association with breast cancer risk (odds ratio (OR)=2.04; 95% CI=1.06-3.93) relative to women with non-detectable levels. The association increased with higher levels of PAH (?median) and by a higher level of absolute breast cancer risk (10-year risk ?3.4%: OR=4.09, 95% CI=1.38-12.13). CONCLUSIONS: These results support that family-based cohorts can be an efficient way to examine gene-environment interactions. PMID- 28350792 TI - Association between delirium superimposed on dementia and mortality in hospitalized older adults: A prospective cohort study. AB - BACKGROUND: Hospitalized older adults with preexisting dementia have increased risk of having delirium, but little is known regarding the effect of delirium superimposed on dementia (DSD) on the outcomes of these patients. Our aim was to investigate the association between DSD and hospital mortality and 12-mo mortality in hospitalized older adults. METHODS AND FINDINGS: This was a prospective cohort study completed in the geriatric ward of a university hospital in Sao Paulo, Brazil. We included 1,409 hospitalizations of acutely ill patients aged 60 y and over from January 2009 to June 2015. Main variables and measures included dementia and dementia severity (Informant Questionnaire on Cognitive Decline in the Elderly, Clinical Dementia Rating) and delirium (Confusion Assessment Method). Primary outcomes were time to death in the hospital and time to death in 12 mo (for the discharged sample). Comprehensive geriatric assessment was performed at admission, and additional clinical data were documented upon death or discharge. Cases were categorized into four groups (no delirium or dementia, dementia alone, delirium alone, and DSD). The no delirium/dementia group was defined as the referent category for comparisons, and multivariate analyses were performed using Cox proportional hazards models adjusted for possible confounders (sociodemographic information, medical history and physical examination data, functional and nutritional status, polypharmacy, and laboratory covariates). Overall, 61% were women and 39% had dementia, with a mean age of 80 y. Dementia alone was observed in 13% of the cases, with delirium alone in 21% and DSD in 26% of the cases. In-hospital mortality was 8% for patients without delirium or dementia, 12% for patients with dementia alone, 29% for patients with delirium alone, and 32% for DSD patients (Pearson Chi-square = 112, p < 0.001). DSD and delirium alone were independently associated with in-hospital mortality, with respective hazard ratios (HRs) of 2.14 (95% CI = 1.33-3.45, p = 0.002) and 2.72 (95% CI = 1.77-4.18, p < 0.001). Dementia alone did not have a significant statistical association with in-hospital mortality (HR = 1.69, 95% CI = 0.72 2.30, p = 0.385). Finally, while 24% of the patients died after discharge, 12-mo mortality was not associated with dementia or delirium in any of the diagnostic groups (DSD: HR = 1.15, 95% CI = 0.79-1.68, p = 0.463; delirium alone: HR = 1.05, 95% CI = 0.71-1.54, p = 0.810; dementia alone: HR = 1.19, 95% CI = 0.79-1.78, p = 0.399). Limitations to this study include not exploring the effects of the duration and severity of delirium on the outcomes. CONCLUSIONS: DSD and delirium alone were independently associated with a worse prognosis in hospitalized older adults. Health care professionals should recognize the importance of delirium as a predictor of hospital mortality regardless of the coexistence with dementia. PMID- 28350793 TI - Correction: Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score. AB - [This corrects the article DOI: 10.1371/journal.pmed.1002258.]. PMID- 28350790 TI - Use of common analgesic medications and ovarian cancer survival: results from a pooled analysis in the Ovarian Cancer Association Consortium. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with improved survival in some cancers, but evidence for ovarian cancer is limited. METHODS: Pooling individual-level data from 12 Ovarian Cancer Association Consortium studies, we evaluated the association between self reported, pre-diagnosis use of common analgesics and overall/progression free/disease-specific survival among 7694 women with invasive epithelial ovarian cancer (4273 deaths). RESULTS: Regular analgesic use (at least once per week) was not associated with overall survival (pooled hazard ratios, pHRs (95% confidence intervals): aspirin 0.96 (0.88-1.04); non-aspirin NSAIDs 0.97 (0.89-1.05); acetaminophen 1.01 (0.93-1.10)), nor with progression-free/disease-specific survival. There was however a survival advantage for users of any NSAIDs in studies clearly defining non-use as less than once per week (pHR=0.89 (0.82 0.98)). CONCLUSIONS: Although this study did not show a clear association between analgesic use and ovarian cancer survival, further investigation with clearer definitions of use and information about post-diagnosis use is warranted. PMID- 28350791 TI - Acid-suppressing therapies and subsite-specific risk of stomach cancer. AB - BACKGROUND: Associations of stomach cancer risk with histamine type-2 receptor antagonists (H2RA) and proton-pump inhibitors (PPI) are controversial. We hypothesised that proximal extension of Helicobacter pylori infection from acid suppression would disproportionately increase cancers at proximal subsites. METHODS: A total of 1 563 860 individuals in the Danish Prescription Drug Registry first prescribed acid-suppressive drugs 1995-2011 were matched to unexposed population-based controls. Hazard ratios (HR) were calculated by Cox proportional hazard regression for stomach cancers diagnosed more than one year after first prescription. RESULTS: There were 703 stomach cancers among H2RA exposed individuals and 1347 among PPI-exposed. Restricted to individuals with five or more prescriptions, subsite-specific HRs for H2RA and PPI were 4.1 and 6.4 for proximal subsites vs 8.0 and 10.3 for distal subsites, respectively. CONCLUSIONS: Moderate exposures to acid-suppressive drugs did not favour proximal tumour localisation. Given confounding by indication, these findings do not resolve potential contribution to gastric carcinogenesis overall. PMID- 28350794 TI - Dementia and aging populations-A global priority for contextualized research and health policy. AB - In this month's Editorial, Guest Editors Carol Brayne and Bruce Miller discuss research and commentary published in March and future directions for dementia research. PMID- 28350795 TI - Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case-control study. AB - BACKGROUND: Alzheimer disease (AD) is a progressive disorder that affects cognitive function. There is increasing support for the role of neuroinflammation and aberrant immune regulation in the pathophysiology of AD. The immunoregulatory human leukocyte antigen (HLA) complex has been linked to susceptibility for a number of neurodegenerative diseases, including AD; however, studies to date have failed to consistently identify a risk HLA haplotype for AD. Contributing to this difficulty are the complex genetic organization of the HLA region, differences in sequencing and allelic imputation methods, and diversity across ethnic populations. METHODS AND FINDINGS: Building on prior work linking the HLA to AD, we used a robust imputation method on two separate case-control cohorts to examine the relationship between HLA haplotypes and AD risk in 309 individuals (191 AD, 118 cognitively normal [CN] controls) from the San Francisco-based University of California, San Francisco (UCSF) Memory and Aging Center (collected between 1999-2015) and 11,381 individuals (5,728 AD, 5,653 CN controls) from the Alzheimer's Disease Genetics Consortium (ADGC), a National Institute on Aging (NIA)-funded national data repository (reflecting samples collected between 1984 2012). We also examined cerebrospinal fluid (CSF) biomarker measures for patients seen between 2005-2007 and longitudinal cognitive data from the Alzheimer's Disease Neuroimaging Initiative (n = 346, mean follow-up 3.15 +/- 2.04 y in AD individuals) to assess the clinical relevance of identified risk haplotypes. The strongest association with AD risk occurred with major histocompatibility complex (MHC) haplotype A*03:01~B*07:02~DRB1*15:01~DQA1*01:02~DQB1*06:02 (p = 9.6 x 10-4, odds ratio [OR] [95% confidence interval] = 1.21 [1.08-1.37]) in the combined UCSF + ADGC cohort. Secondary analysis suggested that this effect may be driven primarily by individuals who are negative for the established AD genetic risk factor, apolipoprotein E (APOE) E4. Separate analyses of class I and II haplotypes further supported the role of class I haplotype A*03:01~B*07:02 (p = 0.03, OR = 1.11 [1.01-1.23]) and class II haplotype DRB1*15:01- DQA1*01:02- DQB1*06:02 (DR15) (p = 0.03, OR = 1.08 [1.01-1.15]) as risk factors for AD. We followed up these findings in the clinical dataset representing the spectrum of cognitively normal controls, individuals with mild cognitive impairment, and individuals with AD to assess their relevance to disease. Carrying A*03:01~B*07:02 was associated with higher CSF amyloid levels (p = 0.03, beta +/- standard error = 47.19 +/- 21.78). We also found a dose-dependent association between the DR15 haplotype and greater rates of cognitive decline (greater impairment on the 11-item Alzheimer's Disease Assessment Scale cognitive subscale [ADAS11] over time [p = 0.03, beta +/- standard error = 0.7 +/- 0.3]; worse forgetting score on the Rey Auditory Verbal Learning Test (RAVLT) over time [p = 0.02, beta +/- standard error = -0.2 +/- 0.06]). In a subset of the same cohort, dose of DR15 was also associated with higher baseline levels of chemokine CC-4, a biomarker of inflammation (p = 0.005, beta +/- standard error = 0.08 +/- 0.03). The main study limitations are that the results represent only individuals of European-ancestry and clinically diagnosed individuals, and that our study used imputed genotypes for a subset of HLA genes. CONCLUSIONS: We provide evidence that variation in the HLA locus-including risk haplotype DR15-contributes to AD risk. DR15 has also been associated with multiple sclerosis, and its component alleles have been implicated in Parkinson disease and narcolepsy. Our findings thus raise the possibility that DR15-associated mechanisms may contribute to pan neuronal disease vulnerability. PMID- 28350797 TI - Dementia in low-income and middle-income countries: Different realities mandate tailored solutions. AB - In a Perspective, Cleusa Ferri and K. S. Jacob discuss the assessment, recognition, and care of people living with dementia in low- and middle-income countries. PMID- 28350796 TI - The impact of individual Cognitive Stimulation Therapy (iCST) on cognition, quality of life, caregiver health, and family relationships in dementia: A randomised controlled trial. AB - BACKGROUND: Cognitive stimulation therapy (CST) is a well-established group psychosocial intervention for people with dementia. There is evidence that home based programmes of cognitive stimulation delivered by family caregivers may benefit both the person and the caregiver. However, no previous studies have evaluated caregiver-delivered CST. This study aimed to evaluate the effectiveness of a home-based, caregiver-led individual cognitive stimulation therapy (iCST) program in (i) improving cognition and quality of life (QoL) for the person with dementia and (ii) mental and physical health (well-being) for the caregiver. METHODS AND FINDINGS: A single-blind, pragmatic randomised controlled trial (RCT) was conducted at eight study sites across the United Kingdom. The intervention and blinded assessment of outcomes were conducted in participants' homes. Three hundred fifty-six people with mild to moderate dementia and their caregivers were recruited from memory services and community mental health teams (CMHTs). Participants were randomly assigned to iCST (75, 30-min sessions) or treatment as usual (TAU) control over 25 wk. iCST sessions consisted of themed activities designed to be mentally stimulating and enjoyable. Caregivers delivering iCST received training and support from an unblind researcher. Primary outcomes were cognition (Alzheimer's Disease Assessment Scale-cognitive [ADAS-Cog]) and self reported QoL (Quality of Life Alzheimer's Disease [QoL-AD]) for the person with dementia and general health status (Short Form-12 health survey [SF-12]) for the caregiver. Secondary outcomes included quality of the caregiving relationship from the perspectives of the person and of the caregiver (Quality of the Carer Patient Relationship Scale) and health-related QoL (European Quality of Life-5 Dimensions [EQ-5D]) for the caregiver. Intention to treat (ITT) analyses were conducted. At the post-test (26 wk), there were no differences between the iCST and TAU groups in the outcomes of cognition (mean difference [MD] = -0.55, 95% CI -2.00-0.90; p = 0.45) and self-reported QoL (MD = -0.02, 95% CI -1.22-0.82; p = 0.97) for people with dementia, or caregivers' general health status (MD = 0.13, 95% CI -1.65-1.91; p = 0.89). However, people with dementia receiving iCST rated the relationship with their caregiver more positively (MD = 1.77, 95% CI 0.26 3.28; p = 0.02), and iCST improved QoL for caregivers (EQ-5D, MD = 0.06, 95% CI 0.02-0.10; p = 0.01). Forty percent (72/180) of dyads allocated to iCST completed at least two sessions per week, with 22% (39/180) completing no sessions at all. Study limitations include low adherence to the intervention. CONCLUSIONS: There was no evidence that iCST has an effect on cognition or QoL for people with dementia. However, participating in iCST appeared to enhance the quality of the caregiving relationship and caregivers' QoL. TRIAL REGISTRATION: The iCST trial is registered with the ISRCTN registry (identified ISRCTN 65945963, URL: DOI 10.1186/ISRCTN65945963). PMID- 28350798 TI - Research priorities for harnessing plant microbiomes in sustainable agriculture. AB - Feeding a growing world population amidst climate change requires optimizing the reliability, resource use, and environmental impacts of food production. One way to assist in achieving these goals is to integrate beneficial plant microbiomes i.e., those enhancing plant growth, nutrient use efficiency, abiotic stress tolerance, and disease resistance-into agricultural production. This integration will require a large-scale effort among academic researchers, industry researchers, and farmers to understand and manage plant-microbiome interactions in the context of modern agricultural systems. Here, we identify priorities for research in this area: (1) develop model host-microbiome systems for crop plants and non-crop plants with associated microbial culture collections and reference genomes, (2) define core microbiomes and metagenomes in these model systems, (3) elucidate the rules of synthetic, functionally programmable microbiome assembly, (4) determine functional mechanisms of plant-microbiome interactions, and (5) characterize and refine plant genotype-by-environment-by-microbiome-by-management interactions. Meeting these goals should accelerate our ability to design and implement effective agricultural microbiome manipulations and management strategies, which, in turn, will pay dividends for both the consumers and producers of the world food supply. PMID- 28350799 TI - Optimization and evaluation of astragalus polysaccharide injectable thermoresponsive in-situ gels. AB - The objective of this study was to develop an injectable in situ forming gel system based on Poloxamer for sustained release of Astragalus polysaccharide (APS), thus achieved once or twice administration instead of frequent dosing during long-term treatment. The optimal formulation is 10 g APS, 18 g poloxamer 407, 2 g poloxamer 188, 0.15 g CMC-Na, 0.85 g sodium chloride in 100 ml gel in situ which had a preferable sol-gel transition temperature(T sol-gel) (34.1 +/- 0.4 degrees C), and good stability. In vitro release studies, all formulations containing polymer additives had prolonged release time and decreased initial burst to some extent. The optimal formulation containing 0.15% CMC-Na showed a best sustained release profile for about 132 h with the lowest initial burst in vitro about 16.30% in 12 h). In vivo, Male BALB/c mice (18-20 g) were administrated with APS in-situ gel just once, the values of immune organ indices, spleen lymphocyte proliferation, and serum IgM, IgG, IL-2 and IL-6 had significant increase, which was consistent with the mice given daily APS injections (7 times), while the above indices were increased more significantly in which administrated with APS in-situ gel twice. Based on these results, it can be concluded that the Poloxamer depot is a promising carrier for the sustained release of APS with an ideal release behavior. PMID- 28350800 TI - Neural correlates of facial expression processing during a detection task: An ERP study. AB - Given finite attentional resources, how emotional aspects of stimuli are processed automatically is controversial. Present study examined the time-course for automatic processing of facial expression by assessing N170, and late positive potentials (LPPs) of event-related potentials (ERPs) using a modified rapid serial visual presentation (RSVP) paradigm. Observers were required to confirm a certain house image and to detect whether a face image was presented at the end of a series of pictures. There were no significant main effects on emotional type for P1 amplitudes, whereas happy and fearful expressions elicited larger N170 amplitudes than neutral expressions. Significantly different LPP amplitudes were elicited depending on the type of emotional facial expressions (fear > happy > neutral). These results indicated that threatening priority was absent but discrimination of expressive vs. neutral faces occurred in implicit emotional tasks, at approximately 250 ms post-stimulus. Moreover, the three types of expressions were discriminated during the later stages of processing. Encoding emotional information of faces can be automated to a relatively higher degree, when attentional resources are mostly allocated to superficial analyzing. PMID- 28350801 TI - APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. AB - BACKGROUND: Amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin 2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series. METHODS AND FINDINGS: We report here a novel update (2012 2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) <=65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 +/- 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers-total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid beta (Abeta)42-in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification. CONCLUSIONS: Our findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants. PMID- 28350802 TI - Impact of lopinavir-ritonavir exposure in HIV-1 infected children and adolescents in Madrid, Spain during 2000-2014. AB - BACKGROUND: The most-used protease-inhibitor in children is Lopinavir-ritonavir (LPV/r), which provides durable suppression of viral load and increases CD4+T counts. This study describes the virological outcome of the HIV-1-infected paediatric population exposed to LPV/r during 15 years in Spain. METHODOLOGY: Patients from the Madrid Cohort of HIV-1-infected-children and adolescents exposed to LPV/r as different line therapy during 2000-2014 were selected. The baseline epidemiological-clinical features, viral suppression, changes in CD4+T CD8+T cell counts and drug susceptibility were recorded before and during LPV/r exposure. Drug resistance mutations (DRM) were identified in viruses from samples collected until 2011. We predicted drug susceptibility to 19 antiretrovirals among those carrying DRM using the Stanford's HIVdb Algorithm. RESULTS: A total of 199 (37.3%) of the 534 patients from the cohort were exposed to LPV/r during 2000-2014 in first (group 1), second (group 2) or more line-therapies (group 3). Patients were mainly Spaniards (81.9%), perinatally infected (96.5%) with subtype B (65.3%) and HIV-diagnosed before year 2000 (67.8%). The mean age at first LPV/r exposure was 9.7 years. After protease-inhibitor exposure, viral suppression was higher in groups 1 and 2 than in group 3. Viral suppression occurred in 87.5%, 68.6% and 64.8% patients from groups 1, 2 and 3, respectively. Among the 64 patients with available resistance data during LPV/r treatment, 27(42.3%) carried DRM to protease-inhibitor, 28 (58.3%) to reverse-transcriptase-inhibitors and 21 (43.7%) to non-reverse-transcriptase-inhibitors. Darunavir/ritonavir, atazanavir ritonavir and tipranavir/ritonavir presented the highest susceptibility and nelfinavir the lowest. CONCLUSIONS: A better lymphocyte recovering occurred when protease-inhibitor was taken as part of a first-line regimen and a higher number of patients reached viral suppression. The least compromised antiretrovirals for rescue antiretroviral regimens, according to DRM in the LPV/r-exposed-paediatric cohort, were mainly the new protease inhibitors. PMID- 28350803 TI - Pharmacogenomic identification of small molecules for lineage specific manipulation of subventricular zone germinal activity. AB - Strategies for promoting neural regeneration are hindered by the difficulty of manipulating desired neural fates in the brain without complex genetic methods. The subventricular zone (SVZ) is the largest germinal zone of the forebrain and is responsible for the lifelong generation of interneuron subtypes and oligodendrocytes. Here, we have performed a bioinformatics analysis of the transcriptome of dorsal and lateral SVZ in early postnatal mice, including neural stem cells (NSCs) and their immediate progenies, which generate distinct neural lineages. We identified multiple signaling pathways that trigger distinct downstream transcriptional networks to regulate the diversity of neural cells originating from the SVZ. Next, we used a novel in silico genomic analysis, searchable platform-independent expression database/connectivity map (SPIED/CMAP), to generate a catalogue of small molecules that can be used to manipulate SVZ microdomain-specific lineages. Finally, we demonstrate that compounds identified in this analysis promote the generation of specific cell lineages from NSCs in vivo, during postnatal life and adulthood, as well as in regenerative contexts. This study unravels new strategies for using small bioactive molecules to direct germinal activity in the SVZ, which has therapeutic potential in neurodegenerative diseases. PMID- 28350804 TI - Syndecan-1 deficiency promotes tumor growth in a murine model of colitis-induced colon carcinoma. AB - Syndecan-1 (Sdc1) is an important member of the cell surface heparan sulfate proteoglycan family, highly expressed by epithelial cells in adult organisms. Sdc1 is involved in the regulation of cell migration, cell-cell and cell-matrix interactions, growth-factor, chemokine and integrin activity, and implicated in inflammatory responses and tumorigenesis. Gastrointestinal tract represents an important anatomic site where loss of Sdc1 expression was reported both in inflammation and malignancy. However, the biological significance of Sdc1 in chronic colitis-associated tumorigenesis has not been elucidated. To the best of our knowledge, this study is the first to test the effects of Sdc1 loss on colorectal tumor development in inflammation-driven colon tumorigenesis. Utilizing a mouse model of colitis-related colon carcinoma induced by the carcinogen azoxymethane (AOM), followed by the inflammatory agent dextran sodium sulfate (DSS), we found that Sdc1 deficiency results in increased susceptibility to colitis-associated tumorigenesis. Importantly, colitis-associated tumors developed in Sdc1-defficient mice were characterized by increased local production of IL-6, activation of STAT3, as well as induction of several STAT3 target genes that act as important effectors of colonic tumorigenesis. Altogether, our results highlight a previously unknown effect of Sdc1 loss in progression of inflammation-associated cancer and suggest that decreased levels of Sdc1 may serve as an indicator of colon carcinoma progression in the setting of chronic inflammation. PMID- 28350805 TI - Enhanced recovery after surgery protocol in oesophageal cancer surgery: Systematic review and meta-analysis. AB - BACKGROUND: Enhanced Recovery After Surgery (ERAS) protocol are well established in many surgical disciplines, leading to decrease in morbidity and length of hospital stay. These multi-modal protocols have been also introduced to oesophageal cancer surgery. This review aimed to evaluate current literature on ERAS in oesophageal cancer surgery and conduct a meta-analysis on primary and secondary outcomes. METHODS: MEDLINE, Embase, Scopus and Cochrane Library were searched for eligible studies. We analyzed data up to May 2016. Eligible studies had to contain four described ERAS protocol elements. The primary outcome was overall morbidity. Secondary outcomes included length of hospital stay, specific complications, mortality and readmissions. Random effect meta-analyses were undertaken. RESULTS: Initial search yielded 1,064 articles. Thorough evaluation resulted in 13 eligible articles which were analyzed. A total of 2,042 patients were included in the analysis (1,058 ERAS group and 984 treated with traditional protocols). Analysis of overall morbidity as well as complication rate did not show any significant reduction. Non-surgical complications and pulmonary complications were significantly lower in the ERAS group, RR = 0.71 95% CI 0.62 0.80, p < 0.00001 and RR = 0.75, 95% CI 0.60-0.94, p = 0.01, respectively. Meta analysis on length of stay presented significant reduction Mean difference = 3.55, 95% CI -4.41 to -2.69, p for effect<0.00001. CONCLUSIONS: This systematic review with a meta-analysis on ERAS in oesophageal surgery indicates a reduction of non-surgical complications and no negative influence on overall morbidity. Moreover, a reduction in the length of hospital stay was presented. PMID- 28350806 TI - Pharmacokinetics of a single 1g dose of azithromycin in rectal tissue in men. AB - Chlamydia is the most common bacterial sexually transmitted infection among men who have sex with men. Repeat infection following treatment with 1g azithromycin is common and treatment failure of up to 22% has been reported. This study measured the pharmacokinetics of azithromycin in rectal tissue in men following a single 1g dose to assess whether azithromycin reaches the rectal site in adequate concentrations to kill chlamydia. Ten healthy men took a single oral dose of 1g azithromycin and provided nine self-collected swabs and one blood sample over 14 days. Participant demographics, medications, sexual behaviour, treatment side effects, lubricant use and douching practices were recorded with each swab. Drug concentration over time was determined using liquid chromatography-mass spectrometry and total exposure (AUC0-infinity) was estimated from the concentration-time profiles. Following 1g of azithromycin, rectal concentrations peaked after a median of 24 hours (median 133mcg/g) and remained above the minimum inhibitory concentration for chlamydia (0.125mcg/mL) for at least 14 days in all men. AUC0-infinity was the highest ever reported in human tissue (13103((mcg/g).hr)). Tissue concentrations were not associated with weight (mg/kg), but data suggest that increased gastric pH could increase azithromycin levels and diarrhoea or use of water-based lubricants could decrease concentrations. High and sustained concentrations of azithromycin were found in rectal tissue following a single 1g dose suggesting that inadequate concentrations are unlikely to cause treatment failure. Factors effecting absorption (pH and diarrhoea) or drug depletion (douching and water-based lubricants) may be more important determinants of concentrations in situ. PMID- 28350807 TI - External validation and comparison of two variants of the Elixhauser comorbidity measures for all-cause mortality. AB - : Assessing prevalent comorbidities is a common approach in health research for identifying clinical differences between individuals. The objective of this study was to validate and compare the predictive performance of two variants of the Elixhauser comorbidity measures (ECM) for inhospital mortality at index and at 1 year in the Cerner Health Facts(r) (HF) U.S. DATABASE: We estimated the prevalence of select comorbidities for individuals 18 to 89 years of age who received care at Cerner contributing health facilities between 2002 and 2011 using the AHRQ (version 3.7) and the Quan Enhanced ICD-9-CM ECMs. External validation of the ECMs was assessed with measures of discrimination [c statistics], calibration [Hosmer-Lemeshow goodness-of-fit test, Brier Score, calibration curves], added predictive ability [Net Reclassification Improvement], and overall model performance [R2]. Of 3,273,298 patients with a mean age of 43.9 years and a female composition of 53.8%, 1.0% died during their index encounter and 1.5% were deceased at 1-year. Calibration measures were equivalent between the two ECMs. Calibration performance was acceptable when predicting inhospital mortality at index, although recalibration is recommended for predicting inhospital mortality at 1 year. Discrimination was marginally better with the Quan ECM compared the AHRQ ECM when predicting inhospital mortality at index (cQuan = 0.887, 95% CI: 0.885-0.889 vs. cAHRQ = 0.880, 95% CI: 0.878-0.882; p < .0001) and at 1-year (cQuan = 0.884, 95% CI: 0.883-0.886 vs. cAHRQ = 0.880, 95% CI: 0.878-0.881, p < .0001). Both the Quan and the AHRQ ECMs demonstrated excellent discrimination for inhospital mortality of all-causes in Cerner Health Facts(r), a HIPAA compliant observational research and privacy-protected data warehouse. While differences in discrimination performance between the ECMs were statistically significant, they are not likely clinically meaningful. PMID- 28350808 TI - Differential recruitment efficacy of patient-derived amyloidogenic and myeloma light chain proteins by synthetic fibrils-A metric for predicting amyloid propensity. AB - BACKGROUND: Monoclonal free light chain (LC) proteins are present in the circulation of patients with immunoproliferative disorders such as light chain (AL) amyloidosis and multiple myeloma (MM). Light chain-associated amyloid is a complex pathology composed of proteinaceous fibrils and extracellular matrix proteins found in all patients with AL and in ~10-30% of patients who presented with MM. Amyloid deposits systemically in multiple organs and tissues leading to dysfunction and ultimately death. The overall survival of patients with amyloidosis is worse than for those with early stage MM. METHODS AND FINDINGS: We have developed a sensitive binding assay quantifying the recruitment of full length, patient-derived LC proteins by synthetic amyloid fibrils, as a method for studying their amyloidogenic potential. In a survey of eight urinary LC, both AL and MM-associated proteins were recruited by synthetic amyloid fibrils; however, AL-associated LC bound significantly more efficiently (p < 0.05) than did MM LCs. The LC proteins used in this study were isolated from urine and presumed to represent a surrogate of serum free light chains. CONCLUSION: The binding of LC to synthetic fibrils in this assay accurately differentiated LC with amyloidogenic propensity from MM LC that were not associated with clinical amyloid disease. Notably, the LC from a MM patient who subsequently developed amyloid behaved as an AL-associated protein in the assay, indicating the possibility for identifying MM patients at risk for developing amyloidosis based on the light chain recruitment efficacy. With this information, at risk patients can be monitored more closely for the development of amyloidosis, allowing timely administration of novel, amyloid-directed immunotherapies-this approach may improve the prognosis for these patients. PMID- 28350810 TI - Risky sexual practice and associated factors among HIV positive adults attending anti-retroviral treatment clinic at Gondar University Referral Hospital, Northwest Ethiopia. AB - INTRODUCTION: Risky sexual practice among people living with HIV/AIDS is a public health concern because of the risk of transmission of the virus to sero discordant partner/s. There is also the risk of re-infection with new, drug resistant viral strains between sero-concordant partners. However, there is lack of information on risky sexual practices among HIV positive adults. Therefore, this study aimed to assess risky sexual practice and associated factors among adult HIV positive clients at Gondar University Referral Hospital, Northwest Ethiopia, 2015. METHODS: An institution based cross sectional study was conducted at Gondar University Referral Hospital from May to June 2015. A pretested structured questionnaire was used to collect the data. Using systematic random sampling technique, a total of 513 respondents were participated in this study. The data were entered into EPI info version 3.5.3 and transferred to SPSS version 20 for analysis. Descriptive, bivariate and multivariate analyses were done. A P value <0.05 was considered to determine the statistical significance of the association between factors (independent variables) and risky sexual practice. The Odds ratio was also used to determine the presence and the degree of association between the dependent and independent variables. RESULTS: A total of 513 respondents were participated in this study. The prevalence of risky sexual practices in the past three months was 38% (95% CI: 33.3%, 42.3%). Being in the age range of 18-29 years (AOR = 2.63, 95% CI: 1.55, 4.47) and 30-39 years (AOR = 2.29, 95% CI: 1.48, 3.53), being single (AOR = 6.32, 95%CI: 2.43, 16.44),being married (AOR = 6.06, 95% CI: 2.81, 13.07), having no child (AOR = 2.58, 95% CI: 1.17, 5.72), and a CD4 count of greater than 500/mm3 were factors significantly associated with risky sexual practices. CONCLUSIONS: A considerable number of HIV positive clients had risky sexual practices. It is strongly recommended that the Regional Health Bureau and health service providers working at Gondar University Hospital especially in the ART Clinic need to work hard on behavioral change communication. PMID- 28350809 TI - The impact of a family skills training intervention among Burmese migrant families in Thailand: A randomized controlled trial. AB - OBJECTIVE: To conduct a randomized controlled trial assessing the impact of a family-based intervention delivered to Burmese migrant families displaced in Thailand on parenting and family functioning. PARTICIPANTS AND PROCEDURES: Participants included 479 Burmese migrant families from 20 communities in Thailand. Families, including 513 caregivers and 479 children aged 7 to 15 years, were randomized to treatment and waitlist control groups. The treatment group received a 12-session family-based intervention delivered to groups of families by lay facilitators. Adapted standardized and locally derived measures were administered before and after the intervention to assess parent-child relationship quality, discipline practices, and family functioning. RESULTS: Compared with controls, intervention families demonstrated improved quality of parent-child interactions on scales of parental warmth and affection (Effect size (ES) = 0.25 caregivers; 0.26 children, both p < 0.05) and negative relationship quality (ES = -0.37, p < 0.001 caregivers; -0.22 children, p < 0.05). Both children and caregivers also reported an effect on relationship quality based on a locally derived measure (ES = 0.40 caregivers, p < .001; 0.43 children, p < .05). Family functioning was improved, including family cohesion (ES = 0.46 caregivers; 0.36 children; both p < 0.001) and decreased negative interactions (ES = -0.30 caregivers, p < 0.01; -0.24 children, p < 0.05). Family communication also improved according to children only (ES = 0.29, p < 0.01). Caregivers, but not children, reported decreased harsh discipline (ES = -0.39, p < 0.001), and no effects were observed on use of positive discipline strategies. Treatment attendance was high, with participants attending a mean of 9.7 out of 12 sessions. CONCLUSION: The intervention increased protective aspects of family well-being for migrant children and caregivers in a middle-income country. The strongest effects were on parent-child relationship quality and family functioning, while results were mixed on changes in discipline practices. Results suggest that a behavioral family-based approach implemented by lay providers in community settings is a promising intervention approach for strengthening families in highly stressed contexts. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01668992. PMID- 28350811 TI - Sampling and detection of airborne influenza virus towards point-of-care applications. AB - Airborne transmission of the influenza virus contributes significantly to the spread of this infectious pathogen, particularly over large distances when carried by aerosol droplets with long survival times. Efficient sampling of virus loaded aerosol in combination with a low limit of detection of the collected virus could enable rapid and early detection of airborne influenza virus at the point-of-care setting. Here, we demonstrate a successful sampling and detection of airborne influenza virus using a system specifically developed for such applications. Our system consists of a custom-made electrostatic precipitation (ESP)-based bioaerosol sampler that is coupled with downstream quantitative polymerase chain reaction (qPCR) analysis. Aerosolized viruses are sampled directly into a miniaturized collector with liquid volume of 150 MUL, which constitutes a simple and direct interface with subsequent biological assays. This approach reduces sample dilution by at least one order of magnitude when compared to other liquid-based aerosol bio-samplers. Performance of our ESP-based sampler was evaluated using influenza virus-loaded sub-micron aerosols generated from both cultured and clinical samples. Despite the miniaturized collection volume, we demonstrate a collection efficiency of at least 10% and sensitive detection of a minimum of 3721 RNA copies. Furthermore, we show that an improved extraction protocol can allow viral recovery of down to 303 RNA copies and a maximum sampler collection efficiency of 47%. A device with such a performance would reduce sampling times dramatically, from a few hours with current sampling methods down to a couple of minutes with our ESP-based bioaerosol sampler. PMID- 28350812 TI - Sports-related sudden cardiac deaths in the young population of Switzerland. AB - BACKGROUND: In Switzerland, ECG screening was first recommended for national squad athletes in 1998. Since 2001 it has become mandatory in selected high-risk professional sports. Its impact on the rates of sports-related sudden cardiac death (SCD) is unknown. OBJECTIVE: We aimed to study the incidence, causes and time trends of sports-related SCD in comparison to SCD unrelated to exercise in Switzerland. METHODS: We reviewed all forensic reports of SCDs of the German speaking region of Switzerland in the age group of 10 to 39 years, occurring between 1999 and 2010. Cases were classified into three categories based on whether or not deaths were associated with sports: no sports (NONE), recreational sports (REC), and competitive sports (COMP). RESULTS: Over the 12-year study period, 349 SCD cases were recorded (mean age 30+/-7 years, 76.5% male); 297 cases were categorized as NONE, 31 as REC, and 21 as COMP. Incidences of SCD per 100,000 person-years [mean (95% CI)] were the lowest in REC [0.43 (0.35-0.56)], followed by COMP [1.19 (0.89-1.60)] and NONE [2.46 (2.27-2.66)]. In all three categories, coronary artery disease (CAD) with or without acute myocardial infarction (MI) was the most common cause of SCD. Three professional athletes were identified in COMP category which all had SCD due to acute MI. There were no time trends, neither in overall, nor in cause-specific incidences of SCD. CONCLUSIONS: The incidence of SCD in young individuals in Switzerland is low, both related and unrelated to sports. In regions, like Switzerland, where CAD is the leading cause of SCD associated with competitions, screening for cardiovascular risk factors in addition to the current PPS recommendations might be indicated to improve detection of silent CAD and further decrease the incidence of SCD. PMID- 28350813 TI - Role of p63 and p73 isoforms on the cell death in patients with hepatocellular carcinoma submitted to orthotopic liver transplantation. AB - BACKGROUND & AIMS: Patients with hepatocellular carcinoma (HCC) submitted to orthotopic liver transplantation (OLT) have a variable 5-year survival rate limited mostly by tumor recurrence. The etiology, age, sex, alcohol, Child-Pugh, and the immunesuppressor have been associated with tumour recurrence. The expression of DeltaNp73 is related to the reduced survival of patients with HCC. The study evaluated the expression of p63 and p73 isoforms and cell death receptors, and their relation to tumour recurrence and survival. The results were in vitro validated in HCC cell lines. METHODS: HCC sections from patients submitted to OLT were used. The in vitro study was done in differentiated hepatitis B virus (HBV)-expressing Hep3B and control HepG2 cells. The expression of cell death receptors and cFLIPS/L, caspase-8 and -3 activities, and cell proliferation were determined in control and p63 and p73 overexpressing HCC cells. RESULTS: The reduced tumor expression of cell death receptors and TAp63 and TAp73, and increased DeltaNp63 and DeltaNp73 expression were associated with tumor recurrence and reduced survival. The in vitro study demonstrated that HBV expressing Hep3B vs HepG2 cells showed reduced expression of p63 and p73, cell death receptors and caspase activation, and increased cFLIPL/cFLIPS ratio. The overexpression of TAp63 and TAp73 exerted a more potent pro-apoptotic and anti proliferative effects in Hep3B than HepG2-transfected cells which was related to cFLIPL upregulation. CONCLUSIONS: The reduction of TAp63 and TAp73 isoforms, rather than alteration of DeltaN isoform expression, exerted a significant functional repercussion on cell death and proliferation in HBV-expressing HepB cells. PMID- 28350815 TI - "The evil virus cell": Students' knowledge and beliefs about viruses. AB - Education about virus biology at school is of pivotal interest to raise public awareness concerning means of disease transmission and, thus, methods to prevent infection, and to reduce unnecessary antibiotic treatment due to patient pressure on physicians in case of viral diseases such as influenza. This study aimed at making visible the knowledge of Austrian high school and university students with respect to virus biology, virus structure and health-education issues. The data presented here stem from comprehensive questionnaire analyses, including the task to draw a virus, from a cross-sectional study with 133 grade 7 and 199 grade 10 high school students, and 133 first-year biology and 181 first-year non-biology university students. Analyses were performed both quantitatively and qualitatively. ANOVA revealed a highly significant group effect for total knowledge relating to virus biology and health issues (F(3, 642) = 44.17, p < 0.01, eta2p = 0.17). Specific post-hoc tests by means of the Tukey test showed significant differences between all groups (p < .01) with the exception of 1st year non-biology students and grade 10 high school students. Students enrolled in university-level biology outperformed all other groups, even though they had not yet encountered this topic at their courses; part of this phenomenon might be due to their affinity for learning about biological topics. However, even many first year biology students had a high number of severe misconceptions, e.g., defining a virus as a pro- or eukaryotic cell, or falsely naming malaria as a viral disease. Since there was no significant difference in virus-related knowledge between high schools, virus biology seems to have been taught similarly among the tested schools. However, the majority of participants stated that the virus related knowledge they had acquired at school was not sufficient. Based on the results presented here we urgently suggest improving and intensifying teaching this topic at school, since virus-related knowledge was by far too fragmentary among many participants. Such lack of health-relevant knowledge may contribute to pressure on physicians by patients to unnecessarily prescribe antibiotics, and possibly lead to potentially dangerous neglect concerning vaccination. The effectiveness of newly developed virus-related teaching units and material could be tested with the instrument used here. PMID- 28350814 TI - Compensatory changes in CYP expression in three different toxicology mouse models: CAR-null, Cyp3a-null, and Cyp2b9/10/13-null mice. AB - Targeted mutant models are common in mechanistic toxicology experiments investigating the absorption, metabolism, distribution, or elimination (ADME) of chemicals from individuals. Key models include those for xenosensing transcription factors and cytochrome P450s (CYP). Here we investigated changes in transcript levels, protein expression, and steroid hydroxylation of several xenobiotic detoxifying CYPs in constitutive androstane receptor (CAR)-null and two CYP-null mouse models that have subfamily members regulated by CAR; the Cyp3a null and a newly described Cyp2b9/10/13-null mouse model. Compensatory changes in CYP expression that occur in these models may also occur in polymorphic humans, or may complicate interpretation of ADME studies performed using these models. The loss of CAR causes significant changes in several CYPs probably due to loss of CAR-mediated constitutive regulation of these CYPs. Expression and activity changes include significant repression of Cyp2a and Cyp2b members with corresponding drops in 6alpha- and 16beta-testosterone hydroxylase activity. Further, the ratio of 6alpha-/15alpha-hydroxylase activity, a biomarker of sexual dimorphism in the liver, indicates masculinization of female CAR-null mice, suggesting a role for CAR in the regulation of sexually dimorphic liver CYP profiles. The loss of Cyp3a causes fewer changes than CAR. Nevertheless, there are compensatory changes including gender-specific increases in Cyp2a and Cyp2b. Cyp2a and Cyp2b were down-regulated in CAR-null mice, suggesting activation of CAR and potentially PXR following loss of the Cyp3a members. However, the loss of Cyp2b causes few changes in hepatic CYP transcript levels and almost no significant compensatory changes in protein expression or activity with the possible exception of 6alpha-hydroxylase activity. This lack of a compensatory response in the Cyp2b9/10/13-null mice is probably due to low CYP2B hepatic expression, especially in male mice. Overall, compensatory and regulatory CYP changes followed the order CAR-null > Cyp3a-null > Cyp2b-null mice. PMID- 28350816 TI - Multi-channel MRI segmentation of eye structures and tumors using patient specific features. AB - Retinoblastoma and uveal melanoma are fast spreading eye tumors usually diagnosed by using 2D Fundus Image Photography (Fundus) and 2D Ultrasound (US). Diagnosis and treatment planning of such diseases often require additional complementary imaging to confirm the tumor extend via 3D Magnetic Resonance Imaging (MRI). In this context, having automatic segmentations to estimate the size and the distribution of the pathological tissue would be advantageous towards tumor characterization. Until now, the alternative has been the manual delineation of eye structures, a rather time consuming and error-prone task, to be conducted in multiple MRI sequences simultaneously. This situation, and the lack of tools for accurate eye MRI analysis, reduces the interest in MRI beyond the qualitative evaluation of the optic nerve invasion and the confirmation of recurrent malignancies below calcified tumors. In this manuscript, we propose a new framework for the automatic segmentation of eye structures and ocular tumors in multi-sequence MRI. Our key contribution is the introduction of a pathological eye model from which Eye Patient-Specific Features (EPSF) can be computed. These features combine intensity and shape information of pathological tissue while embedded in healthy structures of the eye. We assess our work on a dataset of pathological patient eyes by computing the Dice Similarity Coefficient (DSC) of the sclera, the cornea, the vitreous humor, the lens and the tumor. In addition, we quantitatively show the superior performance of our pathological eye model as compared to the segmentation obtained by using a healthy model (over 4% DSC) and demonstrate the relevance of our EPSF, which improve the final segmentation regardless of the classifier employed. PMID- 28350817 TI - Differential associations of plasma lipids with incident dementia and dementia subtypes in the 3C Study: A longitudinal, population-based prospective cohort study. AB - BACKGROUND: Vascular risk factors have been proposed as important targets for the prevention of dementia. As lipid fractions represent easily modifiable targets, we examined the longitudinal relationship of baseline lipid fractions with 13-y incident dementia and its subtypes (Alzheimer disease [AD] and mixed or vascular dementia) in older community-dwelling persons. METHODS AND FINDINGS: Non institutionalized persons aged 65+ y (n = 9,294) were recruited for the Three City Study (3C Study), a population-based cohort study from the electoral rolls of the cities of Dijon, Bordeaux, and Montpellier, France, between March 1999 and March 2001. Follow-up examinations were performed every 2 y after the baseline assessment. The final study sample comprised 7,470 participants from the 3C Study (mean age +/- standard deviation [SD] 73.8 +/- 5.3 y, 61.0% women) who were prospectively followed up for up to 13 y. Fasting lipid fractions (triglycerides [TGs], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], total cholesterol [TC]) were studied as continuous variables, and results are reported per SD increase of each lipid fraction. Incident dementia and its subtypes were studied as censored variables using Cox models with age as time scale. Analyses were adjusted for sex, study center, and educational level, as well as vascular risk factors and apolipoprotein E (APOE) epsilon4 genotype. We corrected for multiple testing, yielding a significance threshold of 0.0169. p-Values above the significance threshold but less than 0.05 were considered nominally significant. During a mean (+/- SD) follow-up period of 7.9 +/- 3.6 y, 779 participants developed incident dementia (n = 532 AD and n = 154 mixed or vascular dementia). Higher LDL-C and TC concentrations at baseline were associated with an increased risk of AD (hazard ratio [HR] per SD increase = 1.13 [95% CI 1.04-1.22], p = 0.0045, and HR = 1.12 [1.03-1.22], p = 0.0072, respectively). These associations were largely unchanged after adjustment for vascular risk factors and were attenuated after adjustment for APOEepsilon4 (HR per SD increase = 1.12 [1.03-1.23], p = 0.0110, and HR = 1.12 [1.02-1.23], p = 0.0171, respectively). Higher TG concentrations at baseline were associated with an increased risk of all dementia (HR per SD increase = 1.11 [1.03-1.19], p = 0.0044) and mixed or vascular dementia (HR = 1.21 [1.04-1.41], p = 0.0163). However, these associations disappeared after adjusting for vascular risk factors (HR = 1.07 [0.98-1.17], p = 0.1374, and HR = 1.17 [0.96-1.42], p = 0.1206, respectively). Main limitations of the study include interval censoring of incident dementia cases, potential selective survival bias, and the fact that variation in lipid concentrations during follow-up could not be accounted for in the analyses. CONCLUSIONS: In a large population-based sample of older community dwelling persons with up to 13 y of follow-up, we observed that higher LDL-C and TC concentrations were associated with an increased risk of AD. This result was independent of vascular risk factors and was attenuated after adjustment for APOEepsilon4 carrier status. TG and HDL-C concentrations were not associated with risk of incident dementia or its subtypes after accounting for vascular risk factors. PMID- 28350818 TI - Effects and mechanisms of auricular electroacupuncture on gastric hypersensitivity in a rodent model of functional dyspepsia. AB - BACKGROUND: Functional dyspepsia (FD) is a common functional gastrointestinal disease, and abdominal pain is one of the main symptoms. The aim of this study was to explore the effects and mechanisms of auricular electro-acupuncture (AEA) on gastric hypersensitivity in a rodent model of FD. METHODS: Ten-day-old pups were gavaged with 0.2 ml of 0.1% iodoacetamide daily for 6 days. AEA at the "stomach" point with different parameters or sham-EA was performed on 8-week-old animals. Gastric sensitivity to gastric distention was measured under different conditions. Autonomic functions were assessed from the spectral analysis of heart rate variability (HRV) derived from the electrocardiogram. Naloxone was injected intraperitoneally before AEA to explore the opioid mechanism. Gastric emptying was measured at the end of the study. RESULTS: 1) Gastric sensitivity to gastric distention was higher in the FD rats. AEA with parameters of 0.1s on, 0.4s off, 100Hz, 0.3ms and 0.4-0.5mA, but not other parameters or sham-EA, decreased gastric hypersensitivity in the FD rats. Naloxone did not block the effect of AEA. 2) Lower vagal activity and higher sympathovagal ratio were noted in the FD rats, compared with the controls. AEA increased vagal activity and improved sympathovagal imbalance. CONCLUSIONS: AEA ameliorates gastric hypersensitivity in FD rats and this effect may be attributed to the improvement of sympathovagal balance. PMID- 28350819 TI - Development and application of a TaqMan single nucleotide polymorphism genotyping assay to study infectious laryngotracheitis virus recombination in the natural host. AB - To date, recombination between different strains of the avian alphaherpesvirus infectious laryngotracheitis virus (ILTV) has only been detected in field samples using full genome sequencing and sequence analysis. These previous studies have revealed that natural recombination is widespread in ILTV and have demonstrated that recombination between two attenuated ILTV vaccine strains generated highly virulent viruses that produced widespread disease within poultry flocks in Australia. In order to better understand ILTV recombination, this study developed a TaqMan single nucleotide polymorphism (SNP) genotyping assay to detect recombination between two field strains of ILTV (CSW-1 and V1-99 ILTV) under experimental conditions. Following in vivo co-inoculation of these two ILTV strains in specific pathogen free (SPF) chickens, recovered viruses were plaque purified and subjected to the SNP genotyping assay. This assay revealed ILTV recombinants in all co-inoculated chickens. In total 64/87 (74%) of the recovered viruses were recombinants and 23 different recombination patterns were detected, with some of them occurring more frequently than others. The results from this study demonstrate that the TaqMan SNP genotyping assay is a useful tool to study recombination in ILTV and also show that recombination occurs frequently during experimental co-infection with ILTV in SPF chickens. This tool, when used to assess ILTV recombination in the natural host, has the potential to greatly contribute to our understanding of alphaherpesvirus recombination. PMID- 28350820 TI - Antibiotic prescribing for acute lower respiratory tract infections (LRTI) - guideline adherence in the German primary care setting: An analysis of routine data. AB - OBJECTIVES: Antibiotic overprescribing in primary care has major impacts on the development of antibiotic resistance. The objective of this study is to provide insight in antibiotics prescriptions for patients suffering from cough, acute bronchitis or community acquired pneumonia in primary care. METHODS: Data from 2009 to 2013 of electronic health records of 12,880 patients in Germany were obtained from a research database. The prescription of antibiotics for acute lower respiratory tract infections was compared to the national S3 guideline cough from the German Society of General Practitioners and Family Medicine. RESULTS: Antibiotics were prescribed in 41% of consultations. General practitioners' decision of whether or not to prescribe an antibiotic was congruent with the guideline in 52% of consultations and the antibiotic choice congruence was 51% of antibiotic prescriptions. Hence, a congruent prescribing decision and a prescription of recommendation was found in only 25% of antibiotic prescriptions. Split by diagnosis we found that around three quarters of antibiotics prescribed for cough (73%) and acute bronchitis (78%) were not congruent to the guidelines. In contrast to that around one quarter of antibiotics prescribed for community acquired pneumonia (28%) were not congruent to the guidelines. CONCLUSIONS: Our results show that there is a big gap between guideline recommendation and actual prescribing, in the decision to prescribe and the choice of antibiotic agent. This gap could be closed by periodic quality circles on antibiotic prescribing for GPs. PMID- 28350822 TI - Asthma, corticosteroid use and schizophrenia: A nationwide population-based study in Taiwan. AB - OBJECTIVE: Asthma and corticosteroid use have been implicated as possible risk factors for schizophrenia. The retrospective cohort study herein aimed to investigate the association between asthma, corticosteroid use, and schizophrenia. METHOD: Longitudinal data (2000 to 2007) from adults with asthma (n = 50,046) and without asthma (n = 50,046) were compared on measures of schizophrenia incidence using Taiwan's National Health Insurance Research Database (NHIRD). Incidence of schizophrenia diagnosis (ICD-9 codes 295.XX) between 2000 and 2007 were compared between groups. Competing risk-adjusted Cox regression analyses were conducted, adjusting for sex, age, residence, socioeconomic status, corticosteroid use, outpatient and emergency room visit frequency, Charlson comorbidity index, and total length of hospital stays days for any disorder. RESULTS: Of the 75,069 subjects, 238 received a diagnosis of schizophrenia. The mean (SD) follow-up interval for all subjects was 5.8 (2.3) years. After adjusting for potential confounding factors, asthma was associated with significantly greater hazard ratio for incident schizophrenia 1.40 (95% CI = 1.05, 1.87). Additional factors associated with greater incidence of schizophrenia were rural residence, lower economic status, and poor general health. Older age (i.e. >=65 years) was negatively associated with schizophrenia incidence. Corticosteroid use was not associated with increased risk for schizophrenia. CONCLUSIONS: Asthma was associated with increased risk for schizophrenia. The results herein suggest that a convergent disturbance in the immune-inflammatory system may contribute to the pathoetiology of asthma and schizophrenia. PMID- 28350821 TI - Neuropathological diagnoses and clinical correlates in older adults in Brazil: A cross-sectional study. AB - BACKGROUND: Clinicopathological studies are important in determining the brain lesions underlying dementia. Although almost 60% of individuals with dementia live in developing countries, few clinicopathological studies focus on these individuals. We investigated the frequency of neurodegenerative and vascular related neuropathological lesions in 1,092 Brazilian admixed older adults, their correlation with cognitive and neuropsychiatric symptoms, and the accuracy of dementia subtype diagnosis. METHODS AND FINDINGS: In this cross-sectional study, we describe clinical and neuropathological variables related to cognitive impairment in 1,092 participants (mean age = 74 y, 49% male, 69% white, and mean education = 4 y). Cognitive function was investigated using the Clinical Dementia Rating (CDR) and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE); neuropsychiatric symptoms were evaluated using the Neuropsychiatric Inventory (NPI). Associations between neuropathological lesions and cognitive impairment were investigated using ordinal logistic regression. We developed a neuropathological comorbidity (NPC) score and compared it to CDR, IQCODE, and NPI scores. We also described and compared the frequency of neuropathological diagnosis to clinical diagnosis of dementia subtype. Forty-four percent of the sample met criteria for neuropathological diagnosis. Among these participants, 50% had neuropathological diagnoses of Alzheimer disease (AD), and 35% of vascular dementia (VaD). Neurofibrillary tangles (NFTs), hippocampal sclerosis, lacunar infarcts, hyaline atherosclerosis, siderocalcinosis, and Lewy body disease were independently associated with cognitive impairment. Higher NPC scores were associated with worse scores in the CDR sum of boxes (beta = 1.33, 95% CI 1.20-1.46), IQCODE (beta = 0.14, 95% CI 0.13-0.16), and NPI (beta = 1.74, 95% CI = 1.33-2.16). Compared to neuropathological diagnoses, clinical diagnosis had high sensitivity to AD and high specificity to dementia with Lewy body/Parkinson dementia. The major limitation of our study is the lack of clinical follow-up of participants during life. CONCLUSIONS: NFT deposition, vascular lesions, and high NPC scorewere associated with cognitive impairment in a unique Brazilian sample with low education. Our results confirm the high prevalence of neuropathological diagnosis in older adults and the mismatch between clinical and neuropathological diagnoses. PMID- 28350824 TI - Time- and radiation-dose dependent changes in the plasma proteome after total body irradiation of non-human primates: Implications for biomarker selection. AB - Acute radiation syndrome (ARS) is a complex multi-organ disease resulting from total body exposure to high doses of radiation. Individuals can be exposed to total body irradiation (TBI) in a number of ways, including terrorist radiological weapons or nuclear accidents. In order to determine whether an individual has been exposed to high doses of radiation and needs countermeasure treatment, robust biomarkers are needed to estimate radiation exposure from biospecimens such as blood or urine. In order to identity such candidate biomarkers of radiation exposure, high-resolution proteomics was used to analyze plasma from non-human primates following whole body irradiation (Co-60 at 6.7 Gy and 7.4 Gy) with a twelve day observation period. A total of 663 proteins were evaluated from the plasma proteome analysis. A panel of plasma proteins with characteristic time- and dose-dependent changes was identified. In addition to the plasma proteomics study reported here, we recently identified candidate biomarkers using urine from these same non-human primates. From the proteomic analysis of both plasma and urine, we identified ten overlapping proteins that significantly differentiate both time and dose variables. These shared plasma and urine proteins represent optimal candidate biomarkers of radiation exposure. PMID- 28350823 TI - Cluster analysis to estimate the risk of preeclampsia in the high-risk Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) study. AB - OBJECTIVES: Preeclampsia is divided into early-onset (delivery before 34 weeks of gestation) and late-onset (delivery at or after 34 weeks) subtypes, which may rise from different etiopathogenic backgrounds. Early-onset disease is associated with placental dysfunction. Late-onset disease develops predominantly due to metabolic disturbances, obesity, diabetes, lipid dysfunction, and inflammation, which affect endothelial function. Our aim was to use cluster analysis to investigate clinical factors predicting the onset and severity of preeclampsia in a cohort of women with known clinical risk factors. METHODS: We recruited 903 pregnant women with risk factors for preeclampsia at gestational weeks 12+0-13+6. Each individual outcome diagnosis was independently verified from medical records. We applied a Bayesian clustering algorithm to classify the study participants to clusters based on their particular risk factor combination. For each cluster, we computed the risk ratio of each disease outcome, relative to the risk in the general population. RESULTS: The risk of preeclampsia increased exponentially with respect to the number of risk factors. Our analysis revealed 25 number of clusters. Preeclampsia in a previous pregnancy (n = 138) increased the risk of preeclampsia 8.1 fold (95% confidence interval (CI) 5.7-11.2) compared to a general population of pregnant women. Having a small for gestational age infant (n = 57) in a previous pregnancy increased the risk of early-onset preeclampsia 17.5 fold (95%CI 2.1-60.5). Cluster of those two risk factors together (n = 21) increased the risk of severe preeclampsia to 23.8-fold (95%CI 5.1-60.6), intermediate onset (delivery between 34+0-36+6 weeks of gestation) to 25.1-fold (95%CI 3.1-79.9) and preterm preeclampsia (delivery before 37+0 weeks of gestation) to 16.4-fold (95%CI 2.0-52.4). Body mass index over 30 kg/m2 (n = 228) as a sole risk factor increased the risk of preeclampsia to 2.1-fold (95%CI 1.1-3.6). Together with preeclampsia in an earlier pregnancy the risk increased to 11.4 (95%CI 4.5-20.9). Chronic hypertension (n = 60) increased the risk of preeclampsia 5.3-fold (95%CI 2.4-9.8), of severe preeclampsia 22.2-fold (95%CI 9.9-41.0), and risk of early-onset preeclampsia 16.7-fold (95%CI 2.0-57.6). If a woman had chronic hypertension combined with obesity, gestational diabetes and earlier preeclampsia, the risk of term preeclampsia increased 4.8-fold (95%CI 0.1-21.7). Women with type 1 diabetes mellitus had a high risk of all subgroups of preeclampsia. CONCLUSION: The risk of preeclampsia increases exponentially with respect to the number of risk factors. Early-onset preeclampsia and severe preeclampsia have different risk profile from term preeclampsia. PMID- 28350825 TI - Antarctica and the strategic plan for biodiversity. AB - The Strategic Plan for Biodiversity, adopted under the auspices of the Convention on Biological Diversity, provides the basis for taking effective action to curb biodiversity loss across the planet by 2020-an urgent imperative. Yet, Antarctica and the Southern Ocean, which encompass 10% of the planet's surface, are excluded from assessments of progress against the Strategic Plan. The situation is a lost opportunity for biodiversity conservation globally. We provide such an assessment. Our evidence suggests, surprisingly, that for a region so remote and apparently pristine as the Antarctic, the biodiversity outlook is similar to that for the rest of the planet. Promisingly, however, much scope for remedial action exists. PMID- 28350826 TI - Expression, purification of metallothionein genes from freshwater crab (Sinopotamon yangtsekiense) and development of an anti-metallothionein ELISA. AB - Using the phoA-fusion technology, the recombinant metallothionein (MT) from freshwater crab (Sinopotamon yangtsekiense) has been successfully produced in Escherichia coli. MT purified from the bacterial suspension showed one polypeptide with a molecular weight of 7 kDa by tricine-sodium dodecyl sulfate polyacrylamide gel electrophoresis (Tricine-SDS-PAGE). Western-blotting confirmed the polypeptides had a specific reactivity with mouse polyclonal MT anti-serum. Based on the purified MT and MT anti-serum, the reaction parameters for an enzyme linked immunosorbent assay (ELISA) were developed. The direct coating ELISA showed a higher linear relationship compared to antibody sandwich coating ELISA. The optimal dilution rates of purified MT anti-serum and coating period were shown to be 1:160,000 and 12 hours at 4 degrees C. At 37 degrees C, the appropriate reaction duration of the first antibody and the second antibody were 2 hours and 1 hour, respectively. According to these optimal parameters, the standard linear equation, y = 0.0032x + 0.1769 (R2 = 0.9779, x, y representing MT concentration and OD450 value), was established for the determination of MT concentration with a valid range of 3.9-500 ng/ml. In verification experiments, the mean coefficients of variation of the intra-assay and inter-assay were 3.260% and 3.736%, respectively. According to the result of MT recovery, ELISA with an approaching 100% MT recovery was more reliable and sensitive than the Cd saturation assay. In conclusion, the newly developed ELISA of this study was precise, stable and repeatable, and could be used as a biomarker tool to monitor pollution by heavy metals. PMID- 28350827 TI - Time spent by Belgian hospital pharmacists on supply disruptions and drug shortages: An exploratory study. AB - INTRODUCTION: Supply problems of drugs are an increasing and worldwide problem, also in Belgium. Hospital pharmacists try to manage drug supply problems to minimize the impact on patient care. This study aims to quantify in a detailed manner how much time employees of 17 Belgian hospital pharmacies spend on drug supply problems. METHODS: During six months, employees of Belgian hospital pharmacies filled in the daily time spent on drug supply problems using a template containing all steps which can be executed to manage drug supply problems. Additionally, Belgian hospital pharmacists were asked to report the drugs which experienced drug supply problems together with the solution for this problem. RESULTS: Hospital pharmacists spent a median of 109 minutes a week on drug supply problems, with a minimum of 40 minutes per week and a maximum of 216 minutes per week. Fifty-nine percent of the total time spent on drug supply problems was executed by hospital pharmacists, 27% by pharmacy technicians; the rest was performed by logistic or administrative personnel. About one third of the total time spent was invested in gathering information on the supply problem. About two third of the supply disruptions caused drug shortages, meaning there was a need to switch to another (generic) therapeutic alternative. For most drug shortages, a Belgian generic medicine could be found. However in some cases, the alternative had to be ordered abroad or for some drug shortages, no alternative was available. CONCLUSION: These exploratory results on time spent by hospital pharmacists on drug supply problems in Belgium highlight the economic impact of drug supply problems for hospital pharmacies. A fully reliable, daily updated list on the federal agencies websites would be a major help to hospital pharmacists. PMID- 28350828 TI - Clustering of four major lifestyle risk factors among Korean adults with metabolic syndrome. AB - The purpose of this study was to investigate the clustering pattern of four major lifestyle risk factors-smoking, heavy drinking, poor diet, and physical inactivity-among people with metabolic syndrome in South Korea. There were 2,469 adults with metabolic syndrome aged 30 years or older available with the 5th Korean National Health and Nutrition Examination Survey dataset. We calculated the ratio of the observed to expected (O/E) prevalence for the 16 different combinations and the prevalence odds ratios (POR) of four lifestyle risk factors. The four lifestyle risk factors tended to cluster in specific multiple combinations. Smoking and heavy drinking was clustered (POR: 1.86 for male, 4.46 for female), heavy drinking and poor diet were clustered (POR: 1.38 for male, 1.74 for female), and smoking and physical inactivity were also clustered (POR: 1.48 for male). Those who were male, younger, low-educated and living alone were much more likely to have a higher number of lifestyle risk factors. Some helpful implications can be drawn from the knowledge on clustering pattern of lifestyle risk factors for more effective intervention program targeting metabolic syndrome. PMID- 28350829 TI - Spatio-temporal variation of fish taxonomic composition in a South-East Asian flood-pulse system. AB - The Tonle Sap Lake (TSL) is a flood-pulse system. It is the largest natural lake in South-East Asia and constitutes one of the largest fisheries over the world, supporting the livelihood of million peoples. Nonetheless, the Mekong River Basin is changing rapidly due to accelerating water infrastructure development (hydropower, irrigation, flood control, and water supply) and climate change, bringing considerable modifications to the annual flood-pulse of the TSL. Such modifications are expected to have strong impacts on fish biodiversity and abundance. This paper aims to characterize the spatio-temporal variations of fish taxonomic composition and to highlights the underlying determinants of these variations. For this purpose, we used data collected from a community catch monitoring program conducted at six sites during 141 weeks, covering two full hydrological cycles. For each week, we estimated beta diversity as the total variance of the site-by-species community matrix and partitioned it into Local Contribution to Beta Diversity (LCBD) and Species Contribution to Beta Diversity (SCBD). We then performed multiple linear regressions to determine whether species richness, species abundances and water level explained the temporal variation in the contribution of site and species to beta diversity. Our results indicate strong temporal variation of beta diversity due to differential contributions of sites and species to the spatial variation of fish taxonomic composition. We further found that the direction, the shape and the relative effect of species richness, abundances and water level on temporal variation in LCBD and SCBD values greatly varied among sites, thus suggesting spatial variation in the processes leading to temporal variation in community composition. Overall, our results suggest that fish taxonomic composition is not homogeneously distributed over space and time and is likely to be impacted in the future if the flood-pulse dynamic of the system is altered by human activities. PMID- 28350830 TI - First year physical activity findings from turn up the HEAT (Healthy Eating and Activity Time) in summer day camps. AB - BACKGROUND: Summer day camps (SDCs) serve 14 million children yearly in the U.S. and aim to provide participating children with 60 minutes of moderate-to-vigorous physical activity (MVPA). This study evaluated an intervention designed to increase the percent of children meeting this MVPA guideline. DESIGN: Two-group, pre-post quasi-experimental. SETTING/PARTICIPANTS: Twenty SDCs serving 1,830 children aged 5-12 years were assigned to MVPA intervention (n = 10) or healthy eating attention control (n = 10). INTERVENTION: The STEPs (Strategies to Enhance Practice) intervention is a capacity-building approach grounded in the Theory of Expanded, Extended and Enhanced Opportunities. Camp leaders and staff receive training to expand (e.g., introduction of activity breaks/active field trips), extend (e.g., schedule minimum of 3 hours/day for PA opportunities), and enhance (e.g., maximize MVPA children accumulate during schedule activity) activity opportunities. Camps in the comparison condition received support for improving the types of foods/beverages served. MAIN OUTCOME MEASURES: Percent of children accumulating the 60min/d MVPA guideline at baseline (summer 2015) and post-test (summer 2016) measured via wrist-accelerometry. RESULTS: Multilevel logistic regression conducted fall 2016 indicated boys and girls attending intervention SDCs were 2.04 (95CI = 1.10,3.78) and 3.84 (95CI = 2.02,7.33) times more likely to meet the 60min/d guideline compared to boys and girls attending control SDCs, respectively. This corresponded to increases of +10.6% (78-89%) and +12.6% (69 82%) in the percentage of boys and girls meeting the guideline in intervention SDCs, respectively. Boys in comparison SDCs increased by +1.6% (81-83%) and girls decreased by -5.5% (76-71%). Process data indicated intervention SDCs successfully extended and enhanced PA opportunities, but were unable to expand PA opportunities, compared to control SDCs. CONCLUSIONS: Although substantial proportions of children met the MVPA guideline at baseline, no SDCs ensured all children met the guideline. This intervention demonstrated that, with support, SDCs can help all children in attendance to accumulate their daily recommended 60min MVPA. TRIAL REGISTRATION: ClinicalTrials.gov NCT02161809. PMID- 28350831 TI - Post-term growth and cognitive development at 5 years of age in preterm children: Evidence from a prospective population-based cohort. AB - While the effects of growth from birth to expected term on the subsequent development of preterm children has attracted plentiful attention, less is known about the effects of post-term growth. We aimed to delineate distinct patterns of post-term growth and to determine their association with the cognitive development of preterm children. Data from a prospective population-based cohort of 3,850 surviving infants born at less than 35 weeks of gestational age were used. Growth was assessed as the Body Mass Index (BMI) Z-scores at 3, 9, 18, 24, 36, 48, and 60 months. Cognitive development at five years of age was evaluated by the Global School Adaptation score (GSA). Latent class analysis was implemented to identify distinct growth patterns and logistic regressions based on propensity matching were used to evaluate the relationship between identified growth trajectories and cognitive development. Four patterns of post-term growth were identified: a normal group with a Z-score consistently around zero during childhood (n = 2,469; 64%); a group with an early rapid rise in the BMI Z-score, but only up to 2 years of age (n = 195; 5%); a group with a slow yet steady rise in the BMI Z-score during childhood (n = 510; 13%); and a group with a negative Z score growth until 3 years of age (n = 676; 18%). The group with a slow yet steady rise in the BMI Z-score was significantly associated with low GSA scores. Our findings indicate heterogeneous post-term growth of preterm children, with potential for association with their cognitive development. PMID- 28350832 TI - Metal removal and associated binding fraction transformation in contaminated river sediment washed by different types of agents. AB - In ex-situ washing, HCl, EDTA and H2O2 solutions can effectively extract heavy metals in river sediment. Nevertheless they often target different sediment components, possibly transforming metal species into more bioavailable and hence toxic ones. This study, in batch settings, investigated the influences of different types of washing agents (i.e. HCl, EDTA and H2O2) on metal (i.e. Cu and Zn) removal from contaminated river sediment, destroy or dissolution of sediment components, and transformation of metal fractions during chemical washing treatment. Additionally, bioavailability of these metals left in the washed sediment was assessed. Results showed that HCl obtained the highest Cu and Zn removal through destroying the reducible, oxidizable and residual sediment components. Meanwhile, it transformed metal fractions to acid extractable one, resulting in an increase in metal bioavailability. Thus, the feasibility of washing with HCl for sediment remediation shall be reconsidered due to the caused high metal bioavailability. EDTA was capable of removing metals via direct complexation of labile metal species and indirect dissolution of reducible and oxidizable sediment components, where the transformation of corresponding metal binding fraction may occur. H2O2 obtained the lowest total Cu and Zn removal, but it preferentially removed the oxidizable metal species by oxidizing sulfides in the sediment. The bioavailable levels of Cu and Zn in the sediment washed by EDTA or H2O2 seemed not increase. To maintain a good balance between labile metal species removal and avoiding increase of metal bioavailability, EDTA and H2O2 are promising additives for metal removal by sediment washing. PMID- 28350833 TI - A fast and frugal algorithm to strengthen diagnosis and treatment decisions for catheter-associated bacteriuria. AB - OBJECTIVES: Guidelines for managing catheter-associated urinary tract infection (CAUTI) and asymptomatic bacteria (ASB) are poorly translated into routine care due in part to cognitive diagnostic errors. This study determines if the accuracy for CAUTI and ASB diagnosis and treatment improves after implementation of a fast and frugal algorithm compared with traditional education methods. MATERIALS AND METHODS: A pre and post-intervention with contemporaneous comparison site involving inpatient and long term care wards at two regional Veterans Affairs Systems in United States. Participants included 216 internal medicine residents and 16 primary care clinicians. Intervention clinicians received training with a fast and frugal algorithm. Comparison site clinicians received guidelines education. Diagnosis and treatment accuracy compared with a criterion standard was assessed during similar three-month, pre- and post-intervention periods. Sensitivity, specificity, and likelihood ratios were compared for both periods at each site. RESULTS: Bacteriuria management was evaluated against criterion standard in 196 cases pre-implementation and 117 cases post-implementation. Accuracy of bacteriuria management among intervention participants was significantly higher, post-implementation, than those at the comparison site (Intervention: positive likelihood ratio (LR+) = 8.5, specificity = 0.89, 95% confidence interval (CI) = 0.78-1.00; comparison: LR+ = 4.62, specificity (95%CI) = 0.79 (0.63-0.95). Further, improvements at the intervention site were statistically significant (pre-implementation: LR+ = 2.1, specificity (95%CI) = 0.60 (0.50-0.71); post-implementation: LR+ = 8.5, specificity (95%CI) = 0.89 (0.78-1.00). At both sites, there were similar improvements in negative LR from pre- to post-implementation: [Intervention site = 0.28 to 0.08; comparison site = 0.13 to 0.04]. Inappropriate management of ASB declined markedly from 32 (40%) to 3 (11%) cases at the intervention site. CONCLUSIONS: A fast and frugal algorithm improves diagnosis and treatment accuracy for CAUTI and reduces inappropriate treatment of ASB. Fast and frugal algorithms that realign diagnostic intuitions and treatment norms can enhance translation of evidence into practice. PMID- 28350834 TI - Development and psychometric testing of the clinical networks engagement tool. AB - BACKGROUND: Clinical networks are being used widely to facilitate large system transformation in healthcare, by engagement of stakeholders throughout the health system. However, there are no available instruments that measure engagement in these networks. METHODS: The study purpose was to develop and assess the measurement properties of a multiprofessional tool to measure engagement in clinical network initiatives. Based on components of the International Association of Public Participation Spectrum and expert panel review, we developed 40 items for testing. The draft instrument was distributed to 1,668 network stakeholders across different governance levels (leaders, members, support, frontline stakeholders) in 9 strategic clinical networks in Alberta (January to July 2014). With data from 424 completed surveys (25.4% response rate), descriptive statistics, exploratory and confirmatory factor analysis, Pearson correlations, linear regression, multivariate analysis, and Cronbach alpha were conducted to assess reliability and validity of the scores. RESULTS: Sixteen items were retained in the instrument. Exploratory factor analysis indicated a four-factor solution and accounted for 85.7% of the total variance in engagement with clinical network initiatives: global engagement, inform (provided with information), involve (worked together to address concerns), and empower (given final decision-making authority). All subscales demonstrated acceptable reliability (Cronbach alpha 0.87 to 0.99). Both the confirmatory factor analysis and regression analysis confirmed that inform, involve, and empower were all significant predictors of global engagement, with involve as the strongest predictor. Leaders had higher mean scores than frontline stakeholders, while members and support staff did not differ in mean scores. CONCLUSIONS: This study provided foundational evidence for the use of this tool for assessing engagement in clinical networks. Further work is necessary to evaluate engagement in broader network functions and activities; to assess barriers and facilitators of engagement; and, to elucidate how the maturity of networks and other factors influence engagement. PMID- 28350835 TI - An information-based network approach for protein classification. AB - Protein classification is one of the critical problems in bioinformatics. Early studies used geometric distances and polygenetic-tree to classify proteins. These methods use binary trees to present protein classification. In this paper, we propose a new protein classification method, whereby theories of information and networks are used to classify the multivariate relationships of proteins. In this study, protein universe is modeled as an undirected network, where proteins are classified according to their connections. Our method is unsupervised, multivariate, and alignment-free. It can be applied to the classification of both protein sequences and structures. Nine examples are used to demonstrate the efficiency of our new method. PMID- 28350836 TI - Perceived psychosocial stress and gestational weight gain among women with gestational diabetes. AB - Growing evidence links perceived stress-a potentially modifiable psychosocial risk factor-with health behaviors and obesity. Yet little is known about the relationship between stress during pregnancy and gestational weight gain, particularly among women with pregnancy complications. We conducted a cross sectional analysis to examine associations between psychosocial stress during pregnancy and gestational weight gain among women with gestational diabetes. We used baseline data from the Gestational Diabetes's Effects on Moms (GEM) study: 1,353 women with gestational diabetes who delivered a term singleton within Kaiser Permanente Northern California were included. Perceived stress near the time of gestational diabetes diagnosis was measured using the validated Perceived Stress Scale (PSS10). Gestational weight gain was categorized according to the 2009 Institute of Medicine recommendations. Binomial regression analyses adjusted for gestational age and maternal age at the time of gestational diabetes diagnosis, and race/ethnicity and estimated rate ratios (RR) and their 95% confidence interval (CI). Among women with a normal pregravid Body Mass Index (BMI 18.5-24.9 kg/m2), there was a significant association between high (Q4) PSS score and risk of both exceeding and gaining below the Institute of Medicine recommendations compared to those with lower stress (Q1) [adjusted RR = 2.16 95% CI 1.45-3.21; RR = 1.39 95% CI 1.01-1.91, respectively.] Among women with pregravid overweight/obesity (BMI>=25 kg/m2), there was no association. Although the temporal relationship could not be established from this study, there may be a complex interplay between psychosocial stress and gestational weight gain among women with gestational diabetes. Further studies examining stress earlier in pregnancy, risk of developing gestational diabetes and excess/inadequate gestational weight gain are warranted to clarify these complex relationships. PMID- 28350837 TI - Semaphorin 3F expression is reduced in pregnancy complicated by preeclampsia. An observational clinical study. AB - BACKGROUND AND OBJECTIVE: Preeclampsia is a systemic disorder, affecting 2-10% of pregnancies, characterized by a deregulated pro- and anti-angiogenic balance. Semaphorin 3F is an angiogenesis inhibitor. We aimed to investigate whether semaphorin 3F expression is modulated in preeclampsia. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: We performed two observational single center cohort studies between March 2013 and August 2014. In the first we enrolled 110 consecutive women, undergoing an elective cesarean section; in the second we included 150 consecutive women undergoing amniocentesis for routine clinical indications at 16-18 week of gestation. Semaphorin 3F concentration was evaluated in maternal peripheral blood, venous umbilical blood and amniotic fluid, along with its placenta protein expression at the time of delivery in the first study group and in the amniotic fluid at 16-18 weeks of gestation in the second study group. RESULTS: In the first study 19 patients presented at delivery with preeclampsia. Semaphorin 3F placenta tissue expression was significantly reduced in preeclampsia. In addition, semaphorin 3F level at delivery was significantly lower in serum, amniotic fluid and venous umbilical blood of preeclamptic patients compared with normal pregnant women. In the prospective cohort study 14 women developed preeclampsia. In this setting, semaphorin 3F amniotic level at 16 18 weeks of gestation was reduced in women who subsequently developed preeclampsia compared to women with a normal pregnancy. ROC curve analysis showed that semaphorin 3F amniotic levels could identify women at higher risk of preeclampsia. CONCLUSIONS: Semaphorin 3F might represent a predictive biomarker of preeclampsia. PMID- 28350838 TI - Function and failure of the fetal membrane: Modelling the mechanics of the chorion and amnion. AB - The fetal membrane surrounds the fetus during pregnancy and is a thin tissue composed of two layers, the chorion and the amnion. While rupture of this membrane normally occurs at term, preterm rupture can result in increased risk of fetal mortality and morbidity, as well as danger of infection in the mother. Although structural changes have been observed in the membrane in such cases, the mechanical behaviour of the human fetal membrane in vivo remains poorly understood and is challenging to investigate experimentally. Therefore, the objective of this study was to develop simplified finite element models to investigate the mechanical behaviour and rupture of the fetal membrane, particularly its constituent layers, under various physiological conditions. It was found that modelling the chorion and amnion as a single layer predicts remarkably different behaviour compared with a more anatomically-accurate bilayer, significantly underestimating stress in the amnion and under-predicting the risk of membrane rupture. Additionally, reductions in chorion-amnion interface lubrication and chorion thickness (reported in cases of preterm rupture) both resulted in increased membrane stress. Interestingly, the inclusion of a weak zone in the fetal membrane that has been observed to develop overlying the cervix would likely cause it to fail at term, during labour. Finally, these findings support the theory that the amnion is the dominant structural component of the fetal membrane and is required to maintain its integrity. The results provide a novel insight into the mechanical effect of structural changes in the chorion and amnion, in cases of both normal and preterm rupture. PMID- 28350840 TI - Effects of element complexes containing Fe, Zn and Mn on artificial morel's biological characteristics and soil bacterial community structures. AB - This study described the effects of elements (including Fe, Zn, Mn and their complexes) on the following factors in artificial morel cultivation: the characteristics of mycelia and sclerotia, soil bacterial community structures, yields and contents of microelements. The results indicated that the groups containing Mn significantly promoted mycelia growth rates, and all the experimental groups resulted in higher yields than the control (P<0.01), although their mycelia and sclerotia did not show obvious differences. It was also found that Proteobacteria, Chloroflexi, Bacteroides, Firmicutes, Actinobacteria, Acidobacteria and Nitrospirae were the dominated bacterial phyla. The Zn.Fe group had an unexpectedly high proportion (75.49%) of Proteobacteria during the primordial differentiation stage, while Pseudomonas also occupied a high proportion (5.52%) in this group. These results suggested that different trace elements clearly affected morel yields and soil bacterial community structures, particularly due to the high proportions of Pseudomonas during the primordial differentiation stage. PMID- 28350841 TI - Correction: Lack of Effect of Oral Sulforaphane Administration on Nrf2 Expression in COPD: A Randomized, Double-Blind, Placebo Controlled Trial. AB - [This corrects the article DOI: 10.1371/journal.pone.0163716.]. PMID- 28350839 TI - Bidirectional association between nonalcoholic fatty liver disease and type 2 diabetes in Chinese population: Evidence from the Dongfeng-Tongji cohort study. AB - OBJECTIVES: The aim of this study is to examine the bidirectional association between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). METHODS: The data was derived from the Dongfeng-Tongji cohort study, which was established in 2008 and followed until October 2013. NAFLD was classified as none, mild, moderate/severe based on ultrasound examination. The analysis to examine the association between NAFLD and incident T2DM risk included 18,111 participants free of diabetes at baseline and the duration of follow-up was 4.60 +/- 0.60 years. Cox proportional regression model was used to calculate the hazard ratio (HR) for the association. The analysis to investigate the association between T2DM and incident NAFLD risk included 12,435 participants free of NAFLD at baseline. Logistic regression model was used to calculate the odd ratio (OR) of NAFLD. RESULTS: Compared with those without NAFLD, individuals with mild or moderate/severe NAFLD had a monotonic elevated risk of developing T2DM (HR: 1.88 [95% CI: 1.63-2.18] and 2.34 [1.85-2.96], respectively) after adjustment for potential confounders. In a parallel analysis, compared to participants with fasting plasma glucose < 6.1 mmol/L, the ORs of developing NAFLD in subjects with impaired fasting glucose and T2DM were 1.35 (95% CI: 1.16 1.57) and 1.40 (95% CI: 1.22-1.62), respectively. CONCLUSIONS: Our results provide compelling evidence that the NAFLD-T2DM association is bidirectional in Chinese population. PMID- 28350842 TI - Combination of mesenchymal stem cell injection with icariin for the treatment of diabetes-associated erectile dysfunction. AB - The present study was aimed to examine whether icariin, a traditional Chinese medicine, could improve therapeutic effects of adipose derived mesenchymal stem cells (ADSCs) for diabetes-associated erectile dysfunction (DMED). DMED were induced in rats by intraperitoneal injection of streptozotocin and confirmed by erectile function measurement. Then, rats of diabetic ED were randomly divided to receive the treatment of saline, ADSCs, icariin or ADSCs combined with icariin respectively. Compared with the treatment by ADSCs or icariin alone, intracavernosum injection of ADSCs combined with the following daily gastric gavage of icariin significantly augmented the value of ICP and ICP/MAP (p<0.01). Meanwhile, the survival of transplanted ADSCs was much improved due to the application of icariin. Similarly, immunofluorescent staining analysis demonstrated that the improved erectile tissue structure by combination of ADSCs and icariin was significantly associated with the increased expression of endothelial markers (vWF) (p<0.01) and smooth muscle markers (alpha-SMA) (p<0.01). Furthermore, the structure changes in corpus cavernosum were further confirmed by the Masson's trichrome staining. To explore the possible mechanism underlying icariin-enhanced therapeutic efficacy of MSCs, we employed an in vitro testing system by introducing H2O2 to imitate oxidative stress condition considering the oxidative environment faced by engrafted ADSCs and anti-oxidative capacity of icariin. In vitro, we found that the addition of icariin considerably reduced the apoptosis of ADSCs, and attenuated the intracellular reactive oxygen species (ROS), the superoxidase dismutase (SOD) activity and the lactate dehydrogenase (LDH). Subsequently, we examined the expression of apoptosis related proteins and explored the potential signaling pathway through which icariin promoted the survival of ADSCs against oxidative stress. It was demonstrated that icariin significantly inhibited the upregulation of apoptosis related proteins under oxidative condition, including Bax and cleaved caspase-3, while promoted the expression of anti-apoptotic factor BCL2. These effects were accompanied with the activation of signal molecules, PI3K/Akt and STAT3. The further signal protein inhibition assays exhibited that the suppression of STAT3 abrogated the icariin-mediated anti-apoptotic effects observed above, while did not influence the expression of PI3K/Akt. However, PI3K inhibition could abrogate icariin-mediated STAT3 activation and achieved a similar effect as STAT3 inhibition. Our results suggested that icariin was an effective adjuvant for enhancing ADSC-based therapy of DMEM, which may be ascribed to their protection of ADSCs against oxidative stress via the regulation of PI3K/Akt-STAT3 signal pathway. PMID- 28350843 TI - High HIV prevalence and incidence among women in Southern Mozambique: Evidence from the MDP microbicide feasibility study. AB - BACKGROUND: The study aimed to assess the feasibility of conducting large scale HIV prevention clinical trials in Mozambique by measuring HIV prevalence and incidence among women of reproductive age. This paper describes the baseline socio-demographic characteristics of the Mozambique Microbicides Development Programme (MDP) feasibility cohort, baseline prevalence of HIV and other STIs, and HIV incidence. METHODS: The Mozambique MDP feasibility study was conducted from September 2007 to August 2009 in urban Mavalane and rural Manhica, in Southern Mozambique. Sexually active, HIV negative women aged 18 years and above were recruited to attend the study clinic every 4 weeks for a total of 40 weeks. At baseline, we collected demographic and sexual behaviour data, samples to test for sexually transmitted infections (STI) and conducted HIV rapid testing. STI and HIV testing were repeated at clinical follow-up visits. We describe HIV prevalence of women at screening, the demographic, behavioural and clinical characteristics of women at enrolment, and HIV incidence during follow-up. RESULTS: We screened 793 women (369 at Mavalane and 424 at Manhica) and enrolled 505 eligible women (254 at Mavalane and 251 at Manhica). Overall HIV prevalence at screening was 17%; 10% at Mavalane and 22% at Manhica. Women screened at Manhica were twice as likely as women screened at Mavalane to be HIV positive and HIV positive status was associated with younger age (18-34), lower educational level, not using a reliable method of contraception and being Zionist compared to other Christian religions. At enrolment contraceptive use was low in both clinics at 19% in Mavalane and 21% in Manhica, as was reported condom use at last sex act at 48% in Mavalane and 25% in Manhica. At enrolment, 8% of women tested positive for Trichomonas vaginalis, 2% for Neisseria gonorrhoeae, 4% for Chlamydia trachomatis and 46% for bacterial vaginosis. In Manhica, 8% of women had active syphilis at screening. HIV incidence was 4.3 per 100 person years at Mavalane and 9.2 per 100 person years at Manhica. CONCLUSIONS: We demonstrated the ability to recruit a cohort of women at risk of HIV who were willing to participate in clinical research. The high HIV incidence necessitates additional action around HIV prevention for women and offers opportunities to evaluate the impact of available prevention options, such as treatment as prevention and oral PrEP. The high HIV incidence and STI prevalence also offers opportunities to evaluate the added benefit of potential prevention options such as new formulations of oral PrEP, vaginal microbicides (also called topical PrEP), vaccines, and multi purpose technologies for HIV, STIs and contraception. PMID- 28350844 TI - Isolation and characterization of alternatively spliced variants of the mouse sigma1 receptor gene, Sigmar1. AB - The sigma1 receptor acts as a chaperone at the endoplasmic reticulum, associates with multiple proteins in various cellular systems, and involves in a number of diseases, such as addiction, pain, cancer and psychiatric disorders. The sigma1 receptor is encoded by the single copy SIGMAR1 gene. The current study identifies five alternatively spliced variants of the mouse sigma1 receptor gene using a polymerase chain reaction cloning approach. All the splice variants are generated by exon skipping or alternative 3' or 5' splicing, producing the truncated sigma1 receptor. Similar alternative splicing has been observed in the human SIGMAR1 gene based on the molecular cloning or genome sequence prediction, suggesting conservation of alternative splicing of SIGMAR1 gene. Using quantitative polymerase chain reactions, we demonstrate differential expression of several splice variants in mouse tissues and brain regions. When expressed in HEK293 cells, all the splice variants fail to bind sigma ligands, implicating that each truncated region in these splice variants is important for ligand binding. However, co-immunoprecipitation (Co-IP) study in HEK293 cells co-transfected with tagged constructs reveals that all the splice variants maintain their ability to physically associate with a mu opioid receptor (mMOR-1), providing useful information to correlate the motifs/sequences necessary for their physical association. Furthermore, a competition Co-IP study showed that all the variants can disrupt in a dose-dependent manner the dimerization of the original sigma1 receptor with mMOR-1, suggesting a potential dominant negative function and providing significant insights into their function. PMID- 28350845 TI - Abnormal expression of mRNA, microRNA alteration and aberrant DNA methylation patterns in rectal adenocarcinoma. AB - AIM: Rectal adenocarcinoma (READ) is a malignancy cancer with the high morbidity and motility worldwide. Our study aimed to explore the potential pathogenesis of READ through integrated analysis of gene expression profiling and DNA methylation data. METHODS: The miRNA, mRNA expression profiling and corresponding DNA methylation data were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed mRNAs/ miRNAs/methylated regions (DEmRNA/DEmiRNAs) were identified in READ. The negatively correlation of DEmiRNA-DEmRNAs and DNA methylation-DEmRNAs were obtained. DEmRNAs expression was validated through quantitative real-time polymerase chain reaction (qRT-PCR) and microarray expression profiling analyses. RESULTS: 1192 dysregulated DEmRNAs, 27 dysregulated DEmiRNAs and 6403 aberrant methylation CpG sites were screened in READ compared to normal controls. 1987 negative interaction pairs among 27 DEmiRNAs and 668 DEmRNAs were predicted. 446 genes with aberrant methylation were annotated. Eventually, 50 DEmRNAs (39 down- and 11 up-regulated DEmRNAs) with hypermethylation, synchronously negatively targeted by DEmiRNAs, were identified through the correlation analysis among 446 genes with aberrant methylation and 668 DEmRNAs. 50 DEmRNAs were significantly enriched in cAMP signaling pathway, circadian entrainment and glutamatergic synapse. The validation results of expression levels of DEmRNAs through qRT-PCR and microarray analyses were compatible with our study. CONCLUSION: 7 genes of SORCS1, PDZRN4, LONRF2, CNGA3, HAND2, RSPO2 and GNAO1 with hypermethylation and negatively regulation by DEmiRNAs might contribute to the tumorigenesis of READ. Our work might provide valuable foundation for the READ in mechanism elucidation, early diagnosis and therapeutic target identification. PMID- 28350846 TI - Dissemination and genetic diversity of chlamydial agents in Polish wildfowl: Isolation and molecular characterisation of avian Chlamydia abortus strains. AB - Wild birds are considered as a reservoir for avian chlamydiosis posing a potential infectious threat to domestic poultry and humans. Analysis of 894 cloacal or fecal swabs from free-living birds in Poland revealed an overall Chlamydiaceae prevalence of 14.8% (n = 132) with the highest prevalence noted in Anatidae (19.7%) and Corvidae (13.4%). Further testing conducted with species specific real-time PCR showed that 65 samples (49.2%) were positive for C. psittaci whereas only one was positive for C. avium. To classify the non identified chlamydial agents and to genotype the C. psittaci and C. avium positive samples, specimens were subjected to ompA-PCR and sequencing (n = 83). The ompA-based NJ dendrogram revealed that only 23 out of 83 sequences were assigned to C. psittaci, in particular to four clades representing the previously described C. psittaci genotypes B, C, Mat116 and 1V. Whereas the 59 remaining sequences were assigned to two new clades named G1 and G2, each one including sequences recently obtained from chlamydiae detected in Swedish wetland birds. G1 (18 samples from Anatidae and Rallidae) grouped closely together with genotype 1V and in relative proximity to several C. abortus isolates, and G2 (41 samples from Anatidae and Corvidae) grouped closely to C. psittaci strains of the classical ABE cluster, Matt116 and M56. Finally, deep molecular analysis of four representative isolates of genotypes 1V, G1 and G2 based on 16S rRNA, IGS and partial 23S rRNA sequences as well as MLST clearly classify these isolates within the C. abortus species. Consequently, we propose an expansion of the C. abortus species to include not only the classical isolates of mammalian origin, but also avian isolates so far referred to as atypical C. psittaci or C. psittaci/C. abortus intermediates. PMID- 28350847 TI - Biophysical characterization of the b-HLH-LZ of DeltaMax, an alternatively spliced isoform of Max found in tumor cells: Towards the validation of a tumor suppressor role for the Max homodimers. AB - It is classically recognized that the physiological and oncogenic functions of Myc proteins depend on specific DNA binding enabled by the dimerization of its C terminal basic-region-Helix-Loop-Helix-Leucine Zipper (b-HLH-LZ) domain with that of Max. However, a new paradigm is emerging, where the binding of the c-Myc/Max heterodimer to non-specific sequences in enhancers and promoters drives the transcription of genes involved in diverse oncogenic programs. Importantly, Max can form a stable homodimer even in the presence of c-Myc and bind DNA (specific and non-specific) with comparable affinity to the c-Myc/Max heterodimer. Intriguingly, alterations in the Max gene by germline and somatic mutations or changes in the gene product by alternative splicing (e.g. DeltaMax) were recently associated with pheochromocytoma and glioblastoma, respectively. This has led to the proposition that Max is, by itself, a tumor suppressor. However, the actual mechanism through which it exerts such an activity remains to be elucidated. Here, we show that contrary to the WT motif, the b-HLH-LZ of DeltaMax does not homodimerize in the absence of DNA. In addition, although DeltaMax can still bind the E-box sequence as a homodimer, it cannot bind non-specific DNA in that form, while it can heterodimerize with c-Myc and bind E-box and non-specific DNA as a heterodimer with high affinity. Taken together, our results suggest that the WT Max homodimer is important for attenuating the binding of c-Myc to specific and non-specific DNA, whereas DeltaMax is unable to do so. Conversely, the splicing of Max into DeltaMax could provoke an increase in overall chromatin bound c-Myc. According to the new emerging paradigm, the splicing event and the stark reduction in homodimer stability and DNA binding should promote tumorigenesis impairing the tumor suppressor activity of the WT homodimer of Max. PMID- 28350849 TI - Science deserves to be judged by its contents, not by its wrapping: Revisiting Seglen's work on journal impact and research evaluation. AB - The scientific foundation for the criticism on the use of the Journal Impact Factor (JIF) in evaluations of individual researchers and their publications was laid between 1989 and 1997 in a series of articles by Per O. Seglen. His basic work has since influenced initiatives such as the San Francisco Declaration on Research Assessment (DORA), the Leiden Manifesto for research metrics, and The Metric Tide review on the role of metrics in research assessment and management. Seglen studied the publications of only 16 senior biomedical scientists. We investigate whether Seglen's main findings still hold when using the same methods for a much larger group of Norwegian biomedical scientists with more than 18,000 publications. Our results support and add new insights to Seglen's basic work. PMID- 28350848 TI - Reduction of oxidative-nitrosative stress underlies anticataract effect of topically applied tocotrienol in streptozotocin-induced diabetic rats. AB - Cataract, a leading cause of blindness, is of special concern in diabetics as it occurs at earlier onset. Polyol accumulation and increased oxidative-nitrosative stress in cataractogenesis are associated with NFkappaB activation, iNOS expression, ATP depletion, loss of ATPase functions, calpain activation and proteolysis of soluble to insoluble proteins. Tocotrienol was previously shown to reduce lens oxidative stress and inhibit cataractogenesis in galactose-fed rats. In current study, we investigated anticataract effects of topical tocotrienol and possible mechanisms involved in streptozotocin-induced diabetic rats. Diabetes was induced in Sprague Dawley rats by intraperitoneal injection of streptozotocin. Diabetic rats were treated with vehicle (DV) or tocotrienol (DT). A third group consists of normal, non-diabetic rats were treated with vehicle (NV). All treatments were given topically, bilaterally, twice daily for 8 weeks with weekly slit lamp monitoring. Subsequently, rats were euthanized and lenses were subjected to estimation of polyol accumulation, oxidative-nitrosative stress, NFkappaB activation, iNOS expression, ATP levels, ATPase activities, calpain activity and total protein levels. Cataract progression was delayed from the fifth week onwards in DT with lower mean of cataract stages compared to DV group (p<0.01) despite persistent hyperglycemia. Reduced cataractogenesis in DT group was accompanied with lower aldose reductase activity and sorbitol level compared to DV group (p<0.01). DT group also showed reduced NFkappaB activation, lower iNOS expression and reduced oxidative-nitrosative stress compared to DV group. Lenticular ATP and ATPase and calpain 2 activities in DT group were restored to normal. Consequently, soluble to insoluble protein ratio in DT group was higher compared to DV (p<0.05). In conclusion, preventive effect of topical tocotrienol on development of cataract in STZ-induced diabetic rats could be attributed to reduced lens aldose reductase activity, polyol levels and oxidative nitrosative stress. These effects of tocotrienol invlove reduced NFkappaB activation, lower iNOS expression, restoration of ATP level, ATPase activities, calpain activity and lens protein levels. PMID- 28350850 TI - Defective bone repair in mast cell-deficient Cpa3Cre/+ mice. AB - In the adult skeleton, cells of the immune system interact with those of the skeleton during all phases of bone repair to influence the outcome. Mast cells are immune cells best known for their pathologic role in allergy, and may be involved in chronic inflammatory and fibrotic disorders. Potential roles for mast cells in tissue homeostasis, vascularization and repair remain enigmatic. Previous studies in combined mast cell- and Kit-deficient KitW-sh/W-sh mice (KitW sh) implicated mast cells in bone repair but KitW-sh mice suffer from additional Kit-dependent hematopoietic and non- hematopoietic deficiencies that could have confounded the outcome. The goal of the current study was to compare bone repair in normal wild type (WT) and Cpa3Cre/+ mice, which lack mast cells in the absence of any other hematopoietic or non- hematopoietic deficiencies. Repair of a femoral window defect was characterized using micro CT imaging and histological analyses from the early inflammatory phase, through soft and hard callus formation, and finally the remodeling phase. The data indicate 1) mast cells appear in healing bone of WT mice but not Cpa3Cre/+ mice, beginning 14 days after surgery; 2) re-vascularization of repair tissue and deposition of mineralized bone was delayed and dis-organised in Cpa3Cre/+ mice compared with WT mice; 3) the defects in Cpa3Cre/+ mice were associated with little change in anabolic activity and biphasic alterations in osteoclast and macrophage activity. The outcome at 56 days postoperative was complete bridging of the defect in most WT mice and fibrous mal-union in most Cpa3Cre/+ mice. The results indicate that mast cells promote bone healing, possibly by recruiting vascular endothelial cells during the inflammatory phase and coordinating anabolic and catabolic activity during tissue remodeling. Taken together the data indicate that mast cells have a positive impact on bone repair. PMID- 28350851 TI - Alcohol-related changes in the intestinal microbiome influence neutrophil infiltration, inflammation and steatosis in early alcoholic hepatitis in mice. AB - BACKGROUND: Alcohol-induced intestinal dysbiosis disrupts homeostatic gut-liver axis function and is essential in the development of alcoholic liver disease. Here, we investigate changes in enteric microbiome composition in a model of early alcoholic steatohepatitis and dissect the pathogenic role of intestinal microbes in alcohol-induced liver pathology. MATERIALS AND METHODS: Wild type mice received a 10-day diet that was either 5% alcohol-containing or an isocaloric control diet plus a single binge. 16S rDNA sequencing defined the bacterial communities in the cecum of alcohol- and pair-fed animals. Some mice were treated with an antibiotic cocktail prior to and throughout alcohol feeding. Liver neutrophils, cytokines and steatosis were evaluated. RESULTS: Acute-on chronic alcohol administration induced shifts in various bacterial phyla in the cecum, including increased Actinobacteria and a reduction in Verrucomicrobia driven entirely by a reduction in the genus Akkermansia. Antibiotic treatment reduced the gut bacterial load and circulating bacterial wall component lipopolysaccharide (LPS). We found that bacterial load suppression prevented alcohol-related increases in the number of myeloperoxidase- (MPO) positive infiltrating neutrophils in the liver. Expression of liver mRNA tumor necrosis factor alpha (Tnfalpha), C-X-C motif chemokine ligand 1 (Cxcl1) and circulating protein monocyte chemoattractant protein-1 (MCP-1) were also reduced in antibiotic-treated alcohol-fed mice. Alcohol-induced hepatic steatosis measured by Oil-Red O staining was significantly reduced in antibiotic treated mice. Genes regulating lipid production and storage were also altered by alcohol and antibiotic treatment. Interestingly, antibiotic treatment did not protect from alcohol-induced increases in serum aminotransferases (ALT/AST). CONCLUSIONS: Our data indicate that acute-on-chronic alcohol feeding alters the microflora at multiple taxonomic levels and identifies loss of Akkermansia as an early marker of alcohol-induced gut dysbiosis. We conclude that gut microbes influence liver inflammation, neutrophil infiltration and liver steatosis following alcohol consumption and these data further emphasize the role of the gut-liver axis in early alcoholic liver disease. PMID- 28350852 TI - Phylodynamics on local sexual contact networks. AB - Phylodynamic models are widely used in infectious disease epidemiology to infer the dynamics and structure of pathogen populations. However, these models generally assume that individual hosts contact one another at random, ignoring the fact that many pathogens spread through highly structured contact networks. We present a new framework for phylodynamics on local contact networks based on pairwise epidemiological models that track the status of pairs of nodes in the network rather than just individuals. Shifting our focus from individuals to pairs leads naturally to coalescent models that describe how lineages move through networks and the rate at which lineages coalesce. These pairwise coalescent models not only consider how network structure directly shapes pathogen phylogenies, but also how the relationship between phylogenies and contact networks changes depending on epidemic dynamics and the fraction of infected hosts sampled. By considering pathogen phylogenies in a probabilistic framework, these coalescent models can also be used to estimate the statistical properties of contact networks directly from phylogenies using likelihood-based inference. We use this framework to explore how much information phylogenies retain about the underlying structure of contact networks and to infer the structure of a sexual contact network underlying a large HIV-1 sub-epidemic in Switzerland. PMID- 28350853 TI - Impacts of 120 years of fertilizer addition on a temperate grassland ecosystem. AB - The widespread application of fertilizers has greatly influenced many processes and properties of agroecosystems, and agricultural fertilization is expected to increase even further in the future. To date, most research on fertilizer impacts has used short-term studies, which may be unrepresentative of long-term responses, thus hindering our capacity to predict long-term impacts. Here, we examined the effects of long-term fertilizer addition on key ecosystem properties in a long-term grassland experiment (Palace Leas Hay Meadow) in which farmyard manure (FYM) and inorganic fertilizer treatments have been applied consistently for 120 years in order to characterize the experimental site more fully and compare ecosystem responses with those observed at other long-term and short-term experiments. FYM inputs increased soil organic carbon (SOC) stocks, hay yield, nutrient availability and acted as a buffer against soil acidification (>pH 5). In contrast, N-containing inorganic fertilizers strongly acidified the soil (20% or to over 55%) in 31 (54.39%) patients with worse baseline cardiac function and ventricular rate control. CONCLUSIONS: Catheter ablation relative to cardioversion of persistent AF with symptomatic heart failure yielded better 12-month SR maintenance and cardiac function. Compared with non-responders, patients with improved LVEF post-ablation had poorer ventricular rate control and cardiac function at baseline, suggesting a significant component of tachycardia-induced cardiomyopathy in this group. PMID- 28350862 TI - Repeated quantitative measurements of De Novo synthesis of albumin and fibrinogen. AB - The possibility of using two different isotopomers, for the incorporation of isotopically labeled amino acids, was explored to enable longitudinal studies of de novo synthesis of two export liver proteins, albumin and fibrinogen. The agreement of the synthesis rates between the two different labels was evaluated along with the reproducibility of repeated experiments using different time intervals. Healthy volunteers were studied in a standardized fed state. Protocol A (n = 10) involved two measurements 48 hours apart. Protocol B (n = 6) involved three measurements at baseline and five hours and then seven days after the initial measurement. De novo synthesis of albumin and fibrinogen by the incorporation of D5-phenylalanine or D8-phenylalanine were measured using the flooding dose technique. Albumin and fibrinogen were isolated from plasma using standard techniques. Fractional and absolute synthesis rates were calculated. Repeated measurements employing the two isotoptomers showed good agreement for albumin fractional synthesis rate after 48 hours (p = 0.92) and after 7 days (p = 0.99), with a coefficient of variation of 5.9% when using the same isotopic label. For fibrinogen, the coefficient of variation for the fractional synthesis rate employing the same isotopic label was 16.6%. Repeated measurements after 48 hours and seven days showed less agreement although there was no statistical difference (P = 0.32 and P = 0.30 respectively). Repeated measurement after five hours showed a statistical significant difference for the fractional synthesis rate of fibrinogen (p = 0.008) but not for albumin (p = 0.12). Repeated measurements of albumin de novo synthesis more than 48 hours apart show acceptable agreement using either one or two different isotopic labels. For fibrinogen the larger intra-individual scatter necessitates larger study groups to detect changes in longitudinal studies. Repeated measurements within 48 hours need to be validated further. PMID- 28350863 TI - The relationship between least-cost and resistance distance. AB - Least-cost modelling and circuit theory are common analogs used in ecology and evolution to model gene flow or animal movement across landscapes. Least-cost modelling estimates the least-cost distance, whereas circuit theory estimates resistance distance. The bias added in choosing one method over the other has not been well documented. We designed an experiment to test whether both methods were linearly related. We also tested the sensitivity of these metrics to variation in Euclidean distance, spatial autocorrelation, the number of pixels representing the landscape, and data aggregation. We found that least-cost and resistance distance were not linearly related unless a transformation was applied. Resistance distance was less sensitive to the number of pixels representing a landscape and was also less sensitive than least-cost distance to the Euclidean distance between nodes. Spatial autocorrelation did not affect either method or the relationship between methods. Resistance distance was more sensitive to aggregation in any form compared to least-cost distance. Therefore, the metric used to infer movement or gene flow and the manipulations applied to the data used to calculate these metrics may govern findings. PMID- 28350864 TI - Codon-level co-occurrences of germline variants and somatic mutations in cancer are rare but often lead to incorrect variant annotation and underestimated impact prediction. AB - Cancer cells explore a broad mutational landscape, bringing the possibility that tumor-specific somatic mutations could fall in the same codons as germline SNVs and leverage their presence to produce substitutions with a larger impact on protein function. While multiple, temporally consecutive mutations to the same codon have in the past been detected in the germline, this phenomenon has not yet been explored in the context of germline-somatic variant co-occurrences during cancer development. We examined germline context at somatic mutation sites for 1395 patients across four cancer cohorts (breast, skin, colon, and head and neck) and found 392 codon-level co-occurrences between germline and somatic variants, including over a dozen in well-known cancer genes. We found that for the majority of these co-occurrence events, traditional somatic calling led to an inaccurate representation of the protein site and a significantly lower predicted impact on protein fitness. We conclude that these events often lead to imprecise annotation of somatic variants but do not appear to be a frequent source of driver events during cancer development. PMID- 28350866 TI - Correction: Fall armyworm migration across the Lesser Antilles and the potential for genetic exchanges between North and South American populations. AB - [This corrects the article DOI: 10.1371/journal.pone.0171743.]. PMID- 28350865 TI - Multi-drug loaded micelles delivering chemotherapy and targeted therapies directed against HSP90 and the PI3K/AKT/mTOR pathway in prostate cancer. AB - BACKGROUND: Advanced prostate cancers that are resistant to all current therapies create a need for new therapeutic strategies. One recent innovative approach to cancer therapy is the simultaneous use of multiple FDA-approved drugs to target multiple pathways. A challenge for this approach is caused by the different solubility requirements of each individual drug, resulting in the need for a drug vehicle that is non-toxic and capable of carrying multiple water-insoluble antitumor drugs. Micelles have recently been shown to be new candidate drug solubilizers for anti cancer therapy. METHODS: This study set out to examine the potential use of multi-drug loaded micelles for prostate cancer treatment in preclinical models including cell line and mouse models for prostate cancers with Pten deletions. Specifically antimitotic agent docetaxel, mTOR inhibitor rapamycin, and HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin were incorporated into the micelle system (DR17) and tested for antitumor efficacy. RESULTS: In vitro growth inhibition of prostate cancer cells was greater when all three drugs were used in combination compared to each individual drug, and packaging the drugs into micelles enhanced the cytotoxic effects. At the molecular level DR17 targeted simultaneously several molecular signaling axes important in prostate cancer including androgen receptor, mTOR, and PI3K/AKT. In a mouse genetic model of prostate cancer, DR17 treatment decreased prostate weight, which was achieved by both increasing caspase-dependent cell death and decreasing cell proliferation. Similar effects were also observed when DR17 was administered to nude mice bearing prostate cancer cells xenografts. CONCLUSION: These results suggest that combining these three cancer drugs in multi-drug loaded micelles may be a promising strategy for prostate cancer therapy. PMID- 28350868 TI - Correction: Quantification of santonin in eight species of Artemisia from Kazakhstan by means of HPLC-UV: Method development and validation. AB - [This corrects the article DOI: 10.1371/journal.pone.0173714.]. PMID- 28350867 TI - Dissociation between skin test reactivity and anti-aeroallergen IgE: Determinants among urban Brazilian children. AB - BACKGROUND: The dissociation between specific IgE and skin prick test reactivity to aeroallergens, a common finding in populations living in low and middle-income countries, has important implications for the diagnosis and treatment of allergic diseases. Few studies have investigated the determinants of this dissociation. In the present study, we explored potential factors explaining this dissociation in children living in an urban area of Northeast Brazil, focusing in particular on factors associated with poor hygiene. METHODS: Of 1445 children from low income communities, investigated for risk factors of allergies, we studied 481 with specific IgE antibodies to any of Blomia tropicalis, Dermatophagoides pteronyssinus, Periplaneta americana and Blatella germanica allergens. Data on demographic, environmental and social exposures were collected by questionnaire; serum IgG and stool examinations were done to detect current or past infections with viral, bacterial, protozoan and intestinal helminth pathogens. We measured atopy by skin prick testing (SPT) and specific IgE (sIgE) to aerollergens in serum (by ImmunoCAP). SIgE reactivity to B. tropicalis extract depleted of carbohydrates was measured by an in-house ELISA. Total IgE was measured by in house capture ELISA. SNPs were typed using Illumina Omni 2.5. RESULTS: Negative skin prick tests in the presence of specific IgE antibodies were frequent. Factors independently associated with a reduced frequency of positive skin prick tests were large number of siblings, the presence of IgG to herpes simplex virus, Ascaris lumbricoides and Trichuris trichiura infections, living in neighborhoods with infrequent garbage collection, presence of rodents and cats in the household and sIgE reactivity to glycosylated B. tropicalis allergens. Also, SNP on IGHE (rs61737468) was negatively associated with SPT reactivity. CONCLUSIONS: A variety of factors were found to be associated with decreased frequency of SPT such as unhygienic living conditions, infections, total IgE, IgE response to glycosylated allergens and genetic polymorphisms, indicating that multiple mechanisms may be involved. Our data, showing that exposures to an unhygienic environment and childhood infections modulate immediate allergen skin test reactivity, provide support for the "hygiene hypothesis". PMID- 28350869 TI - In vitro skin models to study epithelial regeneration from the hair follicle. AB - The development of dermal equivalents (DEs) for the treatment of burns has contributed toward efficient wound closure. A collagen-glycosaminoglycan DE (C GAG) grafted with hair follicles converted a full-thickness wound to partial thickness resulting in complete wound closure and restored hair. In this study we compared the ability of both intact pilosebaceous units (PSU) or truncated hair follicles (THF) to regenerate a multilayered epidermis in vitro when implanted into de-epidermalized dermis (DED) or C-GAG with the epidermis generated in vivo using C-CAG. Keratinocytes explanted from the outer root sheath of PSU and THF in both DED and C-GAG but only formed a multilayered epidermis with PSU in DED. PSU were more effective at forming multilayered epidermis in DED than THF. Both DED and C-GAG skin expressed proliferation (PCNA), differentiation (K1, K10), hyperproliferation (K6, K16), basal (K14), putative stem cell (p63), extracellular matrix protein (Collagen IV), mesenchymal (vimentin) and adherens junction (beta-catenin) markers. These data suggest DEs supported initial maintenance of the implanted hair follicles, in particular PSU, and provide an excellent model with which to investigate the regulation of hair follicle progenitor epithelial cells during epidermal regeneration. Although neither PSU nor THF formed multilayered epidermis in C-CAG in vitro, hair follicles implanted into engrafted C-GAG on a burns patient resulted in epithelial regeneration and expression of proliferation and differentiation markers in a similar manner to that seen in vitro. However, the failure of C-GAG to support epidermal regeneration in vitro suggests in vivo factors are essential for full epidermal regeneration using C-GAG. PMID- 28350870 TI - Bacterial clonal diagnostics as a tool for evidence-based empiric antibiotic selection. AB - Despite the known clonal distribution of antibiotic resistance in many bacteria, empiric (pre-culture) antibiotic selection still relies heavily on species-level cumulative antibiograms, resulting in overuse of broad-spectrum agents and excessive antibiotic/pathogen mismatch. Urinary tract infections (UTIs), which account for a large share of antibiotic use, are caused predominantly by Escherichia coli, a highly clonal pathogen. In an observational clinical cohort study of urgent care patients with suspected UTI, we assessed the potential for E. coli clonal-level antibiograms to improve empiric antibiotic selection. A novel PCR-based clonotyping assay was applied to fresh urine samples to rapidly detect E. coli and the urine strain's clonotype. Based on a database of clonotype specific antibiograms, the acceptability of various antibiotics for empiric therapy was inferred using a 20%, 10%, and 30% allowed resistance threshold. The test's performance characteristics and possible effects on prescribing were assessed. The rapid test identified E. coli clonotypes directly in patients' urine within 25-35 minutes, with high specificity and sensitivity compared to culture. Antibiotic selection based on a clonotype-specific antibiogram could reduce the relative likelihood of antibiotic/pathogen mismatch by >= 60%. Compared to observed prescribing patterns, clonal diagnostics-guided antibiotic selection could safely double the use of trimethoprim/sulfamethoxazole and minimize fluoroquinolone use. In summary, a rapid clonotyping test showed promise for improving empiric antibiotic prescribing for E. coli UTI, including reversing preferential use of fluoroquinolones over trimethoprim/sulfamethoxazole. The clonal diagnostics approach merges epidemiologic surveillance, antimicrobial stewardship, and molecular diagnostics to bring evidence-based medicine directly to the point of care. PMID- 28350871 TI - Oxygen tension regulates the miRNA profile and bioactivity of exosomes released from extravillous trophoblast cells - Liquid biopsies for monitoring complications of pregnancy. AB - Our understanding of how cells communicate has undergone a paradigm shift since the recent recognition of the role of exosomes in intercellular signaling. In this study, we investigated whether oxygen tension alters the exosome release and miRNA profile from extravillous trophoblast (EVT) cells, modifying their bioactivity on endothelial cells (EC). Furthermore, we have established the exosomal miRNA profile at early gestation in women who develop pre-eclampsia (PE) and spontaneous preterm birth (SPTB). HTR-8/SVneo cells were used as an EVT model. The effect of oxygen tension (i.e. 8% and 1% oxygen) on exosome release was quantified using nanocrystals (Qdot(r)) coupled to CD63 by fluorescence NTA. A real-time, live-cell imaging system (IncucyteTM) was used to establish the effect of exosomes on EC. Plasma samples were obtained at early gestation (<18 weeks) and classified according to pregnancy outcomes. An Illumina TrueSeq Small RNA kit was used to construct a small RNA library from exosomal RNA obtained from EVT and plasma samples. The number of exosomes was significantly higher in EVT cultured under 1% compared to 8% oxygen. In total, 741 miRNA were identified in exosomes from EVT. Bioinformatic analysis revealed that these miRNA were associated with cell migration and cytokine production. Interestingly, exosomes isolated from EVT cultured at 8% oxygen increased EC migration, whilst exosomes cultured at 1% oxygen decreased EC migration. These changes were inversely proportional to TNF-alpha released from EC. Finally, we have identified a set of unique miRNAs in exosomes from EVT cultured at 1% oxygen and exosomes isolated from the circulation of mothers at early gestation, who later developed PE and SPTB. We suggest that aberrant exosomal signalling by placental cells is a common aetiological factor in pregnancy complications characterised by incomplete SpA remodeling and is therefore a clinically relevant biomarker of pregnancy complications. PMID- 28350872 TI - RNA-sequence analysis of gene expression from honeybees (Apis mellifera) infected with Nosema ceranae. AB - Honeybees (Apis mellifera) are constantly subjected to many biotic stressors including parasites. This study examined honeybees infected with Nosema ceranae (N. ceranae). N. ceranae infection increases the bees energy requirements and may contribute to their decreased survival. RNA-seq was used to investigate gene expression at days 5, 10 and 15 Post Infection (P.I) with N. ceranae. The expression levels of genes, isoforms, alternative transcription start sites (TSS) and differential promoter usage revealed a complex pattern of transcriptional and post-transcriptional gene regulation suggesting that bees use a range of tactics to cope with the stress of N. ceranae infection. N. ceranae infection may cause reduced immune function in the bees by: (i)disturbing the host amino acids metabolism (ii) down-regulating expression of antimicrobial peptides (iii) down regulation of cuticle coatings and (iv) down-regulation of odorant binding proteins. PMID- 28350873 TI - On-treatment HBV DNA dynamics predict virological breakthrough in entecavir treated HBeAg-positive chronic hepatitis B. AB - BACKGROUND & AIMS: Virological breakthrough (VBT) could be a manifestation of chronic hepatitis B (CHB) in patients treated with long-term nucleot(s)ide analogues. We aimed to determine the association of on-treatment serum hepatitis B virus (HBV) DNA with VBT in HBeAg-positive CHB patients receiving entecavir (ETV) treatment. METHODS: A retrospective cohort study, including 162 consecutive patients (95 men and 67 women; mean age, 43.1+/-13.4 years) with HBeAg-positive CHB treated with ETV for at least 48 weeks between August 2008 and May 2015, was conducted. Univariate and multivariate cox regression analysis were used to identify associations with VBT and clinical factors, including HBV DNA and HBeAg serum status. RESULTS: Among the 162 ETV-treated HBeAg-positive CHB patients, eighteen patients (11.1%) experienced VBT (VBT group), whereas the other 144 patients were without VBT (non-VBT group). The cumulative rate of HBV DNA < 100 IU/mL in the VBT group and the non-VBT group at week 48 were 44.44% and 70.14%, and at week 96 were 58.33% and 92.56%, respectively (p = 0.015). The cumulative rate of HBeAg seroclearance in the VBT group and non-VBT group at week 48 and week 96 were statistically significant (p = 0.014). Multivariate analysis disclosed that failure to achieve HBeAg seroclearance were the factors significantly associated with VBT. CONCLUSIONS: Our results demonstrated that on treatment HBV DNA could probably predict VBT in ETV-treated HBeAg-positive chronic hepatitis B patients. Failure to achieve HBeAg seroclearance was associated with VBT in ETV-treated HBeAg-positive CHB patients. HBV DNA >100IU/mL at 48 weeks is potentially a predictor for VBT. PMID- 28350874 TI - SnoN upregulation ameliorates renal fibrosis in diabetic nephropathy. AB - Progressive reduction of SnoN is associated with gradual elevation of TGF-beta1 during diabetic nephropathy progression, suggesting SnoN to be a possible mediator of TGF-beta1 signaling, with potential therapeutic benefits against TGF- beta1 -induced renal fibrosis. To characterize SnoN for its role in renal fibrosis, we assessed SnoN expression patterns in response to high glucose stress, and evaluated the effects of upregulating SnoN on renal fibrosis. High glucose stress induced significantly elevated SnoN, TGF-beta1, and Arkadia transcription; however, significantly reduced SnoN protein levels were observed under these conditions. Upregulating the SnoN protein was achieved by Arkadia knockdown, which resulted in inhibited high glucose-induced epithelial mesenchymal transition (EMT) in renal tubular cells, the onset phase of renal fibrosis. Alternatively, EMT was suppressed by dominantly expressed exogenous SnoN without interfering with TGF-beta1. Overall, renal SnoN upregulation ameliorates renal fibrosis by relieving high glucose-induced EMT; these findings support a translational approach targeting SnoN for the treatment of diabetic nephropathy. PMID- 28350875 TI - Effects of embryo-derived exosomes on the development of bovine cloned embryos. AB - The developmental competence of in vitro cultured (IVC) embryos is markedly lower than that of their in vivo counterparts, suggesting the need for optimization of IVC protocols. Embryo culture medium is routinely replaced three days after initial culture in bovine, however, whether this protocol is superior to continuous nonrenewal culture method under current conditions remains unclear. Using bovine somatic cell nuclear transfer (SCNT) embryos as the model, our results showed that compared with routine renewal treatment, nonrenewal culture system significantly improved blastocyst formation, blastocyst quality (increased total cell number, decreased stress and apoptosis, enhanced Oct-4 expression and ratio of ICM/TE), as well as following development to term. Existence and function of SCNT embryo-derived exosomes were then investigated to reveal the cause of impaired development induced by culture medium replacement. Exosomes were successfully isolated through differential centrifugation and identified by both electron microscopy and immunostaining against exosomal membrane marker CD9. Supplementation of extracted exosomes into freshly renewed medium significantly rescued not only blastocyst formation and quality (in vitro development), but also following growth to term (in vivo development). Notably, ratio of ICM/TE and calving rate were enhanced to a similar level as that in nonrenewal group. In conclusion, our results for the first time indicate that 1: bovine SCNT embryos can secrete exosomes into chemically defined culture medium during IVC; 2: secreted exosomes are essential for SCNT blastocyst formation, blastocyst quality, and following development to term; 3: removal of exosomes induced by culture medium replacement impairs SCNT embryo development, which can be avoided by nonrenewal culture procedure or markedly recovered by exosome supplementation. PMID- 28350876 TI - MIPE: A metagenome-based community structure explorer and SSU primer evaluation tool. AB - An understanding of microbial community structure is an important issue in the field of molecular ecology. The traditional molecular method involves amplification of small subunit ribosomal RNA (SSU rRNA) genes by polymerase chain reaction (PCR). However, PCR-based amplicon approaches are affected by primer bias and chimeras. With the development of high-throughput sequencing technology, unbiased SSU rRNA gene sequences can be mined from shotgun sequencing-based metagenomic or metatranscriptomic datasets to obtain a reflection of the microbial community structure in specific types of environment and to evaluate SSU primers. However, the use of short reads obtained through next-generation sequencing for primer evaluation has not been well resolved. The software MIPE (MIcrobiota metagenome Primer Explorer) was developed to adapt numerous short reads from metagenomes and metatranscriptomes. Using metagenomic or metatranscriptomic datasets as input, MIPE extracts and aligns rRNA to reveal detailed information on microbial composition and evaluate SSU rRNA primers. A mock dataset, a real Metagenomics Rapid Annotation using Subsystem Technology (MG RAST) test dataset, two PrimerProspector test datasets and a real metatranscriptomic dataset were used to validate MIPE. The software calls Mothur (v1.33.3) and the SILVA database (v119) for the alignment and classification of rRNA genes from a metagenome or metatranscriptome. MIPE can effectively extract shotgun rRNA reads from a metagenome or metatranscriptome and is capable of classifying these sequences and exhibiting sensitivity to different SSU rRNA PCR primers. Therefore, MIPE can be used to guide primer design for specific environmental samples. PMID- 28350878 TI - Correction: Beneficial effects of exercise on offspring obesity and insulin resistance are reduced by maternal high-fat diet. AB - [This corrects the article DOI: 10.1371/journal.pone.0173076.]. PMID- 28350877 TI - Exposure to atheroma-relevant 7-oxysterols causes proteomic alterations in cell death, cellular longevity, and lipid metabolism in THP-1 macrophages. AB - The 7-oxysterols are recognised as strong enhancers of inflammatory processes in foamy macrophages. Atheroma-relevant 7-oxysterol mixtures induce a mixed type of cell death in macrophages, and trigger cellular oxidative stress responses, which mimic oxidative exposures observed in atherosclerotic lesions. However, the macrophage proteome has not previously been determined in the 7-oxysterol treated cell model. The aim of the present study was to determine the specific effects of an atheroma-relevant 7-oxysterol mixture on human macrophage proteome. Human THP 1 macrophages were exposed to an atheroma-relevant mixture of 7beta hydroxycholesterol and 7-ketocholesterol. Two-dimensional gel electrophoresis and mass spectrometry techniques were used to analyse the alterations in macrophage proteome, which resulted in the identification of 19 proteins with significant differential expression upon oxysterol loading; 8 increased and 11 decreased. The expression patterns of 11 out of 19 identified significant proteins were further confirmed by tandem-mass spectrometry, including further validation of increased histone deacetylase 2 and macrophage scavenger receptor types I and II expressions by western blot analysis. Identified proteins with differential expression in the cell model have been associated with i) signalling imbalance in cell death and cellular longevity; ii) lipid uptake and metabolism in foam cells; and iii) inflammatory proteins. The presented findings highlight a new proteomic platform for further studies into the functional roles of macrophages in atherosclerosis, and present a cell model for future studies to modulate the macrophage proteome by potential anti-atherosclerotic agents. PMID- 28350880 TI - Corrosion of dental alloys in artificial saliva with Streptococcus mutans. AB - A comparative study of the corrosion resistance of CoCr and NiCr alloys in artificial saliva (AS) containing tryptic soy broth (Solution 1) and Streptococcus mutans (S. mutans) species (Solution 2) was performed by electrochemical methods, including open circuit potential measurements, impedance spectroscopy, and potentiodynamic polarization. The adherence of S. mutans to the NiCr and CoCr alloy surfaces immersed in Solution 2 for 24 h was verified by scanning electron microscopy, while the results of electrochemical impedance spectroscopy confirmed the importance of biofilm formation for the corrosion process. The R(QR) equivalent circuit was successfully used to fit the data obtained for the AS mixture without S. mutans, while the R(Q(R(QR))) circuit was found to be more suitable for describing the biofilm properties after treatment with the AS containing S. mutans species. In addition, a negative shift of the open circuit potential with immersion time was observed for all samples regardless of the solution type. Both alloys exhibited higher charge transfer resistance after treatment with Solution 2, and lower corrosion current densities were detected for all samples in the presence of S. mutans. The obtained results suggest that the biofilm formation observed after 24 h of exposure to S. mutans bacteria might enhance the corrosion resistance of the studied samples by creating physical barriers that prevented oxygen interactions with the metal surfaces. PMID- 28350879 TI - Maternal psychological responses during pregnancy after ultrasonographic detection of structural fetal anomalies: A prospective longitudinal observational study. AB - In this longitudinal prospective observational study performed at a tertiary perinatal referral centre, we aimed to assess maternal distress in pregnancy in women with ultrasound findings of fetal anomaly and compare this with distress in pregnant women with normal ultrasound findings. Pregnant women with a structural fetal anomaly (n = 48) and normal ultrasound (n = 105) were included. We administered self-report questionnaires (General Health Questionnaire-28, Impact of Event Scale-22 [IES], and Edinburgh Postnatal Depression Scale) a few days following ultrasound detection of a fetal anomaly or a normal ultrasound (T1), 3 weeks post-ultrasound (T2), and at 30 (T3) and 36 weeks gestation (T4). Social dysfunction, health perception, and psychological distress (intrusion, avoidance, arousal, anxiety, and depression) were the main outcome measures. The median gestational age at T1 was 20 and 19 weeks in the group with and without fetal anomaly, respectively. In the fetal anomaly group, all psychological distress scores were highest at T1. In the group with a normal scan, distress scores were stable throughout pregnancy. At all assessments, the fetal anomaly group scored significantly higher (especially on depression-related questions) compared to the normal scan group, except on the IES Intrusion and Arousal subscales at T4, although with large individual differences. In conclusion, women with a known fetal anomaly initially had high stress scores, which gradually decreased, resembling those in women with a normal pregnancy. Psychological stress levels were stable and low during the latter half of gestation in women with a normal pregnancy. PMID- 28350881 TI - Correction: GATA2 Inhibition Sensitizes Acute Myeloid Leukemia Cells to Chemotherapy. AB - [This corrects the article DOI: 10.1371/journal.pone.0170630.]. PMID- 28350882 TI - Correction: G3BP1, G3BP2 and CAPRIN1 Are Required for Translation of Interferon Stimulated mRNAs and Are Targeted by a Dengue Virus Non-coding RNA. AB - [This corrects the article DOI: 10.1371/journal.ppat.1004242.]. PMID- 28350883 TI - Correction: Changes in Prevalence of HIV or Syphilis among Male Sex Workers and Non-Commercial Men Who Have Sex with Men in Shenzhen, China: Results of a Second Survey. AB - [This corrects the article DOI: 10.1371/journal.pone.0167619.]. PMID- 28350884 TI - Impacts of representing sea-level rise uncertainty on future flood risks: An example from San Francisco Bay. AB - Rising sea levels increase the probability of future coastal flooding. Many decision-makers use risk analyses to inform the design of sea-level rise (SLR) adaptation strategies. These analyses are often silent on potentially relevant uncertainties. For example, some previous risk analyses use the expected, best, or large quantile (i.e., 90%) estimate of future SLR. Here, we use a case study to quantify and illustrate how neglecting SLR uncertainties can bias risk projections. Specifically, we focus on the future 100-yr (1% annual exceedance probability) coastal flood height (storm surge including SLR) in the year 2100 in the San Francisco Bay area. We find that accounting for uncertainty in future SLR increases the return level (the height associated with a probability of occurrence) by half a meter from roughly 2.2 to 2.7 m, compared to using the mean sea-level projection. Accounting for this uncertainty also changes the shape of the relationship between the return period (the inverse probability that an event of interest will occur) and the return level. For instance, incorporating uncertainties shortens the return period associated with the 2.2 m return level from a 100-yr to roughly a 7-yr return period (~15% probability). Additionally, accounting for this uncertainty doubles the area at risk of flooding (the area to be flooded under a certain height; e.g., the 100-yr flood height) in San Francisco. These results indicate that the method of accounting for future SLR can have considerable impacts on the design of flood risk management strategies. PMID- 28350885 TI - Glutamate-dependent ectodomain shedding of neuregulin-1 type II precursors in rat forebrain neurons. AB - The neurotrophic factor neuregulin 1 (NRG1) regulates neuronal development, glial differentiation, and excitatory synapse maturation. NRG1 is synthesized as a membrane-anchored precursor and is then liberated by proteolytic processing or exocytosis. Mature NRG1 then binds to its receptors expressed by neighboring neurons or glial cells. However, the molecular mechanisms that govern this process in the nervous system are not defined in detail. Here we prepared neuron enriched and glia-enriched cultures from embryonic rat neocortex to investigate the role of neurotransmitters that regulate the liberation/release of NRG1 from the membrane of neurons or glial cells. Using a two-site enzyme immunoassay to detect soluble NRG1, we show that, of various neurotransmitters, glutamate was the most potent inducer of NRG1 release in neuron-enriched cultures. NRG1 release in glia-enriched cultures was relatively limited. Furthermore, among glutamate receptor agonists, N-Methyl-D-Aspartate (NMDA) and kainate (KA), but not AMPA or tACPD, mimicked the effects of glutamate. Similar findings were acquired from analysis of the hippocampus of rats with KA-induced seizures. To evaluate the contribution of members of a disintegrin and metalloproteinase (ADAM) families to NRG1 release, we transfected primary cultures of neurons with cDNA vectors encoding NRG1 types I, II, or III precursors, each tagged with the alkaline phosphatase reporter. Analysis of alkaline phosphatase activity revealed that the NRG1 type II precursor was subjected to tumor necrosis factor-alpha-converting enzyme (TACE) / a Disintegrin And Metalloproteinase 17 (ADAM17) -dependent ectodomain shedding in a protein kinase C-dependent manner. These results suggest that glutamatergic neurotransmission positively regulates the ectodomain shedding of NRG1 type II precursors and liberates the active NRG1 domain in an activity dependent manner. PMID- 28350886 TI - Parathyroid score can predict the duration of required calcium supplementation after total thyroidectomy. AB - BACKGROUND: Postoperative hypoparathyroidism is the most common complication after total thyroidectomy, owing to unintentional injury or decreased blood flow to the parathyroid glands. Prediction of postoperative hypoparathyroidism would be helpful for surgeons to manage postoperative hypocalcemia. In this study, we scored the discoloration of the parathyroid glands using a new parathyroid scoring system and evaluated the correlation between the parathyroid score and duration of required calcium supplementation after total thyroidectomy. METHODS: A total of 316 patients undergoing total thyroidectomy between November 2009 and April 2010 were enrolled in this retrospective study. Parathyroid scoring was performed by one experienced surgeon. The status of each of the 4 parathyroid glands was classified as normal color (3 points), slightly discolored (2 points), dark discoloration (1 point), or loss of the gland (0 points), resulting in possible total scores of 0-12. Serum parathyroid hormone (PTH), serum calcium, and ionized calcium concentrations were measured at 2 hours, 2 weeks, 3 months, 6 months, and 1 year after surgery. Patients were also divided into three groups based on the duration of required calcium supplementation: no required supplementation (n = 260, 82.3%), required supplementation for <6 months (n = 38, 12%), and required supplementation for >=6 months (n = 18, 5.75%). RESULTS: Parathyroid scores were positively correlated with ionized PTH concentrations at 2 hours (r = 0.053, p < 0.001), 2 weeks (r = 0.056, p < 0.001), 3 months (r = 0.032, p<0.001), 6 months (r = 0.072, p < 0.001), and 1 year (r = 0.071, p < 0.001) after thyroidectomy. Parathyroid scores were significantly and inversely associated with the duration of required calcium supplementation (p = 0.001). CONCLUSIONS: Parathyroid scores at the end of surgery might be helpful for predicting the degree of postoperative hypocalcemia after total thyroidetomy. PMID- 28350887 TI - Auditory steady state responses and cochlear implants: Modeling the artifact response mixture in the perspective of denoising. AB - Auditory steady state responses (ASSRs) in cochlear implant (CI) patients are contaminated by the spread of a continuous CI electrical stimulation artifact. The aim of this work was to model the electrophysiological mixture of the CI artifact and the corresponding evoked potentials on scalp electrodes in order to evaluate the performance of denoising algorithms in eliminating the CI artifact in a controlled environment. The basis of the proposed computational framework is a neural mass model representing the nodes of the auditory pathways. Six main contributors to auditory evoked potentials from the cochlear level and up to the auditory cortex were taken into consideration. The simulated dynamics were then projected into a 3-layer realistic head model. 32-channel scalp recordings of the CI artifact-response were then generated by solving the electromagnetic forward problem. As an application, the framework's simulated 32-channel datasets were used to compare the performance of 4 commonly used Independent Component Analysis (ICA) algorithms: infomax, extended infomax, jade and fastICA in eliminating the CI artifact. As expected, two major components were detectable in the simulated datasets, a low frequency component at the modulation frequency and a pulsatile high frequency component related to the stimulation frequency. The first can be attributed to the phase-locked ASSR and the second to the stimulation artifact. Among the ICA algorithms tested, simulations showed that infomax was the most efficient and reliable in denoising the CI artifact-response mixture. Denoising algorithms can induce undesirable deformation of the signal of interest in real CI patient recordings. The proposed framework is a valuable tool for evaluating these algorithms in a controllable environment ahead of experimental or clinical applications. PMID- 28350889 TI - Cultural representations of dementia. AB - In a Perspective, Alexandra Hillman and Joanna Latimer discuss cultural representations of dementia in the media, film, and literature. PMID- 28350888 TI - Patterns of variation in diversity of the Mississippi river microbiome over 1,300 kilometers. AB - We examined the downriver patterns of variation in taxonomic diversity of the Mississippi River bacterioplankton microbiome along 1,300 river kilometers, or approximately one third the total length of the river. The study section included portions of the Upper, Middle, and Lower Mississippi River, confluences with five tributaries draining distinct sub-basins, river cities, and extended stretches without major inputs to the Mississippi. The composition and proportional abundance of dominant bacterial phyla was distinct for free-living and particle associated cells, and constant along the entire reach, except for a substantial but transient disturbance near the city of Memphis, Tennessee. At a finer scale of taxonomic resolution (operational taxonomic units, OTUs), however, there were notable patterns in downriver variation in bacterial community alpha diversity (richness within a site) and beta diversity (variation in composition among sites). There was a strong and steady increase downriver in alpha diversity of OTUs on suspended particles, suggesting an increase in particle niche heterogeneity, and/or particle colonization. Relatively large shifts in beta diversity of free-living and particle-associated communities occurred following major tributary confluences and transiently at Memphis, while in long stretches between these points diversity typically varied more gradually. We conclude that the Mississippi River possesses a bacterioplankton microbiome distinct in diversity from other large river microbiomes in the Mississippi River Basin, that at major river confluences or urban point sources its OTU diversity may shift abruptly and substantially, presumably by immigration of distinct external microbiomes, but that where environmental conditions are more stable along the downriver gradient, microbiome diversity tends to vary gradually, presumably by a process of successional change in community composition. PMID- 28350890 TI - Quantification of motor network dynamics in Parkinson's disease by means of landscape and flux theory. AB - The basal ganglia neural circuit plays an important role in motor control. Despite the significant efforts, the understanding of the principles and underlying mechanisms of this modulatory circuit and the emergence of abnormal synchronized oscillations in movement disorders is still challenging. Dopamine loss has been proved to be responsible for Parkinson's disease. We quantitatively described the dynamics of the basal ganglia-thalamo-cortical circuit in Parkinson's disease in terms of the emergence of both abnormal firing rates and firing patterns in the circuit. We developed a potential landscape and flux framework for exploring the modulatory circuit. The driving force of the circuit can be decomposed into a gradient of the potential, which is associated with the steady-state probability distributions, and the curl probability flux term. We uncovered the underlying potential landscape as a Mexican hat-shape closed ring valley where abnormal oscillations emerge due to dopamine depletion. We quantified the global stability of the network through the topography of the landscape in terms of the barrier height, which is defined as the potential difference between the maximum potential inside the ring and the minimum potential along the ring. Both a higher barrier and a larger flux originated from detailed balance breaking result in more stable oscillations. Meanwhile, more energy is consumed to support the increasing flux. Global sensitivity analysis on the landscape topography and flux indicates how changes in underlying neural network regulatory wirings and external inputs influence the dynamics of the system. We validated two of the main hypotheses(direct inhibition hypothesis and output activation hypothesis) on the therapeutic mechanism of deep brain stimulation (DBS). We found GPe appears to be another effective stimulated target for DBS besides GPi and STN. Our approach provides a general way to quantitatively explore neural networks and may help for uncovering more efficacious therapies for movement disorders. PMID- 28350892 TI - Dynamic Assessment of Narratives: Efficient, Accurate Identification of Language Impairment in Bilingual Students. AB - Purpose: This study investigated the classification accuracy of a concentrated English narrative dynamic assessment (DA) for identifying language impairment (LI). Method: Forty-two Spanish-English bilingual kindergarten to third-grade children (10 LI and 32 with no LI) were administered two 25-min DA test-teach test sessions. Pre- and posttest narrative retells were scored in real time. Using a structured intervention approach, examiners taught children missing story grammar elements and subordination. A posttest was administered using a parallel story. Results: Four classification predictors were analyzed: posttest scores, gain scores, modifiability ratings, and teaching duration. Discriminant function analysis indicated that an overall modifiability rating was the best classifier, with 100% sensitivity and 88% specificity after 1 DA session and 100% sensitivity and specificity after 2 sessions. Any 2 combinations of posttest scores, modifiability ratings, and teaching duration for just 1 session resulted in sensitivity and specificity rates over 90%. Receiver operating characteristic analyses were used to identify clinically usable cutoff points. Post hoc exploration indicated that similar results could be obtained after only one 5-10 min teaching cycle, potentially further abbreviating the DA process. Conclusion: Concentrated English narrative DA results in high classification accuracy for bilingual children with and without LI. This efficient version of DA is amenable to clinical use. PMID- 28350893 TI - Celiac Disease and Nonceliac Gluten or Wheat Sensitivity: The Risks and Benefits of Diagnosis. PMID- 28350891 TI - An on-chip instrument for white blood cells classification based on a lens-less shadow imaging technique. AB - Routine blood tests provide important basic information for disease diagnoses. The proportions of three subtypes of white blood cells (WBCs), which are neutrophils, monocytes, lymphocytes, is key information for disease diagnosis. However, current instruments for routine blood tests, such as blood cell analyzers, flow cytometers, and optical microscopes, are cumbersome, time consuming and expensive. To make a smaller, automatic low-cost blood cell analyzer, much research has focused on a technique called lens-less shadow imaging, which can obtain microscopic images of cells in a lens-less system. Nevertheless, the efficiency of this imaging system is not satisfactory because of two problems: low resolution and imaging diffraction phenomena. In this paper, a novel method of classifying cells with the shadow imaging technique was proposed. It could be used for the classification of the three subtypes of WBCs, and the correlation of the results of classification between the proposed system and the reference system (BC-5180, Mindray) was 0.93. However, the instrument was only 10 * 10 * 10 cm, and the cost was less than $100. Depending on the lens-free shadow imaging technology, the main hardware could be integrated on a chip scale and could be called an on-chip instrument. PMID- 28350894 TI - Assessing the Amount of Spontaneous Real-World Spoken Language in Aphasia: Validation of Two Methods. AB - Purpose: The purpose of this article is to present the results of a study evaluating the psychometric properties of 2 new measures that exclusively assess the amount of real-world spoken language in patients with aphasia. Method: Forty individuals with aphasia were evaluated on several measures of spoken language in real-world settings. The Verbal Activity Log (VAL; Johnson et al., 2014) has participants, aided by caregivers, indicate current amount and quality of real world spoken language compared with before stroke. In addition, digital voice recorders objectively measured the amount of real-world spoken language. The Communicative Effectiveness Index (Lomas et al., 1989), a previously validated measure of functional communication, was used as a comparison measure. Nineteen participants received follow-up assessment >= 3 weeks later. Results: Validity was supported by Pearson correlations between spoken language recordings and the VAL, r(38) = .70, p < .001. Likewise, correlation with the Communicative Effectiveness Index was strong, r(38) = .73, p < .001. Test-retest reliability for both VAL and audio recording was high, with intraclass correlations >= .96 and .90, respectively. Conclusions: These results present preliminary evidence for the reliability and validity of the VAL and spoken language recording for assessment of the amount of real-world spoken language in aphasia. As a simple patient-reported outcome, the VAL may assist diverse therapies for aphasia. PMID- 28350895 TI - The Antibacterial Resistance Leadership Group: First Steps. PMID- 28350896 TI - The Antibacterial Resistance Leadership Group: Progress Report and Work in Progress. AB - The Antibacterial Resistance Leadership Group (ARLG), with funding from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, was created in June 2013. Its mission is to develop, prioritize, and implement a clinical research agenda that addresses the public health threat of antibacterial resistance. This article reports on the progress that the ARLG has made to date in fulfilling its mission. Since inception, the ARLG has received and reviewed >70 study proposals, initiated >30 studies, executed >300 agreements, included data from >7000 subjects, published >45 manuscripts, and provided opportunities for 26 mentees. Despite this substantial progress, there remains significant work to be accomplished. This article also describes the considerable challenges that lie ahead. PMID- 28350898 TI - Leading Antibacterial Laboratory Research by Integrating Conventional and Innovative Approaches: The Laboratory Center of the Antibacterial Resistance Leadership Group. AB - The Antibacterial Resistance Leadership Group (ARLG) Laboratory Center (LC) leads the evaluation, development, and implementation of laboratory-based research by providing scientific leadership and supporting standard/specialized laboratory services. The LC has developed a physical biorepository and a virtual biorepository. The physical biorepository contains bacterial isolates from ARLG funded studies located in a centralized laboratory and they are available to ARLG investigators. The Web-based virtual biorepository strain catalogue includes well characterized gram-positive and gram-negative bacterial strains published by ARLG investigators. The LC, in collaboration with the ARLG Leadership and Operations Center, developed procedures for review and approval of strain requests, guidance during the selection process, and for shipping strains from the distributing laboratories to the requesting investigators. ARLG strains and scientific and/or technical guidance have been provided to basic research laboratories and diagnostic companies for research and development, facilitating collaboration between diagnostic companies and the ARLG Master Protocol for Evaluating Multiple Infection Diagnostics (MASTERMIND) initiative for evaluation of multiple diagnostic devices from a single patient sampling event. In addition, the LC has completed several laboratory-based studies designed to help evaluate new rapid molecular diagnostics by developing, testing, and applying a MASTERMIND approach using purified bacterial strains. In collaboration with the ARLG's Statistical and Data Management Center (SDMC), the LC has developed novel analytical strategies that integrate microbiologic and genetic data for improved and accurate identification of antimicrobial resistance. These novel approaches will aid in the design of future ARLG studies and help correlate pathogenic markers with clinical outcomes. The LC's accomplishments are the result of a successful collaboration with the ARLG's Leadership and Operations Center, Diagnostics and Devices Committee, and SDMC. This interactive approach has been pivotal for the success of LC projects. PMID- 28350897 TI - Transforming Concepts Into Clinical Trials and Creating a Multisite Network: The Leadership and Operations Center of the Antibacterial Resistance Leadership Group. AB - The Leadership and Operations Center (LOC) is responsible for facilitating, coordinating, and implementing the Antibacterial Resistance Leadership Group (ARLG) scientific agenda by engaging thought leaders; soliciting research proposals; and developing the processes, tools, and infrastructure required to operationalize studies and create and sustain the ARLG network. These efforts are ongoing as new projects are developed and the network expands and grows to address the ever-changing priorities in antibacterial resistance. This article describes the innovations, accomplishments, and opportunities of the LOC since the inception of the ARLG in 2013. PMID- 28350899 TI - Fundamentals and Catalytic Innovation: The Statistical and Data Management Center of the Antibacterial Resistance Leadership Group. AB - The Statistical and Data Management Center (SDMC) provides the Antibacterial Resistance Leadership Group (ARLG) with statistical and data management expertise to advance the ARLG research agenda. The SDMC is active at all stages of a study, including design; data collection and monitoring; data analyses and archival; and publication of study results. The SDMC enhances the scientific integrity of ARLG studies through the development and implementation of innovative and practical statistical methodologies and by educating research colleagues regarding the application of clinical trial fundamentals. This article summarizes the challenges and roles, as well as the innovative contributions in the design, monitoring, and analyses of clinical trials and diagnostic studies, of the ARLG SDMC. PMID- 28350900 TI - Gram-Positive Bacterial Infections: Research Priorities, Accomplishments, and Future Directions of the Antibacterial Resistance Leadership Group. AB - Antimicrobial resistance in gram-positive bacteria remains a challenge in infectious diseases. The mission of the Gram-Positive Committee of the Antibacterial Resistance Leadership Group (ARLG) is to advance knowledge in the prevention, management, and treatment of these challenging infections to improve patient outcomes. Our committee has prioritized projects involving methicillin resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) due to the scope of the medical threat posed by these pathogens. Approved ARLG projects involving gram-positive pathogens include (1) a pharmacokinetics/pharmacodynamics study to evaluate the impact of vancomycin dosing on patient outcome in MRSA bloodstream infection (BSI); (2) defining, testing, and validating innovative assessments of patient outcomes for clinical trials of MRSA-BSI; (3) testing new strategies for "step-down" antibiotic therapy for MRSA-BSI; (4) management of staphylococcal BSIs in neonatal intensive care units; and (5) defining the impact of VRE bacteremia and daptomycin susceptibility on patient outcomes. This article outlines accomplishments, priorities, and challenges for research of infections caused by gram-positive organisms. PMID- 28350901 TI - Gram-Negative Bacterial Infections: Research Priorities, Accomplishments, and Future Directions of the Antibacterial Resistance Leadership Group. AB - Antimicrobial resistance in pathogenic gram-negative bacteria is one of the most pressing challenges in the field of infectious diseases and is one of 4 key areas of unmet medical need identified by the Antibacterial Resistance Leadership Group (ARLG). The mission of the Gram-Negative Committee is to advance our knowledge of these challenging infections and implement studies to improve patient outcomes. Studies have fallen primarily into 2 broad categories: prospective cohort studies and interventional trials. Among the observational studies, CRACKLE (Consortium on Resistance Against Carbapenems in Klebsiella pneumoniae and Other Enterobacteriaceae) has contributed seminal multicenter data describing risk factors and clinical outcomes of carbapenem-resistant Enterobacteriaceae (CRE) in sentinel US hospitals. Building on this success, CRACKLE II will expand the network to hospitals across the United States and Colombia. Similar protocols have been proposed to include Acinetobacter baumannii and Pseudomonas aeruginosa (SNAP and POP studies). In addition, the CREST study (Carbapenem-Resistant Enterobacteriaceae in Solid Organ Transplant Patients) has provided pivotal data on extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and CRE carriage among solid organ transplant recipients to inform management of this vulnerable patient population. Two clinical trials to define novel ways of using an existing antibiotic, fosfomycin, to treat ESBL-producing Enterobacteriaceae (one that has completed enrollment and the other in late protocol development) will determine the clinical efficacy of fosfomycin as step-down oral therapy to treat complicated urinary tract infections. Additional clinical studies and trials using immunotherapeutic or newly approved agents are also in the planning stage, with the main goals of generating actionable data that will inform clinical decision making and facilitate development of new treatment options for highly resistant gram-negative bacterial infections. PMID- 28350902 TI - The Role of Stewardship in Addressing Antibacterial Resistance: Stewardship and Infection Control Committee of the Antibacterial Resistance Leadership Group. AB - Antibacterial resistance is increasing globally and has been recognized as a major public health threat. Antibacterial stewardship is the coordinated effort to improve the appropriate use of antibiotics with the aim to decrease selective pressure for multidrug-resistant organisms in order to preserve the utility of antibacterial agents. This article describes the activities of the Antibacterial Resistance Leadership Group (ARLG) in the area of antibacterial stewardship. To date, the ARLG has focused intensely on development of rapid diagnostic tests, which (when coupled with educational and institutional initiatives) will enable the robust stewardship that is needed to address the current crisis of antibacterial resistance. In addition to exploring the effectiveness of stewardship techniques in community hospitals, the ARLG has also developed strategy trials to assess the feasibility of reducing antibacterial usage while preserving patient outcome. PMID- 28350904 TI - The Female Beautiful Face. PMID- 28350903 TI - Advancing Diagnostics to Address Antibacterial Resistance: The Diagnostics and Devices Committee of the Antibacterial Resistance Leadership Group. AB - Diagnostics are a cornerstone of the practice of infectious diseases. However, various limitations frequently lead to unmet clinical needs. In most other domains, diagnostics focus on narrowly defined questions, provide readily interpretable answers, and use true gold standards for development. In contrast, infectious diseases diagnostics must contend with scores of potential pathogens, dozens of clinical syndromes, emerging pathogens, rapid evolution of existing pathogens and their associated resistance mechanisms, and the absence of gold standards in many situations. In spite of these challenges, the importance and value of diagnostics cannot be underestimated. Therefore, the Antibacterial Resistance Leadership Group has identified diagnostics as 1 of 4 major areas of emphasis. Herein, we provide an overview of that development, highlighting several examples where innovation in study design, content, and execution is advancing the field of infectious diseases diagnostics. PMID- 28350905 TI - Incorrect Value in Figure. PMID- 28350906 TI - The US Preventive Services Task Force Recommendation on Screening for Asymptomatic Celiac Disease: A Dearth of Evidence. PMID- 28350907 TI - Childhood Lead Exposure and Adult Outcomes. PMID- 28350908 TI - Laparoscopic Hysterectomy for Endometrial Cancer: A Procedure 25 Years in the Making. PMID- 28350909 TI - Vitamin D, Calcium, and Cancer: Approaching Daylight? PMID- 28350910 TI - Introduce Peanut-Containing Foods Early, NIH Panel Advises. PMID- 28350911 TI - Increases in Premature Mortality. PMID- 28350912 TI - Conditional Greenlight for Future Trials of Heritable Genome Editing. PMID- 28350914 TI - Professionalism in Health Care Organizations. PMID- 28350915 TI - Notification of Infectious Diseases. PMID- 28350916 TI - Contribution of Assisted Reproductive Technology to Overall Births by Maternal Age in the United States, 2012-2014. PMID- 28350917 TI - In Vitro Fertilization Insurance Coverage and Chances of a Live Birth. PMID- 28350918 TI - Inpatient Palliative Care After Hematopoietic Stem Cell Transplantation. PMID- 28350919 TI - Assessing Performance of Internal Medicine Residents. PMID- 28350920 TI - Priorities for Public Health Spending. PMID- 28350921 TI - Inpatient Palliative Care After Hematopoietic Stem Cell Transplantation-Reply. PMID- 28350923 TI - Priorities for Public Health Spending-Reply. PMID- 28350922 TI - Assessing Performance of Internal Medicine Residents-Reply. PMID- 28350924 TI - Waiting to Clamp Cords Reduces Anemia in High-Risk Infants. PMID- 28350925 TI - Avoiding Unnecessary Prostate Biopsies With MRI. PMID- 28350926 TI - Bezlotoxumab Protects Against Recurrent C difficile Infections. PMID- 28350927 TI - Association of Childhood Blood Lead Levels With Cognitive Function and Socioeconomic Status at Age 38 Years and With IQ Change and Socioeconomic Mobility Between Childhood and Adulthood. AB - Importance: Many children in the United States and around the world are exposed to lead, a developmental neurotoxin. The long-term cognitive and socioeconomic consequences of lead exposure are uncertain. Objective: To test the hypothesis that childhood lead exposure is associated with cognitive function and socioeconomic status in adulthood and with changes in IQ and socioeconomic mobility between childhood and midlife. Design, Setting, and Participants: A prospective cohort study based on a population-representative 1972-1973 birth cohort from New Zealand; the Dunedin Multidisciplinary Health and Development Study observed participants to age 38 years (until December 2012). Exposures: Childhood lead exposure ascertained as blood lead levels measured at age 11 years. High blood lead levels were observed among children from all socioeconomic status levels in this cohort. Main Outcomes and Measures: The IQ (primary outcome) and indexes of Verbal Comprehension, Perceptual Reasoning, Working Memory, and Processing Speed (secondary outcomes) were assessed at age 38 years using the Wechsler Adult Intelligence Scale-IV (WAIS-IV; IQ range, 40-160). Socioeconomic status (primary outcome) was assessed at age 38 years using the New Zealand Socioeconomic Index-2006 (NZSEI-06; range, 10 [lowest]-90 [highest]). Results: Of 1037 original participants, 1007 were alive at age 38 years, of whom 565 (56%) had been lead tested at age 11 years (54% male; 93% white). Mean (SD) blood lead level at age 11 years was 10.99 (4.63) ug/dL. Among blood-tested participants included at age 38 years, mean WAIS-IV score was 101.16 (14.82) and mean NZSEI-06 score was 49.75 (17.12). After adjusting for maternal IQ, childhood IQ, and childhood socioeconomic status, each 5-ug/dL higher level of blood lead in childhood was associated with a 1.61-point lower score (95% CI, -2.48 to 0.74) in adult IQ, a 2.07-point lower score (95% CI, -3.14 to -1.01) in perceptual reasoning, and a 1.26-point lower score (95% CI, -2.38 to -0.14) in working memory. Associations of childhood blood lead level with deficits in verbal comprehension and processing speed were not statistically significant. After adjusting for confounders, each 5-ug/dL higher level of blood lead in childhood was associated with a 1.79-unit lower score (95% CI, -3.17 to -0.40) in socioeconomic status. An association between greater blood lead levels and a decline in IQ and socioeconomic status from childhood to adulthood was observed with 40% of the association with downward mobility mediated by cognitive decline from childhood. Conclusions and Relevance: In this cohort born in New Zealand in 1972-1973, childhood lead exposure was associated with lower cognitive function and socioeconomic status at age 38 years and with declines in IQ and with downward social mobility. Childhood lead exposure may have long-term ramifications. PMID- 28350928 TI - Effect of Total Laparoscopic Hysterectomy vs Total Abdominal Hysterectomy on Disease-Free Survival Among Women With Stage I Endometrial Cancer: A Randomized Clinical Trial. AB - Importance: Standard treatment for endometrial cancer involves removal of the uterus, tubes, ovaries, and lymph nodes. Few randomized trials have compared disease-free survival outcomes for surgical approaches. Objective: To investigate whether total laparoscopic hysterectomy (TLH) is equivalent to total abdominal hysterectomy (TAH) in women with treatment-naive endometrial cancer. Design, Setting, and Participants: The Laparoscopic Approach to Cancer of the Endometrium (LACE) trial was a multinational, randomized equivalence trial conducted between October 7, 2005, and June 30, 2010, in which 27 surgeons from 20 tertiary gynecological cancer centers in Australia, New Zealand, and Hong Kong randomized 760 women with stage I endometrioid endometrial cancer to either TLH or TAH. Follow-up ended on March 3, 2016. Interventions: Patients were randomly assigned to undergo TAH (n = 353) or TLH (n = 407). Main Outcomes and Measures: The primary outcome was disease-free survival, which was measured as the interval between surgery and the date of first recurrence, including disease progression or the development of a new primary cancer or death assessed at 4.5 years after randomization. The prespecified equivalence margin was 7% or less. Secondary outcomes included recurrence of endometrial cancer and overall survival. Results: Patients were followed up for a median of 4.5 years. Of 760 patients who were randomized (mean age, 63 years), 679 (89%) completed the trial. At 4.5 years of follow-up, disease-free survival was 81.3% in the TAH group and 81.6% in the TLH group. The disease-free survival rate difference was 0.3% (favoring TLH; 95% CI, 5.5% to 6.1%; P = .007), meeting criteria for equivalence. There was no statistically significant between-group difference in recurrence of endometrial cancer (28/353 in TAH group [7.9%] vs 33/407 in TLH group [8.1%]; risk difference, 0.2% [95% CI, -3.7% to 4.0%]; P = .93) or in overall survival (24/353 in TAH group [6.8%] vs 30/407 in TLH group [7.4%]; risk difference, 0.6% [95% CI, -3.0% to 4.2%]; P = .76). Conclusions and Relevance: Among women with stage I endometrial cancer, the use of total abdominal hysterectomy compared with total laparoscopic hysterectomy resulted in equivalent disease-free survival at 4.5 years and no difference in overall survival. These findings support the use of laparoscopic hysterectomy for women with stage I endometrial cancer. Trial Registration: clinicaltrials.gov Identifier: NCT00096408; Australian New Zealand Clinical Trials Registry: CTRN12606000261516. PMID- 28350930 TI - Screening for Celiac Disease. PMID- 28350929 TI - Effect of Vitamin D and Calcium Supplementation on Cancer Incidence in Older Women: A Randomized Clinical Trial. AB - Importance: Evidence suggests that low vitamin D status may increase the risk of cancer. Objective: To determine if dietary supplementation with vitamin D3 and calcium reduces the risk of cancer among older women. Design, Setting, and Participants: A 4-year, double-blind, placebo-controlled, population-based randomized clinical trial in 31 rural counties (June 24, 2009, to August 26, 2015 the final date of follow-up). A total of 2303 healthy postmenopausal women 55 years or older were randomized, 1156 to the treatment group and 1147 to the placebo group. Duration of treatment was 4 years. Interventions: The treatment group (vitamin D3 + calcium group) received 2000 IU/d of vitamin D3 and 1500 mg/d of calcium; the placebo group received identical placebos. Main Outcomes and Measures: The primary outcome was the incidence of all-type cancer (excluding nonmelanoma skin cancers), which was evaluated using Kaplan-Meier survival analysis and proportional hazards modeling. Results: Among 2303 randomized women (mean age, 65.2 years [SD, 7.0]; mean baseline serum 25-hydroxyvitamin D level, 32.8 ng/mL [SD, 10.5]), 2064 (90%) completed the study. At year 1, serum 25 hydroxyvitamin D levels were 43.9 ng/mL in the vitamin D3 + calcium group and 31.6 ng/mL in the placebo group. A new diagnosis of cancer was confirmed in 109 participants, 45 (3.89%) in the vitamin D3 + calcium group and 64 (5.58%) in the placebo group (difference, 1.69% [95% CI, -0.06% to 3.46%]; P = .06). Kaplan Meier incidence over 4 years was 0.042 (95% CI, 0.032 to 0.056) in the vitamin D3 + calcium group and 0.060 (95% CI, 0.048 to 0.076) in the placebo group; P = .06. In unadjusted Cox proportional hazards regression, the hazard ratio was 0.70 (95% CI, 0.47 to 1.02). Adverse events potentially related to the study included renal calculi (16 participants in the vitamin D3 + calcium group and 10 in the placebo group), and elevated serum calcium levels (6 in the vitamin D3 + calcium group and 2 in the placebo group). Conclusions and Relevance: Among healthy postmenopausal older women with a mean baseline serum 25-hydroxyvitamin D level of 32.8 ng/mL, supplementation with vitamin D3 and calcium compared with placebo did not result in a significantly lower risk of all-type cancer at 4 years. Further research is necessary to assess the possible role of vitamin D in cancer prevention. Trial Registration: clinicaltrials.gov Identifier: NCT01052051. PMID- 28350931 TI - Retained Lumbar Catheter Tip. PMID- 28350933 TI - The Lisboa Cafe. PMID- 28350935 TI - Screening for Celiac Disease: Evidence Report and Systematic Review for the US Preventive Services Task Force. AB - Importance: Silent or subclinical celiac disease may result in potentially avoidable adverse health consequences. Objective: To review the evidence on benefits and harms of screening for celiac disease in asymptomatic adults, adolescents, and children 3 years and older for the US Preventive Services Task Force. Data Sources: Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews, searched to June 14, 2016. Study Selection: Randomized clinical trials and cohort or case-control studies on clinical benefits and harms of screening vs no screening for celiac disease or treatment vs no treatment for screen-detected celiac disease; studies on diagnostic accuracy of serologic tests for celiac disease. Data Extraction and Synthesis: One investigator abstracted data, a second checked data for accuracy, and 2 investigators independently assessed study quality using predefined criteria. Main Outcomes and Measures: Cancer incidence, gastrointestinal outcomes, psychological outcomes, child growth outcomes, health outcomes resulting from nutritional deficiencies, quality of life, mortality, and harms of screening. No meta-analytic pooling was done. Results: One systematic review and 3 primary studies met inclusion criteria. No trials of screening for celiac disease were identified. One recent, good-quality systematic review of 56 original studies and 12 previous systematic reviews (sample sizes of primary studies ranging from 62 to more than 12 000 participants) found IgA tissue transglutaminase was associated with high accuracy (sensitivity and specificity both >90%) for diagnosing celiac disease. IgA endomysial antibodies tests were associated with high specificity. Only 2 studies of serologic tests for celiac disease involving 62 and 158 patients were conducted in asymptomatic populations and reported lower sensitivity (57% and 71%). One fair-quality, small (n = 40) Finnish treatment trial of asymptomatic adults with screen-detected celiac disease based on positive serologic findings found initiation of a gluten-free diet associated with small improvement in gastrointestinal symptoms compared with no gluten-free diet (difference less than 1 point on a scale of 1 to 7) at 1 year, with no differences on most measures of quality of life. No withdrawals due to adverse events occurred during the trial; no other harms were reported. No studies were identified that addressed the other outcomes. Conclusions and Relevance: Although some evidence was found regarding diagnostic accuracy of tests for celiac disease, little or no evidence was identified to inform most of the key questions related to benefits and harms of screening for celiac disease in asymptomatic individuals. More research is needed to understand the effectiveness of screening and treatment for celiac disease, accuracy of screening tests in asymptomatic persons, and optimal screening strategies. PMID- 28350937 TI - Decline in Postpartum Depression. PMID- 28350938 TI - Less Noise, Better Health. PMID- 28350936 TI - Screening for Celiac Disease: US Preventive Services Task Force Recommendation Statement. AB - Importance: Celiac disease is caused by an immune response in persons who are genetically susceptible to dietary gluten, a protein complex found in wheat, rye, and barley. Ingestion of gluten by persons with celiac disease causes immune mediated inflammatory damage to the small intestine. Objective: To issue a new US Preventive Services Task Force (USPSTF) recommendation on screening for celiac disease. Evidence Review: The USPSTF reviewed the evidence on the accuracy of screening in asymptomatic adults, adolescents, and children; the potential benefits and harms of screening vs not screening and targeted vs universal screening; and the benefits and harms of treatment of screen-detected celiac disease. The USPSTF also reviewed contextual information on the prevalence of celiac disease among patients without obvious symptoms and the natural history of subclinical celiac disease. Findings: The USPSTF found inadequate evidence on the accuracy of screening for celiac disease, the potential benefits and harms of screening vs not screening or targeted vs universal screening, and the potential benefits and harms of treatment of screen-detected celiac disease. Conclusions and Recommendation: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for celiac disease in asymptomatic persons. (I statement). PMID- 28350939 TI - The Advancing Role of Neuromodulation for the Management of Chronic Treatment Refractory Pain. AB - Neuropathic pain is a common cause of disability and health care utilization. While judicious pharmacotherapy and management of comorbid psychological distress can provide for improved quality of life, some patients with treatment-refractory disease require more invasive therapies. Spinal cord stimulation can provide for improvement in pain and decrease in medication utilization, with level 1 evidence supporting its use across various pain etiologies including persistent postoperative neuropathic pain, complex regional pain syndrome, chronic inoperable limb ischemia, treatment refractory angina, and painful diabetic neuropathy. These procedures can be done with acceptably low morbidity and provide a cost-effective solution for those patients in whom medical therapies have failed. Technological innovation in lead design, implantable pulse generator capability, and stimulation algorithms and parameters may further enhance the success of this therapy. Neuromodulation of distal targets such as dorsal root ganglion may permit greater anatomic specificity of the therapy, whereas subthreshold stimulation with high-frequency or burst energy delivery may eliminate noxious and off-target paresthesiae. Such new technologies should be subject to rigorous evaluation as their mechanisms of action and long-term outcomes remain hitherto undefined. PMID- 28350940 TI - Recent and Emerging Advances in Spinal Deformity. AB - BACKGROUND: Over the last several decades, significant advances have occurred in the assessment and management of spinal deformity. OBJECTIVE: The primary focus of this narrative review is on recent advances in adult thoracic, thoracolumbar, and lumbar deformities, with additional discussions of advances in cervical deformity and pediatric deformity. METHODS: A review of recent literature was conducted. RESULTS: Advances in adult thoracic, thoracolumbar, and lumbar deformities reviewed include the growing applications of stereoradiography, development of new radiographic measures and improved understanding of radiographic alignment objectives, increasingly sophisticated tools for radiographic analysis, strategies to reduce the occurrence of common complications, and advances in minimally invasive techniques. In addition, discussion is provided on the rapidly advancing applications of predictive analytics and outcomes assessments that are intended to improve the ability to predict risk and outcomes. Advances in the rapidly evolving field of cervical deformity focus on better understanding of how cervical alignment is impacted by thoracolumbar regional alignment and global alignment and how this can affect surgical planning. Discussion is also provided on initial progress toward development of a comprehensive cervical deformity classification system. Pediatric deformity assessment has been substantially improved with low radiation based 3-D imaging, and promising clinical outcomes data are beginning to emerge on the use of growth-friendly implants. CONCLUSION: It is ultimately through the reviewed and other recent and ongoing advances that care for patients with spinal deformity will continue to evolve, enabling better informed treatment decisions, more meaningful patient counseling, reduced complications, and achievement of desired clinical outcomes. PMID- 28350941 TI - Spine Oncology - Primary Spine Tumors. AB - Primary tumors originating from the spine are very complex and challenging entities to treat. Due to their rarity, a multicenter collaborative network is essential to shepherd the best research and contribute to the dissemination of the best evidence possible. Over the last few years, several advances have occurred in many different fields. Surgery is still the cornerstone of treatment in most cases. The occasional suboptimal outcomes and high morbidity of surgical treatment have however encouraged professionals caring for these patients to explore safer treatment options and alternatives or adjuncts to surgical treatment. A number of novel treatment strategies have emerged from the medical, interventional radiology, radiation oncology, and molecular worlds. This has truly positioned primary spine tumors at the forefront of multidisciplinary care. This article discusses these recent advances in detail to equip the oncologic spine surgeon and their team to better counsel and treat these patients. Most of these advances allow for a more tailored, efficient, and, most importantly, less morbid management of primary spine tumors. Some of these advances are still under investigation, however, and evidence-based oncological principles should still be strongly encouraged. PMID- 28350942 TI - Prevention of Surgical Site Infection in Spine Surgery. AB - BACKGROUND: Spine surgery is complicated by an incidence of 1% to 9% of surgical site infection (SSI). The most common organisms are gram-positive bacteria and are endogenous, that is are brought to the hospital by the patient. Efforts to improve safety have been focused on reducing SSI using a bundle approach. The bundle approach applies many quality improvement efforts and has been shown to reduce SSI in other surgical procedures. OBJECTIVE: To provide a narrative review of practical solutions to reduce SSI in spine surgery. METHODS: Literature review and synthesis to identify methods that can be used to prevent SSI. RESULTS: SSI prevention starts with proper patient selection and optimization of medical conditions, particularly reducing smoking and glycemic control. Screening for staphylococcus organisms and subsequent decolonization is a promising method to reduce endogenous bacterial burden. Preoperative warming of patients and timely administration of antibiotics are critical to prevent SSI. Skin preparation using chlorhexidine and alcohol solutions are recommended. Meticulous surgical technique and maintenance of sterile techniques should always be performed. Postoperatively, traditional methods of tissue oxygenation and glycemic control remain essential. Newer wound care methods such as silver impregnation dressing and wound-assisted vacuum dressing are encouraging but need further investigation. CONCLUSION: Significant reduction of SSIs is possible, but requires a systems approach involving all stakeholders. There are many simple and low-cost components that can be adjusted to reduce SSIs. Systematic efforts including understanding of pathophysiology, prevention strategies, and system wide quality improvement programs demonstrate significant reduction of SSI. PMID- 28350943 TI - Controversies in Spinal Trauma and Evolution of Care. AB - Management of spinal trauma is a complex and rapidly evolving field. To optimize patient treatment algorithms, an understanding of and appreciation for current controversies and advancing technologies in the field of spinal trauma is necessary. Therefore, members of the AOSpine Knowledge Forum Trauma initiative used a modified Delphi method to compile a list of controversial issues and emerging technologies in the field of spinal trauma, and a list of the 14 most relevant topics was generated. A total of 45 440 manuscripts covering the breadth of spine and spinal trauma were initially identified. This broad search was then refined using the 14 categories felt to be most relevant to the current field of spinal trauma. The results were further pared down using inclusion criteria to select for the most relevant topics. The 8 remaining topics were classification schemes, treatment of vertebral compression fractures, treatment of burst fractures, timing of surgery in spinal trauma, hypothermia, the importance of global sagittal balance, lumbar subarachnoid drainage, and diffusion magnetic resonance imaging. These 8 topics were felt to be the most relevant, controversial, rapidly evolving, and most deserving of inclusion in this summary. In summary, despite recent advances, the field of spinal trauma has many ongoing points of controversy. We must continue to refine our ability to care for this patient population through education, research, and development. It is anticipated that the new AOSpine fracture classification system will assist with prospective research efforts. PMID- 28350944 TI - Navigation and Robotics in Spinal Surgery: Where Are We Now? AB - Spine surgery has experienced much technological innovation over the past several decades. The field has seen advancements in operative techniques, implants and biologics, and equipment such as computer-assisted navigation and surgical robotics. With the arrival of real-time image guidance and navigation capabilities along with the computing ability to process and reconstruct these data into an interactive three-dimensional spinal "map", so too have the applications of surgical robotic technology. While spinal robotics and navigation represent promising potential for improving modern spinal surgery, it remains paramount to demonstrate its superiority as compared to traditional techniques prior to assimilation of its use amongst surgeons.The applications for intraoperative navigation and image-guided robotics have expanded to surgical resection of spinal column and intradural tumors, revision procedures on arthrodesed spines, and deformity cases with distorted anatomy. Additionally, these platforms may mitigate much of the harmful radiation exposure in minimally invasive surgery to which the patient, surgeon, and ancillary operating room staff are subjected.Spine surgery relies upon meticulous fine motor skills to manipulate neural elements and a steady hand while doing so, often exploiting small working corridors utilizing exposures that minimize collateral damage. Additionally, the procedures may be long and arduous, predisposing the surgeon to both mental and physical fatigue. In light of these characteristics, spine surgery may actually be an ideal candidate for the integration of navigation and robotic-assisted procedures.With this paper, we aim to critically evaluate the current literature and explore the options available for intraoperative navigation and robotic-assisted spine surgery. PMID- 28350946 TI - Emerging Techniques in Degenerative Thoracolumbar Surgery. AB - There continue to be incremental advances in thoracolumbar spine surgery techniques in attempts to achieve more predictable outcomes, minimize risk of complications, speed recovery, and minimize the costs of these interventions. This paper reviews recent literature with regard to emerging techniques of interest in the surgical treatment of lumbar spinal stenosis, fusion fixation and graft material, degenerative lumbar spondylolisthesis, and thoracolumbar deformity and sacroiliac joint degeneration. There continue to be advances in minimal access options in these areas, although robust outcome data are heterogeneous in its support. The evidence in support of sacroiliac fusion appears to be growing more robust in the properly selected patient. PMID- 28350945 TI - Intervertebral Disk Degeneration and Repair. AB - Intervertebral disk (IVD) degeneration is a natural progression of the aging process. Degenerative disk disease (DDD) is a pathologic condition associated with IVD that has been associated with chronic back pain. There are a variety of different mechanisms of DDD (genetic, mechanical, exposure). Each of these pathways leads to a final common result of unbalancing the anabolic and catabolic environment of the extracellular matrix in favor of catabolism. Attempts have been made to gain an understanding of the process of IVD degeneration with in Vitro studies. These models help our understanding of the disease process, but are limited as they do not come close to replicating the complexities that exist with an in Vivo model. Animal models have been developed to help us gain further understanding of the degenerative cascade of IVD degeneration In Vivo and test experimental treatment modalities to either prevent or reverse the process of DDD. Many modalities for treatment of DDD have been developed including therapeutic protein injections, stem cell injections, gene therapy, and tissue engineering. These interventions have had promising outcomes in animal models. Several of these modalities have been attempted in human trials, with early outcomes having promising results. Further, increasing our understanding of the degenerative process is essential to the development of new therapeutic interventions and the optimization of existing treatment protocols. Despite limited data, biological therapies are a promising treatment modality for DDD that could impact our future management of low back pain. PMID- 28350948 TI - Bending the Cost Curve-Establishing Value in Spine Surgery. AB - BACKGROUND: As publically promoted by all stakeholders in health care reform, prospective outcomes registry platforms lie at the center of all current evidence driven value-based models. OBJECTIVE: To demonstrate the variability in outcomes and cost at population level and individual patient level for patients undergoing spine surgery for degenerative diseases. METHODS: Retrospective analysis of prospective longitudinal spine registry data was conducted. Baseline and postoperative 1-year patient-reported outcomes were recorded. Previously published minimal clinically important difference for Oswestry Disability Index (14.9) was used. Back-related resource utilization and quality-adjusted life years (QALYs) were assessed. Variations in outcomes and cost were analyzed at population level and at the individual patient level. RESULTS: A total of 1454 patients were analyzed. There was significant improvement in patient-reported outcomes at postoperative 1 year ( P < .0001). For patients demonstrating health benefit at population level, 12.5%, n = 182 of patients experienced no gain from surgery and 38%, n = 554 failed to achieve minimal clinically important difference. Mean 1-year QALY-gained was 0.29; 18% of patients failed to report gain in QALY. For patients with 2-year follow-up, surgery resulted in 0.62 QALY gained at average direct cost of $28 953. A wide variation in both QALY-gained and cost was observed. CONCLUSION: Spine treatments that on average are cost effective may have wide variability in value at the individual patient level. The variability demonstrated here represents an opportunity, through registries, to identify specific care that may be less effective, and refine patient-specific care delivery and indications to drive overall group-level treatment value. Understanding value of spine care at an individualized as well as population level will allow clinicians, and eventually payers, to better target resources for improving care for nonresponders, ultimately driving up the average health for the whole population. PMID- 28350947 TI - Traumatic Spinal Cord Injury-Repair and Regeneration. AB - BACKGROUND: Traumatic spinal cord injuries (SCI) have devastating consequences for the physical, financial, and psychosocial well-being of patients and their caregivers. Expediently delivering interventions during the early postinjury period can have a tremendous impact on long-term functional recovery. PATHOPHYSIOLOGY: This is largely due to the unique pathophysiology of SCI where the initial traumatic insult (primary injury) is followed by a progressive secondary injury cascade characterized by ischemia, proapoptotic signaling, and peripheral inflammatory cell infiltration. Over the subsequent hours, release of proinflammatory cytokines and cytotoxic debris (DNA, ATP, reactive oxygen species) cyclically adds to the harsh postinjury microenvironment. As the lesions mature into the chronic phase, regeneration is severely impeded by the development of an astroglial-fibrous scar surrounding coalesced cystic cavities. Addressing these challenges forms the basis of current and upcoming treatments for SCI. MANAGEMENT: This paper discusses the evidence-based management of a patient with SCI while emphasizing the importance of early definitive care. Key neuroprotective therapies are summarized including surgical decompression, methylprednisolone, and blood pressure augmentation. We then review exciting neuroprotective interventions on the cusp of translation such as Riluzole, Minocycline, magnesium, therapeutic hypothermia, and CSF drainage. We also explore the most promising neuroregenerative strategies in trial today including CethrinTM, anti-NOGO antibody, cell-based approaches, and bioengineered biomaterials. Each section provides a working knowledge of the key preclinical and patient trials relevant to clinicians while highlighting the pathophysiologic rationale for the therapies. CONCLUSION: We conclude with our perspectives on the future of treatment and research in this rapidly evolving field. PMID- 28350949 TI - State of the Art in Degenerative Cervical Myelopathy: An Update on Current Clinical Evidence. AB - Degenerative cervical myelopathy (DCM) is a common cause of spinal cord dysfunction that confronts clinicians on a daily basis. Research performed over the past few decades has provided improved insight into the diagnosis, evaluation, and treatment of this disorder. We aim to provide clinicians with an update regarding the state of the art in DCM, focusing on more recent research pertaining to pathophysiology, natural history, treatment, consideration of the minimally symptomatic patient, surgical outcome prediction, and outcome measurement. Current concepts of pathophysiology focus on the combination of static and dynamic elements leading to breakdown of the blood-spinal cord barrier at the site of compression resulting in local inflammation, cellular dysfunction, and apoptosis. With respect to treatment, although there is a dearth of high quality studies comparing surgical to nonoperative treatment, several large prospective studies have recently associated surgical management with clinically and statistically significant improvement in functional, disability, and quality of life outcome at long-term follow-up. When selecting the specific surgical intervention for a patient with DCM, anterior (discectomy, corpectomy, hybrid discectomy/corpectomy), posterior (laminectomy and fusion, laminoplasty), and combined approaches may be considered as options depending on the specifics of the patient in question; evidence supporting each of these approaches is reviewed in detail. Recently developed clinical prediction models allow for accurate forecasting of postoperative outcomes, permitting enhanced communication and management of patient expectations in the preoperative setting. Finally, an overview of outcome measures recommended for use in the assessment of DCM patients is provided. PMID- 28350950 TI - Spine Oncology-Metastatic Spine Tumors. AB - Surgery for spinal metastases remains the mainstay treatment for pain, instability, and neurological deterioration due to tumor infiltration of the spine. However, several new therapies are emerging which may improve outcomes further, and in some cases even replace the need for surgery. We now have a better understanding of which factors influence survival and quality of life after surgery, and this underpins the development and application of new treatments, and assessment of outcome.Depending on genetic subtyping of tumors, novel immunotherapies and chemotherapies may be very effective in prolonging quality of life. New surgical techniques allow smaller, quicker, and safer operations with less blood loss, pain, and quicker recovery after surgery. Radiation treatments have also leapt forward with the greater accuracy and higher doses possible from intensity-modulated photon radiation, stereotactic body radiation treatment, proton beam therapy, or carbon ion treatment. Combined with more advanced materials for vertebral body stabilization, computer navigation systems, and robotics, more can be done at earlier or later stages of the spinal disease than was previously possible, resulting in more options and improved outcomes for patients. PMID- 28350951 TI - Novel Osteobiologics and Biomaterials in the Treatment of Spinal Disorders. AB - Spinal osteobiologics have evolved substantially in this century after the development of many product categories such as growth factors, allograft, and stem cells. The indications for the use of novel biologics within spine surgery are rapidly expanding as the mechanism of each is elucidated. While the knowledge base of bone morphogenetic protein increases with each subsequent year, the application of new nanotechnology and cell-based strategies are being reported. This review will discuss the most recent data in novel osteobiologics, and where we could use future study. PMID- 28350952 TI - Future Advances in Spine Surgery: The AOSpine North America Perspective. AB - This focus issue highlights state-of-the-art techniques, equipment, and practices in the modern era of spine surgery while providing a glimpse into the next generation of patient care. A broad range of topics are presented to cover the full spectrum of the field. Degenerative diseases are discussed in a series of 3 articles on (1) pathophysiology, management, and surgical approaches to degenerative cervical myelopathy; (2) novel approaches to degenerative thoracolumbar disease (eg, interspinous process spacers, minimally invasive/endoscopic approaches); and (3) animal models and emerging therapeutics in degenerative disk disease. Also included is a unique study aiming to establish the critically important cost-benefit relationship for spine procedures with perspectives on how value is defined and how to address variability.Primary and metastatic spine oncology are reviewed with a focus on upcoming targeted biologics, subspecialized radiotherapy (eg, proton-beam, carbon-ion, stereotactic radiosurgery), genetic profiling to stratify risk, and morbidity-reducing surgical approaches (eg, minimally invasive/endoscopic resections, percutaneous instrumentation). Trauma is discussed in 2 high-quality papers on controversies in spinal trauma and neuroprotective/neuroregenerative interventions for traumatic spinal cord injury. A stimulating article on cervical, thoracolumbar, and pediatric deformity highlights the rapid evolution of deformity surgery with a look at innovative tools (eg, high-fidelity 3-dimensional reconstructions, magnetically controlled growing rods) and their impact on quality of life. Additionally, a must-read article on surgical site infections discusses key risk factors and evidence-based preventative techniques to remain aware of. Finally, cutting-edge technologies, including computer-assisted navigation, shared-control robotics, neuromodulation, novel osteobiologics, and biomaterials, are covered in detail in a series of 3 fascinating papers on the next generation of the field.Each section intends to highlight the salient literature and afford insights from multiple key thought leaders in an effort to minimize bias and provide varied perspectives. Overall, we hope this issue provides high-quality, evidence-based data relevant to trainees and practicing surgeons while also stimulating excitement about the future of spine surgery. PMID- 28350953 TI - Degradation of Hole Transport Materials via Exciton-Driven Cyclization. AB - Organic light-emitting diode (OLED) displays have been an active and intense area of research for well over a decade and have now reached commercial success for displays from cell phones to large format televisions. A more thorough understanding of the many different potential degradation modes which cause OLED device failure will be necessary to develop the next generation of OLED materials, improve device lifetime, and to ultimately improve the cost vs performance ratio. Each of the different organic layers in an OLED device can be susceptible to unique decomposition pathways, however stability toward excitons is critical for emissive layer (EML) materials as well as any layer near the recombination zone. This study will specifically focus on degradation modes within the hole transport layer (HTL) with the goal being to identify the general decomposition paths occurring in an operating device and use this information to design new derivatives which can block these pathways. Through post-mortem analyses of several aged OLED devices, an apparently common intramolecular cyclization pathway has been identified that was not previously reported for arylamine-containing HTL materials and that operates parallel to but faster than the previously described fragmentation pathways. PMID- 28350955 TI - Long-Lived Species Enhance Summertime Attribution of North American Ozone to Upwind Sources. AB - Ground-level ozone (O3), harmful to most living things, is produced from both domestic and foreign emissions of anthropogenic precursors. Previous estimates of the linkage from distant sources rely on the sensitivity approach (i.e., modeling the change of ozone concentrations that result from modifying precursor emissions) as well as the tagging approach (i.e., tracking ozone produced from specific O3 precursors emitted from one region). Here, for the first time, we tag all O3 precursors (i.e., nitrogen oxides (NOx), carbon monoxide (CO), and volatile organic compounds (VOCs)) from East Asia and explicitly track their physicochemical evolution without perturbing the nonlinear O3 chemistry. We show that, even in summer, when intercontinental influence on ozone has typically been found to be weakest, nearly 3 parts per billion by volume (ppbv) seasonal average surface O3 over North America can be attributed to East Asian anthropogenic emissions, compared with 0.7 ppbv using the sensitivity approach and 0.5 ppbv by tagging reactive nitrogen oxides. Considering the acute effects of O3 exposure, approximately 670 cardiovascular and 300 respiratory premature mortalities within North America could be attributed to East Asia. CO and longer-lived VOCs, largely overlooked in previous studies, extend the influence of regional ozone precursors emissions and, thus, greatly enhance O3 attribution to source region. PMID- 28350956 TI - Improving the Performance of Hybrid Functional-Based Molecular Dynamics Simulation through Screening of Hartree-Fock Exchange Forces. AB - Density functional theory-based molecular dynamics calculations of condensed phase systems often benefit from the use of hybrid functionals. However, their use is computationally very demanding and severely limits the system size and time scale that can be simulated. Several methods have been introduced to accelerate hybrid functional molecular dynamics including Schwarz screening and the auxiliary density matrix method (ADMM). Here we present a simple screening scheme that can be applied in addition to these methods. It works by examining Hartree-Fock exchange (HFX) integrals and subsequently excluding those that contribute very little to any nuclear force component. The resultant force error is corrected by a history-dependent extrapolation scheme. We find that for systems where the calculation of HFX forces is a major bottleneck, a large fraction of the integrals can be neglected without introducing significant errors in the nuclear forces. For instance, for a 2 * 2 * 2 unit cell of CoO, 92% of the HFX integrals that have passed Schwarz screening within the ADMM approach can be neglected leading to a performance gain of a factor of 3 at a negligible error in nuclear forces (<=5 * 10-4 H bohr-1). We also show that total energy conservation and solvation structures are not adversely affected by the screening method. PMID- 28350954 TI - Integrating Drug's Mode of Action into Quantitative Structure-Activity Relationships for Improved Prediction of Drug-Induced Liver Injury. AB - Drug-induced liver injury (DILI) is complex in mechanism. Different drugs could undergo different mechanisms but result in the same DILI type, while the same drug could lead to different DILI types via different mechanisms. Therefore, predicting a drug's potential for DILI should take its underlying mechanisms into consideration. To achieve that, we constructed a novel approach by incorporating the drug's Mode of Action (MOA) into Quantitative Structure-Activity Relationship (QSAR) modeling. This MOA-DILI approach was examined using a data set of 333 drugs. The drugs were first grouped according to their MOA profiles (positive or negative in each MOA) based on the Tox21 qHTS assays. QSAR models for individual MOA assays were developed and subsequently combined to obtain the MOA-DILI model. A hold-out testing strategy (222 drugs for training and 111 drugs as a test set) was employed, which yielded a predictive accuracy of 0.711. The MOA-DILI model was directly compared with the standard QSAR approach using the same hold-out strategy, and the QSAR model yielded an accuracy of 0.662. To minimize the random chance in splitting training/test sets, the hold-out testing process was repeated 1000 times, and the observed difference in prediction accuracy between MOA-DILI and QSARs was statistically significant (P value <0.0001). Out of 17 MOAs used, four assays (i.e., antioxidant response elements, PPAR-gamma, estrogen receptor, and thyroid receptor assays) contributed most to the improved prediction of the MOA-DILI model over QSARs. In conclusion, the MOA-DILI approach has the potential to significantly improve predictive outcomes and to reveal complex relationships between MOAs and DILI, all of which would be helpful in developing DILI predictive models in drug screening and for risk assessment of industrial chemicals. PMID- 28350958 TI - Photocontrolled SiRNA Delivery and Biomarker-Triggered Luminogens of Aggregation Induced Emission by Up-Conversion NaYF4:Yb3+Tm3+@SiO2 Nanoparticles for Inducing and Monitoring Stem-Cell Differentiation. AB - Controlling the differentiation of stem cells and monitoring cell differentiation has attracted much research interest since the discovery of stem cells. In this regard, a novel near-infrared (NIR) light-activated nanoplatform is obtained by encapsulating the photoactivatable caged compound (DMNPE/siRNA) and combining a MMP13 cleaved imaging peptide-tetrapheny-lethene (TPE) unit conjugated with the mesoporous silica-coated up-conversion nanoparticles (UCNPs) for the remote control of cell differentiation and, simultaneously, for the real-time monitoring of differentiation. Upon NIR light illumination, the photoactivated caged compound is activated, and the siRNA is released from UCNPs, allowing controlled differentiation of stem cells by light. More importantly, MMP13 enzyme triggered by osteogenic differentiation would effectively cleave the TPE probe peptide, thereby allowing the real-time monitoring of differentiation in living stem cells by aggregation-induced emission (AIE). PMID- 28350957 TI - Ion Diffusion Within Water Films in Unsaturated Porous Media. AB - Diffusion is important in controlling local solute transport and reactions in unsaturated soils and geologic formations. Although it is commonly assumed that thinning of water films controls solute diffusion at low water contents, transport under these conditions is not well understood. We conducted experiments in quartz sands at low volumetric water contents (theta) to quantify ion diffusion within adsorbed films. At the lowest water contents, we employed fixed relative humidities to control water films at nm thicknesses. Diffusion profiles for Rb+ and Br- in unsaturated sand packs were measured with a synchrotron X-ray microprobe, and inverse modeling was used to determine effective diffusion coefficients, De, as low as ~9 * 10-15 m2 s-1 at theta = 1.0 * 10-4 m3 m-3, where the film thickness = 0.9 nm. Given that the diffusion coefficients (Do) of Rb+ and Br- in bulk water (30 degrees C) are both ~2.4 * 10-9 m2 s-1, we found the impedance factor f = De/(thetaDo) is equal to 0.03 +/- 0.02 at this very low saturation, in agreement with the predicted influence of interface tortuosity (taua) for diffusion along grain surfaces. Thus, reduced cross-sectional area (theta) and tortuosity largely accounted for the more than 5 orders of magnitude decrease in De relative to Do as desaturation progressed down to nanoscale films. PMID- 28350959 TI - Mapping of Drug-like Chemical Universe with Reduced Complexity Molecular Frameworks. AB - The emergence of the DNA-encoded chemical libraries (DEL) field in the past decade has attracted the attention of the pharmaceutical industry as a powerful mechanism for the discovery of novel drug-like hits for various biological targets. Nuevolution Chemetics technology enables DNA-encoded synthesis of billions of chemically diverse drug-like small molecule compounds, and the efficient screening and optimization of these, facilitating effective identification of drug candidates at an unprecedented speed and scale. Although many approaches have been developed by the cheminformatics community for the analysis and visualization of drug-like chemical space, most of them are restricted to the analysis of a maximum of a few millions of compounds and cannot handle collections of 108-1012 compounds typical for DELs. To address this big chemical data challenge, we developed the Reduced Complexity Molecular Frameworks (RCMF) methodology as an abstract and very general way of representing chemical structures. By further introducing RCMF descriptors, we constructed a global framework map of drug-like chemical space and demonstrated how chemical space occupied by multi-million-member drug-like Chemetics DNA-encoded libraries and virtual combinatorial libraries with >1012 members could be analyzed and mapped without a need for library enumeration. We further validate the approach by performing RCMF-based searches in a drug-like chemical universe and mapping Chemetics library selection outputs for LSD1 targets on a global framework chemical space map. PMID- 28350960 TI - Enhanced Stability of the Magnetic Skyrmion Lattice Phase under a Tilted Magnetic Field in a Two-Dimensional Chiral Magnet. AB - The magnetic skyrmion is a topologically stable vortex-like spin texture that offers great promise as information carriers for future spintronic devices. In a two-dimensional chiral magnet, it was generally considered that a tilted magnetic field is harmful to its formation and stability. Here we investigated the angular dependent stability of magnetic skyrmions in FeGe nanosheets by using high resolution Lorentz transmission electron microscopy (Lorentz TEM). Besides the theoretically predicted destruction of skyrmion lattice state by an oblique magnetic field as the temperature closes to its magnetic Curie temperature Tc ~ 278 K, we also observed an unexpected reentry-like phenomenon at the moderate temperatures near the border between conical and skyrmion phase, Tt ~ 240 K. This behavior is completely beyond the theoretical prediction in a conventional two dimensional (2D) system. Instead, a three-dimensional (3D) model involving the competition between conical phase and skyrmions is likely to play a crucial role. PMID- 28350961 TI - Remediation of a Eutrophic Bay in the Baltic Sea. AB - Eutrophication of coastal ecosystems is a global problem that often results in bottom water oxygen deficiency and in turn promotes sediment phosphorus (P) release (A). In order to increase sediment P retention, we injected dissolved aluminum into the anoxic sediment of a eutrophic semienclosed bay in the Baltic Sea, thereby inhibiting P recycling and further eutrophication (B). The P concentration in the bay remained at half, as did phytoplankton biomass (C), compared to pretreatment conditions and compared to the reference bay. Four years after treatment the water column transparency was increased, allowing submerged vegetation to penetrate deeper, and the habitat suitable for fish and benthic fauna had expanded (D). The lowered P concentration in the bay decreased the P export to the surrounding archipelago. This is the first full-scale marine remediation project using a geo-engineering method that demonstrates a quick recovery. For successful remediation in coastal areas, permanent binding of mobile P in anoxic sediments may be needed together with measures in the catchment area to obtain faster recovery of eutrophicated marine ecosystems. PMID- 28350962 TI - Multidimensional Hybridization of Dark Surface Plasmons. AB - Synthetic three-dimensional (3D) nanoarchitectures are providing more control over light-matter interactions and rapidly progressing photonic-based technology. These applications often utilize the strong synergy between electromagnetic fields and surface plasmons (SPs) in metallic nanostructures. However, many of the SP interactions hosted by complex 3D nanostructures are poorly understood because they involve dark hybridized states that are typically undetectable with far-field optical spectroscopy. Here, we use experimental and theoretical electron energy loss spectroscopy to elucidate dark SPs and their interactions in layered metal-insulator-metal disc nanostructures. We go beyond the established dipole SP hybridization analysis by measuring breathing and multipolar SP hybridization. In addition, we reveal multidimensional SP hybridization that simultaneously utilizes in-plane and out-of-plane SP coupling. Near-field classic electrodynamics calculations provide excellent agreement with all experiments. These results advance the fundamental understanding of SP hybridization in 3D nanostructures and provide avenues to further tune the interaction between electromagnetic fields and matter. PMID- 28350963 TI - Gd-Dots with Strong Ligand-Water Interaction for Ultrasensitive Magnetic Resonance Renography. AB - Magnetic resonance imaging contrast agents with both significantly enhanced relaxivity and minimal safety risk are of great importance for sensitive clinical diagnosis, but have rarely been reported. Herein, we present a simple strategy to improve relaxivity by introducing surface ligands with strong interaction to water molecules. As a proof of concept, NaGdF4 nanoparticles (NPs) capped by poly(acrylic acid) (PAA) show superior relaxivity to those capped by polyethylenimine and polyethylene glycol, which is attributed to the strong hydrogen-bond capacity of PAA to water molecules as revealed by theoretical calculation. Furthermore, benefiting from PAA and ultrasmall particle size, Gd dots, namely PAA-capped GdOF NPs (2.1 +/- 0.2 nm), are developed as a high performance contrast agent, with a remarkable ionic relaxivity of ~75 mM-1 s-1 in albumin solution at 0.5 T. These Gd-dots also exhibit efficient renal clearance with <3% of injected amount left 12 h post-injection. Ultrasensitive MR renography achieved with Gd-dots strongly suggests their great potential for practical applications. PMID- 28350964 TI - Promoting Vaginal Distribution of E7 and MCL-1 siRNA-Silencing Nanoparticles for Cervical Cancer Treatment. AB - There is an urgent need to develop a less aggressive and more effective treatment against cervical lesions induced by different high-risk human papillomavirus (HR HPV). We investigated the potential of a cocktail of small interfering RNA (siRNA) directed against the oncoprotein E6 (E6), the oncoprotein E7 (E7), or the antiapoptotic protein MCL-1 (MCL-1). The combination of siRNA anti-E7 and anti MCL-1 demonstrated high efficacy on multiple HPV16 and HPV18 cell lines and no effects on healthy keratinocytes. This gene therapy has been considered for a vaginal administration since this route of application holds high potential for the treatment of diseases in the female reproductive tracts. Therefore, PEGylated lipoplexes have been designed and characterized to protect siRNA and to diffuse in the mucosal environment before they reach the cervico/vaginal epithelium. This new nanovector complexed to the combination of active siRNA induced an efficient mRNA knockdown since biological effects were obtained in vitro. This work also provided evidence that the PEGylated lipoplexes had appropriate physicochemical properties to diffuse into a mucin network according to size measurement experiments in artificial mucus. After demonstrating the distribution and the efficacy of siRNA into a 3D-cervical model lesion and through porcine vaginal mucosa, in vivo experiments in mouse have been performed under physiological conditions. This study revealed a complete and sustained coverage of the mucosal epithelium following an unique vaginal administration of fluorescent PEGylated lipoplexes. Overall, our results showed the potential of the PEGylated lipoplexes for the prolonged delivery of active siRNA to treat HPV-induced lesions. PMID- 28350965 TI - On Monolayer Formation of Pyrenebutyric Acid on Graphene. AB - As a two-dimensional material with high charge carrier mobility, graphene may offer ultrahigh sensitivity in biosensing. To realize this, the first step is to functionalize the graphene. This is commonly done by using 1-pyrenebutyric acid (PBA) as a linker for biomolecules. However, the adsorption of PBA on graphene remains poorly understood despite reports of successful biosensors functionalized via this route. Here, the PBA adsorption on graphene is characterized through a combination of Raman spectroscopy, ab initio calculations, and spectroscopic ellipsometry. The PBA molecules are found to form a self-assembled monolayer on graphene, the formation of which is self-limiting and Langmuirian. Intriguingly, in concentrated solutions, the PBA molecules are found to stand up and stack horizontally with their edges contacting the graphene surface. This morphology could facilitate a surface densely populated with carboxylic functional groups. Spectroscopic analyses show that the monolayer saturates at 5.3 PBA molecules per nm2 and measures ~0.7 nm in thickness. The morphology study of this PBA monolayer sheds light on the pi-pi stacking of small-molecule systems on graphene and provides an excellent base for optimizing functionalization procedures. PMID- 28350966 TI - Cationic Phosphorus Dendrimer Enhances Photodynamic Activity of Rose Bengal against Basal Cell Carcinoma Cell Lines. AB - In the last couple of decades, photodynamic therapy emerged as a useful tool in the treatment of basal cell carcinoma. However, it still meets limitations due to unfavorable properties of photosensitizers such as poor solubility or lack of selectivity. Dendrimers, polymers widely studied in biomedical field, may play a role as photosensitizer carriers and improve the efficacy of photodynamic treatment. Here, we describe the evaluation of an electrostatic complex of cationic phosphorus dendrimer and rose bengal in such aspects as singlet oxygen production, cellular uptake, and phototoxicity against three basal cell carcinoma cell lines. Rose bengal-cationic dendrimer complex in molar ratio 5:1 was compared to free rose bengal. Obtained results showed that the singlet oxygen production in aqueous medium was significantly higher for the complex than for free rose bengal. The cellular uptake of the complex was 2-7-fold higher compared to a free photosensitizer. Importantly, rose bengal, rose bengal-dendrimer complex, and dendrimer itself showed no dark toxicity against all three cell lines. Moreover, we observed that phototoxicity of the complex was remarkably enhanced presumably due to high cellular uptake. On the basis of the obtained results, we conclude that rose bengal-cationic dendrimer complex has a potential in photodynamic treatment of basal cell carcinoma. PMID- 28350967 TI - Molecular hydrogen potentiates beneficial anti-infarct effect of hypoxic postconditioning in isolated rat hearts: a novel cardioprotective intervention. AB - Generation of free radicals through incomplete reduction of oxygen during ischemia-reperfusion (I/R) is well described. On the other hand, molecular hydrogen (H2) reduces oxidative stress due to its ability to react with strong oxidants and easily penetrate cells by diffusion, without disturbing metabolic redox reactions. This study was designed to explore cardioprotective potential of hypoxic postconditioning (HpostC) against I/R (30 min global I - 120 min R) in isolated rat hearts using oxygen-free Krebs-Henseleit buffer (KHB). Furthermore, the possibility to potentiate the effect of HpostC by H2 using oxygen-free KHB saturated with H2 (H2 + HpostC) was tested. HPostC was induced by 4 cycles of 1 minute perfusion with oxygen-free KHB intercepted by 1-minute perfusion with normal KHB, at the onset of reperfusion. H2 + HPostC was applied in a similar manner using H2-enriched oxygen-free KHB. Cardioprotective effects were evaluated on the basis of infarct size (IS, in % of area at risk, AR) reduction, post-I/R recovery of heart function, and occurrence of reperfusion arrhythmias. HPostC significantly reduced IS/AR compared with non-conditioned controls. H2 present in KHB during HPostC further decreased IS/AR compared with the effect of HPostC, attenuated severe arrhythmias, and significantly restored heart function (vs. controls). Cardioprotection by HpostC can be augmented by molecular hydrogen infusion. PMID- 28350968 TI - Induced pluripotent stem-cell-derived cardiomyocytes: cardiac applications, opportunities, and challenges. AB - Chronic diseases are the primary cause of mortality worldwide, accounting for 67% of deaths. One of the major challenges in developing new treatments is the lack of understanding of the exact underlying biological and molecular mechanisms. Chronic cardiovascular diseases are the single most common cause of death worldwide, and sudden deaths due to cardiac arrhythmias account for approximately 50% of all such cases. Traditional genetic screening for genes involved in cardiac disorders is labourious and frequently fails to detect the mutation that explains or causes the disorder. However, when mutations are identified, human induced pluripotent stem cells (hiPSCs) derived from affected patients make it possible to address fundamental research questions directly relevant to human health. As such, hiPSC technology has recently been used to model human diseases and patient-specific hiPSC-derived cardiomyocytes (hiPSC-CMs) thus offer a unique opportunity to investigate potential disease-causing genetic variants in their natural environment. The purpose of this review is to present the current state of knowledge regarding hiPSC-CMs, including their potential, limitations, and challenges and to discuss future prospects. PMID- 28350969 TI - Mechanisms of spontaneous pacing: sinoatrial nodal cells, neonatal cardiomyocytes, and human stem cell derived cardiomyocytes. AB - The sinoatrial (SA) node is the primary site from which the mammalian heart is paced, but the mechanisms underlying the pacemaking still remain clouded. It is generally believed that the hyperpolarization-activated current If, encoded by hyperpolarization-activated cyclic nucleotide-gated (HCN) genes, contributes significantly to pacing, which in tandem with inward current generated by efflux of Ca2+ via the Na+-Ca2+ exchanger (NCX), resulting from the released Ca2+, mediates the diastolic depolarization. Here, we review the data that implicate If as the "pacemaker current" and conclude that there is not only a significant discrepancy between the range of diastolic depolarization potential (-60 to -40 mV) and the activation potential of If (negative to -70 mV), but that also the kinetics of If and its pharmacology are incompatible with the frequency of a heartbeat in rodents and humans. We propose that If serves as a functional insulator, which protects the SA-nodal cells against the large negative electrical sink of atrial tissue connected to it with connexins. We also evaluate the role of If and calcium signaling in mediating the diastolic depolarization in rat neonatal cardiomyocytes (rN-CM), and human induced pluripotent stem-cell derived cardiomyocytes (hiPSC-CM), and provide evidence for a possible involvement of mitochondrial Ca2+ in initiating the oscillatory events required for the spontaneous pacing. PMID- 28350970 TI - Mannheim Peritonitis Index (MPI) and elderly population: prognostic evaluation in acute secondary peritonitis. AB - INTRODUCTION: Acute Secondary Peritonitis due to abdominal visceral perforation is characterized by high mortality and morbidity risk. Risk stratification allows prognosis prediction to adopt the best surgical treatment and clinical care support therapy. In Western countries elderly people represent a significant percentage of population Aim. Evaluation of Mannheim Peritonitis Index (MPI) and consideration upon old people. PATIENTS AND METHODS: Retrospective study on 104 patients admitted and operated for "Acute Secondary Peritonitis due to visceral perforation". MPI was scored. In our study we want to demonstrate efficacy of MPI and the possibility to consider older age an independent prognostic factor. RESULTS: Mortality was 25.96%. Greatest sensitivity and specificity for the MPI score as a predictor of mortality was at the score of 20. MPI score of <16 had 0.15 times lower risk of mortality compared to patients with MPI score 17 - 21 and 0.61 lower than patients with MPI >22. Patients with MPI score 17-21 had 0.46 times lower risk of mortality compared to patients with MPI score >21. In the group of patients with MPI score of >20 the mortality rate was 48.5% for patients older than 80 years old and 12.1% for younger patients (p < 0.005); in the group with MPI score of < 20 mortality rate was respectively 8.4% and 1.4% (p < 0.005). DISCUSSION AND CONCLUSIONS: Data confirm the accuracy of the test. MPI score and age over 80 years old resulted independent predictors of mortality at multivariate analysis. PMID- 28350971 TI - Early discharge after total thyroidectomy: a retrospective feasibility study. AB - AIM: The continued hospitalization after total thyroidectomy is often due to the onset of hypocalcemic complications more than 24 hours after surgery. So it would be important to predict which patients will not develop the hypocalcemic complication to discharge them early. This was the aim of our study. PATIENTS AND METHODS: Our retrospective study was conducted on 327 consecutive thyroidectomized patients, operated on for benign and malignant diseases. We evaluated the values of preoperative serum calcium levels (Cal0) and of the first postoperative day (Cal1) and two new variables were calculated (dCal and dCaln). The same thing was made on a subgroup of 111 patients in whom also parathiroyd hormone (PTH) values were detected. Statistical analysis was performed with the goal of determining if we could establish a safe criterion for discharge at 24 hours after surgery and if there is a correlation between suitability for discharge and diagnosis. RESULTS: As to discharge, the predictive power of the discriminant function applied was significant both on the total of patients and in the subgroup of 111 patients, but it was clinically unacceptable because it would expose us to a 21% to 27% error rate. It is not possible to identify a threshold, below which to consider patients surely dischargeable. The diagnosis does not appear correlated with the suitability for discharge. CONCLUSION: On the basis of serum calcium and PTH levels in the first postoperative day, it is impossible to predict which patients can be discharged 24 hours after surgery without incurring in hypocalcemic complications. PMID- 28350972 TI - Open sphincter-preserving surgery of extraperitoneal rectal cancer without primary stoma and Fast Track Protocol. AB - AIM: Fast track protocol (FTP) showed to improve perioperative care. The study aims to evaluate the impact of the FTP in the open extraperitoneal rectal cancer (ERC) surgical treatment without a primary derivative stoma (DS) and the QoL in patients with or without a secondary DS. PATIENTS AND METHODS: 50 patients affected by ERC were enrolled and operated on with open low anterior resection without a primary DS. They were randomized in two groups: one was treated perioperativelly in the traditional way (group T), the other using a modif ed FTP (group FT). A QoL questionnaire was administered prior to discharge and at 1 month follow-up. RESULTS: Five courses (10%) were complicated by anastomotic leakage: 3 (12%) in the FT group (2 minor and 1 maior) and 2 (8%) in the T group (1 minor and 1 maior) (p=n.s.). All the maiors and one minor were treated with a DS. Patients of the group FTP were considered dischargeable earlier that those of group T (p<0.05). Patients with DS had a significantly lower QoL score (p<0.0001). CONCLUSION: FTP with minor modifications is feasible and safe in the ERC open surgery without using a DS. Better results were obtained without increasing complication rate. A secondary DS impacts detrimentally on QoL. PMID- 28350973 TI - Is it really useful the Harmonic scalpel in axillary dissection for locally advanced breast cancer? A case series. AB - BACKGROUND: The seroma is one of the most common complications in the axillary lymph nodal dissection (different surgical approaches have been tried to reduce the seroma incidence). In our study we evaluate the outcome of patients using or not the ultrasonic scalpel (Harmonic scalpel) according to a standardized surgical technique. PATIENTS AND METHODS: From January 2011 to December 2015 120 patients underwent axillary dissection for breast cancer. Patients were divided in two groups: patients belonging to the first group underwent Harmonic scalpel dissection and patients belonging to the second group underwent classical dissection. Each group consisted of 60 patients. Quadrantectomy (QUAD) was performed in 54 patients, 66 women underwent mastectomy. In all patients axillary dissection included the I, II and III level. We compared two groups in terms of: time of surgery, hematoma, drainage volume, days of sealing drainage, seroma formation, number of post-seroma aspirations, upper limb lymphedema, wound infections, post-operative pain. RESULTS: Statistically significant results were obtained in terms of the total volume of the breast and axillary drainage in the two techniques. There were no significant differences in the two samples in terms of operative time incidence of seroma, post-operative hematoma, wound infection, and lymphedema of the upper limb. CONCLUSION: The small number of cases did not allow us to reach definitive conclusions. The use of Harmonic scalpel seems to show smaller incidence of seroma and reduction of the amount of both breast and axillary drainages. Further studies are needed to define the real advantage in terms of cost benefit of using these devices in the axillary surgery. PMID- 28350974 TI - Topical hemostasis in laparoscopic surgery. AB - A major goal during any surgical intervention is minimization of blood loss, which reduces the need for blood transfusion. In open surgery, the possibility for the surgeon to use the hands directly in contact with the bleeding tissues for hemostasis, makes mechanical methods, such as compression, ligatures or sutures, important to achieve proper hemostasis. In laparoscopic surgery, where the intervention is performed by means of small incisions through which the surgeon's hand cannot directly achieve the tissues, the problem of hemostasis is critical and needs more attention. Either in open or in laparoscopic surgery, significant bleeding during surgery is controlled through vessel ligation, suturing, and electrocautery. Topical hemostatic agents are useful adjuncts to surgical hemostasis for controlling non-specific bleeding. The introduction of different devices and topical agents has made possible to perform more complex interventions also in laparoscopy. The Authors discuss about the type, the field of application, the side effects of the hemostatic devices and of the topical hemostatic agents. PMID- 28350975 TI - Long lasting postoperative ileus after surgery for intestinal obstruction due to left paraduodenal hernia (LPDH). Case report. AB - Left paraduodenal hernia is a rare congenital anomaly which arises from an error of rotation of the midgut; sometimes can be responsible for intestinal occlusion, that require surgery. In many cases of literature a prompt diagnosis and therapy reduced morbidity and mortality and almost all patients were discharged on 4th or 5th postoperative day (POD). We report a case of a 59 years old patient who underwent surgery for intestinal obstruction due to a massive left paraduodeneal hernia, that had a very long period (20 days) of postoperative ileus. PMID- 28350976 TI - Neuroendocrine tumor of the common bile duct: case report. AB - Neuroendocrine tumors (NET) are a very heterogeneous group of neoplasms; in recent years we have seen an increase in their incidence (3.65 /100.000/year). They can be associated with hereditary endocrine syndromes (MEN, Von Hippel Lindau); they can occur at any age and the incidence is slightly higher in men than women. The aetiology of the neuroendocrine tumors is unclear; in most cases, inflammation of the bile ducts may be the underlying cause and for this reason, the initial patient's evaluation should be focused on the different aspects concerning the oncological one and the possible sequelae of the biliary obstructions that can evolve in biliary sepsis. All neuroendocrine tumors have malignant potential. The most frequent sites of extrahepatic biliary NETs are the common hepatic duct and the distal common bile duct (19.2%), followed by the middle of the common bile duct (17.9%), the cystic duct (16.7%), and the proximal common bile duct (11.5%). We can divide them into: well-differentiated and poorly differentiated. Considering the clinical features, neuroendocrine tumors can be divided into functional and non-functional. As regards the staging, we distinguish localized, regional and metastatic tumors. Tumors derived from the bile duct are difficult to diagnose preoperatively, mainly because of its low incidence and difficult diagnostic process. However since cholangiocarcinomas account for about 80% of all primary biliary tumors, it is important to think about other options despite their low frequency when a patient presents with abnormal characteristics. The most sensitive immunohistochemical markers are expressing neuron-specific enolase, synaptophisin and chromogranin A. Liver function tests, alkaline phosphatase and bilirubin are often high. Sometimes an anemia can appear in the presence of a chronic disease or in patients with more advanced disease. It is known that the measurement of chromogranin A is useful for the preoperative diagnosis of neuroendocrine tumors. Chromogranin A is elevated in 90% of neuroendocrine tumors of the intestine, and the levels correlate with tumor burden and the possibility of recurrence and, therefore, chromogranin A can be an effective biological marker for preoperative diagnosis of neuroendocrine tumors. Bile endocrine tumors remain silent until metastasizing or growing into neighboring organs, because of its uncommon diagnosis in early stages due to its low incidence, absence of serum markers and lack of symptoms related to the hormonal pattern. Preoperative diagnosis of common bile duct carcinoma is extremely difficult, because it is foretold by non-specific symptoms that include pain or discomfort in the right upper quadrant level and weight loss. A 51- year-old woman presented a jaundice and severe bile duct dilatation. The enhanced CT scan showed a mass, approximately 15 mm in diameter, in the distal common biliary duct. The MRI and ERCP confirmed the mass. Cromogranin A value was negative. The diagnosis of well differentiated endocrine tumor of the biliary tract was done after its surgical resection was performed. The postoperative period was uneventful. Extrahepatic biliary NETs are rare, and extrahepatic bile ducts reportedly account for only 0.32% of primary NET sites. The prognosis for NET of the bile duct appears to be poor. PMID- 28350977 TI - Small bowel obstruction caused by Anisakis and Meckel's diverticulum: a rare case. AB - INTRODUCTION: Anisakiasis is a parasitic infection caused by the ingestion of raw fish contaminated by larval nematodes of Anisakis species. Intestinal or extraintestinal manifestations are rated to > 4% and >1% respectively. PRESENTATION OF CASE: A 61-year old patient was admitted to our General Surgical and Emergency Unit because of sudden abdominal pain, vomit and constipation. He had eaten raw fish 3 days before admission. Laboratory data showed high levels of WBC and PCR. CT scanning showed "dilation of jejunum and ileum loops, thickening of the terminal ileum and cecum and signs of inflammation of the intestinal wall and mesentery". The following emergency surgical procedure was performed: laparotomy with evidence of obstruction of the small bowels, a giant Meckel's diverticulum, resection of terminal ileum and cecum and ileocolonic anastomosis. At the microscopic examination, the intestinal wall appeared occupied by a transmural inflammatory infiltrate, mainly eosinophilic, edema and nematode larvae, referable to Anisakis, surrounded by necrotic-inflammatory material. Moreover, there was evidence of giant a Meckel's diverticulum. DISCUSSION: Normally, enteric anisakiasis exhibits leukocytosis with eosinophilia and high CRP levels. There are cases of successful medical treatment and other cases of endoscopic treatment avoiding surgical procedure. In our case, enteric Anisakias had not been taken into consideration at the moment of the operation and only histopathology could reveal Anisakis larvae inside the intestinal wall. CONCLUSION: Our surgical approach is considered in literature as the best one for this clinical presentation. Those patients need to be better studied and more attention should be paid to their history. PMID- 28350978 TI - XIX CONGRESSO MULTIDISCIPLINARE - Ricerca Scientifica ed Innovazione Tecnologica Etica e Sostenibilita. PMID- 28350979 TI - 27 degrees CONGRESSO CHIRURGIA DELL'APPARATO DIGERENTE. PMID- 28350981 TI - Asymmetric Notch Amplification to Secure Stem Cell Identity. AB - Stem cells self-renew and produce progenitors with limited proliferative potential. Reporting in Developmental Cell, Liu et al. (2017) demonstrate that in some neural stem cells, Notch activity is asymmetrically amplified by a positive feedback loop with the super elongation complex (SEC) to quickly differentiate between stem cells and progenitors. PMID- 28350982 TI - MicroRNAs Make a Difference in Cardiovascular Robustness. AB - Invertebrate microRNAs (miRNAs) can suppress developmental variability that is caused by environmental and genetic variation. In this issue of Developmental Cell, Kasper et al. (2017) show that zebrafish miRNAs suppress variability in cardiovascular development during embryogenesis, providing insight into the conserved link between miRNAs and robustness. PMID- 28350983 TI - Pushing Yap into the Nucleus with Shear Force. AB - Endothelial cells line blood vessels and experience shear stress from blood flow. In this issue of Developmental Cell, Nakajima and colleagues (2017) show that in zebrafish Yap responds to blood flow by translocating into the nucleus, where it drives a genetic program to maintain vascular stability. PMID- 28350984 TI - Autophagy: It's in Your Blood. AB - Autophagy, a central pathway for cellular homeostasis, plays diverse roles in development, cancer, aging, and neurodegeneration. In a new report in Nature, Ho et al. (2017) show that autophagy is essential for maintaining the replicative quiescence of hematopoietic stem cells throughout life by limiting the number of active mitochondria. PMID- 28350985 TI - Macrophages Help Cells Connect to Pattern Zebrafish Stripes. AB - Mechanisms that disseminate the proteins that orchestrate organ and tissue development have been a major focus of cell and developmental biology. Reporting in Science, Eom and Parichy (2017) characterize the role that macrophages play in facilitating long-distance signaling between the cells that make stripes in the adult zebrafish. PMID- 28350986 TI - Flow-Dependent Endothelial YAP Regulation Contributes to Vessel Maintenance. AB - Endothelial cells (ECs) line the inside of blood vessels and respond to mechanical cues generated by blood flow. Mechanical stimuli regulate the localization of YAP by reorganizing the actin cytoskeleton. Here we demonstrate blood-flow-mediated regulation of endothelial YAP in vivo. We indirectly monitored transcriptional activity of Yap1 (zebrafish YAP) and its spatiotemporal localization in living zebrafish and found that Yap1 entered the nucleus and promoted transcription in response to blood flow. In cultured human ECs, laminar shear stress induced nuclear import of YAP and its transcriptional activity in a manner independent of Hippo signaling. We uncovered a molecular mechanism by which flow induced the nuclear translocation of YAP through the regulation of filamentous actin and angiomotin. Yap1 mutant zebrafish showed a defect in vascular stability, indicating an essential role for Yap1 in blood vessels. Our data imply that endothelial Yap1 functions in response to flow to maintain blood vessels. PMID- 28350987 TI - The Super Elongation Complex Drives Neural Stem Cell Fate Commitment. AB - Asymmetric stem cell division establishes an initial difference between a stem cell and its differentiating sibling, critical for maintaining homeostasis and preventing carcinogenesis. Yet the mechanisms that consolidate and lock in such initial fate bias remain obscure. Here, we use Drosophila neuroblasts to demonstrate that the super elongation complex (SEC) acts as an intrinsic amplifier to drive cell fate commitment. SEC is highly expressed in neuroblasts, where it promotes self-renewal by physically associating with Notch transcription activation complex and enhancing HES (hairy and E(spl)) transcription. HES in turn upregulates SEC activity, forming an unexpected self-reinforcing feedback loop with SEC. SEC inactivation leads to neuroblast loss, whereas its forced activation results in neural progenitor dedifferentiation and tumorigenesis. Our studies unveil an SEC-mediated intracellular amplifier mechanism in ensuring robustness and precision in stem cell fate commitment and provide mechanistic explanation for the highly frequent association of SEC overactivation with human cancers. PMID- 28350989 TI - miR-219 Cooperates with miR-338 in Myelination and Promotes Myelin Repair in the CNS. AB - A lack of sufficient oligodendrocyte myelination contributes to remyelination failure in demyelinating disorders. miRNAs have been implicated in oligodendrogenesis; however, their functions in myelin regeneration remained elusive. Through developmentally regulated targeted mutagenesis, we demonstrate that miR-219 alleles are critical for CNS myelination and remyelination after injury. Further deletion of miR-338 exacerbates the miR-219 mutant hypomyelination phenotype. Conversely, miR-219 overexpression promotes precocious oligodendrocyte maturation and regeneration processes in transgenic mice. Integrated transcriptome profiling and biotin-affinity miRNA pull-down approaches reveal stage-specific miR-219 targets in oligodendrocytes and further uncover a novel network for miR-219 targeting of differentiation inhibitors including Lingo1 and Etv5. Inhibition of Lingo1 and Etv5 partially rescues differentiation defects of miR-219-deficient oligodendrocyte precursors. Furthermore, miR-219 mimics enhance myelin restoration following lysolecithin-induced demyelination as well as experimental autoimmune encephalomyelitis, principal animal models of multiple sclerosis. Together, our findings identify context-specific miRNA regulated checkpoints that control myelinogenesis and a therapeutic role for miR 219 in CNS myelin repair. PMID- 28350988 TI - MicroRNAs Establish Uniform Traits during the Architecture of Vertebrate Embryos. AB - Proper functioning of an organism requires cells and tissues to behave in uniform, well-organized ways. How this optimum of phenotypes is achieved during the development of vertebrates is unclear. Here, we carried out a multi-faceted and single-cell resolution screen of zebrafish embryonic blood vessels upon mutagenesis of single and multi-gene microRNA (miRNA) families. We found that embryos lacking particular miRNA-dependent signaling pathways develop a vascular trait similar to wild-type, but with a profound increase in phenotypic heterogeneity. Aberrant trait variance in miRNA mutant embryos uniquely sensitizes their vascular system to environmental perturbations. We discovered a previously unrecognized role for specific vertebrate miRNAs to protect tissue development against phenotypic variability. This discovery marks an important advance in our comprehension of how miRNAs function in the development of higher organisms. PMID- 28350991 TI - Serum Proteases Potentiate BMP-Induced Cell Cycle Re-entry of Dedifferentiating Muscle Cells during Newt Limb Regeneration. AB - Limb amputation in the newt induces myofibers to dedifferentiate and re-enter the cell cycle to generate proliferative myogenic precursors in the regeneration blastema. Here we show that bone morphogenetic proteins (BMPs) and mature BMPs that have been further cleaved by serum proteases induce cell cycle entry by dedifferentiating newt muscle cells. Protease-activated BMP4/7 heterodimers that are present in serum strongly induced myotube cell cycle re-entry with protease cleavage yielding a 30-fold potency increase of BMP4/7 compared with canonical BMP4/7. Inhibition of BMP signaling via muscle-specific dominant-negative receptor expression reduced cell cycle entry in vitro and in vivo. In vivo inhibition of serine protease activity depressed cell cycle re-entry, which in turn was rescued by cleaved-mimic BMP. This work identifies a mechanism of BMP activation that generates blastema cells from differentiated muscle. PMID- 28350992 TI - Expression of circadian core clock genes in fibroblasts of human gingiva and periodontal ligament is modulated by L-Mimosine and hypoxia in monolayer and spheroid cultures. AB - OBJECTIVE: The circadian clock is involved in a plethora of physiological processes including bone formation and tooth development. While expression of circadian core clock genes was observed in various tissues, their role in the periodontium is unclear. We hypothesized that periodontal cells express circadian core clock genes and that their levels are modulated by hypoxia mimetic agents and hypoxia. MATERIAL AND METHODS: Fibroblasts of human gingiva (GF) and periodontal ligament (PDLF) in monolayer and spheroid cultures were treated with the hypoxia mimetic agent L-Mimosine (L-MIM) or hypoxia. Reverse transcription and quantitative PCR were performed to assess the impact on mRNA levels of the circadian core clock genes Clock, Bmal1, Cry1, Cry2, Per1, Per2, and Per3. RESULTS: GF and PDLF expressed Clock, Bmal1, Cry1, Cry2, Per1, Per2, and Per3 in monolayer and spheroid cultures. In monolayer cultures, L-MIM significantly reduced Clock, Cry2, and Per3 mRNA expression in GF and Clock, Cry1, Cry2, Per1, and Per3 in PDLF. Hypoxia significantly reduced Clock, Cry2, and Per3 in GF and Cry1, Cry2, and Per3 in PDLF. In spheroid cultures, L-MIM significantly decreased Clock, Cry1, Cry2, and Per3 in GF and PDLF. Hypoxia significantly decreased Cry2 and Per3 in GF and Clock and Per3 in PDLF. CONCLUSIONS: GF and PDLF express circadian core clock genes. The hypoxia mimetic agent L-MIM and hypoxic conditions can decrease the expression of Clock, Cry1-2 and Per1 and Per3. The specific response depends on cell type and culture model. Future studies will show how this effect contributes to periodontal health and disease. PMID- 28350990 TI - The Putative Drp1 Inhibitor mdivi-1 Is a Reversible Mitochondrial Complex I Inhibitor that Modulates Reactive Oxygen Species. AB - Mitochondrial fission mediated by the GTPase dynamin-related protein 1 (Drp1) is an attractive drug target in numerous maladies that range from heart disease to neurodegenerative disorders. The compound mdivi-1 is widely reported to inhibit Drp1-dependent fission, elongate mitochondria, and mitigate brain injury. Here, we show that mdivi-1 reversibly inhibits mitochondrial complex I-dependent O2 consumption and reverse electron transfer-mediated reactive oxygen species (ROS) production at concentrations (e.g., 50 MUM) used to target mitochondrial fission. Respiratory inhibition is rescued by bypassing complex I using yeast NADH dehydrogenase Ndi1. Unexpectedly, respiratory impairment by mdivi-1 occurs without mitochondrial elongation, is not mimicked by Drp1 deletion, and is observed in Drp1-deficient fibroblasts. In addition, mdivi-1 poorly inhibits recombinant Drp1 GTPase activity (Ki > 1.2 mM). Overall, these results suggest that mdivi-1 is not a specific Drp1 inhibitor. The ability of mdivi-1 to reversibly inhibit complex I and modify mitochondrial ROS production may contribute to effects observed in disease models. PMID- 28350993 TI - Convergent strategy for the synthesis of S-linked oligoxylans. AB - Arabinoxylans (AX) are a major class of hemicellulose and an important polysaccharide component of lignocellulosic biomass. To utilize the glycan polymer effectively, it is desirable to learn more about the enzymatic hydrolysis of AXs. Well-defined glycans can help to elucidate these processes. Here, we report the efficient synthesis of a mixed O- and S-linked tetraxylan. This thio oligosaccharide has been developed as a putative inhibitor of arabinoxylan degrading enzymes used for the saccharification of biomass. Two common approaches for the synthesis of thio-oligosaccharides, either involving 1-thioglycoside donors or thioacceptors, are presented and compared regarding byproduct formation and yields. Both methods have shown to be useful for the synthesis of thiolinkages in oligoxylans assembly. However, the success of the reaction is highly dependent on the "match" between donors and acceptors. PMID- 28350994 TI - The reduction of Chlorella vulgaris concentrations through UV-C radiation treatments: A nature-based solution (NBS). AB - Algal blooms have become a pressing issue in inland freshwater systems on local and global scales. A plausible approach to reducing algae without the use of chemical/biological agents is through the use of UV-C radiation from lamps potentially powered by in situ solar panels to eliminate algae. Yet, the quantitative scientific base has not been established. Our objective is to conduct a controlled experiment to quantify the effectiveness of UV-C radiation on the reduction of Chlorella vulgaris, a common algal species in the Great Lakes region. A full factorial design of three intensities of UV-C radiation (0, 15, and 30W) and three sources of C. vulgaris was constructed to test the corresponding hypotheses. Empirical models were constructed to predict the reductions. UV-C radiation effectively reduced the algal concentration with clear differences by radiation level and source of algal water. Algal concentration decreased exponentially over time, with distinct decreasing trends among the radiation intensities and the samples. With 15W UV-C radiation, algal concentration of three samples were reduced to 75.3%, 51.5%, and 70.0% of the initial level within an hour, respectively. We also found a clear density dependent reduction rate by UV radiation. Using this information, more efficient treatment systems could be constructed and implemented for cleaning algae contaminated water. PMID- 28350996 TI - Quality measures of the population-based Finnish Cancer Registry indicate sound data quality for solid malignant tumours. AB - BACKGROUND: The Finnish Cancer Registry (FCR) has collected population-based data on cancer incidence for scientific research and statistical purposes since 1953. Our aim was to provide a comprehensive quality assessment of the current cancer registry data in Finland. METHODS: We used established quantitative and semi quantitative techniques to address four main dimensions of data quality: completeness, comparability, validity and timeliness for the period 1953-2013, with a special focus on cancers diagnosed in 2009-2013. For completeness, hospital admissions and outpatient visits were used as an independent data source. RESULTS: In 2009-2013, 153 147 incident tumours were registered in the FCR. Of them, 91% were solid tumours. The completeness for all solid tumours was estimated at 96%, and for non-solid tumours at 86%. Potential underreporting was most prominent for tumours which are not typically histologically verified such as haematological malignancies and non-malignant tumours of the central nervous system. Of all cancers, 93% were morphologically verified, with variation by primary site. The proportion of cancers with uncertain or ill-defined primary site and the proportion of death certificate only registrations were both low at 1.9% and 2.6%, respectively. CONCLUSIONS: The FCR provides overall accurate and close to complete national cancer data for solid malignant tumours. Registration of tumours with no histology is still compromised. This warrants continuous communication with clinicians to ensure undisturbed data flow, and active trace back using external data sources such as hospital administrative data. In addition, broad diagnosis categories would be less sensitive to diversity of input and data quality when international comparisons are made. PMID- 28350995 TI - The difference in association between aspirin use and other thrombocyte aggregation inhibitors and survival in patients with colorectal cancer. AB - BACKGROUND: Several studies have suggested that the association between aspirin and improved cancer survival is mediated through the mechanism of aspirin as thrombocyte aggregation inhibitors (TAI). The aim of this study was to provide epidemiological evidence for this mechanism assessing the association between overall survival and the use of aspirin and non-aspirin TAI in patients with colorectal cancer. METHODS: In this observational study, data from the Netherlands Comprehensive Cancer Organisation were linked to PHARMO Database Network. Patients using aspirin or aspirin in combination with non-aspirin TAI (dual users) were selected and compared with non-users. The association between overall survival and the use of (non-)aspirin TAI was analysed using Cox regression models with the use of (non-)aspirin TAI as a time-varying covariate. RESULTS: In total, 9196 patients were identified with colorectal cancer and 1766 patients used TAI after diagnosis. Non-aspirin TAI were mostly clopidogrel and dipyridamole. Aspirin use was associated with a significant increased overall survival and hazard ratio (HR) 0.41 (95% confidence interval [CI] 0.37-0.47), and the use of non-aspirin TAI was not associated with survival of HR 0.92 (95% CI 0.70-1.22). Dual users did not have an improved overall survival when compared with patients using solely aspirin. CONCLUSIONS: Aspirin use after diagnosis of colorectal cancer was associated with significantly lower mortality rates and this effect remained significant after adjusting for potential confounders. No additional survival benefit was observed in patients using both aspirin and another TAI. PMID- 28350997 TI - Synthesis and biological evaluation of hypoxia-activated prodrugs of SN-38. AB - We designed new hypoxia-activated prodrugs by conjugating (1-methyl-2-nitro-1H imidazol-5-yl)methanol with 7-ethyl-10-hydroxy camptothecin (SN-38). Initially, we improved the method of multi-gram scale synthesis of (1-methyl-2-nitro-1H imidazol-5-yl)methanol, which increased the yield to 42% compared to 8% by the original synthesis method. The improved method was used to synthesize evofosfamide (TH-302) and hypoxia-activated prodrugs of SN-38. Two different linkages between (1-methyl-2-nitro-1H-imidazol-5-yl)methanol and SN-38 were evaluated that afforded different hypoxia-selectivity and toxicity. Compound 16 (IOS), containing an ether linkage, was considered to be a promising hypoxia selective antitumor agent. PMID- 28350998 TI - Anticancer copper(II) phosphorus dendrimers are potent proapoptotic Bax activators. AB - A multivalent phosphorus dendrimer 1G3 and its corresponding Cu-complex, 1G3-Cu have been recently identified as agents retaining high antiproliferative potency. This antiproliferative capacity was preserved in cell lines overexpressing the efflux pump ABC B1, whereas cross-resistance was observed in ovarian cancer cell lines resistant to cisplatin. Theoretical 3D models were constructed: the dendrimers appear as irregularly shaped disk-like nano-objects of about 22 A thickness and 49 A diameter, which accumulated in cells after penetration by endocytosis. To get insight in their mode of action, cell death pathways have been examined in human cancer cell lines: early apoptosis was followed by secondary necrosis after multivalent phosphorus dendrimers exposure. The multivalent plain phosphorus dendrimer 1G3 moderately activated caspase-3 activity, in contrast with the multivalent Cu-conjugated phosphorus dendrimer 1G3 Cu which strikingly reduced the caspase-3 content and activity. This decrease of caspase activity is not related to the presence of copper, since inorganic copper has no or little effect on caspase-3. Conversely the potent apoptosis activation could be related to a noticeable translocation of Bax to the mitochondria, resulting in the release of AIF into the cytosol, its translocation to the nucleus and a severe DNA fragmentation, without alteration of the cell cycle. The multivalent Cu-conjugated phosphorus dendrimer is more efficient than its non complexed analog to activate this pathway in close relationship with the higher antiproliferative potency. Therefore, this multivalent Cu-conjugated phosphorus dendrimer 1G3-Cu can be considered as a new and promising first-in-class antiproliferative agent with a distinctive mode of action, inducing apoptosis tumor cell death through Bax activation pathway. PMID- 28350999 TI - Discovery of novel 1,2,3,4-tetrahydrobenzo[4, 5]thieno[2, 3-c]pyridine derivatives as potent and selective CYP17 inhibitors. AB - The inhibition of CYP17 to block androgen biosynthesis is a well validated strategy for the treatment of prostate cancer. Herein we reported the design, synthesis and structure-activity relationship (SAR) study for a series of novel 1,2,3,4- tetrahydrobenzo[4,5]thieno[2,3-c]pyridine derivatives. Some analogs demonstrated a potent inhibition to both rat and human CYP17 protein and reduced testosterone production in human H295R cell line. Some analogs also showed high selectivity against other CYP enzymes such as 3A4, 1A2, 2C9, 2C19 and 2D6, which may limit side effects due to drug-drug interactions. Among these analogs, the most potent compound 9c showed 1.5 fold more potent against rat and human CYP17 protein than that of abiraterone (IC50 = 16 nM and 20 nM vs. 25 nM and 36 nM respectively). In NCI-H295R cells, the inhibitory effect of compound 9c on testosterone production (52+/- 2%) was also more potent than that of abiraterone (74+/- 15%) at the concentration of 1 MUM. Further, it was shown that 9c reduced plasma testosterone level in a dose-dependent manner in Sprague-Dawley rats. Thus, analog 9c maybe a potential agent used for the treatment of prostate cancer. PMID- 28351000 TI - Targeted superparamagnetic nanoparticles coated with 2-deoxy-d-gloucose and doxorubicin more sensitize breast cancer cells to ionizing radiation. AB - INTRODUCTION: Nanoparticles are promising as a new approach to enhance chemo- radiotherapy efficiency in breast cancer mainly via targeted therapy. MATERIALS & METHODS: SKBR3 and T47D breast cancer cells were treated with superparamagnetic mesoporous hydroxyapatite nanocomposites (SPmHANs)conjugated with 1 MUM doxorubicin and 0.5 mM 2-Deoxy-d-Glucose and irradiated with 1 and 2 Gy gamma rays in vitro. The treatment toxicity and also the apoptosis/necrosis ratio were measured by MTT assay and also ELISA cell death detection PLUS, respectively. RESULTS: The decreased cell viability with the combined treatment, with determined 42% loading efficiency for 200 ppm 2DG and 93% for5ppm doxorubicin on SPmHANs in PH about 7.4 and 5.5, were calculated to 60.9% and 68% compared to radiotherapy alone inT47D and SKBR3 cells (both with p < 0.05), respectively. CONCLUSION: Breast cancer cure may boost from The combined targeted nanoparticle treatment with doxorubicin and 2-Deoxy-d-Glucose may boost breast cancer radiotherapy by improved chemodrug localization, increased cytotoxicity in tumor cells and decreased single modality treatment doses. PMID- 28351001 TI - Sample size bias in retrospective estimates of average duration. AB - People often estimate the average duration of several events (e.g., on average, how long does it take to drive from one's home to his or her office). While there is a great deal of research investigating estimates of duration for a single event, few studies have examined estimates when people must average across numerous stimuli or events. The current studies were designed to fill this gap by examining how people's estimates of average duration were influenced by the number of stimuli being averaged (i.e., the sample size). Based on research investigating the sample size bias, we predicted that participants' judgments of average duration would increase as the sample size increased. Across four studies, we demonstrated a sample size bias for estimates of average duration with different judgment types (numeric estimates and comparisons), study designs (between and within-subjects), and paradigms (observing images and performing tasks). The results are consistent with the more general notion that psychological representations of magnitudes in one dimension (e.g., quantity) can influence representations of magnitudes in another dimension (e.g., duration). PMID- 28351002 TI - Significance of lipoprotein(a) levels in familial hypercholesterolemia and coronary artery disease. AB - BACKGROUND AND AIMS: Patients with familial hypercholesterolemia (FH) are often characterized by premature coronary artery disease (CAD) with heterogeneity at onset. The aim of the present study was to investigate the associations of lipoprotein (a) [Lp(a)] with the FH phenotype, genotype and roles of Lp(a) in determining CAD risk among patients with and without FH. METHODS: We enrolled 8050 patients undergoing coronary angiography, from our Lipid clinic. Clinical FH was diagnosed using the Dutch Lipid Clinic Network criteria. Mutational analysis (LDLR, APOB, PCSK9) in definite/probable FH was performed by target exome sequencing. RESULTS: Lp(a) levels were increased, with a clinical FH diagnosis (unlikely, possible, definite/probable FH) independent of the patients status, with Lp(a)-hyperlipoproteinemia [Lp(a)-HLP] (median 517.70 vs. 570.98 vs. 604.65 mg/L, p < 0.001) or without (median 89.20 vs. 99.20 vs. 133.67 mg/L, p < 0.001). Patients with Lp(a)-HLP had a higher prevalence of definite/probable FH than those without (6.1% vs. 2.4%, p < 0.05). However, no significant difference in Lp(a) was observed in patients with definite/probable FH phenotype carrying LDLR or LDLR-independent (APOB, PCSK9) or neither mutations (p > 0.05). Multivariate analysis showed that Lp(a) and FH phenotype were both significant determinants in predicting the early onset and severity of CAD. Subsequently, patients with Lp(a) HLP in definite/probable FH increased significantly the CAD risk (all p < 0.05). CONCLUSIONS: Lp(a) levels were higher in patients with FH phenotype than in those without, but no difference were found in FH patients of different mutated backgrounds. Moreover, Lp(a) and FH played a synergistic role in predicting the early onset and severity of CAD. PMID- 28351003 TI - Experimental investigation of cognitive and affective empathy in borderline personality disorder: Effects of ambiguity in multimodal social information processing. AB - Borderline personality disorder (BPD) is characterized by affective instability and interpersonal problems. In the context of social interaction, impairments in empathy are proposed to result in inadequate social behavior. In contrast to findings of reduced cognitive empathy, some authors suggested enhanced emotional empathy in BPD. It was investigated whether ambiguity leads to decreased cognitive or emotional empathy in BPD. Thirty-four patients with BPD and thirty two healthy controls were presented with video clips, which were presented through prosody, facial expression, and speech content. Experimental conditions were designed to induce ambiguity by presenting neutral valence in one of these communication channels. Subjects were asked to indicate the actors' emotional valence, their decision confidence, and their own emotional state. BPD patients showed increased emotional empathy when neutral stories comprised nonverbally expressed emotions. In contrast, when all channels were emotional, patients showed lower emotional empathy than healthy controls. Regarding cognitive empathy, there were no significant differences between BPD patients and healthy control subjects in recognition accuracy, but reduced decision confidence in BPD. These results suggest that patients with BPD show altered emotional empathy, experiencing higher rates of emotional contagion when emotions are expressed nonverbally. The latter may contribute to misunderstandings and inadequate social behavior. PMID- 28351004 TI - Temporal changes in the prevalence of disordered eating behaviors among adolescents living in the metropolitan area of Rio de Janeiro, Brazil. AB - To investigate temporal changes in the prevalence of disordered eating behaviors among adolescents, and their association with socio demographic factors and overweight. Using probability sampling, two population-based cross-sectional surveys were conducted: one in 2005 (n=511) and the other in 2010 (n=314). The frequency of disordered eating behaviors (binge eating, strict dieting or fasting and compensatory behaviors) was investigated using a self-administered questionnaire. The presence of binge eating increased by 18.4% in the 5 years between the two surveys. In 2005, girls were 1.95 times more likely to engage in strict dieting or fasting than boys, and this difference increased to 7.02 times in 2010. Overweight adolescents were 2.29 times more likely to undertake strict dieting than non-overweight adolescents in 2005 and 3.65 times more likely to do so in 2010. No significant associations were found for compensatory behaviors. A pronounced increase in the prevalence of binge eating was observed, and girls and overweight adolescents were more likely to engage in strict dieting or fasting. PMID- 28351006 TI - Variola minor in coalfield areas of England and Wales, 1921-34: Geographical determinants of a national smallpox epidemic that spread out of effective control. AB - This paper uses techniques of binary logistic regression to identify the spatial determinants of the last national epidemic of smallpox to spread in England and Wales, the variola minor epidemic of 1921-34. Adjusting for age and county-level variations in vaccination coverage in infancy, the analysis identifies a dose response gradient with increasing odds of elevated smallpox rates in local government areas with (i) medium (odds ratio [OR] = 5.32, 95% Confidence Interval [95% CI] 1.96-14.41) and high (OR = 11.32, 95% CI 4.20-31.59) coal mining occupation rates and (ii) medium (OR = 16.74, 95% CI 2.24-125.21) and high (OR = 63.43, 95% CI 7.82-497.21) levels of residential density. The results imply that the spatial transmission of variola virus was facilitated by the close spatial packing of individuals, with a heightened transmission risk in coal mining areas of the country. A syndemic interaction between common respiratory conditions arising from exposure to coal dust and smallpox virus transmission is postulated to have contributed to the findings. We suggest that further studies of the geographical intersection of coal mining and acute infections that are transmitted via respiratory secretions are warranted. PMID- 28351005 TI - Nrf-2-driven long noncoding RNA ODRUL contributes to modulating silver nanoparticle-induced effects on erythroid cells. AB - The biosafety and biological effects of silver nanoparticles (AgNPs) on human health attract increasing concern. Although considerable studies have been performed to reveal the molecular mechanisms responsible for AgNP-induced effects, the current understanding mainly focuses on oxidative stress-associated signaling pathways activated by Ag particles and/or Ag ions. However, the molecular bases underlying the activation of these stress signaling pathways have not been thoroughly elucidated yet. In the current study, we aimed to shed light on the molecular bases of AgNP-induced effects on erythroid cells from the perspective of long noncoding RNAs. We identified a long-noncoding RNA molecule, ODRUL, which was substantially enhanced in K562 erythroid cells responding to AgNPs, coupled to accelerated cell death. Further, we uncovered oxidative stress driven Nrf2 transcriptionally promoted ODRUL expression in K562 cells. Downstream of Nrf2-ODRUL activation by AgNPs, ODRUL was recognized to interact with PI4Kalpha protein to modulate the activities of its targets AKT and JNK. As a result, the Bcl-2 level was negatively regulated by PI4K-AKT/JNK signaling under AgNP-induced stress, leading to enhanced cell death. Together, our findings unearthed that Nrf2-mediated lncRNA ODRUL was indispensable for AgNP-induced toxicity in erythroid cells through regulation of AKT/JNK-Bcl-2 signaling dependent on a physical interaction with PI4Kalpha. Thus, this study would open a new path to depict the molecular bases of AgNP-induced effects on erythroid cells. PMID- 28351007 TI - Catalytic role of iron in the formation of silver nanoparticles in photo irradiated Ag+-dissolved organic matter solution. AB - Photo-reduction of Ag+ to silver nanoparticle (AgNPs) by dissolved organic matter (DOM) is a possible source of naturally occurring AgNPs. However, how this photo reduction process is influenced by ubiquitous metal ions is still not well understood. In addition, in previous studies, the formation of AgNPs in DOM solution was usually monitored by UV-Vis spectroscopy, and there is still lack of quantitative analysis for the formed AgNPs. In the present study, the role of Fe2+/Fe3+ at environmental concentration level on this photochemical process was investigated, and the enhanced formation of AgNPs by Fe2+/Fe3+ was probed and quantified by using UV-Vis spectroscopy, transmission electron microscopy, and liquid chromatography-inductively coupled plasma mass spectrometry. It was demonstrated that while Fe3+ can oxidize AgNPs to release Ag+, Fe2+ can reduce Ag+ into AgNPs. However, the DOM-induced reduction of Fe3+ makes iron an effective electron shuttle between DOM and Ag+, and both Fe2+ and Fe3+ enhanced AgNP formation. The impacts of environmentally relevant factors, including DOM concentration and solution pH, on this process were studied comprehensively, which showed that the catalytic role of iron was more significant at higher DOM concentration and lower pH. This iron-enhanced formation of AgNPs in photo irradiated Ag+-DOM solution have great environmental implications on the formation of natural AgNPs and the transformation of engineered AgNPs in acidic surface water with high iron content. PMID- 28351008 TI - Aerosol characteristics and sources in Yangzhou, China resolved by offline aerosol mass spectrometry and other techniques. AB - Detailed chemical characterization of fine aerosols (PM2.5) is important for reducing air pollution in densely populated areas, such as the Yangtze River Delta region in China. This study systematically analyzed PM2.5 samples collected during November 2015 to April 2016 in urban Yangzhou using a suite of techniques, in particular, an Aerodyne soot particle aerosol mass spectrometry (SP-AMS). The techniques used here reconstructed the majority of total PM2.5 measured where extracted species comprised on average 91.2%. Source analyses of inorganic components showed that secondary nitrate, sulfate and chloride were the major species, while primary sources including biomass burning, coal combustion, traffic, industry and re-suspended dust due to nearby demolition activities, could contribute to other species. EC-tracer method estimated that the organic matter (OM) was composed of 65.4% secondary OM (SOM) and 34.6% primary OM (POM), while the SP-AMS analyses showed that the OM was comprised of 60.3% water-soluble OM (WSOM) and 39.7% water-insoluble OM (WIOM). Correlation analyses suggested that WSOM might be rich in secondary organic species, while WIOM was likely mainly comprised of primary organic species. We further conducted positive matrix factorization (PMF) analyses on the WSOM, and identified three primary factors including traffic, cooking and biomass burning, and two secondary factors. We found the secondary factors dominated WSOM mass (68.1%), and their mass contributions increased with the increase of WSOM concentrations. Relatively small contribution of primary sources to WSOM was probably due to their low water solubility, which should be investigated further in future. Overall, our findings improve understanding of the complex aerosol sources and chemistry in this region. PMID- 28351009 TI - The influence of citrate and oxalate on 99TcVII, Cs, NpV and UVI sorption to a Savannah River Site soil. AB - Batch sorption experiments were conducted with 0.5-50 ppb 99Tc, 133Cs, 237Np and U in the presence and absence of citrate and/or oxalate in a 25 g/L Savannah River Site (SRS) soil suspension. Citrate and oxalate were the ligands of choice due to their relevancy to plant exudates, the nuclides were selected for their wide range of biogeochemical behavior, and the soil from SRS was selected as a model Department of Energy (DOE) site soil. Batch samples were continually mixed on a rotary shaker and maintained at a pH of approximately 5. Analysis via ICP-MS indicated that sorption of 237Np increased with ligand concentration compared to baseline studies, as did sorption of 99Tc although to a lesser extent. The increased sorption of 237Np is proposed to be due to a combination of factors that are dependent on the ligand(s) present in the specific system including, ligand dissolution of the soil by citrate and formation of tertiary soil-oxalate Np complexes. The increased 99Tc sorption is attributed to the dissolution of the soil by the ligands, leading to an increase in the number of available sorption sites for 99Tc. Uranium sorption decreased and dissolution of native uranium was also observed with increasing ligand concentration, thought to be a result of the formation of strong U-ligand complexes remaining in the aqueous phase. The majority of these effects were observed at the highest ligand concentrations of 50 mgC/L. No notable changes were observed for the 133Cs system which is ascribed to the minimal interaction of Cs+ with these organic ligands. PMID- 28351010 TI - Vanadium sulfide sub-microspheres: A new near-infrared-driven photocatalyst. AB - Recently, finding a novel near-infrared (NIR) photocatalyst has been the focus in photocatalysis. Here, VS4 sub-microspheres with a chain-like structure were prepared via a facile solvothermal method. As a new photocatalyst, it presents excellent NIR photocatalytic and photoelectrochemical (PEC) activity. Theoretical calculations and experimental results demonstrate that the improved NIR photocatalytic property originated from the narrow band gap of VS4, which significantly improves the NIR light absorption. PMID- 28351011 TI - Fine cutting edge shaped Bi2O3rods/reduced graphene oxide (RGO) composite for supercapacitor and visible-light photocatalytic applications. AB - Bi2O3 rods/RGO composite has been synthesized by a simple precipitation and calcination method. The crystallnity, structural, and morphological features were studied by X-ray diffraction (XRD), field-emission scanning electron microscopy (FE-SEM), and high resolution transmission electron microscopy (HR-TEM) techniques. The supercapacitor behavior was studied using cyclic voltammetry, galvanostatic charge discharge and impedance analysis, respectively. The Bi2O3 rods/RGO nanocomposite exhibits a maximum specific capacitance of 1041Fg-1 at a current density of 2Ag-1. The photocatalytic activity of Bi2O3 rods/RGO composite was evaluated by photocatalytic degradation of methylene blue (MB) dye under visible-light irradiation. The enhancement of photocatalytic properties of Bi2O3 rods/RGO composite attributed to the synergistic effect between Bi2O3 rods and graphene sheets which effectively prevents recombination of the photogenerated electron-hole pairs in Bi2O3 rods. The present study provides a new approach in improving the performance of Bi2O3 rods/RGO composite in energy and environmental applications. PMID- 28351012 TI - A comprehensive overview on electro-active biofilms, role of exo-electrogens and their microbial niches in microbial fuel cells (MFCs). AB - Microbial fuel cells (MFCs) are biocatalyzed systems which can drive electrical energy by directly converting chemical energy using microbial biocatalyst and are considered as one of the important propitious technologies for sustainable energy production. Much research on MFCs experiments is under way with great potential to become an alternative to produce clean energy from renewable waste. MFCs have been one of the most promising technologies for generating clean energy industry in the future. This article summarizes the important findings in electro-active biofilm formation and the role of exo-electrogens in electron transfer in MFCs. This study provides and brings special attention on the effects of various operating and biological parameters on the biofilm formation in MFCs. In addition, it also highlights the significance of different molecular techniques used in the microbial community analysis of electro-active biofilm. It reviews the challenges as well as the emerging opportunities required to develop MFCs at commercial level, electro-active biofilms and to understand potential application of microbiological niches are also depicted. Thus, this review is believed to widen the efforts towards the development of electro-active biofilm and will provide the research directions to overcome energy and environmental challenges. PMID- 28351013 TI - Dynamics of antibiotic resistance genes in microbial fuel cell-coupled constructed wetlands treating antibiotic-polluted water. AB - Microbial fuel cell-coupled constructed wetlands (CW-MFCs) use electrochemical, biological, and ecological functions to treat wastewater. However, few studies have investigated the risks of antibiotic resistance genes (ARGs) when using such systems to remove antibiotics. Therefore, three CW-MFCs were designed to assess the dynamics of ARGs in filler biofilm and effluent over 5000 h of operation. The experimental results indicated that relatively high steady voltages of 605.8 mV, 613.7 mV, and 541.4 mV were obtained at total influent antibiotic concentrations of 400, 1,000, and 1600 MUg L-1, respectively. The 16S rRNA gene level in the cathode layer was higher than those in the anode and two middle layers, but the opposite trend was observed for the sul and tet genes. The relative abundance of the three tested sul genes were in the order sulI > sulII > sulIII, and those of the five tet genes were in the order tetA > tetC > tetW > tetO > tetQ. The levels of sul and tet genes in the media biofilm showed an increase over the treatment period. The effluent water had relatively low abundances of sul and tet genes compared with the filler biofilm. No increases were observed for most ARGs over the treatment period, and no significant correlations were observed between the ARGs and 16S rRNA gene copy numbers, except for sulI and tetW in the effluent. However, significant correlations were observed among most of the ARG copy numbers. PMID- 28351014 TI - Phytostabilisation of severely contaminated mine tailings using halophytes and field addition of organic and inorganic amendments. AB - Phytostabilisation strategies have proven to be an efficient remediation option for mine tailings, but the adequate plant species and amendments have to be carefully selected. A remediation experiment was carried out at the semi-field level in tailings (pH 3.2, ~1100, 4700 and 5000 mg kg-1 of As, Pb and Zn, respectively) from the mining district of La Union-Cartagena (SE Spain). A red mud derivative (Fe/Al oxides), its combination with compost, and hydrated lime (Ca hydroxide) were applied in field plots of 0.25 m2. After four months of field stabilisation, tailings were transferred unaltered to a plant growth facility, and Atriplex halimus and Zygophyllum fabago (halophytes) were sown. Three months later, trace element (TE) solubility, plant accumulation and chemical speciation in the tailings pore water were studied. In unamended tailings, soluble TEs concentrations were very high (e.g., 40 mg Zn l-1), the dominant species being free ions and SO42-- complexes (>70%). The addition of amendments increased tailings pH (6.7-7), reduced TEs solubility and extractability (>80-99%) and changed the dominant species of soluble Al, Cu, Pb and Zn to hydroxides and/or organo-metallic complexes, but increased slightly the extractable As and soluble Tl concentrations. Plants were able to grow only in amended tailings, and both species presented low levels of Al, As, Cd and Zn. Therefore, the use of combined red mud derivative and compost and halophytes was shown to be a good phytostabilisation strategy, although the dose applied must be carefully chosen in order to avoid possible solubilisation of As and Tl. PMID- 28351015 TI - Optimization for zeolite regeneration and nitrogen removal performance of a hypochlorite-chloride regenerant. AB - Simultaneous zeolites regeneration and nitrogen removal were investigated by using a mixed solution of NaClO and NaCl (NaClO-NaCl solution), and effects of the regenerant on ammonium removal performance and textural properties of zeolites were analyzed by long-term adsorption and regeneration operations. Mixed NaClO-NaCl solution removed more NH4+ exchanged on zeolites and converted more of them to nitrogen than using NaClO or NaCl solution alone. Response surface methodological analysis indicated that molar ratio of hypochlorite and nitrogen (ClO-/N), NaCl concentration and pH value all had significant effects on zeolites regeneration and NH4+ conversion to nitrogen, and the optimum condition was obtained at ClO-/N of 1.75, NaCl concentration of 20 g/L and pH of 10.0. Zeolites regenerated by mixed NaClO-NaCl solution showed higher ammonium adsorption rate and lower capacity than unused zeolites. Zeolites and the regeneration solution were both effective even after 20 cycles of use. Composition and morphological analysis revealed that the main mineral species and surface morphology of zeolites before and after NaClO-NaCl regeneration were unchanged. Textural analysis indicated that NaClO-NaCl regeneration leads to an increased surface area of zeolites, especially the microporosity. The results indicated that NaClO NaCl regeneration is an attractive method to achieve sustainable removal of nitrogen from wastewater through zeolite. PMID- 28351016 TI - Nano-enabled paper humidity sensor for mobile based point-of-care lung function monitoring. AB - The frequency of breathing and peak flow rate of exhaled air are necessary parameters to detect chronic obstructive pulmonary diseases (COPDs) such as asthma, bronchitis, or pneumonia. We developed a lung function monitoring point of-care-testing device (LFM-POCT) consisting of mouthpiece, paper-based humidity sensor, micro-heater, and real-time monitoring unit. Fabrication of a mouthpiece of optimal length ensured that the exhaled air was focused on the humidity sensor. The resistive relative humidity sensor was developed using a filter paper coated with nanoparticles, which could easily follow the frequency and peak flow rate of the human breathing. Adsorption followed by condensation of the water molecules of the humid air on the paper-sensor during the forced exhalation reduced the electrical resistance of the sensor, which was converted to an electrical signal for sensing. A micro-heater composed of a copper-coil embedded in a polymer matrix helped in maintaining an optimal temperature on the sensor surface. Thus, water condensed on the sensor surface only during forcible breathing and the sensor recovered rapidly after the exhalation was complete by rapid desorption of water molecules from the sensor surface. Two types of real time monitoring units were integrated into the device based on light emitting diodes (LEDs) and smart phones. The LED based unit displayed the diseased, critical, and fit conditions of the lungs by flashing LEDs of different colors. In comparison, for the mobile based monitoring unit, an application was developed employing an open source software, which established a wireless connectivity with the LFM-POCT device to perform the tests. PMID- 28351017 TI - Performance of a docking/molecular dynamics protocol for virtual screening of nutlin-class inhibitors of Mdmx. AB - A virtual screening protocol involving docking and molecular dynamics has been tested against the results of fluorescence polarization assays testing the potency of a series of compounds of the nutlin class for inhibition of the interaction between p53 and Mdmx, an interaction identified as a driver of certain cancers. The protocol uses a standard docking method (AutoDock) with a cutoff based on the AutoDock score (ADscore), followed by molecular dynamics simulation with a cutoff based on root-mean-square-deviation (RMSD) from the docked pose. An analysis of the experimental and computational results shows modest performance of ADscore alone, but dramatically improved performance when RMSD is also used. PMID- 28351019 TI - Online microdialysis-ultra performance liquid chromatography-mass spectrometry method for comparative pharmacokinetic investigation on iridoids from Gardenia jasminoides Ellis in rats with different progressions of type 2 diabetic complications. AB - Iridoid glycosides consist the main bioactive constituents of Gardenia jasminoides Ellis (G. jasminoides), which is used alone or in combination with other medicine herbs for treatment of diabetes mellitus in China. This paper investigated for the first time comparative pharmacokinetics (PKs) of four unbound iridoids (including genipin, geniposide, gardenoside and geniposidic acid) in rat blood between healthy and type 2 diabetic groups with different disease progressions (9 or 13 weeks). Online microdialysis-ultra performance liquid chromatography-mass spectrometry (MD- UPLC-MS/MS) method was used after oral administration of iridoid extracts obtained from the fruits of G. jasminoides. Student's t-test was used for statistical comparison of PK parameters. Results showed that genipin, geniposide and geniposidic acid feature higher Cmax, larger area under the curve (AUC), lower clearance (CL), longer Tmax and mean residence time (MRT) in type 2 diabetic rats than those in healthy rats (p<0.05). However, no significant difference was observed in PK parameters between the two diabetic groups with different complication progressions (p>0.05). Type 2 diabetic rats showed significantly altered PK behaviors of genipin, geniposide and geniposidic acid (especially systemic exposure, AUCs of genipin, geniposide and geniposidic acid). Online MD-UPLC-MS/MS provides real time sampling and monitoring, these functions can be applied to PKs of iridoids from G. jasminoides. PMID- 28351018 TI - Profiles of amino acids and biogenic amines in the plasma of Cri-du-Chat patients. AB - Cri-du-chat syndrome (CDCS) is a rare innate disease attributed to chromosome 5p deletion characterized by a cat-like cry, craniofacial malformation, and altered behavior of affected children. Metabolomic analysis and a chemometric approach allow description of the metabolic profile of CDCS as compared to normal subjects. In the present work, UHPLC/MS was employed to analyze blood samples withdrawn from CDCS carriers (n=18) and normal parental subjects (n=18), all aged 0-34 years, aiming to set up a representative CDCS profile constructed from 33 targeted amino acids and biogenic amines. Methionine sulfoxide (MetO) was of particular concern with respect to CDCS redox balance. Increased serotonin (3 fold), methionine sulfoxide (2-fold), and Asp levels, and a little lower Orn, citrulline, Leu, Val, Ile, Asn, Gln, Trp, Thr, His, Phe, Met, and creatinine levels were found in the plasma of CDCS patients. Nitrotyrosine and Trp did not differ in normal and CDCS individuals.The accumulated metabolites may reflect, respectively, disturbances in the redox balance, deficient purine biosynthesis, and altered behavior, whereas the amino acid abatement in the latter group may affect the homeostasis of the urea cycle, citric acid cycle, branched chain amino acid synthesis, Tyr and Trp metabolism and amino acid biosynthesis. The identification of enzymatic deficiencies leading to the amino acid burden in CDCS is further required for elucidating its molecular bases and eventually propose specific or mixed amino acid supplementation to newborn patients aiming to balance their metabolism. PMID- 28351021 TI - Effects of handedness & saccadic bilateral eye movements on the specificity of past autobiographical memory & episodic future thinking. AB - The present research investigated the effects of personal handedness and saccadic eye movements on the specificity of past autobiographical memory and episodic future thinking. Handedness and saccadic eye movements have been hypothesised to share a common functional basis in that both influence cognition through hemispheric interaction. The technique used to elicit autobiographical memory and episodic future thought involved a cued sentence completion procedure that allowed for the production of memories spanning the highly specific to the very general. Experiment 1 found that mixed-handed (vs. right handed) individuals generated more specific past autobiographical memories, but equivalent numbers of specific future predictions. Experiment 2 demonstrated that following 30s of bilateral (horizontal) saccades, more specific cognitions about both the past and future were generated. These findings extend previous research by showing that more distinct and episodic-like information pertaining to the self can be elicited by either mixed-handedness or eye movements. The results are discussed in relation to hemispheric interaction and top-down influences in the control of memory retrieval. PMID- 28351020 TI - Optimization of a new methodology for trace determination of elements in biological fluids: Application for speciation of inorganic selenium in children's blood. AB - The continuous sample drop flow microextraction (CSDFME) joined with the iridium modified tube graphite furnace atomic absorption spectrometry (GFAAS) has been developed as a highly sensitive technique for the speciation of selenium in blood samples. In this method 32.0MUl carbon tetrachloride is transferred to the bottom of a conical sample cup. Then the 5.0ml of aqueous solution transforms to fine droplets while passing through the organic solvent. At this stage, Se(IV)-APDC hydrophobic complex is extracted into the organic solvent. After extraction, the conical sample cup is transferred to the GFAAS and 20MUl of extraction solvent was injected into the graphite tube by the aim of autosampler. Under the optimum conditions, the calibration graph was linear in the range of 0.06-3.0MUgl-1 with detection limit of 0.02MUgl-1. The enrichment factor and enhancement factor were 106 and 91, respectively. Repeatability (intra-day) and reproducibility (inter day) of method based on seven replicate measurements of 2.5MUgl-1 of selenium were 3.7% and 4.2%, respectively. Total inorganic Se(IV, VIota) was measured after reduction of Se(VIota) with gentle boiling in 5M HCl medium for 50min and adjusting pH to 3, and the concentration of Se(VIota) was calculated by subtracting the Se(IV) concentration from the total selenium concentration. PMID- 28351022 TI - Reference values and factors associated with musculoskeletal symptoms in healthy adolescents and adults. AB - BACKGROUND: Insufficient attention has been given to individuals who report musculoskeletal symptoms yet experience minimal disability. OBJECTIVES: To examine musculoskeletal symptoms among healthy individuals, and compare demographic, psychological and physical factors between individuals with and without symptoms. DESIGN: Cross-sectional observational study. METHOD: Data were from the 1000 Norms Project which recruited 1000 individuals aged 3-101 years. Participants were healthy by self-report and had no major physical disability. Musculoskeletal symptoms (ache/pain/discomfort, including single-site and multi site symptoms) were assessed in adolescents (11-17y) and adults (18-101y) using the Extended Nordic Musculoskeletal Questionnaire (NMQ-E). To compare individuals with single-site, multi-site and no symptoms, body mass index, grip strength, 6 min walk, 30-s chair stand and timed up-and-down stairs (all participants), and mental health, sleep difficulties, self-efficacy and physical activity (adults), were collected. RESULTS: /findings: Socio-demographic characteristics were similar to the Australian population. Twelve-month period prevalence of all symptoms was 69-82%; point prevalence was 23-39%. Adults with single-site symptoms were more likely to be overweight/obese and had lower sit-to-stand and stair-climbing performance (p < 0.05). Adults with multi-site symptoms were more likely to be female and overweight/obese, had lower mental health, greater sleep difficulties and lower grip strength, 6-min walk and sit-to-stand performance (p < 0.05). Differences were only observed among 50-59, 60-69, 70-79 and 80-101 year olds. CONCLUSIONS: Normative reference data for the NMQ-E have been generated. Musculoskeletal symptoms are common among healthy individuals. In older adults, musculoskeletal symptoms are linked with overweight/obesity, lower mental health, sleep difficulties and lower physical performance, emphasising the importance of multi-dimensional assessments in musculoskeletal disorders. PMID- 28351023 TI - Effect of Door-Locking Policy on Inpatient Treatment of Substance Use and Dual Disorders. AB - OBJECTIVE: Substance use treatment is often performed inside locked wards. We investigate the effects of adopting a policy of open-door treatment for a substance use treatment and dual diagnosis ward. METHODS: This is a prospective open-label study investigating 3-month study periods before opening (P1), immediately after (P2), and 1 year after the first period (P3). Data on committed patients, coercion (seclusion, forced medication, absconding events with subsequent police search), violence, and substance use was collected daily. We applied generalised estimating equation models. RESULTS: The mean daily number of patients with ongoing commitment changed from 2.64 (P1) to 2.12 (P2) to 0.96 (P3), corresponding to a reduction of relative risk (RR) for having an ongoing commitment by 20% in P2 (RR 0.80; 95% CI 0.66-0.98) and 67% in P3 (RR 0.33; 95% CI 0.25-0.42). The mean daily number of coercive events was 0.29, 0.13, and 0.05, corresponding to a risk for undergoing coercive measures reduced by 56% (RR 0.44; 95% CI 0.22-0.90) and 85% (RR 0.15; 95% CI 0.05-0.45). Substance use, violence or ward atmosphere did not differ significantly. CONCLUSIONS: Our results support findings from general psychiatric wards of reduced coercion after adopting a primarily open-door policy. However, coercive events were rare during all periods. The widespread practice of restricting the freedom of inpatients with substance use disorders by locking ward doors is highly questionable. PMID- 28351024 TI - Evaluating the Prognostic Value of microRNA-203 in Solid Tumors Based on a Meta Analysis and the Cancer Genome Atlas (TCGA) Datasets. AB - BACKGROUND: It has been reported that miR-203 expression was aberrant in various types of cancers, and it could be used as a prognostic biomarker. Therefore, in this study, we aimed to evaluate the prognostic value of miR-203 expression in solid tumors by using meta-analysis and The Cancer Genome Atlas (TCGA) datasets. METHODS: By doing a literature research in PubMed, Embase and the Cochrane Library (last update by December 2016), we were able to identify the studies assessing the prognostic role of miR-203 in various tumors. We then used TCGA datasets to validate the results of meta-analysis. RESULTS: 33 studies from 26 articles were qualified and enrolled in this meta-analysis. Pooled analyses showed that higher expression of miR-203 in tissues couldn't predict poor overall survival (OS) and progression-free survival (PFS) in solid tumors. However, the results of subgroup analyses revealed that the upregulation of tissue miR-203 expression was associated with poor OS in colorectal cancer (hazard ratio (HR)=1.81, 95% confidence intervals (CI) 1.31-2.49; P<0.001), pancreatic cancer (HR=1.19, 95% CI 1.09-1.31; P<0.001) and ovarian cancer (HR=1.85, 95% CI 1.45 2.37; P<0.001); but it had opposite association in liver cancer (HR=0.52, 95% CI 0.28-0.97; P=0.040) and esophageal cancer (HR=0.41, 95% CI 0.25-0.66; P<0.001). Based on TCGA datasets, we found the same results for pancreatic cancer and esophageal cancer, but not for colorectal cancer and liver cancer. Moreover, patients with high circulating miR-203 in blood had significantly poor OS and PFS in colorectal cancer and breast cancer. CONCLUSION: Our study showed that the prognostic values of tissue miR-203 varied in different tumor types. In addition, the upregulation of circulating miR-203 in blood was associated with poor prognosis in colorectal cancer and breast cancer. PMID- 28351026 TI - Common Variants of Vitamin D Receptor Gene Polymorphisms and Susceptibility to Coronary Artery Disease: A Systematic Review and Meta-Analysis. AB - BACKGROUND AND AIMS: ApaI, FokI, TaqI, and BsmI polymorphisms in the vitamin D receptor (VDR) gene have been reported to be associated with the risk of coronary artery disease (CAD), although the results of previous studies have been inconsistent. The aim of this study was to explore whether these polymorphisms play a role in the genetic susceptibility to CAD. METHODS: A comprehensive search of Medline and Embase databases was conducted for studies evaluating the association between the VDR polymorphisms and CAD risk. Odds ratios with 95% confidence intervals were calculated to assess the strength of association in the dominant model, recessive model, allelic model, and genotypes contrast. RESULTS: Nine studies involving a total of 5,259 cases and 1,981 controls were finally included in this meta-analysis. Overall, no significant associations were found between ApaI, FokI, TaqI, and BsmI polymorphisms and the risk of CAD in any of the genetic models (all p ? 0.05). Moreover, a subgroup analysis by ethnicity did not reveal a significant relationship between any of the examined polymorphisms and CAD risk in Caucasians and East-Asians for any model (all p ? 0.05). CONCLUSION: Current evidence suggests that the ApaI, FokI, TaqI, and BsmI polymorphisms of the VDR gene might not be associated with genetic susceptibility to CAD. Further well-designed studies with large sample sizes are needed to confirm our results. PMID- 28351025 TI - Decidual Bleeding as a Cause of Spontaneous Hemoperitoneum in Pregnancy and Risk of Preterm Birth. AB - BACKGROUND: Spontaneous hemoperitoneum in pregnancy (SHiP) is a rare, life threatening event, particularly relevant to women with endometriosis or deciduosis. METHODS: To determine the type of lesions leading to SHiP, a literature search was conducted among all published SHiP cases. From a total of 1,339 publications, information on pathological findings at the bleeding site with histological data was found in 24 case reports (16 pregnant, 8 postpartum). RESULTS: Among pregnant women (81% primigravida), 75% had a diagnosis of endometriosis and 25% of deciduosis. Among postpartum women (38% primiparous), 63% had a diagnosis of deciduosis and 25% of endometriosis. In all cases except one, decidual cells, with or without glandular structures, were present at the bleeding site. Decidual vessels were described in 7 cases and all exhibited vascular changes, including distension of the lumen, medial disorganization, or loss of vascular integrity. These vessels were significantly different from arteries seen in the secretory endometrium, showing that structural modifications take place during the initial stage of the remodelling of placental bed spiral arteries. CONCLUSIONS: During pregnancy, a link seems to exist between ectopic decidualization, particularly that occurring in endometriotic foci, and occurrence of SHiP. In addition, subclinical decidual bleeding may be a potential risk factor for preterm labour. PMID- 28351027 TI - Re-Thinking Elective Single Embryo Transfer: Increased Risk of Monochorionic Twinning - A Systematic Review. AB - BACKGROUND/OBJECTIVES: Multiple pregnancies have tripled in the United States over the past 3 decades. Attributed to increasing maternal age at delivery but more so assisted reproductive technological advances, an effort has been made to decrease twinning through elective single embryo transfer. We sought to review and evaluate risks of monochorionic twinning as a predictable consequence of increasing utilization of elective single embryo transfer on perinatal outcomes. Primary outcomes included twinning rates, fetal anomalies, growth, preterm birth, and mortality. Secondary outcomes included neurological and pulmonary disability, intrauterine growth restriction, and congenital cardiac anomalies and twin-twin transfusion syndrome. DATA SOURCES: PubMed and Embase. RESULTS: A total of 106 studies identified by systematic search met the inclusion criteria. The trend for lower numbers of embryos transferred has inadvertently led to an increase in monochorionic twinning. This is associated with worse outcomes compared to dichorionic twinning and singleton gestations for all outcomes studied. DISCUSSION: Of great concern for monochorionic twins is the risk profile of significant morbidity and mortality. Transfer of 2 embryos should be considered to avoid higher risks inherent to the shared placental phenomena related to monochorionic twins. PMID- 28351029 TI - Cytopathological Changes Induced by the Crack Use in Oral Mucosa. AB - AIMS: To evaluate cytological alterations, inflammation, and microbial charge of the oral mucosa epithelium in crack users in in terms of the amount and duration of use. METHODS: Two hundred thirty four crack users (case group) and 120 non users (control group) participated in this study. Clinically healthy epithelial cells were collected from the posterior mouth floor, using the conventional exfoliative cytology. Some of the aspects evaluated were as follows: Papanicolaou classification, nuclear area (NA), cytoplasmic area (CA), nuclear/cytoplasmic area ratio (NA/CA), inflammation, microbial charge, keratinization, enucleated superficial cells, and binucleation. RESULTS: The average time of crack consumption was 9.8 years (+/-7.1) and the average quantity of use was 13.97 g/week (+/-18.5). The average NA values and NA/CA ratio were increased and CA values were decreased in the case group compared to those in the controls (p < 0.05). Papanicolaou class II, intense inflammation, and intense microbial charge were more prevalent in the case group than in the controls (p < 0.05). There was a significant association between high quantity of smoked crack rocks per week and increased CA values, absence of keratinization, and presence of enucleated superficial cells (p < 0.05). CONCLUSION: Crack use seemed to induce inflammatory alterations and early indicators of malignant transformation on the oral mucosa epithelium. PMID- 28351028 TI - Influence of Feeding Types during the First Months of Life on Calciuria Levels in Healthy Infants: A Secondary Analysis from a Randomized Clinical Trial. AB - BACKGROUND/AIMS: Dietary factors can modify calciuria. We aim to investigate urinary calcium excretion in healthy infants according to their protein. METHODS: Secondary data analysis from a randomized clinical trial where healthy term infants were randomized after birth to a higher (HP) or lower (LP) protein content formula that was consumed until age 1 year. A non-randomized group of breastfed (BF) infants was used for reference. Anthropometry, dietary intakes and calciuria (calcium/creatinine ratios) from spot urine samples were assessed at ages 3 and 6 months. At 6 months, the kidney volumes were assessed using ultrasonography, and the serum urea and creatinine levels were determined. RESULTS: BF infants showed the highest calciuria levels, followed by the HP and the LP groups (p < 0.001 for all comparisons). Either protein intakes or formula types modulated the calciuria in linear regression models adjusted for other influencing dietary factors. The usual cut-off values classified 37.8% (BF), 16.8% (HP) and 4.9% (LP) of the infants as hypercalciuric. CONCLUSIONS: Feeding types during the first months of life affect calciuria, with BF infants presenting the highest levels. We propose new cut-off values, based on feeding types, to prevent the overestimation in hypercalciuria diagnoses among BF infants. PMID- 28351030 TI - A Comparison of Different Training Methods in the Successful Learning of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration. AB - BACKGROUND: Standardized training of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS- TBNA) is available only in highly developed countries. OBJECTIVE: To compare the skill differences in the performance of EBUS-TBNA by pulmonologists trained under different learning methods. METHODS: We performed a retrospective study of 145 EBUS-TBNA cases. We set up 3 comparative training groups: a standardized training group, a teaching group, and a self-study group. The main clinical outcomes were sensitivity, specificity and accuracy of EBUS-TBNA. Cumulative sum analysis was used to track EBUS-TBNA proficiency of the 3 groups. RESULTS: The sensitivities of EBUS-TBNA in the different groups were 90, 88, and 67%, respectively. The accuracies of the different groups were 91, 90, and 71%, respectively. With respect to the sensitivity and accuracy, there was no significant difference between the standardized training group and teaching group. However, the self-study group was inferior to the other 2 groups. By comparing the learning curve among the groups, we found that the minimum number of operations needed to reach a 90% accuracy for the standardized training group, the teaching group and the self-study group was 17, 32 and 40 cases, respectively. CONCLUSION: Compared with the teaching and self-study groups, the standardized training group resulted in practitioners achieving high skill levels following the performance of a lower number of cases. Pulmonologists trained in the teaching group achieved a similar level of skills, but required more experience to reach this level. Practitioners in the self-study group did not achieve a satisfactory level of skills, despite performing a high number of cases. PMID- 28351031 TI - Erratum. PMID- 28351032 TI - Baicalein, a Natural Anti-Cancer Compound, Alters MicroRNA Expression Profiles in Bel-7402 Human Hepatocellular Carcinoma Cells. AB - BACKGROUND/AIMS: Baicalein has been shown to possess significant anti-hepatoma activity by inhibiting cell proliferation. Whether the anti-proliferative effect of baicalein is related to its modulation of miRNA expression in hepatocellular carcinoma (HCC) is still unknown. METHODS: The anti-proliferative effects of baicalein on HCC cell line Bel-7402 was assessed by detecting the proliferation activity, cell cycle distribution, expression changes of p21/CDKN1A, P27/CDKN1B, total Akt and phosphoryted AKT. Microarray analysis was conducted to determine the miRNA expression profiles in baicalein-treated or untreated Bel-7402 cells and then validated by qRT-PCR in two HCC cell lines (Bel-7402 and Hep3B). The gain-of-function of miR-3127-5p was performed by detecting anti-proliferative effects after transfecting miRNA mimics in cells. Finally, the expression level of miR-3127-5p in different HCC cell lines was determined by qRT-PCR. RESULTS: Baicalein was able to inhibit the proliferation of Bel-7402 cells by inducing cell cycle arrest at the S and G2/M phase via up-regulating the expression of p21/CDKN1A and P27/CDKN1B and suppressing the PI3K/Akt pathway. Baicalein could alter the miRNA expression profiles in Bel-7402 cells. Putative target genes for differentially expressed miRNAs could be enriched in terms of cell proliferation regulation, cell cycle arrest and were mainly involved in MAPK, PI3K-Akt, Wnt, Hippo and mTOR signaling pathways. MiR- 3127-5p, one of up-regulated miRNAs, exhibits low expression level in several HCC cell lines and its overexpression could inhibit cell growth of Bel-7402 and Hep3B cell lines by inducing S phase arrest by up-regulating the expression of p21and P27 and repressing the PI3K/Akt pathway. CONCLUSIONS: Modulation of miRNA expression may be an important mechanism underlying the anti-hepatoma effects of baicalein. PMID- 28351034 TI - [5. ASORS-Jahreskongress - Supportive Therapie und Rehabilitation bei Krebs - State of the Art 2017. Munchen, 31. Marz - 1. April 2017: Abstracts]. PMID- 28351033 TI - ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasms: Systemic Therapy - Biotherapy and Novel Targeted Agents. PMID- 28351035 TI - Resting-State Functional Connectivity Changes Associated with Visuospatial Cognitive Deficits in Patients with Mild Alzheimer Disease. AB - BACKGROUND/AIMS: Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive disconnection of various brain networks leading to neuropsychological impairment. Pathology in the visual association areas has been documented in presymptomatic AD and therefore we aimed at examining the relationship between brain connectivity and visuospatial (VS) cognitive deficits in early AD. METHODS: Tests for VS working memory, episodic memory and construction were used to classify patients with AD (n = 48) as having severe VS deficits (n = 12, female = 4) or mild deficits (n = 11, female = 4). Resting state functional magnetic resonance imaging and structural images were acquired as per the standard protocols. Between-group differences in resting-state functional connectivity (rsFC) were examined by dual regression analysis correcting for age, gender, and total brain volume. RESULTS: Patients with AD having severe VS deficits exhibited significantly reduced rsFC in bilateral lingual gyri of the visual network compared to patients with mild VS deficits. CONCLUSION: Reduced rsFC in the visual network in patients with more severe VS deficits may be a functional neuroimaging biomarker reflecting hypoconnectivity of the brain with progressive VS deficits during early AD. PMID- 28351036 TI - Hypoxia Induces Multidrug Resistance via Enhancement of Epidermal Growth Factor Like Domain 7 Expression in Non-Small Lung Cancer Cells. AB - Chemotherapy is widely used in non-small cell lung cancer (NSCLC) treatment, yet multidrug resistance (MDR) is a major chemotherapeutic obstacle in both resectable and advanced NSCLC. Epidermal growth factor-like domain 7 (EGFL7), also known as vascular endothelial stain, is an endothelial cell-derived secreted factor that regulates vascular tube formulation. The aim of this study was to investigate the potential relationships between EGFL7 and MDR in NSCLC cells. We first obtained the CDDP-based MDR phenotype cell line A549/CDDP by repeated exposure to a proper concentration of CDDP (cisplatin) from original A549 cells. These A549/CDDP cells, which maintained relative high levels of EGFL7 and P glycoprotein (P-gp), were resistant to other chemotherapy drugs, such as carboplatin (CBP), paclitaxel (TAX), and gemcitabine (GEM) (p < 0.05). We also found that hypoxia significantly reduced the chemosensitivity of NSCLC cells, and hypoxia-induced MDR was mediated by P-gp and EGFL7 (p < 0.05). EGFL7 was veryy relevant to NSCLC cell MDR, and downregulation of EGFL7 could significantly increase the chemosensitivity of NSCLC cells (p < 0.05). Thus, our findings first indicate that hypoxia induced NSCLC cell MDR at least partly by enhancing the expression of EGFL7 protein. EGFL7 might be a feasible target for reversing hypoxia-mediated MDR in NSCLC cells and a promising biomarker for predicting the development of MDR in NSCLC patients on chemotherapy. PMID- 28351037 TI - Impact of Laser Power and Firing Angle on Coagulation Efficiency in Laser Treatment for Twin-Twin Transfusion Syndrome: An ex vivo Placenta Study. AB - OBJECTIVE: To assess the impact of laser power and firing angle on coagulation efficiency for closing placental anastomoses in the treatment of twin-twin transfusion syndrome. METHODS: We used an ex vivo blood-perfused human placenta model to compare time to complete coagulation using 30 vs. 50 W of neodymium doped yttrium aluminum garnet laser power and using a firing angle of 90 degrees vs. 45 degrees . Placentas were perfused with pig blood at 5 mL/min. Differences were analyzed using independent-samples t test, Mann-Whitney U test, or chi2 test as appropriate. RESULTS: Coagulation took less time and energy using 50 W (n = 53) compared to 30 W (n = 52), 11 vs. 22 s (p < 0.001), and 557 vs. 659 J (p = 0.007). Perpendicular coagulation (n = 53) took less time and energy compared to a 45 degrees angle (n = 21), 11 vs. 17 s (p = 0.004), and 557 vs. 871 J (p = 0.004). Bleeding complicated 2 (3%) measurements in the 50-W group, 5 (10%) in the 30-W group, and 3 (14%) in the 45 degrees group. DISCUSSION: In a highly controlled model, a 50-W laser power setting was more energy efficient than 30 W in coagulating a placental vein. A more perpendicular laser firing angle resulted in more efficient coagulation. Furthermore, bleeding due to vessel wall disruption occurred more often with lower power and a more tangential approach. PMID- 28351038 TI - Vitamin D Levels Do Not Affect Natural Fertility and in vitro Fertilization Outcomes. PMID- 28351039 TI - Prognostic Value of the Apparent Diffusion Coefficient in Newborns with Hypoxic Ischaemic Encephalopathy Treated with Therapeutic Hypothermia. AB - BACKGROUND: Apparent diffusion coefficient (ADC) quantification has been proven to be of prognostic value in term newborns with hypoxic-ischaemic encephalopathy (HIE) who were treated under normothermia. OBJECTIVES: To evaluate the prognostic value of ADC in standardized brain regions in neonates with HIE who were treated with therapeutic hypothermia (TH). METHODS: This prospective cohort study included 54 term newborns who were admitted with HIE and treated with TH. All magnetic resonance imaging examinations were performed between days 4 and 6 of life, and ADC values were measured in 13 standardized regions of the brain. At 2 years of age we explored whether ADC values were related to composite outcomes (death or survival with abnormal neurodevelopment). RESULTS: The severity of HIE is inversely related to ADC values in different brain regions. We found that lower ADC values in the posterior limb of the internal capsule (PLIC), the thalami, the semioval centre, and frontal and parietal white matter were related to adverse outcomes. ADC values in the PLIC and thalami are good predictors of adverse outcomes (AUC 0.86 and 0.76). CONCLUSIONS: Low ADC values in the PLIC, thalamus, semioval centre, and frontal and parietal white matter in full-term infants with HIE treated with TH were associated with a poor outcome. PMID- 28351040 TI - Macular Edema: Definition and Basic Concepts. AB - Macular edema is the result of an accumulation of fluid in the retinal layers around the fovea. It contributes to vision loss by altering the functional cell relationship in the retina and promoting an inflammatory reparative response. Macular edema may be intracellular or extracellular. Intracellular accumulation of fluid, also called cytotoxic edema, is an alteration of the cellular ionic distribution. Extracellular accumulation of fluid, which is more frequent and clinically more relevant, is directly associated with an alteration of the blood retinal barrier (BRB). The following parameters are relevant for clinical evaluation of macular edema: extent of the macular edema (i.e., the area that shows increased retinal thickness); distribution of the edema in the macular area (i.e., focal versus diffuse macular edema); central foveal involvement (central area 500 MUm); fluorescein leakage (evidence of alteration of the BRB or 'open barrier') and intraretinal cysts; signs of ischemia (broken perifoveolar capillary arcade and/or areas of capillary closure); presence or absence of vitreous traction; increase in retinal thickness and cysts in the retina (inner or outer), and chronicity of the edema (i.e., time elapsed since initial diagnosis and response to therapy). It is essential to establish associations and correlations of all the different images obtained, regardless of whether the same or different modalities are used. PMID- 28351041 TI - Mechanisms of Retinal Fluid Accumulation and Blood-Retinal Barrier Breakdown. AB - Macular edema is the swelling of the central portion of the human retina and it is associated with increased retinal thickness. It can be simply defined as an excess of fluid within the retinal tissue. It must be realized that the normal retina possesses a functional extracellular space. With regard to the extracellular volume of the retina, there have been few physiologic studies, but there are reported values of 24.8% for the cerebrum and 23.6% for the cerebellum. It is accepted that the retinal extracellular space is similar to the brain. It is generally agreed that the proximate cause of macular edema and retinal fluid accumulation is a breakdown of the blood-retinal barrier (BRB). When there is a breakdown of the BRB, retinal edema can be interpreted in terms of basic principles of capillary filtration (Starling's law). Therefore, the main factors influencing retinal edema formation are BRB permeability, capillary hydrostatic pressure, tissue hydrostatic pressure, tissue osmotic pressure, and plasma osmotic pressure. Active transport by the retinal pigment epithelium is necessary to remove water that percolates through the retina from intraocular pressure and is also as a safety mechanism against fluid accumulation in disease. Clinical evaluation of the BRB and retinal edema can be performed noninvasively by using an OCT-based method designated OCT-Leakage, which is capable of identifying and quantifying sites of alteration of the BRB, and by mapping sites of low optical reflectivity, i.e., changes in the retinal extracellular fluid. PMID- 28351042 TI - Intracellular Edema. AB - The macula is predisposed to edema in various retinal conditions, even when the insult is remote from the macula. The various factors that may predispose the macula to edema include high metabolic activity, radial arrangement of the Henle's layer, lack of inner layers at the fovea, and lack of blood supply at the fovea. The edema is most pronounced in the outer plexiform layer (Henle's layer). Alteration in the blood-retinal barrier and ischemia cause disturbances in vascular permeability as well as with the function of Muller cells. K+ ions and aquaporin-4 play an important role in maintaining the dryness of the macula in physiological conditions. Intracellular edema of Muller cells contributes significantly to macular edema. Steroids and anti-VEGF agents reduce intracellular edema, apart from extracellular edema. Therapeutic targets for improving Muller cell function could play a key role in the development of new molecules. PMID- 28351043 TI - Central Serous Chorioretinopathy. AB - Central serous is an atypical form of macular edema with mostly accumulation of fluid under the retina. It contitutes a pure phenotype of retinal pigment epithelium barrier breakdown. Another particularity is the good visual preservation despite important fluid volume increase in the macula. PMID- 28351044 TI - Diagnosis and Detection. AB - The aim of the chapter is to provide a practical but exhaustive guide in detecting macular edema and to describe its features according to the retinal condition that causes it. The most useful imaging techniques (biomicroscopy, retinography, optical coherence tomography, and fluorescein/indocyanine-green angiography will be analyzed in order to identify the best diagnostic algorithm in each pathology. There is a table at the end of the chapter which summarizes the important points of the chapter. PMID- 28351045 TI - Optical Coherence Tomography Angiography in Macular Edema. AB - OCT angiography is a promising new method to visualize the retinal vasculature and choroidal vascular layers in the macular area and provides depth resolved functional information of the blood flow in the vessels. Given that the main moving elements in the eye fundus are contained in vessels, determining a vascular decorrelation signal enables visualization of 3-dimensional retinal and choroidal vascular network without the administration of intravenous dye and thus reducing the risk of potential adverse events. PMID- 28351046 TI - Retinal Vein Occlusions. AB - Retinal vein occlusions (RVOs) have been defined as retinal vascular disorders characterized by dilatation of retinal veins with retinal and subretinal hemorrhages, macular edema, and a varying degree of retinal ischemia. Retinal angiography, either as fluorescein and indocyanine green (ICG) angiography or in the form of optical coherence tomography (OCT)-based angiography, is essential for the diagnosis and assessment of the prognosis of RVOs. It allows the differentiation of diverse types of RVOs, such as perfused or nonperfused, as well as the detection of different modalities in the natural history of RVOs. OCT angiographic imaging in combination with dye angiography (fluorescein or ICG) is the most effective method to assess the amount and location of cystoid macular edema and the persistence, regression, and degree of ischemia. OCT can additionally display the presence and integrity of the outer limiting membrane and of the inner and outer segments of the photoreceptors as useful biomarkers for the prognosis and as a guide for the treatment of RVO. Due to the relatively often benign and self-limiting course of nonischemic RVOs, therapy may initially be delayed. If macular edema extends into the foveolar region and persists, intravitreal medical therapy including steroids (triamcinolone; fluocinolone or dexamethasone in slow-release devices) and/or anti-VEGF (vascular endothelial growth factor) drugs (bevacizumab, ranibizumab, aflibercept) may be intravitreally administered, avoiding the irreversibly destructive effect of laser coagulation, which previously was applied in a 'grid' pattern over the extrafoveolar leaking area. The side effects of intraocularly applied steroids in relatively young patients including cataract formation and ocular hypertension have to be considered. PMID- 28351047 TI - Postsurgical Cystoid Macular Edema. AB - Cystoid macular edema (CME) is a primary cause of reduced vision following both cataract and successful vitreoretinal surgery. The incidence of clinical CME following modern cataract surgery is 0.1-2.35%. Preexisting conditions such as diabetes mellitus and uveitis as well as intraoperative complications can raise the risk of postsurgical CME. The etiology of CME is not completely understood. Prolapsed or incarcerated vitreous and postoperative inflammatory processes have been proposed as causative agents. Pseudophakic CME is characterized by poor postoperative visual acuity. Fluorescein angiography shows the classical perifoveal petaloid staining pattern and late leakage of the optic disk. Optical coherence tomography is a useful diagnostic tool, which displays cystic spaces in the outer nuclear layer. The most important differential diagnoses include age related macular degeneration and other causes of CME such as diabetic macular edema. Most cases of pseudophakic CME resolve spontaneously. The value of prophylactic treatment is doubtful. First-line treatment of postsurgical CME should include topical nonsteroidal anti-inflammatory drugs and corticosteroids. Oral carbonic anhydrase inhibitors can be considered complementary. In cases of resistant CME, periocular or intraocular corticosteroids present an option. Antiangiogenic agents, though experimental, should be considered for nonresponsive persistent CME. Surgical options should be reserved for special indications. PMID- 28351048 TI - Retinitis Pigmentosa and Other Dystrophies. AB - Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal degenerations characterized by progressive degeneration of rod and cone cells that affects predominantly peripheral visual fields. Macular edema may cause additional central visual acuity decrease. Cystoid macular edema (CME) is one of the few treatable causes of visual loss in RP. The prevalence of CME in RP has been found to be between 10 and 20% on fluorescein angiography-based studies, and as high as 49% on reports based on optical coherence tomography. Macular edema can manifest at any stage of the disease and may be unilateral or bilateral. It can be found in any genetic form, but is more often associated with RP caused by CRB1 mutations. The origin of macular edema in RP patients still remains poorly understood. Some mechanisms have been suggested, including antiretinal antibodies (retinal, carbonic anhydrase, and enolase antibodies), vitreous traction, retinal pigment epithelium dysfunction, and Muller cell edema. There is no gold standard therapeutic strategy. Drug therapy is the primary treatment. Systemic carbonic anhydrase inhibitors, such as oral acetazolamide or topical dorzolamide, are still the mainstays of initial therapy. If CME is refractory to acetazolamide, intravitreal corticosteroid injections may be a therapeutic option. However, antivascular endothelium growth factor injections have limited effect and should be avoided. Vitrectomy has also been evaluated, but its exact role remains to be determined. The benefits of these therapies are variable among patients. The establishment of therapeutic approaches is limited by our poor understanding of the pathophysiology of CME in patients with RP. Autoimmune retinopathies (AIRs) are a group of rare diseases characterized by acute or subacute progressive vision loss and are thought to be mediated by autoantibodies specific to retinal antigens. The AIRs encompass paraneoplastic syndromes, such as cancer-associated retinopathy and melanoma-associated retinopathy, and a larger group of AIRs that have similar clinical and immunological findings but without underlying malignancy. These diseases may also be complicated by macular edema. RP is one of the most common forms of inherited retinal degeneration. It displays extensive clinical and genetic variations and leads to progressive blindness with variable onset. PMID- 28351049 TI - Macular Edema of Choroidal Origin. AB - Macular edema is most often clinically defined as an accumulation of serous fluid within the neurosensory retina with increased thickness of the central retina. In exudative age-related macular degeneration the leakage of fluid from the choroidal new vessels may be the origin of macular edema. Their abnormal permeability and the inflammatory reaction are mechanisms involved in this accumulation of fluid, which occurs in all layers. Cystoid macular edema is more often associated with subepithelial occult choroidal neovascularization (CNV) than it is with pre-epithelial classic CNV. The simultaneous presence of choroidal new vessels and ME implies a number of cellular dysfunctions especially of Muller cells and subsequently metabolic alterations. The leakage from the choroidal new vessels, predominantly vascular endothelial growth factor (VEGF) induced, may produce a large accumulation of fluid under the neurosensory retina. It is also likely that the key signaling steps occur prior to the upregulation of VEGF either initiated by, or facilitated by, cytokines, which act under normal basic conditions to counterbalance the integral VEGF effects and, in pathologic circumstances, may either counteract or serve to amplify the process. PMID- 28351050 TI - Miscellaneous. AB - This chapter provides the reader with practical information to be applied to the various remaining causes of macular edema. Some clinical cases of macular edema linked to ocular diseases like postradiotherapy for ocular melanomas remained of poor functional prognosis due to the primary disease. On the contrary, macular edema occurring after retinal detachment or after diverse systemic or local treatment use is often temporary. Macular edema associated with epiretinal membranes or vitreomacular traction is the main cause of poor functional recovery. In other cases, as in tractional myopic vitreoschisis, the delay to observe a significant improvement of the vision after surgery should be long. Finally, macular edema associated with hemangiomas or macroaneurysms should be treated, if symptomatic, using the same current treatment as in diabetic macular edema or exudative macular degeneration. The miscellaneous chapter is always a challenging one, laden with two serious caveats: being too exhaustive or forgetting common circumstances. The author has attempted to provide the reader with useful, practical information that can be applied to the various causes of macular edema. PMID- 28351051 TI - Insights into the Physiopathology of Inflammatory Macular Edema. AB - Macular edema is one of the most common causes of permanent vision loss in patients with uveitis. The current understanding of water balance and metabolism within the retina has given us better insight into the mechanisms underlying macular edema arising from both acute and chronic inflammation. Uveitic macular edema (UME) occurs when the equilibrium between water influx and efflux is lost, and more importantly when compensatory mechanisms are overwhelmed. While in the acute setting, control of inflammation can reestablish homeostasis, chronic inflammation can lead to alternate pathways to establish a water balance. To understand UME, one must understand the regulation and consequences of inflammation at the tissular level. A fine interplay exists between inflammation and the retina replete with compensatory mechanisms, bystander effects, and structural sequelae once inflammation subsides. This understanding may allow us to develop new therapeutic strategies for the treatment of inflammatory macular edema. PMID- 28351052 TI - Diabetic Macular Edema. AB - Diabetic macular edema (DME), defined as a retinal thickening involving or approaching the center of the macula, represents the most common cause of vision loss in patients affected by diabetes mellitus. In the last few years, many diagnostic tools have proven to be useful in the detection and the monitoring of the features characterizing DME. On the other hand, several therapeutic approaches can now be proposed on the basis of the DME-specific characteristics. The aim of the present chapter is to thoroughly delineate the clinical and morphofunctional characteristics of DME and its current treatment perspectives. The pathogenesis and the course of DME require a complex approach with multidisciplinary intervention both at the systemic and local levels. PMID- 28351053 TI - Macular Edema - Rationale for Therapy. AB - Macular edema represents the end-stage of multiple pathophysiological pathways in a multitude of ocular vascular, inflammatory, and other diseases. The rationale for clinical treatment of macular edema is based on the understanding and the inhibition of these pathophysiological mechanisms. When macular edema is caused by a generalized health problem such as diabetes, high blood pressure, or generalized inflammatory conditions, treatment of these generalized diseases can in many cases cure macular edema directly. In ocular diseases, the local exudation of fluid from blood vessels is governed by Starling's law as well as by intricate cellular mechanisms linked to the tight junctions in the inner and outer blood-retinal barrier. Drugs used in clinical practice, such as nonsteroidal anti-inflammatory drugs, corticosteroids, carbonic anhydrase inhibitors, and anti-vascular endothelial growth factor agents, all act in one way or another through these cellular mechanisms. Novel treatments such as neuroprotective agents like nerve growth factors, somatostatins and antiapoptotic agents like calpain, the glutamate blocker memantine, and different caspase inhibitors may in the future inhibit neuronal cell death in the retina by separate pathways. Using dimmed nocturnal illumination may be an additional novel method to reduce hypoxic stress during dark adaptation of the rod photoreceptors in diabetes. Successful surgical treatment of macular edema using vitrectomy and peeling relies, apart from the evident release of vitreomacular traction, on many other cellular and biochemical mechanisms activated by the surgery such as oxygenation of the inner retina, removal of the posterior hyaloid as a growth factor sink, and possible Muller cell remodeling with fluid redirection after internal limiting membrane peeling. PMID- 28351054 TI - Drug Delivery to the Posterior Segment of the Eye. AB - Drug delivery into the posterior segment of the eye is complicated by the existence of the blood-ocular barrier. Strategies for delivering drugs to the posterior segment include systemic administration, modification of the barrier, and local drug delivery (including transcorneal, transscleral, and intravitreal). The most commonly used method for drug delivery into the posterior segment is by intravitreal injection. Other routes that can be used to achieve therapeutic drug levels in the posterior segment include topical, iontophoretic, and juxtascleral delivery. Extended-release intravitreal drug delivery systems can achieve sustained therapeutic levels with the goal of providing a prolonged clinical benefit with significantly fewer interventions. PMID- 28351055 TI - Comparison of the Induction-to-Delivery Interval in Terminations of Pregnancy with or without Dilapan-S(r). AB - OBJECTIVE: In France, terminations of pregnancy (TOP) for medical reasons beyond the second trimester use mifepristone and misoprostol. We sought to determine the effectiveness of Dilapan-S(r), an osmotic cervical dilator, in shortening the induction-to-delivery interval (IDI). MATERIALS AND METHODS: This retrospective study of TOP in 2010-2012 compared the results from 2 hospitals with different TOP protocols starting at 16 weeks' gestation, one (164 women) with and one (106) without Dilapan-S(r). The principal endpoint was the IDI. Results were analyzed according to 2 definitions of induction onset: definition 1, first dose of misoprostol in both centers, or definition 2, dilator placement if used, and otherwise first dose of misoprostol. RESULTS: With definition 1, the IDI was shorter with dilators (5 h 48 min vs. 10 h 18 min, p < 0.001); the rates of uterine evacuation within 12 and 24 h were higher (94.5 and 100 vs. 68.9 and 91.5%, p < 0.001), and the time between first misoprostol dose and amniotomy was shorter (0 h 47 min vs. 4 h 30 min, p < 0.001). Under definition 2, the IDI was longer with dilators (18 h 24 min vs. 10 h 18 min, p < 0.001), but the rate of evacuation within 24 h did not differ significantly. CONCLUSION: Dilapan-S(r) acts on cervical ripening and dilatation, thereby allowing early amniotomy. Assessing potential side effects and women's satisfaction requires prospective trials. PMID- 28351056 TI - Comparison of Umbilical Serum Copeptin Relative to Erythropoietin and S100B as Asphyxia Biomarkers at Birth. AB - BACKGROUND: Birth asphyxia, estimated to account for a million neonatal deaths annually, can cause a wide variety of neurodevelopmental impairments. There is a need to develop new, swift methods to identify those neonates who would benefit from neuroprotective treatments such as hypothermia. OBJECTIVES: To examine the utility of cord serum copeptin, a stable byproduct of arginine vasopressin release, as a biomarker of birth asphyxia based on a comparison with 2 biomarkers of hypoxia and brain trauma: erythropoietin and S100B. METHODS: The study population consisted of 140 singleton, term neonates: 113 controls and 27 with birth asphyxia (2/3 criteria met: umbilical artery pH <7.10, base excess <=12 mmol/L, and 5-min Apgar score <7). All deliveries were planned vaginal, but 51 neonates were born by emergency cesarean section. Copeptin, S100B, and erythropoietin levels in umbilical artery samples were measured by immunoassays. RESULTS: Copeptin correlated in the entire study population more strongly with umbilical artery base excess than S100B and erythropoietin, and only copeptin correlated with arterial pH. Furthermore, only copeptin levels were significantly higher in cases of birth asphyxia, and in vaginally born neonates they were found to increase as a function of labor duration. Copeptin was elevated in neonates born via vacuum extraction, whereas erythropoietin levels showed a slight increase after emergency cesarean section. CONCLUSIONS: In this study population, S100B and erythropoietin were not valid biomarkers of birth asphyxia. In contrast, our work suggests that copeptin has high potential to become a routinely used biomarker for acute birth asphyxia and neonatal distress. PMID- 28351057 TI - Genome-Wide Identification and Analysis of the Type-B Authentic Response Regulator Gene Family in Peach (Prunus persica). AB - The type-B authentic response regulator (ARR-B) family members serve as DNA binding transcriptional regulators, whose activities are probably regulated by phosphorylation/dephosphorylation, resulting in the rapid induction of type-A ARR genes. Type-B ARRs are believed to be involved in many biological processes, including cytokinin signaling, plant growth, and stress responses through a chaperone or by isomerization of proline residues during protein folding. The public availability of complete peach genome sequences allows the identification of 23 ARR-B genes by HMMER and blast analysis. Scaffold locations of these genes in the peach genome were determined, and the protein domain and motif organization of peach type-B ARRs were analyzed. The phylogenetic relationships between peach type-B ARRs were also assessed. The expression profiles of peach ARR-B genes revealed that most of the type-B ARRs showed high expression levels in tissues undergoing rapid cell division and may engage more cytokinins, like half-opened flowers, fruits at expansion stages, and young leaves. These findings not only contribute to a better understanding of the complex regulation of the peach ARR-B gene family, but also provide valuable information for future research in peach functional genomics. PMID- 28351058 TI - Central Macular Thickness Monitoring after a Taxane-Based Therapy in Visually Asymptomatic Patients. AB - BACKGROUND: Taxanes are drugs used in various chemotherapeutical protocols to treat solid tumors. They have multiple systemic adverse effects, such as bone marrow suppression, alopecia, nausea, and vomiting, and may rarely cause ocular symptoms. In the past decade, a few reported cases have shown the occurrence of a cystoid macular edema with significant visual loss after the use of a taxane based chemotherapy. The aim of this study was to compare the central macular thickness (CMT) before and after the initiation of a taxane-based therapy in visually asymptomatic patients and to elucidate the possible impact of these drugs on the vision of cancer patients. METHODS: Patients with a confirmed diagnosis of a solid tumor were screened for any ophthalmic disease before inclusion and had a baseline macular spectral domain optical coherence tomography (OCT; RTVue-100; Optovue Inc., Fremont, CA, USA) before the initiation of a taxane-based chemotherapy according to different protocols, such as 4EC-4T, 3FEC/3T, or 4TC. OCT was repeated after 4 cycles (or 3 months) of treatment, and CMT was compared to baseline. Patients presenting diabetic retinopathy, age related macular degeneration or any condition that causes macular edema confirmed by ophthalmic examination were excluded. RESULTS: Fifty eyes of 25 patients were included; 92% of the subjects were female with a mean age of 48.52 years, 88% were diagnosed with breast cancer, 8% with esophageal cancer, and 4% with ovarian cancer. Docetaxel was the taxane administered to 92% of the patients. The received dose of docetaxel ranged between 110 and 160 mg. The other patients had paclitaxel in their protocols. No significant macular edema or drop in visual acuity were noted in any patient. Nevertheless, the mean CMT was found to be increased, particularly in the parafoveal and perifoveal areas (mean difference of +2.22 MUm; p = 0.001). CONCLUSION: Taxane-based chemotherapy regimens seem to increase macular thickness, with a relative sparing of the fovea, in patients without significant macular edema. Further research is required to better explain the pathophysiology and possible impact of this phenomenon. PMID- 28351059 TI - Sonographic Markers in the Prediction of Fetal Complex Gastroschisis. AB - OBJECTIVE: To investigate the ultrasound (US) markers predictive of complex gastroschisis (CG), mortality, and morbidity in fetuses with gastroschisis. MATERIALS AND METHODS: This was a retrospective cohort study of 186 pregnancies with isolated fetal gastroschisis. Eight US markers were analyzed. The predictions and associations of US markers with CG, mortality, and morbidity were assessed. Combinations of US markers predictive of CG were investigated. RESULTS: Extra-abdominal bowel dilatation (EABD), intra-abdominal bowel dilatation (IABD), and polyhydramnios were predictive of CG. EABD between 25 and 28 weeks had a sensitivity of 64%, a specificity of 89%, a positive predictive value (PPV) of 56.2%, and negative predictive value (NPV) of 91.8%. The predictions of IABD were sensitivity = 26.7%, specificity = 96.7%, PPV = 61.5%, and NPV = 86.8%. The odds ratios for CG in the presence of 1 and 2 US markers, compared with the absence of a US marker, were 18.3 (95% CI, 3.83-87.64) and 73.3 (95% CI, 6.14-876), respectively. CONCLUSION: US markers predictive of CG were established. The combination of these markers increases the probability of CG. PMID- 28351060 TI - Blood Pressure Variability in Obstructive Sleep Apnoea: Data from 4 Randomised Controlled CPAP Withdrawal Trials. AB - BACKGROUND: Increased daytime blood pressure variability (BPV) is associated with cardiovascular risk. Preliminary data suggest that obstructive sleep apnoea (OSA) might contribute to increased daytime BPV. OBJECTIVE: The aim of this study was to evaluate the effect of continuous positive airway pressure (CPAP) therapy withdrawal on daytime BPV. METHODS: A total of 183 patients previously diagnosed with OSA and treated with CPAP were randomised to either continue or withdraw from CPAP within 4 trials. Office morning BP was measured in triplicate at baseline and at follow-up (day 14). In addition, the participants performed BP measurements at home on a daily basis (days 1-13). The main outcome of interest was the treatment effect on within-visit BPV expressed as the standard deviation (SD) of the triplicate measurements. Additional outcomes included morning home BPV and day-to-day home BPV. RESULTS: Within-visit variability in systolic BP significantly increased in response to recurrence of OSA in the CPAP withdrawal group (difference between groups in SD of systolic BPV, +1.14 mm Hg, 95% CI +0.20/+2.09, p = 0.02). There was no statistically significant effect on within visit variability in diastolic BP (p = 0.38) or heart rate (p = 0.07). Neither morning home BP variability (systolic BPV, p = 0.81; diastolic BPV, p = 0.46) nor day-to-day variability in home BP measurements (systolic BPV, p = 0.61; diastolic BPV, p = 0.58) differed significantly between the groups. CONCLUSION: CPAP withdrawal results in a minor increase in within-visit variability in office systolic BP, but it has no effect on home BPV or day-to-day BPV. Although the treatment effect may be blunted by antihypertensives, it is unlikely that OSA contributes to cardiovascular risk via elevated daytime BPV. PMID- 28351061 TI - Hittability: The Leader's Edge. AB - Mastery of any discipline entails both the requisite skills and the ability to see things as "hittable." However, the concept of "hittability," which, in the context of leadership, refers to whether or not a specific leadership challenge shows up as hittable (or solvable) for those who are responsible for taking it on, is consistently overlooked. Nevertheless, it is a critical determinant of leadership effectiveness. Hittability is a function of the framing lenses-a person's beliefs, values, and worldviews-which frame the way a person "sees" a leadership challenge. Additionally, the future a person is "living into" is the framing lens for the present. In other words, a person's view of the future shapes his or her view of the present and his or her actions within it. Because the beliefs, values, and worldviews that constitute our framing lenses are constituted in and accessible through language (i.e., in the day-to-day stories, or narratives, a person tells him- or herself), reframing them to create a new future requires a new narrative. The ability to shift the previously unhittable to the hittable won't be, primarily, due to some newly acquired knowledge. Rather, it will be the result of reframing our challenges so they show up as hittable. PMID- 28351062 TI - Using National Health Care Databases and Problem-Based Practice Analysis to Inform Integrated Curriculum Development. AB - One challenge when implementing case-based learning, and other approaches to contextualized learning, is determining which clinical problems to include. This article illustrates how health care utilization data, readily available from the National Center for Health Statistics (NCHS), can be incorporated into an educational needs assessment to identify medical problems physicians are likely to encounter in clinical practice. The NCHS survey data summarize patient demographics, diagnoses, and interventions for tens of thousands of patients seen in various settings, including emergency departments (EDs), clinics, and hospitals.Selected data from the National Hospital Ambulatory Medical Care Survey: Emergency Department illustrate how instructional materials can be derived from the results of such public-use health care data. Using fever as the reason for visit to the ED, the patient management path is depicted in the form of a case drill-down by exploring the most common diagnoses, blood tests, diagnostic studies, procedures, and medications associated with fever.Although these types of data are quite useful, they should not serve as the sole basis for determining which instructional cases to include. Additional sources of information should be considered to ensure the inclusion of cases that represent infrequent but high-impact problems and those that illustrate fundamental principles that generalize to other cases. PMID- 28351063 TI - From Communication Skills to Skillful Communication: A Longitudinal Integrated Curriculum for Critical Care Medicine Fellows. AB - PROBLEM: Communication with patients and families in critical care medicine (CCM) can be complex and challenging. A longitudinal curricular model integrating multiple techniques within classroom and clinical milieus may facilitate skillful communication across diverse settings. APPROACH: In 2014-2015, the authors developed and implemented a curriculum for CCM fellows at the Cumming School of Medicine, University of Calgary, to promote the longitudinal development of skillful communication. A departmental needs assessment informed curriculum development. Five 4-hour classroom sessions were developed: basic communication principles, family meetings about goals and transitions of care, discussing patient safety incidents, addressing conflict, and offering organ donation. Teaching methods-including instructor-led presentations incorporating a consistent framework for approaching challenging conversations, simulation and clinical practice, and feedback from peers, trained facilitators, family members, and clinicians-supported integration of skills into the clinical setting and longitudinal development of skillful communication. Seven fellows participated during the first year of the curriculum. OUTCOMES: CCM fellows engaged enthusiastically in the program, commented that the framework provided was helpful, and highly valued the opportunity to practice challenging communication scenarios, learn from observing their peers, and receive immediate feedback. NEXT STEPS: More detailed accounts of fellows', patients', and family members' experiences will be obtained to guide curricular development. The curriculum will be expanded to involve other members of the multidisciplinary intensive care unit team, and faculty education initiatives will be offered to enhance the quality of the feedback provided. The impact of the curriculum on initial skill development, retention, and progression will be assessed. PMID- 28351064 TI - The Early Tech Development Course: Experiential Commercialization Education for the Medical Academician. AB - PROBLEM: Research produced by medical academicians holds promise for developing into biomedical innovations in therapeutics, devices, diagnostics, and health care information technology; however, the road to biomedical innovation is fraught with risk, including the challenge of moving from basic research insight onto a viable commercialization path. Compounding this challenge is the growing demand on medical academicians to be more productive in their clinical, teaching, and research duties within a resource-constrained environment. APPROACH: In 2014, the University of Michigan (UM) Medical School and College of Engineering codesigned and implemented an accelerated, biomedical-focused version of the National Science Foundation (NSF) Innovation Corps (I-Corps) program. The UM Early Tech Development (ETD) Course, designed for medical academicians exploring the commercial potential of early-stage ideas, covers the NSF I-Corps concept; supports the formation of teams of faculty, graduate, and medical students; and accommodates medical academicians' schedules. OUTCOMES: From 2014 to 2015, the ETD Course graduated 39 project teams from UM and other institutions. One-third of the teams have continued to pursue their projects, receiving additional funding, engaging industry partners, or enrolling in the NSF I-Corps program. NEXT STEPS: The ETD Course, a potential pipeline to the NSF I-Corps program, captures a target audience of medical academicians and others in academic medicine. To better understand the long-term effects of the course and its relationship to the NSF I-Corps program, the authors will conduct a study on the careers of all ETD Course graduates, including those who have enrolled in NSF I Corps versus those who have not. PMID- 28351065 TI - Institutional Incentives for Mentoring at the U.S. Department of Veterans Affairs and Universities: Associations With Mentors' Perceptions and Time Spent Mentoring. AB - PURPOSE: Limited empirical attention to date has focused on best practices in advanced research mentoring in the health services research domain. The authors investigated whether institutional incentives for mentoring (e.g., consideration of mentoring in promotion criteria) were associated with mentors' perceptions of mentoring benefits and costs and with time spent mentoring. METHOD: The authors conducted an online survey in 2014 of a national sample of mentors of U.S. Department of Veterans Affairs (VA) Health Services Research and Development Service (HSR&D) mentored career development award recipients who received an award during 2000-2012. Regression analyses were used to examine institutional incentives as predictors of perceptions of benefits and costs of mentoring and time spent mentoring. RESULTS: Of the 145 mentors invited, 119 (82%) responded and 110 (76%) provided complete data for the study items. Overall, mentors who reported more institutional incentives also reported greater perceived benefits of mentoring (P = .03); however, more incentives were not significantly associated with perceived costs of mentoring. Mentors who reported more institutional incentives also reported spending a greater percentage of time mentoring (P = .02). University incentives were associated with perceived benefits of mentoring (P = .02), whereas VA incentives were associated with time spent mentoring (P = .003). CONCLUSIONS: Institutional policies that promote and support mentorship of junior investigators, specifically by recognizing and rewarding the efforts of mentors, are integral to fostering mentorship programs that contribute to the development of early-career health services researchers into independent investigators. PMID- 28351066 TI - Bringing Rounds Back to the Patient: A One-Year Evaluation of the Chiefs' Service Model for Inpatient Teaching. AB - PURPOSE: The Chiefs' Service (CS), a structured approach to inpatient teaching rounds, focuses on resident education and patient-centered care without disrupting patient census sizes or admitting cycles. It has five key elements: morning huddles; bedside rounds; diagnostic "time-outs"; day-of-discharge rounds; and postdischarge follow-up rounds. The authors hypothesized the CS model would be well received by residents and considered more effective than more-traditional rounds. METHOD: The CS was implemented on Penn Presbyterian Medical Center's general medicine inpatient service using a quasi-experimental design. Its first year (January 2013-January 2014) was evaluated with a mixed-methods approach. Residents completed end-of-rotation evaluation questionnaires; 20 CS and 10 traditional service (TS) residents were interviewed. Measures of resident agreement on questionnaire items were compared across groups using independent sample t testing. A modified grounded theory approach was used to assess CS residents' perspectives on the CS elements and identify emergent themes. RESULTS: The questionnaires were completed by 183/188 residents (response rate 97%). Compared with TS residents, CS residents reported significantly greater satisfaction in the domains of resident education and patient care, and they rated the overall value of the rotation significantly higher. The majority of CS residents found the CS elements to be effective. CS residents described the CS as focused on resident education, patient-centered care, and collaboration with an interdisciplinary team. CONCLUSIONS: The CS approach to inpatient rounding is seen by residents as valuable and is associated with positive outcomes in terms of residents' perceptions of learning, interdisciplinary communication, and patient care. PMID- 28351067 TI - Do Medical Students' Narrative Representations of "The Good Doctor" Change Over Time? Comparing Humanism Essays From a National Contest in 1999 and 2013. AB - PURPOSE: To explore medical students' conceptions of "the good doctor" at two points in time separated by 14 years. METHOD: The authors conducted qualitative analysis of narrative-based essays. Following a constant comparative method, an emergent relational coding scheme was developed which the authors used to characterize 110 essays submitted to the Arnold P. Gold Foundation Humanism in Medicine Essay Contest in 1999 (n = 50) and 2013 (n = 60) in response to the prompt, "Who is the good doctor?" RESULTS: The authors identified five relational themes as guiding the day-to-day work and lives of physicians: doctor-patient, doctor-self, doctor-learner, doctor-colleague, and doctor system/society/profession. The authors noted a highly similar distribution of primary and secondary relational themes for essays from 1999 and 2013. The majority of the essays emphasized the centrality of the doctor-patient relationship. Student essays focused little on teamwork, systems innovation, or technology use-all important developments in contemporary medicine. CONCLUSIONS: Medical students' narrative reflections are increasingly used as rich sources of information about the lived experience of medical education. The findings reported here suggest that medical students understand the "good doctor" as a relational being, with an enduring emphasis on the doctor-patient relationship. Medical education would benefit from including an emphasis on the relational aspects of medicine. Future research should focus on relational learning as a pedagogical approach that may support the formation of caring, effective physicians embedded in a complex array of relationships within clinical, community, and larger societal contexts. PMID- 28351068 TI - What Attitudes and Values Are Incorporated Into Self as Part of Professional Identity Construction When Becoming a Surgeon? AB - PURPOSE: To make explicit the attitudes and values of a community of surgeons, with the aim of understanding professional identity construction within a specific group of residents. METHOD: Using a grounded theory method, the authors collected data from 16 postgraduate surgeons through interviews. They complemented these initial interview data with ethnographic observations and additional descriptive interviews to explore the attitudes and values learned by surgeons during residency training (2010-2013). The participants were attending surgeons and residents in a general surgical training program in a university teaching hospital in the United Kingdom. RESULTS: Participating surgeons described learning personal values or attitudes that they regarded as core to "becoming a surgeon" and key to professional identity construction. They described learning to be a perfectionist, to be accountable, and to self-manage and be resilient. They discussed learning to be self-critical, sometimes with the unintended consequence of seeming neurotic. They described learning effective teamwork as well as learning to take initiative and be innovative, which enabled them to demonstrate leadership and drive actions and agendas forward within the health care organization where they worked. CONCLUSIONS: To the authors' knowledge, this is the first study to systematically explore the learning of professional identity amongst postgraduate surgeons. The study contributes to the literature on professional identity construction within medical education. The authors conclude that the demise of the apprenticeship model and the rise of duty hours limitations may affect not only the acquisition of technical skills but, more important, the construction of surgeon professional identity. PMID- 28351069 TI - Transition to Independence: Characteristics and Outcomes of Mentored Career Development (KL2) Scholars at Clinical and Translational Science Award Institutions. AB - PURPOSE: To describe the transition from mentored to independent research funding for clinical and translational scholars supported by institutional KL2 Mentored Career Development programs. METHOD: In 2013, faculty leaders at Clinical and Translational Science Award institutions completed an online survey, reporting characteristics of scholars in their KL2 programs from 2006 to 2013. The primary outcome variable was a report that the scholar had received independent funding as a principal investigator. Data analysis included descriptive summaries and mixed-effects regression models. RESULTS: Respondents from 48 institutions (of 62 eligible; 77%) provided information about 914 KL2 scholars. Of those, 620 (68%) were medical doctors, 114 (12%) had other clinical training, and 177 (19%) were nonclinician PhDs. Fifty-three percent (487) were female; 12% (108/865) were members of racial or ethnic groups underrepresented in medicine (URM). After completing KL2 training, 96% (558/582) remained engaged in research. Among scholars who completed KL2 training two or more years earlier, 39% (149/374) received independent funding. Independent funding was from non-National Institutes of Health (NIH) sources (120 scholars) more often than from NIH (101 scholars). The odds of a nonclinician attaining independent funding were twice those of a clinician (odds ratio 2.05; 95% confidence interval 1.11-3.78). Female and URM scholars were as likely as male and non-URM scholars to attain independent funding. CONCLUSIONS: KL2 programs supported the transition to independent funding for clinical and translational scientists. Female and URM scholars were well represented. Future studies should consider non-NIH funding sources when assessing the transition to research independence. PMID- 28351070 TI - Does Resection of the Posterior Longitudinal Ligament Impact the Incidence of C5 Palsy After Cervical Corpectomy Procedures?: A Review of 459 Consecutive Cases. AB - STUDY DESIGN: Retrospective review. OBJECTIVE: To evaluate key risk factors for the development of C5 palsy after cervical corpectomy, including resection of the posterior longitudinal ligament (PLL). SUMMARY OF BACKGROUND DATA: Postoperative C5 palsy is a well-known complication after cervical spine surgery. It is unknown whether resection of the PLL affects the incidence of C5 palsy. METHODS: We performed a retrospective review of 459 consecutive patients undergoing anterior cervical corpectomies over a 15-year period. Medical records were reviewed to gather demographic data, operative details, and the incidence of C5 palsy. We performed regression analyses to identify variables that predicted the development of C5 palsy. RESULTS: Our final analysis included 397 patients (females 51.4%, mean age 55.6 +/- 11.6 yrs). Anterior corpectomy alone was performed in 255 (64.2%) patients, and combined anterior and posterior fusion was performed in 142 (35.8%) patients. Twenty-four patients (6.0%) developed C5 nerve palsy. Univariable regression demonstrated age greater than 65 (odds ratio, OR 2.7, 95% confidence interval, CI 1.2 to 6.3), corpectomy of three or more levels (OR 6.3, 95% CI 2.1 to 18.9), presence of ossification of the PLL (OR 4.3, 95% CI 1.6 to 11.7), and complete or partial resection of the PLL (OR 2.6, 95% CI 1.0 to 6.7) predicted development of C5 palsy. Multivariable regression demonstrated that the odds of getting C5 palsy with complete or partial resection of the PLL is 4.0 times (95% CI 1.5 to 10.5) higher compared with patients with an intact PLL. There were no significant differences in C5 palsy rates based on surgical approach (anterior vs. anterior plus posterior), sex, smoking status, or diabetes. CONCLUSION: Age greater than 65 years, corpectomy of three or more levels, presence of ossification of the PLL, and complete or partial resection of the PLL significantly predicted the development of C5 palsy. LEVEL OF EVIDENCE: 4. PMID- 28351072 TI - Bringing Clarity to the Treatment of Common Spinal Disorders. PMID- 28351071 TI - Neurologic Deficits Have a Negative Impact on Patient-Related Outcomes in Primary Presentation Adult Symptomatic Lumbar Scoliosis Surgical Treatment at One-Year Follow-up. AB - STUDY DESIGN: A retrospective analysis of prospective, multicenter National Institute of Health clinical trial. OBJECTIVE: The aim of this study was to assess the rate of neurologic complications and impact of new neurologic deficits on 1-year postoperative patient-reported outcomes (PROs). SUMMARY OF BACKGROUND DATA: There are limited studies evaluating the impact of new neurologic deficits on PROs following surgery for primary presentation adult lumbar scoliosis. METHODS: Patients were divided into two groups: new postoperative neurological deficit (Def) or no deficit (NoDef). Preoperative and 1-year follow-up PROs were analyzed [Scoliosis Research Society (SRS) Questionnaire, Oswestry Disability Index (ODI), Short Form-12 Physical/Mental Health Composite Scores (PCS/MCS), and back/leg pain Numerical Rating Scale (NRS)]. RESULTS: One hundred forty-one patients: 14 Def (9.9%), 127 NoDef (90.1%). No differences were observed in demographic, radiographic, or PRO data between groups preoperatively. Def group had longer surgical procedures (8.3 vs. 6.9 hours, P = 0.030), greater blood loss (2832 vs. 2606 mL, P = 0.022), and longer hospitalizations (10.6 vs. 7.8 days, P = 0.004). NoDef group reported significant improvement in all PROs from preop to 1-year postoperative. Def group only had improvement in SRS Pain (2.7 preop to 3.4 postop, P = 0.037) and self-image domains (2.7 to 3.6, p = 0.004), and NRS back pain (6.6 to 3.2, P = 0.004) scores with significant worsening of NRS leg pain (4.1 to 6.1, P = 0.045). Group comparisons of 1-year postop PROs found that Def group reported more NRS leg pain (6.1 vs. 1.7, P < 0.001) and worse outcomes than NoDef group for ODI (35.7 vs. 23.1, P = 0.016) and PCS (32.6 vs. 41.9, P = 0.007). CONCLUSION: We found a 9.9% rate of new neurologic deficits following surgery for symptomatic primary presentation adult lumbar scoliosis, much higher than previous studies. Most neurologic deficits improved by 1-year follow-up, but appeared to have a dramatic negative impact on PROs, with increased postoperative leg pain and greater patient-perceived pathology reported in patients experiencing neurological deficits compared with those who did not. LEVEL OF EVIDENCE: 3. PMID- 28351079 TI - Editorial to Methamphetamine ("Crystal meth") and New Psychoactive Substances. PMID- 28351080 TI - Is Really Crocus Sativus as Effective as Citalopram in the Treatment of Depression? PMID- 28351081 TI - Osteoarthritis Patients' Experiences of Pharmacotherapy for Pain Management in Iran: A Qualitative Study. AB - Despite the effectiveness of pharmacotherapy for pain management in patients with osteoarthritis (OA), personal biases in the selection, administration, and continuation of pharmacotherapy challenge the proper management of symptoms and the effectiveness of the therapy. This study was conducted to carry out an in depth examination of the experiences of patients with OA about their use of pharmacotherapy for the OA pain management and the existing challenges. The present qualitative study was conducted on 17 patients with OA, 5 of their family members and 8 healthcare personnel using a conventional content analysis approach. Data were collected through 35 interviews, which were unstructured at first but became semi-structured later on. Data collection continued until data saturation and analyzed simultaneously. The criteria used to determine the rigor of the study included the credibility, transferability, dependability and conformability of the data. The analysis of the data revealed 3 main categories and 8 subcategories. The main categories including preference for non pharmacological modalities, preference for symptomatic slow-acting drugs for osteoarthritis (SySADOAs) and preference for vitamins and minerals. Briefing the patients on the therapeutic goals, participating them in the clinical decision making process, modifying drug administration patterns through prescribing the minimum effective dosage and substituting alternative therapies whenever possible, consistently monitoring the therapeutic responses and any unexpected complications and use of complementary treatments, makes up strategies that can help improve OA pain management. PMID- 28351082 TI - Future Perspectives for Uterine Cervical Cancer Treatment based on Integrative Genomic and Molecular Characterizations. PMID- 28351083 TI - How to Escape from Primary Aldosteronism? News and Views on an Adrenal Disorder of Salt Retention. AB - The last years have seen substantial progress in primary aldosteronism (PA), which is the most common cause of secondary hypertension. Many programs have been established around the world to meet the needs in healthcare and the management of patients with PA according to published guidelines and clinical protocols. Systematic analysis of emerging data and meticulous scientific work have informed us on the molecular basis of the disease and helped to characterize hereditary forms of PA. Techniques have been developed to better diagnose PA and to establish genotype-phenotype relationships and their impact on hypertension. Studies have been undertaken to stratify patients for risk factors and to ensure quality of best medical treatment. This review focuses on some clinically relevant problems in characterizing autonomous aldosterone secretion and discusses testing and management strategies. Besides, this review puts the emphasis on some colorful studies not to pale soon beside an ever evolving painting background. PMID- 28351084 TI - The Effect of Vitamin D Supplementation on the Androgenic Profile in Patients with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Clinical Trials. AB - It is suggested that vitamin D status is associated with androgenic profile in women with polycystic ovarian syndrome (PCOS). Although several clinical trials are known in this regard, the results were inconsistent. Therefore, this study was aimed to conduct a systematic review and meta-analysis of published clinical trials to elucidate the possible effect of vitamin D supplementation on the androgen levels in adult females with PCOS. PubMed, SCOPUS, and Google Scholar were searched to identify related articles published up to January 2017. Mean +/- standard deviation (SD) of changes in serum total testosterone, sex hormone binding globulin (SHBG), and free testosterone were extracted to calculate Hedges' g to be used as effect size for meta-analysis. DerSimonian and Liard random effects model was incorporated to summarize the effects. Six clinical trials with 183 participants aged 18-41 years with follow-up period between 3-24 weeks were included. Our analysis revealed that vitamin D supplementation significantly reduces total testosterone (Hedges' g=-0.32, 95% CI: -0.55 to 0.10; p=0.005); this effect remained significant in single group trials after subgroup analysis. Vitamin D supplementation did not affect serum free testosterone (Hedges' g=-0.21, 95% CI: -0.44 to 0.079; p=0.08) or SHBG levels (Hedges' g=0, 95% CI, 0.22-0.22; p=0.98). The present systematic review and meta analysis revealed that vitamin D supplementation might significantly affect serum total testosterone while it is not effective in improving other markers of androgenic profile. Future double-blind, placebo-controlled clinical trials are highly recommended. PMID- 28351085 TI - ? AB - The impact of thyroid dysfunction in subclinical ranges on metabolic syndrome (MetS) is not well known. The aim of the present study is to evaluate the association of thyroid dysfunction with MetS and its components. In the cross sectional population-based Tehran Thyroid Study, out of 5 786 randomly selected participants, aged>=20 years, subjects with thyroid nodules and cancer or any severe systemic disease, those who were pregnant and those using thyroid medication were excluded, leaving 5 422 subjects to be investigated. Body weight, waist circumference, and blood pressure were measured. Fasting blood glucose and concentrations of lipids and lipoproteins, free T4, and TSH were assayed. Mean age of the participants was 40.3+/-14.4 of whom 101 (2%) had overt hypothyroidism, 294 (5%) subclinical hypothyroidism, 82 (2%) overt hyperthyroidism, and 178 (3%) had subclinical hyperthyroidism; 1 704 (32%) had MetS. Clinically hypothyroid subjects had the highest prevalence of MetS (41.6%), abdominal obesity (45%), and hypertriglyceridemia (58%) compared to other groups (p<0.05). Significant odds ratio for prevalent MetS was observed only in clinically hypothyroid men [OR: 2.9, 95% CI: 1.04, 8.4, p=0.04]. In women, the association between overt hypothyroidism and MetS was marginally significant only in the crude model [OR: 0.068, 95% CI (0.97-2.42), p=0.06]. There was higher risk of Mets in subclinically hypothyroid subjects, aged>50. Overt and subclinical hyperthyroidism had significantly higher odds of hyperglycemia in men and women after full adjustment for age, smoking, and BMI. Overt hypothyroidism and subclinical hypothyroidism especially in the elderly could be associated with MetS. Hyperthyroidism may induce hyperglycemia. PMID- 28351086 TI - Independent Risk Factors Predicting Central Lymph Node Metastasis in Papillary Thyroid Microcarcinoma. AB - The incidence of papillary thyroid microcarcinoma (PTMC) has risen rapidly in recent years, and PTMC patients with central lymph node metastasis (CLNM) usually have poor prognosis. Independent risk factors predicting CLNM in PTMC have not been well understood. The aim of our study was to identify useful clinicopathological risk factors predicting CLNM in PTMC patients. This was a retrospective study of 917 patients with PTMC treated with surgery from January 2014 to December 2015 in our hospital. The relationship between clinicopathological factors and CLNM was analyzed to identify those factors predicting CLNM in PTMC. Univariate and multivariate logistic regression analyses were further performed. Of 917 PTMC patients, 344 (37.5%) were found to have CLNM confirmed by intraoperative frozen-section examination. Multivariate logistic regression analyses further found several independent factors predicting CLNM in PTMC patients, including male gender (OR=1.75, 95% CI 1.17-2.61; p=0.006), younger age (<45 years) (OR=1.69, 95%CI 1.20-2.38; p=0.002), positive CLNM on ultrasonography (OR=10.20, 95% CI 5.51-18.88; p<0.001), multifocality (OR=1.69, 95% CI 1.00-2.85; p=0.04), and larger tumor size (>5 mm) (OR=2.80, 95% CI 2.01 3.91; p<0.001). The findings of our study identified several useful and independent risk factors predicting CLNM in PTMC patients, such as male gender, younger age, multifocality, positive CLNM on ultrasonography, and larger tumor size. The CLNM is very common in PTMC patients, and routine prophylactic central neck dissection may be recommended in PTMC patients with those independent risk factors of CLNM. PMID- 28351087 TI - How Can Environmental Factors Contribute to the Incidence of Thyroid Cancer? PMID- 28351088 TI - Premature Progesterone Rise Positively Correlates with Clinical Pregnancy Rate in In Vitro Fertilization (IVF) and Intracytoplasmic Sperm Injection (ICSI) Patients with good Ovarian Response. AB - Infertility affects millions of couples worldwide resulting in distress and depression. In the past several decades, in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) have been developed with high efficiency and success rate. The possible effects of gonadotropin administration on follicular metabolism have been discussed but the outcomes remain controversial. The aim of this study was to identify whether serum progesterone on the day of human chorionic gonadotropin (hCG) administration and the ratio of serum progesterone and the number of oocyte retrieved (P/O) had a predictive role for the outcomes of IVF/ICSI. Eight hundred and twenty-five patients were enrolled between January 2012 and December 2012. A positive correlation between progesterone and IVF/ICSI outcomes were found in patients with good ovarian response using receiver operating characteristic (ROC) curve. We found that when progesterone level was higher than 1.04 ng/ml in good ovarian responses, the implantation rate and clinical pregnancy rate were both reduced compared to the rates in patients exhibiting lower progesterone level (progesterone<=1.04 ng/ml). Moreover, the rise of serum progesterone on the day of hCG was negatively correlated with luteinizing hormone (LH) level. This study used 1.04 ng/ml as a definition of progesterone elevation and an adverse effect of serum progesterone rise was observed on clinical pregnancy rate. PMID- 28351089 TI - Leptin and its Receptors in Human Placenta of Small, Adequate, and Large for Gestational Age Newborns. AB - Alterations in birth weight impact postnatal outcome and adult metabolic health. Therefore, fetal growth regulation is crucial for preventing chronic metabolic diseases. Leptin has been suggested to play an important role in placental and fetal growth, albeit its specific mechanisms of action have not been elucidated. The aim of this study was to analyze leptin concentrations in placenta, cord blood, and maternal blood of SGA, AGA, and LGA (small, adequate and large for gestational age, respectively) newborns, as well as placental leptin receptor (LEPRa and LEPRb) protein expression. We performed a cross-sectional comparative study in 3 groups of healthy mothers and their term newborns at delivery (SGA, AGA, and LGA, n=20 per group). Placental, maternal blood, and cord blood leptin content were measured by ELISA. Placental LEPRa and LEPRb protein expression were determined by Western Blot. Maternal leptin concentrations correlated positively with maternal weight before and at the end of gestation, without differences between groups. Cord leptin is higher in LGA and lower in SGA, whereas placental leptin is higher in SGA. Placental leptin was inversely correlated with placental weight, independently from maternal weight and gestational age. Both LEPRa and LEPRb expression are lower in SGA, while LEPRa positively correlated with placental weight and birthweight. The current findings indicate that placental leptin and its receptors are differentially expressed in SGA, AGA, and LGA newborns. We suggest that placental leptin and LEPR protein expression may influence placental growth and thus, birth weight. PMID- 28351090 TI - An Increase in Normal SUA Level Within the Normal Range Predicts Risk of Metabolic Syndrome, Especially in Women: A Cross-Sectional Study. AB - This study was aimed to evaluate the relationship between normal serum uric acid (SUA) level and metabolic syndrome (MetS) risk. This cross-sectional study involved 1914 subjects with MetS and 3 659 healthy controls aged 18-79 years. All participants filled out questionnaires and underwent physical examination and blood sample collection for biochemical examination. Demographic and clinical characteristics data were analyzed by t-test or chi-squared test. Normal SUA levels were divided into quartiles. Associations between quartiles of normal SUA level and the risk of MetS were explored using logistic regression analysis and receiver operating characteristic (ROC) curve analysis. Values of age, waist circumference, blood lipid, blood pressure, fasting plasma glucose, SUA, and body mass index were all higher in subjects with MetS than that of healthy controls significantly. The frequency of MetS increased with SUA level within the normal range. Compared with Q1, the risk of MetS was greater in the other quartiles of SUA level in men (OR, 1.495-2.288); this difference was significant for Q3 and Q4 (p<0.05), but not for Q2. Among women, the risk of MetS also increased with SUA level within the normal range, with all differences showing statistical significance (p<0.05). The area under the ROC curve of normal SUA level for MetS presence was larger for women than for men. In conclusion, the results provide support for the use of normal SUA level as a contributing clinical predictor of MetS, especially in women. PMID- 28351092 TI - National German Audit of Diagnosis, Treatment, and Teaching in Secondary Adrenal Insufficiency. PMID- 28351091 TI - Plasma Betatrophin Levels of Subjects Classified with Normal, Impaired, and Diabetic Glucose Tolerance, and Subjects with Impaired Fasting Glucose. AB - This study was aimed to investigate whether betatrophin shows glucose intolerance or not. To access the plasma betatrophin levels after basal and glucose load, groups were classified as normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and diabetic glucose tolerance (DGT) according to WHO 2012 criteria. An oral glucose tolerance test was performed on age-matched subjects (n=220) with a body mass index (BMI)<27 kg/m2. Subjects were categorized as normoglycemic (n=55), IFG (n=50), IGT (n=60), and DM (n=55) according to the WHO criteria. Baseline betatrophin levels in DGT are significantly higher than in NGT (p<0.005), IFG (p<0.004), and IGT (p<0.001). Male subjects have significantly higher betatrophin levels than female subjects (p<0.01). In DGT, betatrophin of male subjects was found to be significantly higher than the betatrophin of male subjects in NGT (p<0.04), IFG (p<0.01), and IGT (p<0.01). Significant relationship between betatrophin and both ages and HbA1c in all groups were observed. When ages were accepted as an independent factor, significant correlation between betatrophin and ages were found. Betatrophin is increased and associated with age and HbA1c in DGT. Males had higher betatrophin levels compared with females in DGT group. As no obvious betatrophin deficiency to substitute in IFG and IGT individuals were observed, betatrophin levels appeared to be related to the pathogenesis of the diabetic stages rather than prediabetic stages. PMID- 28351093 TI - ANGPTL8 (Betatrophin) is Expressed in Visceral Adipose Tissue and Relates to Human Hepatic Steatosis in Two Independent Clinical Collectives. AB - Angiopoietin-like protein 8 (ANGPTL8)/betatrophin expression in visceral adipose tissue and associations with circulating fatty acid profile have not yet been investigated.Forty subjects were included in a cross-sectional study, 57 in a dietary weight reduction intervention. Circulating Angiopoietin-like protein 8/betatrophin was measured in all subjects. Liver and adipose tissue were sampled and plasma fatty acids and tissue Angiopoietin-like protein 8/betatrophin expression were evaluated in the cross-sectional study. In the intervention study oral glucose testing and liver magnetic resonance scanning at baseline and after 6 months were performed. Angiopoietin-like protein 8/betatrophin mRNA was increased in visceral compared to subcutaneous adipose tissue (p<0.001). Circulating ANGPTL8/betatrophin correlated with liver steatosis (r=0.42, p=0.047), triacylglycerols (r=0.34, p=0.046), saturated (r=0.43, p=0.022), monounsaturated (r=0.51, p=0.007), and polyunsaturated fatty acids (r=-0.53, p=0.004). In the intervention study, baseline Angiopoietin-like protein 8/betatrophin correlated with age (r=0.32, p=0.010) and triacylglycerols (r=0.30, p=0.02) and was increased with hepatic steatosis (p=0.033). Weight loss reduced liver fat by 45% and circulating Angiopoietin-like protein 8/betatrophin by 11% (288+/-17 vs. 258+/-17 pg/ml; p=0.015). Angiopoietin-like protein 8/betatrophin is related to liver steatosis, while visceral adipose tissue represents an additional site of expression in humans. PMID- 28351095 TI - Video Comment on Hiroyuki Odagiri et al. PMID- 28351094 TI - Overexpression of LncRNA HOTAIR is Associated with Poor Prognosis in Thyroid Carcinoma: A Study Based on TCGA and GEO Data. AB - The role of long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) in thyroid carcinoma (TC) remains unclear. The current study was aimed to assess the clinical value of HOTAIR expression levels in TC based on publically available data and to evaluate its potential signaling pathways. The expression data of HOTAIR and clinical information concerning TC were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), respectively. Furthermore, 3 online biological databases, Starbase, Cbioportal, and Multi Experiment Matrix, were used to identify HOTAIR-related genes in TC. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Panther pathway analyses were then undertaken to study the most enriched signaling pathways in TC (EASE score<0.1, Bonferroni<0.05). The TCGA results demonstrated that the expression level of HOTAIR in TC tissues was significantly increased compared with non-cancerous tissues (p<0.001). HOTAIR over-expression was significantly associated with poor survival in TC patients (p=0.03). Meta-analyses of GEO datasets revealed a trend consistent with the above results on HOTAIR expression levels in TC (SMD=0.23; 95%CI, 0.00-0.45; p=0.047). Finally, the results of functional analysis for HOTAIR-related genes indicated that HOTAIR might participate in tumorigenesis via the Wnt signaling pathway. In conclusion, our study demonstrates that HOTAIR may be involved in thyroid carcinogenesis, and the over-expression of HOTAIR could act as a biomarker associated with a poor outcome in TC patients. Moreover, the Wnt signaling pathway may be the key pathway regulated by HOTAIR in TC. PMID- 28351096 TI - Video Comment on Raf Bisschops et al. PMID- 28351097 TI - Video Comment on Aijaz Ahmed Sofi et al. PMID- 28351098 TI - Video Comment on Toshitatsu Takao et al. PMID- 28351099 TI - High-volume esophageal endoscopic submucosal dissection centers: a cut above the rest? PMID- 28351100 TI - Lumen-apposing covered self-expandable metal stents for short-length gastrointestinal strictures: Will they take hold? PMID- 28351101 TI - Focusing on the role of endoscopy in chronic pancreatitis management - taking nature's help. PMID- 28351102 TI - Driving up the adenoma detection rate: is it time to make a U-turn? PMID- 28351103 TI - Endoscopic submucosal dissection using a pocket-creation method: a modified technique of endoscopic submucosal tunnel dissection. PMID- 28351104 TI - Reply to Tan et al. PMID- 28351105 TI - Prevention of stent migration: Which option would patients prefer? PMID- 28351106 TI - Reply to Zhang et al. PMID- 28351107 TI - What is the advantage of a passive bending segment in balloon enteroscopy assisted ERCP? PMID- 28351111 TI - French comment on article Lumen-apposing covered self-expandable metal stents for short benign gastrointestinal strictures: a multicenter study. PMID- 28351108 TI - Reply to Moreels et al. PMID- 28351112 TI - French comment on article Hospital volume and adverse events following esophageal endoscopic submucosal dissection in Japan. PMID- 28351113 TI - French comment on article Improved detection of right colon adenomas with additional retroflexion following two forward-view examinations: a prospective study. PMID- 28351114 TI - French comment on article Virtual chromoendoscopy (I-SCAN) detects more polyps in patients with Lynch syndrome: a randomized controlled crossover trial. PMID- 28351115 TI - French comment on article Meta-analysis of the performance of ultrathin vs. standard colonoscopes. PMID- 28351116 TI - Management of people with early- or very early-stage hepatocellular carcinoma: an attempted network meta-analysis. AB - BACKGROUND: Hepatocellular carcinoma (primary liver cancer) is classified in many ways. The Barcelona Clinic Liver Cancer (BCLC) group staging classifies the cancer based on patient's life expectancy. People with very early- or early-stage hepatocellular carcinoma have single tumour or three tumours of maximum diameter of 3 cm or less, Child-Pugh status A to B, and performance status 0 (fully functional). Management of hepatocellular carcinoma is uncertain. OBJECTIVES: To assess the comparative benefits and harms of different interventions used in the treatment of early or very early hepatocellular carcinoma through a network meta analysis and to generate rankings of the available interventions according to their safety and efficacy. However, it was not possible to assess whether the potential effect modifiers were similar across different comparisons. Therefore, we did not perform the network meta-analysis and instead assessed the benefits and harms of different interventions versus each other or versus sham or no intervention using standard Cochrane methodology. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, and trials registers to September 2016 to identify randomised clinical trials (RCTs) on hepatocellular carcinoma. SELECTION CRITERIA: We included only RCTs, irrespective of language, blinding, or publication status, in participants with very early- or early-stage hepatocellular carcinoma, irrespective of the presence of cirrhosis, portal hypertension, aetiology of hepatocellular carcinoma, size and number of the tumours, and future remnant liver volume. We excluded trials including participants who were previously liver transplanted. We considered interventions compared with each other, sham, or no intervention. DATA COLLECTION AND ANALYSIS: We calculated the odds ratio, mean difference, rate ratio, or hazard ratio with 95% confidence intervals using both fixed-effect and random-effects models based on available-participant analysis with Review Manager 5. We assessed the risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis using Stata, and the quality of the evidence using GRADE. MAIN RESULTS: Eighteen trials met the inclusion criteria for this review. Four trials (593 participants; 574 participants included for one or more analyses) compared surgery versus radiofrequency ablation in people with early hepatocellular carcinoma, eligible to undergo surgery. Fourteen trials (2533 participants; 2494 participants included for various analyses) compared different non-surgical interventions in people with early hepatocellular carcinoma, not eligible to undergo surgery. Overall, the quality of evidence was low or very low for all outcomes for both comparisons. Surgery versus radiofrequency ablationThe majority of participants had cirrhotic livers, and the hepatocellular carcinoma was of viral aetiology. The trials did not report the participants' portal hypertension status or whether they received adjuvant antiviral treatment or adjuvant immunotherapy. The average follow-up ranged from 29 months to 42 months (3 trials).There was no evidence of a difference in all-cause mortality at maximal follow-up for surgery versus radiofrequency ablation (hazard ratio 0.80, 95% confidence interval (CI) 0.60 to 1.08; 574 participants; 4 trials; I2 = 68). Cancer-related mortality was lower in the surgery group (20/115 (17.4%)) than in the radiofrequency ablation group (43/115 (37.4%)) (odds ratio 0.35, 95% CI 0.19 to 0.65; 230 participants; 1 trial). Serious adverse events (number of participants) was higher in the surgery group (14/60 (23.3%)) than in the radiofrequency ablation group (1/60 (1.7%)) (odds ratio 17.96, 95% CI 2.28 to 141.60; 120 participants; 1 trial). The number of serious adverse events was higher in the surgery group (adjusted rate 11.3 events per 100 participants) than in the radiofrequency ablation group (3/186 (1.6 events per 100 participants)) (rate ratio 7.02, 95% CI 2.29 to 21.46; 391 participants; 2 trials; I2 = 0%). None of the trials reported health-related quality of life. One trial was funded by a party with vested interests; three trials were funded by parties without any vested. Non-surgical interventionsThe majority of participants had cirrhotic livers, and the hepatocellular carcinoma was of viral aetiology. Most trials did not report the portal hypertension status of the participants, and none of the trials reported whether the participants received adjuvant antiviral treatment or adjuvant immunotherapy. The average follow-up ranged from 6 months to 37 months (11 trials). Trial participants, who were not eligible for surgery, were treated with radiofrequency ablation, laser ablation, microwave ablation, percutaneous acetic acid injection, percutaneous alcohol injection, a combination of radiofrequency ablation with systemic chemotherapy, a combination of radiofrequency ablation with percutaneous alcohol injection, a combination of transarterial chemoembolisation with percutaneous alcohol injection, or a combination of transarterial chemoembolisation with radiofrequency ablation.The mortality at maximal follow-up was higher in the percutaneous acetic acid injection (hazard ratio 1.77, 95% CI 1.12 to 2.79; 125 participants; 1 trial) and percutaneous alcohol injection (hazard ratio 1.49, 95% CI 1.18 to 1.88; 882 participants; 5 trials; I2 = 57%) groups compared with the radiofrequency ablation group. There was no evidence of a difference in all-cause mortality at maximal follow-up for any of the other comparisons. The proportion of people with cancer-related mortality at maximal follow-up was higher in the percutaneous alcohol injection group (adjusted proportion 16.8%) compared with the radiofrequency ablation group (20/232 (8.6%)) (odds ratio 2.18, 95% CI 1.22 to 3.89; 458 participants; 3 trials; I2 = 0%). There was no evidence of a difference in any of the comparisons that reported serious adverse events (number of participants or number of events). None of the trials reported health-related quality of life. Five trials were funded by parties without any vested interest; the source of funding was not available in the remaining trials. AUTHORS' CONCLUSIONS: The evidence was of low or very low quality. There was no evidence of a difference in all-cause mortality at maximal follow-up between surgery and radiofrequency ablation in people eligible for surgery. All-cause mortality at maximal follow-up was higher with percutaneous acetic acid injection and percutaneous alcohol injection than with radiofrequency ablation in people not eligible for surgery. There was no evidence of a difference in all-cause mortality at maximal follow-up for the other comparisons. High-quality RCTs designed to assess clinically important differences in all-cause mortality and health-related quality of life, and having an adequate follow-up period (approximately five years) are needed. PMID- 28351117 TI - Clinical Characteristics of Patients with Untreated Achalasia. AB - Background/Aims: Patients with untreated achalasia frequently complain of heartburn and regurgitation. The diagnosis of achalasia might be delayed because these symptoms are misinterpreted as gastroesophageal reflux. We aim to evaluate the clinical, radiologic, and manometric findings in patient with untreated achalasia. Methods: The records of patients diagnosed with primary achalasia between July 2004 and January 2012 at Gangnam Severance Hospital, Seoul, Korea were evaluated. We reviewed their clinical history and the findings of barium esophagogram, upper gastrointestinal endoscopy, and esophageal transit scintigraphy. We also compared the clinical, radiologic, and manometric findings of patients according to heartburn symptoms and proton pump inhibitor use. Results: Our study included a total of 64 patients with a median age of 44.5 (interquartile range, 31.5-54.0). The median duration of symptoms was 23.5 (interquartile range, 5.3-57.0) months. Sixty-four patients (100%) had dysphagia, 49 (76.6%) had regurgitation, 35 (54.7%) had chest pain, and 38 (59.4%) had heartburn. Typical clinical features of gastroesophageal reflux disease (GERD) such as regurgitation, heartburn, and chest pain were observed in more than 50% of achalasia patients. Proton pump inhibitors were prescribed for 16 patients (25%) on the assumption that they had GERD. Patients with heartburn were more likely to experience weight loss (P = 0.009), regurgitation (P = 0.001), or chest pain (P = 0.019). Conclusions: Heartburn, regurgitation, and chest pain were commonly observed in patients with untreated achalasia. Therefore, these findings suggest that achalasia should be suspected in patients with refractory GERD. PMID- 28351118 TI - How Will Repealing the ACA Affect Medicaid? Impact on Health Care Coverage, Delivery, and Payment. AB - ISSUE: The Affordable Care Act enhanced Medicaid's role as a health care purchaser by expanding eligibility and broadening the range of tools and strategies available to states. All states have embraced delivery and payment reform as basic elements of their programs. GOAL: To examine the effects of reducing the size and scope of Medicaid under legislation to repeal the ACA. FINDINGS AND CONCLUSIONS: Were the ACA's Medicaid expansion to be eliminated and were federal Medicaid funding to experience major reductions through block grants or per capita caps, the effects on system transformation would be significant. Over 70 percent of Medicaid spending is driven by enrollment in a program that covers 74 million people; on a per capita basis Medicaid costs less than Medicare or commercial insurance. States would need to absorb major financial losses by reducing the number of people served, reducing the scope of services covered, introducing higher cost-sharing, or further reducing already low payments. Far from improving quality and efficiency, these changes would cause the number of uninsured to rise while depriving health care providers and health plans of the resources needed to care for patients and invest in the tools that are essential to system transformation PMID- 28351119 TI - Biotechnology and Consumer Decision-Making. AB - Society is facing major challenges in climate change, health care and overall quality of life. Scientific advances to address these areas continue to grow, with overwhelming evidence that the application of highly tested forms of biotechnology is safe and effective. Despite scientific consensus in these areas,consumers appear reluctant to support their use. Research that helps to understand consumer decision-making and the public's resistance to biotechnologies such as vaccines, fluoridated water programs and genetically engineered food, will provide great social value. This article is forward thinking in that it suggests that important research in behavioral decision making, specifically affect and ambiguity, can be used to help consumers make informed choices about major applications of biotechnology. This article highlights some of the most controversial examples: vaccinations, genetically engineered food, rbST treated dairy cows, fluoridated water, and embryonic stem cell research. In many of these areas, consumers perceive the risks as high, but the experts calculate the risks as low. Four major thematic approaches are proposed to create a roadmap for policymakers to consider for policy design and implementation in controversial areas of biotechnology. This article articulates future directions for studies that implement decision-making research to allow consumers to appropriately assign risk to their options and make informed decisions. PMID- 28351120 TI - Revolutionizing the Mental Health Parity and Addiction Equity Act of 2008. PMID- 28351125 TI - Re: Evaluation of Renal Function after Percutaneous Nephrolithotomy-Does the Number of Percutaneous Access Tracts Matter?: I. Gorbachinsky, K. Wood, M. Colaco, S. Hemal, J. Mettu, M. Mirzazadeh, D. G. Assimos and J. Gutierrez-Aceves J Urol 2016;196:131-136. PMID- 28351121 TI - Probing the Quantum States of a Single Atom Transistor at Microwave Frequencies. AB - The ability to apply gigahertz frequencies to control the quantum state of a single P atom is an essential requirement for the fast gate pulsing needed for qubit control in donor-based silicon quantum computation. Here, we demonstrate this with nanosecond accuracy in an all epitaxial single atom transistor by applying excitation signals at frequencies up to ~13 GHz to heavily phosphorus doped silicon leads. These measurements allow the differentiation between the excited states of the single atom and the density of states in the one dimensional leads. Our pulse spectroscopy experiments confirm the presence of an excited state at an energy ~9 meV, consistent with the first excited state of a single P donor in silicon. The relaxation rate of this first excited state to the ground state is estimated to be larger than 2.5 GHz, consistent with theoretical predictions. These results represent a systematic investigation of how an atomically precise single atom transistor device behaves under radio frequency excitations. PMID- 28351127 TI - Absorption Amelioration of Amorphous Si Film by Introducing Metal Silicide Nanoparticles. AB - Amorphous Si (a-Si) films with metal silicide are expected to enhance the absorption ability of pure a-Si films. In this present study, NiSi (20 nm)/Si (40 nm) and AlSi (20 nm)/Si (40 nm) bilayer thin films are deposited through radio frequency (RF) sputtering at room temperature. The influence of the film's composition and the annealing temperature on the film's optical absorption is investigated. The results show that all the NiSi/Si films and AlSi/Si films possess higher absorption ability compared to a pure a-Si film (60 nm). After annealing from 400 to 600 degrees C under vacuum for 1 h, the Si layer remains amorphous in both NiSi/Si films and AlSi/Si films, while the NiSi layer crystallizes into NiSi2 phase, whereas Al atoms diffuse through the whole film during the annealing process. Consequently, with increasing the annealing temperature, the optical absorption of NiSi/Si films increases, while that of AlSi/Si films obviously degrades. PMID- 28351129 TI - Action-Self Quenching: Dimer-Induced Fluorescence Quenching of Chromophores as a Probe for Biomolecular Structure. AB - To obtain a more detailed understanding of how structure influences the function and interaction of biomolecules, it is important to develop structure sensitive techniques to probe these relationships. Alongside in vivo and in vitro techniques, it is instructive to consider in vacuo methodologies: for example native mass spectrometry, ion mobility mass spectrometry, and FRET. Here, we propose a novel technique for probing biomolecular structure based on the changes in photophysics of a chromophore upon dimer formation. Comparison of solution and gas phase measurements on a doubly tagged tripeptide shows that dimer-induced fluorescence quenching is accompanied by an increase in photofragmentation yield. The 12-28 fragment of amyloid beta was used to show that as the charge state was increased-previously shown to cause a conformational change from compact random coil to extended helical structure-the disappearance of a band at 495 nm could be correlated with the level of self-quenching. The presence of features in the action spectrum of the +3 charge state of both quenched and unquenched chromophores allowed inference of multiple conformations. Single wavelength measurements on doubly tagged ubiquitin cations were performed to show that the technique is feasible on a small protein. These results demonstrate that self quenching is a sensitive and fast gas-phase probe of biomolecular structure that can be directly linked to solution phase measurements. Further, it is capable of probing very small changes in conformation, making it complementary to FRET based techniques, which are insensitive at very short chromophore separations. PMID- 28351130 TI - Synergic Adsorption-Biodegradation by an Advanced Carrier for Enhanced Removal of High-Strength Nitrogen and Refractory Organics. AB - Coking wastewater contains not only high-strength nitrogen but also toxic biorefractory organics. This study presents simultaneous removal of high-strength quinoline, carbon, and ammonium in coking wastewater by immobilized bacterial communities composed of a heterotrophic strain Pseudomonas sp. QG6 (hereafter referred as QG6), ammonia-oxidizing bacteria (AOB), and anaerobic ammonium oxidation bacteria (anammox). The bacterial immobilization was implemented with the help of a self-designed porous cubic carrier that created structured microenvironments including an inner layer adapted for anaerobic bacteria, a middle layer suitable for coaggregation of certain aerobic and anaerobic bacteria, and an outer layer for heterotrophic bacteria. By coating functional polyurethane foam (FPUF) with iron oxide nanoparticles (IONPs), the biocarrier (IONPs-FPUF) could provide a good outer-layer barrier for absorption and selective treatment of aromatic compounds by QG6, offer a conducive environment for anammox in the inner layer, and provide a mutualistic environment for AOB in the middle layer. Consequently, simultaneous nitrification and denitrification were reached with the significant removal of up to 322 mg L-1 (98%) NH4, 311 mg L 1 (99%) NO2, and 633 mg L-1 (97%) total nitrogen (8 mg L-1 averaged NO3 concentration was recorded in the effluent), accompanied by an efficient removal of chemical oxygen demand by 3286 mg L-1 (98%) and 350 mg L-1 (100%) quinoline. This study provides an alternative way to promote synergic adsorption and biodegradation with the help of a modified biocarrier that has great potential for treatment of wastewater containing high-strength carbon, toxic organic pollutants, and nitrogen. PMID- 28351131 TI - Inorganic Surface Engineering to Enhance Perovskite Solar Cell Efficiency. AB - The photoconversion efficiency of perovskite solar cells (PSCs) is enhanced by the deposition of inorganic nanoparticles (NPs) at the interface between the compact TiO2 electron-selective contact and the mesoporous TiO2 film. The NPs used are core/shell Au@SiO2, where a thin SiO2 coating protects the Au core from the direct chemical interaction with CH3NH3PbI3 halide perovskite used as light harvesting material. The samples prepared with Au@SiO2 NPs exhibit a higher external quantum efficiency in the complete wavelength range at which perovskite presents light absorption and not just at the wavelengths at which Au@SiO2 NPs present their absorption peak. This fact rules out a direct plasmonic process as responsible for the enhancement of cell performance. A detailed characterization by photoluminescence, impedance spectroscopy, and open-circuit voltage decay unveils a modification of the interfacial properties with an augmentation of the interfacial electrostatic potential that increases both photovoltage and photocurrent. This article highlights the dramatic role of interfaces in the performance of PSCs. The use of reduced quantities of highly stable inorganic compounds to modify the PSC interface instead of the extensively used organic compounds opens the door to a new surface engineering based on inorganic compounds. PMID- 28351132 TI - Control of Multilevel Resistance in Vanadium Dioxide by Electric Field Using Hybrid Dielectrics. AB - We investigate the effect of electric field on VO2 back-gated field effect transistor (FET) devices. Using hybrid dielectric layers, we demonstrate the highest resistance modulation on the order of 102 in VO2 at a positive gate bias of 80 V (1.6 MV/cm). VO2 FET devices are prepared on SiO2 substrates of different thicknesses (100-300 nm) and hybrid dielectric layers of Al2O3/SiO2 (500 nm). For thicknesses less than 300 nm, no electric-field effects are observed, whereas for a 300 nm thickness, a small decrease in resistance is observed under a 0.2 MV/cm electric field. Under the electrostatic effect, the carrier concentration increases in VO2 devices, decreasing the resistance and the transition temperature from 66.75 to 64 degrees C. The leakage analysis shows that the interface quality of VO2 films on hybrid dielectric layers can be further improved. These studies suggest a multilevel fast resistance switching with the electric field and give an insight into the gate-source leakage current, which limits the phase transition in VO2 in an electric field. PMID- 28351133 TI - Monitoring the Behavior of Emerging Contaminants in Wastewater-Impacted Rivers Based on the Use of Fluorescence Excitation Emission Matrixes (EEM). AB - This study investigated the applicability of fluorescence indexes based on the interpretation of excitation emission matrices (EEMs) by PARAFAC analysis and by selecting fluorescence intensities at a priori defined excitation/emission pairs as surrogates for monitoring the behavior of emerging organic compounds (EOCs) in two catchment basins impacted by wastewater discharges. Relevant EOC and EEM data were obtained for a 90 km stretch of the Simeto River, the main river in Sicily, and the smaller San Leonardo River, which was investigated for a 17 km stretch. The use of fluorescence indexes developed by these two different approaches resulted in similar observations. Changes of the fluorescence indexes that correspond to a group of humic-like fluorescing species were determined to be highly correlated with the concentrations of recalcitrant contaminants such as sucralose, sulfamethoxazole and carbamazepine, which are typical wastewater markers in river water. Changes of the fluorescence indexes related to tyrosine like substances were well correlated with the concentrations of ibuprofen and caffeine, anthropogenic indicators of untreated wastewater discharges. Chemical oxygen demand and dissolved organic carbon concentrations were correlated with humic-like fluorescence indexes. The observed correlations were site-specific and characterized by different regression parameters for every collection event. Caffeine and carbamazepine showed correlations with florescence indexes in the San Leonardo River and in the alluvial plain stretch of the Simeto River, whereas sucralose, sulfamethoxazole and ibuprofen have always been well correlated in all the investigated river stretches. However, when data of different collection events from river stretches where correlations were observed were combined, good linear correlations were obtained for data sets generated via the normalization of the measured concentrations by the average value for the corresponding collection event. These results show that fluorescence based indexes can be used to monitor the behavior of some trace organic contaminants in wastewater impacted rivers and to track wastewater discharges in streams and rivers. PMID- 28351128 TI - Nanoparticles of Titanium and Zinc Oxides as Novel Agents in Tumor Treatment: a Review. AB - Cancer has become a global problem. On all continents, a great number of people are diagnosed with this disease. In spite of the progress in medical care, cancer still ends fatal for a great number of the ill, either as a result of a late diagnosis or due to inefficiency of therapies. The majority of the tumors are resistant to drugs. Thus, the search for new, more effective therapy methods continues. Recently, nanotechnology has been attributed with big expectations in respect of the cancer fight. That interdisciplinary field of science creates nanomaterials (NMs) and nanoparticles (NPs) that can be applied, e.g., in nanomedicine. NMs and NPs are perceived as very promising in cancer therapy since they can perform as drug carriers, as well as photo- or sonosensitizers (compounds that generate the formation of reactive oxygen species as a result of either electromagnetic radiation excitation with an adequate wavelength or ultrasound activation, respectively). Consequently, two new treatment modalities, the photodynamic therapy (PDT) and the sonodynamic therapy (SDT) have been created. The attachment of ligands or antibodies to NMs or to NPs improve their selective distribution into the targeted organ or cell; hence, the therapy effectiveness can be improved. An important advantage of the targeted tumor treatment is lowering the cyto- and genotoxicity of active substance towards healthy cells. Therefore, both PDT and SDT constitute a valuable alternative to chemo- or radiotherapy. The vital role in cancer eradication is attributed to two inorganic sensitizers in their nanosized scale: titanium dioxide and zinc oxide. PMID- 28351134 TI - Counterion Size and Nature Control Structural and Mechanical Response in Cellulose Nanofibril Nanopapers. AB - Nanopapers formed from aqueous dispersions of cellulose nanofibrils (CNFs) combine stiffness, strength, and toughness. Yet, delicate interactions operate between the CNFs during nanopaper formation and mechanical deformation. We unravel in detail how counterions, being either of the organic alkyl ammonium kind (NR4+) or of the earth metal series (Li+, Na+, Cs+), need to be chosen to achieve outstanding combinations of stiffness, strength, and toughness, extending to previously unreached territories. We relate structure formation processes in terms of colloidal stabilization to nanostructural details such as porosity and ability for swelling, as well as to interfibrillar interactions in bulk and macroscale mechanical properties. We demonstrate that our understanding also leads to new levels of ductility in bioinspired CNF/polymer nanocomposites at high levels of reinforcements. These results contribute to future rational design of CNF-based high-performance materials. PMID- 28351135 TI - Fluorous Solid-Phase Extraction Technique Based on Nanographite Fluoride. AB - Fluorous solid-phase extraction (FSPE) has been employed to isolate target compounds from complex chemical or biological samples in many research areas. However, the lack of efficient and economical available perfluorinated materials impeded its development. In this study, we present a novel nanographite fluoride based fluorous solid-phase extraction (GF-FSPE) as a replacement of commercially available cartridge-based FSPE, which showed remarkable selectivity, low LOD, high post enrichment recovery, and large enrichment capacity. To demonstrate the potency of GF-FSPE, it was designed and successfully applied to isolate cysteine containing peptide subsets from complex protein samples to improve the proteome coverage. Additionally, since graphite fluoride was inexpensive and highly commercialized, this study was expected to promote the popularization of FSPE in both chemical and biological separations as well as encourage the synthesis and broaden the application of highly fluorinated carbon fluoride in material science. PMID- 28351136 TI - Bi-directional DNA Walking Machine and Its Application in an Enzyme-Free Electrochemiluminescence Biosensor for Sensitive Detection of MicroRNAs. AB - Herein, a dual microRNA (miRNA) powered bi-directional DNA walking machine with precise control was developed to fabricate an enzyme-free biosensor on the basis of distance-based electrochemiluminescence (ECL) energy transfer for multiple detection of miRNAs. By using miRNA-21 as the driving force, the DNA walker could move forth along the track and generated quenching of ECL response due to the proximity between Au nanoparticles (AuNPs) and Mn2+ doped CdS nanocrystals (CdS:Mn NCs) film as the ECL emitters, realizing ultrasensitive determination of miRNA-21. Impressively, once miRNA-155 was introduced as the driving force, the walker could move back along the track automatically, and surface plasmon resonance (SPR) occurred owing to the appropriate large separation between AuNPs and CdS:Mn NCs, achieving an ECL enhancement and realizing ultrasensitive detection of miRNA-155. The bi-directional movement of the DNA walker on the track led to continuous distance-based energy transfer from CdS:Mn NCs film by AuNPs, which resulted in significant ECL signal variation of CdS:Mn NCs for multiple detection of miRNA-21 and miRNA-155 down to 1.51 fM and 1.67 fM, respectively. Amazingly, the elaborated biosensor provided a new chance for constructing controllable molecular nanomachines in biosensing, disease diagnosis, and clinical analysis. PMID- 28351137 TI - Monolayer Contact Doping from a Silicon Oxide Source Substrate. AB - Monolayer contact doping (MLCD) is a modification of the monolayer doping (MLD) technique that involves monolayer formation of a dopant-containing adsorbate on a source substrate. This source substrate is subsequently brought into contact with the target substrate, upon which the dopant is driven into the target substrate by thermal annealing. Here, we report a modified MLCD process, in which we replace the commonly used Si source substrate by a thermally oxidized substrate with a 100 nm thick silicon oxide layer, functionalized with a monolayer of a dopant-containing silane. The thermal oxide potentially provides a better capping effect and effectively prevents the dopants from diffusing back into the source substrate. The use of easily accessible and processable silane monolayers provides access to a general and modifiable process for the introduction of dopants on the source substrate. As a proof of concept, a boron-rich carboranyl alkoxysilane was used here to construct the monolayer that delivers the dopant, to boost the doping level in the target substrate. X-ray photoelectron spectroscopy (XPS) showed a successful grafting of the dopant adsorbate onto the SiO2 surface. The achieved doping levels after thermal annealing were similar to the doping levels acessible by MLD as demonstrated by secondary ion mass spectrometry measurements. The method shows good prospects, e.g. for use in the doping of Si nanostructures. PMID- 28351138 TI - Eradication of Plasmodium falciparum from Erythrocytes by Controlled Reactive Oxygen Species via Photodynamic Inactivation Coupled with Photofunctional Nanoparticles. AB - We investigated the antimalarial effect of photodynamic inactivation (PDI) coupled with magnetic nanoparticles (MNPs) as a potential strategy to combat the emergence of drug-resistant malaria and resurgence of malaria after treatment. Because the malarial parasite proliferates within erythrocytes, PDI agents need to be taken up by erythrocytes to eradicate the parasite. We used photofunctional MNPs as the PDI agent because nanosized particles were selectively taken up by Plasmodium-infected erythrocytes and remained within the intracellular space due to the enhanced permeability and retention effect. Also, the magnetism of Fe3O4 nanoparticles can easily be utilized for the collection of photofunctional nanoparticles (PFNs), and the uptaken PFNs infected the erythrocytes after photodynamic treatment with external magnetics. Photofunctionality was provided by a photosensitizer, namely, pheophorbide A, which generates reactive oxygen species (ROS) under irradiation. PAs were covalently bonded to the surface of the MNPs. The morphology and structural characteristics of the MNPs were investigated by scanning electron microscopy and X-ray diffraction (XRD), whereas the photophysical properties of the PFNs were studied with Fourier transform infrared, absorption, and emission spectroscopies. Generation of singlet oxygen, a major ROS, was directly confirmed with time-resolved phosphorescence spectroscopy. To evaluate the ability of PFNs to kill malarial parasites, the PDI effect of PFNs was evaluated within the infected erythrocytes. Furthermore, malarial parasites were completely eradicated from the erythrocytes after PDI treatment using PFNs on the basis of an 8 day erythrocyte culture test. PMID- 28351139 TI - Occurrence, Distribution, and Fate of Organic UV Filters in Coral Communities. AB - Organic ultraviolet (UV) filters are widely used in personal care products and occur ubiquitously in the aquatic environment. In this study, concentrations of seven commonly used organic UV filters were determined in seawater, sediment and five coral species collected from the eastern Pearl River Estuary of South China Sea. Five compounds, benzophenone-1, -3, and -8 (BP-1, -3, and -8), octocrylene (OC) and octyl dimethyl-p-aminobenzoic acid (ODPABA), were detected in the coral tissues with the highest detection frequencies (>65%) and concentrations (31.8 +/ 8.6 and 24.7 +/- 10.6 ng/g ww, respectively) found for BP-3 and BP-8. Significantly higher concentrations of BP-3 were observed in coral tissues in the wet season, indicating that higher inputs of sunscreen agents could be attributed to the increased coastal recreational activities. Accumulation of UV filters was only observed in soft coral tissues with bioaccumulation factors (log10-values) ranging from 2.21 to 3.01. The results of a preliminary risk assessment indicated that over 20% of coral samples from the study sites contained BP-3 concentrations exceeding the threshold values for causing larval deformities and mortality in the worst-case scenario. Higher probabilities of negative impacts of BP-3 on coral communities are predicted to occur in wet season. PMID- 28351140 TI - Bendable Photodetector on Fibers Wrapped with Flexible Ultrathin Single Crystalline Silicon Nanomembranes. AB - Silicon (Si) nanomembranes (NMs) enable conformal covering on complicated surfaces for novel applications. We adopt classical fibers as flexible/curved substrates and wrap them with freestanding ultrathin Si-NMs with a thickness of ~20 nm. Intrinsic defects in single-crystalline Si-NMs provide a flow path for hydrofluoric acid (HF) to release the NM with a consecutive area of ~0.25 cm2. Such Si-NMs with ultralow flexural rigidities are transferred onto a single-mode fiber (SMF) and functionalized into bendable photodetectors, which detects the leaked light when the fiber is bent. Our demonstration exemplifies optoelectronic applications in flexible photodetector for Si-NMs in a three-dimensional (3D) geometry. PMID- 28351141 TI - A Total Synthesis of Bifidenone. AB - The first total synthesis of bifidenone, a novel natural tubulin polymerization inhibitor, has been achieved in 12 steps starting from commercially available 1,4 dioxaspiro[4.5]decan-8-one. The synthesis includes a newly developed method to generate the dihydrobenzodioxolone core by palladium-catalyzed aerobic dehydrogenation. The three stereocenters were installed with an AD-mix-beta dihydroxylation step followed by a late-stage palladium-catalyzed decarboxylation allylation procedure. The absolute stereochemistry of 3 was determined via 13a by single-crystal X-ray analysis. PMID- 28351142 TI - Assessing the Source-to-Stream Transport of Benzotriazoles during Rainfall and Snowmelt in Urban and Agricultural Watersheds. AB - While benzotriazoles (BTs) are ubiquitous in urban waters, their sources and transport remain poorly characterized. We aimed to elucidate the origin and hydrological pathways of BTs in Toronto, Canada, by quantifying three BTs, electrical conductivity, and delta18O in high-frequency streamwater samples taken during two rainfall and one snowmelt event in two watersheds with contrasting levels of urbanization. Average concentrations of total BTs (?BT) were 1.3 to 110 times higher in the more urbanized Mimico Creek watershed relative to the primarily agricultural and suburban Little Rouge Creek. Strong correlations between upstream density of major roads and total BT concentrations or BT composition within all events implicate vehicle fluids as the key source of BTs in both watersheds. Sustained historical releases of BTs within the Mimico Creek watershed have likely led to elevated ?BT in groundwater, with elevated concentrations observed during baseflow that are diluted by rainfall and surface runoff. In contrast, relatively constant concentrations, caused by mixing of equally contaminated baseflow and rainfall/surface runoff, are observed in the Little Rouge Creek throughout storm hydrographs, with an occasional first flush occurring at a subsite draining suburban land. During snowmelt, buildup of BTs in roadside snowpiles and preferential partitioning of BTs to the liquid phase of a melting snowpack leads to early peaks in ?BT in both streams, except the sites in the Little Rouge Creek with low levels of vehicle traffic. Overall, a history of BT release and land use associated with urbanization have led to higher levels of BTs in urban areas and provide a glimpse into future BT dynamics in mixed use, (sub)urbanizing areas. PMID- 28351144 TI - Hydrogen Transfer in Energetic Materials from ReaxFF and DFT Calculations. AB - Energetic materials are characterized by fast and complex chemical reactions. It makes them hardly available for kinetic experiments in relevant conditions and a good target for reactive molecular dynamics simulations. In this work, unimolecular and condensed-phase thermal decomposition of pentaerythritol tetranitrate (PETN) are investigated by ReaxFF molecular dynamics. It is shown that the decomposition kinetics in condensed phase may be described with the activation barrier lower by a factor of 2 than that for isolated molecules. The effect of the intermolecular hydrogen transfer is revealed in condensed phase. Energetic barriers for hydrogen transfer in two energetic materials (methyl nitrate, which is a nitroester as well as PETN, and o-nitrotoluene) are studied with ReaxFF and DFT using nudged elastic band technique. The results indicate that ReaxFF gives significantly lower activation energy for intermolecular hydrogen transfer in nitroesters than different DFT approximations, which explains the molecular dynamics results for PETN. PMID- 28351143 TI - Charge Localization after Ultrafast Photoexcitation of a Rigid Perylene Perylenediimide Dyad Visualized by Transient Stark Effect. AB - The intramolecular charge-transfer (CT) dynamics of a rigid and strongly conjugated perylenediimide-bridge-perylene dyad (PDIPe) has been investigated in dichloromethane using ultrafast transient electronic absorption spectroscopy and quantum chemical calculations. The strong electronic coupling between the dyad units gives rise to a CT band. Its photoexcitation forms a delocalized CT state with well-preserved ion bands despite the strong coupling. In the dyad, the electronic transition dipole moment of the electron donor perylene is aligned along the axis of the electric field vector with respect to the CT species. This alignment makes the donor sensitive to the Stark effect and thus charge density fluctuations in the CT state. Charge localization on the picosecond time scale manifests as a time-dependent Stark shift in the visible region. Quantum chemical calculations reveal a twist around the acetylene bridging unit to be the responsible mechanism generating a partial to an almost complete CT state. An estimate of the electric field strength in the CT state yields approximately 25 MV/cm, which increases to around 31 MV/cm during charge localization. Furthermore, the calculations illustrate the complexity of electronic structure in this strongly delocalized superchromophore and reflect the complications in the interpretation of transient absorption results when compared to steady-state approaches such as spectroelectrochemistry and model chromophore experiments such as photoinduced bimolecular charge transfer. PMID- 28351145 TI - Reinvestigation of the Infrared Spectrum of the Gas-Phase Protonated Water Tetramer. AB - Gas-phase H9O4+ has been considered an archetypal Eigen cation, H3O+(H2O)3. Yet ab initio molecular dynamics (AIMD) suggested that its infrared spectrum is explained by a linear-chain Zundel isomer, alone or in a mixture with the Eigen cation. Recently, hole-burning experiments suggested a single isomer, with a second-order vibrational perturbation theory (VPT2) spectrum agreeing with the Eigen cation. To resolve this discrepancy, we have extended both calculations to more advanced DFT functionals, better basis sets, and dispersion correction. For Zundel-isomers, we find VPT2 anharmonic frequencies for four low-frequency modes involving the excess proton unreliable, including the 1750 cm-1 band that is pivotal for differentiating between Zundel and Eigen isomers. Because the analogous bands of the H5O2+ cation show little effect of anharmonicity, we utilize the harmonic frequencies for these modes. With this caveat, both AIMD and VPT2 agree on the spectrum as originating from a Zundel isomer. VPT2 also shows that both isomers have the same spectrum in the high frequency region, so that the hole burning experiments should be extended to lower frequencies. PMID- 28351146 TI - Carborane Derivative Conjugated with Gold Nanoclusters for Targeted Cancer Cell Imaging. AB - Polyhedral borane derivatives have been utilized in the treatment of boron neuron capture therapy (BNCT) for brain glioma, and much attention has been paid to search excellent biocompatible boron-rich composites for effective cancer BNCT therapy. In this study, we have exploited the self-assembly of the gold nanoclusters with carborane amino derivatives (GNCs-CB) for the precise bioimaging of cancer cells and targeted delivery of this carborane compound to the tumors. Our observations demonstrate that the GNCs-CB can readily realize accurate tumor imaging and long-term accumulation in tumor sites by EPR effect and nanometer size effect, and thus efficiently implement tumor-targeting delivery of the carborane derivative and facilitate the real-time fluorescent visualization monitoring of the carborane targeted delivery process. This makes it possible to realize the accurate location of the tumor by the carborane derivative and reduce the damage to normal tissues in the process of boron neutron capture therapy through imaging guided treatment. PMID- 28351147 TI - Adsorption and Aggregation Properties of Homogeneous Polyoxypropylene Polyoxyethylene Alkyl Ether Type Nonionic Surfactants. AB - Homogeneous polyoxypropylene (PO)-polyoxyethylene (EO) alkyl ether type nonionic surfactants comprising alkyl, EO, and PO chains with identical chain length distributions (CnEOxPOy; alkyl chain length n = 10, 12, 14, or 16; EO chain length x = 4, 6, or 8; and PO chain length y = 1, 2, or 3) were synthesized from homogeneous polyoxyethylene alkyl ether bromide and monosodium polyoxypropylene by Williamson ether synthesis. The adsorption and aggregation properties of these surfactants were characterized (cloud point, surface tension, dynamic light scattering, small-angle X-ray scattering, polarization microscopy, and cryogenic transmission electron microscopy) and compared to those of conventional homogeneous EO alkyl ether type nonionic surfactants (CnEOx). The introduction of a PO chain to the EO terminal group of the CnEOx species lowered the cloud points, especially for x = 6. Contrary to our expectations, the CnEOxPOy surfactants adsorbed efficiently at the air/water interface, despite their complex structure (hydrophobic alkyl chain/hydrophilic EO chain/hydrophobic PO chain). They also displayed excellent micelle-forming ability in solution. Furthermore, the CnEOx species formed small micelles in solution at low concentrations and the structures transformed to hexagonal liquid crystals as the surfactant concentration increased. Conversely, CnEOxPOy maintained a micellar structure even at high concentrations. Notably, the introduction of a PO chain into the CnEOx surfactant controlled the formation of aggregates with a higher order structure (hexagonal liquid crystals). PMID- 28351148 TI - Patterning of Nanoclays on Positively Charged Self-Assembled Monolayers via Micromolding in Capillaries. AB - Nanoclays are nanomaterials with versatile adsorptive properties. This contribution describes the generation of micropatterns of a nanoclay ("laponite") on ammonium-terminated, self-assembled monolayers (SAMs) on glass and silicon. Microstructured immobilization of the laponite was performed using micromolding in capillaries (MIMIC). The immobilization was verified using contact angle goniometry, X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), scanning electron microscopy (SEM), time-of-flight secondary ion mass spectrometry (ToF-SIMS), and fluorescence microscopy. Furthermore, laponite was modified with Nile red to generate a fluorescence enhancement-based surface sensor for the vitamin choline. PMID- 28351149 TI - Light Energy Accumulation from Pyrene Derivative to Tris(bipyridine)ruthenium on Clay Surface. AB - A novel type of energy donor-acceptor system on a clay surface has been prepared. The energy transfer between an energy-donating cationic pyrene derivative (An Py2+) and an energy-accepting tris(bipyridine)ruthenium complex (Ru2+) on the clay surface was investigated using absorption, emission, and lifetime measurements. An obvious energy transfer was observed, and one Ru2+ molecule quenched the emission from five molecules of An-Py2+ with an emission quenching efficiency of 85% on the clay surface. This suggests that the light energies absorbed by five of the An-Py2+ molecules were accumulated in the one Ru2+ molecule. Near-quantitative emission quenching was observed for stoichiometric amounts of An-Py2+ and Ru2+. The apparent quenching rate constant is approximately 1017 L mol-1 s-1, and thus the quenching rate constant is 107-108 times higher than the diffusion rate constant in a homogeneous solution. PMID- 28351150 TI - Assembly of Indolenines, 3-Amino Oxindoles, and Aldehydes into Indolenine Substituted Spiro[pyrrolidin-2,3'-oxindoles] via 1,3-Dipolar Cycloaddition with Divergent Diastereoselectivities. AB - A novel one-pot 1,3-dipolar cycloaddition of indolenines, 3-aminooxindoles, and aldehydes is reported. The reaction provides indolenine-substituted spiro[pyrrolidin-2,3'-oxindoles] containing four contiguous stereogenic centers in high yields (up to 99%) and excellent diastereoselectivities (up to >20:1 dr) under mild conditions. Remarkably, the inversion of diastereoselectivity could be readily achieved through slightly modifying the reaction conditions. PMID- 28351151 TI - General and Stereoselective Method for the Synthesis of Sterically Congested and Structurally Diverse P-Stereogenic Secondary Phosphine Oxides. AB - A general and efficient method for the synthesis of bulky and structurally diverse P-stereogenic chiral secondary phosphine oxides (SPOs) by using readily available chiral amino alcohol templates is described. These chiral SPOs could be used as chiral building blocks for the synthesis of difficult-to-access bulky P stereogenic phosphine compounds or ligands for organic catalysis. PMID- 28351154 TI - Use of Continuous-Infusion Ceftolozane/Tazobactam in a Multidrug-Resistant Pseudomonas aeruginosa Urinary Tract Infection in the Outpatient Setting. PMID- 28351153 TI - Gas Chromatography/Mass Spectrometry Metabolomics of Urine and Serum from Nonhuman Primates Exposed to Ionizing Radiation: Impacts on the Tricarboxylic Acid Cycle and Protein Metabolism. AB - Ionizing radiation (IR) directly damages cells and tissues or indirectly damages them through reactive free radicals that may lead to longer term adverse sequelae such as cancers, persistent inflammation, or possible death. Potential exposures include nuclear reactor accidents, improper disposal of equipment containing radioactive materials or medical errors, and terrorist attacks. Metabolomics (comprehensive analysis of compounds <1 kDa) by mass spectrometry (MS) has been proposed as a tool for high-throughput biodosimetry and rapid assessment of exposed dose and triage needed. While multiple studies have been dedicated to radiation biomarker discovery, many have utilized liquid chromatography (LC) MS platforms that may not detect particular compounds (e.g., small carboxylic acids or isomers) that complementary analytical tools, such as gas chromatography (GC) time-of-flight (TOF) MS, are ideal for. The current study uses global GC-TOF-MS metabolomics to complement previous LC-MS analyses on nonhuman primate biofluids (urine and serum) 7 days after exposure to 2, 4, 6, 7, and 10 Gy IR. Multivariate data analysis was used to visualize differences between control and IR exposed groups. Univariate analysis was used to determine a combined 26 biomarkers in urine and serum that significantly changed after exposure to IR. We found several metabolites involved in tricarboxylic acid cycle function, amino acid metabolism, and host microbiota that were not previously detected by global and targeted LC MS studies. PMID- 28351155 TI - The Creative Benefits Scale: Connecting Generativity to Life Satisfaction. AB - Long-term participation in creative activities has benefits for middle-aged and older people that may improve their adaptation to later life. We first investigated the factor structure of the Creative Benefits Scale and then used it to construct a model to help explain the connection between generativity and life satisfaction in adults who participated in creative hobbies. Participants included 546 adults between the ages of 40 and 88 (Mean = 58.30 years) who completed measures of life satisfaction, generativity, and the Creative Benefits Scale with its factors of Identity, Calming, Spirituality, and Recognition. Structural equation modeling was used to examine the connection of age with life satisfaction in older adults and to explore the effects of creativity on this relation. The proposed model of life satisfaction, incorporating age, creativity, and generativity, fit the data well, indicating that creativity may help explain the link between the generativity and life satisfaction. PMID- 28351156 TI - Long-term exercise training and soy isoflavones to improve quality of life and climacteric symptoms. AB - OBJECTIVE: To verify the efficacy of phytoestrogen supplementation combined with aerobic and resistance training on the improvement of climacteric symptoms and health-related quality of life (HRQoL) in postmenopausal women. METHODS: From a pool of women who had participated in a 1-year intervention study and were randomly assigned to either exercise + phytoestrogen (EX + PHY) or exercise + placebo (EX + PL), a total of 31 healthy but overweight women (mean age 59.2 +/- 4.8 years, body mass index 29.1 +/- 3.5 kg/m2) finished the study (EX + PHY, n = 15; EX + PL, n = 16). All the following variables were measured before, after 6 months and after 12 months of intervention: body composition (fat and lean body mass, DXA), HRQoL (SF-36 questionnaire: physical and mental component summaries and subscales; and the 10-item Perceived Stress Scale questionnaire), climacteric symptoms (Kupperman Index questionnaire). RESULTS: After 1 year of intervention, physical functioning (p = 0.003), role-emotional (p = 0.031), vitality (p = 0.007), and global health (p < 0.001) were significantly and similarly increased in both groups. Regarding climacteric symptoms, an improvement in the Kupperman index total score (p = 0.015) was observed. CONCLUSION: Our results demonstrate that adding phytoestrogens to exercise training does not provide the additive effect for HRQoL in postmenopausal and overweight women. Moreover, exercise and phytoestrogen may interfere in the improvement of climacteric symptoms in the long term. PMID- 28351157 TI - Synthetic and phytocompounds based dipeptidyl peptidase-IV (DPP-IV) inhibitors for therapeutics of diabetes. AB - Currently antidiabetic therapeutic strategies are mainly based on synthetic hypoglycemic agent. Antidiabetic drugs are associated with significant adverse effects of hypoglycemia, dysfunction of insulin and weight gain. Nowadays, the novel Dipeptidyl peptidase-IV (DPP-IV) inhibitors unique approach for the management of diabetes has been considered to be safe, as DPP-IV inhibitors reduce blood glucose level by monitoring hyperglycemia including positive effects on body weight as it remains neutral, improves glycated hemoglobin levels and do not induce hypoglycemia. Inhibitors help to protect degradation of Glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), gut hormones which helps to suppresses postprandial glucagon release, delay gastric emptying and regulate satiety. Therefore, the innovation of DPP-IV inhibitor based drugs regulates activity of incretin hormones such as GLP-1 and GIP. Commercially available DPP IV inhibitors are chemically synthesized with good therapeutic value. However, the durability and long-term safety of DPP-IV inhibitors remains to be established. On the other hand, phytocompounds-based DPP-IV inhibitors are alternative and safe to use as compared to synthetic. Numerous novel antidiabetic compounds and group of compounds emerging in clinical development are through DPP IV inhibition. This review summarized recent progress made on DPP-IV inhibitors from both synthetic as well as from natural sources. PMID- 28351158 TI - Stressful and traumatic life events as disruptors to antiretroviral therapy adherence. AB - Stressful and traumatic life events (STLEs) are common among HIV-infected individuals and may affect health behaviors such as adherence to antiretroviral (ARV) therapy, with important implications for treatment outcomes. We examined the association between STLEs and ARV adherence among 289 US-based participants enrolled between 7/1/2010 and 9/1/2013 in a study of depression treatment for HIV infected patients. Participants received monthly telephone calls to assess STLEs and pill count-based ARV adherence. Inverse probability of observation weighting was combined with multiple imputation to address missing data. Participants were mostly male (71%) and black (63%), with a median age of 45 years. Median monthly adherence was 96% (interquartile range (IQR): 85-100%). Participants experienced a mean of 2.48 STLEs (range: 0-14) in the previous month. The presence of >=2 STLEs was associated with a mean change in adherence of -3.67% (95% confidence interval (CI): -7.12%, -0.21%) and decreased likelihood of achieving >=95% adherence (risk ratio (95% CI) = 0.82 (0.71, 0.95)). For each additional STLE, the mean adherence change was -0.90% (95% CI: -1.79%, 0.00%). STLEs were associated with poorer ARV adherence, including decreased likelihood of adhering to >=95% of ARV doses. This level of adherence has a critical role in regimen effectiveness and prevention of resistance. PMID- 28351160 TI - Extensive Bruising and Elevated Rivaroxaban Plasma Concentration in a Patient Receiving Cobicistat-Boosted Elvitegravir. PMID- 28351159 TI - Implementation fidelity of a computer-assisted intervention for children with speech sound disorders. AB - BACKGROUND: Implementation fidelity refers to the degree to which an intervention or programme adheres to its original design. This paper examines implementation fidelity in the Sound Start Study, a clustered randomised controlled trial of computer-assisted support for children with speech sound disorders (SSD). METHOD: Sixty-three children with SSD in 19 early childhood centres received computer assisted support (Phoneme Factory Sound Sorter [PFSS] - Australian version). Educators facilitated the delivery of PFSS targeting phonological error patterns identified by a speech-language pathologist. Implementation data were gathered via (1) the computer software, which recorded when and how much intervention was completed over 9 weeks; (2) educators' records of practice sessions; and (3) scoring of fidelity (intervention procedure, competence and quality of delivery) from videos of intervention sessions. RESULT: Less than one-third of children received the prescribed number of days of intervention, while approximately one half participated in the prescribed number of intervention plays. Computer data differed from educators' data for total number of days and plays in which children participated; the degree of match was lower as data became more specific. Fidelity to intervention procedures, competency and quality of delivery was high. CONCLUSION: Implementation fidelity may impact intervention outcomes and so needs to be measured in intervention research; however, the way in which it is measured may impact on data. PMID- 28351161 TI - Advances in improving fertility in women through stem cell-based clinical platforms. AB - INTRODUCTION: Due to their regenerative ability, stem cells are looked at as a promising tool for improving infertility treatments in women. As the main limiting factor in female fertility is represented by the decrease of ovarian reserve, the main goals of stem cell-based clinical platforms would be to obtain in vitro or in vivo neo-oogenesis. Refractory endometrial factor infertility also represents an obstacle for female reproduction for which stem cells might provide novel treatment strategies. Areas covered: A systematic search of the literature was performed on MEDLINE/PubMed database to identify relevant articles using stem cell based clinical or research platforms in the field of female infertility. Expert opinion: In vitro oogenesis has not so far developed beyond the stage of oocyte-like cells whose normal progression to mature oocytes and ability to be fertilized was not proved. Extensive epigenetic programming of gamete precursors and the complex interactions between somatic and germ cells required for human oogenesis likely represent the main obstacles in stem-cell-based neo-oogenesis. Also resuming oogenesis in vivo in adulthood still appears a distant hypothesis, as there is still a lack of consensus about the existence and functionality of adult ovarian stem cells. PMID- 28351162 TI - The moderating effects of aging and cognitive abilities on the association between work stress and negative affect. AB - OBJECTIVES: Given that the association between work stress and negative affect can exacerbate negative health and workplace outcomes, it is important to identify the protective and risk factors that moderate this association. Socioemotional aging and cognitive abilities might influence how people utilize emotion regulation skills and engage in practical problem solving to manage their work stress. The aim of this study is to examine whether age and cognitive abilities independently and interactively moderate the association between work related stress and negative affect. METHOD: A diverse working adult sample (N = 139, age 25-65, 69% of females) completed a cross-sectional survey that assessed chronic work stress, negative affect, and fluid and crystallized cognitive abilities. RESULTS: Results from regression analyses suggested that both fluid and crystallized cognitive abilities, but not age, moderated the association between work stress and negative affect. Further, we found that crystallized cognition had a stronger attenuating effect on the work stress-negative affect association for older compared to younger workers. The moderating effect of fluid cognition was invariant across age. CONCLUSION: Our findings demonstrate that cognitive abilities are an important personal resource that might protect individuals against the negative impacts of work stress and negative affect. Although the role that fluid cognition plays in work stress-negative affect association is comparably important for both younger and older workers, crystallized cognition might play a more valuable role for older than younger workers. PMID- 28351163 TI - CRP relevance in clinical assessment of chronic spontaneous urticaria Tunisian patients. AB - BACKGROUND: Chronic spontaneous urticaria (CSU) is a common dermatological condition defined by the sudden occurrence of daily wheals and pruritus for at least six weeks. Multifactorial origin is suggested such as oxidative stress. This latter may play a double role as a trigger and remnant agent. OBJECTIVES: The first aim of this study is to investigate antioxidant status, inflammatory proteins, hematologic counts and clinical assessment in CSU patients. The second aim is to evaluate the effect of a first-line treatment: desloratadine 5 mg/d on these different parameters. PATIENTS AND METHODS: This study enrolled 30 CSU patients and same number of controls. We assessed the urticaria activity score (UAS), total antioxidant status (TAS), glutathione S-transferase (GST), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), albumin, alpha1, alpha2, beta1 beta2, gamma globulins, c-reactive protein (CRP) and hematologic numeration. RESULTS: At baseline alpha1, alpha2, beta1, beta2, gamma globulins, CRP, SOD activity, leukocytes and basophils were significantly higher in patients versus controls (p < 0.05). TAS, GST, CAT, GPx and albumin were significantly low in patients versus controls (p < 0.05). After treatment, TAS, GST and GPx were significantly increased in patients versus patients before treatment (p < 0.001). SOD, alpha1, alpha2, beta1, beta2, gamma globulins, CRP, albumin, leukocytes and basophils were significantly decreased after treatment versus before treatment (p < 0.05). A significant correlation between CRP and UAS (r = 0.3; p = 0.011) was noted. UAS assessment revealed the efficacy of 30 d antihistaminic treatment. CONCLUSIONS: Desloratadine exerted anti-inflammatory and antioxidant effects on CSU patients revealed by CRP. Patients' remission was synergistic to CRP attenuation emphasizing CRP relevance for CSU clinical assessment. PMID- 28351165 TI - Two new isobenzofuranone derivatives from the fruiting bodies of Hericium erinaceus. AB - Two new isobenzofuranone derivatives erinaceolactones G and H (1 and 2) were isolated from the ethanolic extract of fruiting bodies of Hericium erinaceus. Their structures were characterized on the basis of spectroscopic evidences. Compound 2 was suggested to be racemic by specific rotation, which was resolved by chiral HPLC into enantiomers. PMID- 28351166 TI - Coaches' Implementation of the USA Football "Heads Up Football" Educational Program. AB - An integral part of the Heads Up Football (HUF) educational program is the Player Safety Coach (PSC), who is responsible for teaching other coaches within a youth football league about safer blocking/tackling and injury prevention. This study examines the association between youth football coaches' interactions with the PSC (i.e., attending the PSC clinic at the beginning of the season and seeing the PSC on-field during practices) and their subsequent implementation of the HUF educational program. Data were collected via online questionnaire completed by 1,316 youth football coaches from HUF leagues. Data were analyzed with frequencies and logistic regression. Nearly half of coaches (44.8%) did not attend the PSC clinic; 25.9% reported not seeing their league's PSC on the field on a regular basis. The lack of PSC on-site presence was significantly associated with worse implementation for "concussion recognition and response," "heat preparedness and hydration," and "sudden cardiac event preparedness." PSC clinic attendance was not associated with implementation. Opportunities exist for improvement in the HUF educational program as there appears to be inconsistent implementation. Further research is warranted to understand how to optimize the role of the PSC in the youth sports context. PMID- 28351167 TI - Talimogene Laherparepvec: An Oncolytic Virus Therapy for Melanoma. AB - OBJECTIVE: To review the efficacy and safety of talimogene laherparepvec (T-VEC) as well as its pharmacology, pharmacokinetics, drug-drug interactions, handling procedures, cost considerations, and place in therapy. DATA SOURCES: Searches of PubMed (1966 to February 2017) and Cochrane Library (1999 to February 2017) were conducted using the terms talimogene laherparepvec, T-VEC, OncoVEX, immunotherapy, melanoma, and oncolytic virus. Additional information was determined from bibliographies, manufacturer product labeling and website, meeting abstracts, Food and Drug Administration website, and clinicaltrials.gov. STUDY SELECTION AND DATA EXTRACTION: A total of 79 English-language publications were identified. Articles that assessed T-VEC's pharmacokinetics, pharmacodynamics, mechanism, dosing, safety, and efficacy were included as well as narrative reviews that provided practical information. DATA SYNTHESIS: Clinical trials have confirmed the safety and efficacy of T-VEC as monotherapy for the treatment of advanced melanoma, with an overall response rate (ORR) of 26%. Relative to granulocyte-macrophage colony-stimulating factor, T-VEC significantly increased durable response rate (DRR; 16.3% vs 2.1%, P < 0.001); however, median overall survival was not improved (23.3 vs 18.9 months, P = 0.051). Phase 1b trials have combined T-VEC and immunotherapies with promising results. T-VEC's adverse effects are generally considered mild to moderate in severity. CONCLUSION: T-VEC is the first approved oncolytic virus for local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in melanoma recurrent after initial surgery. T-VEC improves ORR and DRR as a single agent, shows promise in combination therapy, and is well tolerated. Ongoing trials will determine if T-VEC has a role in early treatment or in combination therapy for melanoma or other malignancies. PMID- 28351168 TI - Long-term follow-up of a randomized controlled trial on additional core stability exercises training for improving dynamic sitting balance and trunk control in stroke patients. AB - OBJECTIVE: Analyse the effect of core stability exercises in addition to conventional physiotherapy training three months after the intervention ended. DESIGN: A randomized controlled trial. SETTING: Outpatient services. SUBJECTS: Seventy-nine stroke survivors. INTERVENTIONS: In the intervention period, both groups underwent conventional physiotherapy performed five days/week for five weeks, and in addition the experimental group performed core stability exercises for 15 minutes/day. Afterwards, during a three-month follow-up period, both groups underwent usual care that could eventually include conventional physiotherapy or physical exercise but not in a controlled condition. MAIN MEASURES: Primary outcome was trunk control and dynamic sitting balance assessed by the Spanish-Version of Trunk Impairment Scale 2.0 and Function in Sitting Test. Secondary outcomes were standing balance and gait evaluated by the Berg Balance Scale, Tinetti Test, Brunel Balance Assessment, Spanish-Version of Postural Assessment Scale for Stroke and activities of daily living using the Barthel Index. RESULTS: A total of 68 subjects out of 79 completed the three month follow-up period. The mean difference (SD) between groups was 0.78 (1.51) points ( p = 0.003) for total score on the Spanish-Version of Trunk Impairment Scale 2.0, 2.52 (6.46) points ( p = 0.009) for Function in Sitting Test, dynamic standing balance was 3.30 (9.21) points ( p= 0.009) on the Berg Balance Scale, gait was 0.82 (1.88) points ( p = 0.002) by Brunel Balance Assessment (stepping), and 1.11 (2.94) points ( p = 0.044) by Tinetti Test (gait), all in favour of core stability exercises. CONCLUSIONS: Core stability exercises plus conventional physiotherapy have a positive long-term effect on improving dynamic sitting and standing balance and gait in post-stroke patients. PMID- 28351169 TI - Pharmacotherapeutic agents in the treatment of methamphetamine dependence. AB - INTRODUCTION: Methamphetamine use is a serious public health concern in many countries and is second to cannabis as the most widely abused illicit drug in the world. Effective management for methamphetamine dependence remains elusive and the large majority of methamphetamine users relapse following treatment. Areas covered: Progression in the understanding of the pharmacological basis of methamphetamine use has provided us with innovative opportunities to develop agents to treat dependence. The current review summarizes relevant literature on the neurobiological and clinical correlates associated with methamphetamine use. We then outline agents that have been explored for potential treatments in preclinical studies, human laboratory phase I and phase II trials over the last ten years. Expert opinion: No agent has demonstrated a broad and strong effect in achieving MA abstinence in Phase II trials. Agents with novel therapeutic targets appear promising. Advancement in MA treatment, including translation into practice, faces several clinical challenges. PMID- 28351170 TI - Effect of topiramate on choroidal thickness and anterior chamber parameters in the treatment of patients with migraine. AB - OBJECTIVE: To investigate the effects of topiramate on choroidal thickness and anterior chamber parameters using optical coherence tomography in the treatment of patients with migraine. METHODS: A total of 22 eyes of 22 adults (12 females, 10 males) diagnosed with migraine and scheduled to topiramate treatment for pain control were recruited in this prospective study. Choroidal thickness (CT), anterior chamber depth (ACD), anterior chamber angle (ACA), spherical refractive equivalent (SphEq) and intraocular pressure (IOP) measurements were recorded at baseline (prior the topiramate therapy), first and second month visits for the statistical analysis. One-way ANOVA with repeated measures test was used for the statistical evaluation. RESULTS: Mean age of the patients was 40.2 +/- 6.5 years. Mean CT at central fovea was 324 +/- 47 MUm initially, 341 +/- 45 MUm in the first month and 344 +/- 46 MUm in the second month, thus first and second month measures were significantly higher than base values (p < 0.001). There was also a slight increase in IOP values among baseline (15.5 +/- 2.4 mmHg) and follow-up visits (17.5 +/- 2.6 mmHg, 19.0 +/- 3.3 mmHg, respectively, ' p = 0.001). Baseline ACD (3.66 +/- 0.22 mm) measures significantly decreased at the first month (3.63 +/- 0.22 mm) and second month (3.62 +/- 0.22 mm, p = 0.009). Also, a significant reduction was detected in the first (36.2 +/- 4.9 degrees ) and second month (35.9 +/- 5.1 degrees ) ACA measures comparing with baseline (39.1 +/- 5.1 degrees , p = 0.05). A significant myopic shift was determined in the first and second month SphEq values (-0.08 +/- 0.6, -0.10 +/- 0.6, respectively, p = 0.05). CONCLUSIONS: The study revealed increased CT and altered anterior chamber parameters and IOP due to topiramate therapy. Therefore, the patients using topiramate should be carefully monitored by an ophthalmologist considering the possible side effects. PMID- 28351171 TI - Releasing the brake: safety profile of immune check-point inhibitors in non-small cell lung cancer. AB - INTRODUCTION: Immune check-point inhibitors are now employed as single-agents in current practice for the treatment of advanced non-small cell lung cancer (NSCLC), while combinations of different inhibitors are being evaluated in clinical trials. Although the safety profile of these compounds, with particular reference to drugs targeting programmed death protein 1 (PD-1) and its ligand (PD L1), is generally considered manageable, peculiar, immune-related toxicities may onset. Areas covered: This review focuses on the immune-related adverse events (irAEs) observed during immune check-point blockade in NSCLC and their management. The authors report the incidence of irAEs based on the currently available data involving NSCLC and provide recommendations on the general approach to irAEs, as well as indications for the most relevant site-specific events. Expert opinion: Since irAEs may involve a wide range of organs and systems and are potentially reversible if promptly treated, early diagnosis should always be achieved; this might be particularly challenging when other potential causes of toxicity are suspected, such as infections or concurrent treatments. Finally, drugs active on the PD-1/PD-L1 axis appear to be generally manageable even when they are administered to patients with relevant comorbidities, provided that adequate clinical monitoring is performed. PMID- 28351172 TI - Current status of mechanical circulatory support for treatment of advanced end stage heart failure: successes, shortcomings and needs. AB - INTRODUCTION: Heart failure (HF) remains a major global burden in terms of morbidity and mortality. Despite advances in pharmacological and resynchronization device therapy, many patients worsen to end-stage HF. Although the gold-standard treatment for such patients is heart transplantation, there will always be a shortage of donor hearts. Areas covered: A left ventricular assist device (LVAD) is a valuable option for these patients as a bridge measure (to recovery, to candidacy for transplant, or to transplant itself) or as destination therapy. This review describes the current indications for and complications of the most commonly implanted LVADs. In addition, we review the potential and promising new LVADs, including the HeartMate 3, MVAD, and other LVADs. Studies investigating each were identified through a combination of online database and direct extraction of studies cited in previously identified articles. Expert commentary: The goal of LVADs has been to fill the gap between patients with end-stage HF who would likely not benefit from heart transplantation and those who could benefit from a donor heart. As of now, the use of LVADs has been limited to patients with end-stage HF, but next-generation LVAD therapy may improve both survival and quality of life in less sick patients. PMID- 28351173 TI - Effects of forage feeding versus grain feeding on the growth performance and meat quality of Yangzhou geese. AB - 1. Highly palatable and nutritious meat products can be produced through dietary interventions. Previous studies have shown that forage feeding has a significant impact on the growth performance and nutrition of cattle in various regions, but whether the same effects can be induced in geese remains unclear. 2. Three hundred and sixty Yangzhou goslings were divided according to body weight at 29 d old, assigned to one of 4 treatments and raised in separate pens. The treatments applied were (A) grazing, (B) grazing, grain supplemental diet (64 to 70 d), (C) grazing, grain supplemental diet and (D) confined. 3. Eviscerated carcass yield was lower in the grazing treatment. Protein content and muscle collagen in both the breast and thigh muscles were significantly higher in the grazing treatment than the confined, while fat content exhibited the opposite tendency. Those fed on grass and supplementary grain had a higher Mg and Cu content in breast muscle. 4. Geese will grow to their full potential when they are allowed to consume grass from pasture supplemented with grain, protein, collagen, Mg and Cu content was greater to a degree, which suggests this feeding regime is an ideal model for goose production. PMID- 28351174 TI - Manufacturing Clinical Grade Recombinant Adeno-Associated Virus Using Invertebrate Cell Lines. AB - Recombinant adeno-associated virus (rAAV) vectors are proving to be a reliable gene transfer system for several clinical applications, with an increasing body of evidence supporting safety and efficacy. Realizing the clinical and commercial potential of rAAV depends on a reliable source of high-quality, well characterized rAAV lots. This requirement has been very challenging to achieve due to limits of manufacturing platforms, lot-to-lot variability, or differences in the rigor applied to quality-control assays. In addition to reliable, high quality vectors, limited quantities of rAAV have hampered clinical development and discouraged investigations into applications that require large therapeutic doses or quantities needed to treat large patient populations. A minimal number of vector production runs should be sufficient to support all phases of clinical development, including non-clinical, pharmacological, and toxicological studies, as well as clinical studies and commercial supply. The production platform using the Sf9 invertebrate cell line has emerged as a scalable and economical source of rAAV. Access to larger quantities of rAAV has now enabled evaluation of gene therapeutics for diseases that require large doses per patient or diseases with large patient populations. The only licensed rAAV product, Glybera, was produced in Sf9 cells, and other rAAV products are in clinical trials in the United States and Europe. The development of the Sf9 rAAV genetics, processes, and overview of the current system are described. PMID- 28351175 TI - Hormonal contraception: venous and arterial disease. AB - OBJECTIVES: The aim of this review was to evaluate whether the biological and epidemiological evidence is concordant in suggesting that levonorgestrel (LNG) based hormonal contraceptives (HCs) are safer than newer formulations with regard to their effect on the cardiovascular system. METHODS: A narrative review was carried out of the modification of risk factors for venous thromboembolism (VTE) and arterial diseases induced by different HCs. Limits and concordance with epidemiological data were addressed. RESULTS: The data indicate general concordance between modifications of risk factors and epidemiology of VTE, with LNG-based HCs showing lower risk compared with most new formulations. Evidence for drospirenone (DRSP)-containing HCs is conflicting. LNG-based HCs are less favourable than HCs containing non-androgenic progestins, particularly DRSP, on risk factors for arterial events. Epidemiological studies do not consistently show a difference in arterial disease outcomes between different HCs; however, by evaluating women up to the age of 50, they do not take into consideration the time lag necessary for atherosclerosis to develop. CONCLUSIONS: As a consequence of the different risk factors involved, and the different time lags between HC use and the manifestation of VTE or arterial diseases, the available epidemiological data do not give a reliable estimate of the cardiovascular risk associated with the use of different HCs. LNG-based HCs are safer than newer HCs as regards VTE risk, but biological data indicate that they are less favourable, particularly than HCs containing DRSP, on risk factors for atherosclerosis. Because of the limits of actual epidemiological evidence regarding arterial disease, modifications of arterial risk factors should be taken into consideration when considering individual long-term safety of HC use. PMID- 28351176 TI - The use of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes and hypertension: a focus on African-American populations. AB - Diabetes, hypertension, and severe kidney disease are all disproportionately prevalent in African-Americans. Clinical trials data from type 2 diabetes (T2D) patients have demonstrated that sodium-glucose cotransporter 2 (SGLT2) inhibitors have a positive effect on cardiovascular risk factors - such as improved blood glucose control, reduced body weight, and reduced blood pressure - and also support a possible renal-protective role for SGLT2 inhibitors. The EMPA-REG OUTCOME(r) trial revealed that empagliflozin was associated with reduced adverse cardiovascular and renal outcomes. Thus, SGLT2 inhibitors could potentially provide clinicians with a treatment option that addresses multiple pathophysiologic aspects of the cardiometabolic disease processes that may affect end-organ function in African-American patients with T2D and hypertension. This review examines some of the clinical issues associated with this patient group and the role that SGLT2 inhibitors may provide in their treatment. PMID- 28351178 TI - Atopic dermatitis management with tacrolimus ointment (Protopic(r)). AB - Tacrolimus ointment is the first of a new class of non-steroidal topical immunomodulators indicated for the treatment of atopic dermatitis. Topical tacrolimushas been subject to an extensive clinical development program involving more than 16,000 patients. A clinical trial program, including vehicle-controlled studies, short- and long-term comparative studies and long-term safety studies, has investigated tacrolimus 0.1%and 0.03%ointment for the treatment of atopic dermatitis in adults and children aged 24 months and older. Tacrolimusmonotherapy is rapidly effective, resulting in clinical improvements within three days of starting therapy, and produces a progressive increase in efficacy that is sustained during long-term treatment. Tacrolimus treats the signs and symptoms of atopic dermatitis, reduces the incidence of flares, and offers the potential for long-term disease control. No major safety concerns have been reported to date. Tacrolimusointment is generally well tolerated, the primary adverse events being mild to moderate and transient application-site reactions: skin burning, pruritus and erythema. Tacrolimus oint-ment is a significant advance in dermatology and provides physicians with an alternative to conventional topical corticosteroid therapy. PMID- 28351177 TI - Direct and indirect cost of managing alzheimer's disease and related dementias in the United States. AB - INTRODUCTION: Care of individuals with Alzheimer's Disease and Related Dementias (ADRD) poses special challenges. As the disease progresses, individuals with ADRD require increasing levels of medical care, caregiver support, and long-term care which can lead to substantial economic burden. Areas covered: In this expert review, we synthesized findings from studies of costs of ADRD in the United States that were published between January 2006 and February 2017, highlighted major sources of variation in costs, identified knowledge gaps and briefly outlined directions for future research and implications for policy and program planning. Expert commentary: A consistent finding of all studies comparing individuals with and without ADRD is that the average medical, non-medical, and indirect costs of individuals with ADRD are higher than those without ADRD, despite the differences in the methods of identifying ADRD, duration of the study, payer type and settings of study population. The economic burden of ADRD may be underestimated because many components such as direct non-medical costs for home safety modifications and adult day care services and indirect costs due to the adverse impact of ADRD on caregivers' health and productivity are not included in cost estimates. PMID- 28351179 TI - Vancomycin-resistant enterococci in acute myeloid leukemia and myelodysplastic syndrome patients undergoing induction chemotherapy with idarubicin and cytarabine. AB - We conducted a retrospective study to determine the risk factors associated with vancomycin-resistant enterococci (VRE) acquisition/infection in newly diagnosed acute myeloid leukemia and myelodysplastic syndrome patients undergoing chemotherapy with the 7 + 3 regimen of cytarabine and idarubicin. Although only 2.5% (6/235) patients were colonized with VRE on admission, 59% (134/229) of patients acquired VRE during their hospitalization. Multivariable analysis identified the use of intravenous vancomycin (p = .024; HR: 1.548) and cephalosporin (p = .009; HR: 1.596) as the risk factors for VRE acquisition. VRE infection developed in 14% (33/229) of patients, with bloodstream infections accounting for 82% (27/33) of cases. VRE infection occurred in 25/126 (20%) of the VRE-colonized patients, but only 8/103 (8%) of those who were not (p = .01). Our study provides the evidence for the role of intravenous cephalosporin and vancomycin in VRE acquisition and highlights the clinical significance of VRE colonization in these patients. PMID- 28351180 TI - PLAC1 immunization does not induce infertility in mice. AB - AIM: Placenta specific 1 (PLAC1) is a protein rarely expressed in normal cells, except it is important for placental development, with a possible role in the establishment of the mother-fetus interface. The gene is also highly active in a wide variety of cancers and therefore, immunization with PLAC1 peptides could possibly be part of future immunotherapeutic strategies. We investigated whether vaccination against PLAC1 could induce infertility. MATERIALS & METHODS: We inoculated female mice with PLAC1 peptides, put them in mating, measured antibody response (ELISA assay) and checked, in immunohistochemistry, binding of the induced antibodies to the native antigen. RESULTS: We demonstrated that mice consistently develop antibody responses. We also demonstrated that female mice, after being inoculated with the PLAC1 peptide mix, do became pregnant and can give birth to normal infants. CONCLUSION: PLAC1 antigens as a specific anti cancer vaccine could induce anti-PLAC1 antibodies which do not necessarily cause infertility. PMID- 28351181 TI - Prognostic models in predicting outcomes in myelodysplastic syndromes after hypomethylating agent failure. AB - Myelodysplastic syndromes (MDS) are clonal stem cell disorders marked by bone marrow failure with varying degrees of cytopenias. MDS are characterized by the accumulation of complex genetic alterations that influence disease pathogenesis and outcomes. Given the heterogeneity of MDS patients, multiple prognostic scoring systems have been developed to predict patient outcomes. Most focus primarily on untreated patients in whom outcomes are predicted accurately only at diagnosis; their application dynamically, during the disease course and especially after hypomethylating agent (HMA) failure, may not be accurate. In this focused review, we discuss the utility of established MDS prognostic models and a novel tool at the time of HMA failure, along with the strengths and limitations of each. PMID- 28351182 TI - Ten-eleven translocation 1 functions as a mediator of SOD3 expression in human lung cancer A549 cells. AB - Superoxide dismutase (SOD) 3, one of the SOD isozymes, plays a pivotal role in extracellular redox homeostasis. The expression of SOD3 is regulated by epigenetics in human lung cancer A549 cells and human monocytic THP-1 cells; however, the molecular mechanisms governing SOD3 expression have not been elucidated in detail. Ten-eleven translocation (TET), a dioxygenase of 5 methylcytosine (5mC), plays a central role in DNA demethylation processes and induces target gene expression. In the present study, TET1 expression was abundant in U937 cells, but its expression was weakly expressed in A549 and THP-1 cells. These results are consistent with the expression pattern of SOD3 and its DNA methylation status in these cells. Moreover, above relationship was also observed in human breast cancer cells, human prostate cancer cells, and human skin fibroblasts. The overexpression of TET1-catalytic domain (TET1-CD) induced the expression of SOD3 in A549 cells, and this was accompanied by the direct binding of TET1-CD to the SOD3 promoter region. Furthermore, in TET1-CD transfected A549 cells, the level of 5-hydroxymethylcytosine within that region was significantly increased, whereas the level of 5mC was decreased. The results of the present study demonstrate that TET1 might function as one of the key molecules in SOD3 expression through its 5mC hydroxylation in A549 cells. PMID- 28351183 TI - Bendamustine as a bridge to allogeneic transplant in relapsed/refractory Hodgkin lymphoma patients who failed salvage brentuximab vedotin postautologous peripheral blood stem cell transplantation. PMID- 28351184 TI - Flow cytometric demonstration of decrease in bone marrow leukemic blasts after 'Day 14' without further therapy in acute myeloid leukemia. PMID- 28351185 TI - Biomechanical evaluation of spring system for implant-supported prosthesis: analysis by photoelasticity and extensometry. AB - New systems are released in the odontological market with the objective of bringing improvements and advancements in the clinical success of implants and implant-supported prostheses. The distribution of tension for the bone/implant system of these new systems is important. The purpose of this work was to evaluate, by photoelastic analysis and strain gauges, the distribution of tension for the bone/implant system, using the Slim system. A photoelastic cast with an external hexagon implant was manufactured and a metal prosthesis was screwed below it, with or without the tested system. For the photoelasticity methodology, a photoelastic cast, with or without the tested system, was positioned in a circular polariscope, and axial loads of 100 N were applied to the centre of the crown. The pattern of tension generated was photographed and analysed qualitatively in an imaging programme. For the extensometry methodology, two extensometers were placed in the mesial and distal region of the implant in the photoelastic cast. The axial loads were applied to the group again, with or without the system (n = 10). The t test of independent samples with a significance level of 5% was used for this analysis. This study demonstrated greater tension values for both the photoelastic and extensometry methods when the tested system was used. Clinical studies must be performed to evaluate the tested system because the results might not be clinically significant to a bone reabsorption. PMID- 28351186 TI - Immunotherapy of elderly acute myeloid leukemia: light at the end of a long tunnel? AB - Although it is possible to induce remission in the majority of the patients with acute myeloid leukemia (AML), many patients still die due to disease relapse. Immunotherapy is an attractive option. It is more specific. The memory T cells induced by immunotherapy may also provide the long-term tumor immunosurveillance to prevent disease relapse. Although immunotherapy of AML started in the early 1970s, its clinical impact has been disappointing. Recent advances in tumor immunology and immunotherapeutic agents have rekindled interest. Here, we provide a review of the history of AML immunotherapy, discuss why AML is well suited for immunotherapeutic approaches and present the biological obstacles that affect the success of immunotherapy. Finally, we put forward a new paradigm of AML immunotherapy that utilizes a combination of immunotherapeutic agents sequentially to enhance the in vivo tumor immunogenicity and effective priming and propagation of tumor-specific cytotoxic T cells. PMID- 28351187 TI - Pneumococcal conjugate vaccine in HIV-infected and HIV-exposed, uninfected children. AB - INTRODUCTION: Incidence of invasive pneumococcal disease (IPD) among HIV-infected children is 20-40 fold greater compared to HIV-uninfected children, including among HIV-infected children on antiretroviral therapy (ART). Also, HIV-exposed, uninfected children have 2.7-fold greater risk of IPD compared to HIV-unexposed children. Areas covered: We reviewed studies identified on Pubmed database with the terms 'PCV' and 'HIV'; studies involving adults only were excluded. Expert commentary: While ART and pneumococcal conjugate vaccines (PCV) have reduced IPD morbidity and mortality in HIV-infected children, ART-naive and immunosuppressed children have inferior immunogenicity to most PCV serotypes; highlighting the need for concomitant use of ART with PCV. Furthermore, studies to determine optimal PCV dosing schedules, timing and number of doses, are urgently required to ensure sustained vaccine efficacy in HIV-infected children. PMID- 28351188 TI - Abortion Facility Closings and Abortion Rates in Texas. AB - From 2004 to 2014, the overall abortion rate in Texas fell by almost a third from 10.7 to 7.2 abortions per 1000 women aged 10 to 49 years. During this same period, the number of abortion clinics operating at least 6 months in the year fell from 40 to 27. We examined the relationship between the abortion rate and the proximity of abortion facilities. We matched annual, county-level data on abortion rates in Texas from 2004 through 2014 with the distance from the county centroids to the nearest abortion facility in operation. Linear regressions were used to estimate the association between abortion rates and proximity to abortion facilities. The regressions controlled for county-level and state-level characteristics as well as the availability of abortion services in neighboring US states and Mexico. We found that a 100-mile increase in distance to the nearest abortion facility was associated with a 10% decrease in the overall abortion rate. The relationship appeared to be driven largely by distances of 200 miles or more. The overall relationship was generally present for whites and blacks, whereas the pattern was less clear for Hispanics. The analysis indicated that the overall association was driven largely by women aged 20 to 34 years. Decreased access to abortion facilities was associated with decreases in the abortion rate, yet the relationship varied by race/ethnicity and age. As such, regulations that affect the operational status of abortion facilities likely have differential effects on women. PMID- 28351189 TI - Effects of an injectable platelet-rich fibrin on osteoblast behavior and bone tissue formation in comparison to platelet-rich plasma. AB - Platelet-rich plasma (PRP) has been utilized for many years as a regenerative agent capable of inducing vascularization of various tissues using blood-derived growth factors. Despite this, drawbacks mostly related to the additional use of anti-coagulants found in PRP have been shown to inhibit the wound healing process. For these reasons, a novel platelet concentrate has recently been developed with no additives by utilizing lower centrifugation speeds. The purpose of this study was therefore to investigate osteoblast behavior of this novel therapy (injectable-platelet-rich fibrin; i-PRF, 100% natural with no additives) when compared to traditional PRP. Human primary osteoblasts were cultured with either i-PRF or PRP and compared to control tissue culture plastic. A live/dead assay, migration assay as well as a cell adhesion/proliferation assay were investigated. Furthermore, osteoblast differentiation was assessed by alkaline phosphatase (ALP), alizarin red and osteocalcin staining, as well as real-time PCR for genes encoding Runx2, ALP, collagen1 and osteocalcin. The results showed that all cells had high survival rates throughout the entire study period irrespective of culture-conditions. While PRP induced a significant 2-fold increase in osteoblast migration, i-PRF demonstrated a 3-fold increase in migration when compared to control tissue-culture plastic and PRP. While no differences were observed for cell attachment, i-PRF induced a significantly higher proliferation rate at three and five days when compared to PRP. Furthermore, i-PRF induced significantly greater ALP staining at 7 days and alizarin red staining at 14 days. A significant increase in mRNA levels of ALP, Runx2 and osteocalcin, as well as immunofluorescent staining of osteocalcin was also observed in the i-PRF group when compared to PRP. In conclusion, the results from the present study favored the use of the naturally-formulated i-PRF when compared to traditional PRP with anti-coagulants. Further investigation into the direct role of fibrin and leukocytes contained within i-PRF are therefore warranted to better elucidate their positive role in i-PRF on tissue wound healing. PMID- 28351190 TI - Hepatosplenic T-cell lymphoma associated with membranoproliferative glomerulonephritis. PMID- 28351191 TI - Acute kidney injury after percutaneous nephrolithotomy for stones in solitary kidneys. AB - OBJECTIVES: The aim of this study was to report the incidence, severity, outcome and risk factors of acute kidney injury (AKI) following percutaneous nephrolithotomy (PNL) in solitary kidneys. METHODS: The study included consecutive adult patients who underwent PNL for treatment of calculi in a solitary kidney between May 2012 and July 2015. Patients with congenital renal anomalies or with stages 4 and 5 chronic kidney disease (CKD) were excluded. Serum creatinine levels were measured the day before PNL, daily after PNL for 2-5 days and after 3 months. AKI was depicted according to changes in early postoperative serum creatinine levels and its severity was determined based on the Acute Kidney Injury Network (AKIN) classification. The outcome of AKI was evaluated after 3 months by changes in the stage of CKD. Univariate and multivariate statistical analyses were conducted to determine risk factors for developing AKI. RESULTS: The study included 100 patients (62 males) with a mean +/- SD age of 50 +/- 11.7 years. Complications were reported for 27 patients. AKI developed in 25 patients; at the 3 month follow-up, 23 of them (92%) had completely recovered from AKI and two (8%) had developed stage 4 CKD. Independent risk factors for developing AKI were multiple PNL tracts and postoperative ureteric obstruction (relative risks were 14 and 22, respectively). CONCLUSIONS: The incidence of AKI was 25% after PNL for a solitary kidney. The likelihood of renal function recovery was 92%. Multiple PNL tracts and postoperative ureteric obstruction were risk factors for developing AKI. PMID- 28351192 TI - Synergistic effect of peptide inhibitors derived from the extracellular and intracellular domain of alphaIIb subunit of integrin alphaIIbbeta3 on platelet activation and aggregation. AB - alphaIIbbeta3, the major platelet integrin, plays a central role in hemostasis and thrombosis. Upon platelet activation, conformation of alphaIIbbeta3 changes and allows fibrinogen binding and, subsequently, platelet aggregation. It was previously shown that a lipid-modified platelet permeable peptide, which corresponds to the intracellular acidic membrane distal sequence 1000LEEDDEEGE1008 of alphaIIb (pal-K-LEEDDEEGE or pal-K-1000-1008), inhibits thrombin-induced human platelet aggregation, by inhibiting talin association with the integrin. YMESRADR, a peptide corresponding to the extracellular sequence 313 320 of alphaIIb, is also a potent platelet aggregation inhibitor by mimicking the effect of a clasp between the head domains of alphaIIb and beta3. The aim of the present study was to investigate the synergistic effect of the intra- and extracellular- peptide inhibitors on platelet aggregation, as well as on the phosphorylation of two signaling proteins, focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK). Platelet preincubation with Pal-K LEEDDEGE followed by YMESRADR showed a synergistic inhibitory activity on platelet aggregation. Platelet incubation with threshold inhibitory concentrations of both peptides provoked almost the total inhibition of aggregation, PAC-1 binding, and fibrinogen binding, but not P-selectin exposure on activated platelets' surface. Like RGDS peptide, this mixture inhibits FAK phosphorylation whose phosphorylation is well known to be consecutive to the aggregation (postoccupancy events). However, in contrast to RGDS peptide that enhances ERK phosphorylation and activation, the mixture of threshold inhibitory concentrations of Pal-K-LEEDDEEGE and YMESRADR inhibits ERK phosphorylation. We suggest that the use of the intracellular in combination with the extracellular peptide inhibitor, acting with a non-RGD-like mechanism, may provide an alternative way to antagonize integrin alphaIIbbeta3 activation. PMID- 28351193 TI - Measurement of serum isoform [-2]proPSA derivatives shows superior accuracy to magnetic resonance imaging in the diagnosis of prostate cancer in patients with a total prostate-specific antigen level of 2-10 ng/ml. AB - OBJECTIVE: More accurate diagnostic procedures for prostate cancer are needed to avoid unnecessary biopsy due to the low specificity of prostate-specific antigen (PSA). Recent studies showed that the percentage of serum isoform [-2]proPSA (p2PSA) to free PSA (%p2PSA), the Prostate Health Index (PHI) and magnetic resonance imaging (MRI) were more accurate than PSA. The aim of this study was to test the accuracy of %p2PSA, PHI and MRI in discriminating patients with and without prostate cancer. MATERIALS AND METHODS: The subjects were 50 consecutive men with a PSA level of 2.0-10.0 ng/ml, who underwent prostate biopsy from October 2012 to July 2014. These patients underwent multiparametric MRI before biopsy, and their serum samples were measured for PSA, free PSA and p2PSA. The sensitivity, specificity and accuracy of PHI, %p2PSA and MRI were compared with PSA in the diagnosis of biopsy-confirmed prostate cancer. RESULTS: In a univariate analysis, %p2PSA [area under the curve (AUC): 0.811] and PHI (AUC 0.795) were more accurate than MRI (AUC: 0.583) and PSA (AUC: 0.554) for prostate cancer detection. At 60% sensitivity, the specificity of PHI (76.5%) was higher than that of MRI (52.9%). For significant cancer detection, %p2PSA (AUC: 0.745), PHI (AUC: 0.791) and MRI (AUC: 0.739) were marginally more accurate than PSA (AUC: 0.696). At 85% sensitivity, the specificity of MRI (62.1%) was higher than that of PHI (34.5%). CONCLUSION: PHI and %p2PSA can be used for screening the general population and MRI can be used for detection of significant cancer in patients suspected, from screening tests, of having prostate cancer. PMID- 28351194 TI - Extraovarian Fibroma With Minor Sex Cord Elements: A Case Report and Literature Review. AB - Extraovarian sex cord-stromal tumor is an exceedingly uncommon entity that may cause a diagnostic dilemma clinically. We report a case of extraovarian fibroma with minor sex cord elements arising in the left broad ligament. The patient was a 66-year-old woman presenting with an intra-abdominal solid mass near the left ovary on magnetic resonance imaging. The tumor was located in the left broad ligament in contact with the left ovary and fallopian tube based on laparotomy findings. Histological examination revealed that the tumor was a fibroma that contained cell nests with aggregates resembling the Call-Exner bodies of granulosa cell tumors and irregularly shaped cell nests composed of undifferentiated sex cord-type cells. Cellular atypia or mitotic figures were not identified in any of the components. It was speculated that the possible site of origin of this tumor might be a supernumerary ovary in the broad ligament that was thought to be derived from embryonic remnants. PMID- 28351195 TI - Utility of Flow Cytometry in Diagnosing Hematologic Malignancy in Tonsillar Tissue. AB - OBJECTIVE: Tonsil surgical biopsy or excision is a very common procedure. However, there exist no consensus guidelines for the pathologic handling of tonsil specimens; gross and/or microscopic evaluation may be used. Diagnosis of tonsillar hematologic malignancy requires histology, immunohistochemistry and/or flow cytometry. Data regarding the utility of flow cytometry in tonsillar tissues are limited. We assessed our experience with flow cytometry for tonsil diagnosis with regard to accuracy and use patterns at a tertiary academic medical center. METHODS: We retrospectively analyzed all surgically biopsied or excised tonsil specimens that underwent flow cytometry evaluation from August 2011 to March 2014. Patient clinical information, intraoperative frozen section, histology, immunohistochemistry, and flow cytometry diagnoses were recorded. RESULTS: The study included 154 tonsil specimens from 89 females and 65 males. Patients averaged 27.4 years old (range 2-87 years); 73 were pediatric. Both histology and flow cytometry were benign for 148 patients (96.1%). Hematolymphoid malignancy was diagnosed in 6 adults by histology/immunohistochemistry: diffuse large B-cell lymphoma (2), small B-cell lymphoma (2), concomitant follicular lymphoma and histiocytic sarcoma (1), and extraosseous plasmacytoma (1). Flow cytometry identified abnormal populations in 5 of 6 cases, and detected clonal populations in 2 reactive follicular hyperplasia cases. CONCLUSION: Tonsillar hematolymphoid malignancy is uncommon, and flow cytometry was less accurate than histology/immunohistochemistry for its diagnosis. Despite the rarity of tonsillar lymphoma in children, nearly half of study patients were pediatric. Intraoperative frozen section diagnosis showed excellent sensitivity for malignancy, and could be used to effectively triage cases for flow cytometry evaluation. PMID- 28351196 TI - Menopausal syndrome limited to hot flushes and sweating a representative survey study. AB - OBJECTIVE: The menopausal syndrome is described as a series of various physical and nonphysical symptoms attributed to perimenopausal changes in hormone levels. However, evidence is biased by focusing research on the target group of middle aged women only. To overcome this bias, we examined the occurrence of menopausal symptoms during the entire life span in both women and men. METHODS: Therefore, we studied the occurrence of menopausal symptoms with the widely used Menopause Rating Scale (MRS) across the entire life span in both women and men. To this end, we performed a nationwide cross-sectional survey study in Germany in which we examined a representative sample of 2527 persons aged from 14 to 95 years. Additionally, sociodemographic factors and self-efficacy were surveyed. RESULTS: Although the overall MRS score was generally higher for women compared to men, there was no specific peak for the time of menopause. Instead the score increased linearly with age for both sexes. Furthermore, it was stronger associated with sociodemographic variables and self-efficacy than with the sex of the participants. Among all assessed symptoms, only hot flushes and sweating, but none of the others, emerged as specific for the menopausal episode. CONCLUSIONS: Our data indicate that among symptoms commonly classified as menopausal only hot flushes and sweating appear to be specific for the perimenopausal episode. Other symptoms may be caused by a multifactorial etiopathogenesis including physical, sociodemographic, cultural and psychological factors that, in turn, might benefit from multimodal treatment regimes. PMID- 28351197 TI - The Human Central Pattern Generator for Locomotion: Does It Exist and Contribute to Walking? AB - The ability of dedicated spinal circuits, referred to as central pattern generators (CPGs), to produce the basic rhythm and neural activation patterns underlying locomotion can be demonstrated under specific experimental conditions in reduced animal preparations. The existence of CPGs in humans is a matter of debate. Equally elusive is the contribution of CPGs to normal bipedal locomotion. To address these points, we focus on human studies that utilized spinal cord stimulation or pharmacological neuromodulation to generate rhythmic activity in individuals with spinal cord injury, and on neuromechanical modeling of human locomotion. In the absence of volitional motor control and step-specific sensory feedback, the human lumbar spinal cord can produce rhythmic muscle activation patterns that closely resemble CPG-induced neural activity of the isolated animal spinal cord. In this sense, CPGs in humans can be defined by the activity they produce. During normal locomotion, CPGs could contribute to the activation patterns during specific phases of the step cycle and simplify supraspinal control of step cycle frequency as a feedforward component to achieve a targeted speed. Determining how the human CPGs operate will be essential to advance the theory of neural control of locomotion and develop new locomotor neurorehabilitation paradigms. PMID- 28351198 TI - Outcomes of a community-based treatment programme for people with acquired brain injury in the chronic phase: a pilot study. AB - The objective of the study was to evaluate the outcomes of Brainz, a low intensity community-based treatment programme for people with acquired brain injury (ABI). Participants were 62 people with sustained ABI (5.2 years post injury, SD = 4.5) and 35 family caregivers. Participants attended two to five cognitive and physical group modules and received two hours of individual home treatment every two weeks. Primary outcomes for people with ABI were participation, perceived difficulties in daily life and need of care, level of goal attainment, and self-esteem. Primary family caregiver outcome was perceived burden of care. Attrition rate of people with ABI was 24% (n = 15), and of family caregivers was 31% (n = 11). People with ABI were more satisfied with the level of their participation after completing Brainz (p < .01), but showed no change in participation frequency or in restrictions (both ps > .01). They perceived fewer difficulties in daily life and less need of care (both ps < .01). Also, in two cognitive modules people improved on their goal achievement (p < .01). However, their self-esteem was reduced (p < .01). Caregiver burden was reduced (p < .01). This study has provided preliminary evidence of the effectiveness of a combined group-based clinical and individual home-based treatment programme, but more research is needed, preferably in larger controlled studies. PMID- 28351199 TI - Pharmacological Management of Psychiatric Symptoms in Frontotemporal Dementia: A Systematic Review. AB - Psychiatric symptoms in patients with frontotemporal dementia (FTD) are highly prevalent and may complicate clinical management of these patients. Purpose of the present article is to present and discuss available data about the pharmacological treatment of psychiatric symptoms in patients with FTD. A research in the main database sources has been conducted to obtain an overview of the pharmacological management of psychiatric symptoms in patients with FTD. The search strategy included the following terms-"FTD and psychiatry," "FTD and behavioural disturbances," and "FTD and treatment". Pathophysiology of psychiatric symptoms in FTD is different from other types of dementia. Although drugs for Alzheimer disease appear to be ineffective for the treatment of psychiatric symptoms of FTD, preliminary evidence supports a possible usefulness of serotonergic antidepressants for these patients. Data are too scanty to draw definitive conclusions, but antidepressant treatment, particularly with serotonergic compounds, may improve psychiatric symptoms in patients with FTD. Large observational studies are needed to confirm this preliminary evidence, and a lot of effort and collaboration between neurologists and psychiatrists will be definitely crucial for future research of effective treatments for FTD. PMID- 28351200 TI - Diagnostic Accuracy and Confidence in the Clinical Detection of Cognitive Impairment in Early-Stage Parkinson Disease. AB - BACKGROUND/AIMS: Mild cognitive impairment (MCI) is present in up to 34% of patients with early-stage Parkinson disease (PD); however, it is difficult to detect subtle impairment without objective cognitive testing. METHODS: Data were obtained from the Parkinson Progression Marker Initiative. All 341 participants were administered the Montreal Cognitive Assessment (MoCA) and a brief neuropsychological battery. Participants were classified as PD-MCI if MoCA was <26 or if they scored >=1 standard deviation below the normative mean in 2 or more domains, based upon established criteria. The sensitivity/specificity for the clinical detection of PD-MCI was determined. RESULTS: Overall accuracy for clinical detection of PD-MCI was 67.4%. Although clinical determination was highly specific (96.3%; 95% confidence interval [CI]: 0.92-0.98), sensitivity was poor (32.0%; 95% CI: 0.25-0.40). CONCLUSION: Identifying MCI in early-stage PD based on clinical interview alone appears to be insufficient. The inclusion of objective cognitive tests allowing for normative sample comparisons is needed to increase the detection of cognitive impairment in this population. PMID- 28351201 TI - Does a single session of electroconvulsive therapy alter the neural response to emotional faces in depression? A randomised sham-controlled functional magnetic resonance imaging study. AB - Negative neurocognitive bias is a core feature of major depressive disorder that is reversed by pharmacological and psychological treatments. This double-blind functional magnetic resonance imaging study investigated for the first time whether electroconvulsive therapy modulates negative neurocognitive bias in major depressive disorder. Patients with major depressive disorder were randomised to one active ( n=15) or sham electroconvulsive therapy ( n=12). The following day they underwent whole-brain functional magnetic resonance imaging at 3T while viewing emotional faces and performed facial expression recognition and dot-probe tasks. A single electroconvulsive therapy session had no effect on amygdala response to emotional faces. Whole-brain analysis revealed no effects of electroconvulsive therapy versus sham therapy after family-wise error correction at the cluster level, using a cluster-forming threshold of Z>3.1 ( p<0.001) to secure family-wise error <5%. Groups showed no differences in behavioural measures, mood and medication. Exploratory cluster-corrected whole-brain analysis ( Z>2.3; p<0.01) revealed electroconvulsive therapy-induced changes in parahippocampal and superior frontal responses to fearful versus happy faces as well as in fear-specific functional connectivity between amygdala and occipito temporal regions. Across all patients, greater fear-specific amygdala - occipital coupling correlated with lower fear vigilance. Despite no statistically significant shift in neural response to faces after a single electroconvulsive therapy session, the observed trend changes after a single electroconvulsive therapy session point to an early shift in emotional processing that may contribute to antidepressant effects of electroconvulsive therapy. PMID- 28351202 TI - History of childhood maltreatment and symptoms of anxiety and depression in women with chronic pelvic pain. AB - OBJECTIVE: To determine the prevalence of physical, sexual and emotional abuse and physical and emotional neglect suffered by women with chronic pelvic pain (CPP) during childhood and whether these occurrences are associated with symptoms of pain, anxiety and depression. METHODS: A case-control study was conducted on 154 women older than 18 years, 77 of them healthy and 77 with CPP. A history of sexual, physical, and emotional abuse and physical and emotional neglect was determined using the Childhood Trauma Questionnaire (CTQ). Anxiety and depression symptoms were determined using the Hospital Anxiety and Depression (HAD) scale. Pain intensity was determined using a visual analog scale (VAS). The quantitative variables were compared by the Wilcoxon test, and the qualitative variables were compared by the Chi-square test or exact Fisher test when appropriate. Correlation between the CTQ, HAD and VAS scores was estimated by the Spearman's p coefficient. Independent association of the variables with the presence of CPP was determined by logistic multiple regression analysis. RESULTS: The prevalence of childhood maltreatment was 77.9% and 64.9%, respectively, for women with CPP and healthy women (p = 0.07). Emotional neglect was more frequent among women with CPP than among healthy women (58.4% versus 41.5%, p = 0.04). There was a moderate correlation between anxiety and depression symptoms and CTQ scores for women with CPP. Unemployment (OR = 4.15, 95% CI 1.73-9.94; ORadj = 3.30, 95% CI 1.26-8.55) was independently associated with the presence of CPP. CONCLUSIONS: Women with CPP reported emotional neglect abuse more frequently than healthy women. There was a direct correlation between maltreatment scores and anxiety and depression scores. On the other hand, CPP was independently associated only with unemployment. PMID- 28351203 TI - Effects of varenicline on alcohol self-administration and craving in drinkers with depressive symptoms. AB - Varenicline (VAR) is approved to aid in smoking cessation and has been shown to be effective for reducing alcohol consumption in heavy drinkers. Little is known, however, about treatment moderators that may influence efficacy. The current study reanalyzed data from a human laboratory study (Verplaetse et al., 2016) to determine whether VAR was more effective at reducing alcohol use among drinkers reporting symptoms of depression. Participants were 60 adults meeting DSM-IV criteria for alcohol use disorders ( n = 60) who were randomly assigned to receive VAR (1 mg/day, 2 mg/day) or placebo. Following 7 days of medication pretreatment, participants attended a laboratory testing session. They provided self-reported ratings of alcohol craving and performed an ad libitum alcohol consumption task after receiving a priming dose of alcohol (target blood alcohol concentration = 0.030 g/dL). Higher blood VAR plasma levels were associated with less alcohol craving and less drinking among participants with more depressive symptoms. Among participants with fewer depressive symptoms, VAR was associated with more drinking during the ad libitum drinking task. These findings show that depression symptoms may be a moderator of VAR efficacy in alcohol users and provides evidence for the role of nAChRs in depression and alcohol use. PMID- 28351204 TI - Results From the VISIBILITY Iliac Study: Primary and Cohort Outcomes at 9 Months. AB - PURPOSE: To evaluate the safety and effectiveness of primary stenting of the common (CIA) or external iliac artery (EIA) using the Visi-Pro Balloon-Expandable Peripheral Stent System for treatment of stenotic, restenotic, or occluded lesions. METHODS: Between 2011 and 2012, 75 patients (mean age 64.2+/-8.9 years; 46 men) with Rutherford category 2-4 ischemia and atherosclerotic lesions <=10 cm in length underwent iliac artery stenting at 17 centers in the United States and Europe. The primary outcome of the study was the major adverse event (MAE) rate at 9 months postprocedure [composite of periprocedural death, in-hospital myocardial infarction, clinically driven target lesion revascularization (CD TLR), and amputation of the treated limb]. Secondary outcomes included 30-day MAE rate, 9-month primary patency, changes in ankle-brachial index (ABI) and the Walking Impairment Questionnaire at 30 days and 9 months postprocedure, device success, and clinically driven target vessel revascularization (CD-TVR) at 30 days and 9 months. Outcomes in specific patient cohorts (ie, gender, stent location, calcification severity, and lesion grade) were analyzed. RESULTS: Eighty-one stents were implanted in 61 CIA and 15 EIA lesions (41 with moderate/severe calcification). The mean lesion treated length was 29.3+/-13.9 mm. All devices were successfully deployed. MAE occurred in 3 (4.0%) of 75 subjects at 9 months. Primary patency and freedom from CD-TVR at 9 months were both 95.8%. ABI improved from 0.67+/-0.14 at baseline to 0.94+/-0.14 and 0.96+/ 0.16 at 30 days and 9-month follow-up, respectively (p<0.001 for both). There were no differences with respect to any of the analyzed patient characteristics, including gender. CONCLUSION: Nine-month results of the VISIBILITY Iliac stent study ( ClinicalTrials.gov identifier NCT01402700) demonstrated safety and effectiveness for the treatment of atherosclerotic CIA and EIA lesions with the Visi-Pro stent across all treated cohorts. PMID- 28351205 TI - Arthroscopic Versus Open Latarjet in the Treatment of Recurrent Anterior Shoulder Dislocation With Marked Glenoid Bone Loss: A Prospective Comparative Study. AB - BACKGROUND: Very few studies have compared open Latarjet versus arthroscopic Latarjet procedures. PURPOSE: To compare the clinical and computed tomographic outcomes between open and arthroscopic Latarjet procedures. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A prospective, comparative study was performed. The open Latarjet group included 44 patients, and the arthroscopic Latarjet group included 46 patients. All patients had more than 2 years of clinical follow-up (range of motion, American Shoulder and Elbow Surgeons [ASES] score, Constant-Murley score, and Rowe score). The position of the transferred coracoid, the screw orientation, and graft resorption were evaluated on computed tomography (CT) scan. RESULTS: The surgery time for the open group was significantly shorter than that for the arthroscopic group ( P = .003). No recurrent dislocation occurred in either group. The apprehension test was negative in all patients in both groups. At the final follow-up, no significant difference was detected between the open group and the arthroscopic group regarding any of the clinical outcome measurements. The transferred coracoid graft was level with the glenoid in all patients in both groups. The open group had better position in the superior-inferior direction compared with the arthroscopic group ( P < .001). No significant difference was found in screw orientation between the 2 groups ( P = .102). At 1 year after surgery, patients in the arthroscopic group had significantly less resorption compared with patients in the open group ( P = .044). CONCLUSION: Both procedures are effective for the treatment of recurrent anterior shoulder dislocation with marked glenoid bone loss. The open group had better position in the superior-inferior direction compared with the arthroscopic group. At 1 year after surgery, patients in the arthroscopic Latarjet group showed notably less graft resorption compared with patients in the open Latarjet group. PMID- 28351206 TI - Intravesical instillations and cancer-specific survival in patients with primary carcinoma in situ of the urinary bladder. AB - OBJECTIVE: The aim of this study was to evaluate the use of intravesical treatment and cancer-specific survival of patients with primary carcinoma in situ (CIS). MATERIALS AND METHODS: Data acquisition was based on the Swedish National Registry of Urinary Bladder Cancer by selecting all patients with primary CIS. The analysis covered gender, age, hospital type and hospital volume. Intravesical treatment and death due to bladder cancer were evaluated by multivariate logistic regression and multivariate Cox analysis, respectively. RESULTS: The study included 1041 patients (median age at diagnosis 72 years) with a median follow-up of 65 months. Intravesical instillation therapy was given to 745 patients (72%), and 138 (13%) died from bladder cancer during the observation period. Male gender [odds ratio (OR) = 1.56, 95% confidence interval (CI) 1.13-2.17] and treatment at county (OR = 1.65, 95% CI 1.17-2.33), university (OR =2.12, 95% CI 1.48-3.03) or high-volume (OR = 1.92, 95% CI 1.34-2.75) hospitals were significantly associated with higher odds of intravesical instillations. The age category >=80 years had a significantly lower chance of receiving intravesical therapy (OR = 0.44, 95% CI 0.26-0.74) and a significantly higher risk of dying from bladder cancer (hazard ratio = 3.03, 95% CI 1.71-5.35). CONCLUSION: Significantly more frequent use of intravesical treatment of primary CIS was found for males and for patients treated at county, university and high-volume hospitals. Age >=80 years was significantly related to less intravesical treatment and poorer cancer-specific survival. PMID- 28351207 TI - The effect of cognitive impairment on prosthesis use in older adults who underwent amputation due to vascular-related etiology: A systematic review of the literature. AB - BACKGROUND: Older adults with amputations secondary to vascular etiologies may additionally present with cognitive impairment. Cognition plays an important role in the adoption of a prosthetic limb, although the degree and type of impact are debated. Previous literature reviews have not been directed at the specific population of older adults who underwent vascular-related lower limb amputation. OBJECTIVES: First, to assess extant literature for relationships between cognitive function and prosthesis-related outcomes in older adults who underwent lower limb amputation for vascular-related etiologies. Second, to perform a critical analysis of prosthesis-related outcomes and cognitive assessments performed in the studies. STUDY DESIGN: Systematic literature review. METHODS: A systematic review of the literature was performed in databases using keyword combinations. A total of nine articles were selected to be included in this review. RESULTS: Seven of the nine included studies found a relationship between decreased cognitive function and reduced performance on a prosthesis-related outcome. There were eight different prosthesis-related outcome measures, with only one study utilizing a comprehensive outcome measure. CONCLUSION: Cognitive impairment can negatively impact successful prosthesis use in older adults with lower limb amputation secondary to vascular complications. Future studies should utilize comprehensive outcome measures that represent the multifaceted constructs of cognition and prosthesis use. Clinical relevance Cognitive assessment of older adults who have undergone lower limb amputation secondary to diabetes related complications or vascular disease can be used to inform clinical decision-making. Clinicians should consider selecting prosthesis-related outcome measures that capture the full breadth of prosthesis use when evaluating patients with cognitive impairment. PMID- 28351208 TI - Angiographic Dissection Patterns and Patency Outcomes After Balloon Angioplasty for Superficial Femoral Artery Disease. AB - PURPOSE: To investigate the angiographic dissection patterns after balloon angioplasty for superficial femoral artery (SFA) lesions, the clinical outcome associated with each dissection pattern, and the predictive factors for severe dissection. METHODS: A retrospective, multicenter analysis examined 621 patients (mean age 72.8+/-9.5 years; 414 men) with 748 symptomatic de novo SFA lesions treated with endovascular therapy. Vessel dissection after the initial balloon angioplasty procedure was graded into 7 types according to a modified version of the coronary artery classification types A to F. Severe vessel dissection patterns were defined as type C or higher. Nitinol stent implantation was performed in 555 (74.2%) lesions for residual stenosis >30% or flow-limiting dissection; 193 lesions (25.8%) were treated with balloon angioplasty only. To determine the clinical outcomes associated with each dissection pattern and identify predictive factors for severe dissection, 2-year follow-up data for the 193 lesions treated with balloon angioplasty only were analyzed for primary patency and clinically driven target lesion revascularization (TLR). RESULTS: No dissection was found in 16% (120/748) of lesions, and types A and B dissections were seen in 19% (142/748) and 23% (172/748), respectively. Dissection grades above type C were observed in 42% of cases, most frequently type D (180/748, 24%) and less often type C (37/748, 5%), type E (67/748, 9%), and type F (30/748, 4%). The bailout stent implantation rate increased according to dissection severity. At up to 2 years, the severe dissection group (types C-F) showed a significantly lower patency rate (p<0.001) and higher clinically driven TLR (p<0.001) compared to the nonsevere group (no dissection and types A and B dissections). Severe dissection was a significant risk factor for restenosis, which rose progressively from types C to F. Multivariate analysis identified a small reference vessel diameter <5 mm (p=0.001), lesion length >15 cm (p=0.001), and chronic total occlusion (p<0.001) as independent predictors of severe dissection. In subgroup analysis, vessels with a small reference diameter and TASC II C and D lesions had a higher prevalence of severe dissection. CONCLUSION: Severe dissection was found in 42% of cases after PTA. A small vessel diameter and/or TASC II C/D lesions were related to a high incidence of dissection. Severe dissection during procedures employing balloon angioplasty only could affect long-term patency. PMID- 28351210 TI - Expression of Pluripotency Markers in Nonpluripotent Human Neural Stem and Progenitor Cells. AB - Nonpluripotent neural progenitor cells (NPCs) derived from the human fetal central nervous system were found to express a number of messenger RNA (mRNA) species associated with pluripotency, such as NANOG, REX1, and OCT4. The expression was restricted to small subpopulations of NPCs. In contrast to pluripotent stem cells, there was no coexpression of the pluripotency-associated genes studied. Although the expression of these genes rapidly declined during the in vitro differentiation of NPCs, we found no evidence that the discrete expression was associated with the markers of multipotent neural stem cells (CD133+/CD24lo), the capacity of sphere formation, or high cell proliferation rates. The rate of cell death among NPCs expressing pluripotency-associated genes was also similar to that of other NPCs. Live cell imaging showed that NANOG- and REX1-expressing NPCs continuously changed morphology, as did the nonexpressing cells. Depletion experiments showed that after the complete removal of the subpopulations of NANOG- and REX1-expressing NPCs, the expression of these genes appeared in other NPCs within a few days. The percentage of NANOG- and REX1 expressing cells returned to that observed before depletion. Our results are best explained by a model in which there is stochastic transient expression of pluripotency-associated genes in proliferating NPCs. PMID- 28351209 TI - Effects of Multiple Injection of Bone Marrow Mononuclear Cells on Spinal Cord Injury of Rats. AB - The effects of multiple injection of bone marrow mononuclear cells (BMNCs) on spinal cord injury (SCI) were compared with those of single injection in rats. BMNCs separated by density-gradient centrifugation from a bone marrow perfusate were injected three times (once weekly) through the cerebrospinal fluid (CSF) via the fourth ventricle, and the locomotor improvement and tissue recovery, including axonal regeneration, were compared with those of single injection. While the single-injection group showed a steep elevation of the Basso-Beattie Bresnahan (BBB) score 1 week after transplantation, the multiple-injection group maintained a similar steep elevation for 2 weeks after transplantation, and the BBB scores of the multiple-injection group remained thereafter at a level approximately 2-3 points higher than those of the single-injection group until the end of the experiment. There were significant differences between the single- and multiple-injection groups at 3, 4, and 8 weeks after transplantation. The difference in BBB scores at 8 weeks after transplantation suggested that there was a marked difference in the quality of locomotor behaviors between the single and multiple-injection groups at this stage. An extensive outgrowth of regenerating axons through the astrocyte-devoid areas and a marked reduction of cavity formation were found in both the single- and multiple-injection groups. There were, however, no significant differences in the density of regenerating axons or volumes of cavities between the single- and multiple-injection groups. These results showed that although tissue recoveries were similar between single and multiple injection, the multiple injection of BMNCs was more beneficial for locomotor improvement than single injection for the treatment of SCI. Considering the technically simple and low-cost procedures for the preparation and injection of BMNCs, multiple injection of BMNCs by lumbar puncture has an advantage over single injection on clinical application. PMID- 28351211 TI - Salivary lactoferrin is transferred into the brain via the sublingual route. AB - Lactoferrin (LF) is produced by exocrine glands including salivary gland, and has various functions including infection defense. However, the transfer of LF from peripheral organs into the brain remains unclear. To clarify the kinetics of salivary LF (sLF), we investigated the consequences of sialoadenectomy and bovine LF (bLF) sublingual administration in rats. The salivary glands were removed from male Wistar rats, and we measured rat LF levels in the blood and brain at 1 week post-surgery. We also examined the transfer of LF into the organs of the rats after sublingual administration of bLF. Rat LF levels in the blood and brain were significantly reduced by sialoadenectomy. Sublingual bLF administration significantly increased bLF levels in the brain, which then decreased over time. These results indicate that LF is transferred from the sublingual mucosa to the brain, in which favorable effects of sLF on brain will be expected via the sublingual mucosa. PMID- 28351212 TI - Release from output interference in recognition memory: A test of the attention hypothesis. AB - Retrieval results in both costs and benefits to episodic memory. Output interference (OI) refers to the finding that episodic memory accuracy decreases with increasing test trials. Release from OI is the restoration of original accuracy at some point during the test. For example, a release from OI in recognition memory testing occurs when the semantic similarity between stimuli decreases midway through testing, suggesting that item representations stored on early trials cause interference on tests occurring on later trials to the extent that the earlier items share features with the latter items. In two recognition memory experiments, we demonstrate release from OI for words and faces. We also test whether release from OI is the result of interference or is due to a boost in attention caused by reorienting to a novel stimulus type. A test for the foils presented during the initial test list supports the interference account of OI. Implications for models of memory are discussed. PMID- 28351213 TI - Perils and positives of science journalism in Australia. AB - Scientists, science communicators and science journalists interact to deliver science news to the public. Yet the value of interactions between the groups in delivering high-quality science stories is poorly understood within Australia. A recent study in New Zealand on the perspectives of the three groups on the challenges facing science journalism is replicated here in the context of New South Wales and the Australian Capital Territory. While all three groups perceived the quality of science journalism as generally high, the limitations of non-specialists and public relation materials were causes for concern. The results indicate that science communicators are considered to play a valuable role as facilitators of information flow to journalists and support for scientists. Future studies on the influence and implications of interactions between these three groups are required. PMID- 28351214 TI - Extremely low-frequency electromagnetic field promotes astrocytic differentiation of human bone marrow mesenchymal stem cells by modulating SIRT1 expression. AB - It has been shown that extremely low-frequency electromagnetic fields (ELFMF) affect regulation of cell fate and differentiation. Thus, the aim of this study was to investigate the role of ELFMFs in the enhancement of astrocytic differentiation. ELFMF exposure reduced the rate of proliferation and enhanced astrocytic differentiation. The ELFMF-treated cells showed increased levels of the astrocyte marker (GFAP), while those of the early neuronal marker (Nestin) and stemness marker (OCT3/4) were downregulated. The reactive oxygen species (ROS) level was observed to be significantly elevated after ELFMF exposure, which strengthens the modulatory role of SIRT1 and SIRT1 downstream molecules (TLE1, HES1, and MASH1) during astrocytic differentiation. After nicotinamide (5 mM) mediated inhibition of SIRT1, levels of TLE1, HES1, and MASH1 were examined; TLE1 was significantly upregulated and MASH1 was downregulated. These results suggest that ELFMFs induce astrocytic differentiation through activation of SIRT1 and SIRT1 downstream molecules. PMID- 28351215 TI - Quantitative analysis of the heterogeneous population of endocytic vesicles. AB - The quantitative characterization of endocytic vesicles in images acquired with microscope is critically important for deciphering of endocytosis mechanisms. Image segmentation is the most important step of quantitative image analysis. In spite of availability of many segmentation methods, the accurate segmentation is challenging when the images are heterogeneous with respect to object shapes and signal intensities what is typical for images of endocytic vesicles. We present a Morphological reconstruction and Contrast mapping segmentation method (MrComas) for the segmentation of the endocytic vesicle population that copes with the heterogeneity in their shape and intensity. The method uses morphological opening and closing by reconstruction in the vicinity of local minima and maxima respectively thus creating the strong contrast between their basins of attraction. As a consequence, the intensity is flattened within the objects and their edges are enhanced. The method accurately recovered quantitative characteristics of synthetic images that preserve characteristic features of the endocytic vesicle population. In benchmarks and quantitative comparisons with two other popular segmentation methods, namely manual thresholding and Squash plugin, MrComas shows the best segmentation results on real biological images of EGFR (Epidermal Growth Factor Receptor) endocytosis. As a proof of feasibility, the method was applied to quantify the dynamical behavior of Early Endosomal Autoantigen 1 (EEA1)-positive endosome subpopulations during EGF-stimulated endocytosis. PMID- 28351216 TI - Self-Reported Usage, Functional Benefit, and Audiologic Characteristics of Cochlear Implant Patients Who Use a Contralateral Hearing Aid. AB - Ninety-four unilateral CI patients with bimodal listening experience (CI plus HA in contralateral ear) completed a questionnaire that focused on attitudes toward hearing aid use postimplantation, patterns of usage, and perceived bimodal benefits in daily life. Eighty participants continued HA use and 14 discontinued HA use at the time of the questionnaire. Participant responses provided useful information for counseling patients both before and after implantation. The majority of continuing bimodal (CI plus HA) participants reported adapting to using both devices within 3 months and also reported that they heard better bimodally in quiet, noisy, and reverberant conditions. They also perceived benefits including improved sound quality, better music enjoyment, and sometimes a perceived sense of acoustic balance. Those who discontinued HA use found either that using the HA did not provide additional benefit over the CI alone or that using the HA degraded the signal from the CI. Because there was considerable overlap in the audiograms and in speech recognition performance in the unimplanted ear between the two groups, we recommend that unilateral CI recipients are counseled to continue to use the HA in the contralateral ear postimplantation in order to determine whether or not they receive functional or perceived benefit from using both devices together. PMID- 28351218 TI - Association Among Serum Insulin-Like Growth Factor-1, Frailty, Muscle Mass, Bone Mineral Density, and Physical Performance Among Community-Dwelling Middle-Aged and Older Adults in Taiwan. AB - Aging is featured by the complex interrelationship among body composition, frailty status, and physical performance. The main aim of this study was to evaluate the association among serum insulin-like growth factor-1 (IGF-1), body composition, and physical function among community-dwelling middle-aged and elderly population in Taiwan. We conducted a cross-sectional study by using the data of I-Lan Longitudinal Aging Study, which recruited a total of 1833 community dwelling people aged more than 50 years. Data of lean body mass (LBM), appendicular skeletal muscle mass (ASM), total fat mass (TFM), bone mineral density (BMD) of L-spine/hip, handgrip strength, walking speed, International Physical Activity Questionnaire (IPAQ), Charlson comorbidity index (CCI), serum levels of growth hormone, IGF-1, albumin, total cholesterol, triglyceride, blood urea nitrogen, and creatinine were retrieved for analysis. The mean age of participants was 63.9 +/- 9.2 years, and 47.5% were men. The serum IGF-1 level was 140.7 +/- 57.6 ng/mL in men and 131.4 +/- 54.5 ng/mL in women. The estimated rates of IGF-1 decline with age were 1.88 ng/mL.year in men and 2.13 ng/mL.year in women. The prevalence of frailty was 6.8% and that of prefrailty was 40.4%. After adjusting for age, albumin, IPAQ, and CCI in multiple linear regression models, LogIGF-1 was positively correlated with LBM, ASM, ASM index, height, BMD, and handgrip strength, and was inversely correlated with weakness in both genders. In men, the LogIGF-1 level was positively correlated with weight, body mass index (BMI), waist circumference, and TFM. Higher serum IGF-1 was independently associated with more muscle mass, higher BMD, and better handgrip performance in both genders. The positive association of IGF-1 with BMI, weight, TFM, and waist circumference was found in men only. Further longitudinal study to evaluate the effect of serum IGF-1 on frailty incidence is needed for its causal effect relationship. PMID- 28351217 TI - * Design of an In Vitro Model of Cell Recruitment for Skeletal Muscle Regeneration Using Hepatocyte Growth Factor-Loaded Fibrin Microthreads. AB - Large skeletal muscle defects that result in volumetric muscle loss (VML) result in the destruction of the basal lamina, which removes key signaling molecules such as hepatocyte growth factor (HGF) from the wound site, eliminating the endogenous capacity of these injuries to regenerate. We recently showed that HGF loaded fibrin microthreads increased the force production in muscle tissues after 60 days in a mouse VML model. In this study, we created an in vitro, three dimensional (3D) microscale outgrowth assay system designed to mimic cell recruitment in vivo, and investigated the effect of HGF-loaded, cross-linked fibrin microthreads on myoblast recruitment to predict the results observed in vivo. This outgrowth assay discretely separated the cellular and molecular functions (migration, proliferation, and chemotaxis) that direct outgrowth from the wound margin, creating a powerful platform to model cell recruitment in axially aligned tissues, such as skeletal muscle. The degree of cross-linking was controlled by pH and microthreads cross-linked using physiologically neutral pH (EDCn) facilitated the release of active HGF; increasing the two-dimensional migration and 3D outgrowth of myoblasts twofold. While HGF adsorbed to uncross linked microthreads, it did not enhance myoblast migration, possibly due to the low concentrations that were adsorbed. Regardless of the amount of HGF adsorbed on the microthreads, myoblast proliferation increased significantly on stiffer, cross-linked microthreads. Together, the results of these studies show that HGF loaded onto EDCn microthreads supported enhanced myoblast migration and recruitment and suggest that our novel outgrowth assay system is a robust in vitro screening tool that predicts the performance of fibrin microthreads in vivo. PMID- 28351219 TI - A global burden of gastric cancer: the major impact of China. AB - INTRODUCTION: Gastric cancer (GC) is a highly aggressive cancer and a major cause of cancer-related deaths worldwide. Approximately half of the world's GC cases and deaths occur in china. GC presents challenges in early diagnosis and effective therapy due to a lack of understanding of the underlying molecular biology. The primary goals of this review are to outline current GC research in china and describe future trends in this field. Areas covered: This review mainly focuses on a series of GC-related advances China has achieved. Considerable progress has been made in understanding the role of H. pylori in GC by a series of population-based studies in well-established high-risk areas; A few germline and somatic alterations have been identified by 'omics' studies; Studies on the mechanisms of malignant phenotypes have helped us to form an in-depth understanding of GC and advance drug discovery. Moreover, identification of potential biomarkers and targeted therapies have facilitated the diagnosis and treatment of GC. However, many challenges remain. Expert commentary: To combat GC, sufficient funding is important. More attention should be paid on early diagnosis and the discovery of novel efficient biomarkers and the development of biomarker-based or targeted therapeutics in GC. PMID- 28351220 TI - Heterogeneous Prognoses for pT3 Papillary Thyroid Carcinomas and Impact of Delayed Risk Stratification. AB - BACKGROUND: Papillary thyroid carcinomas (PTC) in the pT3 category constitute a heterogeneous group of tumors with a variable risk of recurrence. The objectives of this study were (i) to estimate disease-free survival (DFS) and identify prognostic factors associated with recurrence in a cohort of pT3 PTC, and (ii) to evaluate the concept of delayed risk stratification in a cohort of pT3 tumors. METHODS: A total of 560 patients with pT3 PTC, treated and followed at the authors' institution, were studied. They were divided into three groups: group 1, pT3 <=10 mm; group 2, pT3 >10 mm with extrathyroidal invasion (ETI); and group 3, pT3 due to a tumor size >4 cm. DFS was estimated using the Kaplan-Meier method, and associated prognostic features were studied in univariate and multivariate Cox model-based analyses in each group. Then, DFS was studied for each group according to the six- to eight-month status (remission or not). RESULTS: DFS at 10 years was 75% for the entire cohort and was 89%, 67%, and 82% in groups 1, 2, and 3, respectively (p < 0.0001). Multivariate analysis identified three factors significantly associated with reduced DFS: lymph node (LN) involvement, male sex, and group 2 (>1 cm with ETI). A trend toward a worse prognosis in patients with pT3 N0/Nx PTC >10 mm with ETI was found in comparison with the other pT3 N0/Nx patients. When the six- to eight-month checkup was normal, the DFS at 10 years increased to 98%, 96%, and 91% in groups 1-3, respectively. Furthermore, in this case, initial LN involvement no longer seemed to affect the prognosis in those groups. CONCLUSION: PTC <=10 mm with ETI and large tumors >4 cm without ETI both have a low-recurrence risk when there are no adverse associated prognostic features such as LN involvement. LN involvement, especially in the lateral compartment (N1b), is a strong prognostic factor of recurrence in pT3 PTC. Delayed risk stratification can be applied in pT3 PTC patients. Those cured at the first checkup, including those with limited LN involvement, have excellent outcomes, which should prompt clinicians to adapt subsequent management accordingly. PMID- 28351221 TI - * Understanding the Spatiotemporal Degradation Behavior of Aggrecanase-Sensitive Poly(ethylene glycol) Hydrogels for Use in Cartilage Tissue Engineering. AB - Enzyme-sensitive hydrogels are promising cell delivery vehicles for cartilage tissue engineering. However, a better understanding of their spatiotemporal degradation behavior and its impact on tissue growth is needed. The goal of this study was to combine experimental and computational approaches to provide new insights into spatiotemporal changes in hydrogel crosslink density and extracellular matrix (ECM) growth and how these changes influence the evolving macroscopic properties as a function of time. Hydrogels were designed from aggrecanase-sensitive peptide crosslinks using a simple and robust thiol norbornene photoclick reaction. To study the influence of variations in cellular activity of different donors, chondrocytes were isolated from either juvenile or adult bovine donors. Initial studies were performed to validate and calibrate the model against experiments. Through this process, two key features were identified. These included spatial variations in the hydrogel crosslink density in the immediate vicinity of the cell and the presence of cell clustering within the construct. When these spatial heterogeneities were incorporated into the computational model along with model inputs of initial hydrogel properties and cellular activity (i.e., enzyme and ECM production rates), the model was able to capture the spatial and temporal evolution of ECM growth that was observed experimentally for both donors. In this study, the juvenile chondrocytes produced an interconnected matrix within the cell clusters leading to overall improved ECM growth, while the adult chondrocytes resulted in poor ECM growth. Overall, the computational model was able to capture the spatiotemporal ECM growth of two different donors and provided new insights into the importance of spatial heterogeneities in facilitating ECM growth. Our long-term goal is to use this model to predict optimal hydrogel designs for a wide range of donors and improve cartilage tissue engineering. PMID- 28351222 TI - Bone Regenerative Medicine in Oral and Maxillofacial Region Using a Three Dimensional Printer. AB - Bone grafts currently used for the treatment of large bone defect or asymmetry in oral and maxillofacial region include autologous, allogeneic, and artificial bones. Although artificial bone is free from the concerns of donor site morbidity, limitation of volume, disease transmission, and ethical issues, it lacks osteogenic and osteoinductive activities. In addition, molding of the artificial bone is an issue especially when it is used for the augmentation of bone as onlay grafts. To solve this problem, additive manufacturing techniques have been applied to fabricate bones which have outer shapes conformed to patients' bones. We developed a custom-made artificial bone called a computed tomography (CT)-bone. Efficacy of CT-bone was proven in a clinical research and clinical trial, showing good manipulability, stability, and patient satisfaction. However, low replacement rate of artificial bones by endogenous bones remain an unsolved issue. Loading of cells and growth factors will improve the bone replacement by inducing osteogenic and osteoinductive activities. In addition, the three-dimensional bioprinting technique will facilitate bone regeneration by placing cells and biological substances into appropriate sites. PMID- 28351223 TI - Identification of Three Novel Fusion Oncogenes, SQSTM1/NTRK3, AFAP1L2/RET, and PPFIBP2/RET, in Thyroid Cancers of Young Patients in Fukushima. AB - BACKGROUND: The BRAFV600E mutation is the most frequent genetic abnormality in adult papillary thyroid carcinomas (PTCs). On the other hand, various chromosomal rearrangements are more prevalent in childhood and adolescent PTCs. The aim of the present study was to identify novel rearrangements in PTCs from young patients. METHODS: Among 63 postoperative specimens of childhood and adolescent PTCs, which had been discovered by the thyroid ultrasound screening program in Fukushima, nine samples without prevalent known oncogenes, BRAFV600E, RAS, RET/PTC1, RET/PTC3, and ETV6/NTRK3, were analyzed in the current study by quantitative real-time reverse transcription polymerase chain reaction to screen for novel fusion genes by comparing transcript expression between extracellular and kinase domains of ALK, NTRK1, NTRK3, and RET. RESULTS: Of the above nine samples, five samples were suspected to harbor a fusion, and using subsequent 5' rapid amplification of cDNA end (RACE), two already reported fusion oncogenes, STRN/ALK and TPR/NTRK1, and three novel fusions, SQSTM1/NTRK3, AFAP1L2/RET, and PPFIBP2/RET, were identified. Functional analyses of these three chimeric genes were performed, and their transforming abilities were confirmed through the activation of mitogen-activated protein kinase (MAPK). CONCLUSIONS: Three novel fusion oncogenes have been identified in young PTC patients in Fukushima, suggesting that rare fusions may be present among the cases negative for known oncogenes in this age group and that such rearrangements can play a significant role in thyroid carcinogenesis. PMID- 28351224 TI - Dynamic finite element simulation of dental prostheses during chewing using muscle equivalent force and trajectory approaches. AB - The long-term application of dental prostheses inside the bone has a narrow relation to its biomechanical performance. Chewing is the most complicated function of a dental implant as it implements different forces to the implant at various directions. Therefore, a suitable holistic modelling of the jaw bone, implant, food, muscles, and their forces would be deemed significant to figure out the durability as well as functionality of a dental implant while chewing. So far, two approaches have been proposed to employ the muscle forces into the Finite Element (FE) models, i.e. Muscle Equivalent Force (MEF) and trajectory. This study aimed at propounding a new three-dimensional dynamic FE model based on two muscle forces modelling approaches in order to investigate the stresses and deformations in the dental prosthesis as well as maxillary bone during the time of chewing a cornflakes bio. The results revealed that both contact and the maximum von Mises stress in the implant and bones for trajectory approach considerably exceed those of the MEF. The maximum stresses, moreover, are located around the neck of implant which should be both clinically and structurally strong enough to functionally maintain the bone-implant interface. In addition, a higher displacement due to compressive load is observed for the implant head in trajectory approach. The results suggest the benefits provided by trajectory approach since MEF approach would significantly underestimate the stresses and deformations in both the dental prosthesis and bones. PMID- 28351225 TI - Specialization patterns across various youth sports and relationship to injury risk. AB - OBJECTIVES: Current trends among young athletes towards earlier specialization age and year-round training on multiple teams has raised concern for increased injury risk. Our previous analyses showed higher risk for injury in highly specialized young athletes. The goal of this research was to determine whether sports specialization and injury patterns vary by sports type. METHODS: In this clinical case-control study, injured athletes (aged 7-18 years) were recruited from sports medicine clinics and compared to similarly aged uninjured athletes recruited from primary care clinics. Participants completed a survey reporting age, gender, sport type, specialization patterns, and details regarding sports related injuries in the previous 6 months. Clinical diagnoses were collected from patients' medical records. Injuries were classified as acute, overuse, or serious overuse. RESULTS: Of 1,190 athletes enrolled, 26% (313) were single-sport specialized (reported participation in one sport and trained >8 months/year). Sports with the highest proportion of single-sport specialized athletes were tennis (46.7%), gymnastics (30.1%), and dance (26.3%). Single-sport specialized athletes in individual sports started specializing at a younger age (11.2 +/- 2.4 vs. 12.0 +/- 2.7, p = 0.05) and reported higher training volumes (11.8 vs. 10.3 h/week, p = 0.04) than those in team sports. Sports with the youngest specialization age were gymnastics (8.9 +/- 1.7), dance (10.8 +/- 3.0), and soccer (10.9 +/- 2.4). Single-sport specialized athletes in individual sports accounted for a higher proportion of overuse injuries (44.3% vs 32.2%, OR = 1.67, p = 0.037) and serious overuse injuries (23.4% vs 11.6%, OR = 2.38, p = 0.011), but a lower proportion of acute injuries (28.8% vs 13.8%, OR = 0.37, p = 0.001) compared to single-sport specialized athletes involved in team sports. CONCLUSIONS: Athletes in individual sports may be more likely to specialize in a single sport than team sport athletes. Single-sport specialized athletes in individual sports also reported higher training volumes and greater rates of overuse injuries than single-sport specialized athletes in team sports. PMID- 28351226 TI - Fracture of a Supera Interwoven Nitinol Stent After Treatment of Popliteal Artery Stenosis. AB - PURPOSE: To present a Supera stent fracture following treatment of popliteal artery stenosis. CASE REPORT: A 60-year-old man previously treated with angioplasty/stenting of a popliteal artery lesion with a Supera stent presented at 8 months with in-stent occlusion that proved to be secondary to stent fracture. CONCLUSION: Supera interwoven nitinol stents, despite having higher radial force and conformability than classic tube stents, are not free from fracture. Moreover, due to their peculiar structure, a break in these stents results in complete loss of integrity and consequent device collapse, thus jeopardizing endovascular recanalization and relining. PMID- 28351227 TI - Early-Dynamic Positron Emission Tomography (PET)/Computed Tomography and PET Angiography for Endoleak Detection After Endovascular Aneurysm Repair. AB - PURPOSE: To propose a positron emission tomography (PET)/computed tomography (CT) protocol including early-dynamic and late-phase acquisitions to evaluate graft patency and aneurysm diameter, detect endoleaks, and rule out graft or vessel wall inflammation after endovascular aneurysm repair (EVAR) in one examination without intravenous contrast medium. TECHNIQUE: Early-dynamic PET/CT of the endovascular prosthesis is performed for 180 seconds immediately after intravenous injection of F-18-fluorodeoxyglucose. Data are reconstructed in variable time frames (time periods after tracer injection) to visualize the arterial anatomy and are displayed as PET angiography or fused with CT images. Images are evaluated in view of vascular abnormalities, graft configuration, and tracer accumulation in the aneurysm sac. Whole-body PET/CT is performed 90 to 120 minutes after tracer injection. CONCLUSION: This protocol for early-dynamic PET/CT and PET angiography has the potential to evaluate vascular diseases, including the diagnosis of complications after endovascular procedures. PMID- 28351229 TI - Serum Uric Acid Level as a Prognostic Marker in Patients With Acute Respiratory Distress Syndrome. AB - PURPOSE: Uric acid acts as both a pathogenic inflammatory mediator and an antioxidative agent. Several studies have shown that uric acid level correlates with the incidence, severity, and prognosis of pulmonary diseases. However, the association between uric acid level and acute respiratory distress syndrome (ARDS) has not been studied. This study was conducted to elucidate how serum uric acid level is related with clinical prognosis of ARDS. METHODS: A retrospective cohort study with propensity score matching was conducted at a medical intensive care unit of a tertiary teaching hospital. The medical records of patients diagnosed with ARDS admitted from 2005 through 2011 were reviewed. RESULTS: Two hundred thirty-seven patients with ARDS met the inclusion criteria. Patients with a serum uric acid level <3.0 mg/dL were classified into the low uric acid group, and those with a level >=3 mg/dL were classified into the normal to high uric acid group. We selected 40 patients in each group using propensity score matching. A higher percentage of patients in the low uric acid group experienced clinical improvement in ARDS. More patients died from sepsis in the normal to high uric acid group. Kaplan-Meier analysis showed that a low serum uric acid level was significantly associated with better survival rate. CONCLUSION: In patients with ARDS, a low serum uric acid level may be a prognostic marker of a low risk of in-hospital mortality. PMID- 28351228 TI - PEGylated liposomes associate with Wnt3A protein and expand putative stem cells in human bone marrow populations. AB - AIM: To fabricate PEGylated liposomes which preserve the activity of hydrophobic Wnt3A protein, and to demonstrate their efficacy in promoting expansion of osteoprogenitors from human bone marrow. METHODS: PEGylated liposomes composed of several synthetic lipids were tested for their ability to preserve Wnt3A activity in reporter and differentiation assays. Single-molecule microspectroscopy was used to test for direct association of protein with liposomes. RESULTS: Labeled Wnt3A protein directly associated with all tested liposome preparations. However, Wnt3A activity was preserved or enhanced in PEGylated 1,2-dioleoyl-sn-glycero-3 phosphocholine (DOPC) liposomes but not in PEGylated 1,2-dimyristoyl-sn-glycero-3 phosphocholine (DMPC) liposomes. PEGylated Wnt3A liposomes associated with skeletal stem cell populations in human bone marrow and promoted osteogenesis. CONCLUSION: Active Wnt protein-containing PEGylated liposomes may have utility for systemic administration for bone repair. PMID- 28351230 TI - Continuous Monitoring and Visualization of Optimum Spinal Cord Perfusion Pressure in Patients with Acute Cord Injury. AB - The optimum spinal cord perfusion pressure (SCPP) after traumatic spinal cord injury (TSCI) is unknown. Here, we describe techniques to compute and display the optimum SCPP in real time. We recruited adults within 72 h of severe TSCI (American Spinal Injuries Association [ASIA] grades A-C). A pressure probe and a microdialysis catheter were placed on the injured cord. SCPP was computed as mean arterial pressure (MAP) minus intraspinal pressure (ISP), spinal pressure reactivity index (sPRx) as the running ISP/MAP correlation coefficient, and continuous optimum SCPP (cSCPPopt) as the SCPP that minimizes sPRx in a moving 4 h window. In 45 patients, we monitored ISP and blood pressure. In 14 patients, we also monitored injury site metabolism. cSCPPopt could be computed 45% of the time. Mean cSCPPopt varied by up to 60 mm Hg between patients. Each patient's cSCPPopt varied with time (standard deviation 10-20 mm Hg). Color-coded maps showing the sPRx/SCPP curve evolution enhanced visualization of cSCPPopt. Periods when SCPP ~ cSCPPopt were associated with low injury site glucose, high pyruvate, and high lactate. Mean SCPP deviation from cSCPPopt correlated with worse neurological outcome at 9-12 months: ASIA grade improved in 30% of patients with <5 mm Hg deviation, 10% of patients with 5-15 mm Hg deviation, and no one with >15 mm Hg deviation. We conclude that real-time computation and visualization of cSCPPopt after TSCI are feasible. cSCPPopt appears to enhance glucose utilization at the injury site and varies widely between and within patients. Our data suggest that targeting cSCPPopt after TSCI might improve neurological outcome. PMID- 28351231 TI - Utilization of second derivative photoplethysmographic features for myocardial infarction classification. AB - Myocardial infarction (MI) is a common disease that causes morbidity and mortality. The current tools for diagnosing this disease are improving, but still have some limitations. This study utilised the second derivative of photoplethysmography (SDPPG) features to distinguish MI patients from healthy control subjects. The features include amplitude-derived SDPPG features (pulse height, ratio, jerk) and interval-derived SDPPG features (intervals and relative crest time (RCT)). We evaluated 32 MI patients at Pusat Perubatan Universiti Kebangsaan Malaysia and 32 control subjects (all ages 37-87 years). Statistical analysis revealed that the mean amplitude-derived SDPPG features were higher in MI patients than in control subjects. In contrast, the mean interval-derived SDPPG features were lower in MI patients than in the controls. The classifier model of binary logistic regression (Model 7), showed that the combination of SDPPG features that include the pulse height (d-wave), the intervals of "ab", "ad", "bc", "bd", and "be", and the RCT of "ad/aa" could be used to classify MI patients with 90.6% accuracy, 93.9% sensitivity and 87.5% specificity at a cut off value of 0.5 compared with the single features model. PMID- 28351232 TI - Fresh hospital food is reserved for staff rather than patients, report finds. AB - NHS staff are more than twice as likely as patients to be served fresh food in hospitals, according to a new report. PMID- 28351234 TI - Have your say in district nursing caseloads consultation. AB - Draft guidance on safe caseloads in district nursing has been published by NHS Improvement. PMID- 28351233 TI - Keeping complaints in perspective. AB - A while ago, a team of colleagues received a complaint. They are an efficient bunch: thoughtful, caring, the kind of people who are constantly praised by patients for their good practice. So the complaint came as a surprise. PMID- 28351235 TI - Student life - Student to newly qualified nurse: finding out who's who. AB - As a recently qualified staff nurse, I know what it's like to start work in a new area, with lots of people to meet and skills to learn. PMID- 28351236 TI - Readers' panel - Is there a need to improve the image of nursing? AB - Our experts consider a hot topic of the day. PMID- 28351239 TI - True cost of placements. AB - Following the removal of the NHS bursary, nursing and midwifery students will be paying to attend university and placements from September this year. PMID- 28351238 TI - Rock bottom is right. AB - I agree with the findings of your survey of NHS staff (analysis, 22 March). However, I thought the percentage who said morale was at rock bottom would have been higher. PMID- 28351240 TI - Pulse oximetry: what the nurse needs to know. AB - Rationale and key points Measurement of peripheral oxygen saturation (SpO2) is used to identify early hypoxia in patients and evaluate the effectiveness of oxygen therapy. Nurses should be aware of the procedure for using a pulse oximeter to measure SpO2 levels and the normal range for SpO2 readings. " A pulse oximeter is used to measure SpO2 levels, and involves placing a probe on the patient's finger, toe or ear lobe. " A SpO2 level of less than 90% is a clinical emergency. If the SpO2 level is below 94%, the nurse should assume the patient is hypoxic until proven otherwise, and therefore they may require supplemental oxygen administration. " Nurses should be aware of the factors that might affect SpO2 readings, including anaemia, peripheral vasoconstriction, dark skin tone and skin discolouration. PMID- 28351242 TI - Natural Cycles, Birth Control & Ovulation Calc. AB - This fertility tracking app tracks the user's ovulation and period cycle to pinpoint their fertility and help prevent or plan a pregnancy. PMID- 28351241 TI - Who will be this year's Patient's Choice? AB - Our five Patient's Choice finalists have been shortlisted from scores of nominations. The award, sponsored by Yakult, enables members of the public to thank a nurse or midwife who has made a real difference to their care or that of a loved one. Smooth Radio and Good Morning Britain presenter Kate Garraway will announce the winner at the RCNi Nurse Awards ceremony in London on 5 May. RCNi editorial director Graham Scott says: 'Here are five inspirational nurses and five examples of outstanding care that all deserve an award. Typically, these modest nurses would say they are just doing their job, but it is clear from the testimonies that they have each made an enormous difference to the lives of those who nominated them.' PMID- 28351243 TI - Freedom to speak up: extra protection for whistleblowers. AB - NHS whistleblowers will soon have better protection, the government claims, when they look for a new job. Plans have been drawn up to combat the discrimination that often follows nurses who raise concerns about patient care. PMID- 28351244 TI - Patients have a right to know the results of research. AB - As researchers, how do we publicise our results to change practice? How do we reach those who are unlikely to look at academic journals and conference presentations? PMID- 28351245 TI - Letter. AB - Does urging people to plan their own breaks essentially then place responsibility (and the NHS favourite, blame) on staff? Staff often are not in a position to solve the problems that prevent them from taking the breaks in the first place. PMID- 28351246 TI - The problem with breaks. AB - It is interesting to read about the new break initiative at Guy's and St Thomas's hospital (news online, 20 March). I would have been happy with a quick slurp of a coffee between tasks. It's almost impossible to stop what you are doing, make a cuppa and finish it uninterrupted. PMID- 28351247 TI - Don't forget the extraordinary work of district nurses. AB - Last week I took some time out from reflecting on the policy and service challenges of delivering more care in people's homes and shadowed a Queen's Nurse at work. PMID- 28351249 TI - Agency shifts top up low pay. AB - Your story says some nurses will be banned from doing agency shifts at other trusts (news online, 23 March). If we were paid on the same scale as social workers, teachers and police we wouldn't need to work overtime. PMID- 28351253 TI - Emergency response praised. AB - Nurses and other healthcare staff have been praised for their swift and professional response after last week's terrorist attack in Westminster, in which five people died and dozens were injured. PMID- 28351250 TI - Mixed messages. AB - Every year, the NHS in England conducts what is almost certainly the biggest regular staff survey in health care anywhere in the world. The 2016 NHS staff survey involved 316 NHS organisations, with 982,000 NHS staff invited to participate. Returns from more than 423,000 staff equated to a response rate of 44%. The findings were published earlier this month, and as ever with such surveys, some messages instantly emerged. PMID- 28351254 TI - Education review lead backs compulsory preceptorship. AB - All new nurses should complete a mandatory preceptorship year to help them meet new Nursing and Midwifery Council (NMC) requirements, an academic leading the regulator's 'radical' overhaul of education standards has said. PMID- 28351255 TI - Five worthy finalists for our Patient's Choice award. AB - The RCNi Nurse Awards are not only the most prestigious accolades in nursing, they are also the only awards that give patients the opportunity to choose their own nurse of the year. This week we reveal the shortlist for the 2017 RCNi Patient's Choice award, and choosing between the final five will be as challenging as ever. PMID- 28351256 TI - Wernicke-Korsakoff syndrome: recognition and treatment. AB - Wernicke-Korsakoff syndrome is a potentially debilitating and fatal condition that is caused by thiamine (vitamin B1) deficiency in the brain. It can be treated effectively or prevented completely; however, the condition is often undiagnosed and inadequately managed. Wernicke-Korsakoff syndrome is commonly considered to be specific to individuals who misuse alcohol; however, there are many other predisposing factors and causes associated with the condition. This article aims to raise awareness of Wernicke-Korsakoff syndrome, to enable nurses in all practice settings to recognise the signs, symptoms and risk factors associated with the condition and be informed about available treatments. Increased awareness aims to improve early diagnosis of the condition, enabling effective treatment and improving patients' symptoms, such as cognitive impairment. PMID- 28351257 TI - Understanding and responding to severe and enduring patient distress resulting from episodes of healthcare. AB - This article focuses on the severe, long-term and debilitating distress that may be experienced by patients as a result of their interactions with healthcare professionals and services. It is essential for healthcare professionals to be able to respond effectively to severe patient distress resulting from episodes of healthcare. Severe and enduring patient distress can occur in response to neglect - even when unintentional, misdiagnosis, surgical errors and/or deficits in the quality of care. Severe and enduring distress experienced by patients may go unacknowledged; the long-term consequences may not be recognised, or resolution may be presumed following formal apologies or receipt of compensation. An emphasis on the duty of candour has increased awareness of the importance of honesty and acknowledgement of adverse events or 'near misses' in the healthcare setting, in improving the relationship between patients and healthcare professionals. PMID- 28351258 TI - HIV in Primary Care (Third edition) Matthews Philippa Madge Sara Singh Surinder and Theobald Nick HIV in Primary Care (Third edition) 128pp L12 MEDFASH 9780954997373 0954997379 [Formula: see text]. AB - This book is well written and structured with a focus on general practice settings and primary healthcare teams. PMID- 28351259 TI - Law and Ethics in Nursing and Healthcare: An Introduction (Second edition) Avery Graham Law and Ethics in Nursing and Healthcare: An Introduction (Second edition) 392pp L26.99 Sage 9781412961745 1412961742 [Formula: see text]. AB - This book aims to deliver key concepts of law and ethics in an easy-to-read style. In an area of healthcare that is fraught with rapid changes, challenges and misunderstandings, the author achieves this. PMID- 28351260 TI - Tooth loss may increase risk of developing dementia. AB - Older people who have fewer teeth have an increased risk of developing dementia, new study results suggest. PMID- 28351261 TI - Nurses will 'continue to bear the brunt of austerity', as pay cap remains in Scotland. AB - The pay increase for NHS staff in Scotland for 2017-18 will be capped at 1% for those earning over L22,000, the Scottish Government announced. PMID- 28351262 TI - Nurse-led model boosts uptake of type 2 diabetes treatment. AB - A care model led by practice nurses can improve the uptake of insulin treatment among patients with type 2 diabetes, say researchers in Australia. PMID- 28351263 TI - Pelvic fracture linked to higher risk of dying in older people. AB - Older people have an increased risk of dying in the first eight months after a pelvic fracture, new study results suggest. PMID- 28351265 TI - Risk of death lower for older people who are also parents. AB - Parenthood is associated with a longer life than being childless, and increasingly so in old age, say Swedish researchers. PMID- 28351264 TI - Bereaved by suicide. AB - Some of the factors associated with a raised risk of suicide are well established. Men are known to be more vulnerable than women, especially those aged 45-59. People with mental health problems, particularly depression, are at greater risk than the general population, as are those who self-harm or misuse drugs or alcohol. Social isolation is another acknowledged risk factor. PMID- 28351266 TI - Physical activity in childhood starts to decline long before adolescence. AB - Physical activity levels may start to tail off as young as age seven, rather than during adolescence as is widely thought, say UK researchers. PMID- 28351267 TI - Discharging patients. AB - What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? Delayed discharge from hospital can have significant effects on patients and healthcare organisations, for example, longer hospital stays, increased readmissions and financial cost. The CPD article provided information about effective discharge planning, to reduce delays and improve patient care. PMID- 28351268 TI - Find yourself a suitable mentor. AB - Karen Harrison Dening has more than 40 years of nursing experience, more than 30 of which are in dementia care. She has worked for charity Dementia UK for the past ten years, initially as a consultant Admiral Nurse specialist and then as head of research and evaluation. For her PhD from University College London she focused on advance care planning and end of life care in dementia. She holds honorary academic positions at the universities of Liverpool and Nottingham, where she lectures and is involved in research. PMID- 28351269 TI - Head and neck cancer. AB - Essential facts Head and neck cancers include those of the mouth and throat, and rarer forms affecting the sinuses, salivary glands, nose or middle ear. The Oracle Cancer Trust says head and neck cancer is the UKs sixth most common type, with 31 people diagnosed each day. PMID- 28351270 TI - Military families are a 'hidden homeless group'. AB - The number of military families experiencing homelessness is a hidden problem, and the scale of the issue is not fully understood, a senior nurse has said. PMID- 28351271 TI - The nursing innovators who are improving quality of care. AB - 'I am always inspired when I see or hear about great nursing,' says RCN West Midlands regional director Paul Vaughan. 'Nurses and healthcare assistants in this region are doing brilliant work with skill, compassion and passion at a time when they are under unprecedented pressure. PMID- 28351273 TI - Attrition higher with off-campus living. AB - Living off campus can affect student drop-out rates, according to a nurse academic. PMID- 28351276 TI - Learn how to shape policy. AB - Applications are open for a new programme that will bring together nurse leaders from around the world to improve their policy-making and influencing skills. PMID- 28351275 TI - Anger over agency shifts ban for NHS nurses. AB - Nurses have reacted with anger after learning they can no longer take on agency work if they are otherwise employed by an NHS trust. PMID- 28351277 TI - 'Earn as you learn' won't devalue the profession. AB - One of the things I enjoy about my work is seeing the healthcare assistants (HCAs) in our hospice and the care homes we work with gain qualifications that have a positive impact on their practice and improve patient care. PMID- 28351278 TI - Quick action a credit to NHS. AB - Good on the health professionals who rushed out to help those involved in the Westminster attack last week (news online, 23 March). PMID- 28351279 TI - Consent and care go hand in hand. AB - During my placement in a busy emergency department, a woman was admitted with heavy vaginal bleeding. She had undergone a scan at six weeks' pregnant and been told that she was miscarrying. Medical staff had advised her to go home and wait, as she wanted the process to occur naturally. But this was five weeks later, and she still had no signs that she had miscarried fully. PMID- 28351280 TI - Make the most of your annual appraisal. AB - If your heart sinks when your manager approaches you about your appraisal, take comfort in knowing you are not alone. PMID- 28351281 TI - 'My well-being is due to the support and care of this dedicated team'. AB - In 2008 I was diagnosed with ulcerative colitis. My disease was stable until 2013, when I had a severe episode while on holiday in France, requiring a 12-day hospital stay on my return. PMID- 28351282 TI - Do mothers with high sodium levels in their breast milk have high depression and anxiety scores? AB - Objective This study aimed to assess the possible association of high breast milk sodium levels with postpartum depression and anxiety. Methods A total of 150 mothers and their healthy, exclusively breastfed newborns aged 8 to 15 days were recruited. Mothers were asked to complete scales for evaluation of postnatal depression and anxiety following an interview for consent and sociodemographic data collection. Breast milk samples were obtained to measure sodium and potassium (K) levels. Results Forty-nine mothers had higher than expected breast milk Na concentrations and a high Na/K ratio. These mothers scored significantly higher on the scales of postnatal depression and state anxiety ( P = 0.018 and P = 0.048, respectively). Conclusions This study shows that compared to normal breast milk Na levels and Na/K ratio, high breast milk Na and high Na/K ratio, with possible serious consequences in infants, are associated with maternal depressive and anxious symptoms in the postpartum period. PMID- 28351283 TI - Evaluation of GeneXpert MTB/RIF for detecting Mycobacterium tuberculosis in a hospital in China. AB - Objective To evaluate the performance of GeneXpert MTB/RIF in diagnosing pulmonary tuberculosis (TB) in China. Methods This cross-sectional study included sputum specimens of 240 suspected TB cases. Specimens were examined by light microscopy for the presence of acid-fast bacilli, which were cultured by the BACTEC MGIT 960 (M960) system and detected by the GeneXpert MTB/RIF assay. The positive rate, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and average turnaround time of methods were evaluated. Results The positive rate was 36.6% (87/238) for the GeneXpert MTB/RIF assay and 34.0% (81/238) by M960 culture, with no significant difference between methods (chi2 = 0.33, p > 0.05). According to culture results, sensitivity of the GeneXpert MTB/RIF assay was 84.0% (68/81), specificity was 87.8% (129/147), the PPV was 78.2% (68/87), and the NPV was 87.2% (129/148). The agreement for results between Gene Xpert MTB/RIF and the M960 system was 82.8% and the Kappa value was 0.73. Conclusion The GeneXpert MTB/RIF assay is a simple, rapid, and accurate test for detecting Mycobacterium tuberculosis in sputum specimens. PMID- 28351284 TI - Impact of breast cancer awareness month on detection of breast cancer in a private hospital. AB - Objective Breast cancer awareness month increases public awareness in association with increased rates of screening and new diagnoses. This study aimed to evaluate the effect of breast cancer awareness month on primary diagnosis of breast cancer. Methods Asymptomatic women with the intention of breast cancer screening were included. The non-BCAM (Breast cancer awareness month) group were screened from February to September 2016 and the BCAM group during October 2016. Ultrasound and mammography were performed in all women and in those aged >= 40 years, respectively. A BIRADS (Breast Imaging Reporting And Data Systems) score of >=4 and solid palpable masses without features suggestive of malignancy and/or the physician's preference were regarded as indications for histopathological analysis. Requirement for histopathological analysis and detection of breast cancer were identified as the main variables. Results There were 198 women with a mean age of 49.3 +/- 9.5 years. Sixty-nine and 129 women were in the non-BCAM and BCAM groups, respectively. Percutaneous biopsy was performed in seven (10.1%) and three patients (2.3%) in the non-BCAM and BCAM groups, respectively ( P = 0.035). Pathological examinations were benign. Conclusion Although public awareness campaigns lead to increased rates of screening, they may lose their impact on detecting breast cancer because of widespread use of routine screening programs. PMID- 28351285 TI - Heparanase overexpression down-regulates syndecan-1 expression in a gallbladder carcinoma cell line. AB - Objective To discuss the relevance of heparanase and syndecan-1 and regulation of the heparanase-syndecan1 axis in the invasiveness of gallbladder carcinoma cells. Methods 1. Generation of a gallbladder cancer cell line overexpressing a heparanase (GBD-SD) transgene. 2. Western blot analysis of syndecan-1 levels of GBD-SD and control gallbladder carcinoma (GBC-SD) cells. 3. RT-PCR analysis of syndecan-1 mRNA levels of GBD-SD and GBC-SD. 4. Evaluation of invasion and migration of GBD-SD and GBC-SD cells. Results 1. Heparanase expression in GBD-SD cells was significantly increased. 2. The syndecan-1 mRNA level of GBD-SD cells was significantly lower compared with that of GBC-SD cells. 3. The syndecan-1 DNA copy number in GBD-SD cells was significantly lower compared with that of GBC-SD. 4. The invasiveness and migration of GBD-SD cells were significantly higher compared with GBC-SD cells. Conclusions 1. The expression of heparanase negatively correlated with that of syndecan-1 in a gallbladder carcinoma cell line. 2. The expression of heparanase and syndecan-1 in gallbladder carcinomas negatively correlated, similar to other tumours. 3. The heparanase/syndecan1 axis in gallbladder carcinoma plays an important role in the invasion and metastasis, thus providing a new therapeutic target. 4. Further research is required to identify the detailed mechanisms. PMID- 28351286 TI - Root and canal morphology of maxillary second molars by cone-beam computed tomography in a native Chinese population. AB - Objective To evaluate the root and root canal morphology of the maxillary second molars (MSMs) in a native Chinese population by cone-beam computed tomography. Methods Cone-beam computed tomography images of 2412 MSMs from 1294 Chinese patients were analyzed to determine the number and morphology of the roots, the root canal morphology, the bilateral symmetry, and the correlations of these parameters with sex and age. Results The percentage of fused roots increased with age, while the percentage of fused roots in women was higher than that in men. The percentage of second mesiobuccal (MB2) canals in MSMs with three separate roots was higher in men than women. Patients aged 31 to 40 years showed a higher prevalence of MB2 canals, while those aged >=51 years showed the lowest prevalence of MB2 canals among both men and women. There was a significant difference in bilateral symmetry of MSMs between men and women. Conclusion Root fusion of MSMs increased with age, while the root canal morphology was more complex in patients of intermediate ages. PMID- 28351287 TI - Neuromelioidosis: a series of seven cases in Hainan province, China. AB - Melioidosis, which is caused by Burkholderia pseudomallei, is predominately a disease of tropical climates and is especially widespread in south-east Asia and northern Australia. Melioidosis affecting the central nervous system has a low incidence but a high mortality. We present seven cases of neuromelioidosis and analyze the disease characteristics and imaging features. Typical clinical features of this disease included high fever and headache. Five patients had an irregular fever with a temperature >= 39C. Peripheral blood leukocytes and the neutrophil ratio were raised in all patients. On computed tomography and magnetic resonance imaging the disease mainly manifested as intracerebral single or multiple nodules, as well as ring and flake-like enhancements with rapid lesion progression. This study demonstrated the importance of imaging examination in the clinical evaluation and diagnosis of neuromelioidosis. PMID- 28351288 TI - Establishment of a three-dimensional finite element model of severe kyphotic deformity secondary to ankylosing spondylitis. AB - Objective To establish a three-dimensional (3D) finite element (FE) model of ankylosing spondylitis (AS) kyphosis that is a digital platform for further studies. Methods A 30-year-old man with AS kyphosis underwent computed tomography transverse scanning from T1 to the sacrococcyx. The images were imported into Mimics(r) 17.0 software to establish a 3D model of the posterior spine, which was then imported into Studio Geomagic 2013 software. Posterior spine convex geometry was established on the 3D geometric model for subsequent optimization of image processing. Unigraphics NX 8.5 produced the spinal kyphosis surface model. Modeled calcification of ligaments and partial resection of useless sacral bone were added. The model was imported into ANSYS 15.0 FE analysis software. Ligaments were added. Parameters were set to generate a 3D FE model of AS. Results and Conclusion A 3D FE model of AS was successfully established, providing a reliable digital platform for subsequent biomechanical analysis. PMID- 28351289 TI - Bone Morphogenetic Protein 2 Alters Osteogenesis and Anti-Inflammatory Profiles of Mesenchymal Stem Cells Induced by Microtextured Titanium In Vitro. AB - OBJECTIVES: Microtextured titanium (Ti) induces osteoblast differentiation of mesenchymal stem cells (MSCs) in the absence of exogenous osteogenic factors; and high-energy surface modifications speed healing of microrough Ti implants. Bone morphogenetic protein 2 (BMP2) is used clinically to improve peri-implant bone formation and osseointegration but can cause inflammation and bone-related complications. In this study, we determined whether BMP2 alters human MSC differentiation, apoptosis, and inflammatory factor production when grown on Ti implants with different surface properties. MATERIALS AND METHODS: Human MSCs were cultured on Ti substrates (smooth [PT], sandblasted acid-etched [SLA], hydrophilic-SLA [modSLA]), or tissue culture polystyrene (TCPS). After 7 days, inflammatory mRNAs were measured by polymerase chain reaction array. In addition, 7-day cultures were treated with exogenous BMP2 and osteogenic differentiation and production of local factors, proinflammatory interleukins, and anti inflammatory interleukins assessed. Finally, osteogenic markers and interleukins were measured in MSCs cultured for 48 h on BMP2 dip-coated SLA and modSLA surfaces. RESULTS: Expression of interleukins, chemokines, cytokines, and growth factors was affected by surface properties, particularly on modSLA. MSCs on Ti produced fewer resorptive and more osteogenic/anti-inflammatory factors than cells on TCPS. Addition of 100 ng/mL BMP2 not only increased differentiation but also increased proinflammatory and decreased anti-inflammatory/antiresorptive factors. Two hundred nanograms per milliliter BMP2 abolished osteogenesis and dramatically increased pro-osteoclastogenic factors. MSCs cultured on BMP2-dip coated disks produced similar proinflammatory profiles with inhibited osteogenic differentiation and had increased apoptotic markers at the highest doses. CONCLUSIONS: MSCs underwent osteogenesis and regulated inflammatory cytokines on microtextured Ti. Exogenous BMP2 inhibited MSC differentiation and stimulated a dose-dependent proinflammatory and apoptotic response. Use of BMP2 with microtextured metal implants may increase inflammation and possibly delay bone formation dependent on dose, suggesting that application of BMP2 clinically during implant insertion may need to be reevaluated. PMID- 28351290 TI - Keratose Hydrogels Promote Vascular Smooth Muscle Differentiation from C-kit Positive Human Cardiac Stem Cells. AB - Stem cell-based therapies have demonstrated great potential for the treatment of cardiac diseases, for example, myocardial infarction; however, low cell viability, low retention/engraftment, and uncontrollable in vivo differentiation after transplantation are still major limitations, which lead to low therapeutic efficiency. Biomaterials provide a promising solution to overcome these issues due to their biocompatibility, biodegradability, low/nonimmunogenicity, and low/noncytotoxicity. The present study aimed to investigate the impacts of keratose (KOS) hydrogel biomaterial on cellular viability, proliferation, and differentiation of c-kit+ human cardiac stem cells (hCSCs). Briefly, hCSCs were cultured on both KOS hydrogel-coated dishes and regular tissue culture dishes (Blank control). Cell viability, stemness, proliferation, cellular morphology, and cardiac lineage differentiation were compared between KOS hydrogel and the Blank control at different time points. We found that KOS hydrogel is effective in maintaining hCSCs without any observable toxic effects, although cell size and proliferation rate appeared smaller on the KOS hydrogel compared to the Blank control. To our surprise, KOS hydrogel significantly promoted vascular smooth muscle cell (VSMC) differentiation (~72%), while on the Blank control dishes, most of the hCSCs (~78%) became cardiomyocytes. Furthermore, we also observed "endothelial cell tube-like" microstructures formed by differentiated VSMCs only on KOS hydrogel, suggesting a potential capability of the hCSC-derived VSMCs for in vitro angiogenesis. To the best of our knowledge, this is the first report to discover the preferred differentiation of hCSCs toward VSMCs on KOS hydrogel. The underlying mechanism remains unknown. This innovative methodology may offer a new approach to generate a robust number of VSMCs simply by culturing hCSCs on KOS hydrogel, and the resulting VSMCs may be used in animal studies and clinical trials in combination with an injectable KOS hydrogel to treat cardiovascular diseases. PMID- 28351292 TI - Youth self-harm in low- and middle-income countries: Systematic review of the risk and protective factors. AB - BACKGROUND: Self-harm (defined here as an act of intentionally causing harm to own self, irrespective of the type, motive or suicidal intent) is one of the strongest antecedents of suicide in youth. While there have been a number of studies of youth self-harm in low- and middle-income countries (LMICs), there is currently no systematic review of studies of prevalence rates and risk and protective factors. AIM: To systematically review the evidence relating to the prevalence rates and forms of self-harm in youth in LMICs and its relationship to family economic status, family functioning, relationship with the peer group, social relationships and academic performance. METHODS: Electronic searches of three databases, MEDLINE, PsycINFO and Scopus, were performed. In total, 27 school-, community- and hospital-based studies evaluating self-harm in LMICs with youth focus (with participants between 12 and 25 years) were included. RESULTS: The self-harm was divided into suicidal and non-suicidal depending on the nature of self-harm. The 12-month prevalence rates of non-suicidal self-harm varied from 15.5% to 31.3%, and the range of suicidal behaviour rates was from 3.2% to 4.7%. Banging and hitting were the most common in the community-based studies, followed by cutting, scratching and wound picking. Self-poisoning with pesticides was most commonly reported in hospital-based studies. Risk factors for self-harm were family conflict, peer groups with members indulging in self-harm, truancy and school absenteeism. Protective factors were having an understanding family, having friends and higher school competence. Risk factors for suicidal thoughts and attempts were lack of close friends and history of suicide by a friend. CONCLUSION: The 12-month prevalence rates of youth self-harm in LMICs are comparable to high-income countries (HICs). The profile of risk and protective factors suggests that family-based interventions could be useful in treatment and prevention. Future studies should aim for greater consistency in assessment methods and the constructs under evaluation. PMID- 28351291 TI - Hypothyroidism and Hyponatremia: Rather Coincidence Than Causality. AB - BACKGROUND: Hypothyroidism is referred to be a rare but possible cause of hyponatremia. However, there is only poor evidence supporting this association. Since hyponatremia and hypothyroidism are both common conditions themselves, co occurrence does not have to be causal. METHODS: To address a potential relationship, a retrospective analysis of data from the Division of Endocrinology of the Medical University of Vienna from April 2004 to February 2016 was performed. A total of 8053 hypothyroid patients (48 +/- 18 years of age; 71% female) with thyrotropin >4.0 MUIU/mL and available blood tests for free thyroxine and sodium (Na+) within maximal +/- seven days were included and screened for hyponatremia. Patients' records were searched for concomitant disease and medication when Na+ concentration was <135 mmol/L. RESULTS: Hyponatremia was present in 448/8053 (5.56%) patients. Analysis of medical history revealed potential alternative causes of hyponatremia in 442/448 (98.88%) patients (i.e., side effects of medication, concomitant underlying disease, or other endocrine disorders). This distribution did not differ between patients suffering from clinical or subclinical hypothyroidism. No case of clinically relevant hyponatremia (Na+ < 130 mmol/L), present in 111/448 (24.78%) patients could be attributed only to hypothyroidism. There was a very weak but statistically significant trend toward a positive association between thyroid function and serum Na+ levels (Na+/thyrotropin: R = 0.022, p = 0.046; Na+/free thyroxine: R = -0.047, p < 0.001). CONCLUSION: The results suggest that hypothyroid patients with moderate to severe hyponatremia often have other potential explanations for their low serum Na+ concentrations in routine care. PMID- 28351293 TI - The synergy of the refugee crisis and the financial crisis in Greece: Impact on mental health. AB - BACKGROUND: The current global financial crisis that started in 2008 resulted in a significant decline in global trade, slowing/reversing economic growth worldwide, and a dramatic increase in public sector debt. At the same time, the global migrant/refugee crisis has reached extreme rates, with millions of people being forced to abandon their homes and communities because of war, political violence or related threats. There is a broad consensus about the deleterious consequences of these crises on psychological well-being, depression, anxiety disorders, insomnia, alcohol abuse and suicidal behavior. Although the separate consequences of economic recession and immigration are extensively discussed in previous research, we know very little about the processes through which the intersection of economic crisis and migrant crisis contributes to the vulnerabilities of natives and migrants during these crises. Of particular concern is the status of children, adolescents and their families, who constitute one of the most vulnerable groups in society. AIM: To discuss the contexts that economic and migrant crises shape and suggest possible effects of this intersection on mental health risks, especially among children, adolescents and their families, through reflecting on the recent experience in Greece. METHOD: Review of the literature and critical analysis of the effects of the confluent crises. CONCLUSION: The interactive effects of these two crises need further exploration. Novel and diverse models of psychological understanding need to be developed in order to manage the effects of the confluent crises. The role of mental health professionals is crucial in this respect, offering culturally flexible, accommodating and empathetic approaches, allowing healing and acceptance in the face of adversity. PMID- 28351294 TI - Necessity of Internet regulation to prevent suicides in Mexico. PMID- 28351295 TI - Stability of ovine serum protein fractions under different storage conditions. AB - We evaluated the effect of different storage conditions on the concentration of serum total proteins and their electrophoretic fractions in sheep. Blood samples were collected from 12 female Comisana sheep, and each serum obtained was divided into 4 aliquots. The first aliquot was analyzed immediately after separation (T0); the second was refrigerated at 4 degrees C and analyzed after 24 h (T1), 48 h (T2), and 72 h (T3); the third was stored at -20 degrees C immediately after centrifugation and analyzed after 2 days (T4); and the last aliquot was stored at -20 degrees C after 24-h refrigeration and analyzed after 1 wk (T5). The concentrations of serum total proteins and their electrophoretic fractions (albumin, alpha-, beta1-, beta2-, and gamma-globulins) was determined. A statistically significant ( p < 0.05) effect of storage conditions on all serum electrophoretic protein fractions and on the albumin-to-globulin (A/G) ratio was found. The values of albumin, alpha-globulins, and A/G ratio increased at T4 with respect to T0. The levels of alpha-globulins were higher at T1 than T0; the beta1 globulins levels changed at T3, whereas the beta2- and gamma-globulins values as well as the A/G ratio changed at T2 and T3. At T4, we found an increase in the serum concentrations of albumin, alpha1-globulins, and on the A/G ratio, and a decrease of gamma fraction. At T5, the concentration of alpha-globulins was higher than at T0. Hence, we recommend electrophoretic analysis of fresh ovine serum samples or of samples refrigerated for no more than 24 h to obtain accurate data. PMID- 28351296 TI - Regulatory Forum Opinion Piece*: Use and Utility of Animal Models of Disease for Nonclinical Safety Assessment: A Pharmaceutical Industry Survey. AB - An Innovation and Quality (IQ) Consortium focus group conducted a cross-company survey to evaluate current practices and perceptions around the use of animal models of disease (AMDs) in nonclinical safety assessment of molecules in clinical development. The IQ Consortium group is an organization of pharmaceutical and biotechnology companies with the mission of advancing science and technology. The survey queried the utilization of AMDs during drug discovery in which drug candidates are evaluated in efficacy models and limited short duration non-Good Laboratory Practices (GLP) toxicology testing and during drug development in which drug candidates are evaluated in GLP toxicology studies. The survey determined that the majority of companies used AMDs during drug discovery primarily as a means for proactively assessing potential nonclinical safety issues prior to the conduct of toxicology studies, followed closely by the use of AMDs to better understand toxicities associated with exaggerated pharmacology in traditional toxicology models or to derisk issues when the target is only expressed in the disease state. In contrast, the survey results indicated that the use of AMDs in development is infrequent, being used primarily to investigate nonclinical safety issues associated with targets expressed only in disease states and/or in response to requests from global regulatory authorities. PMID- 28351297 TI - EphA4 promotes cell proliferation and cell adhesion-mediated drug resistance via the AKT pathway in multiple myeloma. AB - Eph receptor A4 (EphA4), a member of the erythropoietin-producing hepatocellular (Eph) family, has been reported to upregulate in several tumors. However, the role of EphA4 in multiple myeloma has not been clarified yet. In this study, we found that EphA4 promoted proliferation of multiple myeloma cells via the regulation of cell cycle. Besides, EphA4 was closely related to cell adhesion of multiple myeloma cells and promoted cell adhesion-mediated drug resistance by enhancing the phosphorylation levels of Akt (p-AKT) expression in multiple myeloma. More interestingly, we discovered that EphA4 can interact with cyclin dependent kinase 5 (CDK5) and regulate its expression in multiple myeloma. CDK5 has been reported to be overexpressed in multiple myeloma which mediated bortezomib resistance and also participated in AKT pathway. And we have also proved the fact. So, we supposed that EphA4 interacted with CDK5 and promoted its expression which in turn enhanced p-AKT expression and promoted cell adhesion mediated drug resistance in multiple myeloma. Therefore, this study clarifies the molecular mechanism of cell adhesion-mediated drug resistance and may be useful in identifying potential target for treatment of multiple myeloma. PMID- 28351298 TI - Aberrant gene-specific DNA methylation signature analysis in cervical cancer. AB - Multicomponent molecular modifications such as DNA methylation may offer sensitive and specific cervical intraepithelial neoplasia and cervical cancer biomarkers. In this study, we tested cervical tissues at various stages of tumor progression for 5-methylcytosine and 5-hydroxymethylcytosine levels and also DNA promoter methylation profile of a panel of genes for its diagnostic potential. In total, 5-methylcytosine, 5-hydroxymethylcytosine, and promoter methylation of 33 genes were evaluated by reversed-phase high-performance liquid chromatography, enzyme-linked immunosorbent assay based technique, and bisulfate-based next generation sequencing. The 5-methylcytosine and 5-hydroxymethylcytosine contents were significantly reduced in squamous cell carcinoma and receiver operating characteristic curve analysis showed a significant difference in (1) 5 methylcytosine between normal and squamous cell carcinoma tissues (area under the curve = 0.946) and (2) 5-hydroxymethylcytosine levels among normal, squamous intraepithelial lesions and squamous cell carcinoma. Analyses of our next generation sequencing results and data from five independent published studies consisting of 191 normal, 10 low-grade squamous intraepithelial lesions, 21 high grade squamous intraepithelial lesions, and 335 malignant tissues identified a panel of nine genes ( ARHGAP6, DAPK1, HAND2, NKX2-2, NNAT, PCDH10, PROX1, PITX2, and RAB6C) which could effectively discriminate among the various groups with sensitivity and specificity of 80%-100% (p < 0.05). Furthermore, 12 gene promoters (ARHGAP6, HAND2, LHX9, HEY2, NKX2-2, PCDH10, PITX2, PROX1, TBX3, IKBKG, RAB6C, and DAPK1) were also methylated in one or more of the cervical cancer cell lines tested. The global and gene-specific methylation of the panel of genes identified in our study may serve as useful biomarkers for the early detection and clinical management of cervical cancer. PMID- 28351299 TI - Recognizing and managing on toxicities in cancer immunotherapy. AB - Over the past 4 years, cancer immunotherapy has significantly prolonged survival time of patients with prostate cancer, melanoma, lung cancer, and liver cancer, but its side effects are also impressive. Different types of the immune therapeutic agents have different on-target or off-target toxicity due to high affinity or weak specificity, respectively. Treatment toxicity spectrums vary greatly even in patients with the same type of cancer. Common toxicities are fevers, chills, diarrhea colitis, maculopapular rash, hepatitis, and hormone gland disorder; therefore, routine monitoring of thyroid function, liver function, renal function, and complete blood count are absolutely necessary once treatment begins. Some side effects are reversible, and can be processed through the standard medicines. However, serious toxicities are lethal, which should be frequently followed-up, identified at an early stage and immediately symptomatic treated by high-dose immunosuppressors. In this case, thereafter, the same agent should not be challenged again. PMID- 28351300 TI - Roles of zinc-fingers and homeoboxes 1 during the proliferation, migration, and invasion of glioblastoma cells. AB - Zinc-fingers and homeoboxes 1 (ZHX1) is a nuclear transcription repressor and known to be involved in cell differentiation and tumorigenesis. However, the pathophysiological roles of ZHX1 have not been characterized in glioblastoma. We examined ZHX1 expression in glioblastoma patients' tissues and analyzed overall survival of the patients based on expression level of ZHX1. We also examined the effects of ZHX1 on proliferation and motility of glioblastoma cells. In silico analysis and immunohistochemical studies showed that the messenger RNA and protein expressions of ZHX1 were higher in the tissues of glioblastoma patients than in normal brain tissues, and that its overexpression was associated with reduced survival. In vitro, the downregulation of ZHX1 decreased the proliferation, migration, and invasion of glioblastoma cells, whereas its upregulation had the opposite effects. In addition, we showed ZHX1 could contribute to glioblastoma progression via the regulations of TWIST1 and SNAI2. Taken together, this study demonstrates that ZHX1 plays crucial roles in the progression of glioblastoma, and its findings suggest that ZHX1 be viewed as a potential prognostic maker and therapeutic target of glioblastoma. PMID- 28351301 TI - Amphiregulin impairs apoptosis-stimulating protein 2 of p53 overexpression induced apoptosis in hepatoma cells. AB - Overexpression of apoptosis-stimulating protein 2 of p53 (ASPP2) induces apoptotic cell death in hepatoma cells (e.g. HepG2 cells) by enhancing the transactivation activity of p53, but long-term ASPP2 overexpression fails to induce more apoptosis since activation of the epidermal growth factor/epidermal growth factor receptor/SOS1 pathway impairs the pro-apoptotic role of ASPP2. In this study, in recombinant adenovirus-ASPP2-infected HepG2 cells, ASPP2 overexpression induces amphiregulin expression in a p53-dependent manner. Although amphiregulin initially contributes to ASPP2-induced apoptosis, it eventually impairs the pro-apoptotic function of ASPP2 by activating the epidermal growth factor/epidermal growth factor receptor/SOS1 pathway, leading to apoptosis resistance. Moreover, blocking soluble amphiregulin with a neutralizing antibody also significantly increased apoptotic cell death of HepG2 cells due to treatment with methyl methanesulfonate, cisplatin, or a recombinant p53 adenovirus, suggesting that the function of amphiregulin involved in inhibiting apoptosis may be a common mechanism by which hepatoma cells escape from stimulus induced apoptosis. Thus, our data elucidate an apoptosis-evasion mechanism in hepatocellular carcinoma and have potential implications for hepatocellular carcinoma therapy. PMID- 28351302 TI - The prognostic efficacy and improvements of the 7th edition Union for International Cancer Control tumor-node-metastasis classifications for Chinese patients with gastric cancer: Results based on a retrospective three-decade population study. AB - This study aimed to evaluate survival trends for patients with gastric cancer in northeast China in the most recent three decades and analyze the applicability of the UICC tumor-node-metastasis (TNM) classification 7th edition for Chinese patients with gastric cancer. A review of all inpatient and outpatient records of patients with gastric cancer was conducted in the first hospital of China Medical University and the Liaoning Cancer Hospital and Institute. All patients who met the inclusion criteria and were seen from January 1980 through December 2009 were included in the study. The primary outcome was 5-year survival, which was analyzed according to decade of diagnosis and TNM classifications. From 1980 through 2009, the 5-year survival rates for patients with gastric cancer (n=2414) increased from 39.1% to 57.3%. Decade of diagnosis was significantly associated with patient survival (p = 0.013), and the 5-year survival rate in the 2000s was remarkably higher than that in the 1980s and 1990s (p = 0.004 and 0.049, respectively). When classified according to the UICC TNM classification of gastric cancer 7th edition, the prognoses of stage IIIA and stage IIIB patients were not significantly different (p = 0.077). However, if stage T4b and stage N0 patients were classified as stage IIIA, the prognoses of stage IIIA and stage IIIB patients were significantly different (p < 0.001). Hence, there was a significant difference in survival during the three time periods in Northeast China. Classifying stage T4b and stage N0 patients as stage IIIA according to the 7th edition of UICC gastric cancer TNM classifications better stratified Chinese patients and predicted prognoses. PMID- 28351303 TI - Phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog as therapeutic targets in breast cancer. AB - Breast cancer is the most commonly diagnosed cancer among women in Turkey and worldwide. It is considered a heterogeneous disease and has different subtypes. Moreover, breast cancer has different molecular characteristics, behaviors, and responses to treatment. Advances in the understanding of the molecular mechanisms implicated in breast cancer progression have led to the identification of many potential therapeutic gene targets, such as Breast Cancer 1/2, phosphatidylinositol 3-kinase catalytic subunit alpha, and tumor protein 53. The aim of this review is to summarize the roles of phosphatidylinositol 3-kinase regulatory subunit 1 (alpha) (alias p85alpha) and phosphatase and tensin homolog in breast cancer progression and the molecular mechanisms involved. Phosphatase and tensin homolog is a tumor suppressor gene and protein. Phosphatase and tensin homolog antagonizes the phosphatidylinositol 3-kinase/AKT signaling pathway that plays a key role in cell growth, differentiation, and survival. Loss of phosphatase and tensin homolog expression, detected in about 20%-30% of cases, is known to be one of the most common tumor changes leading to phosphatidylinositol 3-kinase pathway activation in breast cancer. Instead, the regulatory subunit p85alpha is a significant component of the phosphatidylinositol 3-kinase pathway, and it has been proposed that a reduction in p85alpha protein would lead to decreased negative regulation of phosphatidylinositol 3-kinase and hyperactivation of the phosphatidylinositol 3-kinase pathway. Phosphatidylinositol 3-kinase regulatory subunit 1 protein has also been reported to be a positive regulator of phosphatase and tensin homolog via the stabilization of this protein. A functional genetic alteration of phosphatidylinositol 3-kinase regulatory subunit 1 that results in reduced p85alpha protein expression and increased insulin receptor substrate 1 binding would lead to enhanced phosphatidylinositol 3-kinase signaling and hence cancer development. Phosphatidylinositol 3-kinase regulatory subunit 1 underexpression was observed in 61.8% of breast cancer samples. Therefore, expression/alternations of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog genes have crucial roles for breast cancer progression. This review will summarize the biological roles of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog in breast cancer, with an emphasis on recent findings and the potential of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog as a therapeutic target for breast cancer therapy. PMID- 28351304 TI - Expression of lactate dehydrogenase C correlates with poor prognosis in renal cell carcinoma. AB - Lactate dehydrogenase C is an isoenzyme of lactate dehydrogenase and a member of the cancer-testis antigens family. In this study, we aimed to investigate the expression and functional role of lactate dehydrogenase C and its basic mechanisms in renal cell carcinoma. First, a total of 133 cases of renal cell carcinoma samples were analysed in a tissue microarray, and Kaplan-Meier survival curve analyses were performed to investigate the correlation between lactate dehydrogenase C expression and renal cell carcinoma progression. Lactate dehydrogenase C protein levels and messenger RNA levels were significantly upregulated in renal cell carcinoma tissues, and the patients with positive lactate dehydrogenase C expression had a shorter progression-free survival, indicating the oncogenic role of lactate dehydrogenase C in renal cell carcinoma. In addition, further cytological experiments demonstrated that lactate dehydrogenase C could prompt renal cell carcinoma cells to produce lactate, and increase metastatic and invasive potential of renal cell carcinoma cells. Furthermore, lactate dehydrogenase C could induce the epithelial-mesenchymal transition process and matrix metalloproteinase-9 expression. In summary, these findings showed lactate dehydrogenase C was associated with poor prognosis in renal cell carcinoma and played a pivotal role in the migration and invasion of renal cell carcinoma cells. Lactate dehydrogenase C may act as a novel biomarker for renal cell carcinoma progression and a potential therapeutic target for the treatment of renal cell carcinoma. PMID- 28351305 TI - Overexpression of miR-519d in lung adenocarcinoma inhibits cell proliferation and invasion via the association of eIF4H. AB - Lung cancer is one of the deadliest types of cancer worldwide due to its high mortality rate. Adenocarcinoma constitutes 20%-30% of all lung cancers. In recent years, studies on the mechanisms of lung tumorigenesis and development have in part focused on the microRNAs for their crucial role in the progress of different cancers. As for our study, we demonstrated that miR-519d was differently downregulated and eIF4H was significantly overexpressed in lung adenocarcinoma via the detection of quantitative real-time polymerase chain reaction compared with the adjacent normal tissues. Furthermore, Cell Counting Kit-8 assay, colony formation assay, xenograft tumor experiment, Ki67 immunohistochemistry assay and transwell assay were performed to explain that the upregulated miR-519d could inhibit the proliferation and invasion of A549 and H1299 cells. To further advance our understanding of the mechanisms of miR-519d, we performed the bioinformatics analysis and the luciferase report assay. The results from these procedures revealed eIF4H to be one of the targets of miR-519d. Downregulated eIF4H was analogous to the overexpressed miR-519d obtained from miR-519d agomir and si-eIF4H transfection. In summary, it can be concluded that miR-519d targets eIF4H in lung adenocarcinoma to inhibit cell proliferation and invasion. This mechanism may offer new insights into the tumorigenesis and development of lung adenocarcinoma. PMID- 28351306 TI - MTA3 regulates malignant progression of colorectal cancer through Wnt signaling pathway. AB - MTA3 overexpression has been implicated in carcinogenesis. The aim of the present study was to explore the clinical significance and biological roles of MTA3 in human colorectal cancer and colorectal cancer cells. A total of 80 cases of colorectal cancer tissues were examined by immunohistochemistry for MTA3 protein expression. We analyzed the relationship between MTA3 and clinical factors and the results showed that MTA3 was overexpressed in 51.25% (41/80) cancer cases. There was significant associations between MTA3 overexpression and advanced TNM stage (p = 0.0086) and Ki67 index (p = 0.001). We overexpressed MTA3 in LoVo cells and depleted its expression in HCT15 cells. The results showed that MTA3 promoted cancer cell proliferation, invasion, migration, and cell cycle progression, and inhibited 5-fluorouracil-induced apoptosis in LoVo cell line. MTA3 depletion in HCT15 cell line showed the opposite effects. In addition, we found that MTA3 positively regulated cell cycle proteins including cyclin D1 and cyclin E. It also upregulated Bcl2 and downregulated Bax expression. Furthermore, we found that MTA3 could activate Wnt signaling pathway by upregulating Wnt target proteins. Our results demonstrated that MTA3 overexpression contributes to colorectal cancer carcinogenesis, progression, and chemoresistance. MTA3 could serve as a potential therapeutic target in colorectal cancer. PMID- 28351307 TI - Coptisine-induced cell cycle arrest at G2/M phase and reactive oxygen species dependent mitochondria-mediated apoptosis in non-small-cell lung cancer A549 cells. AB - This study aimed to explore the effect of coptisine on non-small-cell lung cancer and its mechanism through various in vitro cellular models (A549). Results claimed significant inhibition of proliferation by coptisine against A549, H460, and H2170 cells with IC50 values of 18.09, 29.50, and 21.60 uM, respectively. Also, coptisine exhibited upregulation of pH2AX, cell cycle arrest at G2/M phase, and downregulation of the expression of cyclin B1, cdc2, and cdc25C and upregulation of p21 dose dependently. Furthermore, induction of apoptosis in A549 cells by coptisine was characterized by the activation of caspase 9, caspase 8, and caspase 3, and cleavage of poly adenosine diphosphate ribose polymerase. In addition, coptisine was found to increase reactive oxygen species generation, upregulate Bax/Bcl-2 ratio, disrupt mitochondrial membrane potential, and cause cytochrome c release into the cytosol. Besides, treatment with a reactive oxygen species inhibitor (N-acetyl cysteine) abrogated coptisine-induced growth inhibition, apoptosis, reactive oxygen species generation, and mitochondrial dysfunction. Thus, the mediation of reactive oxygen species in the apoptosis induced effect of coptisine in A549 cells was corroborated. These findings have offered new insights into the effect and mechanisms of action of coptisine against non-small-cell lung cancer. PMID- 28351308 TI - Sulfiredoxin may promote metastasis and invasion of cervical squamous cell carcinoma by epithelial-mesenchymal transition. AB - Sulfiredoxin (Srx), a novel oxidative stress-induced antioxidant protein, has been reported to be expressed in several human tumour tissues. However, the expression and functions of Srx in cervical squamous cell carcinoma remain unknown. Here, we proved that expression of Srx was upregulated in cervical tissues as revealed by immunohistochemistry, and revealed a close correlation between the protein's expression and the expression level of one core epithelial mesenchymal transition marker, E-cadherin. We demonstrated that Srx was overexpressed in cervical squamous cell carcinoma and its expression level was closely correlated with lymph node metastasis and invasion of cervical squamous cell carcinoma. Meanwhile, Srx expression was negatively correlated with E cadherin expression. The remission time (tumour-free status after surgery) of the Srx strong staining group was significantly shorter than that of the Srx weak staining group. We silenced Srx by short hairpin RNA in HeLa and SiHa cells. Diminished Srx expression upregulated E-cadherin expression. The cell invasion and migration activity in the ShSrx group were obviously decreased in HeLa and SiHa cells. Moreover, Srx regulated the expression of the other marker of epithelial-mesenchymal transition, vimentin. In conclusion, the study suggested that Srx was highly expressed in cervical squamous cell carcinoma and may promote invasion and metastasis of cervical squamous cell carcinoma via regulating epithelial-mesenchymal transition. PMID- 28351309 TI - Plasma microRNA192 in combination with serum CA19-9 as non-invasive prognostic biomarker in periampullary carcinoma. AB - In this study, circulating microRNAs (miRNAs) are being investigated as non invasive biomarkers for early diagnosis and prognosis of human cancers. Since the prognosis for pancreatobiliary subtype of periampullary carcinoma is poor, we assessed the prognostic relevance of miRNAs in combination with CA19-9 as noninvasive biomarker in periampullary carcinoma. Circulating miRNAs in plasma and serum CA19-9 were evaluated in periampullary carcinoma patients (n = 109) undergoing Whipple's pancreaticoduodenectomy and in healthy volunteers (n = 92). Tumour tissues were subjected to staging and subtyping prior to determining differentially expressed miRNAs in them by quantitative real-time polymerase chain reaction (qRT-PCR). Statistical analysis involved correlation, receiver operating characteristic, logistic regression, survival analyses and Cox proportional regression. Of the three differentially expressed circulating miRNA, miRNA192 was significantly increased both in circulation and in tumour tissue and correlated with tumour stage and aggressiveness (r = 0.96, P < 0.0001). Area under the curve of circulating miRNA192 + CA19-9 combination was 0.877 (95% confidence interval, 0.72 to 0.96) for stage III and 0.92 (95% confidence interval, 0.77 to 0.88) for tumour aggressiveness. The combination was associated with poor survival (median: 22 months, P = 0.0008) in stage III patients. Cox proportional regression analysis revealed prognostic importance of combination of circulating miR192 and CA19-9 (HR = 1.005, P = 0.0001) in periampullary carcinoma. In conclusion, combination of circulating miRNA192 with serum CA19-9 is a better prognostic biomarker than CA19-9 alone. PMID- 28351310 TI - One-Year Outcomes of the Paclitaxel-Eluting, Self-Expanding Stentys Stent System in the Treatment of Infrapopliteal Lesions in Patients With Critical Limb Ischemia. AB - PURPOSE: To investigate the efficacy of the paclitaxel-coated, self-expanding, nitinol Stentys Stent System in tibioperoneal lesions <=50 mm long. METHODS: The prospective, single-arm, multicenter PES-BTK-70 trial ( ClinicalTrials.gov identifier NCT01630070) evaluated the safety and efficacy of the coronary Stentys Stent System in the treatment of a stenotic or occlusive lesion <=50 mm long in the tibioperoneal arteries of patients with critical limb ischemia (CLI). Between January 2012 and May 2013, 70 patients (mean age 74.6+/-9.4 years; 45 men) with CLI [Rutherford category 4 (37, 52.9%) or 5 (33, 47.1%)] received a Stentys drug eluting stent for the treatment of infrapopliteal stenosis (60, 85.7%) or occlusion (10, 14.3%). The mean lesion length was 17.2 mm (4.0-58.5). The primary outcome measures were primary patency at 6 months (duplex ultrasound) and 12 months (angiography). Secondary outcomes included limb salvage and freedom from target lesion revascularization (TLR). Kaplan-Meier estimates of the outcomes are given with the 95% confidence intervals (CI). RESULTS: Technical and procedure success (<30% residual stenosis without major complications) was achieved in 68 (97.1%) of 70 cases. Primary patency was 87.6% (95% CI 83.5% to 91.7%) at 6 months and 72.6% (95% CI 66.9% to 78.3%) at 1 year. Freedom from TLR was 79.1% at 1 year (95% CI 73.9% to 84.3) and limb salvage was 98.5% (95% CI 97.0 to 100.0). No stent fractures were found by core laboratory review of all follow-up imaging data available up to 12 months. CONCLUSION: In this study, the self-expanding, nitinol, paclitaxel-eluting, coronary Stentys stent was found to be safe and effective in the below-the-knee region, with results similar to the most recent limus-eluting stent trials. PMID- 28351311 TI - Lessons Learned Regarding Handling and Deployment of the Absorb Bioresorbable Vascular Scaffold in Infrapopliteal Arteries. AB - PURPOSE: To describe relevant technical details with which to facilitate safe and effective use of the Absorb coronary bioresorbable vascular scaffold (BVS) in lower extremity arteries. TECHNIQUE: The Absorb BVS is a balloon-expandable, poly l-lactide structure covered in a poly-d,l-lactide bioresorbable polymer that contains the antiproliferative drug everolimus. As a polymeric structure, it has a number of unique physical, handling, and imaging properties that may differ from metallic stents and pose a challenge to the interventionist. Attention must be paid to lesion selection, preparation, scaffold sizing, deployment, and postdilation to achieve optimal outcomes. A detailed description of these issues and deployment techniques is offered based on experience using this BVS in below the-knee arteries. CONCLUSION: The Absorb BVS may have application in the infrapopliteal circulation; however, its unique properties warrant careful consideration before use in the lower limb. PMID- 28351313 TI - SIRT1 promotes the proliferation and metastasis of human pancreatic cancer cells. AB - SIRT1 plays an important role in human malignant progression, inducing cancer cell proliferation and metastasis by regulating downstream gene expressions. However, little is known about the underlying mechanisms in which SIRT1 promotes pancreatic cancer tumorigenesis. The aim of this study is to investigate the SIRT1 expression levels and biological functions in promoting pancreatic cancer progression. We first investigated the expression of SIRT1 in a series of pancreatic cancer tissues as well as in a panel of pancreatic cancer cell lines. The effect of SIRT1 on cell activity was explored by knockdown experiments. Cell growth was measured using the MTT assay and colony-formation assay. Migration and invasion were tested using transwell assay. Our results showed that the expression of SIRT1 was significantly up-regulated both in pancreatic cancer tissues and cell lines. Knockdown of SIRT1 suppressed cell proliferation and migration of pancreatic cancer cells. This is the first report to disclose the role of SIRT1 in regulation of pancreatic cancer cell proliferation and migration, which may provide a potential therapeutic target for pancreatic cancer patients. PMID- 28351312 TI - Neuropeptide gastrin-releasing peptide induces PI3K/reactive oxygen species dependent migration in lung adenocarcinoma cells. AB - Nerve fibers and neurotransmitters have increasingly been shown to have a role in tumor progression. Gastrin-releasing peptide is a neuropeptide linked to tumor aggressiveness, acting as an autocrine tumor growth factor by binding to its receptor, gastrin-releasing peptide receptor, expressed by many tumors. Although neuropeptides have been previously linked to tumor cell proliferation, more recent studies have uncovered roles for neuropeptides in chemotaxis and metastasis. Understanding the precise roles of such peptides in cancer is crucial to optimizing targeted therapy design. We have previously described that gastrin releasing peptide acts directly as a chemotactic factor for neutrophils, dependent on PI3K, ERK, and p38. In this study, we investigated roles for gastrin releasing peptide in lung adenocarcinoma. We asked if gastrin-releasing peptide would act as a proliferative and/or chemotactic stimulus for gastrin-releasing peptide receptor-expressing tumor cells. In A549 cells, a non-small cell lung carcinoma line, the treatment with gastrin-releasing peptide leads to activation of AKT and ERK1/2, and production of reactive oxygen species. Gastrin-releasing peptide induced migration of A549 cells, dependent on gastrin-releasing peptide receptor and PI3K, but not ERK. However, no proliferation was observed in these cells in response to gastrin-releasing peptide, and gastrin-releasing peptide did not promote resistance to treatment with a chemotherapy drug. Our results suggest that, similar to what happens in neutrophils, gastrin-releasing peptide is a migratory, rather than a proliferative, stimulus, for non-small cell lung carcinoma cells, indicating a putative role for gastrin-releasing peptide and gastrin-releasing peptide receptor in metastasis. PMID- 28351314 TI - Inactivation of parkin by promoter methylation correlated with lymph node metastasis and genomic instability in nasopharyngeal carcinoma. AB - This study aimed to investigate the inactivation of the parkin gene by promoter methylation and its relationship with genome instability in nasopharyngeal carcinoma. Parkin was considered as a tumor suppressor gene in various types of cancers. However, its role in nasopharyngeal carcinoma is unexplored. Genomic instabilities were detected in nasopharyngeal carcinoma tissues by the random amplified polymorphic DNA. The methylation-specific polymerase chain reaction, semi-quantitative reverse transcription polymerase chain reaction, and immunohistochemical analysis were used to detect methylation and mRNA and protein expression of parkin in 54 cases of nasopharyngeal carcinoma tissues and 16 cases of normal nasopharyngeal epithelia tissues, and in 5 nasopharyngeal carcinoma cell lines (CNE1, CNE2, TWO3, C666, and HONE1) and 1 normal nasopharyngeal epithelia cell line (NP69). mRNA expression of parkin in CNE1 and CNE2 was analyzed before and after methyltransferase inhibitor 5-aza-2-deoxycytidine treatment. The relationship between promoter methylation and mRNA expression, demethylation and mRNA expression, and mRNA and protein expression of the gene and clinical factors and genomic instabilities were analyzed. The mRNA and protein expression levels were significantly reduced in 54 cases of human nasopharyngeal carcinoma compared with 16 cases of normal nasopharyngeal epithelia. Parkin-methylated cases showed significantly lower mRNA and protein expression levels compared with unmethylated cases. After 5-aza-2-deoxycytidine treatment, parkin mRNA expression was restored in CNE1 and CNE2; 92.59% (50/54) of nasopharyngeal carcinoma demonstrated genomic instability. Parkin is frequently inactivated by promoter methylation, and its mRNA and protein expression correlate with lymph node metastasis and genomic instability. Parkin deficiency probably promotes tumorigenesis in nasopharyngeal carcinoma. PMID- 28351315 TI - Obesity-associated digestive cancers: A review of mechanisms and interventions. AB - The prevalence of obesity has steadily increased over the past few decades. Previous studies suggest that obesity is an oncogenic factor and that over 20% of all cancers are obesity-related. Among such cancers, digestive system malignancies (including esophageal adenocarcinomas, colorectal cancers, and cancers of the gastric cardia, liver, and pancreas) are reported most frequently. While the 5-year survival rates of cancers of the breast and prostate are 90%, that rate is only 45% for digestive cancers. In this review, the mechanisms of obesity-associated digestive cancers are discussed, with an emphasis on obesity related gene mutations, insulin and insulin-like growth factor signaling pathways, chronic inflammation, and altered adipokine levels. Evidence that these factors often function interdependently rather than independently in carcinogenesis is presented. Recommended interventions that may reduce the burden of obesity-associated digestive cancers, such as participation in physical activity, diet modulation, and calorie restriction, are also described. PMID- 28351316 TI - Novel tetrahydroacridine and cyclopentaquinoline derivatives with fluorobenzoic acid moiety induce cell cycle arrest and apoptosis in lung cancer cells by activation of DNA damage signaling. AB - Lung cancer is still the leading cause of cancer-related death worldwide, indicating a necessity to develop more effective therapy. Acridine derivatives are potential anticancer agents due to their ability to intercalate DNA as well as inhibit enzymes involved in replication and transcription. Recently, we have evaluated anticancer activity of 32 novel acridine-based compounds. We found that the most effective were tetrahydroacridine and cyclopentaquinoline derivatives with fluorobenzoic acid containing eight and nine carbon atoms in the aliphatic chain. The aim of this study was to determine the molecular mechanisms of compounds-induced cell cycle arrest and apoptosis in human lung adenocarcinoma cells. All compounds activated Ataxia telangiectasia mutated kinase and phosphorylated histone H2A.X at Ser139 indicating DNA damage. Treatment of cells with the compounds increased phosphorylation and accumulation of p53 that regulate cell cycle as well as apoptosis. All compounds induced G0/1 cell cycle arrest by phosphorylation of cyclin-dependent kinase 2 at Tyr15 resulting in attenuation of the kinase activity. In addition, cyclopentaquinoline derivatives induced expression of cyclin-dependent kinase 2 inhibitor, p21; however, tetrahydroacridine derivatives had no significant effect on p21. Moreover, all compounds decreased the mitochondrial membrane potential accompanied by increased expression of Bax and down-regulation of Bcl-2, suggesting activation of the mitochondrial pathway. All compounds also significantly attenuated the migration rates of lung cancer cells. Collectively, our findings suggest a central role of activation of DNA damage signaling in response to new acridine derivatives treatment to induce cell cycle arrest and apoptosis in cancer cells and provide support for their further development as potential drug candidates. PMID- 28351317 TI - Impact of epidermal growth factor receptor gene expression level on clinical outcomes in epidermal growth factor receptor mutant lung adenocarcinoma patients taking first-line epidermal growth factor receptor-tyrosine kinase inhibitors. AB - Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are first-choice treatments for advanced non-small-cell lung cancer patients harboring EGFR mutations. Although EGFR mutations are strongly predictive of patients' outcomes and their response to treatment with EGFR-TKIs, early failure of first-line therapy with EGFR-TKIs in patients with EGFR mutations is not rare. Besides several clinical factors influencing EGFR-TKI efficacies studied earlier such as the Eastern Cooperative Oncology Group performance status or uncommon mutation, we would like to see whether semi-quantify EGFR mutation gene expression calculated by 2-DeltaDeltact was a prognostic factor in EGFR-mutant non-small cell lung cancer patients receiving first-line EGFR-TKIs. This retrospective study reviews 926 lung cancer patients diagnosed from January 2011 to October 2013 at the Kaohsiung Chang Gung Memorial Hospital in Taiwan. Of 224 EGFR-mutant adenocarcinoma patients, 148 patients who had 2-DeltaDeltact data were included. The best cutoff values of 2-DeltaDeltact for in-frame deletions in exon 19 (19 deletion) and a position 858 substituted from leucine (L) to an arginine (R) in exon 21 (L858R) were determined using receiver operating characteristic curves. Patients were divided into high and low 2-DeltaDeltact expression based on the above cutoff level. The best cutoff point of 2 DeltaDeltact value of 19 deletion and L858R was 31.1 and 104.7, respectively. In all, 92 (62.1%) patients showed high 2-DeltaDeltact expression and 56 patients (37.9%) low 2-DeltaDeltact expression. The mean age was 65.6 years. Progression free survival of 19 deletion mutant patients with low versus high expression level was 17.07 versus 12.04 months (P = 0.004), respectively. Progression-free survival of L858 mutant patients was 13.75 and 7.96 months (P = 0.008), respectively. EGFR-mutant lung adenocarcinoma patients with lower EGFR gene expression had longer progression-free survival duration without interfering overall survival. PMID- 28351318 TI - Cytotoxicity of citral against melanoma cells: The involvement of oxidative stress generation and cell growth protein reduction. AB - Citral is a natural compound that has shown cytotoxic and antiproliferative effects on breast and hematopoietic cancer cells; however, there are few studies on melanoma cells. Oxidative stress is known to be involved in all stages of melanoma development and is able to modulate intracellular pathways related to cellular proliferation and death. In this study, we hypothesize that citral exerts its cytotoxic effect on melanoma cells by the modulation of cellular oxidative status and/or intracellular signaling. To test this hypothesis, we investigated the antiproliferative and cytotoxic effects of citral on B16F10 murine melanoma cells evaluating its effects on cellular oxidative stress, DNA damage, cell death, and important signaling pathways, as these pathways, namely, extracellular signal-regulated kinases 1/2 (ERK1/2), AKT, and phosphatidylinositol-3 kinase, are involved in cell proliferation and differentiation. The p53 and nuclear factor kappa B were also investigated due to their ability to respond to intracellular stress. We observed that citral exerted antiproliferative and cytotoxic effects in B16F10; induced oxidative stress, DNA lesions, and p53 nuclear translocation; and reduced nitric oxide levels and nuclear factor kappa B, ERK1/2, and AKT. To investigate citral specificity, we used non-neoplastic human and murine cells, HaCaT (human skin keratinocytes) and NIH-3T3 cells (murine fibroblasts), and observed that although citral effects were not specific for cancer cells, non-neoplastic cells were more resistant to citral than B16F10. These findings highlight the potential clinical utility of citral in melanoma, with a mechanism of action involving the oxidative stress generation, nitric oxide depletion, and interference in signaling pathways related to cell proliferation. PMID- 28351320 TI - Promising therapeutic role of miR-27b in tumor. AB - MicroRNAs are small nonprotein-encoding RNAs ranging from 18 to 25 nucleotides in size and regulate multiple biological pathways via directly targeting a variety of associated genes in cancers. MicroRNA-27b is a highly conserved MicroRNA throughout vertebrates and there are two homologs (hsa-miR-27a and hsa-miR-27b) in humans. MicroRNA-27b is an intragenic microRNA located on chromosome 9q22.1 within the C9orf3 gene, clustering with miR-23b and miR-24-1 in human. As a frequently dysregulated microRNA in human cancers, microRNA-27b could function as a tumor suppressor or an oncogenic microRNA. More and more studies indicate that microRNA-27b is involved in affecting various biological processes, such as angiogenesis, proliferation, metastasis, and drug resistance, and thus may act as a promising therapeutic target in human cancers. In this review, we discuss the role of microRNA-27b in detail and offer novel insights into molecular targeting therapy for cancers. PMID- 28351319 TI - SF3B4 is decreased in pancreatic cancer and inhibits the growth and migration of cancer cells. AB - Splicing factor 3b subunit 4, a critical component of pre-message RNA splicing complex, has been reported to play an important part in the tumorigenesis. However, the expression pattern and biological role of splicing factor 3b subunit 4 in pancreatic cancer have never been investigated. In this study, we found that both the messenger RNA ( p < 0.001) and protein level of splicing factor 3b subunit 4 were decreased significantly in pancreatic cancer specimens compared with their adjacent normal tissues. Overexpression of splicing factor 3b subunit 4 in pancreatic cancer cells inhibited cell growth and motility in vitro, while suppressing splicing factor 3b subunit 4 expression promoted the proliferation and migration of pancreatic cancer cells. In addition, splicing factor 3b subunit 4 was found to inhibit the activity of signal transducer and activator of transcription 3 signaling via downregulating the phosphorylation of signal transducer and activator of transcription 3 on a tyrosine residue at position 705. Taken together, these findings demonstrated that splicing factor 3b subunit 4 acted as a suppressive role in pancreatic cancer and indicated that restoring the function of splicing factor 3b subunit 4 might be a strategy for cancer therapy. PMID- 28351321 TI - Mammalian target of rapamycin inhibitors, temsirolimus and torin 1, attenuate stemness-associated properties and expression of mesenchymal markers promoted by phorbol-myristate-acetate and oncostatin-M in glioblastoma cells. AB - The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling pathway is crucial for tumor survival, proliferation, and progression, making it an attractive target for therapeutic intervention. In glioblastoma, activated mammalian target of rapamycin promotes invasive phenotype and correlates with poor patient survival. A wide range of mammalian target of rapamycin inhibitors are currently being evaluated for cytotoxicity and anti-proliferative activity in various tumor types but are not explored sufficiently for controlling tumor invasion and recurrence. We recently reported that mammalian target of rapamycin inhibitors-rapamycin, temsirolimus, torin 1, and PP242-suppressed invasion and migration promoted by tumor necrosis factor-alpha and phorbol-myristate-acetate in glioblastoma cells. As aggressive invasion and migration of tumors are associated with mesenchymal and stem-like cell properties, this study aimed to examine the effect of mammalian target of rapamycin inhibitors on these features in glioblastoma cells. We demonstrate that temsirolimus and torin 1 effectively reduced the constitutive as well as phorbol-myristate-acetate/oncostatin-M induced expression of mesenchymal markers (fibronectin, vimentin, and YKL40) and neural stem cell markers (Sox2, Oct4, nestin, and mushashi1). The inhibitors significantly abrogated the neurosphere-forming capacity induced by phorbol myristate-acetate and oncostatin-M. Furthermore, we demonstrate that the drugs dephosphorylated signal transducer and activator transcription factor 3, a major regulator of mesenchymal and neural stem cell markers implicating the role of signal transducer and activator transcription factor 3 in the inhibitory action of these drugs. The findings demonstrate the potential of mammalian target of rapamycin inhibitors as "stemness-inhibiting drugs" and a promising therapeutic approach to target glioma stem cells. PMID- 28351322 TI - PVT1 affects growth of glioma microvascular endothelial cells by negatively regulating miR-186. AB - Vigorous angiogenesis is one of the reasons for the poor prognosis of glioma. A number of studies have shown that long non-coding RNA can affect a variety of biological behaviors of tumors. However, the influence of long non-coding RNAs on glioma vascular endothelial cells remains unclear. To simulate the glioma microenvironment, we applied glioma-conditioned medium to human cerebral microvascular endothelial cells. The long non-coding RNA PVT1 was found to be highly expressed in glioma vascular endothelial cells. Cell Counting Kit-8, migration, and tube formation assays showed that PVT1 overexpression promoted glioma vascular endothelial cells proliferation, migration, and angiogenesis. We also found that PVT1 overexpression upregulated the expression of the autophagy related proteins Atg7 and Beclin1, which induced protective autophagy. Bioinformatics software and dual-luciferase system analysis confirmed that PVT1 acts by targeting miR-186. In addition, our study showed that miR-186 could target the 3' untranslated region of Atg7 and Beclin1 to decrease their expression levels, thereby inhibiting glioma-conditioned human cerebral microvascular endothelial cell autophagy. In conclusion, PVT1 overexpression increased the expression of Atg7 and Beclin1 by targeting miR-186, which induced protective autophagy, thus promoting glioma vascular endothelial cell proliferation, migration, and angiogenesis. Therefore, PVT1 and miR-186 can provide new therapeutic targets for future anti-angiogenic treatment of glioma. PMID- 28351323 TI - gamma-H2AX: Can it be established as a classical cancer prognostic factor? AB - Double-strand breaks are among the first procedures taking place in cancer formation and progression as a result of endogenic and exogenic factors. The histone variant H2AX undergoes phosphorylation at serine 139 due to double-strand breaks, and the gamma-H2AX is formatted as a result of genomic instability. The detection of gamma-H2AX can potentially serve as a biomarker for transformation of normal tissue to premalignant and consequently to malignant tissues. gamma H2AX has already been investigated in a variety of cancer types, including breast, lung, colon, cervix, and ovary cancers. The prognostic value of gamma H2AX is indicated in certain cancer types, such as breast or endometrial cancer, but further investigation is needed to establish gamma-H2AX as a prognostic marker. This review outlines the role of gamma-H2AX in cell cycle, and its formation as a result of DNA damage. We investigate the role of gamma-H2AX formation in several cancer types and its correlation with other prognostic factors, and we try to find out whether it fulfills the requirements for its establishment as a classical cancer prognostic factor. PMID- 28351324 TI - The 5th Annual One Mind Summit: Lessons Learned About "Science Informing Brain Health Policies and Practice". AB - Advances in science frequently precede changes in clinical care by several years or even decades. To better understand the path to translation, we invited experts to share their perspectives at the 5th Annual One Mind Summit: "Science Informing Brain Health Policies and Practice", which was held on May 24-25, 2016 in Crystal City, VA. While the translation of brain research throughout the pipeline - from basic science research to patient care - was discussed, the focus was on the implementation of "best evidence" into patient care. The Summit identified key steps, including the need for professional endorsement and clinical guidelines or policies, acceptance by regulators and payers, dissemination and training for clinicians, patient advocacy, and learning healthcare models. The path to implementation was discussed broadly, as well as in the context of a specific project to implement concussion screening in emergency and urgent care centers throughout the U.S. PMID- 28351325 TI - Intracellular calcium promotes radioresistance of non-small cell lung cancer A549 cells through activating Akt signaling. AB - Radiotherapy is a major therapeutic approach in non-small cell lung cancer but is restricted by radioresistance. Although Akt signaling promotes radioresistance in non-small cell lung cancer, it is not well understood how Akt signaling is activated. Since intracellular calcium (Ca2+) could activate Akt in A549 cells, we investigated the relationship between intracellular calcium (Ca2+) and Akt signaling in radioresistant A549 cells by establishing radioresistant non-small cell lung cancer A549 cells. The radioresistant cell line A549 was generated by dose-gradient irradiation of the parental A549 cells. The cell viability, proliferation, and apoptosis were, respectively, assessed using the cell counting kit-8, EdU labeling, and flow cytometry analysis. The phosphorylation of Akt was evaluated by Western blotting, and the intracellular Ca2+ concentration was assessed by Fluo 4-AM. The radioresistant A549 cells displayed mesenchymal morphology. After additional irradiation, the radioresistant A549 cells showed decreased cell viability and proliferation but increased apoptosis. Moreover, the intracellular Ca2+ concentration and the phosphorylation level on the Akt473 site in radioresistant A549 cells were higher than those in original cells, whereas the percentage of apoptosis in radioresistant A549 cells was less. All these results could be reversed by verapamil. In conclusion, our study found that intracellular Ca2+ could promote radioresistance of non-small cell lung cancer cells through phosphorylating of Akt on the 473 site, which contributes to a better understanding on the non-small cell lung cancer radioresistance, and may provide a new target for radioresistance management. PMID- 28351326 TI - Suppression of p53-inducible gene 3 is significant for glioblastoma progression and predicts poor patient prognosis. AB - Glioblastoma is the most malignant and invasive brain tumor with extremely poor prognosis. p53-inducible gene 3, a downstream molecule of the tumor suppressor p53, has been found involved in apoptosis and oxidative stress response. However, the functions of p53-inducible gene 3(PIG3) in cancer are far from clear including glioblastoma. In this study, we found that p53-inducible gene 3 expression was suppressed in glioblastoma tissues compared with normal tissues. And the expression of p53-inducible gene 3 was significantly associated with the World Health Organization grade. Patients with high p53-inducible gene 3 expression have a significantly longer median survival time (15 months) than those with low p53-inducible gene 3 expression (8 months). According to Cox regression analysis, p53-inducible gene 3 was an independent prognostic factor with multivariate hazard ratio of 0.578 (95% confidence interval, 0.352-0.947; p = 0.030) for overall survival. Additionally, gain and loss of function experiments showed that knockdown of p53-inducible gene 3 significantly increased the proliferation and invasion ability of glioblastoma cells while overexpression of p53-inducible gene 3 inhibited the proliferation and invasion ability. The results of in vivo glioblastoma models further confirmed that p53-inducible gene 3 suppression promoted glioblastoma progression. Altogether, our data suggest that high expression of p53-inducible gene 3 is significant for glioblastoma inhibition and p53-inducible gene 3 independently indicates good prognosis in patients, which might be a novel prognostic biomarker or potential therapeutic target in glioblastoma. PMID- 28351327 TI - Nigericin decreases the viability of multidrug-resistant cancer cells and lung tumorspheres and potentiates the effects of cardiac glycosides. AB - Multiple factors including tumor heterogeneity and intrinsic or acquired resistance have been associated with drug resistance in lung cancer. Increased stemness and the plasticity of cancer cells have been identified as important mechanisms of resistance; therefore, treatments targeting cancer cells independent of stemness phenotype would be much more effective in treating lung cancer. In this article, we have characterized the anticancer effects of the antibiotic Nigericin in cells displaying varying degrees of stemness and resistance to anticancer drugs, arising from (1) routine culture conditions, (2) prolonged periods of serum starvation. These cells are highly resistant to conventional anticancer drugs such as Paclitaxel, Hydroxyurea, Colchicine, Obatoclax, Wortmannin, and LY294002, and the multidrug-resistant phenotype of cells growing under prolonged periods of serum starvation is likely the result of extensive rewiring of signaling pathways, and (3) lung tumorspheres that are enriched for cancer stem-like cells. We found that Nigericin potently inhibited the viability of cells growing under routine culture conditions, prolonged periods of serum starvation, and lung tumorspheres. In addition, we found that Nigericin downregulated the expression of key proteins in the Wnt canonical signaling pathway such as LRP6, Wnt5a/b, and beta-catenin, but promotes beta catenin translocation into the nucleus. The antitumor effects of Nigericin were potentiated by the Wnt activator HLY78 and by therapeutic levels of the US Food and Drug Administration-approved drug Digitoxin and its novel synthetic analog MonoD. We believe that Nigericin may be used in a co-therapy model in combination with other novel chemotherapeutic agents in order to achieve potent inhibition of cancers that display varying degrees of stemness, potentially leading to sustained anticancer effects. PMID- 28351328 TI - Effect of EBI3 on radiation-induced immunosuppression of cervical cancer HeLa cells by regulating Treg cells through PD-1/PD-L1 pathway. AB - This study aimed to investigate the effect of EBI3 on radiation-induced immunosuppression of cervical cancer HeLa cells by regulating Treg cells through PD-1/PD-L1 signaling pathway. A total of 43 adult female Wistar rats were selected and injected with HeLa cells in the caudal vein to construct a rat model of cervical cancer. All model rats were randomly divided into the radiotherapy group ( n = 31) and the control group ( n = 12). The immunophenotype of Treg cells was detected by the flow cytometry. The protein expressions of EBI3, PD-1, and PD-L1 in cervical cancer tissues were tested by the streptavidin-peroxidase method. HeLa cells in the logarithmic growth phase were divided into four groups: the blank, the negative control group, the EBI3 mimics group, and the EBI3 inhibitors group. Western blotting was used to detect PD-1 and PD-L1 protein expressions. MTT assay was performed to measure the proliferation of Treg cells. Flow cytometry was used to detect cell cycle and apoptosis, and CD4+/CD8+ T cell ratio in each group. Compared with before and 1 week after radiotherapy, the percentages of CD4+T cells and CD8+T cells were significantly decreased in the radiotherapy group at 1 month after radiotherapy. Furthermore, down-regulation of EBI3 and up-regulation of PD-1 and PD-L1 were observed in cervical cancer tissues at 1 month after radiotherapy. In comparison to the blank and negative control groups, increased expression of EBI3 and decreased expressions of PD-1 and PD-L1 were found in the EBI3 mimics group. However, the EBI3 inhibitors group had a lower expression of EBI3 and higher expressions of PD-1 and PD-L1 than those in the blank and negative control groups. The EBI3 mimics group showed an increase in the optical density value (0.43 +/- 0.05), while a decrease in the optical density value (0.31 +/- 0.02) was found in the EBI3 inhibitors group. Moreover, compared with the blank and negative control groups, the apoptosis rates of Treg/CD4+T/CD8+T cells were decreased in the EBI3 mimics group, but the EBI3 inhibitors group exhibited an increase in apoptosis rate. In conclusion, over expression of EBI3 could reduce the apoptosis of Treg/CD4+T/CD8+T cells and prevent radiation-induced immunosuppression of cervical cancer HeLa cells by inhibiting the activation of PD-1/PD-L1 signaling pathway. PMID- 28351329 TI - Crocetin shifts autophagic cell survival to death of breast cancer cells in chemotherapy. AB - The chemotherapy with fluorouracil is not always effective, in which some breast cancer cells may survive the fluorouracil treatment through enhanced autophagy. Crocetin is the major constituent of saffron, a Chinese traditional herb, which has recently found to have multiple pharmacological effects, including anticancer. However, the effects of Crocetin on the outcome of fluorouracil therapy for breast cancer have not been studied. Here, we showed that fluorouracil treatment inhibited the growth of breast cancer cells, in either a Cell Counting Kit-8 assay or an MTT assay. Inhibition of autophagy further suppressed breast cancer cell growth, suggesting that the breast cancer cells increased autophagic cell survival during fluorouracil treatment. However, Crocetin significantly increased the suppressive effects of fluorouracil on breast cancer cell growth, without affecting either cell apoptosis or autophagy. Inhibition of autophagy at the presence of Crocetin partially abolished the suppressive effects on breast cancer cell growth, suggesting that Crocetin may increase autophagic cell death in fluorouracil-treated breast cancer cells. Furthermore, Crocetin decreased Beclin-1 levels but increased ATG1 levels in fluorouracil-treated breast cancer cells. Together, these data suggest that Crocetin may shift autophagic cell survival to autophagic cell death in fluorouracil-treated breast cancer cells, possibly through modulation of the expression of ATG1 and Beclin-1. PMID- 28351330 TI - Stratified aspartate aminotransferase-to-platelet ratio index accurately predicts survival in hepatocellular carcinoma patients undergoing curative liver resection. AB - The aspartate aminotransferase-to-platelet ratio index has been reported to predict prognosis of patients with hepatocellular carcinoma. This study examined the prognostic potential of stratified aspartate aminotransferase-to-platelet ratio index for hepatocellular carcinoma patients undergoing curative liver resection. A total of 661 hepatocellular carcinoma patients were retrieved and the associations between aspartate aminotransferase-to-platelet ratio index and clinicopathological variables and survivals (overall survival and disease-free survival) were analyzed. Higher aspartate aminotransferase-to-platelet ratio index quartiles were significantly associated with poorer overall survival (p = 0.002) and disease-free survival (p = 0.001). Multivariate analysis showed aspartate aminotransferase-to-platelet ratio index to be an independent risk factor for overall survival (p = 0.018) and disease-free survival (p = 0.01). Patients in the highest aspartate aminotransferase-to-platelet ratio index quartile were at 44% greater risk of death than patients in the first quartile (hazard ratio = 1.445, 95% confidence interval = 1.081 - 1.931, p = 0.013), as well as 49% greater risk of recurrence (hazard ratio = 1.49, 95% confidence interval = 1.112-1.998, p = 0.008). Subgroup analysis also showed aspartate aminotransferase-to-platelet ratio index to be an independent predictor of poor overall survival and disease-free survival in patients positive for hepatitis B surface antigen or with cirrhosis (both p < 0.05). Similar results were obtained when aspartate aminotransferase-to-platelet ratio index was analyzed as a dichotomous variable with cutoff values of 0.25 and 0.62. Elevated preoperative aspartate aminotransferase-to-platelet ratio index may be independently associated with poor overall survival and disease-free survival in hepatocellular carcinoma patients following curative resection. PMID- 28351331 TI - MiR-613 suppresses retinoblastoma cell proliferation, invasion, and tumor formation by targeting E2F5. AB - Retinoblastoma is a common intraocular malignancy that occurs during childhood. MicroRNAs play critical roles in the regulation of retinoblastoma initiation and progression, and aberrant expression of miR-613 had been reported in various types of cancer. However, the role and mechanism of its function in retinoblastoma are still unclear. In this study, we found that miR-613 was downregulated in retinoblastoma tissues and cell lines. Overexpression of miR-613 suppressed retinoblastoma cell proliferation, migration, and invasion and induced cell cycle arrest in vitro. Additionally, overexpressed miR-613 also inhibited tumor formation of retinoblastoma cells in vivo. We further identified E2F5 as a direct target of miR-613. Reintroduction of E2F5 without 3'-untranslated region reversed the inhibitory effects of miR-613 on cell proliferation and invasion. Our data collectively indicate that miR-613 functions as a tumor suppressor in retinoblastoma through downregulating E2F5, supporting the targeting of the novel miR-613/E2F5 axis as a potentially effective therapeutic approach for retinoblastoma. PMID- 28351332 TI - Tumor rim cells: From resistance to vascular targeting agents to complete tumor ablation. AB - Current vascular targeting strategies pursue two main goals: anti-angiogenesis agents aim to halt sprouting and the formation of new blood vessels, while vascular disrupting agents along with coaguligands seek to compromise blood circulation in the vessels. The ultimate goal of such therapies is to deprive tumor cells out of oxygen and nutrients long enough to succumb cancer cells to death. Most of vascular targeting agents presented promising therapeutic potential, but the final goal which is cure is rarely achieved. Nevertheless, in both preclinical and clinical settings, tumors tend to grow back, featuring a highly invasive, metastatic, and extremely resistant form. This review highlights the critical significance of tumor rim cells as the main factor, determining therapy success with vascular targeting agents. We present an overview of different single and combination treatments with vascular targeting agents that enable efficient targeting of tumor rim cells and long-lasting tumor cure. Understanding the nature of tumor rim cells, how they establish, how they manage to survive of vascular targeting agents, and how they contribute in tumor refractoriness, may open new avenues to the development of beneficial strategies, capable to eliminate residual rim cells, and enable tumor ablation once and forever. PMID- 28351333 TI - Splicing factor hnRNPA2B1 contributes to tumorigenic potential of breast cancer cells through STAT3 and ERK1/2 signaling pathway. AB - Increasing evidence has indicated that the splicing factor hnRNPA2B1 plays a direct role in cancer development, progression, gene expression, and signal transduction. Previous studies have shown that knocking down hnRNPA2B1 in breast cancer cells induces apoptosis, but the mechanism and other functions of hnRNPA2B1 in breast cancer are unknown. The goal of this study was to investigate the biological function, clinical significance, and mechanism of hnRNPA2B1 in breast cancer. The expression of hnRNPA2B1 in 92 breast cancer and adjacent normal tissue pairs was analyzed by immunohistochemical staining. Stable clones exhibiting knockdown of hnRNPA2B1 via small hairpin RNA expression were generated using RNA interference technology in breast cancer cell lines. The effects of hnRNPA2B1 on cell proliferation were examined by MTT and EdU assay, and cellular apoptosis and the cell cycle were examined by flow cytometry. A nude mouse xenograft model was established to elucidate the function of hnRNPA2B1 in tumorigenesis in vivo. The role of hnRNPA2B1 in signaling pathways was investigated in vitro. Our data revealed that hnRNPA2B1 was overexpressed in breast cancer tissue specimens and cell lines. Knockdown of hnRNPA2B1 reduced breast cancer cell proliferation, induced apoptosis, and prolonged the S phase of the cell cycle in vitro. In addition, hnRNPA2B1 knockdown suppressed subcutaneous tumorigenicity in vivo. On a molecular level, hnRNPA2B1 knockdown decreased signal transducer and activator of transcription 3 and extracellular-signal regulated kinase 1/2 phosphorylation. We concluded that hnRNPA2B1 promotes the tumorigenic potential of breast cancer cells, MCF-7 and MDA-MB-231, through the extracellular-signal-regulated kinase 1/2 or signal transducer and activator of transcription 3 pathway, which may serve as a target for future therapies. PMID- 28351334 TI - Upregulation of SENP3/SMT3IP1 promotes epithelial ovarian cancer progression and forecasts poor prognosis. AB - As a crucial member of the small ubiquitin-like modifier system, SUMO-specific protease 3, was identified to be essential for cell proliferation and ribosomal RNA processing. Recent studies showed that SUMO-specific protease 3 was elevated in ovarian cancer compared to normal tissue samples. However, the connection between SUMO-specific protease 3-specific expression and clinicopathological parameters of epithelial ovarian cancer, as well as the physiologically potential role of SUMO-specific protease 3 in epithelial ovarian cancer remained unclear. In this study, an analysis of 124 paraffin-embedded slices by immunohistochemistry indicated that SUMO-specific protease 3 expression was positively correlated with the International Federation of Gynecology and Obstetrics stages (p = 0.025), tumor grade (p = 0.004), and lymph node metastasis (p = 0.001) and was also a critical prognostic factor for the overall survival of epithelial ovarian cancer patients, as revealed by Kaplan-Meier curve analysis. Knockdown of SUMO-specific protease 3 weakened the proliferation, migration, and invasion capability of ovarian cancer cells, down-regulated the expression of Proliferating Cell Nuclear Antigen, Forkhead Box C2, and N-cadherin, and resulted in upregulation of p21 and E-cadherin. Consistent with our results, SUMO-specific protease 3 had been verified to promote cell proliferation, metastasis, and tumorigenesis in multiple malignant cancers, which was a redox-sensitive molecule mediating the epithelial-mesenchymal transition. Collectively, our findings for the first time specifically supported that SUMO-specific protease 3 might play an important role in the regulation of epithelial ovarian cancer progression and could serve as a potential biomarker for prognosis as well as provide a promising therapeutic target against epithelial ovarian cancer. PMID- 28351335 TI - Prostate-specific membrane antigen-directed nanoparticle targeting for extreme nearfield ablation of prostate cancer cells. AB - Almost all biological therapeutic interventions cannot overcome neoplastic heterogeneity. Physical ablation therapy is immune to tumor heterogeneity, but nearby tissue damage is the limiting factor in delivering lethal doses. Multi walled carbon nanotubes offer a number of unique properties: chemical stability, photonic properties including efficient light absorption, thermal conductivity, and extensive surface area availability for covalent chemical ligation. When combined together with a targeting moiety such as an antibody or small molecule, one can deliver highly localized temperature increases and cause extensive cellular damage. We have functionalized multi-walled carbon nanotubes by conjugating an antibody against prostate-specific membrane antigen. In our in vitro studies using prostate-specific membrane antigen-positive LNCaP prostate cancer cells, we have effectively demonstrated cell ablation of >80% with a single 30-s exposure to a 2.7-W, 532-nm laser for the first time without bulk heating. We also confirmed the specificity and selectivity of prostate-specific membrane antigen targeting by assessing prostate-specific membrane antigen-null PC3 cell lines under the same conditions (<10% cell ablation). This suggests that we can achieve an extreme nearfield cell ablation effect, thus restricting potential tissue damage when transferred to in vivo clinical applications. Developing this new platform will introduce novel approaches toward current therapeutic modalities and will usher in a new age of effective cancer treatment squarely addressing tumoral heterogeneity. PMID- 28351336 TI - B-cell lymphoma 2 inhibitor ABT-737 induces Beclin1- and reactive oxygen species dependent autophagy in Adriamycin-resistant human hepatocellular carcinoma cells. AB - ABT-737, a B-cell lymphoma 2 homology 3 mimetic, not only induces cell apoptosis by inhibiting the interaction of B-cell lymphoma 2 and Bax but also induces cell autophagy by interrupting the interaction of B-cell lymphoma 2 and Beclin1. Several recent studies have reported that ABT-737 has antitumor efficacy in diverse cancers. However, another study showed that hepatocellular carcinoma cells with high B-cell lymphoma 2 expression were resistant to ABT-737 compared to hepatocellular carcinoma cells with low B-cell lymphoma 2 expression. It was also found that ABT-737-induced autophagy is crucial for drug resistance. Here, we observed that of B-cell lymphoma 2 expression in Adriamycin-resistant human hepatocellular carcinoma HepG2/ADM cells is higher than that in human hepatocellular carcinoma HepG2 cells. Therefore, we further confirmed the mechanism and effect of autophagy induced by ABT-737 on apoptosis in HepG2/ADM cells with high B-cell lymphoma 2 expression. Our results showed that ABT-737 induced apoptosis and autophagy in time- and dose-dependent manner in HepG2/ADM cells, and this ABT-737-induced autophagy was Beclin1-dependent. In addition, we demonstrated that ABT-737 induced reactive oxygen species-mediated autophagy, and the reactive oxygen species-inhibitor N-acetyl-l-cysteine suppressed the reactive oxygen species-induced autophagy and ABT-737-induced increase in HepG2/ADM cell apoptosis. Furthermore, autophagy inhibitors increased HepG2/ADM cell apoptosis. In conclusion, our study further confirms that Beclin1- and reactive oxygen species-dependent autophagy induced by ABT-737 also plays a protective function in HepG2/ADM cells, which show B-cell lymphoma 2 expression higher than that in HepG2 cells. PMID- 28351337 TI - Zika virus NS5 protein potential inhibitors: an enhanced in silico approach in drug discovery. AB - The re-emerging Zika virus (ZIKV) is an arthropod-borne virus that has been described to have explosive potential as a worldwide pandemic. The initial transmission of the virus was through a mosquito vector, however, evolving modes of transmission has allowed the spread of the disease over continents. The virus has already been linked to irreversible chronic central nervous system conditions. The concerns of the scientific and clinical community are the consequences of Zika viral mutations, thus suggesting the urgent need for viral inhibitors. There have been large strides in vaccine development against the virus but there are still no FDA approved drugs available. Rapid rational drug design and discovery research is fundamental in the production of potent inhibitors against the virus that will not just mask the virus, but destroy it completely. In silico drug design allows for this prompt screening of potential leads, thus decreasing the consumption of precious time and resources. This study demonstrates an optimized and proven screening technique in the discovery of two potential small molecule inhibitors of ZIKV Methyltransferase and RNA dependent RNA polymerase. This in silico 'per-residue energy decomposition pharmacophore' virtual screening approach will be critical in aiding scientists in the discovery of not only effective inhibitors of Zika viral targets, but also a wide range of anti-viral agents. PMID- 28351338 TI - * Demineralized Bone Matrix as a Carrier for Bone Morphogenetic Protein-2: Burst Release Combined with Long-Term Binding and Osteoinductive Activity Evaluated In Vitro and In Vivo. AB - To allow bone defect regeneration, autologous bone grafting still represents the gold standard. However, autograft harvesting has limitations, including an additional surgery, donor site morbidity, and limited availability. Demineralized bone matrix (DBM) would represent an alternative, yet lacks sufficient osteoinductive properties. Combining DBM with a potent agent, such as bone morphogenetic protein-2 (BMP-2) might be a feasible alternative approach, optimizing an established grafting material with strong osteoinductive properties. A unique mixing device has been developed that enables perioperative handling to reach a homogeneous and standardized paste for bone defect filling. DBM proved in vitro to be a suitable carrier for BMP-2, with a documented release over 56 days at concentrations sufficient to stimulate osteogenic differentiation. At the end of the elution experiment, 56 days, bioactive BMP was still captured within the DBM. Using a sheep drill hole defect model, DBM perioperatively mixed with BMP-2 showed strong osteoinductive properties comparable to those of autologous bone and outnumbering the one of DBM alone or empty defects. Bone defect healing was enabled at diaphyseal and metaphyseal defects and thus BMP-2-doped DBM represented an easy perioperative enriching method and an efficient carrier for BMP-2. With the comparability to the clinical gold standard autologous bone, DBM mixed with BMP-2 might serve as possible alternative grafting material enabling a controlled osteogenic stimulation. PMID- 28351339 TI - Antibiotic resistance patterns of bacteria isolated from indwelling Foley catheters following tube cystostomy in goats with obstructive urolithiasis. AB - Tube cystostomy is a surgical method used for managing obstructive urolithiasis and involves placement of a Foley catheter into the urinary bladder. We identified and evaluated the antibiotic resistance patterns of bacteria isolated from indwelling Foley catheters following tube cystostomy in goats with obstructive urolithiasis. Urine samples collected over a 10-y period from catheter tips at the time of removal were submitted for bacteriologic culture and antibiotic susceptibility testing. Resistance patterns to antibiotics, trends in the resistance patterns over the study period, and the probability of a bacterial isolate being resistant as a function of the identity of the isolate and antibiotic tested were determined. A total of 103 urine samples from 103 male goats with obstructive urolithiasis managed surgically with tube cystostomy were included in the study. Aerococcus (36.9%) and Enterococcus (30.1%) were isolated most frequently. The susceptibility patterns of all bacteria isolated did not change over the study period ( p > 0.05). Proportions of isolates resistant to 1, 2, and >=3 antibiotics were 36.9%, 18.5%, and 23.3%, respectively. Thus, 41.8% of bacterial isolates were resistant to 2 or more antibiotics tested. The probability of Aerococcus spp., Escherichia coli, and Pseudomonas aeruginosa isolates to be resistant to ampicillin, ceftiofur, erythromycin, penicillin, or tetracycline ranged from 0.59 to 0.76. PMID- 28351340 TI - Molecular Pathology of Anaplastic Thyroid Carcinomas: A Retrospective Study of 144 Cases. AB - BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a rare tumor, with poorly defined oncogenic molecular mechanisms and limited therapeutic options contributing to its poor prognosis. The aims of this retrospective study were to determine the frequency of anaplastic lymphoma kinase (ALK) translocations and to identify the mutational profile of ATC including TERT promoter mutations. METHODS AND MATERIALS: One hundred and forty-four ATC cases were collected from 10 centers that are a part of the national French network for management of refractory thyroid tumors. Fluorescence in situ hybridization analysis for ALK rearrangement was performed on tissue microarrays. A panel of 50 genes using next generation sequencing and TERT promoter mutations using Sanger sequencing were also screened. RESULTS: Fluorescence in situ hybridization was interpretable for 90 (62.5%) cases. One (1.1%) case was positive for an ALK rearrangement with a borderline threshold (15% positive cells). Next-generation sequencing results were interpretable for 94 (65.3%) cases, and Sanger sequencing (TERT) for 98 (68.1%) cases. A total of 210 mutations (intronic and exonic) were identified. TP53 alterations were the most frequent (54.4%). Forty-three percent harbored a mutation in the (H-K-N)RAS genes, 13.8% a mutation in the BRAF gene (essentially p.V600E), 17% a PI3K-AKT pathway mutation, 6.4% both RAS and PI3K pathway mutations, and 4.3% both TP53 and PTEN mutations. Nearly 10% of the cases showed no mutations of the RAS, PI3K-AKT pathways, or TP53, with mutations of ALK, ATM, APC, CDKN2A, ERBB2, RET, or SMAD4, including mutations not yet described in thyroid tumors. Genes encoding potentially druggable targets included: mutations in the ATM gene in four (4.3%) cases, in ERBB2 in one (1.1%) case, in MET in one (1.1%) case, and in ALK in one (1.1%) case. A TERT promoter alteration was found in 53 (54.0%) cases, including 43 C228T and 10 C250T mutations. Three out of our cases did not harbor mutations in the panel of genes with therapeutic interest. CONCLUSION: This study confirms that ALK rearrangements in ATC are rare and that the mutational landscape of ATC is heterogeneous, with many genes implicated in the follicular epithelial cell dedifferentiation process. This may explain the limited effectiveness of targeted therapeutic options tested so far. PMID- 28351341 TI - Impact of disease activity on health-related quality of life in systemic lupus erythematosus - a cross-sectional analysis of the Swiss Systemic Lupus Erythematosus Cohort Study (SSCS). AB - BACKGROUND: To assess the impact of disease activity on health-related quality of life (HRQoL) in systemic lupus erythematosus (SLE). METHODS: Cross-sectional study of patients included in the Swiss SLE Cohort Study between April 2007 and June 2014. HRQoL outcomes were based on the Medical Outcome Study Short Form 36 (SF-36). Disease activity was assessed by the SLE Disease Activity Index score with the Safety of Estrogens in SLE National Assessment modification (SELENA SLEDAI) and by the physican's global assessment (PGA). RESULTS: Of the 252 patients included, 207 (82%) were women. Median [interquartile range (IQR)] age was 43 [32-57] years. SLE was active in 125 patients (49.6%). Median [IQR] mental component summary (MCS) in active vs inactive SLE was 40.0 [30.2-51.0] compared to 47.3 [39.2-52.8] (p < 0.01) and median [IQR] physical component summary (PCS) 43.7 [37.0-52.8] compared to 49.1 [38.4-55.6], respectively (p < 0.05). Increase in SELENA-SLEDAI or increase in PGA were negatively correlated with PCS and/or MCS. After adjusting for gender, age and disease duration, disease activity impacted on both PCS and MCS and all subscales except general health. Active lupus nephritis and musculoskeletal involvement were associated with physical limitations and emotional problems, increased bodily pain and poor social functioning. Low complement and/or presence of anti-dsDNA antibodies were associated with increased fatigue and reduced mental health. CONCLUSIONS: In patients with SLE, HRQoL is reduced in those with active disease. Impact of disease activity on HRQoL dimensions depends on SELENA-SLEDAI system components. PMID- 28351342 TI - Erratum to: Multiple controls affect arsenite oxidase gene expression in Herminiimonas arsenicoxydans. PMID- 28351343 TI - Identification of large genomic rearrangement of BRCA1/2 in high risk patients in Korea. AB - BACKGROUND: While the majority of germline inactivating mutations in BRCA1/2 are small-scale mutations, large genomic rearrangements (LGRs) are also detected in a variable proportion of patients. However, routine genetic methods are incapable of detecting LGRs, and comprehensive genetic testing algorithm is necessary. METHODS: We performed multiplex ligation-dependent probe amplification assay for small-scale mutation negative patients at high-risk for LGR, based on previously published LGR risk criteria. The inclusion criteria for the high-risk subgroup were personal history of 1) early-onset breast cancer (diagnosed at <=36 years); 2) two breast primaries; 3) breast cancer diagnosed at any age, with >=1 close blood relatives (includes first-, second-, or third-degree) with breast and/or epithelial ovarian cancer; 4) both breast and epithelial ovarian cancer diagnosed at any age; and 5) epithelial ovarian cancer with >=1 close blood relatives with breast and/or epithelial ovarian cancer. RESULTS: Two LGRs were identified. One was a heterozygous deletion of exon 19 and the other was a heterozygous duplication of exon 4-6. The prevalence of LGRs was 7% among Sanger-negative, high-risk patients, and accounted for 13% of all BRCA1 mutations and 2% of all patients. Moreover, LGRs reported in Korean patients, including our 2 newly identified cases, were found exclusively in families with at least one high-risk feature. CONCLUSIONS: Our result suggests that selective LGR screening for Sanger negative, high-risk patients is necessary for Korean patients. PMID- 28351344 TI - Why do women choose an unregulated birth worker to birth at home in Australia: a qualitative study. AB - BACKGROUND: In Australia the choice to birth at home is not well supported and only 0.4% of women give birth at home with a registered midwife. Recent changes to regulatory requirements for midwives have become more restrictive and there is no insurance product that covers private midwives for intrapartum care at home. Freebirth (planned birth at home with no registered health professional) with an unregulated birth worker who is not a registered midwife or doctor (e.g. Doula, ex-midwife, lay midwife etc.) appears to have increased in Australia. The aim of this study is to explore the reasons why women choose to give birth at home with an unregulated birth worker (UBW) from the perspective of women and UBWs. METHODS: Nine participants (five women who had UBWs at their birth and four UBWs who had themselves used UBWs in the past for their births) were interviewed in depth and the data analysed using thematic analysis. RESULTS: Four themes were found: 'A traumatising system', 'An inflexible system'; 'Getting the best of both worlds' and 'Treated with love and respect versus the mechanical arm on the car assembly line'. Women interviewed for this study either experienced or were exposed to mainstream care, which they found traumatising. They were not able to access their preferred birth choices, which caused them to perceive the system as inflexible. They interpreted this as having no choice when choice was important to them. The motivation then became to seek alternative options of care that would more appropriately meet their needs, and help avoid repeated trauma through mainstream care. CONCLUSION: Women who engaged UBWs viewed them as providing the best of both worlds - this was birthing at home with a knowledgeable person who was unconstrained by rules or regulations and who respected and supported the woman's philosophical view of birth. Women perceived UBWs as not only the best opportunity to achieve a natural birth but also as providing 'a safety net' in case access to emergency care was required. PMID- 28351346 TI - Neural Wiskott-Aldrich syndrome protein (nWASP) is implicated in human lung cancer invasion. AB - : Lung cancer is one of the most commonly diagnosed cancers with survival much lower in patients diagnosed with distal metastases. It is therefore imperative to identify pathways involved in lung cancer invasion and metastasis and to consider the therapeutic potential of agents that can interfere with these molecular pathways. This study examines nWASP expression in human lung cancer tissues and explores the effect of nWASP inhibition and knockdown on lung cancer cell behaviour. METHODS: QPCR has been used to measure nWASP transcript expression in human lung cancer tissues. The effect of wiskostatin, an nWASP inhibitor, on A 549 and SK-MES-1 lung carcinoma cell growth, adhesion, migration and invasion was also examined using several in vitro functional assays, including ECIS, and immunofluorescence staining. The effect of nWASP knockdown using siRNA on particular behaviours of lung cancer cells was also examined. RESULTS: Patients with high levels of nWASP expression in tumour tissues have significantly lower survival rates. nWASP transcript levels were found to correlate with lymph node involvement (p = 0.042). nWASP inhibition and knockdown was shown to significantly impair lung cancer cell growth. nWASP inhibition also affected other cell behaviours, in SK-MES-1 invasion and A-549 cell motility, adhesion and migration. Paxillin and FAK activity are reduced in lung cancer cell lines following wiskostatin and nWASP knockdown as shown by immunofluorescence and western blot. CONCLUSIONS: These findings highlight nWASP as an important potential therapeutic target in lung cancer invasion and demonstrate that inhibiting nWASP activity using the inhibitor wiskostatin can significantly alter cell behaviour in vitro. PMID- 28351345 TI - Short-term increase in prevalence of nasopharyngeal carriage of macrolide resistant Staphylococcus aureus following mass drug administration with azithromycin for trachoma control. AB - BACKGROUND: Mass drug administration (MDA) with azithromycin is a corner-stone of trachoma control however it may drive the emergence of antimicrobial resistance. In a cluster-randomized trial (Clinical trial gov NCT00792922), we compared the reduction in the prevalence of active trachoma in communities that received three annual rounds of MDA to that in communities that received a single treatment round. We used the framework of this trial to carry out an opportunistic study to investigate if the increased rounds of treatment resulted in increased prevalence of nasopharyngeal carriage of macrolide-resistant Staphylococcus aureus. Three cross-sectional surveys were conducted in two villages receiving three annual rounds of MDA (3 * treatment arm). Surveys were conducted immediately before the third round of MDA (CSS-1) and at one (CSS-2) and six (CSS-3) months after MDA. The final survey also included six villages that had received only one round of MDA 30 months previously (1 * treatment arm). RESULTS: In the 3 * treatment arm, a short-term increase in prevalence of S. aureus carriage was seen following MDA from 24.6% at CSS-1 to 38.6% at CSS-2 (p < 0.001). Prevalence fell to 8.8% at CSS 3 (p < 0.001). A transient increase was also seen in prevalence of carriage of azithromycin resistant (AzmR) strains from 8.9% at CSS-1 to 34.1% (p < 0.001) in CSS-2 and down to 7.3% (p = 0.417) in CSS-3. A similar trend was observed for prevalence of carriage of macrolide-inducible-clindamycin resistant (iMLSB) strains. In CSS-3, prevalence of carriage of resistant strains was higher in the 3 * treatment arm than in the 1 * treatment (AzmR 7.3% vs. 1.6%, p = 0.010; iMLSB 5.8% vs. 0.8%, p < 0.001). Macrolide resistance was attributed to the presence of msr and erm genes. CONCLUSIONS: Three annual rounds of MDA with azithromycin were associated with a short-term increase in both the prevalence of nasopharyngeal carriage of S. aureus and prevalence of carriage of AzmR and iMLSB S. aureus. TRIAL REGISTRATION: This study was ancillary to the Partnership for the Rapid Elimination of Trachoma, ClinicalTrials.gov NCT00792922 , registration date November 17, 2008. PMID- 28351348 TI - Systematic review of cost-effectiveness analyses for combinations of prevention strategies against human papillomavirus (HPV) infection: a general trend. AB - BACKGROUND: Due to the arrival of multi-valent HPV vaccines, it is more and more important to have a better understanding of the relationship between vaccination and screening programmes. This review aimed to: (1) collect published evidence on the cost-effectiveness profile of different HPV prevention strategies and, in particular, those combining vaccination with changes in screening practices; (2) explore the cost-effectiveness of alternative preventive strategies based on screening and vaccination. METHODS: A systematic literature review was conducted in order to identify the relevant studies regarding the cost-effectiveness of prevention strategies against HPV infection. Analysis comparing the modelling approaches between studies was made along with an assessment of the magnitude of impact of several factors on the cost-effectiveness of different screening strategies. RESULTS: A total of 18 papers were quantitatively summarised within the narrative. A high degree of heterogeneity was found in terms of how HPV prevention strategies have been assessed in terms of their economic and epidemiological impact, with variation in screening practice and valence of HPV vaccination found to have large implications in terms of cost-effectiveness. CONCLUSIONS: This review demonstrated synergies between screening and vaccination. New prevention strategies involving multi-valence vaccination, HPV DNA test screening, delayed commencement and frequency of screening could be implemented in the future. Strategies implemented in the future should be chosen with care, and informed knowledge of the potential impact of all possible prevention strategies. Highlighted in this review is the difficulty in assessing multiple strategies. Appropriate modelling techniques will need to be utilised to assess the most cost-effective strategies. PMID- 28351347 TI - Sporobolus stapfianus: Insights into desiccation tolerance in the resurrection grasses from linking transcriptomics to metabolomics. AB - BACKGROUND: Understanding the response of resurrection angiosperms to dehydration and rehydration is critical for deciphering the mechanisms of how plants cope with the rigors of water loss from their vegetative tissues. We have focused our studies on the C4 resurrection grass, Sporobolus stapfianus Gandoger, as a member of a group of important forage grasses. METHODS: We have combined non-targeted metabolomics with transcriptomics, via a NimbleGen array platform, to develop an understanding of how gene expression and metabolite profiles can be linked to generate a more detailed mechanistic appreciation of the cellular response to both desiccation and rehydration. RESULTS: The rehydration transcriptome and metabolome are primarily geared towards the rapid return of photosynthesis, energy metabolism, protein turnover, and protein synthesis during the rehydration phase. However, there are some metabolites associated with ROS protection that remain elevated during rehydration, most notably the tocopherols. The analysis of the dehydration transcriptome reveals a strong concordance between transcript abundance and the associated metabolite abundance reported earlier, but only in responses that are directly related to cellular protection during dehydration: carbohydrate metabolism and redox homeostasis. The transcriptome response also provides strong support for the involvement of cellular protection processes as exemplified by the increases in the abundance of transcripts encoding late embryogenesis abundant (LEA) proteins, anti-oxidant enzymes, early light-induced proteins (ELIP) proteins, and cell-wall modification enzymes. There is little concordance between transcript and metabolite abundance for processes such as amino acid metabolism that do not appear to contribute directly to cellular protection, but are nonetheless important for the desiccation tolerant phenotype of S. stapfianus. CONCLUSIONS: The transcriptomes of both dehydration and rehydration offer insight into the complexity of the regulation of responses to these processes that involve complex signaling pathways and associated transcription factors. ABA appears to be important in the control of gene expression in both the latter stages of the dehydration and the early stages of rehydration. These findings add to the growing body of information detailing how plants tolerate and survive the severe cellular perturbations of dehydration, desiccation, and rehydration. PMID- 28351349 TI - Development and validation of the Efficacy Safety Score (ESS), a novel tool for postoperative patient management. AB - BACKGROUND: Several reports have shown that postoperative monitoring of general safety and quality issues, including pain treatment, after discharge from recovery is often non-systematic and inadequate. We suggest a new score with assessment of key recovery parameters, as a supportive tool for postoperative care and a call-out algorithm for need of extra help. The aim of this investigation was to validate the score. METHODS: After suggesting a prototype score from a pilot study in 182 postoperative patients, we performed a Delphi process by using international experts to create consensus on the final score contents and called the revised tool the Efficacy Safety Score (ESS). Then, we performed a prospective observational study with the ESS throughout the first 24 h postoperatively in 207 surgical in-patients. We compared ESS with Modified Early Warning Systems (MEWS), and postoperative journal information. We subsequently validated ESS by addressing recognized quality criteria for measurement of health status questionnaires. RESULTS: A call-out value of ESS >=10 correlated with MEWS > 0 values and journal information about postoperative concerns with a sensitivity of 94% and 92%, respectively. All serious safety issues were identified with the ESS >= 10, and a higher number of quality issues were identified than with routine care or MEWS. We obtained positive ratings for six out of seven tested criteria of questionnaire quality; one criterion had an indeterminate rating. CONCLUSION: ESS fulfils suggested criteria for score quality validation and reflects the patient's postoperative status adequately and with high sensitivity. Further clinical trials are warranted to evaluate the usefulness of ESS as a simple tool for assessment of the postoperative safety and quality of patients. PMID- 28351350 TI - Manifestations and drivers of mistreatment of women during childbirth in Kenya: implications for measurement and developing interventions. AB - BACKGROUND: Disrespect and abuse or mistreatment of women by health care providers in maternity settings has been identified as a key deterrent to women seeking delivery care. Mistreatment includes physical and verbal abuse, stigma and discrimination, a poor relationship between women and providers and policy and health systems challenges. This paper uses qualitative data to describe mistreatment of women in Kenya. METHODS: Data are drawn from implementation research conducted in 13 facilities and communities. Researchers conducted a range of in-depth interviews with women (n-50) who had given birth in a facility policy makers health managers and providers (n-63); and focus group discussions (19) with women and men living around study facilities. Data were captured on paper and audio tapes, transcribed and translated and exported into Nvivo for analysis. Subsequently we applied a typology of mistreatment which includes first order descriptive themes, second and third-order analytical themes. Final analysis was organized around description of the nature, manifestations and experiences, and factors contributing to mistreatment. RESULTS: Women describe: their negative experiences of childbirth; frustration with lack of confidentiality and autonomy; abandonment by the providers, and dirty maternity units. Providers admit to challenges but describe reasons for apparent abuse (slapped on thighs to encourage women to focus on birthing process) and 'detention' is because relatives have abandoned them. Men try to overcome challenges by paying providers to ensure they look after their wives. Drivers of mistreatment are perpetuated by social and gender norms at family and community levels. At facility level, poor managerial oversight, provider demotivation, and lack of equipment and supplies, contribute to a poor experience of care. Weak or non-existent legal redress perpetuate the problem. CONCLUSION: This paper builds on the expanding literature on mistreatment during labour and childbirth outlining drivers from an individual, family, community, facility and policy level. New frameworks to group the manifestations into themes or components makes it increasingly more focused on specific interventions to promote respectful maternity care. The Kenya findings resonate with budding literature - demonstrating that this is indeed a global issue that needs a global solution. PMID- 28351351 TI - The influence of participation in target-shooting sport for children with inattentive, hyperactive and impulsive symptoms - A controlled study of best practice. AB - BACKGROUND: Practising target-shooting sport requires focused attention and motoric steadiness. A previous non-controlled pilot study suggests that children with impairing symptoms of attention-deficit/hyperactivity disorder (ADHD) benefit from participating in target-shooting sport in local shooting associations, as rated by parents and teachers. This study aims at examining if, and to which extent, target-shooting sport reduces parent- and teacher-reported severity of inattentiveness, hyperactivity, and impulsivity in children with attention difficulties, and if, and to which extend, target-shooting sport improves the children's wellbeing and quality of life. METHODS: A mixed method approach is applied. A non-blinded, waiting list controlled study is combined with a case study, consisting of interviews and observations. The intervention consists of children practising target-shooting sport, by attending a local shooting association, once a week for six months, during regular school hours. Data from questionnaires (ADHD-RS, SDQ, Kidscreen-27), as well as a computerized continued performance test (Qb test), measure the children's activity and attention. The study includes 50 children in an intervention group and 50 children in a waiting list control group. The Qb test collects data from at least 20 children from the intervention group and at least 20 children from the waiting list control group. Data from the questionnaires and Qb-test is collected at baseline, and six months post intervention. In addition, a case study is carried out, consisting of interviews of at least five children from the intervention group, their parents, teachers and shooting instructors. Observations are carried out, when children are in school and while they are attending the local shooting association. The case study adds to an in-depth understanding of children's participation in target-shooting sports. DISCUSSION: At present, little is known about the effects and influence of practising target-shooting sport for children experiencing difficulties with inattentiveness, hyperactivity and impulsivity. This study is expected to contribute to an understanding of the influence of participating in target-shooting sports on inattentive, hyperactive and impulsive symptoms, and the effects on the children's psychological wellbeing and quality of life. TRIAL REGISTRATION: Current Controlled Trials NCT02898532 . Retrospectively registered 14 September 2016. PMID- 28351352 TI - Negative lymph node count is an independent prognostic factor for patients with rectal cancer who received preoperative radiotherapy. AB - BACKGROUND: Negative lymph node (NLN) count has been reported to provide more accurate prognostic information than the N stage alone in patients with rectal cancer (RC). Since preoperative radiotherapy (Pre-RT) can significantly affect the LN status, it is unclear whether NLN count still has prognostic value count on survival of patients with RC who received Pre-RT. METHODS: In this study, clinicopathological characteristics, number of positive LNs and survival time were collected from Surveillance, Epidemiology, and End Results Program (SEER) registered RC patients. Univariate and multivariate Cox proportional hazards models were used to assess the risk factors for survival. RESULTS: X-tile plots identified 9 (P < 0.001) as the optimal cutoff NLN value to divide the patients into high and low risk subsets in terms of cause specific survival (CSS). NLN count was validated as independently prognostic factor in univariate and multivariate analysis (P < 0.001). Subgroup analysis showed that NLN count was an independently prognostic factor for patients with stage ypII (P = 0.002) and ypIII (P < 0.001). CONCLUSIONS: Our results firmly demonstrated that NLN count provides accurate prognostic information for RC patients with Pre-RT. PMID- 28351353 TI - The impact of ocular trauma during the Nepal earthquake in 2015. AB - BACKGROUND: Nepal was struck by a massive earthquake on the 25th April 2015 and major aftershock on the 12th of May 2015, resulting in widespread devastation with a death toll in the thousands. The burden of ocular trauma resulting from the recent earthquakes in Nepal has not been described thus far. The aim of this study was to determine the types of ocular injuries sustained in the earthquake in Nepal and its management in Tilganga Institute of Ophthalmology (TIO) in Gaushala, Kathmandu. METHODS: This is a hospital-based retrospective study of patients presenting to TIO following repeated earthquake. Variables that were recorded included patients' presenting symptoms and time to presentation, visual acuities at presentation and at follow-up, diagnosis of ocular injury and surgery performed. RESULTS: There were 59 cases of earthquake victims visiting TIO, Gaushala, Kathmandu from April 2015 to July 2015, with 64 affected eyes due to 5 cases of bilateral involvement. The majority of patients were from the district Sindhupalchowk (14 cases, 23.7%), which was the epicenter of the main earthquake. The average duration between the earthquake and presentation was 13 . 9 days (range 1-120 days). Closed globe injury was most frequent (23 cases), followed by open globe injuries (8 cases). While 24 patients (38%) initially presented with a visual acuity <3/60 in their affected eye, 15 patients (23%) had a visual acuity of <3/60 on follow-up. A variety of surgical treatments were required including anterior and posterior segment repair. CONCLUSIONS: Immediate management of ocular trauma is critical in order to prevent blindness. Characterizing the burden of earthquake-related ocular trauma will facilitate planning for service provision in the event of a future earthquake in Nepal, or in countries, which are similarly at risk of having natural disasters. PMID- 28351354 TI - Case management to increase quality of life after cancer treatment: a randomized controlled trial. AB - BACKGROUND: Case management has been shown to be beneficial in phases of cancer screening and treatment. After treatment is completed, patients experience a loss of support due to reduced contact with medical professionals. Case management has the potential to offer continuity of care and ease re-entry to normal life. We therefore aim to investigate the effect of case management on quality of life in early cancer survivors. METHODS: Between 06/2010 and 07/2012, we randomized 95 patients who had just completed cancer treatment in 11 cancer centres in the canton of Zurich, Switzerland. Patients in the case management group met with a case manager at least three times over 12 months. Patient-reported outcomes were assessed after 3, 6 and 12 months using the Functional Assessment of Cancer Therapy (FACT-G) scale, the Patient Assessment of Chronic Illness Care (PACIC) and the Self-Efficacy scale. RESULTS: The change in FACT-G over 12 months was significantly greater in the case management group than in the control group (16.2 (SE 2.0) vs. 9.2 (SE 1.5) points, P = 0.006). The PACIC score increased by 0.20 (SE 0.14) in the case management group and decreased by 0.29 (SE 0.12) points in the control group (P = 0.009). Self-Efficacy increased by 3.1 points (SE 0.9) in the case management group and by 0.7 (SE 0.8) points in the control group (P = 0.049). CONCLUSIONS: Case management has the potential to improve quality of life, to ease re-entry to normal life and to address needs for continuity of care in early cancer survivors. TRIAL REGISTRATION: The study has been submitted to the ISRCTN register under the name "Case Management in Oncology Rehabilitation" on the 12th of October 2010 and retrospectively registered under the number ISRCTN41474586 on the 24th of November 2010. PMID- 28351355 TI - A process evaluation plan for assessing a complex community-based maternal health intervention in Ogun State, Nigeria. AB - BACKGROUND: Despite increased investment in community-level maternal health interventions, process evaluations of such interventions are uncommon, and can be instrumental in understanding mediating factors leading to outcomes. In Nigeria, where an unacceptably number of maternal deaths occur (maternal mortality ratio of 814/100,000 livebirths), the Community Level Interventions for Pre-eclampsia (CLIP) study (NCT01911494) aimed to reduce maternal and neonatal mortality and morbidity with a complex intervention of five interrelated components. Building from previous frameworks, we illustrate a methodology to evaluate implementation processes of the complex CLIP intervention, assess mechanisms of impact and identify emerging unintended causal pathways. METHODS: The study was conducted from 2013-2016 in five Local Government Areas in Ogun State, Nigeria. A six-step approach was developed to evaluate key constructs of context (external factors related to intervention), implementation (fidelity, dose, reach, and adaption) and mechanisms of impact (unintended outcomes and mediating pathways). The steps are: 1) describing the intervention by a logic model, 2) defining acceptable delivery, 3) formulating questions, 4) determining methodology, 5) planning resources in context, lastly, step 6) finalising the plan in consideration with relevant stakeholders. RESULTS: Quantitative data were collected from 32,785 antenatal and postnatal visits at the primary health care level, from 66 community engagement sessions, training assessments of community health workers, and standard health facility questionnaires. Forty-three focus group discussions, 38 in-depth interviews, and 23 structured observations were conducted to capture qualitative data. A total of 103 community engagement reports and 182 suspected pre-eclampsia case reports were purposively collected. Timing of data collection was staggered to understand feedback mechanisms that may have resulted from the delivery of the intervention. Data will be analysed using R and NVivo. Diffusions of innovations and realist evaluation theories will underpin analysis of the interaction between context, mechanisms and outcomes. CONCLUSION: This comprehensive approach can serve as a guide for researchers and policy makers to plan the evaluation of similar complex health interventions in resource constrained settings, and to aid in measuring 'effectiveness' of interventions and not just 'efficacy'. TRIAL REGISTRATION: This research is a part of the Community Level Interventions for Pre-eclampsia Study, NCT01911494. The trial is registered in Clinicaltrials.gov, the URL is https://clinicaltrials.gov/ct2/show/NCT01911494 The trial was registered on June 28, 2013 and the first participant was enrolled for intervention on March 1, 2014. PMID- 28351356 TI - Erratum to: SWITCH: a dynamic CRISPR tool for genome engineering and metabolic pathway control for cell factory construction in Saccharomyces cerevisiae. PMID- 28351357 TI - Erratum to: The impact of benzodiazepine use in patients enrolled in opioid agonist therapy in Northern and rural Ontario. PMID- 28351360 TI - Erratum to: Allium hookeri root extract exerts anti-inflammatory effects by nuclear factor-kappaB down-regulation in lipopolysaccharide-induced RAW264.7 cells. PMID- 28351359 TI - Conveying practical clinical skills with the help of teaching associates-a randomised trial with focus on the long term learning retention. AB - BACKGROUND: Ensuring that all medical students achieve adequate clinical skills remains a challenge, yet the correct performance of clinical skills is critical for all fields of medicine. This study analyzes the influence of receiving feedback by teaching associates in the context of achieving and maintaining a level of expertise in complex head and skull examination. METHODS: All third year students at a German university who completed the obligatory surgical skills lab training and surgical clerkship participated in this study. The students were randomized into two groups. CONTROL GROUP: lessons by an instructor and peer based practical skills training. Intervention group: training by teaching associates who are examined as simulation patients and provided direct feedback on student performance. Their competency in short- and long-term competence (directly after intervention and at 4 months after the training) of head and skull examination was measured. Statistical analyses were performed using SPSS Statistics version 19 (IBM, Armonk, USA). Parametric and non-parametric test methods were applied. As a measurement of correlation, Pearson correlations and correlations via Kendall's-Tau-b were calculated and Cohen's d effect size was calculated. RESULTS: A total of 181 students were included (90 intervention, 91 control). Out of those 181 students 81 agreed to be videotaped (32 in the control group and 49 in the TA group) and examined at time point 1. At both time points, the intervention group performed the examination significantly better (time point 1, p = <.001; time point 2 (rater 1 p = .009, rater 2 p = .015), than the control group. The effect size (Cohens d) was up to 1.422. CONCLUSIONS: The use of teaching associates for teaching complex practical skills is effective for short- and long-term retention. We anticipate the method could be easily translated to nearly every patient-based clinical skill, particularly with regards to a competence-based education of future doctors. PMID- 28351358 TI - Change in lifestyle behaviors and diabetes risk: evidence from a population-based cohort study with 10 year follow-up. AB - BACKGROUND: Promoting positive changes in lifestyle behavior in the whole population may be a feasible and effective approach to reducing type 2 diabetes burden, but the impact of population shifts of modifiable risk factors remains unclear. Currently most of the evidence on modifiable lifestyle behavior and type 2 diabetes risk on a population level comes from studies of between-individual differences. The objective of the study was to investigate the association and potential impact on disease burden for within-individual change in lifestyle behavior and diabetes risk. METHODS: Population-based prospective cohort study of 35,680 participants aged 30-50 at baseline in 1990-2003 in Vasterbotten County, Sweden (follow-up until 2013). Five self-reported modifiable lifestyle behaviors (tobacco use, physical activity, alcohol intake, dietary fiber intake and dietary fat intake) were measured at baseline and 10 year follow-up. Lifestyle behaviors were studied separately, and combined in a score. Incident diabetes was detected by oral glucose tolerance tests. Multivariate logistic regression models and population attributable fractions (PAF) were used to analyze the association between change in lifestyle behavior between baseline and 10 year follow-up, and risk of incident diabetes. RESULTS: Incident diabetes was detected in 1,184 (3.3%) participants at 10 year follow-up. There was a reduced diabetes risk associated with increase in dietary fiber intake, odds ratio (OR) 0.79 (95% confidence interval (CI) 0.66, 0.96) for increase of at least one unit standard deviation (3.0 g/1,000 kcal) of the baseline distribution, PAF 16.0% (95% CI 4.2, 26.4%). Increase in the lifestyle behavior score was associated with reduced diabetes risk, OR 0.92 (95% CI 0.85, 0.99) per unit increase of the score. CONCLUSIONS: These results support a causal link between lifestyle behavior and type 2 diabetes incidence. A small shift in lifestyle behaviors, in particular intake of dietary fiber, has the potential to reduce diabetes burden in the population and might be a suitable target for public health intervention. PMID- 28351361 TI - Lost in care pathway: a qualitative investigation on the health system delay of extra pulmonary tuberculosis patients in Bangladesh. AB - BACKGROUND: Although extra pulmonary tuberculosis (EPTB) has long been known as a major public health concern globally, the complex healthcare-seeking pathways of EPTB patients are not widely studied. This study aims to explore the pattern of healthcare-seeking pathways of rural and urban EPTB patients registered with the BRAC TB control programme. BRAC is a Bangladesh-based non-governmental organization dedicated to alleviating poverty through empowering the poor. METHOD: Data were collected through 60 in-depth interviews with rural and urban EPTB patients in Bangladesh. RESULTS: The findings reveal that the rural EPTB patients encountered a substantial diagnostic delay as compared to the urban patients. However, the difference between the average number of healthcare providers consulted by the rural verses the urban EPTB patients was not significant. This study also shows that the healthcare-seeking journey of rural and urban EPTB patients usually starts either at pharmacies or private facilities. Through exploring the detailed nature of the pathway, this study reveals the ways in which non-medical informants, mainly relatives and friends, can benefit patients. CONCLUSIONS: The private and informal healthcare providers should receive appropriate training on the diagnosis of EPTB. Such training could effectively shorten the long and complex healthcare-seeking pathways of EPTB patients. PMID- 28351362 TI - A peculiar case report of extraovarian Brenner tumor arising in the omentum. AB - BACKGROUND: Brenner tumors almost always develop in the ovary. Exceptionally, extraovarian Brenner tumors have been reported in the lower abdomen or pelvic organs. Here, we introduce a peculiar case of an extraovarian Brenner tumor arising in the omentum. CASE PRESENTATION: A 43-year-old woman presented with a palpable abdominal mass. Computed tomography (CT) scan revealed a 9.0-cm solid mass in the omentum. The tumor was not associated with pelvic structures, including the ovaries. It was excised under the clinical impression of an extragastrointestinal stromal tumor or neurogenic tumor. Grossly, the mass was a well-circumscribed solid tumor, with yellow-tan cut surface and minute cystic spaces. Microscopically, the tumor showed well-defined epithelial nests with variable cystic changes embedded in an abundant fibrous stroma. The cells within the nests were reminiscent of benign urothelial cells in that they had oval, frequently grooved nuclei. The epithelial cells focally showed a gradual transition into the surrounding stromal cells with short spindled features. The urothelium-like cells were positive for pancytokeratin, WT-1, p63, CK7, uroplakin III, and GATA-3 but were negative for CD34, CD10, CK20, c-KIT, DOG-1, PAX-8, and calretinin. Morphological and immunohistochemical features of the tumor were the same as an ovarian Brenner tumor, and so it was diagnosed as an extraovarian Brenner tumor. CONCLUSIONS: Although the location of the tumor was very unusual, we could diagnose the tumor as an extraovarian Brenner tumor on the basis of the histologic and immunohistochemical findings. This is the first case of extraovarian Brenner tumor arising in the omentum near the stomach ever reported in the English literature. PMID- 28351363 TI - Sedentary behaviour and adiposity in youth: a systematic review of reviews and analysis of causality. AB - BACKGROUND: Sedentary behaviour (sitting time) has becoming a very popular topic for research and translation since early studies on TV viewing in children in the 1980s. The most studied area for sedentary behaviour health outcomes has been adiposity in young people. However, the literature is replete with inconsistencies. METHODS: We conducted a systematic review of systematic reviews and meta-analyses to provide a comprehensive analysis of evidence and state-of the-art synthesis on whether sedentary behaviours are associated with adiposity in young people, and to what extent any association can be considered 'causal'. Searches yielded 29 systematic reviews of over 450 separate papers. We analysed results by observational (cross-sectional and longitudinal) and intervention designs. RESULTS: Small associations were reported for screen time and adiposity from cross-sectional evidence, but associations were less consistent from longitudinal studies. Studies using objective accelerometer measures of sedentary behaviour yielded null associations. Most studies assessed BMI/BMI-z. Interventions to reduce sedentary behaviour produced modest effects for weight status and adiposity. Accounting for effects from sedentary behaviour reduction alone is difficult as many interventions included additional changes in behaviour, such as physical activity and dietary intake. Analysis of causality guided by the classic Bradford Hill criteria concluded that there is no evidence for a causal association between sedentary behaviour and adiposity in youth, although a small dose-response association exists. CONCLUSIONS: Associations between sedentary behaviour and adiposity in children and adolescents are small to very small and there is little to no evidence that this association is causal. This remains a complex field with different exposure and outcome measures and research designs. But claims for 'clear' associations between sedentary behaviour and adiposity in youth, and certainly for causality, are premature or misguided. PMID- 28351366 TI - The translation of sports injury prevention and safety promotion knowledge: insights from key intermediary organisations. AB - BACKGROUND: A recognised research-to-practice gap exists in the health research field of sports injury prevention and safety promotion. There is a need for improved insight into increasing the relevancy, accessibility and legitimacy of injury prevention and safety promotion research knowledge for sport settings. The role of key organisations as intermediaries in the process of health knowledge translation for sports settings remains under-explored, and this paper aims to determine, and describe, the processes of knowledge translation undertaken by a set of key organisations in developing and distributing injury prevention and safety promotion resources. METHODS: The National Guidance for Australian Football Partnerships and Safety (NoGAPS) project provided the context for this study. Representatives from five key NoGAPS organisations participated in individual face-to-face interviews about organisational processes of knowledge translation. A qualitative descriptive methodology was used to analyse participants' descriptions of knowledge translation activities undertaken at their respective organisations. RESULTS: Several themes emerged around health knowledge translation processes and considerations, including (1) identifying a need for knowledge translation, (2) developing and disseminating resources, and (3) barriers and enablers to knowledge translation. CONCLUSIONS: This study provides insight into the processes that key organisations employ when developing and disseminating injury prevention and safety promotion resources within sport settings. The relevancy, accessibility and legitimacy of health research knowledge is foregrounded, with a view to increasing the influence of research on the development of health-related resources suitable for community sport settings. PMID- 28351364 TI - Task-shifting alcohol interventions for HIV+ persons in Kenya: a cost-benefit analysis. AB - BACKGROUND: Among HIV+ patients, alcohol use is a highly prevalent risk factor for both HIV transmission and poor adherence to HIV treatment. The large-scale implementation of effective interventions for treating alcohol problems remains a challenge in low-income countries with generalized HIV epidemics. It is essential to consider an intervention's cost-effectiveness in dollars-per-health-outcome, and the long-term economic impact -or "return on investment" in monetary terms. METHODS: We conducted a cost-benefit analysis, measuring economic return on investment, of a task-shifted cognitive-behavioral therapy (CBT) intervention delivered by paraprofessionals to reduce alcohol use in a modeled cohort of 13,440 outpatients in Kenya. In our base-case, we estimated the costs and economic benefits from a societal perspective across a six-year time horizon, with a 3% annual discount rate. Costs included all costs associated with training and administering task-shifted CBT therapy. Benefits included the economic impact of lowered HIV incidence as well as the improvements in household and labor-force productivity. We conducted univariate and multivariate probabilistic sensitivity analyses to test the robustness of our results. RESULTS: Under the base case, total costs for CBT rollout was $554,000, the value of benefits were $628,000, and the benefit-to-cost ratio was 1.13. Sensitivity analyses showed that under most assumptions, the benefit-to-cost ratio remained above unity indicating that the intervention was cost-saving (i.e., had positive return on investment). The duration of the treatment effect most effected the results in sensitivity analyses. CONCLUSIONS: CBT can be effectively and economically task-shifted to paraprofessionals in Kenya. The intervention can generate not only reductions in morbidity and mortality, but also economic savings for the health system in the medium and long term. The findings have implications for other countries with generalized HIV epidemics, high prevalence of alcohol consumption, and shortages of mental health professionals. TRIAL REGISTRATION: This paper uses data derived from "Cognitive Behavioral Treatment to Reduce Alcohol Use Among HIV-Infected Kenyans (KHBS)" with ClinicalTrials.gov registration NCT00792519 on 11/17/2008; and preliminary data from "A Stage 2 Cognitive-behavioral Trial: Reduce Alcohol First in Kenya Intervention" ( NCT01503255 , registered on 12/16/2011). PMID- 28351365 TI - Basal-like breast cancer: molecular profiles, clinical features and survival outcomes. AB - BACKGROUND: Basal-like constitutes an important molecular subtype of breast cancer characterised by an aggressive behaviour and a limited therapy response. The outcome of patients within this subtype is, however, divergent. Some individuals show an increased risk of dying in the first five years, and others a long-term survival of over ten years after the diagnosis. In this study, we aim at identifying markers associated with basal-like patients' survival and characterising subgroups with distinct disease outcome. METHODS: We explored the genomic and transcriptomic profiles of 351 basal-like samples from the METABRIC and ROCK data sets. Two selection methods, labelled Differential and Survival filters, were employed to determine genes/probes that are differentially expressed in tumour and control samples, and are associated with overall survival. These probes were further used to define molecular subgroups, which vary at the microRNA level and in DNA copy number. RESULTS: We identified the expression signature of 80 probes that distinguishes between two basal-like subgroups with distinct clinical features and survival outcomes. Genes included in this list have been mainly linked to cancer immune response, epithelial mesenchymal transition and cell cycle. In particular, high levels of CXCR6, HCST, C3AR1 and FPR3 were found in Basal I; whereas HJURP, RRP12 and DNMT3B appeared over-expressed in Basal II. These genes exhibited the highest betweenness centrality and node degree values and play a key role in the basal-like breast cancer differentiation. Further molecular analysis revealed 17 miRNAs correlated to the subgroups, including hsa-miR-342-5p, -150, -155, -200c and -17. Additionally, increased percentages of gains/amplifications were detected on chromosomes 1q, 3q, 8q, 10p and 17q, and losses/deletions on 4q, 5q, 8p and X, associated with reduced survival. CONCLUSIONS: The proposed signature supports the existence of at least two subgroups of basal-like breast cancers with distinct disease outcome. The identification of patients at a low risk may impact the clinical decisions-making by reducing the prescription of high-dose chemotherapy and, consequently, avoiding adverse effects. The recognition of other aggressive features within this subtype may be also critical for improving individual care and for delineating more effective therapies for patients at high risk. PMID- 28351368 TI - Nonrigid registration with corresponding points constraint for automatic segmentation of cardiac DSCT images. AB - BACKGROUND: Dual-source computed tomography (DSCT) is a very effective way for diagnosis and treatment of heart disease. The quantitative information of spatiotemporal DSCT images can be important for the evaluation of cardiac function. To avoid the shortcoming of manual delineation, it is imperative to develop an automatic segmentation technique for 4D cardiac images. METHODS: In this paper, we implement the heart segmentation-propagation framework based on nonrigid registration. The corresponding points of anatomical substructures are extracted by using the extension of n-dimensional scale invariant feature transform method. They are considered as a constraint term of nonrigid registration using the free-form deformation, in order to restrain the large variations and boundary ambiguity between subjects. RESULTS: We validate our method on 15 patients at ten time phases. Atlases are constructed by the training dataset from ten patients. On the remaining data the median overlap is shown to improve significantly compared to original mutual information, in particular from 0.4703 to 0.5015 ([Formula: see text]) for left ventricle myocardium and from 0.6307 to 0.6519 ([Formula: see text]) for right atrium. CONCLUSIONS: The proposed method outperforms standard mutual information of intensity only. The segmentation errors had been significantly reduced at the left ventricle myocardium and the right atrium. The mean surface distance of using our framework is around 1.73 mm for the whole heart. PMID- 28351367 TI - Effective behaviour change techniques for physical activity and healthy eating in overweight and obese adults; systematic review and meta-regression analyses. AB - PURPOSE: This systematic review aims to explain the heterogeneity in results of interventions to promote physical activity and healthy eating for overweight and obese adults, by exploring the differential effects of behaviour change techniques (BCTs) and other intervention characteristics. METHODS: The inclusion criteria specified RCTs with >= 12 weeks' duration, from January 2007 to October 2014, for adults (mean age >= 40 years, mean BMI >= 30). Primary outcomes were measures of healthy diet or physical activity. Two reviewers rated study quality, coded the BCTs, and collected outcome results at short (<=6 months) and long term (>=12 months). Meta-analyses and meta-regressions were used to estimate effect sizes (ES), heterogeneity indices (I2) and regression coefficients. RESULTS: We included 48 studies containing a total of 82 outcome reports. The 32 long term reports had an overall ES = 0.24 with 95% confidence interval (CI): 0.15 to 0.33 and I2 = 59.4%. The 50 short term reports had an ES = 0.37 with 95% CI: 0.26 to 0.48, and I2 = 71.3%. The number of BCTs unique to the intervention group, and the BCTs goal setting and self-monitoring of behaviour predicted the effect at short and long term. The total number of BCTs in both intervention arms and using the BCTs goal setting of outcome, feedback on outcome of behaviour, implementing graded tasks, and adding objects to the environment, e.g. using a step counter, significantly predicted the effect at long term. Setting a goal for change; and the presence of reporting bias independently explained 58.8% of inter-study variation at short term. Autonomy supportive and person-centred methods as in Motivational Interviewing, the BCTs goal setting of behaviour, and receiving feedback on the outcome of behaviour, explained all of the between study variations in effects at long term. CONCLUSION: There are similarities, but also differences in effective BCTs promoting change in healthy eating and physical activity and BCTs supporting maintenance of change. The results support the use of goal setting and self-monitoring of behaviour when counselling overweight and obese adults. Several other BCTs as well as the use of a person-centred and autonomy supportive counselling approach seem important in order to maintain behaviour over time. TRIAL REGISTRATION: PROSPERO CRD42015020624. PMID- 28351369 TI - Positional bias in variant calls against draft reference assemblies. AB - BACKGROUND: Whole genome resequencing projects may implement variant calling using draft reference genomes assembled de novo from short-read libraries. Despite lower quality of such assemblies, they allowed researchers to extend a wide range of population genetic and genome-wide association analyses to non model species. As the variant calling pipelines are complex and involve many software packages, it is important to understand inherent biases and limitations at each step of the analysis. RESULTS: In this article, we report a positional bias present in variant calling performed against draft reference assemblies constructed from de Bruijn or string overlap graphs. We assessed how frequently variants appeared at each position counted from ends of a contig or scaffold sequence, and discovered unexpectedly high number of variants at the positions related to the length of either k-mers or reads used for the assembly. We detected the bias in both publicly available draft assemblies from Assemblathon 2 competition as well as in the assemblies we generated from our simulated short read data. Simulations confirmed that the bias causing variants are predominantly false positives induced by reads from spatially distant repeated sequences. The bias is particularly strong in contig assemblies. Scaffolding does not eliminate the bias but tends to mitigate it because of the changes in variants' relative positions and alterations in read alignments. The bias can be effectively reduced by filtering out the variants that reside in repetitive elements. CONCLUSIONS: Draft genome sequences generated by several popular assemblers appear to be susceptible to the positional bias potentially affecting many resequencing projects in non-model species. The bias is inherent to the assembly algorithms and arises from their particular handling of repeated sequences. It is recommended to reduce the bias by filtering especially if higher-quality genome assembly cannot be achieved. Our findings can help other researchers to improve the quality of their variant data sets and reduce artefactual findings in downstream analyses. PMID- 28351370 TI - Erratum to: Loss of plakoglobin promotes cell-cell contact, increased invasion and breast cancer cell dissemination in vivo. PMID- 28351372 TI - Erratum to: Cyclin D1 cooperates with p21 to regulate TGFbeta-mediated breast cancer cell migration and tumor local invasion. PMID- 28351371 TI - Unicompartmental knee arthroplasty, is it superior to high tibial osteotomy in treating unicompartmental osteoarthritis? A meta-analysis and systemic review. AB - BACKGROUND: Debate remains whether high tibial osteotomy (HTO) or unicompartmental knee arthroplasty (UKA) is more beneficial for the treatment of unicompartmental knee osteoarthritis. The purpose of this study was to compare the functional results, knee scores, activity levels, and complications between the two procedures. METHODS: We performed a systematic review of published literature from August 1982 through January 2017. Fifteen papers reporting three prospective randomized trials were subjected to a meta-analysis. RESULTS: No significant difference between the two groups was noted with respect to free walking (velocity), knee score, deterioration of the contralateral or patellofemoral knee, or revision rate and total knee arthroplasty. However, UKA produced better outcomes compared to HTO in terms of the functional results, pain assessment, and complications, although patients who underwent HTO tended to have slightly better range of motion. CONCLUSIONS: Valgus HTO provides better physical activity for younger patients whereas UKA is more suitable for older patients due to shorter rehabilitation time and faster functional recovery. Although UKA patients tended to have improved overall long-term outcomes, which may be due to accurate indications and patient selection, both treatment options yielded pleasing results. Therefore, we are unable to conclude that either method is superior. PMID- 28351373 TI - The antiproliferative ELF2 isoform, ELF2B, induces apoptosis in vitro and perturbs early lymphocytic development in vivo. AB - BACKGROUND: ELF2 (E74-like factor 2) also known as NERF (new Ets-related factor), a member of the Ets family of transcription factors, regulates genes important in B and T cell development, cell cycle progression, and angiogenesis. Conserved ELF2 isoforms, ELF2A, and ELF2B, arising from alternative promoter usage can exert opposing effects on target gene expression. ELF2A activates, whilst ELF2B represses, gene expression, and the balance of expression between these isoforms may be important in maintaining normal cellular function. METHODS: We compared the function of ELF2 isoforms ELF2A and ELF2B with other ELF subfamily proteins ELF1 and ELF4 in primary and cancer cell lines using proliferation, colony forming, cell cycle, and apoptosis assays. We further examined the role of ELF2 isoforms in haemopoietic development using a Rag1 -/-murine bone marrow reconstitution model. RESULTS: ELF2B overexpression significantly reduced cell proliferation and clonogenic capacity, minimally disrupted cell cycle kinetics, and induced apoptosis. In contrast, ELF2A overexpression only marginally reduced clonogenic capacity with little effect on proliferation, cell cycle progression, or apoptosis. Deletion of the N-terminal 19 amino acids unique to ELF2B abrogated the antiproliferative and proapoptotic functions of ELF2B thereby confirming its crucial role. Mice expressing Elf2a or Elf2b in haemopoietic cells variously displayed perturbations in the pre-B cell stage and multiple stages of T cell development. Mature B cells, T cells, and myeloid cells in steady state were unaffected, suggesting that the main role of ELF2 is restricted to the early development of B and T cells and that compensatory mechanisms exist. No differences in B and T cell development were observed between ELF2 isoforms. CONCLUSIONS: We conclude that ELF2 isoforms are important regulators of cellular proliferation, cell cycle progression, and apoptosis. In respect to this, ELF2B acts in a dominant negative fashion compared to ELF2A and as a putative tumour suppressor gene. Given that these cellular processes are critical during haemopoiesis, we propose that the regulatory interplay between ELF2 isoforms contributes substantially to early B and T cell development. PMID- 28351375 TI - Erratum to: Honokiol activates AMP-activated protein kinase in breast cancer cells via LKB1-dependent pathway and inhibits breast carcinogenesis. PMID- 28351374 TI - Working memory training in children with neuropsychiatric disorders and mild to borderline intellectual functioning, the role of coaching; a double-blind randomized controlled trial. AB - BACKGROUND: Working memory training (WMT) has been shown to offer therapeutic benefits to both patients with Attention-Deficit Hyperactivity Disorder (ADHD) and patients with mild to borderline Intellectual Disabilities (MBID; 60 < IQ < 85). However, robust evidence for transfer effects and treatment benefits of WMT over placebo training are lacking. Owing to the nature of double-blind research designs in RCTs, children have received non-specific coaching not based on their actual training performance. Active coaching based on individual training results (such as in clinical practice) might enhance the efficacy of Cogmed WMT. Furthermore, clinical experience and the general treatment approach to these vulnerable children has shown that the intensity and duration of WMT is often too stressful. This study therefore investigated the efficacy of a less intensive, but more prolonged Cogmed WMT (including active personalized coaching and feedback) in reducing behavioral symptoms and improving neurocognitive functioning and academic achievements in children with MBID and neuropsychiatric disorders. METHODS/DESIGN: A double-blind RCT with children (age 10.0-13.11) with neuropsychiatric disorders (ADHD and/or autism spectrum disorder (ASD)) and MBID (IQ: 60 < IQ < 85). Two groups (each n = 26) will receive Cogmed WMT (version R/M) at home or at school for 8 weeks, 4 days a week, at 30 min a day. One group will receive active personalized coaching and feedback based on their actual individual performance during Cogmed training. The other group will only receive general non-personalized coaching (i.e. no receive personalized coaching and feedback). Both groups will undergo a neurocognitive assessment (working memory, executive functioning, academic achievements) before and after training and complete several questionnaires (behavioral problems, parenting style) with a 6 months follow-up. DISCUSSION: This study will add to the literature since the role of coaching in Cogmed WMT has not been studied before. It will also provide opportunities to investigate an alternative version of WMT in a large group of vulnerable children, for whom few evidence-based treatments are available. Ultimately, this will allow us to advise mental health care professionals and special education schools about the use of this type of intervention for children with MBID and neuropsychiatric disorders. TRIAL REGISTRATION: Dutch Trial Register. NTR5223 . Registration date 06-09-2015. PMID- 28351376 TI - An optimised patient information sheet did not significantly increase recruitment or retention in a falls prevention study: an embedded randomised recruitment trial. AB - BACKGROUND: Randomised controlled trials are generally regarded as the 'gold standard' experimental design to determine the effectiveness of an intervention. Unfortunately, many trials either fail to recruit sufficient numbers of participants, or recruitment takes longer than anticipated. The current embedded trial evaluates the effectiveness of optimised patient information sheets on recruitment of participants in a falls prevention trial. METHODS: A three-arm, embedded randomised methodology trial was conducted within the National Institute for Health Research-funded REducing Falls with ORthoses and a Multifaceted podiatry intervention (REFORM) cohort randomised controlled trial. Routine National Health Service podiatry patients over the age of 65 were randomised to receive either the control patient information sheet (PIS) for the host trial or one of two optimised versions, a bespoke user-tested PIS or a template-developed PIS. The primary outcome was the proportion of patients in each group who went on to be randomised to the host trial. RESULTS: Six thousand and nine hundred patients were randomised 1:1:1 into the embedded trial. A total of 193 (2.8%) went on to be randomised into the main REFORM trial (control n = 62, template developed n = 68; bespoke user-tested n = 63). Information sheet allocation did not improve recruitment to the trial (odds ratios for the three pairwise comparisons: template vs control 1.10 (95% CI 0.77-1.56, p = 0.60); user-tested vs control 1.01 (95% CI 0.71-1.45, p = 0.94); and user-tested vs template 0.92 (95% CI 0.65-1.31, p = 0.65)). CONCLUSIONS: This embedded methodology trial has demonstrated limited evidence as to the benefit of using optimised information materials on recruitment and retention rates in the REFORM study. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number registry, ISRCTN68240461 . Registered on 01 July 2011. PMID- 28351378 TI - Melatonin alleviates brain and peripheral tissue edema in a neonatal rat model of hypoxic-ischemic brain damage: the involvement of edema related proteins. AB - BACKGROUND: Previous studies have indicated edema may be involved in the pathophysiology following hypoxic-ischemic encephalopathy (HIE), and melatonin may exhibit neuro-protection against brain insults. However, little is known regarding the mechanisms that involve the protective effects of melatonin in the brain and peripheral tissues after HIE. The present study aimed to examine the effects of melatonin on multiple organs, and the expression of edema related proteins in a neonatal rat model of hypoxic-ischemic brain damage (HIBD). METHODS: One hundred ninety-two neonatal rats were randomly divided into three subgroups that underwent a sham surgery or HIBD. After the HIBD or sham-injury, the rats received an intraperitoneal injection of melatonin or an equal volume vehicle, respectively. We investigated the effects of melatonin on brain, kidney, and colon edema via histological examination and the expression of edema related proteins, including AQP-4, ZO-1 and occludin, via qPCR and western blot. RESULTS: Our data indicated (1) Melatonin reduced the histological injury in the brain and peripheral organs induced by HIBD as assessed via H-E staining and transmission electron microscopy. (2) Melatonin alleviated the HIBD-induced cerebral edema characterized by increased brain water content. (3) HIBD induced significant changes of edema related proteins, such as AQP-4, ZO-1 and occludin, and these changes were partially reversed by melatonin treatment. CONCLUSIONS: These findings provide substantial evidence that melatonin treatment has protective effects on the brain and peripheral organs after HIBD, and the edema related proteins, AQP4, ZO-1, and occludin, may indirectly contribute tothe mechanism of the edema protection by melatonin. PMID- 28351377 TI - Tissue and time specific expression pattern of interferon regulated genes in the chicken. AB - BACKGROUND: Type I interferons are major players against viral infections and mediate their function by the induction of Interferon regulated genes (IRGs). Recently, it became obvious that these cytokines have a multitude of additional functions. Due to the unique features of the chickens' immune system, available data from mouse models are not easily transferable; hence we performed an extensive analysis of chicken IRGs. RESULTS: A broad database search for homologues to described mammalian IRGs (common IRGs, cIRGs) was combined with a transcriptome analysis of spleen and lung at different time points after application of IFNalpha. To apply physiological amounts of IFN, half-life of IFN in the chicken was determined. Interestingly, the calculated 36 min are considerably shorter than the ones obtained for human and mouse. Microarray analysis revealed many additional IRGs (newly identified IRGs; nIRGs) and network analysis for selected IRGs showed a broad interaction of nIRGs among each other and with cIRGs. We found that IRGs exhibit a highly tissue and time specific expression pattern as expression quality and quantity differed strongly between spleen and lung and over time. While in the spleen for many affected genes changes in RNA abundance peaked already after 3 h, an increasing or plateau-like regulation after 3, 6 and 9 h was observed in the lung. CONCLUSIONS: The induction or suppression of IRGs in chickens is both tissue and time specific and beside known antiviral mechanisms type I IFN induces many additional cellular functions. We confirmed many known IRGs and established a multitude of so far undescribed ones, thus providing a large database for future research on antiviral mechanisms and additional IFN functions in non-mammalian species. PMID- 28351379 TI - Efficacy of orally administered prednisolone versus partial endodontic treatment on pain reduction in emergency care of acute irreversible pulpitis of mandibular molars: study protocol for a randomized controlled trial. AB - BACKGROUND: Irreversible pulpitis is a highly painful inflammatory condition of the dental pulp which represents a common dental emergency. Recommended care is partial endodontic treatment. The dental literature reports major difficulties in achieving adequate analgesia to perform this emergency treatment, especially in the case of mandibular molars. In current practice, short-course, orally administered corticotherapy is used for the management of oral pain of inflammatory origin. The efficacy of intraosseous local steroid injections for irreversible pulpitis in mandibular molars has already been demonstrated but resulted in local comorbidities. Oral administration of short-course prednisolone is simple and safe but its efficacy to manage pain caused by irreversible pulpitis has not yet been demonstrated. This trial aims to evaluate the noninferiority of short-course, orally administered corticotherapy versus partial endodontic treatment for the emergency care of irreversible pulpitis in mandibular molars. METHODS/DESIGN: This study is a noninferiority, open-label, randomized controlled clinical trial conducted at the Bordeaux University Hospital. One hundred and twenty subjects will be randomized in two 1:1 parallel arms: the intervention arm will receive one oral dose of prednisolone (1 mg/kg) during the emergency visit, followed by one morning dose each day for 3 days and the reference arm will receive partial endodontic treatment. Both groups will receive planned complete endodontic treatment 72 h after enrollment. The primary outcome is the proportion of patients with pain intensity below 5 on a Numeric Scale 24 h after the emergency visit. Secondary outcomes include comfort during care, the number of injected anesthetic cartridges when performing complete endodontic treatment, the number of antalgic drugs and the number of patients coming back for consultation after 72 h. DISCUSSION: This randomized trial will assess the ability of short-term corticotherapy to reduce pain in irreversible pulpitis as a simple and rapid alternative to partial endodontic treatment and to enable planning of endodontic treatment in optimal analgesic conditions. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02629042 . Registered on 7 December 2015. (Version n degrees 1.1 28 July 2015). PMID- 28351380 TI - MiRNA expression in the cartilage of patients with osteoarthritis. AB - BACKGROUND: Osteoarthritis (OA), the most prevalent disease of articulating joints, is a complex multifactorial disease caused by genetic, mechanical, and environmental factors. In this research, we evaluated miRNA expression in OA. METHODS: Forty tissue samples from 29 patients undergoing joint replacement for OA were evaluated. Tissue from two control patients undergoing hip replacement not related to OA was used as a control. Total RNA (containing miRNA species) from cartilage was isolated using a mirVana miRNA Isolation Kit. Expression of 19 miRNAs was assessed by real-time quantitative polymerase chain reaction. RESULTS: Expression of four miRNAs, miR-138-5p, miR-146a-5p, miR-335-5p, and miR-9-5p, was significantly upregulated in OA tissues (patients vs. control group). CONCLUSIONS: These findings may contribute to disease prevention and the development of therapeutic targets for OA. PMID- 28351381 TI - The role of stromal cancer-associated fibroblasts in pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer generally refractory to conventional treatments. Cancer-associated fibroblasts (CAFs) are cellular components of the desmoplastic stroma characteristic to the tumor that contributes to this treatment resistance. Various markers for CAFs have been explored including palladin and CD146 that have prognostic and functional roles in the pathobiology of PDAC. Mechanisms of CAF-tumor cell interaction have been described including exosomal transfer and paracrine signaling mediated by cytokines such as GM-CSF and IL-6. The role of downstream signaling pathways including JAK/STAT, mTOR, sonic hedge hog (SHH), and NFkB have also been shown to play an important function in PDAC-CAF cross talk. The role of autophagy and other metabolic effects on each cell type within the tumor have also been proposed to play roles in facilitating CAF secretory function and enhancing tumor growth in a low-glucose microenvironment. Targeting the stroma has gained interest with multiple preclinical and clinical trials targeting SHH, JAK2, and methods of either exploiting the secretory capability of CAFs to enhance drug delivery or inhibiting it to prevent its influence on cancer cell chemoresistance. This review summarizes the most recent progress made in understanding stromal formation; its contribution to tumor proliferation, invasion, and metastasis; its role in chemoresistance; and potential therapeutic strategies on the horizon. PMID- 28351382 TI - Erratum to: InteGO2: a web tool for measuring and visualizing gene semantic similarities using Gene Ontology. PMID- 28351385 TI - Erratum to: Cancer progression by breast tumors with Pit-1-overexpression is blocked by inhibition of metalloproteinase (MMP)-13. PMID- 28351383 TI - Diverse interventions that extend mouse lifespan suppress shared age-associated epigenetic changes at critical gene regulatory regions. AB - BACKGROUND: Age-associated epigenetic changes are implicated in aging. Notably, age-associated DNA methylation changes comprise a so-called aging "clock", a robust biomarker of aging. However, while genetic, dietary and drug interventions can extend lifespan, their impact on the epigenome is uncharacterised. To fill this knowledge gap, we defined age-associated DNA methylation changes at the whole-genome, single-nucleotide level in mouse liver and tested the impact of longevity-promoting interventions, specifically the Ames dwarf Prop1 df/df mutation, calorie restriction and rapamycin. RESULTS: In wild-type mice fed an unsupplemented ad libitum diet, age-associated hypomethylation was enriched at super-enhancers in highly expressed genes critical for liver function. Genes harbouring hypomethylated enhancers were enriched for genes that change expression with age. Hypermethylation was enriched at CpG islands marked with bivalent activating and repressing histone modifications and resembled hypermethylation in liver cancer. Age-associated methylation changes are suppressed in Ames dwarf and calorie restricted mice and more selectively and less specifically in rapamycin treated mice. CONCLUSIONS: Age-associated hypo- and hypermethylation events occur at distinct regulatory features of the genome. Distinct longevity-promoting interventions, specifically genetic, dietary and drug interventions, suppress some age-associated methylation changes, consistent with the idea that these interventions exert their beneficial effects, in part, by modulation of the epigenome. This study is a foundation to understand the epigenetic contribution to healthy aging and longevity and the molecular basis of the DNA methylation clock. PMID- 28351384 TI - Maternal characteristics and obstetrical complications impact neonatal outcomes in Indonesia: a prospective study. AB - BACKGROUND: We investigated associations between maternal characteristics, access to care, and obstetrical complications including near miss status on admission or during hospitalization on perinatal outcomes among Indonesian singletons. METHODS: We prospectively collected data on inborn singletons at two hospitals in East Java. Data included socio-demographics, reproductive, obstetric and neonatal variables. Reduced multivariable models were constructed. Outcomes of interest included low and very low birthweight (LBW/VLBW), asphyxia and death. RESULTS: Referral from a care facility was associated with a reduced risk of LBW and VLBW [AOR = 0.28, 95% CI = 0.11-0.69, AOR = 0.18, 95% CI = 0.04-0.75, respectively], stillbirth [AOR = 0.41, 95% CI = 0.18-0.95], and neonatal death [AOR = 0.2, 95% CI = 0.05-0.81]. Mothers age <20 years increased the risk of VLBW [AOR = 6.39, 95% CI = 1.82-22.35] and neonatal death [AOR = 4.10, 95% CI = 1.29-13.02]. Malpresentation on admission increased the risk of asphyxia [AOR = 4.65, 95% CI = 2.23-9.70], stillbirth [AOR = 3.96, 95% CI = 1.41-11.15], and perinatal death [AOR = 3.89 95% CI = 1.42-10.64], as did poor prenatal care (PNC) [AOR = 11.67, 95%CI = 2.71-16.62]. Near-miss on admission increased the risk of neonatal [AOR = 11.67, 95% CI = 2.08-65.65] and perinatal death [AOR = 13.08 95% CI = 3.77 45.37]. CONCLUSIONS: Mothers in labor should be encouraged to seek care early and taught to identify early danger signs. Adequate PNC significantly reduced perinatal deaths. Improved hospital management of malpresentation may significantly reduce perinatal morbidity and mortality. The importance of hospital-based prospective studies helps evaluate specific areas of need in training of obstetrical care providers. PMID- 28351386 TI - Midwife-led maternity care in Ireland - a retrospective cohort study. AB - BACKGROUND: Midwife-led maternity care is shown to be safe for women with low risk during pregnancy. In Ireland, two midwife-led units (MLUs) were introduced in 2004 when a randomised controlled trial (the MidU study) was performed to compare MLU care with consultant-led care (CLU). Following study completion the two MLUs have remained as a maternity care option in Ireland. The aim of this study was to evaluate maternal and neonatal outcomes and transfer rates during six years in the larger of the MLU sites. METHODS: MLU data for the six years 2008-2013 were retrospectively analysed, following ethical approval. Rates of transfer, reasons for transfer, mode of birth, and maternal and fetal outcomes were assessed. Linear-by-Linear Association trend analysis was used for categorical data to evaluate trends over the years and one-way ANOVA was used when comparing continuous variables. RESULTS: During the study period, 3,884 women were registered at the MLU. The antenatal transfer rate was 37.4% and 2,410 women came to labour in the MLU. Throughout labour and birth, 567 women (14.6%) transferred to the CLU, of which 23 were transferred after birth due to need for suturing or postpartum hemorrhage. The most common reasons for intrapartum transfer were meconium stained liquor/abnormal fetal heart rate (30.3%), delayed labour progress in first or second stage (24.9%) and woman's wish for epidural analgesia (15.1%). Of the 1,903 babies born in the MLU, 1,878 (98.7%) were spontaneous vaginal births and 25 (1.3%) were instrumental (ventouse/forceps). Only 25 babies (1.3%) were admitted to neonatal intensive care unit. All spontaneous vaginal births from the MLU registered population, occurring in the study period in both the MLU and CLU settings (n = 2,785), were compared. In the MLU more often 1-2 midwives (90.9% vs 69.7%) cared for the women during birth, more women had three vaginal examinations or fewer (93.6% vs 79.9%) and gave birth in an upright position (standing, squatting or kneeling) (52.0% vs 9.4%), fewer women had an amniotomy (5.9% vs 25.9%) or episiotomy (3.4% vs 9.7%) and more women had a physiological management of third stage of labour (50.9% vs 4.6%). CONCLUSIONS: Midwife-led care is a safe option that could be offered to a large proportion of healthy pregnant women. With strict transfer criteria there are very few complications during labour and birth. Maternity units without the option of MLU care should consider its introduction. PMID- 28351389 TI - Quality of medical service, patient satisfaction and loyalty with a focus on interpersonal-based medical service encounters and treatment effectiveness: a cross-sectional multicenter study of complementary and alternative medicine (CAM) hospitals. AB - BACKGROUND: Treatment effectiveness holds considerable importance in the association between service quality and satisfaction in medical service studies. While complementary and alternative medicine (CAM) use grows more prominent, comprehensive evaluations of the quality of medical service at CAM-oriented hospitals are scarce. This study assesses the quality of medical services provided at a CAM-oriented hospital of Korean medicine using the service encounter system approach and analyzes the influence of treatment effectiveness on patient loyalty. METHODS: A survey study using one-on-one interviews was conducted using a cross-sectional design in outpatients visiting one of fifteen Korean medicine facilities located throughout Korea. A total of 880 surveys were completed from June to July, 2014, and 728 surveys were included in the final analysis after excluding incomplete or incorrect questionnaires. The reliability and validity of the surveys was confirmed using Cronbach's alpha coefficient and confirmatory factor analysis, and a structural equation modeling analysis was performed to verify causality and association between factors (quality of medical service, treatment effectiveness, patient satisfaction, and intent to revisit). RESULTS: The measured factors of physician performance and quality of service procedures had a positive effect on treatment effectiveness. The impression of the facilities and environment directly impacted satisfaction rates for interpersonal-based medical service encounters, while treatment effectiveness positively affected satisfaction regarding quality of medical service. However, treatment effectiveness had a more significant effect on satisfaction compared to facilities and environment, and it indirectly affected satisfaction and directly influenced intent to revisit. Treatment effectiveness and satisfaction both positively influenced intent to revisit. CONCLUSIONS: The importance of treatment effectiveness should be recognized when examining quality of medical services, and we hope that these findings may contribute to future studies. PMID- 28351387 TI - Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism. AB - BACKGROUND: Dietary restriction (DR), a reduction in food intake without malnutrition, increases most aspects of health during aging and extends lifespan in diverse species, including rodents. However, the mechanisms by which DR interacts with the aging process to improve health in old age are poorly understood. DNA methylation could play an important role in mediating the effects of DR because it is sensitive to the effects of nutrition and can affect gene expression memory over time. RESULTS: Here, we profile genome-wide changes in DNA methylation, gene expression and lipidomics in response to DR and aging in female mouse liver. DR is generally strongly protective against age-related changes in DNA methylation. During aging with DR, DNA methylation becomes targeted to gene bodies and is associated with reduced gene expression, particularly of genes involved in lipid metabolism. The lipid profile of the livers of DR mice is correspondingly shifted towards lowered triglyceride content and shorter chain length of triglyceride-associated fatty acids, and these effects become more pronounced with age. CONCLUSIONS: Our results indicate that DR remodels genome wide patterns of DNA methylation so that age-related changes are profoundly delayed, while changes at loci involved in lipid metabolism affect gene expression and the resulting lipid profile. PMID- 28351388 TI - Buyang Huanwu decoction facilitates neurorehabilitation through an improvement of synaptic plasticity in cerebral ischemic rats. AB - BACKGROUND: Loss of neural function is a critical but unsolved issue after cerebral ischemia insult. Neuronal plasticity and remodeling are crucial for recovery of neural functions after brain injury. Buyang Huanwu decoction, which is a classic formula in traditional Chinese medicine, can positively alter synaptic plasticity. This study assessed the effects of Buyang Huanwu decoction in combination with physical exercise on neuronal plasticity in cerebral ischemic rats. METHODS: Cerebral ischemic rats were administered Buyang Huanwu decoction and participated in physical exercise after the induction of a permanent middle cerebral artery occlusion. The neurobehavioral functions and infarct volumes were evaluated. The presynaptic (SYN), postsynaptic (GAP-43) and cytoskeletal (MAP-2) proteins in the coronal brain samples were evaluated by immunohistochemistry and western blot analyses. The ultrastructure of the neuronal synaptic junctions in the same region were analyzed using transmission electron microscopy. RESULTS: Combination treatment of Buyang Huanwu decoction and physical exercise ameliorated the neurobehavioral deficits (p < 0.05), significantly enhanced the expression levels of SYN, GAP-43 and MAP-2 (p < 0.05), and maintained the synaptic ultrastructure. CONCLUSIONS: Buyang Huanwu decoction facilitated neurorehabilitation following a cerebral ischemia insult through an improvement in synaptic plasticity. Graphical abstract The Buyang Huanwu decoction (BYHWD) combined with physical exercise (PE) attenuates synaptic disruption and promotes synaptic plasticity following cerebral ischemia (stroke). PMID- 28351390 TI - Erratum to: Patient preferences for treatment of castration-resistant prostate cancer in Japan: a discrete-choice experiment. PMID- 28351391 TI - The impact on healthcare, policy and practice from 36 multi-project research programmes: findings from two reviews. AB - BACKGROUND: We sought to analyse the impacts found, and the methods used, in a series of assessments of programmes and portfolios of health research consisting of multiple projects. METHODS: We analysed a sample of 36 impact studies of multi project research programmes, selected from a wider sample of impact studies included in two narrative systematic reviews published in 2007 and 2016. We included impact studies in which the individual projects in a programme had been assessed for wider impact, especially on policy or practice, and where findings had been described in such a way that allowed them to be collated and compared. RESULTS: Included programmes were highly diverse in terms of location (11 different countries plus two multi-country ones), number of component projects (8 to 178), nature of the programme, research field, mode of funding, time between completion and impact assessment, methods used to assess impact, and level of impact identified. Thirty-one studies reported on policy impact, 17 on clinician behaviour or informing clinical practice, three on a combined category such as policy and clinician impact, and 12 on wider elements of impact (health gain, patient benefit, improved care or other benefits to the healthcare system). In those multi-programme projects that assessed the respective categories, the percentage of projects that reported some impact was policy 35% (range 5-100%), practice 32% (10-69%), combined category 64% (60-67%), and health gain/health services 27% (6-48%). Variations in levels of impact achieved partly reflected differences in the types of programme, levels of collaboration with users, and methods and timing of impact assessment. Most commonly, principal investigators were surveyed; some studies involved desk research and some interviews with investigators and/or stakeholders. Most studies used a conceptual framework such as the Payback Framework. One study attempted to assess the monetary value of a research programme's health gain. CONCLUSION: The widespread impact reported for some multi-project programmes, including needs-led and collaborative ones, could potentially be used to promote further research funding. Moves towards greater standardisation of assessment methods could address existing inconsistencies and better inform strategic decisions about research investment; however, unresolved issues about such moves remain. PMID- 28351392 TI - Can we use gonadotropin plasma concentration as surrogate marker for BMI-related incomplete estrogen suppression in breast cancer patients receiving anastrozole? AB - BACKGROUND: BMI has been suggested to impact on estrogenic activity in patients receiving anastrozole resulting in a reduced treatment efficacy in obese women. Current evidence in this regard is controversially discussed. Since estradiol is inversely correlated with gonadotropins it can be assumed that an impact of BMI is also reflected by gonadotropin plasma concentrations. We aim at investigating the impact of BMI on the hormonal state of breast cancer (BC) patients receiving anastrozole indicated by LH, FSH and SHBG as well as estradiol. METHODS: We determined gonadotropin-, estradiol- and anastrozole- serum concentrations from postmenopausal, early stage breast cancer patients receiving upfront anastrozole within routine after care. Gonadotropin plasma concentrations were derived from the routine laboratory examination report. A liquid chromatography tandem mass spectrometry method was used for the measurement of anastrozole serum concentrations. BMI was assessed within the routine after-care check-up. RESULTS: The overall sample comprised 135 BC patients with a mean age of 65.3 years. BMI was significantly correlated with LH, FSH and SHBG. This association was neither influenced by age nor by anastrozole serum concentrations according to the regression model. Despite aromatase inhibition 12% of patients had detectable estrogen levels in routine quantification. CONCLUSION: Obese women have an altered hormonal situation compared to normally weight women under the same dose of anastrozole. Our study findings are a further indicator for the relevance of BMI in regard of anastrozole metabolism and possible estrogenic activity indicated by gonadotropin plasma level. PMID- 28351394 TI - Higher education in Gerodontology in European Universities. AB - BACKGROUND: The rapid aging of the European population and the subsequent increase in the oral care needs in older adults necessitates adequate training of dental professionals in Gerodontology (Geriatric Dentistry). This study was designed to investigate the current status of Gerodontology teaching amongst European dental schools at the undergraduate, postgraduate and continuing education levels. METHODS: An electronic questionnaire was developed by a panel of experts and emailed to the Deans or other contact persons of 216 dental schools across 39 European countries. The questionnaire recorded activity levels, contents and methodology of Gerodontology teaching as part of dental education programs. Repeated e-mail reminders and telephone calls were used to encourage non-responders to complete the questionnaire. RESULTS: A total of 123 responses from 29 countries were received (response rate: 56.9%). Gerodontology was taught in 86.2% of schools at the undergraduate level, in 30.9% at the postgraduate level and in 30.1% at the continuing education level. A total of 43.9% of the responding schools had a dedicated Gerodontology program director. Gerodontology was taught as an independent subject in 37.4% of the respondent schools. Medical problems in old age, salivary impairment and prosthodontic management were the most commonly covered topics in Gerodontology teaching. Clinical teaching took place in 64.2% of the respondent schools, with 26.8% offering clinical training in outreach facilities. CONCLUSIONS: The vast majority of European dental schools currently teach Gerodontology at the undergraduate level. More training opportunities in oral care of frail elders should be offered, and more emphasis should be placed on interdisciplinary and interprofessional training, educational collaborations, and the use of modern technologies. Dedicated postgraduate Gerodontology courses need to be developed to create a significant number of specialized dentists and trained academics. PMID- 28351393 TI - Effects of honey supplementation on inflammatory markers among chronic smokers: a randomized controlled trial. AB - BACKGROUND: Honey has been demonstrated to possess anti-inflammatory property. This is a randomized, controlled, open-label trial to determine the effects of 12 week honey oral supplementation on plasma inflammatory markers such as high sensitive C-reactive protein, interleukin-6 and tumor necrosis factor-alpha among chronic smokers. METHODS/DESIGN: A total of 32 non-smokers and 64 chronic smokers from Quit Smoking Clinic and Health Campus, Universiti Sains Malaysia participated in the study. Smokers were then randomized into 2 groups: smokers with honey group that received Malaysian Tualang honey (20 g/day daily for 12 weeks) and smokers without honey group. Blood was obtained from non-smokers and smokers at pre-intervention, and from smokers at post-intervention for measurement of the inflammatory markers. RESULTS: At pre-intervention, smokers had significantly higher high sensitive C-reactive protein than non-smokers. In smokers with honey group, tumor necrosis factor-alpha was significantly increased while high sensitive C-reactive protein was significantly reduced at post intervention than at pre-intervention. CONCLUSION: This study suggests that honey supplementation has opposite effects on tumor necrosis factor-alpha and high sensitive C-reactive protein indicating the inconclusive effect of honey on inflammation among chronic smokers which needs further study on other inflammatory markers. TRIAL REGISTRATION: The Trial has been registered in the Australian New Zealand Clinical Trials Registry: ACTRN12615001236583 . Registered 11 November 2015 (Retrospectively Registered). PMID- 28351395 TI - Follicular thyroid carcinoma metastasis to the facial skeleton: a systematic review. AB - BACKGROUND: Follicular thyroid carcinoma (FTC) metastasis to the facial skeleton is exceedingly rare. A case of FTC metastasizing to the mandible is presented and a systematic review of the literature describing thyroid metastasis to the facial skeleton is performed. CASE PRESENTATION: A 73-year-old female presented with metastatic FTC to the mandible and underwent total thyroidectomy, segmental mandibulectomy, bone impacted fibular free flap reconstruction, and adjuvant radioactive iodine treatment. The PubMed database was searched for literature describing thyroid cancer with facial skeleton metastasis using the key words "thyroid," "cancer," "carcinoma," "metastasis," and "malignancy" with "oral cavity," "maxilla," "mandible," "sinus," "paranasal," and "orbit." Reports that only involved the soft tissues were excluded. Systematic review revealed 59 cases of well-differentiated thyroid cancer with facial skeleton metastasis: 35 mandibular metastases (21 = FTC), 6 maxilla metastases (2 = FTC), 9 orbital metastases (4 = FTC), and 11 paranasal sinus metastases (7 = FTC). Treatment included surgery, RAI, external beam radiotherapy (XRT), or a combination of these modalities. The one, two, and five-year survival rates were 100%, 79%, and 16%, respectively. CONCLUSION: Facial skeleton metastasis of FTC is a rare clinical challenge. Optimal treatment appears to include total thyroidectomy and resection of involved structures with or without adjuvant treatment. PMID- 28351396 TI - Evaluation and treatment for ovotesticular disorder of sex development (OT-DSD) - experience based on a Chinese series. AB - BACKGROUND: The aim of this study is to review and present the clinical features and process of evaluation and treatment for OT-DSD in a single center in recent years in China. METHODS: Sixteen patients with OT-DSD during the past 4 years underwent the evaluation and treatment in a single center. The clinical characteristics and outcomes of surgery were analyzed. RESULTS: The surgical age ranged from 17 months to 66 months with a mean age of 20 months, and the mean follow-up was 30 months (4 months to 56 months). The presentation in 11 patients was ambiguous genitalia, and the rest 5 patients were suspected to have DSD in preoperative examination before hypospadias repair. The karyotypes were 46, XX in 11 patients, 46, XX/46, XY in 3, 46, XX/47, XXY in 1, and 46, XY in 1. Initial reared sex was male in 14 patients, female in 1, and undetermined in 1. After surgery, genders were reassigned in 3 patients, while 15 patients were raised as male with testicular tissue left. Only 1 patient with ovarian tissue left was raised as female. Repair was completed in 11 males and 1 female, and stage I urethroplasty was done in 4 males. No further surgery to remove the gonads was needed for inconsonance of gender assignment. No gonadal tumors were detected. CONCLUSIONS: OT-DSD is a rare and complex deformity with few systematic reports in China. It's important to establish a regular algorithm for evaluation and treatment of OT-DSD. PMID- 28351397 TI - Correlates of meeting the combined and independent aerobic and strength exercise guidelines in hematologic cancer survivors. AB - BACKGROUND: Most previous research on the correlates of physical activity has examined the aerobic or strength exercise guidelines separately. Such an approach does not allow an examination of the correlates of meeting the combined guidelines versus a single guideline, or one guideline versus the other. Here, we report the prevalence and correlates of meeting the combined and independent exercise guidelines in hematologic cancer survivors (HCS). METHODS: In a population-based, cross-sectional survey of 606 HCS from Alberta, Canada using a mailed questionnaire, we obtained separate assessments of aerobic and strength exercise behaviors, as well as separate assessments for motivations, regulations, and reflective processes using the multi-process action control framework (M PAC). RESULTS: Overall, 22% of HCS met the combined exercise guideline, 22% met aerobic-only, 10% met strength-only, and 46% met neither exercise guideline. HCS were more likely to meet the combined guideline over the aerobic-only guideline if they had no children living at home, and over both the aerobic and strength only guidelines if they had completed university. As hypothesized, those meeting the combined guideline also had a more favorable strength-specific M-PAC profile (i.e., motivations, regulations, and reflective processes) than those meeting the aerobic-only guideline, and a more favorable aerobic-specific M-PAC profile than those meeting the strength-only guideline. Interestingly and unexpectedly, HCS meeting the combined guidelines also reported significantly greater aerobic specific perceived control, planning, and obligation/regret than those meeting the aerobic-only guideline, and greater strength-specific perceived control, planning, and obligation/regret than those meeting the strength-only guideline. CONCLUSIONS: Few HCS are meeting the combined exercise guidelines. M-PAC based variables are strong correlates of meeting the combined guidelines compared to aerobic or strength only guidelines. Strategies to help HCS meet the combined guidelines may need to promote more favorable behavioral regulations and reflective processes for both types of exercise rather than just the type of exercise in which HCS are deficient. PMID- 28351398 TI - Genome-wide methylation analysis identifies a core set of hypermethylated genes in CIMP-H colorectal cancer. AB - BACKGROUND: Aberrant DNA methylation profiles are a characteristic of all known cancer types, epitomized by the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC). Hypermethylation has been observed at CpG islands throughout the genome, but it is unclear which factors determine whether an individual island becomes methylated in cancer. METHODS: DNA methylation in CRC was analysed using the Illumina HumanMethylation450K array. Differentially methylated loci were identified using Significance Analysis of Microarrays (SAM) and the Wilcoxon Signed Rank (WSR) test. Unsupervised hierarchical clustering was used to identify methylation subtypes in CRC. RESULTS: In this study we characterized the DNA methylation profiles of 94 CRC tissues and their matched normal counterparts. Consistent with previous studies, unsupervized hierarchical clustering of genome-wide methylation data identified three subtypes within the tumour samples, designated CIMP-H, CIMP-L and CIMP-N, that showed high, low and very low methylation levels, respectively. Differential methylation between normal and tumour samples was analysed at the individual CpG level, and at the gene level. The distribution of hypermethylation in CIMP-N tumours showed high inter-tumour variability and appeared to be highly stochastic in nature, whereas CIMP-H tumours exhibited consistent hypermethylation at a subset of genes, in addition to a highly variable background of hypermethylated genes. EYA4, TFPI2 and TLX1 were hypermethylated in more than 90% of all tumours examined. One hundred thirty-two genes were hypermethylated in 100% of CIMP-H tumours studied and these were highly enriched for functions relating to skeletal system development (Bonferroni adjusted p value =2.88E-15), segment specification (adjusted p value =9.62E-11), embryonic development (adjusted p value =1.52E-04), mesoderm development (adjusted p value =1.14E-20), and ectoderm development (adjusted p value =7.94E-16). CONCLUSIONS: Our genome-wide characterization of DNA methylation in colorectal cancer has identified 132 genes hypermethylated in 100% of CIMP-H samples. Three genes, EYA4, TLX1 and TFPI2 are hypermethylated in >90% of all tumour samples, regardless of CIMP subtype. PMID- 28351399 TI - Effects of hyperthermic baths on depression, sleep and heart rate variability in patients with depressive disorder: a randomized clinical pilot trial. AB - BACKGROUND: Despite advances in the treatment of depression, one-third of depressed patients fail to respond to conventional antidepressant medication. There is a need for more effective treatments with fewer side effects. The primary aim of this study was to determine whether hyperthermic baths reduce depressive symptoms in adults with depressive disorder. METHODS: Randomized, two arm placebo-controlled, 8-week pilot trial. Medically stable outpatients with confirmed depressive disorder (ICD-10: F32/F33) who were moderately depressed as determined by the 17-item Hamilton Scale for Depression (HAM-D) score >=18 were randomly assigned to 2 hyperthermic baths (40 degrees C) per week for 4 weeks or a sham intervention with green light and follow-up after 4 weeks. Main outcome measure was the change in HAM-Dtotal score from baseline (T0) to the 2-week time point (T1). RESULTS: A total of 36 patients were randomized (hyperthermic baths, n = 17; sham condition, n = 19). The intention-to-treat analysis showed a significant (P = .037) difference in the change in HAM-Dtotal score with 3.14 points after 4 interventions (T1) in favour of the hyperthermic bath group compared to the placebo group. CONCLUSIONS: This pilot study suggests that hyperthermic baths do have generalized efficacy in depressed patients. TRIAL REGISTRATION: DRKS00004803 at drks-neu.uniklinik-freiburg.de, German Clinical Trials Register (registration date 2016-02-02), retrospectively registered. PMID- 28351400 TI - Cerebrospinal fluid abnormalities in meningeosis neoplastica: a retrospective 12 year analysis. AB - BACKGROUND: Meningeosis neoplastica is a diffuse metastatic spread of tumor cells in the subarachnoid space. Although first recognized in 1870, systematic investigations regarding cerebrospinal fluid (CSF) constituents in this condition are scarce. METHODS: Routine CSF samples analyzed from 2001 to 2012 at the Laboratory of Clinical Neurochemistry, University of Gottingen, were re evaluated. Patients, whose CSF contained malignant cells were included in this study. RESULTS: Patients (n = 132, age 59.1 +/- 29.1, 58% women) were identified, whose CSF contained malignant cells. The most frequent primary tumor was breast cancer (32.6%), followed by lung cancer (25.0%) and hematologic malignancies (21.2%). The most frequent clinical symptoms were affections of cranial nerves (41.7%), psychiatric abmormalities (32.6%) and radicular lesions of the lower extremities (20.5%). CSF cell counts ranged from 0 to 4692 cells/MUl (median 4 cells/MUl) and were elevated in 50%. The CSF-to-serum albumin ratio was abnormal in 69.4%. It ranged from 1.8 to 330 x 10-3 (median 17.5 x 10-3). Total CSF protein ranged from 166 to 15,840 mg/l (median 1012 mg/l). CSF lactate was elevated (>2.4 mmol/l) in 65.2% [3.6 mmol/l (1.3/15.6 mmol/l); median (minimum/maximum)]. In 50% of all patients CSF lactate was >=3.5 mmol/l. The CSF cell counts correlated significantly with the CSF lactate levels and the CSF protein contents. In 56 of 118 CSF samples (47.5%) ferritin was elevated, and in 25 of 65 carcinoma patients (38.5%) an intrathecal production of carcinoembryonic antigen (CEA) was detected. Granulocytes were found in 52.7% of the CSF samples. The percentages of granulocytes and lymphocytes were higher in samples with an elevated cell count. CONCLUSION: In approximately 50% of CSF samples with meningeosis neoplastica the CSF cell count is not elevated. Diagnosis may be missed when only CSF samples with elevated cell counts are subjected to cytological analysis. CSF lactate and protein and the CSF-to-serum albumin ratio are frequently increased in meningeosis neoplastica. The differential diagnosis between meningeosis neoplastica and central nervous infections, in particular tuberculous or fungal meningitis, can be difficult. PMID- 28351401 TI - Cognitive-enhancing and antioxidant activities of the aqueous extract from Markhamia tomentosa (Benth.) K. Schum. stem bark in a rat model of scopolamine. AB - BACKGROUND: Plants of the genus Markhamia have been traditionally used by different tribes in various parts of West African countries, including Cameroun. Markhamia tomentosa (Benth.) K. Schum. (Bignoniaceae) is used as an antimalarial, anti-inflammatory, analgesic, antioxidant and anti-Alzheimer agent. The current study was undertaken in order to investigate its anti-amnesic and antioxidant potential on scopolamine-induced cognitive impairment and to determine its possible mechanism of action. METHODS: Rats were pretreated with the aqueous extract (50 and 200 mg/kg, p.o.), for 10 days, and received a single injection of scopolamine (0.7 mg/kg, i.p.) before training in Y-maze and radial arm-maze tests. The biochemical parameters in the rat hippocampus were also assessed to explore oxidative status. Statistical analyses were performed using two-way ANOVA followed by Tukey's post hoc test. F values for which p < 0.05 were regarded as statistically significant. RESULTS: In the scopolamine-treated rats, the aqueous extract improved memory in behavioral tests and decreased the oxidative stress in the rat hippocampus. Also, the aqueous extract exhibited anti acetylcholinesterase activity. CONCLUSIONS: These results suggest that the aqueous extract ameliorates scopolamine-induced spatial memory impairment by attenuation of the oxidative stress in the rat hippocampus. PMID- 28351402 TI - Abnormal T2 mapping cardiovascular magnetic resonance correlates with adverse clinical outcome in patients with suspected acute myocarditis. AB - BACKGROUND: While most patients recover from suspected acute myocarditis (sAMC) some develop progressive disease with 5-year mortality up to 20%. Recently, parametric Cardiovascular Magnetic Resonance (CMR) approaches, quantifying native T1 and T2 relaxation time, have demonstrated the ability to increase diagnostic accuracy. However, prognostic implications of T2 values in this cohort are unknown. The purpose of the study was to investigate the prognostic relevance of elevated CMR T2 values in patients with sAMC. METHODS AND RESULTS: We carried out a prospective study in 46 patients with sAMC defined by current ESC recommendations. A combined endpoint was defined by the occurrence of at least one major adverse cardiac event (MACE) and hospitalisation for heart failure. Event rate was 24% (n = 11) for 1-year-MACE and hospitalisation. A follow-up after 11 +/- 7 months was performed in 98% of the patients. Global T2 values were significantly increased at acute stage of disease compared to controls and decreased over time. During acute disease, elevated global T2 time (odds ratio 6.3, p < 0.02) as well as myocardial fraction with T2 time >80 ms (odds ratio 4.9, p < 0.04) predicted occurrence of the combined endpoint. Patients with clinical recovery revealed significantly decreased T2 relaxation times at follow up examinations; however, T2 values were still elevated compared to healthy controls. CONCLUSION: Assessment of myocardial T2 relaxation times at initial presentation facilitates CMR-based risk stratification in patients with acute myocarditis. T2 Mapping may emerge as a new tool to monitor inflammatory myocardial injuries during the course of disease. PMID- 28351403 TI - Childhood neglect predicts the course of major depression in a tertiary care sample: a follow-up study. AB - BACKGROUND: The course of depression is poorer in clinical settings than in the general population. Several predictors have been studied and there is growing evidence that a history of childhood maltreatment consistently predicts a poorer course of depression. METHODS: Between 2008 and 2012, we assessed 238 individuals suffering from a current episode of major depression. Fifty percent of these (N = 119) participated in a follow-up study conducted between 2012 and 2014 that assessed sociodemographic and clinical variables, the history of childhood abuse and neglect (using the Adverse Childhood Experience questionnaire), and the course of depression between baseline and follow-up interview (using the Life Chart method). The Structured Clinical Interview for DSM-IV-TR was used to assess diagnosis at baseline and follow-up interview. Statistical analyses used the life table survival method and Cox proportional hazard regression tests. RESULTS: Among 119 participants, 45.4% did not recover or remit during the follow-up period. The median time to remission or recovery was 28.9 months and the median time to the first recurrence was 25.7 months. Not being married, a chronic index depressive episode, comorbidity with an anxiety disorder, and a childhood history of physical neglect independently predicted a slower time to remission or recovery. The presence of three or more previous depression episodes and a childhood history of emotional neglect were independent predictors of depressive recurrences. CONCLUSIONS: Childhood emotional and physical neglect predict a less favorable course of depression. The effect of childhood neglect on the course of depression was independent of sociodemographic and clinical variables. PMID- 28351404 TI - Longitudinal 10-year changes in dietary intake and associations with cardio metabolic risk factors in the Northern Sweden Health and Disease Study. AB - BACKGROUND: Dietary risks today constitute the largest proportion of disability adjusted life years (DALYs) globally and in Sweden. An increasing number of people today consume highly processed foods high in saturated fat, refined sugar and salt and low in dietary fiber, vitamins and minerals. It is important that dietary trends over time are monitored to predict changes in disease risk. METHODS: In total, 15,995 individuals with two visits 10 (+/-1) years apart in the population-based Vasterbotten Intervention Programme 1996-2014 were included. Dietary intake was captured with a 64-item food frequency questionnaire. Percent changes in intake of dietary components, Healthy Diet Score and Dietary Inflammatory Index were calculated and related to body mass index (BMI), serum cholesterol and triglyceride levels and blood pressure at the second visit in multivariable regression analyses. RESULTS: For both sexes, on group level, proportion of energy intake (E%) from carbohydrates and sucrose decreased (largest carbohydrate decrease among 40 year-olds) and E% protein and total fat as well as saturated and poly-unsaturated fatty acids (PUFA) increased (highest protein increase among 30 year-olds and highest fat increase among 60 year-olds) over the 10-year period. Also, E% trans-fatty acids decreased. On individual basis, for both sexes decreases in intake of cholesterol and trans-fatty acids were associated with lower BMI and serum cholesterol at second visit (all P < 0.05). For men, increases in intake of whole grain and Healthy Diet Score were associated with lower BMI and serum cholesterol at second visit (all P < 0.05). Also for men, decreases in intake of trans-fatty acids and increases in Healthy Diet Score were associated with lower systolic blood pressure at second visit (P = 0.002 and P < 0.000). For women, increases in intake of PUFA and Healthy Diet Score were associated with lower BMI at second visit (P = 0.01 and P < 0.05). Surprisingly, increases in intake of sucrose among women were associated with lower BMI at second visit (P = 0.02). CONCLUSIONS: In this large population-based sample, dietary changes over 10 years towards less carbohydrates and more protein and fat were noted. Individual changes towards the Nordic dietary recommendations were associated with healthier cardio-metabolic risk factor profile at second visit. PMID- 28351405 TI - Dimensions of sustainability for a health communication intervention in African American churches: a multi-methods study. AB - BACKGROUND: Sustainability of evidence-based health promotion interventions has received increased research attention in recent years. This paper reports sustainability data from Project HEAL (Health through Early Awareness and Learning) a cancer communication implementation trial about early detection, based in African American churches. In this paper, we used a framework by Scheirer and Dearing (Am J Publ Health 101:2059-2067, 2011) to evaluate multiple dimensions of sustainability from Project HEAL. METHODS: We examined the following dimensions of sustainability: (a) continued benefits for intervention recipients, (b) continuation of intervention activities, c) maintaining community partnerships, (d) changes in organizational policies or structures, (e) sustained attention to the underlying issues, (f) diffusion to additional sites, or even (g) unplanned consequences of the intervention. Project HEAL provided a three workshop cancer educational series delivered by trained lay peer community health advisors (CHAs) in their churches. Multiple sources of sustainability were collected at 12 and 24 months after the intervention that reflect several levels of analysis: participant surveys; interviews with CHAs; records from the project's management database; and open-ended comments from CHAs, staff, and community partners. RESULTS: Outcomes differ for each dimension of sustainability. For continued benefit, 39 and 37% of the initial 375 church members attended the 12- and 24-month follow-up workshops, respectively. Most participants reported sharing the information from Project HEAL with family or friends (92% at 12 months; 87% at 24 months). For continuation of intervention activities, some CHAs reported that the churches held at least one additional cancer educational workshop (33% at 12 months; 24% at 24 months), but many more CHAs reported subsequent health activities in their churches (71% at 12 months; 52% at 24 months). No church replicated the original series of three workshops. Additional data confirm the maintenance of community partnerships, some changes in church health policies, and continued attention to health issues by churches and CHAs. CONCLUSIONS: The multiple dimensions of sustainability require different data sources and levels of analysis and show varied sustainability outcomes in this project. The findings reinforce the dynamic nature of evidence based health interventions in community contexts. PMID- 28351406 TI - CIDR: Ultrafast and accurate clustering through imputation for single-cell RNA seq data. AB - Most existing dimensionality reduction and clustering packages for single-cell RNA-seq (scRNA-seq) data deal with dropouts by heavy modeling and computational machinery. Here, we introduce CIDR (Clustering through Imputation and Dimensionality Reduction), an ultrafast algorithm that uses a novel yet very simple implicit imputation approach to alleviate the impact of dropouts in scRNA seq data in a principled manner. Using a range of simulated and real data, we show that CIDR improves the standard principal component analysis and outperforms the state-of-the-art methods, namely t-SNE, ZIFA, and RaceID, in terms of clustering accuracy. CIDR typically completes within seconds when processing a data set of hundreds of cells and minutes for a data set of thousands of cells. CIDR can be downloaded at https://github.com/VCCRI/CIDR . PMID- 28351407 TI - Maternal fat free mass during pregnancy is associated with birth weight. AB - BACKGROUND: The relationship between maternal body compositions and birth weight was not definite. Fat Mass (FM) and Fat Free Mass (FFM) can accurately reflect the maternal body fat compositions and have been considered as better predictors of birth weight. Despite its potential role, no studies have been described the maternal compositions during pregnancy in East Asian women previously. We investigated the correlation between birth weight and Maternal body composition including fat mass (FM) and fat free mass (FFM). To determine whether birth weight is associated with maternal body fat FM and FFM during pregnancy and, if so, which trimester and parameter is more critical in determining birth weight. METHODS: A longitudinal prospective observational study performed, 348, 481 and 321 non-diabetics Han Chinese women with a singleton live birth attending a routine visit in their first, second and third trimesters were recruited. Maternal body composition was measured using segmental multi-frequency bioelectrical impedance analysis. Data of the pre-pregnancy body mass index (BMI), maternal BMI, the gestational weight gain (GWG), and placental and birth weight were collected. RESULTS: A significant correlation exists between maternal FFM in the process of pregnancy, placental weight, GWG at delivery, and birth weight (P < 0.05). On stepwise multiple linear regression analysis, material's FFM was the most important factor associated with the birth weight. After adjustment, there was significantly associated with 2.47-fold increase in risk for birth weight more than 4 kg when FFM >= 40.76 kg (Upper quartile of participants). The increased maternal age became a protective factor (OR = 0.69) while the increased pre-pregnancy BMI (OR = 1.50) remained predictors to birth weight more than 4 kg. CONCLUSIONS: The change of maternal FFM during pregnancy is independently affected the birth weight. PMID- 28351408 TI - Application of short message service to control blood cholesterol: a field trial. AB - BACKGROUND: Despite recommendations, many middle-age adults neglect to check their blood cholesterol levels. Short message service (SMS, also known as texting) has been seldom studied for preventive education. We estimated how SMS can be a cost-effective method in encouraging people to check their blood cholesterol levels. METHODS: In a field trial, 3600 cell phone users (age > 30) were randomly assigned to the intervention (N: 1200) and the control groups (N: 2400). An SMS was sent to the intervention group for five rounds every two weeks, which targeted the cognitive and affective learning and finally advised the blood cholesterol level to be checked, if not checked during the past twelve months. Two weeks after the last round, both groups were asked for the time/level of their latest blood cholesterol, family history of early cardiac death and having a family member with coronary heart disease (CHD), and to report their attitude about whether annual blood sampling is worth the cost and time to prevent CHD. Moreover, the intervention group was asked if they remembered the SMS content. The cost-effectiveness was evaluated by estimating the "number needed to treat" (NNT) and calculating the cost of sending SMS to that number of people. RESULTS: In the intervention group, 629 individuals (72.0%) recalled the SMS content. The factors associated with cholesterol screening during the past two years were older age, diabetes, family history of coronary disease, higher education, female gender and being non-smoker. In both groups, women were significantly more aware of their blood cholesterol level (68.7% vs. 53.6%). The relative frequency of respondents who believed it was not worth checking their cholesterol annually was significantly lower in the intervention group (P < 0.001). The intervention group was significantly more likely to check its blood cholesterol levels (OR:1.22) after adjustment for age, diabetes, family history of CHD and smoking. The NNT was estimated ~ 25 for the general population and ~ 11 for those who received SMS and had a family member with CHD. CONCLUSIONS: We would postulate that SMS could affect people's adherence to preventive programs. Relatives of patients admitted with a diagnosis of CHD should be prioritized for superior cost-effectiveness and logistical feasibility. PMID- 28351409 TI - Identification of a novel merozoite surface antigen of Plasmodium vivax, PvMSA180. AB - BACKGROUND: Although a number of Plasmodium vivax proteins have been identified, few have been investigated as potential vaccine candidates. This study characterized the Plasmodium vivax merozoite surface antigen 180 (PvMSA180, PVX_094920), a novel P. vivax antigenic protein. METHODS: The target gene was amplified as four overlapping domains (D1, D2, D3 and D4) to enable expression of the recombinant protein using cell-free and bacterial expression systems. The recombinant PvMSA180 proteins were used in protein microarrays to evaluate the humoral immune response of 72 vivax-infected patients and 24 vivax-naive individuals. Antibodies produced in mice against the PvMSA180-D1 and -D4 domains were used to assess the subcellular localization of schizont-stage parasites with immunofluorescence assays. A total of 51 pvmsa180 sequences from 12 countries (41 sequences from PlasmoDB and 6 generated in this study) were used to determine the genetic diversity and genealogical relationships with DNAsp and NETWORK software packages, respectively. RESULTS: PvMSA180 consists of 1603 amino acids with a predicted molecular mass of 182 kDa, and has a signal peptide at the amino terminus. A total of 70.8% of patients (51/72) showed a specific antibody response to at least one of the PvMSA180 domains, and 20.8% (15/72) exhibited a robust antibody response to at least three of the domains. These findings suggest that PvMSA180 is targeted by the humoral immune response during natural infection with P. vivax. Immunofluorescence analysis demonstrated that PvMSA180 is localized on the merozoite surface of schizont-stage parasites, and pvmsa180 sequences originating from various geographic regions worldwide showed low genetic diversity. Twenty-two haplotypes were found, and haplotype 6 (Hap_6, 77%) of pvmsa180 was detected in isolates from six countries. CONCLUSIONS: A novel P. vivax surface protein, PvMSA180, was characterized in this study. Most of P. vivax-infected patients had specific antibodies against particular antigenic domains, indicating that this protein is immunogenic in naturally exposed populations. Genetic analysis of worldwide isolates showed that pvmsa180 is less polymorphic than other well-known candidates and that some haplotypes are common to several countries. However, additional studies with a larger sample size are necessary to evaluate the antibody responses in geographically separated populations, and to identify the function of PvMSA180 during parasite invasion. PMID- 28351410 TI - Cognitive-behavioral rehabilitation vs. treatment as usual for bipolar patients: study protocol for a randomized controlled trial. AB - BACKGROUND: Bipolar disorder (BD) is commonly associated with cognitive and functional impairments even during remission periods, and although a growing number of studies have demonstrated the benefits of psychotherapy as an add-on to pharmacological treatment, its effectiveness appears to be less compelling in severe presentations of the disorder. New interventions have attempted to improve cognitive functioning in BD patients, but results have been mixed. METHODS: The study consists of a clinical trial comparing a new structured group intervention, called "Cognitive-Behavioral Rehabilitation," with treatment as usual (TAU) for bipolar patients. The new approach is a combination of cognitive behavioral strategies and cognitive remediation exercises, consisting of 12 weekly group sessions of 90 min each. To be included in the study, patients must be diagnosed with BD type I or II, aged 18-55 years, in full or partial remission, and have an IQ of at least 80. A comprehensive neuropsychological battery, followed by mood, social functioning, and quality of life assessments will occur in three moments: pre and post intervention and 12 months later. The primary outcome of the study is to compare the time, in weeks, that the first full mood episode appears in patients who participated in either group of the study. Secondary outcome will include improvement in cognitive functions. DISCUSSION: This is the first controlled trial assessing the validity and effectiveness of the new "Cognitive Behavioral Rehabilitation" intervention in preventing new mood episodes and improving cognitive and functional impairments. TRIAL REGISTRATION: Clinicaltrial.gov, NCT02766361 . Registered on 2 May 2016. PMID- 28351411 TI - Activation of FXR pathway does not alter glial cell function. AB - BACKGROUND: The nuclear receptor farnesoid-X-receptor (FXR; NR1H4) is expressed not only in the liver, gut, kidney and adipose tissue but also in the immune cells. FXR has been shown to confer protection in several animal models of inflammation, including experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). FXR agonists are currently tested in clinical trials for treatment of human metabolic diseases. The beneficial effect of FXR agonists in EAE suggests that FXR might represent a potential target in inflammatory-demyelinating CNS diseases, such as MS. In MS, oligodendrocytes not only undergo cell death but also contribute to remyelination. This repair mechanism is impaired due to a differentiation block of oligodendroglial progenitor cells. Activation of other nuclear receptors that heterodimerize with FXR promote oligodendroglial differentiation. Therefore, we wanted to address the functional relevance of FXR for glial cells, especially for oligodendroglial differentiation. METHODS: We isolated primary murine oligodendrocytes from FXR deficient (FXR Ko) and wild-type (WT) mice and determined the effect of FXR deficiency and activation on oligodendroglial differentiation by analysing markers of oligodendroglial progenitor cells (OPCs) and mature oligodendrocytes (OLs) using qRT-PCR and immunocytochemistry. Additionally, we determined whether FXR activation modulates the pro-inflammatory profile of astrocytes or microglia and whether this may subsequently modulate oligodendroglial differentiation. These in vitro studies were complemented by histological analyses of oligodendrocytes in FXR Ko mice. RESULTS: FXR is expressed by OPCs and mature oligodendrocytes. However, lack of FXR did not affect oligodendroglial differentiation in vitro or in vivo. Furthermore, activation of FXR using the synthetic agonist GW4064 did not affect oligodendroglial differentiation, remyelination in an ex vivo model or the expression of pro-inflammatory molecules in astrocytes or microglia. Concordantly, no effects of supernatants from macrophages cultured in the presence of GW4064 were observed regarding a possible indirect impact on oligodendroglial differentiation. CONCLUSIONS: Our data suggest that FXR is dispensable for oligodendroglial differentiation and that FXR agonists, such as GW4064, represent a potential therapeutic approach for MS which specifically targets peripheral immune cells including macrophages but not brain resident cells, such as oligodendrocytes, astrocytes or microglia. PMID- 28351413 TI - Is neuroendocrine differentiation a prognostic factor in poorly differentiated colorectal cancer? AB - BACKGROUND: To determine the prognostic relevance of neuroendocrine differentiation in poorly differentiated colorectal cancer. METHODS: The clinicopathological features and survival of 70 patients with poorly differentiated colorectal cancer were analyzed retrospectively. Chromogranin A and synaptophysin were used as neuroendocrine markers. Patients were followed-up for more than 3 years or until death. RESULTS: Of these 70 patients, 36 showed neuroendocrine differentiation. In univariate prognostic analysis, the patients with lymph node metastasis (P < 0.001), advanced TNM stage (P < 0.001), and neuroendocrine differentiation (P = 0.003) tended to have a poor prognosis. However, only lymph node metastasis was associated with a poor prognosis in multivariate analysis (P < 0.001). Patients with neuroendocrine differentiation were associated with lymph node metastasis (P = 0.006). CONCLUSIONS: Neuroendocrine differentiation in poorly differentiated colorectal cancer was not a direct prognostic factor in these patients. Lymph node metastasis was a direct prognostic factor in these patients. Patients with neuroendocrine differentiation were associated with lymph node metastasis. PMID- 28351412 TI - Effect of Pycnogenol(r) on attention-deficit hyperactivity disorder (ADHD): study protocol for a randomised controlled trial. AB - BACKGROUND: Methylphenidate (MPH), the first choice medication for attention deficit hyperactivity disorder (ADHD), is associated with serious adverse effects like arrhythmia. Evidence on the association of ADHD with immune and oxidant antioxidant imbalances offers potential for antioxidant and/or immunomodulatory nutritional supplements as ADHD therapy. One small randomised trial in ADHD suggests, despite various limitations, therapeutic benefit from Pycnogenol(r), a herbal, polyphenol-rich extract. METHODS: This phase III trial is a 10-week, randomised, double-blind, placebo and active treatment controlled multicentre trial with three parallel treatment arms to compare the effect of Pycnogenol(r) to MPH and placebo on the behaviour of 144 paediatric ADHD and attention-deficit disorder (ADD) patients. Evaluations of behaviour (measured by the ADHD-Rating Scale (primary endpoint) and the Social-emotional Questionnaire (SEQ)), immunity (plasma cytokine and antibody levels, white blood cell counts and faecal microbial composition), oxidative stress (erythrocyte glutathione, plasma lipid soluble vitamins and malondialdehyde and urinary 8-OHdG levels, as well as antioxidant enzyme activity and gene expression), serum zinc and neuropeptide Y level, urinary catecholamines and physical complaints (Physical Complaints Questionnaire) will be performed in week 10 and compared to baseline. Acceptability evaluations will be based on adherence, dropouts and reports of adverse events. Dietary habits will be taken into account. DISCUSSION: This trial takes into account comorbid behavioural and physical symptoms, as well as a broad range of innovative immune and oxidative biomarkers, expected to provide fundamental knowledge on ADHD aetiology and therapy. Research on microbiota in ADHD is novel. Moreover, the active control arm is rather unseen in research on nutritional supplements, but of great importance, as patients and parents are often concerned with the side effects of MPH. TRIAL REGISTRATION: Clinicaltrials.gov number: NCT02700685 . Registered on 18 January 2016. EudraCT 2016-000215-32 . Registered on 4 October 2016. PMID- 28351415 TI - Role of carbonyl sulfide in acute lung injury following limb ischemia/reperfusion in rats. AB - OBJECTIVE: To investigate the effect of carbonyl sulfide (COS) on limb ischemia/reperfusion (I/R)-induced acute lung injury (ALI) and the associated mechanism in rats. METHODS: ALI was induced by bilateral hind limb I/R in Sprague Dawley (SD) rats. Sixty-four SD rats were randomly divided into the control group, I/R group, I/R + COS group, and I/R + AIR group. We observed the survival rate of the rats and the morphological changes of lung tissues, and we measured the change in the lung coefficient, the expression levels of the intercellular adhesion factor-1 (ICAM-1) protein in lung tissue, the expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-lbeta, and interleukin (IL)-6 in both lung tissue and serum, and cell apoptosis. RESULTS: Limb I/R caused significant lung tissue damage. The number of polymorphonuclear neutrophil in alveolar septa, the expression level of the ICAM-1 protein in lung tissue, the expression levels of TNF-alpha, IL-1, and IL-6 in lung tissue and serum, the lung coefficient, and cell apoptosis all increased. When a low dose of COS gas was administered prior to limb I/R, the variation of the above indicators was significantly reduced, while an increase in the dose of COS did not reduce the lung injury but rather increased the mortality rate. CONCLUSION: Carbonyl sulfide is another new gaseous signaling molecule, and a low dose of exogenous COS may play a protective role in I/R-induced ALI by acting as an anti-inflammatory agent by promoting the production of antioxidants and by inhibiting the expression of adhesion molecule proteins. PMID- 28351416 TI - Erratum to: Ubiquitin-conjugating enzyme complex Uev1A-Ubc13 promotes breast cancer metastasis through nuclear factor-kB mediated matrix metalloproteinase-1 gene regulation. PMID- 28351414 TI - Controlling schistosomiasis with praziquantel: How much longer without a viable alternative? AB - The current approach of morbidity control of schistosomiasis, a helminth disease of poverty with considerable public health and socioeconomic impact, is based on preventive chemotherapy with praziquantel. There is a pressing need for new drugs against this disease whose control entirely depends on this single drug that has been widely used over the past 40 years. We argue that a broader anthelminthic approach supplementing praziquantel with new antischistosomals targeting different parasite development stages would not only increase efficacy but also reduce the risk for drug resistance. Repositioning drugs already approved for other diseases provides a shortcut to clinical trials, as it is expected that such drugs rapidly pass the regulatory authorities. The antischistosomal properties of antimalarial drugs (e.g., semisynthetic artemisinins, synthetic trioxolanes, trioxaquines and mefloquine) and of drugs being developed or registered for other purposes (e.g., moxidectin and miltefosin), administered alone or in combination with praziquantel, have been tested in the laboratory and clinical trials. Another avenue to follow is the continued search for new antischistosomal properties in plants. Here, we summarise recent progress made in schistosomiasis chemotherapy, placing particular emphasis on repositioning of existing drugs against schistosomiasis. PMID- 28351418 TI - Why prudence is needed when interpreting articles reporting clinical trial results in mental health. AB - BACKGROUND: Clinical trial results' reliability is impacted by reporting bias. This is primarily manifested as publication bias and outcome reporting bias. MENTAL HEALTH TRIALS' SPECIFIC FEATURES: Mental health trials are prone to two methodological deficiencies: (1) using small numbers of participants that facilitates false positive findings and exaggerated size effects, and (2) the obligatory use of psychometric scales that require subjective assessments. These two deficiencies contribute to the publication of unreliable results. Considerable reporting bias has been found in safety and efficacy findings in psychotherapy and pharmacotherapy trials. Reporting bias can be carried forward to meta-analyses, a key source for clinical practice guidelines. The final result is the frequent overestimation of treatment effects that could impact patients and clinician-informed decisions. MECHANISMS TO PREVENT OUTCOME REPORTING BIAS: Prospective registration of trials and publication of results are the two major methods to reduce reporting bias. Prospective trial registration will allow checking whether they are published (so it will help to prevent publication bias) and, if published, whether those outcomes and analyses that were deemed as appropriate before trial commencement are actually published (hence helping to find out selective reporting of outcomes). Unfortunately, the rate of registered trials in mental health interventions is low and, frequently, of poor quality. CONCLUSION: Clinicians should be prudent when interpreting the results of published trials and some meta-analyses - such as those conducted by scientists working for the sponsor company or those that only include published trials. Prescribers, however, should be confident when prescribing drugs following the summary of product characteristics, since regulatory agencies have access to all clinical trial results. PMID- 28351417 TI - The choroid plexus as a site of damage in hemorrhagic and ischemic stroke and its role in responding to injury. AB - While the impact of hemorrhagic and ischemic strokes on the blood-brain barrier has been extensively studied, the impact of these types of stroke on the choroid plexus, site of the blood-CSF barrier, has received much less attention. The purpose of this review is to examine evidence of choroid plexus injury in clinical and preclinical studies of intraventricular hemorrhage, subarachnoid hemorrhage, intracerebral hemorrhage and ischemic stroke. It then discusses evidence that the choroid plexuses are important in the response to brain injury, with potential roles in limiting damage. The overall aim of the review is to highlight deficiencies in our knowledge on the impact of hemorrhagic and ischemic strokes on the choroid plexus, particularly with reference to intraventricular hemorrhage, and to suggest that a greater understanding of the response of the choroid plexus to stroke may open new avenues for brain protection. PMID- 28351420 TI - Urinary glutamine/glutamate ratio as a potential biomarker of pediatric chronic intestinal pseudo-obstruction. AB - Chronic intestinal pseudo-obstruction (CIPO) is a rare intestinal motility disorder with significant morbidity and mortality in pediatric patients. The diagnosis of CIPO is difficult, because it is clinically based on the symptoms and signs of bowel obstruction which are similar to the clinical manifestations of other gastrointestinal diseases like short bowel syndrome (SBS). Therefore, it is desirable to identify and establish new laboratory diagnostic markers for CIPO that are reliable and easily accessible. In our study we have identified the ratio of the urinary glutamine and glutamic acid as a promising biomarker for distinguishing suspected CIPO cases and simple SBS cases. The area under ROC curve was 0.83, at cutoff value = 7.04 with sensitivity of 65% and specificity of 92%. PMID- 28351422 TI - Erratum to: Promoting Recruitment using Information Management Efficiently (PRIME): study protocol for a stepped-wedge cluster randomised controlled trial within the REstart or STop Antithrombotics Randomised Trial (RESTART). PMID- 28351421 TI - Erratum to: A novel function for p21 Cip1 and acetyltransferase p/CAF as critical transcriptional regulators of TGFbeta-mediated breast cancer cell migration and invasion. PMID- 28351419 TI - New var reconstruction algorithm exposes high var sequence diversity in a single geographic location in Mali. AB - BACKGROUND: Encoded by the var gene family, highly variable Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1) proteins mediate tissue-specific cytoadherence of infected erythrocytes, resulting in immune evasion and severe malaria disease. Sequencing and assembling the 40-60 var gene complement for individual infections has been notoriously difficult, impeding molecular epidemiological studies and the assessment of particular var elements as subunit vaccine candidates. METHODS: We developed and validated a novel algorithm, Exon Targeted Hybrid Assembly (ETHA), to perform targeted assembly of var gene sequences, based on a combination of Pacific Biosciences and Illumina data. RESULTS: Using ETHA, we characterized the repertoire of var genes in 12 samples from uncomplicated malaria infections in children from a single Malian village and showed them to be as genetically diverse as vars from isolates from around the globe. The gene var2csa, a member of the var family associated with placental malaria pathogenesis, was present in each genome, as were vars previously associated with severe malaria. CONCLUSION: ETHA, a tool to discover novel var sequences from clinical samples, will aid the understanding of malaria pathogenesis and inform the design of malaria vaccines based on PfEMP1. ETHA is available at: https://sourceforge.net/projects/etha/ . PMID- 28351424 TI - Variables associated with unplanned general adult ICU admission in hospitalised patients: protocol for a systematic review. AB - BACKGROUND: Failure to promptly identify deterioration in hospitalised patients is associated with delayed admission to intensive care units (ICUs) and poor outcomes. Existing vital sign-based Early Warning Score (EWS) algorithms do not have a sufficiently high positive predictive value to be used for automated activation of an ICU outreach team. Incorporating additional patient data might improve the predictive power of EWS algorithms; however, it is currently not known which patient data (or variables) are most predictive of ICU admission. We describe the protocol for a systematic review of variables associated with ICU admission. METHODS/DESIGN: MEDLINE, EMBASE, CINAHL and the Cochrane Library, including Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials (CENTRAL) will be searched for studies that assess the association of routinely recorded variables associated with subsequent unplanned ICU admission. Only studies involving adult patients admitted to general ICUs will be included. We will extract data relating to the statistical association between ICU admission and predictor variables, the quality of the studies and the generalisability of the findings. DISCUSSION: The results of this review will aid the development of future models which predict the risk of unplanned ICU admission. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42015029617. PMID- 28351423 TI - Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment. AB - BACKGROUND: Global but predictable changes impact the DNA methylome as we age, acting as a type of molecular clock. This clock can be hastened by conditions that decrease lifespan, raising the question of whether it can also be slowed, for example, by conditions that increase lifespan. Mice are particularly appealing organisms for studies of mammalian aging; however, epigenetic clocks have thus far been formulated only in humans. RESULTS: We first examined whether mice and humans experience similar patterns of change in the methylome with age. We found moderate conservation of CpG sites for which methylation is altered with age, with both species showing an increase in methylome disorder during aging. Based on this analysis, we formulated an epigenetic-aging model in mice using the liver methylomes of 107 mice from 0.2 to 26.0 months old. To examine whether epigenetic aging signatures are slowed by longevity-promoting interventions, we analyzed 28 additional methylomes from mice subjected to lifespan-extending conditions, including Prop1df/df dwarfism, calorie restriction or dietary rapamycin. We found that mice treated with these lifespan-extending interventions were significantly younger in epigenetic age than their untreated, wild-type age matched controls. CONCLUSIONS: This study shows that lifespan-extending conditions can slow molecular changes associated with an epigenetic clock in mice livers. PMID- 28351425 TI - Assessing the psychometric and ecometric properties of neighborhood scales using adolescent survey data from urban and rural Scotland. AB - BACKGROUND: Despite the well-established need for specific measurement instruments to examine the relationship between neighborhood conditions and adolescent well-being outcomes, few studies have developed scales to measure features of the neighborhoods in which adolescents reside. Moreover, measures of neighborhood features may be operationalised differently by adolescents living in different levels of urban/rurality. This has not been addressed in previous studies. The objectives of this study were to: 1) establish instruments to measure adolescent neighborhood features at both the individual and neighborhood level, 2) assess their psychometric and ecometric properties, 3) test for invariance by urban/rurality, and 4) generate neighborhood level scores for use in further analysis. METHODS: Data were from the Scottish 2010 Health Behaviour in School-aged Children Survey, which included an over-sample of rural adolescents. The survey responses of interest came from questions designed to capture different facets of the local area in which each respondent resided. Intermediate data zones were used as proxies for neighborhoods. Internal consistency was evaluated by Cronbach's alpha. Invariance was examined using confirmatory factor analysis. Multilevel models were used to estimate ecometric properties and generate neighborhood scores. RESULTS: Two constructs labeled neighborhood social cohesion and neighborhood disorder were identified. Adjustment was made to the originally specified model to improve model fit and measures of invariance. At the individual level, reliability was .760 for social cohesion and .765 for disorder, and between .524 and .571 for both constructs at the neighborhood level. Individuals in rural areas experienced greater neighborhood social cohesion and lower levels of neighborhood disorder compared with those in urban areas. CONCLUSION: The scales are appropriate for measuring neighborhood characteristics experienced by adolescents across urban and rural Scotland, and can be used in future studies of neighborhoods and health. However, trade-offs between neighborhood sample size and reliability must be considered. PMID- 28351428 TI - Erratum to: JMJD6 is a driver of cellular proliferation and motility and a marker of poor prognosis in breast cancer. PMID- 28351427 TI - Use of whole-genome sequencing to distinguish relapse from reinfection in a completed tuberculosis clinical trial. AB - BACKGROUND: RIFAQUIN was a tuberculosis chemotherapy trial in southern Africa including regimens with high-dose rifapentine with moxifloxacin. Here, the application of whole-genome sequencing (WGS) is evaluated within RIFAQUIN for identifying new infections in treated patients as either relapses or reinfections. WGS is further compared with mycobacterial interspersed repetitive units-variable number tandem repeats (MIRU-VNTR) typing. This is the first report of WGS being used to evaluate new infections in a completed clinical trial for which all treatment and epidemiological data are available for analysis. METHODS: DNA from 36 paired samples of Mycobacterium tuberculosis cultured from patients before and after treatment was typed using 24-loci MIRU-VNTR, in silico spoligotyping and WGS. Following WGS, the sequences were mapped against the reference strain H37Rv, the single-nucleotide polymorphism (SNP) differences between pairs were identified, and a phylogenetic reconstruction was performed. RESULTS: WGS indicated that 32 of the paired samples had a very low number of SNP differences (0-5; likely relapses). One pair had an intermediate number of SNP differences, and was likely the result of a mixed infection with a pre-treatment minor genotype that was highly related to the post-treatment genotype; this was reclassified as a relapse, in contrast to the MIRU-VNTR result. The remaining three pairs had very high SNP differences (>750; likely reinfections). CONCLUSIONS: WGS and MIRU-VNTR both similarly differentiated relapses and reinfections, but WGS provided significant extra information. The low proportion of reinfections seen suggests that in standard chemotherapy trials with up to 24 months of follow-up, typing the strains brings little benefit to an analysis of the trial outcome in terms of differentiating relapse and reinfection. However, there is a benefit to using WGS as compared to MIRU-VNTR in terms of the additional genotype information obtained, in particular for defining the presence of mixed infections and the potential to identify known and novel drug-resistance markers. PMID- 28351426 TI - Associations of estradiol levels and genetic polymorphisms of inflammatory genes with the risk of ischemic stroke. AB - BACKGROUND: Estrogen plays an important role as an anti-inflammatory and neuroprotective agent in ischemic stroke. In this study, we analyzed the effect of a polygenic risk score (PRS) constructed using inflammatory genes and estradiol levels on the risk of ischemic stroke. METHODS: This case-control study was conducted with 624 ischemic stroke patients and 624 age- and gender-matched controls. The PRS estimated the polygenic contribution of inflammatory genes from ischemic stroke susceptibility loci. Estradiol levels were measured using a radioimmunoassay. High and low estradiol levels were defined according to the log transformed median estradiol levels in female and male controls. RESULTS: Subjects in the fourth quartile of the PRS had a significant 1.57-fold risk of ischemic stroke (95% confidence interval [CI], 1.12 ~ 2.19), after adjusting for covariates compared to individuals in the lowest quartile. Compared to individuals with high estradiol levels and a low PRS as the reference group, those exposed to low estradiol levels and a high PRS had an increased risk of ischemic stroke (odds ratio, 3.35; 95% CI, 1.79 ~ 6.28). Similar results were also observed in males when the analysis was stratified by gender. CONCLUSIONS: Our data suggest that the PRS can be useful in evaluating a high risk of ischemic stroke among patients, especially those exposed to low estradiol levels. PMID- 28351429 TI - Corticosteroids in septic shock: a systematic review and network meta-analysis. AB - BACKGROUND: Multiple corticosteroids and treatment regimens have been used as adjuncts in the treatment of septic shock. Qualitative and quantitative differences exist at cellular and tissular levels between the different drugs and their patterns of delivery. The objective of this study was to elucidate any differences between the drugs and their treatment regimens regarding outcomes for corticosteroid use in adult patients with septic shock. METHODS: Network meta analysis of the data used for the recently conducted Cochrane review was performed. Studies that included children and were designed to assess respiratory function in pneumonia and acute respiratory distress syndrome, as well as cross over studies, were excluded. Network plots were created for each outcome, and all analyses were conducted using a frequentist approach assuming a random-effects model. RESULTS: Complete data from 22 studies and partial data from 1 study were included. Network meta-analysis provided no clear evidence that any intervention or treatment regimen is better than any other across the spectrum of outcomes. There was strong evidence of differential efficacy in only one area: shock reversal. Hydrocortisone boluses and infusions were more likely than methylprednisolone boluses and placebo to result in shock reversal. CONCLUSIONS: There was no clear evidence that any one corticosteroid drug or treatment regimen is more likely to be effective in reducing mortality or reducing the incidence of gastrointestinal bleeding or superinfection in septic shock. Hydrocortisone delivered as a bolus or as an infusion was more likely than placebo and methylprednisolone to result in shock reversal. PMID- 28351430 TI - CLINICAL outcomes and loss to follow-up among people living with HIV participating in the NAMWEZA intervention in Dar es Salaam, Tanzania: a prospective cohort study. AB - BACKGROUND: Psychosocial factors have been linked with loss to follow-up (LTFU) and clinical outcomes among people living with HIV (PLH), however little is known about the effect of psychosocial support on LTFU among PLH in treatment and care. The purpose of this study was to explore the effect of NAMWEZA ("Yes, together we can") friends' psychosocial support intervention on clinical outcomes and LTFU among PLH. NAMWEZA is based on a novel program using "appreciative inquiry", positive psychology approaches to empower, promote positive attitudes and foster hope. METHODS: PLH participating in the NAMWEZA intervention in HIV care clinics in Dar es Salaam Tanzania were compared with non-exposed PLH obtained from facilities that routinely collect clinical information and both followed longitudinally for 24 months. Baseline sociodemographic, clinical measures (CD4 cell count, hemoglobin (HGB), weight), and LTFU measures were collected. Chi square, Fisher's exact tests, and t-tests were used to compare the frequencies for categorical variables and the means of continuous variables from the intervention and the comparison groups to identify variables that were significantly different across the two groups. Random effects models were performed to examine the bivariate associations between the intervention status and clinical outcomes. RESULTS: At the end of 24 months of follow-up mean CD4 count and HGB levels increased significantly in both intervention and comparison groups (p = 0.009 and p < 0.0001, respectively). Weight increased significantly only in the intervention group (p = 0.003). Cumulative LTFU was three times higher in the comparison compared to the intervention (p < 0.001) group. Having a low CD4 count, extremes of weight, low HGB, younger age, and male gender were significantly associated with LTFU among the unexposed group, while being on ART for duration of 12 months or more was protective against LTFU in those intervened. CONCLUSION: Among PLH on ART, exposed or not exposed to NAMWEZA intervention, clinical care outcomes improved over time. LTFU was much higher in the comparison group with factors commonly known to predict LTFU only apparent in the comparison group. NAMWEZA could be a promising peer-facilitated model to reduce LTFU among PLH in care that can be integrated in ART services; however, more research is needed to evaluate its longer term effects. PMID- 28351431 TI - A second case of pericardial mesothelioma mimicking systemic lupus erythematosus in the literature in over 30 years: a case report. AB - BACKGROUND: Mesothelioma is a rare neoplasm which commonly develops in the pleura of people exposed to asbestos. Pericardial mesothelioma accounts for only 0.7 % of all malignant mesotheliomas and it usually presents with pericardial effusion, mimicking serositis. To date, there are approximately 200 cases of pericardial mesothelioma described in the medical literature, and little knowledge exists about the systemic manifestations of this pathology. The first and only described case of pericardial mesothelioma with autoimmune features dates back to 1984 and, in our case report, we describe the second. CASE PRESENTATION: We report a case of a 45-year-old white woman whose pericardial mesothelioma was initially misdiagnosed as pericardial involvement of an autoimmune disease (systemic lupus erythematosus). After several relapses of pericardial effusion, a computed tomography scan and a biopsy with histological analysis were performed revealing neoplastic growth. CONCLUSIONS: We describe a rare case of pericardial mesothelioma in a patient with a clinical presentation compatible with lupus serositis. Clinicians should consider malignant mesothelioma in the differential diagnosis of pericardial effusion, especially when it is recurrent and not clearly explained by other causes. Cytological samples should always be obtained and, if imaging tools are suggestive for solid processes, histological confirmation is mandatory. PMID- 28351432 TI - [Genetic obesity: new diagnostic options]. AB - - Obesity is an important risk factor for morbidity and premature death, as well as a contributing factor to psychosocial problems. The incidence of obesity has increased dramatically over the last few decades.- Obesity is considered to be a multifactorial condition in which both environmental factors and genetic factors play a part.- In approximately 5% of patients with morbid obesity, a monogenic cause can be identified. Mutations in the MC4R gene are the most frequently occurring monogenic cause of obesity.- The department of Genetics at the VU University Medical Center Amsterdam offers morbidly obese patients a diagnostic analysis of 50 obesity-associated genes. - An underlying obesity-associated genetic defect can influence patient response to certain treatments. Therefore, if the gene defect is known, it can be taken into account when considering treatment options.- The understanding of the genetics of obesity will significantly contribute to research into the development of personalized treatment options. PMID- 28351433 TI - [A man with black blood]. AB - A 71-year-old man was admitted to the emergency room after high-energy trauma. He suddenly deteriorated several hours after an epidural providing local anaesthetics. At that time, his blood was black and the methaemoglobin level was 69 percent. After administration of methylene blue, he made a full clinical and biochemical recovery. PMID- 28351434 TI - [What is a normal thyroid function?] AB - Thyroid dysfunction is currently defined by a TSH value outside of its statistically established normal range. This definition does not take patients' individual symptoms or long-term risk of disease into account. However, increasing evidence shows that certain variations in thyroid function, even within the normal range, are associated with several adverse clinical outcomes. Also, subclinical thyroid dysfunction in patients, defined by a TSH outside of the normal range and free thyroxine within the normal range, has been shown to be accompanied by more thyroid-related symptoms when compared to the general population. This raises the question whether normal ranges are truly normal, and whether a new definition of thyroid function and thyroid dysfunction should be developed. PMID- 28351435 TI - [Better care and lower costs through registries; a first step to reimbursement based on outcome]. AB - We have recently shown that costs of surgical treatment for colorectal carcinoma differ greatly between various patient groups in the Netherlands. Those cost differences could mostly be explained by the fact that high-risk patients have a greater risk of complications, which generate higher hospital costs. Hospitals with a high-risk population, for instant tertiary referral centres, spend more than hospitals that treat low-risk patients. Currently reimbursement however is not geared to risk differences. In this article we investigate this shortcoming of the current reimbursement system and discuss how a differential rewarding - in which reimbursement is aligned with the patient's risk profile - could serve as a tool to further quality improvement in healthcare. Current clinical registries may provide the necessary details of patient characteristics for risk profiling and may also contribute to the following goal: reimbursement based on the quality of delivered care. PMID- 28351436 TI - [Hybrid cardiac SPECT-CT proves safe and effective: diagnosis of coronary heart disease completed in one day]. AB - Hybrid cardiac SPECT-CT is a technique in which data from both nuclear single photon emission tomography (SPECT) and a CT scan are combined. These techniques are complementary to each other, as CT provides information about anatomy of coronary arteries (stenosis, calcification, aberrant vessels) while SPECT detects functional consequences such as myocardial ischemia. In 2009, the Isala Hospital in Zwolle (the Netherlands) was one of the first centres in Europe to introduce this technique. Hybrid cardiac SPECT-CT has proved to be effective and safe in reaching a comprehensive diagnosis and gives the physician the ability to reach a diagnosis in only one day. In addition, it has led to about 20% fewer invasive coronary angiograms. Utilising this technique requires close collaboration between cardiologists and nuclear medicine specialists. PMID- 28351437 TI - [A neonate with a mass on the upper back]. AB - Immediately after birth, a skin-covered mass with weak consistency was noted on the back of a full-term newborn boy. Ultrasound and MRI (performed to exclude spina bifida occulta) showed a multicystic venolymphatic malformation. Sclerotherapy or surgical excision are possible treatments. In asymptomatic patients, however, a watchful waiting approach is used. PMID- 28351438 TI - [A pregnant woman with acute shoulder pain]. AB - A 34-year-old woman presented with abdominal pain, vaginal blood loss and severe shoulder pain. Ultrasound revealed an ectopic pregnancy. The shoulder pain was due to irritation of the diaphragm caused by bleeding from a ruptured fallopian tube into the abdominal cavity. PMID- 28351440 TI - [High nasal flow, the solution for hypoxaemia?] AB - High nasal flow (HNF) is a new method to deliver a high flow of oxygen (up to 60 l/min) through a nasal cannula. The inspiratory oxygen fraction can be set in a range from 21 to 100%. The inspired air is adjusted to body temperature and saturation. Many patients find it more comfortable than a conventional oxygen mask. In spite of these advantages, the mechanism of action is not completely understood and empirical evidence for its use is limited. This article provides a simplified explanation of variable positive airway pressure generation by HNF and related flushing of the anatomic dead space. Based on a short discussion of recent studies, it is concluded that HNF is a promising technique but that questions remain about the indications for use in clinical practice. PMID- 28351439 TI - [Revision of the Dutch College of General Practitioners practice guideline 'Children with fever']. AB - - Fever in children is usually caused by benign viral infection.- Approximately 1 10% of children with fever has or develops a serious infection such as pneumonia, meningitis or pyelonephritis.- It is more important to timely recognize symptoms that may indicate a potentially serious disease course than to make an exact diagnosis.- Children < 3 months are at greater risk for a serious disease course. During follow-up it is important to provide parents with proper advice on the expected disease course and who they should contact, and when, in cases of deterioration or concern.- Paracetamol or ibuprofen should only be given when there is a combination of fever and pain. Combating fever is not an end in itself. PMID- 28351441 TI - [Oxygen therapy not required for all COPD patients]. AB - Long-term oxygen therapy in patients with pronounced hypoxia is an important and life-extending therapy. Many patients have only mild hypoxia, do not experience nocturnal desaturation, or experience desaturation only during exercise. While often applied in clinical practice, the clinical relevance of oxygen therapy was not clear in these patients. A recent randomized controlled trial has now revealed no additional value for long-term oxygen therapy in subjects with mild oxygen desaturation or exercise-induced oxygen desaturation only. Furthermore, treatment burden, adverse events and healthcare costs associated with oxygen therapy need to be considered; restriction of the prescription of oxygen therapy is, therefore, appropriate. On the other hand, oxygen therapy is still considered important in non-severe hypoxic subjects with severe exercise-related desaturation (< 80%); in selected cases during endurance training in pulmonary rehabilitation; or in individual subjects with desaturation and pronounced and proven benefit of oxygen therapy on their symptoms and exercise capacity. PMID- 28351442 TI - [Oncology is not waiting for "shared decision-making" Patients and doctors generally reach consensus]. AB - In recent times, the importance of shared decision-making (SDM) when making medical decisions has been emphasised. In general, SDM is seen as a consultative communication style, mainly used in reaching important, preference-sensitive decisions when multiple options are available, each with advantages and disadvantages. SDM is particularly advocated in palliative cancer treatments, as patients have different goals for treatment and different trade-offs for side effects. Decision-support tools might facilitate the process of SDM, but might also fill a needs' gap only in a minority of patients. As cancer treatment increasingly becomes more personalised, cancer patients also deserve personalised guidance; sometimes this means sharing decision-making but sometimes paternalistic advice is actually required. It is questionable whether general decision-making tools will have significant impact on patient satisfaction in medical decision-making. PMID- 28351443 TI - Phenotypic and molecular characteristics of Staphylococcus aureus and methicillin resistant Staphylococcus aureus in slaughterhouse pig-related workers and control workers in Guangdong Province, China. AB - Pig farmers and veterinarians have high prevalence of methicillin-resistant Staphylococcus aureus (MRSA) due to the occupational livestock exposure, while few reported this association on slaughterhouse workers. We conducted this cross sectional study to explore the phenotypic and molecular characteristics of S. aureus and MRSA in slaughterhouse pig-related workers and control workers in Guangdong Province, China. Participants were interviewed and provided two nasal swabs. Swabs were tested for S. aureus, and isolates were further tested for antimicrobial susceptibility, virulence genes and multi-locus sequence typing. Compared with control workers, pig-related workers have significantly higher prevalence of MRSA carriage (adjusted odd ratio (aOR) 3.70, 95% CI 1.63-8.40). The proportions of MRSA resistant to clindamycin, erythromycin, tetracycline or chloromycetin were significantly higher in pig-related workers than in control workers. The predominant phenotypes of S. aureus were resistant to penicillin, clindamycin, erythromycin and tetracycline. Three MRSA CC9 isolates with livestock-associated characteristics (resistance to tetracycline and absence of immune evasion cluster (IEC) genes) were detected in pig-related workers but not in control workers. For human-associated CCs (CC7, CC59, CC6, and CC188), there was no significant difference in IEC profile or antimicrobial resistance between the groups. These findings reveal that there may be a potential risk for livestock-to-human transmission of LA-MRSA and human-to-human transmission of human-associated MRSA. PMID- 28351444 TI - Alchemy and psychology. PMID- 28351445 TI - Clinical evaluation of brief cognitive assessment measures for patients with severe dementia. AB - BACKGROUND: Alzheimer's disease has become an important public health burden for older adults. Clinicians face a challenging task to efficiently evaluate cognition in dementia in clinical settings. We sought to assess the validity and inter-correlations of brief cognitive assessments in a cohort of severely demented patients. METHODS: In total, 49 individual patients (N = 49) ranging in age from 62 to 97 years old were included in this performance improvement project. Over the course of two-three sessions, five cognitive instruments were administered to each patient: Severe Impairment Battery (SIB), Severe Impairment Battery-8 (SIB-8), Mini Mental State Examination (MMSE), Severe Mini Mental State Examination (sMMSE) and Brief Interview of Mental Status (BIMS). We sought to assess patient factors that might have been barriers to optimal performance on cognitive/functional tests. Researchers assessed her impression of the participants' difficulty comprehending instructions, distractibility, apparent fatigue, and frustration, which were the four barriers rated. RESULTS: Data were analyzed for 49 patients from the inpatient dementia unit with a total of 51 samples. All of the inter-correlations between the five cognitive instruments had Spearman coefficients of (rs) > 0.7 and were statistically significant with p < 0.001. The SIB-8 and sMMSE were positively correlated with the SIB. The perceived barrier scores ranged from 0- no issue to 1-mild issue on all five cognitive instruments. CONCLUSION: Brief cognitive tests designed for severe dementia such as the SIB-8 and sMMSE have been evaluated in this project to be shorter in administration duration and highly correlated with gold standard instruments: the SIB and MMSE. PMID- 28351446 TI - On the relationship between head circumference, brain size, prenatal long-chain PUFA/5-methyltetrahydrofolate supplementation and cognitive abilities during childhood. AB - Head circumference in infants has been reported to predict brain size, total grey matter volume (GMV) and neurocognitive development. However, it is unknown whether it has predictive value on regional and subcortical brain volumes. We aimed to explore the relationship between several head circumference measurements since birth and distributions of GMV and subcortical volumes at later childhood. We examined seventy-four, Caucasian, singleton, term-born infants born to mothers randomised to receive fish oil and/or 5-methyltetrahydrofolate or placebo prenatal supplementation. We assessed head circumference at birth and at 4 and 10 years of age and cognitive abilities at 7 years of age. We obtained brain MRI at 10 years of age, on which we performed voxel-based morphometry, cortical surface extraction and subcortical segmentation. Analyses were controlled for sex, age, height, weight, family status, laterality and total intracranial volume. Prenatal supplementation did not affect head circumference at any age, cognitive abilities or total brain volumes. Head circumference at 4 years presented the highest correlation with total GMV, white matter volume and brain surface area, and was also strongly associated with GMV of frontal, temporal and occipital areas, as well as with caudate nucleus, globus pallidus, putamen and thalamus volumes. As relationships between brain volumes in childhood and several outcomes extend into adulthood, we have found that ages between 0 and 4 years as the optimal time for brain growth; postnatal factors might have the most relevant impact on structural maturation of certain cortical areas and subcortical nuclei, independent of prenatal supplementation. PMID- 28351447 TI - Near-Infrared Spectroscopy: A Promising Prehospital Tool for Management of Traumatic Brain Injury. AB - : Introduction Early identification of traumatic brain injury (TBI) is essential. Near-infrared spectroscopy (NIRS) can be used in prehospital settings for non invasive monitoring and the diagnosis of patients who may require surgical intervention. METHODS: The handheld NIRS Infrascanner (InfraScan Inc.; Philadelphia, Pennsylvania USA) uses eight symmetrical scan points to detect intracranial bleeding. A scanner was tested in a physician-staffed helicopter Emergency Medical Service (HEMS). The results were compared with those obtained using in-hospital computed tomography (CT) scans. Scan time, ease-of-use, and change in treatment were scored. RESULTS: A total of 25 patients were included. Complete scans were performed in 60% of patients. In 15 patients, the scan was abnormal, and in one patient, the scan resulted in a treatment change. Compared with the results of CT scanning, the Infrascanner obtained a sensitivity of 93.3% and a specificity of 78.6%. Most patients had severe TBI with indication for transport to a trauma center prior to scanning. In one patient, the scan resulted in a treatment change. Evaluation of patients with less severe TBI is needed to support the usefulness of the Infrascanner as a prehospital triage tool. CONCLUSION: Promising results were obtained using the InfraScan NIRS device in prehospital screening for intracranial hematomas in TBI patients. High sensitivity and good specificity were found. Further research is necessary to determine the beneficial effects of enhanced prehospital screening on triage, survival, and quality of life in TBI patients. Peters J , Van Wageningen B , Hoogerwerf N , Tan E . Near-infrared spectroscopy: a promising prehospital tool for management of traumatic brain injury. Prehosp Disaster Med. 2017;32(4):414 418. PMID- 28351448 TI - The legal appearances of dementia in court rulings: mapping the terrain. AB - BACKGROUND: Individuals with dementia may appear before the court in different roles: as victims, as witnesses, and as those standing up for their rights. While there is growing interest in the rights of older persons with dementia, relatively little empirical data exists regarding their actual interactions in courts. Therefore, the goal of this study was to empirically map this legal terrain. METHODS: This study used a descriptive quantitative method. A computerized search of a national legal database limited to the period 2004-2014 and a screening process for the results were used to establish a sample of 280 court rulings that directly addressed dementia. All cases were analyzed and categorized into the following four criteria groups: characteristics of the person with dementia; characteristics of the legal procedure; the legal substance of the case; and the legal outcome. RESULTS: The majority of cases involved a single, very-elderly (i.e. over 80 years) woman, living in the community, with unspecified dementia. The majority of cases were heard and decided in lower level courts, addressing a broad range of primarily non-criminal legal issues. Finally, in the majority of non-criminal cases, the person with dementia was found to be legally capable, whereas in the majority of criminal cases, the person with dementia was found incapable. CONCLUSIONS: The legal needs and rights of persons with dementia are much broader than issues of legal capacity or social protection. Deeper knowledge and more research is needed in order to fully understand the contexts in which dementia is constructed under the law. PMID- 28351449 TI - Aberrant interhemispheric functional connectivity within default mode network and its relationships with neurocognitive features in cognitively normal APOE epsilon 4 elderly carriers. AB - BACKGROUND: Default mode network (DMN) is vulnerable to the effects of APOE genotype. Given the reduced brain volumes and APOE epsilon 4-related brain changes in elderly carriers, it is less known that whether these changes would influence the functional connectivity and to what extent. This study aimed to examine the functional connectivity within DMN, and its diagnostic value with age related morphometric alterations considered. METHODS: Whole brain and seed-based resting-state functional connectivity (RSFC) analysis were conducted in cognitively normal APOE epsilon 4 carriers and matched non-carriers (N=38). The absolute values of mean correlation coefficients (z-values) were used as a measure of functional connectivity strength (FCS) between DMN subregions, which were also used to estimate their diagnostic value by receiver-operating characteristic (ROC) curves. RESULTS: APOE epsilon 4 carriers demonstrated decreased interhemispheric FCS, particularly between right hippocampal formation (R.HF) and left inferior parietal lobular (L.IPL) (t=3.487, p<0.001). ROC analysis showed that the FCS of R.HF and L.IPL could differentiate APOE epsilon 4 carriers from healthy counterparts (AUC value=0.734, p=0.025). Moreover, after adjusting the impact of morphometry, the differentiated value of FCS of R.HF and L.IPL was markedly improved (AUC value=0.828, p=0.002). CONCLUSIONS: Our findings suggest that APOE epsilon 4 allele affects the functional connectivity within posterior DMN, particularly the atrophy-corrected interhemispheric FCS before the clinical expression of neurodegenerative disease. PMID- 28351450 TI - "There isn't an easy way of finding the help that's available." Barriers and facilitators of service use among dementia family caregivers: a qualitative study. AB - BACKGROUND: Family caregivers of people with dementia have significant unmet needs in regard to their caregiving role. Despite this, they are reluctant to utilize services to reduce their burden. The aim of this study was to examine the barriers and facilitators of service use among family caregivers of people with dementia. METHOD: Semi-structured interviews were conducted with 24 family caregivers of community-dwelling people with dementia. Of these, 12 were partner caregivers (4 men, 8 women) and 12 were offspring caregivers (2 men, 10 women). The interviews were transcribed and analyzed using thematic analysis. RESULTS: Six main barriers and three facilitators were identified. These barriers and facilitators were relevant across many types of services and supports. The barriers were: the inability to find information about relevant services or support, the poor quality or mistrust of the services, the inflexibility of services, caregivers' beliefs about their obligations to the caregiving role and resistance by the care recipient. Key facilitators were: having good communication with the care recipient, having an "expert" point of contact, and having beliefs about the caregiving role that enabled the use of services. CONCLUSION: Given the significant changes in the aged care service-system, it is important to discuss the barriers faced by family caregivers of people with dementia. This will inform the development of targeted strategies to address the lack of service use among these family caregivers. PMID- 28351451 TI - Suicide attempts among the elderly in East Asia. AB - Among the one million suicide deaths worldwide each year, as many as 60% occur in Asia. The World Health Organization (WHO) found higher suicide rates among the elderly in rapidly industrialized Asian countries such as China, Hong Kong, Japan, South Korea, Malaysia, and Singapore, compared to the corresponding rates of recently industrializing Asian countries like Vietnam and Sri Lanka (WHO, 2014). As a case in point, suicide rates in South Korea have been the highest in the world since 2003 and are rising especially among older people (Hong and Knapp, 2014). Suicide attempts and older age are strong predictors of completed suicide (Szanto et al., 2002; Simon et al., 2013) and, as such, are important in guiding our efforts for suicide prevention; however, most epidemiological studies focus on completed suicides across all ages rather than understanding the reasons behind suicide attempts in older populations. PMID- 28351453 TI - Editorial. PMID- 28351454 TI - Mechanistic Insights into Gold Organometallic Compounds and their Biomedical Applications. AB - The application of gold in medicine can be traced back several thousand years and Au(i) compounds have been used in the treatment of rheumatoid arthritis since the last century. Recently research into gold-based drugs for a number of human diseases has seen a renaissance due to their markedly different modes of action with respect to the classical platinum chemotherapeutic compounds. Within this research area, organometallic gold complexes have been particularly explored, mainly due to their higher stability in physiological conditions guaranteed by the presence of a direct Au-C bond. Thus, a number of compounds have been tested for their uses as anticancer, antibacterial, antiprotozoal as well as anti-HIV agents. In this review a selection of the main results obtained on the synthesis, chemical properties and biological activities of two of the most explored families of organometallics - Au(i) N-heterocyclic carbenes (NHCs) and cyclometalated Au(iii) compounds - are summarized. Their structure-activity relationships and modes of action at the cellular level are also discussed, which constitute the basis for future drug design. PMID- 28351455 TI - Investigation of Non-covalent Interactions of Metal Complexes with DNA in Cell free Systems. AB - Non-covalent interactions of metallo compounds with DNA range from the simple, unspecific electrostatic binding of a positively charged metal complex to the sequence-selective recognition of DNA binding sites due to shape, size, symmetry and hydrogen bonding complementarity of a rationally designed system. Metal complexes that recognize and target specific DNA sequences or particular structures are of considerable interest as therapeutics, diagnostics or structural probes. To gain molecular level insight into DNA-metal complex interactions, binding studies are carried out in cell-free systems using isolated DNA or short oligonucleotides. For this, a powerful toolbox of complementary spectroscopic and biophysical techniques is available. This review focuses on the most frequently applied spectroscopic methods; UV/Vis, CD, LD, fluorescence emission and NMR spectroscopy and is aimed at giving the reader an overview of the qualitative and/or quantitative information that can be obtained. After a short introduction into DNA structures and non-covalent metal complex-DNA interactions, each spectroscopic method will be discussed. In the last section a few selected studies will be described as illustrative examples for the potential of the various spectroscopic methods. PMID- 28351456 TI - Spectroscopic Approaches to Tracking Metal-based Drugs in Cells and Tissue. AB - Metal-based drugs with novel targets and modes of action are increasingly being developed as alternatives to classical platinum(ii) chemotherapeutics. Imaging methods in tumour cells and tissues offer valuable insights into the behaviour of these novel complexes; however, mapping the distribution of metal ions and complexes within cellular environments remains challenging. The advantages and limitations of three modes of imaging: synchrotron radiation-induced X-ray fluorescence, mass spectrometry, and fluorescence microscopy are discussed in this review, with particular emphasis on their use in imaging ruthenium-based drugs. PMID- 28351457 TI - Transition Metal-based Anticancer Drugs Targeting Nucleic Acids: A Tandem Mass Spectrometric Investigation. AB - The search for effective drugs against cisplatin-resistant tumors resulted in a large number of organometallic compounds that are evaluated for their antiproliferative activity. Among the most promising candidates are bent metallocenes based on various transition metal ions and ligands. The elucidation of structural features and the characterization of the interaction of a drug candidate with its target require accurate and sensitive analytical tools. Tandem mass spectrometry is applied to the investigation of the adduct sites and binding patterns of metallodrugs bound to single-stranded oligonucleotides and higher order nucleic acids. Results reveal the binding specificities of the different metallodrugs and demonstrate the influence they exert on the dissociation pathways of the adducts in the gas-phase. PMID- 28351458 TI - Metabolic Profiling of Cells in Response to Drug Treatment using 1H High resolution Magic Angle Spinning (HR-MAS) NMR Spectroscopy. AB - High-resolution magic angle spinning (HR-MAS) is an NMR technique that provides access to well resolved liquid-like 1H NMR spectra of semi-solid samples. Therefore, 1H HR-MAS NMR spectroscopy has become an important tool for the direct analysis of biological samples such as tissues and cells in a mostly non destructive way. Here, we focus on the application of HR-MAS NMR combined with multivariate statistical methods used for metabolic profiling of cells and in particular for the study of cellular metabolic responses to drug exposure. The principles of HR-MAS and the metabolomic approach are briefly described. As an example, a study on the metabolic response of different cell types towards treatment with a highly cytotoxic hexacationic ruthenium metallaprism as potential anti-cancer drug is presented. Specific metabolites and metabolic pathways are suggested to be associated with the cellular response. The study demonstrates the potential of HR-MAS metabolomics applied to cells for addressing the intracellular processes involved in the treatment with organometallic drugs. PMID- 28351462 TI - Gordon Research Seminar on Physical Virology 2017. PMID- 28351463 TI - Tuberculin skin test and interferon-gamma release assay use among privately insured persons in the United States. AB - OBJECTIVE: To describe tuberculin skin test (TST) and interferon-gamma release assay (IGRA) (i.e., QuantiFERON(r)-TB [QFT] and T-SPOT(r).TB [T-SPOT]) use among privately insured persons in the United States over a 15-year period. METHODS: We used current procedural terminology (CPT) codes for the TST and IGRAs to extract out-patient claims (2000-2014) and determined usage (claims/100 000). The chi2 test for trend in proportions was used to describe usage trends for select periods. RESULTS: The TST was the dominant (>80%) test in each year. Publication of guidelines preceded the assignment of QFT and T-SPOT CPT codes by 1 year (2006 for QFT; 2011 for T-SPOT). QFT usage was higher (P < 0.01) than T-SPOT in each year. The average annual increase in the use of QFT was higher than that of T SPOT (35 vs. 3.8/100 000), and more so when the analytic period was 2011-2014 (65 vs. 38/100 000). However, during that 4-year period (2011-2014), TST use trended downward, with an average annual decrease of 28/100 000. The annual proportion of enrollees tested ranged from 1.1% to 1.5%. CONCLUSIONS: These results suggest a gradual shift from the use of the TST to the newer IGRAs. Future studies can assess the extent, if any, to which the shift from the use of the TST to IGRAs evolved over time. PMID- 28351465 TI - The Natural Course and Treatment of ADHD, and Its Place in Adulthood. PMID- 28351466 TI - ADHD in Germany: Trends in Diagnosis and Pharmacotherapy. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) sometimes persists into adulthood. There have been no studies from Germany until the present time on the diagnosis and treatment of ADHD over the course of patients' lives, in particular during the transition from adolescence to early adulthood. METHODS: We used nationwide routine data of the AOK statutory healthinsurance fund to determine the frequency of ADHD diagnoses and prescriptions of medication for ADHD. We additionally analyzed the care of a transition cohort of initially 15 year-old ADHD patients over a period of six years. RESULTS: From 2009 to 2014, the prevalence of a diagnosis of ADHD rose from 5.0% to 6.1% in persons aged 0 to 17 years (with a maximum of 13.9% in 9-year-old boys) and from 0.2% to 0.4% in persons aged 18 to 69 years. The amount of ADHD medication prescribed to adults with ADHD increased over time, while the amount prescribed to children and adolescents fell. Methylphenidate was the most commonly prescribed drug, followed by atomoxetine and lisdexamfetamine. Only 31.2% of the patients in the transition cohort still carried the diagnosis of ADHD at the end of the six-year period, at age 21. The percentage of patients taking ADHD medication in this group fell from 51.8% at age 15 to 6.6% at age 21. CONCLUSION: The administrative prevalence of a diagnosis of ADHD among adults and the degree of medication use for ADHD by adults have risen in recent years. This can be interpreted as an indication of the sensitization of physicians and patients to the possibility of adult ADHD. Nonetheless, the prevalence of diagnosed ADHD remains less than the prevalence revealed by epidemiologic studies. This may indicate that adults with ADHD are currently underdiagnosed and undertreated. The low rate of use of ADHD medications among adolescents with ADHD who are on the verge of adulthood leads us to the question of whether specific transitional concepts need to be developed for this age group. PMID- 28351468 TI - Is Idiopathic Always Idiopathic? What the Teeth Can Tell Us. PMID- 28351467 TI - Attention-Deficit/Hyperactivity Disorder. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common, early onset, persistent developmental disorder of childhood and adolescence, with a prevalence of approximately 5%. METHODS: This article is based on publications retrieved by a selective search in PubMed with an emphasis on pertinent guidelines and systematic reviews. RESULTS: At least 75% of affected children and adolescents develop a comorbid disorder, which impedes diagnosis and treatment and worsens prognosis. The etiology of ADHD is complex and heterogeneous, involving a major genetic component and diverse neurobiological alterations. Prenatal environmental factors also seem to elevate the risk of ADHD. The mainstays of treatment are psychoeducation, behavioral therapy, and psychoactive drugs, which generally have only mild side effects, such as insomnia or decreased appetite. The indication for treatment in the individual case is based on severity, comorbidity, previous therapy attempts, and the familial, social, and educational framework conditions. CONCLUSION: Translational research is needed to clarify the etiology of ADHD. Epidemiological studies published since 1987 do not reveal any increase in the prevalence of ADHD among children and adolescents. Improved diagnosis necessitates an evidence-based and need-adapted approach to treatment. PMID- 28351469 TI - Renal Cell Carcinoma as an Occupational Disease. PMID- 28351470 TI - In Reply. PMID- 28351471 TI - Mean velocity and peak systolic velocity can help determine ischaemic and non ischaemic priapism. AB - AIM: To determine the threshold waveform characteristics at Doppler ultrasound (DUS) to differentiate between ischaemic and non-ischaemic priapism. MATERIALS AND METHODS: Fifty-two patients were categorised into "ischaemic" and "non ischaemic" types based on clinical and blood-gas findings: 10 patients with non ischaemic priapism; 20 with ischaemic priapism before surgical shunt placement and 22 with ischaemic priapism after surgical shunt placement. DUS traces were analysed: peak systolic velocity (PSV) and mean velocity (MV) were calculated. Histological samples were obtained at the time of surgery. Three clinical outcome groups were defined: (1) normal, (2) regular use of pharmacostimulation, and (3) refractory dysfunction/penile implant. RESULTS: All non-ischaemic priapism cases had a PSV >50 cm/s and all but one had an MV of >6.5 cm/s. In pre-surgery ischaemic cases, all men had a PSV <50 cm/s and MV <6.5 cm/s. Two flow patterns were observed in this group: PSV <25 cm/s in all men scanned before needle aspiration; and in 6/14 after needle aspiration, a high velocity/high resistance (low net inflow) pattern, with peak systolic flows >22 cm/s but diastolic reversal. In post-surgery ischaemic priapism, flow parameters overlapped with the non-ischaemic group. PSV/MV did not predict clinical outcome or histology. CONCLUSION: In the present cohort, PSV <50 cm/s and MV <6.5 cm/s were predictive of ischaemic priapism (pre-shunt; p<0.01). Patients with ischaemic priapism may show PSV >22 cm/s, but have diastolic reversal and therefore low net perfusion. Post-shunt, DUS findings were extremely variable and did not predict histology or clinical outcome. PMID- 28351472 TI - "The missing LINX" for gastroesophageal reflux disease: Operative techniques video for the Linx magnetic sphincter augmentation procedure. AB - In 2012 the FDA approved a magnetic sphincter augmentation (MSA) device (LINX, Torax Medical, Inc) for placement around the lower esophageal sphincter as an alternative approach to fundoplication for gastroesophageal reflux disease (GERD). This is a relatively new procedure and there is not widespread familiarization with the standard indications and techniques of device placement. We present two operative videos to highlight the standard surgical technique and technical points needed for successful LINX placement. First will be placement in a standard indications setting of uncomplicated GERD with no hiatal hernia. Second will be placement with complicated anatomy due to alterations from prior gastric surgery and a hiatal hernia. Our experience has revealed that the LINX device can be placed safely in patients with normal or significantly altered anatomy but requires adherence to several key principles and technical points. This procedure offers a new option that is anatomically and physiologically unique compared to standard fundoplication, and that offers highly effective control of GERD with a less invasive approach. PMID- 28351473 TI - Accuracy of clinical, laboratory, and computed tomography findings for identifying hollow viscus injury in blunt trauma patients with unexplained intraperitoneal free fluid without solid organ injury. AB - BACKGROUND: We sought to define the accuracy of findings for detecting hollow viscus injury (HVI) in patients with blunt abdominal trauma (BAT) and unexplained intra-peritoneal free fluid without solid organ injury (UIPFFWSOI). METHODS: We screened all consecutive hemodynamically stable patients presenting to a quaternary-care trauma-centre who had an abdominal computed tomography (CT) scan for BAT and UIPFFWSOI (January 2007-December 2014). RESULTS: Of 3796 patients identified during the study period, 39 presented with UIPFFWSOI. Fifteen underwent therapeutic laparotomy. Seatbelt sign (+LR approaches infinity), diffuse peritonitis (+LR approaches infinity), number of CT cuts with fluid (c statistic = 0.65), and a lower arterial pH at presentation (c-statistic = 0.62) were most predictive of HVI. Patients operated on within 24 h had shorter stays than those operated on later (median 9 vs. 14 days, p = 0.03). CONCLUSIONS: Our findings suggest that clinical examination and measurements of intraperitoneal fluid volume may help identify HVIs in BAT patients. PMID- 28351474 TI - Treatment of advanced laryngeal cancer and quality of life. Systematic review. AB - INTRODUCTION AND OBJECTIVES: The objective was the comparison of the quality of life in patients with advanced laryngeal cancer treated with organ preservation versus surgical treatment. METHODS: We performed a systematic review in the databases MedLine, EMBASE, and PubMed (2014 1991) and Web of Science (2012 - 2014). The search terms were: Laryngeal cancer, organ preservation, chemotherapy, laryngectomy, treatment outcomes and quality of life. Systematic reviews, meta analysis, reports of health technology assessment and comparative studies with control group, published in Spanish, French or English were included. The selection and quality assessment was made by two researchers. The criteria of the Cochrane Collaboration were used to assess the risk of bias and Scottish Intercollegiate Guidelines Network (SIGN) for the level of evidence. RESULTS: Of the 208 studies identified in the search, three were included a clinical trial and two observational studies, with a total of 211 patients. Quality and level of evidence was low. The results were contradictory, on occasion they favoured surgery, and on other occasions chemotherapy, but in general there were no statistical differences between the treatments. The studies were heterogeneous, with different methodology, undersized, limitations in quality with high risk of bias and use of different measurement scales. CONCLUSIONS: There are not enough studies of quality to establish differences in the quality of life in patients with advanced laryngeal cancer according to the treatment received. PMID- 28351475 TI - That's one small step.... PMID- 28351476 TI - In type A aortic dissection repair, an effective team approach and relational coordination are more important for patients' outcomes than surgeon volume. PMID- 28351478 TI - Form follows function. PMID- 28351477 TI - Mycobacterium chimaera: The ethical duty to disclose the minimal risk of infection to exposed patients. PMID- 28351479 TI - A firm foundation. PMID- 28351480 TI - Melasma treatment: A novel approach using a topical agent that contains an anti estrogen and a vascular endothelial growth factor inhibitor. AB - Melasma is an acquired disorder of pigmentation that presents with asymptomatic symmetric darkening of the face. The pathogenesis of this condition is multifactorial and influenced by several factors including female sex hormones, genetic predisposition and ultraviolet light exposure. The management of melasma is usually directed at more than one of the causative etiologic factors and often incorporates a combination of topical agents, with or without the addition of physical modalities. Estrogen and angiogenesis are significant factors in the etiology of melasma. A useful addition to the therapeutic armentarium for treating melasma would include a topical agent that could effect both of these causative factors. Specifically, a topical preparation consisting of an anti estrogen and a vascular endothelial growth factor inhibitor would accomplish this goal. Suitable candidates that target estrogen receptors and vascular endothelial growth factor are currently used in medical oncology as systemic antineoplastic agents. The anti-estrogen could be either a selective estrogen receptor modulator (such as tamoxifen or raloxifene) or an aromatase inhibitor (such as anastrozole or letrozole or exemestane). The vascular endothelial growth factor inhibitor would be bevacizumab. In conclusion, a novel-topically administered-therapy for melasma would combine an anti-estrogen and a vascular endothelial growth factor inhibitor. PMID- 28351481 TI - Brain temperature as a measure of misfolded proteins metabolism. PMID- 28351482 TI - Fermi-Pasta-Ulam auto recurrence in the description of the electrical activity of the heart. AB - The authors proposed and mathematically described model of a new type of the Fermi-Pasta-Ulam recurrence (the FPU auto recurrence) and hypothesized an adequate description of the heart's electrical dynamics within the observed phenomenon. The dynamics of the FPU auto recurrence making appropriate electrical dynamics of the normal functioning of the heart in the form of an electrocardiogram (ECG) was obtained by a computer model study. The model solutions in the form of the FPU auto recurrence - ECG Fourier spectrum were evaluated for resistance to external disturbances in the form of random effects, as well as periodic perturbation at a frequency close to the heart beating rate of about 1Hz. In addition, in order to simulate the dynamics of myocardial infarction model, studied the effect of the surface area of the myocardium on the stability and shape of the auto recurrence - ECG spectrum. It has been found that the intense external disturbing periodic impacts at a frequency of about 1Hz lead to a sharp disturbance spectrum shape FPU auto recurrence - ECG structure. In addition, the decrease in the surface of the myocardium by 50% in the model led to the destruction of structures of the auto recurrence - ECG, which corresponds to the state of atrial myocardium. Research models have revealed a hypothetical basis of coronary heart disease in the form of increasing the energy of high frequency harmonics spectrum of the auto recurrence by reducing the energy of low frequency harmonic spectrum of the auto recurrence, which ultimately leads to a sharp decrease in myocardial contractility. In order to test the hypothesis has been studied more than 20,000 ECGs both healthy people and patients with cardiovascular disease. As a result of these studies, it was found that the dynamics of the electrical activity of normal functioning of the heart can be interpreted by the display of the detected by authors the FPU auto recurrence, and coronary heart disease is a violation of the energy ratio between the low and high frequency harmonics of the FPU auto recurrence Fourier spectrum equal to the ECG spectrum. Thus, the hypothesis has been confirmed. PMID- 28351483 TI - Surface modified nano-lipid drug conjugates of positive allosteric modulators of M1 muscarinic acetylcholine receptor for the treatment of Alzheimer's disease. AB - Acetyl Cholinesterase (AChE) inhibitors such as Donepezil, Rivastigmine and Galantamine are approved by US-FDA as first line drugs to treat the cognitive symptoms of Alzheimer's disease (AD). Their beneficial effects are attributed to their ability to elevate endogenous acetylcholine (ACh) at the M1 muscarinic receptor in the brain. However, their side effects such as nausea, vomiting, dizziness, insomnia, loss of appetite and altered heart rate are related to non specific activation of M2-M5 muscarinic subtypes in various tissues. It is logical, therefore, to develop agonists with M1 receptor selectivity. Unfortunately, this is limited due to a high degree of orthosteric site homology among the receptor subtypes. In contrast, their allosteric sites are unique and, therefore, allow selective targeting using positive allosteric modulators (PAMs). PAMs of M1 receptors are devoid of agonist activity, however, when bound they enhance the binding affinity of orthosteric ligand, ACh. The major limitation of these PAMs is their bioavailability in the brain. In the current hypothesis, we propose surface modified nano-lipid drug conjugates (LDC-NPs) of PAMs of M1 receptors to improve their bioavailability in brain. When co-administered with AChE inhibitors they are expected to increase their efficacy and reduce their therapeutic dose and side effects. PMID- 28351484 TI - Hypocapnic hypothesis of Leigh disease. AB - Leigh syndrome (LS) is a neurogenetic disorder of children caused by mutations in at least 75 genes which impair mitochondrial bioenergetics. The changes have typical localization in basal ganglia and brainstem, and typical histological picture of spongiform appearance, vascular proliferation and gliosis. ATP deprivation, free radicals and lactate accumulation are suspected to be the causes. Hypocapnic hypothesis proposed in the paper questions the energy deprivation as the mechanism of LS. We assume that the primary harmful factor is hypocapnia (decrease in pCO2) and respiratory alkalosis (increase in pH) due to hyperventilation, permanent or in response to stress. Inside mitochondria, the pH signal of high pH/low bicarbonate ion (HCO-3) is transmitted by soluble adenyl cyclase (sAC) through cAMP dependent manner. The process can initiate brain lesions (necrosis, apoptosis, hypervascularity) in OXPHOS deficient cells residing at the LS area of the brain. The major message of the article is that it is not the ATP depletion but intracellular alkalization (and/or hyperoxia?) which seem to be the cause of LS. The paper includes suggestions concerning the methodology for further research on the LS mechanism and for therapeutic strategy. PMID- 28351485 TI - A new proposition for the screening of platelet function defects using an hematology analyzer. AB - In this paper we suggest a new method for the screening of congenital thrombopathies using an hematology analyzer. This method is an improvement of the platelet count ratio principle which uses an impedance counter to search a decrease of the free platelet count after adding platelet agonist to whole blood. We suggest using novel platelet parameters provided by an optical hematology analyzer such as ADVIA 2120i (Siemens Healthcare Diagnostics) to search morphological and structural changes of platelet that are supposed reflecting platelet activation in normal platelets after addition of an agonist. PMID- 28351487 TI - Viremic attack explains the dual-hit theory of Parkinson's disease. AB - The dual-hit theory of Parkinson's disease proposes that an airborne pathogen attacks both the olfactory and enteric nervous systems to initiate the Lewy pathology, gradually leading to devastating neurodegenerative processes within the brain. Based on published literatures, this article proposes a hypothesis that viruses with viremic potential can simultaneously attack both of these nervous systems via viremia due to the lack of a blood-nerve barrier in these tissues, thereby explaining the dual-hit theory. Understanding the precise mechanisms underlying the neuropathology will facilitate development of better prophylactic and early intervention strategies against Parkinson's disease. PMID- 28351486 TI - Potential usefulness of diastolic parameters measured by strain imaging echocardiography in the early prediction of chemotherapy-induced cardiotoxicity. AB - Over the past decades, chemotherapy has significantly increased the overall prognosis and survival of several patients diagnosed with cancer. However, the usefulness of some chemotherapeutic agents has been hindered by a collateral dose dependent cardiotoxicity. To date, although extensive efforts have been directed to the early detection of subclinical toxicity in patients treated with these drugs, it remains unclear which approach would be best in order to prevent chemotherapy-induced cardiotoxicity (CIC). For many years, conventional echocardiography has been among preferred noninvasive imaging modality to monitor left ventricular ejection fraction (LVEF) in patients undergoing chemotherapy. Unfortunately, a significant reduction in LVEF is not recognized early on after chemotherapy-induced myocardial damage. Moreover, delayed recognition has been associated with poor recovery potential and poor clinical outcome. Thus, there is a critical need to identify early, reliable parameters of subclinical injury. Myocardial deformation imaging, also known as strain imaging echocardiography (SIE), is becoming readily available for advanced routine echocardiography and has shown value in detecting subclinical ventricular dysfunction in several clinical scenarios. Abnormalities in systolic deformation parameters have been identified as early manifestation but left ventricular diastolic properties remain less well defined. We hypothesize that onset as well as progression of cardiotoxicity not only should disturb deformation curves of myocardial contraction, but also relaxation. Hence, SIE may detect subtle myocardial changes in diastole that could be of potential benefit in the early prediction of CIC. If this premise is proven correct, the use of a standardized advanced echocardiographic imaging protocol using both, systolic and diastolic strain imaging, will prove to be a powerful noninvasive tool as baseline and follow-up of these patients. Furthermore, it will foster the developing of more effective screening strategies in at risk cancer survivor populations, or identify the best time to start cardioprotective therapy to prevent CIC. Also, this experience might be extrapolated to other non-oncologic patient population in need of a surveillance tool to early recognize cardiac injury secondary to the use of cardiotoxic medications. PMID- 28351488 TI - Investigating the effect of external trauma through a dynamic system modeling approach for clustering causality in diabetic foot ulcer development. AB - Diabetes and its associated complications are realized as one of the most challenging medical conditions threatening more than 29 million people only in the USA. The forecasts suggest a suffering of more than half a billion worldwide by 2030. Amid all diabetic complications, diabetic foot ulcer (DFU) has attracted much scientific investigations to lead to a better management of this disease. In this paper, a system thinking methodology is adopted to investigate the dynamic nature of the ulceration. The causal loop diagram as a tool is utilized to illustrate the well-researched relations and interrelations between causes of the DFU. The result of clustering causality evaluation suggests a vicious loop that relates external trauma to callus. Consequently a hypothesis is presented which localizes development of foot ulceration considering distribution of normal and shear stress. It specifies that normal and tangential forces, as the main representatives of external trauma, play the most important role in foot ulceration. The evaluation of this hypothesis suggests the significance of the information related to both normal and shear stress for managing DFU. The results also discusses how these two react on different locations on foot such as metatarsal head, heel and hallux. The findings of this study can facilitate tackling the complexity of DFU problem and looking for constructive mitigation measures. Moreover they lead to developing a more promising methodology for managing DFU including better prognosis, designing prosthesis and insoles for DFU and patient caring recommendations. PMID- 28351489 TI - Dying for love: Perimenopausal degeneration of vaginal microbiome drives the chronic inflammation-malignant transformation of benign prostatic hyperplasia to prostatic adenocarcinoma. AB - Prostatic carcinoma is the second commonest cancer in males and is so common as to become almost holoendemic with advancing age. The recent demonstration that far from being benign, "benign" prostatic hypertrophy is a likely a reaction of the prostate to chronic untreated lower genital tract infection, and that this chronic inflammation is likely the usual precursor to the frequent occurrence of prostatic carcinoma has far reaching implications. The obvious source for the chronic inflammatory stimulus in the prostate is the documented dramatically altered lower female genital microbiota associated with the menopause. Hence the major hypothesis is that prostatic cancer may arise due to chronic infection and inflammation in the prostate gland consequent upon the altered microbiome of the menopausal female genital tract. This has implications for testing and diagnosis, treatment, population health and personal hygiene practices. It suggests that male dyspareunia, although almost never encountered in clinical practice may in fact be relatively common in older males, and in particular if diagnosed, represents a critical opportunity for therapeutic intervention to interrupt the chronic inflammation - cancer transformation and progression which has been well documented in other tissues. It implies that the coordinated application of next generation sequencing to the microbiome of the lower genital tracts of male and female couples, including seminal fluid, will have both research applications to further explore this sequence, as well as finding application as a potential population level screening procedure as is presently done for the "Thin Prep" cervical screening for human papillomavirus in females. Moreover this insight opens up new opportunities for chemointervention and chemoprevention for this important clinicopathological progression. These considerations give rise to the exciting possibility that prostatic malignancy may be preventable by various methods of local hygiene in the female partner or some antibacterial method in males. Since the long term application of oral antibiotics is likely to be of limited efficacy this indicates the need for new antimicrobial solutions. PMID- 28351490 TI - High meniscal slope angle as a risk factor for meniscal allograft extrusion. AB - A meniscal graft extrusion is still an unresolved problem that affects most patients after a meniscal transplantation. Despite the advances in surgical techniques, together with the improved methods for a meniscal allograft sizing, success is only observed in up to 75% of patients after they experience a meniscal allograft transplantation. Because a meniscal extrusion is associated with a cartilage deterioration and the progression of osteoarthritis there is a great interest in how to prevent this phenomenon. The crucial factor for the minimisation of a meniscal allograft extrusion is by perfectly matching the implant. Most methods for a meniscal allograft sizing only focus on assessing the length and the width of the meniscus. Even though there is some evidence that there is a relationship between the shape of the meniscus in a cross-sectional plane and the meniscal extrusion, any of the planning methods do not take this factor into consideration. Although there is a large variability of meniscus shapes in cross-section, we hypothesise that by taking the meniscal slope into account during surgical planning, as well as performing the correct adjustments of this particular parameter, we can diminish the risk of a meniscal allograft extrusion. PMID- 28351491 TI - VEGF inhibition as possible therapy in spondyloarthritis patients: Targeting bone remodelling. AB - Spondyloarthritis refers to a group of chronic inflammatory rheumatic diseases that predominantly affects the axial skeleton, causing pain and stiffness. Human bone is highly dynamic organ that interacts with a wide array cells and tissues. Process of bone remodelling relies on a delicate balance between bone formation and bone resorption, orchestrated by osteoblasts and osteoclasts. Disruption of this homeostatic balance of bone removal and replacement can manifest as inappropriate new bone formation found in spondylarthritis. We hypothesize that VEGF may promote bone remodelling, stimulate angiogenesis, and both osteoclastic and osteoblastic activity. Anti VEGF may be tested as a dedicated therapy to prevent bone remodelling in spondyloarthritis patients, namely in cases of aggressive disease. Bone remodelling could be monitored by using [18F]Fluoride PET scan. PMID- 28351492 TI - Prevalence of sleep bruxism and awake bruxism in different chronotype profiles: Hypothesis of an association. AB - Sleep (SB) and awake bruxism (AB) recognize a multifactorial etiology and have a relationship with several psychological factors. Psychological disorders have recently been associated also with the chronotype, which is the propensity for an individual to be especially active at a particular time during a 24-h period. Based on the chronotype, the two extreme profiles are morningness and eveningness individuals. Due to the relationship that both the chronotype and bruxism have with psychological factors and the fact that performing tasks not compatible with chronotype can trigger stress, this review presents the hypothesis that the prevalence of SB and AB can differ with the various chronotype profiles. New perspectives for the study of bruxism etiology may emerge from investigations on the topic. PMID- 28351493 TI - Social death, melancholia, and zombies: Same patterns? PMID- 28351494 TI - Perfusion computed tomography imaging of abdominal aortic aneurysms may be of value for patient specific rupture risk estimation. AB - Abdominal aortic aneurysm (AAA) continues to pose a significant cause of unexpected mortality in the developed countries with its incidence constantly rising. The indication of elective surgical repair is currently based on the maximum diameter and growth rate criteria which represent an oversimplification of the Law of Laplace stating that the stress exerted in a cylinder or sphere is proportional to its radius. These criteria fail to capture the complex pathophysiology of the aneurismal disease thus often leading to therapeutic inaccuracies (treating large AAAs with a very low actual rupture risk while observing smaller ones with a much greater risk). Aneurysmal disease is mainly a degenerative process leading to loss of structural integrity of the diseased aortic wall which cannot withhold the stresses due to systemic pressurization. Moreover aortic wall degeneration has been shown to be a localized phenomenon and rupture depends on the pointwise comparison of strength and stress rather than a global aortic wall weakening. Ex-vivo mechanical studies have related vessel wall hypoxia to loss of structural endurance and reduced wall strength. Therefore a module to capture in vivo variation of aortic wall blood supply and oxygenation would be of value for the evaluation of AAA rupture risk. Perfusion computed tomography (PCT) imaging represents a novel technique which has been already used to estimate tissue vascularity in several clinical conditions but not aneurismal disease. We hypothesize that PCT could be used as an adjunct tool during AAA diagnostics in order to evaluate aortic wall oxygenation in vivo, therefore providing a possible means to identify weak spots making the lesion amenable to rupture. PMID- 28351495 TI - Ethical considerations in providing an upper limb exoskeleton device for stroke patients. AB - The health care system needs to face new and advanced medical technologies that can improve the patients' quality of life by replacing lost or decreased functions. In stroke patients, the disabilities that follow cerebral lesions may impair the mandatory daily activities of an independent life. These activities are dependent mostly on the patient's upper limb function so that they can carry out most of the common activities associated with a normal life. Therefore, an upper limb exoskeleton device for stroke patients can contribute a real improvement of quality of their life. The ethical problems that need to be considered are linked to the correct adjustment of the upper limb skills in order to satisfy the patient's expectations, but within physiological limits. The debate regarding the medical devices dedicated to neurorehabilitation is focused on their ability to be beneficial to the patient's life, keeping away damages, injustice, and risks. PMID- 28351496 TI - A new in vivo method to retard progression of intervertebral disc degeneration through stimulation of endogenous stem cells with simvastatin. AB - Degenerative disc disease is a worldwide problem, however, conservative treatment and surgical treatment can only partly relieve symptoms, but do not have therapeutic effect on the degenerated intervertebral disc (IVD) itself. The use of stem cell transplantation has become one of the most popular treatments. With gradually understanding of the endogenous mechanism of stem cells migration and movement in vivo, endogenous IVD stem cells can be activated to repair and reconstruct the degenerated IVD. Nucleus pulposus mensenchymal stem cells exhibit more potent biological activity in the hypoxic environment of the IVD. Hypoxia inducible factor can regulate the energy metabolism of IVD cells by activating Glucose transporter 1 pathway. The simvastatin can enhance the theraprutic effect of many kinds of stem cells by increasing number and function of the stem cell. Herein we postulate that simvastatin can regulate the differentiation of nucleus pulposus mensenchymal stem cells into nucleus pulposus cell by promoting expression of hypoxia inducible factor to repair and reconstruct degenerated IVD. PMID- 28351497 TI - A preferential delivery method to investigate direct neuromuscular blockade effect of inhaled anesthetics on skeletal muscle. AB - Inhaled anesthetics can enhance the effect of neuromuscular blocker, but whether inhaled anesthetics such as sevoflurane have a direct effect on skeletal muscle contractility is unknown. Selectively blocking skeletal muscle may prevent the interference effect of central nervous system. So we decided to evaluate a local application of neuromuscular blocker (NMB) atracurium to prevent the general effect on skeletal muscle. In part 1, sevoflurane (a inhaled anesthetic) minimum alveolar concentrations (MAC) of 1.0, 1.5 and 2.0 would be applied in succession. Neuromuscular function was assessed at each MAC. In part 2, patients are randomized into four groups: group1 (propofol+NMB, sevoflurane 0 MAC), and groups 2 to 4 (NMB+sevoflurane 1.0, 1.5 and 2.0 MAC respectively). In group 1, patients were anesthetized by propofol, then 0.01mg/kg atracurium was injected into the tested arm intravenously after the arterial blood flow was blocked using a tourniquet. For the other 3 groups, patients inhaled 1.0 MAC, 1.5 MAC, or 2.0 MAC of sevoflurane. Then 0.01mg/kg atracurium was injected. Neuromuscular function was recorded for the 4 groups. Neuromuscular function was assessed by acceleromyography measurement of evoked responses to train-of four (TOF) stimuli (2Hz for 2s applied every 12s) at the adductor pollicis using a TOF-GuardTM neuromuscular transmission monitor. If proven, our hypothesis would demonstrate the inhaled anesthetics have no direct effect on contractility but only by increasing the skeletal muscle sensitivity to NMB. PMID- 28351498 TI - Iron accumulation, glutathione depletion, and lipid peroxidation must occur simultaneously during ferroptosis and are mutually amplifying events. AB - Ferroptosis is a recently discovered form of regulated necrosis that involves iron-dependent lipid peroxidation. How cells die once ferroptosis is triggered remains unclear. Ferroptosis is hypothesized to require three critical events: (1) accumulation of redox-active iron, (2) glutathione depletion, and (3) lipid peroxidation. It is proposed that these three events must unfold simultaneously because stopping any critical event also stops ferroptosis. These events are hypothesized to amplify in severity through positive feedback loops. The cause of death in ferroptosis is therefore the synergistic combination of antioxidant depletion, iron toxicity, and membrane denaturation. The relevance of these feedback loops for cancer and neurodegenerative therapies is discussed. PMID- 28351499 TI - Retina tissue engineering by conjunctiva mesenchymal stem cells encapsulated in fibrin gel: Hypotheses on novel approach to retinal diseases treatment. AB - BACKGROUND: Retinitis pigmentosa (RP) and age related macular degeneration (AMD) are two retinal diseases that progress by photoreceptor cells death. In retinal transplantation studies, stem and progenitor cells inject into the sub retinal space or vitreous and then these cells can be migrate to the site of retinal degeneration and locate in the host retina and restitute vision. PRESENTATION OF THE HYPOTHESIS: Our hypothesis suggests that using human conjunctiva stem cells (as the source for increasing the number of human stem cells progenitor cells in retina dysfunction diseases) with fibrin gel and also assessing its relating in vitro (cellular and molecular processes) and in vivo (vision tests and pathology) could be a promising strategy for treatment of AMD and RP disorders. TESTING THE HYPOTHESIS: In this idea, we describe a novel approach for retina tissue engineering with differentiation of conjunctiva mesenchymal stem cells (CJMSCs) into photoreceptor-like cells in fibrin gel with induction medium contain taurine. For assessment of differentiation, immunocytochemistry and real time PCR are used for the expression of Rhodopsin, RPE65, Nestin as differentiated photoreceptor cell markers in 2D and 3D culture. The results show that fibrin gel will offer a proper 3D scaffold for CJMSCs derived photoreceptor cell-like cells. IMPLICATIONS OF THE HYPOTHESIS: Application of immune-privileged, readily available sources of adult stem cells like human conjunctiva stem cells with fibrin gel would be a promising strategy to increase the number of photoreceptor progenitor cells and promote involuntary angiogenesis needed in retina layer repair and regeneration. PMID- 28351500 TI - Stream of consciousness: Quantum and biochemical assumptions regarding psychopathology. AB - The accepted paradigms of mainstream neuropsychiatry appear to be incompletely adequate and in various cases offer equivocal analyses. However, a growing number of new approaches are being proposed that suggest the emergence of paradigm shifts in this area. In particular, quantum theories of mind, brain and consciousness seem to offer a profound change to the current approaches. Unfortunately these quantum paradigms harbor at least two serious problems. First, they are simply models, theories, and assumptions, with no convincing experiments supporting their claims. Second, they deviate from contemporary mainstream views of psychiatric illness and do so in revolutionary ways. We suggest a possible way to integrate experimental neuroscience with quantum models in order to address outstanding issues in psychopathology. A key role is played by the phenomenon called the "stream of consciousness", which can be linked to the so-called "Gamma Synchrony" (GS), which is clearly demonstrated by EEG data. In our novel proposal, a unipolar depressed patient could be seen as a subject with an altered stream of consciousness. In particular, some clues suggest that depression is linked to an "increased power" stream of consciousness. It is additionally suggested that such an approach to depression might be extended to psychopathology in general with potential benefits to diagnostics and therapeutics in neuropsychiatry. PMID- 28351501 TI - Hypothesis: A perfect day conveys internal time. AB - In 2007 the International Agency for Research on Cancer [IARC] concluded "shift work that involves circadian disruption is probably carcinogenic to humans" (Group 2A). To investigate the "probable" causal link, information on individual chronobiology is needed to specify exposures to circadian disruption associated with shift work. In epidemiological studies this information is usually assessed by questionnaire. The most widely used Morningness-Eveningness-Questionnaire (MEQ) and MunichChronoTypeQuestionnaire (MCTQ) reveal information on circadian type (MEQ) and actual sleep behaviour (MCTQ). As a further option we suggest to obtain preferred sleep times by using what we call the perfect day (PD) approach. We hypothesize that a PD - as a day of completely preferred sleep behaviour - captures pristine internal time. We argue that the PD approach may measure internal time more accurately than the MEQ and MCTQ which convey influences by work and social time pressures. The PD approach may therefore reduce misclassifications of internal time and reveal circadian disruption caused by different shift systems. PMID- 28351502 TI - Complex relationship between plaque characteristics and hemodynamic significance of stenosis: Insights from coronary computed tomography angiography imaging. PMID- 28351503 TI - Natural killer cell response is a predictor of good outcome in MCPyV+ Merkel cell carcinoma: A case series of 23 patients. PMID- 28351504 TI - Changes in nationwide use of preoperative radiotherapy for rectal cancer after revision of the national colorectal cancer guideline. AB - BACKGROUND: The rate of preoperative radiotherapy (RT) for rectal cancer in the Netherlands has been the highest among European countries. Revision of the national guideline on colorectal cancer, officially published in 2014, specifically focussed on the indication for RT and MRI criteria to evaluate mesorectal lymph nodes. The objective of this study was to evaluate implementation of the revised guideline using a national audit. METHODS: Data of the Dutch Surgical Colorectal Audit (DSCA) between 2009 and 2014 were used to evaluate RT use and RT regimen for relevant subgroups of cM0 rectal cancer patients, as well as accuracy of pre-operative MRI. RESULTS: 14,018 patients were included for analysis. Overall RT use in cT1-4N0-2M0 stage ranged from 81.4% to 84.2% between 2009 and 2013, and decreased to 64.4% in 2014. The absolute decrease in RT use from 2013 to 2014 for cT1N0, cT2N0 and cT3N0 stage was 32.8%, 43.5% and 31.6%, respectively. Short course RT with delayed surgery was used as an alternative to chemoradiotherapy up to 2013 in 30.6% of patients over 80 years, and in 12.1% of patients with an ASA score >2; these percentages increased to 45.8% and 19.9% in 2014, respectively. Specificity of MRI for N-stage decreased from 82.9% in 2009 to 62.9% in 2013, with an increase to 73.2% in 2014. CONCLUSION: The revised national guideline on colorectal cancer was rapidly implemented in the Netherlands with a substantial decrease in RT use for low risk resectable rectal cancer, and increased specificity of MRI for N-staging. PMID- 28351505 TI - Corrigendum to "p62 modulates the intrinsic signaling of UVB-induced apoptosis" [Journal of Dermatological Science 83 (2016) 226-233]. PMID- 28351506 TI - 62-Year-Old Man With Back Pain and Lower Extremity Weakness. PMID- 28351507 TI - 40-Year-Old Man With Diarrhea and Lymphadenopathy. PMID- 28351508 TI - Regulation of enterovirus 2A protease-associated viral IRES activities by the cell's ERK signaling cascade: Implicating ERK as an efficiently antiviral target. AB - In a previous study the ERK1/2 pathway was found to be crucially involved in positive regulation of the enterovirus A 71(EV-A71) IRES (vIRES), thereby contributing to the efficient replication of an important human enterovirus causing death in young children (<5yrs) worldwide. This study focuses on unraveling more about the detailed mechanism of ERK's involvement in this regulation of vIRES. Through the use of siRNAs and specifically pharmacological inhibitor U0126, the ERK cascade was shown to positively regulate EV-A71-mediated cleavage of eIF4GI that established the cellular conditions which favour vIRES dependent translation. Site-directed mutagenesis of the viral 2A protease (2Apro) was undertaken to show that the positive regulation of virus replication by the ERK cascade was mediated through effects on both the cis-cleavage of the viral polyprotein by 2Apro and its trans-cleavage of cellular eIF4GI. This ERK-2Apro linked network coordinating vIRES efficiency was also found in other important human enteroviruses. This identification of the ERK cascade as having a key role in maintaining the 2Apro proteolytic activity required to maximize enterovirus IRES activity, expands current understanding of the diverse functions of the ERK signaling cascade in the regulation of viral translation, therefore providing a potentially comprehensive drug target for anti-enterovirus infection. PMID- 28351510 TI - The 2016 Model of the Clinical Practice of Emergency Medicine. PMID- 28351509 TI - Adequate calcium intake during long periods improves bone mineral density in healthy children. Data from the Childhood Obesity Project. AB - BACKGROUND: Bone mineralization can be influenced by genetic factors, hormonal status, nutrition, physical activity and body composition. The association of higher calcium (Ca) intake or Ca supplementation with better bone mineral density (BMD) remains controversial. Furthermore, it has been speculated that maintaining long-term adequate Ca intake rather than having a brief supplementation period is more effective. The aim of the study was to prospectively analyse the influence of adequate Ca intake on BMD at 7 years of age in European children. METHODS: Data from the Childhood Obesity Project were analysed in a prospective longitudinal cohort trial. Dietary intake was recorded using 3-day food records at 4, 5 and 6 years of age. The probability of adequate intake (PA) of Ca was calculated following the American Institute of Medicine guidelines for individual assessments, with FAO, WHO and United Nations University joint expert consultation dietary recommendations. Children were categorised as having high Ca PA (PA >95%) or not (PA <95%). At 7 years, whole body (WB) and lumbar spine (LS) BMD were measured in the Spanish subsample by dual-energy x-ray absorptiometry. Internal BMD z-scores were calculated; BMD below -1 z-score were considered to indicate osteopenia, and BMD z-scores below -2, "low bone mineral density for age". RESULTS: BMD was measured in 179 children. Ca intake at 6 years was positively correlated with LS BMD at 7 years (R = 0.205, p = 0.030). A Ca increase of 100 mg/day explained 19.4% (p = 0.011) of the LS BMD z-score variation, modifying it by 0.089 (0.021, 0.157) units. Children with Ca PA >95% at 5 and 6 or from 4 to 6 years of age showed higher BMD z-scores at the LS and WB levels than children with Ca PA <95% (p < 0.001 and p < 0.05 for LS and WB BMD, respectively). Ca PA >95% maintained over 2 years explained 26.3% of the LS BMD z-score variation (p < 0.001), increasing it by 0.669 (0.202, 1.137). PA >95% maintained over 3 years explained 24.9% of the LS BMD z-score variation, increasing it by 0.773 (0.282, 1.264). The effects of Ca adequacy on WB BMD were similar. Children with PA >95% over 2 years had an Odds ratio of 13.84 and 12 for osteopenia at the LS and WB levels, respectively (p = 0.001). CONCLUSIONS: Long periods of adequate Ca intake in childhood increase BMD and reduce osteopenia risk. The Childhood Obesity Project clinical trial (CHOP) was registered at clinicaltrials.gov as NCT00338689. PMID- 28351511 TI - Reliability, Laterality and the Effect of Respiration on the Measured Corrected Flow Time of the Carotid Arteries. AB - BACKGROUND: Corrected flow time (FTc) measured via sonography of the carotid artery is a novel method that has shown promising results for predicting fluid responsiveness in shock states. It is a rapid and noninvasive examination that can be taught to emergency physicians with ease. However, its reliability has not been assessed, and the effects of several variables, including respiration and side of evaluation, are unclear. OBJECTIVES: The objectives were to compare carotid FTc during different phases of the respiratory cycle, (at end-inspiration and end-expiration), to compare FTc reproducibility among providers, and to compare FTc on the right and left sides in a given individual. METHODS: The FTc of both the right and left carotid arteries was measured in 16 healthy volunteers during an inspiratory hold and an expiratory hold. Examinations were completed by three sonographers blinded to previous results and were analyzed for reliability and reproducibility. RESULTS: Reliability and reproducibility were poor when comparing sonographers under all circumstances. No significant differences were found when comparing left vs. right sides of measurement regardless of respiratory phase. CONCLUSION: Although this method for predicting fluid responsiveness has many promising aspects, reproducibility between sonographers was found to be poor. No significant difference was found between the two sides of the body or respiratory phase. PMID- 28351512 TI - Potential use of targeted enzymatic agents in the treatment of Staphylococcus aureus biofilm-related infections. AB - Staphylococcus aureus is a leading cause of healthcare-associated infections. The ability of S. aureus to attach and subsequently accumulate on the surfaces of implanted medical devices and in host tissues makes infections caused by this pathogen difficult to treat. Current treatments have been shown to have limited effect on surface-associated S. aureus, and may be enhanced by the addition of a dispersal agent. This study assessed the enzymatic agents dispersin B, lysostaphin, alpha amylase, V8 protease and serrapeptase, alone and in combination with vancomycin and rifampicin, against biofilms formed by meticillin resistant and -susceptible strains of S. aureus. The efficacy of both antibiotics was enhanced when combined with any of the dispersal agents. Lysostaphin and serrapeptase were the most effective dispersal agents against all strains tested. These data indicate that combinations of biofilm dispersal agents and antibiotics may extend the therapeutic options for the treatment of S. aureus biofilm associated infections. PMID- 28351513 TI - Aflatoxin biosynthesis control produced by Aspergillus flavus in layer hens feed during storage period of six months. AB - Aflatoxins (AFTs) are a group of closely related toxins that are produced by different fungus species. Food and feed contamination with AFT is a worldwide health-related problem. As a result of fungal attack, the food and feed resulted in a principal socioeconomic loss and toxins produced in feed and food items harm the humans and animals in different ways. The anti-aflatoxigenic effect Psidium guajava, Ficus benghalensis, Gardenia radicans, Punica granatum and Ziziphus jujuba leaves were evaluated against aflatoxins (AFTs), produced by Aspergillus flavus in layer feed during storage. Among the investigated medicinal plant leaves, P. granatum showed highly promising anti-aflatoxigenic activity and completely inhibited the AFTs (B1 and B2) production over storage period without compromising the nutritive quality of feed (ash, protein, fat, fiber, Fe, Ca, P and K contents). Leaves of F. benghalensis and Z. jujuba were also effective however, higher concentration (15%) inhibited the AFTs production up to 99% and also maintained nutritive quality of feed. G. radicans was found least effective in controlling the AFTs production. Results revealed that all plant leaves were effective in controlling AFTs production in layer feed over the storage period of six months and these plants are potential candidate to replace the fungicides used to protect feed and other agricultural commodities from AFTs production during storage. PMID- 28351514 TI - [A form of central areolar choroidal dystrophy]. PMID- 28351515 TI - The expression of sialyltransferases is regulated by the bioavailability and biosynthesis of sialic acids. AB - Glycosylation is the most frequent and important post-translational modification of proteins. It occurs on specific consensus sequences but the final structure of a particular glycan is not coded on the DNA, rather it depends on the expression of the required enzymes and the availability of substrates (activated monosaccharides). Sialic acid (Sia) is the terminal monosaccharide of most glycoproteins or glycolipids (= glycoconjugates) and involved in a variety of function on molecular (e.g. determination of protein stability and half-life) and cellular level (e.g. influenza infection). Sia are synthesized in the cytosol from UDP-GlcNAc by the Roseman-Warren pathway. The key enzyme of this pathway is the UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE). Sia are transferred on glycoconjugates by a family of Golgi-located enzymes, so called sialyltransferases (ST). There are 20 (human) ST known, which all transfer CMP activated Sia to specific acceptor-sites on glycoconjugates. The regulation of the expression of ST is still not understood. Using a GNE-deficient embryonic stem cell line, which cannot synthesize Sia endogenously and by supplementation of soluble Sia precursors, we present data that the cellular availability of Sia strongly regulates the expression of ST on the level of transcription. In summary, we suggest that the concentration of the donor substrate of sialyltransferases, which can be regarded as a sensor for the environmental conditions of a cell, regulates not only total sialylation, but also the quality of sialylation. This allows a cell to response to altered environmental conditions. PMID- 28351517 TI - Enhanced activity of macrophage M1/M2 phenotypes in periodontitis. AB - OBJECTIVE: Monocytes/macrophages play a key role in mobilizing host defense against microbial infection. The selectivity of gene expression can turn macrophages into M1- or M2-type and the plasticity and differentiation of both M1 and M2 macrophages may play important roles in the development of periodontal disease. Our research aimed to study the association between the ratio of M1/M2 macrophage and inflammatory cytokines IL-1beta, MMP-9, and investigate the expressions of M1-and M2-type macrophages in gingivitis and chronic periodontitis. METHODS: Forty specimens were collected from gingivitis individuals (n=20) and chronic periodontitis (n=20). Probing depth (PD), clinical attachment level (CAL), plaque index (PI) and bleeding on probing (BOP) were recorded. The expressions of M1- and M2-type macrophages are detected with immunohistochemical method and the relative expressions of M1-, M2-type macrophage, IL-1beta and MMP-9 were assayed using real-time polymerase chain reactions. RESULTS: The M1 and M2 peptide were mainly observed in the cytoplasm of gingival connective tissue. The ratio of M1/M2 was significant higher in chronic periodontitis group compared with that in gingivitis one. In addition, the relative expressions of IL-1beta and MMP-9 also increased in periodontitis group and was correlated with the ratios of M1/M2. Meanwhile, PD was positively correlated with ratios of M1/M2. CONCLUSIONS: Periodontal inflammation associates with an enhancement of ratio of M1/M2 phenotypes of macrophages. M1/M2 ratio could provide useful information on the periodontal tissue health status. PMID- 28351516 TI - Anterior cervical fusion with interbody cage containing beta-tricalcium phosphate: Clinical and radiological results. AB - AIM: Beta tricalcium phosphate (beta-TCP) is an osteoconductive, resorbable material. Its clinical effectiveness has been proved in many indications. This study was clinical and radiographic study report obtained in patients undergoing anterior cervical discectomy and fusion ACDF in which PEEK cages were filled beta TCP in an injectable form. MATERIAL AND METHODS: Between January 2010 and June 2011, 16 consecutive patients underwent ACDF using PEEK cages with beta-TCP. The cohort compromised 10 men and 6 women with a mean age of 45.2 years. The surgery was performed when the patient had myelopathy or radiculopathy with progressive neurological deficit, or failure of conservative treatment (a minimum of 3 months). The patients were evaluated by Odom criteria preoperatively and postoperative 3rd, 6th, 12th and 24th months. Preop and postop pain was evaluated with visual analogue scala (VAS). Disc height and fusion success rates were evaluated. RESULTS: Preoperative average VAS score was 7.9 (7-10) for neck pain and 8 (7-10) for arm pain. At the final follow-up, these scores became 1.5 and 1.4 for neck and arm pain, respectively. The average improvement rate was 81% for neck pain and 82.5% for arm pain. Postop ODOM's criteria main rate was 3.4. Bone fusion was achieved in 14 segments (70%) at 3rd month, 19 segments (95%) at 12th month follow-up assessment. CONCLUSION: Clinical and radiological results revealed that B-TCP is a good alternative synthetic fusion material for cervical interbody fusion. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 28351518 TI - Use of computerized interview scheduling program for pediatric surgery match applicants. AB - BACKGROUND: Pediatric surgery fellowship applicants and programs coordinate over 20 interviews per cycle. We hypothesized that replacing e-mail and phone communication with a computerized-scheduling program (CSP) could benefit both parties. METHODS: We used a CSP to schedule 2016 interviews. Time to schedule and e-mail communication per applicant was compared to 2015, when traditional scheduling was used. Additionally, 2016 interviewees were surveyed about their experience with the CSP vs. traditional means. Analysis was performed using descriptive statistics and a Student's T-test. RESULTS: We found a significant decrease in mean scheduling time from 14.4 to 1.7h (p<0.001) and in e-mails exchanged from 3.4 to 1.0 (p<0.0001). Survey respondents reported 92% satisfaction with the CSP, and 87% found it easier to schedule interviews. Applicants also reported quicker finalization of interview dates (96%), improved access to interview slots (71%), and easier coordination of additional services and time off (63%). Notably, the mean longest time reported to schedule interviews using traditional methods was 7days (range 1-30). Overall, 84% supported widespread adoption of CSPs. CONCLUSIONS: Using CSPs improved the scheduling process for the significant majority of interviewees, and our program. If widely adopted, this could greatly improve the efficiency of pediatric surgery interview scheduling. LEVEL OF EVIDENCE: N/A. PMID- 28351519 TI - Contrast enhanced ultrasound for the evaluation of blunt pediatric abdominal trauma. AB - INTRODUCTION: Blunt abdominal trauma is a common problem in children. Computed tomography (CT) is the gold standard for imaging in pediatric blunt abdominal trauma, however up to 50% of CTs are normal and CT carries a risk of radiation induced cancer. Contrast enhanced ultrasound (CEUS) may allow accurate detection of abdominal organ injuries while eliminating exposure to ionizing radiation. METHODS: Children aged 7-18years with a CT-diagnosed abdominal solid organ injury underwent grayscale/power Doppler ultrasound (conventional US) and CEUS within 48h of injury. Two blinded radiologists underwent a brief training in CEUS and then interpreted the CEUS images without patient interaction. Conventional US and CEUS images were compared to CT for the presence of injury and, if present, the injury grade. Patients were monitored for contrast-related adverse reactions. RESULTS: Twenty one injured organs were identified by CT in eighteen children. Conventional US identified the injuries with a sensitivity of 45.2%, which increased to 85.7% using CEUS. The specificity of conventional US was 96.4% and increased to 98.6% using CEUS. The positive predictive value increased from 79.2% to 94.7% and the negative predictive value from 85.3% to 95.8%. Two patients had injuries that were missed by both radiologists on CEUS. In a 100kg, 17year old female, a grade III liver injury was not seen by either radiologist on CEUS. Her accompanying grade I kidney injury was not seen by one of the radiologist on CEUS. The second patient, a 16year old female, had a grade III splenic injury that was missed by both radiologists on CEUS. She also had an adjacent grade II kidney injury that was seen by both. Injuries, when noted, were graded within 1 grade of CT 33/35 times with CEUS. There were no adverse reactions to the contrast. CONCLUSION: CEUS is a promising imaging modality that can detect most abdominal solid organ injuries in children while eliminating exposure to ionizing radiation. A multicenter trial is warranted before widespread use can be recommended. LEVEL OF EVIDENCE: Level II; Diagnostic Prospective Study. PMID- 28351520 TI - Toll-like receptor 4 is critical for the development of resection-associated hepatic steatosis. AB - BACKGROUND: A significant number of children with short bowel syndrome experience intestinal failure-associated liver disease. We recently demonstrated accelerated hepatic steatosis after 50% small bowel resection (SBR) in mice. Since SBR is associated with alterations in the gut microbiome, the purpose of this study was to determine whether TLR4 signaling is critical to the development of resection associated hepatic steatosis. METHODS: Male C57BL6 (control) and TLR4-knockout (KO) mice underwent 50% proximal SBR. Liver sections were analyzed to obtain the percent lipid content, and Ileal sections were assessed for morphological adaptation. Intestinal TLR4 mRNA expression was measured at 7days and 10weeks. RESULTS: Compared to controls, TLR4 KO mice demonstrated similar weight gain and morphological adaptation after SBR. Hepatic steatosis was decreased 32-fold in the absence of TLR4. Intestinal TLR4 mRNA expression was significantly elevated 7days after SBR. We also found that TLR4 expression in the intestine was 20-fold higher in whole bowel sections compared with isolated enterocytes. CONCLUSIONS: TLR4 signaling is critical for the development of resection-associated steatosis, but not involved in intestinal adaptation after massive SBR. Further studies are needed to delineate the mechanism for TLR4 signaling in the genesis of resection associated liver injury. LEVEL OF EVIDENCE: Animal study, not clinical. PMID- 28351521 TI - Three-dimensional-guided perineal-based interstitial brachytherapy in cervical cancer: A systematic review of technique, local control and toxicities. AB - OBJECTIVE: To evaluate local control and toxicities of perineal-based interstitial brachytherapy (P-ISBT) in cervical cancers treated with three dimensional (3D) image-based planning through a systematic review. The secondary objective of this review is to summarize the implant and dosimetric techniques in 3D P-ISBT. METHODS: Systematic review of the literature using the PRISMA guideline was conducted through a search of Medline, EMBASE and Cochrane databases. This search resulted in 19 relevant manuscripts. Selected studies evaluated the role of perineal ISBT in cervical tumours treated using 3D planning. Eleven of nineteen manuscripts contained sufficient information for LC and toxicity calculations. Data were extracted by at least two investigators. RESULTS: A total of 672 cervical cancer patients were treated with P-ISBT and planned with 3D image-based planning. Clinical outcomes could be identified for 392 patients and 60% were staged IIIB or higher. Most patients received 45-50.4Gy EBRT to the pelvis followed by a P-ISBT boost with a range of dose between 28 and 48Gy EQD2Gy. Overall LC was 79% (310/392) with a median follow-up ranging from 14 to 55months. Almost half of the patients (48%) had a median follow-up >=35months. Patients treated to a lower tumour EQD2Gy total dose had inferior LC. Procedure related complications were rare (7 infections and 7 episodes of bleeding) and limited. Combined late gastro-intestinal, genitourinary and vaginal grade 3 and 4 toxicity was 12.1%. CONCLUSION: Promising LC rates were found in patients with cervical cancers treated with perineal ISBT with 3D image-based planning. In this systematic review, 60% had stage IIIB disease or higher and yet a LC rate of 79% was found. LC seemed to correlate with the dose delivered to the tumour, while toxicity rates were similar to other cervical cancer series using 3D image-based brachytherapy. Perineal ISBT with 3D planning seems to be an effective and safe treatment for large advanced cervical tumours and may be a reasonable alternative to the increasingly more standard and modern intracavitary/interstitial (IC/IS) approaches such as the 'Vienna' applicator. PMID- 28351522 TI - Dynamic conformal arc radiosurgery for arteriovenous malformations: Outcome and influence of clinical and dosimetrical data. AB - PURPOSE: To assess efficacy, toxicity, and their predictive factors for dynamic conformal arc arteriovenous malformations (AVM) stereotactic radiosurgery. METHOD: Data concerning 90 consecutive patients were retrospectively studied. Clinical, radiological, dosimetrical data and quality indexes were computed. RESULTS: AVM median volume was 1.06cc. Median prescribed dose was 22Gy. Total occlusion was obtained for 69% of patients. Post-radiosurgery annual hemorrhage rate was 2.2%. Predictive factor for total occlusion was delivered dose. Undesirable events occurred for 28% of patients. Predictive factors for adverse events were AVM revealing mode with seizure or headache, age<=28, AVM diameter>=3cm Spetzler-Martin score>=4, V12Gy>=2cc, large target volume and low homogeneity index (p<0.05). Brain parenchymal radiological reactions concerned 23% of patients, and their predictive factors were AVM revelation by seizure, deep localization, AVM diameter>=3cm, Spetzler-Martin score>=4, previous radiosurgery, numerous embolization, target volume, V12Gy and low homogeneity index (p<0.05). CONCLUSION: Occlusion rate and toxicities are comparable to other series. Specific attention must be paid on pre-treatment clinical data, and target volume should be as small as possible, without reducing the delivered dose. PMID- 28351523 TI - Quality assessment of delineation and dose planning of early breast cancer patients included in the randomized Skagen Trial 1. AB - BACKGROUND AND PURPOSE: To report on a Quality assessment (QA) of Skagen Trial 1, exploring hypofractionation for breast cancer patients with indication for regional nodal radiotherapy. MATERIAL AND METHODS: Deviations from protocol regarding target volume delineations and dose parameters (Dmin, Dmax, D98%, D95% and D2%) from randomly selected dose plans were assessed. Target volume delineation according to ESTRO guidelines was obtained through atlas based automated segmentation and centrally approved as gold standard (GS). Dice similarity scores (DSC) with original delineations were measured. Dose parameters measured in the two delineations were reported to assess their dosimetric outcome. RESULTS: Assessment included 88 plans from 12 centres in 4 countries. DSC showed high agreement in contouring, 99% and 96% of the patients had a complete delineation of target volumes and organs at risk. No deviations in the dosimetric outcome were found in 76% of the patients, 82% and 95% of the patients had successful coverage of breast/chestwall and CTVn_L2-4-interpectoral. Dosimetric outcomes of original delineation and GS were comparable. CONCLUSIONS: QA showed high protocol compliance and adequate dose coverage in most patients. Inter-observer variability in contouring was low. Dose parameters were in harmony with protocol regardless original or GS segmentation. PMID- 28351524 TI - G9a governs colon cancer stem cell phenotype and chemoradioresistance through PP2A-RPA axis-mediated DNA damage response. AB - BACKGROUND AND PURPOSE: Neoadjuvant concurrent chemoradiotherapy (CCRT) is a standard treatment of locally advanced colon cancer cell (CRC). In order to maximize efficacy and minimize toxicity, new drugs have been developed and used in combination with CCRT. Recently, it has been shown that G9a plays a role in mediating phenotypes of cancer stem cells (CSCs). This study aimed to characterize G9a as a biomarker in predicting therapy response to prevent overtreatment and adverse effects in CRC patients. EXPERIMENTAL DESIGN: The primary tumors from 39 patients who received CCRT for rectal cancer were selected. In vivo tumor xenograft models for tumorigenic properties in immunodeficient mice were developed. In vitro stemness ability was performed by tumor-sphere assays, cell response to anti-cancer agents and stemness-related genes analysis. RESULTS: Cells survived from radiation treatment, and displayed high levels of G9a. A significantly positive correlation was shown between G9a and CSCs marker CD133 in locally advanced rectal cancer patients with CCRT. Knockdown of G9a increased the sensitivity of cells to radiation treatment and sensitized cells to DNA damage agents through PP2A-RPA axis. CONCLUSIONS: Our study theorized that G9a might serve as a novel target in colon cancer, which offers exciting potential in prediction of response to preoperative chemoradiotherapy in patients with advanced CRC. PMID- 28351525 TI - Patient safety in external beam radiotherapy, results of the ACCIRAD project: Current status of proactive risk assessment, reactive analysis of events, and reporting and learning systems in Europe. AB - PURPOSE: To describe the current status of implementation of European directives for risk management in radiotherapy and to assess variability in risk management in the following areas: 1) in-country regulatory framework; 2) proactive risk assessment; (3) reactive analysis of events; and (4) reporting and learning systems. MATERIAL AND METHODS: The original data were collected as part of the ACCIRAD project through two online surveys. RESULTS: Risk assessment criteria are closely associated with quality assurance programs. Only 9/32 responding countries (28%) with national regulations reported clear "requirements" for proactive risk assessment and/or reactive risk analysis, with wide variability in assessment methods. Reporting of adverse error events is mandatory in most (70%) but not all surveyed countries. CONCLUSIONS: Most European countries have taken steps to implement European directives designed to reduce the probability and magnitude of accidents in radiotherapy. Variability between countries is substantial in terms of legal frameworks, tools used to conduct proactive risk assessment and reactive analysis of events, and in the reporting and learning systems utilized. These findings underscore the need for greater harmonisation in common terminology, classification and reporting practices across Europe to improve patient safety and to enable more reliable inter-country comparisons. PMID- 28351526 TI - Trauma care in Oman: A call for action. AB - Many Arab countries have undergone the epidemiologic transition of diseases with increasing economic development and a proportionately decreasing prevalence of communicable diseases. With this transition, injuries have emerged as a major cause of mortality and morbidity in the Gulf Cooperation Council countries in addition to diseases of affluence. Injuries are the number one cause of years of life lost and disability-adjusted life-years in the Sultanate of Oman. The burden of injuries, which affects mostly young Omani males, has a unique geographic distribution that is in contrast to the trauma care capabilities of the country. The concentration of health care resources in the northern part of the country makes it difficult for the majority of Omanis who live elsewhere to access high quality and time-sensitive care. A broader multisectorial national injury prevention strategy should be evidence based and must strengthen human resources, service delivery, and information systems to improve care of the injured and loss of life. This paper provides a unique overview of the Omani health system with the goal of examining its trauma care capabilities and injury control policies. PMID- 28351527 TI - Imaging practices and radiation doses from imaging in radiotherapy. AB - Modern radiotherapy treatments require frequent imaging for accurate patient positioning relative to the therapeutic radiation beam. Imaging practices in five Finnish radiotherapy clinics were assessed and discussed from the patient dose optimization point of view. The results show that imaging strategies are not jointly established and variations exist. The organ absorbed doses depend on imaging technique and imaging frequency. In particular, organ doses from the cone beam computed tomography can have very large variations (a factor of 10-50 in breast imaging and factor of 5 in prostate imaging). The cumulative imaging organ dose from the treatment can vary by a factor of ten or more for the same treatment, depending on the chosen technique and imaging frequency. Awareness and optimization of the imaging dose in image-guided radiotherapy should be strengthened. PMID- 28351528 TI - Immediate loading for implant restoration compared with early or conventional loading: A meta-analysis. AB - PURPOSE: This meta-analysis was to further confirm the no inferiority of immediate loading in clinical and radiographic outcomes compared with non immediate loadings (early or conventional loading). MATERIALS AND METHODS: Literature search on Pubmed and Embase was performed up to August 2015. The overall risk radios (RRs) and standard mean differences (SMDs) as well as their 95% confidence intervals (CI) were calculated for comparison. RESULTS: Total 29 RCT with 1342 implants receiving immediate loading and 1279 implants receiving non-immediate loadings were included in this meta-analysis. Results indicated that there was no significant difference between immediate and non-immediate loadings in implant failure rate based on patients (RR = 1.45, 95% CI: 0.79 to 2.68) and implants (RR = 1.38, 95% CI: 0.86 to 2.21), MBL (SMD = -0.11, 95% CI: 0.39 to 0.17), and ISQ (SMD = -0.26, 95% CI: -0.53 to 0.01). Meanwhile, immediate loading showed significantly less MBL change than non-immediate loading. In addition, subgroup analyses showed that the immediate loading indicated slightly higher implant failure rate and lower ISQ than conventional loading. CONCLUSIONS: Although overall analysis confirmed no inferiority of immediate loading compared with non-immediate loadings, the technique still need to be explored for improving implant success and stability during immediate loading based on the results in subgroup analyses. PMID- 28351529 TI - Analysis of the regulation of surfactant phosphatidylcholine metabolism using stable isotopes. AB - The pathways and mechanisms that regulate pulmonary surfactant synthesis, processing, secretion and catabolism have been extensively characterised using classical biochemical and analytical approaches. These have constructed a model, largely in experimental animals, for surfactant phospholipid metabolism in the alveolar epithelial cell whereby phospholipid synthesised on the endoplasmic reticulum is selectively transported to lamellar body storage vesicles, where it is subsequently processed before secretion into the alveolus. Surfactant phospholipid is a complex mixture of individual molecular species defined by the combination of esterified fatty acid groups and a comprehensive description of surfactant phospholipid metabolism requires consideration of the interactions between such molecular species. However, until recently, lipid analytical techniques have not kept pace with the considerable advances in understanding of the enzymology and molecular biology of surfactant metabolism. Refinements in electrospray ionisation mass spectrometry (ESI-MS) can now provide very sensitive platforms for the rapid characterisation of surfactant phospholipid composition in molecular detail. The combination of ESI-MS and administration of phospholipid substrates labelled with stable isotopes extends this analytical approach to the quantification of synthesis and turnover of individual molecular species of surfactant phospholipid. As this methodology does not involve radioactivity, it is ideally suited to application in clinical studies. This review will provide an overview of the metabolic processes that regulate the molecular specificity of surfactant phosphatidylcholine together with examples of how the application of stable isotope technologies in vivo has, for the first time, begun to explore regulation of the molecular specificity of surfactant synthesis in human subjects. PMID- 28351531 TI - Two degree of freedom PID based inferential control of continuous bioreactor for ethanol production. AB - This article presents the development of inferential control scheme based on Adaptive linear neural network (ADALINE) soft sensor for the control of fermentation process. The ethanol concentration of bioreactor is estimated from temperature profile of the process using soft sensor. The prediction accuracy of ADALINE is enhanced by retraining it with immediate past measurements. The ADALINE and retrained ADALINE are used along with PID and 2-DOF-PID leading to APID, A2PID, RAPID and RA2PID inferential controllers. Further the parameters of 2-DOF-PID are optimized using Non-dominated sorted genetic algorithm-II and used with retrained ADALINE soft sensor which leads to RAN2PID inferential controller. Simulation results demonstrate that performance of proposed RAN2PID controller is better in comparison to other designed controllers in terms of qualitative and quantitative performance indices. PMID- 28351532 TI - Multiple and recurrent cerebral infarctions in a patient with idiopathic thrombocytopenic purpura. PMID- 28351533 TI - The 100 most influential publications pertaining to intracranial aneurysms and aneurysmal subarachnoid hemorrhage. AB - The study of intracranial aneurysms has grown at an astounding rate since Sir Charles Symond's association of hemorrhage within the subarachnoid space to intracranial aneurysms in 1923. These associations led to the first surgical treatment of an intracranial aneurysm with wrapping by Norman Dott in 1931, and shortly thereafter, clip ligation by Walter Dandy in 1938. Surgical outcomes were improved by the introduction of the operative microscope in the 1960s and perioperative care utilizing induced hypertension, hypovolemia, and hemodilution ("HHH therapy"). Recent monumental advancements, such as coil embolization in 1990 by Guglielmi, have continued to advance the field forward. The authors hope to highlight some of the most seminal and influential works. Herein, we utilize the technique of citation analysis to assemble a list of the 100 most influential works pertaining to aneurysmal subarachnoid hemorrhage published between the years 1900 and 2015 to honor these individuals and to provide guidance to current and future researchers in the field. We additionally calculate the effects of author, journal, topic, and study design on the overall influence of publications in this field. PMID- 28351534 TI - Learning word order at birth: A NIRS study. AB - In language, the relative order of words in sentences carries important grammatical functions. However, the developmental origins and the neural correlates of the ability to track word order are to date poorly understood. The current study therefore investigates the origins of infants' ability to learn about the sequential order of words, using near-infrared spectroscopy (NIRS) with newborn infants. We have conducted two experiments: one in which a word order change was implemented in 4-word sequences recorded with a list intonation (as if each word was a separate item in a list; list prosody condition, Experiment 1) and one in which the same 4-word sequences were recorded with a well-formed utterance-level prosodic contour (utterance prosody condition, Experiment 2). We found that newborns could detect the violation of the word order in the list prosody condition, but not in the utterance prosody condition. These results suggest that while newborns are already sensitive to word order in linguistic sequences, prosody appears to be a stronger cue than word order for the identification of linguistic units at birth. PMID- 28351535 TI - Editorial overview: Protein Folding and Binding, Complexity Comes of Age. PMID- 28351530 TI - Structure, genetics and function of the pulmonary associated surfactant proteins A and D: The extra-pulmonary role of these C type lectins. AB - The collectins family encompasses several collagenous Ca2+-dependent defense lectins that are described as pathogen recognition molecules. They play an important role in both adaptive and innate immunity. Surfactant proteins A and D are two of these proteins which were initially discovered in association with surfactant in the pulmonary system. The structure, immune and inflammatory functions, and genetic variations have been well described in relation to their roles, function and pathophysiology in the pulmonary system. Subsequently, these proteins have been discovered in a wide range of other organs and organ systems. The role of these proteins outside the pulmonary system is currently an active area of research. This review intends to provide a current overview of the genetics, structure and extra-pulmonary functions of the surfactant collectin proteins. PMID- 28351536 TI - Highly selective enrichment of phosphopeptides by titanium (IV) attached monodisperse-porous poly(vinylphosphonic acid-co-ethylene dimethacrylate) microspheres. AB - A seeded polymerization protocol was developed for the synthesis of monodisperse porous poly(vinylphosphonic acid-co-ethylene dimethacrylate), [poly(VPA-co-EDMA)] microspheres with superior porous properties. The protocol allowed the direct synthesis of phosphonic acid functionalized porous microspheres with the mean size of ~4MUm and the specific surface area of 420m2g-1 without applying any complicated post-derivatization protocol for the attachment of phosphonic acid group. The phosphonic acid content of poly(VPA-co-EDMA) microspheres was determined as 1.5mmol H2PO3g-1 microspheres. Ti(IV) ions were attached onto the microspheres via metal-chelate complex formation by phosphonate-groups and Ti(IV) carrying monodisperse-porous poly(vinylphosphonic acid-co-ethylene dimethacrylate), [Ti(IV)@poly(VPA-co-EDMA)] microspheres were obtained as a new sorbent for phosphopeptide enrichment via immobilized metal affinity chromatography. The phosphopeptides in the enriched samples were identified by matrix-assited laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Four different phosphopeptides were detected with extremely high intensity by the treatment of beta-casein digest prepared with the concentration of 10 fmol/mL with Ti(IV)@poly(VPA-co-EDMA) microspheres. Highly selective enrichment of phosphopeptides was also successfully carried out even at trace amounts in a complex mixture of digested proteins (molar ratio of beta-casein to BSA, 1:1000) and eight different phosphorylated peptides from BSA digest were successfully identified. Moreover, four highly intense signals of the phosphopeptides in human serum were observed with high S/N ratio and clear background after enrichment by using Ti(IV)@poly(VPA-co-EDMA) microspheres. PMID- 28351537 TI - Determination of chlorinated volatile organic compounds in polyamine epichlorohydrin solution by headspace gas chromatography. AB - This study demonstrated a headspace gas chromatographic (HS-GC) method for the determination of residual epichlorohydrin (ECH) and the by-product 1,3-dichloro-2 propanol (DCP) in polyamine epichlorohydrin (PAE) solution. It was based on the vapor-liquid phase equilibrium of these analytes at 60 degrees C for 30min in a closed headspace sample vial before GC measurement. It was found that matrix of the PAE solution had the effect on the headspace equilibrium of these species and therefore a standard addition must be applied in the method validation. The results showed that the present method has a good measurement precision (RSD <2.90%) and accuracy (recoveries from 93.6 to 105%), and the limit of quantitation (LOQ) is 3.75mg/L for ECH and 0.8g/L for DCP. The present method is suitable to be used for analyzing the chlorinated volatile organic compounds in the commercial PAE resin solutions. PMID- 28351538 TI - Recovery of monosaccharides from lignocellulosic hydrolysates by ion exclusion chromatography. AB - The production of sugars from lignocellulosic biomass is the key to a sustainable, renewable chemical industry. Glucose, xylose and other monosaccharides can be easily produced by hydrolyzing cellulose and hemicellulose, the primary polysaccharides in biomass. However, the hydrolysis of biomass generates byproducts that, together with the mineral acid normally added in the hydrolysis step, have to be removed before the downstream conversion processes. In this work, the recovery of monosaccharides from lignocellulosic hydrolysates by means of Ion Exclusion Chromatography (IEC) has been studied. The analyzed process relies on new pretreatment and hydrolysis steps, involving the neutralization of the hydrolysate with sodium hydroxide. The adsorption behavior of the main components involved in the separation has been experimentally investigated. Pulse tests at the high loading encountered in preparative conditions have been performed for a selected group of model components found in the hydrolysates. For all the electrolytes, the retention volume fraction was always between the interparticle porosity and the total column porosity, confirming that ion exclusion was the dominant retention mechanism. On the other hand, sugars eluted before the total column porosity, indicating partial steric exclusion from the resin pores. This observation was then confirmed by size exclusion experiments with polyethylene glycol standards, from which the distribution coefficient of the studied sugars has been determined. The comparison between the elution profiles of the same sugars in pure form and as a mixture present in the hydrolysate showed differences in both peak shape and retention times. Therefore, an investigation of the influence of the main electrolytes contained in the hydrolysates on sugars adsorption has been performed through the pulse on a plateau method. The electrolytes were found to enhance the sugars retention by promoting their adsorption onto the resin. However, this effect was not sufficient to explain the observed differences, which were effectively explained in terms of viscous fingering, due to the high viscosity differences between the eluent and the sample. A previously developed model for IEC has been updated to take into account all the observed phenomena and applied to simulate the experimental results. The proposed model was in good agreement with the batch-column elution profiles both for the pure components and for the actual hydrolysate, allowing a quantitative description of the separation. PMID- 28351539 TI - Cardiovascular Autonomic Dysfunction in Children and Adolescents With Rett Syndrome. AB - BACKGROUND: Autonomic dysfunction is common in children with Rett syndrome. They usually manifest with agitation, persistent screaming, constipation, gastroesophageal reflux, aerophagia, hyperventilation, and breath-holding episodes. Cardiovascular autonomic dysfunction may result in fatal a arrhythmia. Many of these events are mistaken for seizures and treated with antiepileptics. METHODS: The present study was conducted in a tertiary care teaching hospital in north India for more than a six month period. MeCP2 mutation positive, 24 cases with Rett syndrome and 24 age-matched healthy girls were evaluated for cardiovascular autonomic dysfunction (heart rate variability, head-up tilt test, and cold pressor test). RESULTS: The mean age was 9.06 years (+/-3.4) and 9.75 years (+/-3.13) for patients and control subjects, respectively. The heart rate variability contributed independently by parasympathetic and sympathetic nervous system was significantly reduced in cases compared with control subjects (P = 0.033 and P = 0.001, respectively). There was significant sympathovagal imbalance with sympathetic overactivity in cases compared with control subjects (P = 0.001). The mean longest QTc interval was significantly prolonged in cases compared with control subjects (P = 0.001). Cold pressor test and head-up tilt test could be done in 16 Rett syndrome patients (because of poor cooperation) and in all 24 control subjects. The change in blood pressure during cold pressor test and head-up tilt test was not significantly different in cases and control subjects. CONCLUSIONS: Children with Rett syndrome exhibited significant cardiovascular autonomic dysfunction in the form of sympathetic overactivity, parasympathetic underactivity, and sympathovagal imbalance. These findings have potentially important therapeutic- and outcome-related implications. PMID- 28351540 TI - 3D correlation NMR spectrum between three distinct heteronuclei for the characterization of inorganic samples: Application on sodium alumino-phosphate materials. AB - We report here an original NMR sequence allowing the acquisition of 3D correlation NMR spectra between three distinct heteronuclei, among which two are half-integer spin quadrupolar nuclei. Furthermore, as two of them exhibit close Larmor frequency, this experiment was acquired using a standard triple-resonance probe equipped with a commercial frequency splitter. This NMR technique was tested and applied to sodium alumino-phosphate compounds with 31P as the spin-1/2 nucleus and 23Na and 27Al as the close Larmor frequencies isotopes. To the best of our knowledge, such experiment with direct 31P and indirect 27Al and 23Na detection is the first example of 3D NMR experiment in solids involving three distinct heteronuclei. This sequence has first been demonstrated on a mixture of Al(PO3)3 and NaAlP2O7 crystalline phases, for which a selective observation of NaAlP2O7 is possible through the 3D map edition. This 3D correlation experiment is then applied to characterize mixing and phase segregation in a partially devitrified glass that has been proposed as a material for the sequestration of radioactive waste. The 31P-{23Na,27Al} 3D experiment conducted on the partially devitrified glass material conclusively demonstrates that the amorphous component of the material does not contain aluminum. The as-synthesized material thus presents a poor resistance against water, which is a severe limitation for its application in the radioactive waste encapsulation domain. PMID- 28351541 TI - Nutrient contributions and biogas potential of co-digestion of feedstocks and dairy manure. AB - This study focused on collection of data on nutrient flow and biogas yield at a commercial anaerobic digester managed with dairy manure from a 1000 cow dairy and co-digestion of additional feedstocks. Feedstocks included: blood, fish, paper pulp, out of date beverages and grease trap waste. Mass flow of inputs and outputs, nutrient concentration of inputs and outputs, and biogas yield were obtained. It was determined that manure was the primary source of nutrients to the anaerobic digester when co-digested with feedstocks. The percentage of contribution from manure to the total nutrient inputs for total nitrogen, ammonia nitrogen, phosphorus and total solids was 46.3%, 67.7%, 32.8% and 23.4%, respectively. On average, manure contributed the greatest amount of total nitrogen and ammonia-nitrogen. Grease trap waste contributed the greatest amount of phosphorus and total solids at approximately 50%. Results demonstrated that a reliable estimate of nutrient inflow could be obtained from the product of the nutrient analyses of a single daily composite of influent subsamples times the total daily flow estimated with an in-line flow meter. This approach to estimate total daily nutrient inflow would be more cost effective than testing and summing the contribution of individual feedstocks. Data collected after liquid-solid separation confirmed that the majority (>75%) of nutrients remain with the liquid effluent portion of the manure stream. It was demonstrated that the ash concentration in solids before and after composting could be used to estimate the mass balance of total solids during the compost process. This data confirms that biogas or methane yield could be accurately measured from the ratio of % volatile solids to % total solids. PMID- 28351542 TI - Service area size assessment for evaluating the spatial scale of solid waste recovery chains: A territorial perspective. AB - Waste recovery is an integrated part of municipal solid waste management systems but its strategic planning is still challenging. In particular, the service area size of facilities is a sensitive issue since its calculation depends on various factors related to treatment technologies (output products) and territorial features (sources waste production and location). This work presents a systemic approach for the estimation of a chain's service area size, based on a balance between costs and recovery profits. The model assigns a recovery performance value to each source, which can be positive, neutral or negative. If it is positive, the source should be included in the facility's service area. Applied to the case of Montreal for food waste recovery by anaerobic digestion, the approach showed that at most 23 out of the 30 districts should be included in the service area, depending on the indicator, which represents around 127,000 t of waste recovered/year. Due to the systemic approach, these districts were not necessarily the closest to the facility. Moreover, for the Montreal case, changing the facility's location did not have a great influence on the optimal service area size, showing that the distance to the facility was not a decisive factor at this scale. However, replacing anaerobic digestion by a composting plant reduced the break-even transport distances and, thus, the number of sources worth collecting (around 68,500 t/year). In this way, the methodology, applied to different management strategies, gave a sense of the spatial dynamics involved in the recovery chain's design. The map of optimal supply obtained could be used to further analyse the feasibility of multi-site and/or multi-technology systems for the territory considered. PMID- 28351543 TI - Corrigendum to "Efficacy of brexpiprazole in patients with acute schizophrenia: Review of three randomized, double-blind, placebo-controlled studies" [Schizophr. Res. 174 (2016) 82-92]. PMID- 28351544 TI - Comparing the effect of clozapine and risperidone on cue reactivity in male patients with schizophrenia and a cannabis use disorder: A randomized fMRI study. AB - OBJECTIVE: Cannabis use disorders (CUDs) are highly comorbid in patients with schizophrenia and associated with poor outcome. Clozapine has been put forward as the first choice antipsychotic in this patient group. However, little is known about the mechanisms underlying the assumed superiority of clozapine. METHODS: A total of 38 patients with DSM-IV schizophrenia (30 with and 8 without a DSM-IV CUD) and 20 healthy comparison subjects were included between April 2009 and June 2012. Patients were randomized to antipsychotic treatment with clozapine or risperidone. At baseline and after 4weeks of medication, brain response to cannabis-related, positive and neutral images was measured using functional MRI. Neural correlates of cue reactivity were assessed in the following regions of interest: amygdala, ventral striatum, insula, thalamus, orbitofrontal cortex and anterior cingulate cortex. Subjective craving was assessed using self-report questionnaires (OCDUS and MCQ). RESULTS: At baseline, patients with a comorbid CUD showed higher subjective craving and greater activation in response to cannabis-related images compared to patients without a CUD and healthy controls in most regions of interest. Clozapine treated patients reported a greater reduction in craving (F(1,28)=6.0, p=0.04) and showed a larger decrease in amygdala activation during cannabis-related images compared to risperidone treated patients (T=3.94, pFWE=0.006). In addition, significant correlations were found between subjective craving and thalamus and insula activation during cannabis-related images. CONCLUSION: These findings provide evidence that clozapine is superior to risperidone in decreasing subjective craving and cue reactivity for cannabis-related images probably due to a differential effect on dopaminergic neurotransmission. TRIAL REGISTRATION: 'Nederlands trial register' (http://www.trialregister.nl), nr NTR1761, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1761. PMID- 28351545 TI - Corrigendum to 'specific changes in the proteomic pattern produced by the BRCA1 Ser1841Asn missense mutation' [International Journal of Biochemistry and Cell Biology (2007) 220-226]. PMID- 28351546 TI - Three-dimensional comparison of alternative screw positions versus actual fixation of scaphoid fractures. AB - PURPOSE: The recommended technique for the fixation of a scaphoid waist fracture involves a headless compression screw placed in the proximal fragment center. This is usually accomplished by placing a longitudinal axis screw as visualized by fluoroscopy. The screw length has been shown to have a biomechanical advantage. An alternative to these options, which has been debated in the literature, is a screw placed perpendicular to the fracture plane and in its center. The perpendicular screw may have a biomechanical advantage despite the fact that it may be shorter. This study examined the differences in location and length in actual patients between a screw in the center of the proximal fragment with a longitudinal axis screw, and the actual fixating screw. These were then compared to a perpendicular axis screw. METHODS: Pre- and post-operative CT scans of 10 patients with scaphoid waist fractures were evaluated using a 3D computer model. Comparisons were made between the length, location and angle of actual and virtual screw alternatives; namely, a screw along the central third of the proximal fragment (central screw axis) where the scaphoid longitudinal axis was calculated mathematically (longitudinal screw axis) and a screw placed at 90 degrees to the fracture plane and in its center (perpendicular screw axis). RESULTS: The longitudinal axis screw was found to be significantly longer than the other axes (28.3mm). There was a significant difference between the perpendicular axis screw and the location and angle of the other screw axis, but it was only shorter than the longitudinal screw (23.6mm versus 25.5mm for the actual screw; ns.). CONCLUSIONS: A computed longitudinal axis screw is longer than a central or actual screw placed longitudinally by visual inspection by the surgeon. Although it needs to be placed using computer assisted (CAS) techniques, it may have the biomechanical advantages of a longer screw in a similar trajectory. The perpendicular screw was found to be significantly different in position and angle but not shorter than the actually placed screw. It has biomechanical advantages and does not require visualization with CAS methods, making it the more attractive alternative. PMID- 28351547 TI - The "Road to Union" protocol for the reconstruction of isolated complex high energy tibial trauma. AB - INTRODUCTION: The purpose of this study was to describe a standardized staged approach, "The Road to Union", for the reconstruction of isolated complex tibial trauma, both acute and chronic in nature. METHODS: This retrospective study included all patients treated for complex tibial trauma at a specialized limb reconstruction centre, including acute open fracture as well as infected and aseptic non-unions. This standardized approach includes eight specific steps, employed in sequence. The time in external fixation (EFT), the external fixation index (EFI), and the distraction consolidation index (DCI) were the primary outcome measures. The relationship between EFI and DCI was assessed using Pearson's moment correlations. RESULTS: Thirty-two patients with a mean age of 34.7+/-14.2years were included; 12 were treated for complex open tibial fractures with bone loss, 13 for infected non-unions, and 6 for aseptic non-union. The mean bone defect was 66+/-32mm. The total EFT was 42.5+/-14.8 weeks; the EFI measured 51.9+/-25.3 days/cm, and the DCI measured 48.3+/-21.4 days/cm. Union was achieved in 29 out of 32 patients (91%), and there was a strong and significant relationship between EFI and DCI (r=0.92, p=0.0001) measurements. Pin site infections were observed in 11 patients, and 3 patients had persistent non-union. Three patients underwent delayed amputations when reconstructive procedures were unable to achieve union. CONCLUSION: The findings of this study demonstrate that a standardized staged treatment protocol of debridement, circular external fixation, soft-tissue management, distraction osteogenesis, and functional rehabilitation can result in a high rate of union in cases of complex tibial trauma, both acute and chronic in nature. LEVEL OF EVIDENCE: Level IV; case series. PMID- 28351548 TI - Behavioral sensitization to methamphetamine induces specific interneuronal mRNA pathology across the prelimbic and orbitofrontal cortices. AB - Schizophrenia is associated with significant pathophysiological changes to interneurons within the prefrontal cortex (PFC), with mRNA and protein changes associated with the GABA network localized to specific interneuron subtypes. Methamphetamine is a commonly abused psychostimulant that can induce chronic psychosis and symptoms that are similar to schizophrenia, suggesting that chronic METH induced psychosis may be associated with similar brain pathology to schizophrenia in the PFC. The aim of this study, therefore, was to examine mRNA expression of interneuron markers across two regions of the PFC (prelimbic (PRL) and orbitofrontal cortices (OFC)) following METH sensitization, an animal model of METH psychosis. We also studied the association between GABA mRNA expression and interneuronal mRNA expression to identify whether particular changes to the GABA network could be localized to a specific inhibitory cellular phenotype. METH sensitization increased the transcriptional expression of calbindin, calretinin, somatostatin, cholecyctokinin and vasoactive intestinal peptide in the PRL while parvalbumin, calbindin, cholectokinin and vasoactive intestinal peptide were upregulated in the OFC. Based on our previous findings, we also found significant correlations between GAD67, GAT1 and parvalbumin while GAD67, GAD65 and GAT1 were positively correlated with cholecystokinin in the PRL of METH sensitized rats. Within the OFC, the expression of GABAAalpha1 was positively correlated with somatostatin while GABAAalpha5 was negatively associated with somatostatin and calbindin. These findings suggest that METH sensitization differentially changes the expression of mRNAs encoding for multiple peptides and calcium binding proteins across the PRL and the OFC. Furthermore, these findings support that changes to the GABA network may also occur within specific cell types. These results, therefore, provide the first evidence that METH sensitization mediates differential interneuronal pathology across the PRL and OFC and such changes could have profound consequences on behavior and cognitive output. PMID- 28351549 TI - Atrial fibrillation that wasn't. PMID- 28351550 TI - Mind the gap. AB - We present a case of a woman with an asymptomatic intermittent 2:1 atrioventricular block. The baseline ECG showed a wide QRS with right bundle branch block pattern. Measurement of the HV interval during electrophysiological study was normal. During electrophysiological stimulation, a unique pattern of paradoxical conduction was seen. We discuss the mechanism of the paradoxical conduction. PMID- 28351551 TI - Effect of nocturnal sound reduction on the incidence of delirium in intensive care unit patients: An interrupted time series analysis. AB - INTRODUCTION: Delirium in critically-ill patients is a common multifactorial disorder that is associated with various negative outcomes. It is assumed that sleep disturbances can result in an increased risk of delirium. This study hypothesized that implementing a protocol that reduces overall nocturnal sound levels improves quality of sleep and reduces the incidence of delirium in Intensive Care Unit (ICU) patients. METHODS: This interrupted time series study was performed in an adult mixed medical and surgical 24-bed ICU. A pre intervention group of 211 patients was compared with a post-intervention group of 210 patients after implementation of a nocturnal sound-reduction protocol. Primary outcome measures were incidence of delirium, measured by the Intensive Care Delirium Screening Checklist (ICDSC) and quality of sleep, measured by the Richards-Campbell Sleep Questionnaire (RCSQ). Secondary outcome measures were use of sleep-inducing medication, delirium treatment medication, and patient perceived nocturnal noise. RESULTS: A significant difference in slope in the percentage of delirium was observed between the pre- and post-intervention periods (-3.7% per time period, p=0.02). Quality of sleep was unaffected (0.3 per time period, p=0.85). The post-intervention group used significantly less sleep inducing medication (p<0.001). Nocturnal noise rating improved after intervention (median: 65, IQR: 50-80 versus 70, IQR: 60-80, p=0.02). CONCLUSIONS: The incidence of delirium in ICU patients was significantly reduced after implementation of a nocturnal sound-reduction protocol. However, reported sleep quality did not improve. PMID- 28351552 TI - Transformation dynamics of Ni clusters into NiO rings under electron beam irradiation. AB - We report the transformation of nickel clusters into NiO rings by an electron beam induced nanoscale Kirkendall effect. High-purity nickel clusters consisting of a few thousand atoms have been used as precursors and were synthesized with the superfluid helium droplet technique. Aberration-corrected, analytical scanning transmission electron microscopy was applied to oxidise and simultaneously analyse the nanostructures. The transient dynamics of the oxidation could be documented by time lapse series using high-angle annular dark field imaging and electron energy-loss spectroscopy. A two-step Cabrera-Mott oxidation mechanism was identified. It was found that water adsorbed adjacent to the clusters acts as oxygen source for the electron beam induced oxidation. The size-dependent oxidation rate was estimated by quantitative EELS measurements combined with molecular dynamics simulations. Our findings could serve to better control sample changes during examination in an electron microscope, and might provide a methodology to generate other metal oxide nanostructures. PMID- 28351553 TI - Performance Assessment of Arthroscopic Rotator Cuff Repair and Labral Repair in a Dry Shoulder Simulator. AB - PURPOSE: To evaluate the use of dry models to assess performance of arthroscopic rotator cuff repair (RCR) and labral repair (LR). METHODS: Residents, fellows, and sports medicine staff performed an arthroscopic RCR and LR on a dry model. Any prior RCR and LR experience was noted. Staff surgeons assessed participants by use of task-specific checklists, the Arthroscopic Surgical Skill Evaluation Tool (ASSET), and a final overall global rating. All procedures were video recorded and were scored by a fellow blinded to the year of training of each participant. RESULTS: A total of 51 participants and 46 participants performed arthroscopic RCR and LR, respectively, on dry models. The internal consistency or reliability (Cronbach alpha) using the total ASSET score for the RCR and LR was high (>0.9). One-way analysis of variance for the total ASSET score showed a difference between participants based on year of training (P < .001) for both procedures. The inter-rater reliability for the ASSET score was excellent (>0.9) for both procedures. A good correlation was seen between the ASSET score and the year of training, as well as the previous number of sports rotations. CONCLUSIONS: The results of this study show evidence of construct validity when using dry models to assess performance of arthroscopic RCR and LR by residents. CLINICAL RELEVANCE: The results of this study support the use of arthroscopic simulation in the training of residents and fellows learning arthroscopic shoulder surgery. PMID- 28351554 TI - What Makes a Successful Survey? A Systematic Review of Surveys Used in Anterior Cruciate Ligament Reconstruction. AB - PURPOSE: To characterize and assess the methodological quality of patient and physician surveys related to anterior cruciate ligament reconstruction, and to analyze the factors influencing response rate. METHODS: The databases MEDLINE, Embase, and PubMed were searched from database inception to search date and screened in duplicate for relevant studies. Data regarding survey characteristics, response rates, and distribution methods were extracted. A previously published list of recommendations for high-quality surveys in orthopaedics was used as a scale to assess survey quality (12 items scored 0, 1, or 2; maximum score = 24). RESULTS: Of the initial 1,276 studies, 53 studies published between 1986 and 2016 met the inclusion criteria. Sixty-four percent of studies were distributed to physicians, compared with 32% distributed to patients and less than 4% to coaches. The median number of items in each survey was 10.5, and the average response rate was 73% (range: 18% to 100%). In-person distribution was the most common method (40%), followed by web-based methods (28%) and mail (25%). Response rates were highest for surveys targeted at patients (77%, P < .0001) and those delivered in-person (94%, P < .0001). The median quality score was 12/24 (range = 8.5/24 to 21/24). There was high inter rater agreement using the quality scale (intraclass correlation coefficient = 0.92), but there was no correlation with the response rate (Rho = -0.01, P = .97). CONCLUSIONS: Response rates vary based on target audience and distribution methods, with patients responding at a significantly higher rate than physicians and in-person distribution yielding significantly higher response rates than web or mail surveys. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies. PMID- 28351555 TI - Taiwanese Dermatological Association consensus for the prevention and management of epidermal growth factor receptor tyrosine kinase inhibitor-related skin toxicities. AB - BACKGROUND/PURPOSE: This report describes the 2016 consensus of the Taiwanese Dermatological Association (TDA) regarding the definition, classification, diagnosis, prevention, and management of skin toxicities resulting from treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). This consensus is distributed to practices throughout Taiwan to provide recommendations for the diagnosis and treatment of such skin toxicities in order to improve the quality of life of patients undergoing EGFR-TKI treatment. The consensus thus serves as an important reference for dermatologists and other interested clinicians, such as oncologists, throughout Taiwan. METHODS: All the consensus contents were voted on by the participating experts, with approval by no less than 75% required for inclusion. RESULTS: The consensus provides a comprehensive overview of EGFR-TKI skin toxicities, including recent advances in identifying their causes and the processes by which they develop. CONCLUSION: All the consensus meeting attendees agreed that there are several major EGFR-TKI related skin toxicities, including acneiform rash (i.e., papulopustular rash), xeroderma, pruritus, paronychia, stomatitis, mucositis, and hair changes (such as hair loss, slowed hair growth, and trichomegaly). The experts were also generally unanimous in their voting on the specific definitions, onset times, and care suggestions for each of those skin toxicities. Furthermore, the recommended treatment algorithms for the various skin toxicities were ultimately approved by 100% (15/15) of the consensus attendees. PMID- 28351556 TI - Diagnostic value of bronchoalveolar lavage in children with nonresponding community-acquired pneumonia. AB - BACKGROUND: Community-acquired pneumonia (CAP) is a common cause of morbidity and mortality in hospitalized children. In CAP, causative agents are seldom identified using noninvasive diagnostic procedures. For those children not responding to empiric antibiotic therapy, it is vital to identify the causative pathogens for further management. METHODS: We aimed to determine the usefulness of identifying the causative agents by bronchoalveolar lavage (BAL) in hospitalized children with nonresponding CAP. Ninety children hospitalized for CAP and treated with empiric antibiotics but having persistent fever >=48 hours were enrolled, and their BAL data were retrospectively reviewed. RESULTS: Aerobic bacteria were isolated from 38 (42%) of 90 cultures, and anaerobic bacteria were isolated from eight (24%) of 33 cultures. The bacteria isolated most frequently were Streptococcus viridians (26.3%), Pseudomonas aeruginosa (23.7%), and Staphylococcus aureus (15.8%). Streptococcus pneumoniae was isolated from the BALs of only two children, and Haemophilus influenzae from none. For positive aerobic culture results, BAL results guided modifications of antibiotic regimens in 21 episodes (21 of 38, 55.3%). CONCLUSION: BAL results guided a change of antimicrobials in 55% of children with positive aerobic cultures (29% of all children in the study) and contributed to a high rate of successful therapy. PMID- 28351557 TI - A Right Model Provides More Essential Information about the Disease. PMID- 28351558 TI - Coagulation defects in thalassemic patients. AB - BACKGROUND: Regular blood transfusion and compliance with iron chelation therapy has markedly improved life expectancy in thalassemia; however, this improvement is accompanied by several complications of this chronic disease including thromboembolic disorders. The objective of this work is to study natural coagulation inhibition as well as the fibrinolysis processes in thalassemic children who are otherwise in a steady state with no overt clinical manifestations of thromboembolism. METHODS: In a case-control study design conducted at Sohag University Hospital, Sohag, Egypt, 50 thalassemic children and 20 age- and sex-matched healthy controls were compared as regards prothrombin concentration, international normalized ratio, partial thromboplastin time, protein C, protein S, antithrombin III, D-dimers, and thrombin activatable fibrinolysis inhibitor (TAFI). RESULTS: When compared to healthy controls, natural coagulation inhibitors (protein C, protein S, and antithrombin-III) were significantly lower in thalassemic children (p < 0.0001). While D-dimers showed a significant increase in thalassemic children, TAFI was significantly lower (p < 0.0001). Splenectomized thalassemic children showed significantly lower levels of protein C, protein S and TAFI (p < 0.001, p < 0.0001, p < 0.0001, respectively) when compared to nonsplenectomized thalassemic children. CONCLUSION: Significant changes in natural coagulation inhibition and fibrinolysis processes favoring thromboembolism can be detected in otherwise healthy thalassemic children. Because these changes are more pronounced in splenectomized patients, study of primary prophylactic strategies in this subgroup is warranted. PMID- 28351559 TI - Hypoxia induced cognitive impairment modulating activity of Cyperus rotundus. AB - Hypobaric hypoxia leads to decrease in cellular oxygen content which subsequently damages the hippocampus with an increase in brain oxidative stress and impairs the memory of the individual. In the present study, we have evaluated the cognitive impairment modulating activity of total oligomeric flavonoids fraction of Cyperus rotundus (TOF) in Sprague Dawley rats. The rats were trained for memory activity for a period of 7days followed by 7days exposure to 25,000ft. altitude and the spatial reference memory was evaluated. Behavioral analysis of the rats by Morris water maze experiment showed that TOF supplementation enhanced the spatial reference memory activity of the rats exposed to hypobaric hypoxia. The decrease in antioxidant status of the animals exposed to hypoxia was restored with TOF supplementation. The increase in ROS, lipid peroxidation products and protein carbonyls of the hippocampus was significantly decreased in animals with TOF administration. The histological assessment of the pyramidal cells of the hippocampus of hypoxia-exposed animals showed nuclear damage and TOF supplementation prevented nuclear damage. TOF administration suppressed hypoxia induced increase in serotonin, dopamine, and norepinephrine. GABA and Ach levels were decreased by hypoxia which was prevented by TOF supplementation. The increase in GFAP, HIF-1alpha and VEGF expression in CA3 region of the hippocampus in hypoxia-exposed rats was decreased in TOF administered rats. Taken together, TOF extract ameliorates hypobaric hypoxia induced memory impairment and neurodegeneration in hippocampus through its anti-stress effects. PMID- 28351561 TI - Salvage surgery in recurrent head and neck squamous cell carcinoma: Oncologic outcome and predictors of disease free survival. AB - OBJECTIVE: Salvage surgery in recurrent SCCHN is associated with poor outcomes. This study aimed to better identify suitable surgical candidates and those at high risk of new recurrence. MATERIALS AND METHODS: Single-center retrospective analysis of 109 patients undergoing salvage surgery for recurrent SCCHN. Univariate and multivariate analyses were used to identify prognostic factors affecting disease-free survival (DFS). RESULTS: The following factors showed a significant impact on DFS: Disease-free interval >6months [HR 0.53; p=0.04], age>70years [HR 0.26; p=0.03], primary chemoradiotherapy [HR 2.39; p<0.01] compared to radiotherapy, oropharynx [HR 5.46; p<0.01] and hypopharynx [HR 3.92; p=<0.01] sites, compared to larynx, initial stage III [HR 7.10; p<0.01] and stage IV [HR 4.13; p<0.01], compared to stage I, locoregional recurrence [HR 4.57; p<0.01], compared to local recurrence. Univariate analysis also identified significant postoperative predictors of poor DFS including flap reconstruction [HR 3.44; p<0.01], postoperative complications [HR 2.09; p=0.01], positive margins [HR 3.64; p<0.01] and close margins [HR 3.83; p<0.01]. On multivariate analysis, oropharynx site [HR 3.98; p<0.01], initial stage III [HR 5.93; p<0.01] and locoregional recurrence [HR 2.93; p=0.04] were independent preoperative prognostic factors for DFS. Positive margins [HR 2.32; p=0.04], close margins [HR 2.94; p=0.02], extracapsular spread (ECS) [HR 4.04; p=0.03] and postoperative complications [HR 3.64; p<0.01] were independent postoperative prognostic factors. CONCLUSIONS: Patients with advanced primary nonlaryngeal tumor and locoregional recurrence have limited success with salvage surgery. Because patients with positive margins and ECS are at high risk of relapse, adjuvant treatment should be discussed. PMID- 28351560 TI - Chronic salt-loading reduces basal excitatory input to CRH neurons in the paraventricular nucleus and accelerates recovery from restraint stress in male mice. AB - Neurons synthesizing corticotrophin-releasing hormone (CRH) in the paraventricular nucleus of the hypothalamus (PVN) are activated during acute stress and act via the hypothalamic-pituitary-adrenal (HPA) axis to increase systemic levels of corticosterone (CORT). Recent data indicates that CRH neurons in the PVN are inhibited by acute salt-loading, and that this inhibition blunts the response to restraint stress as measured by increases in plasma CORT. The current study evaluates the effects of chronic rather than acute salt-loading on stress-induced activation of the HPA axis. Relative to euhydrated controls, chronic salt-loading over a 5-day period elevated plasma sodium and fluid intake without eliciting hypovolemia or substantial alterations in food intake or body weight. Chronic salt-loading also decreased expression of CRH mRNA in the anterior but not posterior portion of the PVN. Similarly, whole cell patch clamp recordings revealed that salt-loading effectively decreases spontaneous excitatory input to CRH neurons in the PVN without altering spontaneous inhibitory input. Generally consistent with these observations, chronic salt attenuated HPA axis activation as indicated by a significant reduction of plasma CORT during recovery from restraint stress. PMID- 28351562 TI - Prospective evaluation of Intensity Modulated Radiation Therapy with Simultaneous Integrated Boost (IMRT-SIB) in head and neck squamous cell carcinoma in patients not suitable for chemo-radiotherapy. AB - BACKGROUND: With conformal radiotherapy techniques, acute and late toxicities can be reduced because of better dose conformity and reduced doses to normal tissue. With Intensity Modulated Radiation Therapy (IMRT) further dose escalation is possible and one of the methods is IMRT with simultaneous integrated boost (IMRT SIB). AIM: To evaluate feasibility, toxicity patterns and loco-regional control rates of IMRT-SIB technique in head and neck cancer patients who are not suitable candidates for concurrent chemoradiation. STUDY DESIGN: Prospective study of 30 patients treated with IMRT-SIB technique and evaluation of clinical results. METHOD AND MATERIALS: 30 patients received definitive treatment using IMRT-SIB without concurrent chemotherapy. Patients were monitored during and after treatment for toxicity using the Radiation Therapy Oncology group (RTOG) criteria. Analysis of acute and late toxicity and early efficacy is presented. RESULTS: The median treatment duration was 42days (range 41-43days). Overall, maximum acute Grade 3 toxicity of mucositis, skin, pharynx/esophageal toxicity and laryngeal were 56.66%, 30%, 26.67%, and 6.67% respectively at treatment completion. None of the patients had Grade 4 acute toxicity. No haematological toxicity was seen. Overall, grade 2 late toxicities were 7% (subcutaneous toxicity) and 13.3% (Xerostomia). Loco regional control rate at a median follow up of 13months was 86%. CONCLUSION: IMRT-SIB is a safe and acceptable treatment option for patients of head and neck squamous cell carcinoma unsuitable for definitive chemo-radiotherapy. PMID- 28351563 TI - Sensitivity of tumor surface brushings to detect human papilloma virus DNA in head and neck cancer. AB - OBJECTIVE: Human papilloma virus (HPV) induced head and neck squamous cell carcinoma (HNSCC) represents a distinct tumor subset. We questioned how accurately a brushing from the tumor surface detects HPV in patients with HNSCC. MATERIALS AND METHODS: Brushings from the tumor surface were compared with HPV DNA isolation from formalin-fixed and paraffin-embedded (FFPE) tumor biopsies, which served as the reference standard. In both matrices, HPV DNA was detected using a commercially available test kit. In addition, p16 was assessed in tumor biopsies by immunohistochemistry (IHC). The tumors were considered p16 positive if 70% or more of cancer cells expressed p16. RESULTS: 93 patients with HNSCC were included. Sensitivity and specificity of the brush test were 83% (95%CI: 67 92%) and 85% (95%CI: 72-93%). Results of p16 IHC were concordant with FFPE samples DNA determinations in 73/93 patients. In 53 patients (57%) the tumor was located in the oropharynx and in 40 patients (43%) the tumor was located in the non-oropharynx region. Sensitivity and specificity of the brush test in patients with oropharyngeal cancer was higher with 86% (95%CI: 70-95%) and 89% (95%CI: 65 99%). CONCLUSION: Superficial brushes from the tumor surface may be used to identify HPV positive HNSCC. PMID- 28351564 TI - Role of cancer stem-cell marker doublecortin-like kinase 1 in head and neck squamous cell carcinoma. AB - BACKGROUND: So far, no data is available on the role of the tumor stem cell marker doublecortin-like kinase 1 (DCLK1) in head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to evaluate DCLK1 expression in HNSCC patients that underwent surgery and postoperative radiotherapy, and to assess its potential as a therapeutic target in vitro. METHODS: We immunohistochemically stained for DCLK1 in 127 sections of HNSCC samples obtained during surgery of HNSCC patients and correlated the expression to patients' overall- and disease-free survival, as well as human papilloma virus (HPV) status. Additionally, we compared our survival data with data obtained from The Cancer Genome Atlas (TCGA). The effects of the DCLK1 inhibitor LRRK-2-in-1 on HNSCC cell lines alone and in combination with irradiation. RESULTS: Expression of DCLK1 in 127 patients was associated with poor survival. In particular, DCLK1 expression had a significant impact on survival of oropharyngeal carcinoma patients. Specifically, DCLK1+/HPV- patients had the worst prognosis after simultaneous assessment of DCLK1 and HPV status in comparison to the other three possible DCLK1/HPV constellations. Higher levels of DCLK1 mRNA were also associated with poor clinical outcome. Inhibition of DCLK1 in our HNSCC cell lines led to growth arrest and induction of apoptosis. The combination of DCLK1 inhibition with irradiation had a synergistic effect. CONCLUSION: Firstly, DCLK1 is a prognostic biomarker for shortened survival. Secondly, through inhibition of DCLK1, it may serve as a therapeutic target as well. PMID- 28351565 TI - New drug development in head and neck squamous cell carcinoma: The PI3-K inhibitors. AB - Over the last few years a number of new different compounds have been developed. They include phosphatidylinositol 3-kinase (PI3-K) inhibitors. Deregulation within the PI3-K pathway is common in head neck squamous cell carcinoma (HNSCC) and it represents a growing area of research. PI3-K inhibitors, including BKM120, PX-866 and BYL719, are being tested in several phase I and phase II studies in patients with locally advanced, recurrent or metastatic disease. This review provides an update of published clinical trials and highlights the challenges of PI3-K inhibitors in HNSCC. PMID- 28351566 TI - MicroRNAs in human tongue squamous cell carcinoma: From pathogenesis to therapeutic implications. AB - Being one of the most aggressive cancers of oral cavity, tongue squamous cell carcinoma (TSCC) constitutes 41% of all oral carcinomas. Despite considerable improvements in multimodal diagnosis and treatment techniques, TSCC still remains to be one of the most lethal cancer types in the head and neck region. MicroRNAs are endogenously synthesized, small, non-coding RNAs, which are responsible for post-transcriptional regulation of mRNA expression. They are involved in regulation of almost all biological processes through their spatial and temporal expression. Their deregulation participates in pathogenesis of various diseases, including human TSCC, where they can act as potent oncogenes or tumor suppressors. Extensive microRNA profiling in TSCC samples and further in vitro and in vivo functional characterization of differentially expressed microRNAs revealed their contribution to the underlying molecular mechanisms of TSCC initiation, development, progression, metastasis, chemo-radioresistance, and recurrence. They are suggested as diagnostic and prognostic biomarkers for TSCC due to their differential expression in tumor tissues and their stability in body fluids like plasma, oral cytology, and saliva. MicroRNAs are, therefore, considered amongst the most promising candidates for development of novel therapeutic approaches against TSCC. In this review, we summarized important findings including our own works on microRNAs as implicated in TSCC and the new insights into the roles of microRNAs in squamous cell carcinoma of tongue. PMID- 28351567 TI - Clonal analysis as a prognostic factor in multiple oral squamous cell carcinoma. AB - OBJECTIVES: A novel classification based on molecular methods to assess clonality defines three types of secondary oral squamous cell carcinoma (OSCC): second primary tumour (SPT) independent from the index tumour, local recurrence (LR), clonally related to the primary tumour, and second field tumour (SFT), derived from the same genetically altered mucosal field as the primary tumour. The present study applied mtDNA analysis in a group of patients experiencing a second loco-regional neoplastic manifestation. The purpose was to differentiate secondary tumours into LRs, SPTs and SFTs and evaluate the prognostic impact in terms of survival rate. MATERIAL AND METHODS: The study population comprised 23 patients who experienced a second neoplastic lesion after a surgical resection of primary OSCC. mtDNA D-loop analysis was applied in paired neoplastic lesions and in clinically and histologically normal mucosa. On the basis of mtDNA results, the second OSCC was classified as LR or SPT or SFT. Disease-free survival was defined as the duration between the appearance of the second neoplastic lesion and death of disease, or last follow-up visit. RESULTS: Seven secondary tumours were classified as LR, 12 as SFT, 4 as SPT. An altered mucosal field proved a variable significantly related to a better survival rate (p<0.05); 2/12 (16.6%) SFT events failed as compared to 5/7 LRs (71.4%) and 3/4 SPTs (75%). CONCLUSION: mtDNA analysis may be considered a useful tool to differentiate secondary tumours and might influence the choice of the most appropriate treatment in patients with multiple OSCCs. PMID- 28351568 TI - Is there an increased risk of cancer among spouses of patients with an HPV related cancer: A systematic review. AB - BACKGROUND: High-risk human papillomaviruses (HR-HPV) are the cause of most ano genital cancers and a fast growing subset of oropharyngeal cancer. As these malignancies occur as a result of an HPV- infection transmitted through intimate contact, many patients with HPV- induced cancer and their partners are concerned about HPV-transmission and the potential partners' cancer risk. Few studies have addressed this issue and whether the HPV-related cancer risk of partners of patients with HPV-related cancers is comparable to or greater than that of the general population. METHODS: We performed a systematic review of the published literature addressing this issue. Out of 1055 references screened, 53 articles were found eligible for inclusion. RESULTS: Regarding the issue of coincidence of HPV-induced oropharyngeal and/or anogenital cancers in couples, 13 case-reports or case-series were reported and 9 larger studies based on population-registries. Four of these registry studies showed an increased risk of cervical cancer in the partner while four did not. Among the four positive studies, odds ratios for the development of HPV-related cancer among spouses were between 2.6 and 6.7. One study showed an increased risk of tongue or tonsil cancer among husbands of women with cervical dysplasia or cancer. Overall the absolute risk increase in all these studies was small, on the order of 1-3%, although potentially underestimated. Indeed, all these studies have assessed partner's cancer risk at only one anatomical site whereas HPV- related malignancies can affect different locations. CONCLUSION: This systematic review suggests a small trend of increase risk in HPV-associated cancers among spouses of patients with HPV-related cancer. PMID- 28351569 TI - Rising incidence of oral tongue cancer among white men and women in the United States, 1973-2012. AB - BACKGROUND: Despite significant reductions in tobacco use in the US, oral tongue cancer incidence has reportedly increased in recent years, particularly in young white women. We conducted age-period-cohort analyses to identify birth cohorts that have experienced increased oral tongue cancer incidence, and compared these with trends for oropharyngeal cancer, a cancer caused by human papillomavirus (HPV) that has also recently increased. METHODS: We utilized cancer incidence data (1973-2012) from 18 registries maintained by the NCI SEER Program. Incidence trends were evaluated using log-linear joinpoint regression and age-period-cohort modeling was utilized to simultaneously evaluate effects of age, calendar year, and birth year on incidence trends. RESULTS: Incidence of oral tongue cancer increased significantly among white women during 1973-2012 (0.6% annual increase, p<0.001) and white men during 2008-2012 (5.1% annual increase, p=0.004). The increase was most apparent among younger white individuals (<50years; annual increase of 0.7% for men [p=0.02] and 1.7% for women [p<0.001] during 1973-2012). Furthermore, the magnitude of the increase during 1973-2012 was similar between young white men and women (2.3 vs. 1.8 cases per million, respectively). Incidence trends for oropharyngeal cancer were similar to trends for oral tongue cancer and similar birth cohorts (born after the 1940s) experienced rising incidence of these cancers (p-value: white men=0.12, white women=0.42), although the magnitude of increase was greater for oropharyngeal cancer. CONCLUSIONS: The incidence of oral tongue and oropharyngeal cancer has significantly increased among young white men and women within the same birth cohorts in the US. PMID- 28351570 TI - Topical agents for oral cancer chemoprevention: A systematic review of the literature. AB - OBJECTIVES/HYPOTHESIS: We review the use of topical chemoprevention agents in patients with oral potentially malignant disorders (PMD). METHODS: A systematic review of studies on topical chemoprevention agents for oral PMD from 1946 to November 2016 was conducted using the MEDLINE database, Embase, and Cochrane Library. Data were extracted and analyzed from selected studies including study type, sample size, demographics, treatment length, response rate, follow-up time, adverse effects, and recurrence. RESULTS: Of 108 studies, twenty-four, representing 679 cases met the inclusion criteria. The clinical lesions evaluated included oral leukoplakia, erythroplakia (OEL), verrucous hyperplasia (OVH), oral lichen planus, larynx squamous cell carcinoma, and oral squamous cell carcinoma (OSCC). The mean complete response rate for topical retinoid therapy was 32%. The mean complete response rate for 1% bleomycin therapy and 0.5% bleomycin was 40.2% and 25%, respectively. The complete response rate of OVH, OEL, and OSCC to photodynamic therapy ranged from 66.7% to 100%. CONCLUSION: There are a paucity of data examining topical treatment of oral PMDs. However, the use of topical agents among patients with oral lesions may be a viable complement or even alternative to traditional surgery, radiation, or systemic chemotherapy, with the advantage of reducing systemic side effects and sparing important anatomic structures. This study of 679 cases represents the largest pooled sample size to date, and the preliminary studies in this systematic review provide support for further inquiry. PMID- 28351571 TI - Complications following transoral robotic surgery (TORS): A detailed institutional review of complications. AB - OBJECTIVES: To report the complications occurring following TORS and to identify the factors predictive of complications. METHODS: Following IRB approval a retrospective analysis of all TORS operations at our institution was performed. Postoperative complications within 45days were collected and graded with the Clavien-Dindo system. Complications were categorized into groups: all complications, not related to TORS and TORS related. Unadjusted odds ratios were calculated to test association between patients with and without a complication. RESULTS: 122 TORS operations were carried out between June 2010 and August 2015. 77% were male, with a median age of 57. There were 92 primary tumor resections, 10second head and neck primary resections, 13 salvage procedures and 7 other indications. Surgical resection involved 1, 2 or >3 sub-sites in 36%, 28% and 36% patients, respectively. Overall, there were 107 complications (66 TORS related, 41 non-TORS related) that occurred in 57 patients (47%). A major complication occurred in 23 patients (18%). 19 patients had a TORS related major complication and 6 patients experienced a non-TORS related major complication. There was a temporal trend in TORS related major complication rate decreasing from 33% in 2010 to 10% in 2015. Statistical analysis showed that the odds of having any complication were 3 times greater in patients over 60years old (p=0.017), and 2.5 times greater when there were more than 2 subsites resected (p=0.022). CONCLUSIONS: Age over 60years and a larger extent of resection were the significant factors predictive of major complications. PMID- 28351572 TI - Combining cetuximab with chemoradiotherapy in patients with locally advanced nasopharyngeal carcinoma: A propensity score analysis. AB - OBJECTIVE: To compare the effectiveness of concurrent cisplatin chemoradiotherapy plus cetuximab with that of concurrent chemoradiotherapy (CCRT) alone in locoregionally advanced nasopharyngeal carcinoma (LRANPC) patients. MATERIALS AND METHODS: A total of 3257 LRANPC patients from a prospectively maintained database were included in this observational study to examine the effectiveness of adding cetuximab to CCRT. We compared overall survival (OS), disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) using the propensity score method. RESULTS: In this cohort, 131 patients received CCRT plus cetuximab. Cetuximab-treated patients were more likely to receive intensity-modulated radiation therapy and were less likely to receive induction chemotherapy or adjuvant chemotherapy. The addition of cetuximab was associated with increased DMFS compared with CCRT alone based on univariable and multivariable analyses (5-year OS, 94.1% vs. 87.3%; P=0.044), but not with increased OS, DFS, or LRRFS. Propensity score matching identified 96 patients in each cohort and confirmed that a DMFS benefit was associated with the addition of cetuximab (HR, 0.38; 95% CI, 0.15-0.99, P=0.044). Subgroup analyses demonstrated a significant DMFS benefit with CCRT plus cetuximab in patients with N2-N3 stage disease compared with N2-N3 patients receiving CCRT alone (87.9% and 66.2%, respectively; P=0.045). CONCLUSIONS: In conclusion, the addition of cetuximab to first-line chemoradiotherapy is associated with an improvement in DMFS in patients with LRANPC. A prospective randomized clinical trial will be necessary to validate this result. PMID- 28351573 TI - Head and neck lymphomas: A 20-year review in an Oral Pathology Unit, Johannesburg, South Africa, a country with the highest global incidence of HIV/AIDS. AB - OBJECTIVES: Non-Hodgkin lymphoma occurs with increasing frequency in HIV/AIDS. As South Africa has the highest incidence of HIV/AIDS worldwide, an epidemiologic study of this nature provides insight into head and neck lymphomas in a defined South African population. This retrospective review evaluated frequency and clinico-pathologic characteristics of patients diagnosed with head and neck lymphoma at the Oral Pathology Department, University of Witwatersrand between 1993 and 2012. MATERIALS AND METHODS: Histopathology reports of patients with head and neck lymphomas (n=504) were reviewed. Demographic (age, gender), clinical (site and size of tumour), laboratory and histological parameters were recorded. RESULTS: There were 504 patients with head and neck lymphomas. The mean age was 40.4years. The male:female ratio was 1.1:1. The cervical lymph node was the most common anatomic site (115 cases) and the maxilla (60 cases) the most common extranodal site. Plasmablastic lymphoma (159 cases) was the most common histologic subtype, seen more frequently as a result of its strong association with HIV/AIDS. The most common Hodgkin's lymphoma was the nodular sclerosing variant (21 cases). Of the head and neck lymphomas in patients with a known HIV status, 56% had plasmablastic lymphoma, 43.9% diffuse large B cell lymphoma and 25% Burkitt lymphoma. CONCLUSION: There is an increase in head and neck lymphoma frequency, contrary to that found in Western countries. The high HIV prevalence in certain lymphomas provides strong indication of the role of HIV/AIDS in pathogenesis of lymphomas. This study serves as a baseline for future studies, especially in South Africa. PMID- 28351574 TI - The impact of time to treatment initiation on survival from head and neck cancer in north-eastern Italy. AB - OBJECTIVES: To evaluate the impact of time to treatment initiation (TTI) on overall survival in patients with head-and-neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: In the period 2003-2009, 1616 HNSCC patients were diagnosed in Friuli Venezia Giulia Region, Northeastern Italy, including 462 oral, 346 oropharyngeal, 212 hypopharyngeal, and 596 laryngeal cancers. Clinical information, including date and type of first treatment, and follow-up were retrieved from the regional Cancer Registry and a population-based health database collecting comprehensive health information on people living in the Region. Multivariate hazard ratio (HR) and confidence intervals (CI) were calculated through Cox model. RESULTS: Overall, the median TTI was 28days, (Q1 Q3: 13-45days), but significant variations emerged according to anatomical site, cancer stage, treatment approach, and care transition to specialized centers. Five-year overall survival decreased with increasing treatment delay from 62% for TTI<30days to 39% for TTI>=90days (p<0.01). HR of death was 1.13 (95% CI: 0.92 1.39) for TTI between 45-89days, and 1.47 (1.05-2.05) for TTI>=90days. The association between TTI and poor prognosis was stronger for laryngeal cancers and early-stage HNSCCs. Further, care transition from community hospitals to specialized centers was associated to a better prognosis (HR=0.73; 95% CI: 0.60 0.88). CONCLUSION: Our study findings suggest that HNSCC patients treated within 45days from diagnosis have increased survival probabilities and that early-stage patients suffered the most from treatment delay. Furthermore, care transition to specialized centers -though competitive to timely treatment- improves survival by providing the most innovative technologies and treatment approaches. PMID- 28351575 TI - High stromal Foxp3-positive T cell number combined to tumor stage improved prognosis in head and neck squamous cell carcinoma. AB - OBJECTIVES: Head and neck squamous cell carcinomas (HNSCC), one of the most frequent cancers in the world, are largely infiltrated by inflammatory immune cells. Our aim was to evaluate the number of Foxp3+ T cells in HNSCC, reporting its prognostic power in comparison to other risk factors. MATERIAL AND METHODS: Our clinical series was composed of 21 tumor-free peri-tumoral epithelia, 49 low grade dysplasia, 43 high grade dysplasia and 110 carcinoma samples including some cases with HPV infection. In vivo experiments were conducted on 80 C3H/HeN mice which were orthotopically injected with SCCVII CT, E7, E6 and E6/E7 cell lines. RESULTS: Foxp3+ T cell infiltration increased with tumor progression from normal epithelia, dysplasia to carcinoma and the increase is more important in HPV+ patients than in negative ones. Animal experiments revealed that E7 oncoprotein expression was significantly associated with an increase in Foxp3+ T cell recruitment in tumor, a delay in tumor onset and improved animal survival. Univariate Cox regression analyses demonstrated that high Foxp3+ T cell number in stromal compartment is associated with longer patient recurrence-free and overall survivals. Foxp3+ T cell number improved the prognostic value of tumor stage. Multivariate analyses reported that stromal Foxp3+ T cell number is a strong prognostic factor independent of classical risk factors such as tobacco, alcohol, and HPV status. CONCLUSION: Foxp3+ T cell number is a significant prognostic factor for HNSCC, improving the tumor stage, and that viral E7 may play a role in the Foxp3+ T cell infiltration to the tumor. PMID- 28351576 TI - Clinical features of ectomesenchymal chondromyxoid tumors: A systematic review of the literature. AB - Ectomesenchymal chondromyxoid tumors are rare, benign neoplasms of the head and neck most commonly found within the oral cavity. While histopathological evaluation has been the primary focus of prior studies, clinical characterization of this rare entity currently remains sparse. Thus, this study was performed to provide insights into the clinical characteristics of ectomesenchymal chondromyxoid tumors to aid clinicians in distinguishing the lesion from other benign and malignant processes for a more accurate diagnosis and treatment. Moreover, this study includes a unique case of ectomesenchymal chondromyxoid tumor arising in the base of tongue, now the fourth to arise at that anatomic site. Including this case, a systematic review of the literature identified only 60 individual cases reported thus far. This study provides a detailed analysis of all 60 cases including demographics, clinical presentation, radiographic imaging, follow-up, and recurrence rate. PMID- 28351577 TI - High-dose versus weekly cisplatin definitive chemoradiotherapy for HPV-related oropharyngeal squamous cell carcinoma of the head and neck. AB - OBJECTIVES: To compare the outcomes and toxicity of high-dose cisplatin (HDC) versus weekly cisplatin (WC) definitive chemoradiotherapy (CRT) for patients with human papillomavirus (HPV) related oropharyngeal squamous cell carcinoma (SCCOPx). METHODS: All patients with p16 positive SCCOPx treated with definitive CRT with cisplatin between 2010 and 2014 at a single institution were retrospectively reviewed. CTCAE v 4.03 toxicity criteria were used. The Kaplan Meier method was used to estimate event-free survival (EFS) and the overall survival (OS). RESULTS: Of the 55 patients included, 22 were patients treated with HDC at dose of 100mg/m2 on days 1 and 22; and the remaining 33 patients were treated with WC at 40mg/m2. Both cohorts received a median total dose of cisplatin of 200mg/m2. At median follow-up of 31months, there was one local failure and no distant failures in the HDC cohort. In the WC group, there were 6 total failures (2 local, 4 distant). Estimated 2-year EFS was better in HDC cohort as compared to WC (96% vs. 75%; p=0.04). There was no significant difference in 2-year OS (95% vs. 94%; p=0.40). Weight loss, gastric tube dependence at six months, acute renal injury and grade 3 or 4 hematological toxicity were all similar between both groups. CONCLUSIONS: HPV-related SCCOPx treated with definitive CRT with either HDC or WC had similar toxicity profile. HDC had better EFS when compared with WC and this seems to be driven by increased distant failure rates, although the OS was similar. PMID- 28351578 TI - Oropharyngeal cancer prognosis by tumour HPV status in France: The multicentric Papillophar study. AB - AIMS: To evaluate the impact of human papillomavirus (HPV) status, tobacco smoking and initial treatment approach on progression-free survival (PFS) and overall survival (OS) for oropharyngeal cancer (OPC) in France, a country where smoking declines started late (1990s). METHODS: 340 OPC patients (median age: 60years) from 14 French hospitals were followed up (median 26.7months). PCR-based positivity for both HPV DNA and E6/E7 mRNA was used to distinguish HPV-positive OPC (27.1%). Hospital-stratified hazard ratios (HR) and corresponding 95% confidence intervals (CI) were used to compare PFS and OS according to HPV and other prognostic factors in hospital-stratified unadjusted and multivariate models. The combined effect of HPV status with either smoking, stage, or initial treatment on PFS was also evaluated. RESULTS: PFS in multivariate analysis was better in HPV-positive patients (HR=0.42; 95% CI: 0.24-0.73) and worse in older patients (HR for 5-year age increase=1.12) and those having had firstly radiotherapy (HR=1.86; 95% CI: 1.19-2.92) or induction chemotherapy (HR=1.73; 95% CI: 1.08-2.79) instead of upfront surgery. Findings for OS were similar. Loco regional recurrences were less frequent in HPV-positive (10.5%) than HPV-negative patients (26.0%) but distant recurrences were similarly frequent. HPV status did not modify the influence of smoking or stage on PFS but the impossibility to perform upfront surgery may be more relevant for HPV-negative patients. CONCLUSIONS: HPV-positive OPC patients fare better than HPV-negative OPC and may benefit from toxicity-sparing. Whether HPV-negative patients responded less well to radiation and chemotherapy because of more severe genomic damage or bulkier tumours is unclear. PMID- 28351579 TI - Validation of published nomograms and accordingly individualized induction chemotherapy in nasopharyngeal carcinoma. AB - OBJECTIVES: We have attempted to validate two published nomograms in nasopharyngeal carcinoma (NPC) and individualize induction chemotherapy (IC) accordingly. MATERIALS AND METHODS: From 2007 to 2011, 920 patients were included in the study. The validity of the nomograms was assessed by Harrell's concordance index (C-index), areas under the curve (AUC), and calibration curves. Disease free survival (DFS) and overall survival (OS) by IC were evaluated in and out of risk stratified patients with and without propensity score matching analysis. RESULTS: Compared with the 7th edition of the Union for International Cancer Control (UICC) staging system, Tang's nomogram better discriminated DFS (C-index 0.629 versus 0.569, P=0.002; AUC 0.635 versus 0.576, P=0.018), whereas Yang's nomogram had no advantage in predicting OS (C-index 0.648 versus 0.606, P=0.184; AUC 0.643 versus 0.604, P=0.157). Calibration curves indicated good agreement between predicted and observed DFS or OS probability. Without risk stratification, patients achieved no benefit from IC in DFS (P?0.101) or OS (P?0.370). However, among 580 high-risk patients stratified by Tang's nomogram, IC improved five-year DFS from 68.8 to 74.8% (P=0.072), and OS from 82.6 to 87.9% (P=0.065), and the improvement of DFS and OS increased to 9.3% (P=0.019) and 7.3% (P=0.036), respectively, in 426 propensity-matched patients. CONCLUSIONS: Tang's nomogram helps to stratify stage III-IVa-b NPC, and IC is beneficial to high-risk patients in clinical practice. PMID- 28351580 TI - Re-irradiation for recurrent and second primary cancers of the head and neck. AB - PURPOSE: To evaluate a single-institutional experience with the use of re irradiation for recurrent and new primary cancers of the head and neck. METHODS: The medical charts of 80 consecutive patients who underwent re-irradiation for local-regionally recurrent or second primary head and neck cancer between November 1998 and December 2015 were analyzed. Multivariate analysis was performed using Cox proportional hazard and logistic regression to determine predictors of clinical outcomes. RESULTS: Seventy-six of the 80 patients were evaluable. The median age was 57.5 (range 26.6-84.9); Intensity-modulated radiotherapy (IMRT) was used in 71 (93.4%) patients with a median dose of 60Gy. Thirty-one patients (40.8%) underwent salvage surgery before re-irradiation and 47 (61.8%) received concurrent systemic therapy. The median time interval between radiation courses was 25.3months (range 2-322months). The 2-year estimates of overall survival, progression free survival, locoregional control, and distant control were 51.0%, 31.3%, 36.8% and 68.3%, respectively. Patients who underwent salvage surgery prior to re-irradiation had significantly improved locoregional control, progression free survival, and overall survival (p<0.05, for all). On multivariate analysis, gross tumor volume (GTV) at re-irradiation and interval between radiation courses were associated with improved overall survival. Severe (grade?3) late complications were observed in 25 patients (32.8%). CONCLUSIONS: Re-irradiation for recurrent or second primary head and neck cancer is feasible and effective in select patients with head and neck cancer. The high observed rate of treatment-related morbidity highlights the continue challenges that accompany this approach. PMID- 28351581 TI - Characterization of PD-L1 expression and immune cell infiltration in nasopharyngeal cancer. AB - OBJECTIVES: Locally recurrent or metastatic nasopharyngeal cancer (NPC) remains an important challenge, with more effective and durable therapeutic options needed. Cancer immunotherapy, and in particular therapies that target the PD L1/PD-1 immune checkpoint pathway, may provide new options to treat NPC patients. This study evaluated PD-L1 and CD8 expression levels and the respective associations with clinical and histopathological characteristics of patients with NPC. MATERIALS AND METHODS: Diagnostic tumour biopsies were obtained before radical radiotherapy with or without chemotherapy from 161 patients with NPC. These biopsies were analysed for PD-L1 expression levels on tumour cells (TC) and tumour-infiltrating immune cells (IC), and for CD8 T-cell infiltration. Results were correlated with baseline characteristics and clinical outcomes with standard of-care treatment regimens. Additionally, pre- and post-treatment-paired tumour samples were analysed (n=146). RESULTS: 75% of tumours expressed PD-L1 on IC and 24% on TC. Baseline clinical characteristics of stage, sex and age did not correlate with PD-L1 expression. Additionally, overall survival and progression free survival of standard-of-care treatment did not correlate with baseline PD-L1 expression. CD8 levels did correlate with clinical outcomes; however, results were confounded by other baseline characteristics. After treatment, PD-L1 expression dropped a median of 1.5% on IC and a median of 2.75% on TC. Median CD8 expression dropped 1.9%. CONCLUSIONS: Majority of NPC biopsy samples demonstrated PD-L1 expression on ?1% of IC, with fewer expressing PD-L1 on TC. In contrast to previous smaller studies, no prognostic value was observed for PD-L1 expression levels in patients with NPC. PMID- 28351582 TI - Defining an inflamed tumor immunophenotype in recurrent, metastatic squamous cell carcinoma of the head and neck. AB - OBJECTIVES: Immune checkpoint inhibitors have demonstrated clinical benefit in recurrent, metastatic (R/M) squamous cell carcinoma of the head and neck (SSCHN), but lacking are biomarkers that predict response. We sought to define an inflamed tumor immunophenotype in this R/M SCCHN population and correlate immune metrics with clinical parameters and survival. METHODS: Tumor samples were prospectively acquired from 34 patients to perform multiparametric flow cytometry and multidimensional clustering analysis integrated with next-generation sequencing data, clinical parameters and outcomes. RESULTS: We identified an inflamed subgroup of tumors with prominent CD8+ T cell infiltrates and high PD-1/TIM3 co expression independent of clinical variables, with improved survival compared with a non-inflamed subgroup (median overall survival 84.0 vs. 13.0months, p=0.004). The non-inflamed subgroup demonstrated low CD8+ T cells, low PD-1/TIM3 co-expression, and higher Tregs. Overall non-synonymous mutational burden did not correlate with response to PD-1 blockade in a subset of patients. CONCLUSION: R/M SCCHN patients with an inflamed tumor immunophenotype demonstrate improved survival. Further prospective studies are needed to validate these findings and explore the use of immunophenotype to guide patient selection for immunotherapeutic approaches. PMID- 28351583 TI - Candidate apoptotic and DNA repair gene approach confirms involvement of ERCC1, ERCC5, TP53 and MDM2 in radiation-induced toxicity in head and neck cancer. AB - INTRODUCTION: Single nucleotide polymorphisms (SNPs) of DNA repair and apoptosis genes have been associated with outcome in head and neck squamous cell carcinoma (HNSCC) patients receiving radiotherapy (RT). Our goal was to conduct a candidate gene study in HNSCC patients receiving RT or chemoRT. METHODS: 122 non-resectable HNSCC patients undergoing RT (N=38) or chemoRT (N=84) between 1992 and 2006 were retrospectively analyzed. ERCC1 Lys259Thr (rs735482), ERCC2 Lys751Gln (rs13181), ERCC5 His46His C>T (rs1047768), XRCC1 Arg399Gln (rs25487), TP53 Arg72Pro (rs1042522) and MDM2 309T>G (rs2279744) were analyzed on tumor DNA. SNP profile was considered to assess RT-related toxicity. RESULTS: All 120 evaluable patients experienced RT-related toxicity at any time. Among them, 83% had G3-4 acute side effects during RT, mainly dysphagia, mucositis, epithelitis and/or xerostomia (DMEX). 28/105 patients (27%) had early G3-4 toxicity up to 3months after the end of RT. 29/96 patients (30%) had G3-4 late toxicity thereafter. The presence of G allele of MDM2 or Thr allele of ERCC1 was associated with a significantly higher risk of acute and/or early DMEX toxicity. The MDM2 309GG genotype was linked to a higher risk of acute G3-4 dermatitis. The ERCC5 TT genotype was associated with more frequent G3-4 late cervical skin fibrosis or xerostomia. Pro allele of TP53 72 was associated with a higher risk of G3-4 osteoradionecrosis. CONCLUSION: Relevant SNPs in DNA repair (ERCC1 and ERCC5) and apoptosis (MDM2 and TP53) genes might influence the severity of radiation-related side-effects in HNSCC patients. Prospective clinical SNP-based validation studies are needed on these bases. PMID- 28351585 TI - Proposal for a new risk classification system for nasopharyngeal carcinoma patients with post-radiation nasopharyngeal necrosis. AB - PURPOSE: To analyze the clinical outcomes of nasopharyngeal carcinoma (NPC) patients with post-radiation nasopharyngeal necrosis (PRNN) and construct a new risk classification system for predicting survival of PRNN. METHODS: A total of 276 patients with PRNN were consecutively enrolled. Complete magnetic resonance (MR) images of the nasopharynx and neck were available for all patients and were used to assess nasopharyngeal necrosis status. After 2010, patients with PRNN were initially treated by radical endoscopic necrectomy followed by reconstruction with nasal flap (ENNF). RESULTS: The 1-year and 2-year overall survival (OS) was 65.0% and 51.6%, respectively. Three variables affected survival: osteoradionecrosis, re-irradiation, and internal carotid artery (ICA) exposure, and only two variables were found to be independent prognostic factors: re-irradiation (hazard ratio [HR] 1.75, P=0.001) and internal carotid artery (ICA) exposure (hazard ratio [HR] 1.80, P=0.001). These two variables were combined to create a new risk classification system for PRNN. 131 (47.5%), 110 (39.9%), and 35 (12.7%) patients were classified into low-, intermediate- and high-risk group, with the 2-year OS rates of 64.8%, 45.1%, and 22.5%, respectively (P<0.001). ENNF was associated with a better OS in these three group patients compared with conservative management with statistical or marginal statistical significance (2-year OS low-risk group, 90.9% vs 61.1%, p=0.081; intermediate-risk group: 100% vs 37.8%, P=0.001; and high-risk group, 57.1% vs 20.8%, p=0.066). CONCLUSION: The new risk classification system provides accurate estimates of prognosis. ENNF surgery may lead to better survival outcome than conservative management in PRNN patients. PMID- 28351584 TI - Human papillomavirus (HPV) 16 antibodies at diagnosis of HPV-related oropharyngeal cancer and antibody trajectories after treatment. AB - OBJECTIVES: Despite the fact that HPV-driven oropharyngeal cancer (HPV-OPC) has relatively low recurrence rates, intensive post-therapy monitoring remains the standard of care. Post-treatment biomarkers are needed to risk stratify HPV-OPC patients for more individualized surveillance intensity and which remain at higher recurrence risk. MATERIALS AND METHODS: 115 HPV-OPC patients (ascertained by p16 immunohistochemistry and/or in-situ hybridization) from a multicenter prospective case study (HOTSPOT) had blood collected at diagnosis, and 64 of these also had blood collected at post-treatment follow-up visits for up to two years. Samples were centrally tested for antibodies to the L1, E1, E2, E4, E6, and E7 proteins of HPV16. RESULTS: At diagnosis, most HPV-OPC cases were seropositive to HPV16 E6 (85%). In post therapeutic samples, HPV16 antibody level decreased slowly over time, but only 3 (of 51 cases seropositive at enrollment) dropped low enough to be classified as seronegative. At 3years after diagnosis, cumulative risk of recurrence was 10.2% and 0% in HPV16 E6 seropositive and E6 seronegative HPV-OPC cases, respectively (p=0.18). Risk of recurrence was increased, although not statistically significant, in those with higher HPV16 E6 antibody levels at diagnosis (per log antibody level, hazard ratio [HR]=1.81, 95%CI=0.47-6.92). CONCLUSION: This study confirms the high seroprevalence of HPV oncogenic antibodies at diagnosis of HPV-OPC. HPV16 E6 antibody levels decrease after treatment, but most cases remain seropositive for up to two years. HPV16 E6 antibody levels at diagnosis did not appear to be a strong predictor of recurrence. PMID- 28351586 TI - Epidemiology of oral, salivary gland and pharyngeal cancer in children and adolescents between 1970 and 2011. AB - OBJECTIVES: The age of oral and pharyngeal cancer patients has reportedly decreased over the last decade, but most of the peer-reviewed literature regarding oral and pharyngeal cancer in individuals 0-19years of age (Y) is limited to specific tumor sites and/or types, or a small number of cases. Our aim is to characterize oral, salivary gland and pharyngeal cancer (OSPC) in 0-19Y in order to improve knowledge of the disease in young individuals. METHODS: Data on OSPC between 1970 and 2011 was taken from the Israel National Cancer Registry, and included patient age, gender, tumor site and tumor type. Data analysis was performed by using IBM SPSS, Winpepi software and Joinpoint Regression Program. alpha<0.05 was deemed statistically significant. RESULTS: A total of 13,863 OSPC cases were diagnosed with 2.6% (N=357) of 0-19Y. The male to female ratio was 1.5:1. The rates of diagnosis decreased between 1991 and 2011 and were not significantly different between the genders. The nasopharynx was the leading tumor site (42.3%) followed by the salivary glands (20.5%), and both were more common in 14-19Y. The tonsils and other pharyngeal sites were common among 0-13Y. The main tumor types were lymphomas (20.7%) and carcinomas (19.9%). CONCLUSIONS: The general characteristics of OSPC remained unchanged over the last four decades. This may imply that environmental factors have not had any effect. Males are affected more than females and might have a genetic predisposition for nasopharyngeal malignancy. Health care providers should be aware of the common sites and tumor types among children and adolescents. PMID- 28351587 TI - Comparative clinical outcomes of Taiwanese patients with resected buccal and tongue squamous cell carcinomas. AB - OBJECTIVES: Although patients with buccal squamous cell carcinoma (SCC) usually show acceptable outcomes, local control and survival rates are generally lower than those observed for tongue SCC. This study was designed to compare the clinical outcomes of Taiwanese patients with these two common oral cavity malignancies. METHODS: Patients with first primary buccal or tongue SCC who were included in the Taiwanese Cancer Registry Database between 2004 and 2012 were eligible. The study sample consisted of 16,379 patients (7870 buccal SCC and 8509 tongue SCC) who received surgery with or without adjuvant therapy. The 5-year disease-specific survival (DSS) and overall survival (OS) rates served as the outcome measures. RESULTS: Compared with tongue SCC, patients with buccal SCC had a higher prevalence of males (95.7% vs. 86.4%, p<0.0001), pT4 disease (21.4% vs. 12.7%, p<0.0001), and p-Stage IV (30.4% vs. 24.8%, p<0.0001) but a lower frequency of pN2 disease (15.2% vs. 18.5%, p<0.0001). The 5-year DSS and OS rates of buccal SCC patients were slightly higher than those of tongue SCC (78% vs. 77%, p=0.0297; and 71% vs. 69%, p=0.0231, respectively). Multivariate analysis identified tumor site (tongue vs. buccal SCC), sex (male vs. female), age (>=65 vs. <65years), pT classification (T4/T3/T2 vs. T1), and pN classification (N3/N2/N1vs. N0) as independent prognostic factors in the entire study cohort. CONCLUSIONS: The survival advantage of buccal SCC over tongue SCC appears significant in large clinical samples, despite a higher prevalence of p-Stage IV disease in the former. PMID- 28351588 TI - Synthesis and anti-HIV activities of unsymmetrical long chain dicarboxylate esters of dinucleoside reverse transcriptase inhibitors. AB - A series of 11 unsymmetrical dicarboxylate conjugates of dinucleoside reverse transcriptase inhibitors were synthesized. Three dicarboxylic acids, succinic acid, suberic acid and 1,14-tetradecandioc acid, were diesterified with either 3' azido-2',3'-dideoxythymidine (AZT), 3'-fluoro-2',3'-dideoxythymidine (FLT), 2',3' dideoxy-3'-thiacytidine (3TC), or 5-fluoro-2',3'-dideoxy-3'-thiacytidine (FTC). The anti-HIV activity of synthesized compounds was evaluated against HIV-1 X4 (IIIB) and R5 (BaL) viral strains in single-round infection assays. Results indicated that the tetradecandioate esters of nucleosides were more active against HIV than the corresponding parent nucleosides and nucleoside conjugates. The tetradecandioate conjugate of FLT and FTC (5) was found to be the most potent compounds with EC50 values of 47 and 75nM against X4 and R5 HIV-1 strains, respectively, while the EC50 values for the parent analogs, FLT and FTC, ranged from 700 to 3300nM. PMID- 28351589 TI - Synthesis and biological evaluation of novel quinazoline-sulfonamides as anti cancer agents. AB - A robust economic approach to N-(quinazoline-4-yl)sulfonamides was developed and synthesized different aryl, hetero aryl, alkyl and cyclopropyl sulfonamides in excellent yields. All the compounds were evaluated for cytotoxic affinity to SKOV3, DU145, THP1, U937, and COLO205 cell lines. Interesting to find that the bulkiness of substituent at C-2 position of quinazoline forces the molecule to flip around in order to bind in the active site, when compared to the binding preference of previously known quinazoline compounds. Among the 21 compounds synthesized 2b, 2d, 2e, 2h, 2i, 3c, 3d, 3f, 3g and 3h found to be active on all the cell lines tested with IC50 values <10ug/mL. Performed docking simulations to understand the binding preference of various C-2 substituted quinazoline sulfonamides. PMID- 28351590 TI - Design, synthesis and evaluation of 4-substituted anthra[2,1-c][1,2,5]thiadiazole 6,11-dione derivatives as novel non-camptothecin topoisomerase I inhibitors. AB - Previously, 4-tosylanthra[1,2-c][1,2,5]thiadiazole-6,11-dione (1) was identified as a novel non-camptothecin topoisomerase I (Top1) inhibitor by structure-based virtual screening. Herein, a series of 4-substituted derivatives were designed and synthesized. Most of them showed potent Top1 inhibitory activity. Their in vitro antiproliferative activity was also evaluated in A549, HCT-116 and ZR-75-30 human cancer cell lines. Compound 8s showed good antiproliferative activity with IC50 of 0.52MUM and 0.42MUM against HCT-116 and ZR-75-30 cell line, respectively. Top1 unwinding assay and molecular modeling studies rationalized the mode of action of this new class of inhibitors. PMID- 28351591 TI - Studies on anti-hepatoma activity of Annona squamosa L. pericarp extract. AB - This study investigated the anti-hepatoma activity of different extracts from A. squamosa pericarps, phytochemistry of the ethyl acetate (EtOAc) fraction and possible anti-hepatoma mechanism of active constituents. The anti-hepatoma activity of different extracts from A. squamosa pericarps were evaluated by MTT assay against SMMC-7721 cells in vitro and verified by using H22 xenografts bearing mice. Phytochemical investigation of the active pericarp extract was carried out. The pro-apoptosis and cycle arrest effects of active constituents were observed by fluorescent microscope and flow cytometry. Western blot assay was conducted to find the possible anti-hepatoma mechanisms of active constituents. The result showed that EtOAc extract was the active fraction. Two ent-kaurane diterpenoids, named ent-kauran-16-en-19-oic acid and ent-kauran-15-en 19-oic acid, were isolated from the active EtOAc fraction. The pro-apoptosis and G1 phase arrest effects of these diterpenoids were found. Western blot assay showed that ent-kauran-16-en-19-oic acid could activate caspase-3,-8,-9, up regulate of Bax and down-regulate of Bcl-2. PMID- 28351592 TI - Synthesis and evaluation of sulfonamide derivatives as potent Human Uric Acid Transporter 1 (hURAT1) inhibitors. AB - This letter presents synthesis and structure-activity relationship study of sulfonamide derivatives as inhibitors of Human Uric Acid Transporter 1 (hURAT1). Among all tested sulfonamide derivatives, compounds 9b, 16i and 19b exhibited excellent inhibition activity with IC50 value of 10, 2, and 83nM, respectively. In addition, compounds 9b and 19b demonstrated moderate PK profile in rats. PMID- 28351593 TI - Triazole-linked fluorescent bisboronic acid capable of selective recognition of the Lewis Y antigen. AB - Cell surface carbohydrates of the Lewis blood group antigens, Lewis X (Lex), Lewis Y (Ley), Lewis A (Lea), and their sialylated derivatives, such as sialy Lewis X (sLex) and sialy Lewis A (sLea), play important roles in various recognition processes. These cell surface carbohydrates have also been associated with the development and progression of many types of cancers. Recently, we synthesized four anthracene-based fluorescent bisboronic acid sensors (compounds 2a-d) linked by 'click' chemistry with tethers of different lengths to match the epitope of various Lewis group of sugars. Among the four compounds, 2a appears to have both high sensitivity and selectivity for Ley among other carbohydrate antigens. PMID- 28351594 TI - New potent and selective alphavbeta3 integrin ligands: Macrocyclic peptides containing RGD motif synthesized by sortase A-mediated ligation. AB - Three 14-mer macrocyclic peptides 1-3 containing mono-, di- and tri-RGD structure motif were designed and synthesized by sortase A-mediated ligation in good yields. The results of in intro cell-based biological assays indicated that linear peptide 5 and macrocyclic peptide 1, containing di-RGD and mono-RGD motif respectively, showed remarkable potency and selectivity to alphavbeta3 integrin. PMID- 28351595 TI - Congenital chylothorax. AB - Congenital chylothorax (CC) results from multiple lymphatic vessel anomalies or thoracic cavity defects and may accompany other congenital anomalies. Fetal chylothorax may increase the risk of death and complications from pleural space lymphatic fluid accumulation, which compromises lung development, pulmonary, and cardiovascular function and from complications arising from the loss of drained lymphatic contents. Prenatal interventions might improve survival in severe cases of fetal chylothorax. The neonatal treatment strategy is generally supportive with interventions that include thoracostomy drainage and attempts to decrease chyle flow using a stepwise approach that begins with the least invasive means. Evidence-based treatment choices are lacking and are much needed. Most cases of CC resolve with time even without specific lymphatic system studies to identify the exact pathology. Expertise in performing lymphatic studies is not universally available. Data on both efficacy and safety of the various therapeutic options are needed to determine the best approach to the treatment of CC. PMID- 28351596 TI - Brain edema with clasmatodendrosis complicating ataxia telangiectasia. AB - Ataxia-telangiectasia is a chronic progressive disorder affecting the nervous and immune systems, caused by a genetic defect in the ATM protein. Clasmatodendrosis, a distinct form of astroglial death, has rarely been reported in ataxia telangiectasia. Neuropathology of our patient disclosed diffuse edema of the cerebral and cerebellar white matter with prominent clasmatodendrosis, implicating ATM in the regulation of astroglial cell death. PMID- 28351597 TI - Neuropsychology of subjects with ultra-high risk (UHR) of psychosis: A critical analysis of the literature. AB - Cognitive disorders are currently considered as central components of disorders found in schizophrenia and are a major handicap for patients day to day. These disorders appear before the first psychotic episode, in the prodromal phase, during which time the symptoms are below the threshold for psychosis. People with these symptoms are considered as presenting an at-risk mental state (or at ultra high risk, UHR of psychosis) and their risk for psychotic transition is between 20% and 40% within one year. Despite a number of studies, the chronology in which cognitive disorders appear in relation to the psychotic symptoms has not clearly been established and the study of the links between cognition and symptoms could improve our understanding of psychotic disorders. The detection of certain cognitive disorders before the onset of psychotic disorders could help improve early detection. We carried out a systematic analysis of the literature exploring cognitive disorders found in subjects with UHR for psychosis. The objective of most studies was to establish the predictive value for psychotic transition. Nevertheless study results have shown little consensus. Faced with this heterogeneity of results from past studies, we carried out a critical analysis of the literature and suggest areas of reflection for future research. PMID- 28351598 TI - Canadian Radiologists Do Not Support Screening Mammography Guidelines of the Canadian Task Force on Preventive Health Care. AB - PURPOSE: The study sought to determine screening mammography recommendations that radiologists in Canada promote to average-risk patients and family or friends, and do or would do for themselves. METHODS: An online survey was delivered from February 19, 2014, to July 11, 2014. Data included radiologists' recommendations for mammography and their personal screening habits based on gender. The 3 radiologists' cohorts were women >=40 years of age, women <40 years of age, and men. The distribution of responses for each question was summarized, and proportions for the entire group and individual cohorts were computed. RESULTS: Of 402 surveys collected, 97% (299 of 309) radiologists recommended screening every 1-2 years, 62% (192 of 309) starting >=40 years of age and 2% (5 of 309) recommended screening every 2-3 years for women 50-74 years of age. Recommendations were similar for family and friends: 96% (294 of 305) recommended screening every 1-2 years, 66% (202 of 305) recommended screening every 1-2 years for women >=40 years of age, and 2% (5 of 305) recommended screening every 2-3 years. For women radiologists >=40 years of age, 76% (48 of 63) underwent screening every 1-2 years and started at 40 years of age, 76% (16 of 21) female radiologists <40 years of age would undergo screening >=40 years of age, 100% every 1-2 years, and 90% (151 of 167) male radiologists would undergo screening every 1-2 years, with 71% (120 of 169) beginning at 40 years of age. CONCLUSION: The majority of Canadian radiologists recommend screening mammography every 1-2 years for average-risk women >=40 years of age, whether they are patients or family and friends. PMID- 28351599 TI - Microbiology Managers: Managerial Training in the RItrain Project. AB - Leaders of research infrastructures (RIs) in Europe who are scientists require competencies in management. RItrain has addressed this issue by identifying skills required, locating relevant courses and finding gaps, whilst establishing a Master of Management programme. We describe how one contributing microbiology RI determined the most relevant skills. PMID- 28351600 TI - The bed nucleus of the stria terminalis in drug-associated behavior and affect: A circuit-based perspective. AB - The bed nucleus of the stria terminalis was first described nearly a century ago and has since emerged as a region central to motivated behavior and affective states. The last several decades have firmly established a role for the BNST in drug-associated behavior and implicated this region in addiction-related processes. Whereas past approaches used to characterize the BNST have focused on a more general role of this region and its subnuclei in behavior, more recent work has begun to reveal its elaborate circuitry and cellular components. Such recent developments are largely owed to methodological advances, which have made possible efforts previously deemed intractable, such as tracing of long-range cell-type specific projections and identifying functional efferent and afferent connections. In this review, we integrate earlier foundational work with more recent and advanced studies to construct a broad overview of the molecular neurocircuitry of the BNST in drug-associated behavior and affect. This article is part of the Special Issue entitled "Alcoholism". PMID- 28351601 TI - [Organic troubles with psychiatric symptoms: What is the appropriate childhood and adolescence psychiatric care? Reflections on disimmune encephalitis cases]. AB - Organic mental disorders are different and further revealed by increasingly advanced research. They are nevertheless misunderstood, without consensus, and raise clinical, diagnostic, and therapeutic questions. These disorders require effective collaboration between practitioners such as pediatricians and child psychiatrists. The subject should not disappear behind the complexity related to the clinical expression of these symptoms. Based on three cases of autoimmune encephalitis, we offer a reflection on the management and assessment of these diseases by a multidisciplinary team with the intention of providing optimal management. The aim of this paper is to override an initial divide posed by a particular clinical presentation. We would like to shed light on the place and legitimacy of child psychiatrists and their clinical expertise. This does not exclude the need for care of the symptoms, considering each subject and her experience. Follow-up is necessary because of the possible, often traumatic, functional and psychological consequences. Finally, the presence of each professional should be specified when the psychiatric symptoms appear to be the result of an organic disease in order to better support the subject in his suffering body. PMID- 28351602 TI - Morphological Analysis of Healthy Aortic Arch. AB - OBJECTIVE/BACKGROUND: This study aimed to describe an arch morphology protocol in a healthy population, and to assess the impact of age and sex. METHODS: A retrospective morphology evaluation was conducted in a population with no personal history of thoracic aorta surgery or pathology, through computed tomography (CT) imaging analysis, using a standardised protocol. Based on centreline three dimensional coordinates, a single investigator calculated a series of parameters in the arch zones and in the total arch, using Matlab scripts. These were categorized as: (i) morphometric data: diameter, length and aortic angle of each zone, total arch angle, and length; (ii) geometric data: tortuosity index (TI), arch width, assimilated curvature radius (CRi), and attachment zone angles. Student or Mann-Whitney tests were used to compare parameter means. Their variability with age and sex was assessed through univariate and multivariate regression analysis. RESULTS: CT images from 123 subjects (mean +/- SD age 53 +/- 19 years) were reviewed. Significant correlation between age and morphology was found. The aorta expanded homogeneously and stretched heterogeneously with age because of posterior arch elongation. TI decrease, CRi, and attachment zone angle increase were also observed with aging. Age remained significantly associated with these morphological parameters, independently of body surface area and hypertension. Sex also affected morphology: longer total arch length and higher CRarch in men; lower zone 3 attachment angle in women CONCLUSION: Using mathematical algorithms, and with a view to improving endovascular arch treatment, this study provides a standardised arch morphology protocol and objectively identifies both age related evolution and sex related variation in the different zones. PMID- 28351604 TI - Stent loss during chronic total occlusion percutaneous coronary intervention: Optical coherence tomography-guided stent 'crushing and trapping'. AB - Stent loss during percutaneous coronary intervention (PCI) is a rare event, which however has been associated with devastating consequences. Adequate management of this complication requires an exact understanding of the location of the lost stent and underlying mechanisms. Our case reports on a 55-year-old man who underwent PCI to a chronic total occlusion of the left anterior descending artery, complicated by stent loss. Successful management involved crushing and trapping of the stent behind a newly implanted stent. The use of optical coherence tomography proved invaluable, clarifying the relationship of the lost stent with side branches, allowing choosing a larger balloon for stent crushing, and suggesting a possible cause for stent loss. Finally, we provide a review on recent literature on stent loss during PCI and offer an algorithm to guide its management. PMID- 28351603 TI - Predictors of HBeAg seroconversion after long-term nucleos(t)ide analogues treatment for chronic hepatitis B: a multicenter study in real clinical setting. AB - AIMS: To evaluate the HBeAg seroconversion rate in real clinical setting and explore its predictors in long-term nucleos(t)ide analogues (NAs) treatment for chronic hepatitis B (CHB). METHODS: 251 patients were recruited from January 2001 to September 2009 in four hospitals in Hebei province, China, for this retrospective study. Clinical and laboratory data before and after treatment with lamivudine (LAM, 100mg daily), adefovir (ADV, 10mg daily), telbivudine (LDT, 600mg daily), entecavir (ETV, 0.5mg daily), and LAM/ADV combination were compared among three groups according to treatment outcomes: synchronous HBeAg loss and HBeAg seroconversion, anti-HBe development after treatment, and no anti-HBe. Adherence was also evaluated. RESULTS: In real clinical setting, cumulative HBeAg seroconversion rates were 14.3%, 32.7%, 43.0%, 46.9%, and 50.5% after 1, 2, 3, 5, and 8 years, respectively. 45 patients (17.9%) were non-adherent. Adherence (p<0.001, Hazard Ratio (HR)=2.203), elevated alanine aminotransferase (ALT) levels (p<0.001, HR=2.049), and non-vertical transmission (p=0.006, HR=1.656) were predictors of HBeAg seroconversion. CONCLUSION: Adherence, elevated ALT, and non-vertical transmission are predictors of HBeAg seroconversion in CHB patients treated with NAs. PMID- 28351605 TI - Infections associated with adventure travel: A systematic review. AB - AIM: To review infections associated with adventure travel. METHODS: The PubMed, Embase and Scopus databases were searched combining the words infection with the following keywords: rafting, whitewater, surfing, (surfer* or windsurf*), (caves or caving or spelunking), (triathlon or trekking) or (hiking or adventure race), bicycling, backpacking, (mountain climb* or bouldering), horseback riding, orienteering, trekking, and skiing. RESULTS: Adventure travel is becoming much more common among travelers and it is associated with a subset of infectious diseases including: leptospirosis, schistosomiasis, viral hemorrhagic fevers, rickettsial diseases and endemic mycosis. Caving and whitewater rafting places individuals at particular risk of leptospirosis, schistosomiasis and endemic mycosis, while adventure races also place individuals at high risk of a variety of infections including campylobacter, norovirus and leptospirosis. CONCLUSION: Travel practitioners need to be aware of the risks associated with adventure travel and should educate individuals about the risks associated with various activities. Doxycycline prophylaxis should be considered for travelers who are susceptible to leptospirosis due to participation in high-risk sports such as whitewater rafting, caving or adventure races. PMID- 28351606 TI - Comparative assessment of a 99mTc labeled H1299.2-HYNIC peptide bearing two different co-ligands for tumor-targeted imaging. AB - Peptides are a class of targeting agents that bind to cancer-specific cell surfaces. Since they specifically target cancer cells, they could be used as molecular imaging tools. In this study, the 15-mer peptide Ac-H1299.2 (YAAWPASGAWTGTAP) was conjugated with HYNIC via lysine amino acid on C-terminus and labeled with 99mTc using tricine and EDDA/tricine as the co-ligands. These radiotracers were evaluated for potential utilization in diagnostic imaging of ovarian cancer cells (SKOV-3). The cell-specificity of these radiolabeled peptides was determined based on their binding on an ovarian cancer cell line (SKOV-3), and displaying a low affinity for lung adenocarcinoma cell line (A549) and breast cancer cell line (MCF7). Biodistribution studies were conducted in normal mice as well as in nude mice bearing SKOV-3 ovarian cancer xenografts. HYNIC-peptide was labeled with 99mTc with more than 99% efficiency and showed high stability in buffer and serum. We observed nanomolar binding affinities for both radiolabeled peptides. The tumor uptakes were 3.27%+/-0.46% and 1.55%+/ 0.20% for tricine and 2.34+/-1.1% and 1.09%+/-0.18% for EDDA/tricine at 1 and 4h after injection, respectively. A higher tumor to background ratio and lower radioactivity in the blood were observed for EDDA/tricine co-ligands, leading to clear tumor visualization in imaging with injection of this peptide. This new 99mTc-labeled peptide selectively targeted ovarian cancer and introduction of a (EDDA/tricine) as a co-ligand improved the pharmacokinetics of 99mTc-labeled H1299.2 for tumor imaging in animals. PMID- 28351607 TI - Discovery of a potent inhibitor of MELK that inhibits expression of the anti apoptotic protein Mcl-1 and TNBC cell growth. AB - Despite recent advances in molecularly directed therapy, triple negative breast cancer (TNBC) remains one of the most aggressive forms of breast cancer, still without a suitable target for specific inhibitors. Maternal embryonic leucine zipper kinase (MELK) is highly expressed in TNBC, where level of overexpression correlates with poor prognosis and an aggressive disease course. Herein, we describe the discovery through targeted kinase inhibitor library screening, and structure-guided design of a series of ATP-competitive indolinone derivatives with subnanomolar inhibition constants towards MELK. The most potent compound, 17, inhibits the expression of the anti-apoptotic protein Mcl-1 and proliferation of TNBC cells exhibiting selectivity for cells expressing high levels of MELK. These studies suggest that further elaboration of 17 will furnish MELK-selective inhibitors with potential for development in preclinical models of TNBC and other cancers. PMID- 28351608 TI - PIFA-BF3.OEt2 mediated intramolecular regioselective domino cyclization of ynamides: A novel method for the synthesis of tetrahydroisoquinoline-oxazol-2(3H) ones. AB - The transition metal-free intramolecular regioselective domino cyclization of N Boc protected ynamides has been developed to provide the corresponding tetrahydroisoquinoline-oxazo-2(3H)-ones in moderate to good yields. PMID- 28351609 TI - Orthoplastic surgical collaboration is required to optimise the treatment of severe limb injuries: A multi-centre, prospective cohort study. AB - Open fractures are severe, complex, limb-threatening and high-energy injuries, often involving lesions of both bone and soft tissues. Traditionally, treatment has been piecemeal by orthopaedic and plastic surgeons. This study aimed to prospectively investigate whether combining orthopaedic and plastic surgery in treating these injuries is more effective than the conventional orthopaedic care. A prospective multi-centre cohort study was conducted. Differences in the type of approach to severe limb trauma allowed a comparison between combined orthoplastic and traditional exclusively orthopaedic treatment. Time for fracture and soft tissue healing and the recovery of limb function were the main outcome measures studied. All patients suffering from a severe open tibial fracture were prospectively included between January 2012 and December 2013 and followed until December 2014. Recruiting units were as follows: (1) an established orthoplastic centre, (2) a unit without experience in the orthoplastic approach and (3) a unit where the orthoplastic approach has been recently introduced in a developing country (Pakistan). A total of 160 patients were included in the study. Of these, 70% were treated with an orthoplastic approach, whereas 30% were treated by an orthopaedic team. All outcome measures were statistically improved by the orthoplastic approach. A coordinated, combined pathway to both the bony and the soft tissue components of open tibial fractures through orthoplastic surgery can be successfully delivered with attention to important timelines to achieve better patient outcomes in different socio-economic settings. PMID- 28351610 TI - Facial nerve regeneration after facial allotransplantation: A longitudinal clinical and electromyographic follow-up of lip movements during speech. AB - INTRODUCTION: Facial allotransplantation constitutes a reconstructive option after extensive damage to facial structures. Functional recovery has been reported but remains an issue. CASE REPORT - METHODS: A patient underwent facial allotransplantation after a ballistic injury with extensive facial tissue damage. Speech motor function was sequentially assessed clinically, along with repeated electromyography of lip movements during a follow-up of 3 years. RESULTS: Facial nerve recovery could be demonstrated within the first month, followed by a gradual increase in electromyographic amplitude and decrease in reaction times. These were accompanied by gradual improvement of clinical assessments. CONCLUSIONS: Axonal recovery starts early after transplantation. Electromyographic testing is sensitive in demonstrating this early recovery, which ultimately results in clinical improvements. PMID- 28351611 TI - Structural Insights of WHAMM's Interaction with Microtubules by Cryo-EM. AB - WASP homolog associated with actin, membranes, and microtubules (WHAMM) is a vertebrate protein functioning in membrane tubulation for intracellular membrane trafficking and specific organelle formation. Composed of multiple domains, WHAMM can bind to membrane and microtubule (MT) and promote actin polymerization nucleation. Previous work revealed that WHAMM's activity to promote actin nucleation is repressed upon binding to MTs. Here, we discovered that WHAMM interacts with alphabeta-tubulin through a small peptide motif within its MT binding domain. We reconstructed a high-resolution structure of WHAMM's MT binding motif (MBM) assembling around MTs using cryo-electron microscopy and verified it with chemical cross-linking and mass spectrometry analysis. We also detected a conformational switch of this motif between the non-MT-bound state and the MT-bound state. These discoveries provide new insights into the mechanism by which WHAMM coordinates actin and MT networks, the two major cytoskeletal systems involved in membrane trafficking and membrane remodeling. PMID- 28351612 TI - A Gibbs Free Energy-Based Assessment of Microbial Electrocatalysis. AB - The use of microbial catalysts for electrode reactions enables novel bioremediation and bioproduction processes. To understand the electrochemical performance of the electrode reactions, knowledge of their thermodynamics is essential. We elaborate here on the Growth Reference System (GRS), simplifying thermodynamic calculations in the aforementioned context to, for example, demonstrate that cathodic bioprocesses generally suffer from higher overpotentials than do anodic processes. Abiotic hydrogen production cannot be thermodynamically excluded for any of the cathodic microbial electrosynthesis processes described thus far. Predictions for maximum biomass production correlated to electron flow are in line with experimental observations. We include a comprehensive set of thermodynamic and electrochemical data to support calculations relevant to the field of microbial electrocatalysis. PMID- 28351613 TI - Why Batch Effects Matter in Omics Data, and How to Avoid Them. AB - Effective integration and analysis of new high-throughput data, especially gene expression and proteomic-profiling data, are expected to deliver novel clinical insights and therapeutic options. Unfortunately, technical heterogeneity or batch effects (different experiment times, handlers, reagent lots, etc.) have proven challenging. Although batch effect-correction algorithms (BECAs) exist, we know little about effective batch-effect mitigation: even now, new batch effect associated problems are emerging. These include false effects due to misapplying BECAs and positive bias during model evaluations. Depending on the choice of algorithm and experimental set-up, biological heterogeneity can be mistaken for batch effects and wrongfully removed. Here, we examine these emerging batch effect-associated problems, propose a series of best practices, and discuss some of the challenges that lie ahead. PMID- 28351614 TI - A cat has 9 lives: The dilemma of diagnosing non hodgkin's lymphoma in intensive care unit. AB - Non hodgkins lymphoma is a common haematological malignancy characterized by abnormal clonal proliferation of T-cells, B-cells or both. The incidence of non hodgkins lymphoma is rapidly rising. The diagnosis and management of NHL presents as a challenge in developing countries like India due to high prevalence of tuberculosis, cost and poor patient compliance. We describe an unusual case of a patient who presented as a diagnostic dilemma and took 8 diagnosis before finally being confirmed as a case of NHL. A suspicion for NHL should always be kept in mind in a patient presenting with pneumonia, bilateral pulmonary infiltrates and eosinophilia. PMID- 28351615 TI - A tantalum oxide-based core/shell nanoparticle for triple-modality image-guided chemo-thermal synergetic therapy of esophageal carcinoma. AB - Early detection and therapy of esophageal cancer is very important for improving the prognosis and survival rate of the patient. A theranostic agent that combines multimodal imaging with cancer therapy may be used for augmenting the visualization and treatment of the cancer. Herein, we report the synthesis of a hollow tantalum oxide (TaOx) nanoparticle that was successfully engineered by encapsulation of polypyrrole (PPy) and doxorubicin (DOX) in the core and conjugation with a near infrared fluorescence dye (NIRDye800) on the shell of the hollow TaOx nanoparticles. The as-prepared core/shell nanoparticles showed multimodal imaging features including computed tomography (CT) (for the preliminary location of the tumor), photoacoustic (for the anatomical localization of the tumor), and fluorescence imaging (for real-time monitoring of the tumor margin) and pH- and thermal-sensitive drug release. Because the early esophageal carcinoma is a type of superficial cancer, a subcutaneous model in the thigh was used for the in vivo study. The core/shell nanoparticles shows high imaging contrast between the tumor and the adjacent tissues and controllable photothermal therapy (PTT) and chemotherapy. Our results indicated that the obtained core/shell nanoparticles had significant potential in the triple modality imaging guided precisely chemo-thermal synergetic therapy of esophageal cancer. In addition, after aerosol administration, our nanoparticles also exhibited comparable therapeutic efficacy with the intravenous administration, which is more suitable for clinical therapy of esophageal carcinoma. PMID- 28351616 TI - Pulsed-field gel electrophoresis does not break E. coli chromosome undergoing excision repair after UV irradiation. AB - We showed before that long linear DNA molecules containing single-strand interruptions and undergoing pulsed-field gel electrophoresis (PFGE) tend to break into subfragments (electrophoretic nick instability). Here we show that circular chromosomal DNA with single-strand interruptions remains in the wells during PFGE. This means that the presence of nicks in immobile circular DNA is not enough to break this DNA during PFGE. In other words, under the conditions of our study, the artifactual conversion of nicks into double-strand breaks that we detect in linear DNA does not contribute to the overall level of chromosomal fragmentation, as measured by PFGE. PMID- 28351617 TI - Interaction of FAM5C with UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1): Implication of N-glycosylation in FAM5C secretion. AB - N-glycosylation of proteins is important for protein folding and function. We have recently reported that FAM5C/BRINP3 contributes to the tumor necrosis factor alpha-induced expression of leukocyte adhesion molecules in vascular endothelial cells (ECs). However, regulatory mechanism of the FAM5C biosynthesis is poorly understood. Co-immunoprecipitation assay revealed the interaction of FAM5C with UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1), a glycoprotein folding sensor enzyme. FAM5C ectopically expressed in HEK293 cells was localized to the endoplasmic reticulum and co-localized with endogenously expressed UGGT1. Molecular size of FAM5C was reduced by treatment with N-glycosidase F and in FAM5C-expressing cells cultured in the presence of the N-glycosylation inhibitor tunicamycin. FAM5C was secreted by the cells and the secretion of FAM5C was blocked by tunicamycin. Among six potential N-glycosylation sites, the potential site at Asn168 was not N-glycosylated, and Asn337, Asn456, Asn562, Asn609, and Asn641 mutants were poorly secreted by the cells. These results demonstrated that FAM5C is an N-glycosylated protein and N-glycosylation is necessary for the secretion of FAM5C. PMID- 28351618 TI - Structure of the MazF-mt9 toxin, a tRNA-specific endonuclease from Mycobacterium tuberculosis. AB - Tuberculosis (TB) is a severe disease caused by Mycobacterium tuberculosis (M. tb) and the well-characterized M. tb MazE/F proteins play important roles in stress adaptation. Recently, the MazF-mt9 toxin has been found to display endonuclease activities towards tRNAs but the mechanism is unknown. We hereby present the crystal structure of apo-MazF-mt9. The enzyme recognizes tRNALys with a central UUU motif within the anticodon loop, but is insensitive to the sequence context outside of the loop. Based on our crystallographic and biochemical studies, we identified key residues for catalysis and proposed the potential tRNA binding site. PMID- 28351619 TI - Activation of hypoxia-inducible factor-1alpha by prolonged in vivo hyperinsulinemia treatment potentiates cancerous progression in estrogen receptor positive breast cancer cells. AB - Despite numerous epidemiological data linking type 2 diabetes mellitus (T2DM) and breast cancer (BCa), there is limited experimental evidence of this association. The clinically relevant question is at what stage diabetes may exert its tumor promoting activity. Moreover, identification of major pathophysiological pathways underlying this activity should provide valuable information for treatment. In the present study, the BCa cells isolated from long-term T2DM-treated tumors from diabetic nude mice were found to have increased cell proliferation, invasiveness and docetaxel (DTX) resistance. Importantly, this stimulatory effect was only observable in estrogen receptor (ER)-positive BCa cells. Mechanistically, T2DM elicited hyperinsulinemia induced HIF-1alpha expression by reducing its ubiquitination, which was accompanied with upregulated oxidative stress. Furthermore, in vivo inhibition of HIF-1alpha expression effectively reversed the above-mentioned tumor-promoting activity and partially attenuated T2DM-elicited oxidative stress. Altogether, the results provide novel and compelling experimental evidence that (i) prolonged exposure to T2DM promotes BCa progression; (ii) the hyperinsulinemia/HIF-1alpha/oxidative stress cascade is the major mediator of this effect. PMID- 28351620 TI - Oxygenated thawing and rewarming alleviate rewarming injury of cryopreserved pancreatic islets. AB - BACKGROUND/AIMS: Pancreatic islet transplantation is an effective treatment for Type 1 diabetic patients to eliminate insulin injections; however, a shortage of donor organs hinders the widespread use. Although long-term islet storage, such as cryopreservation, is considered one of the key solutions, transplantation of cryopreserved islets is still not practical due to the extensive loss during the cryopreservation-rewarming process. We have previously reported that culturing islets in a hyperoxic environment is an effective treatment to prevent islet death from the hypoxic injury during culture. In this study, we explored the effectiveness of thawing and rewarming cryopreserved islets in a hyperoxic environment. METHODS: Following cryopreservation of isolated human islets, the thawing solution and culture media were prepared with or without pre equilibration to 50% oxygen. Thawing/rewarming and the pursuant two-day culture were performed with or without oxygenation. Short-term recovery rate, defined as the volume change during cryopreservation and thawing/rewarming, was assessed. Ischemia-associated and inflammation-associated gene expressions were examined using qPCR after the initial rewarming period. Long-term recovery rate, defined as the volume change during the two-day culture after the thawing/rewarming, was also examined. Islet metabolism and function were assessed by basal oxygen consumption rate and glucose stimulated insulin secretion after long-term recovery. RESULTS: Oxygenated thawing/rewarming did not alter the short-term recovery rate. Inflammation-associated gene expressions were elevated by the conventional thawing/rewarming method and suppressed by the oxygenated thawing/rewarming, whereas ischemia-associated gene expressions did not change between the thawing/rewarming methods. Long-term recovery rate experiments revealed that only the combination therapy of oxygenated thawing/rewarming and oxygenated culture alleviated islet volume loss. These islets showed higher metabolism and better function among the conditions examined. CONCLUSION: Oxygenated thawing/rewarming alleviated islet volume loss, with the help of oxygenated culture. PMID- 28351621 TI - Critical roles of Astrin in the mitosis of immature rat Sertoli cells. AB - Male hypogonadism (hgn/hgn) rats show testicular hypoplasia accompanied by dysplastic development of seminiferous tubules due to loss-of-function mutation of the gene encoding Astrin, which is required for mitotic progression in the division cycle of HeLa cells. In the present study, we examined the cytological base leading to the decrease of Sertoli cells in hgn/hgn testes. In hgn/hgn testes on postnatal day 3, anti-phospho-histone H3 (Ser10) (pH3)-positive mitotic phase and TUNEL-positive apoptosis increased in GATA4-positive Sertoli cells. Isolated immature Sertoli cells from hgn/hgn testes showed increased pH3-assessed mitotic index accompanied by decreased 5-bromo-2'-deoxyuridine-incorporation and increased TUNEL-positive apoptosis, suggesting mitotic delay and cell death. In the visualization of mitotic progression by nocodazole (NOC)-mediated cell cycle arrest and subsequent release, hgn/hgn rat-derived Sertoli cells failed to make the transition from prometaphase to metaphase, and the cells with micronuclei and TUNEL-positive cells gradually increased in a time-dependent manner. Western blot analysis detected ~142 kDa protein expected as Astrin in extracts of +/+ and +/hgn testes and cultured normal Sertoli cells but not in extracts of hgn/hgn testes. CLASP1 was detected in extracts of both normal and hgn/hgn testes, whereas it was localized in kinetochore of normal mitotic Sertoli cells but diffused in cytoplasm of hgn/hgn Sertoli cells. These results indicate that Astrin is required for normal mitotic progression in immature Sertoli cells and that the most severe type of testicullar dysplasia in hgn/hgn rats is caused by mitotic cell death of immature Sertoli cells due to lack of Astrin. PMID- 28351622 TI - Direct labeling of serum proteins by fluorescent dye for antibody microarray. AB - Analysis of serum proteome by antibody microarray is used to identify novel biomarkers and to study signaling pathways including protein phosphorylation and protein-protein interactions. Labeling of serum proteins is important for optimal performance of the antibody microarray. Proper choice of fluorescent label and optimal concentration of protein loaded on the microarray ensure good quality of imaging that can be reliably scanned and processed by the software. We have optimized direct serum protein labeling using fluorescent dye Arrayit Green 540 (Arrayit Corporation, USA) for antibody microarray. Optimized procedure produces high quality images that can be readily scanned and used for statistical analysis of protein composition of the serum. PMID- 28351623 TI - IGF-1 receptor haploinsufficiency leads to age-dependent development of metabolic syndrome. AB - Individuals born small for gestational age (SGA) are at a higher risk of developing the metabolic syndrome later in life. IGF-1 resistance has been reported in placentae from SGA births and mutations in the Igf1 receptor gene have been reported in several cohorts of SGA subjects. We have used the Igf1r heterozygous (Igf1r+/-) male mouse as a model to investigate the mechanisms by which Igf1r haploinsufficiency leads to insulin resistance. Despite exhibiting IGF-1 resistance, insulin signaling is enhanced in young Igf1r+/- mice but is attenuated in the muscle of old Igf1r+/- mice. Although smaller than WT (wild type) mice, old-aged Igf1r+/- had increased adiposity and exhibit increased lipogenesis. We hypothesize that IGF-1 resistance initially causes a transient increase in insulin signaling thereby promoting a lipogenic phenotype, which subsequently leads to insulin resistance. PMID- 28351624 TI - HLA-A*31:01 and lamotrigine-induced severe cutaneous adverse drug reactions in a Korean population. PMID- 28351625 TI - [Utilising statutory health insurance data to evaluate pharmaceutical interventions in secondary care - a pilot study]. AB - BACKGROUND: Intensive pharmaceutical and medical care can lead to fewer drug related problems (DRPs) in hospitals. Currently available methods to track drug changes after transition from inpatient to outpatient care are susceptible to systemic bias. Therefore we analysed the feasibility of a data linkage between prescription data extracted from hospital medical records and claims data from a health insurance company. METHODS: At six Saxonian hospitals, patients with a written informed consent were consecutively assigned to a control (CG) or intervention group (IG) depending on the time of admission. Clinical pharmacists documented predetermined DRPs and prescribed medication on the day of hospital admission and in the discharge letter. In case of DRP (IG) or potentially life threatening DRPs (CG), drug changes were recommended to the hospital physician. These data were patient-individually linked to claims data from a health insurance company comprising a period of six months before and six months after hospitalisation (data linkage). We analysed data consistency within the data linkage and the post-hospital prevalence of DRPs identified in the hospital setting. RESULTS: We enrolled 532 patients (CG/IG 280/252). The data linkage was feasible for 97.0% (CG) and 96.6% (IG) of the patients, respectively. A total of 318 DRPs (CG/IG 176/142) was detected. Because of restrictions in the reimbursement of drugs in the outpatient setting, 22 (12.5%, CG) and 13 (9.2%, IG) DRPs were not analysable. Insurance claims data during a 6-month follow-up showed no statistically significant difference between the CG (without intervention) and in the IG (with intervention) with respect to DRPs (43.4% vs 38.1%; p = 0.472). CONCLUSIONS: The linkage of inpatient and outpatient data was feasible for the majority of enrolled patients. Compared to similar studies, the risk for systemic bias decreased because fewer patients were lost to follow-up. Within this feasibility study the expected difference between IG and CG could not be demonstrated statistically. PMID- 28351626 TI - Integrated immunochromatographic strip with glucometer readout for rapid quantification of phosphorylated proteins. AB - A new technology to quantify phospho-p5315 by converting its content to the amount of glucose which is detectable by a glucometer was developed. An immunochromatographic test strip (ITS) was used as a disposable platform, where primary antibody (Ab1)-modified Fe3O4 magnetic nanoparticles (Fe3O4-Ab1) were settled on the test zone to capture both the target phospho-p5315 and the detection antibody (Ab2)-glucose encapsulating liposome (GEL) conjugate. The measurement was based on the release and subsequent detection of glucose from Ab2 GEL using a glucose meter (GM). The amount of glucose is proportional to the phospho-p5315 concentration from 0.1 to 50 ng mL-1, the limit of detection is 50 pg mL-1 (3S/N). The high sensitivity was a result of the huge number of glucose encapsulated in the liposome. Taking the advantage of low cost, widespread availability and portability of the test trip, together with the personal GM, the presented approach can be easily used to detect other disease biomarkers in medical diagnostics and environmental monitoring. PMID- 28351627 TI - Non-targeted LC-MS based metabolomics analysis of the urinary steroidal profile. AB - The urinary steroidal fraction has been extensively explored as non-invasive alternative to monitor pathological conditions as well as to unveil the illicit intake of pseudo-endogenous anabolic steroids in sport. However, the majority of previous approaches involved the a priori selection of potentially relevant target analytes. Here we describe the non-targeted analysis of the urinary steroidal profiles. The workflow includes minimal sample pretreatment and normalization according to the specific gravity of urine, a 20 min reverse phase ultra-performance liquid chromatographic separation hyphenated to electrospray time-of-flight mass spectrometry. As initial validation, we analyzed a set of quality control urines spiked with glucurono- and sulfo-conjugated steroids at physiological ranges. We then applied the method for the analysis of samples collected after single transdermal administration of testosterone in hypogonadal men. The method allowed profiling of approximately three thousand metabolic features, including steroids of clinical and forensic relevance. It successfully identified metabolic pathways mostly responsible for groups clustering even in the context of high inter-individual variability and allowed the detection of currently unknown metabolic features correlating with testosterone administration. These outcomes set the stage for future studies aimed at implementing currently monitored urinary steroidal markers both in clinical and forensic analysis. PMID- 28351628 TI - Coupling of gas chromatography and electrospray ionization high resolution mass spectrometry for the analysis of anabolic steroids as trimethylsilyl derivatives in human urine. AB - In this study, gas chromatography (GC) was interfaced with high resolution mass spectrometry (HRMS) with electrospray ionization source (ESI) and the relevant parameters were investigated to enhance the ionization efficiency. In GC-ESI, the distances (x-, y- and z) and angle between the ESI needle, GC capillary column and MS orifice were set to 7 (x-distance), 4 (y-distance), and 1 mm (z-distance). The ESI spray solvent, acid modifier and nebulizer gas flow were methanol, 0.1% formic acid and 5 arbitrary units, respectively. Based on these results, analytical conditions for GC-ESI/HRMS were established. In particular, the results of spray solvent flow indicated a concentration-dependent mechanism (peak dilution effect), and other parameters also greatly influenced the ionization performance. The developed GC-ESI/HRMS was then applied to the analysis of anabolic steroids as trimethylsilyl (TMS) derivatives in human urine to demonstrate its application. The ionization profiles of TMS-derivatized steroids were investigated and compared with those of underivatized steroids obtained from gas chromatography-electrospray ionization/mass spectrometry (GC-ESI/MS) and liquid chromatography-electrospray ionization/mass spectrometry (LC-ESI/MS). The steroids exhibited ionization profiles based on their structural characteristics, regardless of the analyte phase or derivatization. Groups I and II with conjugated or unconjugated keto functional groups at C3 generated the [M+H]+ and [M+H-TMS]+ ions, respectively. On the other hand, Groups III and IV gave rise to the characteristic fragment ions [M+H-TMS-H2O]+ and [M+H-2TMS-H2O]+, corresponding to loss of a neutral TMS.H2O moiety from the protonated molecular ion by in-source dissociation. To the best of our knowledge, this is the first study to successfully ionize and analyze steroids as TMS derivatives using ESI coupled with GC. The present system has enabled the ionization of TMS derivatives under ESI conditions and this method has potential as a novel ionization tool. It is also useful for the simultaneous analysis of steroids as TMS derivatives. PMID- 28351629 TI - Detection of sub-pptv benzene, toluene, and ethylbenzene via low-pressure photoionization mass spectrometry. AB - This paper reports on the advanced development of an ultrasensitive method for the detection of benzene, toluene, and ethylbenzene (or BTE) by low-pressure photoionization mass spectrometry (LPPI-MS). The LPPI source is composed of a laboratory-assembled krypton lamp and a stainless steel cylindrical ionizer. A compact V-shaped mass spectrometer is coupled to the LPPI source with a set of ion immigration optics under dc bias. The fixed standard concentration (FSC) and fixed standard volume (FSV) method are employed to calibrate the sensitivities of the instrument. The corresponding detection sensitivity toward BTE is 4-7 counts/pptv and the 2sigma limit of detection (LOD) is 0.5-0.8 part per trillion by volume (pptv). In addition, the measurement accuracy is 95%-105%, and the corresponding precision ranges from 3% to 15% and from 9% to 31% for the FSC and FSV methods, respectively. The stability (standard deviation) of LPPI-MS for a 1 ppbv BTE mixture is less than 0.025 (>12 h). In the detection of BTE, water in ambient air is the most significant interfering factor, leading to the increased background, and inferior LODs of 1-2 pptv for BTE under an RH of ~90% is observed. Experimental results indicated that LPPI-MS is reliable for the detection of sub-pptv levels of BTE under laboratory conditions. PMID- 28351630 TI - Numerical investigation on layout optimization of obstacles in a three dimensional passive micromixer. AB - This paper aims at layout optimization design of obstacles in a three-dimensional T-type micromixer. Numerical analysis shows that the direction of flow velocity change constantly due to the obstacles blocking, which produces the chaotic convection and increases species mixing effectively. The orthogonal experiment method was applied for determining the effects of some key parameters on mixing efficiency. The weights in the order are: height of obstacles > geometric shape > symmetry = number of obstacles. Based on the optimized results, a multi-units obstacle micromixer was designed. Compared with T-type micromixer, the multi units obstacle micromixer is more efficient, and more than 90% mixing efficiency were obtained for a wide range of peclet numbers. It can be demonstrated that the presented optimal design method of obstacles layout in three-dimensional microchannels is a simple and effective technology to improve species mixing in microfluidic devices. The obstacles layout methodology has the potential for applications in chemical engineering and bioengineering. PMID- 28351631 TI - Fluorescent nitrogen and sulfur co-doped carbon dots from casein and their applications for sensitive detection of Hg2+ and biothiols and cellular imaging. AB - Fluorescent nitrogen and sulfur co-doped carbon dots (NSCDs) were synthesized by a one-step pyrolysis strategy using casein as carbon, nitrogen and sulfur sources, and characterized by UV-vis spectrum, fluorescent spectrum, X-ray photoelectron spectroscopy (XPS) and FT-IR, etc. The synthesized NSCDs displayed a blue emission under ultraviolet illumination with a quantum yield of 31.8%, and a good aqueous solubility, photostability and biocompatibility. It was found that the fluorescence intensity of NSCDs could be selectively quenched by Hg2+, so NSCDs was used as an effective probe for the detection of Hg2+. The linear range and the limit of detection (LOD) of the fluorescent sensor based on NSCDs for the detection of Hg2+ were 0.01-0.25 MUM and 6.5 nM, respectively. Spiked water samples were detected by the sensor with the recovery of 95.4-106.3% and relative standard deviation (RSD) of 3.6-8.6%. It was also observed that the quenched NSCDs-Hg2+ system could be restored by the addition of biothiols such as l cysteine (Lcy), homocysteine (Hcy) and glutathione (GSH), thus NSCDs-Hg2+ system was employed as a fluorescent sensor for the detection of biothiols. The linear range and LOD of the NSCDs-Hg2+ system were 1-10 MUM and 23.6 nM for Lcy, 0.2-2.5 MUM and 12.3 nM for Hcy, and 0.1-2.0 MUM and 16.8 nM for GSH, respectively. The NSCDs-Hg2+ system was applied for the detection of biothiols in serum samples with satisfied results. In addition, the study in vitro imaging HeLa cells revealed that the synthesized NSCDs could be used as effective fluorescent probes in cellular imaging without noticeable cytotoxicity. PMID- 28351632 TI - Human telomeric hybrid-2-over-hybrid-1 G-quadruplex targeting and a selective hypersaline-tolerant sensor using abasic site-engineered monomorphism. AB - Coexistence of the polymorphic hybrid-1 and hybrid-2 conformers for a given human telomeric G-quadruplex-forming sequence (htG4) complicates its fine structure identification and limits its application as a sensor element. With help from abasic site (AP site)-engineered htG4s serving as the monomorphic representatives of the two typical hybrid conformers, we found that thioflavin T (ThT) can selectively target the hybrid-2 conformer over the hybrid-1 counterpart in monomer and tandem htG4 molecules. The htG4 that solely adopts the monomorphic hybrid-2 conformer engineered by the AP site is most efficient in lighting up ThT fluorescence in K+ and a selective K+ sensor is realized with a remarkable hypersaline-tolerant capability that can work even in 30000-fold excess of Na+. At 600 mM Na+, the dynamic range for K+ detection can be extended to 30 mM with the limit of detection of 20 MUM. This is the first report on the fluorescence discrimination of these two hybrid conformers of htG4 although they have long been categorized with their characteristically structural topologies. Our work will attract much interest in the development of sensors based on the monomorphic htG4 conformer since such high performance in sensor development has not been previously achieved. PMID- 28351633 TI - Biofunctional polyelectrolytes assembling on biosensors - A versatile surface coating method for protein detections. AB - This paper reports a surface functionalization strategy for protein detections based on biotin-derivatized poly(l-lysine)-grafted oligo-ethylene glycol (PLL-g OEGx-Biotin) copolymers. Such strategy can be used to attach the biomolecule receptors in a reproducible way simply by incubation of the transducer element in a solution containing such copolymers which largely facilitated the sensor functionalization at an industrial scale. As the synthesized copolymers are cationic in physiology pH, surface biotinylation can be easily achieved via electrostatic adsorption on negatively charged sensor surface. Biotinylated receptors can be subsequently attached through well-defined biotin-streptavidin interaction. In this work, the bioactive sensor surfaces were applied for mouse IgG and prostate specific antigen (PSA) detections using quartz crystal microbalance (QCM), optical sensor (BioLayer Interferometry) and conventional ELISA test (colorimetry). A limit of detection (LOD) of 0.5 nM was achieved for PSA detections both in HEPES buffer and serum dilutions in ELISA tests. The synthesized PLL-g-OEGx-Biotin copolymers with different OEG chain length were also compared for their biosensing performance. Moreover, the surface regeneration was achieved by pH stimulation to remove the copolymers and the bonded analytes, while maintaining the sensor reusability as well. Thus, the developed PLL-g-OEGx-Biotin surface assembling strategy is believed to be a versatile surface coating method for protein detections with multi-sensor compatibility. PMID- 28351634 TI - Protocol for the recovery and detection of Escherichia coli in environmental water samples. AB - To achieve active management of bathing areas and to reduce risk associated with the presence of fecal pollution, tests capable of rapid on-site assessment of microbiological water quality are required. A protocol for the recovery and detection of fecal pollution indicator bacteria, E. coli, using beta glucuronidase (GUS) activity was developed. The developed protocol involves two main steps: sample preparation and GUS activity measurement. In the sample preparation step, syringe filters were used with a dual purpose, for the recovery and pre-concentration of E. coli from the water matrix and as MUL reactors for bacteria lysis and GUS extraction. Subsequently, GUS activity was measured using a continuous fluorometric method developed previously. The optimum GUS recovery conditions for the sample preparation step were found to be 100 MUL PELB (supplemented with 1 mg mL-1 lysozyme and 20 mM DTT) at 37 degrees C for 30 min. The protocol was evaluated on environmental samples (fresh and seawater) against an establish GUS assay method (Coliplage(r)). GUS activities corresponding to samples containing as low as 26 MPN E. coli 100 mL-1 were detected for the seawater sample and as low as 110 MPN E. coli 100 mL-1 for the freshwater samples. By comparison with the Coliplage(r) method, this protocol offered an improvement in the measured GUS activities of 3.1 fold for freshwater samples and 4.1 fold for seawater samples. Furthermore, the protocol developed here, has a time-to-result of 75 min, and successfully addresses the requirement for tests capable of rapid assessment of microbiological water quality. PMID- 28351635 TI - Novel polymer-based anion-exchangers with covalently-bonded functional layers of quaternized polyethyleneimine for ion chromatography. AB - For the first time novel pellicular anion-exchangers with functional layers of quaternized branched polyethyleneimine (PEI) covalently bonded to the surface of aminated poly(styrene-divinylbenzene) (PS-DVB) with 1,4-butanediol diglycidyl ether (1,4-BDDGE) as a linker are obtained and studied. The proposed method of synthesis includes alkylation of PS-DVB substrate containing secondary aminogroups with 1,4-BDDGE followed by amination with branched PEI containing primary, secondary, and tertiary amino groups. Quaternization of amino groups of PEI required for increasing ion-exchange capacity of the stationary phase is provided with two epoxides - glycidol and 1,4-BDDGE, which results in the considerable variations of ion-exchange selectivity. Chromatographic properties of the obtained anion-exchangers are evaluated using various model mixtures of anions (F-, HCOO-, CH3COO-, C2H5COO-, Cl-, BrO3-, NO2-, Br-, NO3-, ClO3-, S2O32-, C2O42-, CrO42-, SO42-, PO43-, I-, SCN-) in hydroxide and carbonate/bicarbonte eluents. All anion-exchangers show better selectivity toward the anions of weakly retained organic acids (acetate, formate, propionate) as compared with previously reported chemically derivatized anion-exchangers with monomeric functional sites in the ion-exchange layer. In terms of separation abilities, novel anion exchangers with covalently-bonded PEI are not inferior to some commercial columns with grafted polymeric anion-exchange layer. Anion-exchanger quaternized with more hydrophilic glycidol packed in 10-cm long column enables the separation of 16 anions including weakly retained and highly retained polarizable ones within 26 min using gradient elution. Column efficiencies for both anion-exchangers with quaternized PEI are up to 32000 N/m and 37000 N/m in case of hydroxide and carbonate eluent, respectively, which is comparable with the values demonstrated by commercially available columns of related chemistry. PMID- 28351636 TI - Preparation and application of covalently bonded polysaccharide-modified stationary phase for per aqueous liquid chromatography. AB - The mixed phosphorylated/methacryloyl polysaccharide derivative was prepared and immobilized onto porous silica surface through the radical polymerization. The successful immobilization of polysaccharide on the silica support was confirmed by FT-IR spectra, elemental analysis and transmission electron microscopy (TEM), and so on. The new stationary phase (MCPP-SP) showed both hydrophilic interaction liquid chromatography (HILIC) and per aqueous liquid chromatography (PALC) characteristics. The chromatographic behaviors were evaluated by investigating the effects of water content, column temperature, mobile phase pH and salt concentration, and a typical PALC retention feature of MCPP-SP based column was observed at high percentage of water content. Compared with C18 column, using MCPP-SP column, separation of polar compounds including synthetic pigments and sulfa compounds in the PALC mode was successfully accomplished. The results demonstrated that MCPP-SP column exhibited stronger retention efficiency for various polar compounds. PALC as a green chromatography analytical method was suitable for the replacement of HILIC. PMID- 28351637 TI - Porous monoliths for on-line sample preparation: A review. AB - This review aims at presenting the state of the art concerning monolithic materials for on-line sample preparation emphasizing solid-phase extraction, matrix exchange, and analyte conversion. Emphasis was given to organic and silica based, as well as hybrid monoliths reported in the literature mostly after 2010. The first part of this review presents materials and strategies for enrichment of inorganic species in environmental and biological samples using mostly ICP-MS detectors. In the second part we focus on organic analytes, discussing the role of surface area of the polymer monoliths and density of adsorption sites for specific interactions, including incorporation of nanoparticles, metal organic frameworks, as well as the preparation of hybrid organic-silica monoliths to increase the surface area. Incorporation of ionic liquids to increase the number of types of interaction mechanisms available for retention is also discussed. Monoliths affording molecular recognition properties achieved by including boronate moieties for cis-diol recognition, as well as antibodies and aptamers for specific molecular recognition are also reviewed. The largest number of applications of molecular recognition mechanisms was observed for molecularly imprinted polymer monoliths as a consequence of the simplicity of this approach when compared to the use of immunosorbents or aptamers. The final part examines the on-line applications of immobilized enzyme reactors used for protein digestion in proteomic analysis and for kinetic studies in drug discovery and clinical assays usually coupling the reactors to mass spectrometers. PMID- 28351638 TI - Evaluation of ensemble Monte Carlo variable selection for identification of metabolite markers on NMR data. AB - The aim of this study was to investigate the potential of the recently developed ensemble Monte Carlo Variable Selection (EMCVS) method to identify the relevant portions of high resolution 1H NMR spectra as a metabolite fingerprinting tool and compare to a widely used method (Variable importance on projection (VIP)) and recently proposed variable selected methods i.e. selectivity ratio (SR) and significance multivariate correlation (sMC). As case studies two quantitative publicly available datasets: wine samples, urine samples of rats, and an experiment on mushroom (Agaricus bisporus) were examined. EMCVS outperformed the three other variable selection methods in most cases, selecting fewer chemical shifts and leading to improved classification of mushrooms and prediction of onion by-products intake and wine components. These fewer chemical shift regions facilitate the interpretation of the NMR spectra, fingerprinting and identification of metabolite markers. PMID- 28351639 TI - Untargeted assignment and automatic integration of 1H NMR metabolomic datasets using a multivariate curve resolution approach. AB - In this article, we propose the use of the Multivariate Curve Resolution - Alternating Least Squares (MCR-ALS) chemometrics method to resolve the 1H NMR spectra and concentration of the individual metabolites in their mixtures in untargeted metabolomics studies. A decision tree-based strategy is presented to optimally select and implement spectra estimates and equality constraints during MCR-ALS optimization. The proposed method has been satisfactorily evaluated using different 1H NMR metabolomics datasets. In a first study, 1H NMR spectra of the metabolites in a simulated mixture were successfully recovered and assigned. In a second study, more than 30 metabolites were characterized and quantified from an experimental unknown mixture analyzed by 1H NMR. In this work, MCR-ALS is shown to be a convenient tool for metabolite investigation and sample screening using 1H NMR, and it opens a new path for performing metabolomics studies with this chemometric technique. PMID- 28351640 TI - Polyion oligonucleotide-decorated gold nanoparticles with tunable surface charge density for amplified signal output of potentiometric immunosensor. AB - Methods based on nanostructures have been developed for potentiometric immunosensors, but most involve low sensitivity or weak signal output and are unsuitable for routine use in diagnosis. Herein, we devise an in-situ signal amplification strategy for enhanced electrical readout of potentiometric immunosensor toward target prostate-specific antigen (PSA, one kind of cancer biomarkers), based on polyion oligonucleotide-labeled gold nanoparticles (AuNPs). To decrease the background signal, monoclonal anti-human PSA capture antibody was covalently conjugated onto an activated glassy carbon electrode via typical carbodiimide coupling. AuNPs heavily functionalized with the polyion oligonucleotides and polyclonal anti-PSA detection antibodies (pAb2-AuNP-DNA) were utilized as the signal-generation nanotags. In the presence of target PSA, a sandwich-type immunoreaction was executed between capture antibody and detection antibody on the electrode. The detectable signal derived from the shift in the electric potential as a result of the change in the surface charge before and after the antigen-antibody reaction. With target PSA increased, the captured pAb2 AuNP-DNA to the electrode accompanying detection antibody increased, thereby resulting in the change of the electrode potential. Due to numerous polyion oligonucleotides with the negative charge, the signal readout amplified. Under the optimal conditions, the shift in the output potential was proportional to the logarithm of target PSA concentration and displayed a dynamic linear range from 0.05 to 20 ng mL-1 with a detection limit of 13.6 pg mL-1. An intermediate precision of <=13.2% was accomplished with the batch-to-batch identification. The selectivity was acceptable. The method accuracy was evaluated for human serum specimens, and gave the consistent results between the potentiometric immunosensor and the referenced enzyme-linked immunosorbent assay (ELISA). PMID- 28351641 TI - A review on mass spectrometry-based quantitative proteomics: Targeted and data independent acquisition. AB - Mass spectrometry (MS) based proteomics have achieved a near-complete proteome coverage in humans and in several other organisms, producing a wealth of information stored in databases and bioinformatics resources. Recent implementation of selected/multiple reaction monitoring (SRM/MRM) technology in targeted proteomics introduced the possibility of quantitatively follow-up specific protein targets in a hypothesis-driven experiment. In contrast to immunoaffinity-based workflows typically used in biological and clinical research for protein quantification, SRM/MRM is characterized by high selectivity, large capacity for multiplexing (approx. 200 proteins per analysis) and rapid, cost effective transition from assay development to deployment. The concept of SRM/MRM utilizes triple quadrupole (QqQ) mass analyzer to provide inherent reproducibility, unparalleled sensitivity and selectivity to efficiently differentiate isoforms, post-translational modifications and mutated forms of proteins. SRM-like targeted acquisitions such as parallel reaction monitoring (PRM) are pioneered on high resolution/accurate mass (HR/AM) platforms based on the quadrupole-orbitrap (Q-orbitrap) mass spectrometer. The expansion of HR/AM also caused development in data independent acquisition (DIA). This review presents a step-by-step tutorial on development of SRM/MRM protein assay intended for researchers without prior experience in proteomics. We discus practical aspects of SRM-based quantitative proteomics workflow, summarize milestones in basic biological and medical research as well as recent trends and emerging techniques. PMID- 28351642 TI - Inter-laboratory validation of a thin film microextraction technique for determination of pesticides in surface water samples. AB - The primary goal of the present study is the inter-laboratory evaluation of a thin film microextraction (TFME) technique to be used as an alternative approach to liquid-liquid extraction (LLE). Polydimethylsiloxane/divinylbenzene (PDMS/DVB) and PDMS/DVB-carbon mesh supported membranes were used for the extraction of 23 targeted pesticides, while a thermal desorption unit (TDU) was employed to transfer these analytes to a GC/MS instrument for separation and detection. After optimization of the most critical parameters, both membranes were capable of achieving limits of detection (LOD) in the low ng L-1 range while demonstrating excellent robustness, withstanding up to 100 extractions/desorption cycles. Furthermore, limits of quantification (LOQ) between 0.025 and 0.50 MUg L-1 were achieved for the 23 compounds selected from several classes of pesticides with a wide range of polarities. A wide linear range of 0.025-10.0 MUg L-1 with strong correlation to response (R2 > 0.99) was attained for most of the studied analytes. Both membranes showed good accuracy and repeatability at three levels of concentration. Moreover, the method was also validated through blind split analyses of 18 surface water samples, collected within 3 months, using TFME at the University of Waterloo and LLE at Maxxam Analytics (Mississauga, ON) which is an accredited commercial analytical laboratory. Good agreement between the two methods was achieved with accuracy values ranging from 70 to 130%, for the majority of analytes in the samples collected. At the concentration levels investigated, 90% of the analytes were quantifiable by TFME, whereas only 53% of the compounds were reportable using the LLE method particularly at concentrations lower than 1 MUg L-1. The comparison of TFME and LLE from several analytical aspects demonstrated that the novel TFME method gave similar accuracy to LLE, while providing additional advantages including higher sensitivity, lower sample volume, thus reduced waste production, and faster analytical throughput. Given the sensitivity, simplicity, low cost, accuracy, greenness and relatively fast procedure of TFME, it shows great potential for adoption in analytical laboratories as an alternative to LLE. PMID- 28351643 TI - Chemically modified halloysite nanotubes as a solid-phase microextraction coating. AB - Halloysite nanotubes were modified in three simple steps including etching, hydroxylation and amino grafting. The sol-gel technique was used for the chemical bonding of the modified halloysite nanotubes (MHNTs) to fused-silica support. The MHNTs, as a novel adsorbent was applied as a SPME coating. Diazinon, parathion and fenthion were selected as the model compounds to study the extraction efficiency of the coating. Gas chromatography-corona discharge ion mobility spectrometry was applied for the analysis of the extracted analytes. The parameters influencing the extraction efficiency of the method, such as stirring rate, salt effect, extraction temperature and time were optimized. The results showed that the MHNTs fiber had better extraction efficiency than the commercial SPME (PA, PDMS, and PDMS-DVB), bare silica, silica-based HNTs and HNTs-titanium dioxide fibers. The limits of detection were found to be in the range of 0.01 0.03 MUg L-1. The limits of quantification were in the range of 0.03-0.07 MUg L 1. Also, a good linearity in the range of 0.03-3.0, 0.07-2.0 and 0.03-3.0 MUg L 1, was found for diazinon, fenthion and parathion, respectively. The method precision was lower than 7.0 and 8.7% as the intra- and inter-day relative standard deviations, respectively. Agricultural wastewater, cucumber and apple were chosen as the real samples. The spiking recovery values were between 84 (+/ 9) and 97% (+/-6). The results showed that the method was applicable and suitable for real samples analysis. PMID- 28351644 TI - Silica- and germania-based dual-ligand sol-gel organic-inorganic hybrid sorbents combining superhydrophobicity and pi-pi interaction. The role of inorganic substrate in sol-gel capillary microextraction. AB - Principles of sol-gel chemistry were utilized to create silica- and germania based dual-ligand surface-bonded sol-gel coatings providing enhanced performance in capillary microextraction (CME) through a combination of ligand superhydrophobicity and pi-pi interaction. These organic-inorganic hybrid coatings were prepared using sol-gel precursors with bonded perfluorododecyl (PF C12) and phenethyl (PhE) ligands. Here, the ability of the PF-C12 ligand to provide enhanced hydrophobic interaction was advantageously combined with pi-pi interaction capability of the PhE moiety to attain the desired sorbent performance in CME. The effect of the inorganic sorbent component on microextraction performance of was explored by comparing microextraction characteristics of silica- and germania-based sol-gel sorbents. The germania based dual-ligand sol-gel sorbent demonstrated superior CME performance compared to its silica-based counterpart. Thermogravimetric analysis (TGA) of the created silica- and germania-based dual-ligand sol-gel sorbents suggested higher carbon loading on the germania-based sorbent. This might be indicative of more effective condensation of the organic ligand-bearing sol-gel-active chemical species to the germania-based sol-gel network (than to its silica-based counterpart) evolving in the sol solution. The type and concentration of the organic ligands were varied in the sol-gel sorbents to fine-tune extraction selectivity toward different classes of analytes. Specific extraction (SE) values were used for an objective comparison of the prepared sol-gel CME sorbents. The sorbents with higher content of PF-C12 showed remarkable affinity for aliphatic hydrocarbons. Compared to their single-ligand sol-gel counterparts, the dual-ligand sol-gel coatings demonstrated significantly superior CME performance in the extraction of alkylbenzenes, providing up to ~65.0% higher SE values. The prepared sol-gel CME coatings provided low ng L-1 limit of detections (LOD) (4.2-26.3 ng L-1) for environmentally important analytes including polycyclic aromatic hydrocarbons, ketones and aliphatic hydrocarbons. In CME-GC experiments (n = 5), the capillary to-capillary RSD value was ~2.1%; such a low RSD value is indicative of excellent reproducibility of the sol-gel method used for the preparation of these CME coatings. The dual-ligand sol-gel coating provided stable performance in capillary microextraction of analytes from saline samples. PMID- 28351646 TI - Multifaceted link between metabolism and cancer. PMID- 28351645 TI - Targeting of 12/15-Lipoxygenase in retinal endothelial cells, but not in monocytes/macrophages, attenuates high glucose-induced retinal leukostasis. AB - AIMS: Our previous studies have established a role for 12/15-lipoxygenase (LO) in mediating the inflammatory response in diabetic retinopathy (DR). However, the extent at which the local or systemic induction of 12/15-LO activity involved is unclear. Thus, the current study aimed to characterize the relative contribution of retinal endothelial versus monocytic/macrophagic 12/15-LO to inflammatory responses in DR. MATERIALS & METHODS: We first generated a clustered heat map for circulating bioactive lipid metabolites in the plasma of streptozotocin (STZ) induced diabetic mice using liquid chromatography coupled with mass-spectrometry (LC-MS) to evaluate changes in circulating 12/15-LO activity. This was followed by comparing the in vitro mouse endothelium-leukocytes interaction between leukocytes isolated from 12/15-LO knockout (KO) versus those isolated from wild type (WT) mice using the myeloperoxidase (MPO) assay. Finally, we examined the effects of knocking down or inhibiting endothelial 12/15-LO on diabetes-induced endothelial cell activation and ICAM-1 expression. RESULTS: Analysis of plasma bioactive lipids' heat map revealed that the activity of circulating 12/15-LO was not altered by diabetes as evident by no significant changes in the plasma levels of major metabolites derived from 12/15-lipoxygenation of different PUFAs, including linoleic acid (13-HODE), arachidonic acid (12- and 15- HETEs), eicosapentaenoic acid (12- and 15- HEPEs), or docosahexaenoic acid (17-HDoHE). Moreover, leukocytes from 12/15-LO KO mice displayed a similar increase in adhesion to high glucose (HG)-activated endothelial cells as do leukocytes from WT mice. Furthermore, abundant proteins of 12-LO and 15-LO were detected in human retinal endothelial cells (HRECs), while it was undetected (15-LO) or hardly detectable (12-LO) in human monocyte-like U937 cells. Inhibition or knock down of endothelial 12/15-LO in HRECs blocked HG-induced expression of ICAM-1, a well known identified important molecule for leukocyte adhesion in DR. CONCLUSION: Our data support that endothelial, rather than monocytic/macrophagic, 12/15-LO has a critical role in hyperglycemia-induced ICAM-1 expression, leukocyte adhesion, and subsequent local retinal barrier dysfunction. This may facilitate the development of more precisely targeted treatment strategies for DR. PMID- 28351648 TI - Hormonal control of the floral transition: Can one catch them all? AB - The transition to flowering marks a key adaptive developmental switch in plants which impacts on their survival and fitness. Different signaling pathways control the floral transition, conveying both endogenous and environmental cues. These cues are often relayed and/or modulated by different hormones, which might confer additional developmental flexibility to the floral process in the face of varying conditions. Among the different hormonal pathways, the phytohormone gibberellic acid (GA) plays a dominant role. GA is connected with the other floral pathways through the GA-regulated DELLA proteins, acting as versatile interacting modules for different signaling proteins. In this review, I will highlight the role of DELLAs as spatial and temporal modulators of different consolidated floral pathways. Next, building on recent data, I will provide an update on some emerging themes connecting other hormone signaling cascades to flowering time control. I will finally provide examples for some established as well as potential cross-regulatory mechanisms between hormonal pathways mediated by the DELLA proteins. PMID- 28351647 TI - APOBEC3B cytidine deaminase targets the non-transcribed strand of tRNA genes in yeast. AB - Variations in mutation rates across the genome have been demonstrated both in model organisms and in cancers. This phenomenon is largely driven by the damage specificity of diverse mutagens and the differences in DNA repair efficiency in given genomic contexts. Here, we demonstrate that the single-strand DNA-specific cytidine deaminase APOBEC3B (A3B) damages tRNA genes at a 1000-fold higher efficiency than other non-tRNA genomic regions in budding yeast. We found that A3B-induced lesions in tRNA genes were predominantly located on the non transcribed strand, while no transcriptional strand bias was observed in protein coding genes. Furthermore, tRNA gene mutations were exacerbated in cells where RNaseH expression was completely abolished (Deltarnh1Deltarnh35). These data suggest a transcription-dependent mechanism for A3B-induced tRNA gene hypermutation. Interestingly, in strains proficient in DNA repair, only 1% of the abasic sites formed upon excision of A3B-deaminated cytosines were not repaired leading to mutations in tRNA genes, while 18% of these lesions failed to be repaired in the remainder of the genome. A3B-induced mutagenesis in tRNA genes was found to be efficiently suppressed by the redundant activities of both base excision repair (BER) and the error-free DNA damage bypass pathway. On the other hand, deficiencies in BER did not have a profound effect on A3B-induced mutations in CAN1, the reporter for protein coding genes. We hypothesize that differences in the mechanisms underlying ssDNA formation at tRNA genes and other genomic loci are the key determinants of the choice of the repair pathways and consequently the efficiency of DNA damage repair in these regions. Overall, our results indicate that tRNA genes are highly susceptible to ssDNA-specific DNA damaging agents. However, increased DNA repair efficacy in tRNA genes can prevent their hypermutation and maintain both genome and proteome homeostasis. PMID- 28351649 TI - Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis. AB - BACKGROUND: Complete androgen insensitivity syndrome (CAIS) is an X-linked recessive disorder of sex development (DSD) where affected individuals are phenotypically female, but have an XY karyotype and testes. The risk of gonadal tumour development in CAIS may increase with age; incidence rates have been reported to be 0.8-22% in patients who have retained their gonads into adulthood. Consequently, gonadectomy has been recommended either during childhood or after puberty is complete, although there is no consensus on the optimal timing for this procedure. OBJECTIVE AND HYPOTHESES: To establish the frequency of histological abnormalities in CAIS in relation to the age at gonadectomy. METHOD: Data were collected from the Cambridge DSD database on patients with CAIS (n = 225; age range 3-88 years) who had undergone gonadectomy, and their age of gonadectomy, gonadal histology and immunohistochemistry. RESULTS: Evaluable data were obtained from 133 patients. Median age at gonadectomy was 14.0 years (range: 18 days-68 years). Pubertal status was: prepuberty, n = 62; postpuberty, n = 68. Thirteen cases were aged >20 years at gonadectomy. The pattern of histology is summarised in the Summary table. DISCUSSION: In this large case series of CAIS patients who had undergone gonadectomy, while the combined malignant and premalignant gonadal histology prevalence was 6.0%, the findings confirm the low occurrence of gonadal malignancy in CAIS, with a frequency of 1.5%. The two cases of malignancy were postpubertal. Germ cell neoplasia in situ (GCNIS) was observed in six cases, of which one occurred prepuberty and five postpuberty. The study highlighted difficulties in diagnosis of GCNIS and the need for histological analysis in expert centres. CONCLUSION: The results support the current recommendation that gonads in CAIS can be retained until early adulthood. The small number of individuals with gonadectomy after age 20 years do not allow firm conclusion regarding later adulthood. Therefore, it is recommended that the option of gonadectomy be discussed in adulthood. Some form of regular surveillance of the gonads is then recommended, although none of the available options are ideal. PMID- 28351650 TI - In pursuit of the perfect penis: Hypospadias repair outcomes. AB - Hypospadias is commonly assessed and repaired by pediatric urologists. Mild, distal hypospadias is generally more a cosmetic problem than a functional one and is more frequently encountered than severe, proximal hypospadias. Outcomes following repair, especially of mild phenotypes, are important to understand, but range widely in timing and measurability. Surgical complications, postoperative satisfaction of parents, patients, surgeons and even lay observers, urinary function, sexual function, and quality of life all may be considered as relevant outcomes of hypospadias repair. Existing studies examining these outcomes are diverse in their conclusions, but are important to understand when counseling parents and patients prior to any surgical intervention. PMID- 28351651 TI - A population-based study of prevalence trends and geospatial analysis of hypospadias and cryptorchidism compared with non-endocrine mediated congenital anomalies. AB - INTRODUCTION: Several reports have suggested an increase in the prevalence of hypospadias and cryptorchidism over the last few decades. Endocrine disruption caused by exposure to environmental chemicals has been postulated as a possible cause. OBJECTIVES: The objectives of our study were: 1) to determine whether the prevalence of hypospadias and cryptorchidism is increasing compared with other congenital anomalies not known to be mediated by endocrine factors; and 2) to perform a geospatial analysis of these congenital malformations looking for clustering that could offer insight into environmental risk factors. MATERIAL AND METHODS: Data were obtained from the Nova Scotia ATLEE Perinatal Database containing the perinatal records of all live births in Nova Scotia, Canada since 1988. Records from 1988 to 2013 defined the study cohort. Overall prevalence rates and prevalence trends by year were calculated for hypospadias, cryptorchidism, gastroschisis, and clubfoot. County of residence was collected and spatial autocorrelation testing for clustering was performed for each of the congenital anomalies. RESULTS: There were 258,147 live births during the study period. Overall prevalence rates for the four malformations over the study period were: hypospadias 78 per 10,000 male births, cryptorchidism 75 per 10,000 male births, clubfoot 24 per 10,000 total births, and gastroschisis 4 per 10,000 total births. Incidence rate ratios per year for hypospadias, cryptorchidism, clubfoot, and gastroschisis were 1.00 (0.99-1.01), 0.99 (0.98-1.00), 0.98 (0.97-0.99), and 1.04 (1.04-1.07), respectively. During the study period, the prevalence rates in the region were unchanged for hypospadias, slightly reduced for cryptorchidism and clubfoot, and rising for gastroschisis (Figure). Spatial autocorrelation testing revealed statistically significant clustering for hypospadias (p = 0.03) and cryptorchidism (p = 0.03), while no spatial autocorrelation was observed for the other malformations. DISCUSSION: Contrary to previous studies we show that hypospadias and cryptorchidism prevalence rates are not increasing over time in our region. Nonetheless, rates for these conditions in our area are high compared with other regions of the world. Local clustering of these congenital anomalies without clustering of the control, non-endocrine mediated congenital malformations supports a possible unique spatial distribution associated with environmental exposure. The hotspots identified for hypospadias and cryptorchidism are associated with intense agricultural activity. CONCLUSIONS: Our study found no increase in hypospadias and cryptorchidism prevalence over a 26-year period compared with other congenital anomalies not known to be associated with endocrine factors. Geospatial analysis supports high clustering for hypospadias and cryptorchidism in areas of intense agricultural activity. PMID- 28351652 TI - Gallstones: Bad Company for the Steatotic Liver. PMID- 28351653 TI - Should We All Be Using the Doppler Endoscopic Probe in Nonvariceal Upper Gastrointestinal Bleeding? PMID- 28351654 TI - Lignin-enzyme interaction: Mechanism, mitigation approach, modeling, and research prospects. AB - The adverse environmental impacts of the fossil fuel and the concerns of energy security necessitate the development of alternative clean energy sources from renewable feedstocks. Lignocellulosic biomass is a 2nd generation feedstock used in the production of biofuels and bio-based products that are conventionally derived from fossil resources. The biochemical conversion, which entails biomass pretreatment, enzymatic hydrolysis and fermentation, is one major platform used to transform lignocelluloses into biofuels. However, lignin presents many challenges to enzymatic hydrolysis leading to the need of high enzyme dose, low hydrolysis yield, low level of recyclability, high cost of enzymatic hydrolysis (because of the high cost of enzymes), and so on. Therefore, enzymatic hydrolysis, which is not cost effective, becomes one of major cost contributors. To mitigate the negative effects of lignin, extensive research has been conducted to explore the fundamental mechanisms of lignin-enzyme interactions to develop technologies to overcome the negative effects of lignin on enzymatic hydrolysis. Non-productive adsorption, which is characterized by hydrophobic, electrostatic and/or hydrogen bonding interactions, is widely known as the primary mechanism governing lignin-enzyme interactions. In addition, lignin-enzyme interaction is also influenced by steric hindrance (i.e., the physical blocking of enzyme access to carbohydrates by lignin). However, the mechanisms underlying the lignin-enzyme interactions remain unclear. This article aims to present a comprehensive review on the lignin-enzyme interactions (i.e. the mechanism, governing driving forces, modeling, and technologies for mitigating the negative effect of lignin). The current challenges inherent in this process and possible avenues of research in cellulosic biorefinery conclude this article. PMID- 28351655 TI - Arterial hypertension and aortic valve stenosis: Shedding light on a common "liaison". AB - Arterial hypertension and aortic valve stenosis are common disorders and frequently present as concomitant diseases, especially in elderly patients. The impact of hypertension on heart haemodynamics is substantial, thus affecting the clinical presentation of any coexisting valvulopathy, especially of aortic stenosis. However, the interaction between these 2 entities is not thoroughly discussed in the European or/and American guidelines on the management of hypertension or/and valvular heart disease. The present review summarizes all available evidence on the potential interplay between hypertension and aortic valve stenosis, aiming to help physicians understand the pathophysiology and select the best diagnostic and therapeutic strategies (medical or/and interventional) for better management of these high-risk patients, taking into account the impact on outcome as well as the risk-benefit-ratio. PMID- 28351657 TI - Do opinion articles attract more social attention than original research, relative to their citation counts? PMID- 28351656 TI - Ventricular arrhythmogenic potential assessment in an asymptomatic ischemic cardiomyopathy patient with a normal ejection fraction. PMID- 28351658 TI - Pharyngeal Airway Space and Hyoid Bone Positioning After Different Orthognathic Surgeries in Skeletal Class II Patients. AB - PURPOSE: To obtain good profiles, patients with severe skeletal Class II malocclusion require orthognathic surgery, which might change their airway space and, hence, influence their quality of sleep. The present study aimed to 1) determine the effect of different orthognathic surgeries on pharyngeal airway space and hyoid bone position in patients with skeletal Class II malocclusion and 2) evaluate the stability of changes in the pharyngeal airway space and hyoid bone position after orthognathic surgeries. MATERIALS AND METHODS: Patients with severe skeletal Class II malocclusion who underwent mandibular advancement (MA) or mandibular advancement and maxillary setback (MAMS) were included in this retrospective cohort study. Changes in the pharyngeal airway space and hyoid bone position were evaluated as the primary outcome variables. Measurements were obtained before surgery (T1), 1 month after surgery (T2), and 2 years after surgery (T3) using Dolphin Imaging Software 11.0. Differences in measurements between T2 and T1 and between T3 and T1 were calculated and imported into SPSS 22.0 for data analysis. RESULTS: Fifty patients were included (25 in MA group and 25 in MAMS group). Oropharyngeal and hypopharyngeal airway cross-dimensions and areas were significantly increased in the MA group (P < .05) and the increases were stable at T3. In the MAMS group, the nasopharyngeal airway cross-dimension and area were decreased (P > .05), but the hypopharyngeal cross-dimension and area were significantly increased (P < .05). The hyoid bone moved superiorly and forward after surgery in the MA group (P < .05), and the movement was stable at T3. CONCLUSIONS: MA can widen the oropharyngeal and hypopharyngeal airway space, and maxillary setback can narrow the nasopharyngeal airway space. Some relapse related to the width of the oropharynx and hypopharynx was found at the long-term observation. The hyoid bone moved superiorly and forward in the MA group. PMID- 28351659 TI - Differences in Clinicopathological Characteristics and Prognosis Between Primary and Postirradiation Tongue Squamous Cell Carcinoma. AB - PURPOSE: Many cases of postirradiation oral carcinoma have been reported, but its prognosis and optimal treatment modalities are not clear. Thus, the clinicopathologic characteristics and prognosis between postirradiation tongue squamous cell carcinoma (PTSCC) and primary tongue squamous cell carcinoma (TSCC) were compared. PATIENTS AND METHODS: A retrospective cohort study was conducted to assess patients with PTSCC or TSCC. The primary predictor variable was tumor type. The primary outcome variable was prognosis, and the additional outcome variables were clinicopathologic characteristics. Survival analysis was performed, and Kaplan-Meier analysis was conducted to compare the effects of clinicopathologic factors on survival using SPSS 18.0. Moreover, the Cox model was applied in multivariate analysis. RESULTS: The sample was composed of 449 patients with PTSCC (n = 68; 47 men and 21 women; age range, 31 to 72 yr) and TSCC (n = 381; 247 men and 134 women; age range, 20 to 86 yr). Patients with PTSCC were found to have a substantially poorer prognosis and several specific clinicopathologic characteristics compared with patients with TSCC. CONCLUSION: Patients with PTSCC had several unique biological tumor characteristics and a poorer prognosis than patients with TSCC. Thus, different surgical strategies should be used to treat patients with PTSCC. PMID- 28351661 TI - Immunostimulatory Endogenous Nucleic Acids Drive the Lesional Inflammation in Cutaneous Lupus Erythematosus. AB - Cutaneous lupus erythematosus (CLE) is a photosensitive autoimmune disease characterized by a strong type I IFN-associated inflammation. Keratinocytes are known to determine the interface dermatitis pattern in CLE by production of proinflammatory cytokines in the lower epidermis. These cytokines drive a cytotoxic anti-epithelial immune response resulting in keratinocytic cell death and release of endogenous nucleic acids. We hypothesized that these endogenous nucleic acids (RNA and DNA motifs) have the capacity to activate innate immune pathways in keratinocytes via pathogen recognition receptors. Gene expression analyses showed an excessive activation of innate immune response pathways with strong expression of IFN-regulated cytokines in CLE skin lesions. Cultured keratinocytes produce large amounts of these cytokines in response to stimulation of PRR with endogenous nucleic acids. UV stimulation enhances the immunogenicity of endogenous nucleic acids and induces CLE-like skin lesions in knockout mice lacking the cytosolic DNase TREX1. Our results provide evidence for a pathogenetic role of endogenous nucleic acids in CLE. They are released within the cytotoxic inflammation along the dermo-epidermal junction and have the capacity to drive the CLE-typical inflammation. UV irradiation supports this inflammation by generation of highly immunostimulatory DNA motifs (8 hydroxyguanosine). These findings explain the photosensitivity of patients with lupus and identify pathways of the innate immune system as targets for future therapies. PMID- 28351660 TI - TWEAK/Fn14 Activation Contributes to the Pathogenesis of Bullous Pemphigoid. AB - TWEAK participates in various cellular effects by engaging its receptor of Fn14. Increased levels of soluble TWEAK are associated with systemic autoimmunity in patients with lupus erythematosus, rheumatoid arthritis, or dermatomyositis. However, the role of TWEAK in bullous pemphigoid (BP) remains unknown. In this study, we found an elevated serum level of TWEAK and a positive correlation between serum TWEAK and anti-BP180 antibodies. Immunohistochemistry showed strong TWEAK and Fn14 expression and implied an opposite relationship between the TWEAK and BP180 expression in skin samples from BP patients. In vitro TWEAK stimuli reduced BP180 expression in HaCaT cells and inhibited the adhesion of cells to the culture dish. Consistently, the transfection of Fn14 small interfering RNA preserved BP180 and protected cells from losing adherence. Moreover, such effect of TWEAK correlated with activation of the extracellular signal-regulated kinase and NF-kappaB pathways and downstream ADAMs. By silencing ADAM17 with small interfering RNA, we showed that ADAM17 participated in TWEAK-induced BP180 loss. Therefore, TWEAK may contribute to the pathogenesis of BP by reducing BP180 expression and cellular adherence, involving the activation of ERK and NF-kappaB pathways. TWEAK may serve as a biomarker or therapeutic target of BP. PMID- 28351662 TI - Learning a commonsense moral theory. AB - We introduce a computational framework for understanding the structure and dynamics of moral learning, with a focus on how people learn to trade off the interests and welfare of different individuals in their social groups and the larger society. We posit a minimal set of cognitive capacities that together can solve this learning problem: (1) an abstract and recursive utility calculus to quantitatively represent welfare trade-offs; (2) hierarchical Bayesian inference to understand the actions and judgments of others; and (3) meta-values for learning by value alignment both externally to the values of others and internally to make moral theories consistent with one's own attachments and feelings. Our model explains how children can build from sparse noisy observations of how a small set of individuals make moral decisions to a broad moral competence, able to support an infinite range of judgments and decisions that generalizes even to people they have never met and situations they have not been in or observed. It also provides insight into the causes and dynamics of moral change across time, including cases when moral change can be rapidly progressive, changing values significantly in just a few generations, and cases when it is likely to move more slowly. PMID- 28351664 TI - Analysis of macrobenthic assemblages and ecological health of Yellow River Delta, China, using AMBI & M-AMBI assessment method. AB - Yellow River delta (YRD) is a typical example of a valuable coastal ecosystem that is under increasing anthropogenic threat in China. To understand the current health status of this region, three surveys in 2011 for the abiotic conditions and macrobenthic assemblages were performed. The concentration of trace metals were relatively low in the sediment at all sampling stations representing a good sediment quality. A total of 159 macrobenthic species were identified during the three surveys. ABC curves showed that the macrobenthic fauna at 8 sampling stations suffered disturbances from human activities. M-AMBI index indicates that the benthic ecological quality of YRD is currently still not in a good condition. Five trace metals, water temperature and depth were the main environmental variables affecting the distribution pattern of macrobenthic assemblages. Community succession has occurred over the past 60years, as evidenced by changes of species composition, key species, distribution pattern and range. PMID- 28351663 TI - Effects of sediment contamination on physiological and biochemical responses of the polychaete Diopatra neapolitana, an exploited natural resource. AB - The present study reports metal and arsenic contamination in sediments, as well as element accumulation and partitioning in the polychaete Diopatra neapolitana in the Ria de Aveiro lagoon (Portugal). The polychaetes biochemical performance and tissue regenerative capacity were also evaluated. The concentration of elements in sediments showed an increase of contamination among areas (areas A G), but higher bioaccumulation was observed in organisms from a less contaminated area (area C, BAF>1). This study evidenced that individuals with higher elements bioaccumulation presented higher LPO and lower GSH/GSSG and also exhibited lower capacity for body regeneration. Polychaetes biotransformation capacity as well as antioxidant defense mechanisms were not sufficiently efficient to withstand the excess of ROS leading to increased LPO when organisms presented higher bioaccumulation levels. Additionally, an increase of methalotionines was also observed in individuals with higher bioaccumulation of metals and As, suggesting an induction of detoxification processes. PMID- 28351665 TI - ApoB and apoM - New aspects of lipoprotein biology in uremia-induced atherosclerosis. AB - Chronic kidney disease affects as much as 13% of the population, and is associated with a markedly increased risk of developing cardiovascular disease. One of the underlying reasons is accelerated development of atherosclerosis. This can be ascribed both to increased occurrence of traditional cardiovascular risk factors, and to risk factors that may be unique to patients with chronic kidney disease. The latter is reflected in the observation that the current treatment modalities, mainly directed against traditional risk factors, are insufficient to prevent cardiovascular disease in the patient with chronic kidney disease. This review discusses mechanisms accelerating uremic atherosclerosis with a specific focus on the putative roles of apolipoprotein(apo)s B and M that may be particularly important in patients with chronic kidney disease. PMID- 28351666 TI - Operculina turpethum extract inhibits growth and proliferation by inhibiting NF kappaB, COX-2 and cyclin D1 and induces apoptosis by up regulating P53 in oral cancer cells. AB - OBJECTIVES: Herbal drugs are popularly emerging as complementary and alternative medicines in cancer patients because of their cost effectiveness and minimal side effects. The extract of Operculina turpethum (OT) is known to have antipyretic, anti-inflammatory and purgative properties. Since it is popularly known have antiinflammatory activity, we investigated its anti-tumor activity on four oral squamous cell carcinoma cell lines (OSCC) namely, (SCC-4, KB, SCC-9 and SCC-25). DESIGN: Antitumor activities of Operculina turpathum extract (OTE) was investigated by MTT and clonogenic assay, effect on cell cycle and apoptosis induction by Annexin-V/propidium iodide (PI) staining and flow cytometry and invasive potential of the tumor was determined by matrigel assay. The expression of various proteins involved in these mechanisms was analysed by western blotting. RESULTS: OTE specifically inhibited the growth and colony formation of OSCC cells in a dose-dependent manner via inhibiting NF-kappaB and its downstream target COX-2. It further arrested cell cycle at G0/G1 phase by inhibiting cyclin D1 and induced early apoptosis by up-regulating P53 in OSCC cells. It also limits the invasion capacity of OSCC cells by up to 55-60%. CONCLUSIONS: OTE shows antitumor activities in OSCC cells by inhibiting NF-kappaB, COX-2 and cyclin D1 and upregulation of p53 expression. It may be developed as a safe and promising alternative chemopreventive/chemotherapeutic agent for oral cancer. PMID- 28351667 TI - Pyrilamine-sensitive proton-coupled organic cation (H+/OC) antiporter for brain specific drug delivery. AB - Blood-brain barrier (BBB) represents the greatest challenge that hampers therapeutic molecules entering the brain. Here, we described a novel brain specific delivery strategy targeting to pyrilamine-sensitive H+/OC antiporter to facilitate therapeutic molecules cross the BBB and penetrate into the brain. In this study, four cyclic tertiary amines were selected as the brain-targeting moieties to modify naproxen (NP), a non-steroidal anti-inflammatory drug. The obtained NP conjugates displayed cell uptake efficiencies over 144-fold higher than that of unmodified NP in endothelial cells. The cell uptake process of the conjugates was primarily driven by pyrilamine-sensitive H+/OC antiporter in a pH dependent, Na+-independent, and membrane potential-independent pathway, which could be further inhibited by pyrilamine, propranolol, and imipramine. Moreover, the NP conjugates showed significantly higher AUC0-t and Cmax in the brain compared with unmodified NP, and significantly higher accumulation than NP in the in situ brain perfusion study. Also, the conjugates showed superior neuroprotective effect in vitro and in vivo. Thus, the chemical modification of therapeutics with a cyclic tertiary amine moiety represents a promising and efficient strategy for brain-specific drug delivery via pyrilamine-sensitive H+/OC antiporter. PMID- 28351669 TI - Effect of maximum inhalation flow and inhaled volume on formoterol drug deposition in-vitro from an Easyhaler(r) dry powder inhaler. AB - Most patients using dry powder inhalers (DPIs) do not achieve the inhalation parameters recommended for pharmacopoeial in-vitro dose emission testing. The dose emission characteristics of formoterol from an Easyhaler(r) have been measured using the Andersen Cascade Impactor (ACI) with a maximum inhalation flow (MIF) of 28.3, 60 and 90L/min and inhaled volumes (Vin) of 240, 750, 1500 and 2000mL. The total emitted dose (TED) was significantly higher at 90L/min (p<0.05), but the difference in the TED between low (28.3L/min) and high (90L/min) flow rate was significantly reduced by increasing the Vin. The fine particle dose (FPD) was higher (p<0.05) at 90L/min for all Vin values compared to 28.3 and 60L/min. Similarly the mass median aerodynamic diameter (MMAD) was smaller at 90L/min across all Vin values. Dose emission characteristics were lower at 240mL for both MIFs. The results for 240mL could be due to an insufficient Vin pulled through the ACI or incomplete emptying of the dose metering cup. This study shows that the FPD, %FPF and MMAD were not significantly affected by the vin>=750mL and that an inhaled volume as low as 750mL could be used with the ACI. PMID- 28351668 TI - Polymeric nanoparticles as cancer-specific DNA delivery vectors to human hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the third most deadly cancer in the US, with a meager 5-year survival rate of <20%. Such unfavorable numbers are closely related to the heterogeneity of the disease and the unsatisfactory therapies currently used to manage patients with invasive HCC. Outside of the clinic, gene therapy research is evolving to overcome the poor responses and toxicity associated with standard treatments. The inadequacy of gene delivery vectors, including poor intracellular delivery and cell specificity, are major barriers in the gene therapy field. Herein, we described a non-viral strategy for effective and cancer specific DNA delivery to human HCC using biodegradable poly(beta-amino ester) (PBAE) nanoparticles (NPs). Varied PBAE NP formulations were evaluated for transfection efficacy and cytotoxicity to a range of human HCC cells as well as healthy human hepatocytes. To address HCC heterogeneity, nine different sources of human HCC cells were utilized. The polymeric NPs composed of 2-((3 aminopropyl)amino) ethanol end-modified poly(1,5-pentanediol diacrylate-co-3 amino-1-propanol) ('536') at a 25 polymer-to-DNA weight-to-weight ratio led to high transfection efficacy to all of the liver cancer lines, but not to hepatocytes. Each individual HCC line had a significantly higher percentage of exogenous gene expression than the healthy liver cells (P<0.01). Notably, this biodegradable end-modified PBAE gene delivery vector was not cytotoxic and maintained the viability of hepatocytes above 80%. In a HCC/hepatocyte co-culture model, in which cancerous and healthy cells share the same micro-environment, 536 25 w/w NPs specifically transfected cancer cells. PBAE NP administration to a subcutaneous HCC mouse model, established with one of the human lines tested in vitro, confirmed effective DNA transfection in vivo. PBAE-based NPs enabled high and preferential DNA delivery to HCC cells, sparing healthy hepatocytes. These biodegradable and liver cancer-selective NPs are a promising technology to deliver therapeutic genes to liver cancer. PMID- 28351670 TI - Preemptive analgesia for postoperative hysterectomy pain control: systematic review and clinical practice guidelines. AB - OBJECTIVE: The objective of the study was to investigate the effectiveness of preemptive analgesia at pain control in women undergoing total abdominal hysterectomy. DATA SOURCES: Eligible studies, published through May 31, 2016, were retrieved through Medline, Cochrane Central Register for Controlled Trials, and Cochrane Database of Systematic Reviews. STUDY ELIGIBILITY: We included randomized controlled trials with the primary outcome of pain control in women receiving a preemptive medication prior to total abdominal hysterectomy. Comparators were placebo, different doses of the same medication as intervention, or other nonnarcotic or narcotic medication. STUDY APPRAISAL AND SYNTHESIS METHODS: Study data were extracted by one reviewer and confirmed by a second reviewer. For each outcome we graded the quality of the evidence. Studies were classified by the type of medication used and by outcome type. RESULTS: Eighty four trials met eligibility, with 69 included. Among nonnarcotic medications, paracetamol, gabapentin, and rofecoxib combined with gabapentin resulted in improvements in pain assessment compared with placebo and other nonnarcotic medications. Patient satisfaction was higher in patients who were given gabapentin combined with paracetamol compared with gabapentin alone. Use of preemptive paracetamol, gabapentin, bupivacaine, and phenothiazine resulted in less narcotic usage than placebo. All narcotics (ketamine, morphine, fentanyl) resulted in improved pain control compared with placebo. Narcotics had a greater reduction in pain assessment scores compared with nonnarcotics, and their use resulted in lower total narcotic usage. CONCLUSION: Preemptive nonnarcotic and narcotic medications prior to abdominal hysterectomy decrease total narcotic requirements and improve patient postoperative pain assessment and satisfaction scores. PMID- 28351671 TI - Eating patterns in adolescents with type 1 diabetes: Associations with metabolic control, insulin omission, and eating disorder pathology. AB - OBJECTIVE: The purpose of this study was to investigate eating patterns among male and female adolescents with type 1 diabetes (T1D), and the associations with age, zBMI, eating disorder (ED) pathology, intentional insulin omission, and metabolic control. METHOD: The sample consisted of 104 adolescents (58.6% females) with child-onset T1D, mean age of 15.7 years (SD 1.8) and mean zBMI of 0.4 (SD 0.8). The Child Eating Disorder Examination (ChEDE) assessed meal/snack frequency and ED pathology. T1D clinical data was obtained from the Norwegian Childhood Diabetes Registry. RESULTS: A significantly lower proportion of females than males (73.8% vs 97.7%) consumed breakfast on a daily basis. Approximately 50% of both genders ate lunch and 90% ate dinner daily. Among females, skipping breakfast was significantly associated with higher global ED psychopathology, shape concerns, self-induced vomiting, binge eating, insulin omission due to shape/weight concerns, and poorer metabolic control. Less frequent lunch consumption was significantly associated with poorer metabolic control. Skipping dinner was significantly associated with older age, higher dietary restraint, eating concerns, self-induced vomiting, and insulin omission. Among males, less frequent consumption of lunch and evening snacks was associated with attitudinal features of ED, including shape/weight concerns and dietary restraint. DISCUSSION: Among adolescents with T1D, irregular or infrequent meal consumption appears to signal potential ED pathology, as well as being associated with poorer metabolic control. These findings suggest the importance of routinely assessing eating patterns in adolescents with T1D to improve detection of ED pathology and to facilitate improved metabolic control and the associated risk of somatic complications. PMID- 28351672 TI - Redesigning pH optimum of Geobacillus sp. TF16 endoxylanase through in silico designed DNA swapping strategy. AB - Thermoalkaliphilic xylanases are highly desired and of great importance due to their vast potential in paper pulp and bleaching processes. Here, we report rapid, cost-effective, and result-oriented combinatorial potential of in silico DNA swapping strategy to engineer the pH optimum of industrially crucial enzymes, particularly engineering of Geobacillus sp. TF16 endoxylanase for alkaline environments. The 3D structures of Geobacillus sp. TF16 and donor Bacillus halodurans C-125 endoxylanases were firstly predicted, analyzed, and compared for their similarities before any in silico design of mutants. Reasonably, to improve its alkaline pH tolerance, the corresponding regions in Geobacillus sp.TF16 endoxylanase were further engineered by swapping with negatively-charged amino acid-rich regions from B. halodurans C-125 endoxylanase. Through only two of four in silico-designed mutants, the optimum pH of GeoTF16 endoxylanase was improved from 8.5 to 10.0. Moreover, as compared to GeoTF16 parental enzyme, both GeoInt3 and GeoInt4 mutants revealed (i) enhanced biobleaching performance, (ii) improved adaptability to alkaline conditions, and (iii) better activity for broader pH range. Unlike GeoTF16 losing activity at pH 11.0 completely, GeoInt4 retained 60% and 40% of its activity at pH 11.0 and 12.0, respectively. Thus, GeoInt4 stands out as a more competent biocatalyst that is suitable for alkaline environments of diverse industrial applications. The current study represents an efficient protein engineering strategy to adapt industrial catalysts to diverse processing conditions. Further comprehensive and fine-tuned research efforts may result in biotechnologically more promising outcomes. PMID- 28351674 TI - A simple approach to measure transmissibility and forecast incidence. AB - Outbreaks of novel pathogens such as SARS, pandemic influenza and Ebola require substantial investments in reactive interventions, with consequent implementation plans sometimes revised on a weekly basis. Therefore, short-term forecasts of incidence are often of high priority. In light of the recent Ebola epidemic in West Africa, a forecasting exercise was convened by a network of infectious disease modellers. The challenge was to forecast unseen "future" simulated data for four different scenarios at five different time points. In a similar method to that used during the recent Ebola epidemic, we estimated current levels of transmissibility, over variable time-windows chosen in an ad hoc way. Current estimated transmissibility was then used to forecast near-future incidence. We performed well within the challenge and often produced accurate forecasts. A retrospective analysis showed that our subjective method for deciding on the window of time with which to estimate transmissibility often resulted in the optimal choice. However, when near-future trends deviated substantially from exponential patterns, the accuracy of our forecasts was reduced. This exercise highlights the urgent need for infectious disease modellers to develop more robust descriptions of processes - other than the widespread depletion of susceptible individuals - that produce non-exponential patterns of incidence. PMID- 28351673 TI - Elucidating transmission dynamics and host-parasite-vector relationships for rodent-borne Bartonella spp. in Madagascar. AB - Bartonella spp. are erythrocytic bacteria transmitted via arthropod vectors, which infect a broad range of vertebrate hosts, including humans. We investigated transmission dynamics and host-parasite-vector relationships for potentially zoonotic Bartonella spp. in invasive Rattus rattus hosts and associated arthropod ectoparasites in Madagascar. We identified five distinct species of Bartonella (B. elizabethae 1, B. elizabethae 2, B. phoceensis 1, B. rattimassiliensis 1, and B. tribocorum 1) infecting R. rattus rodents and their ectoparasites. We fit standard epidemiological models to species-specific age-prevalence data for the four Bartonella spp. with sufficient data, thus quantifying age-structured force of infection. Known zoonotic agents, B. elizabethae 1 and 2, were best described by models exhibiting high forces of infection in early age class individuals and allowing for recovery from infection, while B. phoceensis 1 and B. rattimassiliensis 1 were best fit by models of lifelong infection without recovery and substantially lower forces of infection. Nested sequences of B. elizabethae 1 and 2 were recovered from rodent hosts and their Synopsyllus fonquerniei and Xenopsylla cheopsis fleas, with a particularly high prevalence in the outdoor-dwelling, highland-endemic S. fonquerniei. These findings expand on force of infection analyses to elucidate the ecological niche of the zoonotic Bartonella elizabethae complex in Madagascar, hinting at a potential vector role for S. fonquerniei. Our analyses underscore the uniqueness of such ecologies for Bartonella species, which pose a variable range of potential zoonotic threats. PMID- 28351675 TI - Spatial organization of organelles in fungi: Insights from mathematical modelling. AB - Mathematical modelling in cellular systems aims to describe biological processes in a quantitative manner. Most accurate modelling is based on robust experimental data. Here we review recent progress in the theoretical description of motor behaviour, early endosome motility, ribosome distribution and peroxisome transport in the fungal model system Ustilago maydis and illustrate the power of modelling in our quest to understand molecular details and cellular roles of membrane trafficking in filamentous fungi. PMID- 28351677 TI - Toxicological evaluation of ethanolic extract from Stevia rebaudiana Bertoni leaves: Genotoxicity and subchronic oral toxicity. AB - Stevia rebaudiana Bertoni leaves have a long history of use as an abundant source of sweetener. The aqueous extract of stevia leaves and the predominant constitutes steviol glycosides have been intensively investigated. However, rare studies provided toxicological evaluation of bioactive components in the polar extract regarding their safety on human health. This study aimed to evaluate the toxicity of ethanolic extract of Stevia rebaudiana Bertoni leaves through a battery of in vitro and in vivo tests. Negative results were unanimously obtained from bacterial reverse mutation assay, mouse bone marrow micronucleus assay and mouse sperm malformation assay. Oral administration at dietary levels of 1.04%, 2.08% and 3.12% for 90 days did not induce significant behavioral, hematological, clinical, or histopathological changes in rats. Significant reduction of cholesterol, total protein and albumin was observed in female animals only at high dose level. The results demonstrated that Stevia rebaudiana Bertoni leaves ethanolic extract, which is rich in isochlorogenic acids, does not possess adverse effects through oral administration in this study. Our data provided supportive evidence for the safety of Stevia rebaudiana Bertoni leaves that may potentially be used in functional foods as well as nutritional supplements beyond sweetner. PMID- 28351678 TI - The pharmacokinetics and metabolism of lumiracoxib in chimeric humanized and murinized FRG mice. AB - The pharmacokinetics and metabolism of lumiracoxib were studied, after administration of single 10mg/kg oral doses to chimeric liver-humanized and murinized FRG mice. In the chimeric humanized mice, lumiracoxib reached peak observed concentrations in the blood of 1.10+/-0.08MUg/mL at 0.25-0.5h post-dose with an AUCinf of 1.74+/-0.52MUgh/mL and an effective half-life for the drug of 1.42+/-0.72h (n=3). In the case of the murinized animals peak observed concentrations in the blood were determined as 1.15+/-0.08MUg/mL at 0.25h post dose with an AUCinf of 1.94+/-0.22MUgh/mL and an effective half-life of 1.28+/ 0.02h (n=3). Analysis of blood indicated only the presence of unchanged lumiracoxib. Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected. The profiles obtained in humanized mice were different compared to murinized animals with e.g., a higher proportion of the dose detected in the form of acyl glucuronide metabolites and much reduced amounts of taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57bl/6J mice and humans, revealed a greater though not complete match between chimeric humanized mice and humans, such that the liver-humanized FRG model may represent a useful approach to assessing the biotransformation of such compounds in humans. PMID- 28351676 TI - Uncoupling protein 2 and metabolic diseases. AB - Mitochondria are fascinating organelles involved in various cellular-metabolic activities that are integral for mammalian development. Although they perform diverse, yet interconnected functions, mitochondria are remarkably regulated by complex signaling networks. Therefore, it is not surprising that mitochondrial dysfunction is involved in plethora of diseases, including neurodegenerative and metabolic disorders. One of the many factors that lead to mitochondrial associated metabolic diseases is the uncoupling protein-2, a family of mitochondrial anion proteins present in the inner mitochondrial membrane. Since their discovery, uncoupling proteins have attracted considerable attention due to their involvement in mitochondrial-mediated oxidative stress and energy metabolism. This review attempts to provide a summary of recent developments in the field of uncoupling protein 2 relating to mitochondrial associated metabolic diseases. PMID- 28351679 TI - 3D high-resolution two-photon crosslinked hydrogel structures for biological studies. AB - : Hydrogels are widely used as matrices for cell growth due to the their tuneable chemical and physical properties, which mimic the extracellular matrix of natural tissue. The microfabrication of hydrogels into arbitrarily complex 3D structures is becoming essential for numerous biological applications, and in particular for investigating the correlation between cell shape and cell function in a 3D environment. Micrometric and sub-micrometric resolution hydrogel scaffolds are required to deeply investigate molecular mechanisms behind cell-matrix interaction and downstream cellular processes. We report the design and development of high resolution 3D gelatin hydrogel woodpile structures by two photon crosslinking. Hydrated structures of lateral linewidth down to 0.5um, lateral and axial resolution down to a few um are demonstrated. According to the processing parameters, different degrees of polymerization are obtained, resulting in hydrated scaffolds of variable swelling and deformation. The 3D hydrogels are biocompatible and promote cell adhesion and migration. Interestingly, according to the polymerization degree, 3D hydrogel woodpile structures show variable extent of cell adhesion and invasion. Human BJ cell lines show capability of deforming 3D micrometric resolved hydrogel structures. STATEMENT OF SIGNIFICANCE: The design and development of high resolution 3D gelatin hydrogel woodpile structures by two-photon crosslinking is reported. Significantly, topological and mechanical conditions of polymerized gelatin structures were suitable for cell accommodation in the volume of the woodpiles, leading to a cell density per unit area comparable to the bare substrate. The fabricated structures, presenting micrometric features of high resolution, are actively deformed by cells, both in terms of cell invasion within rods and of cell attachment in-between contiguous woodpiles. Possible biological targets for this 3D approach are customized 3D tissue models, or studies of cell adhesion, deformation and migration. PMID- 28351680 TI - Human lung fibroblast-derived matrix facilitates vascular morphogenesis in 3D environment and enhances skin wound healing. AB - : Extracellular matrix (ECM) is crucial to many aspects of vascular morphogenesis and maintenance of vasculature function. Currently the recapitulation of angiogenic ECM microenvironment is still challenging, due mainly to its diverse components and complex organization. Here we investigate the angiogenic potential of human lung fibroblast-derived matrix (hFDM) in creating a three-dimensional (3D) vascular construct. hFDM was obtained via decellularization of in vitro cultured human lung fibroblasts and analyzed via immunofluorescence staining and ELISA, which detect multiple ECM macromolecules and angiogenic growth factors (GFs). Human umbilical vein endothelial cells (HUVECs) morphology was more elongated and better proliferative on hFDM than on gelatin-coated substrate. To prepare 3D construct, hFDM is collected, quantitatively analyzed, and incorporated in collagen hydrogel (Col) with HUVECs. Capillary-like structure (CLS) formation at 7day was significantly better with the groups containing higher doses of hFDM compared to the Col group (control). Moreover, the group (Col/hFDM/GFs) with both hFDM and angiogenic GFs (VEGF, bFGF, SDF-1) showed the synergistic activity on CLS formation and found much larger capillary lumen diameters with time. Further analysis of hFDM via angiogenesis antibody array kit reveals abundant biochemical cues, such as angiogenesis-related cytokines, GFs, and proteolytic enzymes. Significantly up-regulated expression of VE-cadherin and ECM-specific integrin subunits was also noticed in Col/hFDM/GFs. In addition, transplantation of Col/hFMD/GFs with HUVECs in skin wound model presents more effective re-epithelialization, many regenerated hair follicles, better transplanted cells viability, and advanced neovascularization. We believe that current system is a very promising platform for 3D vasculature construction in vitro and for cell delivery toward therapeutic applications in vivo. STATEMENT OF SIGNIFICANCE: Functional 3D vasculature construction in vitro is still challenging due to the difficulty of recapitulating the complex angiogenic extracellular matrix (ECM) environment. Herein, we present a simple and practical method to create an angiogenic 3D environment via incorporation of human lung fibroblast-derived matrix (hFDM) into collagen hydrogel. We found that hFDM offers a significantly improved angiogenic microenvironment for HUVECs on 2D substrates and in 3D construct. A synergistic effect of hFDM and angiogenic growth factors has been well confirmed in 3D condition. The prevascularized 3D collagen constructs also facilitate skin wound healing. We believe that current system should be a convenient and powerful platform in engineering 3D vasculature in vitro, and in delivering cells for therapeutic purposes in vivo. PMID- 28351681 TI - Regional mechanical properties of human brain tissue for computational models of traumatic brain injury. AB - : To determine viscoelastic shear moduli, stress relaxation indentation tests were performed on samples of human brain tissue resected in the course of epilepsy surgery. Through the use of a 500um diameter indenter, regional mechanical properties were measured in cortical grey and white matter and subregions of the hippocampus. All regions were highly viscoelastic. Cortical grey matter was significantly more compliant than the white matter or hippocampus which were similar in modulus. Although shear modulus was not correlated with the age of the donor, cortex from male donors was significantly stiffer than from female donors. The presented material properties will help to populate finite element models of the brain as they become more anatomically detailed. STATEMENT OF SIGNIFICANCE: We present the first mechanical characterization of fresh, post operative human brain tissue using an indentation loading mode. Indentation generates highly localized data, allowing structure-specific mechanical properties to be determined from small tissue samples resected during surgery. It also avoids pitfalls of cadaveric tissue and allows data to be collected before degenerative processes alter mechanical properties. To correctly predict traumatic brain injury, finite element models must calculate intracranial deformation during head impact. The functional consequences of injury depend on the anatomical structures injured. Therefore, morbidity depends on the distribution of deformation across structures. Accurate prediction of structure specific deformation requires structure-specific mechanical properties. This data will facilitate deeper understanding of the physical mechanisms that lead to traumatic brain injury. PMID- 28351682 TI - Two-photon polymerization for production of human iPSC-derived retinal cell grafts. AB - : Recent advances in induced pluripotent stem cell (iPSC) technology have paved the way for the production of patient-specific neurons that are ideal for autologous cell replacement for treatment of neurodegenerative diseases. In the case of retinal degeneration and associated photoreceptor cell therapy, polymer scaffolds are critical for cellular survival and integration; however, prior attempts to materialize this concept have been unsuccessful in part due to the materials' inability to guide cell alignment. In this work, we used two-photon polymerization to create 180MUm wide non-degradable prototype photoreceptor scaffolds with varying pore sizes, slicing distances, hatching distances and hatching types. Hatching distance and hatching type were significant factors for the error of vertical pore diameter, while slicing distance and hatching type most affected the integrity and geometry of horizontal pores. We optimized printing parameters in terms of structural integrity and printing time in order to create 1mm wide scaffolds for cell loading studies. We fabricated these larger structures directly on a porous membrane with 3um diameter pores and seeded them with human iPSC-derived retinal progenitor cells. After two days in culture, cells nested in and extended neuronal processes parallel to the vertical pores of the scaffolds, with maximum cell loading occurring in 25MUm diameter pores. These results highlight the feasibility of using this technique as part of an autologous stem cell strategy for restoring vision to patients affected with retinal degenerative diseases. STATEMENT OF SIGNIFICANCE: Cell replacement therapy is an important goal for investigators aiming to restore neural function to those suffering from neurodegenerative disease. Cell delivery scaffolds are frequently necessary for the success of such treatments, but traditional biomaterials often fail to facilitate the neuronal orientation and close packing needed to recapitulate the in vivo environment. Here, we use two-photon polymerization to create prototype cell scaffolds with densely packed vertical pores for photoreceptor cell loading and small, interconnected horizontal pores for nutrient diffusion. This study offers a thorough characterization of how two photon polymerization parameters affect final structural outcomes and printing time. Our findings demonstrate the feasibility of using two-photon polymerization to create scaffolds that can align neuronal cells in 3D and are large enough to be used for transplantation. In future work, these scaffolds could comprise biodegradable materials with tunable microstructure, elastic modulus and degradation time; a significant step towards a promising treatment option for those suffering from late-stage neurodegeneration, including retinal degenerative blindness. PMID- 28351683 TI - Oleanolic acid from antifilarial triterpene saponins of Dipterocarpus zeylanicus induces oxidative stress and apoptosis in filarial parasite Setaria digitata in vitro. AB - Absence of a drug that kills adult filarial parasites remains the major challenge in eliminating human lymphatic filariasis (LF); the second leading cause of long term and permanent disability. Thus, the discovery of novel antifilarial natural products with potent adulticidal activity is an urgent need. In the present study, methanol extracts of leaves, bark and winged seeds of Dipterocarpus zeylanicus (Dipterocarpaceae) were investigated for macro and microfilaricidal activity. Two antifilarial triterpene saponins were isolated from winged seed extracts by bioactivity guided chromatographic separation and identified using Nuclear Magnetic Resonance and mass spectroscopic analysis as oleanolic acid 3-O beta-D- glucopyranoside (1) (IC50 = 20.54 MUM for adult worms, 19.71 MUM for microfilariae ) and oleanolic acid 3-O-alpha-L-arabinopyranoside (2) (IC50 = 29.02 MUM for adult worms, 25.99 MUM for microfilariae). Acid hydrolysis of both compounds yielded oleanolic acid (3) which was non or least toxic to human peripheral blood mono nuclear cells (Selectivity index = >10) while retaining similar macrofilaricidal (IC50 = 38.4 MUM) and microfilaricidal (IC50 = 35.6 MUM) activities. In adult female worms treated with 50 and 100 MUM doses of oleanolic acid, condensation of nuclear DNA, apoptotic body formation and tissue damage was observed by using Hoechst 33342 staining, TUNEL assay and Hematoxylin and Eosin staining respectively. A dose dependent increase in caspase 3/CED3 activity and decrease in total protein content were also observed in these parasites. A dose dependant DNA fragmentation was observed in adult parasites and microfilariae. Decreased levels of reduced glutathione (GSH) and elevated levels of glutathione S transferase (GST), superoxide dismutase (SOD) and reactive oxygen species (ROS) were also observed in parasites treated with oleanolic acid indicating an oxidative stress mediated apoptotic event. Compound 3/oleanolic acid was thus identified as a potent and safe antifilarial compound in vitro. PMID- 28351684 TI - Tissue distribution and functional analysis of vitellogenin-6 of Toxocara canis. AB - Toxocara canis is an common intestinal nematode of canids and the principal causative agent of human toxocariasis. Vitellogenin (Vg), a source of amino acids and lipids in the eggs, are considered to play an important role in embryo development of a wide range of organisms. In the present study, the transcriptional levels of Tc-vit-6 gene in male and female adult T. canis were determined by quantitative real-time PCR, which indicated high transcription of Tc-vit-6 in the intestine, reproductive tract and body wall of male and female adult T. canis. The fragment of Tc-vit-6 encoding a vWD domain, was cloned and expressed to produce a rabbit anti-TcvWD polyclonal antibody. Tissue distribution of TcVg6 was detected by immunohistochemical assays, which showed predominant distribution of TcVg6 in the tissues of intestine, as well as reproductive tract (including some of the germ cells) and musculature of male and female adult worms. Collectively, these results indicated multiple biological roles of TcVg6 apart from that in the reproduction of T. canis. PMID- 28351685 TI - Transcript and protein expression analysis of proteases in the blood stages of Plasmodium falciparum. AB - Proteases are crucial enzymes with varying roles in living organisms. In the malaria parasite Plasmodium falciparum, the role of proteases has been deciphered mainly in the asexual blood stages and shown to represent promising drug targets. However, little is known about their functions in the sexual blood stages, which are important for transmission of the disease from the human to the mosquito vector. Determination of their stage-specific expression during the malaria life cycle is crucial for the effective design of multi-stage anti-malaria drugs aimed at eradicating the disease. In this study, we screened the P. falciparum genome database for putative proteases and determined the transcript and protein expression profiles of selected proteases in the plasmodial blood stages using semi-quantitative RT-PCR and indirect immunofluorescence assay. Database mining identified a total of 148 putative proteases, out of which 18 were demonstrated to be expressed in the blood stages on the transcript level; for 12 of these proteins synthesis was confirmed. While three of these proteases exhibit gametocyte-specific expression, two are restricted to the asexual blood stages and seven are found in both stages, making them interesting multi-stage drug targets. PMID- 28351686 TI - DNA damage response and autophagy in the degeneration of retinal pigment epithelial cells-Implications for age-related macular degeneration (AMD). AB - In this review we will discuss the links between autophagy, a mechanism involved in the maintenance of cellular homeostasis and controlling cellular waste management, and the DNA damage response (DDR), comprising various mechanisms preserving the integrity and stability of the genome. A reduced autophagy capacity in retinal pigment epithelium has been shown to be connected in the pathogenesis of age-related macular degeneration (AMD), an eye disease. This degenerative disease is a major and increasing cause of vision loss in the elderly in developed countries, primarily due to the profound accumulation of intra- and extracellular waste: lipofuscin and drusen. An abundance of reactive oxygen species is produced in the retina since this tissue has a high oxygen demand and contains mitochondria-rich cells. The retina is exposed to light and it also houses many photoactive molecules. These factors are clearly reflected in both the autophagy and DNA damage rates, and in both nuclear and mitochondrial genomes. It remains to be revealed whether DNA damage and DDR capacity have a more direct role in the development of AMD. PMID- 28351687 TI - EUS-guided removal of a buried lumen-apposing metal stent caused by delayed inward migration after cyst-gastrostomy. PMID- 28351688 TI - Performance of serological and molecular tests within acute HIV infection. AB - BACKGROUND: Early diagnosis of acute HIV infection can be challenging and is critical in regards to early therapeutic decision making. OBJECTIVES: To evaluate the performance of different HIV tests in detecting early infections. STUDY DESIGN: A total of 83 leftover specimens of 61 study participants who seroconverted were used in this sub-study. 35 HIV RNA positive but still seronegative specimens (acute infections) were used for analysis of the sensitivity of the different assays in detecting early infections and 42 HIV RNA and antibody negative specimens were used for specificity analysis. RESULTS: Four (11%) specimens out of 35 acute infections were reactive with the Enzygnost(r) Anti-HIV 1/2 Plus and 12/35 (34%) with the Vironostika(r) HIV Ag/Ab. 16 (46%) specimens were confirmed as acute by the INNOTEST(r) HIV antigen mAb Antigen test. Only three (9%), 10 (29%) and 9 (27%) specimens were reactive with the Determine HIV-1/2 Ag/Ab Combo, SD Bioline HIV Ag/Ab Combo test and the HIV Combo test, respectively. The specificity of the different tests were 100%, 95%, 100%, 93%, 100% and 93% for Enzygnost(r) Anti-HIV 1/2 Plus, Vironostika(r) HIV Ag/Ab, INNO-Test HIV antigen mAb, Determine HIV-1/2 Ag/Ab Combo, SD Bioline HIV Ag/Ab Combo test and HIV Combo test respectively. CONCLUSION: RNA test, 4th generation ELISA and Single Ag test are the most sensitive tests for detection of an acute infection. As an alternative, the HIV Combo test is generally slightly more sensitive compared to its previous version, but the SD Bioline HIV Ag/Ab Combo tests has the best performance compared to the other simple rapid tests (SRTs) but none of them are precise in detecting Ag in the determination of acute infections. PMID- 28351689 TI - Detection of new HIV infections in a multicentre HIV antiretroviral pre-exposure prophylaxis trial. AB - BACKGROUND: Monthly specimens collected from FEM-PrEP-a Phase III trial [1] were investigated for the detection of acute HIV (AHI) infection. OBJECTIVES: To evaluate the efficiency of the study-specific HIV algorithm in detecting AHI, and the performance of each of the serological and molecular tests used in diagnosing new infections, and their contribution to narrowing the window period. STUDY DESIGN: A total of 83 pre-seroconversion specimens from 61 seroconverters from the FEM-PrEP trial were further analyzed in a sub-study. During the trial, HIV seroconversion was diagnosed on site using a testing algorithm with simple/rapid tests (SRTs) and confirmed with a gold standard testing algorithm (see short communication: Fig. 1). The infection date was determined more accurately by the use of standard ELISAs and Nucleic Acid Amplification Tests (NAAT) in a look-back procedure. For this sub-study, the international central laboratory repeated the study algorithm using SRTs. RESULTS: A total of 83 pre-seroconversions specimens from 61 seroconverters were analyzed in a look-back procedure. RNA was detected in 35/61 seroconverters at the visit before the seroconversion visit as determined at the study sites. Four seroconversion dates were inaccurate at one study site as the international central laboratory detected the HIV infection one visit earlier using the same test algorithm. Using the gold standard, an additional seroconversion was detected at an earlier visit. The combined antigen/antibody and the single antigen test had a higher sensitivity compared to the SRTs in detecting acute infections. CONCLUSIONS: In the FEM-PrEP trial, the international central laboratory detected a small number of seroconversions one month earlier than the study sites using the same study algorithm. Standard tests are still the most sensitive tests in detecting pre-seroconversion or acute HIV infection, but they are costly, time consuming and not recommended for use on site in a clinical trial. PMID- 28351690 TI - Tailoring thermal treatment to form liprotide complexes between oleic acid and different proteins. AB - Liprotides are protein-lipid complexes in which the fatty acids form a micelle like core surrounded by a shell of partially unfolded protein molecules. These complexes can be formed in different ways. The simplest approach is a thermal treatment where protein and fatty acid are mixed and then incubated at elevated temperatures. Using this approach we here demonstrate that we can monitor liprotide formation in real time using Small-Angle X-ray Scattering (SAXS). Optimal conditions for liprotide formation, i.e. temperature and incubation times, as well as liprotide stability and structure, vary for different proteins. The apo form of alpha-lactalbumin (aLA) forms liprotides at room temperature, however, Ovalbumin (Ova) and Bovine Serum Albumin (BSA) require elevated temperatures (>=60 degrees C) to form liprotides, and in addition, they need to be returned to lower temperatures to remain stable; repeated cycles of heating and cooling gradually dissociate the liprotides in parallel with the formation of disulfide-bonded aggregates. Real-time tracking of the formation of liprotides of BSA or Ova with OA at 60-65 degrees C showed that liprotide formation takes place within a period of 12-18min and is preceded by a loss of secondary structure of the protein and binding of OA to the protein. Our SAXS-based approach provides a straightforward strategy to optimize liprotide formation for a wide range of different proteins. PMID- 28351691 TI - Optical-flow analysis toolbox for characterization of spatiotemporal dynamics in mesoscale optical imaging of brain activity. AB - Wide-field optical imaging techniques constitute powerful tools to investigate mesoscale neuronal activity. The sampled data constitutes a sequence of image frames in which one can investigate the flow of brain activity starting and terminating at source and sink locations respectively. Approaches to the analyses of information flow include qualitative assessment to identify sources and sinks of activity as well as their trajectories, and quantitative measurements based on computing the temporal variation of the intensity of pixels. Furthermore, in a few studies estimates of wave motion have been reported using optical-flow techniques from computer vision. However, a comprehensive toolbox for the quantitative analyses of mesoscale brain activity data is still lacking. We present a graphical-user-interface toolbox based in Matlab(r) for investigating the spatiotemporal dynamics of mesoscale brain activity using optical-flow analyses. The toolbox includes the implementation of three optical-flow methods namely Horn-Schunck, Combined Local-Global, and Temporospatial algorithms for estimating velocity vector fields of flow of mesoscale brain activity. From the velocity vector fields we determined the locations of sources and sinks as well as the trajectories and temporal velocities of flow of activity. Using simulated data as well as experimentally derived sensory-evoked voltage and calcium imaging data from mice, we compared the efficacy of the three optical-flow methods for determining spatiotemporal dynamics. Our results indicate that the combined local global method we employed, yields the best results for estimating wave motion. The automated approach permits rapid and effective quantification of mesoscale brain dynamics and may facilitate the study of brain function in response to new experiences or pathology. PMID- 28351692 TI - Quasi-experimental study designs series-paper 5: a checklist for classifying studies evaluating the effects on health interventions-a taxonomy without labels. AB - OBJECTIVES: The aim of the study was to extend a previously published checklist of study design features to include study designs often used by health systems researchers and economists. Our intention is to help review authors in any field to set eligibility criteria for studies to include in a systematic review that relate directly to the intrinsic strength of the studies in inferring causality. We also seek to clarify key equivalences and differences in terminology used by different research communities. STUDY DESIGN AND SETTING: Expert consensus meeting. RESULTS: The checklist comprises seven questions, each with a list of response items, addressing: clustering of an intervention as an aspect of allocation or due to the intrinsic nature of the delivery of the intervention; for whom, and when, outcome data are available; how the intervention effect was estimated; the principle underlying control for confounding; how groups were formed; the features of a study carried out after it was designed; and the variables measured before intervention. CONCLUSION: The checklist clarifies the basis of credible quasi-experimental studies, reconciling different terminology used in different fields of investigation and facilitating communications across research communities. By applying the checklist, review authors' attention is also directed to the assumptions underpinning the methods for inferring causality. PMID- 28351693 TI - Quasi-experimental study designs series-paper 6: risk of bias assessment. AB - OBJECTIVES: Rigorous and transparent bias assessment is a core component of high quality systematic reviews. We assess modifications to existing risk of bias approaches to incorporate rigorous quasi-experimental approaches with selection on unobservables. These are nonrandomized studies using design-based approaches to control for unobservable sources of confounding such as difference studies, instrumental variables, interrupted time series, natural experiments, and regression-discontinuity designs. STUDY DESIGN AND SETTING: We review existing risk of bias tools. Drawing on these tools, we present domains of bias and suggest directions for evaluation questions. RESULTS: The review suggests that existing risk of bias tools provide, to different degrees, incomplete transparent criteria to assess the validity of these designs. The paper then presents an approach to evaluating the internal validity of quasi-experiments with selection on unobservables. CONCLUSION: We conclude that tools for nonrandomized studies of interventions need to be further developed to incorporate evaluation questions for quasi-experiments with selection on unobservables. PMID- 28351694 TI - Antibodies - Nature's analytical masterpieces. PMID- 28351695 TI - Antihyperlipidemic and hepatoprotective effects of Gardenin A in cellular and high fat diet fed rodent models. AB - The gum of Gardenia resinifera Roth., is one of the important drugs used in the Indian system of medicine and a source of unique polymethoxylated flavones. This study was aimed to evaluate the antihyperlipidemic and anti-NAFLD effects of Gardenin A (Gar-A) from G. resinifera gum using in vitro and in vivo models. Gar A was isolated from G. resinifera gum and was identified on the basis of the physical and spectral data. Toxicity of Gar-A to HepG2 cells was evaluated using MTT assay. The ability of Gar-A to reduce steatosis was assessed using oleate palmitate induced HepG2 cell lines by estimating the lipid levels by ORO staining and by estimating the intracellular triglyceride content. Effect of Gar-A on amelioration of lipotoxicity was measured by estimating the LDH levels. The doses for in vivo experiments were fixed by Irwin test, between 50 and 100 mg/kg concentrations, through oral route. The acute antihyperlipidemic effect of Gar-A was assessed in Triton WR-1339 induced hyperlipidemic animals. The chronic antihyperlipidemic and anti-NAFLD effects of Gar-A were evaluated in HFD fed rats. In vitro experiments with HepG2 cell line indicated that the cells treated with Gar-A did not show any significant reduction in the viability up to 70 MUg/mL concentration. Steatotic HepG2 cells treated with Gar-A showed a significant reduction in lipid accumulation at 2.5-10 MUg/mL concentrations. In triton induced hyperlipidemic rats, the treatment significantly reduced the lipid levels at the synthesis phase. The treatment with Gar-A to the HFD fed animals significantly lowered the steatosis and transaminase levels. The other biochemical parameters such as TC, TG, LDL-c, ALP and ACP were also decreased significantly. Treatment with Gar-A significantly lowered the hyperlipidemia and fat accumulation in the liver; detailed molecular investigations are necessary to establish the antihyperlipidemic and hepatoprotective potentials of Gar-A. PMID- 28351696 TI - Editorial commentary: New drugs for diabetes: Finally safety and cardiovascular efficacy. PMID- 28351697 TI - Editorial commentary: Non-invasive assessment of myocardial fibrosis: Focus on the substrate of ventricular arrhythmias to improve risk stratification. PMID- 28351698 TI - Pretreatment of poultry manure for efficient biogas production as monosubstrate or co-fermentation with maize silage and corn stover. AB - Water extraction of raw chicken manure elevated the carbon-to-nitrogen ratio 2.7 fold, i.e. from 7.48 to 19.81. The treated chicken manure (T-CM) thus became suitable for biogas fermentation as monosubstrate. Improved methane production was achieved in co-fermentations with either maize silage (24% more methane) or corn stover (19% more methane) relative to T-CM monosubstrate. The standardized biogas potential assay indicated that the methane yields varied with the organic loading rate between 160 and 250 mL CH4/g organic total solid (oTS). Co fermentation with maize silage was sustainable in continuous anaerobic digestion for at least 4 months. PMID- 28351699 TI - Imag(in)ing growth and form. AB - On Growth and Form has stood at the forefront of our understanding of the development of biological form for the past century. In this essay, I take a look at how modern techniques are enabling unprecedented insight into the spatio temporal regulation of development, which facilitates testing of the ideas that D'Arcy Thompson laid down so brilliantly 100years ago. PMID- 28351701 TI - Extracting features from protein sequences to improve deep extreme learning machine for protein fold recognition. AB - Protein fold recognition is an important problem in bioinformatics to predict three-dimensional structure of a protein. One of the most challenging tasks in protein fold recognition problem is the extraction of efficient features from the amino-acid sequences to obtain better classifiers. In this paper, we have proposed six descriptors to extract features from protein sequences. These descriptors are applied in the first stage of a three-stage framework PCA-DELM LDA to extract feature vectors from the amino-acid sequences. Principal Component Analysis PCA has been implemented to reduce the number of extracted features. The extracted feature vectors have been used with original features to improve the performance of the Deep Extreme Learning Machine DELM in the second stage. Four new features have been extracted from the second stage and used in the third stage by Linear Discriminant Analysis LDA to classify the instances into 27 folds. The proposed framework is implemented on the independent and combined feature sets in SCOP datasets. The experimental results show that extracted feature vectors in the first stage could improve the performance of DELM in extracting new useful features in second stage. PMID- 28351700 TI - Sex, Ethnicity, and CVD Among Women of African Descent: An Approach for the New Era of Genomic Research. PMID- 28351702 TI - Effects of operational decisions on the diffusion of epidemic disease: A system dynamics modeling of the MERS-CoV outbreak in South Korea. AB - We evaluated the nosocomial outbreak of Middle East Respiratory Syndrome (MERS) Coronavirus (CoV) in the Republic of Korea, 2015, from a healthcare operations management perspective. Establishment of healthcare policy in South Korea provides patients' freedom to select and visit multiple hospitals. Current policy enforces hospitals preference for multi-patient rooms to single-patient rooms, to lower financial burden. Existing healthcare systems tragically contributed to 186 MERS outbreak cases, starting from single "index patient" into three generations of secondary infections. By developing a macro-level health system dynamics model, we provide empirical knowledge to examining the case from both operational and financial perspectives. In our simulation, under base infectivity scenario, high emergency room occupancy circumstance contributed to an estimated average of 101 (917%) more infected patients, compared to when in low occupancy circumstance. Economic patient room design showed an estimated 702% increase in the number of infected patients, despite the overall 98% savings in total expected costs compared to optimal room design. This study provides first time, system dynamics model, performance measurements from an operational perspective. Importantly, the intent of this study was to provide evidence to motivate public, private, and government healthcare administrators' recognition of current shortcomings, to optimize performance as a whole system, rather than mere individual aspects. PMID- 28351703 TI - A tipping point in parapatric speciation. AB - More than two loci are involved in reproductive isolation in most cases of putative recent speciation. We study the speciation between two geographically isolated populations connected by infrequent migration, in which incompatibility is controlled by quantitative loci. Incompatibility genetic distance is defined as the fraction of compatibility controlling loci that are different between individuals. Speciation is established when genetic distance reaches a threshold level in spite of occasional migration and subsequent hybridization that reduce genetic distance. With stochastic analysis, we investigate how the time to speciation depends on the manner in which the magnitude of incompatibility increases with genetic distance. Results are: (1) The time to speciation is short if the migration rate is smaller than the mutation rate, or if intermediate levels of genetic distance cause mild incompatibility, making migrants less effective in reducing genetic distance. (2) Genetic distance may fluctuate around a positive quasi-equilibrium level for a long time, and suddenly show a quick passage to speciation when it goes beyond a "tipping point." Notably a gradual increase in incompatibility can result in a sudden and rapid formation of a new species. (3) Speciation becomes very slow if incompatibility is effective for individuals differing at only one locus. These findings provide testable predictions on reproductive traits controlled by specific incompatibility accumulation forms that facilitate the speciation process. PMID- 28351704 TI - Effects of rainfall on Culex mosquito population dynamics. AB - The dynamics of a mosquito population depends heavily on climatic variables such as temperature and precipitation. Since climate change models predict that global warming will impact on the frequency and intensity of rainfall, it is important to understand how these variables affect the mosquito populations. We present a model of the dynamics of a Culex quinquefasciatus mosquito population that incorporates the effect of rainfall and use it to study the influence of the number of rainy days and the mean monthly precipitation on the maximum yearly abundance of mosquitoes Mmax. Additionally, using a fracturing process, we investigate the influence of the variability in daily rainfall on Mmax. We find that, given a constant value of monthly precipitation, there is an optimum number of rainy days for which Mmax is a maximum. On the other hand, we show that increasing daily rainfall variability reduces the dependence of Mmax on the number of rainy days, leading also to a higher abundance of mosquitoes for the case of low mean monthly precipitation. Finally, we explore the effect of the rainfall in the months preceding the wettest season, and we obtain that a regimen with high precipitations throughout the year and a higher variability tends to advance slightly the time at which the peak mosquito abundance occurs, but could significantly change the total mosquito abundance in a year. PMID- 28351705 TI - Subregional laminar cartilage MR spin-spin relaxation times (T2) in osteoarthritic knees with and without medial femorotibial cartilage loss - data from the Osteoarthritis Initiative (OAI). AB - OBJECTIVE: To explore whether subregional laminar femorotibial cartilage spin spin relaxation time (T2) is associated with subsequent radiographic progression and cartilage loss and/or whether one-year change in subregional laminar femorotibial cartilage T2 is associated with concurrent progression in knees with established radiographic OA (ROA). METHODS: In this case-control study, Osteoarthritis Initiative (OAI) knees with medial femorotibial progression were selected based on one-year loss in both quantitative cartilage thickness Magnetic resonance imaging (MRI) and radiographic joint space width (JSW). Non-progressor knees were matched by sex, Body mass index (BMI), baseline Kellgren-Lawrence grade (2/3), and pain. Baseline and one-year follow-up superficial and deep cartilage T2 was analyzed in 16 femorotibial subregions using multi-echo spin echo MRI. RESULTS: 37 knees showed medial femorotibial progression whereas 37 matched controls had no medial or lateral compartment progression. No statistically significant baseline differences between progressor and non progressor knees in medial femorotibial cartilage T2 were observed in the superficial (48.9 +/- 3.0 ms; 95% CI: [47.9, 49.9] vs 47.8 +/- 3.6 ms; 95% CI: [46.6, 49.0], P = 0.07) or deep cartilage layer (40.8 +/- 3.6 ms; 95% CI: [39.5, 42.0] vs 40.1 +/- 4.7 ms; 95% CI: [38.5, 41.6], P = 0.29). Concurrent T2 change was more pronounced in the deep than the superficial cartilage layer. In the medial femorotibial compartment (MFTC), longitudinal change was greater in the deep layer of progressor than non-progressor knees (1.8 +/- 4.5 ms; 95% CI: [0.3, 3.3] vs -0.2 +/- 1.9 ms; 95% CI: [-0.8, 0.5], P = 0.02), whereas no difference was observed in the superficial layer. CONCLUSION: Medial compartment cartilage T2 did not appear to be a strong prognostic factor for subsequent structural progression in the same compartment of knees with established ROA, when appropriately controlling for covariates. Yet, deep layer T2 change in the medial compartment occurred concurrent with medial femorotibial progression. PMID- 28351706 TI - Baseline meniscal extrusion associated with incident knee osteoarthritis after 30 months in overweight and obese women. AB - OBJECTIVE: To investigate the association between baseline meniscal extrusion and the incidence of knee osteoarthritis (KOA) after 30 months in a high-risk population of overweight and obese women, free of clinical and radiological KOA at baseline. METHODS: 407 middle-aged overweight women (body mass index - BMI >= 27 kg/m2) were evaluated at baseline and after 30 months of follow-up. Meniscal extrusion was defined as grade >=2 on MRI according to MRI Osteoarthritis Knee Score (MOAKS). The primary outcome measure was KOA after 30 months follow-up, defined using the following criteria: either incidence of radiographic KOA (Kellgren & Lawrence grade 2 or higher), or clinical osteoarthritis (OA) according to the American College of Radiology (ACR) criteria, or medial or lateral joint space narrowing (JSN) of >=1.0 mm. Using generalized estimating equations (GEE), we determined the association between knees with and without meniscal extrusion and both outcomes, corrected for the baseline differences. RESULTS: 640 knees were available at baseline of which 24% (153) had meniscal extrusion. There was a significantly higher incidence of KOA according to the primary outcome measure in women with meniscal extrusion compared to those without extrusion (28.8%, odds ratio - OR 2.39, 95% CI 1.53, 3.73). A significantly higher incidence was found for the development of radiographic KOA (12.4%, OR 2.61, 95% CI 1.11, 6.13) and medial JSN (11.8%, OR 3.19, 95% CI 1.59, 6.41). Meniscal extrusion was not significantly associated with clinical KOA and lateral JSN. CONCLUSION: Meniscal extrusion was associated with a significantly higher incidence of KOA, providing an interesting target for early detection of individuals at risk for developing KOA. PMID- 28351707 TI - Chemokine receptor CCR5 and CXCR4 might influence virus replication during IBDV infection. AB - Both CCR5 and CXCR4 are important chemokine receptors and take vital role in migration, development and distribution of T cells, however, whether they will influence the process of T cell infiltration into bursa of Fabricius during infectious bursal disease virus (IBDV) infection is unclear. In the current study, CCR5 and CXCR4 antagonists, Maraviroc and AMD3100, were administrated into chickens inoculated with IBDV, and the gene levels of IBDV VP2, CCR5, CXCR4 and related cytokines were determined by real-time PCR. The results showed that large number of T cells began to migrate into the bursae on Day 3 post infection with IBDV and the mRNA of chemokine receptors CCR5 and CXCR4 began to increase on Day 1. Moreover, antagonist treatments have increased the VP2, CCR5 and CXCR4 gene transcriptions and influenced on the gene levels of IL-2, IL-6, IL-8, IFN-gamma, TGF-beta4, MHC-I and MDA5. In conclusion, the chemokine receptors CCR5 and CXCR4 might influence virus replication during IBDV infection and further study would focus on the interaction between chemokine receptors and their ligands. PMID- 28351708 TI - Biochemical and inhibition studies of glutamine synthetase from Leishmania donovani. AB - Leishmaniasis is a group of tropical diseases caused by protozoan parasites of the genus Leishmania. Leishmania donovani is a protozoan parasite that causes visceral leishmaniasis, a fatal disease if left untreated. Chemotherapy for leishmaniasis is problematic as the available drugs are toxic, costly and shows drug resistance, hence, there is a necessity to look out for the novel drug targets, chemical entities and vaccine. Glutamine synthetase (GS) catalyzes the synthesis of glutamine from glutamate and ammonia. In the present study, we have identified and characterized GS from L. donovani. The nucleotide sequence encoding putative glutamine synthetase like sequence from L. donovani (LdGS, LDBPK_060370) was cloned. A 43.5 kDa protein with 6X-His tag at the C-terminal end was obtained by overexpression of LdGS in Escherichia coli BL21 (DE3) strain. Expression of native LdGS in promastigotes and recombinant L. donovani glutamine synthetase (rLdGS) was confirmed by western blot analysis. An increase in expression of GS was observed at different phases of growth of the parasite. Expression of LdGS in promastigote and amastigote was confirmed by western blot analysis. Immunofluorescence studies of both the promastigote and amastigote stages of the parasite revealed the presence of LdGS in cytoplasm. GS exists as a single copy gene in parasite genome. Kinetic analysis of GS enzyme revealed Km value of 26.3 +/- 0.4 mM for l- glutamate and Vmax value of 2.15 +/- 0.07 U mg-1. Present study confirms the presence of glutamine synthetase in L. donovani and provides comprehensive overview of LdGS for further validating it as a potential drug target. PMID- 28351709 TI - Protective efficacy of six immunogenic recombinant proteins of Vibrio anguillarum and evaluation them as vaccine candidate for flounder (Paralichthys olivaceus). AB - Vibrio anguillarum is a severe bacterium that causes terminal haemorrhagic septicaemia in freshwater and marine fish. Virulence-associated proteins play an important role in bacterial pathogenicity and could be applied for immunoprophylaxis. In this study, six antigenic proteins from V. anguillarum were selected and the immune protective efficacy of their recombinant proteins was investigated. VirA, CheR, FlaC, OmpK, OmpR and Hsp33 were recombinantly produced and the reactions of recombinant proteins to flounder-anti-V. anguillarum antibodies (fV-ab) were detected, respectively. Then the recombinant proteins were injected to fish, after immunization, the percentages of surface membrane immunoglobulin-positive (sIg+) cell in lymphocytes, total antibodies, antibodies against V. anguillarum, antibodies against recombinant proteins and relative percent survival (RPS) were analyzed, respectively. The results showed that all the recombinant proteins could react to fV-ab, proliferate sIg + cells in lymphocytes and induce production of total antibodies, specific antibodies against V. anguillarum or the recombinant proteins; the RPS of rVirA, rCheR, rFlaC, rOmpK, rOmpR and rHsp33 against V. anguillarum was 70.27%, 27.03%, 16.22%, 62.16%, 45.95% and 81.08%, respectively. The results revealed that rHsp33, rVirA and rOmpK have good protections against V. anguillarum and could be vaccine candidates against V. anguillarum. PMID- 28351710 TI - Sodium acetate inhibits Staphylococcus aureus internalization into bovine mammary epithelial cells by inhibiting NF-kappaB activation. AB - Bovine mastitis is one of the most costly and prevalent disease affecting dairy cows worldwide. It was reported that Staphylococcus aureus could internalize into bovine mammary epithelial cells (bMEC) and induce mastitis. Some short chain fatty acids (SCFA) have shown to suppress S. aureus invasion into bMEC and regulate antimicrobial peptides expression. But it has not been evaluated that sodium acetate has the similar effect. The aim of this study was to investigate the effect of sodium acetate on the invasion of bovine mammary epithelial cells (bMEC) by S. aureus. Gentamicin protection assay showed that the invasion of S. aureus into bMEC was inhibited by sodium acetate in a dose-dependent manner. Sodium acetate (0.25-5 mM) did not affect S. aureus growth and bMEC viability. The TAP gene level was decreased, while the BNBD5 mRNA level was enhanced in sodium acetate treated bMEC. In sodium acetate treated and S. aureus challenged bMEC, the TAP gene expression was increased and BNBD5 gene expression was not modified at low concentrations, but decreased at high concentrations. The Nitric oxide (NO) production of bMEC after S. aureus stimulation was decreased by sodium acetate treatment. Furthermore, sodium acetate treatment suppressed S. aureus induced NF-kappaB activation in bMEC in a dose manner. In conclusion, our results suggested that sodium acetate exerts an inhibitory property on S. aureus internalization and modulates antimicrobial peptides gene expression. PMID- 28351711 TI - Structure based virtual screening for identification of potential quorum sensing inhibitors against LasR master regulator in Pseudomonas aeruginosa. AB - Inter and intracellular communication in bacteria, which is known as quorum sensing (QS), is mediated by small diffusible signaling molecules known as autoinducers. QS regulates various virulence factors responsible for pathogenesis. Increasing resistance of microorganisms against traditional antibiotics has turned the focus towards the QS as it exerts less selective pressure preventing development of resistance among microorganisms. LasR, a transcription factor that controls QS in Pseudomonas aeruginosa, is an attractive therapeutic target for inhibitors. This study aimed to screen natural compounds as potential inhibitors of LasR. About 2603 compounds from ZINC database were virtually screened against the structure of LasR. Then after qualifying compounds were filtered on the parameters of Lipinski's rule and ADME. Six novel potential QS inhibiting compounds were selected on the basis of binding energy. Structures of LasR-ligand complexes were analysed to have insight of binding between inhibitors and target. It is pertinent to mention here that all the molecules are structurally different from 3-oxo-C12HSL,a native autoinducer of LasR, that play key role in formation of LasR dimer which is an active form of the protein to facilitate QS. PMID- 28351712 TI - Bovine leptospirosis: Prevalence, associated risk factors for infection and their cause-effect relation. AB - Leptospirosis is a cosmopolitan infectious disease that causes severe reproductive disorders in cattle, especially those related to abortion. This disease has rodents as main reservoirs; however, cattle are responsible for maintenance of the disease. Thus, the aim of this study was to identify the factors associated with infection and cause-effect relation of leptospirosis in dairy herds from Southern of Brazil. Serum samples of 1242 cows were collected from herds classified as of medium and high density, and tested by microscopic agglutination test (MAT). These farms were located in the West part of Santa Catarina State (Brazil). A total of 80 cows (6.44%) were considered positives for the infection with titration of 1:100. Using a multivariate analysis, we identified two factors associated to bovine leptospirosis: dog access to pastures (p < 0.001) and feed exposure to rodents (p = 0.05). Cause-effect analysis demonstrated that the occurrence of reproductive disorders was significantly (p = 0.01) linked to leptospirosis. Thus, we conclude that leptospirosis is prevalent in dairy cattle in the west part of Santa Catarina state, as well as the access of dogs to pastures and contact of rodents with feed increase the chance of cattle infection by Leptospira spp. PMID- 28351713 TI - In vitro evaluation of cross-strain inhibitory effects of IgY polyclonal antibody against H. pylori. AB - The present study aimed to evaluate in vitro cross-strain inhibitory effects of IgY polyclonal antibody on both growth and urease enzyme of four local strains of H. pylori. Leghorn chickens were immunized with whole cells of four different strains of H. pylori, separately. Rising of specific IgY was detected by ELISA. The IgY purified using polyethylene glycol method and the purity was evaluated by SDS-PAGE and Western blotting. Each strain was treated with its own-specific and also other strain-specific IgYs. The strain-specific IgY could inhibit the growth of specific strains by 49-72% and also other different strains of H. pylori by 29 86%. Our findings revealed that strain-specific IgY could inhibit urease activity of its own by 64-72% and other different strains by 49-79%. These findings confirmed strain-specific and also cross-strain inhibitory effects of the IgY polyclonal antibody on both growth and urease activity of H. pylori. PMID- 28351714 TI - Evaluation of environmental and nutritional factors and sua gene on in vitro biofilm formation of Streptococcus uberis isolates. AB - The pathogenesis of Streptococcus uberis is attributed to a combination of extracellular factors and properties such as adherence and biofilm formation. The aim of this work was to evaluate the influence of different factors, additives and bovine milk compounds on S. uberis biofilm formation, as the presence of the sua gene by PCR. Additionally, extracellular DNA and the effect of DNaseI were evaluated in the biofilms yielded. Optimal biofilm development was observed when the pH was adjusted to 7.0 and 37 degrees C. Additives as glucose and lactose reduced biofilm formation as bovine milk compounds tested. PCR assay showed that not all the isolates yielded sua gene. Extrachromosomal ADN was found in cell free supernatants, suggesting that DNA released spontaneously to the medium. The results contribute to a better understanding of the factors involved in biofilm production of this important pathogen associated with mastitis in order to promote the design of new therapeutic approaches. PMID- 28351715 TI - Estimating bradykinesia severity in Parkinson's disease by analysing gait through a waist-worn sensor. AB - Bradykinesia is a cardinal symptom of Parkinson's disease (PD) and describes the slowness of movement revealed in patients. Current PD therapies are based on dopamine replacement, and given that bradykinesia is the symptom that best correlates with the dopaminergic deficiency, the knowledge of its fluctuations may be useful in the diagnosis, treatment and better understanding of the disease progression. This paper evaluates a machine learning method that analyses the signals provided by a triaxial accelerometer placed on the waist of PD patients in order to automatically assess bradykinetic gait unobtrusively. This method employs Support Vector Machines to determine those parts of the signals corresponding to gait. The frequency content of strides is then used to determine bradykinetic walking bouts and to estimate bradykinesia severity based on an epsilon-Support Vector Regression model. The method is validated in 12 PD patients, which leads to two main conclusions. Firstly, the frequency content of the strides allows for the dichotomic detection of bradykinesia with an accuracy higher than 90%. This process requires the use of a patient-dependant threshold that is estimated based on a leave-one-patient-out regression model. Secondly, bradykinesia severity measured through UPDRS scores is approximated by means of a regression model with errors below 10%. Although the method has to be further validated in more patients, results obtained suggest that the presented approach can be successfully used to rate bradykinesia in the daily life of PD patients unobtrusively. PMID- 28351716 TI - Diagnosis of retinal health in digital fundus images using continuous wavelet transform (CWT) and entropies. AB - Vision is paramount to humans to lead an active personal and professional life. The prevalence of ocular diseases is rising, and diseases such as glaucoma, Diabetic Retinopathy (DR) and Age-related Macular Degeneration (AMD) are the leading causes of blindness in developed countries. Identifying these diseases in mass screening programmes is time-consuming, labor-intensive and the diagnosis can be subjective. The use of an automated computer aided diagnosis system will reduce the time taken for analysis and will also reduce the inter-observer subjective variabilities in image interpretation. In this work, we propose one such system for the automatic classification of normal from abnormal (DR, AMD, glaucoma) images. We had a total of 404 normal and 1082 abnormal fundus images in our database. As the first step, 2D-Continuous Wavelet Transform (CWT) decomposition on the fundus images of two classes was performed. Subsequently, energy features and various entropies namely Yager, Renyi, Kapoor, Shannon, and Fuzzy were extracted from the decomposed images. Then, adaptive synthetic sampling approach was applied to balance the normal and abnormal datasets. Next, the extracted features were ranked according to the significances using Particle Swarm Optimization (PSO). Thereupon, the ranked and selected features were used to train the random forest classifier using stratified 10-fold cross validation. Overall, the proposed system presented a performance rate of 92.48%, and a sensitivity and specificity of 89.37% and 95.58% respectively using 15 features. This novel system shows promise in detecting abnormal fundus images, and hence, could be a valuable adjunct eye health screening tool that could be employed in polyclinics, and thereby reduce the workload of specialists at hospitals. PMID- 28351717 TI - Centralization of extruded medial meniscus delays cartilage degeneration in rats. AB - BACKGROUND: Meniscus extrusion often observed in knee osteoarthritis has a strong correlation with the progression of cartilage degeneration and symptom in the patients. We recently reported a novel procedure "arthroscopic centralization" in which the capsule was sutured to the edge of the tibial plateau to reduce meniscus extrusion in the human knee. However, there is no animal model to study the efficacy of this procedure. The purposes of this study were [1] to establish a model of centralization for the extruded medial meniscus in a rat model; and [2] to investigate the chondroprotective effect of this procedure. METHODS: Medial meniscus extrusion was induced by the release of the anterior synovial capsule and the transection of the meniscotibial ligament. Centralization was performed by the pulled-out suture technique. Alternatively, control rats had only the medial meniscus extrusion surgery. Medial meniscus extrusion was evaluated by micro-CT and macroscopic findings. Cartilage degeneration of the medial tibial plateau was evaluated macroscopically and histologically. RESULTS: By micro-CT analysis, the medial meniscus extrusion was significantly improved in the centralization group in comparison to the extrusion group throughout the study. Both macroscopically and histologically, the cartilage lesion of the medial tibial plateau was prevented in the centralization group but was apparent in the control group. CONCLUSIONS: We developed medial meniscus extrusion in a rat model, and centralization of the extruded medial meniscus by the pull-out suture technique improved the medial meniscus extrusion and delayed cartilage degeneration, though the effect was limited. Centralization is a promising treatment to prevent the progression of osteoarthritis. PMID- 28351718 TI - Progress in unraveling the genetic etiology of rolandic epilepsy. AB - Rolandic epilepsy (RE), or benign epilepsy of childhood with centrotemporal spikes (BECT), is the most frequent idiopathic partial epilepsy syndrome of childhood, where the "idiopathic" implies a genetic predisposition. Although RE has long been presumed to have a genetic component, clinical and genetic studies have shown a complex inheritance pattern. Furthermore, the underlying major genetic influence in RE has been challenged by recent reports of twin studies. Meanwhile, many genes or loci have been shown to be associated the RE/atypical RE (ARE) spectrum, with a higher frequency of causative variants in ARE. However, a full understanding of the genetic basis in the more common forms of the RE spectrum remains elusive. PMID- 28351720 TI - Estradiol effects on hypothalamic AMPK and BAT thermogenesis: A gateway for obesity treatment? AB - In addition to their prominent roles in the control of reproduction, estrogens are important modulators of energy balance, as evident in conditions of deficiency of estrogens, which are characterized by increased feeding and decreased energy expenditure, leading to obesity. AMP-activated protein kinase (AMPK) is a ubiquitous cellular energy gauge that is activated under conditions of low energy, increasing energy production and reducing energy wasting. Centrally, the AMPK pathway is a canonical route regulating energy homeostasis, by integrating peripheral signals, such as hormones and metabolites, with neuronal networks. As a result of those actions, hypothalamic AMPK modulates feeding, as well as brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT). Here, we will review the central actions of estrogens on energy balance, with particular focus on hypothalamic AMPK. The relevance of this interaction is noteworthy, because some agents with known actions on metabolic homeostasis, such as nicotine, metformin, liraglutide, olanzapine and also natural molecules, such as resveratrol and flavonoids, exert their actions by modulating AMPK. This evidence highlights the possibility that hypothalamic AMPK might be a potential target for the treatment of obesity. PMID- 28351721 TI - A rapid, simple and sensitive loop-mediated isothermal amplification method to detect Anaplasma bovis in sheep and goats samples. AB - A loop-mediated isothermal amplification (LAMP) technique has been widely used in detecting the nucleic acid of various pathogenic bacteria. In this study, a set of four LAMP primers was designed to specifically test Anaplasma bovis. The LAMP assay was performed at 62 degrees C for 60min in a water bath. The specificity was confirmed by amplifying A. bovis isolate, while no cross reaction was observed with other five pathogens (Anaplasma bovis, Anaplasma phagocytophilum, Theileria luwenshuni, Babesia motasi and Schistosoma japonicum). The sensitivity of LAMP was 5*100copies/MUL, 100 times more than that of conventional PCR (5*102copies/MUL). Of 120 blood DNA extracted from sheep and goats field samples, 81 (67.5%), 22 (18.3%) and 43 (35.8%) were positively detected by LAMP, conventional PCR and nested PCR, respectively. The findings indicated that the developed LAMP assay is a new convenient tool for rapid and cost-effective detection of A. bovis. PMID- 28351722 TI - A novel method for synthesis of alpha-spinasterol and its antibacterial activities in combination with ceftiofur. AB - In this study, we designed a novel method of the synthesis of alpha-spinasterol from commercially available stigmasterol and explored the combinational effect of the alpha-spinasterol with ceftiofur in vitro against S. pullorum cvcc533, S. pneumoniae CAU0070, E. coli, and S. aureus. alpha-Spinasterol was obtained by a key reaction of Bamford-Stevens reaction with a desirable yield for five steps. The combination of alpha-spinasterol and ceftiofur showed stronger synergetic effect against the four pathogenic strains compared with that of stigmasterol and ceftiofur alone. In time-kill analyses, at concentrations above the MICs, ceftiofur in combination with alpha-spinasterol exhibited time-dependency and concentration-dependency comparing to time dependency with ceftiofur alone. We conclude that the combination usage of alpha-spinasterol and ceftiofur is an effective and promising strategy against the four pathogenic bacterial strains in vitro. PMID- 28351723 TI - Scubatines A-F, new cytotoxic neo-clerodane diterpenoids from Scutellaria barbata D. Don. AB - Phytochemical investigation of the 70% acetone extract of the whole plant of Scutellaria barbata D. Don afforded six new neo-clerodane diterpenoids, scubatines A-F (1-6), and four known analogues (7-10). Their structures were elucidated on the basis of extensive spectroscopic analyses. Cytotoxic activity against the HL-60 and A549 cell lines was assessed for all isolated compounds. Compound 9 exhibited moderate activity against HL-60 with an IC50 value of 5.6MUM. Compound 6 showed weak cytotoxic activity against A549 and HL-60 with IC50 values of 10.4 and 15.3MUM, respectively. PMID- 28351724 TI - Trigeminal Neuralgia Completely Relieved After Stent-Assisted Coiling of a Superior Cerebellar Artery Aneurysm. AB - BACKGROUND: Although secondary trigeminal neuralgia is usually due to tumors or multiple sclerosis, other major neurologic diseases, such as aneurysms, should be taken into account when the history or the symptoms suggest a secondary origin. CASE DESCRIPTION: A 67-year-old lady presented with a 6-month history of trigeminal neuralgia involving exclusively the right ophthalmic division. A dedicated 3-dimensional-magnetic resonance imaging-magnetic resonance angiography study documented rare contact with a wide-necked aneurysm of the superior cerebellar artery, which distorted the trigeminal root. The patient underwent an endovascular treatment by stent-assisted coiling with the complete disappearance of neuralgic pain attacks within 24 hours. CONCLUSION: The complete relief from the neuralgic paroxysms immediately after endovascular stent-assisted occlusion of a superior cerebellar artery aneurysm demonstrates the crucial role of a pulsating stimulus on the demyelinated nerve fibers in evoking the ectopically generated discharges. PMID- 28351725 TI - Accurate Localization of Aneurysm Neck Margins in Clipping of a Carotid Cave Aneurysm Using Intraoperative Dual-Volume 3-Dimensional Volume-Rendering Rotational Angiography. AB - BACKGROUND: Full visualization of the aneurysm neck is usually impossible in a classical pterional craniotomy when a paraclinoid aneurysm is located on the opposite side of the internal carotid artery. Optic nerve (ON) retraction is required for better aneurysmal exposure, but ON injuries may occur. CLINICAL DESCRIPTION: In a case of a 70-year-old female harboring a carotid cave aneurysm, we introduced a new method to delineate better the margins of the aneurysm neck by using intraoperative 3-dimensional (3D) rotational angiography (RA) with dual volume reconstruction. After complete exposure of the aneurysm, we placed a straight clip adjacent to the aneurysm for localization purposes and performed 3D RA to locate the distal end of the aneurysm neck relative to the localization clip. With a better anatomic understanding of the neck position, we were able to reduce ON retraction and position the clip across the aneurysm neck more precisely. CONCLUSIONS: With the advantage of a hybrid operating room, we introduced a novel technique to define the margins of the obscured aneurysm neck more clearly by obtaining a 3D-RA dual-volume reconstruction image to locate the aneurysm neck relative to a localization clip. This technique facilitates the clipping procedure and also reduces the risk related to ON retraction during surgical exposure of a paraclinoid aneurysm. PMID- 28351726 TI - A comprehensive kinetics study of coconut shell waste pyrolysis. AB - Model-free and model-fitting methods were compared for pyrolytic conversion of the coconut shell waste. The apparent activation energy, estimated from differential and integral iso-conversional methods, increased with the progression of pyrolytic conversion. The reaction model, f(alpha)=(1-alpha)4.[ ln(1-alpha)]0.53, indicate that order-based nucleation and growth mechanisms control the solid-state pyrolysis of the coconut shell waste. The active pyrolysis zone was consisted of overlapping multi-component degradation peaks. Average activation energy of the pseudo-components estimated from the Kissinger's method were 21.9kJ.mol-1, 106.4kJ.mol-1 and 108.6kJ.mol-1 for the dehydration, the degradation of pseudo-cellulose and pseudo-hemicellulose, respectively. Pseudo-lignin decomposed over a wide range of temperature with a slower conversion rate as compared to pseudo-hemicellulose and pseudo-cellulose. Average activation energy range of pseudo-lignin was estimated from the combination of model-free and model-fitting methods as 79.1-226.5kJ.mol-1. PMID- 28351719 TI - Reviving the guardian of the genome: Small molecule activators of p53. AB - The tumor suppressor p53 is one of the most important proteins for protection of genomic stability and cancer prevention. Cancers often inactivate it by either mutating its gene or disabling its function. Thus, activating p53 becomes an attractive approach for the development of molecule-based anti-cancer therapy. The past decade and half have witnessed tremendous progress in this area. This essay offers readers with a grand review on this progress with updated information about small molecule activators of p53 either still at bench work or in clinical trials. PMID- 28351727 TI - Evaluation of the solvent water effect on high solids saccharification of alkali pretreated sugarcane bagasse. AB - Solvent water is an essential factor for high solids enzymatic hydrolysis. To investigate its effect on substrate conversion efficiency in high solids hydrolysis of sugarcane bagasse (SCB), oleyl alcohol was used to partially substitute the solvent water. The results in batch hydrolysis tests in which diverse ratio of solvent water was replaced found that the majority of the substrate was insoluble. Then high solids fed-batch hydrolysis with the reaction solution mixed with solvent water and oleyl alcohol in the ratio of 3:1 (solids concentration correspond to 24% (w/v)) was carried out at the final real solids loading of 18% (w/v). The produced sugars were found to be less than pure water system, which indicated that water played a significant role in high solids hydrolysis process, and solids effect was related to the solvent water content. PMID- 28351728 TI - One-step synthesis of high-yield biodiesel from waste cooking oils by a novel and highly methanol-tolerant immobilized lipase. AB - This study reported a novel immobilized MAS1 lipase from marine Streptomyces sp. strain W007 for synthesizing high-yield biodiesel from waste cooking oils (WCO) with one-step addition of methanol in a solvent-free system. Immobilized MAS1 lipase was selected for the transesterification reactions with one-step addition of methanol due to its much more higher biodiesel yield (89.50%) when compared with the other three commercial immobilized lipases (<10%). The highest biodiesel yield (95.45%) was acquired with one-step addition of methanol under the optimized conditions. Moreover, it was observed that immobilized MAS1 lipase retained approximately 70% of its initial activity after being used for four batch cycles. Finally, the obtained biodiesel was further characterized using FT IR, 1H and 13C NMR spectroscopy. These findings indicated that immobilized MAS1 lipase is a promising catalyst for biodiesel production from WCO with one-step addition of methanol under high methanol concentration. PMID- 28351729 TI - Valorization of carob waste: Definition of a second-generation bioethanol production process. AB - The aim of this work was to develop a strategy for second-generation ethanol production from carob solid waste issued from Lebanese food industry. The pros and cons of submerged (SF) and solid-state fermentations (SSF) using S. cerevisiae on ethanol yield and productivity were compared, including the respective roles of upstream and downstream processes, such as the size reduction, or sugar and ethanol recovery processes. The design of experiments methodology was applied. Experimental results demonstrated that SSF applied to cut carob waste from carob syrup preparation was simpler to operate and more cost effective, maintained yield and productivity (0.458g ethanol/g consumed sugar and 4.3g/(kg waste)/h) in comparison to SF (0.450g ethanol/g consumed sugar and 5.7g/(kg waste)/h), and was able to achieve ethanol production up to 155g/(kg waste) at low water demand, while SF reached only 78g/(kg waste) due to the limitations of the sugar extraction pretreatment. PMID- 28351730 TI - Associations of adverse childhood experiences with depression and alcohol abuse among Korean college students. AB - This study investigated adverse childhood experiences of Korean college students and the impact such experiences have on students' depression and alcohol abuse. Using an online questionnaire, 939 college students were surveyed regarding their adverse childhood experiences, depressive symptoms and alcohol use habits. About half of the participants claimed to have experienced at least one adversity in their childhood. Eight percent of participants reported experiencing four or more categories of adversity. The correlations between adverse childhood experiences and depressive symptoms, alcohol abusive behaviors, and the comorbid condition of the two outcomes were significant when students' gender, geographical regions, maternal and paternal education, and family incomes were adjusted. Graded associations of cumulated adverse childhood experiences with the outcome variables were evident. These findings strengthen the link between child maltreatment and adult public health issues carrying socioeconomic burdens, two matters that have not been extensively studied in Korean contexts. PMID- 28351731 TI - The impact of extrafamilial victimization and poly-victimization on the psychological well-being of English young people. AB - Childhood victimization impacts on the well-being of children and young people, particularly those experiencing an extreme amount of different types of victimization (i.e., poly-victims). However, limited attention has been given to the impact of different categories of extrafamilial victimization (experienced outside of the family), particularly in the UK. The intricacies of the significant detrimental impact poly-victimization has on victims are also poorly understood. In this study, 730 young people, aged 13 to 16 years (mean 13.8 years), from one county in the UK, were surveyed about their lifetime and past year experiences of extrafamilial victimization, the locations in which these occurred, and current trauma symptoms. The results showed that interpersonal forms of extrafamilial victimization (e.g., sexual victimization) were significant predictors of trauma, whilst more indirect forms of extrafamilial victimization (e.g., witnessing the victimization of others) were not. When extrafamilial poly-victimization and number of extrafamilial victim locations were accounted for within regression models, however, this impact was reduced. Poly-victimization within the past year was the strongest predictor of trauma symptoms. Number of victim locations did not significantly predict trauma symptoms above and beyond the impact of poly-victimization, although it was a contributory predictor. These findings suggest that a holistic exploration of a young person's extrafamilial victim experiences is needed in any clinical assessment or research into its psychological impact. Specifically, attention should be given to the experiencing of extreme levels of victimization (e.g., poly-victimization). Further longitudinal research is needed to understand why poly-victimization has the greatest impact on psychological well-being. PMID- 28351732 TI - Prevalence of factor H Binding Protein sub-variants among Neisseria meningitidis in China. AB - OBJECTIVE: To study the prevalence of the fHbp genes in Neisseria meningitidis (N. meningitidis) isolates for further evaluation and development of serogroup B meningococcal vaccines in China. METHODS: A panel of 1012 N. meningitidis strains was selected from the national culture collection from 1956 to 2016, according to the years of isolation, locations, and strain sources. These were tested by FHbp variant typing. Multi-locus sequence typing (MLST) was performed on 822 of these samples, including 242 strains from clinical strains and 580 carrier-derived strains. Analysis based on sequence types, serogroups, and FHbp variations were used to summarize the prevalence and characteristics of N. meningitidis. RESULTS: There were 8 serogroups of N. meningitidis as well as a collection of nongroupable strains in this study. 1008 of 1012 N. meningitidis strains tested were positive for the fHbp gene. Serogroup A N. meningitidis (MenA) strains belonging to ST-1 and ST-5 clonal complexes harbored genes only encoding variant 1 (v1) FHbp. All MenW strains encoded v2 FHbp. 61.9% of clinical MenB strains were positive for v2 FHbp vs. 32.1% that were positive for v1. Among fHbp positive carrier-derived MenB strains, v2 FHbp accounted for 90.8%. 79.7% of clinical MenC strains were positive for v1 FHbp and 20.3% were positive for v2 FHbp. Among carrier-derived MenC strains, v2 FHbp predominated. The number of major serogroups of N. meningitidis analyzed by MLST was 822, and the encoded FHbp showed CC- or ST-specific characteristics. CONCLUSION: fHbp genes were detected in almost all N. meningitidis strains in this study. Therefore, it is possible that a vaccine against MenB or meningococci irrespective of serogroups, which includes FHbp, could be developed. Meningococcal vaccine development for China is a complex issue and these findings warrant further attention with respect to vaccine development. PMID- 28351733 TI - Moving the needle on nursing staff influenza vaccination in long-term care: Results of an evidence-based intervention. AB - PURPOSE: Influenza vaccination rates among healthcare providers (HCPs) in long term care facilities (LTCFs) are commonly below the Healthy People 2020 goal of 90%. This study was conducted to develop and evaluate an intervention program designed to increase influenza uptake among HCPs in LTCFs. METHODS: This study was conducted in four Midwestern LTCFs. Baseline interviews, surveys, and administrative data analysis were performed following the 2013-2014 influenza season. Interventions implemented during the 2014-2015 season were based on the health belief and ecological models and included goal-setting worksheets, policy development, educational programs, kick-off events, incentives, a vaccination tracking roster, and facility-wide communication about vaccine uptake among HCPs. Outcomes were evaluated in 2015. RESULTS: At baseline, 50% of 726 nursing staff employed during the 2013-2014 influenza season had documented receipt of influenza vaccine (Site A: 34%; Site B: 5%; Site C: 75%; Site D: 62%), and 31% of 347 survey respondents reported absenteeism due to respiratory illness. At follow up, 85% of HCPs had documented receipt of influenza vaccine (p<0.01) and 19% of 323 survey respondents reported absenteeism due to respiratory illness (p<0.01). Vaccination rates among respondents' family members increased from 31% at baseline to 44% post-intervention (p<0.01). Reasons for declining vaccination did not change following exposure to educational programs, but HCPs were more likely to recommend vaccination to others after program implementation. CONCLUSIONS: Vaccination rates among long-term care HCPs and their family members increased significantly and HCP absenteeism decreased after the implementation of multifaceted interventions based on an ecological model. The findings suggest that major increases in HCP vaccination can be achieved in LTCFs. More research is needed to evaluate the impact of increased HCP vaccination on the health and productivity of LTCF employees, their family members, and residents. PMID- 28351734 TI - Chronic hepatitis B: Immunological profile and current therapeutic vaccines in clinical trials. AB - More than 250million people worldwide are chronically infected with hepatitis B virus (CHB), and over half a million die each year due to CHB-associated liver complications such as cirrhosis and hepatocellular carcinoma. The translation of immunological knowledge about CHB into therapeutic strategies aiming to a sustainable hepatitis B virus (HBV) clearance has been challenging. In recent years, however, the understanding on the immune effectors required to overcome chronicity has notably increased thanks to preclinical and clinical research. Therapeutic vaccination may prove to be useful for treating CHB patients when coupled with current antiviral agents and other immunomodulatory strategies. This review summarizes current data and future perspectives on therapeutic vaccination. Other treatment alternatives that could be combined with vaccines for a complete cure from hepatitis B virus infection are also discussed. PMID- 28351735 TI - Cognitive testing to evaluate revisions to the Vaccine Adverse Event Reporting System (VAERS) reporting form. AB - INTRODUCTION: The Vaccine Adverse Event Reporting System (VAERS) is the spontaneous (passive) reporting system CDC and FDA use to monitor vaccine safety. We used cognitive testing to evaluate proposed revisions to the current VAERS form. METHODS: We conducted in-person cognitive interviews with 22 volunteers to evaluate proposed revisions in a prototype VAERS 2.0 form (new VAERS form). We analyzed data using thematic analysis. RESULTS: Repeating themes included preferences for: brevity, simplicity and clarity; features to minimize time requirements and facilitate ease of completion; logical ordering of questions by topic and importance; and visual cues like color-coded highlighting. Interviews identified instances of discordance between the intended meaning questions (from the perspective of CDC and FDA) and interpretation by volunteers. CONCLUSIONS: Cognitive testing yielded useful information to guide further revisions of the VAERS form. Cognitive testing can be an effective tool for public health programs interested in developing surveys and reporting forms. PMID- 28351736 TI - Musculoskeletal modelling of human ankle complex: Estimation of ankle joint moments. AB - BACKGROUND: A musculoskeletal model for the ankle complex is vital in order to enhance the understanding of neuro-mechanical control of ankle motions, diagnose ankle disorders and assess subsequent treatments. Motions at the human ankle and foot, however, are complex due to simultaneous movements at the two joints namely, the ankle joint and the subtalar joint. The musculoskeletal elements at the ankle complex, such as ligaments, muscles and tendons, have intricate arrangements and exhibit transient and nonlinear behaviour. METHODS: This paper develops a musculoskeletal model of the ankle complex considering the biaxial ankle structure. The model provides estimates of overall mechanical characteristics (motion and moments) of ankle complex through consideration of forces applied along ligaments and muscle-tendon units. The dynamics of the ankle complex and its surrounding ligaments and muscle-tendon units is modelled and formulated into a state space model to facilitate simulations. A graphical user interface is also developed during this research in order to include the visual anatomical information by converting it to quantitative information on coordinates. FINDINGS: Validation of the ankle model was carried out by comparing its outputs with those published in literature as well as with experimental data obtained from an existing parallel ankle rehabilitation robot. INTERPRETATION: Qualitative agreement was observed between the model and measured data for both, the passive and active ankle motions during trials in terms of displacements and moments. PMID- 28351737 TI - Functional characterization of the aspartic proteinase cathepsin D in the beet armyworm (Spodoptera exigua). AB - In insects, proteolytic enzymes are involved in food digestion and the metamorphosis process. In the present study, the full-length cDNA of an aspartic proteinase, Spodoptera exigua cathepsin D (SeCatD), was cloned, and its functions in metamorphosis were characterized. SeCatD contains an open reading frame of 1152 nucleotides, encoding a 384-amino acid polypeptide including a signal peptide and two functional domains (family A1 propeptide of amino acids (19-45) and a cathepsin D-like domain of 327 amino acids (55-381)). Three-dimensional structure analysis indicated that Asp66 and Asp251 may play important role in hydrolysis. Recombinant SeCatD was expressed in Sf9 insect cells and verified via SDS-PAGE and Western blot, the molecular mass of the expressed SeCatD was approximately 42kDa. The enzyme had an optimal pH value of 3 for activity. In addition, the tissue expression profile of SeCatD during metamorphosis was obtained, and the data demonstrated that SeCatD was expressed increasingly in the fat body and midgut, but not in the epidermis. Finally, injection of dsRNA-SeCatD into the fifth-instar larvae significantly reduced SeCatD expression and larvae survival rate compared to a dsRNA-GFP treatment. These data imply that SeCatD may function during metamorphosis and may represent a target for insect control. PMID- 28351738 TI - Scanning indels in the 5q22.1 region and identification of the TMEM232 susceptibility gene that is associated with atopic dermatitis in the Chinese Han population. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease. The 5q22.1 region was found to have an association with AD in our previous genome wide association study (GWAS). OBJECTIVE: To identify the AD susceptibility gene in 5q22.1 and observe its expression in AD tissues. METHODS: Suggestive indels from the GWAS data were genotyped in 3013 AD patients and 5075 controls from the Chinese Han population with the SequenomMassArray system. Association, Bayesian and bioinformatics analyses were used to identify possible causal indels and genes in the 5q22.1 region. Immunohistochemistry (IHC) was performed to observe protein expression in the tissues. PLINK 1.07 software was used for all statistical analyses. RESULTS: The genotyping and association analysis showed that six deletions and four SNPs were associated with AD (P<0.005). The rs11357450 (Pcombined=7.79E-04, OR=1.39, logBayes Factor=1.29) deletion located in TMEM232 was identified to be the strongest variant. Analysis of the genetic model revealed that the dominant model best described rs11357450 (P=1.96E-03, OR=1.22; 95% CI=1.07-1.37). IHC showed that the expression of TMEM232 decreased gradually from the granular layer to the basal layer in AD, but in normal tissues, this trend was reversed. Additionally, positive cytoplasm staining was found in lymphocytes around the blood vessels in AD. CONCLUSIONS: The study indicates that TMEM232 in the 5q22.1 region is the causal gene for AD in the Chinese Han population. PMID- 28351739 TI - Identification, characterization and functional analysis of regulatory region of nanos gene from half-smooth tongue sole (Cynoglossus semilaevis). AB - The nanos gene encodes an RNA-binding zinc finger protein, which is required in the development and maintenance of germ cells. However, there is very limited information about nanos in flatfish, which impedes its application in fish breeding. In this study, we report the molecular cloning, characterization and functional analysis of the 3'-untranslated region of the nanos gene (Csnanos) from half-smooth tongue sole (Cynoglossus semilaevis), which is an economically important flatfish in China. The 1233-bp cDNA sequence, 1709-bp genomic sequence and flanking sequences (2.8-kb 5'- and 1.6-kb 3'-flanking regions) of Csnanos were cloned and characterized. Sequence analysis revealed that CsNanos shares low homology with Nanos in other species, but the zinc finger domain of CsNanos is highly similar. Phylogenetic analysis indicated that CsNanos belongs to the Nanos2 subfamily. Csnanos expression was widely detected in various tissues, but the expression level was higher in testis and ovary. During early development and sex differentiation, Csnanos expression exhibited a clear sexually dimorphic pattern, suggesting its different roles in the migration and differentiation of primordial germ cells (PGCs). Higher expression levels of Csnanos mRNA in normal females and males than in neomales indicated that the nanos gene may play key roles in maintaining the differentiation of gonad. Moreover, medaka PGCs were successfully labeled by the microinjection of synthesized mRNA consisting of green fluorescence protein and the 3'-untranslated region of Csnanos. These findings provide new insights into nanos gene expression and function, and lay the foundation for further study of PGC development and applications in tongue sole breeding. PMID- 28351740 TI - Evidencing 98 secondary metabolites of Penicillium verrucosum using substrate isotopic labeling and high-resolution mass spectrometry. AB - Industrial applications of fungal compounds, coupled with the emergence of fungal threats to natural ecosystems and public health, have increased interest in filamentous fungi. Among all pathogenic fungi, Penicillium verrucosum is one of the most common mold-infecting stored cereals in temperate regions. However, it is estimated that 80% of fungal secondary metabolites remain unknown. To detect new P. verrucosum compounds, an untargeted metabolomic approach was applied to fungus grown on wheat grains labeled with stable isotopes: (i) natural grains (99% 12C); (ii) grains enriched with 97% of 13C; and (iii) grains enriched with 53% of 13C and 97% of 15N. Analyses performed by high-performance liquid chromatography coupled with high-resolution mass spectrometry (HPLC-HRMS) enabled the specific detection of fungal metabolites, and the unambiguous characterization of their chemical formulas. In this way, 98 secondary metabolites were detected and their chemical formulas were determined. Of these, only 18 identifications could be made based on databases, the literature and mass spectrometry fragmentation experiments, with the result that 80 were totally unknown. Molecular networks were generated to analyze these results, leading to the characterization by MSn experiments of a new fungisporin produced by P. verrucosum. More generally, this article provides precise mass spectrometric data about all these compounds for further studies of the Penicillium metabolome. PMID- 28351741 TI - Relationship between ankle frontal plane kinematics during different functional tasks. AB - Increased inversion following lateral ankle sprain and in patients with chronic ankle instability (CAI) is thought to contribute to recurrent injury and feelings of instability, however, there are no biomechanic assessment tools readily available to evaluate for excessive inversion prior to or following lateral ankle sprains. Before establishing a clinically useful biomechanic assessment tool, it is important to understand whether there is a relationship in the extent of ankle frontal plane motion across various tasks to help determine if one task or a combination of tasks would be most appropriate when evaluating patients. The purpose of this preliminary study was to analyze the relationship between ankle frontal plane kinematics during walking, step-down, and jump-landing tasks. Fifty six recreationally active adults (gender=M:26;F:30, age=21.2+/-3.2, height=171.3+/-8.0cm, mass=75.6+/-15.4) volunteered. Main outcome measures were ankle frontal plane motion at initial contact and peak inversion during aerial phases across 3 tasks (walking, step-down, and jump-landing). Relationships between ankle frontal plane kinematics were analyzed by Pearson product-moment correlation coefficient (r). There were strong correlations in peak inversion during the aerial phase between the step-down and walking (r=0.68; p<0.001) and step-down and jump-landing (r=0.75; p<0.001) and at initial contact between step down and walking (r=0.73; p<0.001) and step-down and jump-landing (r=0.72; p<0.001). Moderate correlations were identified during aerial (r=0.32; p=0.015) and at initial contact (r=0.46; p<0.001) between walking and jump-landing. The strong relationship between the amount of inversion exhibited across various tasks suggest that a single evaluation test may be sufficient in the identification of abnormal ankle biomechanics. PMID- 28351742 TI - Effects of treadmill incline and speed on peroneus longus muscle activity in persons with chronic stroke and healthy subjects. AB - OBJECTIVE: To examine the effects of walking at different inclines and speeds on Peroneus Longus (PL) muscle activation and medial gastrocnemius (MG) coactivation with PL in healthy controls and subjects with stroke. DESIGN: Nineteen persons post-stroke (13M/6F) and fifteen healthy controls (10M/5F) walked on a treadmill at different inclines (0 degrees , 3 degrees , and 6 degrees ) and speeds (self selected, self-selected+20%, self-selected+40%). The electromyographic activity of the PL and MG muscles in the stance phase of gait cycle was measured. RESULTS: The paretic PL muscle activity did not change with incline, but increased at +40% speed only (p<0.05). The nonparetic PL increased at 6 degrees incline and at faster speeds (p<0.05). In the healthy group, PL muscle activity increased only on the right side at 6 degrees incline, but increased bilaterally at +40% faster speed (p<0.05). The timing of PL muscle activity did not change with incline (p>0.05), but was significantly delayed at +40% faster speed on the paretic side only (p<0.05). In healthy controls, PL muscle activation timing was unchanged with incline (p>0.05), but was significantly delayed at +40% speed only on the left side (p<0.05). The MG/PL amplitude and timing ratios were not significantly different between various walking conditions (p>0.05). CONCLUSION: An increase in PL activity occurs to provide ankle stability at walking speeds up to 40% faster than the self-selected speed. Important interlimb differences which may be related to leg dominance and motor control were observed in both stroke and healthy control groups in both PL muscle timing and their clinical impact should be investigated in future studies. PMID- 28351743 TI - Effects of treadmill training with load addition on non-paretic lower limb on gait parameters after stroke: A randomized controlled clinical trial. AB - The addition of load on the non-paretic lower limb for the purpose of restraining this limb and stimulating the use of the paretic limb has been suggested to improve hemiparetic gait. However, the results are conflicting and only short term effects have been observed. This study aims to investigate the effects of adding load on non-paretic lower limb during treadmill gait training as a multisession intervention on kinematic gait parameters after stroke. With this aim, 38 subacute stroke patients (mean time since stroke: 4.5 months) were randomly divided into two groups: treadmill training with load (equivalent to 5% of body weight) on the non-paretic ankle (experimental group) and treadmill training without load (control group). Both groups performed treadmill training during 30min per day, for two consecutive weeks (nine sessions). Spatiotemporal and angular gait parameters were assessed by a motion system analysis at baseline, post-training (at the end of 9days of interventions) and follow-up (40days after the end of interventions). Several post-training effects were demonstrated: patients walked faster and with longer paretic and non-paretic steps compared to baseline, and maintained these gains at follow-up. In addition, patients exhibited greater hip and knee joint excursion in both limbs at post training, while maintaining most of these benefits at follow-up. All these improvements were observed in both groups. Although the proposal gait training program has provided better gait parameters for these subacute stroke patients, our data indicate that load addition used as a restraint may not provide additional benefits to gait training. PMID- 28351744 TI - Dynamical analysis of balance in vestibular schwannoma patients. AB - The analysis of the complexity of postural fluctuations is a recent method for assessing postural control. Complexity relates to the irregularity of the center of pressure time series and characterizes the ability of postural control to meet a changing environment. In our study, we used the sample entropy (SampEn) parameter to evaluate the complexity of postural sway velocity time series in patients with vestibular schwannoma (n=19) compared to healthy controls (n=20), using the sensory organization test. Patients performed postural assessments three days before surgical ablation of the tumor, then three times after surgery, at eight, thirty, and ninety days. The control group underwent posturographic tests only once. Our results demonstrated that SampEn values distinguished both groups before surgery only in postural tasks where vestibular afferences significantly contribute to maintaining balance. We also found an immediate decrease of complexity after the surgical resection of the tumor. Our results are in line with the theory of complexity loss of physiological systems stating that reducing the number of their structural components or altering their coupling leads to a decrease in complexity. Finally, our findings showed that progressive restoration of complexity over time was such that no difference was found between the two groups ninety days after surgery, due to the implementation of central adaptive mechanisms and the substitution by other sensory afferences. Thus, the SampEn parameter can highlight the postural effects of vestibular pathology, and complexity analysis appears to be a valuable tool for investigating the temporal structure of CoP time series. PMID- 28351745 TI - The severity and number of musculoskeletal pain associated with gait in community dwelling elderly individuals. AB - BACKGROUND: The association of quantitative gait characteristics, such as gait variability with musculoskeletal pain is poorly understood. We aimed to examine whether gait speed and gait variability are associated with musculoskeletal pain assessed by the severity and the number of sites in community-dwelling elderly individuals. METHODS: A total of 176 elderly individuals participated in this study. The wireless motion-recording sensor units were attached to the lower trunk and heel during gait, and an autocorrelation coefficient was calculated in three directions as parameters of gait variability of trunk movement. Musculoskeletal pain was assessed in two aspects: severity and the number of sites. RESULTS: Moderate/severe pain intensity was significantly associated with slow gait speed and low AC in a mediolateral direction (P=0.024 and 0.026, respectively). Participants with musculoskeletal pain in multiple sites had significantly lower autocorrelation coefficient in mediolateral direction than did those without pain (P=0.003). CONCLUSIONS: Presence of moderate/severe pain intensity in at least one site or any-intensity pain in multiple sites is associated with slower gait speed and higher gait variability of trunk movement in well-functioning elderly individuals living in the community. Additional studies are necessary to elucidate the causal relationships between musculoskeletal pain and gait. PMID- 28351746 TI - Competition and enhancement effect in coremoval of atenolol and copper by an easily regenerative magnetic cation exchange resin. AB - This paper aimed to investigate the removal of combined Cu2+ and atenolol (ATL) in aqueous solution by using a newly synthesized magnetic cation exchange resin (MCER) as the adsorbent. The MCER exhibited efficient removal performance in sole, binary, pre-loading and saline systems. The adsorption kinetics of Cu2+ and ATL fitted both pseudo-first-order and pseudo-second order model, while better described by pseudo-second order model in binary system. In mixed Cu2+ and ATL solution, the adsorption of ATL was suppressed due to direct competition of carboxylic groups, while Cu2+ adsorption was enhanced because of the formation of surface complexes. This increasing in heterogeneity was demonstrated by adsorption isotherms, which were more suitable for Freundlich model in binary system, while better described by Langmuir model in sole system. As proved by FTIR and XPS spectra, both amino and hydroxyl groups of ATL could form complexes with Cu2+. Decomplexing-bridging interaction was elucidated as the leading mechanism in coremoval of Cu2+ and ATL, which involved [Cu-ATL] decomplexing and newly created Cu- or ATL sites for additional bridging. For saline system, the resulting competition and enhancement effects in mixed solution were amplified with the addition of co-existing cations. Moreover, the MCER could be effectively regenerated by 0.01 M HCl solution and maintain high stability over 5 adsorption desorption cycles, which render it great potential for practical applications. PMID- 28351747 TI - Improved contrast for high frame rate imaging using coherent compounding combined with spatial matched filtering. AB - The concept of high frame rate ultrasound imaging (typically greater than 1000 frames per second) has inspired new fields of clinical applications for ultrasound imaging such as fast cardiovascular imaging, fast Doppler imaging and real-time 3D imaging. Coherent plane-wave compounding is a promising beamforming technique to achieve high frame rate imaging. By combining echoes from plane waves with different angles, dynamic transmit focusing is efficiently accomplished at all points in the image field. Meanwhile, the image frame rate can still be kept at a high level. Spatial matched filtering (SMF) with plane wave insonification is a novel ultrafast beamforming method. An analytical study shows that SMF is equivalent to synthetic aperture methods that can provide dynamic transmit-receive focusing throughout the field of view. Experimental results show that plane-wave SMF has better performance than dynamic-receive focusing. In this paper, we propose integrating coherent plane-wave compounding with SMF to obtain greater image contrast. By using a combination of SMF beamformed images, image contrast is improved without degrading its high frame rate capabilities. The performance of compounded SMF (CSMF) is evaluated and compared with that of synthetic aperture focusing technique (SAFT) beamforming and compounded dynamic-receive-focus (CDRF) beamforming. The image quality of different beamforming methods was quantified in terms of contrast-to-noise ratio (CNR). Our results show that the new SMF based plane-wave compounding method provides better contrast than DAS based compounding method. Also CSMF can obtain a similar contrast level to dynamic transmit-receive focusing with only 21 transmit events. PMID- 28351748 TI - Beliefs about physical activity and sedentary behaviors of adults with visual impairments. AB - BACKGROUND: When exploring reasons why individuals with visual impairments (VI) may or may not engage in physical activity (PA) or sedentary behaviors (SB), theoretically grounded research on the determinants of these behaviors is scarce. OBJECTIVE/HYPOTHESIS: Situated in the theory of planned behavior (TpB), the purposes of this study were to: (a) develop a theoretically-sound scale, Beliefs about Physical and Sedentary Behaviors-Visual Impairment (BAPS-VI), to determine if the constructs of TpB are useful in predicting PA and SBs of adults with VI; (b) analyze their beliefs about PA and SBs; and (c) determine which TpB constructs are the best predictors of PA behaviors. METHODS: Data were collected from adults with VI (n = 209, 65.5% women) using on-line survey methodology. Following reliability estimation, the PA and SB items were reduced using separate Principal Components analyses to examine the underlying dimension of the BAPS-VI in relation to TpB. A hierarchical regression model was used to determine what factors predicted self-reports of minutes of PA. RESULTS: Results supported the theoretical framework of the measure and explained 75% of the variance for intention to engage in PA and SB items, respectively. Six new variables, intention, and demographic data were then regressed on physical activity scores with only intention to engage in PA (beta = 0.30, p < 0.01) remaining as a significant predictor of physical activity. CONCLUSIONS: The development of the theoretically driven measure and results of this study can inform future research focusing on exploring PA and SBs of adults with VI. PMID- 28351749 TI - The link between smoking status and co-morbid conditions in individuals with multiple sclerosis (MS). AB - BACKGROUND: In individuals with multiple sclerosis (MS) comorbidities and quality of life (QOL) may be affected by tobacco use. OBJECTIVE: To evaluate the associations between smoking status, in particular quit attempts, and comorbidities among individuals with MS. METHODS: We used a web-based survey to obtain cross-sectional data from 335 individuals with MS who were members of the Gateway Chapter of the National MS Society email registry. We then examined the associations between smoking variables (current use, frequency, and quit attempts) and comorbidities. RESULTS: The prevalence of participants who ever smoked was 50%, which is greater than that reported for the general population; 20% were current smokers. Migraine headaches were associated with current use and everyday smoking, and those with recent failed quit attempts had a higher prevalence of depression than those who were current smokers but who did not attempt to quit or had successfully quit in the past year. CONCLUSION: Given the associations between smoking and comorbidities in individuals with MS, health care providers should both (1) assess smoking history and quit attempts, and (2) encourage individuals with MS who smoke to become non-smokers and refer for treatment, as indicated. In order to increase the chances that individuals will be successful in becoming non-smokers, clinicians would do well to also assess and treat depression in their patients who smoke and are also depressed. PMID- 28351750 TI - A longitudinal DTI and histological study of the spinal cord reveals early pathological alterations in G93A-SOD1 mouse model of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective motor neuron degeneration in the motor cortex, brainstem and spinal cord. It is generally accepted that ALS is caused by death of motor neurons, however the exact temporal cascade of degenerative processes is not yet completely known. To identify the early pathological changes in spinal cord of G93A-SOD1 ALS mice we performed a comprehensive longitudinal analysis employing diffusion-tensor magnetic resonance imaging alongside histology and electron microscopy, in parallel with peripheral nerve histology. We showed the gradient of degeneration appearance in spinal cord white and gray matter, starting earliest in the ventral white matter, due to a cascade of pathological events including axon dysfunction and mitochondrial changes. Notably, we found that even the main sensory regions are affected by the neurodegenerative process at symptomatic disease phase. Overall our results attest the applicability of DTI in determining disease progression in ALS mice. These findings suggest that DTI could be potentially adapted in humans to aid the assessment of ALS progression and eventually the evaluation of treatment efficacy. PMID- 28351751 TI - The pancreas: Bandmaster of glucose homeostasis. AB - The pancreas is a centralized organ vital for whole body metabolic control. Recent advances in the field of metabolism have reinforced its importance for orchestrating endocrine hormone secretion in response to several nutrients including glucose, lipids and amino acids, in addition to hormones and inflammatory signals. Cell types within the pancreas, in particular the insulin producing beta cells, control nutrient breakdown and energy production and are essential to maintain not only efficient hormone secretion, but also cell integrity, survival, and the ability to sense and adapt to changing metabolic environments. The present review highlights recent research advances on how glucolipotoxicity, mitochondrial dysfunction, and systemic inflammation affects pancreatic metabolism, and how new technologies and more advanced research models are improving our ability to study this organ system. Taken together, careful characterization and understanding of the importance of nutrient metabolism within this important, yet complex organ, will help us to better understand pathologies intimately associated with the pancreas and possibly discover new and more effective therapeutic strategies. PMID- 28351752 TI - Deficiency of CKIP-1 aggravates high-fat diet-induced fatty liver in mice. AB - Casein kinase 2 interacting protein-1(CKIP-1) is widely expressed in a variety of tissues and cells, and plays an important role in various critical cellular and physiological processes including cell growth, apoptosis, differentiation, cytoskeleton and bone formation. Here, we found: (1) CKIP-1 deficient mice exhibited increased body weight, liver weight, number and size of lipid droplets, and TG content comparing with WT mice after being exposed to high fat diet (HFD); (2) the levels of serum insulin, liver glycogen, phosphorylated C-Jun-N-terminal kinase-1 (pJNK1) and phosphorylated insulin receptor substrate -1(pIRS1) in CKIP 1-/- mice were higher than those of WT mice; (3) CKIP-1 interacted with JNK1 in vitro. Our results indicate that CKIP-1 deficiency in mice aggravates HFD-induced fatty liver by upregulating JNK1 phosphorylation and further upregulating IRS-1 phosphorylation and RI. PMID- 28351753 TI - The Brief Multidimensional Students' Life Satisfaction Scale (BMSLSS): Reliability, validity, and gender invariance in an Indian adolescent sample. AB - This study examined the internal consistency reliability, factorial, convergent, discriminant, and predictive validity, as well as gender invariance of the Brief Multidimensional Students' Life Satisfaction Scale (BMSLSS; Seligson, Huebner, & Valois, 2003) in a sample of 445 adolescents (Mage = 16.04 years) hailing from the southernmost state of India, Kerala. The study also examined the test-retest reliability (n = 392) of the BMSLSS. The Cronbach's alpha coefficient suggested that the BMSLSS was reliable. Confirmatory factor analyses demonstrated the factorial validity of the BMSLSS. Bivariate correlational analyses provided support for the convergent, discriminant, and predictive validity of the BMSLSS. The test-retest reliability coefficient indicated the temporal stability of the BMSLSS. Finally, multi-group confirmatory factor analysis provided support for the gender invariance of the BMSLSS. PMID- 28351754 TI - Longitudinal left ventricular contractility in young isolated systolic hypertensives. PMID- 28351755 TI - The origins of the vocal brain in humans. AB - The evolution of vocal communication in humans required the emergence of not only voluntary control of the vocal apparatus and a flexible vocal repertoire, but the capacity for vocal learning. All of these capacities are lacking in non-human primates, suggesting that the vocal brain underwent significant modifications during human evolution. We review research spanning from early neurophysiological descriptions of great apes to the state of the art in human neuroimaging on the neural organization of the larynx motor cortex, the major regulator of vocalization for both speech and song in humans. We describe changes to the location, structure, function, and connectivity of the larynx motor cortex in humans compared with non-human primates, including critical gaps in the current understanding of the brain systems mediating vocal control and vocal learning. We explore a number of models of the origins of the vocal brain that incorporate findings from comparative neuroscience, and conclude by presenting a summary of contemporary hypotheses that can guide future research. PMID- 28351756 TI - Oxygenated hypothermic machine perfusion after static cold storage improves endothelial function of extended criteria donor livers. AB - BACKGROUND: Lack of oxygen and biomechanical stimulation during static cold storage (SCS) of donor livers compromises endothelial cell function. We investigated the effect of end-ischemic oxygenated hypothermic machine perfusion (HMP) on endothelial cell function of extended criteria donor (ECD) livers. METHODS: Eighteen livers, declined for transplantation, were transported to our center using static cold storage (SCS). After SCS, 6 livers underwent two hours of HMP, and subsequent normothermic machine perfusion (NMP) to assess viability. Twelve control livers underwent NMP immediately after SCS. mRNA expression of transcription factor Kruppel-like-factor 2 (KLF2), endothelial nitric oxide synthase (eNOS), and thrombomodulin (TM) was quantified by RT-PCR. Endothelial cell function and injury were assessed by nitric oxide (NO) production and release of TM into the perfusate. RESULTS: In HMP livers, mRNA expression of KLF2 (p = 0.043), eNOS (p = 0.028), and TM (p = 0.028) increased significantly during NMP. In parallel, NO levels increased during NMP in HMP livers but not in controls. At the end of NMP cumulative TM release was significantly lower HMP livers, compared to controls (p = 0.028). CONCLUSION: A short period of two hours oxygenated HMP restores endothelial cell viability after SCS and subsequent normothermic reoxygenation of ECD livers. PMID- 28351757 TI - Nanotechnological strategies for nerve growth factor delivery: Therapeutic implications in Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with amyloid-beta peptide misfolding and aggregation. Neurotrophic factors, such as nerve growth factor (NGF), can prevent neuronal damage and rescue the cholinergic neurons that undergo cell death in AD, reverse deposition of extracellular amyloid plaques and improve cognitive deficits. However, NGF administration is hampered by the poor pharmacokinetic profile of the therapeutic protein and its inability to cross the blood-brain barrier, which requires specialised drug delivery systems (DDS) for efficient NGF delivery to the brain. This review covers the main therapeutic approaches that have been developed for NGF delivery targeting the brain, from polymeric implants to gene and cell-based therapies, focusing on the role of nanoparticulate systems for the sustained release of NGF in the brain as a neuroprotective and disease-modifying approach toward AD. Lipid- and polymer-based delivery systems, magnetic nanoparticles and quantum dots are specifically addressed as promising nanotechnological strategies to overcome the current limitations of NGF-based therapies. PMID- 28351758 TI - The mouse cortical meninges are the site of immune responses to many different pathogens, and are accessible to intravital imaging. AB - A wide range of viral and microbial infections are known to cause meningitis, and there is evidence that the meninges are the gateway to pathogenic invasion of the brain parenchyma. Hence observation of these regions has wide application to understanding host-pathogen interactions. Interactions between pathogens and cells of the immune response can be modified by changes in their environment, such as suppression of the flow of blood and lymph, and, particularly in the case of the meninges, with their unsupported membranes, invasive dissection can alter the tissue architecture. For these reasons, intravital imaging through the unperforated skull is the method of choice. We give a protocol for a simple method of two-photon microscopy through the thinned cortical skull of the anesthetized mouse to enable real-time imaging with sub-micron resolution through the meninges and into the superficial brain parenchyma. In reporter mice in which selected cell types express fluorescent proteins, imaging after infection with fluorescent pathogens (lymphocytic choriomeningitis virus, Trypanosoma brucei or Plasmodium berghei) has shown strong recruitment to the cortical meninges of immune cells, including neutrophils, T cells, and putative dendritic cells and macrophages. Without special labeling, the boundaries between the dura mater, the leptomeninx, and the parenchyma are not directly visualized in intravital two photon microscopy, but other landmarks and characteristics, which we illustrate, allow the researcher to identify the compartment being imaged. While most infectious meningitides are localized mainly in the dura mater, others involve recruitment of immune cells to the leptomeninx. PMID- 28351760 TI - Extreme nitrite tolerance in the clown knifefish Chitala ornata is linked to up regulation of methaemoglobin reductase activity. AB - The clown knifefish is a facultative air breather, which is widely farmed in freshwater ponds in Vietnam. Here we report a very high nitrite tolerance (96h LC50 of 7.82mM) in this species and examine the effects of 1mM (LC5) and 2.5mM (LC10) ambient nitrite on haemoglobin (Hb) derivatives, electrolyte levels, acid base status, and total body water content during 7days of exposure. Furthermore, we tested the hypothesis that erythrocyte methaemoglobin (metHb) reductase activity is upregulated by nitrite exposure. Plasma nitrite levels increased for 2-3days but stayed below environmental levels and fell towards control values during the last half of the exposure period. Plasma nitrate, in contrast, rose continuously, reflecting detoxification of nitrite to nitrate. MetHb generated from the reaction between nitrite and erythrocyte Hb reached 38% at day 2, but then decreased to 17% by the end of experiment. The first order rate constant for metHb reduction by erythrocyte metHb reductase increased from 0.01 in controls to 0.046min-1 after 6days of nitrite exposure, showing up-regulation of this enzyme. While such upregulation has been suggested in nitrite-exposed fish species, this study provides the first experimental evidence. PMID- 28351759 TI - Simplified CRISPR tools for efficient genome editing and streamlined protocols for their delivery into mammalian cells and mouse zygotes. AB - Genome editing using the CRISPR/Cas9 system requires the presence of guide RNAs bound to the Cas9 endonuclease as a ribonucleoprotein (RNP) complex in cells, which cleaves the host cell genome at sites specified by the guide RNAs. New genetic material may be introduced during repair of the double-stranded break via homology dependent repair (HDR) if suitable DNA templates are delivered with the CRISPR components. Early methods used plasmid or viral vectors to make these components in the host cell, however newer approaches using recombinant Cas9 protein with synthetic guide RNAs introduced directly as an RNP complex into cells shows faster onset of action with fewer off-target effects. This approach also enables use of chemically modified synthetic guide RNAs that have improved nuclease stability and reduces the risk of triggering an innate immune response in the host cell. This article provides detailed methods for genome editing using the RNP approach with synthetic guide RNAs using lipofection or electroporation in mammalian cells or using microinjection in murine zygotes, with or without addition of a single-stranded HDR template DNA. PMID- 28351761 TI - Interleukin-24 as a target cytokine of environmental aryl hydrocarbon receptor agonist exposure in the lung. AB - Exposure to environmental aryl hydrocarbon receptor (AhR) agonists, such as halogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons (PAHs), has great impacts on the development of various lung diseases. As emerging molecular targets for AhR agonists, cytokines may contribute to the inflammatory or immunotoxic effects of environmental AhR agonists. However, general cytokine expression may not specifically indicate environmental AhR agonist exposure. By comparing cytokine and chemokine expression profiles in human lung adenocarcinoma cell line CL5 treated with AhR agonists and the non-AhR agonist polychlorinated biphenyl (PCB) 39, we identified a target cytokine of environmental AhR agonist exposure of in the lungs. Thirteen cytokine and chemokine genes were altered in the AhR agonists-treated cells, but none were altered in the PCB39-treated cells. Interleukin (IL)-24 was the most highly induced gene among AhR-modulated cytokines. Cotreatment with AhR antagonist completely prevented IL-24 induction by AhR agonists in the CL5 cells. Knockdown AhR expression with short-hairpin RNA (shRNA) significantly reduced benzo[a]pyrene (BaP)-induced IL-24 mRNA levels. We further confirmed that gene transcription, but not mRNA stability, was involved in IL-24 upregulation by BaP. Particulate matter (PM) in the ambient air contains some PAHs and is reported to activate AhR. Oropharyngeal aspiration of PM significantly increased IL-24 levels in lung epithelia and in bronchoalveolar lavage fluid of mice 4weeks after treatment. Thus, our data suggests that IL-24 is a pulmonary exposure target cytokine of environmental AhR agonists. PMID- 28351762 TI - Does Ulipristal Acetate Affect Surgical Experience at Laparoscopic Myomectomy? AB - STUDY OBJECTIVE: To compare surgical experience of laparoscopic/robotic myomectomy in premenopausal patients pretreated with ulipristal acetate (UPA) with women not hormonally pretreated. DESIGN: A retrospective, multicenter cohort study of laparoscopic/robotic myomectomy procedure videos (Canadian Task Force Classification III). SETTING: Multiple university-affiliated tertiary care hospitals. PATIENTS: Fifty-five premenopausal women who underwent laparoscopic/robotic myomectomy for intramural myomas and were either pretreated with 3 months of UPA or had no hormonal pretreatment. INTERVENTIONS: Laparoscopic/robotic myomectomy surgical videos were independently reviewed by 2 gynecologists blinded to whether or not patients received pretreatment with UPA. Each procedure was scored using a novel 22-point surgical global rating tool containing 6 subscales: depth of myometrial incision, ease of myoma-myometrium cleavage plane identification, ease of myoma detachment, blood loss during myoma detachment, myometrial blood loss after myoma detachment, and myoma consistency. MEASUREMENTS AND MAIN RESULTS: Participating surgeons submitted 55 videos of laparoscopic/robotic myomectomy procedures recorded over a 3-year period (2012 2015). Fifty met the inclusion criteria (25 UPA-treated patients and 25 patients without hormonal pretreatment). Patients treated with UPA were more likely to be older than patients with no medical pretreatment (mean age = 33.5 vs 38.3 years, p = .002). There were no statistically significant differences regarding other baseline characteristics such as the largest diameter of myoma removed, the number of myomas removed, or the estimated blood loss. There was no difference in the physician assessors' mean global rating score for patients with UPA pretreatment versus no pretreatment (12.4 vs 13.4, p = .23). Within the 6 subscales, no differences were observed between the 2 groups. Each video was graded independently by 2 assessors, and there was high inter-rater agreement for the total score and each subscale. CONCLUSION: There was no difference in surgical experience for myomectomies of patients pretreated with UPA versus those without medical pretreatment. PMID- 28351763 TI - Does Universal Insurance Mitigate Racial Differences in Minimally Invasive Hysterectomy? AB - STUDY OBJECTIVE: To determine if racial differences exist in receipt of minimally invasive hysterectomy (defined as total vaginal hysterectomy [TVH] and total laparoscopic hysterectomy [TLH]) compared with an open approach (total abdominal hysterectomy [TAH]) within a universally insured patient population. DESIGN: Retrospective data analysis (Canadian Task Force classification II-2). SETTING: The 2006-2010 national TRICARE (universal insurance coverage to US Armed Services members and their dependents) longitudinal claims data. PATIENTS: Women aged 18 years and above who underwent hysterectomy stratified into 4 racial groups: white, African American, Asian, and "other." INTERVENTION: Receipt of hysterectomy (TAH, TVH, or TLH). MEASUREMENTS AND MAIN RESULTS: We used risk adjusted multinomial logistic regression models to determine the relative risk ratios of receipt of TVH and TLH compared with TAH in each racial group compared with referent category of white patients for benign conditions. Among 33 015 patients identified, 60.82% (n = 20 079) were white, 26.11% (n = 8621) African American, 4.63% (n = 1529) Asian, and 8.44% (n = 2786) other. Most hysterectomies (83.9%) were for benign indications. Nearly 42% of hysterectomies (n = 13 917) were TAH, 27% (n = 8937) were TVH, and 30% (n = 10 161) were TLH. Overall, 36.37% of white patients received TAH compared with 53.40% of African American patients and 51.01% of Asian patients (p < .001). On multinomial logistic regression analyses, African American patients were significantly less likely than white patients to receive TVH (relative risk ratio [RRR], .63; 95% confidence interval [CI], .58-.69) or TLH (RRR, .65; 95% CI, .60-.71) compared with TAH. Similarly, Asian patients were less likely than white patients to receive TVH (RRR, .71; 95% CI, .60-.84) or TLH (RRR, .69; 95% CI, .58-.83) compared with TAH. Analyses by benign indications for surgery showed similar trends. CONCLUSION: We demonstrate that racial minority patients are less likely to receive a minimally invasive surgical approach compared with an open abdominal approach despite universal insurance coverage. Further work is warranted to better understand factors other than insurance access that may contribute to racial differences in surgical approach to hysterectomies. PMID- 28351764 TI - Motor learning paradigm and contextual interference in manual computer tasks in individuals with cerebral palsy. AB - BACKGROUND: Cerebral palsy (CP) is a group of disorders of movement and posture that cause activity limitations. Due to the different motor problems these individuals encounter there is a need to offer rehabilitation programs that promote motor learning. Additionally, the understanding of the learning patterns of these individuals can help us attend to their learning needs to maximize their learning efficiency. AIMS: The present study aimed to add to the knowledge base in regards to motor learning and the contextual interference (CI) effect. METHODS AND PROCEDURES: The study included 40 individuals with CP and 40 typically developing (TD) participants matched for age and gender with the CP group. Both groups were divided into 2 subgroups regarding the practice schedule (random or constant practice) of a manual maze test on the computer. The participants who performed in the constant practice schedule performed the same standard maze 30 times, while participants in the random practice schedule performed a total of 30 trials on 5 mazes with a different spatial layout including the standard maze. After 5min of rest, retention was studied with a task in which all participants performed the standard maze. To examine the transfer effect, all participants also performed a maze with a new layout. Time of completion was registered in seconds for each trial. OUTCOMES AND RESULTS: The results showed that the performance was lower in individuals with CP compared to typically developing individuals. In addition, only the participants with CP showed a contextual interference effect, with performance after the random practice schedule being superior compared to participants who practiced with a constant practice schedule. CONCLUSIONS AND IMPLICATIONS: Overall performance was lower in individuals with CP compared to individuals with TD. Additionally, both TD individuals and individuals with CP showed the contextual interference effect in the transfer phase, with the execution of random practice leading to better performance than constant practice. These findings provide important information to assist clinicians in developing rehabilitation programs for children with CP. PMID- 28351765 TI - Health risks posed to infants in rural China by exposure to short- and medium chain chlorinated paraffins in breast milk. AB - Chlorinated paraffins (CPs) are complex mixtures of synthetic chemicals found widely in environmental matrices. Short-chain CPs (SCCPs) are candidate persistent organic pollutants under the Stockholm Convention. There should be great concern about human exposure to SCCPs. Data on CP concentrations in human breast milk is scarce. This is the first study in which background SCCP and medium-chain CP (MCCP) body burdens in the general rural population of China have been estimated and health risks posed to nursing infants by CPs in breast milk assessed. The concentrations of 48 SCCP and MCCP formula congeners were determined in 24 pooled human milk samples produced from 1412 individual samples from eight provinces in 2007 and 16 provinces in 2011. The samples were analyzed by comprehensive two-dimensional gas chromatography electron capture negative ionization high-resolution time-of-flight mass spectrometry. The median SCCP and MCCP concentrations were 303 and 35.7ngg-1 lipid weight, respectively, for the 2007 samples and 360 and 45.4ngg-1 lipid weight, respectively, for the 2011 samples. The C10 and C14 homologs were the dominant CP carbon-chain-length groups, contributing 51% and 82% of the total SCCP and MCCP concentrations, respectively. There are probably multiple CP sources to the general Chinese population and numerous exposure pathways. The median estimated daily SCCP and MCCP intakes for nursing infants were 1310 and 152ngkg-1d-1, respectively, in 2007 and 1520 and 212ngkg-1d-1, respectively, in 2011. SCCPs do not currently pose significant risks to infants in China. However, it is necessary to continuously monitor CP concentrations and health risks because CP concentrations in Chinese human breast milk are increasing. PMID- 28351766 TI - Common cold among pre-school children in China - associations with ambient PM10 and dampness, mould, cats, dogs, rats and cockroaches in the home environment. AB - BACKGROUND: There is some evidence that dampness, mould and cockroaches can increase the risk of respiratory infections in children but few studies exist from China on this topic. Aim To study associations between domestic early life exposure to biological indoor factors (dampness, mould, cats, dogs, rats, cockroaches), cleaning habits and common cold among pre-school children across China. METHODS: Children aged 3-6years (n=39,782) were recruited from randomly selected day care centres in seven cities in China. Data on common cold and prenatal and postnatal exposure to dampness, mould, windowpane condensation in wintertime (WPC), cats, dogs, cockroaches and rats were assessed by a parentally administered questionnaire. Data on annual ambient temperature and PM10 was assessed on city level. Associations between high frequency (>5 colds per year) and long duration (>=2weeks) of common colds in the past year and exposure were calculated by multilevel logistic regression. RESULTS: A total of 9.2% had a high frequency and 11.9% had long duration of common cold. Exposure to mould (OR=1.38, 95% CI 1.24-1.53) and WPC (OR 1.23, 95%CI 1.13-1.33) at birth was associated with frequent common cold. Exposure to dogs at birth was associated with long duration of common cold. (OR=1.22, 95% CI 1.06-1.41). Exposure to mould (OR=1.36, 95% CI 1.22-1.54), WPC (OR=1.27, 95%CI 1.17-1.39) and water leakage (OR 1.34, 95% CI 1.20-1.49) in the current home was associated with frequent common cold. Presence of cockroaches were positively (OR=1.12, 95% CI 1.02-1.24) and presence of rats (OR=0.86, 95% CI 0.77-0.96) negatively associated with high frequency of common cold. Daily cleaning was negatively associated with frequent common cold (OR=0.89, 95% CI 0.81-0.97). Similar associations for mould, WPC, cockroaches and rats were found for long duration. Ambient PM10 (OR=1.21, 95% CI 1.21-1.35 per 10MUg/m3) and temperature (OR=1.13, 95% CI 1.06-1.35 degrees C) on city level were associated with high frequency of common cold. Associations between cat keeping and high frequency of common cold were found only in southern China. Associations with cockroaches were stronger in northern China. Associations with dampness and mould were the same in the north and south. CONCLUSIONS: Indoor mould, water damage, windowpane condensation, cockroaches and keeping cats or dogs as pets can be risk factors for common cold while daily cleaning can be protective factor. PM10 and a warmer climate zone can be other risk factors for common cold. PMID- 28351767 TI - Short-term effects of air temperature and mitochondrial DNA lesions within an older population. AB - BACKGROUND: Previous studies have linked both extreme and sub-optimal air temperature to cardiopulmonary morbidity and mortality, especially in older individuals. However, the underlying mechanisms are yet to be determined. OBJECTIVES: We hypothesized that short-term increases in air temperature may induce blood mitochondrial DNA (mtDNA) lesions in older individuals, which could contribute to temperature-related pathogenesis. METHODS: We repeatedly measured mtDNA lesions in blood samples from 654 participants in the Normative Aging Study from 1999 to 2013 (1142 observations) by quantitative long-amplicon polymerase chain reaction assay. Hourly temperature data were obtained from the Boston Logan Airport weather station (located approximately 12km from the clinical site). We calculated 2-, 7-, and 14-day moving averages of 24-hour mean and 24-hour variability of temperature. We fit covariate-adjusted linear-mixed models accounting for repeated measures to evaluate the association between short-term increases in mean and variability of temperature with mtDNA lesions within each season. RESULTS: Interquartile increases in 7- and 14-day moving averages of 24 hour mean temperature in summer were associated with a 0.17 (95% CI: 0.07, 0.27; p=0.0007) and 0.21 (95% CI: 0.10, 0.32; p=0.0001) increase in the number of mtDNA lesions per 10kb, respectively. Results were similar when we further adjusted for temperature variability. We also observed significant associations between increases in temperature variability and mtDNA lesions independent of mean air temperature. An interquartile range increase in the 7-day moving average of 24 hour standard deviation in summer was associated with a 0.19 (95% CI: 0.07, 0.31; p=0.0023) increase in the number of mtDNA lesions per 10kb. CONCLUSIONS: Short term exposure to higher mean air temperature was associated with increased mtDNA lesions in older adults, supporting the hypothesis that sub-optimal meteorological conditions may induce pathophysiological responses among susceptible populations. PMID- 28351768 TI - Context-sensitive ecological momentary assessments; integrating real-time exposure measurements, data-analytics and health assessment using a smartphone application. AB - INTRODUCTION: Modern sensor technology makes it possible to collect vast amounts of environmental, behavioural and health data. These data are often linked to contextual information on for example exposure sources which is separately collected with considerable lag time, leading to complications in assessing transient and/or highly spatially variable environmental exposures. Context Sensitive Ecological Momentary Assessments1 (CS-EMAs) could be used to address this. We present a case study using radiofrequency-electromagnetic fields (RF EMF) exposure as an example for implementing CS-EMA in environmental research. METHODS: Participants were asked to install a custom application on their own smartphone and to wear an RF-EMF exposimeter for 48h. Questionnaires were triggered by the application based on a continuous data stream from the exposimeter. Triggers were divided into four categories: relative and absolute exposure levels, phone calls, and control condition. After the two days of use participants filled in an evaluation questionnaire. RESULTS: 74% of all CS-EMAs were completed, with an average time of 31s to complete a questionnaire once it was opened. Participants reported minimal influence on daily activities. There were no significant differences found between well-being and type of RF-EMF exposure. CONCLUSIONS: We show that a CS-EMA based method could be used in environmental research. Using several examples involving environmental stressors, we discuss both current and future applications of this methodology in studying potential health effects of environmental factors. PMID- 28351769 TI - Quercetin attenuates high fat diet-induced atherosclerosis in apolipoprotein E knockout mice: A critical role of NADPH oxidase. AB - Reactive oxygen species (ROS) have emerged as important molecules in cardiovascular function. Nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase is the major source of ROS in phagocytic and vascular cells. Several lines of evidence indicate that quercetin contributes to protecting against atherosclerosis. Herein, we investigated the effect of quercetin on alleviating atherosclerosis by regulating NADPH oxidase subunits expression in vivo, and explored the mechanism of quercetin suppressing the ROS overproduction stimulated by ox-LDL in mouse peritoneal macrophages (MPMs). Model ApoE KO mice were fed with either a normal chow diet or a high fat diet (HFD) supplemented with or without dosed quercetin for 24 weeks. Quercetin significantly reduced the atherosclerotic plaque area, alleviated the systemic oxidative stress, and suppressed aortic p47phox, p67phox expressions but partially reversed the NOX4 expression as compared to those in the HFD group. In vitro, quercetin effectively inhibited the ox-LDL induced ROS formation in MPMs, and blocked the vital step in activation of NADPH oxidase - membrane translocation of p47phox. Our findings suggest that regular consumption of dietary quercetin plays a role in preventing atherosclerosis giving its evident regulatory effect on subunits of NADPH oxidase. PMID- 28351770 TI - 2D-NMR investigation and in vitro evaluation of antioxidant, antigenotoxic and estrogenic/antiestrogenic activities of strawberry grape. AB - Strawberry grape is considered beneficial due to its extensive phytochemical properties. To expand the knowledge about the chemical constituents and the biological activities of the whole plant, 2D-NMR investigation has been carried out on pulp, peel, seeds, stalks and leaves. Catechin and epicatechin were identified as the main constituents of the seed extract, quercetin and ferulic acid were detected in the leaves and malvidin and cyanidin glucopyranoside in the peels. The leaf, stalk and seed extracts were found to be very rich in phytochemicals and were tested for their ability to reduce the mutagenicity and genotoxicity of standard agents via Salmonella mutagenicity assay and SOS chromotest, respectively. Moreover, the estrogen/antiestrogen-like activity was evaluated on the MCF-7 estrogen-responsive cells. Seed and stalk extracts had an elevated antimutagenic/antigenotoxic activity. Stalk extracts highly reduced the proliferative effect of natural estrogen, 17beta-estradiol. PMID- 28351771 TI - RIFM fragrance ingredient safety assessment, isoamyl acetate, CAS Registry Number 123-92-2. PMID- 28351772 TI - 28-day repeated dose response study of diglycolic acid: Renal and hepatic effects. AB - The acute oral toxicity of diglycolic acid (DGA) was evaluated. Groups of female rats (n = 8 rats/group) received 28 consecutive daily single doses of 0.3, 1.0, 3.0, 10.0, 30.0, 100.0 or 300.0 mg DGA/kg body weight by gastric intubation. One group of animals served as vehicle control. Tissues and blood serum were collected at necropsy on day 29. Select organs were weighed and fixed in formalin for histopathological analysis. Animals from the 300 mg/kg bw dose group were removed from the study after 5 consecutive days of treatment as a consequence of adverse treatment related effects. The animals in the remaining treatment groups survived the exposure period. No adverse clinical signs were observed throughout the exposure period in the surviving animals. No significant differences from controls were observed for feed and fluid consumption or body weight gain in the surviving animals. Lesions were observed in the kidneys, liver, stomach, intestine, thymus, spleen and bone marrow in rats from the 300 mg/kg dose group and signs of renal tubular regeneration were observed only in the 100 mg/kg dose group. These results suggest that high levels of pure DGA would need to be consumed before renal and other forms of organ toxicity are observed. PMID- 28351773 TI - DNA damage and methylation induced by glyphosate in human peripheral blood mononuclear cells (in vitro study). AB - Glyphosate is a very important herbicide that is widely used in the agriculture, and thus the exposure of humans to this substance and its metabolites has been noted. The purpose of this study was to assess DNA damage (determination of single and double strand-breaks by the comet assay) as well as to evaluate DNA methylation (global DNA methylation and methylation of p16 (CDKN2A) and p53 (TP53) promoter regions) in human peripheral blood mononuclear cells (PBMCs) exposed to glyphosate. PBMCs were incubated with the compound studied at concentrations ranging from 0.1 to 10 mM for 24 h. The study has shown that glyphosate induced DNA lesions, which were effectively repaired. However, PBMCs were unable to repair completely DNA damage induced by glyphosate. We also observed a decrease in global DNA methylation level at 0.25 mM of glyphosate. Glyphosate at 0.25 mM and 0.5 mM increased p53 promoter methylation, while it did not induce statistically significant changes in methylation of p16 promoter. To sum up, we have shown for the first time that glyphosate (at high concentrations from 0.5 to 10 mM) may induce DNA damage in leucocytes such as PBMCs and cause DNA methylation in human cells. PMID- 28351774 TI - RIFM FRAGRANCE INGREDIENT SAFETY ASSESSMENT, Methyl jasmonate, CAS Registry Number 1211-29-6. PMID- 28351775 TI - NOX2, NOX4, and mitochondrial-derived reactive oxygen species contribute to angiopoietin-1 signaling and angiogenic responses in endothelial cells. AB - Angiopoietin-1 (Ang-1) is a ligand of Tie-2 receptors that promotes survival, migration, and differentiation of endothelial cells. Several studies have linked reactive oxygen species (ROS) to Ang-1 signaling and distinct angiogenic responses, but the molecular sources of these ROS have never been clearly identified. In this study, we have identified source-specific contributions of ROS to Ang-1/Tie 2 signaling and angiogenic responses in human umbilical vein endothelial cells (HUVECs), specifically the differential contributions of mitochondrial ROS (mtROS) and ROS from two isoforms of NADPH oxidase (NOX2, NOX4). We demonstrate that: 1) Ang-1 induces significant increases in mtROS production under normal conditions but does not when cells are pre-incubated with mitochondrial antioxidants; 2) Ang-1 induces rapid Tie-2-dependent increases in cytosolic ROS production but does not when NOX2 and NOX4 are knocked down; 3) Ang 1 induces simultaneous increases in phosphorylation of AKT, ERK1/2, p38, and SAPK/JNK proteins within a few minutes of exposure, but this response is strongly and selectively attenuated when NOX2 and NOX4 are knocked down or cells are pre treated with mitochondrial antioxidants; 4) Ang-1 exerts a strong effect on HUVEC survival in serum-deprived medium and enhances cell migration and capillary tube formation, but the survival response is inhibited by NOX2 knockdown and the migration and tube formation responses are entirely absent with NOX4 knockdown or pre-treatment with mitochondrial antioxidants. We conclude that Ang-1 triggers NOX2, NOX4, and the mitochondria to release ROS and that ROS derived from these sources play distinct roles in the regulation of the Ang-1/Tie 2 signaling pathway and pro-angiogenic responses. PMID- 28351776 TI - The hippocampus and dorsal raphe nucleus are key brain areas associated with the antidepressant effects of lithium augmentation of desipramine. AB - Approximately 50% of depressed individuals fail to achieve remission with first line antidepressant drugs and a third remain treatment-resistant. When first-line antidepressant treatment is unsuccessful, second-line strategies include dose optimisation, switching to another antidepressant, combination with another antidepressant, or augmentation with a non-antidepressant medication. Much of the evidence for the efficacy of augmentation strategies comes from studies using lithium to augment the effects of tricyclic antidepressants. The neural circuitry underlying the therapeutic effects of lithium augmentation is not yet fully understood. Recently, we reported that chronic treatment with a combination of lithium and the antidepressant desipramine, exerted antidepressant-like behavioural effects in a mouse strain (BALB/cOLaHsd) that did not exhibit an antidepressant-like behavioural response to either drug alone. In the present study, we used this model in combination with DeltaFosB/FosB immunohistochemistry to identify brain regions chronically affected by lithium augmentation of desipramine when compared to either treatment alone. The data suggest that the dorsal raphe nucleus and the CA3 regions of the dorsal hippocampus are key nodes in the neural circuitry underlying antidepressant action of lithium augmentation of desipramine. These data give new insight into the neurobiology underlying the mechanism of lithium augmentation in the context of treatment-resistant depression. PMID- 28351777 TI - Enhance the anti-renca carcinoma effect of a DNA vaccine targeting G250 gene by co-expression with cytotoxic T-lymphocyte associated antigen-4(CTLA-4). AB - Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a negative regulator of T cell activation, which competes with CD28 for B7.1/B7.2 binding with a greater affinity. Co-expression specific antigens and extracellular domain of CTLA4 represents a promising approach to increase the immunogenicity of DNA vaccines. In this study, we evaluated this interesting approach for its enhancement on G250/MN/CA IX (G250)-specific immune responses and its anti-tumor effects in renal carcinoma mice model. Consequently, we constructed a DNA vaccine containing the G250 and the CTLA-4 gene. Vaccination with the co-expression DNA not only induced much higher level of anti-CTLA4 and anti-G250 antibody, but also increased G250-specific T cell response in mice. To evaluate the anti-tumor efficacy of the plasmids, murine models with G250-expressing tumors were generated. After injection into the tumor-bearing mouse model, the plasmid carrying the co-expression gene of CTLA4 and G250 showed stronger inhibition of tumor growth than the plasmid expressing CTLA4 or G250 alone. These observations emphasize the potential of the CTLA4 and G250 co-expression DNA vaccine, which could represent a promising approach for tumor immunotherapy. PMID- 28351778 TI - The effect of theophylline on acetic acid induced ulcerative colitis in rats. AB - BACKGROUND: Ulcerative colitis is a relapsing inflammatory disorder of the colon. There is a need to explore the new treatments for this disorder. Theophylline, a competitive inhibitor of phosphodiesterase, is shown to have anti-inflammatory properties. However, the effect of theophylline on ulcerative colitis has not yet been investigated. The present study evaluated the effect of theophylline on acetic acid induced ulcerative colitis in rats. MATERIALS AND METHODS: Colitis was induced by instillation of 2ml of acetic acid solution (3%). Colon samples were evaluated grossly and microscopically and assayed for myeloperoxidase (MPO) activity and proinflammatory cytokine concentrations. RESULTS: Treatment with theophylline at the doses of 20 and 50mg/kg attenuated acetic acid induced ulcerative colitis as shown by improvement in body weight loss, macroscopic score, ulcer area, hematocrit and histopathological score. Theophylline treatment also reduced MPO activity and tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1 beta) and interleukin 6 (IL-6) concentrations in inflamed colon. CONCLUSION: Theophylline has a protective effect in acetic acid-induced ulcerative colitis which might be due to its anti-inflammatory activities. Therefore, theophylline has the potential to be used for successful treatment of ulcerative colitis. PMID- 28351779 TI - Prognostic factors for overall survival after lung metastasectomy in renal cell cancer patients: A systematic review and meta-analysis. AB - BACKGROUND: Pulmonary metastasis of Renal cell carcinomas (RCC) is usually considered as a systemic disease. However, some studies revealed potential survival benefits of pulmonary metastasectomies for such patients. The aim of this study was to conduct a systematic review and meta-analysis to assess the prognostic factors for pulmonary metastasectomy of RCC patients. METHODS: An electronic search in MEDLINE, EMBASE, CENTRAL and Chinese BioMedical Literature Database (CBM) were conducted to identify eligible studies. We combined the hazard ratios (HRs) of the identified prognostic factors for overall survival of RCC patients after pulmonary metastasectomy from the eligible studies. RESULTS: Sixteen studies with a total of 1447 patients were included in this meta analysis. The pooled 1, 3, 5, 10-year overall survival rates for RCC patient after pulmonary metastasectomy were 84%, 59%, 43% and 20%, respectively. The poor prognostic factors were lymph node involvement (LNI) of primary RCC (HR 3.44, 95% confidence interval (CI) 1.78-6.67, P = 0.001), incomplete resection of metastases (HR 3.74, 95% CI 2.49-5.61, P = 0.000), multiple metastases (HR 1.55, 95% CI 1.18-2.03, P = 0.002), larger metastases (HR 1.45, 95% CI 1.26-1.66, P = 0.000), LNI of metastases (HR 3.06, 95% CI 1.52-6.19, P = 0.002), synchronous metastasis (HR 2.49, 95% CI 1.46-4.24, P = 0.001) and short disease free interval (DFI). CONCLUSIONS: Surgery may be a promising treatment for pulmonary metastases of RCC patients. A short DFI, LNI of primary RCC, incomplete resection of metastases, multiple metastases, larger metastases, LNI of metastases and synchronous metastasis are predictors of poor survival after pulmonary metastasectomy for RCC patients. PMID- 28351780 TI - Cordycepin negatively modulates lipopolysaccharide-induced cytokine production by up-regulation of heme oxygenase-1. AB - AIMS: The present study is to investigate the effect of cordycepin on the expression of heme oxygenase-1 (HO-1) in lipopolysaccharide (LPS)-activated microphages, as well as its mechanism of action. METHODS: Mouse RAW264.7 cells were treated with different concentrations of cordycepin for 0-16h. Western blotting was used to determine the expression of HO-1 and the phosphorylation of c-Src and the p47phox subunit of NADPH oxidase. Intracellular reactive oxygen species (ROS) level was determined using H2DCFDA as fluorescent probe. Laser scanning confocal microscopy was used to visualize the nuclear translocation of NF-E2-related factor 2 (Nrf2). Enzyme-linked immunosorbent assay was performed to measure the inhibitory effect of cordycepin on LPS-induced secretion of tumor necrosis factor-alpha and interleukin-6. RESULTS: Cordycepin induced the phosphorylation of c-Src and p47phox subunit of NADPH oxidase in RAW264.7 cells. Cordycepin increased the secretion of ROS by activating NADPH oxidase. In addition, cordycepin enhanced the expression of HO-1 in RAW264.7 cells in both dose- and time-dependent manners. Of note, elevated HO-1 expression induced by cordycepin treatment was regulated by c-Src/NADPH oxidase/ROS pathway. HO-1 expression induced by cordycepin was dependent on the activation of Nrf2, which was regulated by c-Src/NADPH oxidase/ROS. Cordycepin reduced LPS-induced secretion of proinflammatory cytokines through up-regulation of HO-1. CONCLUSION: The present study demonstrates that cordycepin induces the expression of HO-1 in RAW264.7 cells via c-Src/NADPH oxidase/ROS/Nrf2 pathway, and plays an anti inflammatory role by inhibiting the secretion of cytokines from macrophages. PMID- 28351781 TI - GEIS guidelines for gastrointestinal sarcomas (GIST). AB - Gastrointestinal stromal sarcomas (GISTs) are the most common mesenchymal tumours originating in the digestive tract. They have a characteristic morphology, are generally positive for CD117 (c-kit) and are primarily caused by activating mutations in the KIT or PDGFRA genes(1). On rare occasions, they occur in extravisceral locations such as the omentum, mesentery, pelvis and retroperitoneum. GISTs have become a model of multidisciplinary work in oncology: the participation of several specialties (oncologists, pathologists, surgeons, molecular biologists, radiologists...) has forested advances in the understanding of this tumour and the consolidation of a targeted therapy, imatinib, as the first effective molecular treatment in solid tumours. Following its introduction, median survival of patients with advanced or metastatic GIST increased from 18 to more than 60months. Sunitinib and Regorafenib are two targeted agents with worldwide approval for second- and third-line treatment, respectively, in metastatic GIST. PMID- 28351782 TI - A Randomized Pragmatic Trial of Changing to and Stepping Down Fluticasone/Formoterol in Asthma. AB - BACKGROUND: Guidelines recommend reducing treatment in patients with well controlled asthma after 3 months of stability. However, there is inadequate real life data to guide physicians on therapy change in daily practice. OBJECTIVE: To assess asthma control after change to and step-down of fluticasone propionate/formoterol fumarate dihydrate (FP/FOR) in real-life patients. METHODS: In a randomized controlled, pragmatic, open-label trial, 225 well-controlled patients with asthma were randomized (1:2) to maintain high-dose fluticasone propionate/salmeterol xinafoate (FP/SAL, 1000/100 MUg) or switch to FP/FOR (1000/40 MUg) daily for 12 weeks (phase 1). One hundred sixteen patients stable on FP/FOR at week 12 were subsequently randomized (1:1) to maintain this therapy, or stepped down to FP/FOR (500/20 MUg) daily for 12 weeks (phase 2). The primary end point was the 7-question Asthma Control Questionnaire (ACQ7) score. RESULTS: In phase 1, FP/FOR (1000/40 MUg) (n = 126) was noninferior to FP/SAL (1000/100 MUg) (n = 73) for ACQ7 (difference in means, -0.12; 95% CI, -0.32 to 0.09). In phase 2, FP/FOR (500/20 MUg) (n = 52) was noninferior to FP/FOR (1000/40 MUg) (n = 52) for ACQ7 (difference in means, 0.01; 95% CI, -0.20 to 0.22). There was no significant difference in exacerbation rate between the groups in either phase. However, 1 to 2 exacerbations in 12 months before phase 1 were associated with the occurrence of an exacerbation after step-down (P = .007). CONCLUSIONS: In patients with well-controlled asthma, a change from FP/SAL to FP/FOR did not compromise asthma control. Step-down of FP/FOR was well tolerated; however, in contrast to current guidelines, our data suggest caution in stepping down patients uncontrolled in the last 12 months. Larger step-down studies are required to confirm these findings. PMID- 28351783 TI - "Real-life" Effectiveness Studies of Omalizumab in Adult Patients with Severe Allergic Asthma: Meta-analysis. AB - BACKGROUND: After the approval of omalizumab for severe allergic asthma, a total of 25 studies have evaluated the effectiveness of omalizumab under "real-life" conditions of heterogeneity in patients, clinicians, sites, and treatment patterns. OBJECTIVE: We conducted a meta-analysis to evaluate the effectiveness of omalizumab focusing on treatment response, lung function, quality of life, symptom control, corticosteroid use, and exacerbations and hospitalizations at 4 6, 12, and 24 months. METHODS: We searched PubMed and Embase for real-life studies on omalizumab in severe asthma published up to 2015. Three effect size types were extracted: single-point proportions; mean +/- SD of change relative to baseline as raw numbers and standardized as Cohen's d; and changes in proportions of patients as relative risk. Random-effects meta-analyses were performed to account for within- and between-study heterogeneity. Studies were weighted by the DerSimonian and Laird method. RESULTS: Per data available at the 3 time points, omalizumab therapy was consistently associated with large proportions of patients classified as "good" to "excellent" treatment responders (Global Evaluation of Treatment Effectiveness scale); improvements in forced expiratory volume in 1 second, quality of life (Asthma-related Quality-of-Life Questionnaire scale), and asthma symptom control (Asthma Control Test scale); reductions in oral and inhaled corticosteroid (ICS) use; and reductions in exacerbations and hospitalizations. CONCLUSIONS: This meta-analysis of noncontrolled studies documents the real-life pharmacotherapeutic effectiveness of omalizumab, as add on treatment to ICS +/- long-acting beta2-agonists agents, in improving outcomes in patients with severe allergic asthma under conditions of heterogeneity in patients, clinicians, sites, and treatment patterns. The results mirror, complement, and extend the efficacy data from randomized controlled trials. PMID- 28351784 TI - Risk Factor Analysis of Anaphylactic Reactions in Patients With Systemic Mastocytosis. AB - BACKGROUND: Systemic mastocytosis (SM) is a rare disorder of abnormal mast cells in at least 1 extracutaneous organ/tissue. Anaphylaxis is an acute, severe systemic hypersensitivity reaction, and a strong association between SM and anaphylaxis has been shown. However, not all patients with SM experience anaphylaxis. Presently, there are no predictive markers to discriminate patients with SM at high risk of anaphylaxis from those at low risk. OBJECTIVE: This study sought to determine risk factors for the occurrence of anaphylaxis in patients with SM. METHODS: A cross-sectional study was conducted in 122 consecutive adult patients with SM admitted to the Mastocytosis Center at Karolinska University Hospital. All patients underwent medical evaluation, including bone marrow biopsy and a thorough allergy workup. To determine risk factors, study subjects were categorized into 2 groups according to the presence (n = 55) or absence (n = 67) of anaphylaxis and compared for their demographic, clinical, and biochemical characteristics. RESULTS: Patients with SM with anaphylaxis had less frequent presence of mastocytosis in the skin (P < .001), more atopic predisposition (P = .021), higher total IgE levels (P < .001), and lower baseline tryptase levels (27 ng/mL vs 42 ng/mL; P = .024) compared with patients with SM without anaphylaxis. CONCLUSIONS: Patients with SM with anaphylaxis display unique clinical and laboratory features. Hence, a risk analysis tool that is capable of discriminating patients with SM at high risk of anaphylaxis from those at low risk with 86% sensitivity was developed by using the variables male sex, absence of mastocytosis in the skin, presence of atopy, IgE levels of 15 kU/L or more, and baseline tryptase levels of less than 40 ng/mL. PMID- 28351785 TI - British Lung Foundation/United Kingdom Primary Immunodeficiency Network Consensus Statement on the Definition, Diagnosis, and Management of Granulomatous Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency Disorders. AB - A proportion of people living with common variable immunodeficiency disorders develop granulomatous-lymphocytic interstitial lung disease (GLILD). We aimed to develop a consensus statement on the definition, diagnosis, and management of GLILD. All UK specialist centers were contacted and relevant physicians were invited to take part in a 3-round online Delphi process. Responses were graded as Strongly Agree, Tend to Agree, Neither Agree nor Disagree, Tend to Disagree, and Strongly Disagree, scored +1, +0.5, 0, -0.5, and -1, respectively. Agreement was defined as greater than or equal to 80% consensus. Scores are reported as mean +/ SD. There was 100% agreement (score, 0.92 +/- 0.19) for the following definition: "GLILD is a distinct clinico-radio-pathological ILD occurring in patients with [common variable immunodeficiency disorders], associated with a lymphocytic infiltrate and/or granuloma in the lung, and in whom other conditions have been considered and where possible excluded." There was consensus that the workup of suspected GLILD requires chest computed tomography (CT) (0.98 +/- 0.01), lung function tests (eg, gas transfer, 0.94 +/- 0.17), bronchoscopy to exclude infection (0.63 +/- 0.50), and lung biopsy (0.58 +/- 0.40). There was no consensus on whether expectant management following optimization of immunoglobulin therapy was acceptable: 67% agreed, 25% disagreed, score 0.38 +/- 0.59; 90% agreed that when treatment was required, first-line treatment should be with corticosteroids alone (score, 0.55 +/- 0.51). PMID- 28351787 TI - Complementary and Alternative Medicine Use Among Allergy Practices: Results of a Nationwide Survey of Allergists. AB - The use of complementary and alternative practices in the field of Allergy/Immunology is growing. A recent survey of American Academy of Allergy, Asthma, and Immunology members examining patterns of complementary and alternative medicine (CAM) use and adverse effects from CAM revealed that a majority of practitioners (81% of respondents) had patients who are using CAM therapies over conventional treatments and many practitioners (60% of survey respondents) have encountered patients experiencing adverse reactions. During routine office visits, a majority of practitioners do not ask patients about CAM use, and when they do, most do not have a standard intake form to take a CAM history. There is a strong need to increase knowledge and improve measures to prevent adverse reactions to CAMs. PMID- 28351786 TI - Association of Clinical Reactivity with Sensitization to Allergen Components in Multifood-Allergic Children. AB - BACKGROUND: Thirty percent of children with food allergies have multiple simultaneous allergies; however, the features of these multiple allergies are not well characterized serologically or clinically. OBJECTIVE: We comprehensively evaluated 60 multifood-allergic patients by measuring serum IgE to key allergen components, evaluating clinical histories and medication use, performing skin tests, and conducting double-blind, placebo-controlled food challenges (DBPCFCs). METHODS: Sixty participants with multiple food allergies were characterized by clinical history, DBPCFCs, total IgE, specific IgE, and component-resolved diagnostics (IgE and IgG4) data. The food allergens tested were almond, egg, milk, sesame, peanut, pecan, walnut, hazelnut, cashew, pistachio, soy, and wheat. RESULTS: Our data demonstrate that of the reactions observed during a graded DBPCFC, gastrointestinal reactions occurred more often in boys than in girls, as well as in individuals with high levels of IgE to 2S albumins from cashew, walnut, and hazelnut. Certain food allergies often occurred concomitantly in individuals (ie, cashew/pistachio and walnut/pecan/hazelnut). IgE testing to components further corroborated serological relationships between and among these clustered food allergies. CONCLUSIONS: Associations of certain food allergies were shown by DBPCFC outcomes as well as by correlations in IgE reactivity to structurally related food allergen components. Each of these criteria independently demonstrated a significant association between allergies to cashew and pistachio, as well as among allergies to walnut, pecan, and hazelnut. PMID- 28351788 TI - Severe Cutaneous Adverse Drug Reactions in Pediatric Patients: A Multicenter Study. AB - BACKGROUND: The severe cutaneous adverse drug reactions (SCARs) are rare but could be life-threatening. These include drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis. OBJECTIVE: The purpose of this study was the evaluation of the clinical characteristics of patients with the diagnosis of SCARs. METHODS: Patients who were diagnosed with SCARs between January 2011 and May 2016 by pediatric allergy clinics in the provinces of Ankara, Trabzon, Izmir, Adana, and Bolu were included in this multicenter study. Clinical and laboratory findings, the time between suspected drug intake and development of clinical findings, treatments they have received, and length of recovery time were recorded. RESULTS: Fifty-eight patients with SCARs were included in this study. The median age of the patients was 8.2 years (interquartile range, 5.25-13 years) and 50% (n = 29) were males. Diagnosis was Stevens-Johnson syndrome/TEN in 60.4% (n = 35), DRESS in 27.6% (n = 16), and acute generalized exanthematous pustulosis in 12% (n = 7) of the patients. In 93.1% of the patients, drugs were the cause of the reactions. Antibiotics ranked first among the drugs (51.7%) and antiepileptic drugs were the second (31%) most common. A patient who was diagnosed with TEN developed lagophthalmos and a patient who was diagnosed with DRESS developed secondary diabetes mellitus. Only 1 patient with the diagnosis of TEN died. CONCLUSIONS: SCARs in children are not common but potentially serious. Early diagnosis and appropriate treatment of SCARs will reduce the incidence of morbidity and mortality. PMID- 28351790 TI - Wells Syndrome with Bullous Lesions. PMID- 28351789 TI - Comparative Effectiveness of Step-up Therapies in Children with Asthma Prescribed Inhaled Corticosteroids: A Historical Cohort Study. AB - BACKGROUND: In children with uncontrolled asthma prescribed low-dose inhaled corticosteroids (ICSs), various step-up options are available: fixed-dose combination ICS/long-acting beta2-agonist (FDC), increasing ICS dose, or adding leukotriene receptor antagonist (LTRA). However, evidence of their relative effectiveness is limited. OBJECTIVE: To compare the effectiveness of step-up treatment to FDC in children with asthma versus increased ICS dose, or LTRA. METHODS: This matched cohort study used UK primary-care databases to study children prescribed their first step-up treatment to FDC, increased ICS dose, or LTRA. A year of baseline data was used for matching and identifying confounders. Outcomes over the following year were examined. The primary outcome was severe exacerbation rate; secondary outcomes included overall asthma control, derived from databases (no asthma-related admissions/hospital attendances/oral corticosteroids or antibiotics prescribed with a respiratory review, and average prescribed salbutamol <=200 MUg/day). RESULTS: There were 971 matched pairs in the FDC and increased ICS dose cohorts (59% males; mean age, 9.4 years) and 785 in the FDC and LTRA cohorts (60% males; mean age, 9.0 years). Exacerbation rates in the outcome year were similar between FDC and increased ICS (adjusted incidence rate ratio [95% CI], 1.09 [0.75-1.59]) and FDC and LTRA (incidence rate ratio, 1.36 [0.93-2.01]). Increased ICS and LTRA significantly reduced the odds of achieving overall asthma control, compared with FDC (odds ratios [95% CI], 0.52 [0.42-0.64] and 0.53 [0.42-0.66], respectively)-this was driven by reduced short-acting beta-agonist use. CONCLUSIONS: FDC is as effective as increased ICS or LTRA in reducing severe exacerbation rate, but more effective in achieving asthma control. PMID- 28351791 TI - A Rare Cause of Duodenal Obstruction: Metastatic Parotid Mucoepidermoid Carcinoma. PMID- 28351792 TI - Pyogenic Granuloma of the Esophagus. PMID- 28351793 TI - Nivolumab-Associated Colitis Mimicking Ulcerative Colitis. PMID- 28351794 TI - Association Between Mechanical, Inflammatory, and Functional Complications of the Ileal Pouch: Another Chicken-Or-Egg Story. PMID- 28351795 TI - Phytobezoar-Induced Small-Bowel Obstruction Successfully Diagnosed and Treated by Single-Balloon Enteroscopy. PMID- 28351796 TI - Endoscopic Appearance of Multifocal Primary Gastric Diffuse Large B-Cell Lymphoma. PMID- 28351797 TI - Comparison study on photocatalytic oxidation of pharmaceuticals by TiO2-Fe and TiO2-reduced graphene oxide nanocomposites immobilized on optical fibers. AB - Incorporating reduced graphene oxide (rGO) or Fe3+ ions in TiO2 photocatalyst could enhance photocatalytic degradation of organic contaminants in aqueous solutions. This study characterized the photocatalytic activities of TiO2-Fe and TiO2-rGO nanocomposites immobilized on optical fibers synthesized by polymer assisted hydrothermal deposition method. The photocatalysts presented a mixture phase of anatase and rutile in the TiO2-rGO and TiO2-Fe nanocomposites. Doping Fe into TiO2 particles (2.40eV) could reduce more band gap energy than incorporating rGO (2.85eV), thereby enhancing utilization efficiency of visible light. Incorporating Fe and rGO in TiO2 decreased significantly the intensity of TiO2 photoluminescence signals and enhanced the separation rate of photo-induced charge carriers. Photocatalytic performance of the synthesized nanocomposites was measured by the degradation of three pharmaceuticals under UV and visible light irradiation, including carbamazepine, ibuprofen, and sulfamethoxazole. TiO2-rGO exhibited higher photocatalytic activity for the degradation of pharmaceuticals under UV irradiation, while TiO2-Fe demonstrated more suitable for visible light oxidation. The results suggested that the enhanced photocatalytic performance of TiO2-rGO could be attributed to reduced recombination rate of photoexcited electrons-hole pairs, but for TiO2-Fe nanocomposite, narrower band gap would contribute to increased photocatalytic activity. PMID- 28351798 TI - Fabrication of heterostructured Bi2O2CO3/Bi2O4 photocatalyst and efficient photodegradation of organic contaminants under visible-light. AB - Heterostructured Bi2O2CO3/Bi2O4 photocatalysts were fabricated by a facile one pot hydrothermal method, in which melem served as the sacrificial reagent to supply carbonate anions. The as-synthesized Bi2O2CO3/Bi2O4 heterojunction catalysts were characterized by X-ray diffraction, UV-vis diffuse reflectance spectra, X-ray photoelectron spectroscopy, scanning electron microscope, and transmission electron microscope. The XRD patterns of Bi2O2CO3/Bi2O4 catalysts showed the distinctive peaks of Bi2O2CO3 and Bi2O4. The SEM and TEM results showed that the pure Bi2O2CO3 possessed large plate morphology, while Bi2O4 were composed of various nanorods and particles. As for Bi2O2CO3/Bi2O4 heterojunction, it was obviously observed that Bi2O4 nanorods and particles were grown on the surfaces of Bi2O2CO3 plates. The visible light driven photocatalytic activity of Bi2O2CO3/Bi2O4 heterojunction photocatalyst was evaluated by decomposing dyes, phenol, and bisphenol A in water. Compared with Bi2O2CO3 and Bi2O4, the Bi2O2CO3/Bi2O4 photocatalysts have exhibited remarkable enhanced activity under visible light. The excellent activity can be mainly attributed to the enhanced separation efficiency of photo-generated carriers. Controlled experiments using different radical scavengers proved that O2- and h+ played the main role in decomposing organic pollutants. The results of this work would provide a new sight for the construction of visible light-responsive photocatalysts with high performance. PMID- 28351799 TI - Immobilization of chymotrypsin on hierarchical nylon 6,6 nanofiber improves enzyme performance. AB - Immobilized enzymes enable advances in bioprocessing efficiency and bioactive packaging. Enzyme immobilization onto macroscale solid supports is often limited by low protein loading, inadequate access to substrate, and non-ideal orientation to the solid support; immobilization on nanomaterials has improved activity retention, protein loading, and enabled improved performance in extreme environments, yet has practical limitations including handling, recovery. This work describes the immobilization of chymotrypsin to nylon 6,6 in two formats: electrospun nanofibers and planar films. Protein loading, enzyme activity, and kinetics were compared to that of commercially available systems (free chymotrypsin and chymotrypsin immobilized on agarose beads). Electrospun nylon 6,6 nanofibers had an average fiber diameter of 161+/-73nm, improving protein loading compared to its planar macroscale counterpart. Chymotrypsin immobilized onto nylon nanofibers exhibited shifts in both working optimum pH and temperature with an increase from pH 7.8 to pH 9, and increased optimum temperature by 10 degrees C compared to free enzyme. The nanofibers also enhanced thermostability compared to native enzyme, enzyme on planar films, and the commercial standard agarose beads with 35% activity retained after 12h at 50 degrees C. This work demonstrates the potential of hierarchical nanomaterials in improving enzyme performance, leveraging benefits of both nano and macroscale supports. PMID- 28351800 TI - Micellization in vegetable oils: A structural characterisation. AB - The solubilisation of polar and polyphenol antioxidant in vegetable oils was studied. It was shown that the use of a polyglyceryl-3-diisostearate (PG3DS), a bio-sourced emulsifier well known in cosmetics, increases the yield of solubilisation thanks to some aggregation properties analysed using x-ray scattering technique. We show indeed that PG3DS forms reverse aggregates with a critical concentration that depends on the oil polarity. PG3DS reverse aggregates are elongated with a polar core and cannot be really swollen by addition of water. This supramolecular organisation allows however an efficient solubilisation of polar antioxidants in vegetable oils. PMID- 28351801 TI - pH-responsive poly (acrylic acid)-gated mesoporous silica and its application in oral colon targeted drug delivery for doxorubicin. AB - Oral chemotherapy is the preferred route for cancer treatment because it can improve the efficacy and decrease the side effects. Unfortunately, most anticancer drugs suffered from their poor oral bioavailability. Herein, we construct a novel pH-triggered oral drug delivery system by capping of mesoporous silica SBA-15 with pH-responsive polymer poly (acrylic acid) (PAA) via a facile graft-onto strategy. The experiment results demonstrated that the PAA brushes were anchored on the pore outlets of mesoporous silica SBA-15, which can be acted as the gatekeeper to control the drug molecules transport in and out of the pore channels. The PAA capped mesoporous SBA-15 (PAA/SBA-15) exhibited a high drug loading capacity (785.7mg/g), excellent pH-sensitivity and good biocompatibility. In gastric environment (pH=2.0), the drug doxorubicin (DOX) molecules were encapsulated in the pore channels because the pore outlets were capped with collapsed PAA. In contrast, in colonic environment (pH=7.6), it exhibited a fast release because of the removal of capping. In addition, the water solubility of DOX in colonic environment was enhanced after DOX being loaded into the pores of PAA/SBA-15. This pH-triggered oral drug delivery system has promising applications for treatment of colon cancer and other colon diseases. PMID- 28351802 TI - Identification of ace inhibitory cryptides in Tilapia protein hydrolysate by UPLC MS/MS coupled to database analysis. AB - An ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry method was developed and applied to identify short angiotensin-I converting enzyme (ACE) inhibitory cryptides in Tilapia (Oreochromis Niloticus) protein hydrolyzate. A database was created with previously identified ACE inhibitory di- and tripeptides and the lowest molecular weight fraction of Tilapia hydrolysate was analysed for coincidences. Only VW and VY were identified. Further analysis of collected fractions conducted to the identification of 51 different peptides in major fractions. 19 peptides selected were synthesised and tested for their ACE inhibitory potential. TL, TI, IK, LR, LD, IQ, DI, AILE, ALLE, ALIE and AIIE were identified as new ACE inhibitors. The findings from this study point UPLC-MS/MS combined with the creation of a database as an efficient technique to identify specific short peptides within a complex hydrolysate, in addition with de novo sequencing. This efficient characterisation of bioactive factors like cryptides in protein hydrolysates will extend their use as functional foods. PMID- 28351803 TI - Establishing a reliable gait evaluation method for rodent studies. AB - BACKGROUND: CatWalk is one of the most popular tools for evaluating gait recovery in preclinical research, however, there is currently no consensus on which of the many gait parameters captured by CatWalk can reliably model recovery. There are conflicting interpretations of results, along with many common but seldom reported problems such as heel walking and poor compliance. NEW METHOD: We developed a systematic manual classification method that overcomes common problems such as heel walking and poor compliance. By correcting automation errors and removing inconsistent gait cycles, we isolated stretches of recordings that are more reliable for analysis. Recovery outcome was also assessed by quantitative histomorphometric analysis of myelinated axons. RESULTS: While 40 60% of runs were erroneously classified without manual intervention, we corrected all errors with our new method, and showed that Stand Time, Duty Cycle, and Swing Speed are able to track significant differences over time and between experimental groups (all p<0.05). The usability of print area and intensity parameters requires further validation beyond the capabilities of CatWalk. COMPARISON WITH EXISTING METHOD(S): There is currently no strategy that addresses problems such as heel walking and poor compliance, and therefore no standard set of parameters that researchers can rely on to report their findings. CONCLUSION: Manual classification is a crucial step to generate reliable CatWalk data, and Stand Time, Duty Cycle, and Swing Speed are suitable parameters for evaluating gait recovery. Static parameters such as print area and intensity should be used with extreme caution. PMID- 28351804 TI - A Prognostic Scoring Model for the Utility of Induction Chemotherapy Prior to Neoadjuvant Chemoradiotherapy in Esophageal Cancer. AB - OBJECTIVES: The aim of this study was to identify patients with esophageal cancer who may benefit from induction chemotherapy (IC) before neoadjuvant chemoradiotherapy (nCRT) on the basis of a prognostic scoring model. METHODS: Between 1998 and 2015, 535 patients with esophageal cancer who underwent nCRT were included for analysis, including 218 patients who received IC before nCRT (IC group) and 317 patients who did not receive IC (non-IC group). A prognostic scoring model was developed to predict disease-free survival (DFS) on the basis of a Cox proportional hazards model. RESULTS: The median follow-up time was 63.5 months (range 8.0-178.5) for survivors. The 5-year DFS rates were similar between the IC and non-IC groups (53.7% vs. 45.1%, p = 0.196). Multivariate analysis determined that histologic grade, tumor location, baseline positron emission tomography maximum standard uptake value, and lymph node size were independent prognostic factors for DFS. A prognostic scoring system was constructed by using these four factors, with the total score ranging from 0 to 6.2. When the median value was used as a cutoff, low-risk (<=3.5) and high-risk (>3.5) groups were identified. In the high-risk group, patients who received IC had a nonsignificantly higher pathologic complete response rate (p = 0.272) and a significantly better DFS (p = 0.03) than patients who did not receive IC. After propensity score matching, the high-risk group demonstrated a significantly improved DFS with IC, a benefit that was not observed in the low-risk group. CONCLUSIONS: On the basis of the prognostic scoring model, the addition of IC to nCRT may provide a DFS benefit in high-risk patients with a risk score higher than 3.5. Prospective validation is warranted. PMID- 28351805 TI - Fragrances in the seawater of Terra Nova Bay, Antarctica. AB - Personal Care Products are emerging pollutants whose distribution in the Antarctic and remote environments is still largely unknown. Among PCPs, long lasting and stable Fragrance Materials were selected to perform a first pilot study on their occurrence in the coastal surface seawater of Terra Nova Bay in the Ross Sea, Antarctica. Ambrofix, Amyl Salicylate, Benzyl Salicylate, Hexyl Salicylate, Lemonile and Okoumal were detected for the first time in Antarctic natural seawater, and reached total concentrations up to 100ngL-1. Treated discharges from the Italian research station Mario Zucchelli (MZS) contain FMs, however concentrations in nearby Tethys Bay increase during the seasonal melt of the sea ice and its snow cover: variability in emissions and distribution, as well as a contribution from atmospheric (long or short-range) transport were hypothesized. PMID- 28351806 TI - Bioaerosol exposure and circulating biomarkers in a panel of elderly subjects and healthy young adults. AB - Numerous studies have found that risk of cardiovascular diseases is associated with increased blood levels of circulating markers of systemic inflammation. We investigated associations of acute exposure to bioaerosols (bacteria and fungi) with blood markers of inflammation and coagulation using panels of elderly subjects and healthy young adults. We conducted a panel study of 44 nonsmoker elderly subjects in a retirement communities and a panel study of 40 healthy young adults living in a school dormitory within Tehran city, Iran. Blood sample biomarkers were measured weekly over 6weeks and including high sensitive C reactive protein (hsCRP), tumor necrosis factor-soluble receptor-II (sTNF-RII), von Willebrand factor (vWF), white blood cells (WBC) count and interleukin-6 (IL 6). We found significant positive associations for IL-6 and WBC with exposure to Aspergillus spp. (As), Cladosporium spp. (Cl), Penicillium spp. (Pe), total fungi (TF) and Micrococcus spp. (MI); vWF with Cl and MI; sTNF-RII with Staphylococcus spp. (ST) in healthy young adults from the current-day and multiday averages. For elderly subjects, we observed significant positive associations for hsCRP, sTNF RII and WBC with exposure to MI, but not with ST and total bacteria (TB). Our results showed the strongest significant positive associations for IL-6 with MI, ST and TB in elderly people. In addition, IL-6 was also positively associated with As, Cl and Pe in elderly. Also, the results showed that increase of vWF was significantly associated with bacterial and fungal aerosols, except Bacillus spp. (BA) at some lags in elderly subjects. Pooled results support the pivotal role of bioaerosols in increasing the level of some of inflammatory biomarkers, especially IL-6 and WBC in healthy young adults but possibly also in elderly people. PMID- 28351807 TI - Profiles, sources and potential exposures of parent, chlorinated and brominated polycyclic aromatic hydrocarbons in haze associated atmosphere. AB - Profiles, sources and potential exposures of chlorinated and brominated polycyclic aromatic hydrocarbons (ClPAHs and BrPAHs) in haze associated atmosphere remain unclear. Haze events happened frequently during heating period in Beijing provided a typical urban context to investigate the concentrations, profiles, sources and potential exposures of ClPAHs, BrPAHs and their non halogenated parent compounds (PAHs) in air samples. Average concentrations of PAHs, ClPAHs and BrPAHs during heating periods (with more frequent haze events) were about 3-9 times higher than during non-heating periods. Concentrations of particulate matter (PM)-associated ClPAHs and BrPAHs were higher in heating period than in non-heating period, while for gas-associated ClPAHs and BrPAHs, this distinction was not significant. Congener patterns and congener profiles indicated that with increasing coal combustion during the heating period, concentrations of PAHs and ClPAHs in air were elevated in comparison to the non heating period. Inhalation of PM-associated PAHs, ClPAHs and BrPAHs accounted for higher exposure than inhalation of gas phase and dermal contact of both gas phase and particulate phase. In this study we found that the particulate phase is the dominant exposure pathway of atmospheric PAHs, ClPAHs and BrPAHs during haze days, which is different from previous studies. PMID- 28351808 TI - Troubled water under the bridge: Screening of River Mur water reveals dominance of CTX-M harboring Escherichia coli and for the first time an environmental VIM-1 producer in Austria. AB - Antibiotic resistant bacteria (ARB) in the aquatic environment are reported from all over the world and their presence in the environment has become quite common. The current most prominent example is the presence of beta-lactamases harboring Enterobacteriaceae. The aim of this study was to investigate the presence and diversity (on the genetic and phenotypic levels) of extended spectrum beta lactamases (ESBL) and carbapenemases harboring Enterobacteriaceae from the River Mur in the center of Graz, Austria's second largest city. Thus over a period of four months water samples were taken, filtrated and screened for these bacteria. All samples revealed ESBL harboring Enterobacteriaceae, of which all with only one exception were Escherichia coli. Dominant ESBL gene family was CTX-M, represented by subgroups CTX-M-1 group, CTX-M-2 group and CTX-M-9 group. Surprisingly co-resistances to non-beta-lactam antibiotics were low, only resistance to trimethoprim was detected in 50% of all (70) isolates. One Klebsiella oxytoca with GES-1 was isolated. To date, GES ESBL has never been reported from Austria before and only rarely from other European countries. Screening for carbapenemase harboring Enterobacteriaceae revealed one Enterobacter cloacae with the gene for VIM-1. Members sharing the same multi locus-sequence-type (MLST) as well as members of the same rep PCR clusters occurred at different sampling time points. ESBL-harboring Enterobacteriaceae are common in Austrian river water, is dominated by Escherichia coli and CTX-M enzymes. Furthermore, some of the isolates could be linked to different origins. PMID- 28351809 TI - A study of torrefied cardboard characterization and applications: Composition, oxidation kinetics and methane adsorption. AB - Torrefaction is proposed as a valorization process for non recycled cardboard. Torrefied cardboard was physically and chemically characterized and it was proposed for energy production and methane adsorption. The surface area and pore volume obtained were among 3.0-6.0m2/g and 5.7.10-3-2.3.10-2cm3/g, respectively. The carbon content increased with temperature and residence time of torrefaction. Oxidation kinetics of torrefied cardboard at different temperatures (250-300 degrees C) and at different plateaus (60-120min) were tested. Torrefied cardboard was chemically treated with KOH in order to study the effect of K on thermal oxidation kinetics. It was observed that high torrefaction temperatures and residence times lead to a more stable char. Furthermore, kinetic parameters were obtained by iso-conversional methods and Coats and Redfern method. Attending to iso-conversional method, a decrease of Ea was observed with both, temperature and residence time of torrefaction. Whereas chemically treated presented highest Ea values than torrefied cardboard. In addition, regarding Coats and Redfern method, the oxidation model was not highly modified by torrefaction temperature and residence time. However, for chemically treated samples the oxidation model was modified by K presence. Finally, CH4 adsorption capacity of torrefied cardboard was studied at 30 degrees C and atmospheric pressure. CH4 partial pressures tested were lower than 0.45kPa. It was observed that CH4 adsorption capacity increased with torrefaction time and decreased with chemical treatment. Thus, for the tested samples, the highest adsorption capacity observed was 5.70mgCH4/g of sample. PMID- 28351810 TI - An interval-possibilistic basic-flexible programming method for air quality management of municipal energy system through introducing electric vehicles. AB - Contradictions of sustainable transportation development and environmental issues have been aggravated significantly and been one of the major concerns for energy systems planning and management. A heavy emphasis is placed on stimulation of electric vehicles (EVs) to handle these problems associated with various complexities and uncertainties in municipal energy system (MES). In this study, an interval-possibilistic basic-flexible programming (IPBFP) method is proposed for planning MES of Qingdao, where uncertainties expressed as interval-flexible variables and interval-possibilistic parameters can be effectively reflected. Support vector regression (SVR) is used for predicting electricity demand of the city under various scenarios. Solutions of EVs stimulation levels and satisfaction levels in association with flexible constraints and predetermined necessity degrees are analyzed, which can help identify the optimized energy supply patterns that could plunk for improvement of air quality and hedge against violation of soft constraints. Results disclose that largely developing EVs can help facilitate the city's energy system with an environment-effective way. However, compared to the rapid growth of transportation, the EVs' contribution of improving the city's air quality is limited. It is desired that, to achieve an environmentally sustainable MES, more concerns should be focused on the integration of increasing renewable energy resources, stimulating EVs as well as improving energy transmission, transport and storage. PMID- 28351811 TI - Process study of biogeochemical cycling of dissolved inorganic arsenic during spring phytoplankton bloom, southern Yellow Sea. AB - Previous studies in the southern Yellow Sea (SYS) suggest that large spring phytoplankton blooms (SPBs) have occurred in recent decades. Elevated primary production in the water column can lead to the accumulation and transformation of trace elements. Two field study cruises (including two drifting anchor surveys) were conducted on 12-19 February and from 24 March to 15 April 2009, to investigate the impact of different SPB development periods on the concentrations of total dissolved inorganic arsenic (TDIAs: [TDIAs]=[As(V)]+[As(III)]) and As(III) (arsenite) in the SYS. The distribution of TDIAs in the study area was similar between the two field studies, with concentrations increasing from coastal to offshore areas. High arsenite concentrations and As(III)/TDIAs ratios were found in areas having high concentrations of chlorophyll-a, particularly in the subsurface waters of the central SYS during the drifting surveys, where a significant SPB occurred. Results show that the integrated arsenite concentrations increased at an average transformation rate of 0.53+/-0.24nmol/L/d within the 15days during the bloom, and data from the anchor drifting surveys indicated that approximately 15.1% of the arsenate in the euphotic zone (~30m depth) was converted to arsenite. In addition, 7.1% of TDIAs was scavenged from the water column by phytoplankton forming the blooms (a factor of 5 higher than expected). A preliminary box model was established to estimate the budget for TDIAs in the SYS in early spring (February to April). This showed that biological scavenging is an important sink for TDIAs, which may promote the transformation and migration of inorganic arsenic species, and thus have a substantial impact on the biogeochemical cycling of this element in the SYS. Depletion of arsenate in the upper waters could lead to arsenate stress, potentially damaging fisheries and the ecosystem. PMID- 28351812 TI - Complex responses of spring alpine vegetation phenology to snow cover dynamics over the Tibetan Plateau, China. AB - Snow cover dynamics are considered to play a key role on spring phenological shifts in the high-latitude, so investigating responses of spring phenology to snow cover dynamics is becoming an increasingly important way to identify and predict global ecosystem dynamics. In this study, we quantified the temporal trends and spatial variations of spring phenology and snow cover across the Tibetan Plateau by calibrating and analyzing time series of the NOAA AVHRR derived normalized difference vegetation index (NDVI) during 1983-2012. We also examined how snow cover dynamics affect the spatio-temporal pattern of spring alpine vegetation phenology over the plateau. Our results indicated that 52.21% of the plateau experienced a significant advancing trend in the beginning of vegetation growing season (BGS) and 34.30% exhibited a delaying trend. Accordingly, the snow cover duration days (SCD) and snow cover melt date (SCM) showed similar patterns with a decreasing trend in the west and an increasing trend in the southeast, but the start date of snow cover (SCS) showed an opposite pattern. Meanwhile, the spatial patterns of the BGS, SCD, SCS and SCM varied in accordance with the gradients of temperature, precipitation and topography across the plateau. The response relationship of spring phenology to snow cover dynamics varied within different climate, terrain and alpine plant community zones, and the spatio-temporal response patterns were primarily controlled by the long-term local heat-water conditions and topographic conditions. Moreover, temperature and precipitation played a profound impact on diverse responses of spring phenology to snow cover dynamics. PMID- 28351813 TI - 1D and 2D diffusion pore imaging on a preclinical MR system using adaptive rephasing: Feasibility and pulse sequence comparison. AB - Diffusion pore imaging (DPI) has recently been proposed as a means to acquire images of the average pore shape in an image voxel or region of interest. The highly asymmetric gradient scheme of its sequence makes it substantially demanding in terms of the hardware of the NMR system. The aim of this work is to show the feasibility of DPI on a preclinical 9.4T animal scanner. Using water filled capillaries with an inner radius of 10MUm, four different variants of the DPI sequence were compared in 1D and 2D measurements. The pulse sequences applied cover the basic implementation using one long and one temporally narrow gradient pulse, a CPMG-like variant with multiple refocusing RF pulses as well as two variants splitting up the long gradient and distributing it on either side of the refocusing pulse. Substantial differences between the methods were found in terms of signal-to-noise ratio, contrast, blurring, deviations from the expected results and sensitivity to gradient imperfections. Each of the tested sequences was found to produce characteristic gradient mismatches dependent on the absolute value, direction and sign of the applied q-value. Read gradients were applied to compensate these mismatches translating them into time shifts, which enabled 1D DPI yielding capillary radius estimations within the tolerances specified by the manufacturer. For a successful DPI application in 2D, a novel gradient amplitude adaption scheme was implemented to correct for the occurring time shifts. Using this adaption, higher conformity to the expected pore shape, reduced blurring and enhanced contrast were achieved. Images of the phantom's pore shape could be acquired with a nominal resolution of 2.2MUm. PMID- 28351814 TI - Combining several interventions to reduce the incidence of OHSS: A prospective cohort study. AB - OBJECTIVE: To assess the outcome of using low-dose aspirin, dopamine agonist and triggering ovulation by low dose of HCG in combination with GnRH agonist in fixed GnRH antagonist protocol in patients at risk of OHSS. STUDY DESIGN: This prospective cohort study was conducted on 50 infertile women who were at high risk of OHSS. They received low dose aspirin from first day of stimulation, cabergoline 0.5mg daily from the day of HCG for 8days and low dose of HCG (2500 IU) in combination with GnRH agonist for final oocyte maturation in fixed GnRH antagonist protocol. RESULTS: The study was conducted on 50 cases and all of them completed the study protocol. The clinical pregnancy rate was 40% (20 cases of 50) and no cases developed severe or critical OHSS. Only 8% (4 cases) developed moderate OHSS. CONCLUSION: Combining aspirin, cabergoline, and triggering with low dose of HCG in combination with GnRH agonist produced excellent clinical pregnancy rate, and decreased hospital admissions with severe or critical OHSS. PMID- 28351815 TI - Neoadjuvant and definitive chemotherapy or chemoradiation for stage III and IV vulvar cancer: A pooled Reanalysis. AB - OBJECTIVES AND METHODS: A number of publications study the treatment of advanced vulvar cancer by neoadjuvant or definitive chemotherapy (CT) or chemoradiation (CRT); however, the reported survival rates vary widely. In a pooled reanalysis of the published data, we studied the factors influencing patients' survival. RESULTS: We included 97 patients with stage III and IV vulvar cancer of publications in our study. In the pooled reanalysis we found that neoadjuvant therapy plus surgery lead to significantly better 5YSR (73%) than definitive CRT (43%) alone. No significant difference was found between CRT (5YSR: 69%) and CT (77%, p=0.11) in the neoadjuvant setting. In addition, patients showing a positive response to CT or CRT had a better 5YSR (67% vs. 20%, p=0.001). CONCLUSION: Neoadjuvant therapy plus surgery can improve survival of patients with advanced vulvar cancer. PMID- 28351816 TI - Rotational forceps versus manual rotation and direct forceps: A retrospective cohort study. AB - OBJECTIVE: Rotational forceps and manual rotation followed by direct forceps are techniques used in the management of malposition of the fetal head in the second stage of labor. However, there is widespread debate regarding their relative safety and utility. We aimed to compare the effectiveness and safety of rotational forceps with manual rotation followed by direct forceps, for management of fetal malposition at full dilation. STUDY DESIGN: A retrospective cohort study in a single tertiary obstetric unit with >6000 births per year. We recorded and analysed outcomes of 104 sequential rotational forceps births over 21 months (Jan 2010-Sept 2012) and 208 matched chronologically sequential attempted manual rotations and direct forceps births (1:2 by number). Univariable and multivariable approaches used for statistical analysis. The main outcome measure was vaginal birth. RESULTS: The rate of vaginal birth was significantly higher with rotational forceps than with manual rotation followed by direct forceps (88.5% vs 82.2%, RR 1.17, 95% CI 1.04-1.31, p=0.017). Births by rotational forceps were associated with a significantly higher rate of shoulder dystocia (19.2% vs 10.6%, RR 2.35, 95% CI 1.23-4.47, p=0.012), but not of neonatal injury. There were no significant differences in all other maternal and neonatal outcomes between the two modes of birth. CONCLUSIONS: The use of rotational forceps was associated with a statistically significantly higher rate of vaginal birth, but also of shoulder dystocia, compared to manual rotation followed by direct forceps. This is the first study to demonstrate a statistically significant increase in the rate of shoulder dystocia following rotational forceps birth. PMID- 28351817 TI - Do forests best mitigate CO2 emissions to the atmosphere by setting them aside for maximization of carbon storage or by management for fossil fuel substitution? AB - Forests' potential to mitigate carbon emissions to the atmosphere is heavily debated and a key question is if forests left unmanaged to store carbon in biomass and soil provide larger carbon emission reductions than forests kept under forest management for production of wood that can substitute fossil fuels and fossil fuel intensive materials. We defined a modelling framework for calculation of the carbon pools and fluxes along the forest energy and wood product supply chains over 200 years for three forest management alternatives (FMA): 1) a traditionally managed European beech forest, as a business-as-usual case, 2) an energy poplar plantation, and 3) a set-aside forest left unmanaged for long-term storage of carbon. We calculated the cumulative net carbon emissions (CCE) and carbon parity times (CPT) of the managed forests relative to the unmanaged forest. Energy poplar generally had the lowest CCE when using coal as the reference fossil fuel. With natural gas as the reference fossil fuel, the CCE of the business-as-usual and the energy poplar was nearly equal, with the unmanaged forest having the highest CCE after 40 years. CPTs ranged from 0 to 156 years, depending on the applied model assumptions. CCE and CPT were especially sensitive to the reference fossil fuel, material alternatives to wood, forest growth rates for the three FMAs, and energy conversion efficiencies. Assumptions about the long-term steady-state levels of carbon stored in the unmanaged forest had a limited effect on CCE after 200 years. Analyses also showed that CPT was not a robust measure for ranking of carbon mitigation benefits. PMID- 28351818 TI - Hydrogen bond docking site competition in methyl esters. AB - The OH?O hydrogen bonds in the 2,2,2-trifluoroethanol (TFE)-methyl ester complexes in the gas phase have been investigated by FTIR spectroscopy and DFT calculations. Methyl formate (MF), methyl acetate (MA), and methyl trifluoroacetate (MTFA) were chosen as the hydrogen bond acceptors. A dominant inter-molecular hydrogen bond was formed between the OH group of TFE and different docking sites in the methyl esters (carbonyl oxygen or ester oxygen). The competition of the two docking sites decides the structure and spectral properties of the complexes. On the basis of the observed red shifts of the OH stretching transition with respect to the TFE monomer, the order of the hydrogen bond strength can be sorted as TFE-MA (119cm-1)>TFE-MF (93cm-1)>TFE-MTFA (44cm 1). Combining the experimental infrared spectra with the DFT calculations, the Gibbs free energies of formation were determined to be 1.5, 4.5 and 8.6kJmol-1 for TFE-MA, TFE-MF and TFE-MTFA, respectively. The hydrogen bonding in the MTFA complex is much weaker than those of the TFE-MA and TFE-MF complexes due to the effect of the CF3 substitution on MTFA, while the replacement of an H atom with a CH3 group in methyl ester only slightly increases the hydrogen bond strength. Topological analysis and localized molecular orbital energy decomposition analysis was also applied to compare the interactions in the complexes. PMID- 28351819 TI - A novel dual-channel chemosensor for CN- using asymmetric double-azine derivatives in aqueous media and its application in bitter almond. AB - In this paper, we have designed and synthesized a novel sensor L1 based on asymmetric double-azine derivatives, which showed both "naked eye" recognition and fluorescence responses for CN- in DMSO/H2O (v/v=4:1, pH=7.20) solution. This simple sensor L1 could distinguish CN- from coexisting anions via the way of deprotonation and sensing mechanism of intramolecular charge transfer (ICT), and the minimum detection limit on fluorescence response of the sensor L1 towards CN- was down to 9.47*10-7M. Moreover, we have successfully utilized the sensor L1 to detect CN- in bitter almond. Test strips containing L1 were also prepared, which could act as a practical colorimetric tool to detect CN- in aqueous media. PMID- 28351820 TI - Experimental evidence for the blue-shifted hydrogen-bonded complexes of CHF3 with pi-electron donors. AB - Blue-shifted hydrogen-bonded complexes of fluoroform (CHF3) with benzene (C6H6) and acetylene (C2H2) have been investigated using matrix isolation infrared spectroscopy and ab initio computations. For CHF3-C6H6 complex, calculations performed at the B3LYP and MP2 levels of theory using 6-311++G (d,p) and aug-cc pVDZ basis sets discerned two minima corresponding to a 1:1 hydrogen-bonded complex. The global minimum correlated to a structure, where the interaction is between the hydrogen of CHF3 and the pi-electrons of C6H6 and a weak local minimum was stabilized through H...F interaction. For the CHF3-C2H2 complex, computation performed at MP2/aug-cc-pVDZ level of theory yielded two minima, corresponding to the cyclic C-H...pi complex A (global) and a linear C-H...F (n sigma) complex B (local). Experimentally a blue-shift of 32.3cm-1 and 7.7cm-1 was observed in the nu1 C-H stretching mode of CHF3 sub-molecule in Ar matrix for the 1:1 C-H...pi complexes of CHF3 with C6H6 and C2H2 respectively. Natural bond orbital (NBO), Atoms-in-molecule (AIM) and energy decomposition (EDA) analyses were carried out to explain the blue-shifting and the nature of the interaction in these complexes. PMID- 28351821 TI - Water quality trading opportunities in two sub-watersheds in the northern Lake Okeechobee watershed. AB - For decades, the increase of nutrient enrichment has threatened the ecological integrity and economic sustainability of many rivers, lakes, and coastal waters, including Lake Okeechobee, the second largest freshwater lake in the contiguous United States. Water quality trading programs have been an area of active development to both, reduce nutrient pollution and minimize abatement costs. The objective of this study was to apply a comprehensive modeling framework, integrating a hydrologic-water quality model with an economic model, to assess and compare the cost-effectiveness of a water quality trading program over a command-and-control approach in order to reduce phosphorus loadings to Lake Okeechobee. The Upper Kissimmee (UK) and Taylor Creek/Nubbin Slough (TCNS) sub watersheds, identified as major sources of total phosphorus (TP) loadings to the lake, were selected for this analysis. The effect of different caps on the market potential was assessed while considering four factors: the least-cost abatement solutions, credit prices, potential cost savings, and credit supply and demand. Hypothetical trading scenarios were also developed, using the optimal caps selected for the two sub-watersheds. In both sub-watersheds, a phosphorus credit trading program was less expensive than the conventional command-and-control approach. While attaining cost-effectiveness, keeping optimal credit prices, and fostering market competition, phosphorus reduction targets of 46% and 32% were selected as the most appropriate caps in the UK and TCNS sub-watersheds, respectively. Wastewater treatment facilities and urban areas in the UK, and concentrated animal feeding operations in the TCNS sub-watershed were identified as potential credit buyers, whereas improved pastures were identified as the major credit sellers in both sub-watersheds. The estimated net cost savings resulting from implementing a phosphorus trading program in the UK and TCNS sub watersheds were 76% ($ 34.9 million per year) and 45% ($ 3.2 million per year), respectively. It is important to note that the realization of the environmental and economic benefits of this market-based alternative is also contingent on other important factors, such as the market structure, the specific program rules, the risk perception, and the education and outreach to develop trusted relationships among regulatory agencies, the public sector, and other stakeholders. Nevertheless, this research provided the foundation for stakeholders to better understand whether water quality trading has the potential to work in the Lake Okeechobee watershed and to facilitate the development of a pilot program. PMID- 28351822 TI - Thermal decomposition of sewage sludge under N2, CO2 and air: Gas characterization and kinetic analysis. AB - Thermochemical valorisation processes that allow energy to be recovered from sewage sludge, such as pyrolysis and gasification, have demonstrated great potential as convenient alternatives to conventional sewage sludge disposal technologies. Moreover, these processes may benefit from CO2 recycling. Today, the scaling up of these technologies requires an advanced knowledge of the reactivity of sewage sludge and the characteristics of the products, specific to the thermochemical process. In this study the behaviour of sewage sludge during thermochemical conversion, under different atmospheres (N2, CO2 and air), was studied, using TGA-FTIR, in order to understand the effects of different atmospheric gases on the kinetics of degradation and on the gaseous products. The different steps observed during the solid degradation were related with the production of different gaseous compounds. A higher oxidative degree of the atmosphere surrounding the sample resulted in higher reaction rates and a shift of the degradation mechanisms to lower temperatures, especially for the mechanisms taking place at temperatures above 400 degrees C. Finally, a multiple first-order reaction model was proposed to compare the kinetic parameters obtained under different atmospheres. Overall, the highest activation energies were obtained for combustion. This work proves that CO2, an intermediate oxidative atmosphere between N2 and air, results in an intermediate behaviour (intermediate peaks in the derivative thermogravimetric curves and intermediate activation energies) during the thermochemical decomposition of sewage sludge. Overall, it can be concluded that the kinetics of these different processes require a different approach for their scaling up and specific consideration of their characteristic reaction temperatures and rates should be evaluated. PMID- 28351823 TI - Proactive sustainability strategy and corporate sustainability performance: The mediating effect of sustainability control systems. AB - This study examines to what extent corporations use sustainability control systems (SCS) to translate proactive sustainability strategy into corporate sustainability performance. The study investigates the mediating effect of SCS on the relationship between proactive sustainability strategy and corporate sustainability performance. Survey data were collected from top managers in 175 multinational and local corporations operating in Sri Lanka and analyzed using Partial Least Squares Structural Equation Modeling (PLS-SEM). SCS were observed to only partially mediate the relationship between proactive sustainability strategy and corporate sustainability performance. The mediating effect of SCS is further examined under three sustainability strategies; environmental and social strategies reveal a partial mediation, while the economic strategy exhibits no mediation. The study also finds that (i) a proactive sustainability strategy is positively associated with SCS and corporate sustainability performance and (ii) SCS are positively associated with corporate sustainability performance. PMID- 28351824 TI - Dynamic models in research and management of biological invasions. AB - Invasive species are increasing in number, extent and impact worldwide. Effective invasion management has thus become a core socio-ecological challenge. To tackle this challenge, integrating spatial-temporal dynamics of invasion processes with modelling approaches is a promising approach. The inclusion of dynamic processes in such modelling frameworks (i.e. dynamic or hybrid models, here defined as models that integrate both dynamic and static approaches) adds an explicit temporal dimension to the study and management of invasions, enabling the prediction of invasions and optimisation of multi-scale management and governance. However, the extent to which dynamic approaches have been used for that purpose is under-investigated. Based on a literature review, we examined the extent to which dynamic modelling has been used to address invasions worldwide. We then evaluated how the use of dynamic modelling has evolved through time in the scope of invasive species management. The results suggest that modelling, in particular dynamic modelling, has been increasingly applied to biological invasions, especially to support management decisions at local scales. Also, the combination of dynamic and static modelling approaches (hybrid models with a spatially explicit output) can be especially effective, not only to support management at early invasion stages (from prevention to early detection), but also to improve the monitoring of invasion processes and impact assessment. Further development and testing of such hybrid models may well be regarded as a priority for future research aiming to improve the management of invasions across scales. PMID- 28351825 TI - Control groups in paediatric epilepsy research: do first-degree cousins show familial effects? AB - To determine whether first-degree cousins of children with idiopathic focal and genetic generalized epilepsies show any association across measures of cognition, behaviour, and brain structure. The presence/absence of associations addresses the question of whether and to what extent first-degree cousins may serve as unbiased controls in research addressing the cognitive, psychiatric, and neuroimaging features of paediatric epilepsies. Participants were children (aged 8-18) with epilepsy who had at least one first-degree cousin control enrolled in the study (n=37) and all enrolled cousin controls (n=100). Participants underwent neuropsychological assessment and brain imaging (cortical, subcortical, and cerebellar volumes), and parents completed the Child Behaviour Checklist (CBCL). Data (based on 42 outcome measures) from cousin controls were regressed on the corresponding epilepsy cognitive, behavioural, and imaging measures in a linear mixed model and case/control correlations were examined. Of the 42 uncorrected correlations involving cognitive, behavioural, and neuroimaging measures, only two were significant (p<0.05). The median correlation was 0.06. A test for whether the distribution of p values deviated from the null distribution under no association was not significant (p>0.25). Similar results held for the cognition/behaviour and brain imaging measures separately. Given the lack of association between cases and first-degree cousin performances on measures of cognition, behaviour, and neuroimaging, the results suggest a non-significant genetic influence on control group performance. First-degree cousins appear to be unbiased controls for cognitive, behavioural, and neuroimaging research in paediatric epilepsy. PMID- 28351826 TI - Erratum. AB - In the review article by Gui et al., entitled "Multidetector CT appearance of the pelvis after cesarean delivery: normal and abnormal acute findings" (Diagn Interv Radiol 2016; 22:534-541. DOI 10.5152/dir.2016.15593) that was published in the November 2016 issue of Diagnostic and Interventional Radiology, an incorrect list of references was published due to a technical error. This has been corrected in the online versions of this article. PMID- 28351827 TI - Systemic Mastocytosis with Associated Chronic Lymphocytic Leukemia: A Matter of Diseases or Prognostic Factors? PMID- 28351828 TI - High Infection-Related Mortality in Pediatric Acute Myeloid Leukemia without Preventive Antibiotics and Antifungals: Retrospective Cohort Study of a Single Center from a Middle-Income Country. AB - OBJECTIVE: This study aimed to evaluate infection-related mortality in patients with acute myeloid leukemia (AML) treated without preventive antibiotics and antifungals in a middle-income country. MATERIALS AND METHODS: Infection-related mortality was evaluated retrospectively in 49 pediatric patients. RESULTS: A total of 173 chemotherapy courses were administered as first-line chemotherapy. Four patients died during induction: one patient due to intracranial bleeding, two patients due to typhlitis, and one patient due to invasive fungal infection with pulmonary vascular invasion and massive bleeding. Another two patients died with resistant disease. During consolidation there were four infection-related deaths and one death due to cardiotoxicity. In first-line chemotherapy mortality was 22% (11/49); infection-related mortality was 14% (7/49). Event-free survival and overall survival at 6 years were 42.9% and 61.2% (95% CI: 44-76 and 66-99 months), respectively. CONCLUSION: Due to considerable infection-related deaths, antibacterial and mold-active antifungal prophylaxis may be tried during neutropenic periods in pediatric AML. PMID- 28351829 TI - Innovations in the Management of Musculoskeletal Pain With Alpha-Lipoic Acid (IMPALA Trial): Study protocol for a Double-Blind, Randomized, Placebo-Controlled Crossover Trial of Alpha-Lipoic Acid for the Treatment of Fibromyalgia Pain. AB - BACKGROUND: Fibromyalgia is a common disorder characterized by chronic widespread pain, sleep disturbance, fatigue, depression, and cognitive dysfunction, resulting in substantial disability. As current analgesics provide incomplete relief and disabling side effects that aggravate fatigue and cognitive dysfunction, there is a need for new pain treatments with better efficacy and tolerability. Alpha-lipoic acid (ALA) is an antioxidant proven effective in painful diabetic neuropathy with minimal side effects. OBJECTIVE: We hypothesize that this agent will provide benefits in fibromyalgia because of several similarities with neuropathic pain and also because it does not cause sedation, fatigue, or mental-slowing. To test this, we have designed a clinical trial that will assess pain, side effects, and other outcomes in participants with fibromyalgia. METHODS: Using a crossover design, 24 adults with fibromyalgia will be randomly allocated to 1 of the 2 sequences of ALA and placebo. Participants will take capsules containing ALA or placebo for 4 weeks followed by a 1-week washout followed by a second 4-week treatment and 1-week washout period. ALA (or matching placebo) capsules will be titrated to 1800 mg/day over each 4-week period. The primary outcome will be mean daily pain intensity (0-10) during week 4 of each period. Secondary outcomes, assessed during week 4 of each period, will include global improvement, adverse events, mood, and quality of life. RESULTS: This trial was registered in the International Standard Randomized Controlled Trial registry March 15, 2016 (Number ISRCTN58259979), and it attained ethics approval on December 3, 2016 (Queen's University Health Sciences & Affiliated Teaching Hospitals Research Ethics Board protocol number ANAE-287-15). The recruitment started in February 2017. CONCLUSIONS: This trial will provide evidence for the efficacy of ALA in fibromyalgia. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 58259979; www.isrctn.com/ISRCTN58259979 (Archived by WebCite at http://www.webcitation.org/6og9JdiyZ). PMID- 28351830 TI - Methodological and Ethical Challenges in a Web-Based Randomized Controlled Trial of a Domestic Violence Intervention. AB - The use of Web-based methods to deliver and evaluate interventions is growing in popularity, particularly in a health care context. They have shown particular promise in responding to sensitive or stigmatized issues such as mental health and sexually transmitted infections. In the field of domestic violence (DV), however, the idea of delivering and evaluating interventions via the Web is still relatively new. Little is known about how to successfully navigate several challenges encountered by the researchers while working in this area. This paper uses the case study of I-DECIDE, a Web-based healthy relationship tool and safety decision aid for women experiencing DV, developed in Australia. The I-DECIDE website has recently been evaluated through a randomized controlled trial, and we outline some of the methodological and ethical challenges encountered during recruitment, retention, and evaluation. We suggest that with careful consideration of these issues, randomized controlled trials can be safely conducted via the Web in this sensitive area. PMID- 28351831 TI - Protocol for Combined Analysis of FOXFIRE, SIRFLOX, and FOXFIRE-Global Randomized Phase III Trials of Chemotherapy +/- Selective Internal Radiation Therapy as First-Line Treatment for Patients With Metastatic Colorectal Cancer. AB - BACKGROUND: In colorectal cancer (CRC), unresectable liver metastases are associated with a poor prognosis. The FOXFIRE (an open-label randomized phase III trial of 5-fluorouracil, oxaliplatin, and folinic acid +/- interventional radioembolization as first-line treatment for patients with unresectable liver only or liver-predominant metastatic colorectal cancer), SIRFLOX (randomized comparative study of FOLFOX6m plus SIR-Spheres microspheres versus FOLFOX6m alone as first-line treatment in patients with nonresectable liver metastases from primary colorectal carcinoma), and FOXFIRE-Global (assessment of overall survival of FOLFOX6m plus SIR-Spheres microspheres versus FOLFOX6m alone as first-line treatment in patients with nonresectable liver metastases from primary colorectal carcinoma in a randomized clinical study) clinical trials were designed to evaluate the efficacy and safety of combining first-line chemotherapy with selective internal radiation therapy (SIRT) using yttrium-90 resin microspheres, also called transarterial radioembolization. OBJECTIVE: The aim of this analysis is to prospectively combine clinical data from 3 trials to allow adequate power to evaluate the impact of chemotherapy with SIRT on overall survival. METHODS: Eligible patients are adults with histologically confirmed CRC and unequivocal evidence of liver metastases which are not treatable by surgical resection or local ablation with curative intent at the time of study entry. Patients may also have limited extrahepatic metastases. Final analysis will take place when all participants have been followed up for a minimum of 2 years. RESULTS: Efficacy and safety estimates derived using individual participant data (IPD) from SIRFLOX, FOXFIRE, and FOXFIRE-Global will be pooled using 2-stage prospective meta-analysis. Secondary outcome measures include progression-free survival (PFS), liver-specific PFS, health-related quality of life, response rate, resection rate, and adverse event profile. The large study population will facilitate comparisons of low frequency adverse events and allow for more robust safety analyses. The potential treatment benefit in those patients who present with disease confined to the liver will be investigated using 1-stage IPD meta analysis. Efficacy will be analyzed on an intention-to-treat basis. CONCLUSIONS: This analysis will assess the impact of SIRT combined with chemotherapy on overall survival in the first-line treatment of metastatic CRC. If positive, the results will change the standard of care for this disease. TRIAL REGISTRATION: FOXFIRE ISRCTN Registry ISRCTN83867919; http://www.isrctn.com/ISRCTN83867919 (Archived by WebCite at http://www.webcitation.org/6oN7axrvA). SIRFLOX ClinicalTrials.gov NCT00724503; https://clinicaltrials.gov/ ct2/show/NCT00724503 (Archived by WebCite at http://www.webcitation.org/6oN7lEGbD). FOXFIRE-Global ClinicalTrials.gov NCT01721954; https://clinicaltrials.gov/ct2/show/NCT01721954 (Archived by WebCite at http://www.webcitation.org/ 6oN7vvQvG). PMID- 28351833 TI - Impact of total knee replacement practice: cost effectiveness analysis of data from the Osteoarthritis Initiative. AB - Objectives To evaluate the impact of total knee replacement on quality of life in people with knee osteoarthritis and to estimate associated differences in lifetime costs and quality adjusted life years (QALYs) according to use by level of symptoms.Design Marginal structural modeling and cost effectiveness analysis based on lifetime predictions for total knee replacement and death from population based cohort data.Setting Data from two studies-Osteoarthritis Initiative (OAI) and the Multicenter Osteoarthritis Study (MOST)-within the US health system.Participants 4498 participants with or at high risk for knee osteoarthritis aged 45-79 from the OAI with no previous knee replacement (confirmed by baseline radiography) followed up for nine years. Validation cohort comprised 2907 patients from MOST with two year follow-up.Intervention Scenarios ranging from current practice, defined as total knee replacement practice as performed in the OAI (with procedural rates estimated by a prediction model), to practice limited to patients with severe symptoms to no surgery.Main outcome measures Generic (SF-12) and osteoarthritis specific quality of life measured over 96 months, model based QALYs, costs, and incremental cost effectiveness ratios over a lifetime horizon.Results In the OAI, total knee replacement showed improvements in quality of life with small absolute changes when averaged across levels of confounding variables: 1.70 (95% uncertainty interval 0.26 to 3.57) for SF-12 physical component summary (PCS); -10.69 (-13.39 to -8.01) for Western Ontario and McMaster Universities arthritis index (WOMAC); and 9.16 (6.35 to 12.49) for knee injury and osteoarthritis outcome score (KOOS) quality of life subscale. These improvements became larger with decreasing functional status at baseline. Provision of total knee replacement to patients with SF-12 PCS scores <35 was the optimal scenario given a cost effectiveness threshold of $200 000/QALY, with cost savings of $6974 ($5789 to $8269) and a minimal loss of 0.008 (-0.056 to 0.043) QALYs compared with current practice. These findings were reproduced among patients with knee osteoarthritis from the MOST cohort and were robust against various scenarios including increased rates of total knee replacement and mortality and inclusion of non-healthcare costs but were sensitive to increased deterioration in quality of life without surgery. In a threshold analysis, total knee replacement would become cost effective in patients with SF-12 PCS scores <=40 if the associated hospital admission costs fell below $14 000 given a cost effectiveness threshold of $200 000/QALY.Conclusion Current practice of total knee replacement as performed in a recent US cohort of patients with knee osteoarthritis had minimal effects on quality of life and QALYs at the group level. If the procedure were restricted to more severely affected patients, its effectiveness would rise, with practice becoming economically more attractive than its current use. PMID- 28351832 TI - Gonad-related factors promote muscle performance gain during postnatal development in male and female mice. AB - To better define the role of male and female gonad-related factors (MGRF, presumably testosterone, and FGRF, presumably estradiol, respectively) on mouse hindlimb skeletal muscle contractile performance/function gain during postnatal development, we analyzed the effect of castration initiated before puberty in male and female mice. We found that muscle absolute and specific (normalized to muscle weight) maximal forces were decreased in 6-mo-old male and female castrated mice compared with age- and sex-matched intact mice, without alteration in neuromuscular transmission. Moreover, castration decreased absolute and specific maximal powers, another important aspect of muscle performance, in 6-mo old males, but not in females. Absolute maximal force was similarly reduced by castration in 3-mo-old muscle fiber androgen receptor (AR)-deficient and wild type male mice, indicating that the effect of MGRF was muscle fiber AR independent. Castration reduced the muscle weight gain in 3-mo mice of both sexes and in 6-mo females but not in males. We also found that bone morphogenetic protein signaling through Smad1/5/9 was not altered by castration in atrophic muscle of 3-mo-old mice of both sexes. Moreover, castration decreased the sexual dimorphism regarding muscle performance. Together, these results demonstrated that in the long term, MGRF and FGRF promote muscle performance gain in mice during postnatal development, independently of muscle growth in males, largely via improving muscle contractile quality (force and power normalized), and that MGFR and FGRF also contribute to sexual dimorphism. However, the mechanisms underlying MGFR and FGRF actions remain to be determined. PMID- 28351834 TI - Cutaneous manifestations of tuberous sclerosis complex and the paediatrician's role. AB - Tuberous sclerosis complex (TSC) is a multisystem genetic disorder stemming from unregulated activation of the mammalian target of rapamycin (mTOR) pathway, resulting in the growth of hamartomas in multiple organs. TSC-related skin lesions often develop early in life and can be disfiguring, emotionally distressful and even painful at times. Recognition of TSC-associated skin features by paediatricians can be a catalyst for facilitating early implementation of treatment strategies and establishing appropriate follow-up care. The range of potential treatment options for symptomatic or disfiguring TSC associated skin lesions includes non-pharmacological (surgical excision, laser therapy) and pharmacological (eg, topical or systemic mTOR inhibitors) alternatives. In this review, we discuss the relevance of TSC-associated skin findings, highlight available treatment options, review guideline recommendations and emphasise the role of the primary care physician in the management of this complex disease. PMID- 28351835 TI - Cross-linking mass spectrometry identifies new interfaces of Augmin required to localise the gamma-tubulin ring complex to the mitotic spindle. AB - The hetero-octameric protein complex, Augmin, recruits gamma-Tubulin ring complex (gamma-TuRC) to pre-existing microtubules (MTs) to generate branched MTs during mitosis, facilitating robust spindle assembly. However, despite a recent partial reconstitution of the human Augmin complex in vitro, the molecular basis of this recruitment remains unclear. Here, we used immuno-affinity purification of in vivo Augmin from Drosophila and cross-linking/mass spectrometry to identify distance restraints between residues within the eight Augmin subunits in the absence of any other structural information. The results allowed us to predict potential interfaces between Augmin and gamma-TuRC. We tested these predictions biochemically and in the Drosophila embryo, demonstrating that specific regions of the Augmin subunits, Dgt3, Dgt5 and Dgt6 all directly bind the gamma-TuRC protein, Dgp71WD, and are required for the accumulation of gamma-TuRC, but not Augmin, to the mitotic spindle. This study therefore substantially increases our understanding of the molecular mechanisms underpinning MT-dependent MT nucleation. PMID- 28351836 TI - Structural and biophysical analyses of the skeletal dihydropyridine receptor beta subunit beta1a reveal critical roles of domain interactions for stability. AB - Excitation-contraction (EC) coupling in skeletal muscle requires a physical interaction between the voltage-gated calcium channel dihydropyridine receptor (DHPR) and the ryanodine receptor Ca2+ release channel. Although the exact molecular mechanism that initiates skeletal EC coupling is unresolved, it is clear that both the alpha1 and beta subunits of DHPR are essential for this process. Here, we employed a series of techniques, including size-exclusion chromatography-multi-angle light scattering, differential scanning fluorimetry, and isothermal calorimetry, to characterize various biophysical properties of the skeletal DHPR beta subunit beta1a Removal of the intrinsically disordered N and C termini and the hook region of beta1a prevented oligomerization, allowing for its structural determination by X-ray crystallography. The structure had a topology similar to that of previously determined beta isoforms, which consist of SH3 and guanylate kinase domains. However, transition melting temperatures derived from the differential scanning fluorimetry experiments indicated a significant difference in stability of ~2-3 degrees C between the beta1a and beta2a constructs, and the addition of the DHPR alpha1s I-II loop (alpha-interaction domain) peptide stabilized both beta isoforms by ~6-8 degrees C. Similar to other beta isoforms, beta1a bound with nanomolar affinity to the alpha interaction domain, but binding affinities were influenced by amino acid substitutions in the adjacent SH3 domain. These results suggest that intramolecular interactions between the SH3 and guanylate kinase domains play a role in the stability of beta1a while also providing a conduit for allosteric signaling events. PMID- 28351839 TI - Margaret McCartney: Nurses must be allowed to exercise professional judgment. PMID- 28351838 TI - Exposure to any antenatal corticosteroids and outcomes in preterm infants by gestational age: prospective cohort study. AB - Objective To determine whether exposure to any antenatal corticosteroids is associated with a lower rate of death at each gestational age at which administration is currently recommended.Design Prospective cohort study.Settings 300 participating neonatal intensive care units of the Pediatrix Medical Group in the United States.Participants 117 941 infants 23 0/7 to 34 6/7 weeks' gestational age born between 1 January 2009 and 31 December 2013.Exposure Any antenatal corticosteroids.Main outcomes measures Death or major hospital morbidities analyzed by gestational age and exposure to antenatal corticosteroids with models adjusted for birth weight, sex, mode of delivery, and multiple births.Results Infants exposed to antenatal corticosteroids (n=81 832) had a significantly lower rate of death before discharge at each gestation 29 weeks or less, 31 weeks, and 33-34 weeks compared with infants without exposure (range of adjusted odds ratios 0.32 to 0.55). The number needed to treat with antenatal corticosteroids to prevent one death before discharge increased from six at 23 and 24 weeks' gestation to 798 at 34 weeks' gestation. The rate of survival without major hospital morbidity was higher among infants exposed to antenatal corticosteroids at the lowest gestations. Infants exposed to antenatal corticosteroids had lower rates of severe intracranial hemorrhage or death, necrotizing enterocolitis stage 2 or above or death, and severe retinopathy of prematurity or death compared with infants without exposure at all gestations less than 30 weeks and most gestations for infants born at 30 weeks' gestation or later.Conclusion Among infants born from 23 to 34 weeks' gestation, antenatal exposure to corticosteroids compared with no exposure was associated with lower mortality and morbidity at most gestations. The effect size of exposure to antenatal corticosteroids on mortality seems to be larger in infants born at the lowest gestations. PMID- 28351837 TI - Cyclin C regulates adipogenesis by stimulating transcriptional activity of CCAAT/enhancer-binding protein alpha. AB - Brown adipose tissue is important for maintaining energy homeostasis and adaptive thermogenesis in rodents and humans. As disorders arising from dysregulated energy metabolism, such as obesity and metabolic diseases, have increased, so has interest in the molecular mechanisms of adipocyte biology. Using a functional screen, we identified cyclin C (CycC), a conserved subunit of the Mediator complex, as a novel regulator for brown adipocyte formation. siRNA-mediated CycC knockdown (KD) in brown preadipocytes impaired the early transcriptional program of differentiation, and genetic KO of CycC completely blocked the differentiation process. RNA sequencing analyses of CycC-KD revealed a critical role of CycC in activating genes co-regulated by peroxisome proliferator activated receptor gamma (PPARgamma) and CCAAT/enhancer-binding protein alpha (C/EBPalpha). Overexpression of PPARgamma2 or addition of the PPARgamma ligand rosiglitazone rescued the defects in CycC-KO brown preadipocytes and efficiently activated the PPARgamma responsive promoters in both WT and CycC-KO cells, suggesting that CycC is not essential for PPARgamma transcriptional activity. In contrast, CycC-KO significantly reduced C/EBPalpha-dependent gene expression. Unlike for PPARgamma, overexpression of C/EBPalpha could not induce C/EBPalpha target gene expression in CycC-KO cells or rescue the CycC-KO defects in brown adipogenesis, suggesting that CycC is essential for C/EBPalpha-mediated gene activation. CycC physically interacted with C/EBPalpha, and this interaction was required for C/EBPalpha transactivation domain activity. Consistent with the role of C/EBPalpha in white adipogenesis, CycC-KD also inhibited differentiation of 3T3-L1 cells into white adipocytes. Together, these data indicate that CycC activates adipogenesis in part by stimulating the transcriptional activity of C/EBPalpha. PMID- 28351840 TI - Macrophages utilize the mitochondrial calcium uniporter for profibrotic polarization. AB - Fibrosis in multiple organs, including the liver, kidney, and lung, often occurs secondary to environmental exposure. Asbestos exposure is one important environmental cause of lung fibrosis. The mechanisms that mediate fibrosis is not fully understood, although mitochondrial oxidative stress in alveolar macrophages is critical for fibrosis development. Mitochondrial Ca2+ levels can be associated with production of reactive oxygen species. Here, we show that patients with asbestosis have higher levels of mitochondrial Ca2+ compared with normal patients. The mitochondrial calcium uniporter (MCU) is a highly selective ion channel that transports Ca2+ into the mitochondrial matrix to modulate metabolism. Asbestos exposure increased mitochondrial Ca2+ influx in alveolar macrophages from wild-type, but not MCU+/-, mice. MCU expression polarized macrophages to a profibrotic phenotype after exposure to asbestos, and the profibrotic polarization was regulated by MCU-mediated ATP production. Profibrotic polarization was abrogated when MCU was absent or its activity was blocked. Of more importance, mice that were deficient in MCU were protected from pulmonary fibrosis. Regulation of mitochondrial Ca2+ suggests that MCU may play a pivotal role in the development of fibrosis and could potentially be a therapeutic target for pulmonary fibrosis.-Gu, L., Larson-Casey, J. L., Carter, A. B. Macrophages utilize the mitochondrial calcium uniporter for profibrotic polarization. PMID- 28351842 TI - Minute Myocardial Injury as Measured by High-Sensitive Troponin T Serum Levels Predicts the Response to Intracoronary Infusion of Bone Marrow-Derived Mononuclear Cells in Patients With Stable Chronic Post-Infarction Heart Failure: Insights From the TOPCARE-CHD Registry. AB - RATIONALE: Cell-based therapies are a promising option in patients with chronic postinfarction heart failure (ischemic cardiomyopathy [ICM]). However, the responses after intracoronary infusion of autologous bone marrow-derived mononuclear cells (BMCs) are heterogeneous, which may be related to impaired cell retention in patients with ICM. Ischemic injury is associated with upregulation of prototypical chemoattractant cytokines mediating retention and homing of circulating cells. The development of ultrasensitive tests to measure high sensitive troponin T (hs-TnT) serum levels revealed the presence of ongoing minute myocardial injury even in patients with stable ICM. OBJECTIVE: To test the hypothesis that serum levels of hs-TnT correlate with cell retention and determine the response to intracoronary BMC application in patients with ICM. METHODS AND RESULTS: About 157 patients with stable ICM and no substantial impairment of kidney function received intracoronary BMC administration. Immediately prior to cell application, hs-TnT levels to measure myocardial injury and NT-proBNP levels as marker of left ventricular wall stress were determined. Patients with elevated hs-TnT were older and had more severe heart failure. Importantly, only patients with elevated baseline hs-TnT>=15.19 pg/mL (upper tertile) demonstrated a significant (P=0.04) reduction in NT-proBNP serum levels (-250 [-1465; 33] pg/mL; relative reduction -24%) 4 months after BMC administration, whereas NT-proBNP levels remained unchanged in patients in the 2 lower hs-TnT tertiles. The absolute decrease in NT-proBNP at 4 months was inversely correlated with baseline hs-TnT (r=-0.27, P=0.001). Finally, retention of intracoronarily infused, 111Indium-labeled cells within the heart was closely associated with hs-TnT levels in patients with chronic ischemic heart failure (P=0.0008, n=10, triple measurements). CONCLUSIONS: The extent of ongoing myocardial injury as measured by serum levels of hs-TnT predicts the reduction of NT-proBNP serum levels at 4 months after intracoronary BMC administration in patients with ICM, suggesting that the beneficial effects of BMC application on LV remodeling and wall stress are confined to patients with ongoing minute myocardial injury. CLINICAL TRIAL REGISTRATION: URL: www.clinicaltrials.gov. Unique identifier: NCT00962364. PMID- 28351841 TI - Maternofetal transport of vitamin B12: role of TCblR/CD320 and megalin. AB - Vitamin B12 deficiency causes megaloblastic anemia and neurologic disorder in humans. Gene defects of transcobalamin (TC) and the transcobalamin receptor (TCblR), needed for cellular uptake of the TC-bound B12, do not confer embryonic lethality. TC deficiency can produce the hematologic and neurologic complications after birth, whereas TCblR/CD320 gene defects appear to produce mild metabolic changes. Alternate maternofetal transport mechanisms appear to provide adequate B12 to the fetus. To understand this mechanism, we evaluated the role of TC, TCblR/CD320, and megalin in maternofetal transport of B12 in a TCblR/CD320 knockout (KO) mouse. Our results showed high expression of TCblR/CD320 in the labyrinth of the placenta, embryonic brain, and spinal column in wild-type (WT) mice. Megalin expression was about the same in both WT and KO mouse visceral yolk sac, brain, and spinal column. Megalin mRNA was down-regulated in the KO embryonic spinal cord (SC) and kidneys. Megalin expression remained unaltered in adult WT and KO mouse brain, SC, and kidneys. Injected dsRed-TC-B12 and TC 57CoB12 accumulated in the visceral yolk sac of KO mice where megalin is expressed and provides an alternate mechanism for the maternofetal transport of Cbl during fetal development.-Arora, K., Sequeira, J. M., Quadros, E. V. Maternofetal transport of vitamin B12: role of TCblR/CD320 and megalin. PMID- 28351844 TI - David Oliver: Confidentiality on the wards-regulations and reality. PMID- 28351843 TI - Five minutes with . . . Kamila Hawthorne. PMID- 28351845 TI - Antenatal corticosteroids for women at risk of preterm delivery. PMID- 28351847 TI - Differentiating Between Postural Tachycardia Syndrome and Vasovagal Syncope. PMID- 28351846 TI - Postural Heart Rate Changes in Young Patients With Vasovagal Syncope. AB - BACKGROUND AND OBJECTIVES: Recurrent postural vasovagal syncope (VVS) is caused by transient cerebral hypoperfusion from episodic hypotension and bradycardia; diagnosis is made by medical history. VVS contrasts with postural tachycardia syndrome (POTS), defined by chronic daily symptoms of orthostatic intolerance with excessive upright tachycardia without hypotension. POTS has recently been conflated with VVS when excessive tachycardia is succeeded by hypotension during tilt testing. We hypothesize that excessive tachycardia preceding hypotension and bradycardia is part of the vasovagal response during tilt testing of patients with VVS. METHODS: We prospectively performed head-up tilt (HUT) testing on patients with recurrent VVS (n = 47, 17.9 +/- 1.1 y), who fainted at least 3 times within the last year, and control subjects (n = 15, 17.1 +/- 1.0 y), from age and BMI-matched volunteers and measured blood pressure, heart rate (HR), cardiac output, total peripheral resistance, and end tidal carbon dioxide. RESULTS: Baseline parameters were the same in both groups. HR (supine versus 5 and 10 minutes HUT) significantly increased in control (65 +/- 2.6 vs 83 +/- 3.6 vs 85 +/- 3.7, P < .001) and patients with VVS (69 +/- 1.6 vs 103 +/- 2.3 vs 109 +/- 2.4, P < .001). HUT in controls maximally increased HR by 20.3 +/- 2.9 beats per minute; the increase in patients with VVS of 39.8 +/- 2.1 beats per minute was significantly greater (P < .001). An increase in HR of >=40 beats per minute by 5 and 10 minutes or before faint with HUT, occurred in 26% and 44% of patients with VVS, respectively, but not in controls. CONCLUSIONS: Orthostasis in VVS is accompanied by large increases in HR that should not be construed as POTS. PMID- 28351848 TI - Human cost of delivering healthcare in unhealthy prisons. PMID- 28351849 TI - Sport medicine at its peak. PMID- 28351850 TI - Paradoxes and personalised medicine: from preseason to post-diagnosis. PMID- 28351851 TI - Centrosome and spindle assembly checkpoint loss leads to neural apoptosis and reduced brain size. AB - Accurate mitotic spindle assembly is critical for mitotic fidelity and organismal development. Multiple processes coordinate spindle assembly and chromosome segregation. Two key components are centrosomes and the spindle assembly checkpoint (SAC), and mutations affecting either can cause human microcephaly. In vivo studies in Drosophila melanogaster found that loss of either component alone is well tolerated in the developing brain, in contrast to epithelial tissues of the imaginal discs. In this study, we reveal that one reason for that tolerance is the compensatory relationship between centrosomes and the SAC. In the absence of both centrosomes and the SAC, brain cells, including neural stem cells, experience massive errors in mitosis, leading to increased cell death, which reduces the neural progenitor pool and severely disrupts brain development. However, our data also demonstrate that neural cells are much more tolerant of aneuploidy than epithelial cells. Our data provide novel insights into the mechanisms by which different tissues manage genome stability and parallels with human microcephaly. PMID- 28351853 TI - Pharmaceutical Characterization of Tropomyosin Receptor Kinase B-Agonistic Antibodies on Human Induced Pluripotent Stem (hiPS) Cell-Derived Neurons. AB - Brain-derived neurotrophic factor (BDNF) is a central modulator of neuronal development and synaptic plasticity in the central nervous system. This renders the BDNF-modulated tropomyosin receptor kinase B (TrkB) a promising drug target to treat synaptic dysfunctions. Using GRowth factor-driven expansion and INhibition of NotCH (GRINCH) during maturation, the so-called GRINCH neurons were derived from human-induced pluripotent stem cells. These GRINCH neurons were used as model cells for pharmacologic profiling of two TrkB-agonistic antibodies, hereafter referred to as AB2 and AB20 In next-generation sequencing studies, AB2 and AB20 stimulated transcriptional changes, which extensively overlapped with BDNF-driven transcriptional modulation. In regard to TrkB phosphorylation, both AB2 and AB20 were only about half as efficacious as BDNF; however, with respect to the TrkB downstream signaling, AB2 and AB20 displayed increased efficacy values, providing a stimulation at least comparable to BDNF in respect to VGF transcription, as well as of AKT and cAMP response element-binding protein phosphorylation. In a complex structure of the TrkB-d5 domain with AB20, determined by X-ray crystallography, the AB20 binding site was found to be allosteric in regard to the BDNF binding site, whereas AB2 was known to act orthosterically with BDNF. In agreement with this finding, AB2 and AB20 acted synergistically at greater concentrations to drive TrkB phosphorylation. Although TrkB downstream signaling declined faster after pulse stimulation with AB20 than with AB2, AB20 restimulated TrkB phosphorylation more efficiently than AB2. In conclusion, both antibodies displayed some limitations and some benefits in regard to future applications as therapeutic agents. PMID- 28351852 TI - Leukocyte immunoglobulin-like receptors in human diseases: an overview of their distribution, function, and potential application for immunotherapies. AB - Myeloid-derived suppressor cells (MDSCs), a population of immature myeloid cells expanded and accumulated in tumor-bearing mice and in patients with cancer, have been shown to mediate immune suppression and to promote tumor progression, thereby, posing a major hurdle to the success of immune-activating cancer therapies. MDSCs, like their healthy counterparts, such as monocytes/macrophages and granulocytes, express an array of costimulatory and coinhibitory molecules as well as myeloid activators and inhibitory receptors, such as leukocyte immunoglobulin-like receptors (LILR) A and B. This review summarizes current findings on the LILR family members in various diseases, their potential roles in the pathogenesis, and possible strategies to revert or enhance the suppressive function of MDSCs for the benefit of patients by targeting LILRs. PMID- 28351854 TI - Discrepant Results of Serum Creatinine and Cystatin C in a Urological Patient. PMID- 28351855 TI - Commentary. PMID- 28351856 TI - Commentary. PMID- 28351857 TI - Correction. PMID- 28351858 TI - A New Monoclonal Band in a Patient with Refractory Multiple Myeloma. PMID- 28351859 TI - Precision Medicine-Right Treatment, Right Patient, Right Time, Wrong Approach? PMID- 28351860 TI - Writing the Genome: Are We Ready? PMID- 28351861 TI - da Vinci's Spirals. PMID- 28351862 TI - Cartoons: Another Long-standing Bridge between Science and the Arts. PMID- 28351864 TI - Spindle orientation: a question of complex positioning. AB - The direction in which a cell divides is determined by the orientation of its mitotic spindle at metaphase. Spindle orientation is therefore important for a wide range of developmental processes, ranging from germline stem cell division to epithelial tissue homeostasis and regeneration. In multiple cell types in multiple animals, spindle orientation is controlled by a conserved biological machine that mediates a pulling force on astral microtubules. Restricting the localization of this machine to only specific regions of the cortex can thus determine how the mitotic spindle is oriented. As we review here, recent findings based on studies in tunicate, worm, fly and vertebrate cells have revealed that the mechanisms for mediating this restriction are surprisingly diverse. PMID- 28351865 TI - Using synthetic biology to explore principles of development. AB - Developmental biology is mainly analytical: researchers study embryos, suggest hypotheses and test them through experimental perturbation. From the results of many experiments, the community distils the principles thought to underlie embryogenesis. Verifying these principles, however, is a challenge. One promising approach is to use synthetic biology techniques to engineer simple genetic or cellular systems that follow these principles and to see whether they perform as expected. As I review here, this approach has already been used to test ideas of patterning, differentiation and morphogenesis. It is also being applied to evo devo studies to explore alternative mechanisms of development and 'roads not taken' by natural evolution. PMID- 28351869 TI - Bone regeneration in the fish fin. PMID- 28351868 TI - Making thalamic neurons in vitro. PMID- 28351866 TI - Shh promotes direct interactions between epidermal cells and osteoblast progenitors to shape regenerated zebrafish bone. AB - Zebrafish innately regenerate amputated fins by mechanisms that expand and precisely position injury-induced progenitor cells to re-form tissue of the original size and pattern. For example, cell signaling networks direct osteoblast progenitors (pObs) to rebuild thin cylindrical bony rays with a stereotypical branched morphology. Hedgehog/Smoothened (Hh/Smo) signaling has been variably proposed to stimulate overall fin regenerative outgrowth or promote ray branching. Using a photoconvertible patched2 reporter, we resolve active Hh/Smo output to a narrow distal regenerate zone comprising pObs and adjacent motile basal epidermal cells. This Hh/Smo activity is driven by epidermal Sonic hedgehog a (Shha) rather than Ob-derived Indian hedgehog a (Ihha), which nevertheless functions atypically to support bone maturation. Using BMS-833923, a uniquely effective Smo inhibitor, and high-resolution imaging, we show that Shha/Smo is functionally dedicated to ray branching during fin regeneration. Hh/Smo activation enables transiently divided clusters of Shha-expressing epidermis to escort pObs into similarly split groups. This co-movement likely depends on epidermal cellular protrusions that directly contact pObs only where an otherwise occluding basement membrane remains incompletely assembled. Progressively separated pObs pools then continue regenerating independently to collectively re form a now branched skeletal structure. PMID- 28351867 TI - Cooperative activation of cardiac transcription through myocardin bridging of paired MEF2 sites. AB - Enhancers frequently contain multiple binding sites for the same transcription factor. These homotypic binding sites often exhibit synergy, whereby the transcriptional output from two or more binding sites is greater than the sum of the contributions of the individual binding sites alone. Although this phenomenon is frequently observed, the mechanistic basis for homotypic binding site synergy is poorly understood. Here, we identify a bona fide cardiac-specific Prkaa2 enhancer that is synergistically activated by homotypic MEF2 binding sites. We show that two MEF2 sites in the enhancer function cooperatively due to bridging of the MEF2C-bound sites by the SAP domain-containing co-activator protein myocardin, and we show that paired sites buffer the enhancer from integration site-dependent effects on transcription in vivo Paired MEF2 sites are prevalent in cardiac enhancers, suggesting that this might be a common mechanism underlying synergy in the control of cardiac gene expression in vivo. PMID- 28351871 TI - Timing is key to turn root into shoot. PMID- 28351870 TI - Turning off translation in germ cells. PMID- 28351872 TI - How cell-cell contact defines fate. PMID- 28351873 TI - Early outcomes in patients undergoing transcatheter versus surgical pulmonary valve replacement. AB - OBJECTIVES: To identify predictors of morbidity and mortality in patients undergoing either transcatheter pulmonary valve replacement (TPVR) or surgical pulmonary valve replacement (SPVR) in an effort to quantify any early benefit of TPVR over SPVR. METHODS: Using a risk-adjusted propensity score model, we compare early major morbidity and mortality between patients undergoing SPVR and TPVR at our institution between January 2006 and January 2014. RESULTS: 145 patients in the SPVR cohort and 78 patients in the TPVR cohort were included. Primary pulmonary regurgitation was more common in the SPVR group (76.6% vs 23.1%, p<0.001) and primary pulmonary stenosis was more common in the TPVR group (9.7% vs 44.9%, p< 0.001). In unadjusted analysis, major morbidity and mortality occurred in 11.7% of SPVR patients versus 3.8% of TPVR patients (p=0.04). However, following risk adjustment and inclusion of a propensity score, no significant difference was seen between the two modalities. A larger right ventricular end-diastolic dimension (RVEDVI) was the only preoperative variable associated with the primary end point (OR 1.013/10 mL/m2 increase, p=0.03). Hospital length of stay was significantly longer in patients undergoing SPVR (6.9+/-1.0 days SPVR vs 1.2+/-0.3 days TPVR, p<0.0001), with similar hospital costs between groups (mean: US$44 660+/-5071 SPVR vs US$48 355+/-1000 TPVR, p=0.7). CONCLUSIONS: Following risk adjustment, no significant differences were observed between SPVR and TPVR strategies. TPVR was associated with a shorter hospitalisation; however, total hospitalisation costs were similar between groups. PMID- 28351874 TI - Just over half of doctors declare fees from drug companies. PMID- 28351863 TI - Systems Chronotherapeutics. AB - Chronotherapeutics aim at treating illnesses according to the endogenous biologic rhythms, which moderate xenobiotic metabolism and cellular drug response. The molecular clocks present in individual cells involve approximately fifteen clock genes interconnected in regulatory feedback loops. They are coordinated by the suprachiasmatic nuclei, a hypothalamic pacemaker, which also adjusts the circadian rhythms to environmental cycles. As a result, many mechanisms of diseases and drug effects are controlled by the circadian timing system. Thus, the tolerability of nearly 500 medications varies by up to fivefold according to circadian scheduling, both in experimental models and/or patients. Moreover, treatment itself disrupted, maintained, or improved the circadian timing system as a function of drug timing. Improved patient outcomes on circadian-based treatments (chronotherapy) have been demonstrated in randomized clinical trials, especially for cancer and inflammatory diseases. However, recent technological advances have highlighted large interpatient differences in circadian functions resulting in significant variability in chronotherapy response. Such findings advocate for the advancement of personalized chronotherapeutics through interdisciplinary systems approaches. Thus, the combination of mathematical, statistical, technological, experimental, and clinical expertise is now shaping the development of dedicated devices and diagnostic and delivery algorithms enabling treatment individualization. In particular, multiscale systems chronopharmacology approaches currently combine mathematical modeling based on cellular and whole-body physiology to preclinical and clinical investigations toward the design of patient-tailored chronotherapies. We review recent systems research works aiming to the individualization of disease treatment, with emphasis on both cancer management and circadian timing system-resetting strategies for improving chronic disease control and patient outcomes. PMID- 28351875 TI - Winners of the Consortium of Universities for Global Health-Global Health: Science and Practice Annual Student Manuscript Contest. PMID- 28351876 TI - "New Users" Are Confusing Our Counting: Reaching Consensus on How to Measure "Additional Users" of Family Planning. PMID- 28351878 TI - Excellent Family Planning Progress in Nigeria Reported by PMA2020. PMID- 28351879 TI - A Non-Gas-Based Cryotherapy System for the Treatment of Cervical Intraepithelial Neoplasia: A Mixed-Methods Approach for Initial Development and Testing. AB - BACKGROUND: Gas-based cryotherapy is the most widely used treatment strategy for cervical intraepithelial neoplasia (CIN) in low-resource settings, but reliance on gas presents challenges in low- and middle-income countries (LMICs). Our team adapted the original CryoPen Cryosurgical System, a cryotherapy device that does not require compressed gas and is powered by electricity, for use in LMICs. METHODS: A mixed-methods approach was used involving both qualitative and quantitative methods. First, we used a user-centered design approach to identify priority features of the adapted device. U.S.-based and global potential users of the adapted CryoPen participated in discussion groups and a card sorting activity to rank 7 features of the adapted CryoPen: cost, durability, efficacy and safety, maintenance, no need for electricity, patient throughput, and portability. Mean and median rankings, overall rankings, and summary rankings by discussion group were generated. In addition, results of several quantitative tests were analyzed including bench testing to determine tip temperature and heat extraction capabilities; a pathology review of CIN grade 3 cases (N=107) to determine target depth of necrosis needed to achieve high efficacy; and a pilot study (N=5) investigating depth of necrosis achieved with the adapted device to assess efficacy. RESULTS: Discussion groups revealed 4 priority themes for device development in addition to the need to ensure high efficacy and safety and low cost: improved portability, durability, ease of use, and potential for cure. Adaptions to the original CryoPen system included a single-core, single-tip model; rugged carrying case; custom circuit to allow car battery charging; and sterilization by high-level disinfection. In bench testing, there were no significant differences in tip temperature or heat extraction capability between the adapted CryoPen and the standard cryotherapy device. In 80% of the cases in the pilot study, the adapted CryoPen achieved the target depth of necrosis 3.5 mm established in the pathology review. CONCLUSION: The LMIC-adapted CryoPen overcomes barriers to standard gas-based cryotherapy by eliminating dependency on gas, increasing portability, and ensuring consistent freeze temperatures. Further testing and evaluation of the adapted CryoPen will be pursued to assess scalability and potential impact of this device in decreasing the cervical cancer burden in LMICs. PMID- 28351877 TI - CDC's Male Circumcision Recommendations Represent a Key Public Health Measure. PMID- 28351880 TI - Preventing Peer Violence Against Children: Methods and Baseline Data of a Cluster Randomized Controlled Trial in Pakistan. AB - BACKGROUND: Violence against and among children is a global public health problem that annually affects 50% of youth worldwide with major impacts on child development, education, and health including increased probability of major causes of morbidity and mortality in adulthood. It is also associated with the experience of and perpetration of later violence against women. The aim of this article is to describe the intervention, study design, methods, and baseline findings of a cluster randomized controlled trial underway in Pakistan to evaluate a school-based play intervention aiming to reduce peer violence and enhance mental health. METHODS: A cluster randomized controlled design is being conducted with boys and girls in grade 6 in 40 schools in Hyderabad, Pakistan, over a period of 2 years. The Multidimensional Peer-Victimization and Peer Perpetration Scales and the Children's Depression Inventory 2 (CDI 2) are being used to measure the primary outcomes while investigator-derived scales are being used to assess domestic violence within the family. Specifics of the intervention, field logistics, ethical, and fidelity management issues employed to test the program's impact on school age youth in a volatile and politically unstable country form this report. BASELINE RESULTS: A total of 1,752 school-age youth were enrolled and interviewed at baseline. Over the preceding 4 weeks, 94% of the boys and 85% of the girls reported 1 or more occurrences of victimization, and 85% of the boys and 66% of the girls reported 1 or more acts of perpetration. Boys reported more depression compared with girls, as well as higher negative mood and self-esteem scores and more interpersonal and emotional problems. INTERPRETATION: Globally, prevalence of youth violence perpetration and victimization is high and associated with poor physical and emotional health. Applying a randomized controlled design to evaluate a peer violence prevention program built on a firm infrastructure and that is ready for scale-up and sustainability will make an important contribution to identifying evidence informed interventions that can reduce youth victimization and perpetration. PMID- 28351881 TI - mJustice: Preliminary Development of a Mobile App for Medical-Forensic Documentation of Sexual Violence in Low-Resource Environments and Conflict Zones. AB - Digital health development and use has been expansive and operationalized in a variety of settings and modalities around the world, including in low- and middle income countries. Mobile applications have been developed for a variety of health professionals and frontline health workers including physicians, midwives, nurses, and community health workers. However, there are no published studies on the development and use of digital health related to human rights fieldwork and to our knowledge no mobile health platforms exist specifically for use by frontline health workers to forensically and clinically document sexual violence. We describe a participatory development and user design process with Congolese end-users of a novel human rights app for clinicians intended to standardize the documentation of sexual violence evidence for forensic and legal purposes, called MediCapt. The app, yet to be launched and still in the future proofing phase, has included several development phases: (1) initial needs assessment conducted in 2011, (2) prototype development and field-testing in 2014 with 8 Congolese physicians, (3) prototype refinement and field-testing in 2015 with 9 clinicians. Feedback from the first field-testing phase was incorporated into the design of the second prototype; key features that were added to MediCapt include the ability for users to take photographs and draw on a pictogram to include as part of the evidence package, as well as the ability to print a form with the completed data. Questionnaires and key-informant interviews during the second and third field-testing phases revealed overall positive attitudes about MediCapt, but multiple perceived and actual barriers to implementation were identified, from personal behaviors, such as individual clinicians' comfort with new technology, to more systemic and infrastructure factors, such as strong cultural preferences for print documentation of evidence and limited Internet connectivity. Next phases of development include consideration of patients' acceptance of this technology, how it actually fits in the clinical workflow, and testing of how to transfer the collected evidence to law enforcement and legal authorities. Ultimately, we plan on conducting a robust evaluation to assess effectiveness of the app on medical, legal, and human rights outcomes. We believe our experience of collecting data that will potentially serve as legal evidence broadens the traditional scope of digital health and crosses a wide range of fields including medical, technological, legal, and ethical, and thus propose refining and defining this unique field of exploration as mobile justice, or mJustice. PMID- 28351883 TI - American Mock World Health Organization: An Innovative Model for Student Engagement in Global Health Policy. AB - The American Mock World Health Organization (AMWHO) is a model for experiential based learning and student engagement in global health diplomacy. AMWHO was established in 2014 at the University of North Carolina at Chapel Hill with a mission to engage students in health policy by providing a simulation of the World Health Assembly (WHA), the policy-forming body of the World Health Organization that sets norms and transforms the global health agenda. AMWHO conferences are designed to allow students to take their knowledge of global health beyond the classroom and practice their skills in diplomacy by assuming the role of WHA delegates throughout a 3-day weekend. Through the process of developing resolutions like those formed in the WHA, students have the unique opportunity to understand the complexities behind the conflict and compromise that ensues through the lens of a stakeholder. This article describes the structure of the first 2 AMWHO international conferences, analyzes survey results from attendees, and discusses the expansion of the organization into a multi campus national network. The AMWHO 2014 and 2015 post-conference survey results found that 98% and 90% of participants considered the conference "good" or "better," respectively, and survey responses showed that participants considered the conference "influential" in their careers and indicated that it "allowed a paradigm shift not possible in class." PMID- 28351882 TI - RAHI-SATHI Indo-U.S. Collaboration: The Evolution of a Trainee-Led Twinning Model in Global Health Into a Multidisciplinary Collaborative Program. AB - BACKGROUND: In recent years there has been a surge in the number of global health programs operated by academic institutions. However, most of the existing programs describe partnerships that are primarily faculty-driven and supported by extramural funding. PROGRAM DESCRIPTION: Research and Advocacy for Health in India (RAHI, or "pathfinder" in Hindi) and Support and Action Towards Health Equity in India (SATHI, or "partnership" in Hindi) are 2 interconnected, collaborative efforts between the University of Massachusetts Medical School (UMMS) and Charutar Arogya Mandal (CAM), a medical college and a tertiary care center in rural western India. The RAHI-SATHI program is the culmination of a series of student/trainee-led research and capacity strengthening initiatives that received institutional support in the form of faculty mentorship and seed funding. RAHI-SATHI's trainee-led twinning approach overcomes traditional barriers faced by global health programs. Trainees help mitigate geographical barriers by acting as a bridge between members from different institutions, garner cultural insight through their ability to immerse themselves in a community, and overcome expertise limitations through pre-planned structured mentorship from faculty of both institutions. Trainees play a central role in cultivating trust among the team members and, in the process, they acquire personal leadership skills that may benefit them in their future careers. CONCLUSION: This paradigm of trainee-led twinning partnership promotes sustainability in an uncertain funding climate and provides a roadmap for conducting foundational work that is essential for the development of a broad, university-wide global health program. PMID- 28351884 TI - Possible Reasons for Limited Effectiveness of a Skills and Drills Intervention to Improve Emergency Obstetric and Newborn Care. PMID- 28351887 TI - Sustainability and transformation plans for the NHS in England: what do they say and what happens next? PMID- 28351885 TI - Loss of the RNA helicase SKIV2L2 impairs mitotic progression and replication dependent histone mRNA turnover in murine cell lines. AB - RNA surveillance via the nuclear exosome requires cofactors such as the helicase SKIV2L2 to process and degrade certain noncoding RNAs. This research aimed to characterize the phenotype associated with RNAi knockdown of Skiv2l2 in two murine cancer cell lines: Neuro2A and P19. SKIV2L2 depletion in Neuro2A and P19 cells induced changes in gene expression indicative of cell differentiation and reduced cellular proliferation by 30%. Propidium iodide-based cell-cycle analysis of Skiv2l2 knockdown cells revealed defective progression through the G2/M phase and an accumulation of mitotic cells, suggesting SKIV2L2 contributes to mitotic progression. Since SKIV2L2 targets RNAs to the nuclear exosome for processing and degradation, we identified RNA targets elevated in cells depleted of SKIV2L2 that could account for the observed twofold increase in mitotic cells. Skiv2l2 knockdown cells accumulated replication-dependent histone mRNAs, among other RNAs, that could impede mitotic progression and indirectly trigger differentiation. PMID- 28351886 TI - 3' Uridylation controls mature microRNA turnover during CD4 T-cell activation. AB - Activation of T lymphocytes requires a tight regulation of microRNA (miRNA) expression. Terminal uridyltransferases (TUTases) catalyze 3' nontemplated nucleotide addition (3'NTA) to miRNAs, which may influence miRNA stability and function. Here, we investigated 3'NTA to mature miRNA in CD4 T lymphocytes by deep sequencing. Upon T-cell activation, miRNA sequences bearing terminal uridines are specifically decreased, concomitantly with down-regulation of TUT4 and TUT7 enzymes. Analyzing TUT4-deficient T lymphocytes, we proved that this terminal uridyltransferase is essential for the maintenance of miRNA uridylation in the steady state of T lymphocytes. Analysis of synthetic uridylated miRNAs shows that 3' addition of uridine promotes degradation of these uridylated miRNAs after T-cell activation. Our data underline post-transcriptional uridylation as a mechanism to fine-tune miRNA levels during T-cell activation. PMID- 28351888 TI - Depletion in LpA-I:A-II particles enhances HDL-mediated endothelial protection in familial LCAT deficiency. AB - The aim of this study was to evaluate the vasoprotective effects of HDL isolated from carriers of LCAT deficiency, which are characterized by a selective depletion of LpA-I:A-II particles and predominance of prebeta migrating HDL. HDLs were isolated from LCAT-deficient carriers and tested in vitro for their capacity to promote NO production and to inhibit vascular cell adhesion molecule-1 (VCAM 1) expression in cultured endothelial cells. HDLs from carriers were more effective than control HDLs in promoting eNOS activation with a gene-dose dependent effect (PTrend = 0.048). As a consequence, NO production induced by HDL from carriers was significantly higher than that promoted by control HDL (1.63 +/ 0.24-fold vs. 1.34 +/- 0.07-fold, P = 0.031). HDLs from carriers were also more effective than control HDLs in inhibiting the expression of VCAM-1 (homozygotes, 65.0 +/- 8.6%; heterozygotes, 53.1 +/- 7.2%; controls, 44.4 +/- 4.1%; PTrend = 0.0003). The increased efficiency of carrier HDL was likely due to the depletion in LpA-I:A-II particles. The in vitro findings might explain why carriers of LCAT deficiency showed flow-mediated vasodilation and plasma-soluble cell adhesion molecule concentrations comparable to controls, despite low HDL-cholesterol levels. These results indicate that selective depletion of apoA-II-containing HDL, as observed in carriers of LCAT deficiency, leads to an increased capacity of HDL to stimulate endothelial NO production, suggesting that changes in HDL apolipoprotein composition may be the target of therapeutic interventions designed to improve HDL functionality. PMID- 28351890 TI - Targeting CD47 and Autophagy Elicited Enhanced Antitumor Effects in Non-Small Cell Lung Cancer. AB - CD47-specific antibodies and fusion proteins that block CD47-SIRPalpha signaling are employed as antitumor agents for several cancers. Here, we investigated the synergistic antitumor effect of simultaneously targeting CD47 and autophagy in non-small cell lung cancer (NSCLC). SIRPalphaD1-Fc, a novel CD47-targeting fusion protein, was generated and was found to increase the phagocytic and cytotoxic activities of macrophages against NSCLC cells. During this process, autophagy was markedly triggered, which was characterized by the three main stages of autophagic flux, including formation and accumulation of autophagosomes, fusion of autophagosomes with lysosomes, and degradation of autophagosomes in lysosomes. Meanwhile, reactive oxygen species and inactivation of mTOR were shown to be involved in autophagy initiation in SIRPalphaD1-Fc-treated cells, indicating a probable mechanism for autophagy activation after targeting CD47 by SIRPalphaD1 Fc. Inhibition of autophagy enhanced macrophage-mediated phagocytosis and cytotoxicity against SIRPalphaD1-Fc-treated NSCLC cells. In addition, simultaneously targeting both CD47 and autophagy in NSCLC xenograft models elicited enhanced antitumor effects, with recruitment of macrophages, activated caspase-3, and overproduction of ROS at the tumor site. Our data elucidated the cytoprotective role of autophagy in CD47-targeted therapy and highlighted the potential approach for NSCLC treatment by simultaneously targeting CD47 and autophagy. Cancer Immunol Res; 5(5); 363-75. (c)2017 AACRSee related Spotlight by Kaufman, p. 355. PMID- 28351892 TI - The BMJ Awards 2017: Palliative and Hospice Care. PMID- 28351891 TI - Squamous Cell Tumors Recruit gammadelta T Cells Producing either IL17 or IFNgamma Depending on the Tumor Stage. AB - The identification of reciprocal interactions between tumor-infiltrating immune cells and the microenviroment may help us understand mechanisms of tumor growth inhibition or progression. We have assessed the frequencies of tumor-infiltrating and circulating gammadelta T cells and regulatory T cells (Treg) from 47 patients with squamous cell carcinoma (SCC), to determine if they correlated with progression or survival. Vdelta1 T cells infiltrated SSC tissue to a greater extent than normal skin, but SCC patients and healthy subjects had similar amounts circulating. However, Vdelta2 T cells were present at higher frequencies in circulation than in the tissue of either cancer patients or healthy donors. Tregs were decreased in the peripheral blood of SCC patients, but were significantly increased in the tumor compartment of these patients. Tumor infiltrating gammadelta T cells preferentially showed an effector memory phenotype and made either IL17 or IFNgamma depending on the tumor stage, whereas circulating gammadelta T cells of SCC patients preferentially made IFNgamma. Different cell types in the tumor microenvironment produced chemokines that could recruit circulating gammadelta T cells to the tumor site and other cytokines that could reprogram gammadelta T cells to produce IL17. These findings suggest the possibility that gammadelta T cells in SCC are recruited from the periphery and their features are then affected by the tumor microenvironment. Elevated frequencies of infiltrating Vdelta2 T cells and Tregs differently correlated with early and advanced tumor stages, respectively. Our results provide insights into the functions of tumor-infiltrating gammadelta T cells and define potential tools for tumor immunotherapy. Cancer Immunol Res; 5(5); 397-407. (c)2017 AACR. PMID- 28351893 TI - Case study on the pathophysiology of Fabry disease: abnormalities of cellular membranes can be reversed by substrate reduction in vitro. AB - It is still not entirely clear how alpha-galactosidase A (GAA) deficiency translates into clinical symptoms of Fabry disease (FD). The present communication investigates the effects of the mutation N215S in FD on the trafficking and processing of lysosomal GAA and their potential association with alterations in the membrane lipid composition. Abnormalities in lipid rafts (LRs) were observed in fibroblasts isolated from a male patient with FD bearing the mutation N215S. Interestingly, LR analysis revealed that the distribution of cholesterol and flotillin-2 are distinctly altered in the Fabry fibroblasts when compared with that of the wild-type cells. Furthermore, increased levels of glycolipid globotriaosylceramide 3 (Gb3) and sphingomyelin (SM) were observed in non-raft membrane fractions of Fabry cells. Substrate reduction with N butyldeoxynojirimycin (NB-DNJ) in vitro was capable of reversing these abnormalities in this patient. These data led to the hypothesis that alterations of LRs may contribute to the pathophysiology of Morbus Fabry. Furthermore, it may be suggested that substrate reduction therapy with NB-DNJ might be a promising approach for the treatment of GAA deficiency at least for the selected patients. PMID- 28351894 TI - Long-term load duration induces N-cadherin down-regulation and loss of cell phenotype of nucleus pulposus cells in a disc bioreactor culture. AB - Long-term exposure to a mechanical load causes degenerative changes in the disc nucleus pulposus (NP) tissue. A previous study demonstrated that N-cadherin (N CDH)-mediated signalling can preserve the NP cell phenotype. However, N-CDH expression and the resulting phenotype alteration in NP cells under mechanical compression remain unclear. The present study investigated the effects of the compressive duration on N-CDH expression and on the phenotype of NP cells in an ex vivo disc organ culture. Porcine discs were organ cultured in a self-developed mechanically active bioreactor for 7 days. The discs were subjected to different dynamic compression durations (1 and 8 h at a magnitude of 0.4 MPa and frequency of 1.0 Hz) once per day. Discs that were not compressed were used as controls. The results showed that long-term compression duration (8 h) significantly down regulated the expression of N-CDH and NP-specific molecule markers (Brachyury, Laminin, Glypican-3 and Keratin 19), attenuated Alcian Blue staining intensity, decreased glycosaminoglycan (GAG) and hydroxyproline (HYP) contents and decreased matrix macromolecule (aggrecan and collagen II) expression compared with the short-term compression duration (1 h). Taken together, these findings demonstrate that long-term load duration can induce N-CDH down-regulation, loss of normal cell phenotype and result in attenuation of NP-related matrix synthesis in NP cells. PMID- 28351895 TI - Magnetic poly(2-hydroxyethyl methacrylate) microspheres for affinity purification of monospecific anti-p46 kDa/Myo1C antibodies for early diagnosis of multiple sclerosis patients. AB - The aim of the present study is to develop new magnetic polymer microspheres with functional groups available for easy protein and antibody binding. Monodisperse macroporous poly(2-hydroxyethyl methacrylate) (PHEMA-COOH) microspheres ~4 um in diameter and containing ~1 mmol COOH/g were synthesized by multistep swelling polymerization of 2-hydroxyethyl methacrylate (HEMA), ethylene dimethacrylate (EDMA), and 2-[(methoxycarbonyl)methoxy]ethyl methacrylate (MCMEMA), which was followed by MCMEMA hydrolysis. The microspheres were rendered magnetic by precipitation of iron oxide inside the pores, which made them easily separable in a magnetic field. Properties of the resulting magnetic poly(2-hydroxyethyl methacrylate) (mgt.PHEMA) particles with COOH functionality were examined by scanning and transmission electron microscopy (SEM and TEM), static volumetric adsorption of helium and nitrogen, mercury porosimetry, Fourier transform infrared (FTIR) and atomic absorption spectroscopy (AAS), and elemental analysis. Mgt.PHEMA microspheres were coupled with p46/Myo1C protein purified from blood serum of multiple sclerosis (MS) patients, which enabled easy isolation of monospecific anti-p46/Myo1C immunoglobulin G (IgG) antibodies from crude antibody preparations of mouse blood serum. High efficiency of this approach was confirmed by SDS/PAGE, Western blot, and dot blot analyses. The newly developed mgt.PHEMA microspheres conjugated with a potential disease biomarker, p46/Myo1C protein, are thus a promising tool for affinity purification of antibodies, which can improve diagnosis and treatment of MS patients. PMID- 28351897 TI - Prevention of Hypoglycemia With Predictive Low Glucose Insulin Suspension in Children With Type 1 Diabetes: A Randomized Controlled Trial. AB - OBJECTIVE: To investigate whether predictive low glucose management (PLGM) of the MiniMed 640G system significantly reduces the rate of hypoglycemia compared with the sensor-augmented insulin pump in children with type 1 diabetes. RESEARCH DESIGN AND METHODS: This randomized, two-arm, parallel, controlled, two-center open-label study included 100 children and adolescents with type 1 diabetes and glycated hemoglobin A1c <=10% (<=86 mmol/mol) and using continuous subcutaneous insulin infusion. Patients were randomly assigned to either an intervention group with PLGM features enabled (PLGM ON) or a control group (PLGM OFF), in a 1:1 ratio, all using the same type of sensor-augmented insulin pump. The primary end point was the number of hypoglycemic events below 65 mg/dL (3.6 mmol/L), based on sensor glucose readings, during a 14-day study treatment. The analysis was performed by intention to treat for all randomized patients. RESULTS: The number of hypoglycemic events below 65 mg/dL (3.6 mmol/L) was significantly smaller in the PLGM ON compared with the PLGM OFF group (mean +/- SD 4.4 +/- 4.5 and 7.4 +/- 6.3, respectively; P = 0.008). This was also true when calculated separately for night (P = 0.025) and day (P = 0.022). No severe hypoglycemic events occurred; however, there was a significant increase in time spent above 140 mg/dL (7.8 mmol/L) in the PLGM ON group (P = 0.0165). CONCLUSIONS: The PLGM insulin suspension was associated with a significantly reduced number of hypoglycemic events. Although this was achieved at the expense of increased time in moderate hyperglycemia, there were no serious adverse effects in young patients with type 1 diabetes. PMID- 28351898 TI - Sodium-Glucose Cotransporter 2 Inhibitors and Diabetic Ketoacidosis: A Case Series From Three Academic Institutions. PMID- 28351896 TI - Enhancers and chromatin structures: regulatory hubs in gene expression and diseases. AB - Gene expression requires successful communication between enhancer and promoter regions, whose activities are regulated by a variety of factors and associated with distinct chromatin structures; in addition, functionally related genes and their regulatory repertoire tend to be arranged in the same subchromosomal regulatory domains. In this review, we discuss the importance of enhancers, especially clusters of enhancers (such as super-enhancers), as key regulatory hubs to integrate environmental cues and encode spatiotemporal instructions for genome expression, which are critical for a variety of biological processes governing mammalian development. Furthermore, we emphasize that the enhancer promoter interaction landscape provides a critical context to understand the aetiologies and mechanisms behind numerous complex human diseases and provides new avenues for effective transcription-based interventions. PMID- 28351902 TI - Risk Stratification for Sudden Cardiac Death: Is It Too Late to Establish a Role for Cardiac MRI? PMID- 28351900 TI - Long Noncoding RNA MANTIS Facilitates Endothelial Angiogenic Function. AB - BACKGROUND: The angiogenic function of endothelial cells is regulated by numerous mechanisms, but the impact of long noncoding RNAs (lncRNAs) has hardly been studied. We set out to identify novel and functionally important endothelial lncRNAs. METHODS: Epigenetically controlled lncRNAs in human umbilical vein endothelial cells were searched by exon-array analysis after knockdown of the histone demethylase JARID1B. Molecular mechanisms were investigated by RNA pulldown and immunoprecipitation, mass spectrometry, microarray, several knockdown approaches, CRISPR-Cas9, assay for transposase-accessible chromatin sequencing, and chromatin immunoprecipitation in human umbilical vein endothelial cells. Patient samples from lung and tumors were studied for MANTIS expression. RESULTS: A search for epigenetically controlled endothelial lncRNAs yielded lncRNA n342419, here termed MANTIS, as the most strongly regulated lncRNA. Controlled by the histone demethylase JARID1B, MANTIS was downregulated in patients with idiopathic pulmonary arterial hypertension and in rats treated with monocrotaline, whereas it was upregulated in carotid arteries of Macaca fascicularis subjected to atherosclerosis regression diet, and in endothelial cells isolated from human glioblastoma patients. CRISPR/Cas9-mediated deletion or silencing of MANTIS with small interfering RNAs or GapmeRs inhibited angiogenic sprouting and alignment of endothelial cells in response to shear stress. Mechanistically, the nuclear-localized MANTIS lncRNA interacted with BRG1, the catalytic subunit of the switch/sucrose nonfermentable chromatin-remodeling complex. This interaction was required for nucleosome remodeling by keeping the ATPase function of BRG1 active. Thereby, the transcription of key endothelial genes such as SOX18, SMAD6, and COUP-TFII was regulated by ensuring efficient RNA polymerase II machinery binding. CONCLUSION: MANTIS is a differentially regulated novel lncRNA facilitating endothelial angiogenic function. PMID- 28351901 TI - Association Between Midwall Late Gadolinium Enhancement and Sudden Cardiac Death in Patients With Dilated Cardiomyopathy and Mild and Moderate Left Ventricular Systolic Dysfunction. AB - BACKGROUND: Current guidelines only recommend the use of an implantable cardioverter defibrillator in patients with dilated cardiomyopathy for the primary prevention of sudden cardiac death (SCD) in those with a left ventricular ejection fraction (LVEF) <35%. However, registries of out-of-hospital cardiac arrests demonstrate that 70% to 80% of such patients have an LVEF >35%. Patients with an LVEF >35% also have low competing risks of death from nonsudden causes. Therefore, those at high risk of SCD may gain longevity from successful implantable cardioverter defibrillator therapy. We investigated whether late gadolinium enhancement (LGE) cardiovascular magnetic resonance identified patients with dilated cardiomyopathy without severe LV systolic dysfunction at high risk of SCD. METHODS: We prospectively investigated the association between midwall LGE and the prespecified primary composite outcome of SCD or aborted SCD among consecutive referrals with dilated cardiomyopathy and an LVEF >=40% to our center between January 2000 and December 2011 who did not have a preexisting indication for implantable cardioverter defibrillator implantation. RESULTS: Of 399 patients (145 women, median age 50 years, median LVEF 50%, 25.3% with LGE) followed for a median of 4.6 years, 18 of 101 (17.8%) patients with LGE reached the prespecified end point, compared with 7 of 298 (2.3%) without (hazard ratio [HR], 9.2; 95% confidence interval [CI], 3.9-21.8; P<0.0001). Nine patients (8.9%) with LGE compared with 6 (2.0%) without (HR, 4.9; 95% CI, 1.8-13.5; P=0.002) died suddenly, whereas 10 patients (9.9%) with LGE compared with 1 patient (0.3%) without (HR, 34.8; 95% CI, 4.6-266.6; P<0.001) had aborted SCD. After adjustment, LGE predicted the composite end point (HR, 9.3; 95% CI, 3.9 22.3; P<0.0001), SCD (HR, 4.8; 95% CI, 1.7-13.8; P=0.003), and aborted SCD (HR, 35.9; 95% CI, 4.8-271.4; P<0.001). Estimated HRs for the primary end point for patients with an LGE extent of 0% to 2.5%, 2.5% to 5%, and >5% compared with those without LGE were 10.6 (95% CI, 3.9-29.4), 4.9 (95% CI, 1.3-18.9), and 11.8 (95% CI, 4.3-32.3), respectively. CONCLUSIONS: Midwall LGE identifies a group of patients with dilated cardiomyopathy and an LVEF >=40% at increased risk of SCD and low risk of nonsudden death who may benefit from implantable cardioverter defibrillator implantation. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00930735. PMID- 28351903 TI - Diaphragm Muscle Thinning in Subjects Receiving Mechanical Ventilation and Its Effect on Extubation. AB - BACKGROUND: Diaphragm muscle weakness and atrophy are consequences of prolonged mechanical ventilation. Our purpose was to determine whether thickness of the diaphragm (TDI) changes over time after intubation and whether the degree of change affects clinical outcome. METHODS: For this prospective, longitudinal observational study, we identified subjects who required mechanical ventilation and measured their TDI by ultrasonography. TDI was measured at baseline and repeated 72 h later and then weekly until the subject was either liberated from mechanical ventilation, was referred for tracheostomy, or died. The analysis was designed to determine whether baseline TDI and change in TDI affect extubation outcome. RESULTS: Of the 57 subjects who underwent both diaphragm measurements at 72 h, 16 died, 33 were extubated, and 8 underwent tracheostomy. Only 14 subjects received mechanical ventilation for 1 week, and 2 subjects received mechanical ventilation for 2 and 3 weeks. Females had significantly thinner baseline TDI (P = .008). At 72 h, TDI had decreased in 84% of subjects. We found no significant association between the rate of thinning and sex (P = .68), diagnosis of COPD (P = .36), current smoking (P = .85), or pleural effusion (P = .83). Lower baseline TDI was associated with higher likelihood of extubation: 12.5% higher for every 0.01-cm decrease in TDI (hazard ratio 0.875, 95% CI 0.80-0.96, P = .003). For every 0.01-cm decrease in TDI at 72 h, the likelihood of extubation increased by 17% (hazard ratio 0.83, 95% CI 0.70-0.99, P = .041). CONCLUSIONS: Although most of the subjects showed evidence of diaphragm thinning, we were unable to find a correlation with outcome of extubation failure. In fact, the thinner the diaphragm at baseline and the greater the extent of diaphragm thinning at 72 h, the greater the likelihood of extubation. Thickening ratio or other measurement may be a more reliable indicator of diaphragm dysfunction and should be explored. PMID- 28351904 TI - Evaluation of the Prevalence and Effectiveness of Education on Metered-Dose Inhaler Technique. AB - BACKGROUND: The objectives of this study were: (1) to assess the prevalence of and types of education methods provided to participants who use a metered-dose inhaler (MDI), (2) to determine the prevalence of MDI misuse in adults using objective and subjective assessments, and (3) to determine whether any associations exist between the education method and the participant's ability to properly use an MDI. METHODS: Adult participants who had a current or previous history of MDI use were recruited from retail pharmacies and physician offices in Laurens County, South Carolina. Exclusion criteria included the use of an MDI spacer, inability to speak/understand English, or current acute respiratory illness. Participants completed a survey regarding inhaler use and previous education, a subjective checklist assessment by demonstrating use of an MDI, and an objective assessment by using the Aerosol Inhalation Monitor (AIM). RESULTS: Of 100 participants, 25% reported never having received education about inhaler technique, and 94% were found to have insufficient MDI technique. No association between the method of education and successful MDI technique with the AIM was identified (P = .31). Participants were less likely to correctly use the AIM if they missed >3 steps in the subjective assessment. (P = .032). CONCLUSIONS: Although most participants received inhaler education, inhaler misuse was very common. No associations were found regarding method of education and proper inhaler technique. PMID- 28351905 TI - Comparison of Cisatracurium Versus Atracurium in Early ARDS. AB - BACKGROUND: Administration of cisatracurium in severe ARDS decreases in-hospital mortality. Whether clinical outcomes are cisatracurium-specific or related with all neuromuscular blockers is unknown. This study aimed to compare outcomes in severe ARDS patients treated with cisatracurium versus atracurium. METHODS: Patients admitted in ICUs with a diagnosis of severe ARDS and treated with neuromuscular blocking agents within 72 h of diagnosis were included. Subjects treated with cisatracurium versus atracurium were compared. The primary outcome was improvement in oxygenation, defined as the difference of PaO2 /FIO2 at 72 h post-initiation of neuromuscular blocking agents. Secondary outcomes were ventilator-free days at day 28, ICU and hospital lengths of stay, and hospital mortality. RESULTS: Seventy-six subjects with ARDS were included in the study. Eighteen subjects (24%) were treated with atracurium, whereas 58 (76%) were treated with cisatracurium. Equivalent dosages of sedation and analgesia as well as use of brain function monitoring technology were similar between both groups. There were no differences in clinical outcomes. Specifically, improvement of PaO2 /FIO2 was a median (interquartile range [IQR]) of 65 (25-162) in the atracurium group and 66 (IQR 16-147) in the cisatracurium group (P = .65). Ventilator-free days at day 28 were 13 d (IQR 0-22 d) and 15 d (IQR 8-21 d) in the atracurium and cisatracurium groups, respectively (P = .72). ICU length or stay was 18 d (IQR 8 34 d) in the atracurium group and 15 d (IQR 9-22 d) in the cisatracurium group (P = .34). In-hospital mortality was 50% for the atracurium population and 62% for the cisatracurium group (P = .42) CONCLUSIONS: Among subjects with early severe ARDS, the utilization of atracurium versus cisatracurium within 72 h of admission was not associated with significant differences in clinical outcomes. PMID- 28351906 TI - Junior doctor who lacked basic knowledge and skills is struck off. PMID- 28351908 TI - Unraveling the Significance of Abnormal Blood Pressure Responses During Dobutamine Stress Echocardiography. PMID- 28351907 TI - Frequency, Predictors, and Implications of Abnormal Blood Pressure Responses During Dobutamine Stress Echocardiography. AB - BACKGROUND: It is not known whether abnormal blood pressure (BP) responses during dobutamine stress echocardiography (DSE) are associated with abnormal test results, nor if such results indicate obstructive coronary artery disease (CAD). We sought to define the frequency of abnormal BP responses during DSE and their impact on accuracy of test results. METHODS AND RESULTS: We studied 21 949 patients who underwent DSE at Mayo Clinic, Rochester, MN, grouped by peak systolic BP achieved during the test. We also analyzed a subgroup who underwent coronary angiography within 30 days after positive DSE. The positive predictive value of DSE was calculated for each BP group. Patients with hypertensive response (n=1905; 9%) were more likely to have positive DSE than those with normal (n=19 770; 90%) or hypotensive (n=274; 1%) BP responses (32% versus 21% versus 23%, respectively; P<0.0001). Angiography, performed in 1126 patients, showed obstructive CAD (>=50% stenosis) in 814 patients and severe CAD (>=70% stenosis) in 708 patients. Positive predictive value of DSE was similar for patients who had hypertensive and normal BP responses (69% versus 73%; P=0.3), considering 50% stenosis cut point. The proportion of severe CAD (>=70% stenosis) was lower in patients who had hypertensive response compared with those who had normal BP response (54% versus 65%; P=0.005). CONCLUSIONS: Patients with hypertensive response during DSE are more likely to have stress-induced myocardial ischemia compared with those with normal or hypotensive BP responses but are not more likely to have false-positive DSE results. They are, however, less likely to have higher grade or multivessel CAD. PMID- 28351909 TI - Stomatal Closure, Basal Leaf Embolism, and Shedding Protect the Hydraulic Integrity of Grape Stems. AB - The time scale of stomatal closure and xylem cavitation during plant dehydration, as well as the fate of embolized organs, are under debate, largely due to methodological limitations in the evaluation of embolism. While some argue that complete stomatal closure precedes the occurrence of embolism, others believe that the two are contemporaneous processes that are accompanied by daily xylem refilling. Here, we utilize an optical light transmission method to continuously monitor xylem cavitation in leaves of dehydrating grapevine (Vitis vinifera) in concert with stomatal conductance and stem and petiole hydraulic measurements. Magnetic resonance imaging was used to continuously monitor xylem cavitation and flow rates in the stem of an intact vine during 10 d of dehydration. The results showed that complete stomatal closure preceded the appearance of embolism in the leaves and the stem by several days. Basal leaves were more vulnerable to xylem embolism than apical leaves and, once embolized, were shed, thereby preventing further water loss and protecting the hydraulic integrity of younger leaves and the stem. As a result, embolism in the stem was minimal even when drought led to complete leaf shedding. These findings suggest that grapevine avoids xylem embolism rather than tolerates it. PMID- 28351911 TI - Fern Stomatal Responses to ABA and CO2 Depend on Species and Growth Conditions. AB - Changing atmospheric CO2 levels, climate, and air humidity affect plant gas exchange that is controlled by stomata, small pores on plant leaves and stems formed by guard cells. Evolution has shaped the morphology and regulatory mechanisms governing stomatal movements to correspond to the needs of various land plant groups over the past 400 million years. Stomata close in response to the plant hormone abscisic acid (ABA), elevated CO2 concentration, and reduced air humidity. Whether the active regulatory mechanisms that control stomatal closure in response to these stimuli are present already in mosses, the oldest plant group with stomata, or were acquired more recently in angiosperms remains controversial. It has been suggested that the stomata of the basal vascular plants, such as ferns and lycophytes, close solely hydropassively. On the other hand, active stomatal closure in response to ABA and CO2 was found in several moss, lycophyte, and fern species. Here, we show that the stomata of two temperate fern species respond to ABA and CO2 and that an active mechanism of stomatal regulation in response to reduced air humidity is present in some ferns. Importantly, fern stomatal responses depend on growth conditions. The data indicate that the stomatal behavior of ferns is more complex than anticipated before, and active stomatal regulation is present in some ferns and has possibly been lost in others. Further analysis that takes into account fern species, life history, evolutionary age, and growth conditions is required to gain insight into the evolution of land plant stomatal responses. PMID- 28351910 TI - Acclimation to High CO2 Requires the omega Subunit of the RNA Polymerase in Synechocystis. AB - Inactivation of the nonessential omega-subunit of the RNA polymerase core in the DeltarpoZ strain of the model cyanobacterium Synechocystis sp. PCC 6803 leads to a unique high-CO2-sensitive phenotype. Supplementing air in the growth chamber with 30 mL L-1 (3%) CO2 accelerated the growth rate of the control strain (CS) 4 fold, whereas DeltarpoZ did not grow faster than under ambient air. The slow growth of DeltarpoZ during the first days in high CO2 was due to the inability of the mutant cells to adjust photosynthesis to high CO2 The light-saturated photosynthetic activity of DeltarpoZ in high CO2 was only half of that measured in CS, Rubisco content was one-third lower, and cells of DeltarpoZ were not able to increase light-harvesting phycobilisome antenna like CS upon high-CO2 treatment. In addition, altered structural and functional organization of photosystem I and photosystem II were detected in the DeltarpoZ strain compared with CS when cells were grown in high CO2 but not in ambient air. Moreover, respiration of DeltarpoZ did not acclimate to high CO2 Unlike the photosynthetic complexes, the RNA polymerase complex and ribosomes were produced in high CO2 similarly as in CS Our results indicate that the deletion of the omega-subunit specifically affects photosynthesis and respiration, but transcription and translation remain active. Thus, the specific effect of the omega-subunit on photosynthesis but not on all household processes suggests that the omega-subunit might have a regulatory function in cyanobacteria. PMID- 28351913 TI - MANAGEMENT OF ENDOCRINE DISEASE: Quality of life tools for the management of pituitary disease. AB - BACKGROUND: In the last few years, quality of life (QoL) has become an outcome measure in patients with pituitary diseases. OBJECTIVE: To describe the available data on QoL impairment evaluated with questionnaires in patients with pituitary diseases. DESIGN: Critical review of the pertinent literature and pragmatic discussion of available information. METHODS: Selection of relevant literature from PubMed and WOK, especially from the last 5 years and comprehensive analysis. RESULTS: QoL is impaired in all pituitary diseases, mostly in acromegaly and Cushing's disease (similar to other causes of Cushing's syndrome), but also in non-functioning pituitary adenomas and prolactinomas, especially in the active phase of the disease. Nevertheless, even after endocrine 'cure', scores tend to be below normative values, indicative of residual morbidity after hormonal control. The presence of hypopituitarism worsens subjective QoL perception, which can improve after optimal substitution therapy, including recombinant human growth hormone, when indicated. CONCLUSIONS: To improve the long-term outcome of pituitary patients, helping them to attain the best possible health, it appears desirable to include subjective aspects captured when evaluating QoL, so that the affected dimensions are identified and if relevant treated. Additionally, being aware that treatment outcome may not always mean complete normalisation of physical and mental issues related to QoL can be a first step to adaptation and conforming to this new status. PMID- 28351912 TI - KNOX Protein OSH15 Induces Grain Shattering by Repressing Lignin Biosynthesis Genes. AB - Seed shattering is an agronomically important trait. Two major domestication factors are responsible for this: qSH1 and SH5. Whereas qSH1 functions in cell differentiation in the abscission zone (AZ), a major role of SH5 is the repression of lignin deposition. We have determined that a KNOX protein, OSH15, also controls seed shattering. Knockdown mutations of OSH15 showed reduced seed shattering phenotypes. Coimmunoprecipitation experiments revealed that OSH15 interacts with SH5 and qSH1, two proteins in the BELL homeobox family. In transgenic plants carrying the OSH15 promoter-GUS reporter construct, the reporter gene was preferentially expressed in the AZ during young spikelet development. The RNA in situ hybridization experiment also showed that OSH15 messenger RNAs were abundant in the AZ during spikelet development. Analyses of osh15 SH5-D double mutants showed that SH5 could not increase the degree of seed shattering when OSH15 was absent, indicating that SH5 functions together with OSH15. In addition to the seed-shattering phenotype, osh15 mutants displayed dwarfism and accumulated a higher amount of lignin in internodes due to increased expression of the genes involved in lignin biosynthesis. Knockout mutations of CAD2, which encodes an enzyme for the last step in the monolignol biosynthesis pathway, caused an easy seed-shattering phenotype by reducing lignin deposition in the AZ This indicated that the lignin level is an important determinant of seed shattering in rice (Oryza sativa). Chromatin immunoprecipitation assays demonstrated that both OSH15 and SH5 interact directly with CAD2 chromatin. We conclude that OSH15 and SH5 form a dimer that enhances seed shattering by directly inhibiting lignin biosynthesis genes. PMID- 28351914 TI - The N-Acetylmuramic Acid 6-Phosphate Phosphatase MupP Completes the Pseudomonas Peptidoglycan Recycling Pathway Leading to Intrinsic Fosfomycin Resistance. AB - Bacterial cells are encased in and stabilized by a netlike peptidoglycan (PGN) cell wall that undergoes turnover during bacterial growth. PGN turnover fragments are frequently salvaged by the cells via a pathway referred to as PGN recycling. Two different routes for the recycling of the cell wall sugar N-acetylmuramic acid (MurNAc) have been recognized in bacteria. In Escherichia coli and related enterobacteria, as well as in most Gram-positive bacteria, MurNAc is recovered via a catabolic route requiring a MurNAc 6-phosphate etherase (MurQ in E. coli) enzyme. However, many Gram-negative bacteria, including Pseudomonas species, lack a MurQ ortholog and use an alternative, anabolic recycling route that bypasses the de novo biosynthesis of uridyldiphosphate (UDP)-MurNAc, the first committed precursor of PGN. Bacteria featuring the latter pathway become intrinsically resistant to the antibiotic fosfomycin, which targets the de novo biosynthesis of UDP-MurNAc. We report here the identification and characterization of a phosphatase enzyme, named MupP, that had been predicted to complete the anabolic recycling pathway of Pseudomonas species but has remained unknown so far. It belongs to the large haloacid dehalogenase family of phosphatases and specifically converts MurNAc 6-phosphate to MurNAc. A DeltamupP mutant of Pseudomonas putida was highly susceptible to fosfomycin, accumulated large amounts of MurNAc 6-phosphate, and showed lower levels of UDP-MurNAc than wild type cells, altogether consistent with a role for MupP in the anabolic PGN recycling route and as a determinant of intrinsic resistance to fosfomycin.IMPORTANCE Many Gram-negative bacteria, but not E. coli, make use of a cell wall salvage pathway that contributes to the pool of UDP-MurNAc, the first committed precursor of cell wall synthesis in bacteria. This salvage pathway is of particular interest because it confers intrinsic resistance to the antibiotic fosfomycin, which blocks de novo UDP-MurNAc biosynthesis. Here we identified and characterized a previously missing enzyme within the salvage pathway, the MurNAc 6-phosphate phosphatase MupP of P. putida MupP, together with the other enzymes of the anabolic recycling pathway, AnmK, AmgK, and MurU, yields UDP-MurNAc, renders bacteria intrinsically resistant to fosfomycin, and thus may serve as a novel drug target for antimicrobial therapy. PMID- 28351915 TI - Comparison of Standard Culture-Based Method to Culture-Independent Method for Evaluation of Hygiene Effects on the Hand Microbiome. AB - Hands play a critical role in the transmission of microbiota on one's own body, between individuals, and on environmental surfaces. Effectively measuring the composition of the hand microbiome is important to hand hygiene science, which has implications for human health. Hand hygiene products are evaluated using standard culture-based methods, but standard test methods for culture-independent microbiome characterization are lacking. We sampled the hands of 50 participants using swab-based and glove-based methods prior to and following four hand hygiene treatments (using a nonantimicrobial hand wash, alcohol-based hand sanitizer [ABHS], a 70% ethanol solution, or tap water). We compared results among culture plate counts, 16S rRNA gene sequencing of DNA extracted directly from hands, and sequencing of DNA extracted from culture plates. Glove-based sampling yielded higher numbers of unique operational taxonomic units (OTUs) but had less diversity in bacterial community composition than swab-based sampling. We detected treatment-induced changes in diversity only by using swab-based samples (P < 0.001); we were unable to detect changes with glove-based samples. Bacterial cell counts significantly decreased with use of the ABHS (P < 0.05) and ethanol control (P < 0.05). Skin hydration at baseline correlated with bacterial abundances, bacterial community composition, pH, and redness across subjects. The importance of the method choice was substantial. These findings are important to ensure improvement of hand hygiene industry methods and for future hand microbiome studies. On the basis of our results and previously published studies, we propose recommendations for best practices in hand microbiome research.IMPORTANCE The hand microbiome is a critical area of research for diverse fields, such as public health and forensics. The suitability of culture independent methods for assessing effects of hygiene products on microbiota has not been demonstrated. This is the first controlled laboratory clinical hand study to have compared traditional hand hygiene test methods with newer culture independent characterization methods typically used by skin microbiologists. This study resulted in recommendations for hand hygiene product testing, development of methods, and future hand skin microbiome research. It also demonstrated the importance of inclusion of skin physiological metadata in skin microbiome research, which is atypical for skin microbiome studies. PMID- 28351916 TI - Identification of MupP as a New Peptidoglycan Recycling Factor and Antibiotic Resistance Determinant in Pseudomonas aeruginosa. AB - Peptidoglycan (PG) is an essential cross-linked polymer that surrounds most bacterial cells to prevent osmotic rupture of the cytoplasmic membrane. Its synthesis relies on penicillin-binding proteins, the targets of beta-lactam antibiotics. Many Gram-negative bacteria, including the opportunistic pathogen Pseudomonas aeruginosa, are resistant to beta-lactams because of a chromosomally encoded beta-lactamase called AmpC. In P. aeruginosa, expression of the ampC gene is tightly regulated and its induction is linked to cell wall stress. We reasoned that a reporter gene fusion to the ampC promoter would allow us to identify mutants defective in maintaining cell wall homeostasis and thereby uncover new factors involved in the process. A library of transposon-mutagenized P. aeruginosa was therefore screened for mutants with elevated ampC promoter activity. As an indication that the screen was working as expected, mutants with transposons disrupting the dacB gene were isolated. Defects in DacB have previously been implicated in ampC induction and clinical resistance to beta lactam antibiotics. The screen also uncovered murU and PA3172 mutants that, upon further characterization, displayed nearly identical drug resistance and sensitivity profiles. We present genetic evidence that PA3172, renamed mupP, encodes the missing phosphatase predicted to function in the MurU PG recycling pathway that is widely distributed among Gram-negative bacteria.IMPORTANCE The cell wall biogenesis pathway is the target of many of our best antibiotics, including penicillin and related beta-lactam drugs. Resistance to these therapies is on the rise, particularly among Gram-negative species like Pseudomonas aeruginosa, a problematic opportunistic pathogen. To better understand how these organisms resist cell wall-targeting antibiotics, we screened for P. aeruginosa mutants defective in maintaining cell wall homeostasis. The screen identified a new factor, called MupP, involved in the recycling of cell wall turnover products. Characterization of MupP and other components of the pathway revealed that cell wall recycling plays important roles in both the resistance and the sensitivity of P. aeruginosa to cell wall-targeting antibiotics. PMID- 28351917 TI - RNA Sequencing Identifies New RNase III Cleavage Sites in Escherichia coli and Reveals Increased Regulation of mRNA. AB - Ribonucleases facilitate rapid turnover of RNA, providing cells with another mechanism to adjust transcript and protein levels in response to environmental conditions. While many examples have been documented, a comprehensive list of RNase targets is not available. To address this knowledge gap, we compared levels of RNA sequencing coverage of Escherichia coli and a corresponding RNase III mutant to expand the list of known RNase III targets. RNase III is a widespread endoribonuclease that binds and cleaves double-stranded RNA in many critical transcripts. RNase III cleavage at novel sites found in aceEF, proP, tnaC, dctA, pheM, sdhC, yhhQ, glpT, aceK, and gluQ accelerated RNA decay, consistent with previously described targets wherein RNase III cleavage initiates rapid degradation of secondary messages by other RNases. In contrast, cleavage at three novel sites in the ahpF, pflB, and yajQ transcripts led to stabilized secondary transcripts. Two other novel sites in hisL and pheM overlapped with transcriptional attenuators that likely serve to ensure turnover of these highly structured RNAs. Many of the new RNase III target sites are located on transcripts encoding metabolic enzymes. For instance, two novel RNase III sites are located within transcripts encoding enzymes near a key metabolic node connecting glycolysis and the tricarboxylic acid (TCA) cycle. Pyruvate dehydrogenase activity was increased in an rnc deletion mutant compared to the wild-type (WT) strain in early stationary phase, confirming the novel link between RNA turnover and regulation of pathway activity. Identification of these novel sites suggests that mRNA turnover may be an underappreciated mode of regulating metabolism.IMPORTANCE The concerted action and overlapping functions of endoribonucleases, exoribonucleases, and RNA processing enzymes complicate the study of global RNA turnover and recycling of specific transcripts. More information about RNase specificity and activity is needed to make predictions of transcript half-life and to design synthetic transcripts with optimal stability. RNase III does not have a conserved target sequence but instead recognizes RNA secondary structure. Prior to this study, only a few RNase III target sites in E. coli were known, so we used RNA sequencing to provide a more comprehensive list of cleavage sites and to examine the impact of RNase III on transcript degradation. With this added information on how RNase III participates in transcript regulation and recycling, a more complete picture of RNA turnover can be developed for E. coli Similar approaches could be used to augment our understanding of RNA turnover in other bacteria. PMID- 28351918 TI - A Novel Mechanism for Protein Delivery by the Type 3 Secretion System for Extracellularly Secreted Proteins. AB - The type 3 secretion system (T3SS) is essential for bacterial virulence through delivering effector proteins directly into the host cytosol. Here, we identified an alternative delivery mechanism of virulence factors mediated by the T3SS, which consists of the association of extracellularly secreted proteins from bacteria with the T3SS to gain access to the host cytosol. Both EspC, a protein secreted as an enteropathogenic Escherichia coli (EPEC) autotransporter, and YopH, a protein detected on the surface of Yersinia, require a functional T3SS for host cell internalization; here we provide biophysical and molecular evidence to support the concept of the EspC translocation mechanism, which requires (i) an interaction between EspA and an EspC middle segment, (ii) an EspC translocation motif (21 residues that are shared with the YopH translocation motif), (iii) increases in the association and dissociation rates of EspC mediated by EspA interacting with EspD, and (iv) an interaction of EspC with the EspD/EspB translocon pore. Interestingly, this novel mechanism does not exclude the injection model (i.e., EspF) operating through the T3SS conduit; therefore, T3SS can be functioning as an internal conduit or as an external railway, which can be used to reach the translocator pore, and this mechanism appears to be conserved among different T3SS-dependent pathogens.IMPORTANCE The type 3 secretion system is essential for injection of virulence factors, which are delivered directly into the cytosol of the host cells for usurping and subverting host processes. Recent studies have shown that these effectors proteins indeed travel inside an "injectisome" conduit through a single step of translocation by connecting the bacterium and host cell cytoplasms. However, all findings are not compatible with this model. For example, both YopH, a protein detected on the surface of Yersinia, and EspC, an autotransporter protein secreted by enteropathogenic E. coli, require a functional T3SS for host cell translocation. Both proteins have an intermediate extracellular step before their T3SS-dependent translocation. Here, we show an alternative delivery mechanism for these extracellularly secreted virulence factors that are then incorporated into the T3SS to enter the cells; this novel mechanism coexists with but diverges from the canonical injection model that involves the passage of the protein inside the injectisome. PMID- 28351920 TI - SpxA1 and SpxA2 Act Coordinately To Fine-Tune Stress Responses and Virulence in Streptococcus pyogenes. AB - SpxA is a unique transcriptional regulator highly conserved among members of the phylum Firmicutes that binds RNA polymerase and can act as an antiactivator. Why some Firmicutes members have two highly similar SpxA paralogs is not understood. Here, we show that the SpxA paralogs of the pathogen Streptococcus pyogenes, SpxA1 and SpxA2, act coordinately to regulate virulence by fine-tuning toxin expression and stress resistance. Construction and analysis of mutants revealed that SpxA1- mutants were defective for growth under aerobic conditions, while SpxA2- mutants had severely attenuated responses to multiple stresses, including thermal and oxidative stresses. SpxA1- mutants had enhanced resistance to the cationic antimicrobial molecule polymyxin B, while SpxA2- mutants were more sensitive. In a murine model of soft tissue infection, a SpxA1- mutant was highly attenuated. In contrast, the highly stress-sensitive SpxA2- mutant was hypervirulent, exhibiting more extensive tissue damage and a greater bacterial burden than the wild-type strain. SpxA1- attenuation was associated with reduced expression of several toxins, including the SpeB cysteine protease. In contrast, SpxA2- hypervirulence correlated with toxin overexpression and could be suppressed to wild-type levels by deletion of speB These data show that SpxA1 and SpxA2 have opposing roles in virulence and stress resistance, suggesting that they act coordinately to fine-tune toxin expression in response to stress. SpxA2- hypervirulence also shows that stress resistance is not always essential for S. pyogenes pathogenesis in soft tissue.IMPORTANCE For many pathogens, it is generally assumed that stress resistance is essential for pathogenesis. For Streptococcus pyogenes, environmental stress is also used as a signal to alter toxin expression. The amount of stress likely informs the bacterium of the strength of the host's defense response, allowing it to adjust its toxin expression to produce the ideal amount of tissue damage, balancing between too little damage, which will result in its elimination, and too much damage, which will debilitate the host. Here we identify components of a genetic circuit involved in stress resistance and toxin expression that has a fine-tuning function in tissue damage. The circuit consists of two versions of the protein SpxA that regulate transcription and are highly similar but have opposing effects on the severity of soft tissue damage. These results will help us understand how virulence is fine-tuned in other pathogens that have two SpxA proteins. PMID- 28351919 TI - Contribution of the Purinergic Receptor P2X7 to Development of Lung Immunopathology during Influenza Virus Infection. AB - An exacerbated immune response is one of the main causes of influenza-induced lung damage during infection. The molecular mechanisms regulating the fate of the initial immune response to infection, either as a protective response or as detrimental immunopathology, are not well understood. The purinergic receptor P2X7 is an ionotropic nucleotide-gated ion channel receptor expressed on immune cells that has been implicated in induction and maintenance of excessive inflammation. Here, we analyze the role of this receptor in a mouse model of influenza virus infection using a receptor knockout (KO) mouse strain. Our results demonstrate that the absence of the P2X7 receptor results in a better outcome to influenza virus infection characterized by reduced weight loss and increased survival upon experimental influenza challenge compared to wild-type mice. This effect was not virus strain specific. Overall lung pathology and apoptosis were reduced in virus-infected KO mice. Production of proinflammatory cytokines and chemokines such as interleukin-10 (IL-10), gamma interferon (IFN gamma), and CC chemokine ligand 2 (CCL2) was also reduced in the lungs of the infected KO mice. Infiltration of neutrophils and depletion of CD11b+ macrophages, characteristic of severe influenza virus infection in mice, were lower in the KO animals. Together, these results demonstrate that activation of the P2X7 receptor is involved in the exacerbated immune response observed during influenza virus infection.IMPORTANCE A hallmark of influenza virus infection is the development of lung pathology induced by an exacerbated immune response. The mechanisms shared by the antiviral host defense required for viral clearance and those required for development of immunopathology are not clearly understood. Purinergic receptors, and in particular the purinergic receptor P2X7 (P2X7r), are involved in activation of the immune response. We used mice lacking the P2X7r (P2X7r KO mice) to better understand the mechanisms that lead to development of lung pathology during influenza virus infection. In our studies, we observed that P2X7r KO mice developed less lung immunopathology and had better survival than the wild-type mice. These results implicate P2X7r in the induction of an exacerbated local immune response to influenza virus and help us to better understand the mechanisms leading to the lung immunopathology observed during severe viral infections. PMID- 28351921 TI - CdiA Effectors Use Modular Receptor-Binding Domains To Recognize Target Bacteria. AB - Contact-dependent growth inhibition (CDI) systems encode CdiA effectors, which bind to specific receptors on neighboring bacteria and deliver C-terminal toxin domains to suppress target cell growth. Two classes of CdiA effectors that bind distinct cell surface receptors have been identified, but the molecular basis of receptor specificity is not understood. Alignment of BamA-specific CdiAEC93 from Escherichia coli EC93 and OmpC-specific CdiAEC536 from E. coli 536 suggests that the receptor-binding domain resides within a central region that varies between the two effectors. In support of this hypothesis, we find that CdiAEC93 fragments containing residues Arg1358 to Phe1646 bind specifically to purified BamA. Moreover, chimeric CdiAEC93 that carries the corresponding sequence from CdiAEC536 is endowed with OmpC-binding activity, demonstrating that this region dictates receptor specificity. A survey of E. coli CdiA proteins reveals two additional effector classes, which presumably recognize distinct receptors. Using a genetic approach, we identify the outer membrane nucleoside transporter Tsx as the receptor for a third class of CdiA effectors. Thus, CDI systems exploit multiple outer membrane proteins to identify and engage target cells. These results underscore the modularity of CdiA proteins and suggest that novel effectors can be constructed through genetic recombination to interchange different receptor-binding domains and toxic payloads.IMPORTANCE CdiB/CdiA two partner secretion proteins mediate interbacterial competition through the delivery of polymorphic toxin domains. This process, known as contact-dependent growth inhibition (CDI), requires stable interactions between the CdiA effector protein and specific receptors on the surface of target bacteria. Here, we localize the receptor-binding domain to the central region of E. coli CdiA. Receptor-binding domains vary between CdiA proteins, and E. coli strains collectively encode at least four distinct effector classes. Further, we show that receptor specificity can be altered by exchanging receptor-binding regions, demonstrating the modularity of this domain. We propose that novel CdiA effectors are naturally generated through genetic recombination to interchange different receptor-binding domains and toxin payloads. PMID- 28351922 TI - Mouse Mammary Tumor Virus Signal Peptide Uses a Novel p97-Dependent and Derlin Independent Retrotranslocation Mechanism To Escape Proteasomal Degradation. AB - Multiple pathogens, including viruses and bacteria, manipulate endoplasmic reticulum-associated degradation (ERAD) to avoid the host immune response and promote their replication. The betaretrovirus mouse mammary tumor virus (MMTV) encodes Rem, which is a precursor protein that is cleaved into a 98-amino-acid signal peptide (SP) and a C-terminal protein (Rem-CT). SP uses retrotranslocation for ER membrane extraction and yet avoids ERAD by an unknown mechanism to enter the nucleus and function as a Rev-like protein. To determine how SP escapes ERAD, we used a ubiquitin-activated interaction trap (UBAIT) screen to trap and identify transient protein interactions with SP, including the ERAD-associated p97 ATPase, but not E3 ligases or Derlin proteins linked to retrotranslocation, polyubiquitylation, and proteasomal degradation of extracted proteins. A dominant negative p97 ATPase inhibited both Rem and SP function. Immunoprecipitation experiments indicated that Rem, but not SP, is polyubiquitylated. Using both yeast and mammalian expression systems, linkage of a ubiquitin-like domain (UbL) to SP or Rem induced degradation by the proteasome, whereas SP was stable in the absence of the UbL. ERAD-associated Derlin proteins were not required for SP activity. Together, these results suggested that Rem uses a novel p97-dependent, Derlin-independent retrotranslocation mechanism distinct from other pathogens to avoid SP ubiquitylation and proteasomal degradation.IMPORTANCE Bacterial and viral infections produce pathogen-specific proteins that interfere with host functions, including the immune response. Mouse mammary tumor virus (MMTV) is a model system for studies of human complex retroviruses, such as HIV-1, as well as cancer induction. We have shown that MMTV encodes a regulatory protein, Rem, which is cleaved into an N-terminal signal peptide (SP) and a C-terminal protein (Rem-CT) within the endoplasmic reticulum (ER) membrane. SP function requires ER membrane extraction by retrotranslocation, which is part of a protein quality control system known as ER-associated degradation (ERAD) that is essential to cellular health. Through poorly understood mechanisms, certain pathogen-derived proteins are retrotranslocated but not degraded. We demonstrate here that MMTV SP retrotranslocation from the ER membrane avoids degradation through a unique process involving interaction with cellular p97 ATPase and failure to acquire cellular proteasome-targeting sequences. PMID- 28351923 TI - Differences in Integron Cassette Excision Dynamics Shape a Trade-Off between Evolvability and Genetic Capacitance. AB - Integrons ensure a rapid and "on demand" response to environmental stresses driving bacterial adaptation. They are able to capture, store, and reorder functional gene cassettes due to site-specific recombination catalyzed by their integrase. Integrons can be either sedentary and chromosomally located or mobile when they are associated with transposons and plasmids. They are respectively called sedentary chromosomal integrons (SCIs) and mobile integrons (MIs). MIs are key players in the dissemination of antibiotic resistance genes. Here, we used in silico and in vivo approaches to study cassette excision dynamics in MIs and SCIs. We show that the orientation of cassette arrays relative to replication influences attC site folding and cassette excision by placing the recombinogenic strands of attC sites on either the leading or lagging strand template. We also demonstrate that stability of attC sites and their propensity to form recombinogenic structures also regulate cassette excision. We observe that cassette excision dynamics driven by these factors differ between MIs and SCIs. Cassettes with high excision rates are more commonly found on MIs, which favors their dissemination relative to SCIs. This is especially true for SCIs carried in the Vibrio genus, where maintenance of large cassette arrays and vertical transmission are crucial to serve as a reservoir of adaptive functions. These results expand the repertoire of known processes regulating integron recombination that were previously established and demonstrate that, in terms of cassette dynamics, a subtle trade-off between evolvability and genetic capacitance has been established in bacteria.IMPORTANCE The integron system confers upon bacteria a rapid adaptation capability in changing environments. Specifically, integrons are involved in the continuous emergence of bacteria resistant to almost all antibiotic treatments. The international situation is critical, and in 2050, the annual number of deaths caused by multiresistant bacteria could reach 10 million, exceeding the incidence of deaths related to cancer. It is crucial to increase our understanding of antibiotic resistance dissemination and therefore integron recombination dynamics to find new approaches to cope with the worldwide problem of multiresistance. Here, we studied the dynamics of recombination and dissemination of gene encoding cassettes carried on integrons. By combining in silico and in vivo analyses, we show that cassette excision is highly regulated by replication and by the intrinsic properties of cassette recombination sites. We also demonstrated differences in the dynamics of cassette recombination between mobile and sedentary chromosomal integrons (MIs and SCIs). For MIs, a high cassette recombination rate is favored and timed to conditions when generating diversity (upon which selection can act) allows for a rapid response to environmental conditions and stresses. In contrast, for SCIs, cassette excisions are less frequent, limiting cassette loss and ensuring a large pool of cassettes. We therefore confirm a role of SCIs as reservoirs of adaptive functions and demonstrate that the remarkable adaptive success of integron recombination system is due to its intricate regulation. PMID- 28351924 TI - Plasmodium falciparum Maf1 Confers Survival upon Amino Acid Starvation. AB - The target of rapamycin complex 1 (TORC1) pathway is a highly conserved signaling pathway across eukaryotes that integrates nutrient and stress signals to regulate the cellular growth rate and the transition into and maintenance of dormancy. The majority of the pathway's components, including the central TOR kinase, have been lost in the apicomplexan lineage, and it is unknown how these organisms detect and respond to nutrient starvation in its absence. Plasmodium falciparum encodes a putative ortholog of the RNA polymerase (Pol) III repressor Maf1, which has been demonstrated to modulate Pol III transcription in a TOR-dependent manner in a number of organisms. Here, we investigate the role of P. falciparum Maf1 (PfMaf1) in regulating RNA Pol III expression under conditions of nutrient starvation and other stresses. Using a transposon insertion mutant with an altered Maf1 expression profile, we demonstrated that proper Maf1 expression is necessary for survival of the dormancy-like state induced by prolonged amino acid starvation and is needed for full recovery from other stresses that slow or stall the parasite cell cycle. This Maf1 mutant is defective in the downregulation of pre-tRNA synthesis under nutrient-limiting conditions, indicating that the function of Maf1 as a stress-responsive regulator of structural RNA transcription is conserved in P. falciparum Recent work has demonstrated that parasites carrying artemisinin-resistant K13 alleles display an enhanced ability to recover from drug-induced growth retardation. We show that one such artemisinin-resistant line displays greater regulation of pre-tRNA expression and higher survival upon prolonged amino acid starvation, suggesting that overlapping, PfMaf1-associated pathways may regulate growth recovery from both artemisinin treatment and amino acid starvation.IMPORTANCE Eukaryote organisms sense changes in their environment and integrate this information through signaling pathways to activate response programs to ensure survival. The TOR pathway is a well-studied signaling pathway found throughout eukaryotes that is known to integrate a variety of signals to regulate organismal growth in response to starvation and other stresses. The human malaria parasite Plasmodium falciparum appears to have lost the TOR pathway over the course of evolution, and it is unclear how the parasite modulates its growth in response to starvation and drug treatment. Here, we show that Maf1, a protein regulated by TOR in other eukaryotes, plays an important role in maintaining the parasite's viability in the face of starvation and other forms of stress. This suggests that PfMaf1 is a component of a yet-to-be-described nutrient and stress response pathway. PMID- 28351925 TI - Serum IgG2 and tissue IgG2 plasma cell elevation in orbital IgG4-related disease (IgG4-RD): Potential use in IgG4-RD assessment. AB - AIMS: To determine the role of serum and tissue IgG2 in orbital biopsies with the histological features of IgG4-related disease (IgG4-RD) in comparison with non IgG4-related orbital inflammatory disorders (OID), including autoimmune disorders. METHODS: This is an international (Sheffield, UK, and Singapore) collaborative, retrospective case review of 69 patients (38 from Singapore National Eye Centre and 31 from Royal Hallamshire Hospital, Sheffield) with orbital inflammatory biopsies between 2002 and 2016. Clinical information and histology were reviewed and cases were classified into three groups: Group 1: IgG4-RD orbital inflammation (n=43); Group 2: idiopathic OID (n=12) and Group 3: autoimmune OID (n=14). Serum IgG1, IgG2, IgG3 and IgG4 levels were collated where available and immunohistochemistry (IHC) for tissue IgG2 plasma cells was performed. RESULTS: Dual IHC showed IgG2 plasma cells as a distinct population from IgG4 plasma cells. Significant (twofold) serum IgG2 elevation was noted among IgG4-RD (group 1), idiopathic (group 2) and autoimmune OID (group 3). Similarly, significant elevation of tissue IgG2 plasma cells was also seen among IgG4-RD (group 1), idiopathic and autoimmune OID (groups 2 and 3). CONCLUSIONS: Significant elevations of serum IgG2 and tissue IgG2 plasma cells are present in orbital IgG4-RD in comparison with non-IgG4 orbital inflammation (idiopathic and autoimmune OID), suggesting that IgG2 may play a role in IgG4-RD. A serum IgG2 cut-off >5.3 g/L was found to be 80% sensitive and 91.7% specific for orbital IgG4-RD, with an accuracy of 0.90. Tissue IgG2 and IgG4 subclass reporting may provide additional insight regarding the 'IgG4-RD' pathogenesis. PMID- 28351926 TI - Epiblepharon in congenital glaucoma: case-control study. AB - BACKGROUND/AIMS: To assess the prevalence, clinical features and risk factors of lower lid epiblepharon among patients with congenital glaucoma. METHODS: Cross sectional, observational, case-control study. Patients diagnosed with congenital glaucoma between August 1999 and November 2014 were included. Demographic and clinical characteristic data were collected. Age-matched normal controls were recruited form general population. Main outcome measures were the prevalence, laterality and factors associated with epiblepharon in patients with congenital glaucoma. RESULTS: The prevalence of lower lid epiblepharon was higher in patients with congenital glaucoma compared with control group (40.7% vs 13.3%, p<0.001). Unilateral epiblepharon was only shown in patients with congenital glaucoma (47.8% vs 0.0%, p<0.001). Multivariate analysis revealed that high intraocular pressure (IOP) at glaucoma diagnosis (OR=1.122), presence of corneal erosion (OR=82.664) and presence of buphthalmos (OR=12.600) were significantly associated with the presence of lower lid epiblepharon. In addition, unilateral epiblepharon was associated with unilateral buphthalmos and unilateral glaucoma (OR of 49.849 and 7.338, respectively). CONCLUSIONS: The prevalence of epiblepharon was higher in patients with congenital glaucoma compared with age matched general population. In patients with congenital glaucoma, epiblepharon was associated with corneal erosions. In addition, buphthalmos and initial high IOP were associated with the development of lower lid epiblepharon. More importantly, unilateral buphthalmos was also significantly associated with unilateral epiblepharon. Therefore, in patients with congenital glaucoma, presence of epiblepharon should be evaluated especially in patients accompanying buphthalmos or corneal erosion. PMID- 28351927 TI - Factors influencing intraocular pressure, corneal thickness and corneal biomechanics after congenital cataract surgery. AB - AIMS: This study aims to compare intraocular pressure (IOP), central corneal thickness (CCT) and corneal biomechanics among patients with aphakia, patients with primary and secondary pseudophakia and matched controls following congenital cataract surgery and to investigate the factors influencing these variables. METHODS: This study included 36 aphakic eyes, 47 primary pseudophakic eyes and 30 secondary pseudophakic eyes. Thirty-four normal eyes of matched volunteers were recruited for comparisons. Postoperative IOP measured with a Goldmann applanation tonometer (IOPGAT), CCT, corneal hysteresis (CH), corneal resistance factor (CRF) and cornea-compensated IOP (IOPCC) were compared among the groups. Univariate analyses and multiple linear regression analyses were used to investigate the influences of independent factors on IOPGAT, CCT, CH, CRF and IOPCC, considering all the operated eyes as one group. RESULTS: IOPGAT was 12.5+/-0.92, 14.7+/-1.9, 13.4+/-2.3 and 15.7+/-2.0 mm Hg in normal, aphakic, primary pseudophakic and secondary pseudophakic eyes, respectively (p<0.001). CCT was 559.5+/-42.7, 628.0+/-61.7, 566.8+/-35.3 and 585.2+/-41.1 um, respectively (p<0.001). CH was 10.87+/-2.47, 10.42+/-2.20, 11.84+/-2.13 and 9.74+/-1.94 mm Hg, respectively (p=0.019). IOPCC was 15.91+/-3.74, 18.40+/-4.35, 14.58+/-4.36 and 19.05+/-4.54 mm Hg, respectively (p<0.001). There was no significant difference in CRF among the groups (p=0.06). Regression analyses revealed that the type of operation was significantly associated with IOPGAT (p=0.04), CCT (p<0.001) and CH (p=0.006). CONCLUSIONS: IOPGAT, CCT, CH and IOPCC were significantly different in treated eyes compared with normal eyes after congenital cataract surgery. These variables were primarily affected by the type of surgery. Primary intraocular lens implantation preserved corneal structure and function of the anterior chamber angle. PMID- 28351928 TI - Ribociclib (LEE011): Mechanism of Action and Clinical Impact of This Selective Cyclin-Dependent Kinase 4/6 Inhibitor in Various Solid Tumors. AB - The cyclin D-cyclin-dependent kinase (CDK) 4/6-p16-retinoblastoma (Rb) pathway is commonly disrupted in cancer, leading to abnormal cell proliferation. Therapeutics targeting this pathway have demonstrated antitumor effects in preclinical and clinical studies. Ribociclib is a selective, orally bioavailable inhibitor of CDK4 and CDK6, which received FDA approval in March 2017 and is set to enter the treatment landscape alongside other CDK4/6 inhibitors, including palbociclib and abemaciclib. Here, we describe the mechanism of action of ribociclib and review preclinical and clinical data from phase I, II, and III trials of ribociclib across different tumor types, within the context of other selective CDK4/6 inhibitors. The pharmacokinetics, pharmacodynamics, safety, tolerability, and clinical responses with ribociclib as a single agent or in combination with other therapies are discussed, and an overview of the broad portfolio of ongoing clinical trials with ribociclib across a wide range of indications is presented. On the basis of the available data, ribociclib has a manageable tolerability profile and therapeutic potential for a variety of cancer types. Its high selectivity makes it an important partner drug for other targeted therapies, and it has been shown to enhance the clinical activity of existing anticancer therapies and delay the development of treatment resistance, without markedly increasing toxicity. Ongoing trials of doublet and triplet targeted therapies containing ribociclib seek to identify optimal CDK4/6-based targeted combination regimens for various tumor types and advance the field of precision therapeutics in oncology. Clin Cancer Res; 23(13); 3251-62. (c)2017 AACR. PMID- 28351930 TI - Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate. AB - Purpose: Checkpoint inhibitors demonstrate salutary anticancer effects, including long-term remissions. PD-L1 expression/amplification, high mutational burden, and mismatch repair deficiency correlate with response. We have, however, observed a subset of patients who appear to be "hyperprogressors," with a greatly accelerated rate of tumor growth and clinical deterioration compared with pretherapy, which was also recently reported by Institut Gustave Roussy. The current study investigated potential genomic markers associated with "hyperprogression" after immunotherapy.Experimental Design: Consecutive stage IV cancer patients who received immunotherapies (CTLA-4, PD-1/PD-L1 inhibitors or other [investigational] agents) and had their tumor evaluated by next-generation sequencing were analyzed (N = 155). We defined hyperprogression as time-to treatment failure (TTF) <2 months, >50% increase in tumor burden compared with preimmunotherapy imaging, and >2-fold increase in progression pace.Results: Amongst 155 patients, TTF <2 months was seen in all six individuals with MDM2/MDM4 amplification. After anti-PD1/PDL1 monotherapy, four of these patients showed remarkable increases in existing tumor size (55% to 258%), new large masses, and significantly accelerated progression pace (2.3-, 7.1-, 7.2- and 42.3 fold compared with the 2 months before immunotherapy). In multivariate analysis, MDM2/MDM4 and EGFR alterations correlated with TTF <2 months. Two of 10 patients with EGFR alterations were also hyperprogressors (53.6% and 125% increase in tumor size; 35.7- and 41.7-fold increase).Conclusions: Some patients with MDM2 family amplification or EGFR aberrations had poor clinical outcome and significantly increased rate of tumor growth after single-agent checkpoint (PD 1/PD-L1) inhibitors. Genomic profiles may help to identify patients at risk for hyperprogression on immunotherapy. Further investigation is urgently needed. Clin Cancer Res; 23(15); 4242-50. (c)2017 AACR. PMID- 28351929 TI - Genetic Heterogeneity in Therapy-Naive Synchronous Primary Breast Cancers and Their Metastases. AB - Purpose: Paired primary breast cancers and metachronous metastases after adjuvant treatment are reported to differ in their clonal composition and genetic alterations, but it is unclear whether these differences stem from the selective pressures of the metastatic process, the systemic therapies, or both. We sought to define the repertoire of genetic alterations in breast cancer patients with de novo metastatic disease who had not received local or systemic therapy.Experimental Design: Up to two anatomically distinct core biopsies of primary breast cancers and synchronous distant metastases from nine patients who presented with metastatic disease were subjected to high-depth whole-exome sequencing. Mutations, copy number alterations and their cancer cell fractions, and mutation signatures were defined using state-of-the-art bioinformatics methods. All mutations identified were validated with orthogonal methods.Results: Genomic differences were observed between primary and metastatic deposits, with a median of 60% (range 6%-95%) of shared somatic mutations. Although mutations in known driver genes including TP53, PIK3CA, and GATA3 were preferentially clonal in both sites, primary breast cancers and their synchronous metastases displayed spatial intratumor heterogeneity. Likely pathogenic mutations affecting epithelial-to-mesenchymal transition-related genes, including SMAD4, TCF7L2, and TCF4 (ITF2), were found to be restricted to or enriched in the metastatic lesions. Mutational signatures of trunk mutations differed from those of mutations enriched in the primary tumor or the metastasis in six cases.Conclusions: Synchronous primary breast cancers and metastases differ in their repertoire of somatic genetic alterations even in the absence of systemic therapy. Mutational signature shifts might contribute to spatial intratumor genetic heterogeneity. Clin Cancer Res; 23(15); 4402-15. (c)2017 AACR. PMID- 28351931 TI - Antibodies inhibit transmission and aggregation of C9orf72 poly-GA dipeptide repeat proteins. AB - Cell-to-cell transmission of protein aggregates is an emerging theme in neurodegenerative disease. Here, we analyze the dipeptide repeat (DPR) proteins that form neuronal inclusions in patients with hexanucleotide repeat expansion C9orf72, the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Sense and antisense transcripts of the (G4C2)n repeat are translated by repeat-associated non-ATG (RAN) translation in all reading frames into five aggregating DPR proteins. We show that the hydrophobic DPR proteins poly-GA, poly-GP, and poly-PA are transmitted between cells using co-culture assays and cell extracts. Moreover, uptake or expression of poly-GA induces nuclear RNA foci in (G4C2)80-expressing cells and patient fibroblasts, suggesting an unexpected positive feedback loop. Exposure to recombinant poly-GA and cerebellar extracts of C9orf72 patients increases repeat RNA levels and seeds aggregation of all DPR proteins in receiver cells expressing (G4C2)80 Treatment with anti-GA antibodies inhibits intracellular poly-GA aggregation and blocks the seeding activity of C9orf72 brain extracts. Poly-GA directed immunotherapy may thus reduce DPR aggregation and disease progression in C9orf72 ALS/FTD. PMID- 28351932 TI - Seeding and transgenic overexpression of alpha-synuclein triggers dendritic spine pathology in the neocortex. AB - Although misfolded and aggregated alpha-synuclein (alpha-syn) is recognized in the disease progression of synucleinopathies, its role in the impairment of cortical circuitries and synaptic plasticity remains incompletely understood. We investigated how alpha-synuclein accumulation affects synaptic plasticity in the mouse somatosensory cortex using two distinct approaches. Long-term in vivo imaging of apical dendrites was performed in mice overexpressing wild-type human alpha-synuclein. Additionally, intracranial injection of preformed alpha synuclein fibrils was performed to induce cortical alpha-syn pathology. We find that alpha-synuclein overexpressing mice show decreased spine density and abnormalities in spine dynamics in an age-dependent manner. We also provide evidence for the detrimental effects of seeded alpha-synuclein aggregates on dendritic architecture. We observed spine loss as well as dystrophic deformation of dendritic shafts in layer V pyramidal neurons. Our results provide a link to the pathophysiology underlying dementia associated with synucleinopathies and may enable the evaluation of potential drug candidates on dendritic spine pathology in vivo. PMID- 28351933 TI - Cytosolic DNA sensor-initiated innate immune responses in mouse ovarian granulosa cells. AB - Viral infections of the ovary may perturb ovarian functions. However, the mechanisms underlying innate immune responses in the ovary are poorly understood. The present study demonstrates that cytosolic viral DNA sensor signaling initiates the innate immune response in mouse ovarian granulosa cells and affects endocrine function. The cytosolic DNA sensors p204 and cGAS and their common signaling adaptor stimulator of interferon (IFN) genes (STING) were constitutively expressed in granulosa cells. Transfection with VACV70, a synthetic vaccinia virus (VACV) DNA analog, induced the expression of type I interferons (IFNA/B) and major inflammatory cytokines (TNFA and IL6) through IRF3 and NF-kappaB activation respectively. Moreover, several IFN-inducible antiviral proteins, including 2',5'-oligoadenylate synthetase, IFN-stimulating gene 15 and Mx GTPase 1, were also induced by VACV70 transfection. The innate immune responses in granulosa cells were significantly reduced by the transfection of specific small-interfering RNAs targeting p204, cGas or Sting Notably, the VACV70 triggered innate immune responses affected steroidogenesis in vivo and in vitro The data presented in this study describe the mechanism underlying ovarian immune responses to viral infection. PMID- 28351934 TI - Genetic profiling of MYC and BCL2 in diffuse large B-cell lymphoma determines cell-of-origin-specific clinical impact. AB - The clinical significance of MYC and BCL2 genetic alterations in diffuse large B cell lymphoma (DLBCL), apart from translocations, has not been comprehensively investigated using high-resolution genetic assays. In this study, we profiled MYC and BCL2 genetic alterations using next-generation sequencing and high-resolution SNP array in 347 de novo DLBCL cases treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) at the British Columbia Cancer Agency. Cell-of-origin (COO) subtype was determined by Lymph2Cx digital gene expression profiling. We showed that the incidence of MYC/BCL2 genetic alterations and their clinical significance were largely dependent on COO subtypes. It is noteworthy that the presence of BCL2 gain/amplification is significantly associated with poor outcome in activated B-cell-like and BCL2 translocation with poor outcome in germinal center B-cell subtypes, respectively. Both have prognostic significance independent of MYC/BCL2 dual expression and the International Prognostic Index (IPI). Furthermore, the combination of BCL2 genetic alterations with IPI identifies markedly worse prognostic groups within individual COO subtypes. Thus, high-resolution genomic assays identify extremely poor prognostic groups within each COO subtype on the basis of BCL2 genetic status in this large, uniformly R-CHOP-treated population-based cohort of DLBCL. These results suggest COO subtype-specific biomarkers based on BCL2 genetic alterations can be used to risk-stratify patients with DLBCL treated with immunochemotherapy. PMID- 28351935 TI - Bidirectional immune tolerance in nonmyeloablative MHC-mismatched BMT for murine beta-thalassemia. AB - Nonmyeloablative conditioning using total lymphoid irradiation (TLI) and rabbit antithymocyte serum (ATS) (the murine preclinical equivalent of antithymocyte globulin [ATG]) facilitates immune tolerance after bone marrow transplantation (BMT) across major histocompatibility complex (MHC) disparities and may be a useful strategy for nonmalignant disorders. We previously reported that donor effector T-cell function and graft-versus-host disease (GVHD) are regulated via recipient invariant natural killer T-cell (iNKT) interleukin-4-driven expansion of donor Foxp3+ naturally occurring regulatory T cells (Tregs). This occurs via recipient iNKT- and STAT6-dependent expansion of recipient myeloid dendritic cells (MDCs) that induce contact-dependent expansion of donor Treg through PD 1/PD ligand signaling. After TLI/ATS + BMT, Gr-1lowCD11c+ MDCs and Gr 1highCD11cneg myeloid-derived suppressor cells (MDSCs) were enriched in GVHD target organs. We now report that the recovery of both recipient MDSCs (P < .01) and MDCs (P < .01) is significantly increased when the alkylator cyclophosphamide (CTX) is added to TLI/ATS conditioning. In a BALB/c -> B6 lethal GVHD model, adoptive transfer of MDSCs from TLI/ATS/CTX-conditioned recipients is associated with significantly improved GVHD colitis and survival (P < .001), conversion of MDSCs to PD ligand-expressing MDCs, and increased donor naturally occurring Treg recovery (P < .01) compared with control treatment. Using BALB/c donors and beta thalassemic HW-80 recipients, we found significantly improved rates of engraftment and GVHD following TLI/ATS/CTX compared with TLI/ATS, lethal or sublethal total body irradiation/ATS/CTX, or CTX/ATS conditioning. These data provide preclinical support for trials of TLI/ATG/alkylator regimens for MHC mismatched BMT for hemoglobinopathies. The data also delineate innate immune mechanisms by which TLI/ATS/CTX conditioning may augment transplantation tolerance. PMID- 28351936 TI - Endoglin: a novel target for therapeutic intervention in acute leukemias revealed in xenograft mouse models. AB - Endoglin (CD105), a receptor of the transforming growth factor-beta superfamily, has been reported to identify functional long-term repopulating hematopoietic stem cells, and has been detected in certain subtypes of acute leukemias. Whether this receptor plays a functional role in leukemogenesis remains unknown. We identified endoglin expression on the majority of blasts from patients with acute myeloid leukemia (AML) and acute B-lymphoblastic leukemia (B-ALL). Using a xenograft model, we find that CD105+ blasts are endowed with superior leukemogenic activity compared with the CD105- population. We test the effect of targeting this receptor using the monoclonal antibody TRC105, and find that in AML, TRC105 prevented the engraftment of primary AML blasts and inhibited leukemia progression following disease establishment, but in B-ALL, TRC105 alone was ineffective due to the shedding of soluble CD105. However, in both B-ALL and AML, TRC105 synergized with reduced intensity myeloablation to inhibit leukemogenesis, indicating that TRC105 may represent a novel therapeutic option for B-ALL and AML. PMID- 28351937 TI - Presentation and outcome of patients with 2016 WHO diagnosis of prefibrotic and overt primary myelofibrosis. AB - The 2016 revision of the World Health Organization (WHO) classification of myeloproliferative neoplasms defines 2 stages of primary myelofibrosis (PMF): prefibrotic/early (pre-PMF) and overt fibrotic (overt PMF) phase. In this work, we studied the clinical and molecular features of patients belonging to these categories of PMF. The diagnosis of 661 PMF patients with a bone marrow biopsy at presentation was revised according to modern criteria; clinical information and annotation of somatic mutations in both driver and selected nondriver myeloid genes were available for all patients. Compared with pre-PMF, overt PMF was enriched in patients with anemia, thrombocytopenia, leukopenia, higher blast count, symptoms, large splenomegaly, and unfavorable karyotype. The different types of driver mutations were similarly distributed between the 2 categories, whereas selected mutations comprising the high mutation risk (HMR) category (any mutations in ASXL1, SRSF2, IDH1/2, EZH2) were more represented in overt PMF. More patients with overt PMF were in higher International Prognostic Scoring System risk categories at diagnosis, and the frequency increased during follow-up, suggesting greater propensity to disease progression compared with pre-PMF. Median survival was significantly shortened in overt PMF (7.2 vs 17.6 years), with triple negativity for driver mutations and presence of HMR mutations representing independent predictors of unfavorable outcome. The findings of this "real-life" study indicate that adherence to 2016 WHO criteria allows for identification of 2 distinct categories of patients with PMF where increased grades of fibrosis are associated with more pronounced disease manifestations, adverse mutation profile, and worse outcome, overall suggesting they might represent a phenotypic continuum. PMID- 28351938 TI - Predictive model for survival in patients with AML/MDS receiving haploidentical stem cell transplantation. PMID- 28351941 TI - Government's childhood obesity plan does not go far enough, say MPs. PMID- 28351939 TI - Cytoreductive conditioning intensity predicts clonal diversity in ADA-SCID retroviral gene therapy patients. AB - Retroviral gene therapy has proved efficacious for multiple genetic diseases of the hematopoietic system, but roughly half of clinical gene therapy trial protocols using gammaretroviral vectors have reported leukemias in some of the patients treated. In dramatic contrast, 39 adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) patients have been treated with 4 distinct gammaretroviral vectors without oncogenic consequence. We investigated clonal dynamics and diversity in a cohort of 15 ADA-SCID children treated with gammaretroviral vectors and found clear evidence of genotoxicity, indicated by numerous common integration sites near proto-oncogenes and by increased abundance of clones with integrations near MECOM and LMO2 These clones showed stable behavior over multiple years and never expanded to the point of dominance or dysplasia. One patient developed a benign clonal dominance that could not be attributed to insertional mutagenesis and instead likely resulted from expansion of a transduced natural killer clone in response to chronic Epstein-Barr virus viremia. Clonal diversity and T-cell repertoire, measured by vector integration site sequencing and T-cell receptor beta-chain rearrangement sequencing, correlated significantly with the amount of busulfan preconditioning delivered to patients and to CD34+ cell dose. These data, in combination with results of other ADA-SCID gene therapy trials, suggest that disease background may be a crucial factor in leukemogenic potential of retroviral gene therapy and underscore the importance of cytoreductive conditioning in this type of gene therapy approach. PMID- 28351942 TI - Targeting the TSH receptor in thyroid cancer. AB - Recent advances in the arena of theranostics have necessitated a re-examining of previously established fields. The existing paradigm of therapeutic thyroid stimulating hormone receptor (TSHR) targeting in the post-surgical management of differentiated thyroid cancer using levothyroxine and recombinant human thyroid stimulating hormone (TSH) is well understood. However, in an era of personalized medicine, and with an increasing awareness of the risk profile of longstanding pharmacological hyperthyroidism, it is imperative clinicians understand the molecular basis and magnitude of benefit for individual patients. Furthermore, TSHR has been recently re-conceived as a selective target for residual metastatic thyroid cancer, with pilot data demonstrating effective targeting of nanoparticles to thyroid cancers using this receptor as a target. This review examines the evidence for TSHR signaling as an oncogenic pathway and assesses the evidence for ongoing TSHR expression in thyroid cancer metastases. Priorities for further research are highlighted. PMID- 28351944 TI - Defining Pediatric Chronic Critical Illness for Clinical Care, Research, and Policy. AB - Chronically critically ill pediatric patients represent an emerging population in NICUs and PICUs. Chronic critical illness has been recognized and defined in the adult population, but the same attention has not been systematically applied to pediatrics. This article reviews what is currently known about pediatric chronic critical illness, highlighting the unique aspects of chronic critical illness in infants and children, including specific considerations of prognosis, outcomes, and decision-making. We propose a definition that incorporates NICU versus PICU stays, recurrent ICU admissions, dependence on life-sustaining technology, multiorgan dysfunction, underlying medical complexity, and the developmental implications of congenital versus acquired conditions. We propose a research agenda, highlighting existing knowledge gaps and targeting areas of improvement in clinical care, research, and policy. PMID- 28351943 TI - Apc inactivation, but not obesity, synergizes with Pten deficiency to drive intestinal stem cell-derived tumorigenesis. AB - Obesity is a major risk factor for colorectal cancer and can accelerate Lgr5+ intestinal stem cell (ISC)-derived tumorigenesis after the inactivation of Apc However, whether non-canonical pathways involving PI3K-Akt signaling in ISCs can lead to tumor formation, and if this can be further exacerbated by obesity is unknown. Despite the synergy between Pten and Apc inactivation in epithelial cells on intestinal tumor formation, their combined role in Lgr5+-ISCs, which are the most rapidly dividing ISC population in the intestine, is unknown. Lgr5+-GFP mice were provided low-fat diet (LFD) or high-fat diet (HFD) for 8 months, and the transcriptome was evaluated in Lgr5+-ISCs. For tumor studies, Lgr5+-GFP and Lgr5+-GFP-Ptenflox/flox mice were tamoxifen treated to inactivate Pten in ISCs and provided LFD or HFD until 14-15 months of age. Finally, various combinations of Lgr5+-ISC-specific, Apc- and Pten-deleted mice were generated and evaluated for histopathology and survival. HFD did not overtly alter Akt signaling in ISCs, but did increase other metabolic pathways. Pten deficiency, but not HFD, increased BrdU-positive cells in the small intestine (P < 0.05). However, combining Pten and Apc deficiency synergistically increased proliferative markers, tumor pathology and mortality, in a dose-dependent fashion (P < 0.05). In summary, we show that HFD alone fails to drive Akt signaling in ISCs and that Pten deficiency is dispensable as a tumor suppressor in Lgr5+-ISCs. However, combining Pten and Apc deficiency in ISCs synergistically increases proliferation, tumor formation and mortality. Thus, aberrant Wnt/beta-catenin, rather than PI3K-Akt signaling, is requisite for obesity to drive Lgr5+ ISC derived tumorigenesis. PMID- 28351945 TI - Caveolin-1-mediated internalization of the vitamin C transporter SVCT2 in microglia triggers an inflammatory phenotype. AB - Vitamin C is essential for the development and function of the central nervous system (CNS). The plasma membrane sodium-vitamin C cotransporter 2 (SVCT2) is the primary mediator of vitamin C uptake in neurons. SVCT2 specifically transports ascorbate, the reduced form of vitamin C, which acts as a reducing agent. We demonstrated that ascorbate uptake through SVCT2 was critical for the homeostasis of microglia, the resident myeloid cells of the CNS that are essential for proper functioning of the nervous tissue. We found that depletion of SVCT2 from the plasma membrane triggered a proinflammatory phenotype in microglia and resulted in microglia activation. Src-mediated phosphorylation of caveolin-1 on Tyr14 in microglia induced the internalization of SVCT2. Ascorbate treatment, SVCT2 overexpression, or blocking SVCT2 internalization prevented the activation of microglia. Overall, our work demonstrates the importance of the ascorbate transport system for microglial homeostasis and hints that dysregulation of ascorbate transport might play a role in neurological disorders. PMID- 28351947 TI - Antidepressants protect bones from metastatic prostate cancer. AB - Monoamine oxidase A-targeted antidepressants inhibit a tumor-stroma loop and could delay the metastatic outgrowth of prostate cancer. PMID- 28351951 TI - Polyglutamine makes the switch. AB - In worms, a regulator of noncoding RNA directly catalyzes formation of toxic protein aggregates in the presence of polyglutamine. PMID- 28351952 TI - Shaping the gut microbiome from the pancreas. AB - The intracellular Ca2+ channel Orai1 in pancreatic acinar cells helps to suppress inflammation-associated bacterial strains in the gut. PMID- 28351946 TI - Stress-induced dynamic regulation of mitochondrial STAT3 and its association with cyclophilin D reduce mitochondrial ROS production. AB - Signal transducer and activator of transcription 3 (STAT3) is associated with various physiological and pathological functions, mainly as a transcription factor that translocates to the nucleus upon tyrosine phosphorylation induced by cytokine stimulation. In addition, a small pool of STAT3 resides in the mitochondria, where it serves as a sensor for various metabolic stressors including reactive oxygen species (ROS). Mitochondrially localized STAT3 largely exerts its effects through direct or indirect regulation of the activity of the electron transport chain (ETC). It has been assumed that the amounts of STAT3 in the mitochondria are static. We showed that various stimuli, including oxidative stress and cytokines, triggered a signaling cascade that resulted in a rapid loss of mitochondrially localized STAT3. Recovery of the mitochondrial pool of STAT3 over time depended on phosphorylation of Ser727 in STAT3 and new protein synthesis. Under these conditions, mitochondrially localized STAT3 also became competent to bind to cyclophilin D (CypD). Binding of STAT3 to CypD was mediated by the amino terminus of STAT3, which was also important for reducing mitochondrial ROS production after oxidative stress. These results outline a role for mitochondrially localized STAT3 in sensing and responding to external stimuli. PMID- 28351954 TI - Indian government agrees radical plan for universal healthcare. PMID- 28351956 TI - Inner Workings: SMART collars help track and conserve wildlife. PMID- 28351953 TI - Sphingosine 1-phosphate signaling through its receptor S1P5 promotes chromosome segregation and mitotic progression. AB - Sphingosine kinase 1 (SphK1) promotes cell proliferation and survival, and its abundance is often increased in tumors. SphK1 produces the signaling lipid sphingosine 1-phosphate (S1P), which activates signaling cascades downstream five G protein-coupled receptors (S1P1-5) to modulate vascular and immune system function and promote proliferation. We identified a new function of the SphK1-S1P pathway specifically in the control of mitosis. SphK1 depletion in HeLa cells caused prometaphase arrest, whereas its overexpression or activation accelerated mitosis. Increasing the abundance of S1P promoted mitotic progression, overrode the spindle assembly checkpoint (SAC), and led to chromosome segregation defects. S1P was secreted through the transporter SPNS2 and stimulated mitosis by binding to and activating S1P5 on the extracellular side, which then activated the intracellular phosphatidylinositol 3-kinase (PI3K)-AKT pathway. Knockdown of S1P5 prevented the S1P-induced spindle defect phenotype. RNA interference assays revealed that the mitotic kinase Polo-like kinase 1 (PLK1) was an important effector of S1P-S1P5 signaling-induced mitosis in HeLa cells. Our findings identify an extracellular signal and the downstream pathway that promotes mitotic progression and may indicate potential therapeutic targets to inhibit the proliferation of cancer cells. PMID- 28351957 TI - Core Concept: Unraveling the enigma of fast radio bursts. PMID- 28351959 TI - The innate immune system in human systemic lupus erythematosus. AB - Although the role of adaptive immune mechanisms, e.g. autoantibody formation and abnormal T-cell activation, has been long noted in the pathogenesis of human systemic lupus erythematosus (SLE), the role of innate immunity has been less well characterized. An intricate interplay between both innate and adaptive immune elements exists in protective anti-infective immunity as well as in detrimental autoimmunity. More recently, it has become clear that the innate immune system in this regard not only starts inflammation cascades in SLE leading to disease flares, but also continues to fuel adaptive immune responses throughout the course of the disease. This is why targeting the innate immune system offers an additional means of treating SLE. First trials assessing the efficacy of anti-type I interferon (IFN) therapy or modulators of pattern recognition receptor (PRR) signalling have been attempted. In this review, we summarize the available evidence on the role of several distinct innate immune elements, especially neutrophils and dendritic cells as well as the IFN system, as well as specific innate PRRs along with their signalling pathways. Finally, we highlight recent clinical trials in SLE addressing one or more of the aforementioned components of the innate immune system. PMID- 28351960 TI - Pathogenesis of white matter changes in cerebral small vessel diseases: beyond vessel-intrinsic mechanisms. AB - Cerebral small vessel diseases (SVDs) are a leading cause of age and hypertension related stroke and dementia. The salient features of SVDs visible on conventional brain magnetic resonance images include white matter hyperintensities (WMHs) on T2-weighted images, small infarcts, macrohemorrhages, dilated perivascular spaces, microbleeds and brain atrophy. Among these, WMHs are the most common and often the earliest brain tissue changes. Moreover, over the past two decades, large population- and patient-based studies have established the clinical importance of WMHs, notably with respect to cognitive and motor disturbances. Here, we seek to provide a new and critical look at the pathogenesis of SVD associated white matter (WM) changes. We first review our current knowledge of WM biology in the healthy brain, and then consider the main clinical and pathological features of WM changes in SVDs. The most widely held view is that SVD-associated WM lesions are caused by chronic hypoperfusion, impaired cerebrovascular reactivity (CVR) or blood-brain barrier (BBB) leakage. Here, we assess the arguments for and against each of these mechanisms based on population, patient and experimental model studies, and further discuss other potential mechanisms. Specifically, building on two recent seminal studies that have uncovered an anatomical and functional relationship between oligodendrocyte progenitor cells and blood vessels, we elaborate on how small vessel changes might compromise myelin remodelling and cause WM degeneration. Finally, we propose new directions for future studies on this hot research topic. PMID- 28351961 TI - Update on the State of the Evidence for Stroke Family Caregiver and Dyad Interventions. PMID- 28351962 TI - Pharmacogenetic Associations of beta1-Adrenergic Receptor Polymorphisms With Cardiovascular Outcomes in the SPS3 Trial (Secondary Prevention of Small Subcortical Strokes). AB - BACKGROUND AND PURPOSE: Functional polymorphisms (Ser49Gly and Arg389Gly) in ADRB1 have been associated with cardiovascular and beta-blocker response outcomes. Herein we examined associations of these polymorphisms with major adverse cardiovascular events (MACE), with and without stratification by beta blocker treatment in patients with a history of stroke. METHODS: Nine hundred and twenty-six participants of the SPS3 trial's (Secondary Prevention of Small Subcortical Strokes) genetic substudy with hypertension were included. MACE included stroke, myocardial infarction, and all-cause death. Kaplan-Meier and multivariable Cox regression analyses were used. Because the primary component of MACE was ischemic stroke, we tested the association of Ser49Gly with ischemic stroke among 41 475 individuals of European and African ancestry in the NINDS (National Institute of Neurological Disorders and Stroke) SiGN (Stroke Genetics Network). RESULTS: MACE was higher in carriers of the Gly49 allele than in those with the Ser49Ser genotype (10.5% versus 5.4%, log-rank P=0.005). Gly49 carrier status was associated with MACE (hazard ratio, 1.62; 95% confidence interval, 1.00-2.68) and ischemic stroke (hazard ratio, 1.81; 95% confidence interval, 1.01 3.23) in SPS3 and with small artery ischemic stroke (odds ratio, 1.14; 95% confidence interval, 1.03-1.26) in SiGN. In SPS3, beta-blocker-treated Gly49 carriers had increased MACE versus non-beta-blocker-treated individuals and noncarriers (hazard ratio, 2.03; 95% confidence interval, 1.20-3.45). No associations were observed with the Arg389Gly polymorphism. CONCLUSION: Among individuals with previous small artery ischemic stroke, the ADRB1 Gly49 polymorphism was associated with MACE, particularly small artery ischemic stroke, a risk that may be increased among beta-blocker-treated individuals. Further research is needed to define beta-blocker benefit among ischemic stroke patients by ADRB1 genotype. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059306. PMID- 28351963 TI - Associations of Ischemic Lesion Volume With Functional Outcome in Patients With Acute Ischemic Stroke: 24-Hour Versus 1-Week Imaging. AB - BACKGROUND AND PURPOSE: Ischemic lesion volume (ILV) on noncontrast computed tomography at 1 week can be used as a secondary outcome measure in patients with acute ischemic stroke. Twenty-four-hour ILV on noncontrast computed tomography has greater availability and potentially allows earlier estimation of functional outcome. We aimed to assess lesion growth 24 hours after stroke onset and compare the associations of 24-hour and 1-week ILV with functional outcome. METHODS: We included 228 patients from MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), who received noncontrast computed tomography at 24-hour and 1-week follow-up on which ILV was measured. Relative and absolute lesion growth was determined. Logistic regression models were constructed either including the 24-hour or including the 1-week ILV. Ordinal and dichotomous (0-2 and 3-6) modified Rankin scale scores were, respectively, used as primary and secondary outcome measures. RESULTS: Median ILV was 42 mL (interquartile range, 21-95 mL) and 64 mL (interquartile range: 30-120 mL) at 24 hours and 1 week, respectively. Relative lesion growth exceeding 30% occurred in 121 patients (53%) and absolute lesion growth exceeding 20 mL occurred in 83 patients (36%). Both the 24-hour and 1-week ILVs were similarly significantly associated with functional outcome (both P<0.001). In the logistic analyses, the areas under the curve of the receiver-operator characteristic curves were similar: 0.85 (95% confidence interval, 0.80-0.90) and 0.87 (95% confidence interval, 0.82-0.91) for including the 24-hour and 1-week ILV, respectively. CONCLUSIONS: Growth of ILV is common 24-hour poststroke onset. Nevertheless, the 24-hour ILV proved to be a valuable secondary outcome measure as it is equally strongly associated with functional outcome as the 1-week ILV. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.com. Unique identifier: ISRCTN10888758. PMID- 28351965 TI - New cardiac magnetic resonance imaging modalities aid in the detection of myocardial fibrosis. PMID- 28351964 TI - Left ventricular remodeling leads to heart failure in mice with cardiac-specific overexpression of VEGF-B167: echocardiography and magnetic resonance imaging study. AB - Cardiac-specific overexpression of vascular endothelial growth factor (VEGF)-B167 is known to induce left ventricular hypertrophy due to altered lipid metabolism, in which ceramides accumulate to the heart and cause mitochondrial damage. The aim of this study was to evaluate and compare different imaging methods to find the most sensitive way to diagnose at early stage the progressive left ventricular remodeling leading to heart failure. Echocardiography and cardiovascular magnetic resonance imaging were compared for imaging the hearts of transgenic mice with cardiac-specific overexpression of VEGF-B167 and wild-type mice from 5 to 14 months of age at several time points. Disease progression was verified by molecular biology methods and histology. We showed that left ventricular remodeling is already ongoing at the age of 5 months in transgenic mice leading to heart failure by the age of 14 months. Measurements from echocardiography and cardiovascular magnetic resonance imaging revealed similar changes in cardiac structure and function in the transgenic mice. Changes in histology, gene expressions, and electrocardiography supported the progression of left ventricular hypertrophy. Longitudinal relaxation time in rotating frame (T1rho ) in cardiovascular magnetic resonance imaging could be suitable for detecting severe fibrosis in the heart. We conclude that cardiac-specific overexpression of VEGF-B167 leads to left ventricular remodeling at early age and is a suitable model to study heart failure development with different imaging methods. PMID- 28351966 TI - The quest for load-independent left ventricular chamber properties: exploring the normalized pressure-volume loop. AB - Left ventricular (LV) pressure-volume (P-V) loop analysis is the gold standard for chamber function assessment. To advance beyond traditional P-V and pressure phase plane (dP/dt-P) analysis in the quest for novel load-independent chamber properties, we introduce the normalized P-V loop. High-fidelity LV pressure and volume data (161 P-V loops) from 13 normal control subjects were analyzed. Normalized LV pressure (PN) was defined by 0 <= P(t) <= 1. Normalized LV volume (VN) was defined as VN=V(t)/Vdiastasis, since the LV volume at diastasis (Vdiastasis) is the in-vivo equilibrium volume relative to which the LV volume oscillates. Plotting PN versus VN for each cardiac cycle generates normalized P-V loops. LV volume at the peak LV ejection rate and at the peak LV filling rate (peak -dV/dt and peak +dV/dt, respectively) were determined for conventional and normalized loops. VN at peak +dV/dt was inscribed at 64 +/- 5% of normalized equilibrium (diastatic) volume with an inter-subject variation of 8%, and had a reduced intra-subject (beat-to-beat) variation compared to conventional P-V loops (9% vs. 13%, respectively; P < 0.005), thereby demonstrating load-independent attributes. In contrast, VN at peak -dV/dt was inscribed at 81 +/- 9% with an inter-subject variation of 11%, and had no significant change in intra-subject (beat-to-beat) variation compared to conventional P-V loops (17% vs. 17%, respectively; P = 0.56), therefore failing to demonstrate load-independent tendencies. Thus, the normalized P-V loop advances the quest for load-independent LV chamber properties. VN at the peak LV filling rate (~sarcomere length at the peak sarcomere lengthening rate) manifests load-independent properties. This novel method may help to elucidate and quantify new attributes of cardiac and cellular function. It merits further application in additional human and animal physiologic and pathophysiologic datasets. PMID- 28351969 TI - Heartbeat: afterload is high (not low) in chronic mitral regurgitation! PMID- 28351968 TI - Effects of GABAa receptor antagonists on motor behavior in pharmacological Parkinson's disease model in mice. AB - The aim of this study was to evaluate the effects of two gamma-amino butyric acid (GABA)a receptor antagonists on motor behavioral tasks in a pharmacological model of Parkinson disease (PD) in rodents. Ninety-six Swiss mice received intraperitoneal injection of Haloperidol (1 mg/kg) to block dopaminergic receptors. GABAa receptors antagonists Bicuculline (1 and 5 mg/kg) and Flumazenil (3 and 6 mg/kg) were used for the assessment of the interaction among these neurotransmitters, in this PD model. The motor behavior of the animals was evaluated in the catalepsy test (30, 60, and 90 min after drugs application), through open field test (after 60 min) and trough functional gait assessment (after 60 min). Both Bicuculline and Flumazenil were able to partially reverse catalepsy induced by Haloperidol. In the open field test, Haloperidol reduced the number of horizontal and vertical exploration of the animals, which was not reversed trough application of GABAa antagonists. Furthermore, the functional gait assessment was not sensitive enough to detect motor changes in this animal model of PD. There is an interaction between dopamine and GABA in the basal ganglia and the blocking GABAa receptors may have therapeutic potential in the treatment of PD. PMID- 28351970 TI - Cautious anticoagulation strategy in patients with dialysis-requiring end-stage kidney disease. PMID- 28351967 TI - Concerted regulation of renal plasma flow and glomerular filtration rate by renal dopamine and NOS I in rats on high salt intake. AB - Under high sodium intake renal dopamine (DA) increases while NOS I expression in macula densa cells (MD) decreases. To explore whether renal DA and NOS I, linked to natriuresis and to the stability of the tubuloglomerular feedback, respectively, act in concert to regulate renal plasma flow (RPF) and glomerular filtration rate (GFR). Male Wistar rats were studied under a normal sodium intake (NS, NaCl 0.24%) or a high sodium intake (HS, NaCl 1% in drinking water) during the 5 days of the study. For the last two days, the specific D1-like receptor antagonist SCH 23390 (1 mg kg bwt-1 day-1, sc) or a vehicle was administered. HS intake increased natriuresis, diuresis, and urinary DA while it decreased cortical NOS I expression (P < 0.05 vs. NS), Nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) activity in MD (P < 0.001 vs. NS) and cortical nitrates+nitrites (NOx) production (NS 2.04 +/- 0.22 vs. HS 1.28 +/- 0.10 nmol mg protein-1, P < 0.01). Treatment with SCH 23390 to rats on HS sharply decreased hydroelectrolyte excretion (P < 0.001 vs. HS) while NOS I expression, NADPH-d activity and NOx production increased (P < 0.05 vs. HS for NOS I and P < 0.001 vs. HS for NADPH-d and NOx). SCH 23390 increased RPF and GFR in HS rats (P < 0.01 HS+SCH vs. HS). It did not cause variations in NS rats. Results indicate that when NS intake is shifted to a prolonged high sodium intake, renal DA through the D1R, and NOS I in MD cells act in concert to regulate RPF and GFR to stabilize the delivery of NaCl to the distal nephron. PMID- 28351971 TI - Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations. AB - Charcot-Marie-Tooth disease type 2D (CMT2D) is a peripheral nerve disorder caused by dominant, toxic, gain-of-function mutations in the widely expressed, housekeeping gene, GARS The mechanisms underlying selective nerve pathology in CMT2D remain unresolved, as does the cause of the mild-to-moderate sensory involvement that distinguishes CMT2D from the allelic disorder distal spinal muscular atrophy type V. To elucidate the mechanism responsible for the underlying afferent nerve pathology, we examined the sensory nervous system of CMT2D mice. We show that the equilibrium between functional subtypes of sensory neuron in dorsal root ganglia is distorted by Gars mutations, leading to sensory defects in peripheral tissues and correlating with overall disease severity. CMT2D mice display changes in sensory behavior concordant with the afferent imbalance, which is present at birth and nonprogressive, indicating that sensory neuron identity is prenatally perturbed and that a critical developmental insult is key to the afferent pathology. Through in vitro experiments, mutant, but not wild-type, GlyRS was shown to aberrantly interact with the Trk receptors and cause misactivation of Trk signaling, which is essential for sensory neuron differentiation and development. Together, this work suggests that both neurodevelopmental and neurodegenerative mechanisms contribute to CMT2D pathogenesis, and thus has profound implications for the timing of future therapeutic treatments. PMID- 28351973 TI - Model of brain activation predicts the neural collective influence map of the brain. AB - Efficient complex systems have a modular structure, but modularity does not guarantee robustness, because efficiency also requires an ingenious interplay of the interacting modular components. The human brain is the elemental paradigm of an efficient robust modular system interconnected as a network of networks (NoN). Understanding the emergence of robustness in such modular architectures from the interconnections of its parts is a longstanding challenge that has concerned many scientists. Current models of dependencies in NoN inspired by the power grid express interactions among modules with fragile couplings that amplify even small shocks, thus preventing functionality. Therefore, we introduce a model of NoN to shape the pattern of brain activations to form a modular environment that is robust. The model predicts the map of neural collective influencers (NCIs) in the brain, through the optimization of the influence of the minimal set of essential nodes responsible for broadcasting information to the whole-brain NoN. Our results suggest intervention protocols to control brain activity by targeting influential neural nodes predicted by network theory. PMID- 28351972 TI - ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer's disease. AB - Proteolytic processing of amyloid precursor protein (APP) C-terminal fragments (CTFs) by gamma-secretase underlies the pathogenesis of Alzheimer's disease (AD). An RNA interference screen using APP-CTF [99-residue CTF (C99)]- and Notch specific gamma-secretase interaction assays identified a unique ErbB2-centered signaling network that was predicted to preferentially govern the proteostasis of APP-C99. Consistently, significantly elevated levels of ErbB2 were confirmed in the hippocampus of human AD brains. We then found that ErbB2 effectively suppressed autophagic flux by physically dissociating Beclin-1 from the Vps34 Vps15 complex independent of its kinase activity. Down-regulation of ErbB2 by CL 387,785 decreased the levels of C99 and secreted amyloid-beta in cellular, zebrafish, and mouse models of AD, through the activation of autophagy. Oral administration of an ErbB2-targeted CL-387,785 for 3 wk significantly improves the cognitive functions of APP/presenilin-1 (PS1) transgenic mice. This work unveils a noncanonical function of ErbB2 in modulating autophagy and establishes ErbB2 as a therapeutic target for AD. PMID- 28351974 TI - Mutational spectra of aflatoxin B1 in vivo establish biomarkers of exposure for human hepatocellular carcinoma. AB - Aflatoxin B1 (AFB1) and/or hepatitis B and C viruses are risk factors for human hepatocellular carcinoma (HCC). Available evidence supports the interpretation that formation of AFB1-DNA adducts in hepatocytes seeds a population of mutations, mainly G:C->T:A, and viral processes synergize to accelerate tumorigenesis, perhaps via inflammation. Responding to a need for early-onset evidence predicting disease development, highly accurate duplex sequencing was used to monitor acquisition of high-resolution mutational spectra (HRMS) during the process of hepatocarcinogenesis. Four-day-old male mice were treated with AFB1 using a regimen that induced HCC within 72 wk. For analysis, livers were separated into tumor and adjacent cellular fractions. HRMS of cells surrounding the tumors revealed predominantly G:C->T:A mutations characteristic of AFB1 exposure. Importantly, 25% of all mutations were G->T in one trinucleotide context (CGC; the underlined G is the position of the mutation), which is also a hotspot mutation in human liver tumors whose incidence correlates with AFB1 exposure. The technology proved sufficiently sensitive that the same distinctive spectrum was detected as early as 10 wk after dosing, well before evidence of neoplasia. Additionally, analysis of tumor tissue revealed a more complex pattern than observed in surrounding hepatocytes; tumor HRMS were a composite of the 10 wk spectrum and a more heterogeneous set of mutations that emerged during tumor outgrowth. We propose that the 10-wk HRMS reflects a short-term mutational response to AFB1, and, as such, is an early detection metric for AFB1-induced liver cancer in this mouse model that will be a useful tool to reconstruct the molecular etiology of human hepatocarcinogenesis. PMID- 28351975 TI - Long noncoding miRNA gene represses wheat beta-diketone waxes. AB - The cuticle of terrestrial plants functions as a protective barrier against many biotic and abiotic stresses. In wheat and other Triticeae, beta-diketone waxes are major components of the epicuticular layer leading to the bluish-white glaucous trait in reproductive-age plants. Glaucousness in durum wheat is controlled by a metabolic gene cluster at the WAX1 (W1) locus and a dominant suppressor INHIBITOR of WAX1 (Iw1) on chromosome 2B. The wheat D subgenome from progenitor Aegilops tauschii contains W2 and Iw2 paralogs on chromosome 2D. Here we identify the Iw1 gene from durum wheat and demonstrate the unique regulatory mechanism by which Iw1 acts to suppress a carboxylesterase-like protein gene, W1 COE, within the W1 multigene locus. Iw1 is a long noncoding RNA (lncRNA) containing an inverted repeat (IR) with >80% identity to W1-COE The Iw1 transcript forms a miRNA precursor-like long hairpin producing a 21-nt predominant miRNA, miRW1, and smaller numbers of related sRNAs associated with the nonglaucous phenotype. When Iw1 was introduced into glaucous bread wheat, miRW1 accumulated, W1-COE and its paralog W2-COE were down-regulated, and the phenotype was nonglaucous and beta-diketone-depleted. The IR region of Iw1 has >94% identity to an IR region on chromosome 2 in Ae. tauschii that also produces miRW1 and lies within the marker-based location of Iw2 We propose the Iw loci arose from an inverted duplication of W1-COE and/or W2-COE in ancestral wheat to form evolutionarily young miRNA genes that act to repress the glaucous trait. PMID- 28351976 TI - Comparing nonpharmaceutical interventions for containing emerging epidemics. AB - Strategies for containing an emerging infectious disease outbreak must be nonpharmaceutical when drugs or vaccines for the pathogen do not yet exist or are unavailable. The success of these nonpharmaceutical strategies will depend on not only the effectiveness of isolation measures but also the epidemiological characteristics of the infection. However, there is currently no systematic framework to assess the relationship between different containment strategies and the natural history and epidemiological dynamics of the pathogen. Here, we compare the effectiveness of quarantine and symptom monitoring, implemented via contact tracing, in controlling epidemics using an agent-based branching model. We examine the relationship between epidemic containment and the disease dynamics of symptoms and infectiousness for seven case-study diseases with diverse natural histories, including Ebola, influenza A, and severe acute respiratory syndrome (SARS). We show that the comparative effectiveness of symptom monitoring and quarantine depends critically on the natural history of the infectious disease, its inherent transmissibility, and the intervention feasibility in the particular healthcare setting. The benefit of quarantine over symptom monitoring is generally maximized for fast-course diseases, but we show the conditions under which symptom monitoring alone can control certain outbreaks. This quantitative framework can guide policymakers on how best to use nonpharmaceutical interventions and prioritize research during an outbreak of an emerging pathogen. PMID- 28351977 TI - Deltex2 represses MyoD expression and inhibits myogenic differentiation by acting as a negative regulator of Jmjd1c. AB - The myogenic regulatory factor MyoD has been implicated as a key regulator of myogenesis, and yet there is little information regarding its upstream regulators. We found that Deltex2 inhibits myogenic differentiation in vitro, and that skeletal muscle stem cells from Deltex2 knockout mice exhibit precocious myogenic differentiation and accelerated regeneration in response to injury. Intriguingly, Deltex2 inhibits myogenesis by suppressing MyoD transcription, and the Deltex2 knockout phenotype can be rescued by a loss-of-function allele for MyoD In addition, we obtained evidence that Deltex2 regulates MyoD expression by promoting the enrichment of histone 3 modified by dimethylation at lysine 9 at a key regulatory region of the MyoD locus. The enrichment is attributed to a Deltex2 interacting protein, Jmjd1c, whose activity is directly inhibited by Deltex2 and whose expression is required for MyoD expression in vivo and in vitro. Finally, we find that Deltex2 causes Jmjd1c monoubiquitination and inhibits its demethylase activity. Mutation of the monoubiquitination site in Jmjd1c abolishes the inhibitory effect of Deltex2 on Jmjd1c demethylase activity. These results reveal a mechanism by which a member of the Deltex family of proteins can inhibit cellular differentiation, and demonstrate a role of Deltex in the epigenetic regulation of myogenesis. PMID- 28351979 TI - Pore translocation of knotted DNA rings. AB - We use an accurate coarse-grained model for DNA and stochastic molecular dynamics simulations to study the pore translocation of 10-kbp-long DNA rings that are knotted. By monitoring various topological and physical observables we find that there is not one, as previously assumed, but rather two qualitatively different modes of knot translocation. For both modes the pore obstruction caused by knot passage has a brief duration and typically occurs at a late translocation stage. Both effects are well in agreement with experiments and can be rationalized with a transparent model based on the concurrent tensioning and sliding of the translocating knotted chains. We also observed that the duration of the pore obstruction event is more controlled by the knot translocation velocity than the knot size. These features should advance the interpretation and design of future experiments aimed at probing the spontaneous knotting of biopolymers. PMID- 28351978 TI - Mouse model of Epstein-Barr virus LMP1- and LMP2A-driven germinal center B-cell lymphoproliferative disease. AB - Epstein-Barr virus (EBV) is a major cause of immunosuppression-related B-cell lymphomas and Hodgkin lymphoma (HL). In these malignancies, EBV latent membrane protein 1 (LMP1) and LMP2A provide infected B cells with surrogate CD40 and B cell receptor growth and survival signals. To gain insights into their synergistic in vivo roles in germinal center (GC) B cells, from which most EBV driven lymphomas arise, we generated a mouse model with conditional GC B-cell LMP1 and LMP2A coexpression. LMP1 and LMP2A had limited effects in immunocompetent mice. However, upon T- and NK-cell depletion, LMP1/2A caused massive plasmablast outgrowth, organ damage, and death. RNA-sequencing analyses identified EBV oncoprotein effects on GC B-cell target genes, including up regulation of multiple proinflammatory chemokines and master regulators of plasma cell differentiation. LMP1/2A coexpression also up-regulated key HL markers, including CD30 and mixed hematopoietic lineage markers. Collectively, our results highlight synergistic EBV membrane oncoprotein effects on GC B cells and provide a model for studies of their roles in immunosuppression-related lymphoproliferative diseases. PMID- 28351980 TI - Transcription factor Etv5 is essential for the maintenance of alveolar type II cells. AB - Alveolar type II (AT2) cell dysfunction contributes to a number of significant human pathologies including respiratory distress syndrome, lung adenocarcinoma, and debilitating fibrotic diseases, but the critical transcription factors that maintain AT2 cell identity are unknown. Here we show that the E26 transformation specific (ETS) family transcription factor Etv5 is essential to maintain AT2 cell identity. Deletion of Etv5 from AT2 cells produced gene and protein signatures characteristic of differentiated alveolar type I (AT1) cells. Consistent with a defect in the AT2 stem cell population, Etv5 deficiency markedly reduced recovery following bleomycin-induced lung injury. Lung tumorigenesis driven by mutant KrasG12D was also compromised by Etv5 deficiency. ERK activation downstream of Ras was found to stabilize Etv5 through inactivation of the cullin-RING ubiquitin ligase CRL4COP1/DET1 that targets Etv5 for proteasomal degradation. These findings identify Etv5 as a critical output of Ras signaling in AT2 cells, contributing to both lung homeostasis and tumor initiation. PMID- 28351981 TI - Range contraction enables harvesting to extinction. AB - Economic incentives to harvest a species usually diminish as its abundance declines, because harvest costs increase. This prevents harvesting to extinction. A known exception can occur if consumer demand causes a declining species' harvest price to rise faster than costs. This threat may affect rare and valuable species, such as large land mammals, sturgeons, and bluefin tunas. We analyze a similar but underappreciated threat, which arises when the geographic area (range) occupied by a species contracts as its abundance declines. Range contractions maintain the local densities of declining populations, which facilitates harvesting to extinction by preventing abundance declines from causing harvest costs to rise. Factors causing such range contractions include schooling, herding, or flocking behaviors-which, ironically, can be predator avoidance adaptations; patchy environments; habitat loss; and climate change. We use a simple model to identify combinations of range contractions and price increases capable of causing extinction from profitable overharvesting, and we compare these to an empirical review. We find that some aquatic species that school or forage in patchy environments experience sufficiently severe range contractions as they decline to allow profitable harvesting to extinction even with little or no price increase; and some high-value declining aquatic species experience severe price increases. For terrestrial species, the data needed to evaluate our theory are scarce, but available evidence suggests that extinction enabling range contractions may be common among declining mammals and birds. Thus, factors causing range contraction as abundance declines may pose unexpectedly large extinction risks to harvested species. PMID- 28351982 TI - The transcription factor Foxo1 controls germinal center B cell proliferation in response to T cell help. AB - Germinal center (GC) B cells cycle between two states, the light zone (LZ) and the dark zone (DZ), and in the latter they proliferate and hypermutate their immunoglobulin genes. How this functional transition takes place is still controversial. In this study, we demonstrate that ablation of Foxo1 after GC development led to the loss of the DZ GC B cells and disruption of the GC architecture, which is consistent with recent studies. Mechanistically, even upon provision of adequate T cell help, Foxo1-deficient GC B cells showed less proliferative expansion than controls. Moreover, we found that the transcription factor BATF was transiently induced in LZ GC B cells in a Foxo1-dependent manner and that deletion of BATF similarly led to GC disruption. Thus, our results are consistent with a model where the switch from the LZ to the DZ is triggered after receipt of T cell help, and suggest that Foxo1-mediated BATF up-regulation is at least partly involved in this switch. PMID- 28351983 TI - CXCR1 remodels the vascular niche to promote hematopoietic stem and progenitor cell engraftment. AB - The microenvironment is an important regulator of hematopoietic stem and progenitor cell (HSPC) biology. Recent advances marking fluorescent HSPCs have allowed exquisite visualization of HSPCs in the caudal hematopoietic tissue (CHT) of the developing zebrafish. Here, we show that the chemokine cxcl8 and its receptor, cxcr1, are expressed by zebrafish endothelial cells, and we identify cxcl8/cxcr1 signaling as a positive regulator of HSPC colonization. Single-cell tracking experiments demonstrated that this is a result of increases in HSPC endothelial cell "cuddling," HSPC residency time within the CHT, and HSPC mitotic rate. Enhanced cxcl8/cxcr1 signaling was associated with an increase in the volume of the CHT and induction of cxcl12a expression. Finally, using parabiotic zebrafish, we show that cxcr1 acts HSPC nonautonomously to improve the efficiency of donor HSPC engraftment. This work identifies a mechanism by which the hematopoietic niche remodels to promote HSPC engraftment and suggests that cxcl8/cxcr1 signaling is a potential therapeutic target in patients undergoing hematopoietic stem cell transplantation. PMID- 28351984 TI - Eros is a novel transmembrane protein that controls the phagocyte respiratory burst and is essential for innate immunity. AB - The phagocyte respiratory burst is crucial for innate immunity. The transfer of electrons to oxygen is mediated by a membrane-bound heterodimer, comprising gp91phox and p22phox subunits. Deficiency of either subunit leads to severe immunodeficiency. We describe Eros (essential for reactive oxygen species), a protein encoded by the previously undefined mouse gene bc017643, and show that it is essential for host defense via the phagocyte NAPDH oxidase. Eros is required for expression of the NADPH oxidase components, gp91phox and p22phox Consequently, Eros-deficient mice quickly succumb to infection. Eros also contributes to the formation of neutrophil extracellular traps (NETS) and impacts on the immune response to melanoma metastases. Eros is an ortholog of the plant protein Ycf4, which is necessary for expression of proteins of the photosynthetic photosystem 1 complex, itself also an NADPH oxio-reductase. We thus describe the key role of the previously uncharacterized protein Eros in host defense. PMID- 28351986 TI - Different Cold-Signaling Pathways Function in the Responses to Rapid and Gradual Decreases in Temperature. AB - In plants, cold temperatures trigger stress responses and long-term responses that result in cold tolerance. In Arabidopsis thaliana, three dehydration responsive element (DRE) binding protein 1/C-repeat binding factors (DREB1/CBFs) act as master switches in cold-responsive gene expression. Induction of DREB1 genes triggers the cold stress-inducible transcriptional cascade, followed by the induction of numerous genes that function in the cold stress response and cold tolerance. Many regulatory factors involved in DREB1 induction have been identified, but how these factors orchestrate the cold stress-specific expression of DREB1s has not yet been clarified. Here, we revealed that plants recognize cold stress as two different signals, rapid and gradual temperature decreases, and induce expression of the DREB1 genes. CALMODULIN BINDING TRANSCRIPTION ACTIVATOR3 (CAMTA3) and CAMTA5 respond to a rapid decrease in temperature and induce the expression of DREB1s, but these proteins do not respond to a gradual decrease in temperature. Moreover, they function during the day and night, in contrast to some key circadian components, including CIRCADIAN CLOCK ASSOCIATED1 and LATE ELONGATED HYPOCOTYL, which regulate cold-responsive DREB1 expression as transcriptional activators only during the day. Thus, plants efficiently control the acquisition of freezing tolerance using two different signaling pathways in response to a gradual temperature decrease during seasonal changes and a sudden temperature drop during the night. PMID- 28351985 TI - Living in an adaptive world: Genomic dissection of the genus Homo and its immune response. AB - More than a decade after the sequencing of the human genome, a deluge of genome wide population data are generating a portrait of human genetic diversity at an unprecedented level of resolution. Genomic studies have provided new insight into the demographic and adaptive history of our species, Homo sapiens, including its interbreeding with other hominins, such as Neanderthals, and the ways in which natural selection, in its various guises, has shaped genome diversity. These studies, combined with functional genomic approaches, such as the mapping of expression quantitative trait loci, have helped to identify genes, functions, and mechanisms of prime importance for host survival and involved in phenotypic variation and differences in disease risk. This review summarizes new findings in this rapidly developing field, focusing on the human immune response. We discuss the importance of defining the genetic and evolutionary determinants driving immune response variation, and highlight the added value of population genomic approaches in settings relevant to immunity and infection. PMID- 28351988 TI - CORRECTION. PMID- 28351987 TI - CALCIUM-DEPENDENT PROTEIN KINASE5 Associates with the Truncated NLR Protein TIR NBS2 to Contribute to exo70B1-Mediated Immunity. AB - Calcium-dependent protein kinases (CPKs) function as calcium sensors and play important roles in plant immunity. Loss of function of the exocyst complex subunit EXO70B1 leads to autoimmunity caused by activation of TN2, a truncated Toll/interleukin-1 receptor-nucleotide binding sequence protein. Here we show, based on a screen for suppressors of exo70B1, that exo70B1-activated autoimmune responses require CPK5 However, the CPK5 homologs CPK4, CPK6, and CPK11, which were previously reported to function redundantly with CPK5 in effector-triggered immunity, did not contribute to exo70B1-associated phenotypes, indicating that CPK5 plays a unique role in plant immunity. Overexpressing CPK5 results in TN2 dependent autoimmunity and enhanced disease resistance, reminiscent of the exo70B1 phenotypes. Ectopic expression of CPK5 in the exo70B1 mutant led to constitutive CPK5 protein kinase activity, which was not detectable in tn2 mutants. Furthermore, TN2 interacts with the CPK5 N-terminal variable and kinase domains, stabilizing CPK5 kinase activity in vitro. This work uncovers a direct functional link between an atypical immune receptor and a crucial component of early immune signaling: increased immunity in exo70B1 depends on TN2 and CPK5 and, in a positive feedback loop, TN2 keeps CPK5 enzymatically active beyond the initiating stimulus. PMID- 28351989 TI - TRAF Family Proteins Regulate Autophagy Dynamics by Modulating AUTOPHAGY PROTEIN6 Stability in Arabidopsis. AB - Eukaryotic cells use autophagy to recycle cellular components. During autophagy, autophagosomes deliver cytoplasmic contents to the vacuole or lysosome for breakdown. Mammalian cells regulate the dynamics of autophagy via ubiquitin mediated proteolysis of autophagy proteins. Here, we show that the Arabidopsis thaliana Tumor necrosis factor Receptor-Associated Factor (TRAF) family proteins TRAF1a and TRAF1b (previously named MUSE14 and MUSE13, respectively) help regulate autophagy via ubiquitination. Upon starvation, cytoplasmic TRAF1a and TRAF1b translocated to autophagosomes. Knockout traf1a/b lines showed reduced tolerance to nutrient deficiency, increased salicylic acid and reactive oxygen species levels, and constitutive cell death in rosettes, resembling the phenotypes of autophagy-defective mutants. Starvation-activated autophagosome accumulation decreased in traf1a/b root cells, indicating that TRAF1a and TRAF1b function redundantly in regulating autophagosome formation. TRAF1a and TRAF1b interacted in planta with ATG6 and the RING finger E3 ligases SINAT1, SINAT2, and SINAT6 (with a truncated RING-finger domain). SINAT1 and SINAT2 require the presence of TRAF1a and TRAF1b to ubiquitinate and destabilize AUTOPHAGY PROTEIN6 (ATG6) in vivo. Conversely, starvation-induced SINAT6 reduced SINAT1- and SINAT2 mediated ubiquitination and degradation of ATG6. Consistently, SINAT1/SINAT2 and SINAT6 knockout mutants exhibited increased tolerance and sensitivity, respectively, to nutrient starvation. Therefore, TRAF1a and TRAF1b function as molecular adaptors that help regulate autophagy by modulating ATG6 stability in Arabidopsis. PMID- 28351990 TI - An NADPH Oxidase RBOH Functions in Rice Roots during Lysigenous Aerenchyma Formation under Oxygen-Deficient Conditions. AB - Reactive oxygen species (ROS) produced by the NADPH oxidase, respiratory burst oxidase homolog (RBOH), trigger signal transduction in diverse biological processes in plants. However, the functions of RBOH homologs in rice (Oryza sativa) and other gramineous plants are poorly understood. Ethylene induces the formation of lysigenous aerenchyma, which consists of internal gas spaces created by programmed cell death of cortical cells, in roots of gramineous plants under oxygen-deficient conditions. Here, we report that, in rice, one RBOH isoform (RBOHH) has a role in ethylene-induced aerenchyma formation in roots. Induction of RBOHH expression under oxygen-deficient conditions was greater in cortical cells than in cells of other root tissues. In addition, genes encoding group I calcium-dependent protein kinases (CDPK5 and CDPK13) were strongly expressed in root cortical cells. Coexpression of RBOHH with CDPK5 or CDPK13 induced ROS production in Nicotiana benthamiana leaves. Inhibitors of RBOH activity or cytosolic calcium influx suppressed ethylene-induced aerenchyma formation. Moreover, knockout of RBOHH by CRISPR/Cas9 reduced ROS accumulation and inducible aerenchyma formation in rice roots. These results suggest that RBOHH-mediated ROS production, which is stimulated by CDPK5 and/or CDPK13, is essential for ethylene induced aerenchyma formation in rice roots under oxygen-deficient conditions. PMID- 28351992 TI - Bile Acid Sodium Symporter BASS6 Can Transport Glycolate and Is Involved in Photorespiratory Metabolism in Arabidopsis thaliana. AB - Photorespiration is an energy-intensive process that recycles 2-phosphoglycolate, a toxic product of the Rubisco oxygenation reaction. The photorespiratory pathway is highly compartmentalized, involving the chloroplast, peroxisome, cytosol, and mitochondria. Though the soluble enzymes involved in photorespiration are well characterized, very few membrane transporters involved in photorespiration have been identified to date. In this work, Arabidopsis thaliana plants containing a T DNA disruption of the bile acid sodium symporter BASS6 show decreased photosynthesis and slower growth under ambient, but not elevated CO2 Exogenous expression of BASS6 complemented this photorespiration mutant phenotype. In addition, metabolite analysis and genetic complementation of glycolate transport in yeast showed that BASS6 was capable of glycolate transport. This is consistent with its involvement in the photorespiratory export of glycolate from Arabidopsis chloroplasts. An Arabidopsis double knockout line of both BASS6 and the glycolate/glycerate transporter PLGG1 (bass6, plgg1) showed an additive growth defect, an increase in glycolate accumulation, and reductions in photosynthetic rates compared with either single mutant. Our data indicate that BASS6 and PLGG1 partner in glycolate export from the chloroplast, whereas PLGG1 alone accounts for the import of glycerate. BASS6 and PLGG1 therefore balance the export of two glycolate molecules with the import of one glycerate molecule during photorespiration. PMID- 28351994 TI - [Erratum: [Acute Sensory Neuropathies and Acute Autonomic Neuropathies]]. AB - Koike H, "[Acute Sensory Neuropathies and Acute Autonomic Neuropathies]," in Brain Nerve. 2015 Nov; 67(11):1377-87. There was a typo in the abstract. Original: "Guillain-Barr?," Corrected: "Guillain-Barre." The online version of this article has been corrected. PMID- 28351991 TI - The Composition of the Arabidopsis RNA Polymerase II Transcript Elongation Complex Reveals the Interplay between Elongation and mRNA Processing Factors. AB - Transcript elongation factors (TEFs) are a heterogeneous group of proteins that control the efficiency of transcript elongation of subsets of genes by RNA polymerase II (RNAPII) in the chromatin context. Using reciprocal tagging in combination with affinity purification and mass spectrometry, we demonstrate that in Arabidopsis thaliana, the TEFs SPT4/SPT5, SPT6, FACT, PAF1-C, and TFIIS copurified with each other and with elongating RNAPII, while P-TEFb was not among the interactors. Additionally, NAP1 histone chaperones, ATP-dependent chromatin remodeling factors, and some histone-modifying enzymes including Elongator were repeatedly found associated with TEFs. Analysis of double mutant plants defective in different combinations of TEFs revealed genetic interactions between genes encoding subunits of PAF1-C, FACT, and TFIIS, resulting in synergistic/epistatic effects on plant growth/development. Analysis of subnuclear localization, gene expression, and chromatin association did not provide evidence for an involvement of the TEFs in transcription by RNAPI (or RNAPIII). Proteomics analyses also revealed multiple interactions between the transcript elongation complex and factors involved in mRNA splicing and polyadenylation, including an association of PAF1-C with the polyadenylation factor CstF. Therefore, the RNAPII transcript elongation complex represents a platform for interactions among different TEFs, as well as for coordinating ongoing transcription with mRNA processing. PMID- 28351993 TI - Mutations in Argonaute5 Illuminate Epistatic Interactions of the K1 and I Loci Leading to Saddle Seed Color Patterns in Glycine max. AB - The soybean (Glycine max) seed coat has distinctive, genetically programmed patterns of pigmentation, and the recessive k1 mutation can epistatically overcome the dominant I and ii alleles, which inhibit seed color by producing small interfering RNAs (siRNAs) targeting chalcone synthase (CHS) mRNAs. Small RNA sequencing of dissected regions of immature seed coats demonstrated that CHS siRNA levels cause the patterns produced by the ii and ik alleles of the I locus, which restrict pigment to the hilum or saddle region of the seed coat, respectively. To identify the K1 locus, we compared RNA-seq data from dissected regions of two Clark isolines having similar saddle phenotypes mediated by CHS siRNAs but different genotypes (homozygous ik K1 versus homozygous ii k1). By examining differentially expressed genes, mapping information, and genome resequencing, we identified a 129-bp deletion in Glyma.11G190900 encoding Argonaute5 (AGO5), a member of the Argonaute family. Amplicon sequencing of several independent saddle pattern mutants from different genetic backgrounds revealed independent lesions affecting AGO5, thus establishing Glyma.11G190900 as the K1 locus. Nonfunctional AGO5 from k1 alleles leads to altered distributions of CHS siRNAs, thus explaining how the k1 mutation reverses the phenotype of the seed coat regions from yellow to pigmented, even in the presence of the normally dominant I or ii alleles. PMID- 28351995 TI - Sirt6 deficiency results in progression of glomerular injury in the kidney. AB - Aging is associated with an increased incidence and prevalence of renal glomerular diseases. Sirtuin (Sirt) 6, a nicotinamide adenine dinucleotide (NAD) dependent histone deacetylase, has been shown to protect against multiple age associated phenotypes; however it is unknown whether Sirt6 has a direct pathophysiologic role in the kidney. In the present study, we demonstrate that Sirt6 is expressed in the kidney and aging Sirt6-deficient mice exhibit renal hypertrophy with glomerular enlargement. Sirt6 deletion induces podocyte injury, including decreases in slit diaphragm proteins, foot process effacement, and cellular loss, resulting in proteinuria. Knockdown of Sirt6 in cultured primary murine podocytes induces shape changes with loss of process formation and cell apoptosis. Moreover, Sirt6 deficiency results in progressive renal inflammation and fibrosis. Collectively, these data provide compelling evidence that Sirt6 is important for podocyte homeostasis and maintenance of glomerular function, and warrant further investigation into the role of Sirt6 in age-associated kidney dysfunction. PMID- 28351998 TI - Analysis of Al2O3-parylene C bilayer coatings and impact of microelectrode topography on long term stability of implantable neural arrays. AB - OBJECTIVE: Performance of many dielectric coatings for neural electrodes degrades over time, contributing to loss of neural signals and evoked percepts. Studies using planar test substrates have found that a novel bilayer coating of atomic layer deposited (ALD) Al2O3 and parylene C is a promising candidate for neural electrode applications, exhibiting superior stability to parylene C alone. However, initial results from bilayer encapsulation testing on non-planar devices have been less positive. Our aim was to evaluate ALD Al2O3-parylene C coatings using novel test paradigms, to rigorously evaluate dielectric coatings for neural electrode applications by incorporating neural electrode topography into test structure design. APPROACH: Five test devices incorporated three distinct topographical features common to neural electrodes, derived from the utah electrode array (UEA). Devices with bilayer (52 nm Al2O3 + 6 um parylene C) were evaluated against parylene C controls (N ? 6 per device type). Devices were aged in phosphate buffered saline at 67 degrees C for up to 311 d, and monitored through: (1) leakage current to evaluate encapsulation lifetimes (>1 nA during 5VDC bias indicated failure), and (2) wideband (1-105 Hz) impedance. MAIN RESULTS: Mean-times-to-failure (MTTFs) ranged from 12 to 506 d for bilayer-coated devices, versus 10 to >2310 d for controls. Statistical testing (log-rank test, alpha = 0.05) of failure rates gave mixed results but favored the control condition. After failure, impedance loss for bilayer devices continued for months and manifested across the entire spectrum, whereas the effect was self-limiting after several days, and restricted to frequencies <100 Hz for controls. These results correlated well with observations of UEAs encapsulated with bilayer and control films. SIGNIFICANCE: We observed encapsulation failure modes and behaviors comparable to neural electrode performance which were undetected in studies with planar test devices. We found the impact of parylene C defects to be exacerbated by ALD Al2O3, and conclude that inferior bilayer performance arises from degradation of ALD Al2O3 when directly exposed to saline. This is an important consideration, given that neural electrodes with bilayer coatings are expected to have ALD Al2O3 exposed at dielectric boundaries that delineate electrode sites. Process improvements and use of different inorganic coatings to decrease dissolution in physiological fluids may improve performance. Testing frameworks which take neural electrode complexities into account will be well suited to reliably evaluate such encapsulation schemes. PMID- 28351996 TI - Daily supplementation with GrandFusion(r) improves memory and learning in aged rats. AB - Studies have shown that supplementation with extracts from various sources, including fruits and vegetables reverse the age-related changes in movement and cognition. We hypothesized that these beneficial effects result from the presence of anti-oxidants and anti-inflammatory compounds in the fruits and vegetables that contribute to reduced oxidative stress, inflammation and cell death while potentially enhancing neurogenesis. The present study was performed to determine the impact of supplementation with GrandFusion(r)(GF) to aged Fisher 344 rats for 4 months to determine the impact on attenuation or reversal of the age-related deficits. When the aged rats consumed a diet enriched with the extracts the results showed an improved motor performance, and enhanced cognitive functions. In addition, the rats showed reduced oxidative stress and inflammation, and enhanced neurogenesis, Nrf2 and anti-oxidant expression. The effect of GF extracts on the augmentation of memory and learning is significant and may function through the modulation of antioxidant enzymes, signaling pathways and additional mechanisms to improve the aging process. These studies further support the recommendation of USDA for the consumption of fruits and vegetables to improve healthy aging. PMID- 28351999 TI - Osteoblast and osteoclast responses to A/B type carbonate-substituted hydroxyapatite ceramics for bone regeneration. AB - The influence of carbonate substitution (4.4 wt%, mixed A/B type) in hydroxyapatite ceramics for bone remodeling scaffolds was investigated by separately analyzing the response of pre-osteoblasts and osteoclast-like cells. Carbonated hydroxyapatite (CHA) (Ca9.5(PO4)5.5(CO3)0.5(OH)(CO3)0.25-CHA), mimicking the chemical composition of natural bone mineral, and pure hydroxyapatite (HA) (Ca10(PO4)6(OH)2-HA) porous ceramics were processed to obtain a similar microstructure and surface physico-chemical properties (grain size, porosity ratio and pore size, surface roughness and zeta potential). The biological behavior was studied using MC3T3-E1 pre-osteoblastic and RAW 264.7 monocyte/macrophage cell lines. Chemical dissolution in the culture media and resorption lacunae produced by osteoclasts occur with both HA and CHA ceramics, but CHA exhibits much higher dissolution and greater bioresorption ability. CHA ceramics promoted a significantly higher level of pre-osteoblast proliferation. Osteoblastic differentiation, assessed by qRT-PCR of RUNX2 and COLIA2, and pre osteoclastic proliferation and differentiation were not significantly different on CHA or HA ceramics but cell viability and metabolism were significantly greater on CHA ceramics. Thus, the activity of both osteoclast-like and osteoblastic cells was influenced by the carbonate substitution in the apatite structure. Furthermore, CHA showed a particularly interesting balance between biodegradation, by osteoclasts and chemical dissolution, and osteogenesis through osteoblasts' activity, to stimulate bone regeneration. It is hypothesized that this amount of 4.4 wt% carbonate substitution leads to an adapted concentration of calcium in the fluid surrounding the ceramic to stimulate the activity of cells. These results highlight the superior biological behavior of microporous 4.4 wt% A/B CHA ceramics that could beneficially replace the commonly used HA of biphasic calcium phosphates for future applications in bone tissue engineering. PMID- 28352000 TI - Crosslinked polymer nanoparticles containing single conjugated polymer chains. AB - Conjugated polymer nanoparticles are widely used in fluorescent labeling and sensing, as they have mean radii between 5 and 100 nm, narrow size dispersion, high brightness, and are photochemically stable, allowing single particle detection with high spatial and temporal resolution. Highly crosslinked polymers formed by linking individual chains through covalent bonds yield high-strength rigid materials capable of withstanding dissolution by organic solvents. Hence, the combination of crosslinked polymers and conjugated polymers in a nanoparticulated material presents the possibility of interesting applications that require the combined properties of constituent polymers and nanosized dimension. In the present work, F8BT@pEGDMA nanoparticles composed of poly(ethylene glycol dimethacrylate) (pEGDMA; a crosslinked polymer) and containing the commercial conjugated polymer poly(9,9-dioctylfluorene-alt benzothiadiazole) (F8BT) were synthesized and characterized. Microemulsion polymerization was applied to produce F8BT@pEDGMA particles with nanosized dimensions in a ~25% yield. Photophysical and size distribution properties of F8BT@pEDGMA nanoparticles were evaluated by various methods, in particular single particle fluorescence microscopy techniques. The results demonstrate that the crosslinking/polymerization process imparts structural rigidity to the F8BT@pEDGMA particles by providing resistance against dissolution/disintegration in organic solvents. The synthesized fluorescent crosslinked nanoparticles contain (for the most part) single F8BT chains and can be detected at the single particle level, using fluorescence microscopy, which bodes well for their potential application as molecularly imprinted polymer fluorescent nanosensors with high spatial and temporal resolution. PMID- 28351997 TI - Mitochondrial protein Fus1/Tusc2 in premature aging and age-related pathologies: critical roles of calcium and energy homeostasis. AB - Decreased energy production and increased oxidative stress are considered to be major contributors to aging and aging-associated pathologies. The role of mitochondrial calcium homeostasis has also been highlighted as an important factor affecting different pathological conditions. Here, we present evidence that loss of a small mitochondrial protein Fus1 that maintains mitochondrial homeostasis results in premature aging, aging-associated pathologies, and decreased survival. We showed that Fus1KO mice develop multiple early aging signs including lordokyphosis, lack of vigor, inability to accumulate fat, reduced ability to tolerate stress, and premature death. Other prominent pathological changes included low sperm counts, compromised ability of adult stem cells to repopulate tissues, and chronic inflammation. At the molecular level, we demonstrated that mitochondria of Fus1 KO cells have low reserve respiratory capacity (the ability to produce extra energy during sudden energy demanding situations), and show significantly altered dynamics of cellular calcium response.Our recent studies on early hearing and memory loss in Fus1 KO mice combined with the new data presented here suggest that calcium and energy homeostasis controlled by Fus1 may be at the core of its aging-regulating activities. Thus, Fus1 protein and Fus1-dependent pathways and processes may represent new tools and targets for anti-aging strategies. PMID- 28352001 TI - Nano-sized Mo- and Nb-doped TiO2 as anode materials for high energy and high power hybrid Li-ion capacitors. AB - Nano-sized Mo-doped titania (Mo0.1Ti0.9O2) and Nb-doped titania (Nb0.25Ti0.75O2) were directly synthesized via a continuous hydrothermal flow synthesis process. Materials characterization was conducted using physical techniques such as transmission electron microscopy, powder x-ray diffraction, x-ray photoelectron spectroscopy, Brunauer-Emmett-Teller specific surface area measurements and energy dispersive x-ray spectroscopy. Hybrid Li-ion supercapacitors were made with either a Mo-doped or Nb-doped TiO2 negative electrode material and an activated carbon (AC) positive electrode. Cells were evaluated using electrochemical testing (cyclic voltammetry, constant charge discharge cycling). The hybrid Li-ion capacitors showed good energy densities at moderate power densities. When cycled in the potential window 0.5-3.0 V, the Mo0.1Ti0.9O2/AC hybrid supercapacitor showed the highest energy densities of 51 Wh kg-1 at a power of 180 W kg-1 with energy densities rapidly declining with increasing applied specific current. In comparison, the Nb0.25Ti0.75O2/AC hybrid supercapacitor maintained its energy density of 45 Wh kg-1 at 180 W kg-1 better, showing 36 Wh g-1 at 3200 W kg-1, which is a very promising mix of high energy and power densities. Reducing the voltage window to the range 1.0-3.0 V led to an increase in power density, with the Mo0.1Ti0.9O2/AC hybrid supercapacitor giving energy densities of 12 Wh kg-1 and 2.5 Wh kg-1 at power densities of 6700 W kg-1 and 14 000 W kg-1, respectively. PMID- 28352002 TI - Optimisation of current injection protocol based on a region of interest. AB - OBJECTIVE: Electrical impedance tomography has the potential to image fast neural activity associated with physiological or epileptic activity throughout the brain. These applications pose a particular challenge as expected voltage changes on the electrodes are less than 1% and geometrical constraints of the body under investigation mean that electrodes can not be evenly distributed around its boundary. Unlike other applications, however, information regarding the location of expected activity is typically available. An informative method for choosing current paths that maximise sensitivity to specific regions is desirable. APPROACH: Two electrode addressing protocol generation methods based on current density vectors concentrated in a region of interest have been proposed. One focuses solely on maximising its magnitude while the other considers its distribution. The quality of reconstructed images using these protocols was assessed in a simulation study conducted in a human and rat mesh and compared to the protocol that maximises distance between injecting electrodes. MAIN RESULTS: When implementing the protocol that focused on maximising magnitude, the current density concentrated in a region of interest increased by up to a factor of 3. When the distribution of the current was maximised, the spread of current density vectors increased by up to fivefold. For the small conductivity changes expected in the applications explored, image quality was best when implementing the protocol that maximised current density. The average image error when using this protocol was 7% better than when employing other protocols. SIGNIFICANCE: We conclude that for fast neural EIT applications, the protocol that maximises current density is the best protocol to implement. PMID- 28352003 TI - Obesity and kidney disease: Hidden consequences of the epidemic. AB - Obesity has become a worldwide epidemic, and its prevalence has been projected to grow by 40% in the next decade. This increasing prevalence has implications for the risk of diabetes, cardiovascular disease and also for chronic kidney disease (CKD). A high body mass index is one of the strongest risk factors for new-onset CKD. In individuals affected by obesity, a compensatory hyperfiltration occurs to meet the heightened metabolic demands of the increased body weight. The increase in intraglomerular pressure can damage the kidneys and raise the risk of developing CKD in the long-term. The incidence of obesity-related glomerulopathy has increased ten-fold in recent years. Obesity has also been shown to be a risk factor for nephrolithiasis, and for a number of malignancies including kidney cancer. This year the World Kidney Day promotes education on the harmful consequences of obesity and its association with kidney disease, advocating healthy lifestyle and health policy measures that makes preventive behaviors an affordable option. PMID- 28352004 TI - Update on pathogenesis, management, and treatment of hypertension in autosomal dominant polycystic kidney disease. AB - Hypertension is a common early finding in autosomal dominant polycystic kidney disease (ADPKD). Improvements in screening and diagnosis of ADPKD have allowed earlier diagnosis, later onset of end-stage renal disease, and better survival. However, the main and most effective therapy remains control of hypertension. Hypertension is the most important modifiable risk factor in ADPKD. Therefore, early management of hypertension reduces the incidence of cardiovascular events in ADPKD patients. Stimulation of the renin-angiotensin-aldosterone system (RAAS) plays a central role in the pathogenesis of hypertension in ADPKD. Therapies that block the RAAS have improved patient management, blood pressure control, and ADPKD patient survival. This review highlights the current understanding of the epidemiology, potential pathogenetic mechanisms and proposes a strategy for the treatment and management of hypertension in ADPKD. PMID- 28352005 TI - Associations between clinical characteristics and angiotensin-converting enzyme gene insertion/deletion polymorphism in Moroccan population with Type-2 diabetic nephropathy. AB - Diabetic nephropathy (DN) is one of the severe complications of Type-2 diabetes mellitus (T2DM) and a major cause of end-stage renal disease in these patients. Results from published studies on the relationship between angiotensin-converting enzyme (ACE) insertion/ deletion (I/D) gene polymorphism and patients with DN are still conflicting. We compared the clinical characteristics and the genotype frequencies of ACE polymorphism in 130 T2DM Moroccan patients with DN and 85 T2DM Moroccan patients without DN (controls) using specific primers in a polymerase chain reaction. The degenerative complications of diabetes were significantly higher in the group with nephropathy. The distribution of the I/D genotypes was in Hardy-Weinberg equilibrium. The D allele was the most frequent allele in the Moroccan population in both groups studied (P = 0.68), however, there was no significant difference between the genotypes in T2DM patients with or without DN (P = 0.78). The ACE gene I/D polymorphism was not associated with an increased risk of DN in the Moroccan population. PMID- 28352006 TI - Assay of urinary protein carbonyl content can predict the steroid dependence and resistance in children with idiopathic nephrotic syndrome. AB - Nephrotic syndrome in pediatric age is mostly idiopathic. Idiopathic nephrotic syndrome (INS) by default is treated with steroids from the very beginning. Some do not respond to steroids and are grouped later as either steroid-resistant (SR) or steroid-dependent (SD) cases. The protein selectivity index often fails to predict the SR and SD cases. The SD and SR cases of INS exhibit higher degrees of oxidative stress compared to steroid responders. Proteins get carbonylated when they are exposed to free radicals. The significance of excretion of these carbonylated proteins in urine is yet to be studied in detail. In this study, 70 cases of INS were enrolled, and urinary protein carbonyl content (UPCC) was estimated by Levine's method before starting the steroid therapy. All the cases were followed up and, based on the response to steroid therapy, were grouped as Group A (n = 47). Steroid sensitive and Group B (n = 23), SD + SR cases. UPCC was significantly higher in Group B compared to Group A. Receiver-operating curve showed at a cutoff limit of 5.10 nmoles/mg of protein, UPCC can predict SD or SR cases with 83.3% sensitivity and 85.2% specificity and area under the curve of 0.833, P<0.05. UPCC levels more than 5.10 nmoles/mg of protein, before starting the therapy can predict SD or SR in pediatric INS cases. PMID- 28352007 TI - Dynamic renal scintigraphic estimation of deceased donor kidneys in a rat model. AB - At present a large number of the renal transplantations are being performed from the deceased donors. The success of these transplantations depends on the viability of the deceased donor kidneys. The aim of this study was to investigate the reliability of scintigraphic estimation of function of deceased donor kidneys by comparing the histopathologic and scintigraphic findings. Ten rats were included in the study (2-3 months old, 250-300 g, all male). Control scintigraphy was performed to all the rats by injection of 37 MBq Tc-99m DTPA from the tail vein in a dynamic manner. Brain death of the rats was achieved by inflation of a Fogartys catheter in the cranial cavity. Immediately, after brain death confirmation, dynamic renal scintigraphy was performed with the same parameters of control scintigraphy. In the comparison of scintigraphies obtained in the before and just after brain death period, there was impairment of tubular functions, concentration and excretion functions in the postbrain death period. In the immediate postbrain death period, there was a significant elevation in the glomerular filtration rate and time to maximum concentration values. In the histopathological evaluation of the kidney samples in the postbrain death period, there were definitive findings of tubular impairment. Dynamic renal scintigraphy also demonstrated definite impairment of tubular system and tubular functions in the deceased donor kidneys. This could explain the reason of the increased frequency of acute tubular necrosis seen among deceased donor kidneys. PMID- 28352008 TI - Spectrum of renal injury in pregnancy-induced hypertension: Experience from a single center in India. AB - Pregnancy-induced hypertension (PIH) is a known complication of late pregnancy and is an important cause of maternal and fetal morbidity and mortality. Data on clinical profile, especially renal profile of preeclampsia and eclampsia in Indian women are lacking. The aim of our study was to examine the renal profile and clinical outcomes of patients diagnosed with PIH in our institution with a focus on the spectrum of acute kidney injury (AKI). In this prospective, observational study, 347 patients with a diagnosis of preeclampsia-eclampsia, who were undergoing treatment at the M. S. Ramaiah Medical College, were included in the study. The study duration was from 2010 to 2014. Details regarding epidemiologic data, obstetric data, laboratory parameters as well as maternal, renal, and fetal outcomes were noted. Patients with preexisting hypertension, diabetes mellitus, or chronic kidney disease were excluded from analysis. The overall incidence of preeclampsia was 3.4%. Hemolysis, elevated liver enzymes, and low platelets syndrome was seen in 31 patients (9%); 56 patients (19%) had AKI with a mean serum creatinine of 3.2 mg/dL and mean proteinuria of 2.8 g/24 h. Nineteen patients required dialysis. Persistent renal failure was seen in 2.5% of the cohort. Maternal mortality was 2.5%, largely secondary to sepsis. Primiparity was a major risk factor. In this study, we found a low rate of preeclampsia in a low-to-moderate risk cohort, with an incidence of AKI and maternal mortality consistent with reported literature. PMID- 28352009 TI - Validation of bioelectrical impedance analysis for assessing dry weight of dialysis patients in Pakistan. AB - Accurate dry weight estimation (DW) to achieve euvolemia is one of the key objectives of hemodialysis (HD). While conventionally DW is estimated by clinical examination, bioelectrical impedance analysis (BIA) has been proposed as an objective method to determine DW and has been tested extensively in the Western population. We aim to validate BIA for determining DW in a Pakistani population against the conventional clinician's method. This is a single-center validation study conducted at two outpatient HD units of Aga Khan Hospital, Karachi. One hundred and forty-eight DW readings of patients who were on maintenance HD were taken both by BIA technology and by clinical assessment. The clinician was blinded to readings obtained by BIA. Data analysis was carried out using the Statistical Package for Social Sciences (SPSS) version 19. Median age of patients was 63 years (range 12-89). Nearly 54.1% of the samples were female (n = 80). Spearman's correlation between the clinician's estimate and BIA-derived DW showed a correlation coefficient of 0.982, which was statistically significant (P <0.001). This association remained significant when stratified analysis was carried out by dividing the sample into subgroups according to age, gender, body mass index, and total body water content. Inter-rater reliability analysis using the kappa statistics showed almost perfect agreement between the two methods, kappa = 0.929 (95% confidence interval, 0.878-0.980, P <0.001). BIA has been validated as a tool for DW assessment of HD patients in Pakistan in comparison to clinical method. PMID- 28352010 TI - Anatomical study of renal and accessory renal arteries. AB - In recent years, more conservative methods of surgery of the renal artery are coming up. Hence, a precise knowledge of renal vasculature has become a necessity. Knowledge of the existence of accessory renal arteries is important; otherwise, they may get inadvertently damaged during renal surgery. Furthermore, their presence must be considered while evaluating a donor's kidney for possible renal transplantation. The study may also be useful to clinicians performing invasive techniques, vascular surgeries, other uro-radiological procedures, and in cases of trauma. Keeping this in mind, this study was conducted on 530 adult cadavers. A total of 1060 kidneys obtained from these cadavers were dissected and accessory renal arteries were looked for; 24.99% of the specimens showed the presence of accessory renal arteries. In 20.75%, one accessory renal artery was found, and in 4.24% of specimens, two accessory renal arteries were seen. PMID- 28352011 TI - Biopsy of small kidneys: A safe and a useful guide to potentially treatable kidney disease. AB - Over the past four years, all patients with unexplained rapid progression of their renal disease were subjected to kidney biopsy, despite their small size (<9 cm), to define its etiology. Children, pregnant women, morbidly obese patients, and those with an unstable cardiovascular state, septicemia, bleeding diathesis as well as those kidney size with size <6 cm were excluded from the study. Doppler ultrasound was used to exclude renovascular/ischemic nephropathy. The procedure was performed by an interventional radiologist using a biopsy gun technique and under ultrasound guidance. The actual diagnosis was established in 29 cases while seven had advanced sclerosing glomerulonephritis. Eleven cases had evidence of vasculitis, of which two were due to polyarteritis nodosa and two were due to crescentic immunoglobulin A disease. The remaining patients had a secondary form of focal segmental glomerulosclerosis (n = 4), interstitial nephritis (n = 4), malignant nephro-angiosclerosis (n = 2), and single patient with primary hyperoxaluria, light chain cast nephropathy, amyloidosis, and thrombotic microangiopathy. All, except eight with advanced glomerulosclerosis, had improved or became stable with specific treatment. Our study shows that biopsy of small-sized kidneys, in patients with unexplained renal deterioration, is safe, and its diagnostic value can improve their morbidity and even mortality. PMID- 28352012 TI - Clinical variables differentiating diabetic from nondiabetic kidney disease in patients with diabetes: A single-center study. AB - Patients with diabetes may have kidney diseases other than the diabetic kidney disease. Kidney biopsy is the investigation of choice when this is suspected. This retrospective analysis included all patients known to have diabetes mellitus (DM) and who had a kidney biopsy at our center between 1998 and 2014. The aim of this study was to assess if an association exists between the clinical factors on the presence or absence of diabetic nephropathy (DNP). A total number of 206 patients were included in our study. The association between the diabetic retinopathy (DRP) and DNP was high (P = 0.001). We found that the DRP is highly specific for the presence of DNP [89.7% (78 out of 87)] whereas sensitivity of DRP for DNP was 56.3% (67 out of 119). Among other factors, only duration of DM showed a significant association (P = 0.005) (odds ratio: 1.1085 and confidence interval: 1.025-1.149) with the development of DNP. We conclude that the absence of DRP is strongly associated with the presence of nondiabetic renal disease while the presence of DRP has a low sensitivity for the presence of DNP. PMID- 28352013 TI - Factors influencing patency of Brescia-Cimino arteriovenous fistulas in hemodialysis patients. AB - Autologous arteriovenous fistula is gold standard to maintain vascular access for hemodialysis patients. As per the Kidney Disease Outcomes Quality Initiative guidelines, distal veins are preferred as the first choice. In this study, a total of 134 patients and 138 fistulas were evaluated from April 2015 to March 2016. Demographic factors and clinical factors were taken into consideration. Our study showed that age, sex, diabetes, and type of construction (end-to-side vs. side-to-side) had no influence over fistula patency rates. Intradialytic hypotension was one of the risk factors for loss of fistula patency. Smoking and history of hypertension were associated with reduced patency rates (P<0.001). Primary failure was more with distal fistulas (15.2%). PMID- 28352014 TI - Risk factors for contrast-induced nephropathy after coronary angiography. AB - Contrast-induced nephropathy (CIN) is of concern after the use of radiocontrast media for coronary angiography (CAG) and percutaneous coronary intervention (PCI). We studied the incidence of CIN and its risk factors in patients undergoing CAG. In this prospective study, we included all patients with normal renal parameters undergoing CAG with nonionic radiocontrast media. We excluded patients with known chronic kidney disease, baseline creatinine more than 1.5 mg/dL, significant hypotension, anemia, and patients with acute myocardial infarction undergoing emergency PCI. Serum creatinine was done at baseline and serially for seven days after the procedure. Appropriate statistical tests were used to analyze the results and P <0.05 was considered statistically significant. The study population (n = 500, 348 males and 152 females) had a mean age of 56.6 +/- 12.5 years. Twelve patients (2.4%) developed CIN and were equally distributed irrespective of the age, diabetes, or PCI procedure. CIN was observed to be more common in patients with hypertension than in those without hypertension (P = 0.0158). The total volume of contrast administered to CIN group (175 +/- 59.3) was not significant as compared to that of non-CIN (159.1 +/- 56) group (P = 0.334). None of the patients in our study required renal replacement therapy, and there was no mortality. CIN is observed in 2.4% of patients undergoing CAG and had a self-limiting course. Hypertension is the only observed risk factor, and further large-scale studies are necessary to delineate the novel risk factors for CIN in the general population with normal kidney function. PMID- 28352015 TI - Association between angiotensin-converting enzyme insertion/deletion gene polymorphism and end-stage renal disease in lebanese patients with diabetic nephropathy. AB - Diabetic nephropathy (DN) is one of the leading causes of end-stage renal disease (ESRD). The development and progression of nephropathy is strongly determined by genetic factors, and few genes have been shown to contribute to DN. An insertion/deletion (I/D) polymorphism of the gene encoding angiotensin-converting enzyme (ACE) was reported as a candidate gene predisposing to DN and ESRD. Accordingly, we investigated the frequency of ACE I/D polymorphism in 50 patients with DN, of whom 33 had ESRD and compared them with 64 patients with type 2 diabetes mellitus (T2DM) but with normal renal function. Polymerase chain reaction amplification, using specific primers, was performed to genotype ACE I/D. Chi-square test was used to assess the differences between the groups. The frequencies of the ACE genotypes were as follows: 48% D/D, 40% I/D, and 12% I/I in patients with DN in contrast to 32.8% D/D, 45.3% I/D, and 21.9% I/I in T2DM. The distribution of the D/D, D/I, and I/I genotypes did not significantly differ between T2DM and DN. However, having the D allele carried a risk for the development of DN [odds ratio (OD), 1.71, P = 0.054]. On the other hand, the distribution of the D/D, D/I, and I/I genotypes was significantly different between T2DM and ESRD patients, chi2 = 7.23, P = 0.027. This was reflected by the D allele which carried a risk for the development of ESRD (OR, 2.51, P = 0.0057). These findings suggest that the D allele may be considered as a risk factor for both the development of DN and the progression of DN to ESRD in Lebanese population with T2DM. PMID- 28352016 TI - Associated anomalies and clinical outcome in children with ectopic kidney. AB - Urological anomalies can be seen in children with renal ectopia (RE) and can result in renal impairment. Therefore, we evaluated associated anomalies and renal outcome in our patients with RE. Sixty-eight children who were diagnosed with RE between January 2009-May 2014 were retrospectively studied. A total of 68 patients, 36 (52.9%) boys, with a median age of 67 months (4-201) and a median follow-up period of 14 months (3-113) were included in the study. Simple RE (S RE) was found in 51 (75%) patients, of which 46 were unilateral and five were bilateral (discoid kidney). Crossed RE (C-RE) was detected in 17 (25%) patients. Voiding cystourethrogram was performed in 21/51 (41.2%) patients in S-RE group and 5/17 (29.4%) in C-RE group. We did not find vesicoureteral reflux (VUR) in any of the patients with C-RE, whereas, in S-RE group, VUR was demonstrated in six (6/21 - 28.6%) patients. Pelviureteric junction obstruction in ectopic kidney was found in two patients with S-RE and one with C-RE. Two patients (2/17 - 11.7%) had neurogenic bladder due to meningomyelocele, accompanied by imperforate anus in C-RE group. There were no significant differences in other associated urological anomalies between two groups. Renal impairment developed mostly in patients with additional urinary anomaly. The children with RE may have associated urinary anomalies, of which VUR is the most common. Complete urological investigation and regular follow-up are required in selected cases. PMID- 28352017 TI - Basilic vein transposition: A viable alternative for multiple failed arteriovenous fistulas - A single center experience. AB - Primary use of the autogenous arteriovenous access is recommended by the National Kidney Foundation-Dialysis Outcomes Quality Initiative guidelines. In spite of troublesome comorbidities associated with basilic vein transposition (BVT), it is still the most preferred technique when autologous veins are not suitable to construct radio-cephalic fistula (RCF) and brachiocephalic fistula (BCF), arteriovenous fistula (AVF). The present study highlights our experience with BVT, with small incision technique, over a period of two years with excellent outcome. This retrospective study included all the patients who underwent BVT at our tertiary care center between March 2013 and March 2015. It was performed in patients with failed previous RCF or BCF or who had small caliber or thrombosed cephalic veins. The patients with minimum 3 mm basilic vein diameter on Doppler were only included in the study. A 3-cm horizontal incision was made in antecubital fossa to expose brachial artery and basilic vein. Multiple longitudinal separate second skin incisions (2-3 cm) were made to explore proximal part of basilic vein. Side branches of the vein were isolated and ligated. The divided basilic vein in antecubital fossa was brought over fascia through newly created subcutaneous tunnel followed by end-to-side anastomosis. A total of 18 (12 males and 6 females) underwent BVT in the two years period. The mean fistula maturation time was 42 +/- 10 days. Maturation rate was 100%, and the postoperative flow rate was 290 +/- 22 (mL/min). No bleeding, thrombosis, failure, pseudo aneurysm, or rupture occurred in our patients. Arm edema occurred in ix (33%) patients, infection in three (17%), and lymphorrhea in five (28%). The mean follow-up was six months. BVT is an alternative method with excellent initial maturation and functional patency rates requiring less extensive skin incision and surgical dissection. It is the most durable hemodialysis access procedure for those patients having multiple forearm AVF surgeries. PMID- 28352018 TI - Depression and anxiety disorders in chronic hemodialysis patients and their quality of life: A cross-sectional study about 106 cases in the northeast of morocco. AB - Hemodialysis (HD) has a severe impact on the life of HD patients. The aim of this work was to assess the prevalence of depression and anxiety disorders, suicidal ideation, and the quality of life among HD patients. Associated factors were also studied. A cross-sectional study was carried out among 103 HD patients treated at the HD Center of Al Farabi Hospital of Oujda during a period of six months in 2015. The Mini-International Neuropsychiatric Interview and European Quality of Life-5 Dimensions (EQ-5D) were used for the assessment. Major depressive episode (MDE) was found in 34% of our patients, whereas anxiety disorder was observed in 25.2%. Suicidal ideation was found in 16.5% and 1.9% of our patients planned their suicide. The EQ-5D index was 0.41 +/- 0.36 and the EQ-Visual Analog Scale score was 45.73 +/- 14. Multivariate analysis showed that MDEs were associated with three factors: marital status, pain, and anxiety disorder. There was also an association between anxiety disorder and age and EQ-Visual Analog Scale score. Suicidal ideation was associated with marital status and anxiety disorders. Together, these results underline the importance of the collaboration between nephrologists and psychiatrists for a better care of HD patients. PMID- 28352019 TI - Analysis of patients with end-stage renal disease on dialysis in Tabuk City, Saudi Arabia: A single-center, three-year retrospective study. AB - This study was performed to analyze various demographic data such as age, gender, nationality, status of the patients, and the causes of end-stage renal disease (ESRD) of 349 patients who were undergoing hemodialysis (HD) during the period from January 2013 to December 2015 at the Dialysis Center of King Khalid Hospital in Tabuk City. One hundred and fifty-two patients (43.6%) were on HD in 2015. Age of the patients ranged from 9 to 93 years and the mean age was 51.3 +/- 17.6 years. Majority of the patients, i.e., 140 (40.1%) were in the age group of 40-59 years, followed by the age group of 60-79 years by 27.8% (97 patients). Saudis constituted 84.2% (294) and non-Saudis accounted 15.8% (55) of the patients over the years studied. There were 198 males (56.7%) and 151 females (43.3%). The death rate in 2014 was 6.2%, whereas it increased in 2015 to 10.5%. The high escape rate (10.3%) of patients was in 2014. Diabetic nephropathy was the most common cause of ESRD, accounting for 30.4% of all cases, followed by unknown etiologies accounting for 25.2%. Nearly 22.6% of all ESRD cases had hypertension. Primary glomerular disease was seen in 8.9% and obstructive uropathy in 3.7%. Other causes constituted 7.4% of the cases. The data of ERSD patients in Tabuk City are comparable with that of other regions of the Kingdom of Saudi Arabia. We conclude that analysis studies of HD centers help to understand the problems and the needs of the patients, find the solutions, and create a connection between the consumers and health-care providers. PMID- 28352020 TI - Profile of glomerular diseases associated with hepatitis B and C: A single-center experience from India. AB - Hepatitis B and C are known to affect kidneys in a number of ways. Glomerular diseases associated with hepatitis B and C include membranous nephropathy (MN), membranoproliferative glomerulonephritis (MPGN), focal segmental glomerulosclerosis, immunoglobulin A nephropathy, rarely amyloidosis, and fibrillary and immunotactoid glomerulopathy. In a retrospective analysis of kidney biopsy of 534 patients, we found 16 (2.9%) patients of hepatitis B and 11 (2.05%) patients of hepatitis C with glomerular disease. The most common form of glomerulonephritis in hepatitis B patient was MN and in hepatitis C patient was MPGN. PMID- 28352021 TI - Prevalence of the metabolic syndrome in kidney transplant recipients: A single center study. AB - Metabolic syndrome (MS) is characterized by a combination of cardiovascular (CV) risk factors (hypertension, dyslipidemia, obesity, and alterations in glucose homeostasis). Insulin resistance is suggested to be the common pathogenic background. This syndrome is also a risk factor for diabetes and chronic kidney disease. In renal transplant recipients, MS has been shown to be an independent risk factor for chronic allograft dysfunction, graft failure, new-onset diabetes, and CV disease. We performed a cross-sectional study on 106 stable renal transplant recipients to detect MS between January 2013 and August 2013. This syndrome was diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III criteria. Patients with history of diabetes mellitus were excluded from the study. In this group of patients, 56 (52.8%) had MS. There were 32 males (57.1%) and 24 females (42.9%). The mean age of the MS group was significantly higher than the non-MS group. The mean serum creatinine was higher in the MS group than the non-MS group, but there was no significant difference between them (P >0.05). The calculated glomerular filtration rate was also similar in the two groups (P >0.05). The patients with MS had higher body weight (64.61 +/- 14.17 kg vs. 58.76 +/- 11.70 kg, P <0.05) and also higher body mass index (BMI) (P <0.05). The prevalence of BMI >25 kg/m2 in the MS group was 75% versus 25% in the non-MS group (P <0.05). Since MS is an important and common risk factor in renal transplant recipients, we have to try to prevent it by educating the patients to control it by modifying their lifestyle. Efforts toward promoting healthy diets, physical activity, and blood pressure control must be undertaken. PMID- 28352022 TI - Analysis of renal diseases detected in renal biopsies of adult patients: A single center experience. AB - Renal biopsy is crucial while evaluating for the diagnosis of glomerular, vascular, tubulointerstitial, and genetic diseases. It gives vital information which helps in estimating the disease prognosis, progression, and management. This is the retrospective analysis of all adult patients aged above 18 years, who underwent percutaneous renal biopsy at The Kidney Center Post Graduate Training Institute, Karachi, over a duration of 18 years, i.e., January 1, 1996, to December 2013. Renal graft biopsies and those which were inadequate were excluded from analysis. Of the1962 biopsies performed, we included 1521 biopsies in our assessment. The mean age of the population was 38 +/- 15.26 years (range 18-88 years). There were 920 (60.5%) males and 601 (39.5%) females. The most common clinical indication of kidney biopsy was nephrotic syndrome, i.e., 741 (45.7%), followed by chronic kidney disease, 253 (16.6%); acute renal failure, 184; (12.1%) and rapidly progressive glomerulonephritis (GN), 124 (8.2%). Primary GN was found in the majority of the patients, 984 (64.7%), followed by secondary GN in 249 (16.4%), tubulointerstitial disease in 224 (14.7%), and vascular disease in 64 (4.2%). In primary GN, focal segmental glomerulosclerosis was the most common histopathological diagnosis in 297 (19.5%) patients, followed by MGN in 224 (14.7%), chronic GN in 98 (6.4%), crescentic GN in 93 (6.1%), minimal change disease in 87 (5.7%), membranoproliferative glomerulonephritis in 58 (3.8%), and postinfection glomerulonephritis in 53 (3.5%) patients. This study shows that focal segmental glomerulosclerosis is the most common lesion in renal biopsy in the young age group followed by membranous nephropathy. Diabetic nephropathy and chronic interstitial nephritis were dominant secondary pathological lesions in older age group, whereas lupus nephritis was the most common secondary disease in young age females. PMID- 28352023 TI - Anti-glomerular basement membrane: A rare cause of renal failure in children. AB - Anti-glomerular basement membrane (GBM) disease is a rare cause of acute renal failure and known to have bad prognosis regarding renal functions recovery and patient survival specially when diagnosed late and presents with severe renal failure that requires dialysis. We report a case of 11-year-old child with acute renal failure secondary to anti-GBM disease and associated with antineutrophil cytoplasmic antibody-positive vasculitis. He was treated with plasmapheresis, steroids, and cyclophosphamide with recovery of his kidney functions. PMID- 28352024 TI - Anesthetic management of two cases of Bardet-Biedl syndrome for renal transplantation. AB - Bardet-Biedl syndrome (BBS) is a multisystem autosomal recessive disorder with clinical and genetic heterogeneity. It is a type of ciliopathy characterized by retinal dystrophy, central obesity, polydactyly, cognitive impairment, and gonadal and renal dysgenesis. It has been suggested that the involved proteins attach to the basal body of ciliated cells making this a disorder of ciliary dysfunction. We report two cases of typical BBS in a 17-year-old female and 29 year-old male patient, who presented for live-related renal transplant. We discuss the relevant points of the syndrome regarding anesthetic management. PMID- 28352025 TI - Eculizumab experience in an adult patient with atypical hemolytic uremic syndrome. AB - Atypical hemolytic-uremic syndrome is a disease characterized by nonimmune hemolytic anemia, thrombocytopenia, and renal failure. In this study, we present a case of a patient with atypical hemolytic-uremic syndrome treated successfully with eculizumab. A 20-year-old female was admitted with clinical signs of atypical hemolytic syndrome. The laboratory findings were as follows: hemoglobin 9.2 g/dL, platelet count 18 * 103/MUL, creatinine 4.69 mg/dL, schistocytes were in peripheral blood smear, lactate dehydrogenase 2080 U/L, and emergency plasmapheresis procedure with fresh frozen plasma were initiated. The patient was anuric within 12 h of her admittance. ADAMTS13 activity was normal. Her mother's cousin developed acute rejection immediately after receiving a renal transplant and died two months later. As she did not respond to the treatment and considering her family history, eculizumab was initiated which resulted in platelet counts starting to rise on day 5, and the patient no longer needed dialysis after 22 days. PMID- 28352026 TI - Hyponatremia secondary to acute urinary retention. AB - Acute urinary retention is a rare cause of hyponatremia. Symptomatic acute hyponatremia is of grave medical concern and needs to be managed aggressively. In our two cases with acute urinary retention, a simple bladder catheterization and drainage of urine followed by conservative management resulted in complete resolution of symptoms and normalization of sodium levels. Association of bladder distension and hyponatremia is considered to be due to release of vasopressin triggered by bladder distension itself or by pain due to bladder distension. These cases are presented to bring to light an unusual and easily treatable cause of hyponatremia. PMID- 28352027 TI - Successful cadaveric transplantation of a splitted crossed fused disc type ectopic kidney to two patients with end-stage renal disease. AB - Cadaveric donors with congenital renal anomalies are often refused because of technical difficulties. As the waiting periods for kidney transplants continue to increase, transplant centers need to consider them also as potential donors. This paper describes transplantation of a crossed fused disc type ectopic kidney to two patients with end-stage renal disease, after parenchymal transection. The transplants were successful with minimal complications, and the recipients had immediate graft function. It is now one year from transplantation, with excellent renal functions. PMID- 28352028 TI - Eosinophilic peritonitis in a continuous ambulatory peritoneal dialysis patient: Inflammation and irritation without infection. AB - A 52-year-old patient developed idiopathic eosinophilic peritonitis (EP) four weeks after starting continuous ambulatory peritoneal dialysis that resolved spontaneously without any clinical sequelae. This case is reported to emphasize the fact that EP can mimic infectious peritonitis in its mode of clinical presentation and that distinction between these two entities is important given their prognostic and therapeutic differences. PMID- 28352029 TI - The mystery of the nonfunctioning catheter: An unusual complication of peritoneal dialysis outflow failure. AB - Noninfectious complications of peritoneal dialysis (PD) remain an important impediment to successful implementation of PD. Rare noninfectious complications of the PD catheter are sparsely reported. We report an unusual complication of outflow failure due to a peritoneal catheter that separated into two distinct intra-abdominal segments, due to an unusual method of placement in which two catheters were connected to make a long intra-abdominal portion to permit a high exit site on the abdominal wall. The application of this unusual rather a unique technique led to separation of the two catheter portions and the outflow failure shortly after the patient started continuous ambulatory PD. We reviewed other unusual causes of PD catheter failure, and these included luminal stones blocking the PD catheter, pneumomediastinum related to inappropriate technique, catheter deformation and leak due to the use of antibiotic ointment at the exit site of polyurethane catheters, vesicoperitoneal fistula and perforation of the bladder from the placement of PD catheters, rare site migrations of the catheter, and subcutaneous titanium connector infection in a presternal catheter. Knowledge of these unusual complications may allow prevention and/or early recognition. PMID- 28352030 TI - Pseudohyperkalemia: Look before you treat. AB - Pseudohyperkalemia is defined as a reported rise in serum potassium concentration along with a normal effective plasma potassium concentration. We present a case report of a 57-year-old gentleman with a history of chronic lymphocytic leukemia, who presented with an elevation in serum potassium along with a normal plasma potassium concentration. Through an exploration of the literature, we demonstrate that pseudohyperkalemia is an important phenomenon to watch for as it may sometimes lead to unnecessary and potentially dangerous treatment. PMID- 28352031 TI - Vasculitis and vasculopathy in Lupus Nephritis: Clinical variability, outcome, and new insight into treatment. AB - More than 50% of patients with systemic lupus erythematosus (SLE) have renal involvement at presentation or during their illness. Lupus nephritis (LN) encompasses several patterns of renal disease, including glomerular, tubulointerstitial, and vascular pathologies. The presence and significance of renal vascular lesions (VLs) are often overlooked. VLs in LN are not rare with an incidence of 10%-40% on renal biopsies from various studies and their presence is often labeled as poor prognostic markers. The current treatment protocol for LN is mainly based on the glomerular pathology, and no guidelines/consensus exists for treatment of LN with VLs. We describe the clinical presentation, course, response to therapy, and outcomes in five patients with SLE with histological evidence of renal VLs. PMID- 28352032 TI - Aggressive angiomyxoma of transplanted kidney mimicking posttransplant lymphoproliferative disorder. AB - Angiomyxoma is a scarce neoplasm arising from the soft tissues of perineum and pelvis, more commonly seen in the females. For such a tumor to arise in a renal allograft is rare and has previously been reported only in few case. We report a case of aggressive angiomyxoma arising de novo in the renal allograft nine-year posttransplantation. We describe its imaging features on ultrasound and computed tomography which closely mimic the more usual tumor of the transplanted kidney, posttransplant lymphoproliferative disorder and suggest that angiomyxoma may be considered as a differential diagnosis in a case of soft tissue mass arising within the renal allograft. PMID- 28352033 TI - Possible effect of statins on serum vitamin D levels in patients with chronic renal disease. PMID- 28352034 TI - The complications of ultrasound-guided percutaneous renal biopsy. PMID- 28352035 TI - Unusual isolated fungal infection of renal allograft. PMID- 28352036 TI - The cutoff 1st day urine specific gravity in critically ill children: Predictive factor for early abnormal glomerular filtration rate. PMID- 28352037 TI - Snakebite-induced acute kidney injury requiring dialysis in second trimester of pregnancy: Successful outcomes in a therapeutic quagmire. PMID- 28352038 TI - Association between autosomal dominant polycystic kidney disease and autoimmune diseases: A simple coincidence or more? PMID- 28352039 TI - Relationship between ABO blood group and end-stage renal disease in Latakia, Syria. PMID- 28352040 TI - Re-emerging diseases and epidemic threats: Ten 'areas of actions' (AA-10) and a case for global solidarity. PMID- 28352041 TI - Challenges for malaria vector control in sub-Saharan Africa: Resistance and behavioral adaptations in Anopheles populations. AB - Over the past decade, global malaria-related mortality has declined dramatically because of combined international actions that have defined and prioritized national and regional efforts to reduce the incidence of malaria, with the ultimate goal of eradication. Vector control strategies using insecticide-treated nets (ITNs) and indoor residual spraying (IRS) in African countries have contributed significantly to the declining incidence of malaria. However, the effectiveness of malaria control is threatened by increasing insecticide resistance and behavioral changes in Anopheles vectors. Thus, there is an urgent need to ensure that future programmes are designed to address these threats and protect the progress made so far in controlling malaria. This review summarizes the current malaria vector control tools and discusses about the critical threats to vector control programme and vector management. PMID- 28352042 TI - Advancements in bait technology to control Glossina swynnertoni Austen, the species of limited distribution in Kenya and Tanzania border: A review. AB - Glossina swynnertoni is a savannah tsetse that is largely confined to the Serengeti-Mara [a very small part of East Africa covering northern Tanzania (Arusha and Manyara regions and parts of Shinyanga and Mara regions) extending Maasai Mara ecosystem in southwestern Kenya]. Nevertheless, it is of great concern to human and animal health and is one of the top target tsetse species for eradication. To achieve this eradication objective, it is important to know about its behaviour so that the appropriate tools/measures especially the right traps can be applied against it. In this paper G. swynnertoni is reviewed in terms of its behaviour, and development of traps for its survey and control. Glossina swynnertoni control is of paramount importance in Tanzania tourism industry and country's income. Since, G. swynnertoni is also distributed in national parks, control is vital as it might reduce tourists excursion/movement, by transmitting the African trypanosomiasis among travelers. Different literature search engines such as Google Scholar and PubMed were deployed for literature search. It was found that the behaviour of G. swynnertoni is relatively similar but unique from other tsetse flies. Its feeding cycle is 21/2-3 days as opposed to 3-4 days observed in other tsetse species. The flight activity pattern varied between sex, with male having their peak at 1100-1200 hrs and females 1400-1600 hrs. The activity in both sexes decline rapidly towards the dusk (1700-1800 hrs). It was further that host odours, relatively smaller and vertically oriented devices, as well as host movement are the main attractive factors to this tsetse species, which can be exploited to design efficient artificial devices for control of G. swynnertoni . Therefore, due to its restricted distribution and threat it poses on tourism industry, deliberate efforts need to be made against G. swynnertoni as a next candidate to be eradicated using artificial bait technology. PMID- 28352043 TI - Development, standardization and validation of molecular techniques for malaria vector species identification, trophic preferences, and detection of Plasmodium falciparum. AB - BACKGROUND & OBJECTIVES: Knowledge on prevalence of malaria vector species of a certain area provides important information for implementation of appropriate control strategies. The present study describes a rapid method for screening of major Anopheline vector species and at the same time detection of Plasmodium falciparum sporozoite infection and blood meal preferences/trophic preferences. METHODS: The study was carried from February 2012 to March 2013 in three seasons, i.e. rainy, winter and summer in Jhumpura PHC of Keonjhar district, Odisha, India. Processing of mosquitoes was carried out in two different methods, viz. mosquito pool (P1) and mosquito DNA pool (P2). Pool size for both the methods was standardized for DNA isolation and multiplex PCR assay. This PCR based assay was employed to screen the major vector com- position in three different seasons of four different ecotypes of Keonjhar district. Pearson's correlation coefficient was determined for a comparative analysis of the morphological identification with the pool prevalence assay for each ecotype. RESULTS: A pool size of 10 was standardized for DNA isolation as well as PCR. PCR assay revealed that the average pool prevalence for all ecotypes was highest for An. annularis in winter and summer whereas for An. culicifacies it was rainy season. Foothill and plain ecotypes contributed to highest and lowest vectorial abundance respectively. The results of the prevalence of vector species in pool from PCR based assay were found to be highly correlated with that of the results of morphological identification. INTERPRETATION & CONCLUSION: Screening by pool based PCR assay is relatively rapid as compared to conventional identification and can be employed as an important tool in malaria control programmes. PMID- 28352045 TI - Repellent effect of microencapsulated essential oil in lotion formulation against mosquito bites. AB - BACKGROUND & OBJECTIVES: Many essential oils have been reported as natural sources of insect repellents; however, due to high volatility, they present low repellent effect. Formulation technique by using microencapsulation enables to control the volatility of essential oil and thereby extends the duration of repellency. In this study, the effectiveness of microencapsulated essential oils of Alpinia galanga, Citrus grandis and C. aurantifolia in the lotion formulations were evaluated against mosquito bites. METHODS: Essential oils and N,N-Diethyl-3 methylbenzamide (DEET) were encapsulated by using interfacial pre- cipitation techniques before incorporation into lotion base to form microencapsulated (ME) formulation. The pure essential oil and DEET were also prepared into lotion base to produce non-encapsulated (NE) formulation. All the prepared formulations were assessed for their repellent activity against Culex quinquefasciatus under laboratory condition. Field evaluations also were conducted in three different study sites in Peninsular Malaysia. In addi- tion, Citriodiol(r) (Mosiquard(r)) and citronella-based repellents (KAPS(r), MozAway(r) and BioZ Natural(r)) were also included for comparison. RESULTS: In laboratory conditions, the ME formulations of the essential oils showed no significant difference with regard to the duration of repellent effect compared to the microencapsulated DEET used at the highest con- centration (20%). It exhibited >98% repellent effect for duration of 4 h (p = 0.06). In the field conditions, these formulations demonstrated comparable repellent effect (100% for a duration of 3 h) to Citriodiol(r) based repellent (Mosiguard(r)) (p = 0.07). In both test conditions, the ME formulations of the essential oils presented longer duration of 100% repellent effect (between 1 and 2 h) compared to NE formulations. INTERPRETATION & CONCLUSION: The findings of the study demonstrate that the application of the microencapsulation technique during the preparation of the formulations significantly increases the duration of the repellent effect of the essential oils, suggesting that the ME formulation of essential oils have potential to be commercialized as an alternative plant-based repellent in the market against the mosquitoes. PMID- 28352044 TI - Seroprevalence and clinical manifestations of chikungunya virus infection in rural areas of Chandrapur, Maharashtra, India. AB - BACKGROUND & OBJECTIVES: Chikungunya virus (CHIKV) infection has recently witnessed re-emergence, affecting rural areas of India with high morbidity rates. This prospective study was conducted to evaluate seroprevalence and clinical manifestation in targeted villages reporting cases of CHIKV infection. METHODS: A total of 482 patients were recruited from Kalmana and Kothari villages of Ballarpur; Chandrapur district of Maharashtra state, India during CHIKV outbreaks in 2011-12. The serum samples from infected CHIKV patients were simultaneously screened through ELISA for detection of antigen and antibodies (IgM and IgG). Chi square analysis was used to evaluate differences in seropositivity between age, gender and clinical manifestations of CHIKV. RESULTS: Out of 482 enrolled participants, 197 (41%) males and 285 (59%) females were aged between 5 and 92 yr. The clinical manifestations such as small joint pain (80%), neck stiffness (75%), fever (49%) and large joint pain (47%) were observed amongst CHIKV infected subjects. Mucocutaneous rashes (91%) on knees (71%), feet (56%), fingers and palms (54%) were also observed. Overall, seroprevalence of CHIKV infection was found to be 46% in infected participants during the epidemic period. Among risk factors, ageing and female gender was strongly associated with a raised seroprevalence of CHIKV infection along with symptoms such as rashes, small joints pain and neck stiffness. INTERPRETATION & CONCLUSION: This study reported high seroprevalence rates of CHIKV infection in targeted popula- tions, suggesting its re-emergence in rural India. Proper surveillance is, therefore, necessary to minimize re-emergence and in controlling these impending and sporadic outbreaks. PMID- 28352046 TI - Evaluation of SYBR green I based visual loop-mediated isothermal amplification (LAMP) assay for genus and species-specific diagnosis of malaria in P. vivax and P. falciparum endemic regions. AB - BACKGROUND & OBJECTIVES: Loop-mediated isothermal amplification (LAMP) is an emerging nucleic acid based diag- nostic approach that is easily adaptable to the field settings with limited technical resources. This study was aimed to evaluate the LAMP assay for the detection and identification of Plasmodium falciparum and P. vivax infection in malaria suspected cases using genus and species-specific assay. METHODS: The 18S rRNA-based LAMP assay was evaluated for diagnosis of genus Plasmodium, and species- specific diagnosis of P. falciparum and P. vivax, infection employing 317 malaria suspected cases, and the results were compared with those obtained by 18S nested PCR (n-PCR). All the samples were confirmed by microscopy for the presence of Plasmodium parasite. RESULTS: The n-PCR was positive in all Plasmodium-infected cases (n=257; P. falciparum=133; P. vivax=124) and negative in microscopy negative cases (n=58) except for two cases which were positive for P. vivax, giving a sen- sitivity of 100% (95% CI: 97.04 100%) and a specificity of 100% (95% CI: 88.45-99.5%). Genus-specific LAMP assay missed 11 (3.2%) microscopy and n-PCR confirmed vivax malaria cases. Considering PCR results as a refer- ence, LAMP was 100% sensitive and specific for P. falciparum, whereas it exhibited 95.16% sensitivity and 96.7% specificity for P. vivax. The n-PCR assay detected 10 mixed infection cases while species-specific LAMP detected five mixed infection cases of P. vivax and P. falciparum, which were not detected by microscopy. INTERPRETATION & CONCLUSION: Genus-specific LAMP assay displayed low sensitivity. Falciparum specific LAMP assay displayed high sensitivity whereas vivax specific LAMP assay displayed low sensitivity. Failed detection of vivax cases otherwise confirmed by the n-PCR assay indicates exploitation of new targets and improved detection methods to attain 100% results for P. vivax detection. PMID- 28352047 TI - Larvicidal activity of Ottonia anisum metabolites against Aedes aegypti: A potential natural alternative source for mosquito vector control in Brazil. AB - BACKGROUND & OBJECTIVES: Aedes aegypti mosquito is the principal vector of the viruses responsible for urban yellow fever, dengue, dengue haemorrhagic fever, as well as Zika and chikungunya in Brazil. The present study was aimed to investigate the insecticidal potential of the extract and fractions of Ottonia anisum, along with special metabolites isolated from it, as natural alternatives against larvae (L3) of Ae. aegypti, vector of potentially deadly tropical infections in Brazil. METHODS: The plant species O. anisum was collected in March 2015, at Xeriotam area, in Rio de Janeiro City, Brazil. Crude extracts and the isolated pure compounds were screened for toxicity against Ae. aegypti larvae (L3). Bioassays were performed on 20 larvae (L3) of Ae. aegypti in triplicate. The samples were dissolved in a mixture of acetone and DMSO at final concentrations of 1-200 MUg/ml. The toxicity of the solutions was evaluated towards the growth and development of Ae. aegypti larvae till emergence of adults. RESULTS: The crude hexane extract showed 100% larval mortality 24 h after treatment at a concentration of 200 MUg/ml. The bioassays using 1-butyl-3,4 methylenedioxybenzene revealed 100% mortality among L3 larvae, 24 h afterthe treatment at a concentration of 30 MUg/ml, the LC recorded was 1.6 MUg/ml. At concentration of 10 MUg/ml, the L3 larval mortality recorded was 92%. INTERPRETATION & CONCLUSION: The metabolite 1-butyl-3,4-methylenedioxybenzene showed potent toxicity against Ae. aegypti larvae. This arylbutanoid agent could be used as a natural alternative adjuvant pesticide, in new compositions that would be environmentally safer. PMID- 28352048 TI - Evidence of JEV in Culex tritaeniorhynchus and pigs from high altitude regions of Tibet, China. AB - BACKGROUND & OBJECTIVES: Culex tritaeniorhynchus is the primary vector of Japanese encephalitis virus (JEV) which is a major threat to animals and humans health. This virus has been reported earlier from low altitude regions of Tibet, in mosquitoes, Tibetan pigs and local Tibetans, but no reports are available for the probable propagation of JE to high altitude regions (3100 m) of Tibet. This study aimed to find the evidence of JEV in Cx. tritaeniorhynchus and pigs from high altitude regions of Tibet, China. METHODS: In total, 102 porcine serum samples and eight pools of Cx. tritaeniorhynchus were subjected to real-time PCR (RT-PCR) for the amplification of a fragment (~ 420 bp) of the NS1 gene. The resultant amplicons of the genes were subsequently analyzed and sequenced. RESULTS: Overall seroprevalence of JE in Tibetan pigs was 6.86%, while five pools of Cx. tritaeniorhynchus were found positive for JEV. Results showed genotype III as the most prevalent (100%) among JEV positive isolates. Furthermore, phylogenetic analysis of the JEV positive strains showed 98.8-99% similarity to four reference strains from China (JEV-Hubei, Whe, HYZ and CQ11-66). INTERPRETATION & CONCLUSION: The present study revealed that JEV has extended its geographic range to high altitude regions of Tibet. The factors like increased tourism and transportation might play key role in the transmission of JE that comprises a potential health risk for humans and animals. PMID- 28352049 TI - Association of CD40L gene polymorphism with severe Plasmodium falciparum malaria in Indian population. AB - BACKGROUND & OBJECTIVES: Many host genetic factors are associated with the disease severity and fatal outcome of falciparum malaria. CD40L gene has been found to be one of the most important factors associated with malaria in African countries. This study was aimed to investigate the possible association of CD40L gene polymorphism in severe falciparum malaria in Indian adults. METHODS: One hundred fifteen adult cases with severe falciparum malaria were included in the study. Two single- nucleotide polymorphisms (SNPs) of CD40L gene, CD40L-726(C/T) and CD40L+220(C/T) were investigated, and the possible association with different clinical sub-phenotypes of severe falciparum malaria were analyzed. RESULTS: Statistically no significant difference was observed in the incidence of CD40L 726C between the patients and control group. The incidence of CD40L+220C allele was found to be significantly higher (OR, 2.25; p = 0.03) in male patients compared to controls but no significant difference was observed in females. Haplotype data showed the susceptibility of -726T/+220C haplotype to severe malaria whereas -726C/+220T was associated with protection against severe malaria. CD40L+220C allele was associated with severe malarial anaemia in males (chi2 = 6.60; p = 0.01). INTERPRETATION & CONCLUSION: CD40L gene polymorphism was found to be associated with severe falciparum malaria in Indian population especially in severe malarial anaemia. CD40L may be considered as a factor of immunity in understanding the pathophysiology of falciparum malaria. PMID- 28352050 TI - Species diversity of black flies (Diptera: Simuliidae) in Oriental region and molecular phylogeny of the subgenus Gomphostilbia members. AB - BACKGROUND & OBJECTIVES: Black flies (Diptera: Simuliidae) are ecologically and medically important insects. Female adults of black flies are the solitary vectors of river blindness (onchocerciasis) and their larvae play a vital role in stream ecosystem. This study examined the distribution of black flies in the Oriental region and analyzed the phylogenetic relationship of the subgenus Gomphostilbia members based on two molecular loci. METHODS: The distribution data of black fly species in different countries of Oriental region were obtained from world black flies geographic inventory. The two gene sequences, COI and ITS1 were used to study the phylogenetic relationships of the members of subgenus Gomphostilbia members. RESULTS: The distribution analysis revealed that out of the 16 subgenera in the genus Simulium Latreille s., the species-level diversity of three subgenera (Gomphostilbia, Nevermannia and Simulium) contributes about thrice of total black fly species diversity. The highest diversity of species was found in the subgenus Simulium. The strict consensus of Tree analysis using New Technology (TNT) and Maximum Likelihood (ML) recovered similar topolo- gies for Gomphostilbia members and they formed as monophyly. The overall sequence identities of the 19 species of subgenus Gomphostilbia were high and shared 55 60% similarity. INTERPRETATION & CONCLUSION: Results of this study highlighted that eight subgenera of Simulium Latreille s. str are commonly distributed in different parts of Oriental region. Among these the subgenera of Simulium, Gomphostilbia and Nevermannia are most common with high diversity in China, Pakistan, Thailand and Vietnam. The phylogenetic analysis of Gomphostilbia members demonstrates the inter-specific divergence, indicating the centre of origin (India) or the recipient of ancestral migrant lineages in Oriental region. PMID- 28352051 TI - Composition and distribution of medically important phlebotomines (Diptera: Psychodidae) in the municipalities of Tierralta and Valencia (Cordoba, Colombia). AB - BACKGROUND & OBJECTIVES: Ecoepidemiological studies of cutaneous leishmaniasis and regular monitoring of Lutzomyia species have generated a knowledge base that can be used for control and prevention strategies targeted at the disease transmission dynamics in focal areas of Colombia. In this study, the presence and spatial distribution of phlebotomines of medical importance in the municipalities of Tierralta (El Loro and Tuis Tuis villages) and Valencia (Guadua and Mieles villages) were determined. METHODS: Entomological surveys were performed in 2015 (months of June, September and November) and samples were collected via CDC-traps located in intradomicilary and peridomiciliary areas in the municipalities of Tierralta and Valencia (Department of Cordoba, Colombia). Active searches were also carried out with a mouth aspirator to collect adult phlebotomines from resting sites. ANOVA and Kruskal-Wallis tests were performed to assess if the differences between the communities of phlebotomines. Spatial distribution maps of the Lutzomyia species were generated. RESULTS: A high species diversity of Lutzomyia was observed with a total of 1677 Lutzomyia individuals belonging to 12 species. Among these species, Lu. panamensis was the most abundant (80.18%). The composition of the intradomicilary and peridomiciliary phlebotomines varied significantly (F = 0.9962; df = 1; p = 0.02895). Species like Lu. carpenteri, Lu. camposi, Lu. dysponeta, Lu. atroclavata and Lu. yuilli yuilli were recorded for the first time in the Department of Cordoba, Colombia. INTERPRETATION & CONCLUSION: The spatial distribution shows that Lu. panamensis and Lu. gomezi are predominant and present in areas with high concentration of houses. This study provides basic information on new records of phlebotomines in the Department of Cordoba. The results suggest that greater vector-human contact occurs in the peridomiciliary environment and that a high number of Lutzomyia species associated with the transmission of leishmaniasis are present in Colombia. PMID- 28352052 TI - Feline visceral leishmaniasis in Kerman, southeast of Iran: Serological and molecular study. AB - BACKGROUND & OBJECTIVES: Visceral leishmaniasis (VL) is a fatal zoonotic disease in tropical and sub-tropical countries including Iran. Dogs constitute the main domestic reservoir for VL (kala-azar) in Iran but incidence of the disease in cats from Fars and East Azerbaijan provinces has led to propose them as secondary reservoirs, and possible expansion of the feline role in the transmission of disease. The aim of this study was to evaluate the prevalence of Leishmania infantum infection in stray cats in Kerman City by ELISA and PCR methods. METHODS: In this cross-sectional descriptive study, 60 stray cats were randomly live trapped from different parts of Kerman City during a six month period between March and September 2014. About 3 ml blood samples were drawn from jugular vein of captured cats and a detailed questionnaire about demographic characteristics and clini- cal status of each cat was recorded by attending veterinarian. The complete blood counts and biochemistry analysis were performed for all cats. Finally collected sera samples were tested by an indirect enzyme linked immunosorbent assay (ELISA) kit and PCR amplification method. RESULTS: Prevalence of Leishmania infantum infection was 6.7 and 16.7% by ELISA and PCR assays, respectively. Infection rate was significantly higher in leukopenic cats, which were older than 3 yr. INTERPRETATION & CONCLUSION: The results of the study indicate that stray cats are at risk of L. infantum infection in Kerman City. Further, studies are required to elucidate the role of cats as potential reservoir host in the epidemiol- ogy of VL in endemic regions. PMID- 28352053 TI - Spontaneous iliopsoas haematoma in a patient with dengue haemorrhagic fever (DHF): A case report. PMID- 28352054 TI - B-cell leukemia/lymphoma and neuroborreliosis: Diagnostic and therapeutic challenges. PMID- 28352055 TI - Progressive Encephalomyelitis with Rigidity and Myoclonus in an Intellectually Disabled Patient Mimicking Neuroleptic Malignant Syndrome. AB - We present a case of 32-year-old male with profound mental retardation and autism spectrum disorder who had presented with seizures, rigidity and elevated creatine kinase and was initially diagnosed as neuroleptic malignant syndrome (NMS). The patient subsequently had a complicated clinical course, developing refractory status epilepticus, which lead to the eventual diagnosis of progressive encephalomyelitis with rigidity and myoclonus (PERM). We discuss the clinical similarities and differences between NMS and PERM, and highlight the need to consider alternative diagnoses when the clinical picture of NMS is atypical, particularly in this patient group where the history and clinical examination may be challenging. PMID- 28352056 TI - Isolated Neurological Manifestation in Silent Celiac Disease. PMID- 28352057 TI - Paroxysmal Kinesigenic Dyskinesia as the Presenting and Only Manifestation of Multiple Sclerosis after Eighteen Months of Follow-Up. AB - Other than tremor, movement disorders are uncommon in multiple sclerosis. Among these uncommon clinical manifestations, paroxysmal kinesigenic dyskinesia is the most frequently reported. It is characterized by episodic attacks of involuntary movements that are induced by repetitive or sudden movements, startling noise or hyperventilation. The diagnosis is essentially clinical and based on a good observation of the attacks. It is very easy to misdiagnose it. We describe the case of a young female patient who presented paroxysmal kinesigenic dyskinesia as the first and only clinical manifestation of multiple sclerosis, with no recurrence of attacks nor any other neurologic symptom after eighteen months of follow-up. PMID- 28352058 TI - The relationship between anti-C-reactive protein and disease activity in patients with systemic lupus erythematosus. AB - Background/Aims: Anti-C-reactive protein (CRP) antibody has been introduced as a potential biologic marker in Systemic lupus erythematosus (SLE). The aim of study is to evaluate the level of anti-CRP antibody in patients with SLE. METHODS: This study investigated the relationship between levels of anti-CRP antibodies and disease activity markers, such as complement, anti-double-stranded DNA antibody, and SLE disease activity index in 34 patients with SLE. RESULTS: The serum anti CRP antibody levels of the patients with SLE were significantly higher than those of the healthy controls (11.3 +/- 5.6 ug/mL vs. 9.1 +/- 2.8 ug/mL). The percentages of the positive anti-CRP antibody were 52.9% in SLE and 27.8% in controls. Disease duration of SLE showed significant correlation with the anti CRP antibody (r = 0.234, p = 0.026). However no significant relationship was observed between the levels of anti-CRP antibodies and disease activity markers. Conclusions: These data show that the anti-CRP antibody levels of the patients with SLE were significantly higher than those of healthy controls. We observed that the presence of the anti-CRP anti-CRP antibody was not associated with disease activity of SLE. PMID- 28352059 TI - Korean version of the Cough Symptom Score: clinical utility and validity for chronic cough. AB - BACKGROUND/AIMS: The Cough Symptom Score (CSS) is a simple, useful tool for measuring cough severity. However, there is no standard Korean version of the CSS. We developed a Korean version of the CSS and evaluated its clinical utility and validity for assessing chronic cough severity. METHODS: The CSS was adapted for Korean use following a forward-backward translation procedure. Patients with chronic cough enrolled from five university hospitals were graded using the CSS and a 100-mm linear visual analog scale (VAS) of cough severity at each visit. Patients completed the Leicester Cough Questionnaire (LCQ) upon presentation and completed the LCQ and Global Rating of Change at follow-up visits after 2 to 4 weeks. The concurrent validity, repeatability, and responsiveness of the Korean version of the CSS were determined. RESULTS: Correlation coefficients between the CSS and LCQ, and between the CSS and VAS, were -0.66 and 0.52, respectively. There was a weak correlation between the scores for night and day symptoms (r = 0.24, p = 0.0006). The repeatability of the CSS in patients with no change in cough (n = 23) was high (intra-class correlation coefficient, 0.75; 95% confidence interval [CI], 0.51 to 0.88). Patients who reported an improvement in cough (n = 30) at follow-up visits had a significant improvement in the CSS (median, -2; 95% CI, -3 to -1; p = 0.0003). CONCLUSIONS: The Korean version of the CSS correlated well with other tools for accessing cough severity in chronic cough patients. Therefore, it could be a reliable method for measuring chronic cough severity. PMID- 28352060 TI - Evaluation of the prevalence and clinical impact of toxocariasis in patients with eosinophilia of unknown origin. AB - BACKGROUND/AIMS: Eosinophilia has numerous diverse causes, and in many patients, it is not possible to establish the cause of eosinophilia. Recently, toxocariasis was introduced as one cause of eosinophilia. The aims of this study were to evaluate the prevalence of toxocariasis and the clinical impact of albendazole treatment for toxocariasis in patients suspected of eosinophilia of unknown origin. METHODS: We performed a retrospective chart review. After evaluation of cause of eosinophilia, the patients suspected of eosinophilia of unknown origin performed immunoglobulin G antibody specific assay for the Toxocara canis larval antigen by enzyme-linked immunosorbent assay. RESULTS: This study evaluated 113 patients, 69 patients (61%) were suspected of eosinophilia of unknown origin. Among these 69 patients, the frequency of T. canis infection was very high (45 patients, 65.2%), and albendazole treatment for 45 eosinophilia with toxocariasis was highly effective for a cure of eosinophilia than no albendazole group regardless of steroid (82.3%, p = 0.007). Furthermore, among the nonsteroid treated small group (19 patients), albendazole treatment for eosinophilia were more effective than no albendazole group, too (83.3% vs. 28.6 %, p = 0.045). CONCLUSIONS: The prevalence of toxocariasis was high among patients suspected of eosinophilia of unknown origin; therefore, evaluation for T. canis infection is recommended for patients with eosinophilia of unknown origin. Furthermore, for patients suspected of eosinophilia of unknown origin who have positive results for T. canis, albendazole treatment may be considered a valuable treatment option. PMID- 28352061 TI - Does the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor differ according to the type of EGFR mutation in non-small cell lung cancer? AB - An exon 19 deletion and a L858R mutation in exon 21 of the epidermal growth factor receptor (EGFR) are the two most common mutations that predict favorable efficacy of EGFR tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). Many retrospective and prospective studies, as well as meta-analyses including patients with NSCLC with various lines of EGFR TKI treatment, have demonstrated longer progression-free survival and sometimes more favorable overall survival in patients with an exon 19 deletion than those with the L858R or other mutations. In contrast, some clinical studies, including phase III trials, have demonstrated no difference in the efficacy of EGFR TKIs according to the EGFR mutation type. Therefore, the existence of clinically significant differences in sensitivity to EGFR-TKIs among different EGFR mutation subtypes remains controversial. In this review, we summarize the evidence suggesting different outcomes according to the type of EGFR mutation in patients with advanced NSCLC who were treated with EGFR-TKIs, along with their clinical significance. We also discuss possible mechanisms that can explain the different sensitivities to EGFR TKIs between cases with an exon 19 deletion and those with the L858R mutation. PMID- 28352062 TI - Atorvastatin inhibits osteoclast differentiation by suppressing NF-kappaB and MAPK signaling during IL-1beta-induced osteoclastogenesis. AB - BACKGROUND/AIMS: To define the effect of statins on interleukin 1beta (IL-1beta) induced osteoclastogenesis and elucidate the underlying mechanisms. METHODS: Bone marrow cells were obtained from 5-week-old male ICR (Institute for Cancer Research) mice, and they were cultured to differentiate them into osteoclasts with macrophage colony-stimulating factor and the receptor activator of nuclear factor (NF)-kappaB ligand in the presence or absence of IL-1beta or atorvastatin. The formation of osteoclasts was evaluated by tartrate-resistant acid phosphatase (TRAP) staining and resorption pit assay with dentine slice. The molecular mechanisms of the effects of atorvastatin on osteoclastogenesis were investigated using reverse transcription polymerase chain reaction and immunoblotting for osteoclast specific molecules. RESULTS: Atorvastatin significantly reduced the number of TRAP-positive multinucleated cells as well as the bone resorption area. Atorvastatin also downregulated the expression of the NF of activated T-cell c1 messenger RNA and inhibited the expression of osteoclast-specific genes. A possible underlying mechanism may be that atorvastatin suppresses the degradation of the inhibitors of NF-kappaB and blocks the activation of the c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38; thus, implicating the NF kappaB and mitogen-activated protein kinases pathway in this process. CONCLUSIONS: Atorvastatin is a strong inhibitor of inflammation-induced osteoclastogenesis in inflammatory joint diseases. PMID- 28352064 TI - Clinical characteristics associated with occurrence and poor prognosis of interstitial lung disease in rheumatoid arthritis. AB - Background/Aims: To analyze clinical characteristics of interstitial lung disease (ILD) associated with rheumatoid arthritis (RA), especially in patients with poor prognosis. Methods: Seventy-seven RA patients with ILD and 231 age, sex, and disease duration-matched RA patients without ILD were enrolled in this retrospective study. Epidemiologic, clinical, and laboratory information were obtained through a medical chart review. Logistic regression analysis was used to estimate the risk of mortality in RA patients with ILD. Results: Compared to the RA without ILD group, the RA with ILD group had significantly higher titers of rheumatoid factor and the anti-cyclic citrullinated peptide (p = 0.001 for both), higher levels of C-reactive protein (CRP) at the time of RA diagnosis (p = 0.014), and a higher erythrocyte sedimentation rate (p = 0.022) and CRP levels (p < 0.001) throughout the 10-year follow-up period. These patients also received a higher mean daily dose of corticosteroids (p < 0.001). In the subgroup analysis of RA patients with ILD, 28 patients (36.4%) died during follow-up. Multivariate analysis revealed that older age at the time of ILD diagnosis was significantly associated with mortality. Usual interstitial pneumonia (UIP) subtype on high resolution computed tomography (HRCT) was also suggested as a poor prognostic factor. Conclusions: The survival of RA patients with ILD is adversely affected by age at the time of ILD diagnosis. RA-ILD patients diagnosed after age 65 or with a UIP subtype on HRCT may have a poor prognosis. PMID- 28352065 TI - Attitudes to proposed assessment of pharmacy skills in Korean pharmacist licensure examination. AB - PURPOSE: The survey aimed to obtain opinions about a proposed implementation of pharmacy skills assessment in Korean pharmacist licensure examination (KPLE). METHODS: A 16-question survey was distributed electronically to 2,738 people including 570 pharmacy professors of 35 pharmacy schools, 550 preceptors from 865 practice sites and 1,618 students who graduated in 2015. The survey solicited responses concerning the adequacy of the current KPLE in assessing pharmacy knowledge/skills/attitudes, deficiencies of pharmacy skills testing in assessing the professional competencies necessary for pharmacists, plans for pharmacy skills tests in the current KPLE, and subject areas of pharmacy practice. RESULTS: A total of 466 surveys were returned. The current exam is not adequate for assessing skills and attitudes according to 42%-48% of respondents. Sixty percent felt that skills test is necessary to assess qualifications and professional competencies. Almost two-thirds of participants stated that testing should be implemented within 5 years. More than 60% agreed that candidates should be graduates and that written and skills test scores can be combined for pass fail decisions. About 70% of respondents felt that the test should be less than 2 hours in duration. Over half of the respondents thought that the assessor should be a pharmacy faculty member with at least 5 years of clinical experience. Up to 70% stated that activities related to patient care were appropriate and practical for the scope of skills test. CONCLUSION: Pharmacy skills assessment was supported by the majority of respondents. PMID- 28352063 TI - Erythromycin infusion prior to endoscopy for acute nonvariceal upper gastrointestinal bleeding: a pilot randomized controlled trial. AB - BACKGROUND/AIMS: The aim of this study was to compare the effects of erythromycin infusion and gastric lavage in order to improve the quality of visualization during emergency upper endoscopy. METHODS: We performed a prospective randomized pilot study. Patients presented with hematemesis or melena within 12 hours and were randomly assigned to the erythromycin group (intravenous infusion of erythromycin), gastric lavage group (nasogastric tube placement with gastric lavage), or erythromycin + gastric lavage group (both erythromycin infusion and gastric lavage). The primary outcome was satisfactory visualization. Secondary outcomes included identification of a bleeding source, the success rate of hemostasis, duration of endoscopy, complications related to erythromycin infusion or gastric lavage, number of transfused blood units, rebleeding rate, and bleeding-related mortality. RESULTS: A total of 43 patients were randomly assigned: 14 patients in the erythromycin group; 15 patients in the gastric lavage group; and 14 patients in the erythromycin + gastric lavage group. Overall satisfactory visualization was achieved in 81% of patients: 92.8% in the erythromycin group; 60.0% in the gastric lavage group; and 92.9% in the erythromycin + gastric lavage group, respectively (p = 0.055). The identification of a bleeding source was possible in all cases. The success rate of hemostasis, duration of endoscopy, and number of transfused blood units did not significantly differ between groups. There were no complications. Rebleeding occurred in three patients (7.0%). Bleeding-related mortality was not reported. CONCLUSIONS: Intravenous erythromycin infusion prior to emergency endoscopy for acute nonvariceal upper gastrointestinal bleeding seems to provide satisfactory endoscopic visualization. PMID- 28352066 TI - Improving student-perceived benefit of academic advising within education of occupational and physical therapy in the United States: a quality improvement initiative. AB - Academic advising is a key role for faculty in the educational process of health professionals; however, the best practice of effective academic advising for occupational and physical therapy students has not been identified in the current literature. The purpose of this quality improvement initiative was to assess and improve the faculty/student advisor/advisee process within occupational and physical therapy programs within a school of allied health professions in the United States in 2015. A quality improvement initiative utilizing quantitative and qualitative information was gathered via survey focused on the assessment and improvement of an advisor/advisee process. The overall initiative utilized an adaptive iterative design incorporating the plan-do-study-act model which included a three-step process over a one year time frame utilizing 2 cohorts, the first with 80 students and the second with 88 students. Baseline data were gathered prior to initiating the new process. A pilot was conducted and assessed during the first semester of the occupational and physical therapy programs. Final information was gathered after one full academic year with final comparisons made to baseline. Defining an effective advisory program with an established framework led to improved awareness and participation by students and faculty. Early initiation of the process combined with increased frequency of interaction led to improved student satisfaction. Based on student perceptions, programmatic policies were initiated to promote advisory meetings early and often to establish a positive relationship. The policies focus on academic advising as one of proactivity in which the advisor serves as a portal which the student may access leading to a more successful academic experience. PMID- 28352067 TI - Presidential address: introduction of smart device-based testing and item exposure policy for Korea Health Personnel Licensing Examination. PMID- 28352068 TI - Systemic Lupus Erythematosus and Bullous Pemphigoid with Dramatic Response to Dapsone. AB - BACKGROUND Bullous pemphigoid is an autoimmune blistering disease, with relapses, isolated or associated with other autoimmune diseases such as systemic lupus erythematosus (SLE). Joint manifestations rapidly respond to small or moderate doses of corticosteroids, whereas skin manifestations usually respond to antimalarial drugs. CASE REPORT We describe the clinical case of an 11-year-old girl with SLE. She showed bullous skin lesions with arthralgia, mild proteinuria, resolved after steroid treatment. At the tapering of her prednisone dose, the patient had new skin lesions requiring an increased dose of prednisone. She started dapsone at the dosage of 1 mg/kg/day, maintaining low dose prednisone; this treatment was successfully followed by the dramatic disappearance of skin lesions and limb pain. CONCLUSIONS Bullous skin lesions can represent the first clinical presentation of pediatric SLE and could influence the treatment and the outcome of these patients. This case showed an atypical course as both skin manifestations and arthritis promptly and persistently resolved with dapsone without the use of high-dose glucocorticoids. Only a few cases of patients with SLE associated with bullous pemphigoid have been reported in the literature, and very few in the pediatric population. PMID- 28352069 TI - Efficacy of N-Butylphthalide and Hyperbaric Oxygen Therapy on Cognitive Dysfunction in Patients with Delayed Encephalopathy After Acute Carbon Monoxide Poisoning. AB - BACKGROUND Delayed encephalopathy after acute carbon monoxide (CO) poisoning (DEACMP) is one of the most serious complications after CO poisoning. This study was conducted to explore the efficacy of the combined application of N Butylphthalide and hyperbaric oxygenation therapy (HBO) on cognitive dysfunction in patients with DEACMP. MATERIAL AND METHODS A total of 184 patients with DEACMP were randomly assigned to either receive HBO or N-Butylphthalide and HBO. Meanwhile, all patients received conventional treatment. The total remission rate (RR) was used to assess the clinical efficacy. The Mini-Mental State Examination (MMSE) was used to assess the cognitive function, and the National Institutes of Health Stroke Scale (NIHSS) was used to assess the neurological function. RESULTS Finally, there were 90 and 94 patients in the control and experimental groups, respectively. After eight weeks of treatment, the total RR in the experimental group (47.9%) was significantly higher than that in the control group (33.3%). Compared to the control group, significantly more patients in the experimental group had MMSE scores of 24-30. The lower NIHSS score in the experimental group showed that N-Butylphthalide had the effect of preservation and restoration of neurological function. No obvious drug toxicity or liver and kidney dysfunction was observed, and there was no significant change in the level of blood glucose and blood lipids. CONCLUSIONS These results indicated that the combined application of N-Butylphthalide and HBO could significantly improve the cognitive dysfunction of patients with DEACMP and have great clinical efficacy, which should be further studied. PMID- 28352070 TI - Dopant size effects on novel functionalities: High-temperature interfacial superconductivity. AB - Among the range of complex interactions, especially at the interfaces of epitaxial oxide systems, contributing to the occurrence of intriguing effects, a predominant role is played by the local structural parameters. In this study, oxide molecular beam epitaxy grown lanthanum cuprate-based bilayers (consisting of a metallic (M) and an insulating phase (I)), in which high-temperature superconductivity arises as a consequence of interface effects, are considered. With the aim of assessing the role of the dopant size on local crystal structure and chemistry, and on the interface functionalities, different dopants (Ca2+, Sr2+ and, Ba2+) are employed in the M-phase, and the M-I bilayers are investigated by complementary techniques, including spherical-aberration corrected scanning transmission electron microscopy. A series of exciting outcomes are found: (i) the average out-of-plane lattice parameter of the bilayers is linearly dependent on the dopant ion size, (ii) each dopant redistributes at the interface with a characteristic diffusion length, and (iii) the superconductivity properties are highly dependent on the dopant of choice. Hence, this study highlights the profound impact of the dopant size and related interface chemistry on the functionalities of superconducting oxide systems. PMID- 28352071 TI - Efficient ECG Compression and QRS Detection for E-Health Applications. AB - Current medical screening and diagnostic procedures have shifted toward recording longer electrocardiogram (ECG) signals, which have traditionally been processed on personal computers (PCs) with high-speed multi-core processors and efficient memory processing. Battery-driven devices are now more commonly used for the same purpose and thus exploring highly efficient, low-power alternatives for local ECG signal collection and processing is essential for efficient and convenient clinical use. Several ECG compression methods have been reported in the current literature with limited discussion on the performance of the compressed and the reconstructed ECG signals in terms of the QRS complex detection accuracy. This paper proposes and evaluates different compression methods based not only on the compression ratio (CR) and percentage root-mean-square difference (PRD), but also based on the accuracy of QRS detection. In this paper, we have developed a lossy method (Methods III) and compared them to the most current lossless and lossy ECG compression methods (Method I and Method II, respectively). The proposed lossy compression method (Method III) achieves CR of 4.5*, PRD of 0.53, as well as an overall sensitivity of 99.78% and positive predictivity of 99.92% are achieved (when coupled with an existing QRS detection algorithm) on the MIT-BIH Arrhythmia database and an overall sensitivity of 99.90% and positive predictivity of 99.84% on the QT database. PMID- 28352072 TI - Functional insights into aberrant brain responses and integration in patients with lifelong premature ejaculation. AB - Even though lifelong premature ejaculation (PE) is highly prevalent, few studies have investigated the neural mechanisms underlying PE. The extent and pattern of brain activation can be determined through a version of functional magnetic resonance imaging (fMRI) with erotic picture stimuli (task fMRI) and a resting state fMRI (rs fMRI). We showed that the brain activity in the left inferior frontal gyrus and left insula was decreased both during the task and in the resting state, while there was higher activation in the right middle temporal gyrus during the task. Higher functional connectivity was found in PE between those three brain areas and the bilateral middle cingulate cortex, right middle frontal gyrus and supplementary motor area. Moreover, the brain activity had positive correlation with clinical rating scales, such as intravaginal ejaculatory latency time (IELT) and the Chinese Index of Premature Ejaculation (CIPE). These findings revealed that brain responses and functional integration in certain brain areas are impaired in cases of PE, which was consistently supported by multiple measurements obtained using a task and rs fMRI approach. PMID- 28352073 TI - Periaqueductal Grey differential modulation of Nucleus Accumbens and Basolateral Amygdala plasticity under controllable and uncontrollable stress. AB - Resilience has been conceptualized in part as a dynamic process that includes the ability to adapt to stressful conditions. As such it encompasses the extent to which neural plasticity may be promoted. The current study examined metaplasticity by referring to the "plasticity of synaptic plasticity" in a neural circuit composed of the basolateral amygdala (BLA) and the nucleus accumbens (NAcc), using behavioural stress controllability with or without preceding stimulation of the dorsal periaqueductal gray (i.e. dPAG priming). A tendency for increased plasticity in the controllable versus the uncontrollable group was found in both the BLA and NAcc. dPAG priming suppressed NAcc LTP in all groups, but it suppressed BLA LTP only in the uncontrollable group, demonstrating dissociation between either controllable and uncontrollable groups or the NAcc and BLA. Thus, metaplasticity in the dPAG-BLA-NAcc circuit regulated differentially by controllable or uncontrollable stress may underlie stress coping, and thus contribute to stress-related psychopathologies. PMID- 28352074 TI - Optimized Mass Spectrometry Analysis Workflow with Polarimetric Guidance for ex vivo and in situ Sampling of Biological Tissues. AB - Spatially Targeted Mass Spectrometry (MS) analysis using survey scans with an imaging modality often requires consecutive tissue slices, because of the tissue damage during survey scan or due to incompatible sample preparation requirements between the survey modality and MS. We report two spatially targeted MS analysis workflows based on polarized light imaging guidance that use the same tissue sample for survey and targeted analysis. The first workflow is applicable for thin-slice analysis, and uses transmission-polarimetry-guided Desorption ElectroSpray Ionization Mass Spectrometry (DESI-MS), and confirmatory H&E histopathology analysis on the same slice; this is validated using quantitative digital pathology methods. The second workflow explores a polarimetry-guided MS platform for thick tissue assessment by developing reflection-mode polarimetric imaging coupled with a hand-held Picosecond InfraRed Laser (PIRL) MS ablation probe that requires minimal tissue removal to produce detectable signal. Tissue differentiation within 5-10 s of sampling with the hand-held probe is shown using multivariate statistical methods of the MS profiles. Both workflows were tasked with differentiating necrotic cancer sites from viable cancers using a breast tumour model, and their performance was evaluated. The use of the same tissue surface addresses mismatches in guidance due to intrinsic changes in tissue morphology over consecutive sections. PMID- 28352075 TI - Elevated COX-2 Expression Promotes Angiogenesis Through EGFR/p38-MAPK/Sp1 Dependent Signalling in Pancreatic Cancer. AB - Cyclooxygenase-2 (COX-2) was stated to be overexpression in various human malignancies associating with angiogenesis, metastasis and chemoresistence. Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease displaying many of these characteristics. A common abnormality of PDAC is overexpression of specificity protein-1 (Sp1), which was said to correlate with malignant phenotypes of human cancers. Using RNA-seq data from The Cancer Genome Atlas (TCGA), we found that Sp1 expression was positively correlated with that of COX-2 in PDAC, and that the inhibition or overexpression of Sp1 in PDAC cells leads to decreased or elevated COX-2 expression. Luciferase reporter gene and chromatin immunoprecipitation (ChIP) assays revealed that elevated transcription of COX-2 requires Sp1 binding to sequence positions around -245/-240 of COX-2 promoter. Activated epidermal growth factor receptor (EGFR) and downstream p38 mitogen activated protein kinase (p38-MAPK) were also profoundly altered in PDAC. The inhibition of EGFR/p38-MAPK signaling resulted in reduced Sp1 activation, decreased COX-2 and vascular endothelial growth factor (VEGF) expression. Thus, Sp1 could transcriptionally activate COX-2 expression in a process relies on activated EGFR/p38-MAPK signaling. Finally, we found that the inhibition of COX-2 leads to decreased angiogenesis in a process dependent on VEGF, which link COX-2 to angiogenesis in PDAC. PMID- 28352076 TI - Interaction of cochlin and mechanosensitive channel TREK-1 in trabecular meshwork cells influences the regulation of intraocular pressure. AB - This work was funded by National Institute of Health Grants R01 EY016112, EY015266, and EY014801 and an unrestricted grant to the University of Miami's Bascom Palmer Eye Institute from Research to Prevent Blindness. Financial support from Fight for Sight is gratefully acknowledged. Funding to XG was provided by Instituto de Salud Carlos III, Spain (FIS PI14/00141 and RETIC RD12/0034/0003) and Generalitat de Catalunya (2014SGR1165). In the eye, intraocular pressure (IOP) is tightly regulated and its persistent increase leads to ocular hypertension and glaucoma. We have previously shown that trabecular meshwork (TM) cells might detect aqueous humor fluid shear stress via interaction of the extracellular matrix (ECM) protein cochlin with the cell surface bound and stretch-activated channel TREK-1. We provide evidence here that interaction between both proteins are involved in IOP regulation. Silencing of TREK-1 in mice prevents the previously demonstrated cochlin-overexpression mediated increase in IOP. Biochemical and electrophysiological experiments demonstrate that high shear stress-induced multimeric cochlin produces a qualitatively different interaction with TREK-1 compared to monomeric cochlin. Physiological concentrations of multimeric but not monomeric cochlin reduce TREK-1 current. Results presented here indicate that the interaction of TREK-1 and cochlin play an important role for maintaining IOP homeostasis. PMID- 28352077 TI - A peculiar lens-shaped structure observed in the South China Sea. AB - Lens-shaped structures within thermocline potentially play a significant role in subsurface transport of mass, heat, and salt in the global ocean. Whilst such structures have been documented in many oceanic regions, none has been observed in the China Seas. This study reports on observations of a lens-shaped structure within thermocline in the southwestern South China Sea in September 2007. This structure had a maximum thickness of approximately 60 m and a horizontal extent exceeding 220 km. This lens was peculiar in that its size is larger than most similar structures documented in the literature. The lens core was characterized by well-mixed water with higher temperature (~28.8 degrees C), lower salinity (~33.3) and lower potential vorticity (PV) compared to the surrounding waters. Based on an ocean reanalysis, possible generation mechanism of the lens is explored by examining the evolution of surface and subsurface thermohaline properties, and an analysis of vertical PV flux. The lens was likely generated by a mixture of the local mixed-layer water and the water from the coastal jet separation site. PMID- 28352078 TI - Mining of efficient microbial UDP-glycosyltransferases by motif evolution cross plant kingdom for application in biosynthesis of salidroside. AB - The plant kingdom provides a large resource of natural products and various related enzymes are analyzed. The high catalytic activity and easy genetically modification of microbial enzymes would be beneficial for synthesis of natural products. But the identification of functional genes of target enzymes is time consuming and hampered by many contingencies. The potential to mine microbe derived glycosyltransferases (GTs) cross the plant kingdom was assessed based on alignment and evolution of the full sequences and key motifs of target enzymes, such as Rhodiola-derived UDP-glycosyltransferase (UGT73B6) using in salidroside synthesis. The GTs from Bacillus licheniformis ZSP01 with high PSPG motif similarity were speculated to catalyze the synthesis of salidroside. The UGTBL1, which had similarity (61.4%) PSPG motif to UGT73B6, displayed efficient activity and similar regioselectivity. Highly efficient glycosylation of tyrosol (1 g/L) was obtained by using engineered E. coli harboring UGTBL1 gene, which generated 1.04 g/L salidroside and 0.99 g/L icariside D2. All glycosides were secreted into the culture medium and beneficial for downstream purification. It was the first report on the genome mining of UGTs from microorganisms cross the plant kingdom. The mining approach may have broader applications in the selection of efficient candidate for making high-value natural products. PMID- 28352080 TI - Rapid generation of a transgene-free powdery mildew resistant tomato by genome deletion. AB - Genome editing has emerged as a technology with a potential to revolutionize plant breeding. In this study, we report on generating, in less than ten months, Tomelo, a non-transgenic tomato variety resistant to the powdery mildew fungal pathogen using the CRISPR/Cas9 technology. We used whole-genome sequencing to show that Tomelo does not carry any foreign DNA sequences but only carries a deletion that is indistinguishable from naturally occurring mutations. We also present evidence for CRISPR/Cas9 being a highly precise tool, as we did not detect off-target mutations in Tomelo. Using our pipeline, mutations can be readily introduced into elite or locally adapted tomato varieties in less than a year with relatively minimal effort and investment. PMID- 28352079 TI - Protein tyrosine phosphatase Shp2 deficiency in podocytes attenuates lipopolysaccharide-induced proteinuria. AB - Podocytes are specialized epithelial cells that play a significant role in maintaining the integrity of the glomerular filtration barrier and preventing urinary protein leakage. We investigated the contribution of protein tyrosine phosphatase Shp2 to lipopolysaccharide (LPS)-induced renal injury. We report increased Shp2 expression in murine kidneys and cultured podocytes following an LPS challenge. To determine the role of podocyte Shp2 in vivo, we generated podocyte-specific Shp2 knockout (pod-Shp2 KO) mice. Following administration of LPS, pod-Shp2 KO mice exhibited lower proteinuria and blood urea nitrogen concentrations than controls indicative of preserved filter integrity. In addition, renal mRNA and serum concentrations of inflammatory cytokines IL-1beta, TNFalpha, INFgamma and IL-12 p70 were significantly decreased in LPS-treated knockout mice compared with controls. Moreover, the protective effects of podocyte Shp2 deficiency were associated with decreased LPS-induced NF-kappaB and MAPK activation, nephrin phosphorylation and attenuated endoplasmic reticulum stress. These effects were recapitulated in differentiated E11 murine podocytes with lentiviral-mediated Shp2 knockdown. Furthermore, Shp2 deficient podocytes displayed reduced LPS-induced migration in a wound healing assay. These findings identify Shp2 in podocytes as a significant contributor to the signaling events following LPS challenge and suggest that inhibition of Shp2 in podocytes may present a potential therapeutic target for podocytopathies. PMID- 28352081 TI - Hydration of Proton-conducting BaCe0.9Y0.1O3-delta by Decoupled Mass Transport. AB - Mass relaxation profile of a perovskite-type oxide, BaCe0.9Y0.1O3-delta, was studied to understand decoupled diffusion of oxygen and hydrogen species during hydration/dehydration. The mass relaxation measurements are performed by thermogravimetric analysis (TGA) under various humidity conditions (Dry, -3.0 <= log(pH2O/atm) <= -1.6) at a constant oxygen partial pressure (log(pO2/atm) = 1.00 +/- 0.01). The decoupled ions participated in hydration/dehydration reactions were proven to be at different ratios from the result introduced by the 8R m function. The enthalpy and entropy of non-stoichiometric hydration reaction, which considers each ratio of charge-carrier species, were -144.7 +/- 3.7 kJ/mol and -147.8 +/- 3.2 J/mol . K, respectively. PMID- 28352083 TI - Novel contactless approach for assessment of venous occlusion plethysmography by video recordings at the green illumination. AB - Occlusion plethysmography is an important method for assessment of the status of the cardiovascular system, which provides valuable information concerning arterial and venous blood flow, including mechanisms of their regulation. All up to-date systems estimate change of the limb's volume during occlusion by contact type sensors. The objective of the research is demonstration of feasibility of the novel approach to measuring the blood flow during venous occlusion by using imaging photoplethysmography (PPG). Twenty healthy individuals participated in the experiment. We used four synchronized video cameras to record all-around view of the forearm illuminated by the green light. After the recording, the PPG waveform was calculated in more than 4000 non-overlapping Regions of Interest (ROI). In the most of the ROIs, the waveform shape was typical for classical plethysmography with the distinctive linear growth of the signal. Speed of the signal change was the same along the forearm but it varied along the forearm's circumference. These findings allows us to hypothesize that the PPG waveform is the direct consequence of the forearm blood flow. Therefore, the novel technique could be applied to the same medical examinations as the classical plethysmography, but it is more advantageous because of non-contact nature and easiness in implementation. PMID- 28352084 TI - Porous Layered Double Hydroxides Synthesized using Oxygen Generated by Decomposition of Hydrogen Peroxide. AB - Porous magnesium-aluminium layered double hydroxides (LDH) were prepared through intercalation and decomposition of hydrogen peroxide (H2O2). This process generates oxygen gas nano-bubbles that pierce holes in the layered structure of the material by local pressure build-up. The decomposition of the peroxide can be triggered by microwave radiation or chemically by reaction with iodide (I-) ions. The carbonate LDH version [Mg0.80Al0.20(OH)2](CO3)0.1?mH2O was synthesized by microwave-assisted urea coprecipitation and further modified by iodide or H2O2 intercalation. High resolution Scanning Electron Microscopy (HR-SEM) and Brunauer Emmet-Teller (BET) analysis were used to assess the morphology and surface area of the new porous materials. The presence of H2O2 in the interlayer region and later decomposition triggered by microwave radiation generated more pores on the surface of the LDH platelets, increasing their specific surface area from initially 9 m2/g to a maximum of 67 m2/g. X-Ray Diffraction showed that the formation of the pores did not affect the remaining crystal structure, allowing possible further functionalization of the material. PMID- 28352082 TI - A normative spatiotemporal MRI atlas of the fetal brain for automatic segmentation and analysis of early brain growth. AB - Longitudinal characterization of early brain growth in-utero has been limited by a number of challenges in fetal imaging, the rapid change in size, shape and volume of the developing brain, and the consequent lack of suitable algorithms for fetal brain image analysis. There is a need for an improved digital brain atlas of the spatiotemporal maturation of the fetal brain extending over the key developmental periods. We have developed an algorithm for construction of an unbiased four-dimensional atlas of the developing fetal brain by integrating symmetric diffeomorphic deformable registration in space with kernel regression in age. We applied this new algorithm to construct a spatiotemporal atlas from MRI of 81 normal fetuses scanned between 19 and 39 weeks of gestation and labeled the structures of the developing brain. We evaluated the use of this atlas and additional individual fetal brain MRI atlases for completely automatic multi atlas segmentation of fetal brain MRI. The atlas is available online as a reference for anatomy and for registration and segmentation, to aid in connectivity analysis, and for groupwise and longitudinal analysis of early brain growth. PMID- 28352085 TI - Bisphenol S negatively affects the meotic maturation of pig oocytes. AB - Bisphenol A (BPA), a chemical component of plastics, is a widely distributed environmental pollutant and contaminant of water, air, and food that negatively impacts human health. Concerns regarding BPA have led to the use of BPA-free alternatives, one of which is bisphenol S (BPS). However, the effects of BPS are not well characterized, and its specific effects on reproduction and fertility remain unknown. It is therefore necessary to evaluate any effects of BPS on mammalian oocytes. The present study is the first to demonstrate the markedly negative effects of BPS on pig oocyte maturation in vitro, even at doses lower than those humans are exposed to in the environment. Our results demonstrate (1) an effect of BPS on the course of the meiotic cell cycle; (2) the failure of tubulin fibre formation, which controls proper chromosome movement; (3) changes in the supply of maternal mRNA; (4) changes in the protein amounts and distribution of oestrogen receptors alpha and beta and of aromatase; and (5) disrupted cumulus cell expansion. Thus, these results confirm that BPS is an example of regrettable substitution because this substance exerts similar or even worse negative effects than those of the material it replaced. PMID- 28352087 TI - Feasibility and applicability of the paper and electronic COPD assessment test (CAT) and the clinical COPD questionnaire (CCQ) in primary care: a clinimetric study. AB - Three questionnaires are recommended in the management of chronic obstructive pulmonary disease by the global initiative for obstructive lung disease, of which two are the more comprehensive assessments: the chronic obstructive pulmonary disease assessment test and the clinical chronic obstructive pulmonary disease questionnaire. Both are carefully designed high-quality questionnaires, but information on the feasibility for routine use is scarce. The aim of this study was to compare the time to complete the chronic obstructive pulmonary disease assessment test and the clinical chronic obstructive pulmonary disease questionnaire and the acceptability of the questionnaires. Furthermore, the agreement between electronic and paper versions of the questionnaires was explored. The time to complete the electronic versions of the questionnaires was 99.6 [IQR 74; 157] vs. 97.5 [IQR 68; 136] seconds for clinical clinical chronic obstructive pulmonary disease questionnaire and chronic obstructive pulmonary disease assessment test, respectively. The difference in time to complete the questionnaire was not significant. The two questionnaires did not differ in "easiness to complete" or "importance of issues raised in questionnaires". Electronic vs. paper versions revealed high agreement (ICC CCQ = 0.815 [0.712; 0.883] and ICC CAT = 0.751 [0.608; 0.847]) between the administration methods. Based on this study it can be concluded that both questionnaires are equally suitable for use in routine clinical practice, because they are both quick to complete and have a good acceptability by the patient. Agreement between electronic and paper versions of the questionnaires was high, so use of electronic versions is justified.COPD: QUESTIONNAIRES EQUALLY SUITABLE FOR CLINICAL PRACTICE: Two questionnaires commonly used to manage chronic obstructive pulmonary diseases (COPD) are equally suitable for routine primary care. Researchers in The Netherlands, led by Janwillem Kocks from the University Medical Center Groningen, administered both the COPD assessment test (CAT) and the clinical COPD questionnaire (CCQ) to 95 patients with the lung disease. These two tests are the most comprehensive assessments recommended by the global initiative for obstructive lung disease for guiding treatment decisions. The researchers found that both tests took approximately 95-100 s on average. Both tests were also equally easy to complete and provided similar types of information. Most patients said they had no preference for either one, and they filled out both electronic and paper versions of the questionnaires in much the same way. The authors conclude that both tests seem fine for routine use. PMID- 28352086 TI - Enhanced generation of human induced pluripotent stem cells by ectopic expression of Connexin 45. AB - Somatic cells can be successfully reprogrammed into pluripotent stem cells by the ectopic expression of defined transcriptional factors. However, improved efficiency and better understanding the molecular mechanism underlying reprogramming are still required. In the present study, a scrape loading/dye transfer assay showed that human induced pluripotent stem cells (hiPSCs) contained functional gap junctions partially contributed by Connexin 45 (CX45). We then found CX45 was expressed in human embryonic stem cells (hESCs) and human dermal fibroblasts (hDFs) derived hiPSCs. Then we showed that CX45 was dramatically upregulated during the reprogramming process. Most importantly, the ectopic expression of CX45 significantly enhanced the reprogramming efficiency together with the Yamanaka factors (OCT4, SOX2, KLF4, cMYC - OSKM), whereas knockdown of endogenous CX45 expression significantly blocked cellular reprogramming and reduced the efficiency. Our further study demonstrated that CX45 overexpression or knockdown modulated the cell proliferation rate which was associated with the reprogramming efficiency. In conclusion, our data highlighted the critical role of CX45 in reprogramming and may increase the cell division rate and result in an accelerated kinetics of iPSCs production. PMID- 28352088 TI - Salt-dependent Blood Pressure in Human Aldosterone Synthase-Transgenic Mice. AB - Hypertension is one of the most important, preventable causes of premature morbidity and mortality in the developed world. Aldosterone is a major mineralocorticoid hormone that plays a key role in the regulation of blood pressure and is implicated in the pathogenesis of hypertension and heart failure. Aldosterone synthase (AS, cytochrome P450 11B2, cyp11B2) is the sole enzyme responsible for the production of aldosterone in humans. To determine the effects of increased expression of human aldosterone synthase (hAS) on blood pressure (BP), we established transgenic mice carrying the hAS gene (cyp11B2). We showed that hAS overexpression increased levels of aldosterone in hAS+/- mice. On high salt diet (HS), BPs of hAS+/- mice were significantly increased compared with WT mice. Fadrozole (an inhibitor of aldosterone synthase) treatment significantly reduced BPs of hAS+/- mice on HS. This is the first time overexpression of AS in a transgenic mouse line has shown an ability to induce HP. Specifically inhibiting AS activity in these mice is a promising therapy for reducing hypertension. This hAS transgenic mouse model is therefore an ideal animal model for hypertension therapy studies. PMID- 28352090 TI - Precise Tuning of the Nanostructured Surface leading to the Luminescence Enhancement in SrAl2O4 Based Core/Shell Structure. AB - Intensive research has been focused on the synthesis of long-lasting SrAl2O4:EuDy in luminescent materials field. Traditionally, SrAl2O4:EuDy is synthesized in bulk form by solid state. However, their development remains restrained due to this technique is not compatible with large-scale production, sustainability and nanometer-scale requirements. Despite nano-range particles have been obtained by chemical routes, photoluminescence response decreases and application became unpractical. It remains a challenge to synthesize nonrare-earth (RE) phosphors with high photoluminescence. One major challenge for the luminescent materials community is to devise methods to deliver innovative, sustainable and cost effective solutions for the reduction of RE because of the lack of RE availability. Here, we suggest a solution based on molten salts, obtaining nanosheets or micro/nanostructured SrAl2O4:Eu, Dy particles with core-shell structure, employing only 50% of standard amounts of RE. Core-size and shell thickness and crystallinity can be tuned by post-thermal treatment, through which can be modulated the Eu+2 fraction. We find that our methodology leads the functional features of the analogous micron counterpart. These results can be considered a great achievement to scale-up the process. Besides, the harmful collateral effect of nanotechnology must be addressed by using new safe by design core-shell nanostructures. PMID- 28352092 TI - The quantum game. PMID- 28352089 TI - Exploring the Association Between Demographics, SLC30A8 Genotype, and Human Islet Content of Zinc, Cadmium, Copper, Iron, Manganese and Nickel. AB - A widely prevalent single nucleotide polymorphism, rs13266634 in the SLC30A8 gene encoding the zinc transporter ZnT8, is associated with an increased risk for T2DM. ZnT8 is mostly expressed in pancreatic insulin-producing islets of Langerhans. The effect of this variant on the divalent metal profile in human islets is unknown. Additionally, essential and non-essential divalent metal content of human islets under normal environmental exposure conditions has not been described. We therefore examined the correlation of zinc and other divalent metals in human islets with rs13266634 genotype and demographic characteristics. We found that the diabetes risk genotype C/C at rs13266634 is associated with higher islet Zn concentration (C/C genotype: 16792 +/- 1607, n = 22, C/T genotype: 11221 +/- 1245, n = 18 T/T genotype: 11543 +/- 6054, n = 3, all values expressed as mean nmol/g protein +/- standard error of the mean, p = 0.040 by ANOVA). A positive correlation between islet cadmium content and both age (p = 0.048, R2 = 0.09) and female gender (women: 36.88 +/- 4.11 vs men: 21.22 +/- 3.65 nmol/g protein, p = 0.007) was observed. Our results suggest that the T2DM risk allele C is associated with higher islet zinc levels and support prior evidence of cadmium's higher bioavailability in women and its long tissue half-life. PMID- 28352093 TI - Addendum: Multiscale metallic metamaterials. PMID- 28352091 TI - Genome sequencing and analysis of Talaromyces pinophilus provide insights into biotechnological applications. AB - Species from the genus Talaromyces produce useful biomass-degrading enzymes and secondary metabolites. However, these enzymes and secondary metabolites are still poorly understood and have not been explored in depth because of a lack of comprehensive genetic information. Here, we report a 36.51-megabase genome assembly of Talaromyces pinophilus strain 1-95, with coverage of nine scaffolds of eight chromosomes with telomeric repeats at their ends and circular mitochondrial DNA. In total, 13,472 protein-coding genes were predicted. Of these, 803 were annotated to encode enzymes that act on carbohydrates, including 39 cellulose-degrading and 24 starch-degrading enzymes. In addition, 68 secondary metabolism gene clusters were identified, mainly including T1 polyketide synthase genes and nonribosomal peptide synthase genes. Comparative genomic analyses revealed that T. pinophilus 1-95 harbors more biomass-degrading enzymes and secondary metabolites than other related filamentous fungi. The prediction of the T. pinophilus 1-95 secretome indicated that approximately 50% of the biomass degrading enzymes are secreted into the extracellular environment. These results expanded our genetic knowledge of the biomass-degrading enzyme system of T. pinophilus and its biosynthesis of secondary metabolites, facilitating the cultivation of T. pinophilus for high production of useful products. PMID- 28352095 TI - Chiral ferromagnetic fluids: Let's twist again. PMID- 28352094 TI - Spectroscopy: Mapping spins in flatland. PMID- 28352096 TI - Quantum optics: A new way to correlate photons. PMID- 28352097 TI - Material witness: Gene memories. PMID- 28352098 TI - Biomedical engineering: In vitro amniogenesis. PMID- 28352099 TI - Removal of Diethylhexyl Phthalate from Hands by Handwashing: Evidence from Experimental N-of-1 and Crossover Designs. AB - Phthalate exposure through skin is often neglected due to the small quantity and limited dermal absorption rate. However, free phthalate can be ingested by hand to-mouth action or by contact with food. To evaluate the effectiveness in removing phthalate exposure on hand, we compare here the removal efficiency of di (2-ethylhexyl)phthalate (DEHP) on hands by handwashing with soap-and-water versus water-only. In two three-day N-of-1 trials, residual DEHP was measured in a single female adult who washed exposed hands with soap-and-water or water-only. Subsequently, a crossover study was performed by randomly assigning another 28 subjects equally to wash with soap-and-water or with water-only, and then each one received the other treatment 24 hrs later. In the N-of-1 trials, mean DEHP removal rates range from 95.9% (SD = 0.1%) to 97.0% (SD = 2.5%) for soap-and water handwashes, and 1.8% (SD = 0.1%) to 7.0% (SD = 0.3%) (n = 3) for water only. In the crossover study, mean removal rate was 94.6% (SD = 6.5%) for handwashing with soap-and-water (n = 28) and 8.7% (SD = 5.7%) for water-only (n = 28). We concluded that handwashing with soap-and-water removes 80% more DEHP than handwashing with water alone, and may be a cost-effective way of removing other endocrine disruptors from hands. PMID- 28352100 TI - Anodal tDCS over the primary motor cortex improves motor imagery benefits on postural control: A pilot study. AB - Performing everyday actions requires fine postural control, which is a major focus of functional rehabilitation programs. Among the various range of training methods likely to improve balance and postural stability, motor imagery practice (MIP) yielded promising results. Transcranial direct current stimulation (tDCS) applied over the primary motor cortex was also found to potentiate the benefits of MIP on upper-limb motor tasks. Yet, combining both techniques has not been tested for tasks requiring fine postural control. To determine the impact of MIP and the additional effects of tDCS, 14 participants performed a postural control task before and after two experimental (MIP + anodal or sham tDCS over the primary motor cortex) and one control (control task + sham tDCS) conditions, in a double blind randomized study. Data revealed a significant decrease of the time required to perform the postural task. Greater performance gains were recorded when MIP was paired with anodal tDCS and when the task involved the most complex postural adjustments. Altogether, findings highlight short-term effects of MIP on postural control and suggest that combining MIP with tDCS might also be effective in rehabilitation programs for regaining postural skills in easily fatigable persons and neurologic populations. PMID- 28352101 TI - Big-data-driven modeling unveils country-wide drivers of endemic schistosomiasis. AB - Schistosomiasis is a parasitic infection that is widespread in sub-Saharan Africa, where it represents a major health problem. We study the drivers of its geographical distribution in Senegal via a spatially explicit network model accounting for epidemiological dynamics driven by local socioeconomic and environmental conditions, and human mobility. The model is parameterized by tapping several available geodatabases and a large dataset of mobile phone traces. It reliably reproduces the observed spatial patterns of regional schistosomiasis prevalence throughout the country, provided that spatial heterogeneity and human mobility are suitably accounted for. Specifically, a fine grained description of the socioeconomic and environmental heterogeneities involved in local disease transmission is crucial to capturing the spatial variability of disease prevalence, while the inclusion of human mobility significantly improves the explanatory power of the model. Concerning human movement, we find that moderate mobility may reduce disease prevalence, whereas either high or low mobility may result in increased prevalence of infection. The effects of control strategies based on exposure and contamination reduction via improved access to safe water or educational campaigns are also analyzed. To our knowledge, this represents the first application of an integrative schistosomiasis transmission model at a whole-country scale. PMID- 28352102 TI - PKCalpha diffusion and translocation are independent of an intact cytoskeleton. AB - Translocation of cytosolic cPKC to the plasma membrane is a key event in their activation process but its exact nature is still unclear with particular dispute whether sole diffusion or additional active transport along the cell's cytoskeleton contributes to cPKC's dynamics. This was addressed by analyzing the recruitment behavior of PKCalpha while manipulating the cytoskeleton. Photolytic Ca2+ uncaging allowed us to quantify the kinetics of PKCalpha redistribution to the plasma membrane when fused to monomeric, dimeric and tetrameric fluorescence proteins. Results indicated that translocation kinetics were modulated by the state of oligomerization as expected for varying Stokes' radii of the participating proteins. Following depolymerization of the microtubules and the actin filaments we found that Ca2+ induced membrane accumulation of PKCalpha was independent of the filamentous state of the cytoskeleton. Fusion of PKCalpha to the photo-convertible fluorescent protein Dendra2 enabled the investigation of PKCalpha-cytoskeleton interactions under resting conditions. Redistribution following spatially restricted photoconversion showed that the mobility of the fusion protein was independent of the state of the cytoskeleton. Our data demonstrated that in living cells neither actin filaments nor microtubules contribute to PKCalpha's cytosolic mobility or Ca2+-induced translocation to the plasma membrane. Instead translocation is a solely diffusion-driven process. PMID- 28352103 TI - Simulation and measurement of optimized microwave reflectivity for carbon nanotube absorber by controlling electromagnetic factors. AB - Heat-treatments may change the defect and surface organic groups of carbon nanotubes (CNTs), and lead to significant changes in the microwave electromagnetic parameter of CNTs. In this paper, the effect of heat-treatment time and temperature on the complex dielectric constant and permeability as well as the microwave reflectivity of CNTs was investigated. The experimental results indicated that the microwave absorption property of CNTs arises mainly from the high permittivity and consequent dielectric loss. Moreover, the heat-treatment resulted in increased dielectric constant of CNTs and significant improvement of the microwave absorption at frequency values of 2-18 GHz. The microwave reflectivity of CNT composites with a coating thickness of 3 mm was simulated by using the electromagnetic parameters. The absorption peak of CNTs treated at 700 degrees C had an amplitude of R = -48 dB, which occurred at 9 GHz. Below -10 dB, the composites treated at 900 degrees C had a bandwidth of 7 GHz. The position of the absorption peak concurred with the measured results. The results indicated that the microwave-absorption properties can be modified by adjusting heat treatment temperature and time. PMID- 28352105 TI - Conjugative ESBL plasmids differ in their potential to rescue susceptible bacteria via horizontal gene transfer in lethal antibiotic concentrations. PMID- 28352106 TI - Bioactive secondary metabolites produced by an endophytic fungus Gaeumannomyces sp. JS0464 from a maritime halophyte Phragmites communis. AB - Endophytes, important plant-associated mycobionts, have attracted a great deal of attention because of their bioactive secondary metabolites. Even though halophytes have been reported to overcome salt stress via associations with their endophytes, few studies have investigated the metabolites produced by the endophytes from halophytes. In this study, a dark septate endophytic fungal strain (JS0464), identified as Gaeumannomyces sp. by ITS sequencing, was isolated from the rhizome of a halophyte, Phragmites communis, in Suncheon bay, South Korea. This strain was cultured on a large scale and extracted with ethyl acetate. Chemical investigations of extracts of JS0464 led to the isolation of two glycosylated dialkylresorcinol derivatives (1-2), an anthraquinone derivative (3) and eight known compounds (4-11), which were identified by spectroscopic analyses incorporating one-dimensional/2D NMR and MS. Nine compounds showed significant nitric oxide reduction activity in lipopolysaccharide-stimulated microglia BV-2 cells, seven of which did not impair cell viability. The results suggest that endophytes from the halophytes could be potential resources for bioactive natural products. PMID- 28352104 TI - Helminth-induced alterations of the gut microbiota exacerbate bacterial colitis. AB - Infection with the intestinal helminth parasite Heligmosomoides polygyrus exacerbates the colitis caused by the bacterial enteropathogen Citrobacter rodentium. To clarify the underlying mechanism, we analyzed fecal microbiota composition of control and helminth-infected mice and evaluated the functional role of compositional differences by microbiota transplantation experiments. Our results showed that infection of Balb/c mice with H. polygyrus resulted in significant changes in the composition of the gut microbiota, characterized by a marked increase in the abundance of Bacteroidetes and decreases in Firmicutes and Lactobacillales. Recipients of the gut microbiota from helminth-infected wide type, but not STAT6-deficient, Balb/c donors had increased fecal pathogen shedding and significant worsening of Citrobacter-induced colitis compared to recipients of microbiota from control donors. Recipients of helminth-altered microbiota also displayed increased regulatory T cells and IL-10 expression. Depletion of CD4+CD25+ T cells and neutralization of IL-10 in recipients of helminth-altered microbiota led to reduced stool C. rodentium numbers and attenuated colitis. These results indicate that alteration of the gut microbiota is a significant contributor to the H. polygyrus-induced exacerbation of C. rodentium colitis. The helminth-induced alteration of the microbiota is Th2 dependent and acts by promoting regulatory T cells that suppress protective responses to bacterial enteropathogens. PMID- 28352107 TI - Forming impressions of facial attractiveness is mandatory. AB - First impressions of social traits, such as attractiveness, from faces are often claimed to be made automatically, given their speed and reliability. However, speed of processing is only one aspect of automaticity. Here we address a further aspect, asking whether impression formation is mandatory. Mandatory formation requires that impressions are formed about social traits even when this is task irrelevant, and that once formed, these impressions are difficult to inhibit. In two experiments, participants learned what new people looked like for the purpose of future identification, from sets of images high or low in attractiveness. They then rated middle-attractiveness images of each person, for attractiveness. Even though instructed to rate the specific images, not the people, their ratings were biased by the attractiveness of the learned images. A third control experiment, with participants rating names, demonstrated that participants in Experiments 1 and 2 were not simply rating the people, rather than the specific images as instructed. These results show that the formation of attractiveness impressions from faces is mandatory, thus broadening the evidence for automaticity of facial impressions. The mandatory formation of impressions is likely to have an important impact in real-world situations such as online dating sites. PMID- 28352110 TI - Adolescence, brain maturation and mental health. PMID- 28352108 TI - Microbial community and metabolic pathway succession driven by changed nutrient inputs in tailings: effects of different nutrients on tailing remediation. AB - To solve the competition problem of acidophilic bacteria and sulfate-reducing bacteria in the practical application of mine tailing bioremediation, research into the mechanisms of using different nutrients to adjust the microbial community was conducted. Competition experiments involving acidophilic bacteria and sulfate-reducing bacteria were performed by supplementing the media with yeast extract, tryptone, lactate, and glucose. The physiochemical properties were determined, and the microbial community structure and biomass were investigated using MiSeq sequencing and qRT-PCR, respectively. Four nutrients had different remediation mechanisms and yielded different remediation effects. Yeast extract and tryptone (more than 1.6 g/L) promoted sulfate-reducing bacteria and inhibited acidophilic bacteria. Lactate inhibited both sulfate-reducing and acidophilic bacteria. Glucose promoted acidophilic bacteria more than sulfate-reducing bacteria. Yeast extract was the best choice for adjusting the microbial community and bioremediation, followed by tryptone. Lactate kept the physiochemical properties stable or made slight improvements; however, glucose was not suitable for mine tailing remediation. Different nutrients had significant effects on the abundance of the second enzyme of the sulfate-reducing pathway (p < 0.05), which is the rate-limiting step of sulfate-reducing pathways. Nutrients changed the remediation effects effectively by adjusting the microbial community and the abundance of the sulfate-reducing rate-limiting enzyme. PMID- 28352111 TI - Motivational neural circuits underlying reinforcement learning. AB - Reinforcement learning (RL) is the behavioral process of learning the values of actions and objects. Most models of RL assume that the dopaminergic prediction error signal drives plasticity in frontal-striatal circuits. The striatum then encodes value representations that drive decision processes. However, the amygdala has also been shown to play an important role in forming Pavlovian stimulus-outcome associations. These Pavlovian associations can drive motivated behavior via the amygdala projections to the ventral striatum or the ventral tegmental area. The amygdala may, therefore, play a central role in RL. Here we compare the contributions of the amygdala and the striatum to RL and show that both the amygdala and striatum learn and represent expected values in RL tasks. Furthermore, value representations in the striatum may be inherited, to some extent, from the amygdala. The striatum may, therefore, play less of a primary role in learning stimulus-outcome associations in RL than previously suggested. PMID- 28352109 TI - IL-1beta induced HIF-1alpha inhibits the differentiation of human FOXP3+ T cells. AB - Differentiation of regulatory Treg (Treg) in the periphery is critical to control inflammatory processes. Although polarization of inducible Treg (iTreg) often occurs in an inflammatory environment, the effects exerted by inflammation on human iTreg differentiation have not been extensively studied. We observed that IL-1beta significantly reduced the frequency of FOXP3+ T cells under iTreg polarizing conditions. Mechanistically, we show that IL-1beta activated mTORC1 and downstream upregulated hypoxia inducible factor-1 (HIF-1alpha) expression. Using specific inhibitors, we demonstrated that both steps were critical in the deleterious effect of IL-1beta on Treg differentiation. Chemical stabilization of HIF-1alpha by Dimethyloxalylglycine (DMOG) also significantly impaired iTreg differentiation. Interestingly, while IL-1beta-treated cells exhibited only minor changes in metabolism, DMOG treatment decreased iTreg mitochondrial respiration and increased their glycolytic capacity. In conclusion, exposure to inflammatory stimuli profoundly inhibits human Treg differentiation HIF-1alpha dependent, suggesting that targeting HIF-1alpha could be a strategy to foster iTreg differentiation in an inflammatory milieu. However, IL-1beta deleterious effect does not appear to be completely driven by metabolic changes. These data thus suggest that several mechanisms contribute to the regulation of iTreg differentiation, but the timing and respective requirement for each pathway vary depending on the milieu in which iTreg differentiate. PMID- 28352112 TI - Cocaine, cadherins and synaptic plasticity. PMID- 28352113 TI - A neuronal mechanism for recall of bad events. PMID- 28352115 TI - Landscape response to progressive tectonic and climatic forcing in NW Borneo: Implications for geological and geomorphic controls on flood hazard. AB - Empirical models have simulated the consequences of uplift and orographic precipitation on the evolution of orogens whereas the effects of these forcings on ridgelines and consequent topography of natural landscapes remain equivocal. Here we demonstrate the feedback of a terrestrial landscape in NW Borneo subject to uplift and precipitation gradient owing to orographic effect, and leading to less-predictable flooding and irreversible damages to life and property. Disequilibrium in a large catchment recording the lowest rainfall rates in Borneo, and adjacent drainage basins as determined through chi, a proxy for steady-state channel elevation, is shown to result in dynamic migration of water divide from the windward-side of the orogen towards the leeward-side to attain equilibrium. Loss of drainage area in the leeward-side reduces erosion rates with progressive shortening resulting in an unstable landscape with tectonic uplift, gravity faults and debris flows. 14C dating of exhumed cut-and-fill terraces reveal a Mid-Pleistocene age, suggesting tectonic events in the trend of exhumation rates (>7 mm a-1) estimated by thermochronology, and confirmed by morphotectonic and sedimentological analyses. Our study suggests that divide migration leads to lowered erosion rates, channel narrowing, and sediment accretion in intermontane basins on the leeward-side ultimately resulting in enhanced flooding. PMID- 28352114 TI - Irreversible inhibition of BTK kinase by a novel highly selective inhibitor CHMFL BTK-11 suppresses inflammatory response in rheumatoid arthritis model. AB - BTK plays a critical role in the B cell receptor mediated inflammatory signaling in the rheumatoid arthritis (RA). Through a rational design approach we discovered a highly selective and potent BTK kinase inhibitor (CHMFL-BTK-11) which exerted its inhibitory efficacy through a covalent bond with BTK Cys481. CHMFL-BTK-11 potently blocked the anti-IgM stimulated BCR signaling in the Ramos cell lines and isolated human primary B cells. It significantly inhibited the LPS stimulated TNF-alpha production in the human PBMC cells but only weakly affecting the normal PBMC cell proliferation. In the adjuvant-induced arthritis rat model, CHMFL-BTK-11 ameliorated the inflammatory response through blockage of proliferation of activated B cells, inhibition of the secretion of the inflammatory factors such as IgG1, IgG2, IgM, IL-6 and PMPhi phagocytosis, stimulation of secretion of IL-10. The high specificity of CHMFL-BTK-11 makes it a useful pharmacological tool to further detect BTK mediated signaling in the pathology of RA. PMID- 28352116 TI - Atomic-level structural correlations across the morphotropic phase boundary of a ferroelectric solid solution: xBiMg1/2Ti1/2O3-(1 - x)PbTiO3. AB - Revelation of unequivocal structural information at the atomic level for complex systems is uniquely important for deeper and generic understanding of the structure property connections and a key challenge in materials science. Here we report an experimental study of the local structure by applying total elastic scattering and Raman scattering analyses to an important non-relaxor ferroelectric solid solution exhibiting the so-called composition-induced morphotropic phase boundary (MPB), where concomitant enhancement of physical properties have been detected. The powerful combination of static and dynamic structural probes enabled us to derive direct correspondence between the atomic level structural correlations and reported properties. The atomic pair distribution functions obtained from the neutron total scattering experiments were analysed through big-box atom-modelling implementing reverse Monte Carlo method, from which distributions of magnitudes and directions of off-centred cationic displacements were extracted. We found that an enhanced randomness of the displacement-directions for all ferroelectrically active cations combined with a strong dynamical coupling between the A- and B-site cations of the perovskite structure, can explain the abrupt amplification of piezoelectric response of the system near MPB. Altogether this provides a more fundamental basis in inferring structure-property connections in similar systems including important implications in designing novel and bespoke materials. PMID- 28352117 TI - Berkson error adjustment and other exposure surrogates in occupational case control studies, with application to the Canadian INTEROCC study. AB - Many epidemiological studies assessing the relationship between exposure and disease are carried out without data on individual exposures. When this barrier is encountered in occupational studies, the subject exposures are often evaluated with a job-exposure matrix (JEM), which consists of mean exposure for occupational categories measured on a comparable group of workers. One of the objectives of the seven-country case-control study of occupational exposure and brain cancer risk, INTEROCC, was to investigate the relationship of occupational exposure to electromagnetic fields (EMF) in different frequency ranges and brain cancer risk. In this paper, we use the Canadian data from INTEROCC to estimate the odds of developing brain tumours due to occupational exposure to EMF. The first step was to find the best EMF exposure surrogate among the arithmetic mean, the geometric mean, and the mean of log-normal exposure distribution for each occupation in the JEM, in comparison to Berkson error adjustments via numerical approximation of the likelihood function. Contrary to previous studies of Berkson errors in JEMs, we found that the geometric mean was the best exposure surrogate. This analysis provided no evidence that cumulative lifetime exposure to extremely low frequency magnetic fields increases brain cancer risk, a finding consistent with other recent epidemiological studies. PMID- 28352118 TI - Body composition and susceptibility to type 2 diabetes: an evolutionary perspective. AB - Type 2 diabetes is rapidly increasing in prevalence worldwide, in concert with epidemics of obesity and sedentary behavior that are themselves tracking economic development. Within this broad pattern, susceptibility to diabetes varies substantially in association with ethnicity and nutritional exposures through the life-course. An evolutionary perspective may help understand why humans are so prone to this condition in modern environments, and why this risk is unequally distributed. A simple conceptual model treats diabetes risk as the function of two interacting traits, namely 'metabolic capacity' which promotes glucose homeostasis, and 'metabolic load' which challenges glucose homoeostasis. This conceptual model helps understand how long-term and more recent trends in body composition can be considered to have shaped variability in diabetes risk. Hominin evolution appears to have continued a broader trend evident in primates, towards lower levels of muscularity. In addition, hominins developed higher levels of body fatness, especially in females in relative terms. These traits most likely evolved as part of a broader reorganization of human life history traits in response to growing levels of ecological instability, enabling both survival during tough periods and reproduction during bountiful periods. Since the emergence of Homo sapiens, populations have diverged in body composition in association with geographical setting and local ecological stresses. These long term trends in both metabolic capacity and adiposity help explain the overall susceptibility of humans to diabetes in ways that are similar to, and exacerbated by, the effects of nutritional exposures during the life-course. PMID- 28352120 TI - Highly Permeable Graphene Oxide/Polyelectrolytes Hybrid Thin Films for Enhanced CO2/N2 Separation Performance. AB - Separation of CO2 from other gasses offers environmental benefits since CO2 gas is the main contributor to global warming. Recently, graphene oxide (GO) based gas separation membranes are of interest due to their selective barrier properties. However, maintaining selectivity without sacrificing permeance is still challenging. Herein, we described the preparation and characterization of nanoscale GO membranes for CO2 separation with both high selectivity and permeance. The internal structure and thickness of the GO membranes were controlled by layer-by-layer (LbL) self-assembly. Polyelectrolyte layers are used as the supporting matrix and for facilitating CO2 transport. Enhanced gas separation was achieved by adjusting pH of the GO solutions and by varying the number of GO layers to provide a pathway for CO2 molecules. Separation performance strongly depends on the number of GO bilayers. The surfaces of the multilayered GO and polyelectrolyte films are characterized by atomic force microscopy and scanning electron microscopy. The (poly (diallyldimethylammonium chloride) (PDAC)/polystyrene sulfonate (PSS)) (GO/GO) multilayer membranes show a maximum CO2/N2 selectivity of 15.3 and a CO2 permeance of 1175.0 GPU. LbL assembled GO membranes are shown to be effective candidates for CO2 separation based on their excellent CO2/N2 separation performance. PMID- 28352119 TI - Identification of small molecule inhibitors of Interleukin-18. AB - Interleukin-18 (IL-18) is a pleiotropic pro-inflammatory cytokine belonging to the IL-1 superfamily. IL-18 plays an important role in host innate and adaptive immune defense but its aberrant activities are also associated with inflammatory diseases such as rheumatoid arthritis and Crohn's disease. IL-18 activity is modulated in vivo by its naturally occurring antagonist, IL-18 Binding Protein (IL-18BP). Recent crystal structures of human IL-18 (hIL-18) in complex with its antagonists or cognate receptor(s) have revealed a conserved binding interface on hIL-18. Through virtual screening of the National Cancer Institute Diversity Set II and in vitro competitive ELISA we have identified three compounds (NSC201631, NSC80734, and NSC61610) that disrupt hIL-18 binding to the ectromelia virus IL 18BP. Through cell-based bioassay, we show that NSC80734 inhibits IL-18-induced production of IFN-gamma in a dose-dependent manner with an EC50 of ~250 nM. Our results and methodology presented here demonstrate the feasibility of developing small molecule inhibitors that specifically target the rather large interface of IL-18 that is involved in extensive protein-protein interactions with both IL 18BP and its cognate receptor(s). Our data therefore provide the basis for an approach by which small molecules can be identified that modulate IL-18 activity. PMID- 28352121 TI - Pepper CaREL1, a ubiquitin E3 ligase, regulates drought tolerance via the ABA signalling pathway. AB - Drought stress conditions in soil or air hinder plant growth and development. Here, we report that the hot pepper (C apsicum a nnuum) RING type E3 Ligase 1 gene (CaREL1) is essential to the drought stress response. CaREL1 encodes a cytoplasmic- and nuclear-localized protein with E3 ligase activity. CaREL1 expression was induced by abscisic acid (ABA) and drought. CaREL1 contains a C3H2C3-type RING finger motif, which functions in ubiquitination of the target protein. We used CaREL1-silenced pepper plants and CaREL1-overexpressing (OX) transgenic Arabidopsis plants to evaluate the in vivo function of CaREL1 in response to drought stress and ABA treatment. CaREL1-silenced pepper plants displayed a drought-tolerant phenotype characterized by ABA hypersensitivity. In contrast, CaREL1-OX plants exhibited ABA hyposensitivity during the germination, seedling, and adult stages. In addition, plant growth was severely impaired under drought stress conditions, via a high level of transpirational water loss and decreased stomatal closure. Quantitative RT-PCR analyses revealed that ABA related drought stress responsive genes were more weakly expressed in CaREL1-OX plants than in wild-type plants, indicating that CaREL1 functions in the drought stress response via the ABA-signalling pathway. Taken together, our results indicate that CaREL1 functions as a negative regulator of ABA-mediated drought stress tolerance. PMID- 28352123 TI - AXL is not essential for Zika virus infection in the mouse brain. PMID- 28352122 TI - Long-term electrical stimulation at ear and electro-acupuncture at ST36-ST37 attenuated COX-2 in the CA1 of hippocampus in kainic acid-induced epileptic seizure rats. AB - Seizures produce brain inflammation, which in turn enhances neuronal excitability. Therefore, anti-inflammation has become a therapeutic strategy for antiepileptic treatment. Cycloxygenase-2 (COX-2) plays a critical role in postseizure brain inflammation and neuronal hyperexcitability. Our previous studies have shown that both electrical stimulation (ES) at the ear and electro acupuncture (EA) at the Zusanli and Shangjuxu acupoints (ST36-ST37) for 6 weeks can reduce mossy fiber sprouting, spike population, and high-frequency hippocampal oscillations in kainic acid (KA)-induced epileptic seizure rats. This study further investigated the effect of long-term ear ES and EA at ST36-ST37 on the inflammatory response in KA-induced epileptic seizure rats. Both the COX-2 levels in the hippocampus and the number of COX-2 immunoreactive cells in the hippocampal CA1 region were increased after KA-induced epileptic seizures, and these were reduced through the 6-week application of ear ES or EA at ST36-ST37. Thus, long-term ear ES or long-term EA at ST36-ST37 have an anti-inflammatory effect, suggesting that they are beneficial for the treatment of epileptic seizures. PMID- 28352124 TI - Discovery and genetic analysis of novel coronaviruses in least horseshoe bats in southwestern China. AB - To investigate bat coronaviruses (CoVs), we collected 132 rectal swabs and urine samples from five bat species in three countries in southwestern China. Seven CoVs belonging to distinct groups of severe acute respiratory syndrome (SARS) like CoVs and alpha-CoVs were detected in samples from least horseshoe bats. Samples from other bat species were negative for these viruses, indicating that the least horseshoe bat represents one of the natural reservoirs and mixers for strains of CoVs and has a pivotal role in the evolution and dissemination of these viruses. The genetic and evolutionary characteristics of these strains were described. Whole-genome sequencing of a new isolate (F46) from a rectal swab from a least horseshoe bat showed that it contained 29 699 nucleotides, excluding the poly (A) tail, with 13 open reading frames (ORFs). Phylogenetic and recombination analyses of F46 provided evidence of natural recombination between bat SARS-like CoVs (Rs3367 and LYRa11) or SARS-CoV (BJ01), suggesting that F46 could be a new recombinant virus from SARS-like CoVs or SARS-CoVs. PMID- 28352125 TI - Hydrogen sulfide ameliorates chronic renal failure in rats by inhibiting apoptosis and inflammation through ROS/MAPK and NF-kappaB signaling pathways. AB - Chronic renal failure (CRF) is a major public health problem worldwide. Hydrogen sulfide (H2S) plays important roles in renal physiological and pathophysiological processes. However, whether H2S could protect against CRF in rats remains unclear. In this study, we found that H2S alleviated gentamicin-induced nephrotoxicity by reducing reactive oxygen species (ROS)-mediated apoptosis in normal rat kidney-52E cells. We demonstrated that H2S significantly improved the kidney structure and function of CRF rats. We found that H2S decreased the protein levels of Bax, Caspase-3, and Cleaved-caspase-3, but increased the expression of Bcl-2. Treatment with H2S reduced the levels of malondialdehyde and ROS and increased the activities of superoxide dismutase and glutathione peroxidase. H2S significantly abolished the phosphorylation of extracellular signal-regulated protein kinase 1/2, c-Jun N-terminal kinase, and p38 in the kidney of CRF rats. Furthermore, H2S decreased the expression levels of tumor necrosis factor-alpha, interleukin (IL)-6, IL-10, and monocyte chemoattractant protein-1, as well as the protein levels of p50, p65, and p-p65 in the kidney of CRF rats. In conclusion, H2S could ameliorate adenine-induced CRF in rats by inhibiting apoptosis and inflammation through ROS/mitogen-activated protein kinase and nuclear factor-kappa B signaling pathways. PMID- 28352126 TI - Social cognition in neuropsychiatric populations: a comparison of theory of mind in schizophrenia and mesial temporal lobe epilepsy. AB - Social cognition deficits are observed both in patients with schizophrenia (SCZ) and in patients with mesial temporal lobe epilepsy (MTLE). This may be due to dysfunction of the amygdala network, which is a common feature of both diseases. In this study, SCZ (n = 48) or MTLE (n = 31) and healthy controls (HC, n = 47) completed assessments of mentalising (Reading Mind in the Eyes Test, RMET) and basic cognitive processing, e.g., working memory, executive functions and psychomotor speed (Trail-Making Test B and Digit Symbol). SCZ were also assessed with the Positive And Negative Syndrome Scale (PANSS). We found that the RMET scores of the two clinical groups were similar (p > 0.05) and lower than in the HCs (SCZ: p < 0.05; MTLE: p < 0.001). In the next step, SCZ were split into two groups with respect to the level of symptoms. Analysis of the RMET scores revealed no differences between the HC (M = 25.7 +/- 4.1) and POS-LO (M = 25.3 +/ 4.8); both groups outperformed the POS-HI group (M = 21.3 +/- 5.2) and the MTLE group (M = 20.8 +/- 4.6). No differences were found for the median-split with regard to negative symptoms. In SCZ, the mind-reading deficit appears to be associated with the level of positive symptoms. Both POS-HI and MTLE patients present significant mentalising deficits compared to healthy controls. PMID- 28352127 TI - Insights from engraftable immunodeficient mouse models of hyperinsulinaemia. AB - Hyperinsulinaemia, obesity and dyslipidaemia are independent and collective risk factors for many cancers. Here, the long-term effects of a 23% Western high-fat diet (HFD) in two immunodeficient mouse strains (NOD/SCID and Rag1 -/-) suitable for engraftment with human-derived tissue xenografts, and the effect of diet induced hyperinsulinaemia on human prostate cancer cell line xenograft growth, were investigated. Rag1 -/-and NOD/SCID HFD-fed mice demonstrated diet-induced impairments in glucose tolerance at 16 and 23 weeks post weaning. Rag1 -/- mice developed significantly higher fasting insulin levels (2.16 +/- 1.01 ng/ml, P = 0.01) and increased insulin resistance (6.70 +/- 1.68 HOMA-IR, P = 0.01) compared to low-fat chow-fed mice (0.71 +/- 0.12 ng/ml and 2.91 +/- 0.42 HOMA-IR). This was not observed in the NOD/SCID strain. Hepatic steatosis was more extensive in Rag1 -/- HFD-fed mice compared to NOD/SCID mice. Intramyocellular lipid storage was increased in Rag1 -/- HFD-fed mice, but not in NOD/SCID mice. In Rag1 -/- HFD fed mice, LNCaP xenograft tumours grew more rapidly compared to low-fat chow-fed mice. This is the first characterisation of the metabolic effects of long-term Western HFD in two mouse strains suitable for xenograft studies. We conclude that Rag1 -/- mice are an appropriate and novel xenograft model for studying the relationship between cancer and hyperinsulinaemia. PMID- 28352128 TI - Recruitment of Lyn from endomembranes to the plasma membrane through calcium dependent cell-cell interactions upon polarization of inducible Lyn-expressing MDCK cells. AB - Src-family kinases, expressed in a wide variety of cell types, are anchored to cellular membranes through posttranslational lipid modifications and involved in diverse cellular signalling. In epithelial cells, Src-family kinases are localized at the plasma membrane and participate in epithelial functions. Epithelial cell polarity is achieved through dynamic reorganization of protein trafficking. To examine the trafficking of Src-family kinases between polarized and non-polarized epithelial cells, we generated an MDCK cell line that can inducibly express a protein of interest in a polarized state at any time. We show here that Lyn, a member of Src-family kinases, mainly localizes to the plasma membrane in polarized MDCK cells and to endomembranes in non-polarized MDCK cells. Cell-cell interactions between adjacent MDCK cells recruit Lyn from endomembranes to the plasma membrane even without cell attachment to extracellular matrix scaffolds, and loss of cell-cell interactions by calcium deprivation relocates Lyn from the plasma membrane to endomembranes through Rab11 mediated recycling. Therefore, using our MDCK cells expressing inducible Lyn, we reveal that calcium-dependent cell-cell interactions play a critical role in plasma membrane localization of Lyn in polarized MDCK cells. PMID- 28352129 TI - Cyclooxygenase-2 Signalling Pathway in the Cortex is Involved in the Pathophysiological Mechanisms in the Rat Model of Depression. AB - This study was designed to investigate the effect of the cortical cyclooxygenase 2 (COX2) pathway on depressive behaviour in rats. Meloxicam, COX2 overexpressed lentivirus and COX2 RNAi lentivirus were administered to Sprague-Dawley rats subjected to chronic unpredictable mild stress (CUMS). Behaviour tests, biochemistry and immunohistochemistry methods, enzyme-linked immunosorbent assays, western blotting and reverse transcription polymerase chain reactions were used to evaluate the changes in rat behaviour and the cortical COX2 pathway. CUMS rats showed depressive-like behaviours. The superoxide dismutase activity and cyclic adenosine monophosphate (cAMP) contents were significantly decreased, the contents of malondialdehyde, prostaglandin E2 (PGE2) and inflammatory cytokines were significantly increased. The expressions of protein kinase A (PKA) and cAMP response element-binding protein (CREB) were decreased, and the levels of brain-derived neurotrophic factor (BDNF) and COX2 were significantly increased. Meloxicam and COX2 RNAi lentivirus significantly alleviated the abnormalities induced by CUMS, while COX2 overexpressed lentivirus aggravated these abnormalities. Our results indicated that the cortical COX2 pathway was activated in CUMS rats. Inhibition of COX2 activity/expression can obviously improve depressive behaviours in CUMS rats. Upregulating COX2 expression can increase the susceptibility of rats to CUMS. An imbalance in the cortical COX2 PGE2-cAMP/PKA-CREB-BDNF signalling pathway participates in the pathogenic mechanism of depression. PMID- 28352131 TI - Drug therapy: Exploiting synthetic lethality to improve cancer therapy. PMID- 28352130 TI - Bats pre-adapt sensory acquisition according to target distance prior to takeoff even in the presence of closer background objects. AB - Animals execute sensorimotor sequences to optimize performance of complex actions series. However, the sensory aspects of these sequences and their dynamic control are often poorly understood. We trained bats to fly to targets at different distances, and analysed their sensory behavior before and during flight to test whether they assess target distance before flight and how they adapt sensory acquisition in different situations. We demonstrate that bats' sensory acquisition during approach-flight is more flexible than previously described. We identified acoustic parameters that illustrate that bats assess target distance before takeoff. We show that bats adapt their echolocation approach-sequences to target distance - ignoring closer background objects. At shorter distances, bats initiated their echolocation approach-sequence with distance-appropriate parameters, thus entering the approach sensory sequence "in step". Our results suggest that in order to perform fine flight-manoeuvres, bats must maintain their sensorimotor plan in phase. To do this, they adapt acquisition according to target distance before initiating a complex sensory sequence based on a sensorimotor feedback-loop, even in complex acoustic environments, which impose other sensory reactions and restrictions. Though studying this in non echolocating animals may prove difficult, such mechanisms are probably widely used in nature whenever complex series of sensorimotor actions are required. PMID- 28352132 TI - Immunotherapy: DLBCL remissions driven by CARs. PMID- 28352134 TI - Diagnosis: Making DESI-MSI desirable. PMID- 28352135 TI - Prostate cancer: Custirsen fails to improve outcomes. PMID- 28352133 TI - Haematological cancer: Anti-PD-1 therapy with nivolumab after allo-HSCT for Hodgkin lymphoma. PMID- 28352136 TI - Prostate cancer: Cabozantinib activates innate immunity. PMID- 28352137 TI - Bladder cancer: TCGA cohort is representative of invasive disease. PMID- 28352138 TI - Prostate cancer: Testosterone replacement affects disease risk. PMID- 28352139 TI - Erratum: Shetti, a simple tool to parse, manipulate and search large dataset of sequences. AB - [This corrects the article DOI: 10.1099/mgen.0.000035.]. PMID- 28352140 TI - Corrigendum: Emergence of a novel lineage containing a prophage in emm/M3 group A Streptococcus associated with upsurge in invasive disease in the UK. AB - [This corrects the article DOI: 10.1099/mgen.0.000059.]. PMID- 28352141 TI - Brain control of body temperature: Central command vs feedback. PMID- 28352142 TI - Fractal analysis of thermoregulatory complexity. PMID- 28352143 TI - How should we measure occupational heat stress? PMID- 28352144 TI - Nutritional strategies for maximizing recovery from strenuous exercise in the heat: An important role for carbohydrate (sago) supplementation. PMID- 28352145 TI - Methotrexate Reduced TNF Bioactivity in Rheumatoid Arthritis Patients Treated with Infliximab. AB - Objectives. To evaluate methotrexate effect on tumor necrosis factor (TNF) alpha bioactivity during infliximab (IFX) therapy in rheumatoid arthritis (RA) patients and to correlate TNF bioactivity with antibody towards IFX (ATI) development and RA clinical response. Materials and Methods. Thirty-nine active women RA patients despite conventional synthetic disease modifying antirheumatic drugs (csDMARDs) requiring IFX therapy were enrolled, and clinical data and blood samples were recorded at baseline (W0) and at 6 weeks (W6), W22, and W54 of IFX treatment. TNF bioactivity as well as IFX trough and ATI concentrations were assessed on blood samples. Results. TNF bioactivity decreased from W0 to W54 with a large range from W22 at the time of ATI detection. From W22, TNF bioactivity was lower in presence of methotrexate as csDMARD compared to other csDMARDs. IFX trough concentration increased from W0 to W54 with a large range from W22, similarly to TNF bioactivity. Methotrexate therapy prevented ATI presence at W22 and reduced TNF bioactivity compared to other csDMARDs (p = 0.002). Conclusion. This suggests that methotrexate plays a key role in TNF bioactivity and against ATI development. PMID- 28352146 TI - Power Morcellation Using a Contained Bag System. AB - BACKGROUND AND OBJECTIVES: The well-known advantages of minimally invasive surgery make the approach well suited for hysterectomy and other gynecological procedures. The removal of specimens excised during surgery has been a challenge that has been answered by the use of power morcellation. With this study we sought to assess the feasibility of power morcellation within a specimen bag. METHODS: This was a retrospective cohort study including patients from a private practice in suburban Chicago, Illinois, who underwent contained electromechanical power morcellation during a laparoscopic or robot-assisted hysterectomy or myomectomy from May 2014 through December 2015. Contained power morcellation was performed with the Espiner EcoSac 230 (Espiner Medical Ltd., North Somerset, United Kingdom) specimen bag. Descriptive statistics were performed for both categorical and continuous data. RESULTS: Of the 187 procedures performed, 73.8% were myomectomies, and 26.2% were hysterectomies. The patients' mean age was 40 (range, 25-54) years and mean body mass index was 28.7 (range, 17.3-57.6). The average specimen weight was 300 g, with the largest weighing 2134 g. Estimated blood loss averaged 98.4 mL. The postoperative admission rate was 12.3%, most of which were due to nausea and urinary retention. Seventeen patients (9.1%) had postoperative complications, most of which were minor, and 4 (2.1%) were readmitted. There were no bag failures or complications that were due to the use of the specimen bag or to power morcellation. CONCLUSIONS: Performing electromechanical power morcellation within the Espiner EcoSac 230 specimen bag was successfully performed in 187 patients with no bag-related complications. This method of contained power morcellation is feasible, reliable, and reproducible, even for a large specimen. PMID- 28352147 TI - Minimally Invasive Hysterectomy for Uteri Greater Than One Kilogram. AB - BACKGROUND AND OBJECTIVES: To assess the feasibility and safety of minimally invasive hysterectomy for uteri >1 kg. METHODS: Clinical and surgical characteristics were collected for patients in an academic tertiary care hospital. Included were patients who underwent minimally invasive hysterectomy by 1 of 3 fellowship-trained gynecologists from January 1, 2009, to July 1, 2015 and subsequently had confirmed uterine weights of 1 kg or greater on pathology report. Both robotic and conventional laparoscopic procedures were included. RESULTS: During the study period, 95 patients underwent minimally invasive hysterectomy with confirmed uterine weight over 1 kg. Eighty-eight percent were performed with conventional laparoscopy and 12.6% with robot-assisted laparoscopy. The median weight (range) was 1326 g (range, 1000-4800). The median estimated blood loss was 200 mL (range, 50-2000), and median operating time was 191 minutes (range, 75-478). Five cases were converted to laparotomy (5.2%). Four cases were converted secondary to hemorrhage and one secondary to extensive adhesions. There were no conversions after 2011. Intraoperative transfusion was given in 6.3% of cases and postoperative transfusion in 6.3% of cases. However, after 2013, the rate of intraoperative transfusion decreased to 1.0% and postoperative transfusion to 2.1%. Of the 95 cases, there were no cases with malignancy. CONCLUSIONS: This provides the largest case series of hysterectomy over 1 kg completed by a minimally invasive approach. Our complication rate improved with experience and was comparable to other studies of minimally invasive hysterectomy for large uteri. When performed by experienced surgeons, minimally invasive hysterectomy for uteri >1 kg can be considered feasible and safe. PMID- 28352148 TI - Laparoscopic and Open Splenectomy and Hepatectomy. AB - BACKGROUND AND OBJECTIVES: Patients undergoing synchronous open splenectomy and hepatectomy (OSH) for concurrent hepatocellular carcinoma (HCC) and hypersplenism usually have major surgical trauma caused by the long abdominal incision. Surgical procedures that contribute to rapid recovery with the least possible impairment are desired by both surgeons and patients. The objective of this study was to explore outcomes in patients treated with simultaneous laparoscopic or open splenectomy and hepatectomy for hepatocellular carcinoma (HCC) with hypersplenism. METHODS: We retrospectively evaluated the treatment outcomes in 23 patients with cirrhosis, HCC, and hypersplenism, who underwent simultaneous laparoscopic splenectomy and hepatectomy (LSH; n = 12) or open splenectomy and hepatectomy (OSH; n = 11) from January 2012 through December 2015. Their perioperative variables were compared. RESULTS: LSH was successful in all patients. There were nonsignificant similarities between the 2 groups in duration of operation, estimated blood loss, and volume of blood transfused (P > .05 each). Compared with OSH, LSH had a significantly shorter postoperative visual analog scale pain score (P < .001); shorter time to first oral intake (P < .001), passage of flatus (P < .05) and off-bed activity (P < .001); shorter postoperative duration of hospitalization (P < .001); fewer days of postoperative temperature >38.0 degrees C (P < .01); fewer postoperative complications (P < .05); and better liver and renal function on postoperative days 7 (P < .05 each). CONCLUSIONS: Simultaneous LSH is safe for selected patients with HCC and hypersplenism associated with liver cirrhosis. PMID- 28352149 TI - Robot-Assisted Partial Nephrectomy for T1b Tumors: Strict Trifecta Outcomes. AB - BACKGROUND AND OBJECTIVES: "Trifecta" in partial nephrectomy consists of negative surgical margins, minimal renal function decrease and absence of complications. In the present article, our single-center robot-assisted partial nephrectomy (RAPN) experience in T1b renal masses is reported in terms of strict Trifecta outcomes. METHODS: This is a retrospective analysis of patients with a tumor diameter between 4 and 7 cm (stage T1b), who underwent RAPN by a single surgeon. Preoperative, intraoperative, and postoperative data were recorded and analyzed to evaluate short-term functional and oncologic outcomes. Patients with absence of grade >= 2 Clavien-Dindo complications, warm ischemia time (WIT) <=25 minutes, <=15% postoperative estimated glomerular filtration rate (eGFR) decrease and negative surgical margins were reported to achieve strict Trifecta outcomes. P < .05 was indicated statistically significant. RESULTS: A total of 150 patients underwent RAPN, and 50 patients were identified with tumor size between 4 and 7 cm. Mean WIT was 20.8 +/- 6.2 minutes and mean estimated blood loss (EBL) was 269 +/- 191 mL. Surgical margins were negative in all patients. Eleven patients (22%) had a >15% eGFR decrease after surgery. Nine patients (18%) had WIT longer than 25 minutes. Four patients (8%) had grade >=2 Clavien-Dindo complications. Twenty nine (58%) patients had strict Trifecta outcomes. Mean follow-up was 44.2 +/- 27.2 months. Tumor recurrence was not observed in any patient. CONCLUSIONS: Robot assisted laparoscopic partial nephrectomy for T1b renal masses can be safely performed in experienced hands. Optimal strict Trifecta outcomes and recurrence rates can be achieved. PMID- 28352150 TI - Clinical and allergological analysis of ocular manifestations of sick building syndrome. AB - PURPOSE: The disease concept of sick building syndrome (SBS) is still unclear. Ocular mucous membrane irritation is one of the major symptoms of SBS. However, the immunological aspects of the ocular complications of SBS are not yet clarified. The clinical and allergological aspects of SBS cases with ocular disorders with special reference to allergic conjunctival diseases (ACD) were analyzed, especially with respect to local immunological features. METHODS: Twelve cases of SBS with ocular findings and 49 cases of ACD (allergic conjunctivitis [AC], atopic keratoconjunctivitis [AKC], and vernal keratoconjunctivitis [VKC]) for comparison were evaluated. The clinical findings in SBS and ACD were scored, and tear film breakup time (BUT) was measured. Cytokine (interferon-gamma [IFN-gamma], interleukin [IL]-2, IL-4, IL-5, IL-6, IL 8, and IL-13) concentrations in tears were analyzed by cytometric bead arrays. Eosinophil count in peripheral blood, total IgE in serum, and multiple allergen simultaneous test (MAST) for antigen-specific IgE were also measured. RESULTS: In SBS, conjunctival lesions were observed in all cases, and corneal abnormalities were found in two-thirds of the cases. Limbal lesions were observed in 2 pediatric cases. Mean serum total IgE level in SBS was significantly higher than that in AC; however, it was significantly lower than that in AKC and VKC. Eosinophil count in peripheral blood and number of positive allergens in MAST were significantly lower in SBS than in AKC and VKC. Significant elevation of tear IL-4 was observed in SBS and ACD. However, in contrast to ACD, elevation of other cytokines in tears was not observed in SBS. Mean tear BUT in SBS was in the normal range. CONCLUSION: From these results, SBS is thought to be partially induced by an allergic response. However, clinical dissociation of the ocular clinical findings and local immunological features in tear cytokines may suggest that SBS belongs to a different entity from ACD. PMID- 28352151 TI - Efficacy of two trabecular micro-bypass stents combined with topical travoprost in open-angle glaucoma not controlled on two preoperative medications: 3-year follow-up. AB - PURPOSE: To evaluate the long-term intraocular pressure (IOP)-lowering effect and safety parameters following treatment with two trabecular micro-bypass stents and topical prostaglandin in phakic eyes with open-angle glaucoma (OAG) not controlled on two preoperative medications. METHODS: This prospective, single arm, unmasked study enrolled 39 qualified phakic eyes with OAG not controlled on 2 medications, preoperative medicated IOP of 18-30 mmHg, and IOP following medication washout of 22-38 mmHg. Two trabecular micro-bypass stents were implanted as a standalone procedure, and travoprost was started on postoperative day 1. Evaluations included IOP, best-corrected visual acuity, medication use, fundus and slit-lamp examinations, visual field, cup:disc ratio, central corneal thickness, and ocular complications. Data through 18 months were summarized previously. Thirty-seven of the original 39 subjects have been followed for 3 years postoperatively; follow-up is continuing for 5 years. RESULTS: At 3 years postoperative, 97% of eyes had achieved an IOP reduction of >=20% from baseline with a reduction of 1 medication. Eighty-six percent of eyes had IOP of <=18 mmHg with a reduction of 1 medication. Mean medicated IOP decreased to 14.0+/-2.6 mmHg on 1 medication versus 22.4+/-2.3 mmHg on 2 medications preoperatively. The mean unmedicated IOP decreased to 17.7+/-1.7 mmHg at 37 months from 25.3+/-1.9 mmHg preoperatively. Long-term postoperative adverse events included cataract surgery in 3 eyes due to cataract progression, and trabeculectomy in 1 eye due to uncontrolled IOP of 23 mmHg. No intraoperative or device-related adverse events occurred. CONCLUSION: Significant and sustained reduction in IOP and medications with a favorable safety profile was shown through 3 years after implantation of 2 trabecular micro-bypass stents combined with postoperative travoprost in phakic OAG eyes uncontrolled on 2 preoperative medications. These findings demonstrate the long-term performance and safety of trabecular bypass stents in combination with topical prostaglandin for OAG patients. PMID- 28352153 TI - Development of erythropoietin receptor-targeted drug delivery system against breast cancer using tamoxifen-loaded nanostructured lipid carriers. AB - Tamoxifen (TAM) has been used in the treatment of breast cancers and is supplemented with erythropoietin (EPO) to alleviate the cancer-related anemia. The purported deleterious effects caused by the use of EPO with chemotherapeutic agents in the treatment of cancer-related anemia vary across studies and remain controversial. The use of nanoparticles as a drug delivery system has the potential to improve the specificity of anticancer drugs. In this study, we simultaneously incorporated two pharmacological active ingredients in one nanocarrier to develop EPO-conjugated TAM-loaded lipid nanoparticles (EPO TAMNLC), a targeted delivery system, to enhance the cytotoxic activity while reducing the side effects of the ingredients. The effect of temperature in modulating the thermodynamic parameters associated with the binding of EPO and TAMNLC was assessed using isothermal titration calorimetry, while the unfolding of EPO structure was determined using fluorescence-quenching approach. The association efficiency of EPO and TAMNLC was 55.43%. Unlike binding of albumin to TAMNLC, the binding of EPO to TAMNLC occurred through endothermic and entropy driven reaction. The EPO-TAMNLC formulation was stable because of the hydrophobic interaction and the high free energy, suggesting the spontaneity of the interactions between EPO and TAMNLC. The EPO-TAMNLC enhanced the in vitro cytotoxicity of TAM to MCF-7 cells. The EPO surface-functionalized TAMNLC could sequentially deliver EPO and TAM as well as improving site-specific delivery of these therapeutic compounds. PMID- 28352152 TI - Glycophenotype of breast and prostate cancer stem cells treated with thieno[2,3 b]pyridine anticancer compound. AB - Tumor progression may be driven by a small subpopulation of cancer stem cells (CSCs characterized by CD44+/CD24- phenotype). We investigated the influence of a newly developed thienopyridine anticancer compound (3-amino-5-oxo-N-naphthyl 5,6,7, 8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide, 1) on the growth, survival and glycophenotype (CD15s and GM3 containing neuraminic acid substituted with acetyl residue, NeuAc) of breast and prostate cancer stem/progenitor-like cell population. MDA-MB-231 and Du-145 cells were incubated with compound 1 alone or in combination with paclitaxel. The cellular metabolic activity was determined by the 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay. The type of cell death induced by 48-h treatment was assessed using a combination of Annexin-V-FITC and propidium iodide staining. Flow cytometric analysis was performed to detect the percentage of CD44+/CD24- cells, and GM3 and CD15s positive CSCs, as well as the expression of GM3 and CD15s per one CSC, in both cell lines. Compound 1 produces a dose- and time-dependent cytotoxicity, mediated mainly by apoptosis in breast cancer cells, and slightly (2.3%) but statistically significant lowering breast CSC subpopulation. GM3 expression per one breast CSC was increased, and the percentage of prostate GM3+ CSC subpopulation was decreased in cells treated with compound 1 compared with non-treated cells. The percentage of CD15s+ CSCs was lower in both cell lines after treatment with compound 1. Considering that triple-negative breast cancers are characterized by an increased percentage of breast CSCs and knowing their association with an increased risk of metastasis and mortality, compound 1 is a potentially effective drug for triple-negative breast cancer treatment. PMID- 28352154 TI - HMGB1 siRNA can reduce damage to retinal cells induced by high glucose in vitro and in vivo. AB - BACKGROUND: Diabetic retinopathy (DR), one of the most common complications of late-phase diabetes, is associated with many risk factors, among which continuous low-grade inflammation is one of the principal ones. As such, lowering inflammation levels and maintain the viability of human retinal endothelial cells (HRECs) are critical for DR therapy. HMGB1 is a well-known proinflammatory cytokine. However, whether HMGB1 small interfering RNA (siRNA) can protect retina cells under a high-glucose environment from morphological changes and functional abnormalities remain undetermined. We aimed to investigate the effect of HMGB1 siRNA on retinal cells in DR. MATERIALS AND METHODS: A total of 80 adult Wistar rats were randomly divided into four groups (n=20 each): normal control, diabetes mellitus (DM), scrambled (Scr) siRNA, and HMGB1 siRNA. Rats in the DM, Scr siRNA, and siRNA groups were established by intraperitoneal injection of streptozotocin. At 16 weeks after injection, rats in the siRNA and Scr-siRNA groups were intravitreally injected with 2 MUL HMGB1 siRNA and 2 MUL Scr-siRNA, while rats in the control and DM groups were intravitreally injected with the same dose of sterile saline. At 1 week after injections, we performed the following experiments. Immunohistochemical staining and real-time quantitative polymerase chain reaction were performed to test HMGB1 protein and messenger RNA expression in retinas. We performed TUNEL assays to detect retinal cell apoptosis and electroretinography to detect retinal function. In HRECs treated with high glucose, proliferation, morphology, apoptosis, super-oxide dismutase (SOD), and reactive oxygen species production were detected. Western blot was applied to determine the expressions of HMGB1 and its related protein and apoptosis protein. RESULTS: Intravitreal injection of HMGB1 siRNA reduced protein and messenger RNA expression of HMGB1 (both P<0.05). Intravitreal injection of HMGB1 siRNA reduced apoptosis of retinal cells (P<0.05), protected morphological changes in the retina, and improved the function of the retina (P<0.05). In HRECs treated with high glucose, HMGB1 siRNA pretreatment increased cell viability, reduced cell apoptosis, and reduced oxidative damage to cells (all P<0.05). Western blot detection found that HMGB1 siRNA pretreatment can inhibit the expression of cleaved caspase 3 and improve the expression of BCL2 (P<0.05). HMGB1 and NFkappaB expression increased in a time-dependent manner in the high-glucose environment and IKKbeta and NFkappaB protein expression decreased significantly after HMGB1 silencing. CONCLUSION: As a therapeutic target, HMGB1 siRNA can reduce retinal cell damage induced by high glucose in vitro and in vivo and delay DR progress through the HMGB1-IKKbeta-NFkappaB signaling pathway. PMID- 28352156 TI - Fixed-dose combination orally disintegrating tablets to treat cardiovascular disease: formulation, in vitro characterization and physiologically based pharmacokinetic modeling to assess bioavailability. AB - Cardiovascular disease (CVD) is the leading cause of death among men and women worldwide. In CVD, hypertension and dyslipidemia commonly coexist and are managed through coadministration of amlodipine and atorvastatin, respectively. The case for fixed-dose combination (FDC) oral dosage forms and orally disintegrating tablet (ODT) technology to enhance outcomes and compliance is strong. This work follows the development and characterization of single and FDC ODTs containing amlodipine and atorvastatin, followed by bioequivalence comparison between these single and FDC formulations, using in vitro dissolution and Caco-2 apparent permeability (Papp) and in silico physiologically based pharmacokinetic modeling approaches. ODTs containing amlodipine (5 mg) and atorvastatin (10 mg) either alone or in combination rapidly disintegrated (<30 s) while displaying a radial crushing strength in excess of 100 N and friability <=1%. In vitro dissolution test was performed in fasted and fed-state simulated intestinal fluid (FeSSIF) and analyzed using high-performance liquid chromatography. Dissolution profiles for single and FDC ODTs were compared using US FDA recommended difference (f1) and similarity (f2) factor testing for bioequivalence. In all cases, there was no difference in active pharmaceutical ingredient dissolution between single or FDC ODTs, with the exception of amlodipine in FeSSIF. Pharmacokinetic clinical trial simulations were conducted using Simcyp (Version 14), incorporating Papp and dissolution data. Simulated clinical trials in healthy volunteers showed no difference in bioavailability based on pharmacokinetic parameters between single and combination doses with either active pharmaceutical ingredient. An increase in Cmax and AUC for atorvastatin in fed subjects was attributed to extended transit along the gut lumen and reduced atorvastatin metabolism due to lower CYP3A4 expression at more distal small intestine absorption sites. The results demonstrated bioequivalence of an FDC ODT for amlodipine and atorvastatin, while highlighting several limitations of f1 and f2 bioequivalence testing and strengths of mechanistic pharmacokinetic modeling for oral drug absorption. PMID- 28352157 TI - Design, synthesis, and antimelanogenic effects of (2-substituted phenyl-1,3 dithiolan-4-yl)methanol derivatives. AB - The authors designed and synthesized 17 (2-substituted phenyl-1,3-dithiolan-4-yl) methanol (PDTM) derivatives to find a new chemical scaffold, showing excellent tyrosinase-inhibitory activity. Their tyrosinase-inhibitory activities were evaluated against mushroom tyrosinase at 50 MUM, and five of the PDTM derivatives (PDTM3, PDTM7-PDTM9, and PDTM13) were found to inhibit mushroom tyrosinase more than kojic acid or arbutin, the positive controls. Of seventeen PDTMs, PDTM3 (half-maximal inhibitory concentration 13.94+/-1.76 MUM), with a 2,4 dihydroxyphenyl moiety, exhibited greatest inhibitory effects (kojic acid half maximal inhibitory concentration 18.86+/-2.14 MUM). Interestingly, PDTM compounds with no hydroxyl group, PDTM7-PDTM9, also had stronger inhibitory activities than kojic acid. In silico studies of interactions between tyrosinase and the five PDTMs suggested their binding affinities were closely related to their tyrosinase inhibitory activities. Cell-based experiments performed using B16F10 mouse-skin melanoma cells showed that PDTM3 effectively inhibited melanogenesis and cellular tyrosinase activity. A cell-viability study conducted using B16F10 cells indicated that the antimelanogenic effect of PDTM3 was not attributable to its cytotoxicity. Kinetic studies showed PDTM3 competitively inhibited tyrosinase, indicating binding to the tyrosinase-active site. We found that PDTM3 with a new chemical scaffold could be a promising candidate for skin-whitening agents, and that the 1,3-dithiolane ring could be used as a chemical scaffold for potent tyrosinase inhibition. PMID- 28352155 TI - Proteinopathy, oxidative stress and mitochondrial dysfunction: cross talk in Alzheimer's disease and Parkinson's disease. AB - Alzheimer's disease and Parkinson's disease are two common neurodegenerative diseases of the elderly people that have devastating effects in terms of morbidity and mortality. The predominant form of the disease in either case is sporadic with uncertain etiology. The clinical features of Parkinson's disease are primarily motor deficits, while the patients of Alzheimer's disease present with dementia and cognitive impairment. Though neuronal death is a common element in both the disorders, the postmortem histopathology of the brain is very characteristic in each case and different from each other. In terms of molecular pathogenesis, however, both the diseases have a significant commonality, and proteinopathy (abnormal accumulation of misfolded proteins), mitochondrial dysfunction and oxidative stress are the cardinal features in either case. These three damage mechanisms work in concert, reinforcing each other to drive the pathology in the aging brain for both the diseases; very interestingly, the nature of interactions among these three damage mechanisms is very similar in both the diseases, and this review attempts to highlight these aspects. In the case of Alzheimer's disease, the peptide amyloid beta (Abeta) is responsible for the proteinopathy, while alpha-synuclein plays a similar role in Parkinson's disease. The expression levels of these two proteins and their aggregation processes are modulated by reactive oxygen radicals and transition metal ions in a similar manner. In turn, these proteins - as oligomers or in aggregated forms - cause mitochondrial impairment by apparently following similar mechanisms. Understanding the common nature of these interactions may, therefore, help us to identify putative neuroprotective strategies that would be beneficial in both the clinical conditions. PMID- 28352159 TI - Estimation of health state utilities in breast cancer. AB - PURPOSE: The aim of this study is to determine the utility of breast cancer health states using the standard gamble (SG) and visual analog scale (VAS) methods in the Korean general population. MATERIALS AND METHODS: Eight hypothetical breast cancer health states were developed based on patient education material and previous publications. Data from 509 individuals from the Korean general population were used to evaluate breast cancer health states using the VAS and the SG methods, which were obtained via computer-assisted personal interviews. Mean utility values were calculated for each human papillomavirus (HPV)-related health state. RESULTS: The rank of health states was identical between two valuation methods. SG values were higher than VAS values in all health states. The utility values derived from SG were 0.801 (noninvasive breast cancer with mastectomy and followed by reconstruction), 0.790 (noninvasive breast cancer with mastectomy only), 0.779 (noninvasive breast cancer with breast conserving surgery and radiation therapy), 0.731 (invasive breast cancer with surgery, radiation therapy, and/or chemotherapy), 0.610 (locally advanced breast cancer with radical mastectomy with radiation therapy), 0.587 (inoperable locally advanced breast cancer), 0.496 (loco-regional recurrent breast cancer), and 0.352 (metastatic breast cancer). CONCLUSION: Our findings might be useful for economic evaluation of breast cancer screening and interventions in general populations. PMID- 28352160 TI - Prospective study on the overuse of blood test-guided antibiotics on patients with acute diarrhea in primary hospitals of China. AB - BACKGROUND: Overuse with antibiotics in the treatment of infectious diseases has become a central focus of public health over the years. The aim of this study was to provide an up-to-date evaluation of the blood test-guided antibiotic use on patients with acute diarrhea in primary hospitals of China. MATERIALS AND METHODS: A cross-sectional survey was conducted on 330 patients with acute diarrhea in Shanghai, People's Republic of China, from March 2013 to February 2016. These patients were treated with or without antibiotics based on the results of their blood tests, including examinations of C-reactive protein (CRP), white blood cells (WBC), and the percentage of neutrophils (Neu%). The infection types, which included bacterial, viral, and combination diarrhea, were determined by microbiological culture methods. Antibiotics used in non-bacterial diarrhea patients were considered misused and overused. RESULTS: There were significant overall differences in the clinical characteristics and blood tests between patients with diarrhea with a bacterial infection and patients with other types of infections. The patients were divided into four grading groups (0-3) according to the number of the positive results from three blood testes (CRP, WBC, and Neu%). The misuse rates of antibiotics in each group (0-3) were 81.3%, 71.1%, 72.4%, and 64.9%, respectively. CONCLUSION: In this prospective study, the current diagnostic criteria (CRP, WBC, and Neu%) based on blood tests are not reliable in diagnosing bacterial diarrhea or guiding antibiotics use. To limit antibiotic overuse, a rapid and accurate differentiation of bacterial diarrhea from other types of diarrhea is pivotal. PMID- 28352158 TI - Cardioprotection with halogenated gases: how does it occur? AB - Numerous studies have studied the effect of halogenated agents on the myocardium, highlighting the beneficial cardiac effect of the pharmacological mechanism (preconditioning and postconditioning) when employed before and after ischemia in patients with ischemic heart disease. Anesthetic preconditioning is related to the dose-dependent signal, while the degree of protection is related to the concentration of the administered drug and the duration of the administration itself. Triggers for postconditioning and preconditioning might have numerous pathways in common; mitochondrial protection and a decrease in inflammatory mediators could be the major biochemical elements. Several pathways have been identified, including attenuation of NFkappaB activation and reduced expression of TNFalpha, IL-1, intracellular adhesion molecules, eNOS, the hypercontraction reduction that follows reperfusion, and antiapoptotic activating kinases (Akt, ERK1/2). It appears that the preconditioning and postconditioning triggers have numerous similar paths. The key biochemical elements are protection of the mitochondria and reduction in inflammatory mediators, both of which are developed in various ways. We have studied this issue, and have published several articles on cardioprotection with halogenated gases. Our results confirm greater cardioprotection through myocardial preconditioning in patients anesthetized with sevoflurane compared with propofol, with decreasing levels of troponin and N terminal brain natriuretic peptide prohormone. The difference between our studies and previous studies lies in the use of sedation with sevoflurane in the postoperative period. The results could be related to a prolonged effect, in addition to preconditioning and postconditioning, which could enhance the cardioprotective effect of sevoflurane in the postoperative period. With this review, we aim to clarify the importance of various mechanisms involved in preconditioning and postconditioning with halogenated gases, as supported by our studies. PMID- 28352162 TI - Determinants of initiation, implementation, and discontinuation of amoxicillin by adults with acute cough in primary care. AB - AIM: To investigate the determinants of adherence to amoxicillin in patients with acute lower respiratory tract infection. MATERIALS AND METHODS: Three European data sets were used. Adherence data were collected using self-reported diaries. Candidate determinants included factors relating to patient, condition, therapy, health care system/provider, and the study in which the patient participated. Logistic and Cox regression models were used to investigate the determinants of initiation, implementation, and discontinuation of amoxicillin. RESULTS: Although initiation differed across samples, implementation and discontinuation were similar. Determinants of initiation were days waited before consulting, duration of prescription, and being in a country where a doctor-issued sick certificate is required for being off work for <7 days. Implementation was higher for older participants or those with abnormal auscultation. Implementation was lower for those prescribed longer courses of amoxicillin (>=8 days). Time from initiation to discontinuation was longer for longer prescriptions and shorter for those from countries where single-handed practices were widespread. CONCLUSION: Nonadherence to amoxicillin was largely driven by noninitiation. Differing sets of determinants were found for initiation, implementation, and discontinuation. There is a need to further understand the reasons for these determinants, the impact of poor adherence to antibiotics on outcomes, and to develop interventions to improve antibiotic use when prescribed. PMID- 28352161 TI - Relationship between depression and medication adherence in cardiovascular disease: the perfect challenge for the integrated care team. AB - Many individuals with cardiovascular disease (CVD) experience depression that is associated with poor health outcomes, which may be because of medication nonadherence. Several factors influence medication adherence and likely influence the relationship between depression and medication adherence in CVD patients. This comprehensive study reviews the existing literature on depression and medication adherence in CVD patients, addresses the methods of and problems with measuring medication adherence, and explains why the integrated care team is uniquely situated to improve the outcomes in depressed CVD patients. This paper also explores how the team can collaboratively target depressive symptoms and medication-taking behavior in routine clinical care. Finally, it suggests the limitations to the integrated care approach, identifies targets for future research, and discusses the implications for CVD patients and their families. PMID- 28352163 TI - The effectiveness of a basic exercise intervention to improve strength and balance in women with osteoporosis. AB - OBJECTIVE: To determine the effects of a simple exercise program on the balance and strength of postmenopausal women with osteoporosis. METHODS: This program was based on low intensity strength and balance exercises, and was carried out with simple, readily available equipment. Sixty five women were randomly assigned to either the experimental group (EG; n=33, age: 57.4+/-4.8 years) or the control group (CG; n=32, age: 58.8+/-4.5 years). Participants in the EG underwent balance and strength training for 60 min, three times/week for 6 months. Each session consisted of warm-up exercises (10 min), balance training (20 min), strength training (20 min), and cooldown (10 min). Participants from the CG were asked not to modify their usual habits during the course of the study. Static balance was evaluated using the blind monopodal stance static balance test. In contrast, dynamic balance was assessed using the "8-foot up and go" test, whereas the strength of the upper and lower limbs was measured using the "arm curl" and "30 s chair stand" tests, respectively. All these variables were assessed at baseline and upon program completion. RESULTS: The EG showed significant improvements (P<0.001) in static balance (21%), dynamic balance (36%), and in the strength of the upper (80%) and lower (47%) limbs in comparison to the CG after the sixth month. Participants in the CG showed significantly lower values (P<0.001) in the four tests. In addition, a significant inverse relationship between static balance and the strength of the upper (r=-0.390; P=0.001) and lower (r=-0.317; P=0.01) limbs was found. CONCLUSION: The present study demonstrates that a physical exercise program based on balance and strength exercises, carried out with simple and readily available equipment, is capable of significantly improving the strength and balance of women with osteoporosis. PMID- 28352164 TI - Oral conditions and dysphagia in Japanese, community-dwelling middle- and older- aged adults, independent in daily living. AB - PURPOSE: Prevention, early detection and effective rehabilitation of dysphagia are important issues to be considered in an aging society. Previous studies have shown conflicting findings regarding the association between dysphagia and its potential risk factors, including age, malnutrition, oral conditions, lifestyle and medical history. Herein, we assessed the prevalence and association of dysphagia with potential risk factors in 50- to 79-year-old adults dwelling in a community in Japan. PATIENTS AND METHODS: In this study, there were 532 participants (185 males and 347 females). Participants who responded positively to the question "Do you sometimes choke on drinks/food such as tea and soup?" or those who presented with abnormal repetitive saliva swallowing test findings were diagnosed with dysphagia. The data collected from these participants included the following: number of teeth, occurrence of oral dryness, age, body mass index, serum albumin concentration, smoking, drinking and exercise habits, presence of diseases, such as diabetes mellitus and hypertension, and questions from the Mini Mental State Examination. RESULTS: Dysphagia was observed in 33 males (17.8%) and 76 females (21.9%). To explore the effect of the potential risk factors on the prevalence of dysphagia, a model was built by multivariate logistic regression analysis. Using the forced entry method, oral dryness (odds ratio [OR] =3.683 and P=0.003 in males; OR =1.797 and P=0.032 in females) and the number of teeth (OR =0.946 and P=0.038 in males) were found to be significantly related to dysphagia. CONCLUSION: This cross-sectional study demonstrated associations between oral conditions and dysphagia. Factors such as oral dryness and number of teeth may contribute to dysphagia more so than aging, lifestyle and comorbidity in community-dwelling adults over the age of 50. PMID- 28352166 TI - Erratum: Health behaviors and their correlates among participants in the Continuing to Confront COPD International Patient Survey [Corrigendum]. AB - [This corrects the article on p. 881 in vol. 11, PMID: 27217741.]. PMID- 28352165 TI - Correlation between thoracolumbar curvatures and respiratory function in older adults. AB - Aging is associated with alterations in thoracolumbar curvatures and respiratory function. Research information regarding the correlation between thoracolumbar curvatures and a comprehensive examination of respiratory function parameters in older adults is limited. The aim of the present study was to examine the correlation between thoracolumbar curvatures and respiratory function in community-dwelling older adults. Thoracolumbar curvatures (thoracic and lumbar) were measured using a motion tracker. Respiratory function parameters such as lung function, respiratory rate, respiratory muscle strength and respiratory muscle thickness (diaphragm and intercostal) were measured using a spirometer, triaxial accelerometer, respiratory pressure meter and ultrasound imaging, respectively. Sixty-eight community-dwelling older males and females from Kuala Lumpur, Malaysia, with mean (standard deviation) age of 66.63 (5.16) years participated in this cross-sectional study. The results showed that mean (standard deviation) thoracic curvature angle and lumbar curvature angles were 46.30 degrees (14.66 degrees ) and 14.10 degrees (10.58 degrees ), respectively. There was a significant negative correlation between thoracic curvature angle and lung function (forced expiratory volume in 1 second: r=-0.23, P<0.05; forced vital capacity: r=-0.32, P<0.05), quiet expiration intercostal thickness (r=-0.22, P<0.05) and deep expiration diaphragm muscle thickness (r= 0.21, P<0.05). The lumbar curvature angle had a significant negative correlation with respiratory muscle strength (r=-0.29, P<0.05) and diaphragm muscle thickness at deep inspiration (r=-0.22, P<0.05). However, respiratory rate was correlated neither with thoracic nor with lumbar curvatures. The findings of this study suggest that increase in both thoracic and lumbar curvatures is correlated with decrease in respiratory muscle strength, respiratory muscle thickness and some parameters of lung function. Clinically, both thoracic and lumbar curvatures, respiratory muscles and lung function should be taken into consideration in the holistic management of respiratory function among older adults. PMID- 28352167 TI - Changes in the number of CD31-CD45-Sca-1+ cells and Shh signaling pathway involvement in the lungs of mice with emphysema and relevant effects of acute adenovirus infection. AB - BACKGROUND: COPD is a leading cause of mortality worldwide, and cigarette smoke is a pivotal risk factor. Adenovirus is a common cause of acute exacerbations of COPD and expedites COPD progression. Lung stem/progenitor cells play an important role in the development of COPD, while the relevant mechanism remains elusive. Here, we investigated the number of lung CD31-CD45-Sca-1+ cells and sonic hedgehog (Shh) signaling pathway expression levels in cigarette smoke extract (CSE)-induced emphysema mice, as well as the relevant effects of acute adenovirus infection (AAI). MATERIALS AND METHODS: BALB/c mice were treated with CSE by intraperitoneal injection and/or adenovirus endotracheal instillation at different time points for 28 days. Lung function, lung histomorphology, CD31-CD45 Sca-1+ cell count, and expression levels of major components in the Shh signaling pathway in the lungs were measured. RESULTS: CSE intraperitoneal injection and adenovirus endotracheal instillation successfully induced emphysema and AAI in mice, respectively. In the lungs of emphysema mice, both the number of CD31-CD45 Sca-1+ cells and expression levels of Shh signaling pathway molecules were reduced. However, AAI increased the number of inhibited CD31-CD45-Sca-1+ cells and activated the suppression of the Shh signaling pathway. CONCLUSION: Both CD31 CD45-Sca-1+ cell numbers and Shh signaling pathway expression levels were downregulated in the lungs of emphysema mice induced by CSE intraperitoneal injection, which likely contributes to the pathogenesis of emphysema. Additionally, these inhibited lung CD31-CD45-Sca-1+ cells and Shh signaling pathway molecules were upregulated during AAI, indicating that they play a protective role in the epithelial repair process after AAI injury. PMID- 28352168 TI - Positive correlation of airway resistance and serum asymmetric dimethylarginine level in COPD patients with systemic markers of low-grade inflammation. AB - The major feature of COPD is a progressive airflow limitation caused by chronic airway inflammation and consequent airway remodeling. Modified arginase and nitric oxide synthase (NOS) pathways are presumed to contribute to the inflammation and fibrosis. Asymmetric dimethylarginine (ADMA) may shunt L arginine from the NOS pathway to the arginase one by uncoupling and competitive inhibition of NOS and by enhancing arginase activity. To attest the interplay of these pathways, the relationship between ADMA and airflow limitation, described by airway resistance (Raw), was investigated in a cohort of COPD patients. Every COPD patient willing to give consent to participate (n=74) was included. Case history, laboratory parameters, serum arginine and ADMA, pulmonary function (whole-body plethysmography), and disease-specific quality of life (St George's Respiratory Questionnaire) were determined. Multiple linear regression was used to identify independent determinants of Raw. The final multiple model was stratified based on symptom control. The log Raw showed significant positive correlation with log ADMA in the whole sample (Pearson's correlation coefficient: 0.25, P=0.03). This association remained significant after adjusting for confounders in the whole data set (beta: 0.42; confidence interval [CI]: 0.06, 0.77; P=0.022) and in the worse-controlled stratum (beta: 0.84; CI: 0.25, 1.43; P=0.007). Percent predicted value of forced expiratory flow between 25% and 75% of forced vital capacity showed that significant negative, elevated C-reactive protein exhibited significant positive relationship with Raw in the final model. Positive correlation of Raw with ADMA in COPD patients showing evidence of a systemic low-grade inflammation implies that ADMA contributes to the progression of COPD, probably by shunting L-arginine from the NOS pathway to the arginase one. PMID- 28352169 TI - Evidence of eosinophil extracellular trap cell death in COPD: does it represent the trigger that switches on the disease? AB - In spite of the numerous studies on chronic obstructive pulmonary disease (COPD), the cellular and molecular basis of the disease's development remain unclear. Neutrophils and eosinophils are known to be key players in COPD. Recently, neutrophil extracellular trap cell death (NETosis), a mechanism due to decondensation and extrusion of chromatin to form extracellular traps, has been demonstrated in COPD. However, there is limited knowledge about eosinophil extracellular trap cell death (EETosis) and its role in the pathogenesis of COPD. The aim of this study was to evaluate EETosis in stable COPD. Induced sputum obtained from healthy smokers and low exacerbation risk COPD A or B group patients or high exacerbation risk COPD C or D group patients were included. Samples were examined using electron microscopy and immunofluorescence. Healthy smokers (n=10) and COPD A (n=19) group exhibited neutrophilic or paucigranulocytic phenotypes, with NETosis being absent in these patients. In contrast, COPD B (n=29), with eosinophilic or mixed phenotypes, showed EETosis and incipient NETosis. COPD C (n=18) and COPD D groups (n=13) were differentiated from low exacerbation rate-COPD group by the abundant cellular debris, with COPD C group having an eosinophilic pattern and numerous cells undergoing EETosis. A hallmark of this group was the abundant released membranes that often appeared phagocytosed by neutrophils, which coincidentally exhibited early NETosis changes. The COPD D group included patients with a neutrophilic or mixed pattern, with abundant neutrophil extracellular trap-derived material. This study is the first to demonstrate EETosis at different stages of stable COPD. The results suggest a role for eosinophils in COPD pathophysiology, especially at the beginning and during the persistence of the disease, regardless of whether the patient quit smoking, with EETosis debris probably triggering uncontrolled NETosis. The main target of these findings should be young smokers with the potential to develop COPD. PMID- 28352170 TI - Clinical application value of impulse oscillometry in geriatric patients with COPD. AB - BACKGROUND: The diagnosis and assessment of COPD rely mainly on the use of spirometry, which is an effort-dependent test and requires good patient cooperation. Impulse oscillometry (IOS) is a non-volitional method that requires less effort and cooperation and presents advantages for geriatric patients. However, the clinical application value of IOS in geriatric patients with COPD remains unclear. AIM: The aim of this study was to investigate the clinical application value of IOS in geriatric patients with COPD. SUBJECTS AND METHODS: A total of 234 subjects were retrospectively enrolled in this study, including 133 patients with COPD and 101 healthy volunteers. All the participants underwent IOS and spirometry examination. The data were collected and analyzed in the overall group, the geriatric group (aged >=65 years), and the advanced elderly group (aged >=80 years). RESULTS: 1) In COPD patients, a significant increase in respiratory impedance (Z5), resonant frequency (Fres), and respiratory resistance (R5, R20, R5-R20) and a decrease in respiratory reactance (X5) were observed in the overall group, the geriatric group, and the advanced elderly group compared with the healthy control subjects. 2) The IOS parameters correlated well with spirometry in COPD. In particular, R5-R20 showed the best correlation with forced expiratory volume in 1 second (FEV1) in the different age groups. 3) Fres and R5 R20 had the best diagnostic efficiency for COPD. The area under the curve (AUC) values for Fres, expressed by the receiver operating characteristic (ROC) curve, were 0.905, 0.909, and 0.914, for the different age groups, respectively. 4) The optimal cutoff values for Fres to diagnose airflow obstruction from ROC curves was 17.715 in the COPD patients. Its sensitivity and specificity were 0.789 and 0.931, respectively, and the cutoff values were similar in geriatric and advanced elderly patients. CONCLUSION: IOS demonstrated good relevance compared with spirometry for geriatric patients with COPD. IOS may serve as an alternative method for spirometry in elderly subjects for the evaluation of the state of COPD. PMID- 28352171 TI - The influence of surface charge on serum protein interaction and cellular uptake: studies with dendritic polyglycerols and dendritic polyglycerol-coated gold nanoparticles. AB - Nanoparticles (NPs) have gained huge interest in the medical field, in particular for drug delivery purposes. However, binding of proteins often leads to fast NP uptake and rapid clearance, thereby hampering medical applications. Thus, it is essential to determine and control the bio-nano interface. This study investigated the serum protein interactions of dendritic polyglycerols (dPGs), which are promising drug delivery candidates by means of two dimensional gel electrophoresis (2DE) in combination with mass spectrometry. In order to investigate the influence of surface charge, sulfated (sulfated dendritic polyglycerol [dPGS]) and non-sulfated (dPGOH) surfaces were applied, which were synthesized on a gold core allowing for easier separation from unbound biomolecules through centrifugation. Furthermore, two different sizes for dPGS were included. Although size had only a minor influence, considerable differences were detected in protein affinity for dPGS versus dPGOH surfaces, with dPGOH binding much less proteins. Cellular uptake into human CD14+ monocytes was analyzed by flow cytometry, and dPGOH was taken up to a much lower extent compared to dPGS. By using a pull-down approach, possible cellular interaction partners of serum pre-incubated dPGS-Au20 NPs from the membrane fraction of THP-1 cells could be identified such as for instance the transferrin receptor or an integrin. Clathrin-mediated endocytosis was further investigated using chlorpromazine as an inhibitor, which resulted in a 50% decrease of the cellular uptake of dPGS. This study could confirm the influence of surface charge on protein interactions and cellular uptake of dPGS. Furthermore, the approach allowed for the identification of possible uptake receptors and insights into the uptake mechanism. PMID- 28352172 TI - Cellulose nanofiber aerogel as a promising biomaterial for customized oral drug delivery. AB - Cellulose nanofiber (CNF) aerogels with favorable floatability and mucoadhesive properties prepared by the freeze-drying method have been introduced as new possible carriers for oral controlled drug delivery system. Bendamustine hydrochloride is considered as the model drug. Drug loading was carried out by the physical adsorption method, and optimization of drug-loaded formulation was done using central composite design. A very lightweight-aerogel-with-matrix system was produced with drug loading of 18.98%+/-1.57%. The produced aerogel was characterized for morphology, tensile strength, swelling tendency in media with different pH values, floating behavior, mucoadhesive detachment force and drug release profiles under different pH conditions. The results showed that the type of matrix was porous and woven with excellent mechanical properties. The drug release was assessed by dialysis, which was fitted with suitable mathematical models. Approximately 69.205%+/-2.5% of the drug was released in 24 hours in medium of pH 1.2, whereas ~78%+/-2.28% of drug was released in medium of pH 7.4, with floating behavior for ~7.5 hours. The results of in vivo study showed a 3.25 fold increase in bioavailability. Thus, we concluded that CNF aerogels offer a great possibility for a gastroretentive drug delivery system with improved bioavailability. PMID- 28352173 TI - Lipid-coated iron oxide nanoparticles for dual-modal imaging of hepatocellular carcinoma. AB - The development of noninvasive imaging techniques for the accurate diagnosis of progressive hepatocellular carcinoma (HCC) is of great clinical significance and has always been desired. Herein, a hepatocellular carcinoma cell-targeting fluorescent magnetic nanoparticle (NP) was obtained by conjugating near-infrared fluorescence to the surface of Fe3O4 (NIRF-Fe3O4) NPs, followed by coating the lipids consisting of tumoral hepatocytes-targeting polymer (Gal-P123). This magnetic NP (GPC@NIRF-Fe3O4) with superparamagnetic behavior showed high stability and safety in physiological conditions. In addition, GPC@NIRF-Fe3O4 achieved more specific uptake of human liver cancer cells than free Fe3O4 NPs. Importantly, with superpara-magnetic iron oxide and strong NIR absorbance, GPC@NIRF-Fe3O4 NPs demonstrate prominent tumor-contrasted imaging performance both on fluorescent and T2-weighted magnetic resonance (MR) imaging modalities in a living body. The relative MR signal enhancement of GPC@NIRF-Fe3O4 NPs achieved 5.4-fold improvement compared with NIR-Fe3O4 NPs. Therefore, GPC@ NIRF-Fe3O4 NPs may be potentially used as a candidate for dual-modal imaging of tumors with information covalidated and directly compared by combining fluorescence and MR imaging. PMID- 28352174 TI - Octanoyl galactose ester-modified microemulsion system self-assembled by coix seed components to enhance tumor targeting and hepatoma therapy. AB - A nanosized drug delivery platform with a combination of rational components and tumor targeting is significant for enhancement of anticancer therapy and reduction of side effects. In this study, we developed a octanoyl galactose ester modified microemulsion system self-assembled by coix seed components (Gal(oct)-C MEs), which improved the tumor accumulation through asialoglycoprotein receptor mediated endocytosis and promoted the antitumor efficacy through multicomponent mediated synergistic effect. Octanoyl galactose ester (Gal(oct)) with a yield of 82.3% was synthesized through a green enzymatic reaction and multidimensional characterization. Gal(oct)-C-MEs with a spherical shape had a small and uniform particle size (58.49+/-1.03 nm), narrow polydispersity index (0.09+/-0.01) and neutral surface charge (-5.82+/-0.57 mV). In the cellular uptake studies, the internalized Gal(oct)-C-ME was 2.28-fold higher relative to that of coix seed component-based microemulsions (C-MEs). The half-maximal inhibitory concentration of Gal(oct)-C-MEs against HepG2 cells was 46.5+/-2.4 MUg/mL, which was notably higher than that of C-MEs. Importantly, the intratumor fluorescence of HepG2 xenograft-bearing nude mice treated with Cy5/Gal(oct)-C-MEs was 1.9-fold higher relative to treatment with Cy5/C-MEs. In the study of antitumor efficacy in vivo, HepG2 xenograft-bearing nude mice intragastrically administered Gal(oct)-C-MEs for 14 days exhibited the strongest inhibition of tumor growth and the lowest toxicity against liver and kidney among all the treatments. In summary, Gal(oct) C-ME, as a highly effective and safe anticancer drug delivery system, showed promising potential for hepatoma therapy. PMID- 28352175 TI - Factors influencing transfection efficiency of pIDUA/nanoemulsion complexes in a mucopolysaccharidosis type I murine model. AB - Mucopolysaccharidosis type I (MPS I) is an autosomal disease caused by alpha-l iduronidase (IDUA) deficiency. This study used IDUA knockout mice as a model to evaluate whether parameters such as dose of plasmid and time of treatment could influence the transfection efficiency of complexes formed with PEGylated cationic nanoemulsions and plasmid (pIDUA), which contains the gene that encodes for IDUA. Formulations were composed of medium chain triglycerides, 1,2-dioleoyl-sn-glycero 3-phosphoethanolamine, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N (amino[polyethylene glycol]-2000), 1,2-dioleoyl-sn-glycero-3-trimethylammonium propane (DOTAP), glycerol, and water and were prepared by the adsorption or encapsulation of preformed pIDUA-DOTAP complexes by high-pressure homogenization. A progressive increase in IDUA expression was observed with an increase in the dose and time of transfection for mice treated with both complexes (adsorbed and encapsulated), especially in the liver. Regardless of the complex administered, a significant increase in IDUA activity was detected in lungs and liver compared with nontreated MPS I when a dose of 60 MUg was administered and IDUA activity was measured 7 days postadministration. Tissue sections of major organs showed no presence of cell necrosis, inflammatory infiltrate, or an increase in apoptosis. Furthermore, immunohistochemistry for CD68 showed no difference in the number of macrophage cells in treated and nontreated animals, indicating the absence of inflammatory reaction caused by the treatment. The data set obtained in this study allowed establishing that factors such as dose and time can influence transfection efficiency in different degrees and that these complexes did not lead to any lethal effect in the MPS I murine model used. PMID- 28352176 TI - Hesperetin-loaded lipid-core nanocapsules in polyamide: a new textile formulation for topical drug delivery. AB - Chronic venous insufficiency is characterized by chronic reflux disorder of blood from the peripheral to the central vein, with subsequent venous hypertension and resulting changes in the skin. Traditionally, nonsurgical treatments relied on the use of compression therapy, and more recently a variety of flavonoids have been shown to have positive effects. There have also been developments of more effective drug delivery systems using various textiles and nanotechnology to provide new therapeutic options. Our objective was to use nanotechnology to develop a new formulation containing hesperetin (Hst), a substance not previously used in the treatment of chronic venous insufficiency, impregnated into textile fibers as a possible alternative treatment of venous diseases. We prepared the nanocapsules using the interfacial deposition of preformed polymer method with an Hst concentration of 0.5 mg/mL and then characterized the size and distribution of particles. To quantify the Hst in the samples, we developed an analytical method using high-performance liquid chromatography. Studies of encapsulation efficiency (98.81%+/-0.28%), microscopy, drug release (free-Hst: 104.96%+/ 12.83%; lipid-core nanocapsule-Hst: 69.90%+/-1.33%), penetration/permeation, drug content (0.46+/-0.01 mg/mL) and the effect of washing the textile after drug impregnation were performed as part of the study. The results showed that nanoparticles of a suitable size and distribution with controlled release of the drug and penetration/permeation into the skin layers were achieved. Furthermore, it was established that polyamide was able to hold more of the drug, with a 2.54 times higher content than the cotton fiber; after one wash and after five washes, this relation was 2.80 times higher. In conclusion, this is a promising therapeutic alternative to be further studied in clinical trials. PMID- 28352177 TI - Lipase degradation of plasticized polyvinyl chloride endotracheal tube surfaces to create nanoscale features. AB - Polyvinyl chloride (PVC) endotracheal tubes (ETTs) nanoetched with a fungal lipase have been shown to reduce bacterial growth and biofilm formation and could be an inexpensive solution to the complex problem of ventilator-associated pneumonia (VAP). Although bacterial growth and colonization on these nanoetched materials have been well characterized, little is known about the mechanism by which the fungal lipase degrades the PVC and, thus, alters its properties to minimize bacteria functions. This study used X-ray photoelectron spectroscopy (XPS) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) to better describe the surface chemistry of both unetched and lipase nanoetched PVC ETT. ATR-FTIR analysis of the unetched and treated surfaces showed a similar presence of a plasticizer. This was confirmed by XPS analysis, which showed an increase of carbon and the presence of oxygen on both unetched and nanoetched surfaces. A quantitative comparison of the FTIR spectra revealed significant correlations (Pearson's correlation, R=0.997 [R2=0.994, P<0.001]) between the unetched and nanomodified PVC ETT spectra, demonstrating similar surface chemistry. This analysis showed no shifting or widening of the bands in the spectra and no significant changes in the intensity of the infrared peaks due to the degradation of the plasticizer by the fungal lipase. In contrast, results from this study did demonstrate significantly increased nanoscale surface features on the lipase etched compared to non-etched PVC ETTs. This led to a change in surface energetics, which altered ion adsorption to the ETTs. Thus, these results showed that PVC surfaces nanoetched with a 0.1% lipase solution for 48 hours have no significant change on surface chemistry but do significantly increase nanoscale surface roughness and alters ion adsorption, which suggests that the unique properties of these materials, including their previously reported ability to decrease bacterial adhesion and growth, are due to the changes in the degree of the nanoscale roughness, not changes in their surface chemistry. PMID- 28352178 TI - Attention-deficit hyperactivity disorder in elementary school students in Shantou, China: prevalence, subtypes, and influencing factors. AB - Attention-deficit hyperactivity disorder (ADHD) is a frequent childhood-onset psychiatric condition and categorized into three subtypes of predominantly inattentive (ADHD-I), hyperactive impulsive (ADHD-H), and combined (ADHD-C). The prevalence and subtypes of ADHD vary considerably. The primary aim of this study was to provide a prevalence estimate of ADHD in elementary school students living in Shantou, a district of China, and in addition to examine the influence of informants, age, and gender on the prevalence. A total of 3,497 students aged 7 12 years were enrolled by random and stratified sampling. In stage I, teachers and parents of all participating students in randomly selected schools were asked to complete Chinese versions of the Conners' 10-item scale. In stage II, students with high scores (>15) were interviewed by a psychiatrist for a diagnosis with or without ADHD. Parents rated many more students with high scores than teachers did in stage I. The prevalence of ADHD determined by Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) was 5.91% (5.27%-6.55%), which is comparable to the rates reported in previous studies with Chinese children. This hits the low border of the ADHD prevalence range from 5.9 to 7.1% worldwide, and is lower than that of Chinese children living in Hong Kong, suggesting an important influence of Chinese culture on the diagnosis of ADHD. The constituent ratios of ADHD-I, ADHD-C, and ADHD-H subtypes were 67.43, 24.57, and 8.00%, respectively. The rate of ADHD-H decreased with age, whereas that of ADHD-I remained at the highest levels in all age groups, suggesting that symptoms in the inattention domain are the most persistent and refractory. PMID- 28352179 TI - Validation and cultural adaptation of the Arabic versions of the Mini-Mental Status Examination - 2 and Mini-Cog test. AB - INTRODUCTION: The elderly population is increasing around the world, and the prevalence of dementia increases with age. Hence, it is expected that the number of people with dementia will increase significantly in the coming years. The Mini Mental Status Examination - 2 (MMSE-2) and Mini-Cog are widely used tests to screen for dementia. These scales have good reliability and validity and are easy to administer in clinical and research settings. AIM: The purpose of this study was to validate the Arabic versions of MMSE-2 and Mini-Cog. These scales were assessed against the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for dementia, as the gold standard. METHODS: The standard versions of the MMSE-2 and Mini-Cog were translated to Arabic following the back-translation method. Then, a trained rater administered these tests to 134 Arab elderly aged >60 years. A physician, blind to the results of these two tests, assessed the participants for vascular dementia or probable Alzheimer's disease, based on the DSM-IV-TR criteria. RESULTS: The sample included 67.2% Qataris. The mean age was 74.86 years (standard deviation =7.71), and 61.9% did not attend school. The mean of the adjusted scores of MMSE-2 based on age and education level was 19.60 (standard deviation =6.58). According to DSM-IV-TR, 17.2% of the participants had dementia. Sensitivity and specificity of the MMSE-2 and the Mini-Cog together were 71.4% and 61.6%, respectively, which were better than those of each test alone. CONCLUSION: Together, the Arabic versions of MMSE-2 and Mini-Cog are good screening tools for cognitive impairment in Arabs. PMID- 28352180 TI - Daily activity level improvement with antidepressant medications predicts long term clinical outcomes in outpatients with major depressive disorder. AB - BACKGROUND: Major depressive disorder (MDD) significantly impacts performance of both work- and nonwork-related routine daily activities. We have shown that work productivity is significantly impaired in employed MDD patients, but the extent of impairments in nonwork-related routine activities and its association with antidepressant treatment outcomes has not been established. MATERIALS AND METHODS: Activity impairment was measured using the sixth item of Work Productivity and Activity Impairment Scale in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial (n=665). Published norms were used to define activity impairment levels. The relationship between activity impairment and baseline sociodemographic and clinical characteristics was evaluated along with changes in activity impairment and its relationship with other clinical outcomes such as symptom severity, function, and side effect burden. Remission status at 3 and 7 months was predicted based on week 6 activity impairment level. RESULTS: Higher psychosocial and cognitive impairments and greater number of comorbid medical conditions were associated with greater activity impairment at baseline. Proportion of participants with severe activity impairment declined from 47.6% at baseline to 18.7% at 3 months, while mean activity impairment decreased from 57.1 at baseline to 32.8 at 3 months. During course of treatment, levels of activity impairment correlated most strongly with psychosocial function among measures of symptom severity, function, quality of life, and side effect burden. No or minimal activity impairment at week 6 was associated with two to three times higher rates of remission at 3 and 7 months as compared to moderate or severe activity impairment levels even after controlling for remission status at week 6 and select baseline variables. CONCLUSION: Depressed patients have high levels of nonwork-related activity impairment at baseline that improves significantly with treatment and independently predicts long-term clinical outcomes. Brief systematic assessment of activity impairment during the course of antidepressant treatment can help inform clinical decision-making. PMID- 28352182 TI - Role of IL-17 in plaque psoriasis: therapeutic potential of ixekizumab. AB - Developments in the understanding of the immunopathogenesis of psoriasis have identified interleukin (IL)-17 as the key proinflammatory cytokine in the pathogenesis of plaque psoriasis, with the consequent development of drugs that target this cytokine or associated receptors. Ixekizumab is a subcutaneously administered humanized monoclonal antibody, which acts to neutralize IL-17A. This article reviews the role of IL-17 in the pathogenesis of psoriasis, the biological and pharmacokinetics of ixekizumab and the safety profile and the clinical efficacy of ixekizumab in Phase III clinical trials. Phase III clinical trials of ixekizumab have so far demonstrated excellent early clinical efficacy, with a comparable safety profile to the existing biologic therapies for psoriasis. To further assess its position in the treatment algorithm for psoriasis, a further head to head RCT with secukinumab could be established, alongside comparative effectiveness studies from observational research. In addition, trials are needed to assess its role in those with tumor necrosis factor inhibitors/ustekinumab resistant disease. However, it is clear that the IL 17 antagonists have changed the benchmark for clinical efficacy, and it is likely that ixekizumab along with the other IL-17 antagonists are set to achieve a new standard of care in the treatment of moderate to severe plaque psoriasis. PMID- 28352183 TI - Clinical characteristics of zinc phosphide poisoning in Thailand. AB - OBJECTIVE: The objectives of this study were to describe the clinical characteristics and outcomes of poisoning by zinc phosphide, a common rodenticide in Thailand, and to evaluate whether these outcomes can be prognosticated by the clinical presentation. MATERIALS AND METHODS: A 3-year retrospective cohort study was performed using data from the Ramathibodi Poison Center Toxic Exposure Surveillance System. RESULTS: In total, 455 poisonings were identified. Most were males (60.5%) and from the central region of Thailand (71.0%). The mean age was 39.91+/-19.15 years. The most common route of exposure was oral (99.3%). Most patients showed normal vital signs, oxygen saturation, and consciousness at the first presentation. The three most common clinical presentations were gastrointestinal (GI; 68.8%), cardiovascular (22.0%), and respiratory (13.8%) signs and symptoms. Most patients had normal blood chemistry laboratory results and chest X-ray findings at presentation. The median hospital stay was 2 days, and the mortality rate was 7%. Approximately 70% of patients underwent GI decontamination, including gastric lavage and a single dose of activated charcoal. In all, 31 patients were intubated and required ventilator support. Inotropic drugs were given to 4.2% of patients. Four moribund patients also received hyperinsulinemia-euglycemia therapy and intravenous hydrocortisone; however, all died. Patients who survived and died showed significant differences in age, duration from taking zinc phosphide to hospital presentation, abnormal vital signs at presentation (tachycardia, low blood pressure, and tachypnea), acidosis, hypernatremia, hyperkalemia, in-hospital acute kidney injury, in hospital hypoglycemia, endotracheal tube intubation, and inotropic requirement during hospitalization (P<0.05). CONCLUSION: Zinc phosphide poisoning causes fatalities. Most patients have mild symptoms, and GI symptoms are the most common. Patients who present with abnormal vital signs or electrolytes might have more severe poisoning and should be closely monitored and aggressively treated. All patients should be observed in the hospital for 2 days and followed up for cardiovascular and respiratory symptoms, electrolyte balances, kidney function, and blood glucose. PMID- 28352184 TI - Aerobic fitness is associated with low cardiovascular disease risk: the impact of lifestyle on early risk factors for atherosclerosis in young healthy Swedish individuals - the Lifestyle, Biomarker, and Atherosclerosis study. AB - BACKGROUND: The progression of cardiovascular disease (CVD) and atherosclerosis is slow and develops over decades. In the cross-sectional Swedish Lifestyle, Biomarker, and Atherosclerosis study, 834 young, self-reported healthy adults aged 18.0-25.9 years have been studied to identify early risk factors for atherosclerosis. PURPOSE: The aims of this study were to 1) assess selected cardiometabolic biomarkers, carotid intima-media thickness (cIMT) as a marker of subclinical atherosclerosis, and lifestyle-related indicators (food habits, handgrip strength, and oxygen uptake, VO2 max); 2) analyze the associations between cIMT and lifestyle factors; and 3) identify subjects at risk of CVD using a risk score and to compare the characteristics of subjects with and without risk of CVD. METHOD: Blood samples were taken in a fasting state, and food habits were reported through a questionnaire. cIMT was measured by ultrasound, and VO2 max was measured by ergometer bike test. The risk score was calculated according to Wildman. RESULT: cIMT (mean +/- standard deviation) was 0.50+/-0.06 mm, and VO2 max values were 37.8+/-8.5 and 42.9+/-9.9 mL/kg/min, in women and men, respectively. No correlation was found between aerobic fitness expressed as VO2 max (mL/kg/min) and cIMT. Using Wildman's definition, 12% of the subjects were classified as being at risk of CVD, and 15% had homeostasis model assessment of insulin resistance. A total of 35% of women and 25% of men had lower high-density lipoprotein cholesterol than recommended. Food habits did not differ between those at risk and those not at risk. However, aerobic fitness measured as VO2 max (mL/kg/min) differed; 47% of the subjects at risk had low aerobic fitness compared to 23% of the nonrisk subjects (P<0.001). CONCLUSION: High aerobic fitness is associated with low CVD risk in Swedish young adults. The high prevalence of young adults observed with unfavorable levels of high-density lipoprotein cholesterol and homeostasis model assessment of insulin resistance raises concerns about future CVD risk. PMID- 28352185 TI - Apatinib treatment combined with chemotherapy for advanced epithelial ovarian cancer: a case report. AB - Apatinib is a novel oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, which has been proved by clinical trials to be effective and safe for patients with chemotherapy-refractory gastric cancer. To date, there is no study or case report on apatinib treatment for patients with ovarian cancer. Here, we present the case of a 50-year-old Chinese woman with advanced ovarian cancer, who received apatinib at a daily dose of 500 mg for 28 days per cycle after failure of fourth-line chemotherapy. Favorable oncologic outcome was achieved in this case after treatment with apatinib. The patient's progression-free survival is now 11.3 months, and she is taking apatinib and capecitabine as maintenance treatment. The common side effect of apatinib was fatigue; however, the toxicity of apatinib was controllable and tolerable. Thus, apatinib may be an option for chemotherapy-refractory advanced epithelial ovarian cancer, but this still warrants further investigation. PMID- 28352181 TI - Neuropsychiatric symptoms in untreated Parkinson's disease. AB - Neuropsychiatric and cognitive symptoms are common in Parkinson's disease (PD) and may precede and exceed motor symptoms as major factors impacting disease course and quality of life. Neuropsychiatric symptoms (NPS) in PD are various and are attributed to pathologic changes within multiple brain regions, to psychological stress, and to adverse effects of dopamine replacement therapy. Sleep disorders and mood symptoms such as apathy, depression, and anxiety may antedate the development of motor symptoms by years, while other NPS such as impulse control disorders, psychosis, and cognitive impairment are more common in later stages of the disease. Few studies report on NPS in the early, untreated phase of PD. We reviewed the current literature on NPS in PD with a focus on the early, drug-naive stages of PD. Among these early disease stages, premotor and early motor phases were separately addressed in our review, highlighting the underlying pathophysiological mechanisms as well as epidemiological characteristics, clinical features, risk factors, and available techniques of clinical assessment. PMID- 28352186 TI - Tyrosine kinase domain mutations of EGFR gene in head and neck squamous cell carcinoma. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) is a commonly altered gene that is identified in various cancers, including head and neck squamous cell carcinoma (HNSCC). Therefore, EGFR is a promising molecular marker targeted by monoclonal antibodies and small molecule inhibitors targeting the tyrosine kinase (TK) domain. OBJECTIVE: The objective of this study was to investigate the spectrum of mutations in exons 18, 19, 20, and 21 of the EGFR gene in HNSCC patients. MATERIALS AND METHODS: This retrospective study included 47 confirmed HNSCC cases. Mutations in the TK domain, exons 18, 19, 20, and 21 of the EGFR gene, were detected by Scorpion(r) chemistry and ARMS(r) technologies on Rotor Gene Q real-time polymerase chain reaction. RESULTS: The tumors exhibited EGFR-TK domain mutations in 57% of cases. Four cases of T790M mutations were reported for the first time among HNSCC patients. Out of the total mutations, L861Q (exon 21), exon 20 insertions and deletions of exon 19 accounted for the majority of mutations (21%, 19%, and 17%, respectively). EGFR mutation status was correlated with the higher grade (P=0.026) and advanced stage (P=0.034) of HNSCC tumors. CONCLUSION: Higher frequency of EGFR-TK domain mutations together with the presence of the T790M mutation suggests that identification of these mutations might streamline the therapy and provide a better prognosis in HNSCC cases. PMID- 28352187 TI - Risk of subsequent primary malignancies among patients with prior colorectal cancer: a population-based cohort study. AB - BACKGROUND: The site-distribution pattern and relative risk of subsequent primary malignancies (SPMs) in colorectal cancer (CRC) patients remains to be determined. MATERIALS AND METHODS: A population-based cohort of 288,390 CRC patients diagnosed between 1973 and 2012 from the Surveillance, Epidemiology, and End Results database was retrospectively reviewed. Standardized incidence ratios were calculated to estimate the relative risk for SPMs. RESULTS: The overall risk of SPMs increased in CRC patients (standardized incidence ratio 1.02) in the first 5 years after CRC diagnosis compared with that in the general population, and was negatively related to age at diagnosis. Risk increased significantly for cancers of the small intestine, ureter, colorectum, renal pelvis, endocrine system, and stomach, and decreased significantly for cancers of the gallbladder, liver, myeloma, and brain, as well as lymphoma. Patients with different prior CRC subsites showed specific sites at high risk of SPM. Prior right-sided colon cancer was associated with cancers of the small intestine, ureter, renal pelvis, thyroid, stomach, pancreas, and breast and prior left-sided colon cancer associated with secondary CRC, whereas rectal cancer was associated with cancers of the vagina, urinary bladder, and lung. CONCLUSION: Risk of SPMs increases in CRC survivors, especially in the first 5 years after prior diagnosis. Intensive surveillance should be advocated among young patients, with specific attention to the small intestine, colorectum, renal pelvis, and ureter. The common sites at high risk of SPM originate from the embryonic endoderm. Genetic susceptibility may act as the main mechanism underlying the risk of multiple cancers. PMID- 28352188 TI - Knockdown of IQGAP1 inhibits proliferation and epithelial-mesenchymal transition by Wnt/beta-catenin pathway in thyroid cancer. AB - BACKGROUND: Thyroid cancer is the most common endocrine malignant disease with a high incidence rate. The expression of IQGAP1 is upregulated in various cancers, including thyroid cancer. However, the role and underlying mechanism of IQGAP1 in thyroid cancer are still not clear. MATERIALS AND METHODS: The expression of IQGAP1 in thyroid cancer tissues and cells was determined by reverse transcription polymerase chain reaction and Western blot analysis. Cells were transfected with different siRNAs using Lipofectamine 2000 or were treated with various concentrations of XAV939. The effects of IQGAP1 knockdown on proliferation and epithelial-mesenchymal transition (EMT) of thyroid cancer cells were determined by MTT assay and Western blot analysis. Animal experiments were performed to investigate the effects of IQGAP1 knockdown on the growth of tumors in vivo. RESULTS: High IQGAP1 expression is found in thyroid cancer tissues and cells. Knockdown of IQGAP1 had inhibitory effects on cell proliferation and EMT, as well as on the Wnt/beta-catenin pathway. Additionally, inactivation of the Wnt/beta-catenin pathway by XAV939 or si-beta-catenin suppressed cell proliferation and EMT. Furthermore, suppression of the Wnt/beta-catenin pathway reversed the positive effects of pcDNA-IQGAP1 on cell proliferation and EMT in vitro. Moreover, downregulation of IQGAP1 suppressed tumor growth and EMT in SW579 tumor xenografts through the Wnt/beta-catenin pathway in vivo. CONCLUSION: Our study demonstrated that knockdown of IQGAP1 inhibited cell proliferation and EMT through blocking the Wnt/beta-catenin pathway in thyroid cancer. PMID- 28352189 TI - Mechanism of immune evasion in breast cancer. AB - Breast cancer (BC) is the most common malignant tumor among women, with high morbidity and mortality. Its onset, development, metastasis, and prognosis vary among individuals due to the interactions between tumors and host immunity. Many diverse mechanisms have been associated with BC, with immune evasion being the most widely studied to date. Tumor cells can escape from the body's immune response, which targets abnormal components and foreign bodies, using different approaches including modification of surface antigens and modulation of the surrounding environment. In this review, we summarize the mechanisms and factors that impact the immunoediting process and analyze their functions in detail. PMID- 28352190 TI - SDF1-3'A polymorphism is associated with increased risk of hematological malignancy: a meta-analysis. AB - CXCL12 (also named SDF1), a member of the chemokine family, has been demonstrated to play an important role in the progression of multiple types of hematological malignancy. Several recent studies have shown that SDF1-3'A polymorphism (rs1801157) is associated with susceptibility to hematological malignancy, but published studies' results are disputed. Therefore, we performed a meta-analysis to evaluate the relationship between SDF1-3'A polymorphism and the risk of hematological malignancy based on the existing literature. We carried out a comprehensive literature search using the Web of Science, PubMed, Cochrane Library, Chinese Wan Fang, and Chinese National Knowledge Infrastructure databases. And the raw data were extracted and calculated in standard steps of meta-analysis. Overall, nine qualified studies containing 1,576 cases and 1,674 controls were included in the ultimate meta-analysis. The pooled results displayed that AA genotype significantly increased the risk of hematological malignancy. The result of subgroup analysis further indicated that SDF1-3'A polymorphism was significantly associated with increased risk of chronic myeloid leukemia, Hodgkin's lymphoma and multiple myeloma, but was not associated with increased risk of acute myeloid leukemia and non-Hodgkin's lymphoma. In addition, SDF1-3'A polymorphism was associated with increased risk of hematological malignancy in Africans and Asians, but not in Caucasians. In conclusion, our meta analysis firstly demonstrated that SDF1-3'A polymorphism may be associated with increased risk of hematological malignancy, especially for chronic myeloid leukemia, Hodgkin's lymphoma, multiple myeloma and the non-Caucasian population. Nevertheless, these conclusions should be reconfirmed by more evidence from large sample sized studies. PMID- 28352192 TI - TCF21 functions as a tumor suppressor in colorectal cancer through inactivation of PI3K/AKT signaling. AB - Colorectal cancer (CRC) has become a major public health problem, ranking as the third most common type of cancer. Our previous study has revealed that TCF21 is frequently silenced by promoter hypermethylation in both CRC cell lines and primary CRC, with TCF21 methylation being significantly correlated with lymph node invasion. In this study, we further analyze the expression of TCF21 in CRC tissues and investigate the role of TCF21 in CRC in vitro and in vivo. We also explore the possible pathway regulated by TCF21. We thus demonstrate that decreased levels of TCF21 are associated with the pathological stage, clinical stage and lymph node metastasis, indicating a poor prognosis in CRC patients; overexpression of TCF21 inhibits cell proliferation, migration and invasion in the colorectal cell lines HCT116 and HT29. Furthermore, TCF21 functions as a tumor suppressor probably through inactivation of PI3K/AKT signaling and inhibition of MMPs. Our results suggest that enhancement of TCF21 levels may be a potential strategy to facilitate the prevention and treatment of CRC in the clinic. PMID- 28352193 TI - CDKL1 promotes tumor proliferation and invasion in colorectal cancer. AB - BACKGROUND: CDKL1 is a member of the cell division cycle 2 (CDC2)-related serine threonine protein kinase family and is overexpressed in malignant tumors such as melanoma, breast cancer, and gastric cancer. OBJECTIVE: This study aimed to evaluate whether CDKL1 can serve as a potential molecular target for colorectal cancer therapy. MATERIALS AND METHODS: Expression of CDKL1 in colorectal cancer tissues and cell lines was measured by immunohistochemistry and Western blot, respectively. To investigate the role of CDKL1 in colorectal cancer, CDKL1-small hairpin RNA-expressing lentivirus was constructed and infected into HCT116 and Caco2 cells. The effects of RNA interference (RNAi)-mediated CDKL1 downregulation on cell proliferation and invasion were assessed by CCK-8, colony formation, transwell, and tumorigenicity assays in nude mice. The effects of CDKL1 downregulation on cell cycle and apoptosis were analyzed by flow cytometry. Furthermore, microarray method and data analysis elucidated the molecular mechanisms underlying the phenomenon. RESULTS: CDKL1 protein was overexpressed in colorectal cancer tissues compared with paired normal tissues. Knockdown of CDKL1 in HCT116 and Caco2 significantly inhibited cell growth, colony formation ability, tumor invasion, and G1-S phase transition of the cell cycle. The knockdown of CDKL1 stimulated the upregulation of p15 and retinoblastoma protein. CONCLUSION: CDKL1 plays a vital role in tumor proliferation and invasion in colorectal cancer in vitro and in vivo and, thus, may be considered as a valuable target for therapeutic intervention. PMID- 28352191 TI - Retinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia: current perspectives. AB - Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) with a unique morphological appearance, associated coagulopathy and canonical balanced translocation of genetic material between chromosomes 15 and 17. APL was first described as a distinct subtype of AML in 1957 by Dr Leif Hillestad who recognized the pattern of an acute leukemia associated with fibrinolysis, hypofibrinogenemia and catastrophic hemorrhage. In the intervening years, the characteristic morphology of APL has been described fully with both classical hypergranular and variant microgranular forms. Both are characterized by a balanced translocation between the long arms of chromosomes 15 and 17, [t(15;17)(q24;q21)], giving rise to a unique fusion gene PML-RARA and an abnormal chimeric transcription factor (PML-RARA), which disrupts normal myeloid differentiation programs. The success of current treatments for APL is in marked contrast to the vast majority of patients with non-promyelocytic AML. The overall prognosis in non-promyelocytic AML is poor, and although there has been an improvement in overall survival in patients aged <60 years, only 30%-40% of younger patients are still alive 5 years after diagnosis. APL therapy has diverged from standard AML therapy through the empirical discovery of two agents that directly target the molecular basis of the disease. The evolution of treatment over the last 4 decades to include all-trans retinoic acid and arsenic trioxide, with chemotherapy limited to patients with high-risk disease, has led to complete remission in 90%-100% of patients in trials and rates of overall survival between 86% and 97%. PMID- 28352194 TI - MicroRNA-145 inhibits the activation of the mTOR signaling pathway to suppress the proliferation and invasion of invasive pituitary adenoma cells by targeting AKT3 in vivo and in vitro. AB - PURPOSE: This study was designed to explore how miR-145 regulates the mTOR signaling pathway in invasive pituitary adenoma (IPA) by targeting AKT3. METHODS: A total of 71 cases of IPA tissues and 66 cases of non-IPA tissues were obtained in this study. In vitro, the IPA cells were assigned into blank control, empty plasmid, miR-145 mimic, miR-145 inhibitor, miR-145 mimic + rapamycin, miR-145 inhibitor + rapamycin and rapamycin groups. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were performed to detect the protein expressions of PI3K, AKT3, mTOR mRNA and the mRNA expression of miR-145 both in vivo and in vitro. Additionally, the S6K and RPS6 mRNA and protein expressions as well as the relative phosphorylation levels were determined in vitro. MTT assay, flow cytometry and transwell assay were used to testify the cell proliferation, apoptosis and invasion ability, respectively. RESULTS: The IPA tissues exhibited significantly lower expression of miR-145 but higher PI3K, AKT3 and mTOR mRNA and protein expressions when compared with the non-IPA tissues. Compared with the blank control and empty plasmid groups, the miR-145 mimic group showed significantly decreased PI3K, AKT3, mTOR, S6K and RPS6 mRNA and protein expressions as well as phosphorylation levels; besides, the IPA cell proliferation, migration and invasion ability were strongly inhibited, accompanied with the increased number of apoptotic cells. In the miR-145 inhibitor group, the PI3K, AKT3, mTOR, S6K and RPS6 mRNA and protein expressions as well as the phosphorylation levels were significantly increased; cell proliferation, migration and invasion ability were remarkably elevated, accompanied with reduced apoptotic cell number. CONCLUSION: The study demonstrates that miR-145 inhibits the mTOR signaling pathway to suppress the IPA cell proliferation and invasion and promotes its apoptosis by targeting AKT3. PMID- 28352195 TI - Evaluation of efficacy of transcatheter arterial chemoembolization for hepatocellular carcinoma using magnetic resonance diffusion-weighted imaging. AB - Although the efficacy of transcatheter arterial chemoembolization (TACE) has been recommended as first-line therapy for nonsurgical patients with hepatocellular carcinoma (HCC), it is difficult to accurately predict the efficacy of TACE. Therefore, this study evaluated the efficacy of TACE for HCC using magnetic resonance (MR) diffusion-weighted imaging (DWI). A total of 84 HCC patients who received initial TACE were selected and assigned to the stable group (n=39) and the progressive group (n=45). Before TACE treatment, a contrast-enhanced MR scan and DWI (b=300, 600, and 800 s/mm2) were performed on all patients. The modified response evaluation criteria in solid tumors were used for evaluation of tumor response. Receiver operating characteristic curve was employed to predict the value of apparent diffusion coefficient (ADC) for TACE efficacy. The ADC values of HCC patients in the progressive group were higher than those in the stable group at different b-values (b=300, 600, and 800 s/mm2) before TACE treatment. The area under the curve of ADC values with b-values of 300, 600, and 800 s/mm2 were 0.693, 0.724, and 0.746; the threshold values were 1.94*10-3 mm2/s, 1.28*10 3 mm2/s, and 1.20*10-3 mm2/s; the sensitivity values were 55.6%, 77.8%, and 73.3%; and the specificity values were 82.1%, 61.5%, and 71.8%, respectively. Our findings indicate that the ADC values of MR-DWI may accurately predict the efficacy of TACE in the treatment of HCC patients. PMID- 28352196 TI - Sonidegib: mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas. AB - The Hedgehog (Hh) pathway is critical for cell differentiation, tissue polarity, and stem cell maintenance during embryonic development, but is silent in adult tissues under normal conditions. However, aberrant Hh signaling activation has been implicated in the development and promotion of certain types of cancer, including basal cell carcinoma (BCC), medulloblastoma, and gastrointestinal cancers. In 2015, the US Food and Drug Administration (FDA) approved sonidegib, a smoothened (SMO) antagonist, for treatment of advanced BCC (aBCC) after a successful Phase II clinical trial. Sonidegib, also named Odomzo, is the second Hh signaling inhibitor approved by the FDA to treat BCCs following approval of the first SMO antagonist vismodegib in 2012. What are the major features of sonidegib (mechanism of action; metabolic profiles, clinical efficacy, safety, and tolerability profiles)? Will the sonidegib experience help other clinical trials using Hh signaling inhibitors in the future? In this review, we will summarize current understanding of BCCs and Hh signaling. We will focus on sonidegib and its use in the clinic, and we will discuss ways to improve its clinical application in cancer therapeutics. PMID- 28352197 TI - Development of an allergy management support system in primary care. AB - BACKGROUND: Management of allergic patients in the population is becoming more difficult because of increases in both complexity and prevalence. Although general practitioners (GPs) are expected to play an important role in the care of allergic patients, they often feel ill-equipped for this task. Therefore, the aim of this study was to develop an allergy management support system (AMSS) for primary care. METHODS: Through literature review, interviewing and testing in secondary and primary care patients, an allergy history questionnaire was constructed by allergists, dermatologists, GPs and researchers based on primary care and specialists' allergy guidelines and their clinical knowledge. Patterns of AMSS questionnaire responses and specific immunoglobulin E (sIgE)-test outcomes were used to identify diagnostic categories and develop corresponding management recommendations. Validity of the AMSS was investigated by comparing specialist (gold standard) and AMSS diagnostic categories. RESULTS: The two-page patient-completed AMSS questionnaire consists of 12 (mainly) multiple choice questions on symptoms, triggers, severity and medication. Based on the AMSS questionnaires and sIgE-test outcome of 118 patients, approximately 150 diagnostic categories of allergic rhinitis, asthma, atopic dermatitis, anaphylaxis, food allergy, hymenoptera allergy and other allergies were identified, and the corresponding management recommendations were formulated. The agreement between the allergy specialists' assessments and the AMSS was 69.2% (CI 67.2-71.2). CONCLUSION: Using a systematic approach, it was possible to develop an AMSS that allows for the formulation of diagnostic and management recommendations for GPs managing allergic patients. The AMSS thus holds promise for the improvement of the quality of primary care for this increasing group of patients. PMID- 28352198 TI - Antimicrobial susceptibility profile, treatment outcome and serotype distribution of clinical isolates of Salmonella enterica subspecies enterica: a 2-year study from Kerala, South India. AB - BACKGROUND/PURPOSE: Typhoid and paratyphoid fever continue to be important causes of illness and death in parts of Asia, being associated with poor sanitation and consumption of unsafe food and water. Antimicrobial resistance has emerged to traditional first-line drugs, namely, the fluoroquinolones, as well as to third generation cephalosporins, posing challenges to treatment. Azithromycin has proven to be an effective alternative for treatment of uncomplicated typhoid fever. The purpose of this study was to determine the antimicrobial susceptibility, clinical outcome and serotype distribution pattern of clinical isolates belonging to Salmonella enterica subspecies enterica. METHODOLOGY: All clinical isolates of S. enterica obtained from blood, sterile body fluids, as well as stool and urine samples at Amrita Institute of Medical Sciences and Research Centre, Kerala, India, between August 2011 and July 2013 were included in the study and processed based on standard microbiology protocols. RESULTS: A total of 118 isolates of Salmonella were obtained during the study period. Out of these, 79 were of S. Typhi (66.95%), followed by isolates of S. Paratyphi A (22; 18.64%) and S. Typhimurium 12 (10.17%). Five isolates could not be identified further. There was 100% susceptibility to ceftriaxone in all S. enterica subspecies. Ciprofloxacin susceptibility was 32.91% for S. Typhi and 40.90% for S. Paratyphi A as determined by the disk diffusion method. The susceptibility profile of S. Typhi isolates to different antimicrobials was as follows: chloramphenicol (94.93%), ampicillin (77.21%), cotrimoxazole (75.94%) and azithromycin (78.48%). For S. Typhi, the minimum inhibitory concentration (MIC) of ciprofloxacin required to inhibit the growth of 50% of organisms was 0.5 MUg/mL (intermediate) and MIC required to inhibit the growth of 90% of organisms was 1 MUg/mL (resistant). S. Typhimurium was 100% susceptible to cotrimoxazole, ampicillin, ceftriaxone, chloramphenicol, ofloxacin and azithromycin. Susceptibility to ciprofloxacin was 66.66%. Patients from whom S. Typhimurium was isolated had comorbidities with documented risk. Of the 118 patients, 3 expired. Two had typhoid fever and were in sepsis at admission. One had S. Typhimurium and was suffering from multiple myeloma. CONCLUSION: S. Typhi was the predominant isolate. All isolates were susceptible to ceftriaxone. Chloramphenicol susceptibility was >90%. No multidrug-resistant Salmonella strains were isolated. Susceptibility to ciprofloxacin for S. Typhi was 33%. Recovery rate was 97%. PMID- 28352199 TI - Survey on attitudes of Italian pediatricians toward cough. AB - CONTEXT: Children's cough is a daily concern for most pediatricians. The management of both acute and chronic cough requires a systematic and comprehensive approach. Despite the approved protocols for management, the pediatric assessment of cough and the corresponding prescribing attitude frequently do not fit these protocols, which can be affected by parental suggestions - sometimes substantially. OBJECTIVE: The objective of this study was to investigate both the perception and the behavior of a representative sample of Italian pediatricians toward cough in real life. METHODS: A specific questionnaire consisting of 18 questions was prepared. The questionnaire was completed by 300 pediatricians (all members of PAIDOSS: Italian National Observatory on Health of Childhood and Adolescence) who represented ~300,000 children. RESULTS: A vast majority of children have cough throughout the year (99.3% of respondents have cough during autumn/winter and 64.7% in spring/summer). Allergic disease is the most frequent suspected cause of chronic cough in children (53%), and this is supported by the high demand for consultations: 73% seek the opinion of allergologists, 62% of otorhinolaryngologists and only 33% of pulmonologists. The majority of pediatricians (92%) reported that they prescribe therapy in acute cough regardless of cough guidelines. Moreover, the survey pointed out the abuse of aerosol therapy (26% in acute cough and 38% in chronic cough) and of antibiotics prescription (22% in acute cough and 42% in chronic cough). CONCLUSION: Our survey suggests that some Italian pediatricians' therapeutic attitudes should be substantially improved in order to achieve better management of cough in children and to minimize the burden of cough. PMID- 28352200 TI - Osteopathy for primary headache patients: a systematic review. AB - OBJECTIVE: This systematic review aimed to assess the efficacy, effectiveness, safety, and tolerability of osteopathic manipulative treatment (OMT) in patients with headache. BACKGROUND: Migraine is one of the most common and disabling medical conditions. It affects more than 15% of the general population, causing high global socioeconomic costs, and the currently available treatment options are inadequate. METHODS: We systematically reviewed all available studies investigating the use of OMT in patients with migraine and other forms of headache. RESULTS: The search of literature produced six studies, five of which were eligible for review. The reviewed papers collectively support the notion that patients with migraine can benefit from OMT. OMT could most likely reduce the number of episodes per month as well as drug use. None of the included studies, however, was classified as low risk of bias according to the Cochrane Collaboration's tool for assessing risk of bias. CONCLUSION: The results from this systematic review show a preliminary low level of evidence that OMT is effective in the management of headache. However, studies with more rigorous designs and methodology are needed to strengthen this evidence. Moreover, this review suggests that new manual interventions for the treatment of acute migraine are available and developing. PMID- 28352201 TI - Tibial nerve stimulation with a miniature, wireless stimulator in chronic peripheral neuropathic pain. AB - Peripheral neuropathic pain (PNP) and complex regional pain syndrome (CRPS) can be effectively treated with peripheral nerve stimulation. In this clinical trial report, effectiveness of novel, miniature, wirelessly controlled microstimulator of tibial nerve in PNP and CRPS was evaluated. In this pilot study the average preoperative visual analog scale (VAS) score in six patients was 7.5, with 1, 3 and 6 months: 2.6 (p=0.03), 1.6 (p=0.03), and 1.3 (p=0.02), respectively. The mean average score in the six patients a week preceding the baseline visit was 7.96, preceding the 1, 3 and 6 month visits: 3.32 (p=0.043), 3.65 (p=0.045), and 2.49 (p=0.002), respectively. The average short-form McGill pain score before surgery was 23.8, and after 1, 3 and 6 months it was 11.0 (p=0.45), 6.3 (p=0.043), and 4.5 (p=0.01), respectively. Applied therapy caused a reduction of pain immediately after its application and clinical improvement was sustained on a similar level in all patients for six months. No complications of the treatment were observed. Intermittent tibial nerve stimulation by using a novel, miniature, wirelessly controlled device can be effective and feasible in PNP and CRPS. It is a safe, minimally invasive, and convenient neuromodulative method. PMID- 28352202 TI - Preexposure of MCF-7 breast cancer cell line to dexamethasone alters the cytotoxic effect of paclitaxel but not 5-fluorouracil or epirubicin chemotherapy. AB - PURPOSE: Glucocorticoids (GCs) are often administered prior to any chemotherapeutics to prevent the secondary effects of anticancer agents. Glucocorticoid receptors (GRs) are expressed in several types of cancer cells, particularly in several histological types of breast cancer. Activation of GRs is not associated with any specific cellular response. Both proapoptotic and antiapoptotic responses have been observed, depending on the study or the type of breast cancer cells. Therefore, it is of relevance to investigate the possible modulation of apoptotic effect of chemotherapeutic agents when cancerous cells have previously been exposed to GCs. METHODS: In vitro cell growth was assayed by counting MCF-7 cells upon exposure to epirubicin (25 nM), 5-fluorouracil (5-FU) (15 uM), and paclitaxel (15 nM), either with or without prior exposure to the GC dexamethasone (Dex) (100 nM). RESULTS: Following preexposure to Dex, the antiapoptotic activity of paclitaxel was significantly reduced by 8.5% (p<0.05), but the activities of epirubicin and 5-FU remained unaltered. CONCLUSION: In light of the finding that the response of MCF-7 cells pretreated with Dex was significantly reduced, we recommend that the function of GCs should be defined more precisely if they are to be used in conjunction with chemotherapy. PMID- 28352203 TI - Missing data and multiple imputation in clinical epidemiological research. AB - Missing data are ubiquitous in clinical epidemiological research. Individuals with missing data may differ from those with no missing data in terms of the outcome of interest and prognosis in general. Missing data are often categorized into the following three types: missing completely at random (MCAR), missing at random (MAR), and missing not at random (MNAR). In clinical epidemiological research, missing data are seldom MCAR. Missing data can constitute considerable challenges in the analyses and interpretation of results and can potentially weaken the validity of results and conclusions. A number of methods have been developed for dealing with missing data. These include complete-case analyses, missing indicator method, single value imputation, and sensitivity analyses incorporating worst-case and best-case scenarios. If applied under the MCAR assumption, some of these methods can provide unbiased but often less precise estimates. Multiple imputation is an alternative method to deal with missing data, which accounts for the uncertainty associated with missing data. Multiple imputation is implemented in most statistical software under the MAR assumption and provides unbiased and valid estimates of associations based on information from the available data. The method affects not only the coefficient estimates for variables with missing data but also the estimates for other variables with no missing data. PMID- 28352204 TI - Marginal fit of all-ceramic crowns fabricated using two extraoral CAD/CAM systems in comparison with the conventional technique. AB - OBJECTIVE: The purpose of this study was to determine the effect of two extraoral computer-aided design (CAD) and computer-aided manufacturing (CAM) systems, in comparison with conventional techniques, on the marginal fit of monolithic CAD/CAM lithium disilicate ceramic crowns. STUDY DESIGN: This is an in vitro interventional study. PLACE AND DURATION OF STUDY: The study was carried out at the Department of Prosthodontics, School of Dentistry, Prince Sattam Bin Abdul Aziz University, Saudi Arabia, from December 2015 to April 2016. METHODOLOGY: A marginal gap of 60 lithium disilicate crowns was evaluated by scanning electron microscopy. In total, 20 pressable lithium disilicate (IPS e.max Press [Ivoclar Vivadent]) ceramic crowns were fabricated using the conventional lost-wax technique as a control group. The experimental all-ceramic crowns were produced based on a scan stone model and milled using two extraoral CAD/CAM systems: the Cerec group was fabricated using the Cerec CAD/CAM system, and the Trios group was fabricated using Trios CAD and milled using Wieland Zenotec CAM. One-way analysis of variance (ANOVA) and the Scheffe post hoc test were used for statistical comparison of the groups (alpha=0.05). RESULTS: The mean (+/-standard deviation) of the marginal gap of each group was as follows: the Control group was 91.15 (+/-15.35) um, the Cerec group was 111.07 (+/-6.33) um, and the Trios group was 60.17 (+/-11.09) um. One-way ANOVA and the Scheffe post hoc test showed a statistically significant difference in the marginal gap between all groups. CONCLUSION: It can be concluded from the current study that all-ceramic crowns, fabricated using the CAD/CAM system, show a marginal accuracy that is acceptable in clinical environments. The Trios CAD group displayed the smallest marginal gap. PMID- 28352205 TI - Syringomyelia presenting with unilateral optic neuropathy: a case report. AB - PURPOSE: In this case report, we present two cases of syringomyelia with optic neuropathy. FINDINGS: In Case 1, a 36-year-old Malay lady presented to our clinic with acute onset of blurring of vision in her left eye that she experienced since past 1 month. She was diagnosed with syringomyelia 12 years ago and was on conservative management. Her visual acuity was 6/6 in the right eye and counting fingers at 1 m in the left. There was a positive relative afferent pupillary defect in her left eye. Optic nerve functions of her left eye were reduced. Visual field showed a left inferior field defect. Her extraocular muscle movements were full. Magnetic resonance imaging of the brain and spine showed syringomyelia at the level of C2-C6 and T2-T9. Both of her optic nerves were normal. Her condition improved with intravenous and oral corticosteroids. In Case 2, a 44-year-old Malay lady presented to our clinic with a progressive central scotoma in her right eye that she experienced since past 1 month. She had previous history of recurrent episodes of weakness in both of her lower limbs from past 8 months. Visual acuity in her right and left eye was 6/9 and 6/6, respectively. The relative afferent pupillary defect in her right eye was positive. Optic nerve functions of her right eye were affected. Visual field showed a central scotoma in her right eye. Her extraocular muscle movements were full. Fundoscopy of her right eye showed a pale optic disc. Her left eye fundus was normal. Magnetic resonance imaging of the brain and spine showed syringomyelia at T3-T6. Both of her optic nerves were normal. A diagnosis of syringomyelia with right optic atrophy was performed. Her condition improved with intravenous and oral corticosteroids. CONCLUSION: Optic neuropathy is a rare neuro-ophthalmic manifestation in patients with syringomyelia. Prompt diagnosis and timely management are essential to avoid a poor visual outcome. Intravenous corticosteroids are beneficial in the treatment of early optic neuropathy in syringomyelia. PMID- 28352206 TI - Color duplex ultrasonography findings of temporal arteries in a case of giant cell arteritis: role in diagnosis and follow-up. AB - Giant cell arteritis (GCA) is a systemic autoimmune disease that affects medium- and large-sized arteries. The diagnostic gold standard is the temporal artery biopsy, but it has limited sensitivity and some difficulties in reproducibility. Color duplex ultrasonography is a noninvasive, reproducible, and inexpensive method for diagnosis of temporal arteries involvement (temporal arteritis [TA]) in GCA with high sensitivity and specificity. We present the ultrasound findings at baseline and during follow-up in a case of TA in a patient with GCA. PMID- 28352207 TI - Improving urban environment through public commitment toward the implementation of clean and healthy living behaviors. AB - BACKGROUND: Some parts of northern Surabaya are slum areas with dense populations, and the majority of the inhabitants are from low-income families. The condition of these areas is seemingly different from the fact that Surabaya city has won awards for its cleanliness, healthy environment preservation, and maintenance. AIM: This study aimed at turning the researched site into a clean and healthy environment. METHODS: The research was conducted using a quasi experiment technique with a non-randomized design and pretest-posttest procedures. The research subjects were 121 inhabitants who actively participated in the public commitment and psychoeducation program initiated by the researchers to learn and practice clean and healthy living behaviors. RESULTS: The statistical data showed that there was a substantial increase in the aspects of public commitment (t-value = 4.008, p = 0.001) and psychoeducation (t-value = 4.038, p = 0.001) to begin and maintain a clean and healthy living behaviors. CONCLUSION: A public commitment in the form of a collective declaration to keep learning and practicing a clean and healthy living behaviors were achieved. This commitment followed by psychoeducation aimed at introducing and exercising such behaviors was found to have effectively increased the research subjects' awareness to actively participate in preserving environmental hygiene. Developing communal behaviors toward clean and healthy living in inhabitants residing in an unhealthy slum area was a difficult task. Therefore, public commitment and psychoeducation must be aligned with the formulation of continuous habits demonstrating a clean and healthy living behaviors. These habits include the cessation of littering while putting trash in its place, optimizing the usage of public toilets, planting and maintaining vegetation around the area, joining and contributing to the "garbage bank" program, and participating in the Green and Clean Surabaya competition. PMID- 28352208 TI - Patient-rated versus proxy-rated cognitive and functional measures in older adults. AB - OBJECTIVES: Patients with cognitive impairment may have difficulty reporting their functional and cognitive abilities, which are important clinical outcomes. Health care proxies may be able to corroborate patient self-reports. Several studies reported discrepancy between patient and proxy ratings, though the literature is sparse on changes over time of these ratings. Our goals in this 12 month study were to compare patient and proxy reports on functioning, cognition, and everyday executive function, and to further elucidate correlates of patient proxy discrepancy. METHODS: This was a prospective cohort study of individuals older than 70 years who ranged from having no cognitive impairment to having moderate dementia who had a proxy available to complete instruments at baseline (N=76). Measurements included Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADLI), Neuro-QOL Executive Function, PROMIS Applied Cognition (PROMIS-Cog), Mini-Mental State Examination (MMSE), and Geriatric Depression Scale. RESULTS: Patient- and proxy-rated ADCS-ADLI were correlated at baseline and at 1-year follow-up. Patient and proxy ratings were discrepant on Neuro-QOL Executive Function and PROMIS-Cog. Greater patient-proxy discrepancy on PROMIS-Cog was associated with younger age and less depression, and greater patient-proxy discrepancy on Neuro-QOL Executive Function was associated with less depression and worse cognitive impairment. Patient-proxy discrepancy increased over time for everyday executive function. Changes in proxy-rated but not patient-rated ADCS-ADLI correlated with MMSE changes. CONCLUSION: Patients and proxies generally agree in reporting on activities of daily living. Patient and proxy reports differ in their respective evaluation of cognitive functioning and everyday executive function. Ratings from both sources may be preferred for these two domains, though studies using gold standard measures are necessary. It is important that clinicians are aware of the differences between patient and proxy perspective to create an accurate clinical picture and guide treatment. PMID- 28352209 TI - Characteristics and Etiologies of Chronic Scrotal Pain: A Common but Poorly Understood Condition. AB - Chronic scrotal pain (CSP) is a common and debilitating condition, but the underlying characteristics and etiology of CSP are poorly understood. The objective of this study is to identify the characteristic and etiologies of CSP. Men presenting for management of CSP completed a standardized questionnaire and underwent a complete physical examination. From Feb 2014 to Sep 2015, a total of 131 men (mean age 43) with CSP were studied. The CSP was of long duration (mean of 4.7 +/- 5.95 years) and dramatically affected men's lives, with adverse effects on normal activities (71.%), ability to work (51.90%), and sexual functioning (61.8%). 50.4% felt depressed on most days, and 67.17% felt either unhappy or terrible with their present condition. Physical examination revealed that the epididymis was the most common tender area found in 70/131 men (53.43%), though a musculoskeletal source for the pain was found in 9.9%. Neuropathic changes were found in 30%. For close to half of the men (43.5%) we were unable to identify any potential cause for the CSP. This study characterizes the dramatic impact that CSP has on the lives of men, while providing an understanding of the common etiologies. PMID- 28352211 TI - Treatment Issues in Patients With HIV/HCV Co-Infection. PMID- 28352210 TI - Proteomic analysis of microparticles isolated from malaria positive blood samples. AB - BACKGROUND: Malaria continues to be a great public health concern due to the significant mortality and morbidity associated with the disease especially in developing countries. Microparticles (MPs), also called plasma membrane derived extracellular vesicles (PMEVs) are subcellular structures that are generated when they bud off the plasma membrane. They can be found in healthy individuals but the numbers tend to increase in pathological conditions including malaria. Although, various studies have been carried out on the protein content of specific cellular derived MPs, there seems to be paucity of information on the protein content of circulating MPs in malaria and their association with the various signs and symptoms of the disease. The aim of this study was therefore to carry out proteomic analyses of MPs isolated from malaria positive samples and compare them with proteins of MPs from malaria parasite culture supernatant and healthy controls in order to ascertain the role of MPs in malaria infection. METHODS: Plasma samples were obtained from forty-three (43) malaria diagnosed patients (cases) and ten (10) healthy individuals (controls). Malaria parasite culture supernatant was obtained from our laboratory and MPs were isolated from them and confirmed using flow cytometry. 2D LC-MS was done to obtain their protein content. Resultant data were analyzed using SPSS Ver. 21.0 statistical software, Kruskal Wallis test and Spearman's correlation coefficient r. RESULTS: In all, 1806 proteins were isolated from the samples. The MPs from malaria positive samples recorded 1729 proteins, those from culture supernatant were 333 while the control samples recorded 234 proteins. The mean number of proteins in MPs of malaria positive samples was significantly higher than that in the control samples. Significantly, higher quantities of haemoglobin subunits were seen in MPs from malaria samples and culture supernatant compared to control samples. CONCLUSION: A great number of proteins were observed to be carried in the microparticles (MPs) from malaria samples and culture supernatant compared to controls. The greater loss of haemoglobin from erythrocytes via MPs from malaria patients could serve as the initiation and progression of anaemia in P.falciparum infection. Also while some proteins were upregulated in circulating MPs in malaria samples, others were down regulated. PMID- 28352213 TI - Prevalence and characteristics of flavoured tobacco use among students in grades 10 through 12: a national cross-sectional study in Canada, 2012-2013. AB - BACKGROUND: Tobacco use is the leading cause of preventable death in Canada and the world. Despite documented decreases in the prevalence of smoking in Canada, increases in flavoured tobacco use by its youth poses a serious public health concern. This study examined the prevalence and characteristics of flavoured tobacco use among a national sample of Canadian students in grades 10 through 12. METHODS: This study used a cross-sectional design on a nationally generalizable, school-based, Youth Smoking Survey (YSS), 2012-2013. It incorporated data from a representative sample of 19,979 students in grades 10-12 from across Canada. Univariate and multivariate logistic regression models were used to examine differences in flavoured tobacco use (menthol cigarettes, flavoured little cigar or cigarillo, flavoured cigar, flavoured tobacco in water pipe [hookah]) by demographic (sex, grade and ethnicity) and social characteristics (friends, siblings, parents/guardians who are smokers and weekly personal spending money). RESULTS: This study found that 14.8% of the participating students used flavoured tobacco in the past 30-days. Results of the logistic regression analysis show that flavoured tobacco use was significantly higher among male students [(OR = 1.63; 95% CI = 1.36-1.95)], who had at least one friend or sibling who smoke [(OR = 2.20; CI = 1.62 to 2.99) and (OR = 1.51; CI = 1.22 to 1.88), respectively] and who received greater than $20/week in personal spending money [(OR = 1.76; CI = 1.26 to 2.45)]. CONCLUSIONS: The results of our study indicate that flavoured tobacco use is a growing public health concern and has a strong appeal among youth in Canada. This is a particularly troubling finding, especially in light of the fact that there is a national ban on certain flavoured tobacco products. To be effective, strategies specifically tailored for youth using flavoured tobacco would require appropriate educational/prevention initiatives, more comprehensive legislation and better regulatory mechanisms. PMID- 28352212 TI - Canagliflozin in the treatment of type 2 diabetes: an evidence-based review of its place in therapy. AB - INTRODUCTION: Deciding on an optimal medication choice for type 2 diabetes is often challenging, due to the increasing number of treatment options. Canagliflozin is a novel glucose-lowering agent belonging to sodium-glucose co transporter 2 (SGLT2) inhibitors. AIM: The aim of this study was to examine and summarize the evidence based on the efficacy, safety, and cost-effectiveness of canagliflozin for type 2 diabetes. EVIDENCE REVIEW: Compared to placebo, canagliflozin 100 and 300 mg lower glycated hemoglobin (HbA1c) by ~0.6%-0.8%, respectively. Canagliflozin appears to be slightly more effective than dipeptidyl peptidase-4 (DPP-4) inhibitors in reducing HbA1c. It also has a favorable effect on body weight and blood pressure, both versus placebo and most active comparators. However, treatment with canagliflozin is associated with increased incidence of genital tract infections and osmotic diuresis-related adverse events. Based on short-term data, canagliflozin is not associated with increased risk for all-cause mortality and cardiovascular outcomes. Economic evaluation studies from various countries indicate that canagliflozin is a cost-effective option in dual- or triple-agent regimens. PLACE IN THERAPY: As monotherapy, canagliflozin could be used in patients for whom metformin is contraindicated or not tolerated. For patients on background treatment with metformin, canagliflozin appears to be superior to sulfonylureas with respect to body weight, blood pressure and risk for hypoglycemia, and to DPP-4 inhibitors in terms of lowering HbA1c, body weight, and blood pressure. Canagliflozin also seems to be cost effective compared with sulfonylureas and DPP-4 inhibitors as add-on to metformin monotherapy, and compared with DPP-4 inhibitors as add-on to metformin and sulfonylurea. CONCLUSION: Current evidence on intermediate efficacy outcomes, short-term safety and cost-effectiveness support the use of canagliflozin in patients on background treatment with metformin. Robust long-term data regarding the effect of canagliflozin on cardiovascular endpoints will be available upon completion of the Canagliflozin Cardiovascular Assessment Study (CANVAS) trial. PMID- 28352214 TI - Embedding and Chemical Reactivation of Green Fluorescent Protein in the Whole Mouse Brain for Optical Micro-Imaging. AB - Resin embedding has been widely applied to fixing biological tissues for sectioning and imaging, but has long been regarded as incompatible with green fluorescent protein (GFP) labeled sample because it reduces fluorescence. Recently, it has been reported that resin-embedded GFP-labeled brain tissue can be imaged with high resolution. In this protocol, we describe an optimized protocol for resin embedding and chemical reactivation of fluorescent protein labeled mouse brain, we have used mice as experiment model, but the protocol should be applied to other species. This method involves whole brain embedding and chemical reactivation of the fluorescent signal in resin-embedded tissue. The whole brain embedding process takes a total of 7 days. The duration of chemical reactivation is ~2 min for penetrating 4 MUm below the surface in the resin embedded brain. This protocol provides an efficient way to prepare fluorescent protein labeled sample for high-resolution optical imaging. This kind of sample was demonstrated to be imaged by various optical micro-imaging methods. Fine structures labeled with GFP across a whole brain can be detected. PMID- 28352215 TI - Myosin IIA-related Actomyosin Contractility Mediates Oxidative Stress-induced Neuronal Apoptosis. AB - Oxidative stress-induced neuronal apoptosis plays an important role in the progression of central nervous system (CNS) diseases. In our study, when neuronal cells were exposed to hydrogen peroxide (H2O2), an exogenous oxidant, cell apoptosis was observed with typical morphological changes including membrane blebbing, neurite retraction and cell contraction. The actomyosin system is considered to be responsible for the morphological changes, but how exactly it regulates oxidative stress-induced neuronal apoptosis and the distinctive functions of different myosin II isoforms remain unclear. We demonstrate that myosin IIA was required for neuronal contraction, while myosin IIB was required for neuronal outgrowth in normal conditions. During H2O2-induced neuronal apoptosis, myosin IIA, rather than IIB, interacted with actin filaments to generate contractile forces that lead to morphological changes. Moreover, myosin IIA knockout using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein-9 nuclease (CRISPR/Cas9) reduced H2O2-induced neuronal apoptosis and the associated morphological changes. We further demonstrate that caspase-3/Rho-associated kinase 1 (ROCK1) dependent phosphorylation of myosin light chain (MLC) was required for the formation of the myosin IIA-actin complex. Meanwhile, either inhibition of myosin II ATPase with blebbistatin or knockdown of myosin IIA with siRNA reversely attenuated caspase-3 activation, suggesting a positive feedback loop during oxidative stress-induced apoptosis. Based on our observation, myosin IIA-actin complex contributes to actomyosin contractility and is associated with the positive feedback loop of caspase-3/ROCK1/MLC pathway. This study unravels the biochemical and mechanistic mechanisms during oxidative stress-induced neuronal apoptosis and may be applicable for the development of therapies for CNS diseases. PMID- 28352216 TI - Mitochondrial Dysfunction in the Pathogenesis of Rett Syndrome: Implications for Mitochondria-Targeted Therapies. AB - First described over 50 years ago, Rett syndrome (RTT) is a neurodevelopmental disorder caused primarily by mutations of the X-linked MECP2 gene. RTT affects predominantly females, and has a prevalence of roughly 1 in every 10,000 female births. Prior to the discovery that mutations of MECP2 are the leading cause of RTT, there were suggestions that RTT could be a mitochondrial disease. In fact, several reports documented altered mitochondrial structure, and deficiencies in mitochondrial enzyme activity in different cells or tissues derived from RTT patients. With the identification of MECP2 as the causal gene, interest largely shifted toward defining the normal function of MeCP2 in the brain, and how its absence affects the neurodevelopment and neurophysiology. Recently, though, interest in studying mitochondrial function in RTT has been reignited, at least in part due to observations suggesting systemic oxidative stress does play a contributing role in RTT pathogenesis. Here we review data relating to mitochondrial alterations at the structural and functional levels in RTT patients and model systems, and present a hypothesis for how the absence of MeCP2 could lead to altered mitochondrial function and elevated levels of cellular oxidative stress. Finally, we discuss the prospects for treating RTT using interventions that target specific aspects of mitochondrial dysfunction and/or oxidative stress. PMID- 28352217 TI - Elucidation of White Matter Tracts of the Human Amygdala by Detailed Comparison between High-Resolution Postmortem Magnetic Resonance Imaging and Histology. AB - The amygdala has attracted considerable research interest because of its potential involvement in various neuropsychiatric disorders. Recently, attempts have been made using magnetic resonance imaging (MRI) to evaluate the integrity of the axonal connections to and from the amygdala under pathological conditions. Although amygdalar pathways have been studied extensively in animal models, anatomical references for the human brain are limited to histology-based resources from a small number of slice locations, orientations and annotations. In the present study, we performed high-resolution (250 MUm) MRI of postmortem human brains followed by serial histology sectioning. The histology data were used to identify amygdalar pathways, and the anatomical delineation of the assigned structures was extended into 3D using the MRI data. We were able to define the detailed anatomy of the stria terminalis and amygdalofugal pathway, as well as the anatomy of the nearby basal forebrain areas, including the substantia innominata. The present results will help us understand in detail the white matter structures associated with the amygdala, and will serve as an anatomical reference for the design of in vivo MRI studies and interpretation of their data. PMID- 28352218 TI - Cinematic Operation of the Cerebral Cortex Interpreted via Critical Transitions in Self-Organized Dynamic Systems. AB - Measurements of local field potentials over the cortical surface and the scalp of animals and human subjects reveal intermittent bursts of beta and gamma oscillations. During the bursts, narrow-band metastable amplitude modulation (AM) patters emerge for a fraction of a second and ultimately dissolve to the broad band random background activity. The burst process depends on previously learnt conditioned stimuli (CS), thus different AM patterns may emerge in response to different CS. This observation leads to our cinematic theory of cognition when perception happens in discrete steps manifested in the sequence of AM patterns. Our article summarizes findings in the past decades on experimental evidence of cinematic theory of cognition and relevant mathematical models. We treat cortices as dissipative systems that self-organize themselves near a critical level of activity that is a non-equilibrium metastable state. Criticality is arguably a key aspect of brains in their rapid adaptation, reconfiguration, high storage capacity, and sensitive response to external stimuli. Self-organized criticality (SOC) became an important concept to describe neural systems. We argue that transitions from one AM pattern to the other require the concept of phase transitions, extending beyond the dynamics described by SOC. We employ random graph theory (RGT) and percolation dynamics as fundamental mathematical approaches to model fluctuations in the cortical tissue. Our results indicate that perceptions are formed through a phase transition from a disorganized (high entropy) to a well-organized (low entropy) state, which explains the swiftness of the emergence of the perceptual experience in response to learned stimuli. PMID- 28352219 TI - Age-Dependent Changes of Thinking about Verbs. AB - We investigated the knowledge of emotional and motor verbs in children and adolescents from three age ranges (8-11, 12-15, 16-19 years). Participants estimated the verbs familiarity, age of acquisition, valence, arousal, imageability, and motor- and emotion-relatedness. Participants were familiar with the verbs in our dataset. The younger (8-11) attributed an emotional character to the verbs less frequently than the middle (12-15) and the older (16-19) groups. In the 8-11 group males rated the verbs as emotion-related less frequently than females. Results indicate that processing verbal concepts as emotion-related develops gradually, and after 12-15 is rather stable. The age of acquisition (AoA) develops late: the older (16-19) had a higher awareness in reporting that they learnt the verbs earlier as compared to the estimations made by the younger (8-11 and 12-15). AoA positively correlated with attribution of emotion relatedness meaning that emotion-related verbs were learned later. Arousal was comparable across ages. Also it increased when attributing motor relatedness to verbs and decreased when attributing emotion relatedness. Reporting the verbs' affective valence (happy vs. unhappy) changes with age: younger (8-11) judged the verbs generally more "happy" than both the older groups. Instead the middle and the older group did not show differences. Happiness increased when processing the verbs as motor related and decreased when processing the verbs as emotion related. Age affected imageability: the younger (8-11) considered the verbs easier to be imagined than the two older groups, suggesting that at this age vividness estimation is still rough, while after 12-15 is stable as the 12-15 and 15-19 group did not differ. Imageability predicted arousal, AoA, emotion- and motor-relatedness indicating that this index influences the way verbs are processed. Imageability was positively correlated to emotion relatedness, indicating that such verbs were harder to be imagined, and negatively to motor relatedness. Imageablity positively correlated with valence meaning that verbs receiving positive valence were also those that were hard to be imagined, and negatively correlated with arousal, meaning that verbs that were harder to be imagined elicited low physiological activation. Our results give an insight in the development of emotional and motor-related verbs representations. PMID- 28352220 TI - The Dorsal Medial Prefrontal Cortex Is Recruited by High Construal of Non-social Stimuli. AB - The dorsomedial prefrontal cortex (dmPFC) is part of the mentalizing network, a set of brain regions consistently engaged in inferring mental states. However, its precise function in this network remains unclear. It has recently been proposed that the dmPFC is involved in high-level abstract (i.e., categorical) identification or construction of both social and non-social stimuli, referred to as "high construal." This was based on the observation of greater activation in the dmPFC shared by a high construal social condition (trait inference based on visually presented behavior) and a high construal non-social condition (categorization of visually presented objects) vs. matched low construal conditions (visual description of the same pictures). However, dmPFC activation has been related to task contexts requiring responses based on self-guided generation of mental content or decisions as compared to responses more directly determined by the experimental context (e.g., free vs. rule-governed choice). The previously reported dmPFC activity may reflect differences in task constraint (i.e., the extent to which the task context guided the process) confounded with the construal manipulation. Therefore, in the present study, we manipulated construal level and constraint independently, while participants underwent functional magnetic resonance imaging (fMRI). As before, participants visually described (low level construal) or categorized (high level construal) pictures of objects. Orthogonal to this, the description or categorization task had to be performed on either one object (low constraint) or on two objects simultaneously (high constraint), limiting the number of possible responses. Statistical analysis revealed common greater activation in both high construal conditions (high and low constraint) than in their low construal counterparts, replicating the influence of construal level on dmPFC activation (greater involvement in high than low construal), but no influence of constraint. In line with previous proposals and earlier work, we suggest that the dmPFC is involved in high construal abstraction across different domains. PMID- 28352221 TI - Commentary: Retrieval practice protects memory against acute stress. PMID- 28352222 TI - Transcranial Electrical Stimulation and Behavioral Change: The Intermediary Influence of the Brain. PMID- 28352223 TI - Musicians' Online Performance during Auditory and Visual Statistical Learning Tasks. AB - Musicians' brains are considered to be a functional model of neuroplasticity due to the structural and functional changes associated with long-term musical training. In this study, we examined implicit extraction of statistical regularities from a continuous stream of stimuli-statistical learning (SL). We investigated whether long-term musical training is associated with better extraction of statistical cues in an auditory SL (aSL) task and a visual SL (vSL) task-both using the embedded triplet paradigm. Online measures, characterized by event related potentials (ERPs), were recorded during a familiarization phase while participants were exposed to a continuous stream of individually presented pure tones in the aSL task or individually presented cartoon figures in the vSL task. Unbeknown to participants, the stream was composed of triplets. Musicians showed advantages when compared to non-musicians in the online measure (early N1 and N400 triplet onset effects) during the aSL task. However, there were no differences between musicians and non-musicians for the vSL task. Results from the current study show that musical training is associated with enhancements in extraction of statistical cues only in the auditory domain. PMID- 28352225 TI - Evolution of Neuroplasticity in Response to Physical Activity in Old Age: The Case for Dancing. AB - From animal research, it is known that combining physical activity with sensory enrichment has stronger and longer-lasting effects on the brain than either treatment alone. For humans dancing has been suggested to be analogous to such combined training. Here we assessed whether a newly designed dance training program that stresses the constant learning of new movement patterns is superior in terms of neuroplasticity to conventional fitness activities with repetitive exercises and whether extending the training duration has additional benefits. Twenty-two healthy seniors (63-80 years) who had been randomly assigned to either a dance or a sport group completed the entire 18-month study. MRI, BDNF and neuropsychological tests were performed at baseline and after 6 and 18 months of intervention. After 6 months, we found a significant increase in gray matter volume in the left precentral gyrus in the dancers compared to controls. This neuroplasticity effect may have been mediated by the increased BDNF plasma levels observed in the dancers. Regarding cognitive measures, both groups showed significant improvements in attention after 6 months and in verbal memory after 18 months. In addition, volume increases in the parahippocampal region were observed in the dancers after 18 months. The results of our study suggest that participating in a long-term dance program that requires constant cognitive and motor learning is superior to engaging in repetitive physical exercises in inducing neuroplasticity in the brains of seniors. Therefore, dance is highly promising in its potential to counteract age-related gray matter decline. PMID- 28352224 TI - Coexistence of Multiple Types of Synaptic Plasticity in Individual Hippocampal CA1 Pyramidal Neurons. AB - Understanding learning and memory mechanisms is an important goal in neuroscience. To gain insights into the underlying cellular mechanisms for memory formation, synaptic plasticity processes are studied with various techniques in different brain regions. A valid model to scrutinize different ways to enhance or decrease synaptic transmission is recording of long-term potentiation (LTP) or long-term depression (LTD). At the single cell level, spike timing-dependent plasticity (STDP) protocols have emerged as a powerful tool to investigate synaptic plasticity with stimulation paradigms that also likely occur during memory formation in vivo. Such kind of plasticity can be induced by different STDP paradigms with multiple repeat numbers and stimulation patterns. They subsequently recruit or activate different molecular pathways and neuromodulators for induction and expression of STDP. Dopamine (DA) and brain-derived neurotrophic factor (BDNF) have been recently shown to be important modulators for hippocampal STDP at Schaffer collateral (SC)-CA1 synapses and are activated exclusively by distinguishable STDP paradigms. Distinct types of parallel synaptic plasticity in a given neuron depend on specific subcellular molecular prerequisites. Since the basal and apical dendrites of CA1 pyramidal neurons are known to be heterogeneous, and distance-dependent dendritic gradients for specific receptors and ion channels are described, the dendrites might provide domain specific locations for multiple types of synaptic plasticity in the same neuron. In addition to the distinct signaling and expression mechanisms of various types of LTP and LTD, activation of these different types of plasticity might depend on background brain activity states. In this article, we will discuss some ideas why multiple forms of synaptic plasticity can simultaneously and independently coexist and can contribute so effectively to increasing the efficacy of memory storage and processing capacity of the brain. We hypothesize that resolving the subcellular location of t-LTP and t-LTD mechanisms that are regulated by distinct neuromodulator systems will be essential to reach a more cohesive understanding of synaptic plasticity in memory formation. PMID- 28352226 TI - Cognitive Control Modulates Effects of Episodic Simulation on Delay Discounting in Aging. AB - Enhancing prospective thinking by tagging the future with specific episodic events has been shown to reduce delay discounting in young age ("tag-effect"). So far, it is unclear whether such beneficial effect extends to old adulthood. Since the general ability of future thinking and cognitive control are crucial modulators of temporal discounting in young age, potential age-related decline in these functions might impact on the effect. We focused on this issue by combining functional magnetic resonance imaging (fMRI) with an established intertemporal choice task including episodic "tags" in healthy older participants. Future thinking ability was assessed using autobiographical interviews for future event simulations and a visual search task was applied to assess participants' cognitive control ability. In contrast to previous data in young adults, the group of older participants did not benefit from tagging the future with episodic events. Older participants' cognitive control function was directly associated with discounting rates in the episodic conditions: the less the older adults were able to focus their attention the less they benefited from the inclusion of episodic events. Consistent with this, imaging results revealed that: (a) subjective value (SV) signals in the hippocampus and the anterior cingulate cortex (ACC) as well as; (b) hippocampal-striatal coupling during the episodic condition were positively related to participants' control capacity. Our findings highlight the critical role of executive functioning for the simultaneous integration of episodic information with future value computation in aging. Boosting delay gratification by including episodic tags might hence be limited in older individuals with pronounced decline in distraction control. PMID- 28352227 TI - A Novel Genetic Screen Identifies Modifiers of Age-Dependent Amyloid beta Toxicity in the Drosophila Brain. AB - The accumulation of amyloid beta peptide (Abeta) in the brain of Alzheimer's disease (AD) patients begins many years before clinical onset. Such process has been proposed to be pathogenic through the toxicity of Abeta soluble oligomers leading to synaptic dysfunction, phospho-tau aggregation and neuronal loss. Yet, a massive accumulation of Abeta can be found in approximately 30% of aged individuals with preserved cognitive function. Therefore, within the frame of the "amyloid hypothesis", compensatory mechanisms and/or additional neurotoxic or protective factors need to be considered and investigated. Here we describe a modifier genetic screen in Drosophila designed to identify genes that modulate toxicity of Abeta42 in the CNS. The expression of Abeta42 led to its accumulation in the brain and a moderate impairment of negative geotaxis at 18 days post eclosion (d.p.e) as compared with genetic or parental controls. These flies were mated with a collection of lines carrying chromosomal deletions and negative geotaxis was assessed at 5 and 18 d.p.e. Our screen is the first to take into account all of the following features, relevant to sporadic AD: (1) pan-neuronal expression of wild-type Abeta42; (2) a quantifiable complex behavior; (3) Abeta neurotoxicity associated with progressive accumulation of the peptide; and (4) improvement or worsening of climbing ability only evident in aged animals. One hundred and ninety-nine deficiency (Df) lines accounting for ~6300 genes were analyzed. Six lines, including the deletion of 52 Drosophila genes with human orthologs, significantly modified Abeta42 neurotoxicity in 18-day-old flies. So far, we have validated CG11796 and identified CG17249 as a strong candidate (whose human orthologs are HPD and PRCC, respectively) by using RNAi or mutant hemizygous lines. PRCC encodes proline-rich protein PRCC (ppPRCC) of unknown function associated with papillary renal cell carcinoma. HPD encodes 4 hydroxyphenylpyruvate dioxygenase (HPPD), a key enzyme in tyrosine degradation whose Df causes autosomal recessive Tyrosinemia type 3, characterized by mental retardation. Interestingly, lines with a partial Df of HPD ortholog showed increased intraneuronal accumulation of Abeta42 that coincided with geotaxis impairment. These previously undetected modifiers of Abeta42 neurotoxicity in Drosophila warrant further study to validate their possible role and significance in the pathogenesis of sporadic AD. PMID- 28352228 TI - Personality, Cortisol, and Cognition in Non-demented Elderly Subjects: Results from a Population-Based Study. AB - Certain personality traits, in particular higher neuroticism, have been associated, on one hand, with elevated cortisol levels, and on the other hand, with poorer cognitive performance. At the same time, several studies highlighted the association between high cortisol and poor cognitive functioning. Here, we hypothesized that increased cortisol may be associated with poorer cognition and with certain personality traits (mainly high neuroticism), and that personality might explain the association between cortisol and cognition. A cross-sectional analysis was conducted using data from Colaus/PsyColaus, a population-based study involving residents of Lausanne, Switzerland. Salivary cortisol samples (upon waking, 30 min after waking, at 11 am and at 8 pm) along with cognitive and personality measures were obtained from 643 non-demented participants aged at least 65. Personality traits were assessed using the NEO Five-Factor Inventory (NEO-FFI). We examined the links between the cortisol Area under the Curve (AUC), the Clinical Dementia Rating Sum of Boxes (CDRSOB) and the NEO-FFI scores. No association was found between personality traits and the CDRSOB or the MMSE score, controlling for age, sex, depression, education and BMI. However, the executive functioning domain z-score was negatively associated with agreeableness (p = 0.005; slope = -0.107 [-0.181; -0.033]) and openness (p = 0.029; slope = 0.081 [-0.154; -0.008]) after controlling for age, sex, depression, education and BMI. The CDRSOB score was positively associated with the cortisol AUC after controlling for age, sex, BMI, education and depression, (p = 0.003; slope = 0.686 [0.240; 1.333]). This association remained significant after controlling for personality traits and for the interaction between personality traits and the cortisol AUC (p = 0.006; slope = 0.792 [0.233; 1.352]. High agreeableness and openness might be associated with poorer executive performance in later life. Increased cortisol may be associated with both specific personality traits (high extraversion, low openness) and worse cognitive performance. Increased salivary cortisol does not mediate the relationship between personality traits and cognitive impairment. PMID- 28352229 TI - Antibiotic Therapy for Chorioamnionitis to Reduce the Global Burden of Associated Disease. AB - Chorioamnionitis is associated with significant maternal and neonatal morbidity and mortality throughout the world. In developed countries, great progress has been made to minimize the impact of chorioamnionitis, through timely diagnosis and appropriate treatment. In the global setting, where many women deliver outside the healthcare facilities, this diagnosis is frequently overlooked and not properly treated. In addition to its impact on maternal health, a significant proportion of neonatal morbidity and mortality can be prevented by both recognition and access to readily available treatment. With the increasing focus on saving the most vulnerable members of society, we echo the need for providing parturient women with suspected chorioamnionitis universal access to appropriate therapy. We describe known effective antibiotic therapies for chorioamnionitis and provide an overview of additional potential antimicrobial treatments that might be effectively implemented in areas with limited access to care. PMID- 28352230 TI - Lead Induced Hepato-renal Damage in Male Albino Rats and Effects of Activated Charcoal. AB - Lead is a multi-organ toxicant implicated in various cancers, diseases of the hepatic, renal, and reproductive systems etc. In search of cheap and readily available antidote this study has investigated the role of activated charcoal in chronic lead exposure in albino rats. Eighteen mature male albino rats were used, divided into three groups of six rats per group. Group 1 (control rats) received deionised water (10 ml/kg), group 2 was given lead acetate solution 60 mg/kg and group 3 rats were given lead acetate (60 mg/kg) followed by Activated charcoal, AC (1000 mg/kg) by oral gavage daily for 28 days. Rats in group 2 showed significant increases in serum Aspartate aminotransferase, Alkaline phosphatase, Alanine aminotransferase, urea, bilirubin, total cholesterol, triglycerides, Low Density Lipoprotein, Very Low Density Lipoproteins, Total White Blood Cell Counts, Malondialdehyde, Interleukin-6, and decreases in Packed Cell Volume, hemoglobin concentration, Red blood cell count, total proteins, albumins, superoxide dismutase, glutathione peroxidase and total glutathione. Co administration of AC significantly decreased these biomarkers with the exception of the sperm parameters. Histopathology of liver and kidney also confirmed the protective effective of AC against lead induced hepato-renal damage. AC may be beneficial in chronic lead induced liver and kidney damage. PMID- 28352232 TI - Dickkopf-3 Upregulates VEGF in Cultured Human Endothelial Cells by Activating Activin Receptor-Like Kinase 1 (ALK1) Pathway. AB - Dkk-3 is a member of the dickkopf protein family of secreted inhibitors of the Wnt pathway, which has been shown to enhance angiogenesis. The mechanism underlying this effect is currently unknown. Here, we used cultured HUVECs to study the involvement of the TGF-beta and VEGF on the angiogenic effect of Dkk-3. Addition of hrDkk-3 peptide (1 or 10 ng/ml) to HUVECs for 6 or 12 h enhanced the intracellular and extracellular VEGF protein levels, as assessed by RTPCR, immunoblotting, immunocytochemistry and ELISA. The increase in the extracellular VEGF levels was associated to the VEGFR2 activation. Pharmacological blockade of VEGFR2 abrogated Dkk-3-induced endothelial cell tubes formation, indicating that VEGF is a molecular player of the angiogenic effects of Dkk-3. Moreover, Dkk-3 enhanced Smad1/5/8 phosphorylation and recruited Smad4 to the VEGF gene promoter, suggesting that Dkk-3 activated ALK1 receptor leading to a transcriptional activation of VEGF. This mechanism was instrumental to the increased VEGF expression and endothelial cell tubes formation mediated by Dkk-3, because both effects were abolished by siRNA-mediated ALK1 knockdown. In summary, we have found that Dkk-3 activates ALK1 to stimulate VEGF production and induce angiogenesis in HUVECs. PMID- 28352231 TI - New Insights toward Colorectal Cancer Chemotherapy Using Natural Bioactive Compounds. AB - Combination therapy consists in the simultaneous administration of a conventional chemotherapy drug (or sometimes, a radiotherapy protocol) together with one or more natural bioactives (usually from plant or fungal origin) of small molecular weight. This combination of anticancer drugs may be applied to cell cultures of tumor cells, or to an animal model for a cancer type (or its xenograft), or to a clinical trial in patients. In this review, we summarize current knowledge describing diverse synergistic effects on colorectal cancer cell cultures, animal models, and clinical trials of various natural bioactives (stilbenes, flavonoids, terpenes, curcumin, and other structural families), which may be important with respect to diminish final doses of the chemotherapy drug, although maintaining its biological effect. This is important as these approaches may help reduce side effects in patients under conventional chemotherapy. Also, these molecules may exerts their synergistic effects via different cell cycle pathways, including different ones to those responsible of resistance phenotypes: transcription factors, membrane receptors, adhesion and structural molecules, cell cycle regulatory components, and apoptosis pathways. PMID- 28352234 TI - Dual Functional Capability of Dendritic Cells - Cytokine-Induced Killer Cells in Improving Side Effects of Colorectal Cancer Therapy. AB - The aim of cancer therapy is to eradicate cancer without affecting healthy tissues. Current options available for treating colorectal cancer (CRC), including surgery, chemotherapy or radiotherapy, usually elicit multiple adverse effects and frequently fail to completely remove the tumor cells. Thus, there is a constant need for seeking cancer cell-specific therapeutics to improve the course of cancer therapy and reduce the risk of relapse. In this review we elaborate on the mechanisms underlying the immunotherapy with dendritic cells (DCs) and cytokine-induced killer (CIK) cells, and summarize their effectiveness and tolerability available clinical studies. Finally, we discuss the up-to-date combinatorial adoptive anti-cancer immunotherapy with CIK cells co-cultured with DCs that recently showed encouraging efficacy and usefulness in treating malignant disease, including CRC. PMID- 28352233 TI - Aldo-Keto Reductase AKR1C1-AKR1C4: Functions, Regulation, and Intervention for Anti-cancer Therapy. AB - Aldo-keto reductases comprise of AKR1C1-AKR1C4, four enzymes that catalyze NADPH dependent reductions and have been implicated in biosynthesis, intermediary metabolism, and detoxification. Recent studies have provided evidences of strong correlation between the expression levels of these family members and the malignant transformation as well as the resistance to cancer therapy. Mechanistically, most studies focus on the catalytic-dependent function of AKR1C isoforms, like their impeccable roles in prostate cancer, breast cancer, and drug resistance due to the broad substrates specificity. However, accumulating clues showed that catalytic-independent functions also played critical roles in regulating biological events. This review summarizes the catalytic-dependent and independent roles of AKR1Cs, as well as the small molecule inhibitors targeting these family members. PMID- 28352235 TI - Mouse Lung Fibroblast Resistance to Fas-Mediated Apoptosis Is Dependent on the Baculoviral Inhibitor of Apoptosis Protein 4 and the Cellular FLICE-Inhibitory Protein. AB - A characteristic feature of idiopathic pulmonary fibrosis (IPF) is accumulation of apoptotic resistant fibroblasts/myofibroblasts in the fibroblastic foci. As caveolin (Cav)-null mice develop pulmonary fibrosis (PF), we hypothesized that the participating fibroblasts display an apoptosis-resistant phenotype. To test this hypothesis and identify the molecular mechanisms involved we isolated lung fibroblasts from Cav-null mice and examined the expression of several inhibitors of apoptosis (IAPs), of c-FLIP, of Bcl-2 proteins and of the death receptor CD95/Fas. We found significant increase in XIAP and c-FLIP constitutive protein expression with no alteration of Bcl-2 and lower levels of CD95/Fas. The isolated fibroblasts were then treated with the CD95/Fas ligand (FasL) to induce apoptosis. While the morphological and biochemical alterations induced by FasL were similar in wild-type (wt) and Cav-null mouse lung fibroblasts, the time course and the extent of the alterations were greater in the Cav-null fibroblasts. Several salient features of Cav-null fibroblasts response such as loss of membrane potential, fragmentation of the mitochondrial continuum concurrent with caspase-8 activation, and subsequent Bid cleavage, prior to caspase-3 activation were detected. Furthermore, M30 antigen formation, phosphatidylserine expression and DNA fragmentation were caspase-3 dependent. SiRNA-mediated silencing of XIAP and c-FLIP, individually or combined, enhanced the sensitivity of lung fibroblasts to FasL-induced apoptosis. Pharmacological inhibition of Bcl-2 had no effect. Together our findings support a mechanism in which CD95/Fas engagement activates caspase-8, inducing mitochondrial apoptosis through Bid cleavage. XIAP and c-FLIP fine tune this process in a cell-type specific manner. PMID- 28352237 TI - Reduced Freezing in Posttraumatic Stress Disorder Patients while Watching Affective Pictures. AB - Besides fight and flight responses, animals and humans may respond to threat with freezing, a response characterized by bradycardia and physical immobility. Risk assessment is proposed to be enhanced during freezing to promote optimal decision making. Indeed, healthy participants showed freezing-like responses to threat cues. Posttraumatic stress disorder (PTSD) patients are characterized by hypervigilance and increased threat responsiveness. We propose that threat responses will be characterized by decreased freezing in PTSD, eliminating possibilities for rejecting cognitive distortions, such as harm expectancy, and thereby contributing to the maintenance of the disorder. However, freezing responses have hardly been investigated in PTSD. Using a stabilometric platform to assess body sway as an indicator of freezing-like behavior, we examined whether veterans with PTSD would show diminished freezing responses to unpleasant versus neutral and pleasant pictures. Fourteen PTSD patients and 14 healthy matched controls watched the pictures, while body sway and heart rate (HR) were continuously assessed. Replicating previous findings, healthy controls showed decreased body sway and HR in response to unpleasant pictures, indicative of freezing-like behavior. In contrast, this response pattern was not observed in PTSD patients. The results may indicate a reduced freezing response in PTSD. As reduced freezing may hinder appropriate risk assessment, it may be an important factor in the maintenance of PTSD. Future research might clarify whether impaired freezing is a PTSD-specific or a transdiagnostic symptom, being present in threat related disorders. PMID- 28352236 TI - Insights and Challenges of Multi-Scale Modeling of Sarcomere Mechanics in cTn and Tm DCM Mutants-Genotype to Cellular Phenotype. AB - Dilated Cardiomyopathy (DCM) is a leading cause of sudden cardiac death characterized by impaired pump function and dilatation of cardiac ventricles. In this review we discuss various in silico approaches to elucidating the mechanisms of genetic mutations leading to DCM. The approaches covered in this review focus on bridging the spatial and temporal gaps that exist between molecular and cellular processes. Mutations in sarcomeric regulatory thin filament proteins such as the troponin complex (cTn) and Tropomyosin (Tm) have been associated with DCM. Despite the experimentally-observed myofilament measures of contractility in the case of these mutations, the mechanisms by which the underlying molecular changes and protein interactions scale up to organ failure by these mutations remains elusive. The review highlights multi-scale modeling approaches and their applicability to study the effects of sarcomeric gene mutations in-silico. We discuss some of the insights that can be gained from computational models of cardiac biomechanics when scaling from molecular states to cellular level. PMID- 28352238 TI - Communicating the Neuroscience of Psychopathy and Its Influence on Moral Behavior: Protocol of Two Experimental Studies. AB - Neuroscience has identified brain structures and functions that correlate with psychopathic tendencies. Since psychopathic traits can be traced back to physical neural attributes, it has been argued that psychopaths are not truly responsible for their actions and therefore should not be blamed for their psychopathic behaviors. This experimental research aims to evaluate what effect communicating this theory of psychopathy has on the moral behavior of lay people. If psychopathy is blamed on the brain, people may feel less morally responsible for their own psychopathic tendencies and therefore may be more likely to display those tendencies. An online study will provide participants with false feedback about their psychopathic traits supposedly based on their digital footprint (i.e., Facebook likes), thus classifying them as having either above-average or below-average psychopathic traits and describing psychopathy in cognitive or neurobiological terms. This particular study will assess the extent to which lay people are influenced by feedback regarding their psychopathic traits, and how this might affect their moral behavior in online tasks. Public recognition of these potential negative consequences of neuroscience communication will also be assessed. A field study using the lost letter technique will be conducted to examine lay people's endorsement of neurobiological, as compared to cognitive, explanations of criminal behavior. This field and online experimental research could inform the future communication of neuroscience to the public in a way that is sensitive to the potential negative consequences of communicating such science. In particular, this research may have implications for the future means by which neurobiological predictors of offending can be safely communicated to offenders. PMID- 28352239 TI - Psychological Interventions for Post-traumatic Stress Symptoms in Psychosis: A Systematic Review of Outcomes. AB - Individuals with severe mental health problems, such as psychosis, are consistently shown to have experienced high levels of past traumatic events. They are also at an increased risk of further traumatisation through victimization events such as crime and assault. The experience of psychosis itself and psychiatric hospitalization have also been recognized to be sufficiently traumatic to lead to the development of post-traumatic stress (PTS) symptoms. Rates of post-traumatic stress disorder (PTSD) are elevated in people with psychosis compared to the general population. The current guidance for the treatment of PTSD is informed by an evidence base predominately limited to populations without co-morbid psychiatric disorders. The systematic review therefore sought to present the current available literature on the use of psychological treatments targeting PTS symptoms in a population with a primary diagnosis of a psychotic disorder. The review aimed to investigate the effect of these interventions on PTS symptoms and also the effect on secondary domains such as psychotic symptoms, affect and functioning. Fifteen studies were identified reporting on cognitive behavior therapy, prolonged exposure, eye movement desensitisation and reprocessing and written emotional disclosure. The review provides preliminary support for the safe use of trauma-focused psychological interventions in groups of people with severe mental health problems. Overall, the interventions were found to be effective in reducing PTS symptoms. Results were mixed with regard to secondary effects on additional domains. Further research including studies employing sufficiently powered methodologically rigorous designs is indicated. PMID- 28352240 TI - Military Service Member and Veteran Reintegration: A Conceptual Analysis, Unified Definition, and Key Domains. AB - Returning military service members and veterans (MSMVs) may experience a variety of stress-related disorders and challenges when reintegrating from the military to the community. Facilitating the reintegration, transition, readjustment and coping, and community integration, of MSMVs is a societal priority. To date, research addressing MSMV reintegration has not identified a comprehensive definition of the term or defined the broader context within which the process of reintegration occurs although both are needed to promote valid and reliable measurement of reintegration and clarify related challenges, processes, and their impact on outcomes. Therefore, this principle-based concept analysis sought to review existing empirical reintegration measurement instruments and identify the problems and needs of MSMV reintegration to provide a unified definition of reintegration to guide future research, clinical practice, and related services. We identified 1,459 articles in the health and social sciences literature, published between 1990 and 2015, by searching multiple electronic databases. Screening of abstracts and full text review based on our inclusion/exclusion criteria, yielded 117 articles for review. Two investigators used constant conceptual comparison to evaluate relevant articles independently. We examined the term reintegration and related terms (i.e., transition, readjustment, community integration) identifying trends in their use over time, analyzed the eight reintegration survey instruments, and synthesized service member and veteran self-reported challenges and needs for reintegration. More reintegration research was published during the last 5 years (n = 373) than in the previous 10 years combined (n = 130). The research suggests coping with life stresses plays an integral role in military service member and veteran post-deployment reintegration. Key domains of reintegration include individual, interpersonal, community organizations, and societal factors that may facilitate or challenge successful reintegration, and results suggest that successful coping with life stressors plays an integral role in post-deployment reintegration. Overall, the literature does not provide a comprehensive representation of reintegration among MSMVs. Although, previous research describes military service member and veteran reintegration challenges, this concept analysis provides a unified definition of the phenomenon and identifies key domains of reintegration that may broaden our understanding and guide reintegration research and practice. PMID- 28352242 TI - Verbal Emotional Disclosure of Traumatic Experiences in Adolescents: The Role of Social Risk Factors. AB - It is well-known that traumatic events and adverse life situations are very important in both physical and psychological health. Prevalence studies suggested that adolescents experience at least one potentially traumatic event before reaching age 18. The paradigm of research centered on expressive writing has evidenced the beneficial effects that the emotional disclosure of previous traumas produces on physical health and psychological adjustment. The aims of the study are threefold: determining the prevalence of adverse or traumatic events; examining the extent to which psychopathological symptoms developed in those exposed to traumatic events; and exploring an verbal emotional disclosure (VED) paradigm in which variations on time spent talking about traumatic experiences to others resulted in a reduction of the psychological impact of trauma in a sample of Spanish adolescents. 422 volunteer adolescents participated, 226 boys and 192 girls, from 10 to 19 years old, all of them living in Tenerife. The mean age was 14.8 years (SD = 1.83). All of them completed the instruments used to assess the psychological impact of traumatic experiences and VED. The main results indicated that 77% of the participants had suffered a traumatic situation. The participants who have been exposed to traumatic events scored significantly higher in measures of post-traumatic stress, disorder, intrusive thoughts, avoidance behaviors, anxiety and depression, compared to those without trauma. Furthermore, results show a decrease in symptomatology scores as a function of time spent disclosing emotional experiences to others, particularly when disclosure occurred several times. In conclusion, stressful events or traumatic experiences and their concomitant emotional effects are highly prevalent in adolescents, and repeated VED to others appears to ameliorate their impact. VED shows greater therapeutic benefits when adolescents narrate the experience on several occasions and in an extensive way. PMID- 28352241 TI - The Sense of 1PP-Location Contributes to Shaping the Perceived Self-location Together with the Sense of Body-Location. AB - Self-location-the sense of where I am in space-provides an experiential anchor for one's interaction with the environment. In the studies of full-body illusions, many researchers have defined self-location solely in terms of body location-the subjective feeling of where my body is. Although this view is useful, there is an issue regarding whether it can fully accommodate the role of 1PP-location-the sense of where my first-person perspective is located in space. In this study, we investigate self-location by comparing body-location and 1PP location: using a head-mounted display (HMD) and a stereo camera, the subjects watched their own body standing in front of them and received tactile stimulations. We manipulated their senses of body-location and 1PP-location in three different conditions: the participants standing still (Basic condition), asking them to move forward (Walking condition), and swiftly moving the stereo camera away from their body (Visual condition). In the Walking condition, the participants watched their body moving away from their 1PP. In the Visual condition, the scene seen via the HMD was systematically receding. Our data show that, under different manipulations of movement, the spatial unity between 1PP location and body-location can be temporarily interrupted. Interestingly, we also observed a "double-body effect." We further suggest that it is better to consider body-location and 1PP-location as interrelated but distinct factors that jointly support the sense of self-location. PMID- 28352243 TI - Behavioral Dynamics in Swimming: The Appropriate Use of Inertial Measurement Units. AB - Motor control in swimming can be analyzed using low- and high-order parameters of behavior. Low-order parameters generally refer to the superficial aspects of movement (i.e., position, velocity, acceleration), whereas high-order parameters capture the dynamics of movement coordination. To assess human aquatic behavior, both types have usually been investigated with multi-camera systems, as they offer high three-dimensional spatial accuracy. Research in ecological dynamics has shown that movement system variability can be viewed as a functional property of skilled performers, helping them adapt their movements to the surrounding constraints. Yet to determine the variability of swimming behavior, a large number of stroke cycles (i.e., inter-cyclic variability) has to be analyzed, which is impossible with camera-based systems as they simply record behaviors over restricted volumes of water. Inertial measurement units (IMUs) were designed to explore the parameters and variability of coordination dynamics. These light, transportable and easy-to-use devices offer new perspectives for swimming research because they can record low- to high-order behavioral parameters over long periods. We first review how the low-order behavioral parameters (i.e., speed, stroke length, stroke rate) of human aquatic locomotion and their variability can be assessed using IMUs. We then review the way high-order parameters are assessed and the adaptive role of movement and coordination variability in swimming. We give special focus to the circumstances in which determining the variability between stroke cycles provides insight into how behavior oscillates between stable and flexible states to functionally respond to environmental and task constraints. The last section of the review is dedicated to practical recommendations for coaches on using IMUs to monitor swimming performance. We therefore highlight the need for rigor in dealing with these sensors appropriately in water. We explain the fundamental and mandatory steps to follow for accurate results with IMUs, from data acquisition (e.g., waterproofing procedures) to interpretation (e.g., drift correction). PMID- 28352244 TI - The Child Attachment Interview: A Narrative Review. AB - Attachment theory promoted an impressive body of research on the psychic developmental processes, resulting in studies on both typical and atypical development. Much of the diffusion of the attachment theory in the clinical field was related to the design of reliable instruments to evaluate the organization of attachment in infancy as well as in adulthood. Until recently, the lack of a suitable instrument to assess attachment in middle childhood as well as in adolescence hindered the expansion of research in these developmental phases during which the parent-child relationship takes on a different, albeit still crucial, role. The Child Attachment Interview (CAI), a measure that was recently designed to assess attachment at a representational level in middle childhood and adolescence, filled the measurement gap. The aim of the current review was to summarize previous empirical investigations concerning CAI in order to (a) provide an overview of the state of current research, (b) identify unanswered questions, and (c) propose future research directions. A narrative review was conducted to map the current research findings by searching for the term "Child Attachment Interview" in the Medline, Scopus, Web of Science, and PsychINFO databases, followed by a search in Mendeley. Limits were set to exclude dissertations, chapters in books, and qualitative or theoretical papers, while empirical studies were included if they used the CAI and were published in English language, peer-reviewed journals by July, 2016. The review, which ultimately included 39 studies meeting the criteria, showed that the CAI is a reliable instrument to assess attachment organization in clinical and non clinical samples, thus providing a worthwhile contribution to the investigation of the influence of the parent-child relationship beyond infancy and early childhood. Nevertheless, the review pointed out a number of relevant open issues, the most critical of which concerned the CAI coding and classification system. In particular, some relevant questions arose about (a) how opportune it would be to maintain a distinct classification for mother and father, (b) coding challenges regarding both the father and the Preoccupied and Disorganized classification, and finally (c) the advantage of a dimensional vs. a categorical approach. PMID- 28352245 TI - Listening and Hearing: A Voice Hearer's Invitation into Relationship. AB - Although historically overlooked, empirical links between trauma and psychosis have received growing attention over the past decade. Increasingly, clinical researchers have also zeroed in on the role that distressing or traumatic life events play in the psychosocial formation and maintenance of psychosis. This paper re-locates anomalous experiences in their human contexts, and asks that clinicians and researchers engage with these contexts. The author shares a first person account of her experience changing her relationships with dominance in order to reclaim and accept her human being-ness, a reorientation supported by her involvement in the world hearing voices network movement and community. She calls for mental health systems, providers, and researchers to collaborate with the persons at the center of their work-to dare to listen, hear, and connect for mutual learning, healing, and wholeness. The article concludes with recommendations and a rallying call for services to be made more inclusive and to re-center in meaningful collaboration with people with lived experience. More comprehensive, meaningful, and accountable practices can be co-created when people are met equally as human subjects, both responsible and accountable for change. PMID- 28352246 TI - Grand Challenges in Eating Behavior Research: Preventing Weight Gain, Facilitating Long-Term Weight Maintenance. PMID- 28352247 TI - Refixation Saccades with Normal Gain Values: A Diagnostic Problem in the Video Head Impulse Test: A Case Report. AB - Refixation saccades with normal gain value occur more frequently with increasing age. The phenomenon has also been observed in different vestibular disorders. In this case, we present a young male with normal gain value and refixation saccades tested with the video head impulse test (vHIT) the day after his cochlear implantation. One month after surgery, refixation saccades were no longer present. This suggests that refixation saccades can occur as a result of temporary pathology such as surgery. Refixation saccades with normal gain values might reflect a partial deficit in the vestibulo-ocular reflex. However, this partial deficit is in conflict with the current way of interpreting vHIT results in which the vestibular function is classified as either normal or pathological based only on the gain value. Refixation saccades, which are evident signs of vestibulopathy, are not considered in the evaluation. A new way of interpreting the vHIT based on the saccades must be considered. PMID- 28352248 TI - Alberta Stroke Program Early CT Score Infarct Location Predicts Outcome Following M2 Occlusion. AB - BACKGROUND: Although it is generally thought that patients with distal middle cerebral artery (M2) occlusion have a favorable outcome, it has previously been demonstrated that a substantial minority will have a poor outcome by 90 days. We sought to determine whether assessing the Alberta Stroke Program Early CT Score (ASPECTS) infarct location allows for identifying patients at risk for a poor 90 day outcome. METHODS: We retrospectively analyzed patients with isolated acute M2 occlusion admitted to a single academic center between January 2010 and August 2012. Infarct regions were defined according to ASPECTS system on the initial head computed tomography. Discriminant function analysis was used to define specific ASPECTS regions that are predictive of the 90-day functional outcome as defined as a modified Rankin Scale score of 3-6. In addition, logistic regression was used to model the relationship between each individual ASPECT region with poor outcome; for evaluation and comparison, odds ratios, c-statistics, and Akaike information criterion values were estimated for each region. RESULTS: Ninety patients with isolated M2 were included in the final analysis. ASPECTS score <=6 predicted poor outcome in this cohort (sensitivity = 0.591, specificity = 0.838, p < 0.001). Using multiple approaches, we found that infarction in ASPECTS regions M3 and M6 were strongly associated with poor functional status by 90 days. CONCLUSION: Infarction in ASPECTS regions M3 and M6 are key predictors of functional outcome following isolated distal M2 occlusion. These findings will be helpful in stratifying outcomes if validated in future studies. PMID- 28352249 TI - High-Fat Feeding Does Not Disrupt Daily Rhythms in Female Mice because of Protection by Ovarian Hormones. AB - Obesity in women is increased by the loss of circulating estrogen after menopause. Shift work, which disrupts circadian rhythms, also increases the risk for obesity. It is not known whether ovarian hormones interact with the circadian system to protect females from obesity. During high-fat feeding, male C57BL/6J mice develop profound obesity and disruption of daily rhythms. Since C57BL/6J female mice did not develop diet-induced obesity (during 8 weeks of high-fat feeding), we first determined if daily rhythms in female mice were resistant to disruption from high-fat diet. We fed female PERIOD2:LUCIFERASE mice 45% high-fat diet for 1 week and measured daily rhythms. Female mice retained robust rhythms of eating behavior and locomotor activity during high-fat feeding that were similar to chow-fed females. In addition, the phase of the liver molecular timekeeping (PER2:LUC) rhythm was not altered by high-fat feeding in females. To determine if ovarian hormones protected daily rhythms in female mice from high fat feeding, we analyzed rhythms in ovariectomized mice. During high-fat feeding, the amplitudes of the eating behavior and locomotor activity rhythms were reduced in ovariectomized females. Liver PER2:LUC rhythms were also advanced by ~4 h by high-fat feeding, but not chow, in ovariectomized females. Together these data show circulating ovarian hormones protect the integrity of daily rhythms in female mice during high-fat feeding. PMID- 28352250 TI - Characteristics of Quinolone Resistance in Salmonella spp. Isolates from the Food Chain in Brazil. AB - Salmonella spp. is an important zoonotic pathogen related to foodborne diseases. Despite that quinolones/fluoroquinolones are considered a relevant therapeutic strategy against resistant isolates, the increase in antimicrobial resistance is an additional difficulty in controlling bacterial infections caused by Salmonella spp. Thus, the acquisition of resistance to quinolones in Salmonella spp. is worrisome to the scientific community along with the possibility of transmission of resistance through plasmids. This study investigated the prevalence of plasmid mediated quinolone resistance (PMQR) in Salmonella spp. and its association with fluoroquinolone susceptibility in Brazil. We evaluated 129 isolates, 39 originated from food of animal sources, and 14 from environmental samples and including 9 from animals and 67 from humans, which were referred to the National Reference Laboratory of Enteric Diseases (NRLEB/IOC/RJ) between 2009 and 2013. These samples showed a profile of resistance for the tested quinolones/fluoroquinolones. A total of 33 serotypes were identified; S. Typhimurium (63) was the most prevalent followed by S. Enteritidis (25). The disk diffusion test showed 48.8% resistance to enrofloxacin, 42.6% to ciprofloxacin, 39.53% to ofloxacin, and 30.2% to levofloxacin. According to the broth microdilution test, the resistance percentages were: 96.1% to nalidixic acid, 64.3% to enrofloxacin, 56.6% to ciprofloxacin, 34.1% to ofloxacin, and 30.2% to levofloxacin. Qnr genes were found in 15 isolates (8 qnrS, 6 qnrB, and 1 qnrD), and the aac(6')-Ib gene in 23. The integron gene was detected in 67 isolates with the variable region between +/-600 and 1000 bp. The increased detection of PMQR in Salmonella spp. is a serious problem in Public Health and must constantly be monitored. Pulsed-field gel electrophoresis was performed to evaluated clonal profile among the most prevalent serovars resistant to different classes of quinolones. A total of 33 pulsotypes of S. Typhimurium were identified with a low percentage of genetic similarity (<=65%). This result demonstrates the presence of high diversity in the resistant clones evaluated in this study. PMID- 28352251 TI - Stochastic and Differential Activation of sigmaB and PrfA in Listeria monocytogenes at the Single Cell Level under Different Environmental Stress Conditions. AB - During host infection, the foodborne pathogen Listeria monocytogenes must sense and respond to rapidly changing environmental conditions. Two transcriptional regulators, the alternative sigma factor B (sigmaB) and the Positive Regulatory Factor A (PrfA), are key contributors to the transcriptomic responses that enable bacterial survival in the host gastrointestinal tract and invasion of host duodenal cells. Increases in temperature and osmolarity induce activity of these proteins; such conditions may be encountered in food matrices as well as within the host gastrointestinal tract. Differences in PrfA and sigmaB activity between individual cells might affect the fate of a cell during host invasion, therefore, we hypothesized that PrfA and sigmaB activities differ among individual cells under heat and salt stress. We used fluorescent reporter fusions to determine the relative proportions of cells with active sigmaB or PrfA following exposure to 45 degrees C heat or 4% NaCl. Activities of both PrfA and sigmaB were induced stochastically, with fluorescence levels ranging from below detection to high among individual cells. The proportion of cells with active PrfA was significantly higher than the proportion with active sigmaB under all tested conditions; under some conditions, nearly all cells had active PrfA. Our findings further support the growing body of evidence illustrating the stochastic nature of bacterial gene expression under conditions that are relevant for host invasion via food-borne, oral infection. PMID- 28352252 TI - Phosphate Limitation Triggers the Dissolution of Precipitated Iron by the Marine Bacterium Pseudovibrio sp. FO-BEG1. AB - Phosphorus is an essential nutrient for all living organisms. In bacteria, the preferential phosphorus source is phosphate, which is often a limiting macronutrient in many areas of the ocean. The geochemical cycle of phosphorus is strongly interconnected with the cycles of other elements and especially iron, because phosphate tends to adsorb onto iron minerals, such as iron oxide formed in oxic marine environments. Although the response to either iron or phosphate limitation has been investigated in several bacterial species, the metabolic interplay between these two nutrients has rarely been considered. In this study we evaluated the impact of phosphate limitation on the iron metabolism of the marine bacterium Pseudovibrio sp. FO-BEG1. We observed that phosphate limitation led to an initial decrease of soluble iron in the culture up to three times higher than under phosphate surplus conditions. Similarly, a decrease in soluble cobalt was more pronounced under phosphate limitation. These data point toward physiological changes induced by phosphate limitation that affect either the cellular surface and therefore the metal adsorption onto it or the cellular metal uptake. We discovered that under phosphate limitation strain FO-BEG1, as well as selected strains of the Roseobacter clade, secreted iron-chelating molecules. This leads to the hypothesis that these bacteria might release such molecules to dissolve iron minerals, such as iron-oxyhydroxide, in order to access the adsorbed phosphate. As the adsorption of phosphate onto iron minerals can significantly decrease phosphate concentrations in the environment, the observed release of iron-chelators might represent an as yet unrecognized link between the biogeochemical cycle of phosphorus and iron, and it suggests another biological function of iron-chelating molecules in addition to metal-scavenging. PMID- 28352253 TI - Nitrate Assimilation in Fusarium fujikuroi Is Controlled by Multiple Levels of Regulation. AB - Secondary metabolite production of the phytopathogenic ascomycete fungus Fusarium fujikuroi is greatly influenced by the availability of nitrogen. While favored nitrogen sources such as glutamine and ammonium are used preferentially, the uptake and utilization of nitrate is subject to a regulatory mechanism called nitrogen metabolite repression (NMR). In Aspergillus nidulans, the transcriptional control of the nitrate assimilatory system is carried out by the synergistic action of the nitrate-specific transcription factor NirA and the major nitrogen-responsive regulator AreA. In this study, we identified the main components of the nitrate assimilation system in F. fujikuroi and studied the role of each of them regarding the regulation of the remaining components. We analyzed mutants with deletions of the nitrate-specific activator NirA, the nitrate reductase (NR), the nitrite reductase (NiR) and the nitrate transporter NrtA. We show that NirA controls the transcription of the nitrate assimilatory genes NIAD, NIIA, and NRTA in the presence of nitrate, and that the global nitrogen regulator AreA is obligatory for expression of most, but not all NirA target genes (NIAD). By transforming a NirA-GFP fusion construct into the DeltaNIAD, DeltaNRTA, and DeltaAREA mutant backgrounds we revealed that NirA was dispersed in the cytosol when grown in the presence of glutamine, but rapidly sorted to the nucleus when nitrate was added. Interestingly, the rapid and nitrate-induced nuclear translocation of NirA was observed also in the DeltaAREA and DeltaNRTA mutants, but not in DeltaNIAD, suggesting that the fungus is able to directly sense nitrate in an AreA- and NrtA-independent, but NR-dependent manner. PMID- 28352254 TI - Distribution of Secretion Systems in the Genus Legionella and Its Correlation with Pathogenicity. AB - The genus Legionella comprises over 60 species, which are important human pathogens. Secretion systems in Legionella pneumophila have been studied extensively because of the essential role of protein secretion in bacterial infection. However, there are few reports describing the secretion systems in non L. pneumophila species. In this study, we analyzed the distribution of secretion systems in L. pneumophila and 18 species of non-L. pneumophila based on whole genome sequences. A total of 74 whole genome sequences from 19 species of Legionella were analyzed. Type II and IVB secretion systems were detected in all Legionella strains, but the type I secretion systems was restricted to L. pneumophila. The type IVA secretion system was randomly distributed among different species. Furthermore, we found the type VI secretion system in three non-L. pneumophila strains (Legionella cherrii DSM 19213, Legionella dumoffii Tex KL, and Legionella gormanii ATCC 33297). In population structure analysis, L. pneumophila formed a conservative cluster and was located at the terminal of the evolutionary tree. At the same time, L. pneumophila, especially eight clone groups (named MCGG1-MCGG8), showed higher intracellular growth ability than non L. pneumophila species. These results suggest that L. pneumophila has acquired additional secretion systems during evolution, resulting in increased pathogenicity. PMID- 28352255 TI - Metaproteogenomics Reveals Taxonomic and Functional Changes between Cecal and Fecal Microbiota in Mouse. AB - Previous studies on mouse models report that cecal and fecal microbial communities may differ in the taxonomic structure, but little is known about their respective functional activities. Here, we employed a metaproteogenomic approach, including 16S rRNA gene sequencing, shotgun metagenomics and shotgun metaproteomics, to analyze the microbiota of paired mouse cecal contents (CCs) and feces, with the aim of identifying changes in taxon-specific functions. As a result, Gram-positive anaerobes were observed as considerably higher in CCs, while several key enzymes, involved in oxalate degradation, glutamate/glutamine metabolism, and redox homeostasis, and most actively expressed by Bacteroidetes, were clearly more represented in feces. On the whole, taxon and function abundance appeared to vary consistently with environmental changes expected to occur throughout the transit from the cecum to outside the intestine, especially when considering metaproteomic data. The results of this study indicate that functional and metabolic differences exist between CC and stool samples, paving the way to further metaproteogenomic investigations aimed at elucidating the functional dynamics of the intestinal microbiota. PMID- 28352257 TI - A Novel Pan-Genome Reverse Vaccinology Approach Employing a Negative-Selection Strategy for Screening Surface-Exposed Antigens against leptospirosis. AB - Reverse vaccinology (RV) has been widely used for screening of surface-exposed proteins (PSEs) of important pathogens, including outer membrane proteins (OMPs), and extracellular proteins (ECPs) as potential vaccine candidates. In this study, we applied a novel RV negative strategy and a pan-genome analysis for screening of PSEs from 17 L. interrogans strains covering 11 predominately epidemic serovars and 17 multilocus typing (MLST) sequence types (STs) worldwide. Our results showed, for instance, out of a total of 633 predicted PSEs in strain 56601, 92.8% were OMPs or ECPs (588/633). Among the 17 strains, 190 core PSEs, 913 dispensable PSEs and 861 unique PSEs were identified. Of the 190 PSEs, 121 were further predicted to be highly antigenic and thus may serve as potential vaccine candidates against leptospirosis. With the exception of LipL45, OmpL1, and LigB, the majority of the 121 PSEs were newly identified antigens. For example, hypothetical proteins BatC, LipL71, and the OmpA family proteins sharing many common features, such as surface-exposed localization, universal conservation, and eliciting strong antibody responses in patients, are regarded as the most promising vaccine antigens. Additionally, a wide array of potential virulence factors among the predicted PSEs including TonB-dependent receptor, sphingomyelinase 2, leucine-rich repeat protein, and 4 neighboring hypothetical proteins were identified as potential antigenicity, and deserve further investigation. Our results can contribute to the prediction of suitable antigens as potential vaccine candidates against leptospirosis and also provide further insights into mechanisms of leptospiral pathogenicity. In addition, our novel negative-screening strategy combined with pan-genome analysis can be a routine RV method applied to numerous other pathogens. PMID- 28352258 TI - 180-Nucleotide Duplication in the G Gene of Human metapneumovirus A2b Subgroup Strains Circulating in Yokohama City, Japan, since 2014. AB - Human metapneumovirus (HMPV), a member of the family Paramyxoviridae, was first isolated in 2001. Seroepidemiological studies have shown that HMPV has been a major etiological agent of acute respiratory infections in humans for more than 50 years. Molecular epidemiological, genetic, and antigenetic evolutionary studies of HMPV will strengthen our understanding of the epidemic behavior of the virus and provide valuable insight for the control of HMPV and the development of vaccines and antiviral drugs against HMPV infection. In this study, the nucleotide sequence of and genetic variations in the G gene were analyzed in HMPV strains prevalent in Yokohama City, in the Kanto area, Japan, between January 2013 and June 2016. As a part of the National Epidemiological Surveillance of Infectious Diseases, Japan, 1308 clinical specimens (throat swabs, nasal swabs, nasal secretions, and nasal aspirate fluids) collected at 24 hospitals or clinics in Yokohama City were screened for 15 major respiratory viruses with a multiplex reverse transcription-PCR assay. HMPV was detected in 91 specimens, accounting for 7.0% of the total specimens, and the nucleotide sequences of the G genes of 84 HMPV strains were determined. Among these 84 strains, 6, 43, 10, and 25 strains were classified into subgroups A2a, A2b, B1, and B2, respectively. Approximately half the HMPV A2b subgroup strains detected since 2014 had a 180 nucleotide duplication (180nt-dup) in the G gene and clustered on a phylogenic tree with four classical 180nt-dup-lacking HMPV A2b strains prevalent between 2014 and 2015. The 180nt-dup causes a 60-amino-acid duplication (60aa-dup) in the G protein, creating 23-25 additional potential acceptor sites for O-linked sugars. Our data suggest that 180nt-dup occurred between 2011 and 2013 and that HMPV A2b strains with 180nt-dup (A2b180nt-dup HMPV) became major epidemic strains within 3 years. The detailed mechanism by which the A2b180nt-dup HMPV strains gained an advantage that allowed their efficient spread in the community and the effects of 60aa-dup on HMPV virulence must be clarified. PMID- 28352256 TI - Redirection of Metabolic Hydrogen by Inhibiting Methanogenesis in the Rumen Simulation Technique (RUSITEC). AB - A decrease in methanogenesis is expected to improve ruminant performance by allocating rumen metabolic hydrogen ([2H]) to more energy-rendering fermentation pathways for the animal. However, decreases in methane (CH4) emissions of up to 30% are not always linked with greater performance. Therefore, the aim of this study was to understand the fate of [2H] when CH4 production in the rumen is inhibited by known methanogenesis inhibitors (nitrate, NIT; 3-nitrooxypropanol, NOP; anthraquinone, AQ) in comparison with a control treatment (CON) with the Rumen Simulation Technique (RUSITEC). Measurements started after 1 week adaptation. Substrate disappearance was not modified by methanogenesis inhibitors. Nitrate mostly seemed to decrease [2H] availability by acting as an electron acceptor competing with methanogenesis. As a consequence, NIT decreased CH4 production (-75%), dissolved dihydrogen (H2) concentration (-30%) and the percentages of reduced volatile fatty acids (butyrate, isobutyrate, valerate, isovalerate, caproate and heptanoate) except propionate, but increased acetate molar percentage, ethanol concentration and the efficiency of microbial nitrogen synthesis (+14%) without affecting gaseous H2. Nitrooxypropanol decreased methanogenesis (-75%) while increasing both gaseous and dissolved H2 concentrations (+81% and +24%, respectively). Moreover, NOP decreased acetate and isovalerate molar percentages and increased butyrate, valerate, caproate and heptanoate molar percentages as well as n-propanol and ammonium concentrations. Methanogenesis inhibition with AQ (-26%) was associated with higher gaseous H2 production (+70%) but lower dissolved H2 concentration (-76%), evidencing a lack of relationship between the two H2 forms. Anthraquinone increased ammonium concentration, caproate and heptanoate molar percentages but decreased acetate and isobutyrate molar percentages, total microbial nitrogen production and efficiency of microbial protein synthesis (-16%). Overall, NOP and AQ increased the amount of reduced volatile fatty acids, but part of [2H] spared from methanogenesis was lost as gaseous H2. Finally, [2H] recovery was similar among CON, NOP and AQ but was largely lower than 100%. Consequently, further studies are required to discover other so far unidentified [2H] sinks for a better understanding of the metabolic pathways involved in [2H] production and utilization. PMID- 28352259 TI - Jumbo Bacteriophages: An Overview. AB - Tailed bacteriophages with genomes larger than 200 kbp are classified as Jumbo phages, and are rarely isolated by conventional methods. These phages are designated "jumbo" owing to their most notable features of a large phage virion and large genome size. However, in addition to these, jumbo phages also exhibit several novel characteristics that have not been observed for phages with smaller genomes, which differentiate jumbo phages in terms of genome organization, virion structure, progeny propagation, and evolution. In this review, we summarize available reports on jumbo phages and discuss the differences between jumbo phages and small-genome phages. We also discuss data suggesting that jumbo phages might have evolved from phages with smaller genomes by acquiring additional functional genes, and that these additional genes reduce the dependence of the jumbo phages on the host bacteria. PMID- 28352260 TI - A Molecular Survey of Babesia Species and Detection of a New Babesia Species by DNA Related to B. venatorum from White Yaks in Tianzhu, China. AB - Bovine babesiosis is a tick-transmitted disease caused by different species of Babesia. The white yak is a unique yak breed that lives only in Tianzhu in the Tibetan Autonomous County, Gansu Province, in northwestern China. Previous research using the ELISA method has confirmed that the white yak could become infected with B. bigemina. The objective of this study was the molecular detection and identification of Babesia species in white yaks. A total of 409 white yak blood samples were collected from 11 areas of the Tianzhu Tibetan Autonomous County in Northwest China from April to August, 2015. The V4 hypervariable region of Babesia 18S rRNA was amplified from extracted genomic DNA using nested PCR and sequenced. The nearly full-length sequence of 18S rRNA including the V4 region from the newly discovered Babesia was amplified and sequenced with Sanger method. PCR detection and sequencing indicated that 4/409 samples were positive for B. bigemina, 3/409 samples were positive for B. bovis, and 5/409 samples were positive for B. ovata. Additionally, a new Babesia species was found in 4/409 white yaks. A unique sequence of 1,627 bp was obtained from two of the four samples. The sequence was similar to Babesia species Akita (98.5%) found in Ixodes ovatus and B. venatorum (98%) and shared a 98% identity with B. divergens and a 98.1% identity with B. odocoilei. This study provides new data about Babesia infections in white yaks in northwestern China, and a new Babesia species similar to B. venatorum was identified in white yaks for the first time. PMID- 28352262 TI - Editorial: Recent Advances in Acidophile Microbiology: Fundamentals and Applications. PMID- 28352261 TI - Analysis of Evolutionary Processes of Species Jump in Waterfowl Parvovirus. AB - Waterfowl parvoviruses are classified into goose parvovirus (GPV) and Muscovy duck parvovirus (MDPV) according to their antigenic features and host preferences. A novel duck parvovirus (NDPV), identified as a new variant of GPV, is currently infecting ducks, thus causing considerable economic loss. This study analyzed the molecular evolution and population dynamics of the emerging parvovirus capsid gene to investigate the evolutionary processes concerning the host shift of NDPV. Two important amino acids changes (Asn-489 and Asn-650) were identified in NDPV, which may be responsible for host shift of NDPV. Phylogenetic analysis indicated that the currently circulating NDPV originated from the GPV lineage. The Bayesian Markov chain Monte Carlo tree indicated that the NDPV diverged from GPV approximately 20 years ago. Evolutionary rate analyses demonstrated that GPV evolved with 7.674 * 10-4 substitutions/site/year, and the data for MDPV was 5.237 * 10-4 substitutions/site/year, whereas the substitution rate in NDPV branch was 2.25 * 10-3 substitutions/site/year. Meanwhile, viral population dynamics analysis revealed that the GPV major clade, including NDPV, grew exponentially at a rate of 1.717 year-1. Selection pressure analysis showed that most sites are subject to strong purifying selection and no positively selected sites were found in NDPV. The unique immune-epitopes in waterfowl parvovirus were also estimated, which may be helpful for the prediction of antibody binding sites against NDPV in ducks. PMID- 28352263 TI - Cold Stress and Nitrogen Deficiency Affected Protein Expression of Psychrotrophic Dyadobacter psychrophilus B2 and Pseudomonas jessenii MP1. AB - Nitrogen (N) deficiency and low temperature conditions are the prominent facet of Western Himalayan agro-ecosystems. A slight change in the environment alters the protein expression of the microorganisms. Therefore, proteomes of the two psychrotrophs Dyadobacter psychrophilus B2 and Pseudomonas jessenii MP1 were analyzed using two dimensional electrophoresis and MALDI-TOF-MS, to determine the physiological response of altitudinally different but indigenous microorganisms in response to cold stress under N depleting conditions. Functional assessment of 150 differentially expressed proteins from both the psychrotrophs revealed several mechanisms might be involved in cold stress adaptation, protein synthesis/modifications, energy metabolism, cell growth/maintenance, etc. In both the proteomes, abundance of the proteins related to energy production and stress were significantly increased while, proteins related to biosynthesis and energy consuming processes decreased. ATP synthase subunit alpha, beta, ATP-dependent Clp protease, Enolase, groL HtpG and N(2)-fixation sustaining protein CowN proteins were found to be expressed in both B2 and MP1, similarly to previously studied diazotrophs under low temperature N2 fixing conditions and therefore, can be considered as a biomarker for monitoring the nitrogen fixation in cold niches. Nevertheless, in both the diazotrophs, a good fraction of the proteins were related to hypothetical proteins which are still uncharacterized, thereby, suggesting the need for in-depth studies on cold adapted diazotrophs and their adaptive mechanisms. PMID- 28352264 TI - Indole-Induced Activities of beta-Lactamase and Efflux Pump Confer Ampicillin Resistance in Pseudomonas putida KT2440. AB - Indole, which is widespread in microbial communities, has received attention because of its effects on bacterial physiology. Pseudomonas putida and Pseudomonas aeruginosa can acquire ampicillin (Amp) resistance during growth on indole-Amp agar. Transcriptome, mutant, and inhibitor studies have suggested that Amp resistance induced by indole can be attributed to increased gene expression of ttgAB encoding two genes of RND-type multidrug efflux operons and an ampC encoding beta-lactamase. Expression, enzyme activities, and mutational analyses indicated that AmpC beta-lactamase is important for acquiring Amp resistance of P. putida in the presence of indole. Here, we show, for the first time, that volatile indole increased Amp-resistant cells. Consistent with results of the volatile indole assay, a low concentration of indole in liquid culture promoted growth initially, but led to mutagenesis after indole was depleted, which could not be observed at high indole concentrations. Interestingly, ttgAB and ampC gene expression levels correlate with the concentration of indole, which might explain the low number of Amp-mutated cells in high indole concentrations. The expression levels of genes involved in mutagenesis, namely rpoS, recA, and mutS, were also modulated by indole. Our data indicates that indole reduces Amp-induced heterogeneity by promoting expression of TtgABC or MexAB-OprM efflux pumps and the indole-induced beta-lactamase in P. putida and P. aeruginosa. PMID- 28352265 TI - The Myxobacterium Myxococcus xanthus Can Sense and Respond to the Quorum Signals Secreted by Potential Prey Organisms. AB - The myxobacterium Myxococcus xanthus is a predatory member of the soil microfauna, able to consume bacteria (Gram-negative, Gram-positive), archaea, and fungi. Many potential prey of M. xanthus communicate amongst themselves using acyl homoserine lactones (AHLs) as quorum signals. M. xanthus cannot itself produce AHLs, but could potentially benefit by responding to exogenous AHLs produced during signaling between proximal prey. Four AHLs of different side chain length were tested and all found to delay sporulation of M. xanthus vegetative cells, and to stimulate germination of myxospores, increasing the proportion of predatory vegetative cells in the population. The predatory activity and expansion rates of M. xanthus colonies were also found to be stimulated by AHLs. Thermally inactivated AHLs had no effect on M. xanthus cells, and the response to AHLs depended (non-linearly) on the length of AHL side chain, suggesting that the effect of AHLs was mediated by specific signaling within M. xanthus, rather than being a consequence of the chemical or physical properties of AHLs. Therefore, it seems that the presence of xenic quorum signaling molecules enhances the predatory activity of M. xanthus. AHLs increase the proportion of the population capable of predation, and stimulate the motility and predatory activity of vegetative cells. We therefore propose that in the wild, M. xanthus uses AHLs as markers of nearby prey, potentially eavesdropping on the conversations between prey organisms. PMID- 28352266 TI - Canonical and Cross-reactive Binding of NK Cell Inhibitory Receptors to HLA-C Allotypes Is Dictated by Peptides Bound to HLA-C. AB - BACKGROUND: Human natural killer (NK) cell activity is regulated by a family of killer cell immunoglobulin-like receptors (KIRs) that bind human leukocyte antigen (HLA) class I. Combinations of KIR and HLA genotypes are associated with disease, including susceptibility to viral infection and disorders of pregnancy. KIR2DL1 binds HLA-C alleles of group C2 (Lys80). KIR2DL2 and KIR2DL3 bind HLA-C alleles of group C1 (Asn80). However, this model cannot explain HLA-C allelic effects in disease or the impact of HLA-bound peptides. The goal of this study was to determine the extent to which the endogenous HLA-C peptide repertoire can influence the specific binding of inhibitory KIR to HLA-C allotypes. RESULTS: The impact of HLA-C bound peptide on inhibitory KIR binding was investigated taking advantage of the fact that HLA-C*05:01 (HLA-C group 2, C2) and HLA-C*08:02 (HLA-C group 1, C1) have identical sequences apart from the key KIR specificity determining epitope at residues 77 and 80. Endogenous peptides were eluted from HLA-C*05:01 and used to test the peptide dependence of KIR2DL1 and KIR2DL2/3 binding to HLA-C*05:01 and HLA-C*08:02 and subsequent impact on NK cell function. Specific binding of KIR2DL1 to the C2 allotype occurred with the majority of peptides tested. In contrast, KIR2DL2/3 binding to the C1 allotype occurred with only a subset of peptides. Cross-reactive binding of KIR2DL2/3 with the C2 allotype was restricted to even fewer peptides. Unexpectedly, two peptides promoted binding of the C2 allotype-specific KIR2DL1 to the C1 allotype. We showed that presentation of endogenous peptides or HIV Gag peptides by HLA-C can promote KIR cross-reactive binding. CONCLUSION: KIR2DL2/3 binding to C1 is more peptide selective than that of KIR2DL1 binding to C2, providing an explanation for KIR2DL3-C1 interactions appearing weaker than KIR2DL1-C2. In addition, cross reactive binding of KIR is characterized by even higher peptide selectivity. We demonstrate a hierarchy of functional peptide selectivity of KIR-HLA-C interactions with relevance to NK cell biology and human disease associations. This selective peptide sequence-driven binding of KIR provides a potential mechanism for pathogen as well as self-peptide to modulate NK cell activation through altering levels of inhibition. PMID- 28352267 TI - Anopheles stephensi Heme Peroxidase HPX15 Suppresses Midgut Immunity to Support Plasmodium Development. AB - The heme peroxidase HPX15 is an evolutionary conserved anopheline lineage specific gene. Previously, we found that this gene is present in the genome of 19 worldwide distributed different species of Anopheles mosquito and its orthologs are absent in other mosquitoes, insects, or human. In addition, 65-99% amino acid identity among these 19 orthologs permitted us to hypothesize that the functional aspects of this gene might be also conserved in different anophelines. In this study, we found that Anopheles stephensi AsHPX15 gene is mainly expressed in the midgut and highly induced after uninfected or Plasmodium berghei-infected blood feeding. RNA interference-mediated silencing of midgut AsHPX15 gene drastically reduced the number of developing P. berghei oocysts. An antiplasmodial gene nitric oxide synthase was induced 13-fold in silenced midguts when compared to the unsilenced controls. Interestingly, the induction of antiplasmodial immunity in AsHPX15-silenced midguts is in absolute agreement with Anopheles gambiae. In A. gambiae, AgHPX15 catalyzes the formation of a dityrosine network at luminal side of the midgut that suppresses the activation of mosquito immunity against the bolus bacteria. Thus, a low-immunity zone created by this mechanism indirectly supports Plasmodium development inside the midgut lumen. These indistinguishable functional behaviors and conserved homology indicates that HPX15 might be a potent target to manipulate the antiplasmodial immunity of the anopheline midgut, and it will open new frontiers in the field of malaria control. PMID- 28352268 TI - Type I and III Interferon in the Gut: Tight Balance between Host Protection and Immunopathology. AB - The intestinal mucosa forms an active interface to the outside word, facilitating nutrient and water uptake and at the same time acts as a barrier toward the highly colonized intestinal lumen. A tight balance of the mucosal immune system is essential to tolerate harmless antigens derived from food or commensals and to effectively defend against potentially dangerous pathogens. Interferons (IFN) provide a first line of host defense when cells detect an invading organism. Whereas type I IFN were discovered almost 60 years ago, type III IFN were only identified in the early 2000s. It was initially thought that type I IFN and type III IFN performed largely redundant functions. However, it is becoming increasingly clear that type III IFN exert distinct and non-redundant functions compared to type I IFN, especially in mucosal tissues. Here, we review recent progress made in unraveling the role of type I/III IFN in intestinal mucosal tissue in the steady state, in response to mucosal pathogens and during inflammation. PMID- 28352269 TI - Monomeric Immunoglobulin A from Plasma Inhibits Human Th17 Responses In Vitro Independent of FcalphaRI and DC-SIGN. AB - Circulating immunoglobulins including immunoglobulin G (IgG) and IgM play a critical role in the immune homeostasis by modulating functions of immune cells. These functions are mediated in part by natural antibodies. However, despite being second most abundant antibody in the circulation, the immunoregulatory function of IgA is relatively unexplored. As Th17 cells are the key mediators of a variety of autoimmune, inflammatory, and allergic diseases, we investigated the ability of monomeric IgA (mIgA) isolated from pooled plasma of healthy donors to modulate human Th17 cells. We show that mIgA inhibits differentiation and amplification of human Th17 cells and the production of their effector cytokine IL-17A. mIgA also suppresses IFN-gamma responses under these experimental conditions. Suppressive effect of mIgA on Th17 responses is associated with reciprocal expansion of FoxP3-positive regulatory T cells. The effect of mIgA on Th17 cells is dependent on F(ab')2 fragments and independent of FcalphaRI (CD89) and DC-SIGN. Mechanistically, the modulatory effect of mIgA on Th17 cells implicates suppression of phosphorylation of signal transducer and activator of transcription 3. Furthermore, mIgA binds to CD4+ T cells and recognizes in a dose dependent manner the receptors for cytokines (IL-6Ralpha and IL-1RI) that mediate Th17 responses. Our findings thus reveal novel anti-inflammatory functions of IgA and suggest potential therapeutic utility of mIgA in autoimmune and inflammatory diseases that implicate Th17 cells. PMID- 28352270 TI - The Immune Epitope Database and Analysis Resource in Epitope Discovery and Synthetic Vaccine Design. AB - The task of epitope discovery and vaccine design is increasingly reliant on bioinformatics analytic tools and access to depositories of curated data relevant to immune reactions and specific pathogens. The Immune Epitope Database and Analysis Resource (IEDB) was indeed created to assist biomedical researchers in the development of new vaccines, diagnostics, and therapeutics. The Analysis Resource is freely available to all researchers and provides access to a variety of epitope analysis and prediction tools. The tools include validated and benchmarked methods to predict MHC class I and class II binding. The predictions from these tools can be combined with tools predicting antigen processing, TCR recognition, and B cell epitope prediction. In addition, the resource contains a variety of secondary analysis tools that allow the researcher to calculate epitope conservation, population coverage, and other relevant analytic variables. The researcher involved in vaccine design and epitope discovery will also be interested in accessing experimental published data, relevant to the specific indication of interest. The database component of the IEDB contains a vast amount of experimentally derived epitope data that can be queried through a flexible user interface. The IEDB is linked to other pathogen-specific and immunological database resources. PMID- 28352271 TI - Sphingosine 1-Phosphate: A Novel Target for Lung Disorders. AB - Sphingosine 1-phosphate (S1P) is involved in a wide range of cellular processes, which include proliferation, apoptosis, lymphocyte egress, endothelial barrier function, angiogenesis, and inflammation. S1P is produced by two isoenzymes, namely, sphingosine kinase 1 and 2 (SphK1 and 2) and once produced, S1P can act both in an autocrine and paracrine manner. S1P can be dephosphorylated back to sphingosine by two phosphatases (SGPP 1 and 2) or can be irreversibly cleaved by S1P lyase. S1P has a diverse range of functions, which is mediated in a receptor dependent, through G-protein coupled receptors (S1PR1-5) or receptor independent manner, through intracellular targets such as HDACs and TRAF2. The involvement of S1P signaling has been confirmed in various disease conditions including lung diseases. The SphK inhibitors and S1PR modulators are currently under clinical trials for different pathophysiological conditions. There is a significant effort in targeting various components of S1P signaling for several diseases. This review focuses on the ways in which S1P signaling can be therapeutically targeted in lung disorders. PMID- 28352273 TI - Biofortification of Wheat Cultivars to Combat Zinc Deficiency. AB - Zinc (Zn) deficiency caused by inadequate dietary intake is a global nutritional problem, particularly in developing countries. Therefore, zinc biofortification of wheat and other cereal crops is being urgently addressed and highly prioritized as a research topic. A field study was planned to evaluate the influence of zinc application on grain yield, grain zinc content, and grain phytic acid concentrations of wheat cultivars, and the relationships between these parameters. Three wheat cultivars, C1 = Faisalabad-2008, C2 = Punjab-2011, and C3 = Millet-2011 were tested with five different methods of zinc application: T1 = control, T2 = seed priming, T3 = soil application, T4 = foliar application, and T5 = soil + foliar application. It was found that grain yield and grain zinc were positively correlated, whereas, grain phytic acid and grain zinc were significantly negatively correlated. Results also revealed that T5, T3, and T4 considerably increased grain yield; however, T2 only slightly enhanced grain yield. Grain zinc concentration increased from 33.1 and 33.7 mg kg-1 in T1 to 62.3 and 63.1 mg kg-1 in T5 in 2013-2014 and 2014-2015, respectively. In particular, T5 markedly decreased grain phytic acid content; however, maximum concentration was recorded in T1. Moreover, all the tested cultivars exhibited considerable variation in grain yield, grain zinc, and grain phytic acid content. In conclusion, T5 was found to be most suitable for both optimum grain yield and grain biofortification of wheat. PMID- 28352272 TI - Solar Radiation-Associated Adaptive SNP Genetic Differentiation in Wild Emmer Wheat, Triticum dicoccoides. AB - Whole-genome scans with large number of genetic markers provide the opportunity to investigate local adaptation in natural populations and identify candidate genes under positive selection. In the present study, adaptation genetic differentiation associated with solar radiation was investigated using 695 polymorphic SNP markers in wild emmer wheat originated in a micro-site at Yehudiyya, Israel. The test involved two solar radiation niches: (1) sun, in between trees; and (2) shade, under tree canopy, separated apart by a distance of 2-4 m. Analysis of molecular variance showed a small (0.53%) but significant portion of overall variation between the sun and shade micro-niches, indicating a non-ignorable genetic differentiation between sun and shade habitats. Fifty SNP markers showed a medium (0.05 <= FST <= 0.15) or high genetic differentiation (FST > 0.15). A total of 21 outlier loci under positive selection were identified by using four different FST -outlier testing algorithms. The markers and genome locations under positive selection are consistent with the known patterns of selection. These results suggested that genetic differentiation between sun and shade habitats is substantial, radiation-associated, and therefore ecologically determined. Hence, the results of this study reflected effects of natural selection through solar radiation on EST-related SNP genetic diversity, resulting presumably in different adaptive complexes at a micro-scale divergence. The present work highlights the evolutionary theory and application significance of solar radiation-driven natural selection in wheat improvement. PMID- 28352275 TI - Influence of Harvest Aid Herbicides on Seed Germination, Seedling Vigor and Milling Quality Traits of Red Lentil (Lens culinaris L.). AB - Most red lentil produced worldwide is consumed in dehulled form, and post-harvest milling and splitting qualities are major concerns in the secondary processing industry. Lentil producers in northern temperate regions usually apply pre harvest desiccants as harvest aids to accelerate the lentil crop drying process and facilitate harvesting operations. This paper reports on field studies conducted at Scott and Saskatoon, Saskatchewan, Canada in the 2012 and 2013 cropping seasons to evaluate whether herbicides applied as harvest aids alone or tank mixed with glyphosate affect seed germination, seedling vigor, milling, and splitting qualities. The site-year by desiccant treatment interaction for seed germination, vigor, and milling recovery yields was significant. Glyphosate applied alone or as tank mix with other herbicides (except diquat) reduced seed germination and seedling vigor at Saskatoon and Scott in 2012 only. Pyraflufen ethyl (20 g ai ha-1) applied with glyphosate as well as saflufenacil (36 g ai ha 1) decreased dehulling efficiency, while saflufenacil and/or glufosinate with glyphosate reduced milling recovery and football recovery, although these effects were inconsistent. Application of diquat alone or in combination with glyphosate exhibited more consistent dehulling efficiency gains and increases in milling recovery yield. Significant but negative associations were observed between glyphosate residue in seeds and seed germination (r = -0.84, p < 0.001), seed vigor (r = -0.62, p < 0.001), dehulling efficiency (r = -0.55, p < 0.001), and milling recovery (r = -0.62, p < 0.001). These results indicate application of diquat alone or in combination with glyphosate may be a preferred option for lentil growers to improve milling recovery yield. PMID- 28352274 TI - Spatial Variation of Leaf Optical Properties in a Boreal Forest Is Influenced by Species and Light Environment. AB - Leaf Optical Properties (LOPs) convey information relating to temporally dynamic photosynthetic activity and biochemistry. LOPs are also sensitive to variability in anatomically related traits such as Specific Leaf Area (SLA), via the interplay of intra-leaf light scattering and absorption processes. Therefore, variability in such traits, which may demonstrate little plasticity over time, potentially disrupts remote sensing estimates of photosynthesis or biochemistry across space. To help to disentangle the various factors that contribute to the variability of LOPs, we defined baseline variation as variation in LOPs that occurs across space, but not time. Next we hypothesized that there were two main controls of potentially disruptive baseline spatial variability of photosynthetically-related LOPs at our boreal forest site: light environment and species. We measured photosynthetically-related LOPs in conjunction with morphological, biochemical, and photosynthetic leaf traits during summer and across selected boreal tree species and vertical gradients in light environment. We then conducted a detailed correlation analysis to disentangle the spatial factors that control baseline variability of leaf traits and, resultantly, LOPs. Baseline spatial variability of the Photochemical Reflectance Index (PRI) was strongly influenced by species and to a lesser extent light environment. Baseline variability of spectral fluorescence derived LOPs was less influenced by species; however at longer near-infrared wavelengths, light environment was an important control. In summary, remote sensing of chlorophyll fluorescence has good potential to detect variation in photosynthetic performance across space in boreal forests given reduced sensitivity to species related baseline variability in comparison to the PRI. Our results also imply that spatially coarse remote sensing observations are potentially unrepresentative of the full scope of natural variation that occurs within a boreal forest. PMID- 28352276 TI - Transcriptome Changes Associated with Boron Deficiency in Leaves of Two Citrus Scion-Rootstock Combinations. AB - Boron (B) deficiency stress is frequently observed in citrus orchards and causes considerable loss of productivity and fruit quality. Carrizo citrange (Cc) has been reported as a rootstock more tolerant to B deficiency than Trifoliate orange (To). The 'Newhall' navel orange (Ns) performed better when grafted onto Cc (Ns/Cc) than when grafted onto To (Ns/To) under long-term B deficiency. The present study confirmed that Ns/Cc had higher boron content, leaf fresh weight, lower leaf chlorosis and stronger photosynthesis ability than Ns/To. Moreover, B deficiency significantly reduced the chlorophyll and carotenoid content in Ns/To. The content of total soluble sugar and lignin were dramatically increased and the expression levels of photosynthesis-related genes were substantially down regulated in Ns/To by B-deficient treatment. B-deficiency also strongly induced expression levels of chlorophyll decomposition-related genes, glucose synthesis related genes and lignin synthesis-related genes, and significantly inhibited the expression of carotenoid synthesis-related genes in Ns/To. Overall, these findings suggested that the influence of To on the scion of Ns was worse than that of Cc due to differently regulating these metabolic pathways under the long term of B-deficiency. The transcriptome analysis provided further information for understanding the mechanism of the different responses of scion-rootstock combinations to B-deficiency stress. PMID- 28352277 TI - Editorial: Charophytes: Evolutionary Ancestors of Plants and Emerging Models for Plant Research. PMID- 28352278 TI - Linking Changes to Intraspecific Trait Diversity to Community Functional Diversity and Biomass in Response to Snow and Nitrogen Addition Within an Inner Mongolian Grassland. AB - In recent years, both the intraspecific and interspecific functional diversity (FD) of plant communities have been studied with new approaches to improve an understanding about the mechanisms underlying plant species coexistence. Yet, little is known about how global change drivers will impact intraspecific FD and trait overlap among species, and in particular how this may scale to impacts on community level FD and ecosystem functioning. To address this uncertainty, we assessed the direct and indirect responses of specific leaf area (SLA) among both dominant annual and subordinate perennial species to the independent and interactive effects of nitrogen and snow addition within the Inner Mongnolian steppe. More specifically, we investigated the consequences for these responses on plant community FD, trait overlap and biomass. Nitrogen addition increased the biomass of the dominant annual species and as a result increased total community biomass. This occurred despite concurrent decreases in the biomass of subordinate perennial species. Nitrogen addition also increased intraspecific FD and trait overlap of both annual species and perennial species, and consequently increased the degree of trait overlap in SLA at the community level. However, snow addition did not significantly impact intraspecific FD and trait overlap of SLA for perennial species, but increased intraspecific FD and trait overlap of annual species, of which scaled to changes in community level FD. We found that the responses of the dominant annual species to nitrogen and snow additions were generally more sensitive than the subordinate perennial species within the inner Mongolian grassland communities of our study. As a consequence of this sensitivity, the responses of the dominant species largely drove impacts to community FD, trait overlap and community biomass. In total, our study demonstrates that the responses of dominant species in a community to environmental change may drive the initial trajectories of change to community FD and functioning. PMID- 28352279 TI - Development of a Double Nuclear Gene-Targeting Method by Two-Step Transformation Based on a Newly Established Chloramphenicol-Selection System in the Red Alga Cyanidioschyzon merolae. AB - The unicellular red alga Cyanidioschyzon merolae possesses a simple cellular architecture that consists of one mitochondrion, one chloroplast, one peroxisome, one Golgi apparatus, and several lysosomes. The nuclear genome content is also simple, with very little genetic redundancy (16.5 Mbp, 4,775 genes). In addition, molecular genetic tools such as gene targeting and inducible gene expression systems have been recently developed. These cytological features and genetic tractability have facilitated various omics analyses. However, only a single transformation selection marker URA has been made available and thus the application of genetic modification has been limited. Here, we report the development of a nuclear targeting method by using chloramphenicol and the chloramphenicol acetyltransferase (CAT) gene. In addition, we found that at least 200-bp homologous arms are required and 500-bp arms are sufficient for a targeted single-copy insertion of the CAT selection marker into the nuclear genome. By means of a combination of the URA and CAT transformation systems, we succeeded in producing a C. merolae strain that expresses HA-cyclin 1 and FLAG-CDKA from the chromosomal CYC1 and CDKA loci, respectively. These methods of multiple nuclear targeting will facilitate genetic manipulation of C. merolae. PMID- 28352281 TI - Vitamin D Deficiency and Its Determinants in Adults: A Sample from Community Based Settings in the United Arab Emirates. AB - Background. Vitamin D deficiency (VDD) is a public health concern in adults worldwide. This study aims to explore the extent of VDD and its associated factors among adults in the United Arab Emirates (UAE). Subjects and Methods. Quantitative, cross-sectional research was used to assess VDD and its associated factors in 216 adults recruited from randomly selected community-based healthcare settings over a six-month period. Recent values of vitamin D and glycated hemoglobin (HbA1c) were abstracted from medical records, followed by interviews with participants to obtain information on factors related to VDD and other covariates and to measure their heights and weights. Results. A total of 74% of participants demonstrated VDD (vitamin D serum level <= 30 nmol/L). Emirati participants had higher odds of having VDD compared to non-Emiratis (OR: 2.95; 95% CI: 1.58-5.52), with also significantly increased odds of the condition appearing in older, less educated, and employed adults. Diabetes type 2 (HbA1c >= 6.5%), depression, and obesity were significantly associated with an increased likelihood of VDD after accounting for other covariates. Conclusion. VDD is a significant problem for UAE adults and requires attention by public health policy makers. Diabetes, obesity, and depression need to be considered when screening for vitamin D. PMID- 28352280 TI - An Insight into microRNA156 Role in Salinity Stress Responses of Alfalfa. AB - Salinity is one of the major abiotic stresses affecting alfalfa productivity. Developing salinity tolerant alfalfa genotypes could contribute to sustainable crop production. The functions of microRNA156 (miR156) have been investigated in several plant species, but so far, no studies have been published that explore the role of miR156 in alfalfa response to salinity stress. In this work, we studied the role of miR156 in modulating commercially important traits of alfalfa under salinity stress. Our results revealed that overexpression of miR156 increased biomass, number of branches and time to complete growth stages, while it reduced plant height under control and salinity stress conditions. We observed a miR156-related reduction in neutral detergent fiber under non-stress, and acid detergent fiber under mild salinity stress conditions. In addition, enhanced total Kjeldahl nitrogen content was recorded in miR156 overexpressing genotypes under severe salinity stress. Furthermore, alfalfa genotypes overexpressing miR156 exhibited an altered ion homeostasis under salinity conditions. Under severe salinity stress, miR156 downregulated SPL transcription factor family genes, modified expression of other important transcription factors, and downstream salt stress responsive genes. Taken together, our results reveal that miR156 plays a role in mediating physiological and transcriptional responses of alfalfa to salinity stress. PMID- 28352282 TI - Poor Sleep Quality Is Associated with Dawn Phenomenon and Impaired Circadian Clock Gene Expression in Subjects with Type 2 Diabetes Mellitus. AB - Aims. We investigated whether poor sleep quality is associated with both dawn phenomenon and impaired circadian clock gene expression in subjects with diabetes. Methods. 81 subjects with diabetes on continuous glucose monitoring were divided into two groups according to the Pittsburgh Sleep Quality Index. The magnitude of dawn phenomenon was quantified by its increment from nocturnal nadir to prebreakfast. Peripheral leucocytes were sampled from 81 subjects with diabetes and 28 normal controls at 09:00. Transcript levels of circadian clock genes (BMAL1, PER1, PER2, and PER3) were determined by real-time quantitative polymerase chain reaction. Results. The levels of HbA1c and fasting glucose and the magnitude of dawn phenomenon were significantly higher in the diabetes group with poor sleep quality than that with good sleep quality. Peripheral leucocytes from subjects with poor sleep quality expressed significantly lower transcript levels of BMAL1 and PER1 compared with those with good sleep quality. Poor sleep quality was significantly correlated with magnitude of dawn phenomenon. Multiple linear regression showed that sleep quality and PER1 were significantly independently correlated with dawn phenomenon. Conclusions. Dawn phenomenon is associated with sleep quality. Furthermore, mRNA expression of circadian clock genes is dampened in peripheral leucocytes of subjects with poor sleep quality. PMID- 28352284 TI - Radiographic Findings in Patients with Medication-Related Osteonecrosis of the Jaw. AB - A retrospective study was conducted of the records and panoramic radiographs of 35 patients treated with bisphosphonates (BP) and diagnosed with MRONJ. Panoramic radiography was used for evaluation, by two examiners, the following findings were subject of search: osteolysis (OT), cortical bone erosion (EC), bone sclerosis focal (FS) and diffuse (DS), bone sequestration (BS), thickening of lamina dura (TD), prominence of the inferior alveolar nerve canal (IAN), persisting alveolar sockets (SK), and the presence of a pathological fracture (PF). Medical information and staging were also recorded in order to correlate with radiographic findings. Bone sclerosis was the most frequent alteration, followed by OT and TD. The mandible was more affected than the maxilla. There was no significant difference between genders or significant correlation between the number of injuries with age and duration of BP usage. Considering the association between the radiographic findings and MRONJ staging, EC was predominant in stage 3 and DS in stage 2. IAN and PF demonstrated greater association with stage 3. In conclusion, the higher the clinical staging, the greater the severity of the bone alteration. Panoramic radiographic examination is a useful screening tool in patients submitted to antiresorptive therapy. PMID- 28352283 TI - Serum ZAG Levels Were Associated with eGFR Mild Decrease in T2DM Patients with Diabetic Nephropathy. AB - Objective. To investigate the changes of serum zinc-alpha2-glycoprotein (ZAG) in type 2 diabetes mellitus (T2DM) with eGFR mild decrease. Subjects and Methods. A total of 438 T2DM patients (61.3 +/- 4.0 y) were recruited and the demographic, anthropometric, and biochemical parameters were all collected. Serum ZAG levels were determined by commercially available ELISA kits. Results. The proportion of T2DM patients with the high tertile ZAG levels was 11.9% higher in patients with mildly decreased estimated glomerular filtration rate (eGFR) (<90 mL/min/1.73 m2) than those with the low tertile ZAG levels (P = 0.038). The probability of the eGFR < 90 mL/min/1.73 m2 in patients with the high ZAG levels was 94% higher than those with the low serum ZAG levels after adjusting for age, gender, and education [OR = 1.94, 95% CI (1.17-3.23), P = 0.0094]. This phenomenon was more likely to be observed in the condition of uACR >= 2.7 mg/mmol, WC >= 90 cm for men, or WC >= 85 cm for women. Conclusion. Serum ZAG levels were firstly found to be related with eGFR in T2DM patients. The patients with the high tertile ZAG levels were more likely to have mildly eGFR decrease, especially for female patients with higher uACR and bigger WC. PMID- 28352285 TI - Effect of Herbal and Fluoride Mouth Rinses on Streptococcus mutans and Dental Caries among 12-15-Year-Old School Children: A Randomized Controlled Trial. AB - To assess and compare the effect of herbal and fluoride mouth rinses on Streptococcus mutans count and glucan synthesis by Streptococcus mutans and dental caries, a parallel group placebo controlled randomized trial was conducted among 240 schoolchildren (12-15 years old). Participants were randomly divided and allocated into Group I (0.2% fluoride group), Group II (herbal group), and Group III (placebo group). All received 10 ml of respective mouth rinses every fortnight for a period of one year. Intergroup and intragroup comparison were done for Streptococcus mutans count and glucan synthesis by Streptococcus mutans and dental caries. Streptococcus mutans count showed a statistically significant difference between Group I and Group III (p = 0.035) and also between Group II and Group III (p = 0.039). Glucan concentration levels showed a statistically significant difference (p = 0.024) between Group II and Group III at 12th month. Mean DMF scores showed no statistical difference between the three groups (p = 0.139). No difference in the level of significance was seen in the intention-to treat and per-protocol analysis. The present study showed that both herbal and fluoride mouth rinses, when used fortnightly, were equally effective and could be recommended for use in school-based health education program to control dental caries. Trial registration number is CTRI/2015/08/006070. PMID- 28352286 TI - An Approach to Developing Local Climate Change Environmental Public Health Indicators in a Rural District. AB - Climate change represents a significant and growing threat to population health. Rural areas face unique challenges, such as high rates of vulnerable populations; economic uncertainty due to their reliance on industries that are vulnerable to climate change; less resilient infrastructure; and lower levels of access to community and emergency services than urban areas. This article fills a gap in public health practice by developing climate and health environmental public health indicators for a local public health department in a rural area. We adapted the National Environmental Public Health Tracking Network's framework for climate and health indicators to a seven-county health department in Western Kentucky. Using a three-step review process, we identified primary climate related environmental public health hazards for the region (extreme heat, drought, and flooding) and a suite of related exposure, health outcome, population vulnerability, and environmental vulnerability indicators. Indicators that performed more poorly at the county level than at the state and national level were defined as "high vulnerability." Six to eight high vulnerability indicators were identified for each county. The local health department plans to use the results to enhance three key areas of existing services: epidemiology, public health preparedness, and community health assessment. PMID- 28352287 TI - Long-Term Body Weight Maintenance among StrongWomen-Healthy Hearts Program Participants. AB - Background. The repeated loss and regain of body weight, referred to as weight cycling, may be associated with negative health complications. Given today's obesity epidemic and related interventions to address obesity, it is increasingly important to understand contexts and factors associated with weight loss maintenance. This study examined BMI among individuals who had previously participated in a 12-week, evidence-based, nationally disseminated nutrition and physical activity program designed for overweight and obese middle-aged and older women. Methods. Data were collected using follow-up surveys. Complete height and weight data were available for baseline, 12-week program completion (post program) and follow-up (approximately 3 years later) for 154 women (response rate = 27.5%; BMI characteristics did not differ between responders and nonresponders). Results. Mean BMI decreased significantly from baseline to post program (-0.5, P < 0.001) and post-program to follow-up (-0.7, P < 0.001). Seventy-five percent of survey respondents maintained or decreased BMI post program to follow-up. Self-efficacy and social support for healthy eating behaviors (but not physical activity) were associated with BMI maintenance or additional weight loss. Conclusions. These findings support the durability of weight loss following participation in a relatively short-term intervention. PMID- 28352289 TI - Prevention of krait bites by sleeping above ground: preliminary results from an observational pilot study. AB - INTRODUCTION: Neurotoxic envenoming following the bites of kraits (Bungarus spp.) is a common cause of death in the dry zone of Sri Lanka and elsewhere in South Asia. Most of these bites occur at night and are inflicted on people sleeping on the ground. Thus we hypothesized that the simple measure of sleeping above ground would help to reduce the number of observed krait bites. METHODS: This study was conducted in two villages of the Kilinochchi district of Sri Lanka which had reported a high number of krait bites in the two years preceding the study. Most of the residents in these two villages slept on the ground. Residents in one area were given beds free of charge, using funds available from the study. Both villages received health education on the prevention of krait bites. RESULTS: Forty five beds were distributed to 45 families in one village. This enabled 115 individuals to sleep above ground level. 6 monthly follow up visits were conducted ensuring the proper utilization of beds. Follow up was continued for 30 months (September 2013-March 2016); during this time period no krait bites were reported in either area. CONCLUSIONS: We observed a dramatic decline of krait bites in both villages. Better awareness with effective health education and clearing of vegetation could have led to the decline in the number of krait bites in both villages. PMID- 28352288 TI - Effect of low-level CO2 on innate inflammatory protein response to organic dust from swine confinement barns. AB - BACKGROUND: Organic hog barn dust (HDE) exposure induces lung inflammation and long-term decreases in lung function in agricultural workers. While concentrations of common gasses in confined animal facilities are well characterized, few studies have been done addressing if exposure to elevated barn gasses impacts the lung immune response to organic dusts. Given the well documented effects of hypercapnia at much higher levels we hypothesized that CO2 at 8 h exposure limit levels (5000 ppm) could alter innate immune responses to HDE. METHODS: Using a mouse model, C57BL/6 mice were nasally instilled with defined barn dust extracts and then housed in an exposure box maintained at one of several CO2 levels for six hours. Bronchiolar lavage (BAL) was tested for several cytokines while lung tissue was saved for mRNA purification and immunohistochemistry. RESULTS: Exposure to elevated CO2 significantly increased the expression of pro-inflammatory markers, IL-6 and KC, in BAL fluid as compared to dust exposure alone. Expression of other pro-inflammatory markers, such as ICAM-1 and matrix metalloproteinase-9 (MMP-9), were also tested and showed similar increased expression upon HDE + CO2 exposure. A chemokine array analysis of BAL fluid revealed that MIP-1gamma (CCL9) shows a similar increased response to HDE + CO2. Further testing showed CCL9 was significantly elevated by barn dust and further enhanced by CO2 co-exposure in a dose-dependent manner that was noticeable at the protein and mRNA levels. In all cases, except for ICAM-1, increases in tested markers in the presence of elevated CO2 were only significant in the presence of HDE as well. CONCLUSIONS: We show that even at mandated safe exposure limits, CO2 is capable of enhancing multiple markers of inflammation in response to HDE. PMID- 28352290 TI - Topological Measurements of DWI Tractography for Alzheimer's Disease Detection. AB - Neurodegenerative diseases affect brain morphology and connectivity, making complex networks a suitable tool to investigate and model their effects. Because of its stereotyped pattern Alzheimer's disease (AD) is a natural benchmark for the study of novel methodologies. Several studies have investigated the network centrality and segregation changes induced by AD, especially with a single subject approach. In this work, a holistic perspective based on the application of multiplex network concepts is introduced. We define and assess a diagnostic score to characterize the brain topology and measure the disease effects on a mixed cohort of 52 normal controls (NC) and 47 AD patients, from Alzheimer's Disease Neuroimaging Initiative (ADNI). The proposed topological score allows an accurate NC-AD classification: the average area under the curve (AUC) is 95% and the 95% confidence interval is 92%-99%. Besides, the combination of topological information and structural measures, such as the hippocampal volumes, was also investigated. Topology is able to capture the disease signature of AD and, as the methodology is general, it can find interesting applications to enhance our insight into disease with more heterogeneous patterns. PMID- 28352291 TI - Ethical considerations for children's participation in data collection activities during humanitarian emergencies: A Delphi review. AB - BACKGROUND: Children's right to participate in data collection during emergencies has been widely recognized by humanitarian actors. However, participation in such activities can expose children to risk. Tensions have been noted between the right to participate and other principles, such as the imperative to 'do no harm.' With little evidence to inform guidance on addressing this tension, our study sought to identify expert consensus on whether and how children participate in emergency-related data collection activities. METHODS: We employed a three round Delphi technique with a purposive sample of 52 child protection specialists. Respondents answered two open-ended questions in round one. A thematic analysis of responses generated a set of unique statements addressing the study questions. In the second round, respondents rated each statement on a five-point scale. In the final round, respondents reviewed the group's average ratings for each statement with the option to revise their own ratings. A statement was said to have reached clear consensus when at least 90% of respondents agreed or strongly agreed with the statement. RESULTS: A total of 124 statements and 14 themes emerged from the thematic analysis, with 46.0% of statements reaching clear consensus in the third round. Respondents strongly supported children's right to participate in data collection in humanitarian settings, while also recognizing that protecting children from harm may "over ride" the participation principle in some contexts. Respondents identified capacity and contextual considerations as important factors influencing participation decisions, though they sometimes disagreed about how these factors should determine participation. Respondents also considered the role of individual child factors and the presence of caregivers in selecting child participants, and proposed best practice approaches for securing children's safe and meaningful participation. CONCLUSIONS: With almost half of statements reaching clear consensus, these findings reflect broad agreement within the sector about engaging children in data collection in emergencies. At the same time, points of ongoing debate around how to factor different risks into child participation decisions may indicate discordant practice. Further reflection is needed around how factors such as the phase of emergency, the existence of basic services, and cultural beliefs should influence whether and how children participate. PMID- 28352292 TI - Climate drives adaptive genetic responses associated with survival in big sagebrush (Artemisia tridentata). AB - A genecological approach was used to explore genetic variation for survival in Artemisia tridentata (big sagebrush). Artemisia tridentata is a widespread and foundational shrub species in western North America. This species has become extremely fragmented, to the detriment of dependent wildlife, and efforts to restore it are now a land management priority. Common-garden experiments were established at three sites with seedlings from 55 source-populations. Populations included each of the three predominant subspecies, and cytotype variations. Survival was monitored for 5 years to assess differences in survival between gardens and populations. We found evidence of adaptive genetic variation for survival. Survival within gardens differed by source-population and a substantial proportion of this variation was explained by seed climate of origin. Plants from areas with the coldest winters had the highest levels of survival, while populations from warmer and drier sites had the lowest levels of survival. Survival was lowest, 36%, in the garden that was prone to the lowest minimum temperatures. These results suggest the importance of climatic driven genetic differences and their effect on survival. Understanding how genetic variation is arrayed across the landscape, and its association with climate can greatly enhance the success of restoration and conservation. PMID- 28352294 TI - Population-specific genotype x genotype x environment interactions in bacterial disease of early life stages of Pacific oyster larvae. AB - The consequences of emerging marine diseases on the evolutionary trajectories of affected host populations in the marine realm are largely unexplored. Evolution in response to natural selection depends on the genetic variation of the traits under selection and the interaction of these traits with the environment (GxE). However, in the case of diseases, pathogen genotypes add another dimension to this interaction. Therefore, the study of disease resistance needs to be extended to the interaction of host genotype, pathogen genotype and environment (GxGxE). In this study, we used a full-sib breeding design crossing two genetically differentiated populations of the Pacific oyster Crassostrea gigas (Thunberg, 1793), to determine the influence of host genotype, pathogen genotype and temperature on disease resistance. Based on a controlled infection experiment on two early life stages, that is, D-larvae and Pediveliger larvae at elevated and ambient water temperatures, we estimated disease resistance to allopatric and sympatric Vibrio sp. by measuring survival and growth within and between genetically differentiated oyster populations. In both populations, survival was higher upon infection with sympatric Vibrio sp., indicating that disease resistance has a genetic basis and is dependent on host genotype. In addition, we observed a significant GxGxE effect in D-larvae, where contrary to expectations, disease resistance was higher at warm than at cold temperatures. Using thermal reaction norms, we could further show that disease resistance is an environment dependent trait with high plasticity, which indicates the potential for a fast acclimatization to changing environmental conditions. These population-specific reaction norms disappeared in hybrid crosses between both populations which demonstrates that admixture between genetically differentiated populations can influence GxGxE interactions on larger scales. PMID- 28352293 TI - Using fine-scale spatial genetics of Norway rats to improve control efforts and reduce leptospirosis risk in urban slum environments. AB - The Norway rat (Rattus norvegicus) is a key pest species globally and responsible for seasonal outbreaks of the zoonotic bacterial disease leptospirosis in the tropics. The city of Salvador, Brazil, has seen recent and dramatic increases in human population residing in slums, where conditions foster high rat density and increasing leptospirosis infection rates. Intervention campaigns have been used to drastically reduce rat numbers. In planning these interventions, it is important to define the eradication units - the spatial scale at which rats constitute continuous populations and from where rats are likely recolonizing, post-intervention. To provide this information, we applied spatial genetic analyses to 706 rats collected across Salvador and genotyped at 16 microsatellite loci. We performed spatially explicit analyses and estimated migration levels to identify distinct genetic units and landscape features associated with genetic divergence at different spatial scales, ranging from valleys within a slum community to city-wide analyses. Clear genetic breaks exist between rats not only across Salvador but also between valleys of slums separated by <100 m-well within the dispersal capacity of rats. The genetic data indicate that valleys may be considered separate units and identified high-traffic roads as strong impediments to rat movement. Migration data suggest that most (71-90%) movement is contained within valleys, with no clear source population contributing to migrant rats. We use these data to recommend eradication units and discuss the importance of carrying out individual-based analyses at different spatial scales in urban landscapes. PMID- 28352295 TI - Keeping things local: Subpopulation Nb and Ne in a stream network with partial barriers to fish migration. AB - For organisms with overlapping generations that occur in metapopulations, uncertainty remains regarding the spatiotemporal scale of inference of estimates of the effective number of breeders (N^b) and whether these estimates can be used to predict generational Ne. We conducted a series of tests of the spatiotemporal scale of inference of estimates of Nb in nine consecutive cohorts within a long term study of brook trout (Salvelinus fontinalis). We also tested a recently developed approach to estimate generational Ne from N^b and compared this to an alternative approach for estimating N^e that also accounts for age structure. Multiple lines of evidence were consistent with N^b corresponding to the local (subpopulation) spatial scale and the cohort-specific temporal scale. We found that at least four consecutive cohort-specific estimates of N^b were necessary to obtain reliable estimates of harmonic mean N^b for a subpopulation. Generational N^e derived from cohort-specific N^b was within 7%-50% of an alternative approach to obtain N^e, suggesting some population specificity for concordance between approaches. Our results regarding the spatiotemporal scale of inference for Nb should apply broadly to many taxa that exhibit overlapping generations and metapopulation structure and point to promising avenues for using cohort-specific N^b for local-scale genetic monitoring. PMID- 28352296 TI - Hidden diversity and phylogeographic history provide conservation insights for the edible seaweed Sargassum fusiforme in the Northwest Pacific. AB - Understanding the evolutionary processes that have created diversity and the genetic potential of species to adapt to environmental change is an important premise for biodiversity conservation. Herein, we used mitochondrial trnW-L and cox3 and plastid rbcL-S data sets to analyze population genetic variation and phylogeographic history of the brown alga Sargassum fusiforme, whose natural resource has been largely exterminated in the Asia-Northwest Pacific in the past decades. Phylogenetic trees and network analysis consistently revealed three major haplotype groups (A, B, and C) in S. fusiforme, with A and B distributed in the Japan-Pacific coast. Group C consisted of three subgroups (C1, C2, and C3) which were distributed in the Sea of Japan, the Yellow-Bohai Sea, and East China Sea, respectively. Isolation-with-migration (IM a) analysis revealed that the three groups diverged approximately during the mid-Pleistocene (c. 756-1,224 ka). Extended Bayesian skyline plots (EBSP) showed that groups A and B underwent relatively long-term stable population size despite a subsequent rapid demographic expansion, while subgroups C2 and C3 underwent a sudden expansion at c. 260 ka. FST and AMOVA detected low population-level genetic variation and high degrees of divergence between groups. The cryptic diversity and phylogeographic patterns found in S. fusiforme not only are essential to understand how environmental shifts and evolutionary processes shaped diversity and distribution of coastal seaweeds but also provide additional insights for conserving and managing seaweed resources and facilitate predictions of their responses to future climate change and habitat loss. PMID- 28352297 TI - Adaptive evolution and demographic history contribute to the divergent population genetic structure of Potato virus Y between China and Japan. AB - Potato virus Y (PVY) is an important plant pathogen causing considerable economic loss to potato production. Knowledge of the population genetic structure and evolutionary biology of the pathogen, particularly at a transnational scale, is limited but vital in developing sustainable management schemes. In this study, the population genetic structure and molecular evolution of PVY were studied using 127 first protein (P1) and 137 coat protein (CP) sequences generated from isolates collected from potato in China and Japan. High genetic differentiation was found between the populations from the two countries, with higher nucleotide diversity in Japan than China in both genes and a KST value of .216 in the concatenated sequences of the two genes. Sequences from the two countries clustered together according to their geographic origin. Further analyses showed that spatial genetic structure in the PVY populations was likely caused by demographic dynamics of the pathogen and natural selection generated by habitat heterogeneity. Purifying selection was detected at the majority of polymorphic sites although some clade-specific codons were under positive selection. In past decades, PVY has undergone a population expansion in China, whereas in Japan, the population size of the pathogen has remained relatively constant. PMID- 28352298 TI - Low genetic diversity but strong population structure reflects multiple introductions of western flower thrips (Thysanoptera: Thripidae) into China followed by human-mediated spread. AB - Historical invasion scenarios based on observational records are usually incomplete and biased, but these can be supplemented by population genetic data. The western flower thrips (WFT), Frankliniella occidentalis, invaded China in the last 13 years and has rapidly become one of the most serious pests in the country. To assess whether this invasion involved a single event or multiple events, we examined patterns of genetic diversity and population structure of WFT across 12 Chinese populations and a native US population based on mitochondrial DNA and/or 18 microsatellite loci. The average allelic richness and haplotype diversity in Chinese populations were significantly lower than in a population from its native range. The distribution of mitochondrial haplotypes suggested multiple independent invasions of WFT into China, including two invasions into the Beijing region. Based on microsatellite data, two distinct clusters were identified, with both of them splitting further into two clusters; in the Beijing region, the microsatellite data also provided evidence for two introductions. Both the absence of isolation by distance and the fact that distant populations were similar genetically suggest patterns of WFT movement linked to human activities. Our study therefore suggests multiple introductions of WFT into China and human-assisted spread. PMID- 28352299 TI - Genomic patterns of diversity and divergence of two introduced salmonid species in Patagonia, South America. AB - Invasive species have become widespread in aquatic environments throughout the world, yet there are few studies that have examined genomic variation of multiple introduced species in newly colonized environments. In this study, we contrast genomic variation in two salmonid species (anadromous Chinook Salmon, Oncorhynchus tshawytscha, 11,579 SNPs and resident Brook Charr Salvelinus fontinalis, 13,522 SNPs) with differing invasion success after introduction to new environments in South America relative to populations from their native range in North America. Estimates of genetic diversity were not significantly different between introduced and source populations for either species, indicative of propagule pressure that has been shown to maintain diversity in founding populations relative to their native range. Introduced populations also demonstrated higher connectivity and gene flow than those in their native range. Evidence for candidate loci under divergent selection was observed, but was limited to specific introduced populations and was not widely evident. Patterns of genomic variation were consistent with general dispersal potential of each species and therefore also the notion that life history variation may contribute to both invasion success and subsequent genetic structure of these two salmonids in Patagonia. PMID- 28352300 TI - Toward facilitating microalgae cope with effluent from anaerobic digestion of kitchen waste: the art of agricultural phytohormones. AB - BACKGROUND: Although numerous studies have used wastewater as substitutes to cultivate microalgae, most of them obtained weaker algal viability than standard media. Some studies demonstrated a promotion of phytohormones on algal growth in standard media. For exploiting a strategy to improve algal biomass accumulation in effluent from anaerobic digestion of kitchen waste (ADE-KW), the agricultural phytohormones gibberellin, indole-3-acetic acid, and brassinolide (GIB) were applied to Chlorella SDEC-11 and Scenedesmus SDEC-13 at different stages of algal growth. Previous studies have demonstrated a promotion of phytohormones on algal growth in standard media, but attempts have been scarce, focusing on wastewater cultivation system. In addition, the effects of wastewater on algal morphology and ultrastructure have not been revealed so far, much less on the mechanism of the role of phytohormones on algae. RESULTS: ADE-KW disrupted the membranes of nuclear and chloroplast in ultrastructural cell of SDEC-11, and reduced the room between chloroplast and cell membrane and increased the starch size of SDEC-13. This reduced algal growth and biocompound accumulation, but SDEC-13 had greater adaptation to ADE-KW than SDEC-11. Moreover, inoculation with an algal seed pretreated with GIB aided the adaptability and viability of algae in ADE-KW, which for SDEC-13 was even promoted to the level in BG11. GIB mitigated the inhibition of ADE-KW on algal cell division and photosynthetic pigments and apparatus, and increased lipid droplets, which might result from the change in the synthesis and the fate of nicotinamide adenine dinucleotide phosphate. GIB addition significantly promoted lipid productivity of the two algal species, following 13 mg L-1 d-1 of SDEC-11 in B+ADE-KW and especially 13 mg L-1 d-1 of SDEC-13 achieved during the priming of algal seed with the hormones, which is 139% higher than 5 mg L-1 d-1 achieved in ADE-KW control. CONCLUSIONS: Agricultural phytohormones could be applied as a strategy for promoting biomass and biocompound accumulation of algae in ADE-KW, in which pretreatment of the algal inoculum with hormones is a unique way to help algae survive under stress. Considering our results and treatment technology for kitchen waste, a more feasible and economic plant can be built incorporating anaerobic digestion, algae cultivation with ADE-KW assisted with phytohormones, and biodiesel production. PMID- 28352301 TI - Functional overexpression of genes involved in erythritol synthesis in the yeast Yarrowia lipolytica. AB - BACKGROUND: Erythritol, a four-carbon polyol synthesized by microorganisms as an osmoprotectant, is a natural sweetener produced on an industrial scale for decades. Despite the fact that the yeast Yarrowia lipolytica has been reported since the 1970s as an erythritol producer, the metabolic pathway of this polyol has never been characterized. It was shown that erythritol synthesis in yeast occurs via the pentose phosphate pathway (PPP). The oleaginous yeast Y. lipolytica is a good host for converting inexpensive glycerol into a value-added product such as erythritol. Glycerol is a renewable feedstock which is produced on a large scale as a waste product by many branches of industry. RESULTS: In this study, we functionally overexpressed four genes involved in the pentose phosphate pathway (PPP): gene YALI0E06479g encoding transketolase (TKL1), gene YALI0F15587g encoding transaldolase (TAL1), gene YALI0E22649g encoding glucose-6 phosphate dehydrogenase (ZWF1), and gene YALI0B15598g encoding 6-phosphogluconate dehydrogenase (GND1). Here, we show that the crucial gene for erythritol synthesis in Y. lipolytica is transketolase. Overexpression of this gene results in a twofold improvement in erythritol synthesis during a shake-flask experiment (58 g/L). Moreover, overexpression of TKL1 allows for efficient production of erythritol independently from the supplied dissolved oxygen. Fermentation conducted in a 5-L bioreactor at low agitation results in almost 70% higher titer of erythritol over the control strain. CONCLUSION: This work presents the importance of the PPP in erythritol synthesis and the feasibility for economic production of erythritol from glycerol by the yeast Y. lipolytica. PMID- 28352302 TI - The development of the Paediatric Virology Study Group: Ten years in the making. PMID- 28352303 TI - Paediatric Virology: A rapidly increasing educational challenge. AB - The '2nd Workshop on Paediatric Virology', which took place on Saturday the 8th of October 2016 in Athens, Greece, provided an overview on recent views and advances on Paediatric Virology. Emphasis was given to HIV-1 management in Greece, a country under continuous financial crisis, hepatitis B vaccination in Africa, treatment options for hepatitis C virus in childhood, Zika virus in pregnancy and infancy, the burden of influenza on childhood, hand-foot-mouth disease and myocarditis associated with Coxsackie viruses. Other general topics covered included a critical evaluation of Paediatric Accident and Emergency viral infections, multimodality imaging of viral infections in children, surgical approaches of otolaryngologists to complex viral infections, new advances in the diagnosis and treatment of viral conjunctivitis and novel molecular diagnostic methods for HPV in childhood. A brief historical overview of the anti-vaccination movement was also provided, as well as presentations on the educational challenge of Paediatric Virology as a new subspecialty of Paediatrics. This review highlights selected lectures and discussions of the workshop. PMID- 28352305 TI - From bench to bedside: Therapeutic potential of interleukin-9 in the treatment of asthma. AB - Initially identified as a T cell and mast cell growth factor, interleukin (IL)-9 has long been recognized as an important mediator of asthma. Recently, accumulating results from transgenic mice demonstrated that systemic or lung specific overexpression of IL-9 caused asthma-associated symptoms. Moreover, anti mIL-9 antibody (Ab) blocking treatment alleviated disease in animal models of asthma. In light of the large quantity of data from the murine models, MEDI-528, a humanized anti-IL-9 monoclonal Ab has been produced to assess the activity of IL-9 on human asthma. In order to ascertain whether it is a successful translation from bench to bedside, the biological features of IL-9 were evaluated and up-to-date information regarding the role of IL-9 in different experimental murine models and human asthma were summarized. PMID- 28352304 TI - Myeloid-derived suppressor cells and myeloid regulatory cells in cancer and autoimmune disorders. AB - Myeloid-derived suppressor cells (MDSCs) were originally described as a heterogeneous population of immature cells derived from myeloid progenitors with immune-suppressive functions in tumor-bearing hosts. In recent years, increasing number of studies have described various populations of myeloid cells with MDSC like properties in murine models of cancer and autoimmune diseases. These studies have observed that the populations of MDSCs are increased during inflammation and autoimmune conditions. In addition, MDSCs can effectively suppress T cell responses and modulate the activity of natural killer cells and other myeloid cells. MDSCs have also been implicated in the induction of regulatory T cell production. Furthermore, these cells have the potential to suppress the autoimmune response, thereby limiting tissue injury. Myeloid regulatory cells (Mregs) are recently attracting increasing attention, since they function in proinflammatory and immune suppression in autoimmune diseases, as well as in various types of cancer. Currently, research focus is directed from MDSCs to Mregs in cancer and autoimmune diseases. The present study reviewed the suppressive roles of MDSCs in various autoimmune murine models, the immune modulation of MDSCs to T helper 17 lymphocytes, as well as the proinflammatory and immunosuppressive roles of Mregs in various types of cancer and autoimmune diseases. PMID- 28352306 TI - Risk of cardiovascular disease in inflammatory bowel disease. AB - Cardiovascular disease (CVD) can arise because of chronic inflammation and inflammatory bowel disease (IBD) is one such disease where the risk for CVD and eventual heart failure is increased considerably. The incidence of IBD, which refers to both ulcerative colitis and Crohn's disease, has been on the increase in several countries and is a potential risk factor for CVD. Although IBD can potentially cause venous thromboembolism, its significance in arterial stiffening, atherosclerosis, ischemic heart disease and myocardial infarction is only being realized now and it is currently under debate. However, several studies with large groups of patients have demonstrated the association of IBD with heart disease. It has been suggested that systemic inflammation as observed in IBD patients leads to oxidative stress and elevated levels of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), which lead to phenotypic changes in smooth muscle cells and sets into motion a series of events that culminate in atherosclerosis and CVD. Besides the endogenous factors and cytokines, it has been suggested that due to the compromised intestinal mucosal barrier, endotoxins and bacterial lipopolysaccharides produced by intestinal microflora can enter into circulation and activate inflammatory responses that lead to atherosclerosis. Therapeutic management of IBD-associated heart diseases cannot be achieved with simple anti-inflammatory drugs such as corticosteroids and anti-TNF-alpha antibodies. Treatment with existing medications for CVDs, aspirin, platelet aggregation inhibitors and statins is found to be acceptable and safe. Nevertheless, further research is needed to assess their efficacy in IBD patients suffering from heart disease. PMID- 28352307 TI - Mumps caused by paraquat-induced poisoning: A case report. AB - Paraquat (PQ) is a highly toxic herbicide that harms the liver, kidney, lungs and heart, and results in a variety of complications. The majority of patients with severe PQ poisoning may succumb to multiple organ failure, and the mortality rate is high. Although a large number of studies have been performed investigating PQ poisoning, cases of mumps caused by PQ-induced poisoning are rare. In the present case report, a 45-year-old female who ingested PQ was admitted to the Emergency Department of Liaocheng People's Hospital (Liaocheng, China). During the development of the disease, mumps was caused by a cavity ulcer following PQ poisoning. To the best of our knowledge, cases of mumps following PQ poisoning are rare. PMID- 28352308 TI - Diagnostic value of multislice computerized tomography angiography for aortic dissection: A comparison with DSA. AB - The aim of the present study was to compare multislice computed tomography angiography (MSCTA) and digital subtraction angiography (DSA) in the diagnosis of aortic dissection. In total, 49 patients with aortic lesions received enhanced computed tomography scanning, and three-dimensional (3D) images were reconstructed by volume rendering (VR), maximum intensity projection (MIP), multiplanar reformation (MPR) and curved planar reconstruction (CPR). The display rate of the entry tear site, intimal flap, true and false lumen from each reconstruction method was calculated. For 30 patients with DeBakey type III aortic dissection, the entry tear site and size of the first intimal flap, aortic maximum diameter at the orifice of left subclavian artery (LSCA), distance between the first entry tear site and the orifice of LSCA, and maximum diameter of aortic true and false lumens were measured prior to implantation of endovascular covered stent-grafts. Data obtained by MSCTA and DSA were then compared. For the entry tear site, MPR, CPR and VR provided a display rate of 95.92, 95.92 and 18.37%, respectively, and the display rate of the intimal flap was 100% in the three methods. MIP did not directly display the entry tear site and intimal flap. For true and false lumens, MPR, CPR, and VR showed a display rate of 100%, while MIP only provided a display rate of 67.35%. When MSCTA was compared with DSA, there was a significant difference in the display of entry site number and position (P<0.05), whereas no significant difference was shown in the measurement of aortic maximum diameter at the orifice of LSCA and the maximum diameter of true and false lumens (P>0.05). In conclusion, among the 3D post processing reconstruction methods of MSCTA used, MPR and CPR were optimal, followed by VR, and MIP. MSCTA may be the preferable imaging method to diagnose aortic dissection and evaluate treatment of endovascular-covered stent-grafting, preoperatively. PMID- 28352309 TI - Asiaticoside ameliorates beta-amyloid-induced learning and memory deficits in rats by inhibiting mitochondrial apoptosis and reducing inflammatory factors. AB - The present study aimed to investigate the effects of asiaticoside (AS) on the pathology and associated mechanisms of beta-amyloid (Abeta)-induced Alzheimer's disease (AD) in rats. An AD rat model was established by lateral intracerebroventricular injection of Abeta 1-42 oligomers. Learning and memory function were evaluated by Morris water maze (MWM) test. In addition, hematoxylin and eosin (H&E) staining, transmission electron microscopy (TEM), immunohistochemistry, ELISA and western blot analysis were performed to evaluate the disease pathogenesis. The results indicated that AS exerted protective effects in rats treated with Abeta oligomers, in a dose-dependent manner, as evidenced by the improved learning and memory function in the MWM test. In addition, H&E staining of hippocampal tissue showed that the histological structure was damaged in the model group, which was restored by AS treatment. Abeta deposition was dramatically increased in the model group, and the pathological changes were reversed by AS treatment. TEM revealed that the subcellular structure was injured by Abeta oligomers, however, the structure was ameliorated by AS treatment. Furthermore, AS was found to reduce the elevated levels of pro-inflammatory cytokines, interleukin-6 and tumor necrosis factor alpha, in the brains of Abeta-treated rats. In addition, AS treatment resulted in a significant decrease in the expression of caspases-3, whereas the expression of B-cell lymphoma-2 was significantly increased, in these Abeta-treated rats. According to the findings of the observed study, AS has a marked protective effect on Abeta-induced AD pathology, and the underlying mechanism may be associated with the alleviation of the mitochondrial injuries, the anti inflammatory activities, and the influence on the expression levels of apoptosis associated proteins. PMID- 28352310 TI - Cell penetrable-mouse forkhead box P3 suppresses type 1 T helper cell-mediated immunity in a murine model of delayed-type hypersensitivity. AB - Forkhead box P3 (FOXP3), which is a transcription factor, has a primary role in the development and function of regulatory T cells, and thus contributes to homeostasis of the immune system. A previous study generated a cell-permeable fusion protein of mouse FOXP3 conjugated to a protein transduction domain (PTD mFOXP3) that successfully blocked differentiation of type 17 T helper cells in vitro and alleviated experimental arthritis in mice. In the present study, the role of PTD-mFOXP3 in type 1 T helper (Th1) cell-mediated immunity was investigated and the possible mechanisms for its effects were explored. Under Th1 polarization conditions, cluster of differentiation 4+ T cells were treated with PTD-mFOXP3 and analyzed by flow cytometry in vitro, which revealed that PTD mFOXP3 blocked Th1 differentiation in vitro. Mice models of delayed type hypersensitivity (DTH) reactions were generated by subcutaneous sensitization and challenge with ovalbumin (OVA) to the ears of mice. PTD-mFOXP3, which was administered via local subcutaneous injection, significantly reduced DTH-induced inflammation, including ear swelling (ear swelling, P<0.001; pinnae weight, P<0.05 or P<0.01 with 0.25 and 1.25 mg/kg PTD-mFOXP3, respectively), infiltration of T cells, and expression of interferon-gamma at local inflammatory sites (mRNA level P<0.05) compared with the DTH group. The results of the present study demonstrated that PTD-mFOXP3 may attenuate DTH reactions by suppressing the infiltration and activity of Th1 cells. PMID- 28352311 TI - Control-released basic fibroblast growth factor-loaded poly-lactic-co-glycolic acid microspheres promote sciatic nerve regeneration in rats. AB - Although peripheral nerve injury may result in a loss of function in innervated areas, the most effective method for nerve regeneration remains to be determined. The aim of the present study was to investigate the effect of control-released basic fibroblast growth factor (bFGF)-loaded poly-lactic-co-glycolic acid (PLGA) microspheres on sciatic nerve regeneration following injury in rats. bFGF-PLGA microspheres were prepared and their characteristics were evaluated. The sciatic nerve was segmentally resected to create a 10 mm defect in 36 Sprague Dawley (SD) rats and, following the anastomosis of the nerve ends with a silicone tube, bFGF PLGA microspheres, free bFGF or PBS were injected into the tube (n=12 in each group). The outcome of nerve regeneration was evaluated using the sciatic function index (SFI), electrophysiological test and histological staining at 6 weeks and 12 weeks post-surgery. The bFGF-PLGA microspheres were successfully synthesized with an encapsulation efficiency of 66.43%. The recovery of SFI and electrophysiological values were significantly greater (P<0.05), and morphological and histological observations were significantly greater (P<0.05) in bFGF-PLGA microspheres and bFGF groups compared with those in the PBS group, and the quickest recovery was observed in the bFGF-PLGA microspheres group. In conclusion, the bFGF-PLGA microspheres may promote nerve regeneration and functional recovery in the sciatic nerve, and may have potential therapeutic applications in peripheral nerve regeneration. PMID- 28352312 TI - Geniposide reverses multidrug resistance in vitro and in vivo by inhibiting the efflux function and expression of P-glycoprotein. AB - Geniposide is a water-soluble iridoid glucoside with anti-oxidant and anti inflammatory biological functions. It has been indicated that geniposide may increase doxorubicin (DOX) accumulation in drug-resistant tumor cells. The present study aimed to investigate the resistance-reversing effect of geniposide in DOX-resistant cells and assess the underlying mechanisms of its action. The results revealed that geniposide itself weakly inhibited tumor cell growth. Furthermore, geniposide effectively reversed DOX resistance in a dose-dependent manner in human osteosarcoma DOX-resistant (MG63/DOX) cells. The action of geniposide was confirmed by increased accumulation of intracellular DOX detected in MG63/DOX cells. Notably, geniposide enhanced the efficacy of DOX against MG63/DOX cancer cell-derived xenografts in nude mice. To study the mechanism, intracellular accumulation of rhodamine 123 was measured using flow cytometry. At concentrations that reversed multidrug resistance (MDR), geniposide significantly downregulated P-glycoprotein (P-gp) expression. Therefore, geniposide reverses P gp-mediated MDR by reducing the expression of P-gp and its transport function. The present study therefore indicated that geniposide may be administered in combination with conventional anti-neoplastic drugs to prevent MDR. PMID- 28352313 TI - Effects of Cimicifugae Rhizoma on the osteogenic and adipogenic differentiation of stem cells. AB - Cimicifugae Rhizoma, a herb with a long history of use in traditional Oriental medicine is reported to have anti-inflammatory, antioxidant, anti-complement and anticancer effects. The aim of the present study was to evaluate the effects of Cimicifugae Rhizoma extracts on the osteogenic and adipogenic differentiation of human stem cells derived from gingiva. Stem cells derived from gingiva were grown in the presence of Cimicifugae Rhizoma at final concentrations of 0.1, 1 and 10 ug/ml. Cell proliferation analyses were performed at day 15. For osteogenic differentiation experiments, the stem cells were cultured in osteogenic media containing beta-glycerophosphate, ascorbic acid-2-phosphate and dexamethasone, and osteogenic differentiation was evaluated by analysis of osteocalcin expression at 21 days. For adipogenic differentiation experiments, the stem cells were grown in adipogenic induction medium, and the adipogenic differentiation was evaluated by analysis of adipocyte fatty acid-binding protein at day 14. The cultures grown in the presence of 0.1 ug/ml Cimicifugae Rhizoma showed a significant increase in cellular proliferation at day 15 compared with the control group. The relative osteogenic differentiation in the presence of Cimicifugae Rhizoma for the 0.1, 1 and 10 ug/ml groups was 171.5+/-13.7, 125.6+/ 28.7 and 150.5+/-9.0, respectively, when that of the untreated control group on day 21 was considered to be 100%. The relative adipogenic differentiation at day 14 of the 0.1, 1 and 10 ug/ml groups in the presence of Cimicifugae Rhizoma was 97.5+/-15.0, 102.9+/-12.8 and 87.0+/-6.8%, respectively when that of the untreated control group on day 14 was considered to be 100%. Within the limits of this study, Cimicifugae Rhizoma increased the proliferation of stem cells derived from the gingiva, and low concentrations of Cimicifugae Rhizoma may increase the osteogenic differentiation of stem cells. PMID- 28352314 TI - VEGF treatment promotes bone marrow-derived CXCR4+ mesenchymal stromal stem cell differentiation into vessel endothelial cells. AB - Stem/progenitor cells serve an important role in the process of blood vessel repair. However, the mechanism of vascular repair mediated by C-X-C chemokine receptor type 4-positive (CXCR4+) bone marrow-derived mesenchymal stem cells (BMSCs) following myocardial infarction remains unclear. The aim of the present study was to investigate the effects of vascular endothelial growth factor (VEGF) on vessel endothelial differentiation from BMSCs. CXCR4+ BMSCs were isolated from the femoral bone marrow of 2-month-old mice and the cells were treated with VEGF. Expression of endothelial cell markers and the functional properties were assessed by reverse transcription-quantitative polymerase chain reaction, flow cytometry and vascular formation analyses. The results indicated that the CXCR4+ BMSCs from femoral bone marrow cells expressed putative cell surface markers of mesenchymal stem cells. Treatment with VEGF induced platelet/endothelial cell adhesion molecule-1 (PECAM-1) and von Willebrand factor (vWF) expression at the transcriptional and translational levels, compared with untreated controls. Moreover, VEGF treatment induced CXCR4+ BMSCs to form hollow tube-like structures on Matrigel, suggesting that the differentiated endothelial cells had the functional properties of blood vessels. The results demonstrate that the CXCR4+ BMSCs were able to differentiate into vessel endothelial cells following VEGF treatment. For cell transplantation in vascular disease, it may be concluded that CXCR4+ BMSCs are a novel source of endothelial progenitor cells with high potential for application in vascular repair. PMID- 28352315 TI - Daphnetin inhibits inflammation in the NZB/W F1 systemic lupus erythematosus murine model via inhibition of NF-kappaB activity. AB - Daphnetin is a compound extracted from Chinese medicinal herbs, which exerts analgesic and anti-inflammatory effects. The present study aimed to investigate the potential therapeutic effect of daphnetin on inflammation in the NZB/W F1 systemic lupus erythematosus (SLE) murine model. Female NZB/WF1 mice (age, 16-18 weeks) were intraperitoneally injected with daphnetin once a day for 12 weeks. It was revealed that daphnetin treatment significantly increased animal survival rates, reduced renal damage and blood urea nitrogen levels, and suppressed serum autoantibody production in the SLE-prone NZB/W F1 mice. In addition, daphnetin treatment significantly decreased the serum levels of tumor necrosis factor-alpha and interleukin-6, inhibited nuclear factor (NF)-kappaB activity, suppressed the protein expression of nuclear factor of activated T-cells and promoted A20 protein expression in SLE-prone NZB/W F1 mice. In conclusion, daphnetin inhibited inflammation in the NZB/W F1 murine SLE model via inhibition of NF-kappaB mediated by upregulation of A20. PMID- 28352316 TI - Monocyte chemoattractant protein-1 contributes to morphine tolerance in rats with cancer-induced bone pain. AB - Cancer-induced bone pain can severely compromise the life quality of patients, while tolerance limits the use of opioids in the treatment of cancer pain. Monocyte chemoattractant protein-1 (MCP-1) is known to contribute to neuropathic pain. However, the role of spinal MCP-1 in the development of morphine tolerance in patients with cancer-induced bone pain remains unclear. The aim of the present study was to investigate the role of spinal MCP-1 in morphine tolerance in bone cancer pain rats (MTBP rats). Bone cancer pain was induced by intramedullary injection of Walker 256 cells into the tibia of the rats, while morphine tolerance was induced by continuous intrathecal injection of morphine over a period of 9 days. In addition, anti-MCP-1 antibodies were intrathecally injected to rats in various groups in order to investigate the association of MCP-1 with mechanical and heat hyperalgesia using the paw withdrawal threshold (PWT) and thermal withdrawal latency (TWL) tests, respectively. Furthermore, MCP-1 and CCR2 expression levels were measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis, and CCR2 expression levels were measured using RT-qPCR. The results indicated that MCP-1 and CCR2 expression levels were significantly increased in the spinal cord of MTBP rats. Intrathecal administration of anti-MCP-1 neutralizing antibodies was observed to attenuate the mechanical and thermal allodynia in MTBP rats. Therefore, the upregulation of spinal MCP-1 and CCR2 expression levels may contribute to the development of mechanical allodynia in MTBP rats. In conclusion, MCP-1/CCR2 signaling may serve a crucial role in morphine tolerance development in rats suffering from cancer-induced bone pain. PMID- 28352317 TI - Activation of peroxisome proliferator-activated receptor gamma inhibits vascular calcification by upregulating Klotho. AB - Cardiovascular diseases are common in patients with chronic kidney disease. One of the key symptoms is the calcification of the vascular smooth muscle cells (VSMCs), which is induced by dysregulated mineral metabolism with high circulating levels of inorganic phosphate (Pi) and calcium. Klotho, which was originally identified as an aging suppressor gene, has been shown to be associated with vascular calcification. Since Klotho was recently identified as a target for nuclear receptor peroxisome proliferator-activated receptor (PPAR) gamma, the present study aimed to determine whether PPARgamma regulates VSMC calcification through modulating the expression levels of Klotho. It was demonstrated that the expression of PPARgamma was downregulated during Pi-induced VSMC calcification. In addition, treatment with PPARgamma agonists inhibited the calcification and enhanced the expression of Klotho in VSMCs in a PPARgamma dependent manner. Of note, loss of Klotho expression by RNA interference abolished the ability of PPARgamma activation to inhibit VSMC calcification. Furthermore, activation of Klotho as well as PPARgamma inhibited the expression of Pi transporter 1/2 and reduced Pi influx into VSMCs. To the best of our knowledge, the present study was the first to demonstrate that PPARgamma regulates VSMC calcification through activating Klotho. PMID- 28352319 TI - Characterizing nanoscale changes in the activity of VEGFR-2 on glioma microvascular endothelial cell membranes using atomic force microscopy. AB - The aim of the current study was to demonstrate the distribution of VEGFR-2 on glioma microvascular endothelial cells on a nanoscale and investigate changes in VEGFR-2 activity following treatment with the VEGFR-2 inhibitor and agonist sorafenib and bradykinin, respectively. Three groups were evaluated in this study: Control glioma microvascular endothelial cells, sorafenib-treated glioma microvascular endothelial cells and bradykinin-treated glioma microvascular endothelial cells. Changes in the activity of VEGFR-2 on the glioma microvascular endothelial cell membranes following treatment with sorafenib and bradykinin were characterized by atomic force microscopy (AFM). Colloidal gold-labeled immune complexes and AFM were used to visualize the distribution of VEGFR-2 on the cell membranes. In the control group, VEGFR-2, which was observed as numerous globular structures, was evenly distributed on the cell surface membranes. The majority of the receptors were active. In the sorafenib group, only a few globular structures were observed on the cell membranes, with a density significantly lower than that in the control group (P<0.01). Furthermore, compared with the control group, fewer of the receptors were active. In the bradykinin group, numerous globular structures were densely distributed on the cell membranes, with a density significantly higher than that in the control group (P<0.01). The distribution and activity of VEGFR-2 on glioma microvascular endothelial cell membranes treated with sorafenib and bradykinin suggested that the activity of VEGFR-2 could be regulated by its inhibitor or agonist. PMID- 28352318 TI - Establishment and evaluation of an experimental rat model for high-altitude intestinal barrier injury. AB - In the present study an experimental high-altitude intestinal barrier injury rat model was established by simulating an acute hypoxia environment, to provide an experimental basis to assess the pathogenesis, prevention and treatment of altitude sickness. A total of 70 healthy male Sprague-Dawley rats were divided into two groups: Control group (group C) and a high-altitude hypoxia group (group H). Following 2 days adaptation, the rats in group H were exposed to a simulated 4,000-m, high-altitude hypoxia environment for 3 days to establish the experimental model. To evaluate the model, bacterial translocation, serum lipopolysaccharide level, pathomorphology, ultrastructure and protein expression in rats were assessed. The results indicate that, compared with group C, the rate of bacterial translocation and the apoptotic index of intestinal epithelial cells were significantly higher in group H (P<0.01). Using a light microscope it was determined that the intestinal mucosa was thinner in group H, there were fewer epithelial cells present and the morphology was irregular. Observations with an electron microscope indicated that the intestinal epithelial cells in group H were injured, the spaces among intestinal villi were wider, the tight junctions among cells were open and lanthanum nitrate granules (from the fixing solution) had diffused into the intestinal mesenchyme. The expression of the tight junction protein occludin was also decreased in group H. Therefore, the methods applied in the present study enabled the establishment of a stable, high-altitude intestinal barrier injury model in rats. PMID- 28352320 TI - Fungal infection involvement in primary biliary cirrhosis: A review of 2 cases. AB - The present study aimed to analyze the imaging, clinical and pathological features of fungal infection involvement in primary biliary cirrhosis (PBC) by retrospectively analyzing and reviewing the features of two patients with fungal infection involvement in PBC. Both patients were female. One patient had a confirmed diagnosis of PBC. The other patient had confirmed Sjogren syndrome and PBC. The two cases of PBC were infected with fungal infection after treatment with hormonal and immunosuppressive agents. RCR of sputum confirmed Pneumocystis spp. infection in the patient with PBC alone. The mucormycosis infection was confirmed in the other patient after pathological examination of a renal biopsy. The state of the illnesses progressed quickly and both patients ultimately succumbed to their conditions. The patient prognosis of fungal infection involvement PBC is poor. Patients treated with long-term hormone and immunosuppressive agents should be monitored. PMID- 28352321 TI - Toll-like receptor 2 agonist exacerbates renal injury in diabetic mice. AB - Inflammation is implicated in the pathogenesis of diabetic nephropathy (DN). Toll like receptor 2 (TLR2) is a ligand-activated membrane-bound receptor, which induces an inflammatory response, thus serving a crucial role in the pathogenesis of DN. The present study aimed to determine whether a TLR2 agonist, Pam3CysSK4, modulates the development of DN. A mouse model of DN was induced using streptozotocin (STZ) and, following the confirmation of hyperglycemia, mice were treated with or without Pam3CysSK4. Pathological and functional markers, including the activation of nuclear factor (NF)-kappaB, expression of TLR2, inflammatory infiltration, myeloid differentiation primary response gene 88 and monocyte chemoattractant protein-1 were assessed. STZ-treated mice exhibited elevated blood glucose levels and increased serum creatinine levels, which increased further following Pam3CysSK4 treatment. In addition, Pam3CysSK4 treatment was observed to increase podocyte foot process formation. Furthermore, STZ-induced renal glomerular sclerosis was significantly exacerbated in Pam3CysSK4-treated mice. Pam3CysSK4-treated mice also exhibited increased levels of collagen IV following renal immunostaining, associated with increased macrophage infiltration. Renal expression of TLR2 was markedly elevated in STZ induced mice; this was further increased in Pam3CysSK4-treated mice, accompanied by upregulation of proinflammatory genes and activation of NF-kappaB. This indicates that enhanced renal expression of TLR2 is associated with inflammatory infiltration in DN and demonstrates that renal injury was exacerbated by the TLR2 agonist in diabetic mice. PMID- 28352322 TI - Effect of Wubeizi ointment aqueous solution on the expression of type I and III procollagen genes in keloid fibroblasts. AB - We evaluated the effect of Wubeizi (WBZ) ointment on keloids. Keloid-derived fibroblast primary cultures were used to evaluate the effect of the different concentration of WBZ ointment on the expression of type I and III procollagen in keloid fibroblast primary cultures using dot blot assay. Type I and II precollagen cDNA probes labeled with non-radioactive digoxin were used for dot blot. Cell cultures were divided into 4 groups: The large dose group received 1 g/ml of WBZ, middle dose, and small dose groups received 0.5 and 0.25 g/ml of WBZ, respectively. The control group received serum-free medium without WBZ. Our results showed that type I and III procollagen mRNA expression was reduced significantly in the large dose and middle dose groups compared to the control group. Type I and III procollagen mRNA expression level in the small dose group had no statistically significant difference with the control group. However, the difference between the large dose group and the small dose group was statistically significant. We concluded that WBZ ointment aqueous solution restricted keloid fibroblast proliferation by downregulating the expression of type I and III procollagen and therefore reducing collagen deposition in keloid tissue. PMID- 28352323 TI - Correlation between genotype and phenotype in three families with Peutz-Jeghers Syndrome. AB - Peutz-Jeghers syndrome (PJS) is a hereditary disorder characterized by mucocutaneous pigmentations, gastrointestinal (GI) polyposis and an increased risk of certain malignancies. Little is known about the causative genes of PJS, or their association with the clinical phenotypes of PJS. The present study reports the results of clinical and genetic analysis of three Chinese families with PJS. In addition, the medical histories and clinical manifestations of these families were compared. DNA was collected from the blood samples of patients with PJS and controls. Serine/threonine kinase 11 (STK11), olfactory receptor family 4 subfamily C member 45 (OR4C45) and zonadhesin (ZAN) were amplified by polymerase chain reaction, and analyzed by sequencing and cloning. Two PJS-affected members of one family had a de novo single base deletion (NM_000455.4:c.842delC) in the STK11 gene, and their clinical presentations reflected the quantity of mutant STK11 copies in a dose-dependent manner. No pathogenic variants of OR4C45 or ZAN were found in the patients with PJS, although a new single nucleotide polymorphism (NM_003386.2:c.5768delG) of ZAN was identified. The results of the current study identified that a STK11 mutation dose-dependent genotype-phenotype relationship exists in patients with PJS. In addition, an early onset and high severity of oral pigmentations in PJS was indicative of serious GI phenotypes. These findings may aid the diagnosis and treatment of PJS. PMID- 28352324 TI - Value of the combined examination of Cys-C and HbA1c for diagnosis of early renal injury in pediatric diabetes. AB - The objective of the present study was to evaluate the combined application of measuring cystatin C (Cys-C) and hemoglobin A1c (HbA1c) levels for early renal injury in pediatric patients with type 2 diabetes. A total of 130 children with type 2 diabetes admitted to our hospital from May 2013 to July 2015 were selected. Patients were divided according to whether there was complication of renal injury. In group A (n=65), the patients had renal injury and in group B (n=65), the patients did not have renal injury. The levels of Cys-C and HbA1c in the two groups were examined. The results showed that the levels of Cys-C and HbA1c of patients in group A were significantly higher than those in group B (P<0.05), and the positive rate of the combined examination of Cys-C and HbA1c in group A was 92.3%, and was higher than that of the individual examinations of either Cys-C or HbA1c (P<0.05). The Spearman's correlation coefficient analysis was applied to group B and showed that Cys-C was positively correlated with HbA1c (r=0.842, P<0.05). From analysis of the receiver operating characteristic curves, the combined examination of Cys-C and HbA1c surpassed the individual examinations of Cys-C or HbA1c in sensitivity and specificity (P<0.05). In conclusion, the positive detection rate of early renal injury was significantly increased by the combined examination of Cys-C and HbA1c in pediatric patients with type 2 diabetes, which is beneficial for early identification and diagnosis of this diseases and is worthy of clinical application. PMID- 28352325 TI - Analysis of clinical effects and mechanism of recombinant human interleukin-11 with glucocorticoids for treatment of idiopathic thrombocytopenic purpura. AB - The aim of the present study was to evaluate the effectiveness and safety of recombinant human interleukin-11 (IL-11) with glucocorticoids for treatment of adult idiopathic thrombocytopenic purpura (ITP) and the regulatory effect on immune mechanisms. A total of 80 patients with initial diagnosis of ITP admitted to our hospital were selected. Patients were randomly divided into the control group and observation group, with 40 cases each. The control group received glucocorticoids treatment, and the observation group received IL-11 and glucocorticoids. The treatment effects were compared. The total effective rate and effective degree of the observation group was higher than in the control group and the difference was statistically significant (P<0.05); comparing the incidence of complications of the two groups, there was no statistical difference (P>0.05). In the observation group, onset time was reduced, platelet recovery level increased and platelet antibody positive rate decreased, and the differences were statistically significant (P<0.05). The total treatment course was shorter and recurrence rate was lower in the observation group compared with the control group, and the differences were statistically significant (P<0.05). The percentage of CD4+CD25+ regulatory T cells decreased in the two groups after treatment, and was more pronounced in the observation group. The difference was statistically significant (P<0.05). In conclusion, IL-11 with glucocorticoids for the treatment of adult ITP is safe and effective, and may be associated with decreased percentage of CD4+CD25+ regulatory T cells. PMID- 28352326 TI - Genetic variants in KCNJ11, TCF7L2 and HNF4A are associated with type 2 diabetes, BMI and dyslipidemia in families of Northeastern Mexico: A pilot study. AB - The aim of the present study was to investigate whether genetic markers considered risk factors for metabolic syndromes, including dyslipidemia, obesity and type 2 diabetes mellitus (T2DM), can be applied to a Northeastern Mexican population. A total of 37 families were analyzed for 63 single nucleotide polymorphisms (SNPs), and the age, body mass index (BMI), glucose tolerance values and blood lipid levels, including those of cholesterol, low-density lipoprotein (LDL), very LDL (VLDL), high-density lipoprotein (HDL) and triglycerides were evaluated. Three genetic markers previously associated with metabolic syndromes were identified in the sample population, including KCNJ11, TCF7L2 and HNF4A. The KCNJ11 SNP rs5210 was associated with T2DM, the TCF7L2 SNP rs11196175 was associated with BMI and cholesterol and LDL levels, the TCF7L2 SNP rs12255372 was associated with BMI and HDL, VLDL and triglyceride levels, and the HNF4A SNP rs1885088 was associated with LDL levels (P<0.05). PMID- 28352327 TI - Downregulated stromal antigen 2 expression in de novo acute myeloid leukemia patients. AB - The stromal antigen 2 (STAG2) gene encodes a component of the cohesin complex that participates in the regulation of sister chromatid separation during mitosis. When activated, STAG2 may act as a 'caretaker' tumor suppressor gene. As it is unknown whether STAG2 gene is responsible for the occurrence and associated with the prognosis of acute myeloid leukemia (AML), the present study analyzed the relative expression levels of STAG2 in 127 de novo AML patients and 17 healthy volunteers using reverse transcription-quantitative polymerase chain reaction. In addition, AML patients were divided into three risk groups using cytogenetic and molecular genetic abnormalities to define their risk status. STAG2 gene expression was found to be significantly downregulated in de novo AML patients, when compared with the healthy controls; however, the expression was not significantly different in the various gender and age subgroups. Furthermore, no significant difference between risk groups was detected in AML patients. Thus, the STAG2 gene may serve an important role in AML development, but is not associated with prognosis in AML. PMID- 28352328 TI - Distribution of human papillomavirus genotypes in cervical lesions. AB - The aims of the present study were to investigate the distribution of human papillomavirus (HPV) genotypes in cervical lesions, and the association between different HPV genotypes and cervical lesions. Between January 2013 and June 2014, the HPV type determinations of nucleic acid by use of fluorescence polymerase chain reaction (PCR) method of 15,192 outpatients in China-Japan Friendship Hospital were performed and the infection status was analyzed. The results showed that: i) 2,366 Cases were HPV positive and 12,826 cases were HPV negative, the overall infection rate was 15.57% (2,366/15,192), in which a single genotype of HPV infection rate was 11.63% (1,767/15,192), and multiple genotypes of HPV infection rate was 3.94% (599/15,192); ii) HPV16, HPV52 and HPV58 infections were the most common HPV genotypes, the infection rates were 3.95% (600/15,192), 2.86% (435/15,192) and 2.67% (406/15,192), respectively; and iii) According to the gold standard of histopathological analysis via hematoxylin-eosin staining, HPV16, HPV52 and HPV58 accounted for 58.80% (154/267) of all CIN2 or above squamous epithelial lesions. Furthermore, three cases with pathological changes of the cervical severe glandular epithelium were all HPV18 infection. The difference was statistically significant (chi2=60.74, P<0.001). Single HPV subtype infection was primarily associated with HPV16, HPV52 and HPV58. In conclusion, HPV type detection had a may be important in screening of cervical lesions as a difference in pathogenic ability was noted among different HPV genotypes. As cervical cancer is an infectious disease, HPV testing may help detect more precancerous lesions, thus reducing the morbidity and mortality of cervical cancer. HPV16, HPV52 and HPV58 were associated with severe cervical squamous epithelial lesions; HPV18 was associated with cervical severe glandular cell pathological changes, although it was not the most common HPV genotype in China. When positive, a clinical cervical examination should be conducted, including colposcopy and biopsy. PMID- 28352329 TI - Matrigel scaffold combined with Ad-hBMP7-transfected chondrocytes improves the repair of rabbit cartilage defect. AB - The aim of this study was to explore an effective method for the repair of cartilage defects using chitosan/glycerophosphate (C/GP) gel- and Matrigel engineered human bone morphogenetic protein 7 (hBMP7)-expressing chondrocytes. Rabbit chondrocytes were obtained, cultured in vitro and transfected with an adenovirus containing hBMP7 and green fluorescent protein (Ad-hBMP7-GFP). The expression of hBMP7 in the transfected cells was tested by reverse transcription polymerase chain reaction (RT-PCR) and western blotting. The phenotype of the transfected cells was evaluated by detecting the yields of collagen II and hyaluronic acid using RT-PCR and enzyme-linked immunosorbent assay (ELISA). The growth of chondrocytes in the C/GP gel and Matrigel was accessed by measuring the cell growth rate, hematoxylin and eosin (H&E) staining and observation under a scanning microscope. Twelve adult male New Zealand white rabbits were randomly divided into three groups. Two cartilage defects were created in the rabbits' knees by aseptic surgery. Group A (n=4) did not receive any treatment, group B (n=4) were treated with C/GP gel and Matrigel-engineered Ad-mock-GFP-transfected chondrocytes, and group C (n=4) were treated with C/GP gel and Matrigel engineered Ad-hBMP7-GFP-transfected chondrocytes. Rabbits were sacrificed at 4 weeks after transplantation, and the repair effect was measured by the Wakitani scoring method. On the basis of the RT-PCR and western blot results, hBMP7 was efficiently overexpressed in the Ad-hBMP7-GFP-transfected chondrocytes. The ELISA results showed that the yields of collagen II and hyaluronic acid in Ad-hBMP7-GFP transfected chondrocytes were significantly higher than those in Ad-mock-GFP transfected chondrocytes. Chondrocytes have a better morphology and arrangement in a Matrigel scaffold than in C/GP, as assessed by H&E staining and scanning microscopy. According to the Wakitani score, Matrigel combined with Ad-hBMP7-GFP transfected chondrocytes successfully promoted the repair of cartilage defects in rabbit knees. PMID- 28352330 TI - Orphan nuclear receptor Nurr1 as a potential novel marker for progression in human pancreatic ductal adenocarcinoma. AB - Nuclear receptor related-1 protein (Nurr1) is a novel orphan member of the nuclear receptor superfamily (the NR4A family) involved in tumorigenesis. The aim of the present study was to investigate the expression and possible function of Nurr1 in pancreatic ductal adenocarcinoma (PDAC). The expression pattern of Nurr1 protein was determined using immunohistochemical staining in 138 patients with PDAC. Elevated Nurr1 expression was more commonly observed in PDAC tissues and cell lines compared with healthy controls. Elevated expression was significantly associated with histological differentiation (P=0.041), lymph node metastasis (P=0.021), TNM classification of malignant tumors stage (P=0.031) and poor survival (P=0.001). Further experiments demonstrated that suppression of endogenous Nurr1 expression attenuated cell proliferation, migration and invasion, and induced apoptosis of PDAC cells. In conclusion, these results suggest that Nurr1 has an important role in the progression of PDAC and may be used as a novel marker for therapeutic targets. PMID- 28352331 TI - Clinical and laboratory analysis of late-onset glutaric aciduria type I (GA-I) in Uighur: A report of two cases. AB - The aim of the present study was to investigate the clinical, biochemical and genetic mutation characteristics of two cases of late-onset glutaric aciduria type I (GA-I) in Uighur. The clinical data and glutaryl-CoA dehydrogenase (GCDH) genetic test results of two cases of late-onset GA-I in Uighur were collected and analyzed, and reviewed with relevant literature. One patient with late-onset GA-I primarily exhibited clinical intermittent headache, while the other patient was asymptomatic. The urinary organic acid analysis detected a large number of glutaric acid and 3-hydroxy glutaric acid, 3-hydroxy-propionic acid. One patient exhibited white matter degeneration in cranial magnetic resonance imaging (MRI) and the other patient showed no abnormality. The two patients both exhibited c. 1204C >T, p.R402W, heterozygous mutation, and c. 532G >A, p.G178R, heterozygous mutation. Besides central nervous system infectious diseases, patients with clinical headache, cranial MRI-suggested bilateral temporal lobe arachnoid cyst and abnormal signals in the basal ganglia should be highly suspected as late onset GA-I. Early diagnosis and correct treatment are key to improve its prognosis. PMID- 28352332 TI - Inhibitory effect of Salvia plebeia leaf extract on ultraviolet-induced photoaging-associated ion channels and enzymes. AB - In traditional Korean/Asian medicine, Salvia plebeia R.Br. (S. plebeia) leaves are used to treat inflammatory diseases, including dermatitis, cough, asthma and toothache. Recently, S. plebeia leaves have been applied in skin care, as they promote skin lightening and elasticity. Therefore, the present study investigated the anti-aging effects of S. plebeia leaf methanolic extract and its fractions (dichloromethane, ethylacetate and n-butanol). The results of a whole-cell patch clamp analysis indicated that the methanolic extract mediated ultraviolet (UV) induced photoaging-associated ion channels, transient receptor potential vanilloid 1 (TRPV1) and calcium release-activated calcium channel protein 1 (ORAI1) channel activity in HEK293T cells overexpressing TRPV1 or ORAI1 and STIM1. Electrophysiological analysis revealed that the butanol fraction inhibited capsaicin-induced TRPV1 (84+/-8% at -60 mV/86+/-1% at 100 mV at 100 ug/ml) and ORAI1 (87+/-2% at -120 mV at 100 ug/ml) currents. Furthermore, the dichloromethane and hexane fractions inhibited tyrosinase activity by 32.4+/-0.69 and 22.6+/-0.96% at 330 ug/ml, respectively. Furthermore, the ethylacetate and butanol fractions inhibited elastase activity by 65.2+/-1.30 and 31.7+/-1.23% at 330 ug/ml, respectively. Tyrosinase and elastase, which are UV-induced photoaging associated enzymes, regulate skin pigmentation and wrinkle formation, respectively. The results of the present study indicated that S. plebeia leaves may be a novel treatment for UV-induced photoaging. PMID- 28352333 TI - Protective effects and mechanism of TPX2 on neurocyte apoptosis of rats in Alzheimer's disease model. AB - We investigated the protective effects and mechanism of TPX2 on apoptosis of rat neurocytes. A total of 90 SD rats were randomly divided into the drug group, the control group and the blank group, with 30 rats in each group. The rats in the drug group and in the blank group were anesthetized with 10% chloral hydrate (at the dose of 0.5 ml/100 g) and Abeta1-42, with the concentration of 5 ul (1 ug/ul), was injected in the exact position of bilateral hippocampal areas of rats to establish the model. The configured TPX2 inhibitors and edible benne oil were mixed and made into a suspension. After model establishment, the rats were given different treatment methods; the rats in the drug group were given gavage administration in the proportion of 75 mg/kg once a day. The rats in the control group were given intragastric administration with the same proportion of physiological saline once a day. The blank group was the normal healthy group and the rats in this group did not undergo any surgery or drug treatment. Brain tissue in rats were divided into two parts, one part was fixed, dehydrated, paraffin-embedded and made into slices of approximately 5 um. TUNEL staining was used to examine the apoptosis of brain tissue, H&E staining was used to observe the brain tissue cells of each group, and western blotting for detecting the MAPK, Erk and expression levels of p38 and RT-polymerase chain reaction method was employed to examine mRNA expression levels of MAPK, Erk and p21. After one week, TUNEL staining showed that apoptosis of brain tissue in the drug group was significantly greater than those of the control and blank groups. The protein expression levels of MAPK, Erk and p38 were significantly higher than those of the control group and the normal healthy group; the differences were statistically significant (P<0.05). Western blotting showed that the protein expression levels of MAPK, Erk and p38 of the drug group were significantly lower than those of the control group but higher than those of the normal healthy group; the differences were statistically significant (P<0.05). TPX2 has a protective effect on the apoptosis of brain tissue processed by Abeta1-42, which plays its role through the inhibition of the protein expression levels of MAPK, Erk and p38. PMID- 28352334 TI - Long non-coding RNA ASncmtRNA-2 is upregulated in diabetic kidneys and high glucose-treated mesangial cells. AB - Diabetic nephropathy (DN) is one of the most frequent complications associated with type I and II diabetes mellitus. Kidneys from patients with DN are characterized by mesangial matrix expansion and increased thickness of the glomerular basement membrane, which are induced by reactive oxygen species (ROS) production. Previous studies have been conducted to investigate this; however, the detailed mechanism of DN progression remains to be elucidated. The present study evaluated the expression of antisense mitochondrial non-coding RNA-2 (ASncmtRNA-2) in an experimental DN model and cultured human mesangial cells. When mice that exhibited genetic type II diabetes developed DN, ASncmtRNA-2 expression was significantly increased (P=0.017) and was positively correlated with pro-fibrotic factor transforming growth factor beta1 (TGFbeta1) expression and its downstream gene, fibronectin. Inhibition of ROS through administration of the nitric oxide synthase inhibitor, NG-nitro-L-Arginine methylester (L-NAME), significantly reduced (P=0.022) the upregulation of ASncmtRNA-2 in DN. In cultured human renal mesangial cells (HRMCs), ASncmtRNA-2 was upregulated by high glucose stimuli in a time-dependent manner. Glucose-induced upregulation of ASncmtRNA-2 was also reduced by co-incubation of HRMCs with L-NAME. Notably, specific short hairpin RNA against ASncmtRNA-2 significantly downregulated the expression of TGFbeta1 in HRMCs. The present study suggests that ASncmtRNA-2 is upregulated by ROS and may promote glomerular fibrosis in DN via positively regulating the expression of pro-fibrotic factors. These findings may provide novel potential therapeutic and preventative treatments for DN. PMID- 28352335 TI - Chitosan hydrogel improves mesenchymal stem cell transplant survival and cardiac function following myocardial infarction in rats. AB - Myocardial infarction (MI) remains the leading cause of cardiovascular-associated mortality and morbidity. Improving the retention rate, survival and cardiomyocyte differentiation of mesenchymal stem cells (MSCs) is important in improving the treatment of patients with MI. In the present study, temperature-responsive chitosan hydrogel, an injectable scaffold, was used to deliver MSCs directly into the infarcted myocardium of rats following MI. Histopathology and immunohistochemical staining were used to evaluate cardiac cell survival and regeneration, and cardiac function was assessed using an echocardiograph. It was demonstrated that chitosan hydrogel increased graft size and cell retention in the ischemic heart, promoted MSCs to differentiate into cardiomyocytes and increased the effects of MSCs on neovasculature formation. Furthermore, chitosan hydrogel enhanced the effect of MSCs on the improvement of cardiac function and hemodynamics in the infarcted area of rats following MI. These findings suggest that chitosan hydrogel is an appropriate material to deliver MSCs into infarcted myocardium. PMID- 28352336 TI - Anthelmintic drug albendazole arrests human gastric cancer cells at the mitotic phase and induces apoptosis. AB - As microtubules have a vital function in the cell cycle, oncologists have developed microtubule inhibitors capable of preventing uncontrolled cell division, as in the case of cancer. The anthelmintic drug albendazole (ABZ) has been demonstrated to inhibit hepatocellular, ovarian and prostate cancer cells via microtubule targeting. However, its activity against human gastric cancer (GC) cells has remained to be determined. In the present study, ABZ was used to treat GC cells (MKN-45, SGC-7901 and MKN-28). A a CCK-8 cell proliferation assay was performed to assess the effects of ABZ on cell viability and cell cycle changes were assessed using flow cytometry. SGC-7901 cells were selected for further study, and flow cytometry was employed to determine the apoptotic rate, immunofluorescence analysis was employed to show changes of the microtubule structure as well as the subcellular localization and expression levels of cyclin B1, and western blot analysis was used to identify the dynamics of microtubule assembly. The expression levels of relevant proteins, including cyclin B1 and Cdc2, the two subunits of mitosis-promoting factor as well as apoptosis-asociated proteins were also assessed by western blot analysis. The results showed that ABZ exerted its anti-cancer activity in GC cell lines by disrupting microtubule formation and function to cause mitotic arrest, which is also associated with the accumulation of cyclin B1, and consequently induces apoptosis. PMID- 28352337 TI - Effect of ticagrelor on the serum level of hs-CRP, ESM-1 and short-term prognosis of patients with acute STEMI. AB - The aim of the present study was to observe and investigate the changes in the serum level of high-sensitivity C-reactive protein (hs-CRP), the endothelial cell specific molecule-1 (ESM-1) and short-term prognosis of patients with ST-segment elevation myocardial infarction (STEMI) treated by ticagrelor. We enrolled 107 patients with acute STEMI who were admitted in the Department of Cardiology for the first time with occurrence of symptoms, and we successfully performed emergency operation of percutaneous coronary intervention. The patients were divided into two groups, 54 patients in the ticagrelor group (treatment group) and 53 patients in the clopidogrel group (control group), according to the administration of ticagrelor or clopidogrel in dual anti-platelet therapy. Then, we observed the changes at the time of admission, at 24 h, and 4th and 7th day after administration and investigated the correlations between them and the effect of ticagrelor on the short-term prognosis of acute STEMI patients. Significant increases of the serum levels of hs-CRP and ESM-1 were seen in patients of the two groups 24 h after administration of drugs with statistically significant differences between the groups (P<0.05), and on the 4th and 7th day we found a downward trend with statistically significant differences (P<0.05). The level of ESM-1 enhanced the increase of hs-CRP, indicating there was a positive correlation between ESM-1 and hs-CRP (r=0.535, P<0.001). A comparison of the occurrence rates of ischemic outcome event, bleeding and overall adverse events between the two groups yielded no statistically significant difference (P>0.05). In conclusion, the present study demonstrates that ticagrelor can reduce the prevalence of inflammatory reactions rapidly and stabilize the functions of vascular endothelium to improve the stability of atherosclerosis plaque and decrease the occurrence rate of thrombosis as well as ischemic outcome event without any obvious increase in the risk of bleeding. Thus, ticagrelor should be recommended in clinical practices for the treatment of patients with STEMI. PMID- 28352338 TI - Evaluation of safety and efficacy of elective PCI in patients with cardiac insufficiency. AB - We analyzed the safety and the efficacy of the treatment with elective percutaneous coronary intervention (PCI) in patients with coronary heart disease complicated with cardiac insufficiency. We enrolled 217 patients diagnosed with chronic ischemic heart disease complicated with cardiac failure. According to the type of treatment they received, patients were divided into 3 groups: i) The conservative treatment group with 60 patients (they received standard medication); ii) the early PCI group with 82 cases (their condition was stabilized, surgical risk was assessed and PCI was taken as early as possible); and iii) the advanced PCI group with 75 cases (ischemic myocardium was corrected and then elective PCI was applied and for aggravated myocardial ischemia cases, PCI was applied after assessing the risk of surgery). Follow-up visits were set for approximately 3 years and clinical outcomes were compared. Our results showed that the survival time in the early PCI group was significantly prolonged and the survival rate was considerably increased during 3 years. Left ventricular ejection fraction in the early PCI group markedly increased and left ventricular end-diastolic diameter and pro-BNP level decreased significantly. The occurrence rates of perioperative complications in the early PCI group and major adverse cardiac events (MACE) during the follow-up period were significantly reduced. Quality of life scores in the early PCI group markedly improved. We concluded that in patients with coronary heart disease complicated with cardiac insufficiency, early PCI treatment was safe and effective. PMID- 28352339 TI - Determination of DNA damage and telomerase activity in stanozolol-treated rats. AB - Anabolic androgenic steroids (AAS) are performance-enhancing drugs commonly abused by atheletes. Stanozolol is a synthetic testosterone-derived anabolic steroid. Although it is well known that AAS have several side-effects, there are only few toxicological studies available on the toxic effects and mechanisms of action of stanozolol. The aim of this study was to investigate the genotoxic effects of stanozolol and to determine its effects on telomerase activity in Sprague-Dawley male rats. For this purpose, 34 male rats were divided into 5 groups as follows: i) the control group (n=5); ii) the propylene glycol (PG) treated group (n=5); iii) the stanozolol-treated group (n=8); iv) the PG-treated group subjected to exercise (n=8); and v) the stanozolol-treated group subjected to exercise (n=8). PG is used as a solvent control in our study. Stanozolol (5 mg/kg) and PG (1 ml/kg) were injected subcutaneously 5 days/week for 28 days. After 28 days, the animals were sacrificed, and DNA damage evaluation (comet assay) and telomerase activity assays were then performed using peripheral blood mononuclear cells (PBMCs). Telomerase activity was measured by using the TeloTAGGG Telomerase PCR ELISA PLUS kit. The results of this study revealed that stanozolol treatment induced DNA damage, while exercise exerted a protective effect. Stanozolol treatment without exercise stimulation was associated with a significant increase in telomerase activity in the PBMCs. PMID- 28352341 TI - Expression and significance of TIMP-3, PACAP and VIP in vaginal wall tissues of patients with stress urinary incontinence. AB - The objective of the present study was to investigate whether tissue inhibitor of metalloproteinase-3 (TIMP-3), pituitary adenylate cyclase-activating polypeptide (PACAP), and vasoactive intestinal peptide (VIP) participate in the occurrence of female stress urinary incontinence (SUI) by measuring the expression levels of TIMP-3, PACAP, and VIP in the vaginal wall and analyzing their correlation to understand the pathogenesis of female SUI. Forty female patients who were admitted to our hospital for tension-free obturator tape surgery for treatment of SUI from April, 2012 to December, 2015 were selected as the study group. Forty patients who underwent vaginal or total abdominal hysterectomy for treatment of non-estrogen-related diseases during the same period were selected as the control group. Tissue samples from the anterior vaginal wall, located at twelve o'clock, were taken from both groups. The expression levels of TIMP-3, PACAP and VIP were detected by immunohistochemistry, and the correlation of integral optical density (IOD) among expressions of TIMP-3, PACAP, and VIP was investigated. The expression of TIMP-3 in vaginal wall tissues of the study group was lower than that of the control group (P<0.05). The expression of PACAP and VIP in vaginal tissues of the study group were lower than those of the control group (P<0.05). In the study group, the IOD of PACAP expression was significantly and positively correlated with that of VIP (r=0.873, P<0.05), the IOD of PACAP expression was significantly and positively correlated with that of TIMP-3 (r=0.802, P<0.05), and the IOD of VIP expression was significantly and positively correlated with that of TIMP-3 (r=0.716, P<0.05). In conclusion, TIMP-3, PACAP and VIP jointly participate in the occurrence of female SUI. Increasing the expression of TIMP-3, PACAP, and VIP, repairing neurons, and enhancing the elasticity of vaginal wall tissues may become a new way to treat female SUI. PMID- 28352340 TI - Clinical efficacy of lumbar interbody fusion using a channel system combined with ozone therapy for the treatment of central-type L3-L4 lumbar disc herniation. AB - The clinical efficacy of minimally invasive lumbar interbody fusion via the intervertebral foramen combined with ozone (O3) therapy for the treatment of L3 L4 central-type lumbar disc herniation was explored. We recruited patients with sciatica who attended our hospital between July 2013 and October 2015 and underwent lumbar X-ray (anteroposterior and lateral view), lumbar flexion extension radiographs, computed tomography, and magnetic resonance imaging after admission. Seventy-four patients with central-type lumbar disc herniation but no other complications were randomly selected and divided into the observation and control groups. The observation group comprised 37 patients treated with lumbar fusion using a channel system combined with O3 therapy, whereas the control group comprised 37 patients treated with lumbar fusion alone. The effects of the two therapies were evaluated using visual analog scale, Japanese Orthopaedic Association, and MacNab scores. There was no significant difference in scores between the two groups before surgery (P>0.05). The scores of the observation group after treatment were significantly lower than those before surgery and those of the control group (P<0.05). One patient in the observation group experienced no obvious improvement in symptoms after surgery, and two patients in the control group experienced postoperative recurrence; these three patients subsequently underwent laminectomy combined with planted bone fusion and internal fixation. There was no significant difference in total efficacy rates between the two groups (P>0.05). Lumbar fusion using a channel system combined with O3 therapy for the treatment of L3-L4 central-type lumbar disc herniation is safe and effective. It has the advantages of reduced trauma, fewer complications, and rapid pain relief, and it promotes the recovery of lumbar function. Strict mastery of the surgical indications is key to the success of the procedure; however, it is worth expanding its use in the clinical setting. PMID- 28352342 TI - Different ventilation modes combined with ambroxol in the treatment of respiratory distress syndrome in premature infants. AB - The aim of the present study was to compare the effectiveness of different modes of mechanical ventilation in combination with secretolytic therapy with ambroxol in premature infants with respiratory distress syndrome. Seventy-three premature infants with hyaline membrane disease (HMD) (stage III-IV), also known as respiratory distress syndrome, who were supported by mechanical ventilation in the neonatal intensive care unit (NICU) of Xuzhou Central Hospital, were involved in the present study, between January 2013 and February 2015. Forty cases were randomly selected and treated with high frequency oscillatory ventilation (HFOV), forming the HFOV group, whereas 33 cases were selected and treated with conventional mechanical ventilation (CMV), forming the CMV group. Patients in the two groups were administered ambroxol intravenously at a dosage rate of 30 mg/kg body weight at the beginning of the study. The present study involved monitoring the blood gas index as well as changes in the respiratory function index in the two groups. Additionally, the incidence of complications in the premature infants in the two groups was observed prior to and following the ventilation. Pulmonary arterial oxygen tension (PaO2), the PaO2/fraction of inspired oxygen (FiO2) ratio, the oxygenation index [OI = 100 * mean airway pressure (MAP) * FiO2/PaO2], as well as the arterial/alveolar oxygen partial pressure ratio (a/APO2) = PaO2/(713 * FiO2 partial pressure of carbon dioxide (PaCO2)/0.8) of the patients in the HFOV group after 1, 12 and 24 h of treatment were significantly improved as compared to the patients of the CMV group. However, there was no significant difference between patients in the two groups with regard to the number of mortalities, complications such as pneumothorax, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), and the time of ventilation. In conclusion, combining HFOV with ambroxol secretolytic therapy is a more viable option, as the combined treatment resulted in significant improvements in arterial blood gas levels, oxygenation and the respiratory function of lungs in preterm infants. PMID- 28352343 TI - Clinical features of multiple primary carcinomas of the oral cavity. AB - The present study aimed to elucidate the clinical characteristics of multiple primary carcinomas of the oral cavity. The clinical records of 1,024 patients who were treated during follow-up for oral cancer at the Department of Stomatology, Henan Provincial People's Hospital, between March 2013 and December 2014 were retrospectively reviewed. The clinical characteristics of 961 patients who developed single primary oral squamous cell carcinoma (SCC) during follow-up and 54 patients who subsequently developed multiple primary carcinomas in the oral cavity were compared. Multiple primary carcinomas exhibited a female predilection, were most prevalent in the gingiva, and tended to show earlier tumor and nodal stages, as compared with single primary carcinomas. The local recurrence rate was higher for multiple primary carcinomas, as compared with single primary carcinomas, and was demonstrated to increase with the number of multiple primary occurrences. The cumulative incidence rates for metachronous second primary carcinomas following the onset of the first carcinoma at 10 years was 8.0%. Recurrence of multiple primary carcinomas did not decrease the survival rates of the patients assessed in the present study. Furthermore, differences were detected in the clinical characteristics between patients with single oral SCC and those with multiple primary oral carcinomas. The results of the present study indicated that early diagnosis and treatment and close long-term follow-up are required for patients with multiple primary oral carcinomas. PMID- 28352344 TI - Diffusion-weighted whole-body imaging with background body signal suppression/T2 image fusion for the diagnosis of colorectal polyp and cancer. AB - Diffusion-weighted whole-body imaging with background body signal suppression/T2 image fusion (DWIBS/T2) is useful for the diagnosis of cancer as it presents a clear contrast between cancerous and non-cancerous tissue. The present study investigated the limitations and advantages of DWIBS/T2 with regards to the diagnosis of colorectal polyp (CP) or cancer (CRC). The current study included patients diagnosed with CP or CRC following colonoscopy, who were subjected to DWIBS/T2 between July 2012 and March 2015. Patient records were analyzed retrospectively. Patients were subjected to DWIBS/T2 when they presented with abdominal cancers or inflammation. Colonoscopy was performed as part of screening, or if patients had suspected colon cancer or inflammatory bowel disease. A total of 8 male and 7 female patients were enrolled in the present study. All patients, with the exception of one who had been diagnosed with CRC following colonoscopy, had positive results and all patients diagnosed with CP following a colonoscopy, with the exception of one, had negative results on DWIBS/T2. Thus, CRC was detected by DWIBS/T2, while CP was not (P=0.0028). The diameter of CRC lesions was significantly larger than that of CP (P<0.0001) and that of lesions positive on DWIBS/T2 was significantly larger than that of negative lesions (P=0.0004). The depth of invasion tended to be greater for lesions positive on DWIBS/T2 compared with that of negative ones. This indicated that DWIBS/T2 may be suitable for the detection of CRC but not for detection of CP. The results of DWIBS/T2 may also be affected by lesion diameter and depth of invasion. PMID- 28352345 TI - Niche astrocytes promote the survival, proliferation and neuronal differentiation of co-transplanted neural stem cells following ischemic stroke in rats. AB - Niche astrocytes have been reported to promote neuronal differentiation through juxtacrine signaling. However, the effects of astrocytes on neuronal differentiation following ischemic stroke are not fully understood. In the present study, transplanted astrocytes and neural stem cells (NSCs) were transplanted into the ischemic striatum of transient middle cerebral artery occlusion (MCAO) model rats 48 h following surgery. It was observed that the co transplantation of astrocytes and NSCs resulted in a higher ratio of survival and proliferation of the transplanted NSCs, and neuronal differentiation, in MCAO rats compared with NSC transplantation alone. These results demonstrate that the co-administration of astrocytes promotes the survival and neuronal differentiation of NSCs in the ischemic brain. These results suggest that the co transplantation of astrocytes and NSCs is more effective than NSCs alone in the production of neurons following ischemic stroke in rats. PMID- 28352346 TI - Salvianolic acid B prevents steroid-induced osteonecrosis of the femoral head via PPARgamma expression in rats. AB - Salvianolic acid B (Sal B) is a water-soluble phenolic compound derived from Salvia Miltiorrhiza. Recent studies show Sal B has a clear function of anti cerebral ischemia injury, which is closely related to antioxidation, free radical scavenging, neuroprotection and the blood brain barrier. The aim of the present study was to verify whether Sal B prevents steroid-induced osteonecrosis of the femoral head and to investigate its underlying pharmacological mechanisms. Steroid-induced osteonecrosis rat models were established to evaluate the effects of Sal B on osteonecrotic changes and repair processes. The use of Sal B improved steroid-induced histopathological scores and inhibited osteoclast differentiation in rats. Notably, Sal B induced bone marrow-derived mesenchymal stem cells into osteogenesis. Moreover, Sal B treatment suppressed peroxisome proliferator activated receptor (PPAR)gamma and AP2 protein expression levels and increased runt-related transcription factor 2 and Collagen I protein expression levels in steroid-induced rats. osteocalcin and alkaline phosphatase content in steroid induced rats was enhanced by treatment with Sal B. These results suggest that Sal B prevents steroid-induced osteonecrosis of the femoral head via PPARgamma expression in rats. The present pilot study provides a brief insight into the effect of Sal B on steroid-induced osteonecrosis. PMID- 28352347 TI - One mechanism of glucocorticoid action in asthma may involve the inhibition of IL 25 expression. AB - While the mechanism of action of classic cytokines in asthma has received increased attention from researchers, certain non-classical cytokines, such as IL 25, also participate in this mechanism. The present study was performed to investigate the changes in IL-25 (IL-17E) mRNA and protein in bronchial asthma and to further characterize the mechanism underlying the action of glucocorticoids in asthma. A total of 96 specific pathogen-free BALB/c male mice were randomly divided into three normal groups (after the first allergization, after the second allergization and after excitation), three asthma groups (with the same three subgroups), a dexamethasone group and a budesonide group (n=12/group). An asthma model was established via the ovalbumin-sensitized excitation method. Mice in the dexamethasone group received intraperitoneal injections of dexamethasone 1 h prior to each excitation, the budesonide group received a budesonide suspension via inhalation 2 h before and after each provocation, and the normal group was sensitized and challenged with isotonic saline. IL-25 protein expression levels in the bronchoalveolar lavage fluid were measured by ELISA, and the relative IL-25 mRNA content in lung tissue was determined by reverse transcription-quantitative polymerase chain reaction. Compared with the normal groups, both the protein and mRNA levels of IL-25 were significantly increased (P<0.05) in the asthma groups. Dexamethasone and budesonide groups exhibited significant protein and mRNA reductions in IL-25, as compared with the asthma group after excitation (P<0.05), whereas these two groups significantly increased levels compared with the normal group after excitation (P<0.05). No significant differences in IL-25 mRNA expression levels were detected in the dexamethasone and budesonide groups when compared with the normal group after excitation. Therefore, we conclude that IL-25 is involved throughout the process of inflammation and inflammatory immune pathogenesis in asthma. One of the mechanisms of glucocorticoid action in asthma may involve inhibition of IL-25 expression. PMID- 28352348 TI - Gambogic acid potentiates the chemosensitivity of colorectal cancer cells to 5 fluorouracil by inhibiting proliferation and inducing apoptosis. AB - Chemotherapy using 5-fluorouracil (5-FU) for colorectal cancer (CRC) has low specificity and response rates, leading to severe side effects. Gambogic acid (GA), a traditional Chinese medicine, has multi-targeted anticancer effects, including growth inhibition and apoptosis induction. However, it is unclear whether a combination of 5-FU and GA has synergistic anticancer effects in CRC cells. In this study, SW480 and HCT116 human CRC cells and human intestinal epithelial cells (IECs) were treated with different concentrations of 5-FU, GA or 5-FU+GA. A Cell Counting kit-8 assay was conducted to quantify cell proliferation. The combination index (CI) was calculated and the median-effect principle was applied to analyze the interaction between 5-FU and GA. Flow cytometry was used to determine the percentage of cells undergoing apoptosis. Reverse transcription-quantitative polymerase chain reaction and western blotting were applied to measure P53, survivin and thymidylate synthase (TS) mRNA and protein levels. It was found that 5-FU+GA more pronouncedly inhibited cell growth and induced apoptosis, compared with either monotherapy. CI values <1 indicated the synergistic effects of the drugs. 5-FU+GA further decreased P53, survivin and TS mRNA and protein levels in the two CRC cell lines compared with single drugs, whereas increased P53 protein levels were observed in HCT116 cells. Moreover, 5 FU+GA did not increase cytotoxicity to IECs. These results demonstrate that GA enhances the anticancer effects of 5-FU on CRC cells. Combined treatment with 5 FU and GA is effective and safe for CRC cells, and may become a promising chemotherapy treatment. PMID- 28352349 TI - Role of mesenchymal stem cells on differentiation in steroid-induced avascular necrosis of the femoral head. AB - Steroids are known to inhibit osteogenic differentiation and decrease bone formation in mesenchymal stem cells (MSCs), while concomitantly inducing steroid induced avascular necrosis of the femoral head (SANFH). The aim of the present study was to evaluate the function of MSCs on differentiation in SANFH and investigate the pathobiological mechanisms underlying SANFH in a rabbit model. MSCs in the control, trauma-induced ANFH (TANFH) and SANFH groups were incubated with low-glucose complete Dulbeccos modified Eagles medium containing 10% fetal bovine serum. A number of adipocytes in the MSCs were stained with Sudan III and counted using a light microscope. The mRNA and protein expression levels of the adipose-specific 422 (AP2), peroxisome proliferator-activated receptor-gamma (PPARgamma), RUNX2, collagen type I (Col I) and miR-103 in the MSCs were determined using quantitative polymerase chain reaction and western blot analysis, respectively. In addition, the activities of osteocalcin (OC), alkaline phosphatase (ALP) and triglyceride (TG) in MSCs were analyzed using radioimmunoassay and determination kits. In the MSCs of the SANFH group, the mRNA and protein expression levels of AP2 and PPARgamma were increased, while those of RUNX2 and Col I were reduced. Furthermore, the levels of OC and ALP activity in the MSCs of the SANFH group were decreased, and the activity of TG in the MSCs of the SANFH group was increased. In addition, the expression of miR-103 in the MSCs of the SANFH group was elevated. Following routine culture of the MSCs for 3 weeks, the number of adipocytes among the MSC population of the SANFH group was increased. Therefore, the results of the present study suggest that the osteogenic differentiation of MSCs in the SANFH was mitigated, while fat differentiation was promoted, which provides a novel explanation for the pathological changes associated with SANFH. PMID- 28352350 TI - Expression of NUAK2 in gastric cancer tissue and its effects on the proliferation of gastric cancer cells. AB - The present study aimed to analyze the expression and effects of NUAK2 in gastric cancer and adjacent normal gastric tissues. The protein expression levels of NUAK2 were detected by western blot analysis. The effects of NUAK2 expression on the proliferation of gastric cancer cells was detected using an MTT and BrdU incorporation assay. Furthermore, the effects of NUAK2 on proliferation and cancer stem cell markers, both protein and microRNA (miRNA), were investigated by western blot analysis and miRNA microarrays, respectively. The results demonstrated that NUAK2 was able to significantly promote the proliferation of SGC-7901 gastric cancer cells. In addition, NUAK2 overexpression decreased the percentage of cells in the G1 phase and increased the percentage of cells in the S phase. Western blot analysis and miRNA microarrays revealed that overexpression of NUAK2 resulted in increased expression levels of proliferation markers, including c-myc, proliferating cell nuclear antigen, cyclin-dependent kinase 2, miRNA 21, and gastric cancer stem cell markers, including aldehyde dehydrogenase 1, CD44 and CD133. In conclusion, NUAK2 expression differed between the tumor and normal gastric tissues. NUAK2 was able to promote the proliferation of gastric cancer cells and regulate their cell cycle. Proliferation and cancer stem cell markers were upregulated by NUAK2 expression. Therefore, the results from the present study suggest that NUAK2 may be a promising target for gastric cancer therapy in the future. PMID- 28352351 TI - MicroRNA-302d downregulates TGFBR2 expression and promotes hepatocellular carcinoma growth and invasion. AB - Hepatocellular carcinoma (HCC) is the second leading cause of cancer-associated mortality in China and the third leading cause worldwide. A number of microRNAs (miRNAs) have been implicated in cell cycle progression, growth, apoptosis, angiogenesis and metastasis in HCC. In the present study, reverse transcription quantitative polymerase chain reaction analysis was used to detect the levels of miR-302d expression in the tissues of 30 patients with HCC. Cell cycle, growth, apoptosis and migration were analyzed using a cell counting kit, flow cytometry and a Transwell migration assay. Dual-luciferase reporter assays and western blotting were also used to analyze the expression levels of transforming growth factor beta type II receptor (TGFBR2) in HCC cells. The present study evaluated the role of miR-302d in the development and progression of HCC. Abnormally high expression of miR-302d was observed in 80% of HCC specimens. Moreover, patients with lower levels of miR-302d expression experienced a longer survival time than those with higher levels of miR-302d expression. It was demonstrated that miR 302d promoted HCC cell growth and migration, suppressed cell apoptosis and affected cell cycle distribution in vitro, and augmented tumorigenicity in vivo. Furthermore, TGFBR2, which is a tumor suppressor, was confirmed as a target of miR-302d in HCC cells. Dual-luciferase reporter assays indicated that TGFBR2 expression was negatively regulated by miR-302d. Taken together, the results of the present study suggest that miR-302d may serve as a valuable tool for predicting the prognosis of patients with HCC. PMID- 28352352 TI - Combination therapy with catechins and caffeine inhibits fat accumulation in 3T3 L1 cells. AB - Catechins and caffeine, which are green tea components, have a slimming effect; however, the combinational effect of fat metabolism in 3T3-L1 cells remains unclear. In the present study, 3T3-L1 cells were treated with catechins and caffeine in combination, and it was found that combination therapy with catechins and caffeine markedly reduced intracellular fat accumulation, mRNA expression levels of peroxisome proliferator-activated receptor-gamma and CCAAT/enhancer binding protein alpha in the early stage of cell differentiation were significantly reduced, and mRNA expression of fatty acid synthetase(FAS) andglycerol-3-phosphate dehydrogenase protein expression levels of FAS were downregulated. Noradrenaline-induced lipolysis was enhanced by caffeine, which markedly increased the protein expression of adipose triglyceride lipase and hormone sensitive lipase. These results indicated that combination therapy with catechins and caffeine synergistically inhibited lipid accumulation by regulating the gene and protein expression levels of lipid metabolism-related enzymes. Therefore, catechins and caffeine combination therapy has potential as a functional food that may be used to prevent obesity and lifestyle-associated diseases. PMID- 28352353 TI - Anticonvulsant effect of piperine ameliorates memory impairment, inflammation and oxidative stress in a rat model of pilocarpine-induced epilepsy. AB - The primary active component of black pepper is piperine, which is purified and used to treat epilepsy, achieving higher efficiency when purified. The present study was conducted to evaluate whether the anticonvulsant effect of piperine ameliorates pilocarpine-induced epilepsy, and to investigate the mechanism underlying these effects. Epilepsy was induced in Sprague Dawley rats using pilocarpine. Pilocarpine-induced epilepsy in the rats was treated with 40 mg/kg piperine for 45 consecutive days. Status epilepticus and a Morris water maze test were used to analyze the anticonvulsant effects of piperine in the epileptic rats. Inflammation and oxidative stress were then measured using commercially available kits following piperine treatment. Lastly, the activity of caspase-3 and the protein expression levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated X protein (Bax) were evaluated using commercially-available kits and western blot analysis, respectively. The results demonstrated that treatment with piperine was able to reduce the status epilepticus and prevented memory impairment following pilocarpine-induced epilepsy in rats. The anticonvulsant effects of piperine decreased inflammation and oxidative stress following pilocarpine-induced epilepsy in rats. The upregulated activity of caspase-3 and expression levels of Bax/Bcl-2 were suppressed following treatment with piperine in the rats with pilocarpine-induced epilepsy. These results suggest that the anticonvulsant effects of piperine ameliorate memory impairment, inflammation and oxidative stress in a rat model of pilocarpine-induced epilepsy. PMID- 28352354 TI - Antifreeze poisoning: A case report. AB - The current study reported the case of a 35-year-old male that presented with antifreeze poisoning. The clinical manifestations, laboratory investigations and treatments were analyzed, and the obtained results were compared with those in previous reports. Subsequent to consuming antifreeze, the patient mainly presented nausea and agitation, without disturbance of consciousness. Laboratory investigations indicated severe metabolic acidosis, renal dysfunction and hyperkalemia. The patient underwent hemodialysis and his condition was significantly improved on the day of admission. Renal function gradually deteriorated, but was eventually improved due to treatment, including hemodialysis, mannitol for catharsis, furosemide for diuresis, Xuebijing for the removal of blood stasis and detoxication, and reduced glutathione for the protection of major organs. The patient was discharged 1 month after hospital admission. In conclusion, the significance and clinical manifestations of antifreeze poisoning should be identified in clinical practice, and active hemodialysis should be provided. The aim of the current study was to summarize the clinical manifestations and treatments of patients with antifreeze poisoning, and to advance the recognition of antifreeze poisoning. PMID- 28352355 TI - Image-guided minimally invasive percutaneous treatment of spinal metastasis. AB - In order to provide effective options for minimally invasive treatment of spinal metastases, the present study retrospectively evaluated the efficacy and safety of image-guided minimally invasive percutaneous treatment of spinal metastases. Image-guided percutaneous vertebral body enhancement, radiofrequency ablation (RFA) and tumor debulking combined with other methods to strengthen the vertebrae were applied dependent on the indications. Percutaneous vertebroplasty (PVP) was used when vertebral body destruction was simple. In addition, RFA was used in cases where pure spinal epidural soft tissue mass or accessories (spinous process, vertebral plate and vertebral pedicle) were destroyed, but vertebral integrity and stability existed. Tumor debulking (also known as limited RFA) combined with vertebral augmentation were used in cases presenting destruction of the epidural soft tissue mass and accessories, and pathological vertebral fractures. A comprehensive assessment was performed through a standardized questionnaire and indicators including biomechanical stability of the spine, quality of life, neurological status and tumor progression status were assessed during the 6 weeks-6 months follow-up following surgery. After the most suitable treatment was used, the biomechanical stability of the spine was increased, the pain caused by spinal metastases within 6 weeks was significantly reduced, while the daily activities and quality of life were improved. The mean progression-free survival of tumors was 330+/-54 days, and no associated complications occurred. Therefore, the use of a combination of image-guided PVP, RFA and other methods is safe and effective for the treatment of spinal metastases. PMID- 28352356 TI - Investigation of the effect of phlomisoside F on complete Freund's adjuvant induced arthritis. AB - Phlomis younghusbandii Mukerjee (Labiatae) has been reported to be effective in the treatment of rheumatoid arthritis (RA). In the present study, the anti inflammatory and anti-arthritic effects of phlomisoside F (PF), isolated from P. younghusbandii Mukerjee (Labiatae), were investigated in male Wistar rats subjected to carrageen-induced paw edema and complete Freund's adjuvant (CFA) induced arthritis. Arthritis scores were evaluated by a 5-point ordinal scale (scores 0-4). Expression levels of TNF-alpha, IL-1beta, IL-6, IL-10, COX-2 and 5 LOX were determined via ELISA and western blot assays. Subsequent to establishing the edema and arthritis models, oral administration of PF (5, 10 and 20 mg/kg) significantly inhibited mean edema rate, compared with the control group in carrageenan-induced paw edema assay. In addition, administration of PF (5, 10 and 20 mg/kg/day) for 28 days markedly exhibited an anti-arthritic activity by offsetting the body weight loss, inhibiting the paw edema, reducing the arthritis scores and the indices of thymus and spleen, inhibiting the expression levels of TNF-alpha, IL-1beta, IL-6, COX-2 and 5-LOX, and increasing the expression of IL 10, when compared with the respective control group in CFA-induced arthritis assay. In conclusion, PF is a valuable anti-arthritic constituent of P. younghusbandii, and the present study results suggest that this herb may be used in the treatment of RA. PMID- 28352357 TI - Comparative analysis of cluster versus conventional immunotherapy in patients with allergic rhinitis. AB - The present study aimed to compare the efficacy and safety of subcutaneous immunotherapy with Dermatophagoides pteronyssinus standardized extract administered in conventional and cluster immunotherapy regiments for patients with persistent allergic rhinitis. A total of 60 patients with moderate to severe allergic rhinitis caused by dust mites were treated for 1 year with either conventional immunotherapy (n=30) or cluster immunotherapy (n=30). Nasal conjunctival symptoms and signs were assessed to evaluate the clinical efficacy of the two regimens, and the incidence of local and systemic adverse reactions were also evaluated. The findings demonstrated that the cluster regimen reduced the duration between the initial and maintenance dose by >60%, and resulted in a significant improvement, as compared with the conventional regimen, after 6 weeks of observation (P<0.05). However, the incidence of local and systemic adverse reactions in the cluster regimen during the dose accumulation phase and the dose maintenance phase was not significantly different, as compared with the conventional immunotherapy regimen. These results suggest that cluster immunotherapy is efficacious and safe to treat patients who are clinically sensitive to dust mites. PMID- 28352358 TI - Alterations in VEGF expression induced by antidepressant drugs in female rats under chronic social stress. AB - Vascular endothelial growth factor (VEGF) is thought to serve a role in neurogenesis and the stress response. Although a definite link between the action of antidepressants and VEGF has not been identified, it is assumed that VEGF, as a neurotrophic factor, serves an important role in the effects of antidepressant treatment. To examine this, the present study subjected adult female rats to four weeks of social instability stress and measured the effect of antidepressant treatment on the expression of VEGF. Firstly, endocrine markers of stress and body weight were measured in parallel with behavioral tests prior to and following subjection to stress. Then, the effect of 28-day daily treatment with desipramine (DMI; 10 mg/kg), fluoxetine (5 mg/kg) or tianeptine (10 mg/kg) on the number of copies of VEGF mRNA in the amygdala, hippocampus and hypothalamus, and on serum VEGF protein levels, of rats subjected to chronic stress was determined. In addition, the weight of the adrenal glands was measured following subjection to stress. Exposure to chronic stress was found to increase the rats' sucrose preference, and diminish their tendency for general exploration and time spent in the open. The relative adrenal weights of the stressed rats were significantly increased compared with the control. Plasma concentrations of corticosterone and adrenocorticotropic hormone were not significantly augmented. In addition, the present study identified that stress elevated VEGF mRNA expression in all studied neural structures. Furthermore, the results identified that the stress-induced increase in VEGF mRNA expression in the amygdala and hypothalamus was attenuated by long-term administration of DMI. Conversely, a decrease in serum VEGF concentration was observed in stressed rats, which was not reversed by treatment with antidepressants. In conclusion, the current study suggests that under conditions of stress, VEGF serves a role in the mechanism of action of DMI, through modulating activity of the norepinephrine system. PMID- 28352359 TI - Platelet to lymphocyte ratio is associated with the severity of coronary artery disease and clinical outcomes of percutaneous coronary intervention in the Chinese Han population. AB - The aim of the present study was to evaluate whether the ratio of the absolute number of platelets to the number of lymphocytes (PLR) correlates with the severity of coronary artery disease (CAD) and major adverse cardiovascular disease (CVD) events in Chinese patients with CAD. PLR was calculated as follows: PLR=platelet count/lymphocyte count, using the complete blood counts of 854 Chinese Han subjects. CAD severity was determined using angiographic evidence by cardiologists unaware of the study aims. The association between PLR and CAD severity was analyzed by logistic regression. Clinical endpoints were evaluated during a median follow-up period of 42 months. The association between PLR and CVD events was assessed using Cox regression models. Patients with PLR>171 exhibited more severe coronary artery stenosis [odds ratio, 2.393; 95% confidence intervals (CI), 1.394-4.108; P=0.002] and worse prognoses, with a higher rate of major adverse CVD events during five years of follow-up (hazard ratio, 1.982; 95% CI, 1.329-2.957; P=0.001). A Kaplan-Meier curve demonstrated that the CVD event rate of 34.27% in patients with PLR>171 was significantly higher than that in patients with PLR<100 (P<0.001). These findings suggest that PLR is independently associated with CAD severity and long-term major adverse CVD events; therefore, high PLR may predict poor prognosis of CAD in the Chinese Han population. PMID- 28352360 TI - Naringenin inhibits migration of lung cancer cells via the inhibition of matrix metalloproteinases-2 and -9. AB - Lung cancer is among the most common causes of cancer-related mortality. It has a high mortality rate and resistance to chemotherapy due to its high metastatic potential. Naringenin, a bioactive compound identified in several fruits, displays anti-inflammatory and antitumor effects. Furthermore, naringenin mitigates the migration of several human cancer cell types. However, the effects of naringenin on lung cancer remain unclear. The current study investigated the mechanisms of naringenin on the migration of lung cancer A549 cells. The results indicate that significant alteration in A549 cell proliferation was observed in response to naringenin (0-300 uM) treatment for 24 and 48 h. Furthermore, a dose dependent migration inhibition of A549 in the presence of naringenin was observed by healing and transwell migration assays. In addition, a zymography assay revealed that naringenin exhibited a concentration-dependent inhibition of matrix metalloproteinase (MMP)-2 and -9 activities. Furthermore, naringenin also inhibited the activities of AKT in a dose-dependent manner. These observations indicated that naringenin inhibited the migration of lung cancer A549 cells through several mechanisms, including the inhibition of AKT activities and reduction of MMP-2 and -9 activities. PMID- 28352361 TI - Casticin inhibits the activity of transcription factor Sp1 and the methylation of RECK in MGC803 gastric cancer cells. AB - The present study investigated the effect of casticin on reversion-inducing cysteine-rich protein with kazal motifs (RECK) gene expression and intracellular methylation levels in MGC803 gastric cancer cells. Cells were treated with 1, 10 and 30 umol/l casticin. Western blotting and reverse transcription-quantitative polymerase chain reaction assays were performed to determine the protein expression and mRNA levels of RECK and DNA methyltransferase 1 (DNMT1), respectively. High-performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry was used to detect RECK methylation. In addition, MGC803 cell proliferation was measured by an MTT assay and the DNA binding activity of transcription factor Sp1 was determined using an enzyme linked immunosorbent assay. The results demonstrated that treatment with 1, 10 and 30 umol/l casticin significantly increased RECK protein expression and mRNA levels. In addition, casticin (30 umol/l) decreased RECK promoter methylation levels by 31%, global DNA methylation levels by 39% and nuclear methylation activity by 71.6%. Furthermore, casticin downregulated the mRNA levels and protein expression of DNMT1. The MTT assay demonstrated that MGC803 cell proliferation was inhibited by casticin treatment and DNA binding assays indicated that casticin reduced the DNA-binding activity of Sp1. The present study therefore indicated that casticin inhibits the proliferation of gastric cancer MGC803 cells by upregulating RECK gene expression and reducing intracellular methylation levels. PMID- 28352362 TI - Feasibility of continuous, catheter-directed thrombolysis using low-dose urokinase in combination with low molecular-weight heparin for acute iliofemoral venous thrombosis in patients at risk of bleeding. AB - The present study aimed to examine the feasibility of catheter-directed thrombolysis (CDT) using continuous infusion of low-dose urokinase in combination with low molecular weight heparin (LMWH) for acute iliofemoral venous thrombosis. This retrospective analysis included patients with symptomatic acute iliofemoral venous thrombosis who received CDT using continuous infusion of low-dose urokinase in combination with LMWH within the past four years. Urokinase was administered at 1*104 U/h and 2*104 U/h in patients at high-risk and low-risk of bleeding, respectively. Measurements included urokinase dosage, duration, clinical outcomes and CDT-related complications. A total of 46 patients were included (high-risk, n=17; low-risk, n=29). In the high-risk patients, 64.7% experienced dissolution of >=50% thrombi after a median CDT duration of 8 days (range, 6-10 days) and median total urokinase dose of 1.92*106 units (range, 1.44 2.4*106 units). In the low-risk patients, 82.8% achieved dissolution of >=50% thrombi after a median CDT duration of 7 days (range, 4-10 days) and a median total urokinase dose of 3.36*106 units (range, 1.92-4.80*106 units). Remission of clinical symptoms after CDT was achieved in 15 (88.2%) and 28 (96.6%) cases in high-risk and low-risk patients, respectively. No treatment-associated pulmonary embolism or major bleeding was observed. Three (6.5%) subjects (high-risk, n=1; low-risk, n=2) experienced minor bleeding. In conclusion, continuous infusion of low-dose urokinase via CDT in combination with LMWH is effective and safe for acute iliofemoral venous thrombosis in patients with one or more risk factor for bleeding. PMID- 28352363 TI - Role of microRNA-130a in myocardial hypoxia/reoxygenation injury. AB - The aim of this study was to investigate the role of microRNA (miR)-130a in the pathogenesis of myocardial hypoxia/reoxygenation (H/R) injury. Primary rat cardiomyocytes were cultured and subjected to H/R treatment. Reverse transcription-quantitative polymerase chain reaction was performed to detect the levels of miR-130a, western blot analysis was used to determine the expression of various proteins, and CCK-8 assay was performed to determine cell viability. In addition, flow cytometry was used to assess apoptosis. The cell viability was significantly decreased and the apoptosis rate was significantly increased in H/R treated primary cardiomyocytes, and the expression level of miR-130a was also elevated in these model cells. Transfection with miR-130a inhibitor significantly elevated the cell viability and reduced the apoptosis rate in H/R-treated cardiomyocytes. Bioinformatics analysis indicated that autophagy-related gene 14 (ATG14) is the target for miR-130a, which was confirmed by dual-luciferase reporter assay and western blot analysis. When the H/R model cells were co transfected with miR-130a inhibitor and small interfering RNA against ATG14, the cell viability was significantly reduced and the apoptosis rate was significantly elevated, compared with that of cells transfected with miR-130a inhibitor alone. miR-130a inhibitor transfection significantly elevated the levels of ATG14 and phosphorylated (p-)Beclin 1, increased the LC3II/LC3I ratio, and decreased the expression levels of P62 and cleaved caspase-3, while the co-transfection of miR 130a inhibitor and siR-ATG14 attenuated these effects in H/R-induced primary cardiomyocytes. These results indicate that miR-130a is involved in H/R-induced injuries in primary cardiomyocytes, and that the inhibition of miR-130a increases the levels of ATG14 and p-Beclin 1, thereby increasing autophagy and inhibiting apoptosis in these cells. PMID- 28352364 TI - 2,4,6-Trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide increases calcium influx in lipopolisaccharide-pre-treated arteries. AB - It has been demonstrated that 2,4,6-trimethyl-N-[3 (trifluoromethyl)phenyl]benzenesulfonamide (m-3M3FBS) activates phospholipase C (PLC) and stimulates apoptosis in smooth muscle cells, which may increase vascular reactivity. The primary aim of the present study was to evaluate the physiological effects of the direct stimulation of PLC by m-3M3FBS on vascular smooth muscle reactivity in arteries pre-treated with lipopolysaccharides (LPS) as a model of septic shock. Experiments were performed on isolated and perfused tail arteries of Wistar rats. The contraction force in the model was measured by assessing increases in perfusion pressure at a constant flow. Parameters describing the concentration-response curves (CRCs) obtained for phenylephrine and arginine-vasopressin in the presence of LPS confirmed a decrease in vessels reactivity. In comparison with the controls, m-3M3FBS treatment caused a significant increase in LPS-untreated as well as pre-treated arteries. Furthermore, in the presence of m-3M3FBS, calcium influx from intra- as well as extracellular calcium stores was significantly higher for LPS-untreated and pre treated arteries. The results of the present study suggested that m-3M3FBS significantly increased the reactivity of vascular smooth muscle cells pre treated with LPS by increasing the calcium influx from intra- and extracellular calcium stores. Further studies investigating this mechanism are required to evaluate whether this pathway may be a potential therapeutic strategy to treat sepsis. PMID- 28352365 TI - Heart failure modulates electropharmacological characteristics of sinoatrial nodes. AB - The impact of heart failure (HF) on sinoatrial node (SAN) channel regulation and electropharmacological responses has remained elusive. The present study aimed to investigate the effects of HF on the electrical activity of SANs with and without pharmacological interventions. Action potentials (APs) were recorded in isolated SANs from normal rabbits (control) and those with HF (rapid ventricular pacing for 4 weeks) prior to and after administration of a funny current blocker (ivabradine; 0.1, 0.3, 3 or 10 uM), a calmodulin kinase II inhibitor (KN-93; 0.3 or 3 uM), a sarcoplasmic reticulum Ca2+ release inhibitor (ryanodine; 0.3 or 3 uM), a sodium current inhibitor (tetrodotoxin; 1, 3 or 10 uM) and a late sodium current inhibitor (ranolazine; 10 uM). Western blot analysis was used to investigate the protein expression in SANs from normal rabbits and those with HF. Control SANs had a higher beating rate than SANs from rabbits with HF (2.3+/-0.1 vs. 1.5+/-0.1 Hz; P<0.001). Similarly, ivabradine (10 uM), KN-93 (3 uM), ranolazine (10 uM) and ryanodine (3 uM) decreased the beating rates of SANs in the control (n=6) and HF (n=6) groups. Ivabradine treatment resulted in a higher incidence of AP block in HF vs. control SANs (66.7 vs. 0%; P<0.05). Tetrodotoxin (1, 3 or 10 uM) decreased the beating rate to a higher extent in SANs from rabbits with HF than in those from control rabbits and induced a higher incidence of AP block (66.7 vs. 0%; P<0.05). Furthermore, SANs from rabbits with HF had higher protein levels of phospholamban (PLB) and lower levels of hyperpolarization-activated cyclic nucleotide-gated potassium channel 4, ryanodine receptor and phosphorylated PLB than control SANs. In conclusion, HF modulates electropharmacological responses in the SAN by channel regulation, which may result in SAN dysfunction. PMID- 28352366 TI - Prolyl oligopeptidase attenuates hepatic stellate cell activation through induction of Smad7 and PPAR-gamma. AB - Prolyl oligopeptidase (POP) is a serine endopeptidase widely distributed in vivo with high activity in the liver. However, its biological functions in the liver have remained largely elusive. A previous study by our group has shown that POP produced N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) and thereby exerted an anti-fibrogenic effect on hepatic stellate cells (HSCs) in vitro. It was therefore hypothesized that POP may affect the activation state of HSCs and has an important role in liver fibrosis. The HSC-T6 immortalized rat liver stellate cell line was treated with the POP inhibitor S17092 or transfected with recombinant lentivirus to overexpress POP. Cell proliferation and apoptosis were determined using a Cell Counting Kit-8 and flow cytometry, respectively. The activation status of HSCs was determined by examination of the expression of alpha-smooth muscle actin (alpha-SMA), collagen I, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor (TGF)-beta-Smad signaling and peroxisome proliferator activated receptor-gamma (PPAR-gamma). Inhibition by S17092 decreased, whereas lentiviral expression increased the activity of POP and cell proliferation, while neither of the treatments affected cell apoptosis. Of note, S17092 significantly increased, whereas POP overexpression decreased the expression of alpha-SMA and MCP-1 without affecting the expression of collagen I and TGF-beta1. Furthermore, S17092 caused a reduction, whereas POP overexpression caused an upregulation of Smad7 protein and PPAR-gamma, but not phosphorylated Smad2/3 expression. In conclusion, POP attenuated the activation of HSCs through inhibition of TGF-beta signaling and induction of PPAR-gamma, which may have therapeutic potential in liver fibrosis. PMID- 28352367 TI - Association between Helicobacter pylori infection and angiographically demonstrated coronary artery disease: A meta-analysis. AB - Coronary artery disease (CAD) is a leading cause of mortality globally. However, the etiology and pathogenesis of CAD are not fully understood. The aim of the present meta-analysis was to estimate the association between the risk of CAD and Helicobacter pylori (H. pylori) infection. A literature search was performed to identify eligible studies published prior to August 14, 2014. Fixed or random effect meta-analytical methods were used to pool the data and perform the subgroup analyses. The effect measures estimated were the odds ratios (OR) for dichotomous data reported with 95% confidence intervals (95% CI). Of the 109 studies identified using the search parameters, 26 cross-sectional studies were eligible involving 3,901 CAD patients and 2,751 controls. H. pylori infection was associated with an increased risk of CAD (OR: 1.96, 95% CI: 1.47-2.63, P<0.00001). When the adjusted ORs were used to conduct another meta-analysis, the OR value decreased, but the association remained significant (OR: 1.42, 95% CI: 1.09-1.86, P=0.008). The association between H. pylori infection and CAD risk was stronger in younger individuals than in older individuals (OR: 2.36, 95% CI 1.50 3.73 vs. OR: 1.59, 95% CI: 1.19-2.11). A significant association was observed in studies from Europe (OR: 2.11, 95% CI: 1.54-2.88, P=0.01) and the USA (OR: 1.43, 95% CI: 1.08-1.91, P=0.36). There is a potential association between H. pylori infection and the risk of CAD. The association may be influenced by age and ethnicity. PMID- 28352368 TI - Metformin reduces the expression of NADPH oxidase and increases the expression of antioxidative enzymes in human monocytes/macrophages cultured in vitro. AB - [This retracts the article DOI: 10.3892/etm.2016.2977.]. PMID- 28352369 TI - ACE I/D Polymorphism in Hypertensive Patients of Kashmiri Population. AB - BACKGROUND: The angiotensin-converting enzyme (ACE) gene in humans has an insertion-deletion (I/D) polymorphic state in intron 16 on chromosome 17q23. This polymorphism has been widely investigated in different diseases. In this study we aimed to investigate the ACE I/D genotype frequency in hypertensive cases in Kashmiri population. MATERIALS AND METHODS: We designed a case control study, where 52 hypertensive cases were studied for ACE I/D polymorphism against 150 age/sex matched controls taken from general population. The polymorphisms of ACE gene were investigated using polymerase chain reaction for detection of ACE I/D genotype. Fisher's Chi square test was used for calculation of P value and OR. RESULTS: We found the frequency of ACE DD genotype to be 46.15% (24/52), II 23.07% (12/52) and DI 30.77% (16/52) in 52 hypertensive cases. CONCLUSIONS: The ACE I/D genotype is positively associated with hypertension in our population. PMID- 28352370 TI - Role of Genetic Polymorphism of Angiotensin-Converting Enzyme, Plasminogen Activator Inhibitor-1 and Endothelial Nitric Oxide Synthase in the Prognosis of Coronary Artery Disease. AB - BACKGROUND: This study was to investigate the effects of multiple genetic polymorphisms and conventional risk factors in the prognosis of coronary artery disease (CAD). METHODS: One hundred and fifty five patients with CAD were prospectively recruited, they were subgrouped as single vessel disease (SVD) and multiple vessel disease (MVD). All patients were detected I/D polymorphism of angiotensin-converting enzyme (ACE) gene, 4G/5G polymorphism of plasminogen activator inhibitor-1 (PAI-1) gene, and G894->T mutation of endothelial nitric oxide synthase (eNOS) gene. The patients were followed up for 10-65 months, mean 35 months. End points were major adverse cardiovascular events (MACE), including angina, myocardial infarction, and cardiac sudden death. RESULTS: During the follow-up period, MACE developed in 81 patients, 73 patients with angina, seven with myocardial infarction, and one with cardiac sudden death. CAD patients with MVD were more probable of developing MACE during follow-up. Distribution of PAI-1 gene polymorphism was significantly different between SVD and MVD patients, p < 0.001. The frequency of DD genotype of ACE and 4G/4G genotype of PAI-1 in patients with MACE were significantly higher than those in patients without MACE, p < 0.001 and p = 0.002, respectively. Incidence of diabetes mellitus was significantly higher in patients with MACE than in patients without MACE, P = 0.03. Cox regression analysis showed that diabetes mellitus (HR 2.36, 95% CI 1.33 4.46, p = 0.003), 4G/4G polymorphism of PAI-1 gene (HR 3.45, 95% CI 1.71-6.56, p = 0.009), and D/D polymorphism of ACE gene (HR 2.99, 95% CI 1.84-5.76, p = 0.005), were independent predictors of the MACE. CONCLUSIONS: Our results showed that the conventional risk factors and genetic polymorphisms have significant influence on prognosis of CAD patients. CAD patients with diabetes mellitus, DD genotype of ACE, and 4G/4G genotype of PAI-1 suggested poor prognosis. PMID- 28352371 TI - The Role of Unknown Risk Factors in Myocardial Infarction. AB - BACKGROUND: Atherosclerosis of coronary arteries is the most common cause of myocardial infarction (MI), which is initiated from childhood and progresses gradually by aging. Several risk factors influence its progress, and are categorized as classic, traditional and novel factors. The role of unknown risk factors is becoming increasingly more significant recently. The aim of this study is to underscore the novel risk factors despite the importance of classic factors and consider these factors for future studies. METHODS: This is a prospective study on 180 myocardial infarction cases, conducted in the cardiology ward and CCU of Imam-Reza hospital (Mashad-IRAN). A number of risk factors identified and evaluated in these patients included: hyperlipidemia, hypertension, diabetes, smoking, activity, stress, hair of external ear canal and ear lobe crease, age, and sex. Then patients without any risk factor or with one or two risk factors were distinguished. RESULTS: The majority of our patients were old men in the age range of 60 - 69 years. Amongst all patients 42.2% were smokers, 68.3% were type A personality group, 19% were active, 81% were physically inactive, 37.2% had hairy ear canal, 35% had hypertension, 21.1% were diabetic, 14.4% had hyperlipidemia and 30% had positive family history of myocardial infarction. Of great interest was the fact that of the patients whose case was studied, many did not have any risk factor or in some cases had only one. CONCLUSIONS: In regard of increasing rate of cardiovascular diseases and myocardial infarction even amongst the young population, and because of considerable need to improve vascular risk detection, much research over the past decade has focused on identification of novel atherosclerotic risk factors, and some of these new risk factors are identified and some may be unknown. Amongst the new risk factors, inflammation has an important role, other risk factors that must be assessed are homocysteine, serum amyloid, and antibodies against Oxidized LDL. So we recommend that governments and heart associations must introduce new plans and policies in order to tackle the problem and reduce the frequency of cardiovascular disease. This requires the understanding of the conventional or classic risk factors and also the less known and new risk factors and ways which they may be prevented. PMID- 28352372 TI - Bortezomib-induced Severe Congestive Heart Failure. AB - The clinical manifestations of anti-cancer drug associated cardiac side effects are diverse and can range from acutely induced cardiac arrhythmias to severe contractile dysfunction, and potentially fatal heart failure. Anthracyclines and trastuzumab cardiac toxicity have been well described and left ventricular ejection fraction (LVEF) evaluation is commonly performed before their use. Bortezomib (Velcade), a potent, specific and reversible proteasome inhibitor is approved for treatment of multiple myeloma (MM). The incidence of cardiac failure associated with bortezomib therapy in clinical trials remains incidental. Acute exacerbation of pre-existing congestive cardiac failure has been associated with this therapy but de novo cardiomyopathy has been reported in only one patient receiving bortezomib for small cell lung cancer. As a result, cardiac evaluation is not normally ordered before its use. We describe a 50-year-old female with newly diagnosed MM and no risk factors for cardiac disease that unexpectedly developed florid heart failure after 2 cycles of bortezomib and low-dose dexamethasone. 2-D echocardiogram showed dilated cardiomyopathy with severely decreased LVEF; no changes consistent with amyloid deposits or myocardial scarring were described. Coronary angiogram ruled out coronary artery disease. The mechanism of bortezomib-induced cardiomyopathy has been postulated to be through fluid retention. Based on literature review we hypothesize that the disruption of the ubiquitin-proteasome system by bortezomib may cause cardiomyopathy and severe cardiac failure. As Bortezomib is a new and promising therapy for MM patients, we recommend routinely monitoring cardiac parameters in patients undergoing this treatment. PMID- 28352373 TI - A Case of Infantile Cardiac Rhabdomyoma Complicated by Tuberous Sclerosis. AB - We experienced a case with fetal cardiac tumor, which was diagnosed by prenatal ultrasonographic examination, and the diagnosis was confirmed after birth. A pregnancy woman of the 26th week of gestation was referred to our hospital for close examinations of fetal cardiac tumor. Ultrasonographic examinations revealed single homogeneous tumor with the diameter of 14 mm intracardiac space. The tumor was considered to emerge from the ventricular septum and to be occupied in left ventricle. Other cardiac abnormalities were not detected. The fetus was diagnosed to be complicated with the intracardiac tumor, and with the possible rhabdomyoma of heart. The serial ultrasonographic examinations revealed that the fetal cardiac function was normal. The size of the tumor gradually increased, although the fetal cardiac function revealed within normal range. The patient delivered a female infant weighing 2716g with the Apgar score of 9 and 10 at one and 5 minutes after delivery. The infant was confirmed to have cardiac tumors after examination by pediatric cardiologist, and the cardiac function of the infant was diagnosed as normal condition. The computed tomography of the head revealed the intracranial multiple calcification lesions, which indicated the symptoms of tuberous sclerosis. PMID- 28352374 TI - Atrial Fibrillation and Transient Ischemic Attack Encountered in the Management of Snake Bite. AB - Thousands of snake bites occur in the world each year, with hundreds of patients receiving antivenom. Incidence rates for immediate hypersensitivity reactions associated with the use of antivenom range vary. This is a case report of a patient with atrial fibrillation (AF) and transient ischemic attack (TIA) induced by vigrous snake bite that was suspected to be caused by the treatment of subcutaneous epinephrine, due to immediate hypersensitivity reaction following the administration of antivenom treatment. PMID- 28352375 TI - Extended Outcomes of Complex Coronary Disease in the Drug Eluting Stent Era. AB - BACKGROUND: Several randomized trials comparing bare-metal stents to Drug-Eluting Stents (DES) have demonstrated a significant reduction in Target Vessel Revascularization (TVR) and Target Lesion Revascularization (TLR) exists with the use of drug-eluting stents, without compromising survival. These conclusions are based on restricted inclusion criteria for patients and lesion. It is unknown if these results can be generalized to an unselected patient population and more complex disease. The objective of this study was to determine to what extent the availability of DES has impacted survival, TVR, and TLR in a large regional experience without the restriction of on-label indications. METHODS: Patients registered with the Northern New England Cardiovascular Disease Study Group's PCI registry with single vessel coronary disease undergoing a first PCI were sorted according to the Bare-Metal stent (BMS) era (2001 - 2002) or the Drug-Eluting stent (DES) era (2004 - 2005) based on the time period their first PCI took place. Totally, 6,093 BMS and 5,651 DES patients were identified. Outcomes of survival, TLR and TVR were measured after one year. RESULTS: After 1 year, survival was comparable, TLR was reduced by 4.9% (absolute) and TVR was reduced by 5.4% (absolute) in the DES era compared to the BMS era. The TLR/TVR differences remained significant after propensity matching in the DES era vs BMS era (Mortality: HR 1.00, 95% CI: 0.83 - 1.28; TLR: HR 0.40, 95% CI 0.32 - 0.46; TVR: HR 0.44, 95% CI 0.38 - 0.51). CONCLUSIONS: In large regional experience with a consecutive series of patients representing the contemporary practice of PCI, including both on and off label use, the frequent use of DES reduces the risk of TVR and TLR without compromising survival. PMID- 28352376 TI - The Influence of Cardiac Risk Factor Burden on Cardiac Stress Test Outcomes. AB - BACKGROUND: Chest pain is the most common admission diagnosis for observation unit patients. These patients often undergo cardiac stress testing to further risk stratify for coronary artery disease (CAD). The decision of whom to stress is currently based on clinical judgment. We sought to determine the influence of cardiac risk factor burden on cardiac stress test outcome for patients tested from an observation unit, inpatient or outpatient setting. METHODS: We performed a retrospective observational cohort study for all patients undergoing stress testing in our institution from June 2006 through July 2007. Cardiac risk factors were collected at the time of stress testing. Risk factors were evaluated in a summative fashion using multivariate regression adjusting for age and known coronary artery disease. The model was tested for goodness of fit and collinearity and the c statistic was calculated using the receiver operating curve. RESULTS: A total of 4026 subjects were included for analysis of which 22% had known CAD. The rates of positive outcome were 89 (12.0%), 95 (12.6%), and 343 (16.9%) for the OU, outpatients, and hospitalized patients respectively. While the odds of a positive test outcome increased for additional cardiac risk factors, ROC curve analysis indicates that simply adding the number of risk factors does not add significant diagnostic value. Hospitalized patients were more likely to have a positive stress test, OR 1.41 (1.10 - 1.81). CONCLUSIONS: Our study does not support basing the decision to perform a stress test on the number of cardiac risk factors. PMID- 28352377 TI - Circadian Patterns of Heart Rate Turbulence, Heart Rate Variability and Their Relationship. AB - BACKGROUND: Heart rate variability (HRV) is an established tool for studying cardiac autonomic activity over time, while heart rate turbulence (HRT) is a recent method used to assess autonomic dysfunction. However, there are different autonomic tones at different times of a day. This study aimed to examine the effect of circadian change of autonomic tone on heart rate turbulence and variability, and determine any relationship between them based on circadian variations. METHODS: Twenty-four-hour Holter recordings from 35 subjects with structurally normal heart were done, and HRV and HRT parameters of turbulence onset (TO) and turbulence slope (TS) were calculated. The 24-hour circadian patterns of these parameters and correlation analysis between them were performed. RESULTS: There were conspicuous diurnal oscillations in TS and HRV parameters, with less prominent variation in TO. TS and high frequency power (HF) shared the similar oscillation patterns in a day. Comparing HRT and HRV based on circadian variation, TS showed positive correlations with HF and low frequency power (LF) to a reasonable degree, while there was an inverse correlation between TS and LF/HF. CONCLUSIONS: Circadian change of TS values throughout the day is more prominent than TO. It also presents as an autonomic activity more than TO. The relationships between HRV and HRT persist independently on the time of a day. PMID- 28352378 TI - Demonstration of TGF-beta and XIIIalpha in Endocardial Biopsies of Carcinoid Heart Disease Patients: an Immunofluorescence Study. AB - BACKGROUND: Serotonin and other vasoactive substances play a critical role in the development of carcinoid heart disease, but the exact etiology of the illness is still unknown. METHODS: By using immunofluorescence microscopy, we investigated the expression of transforming growth factor-beta (TGF-beta) and the presence of fibrin-stabilizing factor (XIIIalpha) in endomyocardial biopsy specimens of patients with carcinoid heart disease. In addition, the tissue integrity of the specimens was studied by staining for laminin. RESULTS: Both TGF-beta and XIIIalpha co-localized in the endocardium beneath carcinoid plaques: while TGF beta was found within myocytes, XIIIalpha was detected on the surface of cells in fibrotic lesions stretching out into the tissue. Laminin staining revealed that the integrity of the endocardium was dissolved and that the tissue consisted of hypertrophic and hypotrophic myocytes. CONCLUSIONS: The results suggest that the presence of TGF-beta and XIIIalpha in carcinoid heart lesions indicates that endocardial damage induced by serotonin and other vasoactive substances gives rise to an overshooting wound healing process. PMID- 28352379 TI - Markedly Elevated Cardiac Bio-Markers at Presentation With Normal Ventricular Function: A Novel Clinical Subset of Myocarditis Manifestation. AB - We present a case of a 19-year-old woman with myocarditis who had significantly elevated cardiac markers at presentation even before any myocardial damage ensued. The patient had complicated clinical course with ventricular arrhythmia and cardiac arrest requiring resuscitation but eventually recovered completely. Though there is limited information available regarding such cases, the significantly elevated initial cardiac markers in the absence of left ventricular decompensation may probably represent a clinical subset of myocarditis and may portend an impending complicated clinical course. Further systematic research is required to define the clinical phenotype and elucidate underlying mechanisms. PMID- 28352380 TI - Senile Cardiac Calcification Syndrome: A Rare Case of Extensive Calcification of Left Ventricular Papillary Muscle. AB - Extensive papillary muscle calcification is uncommon and only scarce literature about causes and the clinical significance is available, whereas small calcific deposits are common findings in elderly people and are located most commonly at the apex. Papillary muscle calcification has been associated with coronary artery disease, dilated cardiomyopathy, mitral valve disease, hypercalcemia, and increased calcium phosphate product in end stage renal disease. We reported a rare case of extensive calcification of anterolateral papillary muscle diagnosed by echocardiography and multidetector computed tomography. PMID- 28352381 TI - Splanchnectopia Accompanied With Atrial Septal Defect: A Case Report. AB - Splanchnetopia accompanied with atrial septal defect is a rare congenital malformation clinically. Recent studies show that the patients are susceptible to lung disease. We present a case of a 62-year-old man who presented to our hospital with cough, palpitation and short of breath after activity. On physical examination, we found cyanosis of lips and face, swollen jugular vein, bubble sounds at the lung bottom, irregular heart rhythm, the large liver under the left rib and the lower limbs edema. Laboratory studies revealed white blood cell 18.6 * 109/L and neutrophils 73.9%. Electrocardiogram showed disappearance of P wave and substituted F wave with irregular R-R interval. Ultrasound cardiogram indicated that there was a 24 mm-long gap in the middle of the atrial septal. Dextrocardia, pulmonary artery extrudes and infection of lung were found by chest x-ray. The abdomen ultrasound indicated organ flip. Clinical diagnosis was congenital heart disease, splanchnectopia, atrial septal defect, Eisenmenger's syndrome, atrial flutter, cardiac function class III and pneumonia. The patient left hospital after 2-week treatment. Its clinical significance is when the thoracic and celiac organs are ill, the position of the symptoms and physical signs are contrary to the normal place. Therefore, we should make a careful and systematic examination of the patients in order to avoid misdiagnosis and delay in treatment. PMID- 28352382 TI - Long-Term Survival Following Cardiac Arrest Without Implantable Defibrillator Protection in a Hypertrophic Cardiomyopathy Patient. AB - Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death in young people. Implantable cardioverter defibrillator (ICD) is the optimal therapy in patients with HCM, both for primary or secondary prevention of sudden death. Left ventricular systolic function in HCM is usually normal. However, in few patients, HCM has been reported to progress to a state that is characterized by left ventricular dilation and systolic dysfunction, resembling dilated cardiomyopathy (DCM). Although arrhythmias are common in HCM, advanced or complete atrioventricular block (AV) is very rare. This case report describes a HCM patient who progressed to DCM with advanced AV block and survived 31 years following cardiac arrest without ICD protection. PMID- 28352383 TI - Exercise Tolerance and the Post Exercise Diastolic Filling Pattern in Patients With the Resting Impaired Relaxation. AB - BACKGROUND: In patients with normal LV systolic function, cardiac output increases with exercise mediated by increased stroke volume early in exercise and an increase in heart rate later in exercise. Despite normal LV systolic function, patients who display an impaired relaxation pattern may have a reduced exercise tolerance. We hypothesized that the resting impaired relaxation pattern that persists during exercise results in reduced LV filling volume and reduced exercise tolerance. METHODS: We evaluated consecutive exercise echocardiograms performed at Harper Hospital from 1998-2000 for patients with sinus rhythm, normal resting wall motion and ejection fraction (> 55%), evidence of resting impaired relaxation, and a negative exercise echocardiogram. There were 49 patients fitting the above criteria who were compared with a group of age and sex matched patients (43 patients) with a normal rest and exercise echocardiogram with normal resting transmitral Doppler. Rest and post exercise echocardiography and Doppler parameters were obtained. RESULTS: Patients in the impaired relaxation group demonstrated shorter exercise times as compared to the normal control group (8.8 +/- 1.6 versus 9.7 +/- 2.0 minutes, P < 0.001). In patients with normal resting transmitral diastolic filling, there was an increased the extent of atrial contribution to LV filling volume post exercise associated with shortening of isovolumic relaxation. Two patterns were seen in the impaired relaxation group post exercise. In 1 subgroup in which E/A ratio decreased post exercise, exercise duration was reduced (7.4 +/- 1.3 minutes, P < 0.001) as compared to the subgroup with E/A increase (9.6 +/- 1.2 minutes) post exercise which was similar to normal controls. Forward stepwise regression indicated that exercise time was primarily related to E/A change post exercise for all patient groups (r = 0.625, P = 0.0008). Specifically, this was true for patients with E/A reversal at rest (r = 0.584, P = 0.0028). However, for patients with normal diastolic filling at rest, the diastolic velocity integral was the major predictor (r = 0.695, P < 0.0084). CONCLUSION: We conclude that the transmitral Doppler pattern post exercise provides insight into the mechanism of reduced exercise tolerance in some patients with the resting impaired relaxation pattern. Preservation of this pattern post exercise is associated with reduced exercise tolerance. PMID- 28352386 TI - RT 3D TEE: Characteristics of Mitral Valve in Ischemic Mitral Regurgitation Evaluated by MVQ Program. AB - AIM: To assess the changes of mitral valve (MV) in ischemic mitral regurgitation (IMR) using Mitral Valve Quantification (MVQ) program. METHODS: We examined 46 patients (18 women) with IMR aged 45-86 and a control group of 33 healthy individuals (14 women) aged 18-88. Following parameters were assessed: Area of minimal surface spanning annulus (A3), annulus height (h), tenting height (Th), exposed area of anterior (AL), posterior (PL) and both leaflets (BL), ejection fraction of the left ventricle (LV EF), regurgitation volume (RV) and BL/A3, AL/A3, PL/A3 ratios. The normal range of BL/A3 ratio was defined as the average +/- 2SD of control group. The study group was separated into subgroup 1 with BL/A3 ratio within normal values and subgroup 2 with pathological BL/A3 ratio. Corresponding parameters of IMR group were compared to the controls and both subgroups were compared to each other using Student t-test. RESULTS: In IMR group, as compared to the controls, A3, AL, PL, BL as well as BL/A3, AL/A3, PL/A3 ratios and Th were significantly increased, conversely, h and LV EF was significantly decreased. In the subgroup 2 as compared to the subgroup 1 there was significant increase of Th, BL, AL and PL, while EF LV was significantly decreased. There was no significant difference between these subgroups in A3, h and RV. CONCLUSION: In ischemic MV remodeling two stages were identified without relation to the severity of IMR. The first stage was mainly influenced by the LV dilatation while LV remodeling was more important in the second stage. PMID- 28352384 TI - Consideration of the Pathological Features of Pediatric Congenital Heart Diseases Which Are Ideally Suitable for Diagnosing With Multidetector-row CT. AB - BACKGROUND: A lots of articles published regarding the usefulness of multidetector-row computed tomography (MDCT) in children with congenital heart disease (CHD) mostly describe that it can be an alternative to the invasive catheterization and angiography. The unique diagnostic features of this imaging modality have been largely ignored or disregarded. We described the pathological conditions that cannot be diagnosed by conventional angiography with cardiac catheterization but can be accurately diagnosed by MDCT. METHODS: We retrospectively reviewed non-ECG-gated MDCT images acquired from 452 children and young adults with CHD between 2005 and 2010 in our institute. In this article, we focused on the diagnostic advantages of MDCT, and indicated five pathological conditions. (1) When Blalock-Taussig shunt total occlusion prevents catheter insertion into the artificial vessel and angiography is ruled out, the peripheral pulmonary artery during the peripheral pulmonary artery can be imaged and diagnosed using MDCT based on blood flow supplied from many small collateral vessels originating from the aorta. (2) The location and protrusion of the device in the vessel after coil embolization to treat patent ductus arteriosus can be accurately visualized by virtual endoscopy using MDCT. (3) Calcification of patches, synthetic blood vessels, and other prostheses that is indistinct on conventional angiograms is clear on MDCT. (4) Simultaneous MDCT observations of the anatomical relationships between arterial and venous systems on the same image can clarify the detail diagnosis for surgical treatment. (5) Compression of the airways by the great vessels and pulmonary segmental emphysematous change can be diagnosed by MDCT. RESULTS AND CONCLUSIONS: Among patients with CHD, MDCT is useful not only as a non-invasive alternative to conventional angiography, but also as a tool for specific morphological diagnoses. In the future, it will be necessary to accumulate experience in the recognition of cardiovascular conditions under which MDCT is necessary and to perform as the appropriate examination. PMID- 28352385 TI - On Arrival High Blood Glucose Level is Associated With Detrimental and Fatal Hospitalization Outcomes for Acute Coronary Syndrome. AB - BACKGROUND: High blood glucose level is frequently encountered in acute coronary syndrome. We investigated the effects of high blood glucose measured on arrival on hospitalization adverse events in acute coronary syndrome. Our study patients were Javanese in ethnicity, which constitute half of population in Indonesia. We hypothesized that elevated blood glucose has detrimental effects on hospitalization for acute coronary syndrome. METHODS: We designed an observasional cohort study and recruited 148 consecutive patients with acute coronary syndrome. Venous blood was collected on hospital arrival. High blood glucose level was determined as plasma glucose > 140 mg/dL. Adverse hospitalization events were recorded, i.e. mortality, acute heart failure, cardiogenic shock and heart rhythm disorders. Echocardiography examination was performed to determine left ventricular function. RESULTS: The prevalence of on arrival high blood glucose among Javanese patients with acute coronary syndrome was considerably high (36%). On arrival high blood glucose was associated with acute heart failure (P < 0.001) and shock cardiogenic (P = 0.02). Heart rhythm disorders were higher in high blood glucose patients (P = 0.004). Left ventricular dysfunction was more prevalent in high blood glucose patients (P = 0.001) and ejection fraction was lower (P = 0.001). On arrival high blood glucose was independently associated with hospitalization adverse events (adjusted odds ratio = 2.3, 95% confidence interval: 1.1-4.9, P = 0.03) and hospital mortality (adjusted odds ratio = 6.9, 95% confidence interval: 1.2-38.6, P = 0.03). CONCLUSIONS: Our study suggests that on arrival high blood glucose among Javanese patients with acute coronary syndrome is considerably high and is associated with detrimental and fatal hospitalization outcomes. PMID- 28352387 TI - Coronary Flow Reserve of the Non-Ischemia Related Coronary Artery During Dobutamine Stress Echocardiography. AB - BACKGROUND: Incorporation of analysis of coronary velocities in stress studies adds diagnostic value to both clinical variables and dobutamine echocardiography. Micorcirculatory abnormalities may precede obstructive corornary disease. Therefore the aim of this study was to assess Doppler derived coronary velocity and flow of the left anterior descending coronary artery (LAD) during dobutamine stress echocardiography (DSE) in patients without LAD-related ischemia. METHODS: Sixty nine patients with chest pain underwent DSE studies to evaluate myocardial ischemia. All had trans-thoracic Doppler interrogation of the distal LAD before and just after termination of the DSE. Coronary velocity reserves (CFR) were calculated as the ratios of post-DSE/baseline diastolic velocities. Volumetric flow in the distal LAD was calculated from the diameter of LAD color jet and velocity integral. Volumetric flow reserve was calculated as the ratio of post DSE baseline LAD flows. RESULTS: At rest all subjects had left ventricular wall motion score index (WMSI) = 1, while in 28, wall motion abnormality appeared in non-LAD territory with WMSI = 1.17 +/- 0.08. Peak diastolic velocity after DSE increased form 28.5 +/- 13.6 to 52.4 +/- 23.7 cm/sec, P = 9.5 * 10-11, and velocity-CFR was 2.08 +/- 0.7. Diastolic LAD flow increased from 36.5 +/- 23.8 to 75.75 +/- 48.7 mL/min, P = 1.21 * 10-7 and volumetric-CFR was 2.6 +/- 2.8. Peak diastolic velocity-CFR in patients without LV wall motion abnormality was 2.4 +/- 0.7 while in those with motion abnormality 1.77 +/- 0.56, P = 0.00008. Flow derived LAD-CFR was 3.3 +/- 3.7 in those without compared to 1.88 +/- 0.57 in patients with wall motion abnormality, P < 0.05. CONCLUSION: LAD velocity and flow reserves are reduced in patients with remote myocardial ischemia, which may indicate early atherosclerotic involvement. PMID- 28352388 TI - A Case of Cardiac Amyloidosis Initially Misdiagnosed as Syndrome X. AB - Cardiac infiltration of amyloid fibril results in progressive cardiomyopathy with a grave prognosis and results in cardiac diseases such as congestive heart disease, cardiomyopathy, valvular heart disease, and arrhythmias. We present a rare case of cardiac amyloidosis initially misdiagnosed as syndrome X in which recurrent chest pain and progressive heart failure could be managed finally by heart transplantation. PMID- 28352389 TI - Acute Chest Pain and Broad Complex Tachycardia. A Non-typical Case of Pre-excited Atrial Fibrillation. AB - Wolff-Parkinson-White syndrome is a common condition in the emergency department. A case is presented of a 76-year-old patient with acute chest pain and broad complex tachycardia. Despite the fact that previous and post cardioversion ECG tracings in sinus rhythm showed no signs of pre-excitation, the characteristic pattern of pre-excited atrial fibrillation (AF) is recognized and after successful DC cardioversion the patient is referred for catheter ablation of the accessory pathway. This case illustrates a non-typical presentation of the WPW syndrome, with an older patient than usual with slight signs of pre-excitation. We highlight the need for high grades of suspicion for the early recognition of pre-excited AF when attending patients with tachycardia and the obligation to know the distinctive aspects of its management for this potentially life threatening arrhythmia. PMID- 28352390 TI - Calcified Thrombus in Right Atrium: Rare but Treatable Complication of Long-term Indwelling Central Venous Catheter. AB - Catheter-related central thrombosis is a rare complication of long-term central line. We describe the case of an asymptomatic boy who was diagnosed a calcified thrombus in right atrium eight years after the removal of a long-term central venous device. Although the most appropriate therapeutic approach for managing floating right heart thrombi remains to be determined, surgical removal is an effective and safe procedure for calcified long-standing thrombus and it is to be preferred in elective conditions especially in young asymptomatic patients without hemodynamic involvement, that are at low risk of surgery-related morbidity and mortality. PMID- 28352391 TI - An Unusual Case of Sinus of Valsalva Aneurysm in a GUCH Patient: An Unusual Side of the Aorto-Cardiac Fistula. AB - Sinus of Valsalva aneurysm can be congenital or acquired. The major complication is rupture: this can represent an evolution or an abrupt event. In case of rupture or of large aneurysm, a surgical approach is justified. We report a case of ruptured sinus of Valsalva aneurysm in a seventeen years old girl, who had underwent surgical correction of Fallot tetralogy. As soon as the rupture of sinus of Valsalva aneurysm is suspected, echocardiographic examination is the easiest and most straightforward tool to make a correct diagnosis. PMID- 28352392 TI - Percutaneous Coronary Intervention on Right Coronary Artery With All Coronary Arteries From Three Separate Ostiums in the Right Sinus of Valsalva. AB - Some of coronary artery anomalies, such as origin of all coronary arteries from three separate ostiums in the right sinus of valsalva, represent a small amount of coronary anomalies. We describe a 63-year-old female patient which coronary angiogram revealed an origin of all coronary arteries from three separate ostiums in the right sinus of valsalva, with significant atherosclerotic plaque at the midportion of the right coronary artery. The stenosis was treated through percutaneous coronary intervention. PMID- 28352394 TI - Outcomes of Patients With Cocaine Induced Chest Pain in An Inner City Hospital. AB - BACKGROUND: Cocaine induced chest pain is a major reason for admission in Safety Net Hospitals in the United States. The majority of patients admitted undergo extensive work-up leading to enormous economic burden. We hypothesize that in individuals with low risk, cocaine does not further increase adverse cardiovascular outcomes. METHODS: We conducted a retrospective chart review of all patients admitted with chest pain to our hospital between 07/01/09 and 06/30/10. We excluded patients with modifiable risk factors for coronary artery disease (CAD). The study population was divided into cocaine and non-cocaine group based on urine drug screen. We analyzed data including demographic, laboratory, cardiac testing, detection of CAD, length of stay and mortality rates. RESULTS: A total of 426 individuals matched our inclusion and exclusion criteria and were considered to have no known modifiable cardiac risk factors; 54 in cocaine group and 372 in non-cocaine group. Based on physician discretion, 41(76%) in the cocaine group and 239(64%) in the non-cocaine group underwent various modalities of cardiac testing. Cardiac testing was positive in 6(2.5%) patients in non-cocaine group and none in the cocaine group (p=0.597). There was no significant difference between length of stay and in-hospital mortality between the two groups. CONCLUSIONS: In individuals at low risk for CAD, cocaine use resulted in higher rate of cardiac testing. However, there is no difference in prevalence of CAD and in-hospital mortality between the two groups. We conclude that cocaine does not increase adverse outcomes in patients with low risk for CAD. PMID- 28352393 TI - Myocardial Contrast Echocardiography in the Evaluation of Hypertensive Heart Disease. AB - Myocardial contrast echocardiography (MCE) has an established role in left ventricular assessment by improving the ventricular opacification and endocardial border definition especially in patients with sub-optimal echocardiographic images. With advances in cardiac ultrasound imaging technology and the development of new contrast agents, the clinical utility of this technique has greatly expanded to include assessment of coronary reperfusion in the setting of acute myocardial infarction, determination of myocardial viability within infarct zones as well as assessment of coronary microcirculation and flow reserve in patients with microvascular coronary disease. Improvements in image quality with intravenous contrast agents can facilitate image acquisition and enhance delineation of regional wall motion abnormalities at peak levels of exercise. Numerous studies have confirmed the clinical utility of contrast enhancement during echocardiographic studies, particularly in patients undergoing stress testing. In this paper, we explore the evidence in support of MCE and its potential clinical applications. Our review aims to summarize (1) the basic principles of myocardial contrast echocardiography including recent advances in the ultrasound technology and contrast agents (2) its clinical applications in the diagnosis of cardiovascular diseases and finally, (3) its potential role in risk stratification and assessment of microvascular perfusion in patients with hypertensive heart disease. PMID- 28352395 TI - Systolic Strain Abnormalities to Predict Hospital Readmission in Patients With Heart Failure and Normal Ejection Fraction. AB - BACKGROUND: Despite intensive investigation, the pathogenesis of heart failure with normal ejection fraction (HFNEF) remains unclear. We hypothesized that subtle abnormalities of systolic function might play a role, and that abnormal systolic strain and strain rate would provide a marker for adverse outcomes. METHODS: Patients of new CHF and left ventricular ejection fraction > 50% were included. Exclusion criteria were recent myocardial infarction, severe valvular heart disease, severe left ventricular hypertrophy (septum >1.8 cm), or a technically insufficient echocardiogram. Average peak systolic strain and strain rate were measured using an off-line grey scale imaging technique. Systolic strain and strain rate for readmitted patients were compared with those who remained readmission-free. RESULTS: One hundred consecutive patients with a 1st admission for HFNEF from January 1, 2004 through December 31, 2007, inclusive, were analyzed. Fifty two patients were readmitted with a primary diagnosis of heart failure. Systolic strain and strain rates were reduced in both study groups compared to controls. However, systolic strain did not differ significantly between the two groups (-11.7% for those readmitted compared with -12.9% for those free from readmission, P = 0.198) and systolic strain rates also were similar (-1.05 s-1 versus -1.09 s-1, P = 0.545). E/e' was significantly higher in readmitted patients compared with those who remained free from readmission (14.5 versus 11.0, P = 0.013). E/e' (OR 1.189, 95% CI 1.026-1.378; P = 0.021) was found to be an independent predictor for HFNEF readmission. CONCLUSIONS: Among patients with new onset HFNEF, SS and SR rates are reduced compared with patients free of HFNEF, but do not predict hospital readmission. Elevated E/e' is a predictor of readmission in these patients. PMID- 28352396 TI - Qualitative Perfusion Cardiac Magnetic Resonance Imaging Lacks Sensitivity in Detecting Cardiac Allograft Vasculopathy. AB - BACKGROUND: Cardiac allograft vasculopathy (CAV) is a major complication after heart transplantation, requiring frequent surveillance angiography. Though cardiac angiography is the gold standard, it is insensitive in detecting transplant vasculopathy and invasive. Perfusion MRI provides a noninvasive alternative and possibly a useful modality for studying CAV. We sought to compare the accuracy of qualitative perfusion MRI to coronary angiography in detecting CAV. METHODS: A retrospective analysis was performed in 68 heart transplant recipients who had simultaneous surveillance cardiac MRI and coronary angiogram and who underwent transplantation between 2000 and 2007. We compared results of qualitative MRI to those of the cardiac angiogram. Sensitivity and specificity of MR were calculated. RESULTS: Sixty-eight patients underwent both cardiac MRI and coronary angiogram. 73.5% were male; mean age was 45.37 +/- 14 years. Mean duration of heart transplantation was 7.9 +/- 5.2 years. The mean ejection fraction was 55% in the patients without CAV and 57.4% in those with CAV. There were 48 normal and 24 abnormal MRI studies. The overall sensitivity was 41% and specificity was 74%. CONCLUSIONS: Qualitative assessment of perfusion cardiac MR has low sensitivity and moderate specificity for detecting CAV. The sensitivity of MRI was slightly improved with severity of disease. PMID- 28352397 TI - Can Computer Tomography Predict Compromise of Cardiac Structures After Percutaneous Closure of Interatrial Septal Defects? AB - BACKGROUND: Erosion of a cardiac structure after device closure of an interatrial septal communication (IASC-C), although rare, is a major and severe adverse event which may be underreported. On the other hand, unexplained episodes of transient chest pain occur more often and may be quite distressing. We sought to define the parameters relating the devices to the adjacent cardiac structures and to determine whether computer tomography (CT) could predict erosion of atrial or aortic wall or precordial pain symptoms occurring in the first months after device implantation. METHODS: Retrospective observational study of 20 patients who underwent CT for de novo chest pain occurring after IASC-C or as a diagnostic test for suspected or proven coronary artery disease (CAD). Clinical follow up was for 20.5 +/- 17.6 (6-84) months. CT was done 18 +/- 10 (2-28) weeks after IASC-C. RESULTS: Indentation of the aortic root was found in 11 (55%) patients, the left atrial wall in 13 (65%) and the right atrial wall in eight (40%) of patients. Contact without indentation was found in nine (45%), 6 (30%) and 11 (55%) of patients respectively. CONCLUSIONS: Device indenting of the left and right atrial, as well as the aortic wall, occured in the majority of the patients examined after IASC-C. This finding may explain bouts of chest pain after the intervention in some patients, but does not predict clinically relevant erosion of a cardiac structure. PMID- 28352398 TI - Incidence and Prognosis of Atrial Fibrillation in Patients With Sepsis. AB - BACKGROUND: Although the mortality rate among patients with sepsis is declining, the incidence of both sepsis and sepsis-related deaths is increasing, likely due to its presence in a growing elderly population. As atrial fibrillation is more common in the elderly, we hypothesize that its presence will be associated with greater mortality among patients with sepsis. METHODS: The Medical Intensive Care Unit (MICU) database of a large tertiary care medical center was queried for sepsis-related codes and atrial fibrillation. RESULTS: Atrial fibrillation was associated with older age and a higher mortality in this series of patients with sepsis. CONCLUSIONS: Whether atrial fibrillation is a marker of disease severity or contributes to mortality is uncertain. Further studies are necessary to determine optimal management. PMID- 28352399 TI - Thrombosis of A Prosthetic Mitral Valve After Withdrawal of Phenprocoumon Therapy. AB - Patients with prosthetic heart valves require lifelong oral anticoagulant therapy based on vitamin K antagonists. These patients may need interruption of their anticoagulant therapy if they have to undergo surgery. The clinical challenge is to identify patients who can safely undergo surgery while continuing their vitamin K antagonist treatment and those who have to take short-acting heparin as part of a bridging therapy. Here we present a case of a patient with a prosthetic mitral valve whose oral anticoagulant therapy was unnecessarily discontinued by the GP prior to an upcoming cataract surgery. As a result, the patient developed thrombosis of the prosthetic mitral valve which needed to be surgically replaced. PMID- 28352400 TI - Aortic Isthmus Arteritis: Report of One Case. AB - An 18-year-old girl was diagnosed as "bronchiectasis" for hemoptysis and treated by using embolization intervention 19 months ago. Two months ago she was diagnosed as iron-deficiency anaemia for fatigue. Eight days ago she was diagnosed again as hypertension for headache, anxiety, frowsty, nausea, vomiting and blood pressure 180/70 mmHg. In order to know the etiology of hypertension she was sent to our hospital. Vascular murmur was heard in bilateral carotid, subclavian and the back. 4 / 6 pan systolic murmur and stronger heart sound were heard in each valve auscultation area. Bilateral radial artery pulsations were symmetrical, but bilateral femoral, popliteal and dorsal arteries of foot were weakened. The results of hemoglobin (HB), globulin, creaction protein (CRP) and erythrocyte sedimentation rate (ESR) were abnormal. Thicker wall and narrower lumen in decreasing aorta were found by aorta CTA scanning. The aorta arteritist was clearly diagnosed and treated by hormone until ESR returned to normal. Finally, artificial vascular was replaced successfully by surgery. Now the patient is fine and has already been working for a year. This case gives us the inspiration: A detailed examination to patient is very important, which avoid missed diagnosis or misdiagnosis and missed the best opportunity for treatment. PMID- 28352401 TI - Giant Aortic Arch Aneurysm and Cardio-vocal Syndrome: Still An Open-surgery Indication. AB - The Cardio-vocal Syndrome (Ortner's syndrome) is described as hoarseness due to the left recurrent laryngeal nerve palsy, caused by a specific cardiovascular pathology. In this case, we present a patient with a giant aortic arch aneurysm with an initial clinical presentation of Cardio-vocal Syndrome. The conventional open-surgery, instead of endovascular approach, was useful to control the morbidity from the compressive effect of adjacent structures, also preventing the aortic rupture. We strongly recommend analyzing carefully the individual case and the clinical targets to resolve, because the new technologies are not always the most effective therapeutic response. PMID- 28352402 TI - Cordarone Extravasation Inducing Volkmann's-like Syndrome. AB - We report a case of Volkmann's-like syndrome occurred after an extravasation of 300 mg of cordarone administrated for a cardiac arrest.The day following the extravasation, an extensive necrosis of the skin and soft tissues occurred. The patient progressively developed a retraction of the muscles of her forearm. To the best of our knowledge this is first the reported case of an acute necrosis of the soft tissue inducing a Volkmann's-like retraction of the upper limb subsequent to a cordarone extravasation. The imaging findings are provided along with a review of the literature. PMID- 28352403 TI - Heart in An Eggshell Calcification: Idiopathic Calcific Constrictive Pericarditis. AB - Constrictive pericarditis is caused by fibrosis and calcification of the pericardium, which inhibits diastolic filling of the heart. Chest roentgenogram can show the calcification as a mass or sheet over the heart and computed tomography scan allows anatomic delineation of the pericardium and determines the extent of calcification. We reported a case of eggshell calcification of idiopathic chronic constrictive pericarditis diagnosed by echocardiography and multi-detector computed tomography. PMID- 28352404 TI - Mature Cardiac Teratoma in an Adult. AB - The incidental diagnosis in adult age is very unusual and the presence of clinical symptoms is related to its location, which is most commonly intrapericardial. The presence of intramyocardial teratoma lesions is even rarer and has been reported in few publications. The recommendations for the diagnosis and management of a cardiac teratoma depends upon the imaging studies and the pathological report after surgical excision. The prognosis of surgically treated patient is very good and a complete surgical excision is preferred in order to avoid complications. PMID- 28352405 TI - Real World Application of Stenting of Unprotected Left Main Coronary Stenosis: A Single-Center Experience. AB - BACKGROUND: The aim of this study was to summarize our single-center real-world experience with percutaneous coronary intervention (PCI) stenting of unprotected left main coronary artery (ULMCA). PCI-stenting of the ULMCA, while controversial, is emerging as an alternative to coronary artery bypass graft (CABG) surgery in select patients and clinical situations. METHODS: Between January 2005 and December 2008, PCI-stenting was performed on 125 patients with ULMCA lesions at our institution. Clinical and procedural data were recorded at the time of procedure, and patients were followed prospectively (mean 1.7 years; range 1 day-4.1 years) for outcomes, including death, myocardial infarction (MI), and target vessel revascularization (TVR). RESULTS: The majority of cases were urgent or emergent (82.5%), 50.4% of patients were non-surgical candidates, and 63.2% had 3 vessel disease. Many emergent patients presented in shock (62.1%), were not surgical candidates (89.7%), and had high mortality (20.7% in-hospital, 44.8% long-term). Mortality in the elective group was 6.3%. Cumulative death and TVR rates were 28.8% and 13.6%, respectively. Independent predictors of mortality were ejection fraction (EF) <= 35% (HR 2.4, CI 1.1 - 5.4) and left main bifurcation (HR 2.7, CI 1.2 - 5.7). CONCLUSIONS: PCI-stenting is a viable option in patients with LMCA disease and extends options to patients who are poor candidates for CABG. Elective PCI in low-risk CABG patients results in good long term survival. Cumulative TVR is 13.6%. EF <= 35% and left main bifurcation are independently associated with increased mortality. PMID- 28352406 TI - Asymmetric Dimethylarginine Levels are Highly Associated With Atrial Fibrillation in an Elderly Population. AB - BACKGROUND: The importance of endothelial dysfunction in atrial fibrillation (AF) is not clarified. The aim of this study was to evaluate endothelial dysfunction assessed by selected inflammatory and haemostatic endothelial markers and nitric oxide (NO) associated variables as related to the presence of AF in an elderly population. NO is known to express anti-thrombotic as well as vasoactive properties. METHODS: This is a cross sectional study of 75-year old subjects with AF (n = 62) and control subjects in sinus rhythm (n = 124), matched for gender. Fasting blood samples were collected for analyses of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO-synthase, L-arginine, E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and von Willebrand factor (vWF). RESULTS: Levels of vWF and ADMA were significantly higher in AF patients vs controls (P = 0.023 and P < 0.001, respectively) and the L-arginine/ADMA ratios were lower (P = 0.015), the latters still significant after adjustment for relevant covariates (P = 0.007 and P = 0.037, respectively). No significant differences in the levels of VCAM-1 and E-selectin were observed between the groups. When dividing the ADMA levels into quartiles there was a significant trend for having AF with increasing levels of ADMA (P < 0.001) with a cut-off at the 25th percentile (< 0.54 umol/L), giving an adjusted OR for having AF of 12.46 (95% CI 3.11 - 49.86) (P < 0.001) with higher levels. A similar inverse trend was seen for the L-arginine/ADMA ratio. CONCLUSION: Our population of 75-year-old AF patients had significantly impaired endothelial function assessed by increased levels of vWF, and more pronounced by high levels of ADMA. The results indicate AF in the elderly to be closely associated with the regulatory pathway of NO. PMID- 28352407 TI - Sirolimus-Versus Zotarolimus-Eluting Stents in Acute Coronary Syndromes With C Type Left Anterior Descending Artery Lesions: A Three-Year Clinical Follow-Up. AB - BACKGROUND: Drug-eluting stents have improved the efficacy of percutaneous coronary intervention and made it the preferred therapy in the treatment of ischemic heart diseases including acute coronary syndromes. The objective of the study was to compare the clinical efficacy and safety of sirolimus-eluting stent with that of zotarolimus-eluting stent following percutaneous coronary intervention for acute coronary syndrome patients with C-type left anterior descending stenosis. METHODS: A total of 154 acute coronary syndrome patients with C-type lesions in the left anterior descending artery, requiring a stent > 28 mm in length, were randomized into two groups to receive either sirolimus- (n = 74) or zotarolimus-eluting stent (n = 80). The follow-up period after stent implantation was approximately 36 months. The primary endpoint was a major cardiac event (a composite of cardiac death, myocardial infarction, or ischemia related target vessel revascularization), and the secondary endpoint included these individual end points plus stent thrombosis. RESULTS: After 3 years follow up, the rate of the primary end point (major cardiac event: cardiac death, myocardial infarction, ischemia-related target vessel revascularization) was 16% in the sirolimus group (n = 12) versus 11.2% in the zotarolimus group (n = 9) (P = 0.2). Although there were four cases of stent thrombosis with sirolimus-eluting stent and one with zotarolimus-eluting stent (4.0% sirolimus vs. 1.25% zotarolimus; P = 0.2), neither non-Q myocardial infarction (4.0%sirolimus vs. 1.25% zotarolimus; P = 0.2) nor stent thrombosis, differed significantly. CONCLUSIONS: Although zotarolimus-eluting stent implantation showed more favorable results with respect to stent thrombosis and major adverse cardiac event rates compared to sirolimus-eluting stent implantation, statistically, both stent groups have nearly similar clinical safety and efficacy in the treatment of acute coronary syndromes with C-type lesions in the left anterior descending artery disease. PMID- 28352408 TI - Renal Dysfunction was an Independent Predictor of In-Hospital Death and Ventricular Rupture in Patients With Acute Myocardial Infarction. AB - BACKGROUND: Apart from the severity of myocardial infarction and coronary artery disease, several predictors of in-hospital death (In-HD) are suggested in patients with acute myocardial infarction (AMI). METHODS: We investigated predictors of In-HD and ventricular rupture (VR) including ventricular septal rupture (VSR) and free wall rupture (FWR) with stepwise multivariable logistic regressions in 1,042 patients admitted to our Cardiovascular Center within 48 hours from symptom onset for the first attack of AMI. RESULTS: In-HD, VSR, and FWR were observed in 78 cases (7.5%), 14 cases of which 13 cases were In-HD, and 13 cases of which 6 cases were In-HD, respectively. Apart from the disease severity, age and renal dysfunction (RD) defined by estimated glomerular filtration rate of lower than 60 mL/min/ 1.73 m2 were independent positive predictors of In-HD (the odds ratios (ORs) (95% confidence interval (CI)): 1.04 (1.01 - 1.06) P = 0.0069 and 5.75 (3.12 - 10.59) P < 0.0001, respectively) and hypercholesterolemia was an independent negative predictor for In-HD (OR (95% CI): 0.34 (0.17 - 0.67) P = 0.0017). After including the categories of coronary disease, ventricular rupture, and ejection fraction in predictors, RD remained an independent predictor of In-HD (OR (95% CI): 6.65 (2.67 - 16.60) P < 0.0001). Age (OR (95% CI): 1.07 (1.02 - 1.12) P = 0.0064), RD (OR (95% CI): 2.77 (1.18 - 6.49) P = 0.019), and diabetes (OR (95% CI): 2.52 (1.12 - 5.71) P = 0.026) were independent predictors of VR. CONCLUSIONS: RD was an independent predictor of In HD and VR in patients with initial AMI. PMID- 28352409 TI - An Unusual Type of Localized Hypertrophic Cardiomyopathy With Wolf Parkinson White Syndrome Presenting With Pulmonary Edema. AB - Hypertrophic cardiomyopathy (HCM) is an autosomal dominant heart disease that is the most common genetic cardiac disorder. The disease is characterized by excessive thickening of the left ventricular myocardium. The anterior portion of the interventricular ventricular septum is often involved. Asymmetric hypertrophy of apical site, left ventricular free wall, and right ventricle are less common in hypertrophic cardiomyopathy that occur in 1% cases. We report a case of a patient with an unusual type of hypertrophic cardiomyopathy and Wolf Parkinson White (WPW) presenting with pulmonary edema. PMID- 28352410 TI - All That Glitters is not Gold: Apical Hypertrophic Cardiomyopathy Mimicking Acute Coronary Syndrome. AB - Hypertrophic cardiomyopathy is characterized by the idiopathic hypertrophy of the left ventricle (and occasionally right ventricle). HCM is an autosomal dominant disease, with variable penetration. In Asian population, apical hypertrophic cardiomyopathy is relatively common (25%). However, this is relatively rare in Caucasian population (0.2%). Patients with HCM, often presents with typical exertional chest pain and shortness of breath. Apical HCM patients tend to have milder symptoms. However, the clinical presentation and electrocardiographic features of Apical HCM often mimic acute coronary syndrome and high index of suspicion is warranted in differentiating this condition. Patients with apical HCM have relatively better prognosis when compare to the other varieties. Here, we are presenting a patient who presented with typical exertional chest pain whose electrocardiographic changes are concerning for acute ischemic changes. PMID- 28352411 TI - A Rare Coronary Artery Anomaly: Single Coronary Artery Originate From Right Sinus Valsalva R-IIP Sub-Group Type. AB - We reported a single coronary artery case that in the R-IIP sub-group which is a rare sub-group comparing with other sub-groups of single coronary artery originating from right sinus valsalva. PMID- 28352412 TI - A Case of Chronic Thromboembolic Pulmonary Hypertension. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe complication of incomplete resolution of large pulmonary embolism (PE).Transthoracic echocardiography (TTE) and chest computed tomography (CT) are useful for the diagnosis and follow-up of CTEPH. We report a case of 40-year-old male who wasadmitted with gradually aggravated dyspnea in recent 2 years and had history of acute PE 10 years ago, was detected CTEPH by TTE and confirmed with chest CT. PMID- 28352414 TI - Asymptomatic Left Bundle Branch Block Predicts New-Onset Congestive Heart Failure and Death From Cardiovascular Diseases. AB - BACKGROUND: Left bundle branch block (LBBB) has been proposed as a risk factor for cardiovascular morbidity and mortality. We sought to characterize the strength of these associations in a population without preexisting clinical heart disease. METHODS: The association between LBBB and new-onset congestive heart failure (CHF) or death from cardiovascular diseases was examined in 1,688 participants enrolled in the SPPARCS study who were free of known CHF or previous myocardial infarction. SPPARCS is a community-based cohort study in residents of Sonoma, California that are > 55 years. Medical history and 12-lead ECGs were obtained every 2 years for up to 6 years of follow-up. LBBB at enrollment or year 2 was considered "baseline" and assessed as a predictor of CHF and cardiovascular death ascertained at years 4 and 6. RESULTS: The prevalence of LBBB at baseline was 2.5% (n = 42). During 6 years of follow-up, 70 (4.8%) people developed new CHF. Incidence of CHF was higher in patients with LBBB than in participants without LBBB. This association persisted after controlling for potential confounders (odds ratio (OR): 2.85; 95% confidence interval (CI): 1.01 - 8.02; P = 0.047). A higher mortality from cardiovascular diseases was also found in participants with LBBB after adjusting for potential confounders (OR: 2.35, 95%CI: 1.02 - 5.41; P = 0.044). CONCLUSIONS: LBBB in the absence of a clinically detectable heart disease is associated with new-onset CHF and death from cardiovascular diseases. Further study is warranted to determine if additional diagnostic testing or earlier treatment in patients with asymptomatic LBBB can decrease cardiovascular morbidity or mortality. PMID- 28352413 TI - Rethinking Heart Failure. AB - An increasing body of clinical observations and experimental evidence suggests that cardiac dysfunction results from autonomic dysregulation of the contractile output of the heart. Excessive activation of the sympathetic nervous system and a decrease in parasympathetic tone are associated with increased mortality. Elevated levels of circulating catecholamines closely correlate with the severity and poor prognosis in heart failure. Sympathetic over-stimulation causes increased levels of catecholamines, which induce excessive aerobic metabolism leading to excessive cardiac oxygen consumption. Resulting impaired mitochondrial function causes acidosis, which results in reduction in blood flow by impairment of contractility. To the extent that the excessive aerobic metabolism resulting from adrenergic stimulation comes to a halt the energy deficit has to be compensated for by anaerobic metabolism. Glucose and glycogen become the essential nutrients. Beta-adrenergic blockade is used successfully to decrease hyperadrenergic drive. Neurohumoral antagonists block adrenergic over-stimulation but do not provide the heart with fuel for compensatory anaerobic metabolism. The endogenous hormone ouabain reduces catecholamine levels in healthy volunteers, promotes the secretion of insulin, induces release of acetylcholine from synaptosomes and potentiates the stimulation of glucose metabolism by insulin and acetylcholine. Ouabain stimulates glycogen synthesis and increases lactate utilisation by the myocardium. Decades of clinical experience with ouabain confirm the cardioprotective effects of this endogenous hormone. The so far neglected sympatholytic and vagotonic effects of ouabain on myocardial metabolism clearly make a clinical re-evaluation of this endogenous hormone necessary. Clinical studies with ouabain that correspond to current standards are warranted. PMID- 28352415 TI - Chronic Ischemic Heart Disease Affects Health Related Quality of Life. AB - BACKGROUND: Chronic diseases endanger not only physical health but also psychological and social health of patient. Thus, evaluation of such patients for psychological treatment decisions is very important. METHOD: This is a descriptive study that was performed with 50 chronic patients (ischemic heart disease) selected from Valiasr and Mousavi at cardiac wards in Zanjan Province. They were given three types of questionnaire: demographic, WHOQOL, and Zung depression and anxiety index. The information was statically analyzed by frequency chart, central indexes, dispersion, Chi-Square and t tests, Pearson's correlation index (P < 0.05). RESULTS: The average of quality of life in all patients were calculated as was respectively 12.19, 11.98, 12.08, and 12.4 in physical, psychological, social and environmental domains respectively, 68 percent of total number of the patients had various degrees of anxiety and 78 percent of them had various degrees of depression. There was a significant relationship between the life quality average in all domains and anxiety intensity and depression intensity (P < 0.05) and there was a significant relationship between life quality average in all domains and income (P < 0.05). CONCLUSION: As the level of depression and anxiety goes up, quality of life decreases pointing out that they have a reverse relationship. Depression and anxiety are one of the most significant factors of quality of life among other variables. Regarding specific conditions of the treatment, it is necessary to pay special attention to psychological aspects. PMID- 28352416 TI - Is There any Time Dependant Echocardiographical Finding in Chronic Hemodialysis Patients? AB - BACKGROUND: Cardiac disease is the main cause of death in hemodialysis patients. In hemodialysis patients cardiovascular complications are great clinical challenge, and function, shape and left ventricle abnormalities are present in 70 - 80 percent of dialysis patients. Changes in heart function occur in hemodialysis period and are effective in patient's prognosis. In this study we aim to evaluate time dependant clinical and echocardiographical findings in chronic hemodialysis patients. METHODS: In a cross-sectional study, 100 adult hemodialysis patients (51% male and 49% female with mean age 52.13 +/- 12.69 years) visiting dialysis unit in Imam Reza and Madani hospitals between years 2010 and 2011 were studied in group 1 (hemodialysis <= 6 months), group 2 (hemodialysis for 6 months to 3 years) and group 3 (hemodialysis >= 3 years). Demographic, laboratory and echocardiographic findings were compared between groups. RESULTS: Among demographic findings, group 3 had significantly higher diastolic blood pressure and weight gain and was older than other two groups (P < 0.05). By increase in hemodialysis period, patients had higher blood urea nitrogen and lower serum albumin levels (P < 0.05). Potassium level in group 2 was significantly higher than group 3 and that was higher than group 1. There was no difference between groups in left ventricular hypertrophy (LVH), left atrium dilatation, ejection fraction and mitral insufficiency. Diastolic dysfunction increased in line with increase in hemodialysis period (P = 0.007). Hemodialysis period was higher in patients with LVH than those without (34.80 +/- 9.2 months versus 18.51 +/- 2.22 months, P = 0.01). CONCLUSION: In hemodialysis patients, diastolic dysfunction increases by the hemodialysis time (years). LVH and LA dilation also increase during time, but not significantly. PMID- 28352417 TI - Infective Endocarditis Complicated by Acute Ischemic Stroke from Septic Embolus: Successful Solitaire FR Thrombectomy. AB - Infective endocarditis (IE) is often complicated by systemic embolization. Acute stroke due to septic emboli is a particularly dreaded complication. Optimal treatment for acute stroke in IE has not been well outlined. Fibrinolytic therapy may be associated with increased risk for hemorrhagic transformation in patients with acute stroke in the setting of IE. We present a case of IE complicated by acute stroke which was successfully treated with mechanical thrombectomy. This case illustrates a role of mechanical thrombectomy devices in this patient population. PMID- 28352418 TI - Simultaneous Thrombosis of Two Drug-Eluting Stents After Discontinuation of Dual Antiplatelet Therapy for a Day. AB - Stent thrombosis is rare but can lead to potential severe consequence. The incidence is relative higher in drug-eluting sent than bare-metal stent implantation. Dual antiplatelet therapy is the major treatment to avoid early and late stent thrombosis. Simultaneous two stents thrombosis is rare. Although mechanical or/and procedure factors may predispose to stent thrombosis occurred, simultaneous two stents thrombosis implies possibly ineffective antiplatelet therapy. We report a case with simultaneous two stent thrombosis and complicated with cardiogenic shock after lost antiplatelet therapy for one day. We try to emphasize to properly educate patients about the importance of continuous drug use to avoid catastrophic tragedy. PMID- 28352419 TI - Adjuvant Role of CT in the Diagnosis of Post-Infarction Left Ventricular Free Wall Rupture. AB - Left ventricular free wall rupture is usually a catastrophic mechanical complication of myocardial infarction. Risk factors include advanced age, female gender and absence of prior infarction. The vast majority of patients succumb rapidly due to cardiac tamponade and electromechanical dissociation. Expedited and accurate diagnosis can improve the chances of survival. Echocardiography has been advocated as the gold standard for diagnosis, but other imaging modalities can provide valuable information in these patients. We present the case of a patient who presented with cardiogenic shock, in which the definitive diagnosis of a left ventricular free wall rupture was accomplished by CT scan with intravenous contrast. PMID- 28352420 TI - A Review of Currently Available Fenofibrate and Fenofibric Acid Formulations. AB - Fenofibrate is a third-generation fibric acid derivative indicated as a monotherapy to reduce elevated low-density lipoprotein cholesterol, total cholesterol, triglycerides, and apolipoprotein B; to increase high-density lipoprotein cholesterol in patients with primary hyperlipidemia or mixed dyslipidemia; and to reduce triglycerides in patients with severe hypertriglyceridemia. In this review, the key characteristics of available fenofibrate formulations are examined. A literature search was conducted, focusing on comparative studies examining bioavailability, food effects, absorption, and lipid efficacy. Fenofibrate is highly lipophilic, virtually insoluble in water, and poorly absorbed. Coadministration with meals was necessary to maximize bioavailability of early formulations. Micronized and nanoparticle formulations of fenofibrate with reduced particle sizes were developed, resulting in greater solubility, improved bioavailability, and in some cases, the ability to be given irrespective of food. A recently introduced hydrophilic choline salt of fenofibric acid also can be taken without regard to meals, is absorbed throughout the gastrointestinal tract, has the highest bioavailability among marketed formulations, and is approved for coadministration with a statin. Differences in bioavailability of fenofibrate formulations have resulted in low-dose (40 - 67) mg and standard-dose (120 - 200 mg) formulations. Different formulations are not equivalent on a milligram-to-milligram basis. In order to prevent medication errors, resulting in underdosing or overdosing with attendant consequences, it is important for healthcare providers to recognize that the formulations of fenofibrate and fenofibric acid that are currently available vary substantially in relation to food effect, equivalency on a milligram-to-milligram basis, and indication to be coadministered with a statin. PMID- 28352421 TI - Effects of Uric Acid on Lipid Levels in CKD Patients in a Randomized Controlled Trial. AB - BACKGROUND: Few studies have been conducted that compared lipid levels and uric acid in CKD or End-Stage Renal Disease (ESRD) patients with most using animal models. The purpose of the study was to explore effects on lipids while controlling uric acid levels in CKD patients. METHODS: Twenty-four CKD patients (N = 24) volunteered to participate in this study. The study was conducted using a double-blind, randomized, placebo controlled experimental protocol. The experimental group was prescribed 300 mg of allopurinol PO daily by their treating physician and followed prospectively for 8-weeks. The control group consumed a similar pill once a day for 8-weeks. RESULTS: ANCOVA revealed significant differences in total cholesterol (P = 0.009) and Apo B (P = 0.006) with lower levels in the allopurinol group. A trend emerged with LDL (P = 0.052) with lower levels in the allopurinol group. No significant differences were discovered in triglycerides (P = 0.403), HDL (P = 0.762) and total Cholesterol/HDL Ratio (P = 0.455). CONCLUSIONS: After statistically controlling for compliance and inflammation significant differences between groups were observed for total cholesterol and Apo B. In both instances the allopurinol group had lower concentrations than the placebo group. Similarly, a trend was observed in LDL with the allopurinol group having lower concentrations than the placebo group. PMID- 28352422 TI - Persistent Left Superior Vena Cava in Patients Undergoing Cardiac Device Implantation: Clinical and Long-Term Data. AB - BACKGROUND: Persistent left superior vena cava (LSVC) is a rare congenital venous anomaly that may be found at the time of cardiac device lead insertion. METHODS: In this case series, we present clinical and long-term data of five patients with LSVC who underwent pacemaker (PM) or cardioverter defibrillator (ICD) implantation during the period of 10 years. RESULTS: Left-sided venous approach was used for device implantation in 3 patients with standard PM indications, whereas a right-sided venous approach and an epicardial approach had to be used in 2 patients who needed an ICD and biventricular PM, respectively. In post implantation period of 44 +/- 29 months, one patient died due to stroke, one underwent heart transplantation, and 3 had atrial fibrillation. CONCLUSION: The long-term outcome of patients with persistent LSVC and implanted cardiac devices is mostly influenced by the presence of underlying heart disease. PMID- 28352423 TI - Outcome of Successful Versus Unsuccessful Percutaneous Coronary Intervention in Chronic Total Occlusions in One Year Follow-Up. AB - BACKGROUND: Chronic total occlusions (CTO) comprises already one-third of percutaneous coronary interventions (PCIs). There is controversy in PCI results considering short-term and long-term outcomes. We aim to compare efficacy and outcome of successful versus unsuccessful PCI in CTO in 1 year follow-up. METHODS: In this retrospective study we choose 330 consecutive patients undergone PCI on a CTO of a native coronary artery (163 successful and 167 unsuccessful) in Madani Heart Hospital, Tabriz, Iran. Patients were followed for a mean period of about 15 +/- 3 months. Major adverse cardiac events (MACE) in hospital and in follow-up were recorded comprising death, acute myocardial infarction, and need for repeat revascularization. RESULTS: Patients with unsuccessful PCI compared to successful PCI were mainly male (87.4% vs. 77.3%; P < 0.02), had a higher incidence of diabetes mellitus (31.1% vs. 20.9%; P < 0.04) and hypertension (53.3% vs. 42.3%; P < 0.04). Most patients in successful group had single vessel disease (63.4% vs. 46.7%; P < 0.001) and less three-vessel disease (11.8% vs. 22.8%) compared to unsuccessful group. In-hospital MACE was insignificantly higher in unsuccessful PCI (17.4% vs. 11%). Unsuccessful PCI was significantly associated with higher rate of 12 months MACE (43.7% vs. 30.1%, P = 0.01), especially revascularization (41.3% vs. 25.2%, P = 0.02). CONCLUSION: Although in hospital outcome was the same between groups, patients with successful PCI of CTO had a better one year follow-up outcome than unsuccessful PCI. However mortality rate was the same and main complications were due to revascularization. PMID- 28352424 TI - Angiographic Coronary Spasm in a Case of Spontaneous Subarachnoid Hemorrhage Mimicking Acute Myocardial Infarction. AB - Neurologic stunned myocardium after subarachnoid hemorrhage (SAH) has been evidenced. Clinical presentations manifested as ST segment elevation by electrocardiography (ECG), left ventricular wall motion abnormality by echocardiography, and abnormal cardiac markers. The pathophysiology remains controversial. Coronary artery spasm has been proposed as a possible mechanism. However, most SAH patients with ECG and echocardiographic findings suggestive of myocardial infarction were lacking of angiographic evidence of vasospasm. We present a case of 66-year-old man complained chest pain with transient conscious loss on the street. He was sent to our emergency room by witness with clear consciousness and electrocardiography showing prominent ST-segment elevation. Because chest tightness was complained, emergent catheterization was arranged immediately. Coronary angiography demonstrated a narrowing lesion on mid right coronary artery without atherosclerotic change on other site. He was successfully treated with primary coronary balloon angioplasty for the narrowing lesion. Then the patient was sent to intensive care unit for further care. His following ECG demonstrated sinus rhythm with ectopic beats without ST segment elevation. Unfortunately, he became irritable and deterioration of conscious level few hour later. Computer tomography revealed subdural and subarachnoid hemorrhage. Conservative treatment was suggested by neurological surgeon consulted. The clinical presentation of the SAH patient mimicked acute myocardial infarction and coronary spasm was evidenced by angiography. We report the case and review the articles. PMID- 28352425 TI - A Case of Fulminant Myocarditis With Preceding Repeated Episodes of Congestive Heart Failure. AB - We report a rare case of fulminant myocarditis that was considered to have smoldered for a few months before it finally exteriorized. An 80-year-old man had had two episodes of mild congestive heart failure with preserved ejection function (HFPEF) within 3 months before he was finally admitted for the treatment of rapidly progressive heart failure. Cardiac function deteriorated remarkably on the final admission. Extracorporeal cardiopulmonary support was used because of pump failure and conduction disability, however, the patient died on the 16th day. Endomyocardial biopsy revealed numerous inflammatory infiltrates in myocardium compatible with fulminant myocarditis. However, advanced fibrosis and increased number of B lymphocytes and plasma cells found in the present case were not typical for fulminant myocarditis. Considering several distinctive findings in clinical and laboratory findings together, two preceding HFPEF episodes were highly likely to be associated with myocarditis. PMID- 28352426 TI - High Take Off Left Main and Abnormal Origin of Right Coronary Artery: A Case Report. AB - Coronary anomalies are rare congenital disorders with mostly benign course. We report a case of 54-year-old white male who was with stable angina scheduled for coronary angiography. Due to the difficulty of catheterization, patient underwent CT angiography and high take off left main and right coronary arteries were revealed. We conclude that anomalous coronary arteries are important and coronary interventions may be difficult in their presence. PMID- 28352427 TI - Physiotherapy as a Rare Cause of Twiddler's Syndrome in a Patient With an Implanted Cardioverter Defibrillator. AB - A 65-year-old male patient with a history of ischemic cardiomyopathy developed ventricular tachycardia resulting in presyncope. An ICD was indicated for secondary prophylaxis of ventricular tachyarrhythmias. A dual chamber ICD was implanted from the right side because insertion of the device from the left side was unfeasible after surgery of a left subscapularis tendon lesion. ICD implantation and testing of defibrillation threshold were uneventful. During early follow-up a progressive increase of the stimulation threshold was detected. On chest X-ray coiling of both atrial and ventricular leads was noted and caused inadvertently by active shoulder-arm physiotherapy. Complete revision of the ICD system was necessary for restoration of the pacemaker function of the ICD. This unique case highlights important steps for early recognition and prevention of Twiddler's syndrome that may occur due to physiotherapy treatment even without abnormal manipulations by the patient. PMID- 28352428 TI - Healthcare Utilization of Patients With Acute Coronary Syndrome in Germany. AB - BACKGROUND: The aim of this study was to determine the health care utilization of patients with acute coronary syndrome (ACS) of one German statutory health insurance. The utilization of ambulatory services as well as of inpatient rehabilitation should be regarded. Moreover, the study should reveal the prescription of drugs for secondary prevention. Here, patients showing guideline corresponding prescriptions should be compared with patients without such prescriptions. METHODS: A retrospective claims data analysis of one German statutory health insurance was conducted. Health care utilization was considered in the first year after an index hospitalization due to ACS. Beneficiaries for whom an ICD-10 discharge diagnosis of ACS was reported between January 1st 2007 and December 31st 2009 were included. In order to reveal differences in health care utilization depending on the type of ACS (STEMI versus NSTEMI/UA) stratified analyses were performed. Another stratification was done for patients with and without defined drug prescriptions. RESULTS: From 45,188 patients with ACS almost three quarters were assigned to the group of NSTEMI/UA. For 8.9% of all ACS patients (18.74% STEMI, 8.89% NSTEMI/UA), inpatient post-hospital rehabilitation related to ACS was recorded. Ambulatory care related to CHD diagnosis was utilized by 77.6% of patients, more often by STEMI than by NSTEMI/UA patients. For 36.7% and 45.7% of ACS patients, a prescription of aspirin or clopidogrel was recorded, respectively, 79.4% of STEMI patients received at least one prescription for antiplatelet drugs, the corresponding proportion of NSTEMI/UA was 59.8%. A considerable part of patients without prescription dropped out within the first 90 days after the index event. CONCLUSIONS: A claims data analysis of one German statutory health insurance fund showed that health care utilization of ACS patients varied depending on the ACS type. It is necessary to distinguish between STEMI and NSTEMI/UA patients when discussing the ambulatory drug utilization. PMID- 28352429 TI - ACP1 Genetic Polymorphism and Coronary Artery Disease: Evidence of Effects on Clinical Parameters of Cardiac Function. AB - BACKGROUND: Kinases and phosphatases have an important role in the susceptibility and clinical variability of cardiac diseases. We have recently reported an association between a phosphoprotein phosphatase controlled by Acid Phosphatase locus 1 (ACP1), and Coronary artery disease (CAD) suggesting an effect on the susceptibility to this disease. In the present note we have investigated a possible role of ACP1 in the variability of clinical parameters of cardiac function. METHODS: We have studied 345 subjects admitted to Valmontone Hospital for cardiovascular diseases: 202 subjects with CAD and 143 without CAD, 53 subjects admitted to Cardiac Surgery Division of Tor Vergata University were also considered. RESULTS: In diabetic patients with CAD there is a significant negative association between Left ventricular ejection fraction (LVEF) and ACP1 S isoform concentration. Genotypes with high S isoform concentration show a lower value of LVEF as compared to genotypes with low S isoform concentration. We have also found a significant positive association between cNYHA class and ACP1 S isoform. After surgical intervention, in subjects with high S isoform concentration the decrease of LVEF is more marked as compared to subjects with low S isoform concentration. Overall these observations indicate that high S isoform activity has negative effects on cardiac function. The observation in patients undergoing cardiac surgery confirms the negative association between high S isoform activity and LVEF. CONCLUSIONS: The present study suggests that ACP1 influences both susceptibility to CAD and clinical manifestations of the disease. PMID- 28352430 TI - Congenital Thrombophilia and Intracardiac Thrombosis: Probably an Underdiagnosed Event. AB - BACKGROUND: To investigate the number of patients with congenital thrombophilia who presented an intracardiac thrombosis. METHODS: Personal files were reevaluated together with a time-unlimited search of the literature. RESULTS: Twenty-five patients with intracardiac thrombosis and congenital thrombophilia have been gathered from the literature including the two personal cases. The distribution observed in thrombophilia patients is similar for left side or right side heart (9 vs 11 cases). The left ventricle and the right ventricle were involved in six or five instances, respectively. In one case, both ventricles were involved. On the contrary, the left atrium was involved in three cases whereas the right atrium was affected in six cases. In the remaining cases, more than one heart chamber was involved. CONCLUSIONS: In "normal" subjects, left side thromboses are predominant once catheter-associated thrombi are excluded. The reason of this discrepancy lies in the greater prothrombotic effect exercised by congenital thrombophilia on venous thrombosis compared to arterial thrombosis. The relative high prevalence of cardiac thrombosis seen in patients with antithrombin and protein C deficiencies indicated that a cardiac evaluation should be carried out in all patients with these two defects. PMID- 28352431 TI - Unroofed Coronary Sinus Presenting as Cerebral Abscess: A Case Report. AB - A sixty eight year-old woman with a long-standing history of hypertension, dizziness and a history of congenital heart disease presented with speech difficulties and disorientation. She was diagnosed with a brain abscess, confirmed by a stereotactic biopsy. Transthoracic echocardiographic evaluation revealed a persistent left superior vena cava (PLSVC) with an unroofed coronary sinus (URCS) along with a small secundum atrial septal defect. Her heart catheterization showed a partially unroofed coronary sinus along with a bidirectional shunt. She was referred for surgical closure of her unroofed coronary sinus and the secundum atrial septal defect. Her brain abscess responded well to antibiotic treatment. While waiting for open-heart surgery, she suffered from an acute myocardial infarction and underwent emergent percutaneous coronary intervention to the right coronary artery. Subsequently, she underwent elective surgical repair of the unroofed coronary sinus, along with closure of the atrial septal defect. When she was seen in follow-up she reported a complete resolution of her dizziness and felt more energetic. Unroofed coronary sinus syndrome (URCS) is a rare congenital cardiac anomaly in which there is a communication between the coronary sinus and the left atrium. While non-invasive imaging with echocardiography, MRI or CT is helpful in making the diagnosis, cardiac catheterization remains integral in the evaluation and management planning. Management is guided by the presence of clinical symptoms with consideration of repair when patients become symptomatic. Prognosis after surgery is excellent, recently transcatheter based treatment therapies are becoming more frequent. We present a rare case of URCS with PLSVC presenting as a cerebral abscess in late adulthood. She had bidirectional shunting manifesting as a cerebral abscess. She responded well to the corrective surgery and was doing well on follow up. PMID- 28352432 TI - Sudden Cardiac Death in a Case of Non-Dominant Coronary Artery Obstruction Without Depressed Left Ventricular Function. AB - Acute myocardial infarction complicated with lethal cardiac arrhythmia remains the major cause of sudden death. The possible clinical presentation leading to lethal ventricular arrhythmia has been demonstrated but the data are limited. The previous study revealed no significant correlation between sudden cardiac death and the location of coronary obstruction site. And the possible mechanism of sudden cardiac death in non-dominant coronary artery obstruction is unclear. We presented a case of acute myocardial infarction with mid left circumflex artery occlusion complicated with new onset atrial fibrillation initially. The rhythm degenerated into ventricular fibrillation immediately and sudden cardiac death occurred. After resuscitation, he received coronary angioplasty, and the rhythm recovered to sinus after the occluded coronary artery reopened. We thick new onset atrial fibrillation could be a potential risk factor leading to sudden death in acute myocardial infarction with obstruction of non-dominant coronary artery. Control of ventricular rate and early restoration of sinus rhythm may be potential benefit. PMID- 28352433 TI - Pregnancy With SLE and Fetal Congenital Heart Block: A Case Report. AB - Autoimmune AV block is usually seen in association with autoimmune antibodies in mother that cross the placenta and damage the AV node of fetus. A 24-year-old primigravida, diagnosed to have SLE, at 25 weeks period of gestation found to have fetal bradycardia. Her ANA was moderately positive, SS-A (Ro) antibodies and SS-B (La) antibodies were positive. Fetal ECHO showed no structural defect but heart rate was 55 - 60 beats per minute. She was put on dexamethasone (4 mg/day). She was lost on follow up and presented at term in emergency with labor pains and fetal bradycardia, underwent a lower segment caesarean section. Baby underwent a temporary cardiac pacing within 10 hours of birth followed by permanent pacing on day 3 of birth. Baby is doing well on follow up. Neonates with isolated congenital heart block who are monitored antenatally and delivered in a planned fashion at an institution capable of early pacing can have favorable outcomes. PMID- 28352434 TI - Postpartum Stanford Type A Aortic Dissection: A Case Report and Review of the Literature. AB - Acute aortic dissection is a life-threatening disease. Approximately half of the aortic dissection observed in women under 45 years old has been reported to be related to pregnancy. Herein, we present a case of type A aortic dissection diagnosed in postpartum period. A 37-year-old woman admitted to the emergency department with the complaint of sudden onset of dyspnea. Arterial blood pressure was measured as 170/100 mmHg in left arm and 90/60 mmHg in right arm. With a prediagnosis of aortic dissection, thoracic and abdominal computed tomograpy was performed and type A aortic dissection extending form carotid artery to renal arterial level was detected. Operation of aortic dissection together with coronary arterial repairment and aortic valve replacement were successfully performed. Aortic dissection is not uncommon in pregnancy and furthermore it is potentially life-threatening for both mother and fetus. A high level of suspicion is required for prompt diagnosis and treatment in the peripartum period. PMID- 28352435 TI - Predictors of Recurrent Atrial Fibrillation Using Mode Switch Quantification. AB - BACKGROUND: The efficacy of mode switching to predict atrial fibrillation has been established in the literature. There have been few studies investigating the incidence and clinical implication of mode switch episodes quantified from implantable cardioverter defibrillator and pacemaker interrogation. We sought to investigate the incidence of mode switch recurrence in patients with implantable cardioverter defibrillators and permanent pacemakers. METHODS: Mode switch was defined as any occurrence documented during device interrogation after the date of implantation. Clinical predictors (age, gender, hypertension, diabetes, syncope, atrial fibrillation (AF)), and medications were analyzed to determine association with single and recurrent mode switch occurrences. RESULTS: There were 21 patients experiencing a mode switch event, identified from a group of 54 patients (42 males; mean age 70 +/- 12 years; mean follow-up 29.1 +/- 22 months (3.4 - 81.4 months)). All but two patients were receiving medical therapy including beta blockers, statins, ace-inhibitors, and anti-arrhythmics. There were 21 subjects who experienced at least one mode switch during their follow-up and 33 subjects who never experienced a mode switch during their follow-up time. The median time to first mode switch from device implantation was 39.3 months. Risk factors individually associated with any mode switch episode included: diabetes (DM) (P < 0.04) and use of digitalis (P = 0.02). Subjects who had a history of DM were 5 times more likely to have at least one mode switch occurrence. There was a significantly higher rate of mode switch among patients who were diabetic than patients who were not (3.7 per follow-up month +/- 5.3 vs. 0.98 per follow-up month +/- 2.02; P = 0.02). There was a significantly higher rate of mode switch among patients who were on digitalis than those who were not (3.1 per follow-up month +/- 4.3 vs. 0.73 per follow-up month +/- 1.9; P = 0.02). CONCLUSION: The main factors associated with any mode switch are having a history of diabetes and digitalis use. Those patients who are diabetics and those on digitalis may warrant closer observation and management for the development of atrial fibrillation. PMID- 28352436 TI - The Link between Right and Left Ventricular Systolic Performance at Rest and after Stress: Insights Into the Mechanism. AB - BACKGROUND: Right ventricular (RV) systolic performance is more difficult for evaluation compared to the left ventricle (LV). Despite differences in structure, RV myocardial fibers are in continuity with those of LV. The aim is assessment of the effects of LV wall motion abnormalities (WMA) on RV systolic function at rest and after stress. METHODS: Fifty nine subjects, 15 with LV-WMA underwent dobuatmine stress echocardiography (DSE) studies using the usual protocol. Measurement of tricuspid annular plane systolic excursion (TAPSE), velocity (TASV), mitral annular plane systolic excursion (MAPSE) and velocity (MASV), were performed before and immediately after DSE studies. RESULTS: TAPSE was lower, in those with LV-WMA than in those without, both at rest 20.5 +/- 4.8 mm versus 24.9 +/- 4.7 mm, P = 0.015 and after DSE studies, 21.5 +/- 5.6 mm versus 27.65 +/- 5.7 mm, P = 0.005. DSE studies did not change TAPSE significantly in the presence of LV-WMA. TASV at rest in those with LV-WMA was 16.5 +/- 2.7 cm/sec and similar to that in those without, 17.6 +/- 3 cm/sec. In both groups the velocity increased after DSE studies, 23.25 +/- 7.5 cm/sec, P = 0.01 with LV-WMA, and 27.5 +/- 6 cm/sec, P = 0.0005, without LV-WMA. Despite similar TASV at rest, the TAPSE/TASV ratio, indicating duration of shortening, was lower (124 +/- 21 msec) in subjects with of LV-WMA, than in those without (145 +/- 27 msec), P = 0.0065, implying increased after load for RV longitudinal shortening in the presence of LV-WMA. CONCLUSIONS: TAPSE is lower at rest and after DSE studies in subjects with LV-WMA than in subjects without; however, DSE studies increase TPASE only in the absence of LV-WMA. TASV increases after DSE studies and is similar at rest in both groups with or without LV-WMA. It seems that LV-WMA increases after load to RV longitudinal motion. PMID- 28352437 TI - Direct Telephonic Communication in a Heart Failure Transitional Care Program: An observational study. AB - BACKGROUND: This study investigated the trend of phone calls in the Banner Good Samaritan Medical Center (BGSMC) Heart Failure Transitional Care Program (HFTCP). The primary goal of the HFTCP is to reduce 30-Day readmissions for heart failure patients by using a multi-pronged approach. METHODS: This study included 104 patients in the HFTCP discharged over a 51-week period who had around-the-clock telephone access to the Transitionalist. Cellular phone records were reviewed. This study evaluated the length and timing of calls. RESULTS: A total of 4398 telephone calls were recorded of which 39% were inbound and 61% were outbound. This averaged to 86 calls per week. During the "Weekday Daytime" period, Eighty five percent of the totals calls were made. There were 229 calls during the "Weekday Nights" period with 1.5 inbound calls per week. The "Total Weekend" calls were 10.2% of the total calls which equated to a weekly average of 8.8. CONCLUSIONS: Our experience is that direct, physician-patient telephone contact is feasible with a panel of around 100 HF patients for one provider. If the proper financial reimbursements are provided, physicians may be apt to participate in similar transitional care programs. Likewise, third party payers will benefit from the reduction in unnecessary emergency room visits and hospitalizations. PMID- 28352438 TI - Comparison of 5-Year Outcomes for Patients With Coronary Artery Disease in Groups With and Without Revascularization With Different Results of Stress Echocardiography. AB - BACKGROUND: There is conflicting data in contemporary literature concerning the best way to treat patients with stable coronary artery disease; specifically, whether medical treatment alone or invasive strategies combined with medical treatment are better. The purpose of this study was to evaluate the clinical outcomes of patients with and without revascularization after stress echocardiography and to create formulas for detecting patients with a very high risk of cardiac death/major adverse cardiac event (MACE) in their present conditions. METHODS: We assessed 323 patients (53.9 +/- 8.4 years, 247 men), undergoing upright bicycle stress echocardiography in 2006 - 2007. During a median follow-up of 5.2 +/- 0.2 years, 21 cardiovascular and 5 confirmed non cardiac deaths occurred. Eighty-three patients underwent revascularization. RESULTS: Stress echocardiography was normal in 32% and abnormal in 68%. All the patients with CAD were prescribed acetylsalicylic acid, statins, beta-blockers and ACE inhibitors. Eighty-seven percents of the patients took medication regularly. The percentage taking medication didn't significantly differ in the subgroups. Two formulas were created for detecting a very high risk of cardiac death (25%) or MACE (68%) within 5 years. All the patients with abnormal stress tests were divided into two subgroups: 80 patients with revascularization and 138 subjects without revascularization. There was a significant difference in 5 year cardiac mortality if the patients had an index of wall motion abnormality (IWMA) after exercise greater than or equal to 1.3. CONCLUSION: It is possible to identify during stress echocardiography subjects with a very high risk for cardiac death/MACE. Patients with IWMA >= 1.3 had improved outcomes following revascularization. PMID- 28352439 TI - The Relationship Between Plasma Eosinophil Count and Coronary Artery Ectasia. AB - BACKGROUND: The pathophysiology of coronary artery ectasia (CAE) has not been clearly identified, although multiple abnormalities including arteritis, endothelial dysfunction, and atherothrombosis have been reported. It is known that eosinophils play an important role in inflammation and thrombosis. Also vascular anomalies such as aneurysm have been noted in patients with hypereosinophilic syndromes. We aimed to compare the numbers of eosinophil counts of the patients CAE versus controls. METHODS: This study included 50 CAE patients (20 male, mean age 60.26 +/- 10.6 years) and 30 control person (10 male, mean age 57.86 +/- 11.6 years). These participants were performed concurrent routine biochemical tests and neutrophil, lymphocyte, eosinophil count and mean platelet volume (MPV) on whole blood count. These parameters were compared between groups. RESULTS: Baseline characteristics of the study groups were comparable. CAE patients had a higher MPV value, eosinophil, neutrophil lymphocyte ratio (NLR) than controls (8.5 +/- 1 vs 76.2 +/- 1.6 fl and 0.198 +/- 0.14 vs 0.093 +/- 0.058 and 3.0 +/- 2.5vs 1.14 +/- 0.9; P < 0.001, 0.002 and 0.028 respectively). CONCLUSION: As a result, our study revealed a relationship between eosinophil count, NLR and MPV in patients with CAE. PMID- 28352440 TI - Right Atrial Mass in a Patient With HIV and Hepatitis B: A Case Report. AB - A 41-year-old man presented to the emergency room for evaluation of substernal chest pain, shortness of breath and generalized failure to thrive. Patient had history of hepatitis B and HIV. During recent evaluation of hepatic mass, patient was found to have hepatocellular carcinoma on biopsy. Patient had no history of cirrhosis of the liver in the past. On Echocardiogram patient was noted to have a large mass filling the right atrial cavity. CT scan of abdomen, pelvis and chest showed a diffusely enlarged heterogeneously enhancing liver consistent with large hepatoma, with portal venous and hepatic vein thrombosis. Tumor thrombus extended through the hepatic veins and upper inferior vena cava into the right atrium. There was 6 cm greatest diameter enhancing mass in the right atrium. Patient had primary hepatocellular carcinoma with extensive invasion into vascular structures. His prognosis was poor and patient opted for palliative care only. In conclusion, patients with co-infection of HIV and Hepatitis B are at risk of developing hepatocellular carcinoma with extension into the right atrium and physicians managing these patients should have high suspicion of right atrial involvement with tumor extension and low threshold to order a screening echocardiogram. PMID- 28352441 TI - The Assessment and Potential Implications of the Myocardial Performance Index Post Exercise in an at Risk Population. AB - BACKGROUND: The myocardial performance index (MPI) first described by Chuwa Tei in 1995 is a relatively new echocardiographic variable used for assessment of overall cardiac function. Previous studies have demonstrated the MPI to be a sum representation of both left ventricular systolic and diastolic function with prognostic value in patients with coronary artery disease as well as symptomatic heart failure. METHODS: Ninety patients with either established coronary artery disease (CAD) or CAD risk factors underwent routine treadmill exercise stress testing with two-dimensional Doppler echocardiography using the standard Bruce protocol. Both resting and stress MPI values were measured for all 90 of the patients. RESULTS: Using a normal MPI cut off of <= 0.47, the prevalence of an abnormal resting MPI in our 90 subjects was 72/90 or 80% and the prevalence of an abnormal stress MPI in our 90 subjects was 48/90 or 53.33%. The average MPI observed in the resting portion of the stress test for the cohort was: 0.636 with a standard deviation of 0.182. The average MPI in the stress portion of the stress test for the cohort was 0.530 with a standard deviation of 0.250. The P value with the use of a one-tailed dependent T test was calculated to be < 0.05. CONCLUSION: We postulate that these findings reflect that the MPI (Tei) index assessed during exercise may be a sensitive indicator of occult coronary disease in an at risk group independent of wall motion assessment. PMID- 28352442 TI - The Prognostic Significance of Resting Regional Left Ventricular Function in Patients With Varying Degrees of Myocardial Ischemia. AB - BACKGROUND: Our aim was to determine whether regional left ventricular (LV) function on a resting transthoracic echo (TTE) provides prognostic information in patients with varying degrees of ischemia on myocardial perfusion imaging. METHODS: Between 2004 - 2009, we identified 503 patients (mean age 69 (SD 11); 79% male) with reversible ischemia on a myocardial SPECT scan who had a TTE within 30 days. We evaluated the rate of subsequent revascularization and death for all patients. RESULTS: Following the SPECT scan and TTE, 246/503(49%) patients underwent revascularization, 64/503 (13%) patients died, 369 (73%) patients had a normal left ventricular ejection fraction (LVEF), 242 (48%) patients had a resting wall motion abnormality (WMA), 21/261 (8%) with no WMA died compared to 43/242 (18%) in patients with a WMA. In patients with a WMA (n = 242) there was no significant difference in mortality when comparing patients with small (< 6 segments) and large (> 6 segments) WMA (P = 0.44). In patients with moderate/severe ischemia, the presence of a resting WMA was associated with a higher mortality rate (18% v 7%; P = 0.005). In a multivariable model, LVEF (< 50%) was associated with a hazard ratio of 2.2 (P = 0.002, 95% CI 1.34 - 3.68) however, WMA and number of abnormal segments did not reach statistical significance. CONCLUSION: A resting wall motion abnormality in patients with moderate/severe ischemia is associated with a higher mortality compared to patients with mild ischemia on myocardial perfusion imaging. Regional left ventricular dysfunction unlike LVEF was not an independent predictor of mortality. PMID- 28352443 TI - The Relationship Between Serum Bilirubin Concentration and Atrial Fibrillation. AB - BACKGROUND: Several studies have demonstrated that higher serum bilirubin inhibits the inflammation and proliferation of vascular smooth muscle cells; also there is a relationship between serum bilirubin and cardiovascular disease. However, the relationship between bilirubin and atrial fibrillation (AF) is still unknown. In our study, we compared serum bilirubin, between nonvalvular AF patients and controls. MATERIALS AND METHOD: One hundred and two patients with nonvalvular chronic AF without any other cardiovascular disease (mean age 62.51 +/- 5.88) were included in our study. One hundred age-matched healthy people with sinus rhythm were accepted as control groups (mean age 61.35 +/- 5.44). Routine biochemical parameters and serum bilirubin levels were performed. RESULTS: No statistically significant difference was found between two groups in terms of basic characteristics. Total, direct and indirect serum bilirubin levels were significantly lower among persons with AF compared to controls (0.82 +/- 0.8 vs. 0.48 +/- 0.5, 0.30 +/- 0.2 vs. 0.19 +/- 0.1 and 0.52 +/- 0.5 vs. 0.29 +/- 0.3 mg/dL; all P < 0.001, respectively). CONCLUSION: As a result, our study revealed a relationship between serum bilirubin and nonvalvular AF. PMID- 28352444 TI - One-Year Outcomes After Everolimus-Eluting Stents Implantation in Ostial Lesions of Left Anterior Descending Coronary Arteries. AB - BACKGROUND: In recent years, stents are increasingly used in variety of coronary lesions. Ostial lesion of left anterior descending coronary artery (LAD) however remains a challenge area because of the invariable involvement of distal left main coronary artery (LMCA). This study was designed to evaluate the clinical and angiographic outcomes of everolimus-eluting stent (EES) implantation for ostial LAD. METHODS: EESs were implanted in 45 consecutive patients with ostial LAD stenoses. For complete lesion coverage, stent positing was extended into the distal LMCA in 6 patients (13.3%) with intermediated LMCA narrowing. We assess MACE during one-year follow-up. RESULTS: In-hospital success rate was 100%; neither cardiac death nor stent thrombosis in our patients, but two patients had myocardial infarction in non-related coronary artery during follow-up. Two patients had angiographic restenosis and underwent TLR. The cumulative MACE-free survival rate was 95.6% at one year. CONCLUSION: EES was in ostial LAD lesions with complete lesion coverage achieving high procedural success rate and acceptable clinical outcomes during one-year follow-up period. PMID- 28352445 TI - The Left Main Complication of the Bentall's Procedure. AB - We present two interesting cases of critical left main stenosis following the Bentall's procedure, with each case having a different outcome. There will also be brief discussion of the treatment for this complication. PMID- 28352446 TI - Acute Myocardial Infarction Complicated With Ventricular Septal Rupture: Report of Three Cases. AB - We reported three cases of ventricular septal rupture (VSR) complicating acute myocardial infarction (AMI), focusing on the causes, diagnosis, treatment and prevention. These three cases were diagnosed based on the findings of electrocardiogram, echocardiogram and blood myocardial markers, and were treated with conservative methods. These three cases were female, and all had history of hypertension and/or diabetes mellitus. In one case with age over 70, AMI was related to percutaneous coronary intervention of left anterior descending branch, and the stenosis of LAD resulted in AMI and subsequently VSR occurred, the patient's condition worsened rapidly and the patient died after. Only one of the three cases survived the VSR. We concluded that the prognosis of VSR complicating AMI is associated with the causes, age, sex and comorbidities, and the prevention is critically important. PMID- 28352447 TI - Rivaroxaban Rebound Acute Coronary Event: A Post Marketing Experience. AB - We present a 65-year-old male who received rivaroxaban therapy prior to and after left knee replacement surgery. The patient developed generalized weakness soon after stopping rivaroxaban. An electrocardiogram showed acute infero-lateral ischemia and an echocardiogram reported an akinetic antero-apical wall segment, an apical clot and a reduced systolic function. A subsequent coronary angiogram revealed two-vessel coronary artery thrombosis. The case illustrates a temporal relationship of coronary thrombosis following rivaroxaban cessation. PMID- 28352449 TI - Interleukin 17A in Patients With Stable Coronary Artery Disease: Are There Differences According to Gender? AB - BACKGROUND: Coronary artery disease (CAD) is a current major public health concern. Immunity and inflammation are involved in all phases of CAD and there is a dynamic balance between cells and molecules. Interleukin 17A (IL17A) concentrations are higher in male patients with acute myocardial infarction than in women. In this study, we evaluated if the IL17A concentrations in male CAD patients (MPs) differed from those in female patients (FPs) and male controls (MCs). Moreover, FPs were compared with female controls (FCs). METHODS: This was a cross-sectional, prospective, and analytical study conducted between March 2012 and August 2013 that enrolled 40 patients (24 men and 16 women) with stable CAD and 20 healthy volunteers (12 men and 8 women) were selected as controls and were matched with the patients (1:2) for sex and age (+/- 3 years). Comparative analyses of IL17A concentrations in serum and cell culture with and without stimulation were performed between MPs and MCs, MPs and FPs, and FPs and FCs. The lower detection limit was 3.91 pg/mL. RESULTS: The comparison of the IL17A concentrations showed: after 48 hours of cell culture with stimulus: MP = 451.67 (99.02 - 892.58) vs. MC = 135 (3.91 - 285), P = 0.04; after 48 hours of cell culture with stimulus: MP = 451.67 (99.02 - 892.58) vs. FP = 131.21 (3.91 - 231.97), P = 0.02; after 48 hours of cell culture with stimulus: FP = 131.21 (3.91 - 231.97) vs. FC = 173.78 (3.91 - 642), P = 0.24. CONCLUSION: This study revealed higher IL17A concentrations in the stimulated cells isolated from the MPs than in those isolated from FPs and MCs. These findings support the hypothesis that when exposed to certain stimuli, cells isolated from MPs with chronic CAD may produce higher IL17A concentrations than those from FPs and MCs. PMID- 28352448 TI - Clinical Long-Term Response to Cardiac Resynchronization Therapy Is Independent of Persisting Echocardiographic Markers of Dyssynchrony. AB - BACKGROUND: The aim of the study was to prove the concept that correction of established parameters of dyssynchrony is a requirement for favorable long-term outcome in patients with cardiac resynchronization therapy (CRT), whereas patients with persisting dyssynchrony should have a less favorable response. METHODS: After CRT implantation and optimization of dyssynchrony parameters, we evaluated whether correction or persistence of dyssynchrony predicted long-term outcome. Primary endpoint was a combination of cardiac mortality/heart transplantation and hospitalization due to worsening heart failure, and secondary endpoint was NYHA class. RESULTS: One hundred twenty-eight consecutive patients (mean age 68 +/- 10 years) undergoing CRT with a mean left ventricular ejection fraction of 27+/-9% were followed for 27 +/- 19 months. All cause mortality was 17.2%, cardiac mortality was 7.8% and 3.1% had to undergo heart transplantation. Rehospitalization due to worsening heart failure was observed in 14.8%. NYHA class before CRT implantation was 2.8 +/- 0.8 and improved during follow-up to 2.0 +/- 0.8 (P < 0.001). A clinical response was observed in 76% (n = 97) and an echocardiographic response was documented in 66% (n = 85). After individually optimized AV and VV intervals with echocardiography, atrioventricular dyssynchrony was still present in 7.2%, interventricular dyssynchrony in 13.3% and intraventricular dyssynchrony in 16.4%. Despite persistent atrioventricular, interventricular and intraventricular dyssynchrony at long-term follow-up, the combined primary and secondary endpoints did not differ compared to the group without mechanical dyssynchrony (P = ns). QRS duration with biventricular stimulation did not differ between responders vs. nonresponders. CONCLUSION: After successful CRT implantation, clinical long-term response is independent of correction of dyssynchrony measured by echocardiographic parameters and QRS width. PMID- 28352450 TI - Effects of Left Ventricular Wall Motion Abnormality on Global and Regional Diastolic Function of the Left and Right Ventricles at Rest and After Stress. AB - BACKGROUND: Diastolic dysfunction precedes systolic dysfunction in patients with coronary artery disease. The aim of the study was to evaluate the effects of left ventricular (LV) wall motion abnormality (WMA) on diastolic LV and right ventricular (RV) function at rest and after stress. METHODS: Fifty-nine subjects, 15 with LV-WMA (abnormal group) and 44 without (normal group), underwent dobutamine stress echocardiography (DSE) studies, in addition to evaluation of LV and RV diastolic function before and after DSE. RESULTS: Resting mitral flow parameters were similar. DSE increased peak A-wave velocities in both groups, and mitral color slope only in normal subjects. After DSE, E-wave peak velocities and mitral color slope were higher in normal subjects, P < 0.05. At rest and after DSE systolic and diastolic pulmonary vein velocities were similar in both groups; however, DSE increased these velocities only in normal subjects, P < 0.05. Regional E-wave peak velocities of LV were higher at rest in normal subjects, P < 0.05. Both LV and RV, regional peak E-wave velocities were not affected by DSE. After DSE, regional A-wave peak velocities increased in all (P < 0.01), except at the lateral region (P = 0.07). DSE increased trans-tricuspid velocities in both groups, P < 0.05. Resting A-wave velocities were higher in normal subjects, P < 0.01. CONCLUSIONS: Global LV early diastolic filling parameters were not affected by LV-WMA at rest. LV-WMA blunted the response after stress. RV E-wave velocities increased after DSE, and were not affected by LV-WMA. LV-WMA reduced regional LV E' velocities at rest but not the reserve. A-wave velocities were not affected by WMA and increased after DSE. PMID- 28352451 TI - Myocardial Performance Index in Neurocardiogenic Syncope Patients. AB - BACKGROUND: Many syncopes resulting from neural reflexes in various conditions are called neurocardiogenic syncope (NCS). We aimed to investigate the presence of left ventricular (LV) myocardial performance index (MPI) in patients with NCS, which was diagnosed with head-up tilt table test (HUTT), and the accurateness of the test in order to use it as a method in patients with NCS. Assuming the MPI as a potential cause of syncope, we assessed the Tei index with non-invasive tissue Doppler echocardiography method. METHODS: Consecutive outpatients with a history of recurrent unexplained syncope underwent HUTT. Twenty-nine HUTT (+) patients (24 female and five male, mean age: 30 +/- 15 years) as the study group and HUTT (-) 23 healthy patients (six female and 17 male, mean age: 34 +/- 16 years) as the control group were included into the study. Conventional and tissue Doppler echocardiography was performed to both groups. The MPI was determined by using PW Doppler. Measurements of Doppler time intervals, according to Tei index ((isovolumic contraction time + isovolumic relaxation time)/ejection time) is calculated as (a - b/b), where "a" is the interval between cessation and onset of the mitral inflow, and "b" is the ejection time (ET) at the LV outflow. RESULTS: When comparing the groups in terms of MPI and ET, there was significant difference between groups. Patients with NCS had significantly longer ET and lower MPI value than control group (284 +/- 24 ms vs. 260 +/- 24 ms, P < 0.001, respectively and 0.44 +/- 0.7 vs. 0.52 +/- 0.8, P < 0.001, respectively). There was no significant difference in ejection fraction between groups. CONCLUSION: In the present study, LV MPI value decreases in patients with NCS. PMID- 28352452 TI - Purulent Pericarditis Leading to Constriction. AB - We report a case of a previously healthy 61-year-old immunocompetent male who was found to have purulent bacterial pericarditis. The patient was initially diagnosed with pneumococcal pneumonia and bacteremia after presenting with chest pain and a productive cough. He was found to have a purulent pericardial effusion and underwent surgical washout and creation of a pericardial window. In short time he developed signs of right heart failure and a cardiac MRI revealed a severely thickened pericardium with evidence of constrictive pericarditis. The patient subsequently underwent pericardiectomy where the diagnosis of constriction was confirmed. Our patient recovered well and had no clinical evidence of heart failure on follow-up. This case demonstrates the importance of rapid identification of bacterial pericarditis and the high likelihood of progression to constriction. PMID- 28352453 TI - Eptifibatide and Cirrhosis: Rethinking GPIIb-IIIa Inhibitors for Acute Coronary Syndrome in the Setting of Liver Dysfunction. AB - Glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, such as eptifibatide, are routinely used in the setting of acute coronary syndrome (ACS) prior to or during percutaneous coronary intervention (PCI). While numerous studies have demonstrated improved clinical outcomes with eptifibatide use, adverse effects including thrombocytopenia have also been noted. For this reason, patients with baseline thrombocytopenia or liver disease should be cautiously evaluated prior to drug administration. Here we report a case of acute profound and prolonged eptifibatide-induced thrombocytopenia in a patient with cirrhotic liver dysfunction. We propose and discuss the need for a risk stratification tool to be established for identifying which patients with ACS in the setting of chronic liver disease receive GPIIb/IIIa inhibitors. PMID- 28352454 TI - Cardiac Cephalgia. AB - Although most of the patients presenting with ischemic heart disease have chest pains, there are other rare presenting symptoms like cardiac cephalgia. In this report, we present a case of acute coronary syndrome with an only presentation of exertional headache. It was postulated as acute presentation of coronary artery disease, due to previous history of similar presentation associated with some chest pains with previous left coronary artery stenting. We present an unusual case with cardiac cephalgia in a young patient under the age of 50 which was not reported at that age before. There are four suggested mechanisms for this cardiac presentation. PMID- 28352455 TI - A Case of Uncorrected Tetralogy of Fallot Undiagnosed Until Adulthood and Presenting With Polycythemia. AB - Congenital heart defects with right-to-left shunt are one of the hypoxia-related causes of acquired secondary polycythemia (SP). Tetralogy of Fallot (ToF) is the most common congenital cyanotic heart disease in children. Cases of uncorrected ToF in adult ages are rare. This paper reports a woman detected with elevated hemoglobin level during routine tests performed for infertility therapy and subsequently diagnosed SP with related ToF. PMID- 28352456 TI - Re-imagining the future of diagnosis of Neglected Tropical Diseases. AB - Neglected Tropical Diseases (NTDs) affect an estimated 1 billion people in 149 countries. The World Health Organization (WHO) prioritised 17 NTDs for control and elimination by 2020 and defined a Road Map to help countries reach these goals. Improved diagnostics for NTDs are essential for guiding treatment strategies at different thresholds of control, interruption of transmission, elimination and post-elimination surveillance. While substantial progress has been made in the last decade with chemotherapy, the same cannot be said of diagnostics, largely due to the perceived lack of a commercially viable market for NTD diagnostics. New sample in-answer out nucleic acid amplification technologies that can be performed at the point-of-care offer improved performance over current technologies and the potential to test for multiple pathogens using a single specimen. Finding commonalities for different NTDs in terms of geographic overlap, sentinel populations and treatment strategy will allow NTD programs to leverage these innovations to build cost-effective multiplex surveillance platforms. Connectivity solutions linking data from diagnostic laboratories and POC test readers/devices provide opportunities for automated surveillance systems to make health systems more efficient, improving patient outcomes and assessing impact of interventions in real time. New models of public-private product development partnerships are critical in leveraging diagnostic innovation in other priority area for better diagnosis, control and elimination of NTDs. PMID- 28352457 TI - A systems science perspective on the capacity for change in public hospitals. AB - Many types of organisation are difficult to change, mainly due to structural, cultural and contextual barriers. Change in public hospitals is arguably even more problematic than in other types of hospitals, due to features such as structural dysfunctionalities and bureaucracy stemming from being publicly-run institutions. The main goals of this commentary are to bring into focus and highlight the "3 + 3 Decision Framework" proposed by Edwards and Saltman. This aims to help guide policymakers and managers implementing productive change in public hospitals. However, while change from the top is popular, there are powerful front-line clinicians, especially doctors, who can act to counterbalance top-down efforts. Front-line clinicians have cultural characteristics and power that allows them to influence or reject managerial decisions. Clinicians in various lower-level roles can also influence other clinicians to resist or ignore management requirements. The context is further complicated by multi-stakeholder agendas, differing goals, and accumulated inertia. The special status of clinicians, along with other system features of public hospitals, should be factored into efforts to realise major system improvements and progressive change. PMID- 27803796 TI - Identifying ELIXIR Core Data Resources. AB - The core mission of ELIXIR is to build a stable and sustainable infrastructure for biological information across Europe. At the heart of this are the data resources, tools and services that ELIXIR offers to the life-sciences community, providing stable and sustainable access to biological data. ELIXIR aims to ensure that these resources are available long-term and that the life-cycles of these resources are managed such that they support the scientific needs of the life sciences, including biological research. ELIXIR Core Data Resources are defined as a set of European data resources that are of fundamental importance to the wider life-science community and the long-term preservation of biological data. They are complete collections of generic value to life-science, are considered an authority in their field with respect to one or more characteristics, and show high levels of scientific quality and service. Thus, ELIXIR Core Data Resources are of wide applicability and usage. This paper describes the structures, governance and processes that support the identification and evaluation of ELIXIR Core Data Resources. It identifies key indicators which reflect the essence of the definition of an ELIXIR Core Data Resource and support the promotion of excellence in resource development and operation. It describes the specific indicators in more detail and explains their application within ELIXIR's sustainability strategy and science policy actions, and in capacity building, life-cycle management and technical actions. The identification process is currently being implemented and tested for the first time. The findings and outcome will be evaluated by the ELIXIR Scientific Advisory Board in March 2017. Establishing the portfolio of ELIXIR Core Data Resources and ELIXIR Services is a key priority for ELIXIR and publicly marks the transition towards a cohesive infrastructure. PMID- 28299173 TI - Systematic assessment of multi-gene predictors of pan-cancer cell line sensitivity to drugs exploiting gene expression data. AB - Background: Selected gene mutations are routinely used to guide the selection of cancer drugs for a given patient tumour. Large pharmacogenomic data sets, such as those by Genomics of Drug Sensitivity in Cancer (GDSC) consortium, were introduced to discover more of these single-gene markers of drug sensitivity. Very recently, machine learning regression has been used to investigate how well cancer cell line sensitivity to drugs is predicted depending on the type of molecular profile. The latter has revealed that gene expression data is the most predictive profile in the pan-cancer setting. However, no study to date has exploited GDSC data to systematically compare the performance of machine learning models based on multi-gene expression data against that of widely-used single gene markers based on genomics data. Methods: Here we present this systematic comparison using Random Forest (RF) classifiers exploiting the expression levels of 13,321 genes and an average of 501 tested cell lines per drug. To account for time-dependent batch effects in IC 50 measurements, we employ independent test sets generated with more recent GDSC data than that used to train the predictors and show that this is a more realistic validation than standard k-fold cross validation. Results and Discussion: Across 127 GDSC drugs, our results show that the single-gene markers unveiled by the MANOVA analysis tend to achieve higher precision than these RF-based multi-gene models, at the cost of generally having a poor recall (i.e. correctly detecting only a small part of the cell lines sensitive to the drug). Regarding overall classification performance, about two thirds of the drugs are better predicted by the multi-gene RF classifiers. Among the drugs with the most predictive of these models, we found pyrimethamine, sunitinib and 17-AAG. Conclusions: Thanks to this unbiased validation, we now know that this type of models can predict in vitro tumour response to some of these drugs. These models can thus be further investigated on in vivo tumour models. R code to facilitate the construction of alternative machine learning models and their validation in the presented benchmark is available at http://ballester.marseille.inserm.fr/gdsc.transcriptomicDatav2.tar.gz. PMID- 28232862 TI - Electroantennogram response of the parasitoid, Microplitis croceipes to host related odors: The discrepancy between relative abundance and level of antennal responses to volatile compound. AB - Herbivores emit volatile organic compounds (VOCs) after feeding on plants. Parasitoids exploit these VOCs as odor cues to locate their hosts. In nature, host-related odors are emitted as blends of various compounds occurring in different proportions, and minor blend components can sometimes have profound effects on parasitoid responses. In a previous related study, we identified and quantified VOCs emitted by cotton plant-fed Heliothis virescens (Lepidoptera: Noctuidae) larvae, an herbivore host of the parasitoid Microplitis croceipes (Hymenoptera: Braconidae). In the present study, the olfactory response of female M. croceipes to synthetic versions of 15 previously identified compounds was tested in electroantennogram (EAG) bioassays. Using M. croceipes as a model species, we further asked the question: does the relative abundance of a volatile compound match the level of antennal response in parasitoids? Female M. croceipes showed varying EAG responses to test compounds, indicating different levels of bioactivity in the insect antenna. Eight compounds, including decanal, 1-octen-3 ol, 3-octanone, 2-ethylhexanol, tridecane, tetradecane, alpha-farnesene and bisabolene, elicited EAG responses above or equal to the 50 th percentile rank of all responses. Interestingly, decanal, which represented only 1% of the total amount of odors emitted by cotton-fed hosts, elicited the highest (0.82 mV) EAG response in parasitoids. On the other hand, ( E)-beta-caryophyllene, the most abundant (29%) blend component, elicited a relatively low (0.17 mV) EAG response. The results suggest that EAG response to host-related volatiles in parasitoids is probably more influenced by the ecological relevance or functional role of the compound in the blend, rather than its relative abundance. PMID- 28352462 TI - Fixation methods can differentially affect ciliary protein immunolabeling. AB - BACKGROUND: Primary cilia are immotile, microtubule-based organelles present on most cells. Defects in primary cilia presence/function result in a category of developmental diseases referred to as ciliopathies. As the cilia field progresses, there is a need to consider both the ciliary and extraciliary roles of cilia proteins. However, traditional fixation methods are not always suitable for examining the full range of localizations of cilia proteins. Here, we tested a variety of fixation methods with commonly used cilia markers to determine the most appropriate fixation method for different cilia proteins. METHODS: Mouse inner medullary collecting duct and human retinal pigmented epithelial cells were grown to confluence, serum starved, and fixed with one of the following fixation agents: paraformaldehyde-sucrose, paraformaldehyde-PBS, methanol, cytoskeletal buffer followed by methanol, or three variations of cytoskeletal buffer paraformaldehyde fixation. Each cell type and fixation method combination was probed with the following ciliary markers: acetylated alpha-tubulin, detyrosinated tubulin, polyglutamylated tubulin, beta-tubulin, adenylyl cyclase 3 (AC3), ADP-ribosylation factor-like protein 13b (Arl13b), centrosome and spindle pole associated protein 1 (CSPP1), or intraflagellar transport protein 20 (IFT20). Intraflagellar transport protein 88 (IFT88) and GM130 (Golgi marker) were also used. We assessed actin (via phalloidin) and microtubule integrity, centrioles, cilia, and two extraciliary sites (mitotic figures and Golgi). RESULTS: For the cilia markers examined, paraformaldehyde fixation preserved cilia immunolabeling of cilia-membrane proteins (AC3 and Arl13b), but failed to reveal cilia immunostaining of axonemal proteins (CSPP1 and IFT20). Methanol revealed cilia labeling for some axonemal proteins, but not others, and this depended on cell type. Generally, any method that first included a wash in cytoskeletal buffer, before fixing, revealed more distinct cilia immunolabeling for axonemal proteins (CSPP1, IFT20, and IFT88), but resulted in the loss of cilia labeling for cilia-membrane proteins (AC3 and Arl13b). All three different post-translational modifications of tubulin antibodies positively immunolabeled cilia in all fixation methods tested. Ultimately, we found that fixing cells in a solution of paraformaldehyde prepared in cytoskeletal buffer allowed for the preservation of cilia immunolabeling for most cilia proteins tested and allowed visualization of two extraciliary sites (mitotic figures and Golgi). CONCLUSION: Some general patterns were observed to guide in the choice of a fixation agent. Cilia-membrane proteins generally benefit from quick fixation with no prior permeabilization, whereas axonemal proteins tend to benefit from permeabilization and use of cytoskeletal buffer. PMID- 28299189 TI - Molecular signature of anastasis for reversal of apoptosis. AB - Anastasis (Greek for "rising to life") is a cell recovery phenomenon that rescues dying cells from the brink of cell death. We recently discovered anastasis to occur after the execution-stage of apoptosis in vitro and in vivo. Promoting anastasis could in principle preserve injured cells that are difficult to replace, such as cardiomyocytes and neurons. Conversely, arresting anastasis in dying cancer cells after cancer therapies could improve treatment efficacy. To develop new therapies that promote or inhibit anastasis, it is essential to identify the key regulators and mediators of anastasis - the therapeutic targets. Therefore, we performed time-course microarray analysis to explore the molecular mechanisms of anastasis during reversal of ethanol-induced apoptosis in mouse primary liver cells. We found striking changes in transcription of genes involved in multiple pathways, including early activation of pro-cell survival, anti oxidation, cell cycle arrest, histone modification, DNA-damage and stress inducible responses, and at delayed times, angiogenesis and cell migration. Validation with RT-PCR confirmed similar changes in the human liver cancer cell line, HepG2, during anastasis. Here, we present the time-course whole-genome gene expression dataset revealing gene expression profiles during the reversal of apoptosis. This dataset provides important insights into the physiological, pathological, and therapeutic implications of anastasis. PMID- 28352463 TI - Pervasive antibiotic misuse in the Cambodian community: antibiotic-seeking behaviour with unrestricted access. AB - BACKGROUND: Antibiotic misuse is widespread in resource-limited countries such as Cambodia where the burden of infectious diseases is high and access to antibiotics is unrestricted. We explored healthcare seeking behaviour related to obtaining antibiotics and drivers of antibiotic misuse in the Cambodian community. METHODS: In-depth interviews were held with family members of patients being admitted in hospitals and private pharmacies termed pharmacy attendants in the catchment areas of the hospitals. Nurses who run community primary healthcare centres located within the hospital catchment areas were invited to attend focus group discussions. Nvivo version 10 was used to code and manage thematic data analysis. RESULTS: We conducted individual interviews with 35 family members, 7 untrained pharmacy attendants and 3 trained pharmacists and 6 focus group discussions with 30 nurses. Self-medication with a drug-cocktail was widespread and included broad-spectrum antibiotics for mild illness. Unrestricted access to antibiotics was facilitated by various community enablers including pharmacies or drug outlets, nurse suppliers and unofficial village medical providers referred to as "village Pett" whose healthcare training has historically been in the field and not at university. These enablers supplied the community with various types of antibiotics including broad spectrum fluoroquinolones and cephalosporins. When treatment was perceived to be ineffective patients would prescriber-shop various suppliers who would unfailingly provide them with antibiotics. The main driver of the community's demand for antibiotics was a mistaken belief in the benefits of antibiotics for a common cold, high temperature, pain, malaria and 'Roleak' which includes a broad catch-all for perceived inflammatory conditions. For severe illnesses, patients would attend a community healthcare centre, hospital, or when their finances permitted, a private prescriber. CONCLUSIONS: Pervasive antibiotic misuse was driven by a habitual supplier-seeking behaviour that was enabled by unrestricted access and misconceptions about antibiotics for mild illnesses. Unofficial suppliers must be stopped by supporting existing regulations with tough new laws aimed at outlawing supplies outside registered pharmacies and fining registered pharmacist/owners of these pharmacies for supplying antibiotics without a prescription. Community primary healthcare centres must be strengthened to become the frontline antibiotic prescribers in the community thereby enabling the community's access to inexpensive and appropriate healthcare. Community-based education program should target appropriate health-seeking pathways and the serious consequences of antibiotic misuse. PMID- 28352464 TI - An overview of the epidemiology and emergence of influenza A infection in humans over time. AB - In recent years multiple novel influenza A strains have emerged in humans. We reviewed publically available data to summarise epidemiological characteristics of distinct avian influenza viruses known to cause human infection and describe changes over time. Most recently identified zoonotic strains have emerged in China (H7N9, H5N6, H10N8) - these strains have occurred mostly in association with visiting a live bird market. Most zoonotic AIVs and swine influenza variants typically cause mild infections in humans however severe illness and fatalities are associated with zoonotic H5N6, H10N8, H7N9 and H5N1 serotypes, and the H1N1 1918 Spanish Influenza. The changing landscape of avian influenza globally indicates a need to reassess the risk of a pandemic influenza outbreak of zoonotic origin. PMID- 28352465 TI - A multifaceted approach to improving the quality of ENT Emergency Clinic referrals. AB - It is imperative that primary care referrals are directed to the appropriate secondary care service. Patients presenting to a primary care physician with ENT conditions may require review in an Emergency Clinic. The latter clinics provide patients with rapid access to secondary care, for urgent, yet non-life threatening conditions. In our department, we noticed that patients with conditions inappropriate to the capabilities of the Clinic were being booked in or reviewed too late; thus causing wasted journeys for the patient. We conducted a Quality Improvement Project to improve the efficiency of the referral process. A prospective evaluation of referrals was collected continuously over a two-month period. Overall, 5 domains were deemed crucial to enable timely and accurate booking of patients to clinic: booking date, urgency, legibility, patient identification and appropriateness. Our proposed standard set for this project was 100% compliance over the 5 domains. Three separate interventions were instigated following the first cycle. The main components of the intervention were the phased development of an electronic referral system and an educational initiative for junior doctors. 20 referral forms were analysed during the initial 3-week period. No referrals met the recommended overall compliance standard of 100% (mean number of domains achieved: 3.38; standard deviation (SD): 0.637). Legibility and patient information were included in 21% and 30% of referrals, respectively. There was a trend of improvement following initiation of interventions. The mean number of domains achieved was 4.27 (SD 0.647; n=13) in the second data collection period, 4.53 (SD 0.514; n=16) in the third, and 4.75 (SD 0.452; n=24) in the fourth. Using linear regression, this change demonstrates a statistically significant improvement (p<0.001). An e-Proforma referral system represents a safe and efficient communication technology. When implementing policy change, it is crucial to acquire managerial and consultant support. PMID- 28352466 TI - Systems for physical health care for mental health patients in the community: different approaches to improve patient care and safety in an Early Intervention in Psychosis Service. AB - Patients with mental illnesses have a high rate of physical comorbidity, and specifically, those with psychosis are at an increased risk of cardiometabolic disease and shortened lifespans, due to medication, lifestyle and illness factors. There are recognised challenges with physical health care in this group. At baseline, no patients on the Bath and North East Somerset Early Intervention in Psychosis caseload had a fully completed physical health assessment. Our aim was to offer a physical health check, blood tests, and ECG for all patients, trialling four phases of interventions. The four phases were (1) increased awareness, education and data collection tools; (2) mobile physical health clinics; (3) letters sent to patients and GPs to request health checks be conducted, (4) a combination of the above approaches, as well as regular caseload reviews and prompts to professionals. At the time of our study (2015-16), many of the above parameters were also incentivised nationally by Commissioning for Quality and Innovation (CQUIN) payments. The mobile physical health clinic offered patient choice of home visits or clinic checks, to increase engagement and provide flexible care. The most successful approach overall was the combination approach, resulting in 48% of all patients having fully completed physical health checks, bloods and ECGs. The mobile clinic resulted in physical health checks completion rates of 60%, and blood tests in 65-70%. 92% of patients undertook ECG's, following letter requests to GPs and patients. Combining mobile physical health clinics, GP letters, financial incentives and managerial engagement produced much improved results, but was very time consuming, and in our case was inefficient due to using multiple professionals. We recommend embedding such approaches within the team, using sustainable systems, and would encourage teams to trial dedicated trained clinicians to establish sustainable systems to improve the physical health care of this vulnerable group. PMID- 28352467 TI - Electronic Printed Ward Round Proformas: Freeing Up Doctors' Time. AB - The role of a junior doctor involves preparing for the morning ward round. At a time when there are gaps on rotas and doctors' time is more stretched, this can be a source of significant delay and thus a loss of working time. We therefore looked at ways in which we could make the ward round a more efficient place by introducing specific electronic, printed ward round proformas. We used the average time taken to write proformas per patient and the average time taken per patient on the ward round. This would then enable us to make fair comparisons with future changes that were made using the plan, do, study, and act principles of quality improvement. Our baseline measurement found that the average time taken to write up the proforma for each patient was 1 minute 9 seconds and that the average time taken per patient on the ward round was 8 minutes 30 seconds. With the changes we made during our 3 PDSA cycles and the implementation of an electronic, printed ward round proforma, we found that we were able to reduce the average time spent per patient on the ward round to 6 minutes 32 seconds, an improvement of 1 min 58 seconds per patient. The project has thus enabled us to reduce the time taken per patient during the ward round. This improved efficiency will enable patients to be identified earlier for discharge. It will also aid in freeing up the time of junior doctors, allowing them to complete discharge letters sooner, order investigations earlier and enable them to complete their allocated tasks within contracted hours. PMID- 28352468 TI - Introduction of a Microsoft Excel-based unified electronic weekend handover document in Acute and General Medicine in a DGH: aims, outcomes and challenges. AB - On-call weekends in medicine can be a busy and stressful time for junior doctors, as they are responsible for a larger pool of patients, most of whom they would have never met. Clinical handover to the weekend team is extremely important and any communication errors may have a profound impact on patient care, potentially even resulting in avoidable harm or death. Several senior clinical bodies have issued guidelines on best practice in written and verbal handover. These include: standardisation, use of pro forma documents prompting doctors to document vital information (such as ceiling of care/resuscitation status) and prioritisation according to clinical urgency. These guidelines were not consistently followed in our hospital site at the onset of 2014 and junior doctors were becoming increasingly dissatisfied with the handover processes. An initial audit of handover documents used across the medical division on two separate weekends in January 2014, revealed high variability in compliance with documentation of key information. For example, ceiling of care was documented for only 14-42% of patients and resuscitation status in 26-72% of patients respectively. Additionally, each ward used their own self-designed pro forma and patients were not prioritised by clinical urgency. Within six months from the introduction of a standardised, hospital-wide weekend handover pro forma across the medical division and following initial improvements to its layout, ceiling of therapy and resuscitation status were documented in approximately 80% of patients (with some minor variability). Moreover, 100% of patients in acute medicine and 75% of those in general medicine were prioritised by clinical urgency and all wards used the same handover pro forma. PMID- 28352469 TI - Successful treatment of pulmonary nocardiosis with fluoroquinolone in bronchial asthma and bronchiectasis. AB - A 72-year-old Japanese woman was admitted at Saga University Hospital for fever, malaise, and productive cough. Six years ago, she had been diagnosed with bronchial asthma and was treated with inhaled corticosteroids. Chest radiograph and computed tomography on admission showed infiltrates in the right middle lobe, a mass lesion in the left lower lobe, and bronchiectasis in both lower lobes. Sputum examination showed Gram-positive rods with phagocytosis by neutrophils. These bacilli were identified as Nocardia otitidiscaviarum by 16S ribosomal RNA sequencing. Therefore, she was diagnosed with pulmonary nocardiosis and was treated with trimethoprim/sulfamethoxazole (TMP-SMX) and minocycline (MINO). However, she had to discontinue these antibiotics because of severe nausea and anorexia and instead was treated with fluoroquinolone for 6 months. There was resolution of the disease thereafter. Pulmonary nocardiosis with bronchial asthma and bronchiectasis can be successfully treated with fluoroquinolone, an alternative to TMP-SMX or MINO. PMID- 28352470 TI - Evaluation of a psychoeducational group intervention for family and friends of youth with borderline personality disorder. AB - BACKGROUND: Despite high levels of burden and distress among families with a member who has borderline personality disorder (BPD), only two BPD specific family psychoeducation groups have been empirically evaluated. Neither of these is designed specifically for the family and friends of young people who are presenting early in the course of BPD. This study aimed to evaluate Making Sense of Borderline Personality Disorder (MS-BPD), a three-session, developmentally tailored, manualised psychoeducational group for the family and friends of youth with BPD features. METHODS: The study employed a pre- and post-intervention, repeated measures design. Twenty-three participants completed self-report measures assessing for family burden, psychological distress, and knowledge about personality disorder. Demographic data were collected for the group participants and for their associated young person with BPD. Paired-samples t-tests were conducted to evaluate the effect of the MS-BPD intervention on participants' burden, distress and personality disorder knowledge. RESULTS: At the completion of session three (day 15), group participants reported significantly decreased subjective burden and increased personality disorder knowledge. Objective burden and distress remained unchanged. CONCLUSIONS: Family and friends of young people with BPD features experienced subjective, but not objective, benefit from attending a brief group-based psychoeducation intervention. Longer follow-up is likely to be required to detect behavioural change. The current findings support proceeding to a randomised controlled trial of MS-BPD. PMID- 28352472 TI - Erratum to: Options in human papillomavirus (HPV) detection for cervical cancer screening: comparison between full genotyping and a rapid qualitative HPV-DNA assay in Ghana. AB - [This corrects the article DOI: 10.1186/s40661-017-0041-1.]. PMID- 28352471 TI - Genetic mapping of principal components of canine pelvic morphology. AB - BACKGROUND: Concentrated breeding effort to produce various body structures and behaviors of dogs to suit human demand has inadvertently produced unwanted traits and diseases that accompany the morphological and behavioral phenotypes. We explored the relationship between pelvic conformation and canine hip dysplasia (HD) because purebred dogs which are predisposed, or not, to HD share common morphologic features, respectively. Thirteen unique bilateral anatomical features of the pelvis were measured on 392 dogs of 51 breeds and 95 mixed breed dogs. Principal components (PCs) were derived to describe pelvic morphology. Dogs were genotyped at ~183,000 single nucleotide polymorphisms and their hip conformation was measured by the Norberg angle and angle of inclination between the femoral neck and diaphysis. RESULTS: No associations reached genome wide significance for the Norberg angle when averaged over both hips. PC1 was negatively correlated with the Norberg angle (r = -0.31; P < 0.05) but not the angle of inclination (r = -0.08; P > 0.05). PC1, 2, 4, and 5 differed significantly between male and female dogs confirming pelvic sexual dimorphism. With sex as a covariate, the eigenvector contribution to PC1 reflected the overall size of the pelvis and was significantly associated with the IGF-1 locus, a known contributor to canine body size. PC3, which represented a tradeoff between ilial length and ischial length in which a longer ischium is associated with a shorter ilium, was significantly associated with a marker on canine chromosome 16:5181388 bp. The closest candidate gene is TPK1, a thiamine-dependent enzyme and part of the PKA complex. Associations with the remaining PCs did not reach genome wide significance. CONCLUSION: IGF-1 was associated with the overall size of the pelvis and sex is related to pelvic size. Ilial/ischial proportion is genetically controlled and the closest candidate gene is thiamine-dependent and affects birth weight and development of the nervous system. Dogs with larger pelves tend to have smaller NAs consistent with increased tendency toward HD in large breed dogs. Based on the current study, pelvic shape alone was not strongly associated with canine hip dysplasia. PMID- 28352473 TI - Ethnic Differences in Risk Factors for Obesity among Adults in California, the United States. AB - Little attention has been given to differences in obesity risk factors by racial/ethnic groups. Using data from the 2011-2012 California Health Interview Survey, we examined differences in risk factors for obesity among Whites, Latinos, Asians, and African Americans among 42,935 adults (24.8% obese). Estimates were weighted to ensure an unbiased representation of the Californian population. Multiple logistic and linear regression analyses were used to examine the differences in risk factors for obesity. Large ethnic disparities were found in obesity prevalence: Whites (22.0%), Latinos (33.6%), African Americans (36.1%), and Asians (9.8%). Differences in risk factors for obesity were also observed: Whites (gender, age, physical activity, smoking, arthritis, and diabetes medicine intake), Latinos (age, arthritis, and diabetes medicine intake), Asians (age, binge drinking, arthritis, and diabetes medicine intake), and African Americans (gender, physical activity, smoking, binge drinking, and diabetes medicine intake). Females were more likely to be obese among African Americans (odds ratio (OR) = 1.43, 95% confidence interval (CI) = 1.05-1.94), but less likely among Whites (OR = 0.80, 95% CI = 0.74-0.87). Race/ethnicity should be considered in developing obesity prevention strategies. PMID- 28352474 TI - Factors Associated with Mortality among Patients on TB Treatment in the Southern Region of Zimbabwe, 2013. AB - Background. In 2013, the tuberculosis (TB) mortality rate was highest in southern Zimbabwe at 16%. We therefore sought to determine factors associated with mortality among registered TB patients in this region. Methodology. This was a retrospective record review of registered patients receiving anti-TB treatment in 2013. Results. Of 1,971 registered TB patients, 1,653 (84%) were new cases compared with 314 (16%) retreatment cases. There were 1,538 (78%) TB/human immunodeficiency virus (HIV) coinfected patients, of whom 1,399 (91%) were on antiretroviral therapy (ART) with median pre-ART CD4 count of 133 cells/uL (IQR, 46-282). Overall, 428 (22%) TB patients died. Factors associated with increased mortality included being >=65 years old [adjusted relative risk (ARR) = 2.48 (95% CI 1.35-4.55)], a retreatment TB case [ARR = 1.34 (95% CI, 1.10-1.63)], and being HIV-positive [ARR = 1.87 (95% CI, 1.44-2.42)] whilst ART initiation was protective [ARR = 0.25 (95% CI, 0.22-0.29)]. Cumulative mortality rates were 10%, 14%, and 21% at one, two, and six months, respectively, after starting TB treatment. Conclusion. There was high mortality especially in the first two months of anti-TB treatment, with risk factors being recurrent TB and being HIV infected, despite a high uptake of ART. PMID- 28352475 TI - Kanamycin Sulphate Loaded PLGA-Vitamin-E-TPGS Long Circulating Nanoparticles Using Combined Coating of PEG and Water-Soluble Chitosan. AB - Kanamycin sulphate (KS) is a Mycobacterium tuberculosis protein synthesis inhibitor. Due to its intense hydrophilicity, KS is cleared from the body within 8 h. KS has a very short plasma half-life (2.5 h). KS is used in high concentrations to reach the therapeutic levels in plasma, which results in serious nephrotoxicity/ototoxicity. To overcome aforementioned limitations, the current study aimed to develop KS loaded PLGA-Vitamin-E-TPGS nanoparticles (KS PLGA-TPGS NPs), to act as an efficient carrier for controlled delivery of KS. To achieve a substantial extension in blood circulation, a combined design, affixation of polyethylene glycol (PEG) to KS-PLGA-TPGS NPs and adsorption of water-soluble chitosan (WSC) (cationic deacetylated chitin) to particle surface, was raised for surface modification of NPs. Surface modified NPs (KS-PEG-WSC NPs) were prepared to provide controlled delivery and circulate in the bloodstream for an extended period of time, thus minimizing dosing frequency. In vivo pharmacokinetics and in vivo biodistribution following intramuscular administration were investigated. NPs surface charge was close to neutral +3.61 mV and significantly affected by the WSC coating. KS-PEG-WSC NPs presented striking prolongation in blood circulation, reduced protein binding, and long drew-out the blood circulation half-life with resultant reduced kidney sequestration vis-a-vis KS-PLGA-TPGS NPs. The studies, therefore, indicate the successful formulation development of KS-PEG-WSC NPs with reduced frequency of dosing of KS indicating low incidence of nephrotoxicity/ototoxicity. PMID- 28352477 TI - Understanding Neuromuscular System Plasticity to Improve Motor Function in Health, Disease, and Injury. PMID- 28352476 TI - CPAP Treatment Adherence in Women with Obstructive Sleep Apnea. AB - Untreated obstructive sleep apnea (OSA) has numerous negative health-related consequences. Continuous positive airway pressure (CPAP) is generally considered the treatment of choice for OSA, but rates of nonadherence are high. It is believed that OSA is more prevalent among men; therefore understanding how OSA presents among women is limited and treatment adherence has received little research attention. For this study, 29 women were recruited from primary care offices. They completed a questionnaire battery and underwent a night of nocturnal polysomnography (PSG) followed by a visit with a sleep specialist. Women diagnosed with OSA were prescribed CPAP; 2 years later CPAP adherence was evaluated. Results show that approximately half the sample was adherent. There were no significant differences between adherent and nonadherent women on OSA severity; however CPAP adherent women had worse nocturnal and daytime functioning scores at the time of diagnosis. Moreover, when the seven nocturnal and daytime variables were used as predictors in a discriminant analysis, they could predict 87% of adherent and 93% of the nonadherent women. The single most important predictor was nonrefreshing sleep. We discuss the implications of the findings for identifying women in primary care with potential OSA and offer suggestions for enhancing treatment adherence. PMID- 28352478 TI - Corrigendum to "Dopaminergic Modulation of Striatal Inhibitory Transmission and Long-Term Plasticity". AB - [This corrects the article DOI: 10.1155/2015/789502.]. PMID- 28352480 TI - Transcatheter Aortic Valve Implantation in an Extremely Tortuous S-Shaped Aorta. AB - Transcatheter aortic valve implantation (TAVI) has emerged as an alternative technique to treating aortic stenosis in patients with high surgical risk. We present a case of a successful transfemoral TAVI in a high-risk patient with an extremely tortuous iliofemoral system and a significant S-type bend in the descending aorta. With careful preprocedure planning and using all the techniques available, TAVI can be performed in the most challenging patients. PMID- 28352479 TI - Effects of Traumatic Stress Induced in the Juvenile Period on the Expression of Gamma-Aminobutyric Acid Receptor Type A Subunits in Adult Rat Brain. AB - Studies have found that early traumatic experience significantly increases the risk of posttraumatic stress disorder (PTSD). Gamma-aminobutyric acid (GABA) deficits were proposed to be implicated in development of PTSD, but the alterations of GABA receptor A (GABAAR) subunits induced by early traumatic stress have not been fully elucidated. Furthermore, previous studies suggested that exercise could be more effective than medications in reducing severity of anxiety and depression but the mechanism is unclear. This study used inescapable foot-shock to induce PTSD in juvenile rats and examined their emotional changes using open-field test and elevated plus maze, memory changes using Morris water maze, and the expression of GABAAR subunits (gamma2, alpha2, and alpha5) in subregions of the brain in the adulthood using western blotting and immunohistochemistry. We aimed to observe the role of GABAAR subunits changes induced by juvenile trauma in the pathogenesis of subsequent PTSD in adulthood. In addition, we investigated the protective effects of exercise for 6 weeks and benzodiazepine (clonazepam) for 2 weeks. This study found that juvenile traumatic stress induced chronic anxiety and spatial memory loss and reduced expression of GABAAR subunits in the adult rat brains. Furthermore, exercise led to significant improvement as compared to short-term BZ treatment. PMID- 28352481 TI - Autotransplantation of Ectopic Permanent Maxillary Incisors. AB - The report presents examples of successful cases of autotransplantation of ectopic teeth as donor in the treatment of clinically missing maxillary anterior teeth in young patients. The transplanted teeth were either severely ectopic, inverted, rotated or in an unfavourable position that they are commonly sacrificed as a result. Details of surgical technique as well as clinical and radiographic assessments were discussed. PMID- 28352482 TI - Haemophilus influenzae Pyomyositis in a Patient with Diabetic Ketoacidosis: A Unique Case and Review of Literature. AB - Haemophilus influenzae is a Gram-negative bacillus commonly known to cause upper respiratory tract infections. Skin and soft tissue infections are very uncommon. Of these, the majority were associated with necrotizing fasciitis requiring emergent debridement. We report a case of pyomyositis caused by Haemophilus influenzae in an adult with diabetes. PMID- 28352483 TI - Ultrasound, Echocardiography, MRI, and Genetic Analysis of a Fetus with Congenital Diaphragmatic Hernia and Partial 11q Trisomy. AB - Congenital diaphragmatic hernia (CDH) is a serious birth defect with a significant mortality and morbidity. The current and constant progress in ultrasound techniques has led to the improvement of the prenatal diagnosis of this malformation. CDH is a developmental defect whose etiology is heterogeneous and takes place when the pleuroperitoneal folds and septum transversum fail to converge and fuse. Survival depends on the extent of pulmonary hypoplasia and the disease may be potentially worsened by the presence of added congenital defects. 40% of CDH cases are associated with at least one additional anomaly. The ultrasound diagnosis is established with essential signs: loss of uniform echogenicity of lungs and marked mediastinal shift. We report the case of a fetus with isolated CDH diagnosed at 21 weeks of gestation by ultrasound and confirmed by RMI, whose genetic analysis of amniotic fluid cells identified a de novo partial trisomy of the long arm of chromosome 11. Different genetic causes have been associated with CDH. Moreover, it is expectable that the use of new techniques for prenatal diagnosis will reveal novel CNVs associated with CDH and will help us to estimate the recurrence risk for this defect as well as for other associated anomalies. PMID- 28352485 TI - Lateral Lumbar Interbody Fusion for Ossification of the Yellow Ligament in the Lumbar Spine: First Reported Case. AB - When ossification of the yellow ligament (OYL) occurs in the lumbar spine and extends to the lateral wall of the spinal canal, facetectomy is required to remove all of the ossified lesion and achieve decompression. Subsequent posterior fixation with interbody fusion will then be necessary to prevent postoperative progression of the ossification and intervertebral instability. The technique of lateral lumbar interbody fusion (LLIF) has recently been introduced. Using this procedure, surgeons can avoid excess blood loss from the extradural venous plexus and detachment of the ossified lesion and the ventral dura mater is avoidable. We present a 55-year-old male patient with OYL at L3/4 and anterior spondylolisthesis of L4 vertebra, with concomitant ossification of the posterior longitudinal ligament, who presented with a severe gait disturbance. He underwent a 2-stage operation without complications: LLIF for L3/4 and L4/5 was performed at the initial surgery, and posterior decompression fixation using pedicle screws from L3 to L5 was performed at the second surgery. His postoperative progress was favorable, and his interbody fusion was deemed successful. Here, we present the first reported case of LLIF for OYL of the lumbar spine. This procedure can be a good option for OYL of the lumbar spine. PMID- 28352484 TI - Primary Pulmonary Malignant Melanoma: Report of an Important Entity and Literature Review. AB - Malignant melanoma involving the respiratory tract is nearly always metastatic in origin, and primary tumors are extremely rare. Published data on primary pulmonary malignant melanomas are limited. Up to now 40 relevant cases have been reported in the English literature. Herein, we report a case of a 56-year-old female patient who presented with intracranial metastases due to primary pulmonary melanoma. She underwent bronchoscopy and died 5 months after the initial diagnosis despite the administered biochemotherapy and subsequent immunotherapy. To establish the diagnosis of primary pulmonary malignant melanoma, any extrapulmonary origin was excluded by detailed examination and radiographic imaging. Moreover, an extensive review of the literature regarding this rare entity has been performed. PMID- 28352486 TI - Unilateral Maxillary Sinus Actinomycosis with a Closed Oroantral Fistula. AB - Actinomycosis is a bacterial infection due to Actinomyces israelii, a gram positive, anaerobic organism that normally affects the cervicofacial region. However, facial injury or trauma (i.e., dental procedures) can allow this bacteria to inhabit other regions. There have been rare reports of actinomycosis of the paranasal sinuses. We present a case of a 50-year-old female who originally presented with a suspected oroantral fistula who subsequently was found to have actinomycosis involving her right maxillary sinus. Additionally, the dental extraction site revealed no connection with the maxillary sinus. We discuss the diagnostic approach and management of this patient as it relates to the limited existing literature. PMID- 28352487 TI - Giant Perineal Solitary Fibrous Tumor: A Rare Case Report. AB - Background. Solitary fibrous tumor (SFT) is a fibroblastic mesenchymal tumor that was initially described from the pleura but currently arises at almost every anatomic site. It is usually benign, and surgical resection is curative. SFT involving the perineum is extremely rare. This is the third case report of a perineal SFT in the literature. Case Presentation. We reported an uncommon case of a 64-year-old man presenting with a huge perineal mass that started growing 3 years before his arrival in our service. He was asymptomatic. A contrast-enhanced CT scan revealed a heterogeneous well-circumscribed perineal mass with soft tissue density. Invasion of the surrounding organs, distal metastasis, and lymph node swelling were absent. The complete resection of mass was done successfully. The specimen was a 23.0 * 14.0 * 8.0 cm encapsulated tumor. Mass weight was 1,170 g. After pathological analysis, we confirmed that the mass was a solitary fibrous tumor. The diagnosis was based on clinical findings and histological morphology and immunohistochemistry study. Conclusion. SFTs are usually indolent tumors with a favorable prognosis. The perineal location is extremely rare. Complete resection of the mass is the treatment of choice. PMID- 28352488 TI - Rare Case of a Well-Differentiated Paratesticular Sarcoma of the Spermatic Cord in a 60-Year-Old Patient. AB - Introduction. Liposarcomas are tumors that occur mostly in the retroperitoneum. Of all liposarcomas only 3 to 7% are found in the paratesticular region. The spermatic cord is the main site of origin in these cases. The patients ages range from 50 to 60 years. This malignant disease can result in a loss of fertility aside from life-threatening sequelae. Case. We present a case of a liposarcoma of the paratesticular region. A 60-year-old man was referred with a painless mass in the scrotum and the right inguinal region. The patient underwent surgery and the mass was removed along with the right testis, the spermatic cord, and the soft tissues to the internal inguinal ring. Histopathological examination found a well differentiated liposarcoma of 80*80 mm. The surgical margins were negative. The adjuvant treatment consisted in radiation therapy of the right inguinoscrotal area to the dose of 54 Gray, 2 Gy per session, 5 times a week. Conclusion. Paratesticular liposarcomas are rare tumors. Surgery with large margin resections was the main treatment in all reported cases. The adjuvant treatment is still unclear especially when the surgical margins are negative. The main factor that indicated this adjuvant treatment was the size of the tumor and the histologic subtype. PMID- 28352489 TI - Nonmotor Symptoms of Parkinson's Disease. PMID- 28352490 TI - Cost of Living with Parkinson's Disease over 12 Months in Australia: A Prospective Cohort Study. AB - Background. Parkinson disease (PD) is a costly chronic condition in terms of managing both motor and nonmotor symptoms. The burden of disease is high for individuals, caregivers, and the health system. The aim of this study is to estimate the annual cost of PD from the household, health system, and societal perspectives. Methods. A prospective cohort study of newly referred people with PD to a specialist PD clinic in Melbourne, Australia. Participants completed baseline and monthly health resource use questionnaires and Medicare data were collected over 12 months. Results. 87 patients completed the 12-month follow-up assessments. The mean annual cost per person to the health care system was $32,556 AUD. The burden to society was an additional $45,000 per annum per person with PD. The largest component of health system costs were for hospitalisation (69% of total costs). The costs for people with moderate to severe disease were almost 4 times those with mild PD ($63,569 versus $17,537 p < 0.001). Conclusion. PD is associated with significant costs to individuals and to society. Costs escalated with disease severity suggesting that the burden to society is likely to grow with the increasing disease prevalence that is associated with population ageing. PMID- 28352491 TI - Acquired factor VIII deficiency: two case reports and a review of literature. AB - BACKGROUND: Acquired factor VIII (FVIII) deficiency, or acquired hemophilia A (AHA), is a rare autoimmune disorder involving antibody-mediated depletion of coagulation FVIII, leading to severe, life-threatening bleeding. The condition is often associated with other autoimmune disorders, and its treatment involves replacement of FVIII and various modes of immunosuppression. Recently, a few noteworthy therapeutic advances have been made. We present two cases of severe AHA in Chinese women. One of these women developed this disorder in the setting of possible parvovirus B19 infection, which has not yet been reported in association with AHA. Other notable features of her case included paradoxical venous thrombosis and possible association with Sjogren's syndrome and myositis. The other woman failed to respond to usual first-line therapies despite exhibiting a less severe clinical course, illustrating the varied but potentially stubborn behavior of this disorder. CASE 1: An 87-year-old woman presented with diffuse ecchymoses, melena, vaginal bleeding. Labs showed hemoglobin (Hgb) nadir of 5.7 mg/dL, elevated partial thromboplastin time (PTT), FVIII level <1%, mixing study consistent with an inhibitor, elevated anti-Sjogren's-Syndrome-related antigen A antibody, elevated creatinine kinase, and elevated parvovirus IgM and IgG. Imaging of her arm showed diffuse myositis and deep venous thrombosis. After intravenous and oral steroids, her FVIII levels normalized, and her symptoms subsided. CASE 2: A 59-year-old woman presented with recurrent ecchymoses and hematomas in her extremities. Labs showed Hgb of 11.7 mg/dL, elevated PTT, FVIII level of 3%, and mixing study consistent with an inhibitor. Despite receiving a long course of steroids, several courses of IVIG, and a few courses of Rituximab, her FVIII level remained critically low. CONCLUSION: The rarity of AHA limits our understanding of this disease and the ability to perform trials to discover optimal therapies. We hope that these case reports and discussion will shed further light on the varied clinical manifestations and natural histories of this disorder to guide better recognition and treatment of AHA. PMID- 28352492 TI - Perceptions of Factors Impacting Longevity among Hawai'i Older Adults. AB - With increased life expectancy, people need more education about healthy aging. This paper examines older adult perceptions regarding various factors impacting longevity, including genetics, lifestyle, and the environment. Data were collected from 733 Hawai'i adults age 50 years and older (39% Caucasian, 27% Japanese, 19% Native Hawaiian and Pacific Islander (NHOPI), 9% Chinese, and 7% Filipino) through randomized telephone interviews. Participants were asked to rate a variety of factors as having "great impact," "some impact," or "no impact" on lifespan. Regardless of ethnicity, more than half of the participants felt that eating habits, exercise, health information, health care, and the environment had great impact on lifespan. Less than half felt that economic status and community had great impact. Compared to the all ethnic groups, Filipino respondents were significantly less likely to feel that smoking (44%, compared with an average across all race/ethnicities of 64%) and stress (48%, average 62%) had great impact. Chinese participants were more likely to feel that drinking alcohol (64%) had great impact (average 38%). Filipinos and Chinese were more likely to perceive that working conditions have great impact (65% and 56%, respectively; average 45%), and NHOPI and Filipinos were more likely to perceive the natural environment as having great impact (59% and 54%, respectively; average 46%). Findings suggest that cultural values and experiences may shape older adults' perceptions of factors associated with lifespan, providing guidance for health professionals on how to tailor health messages to older adults in different ethnic groups. PMID- 28352493 TI - High School Football Players Use Their Helmets to Tackle Other Players Despite Knowing the Risks. AB - There is greater attention to head-related injuries and concussions in American football. The helmet's structural safety and the way that football players use their helmets are important in preventing head injuries. Current strategies include penalizing players for high-risk behavior such as leading with their helmet or hitting an opposing player above the shoulder. Passive strategies include helmet modification to better protect the head of the players or to change the playing style of the players. Hawai'i high school varsity football players were surveyed to determine how they use their helmets and how a new helmet design would affect their style of play. One hundred seventy-seven surveys were completed; 79% said that they used their helmet to hit an opposing player during a tackle and 46% said they made this contact intentionally. When asked about modifying helmets with a soft material on the outside, 48% said they thought putting a soft cover over a regular helmet would protect their head better. However, many participants said that putting a soft cover over their regular helmet was a bad idea for various reasons. Most young football players use their helmets to block or tackle despite being taught they would be penalized or potentially injured if they did so. By gaining a better understanding of why and how players use their helmets and how they would respond to new helmet designs, steps can be taken to reduce head injuries for all levels of play. PMID- 28352494 TI - The Wandering Woman: A Case Study of Catatonia vs Factitious Disorder. AB - A 61-year-old woman with an unknown psychiatric history presented with mutism, stupor, negativism, and withdrawn behavior. She was admitted to the psychiatric unit for what appeared to be catatonia. Medical records were not readily available. A comprehensive evaluation did not uncover any medical etiology. Lorazepam was ineffective at consistently reversing her catatonic symptoms. During week three of hospitalization, she was given olanzapine with subsequent improvement in her negativism. Several physicians believed her catatonic symptoms were feigned given multiple episodes of spontaneous purposeful movement when she was not under the direct supervision of staff. There is minimal literature on distinguishing catatonia and factitious disorder. This distinction is crucial because these diagnoses require very different treatments, and the iatrogenic complications related to the treatment of catatonia with high-dose benzodiazepines and electroconvulsive therapy are significant. Rapid access to electronic health records can facilitate treatment for patients who cannot provide a medical history, especially when factitious disorder is included in the differential diagnosis. PMID- 28352495 TI - Medical School Hotline: Graduate Certificate in Tropical Medicine. PMID- 28352496 TI - Insights in Public Health: Training Today's Students to Meet Tomorrow's Challenges: Undergraduate Public Health at the University of Hawai'i at Manoa. AB - The University of Hawai'i at Manoa (UHM) has long provided public health graduate education. The University's Office of Public Health Studies (OPHS) has recently started to offer a Bachelor of Arts in Public Health (BA PH) degree in response to the growing need for professionals in the health field. The purpose of this paper is to describe how UHM operates the BA PH and how the program complements OPHS's mission and goals. First, we describe the overall scope of the BA PH within OPHS and within UHM. Then we provide examples of how the BA PH program and past undergraduate student projects align with OPHS's four main goals: (1) education, (2) research, (3) service, and (4) program development. PMID- 28352498 TI - Traumatic Cervical Nerve Root Avulsion with Pseudomeningocele Formation. AB - Cervical nerve root avulsion is a well-documented result of motor vehicle collision (MVC), especially when occurring at high velocities. These avulsions are commonly traction injuries of nerve roots that may be accompanied by a tear in the meninges through the vertebral foramina with associated collections of cerebrospinal fluid (CSF), thereby resulting in a pseudomeningocele. We present a case of a 19-year-old male who experienced an MVC and was brought to the emergency department (ED) with right arm paralysis and other injuries. A neurological examination demonstrated intact sensation but 0/5 muscle strength in the right upper extremity. A magnetic resonance imaging (MRI) of the spinal cord demonstrated massive epidural hematomas extending the length of the cervical spine caudally from C2. An MRI of the right brachial plexus showed C3-C7 anterior horn cell edema and associated traumatic nerve root avulsion with pseudomeningoceles on the right from C5-C8. The development of spinal cord hematoma with these injuries has rarely been documented in the literature and the multiple level avulsion described here with extensive hematoma is a rare clinical presentation. A literature review was conducted to determine the diagnostic requirements, treatment strategies, and complications of such an injury. Our patient received conservative treatment of the right brachial plexus injury and was transferred to an inpatient rehabilitation facility 13 days later. PMID- 28352499 TI - Metastatic Prostate Adenocarcinoma to the Brain: Case Reports and Literature Review. AB - Cerebral metastasis secondary to prostatic adenocarcinoma is rare and it is usually a late complication in patients with widespread distant metastases. Here, we report two unusual cases of such a rare condition. Our first case presented with a large frontal contrast-enhancing lesion-associated calcification and a large tumor cyst as shown on computed tomography and magnetic resonance imaging. This is the fifth reported case of prostatic metastasis manifesting as a cystic intraparenchymal tumor in the literature. The second case presented with a large soft tissue mass in the scalp and this lesion appeared to invade through the skull and into the middle cranial fossa. He was not known to have prostate cancer before his initial presentation and it was only diagnosed following histology results of the scalp lesion. PMID- 28352500 TI - Delayed Closure of Giant Omphaloceles in West Africa: Report of Five Cases. AB - Giant omphalocele (GO) management is controversial and not easy. Conservative management at birth and delayed surgical closure is usually mandatory. Postponed surgery may be challenging and carry the risk of intensive care treatment. We report on five children who were treated in our department for GO between 2000 and 2010. Initially, the patients were managed conservatively in West Africa. Delayed closure of the ventral hernia was performed in Switzerland after patient transfer through a nongovernmental organization. Fascial closure was performed at the median age of 23 months. Median diameter of the hernias was 10 * 10 cm ranging from 10 * 8 cm to 24 * 15 cm. Four (80%) patients had associated anomalies. Three children needed mechanical ventilation in the intensive care unit after surgery. Median hospitalization was 19 days. Complications were seen in two patients. The follow-up showed no recurrence of ventral hernia. There was no mortality. This report shows that conservative management of a GO at birth with delayed closure of the ventral hernia after transferring the patients to a European center is a safe approach for West African children and avoids life threatening procedures. Delayed closure of a GO may be nevertheless challenging everywhere. PMID- 28352501 TI - Myocardial Ischemia Caused by Subepicardial Hematoma. AB - Background Bleeding from bypass anastomosis leakage occurs early after coronary artery bypass grafting. Later, once the anastomosis is covered by intima, spontaneous bleeding is unlikely. Case Description A 63-year-old male patient developed a pseudoaneurysm-like, subepicardial late-term bleeding resulting in a hematoma that compromised coronary artery flow by increasing extracoronary pressure. This resulted in severe angina pectoris (Canadian Cardiovascular Society IV) and myocardial ischemia within the affected area. After surgical removal of the hematoma and repair of the anastomosis, the patient's symptoms disappeared and no signs of myocardial ischemia were present. Conclusion Surgical removal is an efficient therapy for subepicardial hematoma inducing myocardial ischemia. PMID- 28352502 TI - An Intervention Featuring Public Posting and Graphical Feedback to Enhance the Performance of Competitive Dancers. AB - This study evaluated an intervention package that used public posting and feedback to enhance dance movements for adolescent dancers on a competition team. Four dancers each performing two or three dance movements (a turn, kick, and/or leap) had their scores posted on a bulletin board at their studio. Dance movements were scored as a percentage correct by using a 14- to 16-step task analysis checklist. Intervention was evaluated in a multiple baseline across behavior design. The students received graphical feedback on their performance from the previous weeks and saw the scoring sheet that reviewed the incorrect and correct aspects of their performance. This study found that this treatment package including public posting and feedback enhanced each of the dance movements for all participants. PMID- 28352503 TI - Maintaining Staff Performance Following a Training Intervention: Suggestions from a 30-Year Case Example. AB - A frequent challenge encountered by behavior analysts in human service agencies is maintaining effects of their training interventions with agency staff. A case example is provided to illustrate how effects of a staff training intervention initiated by a behavior analyst maintained for an extended period in a center based program for adolescents and adults with severe disabilities. The process involved the behavior analyst working closely with the program supervisor and a professional staff member in a collaborative team approach to increase involvement of center participants in functional (vs. nonfunctional) educational tasks. Initially, the team jointly developed an intervention to increase staffs' provision of functional tasks. The behavior analyst subsequently worked with the team members regarding how to implement the intervention by training their staff and providing feedback. The two team members then continued providing feedback during their respective supervisor tenures without continued presence of the behavior analyst. Results indicated that initial increases in participant involvement in functional tasks maintained during follow-up observations encompassing 30 years. Normative comparisons also showed that the levels were well above the level of functional task involvement in other center-based programs across that time period. Results are discussed regarding recommendations for behavior analysts to use a collaborative team approach with supervisors indigenous to an agency to help maintain staff behavior targeted for change by the behavior analysts. PMID- 28352504 TI - Task as Reinforcer: a Reactive Alternative to Traditional Forms of Escape Extinction. AB - Inappropriate behaviors, ranging from passive resistance to physical aggression, property destruction, or self-injurious behavior frequently function for escape from or avoidance of non-preferred activities. Proactive procedures have been shown to be only moderately effective without the use of escape extinction, but escape extinction can produce negative side effects, and efforts have been made to find alternatives. The current study tested the efficacy of a reactive procedure that may serve as an alternative to traditional forms of escape extinction. In a multiple baseline across behavioral excesses, non-preferred activities, and participants, a timeout from the opportunity to work effectively reduced behavioral excesses and increased compliance with non-preferred activities. With one participant, a multiple baseline was implemented across instructional targets, resulting in an increased rate of skill acquisition after "wait outs" were introduced to each program. PMID- 28352505 TI - The Use of Evaluation in Treatment Programs for Children with Autism. AB - Program evaluation is the use of planned activities to monitor process, outcomes, and impact of a health program or intervention. The application of program evaluation to behavioral analytic treatment programs for children with autism is a useful and necessary activity to inform practitioners and other stakeholders of the efficacy of these programs and to promote adherence to best-practice treatments. A brief survey of behavioral providers in California and Texas and search of the behavioral literature suggest that the practice of program evaluation is underutilized among providers of behavioral services. Current organizational practices primarily involve reporting on individualized consumer goals. The purpose of this paper is to provide an introduction to evaluation processes and procedures to promote the implementation of some or all of these components. Areas discussed include defining the population served and program stakeholders, describing the program and intervention, selecting evaluation goals and objectives, ethical considerations, and reporting. PMID- 28352506 TI - Blurred Lines: Ethical Implications of Social Media for Behavior Analysts. AB - Social networking has a long list of advantages: it enables access to a large group of people that would otherwise not be geographically convenient or possible to connect with; it reaches several different generations, particularly younger ones, which are not typically involved in discussion of current events; and these sites allow a cost effective, immediate, and interactive way to engage with others. With the vast number of individuals who use social media sites as a way to connect with others, it may not be possible to completely abstain from discussions and interactions on social media that pertain to our professional practice. This is all the more reason that behavior analysts attend to the contingencies specific to these tools. This paper discusses potential ethical situations that may arise and offers a review of the Behavior Analysis Certification Board (BACB) guidelines pertaining to social networking, as well as provides suggestions for avoiding or resolving potential violations relating to online social behavior. PMID- 28352507 TI - Best Practices in Utilizing the Changing Criterion Design. AB - The changing criterion design (CCD) has been a recognized format of single-case research for four decades. Published examples of the CCD have been limited and the structure of the design used in the literature has varied to a degree that might engender confusion. This review examines the structure of CCD studies published to date to identify prior implementation practices and identify best practices for future use. PMID- 28352508 TI - A Comparison of Procedures for Teaching Receptive Labeling of Sight Words to a Child with Autism Spectrum Disorder. AB - We compared the effectiveness and efficiency of a modified simple-conditional method and the conditional-only method for teaching receptive labeling of sight words. Jon, a 6-year-old boy diagnosed with autism spectrum disorder, participated. Across three comparative evaluations, the conditional-only method resulted in fewer sessions to mastery than a modified simple-conditional method. Textual responses emerged after Jon mastered the sight words as receptive labels. Practitioners should avoid teaching component simple discriminations as a strategy for facilitating conditional discrimination training in clinical practice. PMID- 28352509 TI - Evaluating the Ability of the PBS Children's Show Daniel Tiger's Neighborhood to Teach Skills to Two Young Children with Autism Spectrum Disorder. AB - Daniel Tiger's Neighborhood is a children's television show incorporating many elements of video modeling, an intervention that can teach skills to children with autism spectrum disorders (ASD). This study evaluated the impact of watching Daniel Tiger's Neighborhood episodes on the accurate performance of trying new foods and stopping play politely with two five-year-old children with ASD. Both children showed improved performance of skills only following exposure to episodes of Daniel Tiger's Neighborhood, suggesting that watching episodes can help children with ASD learn specific skills. PMID- 28352510 TI - Using Video Modeling with Voice-over Instruction to Train Public School Staff to Implement a Preference Assessment. AB - The identification of putative reinforcers is a critical component of programming for individuals with disabilities. A multiple stimulus without replacement preference assessment is one option for identifying putative reinforcers; however, staff must be trained on the steps necessary to conduct the assessment for it to be useful in practice. This study examined the effectiveness of using video modeling with voice-over instruction (VMVO) to train two public school staff to conduct this assessment. Results demonstrate that VMVO was effective in training, producing generalized responding, maintenance, and high social validity ratings. PMID- 28352511 TI - Learner Preference Between Massed- and Alternating-Trial Sequencing when Teaching Stimulus Relations to Children with Autism. AB - Two children with autism were assessed for preference between intersession distribution of mastered and unknown instructional trials on a computerized matching-to-sample task consisting of 12 total learning opportunities. Choice responses yielded presentation of either massed-trial sequencing (six unknown/six mastered stimuli relations or vice-versa) or alternating-trial sequencing delivery (alternation of unknown and mastered stimuli relations) followed by reinforcement for correct responses. An extinction condition served as an experimental control. Both children demonstrated a preference for the alternating trial sequencing condition, and implications for instructional programming and possible effects to delays to higher rates of reinforcement are discussed. PMID- 28352512 TI - Effects of Antecedent Manipulations and Social Reinforcement to Increase Lateral Positioning in a Premature Infant with Obstructive Sleep Apnea. AB - Recent research suggests supine positioning for sleeping infants is the safest position to prevent breathing related difficulties; however doing so can significantly increase obstruction in apneic infants resulting in decreased sleep quality. We implemented a multi-component treatment package compromised of antecedent interventions and parent-mediated social reinforcement to increase lateral positioning in a premature infant with obstructive sleep apnea. Results indicate that the intervention increased lateral positioning in the participant by over 80 % in the final phase of the study, indicating efficacy of the intervention. Limitations and suggestions for future research are discussed. PMID- 28352513 TI - Reduction of Rapid Eating in an Adolescent Female with Autism. AB - Rapid eating, a potentially dangerous and socially inappropriate behavior, has received relatively little attention in the literature. This study sought to extend the research in this area by further evaluating the effectiveness of a vibrating pager combined with a rule for increasing inter-response time between bites in one adolescent female diagnosed with autism. Results indicated that inter-response time increased from baseline only after a vocal prompt to "wait" was introduced across clinic and home settings. Implications for promoting autonomy in individuals with developmental disabilities are discussed.This antecedent-based intervention can easily be generalized to caregiversThe unobtrusive nature of the intervention allows for implementation in inclusive settingsThere are implications for promoting social skills in naturalistic environmentsThe intervention can promote independence through teaching self management. PMID- 28352514 TI - Training Staff to Avoid Problem Behavior Related to Restricting Access to Preferred Activities. AB - Some training programs for staff working with individuals with intellectual disabilities fail to equip staff with the practical skills necessary to prevent behavioral episodes. The current research describes the results of a staff training program that, following traditional didactic training, used a card game followed by role-play training to increase staff competence in managing problem behavior. The card game and role-play training was based on behavioral episodes that had occurred previously in the research setting. Post-training observations showed that treatment integrity of trained staff improved. PMID- 28352515 TI - Physical activity levels and pattern of use for youth participants at a traditional aquatic venue. AB - In an effort to encourage youth to acquire recommended levels of moderate to vigorous physical activity (MVPA), we need to examine affordances available to enhance opportunities. Included for consideration should be built environments such as swimming pools which can have significant impacts through leisure service delivery to promote active lifestyles. For this study, The System for Observing Play and Recreation in Communities (SOPARC), was employed at a traditional aquatic venue during July and August in the Midwestern region of the U.S. Data was collected on three physical activity postures for youths age 4 to 18 along with variables including: (a) age, (b) gender, (c) physical activity posture, and (d) areas of participation termed target areas. A total of 3780 observations were taken into account during analysis. To detect differences among key variables, One-Way ANOVA and t-tests were performed. Descriptive results indicated that MVPA accounted for 70% of activity in the aquatic venue. Overall, female youths generated more MVPA within target areas compared to males, and youth as a single group consistently scored higher in all target areas as well as overall in MVPA. Significant differences were discovered in relation to several target areas. Findings from the study indicate that the use of a traditional aquatic venue can have positive impacts on youth physical activity and assist in meeting national standards for daily requirements of MVPA. It is also indicated that design features of an aquatic venue can play a role in determining levels of engagement and physical activity. PMID- 28352516 TI - Extensive carotid atherosclerosis and the diagnostic accuracy of coronary risk calculators. AB - Preventive therapy in primary care is guided by risk thresholds for future cardiovascular events. We aimed to assess whether the sensitivity of various risk calculators for the detection of subclinical carotid atherosclerosis (TPA80) could be improved by lowering risk thresholds in younger age groups. We compared sensitivity, specificity, and discriminatory performance of SCORE, SCORE-HDL, PROCAM, AGLA, FRAM and PCE coronary risk calculators to detect total plaque area > 80 mm2 (TPA80), a coronary risk equivalent, in age groups 40-55, 56-65, 66-75 from Germany (DE, N = 2942) and Switzerland (CH, N = 2202) during the years 2002 to 2016. All calculators showed good to moderate discriminatory performance to detect TPA80 with AUC ranging from 0.74 (CH-AGLA) to 0.87 (DE- SCORE), but the sensitivity of high risk risk thresholds varied widely from 39% for DE-FRAM-CVD to 5% for CH-AGLA. Lowering of the risk threshold increased sensitivity substantially at the expense of minor losses in specificity, but the sensitivity generally remained < 45% at the 90% specificity threshold. Current risk thresholds of American and European coronary risk calculators have a low sensitivity to detect TPA80 in younger individuals. PMID- 28352517 TI - Hidden Renal Artery Pseudoaneurysm: The Need for Repeat Angiographic Intervention in a Symptomatic Patient. AB - Renal artery pseudoaneurysm (RAP) is a well-known and life-threatening complication of partial nephrectomies. Angioembolization is the preferred intervention, allowing for visualization, diagnosis, and treatment in 96% of cases. We report a case of a pseudoaneurysm that was difficult to diagnose even with optimal technique, requiring repeat imaging and additional angiographic intervention. Our case shows that RAP after partial nephrectomies may be difficult to diagnose even with high suspicion and appropriate technique. Repeat angiography may be required. Urologists and interventional radiologists together must keep RAP high on the differential even after a negative angiogram to adequately diagnose and treat symptomatic patients. PMID- 28352518 TI - Isolation and characterization of arsenic-resistant bacteria and possible application in bioremediation. AB - Ground water arsenic contamination is a widespread problem in many developing countries including Bangladesh and India. In recent years development of modern innovative technologies for the removal of arsenic from aqueous system has become an interesting topic for research. In this present study, two rod shaped Gram positive bacteria are being reported, isolated from arsenic affected ground water of Purbasthali block of Burdwan, West Bengal, India, which can tolerate arsenate concentration up to 4500 ppm and 550 ppm of arsenite concentration. From biochemical analysis and 16S rRNA sequencing, they were identified as Bacillus sp. and Aneurinibacillus aneurinilyticus respectively. The isolates SW2 and SW4 can remove 51.45% and 51.99% of arsenite and 53.29% and 50.37% of arsenate, respectively from arsenic containing culture media. Both of the isolate can oxidize arsenite to less toxic arsenate. These two arsenic resistant bacteria can be used as a novel pathway for the bioremediation of arsenic. PMID- 28352519 TI - Heterotrophic cultivation of Nannochloropsis salina for enhancing biomass and lipid production. AB - Response surface methodology (RSM) was used to enhance the biomass and lipid content in Nannochloropsis salina due to its economic importance. Preliminary screening results revealed that the heterotrophically cultivated N. salina with various carbon and nitrogen sources yielded higher biomass (0.91 +/- 0.0035 g/L) and lipid content (37.1 +/- 0.49 mg/L) than that of the photoautotrophical cultivation (0.21 +/- 0.009 g/L and 22.16 +/- 0.27 mg/L). Significant sources that greatly influenced on biomass and lipid content of the alga were optimized through RSM. The medium consisting of glucose (7.959 g/L), sodium acetate (1.46 g/L), peptone (7.6 g/L) and sodium thiosulphate (1.05 g/L) was found to be the optimal concentration for heterotrophic cultivation by response optimizer. Confirmation experiment results for the RSM optimized concentration yielded the biomass of 1.85 g/L and total lipid content of 48.6 mg/L. In this study, we provide with a strategy for enhancing the biomass and lipid content in N. salina. PMID- 28352521 TI - Use of response surface method for maximizing the production of arginine deiminase by Pseudomonas putida. AB - Statistically designed experiments were used to optimize the production of arginine deiminase (ADI) by Pseudomonas putida KT2440 in batch culture. A Plackett-Burman design involving eleven factors showed that ADI production was most influenced by the initial pH and the initial concentrations of glucose and yeast extract. A central composite experimental design showed that the optimal values of these factors were 8.0, 10 g/L and 12.5 g/L, respectively. The other components of the optimal culture medium were bacto peptone 7.5 g/L, Triton X-100 0.30% (v/v), and arginine 3 g/L, for a culture temperature of 25 degrees C. Compared with the basal medium, the ADI activity in the optimized medium had nearly 4.5-fold increase (4.31 U/mL). The optimized medium was then used for a further study of ADI production in a 14 L stirred tank bioreactor. The agitation speed and the aeration rates were varied to determine suitable values of these variables. PMID- 28352520 TI - Approach toward enhancement of halophilic protease production by Halobacterium sp. strain LBU50301 using statistical design response surface methodology. AB - A new potent halophilic protease producer, Halobacterium sp. strain LBU50301 was isolated from salt-fermented fish samples (budu) and identified by phenotypic analysis, and 16S rDNA gene sequencing. Thereafter, sequential statistical strategy was used to optimize halophilic protease production from Halobacterium sp. strain LBU50301 by shake-flask fermentation. The classical one-factor-at-a time (OFAT) approach determined gelatin was the best nitrogen source. Based on Plackett-Burman (PB) experimental design; gelatin, MgSO4.7H2O, NaCl and pH significantly influenced the halophilic protease production. Central composite design (CCD) determined the optimum level of medium components. Subsequently, an 8.78-fold increase in corresponding halophilic protease yield (156.22 U/mL) was obtained, compared with that produced in the original medium (17.80 U/mL). Validation experiments proved the adequacy and accuracy of model, and the results showed the predicted value agreed well with the experimental values. An overall 13-fold increase in halophilic protease yield was achieved using a 3 L laboratory fermenter and optimized medium (231.33 U/mL). PMID- 28352522 TI - Dual bioimprinting of Thermomyces lanuginosus lipase for synthesis of biodiesel. AB - Use of biodiesel as an alternative to non-renewable sources of energy has become an attractive option in recent years. The enzymatic synthesis of biodiesel by transesterification of fats/oils with an alcohol is a much more sustainable route than the chemical method. However, cost effectiveness of the enzymatic route is a major barrier in its commercialization. In this work, a high activity biocatalyst design of Thermomyces lanuginosus lipase is made by dually bioimprinting it with substrate and a surfactant (which is believed to open up the lid covering the active site of the lipase) during precipitation of the lipase in organic solvent. When the lipase was bioimprinted with only the surfactants, 28 U of the enzyme/g of oil could yield 99% biodiesel from soybean oil in about 4 h. However, when dually bioimprinted even very low enzyme load 1.4 U/g of oil, yielded 99% biodiesel within 48 h. PMID- 28352523 TI - Immobilisation of cyclodextrin glucanotransferase into polyvinyl alcohol (PVA) nanofibres via electrospinning. AB - Immobilisation of cyclodextrin glucanotransferase (CGTase) on nanofibres was demonstrated. CGTase solution (1% v/v) and PVA (8 wt%) solution were mixed followed by electrospinning (-9 kV, 3 h). CGTase/PVA nanofibres with an average diameter of 176 +/- 46 nm were successfully produced. The nanofibres that consist of immobilised CGTase were crosslinked with glutaraldehyde vapour. A CGTase/PVA film made up from the same mixture and treated the same way was used as a control experiment. The immobilised CGTase on nanofibres showed superior performance with nearly a 2.5 fold higher enzyme loading and 31% higher enzyme activity in comparison with the film. PMID- 28352524 TI - Immobilization of omega-transaminase by magnetic PVA-Fe3O4 nanoparticles. AB - omega-Transaminase (omega-TA) as a kind of important biocatalyst is widely used in preparation of chiral intermediates. In this paper, a magnetic PVA-Fe3O4 nanoparticles was prepared and employed on immobilization of omega-TA to reduce the cost, increase reusability and enhance stability. The prepared magnetic PVA Fe3O4 nanoparticles were characterized by transmission electron microscope (TEM), X-ray diffraction (XRD) and vibrating sample magnetometer (VSM). The average size of magnetic PVA-Fe3O4 nanoparticles was located between 30-40 nm omega-TA was immobilized onto magnetic PVA-Fe3O4 nanoparticles via glutaraldehyde cross linking, achieving a wider pH range as 6-8 and also a better thermal stability at 60 degrees C. Meanwhile, the immobilized omega-TA could be successfully reused for 13 times in biotransformation. These results therefore indicated that the immobilized omega-TA with high stability might be readily utilized in industrial purposes. PMID- 28352525 TI - Conjugation of biotin-coated luminescent quantum dots with single domain antibody rhizavidin fusions. AB - Straightforward and effective methods are required for the bioconjugation of proteins to surfaces and particles. Previously we demonstrated that the fusion of a single domain antibody with the biotin binding molecule rhizavidin provided a facile method to coat biotin-modified surfaces with a highly active and oriented antibody. Here, we constructed similar single domain antibody-rhizavidin fusions as well as unfused rhizavidin with a His-tag. The unfused rhizavidin produced efficiently and its utility for assay development was demonstrated in surface plasmon resonance experiments. The single domain antibody-rhizavidin fusions were utilized to coat quantum dots that had been prepared with surface biotins. Preparation of antibody coated quantum dots by this means was found to be both easy and effective. The prepared single domain antibody-quantum dot reagent was characterized by surface plasmon resonance and applied to toxin detection in a fluoroimmunoassay sensing format. PMID- 28352526 TI - Influence of nutrient media on callus induction, somatic embryogenesis and plant regeneration in selected Turkish crocus species. AB - Callus induction, somatic embryogenesis and plant regeneration were initiated in selected five species of Turkish crocus using three diffrent explants (leaf, stem and corm) cultured on four different media (MS, GB5, LS and CHE). The highest frequencies of callus induction (100%) and shoot regeneration (70%, with 7.2 shoots/callus) were found in the crocus species Crocus oliveri ssp. Oliveri, using the MS medium containing 5% (w/v) sucrose supplemented with (4 mg/L NAA + 4 mg/L TDZ) and (2 mg/L IAA + 2 mg/L TDZ + 2 mg/L BAP). When the embryogenic calli were transferred into the four nutrient media containing (2 mg/L IAA + 2 mg/L TDZ) and 100 mg/L ABA, these further developed into cotyledonary embryos. Maximum number of somatic embryos (2.9 embryos per leaf explant, with a frequency 46.6%) was obtained in C. oliveri ssp. Oliveri. During subculture using the half strength media, cotyledonary embryos gradually developed into plantlets. PMID- 28352528 TI - Microbial production of succinic acid using crude and purified glycerol from a Crotalaria juncea based biorefinery. AB - Microbial conversion of crude and purified glycerol obtained in the process of biorefining Crotalaria juncea is carried out to produce succinic acid using Escherichia coli. Batch tests are performed for nine different substrate concentrations of commercial, purified and crude glycerol, in order to observe cell growth and substrate utilization rate. Inhibitory (Halden-Andrew, Aiba Edward, Tessier type and Andrews) as well as non-inhibitory (Monod, Moser and Tessier) models are fitted to the relationship between specific growth rate and substrate concentration obtained from the growth curves. Considering the inhibition effect, Aiba-Edward model ranked 1 out of 7 in case of two samples and Haldane-Andrew model ranked 1 in case of one sample. Aiba-Edward model gave the best fitment for a large range of concentrations of all the three types of glycerol, crude, purified and laboratory grade. Maximum production of succinic acid is obtained from commercial glycerol at pH 7 and 37.5 degrees C. PMID- 28352527 TI - Production strategies for active heme-containing peroxidases from E. coli inclusion bodies - a review. AB - Heme-containing peroxidases are frequently used in medical applications. However, these enzymes are still extracted from their native source, which leads to inadequate yields and a mixture of isoenzymes differing in glycosylation which limits subsequent enzyme applications. Thus, recombinant production of these enzymes in Escherichia coli is a reasonable alternative. Even though production yields are high, the product is frequently found as protein aggregates called inclusion bodies (IBs). These IBs have to be solubilized and laboriously refolded to obtain active enzyme. Unfortunately, refolding yields are still very low making the recombinant production of these enzymes in E. coli not competitive. Motivated by the high importance of that enzyme class, this review aims at providing a comprehensive summary of state-of-the-art strategies to obtain active peroxidases from IBs. Additionally, various refolding techniques, which have not yet been used for this enzyme class, are discussed to show alternative and potentially more efficient ways to obtain active peroxidases from E. coli. PMID- 28352529 TI - Simultaneous production of detergent stable keratinolytic protease, amylase and biosurfactant by Bacillus subtilis PF1 using agro industrial waste. AB - The present study is an attempt to optimize simultaneous production of keratinolytic protease, amylase and biosurfactant from feather meal, potato peel and rape seed cake in a single media by response surface methodology to evaluate their biochemical properties for detergent additive. The optimization was carried out using 20 run, 3 factor and 5-level of central composite design on design expert software which resulted in a 1.2, 0.84 and 2.28 fold increase in protease, amylase and biosurfactant production. The proteolytic activity was found to be optimum at pH 9.0 and 60 degrees C while optimum amylolytic activity was recorded at pH 6.0 and 70 degrees C respectively. Both enzymes were found to be stable in the presence of organic solvents, ionic and commercial detergent and oxidizing agents. The biosurfactant was extracted with chloroform and was found to be stable at varying pH and temperature; however a reduction in the activity was observed at temperature higher than 70 degrees C. The isolated enzymes and biosurfactants may find applications in the effective removal of stains. PMID- 28352531 TI - Effect of increasing salinity on biogas production in waste landfills with leachate recirculation: A lab-scale model study. AB - The effects of salinity on anaerobic waste degradation and microbial communities were investigated, in order to propose an appropriate leachate recirculation process in a waste landfill in a tropical region. A salt concentration of 21 mS cm-1 of electrical conductivity (EC) did not affect waste degradation, but a salt concentration of 35 mS cm-1 of EC inhibited CH4 generation. A higher salt concentration of 80 mS cm-1 of EC inhibited not only CH4 and CO2 generation, but also degradation of organic compounds. The bacterial and archaeal community compositions were affected by high salinity. High salinity can exert selective pressure on bacterial communities, resulting in a change in bacterial community structure. Ammonium caused strong, dominant inhibition of biogas production in the salt concentration range of this study. Quality control, especially of ammonium levels, will be essential for the promotion of waste biodegradation in landfills with leachate recirculation. PMID- 28352530 TI - The gamma-aminobutyric acid-producing ability under low pH conditions of lactic acid bacteria isolated from traditional fermented foods of Ishikawa Prefecture, Japan, with a strong ability to produce ACE-inhibitory peptides. AB - Many traditional fermented products are onsumed in Ishikawa Prefecture, Japan, such as kaburazushi, narezushi, konkazuke, and ishiru. Various kinds of lactic acid bacteria (LAB) are associated with their fermentation, however, characterization of LAB has not yet been elucidated in detail. In this study, we evaluated 53 isolates of LAB from various traditional fermented foods by taxonomic classification at the species level by analyzing the 16S ribosomal RNA gene (rDNA) sequences and carbohydrate assimilation abilities. We screened isolates that exhibited high angiotensin-converting enzyme (ACE) inhibitory activities in skim milk or soy protein media and produced high gamma-aminobutyric acid (GABA) concentrations in culture supernatants when grown in de Man Rogosa Sharpe broth in the presence of 1% (w/v) glutamic acid. The results revealed that 10 isolates, i.e., Lactobacillus buchneri (2 isolates), Lactobacillus brevis (6 isolates), and Weissella hellenica (2 isolates) had a high GABA-producing ability of >500 mg/100 ml after 72 h of incubation at 35 degrees C. The ACE inhibitory activity of the whey cultured with milk protein by using L. brevis (3 isolates), L. buchneri (2 isolates), and W. hellenica (2 isolates) was stronger than that of all whey cultured with soy protein media, and these IC50 were < 1 mg protein/ml. Three of 10 isolates had high GABA-producing activities at pH 3, suggesting that they could be powerful candidates for use in the fermentation of food materials having low pH. PMID- 28352533 TI - Conquering climate change: The vital role of industrial biotechnology to meet Paris Agreement's ambitious goals. PMID- 28352532 TI - Strategies to enhance the production of photosynthetic pigments and lipids in chlorophycae species. AB - Microalgae are a major natural source for a vast array of valuable compounds as lipids, proteins, carbohydrates, pigments among others. Despite many applications, only a few species of microalgae are cultured commercially because of poorly developed of cultivation process. Nowadays some strategies of culture have been used for enhancing biomass and value compounds yield. The most strategies applied to microalgae are classified into two groups: nutrimental and physical. The nutrimental are considered as change in media composition as nitrogen and phosphorous limitation and changes in carbon source, while physical are described as manipulation in operational conditions and external factors such as application of high-light intensities, medium salinity and electromagnetic fields. The exposition to electromagnetic field is a promising technique that can improve the pigments and biomass yield in microalgae culture. Therefore, is important to describe the advantages and applications of the overall process. The aim of this review was to describe the main culture strategies used to improve the photosynthetic and lipids content in chlorophyceae species. PMID- 28352535 TI - Bioimprinting as a tool for the detection of aflatoxin B1 using a capacitive biosensor. AB - A strategy for the detection of aflatoxin B1 using a capacitive biosensor has been studied. The use of proteins for the generation of sites with high specificity against aflatoxin B1 are produced via bioimprinting. This technique has become a tool for the detection of aflatoxin B1 using a capacitive biosensor. The results demonstrate the ability to generate specific interactions with aflatoxin B1 with a linear relation between signals registered and log concentration of the target aflatoxin in the concentration range of 3.2 * 10-6 to 3.2 * 10-9 M when using ovalbumin as framework for the bioimprinting. PMID- 28352534 TI - The morphology of Ganoderma lucidum mycelium in a repeated-batch fermentation for exopolysaccharide production. AB - The morphology of Ganoderma lucidum BCCM 31549 mycelium in a repeated-batch fermentation (RBF) was studied for exopolysaccharide (EPS) production. RBF was optimised for time to replace and volume to replace. G. lucidum mycelium showed the ability to self-immobilise and exhibited high stability for repeated use in RBF with engulfed pellets. Furthermore, the ovoid and starburst-like pellet morphology was disposed to EPS production in the shake flask and bioreactor, respectively. Seven RBF could be carried out in 500 mL flasks, and five repeated batches were performed in a 2 L bioreactor. Under RBF conditions, autolysis of pellet core in the shake flask and shaving off of the outer hairy region in the bioreactor were observed at the later stages of RBF (R4 for the shake flask and R6 for the bioreactor). The proposed strategy showed that the morphology of G. lucidum mycelium can withstand extended fermentation cycles. PMID- 28352536 TI - Nitrogen and phosphate removal from wastewater with a mixed microalgae and bacteria culture. AB - Microalgae are able to convert nutrients (nitrogen and phosphorus) from wastewater into biomass and bio-products, thus improving the sustainability of wastewater treatment. In High Rate Algal Ponds (HRAP), biomass productivity and water treatment efficiency are highly dependent on environmental parameters such as temperature, light intensity and photoperiod. The influence of temperature and photoperiod on biomass productivity and the removal of dissolved nitrogen and phosphorus from municipal wastewater by a native microalgae-bacteria consortium was assessed in batch cultures in view of the development of an HRAP at a larger scale. Temperature affected the growth rate and microalgae biomass production as well as ammonium and phosphate removal rates. At the temperatures 15 and 25 degrees C, the average total nitrogen and phosphorus removal extents ranged from 72 to 83% and 100% respectively. Additionally 33.0 +/- 0.1% of the total nitrogen was eliminated by stripping at 25 degrees C, and 50 +/- 2% was assimilated by the microorganisms under all conditions tested. PMID- 28352537 TI - Functional characterization of biomedical potential of biosurfactant produced by Lactobacillus helveticus. AB - Various lactic acid bacteria (LAB) have been isolated and screened for biosurfactant production and their biomedical and food applications. Additionally, various different concentrations of the biosurfactant (0.625-25 mg ml-1) were used to evaluate its antimicrobial and antiadhesive potential against a range of pathogenic microorganisms. Biosurfactant was found to be stable to pH changes over a range of 4.0-12.0, being most effective at pH 7 and showed no apparent loss of surface tension and emulsification efficiency after heat treatment at 125 degrees C for 15 min. Present study demonstrated that biosurfactant obtained from Lactobacillus helveticus has the ability to counteract effectively the initial deposition of biofilm forming pathogens to silicone surfaces and to significantly sluggish biofilm growth. PMID- 28352538 TI - Single step biotransformation of corn oil phytosterols to boldenone by a newly isolated Pseudomonas aeruginosa. AB - A new potent Pseudomonas aeruginosa isolate capable for biotransformation of corn oil phytosterol (PS) to 4-androstene-3, 17-dione (AD), testosterone (T) and boldenone (BOL) was identified by phenotypic analysis and 16S rRNA gene sequencing. Sequential statistical strategy was used to optimize the biotransformation process mainly concerning BOL using Factorial design and response surface methodology (RSM). The production of BOL in single step microbial biotransformation from corn oil phytosterols by P. aeruginosa was not previously reported. Results showed that the pH concentration of the medium, (NH4)2SO4 and KH2PO4 were the most significant factors affecting BOL production. By analyzing the statistical model of three-dimensional surface plot, BOL production increased from 36.8% to 42.4% after the first step of optimization, and the overall biotransformation increased to 51.9%. After applying the second step of the sequential statistical strategy BOL production increased to 53.6%, and the overall biotransformation increased to 91.9% using the following optimized medium composition (g/l distilled water) (NH4)2SO4, 2; KH2PO4, 4; Na2HPO4. 1; MgSO4.7H2O, 0.3; NaCl, 0.1; CaCl2.2H2O, 0.1; FeSO4.7H2O, 0.001; ammonium acetate 0.001; Tween 80, 0.05%; corn oil 0.5%; 8-hydroxyquinoline 0.016; pH 8; 200 rpm agitation speed and incubation time 36 h at 30 degrees C. Validation experiments proved the adequacy and accuracy of model, and the results showed the predicted value agreed well with the experimental values. PMID- 28352539 TI - Antimicrobial activities of secondary metabolites and phylogenetic study of sponge endosymbiotic bacteria, Bacillus sp. at Agatti Island, Lakshadweep Archipelago. AB - Twenty-one species of sponges were recorded under the class of Demospongiae and Calcareous sponges of which 19 species were new to Agatti reef. A total of 113 Sponge endosymbiotic bacterial strains were isolated from twenty-one species of sponges and screened for antimicrobial activity. Five bacterial strains of sponge endosymbiotic bacteria (SEB) namely SEB32, SEB33, SEB36, SEB43 and SEB51 showed antimicrobial activity against virulent marine fish pathogens such as Vibrio alginolyticus, Vibrio vulnificus, Vibrio parahaemolyticus, Aeromonas salmonicida, Flavobacterium sp., Edwardsiella sp., Proteus mirabilis and Citrobacter brackii. The secondary metabolites produced by SEB32 from sponge Dysidea fragilis (Montagu, 1818) [48] was selected with broad range of antibacterial activity and subjected for production, characterization by series of chromatography techniques and spectroscopic methods. Based on the results of FT-IR and mass spectrometry, the active molecule was tentatively predicted as "Pyrrol" and the structure is Pyrrolo[1,2-a]pyrazine-1,4-dione, hexahydro- with molecular formula of C7H10N2O2. The LC50 of active molecule was 31 MUg/ml and molecular weight of the metabolites was 154. The potential strain SEB32 was identified by gene sequence (GenBank Accession number JX985748) and identified as Bacillus sp. from GenBank database. PMID- 28352540 TI - Promoter, transgene, and cell line effects in the transfection of mammalian cells using PDMAEMA-based nano-stars. AB - Non-viral transfection protocols are typically optimized using standard cells and reporter proteins, potentially underestimating cellular or transgene effects. Here such effects were studied for two human (Jurkat, HEK-293) and two rodent (CHO-K1, L929) cell lines and three fluorescent reporter proteins. Expression of the enhanced green fluorescent protein (EGFP) was studied under the control of the human elongation factor 1 alpha promoter and three viral promoters (SV40, SV40/enhancer, CMV), that of ZsYellow1 (yellow fluorescence) and mCherry (red fluorescence) for the CMV promoter. Results varied with the cell line, in particular for the Jurkat cells. Pair-wise co-transfection of the CMV controlled transgenes resulted in a significant fraction of monochromatic cells (EGFP for EGFP/YFP and EGFP/RFP co-transfections, YFP in case of YFP/RFP co-transfections). Only Jurkat cells were almost incapable of expressing YFP. Dilution of the plasmid DNA with a non-expressed plasmid showed cell line dependent effects on transfection efficiency and/or expression levels. PMID- 28352541 TI - Incorporation of a tag helps to overcome expression variability in a recombinant host. AB - Epigenetics have witnessed a renewed interest over the past decade and assays with recombinant histones has become an important tool for uncovering various aspects of histone biology. However, at times absence of recombinant histone accumulation in bacteria is encountered which is also commonly observed for many eukaryotic proteins in general. In this study, we have investigated the effect of multiple parameters on heterologous expression of proteins. We show that there is marked variability in the accumulation of H2A.2, H2B.1, H3.2 and H4 in the recombinant host, possibly owing to translational variability and degradation by the host proteases. We found that the variability could be overcome by incorporation of the commonly used purification tags, like GST or MBP, of appropriate size and position. Our results provide compelling evidence that transcript parameters like rare codon and GC content, mRNA secondary structure etc. together modulate translation kinetics and govern recombinant protein accumulation. PMID- 28352542 TI - Biosynthesis of silver nanoparticle and its application in cell wall disruption to release carbohydrate and lipid from C. vulgaris for biofuel production. AB - Microalgae are the fledging feedstocks yielding raw materials for the production of third generation biofuel. Assorted and conventional cell wall disruption techniques were helpful in extracting lipids and carbohydrates, nevertheless the disadvantages have led the biotechnologists to explore new process to lyse cell wall in a faster and an economical manner. Silver nanoparticles have the ability to break the cell wall of microalgae and release biomolecules effectively. Green synthesis of silver nanoparticles was performed using a novel bacterial isolate of Bacillus subtilis. Characterisation of nanosilver and its effect on cell wall lysis of microalgae were extensively analysed. Cell wall damage was confirmed by lactate dehydrogenase assay and visually by SEM analysis. This first piece of research work on direct use of nanoparticles for cell wall lysis would potentially be advantageous over its conventional approaches and a greener, cost effective and non laborious method for the production of biodiesel. PMID- 28352543 TI - Production of mycophenolic acid by Penicillium brevicompactum-A comparison of two methods of optimization. AB - Production of mycophenolic acid (MPA) by submerged fermentation using the microfungus Penicillium brevicompactum MTCC 8010 is reported here. Screening experiments were used to identify: the suitable media composition; the optimal initial pH; and the optimal incubation temperature to maximize the production of MPA in batch cultures. The initial concentrations of the selected sources of carbon (glucose), nitrogen (peptone) and the precursors (methionine, glycine) were then optimized by: (1) one-at-a-time variation of factors; and (2) a central composite design (CCD) of experiments, in a 12-day batch culture at an initial pH of 5.0, an incubation temperature of 25 degrees C, and an agitation speed of 200 rpm. The medium optimized using the one-at-a-time variation yielded a peak MPA titer of 1232 +/- 90 mg/L. The medium optimized by the CCD method yielded a 40% higher MPA titer of 1737 +/- 55 mg/L. The latter value was nearly 9-fold greater than the titer achieved prior to optimization. PMID- 28352544 TI - Efficient production of recombinant PP2A at a low temperature using a baculovirus expression system. AB - Protein phosphatase 2A (PP2A) is an enzyme useful for detecting several natural toxins represented by okadaic acid and microcystins. We found that the production of the recombinant human PP2A catalytic subunit (rhPP2Ac) in High Five insect cells could markedly increase when the cells were cultured at 19 degrees C instead of 27 degrees C used under conventional conditions. The yield and purity of the enzyme increased four- and three-folds, respectively. The benefit of the altered culturing temperature was observed with the recombinant human protein phosphatase 2B but not 2Calpha. The different responses among the enzymes suggest the involvement of an enzyme-specific mechanism that leads to the catalytic subunit overexpression. This is the first report to produce rhPP2Ac at a temperature lower than that used under conventional culture conditions (27 degrees C) used in the baculovirus expression system with High Five insect cells. PMID- 28352545 TI - KP4 to control Ustilago tritici in wheat: Enhanced greenhouse resistance to loose smut and changes in transcript abundance of pathogen related genes in infected KP4 plants. AB - Ustilago tritici causes loose smut, which is a seed-borne fungal disease of wheat, and responsible for yield losses up to 40%. Loose smut is a threat to seed production in developing countries where small scale farmers use their own harvest as seed material. The killer protein 4 (KP4) is a virally encoded toxin from Ustilago maydis and inhibits growth of susceptible races of fungi from the Ustilaginales. Enhanced resistance in KP4 wheat to stinking smut, which is caused by Tilletia caries, had been reported earlier. We show that KP4 in genetically engineered wheat increased resistance to loose smut up to 60% compared to the non KP4 control under greenhouse conditions. This enhanced resistance is dose and race dependent. The overexpression of the transgene kp4 and its effect on fungal growth have indirect effects on the expression of endogenous pathogen defense genes. PMID- 28352546 TI - Bioactivities of fish protein hydrolysates from defatted salmon backbones. AB - Bioactivities of bulk fish protein hydrolysates (FPH) from defatted salmon backbones obtained with eight different commercial enzymes and their combinations were tested. All FPH showed antioxidative activity in vitro. DPPH scavenging activity increased, while iron chelating ability decreased with increasing time of hydrolysis. All FPH showed ACE inhibiting effect which depended on type of enzyme and increased with time of hydrolysis. The highest effect was found for FPH produced with Trypsin. Bromelain + Papain hydrolysates reduced the uptake of radiolabelled glucose into CaCo-2 cells, a model of human enterocytes, indicating a potential antidiabetic effect of FPH. FPH obtained by Trypsin, Bromelain + Papain and Protamex showed the highest ACE inhibitory, cellular glucose transporter (GLUT/SGLT) inhibitory and in vitro antioxidative activities, respectively. Correlation was observed between the measured bioactivities, degree of hydrolysis and molecular weight profiles, supporting prolonged hydrolysis to obtain high bioactivities. PMID- 28352547 TI - Evaluation of the composition of Carica papaya L. seed oil extracted with supercritical CO2. AB - Among the most important tropical fruit grown in the world today and in Brazil, papaya occupies a prominent place. Native to tropical America, papaya has spread to several regions of the world, and Brazil accounts for 12.74% of the world production, followed by Mexico, Nigeria and India. The culture reached a harvested area of 441,042 ha and production of 12,420,585 t worldwide. The largest interest in this fruit relies on its main constituent compounds, like vitamins A, B and C, alkaloids (carpaine and pseudocarpaine), proteolytic enzymes (papain and quimiopapain) and benzyl isothiocyanate, more known as BITC, which has anthelmintic activity. Because of that, the present work has as objective the evaluation of the efficiency and composition of the oil extracted from Carica papaya L. seeds with supercritical carbon dioxide. The experiments were performed in a unit containing mainly a high-pressure pump and a stainless steel extractor with 42 mL of volume. The sampling was performed at each 20 min until the saturation of the process. About 6.5 g of sample were fed for each experiment done at 40, 60 and 80 degrees C under the pressures of 100, 150 and 200 bar. Samples of the Carica papaya L. fruit were acquired in a popular market and free for personal use intended for the study. After collection, the seeds were crushed with the help of a pestle, and dried at 60 degrees C for 60 min. For each operational condition, the extraction curves were constructed relating cumulative mass of oil extracted in function of the operational time. The better efficiencies were found at 40 degrees C and 200 bar (1.33%) followed by 80 degrees C and 200 bar (2.56%). Gas chromatography and NMR analysis could identify an insecticide component (BITC) that enables new applications of this residue in pharmaceutical and chemical industries. PMID- 28352548 TI - High cell density cultivation of six fungal strains efficient in azo dye bioremediation. AB - This work aims at optimizing the high cell density fungal cultivation for producing large quantities of fungal biomass to be used in azo dye residues bioremediation. In our previous studies the efficacy of using certain fungal strains to decolorize a range of commercial textile dyes of different structures (azo, disazo) were investigated. Several promising fungal strains belonging to Aspergillus tubigenesis, Aspergillus niger, Aspergillus terreus, and Aspergillus fumigates demonstrated high capacity in decolorizing various azo dyes. This study focuses on the high cell density cultivation of the fungal strains identified as potential bioremediation agents. The study includes the optimization of all parameters involved in bioprocess development for high cell density cultivation of six promising fungal strains. The growth of the fungal strains was tested on the sucrose medium in 7 l-fermenter. The growth of these fungal strains having the capacity to accumulate large quantities of biomass was also tested in medium containing molasses as a cheap substrate. The residual molasses, biomass dry weight and protein content of the six fungal strains showed that the strains 20 and 2 were marked by the highest protein content. In this study a comparative analysis between the results of dry weight, residual molasses and protein content of geowth of the strains 20, 5 and 2 under uncontrolled and controlled pH of media in batch fermentation was studied to follow the accumulation of biomass and protein production in the growth media. The results indicate that the dry weight accumulated by strains No. 20, 5 and 2 grown on molasses was better than those of strains grown on sucrose. Fungal strain No. 5 had the highest biomass dry weight accumulation. The study shows that the molasses as cheaper sugar sources were better than sucrose for growing fungal biomass. PMID- 28352549 TI - Evaluation of methods for pore generation and their influence on physio-chemical properties of a protein based hydrogel. AB - Different methods to create and manipulate pore sizes in hydrogel fabrication are available, but systematic studies are normally conducted with hydrogels made of synthetic chemical compounds as backbones. In this study, a hydrogel made of natural and abundant protein in combination with different, well-available techniques was used to produce different architectures within the hydrogel matrix. Pore sizes and distribution are compared and resulting hydrogel properties like swelling ratio, resistance towards external stimuli and enzymatic degradation were investigated. Porous hydrogels were functionalized and two cancer cell lines were successfully adhered onto the material. With simple methods, pores with a radius between 10 and 80 MUm and channels of 25 MUm radius with a length of several hundreds of MUm could be created and analyzed with laser scanning confocal microscopy and electron microscopy respectively. Furthermore, the influence of different methods on swelling ratio, enzymatic degradation and pH and temperature resistance was observed. PMID- 28352550 TI - Synthesis of glycinamides using protease immobilized magnetic nanoparticles. AB - In the present investigation, Bacillus subtilis was isolated from slaughterhouse waste and screened for the production of protease enzyme. The purified protease was successfully immobilized on magnetic nanoparticles (MNPs) and used for the synthesis of series of glycinamides. The binding and thermal stability of protease on MNPs was confirmed by FTIR spectroscopy and TGA analysis. The surface morphology of MNPs before and after protease immobilization was carried out using SEM analysis. XRD pattern revealed no phase change in MNPs after enzyme immobilization. The processing parameters for glycinamides synthesis viz. temperature, pH, and time were optimized using Response Surface Methodology (RSM) by using Design Expert (9.0.6.2). The maximum yield of various amides 2 butyramidoacetic acid (AMD-1,83.4%), 2-benzamidoacetic acid (AMD-2,80.5%) and 2,2'((carboxymethyl) amino)-2-oxoethyl)-2-hydroxysuccinyl)bis(azanediyl))diacetic acid (AMD-3,80.8%) formed was observed at pH-8, 50 degrees C and 30 min. The synthesized immobilized protease retained 70% of the initial activity even after 8 cycles of reuse. PMID- 28352551 TI - An easy method for preparation of Cre-loxP regulated fluorescent adenoviral expression vectors and its application for direct reprogramming into hepatocytes. AB - The recombinant adenoviral gene expression system is a powerful tool for gene delivery. However, it is difficult to obtain high titers of infectious virus, principally due to the toxicity of the expressed gene which affects on virus replication in the host HEK293 cells. To avoid these problems, we generated a Cre loxP-regulated fluorescent universal vector (termed pAxCALRL). This vector produces recombinant adenoviruses that express the red fluorescent protein (RFP) instead of the inserted gene during proliferation, which limits toxicity and can be used to monitor viral replication. Expression of the gene of interest is induced by co-infection with an adenovirus that expresses Cre-recombinase (AxCANCre). Recombinant adenovirus produced by this system that express Hnf4alpha and Foxa2 were used to reprogram mouse embryo fibroblast (MEF) into induced hepatocyte-like cells (iHep) following several rounds of infection, demonstrating the efficacy of this new system. PMID- 28352552 TI - Nucleic acid protocols: Extraction and optimization. AB - Yield and quality are fundamental features for any researchers during nucleic acid extraction. Here, we describe a simplified, semi-unified, effective, and toxic material free protocol for extracting DNA and RNA from different prokaryotic and eukaryotic sources exploiting the physical and chemical properties of nucleic acids. Furthermore, this protocol showed that DNA and RNA are under triple protection (i.e. EDTA, SDS and NaCl) during lysis step, and this environment is improper for RNase to have DNA liberated of RNA and even for DNase to degrade the DNA. Therefore, the complete removal of RNA under RNase influence is achieved when RNase is added after DNA extraction, which gives optimal quality with any protocols. Similarly, DNA contamination in an isolated RNA is degraded by DNase to obtain high-quality RNA. Our protocol is the protocol of choice in terms of simplicity, recovery time, environmental safety, amount, purity, PCR and RT-PCR applicability. PMID- 28352553 TI - Effect of amino acids on the repression of alkaline protease synthesis in haloalkaliphilic Nocardiopsis dassonvillei. AB - A newly isolated salt-tolerant alkaliphilic actinomycete, Nocardiopsis dassonvillei strain OK-18 grows on mineral salts medium with glucose as carbon source. It also grows and produces protease with amino acids as sole carbon source. The synthesis of extracellular alkaline protease parallel to growth was repressible by substrate concentrations. The absolute production of the protease was delinked with growth under nutritional stress, as protease production was high, despite poor growth. When amino acids served as the sole source of carbon and nitrogen, the enzyme production was significantly controlled by the number of amino acids. Maximal protease production was achieved with proline, asparagine, tyrosine, alanine, methionine and valine as sole source of carbon and nitrogen in minimal medium. With the increasing number of different amino acids in the presence and absence of glucose, the protease production was synergistically lower as compared to complex medium. PMID- 28352554 TI - Evaluation of cellobiose dehydrogenase and laccase containing culture fluids of Termitomyces sp. OE147 for degradation of Reactive blue 21. AB - This study evaluates culture filtrate, rich in cellobiose dehydrogenase and laccases, of Termitomyces sp. OE 147, in decolouration and degradation of Reactive blue (RB) 21. About 35% decolouration was achieved at low volumes of the culture supernatant without addition of external redox mediators. An optimized dye to culture fluid ratio (75 ppm: 0.1 ml) at a pH of 4-5 resulted in removal of colour by 60%. The degradation products of RB21 were analysed by Electron Spray Ionization-Mass Spectrometry and several small molecules (of m/z 106-199) were detected. These were concluded to be o-Xylene, 2,3-Dihydro-1H-isoindole, Isoindole-1,3-dione, 2,Benzenesulfonyl-ethanol, (4-Hydroxy-phenyl)-sulfamic acid, 2,3-Dihydro-1H-isoindole-5-sulfonic acid and proposed to result from joint action of cellobiose dehydrogenase, laccase, peroxidases and unidentified oxidoreductases present in the culture fluids. Based on the products formed and the known reactions of these enzymes, a degradation pathway was proposed for RB21. The culture fluid was also effective in decolouration (by about 50%) and detoxification (by ~25%) of the combined effluent collected from a local mill indicating a treatment process that bypasses use of H2O2 and toxic mediators. PMID- 28352555 TI - Effective composting of empty fruit bunches using potential Trichoderma strains. AB - Oil palm fibres are easy to degrade, eco-friendly in nature and once composted, they can be categorized under nutrient-enriched biocompost. Biocompost is not only a good biofertilizer but also a good biocontrol agent against soil-borne pathogens. In this research, experimental works on the composting of empty fruit bunches (EFB) from the oil palm industry were conducted using two potential Trichoderma strains. Analysis of pH initially found the soils to be slightly acidic. However, after composting, the soils were found to be alkaline. Trichoderma propagules increased by 72% in the soils compared to other fungi. Soil electrical conductivity was found to be 50.40 MUS/cm for compost A, 42.10 MUS/cm for compost B and 40.11 MUS/cm for the control. The highest C:N ratio was obtained for compost A at 3.33, followed by compost B at 2.79, and then the control at 1.55. The highest percentages of nitrogen (N), phosphorus (P), and potassium (K) were found in compost A (0.91:2.13:6.68), which was followed by compost B (0.46:0.83:5.85) and then the control (0.32:0.26:5.76). Thus, the biocomposting of oil palm fibres shows great potential for enhancing soil micronutrient, plant growth performance, and crop yield production. PMID- 28352556 TI - Fertilization value of municipal sewage sludge for Eucalyptus camaldulensis plants. AB - The wastewater treatment produces a large amount of sludge. The different uses of eliminations sludge such as landfills or incineration have consequences negative for the environment, the agricultural use has increased worldwide, especially in crops and few or no studies have been conducted with forest plantations in Algeria. The objective of this study is to assess fertilizing characteristics of the sludge from the wastewater treatment plant of Tiaret (Algeria). One-year-old saplings of Eucalyptus camaldulensis were transplanted into pots with sludge/soil mixtures where sludge content was 20%, 40% and 60%. Biometric measurements (height, base diameter, diameter at mid-height and the number of leaves) were performed during six months after planting. Results demonstrated the positive effect of sludge application. A significant difference in height increment and number of leaves was found between the control and sludge-treated plants. Biometric values for all sludge mixtures were higher than those for control plants (100% soil). The mixture, which contained 60% sludge, gives the best result, except for a diameter of stem. Plants grown on sludge/soil mixture had average height 49.4 +/- 24.1 cm and average number of leaves 68.8 +/- 6.2 while average height for plants grown on soil was 34.3 +/- 12.8 cm and average number of leaves was 40 +/- 3.8. Sludge application provides soil amendment and additional nutrient supply for planted trees. PMID- 28352557 TI - Effects of phenol on physicochemical properties and treatment performances of partial nitrifying granules in sequencing batch reactors. AB - This study attempts to investigate the effect of phenol on physicochemical properties and treatment performances of partial nitrifying granules (PNGs). Two sequencing batch reactors (SBRs) fed with synthetic ammonium wastewaters were operated in absence (R1) or presence (R2) of phenol. The PNGs in R1 maintained excellent partial nitrification performance and relatively stable physicochemical properties, and exhibited compact and regular shaped structure with a cocci dominant surface. However, as phenol concentration was stepwise increased from 0 to 300 mg/L in R2, filamentous bacteria appeared and gradually dominated within granules, which in turn resulted in settleability deterioration. Most notably, granules in R2 got easier to agglomerate in the reactor walls and then been washed out with effluent, leading to significant biomass loss, frequent outflow pipe blockage, and eventual system failure. The extracellular polymeric substances (EPS) contents including proteins and polysaccharides in R2 reached 1.8 and 1.7 times of that in R1, respectively, indicating that the presence of phenol played an important role on EPS production. Removal efficiency of ammonium and phenol remained high, but dropped sharply when phenol concentration reached 300 mg/L. Moreover, the failed maintenance of partial nitrification was observed due to the revival of nitrite oxidizing bacteria (NOB) within granules after phenol exposure, which was confirmed by quantitative fluorescence in situ hybridization (FISH) analysis. Overall this study demonstrates that phenol had negative effects on PNGs, and pretreatment to eliminate phenolic substances is recommended when using PNGs for wastewater treatment. PMID- 28352558 TI - Evaluation of in vitro antimicrobial potential and GC-MS analysis of Camellia sinensis and Terminalia arjuna. AB - Traditionally, Camellia sinensis and Terminalia arjuna are being used widely to cure various diseases like cardiovascular diseases, cancer etc. In the present study, extracts of these plants were evaluated for their antimicrobial activities against some human pathogenic bacteria viz. E. coli, P. aeruginosa, S. aureus and fungus C. albicans. In-vitro inhibition of these pathogenic microorganisms produced inhibition zone ranging from 9 to 18 mm. MIC values of these plant extracts ranged from 6.25 to 12.5 mg/ml. MBC of C. sinensis for E. coli, P. aeruginosa and S. aureus was found to be 50 and 12.5 mg/ml, respectively. In case of T. arjuna, the MBC of all the tested microorganisms was found to be 25 mg/ml. The MFC of C. sinensis and T. arjuna against C. albicans was observed to be 50 and 25 mg/ml, respectively. GC-MS analysis of C. sinensis and T. arjuna extract identified 13 and 21 compounds, respectively. PMID- 28352559 TI - Cytological analysis for meiotic patterns in wild rice (Oryza rufipogon Griff.). AB - The present report explores the chromosomal patterns during meiosis as a fundamental cell division study in wild rice (Oryza rufipogon Griff.). Cytological assays revealed normal meiosis in most cases but in some instances meiotic abnormalities such as weak desynapsis, univalent and quadrivalent formation, translocation, spindle abnormalities and precocious movement of chromosomes were noticed. Interestingly, this wild species also has the bi nucleoli in first meiotic stages alike the cultivated species of Oryza (O. sativa). The present investigation emphatically addresses the questions of high adaptability of wild rice supported by high pollen fertility for their potential to strong fitness in nature. PMID- 28352560 TI - Systematic characterization of potential cellulolytic marine actinobacteria Actinoalloteichus sp. MHA15. AB - Cellulose is the most abounding biopolymer in the world and there is a great interest in using this material as a substrate for various applications and it is the most important renewable resource for bioconversion. Therefore, it is necessary to screen the cellulolytic bioorganisms. In this context, actinobacteria are one of the most efficient prokaryotes, economically and biotechnologically, for their production of about half of the discovered bioactive secondary metabolites and they can metabolize many different compounds. Therefore, the present study was carried out to isolate and screen cellulase enzyme producing marine actinobacterial strains from the sediments of the Havelock island, the Andamans. Totally, 19 morphologically distinct actinobacterial strains were isolated and subjected to cellulose degradation assay. Out of the 19, four strains were found to possess good cellulose degradation activity and the strain MHA15 alone produced higher amount of cellulase enzyme (14.379 1U/ml) than the others. Taxonomical study of the strain MHA15 revealed that it belongs to the genus Actinoalloteichus and the molecular characters showed distinct difference in its phylogenetic relationship (8.4%) with A. cyanogriseus. PMID- 28352561 TI - Synergistic effect of haloduracin and chloramphenicol against clinically important Gram-positive bacteria. AB - The emergence of drug-resistant pathogens has triggered the search for more efficient antimicrobial agents and formulations for treatment of infections. In recent years, combination therapy has become one of the effective clinical practices in treating infections. The present study deals with the effect of haloduracin, a lantibiotic bateriocin and chloramphenicol against clinically important bacteria. The combined use of haloduracin and chloramphenicol resulted in remarkable synergy against a spectrum of microorganisms including strains of Staphylococcus aureus, Enterococcus faecium, Enterococcus faecalis and different groups of Streptococcus. The synergy allowed using these antimicrobial agents at substantially reduced concentrations without compromising their efficiency. Use of lower doses of chloramphenicol can avoid the severity of its side effects. In addition to minimizing undesirable side effects of some drugs, this approach brings the possibility of using antibiotics that are no longer effective due to drug resistance. Furthermore, the observed synergy between haloduracin and chloramphenicol opens a new window of using bacteriocins and antibiotics in combination therapy of infections. PMID- 28352562 TI - The importance of arginine codons AGA and AGG for the expression in E. coli of triosephosphate isomerase from seven different species. AB - Rare arginine codons AGA and AGG affect the heterologous expression of proteins in Eschericha coli. The tRNAs necessary for protein synthesis are scarce in E. coli strain BL21(DE3) pLysS and plentiful in strain BL21(DE3) CodonPlus -RIL. We evaluated in both bacterial strains the effect of these rare codons on the expression of triosephosphate isomerases from 7 different species, whose sequences had different dispositions of rare arginine codons. The ratio of expressed protein (CP/Bl21) correlated with the number of rare codons. Our study shows that the number, position and particularities of the combination of rare Arg codons in the natural non-optimized sequences of the triosephosphate isomerases influence the synthesis of heterologous proteins in E. coli and could have implications in the selection of better sequences for engineering enzymes for novel or manipulated metabolic pathways or for the expression levels of non enzymatic proteins.. PMID- 28352563 TI - A valuable peroxidase activity from the novel species Nonomuraea gerenzanensis growing on alkali lignin. AB - Degradation of lignin constitutes a key step in processing biomass to become useful monomers but it remains challenging. Compared to fungi, bacteria are much less characterized with respect to their lignin metabolism, although it is reported that many soil bacteria, especially actinomycetes, attack and solubilize lignin. In this work, we screened 43 filamentous actinomycetes by assaying their activity on chemically different substrates including a soluble and semi-degraded lignin derivative (known as alkali lignin or Kraft lignin), and we discovered a novel and valuable peroxidase activity produced by the recently classified actinomycete Nonomuraea gerenzanensis. Compared to known fungal manganese and versatile peroxidases, the stability of N. gerenzanensis peroxidase activity at alkaline pHs and its thermostability are significantly higher. From a kinetic point of view, N. gerenzanensis peroxidase activity shows a Km for H2O2 similar to that of Phanerochaete chrysosporium and Bjerkandera enzymes and a lower affinity for Mn2+, whereas it differs from the six Pleurotus ostreatus manganese peroxidase isoenzymes described in the literature. Additionally, N. gerenzanensis peroxidase shows a remarkable dye-decolorizing activity that expands its substrate range and paves the way for an industrial use of this enzyme. These results confirm that by exploring new bacterial diversity, we may be able to discover and exploit alternative biological tools putatively involved in lignin modification and degradation. PMID- 28352564 TI - Bacterial Exopolysaccharide mediated heavy metal removal: A Review on biosynthesis, mechanism and remediation strategies. AB - Heavy metal contamination has been recognized as a major public health risk, particularly in developing countries and their toxicological manifestations are well known. Conventional remediation strategies are either expensive or they generate toxic by-products, which adversely affect the environment. Therefore, necessity for an environmentally safe strategy motivates interest towards biological techniques. One of such most profoundly driven approach in recent times is biosorption through microbial biomass and their products. Extracellular polymeric substances are such complex blend of high molecular weight microbial (prokaryotic and eukaryotic) biopolymers. They are mainly composed of proteins, polysaccharides, uronic acids, humic substances, lipids etc. One of its essential constituent is the exopolysaccharide (EPS) released out of self defense against harsh conditions of starvation, pH and temperature, hence it displays exemplary physiological, rheological and physio-chemical properties. Its net anionic makeup allows the biopolymer to effectively sequester positively charged heavy metal ions. The polysaccharide has been expounded deeply in this article with reference to its biosynthesis and emphasizes heavy metal sorption abilities of polymer in terms of mechanism of action and remediation. It reports current investigation and strategic advancements in dealing bacterial cells and their EPS in diverse forms - mixed culture EPS, single cell EPS, live, dead or immobilized EPS. A significant scrutiny is also involved highlighting the existing challenges that still lie in the path of commercialization. The article enlightens the potential of EPS to bring about bio-detoxification of heavy metal contaminated terrestrial and aquatic systems in highly sustainable, economic and eco-friendly manner. PMID- 28352566 TI - White spot syndrome virus infection: Threat to crustacean biodiversity in Vembanad Lake, India. AB - The Vembanad Lake located on the south-west coast of India, an ecological hotspot is the nursing ground of many economically important crustaceans. The prevalence of white spot syndrome virus (WSSV) among crustaceans from farmed, estuarine and marine environments surrounding the Vembanad Lake, India was detected using PCR. A total of 308 samples from aquaculture ponds consisting of six species of crustaceans collected from five different farms were tested for the presence of WSSV. Of these, 67% were found to carry the virus. A total of 258 samples of crustaceans from the Cochin backwater system that forms a part of the Vembanad lake viz., Metapenaeus dobsoni, Metapenaeus monoceros, Penaeus monodon and Penaeus indicus were found to contain WSSV in 62% of the samples. Fifteen species of crustaceans caught from the seas off Cochin were also screened for the presence of WSSV. Out of these, twelve species had WSSV incidence levels ranging from 6-23%. WSSV was not detected from three species of deep sea crustaceans tested. The black tiger shrimp, Penaeus monodon had the highest incidence of WSSV among the species screened in farmed, estuarine and marine environments. PMID- 28352565 TI - Expression analysis of chitinase upon challenge inoculation to Alternaria wounding and defense inducers in Brassica juncea. AB - Chitinases are the hydrolytic enzymes which belong to the pathogenesis-related (PR) protein family and play an important role not only in plant defense but also in various abiotic stresses. However, only a limited number of chitinase genes have been characterised in B. juncea. In this study, we have characterised B. juncea class IV chitinase gene (accession no EF586206) in response to fungal infection, salicylic acid (SA), jasmonic acid (JA) treatments and wounding. Gene expression studies revealed that the transcript levels of Bjchitinase (BjChp) gene increases significantly both in local and distal tissues after Alternaria infection. Bjchitinase gene was also induced by jasmonic acid and wounding but moderately by salicylic acid. A 2.5 kb class IV chitinase promoter of this gene was isolated from B. juncea by Genome walking (accession no KF055403.1). In silico analysis of this promoter revealed a number of conserved cis-regulatory elements related to defense, wounding and signalling molecules like SA, and JA. For validation, chitinase promoter was fused to the GUS gene, and the resultant construct was then introduced into Arabidopsis plants. Histochemical analysis of T2 transgenic Arabidopsis plants showed that higher GUS activity in leaves after fungal infection, wounding and JA treatment but weakly by SA. GUS activity was seen in meristematic tissues, young leaves, seeds and siliques. Finally investigation has led to the identification of a pathogen-inducible, developmentally regulated and organ-specific promoter. Present study revealed that Bjchitinase (BjChp) promoter is induced during biotic and environmental stress and it can be used in developing finely tuned transgenics. PMID- 28352567 TI - n-Butanol derived from biochemical and chemical routes: A review. AB - Traditionally, bio-butanol is produced with the ABE (Acetone Butanol Ethanol) process using Clostridium species to ferment sugars from biomass. However, the route is associated with some disadvantages such as low butanol yield and by product formation (acetone and ethanol). On the other hand, butanol can be directly produced from ethanol through aldol condensation over metal oxides/ hydroxyapatite catalysts. This paper suggests that the chemical conversion route is more preferable than the ABE process, because the reaction proceeds more quickly compared to the fermentation route and fewer steps are required to get to the product. PMID- 28352568 TI - Heterologous overexpression of sfCherry fluorescent protein in Nannochloropsis salina. AB - Oleaginous microalgae of the Nannochloropsis genus are considered excellent candidates for biofuels and value-added products owing to their high biomass productivity and lipid content. Here, we report the first overexpression and detection of a heterologous sfCherry fluorescent protein in Nannochloropsis salina in order to develop a transformation toolbox for future genetic improvements. Particle bombardment was employed for transformation, and expression of Shble under the control of TUB and UEP promoters, cloned from N. salina, was used to confer resistance to Zeocin antibiotics, resulting in 5.9 and 4.7 transformants per 108 cells, respectively. Stable integration of the markers into the genome was confirmed using a restriction enzyme site-directed amplification (RESDA) PCR. The expression of sfCherry fluorescent protein was confirmed by Western blot analysis and confocal microscopy. These results suggest new possibilities of efficient genetic engineering of Nannochloropsis for the production of biofuels and other biochemicals. PMID- 28352569 TI - Development of an aptamer-based affinity purification method for vascular endothelial growth factor. AB - Since aptamers bind their targets with high affinity and specificity, they are promising alternative ligands in protein affinity purification. As aptamers are chemically synthesized oligonucleotides, they can be easily produced in large quantities regarding GMP conditions allowing their application in protein production for therapeutic purposes. Several advantages of aptamers compared to antibodies are described in general within this paper. Here, an aptamer directed against the human Vascular Endothelial Growth Factor (VEGF) was used as affinity ligand for establishing a purification platform for VEGF in small scale. The aptamer was covalently immobilized on magnetic beads in a controlled orientation resulting in a functional active affinity matrix. Target binding was optimized by introduction of spacer molecules and variation of aptamer density. Further, salt induced target elution was demonstrated as well as VEGF purification from a complex protein mixture proving the specificity of protein-aptamer binding. PMID- 28352570 TI - Genome modifications and cloning using a conjugally transferable recombineering system. AB - The genetic modification of primary bacterial disease isolates is challenging due to the lack of highly efficient genetic tools. Herein we describe the development of a modified PCR-based, lambda Red-mediated recombineering system for efficient deletion of genes in Gram-negative bacteria. A series of conjugally transferrable plasmids were constructed by cloning an oriT sequence and different antibiotic resistance genes into recombinogenic plasmid pKD46. Using this system we deleted ten different genes from the genomes of Edwardsiella ictaluri and Aeromonas hydrophila. A temperature sensitive and conjugally transferable flp recombinase plasmid was developed to generate markerless gene deletion mutants. We also developed an efficient cloning system to capture larger bacterial genetic elements and clone them into a conjugally transferrable plasmid for facile transferring to Gram-negative bacteria. This system should be applicable in diverse Gram-negative bacteria to modify and complement genomic elements in bacteria that cannot be manipulated using available genetic tools. PMID- 28352571 TI - Biomedical applications of ferulic acid encapsulated electrospun nanofibers. AB - Ferulic acid is a ubiquitous phytochemical that holds enormous therapeutic potential but has not gained much consideration in biomedical sector due to its less bioavailability, poor aqueous solubility and physiochemical instability. In present investigation, the shortcomings associated with agro-waste derived ferulic acid were addressed by encapsulating it in electrospun nanofibrous matrix of poly (d,l-lactide-co-glycolide)/polyethylene oxide. Fluorescent microscopic analysis revealed that ferulic acid predominantly resides in the core of PLGA/PEO nanofibers. The average diameters of the PLGA/PEO and ferulic acid encapsulated PLGA/PEO nanofibers were recorded as 125 +/- 65.5 nm and 150 +/- 79.0 nm, respectively. The physiochemical properties of fabricated nanofibers are elucidated by IR, DSC and NMR studies. Free radical scavenging activity of fabricated nanofibers were estimated using di(phenyl)-(2,4,6 trinitrophenyl)iminoazanium (DPPH) assay. 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay confirmed the cytotoxicity of ferulic acid encapsulated nanofibers against hepatocellular carcinoma (HepG2) cells. These ferulic acid encapsulated nanofibers could be potentially explored for therapeutic usage in biomedical sector. PMID- 28352572 TI - Optimization of single plate-serial dilution spotting (SP-SDS) with sample anchoring as an assured method for bacterial and yeast cfu enumeration and single colony isolation from diverse samples. AB - We propose a simple technique for bacterial and yeast cfu estimations from diverse samples with no prior idea of viable counts, designated as single plate serial dilution spotting (SP-SDS) with the prime recommendation of sample anchoring (100 stocks). For pure cultures, serial dilutions were prepared from 0.1 OD (100) stock and 20 MUl aliquots of six dilutions (101-106) were applied as 10-15 micro-drops in six sectors over agar-gelled medium in 9-cm plates. For liquid samples 100-105 dilutions, and for colloidal suspensions and solid samples (10% w/v), 101-106 dilutions were used. Following incubation, at least one dilution level yielded 6-60 cfu per sector comparable to the standard method involving 100 MUl samples. Tested on diverse bacteria, composite samples and Saccharomyces cerevisiae, SP-SDS offered wider applicability over alternative methods like drop-plating and track-dilution for cfu estimation, single colony isolation and culture purity testing, particularly suiting low resource settings. PMID- 28352573 TI - Hairy root induction and phytoremediation of textile dye, Reactive green 19A HE4BD, in a halophyte, Sesuvium portulacastrum (L.) L. AB - In this study, we report phytoremediation of textile dyes using hairy roots derived through Agrobacterium rhizogenes (NCIM 5140) infection of in vitro leaf and stem explants of a halophyte Sesuvium portulacastrum (L.) L. Leaf explants showed higher frequency of hairy root induction (70%) than stem explants (30%), and maximum number of roots (leaf 42.3 +/- 2.4 and stem 50.3 +/- 1.7). Transformed nature of hairy roots was ascertained by amplifying 970 bp region of T-DNA of Ri plasmid. Hairy roots were screened for phytoremediation of various textile dyes and results showed that HRs were able to degrade Reactive green 19A HE4BD upto 98% within 5 days of incubation. Spectrophotometric analysis showed decrease in dye concentration while HPLC and FTIR analysis confirmed its degradation. Seed germination assay demonstrated non-toxic nature of the extracted metabolites. This is the first report on induction of hairy root culture in Sesuvium portulacastrum and phytoremediation of textile dyes. PMID- 28352574 TI - A statistical approach for optimization of alkaline lipase production by ascidian associated-Halobacillus trueperi RSK CAS9. AB - A marine ascidian-associated bacterium, Halobacillus trueperi RSK CAS9, was optimized for lipase production by response surface methodology using marine waste as substrate. The central composite design was employed, and the optimal medium constituents for maximum lipase production (1355.81 U/ml) were determined to be tuna powder (14.58 g/l), olive oil (5.05 ml/l); NaCl (72.42 g/l), temperature (45 degrees C) and pH 9.0. An alkaline lipase was purified to 8.46 fold with 1193.59 U mg-1 specific activities with the molecular weight of 44 kDa. The activity was substantially inhibited by EDTA and PMSF, indicating that it was a metalloenzyme serine residue which was essential for catalytic activity. Thus, lipase production by microbial conversion of marine fish wastes in this study suggested its potential utilization for the production of high value products. PMID- 28352575 TI - Production and characterization of a new antibacterial peptide obtained from Aeribacillus pallidus SAT4. AB - A novel thermophilic bacterial strain of the genus Aeribacillus was isolated from Thar Dessert Pakistan. This strain showed significant antibacterial activity against Micrococcus luteus, Staphylococcus aureus, and Pseudomonasaeruginosa. The strain coded as 'SAT4' resembled with Aeribacillus pallidus in the morphological, biochemical and molecular tests. The production of antibacterial metabolites by SAT4 was optimized. These active metabolites were precipitated by 50% ammonium sulphate and purified through sephadex G-75 gel permeation chromatography and reverse phase HPLC. The molecular weight of 37 kDa was examined by SDS-PAGE. The structural elucidation of the purified product was studied by FTIR, 1H and 13C NMR. The X-ray diffractions study showed that the crystals belonged to the primitive orthorhombic lattice (a = 12.137, b = 13.421, c = 14.097 A) and 3D structure (proposed name: Aeritracin) was determined. This new peptide antibacterial molecule can get a position in pharmaceutical and biotechnological industrial research. PMID- 28352576 TI - Heterologous expression, purification and characterization of L-type lectin homologue from Leishmania donovani. AB - Leishmaniasis, a disease of the developing world affects about 12 million people and has limited therapeutic interventions available. L-type lectins, Endoplasmic Reticulum Golgi Intermediate Compartment/Vesicular Integral Proteins (ERGIC 53/VIP36) are involved in protein sorting in luminal compartments of animal cells and are important for parasite biology. A lectin homologue was identified through a bioinformatics analysis of Leishmania genome and it was found to have N terminal conserved carbohydrate recognition domain (CRD) and a unique C-terminal region rich in repetitive amino acids and a poly glutamine tract. The N-terminal CRD region was cloned and expressed in Escherichia coli, but gave an insoluble expression which was re-solubilized by on column refolding. The fold integrity was checked through CD, fluorescence and functional assay of hemagglutination activity using rabbit erythrocyte. Bioinformatics analysis identified 15 members from Tritryps (Leishmania spp., Trypanosoma spp.) and they separate out as a distinct clade in the global phylogenetic analysis of all ERGIC-53/VIP36 sequences downloaded from Uniprot. Our analysis shows that the extended C terminal regions with repeats is unique to Tritryps and this repeat pattern is different in sequences from Leishmania spp. and Trypanosoma spp. and all these features make this protein an interesting candidate for further detailed studies. PMID- 28352577 TI - Vigna subterranea ammonium transporter gene (VsAMT1): Some bioinformatics insights. AB - Ammonium transporters (AMTs) play a role in the uptake of ammonium, the form in which nitrogen is preferentially absorbed by plants. Vigna subterranea (VsAMT1) and Solanum tuberosum (StAMT1) AMT1s were characterized using molecular biology and bioinformatics methods. AMT1-specific primers were designed and used to amplify the AMT1 internal regions. Nucleotide sequencing, alignment and phylogenetic analysis assigned VsAMT1 and StAMT1 to the AMT1 family. The deduced amino acid sequences showed that VsAMT1 is 92% and 89% similar to Phaseolus vulgaris PvAMT1.1 and Glycine max AMT1 respectively, while StAMT1 is 92% similar to Solanum lycopersicum LeAMT1.1, and correspond to the 5th-10th trans-membrane domains. Residues VsAMT1 D23 and StAMT1 D15 are predicted to be essential for ammonium transport, while mutations of VsAMT1 W1A-L and S87A and StAMT1 S76A may further enhance ammonium transport. In addition to nitrogen uptake from the roots, VsAMT1 may also contribute to interactions with rhizobia. PMID- 28352578 TI - Green synthesis of isopropyl myristate in novel single phase medium Part II: Packed bed reactor (PBR) studies. AB - Isopropyl myristate is a useful functional molecule responding to the requirements of numerous fields of application in cosmetic, pharmaceutical and food industry. In the present work, lipase-catalyzed production of isopropyl myristate by esterification of myristic acid with isopropyl alcohol (molar ratio of 1:15) in the homogenous reaction medium was performed on a bench-scale packed bed reactors, in order to obtain suitable reaction performance data for upscaling. An immobilized lipase B from Candida antartica was used as the biocatalyst based on our previous study. The process intensification resulted in a clean and green synthesis process comprising a series of packed bed reactors of immobilized enzyme and water dehydrant. In addition, use of the single phase reaction system facilitates efficient recovery of the product with no effluent generated and recyclability of unreacted substrates. The single phase reaction system coupled with a continuous operating bioreactor ensures a stable operational life for the enzyme. PMID- 28352579 TI - An investigation on cytotoxic effect of bioactive AgNPs synthesized using Cassia fistula flower extract on breast cancer cell MCF-7. AB - A single step protocol to produce biofunctionalized silver nanoparticles (AgNPs) using the aqueous extract of Cassia fistula flower as "natural factory" was investigated. The reaction between silver ions and aqueous flower extract after the bioreduction process has resulted in the formation of reddish brown color colloidal solution. XRD pattern showed the face centered cubic crystalline structure of AgNPs and exhibited spherical morphology as characterized by FE-SEM. FTIR studies identified different functional groups involved in effective capping of AgNPs. The zeta potential affirmed the phytoreduced AgNPs possess good stability and the size of the particle was measured by DLS. The synthesized AgNPs displayed effective cytotoxic potential against MCF7 and the inhibitory concentration (IC50) was recorded at 7.19 MUg/mL. The apoptotic effects of the AgNPs were also confirmed by AO/EB staining. The investigation presents preliminary evidence that biosynthesized AgNPs can be used in the development of novel anticancer drugs. PMID- 28352580 TI - Screening transesterifiable lipid accumulating bacteria from sewage sludge for biodiesel production. AB - Sewage sludge was evaluated as high available and low cost microbial oils feedstock for biodiesel production. Samples from four different wastewater treatment plants from La Araucania Region in Southern Chile presented total lipids content ranging between 7.7 and 12.6%, being Vilcun sewage sludge that with the highest transesterifiable lipids content of about 50% of the total extracted lipids. The most relevant identified bacteria present in sludge samples were Acinetobacter, Pseudomonas and Bacillus, being Bacillus sp. V10 the strain with the highest transesterfiable lipids content of 7.4%. Bacillus sp. V10 was cultured using urban wastewater supplemented with glucose to achieve nitrogen depleted medium and using milk processing wastewater as a low-cost carbon source. Bacillus sp. V10 lipid profile indicates that low degree unsaturated long chain fatty acids such as C18:1 may account for approximately 50% of the lipids content, indicating its suitability to be used as raw material for biodiesel production. PMID- 28352581 TI - Deproteinization potential and antioxidant property of haloalkalophilic organic solvent tolerant protease from marine Bacillus sp. APCMST-RS3 using marine shell wastes. AB - The current increase in the vast amount of marine crustacean shell waste produced by the fish processing industries has led to the need to find new methods for its disposal. Hence, the present study was carried out via marine shell wastes as substrate for protease production. The maximum production (4000.65 U/ml) from Bacillus sp. APCMST-RS3 was noticed in 3:1% shrimp and oyster shell powder (SOSP) as substrate. Purified protease showed 53.22% and 22.66% enzyme yield; 3.48 and 8.49 fold purity with 40 kDa molecular weight; whereas, its Km and Vmax values were 0.6666 g/l, 1111.11 U/ml. This enzyme showed optimum activity at pH 9 and 60 degrees C temperature. Also, it retained maximum protease activity in the presence of NaCl (2.5 M), surfactants (Tween 20, 40, 60, 80 and SDS) and metal ions (MnCl2, CaCl2, HgCl2 and BaCl2) and solvents. The candidate bacterium effectively deproteinized (84.35%) shrimp shell and its antioxidant potentials. PMID- 28352582 TI - Green synthesis of isopropyl myristate in novel single phase medium Part I: Batch optimization studies. AB - Isopropyl myristate finds many applications in food, cosmetic and pharmaceutical industries as an emollient, thickening agent, or lubricant. Using a homogeneous reaction phase, non-specific lipase derived from Candida antartica, marketed as Novozym 435, was determined to be most suitable for the enzymatic synthesis of isopropyl myristate. The high molar ratio of alcohol to acid creates novel single phase medium which overcomes mass transfer effects and facilitates downstream processing. The effect of various reaction parameters was optimized to obtain a high yield of isopropyl myristate. Effect of temperature, agitation speed, organic solvent, biocatalyst loading and batch operational stability of the enzyme was systematically studied. The conversion of 87.65% was obtained when the molar ratio of isopropyl alcohol to myristic acid (15:1) was used with 4% (w/w) catalyst loading and agitation speed of 150 rpm at 60 degrees C. The enzyme has also shown good batch operational stability under optimized conditions. PMID- 28352583 TI - Peganum harmala L.'s anti-growth effect on a breast cancer cell line. AB - This research was done to evaluate the induction of apoptosis in MDA-MB-231 breast cancer cell line by Peganum harmala's extract, in which a significant amount of beta-carbolines is included. The apoptosis incidence was assessed through Annexin-V-Flous kit. The expressions of genes through which intrinsic apoptosis pathway are involved, Bax, Bcl-2, Bid, and Puma, over the genes the expressions of which are linked to extrinsic apoptosis pathway, TRAIL, Caspase8, p21, and p53, were examined by RT-PCR and Real-time PCR. The results demonstrate that the extract decreases the growth rate of the cancer cell line through inducing apoptosis mechanism. As long as the expression of anti-apoptosis Bcl-2 gen reduced dramatically, an over-expression in Bax and Puma genes was monitored indicating activation of intrinsic apoptosis pathway. A notable over-expression observed with TRAIL and Caspase8 genes as well as Bid gene. The latter is an intermediate for both intrinsic and extrinsic pathways of apoptosis. PMID- 28352584 TI - Screening of self-assembled monolayer for aflatoxin B1 detection using immune capacitive sensor. AB - A capacitive biosensor was used for detection of aflatoxin B1. Two different methods for cleaning gold electrodes were evaluated using cyclic voltammetry in the presence of ferricyanide as redox couple. The methods involve use of a sequence of cleaning steps avoiding the use of Piranha solution and plasma cleaner. Anti-aflatoxin B1 was immobilized on self-assembled monolayers (SAM). The immune-capacitive biosensor is able to detect aflatoxin B1 concentrations in a linear range of 3.2 * 10-12 M to 3.2 * 10-9 M when thiourea was used to form the SAM; 3.2 * 10-9 M to 3.2 * 10-7 M when thioctic acid was used. When the gold surface was isolated with tyramine-electropolymerization linear ranges of 3.2 * 10-13 M to 3.2 * 10-7 M and 3.2 * 10-9 M to 3.2 * 10-7 M where obtained, respectively. The results obtained show the difference in linear range, limit of detection, and limit of quantification when different self-assembled monolayers are used for aflatoxin B1 detection. PMID- 28352585 TI - Identification of oxidoreductases from the petroleum Bacillus safensis strain. AB - A gram-positive bacterium, denominated CFA-06, was isolated from Brazilian petroleum in the Campos Basin and is responsible for the degradation of aromatic compounds and petroleum aromatic fractions. The CFA-06 strain was identified as Bacillus safensis using the 16S rRNA and gyrase B sequence. Enzymatic assays revealed the presence of two oxidoreductases: a catalase and a new oxidoreductase. The oxidoreductases were enzymatically digested and analyzed via ESI-LTQ-Orbitrap mass spectrometry. The mass data revealed a novel oxidoreductase (named BsPMO) containing 224 amino acids and 89% homology with a hypothetic protein from B. safensis (CFA-06) and a catalase (named BsCat) with 491 amino acids and 60% similarity with the catalase from Bacillus pumilus (SAFR-032). The new protein BsPMO contains iron atom(s) and shows catalytic activity toward a monooxygenase fluorogenic probe in the presence of cofactors (NADH, NADPH and NAD). This study enhances our knowledge of the biodegradation process of petroleum by B. safensis. PMID- 28352586 TI - Chemical stability of a cold-active cellulase with high tolerance toward surfactants and chaotropic agent. AB - CelE1 is a cold-active endo-acting glucanase with high activity at a broad temperature range and under alkaline conditions. Here, we examined the effects of pH on the secondary and tertiary structures, net charge, and activity of CelE1. Although variation in pH showed a small effect in the enzyme structure, the activity was highly influenced at acidic conditions, while reached the optimum activity at pH 8. Furthermore, to estimate whether CelE1 could be used as detergent additives, CelE1 activity was evaluated in the presence of surfactants. Ionic and nonionic surfactants were not able to reduce CelE1 activity significantly. Therefore, CelE1 was found to be promising candidate for use as detergent additives. Finally, we reported a thermodynamic analysis based on the structural stability and the chemical unfolding/refolding process of CelE1. The results indicated that the chemical unfolding proceeds as a reversible two-state process. These data can be useful for biotechnological applications. PMID- 28352587 TI - Bioconversion technologies of crude glycerol to value added industrial products. AB - Crude glycerol that is produced as the by-product from biodiesel, has to be effectively utilized to contribute to the viability of biodiesel. Crude glycerol in large amounts can pose a threat to the environment. Therefore, there is a need to convert this crude glycerol into valued added products using biotechnological processes, which brings new revenue to biodiesel producers. Crude glycerol can serve as a feedstock for biopolymers, poly unsaturated fatty acids, ethanol, hydrogen and n-butanol production and as a raw material for different value added industrial products. Hence, in this review we have presented different bioconversion technologies of glycerol to value added industrial products. PMID- 28352588 TI - Transient Bluetongue virus serotype 8 capsid protein expression in Nicotiana benthamiana. AB - Bluetongue virus (BTV) causes severe disease in domestic and wild ruminants, and has recently caused several outbreaks in Europe. Current vaccines include live attenuated and inactivated viruses; while these are effective, there is risk of reversion to virulence by mutation or reassortment with wild type viruses. Subunit or virus-like particle (VLP) vaccines are safer options: VLP vaccines produced in insect cells by expression of the four BTV capsid proteins are protective against challenge; however, this is a costly production method. We investigated production of BTV VLPs in plants via Agrobacterium-mediated transient expression, an inexpensive production system very well suited to developing country use. Leaves infiltrated with recombinant pEAQ-HT vectors separately encoding the four BTV-8 capsid proteins produced more proteins than recombinant pTRA vectors. Plant expression using the pEAQ-HT vector resulted in both BTV-8 core-like particles (CLPs) and VLPs; differentially controlling the concentration of infiltrated bacteria significantly influenced yield of the VLPs. In situ localisation of assembled particles was investigated by using transmission electron microscopy (TEM) and it was shown that a mixed population of core-like particles (CLPs, consisting of VP3 and VP7) and VLPs were present as paracrystalline arrays in the cytoplasm of plant cells co-expressing all four capsid proteins. PMID- 28352589 TI - Optimization of biosurfactant production by Bacillus brevis using response surface methodology. AB - The present study aims to evaluate and validate a statistical model for maximizing biosurfactant productivity by Bacillus brevis using response surface methodology. In this respect, twenty bacterial isolates were screened for biosurfactant production using hemolytic activity, oil spreading technique, and emulsification index (E24). The most potent biosurfactant-producing bacterium (B. brevis) was used for construction of the statistical response surface model. The optimum conditions for biosurfactant production by B. brevis were: 33 degrees C incubation temperature at pH 8 for 10 days incubation period and 8.5 g/L glucose concentration as a sole carbon source. The produced biosurfactant (BS) (73%) exhibited foaming activity, thermal stability in the range 30-80 degrees C for 30 min., pH stability, from 4 to 9 and antimicrobial activity against (Escherichia coli). The BS gave a good potential application as an emulsifier. PMID- 28352590 TI - Evaluation of a pilot-scaled paddle dryer for the production of ethanol from lignocellulose including inhibitor removal and high-solids enzymatic hydrolysis. AB - The advantage of using paddle dryers (PD) in the production of sugars and 2nd generation ethanol from pretreated wheat straw was investigated. This machinery was employed in order to detoxify steam-exploded substrates and to mix different slurries in the hydrolysis step. The obtained hydrolysate was fermented by the yeast Saccharomyces cerevisiae. Acetic acid and furfural were reduced up to 11 and 26 fold respectively in the detoxified substrate. When fermentation was carried out at low solid suspension, the use of PD was as effective as water extraction in detoxifying exploded biomass, giving ethanol yields of 90% at 0.05 solid/liquid ratio (S/L) and 80% at 0.10 S/L. Moreover, by using PD the cellulose conversion yield was significantly improved in the hydrolysis step: when operating at higher S/L (0.4), the hydrolysis efficiency was twice the one achieved by using a bioreactor with a Rushton stirrer. PMID- 28352591 TI - Role of pH-induced structural change in protein aggregation in foam fractionation of bovine serum albumin. AB - For reducing protein aggregation in foam fractionation, the role of pH-induced structural change in the interface-induced protein aggregation was analyzed using bovine serum albumin (BSA) as a model protein. The results show that the decrease in pH from 7.0 to 3.0 gradually unfolded the BSA structure to increase the molecular size and the relative content of beta-sheet and thus reduced the stability of BSA in the aqueous solution. At the isoelectric point (pH 4.7), BSA suffered the lowest level in protein aggregation induced by the gas-liquid interface. In the pH range from 7.0 to 4.7, most BSA aggregates were formed in the defoaming process while in the pH range from 4.7 to 3.0, the BSA aggregates were formed at the gas-liquid interface due to the unfolded BSA structure and they further aggregated to form insoluble ones in the desorption process. PMID- 28352592 TI - Comparison of xylose fermentation by two high-performance engineered strains of Saccharomyces cerevisiae. AB - Economical biofuel production from plant biomass requires the conversion of both cellulose and hemicellulose in the plant cell wall. The best industrial fermentation organism, the yeast Saccharomyces cerevisiae, has been developed to utilize xylose by heterologously expressing either a xylose reductase/xylitol dehydrogenase (XR/XDH) pathway or a xylose isomerase (XI) pathway. Although it has been proposed that the optimal means for fermenting xylose into biofuels would use XI instead of the XR/XDH pathway, no clear comparison of the best publicly-available yeast strains engineered to use XR/XDH or XI has been published. We therefore compared two of the best-performing engineered yeast strains in the public domain-one using the XR/XDH pathway and another using XI-in anaerobic xylose fermentations. We find that, regardless of conditions, the strain using XR/XDH has substantially higher productivity compared to the XI strain. By contrast, the XI strain has better yields in nearly all conditions tested. PMID- 28352593 TI - Enzyme-luminescence method: Tool for real-time monitoring of natural neurotoxins in vitro and l-glutamate release from primary cortical neurons. AB - Novel enzyme-luminescence method is used for the rapid and sensitive in vitro detection of natural neurotoxins (e.g., shellfish and mushroom toxins) using model brain cells. Paralytic shellfish poisons gonyautoxins (e.g., GTX2,3 and GTX1,4) were detected at 1 nM level by their inhibition of glutamate release from C6 glioma cells upon drug stimulation (IC50: GTX2,3 = 30 nM and GTX1,4 = 8 nM). Activation of glutamate release from C6 cells by ibotenic acid (a mushroom toxin) was also evaluated (EC50 = 10 nM). The method was tested for real-time detection of glutamate release from primary rat cortical neurons. Dose-dependent effects of KCl (0-200 mM) and NMDA on glutamate release from primary cortical neurons were studied. The effects of different culture conditions on K+-depolarization-induced glutamate release were also investigated. The method may be applicable to screening of drugs and toxins, and finding glutamatergic neurons in brain slices without in situ staining. PMID- 28352594 TI - Evaluation of two cotton varieties CRSP1 and CRSP2 for genetic transformation efficiency, expression of transgenes Cry1Ac + Cry2A, GT gene and insect mortality. AB - Expression of the transgene with a desirable character in crop plant is the ultimate goal of transgenic research. Transformation of two Bt genes namely Cry1Ac and Cry2A cloned as separate cassette under 35S promoter in pKHG4 plant expression vector was done by using shoot apex cut method of Agrobacterium. Molecular confirmation of putative transgenic cotton plants for Cry1Ac, Cry2A and GT gene was done through PCR and ELISA. Transformation efficiency of CRSP-1 and CRSP-2 was calculated to be 1.2 and 0.8% for Cry1Ac while 0.9 and 0.6% for Cry2A and 1.5 and 0.7% for GTG respectively. CRSP-1 was found to adopt natural environment (acclimatized) earlier than CRSP-2 when exposed to sunlight for one month. Expression of Cry1Ac, Cry2A and GTG was found to be 1.2, 1 and 1.3 ng/MUl respectively for CRSP-1 as compared to CRSP-2 where expression was recorded to be 0.9, 0.5 and 0.9 ng/MUl respectively. FISH analysis of the transgenic CRSP-1 and CRSP-2 demonstrated the presence of one and two copy numbers respectively. Similarly, the response of CRSP-1 against Glyphosate @1900 ml/acre was far better with almost negligible necrotic spot and efficient growth after spray as compared to CRSP-2 where some plants were found to have necrosis and negative control where the complete decay of plant was observed after seven days of spray assay. Similarly, almost 100% mortality of 2nd instar larvae of Heliothis armigera was recorded after three days in CRSP-1 as compared CRSP-2 where insect mortality was found to be less than 90%. Quantitatively speaking non transgenic plants were found with 23-90% leaf damage by insect, while CRSP-1 was with less than 5% and CRSP-2 with 17%. Taken together CRSP1 was found to have better insect control and weedicide resistance along with its natural ability of genetic modification and can be employed by the valuable farmers for better insect control and simultaneously for better production. PMID- 28352595 TI - Biodegradation study of enzymatically catalyzed interpenetrating polymer network: Evaluation of agrochemical release and impact on soil fertility. AB - A novel interpenetrating polymer network (IPN) has been synthesized through enzymatic initiation using lipase as initiator, glutaraldehyde as cross-linker, acrylic acid as primary monomer and acrylamide as secondary monomer. Biodegradability of synthesized interpenetrating polymer network was studied through soil burial and composting methods. Synthesized hydrogel was completely degraded within 70 days using composting method, while it was 86.03% degraded within 77 days using soil burial method. This was confirmed by Fourier transform Infrared spectroscopy (FTIR) and Scanning electron microscopy (SEM) techniques. Synthesized interpenetrating polymer network hydrogel was used as a device for controlled release of urea and also act as water releasing device. Their impact on soil fertility and plant growth was also studied. The initial diffusion coefficient has a greater value than the later diffusion coefficient indicating a higher fertilizer release rate during the early stage. Fertilizer release kinetic was also studied which showed Non-Fickian diffusion behavior, as the rate of fertilizer release was comparable to the relaxation time of the synthesized matrix. Synthesized IPN enhance the water uptake capacity up to 6.2% and 7.2% in sandy loam and clay soil, respectively. PMID- 28352596 TI - Some Facts That You Might Be Unaware of About the P-Value. PMID- 28352597 TI - Vessel Remodeling after Intima-to-Intima Contact Anastomosis. AB - BACKGROUND: Intima-to-intima microanastomotic vascular remodeling was explored, utilizing a polylactide-caprolactone absorbable vein coupler model (PAVCM), which was designed to simulate a non-absorbable counterpart system with the sole exception of being absorbable. METHODS: Six New Zealand white rabbits were used. After transection of the jugular vein, 2 PAVCMs were placed, 1 at each transected end. The stumps were slipped through the PAVCMs, and the venous wall was everted 90 degrees to achieve intima-to-intima contact. Reanastomosis of the transected jugular vein was performed bilaterally in 3 rabbits. In the other 3 rabbits, the jugular vein (20 mm) harvested from one side was interpositionally grafted to the jugular vein on the opposite side to ease the anastomotic tension. Patency testing, ultrasonography, and histologic assessments were conducted postoperatively at weeks 2, 4, 12, 16, 22, and 26. RESULTS: All anastomotic sites were patent, without stenosis, occlusion, or dilatation. In the histologic sections, immature endothelial regeneration was observed at week 2, which was completed by week 4. Regeneration of the tunica media was noted at week 12. Between week 22 and week 26, the tunica media fully regenerated and the coupler dissipated entirely. CONCLUSIONS: Despite the absence of a coupler to act as an anastomotic buttress, the structure and function of all the vessels appeared normal, even histologically. These outcomes are true milestones in the development of an absorbable vein coupler. PMID- 28352598 TI - A New Septum in the Female Breast. AB - BACKGROUND: Understanding the female breast fascial system is of paramount importance in breast surgery. Little was written about breast ligaments. Most articles refer to Cooper's work without further anatomical studies. Lately, a horizontal septum has been described conveying nerves and vessels to the nipple areola complex. METHODS: During the surgical dissection of the lower part of the breast, in supero-medial technique for breast reduction operations, a fascial septum between the lower two quadrants was detected. This fibrous septum was studied through anatomic dissection of breast tissues during routine breast reshaping procedures that was done on 30 female patients. Magnetic resonance imaging (MRI) was performed preoperatively in all cases and correlated with the intraoperative findings. In the other five cases, outside the clinical study, the imaging was done during routine investigation for breast swellings. RESULTS: A vertical septum was identified in the lower part of the breast, lying at the breast meridian between the two lower quadrants. It is a tough bi-laminated structure that extends from the middle of the infra-mammary crease caudally to nipple-areola complex cranially and from the pectoral fascia posteriorly to the overlying skin anteriorly. This was proved by MRI findings. CONCLUSIONS: This study describes a new inferior vertical septum which separates the lower half of the breast into two definite anatomical compartments: medial and lateral. PMID- 28352599 TI - Assessment of Tissue Perfusion Following Conventional Liposuction of Perforator Based Abdominal Flaps. AB - BACKGROUND: The effect of liposuction on the perforators of the lower abdominal wall has been investigated in several studies. There are controversial results in the literature that have primarily demonstrated the number and patency of the perforators. The aim of this study was to determine the effect of liposuction on the perfusion of perforator-based abdominal flaps using a combined laser-Doppler spectrophotometer (O2C, Oxygen to See, LEA Medizintechnik). METHODS: Nine female patients undergoing classical abdominoplasty were included in the study. Perforators and the perfusion zones of the deep inferior epigastric artery flap were marked on the patient's abdominal wall. Flap perfusion was quantitatively assessed by measuring blood flow, velocity, capillary oxygen saturation, and relative amount of hemoglobin for each zone preoperatively, after tumescent solution infiltration, following elevation of the flap on a single perforator, and after deep and superficial liposuction, respectively. RESULTS: The measurements taken after elevation of the flap were not significantly different than measurements taken after the liposuction procedures. CONCLUSIONS: The liposuction procedure does not significantly alter the perfusion of perforator based abdominal flaps in the early period. The abdominal tissue discarded in a classic abdominoplasty operation can be raised as a perforator flap and has been demonstrated to be a unique model for clinical research. PMID- 28352600 TI - Soft Tissue Reconstruction of Complete Circumferential Defects of the Upper Extremity. AB - BACKGROUND: Upper extremity soft tissue defects with complete circumferential involvement are not common. Coupled with the unique anatomy of the upper extremity, the underlying etiology of such circumferential soft tissue defects represent additional reconstructive challenges that require treatment to be tailored to both the patient and the wound. The aim of this study is to review the various options for soft tissue reconstruction of complete circumferential defects in the upper extremity. METHODS: A literature review of PubMed and MEDLINE up to December 2016 was performed. The current study focuses on forearm and arm defects from the level at or proximal to the wrist and were assessed based on Tajima's classification (J Trauma 1974). Data reviewed for analysis included patient demographics, causality, defect size, reconstructive technique(s) employed, and postoperative follow-up and functional outcomes (when available). RESULTS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, 14 unique articles were identified for a total of 50 patients (mean=28.1 years). Underlying etiologies varied from extensive thermal or electrical burns to high impact trauma leading to degloving or avulsion, crush injuries, or even occur iatrogenically after tumor extirpation or extensive debridement. Treatment options ranged from the application of negative pressure wound dressings to the opposite end of the spectrum in hand transplantation. CONCLUSIONS: With the evolution of reconstructive techniques over time, the extent of functional and aesthetic rehabilitation of these complex upper extremity injuries has also improved. The proposed management algorithm comprehensively addresses the inherent challenges associated with these complex cases. PMID- 28352601 TI - Systematic Review and Comparative Meta-Analysis of Outcomes Following Pedicled Muscle versus Fasciocutaneous Flap Coverage for Complex Periprosthetic Wounds in Patients with Total Knee Arthroplasty. AB - BACKGROUND: In cases of total knee arthroplasty (TKA) threatened by potential hardware exposure, flap-based reconstruction is indicated to provide durable coverage. Historically, muscle flaps were favored as they provide vascular tissue to an infected wound bed. However, data comparing the performance of muscle versus fasciocutaneous flaps are limited and reflect a lack of consensus regarding the optimal management of these wounds. The aim of this study was to compare the outcomes of muscle versus fasciocutaneous flaps following the salvage of compromised TKA. METHODS: A systematic search and meta-analysis were performed to identify patients with TKA who underwent either pedicled muscle or fasciocutaneous flap coverage of periprosthetic knee defects. Studies evaluating implant/limb salvage rates, ambulatory function, complications, and donor-site morbidity were included in the comparative analysis. RESULTS: A total of 18 articles, corresponding to 172 flaps (119 muscle flaps and 53 fasciocutaneous flaps) were reviewed. Rates of implant salvage (88.8% vs. 90.1%, P=0.05) and limb salvage (89.8% vs. 100%, P=0.14) were comparable in each cohort. While overall complication rates were similar (47.3% vs. 44%, P=0.78), the rates of persistent infection (16.4% vs. 0%, P=0.14) and recurrent infection (9.1% vs. 4%, P=0.94) tended to be higher in the muscle flap cohort. Notably, functional outcomes and ambulation rates were sparingly reported. CONCLUSIONS: Rates of limb and prosthetic salvage were comparable following muscle or fasciocutaneous flap coverage of compromised TKA. The functional morbidity associated with muscle flap harvest, however, may support the use of fasciocutaneous flaps for coverage of these defects, particularly in young patients and/or high-performance athletes. PMID- 28352603 TI - Analysis of Pediatric Tendon Injuries in the Hand in Comparison with Adults. AB - BACKGROUND: The purpose of this study was to identify the epidemiologic characteristics of hand tendon injuries in children and to compare these with those of adults. METHODS: This retrospective study was conducted on acute traumatic tendon injuries of the hand treated at our institution from 2005 to 2013, based on medical records and X-ray findings. Age, sex, hand injured, mechanism of injury, tendons and zones injured, number of affected digits, and comorbidities and complications were analyzed. Patients were divided into 2 groups: a pediatric group (<=15 years) and an adult group (>15 years). RESULTS: Over the 9-year study period, 533 patients were surgically treated for acute traumatic tendon injuries of the hand. In the pediatric group (n=76), being male, the right hand, the extensor tendon, complete rupture, the middle finger, and glass injury predominated in hand tendon injuries. In the adult group (n=457), results were similar, but injury to the index finger and knife injury were the most common. An accompanying fracture was more common in the adult group and complication rates were non-significantly different. CONCLUSIONS: This comparative analysis revealed no significant epidemiologic intergroup differences. The belief that pediatric tendon injuries tend to be less severe is misplaced, and careful physical examination and exploration should be conducted in pediatric cases of hand injury. PMID- 28352602 TI - Peroneal Flap: Clinical Application and Cadaveric Study. AB - BACKGROUND: The goal of this study was to investigate the anatomy of the peroneal artery and its perforators, and to report the clinical results of reconstruction with peroneal artery perforator flaps. METHODS: The authors dissected 4 cadaver legs and investigated the distribution, course, origin, number, type, and length of the perforators. Peroneal artery perforator flap surgery was performed on 29 patients. RESULTS: We identified 19 perforators in 4 legs. The mean number of perforators was 4.8 per leg, and the mean length was 4.8 cm. Five perforators were found proximally, 9 medially, and 5 distally. We found 12 true septocutaneous perforators and 7 musculocutaneous perforators. Four emerged from the posterior tibia artery, and 15 were from the peroneal artery. The peroneal artery perforator flap was used in 29 patients. Retrograde island peroneal flaps were used in 8 cases, anterograde island peroneal flaps in 5 cases, and free peroneal flaps in 16 cases. The mean age was 59.9 years, and the defect size ranged from 2.0 cm*4.5 cm to 8.0 cm*8.0 cm. All the flaps survived. Five flaps developed partial skin necrosis. In 2 cases, a split-thickness skin graft was performed, and the other 3 cases were treated without any additional procedures. CONCLUSIONS: The peroneal artery perforator flap is a good alternative for the reconstruction of soft tissue defects, with a constant and reliable vascular pedicle, thin and pliable skin, and the possibility of creating a composite tissue flap. PMID- 28352604 TI - Osseointegrated Finger Prostheses Using a Tripod Titanium Mini-Plate. AB - BACKGROUND: Digital amputation is a common upper extremity injury and can cause significant impairment in hand function, as well as psychosocial stigma. Currently, the gold standard for the reconstruction of such injuries involves autologous reconstruction. However, when this or other autologous options are not available, prosthetic reconstruction can provide a functionally and aesthetically viable alternative. This study describes a novel technique, known as a tripod titanium mini-plate, for osseointegrated digit prostheses, and reviews the outcomes in a set of consecutive patients. METHODS: A retrospective review of patients who underwent 2-stage prosthetic reconstruction of digit amputations was performed. Demographic information, occupation, mechanism of injury, number of amputated fingers, and level of amputation were reviewed. Functional and aesthetic outcomes were assessed using the quick disabilities of the arm, shoulder, and hand (Q-DASH) scale and a visual analog scale (VAS) score, respectively. In addition, complications during the postoperative period were recorded. RESULTS: Seven patients were included in this study. Their average age was 29 years. Five patients had single-digit amputations and 2 patients had multiple-digit amputations. Functional and aesthetic outcomes were assessed using the Q-DASH score (average, 10.4) and VAS score (average, 9.1), respectively. One episode of mild cellulitis was seen at 24 months of follow-up. However, it was treated successfully with oral antibiotics. No other complications were reported. CONCLUSIONS: When autologous reconstruction is not suitable for digit reconstruction, prosthetic osseointegrated reconstruction can provide good aesthetic and functional results. However, larger series with longer-term follow up are required in order to rule out the possibility of other complications. PMID- 28352605 TI - Photo Epilation with Intense Pulsed Light for Thinning of Anterior Hairline after Hairline Correction Surgery in East Asians. AB - BACKGROUND: Thin hairs are critical to achieve natural result in female hairline correction surgery. However, there are few studies on the usefulness of hair thinning by intense pulsed light (IPL) after hairline correction surgery in East Asian females. METHODS: Hair thinning using IPL was performed in 54 women who had complained about thick hairs along the frontal hairline after hairline correction surgery. Patient mean age was 31.2 years old and patients were an average of 2.1 years post-hairline correction surgery. Initial treatment used 10 J, while second and third sessions were conducted with 10 to 15 J according to responsiveness to treatment. RESULTS: Mean thickness of individual hairs assessed before the procedure was 78.86 um. The mean number of procedures was 1.6 per patient. Forty of 54 subjects (74%) achieved satisfactory hair thinning with only one procedure from 78.01 to 66.14 um after treatment. The measured thickness was 66.43 um at the end of the first year in patients who were satisfied after one procedure. Thirteen cases achieved satisfactory hair thinning after two sessions. Mean thickness was 74.44 um and 67.51 um, before and after the second session. One case required a third session with 15J, thinning from 89.00 to 66.50 um. CONCLUSIONS: Hair thinning by IPL is a very useful method to provide a natural look after hairline correction surgery in East Asians, who have naturally thick hair. PMID- 28352606 TI - Autologous Fat Grafting as a Last Resort for Unsustainable Pain in a Woman with Multiple Osteochondromas. AB - Multiple osteochondromas (MO) is characterized by the formation of osteochondromas throughout the entire body. Although the evidence regarding its pathogenesis is well understood, no curative treatment for the disorder is available. Patients can be treated symptomatically by surgical removal of painful osteochondromas. Unfortunately, some patients still suffer from severe pain, even after surgery. We report on a case concerning a 48-year-old woman with a history of MO who presented with persistent pain after surgical removal of a symptomatic osteochondroma of the left scapula and multiple symptomatic osteochondromas of the left foot and trochanteric region. Several interventions to reduce the pain did not have any lasting effect. Subsequently, she was treated with autologous fat grafting (AFG). After each session she was pain-free for at least one year and reported only partial recurrence of the pain. This is the first case report describing AFG for the treatment of pain after both surgical removal of an osteochondroma and symptomatic osteochondromas in a patient suffering MO with promising results. The treatment is more effective and clearly continues to remain active longer than injection therapy or pain medication. Future studies are necessary to confirm our results. PMID- 28352607 TI - A New Technique for Conchal Cartilage Harvest. AB - The goal of auricular cartilage harvest is to obtain a sufficient amount for reconstruction and to minimize the change in ear shape. The cartilage can be harvested by a posterior or anterior approach, and each method has advantages and disadvantages. The posterior approach presents the advantage of scar concealment, but there are limits to the amount of cymba cartilage that may be harvested. In contrast, the anterior approach may cause a noticeable scar. However, as cartilage is collected, the anterior approach provides a view that facilitates the preservation ear structure. In addition, it is possible to obtain a greater amount of cartilage. From January 2014 to December 2015, we harvested auricular cartilage graft material in 17 patients. To prevent the development of trapdoor scars or linear scar contracture, short incisions were made on the superior border of the cymba and cavum. Two small and narrow incisions were made, resulting in suboptimal exposure of the surgical site, which heightens the potential for damaging the cartilage when using existing tools. To minimize this, the authors used a newly invented ball-type elevator. All patients recovered without complications after surgery and reported satisfaction with the shape of the ear. PMID- 28352608 TI - An Innovative Scalp-Dyeing Technique with Gentian Violet Solution During Follicular Unit Extraction for White-Haired Follicular Units. AB - There exist some restrictions and difficulties in performing follicular unit extraction (FUE) in white-haired patients, for several reasons. In this paper, we introduce a novel technique for visualizing white hair during the punching procedure and graft preparation in FUE for white-haired patients. In white-haired older male patients, we dyed the surrounding scalp skin purple with a gentian violet solution-stained toothpick. Our method has several advantages: surgeons can easily focus on the center of the follicular unit and rapidly perform punching, they can recognize the condition of the harvested follicular units during FUE, and the hair transplant team can secure a clear view for trimming and loading into the implanter. We suggest that scalp dyeing in difficult FUE procedures, especially in patients with white hair, may be a simple method that provides a good visualization for donor site harvesting and for microdissection. PMID- 28352609 TI - Unilateral Failure in Microvascular Bilateral Breast Reconstruction Salvaged by Flap Transfer to the Contralateral Breast. PMID- 28352610 TI - The Optimal Color of Background Sheets for Microsurgery. PMID- 28352612 TI - A Co-infection Model System and the Use of Chimeric Proteins to Study Chlamydia Inclusion Proteins Interaction. AB - Chlamydia trachomatis is an obligate intracellular bacterium associated with trachoma and sexually transmitted diseases. During its intracellular developmental cycle, Chlamydia resides in a membrane bound compartment called the inclusion. A subset of Type III secreted effectors, the inclusion membrane proteins (Inc), are inserted into the inclusion membrane. Inc proteins are strategically positioned to promote inclusion interaction with host factors and organelles, a process required for bacterial replication, but little is known about Inc proteins function or host interacting partners. Moreover, it is unclear whether each Inc protein has a distinct function or if a subset of Inc proteins interacts with one another to perform their function. Here, we used IncD as a model to investigate Inc/Inc interaction in the context of Inc protein expression in C. trachomatis. We developed a co-infection model system to display different tagged Inc proteins on the surface of the same inclusion. We also designed chimeric Inc proteins to delineate domains important for interaction. We showed that IncD can self-interact and that the full-length protein is required for dimerization and/or oligomerization. Altogether our approach can be generalized to any Inc protein and will help to characterize the molecular mechanisms by which Chlamydia Inc proteins interact with themselves and/or host factors, eventually leading to a better understanding of C. trachomatis interaction with the mammalian host. PMID- 28352613 TI - P. acnes-Driven Disease Pathology: Current Knowledge and Future Directions. AB - This review discusses the biology and behavior of Propionibacterium acnes (P. acnes), a dominant bacterium species of the skin biogeography thought to be associated with transmission, recurrence and severity of disease. More specifically, we discuss the ability of P. acnes to invade and persist in epithelial cells and circulating macrophages to subsequently induce bouts of sarcoidosis, low-grade inflammation and metastatic cell growth in the prostate gland. Finally, we discuss the possibility of P. acnes infiltrating the brain parenchyma to indirectly contribute to pathogenic processes in neurodegenerative disorders such as those observed in Parkinson's disease (PD). PMID- 28352611 TI - Targeting the Metabolic Reprogramming That Controls Epithelial-to-Mesenchymal Transition in Aggressive Tumors. AB - The epithelial-to-mesenchymal transition (EMT) process allows the trans differentiation of a cell with epithelial features into a cell with mesenchymal characteristics. This process has been reported to be a key priming event for tumor development and therefore EMT activation is now considered an established trait of malignancy. The transcriptional and epigenetic reprogramming that governs EMT has been extensively characterized and reviewed in the last decade. However, increasing evidence demonstrates a correlation between metabolic reprogramming and EMT execution. The aim of the current review is to gather the recent findings that illustrate this correlation to help deciphering whether metabolic changes are causative or just a bystander effect of EMT activation. The review is divided accordingly to the catabolic and anabolic pathways that characterize carbohydrate, aminoacid, and lipid metabolism. Moreover, at the end of each part, we have discussed a series of potential metabolic targets involved in EMT promotion and execution for which drugs are either available or that could be further investigated for therapeutic intervention. PMID- 28352615 TI - Results of a randomized, prospective, double-dummy, double-blind trial to compare efficacy and safety of a herbal combination containing Tropaeoli majoris herba and Armoraciae rusticanae radix with co-trimoxazole in patients with acute and uncomplicated cystitis. AB - OBJECTIVES: To demonstrate non-inferiority of an herbal combination (horseradish root and nasturtium herb) to an antibiotic (co-trimoxazole) in acute uncomplicated cystitis. DESIGN: Randomized, prospective, double-blind, double dummy, multicenter, phase III clinical study, using block randomization of 4 blocks (size 2). SETTING: Twenty-six centers in Germany, from May 2011 to June 2013. PARTICIPANTS: Adult patients (median age, 38.5 years; 90% female) with acute uncomplicated cystitis confirmed via urinalysis and bacterial counts. INTERVENTIONS: Patients received the herbal combination (five tablets, four times per day) or the antibiotic (two tablets daily) for a period of 7 or 3 days, respectively, followed by a 21-days without drug treatment. Placebos ensured blinding. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was the percentage of responders, expressed as reduction of germ count from >105 to <103 CFU/mL of pathogens between visit 1 (day 0) and 3 (day 15). Secondary endpoints included change of symptom scores, duration of symptoms, efficacy assessments, relapse frequency, and safety. A sample size of 178 patients per group was estimated. RESULTS: Of the 96 randomized patients (intent-to-treat; 45 in the phytotherapy group, 51 in the antibiotic group), 51 were considered per-protocol patients (22 in the phytotherapy group, 29 in the antibiotic group). Responder rates were 10/22 (45.5%) for the phytotherapy group and 15/29 (51.1%) for the antibiotic group (group difference: -6.27% [95% CI: -33.90%-21.3%]). The study was terminated prematurely due to slow recruitment rates. Non-inferiority could not be assumed by predefined criteria. During the follow-up period, one relapse occurred in each group. Both treatments were well tolerated. CONCLUSION: This clinical trial indicates comparable efficacy of the herbal combination and antibiotic, although non-inferiority was not proved. However, the results and lessons learned are important for the planning of future trials. Issues that led to the premature trial discontinuation were considered. PMID- 28352614 TI - In vivo Host Environment Alters Pseudomonas aeruginosa Susceptibility to Aminoglycoside Antibiotics. AB - During host infection, Pseudomonas aeruginosa coordinately regulates the expression of numerous genes to adapt to the host environment while counteracting host clearance mechanisms. As infected patients take antibiotics, the invading bacteria encounter antibiotics in the host milieu. P. aeruginosa is highly resistant to antibiotics due to multiple chromosomally encoded resistant determinants. And numerous in vitro studies have demonstrated the regulatory mechanisms of antibiotic resistance related genes in response to antibiotics. However, it is not well-known how host environment affects bacterial response to antibiotics. In this study, we found that P. aeruginosa cells directly isolated from mice lungs displayed higher susceptibility to tobramycin than in vitro cultured bacteria. In vitro experiments demonstrated that incubation with A549 and differentiated HL60 (dHL60) cells sensitized P. aeruginosa to tobramycin. Further studies revealed that reactive oxygen species produced by the host cells contributed to the increased bacterial susceptibility. At the same concentration of tobramycin, presence of A549 and dHL60 cells resulted in higher expression of heat shock proteins, which are known inducible by tobramycin. Further analyses revealed decreased membrane potential upon incubation with the host cells and modification of lipopolysaccharide, which contributed to the increased susceptibility to tobramycin. Therefore, our results demonstrate that contact with host cells increased bacterial susceptibility to tobramycin. PMID- 28352616 TI - Management of metastatic castration-resistant prostate cancer: Insights from urology experts in Thailand. AB - Treatment options for castration-resistant prostate cancer (CRPC) are available, but clear instructions for the selection of appropriate treatment are lacking. A meeting of urology experts based in Thailand was convened with the following objectives: (1) to reach a consensus and share real-life experiences about how to identify CRPC; (2) to choose the appropriate treatment for CRPC patients; (3) to evaluate disease progression using novel inhibitors of the androgen receptor pathway; (4) to identify the frequency of monitoring disease; and (5) to promote rational use of corticosteroids in CRPC patients. This consensus document can provide guidance to other urologists in Thailand to provide appropriate treatment to metastatic CRPC patients in a timely manner. PMID- 28352617 TI - Support for the use of objective comorbidity indices in the assessment of noncancer death risk in prostate cancer patients. AB - BACKGROUND: Prostate cancer management involves a balance between the risks of cancer death against those from other causes. To evaluate the performance of several comorbidity indices in predicting comorbid death in a prostate cancer radiotherapy cohort. METHODS: 2,131 men with localised prostate cancer treated with radical radiotherapy between 1999 and 2007 were studied. Tumour features, androgen deprivation usage, age, number of prescription medications (PMN) and Adult Comorbidity Evaluation-27 Index (ACE-27) were recorded. Death from prostate cancer (DPC) and death from other causes (DOC) were analysed as competing causes of death using a competing risks model, with discrimination assessed using the concordance index. RESULTS: ACE-27 scores correlated with patient's PMN (median PMN = 2). Tumour features were independent of ACE-27 scores. Estimated cumulative incidences of DOC and DPC at 10 years were 16.4% and 7.7% respectively. In the low/intermediate risk group (n = 1026) there was a 3.4-fold predominance of DOC inside 10 years (cumulative incidence: 15.8% DOC vs 3.4% DPC). High-risk men had approximately equal rates of DPC and DOC at 10 years. Multivariable analysis showed age, ACE-27 score >= 1 and PMN to have significant associations with DOC (P < 0.002 for all). A multivariable model incorporating all 3 variables resulted in C-Index = 0.646. CONCLUSION: Age, ACE-27 score and PMN act as independent prognostic factors for DOC in prostate cancer patients and can improve patient's life expectancy prediction. PMID- 28352618 TI - Safety and feasibility of robot-assisted radical prostatectomy for clinically localized prostate cancer in elderly Japanese patients. AB - BACKGROUND: This study was conducted to assess the safety and feasibility of robot-assisted radical prostatectomy (RARP) for elderly Japanese (aged >= 70 years) patients with clinically localized prostate cancer (PCa). METHODS: From April 2012 to March 2016, a total of 302 consecutive patients with clinically localized PCa underwent RARP at our institute. In this series, 109 (36.1%) and 193 (63.9%) of the patients were divided into older (aged >= 70 years) and younger (aged <70 years) groups, respectively. The correlation between the categorized patient age and various clinicopathological factors, including preoperative characteristics, perioperative outcome, and urinary continence outcome after RARP, was retrospectively analyzed. RESULTS: Except for age and Gleason score at biopsy, there was no difference in the preoperative features between the two groups. A nonnerve-sparing RARP was performed more often in the younger group; however, other perioperative variables in the elderly group were comparable to those in the younger group. Similarly, the urinary continence rates at 1 month, 3 months, and 6 months after the surgery were equally favorable in the younger and older groups. CONCLUSION: RARP may be a reasonable therapeutic option for elderly patients with PCa and provides comparable perioperative and functional outcomes to those in younger patients. PMID- 28352619 TI - Low levels of serum testosterone in middle-aged men impact pathological features of prostate cancer. AB - BACKGROUND: Serum testosterone deficiency increases with aging. Age is also a major risk factor for prostate cancer (PrCa) and PCa tumors are more frequently diagnosed among men >65 years old. We evaluated the relationship between preoperative serum testosterone and clinical/ pathological features of PrCa in middle-aged and elderly patients. METHODS: A total of 605 PrCa patients who underwent robotic-assisted radical prostatectomy between September 2010 and January 2013 at the University of Pennsylvania, and who had serum testosterone levels measured using Elecsys Testosterone II Immunoassay were included in this IRB-approved protocol. Androgen deficiency was determined as serum free testosterone (FT) <47 pg/ml and total testosterone (TT) <193 ng/dl. Demographic, clinical and tumor characteristics of men with low vs. normal TT or FT were compared using t-test or chi-square tests. Logistic regression was used to determine associations of clinical and pathological variables with FT or TT levels. RESULTS: Among middle-aged men (45-64 years; n = 367), those with low FT and low TT had, on average, a higher BMI (29.7 vs. 27.4, P < 0.01; and 32.2 vs. 27.6; P < 0.01, respectively) and higher proportion of Gleason 8-10 PrCa (13.3% vs. 4.8%, P = 0.011; and 19.2% vs. 5.1%, P = 0.012) compared to men with normal FT and normal TT values. Patients with low FT had also higher number of positive cores on biopsy (3.9 vs. 3.1 P = 0.019) and greater tumor volume (7.9 ml vs. 6.1 ml, P = 0.045) compared to those with normal FT. Among men >=65 years (n = 135) there was no difference in prostatectomy specimens of PrCa between patients with low or normal FT or TT. CONCLUSION: Among men aged 45-64 years low serum pretreatment FT and TT predicted more aggressive features of PrCa in prostatectomy specimens. In middle-aged patients low testosterone levels measured pre-operatively may indicate more aggressive disease parameters. PMID- 28352620 TI - Indications for a second prostate biopsy in patients suspected with prostate cancer after an initial negative prostate biopsy. AB - BACKGROUND: The present study aimed to evaluate the indications for a second prostate biopsy in patients suspected with prostate cancer after an initial negative prostate biopsy. METHODS: The present study included 421 patients who underwent repeat prostate biopsy between January 2007 and December 2015 at three hospitals. Clinicopathological data, including patient age, body mass index, history of prostate biopsy, prostate volume, prostate-specific antigen (PSA) level, PSA density, PSA velocity, and PSA fluctuation patterns, were analyzed. The patients were stratified into two groups based on the first PSA pattern (increase/decrease) within 1 year after the initial negative prostate biopsy. RESULTS: Prostate cancer was detected in 100 (23.8%) of the 421 patients at the second prostate biopsy. In patients with a PSA decrease at the first follow-up, prostate volume and number of increases in the PSA level from the initial prostate biopsy were predictors for prostate cancer diagnosis at the second prostate biopsy. In patients with a steady PSA increase after the initial prostate biopsy, prostate volume and number of biopsy cores were predictors for prostate cancer diagnosis at the second prostate biopsy. CONCLUSION: The indications for a second prostate biopsy are a low prostate volume and a high number of increases in the PSA level among patients with a PSA decrease at the first follow-up and a low prostate volume and a high number of biopsy cores among patients with a PSA increase at the first follow-up. PMID- 28352621 TI - Granulomatous prostatitis: clinical and histomorphologic survey of the disease in a tertiary care hospital. AB - BACKGROUND: Granulomatous prostatitis is an uncommon entity that is diagnosed incidentally on histopathology and is broadly classified as nonspecific, specific, postsurgical (post-transurethral resection), or secondary to other rare systemic granulomatous diseases. Only very few studies are available in the literature that describe the clinical and histomorphological spectrum of the disease. METHODS: A retrospective analysis of histopathological records of 1,181 prostatic specimens received in the pathology department was done over a period of 13 years (January 2003 to January 2016). All histologically proven cases of granulomatous prostatitis were retrieved, and relevant clinical data were collected from patients' records. Epstein and Hutchins classification was used to categorize these cases. RESULTS: Twenty-two cases of granulomatous prostatitis were identified, accounting for an incidence of 1.86%. Among these, nonspecific granulomatous prostatitis (n = 10) was the most common followed by tubercular prostatitis (n = 5), posttransurethral resection of the prostate (n = 3), allergic (n = 2), and xanthogranulomatous prostatitis (n = 2). The age range of these patients was between 41 and 75 years, with the majority of patients in their 7th decade. Serum prostate-specific antigen levels ranged between 0.88 ng/mL and 19.22 ng/mL. Hard and fixed nodules were observed on digital rectal examination in 14 cases. Transrectal ultrasound revealed hypoechoic shadows in five cases. CONCLUSION: Despite present-day advances in imaging modalities and serological investigations, it is virtually impossible to identify granulomatous prostatitis clinically. Histopathology remains the gold standard in diagnosing the disease. However, assigning an etiologic cause to the wide spectrum of granulomas in granulomatous prostatitis requires a pathologist's expertise and proper clinical correlation for appropriate patient management. PMID- 28352622 TI - Predictive factor of androgen deprivation therapy for patients with advanced stage prostate cancer. AB - BACKGROUND: The purpose of this study was to identify the predictive factors for the efficacy of androgen deprivation therapy (ADT) in men with hormone-sensitive prostate cancer (PC) with or without distant metastasis. METHODS: A retrospective review of PC patients was conducted of the medical records. We enrolled 246 patients who received primary ADT. PC patients treated with ADT for presumed nonlocalized PC were evaluated on the efficacy of ADT using prostate-specific antigen (PSA) time to progression (TTP) and compared factors associated with TTP in patients with distant metastasis and patients without distant metastasis. RESULTS: A total of 246 patients were treated primarily with ADT. The median follow-up period was 20.2 months. One hundred and ninety-one patients had metastatic disease. The median TTP on ADT for the distant metastasis group was 14.8 months versus 60.1 months in the without distant metastasis group (P < 0.0001). In the univariate analysis only, PSA nadir after ADT was associated with longer TTP (hazard ratio, 10.69; 95% confidence interval, 5.56-20.57). In the multivariate analysis, high grade tumor and PSA nadir were independent factors associated with a shorter TTP. CONCLUSION: In this study of hormone-sensitive PC patients treated with ADT for nonlocalized PC, high grade tumor and PSA nadir were predicting factors of this treatment. PMID- 28352623 TI - Corrigendum to "Modified urethrovesical anastomosis during robot-assisted simple prostatectomy: Technique and results" [Prostate Int 4 (2016) 61-64]. AB - [This corrects the article DOI: 10.1016/j.prnil.2016.04.001.]. PMID- 28352625 TI - Inherited Thrombophilia in Pediatric Venous Thromboembolic Disease: Why and Who to Test. AB - Venous thromboembolic disease in childhood is a multifactorial disease. Risk factors include acquired clinical risk factors such as a central venous catheter and underlying disease and inherited thrombophilia. Inherited thrombophilia is defined as a genetically determined tendency to develop venous thromboembolism. In contrast to adults, acquired clinical risk factors play a larger role than inherited thrombophilia in the development of thrombotic disease in children. The contributing role of inherited thrombophilia is not clear in many pediatric thrombotic events, especially catheter-related thrombosis. Furthermore, identification of inherited thrombophilia will not often influence acute management of the thrombotic event as well as the duration of anticoagulation. In some patients, however, detection of inherited thrombophilia may lead to identification of other family members who can be counseled for their thrombotic risk. This article discusses the potential arguments for testing of inherited thrombophilia, including factor V Leiden mutation, prothrombin mutation, and deficiencies of antithrombin, protein C, or protein S and suggests some patient groups in childhood, which may be tested. PMID- 28352626 TI - Commentary: Growth of Global Health Spending Share in Low and Middle Income Countries. PMID- 28352624 TI - Monitoring Cerebral Oxygenation in Neonates: An Update. AB - Cerebral oxygenation is not always reflected by systemic arterial oxygenation. Therefore, regional cerebral oxygen saturation (rScO2) monitoring with near infrared spectroscopy (NIRS) is of added value in neonatal intensive care. rScO2 represents oxygen supply to the brain, while cerebral fractional tissue oxygen extraction, which is the ratio between rScO2 and systemic arterial oxygen saturation, reflects cerebral oxygen utilization. The balance between oxygen supply and utilization provides insight in neonatal cerebral (patho-)physiology. This review highlights the potential and limitations of cerebral oxygenation monitoring with NIRS in the neonatal intensive care unit. PMID- 28352627 TI - Treatment of Cirrhosis-Associated Hyponatremia with Midodrine and Octreotide. AB - BACKGROUND: Hyponatremia in the setting of cirrhosis is a common electrolyte disorder with few therapeutic options. The free water retention is due to non osmotic vasopressin secretion resulting from the cirrhosis-associated splanchnic vasodilatation. Therefore, vasoconstrictive therapy may correct this electrolyte abnormality. The aim of this study was to assess the efficacy of midodrine and octreotide as a therapeutic approach to increasing urinary electrolyte-free water clearance (EFWC) in the correction of cirrhosis-associated hyponatremia. METHODS: This observational study consisted of 10 patients with cirrhosis-associated hyponatremia. Hypovolemia was ruled out as the cause of the hyponatremia with a 48-h albumin challenge (25 g IV q6 h). Patients whose hyponatremia failed to improve with albumin challenge were started on midodrine and octreotide at 10 mg po tid and 100 MUg sq tid, respectively, with rapid up-titration as tolerated to respective maximal doses of 15 mg tid and 200 MUg tid within the first 24 h. We assessed urinary EFWC and serum sodium concentration before and 72 h after treatment. RESULTS: Pretreatment serum sodium levels ranged from 119 to 133 mmol/L. The mean pretreatment serum sodium concentration +/- SEM was 124 mmol/L +/- 1.6 vs 130 mmol/L +/- 1.5 posttreatment (p = 0.00001). The mean pretreatment urinary EFWC +/- SEM was 0.33 L +/- 0.07 vs 0.82 L +/- 0.11 posttreatment (p = 0.0003). CONCLUSION: Our data show a statistically significant increase in serum sodium concentration and urinary EFWC with the use of midodrine and octreotide in the treatment of cirrhosis-associated hyponatremia. PMID- 28352628 TI - Neuroprotective Effects of Selected Microbial-Derived Phenolic Metabolites and Aroma Compounds from Wine in Human SH-SY5Y Neuroblastoma Cells and Their Putative Mechanisms of Action. AB - Moderate wine consumption has shown the potential to delay the onset of neurodegenerative diseases. This study investigates the molecular mechanisms underlying the protective effects of wine-derived phenolic and aroma compounds in a neuroinflammation model based on SIN-1 stress-induced injury in SH-SY5Y neuroblastoma cells. Cell pretreatment with microbial metabolites found in blood after wine consumption, 3,4-dihydroxyphenylacetic (3,4-DHPA), 3 hydroxyphenylacetic acids and salicylic beta-d-O-glucuronide, at physiologically concentrations (0.1-10 MUM) resulted in increased cell viability versus SIN-1 control group (p < 0.05). Results also showed significant decreases in mitogen activated protein kinase (MAPK) p38 and ERK1/2 activation as well as in downstream pro-apoptotic caspase-3 activity by some of the studied compounds. Moreover, pretreatment with p38, MEK, and ERK1/2-specific inhibitors, which have a phenolic-like structure, also resulted in an increase on cell survival and a reduction on caspase-3 activity levels. Overall, these results contribute with new evidences related to the neuroprotective actions of wine, pointing out that wine-derived human metabolites and aroma compounds may be effective at protecting neuroblastoma cells from nitrosative stress injury by inhibiting neuronal MAPK p38 and ERK1/2, as well as downstream caspase 3 activity. PMID- 28352629 TI - Contained Morcellation: Review of Current Methods and Future Directions. AB - Power morcellation of surgical specimen during laparoscopic surgery is a practical technology that provides the opportunity to perform several minimally invasive procedures. However, this technology brought forward additional risks and complications associated with dissemination of both benign and malignant tissues inside the abdominal cavity. Based on startling cases, Food and Drug Administration (FDA) announced a discouraging statement on the use of power morcellators that decreased the number of minimally invasive approaches in the following period. As a response to these concerns and negative impacts of the FDA statement, researchers developed several new approaches resulting in contained or in-bag morcellation methods. In this review, we aimed to discuss these current methods and provide an insight for future developments. PMID- 28352630 TI - Comparing Methods of Assessing Dog Rabies Vaccination Coverage in Rural and Urban Communities in Tanzania. AB - Rabies can be eliminated by achieving comprehensive coverage of 70% of domestic dogs during annual mass vaccination campaigns. Estimates of vaccination coverage are, therefore, required to evaluate and manage mass dog vaccination programs; however, there is no specific guidance for the most accurate and efficient methods for estimating coverage in different settings. Here, we compare post vaccination transects, school-based surveys, and household surveys across 28 districts in southeast Tanzania and Pemba island covering rural, urban, coastal and inland settings, and a range of different livelihoods and religious backgrounds. These approaches were explored in detail in a single district in northwest Tanzania (Serengeti), where their performance was compared with a complete dog population census that also recorded dog vaccination status. Post vaccination transects involved counting marked (vaccinated) and unmarked (unvaccinated) dogs immediately after campaigns in 2,155 villages (24,721 dogs counted). School-based surveys were administered to 8,587 primary school pupils each representing a unique household, in 119 randomly selected schools approximately 2 months after campaigns. Household surveys were conducted in 160 randomly selected villages (4,488 households) in July/August 2011. Costs to implement these coverage assessments were $12.01, $66.12, and $155.70 per village for post-vaccination transects, school-based, and household surveys, respectively. Simulations were performed to assess the effect of sampling on the precision of coverage estimation. The sampling effort required to obtain reasonably precise estimates of coverage from household surveys is generally very high and probably prohibitively expensive for routine monitoring across large areas, particularly in communities with high human to dog ratios. School-based surveys partially overcame sampling constraints, however, were also costly to obtain reasonably precise estimates of coverage. Post-vaccination transects provided precise and timely estimates of community-level coverage that could be used to troubleshoot the performance of campaigns across large areas. However, transects typically overestimated coverage by around 10%, which therefore needs consideration when evaluating the impacts of campaigns. We discuss the advantages and disadvantages of these different methods and make recommendations for how vaccination campaigns can be better monitored and managed at different stages of rabies control and elimination programs. PMID- 28352631 TI - Guidance on opioids prescribing for the management of persistent non-cancer pain in older adults. AB - Many older adults suffer from persistent pain but prevalence studies consistently showed high levels of untreated or under-treated pain in old population. Both persistent pain and pain under-treatment adversely affect independence and quality of life in geriatric patients. Pain management is challenging in this age group because of the declining organ function, the presence of concurrent diseases and polypharmacy. For all the above reasons, persistent pain in the elderly should be considered a geriatric syndrome per se and effective approaches are warranted. Current guidelines and consensus statements recommend opioid therapy for older adults with moderate-to-severe persistent pain or functional impairment and diminished quality of life due to pain. However clinicians and patients themselves have some concerns about opioids use. Age-related decline in organs functions and warnings about risk of addiction and drug misuse/abuse also in geriatric patients need particular attention for safe prescribing. On the basis of clinical evidence, these practical recommendations will help to improve the competence on opioid role in persistent pain management and the likelihood of a successful analgesic trial in older patients. PMID- 28352632 TI - Decoding white coat hypertension. AB - There is arguably no less understood or more intriguing problem in hypertension that the "white coat" condition, the standard concept of which is significantly blood pressure reading obtained by medical personnel of authoritative standing than that obtained by more junior and less authoritative personnel and by the patients themselves. Using hospital-initiated ambulatory blood pressure monitoring, the while effect manifests as initial and ending pressure elevations, and, in treated patients, a low daytime profile. The effect is essentially systolic. Pure diastolic white coat hypertension appears to be exceedingly rare. On the basis of the studies, we believe that the white coat phenomenon is a common, periodic, neuro-endocrine reflex conditioned by anticipation of having the blood pressure taken and the fear of what this measurement may indicate concerning future illness. It does not change with time, or with prolonged association with the physician, particularly with advancing years, it may be superimposed upon essential hypertension, and in patients receiving hypertensive medication, blunting of the nighttime dip, which occurs in about half the patients, may be a compensatory mechanisms, rather than an indication of cardiovascular risk. Rather than the blunted dip, the morning surge or the widened pulse pressure, cardiovascular risk appears to be related to elevation of the average night time pressure. PMID- 28352633 TI - Bayes syndrome and acute cardioembolic ischemic stroke. AB - Bayes syndrome is an under-recognized clinical condition characterized by advanced interatrial block. Bayes syndrome is a subclinical disease that manifests electrocardiographically as a prolonged P wave duration > 120 ms with biphasic morphology +/- in the inferior leads. The clinical relevance of Bayes syndrome lies in the fact that is a clear arrhythmological syndrome and has a strong association with supraventricular arrhythmias, particularly atypical atrial flutter and atrial fibrillation. Likewise, Bayes syndrome has been recently identified as a novel risk factor for non-lacunar cardioembolic ischemic stroke and vascular dementia. Advanced interatrial block can be a risk for embolic stroke due to its known sequelae of left atrial dilation, left atrial electromechanical dysfunction or atrial tachyarrhythmia (paroxysmal or persistent atrial fibrillation), conditions predisposing to thromboembolism. Bayes syndrome may be responsible for some of the unexplained ischemic strokes and shall be considered and investigated as a possible cause for cryptogenetic stroke. In summary, Bayes syndrome is a poorly recognized cardiac rhythm disorder with important cardiologic and neurologic implications. PMID- 28352635 TI - Pulmonary embolism and internal jugular vein thrombosis as evocative clues of Lemierre's syndrome: A case report and review of the literature. AB - Lemierre's syndrome (LS) is an uncommon condition with oropharyngeal infections, internal jugular vein thrombosis, and systemic metastatic septic embolization as the main features. Fusobacterium species, a group of strictly anaerobic Gram negative rod shaped bacteria, are advocated to be the main pathogen involved. We report a case of LS complicated by pulmonary embolism and pulmonary septic emboli that mimicked a neoplastic lung condition. A Medline search revealed 173 case reports of LS associated with internal jugular vein thrombosis that documented the type of microorganism. Data confirmed high prevalence in young males with Gram negative infections (83.2%). Pulmonary embolism was reported in 8.7% of cases mainly described in subjects with Gram positive infections (OR = 9.786; 95%CI: 2.577-37.168, P = 0.001), independently of age and gender. Only four fatal cases were reported. LS is an uncommon condition that could be complicated by pulmonary embolism, especially in subjects with Gram positive infections. PMID- 28352634 TI - Surveillance of Australian Hajj pilgrims for carriage of potentially pathogenic bacteria: Data from two pilot studies. AB - AIM: To estimate the pharyngeal carriage rate of Neisseria meningitidis (N. meningitidis), Streptococcus pneumoniae (S. pneumoniae) and Staphylococcus aureus (S. aureus) among Australian Hajj pilgrims. METHODS: In 2014, surveillance was conducted in two phases among Australian Hajj pilgrims: The first phase during Hajj in Mina, and the second phase soon after returning home to Australia. Nasopharyngeal or oropharyngeal swabs were taken from participants then tested, firstly by nucleic acid testing, and also by standard culture. RESULTS: Of 183 participants recruited in the first phase, 26 (14.2%) tested positive for S. pneumoniae; 4 had received pneumococcal conjugate vaccine (PCV13). Only one tested positive for N. meningitidis (W). Of 93 2nd phase samples cultured, 17 (18.3%) grew S. aureus, all methicillin sensitive, 2 (2.2%) grew N. meningitidis (on subculture; one serotype B, one negative), and 1 (1%), from an unvaccinated pilgrim, grew S. pneumoniae. CONCLUSION: Relatively high carriage of S. pneumoniae and little meningococcal carriage was found. This indicates the importance of a larger study for improved infection surveillance and possible vaccine evaluation. PMID- 28352636 TI - Unicentric Castleman's disease associated with end stage renal disease caused by amyloidosis. AB - Castleman's disease (CD), also known as angiofolicular lymph node hyperplasia, is a rare heterogenous group of lymphoproliferative disorders. Histologically, it can be classified as hyaline vascular type, plasma cell type, or mixed type. Clinically two different subtypes of the CD are present: Unicentric and multicentric. Unicentric CD is generally asymptomatic and associated with hyaline vascular type, and its diagnoses depend on the localized lymphadenopathy on examination or imaging studies. However, multicentric CD presents with generalized lymphadenopathy and systemic symptoms including malaise, fever, night sweats, weight loss, and it is associated with the plasma cell type and mix type. Herein, we report a patient with unicentric CD of the plasma cell type without systemic symptoms, who developed end stage renal failure caused by amyloidosis 6 years after onset of CD. PMID- 28352637 TI - Neurostimulation for fecal incontinence after correction of repair of imperforate anus. AB - We are reporting the case of a 32-year-old female who had suffered from fecal incontinence (FI). She was born with an imperforate anus and a recto-vaginal fistula; she underwent repair at 6 mo of age. At 29 years of age, she was still fecally incontinent despite extensive pelvic floor reeducation. A magnetic resonance imaging and an anal electromyography were performed. Because her symptoms were considered to be probably due to extra-sphincteric implantation of the neo-anus, a redo was performed of the recto-neo-anal intra-sphincteric anastomosis. A neurostimulator device was subsequently implanted for persistent incontinence. Solid and liquid FI resolved, and her quality of life improved markedly. Combining surgery to correct the position of the neo-anus within the anal sphincter complex and neurostimulation could thus become a new approach in cases of refractory FI for patients with imperforate anus as a newborn. Follow-up into adulthood after pediatric imperforate anus surgery should be recommended for adult patients with persistent FI. PMID- 28352638 TI - Variability in Diagnosing Brain Death at an Academic Medical Center. AB - Objective. Research continues to highlight variability in hospital policy and documentation of brain death. The aim of our study was to characterize how strictly new guidelines of American Academy of Neurology (AAN) for death by neurological criteria were practiced in our hospital prior to appointment of neurointensivists. Method. This is a retrospective study of adults diagnosed as brain dead from 2011 to 2015. Descriptive statistics compared five categories: preclinical testing, neurological examination, apnea tests, ancillary test, and documentation of time of death. Strict adherence to AAN guidelines for brain death determination was determined. Result. 76 patients were included in this study. Preclinical prerequisites were fulfilled in 53.9% and complete neurological examinations were documented in 76.3%. Apnea test was completed in 39.5%. Ancillary test was completed in 29.8%. Accurate documentation of time of death occurred in 59.2%. Overall, strict adherence to current AAN guidelines for death by neurological criteria was correctly documented in 38.2%. Conclusion. Our study shows wide variability in diagnosing brain death. These findings led us to update our death by neurological criteria policy and increase awareness of brain death determination with the goal of improving our documentation following current AAN guidelines. PMID- 28352639 TI - Racial Differences in Expression Levels of miRNA Machinery-Related Genes, Dicer, Drosha, DGCR8, and AGO2, in Asian Korean Papillary Thyroid Carcinoma and Comparative Validation Using the Cancer Genome Atlas. AB - Aberrant regulation of microRNA (miRNA) machinery components is associated with various human cancers, including papillary thyroid carcinoma (PTC), which is the most common type of thyroid cancer, and a higher prevalent female malignancy. The purpose of this study is to investigate racial differences in mRNA expression levels of four miRNA machinery components, Dicer, Drosha, DGCR8, and AGO2, and their correlations with clinicopathological characteristics. Forty PTC samples from female Asian Korean PTC patients were enrolled. Using qPCR, we examined mRNA expression levels of the components and next validated our results by comparison with results of female white American in the TCGA PTC project. Interestingly, mRNA expression levels of the selected factors were altered in the TCGA PTC samples. However, only Drosha showed a significantly lower expression level in Asian Korean PTC samples. Furthermore, the mRNA expression levels of the four components showed no association with clinicopathological characteristics in both groups. On the other hand, positive correlations were observed between altered mRNA expression levels of Dicer and Drosha and DGCR8 and Drosha in TCGA PTC samples. These findings collectively revealed that altered mRNA expression levels of miRNA machinery components might be responsible for racial differences in the carcinogenesis of PTC. PMID- 28352640 TI - A Different Perspective for Management of Diabetes Mellitus: Controlling Viral Liver Diseases. AB - Knowing how to prevent and treat diabetes mellitus (DM) earlier is essential to improving outcomes. Through participating in synthesis and catabolism of glycogen, the liver helps to regulate glucose homeostasis. Viral related liver diseases are associated with glycometabolism disorders, which means effective management of viral liver diseases may be a therapeutic strategy for DM. The present article reviews the correlation between DM and liver diseases to give an update of the management of DM rooted by viral liver diseases. PMID- 28352641 TI - Cardiac Function Remains Impaired Despite Reversible Cardiac Remodeling after Acute Experimental Viral Myocarditis. AB - Background. Infection with Coxsackievirus B3 induces myocarditis. We aimed to compare the acute and chronic phases of viral myocarditis to identify the immediate effects of cardiac inflammation as well as the long-term effects after resolved inflammation on cardiac fibrosis and consequently on cardiac function. Material and Methods. We infected C57BL/6J mice with Coxsackievirus B3 and determined the hemodynamic function 7 as well as 28 days after infection. Subsequently, we analyzed viral burden and viral replication in the cardiac tissue as well as the expression of cytokines and matrix proteins. Furthermore, cardiac fibroblasts were infected with virus to investigate if viral infection alone induces profibrotic signaling. Results. Severe cardiac inflammation was determined and cardiac fibrosis was consistently colocalized with inflammation during the acute phase of myocarditis. Declined cardiac inflammation but no significantly improved hemodynamic function was observed 28 days after infection. Interestingly, cardiac fibrosis declined to basal levels as well. Both cardiac inflammation and fibrosis were reversible, whereas the hemodynamic function remains impaired after healed viral myocarditis in C57BL/6J mice. PMID- 28352642 TI - The Expression of IL-6, TNF-alpha, and MCP-1 in Respiratory Viral Infection in Acute Exacerbations of Chronic Obstructive Pulmonary Disease. AB - Viral infection is a common trigger for acute exacerbations of chronic obstructive pulmonary disease (AECOPD). The aim of this study is to investigate the expression of cytokines in AECOPD. Patients with AECOPD requiring hospitalization were recruited. Meanwhile healthy volunteers of similar age that accepted routine check-ups and showed no clinical symptoms of inflammatory diseases were also recruited. Induced sputum and serum were collected. Induced sputum of participants was processed and tested for thirteen viruses and bacteria. Forty cytokines were assayed in serum using the Quantibody Human Inflammation Array 3 (Ray Biotech, Inc.). The most common virus detected in virus positive AECOPD (VP) was influenza A (16%). No virus was found in controls. Circulating levels of IL-6, TNF-alpha, and MCP-1 were elevated in VP and coinfection subjects (p < 0.05), while the levels of 37 other cytokines showed no difference, compared with virus negative groups and controls (p > 0.05). Additionally, VP patients were less likely to have received influenza vaccination. VP patients had a systemic inflammation response involving IL-6, TNF alpha, and MCP-1 which may be due to virus-induced activation of macrophages. There are important opportunities for further investigating AECOPD mechanisms and for the development of better strategies in the management and prevention of virus-related AECOPD. PMID- 28352643 TI - Update on hypoxia-inducible factors and hydroxylases in oxygen regulatory pathways: from physiology to therapeutics. AB - The "Hypoxia Nantes 2016" organized its second conference dedicated to the field of hypoxia research. This conference focused on "the role of hypoxia under physiological conditions as well as in cancer" and took place in Nantes, France, in October 6-7, 2016. The main objective of this conference was to bring together a large group of scientists from different spheres of hypoxia. Recent advances were presented and discussed around different topics: genomics, physiology, musculoskeletal, stem cells, microenvironment and cancer, and oxidative stress. This review summarizes the major highlights of the meeting. PMID- 28352644 TI - Signaling pathways and tissue interactions in neural plate border formation. AB - The neural crest is a transient cell population that gives rise to various cell types of multiple tissues and organs in the vertebrate embryo. Neural crest cells arise from the neural plate border, a region localized at the lateral borders of the prospective neural plate. Temporally and spatially coordinated interaction with the adjacent tissues, the non-neural ectoderm, the neural plate and the prospective dorsolateral mesoderm, is required for neural plate border specification. Signaling molecules, namely BMP, Wnt and FGF ligands and corresponding antagonists are derived from these tissues and interact to induce the expression of neural plate border specific genes. The present mini-review focuses on the current understanding of how the NPB territory is formed and accentuates the need for coordinated interaction of BMP and Wnt signaling pathways and precise tissue communication that are required for the definition of the prospective NC in the competent ectoderm. PMID- 28352646 TI - 'Blue' voltage-sensitive dyes for studying spatiotemporal dynamics in the brain: visualizing cortical waves. AB - Among many distinct contributions made by Amiram Grinvald's group, the "Blue dyes" is a special gift for visualizing cortical population neuronal activity. The excitation wavelength of blue dyes has minimal overlap with the absorption of hemoglobin, and hence has minimal pulsation artifacts. This advantage leads to high signal-to-noise ratio optical recordings of cortical activity, with sensitivity as good as that of local field potential recordings. High sensitivity imaging allows for recording of spontaneous and evoked activity in single trials without spatial or temporal averaging, and has benefitted many scientists in their research projects. Single trial recording is particularly important for studying the cortex, because spontaneous and ongoing activities interact with sensory evoked events, creating rich dynamics in the wave patterns. Signal averaging in space and time would diminish the dynamic components in the patterns. Here, we discuss how the blue dyes help to achieve high-sensitivity voltage-sensitive dye imaging of spontaneous and evoked cortical activities. Spontaneous cortical activity has a constantly changing spatial pattern and temporal frequency, making it impossible to average in space and time. Amiran Grinvald's invention of blue dyes made it possible to examine the spatiotemporal patterns of cortical dynamics, about 15 years before the first useful genetically coded voltage proteins became available. PMID- 28352647 TI - Single-step Marker Switching in Schizosaccharomyces pombe Using a Lithium Acetate Transformation Protocol. AB - The ability to utilize different selectable markers for tagging or mutating multiple genes in Schizosaccharomyces pombe is hampered by the historical use of only two selectable markers, ura4+ and kanMX6; the latter conferring resistance to the antibiotic G418 (geneticin). More markers have been described recently, but introducing these into yeast cells often requires strain construction from scratch. To overcome this problem we and other groups have created transformation cassettes with flanking homologies to ura4+ and kanMX6 which enable an efficient and time-saving way to exchange markers in existing mutated or tagged fission yeast strains. Here, we present a protocol for single-step marker switching by lithium acetate transformation in fission yeast, Schizosaccharomyces pombe. In the following we describe how to swap the ura4+ marker to a kanMX6, natMX4, or hphMX4 marker, which provide resistance against the antibiotics G418, nourseothricin (clonNAT) or hygromycin B, respectively. We also detail how to exchange any of the MX markers for nutritional markers, such as arg3+, his3+, leu1+ and ura4+ . PMID- 28352645 TI - Toward a better understanding of enteric gliogenesis. AB - Most of gastrointestinal functions are controlled by the enteric nervous system (ENS), which contains a vast diversity of neurons and glial cells. In accordance with its key role, defective ENS formation is the cause of several diseases that affect quality of life and can even be life-threatening. Treatment of these diseases would greatly benefit from a better understanding of the molecular mechanisms underlying ENS formation. In this regard, although several important discoveries have been made over the years, how the full spectrum of enteric neuronal and glial cell subtypes is generated from neural crest cells during development still remains enigmatic. Because they also have stem cell properties, such knowledge would be especially important for the enteric glial cell lineage. In a recent study, we identified the NR2F1 transcription factor as a new key regulator of enteric gliogenesis. Here we discuss our recent findings and briefly review what is already known about the mechanisms and signaling pathways involved in enteric gliogenesis, with an emphasis on Hedgehog and Notch signaling. PMID- 28352648 TI - Prevalence and Bacterial Isolates of Mastitis in Dairy Farms in Selected Districts of Eastern Harrarghe Zone, Eastern Ethiopia. AB - The study was conducted from November 2015 to April 2016 to estimate the prevalence of clinical and subclinical mastitis in lactating cows, to assess the associated risk factors, and to isolate the major bacterial pathogens in dairy farms in selected district of Eastern Harrarghe Zone, Eastern Ethiopia. The study was carried out in 384 dairy cows based on data collection, farm visit, animal examination, California mastitis test (CMT), and isolation bacterial pathogens using standard techniques. In the present study the overall mastitis at cow level was 247 (64.3%). The prevalence of clinical and subclinical mastitis and quarter level prevalence for clinical and subclinical mastitis were 12.5% and 51.8% at cow level and 10.7% and 46.4% at quarter level, respectively. Clinically, 101 (6.6%) quarters which belong to 75 (19.5%) animals were found to be with blind teat. In the present study prevalence of mastitis was significantly associated with parity and age (p < 0.05). Bacteriological examination of milk sample revealed 187 isolates where coagulase negative Staphylococcus species (CNS) (34.2%) was the predominant species while Streptococcus faecalis (2.1%) was identified as the least bacteria. The present study concluded that prevalence of mastitis particularly the subclinical mastitis was major problem of dairy cows in the area and hence warrants serious attention. PMID- 28352649 TI - Attenuated and vectored vaccines protect nonhuman primates against Chikungunya virus. AB - Chikungunya virus (CHIKV) is rapidly spreading across the globe, and millions are infected. Morbidity due to this virus is a serious threat to public health, but at present, there is no vaccine against this debilitating disease. We have recently developed a number of vaccine candidates, and here we have evaluated 3 of them in a nonhuman primate model. A single immunization with an attenuated strain of CHIKV (Delta5nsP3), a homologous prime-boost immunization with a DNA launched RNA replicon encoding CHIKV envelope proteins (DREP-E), and a DREP-E prime followed by a recombinant modified vaccinia virus Ankara encoding CHIKV capsid and envelope (MVA-CE) boost all induced protection against WT CHIKV infection. The attenuated Delta5nsP3 virus proved to be safe and did not show any clinical signs typically associated with WT CHIKV infections such as fever, skin rash, lymphopenia, or joint swelling. These vaccines are based on an East/Central/South African strain of Indian Ocean lineage, but they also generated neutralizing antibodies against an isolate of the Asian genotype that now is rapidly spreading across the Americas. These results form the basis for clinical development of an efficacious CHIKV vaccine that generates both humoral and cellular immunity with long-term immunological memory. PMID- 28352650 TI - Point mutations in murine Nkx2-5 phenocopy human congenital heart disease and induce pathogenic Wnt signaling. AB - Mutations in the Nkx2-5 gene are a main cause of congenital heart disease. Several studies have addressed the phenotypic consequences of disrupting the Nkx2 5 gene locus, although animal models to date failed to recapitulate the full spectrum of the human disease. Here, we describe a new Nkx2-5 point mutation murine model, akin to its human counterpart disease-generating mutation. Our model fully reproduces the morphological and physiological clinical presentations of the disease and reveals an understudied aspect of Nkx2-5-driven pathology, a primary right ventricular dysfunction. We further describe the molecular consequences of disrupting the transcriptional network regulated by Nkx2-5 in the heart and show that Nkx2-5-dependent perturbation of the Wnt signaling pathway promotes heart dysfunction through alteration of cardiomyocyte metabolism. Our data provide mechanistic insights on how Nkx2-5 regulates heart function and metabolism, a link in the study of congenital heart disease, and confirms that our models are the first murine genetic models to our knowledge to present all spectra of clinically relevant adult congenital heart disease phenotypes generated by NKX2-5 mutations in patients. PMID- 28352651 TI - Clinical, virological, and biological parameters associated with outcomes of Ebola virus infection in Macenta, Guinea. AB - BACKGROUND. The pathogenesis of Ebola virus (EBOV) disease (EVD) is poorly characterized. The establishment of well-equipped diagnostic laboratories close to Ebola treatment centers (ETCs) has made it possible to obtain relevant virological and biological data during the course of EVD and to assess their association with the clinical course and different outcomes of the disease. METHODS. We were responsible for diagnosing EBOV infection in patients admitted to two ETCs in forested areas of Guinea. The pattern of clinical signs was recorded, and an etiological diagnosis was established by RT-PCR for EBOV infection or a rapid test for malaria and typhoid fever. Biochemical analyses were also performed. RESULTS. We handled samples from 168 patients between November 29, 2014, and January 31, 2015; 97 patients were found to be infected with EBOV, with Plasmodium falciparum coinfection in 18%. Overall mortality for EVD cases was 58%, rising to 86% if P. falciparum was also present. Viral load was higher in fatal cases of EVD than in survivors, and fatal cases were associated with higher aspartate aminotransferase (AST) and alanine aminotransferase (ALT), C-reactive protein (CRP), and IL-6 levels. Furthermore, regardless of outcome, EVD was characterized by higher creatine kinase (CPK), amylase, and creatinine levels than in febrile patients without EVD, with higher blood urea nitrogen (BUN) levels in fatal cases of EVD only. CONCLUSION. These findings suggest that a high viral load at admission is a marker of poor EVD prognosis. In addition, high AST, ALT, CRP, and IL-6 levels are associated with a fatal outcome of EVD. Damage to the liver and other tissues, with massive rhabdomyolysis and, probably, acute pancreatitis, is associated with EVD and correlated with disease severity. Finally, biochemical analyses provide substantial added value at ETCs, making it possible to improve supportive rehydration and symptomatic care for patients. FUNDING. The French Ministry of Foreign Affairs, the Agence Francaise de Developpement, and Institut Pasteur. PMID- 28352652 TI - Physiologically activated mammary fibroblasts promote postpartum mammary cancer. AB - Women diagnosed with breast cancer within 5 years of childbirth have poorer prognosis than nulliparous or pregnant women. Weaning-induced breast involution is implicated, as the collagen-rich, immunosuppressive microenvironment of the involuting mammary gland is tumor promotional in mice. To investigate the role of mammary fibroblasts, isolated mammary PDGFRalpha+ cells from nulliparous and postweaning mice were assessed for activation phenotype and protumorigenic function. Fibroblast activation during involution was evident by increased expression of fibrillar collagens, lysyl oxidase, Tgfb1, and Cxcl12 genes. The ability of mammary tumors to grow in an isogenic, orthotopic transplant model was increased when tumor cells were coinjected with involution-derived compared with nulliparous-derived mammary fibroblasts. Mammary tumors in the involution fibroblast group had increased Ly6C+ monocytes at the tumor border, and decreased CD8+ T cell infiltration and tumor cell death. Ibuprofen treatment suppressed involution-fibroblast activation and tumor promotional capacity, concurrent with decreases in tumor Ly6C+ monocytes, and increases in intratumoral CD8+ T cell infiltration, granzyme levels, and tumor cell death. In total, our data identify a COX/prostaglandin E2 (PGE2)-dependent activated mammary fibroblast within the involuting mammary gland that displays protumorigenic, immunosuppressive activity, identifying fibroblasts as potential targets for the prevention and treatment of postpartum breast cancer. PMID- 28352653 TI - Defective postsecretory maturation of MUC5B mucin in cystic fibrosis airways. AB - In cystic fibrosis (CF), airway mucus becomes thick and viscous, and its clearance from the airways is impaired. The gel-forming mucins undergo an ordered "unpacking/maturation" process after granular release that requires an optimum postsecretory environment, including hydration and pH. We hypothesized that this unpacking process is compromised in the CF lung due to abnormal transepithelial fluid transport that reduces airway surface hydration and alters ionic composition. Using human tracheobronchial epithelial cells derived from non-CF and CF donors and mucus samples from human subjects and domestic pigs, we investigated the process of postsecretory mucin unfolding/maturation, how these processes are defective in CF airways, and the probable mechanism underlying defective unfolding. First, we found that mucins released into a normal lung environment transform from a compact granular form to a linear form. Second, we demonstrated that this maturation process is defective in the CF airway environment. Finally, we demonstrated that independent of HCO3- and pH levels, airway surface dehydration was the major determinant of this abnormal unfolding process. This defective unfolding/maturation process after granular release suggests that the CF extracellular environment is ion/water depleted and likely contributes to abnormal mucus properties in CF airways prior to infection and inflammation. PMID- 28352654 TI - NET silencing by let-7i in postural tachycardia syndrome. AB - While strongly implicated in postural tachycardia syndrome (POTS), considerable controversy exists regarding norepinephrine transporter (NET) loss of function. POTS is characterized by the clinical symptoms of orthostatic intolerance, lightheadedness, tachycardia, and syncope or near syncope with upright posture. Abnormal sympathetic nervous system activity is typical, of a type which suggests dysfunction of the NET, with evidence that the gene responsible is under tight epigenetic control. Using RNA of isolated chromatin combined with massive parallel sequencing (RICh-seq) we show that let-7i miRNA suppresses NET by methyl CpG-binding protein 2 (MeCP2). Vorinostat restores epigenetic control and NET expression in leukocytes derived from POTS participants. PMID- 28352655 TI - Panobinostat acts synergistically with ibrutinib in diffuse large B cell lymphoma cells with MyD88 L265P mutations. AB - Diffuse large B cell lymphoma (DLBCL) frequently harbors genetic alterations that activate the B cell receptor (BCR) and TLR pathways, which converge to activate NF-kappaB. While selective inhibition of BTK with ibrutinib causes clinical responses in relapsed DLBCL patients, most responses are partial and of a short duration. Here, we demonstrated that MyD88 silencing enhanced ibrutinib efficacy in DLBCL cells harboring MyD88 L265P mutations. Chemical downregulation of MyD88 expression with HDAC inhibitors also synergized with ibrutinib. We demonstrate that HDAC inhibitor regulation of MyD88 expression is mediated by STAT3. In turn, STAT3 silencing caused a decrease in MyD88 mRNA and protein levels, and enhanced the ibrutinib antilymphoma effect in MyD88 mutant DLBCL cells. Induced mutations in the STAT3 binding site in the MyD88 promotor region was associated with a decrease in MyD88 transcriptional activity. We also demonstrate that treatment with the HDAC inhibitor panobinostat decreased phosphorylated STAT3 binding to the MyD88 promotor. Accordingly, combined treatment with panobinostat and ibrutinib resulted in enhanced inhibition of NF-kappaB activity and caused regression of DLBCL xenografts. Our data provide a mechanistic rationale for combining HDAC inhibitors and ibrutinib for the treatment of DLBCL. PMID- 28352656 TI - Trafficking receptor signatures define blood plasmablasts responding to tissue specific immune challenge. AB - Antibody-secreting cells are generated in regional lymphoid tissues and traffic as plasmablasts (PBs) via lymph and blood to target sites for local immunity. We used multiparameter flow cytometry to define PB trafficking programs (TPs, combinations of adhesion molecules and chemoattractant receptors) and their imprinting in patients in response to localized infection or immune insults. TPs enriched after infection or autoimmune inflammation of mucosae correlate with sites of immune response or symptoms, with different TPs imprinted during small intestinal, colon, throat, and upper respiratory immune challenge. PBs induced after intramuscular or intradermal influenza vaccination, including flu-specific antibody-secreting cells, display TPs characterized by the lack of mucosal homing receptors. PBs of healthy donors display diverse mucosa-associated TPs, consistent with homeostatic immune activity. Identification of TP signatures of PBs may facilitate noninvasive monitoring of organ-specific immune responses. PMID- 28352657 TI - Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer. AB - BACKGROUND. EGFR and Src family kinases are upregulated in head and neck squamous cell carcinoma (HNSCC). EGFR interacts with Src to activate STAT3 signaling, and dual EGFR-Src targeting is synergistic in HNSCC preclinical models. pSrc overexpression predicted resistance to the EGFR inhibitor, erlotinib, in a prior window trial. We conducted a 4-arm window trial to identify biomarkers associated with response to EGFR and/or Src inhibition. METHODS. Patients with operable stage II-IVa HNSCC were randomized to 7-21 days of neoadjuvant erlotinib, the Src inhibitor dasatinib, the combination of both, or placebo. Paired tumor specimens were collected before and after treatment. Pharmacodynamic expression of EGFR and Src pathway components was evaluated by IHC of tissue microarrays and reverse phase protein array of tissue lysates. Candidate biomarkers were assessed for correlation with change in tumor size. RESULTS. From April 2009 to December 2012, 58 patients were randomized and 55 were treated. There was a significant decrease in tumor size in both erlotinib arms (P = 0.0014); however, no effect was seen with dasatinib alone (P = 0.24). High baseline pMAPK expression was associated with response to erlotinib (P = 0.03). High baseline pSTAT3 was associated with resistance to dasatinib (P = 0.099). CONCLUSIONS. Brief exposure to erlotinib significantly decreased tumor size in operable HNSCC, with no additive effect from dasatinib. Baseline pMAPK expression warrants further study as a response biomarker for anti-EGFR therapy. Basal expression of pSTAT3 may be independent of Src, explain therapeutic resistance, and preclude development of dasatinib in biomarker-unselected cohorts. TRIAL REGISTRATION. NCT00779389. FUNDING. National Cancer Institute, American Cancer Society, Pennsylvania Department of Health, V Foundation for Cancer Research, Bristol-Myers Squibb, and Astellas Pharma. PMID- 28352658 TI - Priming is key to effective incorporation of image-guided thermal ablation into immunotherapy protocols. AB - Focal therapies play an important role in the treatment of cancers where palliation is desired, local control is needed, or surgical resection is not feasible. Pairing immunotherapy with such focal treatments is particularly attractive; however, there is emerging evidence that focal therapy can have a positive or negative impact on the efficacy of immunotherapy. Thermal ablation is an appealing modality to pair with such protocols, as tumors can be rapidly debulked (cell death occurring within minutes to hours), tumor antigens can be released locally, and treatment can be conducted and repeated without the concerns of radiation-based therapies. In a syngeneic model of epithelial cancer, we found that 7 days of immunotherapy (TLR9 agonist and checkpoint blockade), prior to thermal ablation, reduced macrophages and myeloid-derived suppressor cells and enhanced IFN-gamma-producing CD8+ T cells, the M1 macrophage fraction, and PD-L1 expression on CD45+ cells. Continued treatment with immunotherapy alone or with immunotherapy combined with ablation (primed ablation) then resulted in a complete response in 80% of treated mice at day 90, and primed ablation expanded CD8+ T cells as compared with all control groups. When the tumor burden was increased by implantation of 3 orthotopic tumors, successive primed ablation of 2 discrete lesions resulted in survival of 60% of treated mice as compared with 25% of mice treated with immunotherapy alone. Alternatively, when immunotherapy was begun immediately after thermal ablation, the abscopal effect was diminished and none of the mice within the cohort exhibited a complete response. In summary, we found that immunotherapy begun before ablation can be curative and can enhance efficacy in the presence of a high tumor burden. Two mechanisms have potential to impact the efficacy of immunotherapy when begun immediately after thermal ablation: mechanical changes in the tumor microenvironment and inflammatory mediated changes in immune phenotype. PMID- 28352659 TI - Serum Gp96 is a chaperone of complement-C3 during graft-versus-host disease. AB - Better identification of severe acute graft-versus-host disease (GvHD) may improve the outcome of this life-threatening complication of allogeneic hematopoietic stem cell transplantation. GvHD induces tissue damage and the release of damage-associated molecular pattern (DAMP) molecules. Here, we analyzed GvHD patients (n = 39) to show that serum heat shock protein glycoprotein 96 (Gp96) could be such a DAMP molecule. We demonstrate that serum Gp96 increases in gastrointestinal GvHD patients and its level correlates with disease severity. An increase in Gp96 serum level was also observed in a mouse model of acute GvHD. This model was used to identify complement C3 as a main partner of Gp96 in the serum. Our biolayer interferometry, yeast two-hybrid and in silico modeling data allowed us to determine that Gp96 binds to a complement C3 fragment encompassing amino acids 749-954, a functional complement C3 hot spot important for binding of different regulators. Accordingly, in vitro experiments with purified proteins demonstrate that Gp96 downregulates several complement C3 functions. Finally, experimental induction of GvHD in complement C3-deficient mice confirms the link between Gp96 and complement C3 in the serum and with the severity of the disease. PMID- 28352660 TI - TLR7/8 adjuvant overcomes newborn hyporesponsiveness to pneumococcal conjugate vaccine at birth. AB - Infection is the most common cause of mortality in early life, and immunization is the most promising biomedical intervention to reduce this burden. However, newborns fail to respond optimally to most vaccines. Adjuvantation is a key approach to enhancing vaccine immunogenicity, but responses of human newborn leukocytes to most candidate adjuvants, including most TLR agonists, are functionally distinct. Herein, we demonstrate that 3M-052 is a locally acting lipidated imidazoquinoline TLR7/8 agonist adjuvant in mice, which, when properly formulated, can induce robust Th1 cytokine production by human newborn leukocytes in vitro, both alone and in synergy with the alum-adjuvanted pneumococcal conjugate vaccine 13 (PCV13). When admixed with PCV13 and administered i.m. on the first day of life to rhesus macaques, 3M-052 dramatically enhanced generation of Th1 CRM-197-specific neonatal CD4+ cells, activation of newborn and infant Streptococcus pneumoniae polysaccharide-specific (PnPS-specific) B cells as well as serotype-specific antibody titers, and opsonophagocytic killing. Remarkably, a single dose at birth of PCV13 plus 0.1 mg/kg 3M-052 induced PnPS-specific IgG responses that were approximately 10-100 times greater than a single birth dose of PCV13 alone, rapidly exceeding the serologic correlate of protection, as early as 28 days of life. This potent immunization strategy, potentially effective with one birth dose, could represent a new paradigm in early life vaccine development. PMID- 28352661 TI - Store-operated Ca2+ entry controls ameloblast cell function and enamel development. AB - Loss-of-function mutations in stromal interaction molecule 1 (STIM1) impair the activation of Ca2+ release-activated Ca2+ (CRAC) channels and store-operated Ca2+ entry (SOCE), resulting in a disease syndrome called CRAC channelopathy that is characterized by severe dental enamel defects. The cause of these enamel defects has remained unclear given a lack of animal models. We generated Stim1/2K14cre mice to delete STIM1 and its homolog STIM2 in enamel cells. These mice showed impaired SOCE in enamel cells. Enamel in Stim1/2K14cre mice was hypomineralized with decreased Ca content, mechanically weak, and thinner. The morphology of SOCE deficient ameloblasts was altered, showing loss of the typical ruffled border, resulting in mislocalized mitochondria. Global gene expression analysis of SOCE deficient ameloblasts revealed strong dysregulation of several pathways. ER stress genes associated with the unfolded protein response were increased in Stim1/2-deficient cells, whereas the expression of components of the glutathione system were decreased. Consistent with increased oxidative stress, we found increased ROS production, decreased mitochondrial function, and abnormal mitochondrial morphology in ameloblasts of Stim1/2K14cre mice. Collectively, these data show that loss of SOCE in enamel cells has substantial detrimental effects on gene expression, cell function, and the mineralization of dental enamel. PMID- 28352662 TI - Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window. AB - The testicular dysgenesis syndrome (TDS) hypothesis, which proposes that common reproductive disorders of newborn and adult human males may have a common fetal origin, is largely untested. We tested this hypothesis using a rat model involving gestational exposure to dibutyl phthalate (DBP), which suppresses testosterone production by the fetal testis. We evaluated if induction of TDS via testosterone suppression is restricted to the "masculinization programming window" (MPW), as indicated by reduction in anogenital distance (AGD). We show that DBP suppresses fetal testosterone equally during and after the MPW, but only DBP exposure in the MPW causes reduced AGD, focal testicular dysgenesis, and TDS disorders (cryptorchidism, hypospadias, reduced adult testis size, and compensated adult Leydig cell failure). Focal testicular dysgenesis, reduced size of adult male reproductive organs, and TDS disorders and their severity were all strongly associated with reduced AGD. We related our findings to human TDS cases by demonstrating similar focal dysgenetic changes in testes of men with preinvasive germ cell neoplasia (GCNIS) and in testes of DBP-MPW animals. If our results are translatable to humans, they suggest that identification of potential causes of human TDS disorders should focus on exposures during a human MPW equivalent, especially if negatively associated with offspring AGD. PMID- 28352664 TI - Intranasal siRNA administration reveals IGF2 deficiency contributes to impaired cognition in Fragile X syndrome mice. AB - Molecular mechanisms underlying learning and memory remain imprecisely understood, and restorative interventions are lacking. We report that intranasal administration of siRNAs can be used to identify targets important in cognitive processes and to improve genetically impaired learning and memory. In mice modeling the intellectual deficiency of Fragile X syndrome, intranasally administered siRNA targeting glycogen synthase kinase-3beta (GSK3beta), histone deacetylase-1 (HDAC1), HDAC2, or HDAC3 diminished cognitive impairments. In WT mice, intranasally administered brain-derived neurotrophic factor (BDNF) siRNA or HDAC4 siRNA impaired learning and memory, which was partially due to reduced insulin-like growth factor-2 (IGF2) levels because the BDNF siRNA- or HDAC4 siRNA induced cognitive impairments were ameliorated by intranasal IGF2 administration. In Fmr1-/- mice, hippocampal IGF2 was deficient, and learning and memory impairments were ameliorated by IGF2 intranasal administration. Therefore intranasal siRNA administration is an effective means to identify mechanisms regulating cognition and to modulate therapeutic targets. PMID- 28352663 TI - Retinol-binding protein 7 is an endothelium-specific PPARgamma cofactor mediating an antioxidant response through adiponectin. AB - Impaired PPARgamma activity in endothelial cells causes oxidative stress and endothelial dysfunction which causes a predisposition to hypertension, but the identity of key PPARgamma target genes that protect the endothelium remain unclear. Retinol-binding protein 7 (RBP7) is a PPARgamma target gene that is essentially endothelium specific. Whereas RBP7-deficient mice exhibit normal endothelial function at baseline, they exhibit severe endothelial dysfunction in response to cardiovascular stressors, including high-fat diet and subpressor angiotensin II. Endothelial dysfunction was not due to differences in weight gain, impaired glucose homeostasis, or hepatosteatosis, but occurred through an oxidative stress-dependent mechanism which can be rescued by scavengers of superoxide. RNA sequencing revealed that RBP7 was required to mediate induction of a subset of PPARgamma target genes by rosiglitazone in the endothelium including adiponectin. Adiponectin was selectively induced in the endothelium of control mice by high-fat diet and rosiglitazone, whereas RBP7 deficiency abolished this induction. Adiponectin inhibition caused endothelial dysfunction in control vessels, whereas adiponectin treatment of RBP7-deficient vessels improved endothelium-dependent relaxation and reduced oxidative stress. We conclude that RBP7 is required to mediate the protective effects of PPARgamma in the endothelium through adiponectin, and RBP7 is an endothelium-specific PPARgamma target and regulator of PPARgamma activity. PMID- 28352665 TI - Insulin's direct hepatic effect explains the inhibition of glucose production caused by insulin secretion. AB - Insulin can inhibit hepatic glucose production (HGP) by acting directly on the liver as well as indirectly through effects on adipose tissue, pancreas, and brain. While insulin's indirect effects are indisputable, their physiologic role in the suppression of HGP seen in response to increased insulin secretion is not clear. Likewise, the mechanisms by which insulin suppresses lipolysis and pancreatic alpha cell secretion under physiologic circumstances are also debated. In this study, insulin was infused into the hepatic portal vein to mimic increased insulin secretion, and insulin's indirect liver effects were blocked either individually or collectively. During physiologic hyperinsulinemia, plasma free fatty acid (FFA) and glucagon levels were clamped at basal values and brain insulin action was blocked, but insulin's direct effects on the liver were left intact. Insulin was equally effective at suppressing HGP when its indirect effects were absent as when they were present. In addition, the inhibition of lipolysis, as well as glucagon and insulin secretion, did not require CNS insulin action or decreased plasma FFA. This indicates that the rapid suppression of HGP is attributable to insulin's direct effect on the liver and that its indirect effects are redundant in the context of a physiologic increase in insulin secretion. PMID- 28352666 TI - LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn's disease patients. AB - BACKGROUND. Morphological patterns of Paneth cells are a prognostic biomarker in Western Crohn's disease (CD) patients, and are associated with autophagy associated ATG16L1 and NOD2 variants. We hypothesized that genetic determinants of Paneth cell phenotype in other ethnic CD cohorts are distinct but also involved in autophagy. METHODS. We performed a hypothesis-driven analysis of 56 single nucleotide polymorphisms (SNPs) associated with CD susceptibility or known to affect Paneth cell function in 110 Japanese CD patients who underwent ileal resection. We subsequently performed a genome-wide association analysis. Paneth cell phenotype was determined by defensin-5 immunofluorescence. Selected genotype Paneth cell defect correlations were compared to a Western CD cohort (n = 164). RESULTS. The average percentage of abnormal Paneth cells in Japanese CD was similar to Western CD (P = 0.87), and abnormal Paneth cell phenotype was also associated with early recurrence (P = 0.013). In contrast to Western CD, ATG16L1 T300A was not associated with Paneth cell defect in Japanese CD (P = 0.20). Among the 56 selected SNPs, only LRRK2 M2397T showed significant association with Paneth cell defect (P = 3.62 * 10-4), whereas in the Western CD cohort it was not (P = 0.76). Pathway analysis of LRRK2 and other candidate genes with P less than 5 * 10-4 showed connections with known CD susceptibility genes and links to autophagy and TNF-alpha networks. CONCLUSIONS. We found dichotomous effects of ATG16L1 and LRRK2 on Paneth cell defect between Japanese and Western CD. Genes affecting Paneth cell phenotype in Japanese CD were also associated with autophagy. Paneth cell phenotype also predicted prognosis in Japanese CD. FUNDING. Helmsley Charitable Trust, Doris Duke Foundation (grant 2014103), Japan Society for the Promotion of Science (KAKENHI grants JP15H04805 and JP15K15284), Crohn's and Colitis Foundation grant 274415, NIH (grants 1R56DK095820, K01DK109081, and UL1 TR000448). PMID- 28352667 TI - Hepcidin-mediated iron sequestration protects against bacterial dissemination during pneumonia. AB - Gram-negative pneumonia is a dangerous illness, and bacterial dissemination to the bloodstream during the infection is strongly associated with death. Antibiotic resistance among the causative pathogens has resulted in diminishing treatment options against this infection. Hepcidin is the master regulator of extracellular iron availability in vertebrates, but its role in the context of host defense is undefined. We hypothesized that hepcidin-mediated depletion of extracellular iron during Gram-negative pneumonia protects the host by limiting dissemination of bacteria to the bloodstream. During experimental pneumonia, hepcidin was induced in the liver in an IL-6-dependent manner and mediated a rapid decline in plasma iron. In contrast, hepcidin-deficient mice developed a paradoxical increase in plasma iron during infection associated with profound susceptibility to bacteremia. Incubation of bacteria with iron-supplemented plasma enhanced bacterial growth in vitro, and systemic administration of iron to WT mice similarly promoted increased susceptibility to bloodstream infection. Finally, treatment with a hepcidin analogue restored hypoferremia in hepcidin deficient hosts, mediated bacterial control, and improved outcomes. These data show hepcidin induction during pneumonia to be essential to preventing bacterial dissemination by limiting extracellular iron availability. Hepcidin agonists may represent an effective therapy for Gram-negative infections in patients with impaired hepcidin production or signaling. PMID- 28352668 TI - Genomic profiling reveals mutational landscape in parathyroid carcinomas. AB - Parathyroid carcinoma (PC) is an extremely rare malignancy lacking effective therapeutic intervention. We generated and analyzed whole-exome sequencing data from 17 patients to identify somatic and germline genetic alterations. A panel of selected genes was sequenced in a 7-tumor expansion cohort. We show that 47% (8 of 17) of the tumors harbor somatic mutations in the CDC73 tumor suppressor, with germline inactivating variants in 4 of the 8 patients. The PI3K/AKT/mTOR pathway was altered in 21% of the 24 cases, revealing a major oncogenic pathway in PC. We observed CCND1 amplification in 29% of the 17 patients, and a previously unreported recurrent mutation in putative kinase ADCK1. We identified the first sporadic PCs with somatic mutations in the Wnt canonical pathway, complementing previously described epigenetic mechanisms mediating Wnt activation. This is the largest genomic sequencing study of PC, and represents major progress toward a full molecular characterization of this rare malignancy to inform improved and individualized treatments. PMID- 28352669 TI - Lymphatic deletion of calcitonin receptor-like receptor exacerbates intestinal inflammation. AB - Lymphatics play a critical role in maintaining gastrointestinal homeostasis and in the absorption of dietary lipids, yet their roles in intestinal inflammation remain elusive. Given the increasing prevalence of inflammatory bowel disease, we investigated whether lymphatic vessels contribute to, or may be causative of, disease progression. We generated a mouse model with temporal and spatial deletion of the key lymphangiogenic receptor for the adrenomedullin peptide, calcitonin receptor-like receptor (Calcrl), and found that the loss of lymphatic Calcrl was sufficient to induce intestinal lymphangiectasia, characterized by dilated lacteals and protein-losing enteropathy. Upon indomethacin challenge, Calcrlfl/fl/Prox1-CreERT2 mice demonstrated persistent inflammation and failure to recover and thrive. The epithelium and crypts of Calcrlfl/fl/Prox1-CreERT2 mice exhibited exacerbated hallmarks of disease progression, and the lacteals demonstrated an inability to absorb lipids. Furthermore, we identified Calcrl/adrenomedullin signaling as an essential upstream regulator of the Notch pathway, previously shown to be critical for intestinal lacteal maintenance and junctional integrity. In conclusion, lymphatic insufficiency and lymphangiectasia caused by loss of lymphatic Calcrl exacerbates intestinal recovery following mucosal injury and underscores the importance of lymphatic function in promoting recovery from intestinal inflammation. PMID- 28352670 TI - Integration of human papillomavirus type 16 in cervical cancer cells. AB - Cervical cancer remains an important cause of women morbidity and mortality. The progression of cervical pathology correlates with the HPV integration into the host genome. However, the data on the viral integration status in cervical dysplasias are controversial. The aim of the current study was to evaluate the status of HPV integration in two types of cervical pathology - invasive and non invasive cervical cancer (e.g. carcinoma in situ). 156 women were included in the study: 66 women were diagnosed with invasive cervical cancer (CC) and 90 with non invasive cervical cancer (carcinoma in situ, CIS). 74.2% [95% PI: 63.64/84.76] of specimens collected from women with diagnosed CC and 85.6% [95% PI: 85.53/92.85] of CIS specimens were positive for HPV. The most prevalent HPV genotype in both groups was HPV16. To evaluate HPV integration, three selected HPV16 E2 gene fragments were analyzed by PCR. In the majority of CC and CIS specimens the amplification of all three HPV16 E2 gene fragments was observed. The episomal HPV16 form was detected in the majority of CC and CIS specimens. The deletion of all three HPV16 E2 gene fragments was detected in 9.4% of CC specimens and 2.2% of CIS specimens. Finally, integration status could not be used as diagnostical additional test to distinguish between invasive and non invasive cervical cancer. PMID- 28352671 TI - The effect of glycemic control on CEA, CA 19-9, amylase and lipase levels. AB - BACKGROUND: Diabetes mellitus is closely related to pancreas cancer. In this study we aimed to investigate the effect of hyperglycemia on tumor and inflammation markers, as well as pancreatic exocrine functions. METHODS: A total of 98 consecutive diabetic patients with poor glycemic control, and 50 healthy controls were included in the study. We measured hsCRP, erythrocyte sedimentation rate (ESR), CA19-9, CEA, amylase and lipase in addition to routine biochemistry tests, before and after euglycemia was achieved. RESULTS: Fasting blood glucose, HbA1c, CA19-9, CEA, hsCRP, ESR, triglycerides, AST, ALT, GGT, ALP, total cholesterol and LDL-C levels decreased significantly with the regulation of glycemic control. Amylase and lipase levels increased with the regulation of glycemic control. After glycemic control, CA19-9 and CEA levels were still higher, whereas amylase and lipase levels were still lower in the diabetic group compared with the control group. Basal HbA1c showed significant correlation with CA19-9, CEA, amylase and lipase. CONCLUSIONS: We propose to repeat observations of tumor markers after hyperglycemia is resolved, in order to avoid unnecessary invasive tests. Our data also suggest that pancreatic exocrine function was improved with lowering blood glucose in a short period of time. PMID- 28352672 TI - Insulin resistance and adipokine levels correlate with early atherosclerosis - a study in prediabetic patients. AB - Cardiovascular risk of prediabetes is still subject to controversies. We analyzed the associations between insulin resistance, adipokines and incipient atherosclerosis estimated by intima-media thickness (IMT) in a cross-sectional study on 122 prediabetic subjects without clinical signs of atherosclerotic disease. Homeostasis model assessment of insulin resistance (HOMA-IR, calculated as fasting insulin * fasting plasma glucose / 22.5), adiponectin, leptin, leptin to-adiponectin ratio, carotid and femoral IMT were evaluated. We also assessed other parameters related to insulin resistance and adipokines (HbA1c, anthropometric and lipid parameters), as they may also influence atherosclerosis. Carotid IMT was correlated to adiponectin and leptin-to-adiponectin ratio (all p < 0.05), but not with HOMA-IR or leptin, while femoral IMT showed no relationship with these factors. After adjusting for leptin, leptin-to-adiponectin ratio, triglycerides, HDL-cholesterol, cholesterol-to-HDL ratio, triglycerides-to-HDL ratio and HbA1c, IMT values became correlated with HOMA-IR. Adjustment for HOMA IR induced the appearance of new correlations between adipokines and both IMT values. In conclusion, insulin resistance and adipokines seem related to IMT in prediabetic subjects without clinical signs of arterial obstruction. PMID- 28352674 TI - Isolated myeloid sarcoma of the neck and chest: differential diagnosis and therapeutic approach. AB - In this article, we present the case of a 57-year-old man with cervical and mediastinal tumor mass, normal blood count as well as virusological status. Cervical tumor tissue biopsy revealed cells positive for CD34, CD13, LCA, CD33, and CD163 but negative for T-cell and B-cell markers, NK-cell markers, plasmacytic markers and anaplastic large cell lymphoma markers. These features were consistent with myeloid sarcoma of the neck with involvement of the mediastinum. We discussed differential diagnosis and therapy of isolated myeloid sarcoma and suggest that clinical presentation, cell morphology, complete immunophenotype, and specific genotypic lesions in some cases, must be evaluated. PMID- 28352673 TI - Cost comparison of treating chronic hepatitis C genotype one with pegylated interferons in Ukraine. AB - Based on the pivotal trial showing no clinically relevant differences between pegylated interferon alpha-2b (Peg-alpha-2b) and alpha-2a (Peg-alpha-2a) combined with ribavirin for treatment of chronic hepatitis C virus (HCV) genotype 1 infection in Ukraine, a cost-minimization analysis was performed using a 1 year time horizon and both a health care and patients' perspective. A decision tree reflects treatment pathways. Drug costs were based on drug labeling and adjusted to the average body mass in Ukraine. Subgroup analysis was applied to deal with heterogeneity of patient's weight causing dose changes. A break-even price of Peg alpha-2a and Peg-alpha-2b (based on the average dose) was calculated. Univariate sensitivity analyses and probabilistic sensitivity analysis were carried out to reflect decision uncertainty. For an average body weight, total medical costs per patient differ from US$9220 for Peg-alpha-2b to US$9513 for Peg-alpha-2a from a health care perspective, and from US$15,212 to US$15,696 from a patients' perspective. Sensitivity analyses show these results are robust. With average body weight, the break-even price of Peg-alpha-2b may be 7.3% higher than Peg alpha-2a to have similar total costs. PMID- 28352675 TI - Prolonged paradoxical reaction to anti-tuberculous treatment after discontinuation of TNF-alpha- blocker therapy with adalimumab. Rare clinical documentation. AB - In the past decades, tumor necrosis factor alpha (TNF-a) antagonist has been a milestone in the treatment of many chronic inflammatory diseases. TNF antagonist can increase patients' susceptibility to many different kinds of infections especially those requiring granuloma formations despite regular performance of Screening for latent tuberculosis infection (LTBI). We report 2 cases of patients who developed tuberculosis under treatment with adalimumab, which was discontinued after the diagnosis of tuberculosis. During the tuberculosis therapy they unexpectedly developed a prolonged paradoxical reaction. In both cases we were only able to manage the progress of the paradoxical reaction through high steroid doses. Patients undergoing therapy with TNF- alpha-blocker are prone to develop tuberculosis infection, which could in turn lead to severe prolonged paradoxical reaction during anti-tuberculous treatment. An increased steroid dose may be required and is sometimes necessary. PMID- 28352676 TI - Quick and effective method of bone marrow mesenchymal stem cell extraction. AB - BACKGROUND: Mesenchymal stem cells (MSCs) are currently exploited in numerous clinical trials to investigate their potential in immune regulation, hematopoesis or tissue regeneration. The most common source of MSCs for clinical use is human bone marrow. To generate sufficient numbers of cells relevant to clinical use in most cases the high volumes (20-50 ml) of bone marrow aspirates are taken. METHODS: In this pilot study, 8 healthy bone marrow donors were included. Two different MSC extraction methods were evaluated: MSCs extraction from 60 ml of bone marrow using density gradient and MSCs extraction from 6 ml using red blood cell (RBC) lysis. RESULTS: Our results showed that after RBC lysis the efficient amount of human MSCs can be isolated from 10 times less bone marrow volume (6 ml). Moreover, using small volume of bone marrow the adequate therapeutical dose of MSCs could be achieved during similar period of time (3-4 weeks). In conclusion, we have shown that MSCs isolation using RBC lysis is an effective and more advantageous method in comparison to standard MSCs isolation using density gradient. Using RBC lysis from small volume of bone marrow the same amount of MSCs were obtained as usually using large volume and density-gradient. PMID- 28352677 TI - Amlodipine as an antiischemic drug is superior to long acting nitrates. AB - European Society of Cardiology Guidelines cite results of meta-analysis that the use of calcium channel blockers results in fewer angina episodes per week vs. long-acting nitrates. Moreover, we listed 12 reasons more to prefer amlodipine over long-acting nitrates, especially in stable angina pectoris patients with arterial hypertension. It may be the way to decrease polypharmacy without loosing efficacy. Some important advantages of amlodipine versus long-acting nitrate(s) are: amlodipine also treats hypertension, it helps reducing hypertensive target organ damages (e.g. left ventricular hypertrophy) and prevents morning blood pressure surge. Moreover, amlodipine can be given once daily (which improves adherence), it produces neither tolerance nor rebound, it has less side effects. PMID- 28352678 TI - Correlation between SNPs in CDH1 and gastric cancer in Chinese population. AB - BACKGROUND: Many recent studies revealed that the single nucleotide polymorphisms have considerable effects on the susceptibility of cancer, such as prostate cancer, lung cancer and gastric cancer. The E-cadherin, a calcium-dependent transmembrane glycoprotein encoded by CDH1 gene, is critical for epithelial construction, intercellular adhesion and cell migration. Some associations have been reported between single nucleotide polymorphisms and gastric cancer in the Chinese population. OBJECTIVE: To investigate whether the single nucleotide polymorphism in CDH1 gene is associated with the susceptibility of gastric cancer in the Chinese population. MATERIAL AND METHODS: The genotypes of 5 known single nucleotide polymorphisms (rs33935154, rs121964871, rs121964874, rs121964875, rs121964876) were determined in 359 gastric cancer patients and 368 healthy controls. High resolution melting curve detection and sequencing analysis were used in the present study. RESULTS: There is a statistical significance in the rs121964871 C>G polymorphism between gastric cancer patients and healthy controls (OR=1.769, 95%CI: 1.051-2.976). Elderly male individuals (>50 years of age) carrying this risk factor may be more susceptible to gastric cancer. CONCLUSIONS: The results indicated that the rs121964871 C>G polymorphism is associated with the susceptibility of gastric cancer in the Chinese population, with some age and sex-dependent tendencies observed. PMID- 28352679 TI - How to manage TB in children? Problems and solutions in four cases. AB - Children bear a substantial part of the tuberculosis (TB) epidemic worldwide, and it is estimated that there were ? 500.000 childhood TB cases globally in 2010, although accurate data are problematic to obtain given the many difficulties associated with TB diagnosis in children and the weaknesses of surveillance systems in countries where TB is endemic. The World Health Organization is working hard in order to reduce the TB prevalence rates and deaths by half by 2015. In this challenge, general practitioners and pediatricians play a key role in detecting early cases of suspected TB and sending them to experts in infectious diseases. This will reduce delayed diagnosis and the spread of disease, which is especially important now that the prevalence of multidrug resistant TB is increasing. For this reason, the purpose of this report was to delineate the characteristic clinical features of the most common forms of pediatric TB and to suggest a rational and practical approach to the disease underlining the role of patients and parents personal and clinical history. PMID- 28352680 TI - Endometrial cancer and microsatellite instability status. AB - : Microsatellite instability (MSI) is an important factor in the development of various cancers as an identifier of a defective DNA mismatch repair system. The objective of our study was to define the association between microsatellite instability status and traditional clinicopathologic characteristics of endometrioid type adenocarcinoma. MATERIAL AND METHODS: MSI status of endometrial cancer was examined by employing the Promega MSI Analysis System. This system uses 5 mononucleotide markers to identify MSI in tumour and normal tissue DNA (BAT-25, BAT-26, NR-21, NR-24, and MONO-27), and 2 pentanucleotide markers (Penta C and Penta D) for specimen identification. In this study, we investigated MSI status in 109 endometrial carcinomas. RESULTS AND CONCLUSIONS: One hundred (92%) of 109 endometrial cancers showed endometrioid type histology and only 9 (8%) non endometrioid type. MSI-high was found in 17% (17/100) of endometrioid type adenocarcinomas, in 0% (0/9) of non-endometrioid carcinomas. Selected clinicopathologic parameters for endometrioid type adenocarcinomas were compared to the MSI status which was separated into two groups - MSI-high and MSI stable. The results showed that MSI-high status was related to clinicopathologic parameters such as deep myometrial invasion and higher histologic grade in endometrioid type adenocarcinomas. PMID- 28352681 TI - Submental epidermoid cysts in children. AB - Epidermoid cysts are lesions, which form as a result of implantation of the epidermis in the layers of the dermis or the mucous membrane. The lesions are rare in adults with 7% occurring in the head and neck area and most often located in the submental region. In children population submental epidermoid cysts are extremely rare. The differential diagnosis of the lesions is necessary as it affects the choice of treatment methods. Among the pathological conditions occurring in that region, salivary retention cyst (ranula), thyroglossal duct cyst, vascular lymphatic malformation (cystic hygroma), median neck cyst, lymphadenopathy, thyroid gland tumor, laryngeal cyst, epidermoid and dermoid cysts, submental abscess, sialolithiasis and salivary gland inflammation should be considered. The authors of the present report demonstrate two cases of submental epidermoid cysts in children. Differential diagnosis in case of suspected submental epidermoid cyst in a child with proposed clinical practice and literature review is provided. PMID- 28352682 TI - Rare types of breast carcinoma. AB - Breast cancer (BC) is a heterogeneous disease that encompasses several distinct entities with remarkably different characteristics. Histological type is one of important BC characteristics. Histological type is associated with differences in epidemiology, diagnostic issues, clinical course, prognosis. When we talk about BC, ductal and lobular carcinoma is usually what we have in mind. However, the other types that comprise less than 10% of BC are also very important. The rarity of many of these neoplasms does not allow large or randomized studies to define the optimal treatment. Many of the descriptions are from case reports and small series. The aim of this retrospective study was to analyze the data on rare breast cancers, to describe their main characteristics, and to calculate survival rates. We believe that the experience of our institution will contribute to the available data about these rare breast cancers and help in better understanding of this subgroup. PMID- 28352683 TI - Biomechanical Study of Two Peripheral Suture Methods on Repaired Tendons. AB - Flexor digitorum tendon injuries are challenging conditions to manage to ensure optimal patient outcomes. While several surgical approaches with high success rates have been developed, there remains no gold standard for suture technique for the repair of flexor tendon injuries. In this study, we compared two distinct peripheral suture methods on the strength of repaired tendons. Pig flexor digitorum profundus tendons were used in biomechanical studies and the biomechanical influence on tendon repair of continuous running peripheral suture (CRPS) and continuous locking peripheral suture (CLPS), were compared, using stitch length ranging from 1mm to 5mm. In CRPS, the 1mm stitch length group displayed the highest maximum load and breaking power, which was 1.57 fold higher than the 2mm stitch length group. Pairwise comparison revealed that the 1 and 2mm groups were statistically different from the 3, 4, and 5mm stitch length groups while comparison among the latter groups was not statistically significant. For CLPS, the 1mm group exhibited consistently the highest maximum load strength and breaking power, which was twice the strength displayed by the 2mm group. Pairwise comparisons between groups showed statistical significance. For future repairs of flexor tendon injuries, 1mm stitch length is highly recommended for simple peripheral suture. PMID- 28352684 TI - Surgical tracheotomy performed with and without dual antiplatelet therapy. AB - Some patients who need dual antiplatelet therapy sometimes require tracheotomy. Aim of this study was to compare the rate of complications during and after surgical tracheotomy between patients requiring dual antiplatelet therapy and those without dual antiplatelet therapy. We retrospectively included 79 patients (62% men, mean age 64 +/- 14 years) in the period 2007-2011. The following complications were analyzed: need for surgical revision within 24 hours after tracheotomy, need for bronchoscopy within 24 hour after tracheotomy, need for blood transfusion within 24 hours after tracheotomy, death attributed to tracheotomy and any complication attributed to tracheotomy. We compared patients where tracheotomy was performed while receiving dual antiplatelet therapy (n=27, 34%) to patients where tracheotomy was performed without dual antiplatelet therapy (n=52, 66%). Nonsignificant differences between the two groups were observed general characteristics. There were no statistically significant differences in complications after tracheotomy (surgical revision after tracheotomy p=0.63, bronchoscopy after tracheotomy p=0.74, blood transfusion after tracheotomy p=0.59, death attributed to tracheotomy p=1.00 and any complication attributed to tracheotomy p=1.00). The study shows that tracheotomy is safe in cardiac patients on dual antiplatelet therapy. PMID- 28352685 TI - Relation between bone mineral density and IL-17 serum levels in Serbian patients with early Rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial inflammation and destruction of joint cartilage and bone. Different cytokines play important role in the processes that cause articular destruction and extra-articular manifestations in RA. The contribution of cytokines representing the Th1 (INF-gamma), Th2 (IL-4) and IL-17A to the pathogenesis of early RA and bone mineral density (BMD) loss in still poorly understood. Serum samples of 38 early RA patients were evaluated for erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), C-reactive protein (CRP), anti-cyclic citrullinated peptide antibodies (anti-CCP) and for the tested cytokines (IL-17A, IL-4 and INF-gamma). BMD was evaluated by dualenergy X-ray absorptiometry (DXA). Disease activity score (DAS28) calculation was assessed for all patients. Control serum samples were obtained from 34 healthy volunteers. The levels of tested cytokines were significantly higher (IL-17A, p<0.001; INF-gamma, P<0.001; IL-4, P<0.01) in patients with early RA, compared to the healthy controls. In early RA patients, strong correlation of serum IL-17A was found with DAS28, ESR and CRP. Also, a significant negative correlation was found between serum INF-gamma levels and the DAS28 score. Significantly positive correlation of BMD values and CRP, DAS28 IL-17A were also demonstrated. DXA analysis revealed that the most common site for osteoporosis was the lumbar spine followed by the femoral neck. BMD values significantly correlated with CRP, DAS28 score and IL-17A serum levels. The mean serum IL-17A levels, in patients with early RA, corresponded with disease activity, severity and BMD loss, indicating the potential usefulness of serum IL-17A in defining the disease activity and bone remodeling. PMID- 28352686 TI - Upgrade from ICD to CRT-D: clinical and haemodynamic impact of biventricular pacing in a patient with acquired long QT syndrome. AB - Long QT syndrome (LQTS) is characterised by both the depolarisation and repolarisation disorder of cardiac muscle cells. Cardiac resynchronising therapy (CRT) is an important treatment option for patients with chronic heart failure (CHF) when echocardiographic and electrocardiographic criteria are met. Although CRT was introduced in clinical practice 10 years ago, doubts related to application of this treatment method persist because of its potential proarrhythmogenic effect. This is a case describing a 66-year-old Caucasian female with LQTS coexisting with a left bundle branch branch block (LBBB) and an implantable single-cavity cardioverter-defibrillator (ICD VR), who had repeated appropriate high-energy treatments. The upgrade to resynchronisation therapy defibrillator (CRT-D) significantly reduced frequency of ventricular tachycardia and the need for electrical therapies. The normalisation of the left ventricle size, as seen on echo examination, and the improvement of heart failure symptoms were also observed. PMID- 28352687 TI - Social psychological predictors of satisfaction with intrapartum and postpartum care - what matters to women in Czech maternity hospitals? AB - OBJECTIVE: To identify the social psychological factors affecting women's evaluation of care provided in Czech maternity hospitals using following criteria: satisfaction with intrapartum and postpartum care, willingness to return to a given hospital and to recommend the hospital to others. METHODS: 762 women completed a 71-item original Czech questionnaire KLI-P designed to measure the psychosocial climate in both delivery and after-birth unit on six scales. The sample was representative of the Czech parturients population. Multivariate logistic regression was used to investigate the predictive value of the questionnaire scales for maternal satisfaction, willingness to return to and to recommend a given hospital. RESULTS: For delivery unit, the satisfaction predictors were: helpfulness and empathy of midwives (Chi2=48.9), communication of information and availability of caregivers (Chi2=16.6), helpfulness and empathy of physicians (Chi2=10.9), symmetrical and respectful attitude of staff members (Chi2=9.7) and physical comfort and services (Chi2=7.6). The predictors of satisfaction with after-birth unit included helpfulness and empathy of the staff (Chi2>=42.1), communication of information and availability of caregivers (Chi2=52.5), physical comfort and services (Chi2=30.6), control and involvement in decision-making (Chi2=6.6) and parity (Chi2=8.6). The factors influencing women's willingness to return to and to recommend a hospital differed from the predictors of general satisfaction. CONCLUSIONS: The satisfaction factors revealed in this research correspond predominantly to the results of studies conducted in other countries (warm, non-formal and supportive approach, sufficient and well-timed provision of information and explanation, availability of caregivers, physical environment). However, participation in decision making, which has been repeatedly shown to be among the strongest predictors of childbirth satisfaction, was not important for the Czech parturients' satisfaction with intrapartal care. This finding can be explained by different attitudes and expectations of both parturients and caregivers in a post totalitarian country. PMID- 28352688 TI - Assessment of nutrition and physical activity of 6th-7th grade schoolchildren in the city of Vilnius, Lithuania. AB - BACKGROUND: Evaluation of eating habits and physical activity is very important for health interventions. Our aim in this study was to assess the characteristics of eating and physical activity of 6-7th grade schoolchildren in the city of Vilnius, Lithuania, as well as the association between dietary habits and physical activity. METHODS: The study was conducted within the project "Education of healthy diets and physical activity in schools". The sample consisted of 1008 schoolchildren from 22 schools in the city of Vilnius, and was based on empirical methods, including a questionnaire poll and comparative analysis. Statistical software Stata v.12.1 (Stata corp LP) was used to analyze the data. RESULTS: Our study showed that less than half (37.1%) of study participants had physically active leisure time. Boys were significantly more physically active than girls. More than half (61.4%) of children ate breakfast every day. Girls were more likely to eat vegetables and sweets. Schoolchildren who ate vegetables and dairy products as well as those who got enough information about physical activity and spoke about it with their family members were more physically active. CONCLUSIONS: The results of the study confirmed that schoolchildren were not sufficiently physically active. It was found that low physical activity is related to dietary and other factors, such as lack of information about physical activity and its benefits. PMID- 28352689 TI - Postprandial decrease in LDL-cholesterol in men with metabolic syndrome. AB - BACKGROUND: In some epidemiological studies, blood lipids are determined at non fasting state, which may impact cardiovascular risk estimation. The aim of this study was to evaluate postprandial LDL-C changes in men with newly diagnosed metabolic syndrome (MetSy). METHODS: 36 male patients were examined: 12 men with and 24 men without MetSy. The fat tolerance test was performed before and after a three-month hypolipidemic treatment. Serum lipids were measured using routine methods, lipid peroxides (LPO) colorimetrically, apolipoproteins A-I, B, and hsCRP immunoturbidimetrically. RESULTS: The postprandial increase in triglycerides was associated with a decrease in LDL-C and a small decrease in apo B. In men with MetSy, the mean change in LDL-C (-19.5 +/- 2.3 mg/dl) was greater than in healthy men (-5.7 +/- 3.8 mg/dl). All lipid changes (DeltaTG, DeltaLDL-C and DeltaLPO) were linearly dependent on the postprandial non-LDL-cholesterol. After three months of hypolipidemic treatment, in all men with MetSy, the apoB/apoA-I ratio remained the same as before the therapy. CONCLUSION: In men diagnosed with MetSy, postprandial decreases in LDL-cholesterol may cause underestimation of cardiovascular risk. After three months of hypolipidemic treatment, there was only a partial reduction in this risk, as the apoB/apoA-I ratio remained the same. PMID- 28352690 TI - Strength and aerobic training in overweight females in Gdansk, Poland. AB - We compared the effects of 16-week-training on rest metabolic rate, aerobic power, and body fat, and the post-exercise effects upon rest oxygen uptake and respiratory exchange ratio in overweight middle-aged females. Twenty nine overweight women (BMI 29.9 +/- 1.2 kg*m-2) participated in training (3 days a week). The subjects were divided onto groups of aerobic (AT) and strength (ST) training. The results showed that the total body mass decrease and VO2 max increase did not differ in both groups. Decrease in waist circumference after 16 weeks was higher in the ST group. In the ST group fat-free mass increased during the first 8 weeks. Rest metabolic rate was increased significantly at 16th week compared to initial value in ST group only. Significant increase in post-exercise resting VO2 and respiratory exchange ratio at 12 and 36 h was observed after the strength training session only. Increase in rest metabolic rate and post-exercise rest energy expenditure occurred after strength training but not after aerobic training despite the similar increase in aerobic power. The effect of 8-16 weeks of strength training on body mass decrease was higher in comparison to aerobic training. PMID- 28352692 TI - The association between red blood cell distribution width and acute pancreatitis associated lung injury in patients with acute pancreatitis. AB - BACKGROUND: Red blood cell distribution width (RDW) that describes red blood cell volume heterogeneity is a common laboratory test. Our aim was to focus on the association between RDW and acute pancreatitis associated lung injury (APALI). METHODOLOGY: A total of 152 acute pancreatitis (AP) patients who conformed to the criteria were included in this study. The demographic data, medical histories and laboratory measures was obtained from each patient on admission, further, the medical histories and biological data were analyzed, retrospectively. RESULTS: Increased RDW at admission was observed in patients with APALI compared with the non-APALI groups. Our results exhibited that RDW was an independent risk factor for APALI after adjusting leukocyte, neutrophil percentage, random blood glucose (RBG), total bilirubin (TB) and total bile acid (TBA) (Crude model) (OR=2.671;CI 95% 1.145-6.230; P=0.023), further adjustment based on Crude model for sex and age did not attenuate the significantly high risk of APALI in patients with AP, RWD still remained a roles as an independent risk factor for APALI (OR=2.653;CI95 % 1.123-6.138; P=0.026). CONCLUSIONS: Our study demonstrate that RDW at admission is associated with APALI and should be considered as an underlying risk factor of APALI. PMID- 28352693 TI - Organic food consumption by athletes in Lithuania. AB - BACKGROUND: With environmental pollution increasing, interest in organic farming and organic foodstuffs has been growing all over the world. Data on organic food consumption by Lithuanian athletes is not yet available. This lack of data determined the aim of this study: to identify the particulars of organic foodstuff consumption among athletes. METHODS: In September-November 2012, we polled 158 of the best-performing athletes of the Olympic sports team through direct interviews. An approved questionnaire was used to identify the specifics of organic foodstuff consumption among athletes. RESULTS: The survey results showed that 97% of athletes consume organic foodstuffs, and 80% of athletes highlighted the positive impact of organic food on health. Nevertheless, a slim majority of athletes (51.7%) consume organic foodstuffs seldomly, 2-3 times per week. The range of organic foodstuffs consumed depends on the gender of athletes, and the consumption of some products depends on monthly incomes. CONCLUSIONS: Survey results confirm the need for the production and expansion of the variety of organic foodstuffs. In the course of the development of the organic food market, it should be beneficial for manufacturers to target high-performance athletes and physically active people. PMID- 28352691 TI - Risk factors involved in orofacial cleft predisposition - review. AB - Clefts that occur in children are a special topic. Avoiding risk factors, and also an early diagnosis of cleft possibility can result in minimizing or avoiding them. If on the other hand when clefts occur they require a long-term, multistage specialized treatment. Etiology of clefts seems to be related to many factors. Factors such as genetic, environmental, geographic and even race factors are important. Identification of risk factors can lead to prevention and prophylactic behaviors in order to minimize its occurrence. Exposure to environmental factors at home and work that lead to cleft predisposition should not be disregarded. It seems that before planning a family it would be wise to consult with doctors of different specializations, especially in high-risk families with cleft history in order to analyze previous lifestyle. Clefts are very common in hereditary facial malformations and are causing a lot of other irregularities in the head and neck region. In this paper after a brief papers review authors present socio geographic, environmental and also work place related factors that are influencing pregnant women condition and should be taken under serious consideration. PMID- 28352694 TI - Inclusion body myositis - pathomechanism and lessons from genetics. AB - Inclusion body myositis is a rare, late-onset myopathy. Both inflammatory and myodegenerative features play an important role in their pathogenesis. Overlapping clinicopathological entities are the familial inclusion body myopathies with or without dementia. These myopathies share several clinical and pathological features with the sporadic inflammatory disease. Therefore, better understanding of the genetic basis and pathomechanism of these rare familial cases may advance our knowledge and enable more effective treatment options in sporadic IBM, which is currently considered a relentlessly progressive incurable disease. PMID- 28352696 TI - Changes in biochemical and functional parameters for men during exercise. AB - Benefits of physical activity are undeniable. The aim of the present research was to determine the effects of physical activity and age on cholesterol and glucose levels in the blood, as well as changes in the functional parameters of the cardiovascular system, during stepwise increases in physical load for men employed in the same place, but with different levels of physical activity. The subjects were 95 military officers who were divided into groups according to the level of physical activity of their occupation, with veloergometry used as physical load. Cholesterol and glucose levels in the blood were taken as biochemical indices. The results showed that occupational physical activity had a positive effect on biochemical and cardiovascular functional parameters before, during, and after the physical load. Only the cardiovascular rate (systolic blood pressure) in older subjects was significantly higher than that of the younger persons; for all other parameters, age had no effect at all. PMID- 28352695 TI - Effects of hypothermia on skeletal ischemia reperfusion injury in rats. AB - OBJECTIVE: The aim of this study was to investigate the effect of hypothermia (H) on skeletal ischemia-reperfusion (IR) injury in rats by measuring malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), nitric oxide (NO), and interleukin-1 beta (IL-1beta) in muscle, and measureing immunohistochemical-inducible nitric oxide synthase (iNOS) staining of skeletal muscle. MATERIALS AND METHODS: Eighteen Wistar Albino rats were divided randomly into three groups (sham, IR, hypothermia) (n=6). The sham group had all procedures without the IR period. The lower right extremity of rats in the IR and hypothermia groups was subjected to 2 hours of ischemia and 22 hours of reperfusion by applying a clamp on the common iliac artery and a rubber-band at the level of the lesser trochanter under general anesthesia. Rats in the hypothermia group underwent 4 hours of hypothermia during the first four hours of reperfusion in addition to a 2-hour ischemia and 22-hour reperfusion period. All rats were sacrificed at end of the IR period using a high dose of anesthesia. The tibialis anterior muscles were preserved. Immunohistochemical iNOS staining was performed, and MDA, SOD, GSH-Px, NO, and IL-1beta were measured in the muscle. RESULTS: The level of MDA, NO, and IL-1beta in muscle was increased in the IR group compared with that in the sham group, but these parameters were decreased in the hypothermia group compared with the IR group. The activities of SOD and GSH-Px in muscle were decreased in the IR group; however, these parameters were increased in the hypothermia group. The score and intensity of iNOS staining of skeletal muscle was dens in IR group, mild in hypothermia group, and weak in sham group. CONCLUSION: The present study has shown that hypothermia reduced IR injury in the skeletal muscle by decreasing the levels of MDA, NO, and IL-1beta, and increasing the activities of SOD and GSH-Px. In addition, hypothermia attenuated the score and intensity of iNOS staining. PMID- 28352697 TI - Use of antiviral therapy in patients with chronic hepatitis C. AB - INTRODUCTION: The presence of background HCV infection cannot be overestimated in view of the prevalence of chronic hepatitis C and the risk of adverse outcomes of this disease. Purpose of this study was to evaluate the effectiveness of the combined use of antiviral therapy (Roferon + Vero-Ribavirin) and resort factors in patients with chronic hepatitis C in the phase of replication. MATERIAL AND METHODS: We observed 48 patients with chronic hepatitis C; the minimum level of activity of the process defined the phase of replication. Markers of HCV infection were determined by enzyme linked immunosorbent assay (ELISA) (a-HCV and HCV-Ig M). HCV RNA was determined twice by the polymerase chain reaction (PCR). Genotyping of hepatitis C virus was performed. Biochemical blood analysis and the study of HCV infection markers were carried out four times. Results of therapy were assessed immediately after the end of the resort (spa) treatment, then at 3, 6 and 12 months after starting treatment. At 12 months after starting treatment, all the observed patients had persistent clinical and biochemical remission. Elimination of the virus from the blood was noted in 56% of the control group and 74% of patients in the study group. CONCLUSIONS: For patients with moderately active HCV, the replication phase was characterized by asthenic-vegetative syndrome (100% of patients) with severe depression (22.92%), pain (77.08%) and dyspeptic syndrome (33.33%), moderate hypertransferaseemia (100%), slightly pronounced cholestasis (33% of patients), and signs of mesenchymal-inflammatory response. PMID- 28352698 TI - Dermatology patients' and their doctors' representations about adherence. AB - The aim of our study was to identify representations about patient adherence among dermatologists (N=40) and their patients (N=153). A combined qualitative quantitative methodology was applied. Dermatologists identified good doctor patient relationship, information from the doctor, and background information as the most important determinants of adherence. In patients' rankings, information from the doctor and understandable communication received the highest scores. Multidimensional scaling arranged patients' results into four content groups which helped to reveal the structure of the representations. Our results may contribute to the evidence-based confirmation that transparency of views and expectations in doctor-patient communication is a basic determinant of successful adherence. PMID- 28352699 TI - The bilateral strength and power asymmetries in untrained boys. AB - The aim of the study was to identify the level of isokinetic strength and power of lower limbs in 13-year-old untrained boys (n=22, height: 158.5+/-8.0 cm, mass: 49.1+/-12.6 kg), to determine bilateral deficit between the limbs in the tests and examine their mutual relationship. Maximum peak muscle torque of knee extensors (PTQ) and flexors (PTH) on dominant (DL) and non-dominant leg (NL) were measured by isokinetic dynamometer. Three types of a vertical jump: countermovement jump with (CMJFA) and without arms (CMJ) and squat jump (SJ) were performed on two force platforms. We found the significant effect (p<.01) of independent variables (knee extensors, flexors, AV) and their interaction on PT. AV did not indicate any significant effect on bilateral ratio of knee extensors (F4,84=.74, p>.05, etap2=0.03), however a significant effect of AV was found in knee flexors (F4,84=2.70, p<.05, etap2=.114). The type of jump had no effect on the difference between force exerted by DL and NL (F1,21=.102, p>.05, etap2=.01). Bilateral deficit (Q:Q, H:H) did not significantly correlate with bilateral deficit in jumps (p>.05). Despite the possibility of identifying muscle asymmetries in the sense of strength imbalances, their mutual relationship with results in isokinetic dynamometry and power jump tests is still unclear. PMID- 28352700 TI - Urgent arterial embolization of ruptured renal angiomyolipoma. AB - The most undesired complication of renal angiomyolipoma (AML) is bleeding. Because of tumor rupture, the bleeding can spread to the retroperitoneal field and can be severe enough to be life threatening. We report a case of retroperitoneal hemorrhage caused by a ruptured AML that was successfully treated with transarterial embolization with N-butyl cyanoacrylate. PMID- 28352701 TI - Attempt to assess the infiltration of enamel made with experimental preparation using a scanning electron microscope. AB - INTRODUCTION: The resin infiltration technique, a minimally invasive method, involves the saturation, strengthening, and stabilization of demineralized enamel by a mixture of polymer resins without the need to use rotary tools or the risk of losing healthy tooth structures. AIM OF THE STUDY: To design and synthesize an experimental infiltrant with potential bacteriostatic properties.To compare the depth of infiltration of the designed experimental preparation with the infiltrant available in the market using a scanning electron microscope. MATERIAL AND METHODS: Composition of the experimental infiltrant was established after analysis of 1H NMR spectra of the commercially available compounds that can penetrate pores of demineralized enamel. As the infiltrant should have bacteriostatic features by definition, an addition of 1% of monomer containing metronidazole was made. Thirty extracted human teeth were soaked in an acidic solution, which was to provide appropriate conditions for demineralization of enamel. Afterward, each tooth was divided along the coronal-root axis into two zones. One zone had experimental preparation applied to it (the test group), while the other had commercially available Icon (the control group). The teeth were dissected along the long axis and described above underwent initial observation with use of a Hitachi S-4200 scanning electron microscope. RESULTS: It was found that all samples contained only oxygen and carbon, regardless of the concentration of additions introduced into them. The occurrence of carbon is partially because it is a component of the preparation in question and partially because of sputtering of the sample with it. Hydrogen is also a component of the preparation, as a result of its phase composition; however, it cannot be detected by the EDS method. CONCLUSIONS: SEM, in combination with X-ray microanalysis, does not allow one to explicitly assess the depth of penetration of infiltration preparations into enamel.In order to assess the depth of penetration of infiltration preparations with use of X-ray microanalysis, it is recommended to introduce a contrast agent that is approved for use in dental materials, such as ytterbium III fluoride. PMID- 28352702 TI - Platelet to lymphocyte ratio and neutrophil to lymphocyte ratio in patients with rheumatoid arthritis. AB - OBJECTIVES: It has been well documented that the platelet to lymphocyte ratio (PLR) and the neutrophil to lymphocyte ratio (NLR) are associated with outcomes for patients with gastric cancer, non-small cell lung cancer and acute heart failure. Inflammation may be the hidden factor that explains the correlation between NLP, PLR, and these diseases. However, to date, the data concerning NLR, PLR, and its association with inflammation are lacking in patients with rheumatoid arthritis (RA), thus, our aim to discuss whether NLR and PLR are associated with RA. METHODS: Patients with RA and healthy individuals were included according to the determined criteria, and laboratory indicators were measured. RESULTS: PLR and NLR were significantly higher in RA patients compared with healthy controls (3.20+/-2.06 vs. 1.56+/-0.47, P<0.01; 192.85+/-101.78 vs. 103.49+/-28.68, P<0.01). When leukocytes, neutrophil percentage, neutrophil, lymphocyte, platelet, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF) were considered as confounders (crude model), our results indicated that ESR and RF were correlated to RA. Of note, ESR, RF, and PLR were associated with RA after further adjustment based on crude model for PLR and NLR. Receiver operating characteristic (ROC) curves analysis showed that PLR values higher than >115.7 evaluated RA with a sensitivity of 82.5%, a specificity of 74.8% and area under the curve ( AUC ) of 0.847. CONCLUSIONS: Our results suggest that PLR is associated with RA, and PLR may be an underlying indicator indicating the chronic subclinical inflammation in patients with RA. PMID- 28352703 TI - Potential drug interactions with statins: Estonian register-based study. AB - In Estonia, HMG-CoA reductase inhibitors are widely used to modify lipid levels but there are no current data on additional medicines prescribed alongside the statins. The aim of this study was to identify the frequency of potential clinically relevant interactions at a national level among an outpatient population treated with statins between January and June 2008, based on the prescription database of the Estonian Health Insurance Fund. This retrospective prevalence study included 203,646 outpatients aged 50 years or older, of whom 29,367 received statin therapy. The study analysed individuals who had used at least one prescription medicine for a minimum of 7 days concomitantly with statins. Potential drug interactions were analysed using Epocrates online, Stockley's Drug Interactions, and the drug interaction database developed in Estonia. Statins metabolised by the CYP3A4 isoenzyme were prescribed to 64% of all statin users. Medicines known to have potentially clinically significant interactions with statins were prescribed to 4.6% of patients. The drugs prescribed concomitantly most often with simvastatin were warfarin (5.7%) and amiodarone (3.9%), whereas digoxin (1.2%) and ethinylestradiol (2%) were prescribed with atorvastatin. Potential interactions were not detected in the treatment regimens of rosuvastatin, pravastatin, and fluvastatin users. PMID- 28352704 TI - Trefoil factor 3 as a marker of intestinal cell damage during sepsis. AB - OBJECTIVE: Gastrointestinal dysfunction or gut failure frequently occurs in seriously ill patients and can be responsible for multi-organ failure. Trefoil factor 3 (TFF3) was characterized for its role in reconstitution of an epithelial barrier after mucosal injury in the jejunum. The aims of our study was an analysis of TFF3 levels dynamics in patients with sepsis and the correlation of TFF3 with severity of sepsis and mortality. METHODS: Prospective observational study, a ten days evaluation period in children aged 0-19 years with systemic inflammatory response syndrome or septic state. Blood tests to determine levels of TFF3 were obtained as long as the patient met the criteria for systemic inflammatory response syndrome or sepsis. RESULTS: Analysis of dynamics revealed steady levels of TFF3 during the 10 day period evaluated. TFF3 levels could not differentiate between various septic conditions in patients until a marked organ dysfunction developed. Higher Area Under Curve was noticed between control group and patients with sepsis. We could not make any strong conclusions based on mortality model. CONCLUSIONS: Levels of TFF3 are elevated in paediatric patients with sepsis through organ dysfunction. PMID- 28352705 TI - Effect of puerarin on human choriocarcinoma cells. AB - OBJECTIVE: To discuss the effect of puerarin on human choriocarcinoma cells. METHODS: Survival rates under puerarin monotherapy, fluorouracil (5-FU) monotherapy and puerarin in combination with 5-FU were detected by MTT assay. Apoptotic morphology was observed with Hoechst 33258 staining. Apoptosis rates were detected with flow cytometry. Expressions of AKT, mechanistic target of rapamycin (mTOR), and P70S6K mRNAs and phosphorylated proteins were detected by RT-PCR and Western blot. Tumor-bearing mice were administered puerarin and puerarin+5-FU, and serum levels of beta-human chorionic gonadotropin (beta-HCG) were measured. RESULTS: Proliferation inhibition and apoptosis rates of JEG-3 cells were positively correlated with puerarin concentration, which increased in the puerarin+5-FU group. Expression levels of AKT, mTOR, P70S6K mRNAs, and phosphorylated proteins decreased significantly after action of puerarin at different concentrations. With increasing puerarin concentration, expression of cleaved-caspase-3 in JEG-3 cells increased, whereas that of Bcl-2 decreased. Puerarin significantly inhibited tumor growth in choriocarcinoma-bearing SCID mice. Serum beta-HCG levels were significantly lower than those of control group after administration. Magnitude of beta-HCG decline was positively correlated with concentration.. CONCLUSION: Puerarin+5-FU inhibited proliferation of JEG-3 choriocarcinoma cells and promoted their apoptosis, being associated with the mTOR signaling pathway. PMID- 28352706 TI - Profile of adult acute cholinesterase inhibitors substances poisoning - a 30 years analysis. AB - OBJECTIVES: The objective of this study was to assess the pattern and outcome of acute cholinesterase inhibitors substances (CIS) poisoning cases, in a cohort from a regional tertiary care hospital. METHODS: cases admitted in the Toxicology Clinic of "Sf. Spiridon" Emergency Clinic Hospital Iasi, Romania between 1983 and 2013 were studied. RESULTS: a total number of 606 patients were included. The reason for exposures was intentional in 70% of cases and the commonest route of poisoning was oral in 92.2%. The highest percent of cases was females (56.4), the age group 20-29 (25.4%) and the majority (66.7%) coming from rural areas, 28.2% being agricultural workers. 36.6% of cases were severe clinical forms. Overall mortality rates were 3.8%, more than half of the death patients (65.2%) had concomitant alcohol intake. It was a significant statistical association between decrease level of serum cholinesterase on admittance and severe forms (p 0.000) and between survival and deaths groups (p 0.000). The pattern of poisoning described by our retrospective study suggests that CIS poisoning are mainly preventable. The main effective goals for prevention are restriction in free accessibility to toxic pesticides, together with sustained efforts in education concerning the life-threatening danger of pesticide poisoning. PMID- 28352707 TI - Carotid ultrasound for pulmonary arteriovenous malformation screening. AB - OBJECTIVE: In patients with hereditary hemorrhagic telangiectasia (HHT), pulmonary arteriovenous malformations (PAVMs) can cause serious neurological complications. Our aim was to evaluate the potential of contrast-enhanced Doppler ultrasound (CE-US) of the common carotid artery as a screening test for detection of PAVMs. METHODS: A total of 124 consecutive patients with HHT or a positive family history underwent screening for PAVMs with CE-US and thoracic contrast enhanced magnetic resonance angiography (CE-MRA). CE-US was performed after receiving (D)-galactose microparticulate, and CE-MRA with gadobenate dimeglumine. Twenty-five patients with confirmed PAVMs were referred to conventional pulmonary catheter angiography (PA). Findings on CE-US and CE-MRA were evaluated using contingency tables and McNemar's test. RESULTS: Using CE-MRA as the reference test, CE-US had a sensitivity of 100%, a specificity of 87%, and a negative predictive value of 100%. In 25 patients who underwent PA, PAVMs that had been diagnosed on CE-US and CE-MRA were confirmed. Of the PAVMs detected by CE-MRA, 24% were not identified on PA. CONCLUSION: CE-US is a simple, minimally invasive screening method that can easily be performed in different settings. CE-US can predict PAVMs with high probability of success. CE-US may be a simple alternative to transthoracic echocardiography in the assessment of PAVMs in certain HHT patients. PMID- 28352708 TI - The latent cytomegalovirus decreases telomere length by microcompetition. AB - Reduced telomere length has been associated with aging and age-related diseases. Latent infection with the Cytomegalovirus (CMV) induces telomere shortening in the infected cells. Latent CMV infection may cause reduced telomere length via GABP transcription factor deficiency, according to the Microcompetition Theory. Microcompetition and viral-induced transcription factor deficiency is important since most people harbor a latent viral infection. PMID- 28352709 TI - Ketamine in outpatient arthroscopic shoulder surgery: Effects on postoperative pain, hemodynamic stability and process times. AB - BACKGROUND: Pain after arthroscopic shoulder surgery is often severe, and establishing a pain treatment regimen that does not delay discharge can be challenging. The reported ability of ketamine to prevent opioid-induced hyperalgesia has not been investigated in this particular setting. METHODS: 300 adult patients scheduled for shoulder arthroscopy under general anesthesia were recruited for this observational clinical trial and were allotted to either receive 1mg/kg IV bolus of ketamine before surgery (ketamine group, KG) or to a control group (CG) without ketamine. NRS pain scores were obtained on the operative day and on postoperative days 1 and 2 and compared between groups. Secondary variables were blood pressure, heart rate, process times, satisfaction with the anesthetic and unwanted effects. RESULTS: Pain severity did not differ significantly between the groups at any time. Propofol injection rate and cumulative dose were higher in the KG. Heart rates and blood pressures were similar. Time to emergence and time in PACU were longer and vomiting was more frequent in patients given ketamine. CONCLUSION: Preoperative low-dose ketamine added to a general anesthetic does not reduce perioperative pain after outpatient shoulder arthroscopy. It increases procedural times and the incidence of PONV. PMID- 28352710 TI - Differences of plasma IL-1 and TNF-alpha in healthy Chinese Population. AB - Pleiotropic proinflammatory cytokines, interleukin- 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha), involved in the regulations of various immune responses, inflammatory processes and hematopoiesis. In the present study, the expression levels of IL-1 and TNF-alpha were detected by enzyme-linked immunosorbent assay (ELISA). Following the cytokine blockade as a successful clinical therapy for autoimmune diseases such as rheumatoid arthritis, the patients are more susceptible to a variety of opportunistic infections. IL-1 and TNF-alpha may be useful predictive biomarkers of diseases and offer potential targets for therapeutic intervention of inflammatory diseases. However, our results showed that the plasma IL-1 level was significantly higher in women compared to men (69.5 +/- 19.8 pg/ml in men and 80.1 +/- 19.5 pg/ml in women, respectively); the plasma levels of TNF-alpha were higher in men than women (20.8 +/- 4.9 pg/ml and 18.7 +/- 7.1 pg/ml, respectively). The significant gender difference of plasma interleukin-1 (IL-1) and TNF-alpha levels present in healthy adults in Jiangsu Province, China (P=0.002 and P=0.015, respectively), and may be as a hint for sex differences of susceptibility to many diseases and elementary immune response. PMID- 28352711 TI - TVT-Exact and midurethral sling (SLING-IUFT) operative procedures: a randomized study. AB - OBJECTIVES: The aim of the study is to compare results, effectiveness and complications of TVT exact and midurethral sling (SLING-IUFT) operations in the treatment of female stress urinary incontinence (SUI). METHODS: A single center nonblind, randomized study of women with SUI who were randomized to TVT-Exact and SLING-IUFT was performed by one surgeon from April 2009 to April 2011. SUI was diagnosed on coughing and Valsalva test and urodynamics (cystometry and uroflowmetry) were assessed before operation and 1 year after surgery. This was a prospective randomized study. The follow up period was 12 months. 76 patients were operated using the TVT-Exact operation and 78 patients - using the SLING IUFT operation. There was no statistically significant differences between groups for BMI, parity, menopausal status and prolapsed stage (no patients had cystocele greater than stage II). RESULTS: Mean operative time was significantly shorter in the SLING-IUFT group (19 +/- 5.6 min.) compared with the TVT-Exact group (27 +/- 7.1 min.). There were statistically significant differences in the effectiveness of both procedures: TVT-Exact - at 94.5% and SLING-IUFT - at 61.2% after one year. Hospital stay was statistically significantly shorter in the SLING-IUFT group (1. 2 +/- 0.5 days) compared with the TVT-Exact group (3.5 +/- 1.5 days). Statistically significantly fewer complications occurred in the SLING-IUFT group. CONCLUSION: the TVT-Exact and SLING-IUFT operations are both effective for surgical treatment of female stress urinary incontinence. The SLING-IUFT involved a shorter operation time and lower complications rate., the TVT-Exact procedure had statistically significantly more complications than the SLING-IUFT operation, but a higher effectiveness. PMID- 28352712 TI - High serum lactate level may predict death within 24 hours. AB - BACKGROUND: Unexpected death within 24 hours of admission is a real challenge for the clinician in the emergency room. How to diagnose these patients and the right approach to prevent sudden death with 24 hours is still an enigma. The aims of our study were to find the independent factors that may affect the clinical outcome in the first 24 hours of admission to the hospital. METHODS: We performed a retrospective study defining unexpected death within 24 hours of admission in our Department of Medicine in the last 6 years. We found 43 patients who died within 24 hours of admission, and compared their clinical and biochemical characteristics to 6055 consecutive patients who were admitted in that period of time and did not die within the first 24 hours of admission. The parameters that were used include gender, age, temperature, clinical and laboratory criteria for SIRS, arterial blood lactate, and arterial blood pH. RESULTS: Most of the patients who died within 24 hours had sepsis with SIRS. These patients were older (78.6+/-14.7 vs. 65.2+/-20.2 years [p<.0001]), had higher lactate levels (8.0+/ 4.8 vs. 2.1+/-1.8mmol/L [p<.0001]), and lower pH (7.2+/-0.2 vs. 7.4+/-0.1 [p<.0001]). Logistic regression analysis found that lactate was the strongest independent parameter to predict death within 24 hours of admission (OR 1.366 [95% CI 1.235-1.512]), followed by old age (OR 1.048 [95% CI 1.048-1.075] and low arterial blood pH (OR 0.007 [CI <0.001-0.147]). When gender was analyzed, pH was not an independent variable in females (only in males). CONCLUSIONS: The significant independent variable that predicted death within 24 hours of admission was arterial blood lactate level on admission. Older age was also an independent variable; low pH affected only males, but was a less dominant variable. We suggest use of arterial blood lactate level on admission as a bio marker in patients with suspected sepsis admitted to the hospital for risk assessment and prediction of death within 24 hours of admission. PMID- 28352713 TI - Formaldehyde may be found in cosmetic products even when unlabelled. AB - Concomitant contact allergy to formaldehyde and formaldehyde-releasers remains common among patients with allergic contact dermatitis. Concentration of free formaldehyde in cosmetic products within allowed limits have been shown to induce dermatitis from short-term use on normal skin. The aim of this study was to investigate the formaldehyde content of cosmetic products made in Lithuania. 42 samples were analysed with the chromotropic acid (CA) method for semi quantitative formaldehyde determination. These included 24 leave-on (e.g., creams, lotions) and 18 rinse-off (e.g., shampoos, soaps) products. Formaldehyde releasers were declared on the labels of 10 products. No formaldehyde releaser was declared on the label of the only face cream investigated, but levels of free formaldehyde with the CA method was >40 mg/ml and when analysed with a high performance liquid chromatographic method - 532 ppm. According to the EU Cosmetic directive, if the concentration of formaldehyde is above 0.05% a cosmetic product must be labelled "contains formaldehyde". It could be difficult for patients allergic to formaldehyde to avoid contact with products containing it as its presence cannot be determined from the ingredient labelling with certainty. The CA method is a simple and reliable method for detecting formaldehyde presence in cosmetic products. PMID- 28352714 TI - The impact of Tegillarca granosa extract haishengsu on HL-60 cell. AB - Haishengsu (Hss) is a purified protein from Tegillarca granosa that has been used as a traditional Chinese medicine to treat cancer for more than a century. In this study, we observed the impact of Haishengsu (Hss) on the proliferation and differentiation of HL-60 cells in the leukemic cell line by taking tretinoin and AS2O3 as a positive control and making a comparative analysis between the effect of Hss and tretinoin and AS2O3. We found that Hss could significantly inhibit the proliferation of HL-60 cells and caused most of the cells to stay in the G0/G1 phase. Its effect was much stronger than that of tretinoin and AS2O3, and the ability of Hss to induce differentiation was close to tretinoin. Hss functions probably by inhibiting the expression of the Bcl-2 and MPO genes and further promoting the expression of the Bax gene. Hss has a significant effect on both inhibiting the proliferation and inducing the differentiation of HL-60 cells. It is possible that Hss may be a new kind of clinical differentiation inducer. PMID- 28352715 TI - The local spread of pheochromocytoma after adrenalectomy with a rupture of the tumor capsule at the time of the surgery. AB - INTRODUCTION: We present a case of a 29-year-old patient treated due to fully symptomatic pheochromocytoma of the right adrenal gland. CASE PRESENTATION: Patient was operated on and an open right-sided adrenalectomy was performed. At the time of the surgery, a rupture of the tumor capsule occurred. Five years post operatively, a recurrence of the symptoms of chromaffin-cell tumor was noted. After the exact localization of the multiple recurrences, the patient was reoperated on. CONCLUSION: The case of pheochromocytoma is presented due to the possibility of chromaffin-cell seeding into the peritoneum, with no signs of distal metastases so far. PMID- 28352716 TI - Effects of rivastigmine and memantine alone and in combination on learning and memory in rats with scopolamine-induced amnesia. AB - BACKGROUND: Cholinesterase inhibitors and glutamate blockers are commonly used for the treatment of cognitive impairment in Alzheimer's disease. The aim was to evaluate the effects of rivastigmine and memantine alone or in combination in rats with scopolamine-impaired memory. METHOD: 5 groups of rats were used: control, scopolamine (model), model with rivastigmine, model with memantine, and model with both drugs. Active avoidance test was performed and the number of conditioned responses, unconditioned responses and intertrial crossing were recorded. Passive avoidance tests step-through with criteria latency of reaction 180 s in the light chamber and step-down with criteria latency of reaction 60 s on the platform were done. RESULTS: Control rats learned the task and kept it on memory tests. Scopolamine treated rats failed to perform it. The rivastigmine, memantine and its combination groups showed increased CRs during learning and memory retention tests. In both passive avoidance tests an increased latency of reaction was observed in the drug treated groups. CONCLUSION: The combination of both drugs rivastigmine and memantine is more effective than the use of the single drug in cognitive impaired rats. Cholinesterase inhibitors and NMDA blockers may be combined in the treatment of different kind of dementias. PMID- 28352717 TI - Efficacy of mistletoe for chemical pleurodesis in rats without malignancy. AB - Chemical pleurodesis is an effective treatment modality to reduce recurrence of malignant effusion. Several agents have been used in chemical pleurodesis but, it is not yet clear which is better. Eighteen Sprague-Dawley rats were used and classified into three groups: a group intrapleurally injected normal saline (group A, n=6), 400mg/kg talc (group B, n=6), and 9mg/kg mistletoe extraction (ME) (group C, n=6). Autopsy was performed to evaluate the pleural adhesion, pathologic examination of pleura and lung and bronchoalveolar lavage fluid analysis 4 weeks after pleurodesis. Both group B and C showed an obvious pleural adhesion and there was no significant difference in grade of pleural adhesion between two groups (p=0.58). The parietal pleural thickness in talc group than ME group was significantly thicker (p=0.002) and the visceral pleura of talc group showed marked foreign body reaction with fibrosis and many multinucleated giant cells associated with talc crystal. This study suggests that pleurodesis using ME in condition without malignancy has comparable effect to pleurodesis using talc. However, additional experimental study in large animal or clinical trials would be required to prove a safety and an efficacy of pleurodesis using ME. PMID- 28352718 TI - Mastoscopic sentinel lymph node biopsy in breast cancer. AB - BACKGROUND: Previous studies have demonstrated that mastoscopic sentinel lymph node biopsy (MSLNB) has good identification rate (IR) and low false negative rate (FNR). However, few studies have directly compared the surgical performance and peri- and post-operative factors of MSLNB with conventional sentinel lymph node biopsy (SLNB). METHODOLOGY: Sixty patients diagnosed with breast cancer were recruited and randomly assigned to one of the three groups: MSLNB, SLNB and SLNB with lipolysis injection. Peri- and post-operative parameters were compared using general linear models. To examine the effect of age on these parameters, we performed separate analysis stratified by age (<=50 years old vs. >50 years old). RESULTS: Patients in the MSLNB group experienced longer surgery and suffered higher surgical cost than patients who underwent conventional SLNB or SLNB with lipolysis injection (p<0.0001). Despite this, they had significantly less blood loss than those who underwent conventional SLNB (22.0+/-7.0 ml vs.73.5+/-39.6 ml; p<0.0001). Analysis by age group indicates a similar pattern of difference among the three groups. MSLNB and conventional SLNB have similar IR and FNR. CONCLUSION: As a minimally invasive technique, MSLNB can significantly reduce blood loss while providing similar IR and FNR, indicating that it can be a promising alternative to conventional SLNB. CONCLUSION: Variations in popliteal artery terminal branching pattern occurred in 7.4% to 17.6% of patients. Pre surgical detection of these variations with MD CTA may help to reduce the risk of iatrogenic arterial injury by enabling a better surgical treatment plan. PMID- 28352719 TI - Is cognitive processing affected in adults with hypospadias?: P300 study. AB - BACKGROUND: Hypospadias is a common urogenital system disorder. The frenulum, which is the most sensitive area of the glans penis, is not present in patients with hypospadias. This may lead to a failure in sexual and ejaculatory function, and cause emotional problems affecting cognitive processes. AIM: We aimed to study auditory Event Related Potentials (ERP) in patients with hypospadias to understand the status of cognitive function. MATERIALS AND METHODS: Seventeen patients with hypospadias who presented to the Urology Outpatient Clinic of Canakkale Military Hospital, and 11 healthy individuals of similar age were chosen. The auditory oddball paradigm with ERP from the Cz and Fz head regions were studied. The latency and amplitude of the P300 wave were measured. RESULTS: Both, the study and control groups consisted of young males. Although the study group had a longer P300 latency and lower P300 amplitude when compared to control group, the results were not statistically significant (p: 0.059 and 0.346 respectively). CONCLUSION: Although the results are not statistically significant, our findings indicate that there may be cognitive changes in patients with hypospadias. Further studies of larger sample size and older patient cohorts are needed. PMID- 28352720 TI - Trends in the treatment of risk factors for stroke in a Czech stroke unit. AB - The goal of this study is to evaluate therapeutic trends for several diseases that represent risk factors for stroke. The relative frequency of therapy with compounds that influence the risk factors for stroke was monitored in a group of 3,290 patients who were hospitalised in the Stroke Unit at the University Hospital in Hradec Kralove between 2005 and 2012. For most drugs monitored, the reasons for the significant decrease or increase in use were causes other than the reduction of stroke risk. Despite this finding, the majority of statistically significant changes had, according to review of comparative studies, a positive effect on prevention of stroke. Motivation to change treatment of stroke risk factors, such as hypertension, diabetes mellitus and hypercholesterolemia, was mainly aimed at sufficient disease management with a minimum of adverse effects. On the other hand, optimization of stroke recurrence and economic factors were motivations to treatment changes in prevention with antiplatelets. Antidiabetics were associated with an increase in metformin use and reduction in insulin use. For antihypertensives, the most significant reduction was associated with the use of diuretics, although calcium channel blockers and beta-blockers are also less used. Additionally, the use of the ACE inhibitor ramipril increased. PMID- 28352722 TI - Application of Food-specific IgG Antibody Detection in Allergy Dermatosis. AB - The application of food-specific IgG antibody detection in allergy dermatoses was explored. 181 patients with allergy dermatoses were diagnosed from January to September 2014 and 20 healthy subjects were selected. Fourteen kinds of food specific IgG antibodies were detected by ELISA method among all the subjects. The positive rates of IgG antibody of the patient group and the healthy group were respectively 65.2% and 5.0%. The positive rates of IgG antibody of egg, milk, shrimp and crab took a large proportion in three groups of patients with three kinds of allergy dermatoses of urticaria, eczema and allergic dermatitis, the proportion of which was respectively 70.2%, 77.8% and 71.7%. Among urticaria and allergic dermatitis patients with positive antibody, the positive rate of children was significantly higher than that of adults (p<0.05) while there was no significant difference between children and adults among eczema patients with positive antibody (p>0.05). Allergy dermatoses are closely related to food specific IgG antibodies, and the allergy dermatoses patients have a high incidence rate of food intolerance; detecting IgG antibody in the serum of patients is of great significance for the diagnosis and treatment of allergy dermatoses. PMID- 28352721 TI - Complete acromioclavicular joint dislocation treated with reconstructed ligament by trapezius muscle fascia and observation of fascial metaplasia. AB - We evaluated the long-term clinical results of acute complete acromioclavicular dislocations treated by reconstruction of the acromioclavicular and coracoclavicular ligament using trapezius muscle fascia. Open reduction and internal fixation was performed using the clavicular hook plate in 12 patients with acute complete acromioclavicular joint dislocation, and the acromioclavicular and coracoclavicular ligaments were reconstructed using trapezius muscle fascia. Radiographic evaluations were conducted postoperatively. We evaluated the functional results with constant scoring system and radiological results at the final follow-up visit. The mean Constant score at the final follow up visit was 91.67 (range, 81 to 100). The results were excellent in eight patients (66.7%) and good in four patients (33.3%). Three patients with scores from 80 to 90 had mild pain during activity, but this did not affect the range of motion of the shoulder. All patients have returned to their preoperative work without any limitations. Compared with the contralateral side, radiography showed anatomical reposition in the vertical plane in all cases. The hook-plate fixation with ligament reconstruction was successful in treating AC dislocations. The acromioclavicular and coracoclavicular ligament were reconstructed by trapezius muscle fascia that keep the distal clavicle stable both vertically and horizontally after type III injuries. PMID- 28352723 TI - Analysis of the Best Timing for Applying Tirofiban in PCI Operation for the Patients with ST Segment Elevation Myocardial Infarction. AB - : This study is a comparative analysis of the best timing for applying tirofiban in the PCI emergency treatment for STEMI patients. We selected 109 patients with ST-segment elevation myocardial infarction from October 2013 to October 2014 and divided them into two groups, the early treatment group (53 cases) received tirofiban during the operation and the later treatment group (56 cases) received tirofiban after operation. The analysis was then conducted. RESULTS: The proportion of IRA forward flow in TIMI2-3 for the 1st group during the radiography was higher than 2nd group, 50 cases with TIMI3 blood flow and 52 cases with TIMI3 blood flow in later treatment group. Comparing the TIMI3 flow of both groups, the difference was not statistically significant; for the CK-MB 4h and 8h after operation as well as the LVEF after operation, the differences are were not statistically significant. The occurrence rate of hemorrhage complication was low for both groups. The early use of tirofiban can make the thrombus fully dissolve and coronary blood flow remains in a good state, which is not only beneficial for myocardial perfusion but also helpful for deciding the length and side branch situation of coronary artery pathological changes. PMID- 28352724 TI - Research into the Value of B-Mode Ultrasound, CT and MRI Examinations in the Diagnosis of Preoperative Myometrial Infiltration of Endometrial Cancer and Lymph Node Metastasis. AB - This study is conducted to observe the diagnostic value of B-mode ultrasound, CT and MRI examinations in preoperative myometrial infiltration of endometrial cancer and lymph node metastasis. Retrospectively analyze 50 cases of the patients from Oct. 2010 to Aug. 2013. Before operation all the patients received dilatation & curettage to determine pathological diagnosis and clinical staging. There were 150 cases of patients who received B-mode ultrasound examination, wherein, 93 cases received CT examination and 57 cases received MRI examination as well. In the diagnosis of MIEC the diagnostic indicies of individual MRI examination were higher than that of individual B-mode ultrasound and CT examinations. Consistency of individual MRI examination with pathological diagnosis was significantly higher than that of B-mode and CT examinations. The sensitivity of CT and MRI was significantly higher than that of B-mode ultrasound examination. However, diagnostic indicators of B-mode ultrasound and CT joint examination were higher than B-mode ultrasound examination alone. The consistency of both with pathological diagnosis was significantly increased. B-mode and CT can significantly improve the diagnostic accuracy and has a good consistency with pathological diagnosis, thereby applicable to the clinical diagnosis of preoperative myometrial infiltration of endometrial cancer and lymph node metastasis. PMID- 28352725 TI - Influence of COPD Assessment Text (CAT) evaluation and rehabilitation education guidance on the respiratory and motor functions of COPD patients. AB - The study aimed to evaluate the influence of the COPD Assessment Test (CAT) evaluation and rehabilitation education guidance on the respiratory and motor functions of patients with chronic obstructive pulmonary disease (COPD). Forty five patients with COPD admitted from Nov. 2012 to Nov. 2013 were treated with combined bronchodilators and inhaled corticosteroids. Thirty-five patients admitted from Nov. 2012 to Nov. 2013 and classified as a study group received rehabilitation education guidance on the basis of the treatment of the control group to compare the quality-of-life-scale score, dyspnea index score, and motor function of the two groups of patients after 48 weeks of treatment. After treatment, the CAT score of both groups of patients was significantly lowered. After 48 weeks of treatment, the respiratory function of both groups was significantly improved, but the Medical Research Council (MRC) scale for the study group after treatment was significantly lower than that for the control group. After 48 weeks of rehabilitation exercises, the 6-minute walk test (6MWT) for patients with COPD was significantly prolonged, but the test results were significantly higher for the study group after treatment than for the control group. After receiving CAT rehabilitation education, COPD patients had significantly improved life quality and significantly enhanced exercise tolerance. The treatment mode may be gradually introduced in future clinic and nursing work. PMID- 28352726 TI - Research into the Predictive Effect of TEG in the Changes of Coagulation Functions of the Patients with Traumatic Brain Hemorrhage. AB - To analyze the predictive effect of thrombelastogram (TEG) in the changes of coagulation functions of patients with traumatic brain hemorrhage, as well as to provide a practice basis for clinical guidance. 54 cases were observed from Aug. 2013-Oct. 2014. All patients received a TEG test 1d, 3d and 7d after traumatic injury. According to the statistical analysis, the comparison among the aforementioned coagulation function parameters in each group of patients, K, alpha and Ma all had significant differences. In the comparison between different time points in the same group, there was still a significant difference. Compared to the patients, the changes of R and K reached the lowest at 1d and the highest at 3d, but there was no significant difference between two groups at 7d. The changes of alpha and Ma reached its highest at 1d and the lowest at 3d after traumatic injury, but there was no significant difference at 7d. There was some difference in changes of coagulation functions between all groups. The former was more serious and the changes of coagulation functions had certain regularity, i.e., after traumatic injury, 1d showed a hypercoagulable state; 3d showed a hypocoagulable state; the coagulation functions of 7d returned to normal. PMID- 28352727 TI - Analysis of the relations between allergen specific LgG antibody and allergic dermatosis of 14 kinds foods. AB - To use food-specific IgG antibody detection to explore its application in the allergy dermatoses. 181 patients were included from January 2014 to September 2014. Fourteen food-specific IgG antibodies were detected by ELISA. The positive rates of IgG antibody of the patient group and the healthy group were significantly different. The positive rates of IgG antibody of egg, milk, shrimp and crab took a large proportion in three groups of patients with three kinds of allergy dermatoses of urticaria, eczema and allergic dermatitis, the proportion of which was respectively 70.2%, 77.8% and 71.7%. There was mild and moderate intolerance of food in the allergic dermatitis group while there was no distribution difference of food intolerance in urticaria group and eczema group. Among urticaria and allergic dermatitis patients with positive antibody, the positive rate of children was significantly higher than that of adults while there was no significant difference between children and adults among eczema patients with positive antibody. Allergy dermatoses are closely related to food specific IgG antibody and the allergy dermatoses patients have a high incidence rate of food intolerance; detecting IgG antibody in patients is of great significance for the diagnosis and treatment of allergy dermatoses. PMID- 28352728 TI - Comparative study of the clinical effect and safety of anterior surgical approach and posterior surgical approach in the treatment of thoracolumbar spinal fracture. AB - The clinical effect and safety of the anterior surgical approach and posterior surgical approach in the treatment of thoracolumbar spinal fracture was compared. Retrospective analyses of clinical data for 91 patients observed from March 2010 to September 2014 were made. The pre-operation and post-operation comparisons between two sets of Cobb's angle, affected vertebra height, Frankel's classification of spinal nerves, motion functions, and tactile functions showed statistically significant differences (P<0.05). After having the operation, the Cobb's angle and affected vertebra height of the patient in the anterior approach group were both significantly higher than that of patients in the posterior approach group (P<0.05). The bone graft fusion rate of the patients in the anterior approach group 3 months after operation was higher than that of patients in the control group while the status of complications was worse than that of patients in the posterior approach group, both with a remarkable difference (P<0.05). Both the anterior surgical approach and posterior surgical approach have good clinical outcome for spinal fractures but they all have their respective adaption diseases. The key in the treatment of thoracolumbar spinal fractures lies in choosing proper operative approach. PMID- 28352729 TI - Feasibility and safety of prophylactic tentorium cerebelli hiatus incision in surgery of glioma located in lateral fissure area. AB - To discuss the feasibility and safety of prophylactic tentorium cerebelli hiatus incision in surgery of glioma located in lateral fissure area. There were 80 patients with glioma located in lateral fissure area who received treatment from May 2012 to May 2015, divided into two groups, the research group (n=40) and control group (n=40), and then statistical analysis was carried out. Difference in total resection rate and subtotal resection rate of glioma between patients of the research group and those of the control group was not significant (P>0.05); intracranial pressure of patients in the research group was significantly lower than that of control group (P<0.05), their hospital stay was significantly shorter than that of the control group (P<0.05), times of using mannitol were significantly fewer than control group (P<0.05), but the differences of acute renal function damage and second surgery occurrence rate between patients of the two groups were not significant (P>0.05). Prophylactic tentorium cerebelli hiatus incision in surgery of glioma located in lateral fissure area can effectively reduce patients' intracranial pressure, shorten patients' hospital stay and reduce patients' times of using mannitol without increasing the rate of patients' acute renal function damage and second surgery. PMID- 28352730 TI - Laparoscopic splenectomy and porto-azygos disconnection: clinical research in the treatment of portal hypertension. AB - To investigate the safety and efficacy of laparoscopic splenectomy and portaazygous devascularization, we studied laparoscopic splenectomy and porto azygos devascularization patients within the peri-operative period. Clinical data and curative effect are detailed alongside statistical analysis. The laparoscopic splenectomy and porto-azygos devascularization operation time was 2.56 + 0.62 hours. The intraoperative bleeding and anal exhaust time was 149.5 + 32.7ml 3.47 + 1.32 days, and the hospitalization time was 5.05 + 1.22 days. When the spleen volume was greater than or equal to 1.5 liters, the rate of open abdominal surgery increased significantly. After 1, 2, 3, and 4 years of follow-up, cumulative recurrence bleeding rates were 0, 5.20%, 9.98%, and 15.83%, respectively. Laparoscopic splenectomy and pericardial devascularization is safe, effective, and feasible, and it can be confirmed by enhanced spiral computed tomography (CT). Whether spleen volume greater than 1.5L is suited to laparoscopic surgery requires further research. PMID- 28352731 TI - Artifacts reduction in strain maps of tagged magnetic resonance imaging using harmonic phase. AB - Tagged Magnetic Resonance Imaging (MRI) is a noninvasive technique for examining myocardial function and deformation. Tagged MRI can also be used in quasi-static MR elastography to acquire strain maps of other biological soft tissues. Harmonic phase (HARP) provides automatic and rapid analysis of tagged MR images for the quantification and visualization of myocardial strain. We propose a new artifact reduction method in strain maps. Image intensity of the DC component is estimated and subtracted from spatial modulation of magnetization (SPAMM) tagged MR images. DC peak interference in harmonic phase extraction is greatly reduced after DC component subtraction. The proposed method is validated using both simulated and MR acquired tagged images. Strain maps are obtained with better accuracy and smoothness after DC component subtraction. PMID- 28352732 TI - Assessment of the feasibility of TACE combined with intratumoral injection of cisplatin in hepatocellular carcinoma. AB - The feasibility of transcatheter arterial chemo-embolization (TACE) combined with intratumoral injection of cisplatin as treatment for hepatocellular carcinoma. 30 cases receiving TACE were denoted the TACE group, another 30 cases receiving TACE combined with an intratumoral multi-point injection of cisplatin were denoted the TACE/cisplatin group. Cases with partial remission/complete remission (PR/CR) were analyzed using 2 tests; alpha fetoprotein (AFP), aspartate amino transferase (AST), total bilirubin (TBIL), erythrocyte, and platelet levels were detected and the differences between two groups were analyzed using the Student's t-test; cases with complications, including intrahepatic metastasis (IM), upper gastrointestinal bleeding (UGB), and liver failure were also counted. The correlation of clinical parameters with PR/CR was analyzed using multifactorial correlation analysis. Cases with PR/CR in the TACE/cisplatin group were significantly more than in TACE group, accompanied by significant declination in FAP. There were no significant differences of AST, ALT, TBIL, blood urea nitrogen (BUN), white blood cells (WBC), red blood cells (RBC), and platelets (PLT) between two groups; 3 cases with IM, one case with UGB and one case with LF were found in the TACE group, but only 1 case with IM was found in the TACE/cisplatin group. In addition, tumor stage was correlated with PR/CR. We concluded that TACE combined with intratumoral injection of cisplatin was more effective than TACE, and with fewer complications and side effects. PMID- 28352733 TI - Study on correlation between bone marrow edema, stage of necrosis and area ratio of necrosis with the hip pain grading in nontraumatic osteonecrosis of the femoral head. AB - The objective of this study was to explore the correlation between bone marrow edema, stage of necrosis, and area ratio of necrosis with the hip pain grading in non-traumatic osteonecrosis of the femoral head. Bone marrow edema grading at all levels and the hip pain grade differences were statistically significant (P < 0.001). Bone marrow edema grading increased by levels of 0, 1, and 2, whereas average pain rating increased as well to 40.73, 104.66 and 143.49. I ~ III period stage of necrosis and the hip pain grade difference was statistically significant (P < 0.001), with the average grade progress pain stage by the death of a rank gradually increased, I period, II period, III period was 57.00, 88.58 and 120.62, respectively. Area ratio of necrosis between 0 ~ 3 were positively correlated with pain, compared the two was statistically significant (P < 0.001), and with the degree of pathological changes is aggravating, increase the average rank of levels of pain. 0, 1, 2 and 3 are 36.88, 98.03, 123.87 and 151.93 respectively. We can choose the treatment method and evaluate treatment effect by considering a patients' degree of bone marrow edema, stage of necrosis and area ratio of necrosis. PMID- 28352734 TI - The pharmacological research of Tek-1 relevance to anti-neuroinflammation, a candidate compound based on Telmisartan. AB - In this paper, BV-2 mouse small glial cell inflammation model induced by LPS is established. The experiment used 0.1-10 MUM of telmisartan and Tek-1 to incubate with small glial cell and used telmisartan and Tek-1 to incubate with PPAR gamma special heterosexual antagonistic anti-agent GW9662. The article used ELISA method to dectect TNF-a effect on small glial cell for telmisartan and Tek-1. The article used real-time quantitative PCR method to dectect mRNA level expression effect of CD11b, CD16 and iNOS on small glial cell for telmisartan and Tek-1 and used Western Blot method to dectect MAPKs signal pathway and NF-kappab signal turned guide pathway effect on small glial cell for telmisartan and Tek-1. Results show that Tek-1 had high affinity with AT1 receptor and inhibited intracellular calcium ion activation which can be for the AT1 receptor antagonists. Meanwhile, Tek-1 can partially activate PPAR gamma compared with full agonists of rosiglitazone. PMID- 28352735 TI - The application of moist dressing in treating burn wound. AB - Basic experiments have demonstrated that the effect of wound healing in moist environments is better than that in dry environments; therefore, research on moist dressing is the focus of wound healing research. 42 burn patients receiving treatment in Jiangsu Provincial People's Hospital were selected as experimental cases. Wound surface is divided into treatment group and control group using a self-contrasted method. The treatment group received a moist dressing in the treatment of burn wounds and the control group adopted iodine gauze or Vaseline gauze coverage. Wound healing effect and the impact on the degree of pain of in the two different treatment methods were observed after treatment. The results of 42 patients were included in the analysis. The average healing time of patients' burn wounds in treatment group is (10.9 3.3) d, and the average healing time in control group is (13.8 3.6) d, so, the difference is significant (P<0.01). Wound pain in the treatment group is significantly lower than that in the control group (P<0.01). Using moist dressing (Mepitel and Mepilex, etc.) in the treatment of burn wounds, wound-healing time can be shortened and wound pain can be reduced significantly. PMID- 28352737 TI - The role of 99mTc-MIBI SPECT-CT in reoperation therapy of persistent hyperparathyroidism patients. AB - To compare the role of 99mTc-MIBI SPECT-CT image and US in reoperation of persistent secondary hyperparathyroidism patients. A total of 8 persistent secondary hyperparathyroidism patients underwent parathyroidectomy. The sensitivity and accuracy of US and 99mTc-MIBI images before operation were determined. 9 of 14 surgical resection tissues from 8 persistent secondary hyperparathyroidism patients were confirmed to parathyroid hyperplasia. The results showed that the sensitivities were 77.8% and 100%, respectively, for US and 99mTc-MIBI SPECT-CT images. And the accuracies of US and 99mTc-MIBI dual time planar image and SPECT-CT were 50%, 78.6%, respectively. There was significantly difference between two procedures (P=0.021). The superior and inferior localization of glands were both detected by the ultrasound and scintigraphy. Two ectopic parathyroidism nodules were found by 99mTc-MIBI SPECT-CT imaging, while US provided no consistent findings. There was no significantly difference between two procedures (P=0.3). Although two cases of them were not confirmed by pathology, the iPTH of them (800 and 1429 respectively) were much higher than other four cases (<400) pg/ml. PTX is a safe and effective treatment for the patients with persistent SHPT. 99mTc-MIBI planar and SPECT-CT imaging may provide more helps for clinician's localization the hyperparathyroidism glands accurately. PMID- 28352736 TI - Method and effect of total knee arthroplasty osteotomy and soft tissue release for serious knee joint space narrowing. AB - To discuss the method and effect of total knee arthroplasty osteotomy and soft tissue release for serious knee joint space narrowing. Clinical data of 80 patients from October 2013 to December 2014 was selected with a retrospective method. All patients have undergone total knee arthroplasty. Then the X-rays plain film in weight loading was measured before and after operation and osteotomy was performed accurately according to the knee joint scores and the conditions of lower limb alignments. The average angle of tibial plateau osteotomy of postoperative patients was 4.3 degrees , and the corrective angle of soft tissue balancing was 10.7 degrees ; the postoperative patients' indicies including range of joint motion, knee joint HSS score, angle between articular surfaces, tibial angle, femoral-tibial angle and flexion contracture were distinctly better than the preoperative indicies (p<0.05) and the differences were statistically significant; the postoperative patients' flexion contracture and range of joint motion were distinctly better than the preoperative indicies (p<0.05) and the differences were statistically significant. The effective release of the soft tissue of the posterior joint capsule under direct vision can avoid excess osteotomy and get satisfactory knee replacement space without influencing the patients' joint recovery. PMID- 28352738 TI - Study of the Correlation between the Level of CRP and Chemerin of Serum and the Occurrence and Development of DN. AB - The aim of the study was to find the correlation between CRP and chemerin in development of DN. We choose 90 type-2 diabetic patients between February 2010 and February 2013, who were then divided into DN group and healthy control group. The results of BP showed that there is no difference in SBP and DBP of patients in the three groups. HDL-C of patients in diabetic group and DN group is lower compared with control. CRP in diabetic group and DN group is higher than that of patients in control group. Comparing the patients in DN group with that in diabeteic group, CRP was significantly higher. Chemerin level in the diabetic group and DN group is higher than control group. When comparing the patients in DN group with those in diabeteic group, serum level of chemerin was significantly higher. Serum level of chemerin is negatively correlated with HDL-C and positively correlated with FPG, HbA1c, LDL-C, BUN and Scr. Serum CRP is negatively correlated with HDL-C and positively correlated with FPG, HbA1c, LDL C, BUN and Scr. Serum level of chemerin is positively correlated with CRP (r=0.701, P<0.05). CRP and chemerin of the DN patients rose significantly, and may participate in the occurrence and development of DN. PMID- 28352739 TI - Quaternary ammonium salt of chitosan: preparation and antimicrobial property for paper. AB - A series of 2-hydroxypropyltrimethyl ammonium chloride chitosan (HACC) was prepared by the reaction of chitosan with glycidyl trimethyl ammonium chloride. Structure of HACC was characterized by FT IR and 1H NMR spectroscopies, and it was proved that substitution reaction mainly occurs on the N element. Antimicrobial activities of HACC was examined against S. aureus, E. coli, and A. niger. Results indicatd that the inhibitory effects of HACC solutions were varied with HACC concentration, quaternization degrees, pH values, metal ions, and heat treatment. The antimicrobial properties of handsheets prepared from HACC were studied by the inhibition zone method, and the sheets had good antimicrobial properties against S. aureus and E. coli, and low inhibition rate against A. niger. PMID- 28352740 TI - Research on the treatment of Pseudomonas aeruginosa pneumonia in children by macrolide antibiotics. AB - To observe a therapeutic effect of macrolide antibiotics in children with Pseudomonas aeruginosa pneumonia. Fifty-four cases of children with Pseudomonas aeruginosa pneumonia were randomly divided into an observation group (n=30) and a control group (n=24). The observation group was treated with macrolide antibiotics and cefoperazone/sulbactam. The control group was treated with cefoperazone/sulbactam during a course of 10-14 days. The total effective rate was 93.3% in the observation group, and 58.3% in the control group, and results in the observation group were superior to the control group notably (P>0.05). There were no significant differences in bacterial clearance rate, adverse reaction rate between two groups (P>0.05). The combined application of cefoperazone/sulbactam with macrolide antibiotics to treat Pseudomonas aeruginosa pneumonia in children would be a more effective clinical method. PMID- 28352741 TI - Variants of the popliteal artery terminal branches as detected by multidetector ct angiography. AB - OBJECTIVE: To evaluate variants of the popliteal artery (PA) terminal branches with 64-multidetector computed tomographic angiography (64-MD CTA). MATERIALS AND METHODS: A total of 495 extremities (251 right, 244 left) of 253 patients undergoing a 64-MD CTA examination were included in the study. Of these, 242 extremities were evaluated bilaterally, whereas 11 were evaluated unilaterally. The terminal branching pattern of the PA was classified according to the classification scheme proposed by Kim; the distance between the medial tibial plateau and the origin of the anterior tibial artery (A) and the length of the tibioperoneal trunk (B) have been measured and recorded. RESULTS: In 459 cases (92.7%) branching of PA occurred distal to the knee joint (Type I); in 18 cases (2.8%) PA branching was superior to the knee joint (Type II); and hypoplasia of the PA branches was found in 27 cases (5.5%) (Type III). Among these types the most frequent branching patterns were Type IA (87.5%), Type IIIA (3.9%), and Type IB (3.8%). The ranges of A and B mean distances were 47.6 mm and 29.6 mm, respectively. CONCLUSION: Variations in popliteal artery terminal branching pattern occurred in 7.4% to 17.6% of patients. Pre-surgical detection of these variations with MD CTA may help to reduce the risk of iatrogenic arterial injury by enabling a better surgical treatment plan. PMID- 28352742 TI - An uncommon case of arterial aneurysms association with high plasma levels of Matrix Metalloproteinase-9 and Neutrophil Gelatinase-Associated Lipocalin. AB - The association of an axillary artery aneurysm and an abdominal aortic aneurysm is extremely rare. In this study, we describe this association in a 69 year-old man. We measured this patient's metalloproteinases (MMPs) and Neutrophil Gelatinase - Associated Lipocalin (NGAL) levels over a three years period before the abdominal aortic aneurysm rupture. We speculate that high serium levels of MMPs and NGAL may have a prognostic role and may predict aneurysm rupture in patients with an uncommon association of arterial aneurysms. PMID- 28352743 TI - An unusual evolution of a case of Klippel-Trenaunay syndrome. AB - Klippel-Trenaunay syndrome (KTS) is a rare congenital disorder. KTS can be diagnosed on the basis of any 2 of 3 features: cutaneous capillary malformations, soft tissue or bony hypertrophy and varicose veins. We present an unusual case of KTS complicated by an infection of venous ulcers of the lower limb by larvae. The treatment of infection was a complete debridement; however baseline treatment of KTS is still in evaluation. PMID- 28352744 TI - Epithelioid hemangioma of brachial artery: report of a case and review of the literature. AB - Epithelioid hemangioma (EH) is an uncommon benign vascular lesion, also known as angioblastic lymphoid (or angiolymphoid) hyperplasia with eosinophilia, characterized by an unclear etiopathogenesis. It usually affects young to middle aged adults and develops in the head and neck region, as painless cutaneous or subcutaneous reddish papules or nodules. Large vessels involvement is extremely rare, and to date only two cases affecting the brachial artery have been cited in literature. In this report we present a further case of EH of the brachial artery and review the pertinent literature. PMID- 28352745 TI - Our experience of liver Epithelioid Hemangioendothelioma: from a misdiagnosis to liver transplantation with long term follow-up. AB - Malignant Hepatic Epithelioid hemangioendothelioma (HEHE) is an uncommon vascular tumor of intermediate malignant potential. HEHE is a rare tumor and it is difficult to diagnose for surgeons, hepatologists, radiologists and pathologists. So, misdiagnosis with a delay of the treatment is not uncommon. We describe a case of a young woman with a diagnosis of HEHE made 6 years after the first evidence of liver mass with a very long term follow-up after surgical treatment. She had two diagnoses of Hepatocellurar carcinoma (HCC) and a diagnosis of Cholangiocarcinoma after three different fine needle biopsies. After clinical observation, a new laparoscopic core biopsy was performed. In a first time approach, considering clinical and radiological patterns, a diagnosis of Budd Chiari Syndrome was finally made. For that the patient underwent an orthotopicliver transplantation (OLTx). The surgical sample histological analysis allowed a definitive diagnosis of HEHE. At last, at follow up 7 years after three OLTx the patient is still alive and in good health with no evidence of recurrence. PMID- 28352746 TI - A case of Multiple Unilateral Pulmonary arteriovenous Malformation Relapse: Efficacy of embolization treatment. AB - Pulmonary arteriovenous Malformations (PAVMs) are a rare vascular alteration characterized by abnormal communications between the pulmonary arteries and veins resulting in an extracardiac right-to-left (R-L) shunt. The majority of PAVMs are associated with an autosomal dominant vascular disorder also known as Osler-Weber Rendu Syndrome. PAVMs appearance can be both single and multiple. Clinical manifestations include hypoxemia, dyspnea cyanosis, hemoptysis and cerebrovascular ischemic events or abscesses. We report a case of an 18 year old female with severe respiratory failure caused by a relapse of multiple unilateral pulmonary arterovenous fistula. Symptoms at admission include dyspnea, cyanosis and clubbing. The patient underwent pulmonary angio-TC scan, brain CT and echocardiography. The thoracic angio-CT scan showed the presence of PAVMs of RUL and RLL; a marked increase of right bronchial artery caliber and its branches with an aneurismatic dilatation was also observed. The patient underwent percutaneous transcatheter embolization using Amplatzer Vascular Plug IV; a relevant clinical and functional improvement was subsequently recorded. Embolization is effective in the treatment of relapsing PAVMS. PMID- 28352747 TI - Venous aneurysm complicating arteriovenous fistula access and matrix metalloproteinases. AB - INTRODUCTION: An arteriovenous fistula (AVF) for placed for hemodialysis may be burdened by one particular complication-the formation of a venous aneurysm. It has been shown that matrix metalloproteinases (MMPs) and neutrophil gelatinase associated lipocalin (NGAL) could represent markers of disease in both venous and arterial vessels. MATERIALS AND METHODS: This case study reports a rare case of enormous venous aneurysm-correlated MMP and NGAL levels in a woman with an AVF. RESULTS: Significantly higher levels of plasma MMP-1, MMP-8, MMP-9, and NGAL were detected in this patient during aneurysmal evaluation before the surgery; these levels significantly decreased 1, 3 and 6 months after surgery. CONCLUSION: MMP and NGAL levels could represent a marker of aneurysmal disease, and their plasma evaluation could help physicians to stratify the risk of complications in patients with an AVF. PMID- 28352748 TI - Cavernous hemangioma of rhinopharynx: our experience and review of literature. AB - Hemangiomas are benign tumors originating in the vascular tissues of skin, mucosa, muscles, glands, and bones. Although these tumors are common lesions of the head and neck, they rarely occur in the nasal cavity and paranasal sinuses. Cavernous haemangioma of the lateral wall of the nasopharynx has not previously been reported. We examined the clinical, radiological and therapeutic management of cavernous haemangioma of nasopharynx starting from a clinical case of a 26 year-old woman with a history of recurrent and conspicuous epistaxis and left sided nasal associated severe obstruction. Nasopharynx examination, by flexible endoscopy, showed a cystic mass borne by the left side wall of the nasopharynx, in contact with the soft palate, covered by intact and regular mucosa. Contrast enhanced computed tomography (CT) scan, confirmed these findings and showed contextual lamellar calcifications and inhomogeneous enhancement. The nasal endoscopic approach (FESS), under general anesthesia, allowed removal of the mass, without complications, after careful hemostasis of arterial branches. It was possible to establish the precise site of origin of the tumor only during the surgical procedure. Histopathological study showed mucosa with extensive vascular proliferation, with framework of lacunar/cavernous haemangioma, also present at lamellar bone tissue level. An unusual site and an unspecific clinical appearance can make diagnosis and treatment of a cavernous hemangioma of the nasopharynx difficult. The nasal endoscopic technique proved to be reliable in terms of adequate exposure and visualization of the lesion, control of bleeding, and complete removal of the mass. PMID- 28352749 TI - Hemangiomas of the maxillofacial area: Case Report, Classification and Treatment Planning. AB - Vascular lesions of the maxillofacial area are even more challenging than in other different body district, because of the high aesthetic and functional relevance of this area for the sense organs presence like eye, brain, tongue, ear and nose. For these reasons, we propose an accurate classification based on hemodynamic and histologic aspects usefulthat is for diagnostic and therapeutic planning. A female, 60 years old patient came to our observation showing a vascular lesion of the lower left lip, and complaining for aesthetical and functional impairment. To confirm the diagnosis of vascular malformation and to detect lesion flow rate or other possible localization, a Tc red blood cell scintigraphy was carried out. Result was a venous low flow lesion; hence, sclerotherapy by a 3% Polidocanol solution (Atossisclerol) followed by surgery was planned. The aim of this work was to propose a diagnostic and therapeutic scheme with an integration of ISSVA and a flow rate classifications for a three step planning based on 1) the biological findings in an early age at the lesion discover with a pharmacological treatment; 2) Hemodynamic study of the lesions at growing age followed by sclerotherapy or embolization; 3) Imaging study of these lesions for patients candidate to surgery when after step 1 and step 2 diagnostic and therapeutic planning results were incompletely successful. PMID- 28352750 TI - Abnormal right hepatic artery injury resulting in right hepatic atrophy: diagnosed by laparoscopic cholecystectomy. AB - An intact hepatic artery is the gateway to successful hepato-biliary surgery. Introduction of laproscopic cholecystectomy (LC) has stimulated a renewed interest in the anatomy of hepatic artery. In this case report we have highlighted importance of variations of right hepatic artery in terms of origin and course We present a rare asymptomatic case of liver atrophy due to an intraoperative lesion of right hepatic artery. We also performed a literature review about surgical vascular lesions and tried to confirm the right concept behind "non trivial procedure" of the LC. PMID- 28352751 TI - Tailored treatment of intestinal angiodysplasia in elderly. AB - BACKGROUND: Angiodysplasia of the gastrointestinal tract is an uncommon, but not rare, cause of bleeding and severe anemia in elderly. Different treatments exist for this kind of pathology. METHODS: The aim of this work was to study 40 patients treated for intestinal angiodysplasia with two different kind of endoscopic treatments: argon plasma coagulation (APC) and bipolar electrocoagulation (BEC). RESULTS: Age of patients was similar in both groups (76,2 +/- 10.8 years vs 74,8 +/- 8,7 years, P = 0,005). Angiodysplasia treated were located in small bowel, right colon, left colon, transverse colon and cecum. We analysed number of treatment, recurrence, hospital discharge, needs of blood transfusions before and after endoscopic treatment. Number of treatment was the same in both groups (1,2 +/- 0,2 vs 1,1 +/- 0,1, P < 0,001). We had more recurrence in patients treated with BEC (4/20 vs 2/20, P < 0,001). Hospital discharge was comparable in both groups (5,3 +/- 3,1 days vs 5,4 +/- 2,8 years, P < 0.001). CONCLUSIONS: Treatment of angiodysplasia in elderly is not easy. Different kinds of treatment could be adopted. APC and BEC are both safe and effective. The choice of a treatment should consider several factors: age, comorbidity, source of bleeding. In conclusion we think that treatment of bleeding for angiodysplasia in elder population should be a tailored treatment. PMID- 28352752 TI - Bowel Angiodysplasia and Myocardial Infarction secondary to an ischaemic imbalance: a case report. AB - Angiodysplasia, defined as a vascular ectasia or arteriovenous malformation, is the most frequent cause of occult bleeding in patients older than 60 years and a significant association with several cardiac condition is described. Patients with anemia and negative findings on upper endoscopy and colonoscopy should be referred for further investigation of the small bowel. The investigation of choice, when available, is wireless capsule endoscopy. Several therapeutic options are available in this cases, as we reviewed in this report. We report a case of 78-year old man admitted to our Intensive Coronary Unit for dyspnea and chest pain. A diagnosis of non-ST-segment elevation acute coronary syndrome was made and a concomintant, significant anemia was found (hemoglobin 8.2 g/dl). No cororary disease was found by an angiography though the past medical history revealed systemic hypertension, chronic kidney disease (KDOQY stage III), and diabetes mellitus type II on insuline therapy. A Wireless Video capsule examination was positive for jejunum angiodysplasia and an argon plasma coagulation was chosen as terapeutic option. No subsequent supportive therapy and interventions were required in subsequent one year of follow-up. PMID- 28352754 TI - Retinal tear: an unusual complication of ocular toxoplasmosis. AB - PURPOSE: It is aimed to report on a 16-year-old patient with acquired ocular toxoplasmosis complicated by a retinal tear. METHODS: Retrospective medical chart review. RESULTS: A 16-year-old Caucasian female presented with vision loss in her right eye. In addition to a white active lesion between the fovea and the optic nerve head, marked vitreous opacification was noted. She was diagnosed with ocular toxoplasmosis. The patient was treated with oral azithromycin, clindamycin, and trimethoprimsulfamethoxazole. One month later, retinochoroiditis resolved and vitreous cleared. Three months after onset, patient presented with floaters in the right eye and a retinal tear was located at the temporal region of the retina. Prophylactic argon laser treatment that encircled the retinal tear was performed. No other abnormalities were noted during 6 months of follow-up. CONCLUSIONS: Retinal tear associated with ocular toxoplasmosis is rare; however, a retinal tear can occur due to vitreoretinal traction following post inflammatory structural alteration of the vitreous. Retinal tears may be seen during the healing phase, when the inflammation turns into tightening of vitreous substance. Careful retinal examination in cases of ocular toxoplasmosis is warranted, especially in patients with severe vitreous inflammation. PMID- 28352753 TI - Pulmonary arterovenous malformation causing hemothorax in a pregnant woman without Osler-Weber-Rendu syndrome. AB - : Pulmonary arteriovenous malformations (PAVMs), although most commonly congenital, are usually detected later in life. CASE REPORT: We present a case of a 19-year-old woman with no previous history of AVM or telangiectasia, who presented dyspnea and hypoxia by massive left hemothorax in the 34th week of gestation. After emergent cesarean delivery, a chest computed tomography (CT) with i.v. contrast showed a likely 3 cm area of active contrast in left lower lung. Chest tube placement revealed about 2 liters of blood. The patient was subsequently found to have pulmonary AVM. A successful embolisation of AVM followed by lung atipic resection involving AVM and decortication for lung re expansion were the treatments provided. CONCLUSIONS: Women with known pulmonary AVM should be maximally treated prior to becoming pregnant, and the physician should be alert to complications of pulmonary AVM during pregnancy. PMID- 28352755 TI - Endoscopic ultrasound in the diagnosis of mediastinal diseases. AB - EUS is a useful tool for diagnosis of mediastinal diseases. EUS-FNA plays an important role in staging of lung cancer and in tissue acquisition in patients with mediastinal masses. In this review, the following issues will be addressed: EUS-FNA and EBUS-TBNA, metastatic mediastinal lymph nodes diagnosed by EUS, EUS in assessment of mediastinal lymph node status for staging of lung cancer, mediastinal lymphoma diagnosed by EUS, sarcoidosis and tuberculosis diagnosed by EUS. PMID- 28352756 TI - Canine transmigration accompanying mandibular retrognathism secondary to osteitis. AB - : Transmigration is a tooth pathology in which the migrating tooth bud passes the median plane. METHODS: This study is a presentation of the diagnostic and therapeutic outcomes in the cases of 4 stomach teeth transmigrations diagnosed in 3 patients with mandibular retrognathia which was a complication after osteitis in the postnatal period and infancy. RESULTS: Extending imaging diagnostics to include CT, most preferably CBCT, makes it possible to precisely evaluate a transmigrated canine's position and to plan a course of treatment. CONCLUSIONS: Planning of the treatment of teeth in transmigration in patients with temporomandibular ankylosis should be done by a team consisting of an orthodontist and a surgeon. PMID- 28352757 TI - The possible molecular regulation mechanism of CIK cells inhibiting the proliferation of Human Lung Adenocarcinoma NCL-H157 Cells. AB - Cytokine-induced killer (CIK) cells were isolated and proliferation from human peripheral blood and cultured in appropriate growth medium. The biological characteristics of CIK cells were further determined by the characterization of surface markers by flow cytometry. CIK cells inhibited the proliferation of human lung adenocarcinoma NCL-H157 cells. Vascular endothelial growth factor (VEGF) expression was down-regulated in CIK cells co-cultured with NCL-H157 cells by western blotting analysis. Furthermore, in comparison with cells untreated by CIK, the NCL-H157 had a lower proliferation capacity. We proposed that the pharmacological mechanisms of NCL-H157 promoted by CIK can be estimated possibly with different biological significance that can be ascribed to down-regulated VEGF expression in vitro. The results suggest that the VEGF pathway guides developmental inhibiting of NCL-H157, and we speculate that the function of VEGF pathways is to guide NCL-H157 to inhibition by abundant CIK. PMID- 28352758 TI - Urethral stone of unexpected size: case report and short literature review. AB - Urolithiasis is a well-known disease. Stones can form in all parts of the urinary tract. Diagnosis and treatment usually do not create clinical problems. However from time to time in daily practice doctors are confronted with casuistic cases. Here, we report a 54-year-old man with a large stone localized to the urethra. Because of the size of the stone, confirmed on radiography, and the presence of a cutaneous fistula, open surgery was performed. Due to urethral stricture, the patient required a second stage of reconstructive surgery. This case emphasizes that unusual presentation of urolithiasis may occur, and different surgical approaches as well as other surgical manipulations in such cases must be considered. PMID- 28352759 TI - Complete remission through icotinib treatment in Non-small cell lung cancer epidermal growth factor receptor mutation patient with brain metastasis: A case report. AB - Brain metastasis (BM) has been universally recognized as a poor prognostic factor in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown efficacy in treating BM with an EGFR mutation. This paper reports a case of BM patient with EGFR-mutated NSCLC. According to the findings, a complete remission (CR) of the BM was achieved by icotinib treatment without conducting a radiotherapy, which was followed by a resection of the primary lung cancer lesion and lymph nodes. After one-year follow-up, the disease progressed to liver metastasis and liver lesion biopsy showed a T790M mutation. The patient responded well to the combination treatment of AZD9291 and icotinib after the failure of transcatheter arterial chemoembolization (TACE). This case report suggests that icotinib has a sustainable anticancer response to BM and the combination with icotinib and AZD9291 is effective for liver metastasis with T790M. PMID- 28352760 TI - FPL tendon thickness, tremor and hand functions in Parkinson's disease. AB - INTRODUCTION: In Parkinson's disease (PD), a resting tremor of the thumb may affect the flexor pollicis longus (FPL) and influence hand functions. We investigated the relationship between FPL tendon thickness and hand function in PD patients and compared these characteristics with those in healthy controls. METHODS: The hand grip and pinch strengths were measured. The participants completed the Duruoz hand index, the Sollerman's hand function test, and the Nine Hole Peg Test. The thickness of the FPL tendon was measured using ultrasonography. RESULTS: The FPL tendon was thicker in PD patients but was not associated with tremor severity. In PD patients, despite functional performance of the hands are impaired and grip strength is decreased, pinch strengths are preserved. FPL thickness was not correlated with grip and pinch strengths. CONCLUSION: The thicker FPL tendon may be associated with greater pinch and grip strengths and manual dexterity in healthy individuals. The presence of tremor is associated with a thicker FPL tendon. PMID- 28352761 TI - Diagnostic value of circulating tumor cells in cerebrospinal fluid. AB - OBJECTIVE: To assess circulating tumor cells in cerebrospinal fluid as a diagnostic approach to identify meningeal metastasis in patients with non-small cell lung cancer by using tumor marker immunostaining-fluorescence in situ hybridization (TM-iFISH). METHODS: In 5 non-small cell lung cancer patients who were confirmed to have developed meningeal metastasis by cerebrospinal fluid cytology, 20 ml of cerebrospinal fluid was obtained through lumbar puncture, from which 7.5 ml was utilized for TM-iFISH to identify and quantitate circulating tumor cells, 10ml for cerebrospinal fluid cytology, and 2.5ml for detection of cerebrospinal fluid tumor markers. RESULTS: TM-iFISH examination identified 18 to 1,823 circulating tumor cells per 7.5ml cerebrospinal fluid. In contrast, cytology assessment revealed tumor cells in only 2 cases. The expression levels of cerebrospinal fluid tumor markers were all increased in all 5 patients when compared with their respective serum levels. Contrast-enhanced MRI scans demonstrated presence of meningeal metastasis in all 5 cases. CONCLUSION: TM iFISH may become a novel cerebrospinal fluid-based diagnostic strategy to identify circulating tumor cells and meningeal metastasis as compared to traditional diagnostic approaches, although its superior sensitivity and specificity needs to be confirmed through additional studies with a larger sample size. PMID- 28352762 TI - A meta-analysis of neuroprotective effect for traditional Chinese medicine (TCM) in the treatment of glaucoma. AB - BACKGROUND: The aim of this study was to evaluate the neuroprotective effect of surgery combined with traditional Chinese medicine(TCM)in the treatment of glaucoma by meta-analysis based on clinical controlled trial. METHODS: All the prospective randomized controlled trialsof surgery combined with TCM in the treatment of glaucoma were searched in the databases of Medline (1960-2015.1), CENTRAL (the Cochrane central register of controlled trials 1989-2015.1, EMBASE (1980~2015.1) and CNKI (1979-2015.1). Two reviewers independently assessed the quality of the included studies, extracted the relevant data and performed a cross-check. The pooled relative risk (RR) or standard mean difference (SMD) of surgery combined with TCM versus western medicine or surgery alone were calculated as the effect size by meta-analysis method. All the data was analyzed by stata11.0 software (http://www.stata.com; Stata Corporation, College Station, TX). RESULTS: Finally, eleven clinical controlledtrails with 843 subjects were included in this meta-analysis. The pooled results indicated that the surgery combined with TCM treatment procedure can significant improve the vision recovery rate compared to control group (RR=1.22, 95% CI:1.06~1.40, P=0.005); And after treatment, the visual field in combined group was significantly improved compared to control group (SMD=0.26~95% CI:0.09~0.43, P=0.003). CONCLUSION: Surgery combined with TCM can improve the vision recovery rate and the visual fieldin the treatment of glaucoma compared to surgery or western medicine alone. PMID- 28352763 TI - MiR-218 increases sensitivity to cisplatin in esophageal cancer cells via targeting survivin expression. AB - OBJECTIVES: Increasing evidence showed that microRNAs (miRNAs) were implicated in the chemical resistance of human cancers. We intended to investigate the role of miR-218 in cisplatin sensitivity of esophageal cancer cells. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was carried out to analyze miR-218 expression in human esophageal cancer cell line Eca9706 and a cisplatin-resistant subline (ECa9706-CisR cells). The effects of miR-218 transfection on ECa9706 and ECa9706-CisR cell viability, including cell viability and apoptosis rate were confirmed using MTT assay, or flow cytometry, respectively. qRT-PCR was used to validate survivin as a direct target gene of miR-218 in our system. RESULTS: We found that miR-218 was significantly decreased in ECa9706-CisR cells compared with parent Eca9706 cells. Overexpression of miR 218 by mimics transfection would enhance cisplatin sensitivity evaluated by cell viability inhibition and apoptosis promotion. We validated here survivin as a direct target of miR-218 in ECa9706 cells, which might contribute to the chemoresistance of esophageal cancer cells to cisplatin. CONCLUSIONS: In summary, our data suggest that miR-218 might represent as a promising sensitizer of cisplatin therapy in clinical esophageal cancer patients. PMID- 28352764 TI - Association of HOTAIR expression with PI3K/Akt pathway activation in adenocarcinoma of esophagogastric junction. AB - OBJECTIVES: Although the Hox transcript antisense intergenic RNA (HOTAIR), a vital long non-coding RNA, is known to participate in the development and progression of a wide range of carcinomas, there are still no published reports regarding its expression in adenocarcinoma of esophagogastric junction (AEJ). The aims of this study were to investigate the expression of HOTAIR, and to analyze the association of its expression with PI3K/Akt pathway activation in clinical AEJ patients. METHODS: Nine normal epithelial tissues and 41 samples of AEJ were studied comparably. The expression of HOTAIR was detected by real-time PCR according to the different tumor grades in these AEJ tissues. Western blot was performed to reveal the Ser473-phosphorylated Akt and total Akt levels. Results: HOTAIR was found to be up-regulated in higher grades of AEJ tissues compared to low grades and/or noncancerous tissues. pAkt expression was also found to be up regulated in tissues of higher tumor stages. We found that the overexpression of HOTAIR finely correlated with elevated Ser473-phosphorylated Akt levels. Conclusion: Upregulated HOTAIR was associated with abnormal activated PI3K/Akt pathway, which might serve as a promising therapeutic strategy for AEJ treatment. PMID- 28352765 TI - The role of interleukin genes in the course of depression. AB - BACKGROUND: Research studies conducted in recent years have confirmed that in the absence of medical illnesses, depressive disorders are associated with upregulation of many inflammatory cytokines such as tumor necrosis factor-aplha (TNF-alpha), interleukin-1 and 6 (IL-1,IL-6). The main objective of the study was to examine whether recurrent depressive disorders (rDD) are accompanied by more profound inflammatory disturbances than the first episode of depression (ED-I). The analysis included the expression of mRNA and protein levels of three interleukins namely. IL-1, IL-6 and IL-10. METHODS: The study was carried out in a cohort of 130 patients: ED-I group - 44 patients, rDD group - 86 patients respectively. RESULTS: Our results suggest that there was no significant statistical difference between the analyzed groups as regards the intensity of the depressive disorders. Furthermore, No differences in the expression of IL-1, IL-6 and IL-10 genes on the level of both mRNA and protein were observed among the groups. Additionally, there was no significant interrelation been documented between the number of depression episodes experienced v/s the expression of selected genes. CONCLUSIONS: There is no significant difference in IL-1, IL-6 and IL-10 expression between patients with recurrent depressive disorders and those suffering from the first episode of depression. 2. There seems to be no difference in acute first episode depression vs. acute episode of depression in patients with a recurrent disorder. Further larger trials are needed. PMID- 28352766 TI - A rare case of primary pulmonary diffuse large B cell lymphoma with CD5 positive expression. AB - Primary pulmonary diffuse large B-cell lymphoma (PPDLBCL) is extremely rare. Its clinical symptoms and signs are nonspe cific, and imaging features also have not yet been well-defined. Further description is important for the diagnosis and treatment of PPDLBCL. Herein, we reported a case of a patient who suffered from bilateral chest pain and dyspnea. Computed tomography (CT) of chest demonstrated bilateral lung mass, consolidations and reverse halo sign, while consolidations and reverse halo sign are uncommon according to previous reports. Tissue samples were taken by CT guided needle biopsy. The histological samples showed PPDLBCL. This case was special in view of positive expression of CD5. After the case was treated by cyclophosphamide pirarubicin vindesine dexamethasone (CHOP) chemotherapy for six courses, her clinical symptoms were partially alleviated, while CT showed progression disease. This case report highlights different imaging features and characteristics of molecular biology, and reviews study progress of PPDLBCL. PMID- 28352767 TI - DWI and SPARCC scoring assess curative effect of early ankylosing spondylitis. AB - BACKGROUND: To investigate the magnetic diffusion weighted imaging (DWI) sequence and Spondyloarthritis Research Consortium of Canada (SPARCC) scoring in assessing curative effect of combined treatment of Chinese and Western medicine for early ankylosing spondylitis (AS). METHODS: 48 cases diagnosed as early AS and treated with Chinese and Western medicine were included in the study. Magnetic routine and DWI sequence scanning image were performed to obtain the mean apparent diffusion coefficient (ADC) value of sub-articular surface bone marrow. Combined with SPARCC scoring, statistical analysis was conducted to compare the difference with the information obtained in the previous study. RESULTS: The mean ADC value in the sub-articular surface bone marrow of patients after clinical treatment: (4.34+/-0.55)*10-4mm2/s in ilium and (3.96+/-0.23)*10-4mm2/s in sacrum, which were both significantly lower than that before treatment (p< 0.05). There was highly positive correlation between mean ADC value and SPARCC scoring (P<0.05). The regression relationship could be demonstrated as Y=-64.420+21.262X(Y: SPARCC scoring value; X: mean ADC value). CONCLUSIONS: Magnetic DWI and SPARCC scoring could be applied in accessing AS inflammation activity changes and in reflect of curative effect of early AS patients as well as in providing reliable radiologist evidence for clinical therapeutic efficacy. PMID- 28352768 TI - The diagnostic value of serum CEA, NSE and MMP-9 for on-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is the leading cause of cancer related deaths worldwide. But no one type of serum biomarker was found to be highly sensitive and specific for detection of lung cancer at present. So, the aim of this study was to evaluate a diagnostic value of serum carcinoembryonic antigen (CEA), neuron specific enolase (NSE) and matrix metallo-proteinase (MMP-9) for non-small cell lung cancer. Thirty-six cases with pathology confirmed non-small cell lung cancer and thirty-two of subjects with benign lung disease were reviewed in our hospital and included in this retrospective study. The serum level of CEA, NSE and MMP-9 were tested and compared between the non-small cell lung cancer patients and benign lung disease. The diagnosis sensitivity, specificity and area under the receiver-operating characteristic (ROC) curve (AUC) for serum CEA, NSE and MMP-9 were calculated with STATA10.0 software. The serum CEA, NSE and MMP-9 were 32.0+/-16.7 ng/mL, 51.6+/-68.3 ng/mL, 30.6 +/-15.7 MUg/L for the NSCLC patients and 15.1+/-10.9 ng/mL, 4.9+/-3.1 ng/mL, 9.3+/-5.9 MUg/L for the benign lung disease patients with statistical difference (Pall<0.05); The diagnosis sensitivity, specificity and AUC were 80.0%, 72.2%, 0.84 for the serum CEA; 71.0%, 83.3% and 0.80 for NSE and 87.1%, 80.56%, 0.89 for MMP-9, respectively. The serum CEA, NSE and MMP-9 were generally elevated in patients with non-small cell lung cancer and could be used as potential bio-markers for non-small cell lung cancer diagnosis. PMID- 28352769 TI - Dysphonia - the single symptom of rifampicin resistant laryngeal tuberculosis. AB - : Tuberculosis is still the most frequent granulomatous laryngeal disease. Absence of pathognomonic symptoms and change in clinical pattern frequently leads to misdiagnosis and delayed treatment. Hoarseness is the commonest symptom of laryngeal tuberculosis and constitutional symptoms are usually rare. However dysphonia can be caused by many other more common conditions. Hoarseness can be a symptom of organic (nodules and polyps of vocal folds, tumors, vocal fold paresis) or functional (functional dysphonia, laryngeal conversion disorder, paradoxical vocal folds motion) conditions. Rarely systemic diseases as amyloidosis, sarcoidosis, Wegener's granulomatosis or tuberculosis can cause vocal dysfunction too. That is why laryngeal tuberculosis is often forgotten in case of persistent hoarseness. In this article, we present a case of a young previously healthy woman, complaining of persistent hoarseness with no other leading symptoms. Though endoscopic image suggested a malignancy, histology showed granulomatous lesion. Detailed examination revealed laryngeal and pulmonary tuberculosis resistant to rifampicin. CONCLUSION: Dysphonia can be the only one symptom of laryngeal tuberculosis. The disease should be taken into consideration when a patient complains of persistent hoarseness in order to avoid delays in treatment and spread of infection. PMID- 28352770 TI - Development of epidermal growth factor receptor tyrosine kinase inhibitors against EGFR T790M. Mutation in non small-cell lung carcinoma. AB - Individualized therapies targeting epidermal growth factor receptor (EGFR) mutations show promises for the treatment of non small-cell lung carcinoma (NSCLC). However, disease progression almost invariably occurs 1 year after tyrosine kinase inhibitor (TKI) treatment. The most prominent mechanism of acquired resistance involves the secondary EGFR mutation, namely EGFR T790M, which accounts for 50%-60% of resistant tumors. A large amount of studies have focused on the development of effective strategies to treat TKI-resistant EGFR T790M mutation in lung tumors. Novel generations of EGFR inhibitors are producing encouraging results in patients with acquired resistance against EGFR T790M mutation. This review will summarize the novel inhibitors, which might overcome resistance against EGFR T790M mutation. PMID- 28352771 TI - Negative regulation of CDC42 expression and cell cycle progression by miR-29a in breast cancer. AB - OBJECTIVE: The inhibitory role of microRNA-29a (miR-29a) has been assessed in breast cancer cells. Herein, we analyze the underlying mechanisms of its role in cell cycle progression in breast cancer cells. METHODS: We applied real-time polymerase chain reaction (PCR) to detect the expression of miR-29 in breast cancer cell lines. Then one of the cell lines, MDA-MB-453, was transfected with mimics of miR-29a. The cell cycle was analyzed by fluorescence-activated cell sorting after staining the cells with propidium iodide. Real-time PCR, luciferase assay and western blot were used together to verify the regulation of the predicted target, cell division cycle 42 (CDC42) by miR-29a. RESULTS: MiR-29s were decreased in our selected mammary cell lines, among which miR-29a was the dominant isoform. Overexpression of miR-29a caused cell cycle arrest at the G0/G1 phase. We further found that miR-29a could target the expression of CDC42, which is a small GTPase associated with cell cycle progression. CONCLUSION: We suggest that miR-29a exerts its tumor suppressor role in breast cancer cells partially by arresting the cell cycle through negative regulation of CDC42. PMID- 28352772 TI - Expression analysis of the TGF-beta/SMAD target genes in adenocarcinoma of esophagogastric junction. AB - The TGF-beta/SMAD signaling pathway is found to play pivotal roles in cell growth, differentiation and tumorigenesis. Its target genes are closely related to the biological behaviors of some malignancies. The aim of this study was to analyze the expression of the target genes of this pathway, including growth related c-myc, p21, p15, and metastasis-related Snail, ZEB1 and Twist1 in the adenocarcinomas of esophagogastric junction (AEJ) tissues. Clinical esophagogastric junction tissues from 25 cases of AEJ patients and 10 cases of non-tumorous tissues from the same site were collected. Quantitative real-time poly chain reactions were carried out to analyze the expression of the above referred target genes of TGF-beta/SMAD pathway. A notable up-regulation in the mRNA expression of p15, Snail, ZEB1, down-regulation of c-myc, was found whereas there were no significant change of p21 and Twist1. The findings suggests that the TGF-beta/SMAD pathway might be abnormally activated in AEJ since most of the target genes of this pathway exhibited altered expression at mRNA level. PMID- 28352773 TI - Blood cells in thyroid cancer patients: a possible influence of apoptosis. AB - The side effects of radioactive iodine (131-I) treatment of differentiated thyroid cancer (DTC) patients include reduction of peripheral blood cell counts. The aim of this study was to analyze some potential changes in blood cell counts of DTC patients after 131-I therapy, especially CD3-positive, CD19-positive, and CD56-positive peripheral blood lymphocytes (PBL), as well as the possible role of apoptosis in selected lymphocyte populations. The study group included 24 thyroid cancer patients and 24 control subjects. Peripheral blood samples from patients and controls were analyzed using 5-color flow cytometry. Apoptotic cells were detected using an Annexin V-FITC/7-AAD kit. There was a statistically significant decrease of all blood cells after the 131-I therapy. The CD19+ B lymphocyte population was the most affected (5.82 +/- 3.21% before therapy vs. 3.93 +/- 2.60% after therapy, p = 0.008). This decrease was correlated with the degree of apoptosis of peripheral blood lymphocytes (Spearman's r = 0.563, p =0.013). We concluded that 131-I therapy of DTC patients led to a decrease of all peripheral blood cells, especially CD19+ B lymphocytes. This directly correlated with apoptosis of PBLs, indicating that radiation damage to B cells leads to subsequent elimination by apoptosis. PMID- 28352774 TI - Detected EGFR mutation in cerebrospinal fluid of lung adenocarcinoma patients with meningeal metastasis. AB - OBJECTIVE: To discuss the application of ARMS method to detect EGFR gene mutation in cerebrospinal fluid of lung adenocarcinoma patients with meningeal metastasis. METHODS: 5 cases of lung adenocarcinoma were identified with meningeal metastasis that were cleared EGFR gene mutation by gene sequencing method. From each patient 5ml cerebrospinal fluid was obtained by lumbar puncture. ARMS method was used to detect EGFR mutations in cerebrospinal fluid. RESULTS: 5 samples of cerebrospinal fluid were successfully detected by ARMS method, 3 samples found that EGFR gene mutations, the mutations in line with direct sequencing method. CONCLUSION: ARMS method can be used to detect EGFR gene mutations of cerebrospinal fluid samples in lung adenocarcinoma with meningeal metastasis. But cerebrospinal fluid specimens from histological specimens, blood samples need to be confirmed by further comparative study whether there is advantage. PMID- 28352776 TI - GSTP1 A>G polymorphism and chemosensitivity of osteosarcoma: A meta-analysis. AB - The association between GSTP1 A>G polymorphism and chemosensitivity of osteosarcoma is controversial according to previously published studies. We conducted this meta-analysis to further investigate the role of GSTP1 A>G genetic variation in response to chemotherapy resistance in patients with osteosarcoma. Using the electronic databases of Pubmed, Wanfang and CNIK were searched to find the studies related to the GSTP1 A>G polymorphism and chemosensitivity of osteosarcoma. The genotype of AA, AG and GG were extracted from the chemotherapy sensitivity and chemotherapy resistance group. The association between GSTP1 A>G polymorphism and chemosensitivity was calculated by STATA11.0 software. The correlation between GSTP1 A>G polymorphism and chemotherapy response was assessed by odds ratio (OR) and its 95% confidence interval (95%CI). Four studies with 681 cases were finally included in this meta-analysis. The pooled data indicated that there was no significant association between GSTP1 A>G polymorphism and chemosensitivity in patients with osteosarcoma [Homozygous genetic model (GG vs AA): OR=0.53, 95%CI: 0.25-1.12, P=0.10; recessive genetic model (GG vs GA+AA): OR=0.61, 95%CI:0.34-1.11,P=0.11; and dominant genetic model (GG+AG vs AA): OR=0.67, 95%CI:0.42-1.07,P=0.10]. No correlation between GSTP1 A>G polymorphism and chemosensitivity was found according to this present meta-analysis. However, the small number of cases in each included study and significant statistical heterogeneity among the trials means the conclusion should be regarded as conservative. PMID- 28352775 TI - Pathogenesis-oriented approaches for the management of corticosteroid-resistant or relapsedprimary immune thrombocytopenia. AB - Primary immune thrombocytopenia (ITP) is a complex autoimmune disorder in which the patient's immune system reacts with platelet autoantigens resulting in immune mediated platelet destruction and/or suppression of platelet production. Corticosteroids can induce sustained remission rates in 50% to 75% of patients with active ITP. For these patients who are unresponsive to glucocorticoids, or relapsed after an initial response, multiple second-line treatment modalities can be chosen. However, how to make an optimal therapeutic strategy for a specific patient still remains a major challenge. As the pathogenetic heterogeneity of the ITP is increasingly identified, pathogenesis-oriented approach might offer an opportunity to improve the outcome of corticosteroid-resistant or relapsed ITP. PMID- 28352778 TI - A meta-analysis of adiponectin gene rs22411766 T>G polymorphism and ischemic stroke susceptibility. AB - Several studies have investigated the correlation between adiponectin gene rs22411766 T>G polymorphism and ischemic stroke risk. However, the results were not conclusive with each other. Therefore, to overcome this obstacle, we performed this meta-analysis to further explicate the adiponectin gene rs22411766 T>G polymorphism and ischemic stroke susceptibility. Case-control or cohort studies focused on adiponectin gene rs22411766 T>G polymorphism and ischemic stroke risk were electronic searched in the databases of Medline, Pubmed, Cochrane library, Excerpta Medica database(EMBASE) and China National Knowledge Infrastructure (CNKI). All the potentially relevant studies were included in this meta-analysis. The association between adiponectin gene rs22411766 T>G polymorphism and ischemic stroke was expressed by odds ratio with its confidence interval. Publication bias has been assessed by begg's funnel plot. All the analyses have been performed by Revman 5.1 statistical software. Finally, a total of six studies with 1,345 cases and 1,421 controls were included in this meta analysis. Our results demonstrated that there was a significant association between adiponectin gene rs22411766 T>G polymorphism and ischemic stroke risk (p<0.05). People with G single nucleotide of adiponectin gene have the increased risk of developing ischemic stroke compared to T single nucleotide. PMID- 28352777 TI - Prevention and treatment of peritoneal adhesions in patients affected by vascular diseases following surgery: a review of the literature. AB - Intra-abdominal adhesions are the most frequently occurring postoperative complication following abdomino-pelvic surgery. Abdominal and pelvic surgery can lead to peritoneal adhesion formation causing infertility, chronic pelvic pain, and intestinal obstruction. Laparoscopy today is considered the gold standard of care in the treatment of several abdominal pathologies as well as in a wide range of vascular diseases. Laparoscopy has several advantages in comparison to open surgery. These include rapid recovery times, shorter hospitalisation, reduced postoperative pain, as well as cosmetic benefits. The technological improvements in this particular surgical field along with the development of modern techniques and the acquisition of specific laparoscopic skills have allowed for its wider utilization in operations with fully intracorporeal anastomoses. Postoperative adhesions are caused by aberrant peritoneal healing and are the leading cause of postoperative bowel obstruction. The use of anti-adherence barriers is currently being advocated for their prevention. The outcome of the investigation showed adhesion formation inhibition without direct detrimental effects on anastomotic healing. Poor anasto-motic healing can provoke adhesions even in the presence of anti-adhesion barriers. This review gives a short overview on the current evidence on the pathophysiology and prevention of peritoneal adhesions. PMID- 28352780 TI - The diagnosis and pathological value of combined detection of HE4 and CA125 for patients with ovarian cancer. AB - OBJECTIVE: To evaluate the value of individual and combined measurement of human epididymis protein 4 (HE4) and cancer antigen 125 (CA-125) in the diagnosis of ovarian cancer. METHODS: A clinical case-control study was performed in which the levels of serum HE4 and CA-125 of subjects with malignant, borderline, benign ovarian tumors and healthy women were measured before surgery. An immunohistochemistry method was used to measure the expression of HE4 in different tissues. Statistical analysis was performed to determine the relationship between the level of HE4 and the pathologic type as well as the stage of the ovarian tumors. RESULTS: The level of HE4 in the serum was significantly elevated in the malignant ovarian cancer group compared with other groups. Women with benign ovarian tumors and non-neoplastic lesions, and healthy women were designated as references. When the level of HE4 in the serum was 58.66 pmol/L, the sensitivity and specificity of HE4 in diagnosing malignant ovarian tumors was 82.35% and 96.03%, respectively. The level of HE4 was negatively correlated with the differentiation extent of the tumors whereas positively correlated to the clinical staging. In the groups of malignant and borderline tumors, the levels of HE4 were higher than the other groups. The expression of HE4 was significant higher in the serous types of ovarian tumors than that of the mucous types (P<0.05). The level of HE4 in the serum and tissues were positively correlated with each other. CONCLUSION: HE4 can be used as a novel clinical biomarker for predicting malignant ovarian tumors and its expression was closely related with the clinical pathological features of malignant ovarian tumors. PMID- 28352779 TI - Surgical treatment of recidivist lymphedema. AB - Lymphedema is a chronic disease with a progressively ingravescent evolvement and an appearance of recurrent complications of acute lymphangitic type; in nature it is mostly erysipeloid and responsible for a further rapid increase in the volume and consistency of edema. The purpose of this work is to present our experience in the minimally invasive treatment for recurrence of lymphedema; adapting techniques performed in the past which included large fasciotomy with devastating results cosmetically; but these techniques have been proposed again by the use of endoscopic equipment borrowed from the advanced laparoscopy surgery, which allows a monoskin access of about one cm. PMID- 28352781 TI - SOX7 inhibits tumor progression of glioblastoma and is regulated by miRNA-24. AB - OBJECTIVE: Sex-determining region Y-box 7 (SOX7) is a putative tumor suppressor in various types of human cancers. In the present study, the expression and function of SOX7 was investigated in human glioblastoma (GBM) cells. METHODS: Real-time PCR and western blot were carried out to reveal the expression of SOX7 in GBM specimens and cultured cell lines. A short interfering RNA (siRNA) targeting SOX7 was synthesized and transfected into U87 cells. 3-(4,5 Dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide (MTT) assay was performed to valuate the cell proliferation ability in U87 cells. Bioinformatics analysis further predicted its regulation by microRNA-24 (miR-24). Luciferase reporter assay was performed to prove this regulation. RESULTS: SOX7 was downregulated in GBM specimens and cell lines. Inhibition of SOX7 in cultured U87 cells resulted in a slower growth rate. Mechanically, SOX7 was a target of miR-24, demonstrated by reporter assay. CONCLUSION: SOX7 was a strong tumor suppressor regulated by miR-24 in human GBM cells. PMID- 28352782 TI - Sevoflurane affects evoked electromyography monitoring in cerebral palsy. AB - BACKGROUND: To explore the effect of sevoflurane inhalation anesthesia on evoked electromyography monitoring of spinal nerve root in children associated with cerebral palsy. METHODOLOGY: Children with cerebral palsy (n=40) were selected and further divided into 1MAC (minimum alveolar concentration) sevoflurane group and 2MAC sevoflurane group. Following the induction of anesthesia, Nicolet Endeavor-CR16 channel electrophysiological monitor was used to implement three times of successive electrical stimulation with interval of 5 sec at 3.50 mA. RESULTS: Our results suggested a statistical significance of amplitude retention ratio and latency in the sevoflurane inhalation time (P<0.01), with an interaction effect between the sevoflurane inhalation time and concentration for amplitude retention ratio (P<0.01), while there is no interaction effect between the sevoflurane inhalation time and concentration for latency (P>0.05). Compared to 1MAC sevoflurane group, the amplitude retention ratio of 2MAC sevoflurane group decreased remarkably (P<0.01) and the latency of 2MAC sevoflurane group extended at T3 and T4 (P<0.05 or P<0.01). CONCLUSIONS: In evoked electromyography monitoring of spinal nerve root in children with cerebral palsy, with the increasing of concentration and duration of sevoflurane inhalation, evoked electromyogram retention ratio reduces gradually, latency extends and the retention ratio has more changes than the latency. PMID- 28352783 TI - CT and MR imaging of the thoracic aorta. AB - At present time, both CT and MRI are valuable techniques in the study of the thoracic aorta. Nowadays, CT represents the most widely employed technique for the study of the thoracic aorta. The new generation CTs show sensitivities up to 100% and specificities of 98-99%. Sixteen and wider row detectors provide isotropic pixels, mandatory for the ineludible longitudinal reconstruction. The main limits are related to the X-ray dose expoure and the use of iodinated contrast media. MRI has great potential in the study of the thoracic aorta. Nevertheless, if compared to CT, acquisition times remain longer and movement artifact susceptibility higher. The main MRI disadvantages are claustrophobia, presence of ferromagnetic implants, pacemakers, longer acquisition times with respect to CT, inability to use contrast media in cases of renal insufficiency, lower spatial resolution and less availability than CT. CT is preferred in the acute aortic disease. Nevertheless, since it requires iodinated contrast media and X-ray exposure, it may be adequately replaced by MRI in the follow up of aortic diseases. The main limitation of MRI, however, is related to the scarce visibility of stents and calcifications. PMID- 28352784 TI - A case report of hereditary spherocytosis with concomitant chronic myelocytic leukemia. AB - Hereditary spherocytosis (HS) and Chronic myelocytic leukemia (CML) are both life threatening hemotologic diseases. They are rarely seen to occur simultaneously in one individual patient. Here we demonstrate a case of HS associated with CML in this study. The patient is a young female, diagnosed with HS in 2005, and was given partial embolization of the splenic artery. She got significant remission after the procedure. In 2008, she was found abnormal in blood routine test, after bone marrow routine, chromosome and fusion gene tests, she was diagnosed with CML (chronic phase). She did not receive regular treatment until 3 months prior, and is currently being treated with Dasatimib. She achieved hematological remission, but had no significant improvement in chromosome and fusion gene figures. Due to her severe condition of hemolysis, a splenectomy or an allogeneic hematopoietic stem cell transplantation is considered. PMID- 28352785 TI - A case of giant saphenous vein graft aneurysm followed serially after coronary artery bypass surgery. AB - Saphenous vein graft aneurysm (SVGA) is one of the chronic complications after coronary aorta bypass grafting (CABG) and may be caused by atherosclerosis-like phenomena of the vein graft, weakness around the vein valve, rupturing of the suture of the graft anastomosis, or perioperative graft injury. We describe a case of a large, growing saphenous vein graft aneurysm that was followed serially by chest radiography and computed tomography. Eighteen years after CABG, an SVGA (23 * 24 mm) was incidentally detected. The patient was asymptomatic and was followed conservatively. Four years later, coronary computed tomographic angiography showed that the giant aneurysm had grown to 52.1 by 63.8 mm and revealed a second, smaller aneurysm. Finally, the SVG was ultimately resected without bypass via off-pump surgery. Therefore, this case suggested that aggressive treatment that includes surgical intervention should be considered before the aneurysm becomes larger, even if it is asymptomatic. PMID- 28352786 TI - Role of FDG-PET scan in staging of pulmonary epithelioid hemangioendothelioma. AB - In this report we describe a case of pulmonary epithelioid hemangioendothelioma (PEH) in a young woman. The neoplasm manifested with dry cough, chest pain, finger clubbing, and multiple bilateral pulmonary nodules on chest x-ray and computed tomographic (CT) scan. She underwent thoracoscopy, and the histological features of the lung biopsies were initially interpreted as consistent with a not well-defined interstitial lung disease. Our patient was clinically and radiologically stable over a period of four years, after which the disease progressed to involve not only the lung but also mediastinal lymph nodes, liver and bone. Fiberoptic bronchoscopy showed subtotal occlusion of the right middle and lower lobe bronchi. The histologic examination of bronchial biopsies revealed a poorly differentiated neoplasm immunohistochemically positive for vimentin and vascular markers CD31, CD34 and Factor VIII. A diagnosis of malignant hemangioendothelioma was made. Positron emission tomography (PET) is more sensitive than CT scan and bone scintigraphy in detecting PEH metastases. Furthermore, 18-fluorodeoxyglucose (FDG) uptake seems to be related to the grade of malignancy of PEH lesions. Therefore, we suggest that FDG-PET should be included in the staging system and follow-up of PEH. PMID- 28352787 TI - LncRNA TUG1 is upregulated and promotes cell proliferation in osteosarcoma. AB - OBJECTIVE: To examine the expression and function of long non-coding RNA taurine up-regulated 1 (TUG1) in human osteosarcoma cells. METHODS: Real-time quantitive PCR was used to detect the transcription level of TUG1 in a series of osteosarcoma cell lines. Knockdown of TUG1 in U2OS cells was carried out by transient transfection of siRNAs. MTT assay was performed to access the cell growth rates. Afterwards, RNA and protein of these cells were extracted to analyze the transfection efficient as well as the expression of other molecules. RESULTS: Compared to the normal cell line, TUG1 exhibited a significant upregulation in osteosarcoma cells. Phenotyping analysis showed the growth promotion activity of TUG1, since knockdown of TUG1 resulted in declined proliferation. We also found that AKT phosphorylation was impaired after TUG1 was inhibited, suggesting that the AKT pathway was involved in the regulation of TUG1 in U2OS cells. CONCLUSION: Our data provided evidence that TUG1 was upregulated and acted as a possible oncogene via positively regulating cell proliferation in osteosarcoma cells. PMID- 28352788 TI - Meningioma recurrence. AB - Meningioma accounts for more than 30% of all intracranial tumours. It affects mainly the elderly above the age of 60, at a female:male ratio of 3:2. The prognosis is variable: it is usually favourable with no progression in tumour grade and no recurrence in WHO grade 1 tumours. However, a minority of tumours represent atypical (grade 2) or anaplastic (grade 3) meningiomas; this heterogeneity is also reflected in histopathological appearances. Irrespective of the grade, the size of the tumour and the localisation may have severe, sometimes lethal consequences. Following neurosurgical interventions to remove the tumour, recurrence and progression in WHO grade may occur. Our knowledge on predisposing histomorphological and molecular factors of recurrence is rather limited. These can be classified as I) demographic II) environmental, III) genetic and epigenetic IV) imaging, V) neuropathological, and VI) neurosurgical. In view of the complex background of tumour recurrence, the recognition of often subtle signs of increased risk of recurrence requires close collaboration of experts from several medical specialties. This multidisciplinary approach results in better therapy and fewer complications related to tumour recurrence. PMID- 28352789 TI - Endobronchial amyloidosis mimicking bronchial asthma: a case report and review of the literature. AB - Among two tracheobronchial forms (local and diffuse) and two parenchymal forms (nodular and alveolar septal) that were reported in previous literature, localized endobronchial amyloidosis is an uncommon disease of unknown cause. Bronchial amyloid deposits can occur as focal nodules or multifocal infiltration of the submucosa. We report the case of a 47-year-old man who had complained of dyspnea and wheezing for 1 month and who had been treated for severe asthma at another hospital. Endobronchial amyloidosis was confirmed by histological examination of the bronchial biopsies. PMID- 28352790 TI - A confusing case report of pulmonary langerhans cell histiocytosis and literature review. AB - Pulmonary Langerhans Cell Histiocytosis (PLCH) is a rare disease. From the insidious onset and nonspecific manifestations, it is difficult to diagnose PLCH. To help improve the diagnosis and therapy options of adult PLCH, we present this case report and literature review about a confusing case of PLCH. In this report, we present a 37-year-old male PLCH case that was negative for CD1a and S100 expression. Smoking cessation and use of prescribed Spiriva appeared to improve the patient's symptoms. To the best of our knowledge, this is the first reported case of PLCH in which improved symptoms were seen with the use of Spiriva alone.The mechanism is not clear, but potentially has some relationship with dilating the airway, decreasing the mucous hypersecretion and promoting anti inflammatory pathways. From this patient's case, we may be able to find more cases to then find other first line therapies for PLCH patients. PMID- 28352791 TI - Effect of hesperetin on chaperone activity in selenite-induced cataract. AB - BACKGROUND: Chaperone activity of alpha-crystallin in the lens works to prevent protein aggregation and is important to maintain the lens transparency. This study evaluated the effect of hesperetin on lens chaperone activity in selenite induced cataracts. METHODOLOGY: Thirteen-day-old rats were divided into four groups. Animals were given hesperetin (groups G2 and G4) or vehicle (G1 and G3) on Days 0, 1, and 2. Rats in G3 and G4 were administered selenite subcutaneously 4 hours after the first hesperetin injection. On Days 2, 4, and 6, cataract grades were evaluated using slit-lamp biomicroscopy. The amount of a-crystallin and chaperone activity in water-soluble fraction were measured after animals sacrificed. RESULTS: G3 on day 4 had developed significant cataract, as an average cataract grading of 4.6 +/- 0.2. In contrast, G4 had less severe central opacities and lower stage cataracts than G3, as an average cataract grading of 2.4 +/- 0.4. The a-crystallin levels in G3 lenses were lower than in G1, but the same as G4. Additionally, chaperone activity was weaker in G3 lenses than G1, but the same as in G4. CONCLUSIONS: Our results suggest that hesperetin can prevent the decreasing lens chaperone activity and a-crystallin water solubility by administered of selenite. PMID- 28352792 TI - Clinical value of self-assessment risk of osteoporosis in Chinese. AB - BACKGROUND: Early detection of high-risk population for osteoporosis is the key to preventing this disease. METHODOLOGY: In this cross-sectional study a continuous sample of 270 women and 89 men (age: 20-90 years) was divided into four groups by age (<= 55 or > 55 years) and sex. Participants completed the IOF test. Low-, medium-, and high-risk grades were defined by an OSTA index of greater than -1, -1 to -4, and less than -4, respectively. RESULTS: Most participants were categorized in the low-risk group (240 people, 66.9%), followed by the medium-risk (102 people, 28.4%) and high-risk groups (17 people, 4.7%). Compared to women, men in both age groups had significantly higher OSTA index and greater numbers of positive answers on the IOF test. 64.3% individuals were susceptible to osteoporosis risk (>=1 positive answers on the IOF test). Multiple regression analysis demonstrated that family history of fragility fracture (OR: 0.503, 95% CI: 0.26-0.97), height loss exceeding 3 cm (OR: 2.51, 95% CI: 1.55 4.05), and earlier menopause (OR: 0.434, 95% CI: 0.19-0.97) were associated with higher risk grades. CONCLUSIONS: Combined use of the OSTA and IOF test is a simple and effective method for assessing the risk of osteoporosis. PMID- 28352793 TI - Sternal reconstruction by extracellular matrix: a rare case of phaces syndrome. AB - Congenital defects of the sternum are rare and due to a failure of midline development and fusion of the sternal bones. Surgical correction of a sternal cleft should be preferred during infancy for functional reasons. Chest wall reconstruction represented a complex problem in the last decades. We report our successful outcome of sternal reconstruction in a rare case of PHACES syndrome, in which the patient was submitted to reconstruction of the sternum and complete closure of the thoracic defect by the employ of an extracellular matrix XCM Biologic tissue matrix. We promote the use of extracellular matrix in surgical reconstruction of chest defects for its maneuverability, plasticity, tolerability and the possibility of growing with the children's chest getting a good compliance and optimal cosmetic results. PMID- 28352794 TI - Prenatal diagnosis, 3-D virtual rendering and lung sparing surgery by ligasure device in a baby with "CCAM and intralobar pulmonary sequestration". AB - Congenital cystic lung lesions are a rare but clinically significant group of anomalies, including congenital cystic adenomatoid malformation (CCAM), pulmonary sequestration, congenital lobar emphysema (CLE) and bronchogenic cysts. Despite the knowledge of these lesions increasing in the last years, some aspects are still debated and controversial. The diagnosis is certainly one aspect which underwent many changes in the last 15 years due to the improvement of antenatal scan and the introduction of 3-D reconstruction techniques. As it is known, a prompt diagnosis has an essential role in the management of these children. The new imaging studies as 3D Volume rendering system are the focus of this paper. We describe our preliminary experience in a case of hybrid lung lesion, which we approached by thoracoscopy after a preoperative study with 3D VR reconstruction. Our final balance is absolutely positive. PMID- 28352795 TI - Serum levels of inhibin B in adolescents after varicocelelectomy: A long term follow up. AB - INTRODUCTION: To study the impact on adult's fertility of serum inhibin B levels in adolescent patients with idiopathic varicocele after minimally invasive surgical correction and to compare fluctuation of pituitary-testis hormonal values and testicular volumes. MATERIALS AND METHODS: A case-control study was carried out on a group adolescent patients (n=60) affected by idiopathic left varicocele (group V) and compared with control adolescents (n=40) in the Paediatric Surgery Section of Siena (from June 1993 till September 2013). Inhibin B levels and testicular volume before (T0) and after at 6 and 12 months from surgery (T1 and T2) were evaluated. RESULTS: A positive correlation between testicular growth at T1 and T2 (P<0.001) was found. Linear regression analysis showed a positive correlation between inhibin B levels and testicular volume (expressed as the sum of the right and left values) (P<0.0001). CONCLUSIONS: Inhibin B levels are a valid marker for studying the effects of varicocele on the testicular function and confirm the necessity of early surgical correction for preventing the trophic testicular damage and male infertility. PMID- 28352796 TI - Our experience in the treatment of Malignant Fibrous Hystiocytoma of the larynx: clinical diagnosis, therapeutic approach and review of literature. AB - Hereditary spherocytosis (HS) and Chronic myelocytic leukemia (CML) are both life threatening hemotologic diseases. They are rarely seen to occur simultaneously in one individual patient. Here we demonstrate a case of HS associated with CML in this study. The patient is a young female, diagnosed with HS in 2005, and was given partial embolization of the splenic artery. She got significant remission after the procedure. In 2008, she was found abnormal in blood routine test, after bone marrow routine, chromosome and fusion gene tests, she was diagnosed with CML (chronic phase). She did not receive regular treatment until 3 months prior, and is currently being treated with Dasatimib. She achieved hematological remission, but had no significant improvement in chromosome and fusion gene figures. Due to her severe condition of hemolysis, a splenectomy or an allogeneic hematopoietic stem cell transplantation is considered. PMID- 28352797 TI - Delayed recurrent nerve paralysis following post-traumatic aortic pseudoaneurysm. AB - Blunt trauma to the neck or to the chest are increasingly observed in the emergency clinical practice. They usually follow motor vehicle accidents or may be work or sports related. A wide pattern of clinical presentation can be potentially encountered. We report the uncommon case of a patient who was referred to our observation presenting with hoarseness and disphagia. Twenty days before he had sustained a car accident with trauma to the chest, neck and the mandible. Laryngoscopy showed a left recurrent laryngeal nerve palsy. Further otolaryngo-logical examination showed no other abnormality. At CT and MR imaging a post-traumatic aortic pseudoaneurysm was revealed. The aortic pseudoaneurysm was consequently repaired by implantation of an endovascular stent graft under local anesthesia. The patient was discharged 10 days later. At 30-days follow-up laryngoscopy the left vocal cord palsy was completely resolved. Hoarseness associated with a dilated left atrium in a patient with mitral valve stenosis was initially described by Ortner more than a century ago. Since then several non malignant, cardiovascular, intrathoracic disease that results in embarrassment from recurrent laryngeal nerve palsy usually by stretching, pulling or compression; thus, the correlations of these pathologies was termed as cardiovocal syndrome or Ortner's syndrome. The reported case illustrates that life-threatening cardiovascular comorbidities can cause hoarseness and that an impaired recurrent laryngeal nerve might be correctable. PMID- 28352799 TI - Correlation analysis of VHL and Jade-1 gene expression in human renal cell carcinoma. AB - OBJECTIVE: The aim of this study was to investigate the correlation of von Hippel Lindau tumor suppressor (VHL) mRNA expression and jade family PHD finger 1 (Jade 1) gene expression in patients with renal cell carcinoma (RCC). Another aim of this study was to analyze the relationship of these two genes with clinicalpathological features of the RCC patients. METHODS: A total of 75 RCC patients who received surgically therapy in our hospital were included. All patients had complete pathological data. The expression of VHL/Jade-1 was determined by real-time polymerase chain reaction (RT-PCR). RESULTS: VHL and Jade 1 were both obviously downregulated in RCC tissues than that of the matched normal tissues, and both negatively correlated with tumor size as well as tumor grade. And we found a fine association of VHL gene expression with Jade-1. CONCLUSION: VHL/Jade-1 exhibited significantly decreased expression in RCC tissues and was closely related to the clinical prognosis of patients. The finding of VHL expression positively correlated with Jade-1 expression shed light and provided crucial evidence on the connection of VHL protein with Wnt/b-catenin pathway. PMID- 28352798 TI - Integrated therapeutic approach to giant solitary fibrous tumor of the pleura: report of a case and review of the literature. AB - The fibrous tumors of the pleura are rare primary tumors, accounting for 5% of malignant pleural neoplasms, which generally originate from sub-mesothelial mesenchymal tissue of the visceral pleura. These tumours generally exhibit clinical benign behavior although 12% of solitary fibrous tumors can be malignant and have worse outcomes. These tumors are considered "giant" when the lesion > 15 cm. Surgical treatment is the best choice for both benign and malignant neoplasms. We retrospectively analyzed the main case series of giant fibrous tumors of the pleura. In addition we report our experience of a 76-year-old woman treated by pre-surgical embolization involving implantation of vascular plugs. Surgery was successfully carried out without complications; imaging and functional assessment 6 months post intervention demonstrated both the absence of recurrence and improvement of lung function parameters. PMID- 28352800 TI - Is acute appendicitis still misdiagnosed? AB - OBJECTIVE: The optimal diagnostics and treatment of acute appendicitis continues to be a challenge. A false positive diagnosis of appendicitis may lead to an unnecessary operation, which has been appropriately termed negative appendectomy. The aim of our study was to identify the effectiveness of preoperative investigations in preventing negative appendectomy. METHODS: A retrospective study was performed on adult patients who underwent operation for suspected acute appendicitis from 2008 to 2013 at Vilnius University Hospital Santariskiu Klinikos. Patients were divided into two groups: group A underwent an operation, where appendix was found to be normal (non-inflamed); group B underwent an appendectomy for inflamed appendix. Groups were compared for preoperative data, investigations, treatment results and pathology findings. RESULTS: 554 patients were included in the study. Preoperative laboratory tests results of hemoglobin, hematocrit concentrations and white blood cell count were significantly higher in group B (p<0.001). Ultrasonography was performed for 78 % of patients in group A and 74 % in group B and did not provide any statistically significant results. Comparing Alvarado score results, there were more patients with Alvarado score less than 7 in group A than in group B. In our large series we could find only four independent risk factors, and they could only account for 24 % of cases. CONCLUSIONS: In summary, acute appendicitis is still often misdiagnosed and the ratio of negative appendectomies remains rather high. Additional investigations such as observation and computed tomography should be used to prevent this. PMID- 28352801 TI - Contralateral risk reducing mastectomy in Non-BRCA-Mutated patients. AB - The use of contralateral risk reducing mastectomy (CRRM) is indicated in women affected by breast cancer, who are at high risk of developing a contralateral breast cancer, particularly women with genetic mutation of BRCA1, BRCA2 and P53. However we should consider that the genes described above account for only 20-30% of the excess familiar risk. What is contralaterally indicated when genetic assessment results negative for mutation in a young patient with unilateral breast cancer? Is it ethically correct to remove a contralateral "healthy" breast? CRRM rates continue to rise all over the world although CRRM seems not to improve overall survival in women with unilateral sporadic breast cancer. The decision to pursue CRRM as part of treatment in women who have a low-to-moderate risk of developing a secondary cancer in the contralateral breast should consider both breast cancer individual-features and patients preferences, but should be not supported by the surgeon and avoided as first approach with the exception of women highly worried about cancer. Prospective studies are needed to identify cohorts of patients most likely to benefit from CRRM. PMID- 28352802 TI - Platelet Rich Plasma: a short overview of certain bioactive components. AB - Platelet rich plasma (PRP) represents a relatively new approach in regenerative medicine. It is obtained from patient's own blood and contains different growth factors and other biomolecules necessary for wound healing. Since there are various protocols for PRP preparing, it usually results with PRP generation with different amounts of bioactive substances, which finally may modulate the intensity of wound healing. The reference data about potential effect of some PRP compounds on wound healing, in different tissues, are still controversial. This review summarizes recently known facts about physiological role of certain PRP components and guidance for further research. Also, this review discusses different procedure for PRP generation and potential effect of leukocytes on wound healing. PMID- 28352803 TI - Celiac axis compression syndrome: laparoscopic approach in a strange case of chronic abdominal pain in 71 years old man. AB - Celiac Axis Compression Syndrome by the Median Arcuate Ligament is a very rare condition characterized by chronic postprandial abdominal pain (angina abdominis), nausea, vomiting, which occurs mostly in young patients. The main treatment is a surgical procedure that consists of the division of the arcuate ligament combined with the section of the close diaphragmatic crus and the excision of the celiac plexus. Actually laparoscopic management is feasible and safe. PMID- 28352804 TI - A rare case of persistent hypoglossal artery associated with contralateral proximal subclavian stenosis. AB - The persistent hypoglossal artery is rare vascular anomalies. We report the case of a 50-year old man with right hypoglossal artery, ipsilateral hypoplasic internal carotid artery, associated with left proximal subclavian stenosis with subclavian steal syndrome. Power-Doppler-Ultra-Sonography spectral images obtained after the patient exercised the left arm showed mid-systolic deceleration with retrograde late-systolic velocities. A Computed Tomography Angiography demonstrated a proximal stenosis of the left SA, a mild right ICA hypoplasia and an anomalous artery arising from right ICA at C2-C3 level, entering the cranium via the hypoglossal canal and joining the basilar artery. Usually the presence of PHA may be completely asymptomatic, and detected as an incidental finding by CTA or MRA, but in our case its diagnosis is extremely important because it is often the only vessel supplying blood to the basilar trunk and posterior circulation. PMID- 28352805 TI - Professional dental and oral surgery liability in Italy: a comparative analysis of the insurance products offered to health workers. AB - INTRODUCTION: In Italy there has been an increase in claims for damages for alleged medical malpractice. A study was therefore conducted that aimed at assessing the content of the coverage of insurance policy contracts offered to oral health professionals by the insurance market. MATERIAL AND METHODS: The sample analysed composed of 11 insurance policy contracts for professional dental liability offered from 2010 to 2015 by leading insurance companies operating in the Italian market. RESULTS: The insurance products analysed are structured on the "claims made" clause. No policy contract examined covers the damage due to the failure to acquire consent for dental treatment and, in most cases, damage due to unsatisfactory outcomes of treatment of an aesthetic nature and the failure to respect regulatory obligations on privacy. DISCUSSION: On entering into a professional liability insurance policy contract, the dentist should pay particular attention to the period covered by the guarantee, the risks both covered and excluded, as well as the extent of the limit of liability and any possible fixed/percentage excess. CONCLUSIONS: When choosing a professional liability contract, a dentist should examine the risks in relation to the professional activity carried out before signing. PMID- 28352806 TI - Correlation between CTLA-4 gene rs221775A>G single nucleotide polymorphism and multiple sclerosis susceptibility. A meta-analysis. AB - OBJECTIVE: The aim of this meta-analysis was to undertake a meta-analysis to evaluate the correlation between cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) gene rs221775 A>G single nucleotide polymorphism and the susceptibility of multiple sclerosis (MS) susceptibility. METHOD: Published manuscripts about CTLA-4 gene rs221775A>G single nucleotide polymorphism and multiple sclerosis susceptibility were searched in the computerized bibliographic searches of Pubmed Embase and China National Knowledge Infrastructure (CNKI). Potential studies were screened and data for 5025 MS patients and 4706 controls from 20 publications were included. The association between CTLA-4 gene rs221775A>G single nucleotide polymorphism and multiple sclerosis susceptibility were demonstrated by odds ratio (OR) and 95% confidence interval (95%CI). RESULTS: The pooled results showed no significant association between CTLA-4 gene rs221775A>G single nucleotide polymorphism and multiple sclerosis susceptibility for dominant genetic model [OR=1.02, 95%CI:0.90~1.05, (P=0.80)], homozygous genetic model [OR=0.85,95%CI:0.71 ~1.03,(P=0.10)] and recessive genetic model [OR=0.99,95% CI:0.89~1.10,(P=0.90)]. CONCLUSION: With current evidence, CTLA-4 gene rs221775A>G single nucleotide polymorphism had no association with the susceptibility of multiple sclerosis. PMID- 28352807 TI - Standards of anesthesiology practice during neuroradiological interventions. AB - Interventional radiology is a rapidly growing discipline with an expanding variety of indications and techniques in pediatric and adult patients. Accordingly, the number of procedures during which monitoring either under sedation or under general anesthesia is needed is increasing. In order to ensure high-quality care as well as patient comfort and safety, implementation of anes thesiology practice guidelines in line with institutional radiology practice guidelines is paramount [1]. However, practice guidelines are no substitute for lack of communi-cation between specialties. Interdisciplinary indications within neurosciences call for efficient co-operation among radiology, neurology, neurosurgery, vascular surgery, anesthesiology and intensive care. Anesthesia team and intensive care personnel should be informed early and be involved in coordinated planning so that optimal results can be achieved under minimized risks and pre-arranged complication management. PMID- 28352808 TI - Informed consent in robotic surgery: quality of information and patient perception. AB - INTRODUCTION: Obtaining a valid informed consent in the medical and surgical field is a long debated issue in the literature. In robotic surgery we believe in the necessity to follow three arrangements to make the informed consent more complete. MATERIAL AND METHODS: This study presents correlations and descriptions based on forensic medicine concepts research, literature review, and the proposal of an integration in the classic concept of informed consent. CONCLUSION: In robotic surgery we believe in the necessity to follow three arrangements to make the IC more complete. Integrate the information already present in the informed consent with data on the surgeon's experience in RS, the number of procedures of the department and the regional map of expertises by procedure. PMID- 28352810 TI - Expression and clinical significance of LXRalpha and SREBP-1c in placentas of preeclampsia. AB - OBJECTIVE: To evaluate the expression and correlations of liver X receptor alpha (LXRa) and its target gene sterol regulatory element-binding protein-1c (SREBP 1c) in placentas of preeclampsia (PE) and their significance in PE. METHODS: Pregnancies were divided into two groups, 60 cases (29 cases of mild and 31 cases of severe) of PE group and 56 cases of normal group. The level of mRNA and protein of LXRa and SREBP-1c were analyzed by reverse transcription-polymerase chain reaction (RTPCR) and immunohistochemistry (IHC) in the placentas. RESULTS: RT-PCR and IHC results showed that the mRNA and protein expression of both LXRa and SREBP-1c increased gradually with the extent of PE among normal pregnancy, mild PE and severe PE groups, and the differences were of statistically significance (P<0.01 or P<0.05). There were positive correlations between the expression of LXRa mRNA and SREBP-1c mRNA, also between LXRa mRNA and LXRa protein (r=0.521, P<0.01; r=0.422, P<0.01). The expression of SREBP-1c mRNA positively correlated with its protein level (r=0.598, P<0.01). There were positive correlations between the expression of LXRa protein and SREBP-1c protein (r=0.612, P<0.01). CONCLUSION: The expression of LXRa is elevated significantly in placentas of PE patients, and might contribute for promoting the transcription and translation of its target gene SREBP1-c, which is related to the occurrence and development of PE. PMID- 28352811 TI - ARDS diagnosed by SpO2/FiO2 ratio compared with PaO2/FiO2 ratio: the role as a diagnostic tool for early enrolment into clinical trials. PMID- 28352809 TI - Malfunctions of robotic system in surgery: role and responsibility of surgeon in legal point of view. AB - Robotic surgery (RS) technology has undergone rapid growth in the surgical field since its approval. In clinical practice, failure of robotic procedures mainly results from a surgeon's inability or to a device malfunction. We reviewed the literature to estimate the impact of this second circumstance in RS and its consequent legal implications. According to data from the literature, device malfunction is rare. We believe it is necessary to complement surgical training with a technical understanding of RS devices. PMID- 28352812 TI - Medicolegal implications of surgical errors and complications in neck surgery: A review based on the Italian current legislation. AB - Aim of the present paper is the review of the principal complications associated to endocrine neck surgery considering how expertise, full adoption of guidelines, appropriate technology and proper informed consent may limit the medicolegal claims at the light of the incoming new regulation of the medical professional legal responsibility. A literature search, using the Medline/PubMed database for full-length papers, was used. Postoperative recurrent laryngeal nerve (RLN) palsy and hypoparathy-roidism remain the principal causes of surgical malpractice claims . In the procedure of neck lymphadenctomy intra-operative haemorrhage, thoracic duct injury, injuries to loco-regional nerves can be observed and can be source of claims. After many years of increased medicolegal litigations, the Italian government is proposing a drastic change in the regulations of supposed medical malpractice in order to guarantee the patient's right to a safe treatment and in the meantime to defend clinicians from often unmotivated and prejudicial legal cases. Surgical errors and complications in neck surgery are a relevant clinical issue. Only the combination of surgical and clinical expertise, application of guidelines, appropriate technology and a routinely use of specific informed consent can contain potential medicolegal implications. PMID- 28352814 TI - Donation of the body for scientific purposes in Italy: ethical and medico-legal considerations. AB - In recent years in Italy (and in the other European Countries) a new debated topic involves anatomists and the scientific world: donation of the body after death for scientific purposes. The aim of our analysis is to analyze the issue of voluntary body donation in Italy focusing first of all, on key principles of the disciplines of donation. Considering the rise of exhibitions and events in which death is spectacularized, the debate is focus on will, on respect and overall on the purpose for which the body is donated. Anatomical dissection is considered necessary in the direct learning of the human body, of surgical practices and new scientific techniques but the scarcity of programmes and regulations regarding the donation of bodies for study and research make it an uncommon practice. After discussing what are the constitutional principles underlying the issue we want to emphasize the need of a more effective and updated regulation to set limits and methods of a practice still essential for scientific progress. PMID- 28352813 TI - Iatrogenic splenic injury: review of the literature and medico-legal issues. AB - INTRODUCTION: Iatrogenic splenic injury is a recognized complication in abdominal surgery. The aim of this paper is to understand the medico-legal issues of iatrogenic splenic injuries. We performed a literature review on PubMed and Scopus using iatrogenic splenic or spleen injury and iatrogenic splenic rupture as keywords. Iatrogenic splenic injury cases were identified. Most cases were related to colonoscopy, but we also identified cases related to upper gastrointestinal procedures, colonic surgery, ERCP, left nephrectomy and/or adrenalectomy, percutaneous nephrolithotomy, vascular operations involving the abdominal aorta, gynecological operation, left lung biopsy, chest drain, very rarely spinal surgery and even cardiopulmonary resuscitation. There are several surgical procedures that can lead to a splenic injury. However, from a medico legal point of view, it is important to assess whether the cause can be attributed to a technical error of the operator rather than being an unpredictable and unpreventable complication. It is important for the medico legal expert to have great knowledge on iatrogenic splenic injuries because it is important to evaluate every step of the first procedure performed, how a splenic injury is produced, and whether the correct treatment for the splenic injury was administered in a judgment. PMID- 28352815 TI - Voluntary termination of pregnancy (medical or surgical abortion): forensic medicine issues. AB - In Italy, Law 194 of 22 May 1978 provides for and regulates the voluntary termination of pregnancy (VTP). Medical abortion became popular nationwide after Mifepristone (RU-486) was authorized for the market by AIFA (Italian Drug Agency) in July 2009. We searched articles in medical literature database with these terms: "medical abortion", "RU486", "surgical abortion". We also searched laws and judgments concerning abortion in national legal databases. Ministerial guidelines were searched on official website of Italian Ministry of Health. We found many medical studies about medical and surgical abortion. We found also ministerial and regional guidelines, which were analyzed. From the point of view of legal medicine, the issues related to abortion with the pharmacological method consist in verifying compatibility and consistency with the safety principles and the parameters imposed by Law n. 194 of 1978, using off-label Misoprostol, what inpatient care should be used and informed consent. The doctor's job is to provide the patient with comprehensive and clear information about how the procedure will be performed, any complications and the time period needed for both procedures. PMID- 28352816 TI - Cosmetic surgery: medicolegal considerations. AB - : Cosmetic surgery is one of the two branches of plastic surgery. The characteristic of non-necessity of this surgical speciality implies an increased severity in the evaluation of the risk-benefit balance. Therefore, great care must be taken in providing all the information necessary in order to obtain valid consent to the intervention. We analyzed judgments concerning cosmetic surgery found in national legal databases. A document of National Bioethics Committee (CNB) was also analyzed. CONCLUSION: The receipt of valid, informed consent is of absolute importance not only to legitimise the medical-surgical act, but it also represents the key element in the question concerning the existence of an obligation to achieve certain results/use of certain methods in the cosmetic surgery. PMID- 28352817 TI - Impact of sensory integration training on balance among stroke patients: sensory integration training on balance among stroke patients. AB - This study attempts to investigate the impact that the sensory integration training has on the recovery of balance among patients with stroke by examining the muscle activity and limit of stability (LOS). A total of 28 subjects participated. The subjects were randomly allocated by the computer program to one of two groups: control (CON) group (n=15), sensory integration training (SIT) group (n=13). The research subjects received intervention five days a week for a total of four weeks. The CON group additionally received 30-minute general balance training, while the SIT group additionally received 30-minute sensory integration training. In the muscle activity, the improvement of Erector spinae (ES) and Gluteus medius (GM) was more significant in the SIT group than in the CON group. In the LOS, the improvement of affected side and forward side was significantly higher in the SIT group compared to the CON group. Sensory integration training can improve balance ability of patients with stroke by increasing muscle activity of stance limb muscles such as GM and trunk extensor such as ES along with enhancement of the limit of stability. PMID- 28352819 TI - Influenza A(H1N1)pdm09 and postpandemic influenza in Lithuania. AB - The objective of this study is to describe the clinical and epidemiological characteristics of patients hospitalized in Lithuania who are infected with influenza A(H1N1)pdm09 and to compare pandemic A(H1N1) pdm09 infection with postpandemic. In total, 146 subjects hospitalized with influenza A(H1N1) pdm09 were identified from 2009-2011. There were 53 during the initial pandemic wave in the summer of 2009, 69 during the peak pandemic period, and 24 during the "postpandemic" period that we included in this study. There were 22 subjects who died after laboratory confirmation of influenza A(H1N1)pdm09. No deaths were documented during the first wave. Subjects presenting during the peak of pandemic influenza had a greater incidence of fever (100% vs 77.4%; p<0.001), dry cough (95.7% vs 82.7%; p=0.01), and vomiting (26.1% vs 1.9%, p<0.001) as compared with patients infected during the first wave. The rate of bacterial pneumonia was 18.8% (13/69) during the peak pandemic period and 12.5% (3/24, p=0.754) during the postpandemic period. None of the postpandemic influenza subjects' intensive care unit stays were due to pneumonia. The hospitalized early 2009 H1N1 pandemic cases and postpandemic cases were milder compared with those at the peak of pandemic activity. PMID- 28352818 TI - MicroRNAs as regulatory elements in psoriasis. AB - Psoriasis is a chronic, autoimmune, and complex genetic disorder that affects 23% of the European population. The symptoms of Psoriatic skin are inflammation, raised and scaly lesions. microRNA, which is short, nonprotein-coding, regulatory RNAs, plays critical roles in psoriasis. microRNA participates in nearly all biological processes, such as cell differentiation, development and metabolism. Recent researches reveal that multitudinous novel microRNAs have been identified in skin. Some of these substantial novel microRNAs play as a class of posttranscriptional gene regulator in skin disease, such as psoriasis. In order to insight into microRNAs biological functions and verify microRNAs biomarker, we review diverse references about characterization, profiling and subtype of microRNAs. Here we will share our opinions about how and which microRNAs are as regulatory in psoriasis. PMID- 28352820 TI - Garengeot's hernia: two case reports with CT diagnosis and literature review. AB - : Garengeot's hernia (GH) is defined as the presence of the appendix inside a femoral hernia. It occurs in 0.9% of femoral hernias and is usually an incidental finding during surgery. Its treatment is controversial and the aim of this article is to review the diagnostic methods and surgical considerations. We report two cases diagnosed preoperatively by contrast-enhanced computed tomography (CT) and discuss the treatment options based on a review of the literature published in PubMed updated on 1 December, 2015. Fifty articles reporting 64 patients (50 women, mean age 70 years) with GH were included in the analysis. Diagnosis was performed by preoperative CT in only 24 cases, including our two. The treatment of GH is emergency surgery. Several options are available laparoscopic or open approach: insertion of a mesh or simple herniorrhaphy, with or without appendectomy. CONSLUSION: The preoperative diagnosis with CT can guide the choice of treatment. Appendectomy and hernioplasty should be performed via inguinotomy, if there is no perforation or abscess formation. PMID- 28352822 TI - Endoscopic diagnosis and treatment of neuroendocrine tumors of the digestive system. AB - The authors evaluated the role of endoscopic techniques in the diagnosis and in the potential treatment of neuroendocrine tumors (NET) localized in the gastro entero-pancreatic system, on the basis of their experience and of the international literature. NET are rare tumors that arise from neuroendocrine cells of the gastrointestinal tract and pancreas. It is a possibility that both the digestive endoscopy and EUS play an important role in the diagnosis, staging and surveillance of this disease. In some cases, especially in the early stages, surgical endoscopy allows the treatment of such tumors. PMID- 28352821 TI - Role of Laparoscopic Splenectomy in Elderly Immune Thrombocytopenia. AB - The management of older patients with chronic primary immune thrombocytopenia (ITP) is still very challenging because of the fragility of older patients who frequently have severe comorbidities and/or disabilities. Corticosteroid-based first-line therapies fail in most of the cases and patients require a second-line treatment, choosing between rituximab, thrombopoietin-receptor agonists and splenectomy. The choice of the best treatment in elderly patients is a compromise between effectiveness and safety and laparoscopic splenectomy may be a good option with a complete remission rate of 67% at 60 months. But relapse and complication rates remain higher than in younger splenectomized ITP patients because elderly patients undergo splenectomy with unfavorable conditions (age >60 year-old, presence of comorbidities, or multiple previous treatments) which negatively influence the outcome, regardless the hematological response. For these reasons, a good management of concomitant diseases and the option to not use the splenectomy as the last possible treatment could improve the outcome of old splenectomized patients. PMID- 28352823 TI - Efficacy and safety of splenectomy in adult autoimmune hemolytic anemia. AB - Autoimmune hemolytic anemia (AIHA) is a rare hematologic disease, primarily affecting adults or children with immunodeficiency disease. First-line therapy consists of long course of steroids administration, with an early complete response rate (CRr) of 75-80%, but up to 20-30% of patients requires a second line therapy. Rituximab is the first choice in refractory old AIHA patients, because of its safety and efficacy (early CRr at 80-90% and at 68% at 2-3 years). For this reason, splenectomy is even less chosen as second-line therapy in elderly, even though laparoscopic technique decreased complication and mortality rates. However, splenectomy can be still considered a good therapeutic option with a CRr of 81% at 35.6 months in patients older than 60 year-old, when rituximab administration cannot be performed. PMID- 28352824 TI - Relationship between gastroesophageal reflux disease and Ph nose and salivary: proposal of a simple method outpatient in patients adults. AB - INTRODUCTION: The frequency of gastroesophageal reflux disease (GERD) is increasing, in part through easy inspection of the upper digestive tract, but especially for a real spread of the disease as a consequence of modernity, lifestyle, incorrect dietary rules, and stress arising from social norms. It is a common chronic gastrointestinal disorder in Europe and the United States. MATERIALS AND METHODS: The aim of our study is to highlight a relationship between gastroesophageal reflux disease and salivary pH as evidenced by indicator strips, especially in the outpatient field. Twenty adult subjects (10 males and 10 females) aged between 18 and 50 years (GROUP A)_ were selected. How to control a homogeneous group of 20 patients without GERD, or from any type of allergies (GROUP B) was enlisted. RESULTS: This method has provided excellent results showing no difference in the measured values compared with the traditional instrumental measurement. CONCLUSION: Our study has allowed us to observe a strong correlation between the saliva pH, nasal cavities and the interaction between the two districts, and could be the basis for a diagnosis of GERD especially in primary health care clinics and in the initial stage of the disease. PMID- 28352825 TI - Concept of experimental preparation for treating dentin hypersensitivity. AB - BACKGROUND: Dentinal hypersensitivity (DH) is a diagnostic and therapeutic problem that is now appearing more frequently in modern dentistry. The aim of this work was to elaborate formulation of a new, original desensitizing preparation with prolonged action based on the knowledge of similar commercializations and to compare their performance in vitro. METHODOLOGY: The analyses were performed with the aid of NMR spectroscopy. The experimental and commercial preparations were examined in vitro after thermocycling on human teeth by optical microscopy. The presence of the material on tooth tissue, its ability to penetrate into the tooth structure and its layer thickness were subjected to statistical analysis. RESULTS: A detailed knowledge on composition of commercial material was achieved from spectroscopic measurements. A new adhesive monomer was synthesized and incorporated into an experimental desensitizing formulation. The new monomer appeared to have comparable performance to the commercial one when regarding the affinity to tooth tissue and resistance to thermocycling. CONCLUSIONS: The experimental formulation comprising a new adhesive monomer seems to be promising and could be applied in dental practice providing that biocompatibility is satisfactory. PMID- 28352827 TI - Hydrogen water reduces NSE, IL-6, and TNF-alpha levels in hypoxic-ischemic encephalopathy. AB - This study retrospectively analyzed the efficacy of hydrogen water in the treatment of neonatal hypoxic-ischemic encephalopathy (HIE) and its effect on serum neuron-specific enolase (NSE), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) levels. Forty newborns with HIE who received treatment from April 2014 to April 2015 were divided into a conventional care group and a hydrogen water group according to the different treatment methods applied. Twenty healthy full-term newborns comprised the control group. In the hydrogen water group, 5-mL/kg hydrogen water was orally administered two days after birth daily for 10 days in addition to conventional treatment. After 10 days, efficacy indicators were examined in the HIE groups. The NSE, IL-6, and TNF-alpha levels were compared among all three groups. The efficacy indicators were significantly lower in the hydrogen water group compared with the conventional group. Before treatment, the serum NSE, IL-6, and TNF-alpha levels in the HIE groups were higher than those in the control group. After treatment, these levels in the hydrogen water group were lower than those in the conventional group. Hydrogen water lowers serum NSE, IL-6, and TNF-alpha levels in HIE newborns, thereby exerting a protective effect. PMID- 28352828 TI - Morbid Obesity: treatment with Bioenterics Intragastric Balloon (BIB), psychological and nursing care: our experience. AB - Obesity is considered a chronic disease, difficult to treat, and is the first cause of death in the world that is predictable. The surgical approach is limited to patients with severe obesity but there is an intermediate group who are not candidates for immediate surgery. The BioEnterics Intragastric Balloon (BIB) is recommended for weight reduction as a bridge to bariatric surgery. All patients in the study underwent a psychological evaluation prior to placement of the BIB. PMID- 28352826 TI - Idiopathic pleural panniculitis with recurrent pleural effusion not associated with Weber-Christian disease. AB - A 82-year-old patient with dyspnea and a recurrent history of pleural effusion was admitted into our unit. He performed a Chest computed tomography showing right pleural effusion. Video-assisted thoracoscopy (VATS) exploratory showed parietal pleural thickening of adipose tissue. The surgical procedure consisted, therefore, in the execution of multiple biopsies of the parietal pleura which appeared covered, on the whole surface, by islands of adipose tissue, without macroscopic pathological aspects. After the procedure was performed pleurodesis with talc. The definitive histological examination consisted of normal mesothelial cells surrounded by fatty tissue infiltrated by small lymphocytes in a patient without skin lesions or visceral or systemic signs of inflammatory involvement of the adipose tissue. We reported a rare case of idiopathic pleural panniculitis with recurrent pleural effusion not associated with Weber-Christian disease. PMID- 28352829 TI - Uncommon primary hydatid cyst occupying the adrenal gland space, treated with laparoscopic surgical approach in an old patient. AB - : Hydatid disease (HD) is caused by Echinococcus Granulosus (EG), which is a larva endemic in many undeveloped areas. The most common target is the liver (59% 75%). The retroperitoneal space is considered as a rare localization. We report an uncommon case of HD located in the adrenal gland space. PRESENTATION OF CASE: This is a 78-year-old Moroccan woman, with right flank pain for eight months previously. She denied contact with dogs or sheep. Her physical examination was normal. There was no pathological alteration of laboratory exams. CT scan measuring 5 cm without clear signs for a sure diagnosis found a round lesion in the right adrenal gland. An abdominal MRI showed a round mass of 34 x 27 mm with fluid component without a clear plane of dissection from kidney and liver. A laparoscopic procedure was performed to obtain a histological diagnosis. We reached a conclusive diagnosis of Hydatid cyst of right adrenal gland space. Hydatid cysts often develop in the liver. The location in the adrenal bed is rare without clinical signs related to alteration of the gland's secretion. Hydatid cyst identification in the adrenal gland space is based on ultrasonography, CT or MRI scans. The differential diagnosis includes various benign and malignant lesions. Laparoscopic procedure is the best approach available to obtain a histological diagnosis and a curative treatment. The best treatment for HD is the pericystectomy. Laparoscopic surgery can guarantee a radical resection of these lesions when it performed by an expert surgeon. PMID- 28352830 TI - Learning curve for endorectal ultrasound in young and elderly: lights and shades. AB - Aim of the study is to highlight difficulties faced by an inexperienced surgeon in approaching endorectal-ultrasound, trying to define when learning curve can be considered complete. A prospective analysis was conducted on endorectal ultrasound performed for subperitoneal rectal adenocarcinoma staging in the period from January 2008 to July 2013, reported by a single surgeon of Department of Oncology, Section of General Surgery, "San Luigi Gonzaga" Teaching Hospital, Orbassano (Turin, Italy); the surgeon had no previous experience in endorectal ultrasound. Fourty-six endorectal-ultrasounds were divided into two groups: early group (composed by 23 endorectal-ultrasounds, made from January 2008 to May 2009) and late group (composed by 23 endorectal-ultrasound, carried out from June 2009 to July 2013). In our experience, the importance of a learning curve is evident for T staging, but no statystical significance is reached for results deal with N stage. We can conclude that ultrasound evaluation of anorectal and perirectal tissues is technically challenging and requires a long learning curve. Our learning curve can not be closed down, at least for N parameter. PMID- 28352832 TI - Laparoscopic antegrade cholecystectomy: a standard procedure? AB - : Retrograde approach ("fundus first") is often used in open surgery, while in laparoscopic cholecystectomy (LC) is less frequent. LC, with antegrade access, is done by putting in traction the infundibulum and going up to the fundus before to clip the cystic. Our study analyzes a number of surgical procedures performed by experienced surgeons in laparoscopy. From 2002 to 2015, 1740 laparoscopic cholecystectomies were performed at our Institution. The operative procedure performed since 2002 consists of the incision of the visceral peritoneum from the infundibulum away from Calot's triangle along the gallbladder bed up to the fundus. Then it continues from the fundus up to the infundibulum. RESULTS: There were no bile duct injuries. Average operative time was 40 min. 22 conversions to an open procedure (1.3%) occurred, in cases of acute cholecystitis and cirrhotic patient. Postoperative stay was mean 2 days with no delayed sequelae on follow up. CONCLUSIONS: gallbladder antegrade dissection for laparoscopic cholecystectomy can reduce the time of surgery and is an easier technique to perform. Therefore, it can be proposed as the standard procedure and not only be used for difficult cholecystectomies. PMID- 28352831 TI - Xanthogranuloma of the sellar region diagnosed by frozen section. AB - Xanthogranuloma (XG) of the sellar region is uncommon and is difficult to diagnose based on intraoperative frozen sections. This study is a case presentation and review of the literature, highlighting the need to explore underlying diseases in order to guarantee an accurate patient diagnosis. Herein, we presented the case of a 43-year-old woman who was afflicted with xanthogranuloma of the sellar region; the patient had a history of headache and lengthened menstrual cycles over the 6 months prior to presentation. Endocrinology tests revealed that the patient's levels of prolactin were high and the MRI of the patient showed a clearly defined sellar mass. As a result, the patient was considered to have prolactinoma prior to undergoing surgery. The tumor was completely removed using a transsphenoidal approach, and intraoperative frozen section revealed histology similar to xanthogranuloma. When the tumor was removed by surgical operation, the patient's visual field defects and headache were relieved. Although intraoperative frozen section should provide some guidance with regard to the diagnosis, a pathological study is conducted to confirm the actual diagnosis. PMID- 28352833 TI - Distraction techniques for face and smile aesthetic preventing ageing decay. AB - Modern concepts in the world of beauty arise from popular models, beautiful faces of actors document a bi-protrusive asset with high tension for soft tissues. Facial symmetry has been proposed as a marker of development and stability that may be important in human mate choice. For various traits any deviation from perfect symmetry can be considered a reflection of imperfect development. Additionally, bi-protrusive profile is dependent on the hormonal level regardless of male or female sex. The goal of maxillofacial surgery is to provide best results both for aesthetic and functional aspects. Following these new concepts of aesthetic of the face, new surgical procedure by osteodistraction techniques will lead to a very natural result by harmonizing the face also preventing aesthetic decay in aging faces. Ten cases with a feedback on the aesthetic results using the fivepoint scale of Likert after orthognatic surgery performed following distraction new techniques in combination with ancillary surgical procedures. The aesthetic results in all patients were highly satisfactory. All the patients accepted the new aesthetic of the face avoiding elements of discrepancy and consequently medico-legal problems. PMID- 28352834 TI - Preoperative high-intensity training in frail old patients undergoing pulmonary resection for NSCLC. AB - Thoracic surgery remains the better therapeutic option for non-small cell lung cancer patients that are diagnosed in early stage disease. Preoperative lung function assessment includes respiratory function tests (RFT) and cardio pulmonary exercise testing (CPET). Vo2 peak, FEV1 and DLCO as well as recognition of performance status, presence of co-morbidities, frailty indexes, and age predict the potential impact of surgical resection on patient health status and survival risk. In this study we have retrospectively assessed the benefit of a high-intensity preoperative pulmonary rehabilitation program (PRP) in 14 patients with underlying lung function impairment prior to surgery. Amongst these, three patients candidate to surgical resection exhibited severe functional impairment associated with high score of frailty according CHS and SOF index, resulting in a substantial mortality risk. Our observations indicate that PRP appear to reduce the mortality and morbidity risk in frail patients with concurrent lung function impairment undergoing thoracic surgery. PRP produced improvement of VO2 peak degree and pulmonary function resulting in reduced postoperative complications in high-risk patients from our cases. Our results indicate that a preoperative training program may improve postoperative clinical outcomes in fraillung cancer patients with impaired lung function prior to surgical resection. PMID- 28352836 TI - Sialoendoscopy, sialography, and ultrasound: a comparison of diagnostic methods. AB - OBJECTIVE: To compare the accuracy of ultrasound, sialography, and sialendoscopy for examining benign salivary gland obstructions. METHODS: In this prospective study, patients with symptoms of obstruction of the major salivary gland duct system presenting at the ENT Clinic University Hospital, Ostrava, from June 2010 to December 2013 were included. All patients (n=76) underwent ultrasound, sialography, and sialoendoscopy. The signs of sialolithiasis, ductal stenosis, or normal findings were recorded after the examinations. Statistical analysis of the sensitivity and specificity of all the methods was performed, as well as a comparison of the accuracy of each method for different kinds of pathology (sialolithiasis or stenosis). RESULTS: The sensitivity of ultrasound, sialography, and sialoendoscopy for sialolithiasis findings were 71.9%, 86.7 %, and 100%, respectively. The sensitivity of sialography and sialoendoscopy for stenosis of the duct was 69.0%, and 100%, respectively. The study showed impossibility of ultrasonic diagnostics of ductal stenosis. The sensitivity of sialoendoscopy for both pathologies was significantly higher than that from ultrasound or sialography (p<0.05). The specificity of sialoendoscopy was significantly higher than that from by ultrasound or sialography (p<0.05). CONCLUSION: Sialoendoscopy was the most accurate method for examination ductal pathology, with significantly higher sensitivity and specificity than by ultrasound or sialography. PMID- 28352835 TI - Descending necrotizing mediastinitis in the elderly patients. AB - Descending Necrotizing Mediastinitis (DNM) is a polymicrobic, dangerous and often fatal process, arising from head or neck infections and spreading along the deep fascial cervical planes, descending into the mediastinum. It can rapidly progress to sepsis and can frequently lead to death. It has a high mortality rate, up to 40% in the different series, as described in the literature. Surgical and therapeutic management has been discussed for long time especially in an elderly patient population. The literature has been reviewed in order to evaluate different pathogenesis and evolution and to recognise a correct therapeutic management. PMID- 28352837 TI - Maxillary fibrous dysplasia associated with McCune-Albright syndrome. A case study. AB - McCune Albright syndrome (MCA) is a rare complication of genetic origin. The authors present a case study of a patient with MCA diagnosed with multifocal fibrous dysplasia in his limb and craniofacial bones. The symptoms of the disease in the patient's facial and oral tissue and the treatment administered have been described. PMID- 28352838 TI - Prophylactic GSV surgery in elderly candidates for hip or knee arthroplasty. AB - : Aging is one of the major risk factors for varicose veins. The same is for Knee and Hip Osteoarthritis. Most of the patients undergoing to Hip (THA) or Knee (TKA) arthroplasty are over sixteen. Varicose veins, excluding thrombophilia, are the most significant risk factors for VTE after THA and TKA. This study investigates on the usefulness of prophylactic treatment of GSV insufficiency in elderly patients undergoing to orthopedic surgery. A retrospective study enrolling 44 over-sixty five patients, undergoing to TKA or THA. 24 patients underwent to traditional surgery and 20 to EVLA. The presence of evident varicosities and/or a saphenic reflux lasting > 500 ms has been considered as operability criterion. Both in surgery and EVLA group has been performed the ablation of visible varicosities and only saphenic refluxing traits. RESULTS: 1 case of symptomatic DVT was recorded after arthroplasty. A statistically significant difference (p = 0.006) of recovery time between surgery and EVLA groups has been detected. There is not a statistically significant difference in long-term recurrence rate between surgery and EVLA. CONCLUSIONS: It is useful to program GSV surgery, before treat hip or knee. This study showed a 50% decrease in the incidence of postoperative DVT. PMID- 28352839 TI - Diagnostic yield and safety of C-TBNA in elderly patients with lung cancer. AB - Conventional transbronchial needle aspiration (C-TBNA) is a minimally invasive technique used primarily in the diagnosis and staging of lung cancer. Currently lung cancer is mostly considered a disease of the elderly and the management of this disease in older patients is a growing concern. In this study we aimed to assess the diagnostic yield and safety of C-TBNA in elderly patients. A retrospective review of 88 consecutive C-TBNA procedures for nodal staging in suspected or confirmed primary lung cancer or pathological confirmation in suspected advanced lung cancer was performed. Patients were divided into less than 70 (<70yrs) or 70 and older (>=70yrs) age groups for analysis. There were no significant differences either in the diagnostic yield (69% in patients aged < 70 yrs and 74% patients aged >= 70 yrs (p=0.5) nor in the complication rate (respectively 8.8% in patients aged < 70 yrs and 6.9% in patients aged >= 70 yrs (p=0.7) between the two age groups. Reported complications were minor bleeding and poor tolerance; no major complications were observed. Based on our experience, C-TBNA represents a useful and safe alternative procedure for the diagnosis and staging of lung cancer in elderly patients. PMID- 28352840 TI - Antibody Response to Live Attenuated Vaccines in Adults in Japan. AB - The purpose of this study was to examine the efficacy rendered with a single dose of live attenuated measles, rubella, mumps, and varicella containing vaccine. We inoculated healthcare workers (HCWs) with a single dose of vaccine to a disease lacking in antibody titer for those not meeting the criteria of our hospital (measles: <16.0 (IgG enzyme immunoassay (EIA)), rubella: <=1:32 (hemagglutination inhibition), mumps: <4.0 (IgG EIA), and varicella: <4.0 (IgG EIA)). At 28-60 days after vaccination, the antibody titer was tested again. We included 48 HCWs. A total of 32, 15, 31, and 10 individuals were inoculated with a single dose of measles-containing, rubella-containing, mumps, or varicella vaccine, respectively, and showed significant antibody elevation (9.2 +/- 12.3 to 27.6 +/- 215.6, p<0.001; 8 +/- 1.2 to 32 +/- 65.5, p<0.001; 3.0 +/- 1.0 to 13.1 +/- 8.6, p<0.05; and 2.6 +/- 1.3 to 11.8 +/- 8.1, p<0.001, respectively). Major side effects were not observed. In a limited population, a single dose of live attenuated vaccine showed elevation of antibody titer without any severe adverse reactions. However, whether the post-vaccination response rate criteria of our university was fulfilled could not be determined owing to limited sample size. PMID- 28352841 TI - The learning curve of laparoscopic holecystectomy in general surgery resident training: old age of the patient may be a risk factor? AB - : A well-designed learning curve is essential for the acquisition of laparoscopic skills: but, are there risk factors that can derail the surgical method? From a review of the current literature on the learning curve in laparoscopic surgery, we identified learning curve components in video laparoscopic cholecystectomy; we suggest a learning curve model that can be applied to assess the progress of general surgical residents as they learn and master the stages of video laparoscopic cholecystectomy regardless of type of patient. Electronic databases were interrogated to better define the terms "surgeon", "specialized surgeon", and "specialist surgeon"; we surveyed the literature on surgical residency programs outside Italy to identify learning curve components, influential factors, the importance of tutoring, and the role of reference centers in residency education in surgery. From the definition of acceptable error, self efficacy, and error classification, we devised a learning curve model that may be applied to training surgical residents in video laparoscopic cholecystectomy. Based on the criteria culled from the literature, the three surgeon categories (general, specialized, and specialist) are distinguished by years of experience, case volume, and error rate; the patients were distinguished for years and characteristics. The training model was constructed as a series of key learning steps in video laparoscopic cholecystectomy. Potential errors were identified and the difficulty of each step was graded using operation-specific characteristics. On completion of each procedure, error checklist scores on procedure-specific performance are tallied to track the learning curve and obtain performance indices of measurement that chart the trainee's progress. CONCLUSIONS: The concept of the learning curve in general surgery is disputed. The use of learning steps may enable the resident surgical trainee to acquire video laparoscopic cholecystectomy skills proportional to the instructor's ability, the trainee's own skills, and the safety of the surgical environment. There were no patient characteristics that can derail the methods. With this training scheme, resident trainees may be provided the opportunity to develop their intrinsic capabilities without the loss of basic technical skills. PMID- 28352843 TI - Anal sphincter dysfunction in multiple sclerosis: an observation manometric study. AB - : Constipation, obstructed defecation, and fecal incontinence are frequent complaints in multiple sclerosis. The literature on the pathophysiological mechanisms underlying these disorders is scant. Using anorectal manometry, we compared the anorectal function in patients with and without multiple sclerosis. 136 patients referred from our Center for Multiple Sclerosis to the Coloproctology Outpatient Clinic, between January 2005 and December 2011, were enrolled. The patients were divided into four groups: multiple sclerosis patients with constipation (group A); multiple sclerosis patients with fecal incontinence (group B); non-multiple sclerosis patients with constipation (group C); non multiple sclerosis patients with fecal incontinence (group D). Anorectal manometry was performed to measure: resting anal pressure; maximum squeeze pressure; rectoanal inhibitory reflex; filling pressure and urge pressure. The difference between resting anal pressure before and after maximum squeeze maneuvers was defined as the change in resting anal pressure calculated for each patient. RESULTS: Group A patients were noted to have greater sphincter hypotonia at rest and during contraction compared with those in group C (p=0.02); the rectal sensitivity threshold was lower in group B than in group D patients (p=0.02). No voluntary postcontraction sphincter relaxation was observed in either group A or group B patients (p=0.891 and p=0.939, respectively). CONCLUSIONS: The decrease in the difference in resting anal pressure before and after maximum squeeze maneuvers suggests post-contraction sphincter spasticity, indicating impaired pelvic floor coordination in multiple sclerosis patients. A knowledge of manometric alterations in such patients may be clinically relevant in the selection of patients for appropriate treatments and for planning targeted rehabilitation therapy. PMID- 28352844 TI - Excellence and safety in surgery require excellent and safe tutoring. AB - : The surgical education in Italy has always been a very important issue. The aim of this article is to bring together the feedback of the definitions of the various components of the learning scheme and to evaluate the importance of the legal point. In March 2016 we performed a literature review. We have also examinated the internet pages of the Italian Department of Education, Health and Medical Order. In Italy the tutor had an unclear role from a legal point of view. He is the person who must be able to perform a specific procedure with expert technical and who must know how to stop the student if this is about to perform a dangerous maneuver. In Italy the ability to work for the trainee is limited in all reality, it depends on several factors including the increase of numbers of medical-legal disputes, the timing, the commitment it requires mentoring and a lack of mentors. CONCLUSION: In surgery, the problem is greater because of the increasingly of medico-legal implications that we are after surgical procedure. It would be necessary to define a role of the tutor in a regular protocol and a proper assessment of his performance. PMID- 28352842 TI - Self-gripping mesh versus fibrin glue fixation in laparoscopic inguinal hernia repair: a randomized prospective clinical trial in young and elderly patients. AB - Laparoscopic transabdominal preperitoneal inguinal hernia repair is a safe and effective technique. In this study we tested the hypothesis that self-gripping mesh used with the laparoscopic approach is comparable to polypropylene mesh in terms of perioperative complications, against a lower overall cost of the procedure. We carried out a prospective randomized trial comparing a group of 30 patients who underwent laparoscopic inguinal hernia repair with self-gripping mesh versus a group of 30 patients who received polypropylene mesh with fibrin glue fixation. There were no statistically significant differences between the two groups with regard to intraoperative variables, early or late intraoperative complications, chronic pain or recurrence. Self-gripping mesh in transabdominal hernia repair was found to be a valid alternative to polypropylene mesh in terms of complications, recurrence and postoperative pain. The cost analysis and comparability of outcomes support the preferential use of self-gripping mesh. PMID- 28352845 TI - Suggestions on how to make suboptimal kidney transplantation an ethically viable option. AB - To overcome kidney donation, the pool of potentially eligible donors has been widened by using suboptimal organs harvested from living donors or cadavers. These organs may engender health complications as age, risk factors, and pathologies of donors fail to meet the standard donor criteria. After examining a wide array of literature on suboptimal kidney transplants, we evidenced two major issues: the lack of standardized terminology and the lack of longterm data on the health outcomes of both suboptimal living donors and recipients. Consequently, surgeons are still unable to provide patients with thorough information to obtain a well-informed consent. Suboptimal kidney transplantation still remains in its experimental stage, thereby raising many ethical and medico-legal concerns. We suggest that one possible solution to overcome some of the ethical shortcomings of suboptimal kidney donations is to provide living donors and recipients honest, accurate, and thorough information about its health risks. To this aim, we advocate adopting a widely standardized terminology that would embrace the whole concept of suboptimal kidney transplantation, increasing the number of future publications on the health outcomes of living donors and recipients, spurring ethical reflection to improve the experience of suboptimal kidney transplantation and reduce the waiting-list for kidney transplantation. PMID- 28352846 TI - Ectopic pregnancy treatment by combination therapy. AB - Detectability of early stages of ectopic pregnancies has increased due to improvements in ultrasonographic and biochemical techniques. Since the patients' future procreative plans must be taken into consideration when commencing treatment, the goal of this work was to compare the effects of treatment methods and their impact on fertility. The study included 91 patients treated surgically for ectopic pregnancy. The choice of treatment depended on patients' general condition, ultrasonographic evaluation and serum level of beta-hCG. A combination of laparoscopic and conservative systemic treatment was applied in 70% of cases. More rapid beta-hCG reduction was noted when laparoscopy and intra-oviductal injection of hyperosmolar glucose or methotrexate (MTX) were combined with intramuscular administration of MTX at a dose of 50 mg/m2. Follow-up examination of 66 patients revealed that the greatest number of spontaneous pregnancies (48%) resulted after this combination therapy. We conclude that this combination treatment is safe and provides satisfactory results in terms of future fertility. PMID- 28352848 TI - Cusum analysis for learning curve of videothoracoscopic lobectomy. AB - BACKGROUND: Video assisted thoracoscopic (VATS) lobectomy has a demanding learning curve due to its technical complexity and risk of uncontrollable bleeding. We investigated the case number required for gaining technical proficiency by applying cumulative sum analysis on initial VATS lobectomy operations of a single surgeon. METHODS: CALGB definition was used for the definition of VATS lobectomy. The data of the initial cases evaluated and cumulative sum (CUSUM) analysis was applied to duration of the operations and length of hospital stay. RESULTS: Fifty-eight patients underwent VATS lobectomy. Of those 51 were malignant and 7 were benign. Fifty-five of the procedures were lobectomy, 2 were inferior bi-lobectomy and 1 was left upper lobectomy with chest wall resection. CUSUM analysis reached to proficiency at 27 cases for duration of the operations. CONCLUSIONS: The length of learning curve depends on previous experience of the surgeon on open lobectomy and simpler VATS operations, potential number of VATS lobectomy cases and VATS capability of the surgeon. Depending on these factors, it is possible to obtain technical proficiency with an inferior number of procedures compared with existing literature (50-200). PMID- 28352847 TI - Use of a simplified consent form to facilitate patient understanding of informed consent for laparoscopic cholecystectomy. AB - BACKGROUND: Surgical informed consent forms can be complicated for patients to read and understand. We created a consent form with key information presented in bulleted texts and diagrams combined in a graphical format to facilitate the understanding of information during the verbal consent discussion. METHODS: This prospective, randomized study involved 70 adult patients awaiting cholecystectomy for gallstones. Consent was obtained after standard verbal explanation using either a graphically formatted (study group, n=33) or a standard text document (control group, n=37). Comprehension was evaluated with a 9-item multiple-choice questionnaire administered before surgery and factors affecting comprehension were analyzed. RESULTS: Comparison of questionnaire scores showed no effect of age, sex, time between consent and surgery, or document format on understanding of informed consent. Educational level was the only predictor of comprehension. CONCLUSIONS: Simplified surgical consent documents meet the goals of health literacy and informed consent. Educational level appears to be a strong predictor of understanding. PMID- 28352849 TI - A meta-analysis of association between glutathione S-transferase M1 gene polymorphism and Parkinson's disease susceptibility. AB - The aim of this meta-analysis was to evaluate whether there was an association between glutathione S-transferase M1(GSTM1)gene polymorphism and Parkinson's disease (PD) susceptibility by pooling published data. We performed comprehensive electronic database search for articles published between February12,2015 and April30 2016. The published case-control or cohort studies related to GSTM1 gene polymorphism and Parkinson's disease susceptibility were screened, reviewed, and included in this meta-analysis. The correlation between GSTM1 gene polymorphism and PD susceptibility was expressed by odds ratio (OR) and its corresponding 95% confidence interval (95%CI). Publication bias was evaluated by Begg's funnel plot and Egger's line regression test. All analysis was done by stata11.0 software. After searching the PubMed, EMBASE, and CNKI databases, seventeen case-control studies with 3,538 PD and 5,180 controls were included in the final meta analysis. The data was pooled by a fixed-effect model for lack of statistical heterogeneity across the studies; the results showed GSTM1 null expression can significant increase the susceptibility of PD (OR=1.11, 95% CI:1.01-1.21, P<0.05). Subgroup analysis indicated GSTM1 gene polymorphism was associated with PD susceptibility in the Caucasian ethnic group (OR=1.15, 95% CI:1.05-1.27, P<0.05) but not in the Asian ethnic group (OR=0.89, 95% CI:0.70-1.12, P>0.05). Begg's funnel plot and Egger's line regression test showed no significant publication bias. Based on the present evidence, GSTM1 null expression can significant increase the susceptibility of PD in persons of Caucasian ethnicity. PMID- 28352850 TI - Plastination: ethical and medico-legal considerations. AB - The international plastination phenomenon has proved to be immensely popular with audiences world-wide. Never before has the human body been exposed to public gaze in such an accessible manner. The exhibitions have perplexed many, included anatomists, some of whom find the display of human bodies unethical. The objective of this study is to review the attention on the use of plastination and exhibition of entire human bodies for non-educational or commercial purposes. The nature of these exhibitions and the uneasy balance between entertainment and education has caused heated debate. The possible legitimacy of the expression of one's will as far as exhibition purposes isn't considered sufficient for the indiscriminate use of a corpse despite the ethical necessity of respecting the wishes of individuals based on respect for the deceased. The informed consent of an individual represents only the most basic and minimal prerequisite for the use of the deceased's body for exhibition purposes, and is absolutely not enough on its own to justify its use in entertainment exhibitions or for the commercialization of the death. PMID- 28352851 TI - Investigation and control of a suspected nosocomial outbreak of pan-drug resistant Acinetobacter baumannii in an intensive care unit. AB - Acinetobacter baumannii, a non-fermenting Gram-negative bacterium, is a common pathogen in intensive care units (ICU) that is easily spread through contact and can cause nosocomial outbreaks. This study investigated the risk factors associated with outbreaks of pan-drug resistant Acinetobacter baumannii (PDR-Ab) infection by studying a suspected nosocomial outbreak in a comprehensive ICU in a teaching hospital in China, and discusses the effectiveness of current prevention and control measures. Pathogen detection methods involving pulsed field gel electrophoresis (PFGE) were employed to survey patients infected or colonized with PDR-Ab. An epidemiological investigation was conducted to determine the risk factors for infection or colonization with PDR-Ab between 1 October 2014 and 16 January 2015. The rate of PDR-Ab infection in the ICU was higher during the period from 1 October 2014 to 16 January 2015 than it was between 1 October 2013 and 16 January 2014. Only two cases were confirmed to have the same genotype. Risk factors were explored and the rate of infection was found to be controlled by interventions targeting these risk factors. A decrease in the number of infections was observed after multiple prevention and control measures were implemented, preventing the outbreak of a nosocomial infection. PMID- 28352852 TI - Multifactorial analysis of fatigue scale among nurses in Poland. AB - : Significant progress in the field of nursing has contributed to the widening of range of functions and professional duties of nurses. More frequent lack of nursing personnel has an impact on negative reception of work, it decreases sense of professional satisfaction and increases the level of burden and fatigue. METHODS: The study applied the non-experimental method - a descriptive comparative study without a control group. The data was collected on the basis of Polish-language version of a Japanese questionnaire. In order to evaluate the level of physical fatigue the pedometer was used. RESULTS: 158 respondents of a group of 160 were included in the statistical analysis. The study group was internally diversified. The research project assessed the usefulness of the multifactorial analysis in evaluating the main components of nursing fatigue. Multifactorial analysis has shown that mental fatigue concentrated with changes in activeness, motivation and physical fatigue are strongly correlated with age, professional experience and education. CONCLUSION: Nursing is a profession of a special character and mission. Regardless of the place of work, nursing staff should be given the possibility of pursuing their profession under conditions ensuring the sense of security and protecting them from harmful effects on health. PMID- 28352853 TI - Smoking cessation for free: outcomes of a study of three Romanian clinics. AB - In 2007, Romania implemented a national program for smoking cessation, providing medication and counseling, entirely for free. The present study focuses on the results of the program among participating smokers treated in three smoking cessation centers from three main cities of Romania: Iasi, Targu Mures and Cluj. Telephone interviews of 832 subjects from three databases of the Romanian cessation clinics of Iasi, Cluj and Targu Mures cities were conducted. These interviews were based on a standard Romanian guideline follow-up questionnaire. At 3 months follow up, abstinence was quite high (53.4%); at 12 months post quit date the study found 18.6% still abstinent subjects. More severely addicted smokers have quit with varenicline and the most difficult category of patients was represented by heavy smokers with respiratory co-morbidities. 61.5% of smokers and 97.2% of non-smokers were willing to receive relapse prevention counseling. Many subjects achieved a long duration partial abstinence (154 days +/- 180 SD abstinence days). This is the first study in Romanian smoking cessation centers to analyze the long term impact of fully reimbursed smoking cessation, covering three months pharmacotherapy and counseling. Providing smoking cessation for free had a positive long term impact on program participants. PMID- 28352855 TI - Fabrication of conjugated microporous polytriazine nanotubes and nanospheres for highly selective CO2 capture. AB - A one-spot template approach for fabricating porous organic nanotubes was developed and a molecular design, i.e. introducing thiophene and s-triazine functionalities to enhance host-guest interactions, lead to novel porous solids with high capacities for CO2 and exceptionally high ideal selectivities over N2 for effective gas storage and separation. PMID- 28352854 TI - Clinical efficacy and safety of tripterygium glycosides in treatment of stage IV diabetic nephropathy: A meta-analysis. AB - The aim of this meta-analysis was to evaluate the clinical efficacy and safety of tripterygium glycosides in treatment of stage IV diabetic nephropathy. Methods Through searching the PubMed and CNKI databases, the open published clinically controlled trials related to efficacy and safety of tripterygium glycosides in the treatment of stage IV diabetic nephropathy were collected. The pooled total efficacy, 24h urinary protein, serum creatinine and tripterygium glycosides related toxicity were calculated using Stata 11.0 software. Results Fourteen publications including 992 subjects (512 in the experimental group and 480 in the control group) were included in this study. Eight studies reported the total clinical efficacy comparing the experiment and control groups. No significant statistical heterogeneity was found in total efficacy (I2=24.9%, p>0.05). Thus, the combined odds ratio (OR) was pooled by fixed effect model. The pooled OR=4.16 with its 95% CI 2.71~6.37 (p<0.05), which indicated the total efficacy in the experiment group, was significant higher than that of control group (p<0.05); Thirteen studies reported the post-treatment 24h urinary protein value. Statistical heterogeneity analysis indicated significant heterogeneity across studies (I2=91.1%, p<0.05); that data was pooled by a random effects model. The combined standardized mean difference (SMD) was -1.55 with its 95% I -2.06~1.03, (p<0.05). The results indicated that post-treatment 24h urinary protein in the experiment group was significant lower than that in control group (p<0.05); Ten studies reported the post-treatment serum creatinine. Significant heterogeneity existed across those studies (I2=82.3%, p<0.05). Thereafter, the data was pooled by a random effect model. The combined standardized mean difference (SMD) was 0.24 with its 95%CI -0.40~0.09, (p<0.05). The results indicated that the post treatment serum creatinine in experiment group was significant lower than that of control group (p<0.05); Eight studies reported tripterygium glycoside-associated toxicity such as liver function damage, gastrointestinal reactions and menstrual disorders. With no statistical heterogeneity among the studies, the data was pooled by fixed effect model. The pooled OR=6.42 (95%CI 2.23~18.48, p<0.05). The pooled results showed the tripterygium glycoside- associated toxicity incidence rate was significant higher in the experiment group than that of the control group (p<0.05); There were no publication bias for effect size of total efficacy, 24h urinary protein, and serum creatinine. However, for tripterygium glycoside related toxicity, the publication bias was significant (t=-3.55, p<0.05). Conclusion The present evidence shows that tripterygium glycosides can improve clinical efficacy, reduce the 24h urinary protein and serum creatinine, but that they increase the tripterygium glycoside-related toxicity in treatment of stage IV diabetic nephropathy. PMID- 28352857 TI - Facile construction of mitochondria-targeting nanoparticles for enhanced phototherapeutic effects. AB - Phototherapy, as a noninvasive therapeutic procedure, has been applied to treat tumors. However, the application of phototherapy is often compromised by its low efficiency. Herein, we developed a novel nanoplatform based on cationic amphiphilic polymer-wrapped carbon nanotubes (rPAA@SWCNTs) with a photosensitizer, indocyanine green (ICG), for phototherapy. The as-prepared nanoparticles exhibited excellent mitochondria targeting due to the synergistic properties of highly positive charges from the polycations on the corona and the high hydrophobicity from the carbon nanotubes in the core. Moreover, the high buffer capacity of the polycations facilitated the endosomal escape of nanoparticles via a proton-sponge effect. When irradiated with an 808 nm NIR laser, ICG/rPAA@SWCNTs could precisely damage mitochondria with high efficiency and produce reactive oxygen species (ROS) and hyperthermia, which further induced the ROS burst from damaged mitochondria. The overproduced ROS accumulated in mitochondria ultimately resulted in mitochondrial damage and cell death. Therefore ICG/rPAA@SWCNTs may be able to achieve an amplifying phototherapeutic effect. PMID- 28352858 TI - N-Heterocyclic carbene copper-catalyzed direct alkylation of terminal alkynes with non-activated alkyl triflates. AB - (NHC)-Cu-catalyzed C(sp)-C(sp3) bond formation has been successfully achieved under mild conditions. Nonactivated alkyl triflates, which could be easily derived from alcohols, were utilized as C-O electrophiles. Mechanistic studies suggested that copper acetylide was the active species. Scale-up reactions further demonstrated the practicality and efficiency of the developed strategy. PMID- 28352859 TI - How RNase HI (Escherichia coli) promoted site-selective hydrolysis works on RNA in duplex with carba-LNA and LNA substituted antisense strands in an antisense strategy context? AB - A detailed kinetic study of 36 single modified AON-RNA heteroduplexes shows that substitution of a single native nucleotide in the antisense strand (AON) by locked nucleic acid (LNA) or by diastereomerically pure carba-LNA results in site dependent modulation of RNase H promoted cleavage of complementary mRNA strands by 2 to 5 fold at 5'-GpN-3' cleavage sites, giving up to 70% of the RNA cleavage products. The experiments have been performed using RNase HI of Escherichia coli. The 2nd best cleavage site, being the 5'-ApN-3' sites, cleaves up to 23%, depending upon the substitution site in 36 isosequential complementary AONs. A comparison of the modified AON promoted RNA cleavage rates with that of the native AON shows that sequence-specificity is considerably enhanced as a result of modification. Clearly, relatively weaker 5'-purine (Pu)-pyrimidine (Py)-3' stacking in the complementary RNA strand is preferred (giving ~90% of total cleavage products), which plays an important role in RNase H promoted RNA cleavage. A plausible mechanism of RNase H mediated cleavage of the RNA has been proposed to be two-fold, dictated by the balancing effect of the aromatic character of the purine aglycone: first, the locally formed 9-guanylate ion (pKa 9.3, ~18-20% N1 ionized at pH 8) alters the adjoining sugar-phosphate backbone around the scissile phosphate, transforming its sugar N/S conformational equilibrium, to preferential S-type, causing preferential cleavage at 5'-GpN-3' sites around the center of 20 mer complementary mRNA. Second, the weaker nearest neighbor strength of 5'-Pu-p-Py-3' stacking promotes preferential 5'-GpN-3' and 5'-ApN-3' cleavage, providing ~90% of the total products, compared to ~50% in that of the native one, because of the cLNA/LNA substituent effect on the neighboring 5'-Pu-p-Py-3' sites, providing both local steric flexibility and additional hydration. This facilitates both the water and water/Mg2+ ion availability at the cleavage site causing sequence-specific hydrolysis of the phosphodiester bond of scissile phosphate. The enhancement of the total rate of cleavage of the complementary mRNA strand by up to 25%, presented in this work, provides opportunities to engineer a single modification site in appropriately substituted AONs to design an effective antisense strategy based on the nucleolytic stability of the AON strand versus RNase H capability to cleave the complementary RNA strand. PMID- 28352860 TI - Mesoscopic helical architectures via self-assembly of porphyrin-based discotic systems. AB - Mesoscopic super-helices with preferred helicity have been serendipitously formed from the self-assembly of electroactive extended core discotic molecules. The investigation at dilute concentrations reveals intramolecular hydrogen-bonding and pi-pi stacking interactions as the driving force of the chiral self-assembly at different length scales. PMID- 28352862 TI - Simultaneous observation of surface- and edge-states of a 2D topological insulator through scanning tunneling spectroscopy and differential conductance imaging. AB - A 2D form of Bi2Se3 which acts as a topological insulator was grown through colloidal synthesis method. The surface-states and edge-states of the nanoplates were simultaneously probed through scanning tunneling spectroscopy (STS). At the interior, density of states (DOS) revealed the location of conduction and valence band edges. The DOS at the edges, on the other hand, brought out gapless conducting states along with a Dirac point at a non-zero value below the Fermi energy representing the Dirac cone of a 2D topological insulator. In differential tunnel conductance (dI/dV), images are recorded at different voltages and the two sections of the topological insulator can be viewed selectively or simultaneously with a clear contrast in illumination. Upon increasing the 2D-nanoplates thickness, the material turned into a 3D topological insulator with gapless surface states. PMID- 28352861 TI - Morphological and chemical transformations of single silica-coated CdSe/CdS nanorods upon fs-laser excitation. AB - Radiation-induced modifications of nanostructures are of fundamental interest and constitute a viable out-of-equilibrium approach to the development of novel nanomaterials. Herein, we investigated the structural transformation of silica coated CdSe/CdS nanorods (NRs) under femtosecond (fs) illumination. By comparing the same nanorods before and after illumination with different fluences we found that the silica-shell did not only enhance the stability of the NRs but that the confinement of the NRs also led to novel morphological and chemical transformations. Whereas uncoated CdSe/CdS nanorods were found to sublimate under such excitations the silica-coated nanorods broke into fragments which deformed towards a more spherical shape. Furthermore, CdS decomposed which led to the formation of metallic Cd, confirmed by high-resolution electron microscopy and energy dispersive X-ray spectrometry (EDX), whereby an epitaxial interface with the remaining CdS lattice was formed. Under electron beam exposure similar transformations were found to take place which we followed in situ. PMID- 28352864 TI - The convergent chemical synthesis of histone H3 protein for site-specific acetylation at Lys56 and ubiquitination at Lys122. AB - Deposition of (H3-H4)2 tetramers is believed to be the critical step in nucleosome assembly. Site-specific acetylation and ubiquitination of histone H3 have been speculated to synergistically facilitate the formation and deposition of (H3-H4)2 tetramers. Here we report our endeavors toward the first chemical synthesis of homogenous histone H3, which bears Lys56 acetylation and Lys122 ubiquitination, for in vitro biochemical and biophysical studies. PMID- 28352865 TI - Effects of synthetic iron and aluminium oxide surface charge and hydrophobicity on the formation of bacterial biofilm. AB - In this research, bacterial cell attachments to hematite, goethite and aluminium hydroxide were investigated. The aim was to study the effects of these minerals' hydrophobicity and pH-dependent surface charge on the extent of biofilm formation using six genetically diverse bacterial strains: Rhodococcus spp. (RC92 & RC291), Pseudomonas spp. (Pse1 & Pse2) and Sphingomonas spp. (Sph1 & Sph2), which had been previously isolated from contaminated environments. The surfaces were prepared in a way that was compatible with the naturally occurring coating process in aquifers: deposition of colloidal particles from the aqueous phase. The biofilms were evaluated using a novel, in situ and non-invasive technique developed for this purpose. A manufactured polystyrene 12-well plate was used as the reference surface to be coated with synthesized minerals by deposition of their suspended particles through evaporation. Planktonic phase growth indicates that it is independent of the surface charge and hydrophobicity of the studied surfaces. The hydrophobic similarities failed to predict biofilm proliferation. Two of the three hydrophilic strains formed extensive biofilms on the minerals. The third one, Sph2, showed anomalies in contrast to the expected electrostatic attraction between the minerals and the cell surface. Further research showed how the solution's ionic strength affects Sph2 surface potential and shapes the extent of its biofilm formation; reducing the ionic strength from ~200 mM to ~20 mM led to a tenfold increase in the number of cells attached to hematite. This study provides a technique to evaluate biofilm formation on metal-oxide surfaces, under well-controlled conditions, using a simple yet reliable method. The findings also highlight that cell numbers in the planktonic phase do not necessarily show the extent of cell attachment, and thorough physicochemical characterization of bacterial strains, substrata and the aquifer medium is fundamental to successfully implementing any bioremediation projects. PMID- 28352866 TI - Missing metal-linker connectivities in a 3-D robust sulfonate-based metal-organic framework for enhanced proton conductivity. AB - A rare example of a robust, sulfonate-based metal-organic framework (MOF) with a prototypical primitive-cubic topology has been successfully synthesized. Importantly, one-fourth of the metal-ligand connectivities residing in the MOF are missing, resulting in the appearance of coordinatively accessible Cu2+ sites and pendant sulfonate groups. This unprecedented crystal irregularity phenomenon of MOFs substantially enhances their affinity towards water molecules, thus increasing the proton conductivity by two orders of magnitude. PMID- 28352867 TI - Metal salts and complexes of 1,1'-dinitramino-5,5'-bitetrazole. AB - Potassium 1,1'-dinitramino-5,5'-bitetrazolate is one of the most promising primary explosives which is currently under investigation for different applications. This is due to its high initiation power and the exclusion of heavy metals. To close the gap, the remaining alkali metal salts such as the lithium 6, sodium 7, rubidium 8 and cesium 9 salts were synthesized by reaction of the highly soluble ammonium salt 5 with its corresponding metal hydroxide solutions. In addition, the highly explosive silver salt 10 as well as several other transition metal(ii) amine complexes with nickel(ii) 11, copper(ii) 12 and zinc(ii) 13 were prepared in a similar manner. The structure of all compounds was determined by X-ray diffraction. The sensitivities toward impact, friction, heat and electrostatic discharge as well as their behavior on laser irradiation of the transition metal complexes were explored. PMID- 28352868 TI - Flexible organofunctional aerogels. AB - Flexible inorganic-organic silica aerogels based on methyltrimethoxysilane (MTMS, CH3Si(OCH3)3) can overcome the drawbacks of conventional silica aerogels by introducing high mechanical strength, elastic recovery and hydrophobicity to monolithic materials. In this work, MTMS is co-condensed with organofunctional alkoxysilanes RSi(OMe)3 (R = vinyl, chloropropyl, mercaptopropyl, methacryloxypropyl, etc.) yielding aerogels that are not only flexible but also contain reactive functional groups. Sol-gel parameters, such as the MTMS/RSi(OMe)3 ratio, have been systematically investigated in terms of gelation behavior, complete/incomplete incorporation of the functional organic groups (confirmed by FTIR-ATR and Raman spectroscopy) and flexibility of the resulting gel. Sterically more demanding functional moieties lead to macroscopic phase separation; however, this problem was overcome by the employment of surfactants. Functional aerogels dried by supercritical extraction with carbon dioxide showed promising results in uniaxial compression tests and had an elastic recovery up to 60%. Furthermore, the accessibility of the functional groups was demonstrated by simple reactions, e.g. conversion of the chloro into azido groups via a nucleophilic substitution reaction with NaN3 followed by click reactions. PMID- 28352870 TI - Assessing cooperativity in supramolecular systems. AB - This tutorial review summarises different aspects of cooperativity in supramolecular complexes. We propose a systematic categorisation of cooperativity into cooperative aggregation, intermolecular (allosteric) cooperativity, intramolecular (chelate) cooperativity and interannular cooperativity and discuss approaches to quantify them thermodynamically using cooperativity factors. A brief summary of methods to determine the necessary thermodynamic data is given with emphasis on isothermal titration calorimetry (ITC), a method still underrepresented in supramolecular chemistry, which however offers some advantages over others. Finally, a discussion of very few selected examples, which highlight different aspects to illustrate why such an analysis is useful, rounds up this review. PMID- 28352869 TI - Biophysical isolation and identification of circulating tumor cells. AB - Isolation and enumeration of circulating tumor cells (CTCs) from blood is important for determining patient prognosis and monitoring treatment. Methods based on affinity to cell surface markers have been applied to both purify (via immunoseparation) and identify (via immunofluorescence) CTCs. However, variability of cell biomarker expression associated with tumor heterogeneity and evolution and cross-reactivity of antibody probes have long complicated CTC enrichment and immunostaining. Here, we report a truly label-free high-throughput microfluidic approach to isolate, enumerate, and characterize the biophysical properties of CTCs using an integrated microfluidic device. Vortex-mediated deformability cytometry (VDC) consists of an initial vortex region which enriches large CTCs, followed by release into a downstream hydrodynamic stretching region which deforms the cells. Visualization and quantification of cell deformation with a high-speed camera revealed populations of large (>15 MUm diameter) and deformable (aspect ratio >1.2) CTCs from 16 stage IV lung cancer samples, that are clearly distinguished by increased deformability compared to contaminating blood cells and rare large cells isolated from healthy patients. The VDC technology demonstrated a comparable positive detection rate of putative CTCs above healthy baseline (93.8%) with respect to standard immunofluorescence (71.4%). Automation allows full enumeration of CTCs from a 10 mL vial of blood within <1 h after sample acquisition, compared with 4+ hours with standard approaches. Moreover, cells are released into any collection vessel for further downstream analysis. VDC shows potential for accurate CTC enumeration without labels and confirms the unique highly deformable biophysical properties of large CTCs circulating in blood. PMID- 28352871 TI - Intrinsic point defects in buckled and puckered arsenene: a first-principles study. AB - Using first-principles calculations, we study the structural, energetic, and electronic properties of various point defects in arsenene. Stone-Wales defects are found to be thermodynamically favorable and are predicted to be stable at room temperature. Defects are found to significantly influence the electronic properties in buckled phase. In particular, single vacancies generate gap states whereas strain induced states close to the valence and conduction band edges are observed for Stone-Wales and di-vacancy defects. The computed band structures of di-vacancy defects in puckered phase are less disturbed compared to the corresponding band structures in the buckled one. The influence of a hydrogen rich atmosphere on the electronic properties of defective arsenene is also investigated. Hydrogen termination of mono/di-vacancies is an exothermic process which removes all defect induced gap states. PMID- 28352873 TI - Molecular control over colloidal assembly. AB - Contemporary chemical and material engineering often takes inspiration from nature, targeting for example strong yet light materials and materials composed of highly ordered domains at multiple different lengthscales for fundamental science and applications in e.g. sensing, catalysis, coating technology, and delivery. The preparation of such hierarchically structured functional materials through guided bottom-up assembly of synthetic building blocks requires a high level of control over their synthesis, interactions and assembly pathways. In this perspective we showcase recent work demonstrating how molecular control can be exploited to direct colloidal assembly into responsive materials with mechanical, optical or electrical properties that can be adjusted post-synthesis with external cues. PMID- 28352874 TI - Simultaneous viscosity and density measurement of small volumes of liquids using a vibrating microcantilever. AB - Many industrial and technological applications require precise determination of the viscosity and density of liquids. Such measurements can be time consuming and often require sampling substantial amounts of the liquid. These problems can partly be overcome with the use of microcantilevers but most existing methods depend on the specific geometry and properties of the cantilever, which renders simple, accurate measurement difficult. Here we present a new approach able to simultaneously quantify both the density and the viscosity of microliters of liquids. The method, based solely on the measurement of two characteristic frequencies of an immersed microcantilever, is completely independent of the choice of a cantilever. We derive analytical expressions for the liquid's density and viscosity and validate our approach with several simple liquids and different cantilevers. Application of our model to non-Newtonian fluids shows that the calculated viscosities are remarkably robust when compared to measurements obtained from a standard rheometer. However, the results become increasingly dependent on the cantilever geometry as the frequency-dependent nature of the liquid's viscosity becomes more significant. PMID- 28352875 TI - Controlling the formation process and atomic structures of single pyrazine molecular junction by tuning the strength of the metal-molecule interaction. AB - The formation process and atomic structures were investigated for single pyrazine molecular junctions sandwiched by three different Au, Ag, and Cu electrodes using a mechanically controllable break junction technique in ultrahigh vacuum conditions at 300 K. We demonstrated that the formation process of the single molecule junction crucially depended on the choice of the metal electrodes. While single-molecule junction showing two distinct conductance states were found for the Au electrodes, only the single conductance state was evident for the Ag electrodes, and there was no junction formation for the Cu electrodes. These results suggested that metal-molecule interaction dominates the formation process and probability of the single-molecule junction. In addition to the metal molecule interaction, temperature affected the formation process of the single molecule junction. The single pyrazine molecular junction formed between Au electrodes exhibited significant temperature dependence where the junction formation probability was about 8% at 300 K, while there was no junction formation at 100 K. Instead of the junction formation, an Au atomic wire was formed at the low temperature. This study provides insight into the tuning of the junction-forming process for single-molecule junctions, which is needed to construct device structures on a single molecule scale. PMID- 28352876 TI - Recent advances in the design of polymeric microneedles for transdermal drug delivery and biosensing. AB - Microneedles are an efficient and minimally invasive approach to transdermal drug delivery and extraction of skin interstitial fluid. Compared to solid microneedles made of silicon, metals and ceramics, polymeric microneedles have attracted extensive attention due to their excellent biocompatibility, biodegradability and nontoxicity. They are easy to fabricate in large scale and can load drugs in high amounts. More importantly, polymers with different degradation profiles, swelling properties, and responses to biological/physical stimuli can be employed to fabricate polymeric microneedles with different mechanical properties and performance. This review provides a guideline for the selection of polymers and the corresponding fabrication methods for polymeric microneedles while summarizing their recent application in drug delivery and fluid extraction. It should be noted that although polymeric microneedles can achieve efficient transdermal delivery of drugs, their wide applications were limited by their unsatisfactory transdermal therapeutic efficiency. Delivery of nanomedicines that incorporate drugs into functional nanoparticles/capsules can address this problem and thus may be an interesting direction in the future. PMID- 28352877 TI - endo-Cyclization of unsaturated RO2 radicals from the gas-phase ozonolysis of cyclohexadienes. AB - Unsaturated RO2 radicals from the ozonolysis of cyclodienes can readily undergo an endo-cyclization step under atmospheric conditions forming a new ring containing RO2 radical after further O2 addition. This path represents an extension of the atmospheric autoxidation scheme forming highly oxidized multifunctional organic compounds (HOMs). HOMs play an important role for Earth's organic aerosol burden. PMID- 28352879 TI - Carbon nanotubes kirigami mechanical metamaterials. AB - Imparting elasticity and functionality to materials is one of the key objects of materials science research. Here, inspired by the art of kirigami, mechanical metamaterials comprising carbon nanotubes (CNTs) are hypothetically constructed. Using classical molecular dynamics (MD) simulations, a systematic study of the elastic limit, extensibility and yield stress of as-generated CNTs kirigami (CNT k) is performed. Three designated kirigami patterns are employed to achieve high stretchability of CNTs. It is shown that CNT-k typically exhibits three distinct deformation stages, of which the first stage, which is referred to as geometric deformation, contributes quite a high proportion of the ductility. Various geometric parameters of CNT-k that influence the key mechanical properties of interest are respectively discussed. Three types of CNT-k with specifically identical geometric parameters exhibit distinct mechanical characteristics. This study provides an interesting example of interplay between the geometry, ductility, and mechanical characteristics of tubular materials. PMID- 28352880 TI - Nano-thin walled micro-compartments from transmembrane protein-polymer conjugates. AB - The high interfacial activity of protein-polymer conjugates has inspired their use as stabilizers for Pickering emulsions, resulting in many interesting applications such as synthesis of templated micro-compartments and protocells or vehicles for drug and gene delivery. In this study we report, for the first time, the stabilization of Pickering emulsions with conjugates of a genetically modified transmembrane protein, ferric hydroxamate uptake protein component A (FhuA). The lysine residues of FhuA with open pore (FhuA DeltaCVFtev) were modified to attach an initiator and consequently controlled radical polymerization (CRP) carried out via the grafting-from technique. The resulting conjugates of FhuA DeltaCVFtev with poly(N-isopropylacrylamide) (PNIPAAm) and poly((2-dimethylamino)ethyl methacrylate) (PDMAEMA), the so-called building blocks based on transmembrane proteins (BBTP), have been shown to engender larger structures. The properties such as pH-responsivity, temperature-responsivity and interfacial activity of the BBTP were analyzed using UV-Vis spectrophotometry and pendant drop tensiometry. The BBTP were then utilized for the synthesis of highly stable Pickering emulsions, which could remain non-coalesced for well over a month. A new UV-crosslinkable monomer was synthesized and copolymerized with NIPAAm from the protein. The emulsion droplets, upon crosslinking of polymer chains, yielded micro-compartments. Fluorescence microscopy proved that these compartments are of micrometer scale, while cryo-scanning electron microscopy and scanning force microscopy analysis yielded a thickness in the range of 11.1 +/- 0.6 to 38.0 +/- 18.2 nm for the stabilizing layer of the conjugates. Such micro compartments would prove to be beneficial in drug delivery applications, owing to the possibility of using the channel of the transmembrane protein as a gate and the smart polymer chains as trigger switches to tune the behavior of the capsules. PMID- 28352881 TI - Correlated mass spectrometry and confocal microscopy imaging verifies the dual targeting action of an organoruthenium anticancer complex. AB - An addressable single cell imaging strategy combining ToF-SIMS and confocal fluorescence microscopy imaging has been developed, and sucessfully applied to visualize the subcellular distribution of an organoruthenium anticancer complex, [(eta6-benzene)Ru(N,N-L)Cl]+ (1; L: 4-anilinoquinazoline ligand), showing its accumulation in both cell membrane and nuclei, and verifying its dual-targeting feature. PMID- 28352883 TI - Direct Csp2-H enolization: an allenoate alkylation cascade toward the assembly of multi-substituted furans. AB - A new disconnection toward tri- and tetrasubstituted furans has been conceptualized and demonstrated. A mild, base-mediated reaction of an allenoate pronucleophile with alpha-halo ketones/dicarbonyl compounds results in a Csp2 alkylation/enolization/O-vinylation sequence to ultimately afford substituted furan derivatives. The reaction offers a broad scope, provides a facile access to alkyl and aryl substituted furans, and demonstrates the application of the allene functionality as a two-carbon component in the construction of furans. PMID- 28352884 TI - Fountain streaming contributes to fast tip-growth through regulating the gradients of turgor pressure and concentration in pollen tubes. AB - Fountain streaming is a typical microfluidic pattern in plant cells, especially for cells with a high aspect ratio such as pollen tubes. Although it has been found that fountain streaming plays crucial roles in the transport of nutrients and metabolites, the positioning of organelles and the mixing of cytoplasms, its implications for the fast tip growth of pollen tubes remain a mystery. To address this, based on the observations of asiatic lily Lilium Casablanca, we developed physical models for reverse fountain streaming in pollen tubes and solved the hydrodynamics and advection-diffusion dynamics of viscous Stokes flow in the shank and apical region of pollen tubes. Theoretical and numerical results demonstrated that the gradients of turgor pressure and concentration of wall materials along the length of pollen tubes provide undamped driving force and high-efficiency materials supply, which are supposed to contribute to the fast tip-growth of pollen tubes. The sample experimental results show that the tip growth will be abnormal when the gradients of turgor pressure change under osmotic stress induced by different concentrations of PEG-6000 (a dehydrant). PMID- 28352885 TI - Enhanced emission of encaged-OH--free Ca12(1-x)Sr12xAl14O33:0.1%Gd3+ conductive phosphors via tuning the encaged-electron concentration for low-voltage FEDs. AB - Encaged-OH--free Ca12(1-x)Sr12xAl14O33:0.1%Gd3+ conductive phosphors were prepared through a melt-solidification process in combination with a subsequent heat treatment. Absorption spectra showed that the maximum encaged-electron concentration was increased to 1.08 * 1021 cm-3 through optimizing the doping amount of Sr2+ (x = 0.005). Meanwhile, FTIR and Raman spectra indicated that pure Ca11.94Sr0.06Al14O33:0.1%Gd3+ conductive phosphor without encaged OH- and C22- anions was acquired. For the conductive powders heat-treated in air for different times, the encaged-electron concentrations were tuned from 1.02 * 1021 to 8.3 * 1020 cm-3. ESR, photoluminescence, and luminescence kinetics analyses indicated that the emission at 312 nm mainly originated from Gd3+ ions surrounded by encaged O2- anions, while Gd3+ ions surrounded by encaged electrons had a negative contribution to the UV emission due to the existence of an energy transfer process. Under low-voltage electron-beam excitation (3 kV), enhanced cathodoluminescence (CL) of the conductive phosphors could be achieved by tuning the encaged-electron concentrations. In particular, for the encaged-OH--free conductive phosphor, the emission intensity of the CL was about one order of magnitude higher than that of the conductive phosphor containing encaged OH- anions. Our results suggested that the encaged-OH--free conductive phosphors have potential application in low-voltage FEDs. PMID- 28352886 TI - Armoring confined bubbles in the flow of colloidal suspensions. AB - We study the process of coating the interface of a long gas bubble, which is translating in a horizontal circular capillary tube filled with a colloidal suspension. A typical elongated confined bubble is comprised of three distinct regions: a spherical front cap, a central body that is separated from the tube wall by a thin liquid film, and a spherical cap at the back. These three regions are connected by transitional sections. Particles gradually coat the bubble from the back to the front. We investigate the mechanisms that govern the initial accumulation of the particles and the growth of the particle-coated area on the interface of the bubble. We show that the initial accumulation of particles starts at the stable stagnation ring on the rear cap of the bubble, and the particles will completely coat the spherical cap at the back of the bubble before accumulating on the central body. Armoring the central interface of the bubble with particles thickens the liquid film around the bubble relative to that around the particle-free interface. This effect creates a rather sharp step on the interface of the bubble in the central region, which separates the armored region from the particle-free region. After the bubble is completely coated, the liquid film around the body of the bubble will adjust again to an intermediate thickness. We show that the three distinct thicknesses that the liquid film acquires during the armoring process can be well described analytically. PMID- 28352887 TI - Probing glycosaminoglycan spectral signatures in live cells and their conditioned media by Raman microspectroscopy. AB - Spectroscopic markers characteristic of reference glycosaminoglycan molecules were identified previously based on their vibrational signatures. Infrared spectral signatures of glycosaminoglycans in fixed cells were also recently demonstrated but probing live cells still remains challenging. Raman microspectroscopy is potentially interesting to perform studies under physiological conditions. The aim of the present work was to identify the Raman spectral signatures of GAGs in fixed and live cells and in their conditioned media. Biochemical and Raman analyses were performed on five cell types: chondrocytes, dermal fibroblasts, melanoma (SK-MEL-28), wild type CHO, and glycosaminoglycan-defective mutant CHO-745 cells. The biochemical assay of sulfated GAGs in conditioned media was only possible for chondrocytes, dermal fibroblasts, and wild type CHO due to the detection limit of the test. In contrast, Raman microspectroscopy allowed probing total glycosaminoglycan content in conditioned media, fixed and live cells and the data were analysed by principal component analysis. Our results showed that the Raman technique is sensitive enough to identify spectral markers of glycosaminoglycans that were useful to characterise the conditioned media of the five cell types. The results were confirmed at the single cell level on both live and fixed cells with a good differentiation between the cell types. Furthermore, the principal component loadings revealed prominent glycosaminoglycan-related spectral information. Raman microspectroscopy allows monitoring of the glycosaminoglycan profiles of single live cells and could therefore be developed for cell screening purposes and holds promise for identifying glycosaminoglycan signatures as a marker of cancer progression in tissues. PMID- 28352888 TI - NMR analysis of an Fe(i)-carbene complex with strong magnetic anisotropy. AB - A tricoordinated FeI complex with two cyclic-alkyl(amino) carbene (cAAC) and one chlorido ligand, (cAAC)2FeCl (1), is studied by means of 1H NMR spectroscopy and DFT calculations. Due to the cAAC ligands, which can take significant amounts of spin density from the metal center, and due to the magnetic anisotropy of the FeI ion (P. P. Samuel et al., J. Am. Chem. Soc., 2014, 136, 11964-11971), compound 1 is a rare example of a paramagnetic d-block compound which is expected to have significant contributions from both contact and pseudocontact terms to the hyperfine NMR shift. Compound 1 is fluxional, which makes the analysis of its 1H NMR spectrum more difficult but allows a preliminary assignment from EXSY spectra. Then, a software-aided approach enabled a satisfactory signal assignment of all protons which are distanced from the FeI center and carbene cyclic core, and thereby the extraction of the axial and rhombic components of the magnetic susceptibility anisotropy tensor (Deltachi). Components of Deltachi enable the calculation of zero-field spitting D and E parameters from solution NMR measurements of 1, and these parameters are compared to previously reported experimental and theoretical values. PMID- 28352891 TI - A study of the water molecule using frequency control over nuclear dynamics in resonant X-ray scattering. AB - In this combined theoretical and experimental study we report a full analysis of the resonant inelastic X-ray scattering (RIXS) spectra of H2O, D2O and HDO. We demonstrate that electronically-elastic RIXS has an inherent capability to map the potential energy surface and to perform vibrational analysis of the electronic ground state in multimode systems. We show that the control and selection of vibrational excitation can be performed by tuning the X-ray frequency across core-excited molecular bands and that this is clearly reflected in the RIXS spectra. Using high level ab initio electronic structure and quantum nuclear wave packet calculations together with high resolution RIXS measurements, we discuss in detail the mode coupling, mode localization and anharmonicity in the studied systems. PMID- 28352890 TI - High-affinity metal binding by the Escherichia coli [NiFe]-hydrogenase accessory protein HypB is selectively modulated by SlyD. AB - [NiFe]-hydrogenase, which catalyzes the reversible conversion between hydrogen gas and protons, is a vital component of the metabolism of many pathogens. Maturation of [NiFe]-hydrogenase requires selective nickel insertion that is completed, in part, by the metallochaperones SlyD and HypB. Escherichia coli HypB binds nickel with sub-picomolar affinity, and the formation of the HypB-SlyD complex activates nickel release from the high-affinity site (HAS) of HypB. In this study, the metal selectivity of this process was investigated. Biochemical experiments revealed that the HAS of full length HypB can bind stoichiometric zinc. Moreover, in contrast to the acceleration of metal release observed with nickel-loaded HypB, SlyD blocks the release of zinc from the HypB HAS. X-ray absorption spectroscopy (XAS) demonstrated that SlyD does not impact the primary coordination sphere of nickel or zinc bound to the HAS of HypB. Instead, computational modeling and XAS of HypB loaded with nickel or zinc indicated that zinc binds to HypB with a different coordination sphere than nickel. The data suggested that Glu9, which is not a nickel ligand, directly coordinates zinc. These results were confirmed through the characterization of E9A-HypB, which afforded weakened zinc affinity compared to wild-type HypB but similar nickel affinity. This mutant HypB fully supports the production of [NiFe]-hydrogenase in E. coli. Altogether, these results are consistent with the model that the HAS of HypB functions as a nickel site during [NiFe]-hydrogenase enzyme maturation and that the metal selectivity is controlled by activation of metal release by SlyD. PMID- 28352892 TI - Unique perforated graphene derived from Bougainvillea flowers for high-power supercapacitors: a green approach. AB - Herein, we demonstrated a green approach for the synthesis of high surface area (850 m2 g-1) mesoporous perforated graphene (PG) from Bougainvillea flower for the first time using a template free single-step method. The existence of PG was confirmed by XRD, Raman spectroscopy, FESEM, and FETEM. Surprisingly, FETEM clearly showed 5-10 nm perforation on the graphene sheets. More significantly, these mesoporous perforated graphene sheets can be produced in large scale using the present green approach. Considering high surface area and unique perforated graphene architecture, these PGs were studied for supercapacitor applications in detail without any chemical or physical activation. The nanoporosity and high conductivity of PG derived from Bougainvillea flower exhibited excellent supercapacitive performance. According to the supercapacitor study, the synthesized perforated graphene sheets conferred a very high specific capacitance of 458 F g-1 and an energy density of 63.7 Wh kg-1 at the power density of around 273.2 Wh kg-1 in aqueous 1 M Na2SO4. Significantly, the areal capacitance of PG was observed to be very high, i.e. 67.2 mF cm-2. The cyclability study results showed excellent stability of synthesized perforated graphene sheets up to 10 000 cycles. Note that the specific and areal capacitance and the energy density of the synthesized PGs are much higher than the earlier reported values. The high supercapacitive performance may be due to high surface area and mesoporosity of PG. The present approach has a good potential to produce cheaper and high surface area PG. These PGs are good candidates as an anode material in the lithium-ion battery. PMID- 28352894 TI - Synthesis of Janus Au@periodic mesoporous organosilica (PMO) nanostructures with precisely controllable morphology: a seed-shape defined growth mechanism. AB - Janus nanostructures that possess two or more distinct components and surface functions have attracted more and more attention. Here, we present a seed-shape defined growth mechanism for the preparation of anisotropic Janus nanostructures, in which the shape of periodic mesoporous organosilica (PMO) is determined by the shape of Au nanoparticles. Various shaped Au@PMO composite nanostructures, such as rods, spheres, and plates, are prepared based on this general growth mechanism. By adjusting the reaction parameters (temperature, surfactant), various shaped AuNR@PMO Janus nanostructures, including horsebean- and fingernail like nanostructures, have been successfully prepared. We also demonstrate the potential applications of such composite nanostructures. As an example, the as prepared rod-like Janus Au@PMO nanostructures show great performance in chemo photothermal combination therapy because of the excellent photothermal effect of Au nanorods and the high surface area of PMO nanorods. This research may open a new direction to the controllable synthesis and practical application of dedicated nanostructures with desired properties. PMID- 28352893 TI - Structural and energetic study of cation-pi-cation interactions in proteins. AB - Cation-pi interactions of aromatic rings and positively charged groups are among the most important interactions in structural biology. The role and energetic characteristics of these interactions are well established. However, the occurrence of cation-pi-cation interactions is an unexpected motif, which raises intriguing questions about its functional role in proteins. We present a statistical analysis of the occurrence, composition and geometrical preferences of cation-pi-cation interactions identified in a set of non-redundant protein structures taken from the Protein Data Bank. Our results demonstrate that this structural motif is observed at a small, albeit non-negligible frequency in proteins, and suggest a preference to establish cation-pi-cation motifs with Trp, followed by Tyr and Phe. Furthermore, we have found that cation-pi-cation interactions tend to be highly conserved, which supports their structural or functional role. Finally, we have performed an energetic analysis of a representative subset of cation-pi-cation complexes combining quantum-chemical and continuum solvation calculations. Our results point out that the protein environment can strongly screen the cation-cation repulsion, leading to an attractive interaction in 64% of the complexes analyzed. Together with the high degree of conservation observed, these results suggest a potential stabilizing role in the protein fold, as demonstrated recently for a miniature protein (Craven et al., J. Am. Chem. Soc. 2016, 138, 1543). From a computational point of view, the significant contribution of non-additive three-body terms challenges the suitability of standard additive force fields for describing cation-pi-cation motifs in molecular simulations. PMID- 28352895 TI - Partial to complete wetting transitions in immiscible ternary blends with PLA: the influence of interfacial confinement. AB - In this study it is shown that the three different intermediate phases in melt blended ternary PLA/PHBV/PBS, PLA/PBAT/PE and PLA/PE/PBAT systems all demonstrate partial wetting, but have very different wetting behaviors as a function of composition and annealing. The interfacial tension of the various components, their spreading coefficients and the contact angles of the confined partially wet droplets at the interface are examined in detail. A wetting transition from partially wet droplets to a complete layer at the interface is observed for both PHBV and PBAT by increasing the concentration and also by annealing. In contrast, in PLA/PE/PBAT, the partially wet droplets of PE at the interface of PLA/PBAT coalesce and grow in size, but remain partially wet even at a high PE concentration of 20% and after 30 min of quiescent annealing. The dewetting speed of the intermediate phase is found to be the principal factor controlling these wetting transitions. This work shows the significant potential for controlled wetting and structuring in ternary polymer systems. PMID- 28352900 TI - Tuning the Seebeck coefficient of naphthalenediimide by electrochemical gating and doping. AB - We investigate the sign and magnitude of the single-molecule Seebeck coefficient of naphthalenediimide (NDI) under the influence of electrochemical gating and doping. The molecule consists of a NDI core with two alkyl chains in the bay-area position, connected to gold electrodes via benzothiophene (DBT) anchor groups. By switching between the neutral, radical and di-anion charge states, we are able to tune the molecular energy levels relative to the Fermi energy of the electrodes. The resulting single-molecule room-temperature Seebeck coefficents of the three charge states are -294.5 MUV K-1, 122 MUV K-1 and 144 MUV K-1 respectively and the room-temperature power factors are 4.4 * 10-5 W m-1 K-2, 3 * 10-5 W m-1 K-2 and 8.2 * 10-4 W m-1 K-2. As a further strategy for optimising thermoelectric properties, we also investigate the effect on both phonon and electron transport of doping the NDI with either an electron donor (TTF) or an electron acceptor (TCNE). We find that doping by TTF increases the room-temperature Seebeck coefficient and power factor from -73.7 MUV K-1 and 2.6 * 10-7 W m-1 K-2 for bare NDI to -105 MUV K-1 and 3.6 * 10-4 W m-1 K-2 in presence of TTF. The low thermal conductance of NDI-TTF, combined with the higher Seebeck coefficient and higher electrical conductance lead to a maximum thermoelectric figure of merit of ZT = 1.2, which is higher than that of bare NDI in several orders of magnitude. This demonstrates that both the sign and magnitude of NDI Seebeck coefficient can be tuned reversibly by electrochemical gating and doping, suggesting that such redox active molecules are attractive materials for ultra-thin-film thermoelectric devices. PMID- 28352902 TI - Self-assembly of gradient copolymers synthesized in semi-batch mode by nitroxide mediated polymerization. AB - The effect of diffuse compositional interfaces on copolymer self-assembly was studied via gradient copolymers (GCP). Poly(methyl methacrylate)-grad-(styrene) (PMMA-grad-PSt) copolymers were synthesized in semi-batch mode using nitroxide mediated polymerization (NMP) with varied monomer injection protocols to produce varied diffuse interfaces (number average molecular weights (Mn) ranged from 62 000 g mol-1 to 94 000 g mol-1 with dispersities (D) between 1.35 and 1.59). The GCPs were spun into thin films on substrates made neutral by (St-ran-MMA-ran hydroxyethyl methacrylate) terpolymers and annealed at elevated temperature to produce vertically oriented microphase-separated domains. The GCPs were found to have domain spacing larger than equivalent monodisperse BCPs, due to their polydisperse nature. This effect was partially offset by the decrease in chi due to the gradient. GCPs synthesized with a single-injection protocol (i.e. less diffuse interfaces) were found to self-assemble into ordered domains. However, GCPs synthesized with long injection times (i.e. more diffuse interfaces) exhibited poor self-assembly attributed to their predicted statistical-copolymer like middle sequence, which caused a reduction of the effective enthalpic interaction parameter. PMID- 28352901 TI - Chemoproteomics-enabled covalent ligand screen reveals a cysteine hotspot in reticulon 4 that impairs ER morphology and cancer pathogenicity. AB - Chemical genetics has arisen as a powerful approach for identifying novel anti cancer agents. However, a major bottleneck of this approach is identifying the targets of lead compounds that arise from screens. Here, we coupled the synthesis and screening of fragment-based cysteine-reactive covalent ligands with activity based protein profiling (ABPP) chemoproteomic approaches to identify compounds that impair colorectal cancer pathogenicity and map the druggable hotspots targeted by these hits. Through this coupled approach, we discovered a cysteine reactive acrylamide DKM 3-30 that significantly impaired colorectal cancer cell pathogenicity through targeting C1101 on reticulon 4 (RTN4). While little is known about the role of RTN4 in colorectal cancer, this protein has been established as a critical mediator of endoplasmic reticulum tubular network formation. We show here that covalent modification of C1101 on RTN4 by DKM 3-30 or genetic knockdown of RTN4 impairs endoplasmic reticulum and nuclear envelope morphology as well as colorectal cancer pathogenicity. We thus put forth RTN4 as a potential novel colorectal cancer therapeutic target and reveal a unique druggable hotspot within RTN4 that can be targeted by covalent ligands to impair colorectal cancer pathogenicity. Our results underscore the utility of coupling the screening of fragment-based covalent ligands with isoTOP-ABPP platforms for mining the proteome for novel druggable nodes that can be targeted for cancer therapy. PMID- 28352904 TI - Thermal conductivity of glassy GeTe4 by first-principles molecular dynamics. AB - A transient thermal regime is achieved in glassy GeTe4 by first-principles molecular dynamics following the recently proposed "approach-to-equilibrium" methodology. The temporal and spatial evolution of the temperature do comply with the time-dependent solution of the heat equation. We demonstrate that the time scales required to create the hot and the cold parts of the system and observe the resulting approach to equilibrium are accessible to first-principles molecular dynamics. Such a strategy provides the thermal conductivity from the characteristic decay time. We rationalize in detail the impact on the thermal conductivity of the initial temperature difference, the equilibration duration, and the main simulation features. PMID- 28352903 TI - Rationalizing the relative abundances of trimetallic nitride template-based endohedral metallofullerenes from aromaticity measures. AB - The synthesis of endohedral metallofullerenes (EMFs) from a carbon soot sample of an arc discharge leads to a variety of EMFs that are obtained in different relative abundances. In the present work, we show that these abundances can be predicted from aromaticity calculations. In particular, we use the normalized Additive Local Aromaticity (ALAN) index. Our results show that the most abundant Sc3N-based and Y3N-based EMFs in fullerene soot are the most aromatic. This study reinforces the idea that aromaticity plays a key role in determining the stability of EMFs. PMID- 28352905 TI - Site-specific antibody modification and immobilization on a microfluidic chip to promote the capture of circulating tumor cells and microemboli. AB - We design and synthesize EpCAM antibodies with Fc-domain site-specific linkers that allow preferential alignment when coated on microfluidic devices for capturing circulating tumor cells (CTCs) from colorectal cancer patients. The aligned coating is shown to increase the capture efficiency of CTCs and microemboli by 1.6 and 3.0-fold, respectively (both P < 0.05). PMID- 28352906 TI - Epigenetic modification of nucleic acids: from basic studies to medical applications. AB - The epigenetic modification of nucleic acids represents one of the most significant areas of study in the field of nucleic acids because it makes gene regulation more complex and heredity more complicated, thus indicating its profound impact on aspects of heredity, growth, and diseases. The recent characterization of epigenetic modifications of DNA and RNA using chemical labelling strategies has promoted the discovery of these modifications, and the newly developed single-base or single-cell resolution mapping strategies have enabled large-scale epigenetic studies in eukaryotes. Due to these technological breakthroughs, several new epigenetic marks have been discovered that have greatly extended the scope and impact of epigenetic modifications in nucleic acids over the past few years. Because epigenetics is reversible and susceptible to environmental factors, it could potentially be a promising direction for clinical medicine research. In this review, we have comprehensively discussed how these epigenetic marks are involved in disease, including the pathogenesis, prevention, diagnosis and treatment of disease. These findings have revealed that the epigenetic modification of nucleic acids has considerable significance in various areas from methodology to clinical medicine and even in biomedical applications. PMID- 28352908 TI - Uranium mobility and accumulation along the Rio Paguate, Jackpile Mine in Laguna Pueblo, NM. AB - The mobility and accumulation of uranium (U) along the Rio Paguate, adjacent to the Jackpile Mine, in Laguna Pueblo, New Mexico was investigated using aqueous chemistry, electron microprobe, X-ray diffraction and spectroscopy analyses. Given that it is not common to identify elevated concentrations of U in surface water sources, the Rio Paguate is a unique site that concerns the Laguna Pueblo community. This study aims to better understand the solid chemistry of abandoned mine waste sediments from the Jackpile Mine and identify key hydrogeological and geochemical processes that affect the fate of U along the Rio Paguate. Solid analyses using X-ray fluorescence determined that sediments located in the Jackpile Mine contain ranges of 320 to 9200 mg kg-1 U. The presence of coffinite, a U(iv)-bearing mineral, was identified by X-ray diffraction analyses in abandoned mine waste solids exposed to several decades of weathering and oxidation. The dissolution of these U-bearing minerals from abandoned mine wastes could contribute to U mobility during rain events. The U concentration in surface waters sampled closest to mine wastes are highest during the southwestern monsoon season. Samples collected from September 2014 to August 2016 showed higher U concentrations in surface water adjacent to the Jackpile Mine (35.3 to 772 MUg L 1) compared with those at a wetland 4.5 kilometers downstream of the mine (5.77 to 110 MUg L-1). Sediments co-located in the stream bed and bank along the reach between the mine and wetland had low U concentrations (range 1-5 mg kg-1) compared to concentrations in wetland sediments with higher organic matter (14 15%) and U concentrations (2-21 mg kg-1). Approximately 10% of the total U in wetland sediments was amenable to complexation with 1 mM sodium bicarbonate in batch experiments; a decrease of U concentration in solution was observed over time in these experiments likely due to re-association with sediments in the reactor. The findings from this study provide new insights about how hydrologic events may affect the reactivity of U present in mine waste solids exposed to surface oxidizing conditions, and the influence of organic-rich sediments on U accumulation in the Rio Paguate. PMID- 28352896 TI - New advances in probing cell-extracellular matrix interactions. AB - The extracellular matrix (ECM) provides structural and biochemical support to cells within tissues. An emerging body of evidence has established that the ECM plays a key role in cell mechanotransduction - the study of coupling between mechanical inputs and cellular phenotype - through either mediating transmission of forces to the cells, or presenting mechanical cues that guide cellular behaviors. Recent progress in cell mechanotransduction research has been facilitated by advances of experimental tools, particularly microtechnologies, engineered biomaterials, and imaging and analytical methods. Microtechnologies have enabled the design and fabrication of controlled physical microenvironments for the study and measurement of cell-ECM interactions. Advances in engineered biomaterials have allowed researchers to develop synthetic ECMs that mimic tissue microenvironments and investigate the impact of altered physicochemical properties on various cellular processes. Finally, advanced imaging and spectroscopy techniques have facilitated the visualization of the complex interaction between cells and ECM in vitro and in living tissues. This review will highlight the application of recent innovations in these areas to probing cell-ECM interactions. We believe cross-disciplinary approaches, combining aspects of the different technologies reviewed here, will inspire innovative ideas to further elucidate the secrets of ECM-mediated cell control. PMID- 28352910 TI - Coordination abilities of polycyano anions in the solid state: coordination geometries and d-d transition energies of mixed-ligand solvatochromic copper(ii) complexes with B(CN)4, C(CN)3, and N(CN)2 anions. AB - B(CN)4-, C(CN)3-, and N(CN)2- are highly versatile polycyano anions that produce various functional compounds. To investigate the coordination abilities of these anions in the solid state quantitatively, we synthesized mixed-ligand Cu(ii) complexes: [Cu(R-acac)(tmen)X] (X = polycyano anion, R-acac = acetylacetonate or butyl-acetylacetonate, tmen = tetramethylethylenediamine). The coordination abilities of the anions, increasing in the order B(CN)4- < C(CN)3- < N(CN)2-, result in a decrease in the d-d transition energies of the complexes and the shortening of the axial coordination distance. The influence of crystal packing on the coordination geometries and d-d transition energies of the complexes was also demonstrated. The donor numbers of the anions were determined from the d-d transition energies in solution. PMID- 28352909 TI - Iron chelators inhibit the heme-degradation reaction by HutZ from Vibrio cholerae. AB - HutZ is a heme-degrading enzyme. We found that the heme-degradation reaction by HutZ is inhibited by the iron chelators. Kinetic analysis of each heme degradation step suggests that water molecules hydrogen bonded to Thr27 are involved in proton transfer to Fe(iii)-OO-, and that this step is inhibited by iron chelators. PMID- 28352913 TI - Highly durable photochromic radical complexes having no steric protections of radicals. AB - Steric protection groups are usually necessary for stable radicals. However, here, we developed novel photochromic radical complexes which generate sterically unprotected imidazolyl and phenoxyl radicals upon UV light irradiation based on the phenoxyl-imidazolyl radical complex (PIC) framework. These photochromic compounds show excellent durability against repeated irradiation of intense nanosecond laser pulses even in polar protic solvents, such as ethanol. PMID- 28352912 TI - Post-synthetic modification of tryptophan containing peptides via NIS mediation. AB - A new efficient method was developed to provide modified tryptophan peptides through NIS (N-iodosuccinimide) mediated N2-selective coupling of a Trp unit with 1,2,3-triazoles, of which, the preliminary spectral properties were also studied. PMID- 28352914 TI - Rational design of a luminescent nanoprobe for hypoxia imaging in vivo via ratiometric and photoluminescence lifetime imaging microscopy. AB - A luminescent nanoprobe has been designed for detection of oxygen. The nanoprobe exhibits high sensitivity, selectivity and excellent reversibility, and has been employed for hypoxia imaging in vitro and in vivo by ratiometric and photoluminescence lifetime imaging techniques. PMID- 28352915 TI - Towards the biodegradation pathway of fosfomycin. AB - Three functionalised propylphosphonic acids were synthesised to study C-P bond cleavage in R. huakuii PMY1. (R)-1-Hydroxy-2-oxopropylphosphonic acid [(R)-5] was prepared by chiral resolution of (+/-)-dimethyl 1-hydroxy-2 methylallyllphosphonate [(+/-)-12], followed by ozonolysis and deprotection. The N-(l-alanyl)-substituted (1R,2R)-2-amino-1-hydroxypropylphosphonic acid 10, a potential precursor for 2-oxopropylphosphonic acid (5) in cells, was obtained by coupling the aminophosphonic acid with benzotriazole-activated Z-l-alanine and hydrogenolytic deprotection. (1R*,2R*)-1,2-Dihydroxy-3,3,3 trifluoropropylphosphonic acid, a potential inhibitor of C-P bond cleavage after conversion into its 2-oxo derivative in the cell, was accessed from trifluoroacetaldehyde hydrate via hydroxypropanenitrile 21, which was silylated and reduced to the aldehyde (+/-)-23. Diastereoselective addition of diethyl trimethylsilyl phosphite furnished diastereomeric alpha-siloxyphosphonates. The less polar one was converted to the desired racemic phosphonic acid (+/-) (1R*,2R*)-9 as its ammonium salt. PMID- 28352918 TI - Probing the bonding of CO to heteronuclear group 4 metal-nickel clusters by photoelectron spectroscopy. AB - A series of heterobinuclear group 4 metal-nickel carbonyls MNi(CO)n- (M = Ti, Zr, Hf; n = 3-7) has been generated via a laser vaporization supersonic cluster source and characterized by mass-selected photoelectron velocity-map imaging spectroscopy. Quantum chemical calculations have been carried out to elucidate the geometric and electronic structures and support the spectral assignments. The n = 3 cluster is determined to be capable of simultaneously accommodating three different types of CO bonds (i.e., side-on-bonded, bridging, and terminal modes), resulting in a MNi[eta2(MU2-C, O)](MU-CO)(CO)- structure, which represents the smallest metal carbonyl with the involvement of all the main modes of metal-CO coordination to date. The building block of three bridging CO molecules is favored at n = 4, the structure of which persists up to n = 7. The additional CO ligands are bonded terminally to the metal atoms. The present findings provide important new insight into the structure and bonding mechanisms of CO molecules with heteronuclear transition metals, which would have important implications for understanding chemisorbed CO molecules on alloy surfaces. PMID- 28352916 TI - A threonine turnstile defines a dynamic amphiphilic binding motif in the AAA ATPase p97 allosteric binding site. AB - The turnstile motion of two neighboring threonines sets up a dynamic side chain interplay that can accommodate both polar and apolar ligands in a small molecule allosteric protein binding site. A computational model based on SAR data and both X-ray and cryo-EM structures of the AAA ATPase p97 was used to analyze the effects of paired threonines at the inhibitor site. Specifically, the Thr side chain hydroxyl groups form a hydrogen bonding network that readily accommodates small, highly polar ligand substituents. Conversely, diametric rotation of the chi1 torsion by 150-180 degrees orients the side chain beta-methyl groups into the binding cleft, creating a hydrophobic pocket that can accommodate small, apolar substituents. This motif was found to be critical for rationalizing the affinities of a structurally focused set of inhibitors of p97 covering a > 2000 fold variation in potencies, with a preference for either small-highly polar or small-apolar groups. The threonine turnstile motif was further validated by a PDB search that identified analogous binding modes in ligand interactions in PKB, as well as by an analysis of NMR structures demonstrating additional gear-like interactions between adjacent Thr pairs. Combined, these data suggest that the threonine turnstile motif may be a general feature of interest in protein binding pockets. PMID- 28352922 TI - Luminescence spectroscopy of chalcogen substituted rhodamine cations in vacuo. AB - Intrinsic optical properties of several rhodamine cations were probed by measuring their dispersed fluorescence spectra in vacuo. Three different rhodamine structures were investigated, each with four different chalcogen heteroatoms. Fluorescence band maxima were blue-shifted by between 0.15 and 0.20 eV (1200-1600 cm-1) relative to previous solution-phase measurements. Trends in emission wavelengths and fluorescence quantum yields previously measured in solution are generally reproduced in the gas phase, confirming the intrinsic nature of these effects. One important exception is gas-phase brightness of the Texas Red analogues, which is significantly higher than the other rhodamine structures studied, despite having similar fluorescence quantum yields in solution. These results expand the library of fluorophores for which gas-phase photophysical data is available, and will aid in the design of experiments utilizing gas-phase structural biology methods such as Forster resonance energy transfer. PMID- 28352920 TI - A quantum-rovibrational-state-selected study of the reaction in the collision energy range of 0.05-10.00 eV: translational, rotational, and vibrational energy effects. AB - We report detailed absolute integral cross sections (sigma's) for the quantum rovibrational-state-selected ion-molecule reaction in the center-of-mass collision energy (Ecm) range of 0.05-10.00 eV, where (vvv) = (000), (100), and (020), and . Three product channels, HCO+ + OH, HOCO+ + H, and CO+ + H2O, are identified. The measured sigma(HCO+) curve [sigma(HCO+) versus Ecm plot] supports the hypothesis that the formation of the HCO+ + OH channel follows an exothermic pathway with no potential energy barriers. Although the HOCO+ + H channel is the most exothermic, the sigma(HOCO+) is found to be significantly lower than the sigma(HCO+). The sigma(HOCO+) curve is bimodal, indicating two distinct mechanisms for the formation of HOCO+. The sigma(HOCO+) is strongly inhibited at Ecm < 0.4 eV, but is enhanced at Ecm > 0.4 eV by (100) vibrational excitation. The Ecm onsets of sigma(CO+) determined for the (000) and (100) vibrational states are in excellent agreement with the known thermochemical thresholds. This observation, along with the comparison of the sigma(CO+) curves for the (100) and (000) states, shows that kinetic and vibrational energies are equally effective in promoting the CO+ channel. We have also performed high-level ab initio quantum calculations on the potential energy surface, intermediates, and transition state structures for the titled reaction. The calculations reveal potential barriers of ~0.5-0.6 eV for the formation of HOCO+, and thus account for the low sigma(HOCO+) and its bimodal profile observed. The Ecm enhancement for sigma(HOCO+) at Ecm ~ 0.5-5.0 eV can be attributed to the direct collision mechanism, whereas the formation of HOCO+ at low Ecm < 0.4 eV may involve a complex mechanism, which is mediated by the formation of a loosely sticking complex between HCO+ and OH. The direct collision and complex mechanisms proposed also allow the rationalization of the vibrational inhibition at low Ecm and the vibrational enhancement at high Ecm observed for the sigma(HOCO+). PMID- 28352923 TI - [Diagnostic approach and management of hypercalcaemia in dogs exemplary of primary hyperparathyroidism]. AB - Hypercalcaemia can be caused by many different diseases. This article summarizes the causes, pathophysiologic mechanisms and diagnostic procedures as well as treatment recommendations. The main focus is on hypercalcaemia in primary hyperparathyroidism (PH), complemented by a case report. An elevated total calcium level should generally be investigated and verified by measurement of ionized calcium concentration. The further diagnostic approach depends on the phosphate level. Tumour screening, measurement of parathormone and parathromone related protein and sonography of parathyroid glands may be necessary. If the calcium-phosphate-product exceeds 60 mg/dl, there is a risk of tissue mineralisation and a rapid treatment of hypercalcaemia is required. For acute therapy, sodium chloride infusion, furosemide and glucocorticoids can be used. Glucocorticoids should only be given after strict indication and after a definite diagnosis. For long-term management, bisphosphates, particularly alendronate, are increasingly used successfully. Causal therapy of PH can be performed by parathyreoidectomy, heat ablation or ethanol ablation. Thereafter, particularly in cases of severe preoperative hypercalcaemia, hypocalcaemia can occur. Treatment is performed using vitamin D3 (calcitriol), which may also be given preoperatively in cases of severe hypercalcaemia. A concomitant oral calcium supplementation using calcium carbonate as medication of choice is contentious. Due to a potential relapse after successful excision of the affected parathyroid gland in PH, the serum calcium level should be monitored periodically. PMID- 28352924 TI - [Abomasal ulcers in cattle]. AB - Abomasal ulcers lead to several problems. They cause pain resulting in a decrease in productivity and even the possible loss of the animal. Because they are frequently difficult to diagnose, information on their prevalence is variable. Additionally, therapeutic options are limited. Abomasal ulcers are graded as type 1 through 4, type 1 being a superficial defect and type 2 an ulcer where a large blood vessel has been eroded, leading to substantial blood loss. Types 3 and 4 are perforated abomasal ulcers leading to local and diffuse peritonitis, respectively. Causes of abomasal ulcers are multifactorial, for example, mistakes in feeding that lead to gastrointestinal disturbances or other diseases that induce stress. Ulcers can also result from side effects of nonsteroidal anti inflammatory drugs. In principal, the pathophysiological cause is the disturbance of the balance between protective and aggressive mechanisms at the abomasal mucosa due to stress. Clinical symptoms vary and are mostly non-specific. Fecal occult blood tests, hematology and blood chemistry as well as ultrasonographic examination and abdominocentesis can help to establish the diagnosis. Ulcers can be treated symptomatically, surgically and medically. To prevent abomasal ulcers, animals should be kept healthy by providing adequate nutrition and housing as well as early and effective medical care. Stressful management practices, including transport and commingling, should be avoided. PMID- 28352925 TI - Implementation of a single sign-on system between practice, research and learning systems. AB - BACKGROUND: Multiple specialized electronic medical systems are utilized in the health enterprise. Each of these systems has their own user management, authentication and authorization process, which makes it a complex web for navigation and use without a coherent process workflow. Users often have to remember multiple passwords, login/logout between systems that disrupt their clinical workflow. Challenges exist in managing permissions for various cadres of health care providers. OBJECTIVES: This case report describes our experience of implementing a single sign-on system, used between an electronic medical records system and a learning management system at a large academic institution with an informatics department responsible for student education and a medical school affiliated with a hospital system caring for patients and conducting research. METHODS: At our institution, we use OpenMRS for research registry tracking of interventional radiology patients as well as to provide access to medical records to students studying health informatics. To provide authentication across different users of the system with different permissions, we developed a Central Authentication Service (CAS) module for OpenMRS, released under the Mozilla Public License and deployed it for single sign-on across the academic enterprise. The module has been in implementation since August 2015 to present, and we assessed usability of the registry and education system before and after implementation of the CAS module. 54 students and 3 researchers were interviewed. RESULTS: The module authenticates users with appropriate privileges in the medical records system, providing secure access with minimal disruption to their workflow. No passwords requests were sent and users reported ease of use, with streamlined workflow. CONCLUSIONS: The project demonstrates that enterprise-wide single sign-on systems should be used in healthcare to reduce complexity like "password hell", improve usability and user navigation. We plan to extend this to work with other systems used in the health care enterprise. PMID- 28352926 TI - The effect of requesting a reason for non-adherence to a guideline in a long running automated reminder system for PONV prophylaxis. AB - BACKGROUND: Automated reminders are employed frequently to improve guideline adherence, but limitations of automated reminders are becoming more apparent. We studied the reasons for non-adherence in the setting of automated reminders to test the hypothesis that a separate request for a reason in itself may further improve guideline adherence. METHODS: In a previously implemented automated reminder system on prophylaxis for postoperative nausea and vomiting (PONV), we included additional automated reminders requesting a reason for non-adherence. We recorded these reasons in the pre-operative screening clinic, the OR and the PACU. We compared adherence to our PONV guideline in two study groups with a historical control group. RESULTS: Guideline adherence on prescribing and administering PONV prophylaxis (dexamethasone and granisetron) all improved compared to the historical control group (89 vs. 82% (p< 0.0001), 96 vs 95% (not significant) and 90 vs 82% (p<0.0001)) while decreasing unwarranted prescription for PONV prophylaxis (10 vs. 13 %). In the pre-operative screening clinic, the main reason for not prescribing PONV prophylaxis was disagreement with the risk estimate by the decision support system. In the OR/PACU, the main reasons for not administering PONV prophylaxis were: 'unintended non-adherence' and 'failure to document'. CONCLUSIONS: In this study requesting a reason for non-adherence is associated with improved guideline adherence. The effect seems to depend on the underlying reason for non-adherence. It also illustrates the importance of human factors principles in the design of decision support. Some reasons for non adherence may not be influenced by automated reminders. PMID- 28352927 TI - Coverage of Acta Dermatovenerologica Alpina, Pannonica et Adriatica in Elsevier's CiteScore index: a new tool for measuring the citation impact of academic journals. AB - In December 2016, Elsevier launched a new tool that helps measure the citation impact of academic journals, called the CiteScore index. The CiteScore index values for 2015 confirmed the status of Acta Dermatovenerologica Alpina, Pannonica et Adriatica (Acta Dermatovenerol APA) as the leading journal in dermatology and sexually transmitted infections in the region. Sixty-five articles published in Acta Dermatovenerol APA from 2012 to 2014 received a total of 77 citations in 2015, resulting in a CiteScore index value of 1.18 for the journal. More than half of the articles published from 2012 to 2014 received at least one citation in 2015. Acta Dermatovenerol APA performed well in all three categories listed because it is ranked 384th out of 1,549 journals in the category General Medicine (75th percentile), 53rd out of 122 journals in the category Dermatology (56th percentile), and 142nd out of 246 journals in the category Infectious Diseases (42nd percentile). PMID- 28352928 TI - Evaluation of psoriasis severity and inflammatory responses under concomitant treatment with methotrexate plus micronutrients for psoriasis vulgaris: a randomized double blind trial. AB - INTRODUCTION: We evaluated the effectiveness of concomitant treatment with methotrexate (MTX) plus micronutrients in comparison with monotherapy with MTX only in psoriasis patients. Plasma levels of interleukin-1 beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) were also measured and their association with clinical severity was evaluated. METHODS: Thirty psoriasis patients 20 to 50 years old with a PASI score > 10 were divided randomly into two groups. Both groups were given oral methotrexate (0.2-0.3 mg/kg/week) for 12 weeks. In addition, Group B received one tablet of micronutrient supplement daily. Disease severity was calculated using the psoriasis area and severity index (PASI) score before and after 12 weeks. Levels of IL-1beta and TNF-alpha were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: We found that 13 (86.6%) patients in Group B and 8 (53.3%) patients in Group A attained a mild PASI score (<= 10% body involvement). IL-1beta and TNF-alpha levels were significantly decreased in favor of Group B (p < 0.05). There was a significant correlation between changes in both IL-1beta and TNF-alpha levels and PASI score after the study (p < 0.05). CONCLUSION: The results obtained were positive, and therefore double-blind randomized trials with a larger sample size are highly suggested to confirm or reject these results. PMID- 28352929 TI - Effectiveness of adalimumab in the treatment of scalp and nail affection in patients with moderate to severe plaque psoriasis in routine clinical practice. AB - INTRODUCTION: Data on the effectiveness of biologics in the treatment of nail and scalp psoriasis (PSO) in a routine clinical setting are scarce. The aim of this study was therefore to evaluate the effectiveness of adalimumab in the treatment of nail and scalp psoriatic lesions in routine dermatologic practice. METHODS: Five hundred one patients were analyzed in this observational study; 157 patients had nail involvement (nail PSO set; NPS) and 404 had scalp involvement (scalp PSO set; SPS). Patients treated with adalimumab were observed for up to 12 months. Outcomes were evaluated via changes in the Nail Psoriasis Severity Index (NAPSI), Psoriasis Scalp Severity Index (PSSI), Psoriasis Area and Severity Index (PASI), and QoL (using the Dermatology Life Quality Index). RESULTS: Eighty-four percent of the patients in the NPS and 93.8% in the SPS achieved a good clinical response upon treatment with adalimumab. Complete clearing of local symptoms was achieved by 33.3% of the patients with nail involvement and 66.7% of the patients with scalp involvement. There was also a marked improvement in QoL. CONCLUSION: Adalimumab appears to be an effective treatment for scalp and nail PSO in patients with moderate to severe plaque PSO. No new clinical concerns were established. PMID- 28352930 TI - Pilonidal sinus disease can be treated with crystallized phenol using a simple three-step technique. AB - INTRODUCTION: Pilonidal sinus disease can be treated with various surgical techniques. However, invasive surgical techniques harbor the risk of wound infection and require a long postoperative wound healing period. The treatment of pilonidal sinus disease with crystallized phenol is minimally invasive with a short postoperative recovery period. This article explains how to treat pilonidal sinus disease with crystallized phenol using a quick and easy three-step technique. METHODS: Between August 2014 and January 2016, 43 male and 7 female patients with pilonidal sinus disease were treated with crystallized phenol. Hair was gently removed from the sinus openings with a mosquito clamp. Afterwards, the pilonidal sinus openings were gently filled with crystallized phenol. RESULTS: The closure of pilonidal sinus openings without any leakage after a single application of crystallized phenol was accepted as healing. The treatment failed in two of the female patients, who had had prior pilonidal sinus surgery, and in four of the male patients, who had a recurrence after wound site infection. The overall cure rate was 88%. CONCLUSIONS: Treatment of pilonidal sinus disease with crystallized phenol using the three-step technique is simple, fast, and comfortable. Therefore, crystallized phenol should be preferentially considered in the treatment of pilonidal sinus disease. PMID- 28352931 TI - Near-total lower lip reconstruction: combined Karapandzic and Bernard-Burrow Webster flap. AB - Lip carcinoma is a common cancer of the head and neck region. It more often affects the lower lip (> 90%), and squamous cell carcinoma represents 95% of the cases. The authors present a reconstruction of the lower lip combining two classical flaps: the Karapandzic and Bernard-Burrow-Webster flap. The surgical technique is discussed. PMID- 28352932 TI - Hidradenitis suppurativa in Crohn's disease during adalimumab therapy: a paradox? AB - A sporadic association between hidradenitis suppurativa and other diseases is reported in the literature, but few authors have described the association with Crohn's disease. Adalimumab is a fully human monoclonal antibody targeted at tumor necrosis factor alpha approved for the treatment of Crohn's disease and, recently, for active moderate to severe hidradenitis suppurativa in adult patients that do not respond adequately to systemic conventional treatment. We report an unusual case of a paradoxical effect of adalimumab in the onset of hidradenitis suppurativa in a 40-year-old woman during the treatment of Crohn's disease. PMID- 28352933 TI - Erythema multiforme following pneumococcal vaccination. AB - Erythema multiforme (EM) is an acute and usually self-limited immune-mediated mucocutaneous disorder that is a hypersensitivity reaction to drugs, infections, and vaccines. Clinically, it is characterized by maculopapular, target-like lesions symmetrically distributed on the extremities (minor form) or additionally affecting one or more mucous membranes and causing epidermal detachment involving < 10% of the total body surface area (major form). We report a novel association between pneumococcal vaccination and the development of EM in a 2.5-year-old boy. The introduction of 13-valent-polysaccharide-pneumococcal-conjugate vaccine (PCV13) into vaccination programs has resulted in a reduced incidence of pneumococcal disorders. Systemic side effects of PCV13 include chills, fever, headache, vomiting, fatigue, arthralgia, myalgias, decreased appetite, and diarrhea, whereas its cutaneous adverse reactions are local injection site reactions, Sweet's syndrome, and deep morphea. EM is triggered by a variety of vaccines; however, as far as we know, it has not previously been reported in association with pneumococcal vaccine. Although a fortuitous occurrence of EM in our patient cannot be absolutely excluded, it appears very likely that PCV13 caused the patient's eruption, considering the history and the laboratory data, which point toward a lack of any other causative factors. PMID- 28352936 TI - Pre-surgery exercise and post-operative physical function of people undergoing knee replacement surgery: A systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVE: To summarize the evidence regarding the effectiveness and dose response characteristics of pre-operative exercise programmes on post-operative physical function following total knee arthroplasty. DATA SOURCES: CINAHL, Cochrane Library, PubMed, SPORTDiscus and EMBASE. STUDY SELECTION: Randomized controlled trials were eligible if they provided full description of physiological stress (i.e. mode, frequency, intensity and duration). DATA EXTRACTION: Data extraction and evaluation were performed by one reviewer. Methodological quality of the selected studies was assessed using the Physiotherapy Evidence Database scale. DATA SYNTHESIS: Twelve candidate studies were identified, but only 3 papers satisfied all inclusion criteria: 2 studies evaluated the effect of resistance training and 1 trial investigated proprioceptive training. The latter study elicited significantly enhanced post operative gains in function for indices of standing balance (overall stability index: Hedges' g = -1; anteroposterior stability index: Hedges' g = -1.15; 6 weeks post-surgery). Results of meta-analysis based on the findings of 2 studies showed that, compared with controls, prehabilitative exercise involving resistance training offered no additional gains in isometric quadriceps muscle strength at 6 and 12 weeks post-operatively. CONCLUSION: Despite a potential for efficacy of exercise-based conditioning, this review highlights the scarcity of robust dose-response evidence to guide the formulation of total knee arthroplasty prehabilitation effectively. PMID- 28352935 TI - Lower-limb motor coordination is significantly impaired in ambulatory people with chronic stroke: A cross-sectional study. AB - OBJECTIVES: To establish the deficits of motor coordination of the lower limbs after stroke, in comparison with healthy controls, and to investigate whether the magnitude of the deficits would be influenced by the levels of motor recovery. DESIGN: Cross-sectional study. SUBJECTS: Chronic stroke patients and healthy subjects. METHODS: Lower-limb motor coordination of both stroke and healthy volunteers was measured using the Lower Extremity Motor Coordination Test (LEMOCOT). The motor coordination deficits of the participants with stroke were analysed all together and separated, according to their levels of motor recovery, measured using the Fugl-Meyer lower-limb motor section scores. RESULTS: Ninety seven individuals with chronic stroke, 55 men, mean age 58 years, were evaluated. Motor coordination was significantly impaired on both paretic (mean: -22 touches; 95% confidence interval (95% CI) -24 to -19; deficit: 61%) and non-paretic (mean 6 touches; 95% CI -8 to -4; deficit: 17%) lower limbs. Significant differences in the LEMOCOT scores were found between the levels of motor recovery (p < 0.01), except between the participants with marked and moderate impairments. CONCLUSION: Motor coordination of the lower limbs is significantly impaired after stroke, but the deficits of the non-paretic lower limb (17%) appear not to be clinically relevant. These findings suggest that interventions prescribed to improve motor coordination after stroke should focus on the paretic lower limb and/or include bilateral activities. PMID- 28352937 TI - Impact of emotional distress and pain-related fear on patients with chronic pain: Subgroup analysis of patients referred to multimodal rehabilitation. AB - OBJECTIVE: Multimodal rehabilitation programmes (MMRP) for chronic pain could be improved by determining which patients do not benefit fully. General distress and pain-related fear may explain variations in the treatment effects of MMRP. DESIGN: Cohort study with a cross-sectional, prospective part. PATIENTS: Chronic musculoskeletal pain patients referred to 2 hospital-based pain rehabilitation clinics. METHODS: The cross-sectional part of this study cluster analyses patients (n = 1,218) with regard to distress and pain-related fear at first consultation in clinical pain rehabilitation and describes differences in external variables between clusters. The prospective part follows the subsample of patients (n = 260) participating in MMRP and describes outcome post-treatment. RESULTS: Four distinct subgroups were found: (i) those with low levels of distress and pain-related fear; (ii) those with high levels of pain-related fear; (iii) those with high levels of distress; and (iv) those with high levels of distress and pain-related fear. These subgroups showed differences in demogra phics, pain characteristics, quality of life, and acceptance, as well as the degree of MMRP participation and MMRP outcome. CONCLUSION: Among patients with chronic pain referred to MMRP there are subgroups with different profiles of distress and pain-related fear, which are relevant to understanding the adaptation to pain and MMRP outcome. This knowledge may help us to select patients and tailor treatment for better results. PMID- 28352938 TI - Reliability of the 2- and 6-minute walk tests in neuromuscular diseases. AB - OBJECTIVE: The 2- and 6-minute walk tests are used to evaluate walking capacity, but reliability has been sparsely investigated in patients with neuromuscular diseases. The aim of this study was to investigate the relative and absolute reliability of the 2- and 6-minute walk tests in patients with neuromuscular diseases. DESIGN: Each patient performed a 2- and a 6-minute walk test on 2 test days separated by 1-2 weeks. SUBJECTS: A total of 93 adult patients (mean age 53 years, age range 22-83 years) with 12 different neuromuscular diseases were included. RESULTS: The mean walking distance increased by 4.3 and 11.2 m (p < 0.001) in repeated 2- and 6-minute walk tests, respectively. Intraclass correlation coefficient in the 2- and 6-minute walk tests was 0.99 (p < 0.001). Standard error of measurement was 4.9 m in the 2-minute walk test and 14.0 m in the 6-minute walk test. Minimal detectable difference was 13.7 m in the 2-minute walk test and 38.8 m in the 6-minute walk test. CONCLUSION: These findings show good relative reliability of the 2- and 6-minute walk tests in patients with neuromuscular diseases. However, absolute reliability demonstrated variability in neuromuscular diseases. This should be considered when interpreting a change in walking distance. PMID- 28352939 TI - Rigid shoulder taping with physiotherapy in patients with subacromial pain syndrome: A randomized controlled trial. AB - OBJECTIVE: To assess the effectiveness of individualized physiotherapy in combination with rigid taping compared with individualized physiotherapy alone in patients with subacromial pain syndrome. DESIGN: A prospective randomized trial with concealed allocation. PATIENTS: A total of 140 patients between 18 and 65 years of age from primary physiotherapy settings. METHODS: The intervention group received individualized physiotherapy and shoulder taping. The control group received individualized physiotherapy only. Primary outcomes were: pain intensit (numerical rating scale) and functioning (Simple Shoulder Test). Secondary outcomes were: global perceived effect and patient-specific complaints. Data were collected at baseline, and at 4, 12 and 26 weeks' follow-up. RESULTS: During the 6-month follow-up period multilevel analysis showed a significant difference between groups favouring the control group on pain intensity (p = 0.02), but not on functioning. Regarding secondary outcomes, a significant difference between groups was found favouring the intervention group for global perceived effect (p = 0.02), but not for patient-specific complaints. CONCLUSION: Rigid shoulder taping, as used in this study, cannot be recommended for improving physiotherapy outcomes in people with subacromial pain syndrome. PMID- 28352941 TI - EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease in severely obese people: do they lead to over-referral? AB - AIMS/HYPOTHESIS: We aimed to assess the application of the recent European Association for the Study of the Liver (EASL)-European Association for the Study of Diabetes (EASD)-European Association for the Study of Obesity (EASO) clinical practice guidelines for the management of non-alcoholic fatty liver disease (NAFLD) in severely obese individuals in routine clinical practice. METHODS: We performed a single-centre retrospective observational study of 385 patients referred for severe obesity (BMI >= 35 kg/m2) to our Endocrinology, Diabetes and Nutrition department, between 1 November 2014 and 31 December 2015. The recent EASL-EASD-EASO clinical practice guidelines for the management of NAFLD were retrospectively applied to the cohort using, successively, the NAFLD fibrosis score (NFS) and a combination of the NFS and transient elastography (TE) measurement in a subgroup of individuals. RESULTS: We identified 313 (81.3%) individuals with NAFLD in the cohort. The application of the EASL-EASD-EASO guidelines using NFS would lead to referral to a specialist for up to 289 individuals (75.1%) in the cohort. The combination of NFS and TE measurement reclassified 28 (25%) individuals from the medium/high risk group to low risk and would lead to the referral of 261 (67.7%) individuals to a specialist. These proportions appear to be excessive given the expected prevalence of advanced fibrosis and non-alcoholic steatohepatitis (NASH) of around 10% and 30%, respectively, in the severely obese population. CONCLUSIONS/INTERPRETATION: This is the first study to assess the strategy proposed by the EASL-EASD-EASO clinical practice guidelines for the management of NAFLD in severely obese individuals. The retrospective application of the guidelines in a cohort representing the routine clinical practice in our department would lead to an excessive number of specialist referrals and would also lead to an unjustified increase in health costs. Biomarkers and specific strategy for the screening of NASH and advanced fibrosis in morbidly obese individuals are thus crucially needed and would help to improve the actual guidelines. PMID- 28352940 TI - Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to insulin sensitivity in mice and in humans. AB - AIMS/HYPOTHESIS: Insulin resistance is frequently associated with hypertension and type 2 diabetes. The cytochrome P450 (CYP) arachidonic acid epoxygenases (CYP2C, CYP2J) and their epoxyeicosatrienoic acid (EET) products lower blood pressure and may also improve glucose homeostasis. However, the direct contribution of endogenous EET production on insulin sensitivity has not been previously investigated. In this study, we tested the hypothesis that endogenous CYP2C-derived EETs alter insulin sensitivity by analysing mice lacking CYP2C44, a major EET producing enzyme, and by testing the association of plasma EETs with insulin sensitivity in humans. METHODS: We assessed insulin sensitivity in wild type (WT) and Cyp2c44 -/- mice using hyperinsulinaemic-euglycaemic clamps and isolated skeletal muscle. Insulin secretory function was assessed using hyperglycaemic clamps and isolated islets. Vascular function was tested in isolated perfused mesenteric vessels. Insulin sensitivity and secretion were assessed in humans using frequently sampled intravenous glucose tolerance tests and plasma EETs were measured by mass spectrometry. RESULTS: Cyp2c44 -/- mice showed decreased glucose tolerance (639 +/- 39.5 vs 808 +/- 37.7 mmol/l * min for glucose tolerance tests, p = 0.004) and insulin sensitivity compared with WT controls (hyperinsulinaemic clamp glucose infusion rate average during terminal 30 min 0.22 +/- 0.02 vs 0.33 +/- 0.01 mmol kg-1 min-1 in WT and Cyp2c44 -/- mice respectively, p = 0.003). Although glucose uptake was diminished in Cyp2c44 -/- mice in vivo (gastrocnemius Rg 16.4 +/- 2.0 vs 6.2 +/- 1.7 MUmol 100 g-1 min-1, p < 0.01) insulin-stimulated glucose uptake was unchanged ex vivo in isolated skeletal muscle. Capillary density was similar but vascular KATP-induced relaxation was impaired in isolated Cyp2c44 -/- vessels (maximal response 39.3 +/ 6.5% of control, p < 0.001), suggesting that impaired vascular reactivity produces impaired insulin sensitivity in vivo. Similarly, plasma EETs positively correlated with insulin sensitivity in human participants. CONCLUSIONS/INTERPRETATION: CYP2C-derived EETs contribute to insulin sensitivity in mice and in humans. Interventions to increase circulating EETs in humans could provide a novel approach to improve insulin sensitivity and treat hypertension. PMID- 28352942 TI - Long-term dietary nitrite and nitrate deficiency causes the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice. AB - AIMS/HYPOTHESIS: Nitric oxide (NO) is synthesised not only from L-arginine by NO synthases (NOSs), but also from its inert metabolites, nitrite and nitrate. Green leafy vegetables are abundant in nitrate, but whether or not a deficiency in dietary nitrite/nitrate spontaneously causes disease remains to be clarified. In this study, we tested our hypothesis that long-term dietary nitrite/nitrate deficiency would induce the metabolic syndrome in mice. METHODS: To this end, we prepared a low-nitrite/nitrate diet (LND) consisting of an amino acid-based low nitrite/nitrate chow, in which the contents of L-arginine, fat, carbohydrates, protein and energy were identical with a regular chow, and potable ultrapure water. Nitrite and nitrate were undetectable in both the chow and the water. RESULTS: Three months of the LND did not affect food or water intake in wild-type C57BL/6J mice compared with a regular diet (RD). However, in comparison with the RD, 3 months of the LND significantly elicited visceral adiposity, dyslipidaemia and glucose intolerance. Eighteen months of the LND significantly provoked increased body weight, hypertension, insulin resistance and impaired endothelium dependent relaxations to acetylcholine, while 22 months of the LND significantly led to death mainly due to cardiovascular disease, including acute myocardial infarction. These abnormalities were reversed by simultaneous treatment with sodium nitrate, and were significantly associated with endothelial NOS downregulation, adiponectin insufficiency and dysbiosis of the gut microbiota. CONCLUSIONS/INTERPRETATION: These results provide the first evidence that long term dietary nitrite/nitrate deficiency gives rise to the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice, indicating a novel pathogenetic role of the exogenous NO production system in the metabolic syndrome and its vascular complications. PMID- 28352944 TI - Quantitative proteomic studies in resistance mechanisms of Eimeria tenella against polyether ionophores. AB - Polyether ionophores are widely used to treat and control coccidiosis in chickens. Widespread use of anticoccidials resulted in worldwide resistance. Mechanisms of resistance development and expansion are complex and poorly understood. Relative proteomic quantification using LC-MS/MS was used to compare sensitive reference strains (Ref-1, Ref-2) with putatively resistant and moderately sensitive field strains (FS-R, FS-mS) of Eimeria tenella after isotopic labelling with tandem mass tags (TMT). Ninety-seven proteins were identified, and 25 of them were regulated. Actin was significantly upregulated in resistant strains in comparison with their sensitive counterparts. On the other hand, microneme protein (MIC4) was downregulated in resistant strains. Optimization of labelling E. tenella sporozoites by TMT might identify further proteins that play a role in the obvious complex mechanism leading to resistance against Monensin. PMID- 28352946 TI - New Price, New Hope? An Examination of the Effects of Doubling the Ticket Price in UK Lotto. AB - The UK Lotto game was introduced in November 1994 with a standard 6/49 format and an entry fee of L1 per ticket. After several years, revenue began to fall despite extensive publicity and a variety of inducements. By 2013, nominal weekly revenue was less than half the 1995 level. In October 2013, the operator doubled the price of a ticket to L2 and made a number of changes to the pay-out structure of smaller prizes. The intent of the changes was to reverse the long downward trend in game revenue by encouraging higher jackpots and offering more pay-out opportunities for each ticket. We use draw by draw revenue and other data to evaluate how players responded to these changes and find that, while ticket sales fell dramatically, total revenue rose following the changes. Primarily this appears to have been the consequence of increased frequency of rollovers (and therefore of more frequent high jackpot draws) rather than ticket price inelasticity. However, although there was a short-term gain in revenue, the changes did not arrest, and indeed seem to have accentuated, the long-run trend decrease in the revenue generated by the game. PMID- 28352943 TI - Function of Nanos1 gene in the development of reproductive organs of Schistosoma japonicum. AB - Nanos is a necessary factor in the differentiation and migration of primordial germ cells. It is closely associated with the development of genitalia in a wide range of species. We questioned whether Nanos was involved in the reproductive organ development of Schistosoma japonicum. Firstly, by in situ hybridization, S. japonicum Nanos1 (SjNanos1 ) gene was expressed mainly in reproductive organs of S. japonicum. Then, the paired schistosome of 28 days post-infection (dpi) was transfected with SjNanos1 small interfering RNA three times and cultured in vitro for 10 days. SjNanos1 expression suppression in the mRNA and protein levels were confirmed compared to that of the controls. The morphological changes in reproductive organs and egg production were observed after SjNanos1 gene knockdown. The results observed by confocal laser scanning microscopy showed significant changes in the morphology of reproductive organs of parasites, especially the female ovaries, vitellarium, and the male testes, after RNAi. In addition, SjNanos1 silencing also induced the reduction of eggs, and affected the changes of reproduction-related genes, like Pumilio, CNOT6L, and Fs800. Therefore, our findings demonstrate that the SjNanos1 gene is essential in the development of reproductive organs and the egg production of S. japonicum. PMID- 28352945 TI - Shunt overdrainage syndrome: review of the literature. AB - Shunt overdrainage in patients with hydrocephalus still represents a challenge for neurosurgeons, in part due to the lack of agreement or uniformity concerning the entity. Important problems exist relating to the real incidence of the entity, its definition, classification, and the pathophysiological theories behind the various treatment strategies proposed. Recent reports have suggested that the evidence about overdrainage and its consequences is not so robust as presumed. Consequently, the topic requires more detailed examination. In this review, we comment on all the main facets related with shunt overdrainage. PMID- 28352947 TI - The knowns and unknowns of boredom: a review of the literature. AB - Despite the ubiquitous nature of boredom, the definition, function, and correlates of boredom are still poorly understood. In this review, we summarize the "known" (consistent evidence) and "unknown" (inconsistent evidence) correlates of boredom. We show that boredom is consistently related to negative affect, task-unrelated thought, over-estimation of elapsed time, reduced agency, as well as to over- and under-stimulation. Activation of the default mode network was consistent across the few available fMRI studies, while the recruitment of other brain areas such as the hippocampus and anterior insular cortex, was a notable but less consistent correlate of boredom. Other less consistent correlates of boredom are also reviewed, such as the level of arousal and the mental attributions given to fluctuations of attention. Finally, we identify two critical factors that may contribute to current inconsistencies in the literature and may hamper further progress in the field. First, there is relatively little consistency in the way in which boredom has been operationalized across studies to date, with operationalizations of boredom ranging from negative affect paired with under-stimulation, over-stimulation, to negative affect paired with a lack of goal-directed actions. Second, preliminary evidence suggests the existence of distinct types of boredom (e.g., searching vs. apathetic) that may have different and sometimes even opposing correlates. Adopting a more precise and consistent way of operationalizing boredom, and arriving at an empirically validated taxonomy of different types of boredom, could serve to overcome the current roadblocks to facilitate further progress in our scientific understanding of boredom. PMID- 28352948 TI - Visual information from observing grasping movement in allocentric and egocentric perspectives: development in typical children. AB - Development of the motor system lags behind that of the visual system and might delay some visual properties more closely linked to action. We measured the developmental trajectory of the discrimination of object size from observation of the biological motion of a grasping action in egocentric and allocentric viewpoints (observing action of others or self), in children and adolescents from 5 to 18 years of age. Children of 5-7 years of age performed the task at chance, indicating a delayed ability to understand the goal of the action. We found a progressive improvement in the ability of discrimination from 9 to 18 years, which parallels the development of fine motor control. Only after 9 years of age did we observe an advantage for the egocentric view, as previously reported for adults. Given that visual and haptic sensitivity of size discrimination, as well as biological motion, are mature in early adolescence, we interpret our results as reflecting immaturity of the influence of the motor system on visual perception. PMID- 28352950 TI - Effect of threshold growth as a major feature on LI-RADS categorization. AB - PURPOSE: Liver Imaging Reporting and Data System (LI-RADS) uses major features (arterial phase hyperenhancement [APHE], "washout" [WO], "capsule," diameter, threshold growth [TG]) to codify probability of hepatocellular carcinoma for each observation. This study assessed the effect of removing TG as a major feature on LI-RADS categorization. MATERIALS AND METHODS: In this HIPAA-compliant, IRB approved study, all MR and CT clinical reports containing a standardized LI-RADS v2014 template between 4/15-1/17 were retrospectively reviewed for each LR-3, LR 4, and LR-5 reported observation. Two LI-RADS categories were then assigned: one using all LI-RADS major features and one after removing TG as a major feature. The two categories were compared descriptively. RESULTS: The study included 265 patients (172 [65%] male, mean age 63 [+/-10] years) with 489 observations (median diameter 14 mm, IQR 10-20 mm), of which 345 (71%) had APHE, 307 (63%) had WO, 86 (18%) had "capsule," and 72 (15%) had TG. Of 86 observations with TG, 47 (65%) were new observations >=10 mm, 14 (19%) had diameter increase >=50% in <=6 months, and 11 (15%) had diameter increase >=100% in >6 months. Using all major features, 214/489 (44%) observations were LR-3, 129/489 (26%) were LR-4, and 146/489 (30%) were LR-5. After removing TG, 237/489 (48%) were LR-3, 119/489 (24%) were LR-4, and 133 (27%) were LR-5. Removing TG caused a category downgrade for 35/489 (7%, 95% CI 5-10) observations, including 13/146 (9%, 95% CI 3-14) LR 5 observations. CONCLUSION: 9% of LR-5 observations would be downgraded without TG. PMID- 28352949 TI - From prescription-only (Rx) to over-the-counter (OTC) status in Germany 2006 2015: pharmacological perspectives on regulatory decisions. AB - PURPOSE: Little is known about the extent of switches from prescription-only (Rx) to over-the-counter (OTC) status in Europe and about the pharmacological properties of the switched substances. The objectives of this study were to provide an overview of the substances that were switched from Rx to OTC status in Germany between 2006 and 2015 and to assess their pharmacological properties. METHODS: Session minutes of the German Expert Advisory Committee for Prescription Only Issues, changes to the German Ordinance on Prescription-Only Medicines and the Summary of Product Characteristics of the switched substances were analysed. Pharmacological properties were studied in relation to the EU Guideline on Changing the Classification for the Supply of a Medicinal Product for Human Use (the 'EU switch guide'). RESULTS: Between 2006 and 2015, seven substances (almotriptan, omeprazole, benzydamine, ibuprofen/pseudoephedrine, racecadotril, ketotifen and levonorgestrel) were switched from Rx to OTC status in Germany. In all cases, the OTC status was restricted to certain indications, doses, pack sizes, or other limitations. Notwithstanding recommendations of the EU switch guide, some of the switched substances might interact with commonly used drugs potentially resulting in serious adverse drug reactions or have contraindications or warnings regarding substantial parts of the population. CONCLUSIONS: The stipulations of the EU switch guide were fully met for only some switches, while this was not completely the case for others. Further development of guidance on balancing risks and benefits of OTC availability is recommended. PMID- 28352952 TI - ? PMID- 28352951 TI - The value of adding diffusion-weighted images for tumor detection and preoperative staging in renal pelvic carcinoma for the reader's experience. AB - PURPOSE: This retrospective study aimed to assess the value of adding diffusion weighted magnetic resonance imaging (DWI) or gadolinium-enhanced fat-suppressed T1WI (CEI) to T2-weighted imaging (T2WI) for preoperative T categorization in renal pelvic carcinoma by the reader's experience using surgical specimens as the reference standard. METHODS: Two radiologists (Reader 1; 3 years, 2; 13 years) reviewed 49 cases with urothelial carcinoma who underwent magnetic resonance imaging examination before surgery, independently, using three image sets: T2WI alone, T2WI plus DWI, and T2WI plus CEI for tumor detection and T categorization. The differences in the apparent diffusion coefficient values between tumors and renal parenchyma, histopathologic grade were analyzed. RESULTS: T2WI plus CEI or DWI had high detection rates (93.4%) compared to T2WI alone. When discriminating T3a/T3b, for Reader 1, the use of T2WI plus DWI (88.0%) and T2WI plus CEI (92.0%) was significantly more accurate than T2WI alone (73%), with AUCs of 0.86, 0.86 and 0.77, respectively. For Reader 2, the accuracies were high on all image sets, with AUCs of 0.87-0.95, and the mean ADC of the tumors was significantly lower than that of the normal renal parenchyma. In addition, the mean ADC values of high-grade tumors were significantly lower than that of low-grade tumors. CONCLUSIONS: DWI and CEI could be more helpful than T2WI alone for preoperative T categorization by less-experienced reader and DWI could be used for preoperative T categorization and for predicting the histopathologic grade of renal pelvic carcinoma. PMID- 28352953 TI - Three-dimensional volume rendering of pelvic models and paraurethral masses based on MRI cross-sectional images. AB - AIMS: Our aim was to assess the feasibility of rendering 3D pelvic models using magnetic resonance imaging (MRI) scans of patients with vaginal, urethral and paraurethral lesions and obtain additional information previously unavailable through 2D imaging modalities. METHODS: A purposive sample of five female patients 26-40 years old undergoing investigations for vaginal or paraurethral mass was obtained in a tertiary teaching hospital. 3D volume renderings of the bladder, urethra and paraurethral masses were constructed using 3D-Slicer v.3.4.0. Spatial dimensions were determined and compared with findings from clinical, MRI, surgical and histopathological reports. The quality of information regarding size and location of paraurethral masses obtained from 3D models was compared with information from cross-sectional MRI and review of clinical, surgical and histopathological findings. RESULTS: The analysis of rendered 3D models yielded detailed anatomical dimensions and provided information that was in agreement and in higher detail than information based on clinical examination, cross-sectional 2D MRI analysis and histopathological reports. High-quality pelvic 3D models were rendered with the characteristics and resolution to allow identification and detailed viewing of the spatial relationship between anatomical structures. CONCLUSIONS: To our knowledge, this is the first preliminary study to evaluate the role of MRI-based 3D pelvic models for investigating paraurethral masses. This is a feasible technique and may prove a useful addition to conventional 2D MRI. Further prospective studies are required to evaluate this modality for investigating such lesions and planning appropriate management. PMID- 28352954 TI - Dietary enzymatically treated Artemisia annua L. supplementation alleviates liver oxidative injury of broilers reared under high ambient temperature. AB - Heat stress induced by high ambient temperature is a major concern in commercial broiler production. To evaluate the effects of dietary enzymatically treated Artemisia annua L. (EA) supplementation on growth performance and liver oxidative injury of broilers reared under heat stress, a total of 320 22-day-old male broilers were randomly allotted into five groups with eight replicates of eight birds each. Broilers in the control group were housed at 22 +/- 1 degrees C and fed the basal diet. Broilers in the HS, HS-EA1, HS-EA2, and HS-EA3 groups were fed basal diet supplemented with 0, 0.75, 1.00, and 1.25 g/kg EA, respectively, and reared under cyclic high temperature (34 +/- 1 degrees C for 8 h/day and 22 +/- 1 degrees C for 16 h/day). Broilers fed EA diets had higher final body weight, average daily body weight gain, and average daily feed intake, as well as liver concentration of reduced glutathione, activities of antioxidant enzymes, abilities to inhibit hydroxyl radical and superoxide radical (HS-EA2 and HS-EA3), and lower liver concentrations of reactive oxygen metabolites, malondialdehyde, and protein carbonyl (HS-EA1, HS-EA2, and HS-EA3) than HS group (P < 0.05). EA treatment downregulated the mRNA levels of heat shock proteins 70 and 90, upregulated the mRNA levels of nuclear factor erythroid 2-related factor 2 (HS EA1, HS-EA2, and HS-EA3) and heme oxygenase 1 (HS-EA2 and HS-EA3) in liver of heat-treated broilers (P < 0.05). In conclusion, EA alleviated heat stress induced growth depression and liver oxidative injury in broilers, possibly through improving the antioxidant capacity and regulating the pertinent mRNA expression. The appropriate inclusion level of EA in broiler diet is 1.00-1.25 g/kg. PMID- 28352955 TI - The concomitants of conspiracy concerns. AB - PURPOSE: A conspiracy world view may be a form of mistrust that is typically corrosive to individual and societal well-being. Our aim was to establish the correlates of conspiracy thinking in an epidemiologically representative sample. METHODS: US National Comorbidity Survey-Replication (NCS-R) data were analysed from 5645 people who had completed the item "I am convinced there is a conspiracy behind many things in the world." Results were weighted to be representative of the US adult English speaking household population. RESULTS: 1618 people (weighted 26.7%) endorsed the conspiracy belief item. These individuals were more likely to be: male; currently unmarried; less educated; in a lower income household; outside the labour force; from an ethnic minority group; not attending religious services; taking a weapon outside; and perceiving themselves as of lower social standing compared to others. Individuals endorsing the conspiracy belief item had lower levels of physical and psychological well-being, higher levels of suicidal ideation, weaker social networks, less secure attachment style, difficult childhood family experiences, and were more likely to meet criteria for a psychiatric disorder. There were no differences between those who endorsed conspiracy beliefs and those who did not in age, importance of religious beliefs in daily life, body mass index, or in having a gun at home. CONCLUSIONS: Viewing conspiracies in the world is associated with a raised risk of a wide range of adverse circumstances. It is a type of cognitive style that requires systematic empirical study, including monitoring of prevalence, tests of causation, and modelling of propagation. PMID- 28352956 TI - Expert's Comment concerning Grand Rounds case entitled "Acute non-traumatic idiopathic spinal subdural hematoma: radiographic findings and surgical results with a literature review" by K. Kobayashi, S. Imagama, K. Ando, Y. Nishida, N. Ishiguro (Eur Spine J; 2017). PMID- 28352957 TI - Growing from dilemmas: developing a professional identity through collaborative reflections on relational dilemmas. AB - Health educators nurture future generations of professionals by helping them to navigate the complex transition from students to therapists. The purpose of this study was to illustrate how a pedagogical method of collaborative reflection (involving reflective writing, sharing, and discussion) on relational dilemmas with role partners can develop occupational therapists' professional identity. The course, in which this method was applied, implemented the supervision and peer learning frameworks as related to student's fieldwork experiences, and is based on the perception of growing from conflicts and exploration. The study is based on analyzing qualitative data of 392 dilemma cases and 196 texts of personal reflection on classroom work of undergraduate students in occupational therapy. A thematic analysis of the case studies revealed six overarching relational dilemmas that novice therapists are often called upon to deal with when working with patients, patients' families and colleagues from other health professions. Analyzing the personal texts of reflection highlighted the effectiveness of collaborative reflection in bridging the gap between theory and practice, and in helping students develop their professional identity. The method can be adapted to curricula for students and therapists in other health professions, in undergraduate courses, and in group supervision programs. PMID- 28352961 TI - Chronic swelling of the foot. PMID- 28352960 TI - Periosteal mesenchymal chondrosarcoma of the tibia with multifocal bone metastases: a case report. AB - Mesenchymal chondrosarcoma of bone is a rare high-grade variant of chondrosarcoma, which typically has central intramedullary location. The tumor is characterized by admixture of highly anaplastic small round malignant cells and islands of mineralized low-grade hyaline cartilage. It is most unusual for this tumor to arise on the surface of a long bone. We describe a patient with periosteal mesenchymal chondrosarcoma that arose at the surface of the right tibia with multifocal bone metastases. Radiographic, CT, MRI, and PET-CT features of this unusual tumor are presented. PMID- 28352958 TI - The epigenetic landscape of age-related diseases: the geroscience perspective. AB - In this review, we summarize current knowledge regarding the epigenetics of age related diseases, focusing on those studies that have described DNA methylation landscape in cardio-vascular diseases, musculoskeletal function and frailty. We stress the importance of adopting the conceptual framework of "geroscience", which starts from the observation that advanced age is the major risk factor for several of these pathologies and aims at identifying the mechanistic links between aging and age-related diseases. DNA methylation undergoes a profound remodeling during aging, which includes global hypomethylation of the genome, hypermethylation at specific loci and an increase in inter-individual variation and in stochastic changes of DNA methylation values. These epigenetic modifications can be an important contributor to the development of age-related diseases, but our understanding on the complex relationship between the epigenetic signatures of aging and age-related disease is still poor. The most relevant results in this field come from the use of the so called "epigenetics clocks" in cohorts of subjects affected by age-related diseases. We report these studies in final section of this review. PMID- 28352959 TI - Inheritance, fine-mapping, and candidate gene analyses of resistance to soybean mosaic virus strain SC5 in soybean. AB - Soybean mosaic virus (SMV) is one of the most devastating pathogens for soybeans in China. Among the country-wide 22 strains, SC5 dominates in Huang-Huai and Changjiang valleys. For controlling its damage, the resistance gene was searched through Mendelian inheritance study, gene fine-mapping, and candidate gene analysis combined with qRT-PCR (quantitative real-time polymerase chain reaction) analysis. The parents F1, F2, and RILs (recombinant inbred lines) of the cross Kefeng-1 (Resistance, R) * NN1138-2 (Susceptible, S) were used to examine the inheritance of SC5-resistance. The F1 was resistant and the F2 and RILs segregated in a 3R:1S and 1R:1S ratio, respectively, indicating a single dominant gene conferring the Kefeng-1 resistance. Subsequently, the genomic region conferring the resistance was found in "Bin 352-Bin353 with 500 kb" on Chromosome 2 using the phenotyping data of the 427 RILs and a high-density genetic map with 4703 bin markers. In the 500 kb genomic region, 38 putative genes are contained. The association analysis between the SNPs in a putative gene and the resistance phenotype for the 427 RILs prioritized 11 candidate genes using Chi-square criterion. The expression levels of these genes were tested by qRT-PCR. On infection with SC5, 7 out of the 11 genes had differential expression in Kefeng-1 and NN1138-2. Furthermore, integrating SNP-phenotype association analysis with qRT-PCR expression profiling analysis, Glyma02g13495 was found the most possible candidate gene for SC5-resistance. This finding can facilitate the breeding for SC5-resistance through marker-assisted selection and provide a platform to gain a better understanding of SMV-resistance gene system in soybean. PMID- 28352962 TI - Helminthiasis characterization and anthelmintic efficacy for ewes and lambs raised in tropical semiarid region. AB - In this study the helminthiasis and anthelmintic effectiveness in ewes and lambs were evaluated in a semiarid region of Brazil. Twelve sheep farms were investigated using semi-structured questionnaires and fecal egg count (FEC) reduction test was employed to analyze the profile of anthelmintic resistance. Groups of at least 10 animals with FEC >= 300 were selected. After 12 h of fasting, homogeneous groups of lambs or ewes were treated with albendazole, levamisole moxidectin, or oxfendazole and control groups were not treated. Feces were collected before treatments and 14 days after, and larvae genera were identified after cuprocultures in both periods. Extensive grazing was the predominant creation system, using hybrid Santa Ines animals. The separation by age was promoted in 75% of herds; however, maternity pickets there were only in three farms. The strategic treatments were performed only in 8.4% of sheep farms and 16.6% used the anthelmintic efficacy test and alternated anthelmintic classes after 1 year. The initial FEC means for lambs were significantly higher than ewe FEC averages. For lamb tests, moxidectin and levamisole showed higher efficacy (p <= 0.05) than benzimidazoles. For ewe tests, moxidectin and levamisole showed efficiencies >75%. Haemonchus spp. and Trichostrongylus spp. were the most frequent nematodes before treatments and the genus Haemonchus was the most prevalent after anthelmintic treatments (p < 0.05). Variations of anthelmintic susceptibility were observed for categories and herds evaluated, which emphasizes the importance of the effectiveness tests for the choice of anthelmintics for ewes and lambs. PMID- 28352963 TI - External ear findings during anaphylaxis. PMID- 28352964 TI - The limits of weak selection and large population size in evolutionary game theory. AB - Evolutionary game theory is a mathematical approach to studying how social behaviors evolve. In many recent works, evolutionary competition between strategies is modeled as a stochastic process in a finite population. In this context, two limits are both mathematically convenient and biologically relevant: weak selection and large population size. These limits can be combined in different ways, leading to potentially different results. We consider two orderings: the [Formula: see text] limit, in which weak selection is applied before the large population limit, and the [Formula: see text] limit, in which the order is reversed. Formal mathematical definitions of the [Formula: see text] and [Formula: see text] limits are provided. Applying these definitions to the Moran process of evolutionary game theory, we obtain asymptotic expressions for fixation probability and conditions for success in these limits. We find that the asymptotic expressions for fixation probability, and the conditions for a strategy to be favored over a neutral mutation, are different in the [Formula: see text] and [Formula: see text] limits. However, the ordering of limits does not affect the conditions for one strategy to be favored over another. PMID- 28352965 TI - Dual-Energy CT to Diagnose Pseudoedema in Contrast-Induced Encephalopathy Following Cerebral Angiography. AB - BACKGROUND: Contrast-induced encephalopathy (CIE) is a syndrome that may be clinically unrecognized and misdiagnosed as cerebral edema. METHODS: Case report and review. RESULTS: A 72-year-old woman was admitted for elective endovascular embolization of a 10-mm left anterior communicating artery aneurysm. One hour post-procedure, she acutely developed global aphasia. Emergent head computed tomography (CT) and computed tomography-angiography (CTA) showed high attenuation of the left hemispheric subarachnoid spaces interpreted as hemispheric edema; emergent magnetic resonance imaging revealed left hemispheric punctate infarcts. At 12 h, she developed right hemiparesis and encephalopathy. Repeat CTA and CT perfusion revealed decreased left hemisphere cerebral blood flow and diminutive caliber of distal left middle cerebral artery territory vasculature. Repeated angiography with intra-arterial verapamil and systemic blood pressure augmentation were performed for presumed vasospasm. At 20 h, head CT was concerning for worsening left hemispheric edema, but dual-energy, iodine subtracting sequences revealed significant contrast extravasation contributing to the appearance of sulcal effacement but without actual edema. Out of concern for blood-brain barrier breakdown from CIE, pressor augmentation was discontinued and the patient gradually improved to full neurological recovery within 72 h of symptom onset. CONCLUSIONS: Our case is the first known to report the use of dual energy, iodine-subtracting CT as a diagnostic tool in differentiating between cerebral edema and pseudoedema in CIE. PMID- 28352966 TI - Cold Blooded: Evaluating Brain Temperature by MRI During Surface Cooling of Human Subjects. AB - BACKGROUND: Targeted temperature management (TTM) confers neurological and survival benefits for post-cardiac arrest patients with return of spontaneous circulation (ROSC) who remain comatose. Specialized equipment for induction of hypothermia is not available in the prehospital setting, and there are no reliable methods for emergency medical services personnel to initiate TTM. We hypothesized that the application of surface cooling elements to the neck will decrease brain temperature and act as initiators of TTM. METHODS: Magnetic resonance (MR) spectroscopy was used to evaluate the effect of a carotid surface cooling element on brain temperature in healthy adults. RESULTS: Six individuals completed this study. We measured a temperature drop of 0.69 +/- 0.38 degrees C (95% CI) in the cortex of the brain following the application of the cooling element. Application of a room temperature element also caused a measurable decrease in brain temperature of 0.66 +/- 0.41 degrees C (95% CI) which may be attributable to baroreceptor activation. CONCLUSION: The application of surface cooling elements to the neck decreased brain temperature and may serve as a method to initiate TTM in the prehospital setting. PMID- 28352967 TI - Alternative splicing affects the targeting sequence of peroxisome proteins in Arabidopsis. AB - KEY MESSAGE: A systematic analysis of the Arabidopsis genome in combination with localization experiments indicates that alternative splicing affects the peroxisomal targeting sequence of at least 71 genes in Arabidopsis. Peroxisomes are ubiquitous eukaryotic cellular organelles that play a key role in diverse metabolic functions. All peroxisome proteins are encoded by nuclear genes and target to peroxisomes mainly through two types of targeting signals: peroxisomal targeting signal type 1 (PTS1) and PTS2. Alternative splicing (AS) is a process occurring in all eukaryotes by which a single pre-mRNA can generate multiple mRNA variants, often encoding proteins with functional differences. However, the effects of AS on the PTS1 or PTS2 and the targeting of the protein were rarely studied, especially in plants. Here, we systematically analyzed the genome of Arabidopsis, and found that the C-terminal targeting sequence PTS1 of 66 genes and the N-terminal targeting sequence PTS2 of 5 genes are affected by AS. Experimental determination of the targeting of selected protein isoforms further demonstrated that AS at both the 5' and 3' region of a gene can affect the inclusion of PTS2 and PTS1, respectively. This work underscores the importance of AS on the global regulation of peroxisome protein targeting. PMID- 28352969 TI - Transgenic pigeonpea events expressing Cry1Ac and Cry2Aa exhibit resistance to Helicoverpa armigera. AB - KEY MESSAGE: Independent transgenic pigeonpea events were developed using two cry genes. Transgenic Cry2Aa-pigeonpea was established for the first time. Selected transgenic events demonstrated 100% mortality of Helicoverpa armigera in successive generations. Lepidopteran insect Helicoverpa armigera is the major yield constraint of food legume pigeonpea. The present study was aimed to develop H. armigera-resistant transgenic pigeonpea, selected on the basis of transgene expression and phenotyping. Agrobacterium tumefaciens-mediated transformation of embryonic axis explants of pigeonpea cv UPAS 120 was performed using two separate binary vectors carrying synthetic Bacillus thuringiensis insecticidal crystal protein genes, cry1Ac and cry2Aa. T0 transformants were selected on the basis of PCR and protein expression profile. T1 events were exclusively selected on the basis of expression and monogenic character for cry, validated through Western and Southern blot analyses, respectively. Independently transformed 12 Cry1Ac and 11 Cry2Aa single-copy events were developed. The level of Cry-protein expression in T1 transgenic events was 0.140-0.175% of total soluble protein. Expressed Cry1Ac and Cry2Aa proteins in transgenic pigeonpea exhibited significant weight loss of second-fourth instar larvae of H. armigera and ultimately 80-100% mortality in detached leaf bioassay. Selected Cry-transgenic pigeonpea events, established at T2 generation, inherited insect-resistant phenotype. Immunohistofluorescence localization in T3 plants demonstrated constitutive accumulation of Cry1Ac and Cry2Aa in leaf tissues of respective transgenic events. This study is the first report of transgenic pigeonpea development, where stable integration, effective expression and biological activity of two Cry proteins were demonstrated in subsequent three generations (T0, T1, and T2). These studies will contribute to biotechnological breeding programmes of pigeonpea for its genetic improvement. PMID- 28352968 TI - Silencing SlAGL6, a tomato AGAMOUS-LIKE6 lineage gene, generates fused sepal and green petal. AB - KEY MESSAGE: Silencing SlAGL6 in tomato leads to fused sepal and green petal by influencing the expression of A-, B-class genes. AGAMOUS-LIKE6 (AGL6) lineage is an important clade MADS-box transcription factor and plays essential roles in various developmental programs especially in flower meristem and floral organ development. Here, we isolated a tomato AGL6 lineage gene SlAGL6 and successfully obtained several RNA interference (RNAi) lines. Silencing SlAGL6 led to abnormal fused sepals and light green petals with smaller size. The total chlorophyll content in transgenic petals increased and the morphology of epidermis cells altered. Further analysis showed that A-class gene MACROCALYX (MC) participating in sepal development and a NAC-domain gene GOBLET involving in boundary establishment were down-regulated in transgenic lines. In transgenic petals, two chlorophyll synthesis genes, Golden2-like1 (SlGLK1) and Golden2-like2 (SlGLK2), two photosystem-related genes, ribulose bisphosphate carboxylase small chain 3B (SlrbcS3B) and chlorophyll a/b-binding protein 7 (SlCab-7) were induced and three B-class genes TM6, TAP3 and SlGLO1 were repressed. These results suggest that SlAGL6 involves in tomato sepal and petal development. PMID- 28352971 TI - IR Spectra of Different O2-Content Hemoglobin from Computational Study: Promising Detector of Hemoglobin Variant in Medical Diagnosis. AB - IR spectra of heme and different O2-content hemoglobin were studied by the quantum computation method at the molecule level. IR spectra of heme and different O2-content hemoglobin were quantificationally characterized from 0 to 100 THz. The IR spectra of oxy-heme and de-oxy-heme are obviously different at the frequency regions of 9.08-9.48, 38.38-39.78, 50.46-50.82, and 89.04-91.00 THz. At 24.72 THz, there exists the absorption peak for oxy-heme, whereas there is not the absorption peak for de-oxy-heme. Whether the heme contains Fe-O-O bond or not has the great influence on its IR spectra and vibration intensities of functional groups in the mid-infrared area. The IR adsorption peak shape changes hardly for different O2-content hemoglobin. However, there exist three frequency regions corresponding to the large change of IR adsorption intensities for containing-O2 hemoglobin in comparison with de-oxy-hemoglobin, which are 11.08 15.93, 44.70-50.22, and 88.00-96.68 THz regions, respectively. The most differential values with IR intensity of different O2-content hemoglobin all exceed 1.0 * 104 L mol-1 cm-1. With the increase of oxygen content, the absorption peak appears in the high-frequency region for the containing-O2 hemoglobin in comparison with de-oxy-hemoglobin. The more the O2-content is, the greater the absorption peak is at the high-frequency region. The IR spectra of different O2-content hemoglobin are so obviously different in the mid-infrared region that it is very easy to distinguish the hemoglobin variant by means of IR spectra detector. IR spectra of hemoglobin from quantum computation can provide scientific basis and specific identification of hemoglobin variant resulting from different O2 contents in medical diagnosis. PMID- 28352972 TI - Gerald E. McClearn 1927-2017: A Founding Father of Behavioral Genetics. PMID- 28352973 TI - Incidence and molecular diversity of poleroviruses infecting cucurbit crops and weed plants in Thailand. AB - Overall, 244 samples of cucurbit crops with yellowing symptoms and selected weed species, from 15 provinces in Thailand, were screened by RT-PCR using primers Polero-CP-F and Polero-CP-R. A total of 160 samples (~66%) were infected by poleroviruses. Analysis of a 1.4 kb region covering the 3' RNA-dependent RNA polymerase (RdRp) gene, the intergenic non-coding region (iNCR), and the coat protein (CP), showed that four poleroviruses, namely, cucurbit aphid-borne yellows virus (CABYV), luffa aphid-borne yellows virus (LABYV), melon aphid-borne yellows virus (MABYV) and suakwa aphid-borne yellows virus (SABYV) were associated with the yellowing symptoms in cucurbit crops. Further analyses indicated presence of putative recombinant viruses referred to as CABYV-R and SABYV-R. CABYV-R was derived from the recombination between MABYV and the common strain of CABYV (CABYV-C). SABYV-R was derived from the recombination of MABYV and SABYV. PMID- 28352974 TI - Myocardial stunning occurs during intermittent haemodialysis for acute kidney injury. PMID- 28352975 TI - Empathy: some thoughtful reflections among a favorable attitude. PMID- 28352976 TI - Did KDIGO guidelines on acute kidney injury improve patient outcome? PMID- 28352977 TI - Single-energy pediatric chest computed tomography with spectral filtration at 100 kVp: effects on radiation parameters and image quality. AB - BACKGROUND: Most of the applied radiation dose at CT is in the lower photon energy range, which is of limited diagnostic importance. OBJECTIVE: To investigate image quality and effects on radiation parameters of 100-kVp spectral filtration single-energy chest CT using a tin-filter at third-generation dual source CT in comparison to standard 100-kVp chest CT. MATERIALS AND METHODS: Thirty-three children referred for a non-contrast chest CT performed on a third generation dual-source CT scanner were examined at 100 kVp with a dedicated tin filter with a tube current-time product resulting in standard protocol dose. We compared resulting images with images from children examined using standard single-source chest CT at 100 kVp. We assessed objective and subjective image quality and compared radiation dose parameters. RESULTS: Radiation dose was comparable for children 5 years old and younger, and it was moderately decreased for older children when using spectral filtration (P=0.006). Effective tube current increased significantly (P=0.0001) with spectral filtration, up to a factor of 10. Signal-to-noise ratio and image noise were similar for both examination techniques (P>=0.06). Subjective image quality showed no significant differences (P>=0.2). CONCLUSION: Using 100-kVp spectral filtration chest CT in children by means of a tube-based tin-filter on a third-generation dual-source CT scanner increases effective tube current up to a factor of 10 to provide similar image quality at equivalent dose compared to standard single-source CT without spectral filtration. PMID- 28352978 TI - Transcranial Sonography in Mitochondrial Membrane Protein-Associated Neurodegeneration. AB - INTRODUCTION: Although the nature of basal ganglia hyperechogenicity in transcranial sonography (TCS) examinations remains unclear, many studies have shown associations between hyperechogenicity and iron accumulation. The role of iron in basal ganglia hyperechogenicity raises interest in the use of TCS in forms of neurodegeneration with brain iron accumulation (NBIA). Here we analyzed TCS and magnetic resonance imaging (MRI) findings among patients affected by one type of NBIA, mitochondrial membrane protein-associated neurodegeneration (MPAN). METHODS: Investigations using MRI and TCS were performed on 13 patients exhibiting a C19orf12 gene mutation. RESULTS: The use of T2/T2* MRI revealed hypointense lesions restricted to the globus pallidus and substantia nigra. Using TCS examination, 12 patients exhibited bilateral hyperechogenicity of the lenticular nucleus, while no patients showed substantia nigra hyperechogenicity. CONCLUSION: Investigations with TCS revealed a distinctive hyperechogenicity pattern of the basal ganglia in MPAN patients, which might be useful for differential diagnostics. The variable TCS imaging findings in NBIA patients may result from the presence of different iron content, iron binding partners, such as ferritin and neuromelanin, as well as structural changes, such as gliosis. PMID- 28352979 TI - Time-resolved 3D Rotational Angiography (4D DSA) of the Lenticulostriate Arteries: Display of Normal Anatomic Variants and Collaterals in Cases with Chronic Obstruction of the MCA. AB - PURPOSE: The lenticulostriate arteries (LSA) and other perforators may play a role for collateral supply in cases with ischemia due to stenosis or occlusions of the middle cerebral artery (MCA). Purpose of this case series was to evaluate the potential of time-resolved 3D rotational angiography data sets (4D DSA) for detailed visualization of anatomic variants of LSA feeders and for display of local collaterals involving the LSA in cases with chronic MCA obstruction. METHODS: Multiplanar and volume rendering reconstructions of 4D DSA data were computed in addition to standard postprocessing in 24 patients who had indications for 3D rotational angiography (3DRA) of the internal carotid artery (ICA) without pathologies of the ICA, middle cerebral artery (MCA) and anterior cerebral artery (ACA) main stems (n = 18) or with stenosis or chronic occlusion of the MCA (n = 6). For acquisition of 3DRA, we used a modified digital subtraction angiography (DSA) image acquisition protocol with an extended rotation angle of 260 degrees and a prolonged scan time of 12 s on a Siemens Axiom Artis Zee biplane neuroangiography equipment. The 4D reconstructions of existing 3DRA data were computed on a dedicated workstation. Origin and course of LSA and other perforators were analyzed according to coronal multiplanar reconstructions (MPRs) with slice thicknesses between 6 and 28 mm. RESULTS: In all cases 4D reconstructions of the LSA were technically feasible and evaluable. As expected, origin and course of LSA showed a wide range of variations: The most common pattern was a common trunk dividing into multiple ascending branches originating from the proximal M1 (n = 5) or the proximal A1 segment (n = 4). Alternatively, 8 patients showed several individual branches that directly originated from the proximal M1 segment of the MCA and occasionally from the A1 segment of the ACA. In patients with M1 stenosis or occlusion, 4 out of 6 cases had local collaterals with involvement of proximal LSA trunks and a network parallel to the obstructed vessel segment. The 4D reconstructions were found to be equivalent (n = 16) or superior to 3D reconstructions (n = 8). CONCLUSION: The 4D DSA reconstructions provide a reliable display of normal LSA variants and connections to local collateral networks in cases with chronic MCA obstruction. The possibility to select a correct angiographic phase is advantageous compared to 3D DSA. PMID- 28352970 TI - Quantitative trait loci from identification to exploitation for crop improvement. AB - Advancement in the field of genetics and genomics after the discovery of Mendel's laws of inheritance has led to map the genes controlling qualitative and quantitative traits in crop plant species. Mapping of genomic regions controlling the variation of quantitatively inherited traits has become routine after the advent of different types of molecular markers. Recently, the next generation sequencing methods have accelerated the research on QTL analysis. These efforts have led to the identification of more closely linked molecular markers with gene/QTLs and also identified markers even within gene/QTL controlling the trait of interest. Efforts have also been made towards cloning gene/QTLs or identification of potential candidate genes responsible for a trait. Further new concepts like crop QTLome and QTL prioritization have accelerated precise application of QTLs for genetic improvement of complex traits. In the past years, efforts have also been made in exploitation of a number of QTL for improving grain yield or other agronomic traits in various crops through markers assisted selection leading to cultivation of these improved varieties at farmers' field. In present article, we reviewed QTLs from their identification to exploitation in plant breeding programs and also reviewed that how improved cultivars developed through introgression of QTLs have improved the yield productivity in many crops. PMID- 28352981 TI - Fasting but not casual blood glucose is associated with pancreatic cancer mortality in Japanese: EPOCH-JAPAN. AB - PURPOSE: The dose-response relationship between fasting blood glucose levels and risk of pancreatic cancer has been investigated, but the association between casual blood glucose levels and pancreatic cancer death has not been examined. We examined the association between casual and fasting blood glucose levels and death due to pancreatic cancer in Japanese. METHODS: We performed a pooled analysis of the individual Japanese including 46,387 participants aged 40-79 years from ten cohorts. Participants were classified into five groups: low normal, middle normal, high normal, prediabetes (casual blood glucose 140-199 mg/dl, or fasting blood glucose 110-125 mg/dl), and diabetes (casual blood glucose >=200 mg/dl, fasting blood glucose >=126 mg/dl, or anti-diabetic drug use). Low normal, middle normal, and high normal were defined according to tertiles of casual or fasting normal blood glucose levels. Hazard ratios (HRs) and 95% confidence intervals (CIs) for pancreatic cancer mortality were estimated stratifying casual and fasting blood glucose by cohort-stratified Cox proportional hazards regression analysis, with low normal (casual blood glucose <94 mg/dl, or fasting blood glucose <90 mg/dl) as a reference. RESULTS: Fasting blood glucose showed a dose-response relationship with pancreatic cancer mortality (p for trend = 0.005). After adjusting for covariates, HRs (95% CIs) were 2.83 (1.18-6.76) for prediabetes and 3.96 (1.56-10.08) for diabetes. However, there were no significant associations with casual blood glucose. These tendencies were observed after the exclusion of participants who were censored for the first 5 years of follow-up. CONCLUSIONS: Fasting blood glucose is a better predictor of pancreatic cancer death than casual blood glucose. PMID- 28352980 TI - Symptom clusters for revising scale membership in the analysis of prostate cancer patient reported outcome measures: a secondary data analysis of the Medical Research Council RT01 trial (ISCRTN47772397). AB - PURPOSE: To investigate the role of symptom clusters in the analysis and utilisation of patient reported outcome measures (PROMs) for data modelling and clinical practice. To compare symptom clusters with scales, and to explore their value in PROMs interpretation and symptom management. METHODS: A dataset called RT01 (ISCRTN47772397) of 843 prostate cancer patients was used. PROMs were reported with the University of California, Los Angeles Prostate Cancer Index (UCLA-PCI). Symptom clusters were explored with hierarchical cluster analysis (HCA) and average linkage method (correlation > 0.6). The reliability of the Urinary Function Scale was evaluated with Cronbach's Alpha. The strength of the relationship between the items was investigated with Spearman's correlation. Predictive accuracy of the clusters was compared to the scales by receiver operating characteristic (ROC) analysis. Presence of urinary symptoms at 3 years measured with the late effects on normal tissue: subjective, objective, management tool (LENT/SOM) was an endpoint. RESULTS: Two symptom clusters were identified (urinary cluster and sexual cluster). The grouping of symptom clusters was different than UCLA-PCI Scales. Two items of the urinary function scales ("number of pads" and "urinary leak interfering with sex") were excluded from the urinary cluster. The correlation with the other items in the scale ranged from 0.20 to 0.21 and 0.31 to 0.39, respectively. Cronbach's Alpha showed low correlation of those items with the Urinary Function Scale (0.14-0.36 and 0.33 0.44, respectively). All urinary function scale items were subject to a ceiling effect. Clusters had better predictive accuracy, AUC = 0.70 -0.65, while scales AUC = 0.67-0.61. CONCLUSION: This study adds to the knowledge on how cluster analysis can be applied for the interpretation and utilisation of PROMs. We conclude that multiple-item scales should be evaluated and that symptom clusters provide a study-specific approach for modelling and interpretation of PROMs. PMID- 28352983 TI - An update on the Barriers to Adherence and a Definition of Self-Report Non adherence Given Advancements in Antiretroviral Therapy (ART). AB - Relying on the most frequently reported barriers to adherence and convenient definitions of non-adherence may lead to less valid results. We used a dominance analysis (a regression-based approach) to identify the most important barriers to adherence based on effect size using data collected through an online survey. The survey included the Adherence Barrier Questionnaire, self-reported non-adherence defined as a 4-day treatment interruption, and HIV clinical outcomes. The sample (N = 1217) was largely male, gay identified, and White. Nearly 1 in 3 participants reported "simply forgot" as a barrier; however, in a dominance analysis, it yielded a small effect size it its association with a 4-day treatment interruption. Further, dominance analyses stratified by race/ethnicity and age suggested that not all barriers impact all groups equally. The most frequently reported barriers to adherence were not the most important, and interventions should focus on barriers more strongly linked to clinical outcomes. PMID- 28352982 TI - Alcohol Use, Socioeconomic Status and Risk of HIV Infections. AB - The present study investigated the associations among alcohol use, socioeconomic status (SES), and human immunodeficiency virus (HIV) status, in the South African context. It was hypothesized that SES (predictor; measured as median split asset score) and alcohol use in the past 12 months (predictor) would interact such that current drinkers of low SES would be at an increased risk of testing HIV-positive (outcome). Nationally representative, cross-sectional survey data from 2005 (N = 16,110), 2008 (N = 13,055), and 2012 (N = 25,979) were analyzed using multinomial regression models. Current drinkers of low SES had an elevated risk of HIV infection in all survey years, ranging from a relative risk ratio (RRR) of 1.94 (95% confidence interval (CI) 1.29-3.00, t = 2.93, p = 0.002) in 2012 to RRR of 3.51 (95% CI 2.02-6.08, t = 4.47, p < 0.001) in 2008. Targeting preventive strategies to alcohol users of low SES could help reduce HIV burden and associated socioeconomic differences. PMID- 28352984 TI - A Longitudinal Analysis of Treatment Optimism and HIV Acquisition and Transmission Risk Behaviors Among Black Men Who Have Sex with Men in HPTN 061. AB - Little is known about HIV treatment optimism and risk behaviors among Black men who have sex with men (BMSM). Using longitudinal data from BMSM in the HPTN 061 study, we examined participants' self-reported comfort with having condomless sex due to optimistic beliefs regarding HIV treatment. We assessed correlates of treatment optimism and its association with subsequent risk behaviors for HIV acquisition or transmission using multivariable logistic regression with generalized estimating equations. Independent correlates of treatment optimism included age >=35 years, annual household income <$20,000, depressive symptoms, high HIV conspiracy beliefs, problematic alcohol use, and previous HIV diagnosis. Treatment optimism was independently associated with subsequent condomless anal sex with a male partner of serodiscordant/unknown HIV status among HIV-infected men, but this association was not statistically significant among HIV-uninfected men. HIV providers should engage men in counseling conversations to assess and minimize willingness to have condomless sex that is rooted in optimistic treatment beliefs without knowledge of viral suppression. PMID- 28352985 TI - A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer. AB - PURPOSE: Cabozantinib is a multi-kinase inhibitor that targets MET, AXL, and VEGFR2, and may synergize with EGFR inhibition in NSCLC. Cabozantinib was assessed alone or in combination with erlotinib in patients with progressive NSCLC and EGFR mutations who had previously received erlotinib. METHODS: This was a phase Ib/II study (NCT00596648). The primary objectives of phase I were to assess the safety, pharmacokinetics, and pharmacodynamics and to determine maximum tolerated dose (MTD) of cabozantinib plus erlotinib in patients who failed prior erlotinib treatment. In phase II, patients with prior response or stable disease with erlotinib who progressed were randomized to single-agent cabozantinib 100 mg qd vs cabozantinib 100 mg qd and erlotinib 50 mg qd (phase I MTD), with a primary objective of estimating objective response rate (ORR). RESULTS: Sixty-four patients were treated in phase I. Doses of 100 mg cabozantinib plus 50 mg erlotinib, or 40 mg cabozantinib plus 150 mg erlotinib were determined to be MTDs. Diarrhea was the most frequent dose-limiting toxicity and the most frequent AE (87.5% of patients). The ORR for phase I was 8.2% (90% CI 3.3-16.5). In phase II, one patient in the cabozantinib arm (N = 15) experienced a partial response, for an ORR of 6.7% (90% CI 0.3-27.9), with no responses for cabozantinib plus erlotinib (N = 13). There was no evidence that co administration of cabozantinib markedly altered erlotinib pharmacokinetics or vice versa. CONCLUSIONS: Despite responses with cabozantinib/erlotinib in phase I, there were no responses in the combination arm of phase II in patients with acquired resistance to erlotinib. Cabozantinib did not appear to re-sensitize these patients to erlotinib. PMID- 28352987 TI - Hemolytic uremic syndrome caused by E. coli O157 infection. PMID- 28352986 TI - Genetic associations with lipoprotein subfraction measures differ by ethnicity in the multi-ethnic study of atherosclerosis (MESA). AB - A recent genome-wide association study associated 62 single nucleotide polymorphisms (SNPs) from 43 genomic loci, with fasting lipoprotein subfractions in European-Americans (EAs) at genome-wide levels of significance across three independent samples. Whether these associations are consistent across ethnicities with a non-European ancestry is unknown. We analyzed 15 lipoprotein subfraction measures, on 1677 African-Americans (AAs), 1450 Hispanic-Americans (HAs), and 775 Chinese-Americans (CHN) participating in the multi-ethnic study of atherosclerosis (MESA). Genome-wide data were obtained using the Affymetrix 6.0 and Illumina HumanOmni chips. Linear regression models between genetic variables and lipoprotein subfractions were adjusted for age, gender, body mass index, smoking, study center, and genetic ancestry (based on principal components), and additionally adjusted for Mexican/Non-Mexican status in HAs. A false discovery rate correction was applied separately within the results for each ethnicity to correct for multiple testing. Power calculations revealed that we did not have the power for SNP-based measures of association, so we analyzed phenotype specific genetic risk scores (GRSs), constructed as in the original genome-wide analysis. We successfully replicated all 15 GRS-lipoprotein associations in 2527 EAs. Among the 15 significant GRS-lipoprotein associations in EAs, 11 were significant in AAs, 13 in HAs, and 1 in CHNs. Further analyses revealed that ethnicity differences could not be explained by differences in linkage disequilibrium, lipid lowering drugs, diabetes, or gender. Our study emphasizes the importance of ethnicity (here indexing genetic ancestry) in genetic risk for CVD and highlights the need to identify ethnicity-specific genetic variants associated with CVD risk. PMID- 28352988 TI - Differentiation of hemopericardium due to ruptured myocardial infarction or aortic dissection on unenhanced postmortem computed tomography. AB - The aim of the study was to evaluate unenhanced postmortem computed tomography (PMCT) in cases of non-traumatic hemopericardium by establishing the sensitivity, specificity and accuracy of diagnostic criteria for the differentiation between aortic dissection and myocardial wall rupture due to infarction. Twenty six cases were identified as suitable for evaluation, of which ruptured aortic dissection could be identified as the underlying cause of hemopericardium in 50% of the cases, and myocardial wall rupture also in 50% of the cases. All cases underwent a PMCT and 24 of the cases also underwent one or more additional examinations: a subsequent autopsy, or a postmortem magnetic resonance (PMMR), or a PMCT angiography (PMCTA), or combinations of the above. Two radiologists evaluated the PMCT images and classified each case as "aortic dissection", "myocardial wall rupture" or "undetermined". Quantification of the pericardial blood was carried out using segmentation techniques. 17 of 26 cases were correctly identified, either as aortic dissections or myocardial ruptures, by both readers. 7 of 13 myocardial wall ruptures were identified by both readers, whereas both readers identified correctly 10 of 13 aortic dissection cases. Taking into account the responses of both readers, specificity was 100% for both causes of hemopericardium and sensitivity as well as accuracy was higher for aortic dissections than myocardial wall ruptures (72.7% and 87.5% vs 53.8% and 75% respectively). Pericardial blood volumes were constantly higher in the aortic dissection group, but a statistical significance of these differences could not be proven, since the small count of cases did not allow for statistical tests. This study showed that diagnostic criteria for the differentiation between ruptured aortic dissection and myocardial wall rupture due to infarction are highly specific and accurate. PMID- 28352989 TI - Electric fences and accidental death. AB - Deaths which occur in association with agricultural electric fences are very rare. In fact, electric fences have undoubtedly saved numerous human and animal lives by safely and reliably keeping livestock confined to their fields and enclosures and thus preventing motor vehicle incidents when livestock get onto roads and highways. Accidental and intentional human contact with electric fences occurs regularly and causes little more than transient discomfort, however, on exceptional occasions, contact with electric fences appears to be directly related to the death of the individual. The precise pathophysiological cause of these deaths is unclear. We present two cases of deaths associated with electric fences, discuss the possible pathophysiological mechanisms in these cases, and suggest a universal approach to the medico-legal investigation and documentation of these deaths. PMID- 28352991 TI - Dynamic analysis of the light scattered by the non-equilibrium fluctuations of a ternary mixture of polystyrene-toluene-n-hexane. AB - Dynamic analysis of the light scattered by non-equilibrium fluctuations in a thermodiffusion experiment has been performed on a sample of polystyrene-toluene n -hexane, at 0.9-49.55-49.55% mass fraction. Time decays of the non-equilibrium fluctuations have been obtained revealing the accurate detectability of three modes. The slowest mode has been attributed to the mass diffusion of the polymer into the binary solvent; the intermediate one to mass diffusion of the two molecular components of the solvent; finally, the fastest one has been attributed to the thermal diffusivity of the overall mixture. The two eigenvalues of the mass diffusion matrix have been evaluated with accuracy in the order of 1%. Neglecting cross-diffusion effects we obtain a simplified expression for the relative amplitude of the two mass diffusion modes, allowing a parameterized determination of polystyrene and toluene Soret coefficients in the ternary mixture. We suggest that a two wavelength shadowgraph experiment is needed for a complete determination of all the coefficients. PMID- 28352990 TI - Choosing the right interface for positive airway pressure therapy in patients with obstructive sleep apnea. AB - PURPOSE: Positive airway pressure (PAP) is the standard and most effective treatment for obstructive sleep apnea (OSA). It provides a continuous stream of air under positive pressure through the nose, mouth, or both, which prevents collapse of the upper airway. This allows the patient to breathe freely during sleep. The success of PAP therapy depends largely on the selection of the proper interface (mask). The choice and application of the interface in patients with OSA is a great challenge that greatly affects the long-term compliance to PAP therapy. METHODS: This article discusses the different types of masks that can be used in patients with OSA, including the differences between nasal, oro-nasal, and total face masks, breathing during wakefulness and sleep, and the impact of interface type on upper airway patency and mask fitting. We also discuss the steps to be considered in choosing the proper interface and potential problems that may arise during long-term use. RESULTS AND CONCLUSION: Current evidence suggests that the nasal mask is better tolerated, requires lower pressure to eliminate obstructive respiratory events, and is associated with a better sleep quality and better PAP therapy compliance. Nevertheless, the best mask is the one that patient will wear. PMID- 28352992 TI - Kinetic modeling of electron transfer reactions in photosystem I complexes of various structures with substituted quinone acceptors. AB - The reduction kinetics of the photo-oxidized primary electron donor P700 in photosystem I (PS I) complexes from cyanobacteria Synechocystis sp. PCC 6803 were analyzed within the kinetic model, which considers electron transfer (ET) reactions between P700, secondary quinone acceptor A1, iron-sulfur clusters and external electron donor and acceptors - methylviologen (MV), 2,3-dichloro naphthoquinone (Cl2NQ) and oxygen. PS I complexes containing various quinones in the A1-binding site (phylloquinone PhQ, plastoquinone-9 PQ and Cl2NQ) as well as F X-core complexes, depleted of terminal iron-sulfur F A/F B clusters, were studied. The acceleration of charge recombination in F X-core complexes by PhQ/PQ substitution indicates that backward ET from the iron-sulfur clusters involves quinone in the A1-binding site. The kinetic parameters of ET reactions were obtained by global fitting of the P700+ reduction with the kinetic model. The free energy gap DeltaG 0 between F X and F A/F B clusters was estimated as -130 meV. The driving force of ET from A1 to F X was determined as -50 and -220 meV for PhQ in the A and B cofactor branches, respectively. For PQ in A1A-site, this reaction was found to be endergonic (DeltaG 0 = +75 meV). The interaction of PS I with external acceptors was quantitatively described in terms of Michaelis-Menten kinetics. The second-order rate constants of ET from F A/F B, F X and Cl2NQ in the A1-site of PS I to external acceptors were estimated. The side production of superoxide radical in the A1-site by oxygen reduction via the Mehler reaction might comprise >=0.3% of the total electron flow in PS I. PMID- 28352993 TI - Preclinical Evaluation of the Short-Term Toxicity of 4-(N)-Docosahexaenoyl 2', 2' Difluorodeoxycytidine (DHA-dFdC). AB - PURPOSE: This study was designed to test the short-term toxicity of DHA-dFdC in a mouse model and its efficacy in a mouse model of leukemia at or below its repeat dose maximum tolerated dose (RD-MTD). METHOD: A repeat-dose dose-ranging toxicity study was designed to determine the tolerability of DHA-dFdC when administered to DBA/2 mice by intravenous (i.v.) injection on a repeat-dose schedule (i.e. injections on days 0, 3, 7, 10, and 13). In order to determine the effect of a lethal dose of DHA-dFdC, mice were injected i.v. with three doses of DHA-dFdC at 100 mg/kg on days 0, 3, and 5 (i.e. a lethal-RD). The body weight of mice was recorded two or three times a week. At the end of the study, major organs (i.e. heart, liver, spleen, kidneys, lung, and pancreas) of mice that received the lethal-RD or RD-MTD were weighed, and blood samples were collected for analyses. Finally, DHA-dFdC was i.v. injected into DBA/2 mice with syngeneic L1210 mouse leukemia cells to evaluate its efficacy at or below RD-MTD. RESULTS: The RD-MTD of DHA-dFdC is 50 mg/kg. At 100 mg/kg, a lethal-RD, DHA-dFdC decreases the weights of mouse spleen and liver and significantly affected certain blood parameters (i.e. white blood cells, lymphocytes, eosinophils, and neutrophil segmented). At or below its RD-MTD, DHA-dFdC significantly prolonged the survival of L1210 leukemia-bearing mice. CONCLUSION: DHA-dFdC has dose-dependent toxicity, affecting mainly spleen at a lethal-RD. At or below its RD-MTD, DHA-dFdC is effective against leukemia in a mouse model. PMID- 28352994 TI - Impact of Micellar Surfactant on Supersaturation and Insight into Solubilization Mechanisms in Supersaturated Solutions of Atazanavir. AB - PURPOSE: The goals of this study were to determine: 1) the impact of surfactants on the "amorphous solubility"; 2) the thermodynamic supersaturation in the presence of surfactant micelles; 3) the mechanism of solute solubilization by surfactant micelles in supersaturated solutions. METHODS: The crystalline and amorphous solubility of atazanavir was determined in the presence of varying concentrations of micellar sodium dodecyl sulfate (SDS). Flux measurements, using a side-by-side diffusion cell, were employed to determine the free and micellar bound drug concentrations. The solubilization mechanism as a function of atazanavir concentration was probed using fluorescence spectroscopy. Pulsed gradient spin-echo proton nuclear magnetic resonance (PGSE-NMR) spectroscopy was used to determine the change in micelle size with a change in drug concentration. RESULTS: Changes in the micelle/water partition coefficient, K m/w , as a function of atazanavir concentration led to erroneous estimates of the supersaturation when using concentration ratios. In contrast, determining the free drug concentration using flux measurements enabled improved determination of the thermodynamic supersaturation in the presence of micelles. Fluorescence spectroscopic studies suggested that K m/w changed based on the location of atazanavir solubilization which in turn changed with concentration. Thus, at a concentration equivalent to the crystalline solubility, atazanavir is solubilized by adsorption at the micelle corona, whereas in highly supersaturated solutions it is also solubilized in the micellar core. This difference in solubilization mechanism can lead to a breakdown in the prediction of amorphous solubility in the presence of SDS as well as challenges with determining supersaturation. PGSE NMR suggested that the size of the SDS micelle is not impacted at the crystalline solubility of the drug but increases when the drug concentration reaches the amorphous solubility, in agreement with the proposed changes in solubilization mechanism. CONCLUSIONS: Micellar solubilization of atazanavir is complex, with the solubilization mechanism changing with differences in the degree of (super)saturation. This can result in erroneous predictions of the amorphous solubility and thermodynamic supersaturation in the presence of solubilizing additives. This in turn hinders understanding of the driving force for phase transformations and membrane transport, which is essential to better understand supersaturating dosage forms. PMID- 28352995 TI - Association between obesity and femoral neck strength according to age, sex, and fat distribution. AB - : Indicators of total and abdominal obesity were negatively associated with femoral neck strength indices. There are age-, sex-, and fat distribution specific differences in the magnitude of these associations. These suggested that indicators of obesity with different magnitude according to age, sex, and fat distribution associated with poor bone health. INTRODUCTION: Fat regulates bone metabolism, but the associations of total and abdominal obesity with bone health are inconsistent. We investigated the association between indicators of obesity and composite indices of femoral neck (FN) strength reflecting the risk of hip fracture. METHODS: This population-based cross-sectional study examined data from the Korea National Health and Nutrition Examination Surveys. Participants were divided into groups according to age (25-49/>=50 years) and sex. We examined total fat mass (TFM) and percentage fat mass (pFM) as indicators of total obesity and truncal fat mass (TrFM) as an indicator of abdominal obesity. We calculated the composite indices of FN strength and anthropometric clinical indicators of abdominal obesity. RESULTS: TFM, pFM, and TrFM were negatively associated with the composite indices, irrespective of age and sex (P < 0.001-0.005). Most anthropometric clinical indicators of abdominal obesity showed negative associations with the composite indices regardless of age and sex (P < 0.001 0.048), except for women aged 25-49 years. In men, magnitudes of the negative contributions of TFM to the composite indices were significantly stronger at age 25-49 years than at age >=50 years. Magnitudes of negative associations of TFM with the composite indices were greater in men than in women. TrFM had a more detrimental effect than TFM on FN strength in men aged 25-49 years and in women of both ages. CONCLUSION: Indicators of total and abdominal obesity negatively associated with FN strength, and magnitudes of their effects on bone health differed according to age, sex, and fat distribution. PMID- 28352997 TI - Deprivation of asparagine triggers cytoprotective autophagy in laryngeal squamous cell carcinoma. AB - Laryngeal squamous cell carcinoma (LSCC), one of the most common malignancies in the head and neck, has poor prognosis and high mortality. The need of novel and effective treatment for LSCC is urgent. Asparaginase, an enzyme-depriving asparagine, has been employed for the treatment of various cancers. In this study, we reported for the first time that asparaginase could induce remarkable cytotoxicity and caspase-dependent apoptosis in human LSCC Tu212 and Tu686 cells. Meanwhile, autophagy was triggered by asparaginase in LSCC cells, which was confirmed by accumulation of autophagosomes and the conversion of light chain 3-I (LC3-I) to LC3-II. Importantly, inhibition of autophagy by chloroquine (CQ) significantly enhanced asparaginase-induced cytotoxicity, indicating that autophagy has a cytoprotective role in asparaginase-treated LSCC cells. Meanwhile, we found that mitochondrial-originated reactive oxygen species (ROS) participated in asparaginase-induced autophagy and cytotoxicity. N-acetyl-L cysteine (NAC), a common antioxidant, was employed to scavenge ROS, and our results demonstrated that NAC could significantly block asparaginase-induced autophagy and attenuate asparaginase-induced cytotoxicity, indicating that intracellular ROS played a crucial role in asparagine deprivation therapy. Furthermore, western blot analysis showed that asparaginase-induced autophagy was mediated by inactivation of Akt/mTOR and activation of the Erk signaling pathway in Tu212 and Tu686 cells. Therefore, these results indicated the protective role of autophagy in asparaginase-treated LSCC cells and provided a new attractive therapeutic strategy for LSCC by asparaginase alone or in combination with autophagic inhibitors. PMID- 28352998 TI - An external substrate-free blue/white screening system in Escherichia coli. AB - Since the lacZalpha-based blue/white screening system was introduced to molecular biology, several different visual reporter systems were developed and used for various purposes in Escherichia coli. A common limit to the existent visual reporter systems is that an extracellular chromogenic substrate has to be added for the visible pigment production. In this study, we developed a new blue/white screening system based on a non-ribosomal peptide synthetase encoded by idgS from Streptomyces and a phosphopantetheinyl transferase encoded by sfp from Bacillus. When IdgS is activated from an apo-form to a holo-form via a posttranslational modification catalyzed by Sfp, it can synthesize a blue pigment indigoidine using L-glutamine, the amino acid abundant in cells, as a substrate. The new blue/white screening system contains a recipient E. coli strain with an optimized idgS gene cassette and a cloning vector harboring an sfp gene with an in-frame insertion of a multiple cloning site close to its N-terminal. We demonstrated that the IdgS/Sfp-based blue/white screening system is a powerful alternative to the lacZalpha-based screening system, which does not require any external substrate addition. PMID- 28352999 TI - Inoculation of a phenanthrene-degrading endophytic bacterium reduces the phenanthrene level and alters the bacterial community structure in wheat. AB - Colonization by polycyclic aromatic hydrocarbon (PAH)-degrading endophytic bacteria (PAHDEB) can reduce the PAH contamination risk in plant. However, little information is available on the impact of PAHDEB colonization on the endophytic bacterial community of inner plant tissues. A phenanthrene-degrading endophytic bacterium (PDEB), Massilia sp. Pn2, was inoculated onto the roots of wheat and subjected to greenhouse container experiments. The endophytic bacterial community structure in wheat was investigated using high-throughput sequencing technology. The majority of endophytic bacteria in wheat were Proteobacteria, and the dominant genus was Pseudomonas. Phenanthrene contamination clearly increased the diversity of endophytic bacteria in wheat. The cultivable endophytic bacteria counts in wheat decreased with increasing the level of phenanthrene contamination; the endophytic bacterial community structure changed correspondingly, and the bacterial richness first increased and then decreased. Inoculation of strain Pn2 reduced the phenanthrene contamination in wheat, enlarged the biomass of wheat roots, changed the bacterial community structure and enhanced the cell counts, diversity and richness of endophytic bacteria in phenanthrene-contaminated wheat in a contamination level-dependent manner. The findings of this investigation provide insight into the responses of endophytic bacterial community in plant to external PAH contamination and PAHDEB colonization. PMID- 28353000 TI - Protection of chickens against H9N2 avian influenza virus challenge with recombinant Lactobacillus plantarum expressing conserved antigens. AB - Avian influenza virus (AIV) is spreading worldwide and is a serious threat to the health of poultry and humans. In many countries, low pathogenic AIVs, such as H9N2, have become an enormous economic burden on the commercial poultry industry because they cause mild respiratory disease and decrease egg production. A recombinant Lactobacillus plantarum NC8 strain expressing NP-M1-DCpep from H9N2 AIV has been studied in a mouse model. However, it remains unknown whether this L. plantarum strain can induce an immune response and provide protection against H9N2 AIV in chickens. In this study, chickens that were orally vaccinated with NC8-pSIP409-NP-M1-DCpep exhibited significantly increased T cell-mediated immune responses and mucosal sIgA and IgG levels, which provided protection against H9N2 AIV challenge. More importantly, compared with oral administration of NC8-pSIP409 NP-M1-DCpep, intranasal administration induced stronger immune responses and provided effective protection against challenge with the H9N2 virus by reducing body weight loss, lung virus titers, and throat pathology. Taken together, these findings suggest that L. plantarum expressing NP-M1-DCpep has potential as a vaccine to combat H9N2 AIV infection. PMID- 28353003 TI - Coexistence of meningoencephalocele and hippocampal sclerosis: a new type of dual pathology. AB - Both temporal lobe meningoencephalocele (TE) and hippocampal sclerosis (HS) are causes of drug-resistant temporal lobe epilepsy. Spontaneous TE constitutes a rare but well-known and increasingly recognised cause of refractory epilepsy. It is well known that HS may be associated with another neocortical lesion (dual pathology). Here we report for the first time a new type of dual pathology; namely, the coexistence of temporal pole meningoencephalocele and HS. PMID- 28352996 TI - Mechanisms and consequences of intestinal dysbiosis. AB - The composition of the gut microbiota is in constant flow under the influence of factors such as the diet, ingested drugs, the intestinal mucosa, the immune system, and the microbiota itself. Natural variations in the gut microbiota can deteriorate to a state of dysbiosis when stress conditions rapidly decrease microbial diversity and promote the expansion of specific bacterial taxa. The mechanisms underlying intestinal dysbiosis often remain unclear given that combinations of natural variations and stress factors mediate cascades of destabilizing events. Oxidative stress, bacteriophages induction and the secretion of bacterial toxins can trigger rapid shifts among intestinal microbial groups thereby yielding dysbiosis. A multitude of diseases including inflammatory bowel diseases but also metabolic disorders such as obesity and diabetes type II are associated with intestinal dysbiosis. The characterization of the changes leading to intestinal dysbiosis and the identification of the microbial taxa contributing to pathological effects are essential prerequisites to better understand the impact of the microbiota on health and disease. PMID- 28353001 TI - De novo biosynthesis of trans-cinnamic acid derivatives in Saccharomyces cerevisiae. AB - The production of natural aroma compounds is an expanding field within the branch of white biotechnology. Three aromatic compounds of interest are cinnamaldehyde, the typical cinnamon aroma that has applications in agriculture and medical sciences, as well as cinnamyl alcohol and hydrocinnamyl alcohol, which have applications in the cosmetic industry. Current production methods, which rely on extraction from plant materials or chemical synthesis, are associated with drawbacks regarding scalability, production time, and environmental impact. These considerations make the development of a sustainable microbial-based production highly desirable. Through steps of rational metabolic engineering, we engineered the yeast Saccharomyces cerevisiae as a microbial host to produce trans-cinnamic acid derivatives cinnamaldehyde, cinnamyl alcohol, and hydrocinnamyl alcohol, from externally added trans-cinnamic acid or de novo from glucose as a carbon source. We show that the desired products can be de novo synthesized in S. cerevisiae via the heterologous overexpression of the genes encoding phenylalanine ammonia lyase 2 from Arabidopsis thaliana (AtPAL2), aryl carboxylic acid reductase (acar) from Nocardia sp., and phosphopantetheinyl transferase (entD) from Escherichia coli, together with endogenous alcohol dehydrogenases. This study provides a proof of concept and a strain that can be further optimized for production of high-value aromatic compounds. PMID- 28353004 TI - The effectiveness of a population-based skin cancer screening program: evidence from Germany. AB - In this paper, we analyze how a nationwide population-based skin cancer screening program (SCS) implemented in Germany in 2008 has impacted the number of hospital discharges following malignant skin neoplasm diagnosis and the malignant melanoma mortality rate per 100,000 inhabitants. Our panel data, drawn from the Eurostat database, cover subregions in 22 European countries, measured at the lowest nomenclature of territorial units for statistics (NUTS) level for 2000-2013. Applying fixed effects methods, we find a significantly positive and robust effect of the German SCS on the number of patients diagnosed with malignant skin neoplasm. However, the program does not significantly influence the melanoma mortality rate. This finding conflicts with the decreased melanoma mortality rate found for the pilot SCS program in northern Germany. Our results indicate that Germany's nationwide SCS program is effective in terms of a higher diagnosis rate for malignant skin neoplasms and thus may contribute to an improvement in the early detection of skin cancer. PMID- 28353005 TI - Management and outcome of children with neuroendocrine tumors of the appendix in Spain: Is there room for improvement? AB - PURPOSE: Neuroendocrine tumors (NETs) are, after lymphomas, the most frequent gastrointestinal tumors in children, mainly located in the appendix. Best management remains unclear, given the absence of pediatric guidelines. We present the first Spanish series of pediatric patients with NETs. PATIENTS AND METHODS: Retrospective study of all pediatric patients (<18 years) with NET treated in four oncology reference institutions in Spain between 1994 and 2015. RESULTS: Seventeen patients were included. All patients presented with acute abdomen. TNM stage was T1a (82%) and T1b (12%). Extension study was heterogenous, with only 4 patients undergoing an OctreoScan. Four patients met criteria for second surgery (affected surgical margins or mesoappendix invasion), but it was only performed in two. Despite the diverse management, none of the patients relapsed during follow-up. CONCLUSIONS: The disparity in diagnostic tests, second surgery criteria and follow-up shown in this study highlights the need for specific pediatric guidelines. PMID- 28353006 TI - Efficacy and cost-effectiveness of second-line chemotherapy in elderly patients with advanced gastric cancer. AB - PURPOSE: Second-line chemotherapy has been shown to benefit patients with advanced gastric cancer (AGC), extending the overall survival (OS) and progression-free survival (PFS). This study aimed to assess the efficacy and cost effectiveness of second-line treatment for elderly patients with AGC. METHODS: Medical records and follow-up information of elderly patients (>=70 years) with AGC who received second-line chemotherapy were collected. A Markov model comprising three health states PFS, progressive disease and death was developed to simulate the process of AGC. Cost was calculated from the perspective of Chinese society. Sensitivity analyses were applied to explore the impact of essential variables. RESULTS: Forty-three elderly patients with AGC receiving second-line chemotherapy were included in our study. The median OS was 6.0 months (95% confidence interval (CI) 3.90-8.10) and PFS was 3.1 months (95% CI 1.38 4.82). No treatment-related death occurred. The most frequently drug-related grade 3/4 AEs were diarrhea (2.3%), leukopenia (16.3%) and nausea (7.0%). The incremental cost-effective ratio was $18,223.75/QALY for second-line chemotherapy versus BSC, which was below the threshold of 3* the per capita GDP of China, $23,970.00. CONCLUSION: Second-line chemotherapy was an optimal strategy for elderly AGC patients in China from the efficacy and cost-effectiveness perspective. PMID- 28353008 TI - Barriers to Hepatitis C Screening in a Minority Population: A Comparison of Hepatitis C and Human Immunodeficiency Virus Screening Rates at a Community STD Clinic in Miami, Florida. AB - METHODS: 357 patients at a free STD clinic in Miami, FL were screened for HCV. Surveys were administered assessing risk factors for infectious disease transmission, and HCV and HIV screening history. RESULTS: 15.1% of participants had been screened for HCV before whereas 83.8% had been screened for HIV (n = 356). Of the patients previously screened for HCV (n = 54), 98.2% of these patients had previously been screened for HIV as well. CONCLUSION: This data shows the low prevalence of prior HCV screenings in a high-risk population in Miami, FL. Participants who had previously received an HIV screening test were more likely to report receiving a prior HCV screening. Despite the high prevalence of HCV, most HCV infections are undiagnosed. Mortality from HIV has been declining in the United States while mortality from HCV is increasing. To decrease HCV related mortality, we recommend offering HCV screening in conjunction with HIV screening. PMID- 28353007 TI - Clarifying Values and Preferences for Care Near the End of Life: The Role of a New Lay Workforce. AB - Community health workers (CHWs) can engage elderly persons in advance care planning (ACP) conversations. We report how trained CHWs used Go Wish cards (GW R cards) to identify patients' highest priority preferences and evaluated whether engaging in ACP conversations was associated with subsequent health care utilization. A one-year long, pre-post longitudinal design was used to evaluate our educational intervention using mixed-methods. 392 patients (mean of 73.3 years, 82% women, 48% African American, 43% Caucasian) enrolled in the Aging Brain Care (ABC) program and participated in ACP discussions with CHWs. We expanded the role of the ABC's CHW, who work directly with individuals and caregivers during home visits to monitor bio-psycho-social needs, to include ACP conversations. The CHWs received ACP training, practice with tools such as GW R cards, and support from an electronic health record (EHR) clinical decision support tool. Quantitative measures of patients' ACP preferences and health care utilization were abstracted from the EHR. Qualitative data about patients' perceptions of CHWs in facilitating ACP discussions was obtained through semi structured interviews. Eighty-six patients' data indicated that they had engaged in a preferences-for-care process using GW R cards. The top-three card choices by patients was attending to spirituality and religious concerns, preparing for end of life, and maintaining personal wholeness. CHWs were able to effectively engage in ACP conversations with patients and GW R cards were a positive way to stimulate discussion of issues previously undiscussed. PMID- 28353010 TI - Children with Henoch-Schonlein purpura with low complement levels: follow-up for >6 years. PMID- 28353009 TI - Acute kidney injury in children with sickle cell disease-compounding a chronic problem. AB - In an article recently published in Pediatric Nephrology, Baddam and colleagues discuss the relatively underreported clinical problem of repeated episodes of acute kidney injury (AKI) in children with sickle cell disease (SCD). Their report is a cautionary note about the importance of repeated kidney injury on the background of underlying chronic kidney injury and its potential implications on long-term kidney outcome. In children and adults with SCD, this includes the effects of repeated vaso-occlusive crises and the management of these painful episodes with non-steroidal anti-inflammatory drugs. Here we review the scope of kidney involvement in SCD in children and discuss the potential short- and long term consequences of AKI in children with SCD. PMID- 28353011 TI - ? PMID- 28353012 TI - Re: Internal limiting membrane (ILM) transplantation for unclosed and large macular holes (MH). PMID- 28353013 TI - Quantification of changes in foveal capillary architecture caused by idiopathic epiretinal membrane using OCT angiography. AB - PURPOSE: To quantify the extent and depth of distortion of the foveal capillary architecture due to traction of an idiopathic epiretinal membrane (ERM) using optical coherence tomography angiography (OCT-A). METHODS: Multimodal imaging including OCT-A (Angiovue, Optovue) was performed in 42 eyes with idiopathic ERM (72.4 years +/-6.8). Best corrected visual acuity (BCVA), OCT-A vessel density of the foveal (VDfo) and parafoveal (VDp) region were assessed. Based on 6 * 6-mm2 OCT-A images, a macular vessel density ratio (MVR = VDfo/VDp) was calculated for the superficial (s), deep (d) and full-thickness (f) slabs to assess a depth resolved, non-invasive evaluation of foveal distortion. The acquired data were subdivided in a patient group with mild and significant BCVA reduction due to ERM. Data was compared to age-matched healthy controls. RESULTS: In all three slabs, MVR was significantly smaller in the control group in comparison with the ERM group: MVRs: 0.63 +/- 0.1 vs 0.83 +/- 0.1 (p > 0.001); MVRd: 0.60 +/- 0.1 vs 0.73 +/- 0.1 (p < 0.001); MVRf: 0.68 +/- 0.1 vs 0.82 +/- 0.1 (p < 0.001). Group 1 (BCVA <0.4 LogMar) showed a significantly higher MVR in comparison with the control group in the superficial plexus only: MVRs: 0.64 +/- 0.1 vs 0.78 +/- 0.1 (p < 0.001); MVRd: 0.60 +/- 0.1 vs 0.65 +/- 0.2 (p = 0.3); MVRf: 0.68 +/- 0.1 vs 0.77 +/- 0.1 (p = 0.01). However, group 2 (BCVA > = 0.4 LogMar) showed a significantly higher MVR in all three slabs: MVRs: 0.64 +/- 0.1 vs 0.86 +/- 0.1 (p < 0.001); MVRd: 0.60 +/- 0.1 vs 0.77 +/- 0.2 (p < 0.001); MVRf: 0.68 +/- 0.1 vs 0.85 +/- 0.1 (p < 0.001). CONCLUSION: Assessing MVR using OCT-A may serve as a tool to quantify the extent and depth of distortion of the foveal capillary architecture due to traction of ERM. BCVA reduction appears to be associated with extent and depth of distortion. PMID- 28353014 TI - Deep sequencing analysis of quasispecies in the HBV pre-S region and its association with hepatocellular carcinoma. AB - BACKGROUND: The association between the evolution of hepatitis B virus (HBV) quasispecies and the development of hepatocellular carcinoma (HCC) is unknown. METHODS: We used deep sequencing to examine the dynamics of HBV quasispecies and their relationship to HCC development. Thirty-two chronic hepatitis B (CHB) patients with HCC (HCC group) and 32 matched CHB patients without HCC (controls) were recruited. Fourteen patients from each group had serial sera available up to 9 years before the time of the present study. Deep sequencing of the HBV pre-S regions was performed. HBV quasispecies complexity, diversity, and intrapatient prevalence of pre-S deletions/mutations were analyzed. RESULTS: Compared with control patients, HCC patients had a significant greater quasispecies complexity (p = 0.04 at the nucleotide level), greater diversity (p = 0.004 and 0.009 at the nucleotide level and the amino acid level respectively), and a trend of greater complexity at the amino acid level (p = 0.065). HCC patients had a higher intrapatient prevalence of pre-S deletions and point mutations (at codons 4, 27, and 167) compared with the control patients (all p < 0.05). Longitudinal observation in the sera of 14 HCC patients showed that quasispecies complexity (p = 0.027 and 0.024 at the nucleotide level and the amino acid level respectively) and diversity (p = 0.035 and 0.031 at the nucleotide level and the amino acid level respectively) increased as the disease progressed to HCC. CONCLUSIONS: Increased HBV quasispecies complexity and diversity in the pre-S region, probably reflecting enhanced virus-host interplay, was associated with disease progression from CHB to HCC. PMID- 28353015 TI - Psychosocial Factors Impacting Workplace Injury Rehabilitation: Evaluation of a Concise Screening Tool. AB - Purpose To determine whether the delayed recovery often observed in simple musculoskeletal injuries occurring at work is related to poor workplace and home social support. Method A four question psychosocial screening tool called the "How are you coping gauge?" (HCG) was developed. This tool was implemented as part of the initial assessment for all new musculoskeletal workplace injuries. Participants were excluded if they did not meet the strict criteria used to classify a musculoskeletal injury as simple. The HCG score was then compared to the participant's number of days until return to full capacity (DTFC). It was hypothesised that those workers indicating a poorer level of workplace and home support would take longer time to return to full capacity. Results A sample of 254 participants (316 excluded) were included in analysis. Significant correlation (p < 0.001) was observed between HCG scores for self-reported work and home support and DTFC thereby confirming the hypothesis. Path analysis found workplace support to be a significant moderate-to-strong predictor of DTFC ( 0.46). Conclusion A correlation was observed between delayed workplace injury recovery and poor perceived workplace social support. The HCG may be an effective tool for identifying these factors in musculoskeletal workplace injuries of a minor pathophysiological nature. There may be merit in tailoring injury rehabilitation towards addressing psychosocial factors early in the injury recovery process to assist with a more expedient return to full work capacity following simple acute musculoskeletal injury. PMID- 28353018 TI - Effect of room temperature on tests for diagnosing vibration-induced white finger: finger rewarming times and finger systolic blood pressures. AB - PURPOSE: This study investigates the effects of room temperature on two standard tests used to assist the diagnosis of vibration-induced white finger (VWF): finger rewarming times and finger systolic blood pressures. METHODS: Twelve healthy males and twelve healthy females participated in four sessions to obtain either finger skin temperatures (FSTs) during cooling and rewarming of the hand or finger systolic blood pressures (FSBPs) after local cooling of the fingers to 15 and 10 degrees C. The measures were obtained with the room temperature at either 20 or 28 degrees C. RESULTS: There were lower baseline finger skin temperatures, longer finger rewarming times, and lower finger systolic blood pressures with the room temperature at 20 than 28 degrees C. However, percentage reductions in FSBP at 15 and 10 degrees C relative to 30 degrees C (i.e. %FSBP) did not differ between the two room temperatures. Females had lower baseline FSTs, longer rewarming times, and lower FSBPs than males, but %FSBPs were similar in males and females. CONCLUSIONS: Finger rewarming times after cold provocation are heavily influenced by room temperature and gender. For evaluating peripheral circulatory function using finger rewarming times, the room temperature must be strictly controlled, and a different diagnostic criterion is required for females. The calculation of percentage changes in finger systolic blood pressure at 15 and 10 degrees C relative to 30 degrees C reduces effects of both room temperature and gender, and the test may be used in conditions where the +/-1 degrees C tolerance on room temperature required by the current standard cannot be achieved. PMID- 28353016 TI - New Therapeutic Strategies in Acute Lymphocytic Leukemia. AB - Most drugs used in standard regimens for acute lymphoblastic leukemia (ALL) were developed more than 30 years ago. Since that time, several new drugs have been developed and incorporated into ALL treatment. In spite of this, novel therapeutic approaches are still needed to improve outcomes for high-risk or relapsed ALL. This manuscript discusses newer treatment strategies, including purine nucleoside analogs, monoclonal antibodies, antibody drug conjugates, mammalian target of rapamycin (mTOR) inhibitors, proteasome inhibitors, histone deacetylase (HDAC) inhibitors, hypomethylating agents, spleen tyrosine kinase inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, Janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibitors, anti-programmed cell death protein (anti-PD-1) antibodies, mitogen-activated protein kinase (MEK) inhibitors, CXCR4 antagonists, poly (ADP-ribose) polymerase (PARP) inhibitors, and FMS-like tyrosine kinase 3 (FLT3) inhibitors. Additionally, this manuscript discusses the impact of diagnostic approaches on management of ALL. Specifically, minimal residual disease is increasingly felt to be important and will likely dramatically impact the care of ALL patients in the near future. PMID- 28353017 TI - Treatment of Young Adults with Acute Lymphoblastic Leukemia. AB - Young adults with acute lymphoblastic leukemia are a distinctive category of patients, with substantial difference in disease biology and response to therapy; hence, they pose unique challenges and issues beyond those faced by children and older adults. Despite inferior survival compared to children, there is growing evidence to suggest that young adults have improved outcomes when treated with pediatric-based approaches. With better supportive care and toxicity management and multidisciplinary team and approach, we have made great improvement in outcomes of young adults with ALL. However, despite significant progress, patients with persistence of minimal residual disease have a poor prognosis. This review discusses current controversies in the management of young adults with ALL, outcomes following pediatric and adult protocols, and the role of allogeneic stem cell transplantation. We also explore recent advances in disease monitoring and highlight our approach to incorporation of novel therapies in the management of young adults with ALL. PMID- 28353019 TI - Brief alcohol intervention in alcohol involved facial fracture patients-a survey of patient attitudes to screening and intervention. AB - PURPOSE: Alcohol intoxication is an important contributor to traumatic facial injuries. The period following injuries afford clinicians a useful window of opportunity to provide alcohol screening and brief intervention (SBI) which may affect changes in patients' future drinking behaviour. Although SBI has been reported to decrease at risk drinking and potentially trauma recurrence, it is not routinely utilised in most clinical settings in the world. This study aims to assess utilisation of, as well as patients' knowledge and attitude towards SBI in the management of patients presenting with alcohol-related facial fractures. METHODS: Twenty consecutive patients who presented to Western Health with facial fractures who met selection criteria were offered an alcohol screening and survey questionnaire. RESULTS: Ninety percent of patients were male and 50% were aged between 19 and 34. ASSIST score showed 65% were in the moderate risk category; 75% reported this was their first admission with alcohol related trauma. Although 75% acknowledged alcohol as a main cause of injury, only 40% agreed they drink too much. Forty-four percent felt that talking to a healthcare worker might help and 33% would consider accepting help. Forty-seven percent felt reading materials would be helpful in changing future drinking habits. Whilst 63% would like to know safe drinking limit, only 45% would like to have a discussion about alcohol related harms. CONCLUSIONS: Most patients presented in this survey were in moderate risk category who are amenable to behavioural change with provision of SBI. However, there is resistance to implementation of this intervention due to lack of knowledge, self-awareness and willingness to change. Nonetheless, patients are prepared to accept advice from clinicians and some formats of intervention. It is important to formulate a simple screening questionnaire and intervention strategy that are easy to administer to affect positive changes in patients with harmful drinking behaviours. PMID- 28353020 TI - Association Between Waiting Time from Diagnosis to Treatment and Survival in Patients with Curable Gastric Cancer: A Population-Based Study in the Netherlands. AB - BACKGROUND: In the Netherlands, a maximum waiting time from diagnosis to treatment (WT) of 5 weeks is recommended for curative cancer treatment. This study aimed to evaluate the association between WT and overall survival (OS) in patients undergoing gastrectomy for cancer. METHODS: This nationwide study included data from patients diagnosed with curable gastric adenocarcinoma between 2005 and 2014 from the Netherlands Cancer Registry. Patients were divided into two groups: patients who received neoadjuvant therapy followed by gastrectomy, or patients who underwent gastrectomy as primary surgery. WT was analyzed as a categorical (<=5 weeks [Reference], 5-8 weeks, >8 weeks) and as a discrete variable. Multivariable Cox regression analysis was used to assess the influence of WT on OS. RESULTS: Among 3778 patients, 1701 received neoadjuvant chemotherapy followed by gastrectomy, and 2077 underwent primary gastrectomy. In the neoadjuvant group, median WT to neoadjuvant treatment was 4.6 weeks (interquartile range [IQR] 3.4-6.0), and median OS was 32 months. In the surgery group, median WT to surgery was 6.0 weeks (IQR 4.3-8.4), and median OS was 25 months. For both groups, WT did not influence OS (neoadjuvant: 5-8 weeks, hazard ratio [HR] 0.82, p = 0.068; >8 weeks, HR 0.85, p = 0.354; each additional week WT, HR 0.96, p = 0.078; surgery: 5-8 weeks, HR 0.91, p = 0.175; >8 weeks, HR 0.92, p = 0.314; each additional week WT, HR 0.99, p = 0.264). CONCLUSIONS: Longer WT until the start of curative treatment for gastric cancer is not associated with worse OS. These results could help to put WT into perspective as indicator of quality of care and reassure patients with gastric cancer. PMID- 28353021 TI - Effect of periodontitis history on implant success: a long-term evaluation during supportive periodontal therapy in a university setting. AB - OBJECTIVES: The aim of this retrospective study was to evaluate the long-term implant survival in patients with a history of chronic periodontitis, during supportive periodontal therapy (SPT), compared to periodontally healthy patients. MATERIALS AND METHODS: Twenty-nine periodontitis patients (test) with SPT for >=9 years and implant-supported restorations (>=5 years follow-up) were recruited and pair-matched with 29 periodontally healthy patients (control). Subjects in both groups were examined following active periodontal therapy and/or implantation (T1) (test 69 implants, control 76 implants) and at end of SPT or supportive postimplant therapy (T2). Differences between the groups in implant survival (primary outcome), mean marginal bone loss (MBL) and pocket probing depths (PPDs) (secondary outcomes) were evaluated. RESULTS: Implant survival over 5 years was 97.1% in test compared to 97.4% in control group (p = 0.562). MBL was significantly different (test 18.7 +/- 18.2%; control 12.5 +/- 21.3%) (p < 0.05). PPDs increased at T2 in both groups (test: T1 3.4 +/- 1.0 mm; T2 4.2 +/- 1.6 mm; control: T1 1.0 +/- 1.2 mm; T2 2.9 +/- 0.8 mm; p < 0.05 between groups). Prognostic factors for implant loss appeared to be the presence of residual periodontal pockets of >=4 mm (OR 1.90), bone height (OR 1.81) and age (OR 1.16) at T1. CONCLUSION: In terms of implant survival, no differences were observed between periodontitis and periodontally healthy patients. However, patients with history of periodontitis showed higher MBL and PPDs compared to periodontally healthy patients. CLINICAL RELEVANCE: The presence of a good periodontal maintenance program with preceding successful active periodontal treatment seems to be indispensable components of successful implant treatment in patients with history of chronic periodontitis. PMID- 28353022 TI - Topical application of morphine for wound healing and analgesia in patients with oral lichen planus: a randomized, double-blind, placebo-controlled study. AB - OBJECTIVE: The objective of this study was to investigate the effect of topical morphine on erosive/ulcerative lesions in patients with oral lichen planus (OLP). Previous studies reported on an enhanced remission of skin wounds when morphine was applied topically. MATERIALS AND METHODS: This was single-center, prospective, double-blind, placebo-controlled, randomized, multi-arm (3), phase II study (RCT). Patients diagnosed with erosive and/or ulcerative OLP applied 0.2 or 0.4 mg morphine dissolved in glycerine, three times a day for 5 days. The primary outcome was the extent of healing. Secondary outcomes were as follows: (1) effect on pain, (2) presence and severity of opioid-related central and local side effects, (3) whether patients required 'rescue medication' for treatment of pain, and (4) total intake of test substance. RESULTS: A total of 123 patients were screened for eligibility, 45 patients were recruited into the study, and 43 completed it. Patients applied a solution of either placebo or 0.2 or 0.4% morphine in groups of n = 12, n = 15, and n = 16, respectively. Extent of healing was similar in the three groups. Severity of pain was minor pre-treatment and throughout the course of the study. Only minor adverse events were reported (dry mouth, burning sensation). CONCLUSION: Morphine did not enhance wound healing compared to placebo-treated patients. Healing was observed in all groups, which may be attributed to an effect of glycerine or to the natural course of the disease. Patients experienced only mild levels of pain, rendering the model insensitive for assessing pain. CLINICAL RELEVANCE: OLP is a chronic disease and current treatment options are limited. Healing occurred in all three study groups, an effect we attribute to the carrier. PMID- 28353023 TI - Efficacy of GUM(r) Hydral versus Biotene(r) Oralbalance mouthwashes plus gels on symptoms of medication-induced xerostomia: a randomized, double-blind, crossover study. AB - OBJECTIVES: The objective of this study is to determine the efficacy of GUM(r) Hydral versus Biotene(r) Oralbalance (both a mouthwash plus gel) on the subjective burden and clinical symptoms of patients with medication-induced xerostomia. MATERIALS AND METHODS: Subjects (N = 40) with medication-induced xerostomia (minimum 4/10 mm visual analog scale [VAS]) were randomized to treatment with GUM Hydral or Biotene Oralbalance mouthwash, both with gel, for 28 days. Subjects then entered a 21-day wash-out period, before crossing over to the other treatment for 28 days. Outcomes measured included the VAS, German Oral Health Impact Profile (OHIPG)-14, Xerostomia Questionnaire (XQ), after-use questionnaire, and clinical parameters. RESULTS: Both GUM Hydral and Biotene Oralbalance significantly (p < 0.05) reduced VAS, OHIPG-14 total score and single items, and XQ Part 1 (oral dryness, oral pain, taste loss) and Part 2 items. GUM Hydral also significantly reduced the XQ Part 1 dysphagia score, while Biotene Oralbalance significantly reduced the halitosis organoleptic score and plaque index. Significant increases in saliva secretion did not reach clinical relevance. No significant between-group differences were observed, apart from OHIPG-14 items "trouble pronouncing words" and "uncertainty" in favor of GUM Hydral. No adverse effects were reported. CONCLUSIONS: Both products effectively improve oral health and xerostomia-related quality of life. However, they cannot completely substitute the continuous in-mouth secretion of saliva, and symptomatic relief is temporary. Product selection will be based on personal preference. CLINICAL RELEVANCE: Both products diminish xerostomic burden and should be part of the management strategy. Affected patients should be informed of these treatments, since no adverse effects were reported. PMID- 28353024 TI - Teaching an Old Dog New Tricks: Colchicine in Cardiovascular Medicine. AB - Colchicine is one of the oldest known drugs that remains part of the current pharmacopeia. Recent studies have examined the efficacy of colchicine in cardiology with promising results. We conducted a search of electronic databases for studies on colchicine in cardiovascular medicine published through October 2016. As the utilization of colchicine in the management of cardiac conditions grows, it is paramount that internists and cardiologists are familiarized with its benefits and risks. We present a comprehensive review of the role of colchicine in the management of cardiovascular diseases with a strong emphasis on side effects and potential drug interactions. PMID- 28353025 TI - Coxibs Refocus Attention on the Cardiovascular Risks of Non-Aspirin NSAIDs. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) were differentiated from steroidal anti-inflammatory medicines to help clinicians who needed to use anti inflammatory agents that were safer than steroids. With market entry of rofecoxib in 1999, NSAIDs were then further classified into traditional NSAIDs and cyclooxygenase (COX)-2 inhibitors (coxibs), the latter posing potentially fewer gastrointestinal risks. In 2005, rofecoxib was withdrawn from the market because of concerns about the risk of heart attack and stroke with long-term use, and clinical practice began focusing more on the cardiovascular versus gastrointestinal safety of coxibs. Since then, many coxibs have remained unapproved by the US FDA or have been removed from the market. This article explains how coxibs refocused attention on the cardiovascular safety of NSAIDs and the general implications of that. COX-2 activity/specificity is one factor associated with increased cardiovascular risks; however, these risks cannot be attributed to coxibs alone. The traditional NSAIDs (i.e., meloxicam, etodolac, and nabumetone) have significant COX-2 specificity, but naproxen and ibuprofen have less specificity. All NSAIDs, whether traditional or a coxib, pose some cardiovascular risks. It is possible that clinicians continue to focus more on decreasing the immediate gastric risks than preventing the later cardiovascular risks. The cardiovascular risks posed by NSAIDs should not be disregarded for the sake of achieving gastrointestinal benefits. Current recommendations suggest NSAIDs should be considered a single class of non-aspirin NSAIDs. Preferred NSAIDs are ibuprofen and naproxen. Coxibs are preferred in patients with low cardiovascular risk and high gastrointestinal risk who are intolerant to anti dyspepsia therapy. PMID- 28353026 TI - Effect of Milrinone Infusion on Pulmonary Vasculature and Stroke Work Indices: A Single-Center Retrospective Analysis in 69 Patients Awaiting Cardiac Transplantation. AB - BACKGROUND: Although milrinone infusion is reported to benefit left ventricular function in chronic left heart failure, few insights exist regarding its effects on pulmonary circulation and right ventricular function. METHODS: We retrospectively reviewed right heart catheterization data at baseline and during continuous infusion of milrinone in 69 patients with advanced heart failure and analyzed the effects on ventricular stroke work indices, pulmonary vascular resistance and pulmonary arterial compliance. RESULTS: Compared to baseline, milrinone infusion after a mean 58 +/- 61 days improved mean left ventricular stroke work index (1540 +/- 656 vs. 2079 +/- 919 mmHg.mL/m2, p = 0.0007) to a much greater extent than right ventricular stroke work index (616 +/- 346 vs. 654 +/- 332, p = 0.053); however, patients with below median stroke work indices experienced a significant improvement in both left and right ventricular stroke work performance. Overall, milrinone reduced left and right ventricular filling pressures and pulmonary and systemic vascular resistance by approximately 20%. Despite an increase in pulmonary artery capacitance (2.3 +/- 1.6 to 3.0 +/- 2.0, p = 0.013) and a reduction in pulmonary vascular resistance (3.8 +/- 2.3 to 3.0 +/- 1.7 Wood units), milrinone did not reduce the transpulmonary gradient (13 +/- 7 vs. 12 +/- 6 mmHg, p = 0.252), the pulmonary artery pulse pressure (25 +/- 10 vs. 24 +/- 10, p = 0.64) or the pulmonary artery diastolic to pulmonary capillary wedge gradient (2.0 +/- 6.5 vs. 2.4 +/- 6.0, p = 0.353). CONCLUSION: Milrinone improved left ventricular stroke work indices to a greater extent than right ventricular stroke work indices and had beneficial effects on right ventricular net input impedance, predominantly via augmentation of left ventricular stroke volume and passive unloading of the pulmonary circuit. Patients who had the worst biventricular performance benefited the most from chronic milrinone infusion. PMID- 28353027 TI - The association of childhood maltreatment with depression and anxiety is not moderated by the oxytocin receptor gene. AB - BACKGROUND: The oxytocin receptor (OXTR) gene may be involved in resilience or vulnerability towards stress, and hence in the development of stress-related disorders. There are indications that OXTR single nucleotide polymorphisms (SNPs) interact with early life stressors in predicting levels of depression and anxiety. To replicate and extend these findings, we examined whether three literature-based OXTR SNPs (rs2254298, rs53576, rs2268498) interact with childhood maltreatment in the development of clinically diagnosed depression and anxiety disorders. METHODS: We included 2567 individuals from the Netherlands Study of Depression and Anxiety. This sample consisted of 387 healthy controls, 428 people with a current or past depressive disorder, 243 people with a current or past anxiety disorder, and 1509 people with both lifetime depression and anxiety diagnoses. Childhood maltreatment was measured with both an interview and via self-report. Additional questionnaires measured depression and anxiety sensitivity. RESULTS: Childhood maltreatment was strongly associated with both lifetime depression and anxiety diagnoses, as well as with depression and anxiety sensitivity. However, the OXTR SNPs did not moderate these associations nor had main effects on outcomes. CONCLUSIONS: The three OXTR gene SNPs did not interact with childhood maltreatment in predicting lifetime depression and anxiety diagnoses or sensitivity. This stresses the importance of replication studies with regard to OXTR gene variants in general populations as well as in clearly established clinical samples. PMID- 28353030 TI - Creutzfeldt-Jacob disease: new directions in diagnosis and therapeutics. PMID- 28353028 TI - Decreased memory confidence in obsessive-compulsive disorder for scenarios high and low on responsibility: is low still too high? AB - Previous research suggests that patients with obsessive-compulsive disorder (OCD), particularly checkers, display an inflated sense of responsibility. For the present study, we tested whether memory confidence in OCD is reduced under conditions of heightened responsibility and/or reflects poor memory vividness. A computerized task designed to modulate perceived responsibility was administered to 26 OCD patients (12 checkers) and 21 healthy controls. In the experimental condition (high responsibility), participants had to allocate daily medications to ten fictive patients in a hospital emergency ward, whereas in the control condition (low responsibility) participants had to allocate bath essences for ten hotel guests. Participants' response time and accuracy were recorded as well as their memory confidence, memory vividness, and subjective success. Irrespective of the condition, OCD patients performed as accurately as healthy controls, but appraised their performance as worse than that of controls. Memory confidence was decreased in patients, particularly checkers. No group differences emerged on vividness, and none of the effects were moderated by the condition (high versus low responsibility). The relationship between responsibility and OCD behavior is complex. Results suggest metamemory problems in OCD checkers, even when induced responsibility is low. The findings speak against "cold" memory deficits in OCD, as patients did not differ from controls on accuracy, reaction time, or vividness. Future research should focus on idiosyncratic beliefs and scenarios that inflate responsibility and elicit cognitive biases. PMID- 28353029 TI - Sex Differences in Macrophage Functions in Middle-Aged Rats: Relevance of Estradiol Level and Macrophage Estrogen Receptor Expression. AB - The aim of this study was to examine the influence of sex on age-related changes in phenotype and functional capacity of rat macrophages. The potential role of estradiol as a contributing factor to a sex difference in macrophage function with age was also examined. Thioglycollate-elicited peritoneal macrophages derived from the young (2 months old) and the naturally senescent intact middle aged (16 months old) male and female rats were tested for cytokine secretion and antimicrobial activity (NO and H2O2 production and myeloperoxidase activity). Serum concentration of estradiol and the expression of estrogen receptor (ER)alpha and ERbeta on freshly isolated peritoneal macrophages were also examined. Decreased secretion of IL-1beta and IL-6 by macrophages from middle aged compared to the young females was accompanied with the lesser density of macrophage ERalpha expression and the lower systemic level of estradiol, whereas the opposite was true for middle-aged male rats. Macrophages in the middle-aged females, even with the diminished circulating estradiol levels, produce increased amount of IL-6, and comparable amounts of IL-1beta, TNF-alpha, and NO to that measured in macrophages from the middle-aged males. Age-related changes in macrophage phenotype and the antimicrobial activity were independent of macrophage ERalpha/ERbeta expression and estradiol level in both male and female rats. Although our study suggests that the sex difference in the level of circulating estradiol may to some extent contribute to sex difference in macrophage function of middle-aged rats, it also points to more complex hormonal regulation of peritoneal macrophage activity in females. PMID- 28353031 TI - Abortion for fetal defects: two current arguments. AB - A common utilitarian argument in favor of abortion for fetal defects rests on some controversial assumptions about what counts as a life worth living. Yet critics of abortion for fetal defects are also in need of an argument free from controversial assumptions about the future child's quality of life. Christopher Kaczor (in: Kaczor (ed), The ethics of abortion: women's rights, human life, and the question of justice, Routledge, New York, 2011) has devised an analogy that apparently satisfies this condition. On close scrutiny, however, Kaczor's analogy is too weak to debunk the common-morality intuition that at least some abortions for fetal defects are morally permissible. The upshot of this discussion is that, on the moral permissibility of abortions for fetal defects, a case-by-case approach is to be preferred. PMID- 28353032 TI - alpha-Synuclein Enhances Cadmium Uptake and Neurotoxicity via Oxidative Stress and Caspase Activated Cell Death Mechanisms in a Dopaminergic Cell Model of Parkinson's Disease. AB - This study examined the role of alpha-synuclein in regulating cadmium (Cd) induced neurotoxicity using the N27 dopaminergic neuronal model of Parkinson's disease (PD) that stably expresses wild-type human alpha-synuclein (alpha-Syn) or empty vector (Vec) control. We report that alpha-Syn significantly increased Cd induced cytotoxicity as compared to Vec control cells upon 24 h exposure. To explore the cellular mechanisms, we examined oxidative stress, caspase activation, and Cd uptake and intracellular accumulation. Expression of alpha-Syn coupled with Cd-induced cytotoxicity increased oxidative stress. Inductively coupled plasma-mass spectrometry (ICP-MS) revealed an increase in Cd uptake and intracellular accumulation in alpha-Syn-expressing cells upon Cd exposure. Analysis of the mitochondrial mediated apoptotic pathway showed greater activation of caspase-9 and caspase-3 in alpha-Syn cells. To functionally evaluate the role of metal transporters in the altered Cd phenotype, we examined Cd toxicity in the presence of nontoxic levels of divalent manganese Mn(II) and iron Fe(II). Co-treatment with Fe(II) or Mn(II) did not significantly attenuate Cd-induced cytotoxicity. We report that Cd exposure decreased the divalent metal transporter 1 and Akt protein levels in the alpha-Syn-expressing cells without altering native PKCdelta protein levels in both Vec control and alpha-Syn lines. In addition, we show decreased basal metallothionein-3 protein expression in alpha-Syn-expressing cells. Co-treatment with N-acetyl-L-cysteine was sufficient to attenuate and abolish the alpha-Syn * Cd-induced cytotoxicity. Collectively, these results demonstrate that alpha-Syn exhibits neurotoxic properties upon acute Cd exposure to cause cell death by causing oxidative stress, increasing Cd uptake, altering caspase-9 and caspase-3 activation, and diminishing the neuroprotective effect of Akt in a dopaminergic neuronal model of PD. PMID- 28353033 TI - A novel all-in-one intraoperative genotyping system for IDH1-mutant glioma. AB - IDH1 gene mutation has been demonstrated to be an oncogenic driver in a majority of lower-grade gliomas (LGGs). In contrast to other central nervous neoplasms and normal brain tissue without IDH1 mutation, almost 80% of LGGs exhibit IDH1 mutation. Therefore, expeditious detection of IDH1 mutation is useful, not only for intraoperative diagnosis of these gliomas but also for determination of the border between the tumor and normal brain tissue. In this study, we established a rapid genotyping assay with a simple DNA extraction method, involving only incubation of the tumor specimen with Tris-EDTA buffer, which can be easily performed in an operating room. In all 11 tested cases, we could identify the IDH1 status within 90-100 min intraoperatively. In a case of anaplastic astrocytoma, IDH-mutant, we could detect the tumor border by IDH1 profiling. In addition, with this assay, we could detect IDH1 mutation using cell-free tumor DNA derived from cerebrospinal fluid in a case of glioblastoma, IDH-mutant. Considering that clinical trials of mutated IDH1 inhibitors are ongoing, less invasive intraoperative IDH1 gene profiling might be useful for decision making of the overall treatment strategy of LGGs. Our assay might be a useful tool for precision medicine and surgery of IDH1-mutant gliomas. PMID- 28353034 TI - Coronary flow capacity: concept, promises, and challenges. AB - The vasodilator capacity of the coronary circulation is an important diagnostic and prognostic characteristic, and its accurate assessment is therefore an important frontier. The coronary flow capacity (CFC) concept was introduced to overcome the limitations associated with the use of coronary flow reserve (CFR) for this purpose, which are related to the sensitivity of CFR to physiological alterations in systemic and coronary hemodynamics. CFC was developed from positron emission tomography, and was subsequently extrapolated to invasive coronary physiology. These studies suggest that CFC is a robust framework for the identification of clinically relevant coronary flow abnormalities, and improves identification of patients at risk for adverse events over the use of CFR alone. This Review will discuss the concept of CFC, its promises in the setting of ischaemic heart disease, and its challenges both in theoretical and practical terms. PMID- 28353035 TI - The Roles of Opioid Receptors in Cutaneous Wound Healing. AB - The process of recovery from skin wounding can be protracted and painful, and scarring may lead to weakness of the tissue, unpleasant sensations such as pain or itch, and unfavorable cosmetic outcomes. Moreover, some wounds simply fail to heal and become a chronic burden for the sufferer. Understanding the mechanisms underlying wound healing and the concomitant sensory disorders and how they might be manipulated for therapeutic benefit has attracted much interest in recent years, and here we discuss the latest developments in the field, focusing on the emergent roles of the peripheral opioid receptor (OPr) system. PMID- 28353036 TI - Resistance to Hormonal Therapy in Prostate Cancer. AB - Several therapeutic strategies are actually available in the management of prostate cancer: Targeting the androgen receptor (AR) is the goal both for initial androgen deprivation therapy (ADT) and second-generation androgen ablative agents (abiraterone and enzalutamide). Chemotherapy with taxanes, administered upon progression or as first line approach in association with ADT, is another therapeutic option. Unfortunately, none of these therapies is curative and patients are destined to develop a resistant phenotype.Progression to ADT leads to the attainment of a castration resistant disease whose mechanisms remain incompletely understood. Reactivation of AR has been shown to occur and second generation of AR targeting drugs are usually prescribed. Upon progression to these agents AR signaling still remains the primary driver although it often becomes ligand independent, since it can be either restored through mutations on the ligand binding domain and/or formation of AR splicing variants or by passed through a cross talk with other oncogenic signaling pathways.AR-independent signaling pathways may represent additional mechanisms underlying castration resistant progression. It is clear that castration resistant prostate cancer is a group of diverse diseases and new treatment paradigms need to be developed. PMID- 28353037 TI - Critical review of current clinical practice guidelines for antifungal therapy in paediatric haematology and oncology. PMID- 28353038 TI - A scoring system to guide the decision for a new systemic treatment after at least two lines of palliative chemotherapy for metastatic cancers: a prospective study. AB - PURPOSE: A four-parameter score has been identified as associated with overall survival (OS) in patients with advanced cancer with an estimated survival inferior to 6 months. Here, we tested its prognostic value for OS in patients who had received more than two lines of systemic therapy. METHODS: We prospectively enrolled patients with advanced cancer who were going to receive a third or more therapeutic line outside classical clinical guidelines. The four parameters (Eastern Cooperative Oncology Group performance status, number of metastatic sites, serum LDH, and serum albumin) were collected at baseline, allowing to calculate the score, which sorted the patients in three groups, A, B, and C (low, intermediate, and high score, respectively). We then searched for correlations between this grouping and clinicopathological features particularly OS. RESULTS: From August 2013 to March 2014, 65 patients were enrolled and corresponded after determining their score to 26 patients in group A, 30 in B, and 9 in C. The median OS of the cohort was 4.4 months, and the 6-month OS was 42%. Overall survival was different between the three groups, with respective 6-month OS equal to 80% in group A, 17% in group B, and 0% in group C and respective median OS of 9, 2.3, and 1.6 months. Such prognostic value persisted in multivariate analysis. Similar OS differences were observed in patients with PS <=2. CONCLUSION: This simple scoring should help oncologists identify which patients, after at least two lines of systemic therapy, might benefit from best supportive care alone. PMID- 28353039 TI - A feasibility and efficacy trial of a hand-held humidification device in patients undergoing radiotherapy for head and neck cancer. AB - PURPOSE: This study aimed to evaluate the effects of warm-mist humidification during and after head and neck radiation therapy (HN RT) on quality of life (QOL), as measured by the M. D. Anderson Symptom Inventory-Head and Neck (MDASI HN) HN score. A secondary aim was to compare QOL among compliers (>=60% of protocol-recommended usage) versus non-compliers. METHODS: Twenty patients self administered a hand-held, self-sterilizing humidification device for a recommended time of at least 15 min twice daily for 12 weeks. Patients completed the MDASI-HN instrument at RT start, after 6 weeks, and after 12 weeks. Compliance was reported weekly. RESULTS: The average HN score at baseline was 1.7 (SD = 1.8) and increased to 6.0 (SD = 1.6) after 6 weeks; this increase was much higher than anticipated and the primary endpoint could not be reached. However, compliers had an average of nearly two less HN symptoms (-1.8, 95% CI -4 to 0.2; p = 0.08) than non-compliers at 6 weeks and fewer symptoms at 12 weeks as well ( 0.9, 95% CI -2.9 to 1.2; p = 0.39). The most common terms patients used to describe humidification were "helpful" and "soothing." CONCLUSIONS: Compliance with humidification during RT was associated with fewer reported HN symptoms and a strong trend to better QOL. Improvements were seen from compliance with occasional required use of a portable, inexpensive device. Our findings support continued efforts to reduce barriers to humidification, as an intervention that should be considered for standard HN RT clinical practice. PMID- 28353040 TI - Confounding factors associated with oral mucositis assessment in patients receiving chemoradiotherapy for head and neck cancer. AB - PURPOSE: The aim of this study was to identify patient-centered, mucositis associated adverse impact factors and events that might confound physician assessed oral mucositis (OM) in head and neck cancer (HNC) patients receiving chemoradiotherapy. METHODS: This was a post hoc analysis of a previously conducted randomized trial to determine the efficacy of 5% phenylbutyrate mouthwash in preventing chemoradiotherapy-induced OM. This analysis identified patient-centered symptomatic, observable, and measurable factors that may confound physician scoring of the severity of OM during chemoradiotherapy. Confounding factors were then combined with physician-rated OM scores according to World Health Organization (WHO) and OM Assessment Scale (OMAS) criteria to investigate the therapeutic implications of OM treatment. RESULTS: The original analysis found no significant differences between experimental and placebo groups with respect to the cumulative incidence of physician-recorded severe OM (WHO >=3 or OMAS >=2), patient-reported adverse events, and opioid use. However, patients in the experimental arm had relatively lower rates of OM-associated adverse clinical issues including unplanned short radiation breaks, skipping of chemotherapy, nausea/vomiting, late loss of body weight, and early opioid use, all of which could potentially interfere with physician-assessed OM scoring. When WHO OM grade (functional impact and pain), OMAS ulceration size (organic impact), and prolonged radiation treatment time (cancer treatment impact) were combined, there were significantly fewer interruptions of chemoradiotherapy treatment in symptomatic OM patients in the experimental compared to the placebo group. The benefits conferred by reducing the amount of chemoradiotherapy-related, OM associated adverse impacts in the experimental group were reflected by better 5 year locoregional recurrence-free survival. CONCLUSIONS: This exploratory study raises questions as to whether the severity reflected by physician-rated OM scores is in concordance with OM-induced adverse impacts on HNC patients. Further investigations are warranted to identify patient-related and cancer-associated symptom burdens that may affect tolerance, compliance, and outcome of chemoradiotherapy and confound the evaluation of therapeutic effects on chemoradiotherapy-induced OM. PMID- 28353041 TI - The Inhibitory Effect of Mesenchymal Stem Cells with rAd-NK4 on Liver Cancer. AB - Mesenchymal stem cells (MSCs) can migrate to the tumor site and integrate into the tumor tissue. As a delivery vehicle of antitumor factors, MSCs have been tried in various tumor therapies. NK4 can both inhibit the growth, metastasis, and invasion of tumor cells induced by hepatocyte growth factor (HGF) and suppress tumor angiogenesis that is independent on HGF/cellular-mesenchymal-to transition factor pathway. Adenovirus can directly deliver NK4 for tumor treatment but may induce immunological rejection. We combined MSCs with an adenovirus vector to deliver NK4 for liver tumor treatment. This study detected the migration of MSCs to high metastasis liver carcinoma cells MHCC-97H in vitro, investigated the inhibitory effect of rAd-NK4-MSCs on the growth and metastasis of MHCC-97H cells, further explored the inhibitory mechanism of rAd-NK4-MSCs to MHCC-97H cell metastasis, and examined the inhibitory effect of rAd-NK4-MSCs on the migration of human umbilical vein endothelial cells (HUVECs) in vitro. In this study, migration experiment was used for the potential capacity of MSCs and inhibition on migration of rAd-NK4-MSCs. Western blot was used for detecting the inhibition mechanism of rAd-NK4-MSCs to MHCC-97H cells. And, animal transplantation experiment was used for the inhibition of rAd-NK4-MSCs in vivo. MSC migration assay showed MSCs can significantly migrate to MHCC-97H cells. Co culture results indicated that rAd-NK4-MSCs significantly inhibited the proliferation and migration of MHCC-97H cells in vitro. Western blot results proved that rAd-NK4-MSCs inhibited MHCC-97H cell migration correlating with suppressing Erk1/2 phosphorylation. HUVEC migration experiment suggested that rAd NK4-MSCs had a potential of inhibiting tumor angiogenesis. Animal transplantation experiment showed that the tumor growth was significantly inhibited in the rAd NK4-MSC group. Taken together, this study proved that NK4-modified MSCs had an inhibitory effect on the growth and migration of MHCC-97H cells and tumor angiogenesis, which provided a new strategy for liver tumor target therapy. PMID- 28353042 TI - Beneficial Effects of Phyllanthus amarus Against High Fructose Diet Induced Insulin Resistance and Hepatic Oxidative Stress in Male Wistar Rats. AB - Insulin resistance (IR) is a characteristic feature of obesity, type 2 diabetes mellitus, and cardiovascular diseases. Emerging evidence suggests that the high fructose consumption is a potential and important factor responsible for the rising incidence of IR. The present study investigates the beneficial effects of aqueous extract of Phyllanthus amarus (PAAE) on IR and oxidative stress in high fructose (HF) fed male Wistar rats. HF diet (66% of fructose) and PAAE (200 mg/kg body weight/day) were given concurrently to the rats for a period of 60 days. Fructose-fed rats showed weight gain, hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired insulin sensitivity, dyslipidemia, hyperleptinemia, and hypoadiponectinemia (P < 0.05) after 60 days. Co-administration of PAAE along with HF diet significantly ameliorated all these alterations. Regarding hepatic antioxidant status, higher lipid peroxidation and protein oxidation, lower reduced glutathione levels and lower activities of enzymatic antioxidants, and the histopathological changes like mild to severe distortion of the normal architecture as well as the prominence and widening of the liver sinusoids observed in the HF diet-fed rats were significantly prevented by PAAE treatment. These findings indicate that PAAE is beneficial in improving insulin sensitivity and attenuating metabolic syndrome and hepatic oxidative stress in fructose-fed rats. PMID- 28353043 TI - Immobilization of Candida antarctic Lipase B on Functionalized Ionic Liquid Modified MWNTs. AB - Multiwalled carbon nanotubes (MWNTs) were modified by imidazole-based ionic liquids with different alkyl groups. The modified support samples were characterized by scanning transmission electron microscopy, Raman spectra, thermogravimetric analyses, and X-ray photoelectron spectroscopy. The samples were used to immobilize Candida antarctic lipase (CALB) and the influence of alkyl chain length of ionic liquids on enzymatic properties was investigated by the hydrolysis reaction of triacetin. The results revealed that functionalized ionic liquids modification did not destroy the structure of MWNTs. Compared with the immobilized CALB on MWNTs, the immobilized CALB on novel carriers all exhibited higher activity, thermal stability, and reusability. Especially, the activity of MWNTs-IL (8C)-CALB improved 15.23-folds than MWNTs-CALB, meanwhile, after incubation at 70 degrees C for 20 min, residual enzyme activity of MWNTs IL (8C)-CALB was 46% of the initial activity, while MWNTs-CALB already lost all activity. Besides, MWNTs-IL (8C)-CALB retained 64.5% of its initial activity after 4 cycles, while MWNTs-CALB retained only 2.12%. Graphical Abstract ?. PMID- 28353044 TI - Preparation of Biodiesel with Liquid Synergetic Lipases from Rapeseed Oil Deodorizer Distillate. AB - To reduce industrial production cost, cheap and easily available rapeseed oil deodorizer distillates were used as feedstock to prepare biodiesel in this study. As a result, liquid forms of Candida rugosa lipase and Rhizopus oryzae lipase (ROL) were functioned as new and effective catalysts with biodiesel yield of 92.63% for 30 h and 94.36% for 9 h, respectively. Furthermore, the synergetic effect between the two lipases was employed to enhance biodiesel yield with a result of 98.16% in 6 h under optimized conditions via response surface methodology. The obtained conversion rate surpassed both yields of the individual two lipases and markedly shortened the reaction time. The resultant optimal conditions were ROL ratio 0.84, water content 46 wt% (w/w), reaction temperature 34 degrees C, and reaction time 6 h. PMID- 28353045 TI - Artificial Intelligence and the 'Good Society': the US, EU, and UK approach. AB - In October 2016, the White House, the European Parliament, and the UK House of Commons each issued a report outlining their visions on how to prepare society for the widespread use of artificial intelligence (AI). In this article, we provide a comparative assessment of these three reports in order to facilitate the design of policies favourable to the development of a 'good AI society'. To do so, we examine how each report addresses the following three topics: (a) the development of a 'good AI society'; (b) the role and responsibility of the government, the private sector, and the research community (including academia) in pursuing such a development; and (c) where the recommendations to support such a development may be in need of improvement. Our analysis concludes that the reports address adequately various ethical, social, and economic topics, but come short of providing an overarching political vision and long-term strategy for the development of a 'good AI society'. In order to contribute to fill this gap, in the conclusion we suggest a two-pronged approach. PMID- 28353046 TI - CORR Insights(r): What Influence Does Progression of a Nonhealing Rotator Cuff Tear Have on Shoulder Pain and Function? PMID- 28353047 TI - Editorial: Federal Restrictions on Gun Research Should Be Lifted. PMID- 28353048 TI - What Factors Influence the Biomechanical Properties of Allograft Tissue for ACL Reconstruction? A Systematic Review. AB - BACKGROUND: Allograft tissue is used in 22% to 42% of anterior cruciate ligament (ACL) reconstructions. Clinical outcomes have been inconsistent with allograft tissue, with some series reporting no differences in outcomes and others reporting increased risk of failure. There are numerous variations in processing and preparation that may influence the eventual performance of allograft tissue in ACL reconstruction. We sought to perform a systematic review to summarize the factors that affect the biomechanical properties of allograft tissue for use in ACL reconstruction. Many factors might impact the biomechanical properties of allograft tissue, and these should be understood when considering using allograft tissue or when reporting outcomes from allograft reconstruction. QUESTIONS/PURPOSES: What factors affect the biomechanical properties of allograft tissue used for ACL reconstruction? METHODS: We performed a systematic review to identify studies on factors that influence the biomechanical properties of allograft tissue through PubMed and SCOPUS databases. We included cadaveric and animal studies that reported on results of biomechanical testing, whereas studies on fixation, histologic evaluation, and clinical outcomes were excluded. There were 319 unique publications identified through the search with 48 identified as relevant to answering the study question. For each study, we recorded the type of tissue tested, parameters investigated, and the effects on biomechanical behavior, including load to failure and stiffness. Primary factors identified to influence allograft tissue properties were graft tissue type, sterilization methods (irradiation and chemical processing), graft preparation, donor parameters, and biologic adjuncts. RESULTS: Load to failure and graft stiffness varied across different tissue types, with nonlooped tibialis grafts exhibiting the lowest values. Studies on low-dose irradiation showed variable effects, whereas high-dose irradiation consistently produced decreased load to failure and stiffness values. Various chemical sterilization measures were also associated with negative effects on biomechanical properties. Prolonged freezing decreased load to failure, ultimate stress, and ultimate strain. Up to eight freeze-thaw cycles did not lead to differences in biomechanical properties of cadaveric grafts. Regional differences were noted in patellar tendon grafts, with the central third showing the highest load to failure and stiffness. Graft diameter strongly contributed to load-to-failure measurements. Age older than 40 years, and especially older than 65 years, negatively impacted biomechanical properties, whereas gender had minimal effect on the properties of allograft tissue. Biologic adjuncts show potential for improving in vivo properties of allograft tissue. CONCLUSIONS: Future clinical studies on allograft ACL reconstruction should investigate in vivo graft performance with standardized allograft processing and preparation methods that limit the negative effects on the biomechanical properties of tissue. Additionally, biologic adjuncts may improve the biomechanical properties of allograft tissue, although future preclinical and clinical studies are necessary to clarify the role of these treatments. CLINICAL RELEVANCE: Based on the findings of this systematic review that emphasize biomechanical properties of ACL allografts, surgeons should favor the use of central third patellar tendon or looped soft tissue grafts, maximize graft cross sectional area, and favor grafts from donors younger than 40 years of age while avoiding grafts subjected to radiation doses > 20 kGy, chemical processing, or greater than eight freeze-thaw cycles. PMID- 28353050 TI - Do Surgeon Expectations Predict Clinically Important Improvements in WOMAC Scores After THA and TKA? AB - BACKGROUND: Failure of THA or TKA to meet a patient's expectations may result in patient disappointment and litigation. However, there is little evidence to suggest that surgeons can consistently anticipate which patients will benefit from those interventions. QUESTIONS/PURPOSES: To determine the ability of surgeons to identify, in advance of surgery, patients who will benefit from THA or TKA and those who will not, where 'benefit' is defined as a clinically important improvement in a validated patient-reported outcomes score. METHODS: In this prospective study, eight high-volume orthopaedic surgeons completed validated THA and TKA expectations questionnaires (score 0-100, 100 being the highest expectation) as part of preoperative assessment of all their patients scheduled for a THA or TKA and enrolled in the Hospital for Special Surgery institutional registry. Enrolled patients completed the WOMAC preoperatively and at 2 years. Successful outcomes were defined as achieving the minimum clinically important difference (MCID) in WOMAC pain and function subscales. Sensitivity, specificity, and receiver operating characteristic (ROC) curves were used to evaluate the ability of surgeons' expectation scores to identify patients likely to achieve the MCID on the WOMAC scale. Analyses were run separately for patients having THA and TKA. We enrolled 259 patients undergoing THA and 247 undergoing TKA, of whom 77% (n = 200) and 77% (n = 191) completed followup surveys 2 years after their procedures, respectively. RESULTS: Surgeons' expectation scores effectively anticipated patients who would improve after THA, but they were no better than chance in identifying patients who would achieve the MCID on the WOMAC score 2 years after TKA. For patients having THA, the areas under the ROC curve were 0.67 (95% CI, 0.53-0.82; p = 0.02) and 0.74 (95% CI, 0.63-0.85; p < 0.01) for WOMAC function and pain outcomes, respectively, indicating good accuracy. Sensitivity and specificity were maximized on WOMAC pain and function scores (sensitivity = 0.69, specificity = 0.72, both for pain and function) at an expectations score of 83 or greater of 100. Surgeons' expectations were more accurate for patients who were men, who had a BMI less than 30 kg/m2, who had more than one comorbidity, and who were older than 65 years. For patients having TKA, surgeons' expectation scores were not better than chance for identifying those who would experience a clinically important improvement on the WOMAC scale (area under ROC curve: Function = 0.51, [95% CI, 0.42-0.61], p = 0.78; Pain = 0.51, [95% CI, 0.40-0.61], p = 0.92). CONCLUSIONS: Most patients having THA and TKA achieved the MCID improvement after surgery. However, the inability of surgeons' expectation scores to discriminate accurately between patients who benefit and those who do not among patients scheduled for THA who are young, with no comorbidities, and with elevated BMIs, and among all patients scheduled for TKA, calls for surgeons to spend more time with these patients to fully understand and address their needs and expectations. Using standardized assessment tools to compare surgeons' expectations and those of their patients may help focus the surgeon-patient discussion further, and address patients' expectations more effectively. LEVEL OF EVIDENCE: Level II, therapeutic study. PMID- 28353049 TI - Single-stage Acetabular Revision During Two-stage THA Revision for Infection is Effective in Selected Patients. AB - BACKGROUND: The treatment of periprosthetic infections of hip arthroplasties typically involves use of either a single- or two-stage (with implantation of a temporary spacer) revision surgery. In patients with severe acetabular bone deficiencies, either already present or after component removal, spacers cannot be safely implanted. In such hips where it is impossible to use spacers and yet a two-stage revision of the prosthetic stem is recommended, we have combined a two stage revision of the stem with a single revision of the cup. To our knowledge, this approach has not been reported before. QUESTIONS/PURPOSES: (1) What proportion of patients treated with single-stage acetabular reconstruction as part of a two-stage revision for an infected THA remain free from infection at 2 or more years? (2) What are the Harris hip scores after the first stage and at 2 years or more after the definitive reimplantation? METHODS: Between June 2009 and June 2014, we treated all patients undergoing surgical treatment for an infected THA using a single-stage acetabular revision as part of a two-stage THA exchange if the acetabular defect classification was Paprosky Types 2B, 2C, 3A, 3B, or pelvic discontinuity and a two-stage procedure was preferred for the femur. The procedure included removal of all components, joint debridement, definitive acetabular reconstruction (with a cage to bridge the defect, and a cemented socket), and a temporary cemented femoral component at the first stage; the second stage consisted of repeat joint and femoral debridement and exchange of the femoral component to a cementless device. During the period noted, 35 patients met those definitions and were treated with this approach. No patients were lost to followup before 2 years; mean followup was 42 months (range, 24-84 months). The clinical evaluation was performed with the Harris hip scores and resolution of infection was assessed by the absence of clinical signs of infection and a C-reactive protein level less than 10 mg/L. All patients were assessed before surgery, between stages, every 3 months during the first year after surgery, every 6 months during the second year postoperative, and at latest followup, and were retrospectively drawn from a longitudinally maintained institutional database. RESULTS: Thirty-four of 35 patients (97.2%; 95% CI, 85.4% 99.5%) appeared free of infection by criteria of Masri et al. and Zimmerli et al. at latest followup. The Harris hip score was 61 +/- 13 points after the first operation and 82 +/- 16 points 2 years after the second operation. CONCLUSIONS: This technique is a promising treatment option for periprosthetic infections of the hip in which substantial acetabular defects exclude implantation of a normal spacer and a two-stage revision of the femoral component is favored. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 28353051 TI - Is there evidence that the outcomes of primary anatomic and reverse shoulder arthroplasty are getting better? AB - PURPOSE: Have the results of shoulder arthroplasty got better over the last two decades? To answer this question, we sought published evidence that the patient reported outcomes and re-operation rates have improved in reports of more recently performed anatomic (TSA) and reverse (RSA) total shoulder arthroplasties. METHODS: We analyzed the arthroplasty results among studies published from 1990 to 2015, adjusting for the fact that the different publications presented patient groups with different combinations of diagnoses, used various outcome scales, and had different lengths of follow-up. RESULTS: The adjusted clinical outcomes (p = 0.048), but not the revision rates (p = 0.3), were significantly better for articles reporting more recent TSA procedures. Neither the clinical outcomes (p = 0.9) nor the revision rates (p = 0.4) were significantly better in articles reporting more recent RSA surgeries. CONCLUSIONS: Better evidence from reports with greater detail will be necessary to show that patients are realizing progressively better outcomes from shoulder arthroplasty. LEVEL OF EVIDENCE: Level IV. PMID- 28353052 TI - The effect of screw tunnels on the biomechanical stability of vertebral body after pedicle screws removal: a finite element analysis. AB - PURPOSE: Posterior reduction and pedicle screw fixation is a widely used procedure for thoracic and lumbar vertebrae fractures. Usually, the pedicle screws would be removed after the fracture healing and screw tunnels would be left. The aim of this study is to evaluate the effect of screw tunnels on the biomechanical stability of the lumbar vertebral body after pedicle screws removal by finite element analysis (FEA). METHODS: First, the CT values of the screw tunnels wall in the fractured vertebral bodies were measured in patients whose pedicle screws were removed, and they were then compared with the values of vertebral cortical bone. Second, an adult patient was included and the CT images of the lumbar spine were harvested. Three dimensional finite element models of the L1 vertebra with unilateral or bilateral screw tunnels were created based on the CT images. Different compressive loads were vertically acted on the models. The maximum loads which the models sustained and the distribution of the force in the different parts of the models were recorded and compared with each other. RESULTS: The CT values of the tunnels wall and vertebral cortical bone were 387.126+/-62.342 and 399.204+/-53.612, which were not statistically different (P=0.149). The models of three dimensional tetrahedral mesh finite element of normal lumbar 1 vertebra were established with good geometric similarity and realistic appearance. After given the compressive loads, the cortical bone was the first one to reach its ultimate stress. The maximum loads which the bilateral screw tunnels model, unilateral screw tunnel model, and normal vertebral model can sustain were 3.97 Mpa, 3.83 Mpa, and 3.78 Mpa, respectively. For the diameter of the screw tunnels, the model with a diameter of 6.5 mm could sustain the largest load. In addition, the stress distributing on the outside of the cortical bone gradually decreased as the thickness of the tunnel wall increased. CONCLUSIONS: Based on the FEA, pedicle screw tunnels would not decrease the biomechanical stability and strength of the vertebral body. A large diameter of screw tunnel and thick tunnel wall were helpful for the biomechanical stability of the vertebral body. PMID- 28353053 TI - Influence of physico-chemical properties of soil clay fractions on the retention of dissolved organic carbon. AB - This study investigated the effects of surface functional groups, cation exchange capacity (CEC), surface charge, sesquioxides and specific surface area (SSA) of three soil clay fractions (SCFs) (kaolinite-illite, smectite and allophane) on the retention of dissolved organic carbon (DOC) in soils. Physico-chemical properties of the SCFs before and after removing native carbon and/or sesquioxides were characterised, and the DOC adsorption-desorption tests were conducted by a batch method. Native organic carbon (OC)/sesquioxide removal treatments led to a small change in the CEC values of kaolinite-illite, but significant changes in those of smectite and allophane. The net negative surface charge increased in all samples with an increase in pH indicating their variable charge characteristics. The removal of native OC resulted in a slight increase in the net positive charge on soil clay surfaces, while sesquioxide removal increased the negative charge. Changes in the functional groups on the SCF surfaces contributed to the changes in CEC and zeta potential values. There was a strong relationship (R 2 = 0.93, p < 0.05) between the Langmuir maximum DOC adsorption capacity (Q max) and SSA. The Q max value also showed a moderately strong relationship (R 2 = 0.55, p < 0.05) with zeta potential (at pH 7). Q max was only poorly correlated with CEC and native OC content. Therefore, along with SSA, the surface charge and functional groups of SCFs played the key role in determining the adsorption affinity and hence retention of DOC in soils. PMID- 28353054 TI - Application of artificial neural network in medical geochemistry. AB - For the evaluation of various adverse health effects of chemical elements occurring in the environment on humans, the comparison and linking of geochemical data (chemical composition of groundwater, soils, and dusts) with data on health status of population (so-called health indicators) play a key role. Geochemical and health data are predominantly nonlinear, and the use of standard statistical methods can lead to wrong conclusions. For linking such data, we find appropriate the use method of artificial neural networks (ANNs) which enable to eliminate data inhomogeneity and also potential data errors. Through method of ANNs, we are able to determine the order of influence of chemical elements on health indicators as well as to define limit values for the influential elements at which the health status of population is the most favourable (i.e. the lowest mortality, the highest life expectancy). For determination of dependence between the groundwater contents of chemical elements and health indicators, we recommend to create 200 ANNs. In further calculations performed for identification of order of influence of chemical elements as well as definition of limit values, we propose to work with median or mean values from calculated 200 ANNs. The ANN represents an appropriate method to be used for environmental and health data analysis in medical geochemistry. PMID- 28353055 TI - Accounting for Pharmacokinetic Variability of Certolizumab Pegol in Patients with Crohn's Disease. AB - BACKGROUND: Certolizumab pegol is an effective biologic for patients with Crohn's disease (CD). Individual differences in certolizumab pegol apparent clearance (CL/F) affect exposure and possibly efficacy. A previously developed population pharmacokinetic (PK) model did not account for dynamic changes in clinical parameters during therapy. OBJECTIVE: The aim of this study was to refine the existing PK model to capture the time-varying influence of covariates. METHODS: Data collected from 2157 Crohn's disease patients in nine studies were analyzed using nonlinear mixed-effects modeling software (NONMEM). Certolizumab pegol concentration-time data were described by a one-compartment PK model with first order absorption, and one-compartment disposition with linear, time-dependent elimination using antidrug antibody (ADAb) concentration as a continuous variable. RESULTS: The final dataset consisted of 12,926 analyzable records. Parameter estimates were absorption rate constant 1.83/day, CL/F 0.527 L/day, and apparent volume of distribution (V/F) 8.33 L. ADAb concentration (2.5-214 units/mL) increased the median CL/F by 142-174%. For a typical patient, body weight (46.8-100.5 kg) increased the median CL/F and V/F from 82 to 120%. Albumin (32-48 g/L) decreased and C-reactive protein (0.5-54.0 mg/L) increased the median CL/F from 123 to 85% and from 83 to 113%, respectively. Between-patient variability of CL/F was 19.6%. CONCLUSIONS: By incorporating time-varying covariates, this population PK model reduces between-patient variability on CL/F estimates, and the relative influence of ADAb can now be assessed. As Crohn's disease patient covariates are often time-dependent, this model is more reflective of patient drug exposure with sustained treatment. PMID- 28353056 TI - Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults. AB - INTRODUCTION: Psilocybin is a psychedelic tryptamine that has shown promise in recent clinical trials for the treatment of depression and substance use disorders. This open-label study of the pharmacokinetics of psilocybin was performed to describe the pharmacokinetics and safety profile of psilocybin in sequential, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults. METHODS: Eligible healthy adults received 6-8 h of preparatory counseling in anticipation of the first dose of psilocybin. The escalating oral psilocybin doses were administered at approximately monthly intervals in a controlled setting and subjects were monitored for 24 h. Blood and urine samples were collected over 24 h and assayed by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for psilocybin and psilocin, the active metabolite. The pharmacokinetics of psilocin were determined using both compartmental (NONMEM) and noncompartmental (WinNonlin) methods. RESULTS: No psilocybin was found in plasma or urine, and renal clearance of intact psilocin accounted for less than 2% of the total clearance. The pharmacokinetics of psilocin were linear within the twofold range of doses, and the elimination half-life of psilocin was 3 h (standard deviation 1.1). An extended elimination phase in some subjects suggests hydrolysis of the psilocin glucuronide metabolite. Variation in psilocin clearance was not predicted by body weight, and no serious adverse events occurred in the subjects studied. CONCLUSIONS: The small amount of psilocin renally excreted suggests that no dose reduction is needed for subjects with mild moderate renal impairment. Simulation of fixed doses using the pharmacokinetic parameters suggest that an oral dose of 25 mg should approximate the drug exposure of a 0.3 mg/kg oral dose of psilocybin. Although doses of 0.6 mg/kg are in excess of likely therapeutic doses, no serious physical or psychological events occurred during or within 30 days of any dose. CLINICAL TRIALS IDENTIFIER: NCT02163707. PMID- 28353058 TI - Objectively-Measured Free-Living Physical Activity and Heart Rate Recovery. AB - The purpose of this study was to examine the association of free-living, objectively-measured physical activity on treadmill-based heart rate recovery (HRR), a parameter known to associate with morbidity and mortality. Data was used from 2003 to 2004 NHANES. Physical activity was assessed via accelerometry, with HRR recovery assessed from a treadmill-based test. Heart rate recovery minute 1 (HRR1) and minute 2 (HRR2) were calculated. After adjustment, light and vigorous intensity free-living physical activity, respectively, were associated with HRR1 (betaadjusted = 0.69, 95% CI 0.22-1.14; betaadjusted 1.94, 95% CI 0.01-3.9) and HRR2 (betaadjusted = 0.99, 95% CI 0.35-1.62; betaadjusted = 5.88, 95% CI 2.63 9.12). Moderate physical activity was not associated with HRR1 (betaadjusted = 0.60, 95% CI -0.41 to 1.62), but was with HRR2 (betaadjusted = 2.28, 95% CI 1.27 3.28). As free-living physical activity intensity increased, there was a greater association with HRR. This finding may provide mechanistic insight of previous research observations demonstrating intensity-specific effects of physical activity on various health outcomes. PMID- 28353057 TI - Levetiracetam Clinical Pharmacokinetic Monitoring in Pediatric Patients with Epilepsy. AB - Levetiracetam is a broad-spectrum antiepileptic drug (AED) with a unique mechanism of action. Older AEDs can cause serious short- and long-term adverse drug reactions and complications, rendering them undesirable to use in pediatric patients. Characteristics that make levetiracetam a near-ideal AED include its broad spectrum of activity, good tolerability profile, and minimal drug-drug interactions. Clinical pharmacokinetic monitoring (CPM) is often recommended in pediatric patients for certain AEDs due to large interindividual pharmacokinetic differences and unpredictable drug disposition. Our objective was to determine whether monitoring levetiracetam concentrations is warranted for pediatric patients with epilepsy, using a previously published 9-step decision-making algorithm. A literature search of the MEDLINE (1946-August 2016), EMBASE (1974 August 2016), CENTRAL, and Google Scholar databases was performed to identify relevant English-language articles and answer the questions posed in the algorithm for levetiracetam CPM in pediatric epilepsies. Additional articles were identified from a manual bibliographic review of the relevant literature. We found that levetiracetam CPM met some criteria of the algorithm: levetiracetam is an appropriate adjunctive or monotherapy for pediatric patients with either focal or generalized seizures; it is readily measurable in plasma, with an appropriate degree of sensitivity, accuracy, and precision; it exhibits interindividual variation in pharmacokinetics; often, its pharmacologic effect cannot be easily measured; and the duration of therapy is expected to be long-term. However, important criteria not met include the following: there is no clear evidence for a concentration-response relationship for efficacy or toxicity; the proposed therapeutic range of 12-46 MUg/mL is not well-defined and is generally considered as wide. Thus, clinical decision making is unlikely to be affected as a result of routine levetiracetam CPM. In general, routine CPM of levetiracetam cannot be recommended for pediatric patients with epilepsy. However, CPM may be beneficial in select cases, such as patients in whom noncompliance is suspected, those who have severe overdoses, those switching between product brands, or patients for whom an 'individual therapeutic concentration' is documented. Nonetheless, in the majority of pediatric patients with epilepsy, measurement of levetiracetam concentrations is not expected to yield a therapeutic benefit. Thus, clinical assessment and judgment, without measuring drug concentrations, remain the monitoring strategy of choice for levetiracetam therapy. PMID- 28353059 TI - Getting satisfied with "satisfaction of search": How to measure errors during multiple-target visual search. AB - Visual search studies are common in cognitive psychology, and the results generally focus upon accuracy, response times, or both. Most research has focused upon search scenarios where no more than 1 target will be present for any single trial. However, if multiple targets can be present on a single trial, it introduces an additional source of error because the found target can interfere with subsequent search performance. These errors have been studied thoroughly in radiology for decades, although their emphasis in cognitive psychology studies has been more recent. One particular issue with multiple-target search is that these subsequent search errors (i.e., specific errors which occur following a found target) are measured differently by different studies. There is currently no guidance as to which measurement method is best or what impact different measurement methods could have upon various results and conclusions. The current investigation provides two efforts to address these issues. First, the existing literature is reviewed to clarify the appropriate scenarios where subsequent search errors could be observed. Second, several different measurement methods are used with several existing datasets to contrast and compare how each method would have affected the results and conclusions of those studies. The evidence is then used to provide appropriate guidelines for measuring multiple-target search errors in future studies. PMID- 28353060 TI - Response. PMID- 28353061 TI - Dose intensity and efficacy of the combination of everolimus and exemestane (EVE/EXE) in a real-world population of hormone receptor-positive (ER+/PgR+), HER2-negative advanced breast cancer (ABC) patients: a multicenter Italian experience. AB - AIM: This retrospective analysis focused on the effect of treatment with EVE/EXE in a real-world population outside of clinical trials. We examined the efficacy of this combination in terms of PFS and RR related to dose intensity (5 mg daily versus 10 mg daily) and tolerability. METHODS: 163 HER2-negative ER+/PgR+ ABC patients, treated with EVE/EXE from May 2011 to March 2016, were included in the analysis. The primary endpoints were the correlation between the daily dose and RR and PFS, as well as an evaluation of the tolerability of the combination. Secondary endpoints were RR, PFS, and OS according to the line of treatment. Patients were classified into three different groups, each with a different dose intensity of everolimus (A, B, C). RESULTS: RR was 29.8% (A), 27.8% (B) (p = 0.953), and not evaluable (C). PFS was 9 months (95% CI 7-11) (A), 10 months (95% CI 9-11) (B), and 5 months (95% CI 2-8) (C), p = 0.956. OS was 38 months (95% CI 24-38) (A), median not reached (B), and 13 months (95% CI 10-25) (C), p = 0.002. Adverse events were stomatitis 57.7% (11.0% grade 3-4), asthenia 46.0% (6.1% grade 3-4), hypercholesterolemia 46.0% (0.6% grade 3-4), and hyperglycemia 35.6% (5.5% grade 3-4). The main reason for discontinuation/interruption was grade 2-3 stomatitis. CONCLUSIONS: No correlation was found between dose intensity (5 vs. 10 mg labeled dose) and efficacy in terms of RR and PFS. The tolerability of the higher dose was poor in our experience, although this had no impact on efficacy. PMID- 28353062 TI - Self-reported long-term cardiac morbidity in breast cancer patients: a retrospective cohort study in Germany (PASSOS Heart Study). AB - PURPOSE: Improved survival after locoregional breast cancer has increased the concern about late adverse effects after therapy. In particular, radiotherapy was identified as a risk factor for major cardiac events in women treated until the 1990s. While modern radiotherapy with computerized planning based on 3D-imaging can help spare organs at risk, heart exposure may remain substantial. In a retrospective cohort study of women treated for locoregional breast cancer, we investigated whether current radiotherapy is associated with an elevated long term cardiac morbidity risk. METHODS: The study included 11,982 women diagnosed with breast cancer in Germany in 1998-2008. After an individual mortality follow up, 9338 questionnaires on cardiac events before or after therapy and on associated risk factors were sent out in 2014. Based on 4434 questionnaires from women with radiotherapy, we used Cox regression to analyze the association between self-reported cardiac morbidity and breast cancer laterality as a surrogate measure of radiation exposure. RESULTS: After a median follow-up of 8.3 years, there was no significant association of tumor laterality with cardiac morbidity in irradiated patients (458 events, hazard ratio for left-sided vs. right-sided tumors 1.07, 95% CI 0.89-1.29). Significant risk factors for any cardiac event included age at diagnosis, chemotherapy, hypertension, hypercholesteremia, and chronic kidney disease. CONCLUSIONS: For contemporary radiotherapy, we found no evidence for a significantly elevated cardiac morbidity risk in left-sided versus right-sided breast cancer. Possible reasons for failing to confirm earlier reports on increased risk include shorter follow-up, application of newer radiotherapy techniques, and improved health monitoring. PMID- 28353064 TI - Radiological imaging features of the basal ganglia that may predict progression to hemicraniectomy in large territory middle cerebral artery infarct. AB - PURPOSE: Predicting which patients are at risk for hemicraniectomy can be helpful for triage and can help preserve neurologic function if detected early. We evaluated basal ganglia imaging predictors for early hemicraniectomy in patients with large territory anterior circulation infarct. METHODS: This retrospective study evaluated patients with ischemic infarct admitted from January 2005 to July 2011. Patients with malignant cerebral edema refractory to medical therapy or with herniating signs such as depressed level of consciousness, anisocoria, and contralateral leg weakness were triaged to hemicraniectomy. Admission images were reviewed for presence of caudate, lentiform nucleus (putamen and globus pallidus), or basal ganglia (caudate + lentiform nucleus) infarction. RESULTS: Thirty-one patients with large territory MCA infarct, 10 (32%), underwent hemicraniectomy. Infarction of the caudate nucleus (9/10 vs 6/21, p = 0.002) or basal ganglia (5/10 vs 2/21, p = 0.02) predicted progression to hemicraniectomy. Infarction of the lentiform nucleus only did not predict progression to hemicraniectomy. Sensitivity for patients who did and did not have hemicraniectomy were 50% (5/10) and 90.5% (19/21). For caudate nucleus and caudate plus lentiform nucleus infarcts, the crude- and age-adjusted odds of progression to hemicraniectomy were 9.5 (1.4-64.3) and 6.6 (0.78-55.4), respectively. CONCLUSION: Infarction of the caudate nucleus or basal ganglia correlated with patients progressing to hemicraniectomy. Infarction of the lentiform nucleus alone did not. PMID- 28353063 TI - The microRNA-7-mediated reduction in EPAC-1 contributes to vascular endothelial permeability and eNOS uncoupling in murine experimental retinopathy. AB - AIMS: To investigate the consequences of oxidative stress and hypoxia on EPAC-1 expression during retinopathy. METHODS: Oxygen-induced retinopathy was induced in mice and EPAC-1 expression investigated by immunofluorescence. In silico analyses were used to identify a link between EPAC-1 expression and microRNA-7-5p in endothelial cells and confirmed by western blot analyses on cells expressing microRNA-7-5p. In vitro, endothelial cells were either incubated at 2% oxygen or transfected with microRNA-7-5p, and the effects of these treatments on EPAC-1 expression, endothelial hyperpermeability and NO production were assessed. In the Ins2Akita mouse model, levels of EPAC-1 expression as well as microRNA-7-5p were assessed by qPCR. Endothelial nitric oxide synthase was assessed by immunoblotting in the Ins2Akita model. RESULTS: Hypoxia induces the expression of microRNA-7-5p that translationally inhibits the expression of EPAC-1 in endothelial cells, resulting in hyperpermeability and the loss of eNOS activity. Activation of EPAC-1 by the cAMP analogue 8-pCPT-2'-O-Me-cAMP reduced the sensitivity of EPAC-1 to oxidative stress and restored the endothelial permeability to baseline levels. Additionally, 8-pCPT-2'-O-Me-cAMP rescued eNOS activity and NO production. In mouse models of retinopathy, i.e., oxygen-induced retinopathy and the spontaneous diabetic heterozygous Ins2Akita mice, EPAC-1 levels are decreased which is associated with an increase in microRNA-7-5p expression and reduced eNOS activity. CONCLUSION/INTERPRETATION: In retinopathy, EPAC-1 expression is decreased in a microRNA-7-mediated manner, contributing to endothelial dysfunction. Pharmacological activation of remnant EPAC-1 rescues endothelial function. Collectively, these data indicate that EPAC-1 resembles an efficacious and druggable target molecule for the amelioration of (diabetic) retinopathy. PMID- 28353065 TI - Four reasons to prefer Bayesian analyses over significance testing. AB - Inference using significance testing and Bayes factors is compared and contrasted in five case studies based on real research. The first study illustrates that the methods will often agree, both in motivating researchers to conclude that H1 is supported better than H0, and the other way round, that H0 is better supported than H1. The next four, however, show that the methods will also often disagree. In these cases, the aim of the paper will be to motivate the sensible evidential conclusion, and then see which approach matches those intuitions. Specifically, it is shown that a high-powered non-significant result is consistent with no evidence for H0 over H1 worth mentioning, which a Bayes factor can show, and, conversely, that a low-powered non-significant result is consistent with substantial evidence for H0 over H1, again indicated by Bayesian analyses. The fourth study illustrates that a high-powered significant result may not amount to any evidence for H1 over H0, matching the Bayesian conclusion. Finally, the fifth study illustrates that different theories can be evidentially supported to different degrees by the same data; a fact that P-values cannot reflect but Bayes factors can. It is argued that appropriate conclusions match the Bayesian inferences, but not those based on significance testing, where they disagree. PMID- 28353066 TI - [Comment on: What is the appropriate anesthesia for thrombectomy?] PMID- 28353067 TI - [Conflict matrix : Risk management tool in the operating room]. AB - BACKGROUND: In business conflicts have long been known to have a negative effect on costs and team performance. In medicine this aspect has been widely neglected, especially when optimizing processes for operating room (OR) management. In the multidisciplinary setting of OR management, shortcomings in rules for decision making and lack of communication result in members perceiving themselves as competitors in the patient's environment rather than acting as art of a multiprofessional team. This inevitably leads to the emergence and escalation of conflicts. OBJECTIVE: We developed a conflict matrix to provide an inexpensive and objective way for evaluating the level of escalation of conflicts in a multiprofessional working environment, such as an OR. MATERIAL AND METHODS: The senior members of all involved disciplines were asked to estimate the level of conflict escalation between the individual professional groups on a scale of 0-9. By aggregating the response data, an overview of the conflict matrix within this OR section was created. RESULTS: No feedback was received from 1 of the 11 contacted occupational groups. By color coding the median, minimum and maximum values of the retrieved data, an intuitive overview of the escalation levels of conflict could be provided. The value range of all feedbacks was between 0 and 6. Estimation of the escalation levels differed widely within one category, showing a range of up to 6 (out of 6) levels. CONCLUSION: The presented assessment using a conflict matrix is a simple and cost-effective method to assess the conflict landscape, especially in multidisciplinary environments, such as OR management. The chance of conflict prevention or the early recognition of existing conflicts represents an enormous potential for cost and risk saving and might have positive long-term effects by building a culture of conflict prevention at the workplace and a positive influence on interdisciplinary cooperation in this working environment. PMID- 28353068 TI - [Interhospital transport of patients with ARDS]. AB - In patients with severely compromised gas exchange, interhospital transportation is frequently necessary due to the need to provide access to specialized care. Risks are inherent during transport, so the anticipated benefits of transportation must be weighed against the possible negative outcome during the transport. The use of specialized teams during transportation can help to reduce adverse events. Diligent planning of the transportation, monitoring and medical staff during transport can decrease adverse events and reduce risks. This article defines the group of patients that may benefit from referral. This article discusses the risks associated with the transportation of patients with severely impaired gas exchange and the risks related to different means of transportation. The decisions required before transportation are described as well as the practical approach starting at the transferring hospital until arrival at the admitting hospital. PMID- 28353069 TI - Epigenetic regulation of muscle development. AB - In eukaryote cells, chromatin appears in several forms and is composed of genomic DNA, protein and RNA. The protein content of chromatin is composed primarily of core histones that are packaged into nucleosomes resulting in the condensation of the DNA. Several epigenetic mechanisms regulate the stability of the nucleosomes and the protein-protein interactions that modify the transcriptional activity of the DNA. Interestingly, epigenetic control of gene expression has recently emerged as a relevant mechanism involved in the regulation of many different biological processes including that of muscle development, muscle mass maintenance, function, and phenotype in health and disease. Recent investigations have shed light into the epigenetic control of biological mechanisms that are key regulators of embryonic muscle development and postnatal myogenesis. In the present review article, we provide a summary of the contents discussed in session 08, titled "Epigenetics of muscle regeneration", during the course of the 45th European Muscle Conference, which was celebrated in Montpellier (France) in September 2016. The main theme of that session was to highlight the most recent progress on the role of epigenetics in the regulation of muscle development and regeneration. The current mini-review has been divided into two major sections. On the one hand, a brief introduction on the topic of myogenesis is offered for the non-specialized reader. On the other, a brief overview of the most relevant epigenetic players that have been shown to control muscle development and regeneration is given. PMID- 28353070 TI - Effect of AHA dietary counselling on added sugar intake among participants with metabolic syndrome. AB - BACKGROUND: High added sugar consumption has been associated with the development of metabolic syndrome (MetS). The American Heart Association (AHA) diet is designed to prevent and treat MetS; however, it remains unclear whether the AHA diet is effective on decreasing added sugar consumption. The aim of our study was to evaluate the effect of the AHA dietary counselling on added sugar consumption among participants with MetS. METHODS: The AHA dietary counselling was conducted among 119 participants with MetS from June 2009 to January 2014 (ClinicalTrials.gov: NCT00911885). Unannounced 24-hour recalls were collected at baseline, 3, 6 and 12 months. Added sugar consumption patterns over time were examined using linear mixed models. RESULTS: After 1-year dietary counselling, intake of added sugars decreased by 23.8 g/day (95% CI 15.1, 32.4 g/day); intake of nonalcoholic beverages dropped from the leading contributor of added sugar intake to number 7 (from 11.9 to 4.4%); the Alternative Healthy Eating Index (AHEI) score increased by 5.4 (95% CI 2.9, 8.0); however, added sugar intake for 48% participants still exceeded the recommendation. Added sugar intake per meal among different meal type was similar (24.2-25.8%) at baseline. After the 1-year dietary counselling, breakfast became the major resource of added sugar intake (33.3%); the proportion of added sugar intake from snacks decreased from 25.8% (CI 23.1, 28.5%) to 20.9% (CI 19.6, 22.3%). CONCLUSION: Although the consumption of added sugars in participants with MetS decreased after the 1-year AHA dietary counselling, added sugar intake from majority of participants still exceeds recommended limits. Actions of successful public health strategies that focus on reducing added sugar intake are needed. PMID- 28353071 TI - The preliminary study of prebiotic potential of Polish wild mushroom polysaccharides: the stimulation effect on Lactobacillus strains growth. AB - PURPOSE: According to the vast body of evidence demonstrating that the intestinal microbiota is undoubtedly linked with overall health, including cancer risk, searching for functional foods and novel prebiotic influencing on beneficial bacteria is necessary. The present study aimed to investigate the potential of polysaccharides from 53 wild-growing mushrooms to stimulate the growth of Lactobacillus acidophilus and Lactobacillus rhamnosus and to determine the digestibility of polysaccharide fractions. METHODS: Mushroom polysaccharides were precipitated with ethanol from aqueous extracts. Determination of growth promoting activity of polysaccharides was performed in U-shaped 96-plates in an ELISA reader in relation to the reference strain of L. acidophilus and two clinical strains of L. rhamnosus. The digestibility of mushroom polysaccharides was investigated in vitro by exposing them to artificial human gastric juice. RESULTS: Obtained results revealed that fungal polysaccharides stimulate the growth of Lactobacillus strains stronger than commercially available prebiotics like inulin or fructooligosaccharides. Moreover, selected polysaccharides were subjected to artificial human gastric juice and remain undigested in more than 90%. CONCLUSION: Obtained results indicate that mushroom polysaccharides are able to pass through the stomach unchanged, reaching the colon and stimulating the growth of beneficial bacteria. Majority of 53 polysaccharide fractions were analysed for the first time in our study. Overall, our findings suggest that polysaccharide fractions from edible mushrooms might be useful in producing functional foods and nutraceuticals. PMID- 28353073 TI - Erratum to: Ongoing Response in BRAF V600E-Mutant Melanoma After Cessation of Intermittent Vemurafenib Therapy: A Case Report. PMID- 28353072 TI - Changes in plasma concentrations of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D during pregnancy: a Brazilian cohort. AB - PURPOSE: To characterize the physiological changes in 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] throughout pregnancy. METHODS: Prospective cohort of 229 apparently healthy pregnant women followed at 5th-13th, 20th-26th, and 30th-36th gestational weeks. 25(OH)D and 1,25(OH)2D concentrations were measured by LC-MS/MS. Statistical analyses included longitudinal linear mixed-effects models adjusted for parity, season, education, self-reported skin color, and pre-pregnancy BMI. Vitamin D status was defined based on 25(OH)D concentrations according to the Endocrine Society Practice Guideline and Institute of Medicine (IOM) for adults. RESULTS: The prevalence of 25(OH)D <75 nmol/L was 70.4, 41.0, and 33.9%; the prevalence of 25(OH)D <50 nmol/L was 16.1, 11.2, and 10.2%; and the prevalence of 25(OH)D <30 nmol/L was 2, 0, and 0.6%, at the first, second, and third trimesters, respectively. Unadjusted analysis showed an increase in 25(OH)D (beta = 0.869; 95% CI 0.723-1.014; P < 0.001) and 1,25(OH)2D (beta = 3.878; 95% CI 3.136-4.620; P < 0.001) throughout pregnancy. Multiple adjusted analyses showed that women who started the study in winter (P < 0.001), spring (P < 0.001), or autumn (P = 0.028) presented a longitudinal increase in 25(OH)D concentrations, while women that started during summer did not. Increase of 1,25(OH)2D concentrations over time in women with insufficient vitamin D (50-75 nmol/L) at baseline was higher compared to women with sufficient vitamin D (>=75 nmol/L) (P = 0.006). CONCLUSIONS: The prevalence of vitamin D inadequacy varied significantly according to the adopted criteria. There was a seasonal variation of 25(OH)D during pregnancy. The women with insufficient vitamin D status present greater longitudinal increases in the concentrations of 1,25(OH)2D in comparison to women with sufficiency. PMID- 28353074 TI - Gemcitabine in Combination with a Second Cytotoxic Agent in the First-Line Treatment of Locally Advanced or Metastatic Pancreatic Cancer: a Systematic Review and Meta-Analysis. AB - BACKGROUND: It remains controversial whether the addition of a second cytotoxic agent can further improve the therapeutic effect of gemcitabine monotherapy in advanced or metastatic pancreatic cancer (LA/MPC). OBJECTIVE: The objective of the present systematic review and meta-analysis was to investigate the efficacy and safety of gemcitabine-based doublet chemotherapy regimens compared to single agent gemcitabine in the first-line treatment of unresectable LA/MPC. METHODS: We searched for randomized controlled trials (RCTs) of gemcitabine monotherapy versus gemcitabine in combination with a second cytotoxic agent in patients with LA/MPC. The last search date was December 31, 2016. RESULTS: Twenty-seven RCTs were identified and included in the present systematic review and meta-analysis, involving a total of 7343 patients. The meta-analysis showed that gemcitabine based combination therapy significantly improved overall survival (OS) (HR: 0.89; 95% confidence interval (CI): 0.85-0.94; P < 0.0001), progression-free survival (PFS) (HR: 0.80; 95% CI: 0.73-0.88; P < 0.0001), and overall response rate (ORR) (RR: 1.83; 95% CI: 1.62-2.07; P < 0.0001) in comparison to single-agent gemcitabine. Subgroup analysis suggested that the antitumor activity differed between gemcitabine-based combination regimens: doublet regimens of gemcitabine plus a taxoid, and gemcitabine plus a fluoropyrimidine, in particular an oral fluoropyrimidine, resulted in a significant OS benefit for the patients. However, the combination of gemcitabine with other cytotoxic agents, such as platinum compounds or topoisomerase inhibitors failed to reduce the mortality risk. Combination therapy caused more grade 3/4 toxicities, including neutropenia, thrombocytopenia, vomiting, diarrhea, and fatigue. CONCLUSIONS: Gemcitabine-based doublet regimens demonstrated superiority over gemcitabine monotherapy in overall efficacy, but were associated with increased toxicity. Different gemcitabine based combinations showed different antitumor activity, and doublet regimens of gemcitabine in combination with a taxoid or a fluoropyrimidine, in particular an oral fluoropyrimidine provided significant survival benefits in the first-line treatment of unresectable LA/MPC. PMID- 28353075 TI - Oral Microbiome and Nitric Oxide: the Missing Link in the Management of Blood Pressure. AB - Having high blood pressure puts you at risk for heart disease and stroke, which are leading causes of death in the USA and worldwide. One out of every three Americans has hypertension, and it is estimated that despite aggressive treatment with medications, only about half of those medicated have managed blood pressure. Recent discoveries of the oral microbiome that reduces inorganic nitrate to nitrite and nitric oxide provide a new therapeutic target for the management of hypertension. The presence or absence of select and specific bacteria may determine steady-state blood pressure levels. Eradication of oral bacteria through antiseptic mouthwash or overuse of antibiotics causes blood pressure to increase. Allowing recolonization of nitrate- and nitrite-reducing bacteria can normalize blood pressure. This review will provide evidence of the link between oral microbiota and the production of nitric oxide and regulation of systemic blood pressure. Management of systemic hypertension through maintenance of the oral microbiome is a completely new paradigm in cardiovascular medicine. PMID- 28353076 TI - DOCA-Salt Hypertension: an Update. AB - Hypertension is a multifaceted disease that is involved in ~40% of cardiovascular mortalities and is the result of both genetic and environmental factors. Because of its complexity, hypertension has been studied by using various models and approaches, each of which tends to focus on individual organs or tissues to isolate the most critical and treatable causes of hypertension and the related damage to end-organs. Animal models of hypertension have ranged from Goldblatt's kidney clip models in which the origin of the disease is clearly renal to animals that spontaneously develop hypertension either through targeted genetic manipulations, such as the TGR(mRen2)27, or selective breeding resulting in more enigmatic origins, as exemplified by the spontaneously hypertensive rat (SHR). These two genetically derived models simulate the less-common human primary hypertension in which research has been able to define a Mendelian linkage. Several models are more neurogenic or endocrine in nature and illustrate that crosstalk between the nervous system and hormones can cause a significant rise in blood pressure (BP). This review will examine one of these neurogenic models of hypertension, i.e., the deoxycorticosterone acetate (DOCA), reduced renal mass, and high-salt diet (DOCA-salt) rodent model, one of the most common experimental models used today. Although the DOCA-salt model is mainly believed to be neurogenic and has been shown to impact the central and peripheral nervous systems, it also significantly involves many other body organs. PMID- 28353078 TI - [Imaging for surgical planning : Tumor surgery including reconstructive procedures]. AB - Alongside clinical investigation, imaging is an important diagnostic modality for guiding treatment decisions and particularly for surgical planning in head and neck cancer. The significance and type of imaging depends on localization of the primary tumor. Beside the primary tumor, each imaging procedure must also include the lymph nodes, in order to develop an overall concept of surgical treatment. In addition to the superficial growth of a tumor, it is of utmost importance that its infiltration also be detected by imaging, in order to define the extent of tumor resection and identify potentially necessary reconstructive procedures. The type of imaging needed to understand tumor localization and size, e.g., CT or MRI, depends on the region. In some cases the methods are complementary. PMID- 28353079 TI - Biological therapies in otology. AB - Hearing loss is present in millions of people worldwide. Current treatment for patients with severe to profound hearing loss consists of cochlear implantation. Providing the cochlear nerve is intact, patients generally benefit greatly from this intervention, frequently achieving significant improvements in speech comprehension. There are, however, some cases where current technology does not provide patients with adequate benefit. Ongoing research in cell transplantation and gene therapy promises to lead to new developments that will improve the function of cochlear implants. Translation of these experimental approaches is presently at an early stage. This review focuses on the application of biological therapies in severe hearing loss and discusses some of the barriers to translating basic scientific research into clinical reality. We emphasize the application of these novel therapies to cochlear implantation. PMID- 28353077 TI - Role of Orexin-A in Hypertension and Obesity. AB - PURPOSE OF REVIEW: Hypertension is one of the most challenging health problems inducing cerebrovascular disease and high percentage of death when associated with diabetes, dyslipidemias, and obesity. Orexin/hypocretin is a peptide expressed by a small number of neurons of the dorsolateral hypothalamus, a brain feeding and autonomic "fight-or-flight" regulatory center. According to this function, orexin has been demonstrated to evoke cardiovascular responses, heart rate, hypertension, hyperarousal, hyperphagia, and obesity. The focus of this review is to provide an overview about the mechanism through which orexin regulates food intake and cardiovascular responses and its role in the pathogenesis of obesity and hypertension which could be of great interest to establish possible new therapies. RECENT FINDINGS: In normal rats and mice, central administration of orexin increases food intake, blood pressure, and sympathetic nerve activity and these effects are blocked by selective orexin receptor antagonist SB-334867 or almorexant. Moreover, upregulation of orexin signaling, in combination with elevation of epinephrine and norepinephrine circulating levels, occurs in rats exposed to chronic stress, in models of spontaneous hypertension (SHR and BPH/2J Schlager mice) and in obese mice (ob/ob or mice fed with high fat diet). Therefore, hyperactivity of orexinergic neurons could be a factor in the development of obesity and essential hypertension. Because of their widespread projections to the brain regions involved in appetite and cardiovascular responses, as far down as sympathetic preganglionic neurons in the spinal cord, orexin evokes sympathetically mediated cardiovascular responses. Lasting upregulation of orexin signaling can lead to hyperphagia, obesity, and hypertensive state. Dual orexin receptor antagonists (DORAs) and selective orexin receptor antagonists (SORAs) have antihypertensive effects that could be of clinical use for regulation of food intake and hypertension, supporting the role of orexinergic neurons as critical checkpoint in the neurogenic control of metabolic and cardiovascular functions. PMID- 28353080 TI - Serological, culture and molecular survey of Mycobacterium avium paratuberculosis in a goat flock in Tuscany. AB - Mycobacterium avium paratuberculosis (Map) is a pathogen which causes a chronic progressive granulomatous enteritis known as paratuberculosis or Johne's disease and it primarily affects wild and domestic ruminants. The aim of this research was to examine a flock which consisted of 294 goats and was located in Garfagnana district (Tuscany, Italy) performing ELISA tests, culture and IS900 PCR assay; direct diagnostic methods were carried out not only on bulk tank milk and cheese samples but also on individual milk and tissue specimens collected from nine subjects positive to ELISA tests. Out of 294 animals, 20 goats (6.8%) were positive to ELISA surveys. Bulk tank milk samples were negative to culture and to PCR assay carried out on the DNA extracted directly from them, while, with respect to cheese, Map was detected by culture in 2/12 (16.66%) cheeses ripened for 3-7 days, and by PCR in 2/12 (16.66%) cheeses ripened for 3-7 days and in 3/12 (25%) cheeses ripened for 45 days. Regarding individual milk samples, Map was detected by culture in 2/9 (22.22%) specimens and by PCR in 5/9 (55.55%) samples. Furthermore, Map was isolated from the intestine in 9/9 (100%) animals, from the mesenteric lymph nodes in 8/9 (88.88%) subjects, from the liver in 4/9 (44.44%) goats, from the spleen in 5/9 (55.55%) animals, while Map DNA was found in all the tissue samples analyzed.The results demonstrated the presence of paratuberculosis in a goat flock located in Garfagnana district (Tuscany, Italy). PMID- 28353081 TI - Gastrointestinal manifestations of melioidosis: A single center experience. AB - Melioidosis, being increasing, is reported from India. Gastrointestinal manifestations are typically reported as unusual cause of liver and/or splenic abscess. We aimed to describe various gastrointestinal manifestation of melioidosis in the present study. We retrospectively collected data of culture positive melioidosis cases from hospital database during August 2014-October 2016 at Asian Institute of Gastroenterology, Hyderabad. A total of nine culture positive cases (8 male) of melioidosis with median age of 40 years (range 23-66) were analyzed. Median duration of symptoms was 45 days. Two patients were being treated as tuberculosis. Three patients presented with liver abscess with two of them having simultaneous splenic abscess, and one had prostatic abscess. Three patients (43%) with history of acute pancreatitis had infected pancreatic collection, and one patient had left empyema with splenic abscess. One patient had wound infection with left lower limb cellulitis, presented as acute in chronic liver failure and another as spontaneous bacterial peritonitis (SBP). Diabetes and/or alcoholism was present in all patients. Seven patients had disseminated organ involvement. Seven patients underwent percutaneous intervention for drainage of abscess. Induction therapy as ceftazidime (n=4) or meropenem (n=5) followed by continuation therapy as oral cotrimoxazole (n=6) and doxycycline (n=1) was given. Six patients completed therapy and asymptomatic at end of follow up. Two patients died in the study period. One patient died due to acute-on-chronic liver failure (ACLF) with acute kidney injury and the other due to cardiac failure. One patient with SBP had lost to follow up. Apart from being unusual cause of liver/splenic abscess, melioidosis can present with infection of pancreatic collection, SBP, and infection in a compensated cirrhosis which can precipitate ACLF. Early recognition and specific therapy can improve prognosis. PMID- 28353082 TI - Erratum to: The effect of sinomenine in diabetic neuropathic pain mediated by the P2X3 receptor in dorsal root ganglia. PMID- 28353083 TI - Facts and alternative facts - basic principles of scientific work. PMID- 28353085 TI - Alterations in mechanical properties of the patellar tendon is associated with pain in athletes with patellar tendinopathy. AB - PURPOSE: To compare tendon strain and stiffness between athletes with patellar tendinopathy and healthy controls, and explore whether the intensity of pain and dysfunction were related to the mechanical properties of the tendon. METHODS: Thirty-four male athletes with patellar tendinopathy and 13 healthy controls matched by age and activity levels were recruited. The in vivo mechanical properties of the patellar tendon were examined by ultrasonography and dynamometry. In subjects with patellar tendinopathy, the intensities of self perceived pain (maximal pain in the past 7 days and pain during a single-legged declined-squat test) using the visual analogue scale and the assessment of functional disability using the Victorian Institute of Sport Assessment-patellar questionnaire, were collected. RESULTS: In subjects with patellar tendinopathy, tendon strain was significantly reduced by 22% (8.9 +/- 3.7 vs. 14.3 +/- 4.7%, P = 0.005) when compared with healthy controls. There was no significant group difference in tendon stiffness (P = 0.27). Significant negative correlations between tendon strain and the maximal self-perceived pain over 7 days (r = -0.37, P = 0.03), and pain during a single-legged declined-squat test (r = -0.37, P = 0.03) were detected. A trend of significant positive correlation was found between tendon stiffness and pain during a single-legged declined-squat test (r = 0.30, P = 0.09). CONCLUSION: Our findings show that tendon strain is reduced in athletes with patellar tendinopathy, and a lower tendon strain is associated with a greater magnitude of pain perceived. PMID- 28353086 TI - Intraductal papilloma of the breast in an 11-year-old male patient: a case report. AB - Intraductal papilloma (IP) constitutes a rare benign neoplasm among male population with only few reports on childhood patients. Herein, we describe an 11 year-old IP male patient who presented with spontaneous nipple discharge of his right breast. PMID- 28353087 TI - Erratum to: The conversion rate of tuberculosis screening tests during biological therapies in patients with rheumatoid arthritis. PMID- 28353088 TI - Validation of the Mini-OAKHQOL for use in patients with osteoarthritis in Spain. AB - The Mini-Osteoarthritis Knee and Hip Quality of Life (Mini-OAKHQOL) questionnaire osteoarthritis is specific to individuals with knee or hip osteoarthritis. The objective of this study was to perform a validation of the Mini-OAKHQOL for use in Spain in terms of its psychometric properties of reliability, validity and responsiveness. Patients with osteoarthritis from the waiting list for a joint replacement completed the OAKHQOL, Short Form 36 Health Survey and Western Ontario and McMaster Universities Osteoarthritis Index. Reliability was assessed in terms of internal consistency and test-retest data, and convergent validity using Spearman's correlation coefficient. Structural validity was investigated by confirmatory factor analysis, and Rasch analysis was used to examine the unidimensionality of the scales. Responsiveness was assessed by calculating effect sizes. Confirmatory factor analysis confirmed the five-factor model, and the results of the Rasch analyses supported the unidimensionality assumption, with infit and outfit statistics. Cronbach's alpha ranged from 0.76 to 0.89 for all except the social dimensions. Statistically significant differences were observed between patients with different degrees of disease severity on all dimensions. There was convergent validity among dimensions expected to be correlated. The OAKHQOL questionnaire showed good responsiveness, with large changes for all dimensions apart from the two social dimensions, which had small effect sizes. Results of the study support the view that the Spanish version of the Mini-OAKHQOL questionnaire is a valid instrument to measure health-related quality of life in patients with osteoarthritis of the lower limb. PMID- 28353089 TI - Histological, immunohistological and molecular characteristics of intraductal precursor of carcinoma ex pleomorphic adenoma support a multistep carcinogenic process. AB - In recent years, multistep carcinogenesis of carcinoma ex pleomorphic adenoma (CEPA) has been identified, starting with intraductal neoplasia within pre existent pleomorphic adenoma (PA). However, as yet there is no consensus regarding clinical relevance and appropriate terminology of precursor lesions in CEPA. We therefore decided to investigate precursor lesions, especially intraductal carcinoma, in a series of 85 cases of CEPA. Intraductal carcinoma confined by benign myoepithelial cells was found in 60 cases and mostly exhibited high-grade cellular atypia, increased cellular proliferation and frequent genetic alterations (TP53, Her2-neu, androgen receptor). Intraductal carcinoma was absent only in the myoepithelial type of CEPA. In 26 cases, purely intraductal CEPA with extensive intraductal expansion was found. This suggests that there is a long period of intraductal growth before extraductal intracapsular infiltration of the PA. We identified two different histomorphological types of intraductal carcinoma, which we call 'clinging' and 'solid' types. In summary, combined histological, immunohistological and molecular data strongly support multistep carcinogenesis starting with intraductal carcinoma for all non-myoepithelial types of CEPA. The clinical significance of our finding of two histomorphological types of intraductal carcinoma (clinging and solid) is not yet clear. Intraductal carcinoma, intracapsular invasive CEPA and minor extracapsular invasive CEPA (up to about 6 mm) all show favourable prognosis and together comprise half of the cases in our study. PMID- 28353090 TI - Tissue inhibitors of metalloproteinase-expressing cells in human anterior pituitary and pituitary adenoma. AB - Extracellular matrix (ECM) is essential in tissue physiology and pathologic conditions such as tumorigenesis. It affects tumor cell behavior, proliferation, and metastasis. Pituitary adenomas differ in their clinical characteristics, including ECM deposition, and we recently reported that the characteristics of collagen-producing cells differed between control human anterior pituitary gland and pituitary adenomas. ECM deposition is not defined solely by production; degradation and maintenance are also important. Tissue inhibitors of metalloproteinases (TIMPs) help maintain ECM by inhibiting degradation caused by matrix metalloproteases. The present study attempted to characterize TIMP expressing cells in the human anterior pituitary. Specimens of human pituitary adenomas and control pituitary were obtained during surgery, and in situ hybridization for TIMP1, TIMP2, TIMP3, and TIMP4, followed by immunohistochemistry, was used to characterize TIMP-expressing cells. TIMP expression exhibited a distinct pattern in the human anterior pituitary. Azan staining showed that fibrous matrix deposition varied among pituitary adenomas and that the area of fibrosis was associated with the number and number of types of TIMP3-expressing cells. These results suggest that TIMPs are important in the maintenance of ECM in human pituitary and that TIMP expressions are altered in fibrosis associated with pituitary adenoma. PMID- 28353091 TI - Diversity of culturable fungi inhabiting petroleum-contaminated soils in Southern Iran. AB - The present study was aimed at characterising species diversity of fungi inhabiting petroleum-contaminated soils of oil fields in a southern region of Iran. Two different techniques were used for fungal isolation including enrichment on atmospheres of phenolic hydrocarbons and crude oil as substrate. Phylogenetic analysis of the internal transcribed spacer of ribosomal DNA was used for taxonomic identification with additional information from the beta tubulin gene for selected taxa. Overall, 183 strains from 14 genera and five orders were obtained: Pleosporales (Alternaria, Curvularia, Stemphylium, Ulocladium), Chaetothyriales (Exophiala), Eurotiales (Aspergillus), Hypocreales (Acremonium, Emericellopsis, Sarocladium, Stachybotrys, Fusarium, Trichoderma, Beauveria), and Capnodiales (Cladosporium). The most frequently isolated strains belonged to the genera Alternaria, Exophiala and Aspergillus. The crude oil substrate was the most successful isolation method, and among the four hydrocarbon enrichments, toluene substrate yielded the highest number of strains. Enrichment on xylene and benzene also yielded herpotrichiellaceous and other filamentous fungi. PMID- 28353092 TI - Functional and phylogenetic diversity of cultivable rhizobacterial endophytes of sorghum [Sorghum bicolor (L.) Moench]. AB - A diverse group of bacteria colonize the exo- and endo-rhizospheres of sorghum and play a critical role in its tolerance to drought and other abiotic stresses. Two hundred and eighty endophytic bacteria were isolated from the surface sterilized roots of four sorghum cultivars that were grown on three soil types at three different phenological stages of growth. The isolates were subjected to in vitro screening for their plant growth promoting traits. Out of 280 isolates, 70 could produce Indole 3-Acetic Acid (IAA), 28 showed N-fixation, 28 could solubilize phosphate, 24 had ACC deaminase activity and 13 isolates were able to produce siderophores. Functional diversity grouping of the isolates indicated one isolate having five PGP traits and two isolates having four PGP traits; two and 29 isolates having three and two PGP traits, respectively. Among the thirty-four isolates that possessed multiple PGP traits, 19 and 17 isolates were able to produce significant quantities of IAA in the presence and absence of L tryptophan, an inducer. Eight isolates possessed high levels of ACC deaminase activity. PCR-RFLP of the 16Sr RNA gene revealed a distinct clustering and considerable genetic diversity among these functionally characterized isolates. The 16S rRNA gene based identification of the isolates of single and multiple PGP traits revealed phylogenetic dominance of Firmicutes; Acinetobacter, Bacillus, Enterobacter, Geobacillus, Lysinibacillus, Microbacterium, Ochrobactrum, Paenibacillus and Pseudomonas were the major genera present in the endo rhizosphere of sorghum. Results of this study are constructive in selection of effective rhizobacterial endophytes or consortia for drought stress alleviation in sorghum. PMID- 28353093 TI - PD-L2: A prognostic marker in chromophobe renal cell carcinoma? AB - In the context of cancer immunotherapy, PD-1 as well as PD-L1 has been widely studied in renal cell carcinoma (RCC). PD-1 and PD-L1 play a significant role as prognostic markers in clear cell renal cell carcinoma. In contrast, little is known about PD-L2 expression patterns in RCC, especially in rarer subtypes. The aim of this study was to evaluate the prevalence, distribution and prognostic impact of PD-L2 expression in chromophobe (ch)RCC. Eighty-one patients who underwent renal surgery due to chRCC were retrospectively evaluated. Tumor specimens were analyzed for PD-L2 expression by immunohistochemistry. Expression data were associated with clinicopathological parameters and overall survival (OS). Twenty-three (28.4%) patients showed a PD-L2 > median (PD-L2 high) staining intensity. No significant association between clinicopathological parameters and PD-L2 expression was identified. A significant difference between 5- and 10-year OS in dependence of PD-L2 expression was found (PD-L2 low 96.4 and 87.7% vs. PD L2 high 87.1 and 56%; log rank, p = 0.029). However, in multivariate analysis PD L2 expression failed to be proofed as an independent prognostic factor. In conclusion, to our knowledge this is the first study evaluating the prognostic impact of PD-L2 in a considerably large cohort of chRCC. Our results showed a significant diminished OS in dependence of PD-L2 expression. This implicates that PD-L2 might play a role as prognostic marker in chRCC demanding further evaluation. PMID- 28353094 TI - Systematic review: isocaloric ketogenic dietary regimes for cancer patients. AB - The efficacy and benefits of ketogenic diets (KD) have recently been gaining worldwide and remain a controversial topic in oncology. This systematic review therefore presents and evaluates the clinical evidence on isocaloric KD dietary regimes and reveals that evidence supporting the effects of isocaloric ketogenic dietary regimes on tumor development and progression as well as reduction in side effects of cancer therapy is missing. Furthermore, an array of potential side effects should be carefully considered before applying KD to cancer patients. In regard to counseling cancer patients considering a KD, more robust and consistent clinical evidence is necessary before the KD can be recommended for any single cancer diagnosis or as an adjunct therapy. PMID- 28353096 TI - Alexithymia and weight loss in obese patients underwent laparoscopic sleeve gastrectomy. AB - PURPOSE: Obesity is a multifactorial disease characterized by genetic, social, cultural and psychological factors. Currently, bariatric surgery represents the gold-standard intervention to treat morbid obesity in order to counteract associated disabling comorbidities. Several studies showed correlation between post-surgery weight loss and psychological factors. Also, the alexithymia may have a role in affecting post-surgery outcomes in bariatric patients, even if there are no studies investigating its role at 12-month follow-up. The purpose of the present study was to investigate the association between alexithymia and the postoperative weight loss 12 months after laparoscopic sleeve gastrectomy. METHODS: Seventy-five patients undergoing laparoscopic sleeve gastrectomy were enrolled. The Toronto Alexithymia Scale (TAS-20) was administered to patients. A postoperative weight loss check was performed at 3 and then 12 months after surgery. RESULTS: The TAS-20 total score was negatively correlated with the percent of excess weight loss (%EWL) at the 12-month follow-up (r = -0.24; p = 0.040). The analysis showed that non-alexithymic patients had a greater weight loss at 12 months after surgery compared to both probably alexithymics (71.88 +/- 18.21 vs. 60.7 +/- 12.5; p = 0.047) and probably alexithymic patients (71.88 +/- 18.21 vs. 56 +/- 22.8; p = 0.007). The preoperative BMI was a significant covariate [F(1,70) = 6.13 (p = 0.016)]. CONCLUSION: In the present study, the patients with higher preoperative BMI and identified as alexithymic showed lower %EWL at 12 months after laparoscopic sleeve gastrectomy. Findings point out the importance to take into consideration possible psychological treatments focused on improving emotional regulations of patients who are seeking bariatric surgery. PMID- 28353095 TI - Selenoamino Acid-Enriched Green Pea as a Value-Added Plant Protein Source for Humans and Livestock. AB - Selenium deficiency in various degrees affects around 15% of the world's population, contributing to a variety of health problems. In this study, we examined the accumulation and biotransformation of soil applied Se supplementation (sodium selenite and sodium selenate forms) at different concentrations, along with growth and yield formation of green pea, in a greenhouse experiment. Biotransformation of inorganic Se was evaluated using HPLC ICP-MS for Se-species separation in the above ground parts of green pea. Results showed 3 mg kg-1 SeIV increased green pea growth biomarkers and also caused an increase in protein content in leaves by 17%. Selenomethionine represented 65% of the total selenium content in shoots, but was lower in pods and seeds (54 and 38%, respectively). Selenomethionine was the major species in all plant parts and the only organic selenium form in the lower SeIV concentration range. Elevating the dose of SeIV (>=30 mg kg-1) triggered detrimental effects on growth and protein content and caused higher accumulation of inorganic Se in forms of SeVI and SeIV. Selenocysteine, another organic form of proteinogenic amino acid, was determined when SeIV (>=10 mg kg-1) was applied in higher concentrations. Thus, agronomic biofortification using the appropriate chemical form and concentration of Se will have positive effects on green pea growth and its enriched shoots and seeds provide a value-added protein source for livestock and humans with significant increased selenomethionine. PMID- 28353097 TI - Influence of natural zeolite and nitrification inhibitor on organics degradation and nitrogen transformation during sludge composting. AB - Sludge composting is one of the most widely used treatments for sewage sludge resource utilization. Natural zeolite and nitrification inhibitor (NI) are widely used during composting and land application for nitrogen conservation, respectively. Three composting reactors (A-the control, B-natural zeolite addition, and C-3,4-dimethylpyrazole phosphate (DMPP) addition) were established to investigate the influence of NI and natural zeolite addition on organics degradation and nitrogen transformation during sludge composting conducted at the lab scale. The results showed that, in comparison with the control, natural zeolite addition accelerated organics degradation and the maturity of sludge compost was higher, while the DMPP addition slowed down the degradation of organic matters. Meanwhile, the nitrogen transformation functional genes including those responses for nitrification (amoA and nxrA) and denitrification (narG, nirS, nirK, and nosZ) were quantified through quantitative PCR (qPCR) to investigate the effects of natural zeolites andDMPP addition on nitrogen transformation. Although no significant difference in the abundance of nitrogen transformation functional genes was observed between treatments, addition of both natural zeolite and DMPP increases the final total nitrogen content by 48.6% and 23.1%, respectively. The ability of natural zeolite for nitrogen conservation was due to the absorption of NH3 by compost, and nitrogen conservation by DMPP was achieved by the source reduction of denitrification. Besides, it was assumed that the addition of natural zeolite and DMPP may affect the activity of these genes instead of the abundance. PMID- 28353098 TI - Cholinesterase characterization of two autochthonous species of Ria de Aveiro (Diopatra neapolitana and Solen marginatus) and comparison of sensitivities towards a series of common contaminants. AB - Biomonitoring of chemical contamination requires the use of well-established and validated tools, including biochemical markers that can be potentially affected by exposure to important environmental toxicants. Cholinesterases (ChEs) are present in a large number of species and have been successfully used for decades to discriminate the environmental presence of specific groups of pollutants. The success of cholinesterase inhibition has been due to their usefulness as a biomarker to address the presence of organophosphate (OP) and carbamate (CB) pesticides. However, its use in ecotoxicology has not been limited to such chemicals, and several other putative classes of contaminants have been implicated in cholinesterasic impairment. Nevertheless, the use of cholinesterases as a monitoring tool requires its full characterization in species to be used as test organisms. This study analyzed and differentiated the various cholinesterase forms present in two autochthonous organisms from the Ria de Aveiro (Portugal) area, namely the polychaete Diopatra neapolitana and the bivalve Solen marginatus, to be used in subsequent monitoring studies. In addition, this study also validated the putative use of the now characterized cholinesterasic forms by analyzing the in vitro effects of common anthropogenic contaminants, such as detergents, pesticides, and metals. The predominant cholinesterasic form found in tissues of D. neapolitana was acetylcholinesterase, while homogenates of S. marginatus were shown to possess an atypical cholinesterasic form, with a marked preference for propionylthiocholine. Cholinesterases from D. neapolitana were generally non-responsive towards the majority of the selected chemicals. On the contrary, strong inhibitory effects were reported for ChEs of S. marginatus following exposure to the selected pesticides. PMID- 28353100 TI - Characterization of suspended bacteria from processing units in an advanced drinking water treatment plant of China. AB - For the drinking water treatment plant (DWTP), the organic pollutant removal was the primary focus, while the suspended bacterial was always neglected. In this study, the suspended bacteria from each processing unit in a DWTP employing an ozone-biological activated carbon process was mainly characterized by using heterotrophic plate counts (HPCs), a flow cytometer, and 454-pyrosequencing methods. The results showed that an adverse changing tendency of HPC and total cell counts was observed in the sand filtration tank (SFT), where the cultivability of suspended bacteria increased to 34%. However, the cultivability level of other units stayed below 3% except for ozone contact tank (OCT, 13.5%) and activated carbon filtration tank (ACFT, 34.39%). It meant that filtration processes promoted the increase in cultivability of suspended bacteria remarkably, which indicated biodegrading capability. In the unit of OCT, microbial diversity indexes declined drastically, and the dominant bacteria were affiliated to Proteobacteria phylum (99.9%) and Betaproteobacteria class (86.3%), which were also the dominant bacteria in the effluent of other units. Besides, the primary genus was Limnohabitans in the effluents of SFT (17.4%) as well as ACFT (25.6%), which was inferred to be the crucial contributors for the biodegradable function in the filtration units. Overall, this paper provided an overview of community composition of each processing units in a DWTP as well as reference for better developing microbial function for drinking water treatment in the future. PMID- 28353101 TI - Fe plaque-related aquatic uranium retention via rhizofiltration along a redox state gradient in a natural Phragmites australis Trin ex Steud. wetland. AB - Studies have revealed that the rhizofiltration is a feasible plant-based technology for aquatic metal/metalloid removal. However, the performance of aquatic U retention via rhizofiltration has not been fully revealed yet. In this study, a field investigation was conducted in a Phragmites australis Trin ex Steud. dominated wetland to estimate the efficiency of Fe plaque (IP)-assisted U rhizofiltration, with redox-state gradient (-179 to 220 mV) and low aquatic U level (66.7 to 92.0 MUg l-1). The U concentrations were determined in soil, root, and aboveground biomass of P. australis. The IP on root surface was extracted via DCB extraction procedure. The bio-concentration factor (BCF) was applied to evaluate the aquatic U transfer capacity from root to above ground biomass of P. australis. The result suggested that root of P. australis was highly effective for aquatic U uptake via rhizofiltration (BCF 1025 to 1556). It also benefited the real U accumulation in aboveground biomass of P. australis (up to 0.4 mg m-2) and related plant-water-soil U recycling. The IP and associated microbial community in rhizosphere was effective mediator for aquatic U retention on root surface (BCF 1162 to 847). The IP-assisted aquatic U rhizofiltration was significantly promoted in relatively reductive environment. It was benefited by the enhanced root uptake of Fe due to lower oxidizers (e.g., DO and NO3-) availability. On the other hand, the competitive adsorption effect from co existing IP-affinitive elements (e.g., As) also possibly impaired the real capacity of IP-assisted aquatic U rhizofiltration via P. australis. PMID- 28353099 TI - Occurrence and geographic distribution of polycyclic aromatic hydrocarbons in agricultural soils in eastern China. AB - Polycyclic aromatic hydrocarbons (PAHs) in agricultural soils, eastern China, were studied through a collection of surface samples at 109 sites. The study covered US EPA priority pollutants but also several non-priority isomers including some dibenzopyrenes which are expected to have higher toxic potentials. The total PAH concentrations varied extensively from 8.8 to 3880 MUg/kg, with a geometric mean of 158 MUg/kg. There were significant differences in both the concentrations and composition profiles between the south and the north regions. The overall geographical distribution pattern was strongly influenced by both the per capita gross domestic product and soil organic carbon (SOC) content. The former is an indicator of anthropogenic emissions while soil SOC content is associated with the accumulative capacities of the soils. The sequestration mechanism is an important process controlling fates of PAHs in agricultural soil. PMID- 28353102 TI - Effect of humic acid preloading on phosphate adsorption onto zirconium-modified zeolite. AB - A zirconium-modified zeolite (ZrMZ) was prepared, and then, humic acid (HA) was immobilized on the ZrMZ surface to prepare HA-loaded ZrMZ (HA-ZrMZ). The obtained ZrMZ and HA-ZrMZ were characterized by energy dispersive X-ray spectroscopy, elemental analyzer, N2 adsorption/desorption isotherms, pH at the point of zero charge, and X-ray photoelectron spectroscopy. The adsorption characteristics of phosphate on ZrMZ and HA-ZrMZ were comparatively investigated in batch mode. The adsorption mechanism of phosphate on ZrMZ and HA-ZrMZ was investigated by ionic strength effect and 31P nuclear magnetic resonance. The mechanism for phosphate adsorption onto ZrMZ was the formation of inner-sphere phosphate complexes at the solid/solution interface. The preloading of HA on ZrMZ reduced the phosphate adsorption capacity, and the more the HA loading amount, the lower the phosphate adsorption capacity. However, the preloading of HA on ZrMZ did not change the phosphate adsorption mechanism; i.e., the formation of inner-sphere phosphate surface complexes was still responsible for the adsorption of phosphate on HA ZrMZ. The decreased phosphate adsorption capacity for ZrMZ after HA coating could be attributed to the fact that the coating of HA on ZrMZ reduced the amount of binding active sites available for phosphate adsorption, changed the adsorbent surface charges, and reduced the specific surface areas and pore volumes of ZrMZ. PMID- 28353103 TI - The geochemical release feature of Tl in Tl-rich pyrite mine wastes: a long-term leaching test. AB - Identifying and revealing the geochemical behaviour of Tl during mine waste weathering are very important to assess the potential environmental impact of Thallium (Tl) from open mine-waste piles. Herein, two methods including the modified BCR sequential extraction and the long-term humidity cell tests (HCT) were employed to understand the Tl chemical fractions and to stimulate intense chemical weathering process, respectively. The results from BCR sequential extraction showed that the Tl concentration in the studied sample was 18.78 mg/kg, containing 1.878 mg/kg oxidisable, 0.282 mg/kg acid exchangeable and 1.596 mg/kg reducible Tl. The acid exchangeable fraction contributed to a particular potential risk to the aquatic marine life in the early stages and the Fe/Mn oxidisable fraction posed a potential risk being dissolved into solution at low pH (i.e. acidic conditions). The variations of Tl concentration in leachates were classified as two period as the pH values decrease. In the first period, the Tl concentrations decreased positively with pH value with poor correlation between pH value and SO42- concentration in leachates. Drastic release of Tl was observed in the early period once the material was exposed to air and water, being ascribe to the acid exchangeable fraction bound to carbonate as dissolved by acid. During the second period, three increased peaks of Tl concentration (11.02, 16.03, 43.15 MUg/L) and four increased peaks of SO42- concentration (315, 390, 899.61 and 2670 mg/L) were observed. A good correlation (R 2 = 0.8384) between the concentrations of Tl and SO42- was observed, indicating the Tl was mainly released from the oxidation of sulphide. PMID- 28353104 TI - Removal of sulfamethoxazole (SMX) and sulfapyridine (SPY) from aqueous solutions by biochars derived from anaerobically digested bagasse. AB - This study explored the sorption of sulfamethoxazole (SMX) and sulfapyridine (SPY) onto biochars produced from raw and anaerobically digested bagasse. Initial evaluation of six bagasse biochars showed that digested bagasse biochar prepared at 600 degrees C (DBG600) was the best adsorbent to remove SMX and SPY. Further laboratory batch sorption experiments showed that DBG600 adsorbed SMX and SPY from aqueous solution with maximum adsorption capacity of 54.38 and 8.60 mg g-1, respectively. Solution pH showed strong effect on the sorption ability of DBG600 to the two antibiotics, and the sorption decreased with increasing of solution pH. Experimental and model results suggested that adsorption of SMX and SPY onto DBG600 might be controlled by the pi-pi interaction. PMID- 28353105 TI - Response to the letter to editor "Cadmium exposure and urinary N-acetyl-beta-D glucosaminidase: a meta-analysis". PMID- 28353106 TI - Potential of used frying oil in paving material: solution to environmental pollution problem. AB - The improper disposal of used frying oil (UFO) presents numerous ecological, environmental and municipal problems. Of great concern is the resultant blockage of municipal drainage systems and water treatment facilities, harm to wildlife when they become coated in it and detriment to aquatic life and ecosystems due to the depletion of the oxygen content in water bodies such as rivers and lakes that have become contaminated. Statistics show that in Trinidad and Tobago, in excess of one million liters of used cooking oil is collected annually from various restaurant chains. This paper investigated the potential of using UFO as a performance enhancing additive for road paving applications utilizing Trinidad Lake Asphalt (TLA) and Trinidad Petroleum Bitumen (TPB) as a mitigation strategy for improper UFO disposal. Modified blends containing various additions of UFO (2 10% wt) were prepared for the TLA and TPB asphaltic binders. Results demonstrated in terms of stiffness, increasing the dosage of UFO in TLA and TPB base binders resulted in a gradual decrease in stiffness (G* value decreased). In terms of elasticity, increasing the dosage of the UFO additive in TLA resulted in a general decrease in the elasticity of the blends indicated by an increase in phase angle or phase lag (delta). Increasing dosages of the UFO additive in TPB resulted in a significant decrease in delta where the most elastic blend was at the 6% UFO level. TLA and UFO-TLA modified blends exhibited significantly lower values of delta and higher values of G* confirming the superiority of the TLA material. Incorporation of the UFO in the blends led to a decrease in the rutting resistance and increase in the fatigue cracking resistance (decrease in G*/sindelta and G*sindelta, respectively). This study highlighted the potential for the reuse of UFO as an asphalt modifier capable of producing customized UFO modified asphaltic blends for special applications and confirms its feasibility as an environmentally attractive means of reusing the waste/hazardous UFO material locally. PMID- 28353107 TI - Enhancing anti-microbial properties of wood-plastic composites produced from timber and plastic wastes. AB - Considering the resource waste and environmental burden for timber and plastic materials ending up at landfills, this study proposed upcycling wood and plastic waste into value-added wood-plastic composites (WPCs), complying with the standard requirements of flexural strength, thickness swelling, water absorption and thermal insulation. Biological deterioration is a major concern of WPCs. Bacterial survival, fungal attack and algal growth of bactericide-treated WPCs were holistically analysed. Melamine resin was adopted for impregnating anti microbial agents on the surface. All the agents showed excellent bactericidal rate (Escherichia coli), yet poly-diallyl-dimethyl-ammonium chloride (PolyDADMAC) and silver had the lowest minimum inhibitory concentrations. In terms of weight loss and strength reduction due to fungal decay (Coriolus versicolor), PolyDADMAC, silver and cetyltrimethylammonium bromide (CTAB) imparted the highest resistance on the WPCs. Moreover, PolyDADMAC and copper provided the most protection against algal growth (Chlorella vulgaris), and the former presented durable inhibitory effect. This study presents a value-added solution to wood/plastic waste recycling. PMID- 28353108 TI - Curzerene, trans-beta-elemenone, and gamma-elemene as effective larvicides against Anopheles subpictus, Aedes albopictus, and Culex tritaeniorhynchus: toxicity on non-target aquatic predators. AB - A wide number of studies dealing with mosquito control focus on toxicity screenings of whole plant essential oils, while limited efforts shed light on main molecules responsible of toxicity, as well as their mechanisms of action on non-target organisms. In this study, GC-MS shed light on main essential oil components extracted from leaves of the Suriname cherry Eugenia uniflora, i.e., curzerene (35.7%), trans-beta-elemenone (11.5%), and gamma-elemene (13.6%), testing them on Anopheles subpictus, Aedes albopictus, and Culex tritaeniorhynchus larvae. Non-target toxicity experiments were carried out on four species of aquatic larvivorous organisms, including fishes, backswimmers, and waterbugs. The essential oil from E. uniflora leaves tested on An. subpictus, Ae. Albopictus, and Cx. tritaeniorhynchus showed LC50 of 31.08, 33.50, and 36.35 MUg/ml, respectively. Curzerene, trans-beta-elemenone, and gamma-elemene were extremely toxic to An. subpictus (LC50 = 4.14, 6.13, and 10.53 MUg/ml), Ae. albopictus (LC50 = 4.57, 6.74, and 11.29 MUg/ml), and Cx. tritaeniorhynchus (LC50 = 5.01, 7.32, and 12.18 MUg/ml). The essential oil from E. uniflora leaves, curzerene, trans-beta-elemenone, and gamma-elemene showed low toxicity to larvivorous fishes, backswimmers, and waterbugs, with LC50 ranging from 303.77 to 6765.56 MUg/ml. Predator safety factor (PSF) ranged from 55.72 to 273.45. Overall, we believe that curzerene isolated from the essential oil from E. uniflora leaves can represent an ideal molecule to formulate novel mosquito larvicides, due to its extremely low LC50 on all tested mosquito vectors (4.14 5.01 MUg/ml), which far encompasses most of the botanical pesticides tested till now. Notably, the above-mentioned LC50 did not damage the four aquatic predators tested in this study. PMID- 28353109 TI - Exploring the Legionella pneumophila positivity rate in hotel water samples from Antalya, Turkey. AB - The genus Legionella is a fastidious Gram-negative bacteria widely distributed in natural waters and man made water supply systems. Legionella pneumophila is the aetiological agent of approximately 90% of reported Legionellosis cases, and serogroup 1 is the most frequent cause of infections. Legionnaires' disease is often associated with travel and continues to be a public health concern at present. The correct water management quality practices and rapid methods for analyzing Legionella species in environmental water is a key point for the prevention of Legionnaires' disease outbreaks. This study aimed to evaluate the positivity rates and serotyping of Legionella species from water samples in the region of Antalya, Turkey, which is an important tourism center. During January December 2010, a total of 1403 samples of water that were collected from various hotels (n = 56) located in Antalya were investigated for Legionella pneumophila. All samples were screened for L. pneumophila by culture method according to "ISO 11731-2" criteria. The culture positive Legionella strains were serologically identified by latex agglutination test. A total of 142 Legionella pneumophila isolates were recovered from 21 (37.5%) of 56 hotels. The total frequency of L. pneumophila isolation from water samples was found as 10.1%. Serological typing of 142 Legionella isolates by latex agglutination test revealed that strains belonging to L. pneumophila serogroups 2-14 predominated in the examined samples (85%), while strains of L. pneumophila serogroup 1 were less numerous (15%). According to our knowledge, our study with the greatest number of water samples from Turkey demonstrates that L. pneumophila serogroups 2-14 is the most common isolate. Rapid isolation of L. pneumophila from environmental water samples is essential for the investigation of travel related outbreaks and the possible resources. Further studies are needed to have epidemiological data and to determine the types of L. pneumophila isolates from Turkey. PMID- 28353111 TI - The search for an alternative to piped water and sewer systems in the Alaskan Arctic. AB - Forty-two communities in rural Alaska are considered unserved or underserved with water and sewer infrastructure. Many challenges exist to provide centralized piped water and sewer infrastructure to the homes, and they are exacerbated by decreasing capital funding. Unserved communities in rural Alaska experience higher rates of disease, supporting the recommendation that sanitation infrastructure should be provided. Organizations are pursuing alternative solutions to conventional piped water and sewer in order to maximize water use and reuse for public health. This paper reviews initiatives led by the State of Alaska, the Alaska Native Tribal Health Consortium, and the Yukon Kuskokwim Health Corporation to identify and develop potential long-term solutions appropriate and acceptable to rural communities. Future developments will likely evolve based on the lessons learned from the initiatives. Recommendations include Alaska-specific research needs, increased end-user participation in the design process, and integrated monitoring, evaluation, and information dissemination in future efforts. PMID- 28353110 TI - Heavy metal monitoring, analysis and prediction in lakes and rivers: state of the art. AB - Several research efforts have been conducted to monitor and analyze the impact of environmental factors on the heavy metal concentrations and physicochemical properties of water bodies (lakes and rivers) in different countries worldwide. This article provides a general overview of the previous works that have been completed in monitoring and analyzing heavy metals. The intention of this review is to introduce the historical studies to distinguish and understand the previous challenges faced by researchers in analyzing heavy metal accumulation. In addition, this review introduces a survey on the importance of time increment sampling (monthly and/or seasonally) to comprehend and determine the rate of change of different parameters on a monthly and seasonal basis. Furthermore, suggestions are made for future research to achieve more understandable figures on heavy metal accumulation by considering climate conditions. Thus, the intent of the current study is the provision of reliable models for predicting future heavy metal accumulation in water bodies in different climates and pollution conditions so that water management can be achieved using intelligent proactive strategies and artificial neural network (ANN) techniques. PMID- 28353112 TI - Disinfection and removal of human pathogenic bacteria in arctic waste stabilization ponds. AB - Wastewater stabilization ponds (WSPs) are commonly used to treat municipal wastewater in Arctic Canada. The biological treatment in the WSPs is strongly influenced by climatic conditions. Currently, there is limited information about the removal of fecal and pathogenic bacteria during the short cool summer treatment season. With relevance to public health, the objectives of this paper were to determine if treatment in arctic WSPs resulted in the disinfection (i.e., removal of fecal indicator bacteria, Escherichia coli) and removal of selected human bacterial pathogens from the treated effluent. The treatment performance, with focus on microbial removal, was assessed for the one-cell WSP in Pond Inlet (Nunavut [NU]) and two-cell WSP in Clyde River (NU) over three consecutive (2012 2014) summer treatment seasons (late June-early September). The WSPs provided a primary disinfection treatment of the wastewater with a 2-3 Log removal of generic indicator E. coli. The bacterial pathogens Salmonella spp., pathogenic E. coli, and Listeria monocytogenes, but not Campylobacter spp. and Helicobacter pylori, were detected in the untreated and treated wastewater, indicating that human pathogens were not reliably removed. Seasonal and annual variations in temperature significantly (p < 0.05) affected the disinfection efficiency. Improved disinfection and pathogen removal was observed for the two-cell system in Clyde River as compared to the one-cell system in Pond Inlet. A quantitative microbial risk assessment should be performed to determine if the release of low levels of human pathogens into the arctic environment poses a human health risk. PMID- 28353113 TI - Plastisphere in action: evidence for an interaction between expanded polystyrene and dunal plants. AB - Among the many threats that can be recorded on sandy beaches, plastic litter represents a serious problem for these complex and endangered ecosystems. Expanded polystyrene (EPS) is increasingly abundant as a form of plastic litter in natural environments, particularly along shores and waterways. Nevertheless, despite the great number of scientific articles concerning the impact of litter on animal species, there are still no research focusing on the interaction between this type of beach litter and other biodiversity components. In this work, we reported the first evidence of interactions between EPS and living plants along a sandy beach of Tyrrhenian central Italy. We sampled 540 EPS items, mainly deriving from fishery activities (>75%). We obtained evidence for an interaction between EPS and plants: about 5% of items resulted perforated or have roots of three species (Phragmites australis, Spartina versicolor, Anthemis maritima). Apparently, we did not observed a relationship between plants and EPS items size. More research is needed to assess if the plant assemblage growing on EPS is random or if peculiar substrate exerts some sort of selection on the plant community. PMID- 28353114 TI - Blood Biomarkers in Idiopathic Pulmonary Fibrosis. AB - PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease of unknown origin whose incidence has been increasing over the latest decade partly as a consequence of population ageing. New anti-fibrotic therapy including pirfenidone and nintedanib have now proven efficacy in slowing down the disease. Nevertheless, diagnosis and follow-up of IPF remain challenging. METHODS: This review examines the recent literature on potentially useful blood molecular and cellular biomarkers in IPF. Most of the proposed biomarkers belong to chemokines (IL-8, CCL18), proteases (MMP-1 and MMP-7), and growth factors (IGBPs) families. Circulating T cells and fibrocytes have also gained recent interest in that respect. Up to now, though several interesting candidates are profiling there has not been a single biomarker, which proved to be specific of the disease and predictive of the evolution (decline of pulmonary function test values, risk of acute exacerbation or mortality). CONCLUSION: Large scale multicentric studies are eagerly needed to confirm the utility of these biomarkers. PMID- 28353115 TI - Impact of Radiation Therapy in Surgically Resected Limited-Stage Small Cell Lung Carcinoma. AB - PURPOSE: To elucidate the role of radiation therapy (RT) in the treatment of surgically resected limited-stage small cell lung carcinoma (LSCLC). METHODS: We queried the SEER database from 1998 to 2012 to identify patients who were diagnosed with LSCLC as their only primary tumor. Kaplan-Meier analysis was utilized to determine disease-specific survival (DSS) and overall survival (OS), while multivariate analysis was used to compare survival in terms of patients and treatment characteristics. RESULTS: Eight hundred twenty-three LSCLC patients were identified for inclusion within the study. 12-month DSS for patients who did not receive surgery or RT was 31.9% (95% CI 27.7-36.3), 93.3% (95% CI 71.6-90.5) for surgery alone, and 81.0% (95% CI 69.3-88.6) for surgery + RT. 12-month OS was 27.2% (95% CI 23.4-31.1), 74.7% (95% CI 62.6-83.4), and 78.3% (95% CI 66.4-86.4) for no surgery or RT, for surgery alone, and for surgery + RT, respectively. In terms of multivariate analysis, patients receiving surgery alone and patients receiving surgery + RT had a better DSS and OS than those who received neither treatment. However, OS (HR 1.60; 95% CI 0.93-2.75, p = 0.09) and DSS (HR 1.34; 95% CI 0.72-2.51, p = 0.37) were not significantly associated with patients receiving surgery alone compared to surgery + RT. CONCLUSIONS: Surgery alone and surgery + RT were positively associated with DSS and OS compared to patients who did not receive surgery or RT. However, the addition of RT to surgery did not significantly predict DSS or OS compared to surgery alone. PMID- 28353117 TI - Continuous Cough Monitoring Using Ambient Sound Recording During Convalescence from a COPD Exacerbation. AB - PURPOSE: Cough is common in chronic obstructive pulmonary disease (COPD) and is associated with frequent exacerbations and increased mortality. Cough increases during acute exacerbations (AE-COPD), representing a possible metric of clinical deterioration. Conventional cough monitors accurately report cough counts over short time periods. We describe a novel monitoring system which we used to record cough continuously for up to 45 days during AE-COPD convalescence. METHODS: This is a longitudinal, observational study of cough monitoring in AE-COPD patients discharged from a single teaching hospital. Ambient sound was recorded from two sites in the domestic environment and analysed using novel cough classifier software. For comparison, the validated hybrid HACC/LCM cough monitoring system was used on days 1, 5, 20 and 45. Patients were asked to record symptoms daily using diaries. RESULTS: Cough monitoring data were available for 16 subjects with a total of 568 monitored days. Daily cough count fell significantly from mean +/- SEM 272.7 +/- 54.5 on day 1 to 110.9 +/- 26.3 on day 9 (p < 0.01) before plateauing. The absolute cough count detected by the continuous monitoring system was significantly lower than detected by the hybrid HACC/LCM system but normalised counts strongly correlated (r = 0.88, p < 0.01) demonstrating an ability to detect trends. Objective cough count and subjective cough scores modestly correlated (r = 0.46). CONCLUSIONS: Cough frequency declines significantly following AE-COPD and the reducing trend can be detected using continuous ambient sound recording and novel cough classifier software. Objective measurement of cough frequency has the potential to enhance our ability to monitor the clinical state in patients with COPD. PMID- 28353116 TI - Repository corticotropin for Chronic Pulmonary Sarcoidosis. AB - PURPOSE: The dose of repository corticotropin (RCI) and need for a loading dose in sarcoidosis patients receiving chronic corticosteroids are unclear. We performed a single-blind prospective study, comparing two doses of RCI in sarcoidosis. METHODS: Chronic pulmonary sarcoidosis patients receiving prednisone therapy with deterioration by 5% in FVC in the previous year were studied. RCI was administered subcutaneously at a loading dose of 80 units RCI for 10 days. Patients were randomized at day 14 to receive either 40- or 80-unit RCI twice a week. The dose of prednisone was modified by the clinician who was blinded to the patient's dosage of RCI. RESULTS: Sixteen patients completed the full 24 weeks of the study. At week 24, there was a decrease in the dose of prednisone, and improvements in DLCO, King's Sarcoidosis Questionnaire health status and fatigue score. There was no significant change in FVC % predicted. For the PET scan, there was a significant fall in the standard uptake value (SUV) of the lung lesions. Only 3/8 patients remained on 80 units RCI for full 24 weeks. There was no significant difference in the response to therapy for those treated with 40- versus 80-unit RCI. CONCLUSIONS: Repository corticotropin treatment was prednisone-sparing and associated with significant improvement in DLCO, PET scan, and patient-reported outcome measures. A dose of 40-unit RCI twice a week was as effective as 80-unit RCI and was better tolerated. PMID- 28353118 TI - Computed Tomography Findings of Bronchiectasis in Different Respiratory Phases Correlate with Pulmonary Function Test Data in Adults. AB - OBJECTIVE: To investigate bronchiectasis variations in different computed tomography (CT) respiratory phases, and their correlation with pulmonary function test (PFT) data, in adults. METHODS: Retrospective data analysis from 63 patients with bronchiectasis according to CT criteria selected from the institution database and for whom PFT data were also available. Bronchiectasis diameter was measured on inspiratory and expiratory phases. Its area and matched airway-vessel ratios in both phases were also calculated. Finally, PFT results were compared with radiological measurements. RESULTS: Bronchiectatic airways were larger on inspiration than on expiration (mean cross-sectional area, 69.44 vs. 40.84 mm2; p < 0.05) as were airway-vessel ratios (2.1 vs. 1.4; p < 0.05). Cystic bronchiectasis cases showed the least variation in cross-sectional area (48%). Mean predicted values of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were 81.5 and 77.2%, respectively, in the group in which bronchiectasis could not be identified on expiratory images, and 58.3 and 56.0%, respectively, in the other group (p < 0.05). Variation in bronchiectasis area was associated with poorer lung function (r = 0.32). CONCLUSION: Bronchiectasis detection, diameter, and area varied significantly according to CT respiratory phase, with non-reducible bronchiectasis showing greater lung function impairment. PMID- 28353119 TI - Safety and Feasibility of Pleural Cryobiopsy Compared to Forceps Biopsy During Semi-rigid Pleuroscopy. AB - BACKGROUND: Pleural biopsy is often obtained in patients with undiagnosed exudative pleural effusion during pleuroscopy. Standard forceps have been traditionally used for the biopsy. Cryoprobes are being increasingly used for transbronchial lung biopsy as they obtain larger specimens and have less crush artifact. However, the safety and feasibility of cryoprobe biopsy compared to standard forceps for pleural biopsy has not been fully assessed. OBJECTIVES: The objective of this study was to demonstrate the safety and feasibility of cryoprobe biopsy in the pleural space using semi-rigid pleuroscopy. METHODS: Patients with idiopathic exudative pleural effusions underwent pleuroscopy. The procedure was done in the endoscopy suite with full barrier precautions and moderate sedation. Pleural biopsies were initially taken with a 2.0-mm saw toothed forceps followed by a 2.4-mm cryoprobe (ERBECRYO, ERBE, US). The freeze time for each biopsy was 3 s. RESULTS: There were a total of ten patients, five males and five females. The mean age was 69 years (SD +/- 11 years). The mean number of biopsies taken from the parietal pleura using forceps was 4.5 (SD +/- 1.5) vs. 3.7 (SD +/- 1.4) using cryoprobe. The mean cumulative tissue volume with forceps biopsy was 80 cu. mm; the mean cumulative tissue volume with cryobiopsy was 320 cu. mm, p = 0.007. The diagnostic yields were similar in both the groups. There was no increased incidence of bleeding, chest wall injury, or pain using cryoprobe in any of the patients. CONCLUSION: The use of cryoprobe for parietal pleural biopsy via semi-rigid pleuroscopy was feasible and safe in this small pilot study. PMID- 28353120 TI - The Molecular Basis of Evolution and Disease: A Cold War Alliance. AB - This paper extends previous arguments against the assumption that the study of variation at the molecular level was instigated with a view to solving an internal conflict between the balance and classical schools of population genetics. It does so by focusing on the intersection of basic research in protein chemistry and the molecular approach to disease with the enactment of global health campaigns during the Cold War period. The paper connects advances in research on protein structure and function as reflected in Christian Anfinsen's The molecular basis of evolution, with a political reading of Emile Zuckerkandl and Linus Pauling's identification of molecular disease and evolution. Beyond atomic fallout, these advances constituted a rationale for the promotion of genetic surveys of human populations in the Third World, in connection with international health programs. Light is shed not only on the experimental roots of the molecular challenge but on the broader geopolitical context where the rising role of biomedicine and public health (particularly the malaria eradication campaigns) had an impact on evolutionary biology. PMID- 28353121 TI - Temperature-monitored optical treatment for radial tissue expansion. AB - Esophageal stricture occurs in 7-23% of patients with gastroesophageal reflux disease. However, the current treatments including stent therapy, balloon dilation, and bougienage involve limitations such as stent migration, formation of the new strictures, and snowplow effect. The purpose of the current study was to investigate the feasibility of structural expansion in tubular tissue ex vivo during temperature-monitored photothermal treatment with a diffusing applicator for esophageal stricture. Porcine liver was used as an ex vivo tissue sample for the current study. A glass tube was used to maintain a constant distance between the diffuser and tissue surface and to evaluate any variations in the luminal area after 10-W 1470-nm laser irradiation for potential stricture treatment. The 3D goniometer measurements confirmed roughly isotropic distribution with less than 10% deviation from the average angular intensity over 2pi (i.e., 0.86 +/- 0.09 in arbitrary unit) from the diffusing applicator. The 30-s irradiation increased the tissue temperature up to 72.5 degrees C, but due to temperature feedback, the interstitial tissue temperature became saturated at 70 degrees C (i.e., steady-state error = +/-0.4 degrees C). The irradiation times longer than 5 s presented area expansion index of 1.00 +/- 0.04, signifying that irreversible tissue denaturation permanently deformed the lumen in a circular shape and secured the equivalent luminal area to that of the glass tube. Application of a temperature feedback controller for photothermal treatment with the diffusing applicator can regulate the degree of thermal denaturation to feasibly treat esophageal stricture in a tubular tissue. PMID- 28353122 TI - Phase II study of the Multikinase inhibitor of angiogenesis, Linifanib, in patients with metastatic and refractory colorectal cancer expressing mutated KRAS. AB - Background Targeting angiogenesis in advanced colorectal cancer (CRC) has been one of the many factors prolonging survival. Bevacizumab was the first agent to demonstrate this, but even after progression on bevacizumab, continued VEGF inhibition continues to improve survival. Combining epidermal growth factor receptor monoclonal antibodies with standard frontline therapies have also improved clinical outcomes, yet the improved benefit is not observed in patients with mutant KRAS. Thus, an unmet medical need exists to develop additional therapeutic options for patients with KRAS mutant CRC. Methods Patients received the anti-angiogenic agent linifanib at the recommended phase II dose of 17.5 mg. Primary endpoint was objective response rate (ORR), with a goal of 10%. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Simon's optimal two-stage design was used to assess futility. Linifanib was considered inactive if two or fewer patients among the first 30 achieved an objective response. Results Thirty patients were enrolled on study. Grade 3 treatment-related toxicities occurring in at least two patients were fatigue, hypertension, proteinuria, diarrhea, nausea, oral pain, vomiting, thrombocytopenia, and arthralgia. Although no responses were observed, 63.5% of patients achieved stable disease. The median PFS and OS were 4.7 months and 9.5 months, respectively. Stopping rules for lack of clinical efficacy led to study closure. Conclusion Despite observing zero responses, a majority of patients had stable disease and eight patients had stable disease lasting longer than 5 months. These results suggest that linifanib has some anti-tumor activity in KRAS mutant metastatic and refractory CRC. PMID- 28353123 TI - A phase 1, open label, dose escalation study to investigate the safety, tolerability, and pharmacokinetics of MG1102 (apolipoprotein(a) Kringle V) in patients with solid tumors. AB - Purpose MG1102 is a potent inhibitor of angiogenesis in both in vitro and in vivo models. The purpose of the study was to investigate the safety and tolerability, pharmacokinetic (PK) profile, and preliminary antitumor efficacy of MG1102. Methods Patients with refractory solid tumors were eligible. Each patient received 1 dose of MG1102 followed by a 6-day rest period, during which they underwent PK assessments and safety monitoring. If the initial dose was tolerated, the patient continued with the 21-day treatment of MG1102 (5 days on, 2 days off for 3 weeks). Dose escalation was planned in 6 cohorts (6, 12, 24, 48, 96, and 192 mg/m2). Primary objectives included safety and maximum tolerated dose (MTD) assessment. Secondary objectives included assessment of PK, pharmacodynamics, and efficacy. Results A total of 16 patients were enrolled and 12 (75%) completed the study. The most common cancer type was colorectal cancer (n = 10). There was no dose limiting toxicity and the MTD was not reached at 192 mg/m2. The most frequent treatment-emergent adverse events were gastrointestinal disorders, including nausea (30.8%), abdominal pain (23.1%), constipation (23.1%), and dyspepsia (23.1%). The PK of MG1102 was slightly less than dose proportional from Cohorts 3 to 6. Among 13 response-evaluable patients, 1 unconfirmed partial response (PR) was seen (in the 48 mg/m2 cohort) and 4 patients had stable disease. Conclusions The safety profile of MG1102 was generally manageable and the toxicities resolved quickly. Potential antitumor activity was observed with 1 unconfirmed PR (60% size reduction). PMID- 28353124 TI - Nrf2: a potential therapeutic target for diabetic neuropathy. AB - Different aspects involved in pathophysiology of diabetic neuropathy are related to inflammatory and apoptotic pathways. This article summarizes evidence that Nrf2 acts as a bridging link in various inflammatory and apoptotic pathways impacting progression of diabetic neuropathy. Nrf2 is involved in expression of various antioxidant proteins (such as detoxifying enzymes) via antioxidant response element (ARE) binding site. Under normal conditions, Nrf2 is inactive and remains in the cytosol. Hyperglycemia is a strong stimulus for oxidative stress and inflammation that downregulates the activity of Nrf2 through various neuroinflammatory pathways. Acute hyperglycemia increases the expression of Nrf2, but persistent hyperglycemia decreases its expression. This downregulation of Nrf2 causes various microvascular changes, which result in diabetic neuropathy. The key contribution of Nrf2 in progression of diabetic neuropathy has been summarized in the article. Despite involvement of Nrf2 in progression of diabetic neuropathy, targeting Nrf2 activators as a therapeutic potential will provide important new insights into the ways that influence treatment of diabetic neuropathy. PMID- 28353126 TI - Preventing Adolescent Substance Use Through an Evidence-Based Program: Effects of the Italian Adaptation of Life Skills Training. AB - Evidence-based preventive interventions for adolescent substance use, violence, and mental health issues are increasingly being adapted and disseminated internationally. In the present paper, we report the results of an effectiveness study that was part of a comprehensive initiative by a coalition of health promotion organizations in the Lombardy region of Italy to select, culturally adapt, implement, evaluate, and sustain an evidence-based drug abuse prevention program developed in the USA. Findings are presented from a large-scale effectiveness study of the Life Skills Training prevention program among over 3000 students attending 55 middle schools in Italy. The prevention program taught drug refusal skills, antidrug norms, personal self-management skills, and general social skills. Relative to comparison group students, students who received the prevention program were less likely to initiate smoking at the post-test and 2 year follow-up, and less likely to initiate weekly drunkenness at the 1-year follow-up. The program had direct positive effects on several cognitive, attitudinal, and skill variables believed to play a protective role in adolescent substance use. The findings from this study show that a drug abuse prevention program originally designed for adolescents in the USA is effective in a sample of Italian youth when a rigorous and systematic approach to cultural adaptation is followed that incorporates the input of multiple stakeholders. PMID- 28353127 TI - Testicular Tissue Cryopreservation and Ethical Considerations: A Scoping Review. AB - Testicular tissue cryopreservation (TTCP) aims to preserve the future option of genetic reproduction for prepubescent cancer patients who are at risk of infertility as a result of their cancer therapies. This technology is experimental and currently only offered in the research context. As TTCP moves towards becoming more widely available, it is imperative that healthcare providers recognize the complex ethical issues surrounding this technology. This scoping review study identifies and assesses the range and depth of ethical concerns related to this testicular tissue cryopreservation technology. At present, no such scoping review of ethical concerns exists in the TTCP literature. The forty-three full-text articles included in this study yielded twenty-two different ethical considerations discussed in relation to TTCP. It was observed that these ethical considerations fit within a mainstream Principlism approach to bioethics. Accordingly, there are ethical gaps in the TTCP literature that can be identified with alternative moral lenses. In particular, it was found that ethical concerns related to context and relational aspects of identity were absent in nearly all ethical examinations of TTCP. Furthermore, only 9 per cent of articles reviewed in this study focused primarily on the ethics of TTCP, thus demonstrating a need for further in depth ethical analyses of this technology. The results of this study are important for supporting the ethical provision of TTCP and can contribute to policy and guideline development. The findings of this study demonstrate the need for greater depth and diversity in analyses of ethical considerations related to this technology. PMID- 28353125 TI - Potential drug targets and treatment of schizophrenia. AB - Schizophrenia is one of the most prevalent chronic psychiatric disorders that affect 1% of the world's population. Despite its societal burden, pathophysiology of schizophrenia remains poorly understood. Currently available drugs predominantly control positive symptoms, and often have no or poor control on negative and related cognitive symptoms, which strongly affect functional outcome in schizophrenia. The present article is an attempt to provide a critical review of recent hypothesis to understand pathophysiology of schizophrenia and to highlight exploitable molecular drug targets other than dopaminergic systems to treat and manage schizophrenia effectively. PMID- 28353128 TI - Clinical Signs and Diagnostic Tests in Acute Respiratory Infections: Correspondence. PMID- 28353129 TI - Management of Hepatoblastoma: ICMR Consensus Document. AB - Dramatic advancement has been made in the management of children with hepatoblastoma (HB) over the past 3 decades owing to the improvement in diagnostic imaging, new chemotherapeutic agents, better surgical care and availability of liver transplantation. These advances are the end results of contributions from 4 major study groups across the globe including International Society of Pediatric Oncology - Liver Tumor Strategy Group (SIOPEL), Children's Oncology Group (COG), German Pediatric Hematology Oncology Group (GPOH) and Japanese Pediatric Liver Tumor Study Group (JPLT). The current manuscript is written with the objective of developing a consensus guideline for practitioners at a National level. Based on literature and personal experience over last 3 decades, the Indian Council of Medical Research (ICMR) Expert group has made recommendations for management of children with HB in resource-challenged nations including India. PMID- 28353130 TI - Coloboma of the Optic Disc and Retina. PMID- 28353131 TI - Frequent visitors at the psychiatric emergency room - A literature review. AB - Frequent visitors at the psychiatric emergency room (PER) constitute a small subgroup of patients, yet they are responsible for a disproportionate number of visits and thus claim considerable resources. Their needs are often left unmet and their repetitive visits reflect their dissatisfaction as well as that of PERs' staff. Motivated by these dilemmas, this study systematically reviews the literature about frequent visitors at PER and seeks to answer two questions: What characterizes frequent visitors at PER in the literature? and What characterizes PER in the literature? Based on 29 studies, this paper offers answers to the two questions based on a strength weakness opportunities and threats (SWOT) analysis. The results of the review and subsequent analysis of the literature revealed the multiplicity and complexity of frequent visitors' characteristics and how they appear to converge. Commonalities were more difficult to identify in PER characteristics. In some cases, this happened because the characteristics were poorly described or were context specific. As a result, it was not easy to compare the studies on PER. Based on SWOT and the findings of the analysis, the paper proposes new venues of research and suggests how the field of mental health might develop by taking into account its opportunities and threats. PMID- 28353132 TI - Evaluation of the parameters affecting bone temperature during drilling using a three-dimensional dynamic elastoplastic finite element model. AB - A three-dimensional dynamic elastoplastic finite element model was constructed and experimentally validated and was used to investigate the parameters which influence bone temperature during drilling, including the drill speed, feeding force, drill bit diameter, and bone density. Results showed the proposed three dimensional dynamic elastoplastic finite element model can effectively simulate the temperature elevation during bone drilling. The bone temperature rise decreased with an increase in feeding force and drill speed, however, increased with the diameter of drill bit or bone density. The temperature distribution is significantly affected by the drilling duration; a lower drilling speed reduced the exposure duration, decreases the region of the thermally affected zone. The constructed model could be applied for analyzing the influence parameters during bone drilling to reduce the risk of thermal necrosis. It may provide important information for the design of drill bits and surgical drilling powers. PMID- 28353133 TI - Automatic recognition of severity level for diagnosis of diabetic retinopathy using deep visual features. AB - Diabetic retinopathy (DR) is leading cause of blindness among diabetic patients. Recognition of severity level is required by ophthalmologists to early detect and diagnose the DR. However, it is a challenging task for both medical experts and computer-aided diagnosis systems due to requiring extensive domain expert knowledge. In this article, a novel automatic recognition system for the five severity level of diabetic retinopathy (SLDR) is developed without performing any pre- and post-processing steps on retinal fundus images through learning of deep visual features (DVFs). These DVF features are extracted from each image by using color dense in scale-invariant and gradient location-orientation histogram techniques. To learn these DVF features, a semi-supervised multilayer deep learning algorithm is utilized along with a new compressed layer and fine-tuning steps. This SLDR system was evaluated and compared with state-of-the-art techniques using the measures of sensitivity (SE), specificity (SP) and area under the receiving operating curves (AUC). On 750 fundus images (150 per category), the SE of 92.18%, SP of 94.50% and AUC of 0.924 values were obtained on average. These results demonstrate that the SLDR system is appropriate for early detection of DR and provide an effective treatment for prediction type of diabetes. PMID- 28353134 TI - Ontogeny of ramified CD45 cells in chicken embryo and their contribution to bursal secretory dendritic cells. AB - Embryonic tissues contain highly ramified stellate-shaped cells expressing CD45 and MHC II antigens but their origin and immunophenotype are unknown. Using staged avian embryos and cell-type-specific antibodies, we establish a detailed spatiotemporal ontogeny of cells that express CD45, the earliest marker of hematopoietic stem cells in the chick. CD45 immunostaining marks three distinct embryonic cell populations: round, ramified and amoeboid cells. The round and ramified CD45+ cells appear first in yolk-sac blood islands before the onset of circulation. A subpopulation of round cells co-expresses the thrombocyte-specific CD51/CD61 antigen. Amoeboid cells express macrophage-specific antigens and frequently occur in regions of apoptosis. Ramified cells are distributed uniformly in the embryonic mesenchyme, colonize lymphoid and non-lymphoid organs and later express MHC II. To study the origin of CD45+ cells, 2-day-old chick embryos were ablated from the yolk sac before the establishment of circulation and incubated for 2-5 days. Large numbers of CD45+MHC II+ ramified cells differentiated in the yolk sac. Yolk-sac chimeras were generated by grafting embryos into GFP-expressing de-embryonated yolk sacs. GFP/CD45 co-expressing ramified and amoeboid cells colonized all organ primordia in the donor embryo. We also recombined GFP+ yolk sac with the bursa of Fabricius and found ramified GFP+CD45+ cells in the bursa where they differentiated into dendritic cells. Thus, CD45 cells are first present in the yolk sac during primitive hematopoiesis and then migrate from the extra-embryonic yolk sac to give rise to cells throughout all organ primordia, including dendritic cells in the bursa of Fabricius. PMID- 28353136 TI - Negative functional brain networks. AB - The anticorrelations in fMRI measurements are still not well characterized, but some new evidences point to a possible physiological role. We explored the topology of functional brain networks characterized by negative edgess and their possible alterations in schizophrenia, using functional images of 8 healthy subjects and 8 schizophrenic patients in a resting state condition. In order to minimize the insertion of artifactual negative correlations, the preprocessing of images was carried out by the CompCorr procedure, and the results compared with the Global Signal Regression (GSR) procedure. The degree distribution, the centrality, the efficiency and the rich-club behavior were used to characterize the functional brain network with negative links of healthy controls in comparison with schizophrenic patients. The results show that functional brain networks with both positive and negative values have a truncated power-law degree distribution. Moreover, although functional brain networks characterized by negative values have not small-world topology, they show a specific disassortative configuration: the more connected nodes tend to have fewer connections between them. This feature is lost using the GSR procedure. Finally, the comparison with schizophrenic patients showed a decreased (local and global) efficiency associated to a decreased connectivity among central nodes. As a conclusion, functional brain networks characterized by negative values, despite lacking a well defined topology, show specific features, different from random, and indicate an implication in the alterations associated to schizophrenia. PMID- 28353135 TI - Abnormal brain structure implicated in patients with functional dyspepsia. AB - Recent studies suggest dysfunctional brain-gut interactions are involved in the pathophysiology of functional dyspepsia (FD). However, limited studies have investigated brain structural abnormalities in FD patients. This study aimed to identify potential differences in both cortical thickness and subcortical volume in FD patients compared to healthy controls (HCs) and to explore relationships of structural abnormalities with clinical symptoms. Sixty-nine patients and forty nine HCs underwent 3T structural magnetic resonance imaging scans. Cortical thickness and subcortical volume were compared between the groups across the cortical and subcortical regions, respectively. Regression analysis was then performed to examine relationships between the structure alternations and clinical symptoms in FD patients. Our results showed that FD patients had decreased cortical thickness compared to HCs in the distributed brain regions including the dorsolateral prefrontal cortex (dlPFC), ventrolateral prefrontal cortex (vlPFC), medial prefrontal cortex (mPFC), anterior/posterior cingulate cortex (ACC/PCC), insula, superior parietal cortex (SPC), supramarginal gyrus and lingual gyrus. Significantly negative correlations were observed between the Nepean Dyspepsia Index (NDI) and cortical thickness in the mPFC, second somatosensory cortex (SII), ACC and parahippocampus (paraHIPP). And significantly negative correlations were found between disease duration and the cortical thickness in the vlPFC, first somatosensory cortex (SI) and insula in FD patients. These findings suggest that FD patients have structural abnormalities in brain regions involved in sensory perception, sensorimotor integration, pain modulation, affective and cognitive controls. The relationships between the brain structural changes and clinical symptoms indicate that the alternations may be a consequence of living with FD. PMID- 28353137 TI - High-risk Trans-Catheter Aortic Valve Replacement in a Failed Freestyle Valve with Low Coronary Height: A Case Report. AB - A 55-year-old male with a history of two prior cardiac surgeries presented with decompensated heart failure due to severe bioprosthetic aortic valve insufficiency. A third operation was viewed prohibitively high risk and valve-in valve trans-catheter aortic valve replacement was considered. There were however several high-risk features and technically challenging aspects including low coronary ostia height, poor visualization of the aortic sinuses, and difficulty in identification of the coplanar view due to severe aortic insufficiency, and a highly mobile aortic valve mass. After meticulous peri-procedural planning, trans catheter aortic valve replacement was carried out with a SAPIEN 3 balloon expandable valve without any complication. Strategies undertaken to navigate the technically challenging aspects of the case are discussed. PMID- 28353138 TI - Effects of the Oral Administration of K2Cr2O7 and Na2SeO3 on Ca, Mg, Mn, Fe, Cu, and Zn Contents in the Heart, Liver, Spleen, and Kidney of Chickens. AB - This study aimed to investigate the effects of selenium on the ion profiles in the heart, liver, spleen, and kidney through the oral administration of hexavalent chromium. Approximately 22.14 mg/kg b.w. K2Cr2O7 was added to water to establish a chronic poisoning model. Different selenium levels (0.00, 0.31, 0.63, 1.25, 2.50, and 5.00 mg Na2SeO3/kg b.w.) around the safe dose were administered to the experimental group model. Ca, Mg, Mn, Fe, Cu, and Zn were detected in the organs through flame atomic absorption spectrometry after these organs were exposed to K2Cr2O7 and Na2SeO3 for 14, 28, and 42 days. Results showed that these elements exhibited various changes. Ca contents declined in the heart, liver, and spleen. Ca contents also decreased on the 28th day and increased on the 42nd day in the kidney. Mn contents declined in the heart and spleen but increased in the kidney. Mn contents also decreased on the 28th day and increased on the 42nd day in the liver. Cu contents declined in the heart and spleen. Cu contents increased on the 28th day and decreased on the 42nd day in the liver and kidney. Zn contents declined in the heart and spleen. Zn contents increased on the 28th day and decreased on the 42nd day in the liver and kidney. Fe contents decreased in the heart and liver. Fe contents increased on the 28th day and decreased on the 42nd day in the spleen and kidney. Mg contents did not significantly change in these organs. Appropriate selenium contents enhanced Mn and Zn contents, which were declined by chromium. Conversely, appropriate selenium contents reduced Ca, Fe, and Cu contents, which were increased by chromium. In conclusion, the exposure of chickens to K2Cr2O7 induced changes in different trace elements, and Na2SeO3 supplementation could alleviate this condition. PMID- 28353139 TI - Bioaccumulation of Heavy Metals in Various Tissues of Some Fish Species and Green Tiger Shrimp (Penaeus semisulcatus) from Iskenderun Bay, Turkey, and Risk Assessment for Human Health. AB - In this study, concentrations of heavy metals were determined by ICP-MS in the edible tissues of common sole (Solea solea Linnaeus, 1758), whiting (Merlangius merlangus Linnaeus, 1758), silver sillago (Sillago sihama Forsskal, 1775) and muscle-exoskeleton of green tiger shrimp (Penaeus semisulcatus De Haan, 1844), from the seas of Iskenderun Bay, Eastern Mediterranean, Turkey, in January February, 2016. The lowest and highest mean concentrations of Mn, Cr, Cd, Ni, Hg, As, Pb, and Co in fish and shrimp' muscles were found, respectively, as follows: 0.166-0.382, 0.134-0.336, 0.005-0.008, 0.091-0.140, 0.026-0.228, 1.741-29.254, 0.087-0.110, and <0.0005-0.027 mg kg-1; in the skin and exoskeleton, the values were found, respectively, as 0.103-15.819, 0.301-0.778, 0.007-0.026, 0.115-0.513, 0.021-0.243, 1.548-17.930, 0.148-0.295, and <0.0005-0.140 mg kg-1. According to the results, mean concentrations of all metals in the muscles of fish, except for arsenic and chromium, were found to be below certain legal limit values, especially arsenic levels in shrimp that were found to be above all the legal limit values. Also, the hazard quotients (HQ) of individual heavy metals in fish and shrimp, except for As, revealed safe levels for human consumption. However, the HQ values of estimated inorganic As exceeded 1 in the muscles of shrimp (P. semisulcatus), which may constitute a risk to public health. PMID- 28353141 TI - A Focused Systematic Review of Pharmacological Treatment for Borderline Personality Disorder. AB - BACKGROUND: Medicines are routinely prescribed to treat borderline personality disorder (BPD) despite a relative lack of high-quality evidence and in breach of some treatment guidelines. An earlier Cochrane review of pharmacotherapy in BPD underlined the lack of evidence, encouraged the replication of earlier studies, but also emphasised the pressing need for more randomised placebo-controlled trials, and for those studies to employ broadened inclusion criteria. METHOD: The authors searched bibliographic databases, reference lists of articles and trials registers. Records were screened to identify those that met the inclusion criteria. Full-text articles were screened and assessed for eligibility. On-going trials of pharmacotherapy in BPD were also identified. RESULTS: Fifteen new studies of pharmacotherapy for BPD were identified since the earlier review. Eight of those examined second generation antipsychotics, two investigated mood stabilisers, three investigated antidepressants and two studied the effectiveness of opioid antagonists. Results for the effectiveness of antipsychotics appeared to be mixed. There has been little recent evidence to support the use of mood stabilisers. There is a lack of new placebo-controlled, randomised controlled trials investigating antidepressants and limited new evidence to support the use of opioid antagonists. CONCLUSIONS: The review revealed that there remains a dearth of high-quality research evidence to help patients, carers and clinicians make sound and safe evidence-based decisions about medicines to treat BPD. PMID- 28353140 TI - Antimicrobial Use in Patients with Dementia: Current Concerns and Future Recommendations. AB - Infections are common in people with dementia, and antibiotic use is widespread, albeit highly variable, across healthcare settings and countries. The few studies conducted to date that consider the appropriateness of antibiotic prescribing specifically for people with dementia focus on people with advanced dementia and suggest that much of the prescribing of antibiotics for these patients may be potentially inappropriate. We suggest that clinicians must consider a number of factors to determine appropriateness of antimicrobial prescribing for people with dementia, including the risks and benefits of assessing and treating infections, the uncertainty regarding the effects of antibiotics on patient comfort, goals of care and treatment preferences, hydration status, dementia severity and patient prognosis. Future research should examine antibiotic prescribing and its appropriateness across the spectrum of common infections, dementia severities, care settings and countries, and should consider how antibiotic therapy should be considered in discussions regarding treatment preferences, goals of care and/or advance care planning between clinicians, patients and families. PMID- 28353142 TI - Analysis of Species-Selectivity of Human, Mouse and Rat Cytochrome P450 1A and 2B Subfamily Enzymes using Molecular Modeling, Docking and Dynamics Simulations. AB - Cytochrome P450 (CYP) 1A and 2B subfamily enzymes are important drug metabolizing enzymes, and are highly conserved across species in terms of sequence homology. However, there are major to minor structural and macromolecular differences which provide for species-selectivity and substrate-selectivity. Therefore, species selectivity of CYP1A and CYP2B subfamily proteins across human, mouse and rat was analyzed using molecular modeling, docking and dynamics simulations when the chiral molecules quinine and quinidine were used as ligands. The three dimensional structures of 17 proteins belonging to CYP1A and CYP2B subfamilies of mouse and rat were predicted by adopting homology modeling using the available structures of human CYP1A and CYP2B proteins as templates. Molecular docking and dynamics simulations of quinine and quinidine with CYP1A subfamily proteins revealed the existence of species-selectivity across the three species. On the other hand, in the case of CYP2B subfamily proteins, no role for chirality of quinine and quinidine in forming complexes with CYP2B subfamily proteins of the three species was indicated. Our findings reveal the roles of active site amino acid residues of CYP1A and CYP2B subfamily proteins and provide insights into species-selectivity of these enzymes across human, mouse, and rat. PMID- 28353143 TI - Cervical disc replacement surgery: biomechanical properties, postoperative motion, and postoperative activity levels. AB - PURPOSE OF REVIEW: Cervical disc arthroplasty (CDA) is an evolving technique used in the treatment of cervical disc disease. To remain up to date on studies regarding its efficacy, we sought to answer three questions: What do biomechanical studies demonstrate in regard to the kinematics of CDA? How does CDA affect cervical motion? What are the postoperative activity levels of patients after cervical disc arthroplasty? RECENT FINDINGS: 1) In regard to biomechanics, recent data suggests that CDA maintains motion while possibly altering facet biomechanics. 2) Radiographic data indicates a reliable maintenance of motion in the short and medium term. 3) Postoperative activity levels are assessed with clinical outcome data which demonstrate reliable improvement in pain and function. The data reviewed here establishes CDA as an efficacious treatment in the relief of symptoms from CDD. It is important to note however that an evaluation of CDA would benefit from more robust data, specifically in regards to long-term clinical outcomes. PMID- 28353145 TI - MAPK/ERK signalling is required for zebrafish cardiac regeneration. AB - OBJECTIVES: To better understand the molecular mechanisms of regeneration and explore the potential signalling pathways as therapeutic targets for heart attacks. RESULTS: After treatment with the MEK inhibitor AZD6244 upon cardiac injury, the core members in MAPK/ERK signalling-mek and erk-demonstrate elevated expression, and these proteins are deposited at the injury site in zebrafish. pERK is also induced in non-cardiomyocytes near the injury site. Furthermore, the induced expression of a dominant-negative form of MEK1 inhibits zebrafish cardiac regeneration, characterized by increased cardiac fibrosis (a hallmark of regenerative failure), reduced or delayed production of regenerative myocardium, and migration of FLI1+ endothelial cells, without direct inhibition of cardiomyocyte proliferation. CONCLUSION: Appropriate activation of MAPK/ERK signalling is essential for zebrafish cardiac regeneration. PMID- 28353144 TI - Comparing the Administration of Letrozole and Megestrol Acetate in the Treatment of Women with Simple Endometrial Hyperplasia without Atypia: A Randomized Clinical Trial. AB - INTRODUCTION: The present study was conducted as a pilot to compare the therapeutic effects and the potential side effects of oral Megestrol acetate and Letrozole in the treatment of simple hyperplasia in perimenopausal women. METHODS: The participants of this randomized clinical trial consisted of two groups of 25 women aged 44-50 presenting with abnormal uterine bleeding diagnosed with simple endometrial hyperplasia without cytologic atypia confirmed by transvaginal ultrasonography and biopsy. The first group received 40-mg doses of Megestrol acetate for 2 weeks per month for a total period of 2 months. The second group received 2.5-mg daily doses of Letrozole for a total period of 2 months. The differences in terms of quantitative measurements were analyzed using the independent two-sample t test and the paired t test. To compare the two groups in terms of the distribution of the categorical variables, Pearson's Chi square and Fisher's Exact tests were used at the significance level of 0.05 by Stata-9.2. RESULTS: Although the intervention led to significant improvements in both groups (P < .001), there was no difference between the groups in terms of accomplishing resolution (P = .74) [seven (28%) patients in the Letrozole group and five (20%) in the Megestrol group], while two patients in the Letrozole group and nine in the Megestrol group suffered from side effects, suggesting significantly lower side effects in the Letrozole group (P = .02). CONCLUSION: Letrozole and Megestrol acetate seem to have similar effects on the treatment of simple endometrial hyperplasia, the only difference being that Letrozole presents fewer side effects than Megestrol acetate in patients with this condition. FUNDING: Abnormal Uterine Bleeding Research Center of Semnan University of Medical Sciences, Semnan, Iran. TRIAL REGISTRATION: IRCT2015031011504N5. PMID- 28353146 TI - The lacrimal gland: development, wound repair and regeneration. AB - The lacrimal gland (LG) is important as it has a significant role in maintaining the stability of the microenvironment of the ocular surface. When a loss of function occurs in the LG, a significant reduction in tear production and dry eye disease (DED) may occur. A mammalian LG is a secretory gland consisting of acini and ducts. The interaction between epithelial cells and mesenchymal cells plays a major role during development and the self-restoration process of the gland. Some factors, such as fibroblast growth factor 10 and bone morphogenetic protein 7, are associated with these processes. Though several strategies for LG regeneration have been established, there is still a long way to go before there is clarity about LG stem cells. In this review, current knowledge on LG development, LG self-repair, DED and correlative regeneration therapies are summarized. PMID- 28353147 TI - Bioconversion of lutein by Enterobacter hormaechei to form a new compound, 8 methyl-alpha-ionone. AB - OBJECTIVES: To investigate the final product of the bioconversion of lutein by a novel lutein-degrading bacterium, Enterobacter hormaechei A20, and the kinetics of the process. RESULTS: A new product, 8-methyl-alpha-ionone, was resolved by GC MS. The compound was further identified by NMR. A conversion yield of 90% was achieved by E. hormaechei in 36 h with 10 g lutein l-1. CONCLUSIONS: This is the first report of the bioconversion of lutein to form 8-methyl-alpha-ionone. A degradation pathway is proposed. PMID- 28353148 TI - Molecular and biochemical characterization of squalene synthase from Siraitia grosvenorii. AB - OBJECTIVES: To clone and characterize the squalene synthase from Siraitia grosvenorii (SgSQS). RESULTS: The gene encoding SgSQS was cloned. SgSQS has 417 amino acid residues with an pI of 7.3. There are 32 phosphorylation sites in its sequence: S48 as well as S196 play important roles in regulation of enzyme activity. The enzyme is a monomeric protein with a cave-like active center formed by alpha helixes and has two transmembrane domains at its C-terminus. SgSQS mRNA expression in stem and root were about twice as much as that in leaf and peel. Full-length SgSQS with measurable catalytic activity was expressed in Escherichia coli. SgSQS activity was optimal at 37 degrees C and pH 7.5 respectively. CONCLUSION: SgSQS gene was cloned, and the molecular structure and biochemical function of SgSQS were characterized. PMID- 28353149 TI - Toxicity of an Annonin-Based Commercial Bioinsecticide Against Three Primary Pest Species of Stored Products. AB - The effects of a bioinsecticide formulation based on extract of Annona squamosa L. (Annonaceae) containing 10,000 mg L-1 of acetogenin annonin as the main active ingredient were investigated against three primary pest species of stored grains in Brazil [maize weevil Sitophilus zeamais Motschulsky (Coleoptera: Curculionidae), Mexican bean weevil Zabrotes subfasciatus (Boheman) (Coleoptera: Chrysomelidae: Bruchinae), and cowpea weevil Callosobruchus maculatus (Fabricius) (Coleoptera: Chrysomelidae: Bruchinae)] by means of residual contact bioassays. In a concentration-dependent manner, the annonin-based commercial bioinsecticide caused significant adult mortality of C. maculatus (LC50 = 6890 MUL kg-1), S. zeamais (LC50 = 2781 MUL kg-1), and Z. subfasciatus (LC50 = 2120 MUL kg-1) after 120 h of residual contact exposure. In addition to acute toxicity, the tested bioinsecticide also promoted a significant reduction of the number of eggs laid by females of C. maculatus (EC50 = 5949.7 MUL kg-1) and Z. subfasciatus (EC50 = 552.7 MUL kg-1). Moreover, the bioinsecticide significantly reduced the number of emerged insects (F1 generation) of C. maculatus (EC50 = 2763.0 MUL kg-1), S. zeamais (EC50 = 1380.8 MUL kg-1), and Z. subfasciatus (EC50 = 561.5 MUL kg-1). The bioinsecticide also reduced the percentage of damaged grains for the three pest species studied, and its grain-protectant properties are comparable to or superior in efficacy in relation to a diatomaceous earth-based insecticide (Insecto(r) at 1000 mg kg-1) used as a positive control. Thus, this standardized formulation has promising bioactivity against stored insect species and can be a useful component for IPM of stored grains in Brazil and elsewhere. PMID- 28353150 TI - Gene methylation parallelisms between peripheral blood cells and oral mucosa samples in relation to overweight. AB - Epigenetics has an important role in the regulation of metabolic adaptation to environmental modifications. In this sense, the determination of epigenetic changes in non-invasive samples during the development of metabolic diseases could play an important role in the procedures in primary healthcare practice. To help translate the knowledge of epigenetics to public health practice, the present study aims to explore the parallelism of methylation levels between white blood cells and buccal samples in relation to obesity and associated disorders. Blood and buccal swap samples were collected from a subsample of the Spanish cohort of the Food4Me study. Infinium HumanMethylation450 DNA Analysis was carried out for the determination of methylation levels. Standard deviation for beta values method and concordance correlation analysis were used to select those CpG which showed best parallelism between samples. A total of 277 CpGs met the criteria and were selected for an enrichment analysis and a correlation analysis with anthropometrical and clinical parameters. From those selected CpGs, four presented high associations with BMI (cg01055691 in GAP43; r = -0.92 and rho = 0.84 for blood; r = -0.89 and rho = -0.83 for buccal sample), HOMA-IR (cg00095677 in ATP2A3; r = 0.82 and rho = -0.84 for blood; r = -0.8 and rho = -0.83 for buccal sample) and leptin (cg14464133 in ADARB2; r = -0.9182 and rho = -0.94 for blood; r = -0.893 and rho = -0.79 for buccal sample). These findings demonstrate the potential application of non-invasive buccal samples in the identification of surrogate epigenetic biomarkers and identify methylation sites in GAP43, ATP2A3 and ADARB2 genes as potential targets in relation to overweight management and insulin sensibility. PMID- 28353151 TI - The Use of Brain Stimulation in Dysphagia Management. AB - Dysphagia is common sequela of brain injury with as many as 50% of patients suffering from dysphagia following stroke. Currently, the majority of guidelines for clinical practice in the management of dysphagia focus on the prevention of complications while any natural recovery takes place. Recently, however, non invasive brain stimulation (NIBS) techniques like transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) have started to attract attention and are applied to investigate both the physiology of swallowing and influences on dysphagia. TMS allows for painless stimulation of the brain through an intact skull-an effect which would normally be impossible with electrical currents due to the high resistance of the skull. By comparison, tDCS involves passing a small electric current (usually under 2 mA) produced by a current generator over the scalp and cranium external to the brain. Initial studies used these techniques to better understand the physiological mechanisms of swallowing in healthy subjects. More recently, a number of studies have investigated the efficacy of these techniques in the management of neurogenic dysphagia with mixed results. Controversy still exists as to which site, strength and duration of stimulation yields the greatest improvement in dysphagia. And while multiple studies have suggested promising effects of NIBS, more randomised control trials with larger sample sizes are needed to investigate the short- and long-term effects of NIBS in neurogenic dysphagia. PMID- 28353152 TI - The effect of epigenetic modifications on the secondary structures and possible binding positions of the N-terminal tail of histone H3 in the nucleosome: a computational study. AB - The roles of histone tails as substrates for reversible chemical modifications and dynamic cognate surfaces for the binding of regulatory proteins are well established. Despite these crucial roles, experimentally derived knowledge of the structure and possible binding sites of histone tails in chromatin is limited. In this study, we utilized molecular dynamics of isolated histone H3 N-terminal peptides to investigate its structure as a function of post-translational modifications that are known to be associated with defined chromatin states. We observed a structural preference for alpha-helices in isoforms associated with an inactive chromatin state, while isoforms associated with active chromatin states lacked alpha-helical content. The physicochemical effect of the post translational modifications was highlighted by the interaction of arginine side chains with the phosphorylated serine residues in the inactive isoform. We also showed that the isoforms exhibit different tail lengths, and, using molecular docking of the first 15 N-terminal residues of an H3 isoform, identified potential binding sites between the superhelical gyres on the octamer surface, close to the site of DNA entry/exit in the nucleosome. We discuss the possible functional role of the binding of the H3 tail within the nucleosome on both nucleosome and chromatin structure and stability. PMID- 28353153 TI - Good tolerability of high dose colistin-based therapy in patients with haematological malignancies. AB - PURPOSE: Colistin is usually the only drug fully active against multi-drug resistant Gram-negative bacteria, but its nephrotoxicity might limit its use. Recent pharmacokinetic/pharmacodynamic data suggest that high dose of colistin, preceded by a loading dose, are needed to maximize its antibacterial effect. The aim of this study was to determine the safety of high doses colistin, in haematology population. METHODS: A retrospective review of haematology patients who received high dose colistin-based therapy in years 2011-2016 was performed. Nephrotoxicity was assessed using RIFLE criteria. RESULTS: Thirty patients who received 38 courses of colistin were included in the study. Colistin was always administered together with other antibiotics. Colistin was well tolerated, with one case of neurological toxicity and one of cutaneous reaction. There were 22 (58%) treatment cycles without any nephrotoxicity, even though during 16 of these cycles other nephrotoxic drugs were administered. Severe (injury or failure) renal toxicity occurred during 6 (16%) treatment courses, requiring colistin discontinuation in 2 patients and colistin dose reduction in 1. Poorer renal function at baseline and younger age were the only variables associated with increased renal toxicity (p = 0.011 and p = 0.031, respectively). Overall mortality was 18% (7/38) and 29% (11/38) at 7 and 30 days after the treatment onset. CONCLUSIONS: In adult haematology population, high dose colistin therapy is safe and efficacious, despite high frequency of concomitant nephrotoxic treatment. PMID- 28353154 TI - Physiome approach for the analysis of vascular flow reserve in the heart and brain. AB - This work reviews the key aspects of coronary and neurovascular flow reserves with an emphasis on physiomic modeling characteristics by the use of a variety of numerical approaches. First, we explain the definition of fractional flow reserve (FFR) in coronary artery and introduce its clinical significance. Then, computational researches for obtaining FFR are reviewed, and their clinical outcomes are compared. In the case of cerebrovascular reserve (CVR), in spite of substantial progress in the simulation of cerebral hemodynamics, only a few computational studies exist. Thus, we discuss the limitations of CVR simulation study and suggest the challenging issue to overcome these. Also, the future direction of physiomic researches for the flow reserves in coronary arteries and cerebral arteries is described. Also, we introduce a machine learning algorithm trained by the existing physiomic simulation data of flow reserve and suggest a prospective research direction related to this. PMID- 28353155 TI - Occurrence of Potential Adverse Drug Events from Prescribing Errors in a Pediatric Intensive and High Dependency Unit in Hong Kong: An Observational Study. AB - BACKGROUND: Critically ill pediatric patients are considered at high risk for medication errors. Although much research focuses on the actual errors, equally important are medication errors that, although intercepted, carried the potential for an adverse drug event. The aim of this study was to determine the occurrence of prescribing errors and potential adverse drug events (pADEs) in a local pediatric intensive and critical care unit (PICU) in Hong Kong. Our secondary objective was to determine the type of error, nature of medication involved and the time of error occurrence. METHODS: We conducted a prospective observational chart review among patients in a pediatric intensive and high dependency unit between January 16, 2015 and April 20, 2015. Medical charts for each patient were reviewed for the occurrence of a prescribing error or pADE. Each pADE was assessed for the type of error, the classification of agent involved, clinical severity of the error, and the time the error occurred. RESULTS: Forty-one patients with a mean age of 3.2 years were included in our study. Of these patients, 19 (46.3%) experienced at least one pADE. We identified 131 pADEs, 129 of which were prescribing errors conferring a rate of 6.8 errors per affected patient or 3.1 errors per patient admitted to the PICU. The most common error found in the study was incorrect dose calculation (48.1%), with intravenous fluids (41.7%), cardiovascular agents (15.0%), and anti-infectives (12.5%) the most common agents involved with an error. The majority of the pADEs in our study were either clinically serious (33.1%) or significant (44.9%) in nature. Nearly one in every four errors required monitoring and/or intervention to prevent harm, and almost all (96.9%) of the prescribing errors were intercepted before reaching the patient. CONCLUSION: This study highlights incorrect dose calculation as the most common prescribing error in a pediatric critical care setting. Intravenous fluids, cardiovascular agents, and anti-infectives were the classes of medication most commonly involved with a pADE. Due to the high-risk nature of medications used and the critical condition of these patients, more than three-quarters of pADEs were considered to be clinically serious or significant in causing patient harm. PMID- 28353157 TI - Spontaneously Reported Adverse Reactions for Herbal Medicinal Products and Natural Remedies in Sweden 2007-15: Report from the Medical Products Agency. AB - BACKGROUND: In relation to the extensive use of herbal medicinal products in self care, the safety information is limited and there is a need for improvement. This study describes spontaneously reported adverse reactions related to herbal medicinal products and natural remedies in Sweden. OBJECTIVES: To evaluate the characteristics and frequency of adverse events recorded by the Swedish Medical Products Agency, where herbal medicinal products and natural remedies were suspected as causative agents. METHODS: Adverse drug reactions reported to the Swedish Medical Product Agency during 2007-15 related to approved herbal medicinal products or natural remedies were included and analysed in the retrospective study. Reports had been assessed for causality when they were lodged and only reports that had been assessed as at least possible were included in the study. RESULTS: In total, 116 reports (concerning 259 adverse reactions) related to herbal medicinal products or natural remedies were found in the Swedish national pharmacovigilance database. The active ingredients most frequently suspected during the study period were black cohosh rhizome (15 reports), purple coneflower herb (14 reports) and a combination of extracts of pollen (13 reports). Adverse reactions related to skin and subcutaneous tissue were the most commonly reported reactions. CONCLUSIONS: No previously unknown safety problems have been discovered in the present study. This finding could be explained by a thorough pre-approval assessment of medicinal products and the fact that most herbal preparations in medicinal products have been in clinical use for many years (for traditional herbal medicinal products, the requirements are >=30 years), i.e. adverse reactions are acknowledged and assessed before approval. PMID- 28353158 TI - Pretreatment methods of lignocellulosic biomass for anaerobic digestion. AB - Agricultural residues, such as lignocellulosic materials (LM), are the most attractive renewable bioenergy sources and are abundantly found in nature. Anaerobic digestion has been extensively studied for the effective utilization of LM for biogas production. Experimental investigation of physiochemical changes that occur during pretreatment is needed for developing mechanistic and effective models that can be employed for the rational design of pretreatment processes. Various-cutting edge pretreatment technologies (physical, chemical and biological) are being tested on the pilot scale. These different pretreatment methods are widely described in this paper, among them, microaerobic pretreatment (MP) has gained attention as a potential pretreatment method for the degradation of LM, which just requires a limited amount of oxygen (or air) supplied directly during the pretreatment step. MP involves microbial communities under mild conditions (temperature and pressure), uses fewer enzymes and less energy for methane production, and is probably the most promising and environmentally friendly technique in the long run. Moreover, it is technically and economically feasible to use microorganisms instead of expensive chemicals, biological enzymes or mechanical equipment. The information provided in this paper, will endow readers with the background knowledge necessary for finding a promising solution to methane production. PMID- 28353156 TI - Restless legs syndrome in maintenance hemodialysis patients: an epidemiologic survey in Hefei. AB - OBJECTIVE: To investigate the prevalence of restless legs syndrome (RLS) in maintenance hemodialysis (MHD) patients and its possible influencing factors. METHODS: MHD patients were consecutively enrolled from five hemodialysis centers in Hefei. Clinical, demographics, and laboratory data were recorded from December 2013 to March 2014. RLS diagnosis scale, Zung Self-Rating Depression Scale (SDS), Zung Self-Rating Anxiety Scale (SAS), Pittsburgh Sleep Quality Index (PSQI), and kidney disease and quality of life (KDQOLTM-36) were used for analysis. RESULTS: A total of 269 MHD patients (81 women, 188 men) were enrolled, among which 39 patients were diagnosed as RLS. The median duration of dialysis therapy was 33 months and the prevalence of RLS was 14.5%. Compared with RLS-negative patients, RLS-positive patients had lower hemoglobin level (98.67 +/- 13.50 vs 106.34 +/- 17.75, P = 0.011) and higher alkaline phosphatase concentration [131.0 (98.0, 226.0) vs 94.0 (69.8, 157.5), P = 0.001]. The multivariate logistic regression showed that high hemoglobin level (OR 0.975, 95% CI 0.956-0.995, P = 0.015) was a protective factor for RLS, while high alkaline phosphatase (OR 1.003, 95% CI 1.001-1.005, P = 0.018) was an independent risk factor for RLS. RLS patients had significantly higher PSQI scores (P < 0.001), reduced subjective sleep quality (P < 0.001), increased sleep latency (P < 0.007), shorter sleep duration (P < 0.001), lower sleep efficiency (P = 0.001), higher sleep disturbances (P < 0.001), and increased daytime dysfunction (P = 0.019). CONCLUSION: Our findings demonstrated that the prevalence of RLS was 14.5% in Hefei. High hemoglobin level was a protective factor for RLS, and high alkaline phosphatase was an independent risk factor. RLS affects many aspects of quality of life and sleep quality, which may contribute to the presence of depression and anxiety. PMID- 28353159 TI - A case of successful transluminal drainage of walled-off necrosis under contrast enhanced harmonic endoscopic ultrasonography guidance. AB - We report a case of successful transluminal drainage of walled-off necrosis (WON) under contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) guidance. Recently, EUS-guided transluminal drainage (EUS-TD) of WON has been increasingly used as a minimally invasive treatment option with reportedly high technical and clinical success rates; however, B-mode EUS occasionally fails to depict the target lesion and its margins, particularly in cases where the target shows a heterogeneous echogenicity. In our case, EUS-TD was attempted for infected WON, but visualization using B-mode EUS imaging was poor. Thus, CH-EUS was performed to enhance the contrast between the targeted WON and its surrounding tissues. Immediately after injecting a sonographic contrast agent, WON and its margins were clearly identified as an avascular area and were punctured under CH-EUS guidance. CH-EUS enables the assessment of the microvasculature and hemodynamics of the target lesion in real time. It may also provide valuable information and could be a useful modality for EUS-TD to clearly visualize target lesions and their margins and to decisively puncture them, even when they could not be identified using B-mode EUS. PMID- 28353162 TI - Living Donor Liver Transplantation for Hepatocellular Carcinoma with Bile Duct Tumor Thrombi. PMID- 28353160 TI - Evolutionary consequences of historical metal contamination for natural populations of Chironomus riparius (Diptera: Chironomidae). AB - Populations inhabiting metal-impacted freshwater systems located nearby industrial and urban areas may be under intense selection. The present study aims to address two fundamental microevolutionary aspects of metal contamination in the midge Chironomus riparius (Meigen): Are populations inhabiting historically metal contaminated sites genetically adapted to metals? And, are populations from these sites genetically eroded? To answer these questions, C. riparius populations were sampled from three sites with well-known histories of metal contamination and three nearby-located references. Genetic adaptation to metals was investigated through acute and chronic exposures to cadmium (Cd), after rearing all populations for at least six generations under laboratory clean conditions. Genetic diversity was estimated based on the allelic variation of seven microsatellite markers. Results showed higher acute tolerance to Cd in populations originating from metal contaminated sites compared to their respective references and significant differences in two out of three pairwise comparisons. However, there was a mismatch between acute and chronic tolerance to Cd with results of the partial life-cycle tests suggesting fitness costs under control clean conditions in two metal-adapted populations. Despite no evidences of genetic erosion in populations sampled from metal contaminated sites, our results suggest genetically inherited tolerance to Cd in populations inhabiting historically contaminated sites. These findings lend support to the use of C. riparius as a model organism in evolutionary toxicology and highlight the importance of coupling measures of neutral genetic diversity with assessments of chemical tolerance of populations for a better understanding of contaminant induced adaptation and evolutionary processes. PMID- 28353161 TI - Thyroid hormone related gene transcription in southern sand flathead (Platycephalus bassensis) is associated with environmental mercury and arsenic exposure. AB - Arsenic (As) and mercury (Hg) are ubiquitous elements known to disrupt thyroid function in vertebrates. To explore the underlying mechanisms of Hg and As on the fish thyroid system, we investigated the associations between muscle concentrations of Hg and As with thyroid-related gene transcription in flathead (Platycephalus bassensis) from a contaminated estuary. We sampled fish at several sites to determine the hepatic expression of genes including deiodinases (D1 and D2), transthyretin (TTR), thyroid hormone receptors (TRalpha and TRbeta) and related them to Hg and As levels in the same individuals. Negative correlations were observed between Hg levels and D2, TTR, TRalpha and TRbeta, whereas positive associations were found between As concentrations and TTR and TRbeta. These results suggest that Hg and As exposures from environmental pollution affect the regulation of genes important for normal thyroid function in fish. These thyroid related genes could be used as biomarkers for monitoring environmental thyroid hormone disrupting chemicals. PMID- 28353163 TI - Expression of S100A2 and S100P in human eccrine sweat glands and their application in differentiating secretory coil-like from duct-like structures in the 3D reconstituted eccrine sweat spheroids. AB - Secretory coils and ducts are two components of eccrine sweat glands with different structures and functions. In our previous study, we combined keratins and alpha-SMA to distinguish between secretory coils and ducts. However, the key deficiency of the method was that none of the antibodies used was specific for ducts. In this study, we first examined the co-localization of K5/K7, alpha SMA/K14, K7/S100P and alpha-SMA/S100A2 by double-immunofluorescence staining to confirm the localization of S100P and S100A2 in native human eccrine sweat glands, and second we identified secretory coil-like and duct-like structures in the 3D reconstituted eccrine sweat gland spheroids by double-immunofluorescence staining for K7/S100P and alpha-SMA/S100A2. In native human eccrine sweat glands, S100A2 immunoreactivity was confined to the outer layer and S100P to the inner layer of the duct. In 12-week Matrigel plugs containing eccrine sweat gland cells, double-immunofluorescence staining for K7/S100P and alpha-SMA/S100A2 could easily distinguish duct-like structures from secretory coil-like structures. We conclude that S100A2 and S100P can be used as specific duct markers in eccrine sweat glands, and combined use of S100P or S100A2 with keratins enables easy to distinction between secretory coils and ducts. PMID- 28353164 TI - Preference of Genetic Diagnosis of CXCR4 Mutation Compared with Clinical Diagnosis of WHIM Syndrome. PMID- 28353165 TI - Poikiloderma with Neutropenia in Morocco: a Report of Four Cases. AB - PURPOSE: Poikiloderma with Neutropenia (PN) is inherited genodermatosis which results from a biallelic mutation in the USB1 gene (U Six Biogenesis 1). PN, first described in Navajo Native Americans, is characterized by early onset poikiloderma, pachyonychia, palmo-plantar hyperkeratosis, and permanent neutropenia. This condition results in frequent respiratory tract infections during infancy and childhood. From 2011 to 2013, four cases of PN were diagnosed in Morocco. In this paper, we report the first four cases of PN diagnosed in Morocco, out of three unrelated consanguinous families. METHODS: We investigated the genetic, immunological, and clinical features of four Moroccan patients with PN from three unrelated consanguinous families. RESULTS: Mean age at onset was 3 months and mean age at diagnosis was 7.5 years. The diagnosis of these PN patients was made based on clinical features and confirmed by molecular analysis for three cases. We identified two undescribed homozygous mutations in the USB1 gene: c.609 + 1G>A in two siblings and c.518 T>G(p.(Leu173Arg)) in the other case. CONCLUSION: This report confirms the clinical and genetic identity of Poikiloderma with Neutropenia syndrome. PMID- 28353170 TI - Impact of Guidance on the Prescription Patterns of G-CSFs for the Prevention of Febrile Neutropenia Following Anticancer Chemotherapy: A Population-Based Utilization Study in the Lazio Region. AB - BACKGROUND: Current guidelines recommend prophylaxis with granulocyte colony stimulating factors (G-CSFs) for patients with cancer who are at greater risk of febrile neutropenia (FN) while receiving chemotherapy. G-CSF biosimilars are available and represent a savings opportunity; however, their uptake has thus far been low. OBJECTIVE: Our objective was to evaluate prescribing patterns for G CSFs in the prevention of chemotherapy-related FN and to evaluate the impact of regional guidance on G-CSF prescription. METHODS: We conducted an observational drug-utilization study in the Lazio region of Italy using the Electronic Therapeutic Plan Registry, which collects information on G-CSF prescriptions reimbursed by the regional health service. This registry includes information on demographics, tumour, indication for G-CSF use and previous G-CSF exposure. All therapeutic plans (TPs) registered from 1 July 2015 to 30 June 2016 were selected. A pharmaceutical policy intervention was implemented in November 2015. We evaluated temporal trends regarding G-CSF substances and compared the frequency of TPs for each G-CSF substance during the pre- and post-intervention periods. RESULTS: A total of 7082 TPs were eligible for the analysis, corresponding to 6592 patients. The frequency of TPs prescribed after the intervention indicated a significant increase in the use of a filgrastim biosimilar (% difference: 14.4; p < 0.001) and significant decreases in the use of lenograstim (% difference: -6.0; p < 0.001) and pegfilgrastim (% difference: 7.8; p < 0.001). The temporal trends analysis showed an increase in TPs using a filgrastim biosimilar (from 34.4% in July 2015 to 49.8% in June 2016; p < 0.0001) and a decrease in TPs using lenograstim and pegfilgrastim. CONCLUSIONS: This study shows it is possible to change attitudes towards the prescription of less expensive G-CSFs in the FN setting when the prescriber's decision-making processes are supported by evidence that includes both regulatory and clinical information and the analysis of clinical practice data. PMID- 28353166 TI - Immunodeficiencies Associated with Abnormal Newborn Screening for T Cell and B Cell Lymphopenia. AB - Newborn screening for SCID has revealed the association of low T cells with a number of unexpected syndromes associated with low T cells, some of which were not appreciated to have this feature. This review will discuss diagnostic approaches and the features of some of the syndromes likely to be encountered following newborn screening for immune deficiencies. PMID- 28353169 TI - The Effect of Single and Multiple Doses of Rifampin on the Pharmacokinetics of Doravirine in Healthy Subjects. AB - BACKGROUND AND OBJECTIVE: Doravirine is a novel, next-generation, non-nucleoside reverse transcriptase inhibitor in development for the treatment of human immunodeficiency virus-1 infection in combination with other antiretrovirals. Doravirine is a substrate for cytochrome P450 (CYP) 3A and P-glycoprotein. Rifampin (rifampicin) is used for treating tuberculosis in patients who are co infected with human immunodeficiency virus. Rifampin demonstrates organic anion transporting polypeptide 1B1 and P-glycoprotein inhibition after single-dose administration and CYP3A and P-glycoprotein induction after multiple-dose administration. The objective of this study was to evaluate the effects of co administration of single and multiple doses of rifampin on doravirine pharmacokinetics. METHODS: In period 1 of this open-label, two-period, fixed sequence study in healthy adults, subjects received single-dose doravirine 100 mg; blood samples for measuring plasma concentration were collected pre-dose and up to 72 h post-dose. In period 2, following a 7-day washout, subjects received doravirine 100 mg and rifampin 600 mg on day 1, rifampin 600 mg daily on days 4 18, with doravirine 100 mg co-administered on day 17; blood samples were collected pre-dose and up to 72 h post-dose on day 1 and up to 48 h post-dose on day 17. Safety assessments included adverse events, physical examinations, vital signs, and clinical laboratory measurements. RESULTS: Ten subjects completed the study. Doravirine area under the concentration-time curve from time zero extrapolated to infinity and plasma concentration at 24 h post-dose were comparable in the presence and absence of single-dose rifampin [geometric mean ratios (90% confidence intervals)] of 0.91 (0.78-1.06) and 0.90 (0.80-1.01), respectively. Doravirine maximum plasma concentration increased when co administered with single-dose rifampin vs. doravirine alone, geometric mean ratio (90% confidence interval): 1.40 (1.21-1.63). Reductions in doravirine geometric mean ratios (90% confidence interval), area under the concentration-time curve from time zero extrapolated to infinity: 0.12 (0.10-0.15), plasma concentration at 24 h post-dose: 0.03 (0.02-0.04), maximum plasma concentration: 0.43 (0.35 0.52), and apparent terminal half-life were observed when co-administered with multiple-dose rifampin vs. doravirine administered alone. Doravirine was well tolerated. Adverse events were mild and resolved by study completion. CONCLUSIONS: Doravirine co-administration with single-dose rifampin indicated that inhibition of organic anion-transporting polypeptide uptake transporters and P-glycoprotein has little impact on doravirine pharmacokinetics. Long-term co administration of rifampin or other strong CYP3A inducers with doravirine will likely reduce its efficacy. PMID- 28353171 TI - Lidocaine-loaded fish scale-nanocellulose biopolymer composite microneedles. AB - Microneedle (MN) technology has emerged as an effective drug delivery system, and it has tremendous potential as a patient friendly substitute for conventional methods for transdermal drug delivery (TDD). In this paper, we report on the preparation of lidocaine-loaded biodegradable microneedles, which are manufactured from fish scale-derived collagen. Lidocaine, a common tissue numbing anaesthetic, is loaded in these microneedles with an aim of delivering the drug with controlled skin permeation. Evaluation of lidocaine permeation in porcine skin has been successfully performed using Franz diffusion cell (FDC) which has shown that the drug permeation rate increases from 2.5 to 7.5% w/w after 36 h and pseudo steady state profile is observed from 5.0 to 10.0% w/w lidocaine-loaded microneedle. Swelling experiments have suggested that the microneedles have negligible swellability which implies that the patch would stick to the tissue when inserted. The experiments on MN dissolution have depicted that the lidocaine loaded in the patch is lower than the theoretical loading, which is expected as there can be losses of the drug during initial process manufacture. PMID- 28353172 TI - Dodecylamine Template-Based Hexagonal Mesoporous Silica (HMS) as a Carrier for Improved Oral Delivery of Fenofibrate. AB - The aim of present investigation was the preparation of dodecylamine template based hexagonal mesoporous silica (HMS) as a carrier for poorly water-soluble drug (fenofibrate). HMS material has distinctive characteristics such as easy synthesis, high surface area and wormhole pores. These characteristics are highly admirable to make use of it as a carrier in drug delivery system. HMS was prepared by pH and temperature-independent process. Fenofibrate was loaded into the HMS by solvent immersion method using organic solvent. The BET surface area of HMS was evaluated by nitrogen adsorption/desorption analysis. HMS and drug loaded HMS were characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and contact angle study. The HMS-based system was also evaluated for in vitro and in vivo study as compared to plain drug. The BET surface area of HMS was found 974 m2/g with a narrow pore size average of 2.6 nm. The DSC and XRD study confirmed the amorphization of drug within the HMS. SEM and TEM study showed morphological features of HMS as well as revealed the wormhole porous structure. Contact angle study showed improvement in aqueous wetting property of drug within the HMS (contact angle 46 degrees ). The In vitro drug release study showed a remarkable dissolution enhancement in HMS-based system as compared to plain drug. In vivo pharmacodynamic study (hyperlipidaemia model) exhibited HMS-based formulation was significantly improved the bioavailability of fenofibrate. Thus, HMS has admirable properties; makes it a potential carrier for delivery system of poorly water-soluble drugs. PMID- 28353173 TI - Recent Trends in the Development of Chitosan-Based Drug Delivery Systems. PMID- 28353174 TI - Application of Quality by Design: Development to Manufacturing of Diclofenac Sodium Topical Gel. AB - The objective of the present study was to develop and optimize generic topical gel formulation of diclofenac sodium through quality by design approaches. The quality target product profile was set for the critical quality attributes of the gel. The key material variables like hydrophilic gelling agent carbopol and penetration enhancer kolliphor were optimized using design of experiments. A central composite design was used considering viscosity and cumulative percent diffusion of the drug after 0.5, 1, 2, 4 and 6 h as responses. The p values for all models generated for different responses were statistically significant (<0.5). Design space was established and verified at the laboratory scale. The predicted and observed values were in close agreement. The robustness of the formula was tested at a higher scale (10X and 200X). The capability index was calculated followed by Monte Carlo simulation and the Cpk values for all the responses were more than 1.33. PMID- 28353176 TI - Mathematical investigation of IP3-dependent calcium dynamics in astrocytes. AB - We study evoked calcium dynamics in astrocytes, a major cell type in the mammalian brain. Experimental evidence has shown that such dynamics are highly variable between different trials, cells, and cell subcompartments. Here we present a qualitative analysis of a recent mathematical model of astrocyte calcium responses. We show how the major response types are generated in the model as a result of the underlying bifurcation structure. By varying key channel parameters, mimicking blockers used by experimentalists, we manipulate this underlying bifurcation structure and predict how the distributions of responses can change. We find that store-operated calcium channels, plasma membrane bound channels with little activity during calcium transients, have a surprisingly strong effect, underscoring the importance of considering these channels in both experiments and mathematical settings. Variation in the maximum flow in different calcium channels is also shown to determine the range of stable oscillations, as well as set the range of frequencies of the oscillations. Further, by conducting a randomized search through the parameter space and recording the resulting calcium responses, we create a database that can be used by experimentalists to help estimate the underlying channel distribution of their cells. PMID- 28353175 TI - Current Concepts in Treatment of Barrett's Esophagus With and Without Dysplasia. AB - BACKGROUND: Around 10-15% of patients with gastroesophageal reflux disease will develop Barrett's esophagus (BE). The development of novel endoscopic modalities has changed the management of BE in the last decade. AIM: The aim of this study was to review the current evidence for the treatment of BE with and without dysplasia. RESULTS: In patients with BE without dysplasia, antireflux surgery should not be suggested as a modality to prevent the malignant transformation of BE, but its indications should be the same as for other patients with gastroesophageal reflux. Endoscopic surveillance at intervals of 3-5 years is recommended for these patients. For patients with BE with low-grade dysplasia, radiofrequency ablation (RFA) is the preferred treatment modality, while endoscopic surveillance every 12 months is an acceptable alternative in patients with life-limiting comorbidities. For most patients with BE and high-grade dysplasia, RFA is the preferred treatment strategy. Patients with intramucosal adenocarcinoma (T1a), should be treated with EMR followed by ablative therapy, in order to eradicate the remaining intestinal metaplasia. Endoscopic resection may be suitable for low-risk T1b tumors (well-differentiated, without lymphovascular invasion, and with superficial submucosal invasion); however, further data are necessary to better risk stratify this group. CONCLUSIONS: Patients with BE without dysplasia should undergo endoscopic surveillance every 3-5 years. Endoscopic ablative therapy (RFA) is the preferred treatment modality for dysplastic BE. Patients with T1a adenocarcinoma should be treated with EMR followed by ablative therapy. Low-risk T1b tumors may be suitable for endoscopic resection. PMID- 28353177 TI - Embracing heterothermic diversity: non-stationary waveform analysis of temperature variation in endotherms. AB - Recent research is revealing incredible diversity in the thermoregulatory patterns of wild and captive endotherms. As a result of these findings, classic thermoregulatory categories of 'homeothermy', 'daily heterothermy', and 'hibernation' are becoming harder to delineate, impeding our understanding of the physiological and evolutionary significance of variation within and around these categories. However, we lack a generalized analytical approach for evaluating and comparing the complex and diversified nature of the full breadth of heterothermy expressed by individuals, populations, and species. Here we propose a new approach that decomposes body temperature time series into three inherent properties-waveform, amplitude, and period-using a non-stationary technique that accommodates the temporal variability of body temperature patterns. This approach quantifies circadian and seasonal variation in thermoregulatory patterns, and uses the distribution of observed thermoregulatory patterns as a basis for intra- and inter-specific comparisons. We analyse body temperature time series from multiple species, including classical hibernators, tropical heterotherms, and homeotherms, to highlight the approach's general usefulness and the major axes of thermoregulatory variation that it reveals. PMID- 28353178 TI - Identification of HIF-1 signaling pathway in Pelteobagrus vachelli using RNA-Seq: effects of acute hypoxia and reoxygenation on oxygen sensors, respiratory metabolism, and hematology indices. AB - Oxygen is a vital element in aquatic environments. The concentration of oxygen to which aquatic organisms are exposed is influenced by salinity, water temperature, weather, and surface water runoff. Hypoxia has a serious effect on fish populations, and can lead to the loss of habitat and die-offs. Therefore, in the present study we used next-generation sequencing technology to characterize the transcriptomes of Pelteobagrus vachelli and identified 70 candidate genes in the HIF-1 signaling pathway that are important for the hypoxic response in all metazoan species. For the first time, the present study reported the effects of acute hypoxia and reoxygenation on oxygen sensors, respiratory metabolism, and hematology indices in P. vachelli. The predicted physiological adjustments show that P. vachelli's blood oxygen-carrying capacity was increased through increased RBC, HB, and SI after hypoxia exposure. Glycolysis-related enzyme activities (PFK, HK, and PK) and LDH in the brain and liver also increased, indicating a rise in anaerobic metabolism. The observed reduction in oxidative enzyme level (CS) in the liver during hypoxia suggests a concomitant depression in aerobic metabolism. There were significant increases in oxygen sensor mRNA expression and HIF-1alpha protein expression during hypoxia and reoxygenation exposure, suggesting that the HIF-1 signaling pathway was activated in the liver and brain of P. vachelli in response to acute hypoxia and reoxygenation. Our findings suggest that oxygen sensors (e.g., HIF-1alpha) of P. vachelli are potentially useful biomarkers of environmental hypoxic exposure. These data contribute to a better understanding of the molecular mechanisms of the hypoxia signaling pathway in fish under hypoxia and reoxygenation. PMID- 28353179 TI - Genotypic and Environmental Variations in Grain Cadmium and Arsenic Concentrations Among a Panel of High Yielding Rice Cultivars. AB - BACKGROUND: Rice is a major dietary source of cadmium (Cd) and arsenic (As) for populations consuming rice as the staple food. Excessive Cd and As accumulation in rice grain is of great concern worldwide, especially in South China where soil contamination with heavy metals and metalloids is widespread. It is important to reduce Cd and As accumulation in rice grain through selection and breeding of cultivars accumulating low levels of Cd or As. RESULTS: To assess the genetic and environmental variations in the concentrations of Cd and As in rice grains, 471 locally adapted high-yielding rice cultivars were grown at three moderately contaminated sites in South China for two years. Cadmium and As concentrations in brown rice varied by 10 - 32 and 2.5 - 4 fold, respectively. Genotype (G), environment (E) and G x E interactions were highly significant factors explaining the variations. Brown rice Cd concentration was found to correlate positively with the heading date among different cultivars, whereas As concentration and heading date correlated negatively. There was a significant and negative correlation between grain Cd and As concentrations. CONCLUSIONS: Eight and 6 rice cultivars were identified as stable low accumulators of Cd and As, respectively, based on the multiple site and season trials. These cultivars are likely to be compliant with the grain Cd or As limits of the Chinese Food Safety Standards when grown in moderately contaminated paddy soils in South China. PMID- 28353180 TI - Efficacy and Safety of the Over-the-Scope Clip (OTSC) System in the Management of Leak and Fistula After Laparoscopic Sleeve Gastrectomy: a Systematic Review. AB - BACKGROUND: Endoscopic management of leaks/fistulas after laparoscopic sleeve gastrectomy (LSG) is gaining popularity in the bariatric surgery. OBJECTIVES: This study aimed to review the efficacy and safety of over-the-scope-clip (OTSC) system in endoscopic closure of post-LSG leak/fistula. METHODS: PubMed/Medline and major journals of the field were systematically reviewed for studies on endoscopic closure of post-LSG leaks/fistula by means of the OTSC system. RESULTS: A total of ten eligible studies including 195 patients with post-LSG leaks/fistula were identified. The time between LSG and leak/fistula ranged from 1 day to 803 days. Most of the leaks/fistula were located at the proximal staple line, and they sized from 3 to 20 mm. Time between leak diagnosis and OTSC clipping ranged from 0 to 271 days. Thirty-three out of 53 patients (63.5%) required one clip for closure of the lesion. Regarding the OTSC-related complications, a leak occurred in five patients (9.3%) and OTSC migration, stenosis, and tear each in one patient (1.8%). Of the 73 patients with post-LSG leak treated with OTSC, 63 patients had an overall successful closure (86.3%). CONCLUSION: OTSC system is a promising endoscopic approach for management of post LSG leaks in appropriately selected patients. Unfortunately, most studies are series with a small sample size, short-term follow-up, and mixed data of concomitant procedures with OTSC. Further studies should distinguish the net efficacy of the OTSC system from other concomitant procedures in treatment of post-LSG leak. PMID- 28353182 TI - An international qualitative study of ability and disability in ADHD using the WHO-ICF framework. AB - This is the third in a series of four cross-cultural empirical studies designed to develop International Classification of Functioning, Disability and Health (ICF, and Children and Youth version, ICF(-CY) Core Sets for Attention-Deficit Hyperactivity Disorder (ADHD). To explore the perspectives of individuals diagnosed with ADHD, self-advocates, immediate family members and professional caregivers on relevant areas of impairment and functional abilities typical for ADHD across the lifespan as operationalized by the ICF(-CY). A qualitative study using focus group discussions or semi-structured interviews of 76 participants, divided into 16 stakeholder groups. Participants from five countries (Brazil, India, Saudi Arabia, South Africa and Sweden) were included. A deductive qualitative content analysis was conducted to extract meaningful functioning and disability concepts from verbatim material. Extracted concepts were then linked to ICF(-CY) categories by independent researchers using a standardized linking procedure. In total, 82 ICF(-CY) categories were identified, of which 32 were related to activities and participation, 25 to environmental factors, 23 to body functions and 2 to body structures. Participants also provided opinions on experienced positive sides to ADHD. A high level of energy and drive, creativity, hyper-focus, agreeableness, empathy, and willingness to assist others were the most consistently reported strengths associated with ADHD. Stakeholder perspectives highlighted the need to appraise ADHD in a broader context, extending beyond diagnostic criteria into many areas of ability and disability as well as environmental facilitators and barriers. This qualitative study, along with three other studies (comprehensive scoping review, expert survey and clinical study), will provide the scientific basis to define ICF(-CY) Core Sets for ADHD, from which assessment tools can be derived for use in clinical and research setting, as well as in health care administration. PMID- 28353181 TI - Effects of UPR and ERAD pathway on the prolyl endopeptidase production in Pichia pastoris by controlling of nitrogen source. AB - Prolyl endopeptidase (PEP) is very useful in various industries, while the high cost of enzyme production remains a major obstacle for its industrial applications. Pichia pastoris has been used for the PEP production; however, the fermentation process has not be investigated and little is known about the impact of excessive PEP production on the host cell physiology. Here, we optimized the nitrogen source to improve the PEP expression level and further evaluated the cellular response including UPR and ERAD. During methanol induction phase the PEP activity (1583 U/L) was increased by 1.48-fold under the optimized nitrogen concentration of NH4+ (300 mmol/L) and casamino acids [1.0% (w/v)] in a 3-L bioreactor. Evaluated by RT-PCR the UPR and ERAD pathways were confirmed to be activated. Furthermore, a strong decrease of ERAD-related gene transcription was observed with the addition of nitrogen source, which contributed to a higher PEP expression level. PMID- 28353183 TI - Tetanus in adults: results of the multicenter ID-IRI study. AB - Tetanus is an acute, severe infection caused by a neurotoxin secreting bacterium. Various prognostic factors affecting mortality in tetanus patients have been described in the literature. In this study, we aimed to analyze the factors affecting mortality in hospitalized tetanus patients in a large case series. This retrospective multicenter study pooled data of tetanus patients from 25 medical centers. The hospitals participating in this study were the collaborating centers of the Infectious Diseases International Research Initiative (ID-IRI). Only adult patients over the age of 15 years with tetanus were included. The diagnosis of tetanus was made by the clinicians at the participant centers. Izmir Bozyaka Education and Research Hospital's Review Board approved the study. Prognostic factors were analyzed by using the multivariate regression analysis method. In this study, 117 adult patients with tetanus were included. Of these, 79 (67.5%) patients survived and 38 (32.5%) patients died. Most of the deaths were observed in patients >60 years of age (60.5%). Generalized type of tetanus, presence of pain at the wound area, presence of generalized spasms, leukocytosis, high alanine aminotransferase (ALT) and C-reactive protein (CRP) values on admission, and the use of equine immunoglobulins in the treatment were found to be statistically associated with mortality (p < 0.05 for all). Here, we describe the prognostic factors for mortality in tetanus. Immunization seems to be the most critical point, considering the advanced age of our patients. A combination of laboratory and clinical parameters indicates mortality. Moreover, human immunoglobulins should be preferred over equine sera to increase survival. PMID- 28353184 TI - High pneumococcal DNA load, procalcitonin and suPAR levels correlate to severe disease development in patients with pneumococcal pneumonia. AB - Community-acquired pneumonia (CAP) is mostly caused by Streptococcus pneumoniae. Identification of the pathogen causing CAP can be achieved by conventional culture techniques of sputum and/or blood, antigen detection from urine or molecular analysis. However, it remains difficult to determine patients who are at risk of severe disease development (intensive care unit [ICU] admittance and/or death). In this retrospective study, 121 patients admitted to the emergency department with pneumonia symptoms were included. Several markers of infection (pneumococcal DNA load in blood (real-time LytA PCR), white blood cell (WBC) count, C-reactive protein (CRP), procalcitonin (PCT) and soluble urokinase plasminogen activator receptor (suPAR) levels) were assessed for their ability to predict severe disease development. Of 121 patients, 6 were excluded from the study because of an alternative diagnosis, whereas 8 were excluded from biomarker analysis because of the presence of co-morbidities. Of the 115 patients analysed by the LytA PCR, 23 were positive. PCR detected S. pneumoniae DNA in 82% of patients with positive blood culture for S. pneumoniae. PCR missed three samples from patients in which S. pneumoniae was recovered by blood cultures. However, eight additional LytA PCR-positive samples were detected from patients whose blood cultures remained negative. Pneumococcal DNA load was also monitored in time for 31 patients, of whom 11 had positive PCR results. For 10 out of 11 (91%) positive PCR patients, a clear increase in Ct-values was observed, indicating a lower pneumococcal DNA load in the blood as a result of antibiotic therapy. Biomarker analysis was performed in 107 patients, of whom 29 showed severe disease development. Pneumococcal DNA load (p = 0.026), PCT (p = 0.046) and suPAR (p = 0.001) levels most reliably predicted severe disease development. In conclusion, in patients with CAP, higher pneumococcal DNA load, PCT and suPAR values are associated with severe disease development (ICU admission and/or death). These biomarkers may be useful tools for triage of patients suspected of having CAP in the emergency department. PMID- 28353185 TI - PK-PD Compass: bringing infectious diseases pharmacometrics to the patient's bedside. AB - Antimicrobial stewardship programs face many challenges, one of which is a lack of guidance regarding antimicrobial dose, interval, and duration. There is no tool that considers patient demographic, pathogen susceptibility, and pharmacokinetic-pharmacodynamic (PK-PD) targets for efficacy in order to evaluate appropriate antimicrobial dosing regimens. The PK-PD Compass, an educational mobile application, was developed to address this unmet need. The application consists of a Monte Carlo simulation algorithm which integrates pharmacokinetic (PK) and PK-PD data, patient-specific characteristics, and pathogen susceptibility data. Through the integration of these data, the application allows practitioners to assess the percent probability of PK-PD target attainment for 35 intravenous antimicrobial agents across 29 infection categories. Population PK models for each drug were identified, evaluated, and refined as needed. Susceptibility breakpoints were based upon FDA and CLSI criteria. By incorporating these data into one interface, clinicians can select the infection, pathogen, and antimicrobial agents of interest and obtain the percent probability of PK-PD target attainment for each regimen based upon patient-specific characteristics. The antimicrobial dosing regimens provided include those recommended by standard guidelines and reference texts. However, unlike these references, potential choices are prioritized based on percent probabilities of PK-PD target attainment. Such data will educate clinicians on selecting optimized antibiotic regimens through the lens of PK-PD. PMID- 28353187 TI - Noradrenergic beta-Adrenoceptor-Mediated Intracellular Molecular Mechanism of Na K ATPase Subunit Expression in C6 Cells. AB - Rapid eye movement sleep deprivation-associated elevated noradrenaline increases and decreases neuronal and glial Na-K ATPase activity, respectively. In this study, using C6 cell-line as a model, we investigated the possible intracellular molecular mechanism of noradrenaline-induced decreased glial Na-K ATPase activity. The cells were treated with noradrenaline in the presence or absence of adrenoceptor antagonists, modulators of extra- and intracellular Ca++ and modulators of intracellular signalling pathways. We observed that noradrenaline acting on beta-adrenoceptor decreased Na-K ATPase activity and mRNA expression of the catalytic alpha2-Na-K ATPase subunit in the C6 cells. Further, cAMP and protein kinase-A mediated release of intracellular Ca++ played a critical role in such decreased alpha2-Na-K ATPase expression. In contrast, noradrenaline acting on beta-adrenoceptor up-regulated the expression of regulatory beta2-Na-K ATPase subunit, which although was cAMP and Ca++ dependent, was independent of protein kinase-A and protein kinase-C. Combining these with previous findings (including ours) we have proposed a working model for noradrenaline-induced suppression of glial Na-K ATPase activity and alteration in its subunit expression. The findings help understanding noradrenaline-associated maintenance of brain excitability during health and altered states, particularly in relation to rapid eye movement sleep and its deprivation when the noradrenaline level is naturally altered. PMID- 28353186 TI - A novel phenotypic assay of hepatitis B virus polymerase with extensive site specific mutagenesis. PMID- 28353188 TI - Feasibility of standardized methods to specify behavioral pediatric obesity prevention interventions. AB - Standardized methods are needed to evaluate what occurs within the 'black box' of behavioral interventions to prevent pediatric obesity. The purpose of this research is to evaluate methods to specify the behavior change techniques used and the amount of time spent discussing target weight-related behaviors in an intervention for parents of children at risk for becoming overweight or obese. Independent coders were trained to identify behavior change techniques and time spent discussing weight-related behaviors in audio recordings and transcripts of intervention sessions from 100 randomly selected participants. The behavior change technique taxonomy (BCTTv1) was used to code techniques present in sessions. A newly-developed tool was used to code time spent discussing each target weight-related behavior (e.g., physical activity, screen time). Sessions from a subset of these participants (N = 20) were double coded to evaluate inter rater reliability. After revisions to coding protocols, coders reliably coded behavior change techniques used and time spent discussing target weight-related behaviors in sessions from the subset of 20 participants. The most commonly discussed target weight-related behavior was physical activity followed by energy intake and fruit and vegetable intake. On average, 13.9 (SD = 2.8) unique behavior change techniques were present across sessions for a given participant. These results offer reliable methods for systematically identifying behavior change techniques used and time spent discussing weight-related behaviors in a pediatric obesity prevention intervention. This work paves the way for future research to identify which specific target behaviors and techniques are most associated with the prevention of unhealthy weight gain in children. PMID- 28353189 TI - Reflections on Ethics and Humanity in Pediatric Neurology: the Value of Recognizing Ethical Issues in Common Clinical Practice. AB - Our goals in this reflection are to (i) identify the ethical dimensions inherent in any clinical encounter and (ii) bring to the forefront of our pediatric neurology practice the myriad of opportunities to explore and learn from these ethical questions. We highlight specifically Beauchamp and Childress's principles of biomedical ethics. We use the terms ethics in common clinical practice and an ethical lens to remind people of the ubiquity of ethical situations and the usefulness of using existing ethical principles to analyze and resolve difficult situations in clinical practice. We start with a few common situations with which many of us tend to struggle. We describe what we understand as ethics and how and why developments in technology, novel potential interventions, policies, and societal perspectives challenge us to think about and debate ethical issues. Individual patients are not a singular population; each patient has their own unique life situations, culture, goals, and expectations that need to be considered with a good dose of humanity and humility. We believe that using an ethical lens-by which we mean making an explicit effort to identify and consider these issues openly-will help us to achieve this goal in practice, education, and research. PMID- 28353190 TI - The day after the 7th day of the Creation: Breakthrough of human embryo in vitro culture. PMID- 28353191 TI - Long-Term Maintenance of Certolizumab Pegol Safety and Efficacy, in Combination with Methotrexate and as Monotherapy, in Rheumatoid Arthritis Patients. AB - INTRODUCTION: The safety and efficacy of certolizumab pegol (CZP) 400 mg every 4 weeks (Q4W) monotherapy (FAST4WARD/NCT00548834) and in combination with methotrexate (MTX) (014/NCT00544154) in active rheumatoid arthritis (RA) has been published previously. This report outlines final long-term outcomes from the open label extension (OLE) study (015/NCT00160693), which enrolled patients from these randomized controlled trials (RCTs). METHODS: Patients who withdrew from or completed the 24-week 014/FAST4WARD RCTs were enrolled and received CZP 400 mg Q4W with/without MTX. Exposure-adjusted event rates (ER) per 100 patient-years (PYs) of adverse events (AEs) and serious AEs (SAEs) were reported for all patients receiving >=1 dose of CZP in RCTs or OLE (N = 427) between first CZP dose and up to 24 weeks after last CZP dose or study withdrawal. Efficacy assessments included clinical (ACR20/50/70 response rates, TJC, SJC) and patient reported outcomes (HAQ-DI, PtGADA, pain, fatigue) to week 304 (5.8 years) in the CZP intent-to-treat population. SDAI and CDAI outcomes were analyzed post hoc. Outcomes for CZP monotherapy and CZP+MTX combination-therapy were compared. RESULTS: Globally, ERs of AEs and SAEs were 408.1 and 25.2 per 100 PY, respectively. Eleven patients had AEs leading to death (ER 0.6). Improvements in clinical and patient-reported outcomes during the 24-week RCTs were maintained to week 304, and were similar between all subpopulations. CONCLUSIONS: The longest exposure duration to date with CZP 400 mg Q4W treatment confirmed the safety profile observed in previous studies. Initial improvements in signs and symptoms of RA, including PROs, were maintained in both CZP monotherapy and CZP + MTX combination-therapy patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT00160693. FUNDING: UCB Pharma. PMID- 28353192 TI - Three cases of relapsed/refractory multiple myeloma under hemodialysis treated with panobinostat/bortezomib/dexamethasone (FVD). AB - Three patients under hemodialysis (HD) with relapsed/refractory multiple myeloma (MM) were administered panobinostat/bortezomib/dexamethasone (FVD). Case 1: The patient was a 66-year-old male with BJP-kappa. FVD was effective, but HD could not be discontinued. He developed Grade 3 adverse events (AEs), including nausea, dehydration, and fatigue, following the common terminology criteria for adverse events v4.0. FVD was discontinued after the third course, while HD was continued. Case 2: The patient was a 65-year-old female with IgG-lambda + BJP-lambda. Amyloidosis was complicated. The first course of FVD was effective, but HD could not be discontinued. She developed G2 AEs, including nausea and fatigue. The cardiac amyloidosis worsened, and she died of heart and renal failure. Case 3: The patient was a 79-year-old male with BJP-kappa. FVD was effective, and the HD could be discontinued on day 12 of treatment. No AEs were noted. However, he declined continuation of the FVD and died of MM relapse and renal failure. We analyzed the pharmacokinetics of panobinostat. There were no correlations between dose level and blood level of panobinostat or between blood level, efficacy, and incidence of AEs. We additionally measured the rate of elimination of the drug by HD. PMID- 28353193 TI - Exome sequencing for simultaneous mutation screening in children with hemophagocytic lymphohistiocytosis. AB - In the present study, we used exome sequencing to analyze PRF1, UNC13D, STX11, and STXBP2, as well as genes associated with primary immunodeficiency disease (RAB27A, LYST, AP3B1, SH2D1A, ITK, CD27, XIAP, and MAGT1) in Thai children with hemophagocytic lymphohistiocytosis (HLH). We performed mutation analysis of HLH associated genes in 25 Thai children using an exome sequencing method. Genetic variations found within these target genes were compared to exome sequencing data from 133 healthy individuals. Variants identified with minor allele frequencies <5% and novel mutations were confirmed using Sanger sequencing. Exome sequencing data revealed 101 non-synonymous single nucleotide polymorphisms (SNPs) in all subjects. These SNPs were classified as pathogenic (n = 1), likely pathogenic (n = 16), variant of unknown significance (n = 12), or benign variant (n = 72). Homozygous, compound heterozygous, and double-gene heterozygous variants, involving mutations in PRF1 (n = 3), UNC13D (n = 2), STXBP2 (n = 3), LYST (n = 3), XIAP (n = 2), AP3B1 (n = 1), RAB27A (n = 1), and MAGT1 (n = 1), were demonstrated in 12 patients. Novel mutations were found in most patients in this study. In conclusion, exome sequencing demonstrated the ability to identify rare genetic variants in HLH patients. This method is useful in the detection of mutations in multi-gene associated diseases. PMID- 28353195 TI - Intrinsic worker mortality depends on behavioral caste and the queens' presence in a social insect. AB - According to the classic life history theory, selection for longevity depends on age-dependant extrinsic mortality and fecundity. In social insects, the common life history trade-off between fecundity and longevity appears to be reversed, as the most fecund individual, the queen, often exceeds workers in lifespan several fold. But does fecundity directly affect intrinsic mortality also in social insect workers? And what is the effect of task on worker mortality? Here, we studied how social environment and behavioral caste affect intrinsic mortality of ant workers. We compared worker survival between queenless and queenright Temnothorax longispinosus nests and demonstrate that workers survive longer under the queens' absence. Temnothorax ant workers fight over reproduction when the queen is absent and dominant workers lay eggs. Worker fertility might therefore increase lifespan, possibly due to a positive physiological link between fecundity and longevity, or better care for fertile workers. In social insects, division of labor among workers is age-dependant with young workers caring for the brood and old ones going out to forage. We therefore expected nurses to survive longer than foragers, which is what we found. Surprisingly, inactive inside workers showed a lower survival than nurses but comparable to that of foragers. The reduced longevity of inactive workers could be due to them being older than the nurses, or due to a positive effect of activity on lifespan. Overall, our study points to behavioral caste-dependent intrinsic mortality rates and a positive association between fertility and longevity not only in queens but also in ant workers. PMID- 28353194 TI - Impact of maxillary sinus augmentation on oral health-related quality of life. AB - BACKGROUND: The aim of this study was to measure the oral health-related quality of life (OHRQoL) after maxillary sinus augmentation to determine the physical and psychological impact of this procedure for the patient. METHODS: Three hundred sixteen patients treated with an external or internal maxillary sinus augmentation and a total of 863 implants in the Department of Oral and Maxillofacial Surgery, Johannes Gutenberg University, Mainz, Germany, between July 2002 and December 2007 were included in this retrospective study. Total implant survival was assessed. Completion of a modified 26-item version of the Oral Health Impact Profile (OHIP-G) for assessing the oral health-related quality of life before and after the treatment was asked for. Subcategories were (1) functional limitations, (2) physical and psychological disabilities, and (3) complaints due to the surgical procedure. In 53 patients available for clinical follow-up examination, assessment of soft tissue parameters was performed. RESULTS: After an average time in situ of 41.2 +/- 27 months (3.4 years), the in situ rate was 95.4%. One-year survival rate and five-year survival rate according to Kaplan Meier were 95.4 and 94.4%. Concerning functional limitations, significant better values for OHRQoL after sinus augmentation procedure than before the treatment (p < 0.001) were seen. In the subcategory physical and psychological disabilities, all questions had significant better values after the sinus lift (p < 0.001). Concerning complaints due to the surgical procedure, mean total scores were 5.1 +/- 5.4 pre-operative, 6.9 +/- 6.1 (0-31) post-operative, and 2.4 +/- 3.7 recently. This meant a significant difference between "pre operative" vs. "post-operative" (p = 0.003), "pre-operative" vs. "recently" (p < 0.001), and "post-operative" vs. "recently" (p < 0.001). Concerning the influence of implant indication, edentulous patients showed the most distinct improvement after the procedure. Clinical assessment showed stable soft tissue parameters. CONCLUSIONS: Evaluation of OHRQoL after sinus augmentation showed a significant improvement indicating a remarkable benefit for the patients through this procedure. PMID- 28353196 TI - Robotic-assisted vesicovaginal fistula repair using an extravesical approach without interposition grafting. AB - BACKGROUND: Post-hysterectomy vesicovaginal fistula (VVF) is rare. In addition to conventional abdominal and vaginal approaches, robotic-assisted VVF repairs have recently been described. We present a case of an extravesical, robotic-assisted VVF repair, without placement of an interposition graft performed in a Canadian teaching center. CASE: A 51-year-old woman presented with urinary incontinence 5 days after laparoscopic hysterectomy. Computed tomography cystogram, cystoscopy, and methylene blue dye test, confirmed a VVF above the bladder trigone. The patient underwent a robotic-assisted VVF repair 3 months after presentation, without complication. An abdominal, extravesical approach was used. Operative time was 116 min and repeat CT cystogram showed no evidence of persistent. CONCLUSION: We have demonstrated that a VVF repair, using a robotic-assisted, extravesical approach without interposition graft placement, can be safe, less invasive and have a successful outcome at 1 year of follow-up. PMID- 28353197 TI - Comparison of 18F-FDG-PET/CT and 18F-FDG-PET/MR imaging in oncology: a systematic review. AB - OBJECTIVE: The aim of this study was to systematically review the literature to evaluate the clinical performance of integrated 18F-FDG PET/MR as compared with 18F-FDG PET/CT in oncologic imaging. METHODS: The literature was searched using MEDLINE and EMBASE via OVID. Studies comparing the diagnostic accuracy of integrated 18F-FDG PET/MR and 18F-FDG PET/CT in the diagnosis, staging/restaging, assessment of treatment response, or evaluation of metastasis in patients with suspected or diagnosed cancers were deemed eligible for inclusion. Risk of bias and applicability concerns were assessed using the QUADAS-2 tool. RESULTS: Twenty studies met the inclusion criteria. The overall quality of the studies was rated favorably with bias or applicability concerns in a few studies. Our review suggests that 18F-FDG PET/MR performs comparably to 18F-FDG PET/CT in the detection of local lymph node and distant metastases and superiorly in determining the local extent of tumor. SUV obtained from 18F-FDG PET/MR correlated highly with those obtained from 18F-FDG PET/CT. CONCLUSIONS: Based on early evidence, 18F-FDG PET/MR is comparable to 18F-FDG PET/CT in the clinical scenarios examined in this review. The potential for interchangeability of 18F FDG PET/MR with 18F-FDG PET/CT will vary by indication and the body site that is being imaged, with PET scanners integrated with MRI predicted to provide greater detail in the evaluation of local tumor extent, where 18F-FDG PET/CT can be limited. PMID- 28353198 TI - Is there sufficient evidence to support an optimum time for the extraction of first permanent molars? AB - AIM: To evaluate whether the literature contains evidence, of an appropriate quality, to support the fundamental belief that there is an "optimal time" for extraction of FPMs with a poor prognosis. METHODS: A comprehensive search, limited to human studies, was performed using five databases. PICO based inclusion and exclusion criteria were employed to facilitate article selection. Three independent reviewers assessed the quality of included studies using STROBE and GRADE criteria. RESULTS: Initially, 56 articles were selected, of which 9 were included for final assessments. None of the included studies obtained moderate or high GRADE level rating and neither did they meet all of the STROBE requirements with only one study satisfying 95%, and another study satisfying 73%, of the requirements. The inter-observer agreement was excellent. CONCLUSION: There is no scientific evidence, of an appropriate quality, to support the "optimal time" for extraction of FPMs with a poor prognosis. PMID- 28353199 TI - Lenticular nucleus correlates of general self-efficacy in young adults. AB - General self-efficacy (GSE) is an important factor in education, social participation, and medical treatment. However, the only study that has investigated the direct association between GSE and a neural correlate did not identify specific brain regions, rather only assessed brain structures, and included older adult subjects. GSE is related to motivation, physical activity, learning, the willingness to initiate behaviour and expend effort, and adjustment. Thus, it was hypothesized in the present study that the neural correlates of GSE might be related to changes in the basal ganglia, which is a region related to the abovementioned self-efficacy factors. This study aimed to identify the brain structures associated with GSE in healthy young adults (n = 1204, 691 males and 513 females, age 20.7 +/- 1.8 years) using regional grey matter density and volume (rGMD and rGMV), fractional anisotropy (FA) and mean diffusivity (MD) analyses of magnetic resonance imaging (MRI) data. The findings showed that scores on the GSE Scale (GSES) were associated with a lower MD value in regions from the right putamen to the globus pallidum; however, there were no significant association between GSES scores and regional brain structures using the other analyses (rGMD, rGMV, and FA). Thus, the present findings indicated that the lenticular nucleus is a neural correlate of GSE. PMID- 28353201 TI - The Importance of Recognizing Cannabinoid Hyperemesis Syndrome from Synthetic Marijuana Use. PMID- 28353200 TI - Asymptomatic acute hepatitis E in a female patient with ulcerative colitis. AB - We present a 60-year-old female patient with asymptomatic acute hepatitis E that was fortuitously detected during the course of ulcerative colitis (UC). She was admitted to hospital on October 30, 2015. Endoscopy and histological examination of the colon showed typical findings of UC. All parameters of liver function tests were normal on this date. Combination therapy with oral prednisolone and mesalazine was started and intravenous administration of infliximab once every 8 weeks was added later. Her symptoms gradually improved after these treatments, and she was discharged on February 7, 2016. In a periodic check-up on July 7, 2016, high levels of serum transaminases were detected in liver function tests. Although drug-induced liver injury was first suspected, anti-hepatitis E virus (HEV) immunoglobulin A was positive. The genotype and subgenotype of this HEV are 3 and 3a, respectively, although the infectious route of the HEV was unclear. Within 2 weeks after the onset of acute liver injury, the HEV viremia disappeared and her liver function tests improved. Examination of serum anti-HEV immunoglobulin A should be added at the time of abnormal liver function tests in patients with UC receiving immunosuppressive and biological drugs. PMID- 28353202 TI - A single dialysis session of hemodiafiltration with sorbent-regenerated endogenous ultrafiltrate reinfusion (HFR) removes hepcidin more efficiently than bicarbonate hemodialysis: a new approach to containing hepcidin burden in dialysis patients? AB - BACKGROUND: Most hemodialysis patients have high Hepcidin-25 levels, which may be involved in the pathogenesis of several uremic complications related to an altered iron biology. The hemodialysis procedure itself can influence Hepcidin-25 levels by removing Hepcidin-25 and maybe stimulating its production due to a pro inflammatory effect. METHODS: To assess the relationship between dialysis-related inflammation and intradialysis changes in Hepcidin-25, we performed a crossover trial in 28 hemodialysis patients to compare the effects on serum levels of Hepcidin-25 and inflammatory markers activated during dialysis [Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin-6, C-reactive protein (CRP), Pentraxin-3] of a single dialysis session using a technique capable of reducing inflammation, HFR (Hemo Filtrate Reinfusion: a hemodiafiltration system combining convection, diffusion and adsorption) or bicarbonate-dialysis using either the same low-flux membrane as in the diffusion stage of HFR (LFBD) or a high-flux membrane (HFBD). RESULTS: HFR achieved a greater reduction in Hepcidin-25 levels than both LFBD [ 72% (95% CI: -11 to -133), p = 0.022] and HFBD [-137% (95% CI: -2 to -272), p = 0.047], conceivably due to both a greater removal (because of its convective/adsorptive component) and a lower inflammation-related Hepcidin-25 production. HFR also led to a greater decrease in TNF-alpha than LFBD [-277% (95% CI: -59 to -494), p = 0.014], while the two methods induced similar changes in Interleukin-6, CRP and Pentraxin-3 levels. CONCLUSIONS: Our findings suggest that a single bicarbonate-dialysis session can upregulate Hepcidin-25 synthesis and that HFR can fully overcome this effect, enabling a greater Hepcidin-25 removal during dialysis. Adequately-designed studies are needed, however, to establish whether the beneficial effect of HFR emerging from our study could reduce Hepcidin-25 (and TNF-alpha) burden and improve clinically-relevant outcomes. TRIAL REGISTRATION: ISRCTN15957905. PMID- 28353204 TI - Large-scale carbon stock assessment of woody vegetation in tropical dry deciduous forest of Sathanur reserve forest, Eastern Ghats, India. AB - Tropical dry forests are one of the most widely distributed ecosystems in tropics, which remain neglected in research, especially in the Eastern Ghats. Therefore, the present study was aimed to quantify the carbon storage in woody vegetation (trees and lianas) on large scale (30, 1 ha plots) in the dry deciduous forest of Sathanur reserve forest of Eastern Ghats. Biomass of adult (>=10 cm DBH) trees was estimated by species-specific allometric equations using diameter and wood density of species whereas in juvenile tree population and lianas, their respective general allometric equations were used to estimate the biomass. The fractional value 0.4453 was used to convert dry biomass into carbon in woody vegetation of tropical dry forest. The mean aboveground biomass value of juvenile tree population was 1.86 Mg/ha. The aboveground biomass of adult trees ranged from 64.81 to 624.96 Mg/ha with a mean of 245.90 Mg/ha. The mean aboveground biomass value of lianas was 7.98 Mg/ha. The total biomass of woody vegetation (adult trees + juvenile population of trees + lianas) ranged from 85.02 to 723.46 Mg/ha, with a mean value of 295.04 Mg/ha. Total carbon accumulated in woody vegetation in tropical dry deciduous forest ranged from 37.86 to 322.16 Mg/ha with a mean value of 131.38 Mg/ha. Adult trees accumulated 94.81% of woody biomass carbon followed by lianas (3.99%) and juvenile population of trees (1.20%). Albizia amara has the greatest biomass and carbon stock (58.31%) among trees except for two plots (24 and 25) where Chloroxylon swietenia contributed more to biomass and carbon stock. Similarly, Albizia amara (52.4%) showed greater carbon storage in juvenile population of trees followed by Chloroxylon swietenia (21.9%). Pterolobium hexapetalum (38.86%) showed a greater accumulation of carbon in liana species followed by Combretum albidum (33.04%). Even though, all the study plots are located within 10 km radius, they show a significant spatial variation among them in terms of biomass and carbon stocks which could be attributed to variation in anthropogenic pressures among the plots as well as to changes in tree density across landscapes. Total basal area of woody vegetation showed a significant positive (R 2 = 0.978; P = 0.000) relationship with carbon storage while juvenile tree basal area showed the negative relationship (R 2 = 0.4804; P = 0.000) with woody carbon storage. The present study generates a large-scale baseline data of dry deciduous forest carbon stock, which would facilitate carbon stock assessment at a national level as well as to understand its contribution on a global scale. PMID- 28353203 TI - Gene structure of the pregnancy-associated glycoprotein-like (PAG-L) in the Eurasian beaver (Castor fiber L.). AB - The pregnancy-associated glycoprotein-like family (PAG-L) is a large group of chorionic products, expressed in the pre-placental trophoblast and later in the post-implantational chorionic epithelium, and are involved in proper placenta development and embryo-maternal interaction in eutherians. This study describes identification of the PAG-L family in the genome of the Eurasian beaver (Castor fiber L.), named CfPAG-L. We identified 7657 bp of the CfPAG-L gDNA sequence (Acc. No. KX377932), encompassing nine exons (1-9) and eight introns (A-H). The length of the CfPAG-L exons (59-200 bp) was equivalently similar to the only known counterparts of bPAG1, bPAG2, and pPAG2. The length of the CfPAG-L introns ranged 288-1937 bp and was completely different from previously known PAG introns. The exonic CfPAG-L regions revealed 50.3-72.9% homology with equivalent segments of bPAG1 and pPAG2 structure. The intronic CfPAG-L regions alignments revealed a lack of homology. Within the entire CfPAG-L gene, 31 potential single nucleotide variants (SNV: 7 transversions and 24 transitions) were predicted. The identified exonic polymorphic loci did not affect the amino acid sequence of the CfPAG-L polypeptide precursor. This is the first report describing the CfPAG-L gene sequence, structural organization, and SNVs in the Eurasian beaver, one of the largest rodents. PMID- 28353205 TI - Earth-tide-induced fluctuations in the salinity of an inland river, New South Wales, Australia: a short-term study. AB - Wybong Creek discharges salts into the agriculturally and industrially important Hunter River in New South Wales, Australia. Abrupt increases in salinity occur periodically in the mid-Wybong Creek catchment. In order to understand the processes which cause these abrupt increases, changes in surface and groundwater were investigated. It is shown that salinity increases can be attributed to highly discrete groundwater discharge directly into the river from below. Hourly electrical conductivity data measured in the river showed regular, diurnal electrical conductivity fluctuations of up to 350 MUS cm-1. These fluctuations could not be attributed to barometric pressure, temperature, or evapotranspiration. Instead, a similar periodicity in surface water electrical conductivity and groundwater height in nearby groundwater wells was found. Fluctuations were of similar periodicity to the orthotides which cause fluctuations in surface water height and are induced by Earth tides. The geology in the mid-catchment area indicates conditions are optimal for Earth tides to impact groundwater. The reporting of orthotidal changes in water chemistry in this article is believed to be the first of its kind in the scientific literature, with the large fluctuations noted having important implications for water monitoring and management in the catchment. Further research investigating Earth-tide-induced phases of groundwater heights will better constrain the relationships between surface water chemistry and groundwater height. PMID- 28353207 TI - Management of lung nodules newly found by virtual-assisted lung mapping: a case report. AB - BACKGROUND: Virtual-assisted lung mapping is a novel bronchoscopic lung marking technique that uses virtual images to perform multiple concurrent dye marking of barely palpable pulmonary tumors. Subsequent chest computed tomography is required to confirm the locations marked. We here report a patient in whom computed tomography after virtual-assisted lung mapping unexpectedly revealed additional tiny pulmonary nodules. CASE PRESENTATION: A 64-year-old woman with a history of renal cell carcinoma presented with two pulmonary nodules suspicious of metastases from renal cell carcinoma. Because we anticipated that the nodules would be difficult to palpate intraoperatively, we performed virtual-assisted lung mapping prior to attempting to resect them. Computed tomography after mapping unexpectedly detected two additional nodules. Although the existing markings did not relate to the newly found nodules, we used imaginary auxiliary lines and anatomical landmarks to extend the lung map to incorporate the unexpected nodules. The additional nodules were successfully resected by thoracoscopic wedge resection. Pathologic examination identified all nodules as metastases from renal cell carcinoma, and the surgical margins were negative. CONCLUSIONS: Imaginary auxiliary lines and anatomical landmarks extended the existing lung map of virtual-assisted lung mapping, enabling resection of unexpected pulmonary nodules found in post-mapping computed tomography images. PMID- 28353206 TI - Assessing spatio-temporal trend of vector breeding and dengue fever incidence in association with meteorological conditions. AB - Th aim of this study is to investigate spatio-temporal trends of dengue vector breeding and epidemic (disease incidence) influenced by climatic factors. The spatio-temporal (low-, medium-, and high-intensity periods) evaluation of entomological and epidemiological investigations along with climatic factors like rainfall (RF), temperature (Tmax), relative humidity (RH), and larval indexing was conducted to develop correlations in the area of Lahore, Pakistan. The vector abundance and disease transmission trend was geo-tagged for spatial insight. The sufficient rainfall events and optimum temperature and relative humidity supported dengue vector breeding with high larval indices for water-related containers (27-37%). Among temporal analysis, the high-intensity period exponentially projected disease incidence followed by post-rainfall impacts. The high larval incidence that was observed in early high-intensity periods effected the dengue incidence. The disease incidence had a strong association with RF (r = 0.940, alpha = 0.01). The vector larva occurrence (r = 0.017, alpha = 0.05) influenced the disease incidence. Similarly, RH (r = 0.674, alpha = 0.05) and average Tmax (r = 0.307, alpha = 0.05) also induced impact on the disease incidence. In this study, the vulnerability to dengue fever highly correlates with meteorological factors during high-intensity period. It provides area specific understanding of vector behavior, key containers, and seasonal patterns of dengue vector breeding and disease transmission which is essential for preparing an effective prevention plan against the vector. PMID- 28353210 TI - Nuclear cardiology in the literature: A selection of recent, original research papers. PMID- 28353208 TI - Synthesis of Two Coumarin-Derived Schiff Bases and Investigation of theirs Selectivity for Zn2. AB - In this study, the coumarin-derived schiff bases (HL1 and HL2) have been designed and synthesized. Upon the addition of Zn2+, both of them show significant fluorescence enhancement owing to inhibits PET and ESIPT process respectively. However, the receptor HL2 response toward Cd2+, Mg2+, Ba2+, Ca2+ besides Zn2+ and exhibits fluorescence enhancement but not enough to detection of the concentration levels of Zn2+. PMID- 28353211 TI - Current status of stress myocardial perfusion imaging pharmaceuticals and radiation exposure in Japan: Results from a nationwide survey. AB - BACKGROUND: Ionizing radiation generated during medical imaging procedures is a matter of concern. However, the current status of radiopharmaceutical use in stress myocardial perfusion imaging (MPI) and the radiation exposure from these radiopharmaceuticals is unknown in Japan. METHODS AND RESULTS: A nationwide survey was conducted from June through July 2016. The questionnaires on the radiopharmaceuticals used and their administered doses during stress MPI were sent to 641 nuclear medicine facilities. The responses were collected from 431 facilities and the effective dose (ED) for an adult with standard body weight was calculated. Forty-three percent of the facilities used only 201TlCl, 35% used only 99mTc radiopharmaceuticals, and the remaining 22% used both. The two main reasons for using 201TlCl instead of 99mTc radiopharmaceuticals were "more familiarity with the usage of 201TlCl than 99mTc radiopharmaceuticals" and "apprehension about increasing the burden of physicians performing tracer injection twice." The mean ED was 14.0 +/- 5.5 mSv (range, 3.9 to 25.2 mSv), which was higher than that reported in other countries. CONCLUSIONS: The ED of stress MPI radiopharmaceuticals in Japan is probably higher than the world standard because more than 50% of the facilities still use 201TlCl. We recommend revising the routine stress MPI protocol to reduce the effects of ionizing radiation. PMID- 28353212 TI - Stress-induced alteration of left ventricular eccentricity: An additional marker of multivessel CAD. AB - BACKGROUND: Abnormal left ventricular (LV) eccentricity index (EI) is a marker of adverse cardiac remodeling. However, the interaction between stress-induced alterations of EI and major cardiac parameters has not been explored. We sought to evaluate the relationship between LV EI and coronary artery disease (CAD) burden in patients submitted to myocardial perfusion imaging (MPI). METHODS AND RESULTS: Three-hundred and forty-three patients underwent MPI and coronary angiography. LV ejection fraction (EF) and EI were computed from gated stress images as measures of stress-induced functional impairment. One-hundred and thirty-six (40%), 122 (35%), and 85 (25%) patients had normal coronary arteries, single-vessel CAD, and multivessel CAD, respectively. Post-stress EI was lower in patients with multivessel CAD than in those with normal coronary arteries and single-vessel CAD (P = 0.001). This relationship was confirmed only in patients undergoing exercise stress test, where a lower post-stress EI predicted the presence of multivessel CAD (P = 0.039). CONCLUSIONS: Post-stress alterations of LV EI on MPI may unmask the presence of multivessel CAD. PMID- 28353213 TI - Development and validation of an automatic method to detect the latest contracting viable left ventricular segments to assist guide CRT therapy from gated SPECT myocardial perfusion imaging. AB - OBJECTIVES: The purpose of this study is to use ECG-gated SPECT MPI to detect the latest contracting viable left ventricular (LV) segments to help guide the LV probe placement used in CRT therapy and to validate segment selection against the visual integration method by experts. METHODS: For each patient, the resting ECG gated SPECT MPI short-axis images were sampled in 3D to generate a polar map of the perfusion distribution used to determine LV myocardial viability, and to measure LV synchronicity using our phase analysis tool. In the visual integration method, two experts visually interpreted the LV viability and mechanical dyssynchrony from the short-axis images and polar maps of viability and phase, to determine the latest contracting viable segments using the 17-segment model. In the automatic method, the apical segments, septal segments, and segments with more than 50% scar were excluded as these are not candidates for CRT LV probe placement. Amongst the remaining viable segments, the segments, whose phase angles were within 10 degrees of the latest phase angle (the most delayed contracting segment), were identified for potential CRT LV probe placement and ranked based on the phase angles of the segments. Both methods were tested in 36 pre-CRT patients who underwent ECG-gated SPECT MPI. The accuracy was determined as the percent agreement between the visual integration and automatic methods. The automatic method was performed by a second independent operator to evaluate the inter-operator processing reproducibility. RESULTS: In all the 36 patients, the LV lead positions of the 1st choices recommended by the automatic and visual integration methods were in the same segments in 35 patients, which achieved an agreement rate of 97.2%. In the inter-operator reproducibility test, the LV lead positions of the 1st choices recommended by the two operators were in the same segments in 25 patients, and were in the adjacent segments in 7 patients, which achieved an overall agreement of 88.8%. CONCLUSIONS: An automatic method has been developed to detect the latest contracting viable LV segments to help guide the LV probe placement used in CRT therapy. The retrospective clinical study with 36 patients suggests that this method has high agreement against the visual integration method by experts and good inter-operator reproducibility. Consequently, this method is promising to be a clinical tool to recommend the CRT LV lead positions. PMID- 28353214 TI - Playing slot to hitting the jackpot in molecular imaging: On probability of uncovering subcellular pathogenesis vs achieving clinical applicability. PMID- 28353216 TI - Dissolution comparisons using a Multivariate Statistical Distance (MSD) test and a comparison of various approaches for calculating the measurements of dissolution profile comparison. AB - The f 2 test is generally used for comparing dissolution profiles. In cases of high variability, the f 2 test is not applicable, and the Multivariate Statistical Distance (MSD) test is frequently proposed as an alternative by the FDA and EMA. The guidelines provide only general recommendations. MSD tests can be performed either on raw data with or without time as a variable or on parameters of models. In addition, data can be limited-as in the case of the f 2 test-to dissolutions of up to 85% or to all available data. In the context of the present paper, the recommended calculation included all raw dissolution data up to the first point greater than 85% as a variable-without the various times as parameters. The proposed MSD overcomes several drawbacks found in other methods. PMID- 28353215 TI - Severe Asthma in Children. AB - PURPOSE OF REVIEW: The aim of this study is to characterize, diagnose, evaluate, and treat severe childhood asthma. RECENT FINDINGS: Understanding the occurrence of the physiologic and clinical presentations of childhood severe asthma, the treatment and response may be predicted by biomarkers, but the patient's response is highly variable. The onset of severe asthma occurs early and is primarily predicted by severity of viral infection and coexistence of the atopic state. PMID- 28353218 TI - The 13-year observation of hip fracture in Poland-worrying trend and prognosis for the future. AB - INTRODUCTION: Hip fractures are often considered to be one of the most common osteoporotic fractures. In our previous study, we noted the increasing trend in the total number of hip fractures as well as crude and standardized rates, for both women and men. This observation enabled us to delve deeper into the study of osteoporotic fractures. METHODS: Hospital records between 1.01.2002 and 31.12.2014 with ICD-10 codes S72.0. S72.1 and S72.2 (femoral neck. intertrochanteric, subtrochanteric, and inter and subtrochanteric fracture) were analysed. All fractures occurred in citizens who lived in the district Tarnowskie Gory and the city of Piekary Slaskie aged 50 years and more. RESULTS: 1507 fragility hip fractures (400 in men, and 1107 in women) were registered. The rates increase in both sexes was still observed. The tendency to sustain fractures was lower in female (29.3%) than in the male population (63.6%). We observed a lower increase in urban (35.8%) population when compared to rural (40.8%) population. Incidence rate ratios for female gender were 1.89 (95% CI 1.65-2.18). The rates in 2014 were as follows: crude rate of 216.2 (men 140.9; women 276.5) and standardized 183.9 (131.6 and 219.4, respectively). This observation allowed as to project a total crude rate of 467.2 (men 329.6; women 584.7) for the year 2050. CONCLUSIONS: The number of osteoporotic hip fractures in Polish men and women is still relatively low, but the epidemiological situation is getting worse. The over 13 years of follow-up demonstrated that the trend to increase in total number of hip fractures for men and women is still observed. This prognosis is of a major concern. PMID- 28353219 TI - Prevalence and conversion to dementia of Mild Cognitive Impairment in an elderly Italian population. AB - BACKGROUND: Mild Cognitive Impairment (MCI) represents a significant risk factor for dementia but there are only a few Italian population studies on its prevalence and its rate of conversion to dementia. AIMS: Aim of this study was to assess the prevalence of MCI, its subtypes, and rates of conversion to dementia 1 year later in an elderly Italian population. METHODS: The data are based on an Italian multicenter population-based cohort study with both cross-sectional and longitudinal components. Two thousand three hundred thirty-seven individuals over 65 underwent screening, clinical confirmation and 1-year follow-up. RESULTS: The prevalence of MCI was 21.6% and the amnestic multiple domain was the most frequent subtype (63.2%). The conversion rate to dementia was 4.1% and was found only in the amnestic multiple domain and in the unclassifiable subjects, persons with cognitive deficit but neither demented nor with MCI. DISCUSSION: The prevalence of MCI in this population sample was similar to that found in other population studies using Petersen's modified MCI criteria as well as his original criteria. With regard to conversion to dementia, our results emphasize the importance to better classify the unclassifiable subjects at high risk of progression to dementia and also at risk of being undiagnosed and untreated. CONCLUSION: MCI is characterized by extreme variability and instability. Data on the prevalence and the rate of conversion from MCI to dementia are difficult to compare given the important differences from study to study especially with regard to the diagnostic criteria utilized and their operationalization. PMID- 28353217 TI - Hypoxic Stress and Inflammatory Pain Disrupt Blood-Brain Barrier Tight Junctions: Implications for Drug Delivery to the Central Nervous System. AB - A functional blood-brain barrier (BBB) is necessary to maintain central nervous system (CNS) homeostasis. Many diseases affecting the CNS, however, alter the functional integrity of the BBB. It has been shown that various diseases and physiological stressors can impact the BBB's ability to selectively restrict passage of substances from the blood to the brain. Modifications of the BBB's permeability properties can potentially contribute to the pathophysiology of CNS diseases and result in altered brain delivery of therapeutic agents. Hypoxia and/or inflammation are central components of a number of diseases affecting the CNS. A number of studies indicate hypoxia or inflammatory pain increase BBB paracellular permeability, induce changes in the expression and/or localization of tight junction proteins, and affect CNS drug uptake. In this review, we look at what is currently known with regard to BBB disruption following a hypoxic or inflammatory insult in vivo. Potential mechanisms involved in altering tight junction components at the BBB are also discussed. A more detailed understanding of the mediators involved in changing BBB functional integrity in response to hypoxia or inflammatory pain could potentially lead to new treatments for CNS diseases with hypoxic or inflammatory components. Additionally, greater insight into the mechanisms involved in TJ rearrangement at the BBB may lead to novel strategies to pharmacologically increase delivery of drugs to the CNS. PMID- 28353220 TI - Patient Experience of Symptoms and Side Effects when Treated with Osimertinib for Advanced Non-Small-Cell Lung Cancer: A Qualitative Interview Substudy. AB - INTRODUCTION: Capturing the patient experience during treatment is important to both regulatory authorities and to patients starting treatment. We identified the symptoms and side effects experienced by patients with advanced non-small-cell lung cancer during osimertinib treatment, to understand treatment expectations, satisfaction, and the level of difficulty coping with the side effects experienced during treatment. METHODS: Qualitative interviews (approximately 4-6 weeks after treatment initiation and again after approximately 4 months of treatment) were conducted during the phase I/II AURA clinical trial of osimertinib, a tyrosine kinase inhibitor of epidermal growth factor receptor sensitizing and T790M resistance mutations. RESULTS: During the first interview (23 patients), the most commonly reported symptoms/side effects were coughing, itching, tiredness (each reported by 56.5% of patients), and rash (43.5%). During the second interview (21 patients), compared with the first interview, shortness of breath and diarrhea were reported by more patients (57.1 and 38.1%, respectively; both increased from 34.8%); tiredness remained predominant (42.9%); and itching (38.1%), coughing (38.1%), and rash (14.3%) were reported by fewer patients. At both interviews, the most frequently reported symptoms/side effects were also those most often rated by patients for bothersomeness and severity, and generally received mean scores in the low-to-moderate range. However, several rarely expressed symptoms/side effects (e.g., abdominal pain, frequent day time urination) received high bothersomeness ratings. At the second interview, patients were highly satisfied with osimertinib and had a low level of difficulty in coping with side effects during treatment. CONCLUSIONS: These data enhance our understanding of patients' experiences of symptoms/side effects, which could increase the accuracy of the osimertinib benefit-risk assessment, guide management of adverse events, and improve the information given to patients receiving the drug. PMID- 28353222 TI - Application of Proteomic Techniques for Improved Stratification and Treatment of Schizophrenia Patients. AB - For major psychiatric disorders such as schizophrenia, there have been shortcomings in the translation of scientific findings into new treatments and this has led to diminished interest for large pharmaceutical companies. This chapter describes how incorporation of proteomic approaches into the clinical pipeline can lead to identification and implementation of biomarker tests for improved patient characterization, prediction of treatment response and monitoring treatment effects to help revitalize efforts in this important area. In addition, the construction of specific biomarker tests for disease prediction should smooth the progress of early intervention strategies which, in turn, may help to slow disease onset or progression. Finally, the development of purpose built biomarker tests using lab-on-a-chip platforms with smartphone readouts will help to shift the diagnosis and treatment of this major psychiatric disorder into point-of-care settings for increased effectiveness and improved patient outcomes. PMID- 28353223 TI - Multiplexing Biomarker Methods, Proteomics and Considerations for Alzheimer's Disease. AB - Biomarker research for Alzheimer's disease (AD) has been growing rapidly over recent years especially as the number of persons affected by this disease is nearing approximately 46 million worldwide. Single biomarker assays are challenging to establish since AD is multifactorial and complex. In addition to the classic signs of diminished cognition and memory, AD patients can also exhibit symptoms which may be confused with some psychiatric disorders, such as depression. No molecular biomarkers have been established or translated into clinical tools although recent efforts have resulted in addition of molecular biomarker profiles to the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association criteria for research purposes. The three accepted molecular biomarkers are amyloid-betaeta peptide 1-42, total tau protein and hyperphosphorylated tau at threonine 181 in human cerebrospinal fluid (CSF). Aside from these three CSF markers, a number of potential candidates have been identified in CSF and other body fluids. In order to identify biomarkers for diagnosis, early prevention, prognosis and response to therapeutic treatment, multiplex biomarker tests will be required. These include multiplex immunoassay and mass spectrometry-based proteomics platforms. Proteomics analyses of bodily fluids such as plasma are growing in number and providing potential targets for further investigation and validation in AD research. This chapter highlights proteomic biomarker assays and their applications and potential use for clinical diagnosis and prognosis of AD. PMID- 28353221 TI - Health-Related Quality of Life in Chronic HCV-Infected Patients Switching to Pegylated-Interferon-Free Regimens (ANRS CO20 CUPIC Cohort Study and SIRIUS Trial). AB - OBJECTIVE: We aimed to compare health-related quality of life (HRQL) during and after hepatitis C virus (HCV) treatment in patients receiving pegylated interferon (PEG-IFN)-containing therapy (including boceprevir or telaprevir-ANRS CO20 CUPIC cohort) who subsequently switched to PEG-IFN-free regimens (sofosbuvir + ledipasvir with or without ribavirin [RBV]-SIRIUS trial). METHODS: Two analyses were performed. The first compared physical (PCS) and mental (MCS) HRQL (MOS SF 12) scores during treatment between CUPIC and SIRIUS. The second compared PCS and MCS scores after treatment end between CUPIC and SIRIUS. The analyses used linear regression mixed models adjusted for pre-treatment HRQL scores, gender, and age at each visit. RESULTS: Among patients enrolled successively in both studies, 43 (corresponding to 212 HRQL assessments) and 43 (82 HRQL assessments) were eligible for the 'during' and 'post' treatment analyses, respectively. In the 'during-treatment' analysis, we found significantly higher PCS and MCS values during PEG-IFN-free treatment than for PEG-IFN-containing treatment. In the 'post treatment' analysis, results showed significantly higher MCS values after PEG-IFN free treatment than after PEG-IFN-containing treatment. No significant difference was found for PCS in the post-treatment analysis. CONCLUSIONS: These results highlight an improvement in both physical and mental HRQL during HCV treatment, but no major improvement in physical HRQL after treatment end, when comparing PEG IFN-free regimens with PEG-IFN-containing regimens. This suggests that in the PEG IFN-free regimens era, screening and comprehensive care of comorbidities and residual somatic symptoms during treatment, and especially after HCV clearance, are still needed to improve patient outcomes. PMID- 28353224 TI - What Have Proteomic Studies Taught Us About Novel Drug Targets in Autism? AB - Autism spectrum disorders (ASDs) are a heterogeneous group of conditions with complex behavioural phenotypes. Although ASDs show a high rate of heritability, genetic research alone has not provided a complete understanding of the underlying causes. Recent developments using imaging techniques and proteomic based molecular profiling approaches have now begun to generate new insights into the underlying pathways affected in both the brain and the periphery in individuals with these conditions. Of potential high importance is the constant finding of gender-specific biomarker profiles in ASD patients. This suggests that there are either distinct adaptive mechanisms or different aetiological causes in male and female ASD patients. This chapter addresses the findings using these approaches with a view to identification of novel drug targets or new treatment strategies based on personalized medicine objectives. Eventually, this will lead to a better disease understanding of ASD at the physiological and molecular levels, which may facilitate novel drug discovery efforts in this challenging area of medicine. PMID- 28353225 TI - Application of Proteomic Approaches to Accelerate Drug Development for Psychiatric Disorders. AB - Proteomic-based biomarkers are now an integral part of the drug development process. This chapter covers the role of proteomic biomarker tests as useful tools for improving preclinical research and clinical development. One medical area that has been lagging behind this process is the study of psychiatric disorders, and this is most likely due to the complexity of these diseases. The potential of incorporating biomarkers in the clinical pipeline to improve decision-making, accelerate drug development, improve translation and reduce development costs is also discussed, with a focus on psychiatric diseases like schizophrenia. This chapter will also discuss the next steps that must be taken to keep moving this process forwards. PMID- 28353226 TI - Proteomic Biomarker Identification in Cerebrospinal Fluid for Leptomeningeal Metastases with Neurological Complications. AB - Leptomeningeal metastases (LM) from solid tumours, lymphoma and leukaemia are characterized by multifocal neurological deficits with a high mortality rate. Early diagnosis and initiation of treatment are essential to kerb neurological deterioration. However, this is not always possible as 25% of cerebrospinal fluid samples produce false-negative results at first cytological examination. The identification of biomarkers that allow stratification of individuals according to risk for developing LM would be a major benefit. Proteomic-based approaches are now in increasing use for this purpose, and these are reviewed in this chapter with a focus on cerebrospinal fluid (CSF) analyses. The construction of a CSF proteome disease database would also facilitate analysis of other neurological disorders. PMID- 28353227 TI - Connecting Brain Proteomics with Behavioural Neuroscience in Translational Animal Models of Neuropsychiatric Disorders. AB - Modelling psychiatric disorders in animals has been hindered by several challenges related to our poor understanding of the disease causes. This chapter describes recent advances in translational research which may lead to animal models and relevant proteomic biomarkers that can be informative about disease mechanisms and potential new therapeutic targets. The review focuses on the behavioural and molecular correlates in models of schizophrenia and major depressive disorder, as guided by recently established Research Domain Criteria (RDoC). This approach is based on providing proteomic data for aetiologically driven, behaviourally well-characterised animal models to link discovered biomarker candidates with the human disease. PMID- 28353228 TI - LC-MSE for Qualitative and Quantitative Proteomic Studies of Psychiatric Disorders. AB - This chapter describes the advantages and disadvantages of label-free liquid chromatography mass spectrometry in data-independent analysis mode (LC-MSE) in the identification of disease biomarkers in studies of psychiatric disorders. Along with the description of the technology, we discuss some of the most significant findings from various studies of post-mortem brain and neuroendocrine tissues from psychiatric disorder patients compared with controls. In addition, we describe some of the needs and challenges of performing these analyses in body fluids and peripheral tissues from living patients in order to increase translation of the findings into the clinical environment. PMID- 28353229 TI - The Utility of Multiplex Assays for Identification of Proteomic Signatures in Psychiatry. AB - As substantial efforts are being made to identify biological markers of psychiatric illnesses, it is becoming clear that clinically useful accuracy will require larger sets of readouts that potentially span different technological platforms. For discovery of proteomic biomarkers, simultaneous measurement of analytes in small sample quantities has developed into a widely used technology of similar quality as the respective single-plex assays. Multiplex assay systems therefore hold promise for biomarker discovery and development in many complex disease areas including psychiatry. However, analysis of the derived data is subject to substantial challenges that may impede the possibility of obtaining meaningful findings. This chapter discusses potential applications of multiplexed assay technologies during biomarker development and highlights potential challenges for machine learning analysis of derived data. PMID- 28353230 TI - Blood Sampling and Preparation Procedures for Proteomic Biomarker Studies of Psychiatric Disorders. AB - A major challenge in proteomic biomarker discovery and validation for psychiatric diseases is the inherent biological complexity underlying these conditions. There are also many technical issues which hinder this process such as the lack of standardization in sampling, processing and storage of bio-samples in preclinical and clinical settings. This chapter describes a reproducible procedure for sampling blood serum and plasma that is specifically designed for maximizing data quality output in two-dimensional gel electrophoresis, multiplex immunoassay and mass spectrometry profiling studies. PMID- 28353232 TI - Sequential Immunoprecipitation of Secretory Vesicle Proteins from Biosynthetically Labelled Cells. AB - Pulse radiolabelling of cells with radioactive amino acids is a common method for studying the biosynthesis of proteins. The labelled proteins can then be immunoprecipitated and analysed by electrophoresis and imaging techniques. This chapter presents a protocol for the biosynthetic labelling and immunoprecipitation of pancreatic islet proteins which are known to be affected in psychiatric disorders such as schizophrenia. PMID- 28353231 TI - Multiplex Immunoassay Profiling of Serum in Psychiatric Disorders. AB - Multiplex immunoassays allow for the rapid profiling of biomarker proteins in biological fluids, using less sample and labour than in single immunoassays. This chapter details the methods to develop and manufacture a 5-plex immunoassay for the Luminex(r) platform. Although assay development is not included here, the same methods can be used to covalently couple antibodies to the Luminex beads and to label antibodies for the screening of sandwich pairs, if needed. An example will be given for the analysis of five hormones (glucagon-like peptide 1, growth hormone, insulin, leptin and thyroid-stimulating hormone) in serum samples from schizophrenia patients and controls. PMID- 28353233 TI - 2D Gel Electrophoresis of Insulin Secretory Granule Proteins from Biosynthetically Labelled Pancreatic Islets. AB - Pulse radiolabelling of cells with radioactive amino acids such is a common method for investigating the biosynthetic rates of proteins. In this way, the abundance of newly synthesized proteins can be determined by several proteomic techniques including 2D gel electrophoresis (2DE). This chapter describes a protocol for labelling pancreatic islets with 35S-methionine in the presence of low and high concentrations of glucose, followed by subcellular fractionation enrichment of secretory granule proteins and analysis of the granule protein contents by 2DE. This demonstrated that the biosynthetic rates of most of the granule proteins are co-ordinately regulated in the presence of stimulatory glucose concentrations. PMID- 28353235 TI - A Two-Dimensional Difference Gel Electrophoresis (2D-DIGE) Protocol for Studies of Neural Precursor Cells. AB - This chapter describes the basics of two-dimensional difference gel electrophoresis (2D-DIGE) for multiplex analysis of up to distinct proteomes. The example given describes the analysis of undifferentiated and differentiated neural precursor cells labelled with fluorescent Cy3 and Cy5 dyes in comparison to a pooled standard labelled with Cy2. After labelling, the proteomes are mixed together and electrophoresed on the same 2D gels. Scanning the gels at wavelengths specific for each dye allows direct overlay of the two different proteomes and the differences in abundance of specific protein spots can be determined through comparison to the pooled standard. PMID- 28353234 TI - Two-Dimensional Gel Electrophoresis: A Reference Protocol. AB - Two-dimensional gel electrophoresis (2DE) has been a mainstay of proteomic techniques for more than four decades. It was even in use for several years before the term proteomics was actually coined in the early 1990s. Over this time, it has been used in the study of many diseases including cancer, diabetes, heart disease, and psychiatric disorders through the proteomic analysis of body fluids and tissues. This chapter presents a general protocol which can be applied in the study of biological samples such as blood serum or plasma and multiple tissues including the brain. PMID- 28353236 TI - Identifying Biomarker Candidates in the Blood Plasma or Serum Proteome. AB - Brain disorders are among the most complex and difficult to understand of human disorders in terms of pathophysiology and etiology. Differently from other human diseases such as cancer, which uses biomarkers in clinical practice, there are no prognostic and diagnostic biomarkers available for psychiatric disorders. Those associated with the likelihood of a successful medication are also not existent, impairing treatment strategies. Proteomics is a suitable tool for identifying such biomarkers to be validated and further implemented in the clinic. Here we present a protocol for the proteome analyses of blood plasma and serum collected in vivo, aiming for the discovery of potential biomarkers and the comprehension of the molecular bases of diseases and treatments. PMID- 28353237 TI - Selective Reaction Monitoring Mass Spectrometry for Quantitation of Glycolytic Enzymes in Postmortem Brain Samples. AB - Patients with psychiatric disorders exhibit dysfunctions in peripheral and central metabolism. This may be a root cause of impaired neuronal function, manifested as changes in mood, behavior, and cognitive capabilities in patients suffering with these conditions. Here we describe a selective reaction monitoring mass spectrometry (SRM-MS)-based targeted proteomic protocol for precise simultaneous quantitation of three glycolytic enzymes in postmortem brain tissue extracts. The SRM-MS approach has several advantages in terms of sensitivity, reproducibility, and reduced sample consumption, compared to traditional MS methods. PMID- 28353238 TI - A Selected Reaction Monitoring Mass Spectrometry Protocol for Validation of Proteomic Biomarker Candidates in Studies of Psychiatric Disorders. AB - Most biomarker candidates arising from proteomic studies of psychiatric disorders have not progressed for use in clinical studies due to insufficient validation steps. Here we describe a selective reaction monitoring mass spectrometry (SRM MS) approach that could be used as a follow-up validation tool of proteins identified in blood serum or plasma. This protocol specifically covers the stages of peptide selection and optimization. The increasing application of SRM-MS should enable fast, sensitive, and robust methods with the potential for use in clinical studies involving sampling of serum or plasma. Understanding the molecular mechanisms and identifying potential biomarkers for risk assessment, diagnosis, prognosis, and prediction of drug response goes toward the implementation of translational medicine strategies for improved treatment of patients with psychiatric disorders and other debilitating diseases. PMID- 28353239 TI - Application of iTRAQ Shotgun Proteomics for Measurement of Brain Proteins in Studies of Psychiatric Disorders. AB - Shotgun proteomics has been used successfully for more than two decades for measurement of proteins from diverse biological systems. This has led to new insights and identification of potential biomarkers and drug targets for numerous medical conditions. The advent of mass-labeling approaches such as isobaric tagging for relative and absolute quantitation (iTRAQ) has allowed multiplexing of samples to improve the accuracy and throughput of experiments and the reduction of costs. Here, we describe a detailed iTRAQ mass spectrometry protocol for simultaneous analysis of four proteomes from postmortem brain tissue extracts. In addition, a post-labeling procedure for peptide fractionation is presented. PMID- 28353241 TI - Sequential Co-immunoprecipitation and Immunoblot Approach to Determine Oligomerisation of G-Protein-Coupled Receptors. AB - G-protein-coupled receptors (GPCRs) play a major role in psychiatric disorders and are the targets of several current therapeutic approaches in this field. A number of studies have now shown that GPCRs can assemble as high molecular weight homo- and hetero-oligomers, which could affect ligand binding, intracellular signalling or trafficking. This information could be critical in design of new drugs to treat neurological and psychiatric disorders. This chapter describes a sequential co-immunoprecipitation and immunoblot protocol for determining oligomerisation of the 5-hydroxytryptamine (HT)1A receptor with other GPCRs in co transfected HEK-293 cells. PMID- 28353240 TI - Co-immunoprecipitation for Deciphering Protein Interactomes. AB - A single protein is often capable of binding with many partners, enabling potential effects on either protein, such as modifying its expression or activity. However, due to the complex nature of in vivo systems, it is often difficult to perform nontargeted assays with a protein of interest. Methods in discovery proteomics must be used to find potential interactors to pave the way for additional, more focused studies. This protocol describes the biological steps needed to create an interactome focused on a single protein target through co-immunoprecipitation. PMID- 28353243 TI - A Protocol for Producing the Maternal Low-Protein Rat Model: A Tool for Preclinical Proteomic Studies. AB - Epidemiological studies have shown that periods of poor nutrition during pregnancy can lead to an increased risk of metabolic and psychiatric disorders in the offspring. In addition, some individuals with disorders such as schizophrenia show signs of impaired insulin signalling. These findings indicate that there may be a link between metabolism and neuronal function and they also provide supporting evidence for neurodevelopmental origins of mental illness. This chapter gives a detailed protocol for generation of the maternal low-protein (LP) rat model, which leads to metabolic disturbances in the offspring. This model has been used in proteomic studies of several disorders including schizophrenia. PMID- 28353242 TI - A Clinical Study Protocol to Identify Serum Biomarkers Predictive of Response to Antipsychotics in Schizophrenia Patients. AB - An increasing number of studies are now exploring the potential of using blood based biomarkers for prediction of antipsychotic treatment response in studies of schizophrenia patients. Here we describe the detailed setup of a clinical study to identify biomarker candidates for prediction of response of patients prior to receiving antipsychotics over a 6-week treatment period. The main emphasis is on study design, patient recruitment, sampling and outcome measures. PMID- 28353244 TI - Generation of the Acute Phencyclidine Rat Model for Proteomic Studies of Schizophrenia. AB - Administration of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (PCP) to rodents has been used as the gold standard preclinical model for schizophrenia. PCP treatment induces hyperlocomotion and stereotypic behaviour, which resemble the positive symptoms of schizophrenia. In addition, proteomic studies have identified changes in proteins associated with energy metabolism and neurotransmission which are typical hallmarks of the disease. This chapter presents a protocol for the generation of this model, behavioural assessment and preparation of key bio-samples to provide the raw materials for proteomic analyses. PMID- 28353245 TI - A Protocol for Generation of a Corticosterone Model of Psychiatric Disorders. AB - Some patients with psychiatric disorders show hyperactivity of the hypothalamic pituitary-adrenal (HPA) axis. This may be due to an impaired feedback inhibition and can be seen through increased levels of circulating cortisol. Here a protocol is described to mimic this situation by subcutaneous implantation of corticosterone pellets in mice. We also present characterization of the model by looking at effects on neuronal proliferation in hippocampus, one of the main tissues known to be affected by HPA axis hyper-activation. Such tissues could be used in analyses by proteomic platforms. PMID- 28353246 TI - MK-801-Treated Oligodendrocytes as a Cellular Model to Study Schizophrenia. AB - Glutamate is the most important excitatory neurotransmitter in the brain. The N methyl-D-aspartate (NMDA) subtype of glutamate receptor is found both in neurons and glial cells such as oligodendrocytes, which have been shown to be dysfunctional in schizophrenia. For this reasons, the oligodendrocyte MO3.13 cell line has been used to study glutamatergic dysfunction as a model of schizophrenia using the NMDA receptor antagonists such as MK-801 to block receptor function. Here, we describe a comprehensive protocol for culturing and carrying out proteomic analyses of MK-801-treated MO3.13 cells as a means of identifying potential new biomarkers and targets for drug discovery in schizophrenia research. PMID- 28353247 TI - Combining Patient-Reprogrammed Neural Cells and Proteomics as a Model to Study Psychiatric Disorders. AB - The mechanisms underlying the pathophysiology of psychiatric disorders are still poorly known. Most of the studies about these disorders have been conducted on postmortem tissue or in limited preclinical models. The development of human induced pluripotent stem cells (iPSCs) has helped to increase the translational capacity of molecular profiling studies of psychiatric disorders through provision of human neuronal-like tissue. This approach consists of generation of pluripotent cells by genetically reprogramming somatic cells to produce the multiple neural cell types as observed within the nervous tissue. The finding that iPSCs can recapitulate the phenotype of the donor also affords the possibility of using this approach to study both the disease and control states in a given medical area. Here, we present a protocol for differentiation of human pluripotent stem cells to neural progenitor cells followed by subcellular fractionation which allows the study of specific cellular organelles and proteomic analysis. PMID- 28353249 TI - Preparation of Peripheral Blood Mononuclear Cells (PBMCs) as a Model for Proteomic Studies of Psychiatric Disorders. AB - Peripheral blood mononuclear cells (PBMCs) have been used as a surrogate model of brain function in studies of psychiatric disorders, such as schizophrenia. This chapter describes the preparation of PBMCs from whole blood using a density gradient/cell culture protocol. This includes collection of the PBMC culture media and preparation of cell extracts in order to provide the raw materials for proteomic analyses. PMID- 28353248 TI - SILAC Mass Spectrometry Profiling: A Psychiatric Disorder Perspective. AB - Stable isotope labelling by amino acids in cell culture (SILAC) is a technique that allows proteomic profiling of cells. In this chapter we describe a protocol for the identification and quantification of newly synthesised proteins. The methodology can be applied to any cultured cell system with relevance to schizophrenia, affective disorders and autism spectrum conditions including those addressing responses to pharmacological stimuli. PMID- 28353250 TI - Proteomic Profiling of Skin Fibroblasts as a Model of Schizophrenia. AB - Since many aspects of schizophrenia are also manifested at the peripheral level in proliferating cell types, this chapter describes the analysis of skin fibroblasts biopsied from living patients. The method focuses on cell culture and sample preparation for characterization of the model. The resulting cell extracts can be analysed by any number of proteomic techniques for identification of biomarker candidates. This approach could help to elucidate the molecular mechanisms associated with the pathophysiology of schizophrenia and provide a useful model for a new target and drug discovery. PMID- 28353251 TI - Proteomic Profiling of the Pituitary Gland in Studies of Psychiatric Disorders. AB - Psychiatric disorders have been associated with perturbations of the hypothalamic pituitary-adrenal axis. Therefore, proteomic studies of the pituitary gland have the potential to provide new insights into the underlying pathways affected in these conditions as well as identify new biomarkers or targets for use in developing improved medications. This chapter describes a protocol for preparation of pituitary protein extracts followed by characterization of the pituitary proteome by label-free liquid chromatography-tandem mass spectrometry in expression mode (LC-MSE). The main focus was on establishing a method for identifying the major pituitary hormones and accessory proteins as many of these have already been implicated in psychiatric diseases. PMID- 28353252 TI - Development of an Assay for Measuring Proprotein-Conversion Activity on a Multiplex Magnetic Bead-Based Array Platform. AB - This chapter describes a protocol for measuring prolyl oligopeptidase (POP) activity using a biotinylated peptide substrate coupled to magnetic microspheres. The complex is incubated in the presence of a pituitary extract and activity can be detected by loss of the biotin label. The assay can be multiplexed for measuring multiple proprotein-cleaving enzymes simultaneously and can be used in analyses of neuropsychiatric diseases in which proteolytic cleavage of biologically active peptides is known to play a role. PMID- 28353253 TI - Phenotyping Multiple Subsets of Immune Cells In Situ in Formalin-Fixed, Paraffin Embedded Tissue Sections. AB - Some somatic illnesses such as peripheral tumours can present with psychiatric symptoms. Many of these are characterized by changes in biomarkers related to the inflammation or immune response. Here, we describe a multispectral imaging protocol that can be used to phenotype immune and other cell types through simultaneous imaging of multiple proteins in sections of peripheral solid tumours and other tissues. This approach can also be used to assess the spatial organization of these cells within the tissue. PMID- 28353254 TI - Lab-on-a-Chip Proteomic Assays for Psychiatric Disorders. AB - Lab-on-a-chip assays allow rapid identification of multiple parameters on an automated user-friendly platform. Here we describe a fully automated multiplex immunoassay and readout in less than 15 min using the Fraunhofer in vitro diagnostics (ivD) platform to enable inexpensive point-of-care profiling of sera or a single drop of blood from patients with various diseases such as psychiatric disorders. PMID- 28353255 TI - Development of a User-Friendly App for Testing Blood Coagulation Status in Schizophrenia Patients. AB - Blood coagulation time is an important factor to consider for postoperative and cardiac disorder patients who have been prescribed anticoagulant coagulant medications. The coagulation process is also known to be perturbed in some individuals with psychiatric disorders, such as schizophrenia. This chapter describes a patient self-management system for a functional assessment of blood coagulation activity, determining the appropriate anticoagulant dosages using a test strip device and the Coagu app. The app can also be used as a patient reminder of treatment times and to monitor treatment and effects over time. PMID- 28353256 TI - Proteomic Approaches to Enable Point-of-Care Testing and Personalized Medicine for Psychiatric Disorders. AB - This chapter describes how innovations that are driven by proteomic biomarker techniques can facilitate earlier and better treatment of patients who suffer from psychiatric disorders. The application of new micro-fluidic devices along with miniaturized biosensors and transducers will enable the development of handheld point-of-care testing instruments which can analyse a drop of a blood within the time span of a single visit to the doctor's office. It is anticipated that these approaches will incorporate both biochemical and clinical information, resulting in unique profiles for each test subject. These profiles can in turn be used to drive personalized medicine approaches in this devastating disease area. In addition, smartphone applications (apps) for self-monitoring will see increasing use for improved patient outcomes. PMID- 28353257 TI - Waste Printed Circuit Board (PCB) Recycling Techniques. AB - With the development of technologies and the change of consumer attitudes, the amount of waste electrical and electronic equipment (WEEE) is increasing annually. As the core part of WEEE, the waste printed circuit board (WPCB) is a dangerous waste but at the same time a rich resource for various kinds of materials. In this work, various WPCB treatment methods as well as WPCB recycling techniques divided into direct treatment (landfill and incineration), primitive recycling technology (pyrometallurgy, hydrometallurgy, biometallurgy and primitive full recovery of NMF-non metallic fraction), and advanced recycling technology (mechanical separation, direct use and modification of NMF) are reviewed and analyzed based on their advantages and disadvantages. Also, the evaluation criteria are discussed including economic, environmental, and gate-to market ability. This review indicates the future research direction of WPCB recycling should focus on a combination of several techniques or in series recycling to maximize the benefits of process. PMID- 28353258 TI - Stem Cell Banking: A Global View. AB - Stem cell banking has been a topic of discussion and debate for more than a decade since the first public services to supply human embryonic stem cells (hESCs) were established in the USA and the UK. This topic has received a recent revival with numerous ambitious programmes announced to deliver large collections of human induced pluripotency cell (hiPSC) lines. This chapter will provide a brief overview charting the development of stem cell banks, their value, and their likely role in the future. PMID- 28353260 TI - Acquisition and Reception of Primary Tissues, Cells, or Other Biological Specimens. AB - The use and banking of biological material for research or clinical application is a well-established practice. The material can be of human or non-human origin. The processes involved in this type of activity, from the sourcing to receipt of materials, require adherence to a set of best practice principles that assure the ethical and legal procurement, traceability, and quality of materials. PMID- 28353259 TI - Quality Assurance in Stem Cell Banking: Emphasis on Embryonic and Induced Pluripotent Stem Cell Banking. AB - For quality assurance (QA) in stem cell banking, a planned system is needed to ensure that the banked products, stem cells, meet the standards required for research, clinical use, and commercial biotechnological applications. QA is process oriented, avoids, or minimizes unacceptable product defects, and particularly encompasses the management and operational systems of the bank, as well as the ethical and legal frameworks. Quality control (QC ) is product oriented and therefore ensures the stem cells of a bank are what they are expected to be. Testing is for controlling, not assuring, product quality, and is therefore a part of QC , not QA. Like QA, QC is essential for banking cells for quality research and translational application (Schwartz et al., Lancet 379:713 720, 2012). Human embryonic stem cells (hESCs), as cells derived from donated supernumerary embryos from in vitro fertilization (IVF) therapy, are different from other stem cell types in resulting from an embryo that has had two donors . This imposes important ethical and legal constraints on the utility of the cells, which, together with quite specific culture conditions, require special attention in the QA system. Importantly, although the origin and derivation of induced pluripotent stem cells (iPSCs ) differ from that of hESCs, many of the principles of QA for hESC banking are applicable to iPSC banking (Stacey et al., Cell Stem Cell 13:385-388, 2013). Furthermore, despite differences between the legal and regulatory frameworks for hESC and iPSC banking between different countries, the requirements for QA are being harmonized (Stacey et al., Cell Stem Cell 13:385 388, 2013; International Stem Cell Banking Initiative, Stem Cell Rev 5:301-314, 2009). PMID- 28353261 TI - Information Management. AB - The collection and storage of human tissue samples has been undertaken in medicine for centuries; however, biobanking has only recently become a dedicated activity. The technological developments that have allowed the procurement and long-term storage of viable human cells ex vivo, and to obtain relevant scientific information, including genetic information, provide tremendous possibilities for advancing biomedical research. At the same time, these possibilities have raised complex information management issues regarding samples, processing, donor information, traceability, and use of the sample. This chapter considers the requirements for managing information within biobanks, critical to their operation. Special consideration is given to Laboratory Information Managing Systems (LIMS) as a tool for comprehensive access and storage of information. PMID- 28353262 TI - Cryopreservation: Vitrification and Controlled Rate Cooling. AB - Cryopreservation is the application of low temperatures to preserve the structural and functional integrity of cells and tissues. Conventional cooling protocols allow ice to form and solute concentrations to rise during the cryopreservation process. The damage caused by the rise in solute concentration can be mitigated by the use of compounds known as cryoprotectants. Such compounds protect cells from the consequences of slow cooling injury, allowing them to be cooled at cooling rates which avoid the lethal effects of intracellular ice. An alternative to conventional cooling is vitrification. Vitrification methods incorporate cryoprotectants at sufficiently high concentrations to prevent ice crystallization so that the system forms an amorphous glass thus avoiding the damaging effects caused by conventional slow cooling. However, vitrification too can impose damaging consequences on cells as the cryoprotectant concentrations required to vitrify cells at lower cooling rates are potentially, and often, harmful. While these concentrations can be lowered to nontoxic levels, if the cells are ultra-rapidly cooled, the resulting metastable system can lead to damage through devitrification and growth of ice during subsequent storage and rewarming if not appropriately handled.The commercial and clinical application of stem cells requires robust and reproducible cryopreservation protocols and appropriate long-term, low-temperature storage conditions to provide reliable master and working cell banks. Though current Good Manufacturing Practice (cGMP) compliant methods for the derivation and banking of clinical grade pluripotent stem cells exist and stem cell lines suitable for clinical applications are available, current cryopreservation protocols, whether for vitrification or conventional slow freezing, remain suboptimal. Apart from the resultant loss of valuable product that suboptimal cryopreservation engenders, there is a danger that such processes will impose a selective pressure on the cells selecting out a nonrepresentative, freeze-resistant subpopulation. Optimizing this process requires knowledge of the fundamental processes that occur during the freezing of cellular systems, the mechanisms of damage and methods for avoiding them. This chapter draws together the knowledge of cryopreservation gained in other systems with the current state-of-the-art for embryonic and induced pluripotent stem cell preservation in an attempt to provide the background for future attempts to optimize cryopreservation protocols. PMID- 28353263 TI - Quality Assured Characterization of Stem Cells for Safety in Banking for Clinical Application. AB - The promise of human pluripotent stem cells to serve as a scalable and renewable starting material for "off the shelf" therapeutic cell products to repair or replace cells and tissues damaged by disease or injury is unparalleled. Whether originating from embryos or the genetic manipulation of adult tissue-derived cells, this prospective impact dictates a comprehensive yet practicable standard of quality assured characterization, blending existing and bespoke standards and considerations. Here, we provide a guide to qualifying the suitability of this resource for human clinical application. PMID- 28353265 TI - Derivation of Human Embryonic Stem Cells. AB - Embryonic stem cells (ESCs) represent a mainstay for pluripotent stem cell research and development (R&D) and provide tangible opportunities for clinical translation including cell therapies and drug discovery. Moreover, in spite of the discovery of induced pluripotent stem cells (iPSCs), ESCs are an essential reference point, against which other pluripotent cells are compared. Hence, there is an ongoing need to derive and bank quality-controlled research-grade and clinical-grade ESC lines using established and standardized methods. Here, we provide a concise, step-by-step protocol for the derivation of ESCs from human embryos. While largely based on previously reported method for clinical-grade human ESC (hESC) line derivation, the protocol is suitable for routine application, although adaptable for clinical-compliance. PMID- 28353264 TI - Ethics and Governance of Stem Cell Banks. AB - This chapter examines the ethical principles and governance frameworks for stem cell banks. Good governance of stem cell banks should balance facilitation of the clinical use of stem cells with the proper respect and protection of stem cell sample providers and stem cell recipients and ensure compliance with national regulatory requirements to foster public trust in the use of stem cell technology. Stem cell banks must develop with regard to the science, the needs of scientists, and the requirements of the public, which will benefit from this science. Given the international reach of this promising research and its clinical application, it is necessary for stem cell bank governance frameworks to be harmonized across jurisdictions. PMID- 28353266 TI - Derivation of Human-Induced Pluripotent Stem Cells in Chemically Defined Medium. AB - Human somatic cells can be reprogrammed by defined factors to induced pluripotent stem cells (iPSCs). Importantly, the quality of iPSCs could impact the potential of these cells in basic and clinic research. Here, we describe a method to reprogram human fibroblast cells with Sendai virus in chemically defined conditions, to generate iPSCs that are integration-free and suitable for research and translational applications. PMID- 28353267 TI - Culture, Adaptation, and Expansion of Pluripotent Stem Cells. AB - The ability of human pluripotent stem cells (hPSCs) to proliferate indefinitely in culture while maintaining their pluripotent properties makes them a powerful tool for use in research, and provides tremendous potential for diagnostic testing, and therapeutic application. Success in these areas, however, is dependent on the ability to effectively expand them in long-term culture while preserving their distinct nature. Contained in this chapter are detailed protocols for the feeder-independent culture and expansion of hPSCs using mTeSR1 medium and Matrigel matrix, and guidelines for the successful transfer of those cells to alternative platforms. These protocols have been used widely by laboratories around the world to successfully expand hPSCs for long-term culture while maintaining their undifferentiated, pluripotent state. PMID- 28353268 TI - Cryobanking Pluripotent Stem Cells. AB - Cryobanking human pluripotent stem cells (hPSCs), be they human embryonic (hESCs) or induced pluripotent stem cells (iPSCs), is essential for their use in research and cell-based therapeutics. Working and master cell banks can be generated with a desired level of quality assurance applied during cell freezing and storage. Conventional vitrification has evolved to more advanced control rate freezing, culminating in a myriad of published protocols with variable proficiencies and clinical efficacies. Notwithstanding, standardized and reliable protocols are necessary for basic science through to applied research and clinical product development. This chapter details several methods for hPSC cryopreservation, suitable for routine application, high-quality research, and adaptable for clinical compliance. PMID- 28353269 TI - Genome Editing in Human Pluripotent Stem Cells. AB - Genome editing in human pluripotent stem cells (hPSCs) enables the generation of reporter lines and knockout cell lines. Zinc finger nucleases, transcription activator-like effector nucleases (TALENs), and CRISPR/Cas9 technology have recently increased the efficiency of proper gene editing by creating double strand breaks (DSB) at defined sequences in the human genome. These systems typically use plasmids to transiently transcribe nucleases within the cell. Here, we describe the process for preparing hPSCs for transient expression of nucleases via electroporation and subsequent analysis to create genetically modified stem cell lines. PMID- 28353270 TI - Isolation, Culture, and Expansion of Mesenchymal Stem Cells. AB - Mesenchymal stem cells (MSCs), together with hematopoietic stem cells (HSCs), are the most frequently used cell type for cell-based therapeutics. As for other cell types intended for research and translational use, it is important to establish correctly typed cell lines from human tissue donations. Here, we describe methods for isolating, culturing, and identifying MSCs from various tissues obtained through human tissue donation. The methods have been used in the context of a biobank, prepared as standard operating procedures (SOPs), ensuring traceability and reproducibility of cell production. PMID- 28353271 TI - Cryobanking Mesenchymal Stem Cells. AB - Cryopreservation and storage of culture-expanded mesenchymal stem cells (MSCs) is essential for a biobank to maintain a collection of cell lines for research and clinical use. Optimization of cryopreservation protocols and methods to minimize damage to cells during freezing and thawing is critical to ensure reliable availability of viable cells. Controlling the freezing rate and the use of appropriate cryoprotectant, as well as stable storage temperature, can minimize the negative effects on cell viability. In this chapter, protocols for cryopreserving MSCs are described. PMID- 28353272 TI - Culturing and Cryobanking Human Neural Stem Cells. AB - The discovery and study of human neural stem cells has advanced our understanding of human neurogenesis, and the development of novel therapeutics based on neural cell replacement. Here, we describe methods to culture and cryopreserve human neural stem cells (hNSCs) for expansion and banking. Importantly, the protocols ensure that the multipotency of hNSCs is preserved to enable differentiation to neurons and supporting neuroglia. PMID- 28353274 TI - Relative hepatic weight using body weight may be not accurate. PMID- 28353273 TI - Clinical characteristics of children with hemolytic uremic syndrome in Hangzhou, China. AB - BACKGROUND: Hemolytic uremic syndrome (HUS) is a main cause of acute renal failure in children. This study aimed to analyze the clinical characteristics of HUS. METHODS: A retrospective analysis was performed in 46 children with sporadic HUS. RESULTS: Of the 46 HUS patients, 20 (43.5%) were diarrhea-related HUS, and 26 (56.5%) were atypical HUS. Anemia, edema, oliguria, hemoglobinuria and hypertension were the most common manifestations. Thrombocytopenia, hyponatremia, hypocalcemia, hyperkalemia, metabolic acidosis, increased fibrinogen and hypocomplementemia were found in most patients. The age of onset (younger than 2 years or not, P=0.009), the duration of oliguria or anuria (more than one week or not, P=0.005), accompanied with extrarenal complications or not (P=0.005), dialysis and plasma exchange (P=0.04) were associated with the mortality rate. CONCLUSIONS: The age of onset younger than 2 years, oliguria/anuria more than 1 week, and associated with extrarenal complications were predictive factors of poor prognosis. PMID- 28353275 TI - Relative hepatic weight using body weight may be not accurate. PMID- 28353276 TI - Leucine-Rich Repeat Kinase (LRRK2) Genetics and Parkinson's Disease. AB - The discovery of LRRK2 mutations as a cause of Parkinson's disease (PD), including the sporadic late-onset form, established the decisive role of genetics in the field of PD research. Among LRRK2 mutations, the G2019S, mostly lying in a haplotype originating from a common Middle Eastern ancestor, has been identified in different populations worldwide. The G2385R and R1628P variants represent validated risk factors for PD in Asian populations. Here, we describe in detail the origin, the present worldwide epidemiology, and the penetrance of LRRK2 mutations. Furthermore, this chapter aims to characterize other definitely/probably pathogenic mutations and risk variants of LRRK2. Finally, we provide some general guidelines for a LRRK2 genetic testing and counseling. In summary, LRRK2 discovery revolutionized the understanding of PD etiology and laid the foundation for a promising future of genetics in PD research. PMID- 28353277 TI - Clinical Features of LRRK2 Carriers with Parkinson's Disease. AB - LRRK2 mutations are present in 1% of all sporadic Parkinson's disease (PD) cases and 5% of all familial PD cases. Several mutations in the LRRK2 gene are associated with PD, the most common of which is the Gly2019Ser mutation. In the following review, we summarize the demographics and motor and non-motor symptoms of LRRK2 carriers with PD, as well as symptoms in non-manifesting carriers. The clinical features of LRRK2-associated PD are often indistinguishable from those of idiopathic PD on an individual basis. However, LRRK2 PD patients are likely to have less non-motor symptoms compared to idiopathic PD patients, including less olfactory and cognitive impairment. LRRK2-associated PD patients are less likely to report REM sleep behavior disorder (RBD) than noncarriers. In addition, it is possible that carriers are more prone to cancer than noncarriers with PD, but larger studies are required to confirm this observation. Development of more sensitive biomarkers to identify mutation carriers at risk of developing PD, as well as biomarkers of disease progression among LRRK2 carriers with PD, is required. Such biomarkers would help evaluate interventions, which may prevent PD among non-manifesting carriers, or slow down disease progression among carriers with PD. PMID- 28353278 TI - LRRK2 Phosphorylation. AB - Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene were discovered in 2004 and have been found to be the most frequently mutated gene in Parkinson's disease. LRRK2 is a large multi-domain protein with a functional GTPase and kinase domain. The signal transduction pathways in which LRRK2 is dysfunctional in the disease state are only now being resolved, but we do know that LRRK2 is, itself, a substrate of multiple kinases and phosphatases and exists in variable phosphorylated states. Autophosphorylation of LRRK2 can impact GTPase and pathological outcomes. LRRK2 serines (910/935/955/973) are differentially phosphorylated in pathogenic PD mutations and after LRRK2 kinase inhibition. The phosphorylation status of LRRK2 can therefore provide key insight into the mechanisms of kinase dysfunction during disease. This chapter will describe the identification of LRRK2 phosphorylation sites and how phosphoregulation of LRRK2 reveals its own kinase activity and regulates its ubiquitination and localization in vitro, in cells, and in tissues. PMID- 28353280 TI - LRRK2 and Autophagy. AB - Leucine-rich repeat kinase 2 (LRRK2) has been implicated in a wide range of cellular processes, including the catabolic pathways collectively described as autophagy. In this chapter, the evidence linking LRRK2 to autophagy will be examined, along with how regulation of autophagy and lysosomal pathways may provide a nexus between the physiological function of this protein and the different diseases with which it has been associated. Data from cellular and animal models for LRRK2 function and dysfunction support a role in the regulation and control of autophagic pathways in the cell, although the extant results do not provide a clear indication as to whether LRRK2 is a positive or negative regulator of these pathways, and there are conflicting data as to the impact of mutations in LRRK2 causative for Parkinson's disease. Given that LRRK2 is a priority drug target for Parkinson's, the evidence suggesting that knockout or inhibition of LRRK2 can result in deregulation of autophagy may have important implications and is discussed in the context of our wider understanding of LRRK2. PMID- 28353279 TI - Understanding the GTPase Activity of LRRK2: Regulation, Function, and Neurotoxicity. AB - Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of Parkinson's disease (PD) with late-onset and autosomal-dominant inheritance. LRRK2 belongs to the ROCO superfamily of proteins, characterized by a Ras-of-complex (Roc) GTPase domain in tandem with a C-terminal-of-Roc (COR) domain. LRRK2 also contains a protein kinase domain adjacent to the Roc-COR tandem domain in addition to multiple repeat domains. Disease-causing familial mutations cluster within the Roc-COR tandem and kinase domains of LRRK2, where they act to either impair GTPase activity or enhance kinase activity. Familial LRRK2 mutations share in common the capacity to induce neuronal toxicity in cultured cells. While the contribution of the frequent G2019S mutation, located within the kinase domain, to kinase activity and neurotoxicity has been extensively investigated, the contribution of GTPase activity has received less attention. The GTPase domain has been shown to play an important role in regulating kinase activity, in dimerization, and in mediating the neurotoxic effects of LRRK2. Accordingly, the GTPase domain has emerged as a potential therapeutic target for inhibiting the pathogenic effects of LRRK2 mutations. Many important mechanisms remain to be elucidated, including how the GTPase cycle of LRRK2 is regulated, whether GTPase effectors exist for LRRK2, and how GTPase activity contributes to the overall functional output of LRRK2. In this review, we discuss the importance of the GTPase domain for LRRK2-linked PD focusing in particular on its regulation, function, and contribution to neurotoxic mechanisms. PMID- 28353282 TI - LRRK2 and the Immune System. AB - Polymorphisms in leucine-rich repeat kinase 2 (LRRK2) have been linked to familial Parkinson's disease, increased risk of sporadic Parkinson's disease, increased risk of Crohn's inflammatory bowel disease, and increased susceptibility to leprosy. As well as LRRK2 mutations, these diseases share in common immune dysfunction and inflammation. LRRK2 is highly expressed in particular immune cells and has been biochemically linked to the intertwined pathways regulating inflammation, mitochondrial function, and autophagy/lysosomal function. This review outlines what is currently understood about LRRK2 function in the immune system and the potential implications of LRRK2 dysfunction for diseases genetically linked to this enigmatic enzyme. PMID- 28353281 TI - Molecular Insights and Functional Implication of LRRK2 Dimerization. AB - The Parkinson's disease protein leucine-rich repeat kinase 2 (LRRK2) is a multidomain protein with an enzymatic core comprising serine-threonine kinase and GTPase activities and a number of protein-protein interaction domains. While the complex domain architecture of LRRK2 has hampered its structural investigation, there is convincing evidence that LRRK2 can form dimers in solution and in the cell and that the GTPase/ROC domain plays a central role in this process. This chapter focuses on recent studies addressing the molecular nature, the functional significance, and the pathological implication of LRRK2 dimerization. PMID- 28353283 TI - Regulation of LRRK2 by Phosphatases. AB - LRRK2 is a highly phosphorylated protein, and evidence of a physiological role for LRRK2 phosphorylation has accumulated in recent years for cellular phosphosites, many of which are found in the ANK-LRR interdomain region, i.e., the S910/S935/S955/S973 sites as well as recently for autophosphorylation sites, at least one of which has been confirmed in cells, S1292. LRRK2 phosphorylation is modulated in several disease or potential therapy relevant conditions such as in disease mutant variants of LRRK2 or following LRRK2 kinase inhibitor treatment. This chapter will focus on the regulation of LRRK2 phosphorylation and more specifically the role of phosphatases in LRRK2 dephosphorylation. This will include reviewing the conditions in which LRRK2 is found to be dephosphorylated, the molecular partners and phosphatases involved in regulating LRRK2 phosphorylation, as well as discussing how LRRK2 phosphatases may be therapeutic targets or biomarkers in their own right. PMID- 28353285 TI - LRRK2 and the "LRRKtosome" at the Crossroads of Programmed Cell Death: Clues from RIP Kinase Relatives. AB - Since its cloning and identification in 2004, considerable gains have been made in the understanding of the basic functionality of leucine-rich repeat kinase 2 (LRRK2), including its kinase and GTPase activities, its protein interactors and subcellular localization, and its expression in the CNS and peripheral tissues. However, the mechanism(s) by which expression of mutant forms of LRRK2 lead to the death of dopaminergic neurons of the ventral midbrain remains largely uncharacterized. Because of its complex domain structure, LRRK2 exhibits similarities with multiple protein families including ROCO proteins, as well as the RIP kinases. Cellular models in which mutant LRRK2 is overexpressed in neuronal-like cell lines or in primary neurons have found evidence of apoptotic cell death involving components of the extrinsic as well as intrinsic death pathways. However, since the expression of LRRK2 is comparatively quite low in ventral midbrain dopaminergic neurons, the possibility exists that non-cell autonomous signaling also contributes to the loss of these neurons. In this chapter, we will discuss the different neuronal death pathways that may be activated by mutant forms of LRRK2, guided in part by the behavior of other members of the RIP kinase protein family. PMID- 28353286 TI - Interaction of LRRK2 and alpha-Synuclein in Parkinson's Disease. AB - Parkinson's disease (PD) is a progressively debilitating neurodegenerative syndrome. It is best described as a movement disorder characterized by motor dysfunctions, progressive degeneration of dopaminergic neurons of the substantia nigra pars compacta, and abnormal intraneuronal protein aggregates, named Lewy bodies and Lewy neurites. Nevertheless, knowledge of the molecular events leading to this pathophysiology is incomplete. To date, only mutations in the alpha synuclein and LRRK2-encoding genes have been associated with typical findings of clinical and pathologic PD. LRRK2 appears to have a central role in the pathogenesis of PD as it is associated with alpha-synuclein pathology and other proteins implicated in neurodegeneration. Thus, LRRK2 dysfunction may influence the accumulation of alpha-synuclein and its pathology through diverse pathomechanisms altering cellular functions and signaling pathways, including immune system, autophagy, vesicle trafficking, and retromer complex modulation. Consequently, development of novel LRRK2 inhibitors can be justified to treat the neurodegeneration associated with abnormal alpha-synuclein accumulation. PMID- 28353287 TI - Mechanisms of Mutant LRRK2 Neurodegeneration. AB - LRRK2 mutations are associated with the loss of neurons, that is to say toxicity, in patients and in experimental model systems. However, the mechanisms by which mutations can be linked to neurodegeneration are not fully defined. Here I will argue that mechanism in this context encompasses a variety of levels of information. Mutations or alterations in gene expression at a genetic level are one set of mechanisms that are reflected at the biochemical level likely in enhanced or persistent function of LRRK2. By impacting cellular pathways, prominently including changes in autophagy but also microtubule function, mitochondria and protein synthesis, in neurons and immune cells, the LRRK2 brain is primed for neurodegeneration in an age-dependent manner. These concepts have implications for not only modeling LRRK2 disease but also perhaps for Parkinson's disease more generally, including the development of therapeutic modalities. PMID- 28353284 TI - Models of LRRK2-Associated Parkinson's Disease. AB - Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic causes of Parkinson's disease (PD) and also one of the strongest genetic risk factors in sporadic PD. The LRRK2 protein contains a GTPase and a kinase domain and several protein-protein interaction domains. Both in vitro and in vivo assays in different model systems have provided tremendous insights into the molecular mechanisms underlying LRRK2-induced dopaminergic neurodegeneration. Among all the model systems, animal models are crucial tools to study the pathogenesis of human disease. How do the animal models recapitulate LRRK2 induced dopaminergic neuronal loss in human PD? To answer this question, this review focuses on the discussion of the animal models of LRRK2-associated PD including genetic- and viral-based models. PMID- 28353288 TI - Small-Molecule Inhibitors of LRRK2. AB - Mutations in the leucine-rich repeat kinase 2 (LRRK2) protein have been genetically and functionally linked to Parkinson's disease (PD). The kinase activity of LRRK2 is increased by pathogenic mutations; therefore, modulation of LRRK2 kinase activity by a selective small-molecule inhibitor has been proposed as a potentially viable treatment for Parkinson's disease. This chapter presents a historical overview of the development and bioactivity of several small molecule LRRK2 inhibitors that have been used to inhibit LRRK2 kinase activity in vitro or in vivo. These compounds are important tools for understanding the cellular biology of LRRK2 and for evaluating the potential of LRRK2 inhibitors as disease-modifying PD therapies. PMID- 28353289 TI - Factor structure and concurrent construct validity of ICG among bereaved substance users. AB - BACKGROUND: It is important to understand the repercussions of Complicated Grief (CG) symptoms in addictions. There are no studies to date which have examined the psychometric properties of any test of bereavement among people with substance use disorder (SUD). Participants with SUD can have a different experience of bereavement from other people and therefore could respond differently to the usual instruments which assess CG symptomatology. METHOD: This study aims to establish the psychometric properties of the Spanish adaption of the Inventory of Complicated Grief (ICG) in a sample of 196 bereaved drug dependent patients. RESULTS: Results indicate that the internal consistency of the Spanish ICG was high (Cronbach’s alpha=0.922). The Spanish IDC shows good psychometric properties and it is a useful tool to discriminate adaptive reactions to symptomatology of complicated grief. Four factors were identified: discomfort, non-acceptance, loneliness-isolation and presence of deceased. Those factors showed a good internal reliability (minimum Cronbach’s alpha=0.78). CONCLUSIONS: The results of the current study confirm the multidimensionality of CG’s symptomatology construct. PMID- 28353291 TI - Problematic Technology Use in a clinical sample of children and adolescents. Personality and behavioral problems associated. AB - INTRODUCTION: In parallel to the rapid growth of access to new technologies (NT) there has been an increase in the problematic use of the same, especially among children and adolescents. Although research in this field is increasing, the studies have mainly been developed in the community, and the characteristics associated with the problematic use of NT are unknown in samples that require clinical care. Therefore, the aim of this study is to analyze the relationship between problematic use of video games (UPV) and Internet (UPI) and personality traits and behavior problems in a clinical sample of children and adolescents. METHODOLOGY: The sample consists of 88 patients who were examined in the clinical psychology consultation in the Mental Health Unit for Children and Adolescents of the University Hospital of Santiago de Compostela. Data were obtained from self reports and rating scales filled out by parents. RESULTS: 31.8% of the participants present UPI and 18.2%, UPV. The children and adolescents with UPNT have lower levels of Openness to experience, Conscientiousness and Agreeableness and higher levels of Emotional instability, global Impulsivity and Externalizing behavior problems, as well as Attention and Thought problems. CONCLUSIONS: UPNT is a problem that emerges as an important issue in clinical care for children and adolescents, so its study in child and youth care units is needed. Understanding the psychopathological profile of children and adolescents with UPNT will allow for the development of differential and more specific interventions. PMID- 28353290 TI - Validation of the Portuguese version of the Psychotic Symptom Rating Scales (PSYRATS). AB - The Psychotic Symptom Rating Scales (PSYRATS) is a clinical assessment tool that focuses on the detailed measurement of delusions and hallucinations in patients with psychosis. The goal of this study was to examine the psychometric properties of the Portuguese version of the PSYRATS. A sample of 92 outpatients suffering from schizophrenia or schizoaffective disorders and presenting persistent psychotic symptoms was assessed using the PSYRATS and the Positive and Negative Syndrome Scale (PANSS). Good inter-rater reliability, test-retest reliability, concurrent validity and internal consistency were found. Factor analysis of the auditory hallucinations scale items disclosed a four-factor solution: emotion characteristics and disruption factor (factor 1), a physical characteristics factor (factor 2), a control characteristics factor (factor 3) and a cognitive attribution factor (factor 4). Regarding the delusions scale items, a two-factor solution was found: cognitive interpretation and disruption factor (factor 1) and an emotional characteristics (factor 2). The Portuguese version of the PSYRATS partially replicates previously published results in other countries. PMID- 28353292 TI - Psychosis management in patients with hiv: case report. AB - Human immunodeficiency virus (HIV) infection can cause neuropsychiatric disorders such as cognitive impairment, behavioural difficulties or psychiatric symptoms –for instance, mania and psychosis. HIV patients with psychiatric comorbidities need an appropriate treatment which tackles the HIV infection as much as the particular mental symptoms. Here we present the case of a patient suffering from delusions, which turned out to be caused by encephalitis secondary to a previously unknown HIV infection. A review of psychosis in HIV-infected patients is also presented. This review is focused on the epidemiology, etiopathogenesis and clinical presentation of HIV-induced psychosis, as well as the recommended pharmacological treatment (antiretroviral therapy and antipsychotic medication) and the expected treatment response. We also present wide information concerning pharmacological interactions between antiretroviral and antipsychotic medications that we hope will help the clinician to better manage this complex condition. PMID- 28353293 TI - Unconjugated bilirubin and acute schizophrenia: a probable correlation? PMID- 28353294 TI - Delusional psychosis induced by dopamine agonists in the treatment of Parkinson’s disease: four clinical cases. PMID- 28353295 TI - Comorbidity of autism spectrum disorder and bipolar disorder. PMID- 28353296 TI - Preliminary versions of the chapter on mental disorders of the ICD-11. PMID- 28353299 TI - An unusual case of accessory head of coracobrachialis muscle involving lateral cord of brachial plexus and its clinical significance. AB - Knowledge of anatomical variations in the peripheral nervous system is key in the interpretation of unusual clinical signs or during physical or diagnostic imaging. This case study is a description of an anatomical variation between the coracobrachialis muscle and brachial plexus. In a routine dissection in the human anatomy laboratory, we were faced with an anatomical variation in the coracobrachialis muscle, observed in the upper right limb of a male cadaver. The coracobrachialis muscle had a common origin at the apex of the coracoid process and then divided into two heads. The lateral head followed its normal course until insertion into the middle third of the humerus, while the medial head involved the lateral cord of the brachial plexus before insertion into the intermuscular septum in the proximal third of the humerus. Atypical anatomical variations have clinical and surgical implications in procedures such as brachial plexus block and lateral cord compression. In these cases the result could be paralysis of the flexor musculature of the forearm and hypoesthesia of the forearm. PMID- 28353300 TI - Morphological variations of the vermiform appendix in Iranian cadavers: a study from developing countries. AB - BACKGROUND: The vermiform appendix is a worm like tube containing a large amount of lymphoid follicles. In our knowledge, there is a little standard data about the vermiform appendix in Iranian population. Therefore, the objective of this study was to investigate the normal appendix size in Iranian cadavers. MATERIALS AND METHODS: A cross-sectional study was undertaken between June 2014 and July 2015, in the autopsy laboratory, Legal Medicine Organization, Razavi Khorasan province, Iran. A total of 693 cadavers with the mean age of 40.46+/-20.99 years were divided into 10 groups. After writing down position of the appendix, the length, diameter and weight of appendix were measured. Statistical analysis was performed using SPSS software. RESULTS: The mean values of the demographic characteristics included: age= 40.46 +/- 20.99 years; weight = 63.47 +/- 17.84 kg; height = 159.95 +/- 28.23 cm. The mean values of the appendix length, diameter, weight and index in the cadavers were 8.52 +/- 2.99 cm, 12.17 +/- 4.53 mm, 6.43 +/- 3.26 grams and 0.013 +/- 0.01, respectively. The most common position of appendix was retrocecal in 71.7% of cases. A significant correlations were evident between the value of demographic data and appendix size (P<0.05). The diameter (P=0.002) and index of appendix (P=0.003) showed significant difference between males and females. CONCLUSIONS: Having standard data on the vermiform appendix is useful for clinicians as well as anthropologists. The findings of the present study can provide information about morphologic variations of the appendix in Iranian population. PMID- 28353302 TI - Prevalence and morphometric features of fossa navicularis on cone beam computed tomography in Turkish population. AB - BACKGROUND: The objective of this study is to determine the prevalence and morphometric features of fossa navicularis, a close radiographic anatomic variation of canalis basilaris medianus of the basiocciput, in a Turkish population using cone beam computed tomography (CBCT). MATERIALS AND METHODS: The study group consisted of 723 patients (female: 420, male: 303) having CBCT scans. The patients had no syndromes, history of neurological diseases or surgery in the area of interest. On the images that revealed a fossa navicularis, the depth, length, and width measurements were performed, and were compared to the age and gender of the patients. The shape and number of fossa navicularis were also recorded. RESULTS: Fossa navicularis was identified in 48 (6.6%) patients. Among these patients, 19 were female (4.5% of all female patients), whereas 29 were male (9.6% of all male patients), and their age ranged between 10 and 68 (mean age: 34.0+/-18.7). No significant difference was found between genders and age groups in terms of depth, length, and width measurements (p>0.05). In 39 patients (5.4%), fossa navicularis presented oval in shape. CONCLUSIONS: Even though the prevalence of fossa navicularis was found to be higher than previously reported, it still seems to be rare. Anatomical structure of the fossa navicularis can be studied effectively on CBCT images. PMID- 28353301 TI - Anatomical structure of the coracohumeral ligament and its effect on shoulder joint stability. AB - BACKGROUND: In this study, coracohumeral ligament (CHL) specimens were carefully dissected to observe its length, width, thickness and tension at different positions of the shoulder joint, thereby elucidating its effects on shoulder joint stability. MATERIALS AND METHODS: Fresh frozen shoulder joints from 40 normal adult cadaveric specimens were dissected to reveal the CHL. With the shoulder joints placed at different positions, the length of the CHL and the width and thickness of the middle part of the ligament were measured. The changes in tension of the CHL were also observed. When the shoulder joint maintained the neutral position, the length of the CHL was 52.23 +/- 1.02 mm and the width and thickness of the middle part of the ligament were 15.95 +/- 0.59 and 1.46 +/- 0.06 mm, respectively. RESULTS: When the shoulder joint moved from the neutral position to 90 degrees external rotation, from the neutral position to 30 degrees adduction or from the neutral position to 30 degrees flexion/extension or when the shoulder joint is pulled down with a 5 kg weight, the CHL was elongated and thinned, maintaining a strained state. When the shoulder joint moved from the neutral position to 90 degrees internal rotation, from the neutral position to 90 degrees abduction or from the neutral position to 30 degrees flexion/extension, the CHL was shortened and thickened, maintaining a relaxed state. CONCLUSIONS: The CHL may limit the external rotation, adduction and downward movement of the shoulder joint and the process from the neutral position to the 30 degrees flexion/extension, maintaining shoulder joint stability. PMID- 28353303 TI - Stroke Bricks - spatial brain regions to assess ischaemic stroke localisation. AB - Computer-aided analysis of non-contrast computed tomography (NCCT) images for rapid diagnosis of ischaemic stroke is based on the augmented visualisation of evolving ischaemic lesions. Computerised support of NCCT often leads to overinterpretation of ischaemic areas, thus it is of great interest to provide neurologically verified regions in order to improve accuracy of subsequent radiological assessment. We propose Stroke Bricks (StBr) as an arbitrary spatial division of brain tissue into the regions associated with specific clinical symptoms of ischaemic stroke. Neurological stroke deficit is formally translated into respective areas of possible ischaemic lesions. StBr were designed according to formalised mapping of neurological symptoms and were attributed to the uniquely defined areas of impaired blood supply. StBr concept may be useful for an integrated radiological CT-based assessment of suspected stroke cases or can be included into computer-aided tools to optimise the evaluation of stroke site and its extent. These data in turn are appropriable for further diagnosis, predicting the therapeutic outcome as well as for patients' qualification for an appropriate form of reperfusion therapy. The usefulness of StBr was illustrated in the case studies. PMID- 28353304 TI - Radiological anatomy of distal phalanx of front foot in the pure Iranian Arabian horse. AB - Among the different breeds of horses, Asil horses with a five thousand year history have played an important role in human life. This study was designed as a result of the lack of information about the normal radiographic anatomy of this breed. Radiography of the distal phalanx and associated soft-tissue structures of the front feet of 10 healthy pure Iranian Arabian horses was performed on lateromedial radiographic projection to determine normal radiographic morphometry of this part. There were no problems in their limbs and in their history. Obtained radiograph of each front distal phalanx was used to measure important distances, angles and ratios of the hoof wall. There was no significant difference between left and right digits for any radiographic determination. Measurements of this study differed with those reported from other breeds, so it can be used in the future as reference values for diagnosis of laminitis in front feet of Iranian Arabian horses. PMID- 28353305 TI - Anatomical changes in the East Asian midface skeleton with aging. AB - PURPOSE: Understanding the aging process of the midface skeleton is considered crucial for correct facial rejuvenation. However, the canine fossa, an important morphological feature of the midface skeleton, has not yet been observed in connection with aging, despite the fact that it is the most main part of the maxillary bone. Here, the authors focus on the depression of the canine fossa to evaluate the Asian midface skeleton. METHODS: Computed tomography (CT) scans of the facial skeleton of 114 Koreans (59 males and 55 females) were reconstructed to three-dimensional (3-D) images using a 3-D analysis software program. The study subjects included 27 young males, 32 old males, 28 young females and 27 old females. The angular measurements of 3 bony regions were measured for each 3-D model: the canine fossa angle (assessing depth of the canine fossa), the maxillary angle (assessing orientation of the lateral maxilla) and the piriform angle (assessing orientation of the medial maxilla). RESULTS: The canine fossa angle showed a statistically significant decrease with aging in both sexes, indicating the canine fossa actually becomes more concave with age. In contrast, the maxillary and piriform angle showed statistically insignificant changes with aging in female subjects. CONCLUSIONS: These results suggest that the canine fossa may be one of the effective markers to evaluate the anatomical changes to the facial skeleton with midface aging. PMID- 28353306 TI - Anatomical variations of the sternal angle and anomalies of adult human sterna from the Galloway osteological collection at Makerere University Anatomy Department. AB - BACKGROUND: Anatomical variations of the sternal angle and anomalies of the sternum are unique happenings of major clinical significance.It is known that misplaced sternal angles may lead to inaccurate counting of ribs and create challenges with intercostal nerve blocks and needle thoracostomies. Sternal foramina may pose a great hazard during sternal puncture, due to inadvertent cardiac or great vessel injury. These sternal variations and anomalies are rarely reported among Africans. The aim of this study was to determine the anatomical variations of the sternal angle and anomalies of the sternum among adult dry human sterna at the Galloway osteological collection, Makerere University, Uganda. METHODS: This was a descriptive cross sectional study in which quantitative and qualitative data were collected. The study examined 85 adult human sterna at the Department of Anatomy, Makerere University. Univariate and bivariate analyses were done using SPSS 21.0 for windows. RESULTS: Over 40% (36/85) of the specimens had variations in size, location and fusion of the sternal angle. There was no significant difference in the mean size of the sternal angle in males at 163.40 (SD 6.7) compared with 165.00 (SD 6.4) in females (p=0.481). Of the 85 specimens examined, only 21 (24.7%) had a xiphoid process. The most frequent sternal anomalies were bifid xiphoid process 42.9% (9/21) and sternal foramen 12.9% (11/85). CONCLUSIONS AND RECOMMENDATIONS: Sternal variations and anomalies are prevalent in the Galloway osteological collection and there is need for increased awareness of these findings as they may determine the accuracy of clinical and other procedures in the thoracic region. PMID- 28353307 TI - Prediction of unstable anticoagulation with acenocoumarol versus warfarin in atrial fibrillation. AB - BACKGROUND: The SAMe-TT2R2 (sex female, age, medical history, treatment, tobacco use, race) score was developed in patients with atrial fibrillation (AF) on warfarin. The present study aimed to 1) compare the anticoagulation quality and management of AF patients treated with warfarin with those on acenocoumarol and 2) optimize the SAMe-TT2R2 score to detect AF patients at high risk of unstable anticoagulation with acenocoumarol and warfarin. METHODS: In a single-center retrospective study, 320 patients with AF, including 15 (5%) after valve replacement, aged 40-82 (median 70) years, including 203 (63%) receiving acenocoumarol and 117 (37%) treated with warfarin, were studied. The SAMe-TT2R2 score was modified based on the candidate factors retrieved from univariate regression and assessed using the receiver operating curves (ROC). RESULTS: A median SAMe-TT2R2 score was 2 (1-3). Proportions of patients with >= 2 points and 0-1 points in the SAMe-TT2R2 score who had the time in therapeutic range (TTR) <= 70% were similar (61 [67%] vs. 63 [56%], p = 0.11). A modified score, involving medical history (myocardial infarction [MI] and chronic obstructive pulmonary disease [COPD], 1 point), statin treatment (1 point) and tobacco use (2 points) had a higher area under the curve (AUC) in patients on acenocoumarol compared to SAMe- TT2R2 (0.66; 95% confidence interval 0.58-0.73 vs. 0.56; 0.48-0.64, p = 0.042); >= 1 point indicated TTR > 70% with a sensitivity and specificity of 61% and 63%, respectively. CONCLUSIONS: The SAMe-TT2R2 score is less effective in predicting unstable anticoagulation with acenocoumarol versus warfarin. Adding statin use and highlighting COPD and previous MI increases a predictive value of this score for acenocoumarol. PMID- 28353308 TI - Prognostic value of red blood cell distribution width in patients with left ventricular systolic dysfunction: Insights from the COMMIT-HF registry. AB - BACKGROUND: Previous studies have reported that in patients with heart failure, an increased value of red cell distribution width (RDW) is associated with adverse outcomes. Nonetheless, data regarding the association between RDW values and long-term mortality in patients with left ventricular systolic dysfunction (LVSD) are lacking. The aim of this investigation was to examine the relationship between mortality and RDW in patients with ischemic and non-ischemic LVSD. METHODS: Under analysis was 1734 patients with a left ventricular ejection fraction (LVEF) <= 35% of whom were hospitalized between 2009 and 2013. Patients were divided into three groups based on RDW tertiles. Low, medium and high tertiles were defined as RDW <= 13.4%, 13.4% < RDW <= 14.6% and RDW > 14.6%, respectively. RESULTS: There was a stepwise relationship between RDW intervals and comorbidities. Patients with the highest RDW values were older and more often diagnosed with anemia, diabetes, atrial fibrillation and chronic kidney disease. The main finding of our analysis was the presence of an 8-fold increase in all cause mortality in the entire cohort between high and low RDW tertile. Cox hazard analysis identi-fied RDW as an independent predictive factor of mortality in all patients (HR 2.8; 95% CI 2.1-3.8; p < 0.0001) and in subgroups of patients with ischemic (HR 2.8; 95% CI 2.0-3.9; p < 0.0001) and non-ischemic (HR 3.3; 95% CI 2.01-5.5; p < 0.0001) LVSD. CONCLUSIONS: The highest RDW tertile was independently associated with higher long-term mortality compared with low and medium tertiles, both in all patients with a LVEF <= 35% and in subgroups of patients with ischemic and non-ischemic LVSD. PMID- 28353309 TI - Cardiac magnetic resonance imaging derived quantification of myocardial ischemia and scar improves risk stratification and patient management in stable coronary artery disease. AB - BACKGROUND: Quantification of myocardial ischemia and necrosis might ameliorate prognostic models and lead to improved patient management. However, no standardized consensus on how to assess and quantify these parameters has been established. The aim of this study was to quantify these variables by cardiac magnetic resonance imaging (CMR) and to establish possible incremental implications in cardiovascular risk prediction. METHODS: This study is a retrospective analysis of patients with known or suspected coronary artery disease (CAD) referred for adenosine perfusion CMR was performed. Myocardial ischemia and necrosis were assessed and quantified using an algorithm based on standard first-pass perfusion imaging and late gadolinium enhancement (LGE). The combined primary endpoint was defined as cardiac death, non-fatal myocardial infarction, and stroke. RESULTS: 845 consecutive patients were enrolled into the study. During the median follow-up of 3.64 [1.03; 10.46] years, 61 primary endpoints occurred. Patients with primary endpoint showed larger extent of ischemia (10.7 +/- 12.25% vs. 3.73 +/- 8.29%, p < 0.0001) and LGE (21.09 +/- 15.11% vs. 17.73 +/- 10.72%, p < 0.0001). A risk prediction model containing the extent of ischemia and LGE proved to be superior in comparison to all other models (chi2 increase: from 39.678 to 56.676, integrated discrimination index: 0.3851, p = 0.0033, net reclassification index: 0.11516, p = 0.0071). The ben eficial effect of revascularization tended to be higher in patients with greater extents of ischemia, though statistical significance was not reached. CONCLUSIONS: Quantification of myocardial ischemia and LGE was shown to significantly improve existing risk prediction models and might thus lead to an improvement in patient management. PMID- 28353311 TI - Blockade of beta2-adrenoceptor, rather than beta1-adrenoceptor, deteriorates cardiac anaphylaxis in isolated blood-perfused rat hearts. AB - BACKGROUND: Cardiac anaphylaxis is one of the features of anaphylactic hypotension. Patients treated with propranolol, a nonselective beta-adrenoceptor (AR) antagonist, develop severe anaphylaxis, but the mechanism remains unknown. Under examination were the effects of beta1- and beta2-AR antagonist on anaphylaxis-induced coronary vasoconstriction and cardiac dysfunction in isolated blood-perfused rat hearts. METHODS: Isolated hearts from ovalbumin-sensitized Wistar rats were subjected to coronary perfusion with blood at a constant pressure and measurements were made of coronary blood flow and left ventricu-lar (LV) pressure. Following pretreatment with selective beta2-AR antagonist ICI118,551 or selective beta1-AR antagonist atenolol, cardiac anaphylaxis was induced by intracoronary injections of ovalbumin antigen. LV contractility was evaluated by the maximum increasing rate of systolic LV pressure (dP/dtmax). RESULTS: In response to antigen administrations, ICI118,551 pretreated hearts showed a greater de-crease in coronary blood flow and consequently a greater increase in coronary vascular resistance than the atenolol pretreated hearts. Pretreatment with ICI118,551 caused a greater decrease in dP/dtmax than those with atenolol. CONCLUSIONS: Cardiac anaphylaxis-induced contractile dysfunction and coronary spasm are severe in b2-, rather than beta1-AR antagonist, pretreated isolated blood-perfused rat hearts. PMID- 28353310 TI - The early variation of left ventricular twisting function in patients with lymphoma received anthracycline therapy assessed by three-dimensional speckle tracking echocardiography. AB - BACKGROUND: Anthracycline-induced cardiotoxicity remains a significant and unresolved issue in patients receiving chemotherapy. The aim of this study was to evaluate left ventricular (LV) twisting function by three-dimensional speckle tracking echocardiography (3D-STE) in patients with lymphoma after anthracycline therapy. METHODS: One hundred and one patients with newly diagnosed diffuse large B-cell lymphoma who had planned to receive anthracycline chemotherapy were enrolled. LV apical rotation, basal rotation, twist, torsion, time to peak apical rotation and time to peak basal rotation were measured by 3D-STE at baseline, after the completion of two cycles and four cycles of the regimen, respectively. Apical-basal rotation delay was calculated as the difference between time to basal and time to apical rotation. RESULTS: The results showed that LV apical rotation, basal rotation, twist and torsion declined progressively during the whole procedure (baseline vs. two and four cycles of the regimen, apical rotation: 12.5 +/- +/- 4.5 degrees vs. 8.8 +/- 3.6 degrees vs. 6.0 +/- 3.2 degrees ; basal rotation: -7.7 +/- 3.0 degrees vs. -5.9 +/- 2.6 degrees vs. 4.4 +/- 2.5 degrees ; twist: 20.0 +/- 6.4 degrees vs. 14.5 +/- 5.1 degrees vs. 9.8 +/- 4.5 degrees ; torsion: 2.9 +/- 0.9 degrees /cm vs. 2.1 +/- 0.9 degrees /cm vs. 1.4 +/- 0.7 degrees /cm; all p < 0.01). Furthermore, apical-basal rotation delay increased significantly after two cycles as well as after four cycles of the regimen (38.3 +/- 67.9 ms vs. 66.7 +/- 73.9 ms vs. 92.6 +/- 96.9 ms; p < 0.01). CONCLUSIONS: LV twisting function deteriorated in the early stage of anthracycline therapy in patients with lymphoma, which could be detected by 3D STE sensitively. PMID- 28353312 TI - Prediction of coronary artery disease severity in lower extremity artery disease patients: A correlation study of TASC II classification, Syntax and Syntax II scores. AB - BACKGROUND: Lower extremity arterial disease (LEAD) is a well-established risk factor for concomitant coronary artery disease (CAD). There are no published data combining all three lower limb arterial segments (aortoiliac, femoropopliteal and below the knee vessels) in order to estimate CAD severity in LEAD patients. Herein has been derived a new scoring system for this purpose, which uses the wellknown TASC II classification, Syntax score and, for the first time in medical literature, a Syntax II score. METHODS: The study population consisted of 178 patients who underwent lower limb and coronary diagnostic angiography for assessment of LEAD and CAD at the same session. Syntax and Syntax II scores were calculated. TASC II classifications of the lower limb arteries were done. A new scoring system, called "Total Peripheral Score" (TPS), for lower limbs was also calculated. RESULTS: A positive correlation was found between TPS and Syntax score and a less prominent positive correlation between TPS and Syntax II score (p < 0.001). A cut-off value of '6' for the new score was found for estimating high risk subgorup of CAD (Syntax score > 32; p < 0.001). Critical femoropopliteal arterial segment stenosis was the most predictive lower limb arterial zone for presence of severe CAD (Syntax score > 32; p = 0.011). CONCLUSIONS: Taking into account all lower limb arterial segments for predicting CAD during lower limb arterial angiography was recommended. A TPS of more than '6' is the practical cut-off value for estimating severe CAD. Femoropopliteal arterial critical stenosis is the most predictive arterial zone for estimating severe CAD. PMID- 28353313 TI - Echocardiographic evaluation of diastolic functions in patients with polycystic ovary syndrome: A comperative study of diastolic functions in sub-phenotypes of polycystic ovary syndrome. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder among reproductive-aged women. It is known to be associated with cardiovascular diseases. The aim of this study was to determine and compare the echocardiographic data of patients according to the phenotypes of PCOS. METHODS: This study included 113 patients with PCOS and 52 controls. Patients were classified into four potential PCOS phenotypes. Laboratory analyses and echocardiographic measurements were performed. Left ventricular mass was calculated by using Devereux formula and was indexed to body surface area. RESULTS: Phenotype-1 PCOS patients had significantly higher homeostasis model assessment - insu-lin resistance (HOMA-IR) (p = 0.023), free testosterone (p < 0.001), LDL cholesterol levels (p < 0.001) and free androgen index (p < 0.001) compared with the control group. There were significant differences between groups regarding the septal thickness, posterior wall thickness, Left ventricular ejection frac-tion, E/A ratio and left ventricular mass index (for all, p < 0.05). PCOS patients with phenotype 1 and 2 had significantly higher left ventricular mass index than the control group (p < 0.001). In univariate and multivariate analyses, PCOS phenotype, modified Ferriman-Gallwey Score and estradiol were found as variables, which independently could affect the left ventricular mass index. CONCLUSIONS: This study showed that women in their twenties who specifically fulfilled criteria for PCOS phenotype-1 according to the Rotterdam criteria, had higher left ventricular mass index and decreased E/A ratio, which might be suggestive of early stage diastolic dysfunction. (Cariol J 2017; 24, 4: 364-373). PMID- 28353315 TI - Comparison of leukocyte IL6 expression in patients with gestational diabetes mellitus (GDM) diagnosed by the Polish Diabetes Association (PDA) 2011 and 2014 criteria. AB - INTRODUCTION: Controversial data exist in the literature regarding relationship of IL-6 with gestational diabetes mellitus (GDM), partially resulting from different criteria for GDM classification. In the present study, we revised this linkage by investigating leukocyte IL6 expression and its associations with clinical characteristics of patients diagnosed by the Polish Diabetes Association (PDA) 2011 and 2014 criteria. MATERIAL AND METHODS: A total of 145 pregnant women underwent 75 g two-hour OGTT, and GDM was diagnosed according to PDA 2011 criteria (GDM/PDA 2011 group; n = 113) and PDA 2014 criteria (GDM/PDA 2014 group; n = 104). IL6 gene expression was investigated in leukocytes of all participants by using real-time PCR method. RESULTS: Compared to respective NGT control groups, the GDM/PDA 2011 group exhibited higher FPG, two-hour OGTT, HbA1C and IL6 expression and lower HDL-C, whereas the GDM/PDA 2014 group had higher FPG, one hour and two-hour OGTT, HbA1C and HOMA-IR, lower QUICKI-IS, and unchanged IL6 expression. No differences in metabolic parameters and IL6 expression were found between the two GDM groups. Compared to the NGT/PDA 2011 group, the NGT/PDA 2014 group had lower one-hour and higher two-hour OGTT and increased IL6 expression. With PDA 2014 criteria, IL6 expression correlated positively with two-hour OGTT in both NGT and GDM groups as well as with LDL-C in NGT group, and negatively with HDL-C in NGT group. With PDA 2011 criteria, no associations were evident in NGT and GDM groups. Nevertheless, significant positive correlation of IL6 mRNA with two-hour OGTT was observed in the entire study group. CONCLUSIONS: Differences in metabolic phenotypes as well as gene expression and correlation data between GDM and NGT groups, categorised based on PDA 2011 and 2014 criteria, are related to changes in gestational glucose tolerance status resulting from using PDA 2014 criteria. Moreover, our findings support the hypothesis that IL-6 is associated with glucose metabolism during pregnancy. PMID- 28353314 TI - Chemerin as a marker of subclinical cardiac involvement in psoriatic patients. AB - BACKGROUND: Chemerin has been associated with psoriasis and inflammation, but there are no studies demonstrating an association between chemerin and subclinical cardiac involvement in psoriatic patients. Therefore, the present study aimed to evaluate whether psoriatic patients with increased epicardial fat tissue, impaired flow-mediated dilatation, and diastolic dysfunction have higher serum chemerin levels than a healthy control group. METHODS: The study included 60 psoriatic patients and 32 healthy controls. Echocardiographic parameters, epicardial fat tissue, flow-mediated dilatation, and chemerin levels were recorded for both groups. RESULTS: The serum levels of chemerin in the psoriatic patients were significantly higher than in the control group. The diastolic function parameters, including isovolumic contraction and relaxation time, E'/A' (early diastolic mitral annular velocity/late diastolic mitral annular velocity), and E/E' (early diastolic peak velocity of mitral inflow/early diastolic mitral annular velocity) values, differed significantly between the groups. Epicardial fat tissue was significantly higher and flow-mediated dilatation was significantly lower in psoriatic patients than in the controls. Chemerin was significantly positively correlated with age, body mass index, systolic and diastolic blood pressures, waist circumference, E/E', and epicardial fat tissue. Serum chemerin was significantly negatively correlated with E', E'/A', and flow mediated dilatation. A multiple linear regression analysis showed that chemerin was independently correlated with E/E'. CONCLUSIONS: Psoriatic patients exhibit early subclinical atherosclerosis and diastolic dysfunction. Chemerin can be used as a marker to screen for patients with subclinical cardiac involvement. PMID- 28353316 TI - Quality of care of hospitalised patients with heart failure in Poland in 2013: results of the second nationwide survey. AB - BACKGROUND: Optimal management of heart failure (HF) patients is crucial to reduce both mortality and the number of hospital admissions, at the same time improving patients' quality of life. AIM: The aim of the study was to assess the quality of care of hospitalised patients with HF in Poland in 2013 and compare it with the results of a similar survey performed in 2005. METHODS: The presented study was conducted from April to November 2013 in a sample of 260 hospital wards in Poland, recruited by stratified proportional sampling. Similarly to the first study edition in 2005, a trained nurse contacted physicians, who filled out the study questionnaires on the last five patients with HF, who had been discharged from an internal or cardiological ward. HF did not have to be a major cause of hospital admission. RESULTS: The mean age of the 1300 hospitalised patients was 72.1 years, an increase of 2.3 years since the 2005 survey. The proportion of patients classified as New York Heart Association IV decreased from 28.5% in 2005 to 22.1% in 2013. In comparison with 2005, more patients had concomitant disorders such as hypertension (79.5% vs. 71.0%), diabetes (46.2% vs. 33.2%), and chronic renal failure (33.4% vs. 19.4%). Access to echocardiography has improved in recent years: it was available for 98.9% of the surveyed hospital wards (93% in 2005) and it was performed during the hospitalisation in 60.2% of the patients (58.8% in 2005). In 2013 N-terminal pro-B-type natriuretic peptide was accessible for 80.8% of hospital wards (12.8% in 2005) and the test was performed in 31.3% of the hospitalised patients (3.3% in 2005). Angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blockers (ARB) were administered in 68.9% of HF discharged patients, beta-blockers in 84.8%, mineralocorticoid receptor antagonist (MRA) in 57.9%, diuretics in 85.9%, and digoxin in 23%. The respective numbers in 2005 were 85.9%, 76.0%, 65.4%, 88.9%, and 38.4%. The decrease in prescription of ACEI or ARB resulted from lesser usage of these drugs in internal medicine wards (from 84.3% in 2005 to 55.6% in 2013). CONCLUSIONS: In comparison to the analogous project run in 2005, an improvement in some areas of HF treatment was observed in Polish hospitals, such as accessibility to echocardiography and natriuretic peptide measurement as well as beta-blocker and MRA use. At the same time, a meaningful decrease in ACEIs or ARBs usage in internal wards was observed, which might be the result of the ageing of the HF population and an increased number of comorbidities. PMID- 28353318 TI - High-flow nasal cannula therapies for respiratory management in pediatric patients. AB - High-flow nasal cannula (HFNC) oxygen therapy is a non-invasive form of respiratory support that is rapidly being taken up in pediatric intensive care units (PICU). For infants with bronchiolitis, who are the largest non-elective source of admissions to a PICU, there is some evidence that using HFNC therapy reduces the need for intubation and mechanical ventilation. The aim of this review article is to explore, describe, critique and add to the evidence surrounding the use of HFNC therapy in the pediatric population for the management of respiratory distress. PMID- 28353317 TI - Self-expanding STENTYS stents in daily routine use. AB - BACKGROUND: In the era of modern interventional cardiology, implantation of a balloon expandable stent is the finishing touch of almost every coronary angioplasty. However, sometimes we face a clinical situation in which the decision regarding the stent diameter is complicated, especially in the ectatic part of arteries, in situations when the artery lumen is obscured with the thrombus, or when the reference diameter of the proximal and distal part of the lesion vary greatly. That is why the idea of a self-apposing stent similar to the one used in peripheral vascular interventions was adopted into cardiology. AIM: The aim of this study was to present a single-centre registry of STENTYS(r) stent implantation in 40 selected patients with acute coronary syndromes (ACS) or with stable angina (coronary artery disease [CAD]) treated with this self-expandable stent. METHODS AND RESULTS: The device was successfully implanted in all patients. During in-hospital observation and 30-day follow-up there were two cases of death, but none of the patients had acute stent thrombosis or ACS ST elevation myocardial infarction. In one case ACS type 4b was diagnosed. In all patients the stent was delivered in the target lesion. In two cases the procedure was performed in patients with multivessel CAD extending into the left main stem in a state of cardiogenic shock. These patients died immediately after the procedure. There were two procedure complications: in one case dissection after post dilatation occurred distally to the stent, and in one patient the calcified proximal part of the left anterior descending artery was dissected with system passage. Thirty-eight patients survived the 12-month follow-up period, and three (7.8%) patients underwent repeated target-lesion revascularisation. CONCLUSIONS: In the presented single-centre registry the STENTYS(r) stent was used with a high delivery and procedural success rate. Satisfactory clinical long-term outcome both in stable patients and ACS patients with a repeated revascularisation ratio of 7.8% was observed. The stent design allowed successful treatment of bifurcation lesions. PMID- 28353320 TI - Pediatric exercise induced bronchoconstriction: a review. PMID- 28353319 TI - Early childhood caries: a review. AB - Early childhood tooth problems are associated with variations in intrauterine and postnatal growth. Both premature and delayed timing of this physiological process might be a manifestation of local and/or systemic alterations. Presently, most clinicians agree that teething does not serious cause life taking pathological state, however, they disagree about reasons responsible for tooth eruption. The distinctive clinical presentation of dental caries in infants and toddlers, which is often known as early childhood caries (ECC), and are influenced by the eruption sequence of the primary dentition. Partial evidence exists in the context of ECC development, pathways, and disease rates in infants and toddlers. The present review article is focused on the current views of ECC. PMID- 28353321 TI - Breastfeeding from mothers carrying HBV would not increase the risk of HBV infection in infants after proper immunoprophylaxis. AB - BACKGROUND: Previously meta-analysis had different conclusions about the role of breastfeeding in mother-to-child transmission (MTCT) of hepatitis B virus (HBV). We aimed to carry out an updated meta-analysis based on current published evidence to explore whether breastfeeding increase the risk of HBV infection from mothers carrying HBV after proper immunoprophylaxis in the infants or not. METHODS: Databases searched from January 1st,2000 to August 1st,2016 included PubMed searching engine, Cochrane Library, Embase database, Chinese National Knowledge Infrastructure, VIP Chinese database, and Wanfang Chinese database. RESULTS: 17 studies were incorporated into our meta-analysis. Our result showed that there was no significant difference between the breastfeeding group and the non-breastfeeding group (ORs = 1.01, 95%CI: 0.75-1.36, I2 = 0). Further, there was no significant difference between the cases and controls in HBVac group (ORs = 1.08, 95%CI: 0.42-2.76, I2 = 0) and in HBIG combined with HBVac group (ORs = 0.97, 95%CI: 0.68-1.37, I2 = 0). CONCLUSIONS: Our update meta-analysis indicated that breastfeeding would not increase the risk of HBV injection from mothers carrying HBV after proper immunoprophylaxis in the infants. The results suggest that mother carrying HBV can breastfeed their babies after proper immunoprophylaxis in the infants. PMID- 28353322 TI - Recent perspectives of cerebral palsy (CP) in children: a review. AB - The movement and posture disorder of cerebral palsy (CP) is presumed to mainly be a consequence of the motor disorder, but accompanying disturbances with sensations and perception have also been suggested to influence motor function. The heterogeneous condition of cerebral palsy (CP) is caused by an injury to the immature brain affecting movement and posture development. The attainment of standing and walking can be difficult and an assistive device to accomplish the tasks may be required for some children with CP. In this review, we enlightened the role of possible sensory and perceptual disturbances for standing difficulties in children with CP. PMID- 28353323 TI - Pediatric patellar dislocation: a review. AB - Acute patellar dislocation affects approximately 1:1000 healthy children 9- 15 years of age, and up to 50% are at risk for recurrent dislocations. In adults the condition is associated with long-term complications, such as osteoarthritis and impairment of knee function. However, literature describing the outcome in a pediatric population is sparse. The present review article evaluate the long-term effects on knee function and cartilage quality after traumatic patellar dislocation in childhood, and also to evaluate the reliability of two clinical tests of medio-lateral knee position, in healthy children. PMID- 28353324 TI - Influence of psychological nursing intervention in the recovery of children with Wilms' tumor. PMID- 28353326 TI - Immunotherapeutic approaches in pediatric osteosarcoma. PMID- 28353325 TI - The effect of preoperative anxiety on the pain and opioid consumption of children after tonsillectomy and adenoidectomy. PMID- 28353327 TI - Disaster Averted, For Now: How the American Health Care Act Would Have Affected Californians. AB - Although the American Health Care Act (AHCA) was recently defeated, the policies in the bill represented a mix of ideas long favored by conservatives. If enacted, this repeal-and-replace bill would have had devastating consequences for most of the5 million Californians currently receiving direct benefits from the Affordable Care Act (ACA), including more than 1 million who receive subsidies through Covered California and almost 4 million who have enrolled in the Medi-Cal expansion. Although the bill failed to garner enough votes for passage, it is likely that efforts to chip away at the ACA will continue and that some of the ideas contained within the AHCA will be revisited. This policy brief summarizes some of the most significant reversals that wouldhave occurred under the Republican plan in the individual and small group insurance markets. PMID- 28353328 TI - The frontline in the battle to eliminate major amputation from the landscape of treatment for CLI. PMID- 28353329 TI - The essential role of leadership in developing a safety culture. PMID- 28353330 TI - Robust, Self-Healing, and Multistimuli-Responsive Supergelator for the Visual Recognition and Separation of Short-Chain Cycloalkanes and Alkanes. AB - In this study, we show that a novel kind of cholesterol-based gelator NPS containing pyridyl and naphthalimide units can visually discriminate cyclohexane/cyclopentane from hexane/pentane on the basis of distinct optical differences in the gel platform, which is not observed in solution. The effect of congeneric solvents on the gel properties, such as morphology, rheology, and stimuli-responsive properties, is also studied. Intriguingly, NPS can form self supporting, self-healing, fluorescent, and highly visible transmittance gels in cyclohexane that can selectively and visually respond to picric acid. It is deduced that NPS adopted H-type aggregation mode in cyclohexane, and the gel exhibits a strong green emission, whereas, in hexane, J-type aggregates of NPS molecules are observed with yellow emission. Correlations between the gelation properties and Hansen solubility parameters indicate that the dispersion interactions are the main factor for the selective gelation of NPS toward short chain alkanes. A comparison of Hansen solvent parameters indicated that a similar energetic weight of the hydrogen-bonding units is the major contribution for the strong and specific interaction between NPS and cyclohexane. Furthermore, we demonstrated that the NPS xerogel can selectively solidify cyclohexane in the single-phase liquid of solvent mixtures, exhibiting fast gelation, high separation efficiency (>92%), and easy recycling of gelator and liquids. To the best of our knowledge, herein, we report the first paradigm that molecular gel formation is developed to visually discriminate and separate organic analogues of solvents with similar polarity. PMID- 28353331 TI - Paper/PMMA Hybrid 3D Cell Culture Microfluidic Platform for the Study of Cellular Crosstalk. AB - Studying cellular crosstalk is important for understanding tumor initiation, progression, metastasis, and therapeutic resistance. Moreover, a three dimensional (3D) cell culture model can provide a more physiologically meaningful culture microenvironment. However, studying cellular crosstalk in a 3D cell culture model involves tedious processing. In this study, a paper/poly(methyl methacrylate) (PMMA) hybrid 3D cell culture microfluidic platform was successfully developed for the study of cellular crosstalk. The platform was a paper substrate with culture microreactors placed on a PMMA substrate with hydrogel-infused channels. Different types of cells were directly seeded and cultured in the microreactors. Aberrant cell proliferation of the affected cells was induced by secretions from transfected cells, and the proliferation ratios were investigated using a colorimetric method. The results showed that the responses of cellular crosstalk were different in different types of cells. Moreover, neutralizing and competitive assays were performed to show the functionality of the platform. Additionally, the triggered signaling pathways of the affected cells were directly analyzed by a subsequent immunoassay. The microfluidic platform provides a simple method for studying cellular crosstalk and the corresponding signaling pathways in a 3D culture model. PMID- 28353332 TI - Adapting Data-Independent Acquisition for Mass Spectrometry-Based Protein Site Specific N-Glycosylation Analysis. AB - A hallmark of protein N-glycosylation is extensive heterogeneity associated with each glycosylation site. In human cells, the constituent glycoforms differ mostly in numerous ways of extensions from an invariable trimannosyl core and terminal modifications. The efficient identification of these glycoforms at the glycopeptide level by mass spectrometry (MS) requires a precursor sampling technique that is not dictated by signal intensity or by preset targets during MS2 data acquisition. We show here that the recently developed data-independent acquisition (DIA) approach is best suited to this demanding task. It allows postacquisition extraction of glycopeptide-specific fragment-ion chromatograms to be aligned with that of precursor MS1 ion by nanoLC elution time. For any target glycoprotein, judicious selection of the most favorable MS1/MS2 transitions can first be determined from prior analysis of a purified surrogate standard that carries similar site-specific glycosylation but may differ in its exact range of glycoforms. Since the MS2 transitions to be used for extracting DIA data is common to that glycosylation site and not dictated by a specific MS1 value, our workflow applies equally well to the identification of both targeted and unexpected glycoforms. Using a case example, we show that, in targeted mode, it identified more site-specific glycoforms than the more commonly used data dependent acquisition method when the amount of the target glycoprotein was limited in a sample of high complexity. In discovery mode, it allows detection, with supporting MS2 evidence, of under-sampled glycoforms and of those that failed to be identified by searching against a predefined glycan library owing to unanticipated modifications. PMID- 28353334 TI - Rising Temperatures, Rising Risks: The Food-Energy-Water Nexus in the Persian Gulf. PMID- 28353333 TI - Tomographic Mapping Analysis in the Depth Direction of High-Ge-Content SiGe Layers with Compositionally Graded Buffers Using Nanobeam X-ray Diffraction. AB - A high-Ge-content Si1-yGey/compositionally graded Si1-xGex-stacked structure grown on Si(001) is now considered to be an important platform for the realization of advanced nanometer-scale complementary metal oxide semiconductor devices with high-mobility channel materials, such as III-V materials and Ge, and monolithically integrated photonic modules. The performance of such advanced devices is critically influenced by crystalline inhomogeneity in the stacked structure; therefore, precise characterization of the crystallinity is important. In particular, the development of a characterization method not only for in-plane crystallinity but also for in-depth crystallinity is strongly required. This is because the crystalline quality of the constant composition Si1-yGey is sensitively dependent on that of the compositionally graded Si1-xGex layers underneath. Here, we have demonstrated in-depth tomographic mapping of a high-Ge content Si1-yGey/compositionally graded Si1-xGex-stacked structure using position dependent omega-2theta map measurement using nanobeam X-ray diffraction. This mapping technique is based on the correspondence of each 2theta value in the omega-2theta map to the lattice constant of stacked layers in the depth direction. Application of the proposed analytical procedure provides tomographic maps of the local variation in lattice plane tilting (VLPT) from the obtained omega-2theta maps. It is quantitatively verified that the local crystallinity in the layer at a certain depth is strongly influenced by that underneath the layer. The correlation between the local VLPT and real structural defects in the stacked structure is also discussed in detail. PMID- 28353335 TI - Porous Functionalized Self-Standing Carbon Fiber Paper Electrodes for High Performance Capacitive Energy Storage. AB - A facile and cost-efficient approach to functionalize raw carbon fiber paper (CFP) used for a self-standing capacitive electrode has been proposed here. Benefiting from the improved specific surface area and surface functional groups, the functionalized CFP (F-CFP) showed much enhanced capacitive performance, 3 orders of magnitude higher than that of the raw CFP. It delivered the areal capacitance of 1275 mF cm-2 at 5 mA cm-2 with a rather wide voltage window of 1.4 V (-0.4 to 1 V vs Ag/AgCl) in 0.5 M H2SO4. However, in a neutral 1 M Na2SO4 aqueous solution, although the areal capacitance of 1115 mF cm-2 at 3 mA cm-2 is slightly smaller, the potential window is much wider (2 V, -1 to 1 V vs Ag/AgCl), indicating a high overpotential of hydrogen evolution. The areal capacitance was still as high as 722 mF cm-2 at a very fast charge-discharge current density of 50 mA cm-2, and about 66% of the initial capacitance (at 3 mA cm-2) was remained in Na2SO4, indicating considerable rate capability. PMID- 28353336 TI - Simultaneous Measurement of Glucose-6-phosphate 3-Dehydrogenase (NtdC) Catalysis and the Nonenzymatic Reaction of Its Product: Kinetics and Isotope Effects on the First Step in Kanosamine Biosynthesis. AB - Glucose-6-phosphate 3-dehydrogenase (NtdC) is an NAD-dependent oxidoreductase encoded in the NTD operon of Bacillus subtilis. The oxidation of glucose 6 phosphate by NtdC is the first step in kanosamine biosynthesis. The product, 3 oxo-d-glucose 6-phosphate (3oG6P), has never been synthesized or isolated. The NtdC-catalyzed reaction is very slow at low and neutral pH, and its rate increases to a maximum near pH 9.5. However, under alkaline conditions, the product is not stable because of ring opening followed by deprotonation of the 1,3-dicarbonyl compound. The absorbance band due to this enolate at 310 nm overlaps with that of the other enzymatic product, NADH, complicating kinetic measurements. We report the deconvolution of the resulting spectra of the reaction to determine the rate constants and likely kinetic mechanism. In doing so, we were able to determine the extinction coefficient of the enolate of 3oG6P (23000 M-1 cm-1), which allowed the measurement of the first-order rate constant (5.51 * 10-3 s-1) and activation energy (93 kJ mol-1) of nonenzymatic enolate formation. Using deuterium-labeled substrates, we show that hydride transfer from carbon 3 is partially rate-limiting in the enzymatic reaction, and deuterium substitution on carbon 2 has no significant effect on the enzymatic reaction but lowers the rate of deprotonation of 3oG6P 4-fold. These experiments clearly establish the regiochemistry of the reactions. Coupling of the NtdC reaction with the subsequent step in the pathway, NtdA-catalyzed glutamate-dependent amino transfer, has a small but significant effect on the rate of NAD reduction, consistent with these enzymes working together to process the unstable metabolite. PMID- 28353337 TI - Correction to Multilayer Heterojunction Anodes for Saline Wastewater Treatment: Design Strategies and Reactive Species Generation Mechanisms. PMID- 28353338 TI - Proton-Based Ultrafast Magic Angle Spinning Solid-State NMR Spectroscopy. AB - Protons are vastly abundant in a wide range of exciting macromolecules and thus can be a powerful probe to investigate the structure and dynamics at atomic resolution using solid-state NMR (ssNMR) spectroscopy. Unfortunately, the high signal sensitivity, afforded by the high natural-abundance and high gyromagnetic ratio of protons, is greatly compromised by severe line broadening due to the very strong 1H-1H dipolar couplings. As a result, protons are rarely used, in spite of the desperate need for enhancing the sensitivity of ssNMR to study a variety of systems that are not amenable for high resolution investigation using other techniques including X-ray crystallography, cryo-electron microscopy, and solution NMR spectroscopy. Thanks to the remarkable improvement in proton spectral resolution afforded by the significant advances in magic-angle-spinning (MAS) probe technology, 1H ssNMR spectroscopy has recently attracted considerable attention in the structural and dynamics studies of various molecular systems. However, it still remains a challenge to obtain narrow 1H spectral lines, especially from proteins, without resorting to deuteration. In this Account, we review recent proton-based ssNMR strategies that have been developed in our laboratory to further improve proton spectral resolution without resorting to chemical deuteration for the purposes of gaining atomistic-level insights into molecular structures of various crystalline solid systems, using small molecules and peptides as illustrative examples. The proton spectral resolution enhancement afforded by the ultrafast MAS frequencies up to 120 kHz is initially discussed, followed by a description of an ensemble of multidimensional NMR pulse sequences, all based on proton detection, that have been developed to obtain in-depth information from dipolar couplings and chemical shift anisotropy (CSA). Simple single channel multidimensional proton NMR experiments could be performed to probe the proximity of protons for structure determination using 1H-1H dipolar couplings and to evaluate the changes in chemical environments as well as the relative orientation to the external magnetic field using proton CSA. Due to the boost in signal sensitivity enabled by proton detection under ultrafast MAS, by virtue of high proton natural abundance and gyromagnetic ratio, proton-detected multidimensional experiments involving low-gamma nuclei can now be accomplished within a reasonable time, while the higher dimension also offers additional resolution enhancement. In addition, the application of proton-based ssNMR spectroscopy under ultrafast MAS in various challenging and crystalline systems is also presented. Finally, we briefly discuss the limitations and challenges pertaining to proton-based ssNMR spectroscopy under ultrafast MAS conditions, such as the presence of high-order dipolar couplings, friction-induced sample heating, and limited sample volume. Although there are still a number of challenges that must be circumvented by further developments in radio frequency pulse sequences, MAS probe technology and approaches to prepare NMR-friendly samples, proton-based ssNMR has already gained much popularity in various research domains, especially in proteins where uniform or site-selective deuteration can be relatively easily achieved. In addition, implementation of the recently developed fast data acquisition approaches would also enable further developments in the design and applications of proton-based ultrafast MAS multidimensional ssNMR techniques. PMID- 28353339 TI - Label-Free and Real-Time Detection of Protein Ubiquitination with a Biological Nanopore. AB - The covalent addition of ubiquitin to target proteins is a key post-translational modification that is linked to a myriad of biological processes. Here, we report a fast, single-molecule, and label-free method to probe the ubiquitination of proteins employing an engineered Cytolysin A (ClyA) nanopore. We show that ionic currents can be used to recognize mono- and polyubiquitinated forms of native proteins under physiological conditions. Using defined conjugates, we also show that isomeric monoubiquitinated proteins can be discriminated. The nanopore approach allows following the ubiquitination reaction in real time, which will accelerate the understanding of fundamental mechanisms linked to protein ubiquitination. PMID- 28353340 TI - Cysteine Addition Promotes Sulfide Production and 4-Fold Hg(II)-S Coordination in Actively Metabolizing Escherichia coli. AB - The bacterial uptake of mercury(II), Hg(II), is believed to be energy-dependent and is enhanced by cysteine in diverse species of bacteria under aerobic and anaerobic conditions. To gain insight into this Hg(II) biouptake pathway, we have employed X-ray absorption spectroscopy (XAS) to investigate the relationship between exogenous cysteine, cellular metabolism, cellular localization, and Hg(II) coordination in aerobically respiring Escherichia coli (E. coli). We show that cells harvested in exponential growth phase consistently display mixtures of 2-fold and 4-fold Hg(II) coordination to sulfur (Hg-S2 and Hg-S4), with added cysteine enhancing Hg-S4 formation. In contrast, cells in stationary growth phase or cells treated with a protonophore causing a decrease in cellular ATP predominantly contain Hg-S2, regardless of cysteine addition. Our XAS results favor metacinnabar (beta-HgS) as the Hg-S4 species, which we show is associated with both the cell envelope and cytoplasm. Additionally, we observe that added cysteine abiotically oxidizes to cystine and exponentially growing E. coli degrade high cysteine concentrations (100-1000 MUM) into sulfide. Thermodynamic calculations confirm that cysteine-induced sulfide biosynthesis can promote the formation of dissolved and particulate Hg(II)-sulfide species. This report reveals new complexities arising in Hg(II) bioassays with cysteine and emphasizes the need for considering changes in chemical speciation as well as growth stage. PMID- 28353341 TI - Study of Electrocatalytic Properties of Metal-Organic Framework PCN-223 for the Oxygen Reduction Reaction. AB - A highly robust metal-organic framework (MOF) constructed from Zr6 oxo clusters and Fe(III) porphyrin linkers, PCN-223-Fe was investigated as a heterogeneous catalyst for oxygen reduction reaction (ORR). Films of the framework were grown on a conductive FTO substrate and showed a high catalytic current upon application of cathodic potentials and achieved high H2O/H2O2 selectivity. In addition, the effect of the proton source on the catalytic performance was also investigated. PMID- 28353342 TI - Superconducting Continuous Graphene Fibers via Calcium Intercalation. AB - Superconductors are important materials in the field of low-temperature magnet applications and long-distance electrical power transmission systems. Besides metal-based superconducting materials, carbon-based superconductors have attracted considerable attention in recent years. Up to now, five allotropes of carbon, including diamond, graphite, C60, CNTs, and graphene, have been reported to show superconducting behavior. However, most of the carbon-based superconductors are limited to small size and discontinuous phases, which inevitably hinders further application in macroscopic form. Therefore, it raises a question of whether continuously carbon-based superconducting wires could be accessed, which is of vital importance from viewpoints of fundamental research and practical application. Here, inspired by superconducting graphene, we successfully fabricated flexible graphene-based superconducting fibers via a well established calcium (Ca) intercalation strategy. The resultant Ca-intercalated graphene fiber (Ca-GF) shows a superconducting transition at ~11 K, which is almost 2 orders of magnitude higher than that of early reported alkali metal intercalated graphite and comparable to that of commercial superconducting NbTi wire. The combination of lightness and easy scalability makes Ca-GF highly promising as a lightweight superconducting wire. PMID- 28353343 TI - Small Molecule and Peptide Recognition of Protein Transmembrane Domains. AB - Membrane proteins play vital roles in cell signaling, molecular transportation, and cell adhesion. The interactions of transmembrane domains are much less well understood than those of their water-soluble counterparts, and they have been deemed "undruggable" despite their important biological functions such as protein anchoring, signal transduction, and ligand recognition. Nevertheless, continual developments in this area have revealed useful probes for investigating and regulating these membrane proteins. This review summarizes and evaluates the strategies available for discovering small molecules and peptides that recognize the protein transmembrane domains of membrane proteins, with a particular focus on rational design and library screening. PMID- 28353344 TI - On the Importance of Electronic Symmetry for Triplet State Delocalization. AB - The influence of electronic symmetry on triplet state delocalization in linear zinc porphyrin oligomers is explored by electron paramagnetic resonance techniques. Using a combination of transient continuous wave and pulse electron nuclear double resonance spectroscopies, it is demonstrated experimentally that complete triplet state delocalization requires the chemical equivalence of all porphyrin units. These results are supported by density functional theory calculations, showing uneven delocalization in a porphyrin dimer in which a terminal ethynyl group renders the two porphyrin units inequivalent. When the conjugation length of the molecule is further increased upon addition of a second terminal ethynyl group that restores the symmetry of the system, the triplet state is again found to be completely delocalized. The observations suggest that electronic symmetry is of greater importance for triplet state delocalization than other frequently invoked factors such as conformational rigidity or fundamental length-scale limitations. PMID- 28353345 TI - Defect-Induced Band-Edge Reconstruction of a Bismuth-Halide Double Perovskite for Visible-Light Absorption. AB - Halide double perovskites have recently been developed as less toxic analogs of the lead perovskite solar-cell absorbers APbX3 (A = monovalent cation; X = Br or I). However, all known halide double perovskites have large bandgaps that afford weak visible-light absorption. The first halide double perovskite evaluated as an absorber, Cs2AgBiBr6 (1), has a bandgap of 1.95 eV. Here, we show that dilute alloying decreases 1's bandgap by ca. 0.5 eV. Importantly, time-resolved photoconductivity measurements reveal long-lived carriers with microsecond lifetimes in the alloyed material, which is very promising for photovoltaic applications. The alloyed perovskite described herein is the first double perovskite to show comparable bandgap energy and carrier lifetime to those of (CH3NH3)PbI3. By describing how energy- and symmetry-matched impurity orbitals, at low concentrations, dramatically alter 1's band edges, we open a potential pathway for the large and diverse family of halide double perovskites to compete with APbX3 absorbers. PMID- 28353346 TI - Csp-Csp3 Bond Formation via Iron(III)-Promoted Hydroalkynylation of Unactivated Alkenes. AB - An iron(III)-promoted hydroalkynylation of unactivated alkenes toward Csp-Csp3 bond formation has been developed. Various alkenes, including mono-, di-, and trisubstituted alkenes, could all smoothly convert to structural diversified alkynes in this chemoselective protocol. Additionally, the scalability was unraveled and the further divergent transformations of products were conducted to demonstrate the synthetic utility. PMID- 28353347 TI - Conformation-Specific Infrared and Ultraviolet Spectroscopy of Cold [YAPAA+H]+ and [YGPAA+H]+ Ions: A Stereochemical "Twist" on the beta-Hairpin Turn. AB - Incorporation of the unnatural d-proline (DP) stereoisomer into a polypeptide sequence is a typical strategy to encourage formation of beta-hairpin loops because natural sequences are often unstructured in solution. Using conformation specific IR and UV spectroscopy of cold (~10 K) gas-phase ions, we probe the inherent conformational preferences of the DP and LP diastereomers in the protonated peptide [YAPAA+H]+, where only intramolecular interactions are possible. Consistent with the solution-phase studies, one of the conformers of [YADPAA+H]+ is folded into a charge-stabilized beta-hairpin turn. However, a second predominant conformer family containing two sequential gamma-turns is also identified, with similar energetic stability. A single conformational isomer of the LP diastereomer, [YALPAA+H]+, is found and assigned to a structure that is not the anticipated "mirror image" beta-turn. Instead, the LP stereocenter promotes a cis-alanine-proline amide bond. The assigned structures contain clues that the preference of the DP diastereomer to support a trans-amide bond and the proclivity of LP for a cis-amide bond is sterically driven and can be reversed by substituting glycine for alanine in position 2, forming [YGLPAA+H]+. These results provide a basis for understanding the residue-specific and stereospecific alterations in the potential energy surface that underlie these changing preferences, providing insights to the origin of beta-hairpin formation. PMID- 28353348 TI - Synthesis of Pt3Y and Other Early-Late Intermetallic Nanoparticles by Way of a Molten Reducing Agent. AB - Early-late intermetallic phases have garnered increased attention recently for their catalytic properties. To achieve the high surface areas needed for industrially relevant applications, these phases must be synthesized as nanoparticles in a scalable fashion. Herein, Pt3Y-targeted as a prototypical example of an early-late intermetallic-has been synthesized as nanoparticles approximately 5-20 nm in diameter via a solution process and characterized by XRD, TEM, EDS, and XPS. The key development is the use of a molten borohydride (MEt3BH, M = Na, K) as both the reducing agent and reaction medium. Readily available halide precursors of the two metals are used. Accordingly, no organic ligands are necessary, as the resulting halide salt byproduct prevents sintering, which further permits dispersion of the nanoscale intermetallic onto a support. The versatility of this approach was validated by the synthesis of other intermetallic phases such as Pt3Sc, Pt3Lu, Pt2Na, and Au2Y. PMID- 28353349 TI - Biochar Soil Additions Affect Herbicide Fate: Importance of Application Timing and Feedstock Species. AB - Biochar (BC), solid biomass subjected to pyrolysis, can alter the fate of pesticides in soil. We investigated the effect of soil amendment with several biochars on the efficacy of two herbicides, clomazone (CMZ) and bispyribac sodium (BYP). To this aim, we evaluated CMZ and BYP sorption, persistence, and leaching in biochar-amended soil. Sorption of CMZ and BYP was greater in soil amended with BC produced at high temperature (700 degrees C). Significant sorption of the neutral CMZ herbicide also occurred in amended soil with BC prepared at low temperature (350 and 500 degrees C). For both herbicides, desorption possessed higher hysteretic behavior in soil amended with BC made at 700 degrees C (pyrolysis temperature). Dissipation of CMZ was enhanced after addition of BCs to soil, but no correlation between persistence and sorption was observed. Persistence of BYP was up to 3 times greater when BC made at 700 degrees C was added to soil. All BCs suppressed the leaching of CMZ and BYP as compared to the unamended soil. Amendment with 700 degrees C BC inhibited the action of CMZ against weeds, but 350 and 500 degrees C BCs had no such effect when added to soil. BYP activity was similar to that exhibited by unamended soil after the addition of 700 degrees C BC. From these results, biochar amendments can be a successful strategy to reduce the environmental impact of CMZ and BYP in soil. However, the phytotoxicity of soil-applied herbicides will depend on BC sorption characteristics and the pesticide's chemical properties, as well as the pesticide application timing (e.g., pre- or postemergence). According to our results, proper biochar screening with intended pesticides in light of the application mode (pre- or postemergence) is required prior to use to ensure adequate efficacy. PMID- 28353352 TI - Detecting Changes in Newspaper Reporting of Suicide after a Statewide Social Marketing Campaign. AB - A social marketing campaign was introduced in California in 2012, promoting media adherence to consensus-based guidelines on reporting about suicide. We examine adherence to these guidelines by applying quantitative scores to articles in California and a national control group in two six-month intervals prior to and following campaign implementation. Utilizing a difference-in-difference approach, we found no significant effect of the campaign, though the type of article content was a significant indicator of the overall score. Findings also demonstrated a nation-wide downward trend in the quality of reporting. Qualitative results suggest a need for more flexible guidelines in light of a technologically driven news culture. PMID- 28353350 TI - Multi-Level Characterization of the Membrane Properties of Resveratrol Incorporated Liposomes. AB - Resveratrol (RES) is a type of polyphenolic compound discovered from grapes and has gained prominence as a possible contributor to many disease treatments. Herein, three different types of liposomes were prepared as model cell membranes, and then the influence of the incorporation of RES on their membrane properties was evaluated by utilizing membrane-binding fluorescent probes. The binding of RES lead to the membrane polarities decreasing slightly, regardless of the phase states of the membrane, while the membrane fluidities decreased only in the case of liquid-disordered phase. In each model membrane system, the incorporation of RES dramatically dehydrated the membrane surface, which could prevent the permeation of water-soluble materials. Fluorescence quenching of Laurdan indicated less accessibility of hydroxyl radial into the inner region of the RES incorporated membrane. The comparison between the mass spectra of oxidized DOPC molecules treated with hydroxyl radical revealed that the RES-incorporation into DOPC membranes can contribute to prevent lipid oxidation. It is concluded that the binding of RES to the lipid membrane can play a key role in affecting membrane properties and functions. PMID- 28353351 TI - Effects of human umbilical cord blood mononuclear cells on respiratory system mechanics in a murine model of neonatal lung injury. AB - BACKGROUND: Mononuclear cells (MNCs) have well-documented beneficial effects in a wide range of adult pulmonary diseases. The effects of human umbilical cord blood derived MNCs on neonatal lung injury, highly relevant for potential autologous application in preterm newborns at risk for bronchopulmonary dysplasia (BPD), remain incompletely established. The aim of this study was to determine the long term morphologic and functional effects of systemically delivered MNCs in a murine model of neonatal lung injury. MATERIALS AND METHODS: MNCs from cryopreserved cord blood (1 * 106 cells per pup) were given intravenously to newborn mice exposed to 90% O2 from birth; controls received cord blood total nucleated cells (TNCs) or granular cells, or equal volume vehicle buffer (sham controls). In order to avoid immune rejection, we used SCID mice as recipients. Lung mechanics (flexiVentTM), engraftment, growth, and alveolarization were evaluated eight weeks postinfusion. RESULTS: Systemic MNC administration to hyperoxia-exposed newborn mice resulted in significant attenuation of methacholine-induced airway hyperreactivity, leading to reduction of central airway resistance to normoxic levels. These bronchial effects were associated with mild improvement of alveolarization, lung compliance, and elastance. TNCs had no effects on alveolar remodeling and were associated with worsened methacholine-induced bronchial hyperreactivity. Granular cell administration resulted in a marked morphologic and functional emphysematous phenotype, associated with high mortality. Pulmonary donor cell engraftment was sporadic in all groups. CONCLUSIONS: These results suggest that cord blood MNCs may have a cell type-specific role in therapy of pulmonary conditions characterized by increased airway resistance, such as BPD and asthma. Future studies need to determine the active MNC subtype(s), their mechanisms of action, and optimal purification methods to minimize granular cell contamination. PMID- 28353354 TI - Erratum. PMID- 28353353 TI - Risk of Malignancy in Thyroid Incidentaloma is Not Increased in Overweight or Obese Patients, but in Young Patients. AB - Thyroid incidentaloma is defined as an unsuspected, asymptomatic thyroid lesion that is discovered on an imaging study or during an operation unrelated to the thyroid gland. We aim to evaluate the relationship between overweight or obese and risk of malignancy in patients with thyroid incidentaloma detected by F18 flurodeoxyglucose positron emission tomography/computed tomography and factors to predict risk of malignancy in thyroid incidentaloma. From January 2010 to December 2013, a total of 238 patients were eligible for this study. Using the Bethesda system for reporting thyroid cytopathology, categories I-III were defined as a nonmalignancy and categories V-VI were defined as a malignancy. When patients with body mass index (BMI) of less than 23 and 23 or more were divided into two groups of normal and overweight or obese, risk of malignancy of thyroid incidentaloma was not significantly different between two groups (P = 0.1812). In logistic regression analysis, age was the only variable that showed a significant association with malignancy of thyroid incidentaloma (odds ratio 0.9608, P = 0.0021). However, none of sex, height, weight, and BMI was predictor of malignancy of thyroid incidentaloma. We demonstrated that being overweight or obese did not increase rate of malignancy in patients with thyroid incidentaloma. PMID- 28353355 TI - Phase Angle of Bioelectrical Impedance Analysis as Prognostic Factor in Palliative Care Patients at the National Cancer Institute in Mexico. AB - Patients with advanced cancer often experience symptoms of disease and treatment that contribute to distress such as weight loss, which is present in up to 85% of cancer patients. Palliative care in these patients focuses on care aimed at improving quality of life. Phase angle (PA) is obtained by bioelectric impedance analysis (BIA) and is associated with cellular function. It is considered a reliable marker of malnutrition. A low PA may suggest deterioration of the cell membrane, which in palliative patients may result in a short-term survival. The aim of this study was to associate PA and survival in palliative patients of the National Cancer Institute of Mexico. We included 452 patients (women, 56.4%); the average PA was 4.0 degrees . The most frequent disease was gastric cancer (39.2%). Mean body mass index (BMI) was 22.84. The average survival of patients with PA <= 4 degrees was 86 days, while in the group with PA > 4 degrees , it was 163 days (P > 0.0001). PA showed significant positive correlation with survival time and BMI. Our results corroborate the reliability of PA in Mexican population, as an indicator of survival in palliative care patients compared to the reported literature in other countries. PMID- 28353357 TI - "The Scarlet C": Exploring Caesarean Section Stigma. AB - In this article, I explore my own journey with delivering my first child via Caesarean section. I discuss the discourse in society surrounding childbirth and the stigma associated with giving birth via C-section, as well as the impacts that this discourse has for women whose births don't go according to plan and who end up requiring medical intervention. PMID- 28353356 TI - Causative mutations and premature cardiovascular disease in patients with heterozygous familial hypercholesterolaemia. AB - Background Familial hypercholesterolemia is a common autosomal dominant disease, caused by mutations leading to elevated low-density lipoprotein (LDL) cholesterol and, if untreated, to premature cardiovascular disease. Methods Patients (young adults with a family history of hypercholesterolaemia or premature cardiovascular disease) with LDL cholesterol concentration >=4.9 mmol/l, after excluding Familial Combined Hyperlipidaemia, were evaluated for causative mutations, Dutch Lipid Clinic Network score calculation and non-invasive ultrasound examination of carotid arteries. Results Of the 263 patients, 210 were heterozygotes for LDL receptor ( LDLR) mutations, four had APOB gene mutations, one PCSK9 gene mutation, while 48 had no evidence of mutations. Among 194 unrelated index cases 149 had mutations (77%). Among patients with LDLR mutations ( n = 145), there were five compound heterozygotes, 75 patients with null mutations and 65 with missense mutations. As many as 178 patients underwent a follow-up and treatment (statin +/- ezetimibe), achieving a mean reduction of 49% in LDL cholesterol, with 21% of patients reaching the LDL goal of 2.6 mmol/l. In a multivariate analysis, carotid plaques, at ultrasound examination, were associated with the presence of genetic mutation ( p = 0.001), LDL cholesterol ( p < 0.001), Dutch Lipid Clinic Network score ( p < 0.001), independently of age, gender, smoking habits and systolic blood pressure. The presence of carotid plaque ( p = 0.017), LDL cholesterol ( p < 0.003), Dutch Lipid Clinic Network score ( p < 0.001) were independently associated with premature cardiovascular disease. Conclusions We identified patients with causative mutations in 82% of the cases under study. In addition to LDL cholesterol and Dutch Lipid Clinic Network score, carotid plaques in ultrasound evaluation provide direct evidence of premature vascular disease and are associated with high risk for cardiovascular events. PMID- 28353358 TI - Financial Sustainability of Biobanks: From Theory to Practice. PMID- 28353359 TI - Impact of Undernutrition on the Pharmacokinetics and Pharmacodynamics of Anticancer Drugs: A Literature Review. AB - The etiology of undernourishment in cancer patients is multifactorial: tumor related mechanisms (such as obstruction, metabolic abnormalities, and functionality changes) in addition to the influence of anticancer therapies, which can induce or worsen undernutrition. The evident role of undernutrition in cancer treatment outcomes suggests the need of considering nutritional status when evaluating anticancer drugs. In order to merge the available data and offer researchers and clinicians a global view of this phenomenon, the present manuscript reviews on a drug-by-drug basis the undernutrition-related pharmacokinetic and pharmacodynamic aspects of anticancer treatments. This review notes interesting trends in the relationship between undernourishment and pharmacokinetics across studies, and indicates that dosing modifications of these drugs may be necessary to optimize chemotherapeutic treatments. Furthermore, this review has compiled evidence regarding undernourishment's capacity of enhancing treatment-related myelosuppression, cardiotoxicity, ototoxicity, neurotoxicity, and malignancies. PMID- 28353360 TI - Association between psychological measures with inflammatory anddisease-related markers of inflammatory bowel disease. AB - OBJECTIVE: This study aimed at investigating the associations between inflammatory mediators, symptoms and psychological disturbances in inflammatory bowel disease (IBD) patients. METHODS: IBD patients and patient controls were examined during a single visit to a gastroenterology clinic. Disease activity was assessed using the Mayo index for ulcerative colitis (UC), inflammatory bowel disease questionnaire (IBDQ), Crohn's disease activity index (CDAI) and Crohn's disease endoscopic index of severity (CDEIS). Gene expression of inflammatory mediators were measured in intestinal biopsies and whole blood samples along with circulating concentrations of interleukin (IL)-6, interferon (IFN)gamma, C reactive protein (CRP), kynurenine and tryptophan. Validated depression, anxiety and quality of life scores were used to assess psychological well-being. RESULTS: Patients who were symptomatic had the highest depression and anxiety scores, together with increased intestinal expression of IL-1beta, IL-6 and matrix metalloproteinase-9, increased circulating IL-6 and CRP, and an increased circulating kynurenine:tryptophan ratio. Increased Hamilton depression (HAM-D) scores in IBD patients were observed independent of the psychological impact of acute symptoms. CONCLUSIONS: Active IBD is associated with symptoms of depression and anxiety and with a raised circulating inflammatory mediator profile. Patients with active IBD exhibiting psychological symptoms should undergo psychological evaluation to ensure the psychological aspects of the condition are considered and addressed. PMID- 28353361 TI - Enhancement of the Antitumor Effect of Methotrexate on Colorectal Cancer Cells via Lactate Calcium Salt Targeting Methionine Metabolism. AB - Methionine (Met) is involved in one-carbon de novo nucleotide synthesis and is an essential amino acid for cell survival. The impact of lactate calcium salt (CaLa) on the Met metabolism was investigated to evaluate the enhanced antitumor effect of methotrexate (MTX) on colorectal cancer (CRC) cells. Met dependency relating to homocysteine (Hcy) and betaine was investigated in human CRC cells (HCT-116 and HT-29) using a viability assay and liquid chromatography-mass spectrometry. Expression of betaine transporter-1 (BGT-1) following treatment with MTX alone or with CaLa was determined by Western blot. Enhanced antitumor effect due to malfunction of Met synthesis was confirmed. CRC cell viability decreased in Met restricted medium, but was maintained after Hcy and betaine treatment while overcoming Met restriction. BGT-1 expression was downregulated following the treatment of dose-increased CaLa, whereas there was no effect on BGT-1 expression after MTX treatment. CaLa in combination with MTX induced reduced Met synthesis when CRC cell viability was reduced. The results indicated that CaLa-mediated BGT 1 downregulation inhibits Met synthesis by disrupting betaine homeostasis. CaLa raised the antitumor effect of MTX via secondary role in the inhibition of the de novo nucleotide synthesis. Combination therapy of MTX and CaLa could maximize the effectiveness of CRC treatment. PMID- 28353362 TI - Anti-coagulation complications in pregnancies with severe pulmonary arterial hypertension. AB - BACKGROUND: Epoprostenol, a potent vasodilator, is the treatment of choice for severe pulmonary arterial hypertension (PAH) in pregnancy. However, its inhibition of platelet aggregation increases the risk of coagulation complications with conjunctive use of anti-coagulants for thromboprophylaxis. CASES: Case 1 demonstrates a pregnancy complicated by thrombocytopenia. Case 2 describes a pregnancy with newly diagnosed PAH at 35 weeks who delivered by repeat cesarean delivery complicated by a wound hematoma. Case 3 describes a patient who delivered at 32 weeks. She required extracorporeal membrane oxygenation and a heart-lung transplant. Her care was further complicated by severe thrombocytopenia with postpartum hemorrhage refractory to usual conservative measures. CONCLUSIONS: This case series describes three patients with severe PAH in pregnancy and the range of different complications that arose from anticoagulation in the setting of epoprostenol. PMID- 28353364 TI - Health Meanings among Foreign Domestic Workers in Singapore: A Culture-Centered Approach. AB - Economic migration is integral to processes of globalization, with large numbers of the global poor moving across borders in search of employment in the face of structural adjustment programs and large-scale displacement of the poor from traditional forms of livelihood. One such group are foreign domestic workers (FDWs). In this culture-centered study, we listen to the voices of FDWs in Singapore to understand the key meanings of health held by this group of migrant workers as they negotiate living and working in Singapore. Through the representation of FDW voices at sites where they have previously been excluded, we hope to co-create participatory spaces in national discourse so that policies and interventions can be developed to address the health needs of FDWs. The results represented in this essay are part of a larger project engaging the CCA to foster communicative platforms for structural transformation. PMID- 28353363 TI - Does chronomodulated radiotherapy improve pathological response in locally advanced rectal cancer? AB - The predominant mode of radiation-induced cell death for solid tumours is mitotic catastrophe, which is in part dependent on sublethal damage repair being complete at around 6 h. Circadian variation appears to play a role in normal cellular division, and this could influence tumour response of radiation treatment depending on the time of treatment delivery. We tested the hypothesis that radiation treatment later in the day may improve tumour response and nodal downstaging in rectal cancer patients treated neoadjuvantly with radiation therapy. Recruitment was by retrospective review of 267 rectal cancer patients treated neoadjuvantly in the Department of Radiation Oncology at the Canberra Hospital between January 2010 and November 2015. One hundred and fifty-five patients met the inclusion criteria for which demographic, pathological and imaging data were collected, as well as the time of day patients received treatment with each fraction of radiotherapy. Data analysis was performed using the Statistical Package R with nonparametric methods of significance for all tests set at p < 0.05. Of the 45 female and 110 male patients, the median age was 64. Seventy-three percent had cT3 disease and there was a mean tumour distance from the anal verge of 7 cm. Time to surgical resection following radiotherapy ranged from 4 to 162 days with a median of 50 days, with a complete pathological response seen in 21% of patients. Patients exhibiting a favourable pathological response had smaller median pre- and postradiotherapy tumour size and had a greater change in tumour size following treatment (p < 0.01). Patients who received the majority of their radiotherapy fractions after 12:00 pm were more likely to show a complete or moderate pathological response (p = 0.035) and improved nodal downstaging. There were also more favourable responses amongst patients with longer time to surgical resection postradiotherapy (p < 0.004), although no relationship was seen between response and tumour distance from the anal verge. Females were less likely to exhibit several of the above responses. Neoadjuvant radiotherapy for locally advanced rectal cancer performed later in the day coupled with a longer time period to surgical resection may improve pathological tumour response rates and nodal downstaging. A prospective study in chronomodulated radiotherapy in this disease is warranted. PMID- 28353366 TI - Selenium Administration Attenuates 5-Flurouracil-Induced Intestinal Mucositis. AB - Chemotherapy-induced mucositis is mediated by the release of proinflammatory cytokines and reactive oxygen species. Selenium has several metabolic functions, including the protection of membrane lipids and macromolecules against oxidative damage. However, to date, there is little evidence on the effect of trace elements on intestinal mucositis after chemotherapy. This study investigated the protective effect of selenium against chemotherapy-induced mucositis in rats. Twenty-four 9-wk-old female Wistar rats were randomized to 4 groups: control, selenium, 5-fluorouracil (5-FU), and 5-FU plus selenium. Mucositis was induced by a single dose of 5-FU (400 mg/kg BW) via intraperitoneal injection, and selenium was administered by a single intraperitoneal dose of sodium selenite (0.2 mg/kg BW). Diarrhea and weight loss after 5-FU administration were attenuated by selenium treatment. The mean villus height in the 5-FU plus selenium group was significantly taller than rats administered with 5-FU alone, but not significantly different compared to the control group. Interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha mRNA expression were significantly lower in the 5-FU plus selenium group than in the 5-FU only group (IL-1beta, P < 0.01; TNF alpha, P < 0.05). These findings indicate that selenium protects the mucosa during chemotherapy via its anti-inflammatory effects and its suppression of cytotoxic cytokine production. PMID- 28353367 TI - Infant Behavior Questionnaire-Revised Very Short Form: A New Factor Structure's Associations With Parenting Perceptions and Child Language Outcomes. AB - The Infant Behavior Questionnaire Revised-Very Short Form (IBQ-R VSF; Putnam, Helbig, Gartstein, Rothbart, & Leerkes, 2014 ) is a new publicly available measure of infant temperament measuring positive affectivity/surgency (PAS), negative emotionality (NEG), and orienting and regulatory capacity (ORC). Although the initial psychometric properties of the 3-factor model appear promising, it has not been administered to a large and diverse sample and its predictive validity has not been established. This study administered the IBQ-R VSF to a diverse sample of 5,639 mothers of infants aged between 23 and 52 weeks. Confirmatory factor analysis found that the 3-factor solution did not meet the requirement for satisfactory model fit. Exploratory factor analysis found that a 5-factor solution (PAS, NEG, Orienting Capacity, Affiliation/Regulation, and Fear) was statistically and conceptually the most parsimonious. All 5 temperament dimensions were found to relate to both mother- and partner-reported infant closeness, parenting confidence, and parenting satisfaction, and four of the dimensions (PAS, Orienting Capacity, NEG, and Fear) related to the infants' communication development. Some parental differences were also found. Together these findings suggest that the 5-factor IBQ-R VSF is a promising measure of infant temperament and is related to parenting perceptions and child language development. PMID- 28353368 TI - Explicating the Appraisal Dimension of the Communal Coping Model. AB - The communal coping model argues that people cope with stress in the context of their relationships and that coping responses are both cognitive and behavioral in nature. However, the cognitive dimension of the model (appraisal) has not been explicated in extant research. The purpose of this study is to fill that gap by conceptualizing the appraisal dimension of communal coping in the context of families managing one member's type 2 diabetes. Analysis of interviews with individuals with type 2 diabetes and their family members (N = 28) revealed that appraisal consists of problem ownership and perceived problem influence and that appraisals are influenced by knowledge of the disease and changing health status. Theoretical and practical implications are discussed. PMID- 28353369 TI - Cystoid Macular Edema in Retinitis Pigmentosa with Intermediate Uveitis Responded Well to Oral and Posterior Subtenon Steroid. PMID- 28353371 TI - The Systemic Synuclein Sampling Study: toward a biomarker for Parkinson's disease. AB - The search for a biomarker for Parkinson's disease (PD) has led to a surge in literature describing peripheral alpha-synuclein (aSyn) in both biofluids and biopsy/autopsy tissues. Despite encouraging results, attempts to capitalize on this promise have fallen woefully short. The Systemic Synuclein Sampling Study (S4) is uniquely designed to identify a reproducible diagnostic and progression biomarker for PD. S4 will evaluate aSyn in multiple tissues and biofluids within the same subject and across the disease spectrum to identify the optimal biomarker source and provide vital information on the evolution of peripheral aSyn throughout the disease. Additionally, S4 will correlate the systemic aSyn profile with an objective measure of nigrostriatal dopaminergic function furthering our understanding of the pathophysiological progression of PD. PMID- 28353372 TI - Satisfaction, quality of life and perception of patients regarding burdens and benefits of vitamin K antagonists compared with direct oral anticoagulants in patients with nonvalvular atrial fibrillation. AB - AIM: To compare the satisfaction of patients treated with vitamin K antagonists (VKA) with that of patients treated with direct oral anticoagulants (DOACs) and to determine the impact on quality of life of both treatments in patients with nonvalvular atrial fibrillation (NVAF). METHODS: Cross-sectional multicenter study in which outpatients with NVAF completed the ACTS (Anti-Clot Treatment Scale), SAT-Q (Satisfaction Questionnaire) and EQ-5D-3L (EuroQol 5 dimensions questionnaire, 3 level version) questionnaires. RESULTS: The study population comprised 1337 patients, of whom 587 were taking DOACs and 750 VKAs. Compared with VKAs, DOACs were more commonly prescribed in patients with a history of stroke and in patients with a higher thromboembolic risk. The study scores were as follows: SAT-Q: 63.8 +/- 17.8; EQ-5D-3L total score: 75.6 +/- 20.9; visual analog scale: 63.1 +/- 20.6; ACTS Burdens: 51.8 +/- 8.4 and ACTS Benefits: 11.9 +/- 2.4. The ACTS Burdens score and ACTS Benefits score were higher with DOACs than with VKAs (54.83 +/- 6.11 vs 49.50 +/- 9.15; p < 0.001 and 12.36 +/- 2.34 vs 11.48 +/- 2.46; p < 0.001 respectively). CONCLUSION: NVAF patients treated with oral anticoagulants had many comorbidities and a high thromboembolic risk. Satisfaction and quality of life with oral anticoagulants were high, although they were both better with DOACs than with VKAs. PMID- 28353373 TI - A Cross-Cultural Analysis of the Infant Behavior Questionnaire Very Short Form: An Item Response Theory Analysis of Infant Temperament in New Zealand. AB - The Infant Behavior Questionnaire-Revised Very Short Form (IBQ-R VSF; Putnam, Helbig, Gartstein, Rothbart, & Leerkes, 2014 ) is a newly published measure of infant temperament with a 3-factor structure. Recently Peterson et al. ( 2017 ) suggested that a 5-factor structure (Positive Affectivity/Surgency, Negative Emotionality, Orienting Capacity, Affiliation/Regulation, and Fear) was more parsimonious and showed promising reliability and predictive validity in a large, diverse sample. However, little is known about the 5-factor model's precision across the temperament dimensions range and whether it discriminates equally well across ethnicities. A total of 5,567 mothers responded to the IBQ-R VSF in relation to their infants (N = 5,639) between 23 and 52 weeks old. Using item response theory, we conducted a series of 2 parameter logistic item response models and found that 5 IBQ-R VSF temperament dimensions showed a good distribution of estimates across each latent trait range and these estimates centered close to the population mean. The IBQ-R VSF was also similarly precise across 4 ethnic groups (European, Maori, Pacific peoples, and Asians), suggesting that it can be used as comparable measure for infant temperament in a diversity of ethnic groups. PMID- 28353374 TI - Prediction of Poor Short-Term Prognosis and Unmet Needs in Advanced Chronic Obstructive Pulmonary Disease: Use of the Two-Minute Walking Distance Extracted from a Six-Minute Walk Test. AB - OBJECTIVES: Prognostic challenges hinder the identification of patients with advanced chronic obstructive pulmonary disease (COPD) for timely palliative interventions. We postulate that a two-minute derivative (two-minute walking distance [2MWD]) of a standard six-minute walk test (6MWT) can identify frail subjects with poorer survival for early palliative intervention. The primary outcome of interest is mortality at 18 months. Secondary objectives include evaluation of the relationship between the 2MWD and ability to self-care, dyspnea related disabilities, nutrition, forced expiratory volume in first second (FEV1), quality of life (QoL), and comorbidity burden. DESIGN AND SETTING: One hundred twenty-four subjects with stage 3 and 4 COPD were recruited and followed up. Ability to self-care, dyspnea-related disabilities, airflow limitation, nutrition, and QoL were measured by using modified Barthel index (MBI), Modified Medical Research Council (MMRC) dyspnea scale, FEV1 (% predicted), BODE [BMI(B), FEV1(O), MMRC(D), 6MWT(E)] index, updated ADO [Age(A), MMRC(D), FEV1(O)] index, Subjective Global Assessment (SGA), and St. George's Respiratory Questionnaire (SGRQ), respectively. Survival data were prospectively collected and analyzed. RESULTS: The 2MWD correlates highly with BODE and predicts updated ADO independent of age, co-morbidities, long-term oxygen therapy (LTOT), body mass index, and FEV1. Log-rank test performed with Kaplan-Meier plots demonstrates that 2MWD <=80 m significantly predicts survival time (p < 0.05). Cox proportional hazard regression shows a 3.6-time greater probability of 18-month mortality (hazard ratio [HR] 3.57; 95% confidence interval [CI] 1.26-10.13; p < 0.05). In addition, 2MWD strongly predicted MBI and MMRC, independent of age, co morbidities, LTOT, body mass index, and FEV1. Subjects with 2MWD <=80 m have a poorer ability to self-care (median MBI 90 vs. 100), lower FEV1 (32.9% +/- 9.8% vs. 38.1% +/- 9.4%), poorer QoL (mean SGRQ 46.6 +/- 16.2 vs. 36.6 +/- 13.3), and greater dyspnea-related disability (mean MMRC 1.7 +/- 0.7 vs. 0.9 +/- 0.6), and they are more malnourished (40.4% vs. 9.7%; RR 1.51) (all p < 0.001). CONCLUSION: 2MWD <=80 m identifies subjects with higher mortality, greater functional dependence, poorer in nutrition, greater dyspnea, and lower QoL. Incorporation of 2MWD into composite prognostic indices can enhance predictive accuracy and identify patients requiring early proactive palliative interventions. PMID- 28353375 TI - Determination of serum carbamazepine concentration using dried blood spot specimens for resource-limited settings. AB - OBJECTIVES: Carbamazepine (CBZ) is a commonly used anti-epileptic in rural hospitals in India. These hospitals lack the facilities to measure CBZ concentration; however, in larger hospitals this is performed using high performance liquid chromatography (HPLC). Dried blood spot (DBS) represents a feasible matrix for safe transportation by post/courier. This study was to determine whether the concentration of CBZ in serum can be predicted from that measured in DBS using an inexpensive HPLC method and inexpensive standard filter paper. METHODS: CBZ in serum and DBS from 80 epileptic patients were measured using a validated HPLC assay. The data was then randomly divided into two groups; simple Deming regression was performed with the first group and validation was performed using the second. RESULTS: There was a good correlation between the serum and DBS concentrations (r = 0.932) in the first group. The regression equation obtained was: predicted serum concentration = DBS concentration x 0.83 + 1.09. In the validation group, the correlation between the predicted and actual serum concentrations was also good (r = 0.958), and the mean difference between them was only 0.28 MUg/ml (p = 0.8062). The imprecision and bias in both the groups were acceptable. CONCLUSION: Using inexpensive materials, serum CBZ concentrations can be accurately predicted from DBS specimens. This method can be recommended for the therapeutic drug monitoring of CBZ in resource-limited settings. PMID- 28353376 TI - Acquired Cystic Disease-Associated Renal Cell Carcinoma: Review of Pathogenesis, Morphology, Ancillary Tests, and Clinical Features. AB - Acquired cystic disease-associated renal cell carcinoma (ACD-RCC) is a recently described subtype of RCC found in individuals with ACD of the kidney. Because of underrecognition, information regarding this lesion is sparse but continues to accumulate with each new report. Herein, a thorough literature review amassing the current understanding of this unique neoplasm is presented. Discussion focuses on clinical features, pathogenesis, disease outcome, and relation to the duration of dialysis. The macroscopic and characteristic microscopic features are described with illustrations. Compared with previous opinion, compiled immunohistochemical data may now allow for recognition of a unique immunophenotypic pattern of ACD-RCC. Distinction of ACD-RCC from clear cell and papillary RCCs based on molecular genetic information is deliberated, including a summary of the most frequently detected cytogenetic abnormalities. The key morphologic and immunophenotypic patterns used to distinguish this entity from a comprehensive differential diagnosis are provided. PMID- 28353378 TI - Follicular Dendritic Cell Sarcoma. AB - Follicular dendritic cell sarcoma is a rare tumor that typically arises within lymph nodes but can also occur extranodally. It is important to have a high index of suspicion, so follicular dendritic cell sarcoma is included in the differential diagnosis of a spindle cell neoplasm in the appropriate clinical and morphologic settings. When included in the differential diagnosis, immunohistochemistry is generally sufficient to substantiate the diagnosis of follicular dendritic cell sarcoma. In this review, we discuss the clinicopathologic features of follicular dendritic cell sarcoma, recent molecular and cytogenetic findings, prognosis, and current approaches to treatment. PMID- 28353377 TI - New Developments in Breast Cancer and Their Impact on Daily Practice in Pathology. AB - Advances in research have transformed our understanding of breast cancers and have altered the daily practice of pathology. Theranostic evaluations performed by pathologists are now critical in triaging the patients into appropriate treatment groups, as are new guidelines that were recently established for the evaluation of HER2/neu gene amplification. Emerging molecular classifications of breast cancers bring novel perspectives to the assessment of individual cases, and opportunities for better treatments. Molecular studies have particularly shed light on distinct biological subsets of triple-negative breast cancers, for which new targeted therapies are being developed. The prognostic and therapeutic utility of new histopathologic parameters, such as tumor-infiltrating lymphocytes, are also being elucidated, and new protocols have been devised for the pathologic evaluation of breast specimens that have undergone neoadjuvant treatment. Novel clinical practices, such as radioactive seed localization, also affect the way breast specimens are processed and evaluated. In this brief review, we highlight the developments that are most relevant to pathology and are changing or could potentially impact our daily practice. PMID- 28353379 TI - Benchmarking After Large-Scale, Comparative Data Analysis Improves the Use of Laboratory Tests: Lessons From the REDCONLAB Initiative. PMID- 28353380 TI - Characteristics of a Breast Pathology Consultation Practice. AB - CONTEXT: - Intradepartmental consultation is a routine practice commonly used for new diagnoses. Expert interinstitutional case review provides insight into particularly challenging cases. OBJECTIVE: - To investigate the practice of breast pathology consultation at a large tertiary care center. DESIGN: - We reviewed breast pathology cases sent for private consultation and internal cases reviewed by multiple pathologists at a tertiary center. Requisitions and reports were evaluated for diagnostic reason for consultation, rate of multiple pathologist review at the tertiary center, use of immunohistochemistry, and, for private consultation cases, type of sender and concordance with the outside diagnosis. RESULTS: - In the 985 private consultation cases, the most frequent reasons for review were borderline atypia (292 of 878; 33.3%), papillary lesion classification (151 of 878; 17.2%), evaluating invasion (123 of 878; 14%), subtyping carcinoma (75 of 878; 8.5%), and spindle cell (67 of 878; 7.6%) and fibroepithelial (65 of 878; 7.4%) lesion classification. Of 4981 consecutive internal cases, 358 (7.2%) were reviewed, most frequently for borderline atypia (90 of 358; 25.1%), subtyping carcinoma (63 of 358; 17.6%), staging/prognostic features (59 of 358; 16.5%), fibroepithelial lesion classification (45 of 358; 12.6%), evaluating invasion (37 of 358; 10.3%), and papillary (20 of 358; 5.6%) and spindle cell (18 of 358; 5.0%) lesion classification. Of all internal cases, those with a final diagnosis of atypia had a significantly higher rate of review (58 of 241; 24.1%) than those with benign (119 of 2933; 4.1%) or carcinoma (182 of 1807; 10.1%) diagnoses. Immunohistochemistry aided in diagnosis of 39.7% (391 of 985) and 21.2% (76 of 359) of consultation and internally reviewed cases, respectively. CONCLUSIONS: - This study confirms areas of breast pathology that represent diagnostic challenge and supports that pathologists are appropriately using expert consultation. PMID- 28353381 TI - To Fast or Not to Fast?: Comments on the Consensus Statement From the European Atherosclerosis Society/European Federation of Clinical Chemistry and Laboratory Medicine. PMID- 28353382 TI - New-Generation Thromboelastography: Comprehensive Evaluation of Citrated and Heparinized Blood Sample Storage Effect on Clot-Forming Variables. AB - CONTEXT: - Thromboelastography (TEG) is a whole blood, real-time analyzer measuring the viscoelastic properties of the hemostasis process and allowing for individualized goal-directed therapy. However, routine use of TEG requires validation of sample storage effect on clot parameters. OBJECTIVES: - To establish the minimum time required for equilibration time and the maximum time for sample storage for all commercially available TEG tests for the new generation TEG 6s and to determine how those times compare with the older generation TEG 5000. DESIGN: - Citrated and heparinized whole blood samples obtained from 20 healthy donors were analyzed for clot parameters at multiple time points for both the TEG 6s and the TEG 5000. Samples were activated with the citrated multichannel cartridge or the platelet-mapping cartridge in the TEG 6s or with recalcified kaolin in the TEG 5000. RESULTS: - All blood samples yielded TEG parameter results within reference ranges and had a tendency toward hypercoagulable profiles with increased storage time. Sample storage resulted in increased platelet inhibition with significant differences at 4 hours in the platelet-mapping cartridge (arachidonic acid percentage of inhibition, P = .002; adenosine diphosphate percentage of inhibition, P = .02). CONCLUSIONS: - For nonemergent cases or in a central laboratory setting, all tests provided reliable results for up to 4 hours in the citrated multichannel cartridge and for 3 hours for platelet function information in the platelet-mapping cartridge. In emergent/urgent situations in which the sample needs to be run immediately, RapidTEG and functional fibrinogen tests may be preferred. PMID- 28353383 TI - SP174, NRAS Q61R Mutant-Specific Antibody, Cross-Reacts With KRAS Q61R Mutant Protein in Colorectal Carcinoma. AB - CONTEXT: - NRAS is a member of the RAS family oncoproteins implicated in cancer. Gain-of-function NRAS mutations were reported in a subset of colorectal cancers. These mutations occur at codons 12, 13, and 61 and are detected by molecular genetic testing. Recently, an antibody (clone SP174) became available to immunohistochemically pinpoint NRAS Q61R mutant protein. In malignant melanoma, NRAS Q61R mutant-specific immunohistochemistry was shown to be a valuable supplement to traditional genetic testing. OBJECTIVE: - To evaluate the significance of NRAS Q61R mutant-specific immunohistochemistry in a cohort of colorectal carcinomas. DESIGN: - A total of 1185 colorectal carcinomas were immunohistochemically evaluated with SP174 antibody. NRAS Q61R mutant-specific immunohistochemistry was validated by molecular genetic testing including Sanger sequencing, quantitative polymerase chain reaction (qPCR), and next-generation sequencing. RESULTS: - Twelve tumors showed strong SP174 immunoreactivity. Sanger sequencing detected an identical c.182A>G substitution, causing NRAS Q61R mutation at the protein level, only in 8 SP174-positive cases. These results were confirmed by qPCR study. Subsequently, NRAS wild-type tumors with strong SP174 staining were evaluated by next-generation sequencing and revealed KRAS c.182A>G substitutions predicted to cause KRAS Q61R mutation. Review of colorectal carcinomas with known KRAS and NRAS genotype revealed that none of 62 wild-type tumors or 47 mutants other than Q61R were SP174 positive. CONCLUSION: - SP174 immunohistochemistry allows sensitive detection of NRAS and KRAS Q61R mutants. However, molecular genetic testing is necessary to determine specifically which RAS gene is mutated. PMID- 28353384 TI - Professional Practice Evaluation for Pathologists: The Development, Life, and Death of the Evalumetrics Program. AB - CONTEXT: - In 2008, the Joint Commission (JC) implemented a standard mandating formal monitoring of physician professional performance as part of the process of granting and maintaining practice privileges. OBJECTIVE: - To create a pathology specific management tool to aid pathologists in constructing a professional practice-monitoring program, thereby meeting the JC mandate. DESIGN: - A total of 105 College of American Pathologists (CAP)-defined metrics were created. Metrics were based on the job descriptions of pathologists' duties in the laboratory, and metric development was aided by experience from the Q-Probes and Q-Tracks programs. The program was offered in a Web-based format, allowing secure data entry, customization of metrics, and central data collection for future benchmarking. RESULTS: - The program was live for 3 years, with 347 pathologists subscribed from 61 practices (median, 4 per institution; range, 1-35). Subscribers used 93 of the CAP-defined metrics and created 109 custom metrics. The median number of CAP-defined metrics used per pathologist was 5 (range, 1 43), and the median custom-defined metrics per pathologist was 2 (range, 1-5). Most frequently, 1 to 3 metrics were monitored (42.7%), with 20% each following 4 to 6 metrics, 5 to 9 metrics, or greater than 10 metrics. Anatomic pathology metrics were used more commonly than clinical pathology metrics. Owing to low registration, the program was discontinued in 2016. CONCLUSIONS: - Through careful vetting of metrics it was possible to develop a pathologist-specific management tool to address the JC mandate. While this initial product failed, valuable metrics were developed and implementation knowledge was gained that may be used to address new regulatory requirements for emerging value-based payment systems. PMID- 28353385 TI - Erratum. PMID- 28353386 TI - The Effects of Computerized Clinical Decision Support Systems on Laboratory Test Ordering: A Systematic Review. AB - CONTEXT: - Inappropriate laboratory test ordering has been shown to be as high as 30%. This can have an important impact on quality of care and costs because of downstream consequences such as additional diagnostics, repeat testing, imaging, prescriptions, surgeries, or hospital stays. OBJECTIVE: - To evaluate the effect of computerized clinical decision support systems on appropriateness of laboratory test ordering. DATA SOURCES: - We used MEDLINE, Embase, CINAHL, MEDLINE In-Process and Other Non-Indexed Citations, Clinicaltrials.gov, Cochrane Library, and Inspec through December 2015. Investigators independently screened articles to identify randomized trials that assessed a computerized clinical decision support system aimed at improving laboratory test ordering by providing patient-specific information, delivered in the form of an on-screen management option, reminder, or suggestion through a computerized physician order entry using a rule-based or algorithm-based system relying on an evidence-based knowledge resource. Investigators extracted data from 30 papers about study design, various study characteristics, study setting, various intervention characteristics, involvement of the software developers in the evaluation of the computerized clinical decision support system, outcome types, and various outcome characteristics. CONCLUSIONS: - Because of heterogeneity of systems and settings, pooled estimates of effect could not be made. Data showed that computerized clinical decision support systems had little or no effect on clinical outcomes but some effect on compliance. Computerized clinical decision support systems targeted at laboratory test ordering for multiple conditions appear to be more effective than those targeted at a single condition. PMID- 28353387 TI - Recent Developments in Surgical Pathology of the Uterine Corpus. AB - There have been several updates recently on the classification of uterine tumors. Endometrial carcinomas have traditionally been divided into 2 types, but some are difficult to classify and do not fit readily into either of the currently recognized categories. The Cancer Genome Atlas Research Network has recently defined 4 new categories of endometrial cancer on the basis of mutational spectra, copy number alteration, and microsatellite instability, which might provide independent prognostic information beyond established risk factors. The Society of Gynecologic Oncology, moreover, now recommends systematic screening of every patient with endometrial cancer for Lynch syndrome. The new definition of high-grade endometrial stromal sarcoma disregards the number of mitotic figures as a primary diagnostic criterion and instead specifies moderate atypia still resembling stromal origin but lacking the pleomorphism of undifferentiated uterine sarcoma; these tumors also harbor a JAZF1-SUZ12 gene rearrangement. Mitotic count, atypia, and coagulative necrosis are the main histologic criteria that define leiomyosarcoma. Determining the type of necrosis can be very challenging in patients receiving various treatment modalities for symptomatic fibroids before myomectomy, since key histologic features of ischemic-type necrosis are often absent. Ancillary stains including p16, p53, MIB-1, trichrome, and reticulin may be helpful in tumors harboring necrosis that is difficult to classify. Minimally invasive gynecologic surgeries have introduced histologic artifacts that complicate the diagnosis. It is essential to recognize these as procedure-related artifacts to avoid upstaging tumors and triggering unnecessary adjuvant treatment. PMID- 28353388 TI - Children's Experiences and Awareness about Impact of Digital Media on Health. AB - Previous research has focused on the associations between technology use and children's health, using mainly quantitative designs. This qualitative study describes technology's impact on physical and mental health from children's perspectives. The differences between children's experiences and awareness of the health-related consequences associated with digital media use were examined. Focus groups and interviews were conducted with children between the ages of 9 and 16 in nine European countries (N = 368). Results of this study indicate that children's experiences of health-related technology impacts are different from their awareness of these impacts. Children's direct experiences with media were less extreme in contrast to their awareness of health problems, which typically involved extreme examples of possible consequences, such as killing people, kidnapping, blindness, and developing learning or psychological disorders. The results are discussed in the context of the "media panic" and "third person effect" theories. PMID- 28353389 TI - Aminocyclopyrachlor sorption-desorption and leaching from three Brazilian soils. AB - This study aimed to evaluate the sorption-desorption and leaching of aminocyclopyrachlor from three Brazilian soils. The sorption-desorption of 14C aminocyclopyrachlor was evaluated using the batch method and leaching was assessed in glass columns. The Freundlich model showed an adequate fit for the sorption-desorption of aminocyclopyrachlor. The Freundlich sorption coefficient [Kf (sorption)] ranged from 0.37 to 1.34 umol (1-1/n) L1/n kg-1 and showed a significant positive correlation with the clay content of the soil, while the Kf (desorption) ranged from 3.62 to 5.36 umol (1-1/n) L1/n kg-1. The Kf (desorption) values were higher than their respective Kf (sorption), indicating that aminocyclopyrachlor sorption is reversible, and the fate of this herbicide in the environment can be affected by leaching. Aminocyclopyrachlor was detected at all depths (0-30 cm) in all the studied soils, where leaching was influenced by soil texture. The total herbicide leaching from the sandy clay and clay soils was <0.06%, whereas, ~3% leached from the loamy sand soil. The results suggest that aminocyclopyrachlor has a high potential of leaching, based on its low sorption and high desorption capacities. Therefore, this herbicide can easily contaminate underground water resources. PMID- 28353390 TI - Evidence for a differential interference of noise in sub-lexical and lexical reading routes in healthy participants and dyslexics. AB - The ineffective exclusion of surrounding noise has been proposed to underlie the reading deficits in developmental dyslexia. However, previous studies supporting this hypothesis focused on low-level visual tasks, providing only an indirect link of noise interference on reading processes. In this study, we investigated the effect of noise on regular, irregular, and pseudoword reading in 23 dyslexic children and 26 age- and IQ-matched controls, by applying the white noise displays typically used to validate this theory to a lexical decision task. Reading performance and eye movements were measured. Results showed that white noise did not consistently affect dyslexic readers more than typical readers. Noise affected more dyslexic than typical readers in terms of reading accuracy, but it affected more typical than dyslexic readers in terms of response time and eye movements (number of fixations and regressions). Furthermore, in typical readers, noise affected more the speed of reading of pseudowords than real words. These results suggest a particular impact of noise on the sub-lexical reading route where attention has to be deployed to individual letters. The use of a lexical route would reduce the effect of noise. A differential impact of noise between words and pseudowords may therefore not be evident in dyslexic children if they are not yet proficient in using the lexical route. These findings indicate that the type of reading stimuli and consequent reading strategies play an important role in determining the effects of noise interference in reading processing and should be taken into account by further studies. PMID- 28353392 TI - Epidemiology and Molecular Basis of Resistance to Fluconazole Among Clinical Candida parapsilosis Isolates in Kuwait. AB - Fluconazole resistance among clinical Candida parapsilosis isolates is an emerging problem in many countries, including Kuwait. Resistance to fluconazole is mediated by amino acid substitutions in ERG11 and/or by overexpression of efflux pumps MDR1 and CDR1. Clinical C. parapsilosis sensu stricto isolates (n = 442) were tested for susceptibility to fluconazole by Etest, Vitek II, and broth microdilution methods. ERG11 was analyzed from fluconazole-resistant, fluconazole susceptible dose-dependent, and selected fluconazole-susceptible isolates. Of 442 C. parapsilosis isolates, 425, 2, and 15 were identified as susceptible, susceptible dose-dependent, and resistant to fluconazole, respectively. PCR sequencing of ERG11 identified Y132F mutation in 5 of 11 fluconazole-resistant isolates available for analysis. This mutation was absent in 46 fluconazole susceptible and 2 fluconazole-susceptible dose-dependent isolates. A multiplex allele-specific PCR was developed for detection of Y132F mutation in ERG11, and results correlated perfectly with PCR sequencing data for ERG11 codon 132 for all isolates analyzed. Detection of resistance in 15 and reduced susceptibility in 2 among 442 C. parapsilosis isolates highlights emerging resistance to fluconazole in Kuwait. The Y132F mutation in ERG11 was found in 5 of 11 (45%) fluconazole resistant isolates only. Detection of fluconazole resistance in C. parapsilosis will help in proper management of patients infected with this species. PMID- 28353393 TI - Toward a humanistic model in health communication. AB - Since the key to effective health communication lies in its ability to communicate well, some of its core problems are those that relate to the sharing of meaning between communicators. In elaborating on these problems, this paper offers two key propositions: one, health communication has to pass through the filter of a particular world view that creates a discrepancy between expected and actual message reception and response. Two, the assumption of a rational human actor made implicitly by most health psychological models is a contestable issue, as many times message recipients do not follow a cognitive judgment process. The phenomenon of resisting health messages by reasonable people asks the question whether we ought to rethink our adherence to a particular vision of human health as many times the adverse reaction to behaviour modification occurs as the result of a particular dialogical or discursive situation. At the same time, most motivational decisions in people's daily routines are automatic and use a concept known as self-identity to give stability to their behaviour patterns. Finally, health communication as part of organised government practices adheres to predominant value perspectives within health promotion practice that affect the manner in which health issues become problematised. This paper proposes a humanistic model that aims to pay attention to the intricacies of human communication by addressing all of the above problems in turn. It interprets the sharing of meaning element in human communication and addresses the question of how the idea of health is created through discourse. As such, it offers a complementary and constructive paradigm and set of approaches to understand health, its meanings and communication. PMID- 28353391 TI - Validity of self-reported concentration and memory problems: Relationship with neuropsychological assessment and depression. AB - BACKGROUND: This study investigated the validity of self-reported concentration and memory problems (CMP) in residents environmentally exposed to manganese (Mn). METHOD: Self-report of CMP from a health questionnaire (HQ) and the Symptom Checklist-90-Revised (SCL-90-R) was compared to neuropsychological assessment (Trails A&B; Digit Span; Digit Symbol; Similarities; Auditory Consonant Trigrams, ACT; NAB Memory; Rey-Osterrieth, Rey-O, Delayed). Participants included 146 residents from Ohio exposed to air-Mn, with a modeled average concentration of 0.55 ug m-3 (range = 0.01-4.58). RESULTS: Residents were primarily White (94.5%), aged 30-64 years (M = 51.24), with a minimum of 10 years of residence (range = 10 64). Ninety-four (65.3%) participants reported concentration problems, and 107 residents (73.3%) reported memory problems. More participants endorsed CMP on the SCL-90-R than on the HQ. The prevalence of self-reported CMP was higher for women than for men (88.4% vs. 68.3%). Point-biserial and Pearson's correlations between self-reported CMP and neuropsychological test scores were nonsignificant and weak for both the HQ (rpb = -.20 to rpb = .04) and the SCL-90-R (r = -.12 to r = .007). Greater levels of depression, anxiety, and female sex predicted having more self-reported CMP on both the HQ and the SCL-90-R. Air-Mn and blood-Mn were not associated with self-reported CMP. Residential distance from the Mn source accounted for a small proportion of variance (sr2 = .04), although depression remained the largest predictor (sr2 = .21). CONCLUSION: These results indicate that self-report of CMP in Mn-exposed residents appear to be invalid when compared to neuropsychological test scores. The participants' misperception of having CMP is associated with less education and higher levels of depression. Neuropsychological assessment is recommended to attain valid results. PMID- 28353394 TI - LC-MS/MS determination of pesticide residues in fruits and vegetables. AB - The aim of the research is to evaluate pesticide residue contamination of fresh and frozen fruits and vegetables, agricultural raw material, purchased from Polish farmers for production of frozen fruits and vegetables, and the estimation of the multiresidue method effectiveness expressed as the proportion of pesticides detected in food samples to the total number of pesticides analyzed by multiresidue methods. A total of 144 samples (of black currants, red currants, raspberries, cherries, strawberries, blackberries, cauliflowers and broccoli) were analyzed using LC-MS/MS method for the determination of 60 pesticides. QuEChERS extraction, matrix-matched calibration and dynamic multiple reaction monitoring method were used. Residues of 15 compounds, mainly fungicides and insecticides, were detected in 46 samples. The percentage of samples with residues above the maximum residue levels (MRL) was 15%, whereas samples with residues below MRL were 17%. A total of 13 samples contained more than one pesticide residue. Pesticide residues were detected most often in samples of black currants (50%), broccoli (36.4%), raspberries (29%) and red currants (21.8%). The most frequently detected pesticides were carbendazim and acetamiprid. The proportion of pesticides detected during our study to the total number of analyzed pesticides amounted to 25%. It was compared to literature findings. For three fourth of multiresidue methods, the proportion was below 50% for methods developed for the analysis of less than 100 pesticides, and below 30% for methods developed for the analysis of more than 100 pesticides. It appears that a lot of efforts and means is lost on pesticides never or rarely detected in examined samples. The workload and cost effectiveness of the development and application of multiresidue methods along with the range of pesticides covered by the method should be carefully and thoroughly considered anytime when a new method or workflow is developed. Including non-targeted screenings in pesticide residue control seems to be an alternative worth considering. PMID- 28353395 TI - Comparison of atmospheric concentrations of currently used pesticides between urban and rural areas during intensive application period in Alsace (France) by using XAD-2(r) based passive samplers. AB - XAD-2(r) passive samplers (PAS) have been exposed simultaneously for 14 days on two sites, one rural and one urban, situated in Alsace (East of France) during intensive pesticides application in agriculture (between March and September). PAS have been extracted and analyzed for current-used pesticides and lindane with an analytical method coupling accelerated solvent extraction (ASE), solid-phase microextraction (SPME) and GC/MS/MS. Results show the detection of pesticides is linked to the period of application and spatial and temporal variabilities can be observed with these PAS during the selected sampling period. The spatial and temporal variability is comparable to the one previously observed by comparing data obtained with PAS with data from Hi.-Vol. samplers in an urban area. Sampling rates were calculated for some pesticides and values are comparable to the data already available in the literature. From these sampling rates, concentrations in ng m-3 of pesticides in PAS have been calculated and are in the same order of magnitude as those obtained with Hi.Vol. sampling during the same period of time. PMID- 28353396 TI - Using sustainability as a collaboration magnet to encourage multi-sector collaborations for health. AB - The World Health Organization Commission on Social Determinants of Health (SDH) places great emphasis on the role of multi-sector collaboration in addressing SDH. Despite this emphasis on this need, there is surprisingly little evidence for this to advance health equity goals. One way to encourage more successful multi-sector collaborations is anchoring SDH discourse around 'sustainability', subordinating within it the ethical and empirical importance of 'levelling up'. Sustainability, in contrast to health equity, has recently proved to be an effective collaboration magnet. The recent adoption of the Sustainable Development Goals (SDGs) provides an opportunity for novel ways of ideationally re-framing SDH discussions through the notion of sustainability. The 2030 Agenda for the SDGs calls for greater policy coherence across sectors to advance on the goals and targets. The expectation is that diverse sectors are more likely and willing to collaborate with each other around the SDGs, the core idea of which is 'sustainability'. PMID- 28353397 TI - Elemental composition and nutritional value of the edible fruits of coastal red milkwood (Mimusops caffra) and impact of soil quality on their chemical characteristics. AB - In this study, the elemental distribution of essential and toxic elements in the soil and fruits of the indigenous plant species, Mimusops caffra, from ten sites along the KwaZulu-Natal east coast was investigated using inductively coupled plasma-optical emission spectrometry. This was done to determine the nutritional value of the fruits as well as to evaluate the impact of soil quality on elemental uptake by the plant. The elemental concentrations in the fruits (in descending order) were found to be K > Na > Ca > Mg > Si > Al > Fe > Zn > Mn > Ni > Cr > Cu > Pb > Mo > Sb > As > Se > V > Cd > Co. The results show that approximately 10 g of fruit would contribute more than 85% towards the recommended dietary allowance for Fe and Si for most adults. The proximate chemical composition revealed the fruits to contain approximately 84% moisture, 4.7% ash, 6.9% protein, 1.7% oil and 2.7% carbohydrates. The study indicates that the fruits of this indigenous plant species are a good source of essential elements with low levels of potentially toxic elements (Pb, As and Cd) which makes the plant a good indigenous food source especially for vulnerable communities that need food security. PMID- 28353399 TI - The Bacterial Effector AvrB-Induced RIN4 Hyperphosphorylation Is Mediated by a Receptor-Like Cytoplasmic Kinase Complex in Arabidopsis. AB - Bacterial pathogen Pseudomonas syringae delivers diverse type III effectors into host cells to interfere with their immune responses. One of the effectors, AvrB, targets a host guardee protein RIN4 and induces RIN4 phosphorylation in Arabidopsis. Phosphorylated RIN4 activates the immune receptor RPM1 to mount defense. AvrB-induced RIN4 phosphorylation depends on RIPK, a receptor-like cytoplasmic kinase (RLCK). In this study, we found several other RLCKs that were also able to phosphorylate RIN4. We demonstrated that these RLCKs formed a complex with RIPK and were functionally redundant to RIPK. We also found that unphosphorylated RIN4 was epistatic to phosphorylated RIN4 in terms of RPM1 activation. AvrB-induced RLCK gene expression and phosphorylated RIN4-triggered RPM1 activation required RAR1, a central regulator in plant innate immunity. Our results unravel a mechanism in which plants employ multiple kinases to hyperphosphorylate the guardee protein RIN4 to ensure immune activation during pathogen invasion. PMID- 28353400 TI - Evolutionary History of Subtilases in Land Plants and Their Involvement in Symbiotic Interactions. AB - Subtilases, a family of proteases involved in a variety of developmental processes in land plants, are also involved in both mutualistic symbiosis and host-pathogen interactions in different angiosperm lineages. We examined the evolutionary history of subtilase genes across land plants through a phylogenetic analysis integrating amino acid sequence data from full genomes, transcriptomes, and characterized subtilases of 341 species of diverse green algae and land plants along with subtilases from 12 species of other eukaryotes, archaea, and bacteria. Our analysis reconstructs the subtilase gene phylogeny and identifies 11 new gene lineages, six of which have no previously characterized members. Two large, previously unnamed, subtilase gene lineages that diverged before the origin of angiosperms accounted for the majority of subtilases shown to be associated with symbiotic interactions. These lineages expanded through both whole-genome and tandem duplication, with differential neofunctionalization and subfunctionalization creating paralogs associated with different symbioses, including nodulation with nitrogen-fixing bacteria, arbuscular mycorrhizae, and pathogenesis in different plant clades. This study demonstrates for the first time that a key gene family involved in plant-microbe interactions proliferated in size and functional diversity before the explosive radiation of angiosperms. PMID- 28353398 TI - A fly view on the roles and mechanisms of the m6A mRNA modification and its players. AB - RNA modifications are an emerging layer of posttranscriptional gene regulation in eukaryotes. N6-methyladenosine (m6A) is among the most abundant modifications in mRNAs (mRNAs) that was shown to influence many physiological processes from yeast to mammals. Like DNA methylation, m6A in mRNA is dynamically regulated. A conserved methyltransferase complex catalyzes the deposition of the methyl group on adenosine, which can be removed by specific classes of demethylases. Furthermore, YTH-domain containing proteins can recognize this modification to mediate m6A-dependent activities. Here we review the functions and mechanisms of the main m6A players with a particular focus on Drosophila melanogaster. PMID- 28353401 TI - Effect of NK cell immunotherapy on immune function in patients with hepatic carcinoma: A preliminary clinical study. AB - We investigated the effectiveness of adoptive transfer of KIR ligand-mismatched highly activated nature killer (HANK) cells in patients with hepatic carcinoma. Peripheral blood mononuclear cells were obtained and cultured in vitro to induce expansion and activation of HANK cells. After 12 d of culture, the cells were divided into 3 parts and infused intravenously on days 13 to 15. The patients (n = 16) were given one to 6 courses of immunotherapy. No side effects were observed. The lymphocyte subsets and cytokine, thymidine kinase 1 (TK1) and circulating tumor cell (CTC) levels were measured 1 day before treatment and 1 month after the final infusion: the absolute number of total T cells and NK cells and the IL-2 and TNF-beta levels were significantly higher, and the TK1 and CTC levels were significantly lower at 1 month after treatment. The percentage of patients who experienced partial response, disease stabilization, and disease progression at 3 months after treatment was 18.8%, 50.0% and 31.2%, respectively. The total follow-up period was 2-12 months. The median progression-free survival from treatment was 7.5 months. This is the first study on the benefits of HANK cell immunotherapy for hepatic carcinoma These encouraging preliminary observations imply that HANK cell immunotherapy is safe, can improve the immune function of patients with liver cancer, and may even reduce the rate of tumor metastasis and recurrence. However, further studies on larger samples of patients with a longer follow-up period are required to confirm these findings. PMID- 28353402 TI - Everyday ethics of participation: a case study of a CBPR in Nunavik. AB - INTRODUCTION: Multiple reports highlight the need for community-based family oriented prevention services for Aboriginal peoples in order to address important health and social inequalities. Participatory, empowerment-based approaches are generally favoured for these means. Faced with important social issues, in a context of colonisation and complex power dynamics, we question how community members experience participation, as well as the everyday dynamics that take place when attempting to create community-level change. CONTEXT: The initial steps of this community-based participatory research (CBPR) took place over a two year period in a community of Nunavik, a large northern region of the province of Quebec. The objective of the CBPR was to develop a community-driven project aimed at supporting families to be able to keep children within their homes or communities, rather than having to be placed under child welfare services. METHOD: We participated in, and documented, various group meetings, community workshops, informal reflexive discussions, and formal interviews with community partners to explore their everyday experiences of participation in community based change. RESULTS: We describe some of the initial actions taken in this project. We describe how certain social and power dynamics infiltrated into the process of participation leading to various tensions, personal and interpersonal experiences and needs. DISCUSSION: We discuss how these experiences led to everyday ethical dilemmas regarding participation. We conclude that although participatory approaches towards community change may be effective, they are also ethically challenging and at times disempowering for those who participate. We describe some of the approaches used to work with these ethical challenges. PMID- 28353403 TI - The urgent need for health impact assessment: proposing a transdisciplinary approach to the e-waste crisis in sub-Saharan Africa. AB - Electronic waste (e-waste) is a growing health and environmental concern in developing countries. In the sub-Saharan African region e-waste is considered a crisis with no end in sight yet; there is lack of structures and regulations to manage the problem. In this article, we discuss the potential of Health Impact Assessment (HIA) in addressing the health, environmental, and social impacts of e waste in sub-Saharan Africa. We draw from environmental policy, environmental communication, global health policy, and health communication to argue that managing e-waste could be framed as ongoing HIA where all the steps of HIA are performed on a rolling basis with input from local communities. Further, we suggest that HIA should be infused into recycling legislation to help streamline the practice in order to make it safe for health and the environment and to maximize the economic benefits. PMID- 28353404 TI - Different shades of Newton: Herman Boerhaave on Newton mathematicus, philosophus, and optico-chemicus. AB - In this paper I will probe into Herman Boerhaave's (1668-1738) appropriation of Isaac Newton's natural philosophy. It will be shown that Newton's work served multiple purposes in Boerhaave's oeuvre, for he appropriated Newton's work differently in different contexts and in different episodes in his career. Three important episodes in, and contexts of, Boerhaave's appropriation of Newton's natural philosophical ideas and methods will be considered: 1710-11, the time of his often neglected lectures on the place of physics in medicine; 1715, when he delivered his most famous rectorial address; and, finally, 1731/2, in publishing his Elementa chemiae. Along the way, I will spell out the implications of Boerhaave's case for our understanding of the reception, or use, of Newton's ideas more generally. PMID- 28353406 TI - Conference Scene: The 2015 Tissue Engineering Congress, London, UK, 8-10 September 2015. AB - The 2015 Tissue Engineering Congress, held in London, UK on 8-10 September 2015, brought together the principles of engineering and life sciences in tissue development and regenerative medicine to discuss scientific research and developments of clinical applications from leading experts in the field. The newest research and developing technology were presented in the field of stem cell biology, tissue regeneration, 3D culture and scaffolds and biomaterials. The focus was on interdisciplinary approaches based on the combination of new generation biomaterials and cell-based therapies, which can lead to breakthroughs in regenerating tissues in the future. PMID- 28353407 TI - Replicated evidence for aminoacylase 3 and nephrin gene variations to predict antihypertensive drug responses. AB - AIM: To replicate the genome-wide associations of the antihypertensive effects of bisoprolol and losartan in GENRES, using the Finnish patients of LIFE study. PATIENTS & METHODS: We analyzed association of four SNPs with atenolol and three SNPs with losartan response in 927 Finnish LIFE patients (467 for atenolol and 460 for losartan). RESULTS: rs2514036, a variation at a transcription start site of ACY3, was associated with blood pressure response to atenolol in men in LIFE. Response to bisoprolol was correlated to baseline plasma levels of N acetylphenylalanine and phenylalanine (ACY3 substrate and end product, respectively) in GENRES study. NPHS1 variation rs3814995 was associated with losartan effect in LIFE. CONCLUSION: We provide support for two pharmacogenomic markers for beta-blockers and angiotensin receptor antagonists. PMID- 28353408 TI - Characterization of Small Focal Renal Lesions: Diagnostic Accuracy with Single Phase Contrast-enhanced Dual-Energy CT with Material Attenuation Analysis Compared with Conventional Attenuation Measurements. AB - Purpose To determine whether single-phase contrast material-enhanced dual-energy material attenuation analysis improves the characterization of small (1-4 cm) renal lesions compared with conventional attenuation measurements by using histopathologic analysis and follow-up imaging as the clinical reference standards. Materials and Methods In this retrospective, HIPAA-compliant, institutional review board-approved study, 136 consecutive patients (95 men and 41 women; mean age, 54 years) with 144 renal lesions (111 benign, 33 malignant) measuring 1-4 cm underwent single-energy unenhanced and contrast-enhanced dual energy computed tomography (CT) of the abdomen. For each renal lesion, attenuation measurements were obtained; attenuation change of greater than or equal to 15 HU was considered evidence of enhancement. Dual-energy attenuation measurements were also obtained by using iodine-water, water-iodine, calcium water, and water-calcium material basis pairs. Mean lesion attenuation values and material densities were compared between benign and malignant renal lesions by using the two-sample t test. Diagnostic accuracy of attenuation measurements and dual-energy material densities was assessed and validated by using 10-fold cross validation to limit the effect of optimistic bias. Results By using cross validated optimal thresholds at 100% sensitivity, iodine-water material attenuation images significantly improved specificity for differentiating between benign and malignant renal lesions compared with conventional enhancement measurements (93% [103 of 111]; 95% confidence interval: 86%, 97%; vs 81% [90 of 111]; 95% confidence interval: 73%, 88%) (P = .02). Sensitivity with iodine-water and calcium-water material attenuation images was also higher than that with conventional enhancement measurements, although the difference was not statistically significant. Conclusion Contrast-enhanced dual-energy CT with material attenuation analysis improves specificity for characterization of small (1-4 cm) renal lesions compared with conventional attenuation measurements. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28353410 TI - Between distrust of science and scientism. PMID- 28353409 TI - What do we know about the role of regulatory B cells (Breg) during the course of infection of two major parasitic diseases, malaria and leishmaniasis? AB - Parasitic diseases, such as malaria and leishmaniasis, are relevant public health problems worldwide. For both diseases, the alarming number of clinical cases and deaths reported annually has justified the incentives directed to better understanding of host's factors associated with susceptibility to infection or protection. In this context, over recent years, some studies have given special attention to B lymphocytes with a regulator phenotype, known as Breg cells. Essentially important in the maintenance of immunological tolerance, especially in autoimmune disease models such as rheumatoid arthritis and experimentally induced autoimmune encephalomyelitis, the function of these lymphocytes has so far been poorly explored during the course of diseases caused by parasites. As the activation of Breg cells has been proposed as a possible therapeutic or vaccine strategy against several diseases, here we reviewed studies focused on understanding the relation of parasite and Breg cells in malaria and leishmaniasis, and the possible implications of these strategies in the course of both infections. PMID- 28353411 TI - Polymyxin-B and vancomycin-associated acute kidney injury in critically ill patients. AB - BACKGROUND: This study aims to investigate renal toxicities of Polymyxin B and Vancomycin among critically ill patients and risk factors for acute kidney injury (AKI). METHODS: This is a cross-sectional study conducted with patients admitted to an intensive care unit (ICU) of a tertiary hospital in Brazil. Patients were divided into two groups: those who used association of Polymyxin B + Vancomycin (Group I) and those who used only Polymyxin B (Group II). Risk factors for AKI were also analyzed. RESULTS: A total of 115 patients were included. Mean age was 59.2 +/- 16.1 years, and 52.2% were males. Group I presented higher GFR (117.1 +/ 70.5 vs. 91.5 +/- 50 ml/min/1.73 m2, p = 0.02) as well as lower creatinine (0.9 +/- 0.82 vs. 1.0 +/- 0.59 mg/dL, p = 0.014) and urea (51.8 +/- 23.7 vs. 94.5 +/- 4.9 mg/dL, p = 0.006) than group II on admission. Group I also manifested significantly higher incidence of AKI than group II (62.7% vs. 28.5%, p = 0.005), even when stratified according to RIFLE criteria ('Risk' 33.9% vs. 10.7%; 'Injury' 10.2% vs. 8.9%; 'Failure' 18.6% vs. 8.9%; p = 0.03). Accumulated Polymyxin B dose > 10 million IU was an independent predictor for AKI (OR = 2.72, 95% CI = 1.13-6.51, p = 0.024). CONCLUSIONS: Although patients who received Polymyxin B plus vancomycin had more favorable clinical profile and higher previous GFR, they presented a higher AKI incidence than those patients who received Polymyxin B alone. Cumulative Polymyxin B dose > 10 million IU was independently associated to AKI. PMID- 28353413 TI - Undergraduate nursing students and the elderly: An assessment of attitudes in a Turkish university. AB - At times when populations are aging and nursing services for elders are needed, gerontology as a nursing specialty is not a highly sought career choice. The purposes of this study were to assess the overall attitudes of nursing students at a Turkish university toward the elderly and to identify the effects of demographic and social factors on attitudes. Using a non-experimental design, the Turkish version of the Kogan's Attitudes towards Old People (KAOP) Scale was given to undergraduate nursing students. Significant findings demonstrated that the older the student, the worse the attitude and that students willing to work with elders had significantly better total KAOP and better positive item scores than those not willing to work with elders. The findings support educational preparation as a major factor in shaping student attitudes. Geriatric education should be integral to nursing education to help ensure sustainability of nursing services for the elderly population. PMID- 28353412 TI - Safety of endovascular treatment in acute stroke patients taking oral anticoagulants. AB - Background The endovascular treatment of acute cerebral ischemia has been proven beneficial without major safety concerns. To date, the role of endovascular treatment in patients treated with oral anticoagulants, which may be associated with periprocedural intracranial bleeding, remains uncertain. Aims The objective of the current analysis is to evaluate the safety of endovascular treatment in patients treated with oral anticoagulants. Methods The ENDOSTROKE-Registry is a commercially independent, prospective observational study in 12 stroke centers in Germany and Austria collecting pre-specified variables about endovascular stroke therapy. Results Data from 815 patients (median age 70 (interquartile range (IQR) 20), 57% male) undergoing endovascular treatment with known anticoagulation status were analyzed. A total of 85 (median age 76 (IQR 8), 52% male) patients (10.4%) took vitamin-K-antagonists prior to endovascular treatment. Anticoagulation status as measured with international normalized ratio was above 2.0 in 31 patients. Intracranial hemorrhage occurred in 11.8% of patients taking vitamin-K-antagonists compared to no-vitamin-K-antagonists (12.2%, p = 0.909). After adjustment for confounding factors which were unbalanced at univariate level such as NIHSS and age, anticoagulation status was not found to significantly influence clinical outcome (modified Rankin Scale 3-6) and occurrence of intracranial hemorrhage in a multivariate logistic regression analysis. Conclusion Prior use of vitamin-K-antagonists was not associated with a higher rate of periprocedural intracranial hemorrhage after endovascular treatment or worse outcome. Endovascular treatment should be considered as an important treatment option in patients taking vitamin-K-antagonists. PMID- 28353414 TI - Emerging technology for increasing glucosinolates in arugula and mustard greens. AB - Two plant species, arugula (Eruca sativa) and mustard (Brassica juncea) were field-grown under four soil management practices: soil mixed with municipal sewage sludge (SS), soil mixed with horse manure (HM), soil mixed with chicken manure (CM), and no-mulch bare soil (NM) to investigate the impact of soil amendments on the concentration of glucosinolates (GSLs) in their shoots. GSLs, hydrophilic plant secondary metabolites in arugula and mustard were extracted using boiling methanol and separated by adsorption on sephadex ion exchange disposable pipette tips filled with DEAE, a weak base, with a net positive charge that exchange anions such as GSLs. Quantification of GSLs was based on inactivation of arugula and mustard myrosinase and liberation of the glucose moiety from the GSLs molecule by addition of standardized myrosinase (thioglucosidase) and spectrophotometric quantification of the liberated glucose moiety. Overall, GSLs concentrations were significantly greater (1287 ug g-1 fresh shoots) in plants grown in SS compared to 929, 890, and 981 ug g-1 fresh shoots in plants grown in CM, HM, and NM soil, respectively. Results also revealed that mustard shoots contained greater concentrations of GSLs (974 ug g-1 fresh shoots) compared to arugula (651 ug g-1 fresh shoots). PMID- 28353415 TI - Casting and Splinting Management for Hand Injuries in the In-Season Contact Sport Athlete. AB - CONTEXT: Upper extremity injuries are extremely common in contact sports such as football, soccer, and lacrosse. The culture of competitive athletics provides an environment where hand injuries are frequently downplayed in an effort to prevent loss of game time. However, studies have shown that many sport-induced hand injuries do not actually require immediate surgical attention and can be safely treated through immobilization so that the athlete may complete the athletic season. In these cases, appropriate casting and splinting measures should be taken to ensure protection of the injured player and the other competitors without causing loss of game time. EVIDENCE ACQUISITION: Articles published between 1976 and 2015 were reviewed to capture historical and current views on the treatment of hand injuries in the in-season athlete. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 5. RESULTS: Although traditionally many sports induced traumatic injuries to the hand held the potential to be season-ending injuries, experience has shown that in-season athletes do not necessarily need to lose game time to receive appropriate treatment. A thorough knowledge of converting everyday splints and casts into game day, sport-approved protective immobilization devices is key to safely allowing athletes with select injuries to play while injured. CONCLUSION: Protective techniques allow for maximum functionality during gameplay while safely and effectively protecting the injury from further trauma while bony healing takes place. PMID- 28353417 TI - Do Patients with Pre-Existing Psychiatric Illness Have an Increased Risk of Infection after Injury? AB - BACKGROUND: Trauma remains a leading cause of death and long term-morbidity. We have shown that patients who sustain traumatic injuries are at increased risk for the development of infectious complications. Psychiatric illnesses (PIs) are also noted to occur frequently among the general population. The presence of a PI has been shown to be a risk factor for the development of infections. Despite the prevalence of both traumatic injuries and psychiatric diseases, there are little data relating the impact of PI on the outcome of patients with trauma. We hypothesize that the presence of a PI will be associated with an increased risk of an infection developing after injury. PATIENTS AND METHODS: This is a five year retrospective chart review of all admitted patients with trauma age 18 years and older. Patients with and without a major psychiatric illness were compared. Demographic data, mechanism of injury and Injury Severity Score (ISS) were reviewed. Co-morbidities included diabetes mellitus, obesity, pre-injury steroid use, and International Classification of Diseases, 9th edition, based psychiatric illness. All infections were diagnosed by microbiologic criteria (urinary tract infection [UTI], ventilator-associated pneumonia) or Centers for Disease Control and Prevention criteria for clinically evident infections (surgical site infection). RESULTS: Of the 11,147 admitted trauma patients, 14.5% had a pre injury PI diagnosis. The PI patients were older (61.5 +/- 0.5 vs. 54.3; p < 0.001), more often female (56% vs. 39.1%; p < 0.001), and had no difference in blunt mechanism rates (88.4% vs. 89.9%; p = 0.06) or median ISS (9 vs. 9; p = 0.06). There was no difference between PI and non-PI patients in pre-injury diabetes mellitus (13.4% vs. 12.7%; p = 0.4), steroid use (2.5% vs. 1.9%; p = 0.1), but patients with PI were more likely to be obese (15.7% vs. 13.6%; p = 0.03). Patients with PI were more likely to have an infection develop (10.4% vs. 7.5%; p < 0.001). The most common infection in both groups was UTI (6.9% vs. 4.2%; p < 0.001). Compared with non-PI patients, adjusting for age, gender, ISS, diabetes mellitus, and obesity, patients with PI were more likely to have an infection develop (odds ratio 1.3, 95% confidence interval = 1.1-1.5) Conclusions: Patients with an underlying PI are at increased risk of having a UTI after traumatic injury. This study identifies a previously unknown independent risk factor for UTIs in patients with trauma. This stresses the need for increased awareness and attention to this vulnerable population. PMID- 28353416 TI - Resting state fMRI: A review on methods in resting state connectivity analysis and resting state networks. AB - The inquisitiveness about what happens in the brain has been there since the beginning of humankind. Functional magnetic resonance imaging is a prominent tool which helps in the non-invasive examination, localisation as well as lateralisation of brain functions such as language, memory, etc. In recent years, there is an apparent shift in the focus of neuroscience research to studies dealing with a brain at 'resting state'. Here the spotlight is on the intrinsic activity within the brain, in the absence of any sensory or cognitive stimulus. The analyses of functional brain connectivity in the state of rest have revealed different resting state networks, which depict specific functions and varied spatial topology. However, different statistical methods have been introduced to study resting state functional magnetic resonance imaging connectivity, yet producing consistent results. In this article, we introduce the concept of resting state functional magnetic resonance imaging in detail, then discuss three most widely used methods for analysis, describe a few of the resting state networks featuring the brain regions, associated cognitive functions and clinical applications of resting state functional magnetic resonance imaging. This review aims to highlight the utility and importance of studying resting state functional magnetic resonance imaging connectivity, underlining its complementary nature to the task-based functional magnetic resonance imaging. PMID- 28353418 TI - Factors Associated with the Development of Tertiary Peritonitis in Critically Ill Patients. AB - BACKGROUND: Critically ill surgical patients remain at a high risk of adverse outcomes as a result of secondary peritonitis (SP). The risk is even higher if tertiary peritonitis (TP) develops. Factors related to the development of TP, however, are scarce in the literature. The main aim of our study was to identify factors associated with the development of TP in patients with SP in the intensive care unit (ICU), and also to report differences in microbiologic patterns and antibiotic therapy in patients with the two conditions. PATIENTS AND METHODS: A prospective, observational study was conducted at our institution from 2010 to 2014. Baseline characteristics on admission, outcomes, microbiologic results, and antibiotic therapy were recorded for analysis. RESULTS: We included 343 patients with SP, of whom TP developed in 185 (53.9%). Almost two-thirds (64.4%) were male; mean age was 63.7 +/- 14.3 years, and mean APACHE was 19.4 +/- 7.8. In-hospital death was 42.6% (146). Multivariable analysis showed that longer ICU stay (odds ratio [OR]: 1.019; 95% confidence interval [CI]: 1.004-1.034; p = 0.010), urgent operation on hospital admission (OR: 3.247; 95% CI: 1.392-7.575; p = 0.006), total parenteral nutrition (TPN) (OR: 3.079; 95% CI: 1.535-6.177; p = 0.002) and stomach-duodenum as primary infection site (OR: 4.818; 95% CI: 1.429 16.247; p = 0.011) were factors associated with the development of TP, whereas patients with localized peritonitis were less prone to have TP develop (OR: 0.308; 95% CI: 0.152-0.624; p = 0.001). Higher incidences of Candida spp. (OR: 1.275; 95% CI: 1.096-1.789; p = 0.016), Enterococcus faecium (OR: 1.085; 95% CI: 1.018-1.400; p = 0.002), and Enterococcus spp. (OR: 1.370; 95% CI: 1.139-1.989; p = 0.047) were found in TP, and higher rates of cephalosporin use in SP (OR: 3.51; 95% CI: 1.139-10.817; p = 0.035). CONCLUSIONS: Complicated peritonitis remains a cause of a high numbers of deaths in the ICU. The need for TPN, urgent operation on hospital admission, and particularly surgical procedures in the proximal gastrointestinal tract were factors associated with development of TP and may potentially help to identify patients with SP at risk for development of TP. Physicians should be aware concerning multi-drug-resistant germs when treating these patients. PMID- 28353419 TI - A new anti-mesothelin antibody targets selectively the membrane-associated form. AB - Mesothelin is a glycosylphosphatidylinositol (GPI)-anchored membrane protein that shows promise as a target for antibody-directed cancer therapy. High levels of soluble forms of the antigen represent a barrier to directing therapy to cellular targets. The ability to develop antibodies that can selectively discriminate between membrane-bound and soluble conformations of a specific protein, and thus target only the membrane-associated antigen, is a substantive issue. We show that use of a tolerance protocol provides a route to such discrimination. Mice were tolerized with soluble mesothelin and a second round of immunizations was performed using mesothelin transfected P815 cells. RNA extracted from splenocytes was used in phage display to obtain mesothelin-specific antigen-binding fragments (Fabs) that were subsequently screened by flow cytometry and ELISA. This approach generated 147 different Fabs in 34 VH-CDR3 families. Utilizing competition assays with soluble protein and mesothelin-containing serum obtained from metastatic cancer patients, 10 of these 34 VH-CDR3 families were found to bind exclusively to the membrane-associated form of mesothelin. Epitope mapping performed for the 1H7 clone showed that it does not recognize GPI anchor. VH-CDR3 sequence analysis of all Fabs showed significant differences between Fabs selective for the membrane-associated form of the antigen and those that recognize both membrane bound and soluble forms. This work demonstrates the potential to generate an antibody specific to the membrane-bound form of mesothelin. 1H7 offers potential for therapeutic application against mesothelin-bearing tumors, which would be largely unaffected by the presence of the soluble antigen. PMID- 28353421 TI - LGBT-Competence in Social Work Education: The Relationship of School Contexts to Student Sexual Minority Competence. AB - This study examined the relationship between master of social work programs' (MSW) support of lesbian, gay, bisexual, and transgender people (LGBT-competence) and the sexual minority competence (LGB-competence) of social work students. Data were gathered from a sample of MSW program directors, faculty members, and students (N = 1385) within 34 MSW programs in the United States. A series of hierarchical linear models tested if a MSW program's LGBT-competence was associated with the LGB-competence of its students. Results showed a significant relationship between organizational LGBT-competence and individual LGB-competence within schools of social work, and that programs with greater LGBT-competence also had students who felt more competent to work with sexual minorities. These findings suggest schools of social work can take substantive action at an organizational level to improve the professional LGB-competence of future social workers. Implications for social work education are discussed. PMID- 28353422 TI - Clinical trial research in focus: overcoming barriers in MDR-TB clinical trials. PMID- 28353420 TI - Antibody adsorption on the surface of water studied by neutron reflection. AB - Surface and interfacial adsorption of antibody molecules could cause structural unfolding and desorbed molecules could trigger solution aggregation, resulting in the compromise of physical stability. Although antibody adsorption is important and its relevance to many mechanistic processes has been proposed, few techniques can offer direct structural information about antibody adsorption under different conditions. The main aim of this study was to demonstrate the power of neutron reflection to unravel the amount and structural conformation of the adsorbed antibody layers at the air/water interface with and without surfactant, using a monoclonal antibody 'COE-3' as the model. By selecting isotopic contrasts from different ratios of H2O and D2O, the adsorbed amount, thickness and extent of the immersion of the antibody layer could be determined unambiguously. Upon mixing with the commonly-used non-ionic surfactant Polysorbate 80 (Tween 80), the surfactant in the mixed layer could be distinguished from antibody by using both hydrogenated and deuterated surfactants. Neutron reflection measurements from the co-adsorbed layers in null reflecting water revealed that, although the surfactant started to remove antibody from the surface at 1/100 critical micelle concentration (CMC) of the surfactant, complete removal was not achieved until above 1/10 CMC. The neutron study also revealed that antibody molecules retained their globular structure when either adsorbed by themselves or co-adsorbed with the surfactant under the conditions studied. PMID- 28353423 TI - Congestion of the streets and lungs in India. PMID- 28353424 TI - Florence Seibert. PMID- 28353425 TI - What has Europe ever done for health? PMID- 28353426 TI - Trauma for migrant children stranded in Greece. PMID- 28353427 TI - Preparing for future global health emergencies. PMID- 28353428 TI - Reducing global tuberculosis deaths-time for India to step up. PMID- 28353429 TI - Sustaining tuberculosis decline in the UK. PMID- 28353430 TI - Encountering pain. PMID- 28353431 TI - Offline: The dark heart of the wood. PMID- 28353432 TI - US health and science advocates gear up for battle over EPA. PMID- 28353433 TI - Iraq's health system under pressure as fighting escalates. PMID- 28353434 TI - New plan to end tuberculosis in south and southeast Asia. PMID- 28353435 TI - Ana Mari Cauce: leader of a new initiative in population health. PMID- 28353436 TI - Getting pandemic prevention right. PMID- 28353437 TI - The need to revise the Helsinki Declaration. PMID- 28353438 TI - Tracheal implants revisited. PMID- 28353439 TI - Feedback of results to trial participants: be upfront or risk affront. PMID- 28353440 TI - ANTARCTIC: platelet function testing to adjust therapy. PMID- 28353441 TI - ANTARCTIC: platelet function testing to adjust therapy - Authors' reply. PMID- 28353442 TI - ANTARCTIC: platelet function testing to adjust therapy. PMID- 28353443 TI - Department of Error. PMID- 28353444 TI - Department of Error. PMID- 28353445 TI - Department of Error. PMID- 28353446 TI - Decline and changing profile of hepatitis delta among injection drug users in Spain. AB - BACKGROUND: Roughly 15 million people worldwide have hepatitis delta, the most severe form of chronic viral hepatitis that often leads to cirrhosis and liver cancer. Injection drug users (IDUs) are the largest HDV reservoir. Their resurgence in North America and Europe may represent a new opportunity for HDV to spread more widely. METHODS: We examined all consecutive active IDUs seen for the first time and enrolled in detoxification programmes at two clinics in Spain during two periods (1993-1996 and 2011-2014, respectively). Serum markers of HIV, HBV and HDV infection were tested. RESULTS: A total of 209 IDUs were examined in the first period. Mean age was 27-years-old. All had markers of past or current HBV infection. The rate of HIV-antibody (Ab), hepatitis B surface antigen (HBsAg) and HDV-Ab was as follows: 122 (58.4%), 73 (34.9%) and 62 (29.7%), respectively. Serum HDV-Ab was recognized in 53.4% of HBsAg+ and 16.9% of HBsAg- patients (P<0.001). Positivity for HDV-Ab was associated with HIV regardless HBsAg status. In the second period we tested 47 active IDUs. Anti-HDV was found in only two (4.2%), both immigrants from HDV endemic countries and with HBsAg+. CONCLUSIONS: Acute HBV-HDV coinfections and self-limited HDV infections were frequent in the 1990s among IDUs in Spain, especially in HIV+ individuals. In contrast, circulation of HDV has dramatically declined among active IDUs in Spain and is currently very rare, being concentrated in foreign immigrants. It may reflect the benefit of universal HBV vaccination as well as the success of needle exchange programmes in Spain. PMID- 28353447 TI - On the experimental validation of model-based dose calculation algorithms for 192Ir HDR brachytherapy treatment planning. AB - There is an acknowledged need for the design and implementation of physical phantoms appropriate for the experimental validation of model-based dose calculation algorithms (MBDCA) introduced recently in 192Ir brachytherapy treatment planning systems (TPS), and this work investigates whether it can be met. A PMMA phantom was prepared to accommodate material inhomogeneities (air and Teflon), four plastic brachytherapy catheters, as well as 84 LiF TLD dosimeters (MTS-100M 1 * 1 * 1 mm3 microcubes), two radiochromic films (Gafchromic EBT3) and a plastic 3D dosimeter (PRESAGE). An irradiation plan consisting of 53 source dwell positions was prepared on phantom CT images using a commercially available TPS and taking into account the calibration dose range of each detector. Irradiation was performed using an 192Ir high dose rate (HDR) source. Dose to medium in medium, [Formula: see text], was calculated using the MBDCA option of the same TPS as well as Monte Carlo (MC) simulation with the MCNP code and a benchmarked methodology. Measured and calculated dose distributions were spatially registered and compared. The total standard (k = 1) spatial uncertainties for TLD, film and PRESAGE were: 0.71, 1.58 and 2.55 mm. Corresponding percentage total dosimetric uncertainties were: 5.4-6.4, 2.5-6.4 and 4.85, owing mainly to the absorbed dose sensitivity correction and the relative energy dependence correction (position dependent) for TLD, the film sensitivity calibration (dose dependent) and the dependencies of PRESAGE sensitivity. Results imply a LiF over-response due to a relative intrinsic energy dependence between 192Ir and megavoltage calibration energies, and a dose rate dependence of PRESAGE sensitivity at low dose rates (<1 Gy min-1). Calculations were experimentally validated within uncertainties except for MBDCA results for points in the phantom periphery and dose levels <20%. Experimental MBDCA validation is laborious, yet feasible. Further work is required for the full characterization of dosimeter response for 192Ir and the reduction of experimental uncertainties. PMID- 28353448 TI - Predictive value of fever following arthroplasty in diagnosing an early infection. AB - Postoperative fever after orthopaedic surgery is a controversial clinical problem in daily practice because damaged tissue due to surgical intervention can induce the production of proinflammatory cytokines responsible of the systemic inflammatory response syndrome. No current diagnostic marker can differentiate with sufficient accuracy infectious from non-infectious fever in patients undergoing orthopaedic surgery, but early diagnosis of postoperative orthopaedic infections is important in order to rapidly initiate adequate antimicrobial therapy. Review of clinical trials on fever did not establish the parameters reporting sufficient diagnostic accuracy. Blood cultures, white blood-cent count, erythrocyte sedimentation rate and C-reactive protein have low specificity. Procalcitonin and IL-6 can be helpful diagnostic markers supporting clinical findings. An algorithm for evaluation of fever in orthopaedic surgery may be a helpful tool. PMID- 28353449 TI - Influence of socio-economic inequality measured by the Gini coefficient on meningitis incidence caused by Mycobacterium tuberculosis and Haemophilus influenzae in Colombia, 2008-2011. AB - Bacterial meningitis is an important cause of infectious neurological morbidity and mortality. Its incidence has decreased with the introduction of vaccination programmes against preventable agents. However, low-income and middle-income countries with poor access to health care still have a significant burden of the disease. Thus, the relationship between the Gini coefficient and H. influenzae and M. tuberculosis meningitis incidence in Colombia, during 2008-2011, was assessed. In this ecological study, the Gini coefficient was obtained from the Colombian Department of Statistics, incidence rates were calculated (cases/1,000,000 pop) and linear regressions were performed using the Gini coefficient, to assess the relationship between the latter and the incidence of meningitis. It was observed that when inequality increases in the Colombian departments, the incidence of meningitis also increases, with a significant association in the models (p<0.01) for both M. tuberculosis (r2=0.2382; p<0.001) and H. influenzae (r2=0.2509; p<0.001). This research suggests that high Gini coefficient values influence the incidence of Mycobacterium tuberculosis and Haemophilus influenzae meningitis, showing that social inequality is critical to disease occurrence. Early detection, supervised treatment, vaccination coverage, access to health care are efficient control strategies. PMID- 28353451 TI - The prevalence and resistance patterns of Pseudomonas aeruginosa in a tertiary care hospital in Kosovo. AB - Pseudomonas aeruginosa is a Gram-negative bacterium that continues to a leading cause of opportunistic nosocomial infections. The rapid increase in drug resistance in clinical isolates of this pathogen is a worldwide concern. The aim of this study was to investigate the distribution rate, prevalence and resistance patterns of P. aeruginosa in clinical specimens from the University Clinical Centre of Kosovo (UCCK). During a three-year period, 553 P. aeruginosa isolates were collected from patients admitted to a variety of UCCK units. The P. aeruginosa isolates were identified using standard laboratory procedures, and the susceptibility of the isolates to antimicrobial agents was investigated using the Kirby-Bauer disk diffusion assay according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) (2013-2015) guidelines. P. aeruginosa was the second most frequently isolated pathogen. The isolation rate of P. aeruginosa was 7.6%, 10.1% and 8.6% in 2013, 2014 and 2015, respectively. Most clinical samples were from ICU (380, 68.7%). There was a statistically significant difference between ICU and non-ICU (p<0.05). P. aeruginosa isolates were most frequently isolated from the respiratory tract (323, 58.4%). The rate of resistance against most of the tested antimicrobials has increased, especially for carbapenems. Imipenem resistance was 25.2%, 26.5%, and 37.7% and meropenem resistance was 20.1%, 23.4%, and 36% in 2013, 2014 and 2015, respectively. This study provides important data on current antimicrobial resistance, and the results demonstrate that the resistance rates are progressively increasing. There is an urgent need to emphasise the prudent use of antibiotics and strictly adhere to the concept of "reserve drugs" to minimise the misuse of available antimicrobials. The acquisition and analysis of prevalence and resistance data will be an important tool to identify targets for quality improvement in Kosovo and will support the preparation of guidelines and protocols for the prudent use of antibiotics. PMID- 28353450 TI - Predominance of Clostridium difficile 027 during a five-year period in Bolzano, Northern Italy. AB - Toxigenic Clostridium difficile is responsible for antibiotic-associated diarrhoea and other diseases. The increasing frequency and severity is attributed to highly-virulent ribotypes such as 027. The aim of the study was to collect epidemiological and molecular data for C. difficile isolates during 2009-2013 in the Central Hospital of Bolzano, Northern Italy. Stool samples from inpatients of the Bolzano Central Hospital were screened for toxins A and B, and C. difficile was cultured and tested for antibiotic susceptibility. PCRs were performed for genes of toxin A, toxin B, binary toxin and ribotyping. During the period 2009-13 from 320 patients (9% of patients tested) at least one stool sample proved positive for C. difficile toxins, and incidences for all hospital inpatients per 10,000 patient days (per 1,000 admissions) varied between 2.2 (1.5) and 4.3 (3.0). Out of 138 isolates (43% of total isolates were studied), 24 different ribotypes were identified. Isolates with ribotype 027 were predominant (38%), followed by 018 (13%) and 607 (10%). Whereas for ribotype 018 a significant decrease was seen during the five-year period, ribotype 027 increased significantly from 0% in 2009 to 64% in 2012, decreasing then to 10% in 2013. Isolates were sensitive to metronidazole and vancomycin, whereas isolates of the three major ribotypes were resistant to moxifloxacin. Our data indicates a significant change in C. difficile incidence rates and ribotype frequencies during the five-year period in the Central Hospital in Bolzano. PMID- 28353452 TI - Molecular characterization and antibiotic susceptibility of Haemophilus influenzae clinical isolates. AB - Haemophilus influenzae can cause invasive and severe infections in both adults and children such as otitis media, sinusitis, pneumonia, meningitis and bacteremia. The emerging antibiotic resistance in recent years against ampicillin and several other antibiotics among strains of H. influenzae gives cause for serious concern. Here, we investigate beta-lactamase (BL) activity in clinical isolates of H. influenzae, profile their resistance to antibiotics, and characterize the clonal relationship of the isolates. Antibiotic susceptibilities of 92 clinical isolates of H. influenzae (March 2011-May 2012) were determined using the disk diffusion method according to the Clinical & Laboratory Standards Institute (CLSI), and BL activity was detected using the nitrocefin disk method. The Rep-PCR method was used to characterize clonality of the isolates. All strains were found to be susceptible to levofloxacin and cefotaxime. Four isolates out of 92 (4.3%) were found resistant to ampicillin, one isolate (1.1%) was resistant to amoxicillin/clavulanic acid, 21 isolates (22.8%) were resistant to trimethoprim-sulfamethoxazole (SXT), and three isolates (3.3%) showed BL activity. One strain was BL-negative but resistant to ampicillin. The three isolates with BL activity and four isolates with resistance to ampicillin did not have a clonal relationship. Three distinct clones [clone A (with subclones A1 and A2), clone B, and clone C] were identified among the SXT-resistant strains. Most of the H. influenzae isolates in this study were susceptible to the antibiotics while SXT resistance was relatively more prevalent, which suggests that significant obstacles in the therapeutic use of antibiotics against H. influenzae strains are not expected in our region. PMID- 28353453 TI - A change for the antibacterial treatment policy to decrease carbapenem consumption at a haematopoietic stem cell transplantation centre. AB - After experiencing a high rate of carbapenem-resistant Gram-negative bacilli infections in febrile neutropenic patients, a two-stage intervention was introduced in the haematopoietic stem cell transplantation (HSCT) centre. During the first eight months of 2014, carbapenems remained the first choice for the empirical treatment of febrile neutropenia while the use of piperacillin/tazobactam (TZP) was encouraged in patients with stable clinical condition. When blood cultures were reported as negative and the patient was clinically stable the carbapenem/TZP treatment was stopped regardless of continuous fever and neutrophil count. From October 2014, TZP (with prolonged infusion) with or without amikacin replaced carbapenems as the first line therapy of neutropenic fever except for high-risk patients previously known as colonized or infected with extended spectrum beta-lactamase (ESBL) producing Enterobacteriaceae, who presented with severe sepsis, septic shock or nosocomial pneumonia, and recently transferred from the intensive care unit with a high endemicity of multidrug-resistant Gram-negative bacilli. Vancomycin or teicoplanin was used when there was suspicion of septic shock or detection of severe mucositis and central-line associated bacteraemia. The antibacterial therapy was escalated or de-escalated in culture-positive patients according to the antimicrobial susceptibility reports and clinical progress. Daily defined dosages (DDD) per 1000 patient days were calculated for all antibiotics by the hospital pharmacist for each year. A total of 913 admissions with 11,544 patient days were followed in 2013; and 1,072 admissions with 11,843 patient-days were followed in 2014. The rate of ESBL production in Enterobacteriaceae bacteraemia was as 31.8% in 2013 and 47.3% in 2014. All staphylococci isolated from blood culture were methicillin-resistant for both years. All Enterococcus faecium isolates but one from blood cultures were resistant to ampicillin. The number of the patients who died during hospitalization was 24 in 2013, and 17 patients died in 2014. The DDDs/1000 patient days for imipenem, meropenem, vancomycin, teicoplanin, daptomycin, linezolid, colistin, piperacillin/tazobactam and amikacin in 2013 and 2014 were respectively as follows; 201 vs 19 (p<0.001); 1,578 vs 1,092 (p<0.001); 533 vs 251 (p<0.001); 205 vs 159 (p<0.001); 56 vs 14 (p<0.001); 76 vs 26 (p<0.001); 188 vs 154 (p<0.001); 157 vs 254 (p<0.001); and 5 vs 41 (p<0.001). Our study showed that a febrile neutropenia pathway guided by local epidemiology and international guidelines can reduce the use of antibiotics in haematological cancer or HSCT patients. The sustainability of such an intervention requires strong multidisciplinary cooperation. PMID- 28353454 TI - Utility of the Aspergillus galactomannan antigen testing for neutropenic paediatric patients. AB - Invasive aspergillosis (IA) is an increasingly important cause of morbidity and mortality particularly in paediatric patients. Early diagnosis and the initiation of efficacious antifungal treatments could affect the prognosis of these patients. The aim of this study was to determine the clinical contribution of Galactomannan (GM) screening in paediatric patients. We reviewed the records of all in-patients, and followed up, in the various units at the Medical Faculty Children's Hospital of Erciyes University (Kayseri, Turkey), those who had at least one GM assay result from August 2009 to April 2012. Paediatric patients were classified as proven, probable or possible, according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG). Twenty-five patients, with proven IA (n=3), probable IA (n=9) and possible IA (n=13) were included in the study. The GM antigen assay results were analysed in 158 blood samples from 47 patients. At the cut-off value of 0.5 ng/ml, the sensitivity was 68% [95% confidence interval (CI); 47-85]; specificity, 77% (95% CI; 55-92). To obtain more accurate results with GM testing, the diagnosis of IA should be confirmed by clinical investigation and the factors causing false positivity of the test should also be considered. PMID- 28353455 TI - Pharmacogenomic influence on sepsis outcome in critically ill patients. AB - In infectious and inflammatory diseases, pharmacogenetics affects treatment efficacy and toxicity. Moreover, recent studies suggest its important role in predicting the clinical outcome of sepsis. Our aim was to investigate the influence of single nucleotide polymorphisms (SNPs) in genes which we supposed to be involved in linezolid elimination upon sepsis outcome. Fourteen ICU-admitted patients in therapy with intravenous linezolid (600mg q12h) were enrolled and classified into three groups: group 0 for sepsis, 1 for severe sepsis and 2 for septic shock. Genotyping for SNPs in MDR1 3435 rs1045642 C>T, 2677 rs2032582 G>T and 1236 rs1128503 C>T, MRP2 -24 rs717620 G>A and 1249 rs2273697 G>A, MRP4 *879 rs1059751 T>C and 3348 rs1751034 T>C, BCRP1 421 rs2231142 C>A and 1194+928 rs13120400 T>C, -127 rs4149170 G>A and OCT1 480 rs683369 C>G genes was done using real-time PCR allelic discrimination assay. The Mann-Whitney statistical test was used to analyse variables. MDR1 2677 (p= 0.012), MRP2 1249 (p= 0.038), MRP4 *879 (p= 0.032) and 3348 SNPs significantly influenced the sepsis score. Our study, despite its limited sample size, could be decisive for early sepsis prediction and may improve the management of critically ill patients. PMID- 28353457 TI - Infectious diseases among foreign prisoners: results of a hospital-based management model in Palermo. AB - Foreign prisoners have a high vulnerability in terms of morbidity and access to care in overcrowded Italian prisons. This paper presents and comments on the management model of infectious diseases in foreign prisoners at our outpatient clinic, in order to describe a model of management for these conditions. Overall, 133 subjects (mean age 35.5 years) from 29 countries were followed for a period of 15 years. The most commonly represented area of origin (54.1%) was the Maghreb region. HCV infection (40.6%), HIV (22.5%), HBV (9.8%) and co-infection (15%, HIV/HCV or HIV/HBV) were observed. Ten subjects had tuberculosis, and only 30% of them were compliant with the treatment. Only 46.3% of HCV mono-infected patients completed the entire diagnostic process and even a lower percentage (37%) of them took treatment regularly. 90% of HBV mono-infected patients and 84% of those HIV mono- and co-infected completed the diagnostic workout. 77% of patients in each group took therapy regularly. Overall, the results show limited effectiveness. Therefore, it would be necessary to improve communication between healthcare professionals and correctional systems. Moreover, it appears urgent to reduce overcrowding in prisons to limit morbidity in prisoners. PMID- 28353456 TI - Comparison of IIF, ELISA and IgG avidity tests for the detection of anti Toxoplasma antibodies in single serum sample from pregnant women. AB - A valid estimate of test efficiency is needed to choose adequate screening and detecting strategies in diagnosis of acute toxoplasmosis. Therefore, in the present study we evaluated the efficiency of diagnostic laboratory methods to detect anti-toxoplasma antibodies in single serum samples of pregnant women by indirect immunofluorescence test (IIF), enzyme-linked immunosorbent assay (ELISA) and IgG avidity tests in north-western Iran. In an analytical-descriptive study, during March 2010 to April 2013, 391 pregnant women aged 21 to 35 years who were referred by gynaecologists or infectious disease specialists for anti-toxoplasma antibody evaluation were studied. A peripheral blood sample was collected from individuals and serum was prepared immediately for anti-toxoplasma antibody evaluation by IIF, ELISA and IgG avidity tests. ELISA and IgG avidity tests were used as gold standard. Evaluation of anti-toxoplasma antibodies by IIF revealed that 280 cases (71.61%) were seropositive and 111 (28.38%) seronegative, while evaluation by ELISA revealed that 267 cases (68.28%) were seropositive and 124 (31.70%) seronegative; 65 (16.62%) were IgM positive by both IIF and ELISA tests. There were 45 (69.23%) and 7 (10.76%) IgM positive suspected cases respectively in IIF and ELISA confirmed by the IgG avidity test for recent toxoplasmosis. This study highlights how to manage and evaluate pregnant women who are suspected to be infected with toxoplasmosis by using diagnostic tests, especially in a single serum sample indication. PMID- 28353458 TI - Suicidal behaviour in HIV-infected patients in Greece. AB - This study investigated suicide completion and suicide attempts by HIV-infected patients in Greece, which, from the existing literature, are more frequent than those among the general population. The study sample comprised HIV-infected patients who had been monitored for a minimum period of six months from 1992 through 2012 at the "Andreas Sygros" University Hospital in Athens. Among the 1884 patients who were monitored during the study period, 37 suicides were attempted by 28 (1.48%) patients (27 men and 1 woman). Six of them were fatal (0.3%, 52/100,000 person-years) while over the study, 397 patients died. No significant differences concerning main characteristics were recorded among patients with an attempted and those with a completed suicide. Seventeen of the 28 patients (60.71%) demonstrated psychiatric morbidities. Suicide attempts were more numerous before the advent of combined antiretroviral therapy (cART), whereas there was no difference in attempts before and after the Greek financial crisis in 2009. The suicide frequency was higher than that of the general population for the same period. However, it decreased after the introduction of cART. Special attention is required in recording coexisting mental disorders and providing specialized psychiatric care to HIV-infected patients. PMID- 28353459 TI - First report of Kocuria marina bloodstream infection unrelated to a central venous catheter: a mini-review on an emerging and under-recognized opportunistic pathogen. AB - We report a case of sepsis by Kocuria marina in a 45-year-old woman carrying a midline venous catheter to provide total parenteral nutrition. Despite the finding of K. marina bacteraemia, no bacteria grew from the culture of the catheter tip. As the patient was affected with severe leg ulcers, K. marina bloodstream infection from a skin breakage other than CVC was supposed. K. marina is an emerging opportunistic agent deserving attention and probably under recognized, as it can be misdiagnosed as Staphylococcus if only conventional microbiological analyses are performed for bacterial identification. PMID- 28353460 TI - From soil to blood: first human case of Sphingobacterium hotanense bacteraemia. AB - This report describes a case of Sphingobacterium hotanense bacteraemia in a patient scratched by a rooster on the right arm. Diagnostic, clinical and therapeutic features are discussed. To the best of our knowledge, this is the first case of Sphingobacterium hotanense bacteremia reported in the medical literature. PMID- 28353461 TI - Saint Louis Encephalitis Virus, another re-emerging arbovirus: a literature review of worldwide research. AB - Not available. PMID- 28353462 TI - Tuberculin skin test and/or interferon gamma release assay: is it still time to debate? AB - Not available. PMID- 28353463 TI - Escherichia coli, a "symbiosis masquerade". AB - Not available. PMID- 28353464 TI - Wartime infections and tragedies at the beginning of the 20th century in the Eastern part of Turkey. AB - In the early 20th century, Europe and the Ottoman Empire as a whole experienced a large number of epidemic diseases, and several wars. During World War I (WW1) a general mobilization of the medical services under Ottoman Empire rule was enacted. However, shortages of food and water, unfavourable weather and poor sanitary conditions resulted in numerous diseases at the battle fronts. Indeed, during the Ottoman-Russian war on the Eastern Front, the Turks suffered massive loss of life. This article therefore emphasises that during WW1, such loss of life in the Ottoman Army on the Eastern Front, which was one of the key fronts of the war, was mainly due to epidemic diseases rather than battles. PMID- 28353465 TI - Assessing Impressions of Community Health Worker Use of Tablet-Based Medication Documentation Software. AB - Community health workers, an important and emerging role in the evolution of the care delivery system, are uniquely positioned to play a vital role in information gathering and exchange. NewYork-Presbyterian Hospital carried out a feasibility study to assess community health worker use and impressions of a medication documentation application that runs on a tablet. The nine community health workers successfully collected data on 16 patients in the home setting. On average, 10 medications were collected per patient, and the average time to collect the medication data was 1 hour. Key findings from the focus groups included the need for additional training and the desire to use the device to streamline other documentation activities. In general, the software was judged to be suitable for the proposed task and represents a starting point for further use of tools that leverage the community health worker in a team-based workflow. PMID- 28353466 TI - Associations Between Khat Use and HIV Risk and Status Among Voluntary Counseling and Testing Center Clients in Addis Ababa, Ethiopia. AB - OBJECTIVES: Ethiopia is 1 of 15 countries that account for nearly 75% of all people living with HIV. Khat use, a common practice in Ethiopia and sub-Saharan Africa, has gained attention as a potential risk factor for HIV. Our objective was to evaluate associations between khat use and demographic and risk-taking characteristics (alcohol use, sexual behavior), and also associations between HIV status and these characteristics among voluntary counseling and testing clients in Addis Ababa, Ethiopia. METHODS: This cross-sectional study was conducted among Pro Pride voluntary counseling and testing center clients, aged 18 to 49 years, from November 2009 to March 2010. All clients were approached, and 98.8% of these (684) completed a self-administered questionnaire. Associations between khat use, alcohol use, multiple sexual partners, and HIV status were assessed using logistic regression models. RESULTS: Using khat in the past 90 days (current khat use) was significantly associated with being Muslim, being male, alcohol use, and having a greater number of sex partners in one's lifetime. The adjusted odds of current khat use was almost 7-fold higher in those having 4 or more sexual partners in their lifetime (adjusted odds ratio 6.89, 95% confidence interval 3.87, 12.25) as compared with those with 1 or none. HIV-positive status was significantly associated with age, employment, marital status, number of sex partners in one's lifetime, and khat use. Having used khat in one's lifetime, but not currently, past khat use, was associated with over a 2-fold increased adjusted odds (adjusted odds ratio 2.64, 95% confidence interval 1.13, 6.19) of being HIV-infected. CONCLUSIONS: Our findings highlight associations between current khat use and the modifiable factors of number of lifetime sexual partners and alcohol use. In addition, we observed the association between HIV status and past khat use after adjusting for age, marital status, and number of sex partners in one's lifetime. PMID- 28353468 TI - Primary Budd-Chiari Syndrome in Children: King's College Hospital Experience. AB - Primary Budd-Chiari syndrome is a rare cause of liver disease in children in the western world. Here we present a retrospective review of children with Primary Budd-Chiari syndrome presenting from January 2001 to November 2015 to our hospital. Seven children were identified. Their presentation was mostly chronic. All had predisposing factors for thrombosis and were started on anticoagulation. Radiological interventions (2 transjugular intrahepatic portosystemic shunts and 1 hepatic vein stenting), liver transplant and mesocaval shunt were done in 3, 2, and 1 patients, respectively; 1 child underwent bone marrow transplantation following transjugular intrahepatic portosystemic shunts and 1 child was managed only medically. After liver transplantation, one child died 3 years later as a result of subarachnoid haemorrhage, whereas others remain well at a median follow up of 6 years. Despite high morbidity, the disease can have a good long-term outcome with a multidisciplinary approach. PMID- 28353467 TI - Safety of a Rapidly Dissolving Buprenorphine/Naloxone Sublingual Tablet (BNX-RDT) for Treatment of Opioid Dependence: A Multicenter, Open-label Extension Study. AB - OBJECTIVE: To assess the safety of rapidly dissolving buprenorphine/naloxone sublingual tablets (BNX-RDT) in opioid-dependent patients. METHODS: This open label, 24-week extension study enrolled patients who completed primary trials of BNX-RDT. Daily tablet doses ranged from 5.7 to 17.1 mg. The primary endpoint was safety; secondary assessments included opioid cravings, addiction severity, health-related quality of life (QOL), and workplace productivity at screening (final day of the primary trials) through study end, with changes measured from baseline of the primary trials. RESULTS: In all, 665 patients received treatment; 292 (43.9%) completed the study. A total of 258 patients (38.8%) reported 557 treatment-emergent adverse events, most commonly headache (3.2%) and constipation (3.0%). Craving scores showed continued improvement on 100-mm visual analog scale (mean change from primary trial baseline, -52.8 at screening; mean change from extension trial baseline, -60.5 at week 24). Reductions in addiction severity from baseline of both the primary and extension trial were maintained through week 24 on multiple assessments, as were improvements in QOL on Short Form 36. Employment increased by 15% and mean (SD) hours worked per week increased by 4.6 (20.1) from baseline to study end. Mean (SD) scores for impact of opioid dependence on work productivity improved from 4.7 (3.0) at baseline to 0.9 (1.8) at study end (11-point scale). CONCLUSIONS: Extended treatment with BNX-RDT demonstrated a safety profile similar to other BNX formulations, reduced opioid cravings, and improved both QOL and work productivity. Continued treatment may enable patients to advance in recovery and return to normal functioning. PMID- 28353469 TI - Recommendations on Surveillance and Management of Biallelic Mismatch Repair Deficiency (BMMRD) Syndrome: A Consensus Statement by the US Multi-society Task Force on Colorectal Cancer. PMID- 28353470 TI - The Impact of Nursing Leader's Behavioral Integrity and Intragroup Relationship Conflict on Staff Nurses' Intention to Remain. AB - OBJECTIVE: This study tested a multilevel model examining the effect of nursing leader's behavioral integrity and intragroup relationship conflict on staff nurses' intent to remain. BACKGROUND: In the challenging situation of nursing shortage, nurse executives are required to focus on the retention of nurses. No previous studies have examined the impact of nursing leader's behavioral integrity and intragroup relationship conflict on nurses' intention to remain. METHODS: A cross-sectional survey of 480 RNs in 34 nursing units of a large public hospital in South Korea was conducted to test the hypothesized multilevel model. RESULTS: Nursing leader's behavioral integrity was positively related to nurses' intention to remain (b = 0.34, P < .001). This relationship was enhanced when the level of intragroup relationship conflict was high (b = 0.21, P < .05). CONCLUSIONS: Nursing leaders assigned to units with a high level of intragroup relationship conflict should endeavor to maintain their behavioral integrity to promote nurses' intention to remain. PMID- 28353471 TI - The Phenylephrine Test Revisited. AB - PURPOSE: To characterize the phenylephrine test in ptotic patients to help clinicians perform the test more efficiently. METHODS: Adults with involutional ptosis (n = 24, 30 eyes) were assessed with digital photographs for response to topical 2.5% phenylephrine drop instillation. Patient characteristics (age, gender, iris color, dermatochalasis, brow ptosis, and baseline marginal reflex distance-1 [MRD-1] height) were recorded. From the photographs, change in (MRD 1), presence of conjunctival blanching, pupillary dilation, and Hering effect were recorded at specified time intervals, 1 minute to 1 hour after drop placement. Correlations between patient characteristics and measured outcomes were evaluated using analysis of variance, Pearson coefficient, or chi-square tests. RESULTS: The authors found that 73% of eyes had eyelid elevation with phenylephrine. Of these, 50% reached maximal eyelid elevation by 5 minutes, and 86% by 10 minutes after drop placement, but 14% did not reach maximal MRD-1 until 30 minutes. There is a negative correlation between the maximum MRD-1 and the baseline MRD-1 eyelid height (r = -0.5330, p < 0.01). There is no significant relationship between time to pupillary dilation with either time to max eyelid elevation or max eyelid elevation. No patient characteristic studied affected the likelihood of eyelid response to phenylephrine or presence of Hering effect. CONCLUSIONS: Although most ptotic eyelids demonstrate a response to 2.5% phenylephrine within 10 minutes, there is a subset of patients that respond much later. More ptotic eyelids had greater eyelid elevation with phenylephrine. Pupillary dilation and conjunctival blanching are neither predictive of nor temporally associated with eyelid height elevation. The authors did not identify any patient factors (e.g., dermatochalasis, brow ptosis) that can predict the likelihood of response to phenylephrine. PMID- 28353472 TI - Orbital Schwannoma: Radiographic and Histopathologic Correlation in 15 Cases. AB - PURPOSE: To evaluate the relationship between radiographic and histopathologic features of orbital schwannoma. METHODS: Retrospective review of 15 patients with orbital schwannoma managed at an ocular oncology service. RESULTS: The mean patient age at the time of presentation was 42 years old (median 40, range 15-64 years). The orbital schwannoma was found incidentally (n = 2) or with symptoms of proptosis (n = 2), blurred vision (n = 3), pain (n = 3), eyelid swelling (n = 2), diplopia (n = 2), or headache (n = 1). The mean duration of symptoms was 15 months (median, 9; range 1-60 months). The tumor occupied the superior (n = 11) or inferior (n = 4) orbit. Antero-posterior tumor location involved the anterior (n = 2), middle (n = 3), posterior (n = 4), or entire (n = 6) orbit. MRI was performed in 12 patients (80%) and CT was the only form of imaging in 3 patients (20%). The T1-weighted MRI (n = 11) showed the mass as isointense (n = 10) or hyperintense (n = 1) to the extraocular muscles). On T2-weighted MRI (n = 10), the mass demonstrated hyperintensity (n = 9) or hypointensity (n = 1). Histopathologic assessment demonstrated Antoni A (n = 12) and Antoni B (n = 12) patterns. Antoni A pattern correlated with hyperintensity on T1-weighted MRI and hypointensity on T2-weighted MRI. Antoni B pattern correlated with hypointensity on T1-weighted MRI and hyperintensity on T2-weighted MRI. As Antoni B approached >50% of the solid mass (n = 8), both T1- and T2-weighted MRI images were more likely to be heterogeneous (n = 7, 88% and n = 6, 75%, respectively). CONCLUSION: Orbital schwannomas are nearly always benign, well-encapsulated slowly progressive tumors. Due to the biphasic distribution of Antoni A and Antoni B pattern, the appearance on MRI has a variable degree of heterogeneity. Antoni A pattern correlated with hyperintensity and Antoni B pattern correlated with hypointensity on T1-weighted MRI. PMID- 28353474 TI - Straight talk: Nurse manager role stress. PMID- 28353473 TI - Invasive Aspergillosis Masquerading as a Lacrimal Sac Abscess. PMID- 28353475 TI - Retention remedy: Building a sense of community through appreciative inquiry. PMID- 28353476 TI - The nurse manager and educator QI partnership. PMID- 28353477 TI - Cybersecurity awareness: Protecting data and patients. PMID- 28353478 TI - Demystifying nursing Research at the Bedside. PMID- 28353479 TI - NSI reports: Supporting Australian healthcare governance. PMID- 28353480 TI - What's your agility ability? PMID- 28353481 TI - The art of leadership diplomacy. PMID- 28353482 TI - How to defeat self-sabotaging behaviors. PMID- 28353483 TI - Ebola Preparedness in the Netherlands: The Need for Coordination Between the Public Health and the Curative Sector. AB - CONTEXT: During the Ebola outbreak in West Africa in 2014-2015, close cooperation between the curative sector and the public health sector in the Netherlands was necessary for timely identification, referral, and investigation of patients with suspected Ebola virus disease (EVD). OBJECTIVE: In this study, we evaluated experiences in preparedness among stakeholders of both curative and public health sectors to formulate recommendations for optimizing preparedness protocols. Timeliness of referred patients with suspected EVD was used as indicator for preparedness. DESIGN: In focus group sessions and semistructured interviews, experiences of curative and public health stakeholders about the regional and national process of preparedness and response were listed. Timeliness recordings of all referred patients with suspected EVD (13) were collected from first date of illness until arrival in the referral academic hospital. RESULTS: Ebola preparedness was considered extensive compared with the risk of an actual patient, however necessary. Regional coordination varied between regions. More standardization of regional preparation and operational guidelines was requested, as well as nationally standardized contingency criteria, and the National Centre for Infectious Disease Control was expected to coordinate the development of these guidelines. For the timeliness of referred patients with suspected EVD, the median delay between first date of illness until triage was 2.0 days (range: 0-10 days), and between triage and arrival in the referral hospital, it was 5.0 hours (range: 2-7.5 hours). In none of these patients Ebola infection was confirmed. CONCLUSIONS: Coordination between the public health sector and the curative sector needs improvement to reduce delay in patient management in emerging infectious diseases. Standardization of preparedness and response practices, through guidelines for institutional preparedness and blueprints for regional and national coordination, is necessary, as preparedness for emerging infectious diseases needs a multidisciplinary approach overarching both the public health sector and the curative sector. In the Netherlands a national platform for preparedness is established, in which both the curative sector and public health sector participate, in order to implement the outcomes of this study. PMID- 28353484 TI - The Why Behind the What: Teaching With a Purpose. PMID- 28353485 TI - Peer Incivility Among Prelicensure Nursing Students: A Call to Action for Nursing Faculty. AB - This article reports findings from a study that examined the prevalence of peer incivility among nursing students and the impact of incivility on students' physical and mental health and their perceived stress level. Students who experienced high levels of peer incivility had lower mental health scores (P = .0002), lower physical health scores (P = .0069), and higher stress levels (P = .0016). Students who experienced incivility in the classroom had higher levels of peer incivility (P < .001) and lower physical health scores (P < .05). PMID- 28353486 TI - Adjunct Nurse Faculty Demographics and Intent to Stay Teaching. AB - Adjunct nurse educators have become a primary facilitator of students' clinical learning in nursing education. However, studies are lacking as to variables that correlate with their intent to stay teaching. This study examined demographic variables that had an impact on adjunct clinical educators' decisions about whether to leave a teaching position in an associate degree nursing program. Full time employment in addition to teaching as an adjunct faculty member predicted intent to leave the role. Measures to improve adjunct nurse faculty intent to stay are included. PMID- 28353487 TI - Pressure Mapping of a Standard Hospital Recliner and Select Cushions With Healthy Adults: A Comparative Study. AB - PURPOSE: The aim of the study was to compare the degree of pressure created when healthy adult volunteers sat on a hospital recliner chair in various positions and on various cushions. DESIGN: Comparative cross-sectional study. SUBJECTS AND SETTING: Thirty-four healthy subjects were recruited from the community, an urban city in a rural area of Eastern North Carolina. METHODS: Interface pressure measurements were taken by the investigators for each subject sitting on a standard hospital recliner under each of the following conditions: no cushion, foam cushion, nonadjustable air cushion, nonadjustable air/foam cushion, and adjustable air cushion. Subject positions, upright sitting and reclined, were randomly selected. Analyses consisted of data visualizations by investigators and univariate statistics. For each surface, mean pressure, peak pressure, and Pressure Area Index (PAI) were obtained and compared. Inferences were drawn from a repeated-measures analysis-of-covariance model. RESULTS: Subject position was not associated with any of the measures for each surface after adjusting for other variables (average pressure P = .1094, maximum/peak pressure P = .1318, PAI P = .4336). Subject weight, the type of surface, and their interaction do impact the results (average pressure, maximum/peak pressure, and PAI, P < .0001). The foam cushion had the highest mean and average interface pressures and the lowest PAI. The nonadjustable air and air/foam cushions performed most similarly to each other, showing lowest mean and average interface pressures and the highest PAI. CONCLUSION: Position of a hospital recliner chair in the 2 positions studied had no association with interface pressure outcomes; therefore, other methods of pressure redistribution need to be utilized by clinicians. Based on the results of this study, clinicians may need to reevaluate the type of cushion used in the acute hospital setting, as a standard foam cushion was found to increase interface pressures when compared to other cushions and a standard hospital recliner. PMID- 28353488 TI - Management of Central Venous Access Device-Associated Skin Impairment: An Evidence-Based Algorithm. AB - Patients relying on central venous access devices (CVADs) for treatment are frequently complex. Many have multiple comorbid conditions, including renal impairment, nutritional deficiencies, hematologic disorders, or cancer. These conditions can impair the skin surrounding the CVAD insertion site, resulting in an increased likelihood of skin damage when standard CVAD management practices are employed. Supported by the World Congress of Vascular Access (WoCoVA), developed an evidence- and consensus-based algorithm to improve CVAD-associated skin impairment (CASI) identification and diagnosis, guide clinical decision making, and improve clinician confidence in managing CASI. A scoping review of relevant literature surrounding CASI management was undertaken March 2014, and results were distributed to an international advisory panel. A CASI algorithm was developed by an international advisory panel of clinicians with expertise in wounds, vascular access, pediatrics, geriatric care, home care, intensive care, infection control and acute care, using a 2-phase, modified Delphi technique. The algorithm focuses on identification and treatment of skin injury, exit site infection, noninfectious exudate, and skin irritation/contact dermatitis. It comprised 3 domains: assessment, skin protection, and patient comfort. External validation of the algorithm was achieved by prospective pre- and posttest design, using clinical scenarios and self-reported clinician confidence (Likert scale), and incorporating algorithm feasibility and face validity endpoints. The CASI algorithm was found to significantly increase participants' confidence in the assessment and management of skin injury (P = .002), skin irritation/contact dermatitis (P = .001), and noninfectious exudate (P < .01). A majority of participants reported the algorithm as easy to understand (24/25; 96%), containing all necessary information (24/25; 96%). Twenty-four of 25 (96%) stated that they would recommend the tool to guide management of CASI. PMID- 28353489 TI - Sharing a Personal Trainer: Personal and Social Benefits of Individualized, Small Group Training. AB - Wayment, HA and McDonald, RL. Sharing a personal trainer: personal and social benefits of individualized, small-group training. J Strength Cond Res 31(11): 3137-3145, 2017-We examined a novel personal fitness training program that combines personal training principles in a small-group training environment. In a typical training session, exercisers warm-up together but receive individualized training for 50 minutes with 1-5 other adults who range in age, exercise experience, and goals for participation. Study participants were 98 regularly exercising adult members of a fitness studio in the southwestern United States (64 women and 32 men), aged 19-78 years (mean, 46.52 years; SD = 14.15). Average membership time was 2 years (range, 1-75 months; mean, 23.54 months; SD = 20.10). In collaboration with the program directors, we developed a scale to assess satisfaction with key features of this unique training program. Participants completed an online survey in Fall 2015. Hypotheses were tested with a serial mediator model (model 6) using the SPSS PROCESS module. In support of the basic tenets of self-determination theory, satisfaction with small-group, individualized training supported basic psychological needs, which in turn were associated with greater autonomous exercise motivation and life satisfaction. Satisfaction with this unique training method was also associated with greater exercise self-efficacy. Autonomous exercise motivation was associated with both exercise self-efficacy and greater self-reported health and energy. Discussion focuses on why exercise programs that foster a sense of social belonging (in addition to motivation and efficacy) may be helpful for successful adherence to an exercise program. PMID- 28353490 TI - Accuracy of Clinician Assessments of Medication Status in the Emergency Setting: A Comparison of Clinician Assessment of Antipsychotic Usage and Plasma Level Determination. AB - PURPOSE: The present study aimed to assess the level of agreement between clinicians' routine assessments of medication status and plasma levels of commonly prescribed antipsychotic medications in patients presenting to an emergency room with an exacerbation of psychosis. METHODS: We studied 105 patients presenting to an emergency room and admitted to an inpatient psychiatric unit with a diagnosis of schizophrenia, schizoaffective disorder, bipolar I disorder, or psychotic disorder not otherwise specified and a prior outpatient medication regimen including risperidone, olanzapine, quetiapine, aripiprazole, or paliperidone. Plasma levels of antipsychotics were drawn and sent to a specialty laboratory for testing. FINDINGS: Of the 97 patients with usable samples, 33 (34%) were found to have therapeutic antipsychotic levels. Of these, 22 were judged by emergency room staff to be taking their medications at the appropriately prescribed doses, whereas 11 were judged not to be taking medication at all. Sixty-four patients were found to have subtherapeutic antipsychotic levels, 31 of whom had been assessed to be taking medication as prescribed. Emergency assessment of medication status predicted therapeutic and nontherapeutic antipsychotic levels at rates of 41.5% and 75%, respectively. Emergency staff assessment was statistically independent from the likelihood of having a therapeutic antipsychotic level. IMPLICATIONS: In patients presenting to emergency rooms with exacerbations of psychosis who are subsequently admitted to an inpatient facility, common assessments of medication status are frequently misleading. Readily available methods for rapidly measuring antipsychotic plasma levels in clinical settings are needed for clinicians to make reliable assessments. PMID- 28353491 TI - Nonprogrammed Vascular Access Is Associated With Greater Mortality in Patients Who Return to Hemodialysis With a Failing Renal Graft. AB - BACKGROUND: In incident hemodialysis (HD) patients, the use of catheters is associated with a worse prognosis when compared with those with an arteriovenous fistula, but the role of vascular access (VA) type in the morbidity and mortality of patients returning to HD with a failing renal allograft is unknown. We aimed to determine the associations between the type of VA and mortality in this population. METHODS: This was a retrospective observational cohort study of 138 patients who initiated dialysis after kidney transplant failure between 1995 and 2014. We recorded access type, laboratory values at entry, stratified patients per risk, and determined the effect on mortality of programmed VA (PVA), (arteriovenous fistula or PTFE graft) and nonprogrammed VA (UPVA) (tunneled or nontunneled catheters) at the initiation of HD. RESULTS: Eighty-five (61.6%) and 53 (38.4%) patients initiated therapy with PVA and UPVA, respectively. Overall mortality was 14.6% at 1 year. Patients using catheters had greater mortality than those with a PVA (log rank P <0.0001). At 24 months, 7 patients died in PVA group versus 22 in UPVA group. Multivariate Cox analysis showed that initiation of HD with a catheter (hazard ratio, 5.90; 95%, confidence interval, 2.83-12.31) was independently associated with greater mortality after adjusting for confounders. CONCLUSIONS: Nonprogrammed VA with a catheter predicted all-cause mortality among patients with transplant failure reentering HD. PMID- 28353493 TI - Hypothermic Machine Perfusion of Liver Grafts Can Safely Extend Cold Ischemia for Up to 20 Hours in Cases of Necessity. PMID- 28353492 TI - Wait Time of Less Than 6 and Greater Than 18 Months Predicts Hepatocellular Carcinoma Recurrence After Liver Transplantation: Proposing a Wait Time "Sweet Spot". AB - BACKGROUND: It has been postulated that short wait time before liver transplant (LT) for hepatocellular carcinoma (HCC) results in the inclusion of tumors with aggressive biology, but prolonged wait time could result in a shift to more aggressive tumor behavior. We therefore test the hypothesis that a wait time "sweet spot" exists with a lower risk for HCC recurrence compared with the other 2 extremes. METHODS: This multicenter study included 911 patients from 3 LT centers with short, medium, and long wait times (median of 4, 7, and 13 months, respectively) who received Model for End Stage Liver Disease exception listing for HCC from 2002 to 2012. RESULTS: Wait time, defined as time from initial HCC diagnosis to LT, was less than 6 months in 32.4%, 6 to 18 months in 53.7%, and greater than 18 months in 13.9%. Waitlist dropout was observed in 18.4% at a median of 11.3 months. Probability of HCC recurrence at 1 and 5 years were 6.4% and 15.5% with wait time of less than 6 or greater than 18 months (n = 343) versus 4.5% and 9.8% with wait time of 6 to 18 months (n = 397), respectively (P = 0.049). When only pre-LT factors were considered, wait time of less than 6 or greater than 18 months (HR, 1.6; P = 0.043) and AFP greater than 400 at HCC diagnosis (HR, 3.0; P < 0.001) predicted HCC recurrence in multivariable analysis. CONCLUSIONS: This large multicenter study provides evidence of an association between very short (<6 months) or very long (>18 months) wait times and an increased risk for HCC recurrence post-LT. The so-called sweet spot of 6 to 18 months should be the target to minimize HCC recurrence. PMID- 28353494 TI - Increased Risk of Tics in Children Infected with Enterovirus: A Nationwide Population-Based Study. AB - OBJECTIVE: Both tics and enterovirus (EV) infections are common in children. The association between EV infections and tics has been seldom evaluated. The aim of this study was to evaluate the risk of diagnosed tics after EV infections in children. METHODS: A nationwide retrospective cohort study was conducted to determine the risk of tics after EV infections by analyzing data from the National Health Insurance Research Database in Taiwan. Children aged < 18 years with EV infection during 2000 to 2007 were enrolled. For comparison, non-EV infected children were randomly selected and matched with EV-infected children at a 1:1 ratio according to sex, age, urbanization level, parental occupation, and the year of EV infection. All patients were followed up until the diagnosis of tics, death, loss to follow-up, withdrawal from the insurance system, or December 31, 2008. RESULTS: A total of 282,321 EV-infected and 282,317 non-EV-infected children were included in this study. The mean age was 2.39 years in both cohorts. The overall incidences of tics were 9.12 and 6.21 per 10,000 person years in the EV-infected and non-EV-infected cohorts, respectively. Children with EV infection were significantly associated with an increased risk of tics compared with those without EV infection (adjusted hazard ratio, 1.38; 95% confidence interval, 1.27-1.5). Multivariable analyses showed that boys, children living in urbanized areas, children whose parents had white-collar jobs, and children with allergic rhinitis or bronchial asthma exhibited a significantly increased risk of tics. CONCLUSION: This study revealed an increased risk of tics after EV infection in children. PMID- 28353497 TI - Recruiting and Retaining Community-Based Preceptors: A Multicenter Qualitative Action Study of Pediatric Preceptors. AB - PURPOSE: The recruitment and retention of community preceptors to teach medical students is difficult. The authors sought to characterize the underlying motivational factors for becoming a preceptor and to identify strategies for recruiting and retaining community-based pediatric preceptors. METHOD: This multicenter qualitative action study included semistructured interviews with community-based pediatric preceptors affiliated with 12 institutions from August to December 2015. Only active preceptors were included, and participating institutions were diverse with respect to geographic location and class size. Interviews were conducted over the telephone and transcribed verbatim. Six investigators used deidentified transcripts to develop a codebook. Through a constant comparative method, codes were revised as data were analyzed and disagreements were resolved through discussion. All investigators organized the themes into dimensions. RESULTS: Fifty-one preceptors were interviewed. Forty-one themes coalesced into four dimensions: (1) least liked aspects of teaching, (2) preparation to teach, (3) inspiration to teach, and (4) ways to improve recruitment and retention. Time constraints and patient care demands were the most commonly cited deterrents to teaching. Successful preceptors balanced their clinical demands with their desire to teach using creative scheduling. External rewards (e.g., recognition, continuing medical education credit) served as incentives. Internal motivation inspired participants to share their enthusiasm for pediatrics and to develop longitudinal relationships with their learners. CONCLUSIONS: Changes in health care delivery have imposed more time constraints on community-based preceptors. However, this study identified underlying factors motivating physicians to volunteer as preceptors. Strategies to recruit new and retain current preceptors must be collaborative. PMID- 28353498 TI - Validating Domains of Patient Contextual Factors Essential to Preventing Contextual Errors: A Qualitative Study Conducted at Chicago Area Veterans Health Administration Sites. AB - PURPOSE: "Patient context" indicates patient circumstances and characteristics or states that are essential to address when planning patient care. Specific patient "contextual factors," if overlooked, result in an inappropriate plan of care, a medical error termed a "contextual error." The myriad contextual factors that constitute patient context have been grouped into broad domains to create a taxonomy of challenges to consider when planning care. This study sought to validate a previously identified list of contextual domains. METHOD: This qualitative study used directed content analysis. In 2014, 19 Department of Veterans Affairs (VA) providers (84% female) and 49 patients (86% male) from two VA medical centers and four outpatient clinics in the Chicago area participated in semistructured interviews and focus groups. Topics included patient-specific, community, and resource-related factors that affect patients' abilities to manage their care. Transcripts were analyzed with a previously identified list of contextual domains as a framework. RESULTS: Analysis of responses revealed that patients and providers identified the same 10 domains previously published, plus 3 additional ones. Based on comments made by patients and providers, the authors created a revised list of 12 domains from themes that emerged. Six pertain to patient circumstances such as access to care and financial situation, and 6 to patient characteristics/states including skills, abilities, and knowledge. CONCLUSIONS: Contextual factors in patients' lives may be essential to address for effective care planning. The rubric developed can serve as a "contextual differential" for clinicians to consider when addressing challenges patients face when planning their care. PMID- 28353499 TI - Emotional Learning and Identity Development in Medicine: A Cross-Cultural Qualitative Study Comparing Taiwanese and Dutch Medical Undergraduates. AB - PURPOSE: Current knowledge about the interplay between emotions and professional identity formation is limited and largely based on research in Western settings. This study aimed to broaden understandings of professional identity formation cross-culturally. METHOD: In fall 2014, the authors purposively sampled 22 clinical students from Taiwan and the Netherlands and asked them to keep audio diaries, narrating emotional experiences during clerkships using three prompts: What happened? What did you feel/think/do? How does this interplay with your development as a doctor? Dutch audio diaries were supplemented with follow-up interviews. The authors analyzed participants' narratives using a critical discourse analysis informed by Figured Worlds theory and Bakhtin's concept of dialogism, according to which people's spoken words create identities in imagined future worlds. RESULTS: Participants talked vividly, but differently, about their experiences. Dutch participants' emotions related to individual achievement and competence. Taiwanese participants' rich, emotional language reflected on becoming both a good person and a good doctor. These discourses constructed doctors' and patients' autonomy in culturally specific ways. The Dutch construct centered on "hands-on" participation, which developed the identity of a technically skilled doctor, but did not address patients' self-determination. The Taiwanese construct located physicians' autonomy within moral values more than practical proficiency, and gave patients agency to influence doctor-patient relationships. CONCLUSIONS: Participants' cultural constructs of physician and patient autonomy led them to construct different professional identities within different imagined worlds. The contrasting discourses show how medical students learn about different meanings of becoming doctors in culturally specific contexts. PMID- 28353500 TI - How Can Medical Students Add Value? Identifying Roles, Barriers, and Strategies to Advance the Value of Undergraduate Medical Education to Patient Care and the Health System. AB - PURPOSE: As health systems evolve, the education community is seeking to reimagine student roles that combine learning with meaningful contributions to patient care. The authors sought to identify potential stakeholders regarding the value of student work, and roles and tasks students could perform to add value to the health system, including key barriers and associated strategies to promote value-added roles in undergraduate medical education. METHOD: In 2016, 32 U.S. medical schools in the American Medical Association's (AMA's) Accelerating Change in Education Consortium met for a two-day national meeting to explore value-added medical education; 121 educators, systems leaders, clinical mentors, AMA staff leadership and advisory board members, and medical students were included. A thematic qualitative analysis of workshop discussions and written responses was performed, which extracted key themes. RESULTS: In current clinical roles, students can enhance value by performing detailed patient histories to identify social determinants of health and care barriers, providing evidence-based medicine contributions at the point-of-care, and undertaking health system research projects. Novel value-added roles include students serving as patient navigators/health coaches, care transition facilitators, population health managers, and quality improvement team extenders. Six priority areas for advancing value-added roles are student engagement, skills, and assessments; balance of service versus learning; resources, logistics, and supervision; productivity/billing pressures; current health systems design and culture; and faculty factors. CONCLUSIONS: These findings provide a starting point for collaborative work to positively impact clinical care and medical education through the enhanced integration of value-added medical student roles into care delivery systems. PMID- 28353501 TI - Cooperative Extension as a Framework for Health Extension: The Michigan State University Model. AB - PROBLEM: The Affordable Care Act charged the Agency for Healthcare Research and Quality to create the Primary Care Extension Program, but did not fund this effort. The idea to work through health extension agents to support health care delivery systems was based on the nationally known Cooperative Extension System (CES). Instead of creating new infrastructure in health care, the CES is an ideal vehicle for increasing health-related research and primary care delivery. APPROACH: The CES, a long-standing component of the land-grant university system, features a sustained infrastructure for providing education to communities. The Michigan State University (MSU) Model of Health Extension offers another means of developing a National Primary Care Extension Program that is replicable in part because of the presence of the CES throughout the United States. A partnership between the MSU College of Human Medicine and MSU Extension formed in 2014, emphasizing the promotion and support of human health research. The MSU Model of Health Extension includes the following strategies: building partnerships, preparing MSU Extension educators for participation in research, increasing primary care patient referrals and enrollment in health programs, and exploring innovative funding. OUTCOMES: Since the formation of the MSU Model of Health Extension, researchers and extension professionals have made 200+ connections, and grants have afforded savings in salary costs. NEXT STEPS: The MSU College of Human Medicine and MSU Extension partnership can serve as a model to promote health partnerships nationwide between CES services within land-grant universities and academic health centers or community-based medical schools. PMID- 28353503 TI - What Should Guide Health Policy? A Perspective Beyond Politics. AB - As the U.S. electorate has become increasingly polarized, these divisions are poised to shape legislative and regulatory work in the years ahead. For those whose focus is on the public goods of health care for all, the advancement of science through rigorous research, and the contribution of higher education to the continual improvement of the nation's workforce, there is profound uncertainty about the future. There are several pressing questions facing the nation and academic medicine, including the future of affordable, accessible insurance; acceptance of scientific evidence; sustainable learning and teaching methodologies; and the well-being and preparation of the nation's health workforce to care for an increasingly diverse nation. For those in academic medicine and policy making alike, the authors propose a framework, grounded in scientific evidence and guided by clinical ethics, for designing and evaluating health policy solutions for these and other pressing questions. PMID- 28353504 TI - Ways to Write a Milestone: Approaches to Operationalizing the Development of Competence in Graduate Medical Education. AB - PURPOSE: To identify approaches to operationalizing the development of competence in Accreditation Council for Graduate Medical Education (ACGME) milestones. METHOD: The authors reviewed all 25 "Milestone Project" documents available on the ACGME Web site on September 11, 2013, using an iterative process to identify approaches to operationalizing the development of competence in the milestones associated with each of 601 subcompetencies. RESULTS: Fifteen approaches were identified. Ten focused on attributes and activities of the learner, such as their ability to perform different, increasingly difficult tasks (304/601; 51%), perform a task better and faster (171/601; 45%), or perform a task more consistently (123/601; 20%). Two approaches focused on context, inferring competence from performing a task in increasingly difficult situations (236/601; 29%) or an expanding scope of engagement (169/601; 28%). Two used socially defined indicators of competence such as progression from "learning" to "teaching," "leading," or "role modeling" (271/601; 45%). One approach focused on the supervisor's role, inferring competence from a decreasing need for supervision or assistance (151/601; 25%). Multiple approaches were often combined within a single set of milestones (mean 3.9, SD 1.6). CONCLUSIONS: Initial ACGME milestones operationalize the development of competence in many ways. These findings offer insights into how physicians understand and assess the developmental progression of competence and an opportunity to consider how different approaches may affect the validity of milestone-based assessments. The results of this analysis can inform the work of educators developing or revising milestones, interpreting milestone data, or creating assessment tools to inform milestone-based performance measures. PMID- 28353502 TI - Looking Under the Streetlight? A Framework for Differentiating Performance Measures by Level of Care in a Value-Based Payment Environment. AB - The majority of quality measures used to assess providers and hospitals are based on easily obtained data, focused on a few dimensions of quality, and developed mainly for primary/community care and population health. While this approach supports efforts focused on addressing the triple aim of health care, many current quality report cards and assessments do not reflect the breadth or complexity of many referral center practices.In this article, the authors highlight the differences between population health efforts and referral care and address issues related to value measurement and performance assessment. They discuss why measures may need to differ across the three levels of care (primary/community care, secondary care, complex care) and illustrate the need for further risk adjustment to eliminate referral bias.With continued movement toward value-based purchasing, performance measures and reimbursement schemes need to reflect the increased level of intensity required to provide complex care. The authors propose a framework to operationalize value measurement and payment for specialty care, and they make specific recommendations to improve performance measurement for complex patients. Implementing such a framework to differentiate performance measures by level of care involves coordinated efforts to change both policy and operational platforms. An essential component of this framework is a new model that defines the characteristics of patients who require complex care and standardizes metrics that incorporate those definitions. PMID- 28353505 TI - Changes in Resident Well-Being at One Institution Across a Decade of Progressive Work Hours Limitations. AB - PURPOSE: To measure changes in markers of resident well-being over time as progressive work hours limitations (WHLs) were enforced, and to investigate resident perceptions of the 2011 WHLs. METHOD: A survey study of internal medicine residents was conducted at the University of Washington's multihospital residency program in 2012. The survey included validated well-being questions: the Maslach Burnout Inventory, the two-question PRIME-MD depression screen, and career satisfaction questions. Chi-square tests were used to compare 2012 well being questionnaire responses against nearly identical surveys conducted in 2001 and 2004 at the same institution. In addition, residents were asked to rate the impact of WHLs on resident well-being and education as well as patient care, and to state preferences for future WHLs. RESULTS: Significantly different proportions of residents met burnout criteria across time, with fewer meeting criteria in 2012 than in 2001 (2001: 76% [87/115]; 2004: 64% [75/118]; 2012: 61% [68/112]; P = .039). Depression screening results also differed across time, with fewer screening positive in 2012 than in 2004 (2001: 45% [52/115]; 2004: 55% [65/118]; 2012 [35/112]: 31%; P = .001). Residents, especially seniors, reported perceived negative impacts of WHLs on their well-being, education, and patient care. Most senior residents favored reverting to the pre-July 2011 system of WHLs. Interns were more divided. CONCLUSIONS: Validated measures of resident well being changed across the three time points measured. Residents had the lowest rates of burnout and depression in 2012. Resident perceptions of the 2011 WHLs, however, were generally negative. PMID- 28353506 TI - A Foundation for Vital Academic and Social Support in Clerkships: Learning Through Peer Continuity. AB - Most medical students on clerkships currently experience lack of continuity of patient care, disjointed learning, and frequent changes in supervisors. Clerkship programs with continuity of care, curriculum, and supervisors appear to benefit student learning and patient-centeredness. A fourth form of continuity is proposed: continuity of peers, in which a stable cohort of students frequently meets to process their experiences on clerkships. This structure builds on benefits previously seen in peer-assisted learning, including enhanced knowledge, technical skills, and collegial peer relationships. Additional advantages of peer continuity in clerkships include facilitated integration into the workplace, social support, and enhanced clinical and professional learning. Practical components required for a successful peer continuity structure include intentional formation of peer cohorts; regular meetings that cover didactic or clinical skills learning; frequent opportunities for reflection on patient care, professional development, and well-being; and skilled facilitators without evaluative roles. Theoretical support for peer continuity comes from social cognitive theory, communities of clinical practice, and social comparison theory. Therefore, in conjunction with empirical programs that have shown benefits of developing these structures, peer continuity should become a formalized educational structure in clerkships. PMID- 28353507 TI - Patient Safety. PMID- 28353509 TI - Innovative Urgent Care for the Palliative Patient at Home. AB - Palliative and end-of-life patients in their homes are at risk of developing symptom crises requiring urgent care. The usual care for these patients involves transport to an Emergency Department (ED) despite the preference of most palliative patients to stay home. The objective of this initiative was to develop an innovative strategy to provide collaborative care in the home to alleviate symptoms and avoid transport. A partnership was created among Emergency Medical Services and Community Care staff, physicians, and leaders to enable patients to stay at home with existing resources during symptom crisis. As a result of the initiative, patients were able to stay at home more frequently. When patients required transport to the ED, it occurred after attempted symptom management in the home. A total of 110 calls were tracked in the first 18 months of the initiative. Of those, 61% ended with the patient staying home, in alignment with their preferred place of care at the end of life. A collaborative approach by care providers in the community enabled patients to stay home despite symptom crisis near the end of life. PMID- 28353510 TI - Home Telehealth Interventions for Older Adults With Diabetes. AB - The purpose of this literature review was to explore home telemedicine interventions for the treatment of older adults with diabetes. Eight databases were searched for articles published between 2011 and 2016, in the English language, and in peer-reviewed journals, resulting in 1,274 relevant articles. Following review against inclusion and exclusion criteria, six articles were retained. Studies included participants with a mean age from 68 to 76.8 years and from three different countries, with either Type 1 or Type 2 Diabetes Mellitus. The articles reviewed suggest that case management, education, closed-loop feedback and communication, home telemonitoring devices or units, and motivational interviewing or coaching can effectively decrease admissions, costs per person per year, mortality, and cognitive decline in older adults with diabetes. The scarcity of high-quality studies is consistent with findings from previous systematic reviews, and highlights the need for additional investigation before applying the results in practice. PMID- 28353511 TI - Caring for Chinese-American Home Care Patients. AB - Chinese-Americans are the largest group of Asian Americans. Home care providers in the United States will encounter patients with various levels of traditional Chinese lifestyles, cultural expressions, and health practices. A description of how to prepare for and conduct a home care visit with a patient from China is described. This article integrates recent research about Chinese-American elders and basics of Chinese culture to assist healthcare clinicians in providing supportive, culturally sensitive home care for Chinese patients and developing rapport and trust with them. PMID- 28353512 TI - New-Onset Atrial Fibrillation: What's the Significance? PMID- 28353513 TI - How an Aging Population Is Transforming Nursing. PMID- 28353514 TI - Caring for the Older Adult With Sensory Impairment. PMID- 28353515 TI - Accidental Overdoses Involving Fluorouracil Infusions. PMID- 28353516 TI - A Day in the Life of a Medicare Provider Outreach & Education Manager. PMID- 28353517 TI - Risks and Benefits of Warfarin Versus New Oral Anticoagulant Drugs. PMID- 28353519 TI - The Value of Letters to the Editor. PMID- 28353518 TI - Sepsis: A Call for Action. PMID- 28353520 TI - New-Onset Atrial Fibrillation: What's the Significance? PMID- 28353521 TI - Consequences of Early Conductive Hearing Loss on Long-Term Binaural Processing. AB - OBJECTIVES: The aim of the study was to investigate the long-term effects of early conductive hearing loss on binaural processing in school-age children. DESIGN: One hundred and eighteen children participated in the study, 82 children with a documented history of conductive hearing loss associated with otitis media and 36 controls who had documented histories showing no evidence of otitis media or conductive hearing loss. All children were demonstrated to have normal-hearing acuity and middle ear function at the time of assessment. The Listening in Spatialized Noise Sentence (LiSN-S) task and the masking level difference (MLD) task were used as the two different measures of binaural interaction ability. RESULTS: Children with a history of conductive hearing loss performed significantly poorer than controls on all LiSN-S conditions relying on binaural cues (DV90, p = <0.001 and SV90, p = 0.003). No significant difference was found between the groups in listening conditions without binaural cues. Fifteen children with a conductive hearing loss history (18%) showed results consistent with a spatial processing disorder. No significant difference was observed between the conductive hearing loss group and the controls on the MLD task. Furthermore, no correlations were found between LiSN-S and MLD. CONCLUSIONS: Results show a relationship between early conductive hearing loss and listening deficits that persist once hearing has returned to normal. Results also suggest that the two binaural interaction tasks (LiSN-S and MLD) may be measuring binaural processing at different levels. Findings highlight the need for a screening measure of functional listening ability in children with a history of early otitis media. PMID- 28353522 TI - Effects of Simulated Hearing Loss on Bilingual Children's Consonant Recognition in Noise. AB - OBJECTIVE: This study investigated the possible impact of simulated hearing loss on speech perception in Spanish-English bilingual children. To avoid confound between individual differences in hearing-loss configuration and linguistic experience, threshold-elevating noise simulating a mild-to-moderate sloping hearing loss was used with normal-hearing listeners. The hypotheses were that: (1) bilingual children can perform similarly to English-speaking monolingual peers in quiet; (2) for both bilingual and monolingual children, noise and simulated hearing loss would have detrimental impacts consistent with their acoustic characteristics (i.e., consonants with high-frequency cues remain highly intelligible in speech-shaped noise, but suffer from simulated hearing loss more than other consonants); (3) differences in phonology and acquisition order between Spanish and English would have additional negative influence on bilingual children's recognition of some English consonants. DESIGN: Listeners were 11 English-dominant, Spanish-English bilingual children (6 to 12 years old) and 12 English-speaking, monolingual age peers. All had normal hearing and age appropriate nonverbal intelligence and expressive English vocabulary. Listeners performed a listen-and-repeat speech perception task. Targets were 13 American English consonants embedded in vowel-consonant-vowel (VCV) syllables. VCVs were presented in quiet and in speech-shaped noise at signal-to-noise ratios (SNRs) of -5, 0, 5 dB (normal-hearing condition). For the simulated hearing-loss condition, threshold-elevating noise modeling a mild-to-moderate sloping sensorineural hearing loss profile was added to the normal-hearing stimuli for 0, 5 dB SNR, and quiet. Responses were scored for consonant correct. Individual listeners' performance was summarized for average across 13 consonants (overall) and for individual consonants. RESULTS: Groups were compared for the effects of background noise and simulated hearing loss. As predicted, group performed similarly in quiet. The simulated hearing loss had a considerable detrimental impact on both groups, even in the absence of speech-shaped noise. Contrary to our prediction, no group difference was observed at any SNR in either condition. However, although nonsignificant, the greater within-group variance for the bilingual children in the normal-hearing condition indicated a wider "normal" range than for the monolingual children. Interestingly, although it did not contribute to the group difference, bilingual children's overall consonant recognition in both conditions improved with age, whereas such a developmental trend for monolingual children was observed only in the simulated hearing-loss condition, suggesting possible effects of experience. As for the recognition of individual consonants, the influence of background noise or simulated hearing loss was similar between groups and was consistent with the prediction based on their acoustic characteristics. CONCLUSIONS: The results demonstrated that school age, English-dominant, Spanish-English bilingual children can recognize English consonants in a background of speech-shaped noise with similar average accuracy as English-speaking monolingual age peers. The general impact of simulated hearing loss was also similar between bilingual and monolingual children. Thus, our hypothesis that bilingual children's English consonant recognition would suffer from background noise or simulated hearing loss more than the monolingual peers was rejected. However, the present results raise several issues that warrant further investigation, including the possible difference in the "normal" range for bilingual and monolingual children, influence of experience, impact of actual hearing loss on bilingual children, and stimulus quality. PMID- 28353524 TI - Massive Mesenteric Lymphadenopathy Causing Protein-losing Enteropathy in Gaucher Disease: Retraction. PMID- 28353523 TI - Early Hearing Detection and Intervention-Pediatric Audiology Links to Services EHDI-PALS: Building a National Facility Database. AB - OBJECTIVES: To create a searchable web-based national audiology facility directory using a standardized survey, so parents and providers could identify which facilities had capacity to provide appropriate services based on child's age. DESIGN: An Early Hearing Detection and Intervention-Pediatric Audiology Links to Services expert panel was convened to create a survey to collect audiology facility information. Professional practice documents were reviewed, a survey was designed to collect pertinent test protocols of each audiology facility, and a standard of care template was created to cross-check survey answers. Audiology facility information across the United States was collected and compiled into a directory structured and displayed in an interactive website, ehdipals.org. RESULTS: Since November 7, 2012, to May 21, 2016, over 1000 facilities have completed the survey and become listed in the Early Hearing Detection and Intervention-Pediatric Audiology Links to Services directory. The site has registered 10,759 unique visitors, 151,981 page views, and 9134 unique searches from consumers. User feedback has been positive overall. CONCLUSION: A searchable, web-based facility directory has proven useful to consumers as a tool to help them differentiate whether a facility was set up to test newborns versus young children. Use of a preprogrammed standard of practice template to cross check survey answers was also shown to be a practical aid. PMID- 28353525 TI - Rickettsialpox in a Pediatric Patient. AB - Rickettsialpox is a rare vector-borne rickettsiosis that manifests in hosts living in urban populations, particularly in New York City. The following is a case discussion of a 12-year-old girl with history of fever and right-ankle swelling. She was initially evaluated and treated for cellulitis. She later developed a maculopapular rash completing the classic triad for rickettsialpox: black eschar, papular rash, and fever. Her convalescent rickettsial titers returned positive, confirming the diagnosis of rickettsialpox. PMID- 28353526 TI - Raised in Darkness: A 7-Month-Old With Nystagmus From Severe Visual Deprivation. AB - Child neglect is the most common form of child maltreatment and accounts for 60% of all cases reported to child protective services. Whereas physical and emotional neglect account for a quarter of the reported cases of child neglect, educational neglect accounts for half of the cases. We describe a 7-month-old infant with several manifestations of physical and emotional neglect including excessive quietness, failure to thrive, global developmental delay, and a gastric lactobezoar. In addition, our patient had a fine, lateral nystagmus likely due to being kept in the dark for long periods. To our knowledge, this is the first reported case of acquired nystagmus due to visual deprivation from child neglect. PMID- 28353527 TI - Baclofen Pumps: Uses and Complications. AB - Intrathecal baclofen therapy, given via an implanted pump in the abdominal wall either as a continuous infusion or bolus dosing, has been used for more than 25 years to treat the spasticity and dystonia associated with various brain and spinal cord conditions. Pediatric clinicians occasionally encounter baclofen pumps, and in the pediatric setting, significant morbidity can arise from their use. This article presents the background, mechanism of action, uses, and complications of intrathecal baclofen therapy and discusses various management strategies should complications occur. PMID- 28353529 TI - An Infant Diagnosed With Hydrocephalus by Point-of-Care Ultrasound. AB - Point-of-care ultrasound has become a valuable tool for pediatric emergency physicians, with an increasing number of indications being described. In this case presentation, we demonstrate the use of point-of-care ultrasound in the pediatric emergency department to diagnose ventriculomegaly in an infant presenting with a seizure. PMID- 28353530 TI - Cranium-Penetrating Mass Detected by Ultrasound Expedited Management of Langerhans Cell Histiocytosis. AB - A 6-year-old boy presented to the pediatric emergency department with a unilateral 5 * 3-cm superficial mass on the postauricular region growing for 1 month. Point-of-care ultrasound was used to evaluate the mass, which revealed a complex cystic mass penetrating the temporal bone. After confirmatory magnetic resonance imaging, the patient was transferred for neurosurgical evaluation, and the tumor was excised. Pathology revealed Langerhans cell histiocytosis. PMID- 28353531 TI - Pediatric Emergency Medicine: Legal Briefs. PMID- 28353532 TI - Acute Illness Protocol for Fatty Acid Oxidation and Carnitine Disorders. AB - Inborn errors of metabolism (IEMs) are genetic disorders that disrupt enzyme activity, cellular transport, or energy production. They are individually rare but collectively have an incidence of 1:1000. Most patients with IEMs are followed by a physician with expertise in biochemical genetics (metabolism) but may present outside this setting. Because IEMs can present acutely with life threatening crises that require specific interventions, it is critical for the emergency medicine physicians, pediatricians, internists, critical care physicians, and biochemical geneticists to be familiar with the initial assessment and management of patients with these disorders. Appropriate early care can be lifesaving. This protocol is not designed to replace the expert consultation of a biochemical geneticist but rather to improve early care and increase the level of comfort of the acute care physician with initial management of fatty acid oxidation and carnitine disorders until specialty consultation is obtained. PMID- 28353534 TI - ECGs in the ED. PMID- 28353539 TI - Coronary artery endothelial dysfunction is present in HIV-positive individuals without significant coronary artery disease. AB - OBJECTIVE: HIV-positive (HIV+) individuals experience an increased burden of coronary artery disease (CAD) not adequately accounted for by traditional CAD risk factors. Coronary endothelial function (CEF), a barometer of vascular health, is depressed early in atherosclerosis and predict future events but has not been studied in HIV+ individuals. We tested whether CEF is impaired in HIV+ patients without CAD as compared with an HIV-negative (HIV-) population matched for cardiac risk factors. DESIGN/METHODS: In this observational study, CEF was measured noninvasively by quantifying isometric handgrip exercise-induced changes in coronary vasoreactivity with MRI in 18 participants with HIV but no CAD (HIV+CAD-, based on prior imaging), 36 age-matched and cardiac risk factor matched healthy participants with neither HIV nor CAD (HIV-CAD-), 41 patients with no HIV but with known CAD (HIV-CAD+), and 17 patients with both HIV and CAD (HIV+CAD+). RESULTS: CEF was significantly depressed in HIV+CAD- patients as compared with that of risk-factor-matched HIV-CAD- patients (P < 0.0001) and was depressed to the level of that in HIV- participants with established CAD. Mean IL 6 levels were higher in HIV+ participants (P < 0.0001) and inversely related to CEF in the HIV+ patients (P = 0.007). CONCLUSION: Marked coronary endothelial dysfunction is present in HIV+ patients without significant CAD and is as severe as that in clinical CAD patients. Furthermore, endothelial dysfunction appears inversely related to the degree of inflammation in HIV+ patients as measured by IL-6. CEF testing in HIV+ patients may be useful for assessing cardiovascular risk and testing new CAD treatment strategies, including those targeting inflammation. PMID- 28353541 TI - Dose-Response Relationship Between Exercise Intensity, Mood States, and Quality of Life in Patients With Heart Failure. AB - BACKGROUND: We conducted a secondary analysis to (1) compare changes in mood disorders and quality of life (QOL) among 4 groups of patients with heart failure in a home-based exercise program who had varying degrees of change in their exercise capacity and (2) determine whether there was an association between exercise capacity, mood disorders, and QOL. METHODS: Seventy-one patients were divided into 4 groups based on changes in exercise capacity from baseline to 6 months: group 1showed improvements of greater than 10% (n = 19), group 2 showed improvements of 10% or less (n = 16), group 3 showed reductions of 10% or less (n = 9), and group 4 showed reductions of greater than 10% (n = 27). RESULTS: Over time, patients in all 4 groups demonstrated significantly lower levels of depression and hostility (P < .001) and higher levels of physical and overall quality of life (P = .046). Group differences over time were noted in anxiety (P = .009), depression (P = .015), physical quality of life (P < .001), and overall quality of life (P = .002). Greater improvement in exercise capacity was strongly associated with lower depression scores (r = -0.49, P = .01). CONCLUSIONS: An improvement in exercise capacity with exercise training was associated with a decrease in depression and anxiety and an increase in QOL in patients with heart failure. PMID- 28353537 TI - Defining HIV-1 transmission clusters based on sequence data. AB - : Understanding HIV-1 transmission dynamics is relevant to both screening and intervention strategies of HIV-1 infection. Commonly, HIV-1 transmission chains are determined based on sequence similarity assessed either directly from a sequence alignment or by inferring a phylogenetic tree. This review is aimed at both nonexperts interested in understanding and interpreting studies of HIV-1 transmission, and experts interested in finding the most appropriate cluster definition for a specific dataset and research question. We start by introducing the concepts and methodologies of how HIV-1 transmission clusters usually have been defined. We then present the results of a systematic review of 105 HIV-1 molecular epidemiology studies summarizing the most common methods and definitions in the literature. Finally, we offer our perspectives on how HIV-1 transmission clusters can be defined and provide some guidance based on examples from real life datasets. PMID- 28353542 TI - Promoting Heart Health Among Rural African Americans. AB - BACKGROUND: Cardiovascular disease is a major cause of death for people living in the United States. African Americans bear a disproportionate burden of cardiovascular disease. Interventions designed to target multiple risk factors may facilitate elimination of cardiovascular disease health disparities. OBJECTIVE: The purpose of this study was to evaluate a culturally relevant cardiovascular health promotion intervention that could potentially reduce cardiovascular disease risk among a group of rural African American adults by improving intentions, attitudes, norms, and self-efficacy to increase produce consumption, reduce dietary saturated fat intake, and increase exercise. METHODS: A cluster randomized controlled trial design was used to evaluate the effect of the "With Every Heartbeat Is Life" cardiovascular health promotion program among rural African Americans. The African American congregants of 12 rural churches located in northern Florida were randomly assigned to either an intervention group that received a culturally relevant cardiovascular health promotion intervention or a control group. Data analysis using linear mixed model was performed to compare group differences from pretest to posttest. RESULTS: The cardiovascular health promotion intervention had a positive influence on the intentions, attitudes, norms, and self-efficacy of rural African Americans to increase produce consumption and reduce dietary saturated fat. The intervention also enhanced participants' attitudes and self-efficacy regarding exercise. CONCLUSION: The culturally relevant cardiovascular health promotion program presented to cluster groups of rural African American participants had positive influences on psychosocial variables associated with engaging in cardiovascular health recommendations. Nurse-led interventions in community settings can potentially reduce cardiovascular disease risk. PMID- 28353543 TI - Identifying a Relationship Between Physical Frailty and Heart Failure Symptoms. AB - BACKGROUND: Heart failure (HF) is a complex clinical syndrome associated with significant symptom burden; however, our understanding of the relationship between symptoms and physical frailty in HF is limited. OBJECTIVE: The aim of this study was to quantify associations between symptoms and physical frailty in adults with HF. METHODS: A sample of adults with symptomatic HF were enrolled in a cross-sectional study. Physical symptoms were measured with the HF Somatic Perception Scale-Dyspnea subscale, the Epworth Sleepiness Scale, and the Brief Pain Inventory short form. Affective symptoms were measured with the Patient Health Questionnaire-9 and the Brief Symptom Inventory-Anxiety scale. Physical frailty was assessed according to the Frailty Phenotype Criteria: shrinking, weakness, slowness, physical exhaustion, and low physical activity. Comparative statistics and generalized linear modeling were used to quantify associations between symptoms and physical frailty, controlling for Seattle HF Model projected 1-year survival. RESULTS: The mean age of the sample (n = 49) was 57.4 +/- 9.7 years, 67% were male, 92% had New York Heart Association class III/IV HF, and 67% had nonischemic HF. Physically frail participants had more than twice the level of dyspnea (P < .001), 75% worse wake disturbances (P < .001), and 76% worse depressive symptoms (P = .003) compared with those who were not physically frail. There were no differences in pain or anxiety. CONCLUSIONS: Physically frail adults with HF have considerably worse dyspnea, wake disturbances, and depression. Targeting physical frailty may help identify and improve physical and affective symptoms in HF. PMID- 28353544 TI - Changes in small artery structure in hypertension: ready for prognostic translation? PMID- 28353545 TI - Orthostatic hypotension: new views for an old problem. PMID- 28353546 TI - Obstructive sleep apnea, hypertension, and fibrin clot properties: a novel pathogenetic link with cardiovascular disease? PMID- 28353547 TI - Hemodynamic effects by glucagon-like peptide-1 receptor analogues: what should be measured? PMID- 28353548 TI - Is renal denervation an alternative or a complement to aldosterone antagonists in treatment of resistant hypertension? PMID- 28353549 TI - Traditional vs. nontraditional risk factor assessment in chronic kidney disease: a case for laser Doppler flowmetry? PMID- 28353550 TI - Estimation of populational 24-h urinary sodium and potassium excretion from spot urine samples: evaluation of four formulas in a large national representative population. PMID- 28353551 TI - Reply. PMID- 28353552 TI - Magnesium, cardiovascular-renal disease and the Gitelman's syndrome paradox. PMID- 28353553 TI - Effect of estrogen on the change of GABA function in the vasopressin neurons of salt-dependent hypertension model rats: Retraction. PMID- 28353554 TI - In Reply. PMID- 28353556 TI - Granulomatosis with polyangiitis presenting with diffuse alveolar hemorrhage requiring extracorporeal membrane oxygenation with rapid multiorgan relapse: A case report. AB - RATIONALE: Granulomatosis with polyangiitis (GPA) is an antineutrophil cytoplasmatic antibodies (ANCA)-associated vasculitis affecting small- and medium sized blood vessels, mostly involving lung and kidney. PATIENT CONCERNS: We report the case of a 33-year-old man that presented with acute respiratory distress syndrome caused by alveolar hemorrhage. DIAGNOSES: Aggressive GPA presenting with diffuse alveolar hemorrhage and multiorgan involvement. INTEVENTIONS: Immunosuppressive therapy, plasma exchange, extracorporeal membrane oxygenation (ECMO). OUTCOMES: Relapse occurred very early, despite immunosuppressive treatment, with a rare involvement of genital system (epididymitis) and rapidly progressive glomerulonephritis difficult to treat. LESSONS: GPA is a challenging, multifaceted disease that can require aggressive supportive therapy and is associated with a high rate of relapse that may present with uncommon site of involvement. PMID- 28353555 TI - Effect of dyad training on medical students' cardiopulmonary resuscitation performance. AB - We investigated the effects of dyadic training on medical students' resuscitation performance during cardiopulmonary resuscitation (CPR) training.We provided students with a 2-hour training session on CPR for simulated cardiac arrest. Student teams were split into double groups (Dyad training groups: Groups A and B) or Single Groups. All groups received 2 CPR simulation rounds. CPR simulation training began with peer demonstration for Group A, and peer observation for Group B. Then the 2 groups switched roles. Single Groups completed CPR simulation without peer observation or demonstration. Teams were then evaluated based on leadership, teamwork, and team member skills.Group B had the highest first simulation round scores overall (P = 0.004) and in teamwork (P = 0.001) and team member skills (P = 0.031). Group B also had the highest second simulation round scores overall (P < 0.001) and in leadership (P = 0.033), teamwork (P < 0.001), and team member skills (P < 0.001). In the first simulation, there were no differences between Dyad training groups with those of Single Groups in overall scores, leadership scores, teamwork scores, and team member scores. In the second simulation, Dyad training groups scored higher in overall scores (P = 0.002), leadership scores (P = 0.044), teamwork scores (P = 0.005), and team member scores (P = 0.008). Dyad training groups also displayed higher improvement in overall scores (P = 0.010) and team member scores (P = 0.022).Dyad training was effective for CPR training. Both peer observation and demonstration for peers in dyad training can improve student resuscitation performance. PMID- 28353557 TI - High blood pressure and associated risk factors as indicator of preclinical hypertension in rural West Africa: A focus on children and adolescents in The Gambia. AB - Hypertension is fast becoming a major public health problem across sub-Saharan Africa. We sought to determine the prevalence of high blood pressure (BP) and associated risk factors as indicator of preclinical hypertension in a rural Gambian population.We analyzed data on 6160 healthy Gambians cross-sectionally. Attention was given to 5 to <18-year olds (N = 3637), as data from sub-Saharan Africa on this young age group are scarce. High BP was defined as systolic blood pressure (SBP) above the 95th percentile for age-sex specific height z scores in <18-year olds employing population-specific reference values. Standard high BP categories were applied to >=18-year olds.In <18-year olds, the multivariable analysis gave an adjusted high BP prevalence ratio of 0.95 (95% confidence interval [CI] 0.92-0.98; P = 0.002) for age and 1.13 (95% CI 1.06-1.19; P < 0.0001) for weight-for-height z score (zWT-HT); sex and hemoglobin were not shown to affect high BP. In adults age 1.05 (95% CI 1.04-1.05; P < 0.0001), body mass index z score 1.28 (95% CI 1.16-1.40; P < 0.0001), hemoglobin 0.90 (95% CI 0.85 0.96; P < 0.0001) and high fasting glucose 2.60 (95% CI 2.02-3.36; P < 0.0001, though the number was very low) were confirmed as risk factors for high BP prevalence; sex was not associated.The reported high BP prevalence and associated risk factors in adults are comparable to other studies conducted in the region. The observed high BP prevalence of 8.2% (95% CI 7.4-9.2) in our generally lean young Gambians (<18 years) is alarming, given that high BP tracks from childhood to adulthood. Hence there is an urgent need for further investigation into risk factors of pediatric high BP/hypertension even in rural African settings. PMID- 28353558 TI - Transplanted lungs and the "white plague": A case-report and review of the literature. AB - RATIONALE: Solid organ transplant recipients, especially after lung transplantation, are at increased risk for Mycobacterium tuberculosis pulmonary tuberculosis due to lifelong immunosuppression. PATIENT CONCERNS: A 41-year-old woman underwent a second bilateral lung transplantation that was complicated by fatal pulmonary tuberculosis. DIAGNOSES: Histological examination of a lung biopsy performed 6 weeks after retransplantation revealed a caseating granuloma and necrosis. Acid-fast bacilli were identified as rifampicin-susceptible M. tuberculosis by real-time polymerase chain reaction (PCR), confirmed by culture 2 weeks later. INTERVENTIONS: Our investigation led us to highly suspect that the transplanted lungs were the source of M. tuberculosis transmission. LESSONS: In order to optimize diagnosis and treatment for lung recipients with latent or active tuberculosis, regular assessment of lower respiratory samples for M. tuberculosis, particularly during the 12-month period posttransplant should be implemented. Regarding donor-derived transmission, screening donor grafts with latent tuberculosis by M. tuberculosis real-time PCR in lymphoid and adipose tissues is an option that should be considered. PMID- 28353559 TI - Hyperactivity of the default-mode network in first-episode, drug-naive schizophrenia at rest revealed by family-based case-control and traditional case control designs. AB - Abnormal regional activity and functional connectivity of the default-mode network (DMN) have been reported in schizophrenia. However, previous studies may have been biased by unmatched case-control design. To limit such bias, the present study used both the family-based case-control design and the traditional case-control design to investigate abnormal regional activity of the DMN in patients with schizophrenia at rest.Twenty-eight first-episode, drug-naive patients with schizophrenia, 28 age-, sex-matched unaffected siblings of the patients (family-based controls, FBC), and 40 healthy controls (HC) underwent resting-state functional magnetic resonance imaging (fMRI) scans. The group independent component analysis and fractional amplitude of low-frequency fluctuation (fALFF) methods were used to analyze the data.Patients with schizophrenia show increased fALFF in an overlapped region of the right superior medial prefrontal cortex (MPFC) relative to the FBC and the HC. Compared with the HC, the patients and the FBC exhibit increased fALFF in an overlapped region of the left posterior cingulate cortex/precuneus (PCC/PCu). Furthermore, the z values of the 2 overlapped regions can separate the patients from the FBC/HC, and separate the patients/FBC from the HC with relatively high sensitivity and specificity.Both the family-based case-control and traditional case-control designs reveal hyperactivity of the DMN in first-episode, drug-naive patients with paranoid schizophrenia, which highlights the importance of the DMN in the neurobiology of schizophrenia. Family-based case-control design can limit the confounding effects of environmental factors in schizophrenia. Combination of the family-based case-control and traditional case-control designs may be a viable option for the neuroimaging studies. PMID- 28353561 TI - Combination of laparoscope and choledochoscope to treat biliary ascariasis: A CARE-compliant case report. AB - RATIONALE: Ascariasis is an endemic parasitic disease caused by Ascaris lumbricoides, which severely burdens the healthcare system as well as harms the personal life quality, especially among less developed regions. Biliary ascariasis is a critical complication of intestinal ascariasis with painful and life-threatening manifestations. The exploration of proper strategies as its medical interventions remains largely controversial. PATIENT CONCERNS: A 16 year old patient complained of abdominal pain and yellow sclera. DIAGNOSES: Biliary ascariasis INTERVENTIONS:: Laparoscopic cholecystectomy and bile duct exploration. OUTCOMES: More than one hundred ascarids were extracted and the patient had been discharged from hospital without any complications. LESSONS: The combination of laparoscope and choledochoscope is an efficient method to treat biliary ascariasis, despite of large worm burden in the common bile duct. PMID- 28353560 TI - A life-threatening case of TAFRO syndrome with dramatic response to tocilizumab, rituximab, and pulse steroids: The first case report in Latin America. AB - RATIONALE: This is the report of the first case of TAFRO syndrome (Thrombocytopenia, Anasarca, myelofibrosis, Renal dysfunction, Organomegaly) in Latin America. PATIENT CONCERNS: The patient was a 61-year-old white woman of Ashkenazi Jewish descent, who presented with a history of 8 days of nausea, vomiting, and fever; severe pitting edema in both legs, ascites, splenomegaly, and palpable axillary lymph nodes. DIAGNOSES: Abdominal computed tomography (CT) showed bilateral pleural effusion and retroperitoneal lymph node enlargement. INTERVENTIONS: Anasarca and worsening of renal function led to admission to the intensive care unit (ICU) with multiple organ failure, requiring mechanical ventilation, vasopressor medications, and continuous renal replacement therapy (CRRT). Diagnosis of TAFRO syndrome was made on day 18 after admission, based on clinical findings and results of bone marrow and lymph node biopsies. She was treated with methylprednisolone, tocilizumab, and rituximab. One week after the first tocilizumab dose, she had dramatic improvements in respiratory and hemodynamic status, and was weaned from ventilator support and vasopressor medications. OUTCOMES: After 2 weeks of therapy, CRRT was switched to intermittent hemodialysis. On day 46, the patient was discharged from the ICU to the general ward, and 3 months after admission, she went home. LESSONS: Provided the interleukin-6 measurement is available, this approach is suggested in cases of TAFRO syndrome, in order to customize the treatment. PMID- 28353563 TI - Tissue expansion in the treatment of giant congenital melanocytic nevi of the upper extremity. AB - The aim of our study was to use tissue expansion for the treatment of giant congenital melanocytic nevi of the upper extremity and examine potential advantages over traditional techniques.There were 3 stages in the treatment of giant congenital melanocytic nevi of the upper extremities using tissue expansion: first, the expander was inserted into the subcutaneous pocket; second, the expander was removed, lesions were excised, and the wound of the upper extremity was placed into the pocket to delay healing; third, the residual lesion was excised and the pedicle was removed. The pedicle flap was then unfolded to resurface the wound.During the period between June 2007 and December 2015, there were 11 patients with giant congenital melanocytic nevi of the upper extremities who underwent reconstruction at our department with skin expansion. Few complications were noted in each stage of treatment. The functional and aesthetic results were observed and discussed in this study.Optimal aesthetic and functional results were obtained using tissue expansion to reconstruct the upper extremities due to the giant congenital melanocytic nevi. PMID- 28353562 TI - Primary hepatic extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type: A case report and literature review. AB - RATIONALE: Primary hepatic mucosa-associated lymphoid tissue (MALT) lymphoma is an extremely rare disease. To the best of our knowledge, only 67 cases had been reported in 39 English literatures to date. The aim of this study was to add a new case of this disease to the literature and to review the current literature. PATIENT CONCERNS: A 50-year-old man was incidentally identified with a solitary mass of 5 cm in diameter in the left lobe of the liver. DIAGNOSES: Based on the results of imaging studies, intrahepatic cholangiocellular carcinoma was suspected, and then surgery was performed. Microscopic findings showed that the tumor was a hepatic MALT lymphoma, and immunohistochemical analysis revealed that the lymphoma cells were CD20+, CD79a+, BCL-2+, CD3-, and CD5-. INTERVENTIONS: The patient received rituximab after surgery. OUTCOMES: He was free of disease for 13 months at the time of this report. LESSONS: Since previously published case reports and our case described nonspecific clinical features of this rare disease, it was usually misdiagnosed before histological confirmation and surgery resection may be a good choice for both diagnosis and local therapy. PMID- 28353565 TI - Perioperative intravenous glucocorticoids can decrease postoperative nausea and vomiting and pain in total joint arthroplasty: A meta-analysis and trial sequence analysis. AB - BACKGROUND: This meta-analysis aimed to demonstrate the efficacy and safety of intravenous glucocorticoids for reducing pain intensity and postoperative nausea and vomiting (PONV) in patients undergoing total joint arthroplasty (TJA). METHODS: PubMed, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and Google databases were searched for randomized controlled trials (RCTs) comparing intravenous glucocorticoids versus no intravenous glucocorticoids or sham for patients undergoing TJA. Outcomes included visual analogue scale (VAS) pain at 12, 24, and 48 hours; the occurrence of PONV; length of hospital stay; the occurrence of infection; and blood glucose levels after surgery. We calculated risk ratios (RR) with a 95% confidence interval (CI) for dichotomous outcomes and the weighted mean difference (WMD) with a 95% CI for continuous outcomes. Trial sequential analysis was also used to verify the pooled results. RESULTS: Thirteen clinical trials involving 821 patients were ultimately included in this meta-analysis. The pooled results indicated that intravenous steroids can decrease VAS at 12 hours (WMD = -8.54, 95% CI -11.55 to -5.53, P = 0.000; I = 35.1%), 24 hours (WMD = -7.48, 95% CI 13.38 to -1.59, P = 0.013; I = 91.8%), and 48 hours (WMD = -1.90, 95% CI -3.75 to -0.05, P = 0.044; I = 84.5%). Intravenous steroids can decrease the occurrence of PONV (RR = 0.56, 95% CI 0.44-0.73, P = 0.000; I = 33.1%). There was no significant difference in the length of hospital stay, occurrence of infection, and blood glucose levels after surgery. CONCLUSION: Intravenous glucocorticoids not only alleviate early pain intensity but also decrease PONV after TJA. More high-quality RCTs are required to determine the safety of glucocorticoids before making final recommendations. PMID- 28353564 TI - Accuracy of using serum D-dimer for diagnosis of acute intestinal ischemia: A meta-analysis. AB - OBJECTIVE: The purpose of this meta-analysis is to comprehensively assess the accuracy of serum D-dimer for the diagnosis of acute intestinal ischemia. METHODS: Diagnostic studies of D-dimer for accurate diagnosis of acute intestinal ischemia were extracted from 6 databases, and prospective and retrospective studies that provided adequate data on sensitivity and specificity were included here. Sensitivity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were calculated. The overall diagnostic performance of D-dimer was assessed by plotting a summary receiver operating characteristic curve (SROC) and calculating the area under the curve (AUC). RESULTS: A total of 1300 patients with suspected acute intestinal ischemia from 12 studies met the inclusion criteria. The combined sensitivity, specificity, PLR, NLR, and DOR were 0.94 (95% CI: 0.87-0.97), 0.50 (95% CI: 0.40-0.61), 1.9 (95% CI: 1.5-2.3), 0.12 (95% CI: 0.05-0.26), and 16 (95% CI: 7-39), respectively. The AUC was 0.81 (95% CI: 0.78-0.84). CONCLUSION: The results of this meta analysis suggested that plasma D-dimer detection might be a useful means of identifying patients with acute intestinal ischemia of the abdomen. PMID- 28353567 TI - Are "normal hips" being labeled as femoroacetabular impingement due to EE angle? AB - Gluteal muscle contracture (GMC) is a clinical syndrome characterized by gait abnormality and limb dysfunction, as well as secondary deformities of pelvis and femur. Femoroacetabular impingement (FAI) typically could be diagnosed on the basis of computed tomography (CT) such as the equatorial-edge angle (EE angle), but it did not work well in GMC patients. In this study, we retrospected all image data and found small EE angles in GMCs, which meant retroverted acetabulum; however, none of them showed no symptoms and signs of FAI. Therefore, we had reasons to think that, some normal hips with unbalanced hip myodynamia as same as GMCs, may be incorrectly diagnosed as FAI through measuring EE angle only.In consequence, the paper was designed to assess the use of the EE angle in the assessment of FAI in the diagnosis, as described by Werner.Twenty-three patients (46 hips) were collected and calculated with the "equatorial-edge angle" (EE angle) by CT scans. All of them were excluded from FAI.Review of the hips showed a mean EE angle was 12.93 degrees , with a minimum of -3.42 degrees and a maximum of 24.08 degrees . The mean value for males and females were 13.52 degrees and 12.40 degrees , respectively, without statistical significance, although the mean value of left hips and right sides reached 13.32 degrees and 12.54 degrees individually, not having statistical differences neither. There were not any symptoms or signs of FAI in all patients. Thus, the reduced EE angle could suggest the local excessive coverage of the femoral head by the anterior acetabular edge, but might not be a reasonably good predictor of FAI.GMC patient's acetabular deformity mainly manifests as increased retroversion, which may be the anatomical basis for FAI and lead to high risks of the acetabular impingement. However, all patients in this study showed no symptoms and signs of FAI, suggesting that the measurement of EE angle can only be applied to assessing those people with normal hip myodynamia, and the bone deformity and the muscular disorder should be both considered in the diagnosis of FAI. PMID- 28353566 TI - Do renin-angiotensin system inhibitors influence the recurrence, metastasis, and survival in cancer patients?: Evidence from a meta-analysis including 55 studies. AB - BACKGROUND: Renin-angiotensin system inhibitors (RAS inhibitors) are antihypertensive agents with potential antitumor effects. However, various studies have yielded conflicting results on the influence of RAS inhibitors on survival of cancer patients. The aim of this study was to evaluate the effect of RAS inhibitors on recurrence, metastasis, and survival in cancer patients through a meta-analysis. METHODS: PubMed, Web of Science, EMBASE, and Cochrane Library were systematically searched from inception to December 2016. The pooled hazard ratio (HR) with its 95% confidence interval (95% CI) was calculated to evaluate the association between RAS inhibitors and recurrence, metastasis, and survival in cancer patients. RESULTS: Fifty-five eligible studies were included in the present meta-analysis. Results showed that there were significant improvements in overall survival (OS) (HR = 0.82; 95% CI: 0.77-0.88; P < 0.001), progression-free survival (HR = 0.74; 95% CI: 0.66-0.84; P < 0.001), and disease-free survival (HR = 0.80; 95% CI: 0.67-0.95; P = 0.01) in RAS inhibitor users compared with nonusers. Subgroup analyses revealed that the effect of RAS inhibitors on OS depended on the cancer type or different RAS inhibitors. CONCLUSION: This meta analysis suggests that RAS inhibitors could improve the survival of cancer patients and depend on cancer type and types of RAS inhibitors. PMID- 28353568 TI - Angiogenesis inhibitors for the treatment of small cell lung cancer (SCLC): A meta-analysis of 7 randomized controlled trials. AB - BACKGROUND: This study aimed to assess the effectiveness and safety of angiogenesis inhibitors for the treatment of patients with small cell lung cancer (SCLC) via meta-analysis. METHODS: Electronic databases including PubMed, Embase, and Cochrane Library were searched to look for eligible studies through February 1, 2016. RCTs comprising angiogenesis inhibitors and nonangiogenesis inhibitors for SCLC patients were investigated. The extracted data including overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were summarized. In addition, the common adverse events (AEs) were also explored. RESULTS: There were 7 phase II/III RCTs, encompassing 1322 SCLC patients eligible for meta-analysis. In comparison to nonangiogenesis inhibitors, angiogenesis inhibitors treatment was not associated with improvement of PFS [HR = 0.87, 95% CI (0.74-1.02), P = 0.09), OS [HR = 0.99, 95% CI (0.88-1.12), P = 0.91], or ORR [OR = 1.12, 95% CI (0.85-1.47), P = 0.41). Also, there was no improvement in 1 year survival rate [OR = 0.96, 95% CI (0.74-1.19), P = 0.63)], 2-year survival rate [OR = 1.00, 95% CI (0.66-1.51), P = 1.00)] or 1-year progression-free survival rates [OR = 0.95, 95% CI (0.69-1.31), P = 0.76)]. However, from subgroup analyses, it was observed that angiogenesis inhibitors improved ORR [HR = 1.66 (95% CI 1.02-2.71), P = 0.04] in phase II studies and bevacizumab improved PFS [HR = 0.73 (95% CI 0.42-0.97), P = 0.04]. It is important to note that angiogenesis inhibitors reduced emesis [OR = 0.38, 95% CI (0.17-0.85), P = 0.02], but increased incidence of constipation [OR = 4.02, 95% CI (2.14-7.55), P < 0.0001) and embolism [OR = 2.24, 95% CI (1.45-3.47), P = 0.0003). CONCLUSION: Adding angiogenesis inhibitors to chemotherapy did not improve PFS, OS, ORR, 1 year survival rate, 2-year survival rate or 1-year progression-free survival rate for SCLC. However, subgroup analysis revealed that bevacizumab enhanced PFS. Angiogenesis inhibitors also had a high incidence of constipation and embolism. PMID- 28353569 TI - Case report and systematic literature review of a novel etiology of sinistral portal hypertension presenting with UGI bleeding: Left gastric artery pseudoaneurysm compressing the splenic vein treated by embolization of the pseudoaneurysm. AB - INTRODUCTION: A novel case is reported of upper gastrointestinal (UGI) bleeding from sinistral portal hypertension, caused by a left gastric artery (LGA) pseudoaneurysm (PA) compressing the splenic vein (SV) that was successfully treated with PA embolization. CASE REPORT: A 41-year-old man with previous medical history of recurrent, alcoholic pancreatitis presented with several episodes of hematemesis and abdominal pain for 48 hours. Physical examination revealed a soft abdomen, with no abdominal bruit, no pulsatile abdominal mass, and no stigmata of chronic liver disease. The hemoglobin declined acutely from 12.3 to 9.3 g/dL. Biochemical parameters of liver function and routine coagulation profile were entirely within normal limits. Abdominal CT revealed a 5 cm-wide peripancreatic mass compressing the stomach and constricting the SV. Esophagogastroduodenoscopy showed blood oozing from portal hypertensive gastropathy, small nonbleeding gastric cardial and fundal varices, gastric compression from the extrinsic mass, and no esophageal varices. MRCP and angiography showed that the mass was vascular, arose from the LGA, compressed the mid SV without SV thrombosis, and caused sinistral portal hypertension. At angiography, the PA was angioembolized and occluded. The patient has been asymptomatic with no further bleeding and a stable hemoglobin level during 8 weeks of follow-up. DISCUSSION: Literature review of the 14 reported cases of LGA PA revealed that this report of acute UGI bleeding from sinistral portal hypertension from a LGA PA constricting the SV is novel; one previously reported patient had severe anemia without acute UGI bleeding associated with sinistral portal hypertension from a LGA PA. CONCLUSION: A patient presented with UGI bleeding from sinistral portal hypertension from a LGA PA compressing the SV that was treated by angiographic obliteration of the PA which relieved the SV compression and arrested the UGI bleeding. Primary therapy for this syndrome should be addressed to obliterate the PA and not the secondarily constricted SV. PMID- 28353570 TI - Nonspecific ST-T changes associated with unsatisfactory blood pressure control among adults with hypertension in China: Evidence from the CSPTT study. AB - Nonspecific ST-segment and T-wave (ST-T) changes represent one of the most prevalent electrocardiographic abnormalities in hypertensive patients. However, a limited number of studies have investigated the association between nonspecific ST-T changes and unsatisfactory blood pressure (BP) control in adults with hypertension.The study population comprised 15,038 hypertensive patients, who were selected from 20,702 participants in the China Stroke Primary Prevention Trial. The subjects were examined with electrocardiogram test at the initial visit in order to monitor baseline heart activity. According to the results of the electrocardiogram (defined by Minnesota coding), the subjects were divided into 2 groups: ST-T abnormal and ST-T normal. Unsatisfactory BP control was defined as systolic BP >=140 mm Hg or diastolic BP >=90 mm Hg following antihypertensive treatment during the 4.5-year follow-up period. Multivariate analysis was used to analyze the association between nonspecific ST-T abnormalities and unsatisfactory BP control.Nonspecific ST-T changes were common in hypertensive adults (approximately 8.5% in the study), and more prevalent in women (10.3%) and diabetic patients (13.9%). The unsatisfactory BP control rate was high in the total population (47.0%), notably in the ST-T abnormal group (55.5%). The nonspecific ST-T abnormal group exhibited a significantly greater rate of unsatisfactory BP control (odds ratio [OR] 1.20, 95% confidence interval [CI] [1.06, 1.36], P = 0.005]), independent of traditional risk factors, as demonstrated by multivariate regression analysis. Notable differences were further observed in male subjects (OR 1.51, 95% CI [1.17, 1.94], P = 0.002) and in patients with comorbid diabetes (OR 1.47, 95% CI [1.04, 2.07], P = 0.029).Greater rates of unsatisfactory BP control in hypertensive patients with electrocardiographic nonspecific ST-T abnormalities were observed, notably in the subcategories of the male subjects and the diabetic patients. PMID- 28353571 TI - Green tea and the risk of prostate cancer: A systematic review and meta-analysis. AB - Prostate cancer (PCa) now remains the 2nd most frequently diagnosed cancer. In recent years, chemoprevention for PCa becomes a possible concept. Especially, many phytochemicals rich foods are suggested to lower the risk of cancer. Among these foods, green tea is considered as effective prevention for various cancers. However, clinical trials and previous meta-analyses on the relationship between green tea consumption and the risk of PCa have produced inconsistent outcomes. This study aims to determine the dose-response association of green tea intake with PCa risk and the preventive effect of green tea catechins on PCa risk. Seven observational studies and 3 randomized controlled trials were retrieved from Cochrane Library, PubMed, Sciencedirect Online, and hand searching. The STATA (version 12.0) was applied to analyze the data. The relative risks (RRs) and 95% confidence intervals were pooled by fixed or random effect modeling. Dose response relations were evaluated with categories of green tea intake. Although there was no statistical significance in the comparison of the highest versus lowest category, there was a trend of reduced incidence of PCa with each 1 cup/day increase of green tea (P = 0.08). Our dose-response meta-analysis further demonstrated that higher green tea consumption was linearly associated with a reduced risk of PCa with more than 7 cups/day. In addition, green tea catechins were effective for preventing PCa with an RR of 0.38 (P = 0.02). In conclusion, our dose-response meta-analysis evaluated the association of green tea intake with PCa risk systematically and quantitatively. And this is the first meta analysis of green tea catechins consumption and PCa incidence. Our novel data demonstrated that higher green tea consumption was linearly reduced PCa risk with more than 7 cups/day and green tea catechins were effective for preventing PCa. However, further studies are required to substantiate these conclusions. PMID- 28353572 TI - New insight on antimicrobial therapy adjustment strategies for gram-negative bacterial infection: A cohort study. AB - Gram-negative bacterial infections, especially multidrug-resistant (MDR) bacterial infection, are becoming a serious threat to public health. Although it is widely accepted that both appropriate initial empirical therapy and targeted therapy are important, but for patients needing therapy adjustment, few studies have explored whether adjustment strategy based on microbiologic susceptibility test (MST) brings better outcome compared with empirical adjustment.A total of 320 patients with gram-negative bacterial infection (airway, blood, or pleural effusion) were selected and a prospective cohort study was conducted. Baseline characteristics and outcomes (microbiologic, clinical, and economic) were documented during follow-up.MDR and nosocomial infections were common among subjects. Initial therapies consistent with MST could result in reduced in hospital mortality, treatment failure rate, infection-related death, percentages of patients needing therapy adjustment, and daily hospitalization cost with increased successful treatment rate compared with inconsistent with MST, and microbiologic outcomes were also better with appropriate therapies.For patients needing therapy adjustment, relying on MST gained no significant benefit on mortality, clinical, or microbiologic outcomes compared with depending on clinical experience. But for patients with MDR infection, adjustment relying on MST gained more benefit than non-MDR infection.Appropriate initial therapy significantly improved the prognosis of patients with gram-negative bacterial infections, but improvement was not that obvious for patients needing therapy adjustment which was based on MST compared with clinical experience, and more beneficial effects of adjustment relying on MST were obtained for patients with MDR bacterial infection. PMID- 28353573 TI - Aneurysm-related ischemic ventricular tachycardia: safety and efficacy of catheter ablation. AB - Left ventricular aneurysm (LVA) postmyocardial infarction (MI) might be an arrhythmogenic substrate. We examined the safety and efficacy of catheter ablation of LVA-related ventricular tachycardia (VT).Thirty-three consecutive patients who underwent primary catheter ablation of ischemic VT were divided into LVA group (11 patients, mean age 61.9 years, 10 men) and none LVA group. Acute procedural outcomes, complications, and long-term outcomes were assessed.In LVA group, average number of induced VTs were 3.2 +/- 2.6 (range 1-7), clinical VTs were located in the ventricular septum scar zone in 4 (36.4%) patients, acute success was achieved in 7 (63.6%) patients, partial success in 3 (27.3%) and failure in 1 patient, while none LVA group showing a statistically similar distribution of acute procedural outcomes (P = 0.52). There were no major or life threatening complications. VT-free survival rate at median 19 (1-44) months follow-up was numerically but not significantly lower in LVA versus none LVA group (48.5% vs 62.8%, log-rank P = 0.40).Catheter ablation of ischemic VT in the presence of LVA appears feasible and effective, with about one-third of cases having septal ablation targets. Further studies are warranted. PMID- 28353574 TI - A crucial temporal accuracy test of combining EEG and Tobii eye tracker. AB - Eye tracking and event-related potentials have been widely used in the field of cognitive psychology and neuroscience. Both techniques have the ability to refine cognitive models through a precise timeline description; nevertheless, they also have severe limitations. Combining measures of event-related potentials and eye movements can contribute to cognitive process capture, which provides the possibility to determine precisely when and in which order different cognitive operations occur. Combining of event-related potentials and eye movements has been recently conducted by synchronizing measures from an infrared eye tracker with an electroencephalograph to allow simultaneous data recording. Here, we describe in detail 4 types of co-registration methods for event-related potentials and eye movements on the Tobii platform. Moreover, the present investigation was designed to evaluate the temporal accuracy of data obtained using the 4 methods. We found that the method based on the Tobii Pro Analytics software development kit had a higher degree of temporal accuracy than the other co-registration methods. Furthermore, the reasons for the different temporal accuracies were assessed, and potential measures to correct clock drift were taken. General suggestions are made regarding timing in the co-registration of the electroencephalograph and eye tracker. PMID- 28353575 TI - Association between serum 25-hydroxyvitamin D and carotid atherosclerotic plaque in Chinese type 2 diabetic patients. AB - In this study, we investigated the distribution of vitamin D and its association with carotid atherosclerotic plaque (CP) in Chinese type 2 diabetic (T2D) patients. We performed a cross-sectional study in 210 T2D and 94 age- and gender matched nondiabetic patients during winter months, by determining serum 25 hydroxyvitamin D (25(OH)D) levels in both diabetic and nondiabetic controls. We carried out measurements of B-mode ultrasonography of carotid arteries in each T2D patient. The 25(OH)D concentration was 26.25 nmol/L among the T2D patients. About 93.3% T2D patients suffered from hypovitaminosis D. First, we found a clear inverse correlation between the 25(OH)D concentration and CP (P <0.001). Second, an association between 25(OH)D and macrovascular disease was significant (P = 0.005). In multivariate logistic regression analysis, decreasing 25(OH)D concentration was markedly associated with CP in T2D patients. Third, after adjusting for the confounding factors, we also observed a positive correlation between low levels of 25(OH)D in T2D patients with CP, when the following parameters were measured: old age (odds ratio [OR] = 2.533, P = 0.013); smoking (OR = 3.872, P = 0.001); and high level of low-density lipoprotein (LDL) cholesterol (OR = 2.776, P = 0.009). Thus, we concluded that high prevalence of hypovitaminosis D exists in Chinese T2D patients. Further, we found a significant association between low concentration of serum 25(OH)D and the existence of high body mass index, and high circulating LDL to be substantially positive predictors of patients with CP in T2D. PMID- 28353577 TI - Effect of different types of anesthesia on intraoperative blood glucose of diabetic patients: A PRISMA-compliant systematic review and meta-analysis. AB - BACKGROUND: Systematic review which analyzes the impact of different anesthesia on intraoperative blood glucose levels of diabetes patients. METHODS: We searched Medline (via PubMed), Embase, Cochrane Library, Web of Science, Wangfang, CNKI, and CBM database through June 2016, included in randomized controlled trial (RCT), about different anesthesia on intraoperative blood glucose levels in patients with diabetes. Two researchers in 1 group independently screened literatures with eligibility criteria, extracted information, and used RevMan5.3 software to perform meta-analysis. RESULTS: We included 11 trials and performed the meta-analysis with 10 trials. The meta-analysis results suggested that compared with general anesthesia, the combined general-epidural anesthesia has a better glycemic control in intraoperative blood glucose levels (WMD -1.26, 95% confidence interval [CI] -1.77 to 0.76), the epidural anesthesia had no significant effects compared with general anesthesia (WMD -0.74, 95% CI 4.41 2.92), and the combined spinal-epidural anesthesia had no significant effects compared with epidural anesthesia (WMD -0.28, 95% CI -1.02 to 0.46). One study suggested that compared with epidural anesthesia, the combined general-epidural anesthesia can lower blood glucose levels CONCLUSION:: Existing evidence showed that compared with general anesthesia, the combined general-epidural anesthesia has a better glycemic control in intraoperative blood glucose levels. PMID- 28353576 TI - Clinical and microbiological features of invasive nontyphoidal Salmonella associated with HIV-infected patients, Gauteng Province, South Africa. AB - The aim of this study was to define factors associated with HIV-infected versus uninfected patients with invasive nontyphoidal Salmonella (iNTS) and factors associated with mortality, which are inadequately described in Africa.Laboratory based surveillance for iNTS was undertaken. At selected sentinel sites, clinical data (age, sex, HIV status, severity of illness, and outcome) were collected.Surveillance was conducted in Gauteng, South Africa, from 2003 to 2013. Clinical and microbiological differences between HIV-infected and uninfected patients were defined and risk factors for mortality established.Of 4886 iNTS infections in Gauteng from 2003 to 2013, 3106 (63.5%) were diagnosed at sentinel sites. Among persons with iNTS infections, more HIV-infected persons were aged >=5 years (chi = 417.6; P < 0.001) and more HIV-infected children were malnourished (chi = 5.8; P = 0.02). Although 760 (30.6%) patients died, mortality decreased between 2003 [97/263 (36.9%)] and 2013 [926/120 (21.7%)]. On univariate analysis, mortality was associated with patients aged 25 to 49 years [odds ratio (OR) = 2.2; 95% confidence interval (CI) = 1.7-2.7; P < 0.001 and >=50 years (OR = 3.0; 95% CI = 2.2-4.1; P < 0.001) compared with children < 5 years, HIV infected patients (OR = 2.4; 95% CI = 1.7-3.4; P < 0.001), and severe illness (OR = 5.4; 95% CI = 3.6-8.1; P < 0.001). On multivariate analysis, mortality was associated with patients aged >=50 years [adjusted OR (AOR) = 3.6, 95% CI = 2.1 6.1, P < 0.001] and severe illness (AOR = 6.3; 95% CI = 3.8-10.5; P < 0.001).Mortality due to iNTS in Gauteng remains high primarily due to disease severity. Interventions must be aimed at predisposing conditions, including HIV, other immune-suppressive conditions, and malignancy. PMID- 28353578 TI - Rocuronium-induced neuromuscular block and sugammadex in pediatric patient with duchenne muscular dystrophy: A case Report. AB - INTRODUCTION: Anesthetic management of patients with Duchenne muscular dystrophy (DMD) is complicated because these patients are more sensitive to nondepolarizing neuromuscular blocking agents (NMBAs) and are vulnerable to postoperative complications, such as postoperative residual curarization and respiratory failure. Sugammadex is a new reversal agent for aminosteroidal NMBAs, but its safety in children is controversial. CLINICAL FEATURES: An 11-year-old boy with DMD underwent general anesthesia for a percutaneous nephrolithotomy. We used rocuronium bromide and sugammadex to reverse the deep neuromuscular block. Reversal of neuromuscular block was done 15 minutes after administration of 2 mg/kg of sugammadex. The patient's recovery from anesthesia was uneventful, and he was discharged to the postoperative recovery ward. CONCLUSION: A delayed recovery was achieved, but no adverse events were observed, such as recurarization or hypersensitivity to sugammadex. We report safe use of 2 mg/kg of sugammadex to reverse a deep neuromuscular block in a child with DMD. PMID- 28353579 TI - Intensive insulin therapy for preventing postoperative infection in patients with traumatic brain injury: A randomized controlled trial. AB - OBJECTIVE: To assess the effect of intensive insulin therapy (IIT) for preventing postoperative infection in patients with traumatic brain injury (TBI). METHODS: In total, 88 patients with TBI were randomly divided into 2 groups, 44 in each group. One group (group ITT) received IIT and the other group (group CIT) received conventional insulin therapy (CIT). This study was conducted between February 2013 and January 2016. Outcomes included infection rate, mortality, and neurological outcome (measured by the Glasgow Outcome Scale [GOS]). RESULTS: A total of 81 patients completed the study. IIT showed greater efficacy than CIT, with a decreased infection rate in the IIT group compared to the CIT group (31.9% vs 52.3%, P = 0.03), and also a reduced duration of stay in intensive care unit (ICU) (IIT group, 4.5 +/- 2.1 days vs CIT group, 5.7 +/- 2.8 days, P = 0.02). In addition, a significant difference in scores on the GOS scale was observed between the 2 groups (P = 0.04). The mortality rates in hospital and at the 26 week follow-up were similar between the 2 groups. CONCLUSION: IIT leads to a reduced infection rate, shorter stays in ICU, and improved neurological outcome. PMID- 28353580 TI - Comparison of periarticular anesthesia with liposomal bupivacaine with femoral nerve block for pain control after total knee arthroplasty: A PRISMA-compliant meta-analysis. AB - BACKGROUND: Periarticular anesthesia (PAI) with liposomal bupivacaine (LB) and femoral nerve block (FNB) were 2 common type of pain management after total knee arthroplasty (TKA). There is no consensus about PAI with LB shows better clinical outcome than FNB. Thus, we performed a systematic review and meta-analysis to compare the efficacy and safety of PAI with LB and FNB for patients prepared for TKA. METHODS: Randomized controlled trials (RCTs) and non-RCTs from PubMed (1966 2017.2), EMBASE (1980-2017.2), and the Cochrane Central Register of Controlled Trials (CENTRAL, 2017.2), Web of Science (1966-2017.2), and Chinese Wanfang database (1980-2017.2) were searched. Continuous outcomes including visual analogue scale (VAS) at 24, 48, and 72 hours, total morphine consumption, length of hospital, and range of motion (ROM) were reported as the weighted mean difference with 95% and confidence interval (CI) and discontinuous outcomes (the occurrence of postoperative nausea and vomiting [PONV]) were presented as relative risk with 95% CI. Random-effects model was adopted to analyze the relevant data. RESULTS: According to the inclusion and exclusion criteria, 8 studies with 2407 patients were eligible and finally included in this meta analysis (LB = 1114, FNB = 1293). There was no significant difference between VAS at 24, 4, and 72 hours, ROM, and the occurrence of PONV between PAI with LB group versus FNB group (P > 0.05). Compared with the FNB group, PAI with LB was associated with a significant decrease in length of hospital stay by 0.43 day (MD = -0.43; 95% CI -0.60 to -0.27; P = 0.001) and the total dose of total morphine consumption by (MD = -29.32; 95% CI -57.55 to -1.09; P = 0.042). CONCLUSIONS: The review of trials found that PAI with LB provided a significant beneficial effect over FNB in improving the pain or decreased the total morphine consumption in patients who underwent TKA. However, PAI with LB associated with less LOS than FNB. More high quality RCTs are still needed to identify the effects and optimal dose of LB for pain management after TKA. PMID- 28353581 TI - Prognostic implication of hepatoduodenal ligament lymph nodes in gastric cancer. AB - There has been controversy regarding whether hepatoduodenal lymph node (HDLN) metastasis in gastric cancer is distant or regional metastasis. HDLN positivity was classified as distant metastasis in the 7th American Joint Committee on Cancer (AJCC) classification, but it was reclassified as regional lymph node metastasis in the 8th AJCC classification. The aim of our study is to verify prognostic significance of HDLN metastasis in gastric cancer.This retrospective study enrolled patients with gastric cancer who underwent D2 gastrectomy from January 2007 to June 2010. HDLN was classified as a regional lymph node.Total number of patients was 3175; 143 (4.5%) of them had HDLN metastasis. The HDLN positivity was significantly associated with older age, more advanced tumor stage, undifferentiated histologic type, and pathologic diagnosis of lymphatic, vascular, and perineural invasions. Five-year survival rate of HDLN-positive patients with stages I to III disease was significantly higher than that of stage IV group (59.3% vs 18.8%, P = 0.001). In patients with stage III disease, 5-year survival rate of HDLN-positive group was significantly lower than that of HDLN negative group (51.7% vs 66.3%, P = 0.001). Multivariate analysis showed that HDLN metastasis was an independent prognostic factor.HDLN has a different prognostic significance from other regional lymph nodes in advanced stage of gastric cancer though its positivity is not considered as distant metastasis. HDLN positivity itself seems to be an independent prognostic factor in gastric cancer, and the survival outcomes of patients with stage III disease need to be reconsidered according to HDLN positivity. PMID- 28353582 TI - Association between pet ownership and coronary artery disease in a Chinese population. AB - A number of studies have suggested the benefits of pet ownership to human health, including cardiovascular disease (CVD). However, there are few findings regarding pet ownership and coronary artery disease (CAD). The objective of this study is to investigate the association between pet ownership and CAD in a Chinese population. From October 2015 to May 2016, a survey consisting of 561 consecutive patients was done in Nanjing, China. Based on the results of coronary arteriography for the first time, participants were divided into 2 groups (non CAD and CAD groups). Pet ownership information was collected by using a questionnaire. After multivariate adjustments, pet ownership was associated with a decreased CAD risk (odds ratios [OR]: 0.504, 95% confidence intervals [CIs]: 0.310-0.819). There was a reduced CAD risk among dog owners (OR: 0.420, 95% CI: 0.242-0.728) when compared with the cat group (OR: 0.738, 95% CI: 0.240-2.266) and the cat and dog group (OR: 1.052, 95% CI: 0.330-3.355). With the increase of pet ownership duration, there was a decreased tendency of CAD risk, including years of keeping pets (P for trend = 0.008) and time of playing with pets per day (P for trend = 0.001). In addition, similar dose-response relationship was observed for starting age of keeping pets (P for trend = 0.002). Pet ownership, especially dog ownership, can be a protective factor for CAD in Chinese patients. PMID- 28353583 TI - Influence of cyclosporine and everolimus on the main mycophenolate mofetil pharmacokinetic parameters: Cross-sectional study. AB - The objective of the present study was to assess the effect of cyclosporine (CsA) on the pharmacokinetic parameters of mycophenolic acid (MPA), an active mycophenolate mofetil (MMF) metabolite, and to compare with the effect of everolimus (EVR).Anonymized medical records of 404 kidney recipients were reviewed. The main MPA pharmacokinetic parameters (AUC(0-12) and Cmax) were evaluated.The patients treated with a higher mean dose of CsA displayed higher MPA AUC(0-12) exposure in the low-dose MMF group (1000 mg/day) (40.50 +/- 10.97 vs 28.08 +/- 11.03 h mg/L; rs = 0.497, P < 0.05), medium-dose MMF group (2000 mg/day) (43.00 +/- 6.27 vs 28.85 +/- 11.08 h mg/L; rs = 0.437, P < 0.01), and high-dose MMF group (3000 mg/day) (56.75 +/- 16.78 vs 36.20 +/- 3.70 h mg/L; rs = 0.608, P < 0.05).A positive correlation was also observed between the mean CsA dose and the MPA Cmax in the low-dose MMF group (Cmax 22.83 +/- 10.82 vs 12.08 +/ 5.59 mg/L; rs = 0.507, P < 0.05) and in the medium-dose MMF group (22.77 +/- 8.86 vs 13.00 +/- 6.82 mg/L; rs = 0.414, P < 0.01).The comparative analysis between 2 treatment arms (MMF + CsA and MMF + EVR) showed that MPA AUC(0-12) exposure was by 43% higher in the patients treated with a medium dose of MMF and EVR than in the patients treated with a medium dose of MMF and CsA.The data of the present study suggest a possible CsA versus EVR influence on MMF pharmacokinetics. Study results show that CsA has an impact on the main MPA pharmacokinetic parameters (AUC(0-12) and Cmax) in a CsA dose-related manner, while EVR mildly influence or does not affect MPA pharmacokinetic parameters. Low dose CsA (lower than 180 mg/day) reduces MPA AUC(0-12) exposure under the therapeutic window and may lead to ineffective therapy, while a high-dose CsA (>240 mg/day) is related to greater than 10 mg/L MPA Cmax and increases the likelihood of adverse events. PMID- 28353584 TI - Peliosis hepatis: 2 case reports of a rare liver disorder and its differential diagnosis. AB - RATIONALE: Peliosis hepatis (PH) is a rare tumor-like liver lesion composed of multiple blood-filled cavities within the liver parenchyma. It is hard to differentiate PH from other liver lesions by imaging, such as carcinoma, metastases, or abscess. PATIENT CONCERNS: Here, we reported 2 cases that presented with liver lesions under ultrasound and computed tomography (CT) scanning, without any history of liver diseases or drug usage traced back. DIAGNOSES: Liver biopsy and laparoscopy were processed, and the lesions were eventually diagnosed as PH by histopathology, which microscopically presented with multiple sinusoidal dilatations with blood-filled cystic spaces. INTERVENTIONS: After the liver biopsy or laparoscopy, the patients were discharged and followed up in the clinic. OUTCOMES: Both patients were followed up for at least 1 year with good recovery. LESSONS: PH should always be recognized in the differentiation of liver lesions, particularly indistinctive lesion(s) without any history of liver-related diseases. PMID- 28353585 TI - Relationship of oestrogen receptor alpha gene polymorphisms with risk for benign prostatic hyperplasia and prostate cancer in Chinese men. AB - The relationship of oestrogen receptor with benign prostatic hyperplasia (BPH) and prostate cancer (PC) is not clear at present. This study aimed to investigate the molecular mechanism underlying the occurrence and development of BPH and prostate.Two hundred forty-four PC cases, 260 BPH patients, and 222 healthy men were recruited from Han people in China, and the oestrogen receptor alpha (ESRalpha) gene polymorphism (rs2234693 [PvuII] and rs9340799 [XbaI]) on intron 1 was determined. The relationship of gene polymorphism with PC and BPH was evaluated with Logistic regression, and the linkage disequilibrium and haplotyping were assessed with SHEsis software.The risk for PC in BPH patients with PvuII C allele was higher (OR = 1.437, 95% CI: 1.110-1.859), but the differentiation degree of cancer cells was relatively better in PC patients with PvuII C allele (OR = 0.419, 95% CI: 0.285-0.616), and most of them are circumscribed (OR = 0.706, 95% CI: 0.485-1.02). There was significant linkage disequilibrium between PvuII and XbaI. The genotype TTAG not only induced BPH (OR = 6.260, 95% CI: 1.407-27.852), but increased the risk for PC (OR = 6.696, 95% CI: 1.504-29.801). However, the genotype TTAG in BPH patients had no relationship with the risk for PC (P > 0.05). Furthermore, men with haplotype TG were more likely to suffer PC (OR = 9.168, 95% CI: 2.393-35.119), but men with haplotype TA and enlarged prostate had a low risk for PC (OR = 0.708, 95% CI: 0.551 0.912).These results show the relationship between ESRalpha gene polymorphism and susceptibility to PC and BPH in Chinese men, and the ethnic and regional difference as well. PMID- 28353586 TI - Association of depressive symptoms and suicidal ideation among university students in China: A systematic review and meta-analysis. AB - The aim of this study was to investigate whether depressive symptoms are associated with suicidal ideation among university students in China.Five Chinese and English electronic databases (EBSCO, PubMed, Chinese Web of Knowledge, Wanfang, and Weipu) were searched to identify relevant studies. Cross-sectional studies published from 2000 to 2016 reporting about the association between depressive symptoms and suicidal ideation among university students in China were used for meta-analysis to approximate the overall association between depression and suicidal ideation among university students in mainland China. StatsDirect 3 was used for meta-analysis of included literatures.Of 513 initially identified references, 44 studies were selected, including 88,431 participants with depressive symptoms. The combined odd ratio of the relationship was 2.174 (95% confidence interval: 2.027-2.333; P < 0.0001).There exists a moderate association between depressive symptoms and suicidal ideation among university students in China, and depressive symptoms contribute to the development of suicidal ideation. In particular, university students from western regions of China, from nonmedical background, should be provided more psychological and clinical assistance. PMID- 28353587 TI - Sex differences in prevalence and risk factors of asymptomatic cholelithiasis in Korean health screening examinee: A retrospective analysis of a multicenter study. AB - The aim of this study was to evaluate sex difference in the prevalence and risk factors for asymptomatic cholelithiasis in Korean health screening examinees.Examinees who underwent examination through health promotion center at 5 hospitals of Daegu-Gyeongbuk province in 2014 were analyzed retrospectively. All examinees were checked for height, weight, waist circumference, and blood pressure, and underwent laboratory tests and abdominal ultrasound. Diagnosis of cholelithiasis was made by ultrasound.Of the total of 30,544 examinees, mean age was 47.3 +/- 10.9 years and male to female ratio was 1.4:1. Asymptomatic cholelithiasis was diagnosed in 1268 examinees with overall prevalence of 4.2%. In age below 40 years, females showed higher prevalence of asymptomatic cholelithiasis than males (2.7% vs. 1.9%, P = 0.020), whereas prevalence of asymptomatic cholelithiasis was higher in males than females older than 50 years (6.2% vs. 5.1%, P = 0.012). Multiple logistic regression analysis revealed age (>=50 years), obesity, and high blood pressure as risk factors for asymptomatic cholelithiasis in males and age, obesity, hypertriglyceridemia, and chronic hepatitis B infection in females (P < 0.05).Overall prevalence of asymptomatic cholelithiasis was 4.2% in Korean health screening examinees. Females showed higher prevalence of asymptomatic cholelithiasis than males younger than 40 years, whereas it was higher in males older than 50 years. Age and obesity were risk factors for asymptomatic cholelithiasis in both sexes. Males had additional risk factors of high blood pressure and females had hypertriglyceridemia and chronic hepatitis B infection. PMID- 28353588 TI - Primary esophageal mucosa-associated lymphoid tissue lymphoma: A case report and review of literature. AB - RATIONALE: Mucosa-associated lymphoid tissue (MALT) lymphoma is a low grade malignant B cell lymphoma which occurs mainly in the organs having mucosal layer. Though gastrointestinal tract is the most commonly involved extranodal site, primary esophageal MALT lymphoma is very rare with less than 20 cases reported in literature. PATIENT CONCERNS: A 75-year-old man was referred to our hospital for evaluation of dysphagia. Endoscopy revealed a submucosal tumor located in the middle and lower third of esophagus. CT chest and endoscopic ultrasound revealed a 15.5 * 5.9 * 4.0 cm well circumscribed submucosa esophageal tumor. Test for serum antibody against H. pylori was negative. Due to the large tumor size, patient underwent surgical resection. Histological examination showed a submucosal tumor consisting of multiple nodules of varying sizes with intact covering squamous epithelium. The nodules were mainly composed of diffusely and monoclonal proliferating centrocyte-like or monocyte-like cells. Follicular colonizations were observed without lymphoepithelial lesions. The tumor cells were diffusely positive for CD20, PAX-5, Bcl-2 and follicular dendritic cells were positive for CD21, CD23. Monoclonal gene rearrangement was positive for immunoglobulin heavy chain gene, Kappa light chain gene and Lambda light chain gene. DIAGNOSES: Based on these findings, final diagnosis of esophageal MALT lymphoma was made. OUTCOMES: At 8 month follow up, no recurrence or metastases was detected. LESSONS: Esophageal MALT lymphoma is a rare disease with definitive diagnosis possible only after histopathological examination. It carries good prognosis due to low malignant potential. PMID- 28353589 TI - Depressive symptoms in Chinese family caregivers of patients with heart failure: A cross-sectional study. AB - Depressive symptoms are related to negative health outcomes in caregivers of patients with HF. Understanding the factors that are associated with depressive symptoms among caregivers is essential to providing appropriate interventions. Little is known about which status and factors are related to depressive symptoms among Chinese caregivers of patients with heart failure. This study aimed to investigate the status of depressive symptoms and to identify the factors that are associated with depressive symptoms in family caregivers of patients with heart failure in China.A cross-sectional design and a convenience sample were used. Participants (N = 134) from 1 hospital in Chengdu were recruited from June 2013 to June 2014. The following measurement tools were used in this study: Center for Epidemiologic Studies Depression Scale, Hospital Anxiety and Depression Scale, Coping Strategies Simplified Coping Style Questionnaire, and Zarit Burden Interview. A hierarchical multiple linear regression analysis was used to determine which factors were associated with depressive symptoms.The results showed that 31% of the caregivers experienced depressive symptoms. The type of payment for treatment (b = -0.312, P < 0.01), readmissions within the last 3 months (b = 0.397, P < 0.01), duration of caregiving (b = -0.213, P < 0.05), caregiver burden (b = 0.299, P < 0.05), active coping (b = -0.235, P < 0.01), and negative coping (b = 0.245, P < 0.05) were related to caregivers' depressive symptoms. Fifty-four percent of the variance in caregivers' depressive symptoms was explained by these factors.The caregiver depressive symptoms in China were higher than those reported in studies that were conducted in Western countries. Caregiver depressive symptoms can be improved by providing support for new caregivers (with a caregiving duration of less than 1 year), reducing readmissions, easing caregiver burden, and promoting their coping strategies. PMID- 28353591 TI - Systematic review and meta-analysis of preoperative chemoradiotherapy with or without oxaliplatin in locally advanced rectal cancer. AB - BACKGROUND: Preoperative chemoradiotherapy has become the current standard regimen for locally advanced rectal cancer (LARC). However, the additional benefit of oxaliplatin to preoperative chemotherapy was still controversial. On one hand, oxaliplatin may improve the tumor response rate of even prolong the survival time. On the other hand, it can bring a series of adverse effects. Opinions vary from studies to studies. We aim to perform a meta-analysis to evaluate the efficacy, safety, and long-term survival of oxaliplatin in preoperative chemoradiotherapy for LARC. METHOD: To identify clinical trials fusing oxaliplatin in preoperative chemoradiotherapy for LARC published until December 2015, we searched PubMed, the Cochrane Library, and the Springer Link databases by combining various key words. We also search for relevant ASCO conferences. Data were extracted from every study to perform a meta-analysis using STATA 12.0 software. RESULT: Eleven articles or ASCO abstracts from 8 studies with a total of 5597 patients were included. Adding oxaliplatin to preoperative chemoradiotherapy can significantly improve the ypCR rate [risk ratio (RR) = 1.208, 95% confidence interval (95% CI): 1.070-1.364, P = 0.002, I = 14.5%], and decrease the preoperative metastasis (RR = 0.494, 95% CI: 0.256 0.954, P = 0.036, I = 53.9%) and local recurrence rate (RR = 0.761, 95% CI: 0.616 0.941, P = 0.012, I = 26.1%). What's more, oxaliplatin can prolong the disease free survival (DFS) [hazard ratio (HR) = 0.867, 95% CI: 0.741-0.992, P = 0.000, I = 16.3%]. However, oxaliplatin can increase the chemoradiotherapy-related toxicities (RR = 1.858, 95% CI 1.427-2.419, P = 0.000, I = 84.7%). There was no significant difference between the groups with and without oxaliplatin in operation rate, R0 resection rate, sphincter preservation rate, permanent stoma rate, postoperative complication, mortality, and overall survival. CONCLUSION: Preoperative chemoradiotherapy with oxaliplatin bring both advantage and disadvantage to LARC. Whether to use oxaliplatin should be decided by patient's general condition and tolerance. Although oxaliplatin can prolong the DFS, survival benefit should be proved by further data. PMID- 28353590 TI - Point prevalence and epidemiological characteristics of chronic cough in the general adult population: The Korean National Health and Nutrition Examination Survey 2010-2012. AB - Cough is frequently self-limiting, but may persist longer in certain individuals. Most of previous studies on the epidemiology of chronic cough have only measured period prevalence, and thus have afforded limited information on the burden and natural course. We aimed to investigate the epidemiology of chronic cough by using a point prevalence measure in a large-scale general population.We analyzed cross-sectional data collected from 18,071 adults who participated in the Korean National Health and Nutrition Examination Survey 2010-2012. Presence and duration of current cough was ascertained by structured questionnaires, and cough was classified into acute (<3 weeks), subacute (3-8 weeks), or chronic cough (>=8 weeks). Demographic and clinical parameters were examined in relation to chronic cough.The point prevalences of acute, subacute, and chronic cough were 2.5 +/- 0.2%, 0.8 +/- 0.1% and 2.6 +/- 0.2%, respectively. The proportion of current cough showed a steep decrease after 1 week of duration. However, 2 peaks in the prevalence of current cough were revealed; cough durations of less than 1 week and longer than 1 year were most common (31.1% and 27.7% of current cough, respectively). Subacute and chronic cough were more prevalent in the elderly (>=65 years); the positive associations with older age were independent of other confounders, including current smoking and comorbidities.This is the first report on the epidemiology of cough using a point prevalence measure in a nationally representative population sample. Our findings indicate a high burden of chronic cough among adults with current cough in the community. The dual-peak of cough duration suggested that the pathophysiology of acute and chronic cough may differ. The preponderance of elderly people in the prevalence of chronic cough warrants further investigation. In addition, more sophistication and validation of tools to define chronic cough will help our understanding of the epidemiology. PMID- 28353593 TI - Warming infusion improves perioperative outcomes of elderly patients who underwent bilateral hip replacement. AB - BACKGROUND: This prospective, randomized, and controlled study was performed to determine the benefits of prewarmed infusion in elderly patients who underwent bilateral hip replacement. METHODS: Between September 2015 and April 2016, elderly patients who underwent bilateral hips replacement that met the inclusion and exclusion criteria were included in this study. After inclusion, patients were randomized into one of the study groups: in the control group, patients received an infusion of fluid kept at room temperature (22-23 degrees C); in the warming infusion group, patients received an infusion of fluid warmed using an infusion fluid heating apparatus (35 degrees C). Postoperative outcomes, including recovery time, length of hospital stay, visual analogue scale (VAS) score, and postoperative complications rate of patients from both groups, were compared. RESULTS: A total of 64 patients were included in our study (71.2 +/- 7.6 years, 53.1% males), with 32 patients in the control group and 32 patients in warming infusion group. No significant difference was found in terms of demographic data and intraoperative blood transfusion rate between 2 groups (P > 0.05). Patients receiving a prewarmed infusion had a significantly shorter time to spontaneous breath, eye opening, consciousness recovery, and extubation than the control group (P < 0.05). In addition, significant differences were found in Steward score and VAS score between 2 groups (P < 0.05). Moreover, warming infusion group also showed an obviously decreased incidence of shivering and postoperative cognitive dysfunction (P < 0.05). CONCLUSION: A prewarmed infusion could reduce the incidence of perioperative hypothermia and improve outcomes in the elderly during bilateral hip replacement. PMID- 28353592 TI - The effect of MDR1 C3435T polymorphism on the eradication rate of H. pylori infection in PPI-based triple therapy: A meta-analysis. AB - BACKGROUND: Several studies have reported that multidrug resistance gene 1 (MDR1) C3435T polymorphism was associated with the rate of Helicobacter pylori (H. pylori) eradication in proton pump inhibitor (PPI)-based triple therapy. However, the conclusions were inconsistent. Therefore, this meta-analysis was conducted to evaluate the impact of MDR1 C3435T polymorphism on H. pylori eradication by PPI based triple therapy. METHODS: Seven eligible studies published up to August 2016 and including 1019 patients were identified by searching the Chinese Biomedical Literature database, Wan fang, PubMed, and the Web of Science electronic databases. Consequently, a meta-analysis was conducted with STATA software, using summary odds ratios (OR) and a 95% confidence interval (CI). RESULTS: Overall, there was no significant difference between MDR1 C3435T polymorphism and the eradication rate of H. pylori in the entire genetic model, irrespective of the PPI used. Furthermore, in Asian populations, the TT genotype decreased H. pylori eradication (TT vs CT+CC: OR=0.411, 95% CI = 0.280-0.602, P = 0.000). In addition, a significantly low eradication rate was observed in a recessive model, in which either lansoprazole (TT vs CT+CC: OR = 0.305, 95% CI = 0.184-0.504, P = 0.000) or omeprazole (TT vs CT+CC: OR = 0.229, 95% CI = 0.069-0.763, P = 0.016) was taken, in a subanalysis of individual PPIs. In the analyses that were stratified by disease type, no significant difference was observed in the peptic ulcer group and the combined diseases subgroup. CONCLUSION: This meta-analysis indicated that the TT genotype of the MDR1 C3435T polymorphism decreased H. pylori eradication in Asian populations and was also associated with a low cure rate of H. pylori in patients taking lansoprazole- and omeprazole-based triple therapies. However, future studies using larger sample sizes are required. PMID- 28353594 TI - Does the pancreatic volume reduction rate using serial computed tomographic volumetry predict new onset diabetes after pancreaticoduodenectomy? AB - Volume reduction of the pancreatic tissues following a pancreatectomy can lead to the deterioration of glucose homeostasis. This is defined as pancreatogenic diabetes mellitus (DM). The objective of this study was to investigate the occurrence of new-onset DM (NODM) and evaluate the risk factors, including the pancreas volume reduction rate in patients undergoing pancreaticoduodenectomy (PD).Sixty-six patients without preoperative DM underwent PD for periampullary tumors between August 2007 and December 2012 and were included in this analysis. These patients underwent follow-up tests and abdominal computed tomography (CT) scan 7 days, 6 months, 12 months, 24 months, and 36 months after the operation. The pancreas volume reduction rate was calculated by CT volumetry. The patients were divided into 2 groups according to the postoperative development of DM.After PD, newly diagnosed DM occurred in 16 patients (24.2%). The incidence of DM was highest among patients with carcinomas with an advanced T stage. The pancreatic volume reduction rate after 6 and 12 months in the NODM group was significantly higher than the normal glucose group in the univariate analysis. In the multivariate analysis, the pancreatic volume reduction rate 6 months after PD was the only significant predictive factor for the development of NODM (P = 0.002).This study suggests that the pancreatic volume reduction rate 6 months after PD was the only significant predictive factor for the development of NODM. CT volumetry of the pancreas may be useful as a predictor of NODM after PD. PMID- 28353596 TI - Adult-onset hypophosphatemic osteomalacia associated with Sjogren syndrome: Clinical case report. AB - RATIONALE: Hypophosphatemic osteomalacia (HO) is a metabolic bone disease, exhibiting different etiologies such as genetic mutation, tumor induction, dysimmunity, or renal disease. Sjogren's syndrome (SS) is a connective tissue disorder commonly involving exocrine glands; however kidney involvement is also encountered, leading to abnormal phosphorus metabolism, even HO. PATIENT CONCERNS: A 47-year-old female patient presented progressively worsening pain in the chest wall, back and bilateral lower extremities as well as muscle weakness was referred to our department. DIAGNOSES, INTERVENTIONS AND OUTCOMES: Due to the laboratory test results, radiographic findings and pathologic results, she was diagnosed with adult-onset HO associated with SS. She was then treated with alkalinization, steroids, neutral phosphate, calcium supplements together with activated vitamin D. So far, she recovered uneventfully with relieved pain and increased serum phosphorus level. LESSONS: HO may be secondary to renal tubular acidosis of SS patients, and it might be a diagnostic challenge when the kidney involvement in SS is latent and precede the typical sicca symptoms. PMID- 28353595 TI - Eotaxin and IL-4 levels are increased in induced sputum and correlate with sputum eosinophils in patients with nonasthmatic eosinophilic bronchitis. AB - Nonasthmatic eosinophilic bronchitis (NAEB) is characterized by chronic cough and airway eosinophilic inflammation. Airway and systemic inflammation cytokine profile have not been comprehensively described in patients with NAEB.The aim of the study was to identify the cytokine profile in sputum and serum of NAEB patients. Furthermore, the relationship between cytokines and clinical features would be evaluated.Induced sputum and serum were collected from untreated NAEB patients and healthy subjects. The cytokine profile in sputum and serum was analyzed by a bead-based multiplex cytokine assay including 21 cytokines.The levels of EGF, eotaxin, GM-CSF, GRO, IFN-gamma, IL-1beta, IL-4, IL-6, IL-17A, IP 10, MIP-1alpha, and TNF-alpha in sputum were significantly higher in NAEB patients than that in healthy subjects (all P < 0.05). Values of area under the receiver operating characteristic curve (AUROC) of these cytokines were all above 0.750. The concentrations of eotaxin and IL-4 were positively correlated with sputum eosinophil percentage (r = 0.726, P = 0.002; r = 0.511, P = 0.043; respectively). No significant correlations between other cytokines (EGF, GM-CSF, GRO, IFN-gamma, IL-1beta, IL-6, IL-17A, IP-10, MIP-1alpha, and TNF-alpha) in sputum and sputum eosinophil percentage were found. The level of IL-4 in serum was slightly higher in NAEB patients than in healthy subjects. However, there was no correlation between serum IL-4 levels and sputum eosinophil percentage.We identified the cytokine profile in sputum and serum from NAEB patients. Sputum eotaxin and IL-4 could have the potential to become the biomarkers for NAEB and might be useful to assist in the diagnosis of NAEB. PMID- 28353597 TI - Ovarian response prediction in controlled ovarian stimulation for IVF using anti Mullerian hormone in Chinese women: A retrospective cohort study. AB - The predictive value of anti-Mullerian hormone (AMH) in Chinese women undergoing in vitro fertilization (IVF) treatment is data deficient. To determine the attributes of AMH in IVF, oocyte yield, cycle cancellation, and pregnancy outcomes were analyzed. All patients initiating their first IVF cycle with gonadotropin-releasing hormone agonist treatment in our center from October 2013 through December 2014 were included, except patients diagnosed with polycystic ovarian syndrome. Serum samples collected prior to IVF treatment were used to determine serum AMH levels. A total of 4017 continuous cycles were analyzed. The AMH level was positively correlated with the number of oocytes retrieved. Overall, AMH was significantly correlated with risk of cycle cancellation, poor ovarian response (POR, 3, or fewer oocytes retrieved) and high response (>15 oocytes), with an area under the curve (AUC) of 0.83, 0.89, and 0.82 respectively. An AMH cutoff of 0.6 ng/mL had a sensitivity of 54.0% and a specificity of 90.0% for the prediction of cycle cancellation, and cutoff of 0.8 ng/mL with a sensitivity of 55.0% and a specificity of 94.0% for the prediction of POR. Compared with AMH >2.0 ng/mL, patients with AMH < 0.6 ng/mL had a 53.6 fold increased risk of cancellation (P < 0.001), and AMH <0.80 ng/mL were 17.5 times more likely to experience POR (P < 0.001). However, AMH was less predictive of pregnancy and live birth, with AUCs of 0.55 and 0.53, respectively. Clinical pregnancy rate, ongoing pregnancy rate, and live birth rate per retrieval according to the AMH level (<=0.40, 0.41-0.60, 0.61-0.80, 0.81-1.00, 1.01-1.50, 1.51-2.00, and >2.00 ng/mL) showed no significant differences. Even with AMH<=0.4 ng/mL, 50.0% of all the patients achieved pregnancy and 34.8% of patients achieved live birth after transfer. Our results suggested that AMH is a fairly robust metric for the prediction of cycle cancellation and oocyte yield for Chinese women, but it is a relatively poor test for prediction of pregnancy outcomes. Patients with low levels of AMH still can achieve reasonable treatment outcomes and low AMH levels in isolation do not represent an appropriate marker for withholding fertility treatment. PMID- 28353598 TI - Increase in the prevalence of arthritis in adulthood among adults exposed to Chinese famine of 1959 to 1961 during childhood: A cross-sectional survey. AB - The developmental origins hypothesis postulates that under-nutrition in the early stage of life is associated with an increased risk of disease in adulthood. This study aimed to examine the association of exposure to the Chinese famine of 1959 to 1961 in early life with the risk of arthritis in adulthood.From July to September 2009, the study adopted multistage stratified random sampling cross sectional survey to recruit 1224 eligible adults in Chongqing. Famine exposure groups were categorized into 3 groups: (1) childhood exposure, (2) fetal exposure, and (3) nonexposure. Self-reported arthritis of physician diagnosis was obtained. A total of 1224 eligible respondents were interviewed, including 299 individuals exposed during childhood, 455 exposed when fetal, and 470 without exposure.The prevalence of arthritis in adulthood among individuals exposed to famine during childhood was significantly higher than those not exposed (17.39% vs 11.28%, odds ratio [OR] = 1.573 with a 95% confidence interval of [CI] [1.020, 2.424]). Persons exposed to famine during the fetal period did not significantly contribute to a higher rate of arthritis in adulthood than those who were not exposed to famine (13.19% vs 11.28%, OR = 1.072, 95% CI = 0.713, 1.613). In addition, education level, the average monthly income, sleep status, and satisfaction of the present living condition were associated with the risk of arthritis in adulthood.Exposure to the Chinese famine during childhood may be associated with an increased risk of arthritis in adulthood. This study suggests that early life nutrition may have an effect on the risk of arthritis in adulthood. PMID- 28353599 TI - Glioblastoma multiforme in conus medullaris with intracranial metastasis after postoperative adjuvant therapy. AB - Spinal glioblastoma multiforme is not common among spinal cord tumors. According to our literature review, only 27 cases originating from the conus medullaris were reported. We herein reported a case of a 10-year-old child diagnosed with glioblastoma multiforme. The patient received adjuvant radiotherapy and standard temozolomide chemotherapy after total excision. Intracranial lesions were found 1 month after postoperative adjuvant therapy. We described the clinical characteristics and postoperative therapy of the patient, and reviewed all of the published cases of conus medullaris glioblastoma. Location, age, leptomeningeal spread, and secondary hydrocephalus may be predictive factors. Immunohistochemical factors such as p53 and Ki-67 are also important. Combined treatment of surgery and postoperative adjuvant therapy is commonly used, but is controversial. PMID- 28353600 TI - Influence of gum-chewing on postoperative bowel activity after laparoscopic surgery for gastric cancer: A randomized controlled trial. AB - BACKGROUND: In some studies, gum-chewing was demonstrated to have a beneficial effect on resumption of bowel function; however, other contradictory findings in other studies refute the effects of gum-chewing on peristaltic movements and digestive system stimulation. In addition, most previous studies were after colorectal or gynecology surgery, whereas few reports focused on the effect of gum-chewing after gastrectomy. The aim of this randomized controlled trial was to assess the effectiveness of gum-chewing on postoperative bowel function in patients who had undergone laparoscopic gastrectomy. METHODS: From March 2014 to March 2016, 75 patients with gastric cancer received elective laparoscopic surgery in Shanghai Tongji hospital and were postoperatively randomly divided into 2 groups: 38 in a gum-chewing (Gum) group and 37 in a control (No gum) group. The patients in the Gum group chewed sugarless gum 3 times daily, each time for at least 15 minutes, until the day of postoperative exhaust defecation. RESULTS: The mean time to first flatus (83.4 +/- 35.6 vs. 79.2 +/- 24.2 hours; P = 0.554) and the mean time to first defecation (125.7 +/- 41.2 vs. 115.4 +/- 34.2 hours; P = 0.192) were no different between the no gum and Gum groups. There was also no significant difference in the incidence of postoperative ileus (P = 0.896) and postoperative hospital stay (P = 0.109) between the 2 groups. The postoperative pain score at 48 hours (P = 0.032) in the Gum group was significantly higher than in the no gum group. There was no significant difference between the 2 groups in regards to patient demographics, comorbidities, duration of surgery, complications, and nausea/vomiting score. CONCLUSION: Gum-chewing after laparoscopic gastrectomy did not hasten the return of gastrointestinal function. In addition, gum-chewing may increase patient pain on the second postoperative day. PMID- 28353601 TI - Urethral hemangioma in a prepubertal female patient: Report of a rare case. AB - RATIONALE: Urethral hemangiomas commonly occur in men or elderly women. We presented a rare case of urethral hemangioma in a prepubertal female patient. PATIENTS CONCERNS: An 8-year-old girl had the complaints of bloody staining of clothing, a foul perineal odor, and urethral pain. She was brought to our genitourinary outpatient department for survey and a single, 1-cm compressible reddish nodule at the 10-2 o'clock position in the distal urethra was found. DIAGNOSES: Urethral hemangioma in a prepubertal girl was diagnosed after excision of the urethral nodule. INTERVENTIONS: Excision with 8 "stay" sutures in the protruding urethral mucosa was performed. OUTCOMES: Normal micturition without symptom recurrence was noted at the 3-month follow-up. LESSONS: Urethral hemangioma is also found in prepubertal female patient. Increased physician awareness and early recognition of a urethral hemangioma can avoid unnecessary examinations and patient anxiety. The procedure of excision with 8 "stay" sutures in the protruding urethral mucosa facilitates mobilization from the distal urethra and provides a good surgical view of abnormal proliferative blood vessels. Therefore, the lesion can be removed as clean as possible. PMID- 28353602 TI - Association between genetic polymorphism of telomere-associated gene ACYP2 and the risk of HAPE among the Chinese Han population: A Case-control study. AB - High-altitude pulmonary edema (HAPE) is a hypoxia-induced, life-threatening, pulmonary edema, which is characterized by exaggerated pulmonary hypertension caused by stress failure. ACYP2 was found to associated with telomere length, the aim of this study was to identify whether ACYP2 polymorphisms increase or decrease HAPE risk in the Chinese Han individuals.In present study, we have genotyped 7 single-nucleotide polymorphisms (SNPs) in ACYP2 to determine the haplotypes in a case-control study with 265 HAPE patients and 303 healthy individuals. Genotypes were determined using the Sequenom MassARRAY method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression with adjustment for gender and age. We found 3 SNPs yielded significant evidence for association with HAPE risk which had not been investigated before. Rs6713088 was found to have a 1.85- and 1.30-fold increased risk of HAPE in the recessive and additive model. The GT of rs843752 also conferred an increased risk of HAPE (GT/TT: OR = 1.51, 95% CI: 1.05-2.16, P = 0.026) and the genotype frequency distributions of rs843752 had significant difference between cases and controls. The CC genotype of rs17045754 had a protect effect on HAPE patients, and it was found to have a 0.29-fold reduced risk of HAPE in the recessive model.Although additional, larger population-based studies are needed to confirm these findings, our study shed light on the association between ACYP2 variant and HAPE risk in Han Chinese population for the first time. PMID- 28353603 TI - Facial flushing after alcohol consumption and the risk of cancer: A meta analysis. AB - BACKGROUND: The association between facial flushing after alcohol consumption and the risk of cancer remains controversial. The aim of this study was to evaluate the relation between facial flushing and cancer risk. METHODS: PubMed, EMBASE, and Cochrane Library were searched for relevant literature. The patients' baseline characteristics and estimated risks were extracted. Odds ratios (ORs) with 95% confidence intervals (CIs) were pooled to estimate the risk of facial flushing in cancer, and subgroup analysis was performed. RESULTS: Ten studies with 89,376 participants from East Asia were included. The pooled OR of facial flushing in all cancers was 1.43 (95% CI, 1.08-1.91), with the pooled ORs of 1.94 (95% CI, 1.33-2.83) and 0.95 (95% CI, 0.80-1.12) in men and women, respectively. The pooled ORs were also estimated in different cancer types. CONCLUSION: Our results showed that facial flushing response to alcohol was associated with higher cancer risk in men in East Asia, especially in esophageal squamous cell carcinoma, yet facial flushing was not significantly associated with cancer risk among women. PMID- 28353604 TI - A case report of PVOD patient combined with pulmonary embolism: Anticoagulation or not? AB - RATIONALE: Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary arterial hypertension (PAH). Oral anticoagulation is confined to patients with idiopathic PAH (IPAH), but no oral anticoagulation has been recommended for PVOD, because occult pulmonary hemorrhage was a common finding in PVOD. PATIENT CONCERNS: We report a case of PVOD, who was misdiagnosed as IPAH for 5 years with worsening dyspnea and two episodes of pulmonary embolism (PE). DIAGNOSES: He was confirmed as PVOD combined with PE by biopsy of the explanted lung specimen. INTERVENTIONS: He took oral anticoagulation, warfarin, to treat his first-time PE in July 2010, and his disease was kept stable for about 4 years, until he discontinued the anticoagulation therapy by himself sometime in 2014. Later on, a life-threatening PE recurred in January 2015, so he resumed the anticoagulation therapy. OUTCOMES: Fortunately, the bilateral sequential lung transplantation that was performed in July 2015 in time saved his life. He has been living well without dyspnea and the echocardiography showed the normalizations of the once increased pulmonary arterial pressure and the once enlarged right ventricle of his heart. In addition, to the best of my knowledge, he was the first PVOD patient receiving lung transplantation in China. LESSONS: We recommend that PVOD patients combined with PE should be treated with anticoagulation therapy indefinitely to prevent the recurrence of life-threatening PE until they get a chance for lung transplantation. PMID- 28353605 TI - Diabetes mellitus increases the risk of hepatocellular carcinoma in treatment naive chronic hepatitis C patients in China. AB - We investigated the link between diabetes mellitus (DM) and hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) risk in treatment-naive chronic hepatitis C (CHC) patients in China.To examine the association between DM and HCC, we conducted a case-control study of 300 Chinese CHC patients with HCC, compared to an age- and sex-matched control group of 517 CHC patients not diagnosed with HCC.We found that DM was more prevalent in the HCC patient group (18.7%) than in the CHC-only patient group (10.8%). We conducted logistic regression analyses adjusting for demographics features and other HCC risk factors and found that DM increased the risk of HCC development nearly 2-fold [adjusted odds ratio (AOR), 95% confidence interval (95% CI), 1.80 (1.17-2.75)]. Meanwhile, the proportion of HCC patients and CHC-only patients with liver cirrhosis were 79.3% and 46.2%, respectively, yielding an AOR of 4.62 (95% CI, 3.31-6.46). Multivariate analyses comparing the risk of HCV-related HCC development in DM patients with and without liver cirrhosis revealed that the estimated AOR (95% CI) for those with liver cirrhosis was 5.60 (2.25-13.96). However, the HCC risk decreased significantly with a later age of diabetes onset (AOR [95% CI], 0.94 [0.89-0.99]).DM was associated with an increased risk for HCC development in treatment-naive CHC patients in China. Furthermore, liver cirrhosis and an early DM diagnoses further increased the risks of HCC development in patients diagnosed with both CHC and DM. PMID- 28353606 TI - Prophylactic vacuum sealing drainage (VSD) in the prevention of postoperative surgical site infections in pediatric patients with contaminated laparotomy incisions. AB - Surgical site infection (SSI) continues to be an issue in abdominal surgery, especially for contaminated (class III) and dirty-infected (class IV) wounds. Vacuum sealing drainage (VSD) was reported effective in the management of various types of wounds or skin grafts. Our goal was to investigate the efficacy of prophylactic VSD to better orient their medicosurgical care of high-risk incisions following laparotomy in a pediatric population.A total of 331 pediatric patients with contaminated (class III) and dirty-infected (class IV) wounds following emergency laparotomy were retrospectively reviewed between January 2005 and January 2013. Among them, 111 cases were placed with prophylactic VSD when incisions were closed. Clinical outcomes, including, overall surgical site complication, device effectiveness, and mean postoperative LOS were evaluated based on VSD usage or not.VSD was applied for an average of 5.8 days (range, 5-7 days), with 3 to 15 mL sucked fluid. The overall SSIs rate was 3% for patients with prophylactic VSD and 17% for patients with convention dressing (OR, 0.27; 95% CI, 0.10-0.71, P = 0.004). In patients with prophylactic VSD, only 1 of 96 wound developed postoperative incision dehiscence, which is significant reduced compared with patients for conventional dressings (OR, 0.12; 95% CI, 0.01-0.95; P = 0.017) (Table 2). It also exhibited a decreased mean postoperative LOS (P < 0.001) for prophylactic VSD over conventional dressings.Our study demonstrated beneficial postoperative clinical effects of prophylactic VSD for high-risk laparotomy incisions following emergency laparotomy, such as shorter length of hospitalization, which may be attributed to the reduced overall SSIs rate. PMID- 28353607 TI - Specimen acquisition training with a new biosimulator in endobronchial ultrasound guided transbronchial needle aspiration. AB - Training for endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has focused on the procedure itself; however, the techniques for obtaining adequate sample are also important for achieving a pathological diagnosis as well as for molecular testing. The aim of this study was to evaluate the feasibility and efficacy of a biosimulator for training subjects in adequate sample acquisition during EBUS-TBNA.A total of 19 bronchoscopists voluntarily participated in this study. A biosimulator (ArtiCHEST, HARADA Corporation, Tokyo, Japan) was used for the training. After a 10-minute briefing, the first pass was performed by pairs of trainees. The trainees then received a 30-minute lecture that focused on the acquisition of samples using EBUS-TBNA. The trainees next performed their second pass under the supervision of the trainers. Each participant obtained a cytological smear that was coded and evaluated for quantity as well as quality by an independent cytotechnologist.The trainees had an average of 5.9 years of bronchoscopy experience. With regard to the quantity evaluation, 9 (47.4%) subjects sampled a greater number of lymphocytes on the second pass than on the first, whereas 2 were better on the first pass, and the others sampled roughly the same amount both times. With regard to the quality assessment, 9 (47.4%) subjects obtained better quality samples on the second pass, whereas the quality of the first and second pass was deemed to be roughly the same for the remaining subjects.A biosimulator can be used to train doctors in specimen acquisition and evaluate their skills with sampling using EBUS-TBNA. PMID- 28353608 TI - Chemotherapy-induced prospective memory impairment in breast cancer patients with different hormone receptor expression. AB - This study aimed to investigate prospective memory impairment in patients with breast cancer with different expression of hormone receptors, including the estrogen receptor (ER) and the progesterone receptor (PR).A total of 120 patients with breast cancer who underwent chemotherapy following surgery were divided into 2 groups. The A group included 60 patients with ER/PR status, and the B group included 60 patients with ER/PR status. After 6 cycles of postoperative adjuvant chemotherapy, all patients were administered neuropsychological and prospective memory tests, such as the Mini-Mental State Examination (MMSE), verbal fluency test (VFT), and digit span test (DST), as well as examination of event-based prospective memory (EBPM) and time-based prospective memory (TBPM).As the neuropsychological background test results showed, there were no significant differences in MMSE, DST, and TBPM scores (*:P > 0.05) between patients with breast cancer in the ER/PR and ER/PR groups, while the VFT and EBPM scores were significantly greater in patients with breast cancer with ER/PR status than in those with ER/PR status (**: P < 0.01), indicating that patients with ER/PR status have significant impairment in EBPM, although not in TBPM.The results of the present study indicate that different hormone receptor expression in patients with breast cancer may be associated with heterogeneity of chemotherapy-induced prospective memory impairment. PMID- 28353609 TI - Assessing practical skills in cardiopulmonary resuscitation: Discrepancy between standard visual evaluation and a mechanical feedback device. AB - This paper aims to analyze agreement in the assessment of external chest compressions (ECC) by 3 human raters and dedicated feedback software.While 54 volunteer health workers (medical transport technicians), trained and experienced in cardiopulmonary resuscitation (CPR), performed a complete sequence of basic CPR maneuvers on a manikin incorporating feedback software (Laerdal PC v 4.2.1 Skill Reporting Software) (L), 3 expert CPR instructors (A, B, and C) visually assessed ECC, evaluating hand placement, compression depth, chest decompression, and rate. We analyzed the concordance among the raters (A, B, and C) and between the raters and L with Cohen's kappa coefficient (K), intraclass correlation coefficients (ICC), Bland-Altman plots, and survival-agreement plots.The agreement (expressed as Cohen's K and ICC) was >=0.54 in only 3 instances and was <=0.45 in more than half. Bland-Altman plots showed significant dispersion of the data. The survival-agreement plot showed a high degree of discordance between pairs of raters (A-L, B-L, and C-L) when the level of tolerance was set low.In visual assessment of ECC, there is a significant lack of agreement among accredited raters and significant dispersion and inconsistency in data, bringing into question the reliability and validity of this method of measurement. PMID- 28353610 TI - Association of high waist-to-height ratio with functional outcomes in patients with acute ischemic stroke: A report from the ACROSS-China study. AB - The aim of our study was to investigate the relationship between the waist-to height ratio (WHR) and all-cause mortality and functional outcomes after acute ischemic stroke in a prospective cohort study.A total of 2076 patients (36.66% females) with ischemic stroke were analyzed from ACROSS-China, which is a nationwide, prospective, hospital-based stroke registry aimed to detect the glucose abnormality in China. One-year follow-up evaluation was done by telephone interview. Outcome measures were all-cause mortality and functional outcome defined as modified Rankin score being 6 and from 0 to 6, respectively. We identified predictors for functional outcomes using logistic regression analysis, and mortality outcome using Cox proportional hazards model which incorporated covariates with P value of < 0.2 in the univariate analysis and those of clinical importance.The higher WHR was associated with worse functional outcome, but not predictive of the patients' mortality outcomes. Compared with the first quartile (<=0.48), the fourth quartile of the WHR was more likely to be associated with poor functional recovery (fourth quartile (>=0.56), OR = 1.38, CI: 1.08-1.77, P = 0.01; third quartile OR = 1.10, CI: 0.86-1.40, P = 0.45; second quartile OR = 1.05, CI: 0.83-1.33, P = 0.71).Our findings suggest that abdominal fat accumulation may be associated with functional recovery after stroke, and is not associated with mortality after stroke. Compared with the lowest quartile, the highest quartile of WHR at admission was possibly associated with worse postacute ischemic stroke functional recovery. PMID- 28353611 TI - Comparison of intra-articular lumbar facet joint pulsed radiofrequency and intra articular lumbar facet joint corticosteroid injection for management of lumbar facet joint pain: A randomized controlled trial. AB - BACKGROUND: This study aimed to demonstrate the effect of intra-articular (IA) lumbar facet joint (LFJ) pulsed radiofrequency (PRF) for the management of LFJ pain, and to compare the effect of IA LFJ PRF to IA corticosteroid injection (ICI). Pathology in the LFJ is a common source of lower back pain (LBP). It is responsible for chronic LBP in approximately 15% to 45% of patients. It has been reported that PRF stimulation can effectively reduce refractory joint pain. METHODS: Sixty patients with LFJ pain were recruited and randomly assigned to 1 of 2 groups: the IA PRF group and the ICI group. There were 30 patients in each group. At pretreatment, 2 weeks, 1, 3, and 6 months after treatment, we assessed the severity of LBP using a numeric rating scale (NRS). RESULTS: Compared with the pretreatment NRS scores, patients in both groups showed a significant decrease in NRS scores at 2 weeks, and 1, 3, and 6 months after each treatment. Between groups, changes in the NRS scores were significantly different over time. At 2 weeks and 1 month after each procedure, the NRS score after ICI was significantly lower than that after the PRF stimulation. However, at 3 and 6 months after the procedures, the decrements of NRS scores were not significantly different between the 2 groups. Six months after treatment, about half of patients in both groups reported successful pain relief (pain relief of >=50%). CONCLUSION: In the current study, both IA PRF stimulation and ICI into the LFJ significantly relieved LFJ pain. Their effects persisted for at least 6 months after the procedure. Thus, IA PRF is a useful therapeutic option for the management of LFJ pain. PMID- 28353612 TI - The effectiveness and safety of angiotensin-converting enzyme inhibition or receptor blockade in vascular diseases in patients with hemodialysis. AB - Patients with end-stage renal disease (ESRD) who are on hemodialysis have high risk of vascular diseases. Our study sought to examine whether angiotensin converting enzyme inhibitors (ACEIs) or angiotensin type 1 receptor blockers (ARBs) could reduce the frequencies of cardiovascular and cerebrovascular events in patients receiving hemodialysis using the medication possession ratio (MPR) method of analysis.This retrospective cohort study identified cases of ESRD with dialysis from the National Health Insurance Research Database between 1999 and 2006, and used Cox-regression methods to evaluate risk of poor outcomes. Primary outcomes, including death from any cause, and secondary outcomes, including admission for stroke, myocardial infarction, and heart failure, were examined.Compared to the nonuser group, the adjusted HRs for mortality of the nonadherence group and the adherence group were 0.81 (95% CI: 0.76-0.86) and 0.98 (95% CI: 0.86-1.13), respectively. Cardiovascular events were more frequent in patients with ESRD receiving ACEIs /ARBs than in nonusers. Compared with nonusers, the hazard of secondary outcome significantly increased in the nonadherence group or adherence group in 10 years follow-up.Compared with patients with diabetes or chronic kidney disease, patients on hemodialysis may not experience the same cardiovascular and cerebrovascular benefits from ACEIs/ARBs use. PMID- 28353613 TI - Severe pneumonia due to Nocardia otitidiscaviarum identified by mass spectroscopy in a cotton farmer: A case report and literature review. AB - RATIONALE: Nocardia species are aerobic saprophytic bacilli. Among Nocardia species, Nocardia otitidiscaviarum (N otitidiscaviarum) is rarely reported in pulmonary infection. PATIENT CONCERNS: We reported a case of N otitidiscaviarum pneumonia in a cotton farmer. DIAGNOSES: N otitidiscaviarum pneumonia was identified by mass spectroscopy. INTERVENTIONS: Combined treatments (amikacin, imipenem and trimethoprim-sulfamethoxazole) were administered after identification of N otitidiscaviarum. OUTCOMES: The patient eventually died from severe respiratory insufficiency in the hospital. LESSONS: Early precise diagnosis and prompt combined therapy are of vital importance in severe Nocardia pulmonary infection. PMID- 28353614 TI - Using health-system-wide data to understand hepatitis B virus prophylaxis and reactivation outcomes in patients receiving rituximab. AB - Hepatitis B virus (HBV) reactivation in the setting of rituximab use is a potentially fatal but preventable safety event. The rate of HBV screening and proportion of patients at risk who receive antiviral prophylaxis in patients initiating rituximab is unknown.We analyzed electronic health record (EHR) data from 2 health systems, a university center and a safety net health system, including diagnosis grouper codes, problem lists, medications, laboratory results, procedures codes, clinical encounter notes, and scanned documents. We identified all patients who received rituximab between 6/1/2012 and 1/1/2016. We calculated the proportion of rituximab users with inadequate screening for HBV according to the Centers for Disease Control guidelines for detecting latent HBV infection before their first rituximab infusion during the study period. We also assessed the proportion of patients with positive hepatitis B screening tests who were prescribed antiviral prophylaxis. Finally, we characterized safety failures and adverse events.We included 926 patients from the university and 132 patients from the safety net health system. Sixty-one percent of patients from the university had adequate screening for HBV compared with 90% from the safety net. Among patients at risk for reactivation based on results of HBV testing, 66% and 92% received antiviral prophylaxis at the university and safety net, respectively.We found wide variations in hepatitis B screening practices among patients receiving rituximab, resulting in unnecessary risks to patients. Interventions should be developed to improve patient safety procedures in this high-risk patient population. PMID- 28353615 TI - A new method for estimating the prevalence of clonorchiasis in Korea: A proposal to replace arbitrary riverside sampling. AB - South Korea presently uses an arbitrary sampling method to monitor the prevalence of Clonorchis sinensis infection in the endemic areas of the country. However, the present method is not standardized and focuses primarily on individuals who reside nearest to the mainstream river. We propose a new sampling method that combines cluster sampling with proportionate quota sampling to ensure that the entire endemic area is accurately represented. We tested the new method in Okcheon-gun, South Korea, and determined that the C sinensis infection prevalence (8.9%) in 2013 was higher than that (6.9%) estimated in 2012 when the arbitrary method was used. Additionally, no difference was observed in the prevalence based on the distance from the riverside areas, including branches and creeks, between the areas <1 and >1 km away from the riversides. Therefore, health authorities should place equal emphasis on all regions within the endemic areas. Based on the findings, we recommend the following: the clonorchiasis prevalence rate must be measured using probability sampling, (clear guidelines on survey coverage should be provided to include the riverside areas and all areas nearby branch streams, and regional cohorts should be created for continuous monitoring of prevalence rates across the region. PMID- 28353616 TI - Associations between polymorphisms in coagulation-related genes and venous thromboembolism: A meta-analysis with trial sequential analysis. AB - BACKGROUND: Recently, several studies showed that the polymorphisms in the coagulation-related genes might be associated with venous thromboembolism (VTE); however, the results were still controversial. We performed a meta-analysis with trial sequential analysis to investigate the associations between the endothelial cell-activated protein C receptor (EPCR) rs9574, F11 rs2289252, F11 rs2036914, FGG rs2066865, FGG rs1049636, CYP4V2 rs13146272, SERPINC1 rs2227589, and GP6 rs1613662 polymorphisms with the risk of VTE. METHODS: We searched both the common English-language databases and the Chinese literature databases. Two authors selected studies according to inclusion and exclusion criteria. Crude odds ratios with 95% confidence intervals (CI) were calculated to estimate the strength of this association. Between-study heterogeneity was assessed with the chi-square-based Q test and the I statistic. RESULTS: Overall, a total of 20 studies were included. The meta-analysis revealed that the F11 rs2289252, F11 rs2036914, FGG rs2066865, and CYP4V2 rs13146272 polymorphisms were closely related to the development of VTE in the white race under the best genetic models after multiple testing adjustments. The EPCR rs9574, FGG rs1049636, SERPINC1 rs2227589, and GP6 rs1613662 polymorphisms might be potential candidates in the pathogenesis of VTE, but trial sequential analyses and sensitivity analyses indicated that the evidences were limited. Larger scale studies were demanded to avoid false-positive outcomes. CONCLUSIONS: Finally, our study demonstrated the important role of rs2289252, rs2036914, rs2066865, and rs13146272 polymorphisms in the development of VTE in the white race. Rs9574, rs1049636, rs2227589 and rs1613662 polymorphisms might be risk factors of VTE. However, more studies involving diverse races are needed to probe the ethnic difference and the underlying mechanisms of significant associations. PMID- 28353617 TI - A step-by-step regressed pediatric kidney depth formula validated by a reasonable index. AB - In predicting pediatric kidney depth, we are especially interested in that the errors of most estimates are within a narrow range. Therefore, this study was intended to use the proportion of estimates within a range of -5 to 5 mm (P5 mm) to evaluate the formulas and tried to regress a kidney depth formula for children. The enrolled children aged from 1 to 19 years were randomly sampled into group A and group B (75% and 25% of all recruits, respectively). Using data of the group A, the test formula was regressed by nonlinear regression and subsequently Passing & Bablok regression, and validated in group B. The Raynaud, Gordon, Tonnesen, Taylor, and the test formulas were evaluated in the 2 groups. Accuracy was evaluated by bias, absolute bias, and P5 mm; and precision was evaluated by correlation coefficient. In addition, root-mean square error was used as a mixed index for both accuracy and precision. Body weight, height, and age did not have significant differences between the 2 groups. In the nonlinear regression, coefficients of the formula (kidney depth = a * weight/height + b * age) from group A were in narrower 95% confidence intervals. After the Passing & Bablok regression, biases of left and right kidney estimates were significantly decreased. In the evaluation of formulas, the test formula was obviously better than other formulas mentioned above, and P5 mm for left and right kidneys was about 60%. Among children younger than 10 years, P5 mm was even more than 70% for left and right kidney depths. To predict pediatric kidney depth, accuracy and precision of a step-by-step regressed formula were better than the 4 "standard" formulas. PMID- 28353618 TI - Relationship of active trigger points with related disability and anxiety in people with tension-type headache. AB - To investigate the differences in the presence of trigger points (TrPs) and their association with headache-related disability and mood disorders in people with frequent episodic tension-type headache (TTH) (FETTH) and chronic TTH (CTTH). One hundred twenty-two individuals with TTH participated. Clinical features of headache (i.e., intensity, duration, and frequency) were recorded on a headache diary. Headache-related disability was assessed with the Headache Disability Inventory, trait and state anxiety levels with State-Trait Anxiety Inventory, and depression with the Hospital Anxiety and Depression Scale. TrPs were bilaterally explored in the temporalis, masseter, suboccipital, upper trapezius, splenius capitis, and sternocleidomastoid muscles. Sixty-two (51%) patients were classified as FETTH, whereas 60 (49%) were classified as CTTH. Individuals with CTTH showed higher burden of headache and depression than FETTH (P < 0.001). Subjects with FETTH showed similar number of TrPs (total number: 5.9 +/- 3.1, active TrPs: 4.7 +/- 2.5, and latent TrPs: 1.2 +/- 1.9) than those with CTTH (total number: 5.7 +/- 3.2, active TrPs: 4.2 +/- 3.0, and latent TrPs: 1.5 +/- 1.8). The number of active TrPs was significantly associated with the burden of headache (r = 0.189; P = 0.037) and trait anxiety (r = 0.273; P = 0.005): the higher the number of active TrPs, the greater the physical burden of headache or the more the trait anxiety level. No association with the depression was observed. The presence of active TrPs in head and neck/shoulder muscles was similar between individuals with FETTH and CTTH and associated with the physical burden of headache and trait anxiety levels independently of the subgroup of TTH. PMID- 28353619 TI - Role of quantitative hepatitis B surface antigen in predicting inactive carriers and HBsAg seroclearance in HBeAg-negative chronic hepatitis B patients. AB - To evaluate quantitative hepatitis B surface antigen (qHBsAg) as a diagnostic marker for inactive carriers (ICs) and hepatitis B surface antigen (HBsAg) seroclearance in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients. We retrospectively studied 300 HBeAg-negative CHB patients with initial serum hepatitis B virus (HBV) Deoxyribonucleic acid (DNA) levels <2000 IU/mL. Serum HBV DNA and alanine aminotransferase (ALT) levels were monitored every 6 months for 24 months. ICs were identified as having persistent HBV DNA levels <2000 IU/mL and normal ALT levels, whereas active carriers (ACs) were identified as having HBV DNA levels >=2000 IU/mL, with or without elevated ALT levels. The serum qHBsAg level was defined at baseline and evaluated as a diagnostic predictor using a receiver-operating characteristic curve. The study group comprised 134 men and 166 women with a median age of 41.5 years. At baseline, 200 ICs displayed lower levels of qHBsAg (1492 IU/mL) compared with 100 ACs (2936 IU/mL) (P = 0.005). The qHBsAg level was independently associated with the IC state and HBsAg seroclearance. Baseline qHBsAg levels <1000 IU/mL and HBV DNA levels <2000 IU/mL, when detected simultaneously, allowed for identification of ICs with 41% sensitivity and 72% specificity. Fifteen patients (5%) displayed HBsAg seroclearance after 24 months. A qHBsAg cutoff value of <50 IU/mL provided 100% sensitivity and 92% specificity in predicting HBsAg seroclearance. The qHBsAg level at a single timepoint among HBeAg-negative CHB patients with low HBV DNA levels at baseline was not a predictive marker for ICs; however, it accurately predicted spontaneous HBsAg seroclearance at 24 months. PMID- 28353620 TI - Electrode Array Displacement into the Fallopian Canal in Revisions of Long standing Cochlear Implants. AB - OBJECTIVE: To describe extracochlear extension of revision cochlear implant arrays into the Fallopian canal. PATIENTS: Two adult patients with extension of revision cochlear implant arrays into the Fallopian canal. INTERVENTIONS: Computed tomography (CT), selective deactivation of non-functional electrodes. MAIN OUTCOME MEASURES: Facial nerve function, facial nerve stimulation, cochlear implant electrode position, radiography, functional hearing. RESULTS: Two patients presented with failure of their long-standing cochlear implants (CIs). One patient with presumed postviral hearing loss presented with declining function and increasing facial stimulation from an implant placed 30 years previous. A second with postmeningitic hearing loss presented with a draining mastoid fistula from an implant placed 7 years before. Both patients were reimplanted with minimal insertion resistance via the established electrode tract, yet demonstrated facial nerve stimulation during intraoperative telemetry and on device activation. Postoperative CTs of each patient showed exit of the electrode from the cochlea into the tympanic or labyrinthine Fallopian canal. Both patients can use their devices effectively with selective electrode deactivation. CONCLUSIONS: Our cases illustrate the potential association of long standing electrodes with otic capsule changes, allowing extracochlear malposition of subsequent arrays. This can occur despite apparently uneventful reinsertion of a flexible array without undue force. Previously reported histopathology confirms the potential for a reactive osteitis from arrays that may contribute to this phenomenon. Intraoperative facial stimulation with neural telemetry testing can raise suspicion of a malpositioned array involving the Fallopian canal. Such cases can be effectively managed with selective deactivation of malpositioned electrode contacts. PMID- 28353621 TI - The Effect of Soft Tissue Infections on Device Performance in Adult Cochlear Implant Recipients. AB - OBJECTIVE: The aim of this study was to examine the effect of cochlear implant (CI) site infection and its subsequent management on CI mapping and CI performance. Risk factors for CI infections and pathogens causing infections were reviewed. Treatment options for CI infections were examined. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Adult patients with a significant CI soft tissue infection from the Northern Cochlear Implant Programme, New Zealand over a 10-year period (August 2004 until August 2014). INTERVENTION: Patients were treated with intravenous antibiotics, washout and debridement or ex-plantation and reimplantation of CI. MAIN OUTCOME MEASURE: CI mapping results and implant performance before and after management of CI infections were compared. RESULTS: There were nine CI infections. Most patients (7/9) were treated with washout and debridement. One patient required removal of the CI and one patient was deemed medically unfit for a general anaesthetic and was managed conservatively with antibiotics alone. Seven patients received long term antibiotics. Four patients were able to maintain CI performance after salvage treatment of the CI infection. Three patients had poorer CI performance after salvage treatment. One patient had reimplantation and became a nonuser due to only partial reinsertion. CONCLUSION: The pathophysiology of CI infections is complex. Infections can occur many years after CI surgery. The most common bacteria identified were Staphylococcus aureus, Pseudomonas aeruginosa, and skin commensals. Biofilms are present around implants that are removed from patients and biofilms may play a role in CI infections, but the mechanism of infection is not clear. PMID- 28353622 TI - Hearing Preservation Outcomes for 139 Cochlear Implant Recipients Using a Thin Straight Electrode Array. AB - OBJECTIVE: To assess the hearing preservation outcomes in a large group of adult cochlear implant recipients implanted with a thin straight electrode array using atraumatic surgical techniques. Factors affecting hearing preservation will be investigated. STUDY DESIGN: Prospective cohort study undertaken at the Royal Victorian Eye and Ear Hospital in Melbourne, Australia from December 2010 to May 2015. SETTING: Tertiary academic hospital. PATIENTS: One hundred thirty-nine adults undergoing cochlear implantation (CI). MAIN OUTCOME MEASURE: Primary outcome measure of interest was pre and postoperative pure-tone audiometry. RESULTS: Median low-frequency hearing change for the whole group of 139 recipients was -22.5 dB at the 3 months postop point. Eighty-six participants had functional preoperative low-frequency hearing (<=70 dB average at 250 and 500 Hz). Of these, 90.7% retained measureable hearing at 3 months postimplant. 39.5% of this original 86 participants retained functional hearing at 3 months postimplant. At 12 months postimplant, those who retained functional hearing at 3 months had no significant change in hearing. The group who lost functional hearing continued to have a significant deterioration in low-frequency hearing. Degree of hearing loss preimplant was identified as a predictor for the preservation of hearing postoperatively. CONCLUSION: Preservation of hearing is possible following atraumatic cochlear implant surgery with a thin straight electrode array. The amount of hearing preserved seems to be variable, and factors related to this variability are not yet known. The results of the present study suggest preoperative low-frequency hearing at or better than 45 dB may be related to preservation of functional hearing. PMID- 28353623 TI - Preoperative CT Assessment in CI: Dehiscence of the Labyrinthine Segment of the Facial Nerve Causing Facial Nerve Stimulation. PMID- 28353624 TI - Cochlear Implants Versus Hearing Aids in a Middle-Income Country: Costs, Productivity, and Quality of Life. AB - OBJECTIVE: In Colombia there are three main treatment approaches for bilateral profound sensorineural hearing loss, also known as profound deafness (PD): cochlear implants (CI), hearing aids (HA), and no treatment (NT). The objective of this study is to determine the optimal treatment approach for PD in terms of productivity and cost-effectiveness. STUDY DESIGN: Hearing levels and SES data were obtained from audiometric tests conducted on 100 patients with CI. For each treatment approach, productivity and cost-effectiveness assessments were estimated using influence diagrams and Monte Carlo simulations. Productivity was calculated as the net present value of a patient's lifetime income divided by total health-related and educational costs. For the CI and HA, the cost effectiveness indicator was calculated as quality-adjusted life-years (QALYs) gained in comparison with the NT approach divided by the total cost of the treatment option. RESULTS: The results for the CI, the HA, and NT in terms of productivity ratio were 1.53, 0.94, and 1.47, respectively. Patients using CI had a gain of 5.7 QALYs, whereas patients using HA had a gain of 4.6 QALYs. The results for the CI and the HA in terms of cost-effectiveness were $15,169 and $15,430 per QALY, respectively. CONCLUSION: The CI was found to be the optimal treatment for PD, as it was the most efficient and cost-effective in terms of improving patients' productivity and quality of life. We observed that children who had received CI developed hearing and speech abilities that contributed to their productivity and quality of life to a greater extent than those with HA. PMID- 28353626 TI - Retraction: Khan et al. Structural and Magnetic Response in Bimetallic Core/Shell Magnetic Nanoparticles. Nanomaterials 2016, 6, 72. AB - It has come to our attention that Figure 3 of the title paper [1] contains unacceptable levels of image manipulation and thus does not provide firm evidence of the particles reported [...]. PMID- 28353627 TI - Effects of Storage Time on Glycolysis in Donated Human Blood Units. AB - Background: Donated blood is typically stored before transfusions. During storage, the metabolism of red blood cells changes, possibly causing storage lesions. The changes are storage time dependent and exhibit donor-specific variations. It is necessary to uncover and characterize the responsible molecular mechanisms accounting for such biochemical changes, qualitatively and quantitatively; Study Design and Methods: Based on the integration of metabolic time series data, kinetic models, and a stoichiometric model of the glycolytic pathway, a customized inference method was developed and used to quantify the dynamic changes in glycolytic fluxes during the storage of donated blood units. The method provides a proof of principle for the feasibility of inferences regarding flux characteristics from metabolomics data; Results: Several glycolytic reaction steps change substantially during storage time and vary among different fluxes and donors. The quantification of these storage time effects, which are possibly irreversible, allows for predictions of the transfusion outcome of individual blood units; Conclusion: The improved mechanistic understanding of blood storage, obtained from this computational study, may aid the identification of blood units that age quickly or more slowly during storage, and may ultimately improve transfusion management in clinics. PMID- 28353628 TI - PI3K Signaling in Tissue Hyper-Proliferation: From Overgrowth Syndromes to Kidney Cysts. AB - The members of the PhosphoInositide-3 Kinase (PI3K) protein family are well-known regulators of proliferative signals. By the generation of lipid second messengers, they mediate the activation of AKT/PKB (AKT) and mammalian Target Of Rapamycin (mTOR) pathways. Although mutations in the PI3K/AKT/mTOR pathway are highly characterized in cancer, recent evidence indicates that alterations in the proliferative signals are major drivers of other diseases such as overgrowth disorders and polycystic kidney disease. In this review, we briefly summarize the role of the PI3K/AKT/mTOR pathway in cell proliferation by comparing the effect of alterations in PI3K enzymes in different tissues. In particular, we discuss the most recent findings on how the same pathway may lead to different biological effects, due to the convergence and cooperation of different signaling cascades. PMID- 28353629 TI - Imprinting of Microorganisms for Biosensor Applications. AB - There is a growing need for selective recognition of microorganisms in complex samples due to the rapidly emerging importance of detecting them in various matrices. Most of the conventional methods used to identify microorganisms are time-consuming, laborious and expensive. In recent years, many efforts have been put forth to develop alternative methods for the detection of microorganisms. These methods include use of various components such as silica nanoparticles, microfluidics, liquid crystals, carbon nanotubes which could be integrated with sensor technology in order to detect microorganisms. In many of these publications antibodies were used as recognition elements by means of specific interactions between the target cell and the binding site of the antibody for the purpose of cell recognition and detection. Even though natural antibodies have high selectivity and sensitivity, they have limited stability and tend to denature in conditions outside the physiological range. Among different approaches, biomimetic materials having superior properties have been used in creating artificial systems. Molecular imprinting is a well suited technique serving the purpose to develop highly selective sensing devices. Molecularly imprinted polymers defined as artificial recognition elements are of growing interest for applications in several sectors of life science involving the investigations on detecting molecules of specific interest. These polymers have attractive properties such as high bio-recognition capability, mechanical and chemical stability, easy preparation and low cost which make them superior over natural recognition reagents. This review summarizes the recent advances in the detection and quantification of microorganisms by emphasizing the molecular imprinting technology and its applications in the development of sensor strategies. PMID- 28353630 TI - Detection of 17 beta-Estradiol in Environmental Samples and for Health Care Using a Single-Use, Cost-Effective Biosensor Based on Differential Pulse Voltammetry (DPV). AB - Environmental estrogen pollution and estrogen effects on the female reproductive system are well recognized scientifically. Among the estrogens, 17 beta-estradiol is a priority in environmental estrogen pollution, and it is also a major contributor to estrogen which regulates the female reproductive system. 17 beta estradiol is carcinogenic and has a tumor promotion effect relating to breast cancer, lung cancer and others. It also affects psychological well-being such as depression, fatigue and others. Thus, a simple method of detecting 17 beta estradiol will be important for both environmental estrogen pollution and health care. This study demonstrates a single-use, cost-effective 17 beta-estradiol biosensor system which can be used for both environmental and health care applications. The bio-recognition mechanism is based on the influence of the redox couple, K3Fe(CN)6/K4Fe(CN)6 by the interaction between 17 beta-estradiol antigen and its alpha-receptor (ER-alpha; alpha-estrogen antibody). The transduction mechanism is an electrochemical analytical technique, differential pulse voltammetry (DPV). The levels of 17 beta-estradiol antigen studied were between 2.25 pg/mL and 2250 pg/mL; Phosphate buffered saline (PBS), tap water from the Cleveland regional water district, and simulated urine were used as the test media covering the potential application areas for 17 beta-estradiol detection. An interference study by testosterone, which has a similar chemical structure and molecular weight as those of 17 beta-estradiol, was carried out, and this 17 beta-estradiol biosensor showed excellent specificity without any interference by similar chemicals. PMID- 28353631 TI - Characterization and Potential Antitumor Activity of Polysaccharide from Gracilariopsis lemaneiformis. AB - Substances with valuable antitumor properties have been identified in many marine algae, including an edible polysaccharide from the marine alga Gracilariopsis lemaneiformis (PGL). We previously reported transcriptome profiling data showing that PGL induced transcriptional alterations generate anti-lung cancer activity. To identify how PGL is detrimental to tumors, we purified PGL to characterize its chemical composition, molecular weight, and sugar and protein content and investigated its antitumor activity. We demonstrated that PGL exerted its antitumor activities by modulating cell viability, morphology, apoptosis, and the apoptosis-related Fas/FasL signaling pathway in the human lung cancer cell line A549, the gastric cancer cell line MKN28, and the mouse melanoma cell line B16. Our data provide the first evidence that PGL inhibits cell proliferation by inducing apoptosis, which is largely mediated by Fas/FasL in cancer cells, suggesting that PGL might be a novel therapeutic agent against cancer. PMID- 28353632 TI - Attenuation of Bleomycin-Induced Pulmonary Fibrosis in Rats with S-Allyl Cysteine. AB - Pulmonary fibrosis is a complex disease with high mortality and morbidity. As there are currently no effective treatments, development of new strategies is essential for improving therapeutic outcomes. S-allyl cysteine (SAC) is a constituent of aged garlic extract that has demonstrated efficacy as an antioxidant and anti-inflammatory agent. The current study examines the effects of SAC on pulmonary fibrosis induced by a single intratracheal instillation of bleomycin (2.5 mg/kg). SAC was administered to rats as 0.15% SAC-containing diet from seven days prior to instillation up until the conclusion of the experiment (14 days post-instillation). SAC significantly reduced collagen mRNA expression and protein deposition (33.3 +/- 2.7 MUg/mg and 28.2 +/- 2.1 MUg/mg tissue in vehicle- and SAC-treated rats, respectively), and decreased fibrotic area, as assessed histologically. In the rats' lungs, SAC also attenuated the increased expression of transforming growth factor-beta1 (TGF-beta1), a central regulator of myofibroblast recruitment, activation, and differentiation. While bleomycin instillation increased the number of myofibroblasts within the lung mesenchymal area, this change was significantly reduced by SAC treatment. SAC may exert efficacy as an anti-fibrotic by attenuating myofibroblast differentiation through TGF-beta1-mediated fibroproliferative processes. Thus, our results indicate SAC may be useful for the prevention or treatment of pulmonary fibrosis. PMID- 28353633 TI - Another Look at Pyrroloiminoquinone Alkaloids-Perspectives on Their Therapeutic Potential from Known Structures and Semisynthetic Analogues. AB - This study began with the goal of identifying constituents from Zyzzya fuliginosa extracts that showed selectivity in our primary cytotoxicity screen against the PANC-1 tumor cell line. During the course of this project, which focused on six Z. fuliginosa samples collected from various regions of the Indo-Pacific, known compounds were obtained consisting of nine makaluvamine and three damirone analogues. Four new acetylated derivatives were also prepared. High-accuracy electrospray ionization mass spectrometry (HAESI-MS) m/z ions produced through MS2 runs were obtained and interpreted to provide a rapid way for dereplicating isomers containing a pyrrolo[4,3,2-de]quinoline core. In vitro human pancreas/duct epithelioid carcinoma (PANC-1) cell line IC50 data was obtained for 16 compounds and two therapeutic standards. These results along with data gleaned from the literature provided useful structure activity relationship conclusions. Three structural motifs proved to be important in maximizing potency against PANC 1: (i) conjugation within the core of the ABC-ring; (ii) the presence of a positive charge in the C-ring; and (iii) inclusion of a 4-ethyl phenol or 4-ethyl phenol acetate substituent off the B-ring. Two compounds, makaluvamine J (9) and 15-O-acetyl makaluvamine J (15), contained all three of these frameworks and exhibited the best potency with IC50 values of 54 nM and 81 nM, respectively. These two most potent analogs were then tested against the OVCAR-5 cell line and the presence of the acetyl group increased the potency 14-fold from that of 9 whose IC50 = 120 nM vs. that of 15 having IC50 = 8.6 nM. PMID- 28353634 TI - Vitamin D Insufficiency Exacerbates Adipose Tissue Macrophage Infiltration and Decreases AMPK/SIRT1 Activity in Obese Rats. AB - Obesity is recognized as a state of chronic low-grade systemic inflammation due to adipose tissue macrophage infiltration and production of proinflammatory adipokines. Decreased vitamin D status is associated with obesity. The specific aim of the present study is to investigate the effects of vitamin D on obesity induced adipose tissue inflammation. Male Sprague-Dawley rats were randomized and fed a normal diet (NOR, 1000 IU vitamin D/kg diet), a 45% high-fat diet (HF, 1000 IU vitamin D/kg diet), or a 45% high-fat diet containing 25 IU vitamin D/kg diet (HF+LVD) for 12 weeks. The vitamin D-insufficient diet (HF+LVD) led to vitamin D inadequacy as determined by serum 25(OH)D level, 68.56 +/- 7.97 nmol/L. The HF+LVD group exacerbated HF-increased adipocyte size, adipogenic gene expression of PPARgamma, adipose tissue macrophage recruitment, and proinflammatory cytokine IL-6 and TNFalpha levels in epididymal white adipose tissue. In addition, vitamin D insufficiency significantly decreased mRNA levels of beta-oxidation-related genes such as CPT1alpha, PGC1alpha, PPARalpha, VLCAD, LCAD, MCAD, and UCP1. Moreover, significant decrements of SIRT1 and AMPK activity were noted in obese rats fed with a vitamin D-insufficient diet. The observed deleterious effects of vitamin D insufficiency on adipose tissue expansion, immune cell infiltration and inflammatory status suggest vitamin D plays a beneficial role in adipocyte metabolic metabolism and obesity progression. SIRT1 and AMPK activity may play a role in the mechanism of vitamin D action. PMID- 28353636 TI - Zinc and Oxidative Stress: Current Mechanisms. AB - Oxidative stress is a metabolic dysfunction that favors the oxidation of biomolecules, contributing to the oxidative damage of cells and tissues. This consequently contributes to the development of several chronic diseases. In particular, zinc is one of the most relevant minerals to human health, because of its antioxidant properties. This review aims to provide updated information about the mechanisms involved in the protective role of zinc against oxidative stress. Zinc acts as a co-factor for important enzymes involved in the proper functioning of the antioxidant defense system. In addition, zinc protects cells against oxidative damage, acts in the stabilization of membranes and inhibits the enzyme nicotinamide adenine dinucleotide phosphate oxidase (NADPH-Oxidase). Zinc also induces the synthesis of metallothioneins, which are proteins effective in reducing hydroxyl radicals and sequestering reactive oxygen species (ROS) produced in stressful situations, such as in type 2 diabetes, obesity and cancer. Literature provides strong evidence for the role of zinc in the protection against oxidative stress in several diseases. PMID- 28353635 TI - Effects of Fruit and Vegetable Consumption on Risk of Asthma, Wheezing and Immune Responses: A Systematic Review and Meta-Analysis. AB - Abstract: Evidence suggests that reduced intake of fruit and vegetables may play a critical role in the development of asthma and allergies. The present review aimed to summarize the evidence for the association between fruit and vegetable intake, risk of asthma/wheeze and immune responses. Databases including PubMed, Cochrane, CINAHL and EMBASE were searched up to June 2016. Studies that investigated the effects of fruit and vegetable intake on risk of asthma/wheeze and immune responses were considered eligible (n = 58). Studies used cross sectional (n = 30), cohort (n = 13), case-control (n = 8) and experimental (n = 7) designs. Most of the studies (n = 30) reported beneficial associations of fruit and vegetable consumption with risk of asthma and/or respiratory function, while eight studies found no significant relationship. Some studies (n = 20) reported mixed results, as they found a negative association between fruit only or vegetable only, and asthma. In addition, the meta-analyses in both adults and children showed inverse associations between fruit intake and risk of prevalent wheeze and asthma severity (p < 0.05). Likewise, vegetable intake was negatively associated with risk of prevalent asthma (p < 0.05). Seven studies examined immune responses in relation to fruit and vegetable intake in asthma, with n = 6 showing a protective effect against either systemic or airway inflammation. Fruit and vegetable consumption appears to be protective against asthma. PMID- 28353637 TI - Current Status of Marine-Derived Compounds as Warheads in Anti-Tumor Drug Candidates. AB - In this review, we have attempted to describe all of the antibody-drug conjugates using a marine-derived compound as the "warhead", that are currently in clinical trials as listed in the current version of the NIH clinical trials database (clinicaltrials.gov). In searching this database, we used the beta-test version currently available, as it permitted more specific search parameters, since the regular version did not always find trials that had been completed in the past with some agents. We also added small discussion sections on candidates that are still at the preclinical stage, including a derivative of diazonamide that has an unusual interaction with tubulin (DZ-23840), which may also be a potential warhead in the future. PMID- 28353638 TI - A Specific Peptide with Calcium-Binding Capacity from Defatted Schizochytrium sp. Protein Hydrolysates and the Molecular Properties. AB - Marine microorganisms have been proposed as a new kind of protein source. Efforts are needed in order to transform the protein-rich biological wastes left after lipid extraction into value-added bio-products. Thus, the utilization of protein recovered from defatted Schizochytrium sp. by-products presents an opportunity. A specific peptide Tyr-Leu (YL) with calcium-binding capacity was purified from defatted Schizochytrium sp. protein hydrolysates through gel filtration chromatography and RP-HPLC. The calcium-binding activity of YL reached 126.34 +/- 3.40 MUg/mg. The calcium-binding mechanism was investigated through ultraviolet, fluorescence and infrared spectroscopy. The results showed that calcium ions could form dative bonds with carboxyl oxygen atoms and amino nitrogen atoms as well as the nitrogen and oxygen atoms of amide bonds. YL-Ca exhibited excellent thermal stability and solubility, which was beneficial for its absorption and transport in the basic intestinal tract of the human body. Moreover, the cellular uptake of calcium in Caco-2 cells showed that YL-Ca could enhance calcium uptake efficiency and protect calcium ions against precipitation caused by dietary inhibitors such as tannic acid, oxalate, phytate and metal ions. The findings indicate that the by-product of Schizochytrium sp. is a promising source for making peptide-calcium bio-products as algae-based functional supplements for human beings. PMID- 28353639 TI - Influence of MTHFR Genetic Background on p16 and MGMT Methylation in Oral Squamous Cell Cancer. AB - Genetic polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) enzyme may influence DNA methylation. Alterations in DNA methylation patterns of genes involved in the regulation of the cell cycle, DNA repair, cell adherence and metastasis process are known to contribute to cancer development. In this study, the influence of the MTHFR C677T and A1298C gene polymorphisms on global DNA methylation and site-specific methylation on p16 and O6-methylguanine-DNA methyltransferase (MGMT) gene promoters was investigated in patients with oral squamous cell cancer (OSCC). To this aim, methylation studies were carried out by using genomic DNA isolated from saliva samples of 58 OSCC patients and 90 healthy controls. The frequency of the CT/AC and TT/AA genotypes was significantly higher in patients than in controls. Whereas no difference in global DNA methylation levels was observed between patients and controls, a higher frequency of methylation at both p16 and MGMT gene promoters was detected in patients compared with controls. A significant association between MTHFR gene polymorphisms and p16 and MGMT gene promoter methylation was found. The frequency of p16 and MGMT methylation was around 60% in patients with either the CT/AC or TT/AA genotype. Our results suggest that hypermethylation of cancer-related genes may be affected by MTHFR polymorphisms. PMID- 28353640 TI - Bisarylureas Based on 1H-Pyrazolo[3,4-d]pyrimidine Scaffold as Novel Pan-RAF Inhibitors with Potent Anti-Proliferative Activities: Structure-Based Design, Synthesis, Biological Evaluation and Molecular Modelling Studies. AB - RAF (Ras activating factor) kinases are important and attractive targets for cancer therapy. With the aim of discovering RAF inhibitors that bind to DFG-out inactive conformation created by the movement of Asp-Phe-Gly (DFG), we conducted structure-based drug design using the X-ray cocrystal structures of BRAF (v-raf murine sarcoma viral oncogene homolog B1), starting from bisarylurea derivative based on 1H-pyrazolo[3,4-d]pyrimidine scaffold 1a. Most of the synthesized compounds showed good to excellent inhibitory activities against BRAFV600E kinase, possessed moderate to potent anti-proliferative activities against four tumor cell lines (A375, HT-29, PC-3 and A549) and good selectivity towards cancer cells rather normal cells (Madin-Darby canine kidney, MDCK). The most promising compound, 1v, exhibited potent inhibitory activity against not only BRAFV600E (half maximal inhibitory concentration, IC50 = 23.6 nM) but also wild-type BRAF (IC50 = 51.5 nM) and C-RAF (IC50 = 8.5 nM), and effective cellular anti proliferative activities against A375, HT-29, PC-3 and A549 cell lines as well as a very good selectivity profile. Moreover, compound 1v mainly arrested the A375 cell line in the G0/G1 stage, and showed significant suppression of MEK (mitogen activated protein kinase kinase) phosphorylation in A375 and HT-29 cell lines. Taken together, the optimal compound 1v showed excellent in vitro potency as a pan-RAF inhibitor. In addition, the promise of compound 1v was further confirmed by molecular dynamics simulation and binding free energy calculations. PMID- 28353641 TI - Rapid Determination of 30 Polyphenols in Tongmai Formula, a Combination of Puerariae Lobatae Radix, Salviae Miltiorrhizae Radix et Rhizoma, and Chuanxiong Rhizoma, via Liquid Chromatography-Tandem Mass Spectrometry. AB - Tongmai formula (TMF) is a herbal preparation composed of three traditional Chinese medicinal materials: Puerariae Lobatae Radix (Gegen), Salviae Miltiorrhizae Radix et Rhizoma (Danshen) and Chuanxiong Rhizoma (Chuanxiong). It has been used to treat cardiovascular diseases for decades. To develop a reliable and convenient analytical method for a comprehensive determination of polyphenols in TMF and the ascertainment of their chemical correlations with its herbal components, a method combining high-performance liquid chromatography with electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) was developed and validated for rapid determination of 30 polyphenols in TMF and its three herbal components. The chromatographic separation was carried out on a Chromolith Fastgradient RP-18 endcapped 50-2 column using an optimized gradient elution. Statistical analysis of obtained data demonstrated that the method had a desirable linearity, precision, and accuracy, as well as excellent sensitivity. The obtained results indicated that, among the 30 polyphenols in TMF, 22 originated from Gegen, 6 originated from Danshen, and 2 originated from Chuanxiong. The major polyphenols in TMF have been identified as puerarin, mirificin, salvianolic acid B, salvianic acid A, 3'-hydroxypuerarin, 3' methoxypuerarin, and salvianolic acid A, with a combined contribution of 19.2% of the preparation. The development and validation of this method will greatly facilitate future pharmacological studies of TMF and its herbal components, as well as polyphenols in cardiovascular therapies. PMID- 28353642 TI - Dysregulated IER3 Expression is Associated with Enhanced Apoptosis in Titin-Based Dilated Cardiomyopathy. AB - Apoptosis (type I programmed cell death) of cardiomyocytes is a major process that plays a role in the progression of heart failure. The early response gene IER3 regulates apoptosis in a wide variety of cells and organs. However, its role in heart failure is largely unknown. Here, we investigate the role of IER3 in an inducible heart failure mouse model. Heart failure was induced in a mouse model that imitates a human titin truncation mutation we found in a patient with dilated cardiomyopathy (DCM). Transferase dUTP nick end labeling (TUNEL) and ssDNA stainings showed induction of apoptosis in titin-deficient cardiomyocytes during heart failure development, while IER3 response was dysregulated. Chromatin immunoprecipitation and knock-down experiments revealed that IER3 proteins target the promotors of anti-apoptotic genes and act as an anti-apoptotic factor in cardiomyocytes. Its expression is blunted during heart failure development in a titin-deficient mouse model. Targeting the IER3 pathway to reduce cardiac apoptosis might be an effective therapeutic strategy to combat heart failure. PMID- 28353643 TI - Plasma Vitamin D Deficiency Is Associated With Poor Sleep Quality and Night-Time Eating at Mid-Pregnancy in Singapore. AB - Plasma 25-hydroxyvitamin D (25OHD) deficiency, poor sleep quality, and night-time eating, have been independently associated with adverse pregnancy outcomes, but their inter-relationships are yet to be evaluated. We aimed to investigate the associations between maternal plasma 25OHD status and sleep quality and circadian eating patterns during pregnancy. Data on pregnant women (n = 890) from a prospective cohort (Growing Up in Singapore Towards healthy Outcomes) were analyzed. Plasma 25OHD concentration was measured, while the Pittsburgh sleep quality index (PSQI) and 24-h dietary recall were administered to women at 26-28 weeks' gestation. Plasma 25OHD status was defined as sufficient (>75 nmol/L), insufficient (50-75 nmol/L), or deficient (<50 nmol/L). Poor sleep quality was defined by a total global PSQI score >5. Predominantly day-time (pDT) and predominantly night-time (pNT) were defined according to consumption of greater proportion of calories (i.e., >50%) from 07:00-18:59 and from 19:00-06:59, respectively. After adjustment for confounders, women with plasma 25OHD deficiency had higher odds of poor sleep quality (odds ratio (OR) 3.49; 95% confidence interval (CI) 1.84-6.63) and pNT eating (OR: 1.85; 95% CI 1.00-3.41) than those who were 25OHD sufficient. Our findings show the association of maternal plasma 25OHD deficiency with poor sleep quality and pNT eating at mid pregnancy. PMID- 28353644 TI - Methylmercury Induced Neurotoxicity and the Influence of Selenium in the Brains of Adult Zebrafish (Danio rerio). AB - The neurotoxicity of methylmercury (MeHg) is well characterised, and the ameliorating effects of selenium have been described. However, little is known about the molecular mechanisms behind this contaminant-nutrient interaction. We investigated the influence of selenium (as selenomethionine, SeMet) and MeHg on mercury accumulation and protein expression in the brain of adult zebrafish (Danio rerio). Fish were fed diets containing elevated levels of MeHg and/or SeMet in a 2 * 2 full factorial design for eight weeks. Mercury concentrations were highest in the brain tissue of MeHg-exposed fish compared to the controls, whereas lower levels of mercury were found in the brain of zebrafish fed both MeHg and SeMet compared with the fish fed MeHg alone. The expression levels of proteins associated with gap junction signalling, oxidative phosphorylation, and mitochondrial dysfunction were significantly (p < 0.05) altered in the brain of zebrafish after exposure to MeHg and SeMet alone or in combination. Analysis of upstream regulators indicated that these changes were linked to the mammalian target of rapamycin (mTOR) pathways, which were activated by MeHg and inhibited by SeMet, possibly through a reactive oxygen species mediated differential activation of RICTOR, the rapamycin-insensitive binding partner of mTOR. PMID- 28353645 TI - Inhibition or Stimulation of Autophagy Affects Early Formation of Lipofuscin-Like Autofluorescence in the Retinal Pigment Epithelium Cell. AB - The accumulation of lipofuscin in the retinal pigment epithelium (RPE) is dependent on the effectiveness of photoreceptor outer segment material degradation. This study explored the role of autophagy in the fate of RPE lipofuscin degradation. After seven days of feeding with either native or modified rod outer segments, ARPE-19 cells were treated with enhancers or inhibitors of autophagy and the autofluorescence was detected by fluorescence activated cell sorting. Supplementation with different types of rod outer segments increased lipofuscin-like autofluorescence (LLAF) after the inhibition of autophagy, while the induction of autophagy (e.g., application of rapamycin) decreased LLAF. The effects of autophagy induction were further confirmed by Western blotting, which showed the conversion of LC3-I to LC3-II, and by immunofluorescence microscopy, which detected the lysosomal activity of the autophagy inducers. We also monitored LLAF after the application of several autophagy inhibitors by RNA-interference and confocal microscopy. The results showed that, in general, the inhibition of the autophagy-related proteins resulted in an increase in LLAF when cells were fed with rod outer segments, which further confirms the effect of autophagy in the fate of RPE lipofuscin degradation. These results emphasize the complex role of autophagy in modulating RPE autofluorescence and confirm the possibility of the pharmacological clearance of RPE lipofuscin by small molecules. PMID- 28353646 TI - Intraguild Predation Dynamics in a Lake Ecosystem Based on a Coupled Hydrodynamic Ecological Model: The Example of Lake Kinneret (Israel). AB - The food web of Lake Kinneret contains intraguild predation (IGP). Predatory invertebrates and planktivorous fish both feed on herbivorous zooplankton, while the planktivorous fish also feed on the predatory invertebrates. In this study, a complex mechanistic hydrodynamic-ecological model, coupled to a bioenergetics based fish population model (DYCD-FISH), was employed with the aim of revealing IGP dynamics. The results indicate that the predation pressure of predatory zooplankton on herbivorous zooplankton varies widely, depending on the season. At the time of its annual peak, it is 10-20 times higher than the fish predation pressure. When the number of fish was significantly higher, as occurs in the lake after atypical meteorological years, the effect was a shift from a bottom-up controlled ecosystem, to the top-down control of planktivorous fish and a significant reduction of predatory and herbivorous zooplankton biomass. Yet, seasonally, the decrease in predatory-zooplankton biomass was followed by a decrease in their predation pressure on herbivorous zooplankton, leading to an increase of herbivorous zooplankton biomass to an extent similar to the base level. The analysis demonstrates the emergence of non-equilibrium IGP dynamics due to intra-annual and inter-annual changes in the physico-chemical characteristics of the lake, and suggests that IGP dynamics should be considered in food web models in order to more accurately capture mass transfer and trophic interactions. PMID- 28353647 TI - Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells. AB - Wedelolactone is a multi-target natural plant coumestan exhibiting cytotoxicity towards cancer cells. Although several molecular targets of wedelolactone have been recognized, the molecular mechanism of its cytotoxicity has not yet been elucidated. In this study, we show that wedelolactone acts as an inhibitor of chymotrypsin-like, trypsin-like, and caspase-like activities of proteasome in breast cancer cells. The proteasome inhibitory effect of wedelolactone was documented by (i) reduced cleavage of fluorogenic proteasome substrates; (ii) accumulation of polyubiquitinated proteins and proteins with rapid turnover in tumor cells; and (iii) molecular docking of wedelolactone into the active sites of proteasome catalytic subunits. Inhibition of proteasome by wedelolactone was independent on its ability to induce reactive oxygen species production by redox cycling with copper ions, suggesting that wedelolactone acts as copper independent proteasome inhibitor. We conclude that the cytotoxicity of wedelolactone to breast cancer cells is partially mediated by targeting proteasomal protein degradation pathway. Understanding the structural basis for inhibitory mode of wedelolactone might help to open up new avenues for design of novel compounds efficiently inhibiting cancer cells. PMID- 28353650 TI - Text Messaging: An Intervention to Increase Physical Activity among African American Participants in a Faith-Based, Competitive Weight Loss Program. AB - African American adults are less likely to meet the recommended physical activity guidelines for aerobic and muscle-strengthening activity than Caucasian adults. The purpose of this study was to assess whether a text message intervention would increase physical activity in this population. This pilot study used a pre-/post questionnaire non-randomized design. Participants in a faith-based weight loss competition who agreed to participate in the text messaging were assigned to the intervention group (n = 52). Participants who declined to participate in the intervention, but agreed to participate in the study, were assigned to the control group (n = 30). The text messages provided strategies for increasing physical activity and were based on constructs of the Health Belief Model and the Information-Motivation-Behavioral Skills Model. Chi square tests determined the intervention group participants increased exercise time by approximately eight percent (p = 0.03), while the control group's exercise time remained constant. The intervention group increased walking and running. The control group increased running. Most participants indicated that the health text messages were effective. The results of this pilot study suggest that text messaging may be an effective method for providing options for motivating individuals to increase physical activity. PMID- 28353651 TI - Pigments in Extra-Virgin Olive Oils Produced in Tuscany (Italy) in Different Years. AB - Pigments are responsible for the color of olive oils, and are an important ingredient that is directly related to the quality of this food. However, the concentration of pigments can vary significantly depending on the climate conditions, harvesting time, and olive cultivars. In this work, we quantified the main pigments in several extra-virgin olive oils produced from a blend of three cultivars (Moraiolo, Frantoio, and Leccino) typical of Tuscany (Italy) harvested in three different years: 2012, 2013, and 2014. Pigments-namely, beta-carotene, lutein, pheophytin A, and pheophytin B-were quantified by a method based on the mathematical analysis of the near ultraviolet-visible absorption spectra of the oils. Data were analyzed by a multivariate statistical approach. The results show that the pigments' content of extra-virgin olive oils produced in 2014 can be well distinguished with respect to previous years. This can be explained by the anomalous climate conditions, which strongly affected Italy and, in particular, Tuscany, where the olives were harvested. This study represents an interesting example of how pigment content can be significant in characterizing olive oils. Moreover, this is the first report of pigment quantification in extra-virgin olive oils produced in Tuscany. PMID- 28353648 TI - Vitamin C and Infections. AB - In the early literature, vitamin C deficiency was associated with pneumonia. After its identification, a number of studies investigated the effects of vitamin C on diverse infections. A total of 148 animal studies indicated that vitamin C may alleviate or prevent infections caused by bacteria, viruses, and protozoa. The most extensively studied human infection is the common cold. Vitamin C administration does not decrease the average incidence of colds in the general population, yet it halved the number of colds in physically active people. Regularly administered vitamin C has shortened the duration of colds, indicating a biological effect. However, the role of vitamin C in common cold treatment is unclear. Two controlled trials found a statistically significant dose-response, for the duration of common cold symptoms, with up to 6-8 g/day of vitamin C. Thus, the negative findings of some therapeutic common cold studies might be explained by the low doses of 3-4 g/day of vitamin C. Three controlled trials found that vitamin C prevented pneumonia. Two controlled trials found a treatment benefit of vitamin C for pneumonia patients. One controlled trial reported treatment benefits for tetanus patients. The effects of vitamin C against infections should be investigated further. PMID- 28353649 TI - High Dietary Fructose: Direct or Indirect Dangerous Factors Disturbing Tissue and Organ Functions. AB - High dietary fructose is a major contributor to insulin resistance and metabolic syndrome, disturbing tissue and organ functions. Fructose is mainly absorbed into systemic circulation by glucose transporter 2 (GLUT2) and GLUT5, and metabolized in liver to produce glucose, lactate, triglyceride (TG), free fatty acid (FFA), uric acid (UA) and methylglyoxal (MG). Its extrahepatic absorption and metabolism also take place. High levels of these metabolites are the direct dangerous factors. During fructose metabolism, ATP depletion occurs and induces oxidative stress and inflammatory response, disturbing functions of local tissues and organs to overproduce inflammatory cytokine, adiponectin, leptin and endotoxin, which act as indirect dangerous factors. Fructose and its metabolites directly and/or indirectly cause oxidative stress, chronic inflammation, endothelial dysfunction, autophagy and increased intestinal permeability, and then further aggravate the metabolic syndrome with tissue and organ dysfunctions. Therefore, this review addresses fructose-induced metabolic syndrome, and the disturbance effects of direct and/or indirect dangerous factors on the functions of liver, adipose, pancreas islet, skeletal muscle, kidney, heart, brain and small intestine. It is important to find the potential correlations between direct and/or indirect risk factors and healthy problems under excess dietary fructose consumption. PMID- 28353652 TI - Inhibitory Effect of Lychee Seed Saponins on Apoptosis Induced by Abeta25-35 through Regulation of the Apoptotic and NF-kappaB Pathways in PC12 Cells. AB - Neuronal apoptosis plays a critical role in the pathogenesis of Alzheimer's disease (AD). Previous studies have shown that lychee seed saponins (LSS), isolated and extracted from traditional Chinese medicine lychee seeds, possess many beneficial activities including anti-oxidation, anti-diabetes, anti-AD, etc. In the present study, we established an in vitro neuronal apoptotic model of PC12 cells induced by Abeta25-35 and studied the effect of LSS on apoptosis by the methods of Hoechst 33342/propidium iodide (PI) fluorescence double staining, Annexin V/PI double staining, and terminal deoxynucleotidyl transferase (TdT) mediated dUTP nick-end labeling (TUNEL). We also investigated the effects of LSS on mitochondria membrane potential, the expressions of Bcl-2 and Bax proteins, and the mRNA expression and the nuclear translocation of NF-kappaBp65 in PC12 cells. The results showed that LSS markedly inhibited apoptosis, improved the mitochondria membrane potentials, upregulated the expression of Bcl-2 protein, downregulated the expression of Bax protein, and decreased the mRNA expression and nuclear translocation of NF-kappaBp65 in PC12 cells. The study demonstrated that LSS significantly inhibited apoptosis induced by Abeta25-35 via regulation of the apoptotic and NF-kappaB pathways in PC12 cells. Therefore, LSS has the potential to be developed as a novel agent or nutrient supplement for the prevention and/or treatment of AD. PMID- 28353653 TI - Changes in the Fusarium Head Blight Complex of Malting Barley in a Three-Year Field Experiment in Italy. AB - In this study, conducted for three years on eleven malting barley varieties cultivated in central Italy, the incidence of different mycotoxigenic fungal genera, the identification of the Fusarium species associated with the Fusarium Head Blight (FHB) complex, and kernels contamination with deoxynivalenol (DON) and T-2 mycotoxins were determined. The influence of climatic conditions on Fusarium infections and FHB complex composition was also investigated. Fusarium species were always present in the three years and the high average and maximum temperatures during anthesis mainly favored their occurrence. The FHB complex was subject to changes during the three years and the main causal agents were F. poae, F. avenaceum, F. tricinctum and F. graminearum, which, even if constantly present, never represented the principal FHB agent. The relative incidence of Fusarium species changed because of climatic conditions occurring during the seasons. The FHB complex was composed of many different Fusarium species and some of them were associated with a specific variety and/or with specific weather parameters, indicating that the interaction between a certain plant genotype and climatic conditions may influence the presence of Fusarium spp. causing infections. With regard to mycotoxin contamination, T-2 toxin, in some cases, was found in kernels at levels that exceeded EU recommended values. PMID- 28353654 TI - The 'Molecule of the Month' Website-An Extraordinary Chemistry Educational Resource Online for over 20 Years. AB - The Molecule of the Month website (http://www.chm.bris.ac.uk/motm/motm.htm) is an educational resource that is celebrating its 20th anniversary. Here we reflect on its pioneering role in promoting new technology for visualizing and presenting chemical information on the web, as well as its achievements, as a free educational resource, both as a teaching aid and as a multi-user, multi-author learning platform. We discuss the legal aspects of such sites, as well as issues around how to make the content permanent. Finally, we look forward to how such sites may evolve in the future. PMID- 28353655 TI - Effects of Two Different Dietary Patterns on Inflammatory Markers, Advanced Glycation End Products and Lipids in Subjects without Type 2 Diabetes: A Randomised Crossover Study. AB - Epidemiological studies suggest that consumption of red and processed meat and refined grains are associated with type 2 diabetes and metabolic syndrome and increased inflammatory and fibrinolytic markers. We hypothesised that a diet high in red and processed meat and refined grains (HMD) would increase inflammatory markers and advanced glycation end products (AGEs) compared with a diet high in dairy, whole grains, nuts and legumes (HWD). We performed a randomised crossover study of two four-week interventions in 51 participants without type 2 diabetes (15 men and 36 women aged 35.1 +/- 15.6 years; body mass index: 27.7 +/- 6.9 kg/m2). No baseline measurements were performed. Plasma fluorescent AGEs, carboxymethyllysine, glucose, insulin, lipids, hs-CRP, interleukin 6 (IL-6) and plasminogen activator inhibitor-1 (PAI-1) were analysed after four weeks on each diet. IL-6, hs-CRP, AGEs and carboxymethyllysine were not different between diets but PAI-1 was higher after the HMD than after HWD ((median and interquartile range) 158, 81 vs. 121, 53 ng/mL p < 0.001). PAI-1 on the HWD diet was inversely correlated with whole grains intake (p = 0.007). PAI-1 was inversely correlated with insulin sensitivity index (r = -0.45; p = 0.001) and positively correlated with serum total cholesterol (r = 0.35; p = 0.012) and serum triglyceride (r = 0.32; p = 0.021) on HMD. This trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12614000519651). PMID- 28353656 TI - Volatiles Emitted at Different Flowering Stages of Jasminum sambac and Expression of Genes Related to alpha-Farnesene Biosynthesis. AB - Fresh jasmine flowers have been used to make jasmine teas in China, but there has been no complete information about volatile organic compound emissions in relation to flower developmental stages and no science-based knowledge about which floral stage should be used for the infusion. This study monitored volatile organic compounds emitted from living flowers of Jasminum sambac (L.) Ait. 'Bifoliatum' at five developmental stages and also from excised flowers. Among the compounds identified, alpha-farnesene, linalool, and benzyl acetate were most abundant. Since alpha-farnesene is synthesized through the Mevalonate pathway, four genes encoding 3-hydroxy-3-methylglutaryl coenzyme A synthase, 3-hydroxy-3 methylglutaryl coenzyme A reductase (HMGR), farnesyl pyrophosphate synthase, and terpene synthase were isolated. Their expression patterns in living flowers at the five stages and in excised flowers coincided with the emission patterns of alpha-farnesene. Application of lovastatin, a HMGR inhibitor, significantly reduced the expression of the genes and greatly decreased the emission of alpha farnesene. The sweet scent was diminished from lovastatin-treated flowers as well. These results indicate that alpha-farnesene is an important compound emitted from jasmine flowers, and its emission patterns suggest that flowers at the opening stage or flower buds 8 h after excision should be used for the infusion of tea leaves. PMID- 28353657 TI - Urinary Concentrations of Insecticide and Herbicide Metabolites among Pregnant Women in Rural Ghana: A Pilot Study. AB - : Use of pesticides by households in rural Ghana is common for residential pest control, agricultural use, and for the reduction of vectors carrying disease. However, few data are available about exposure to pesticides among this population. Our objective was to quantify urinary concentrations of metabolites of organophosphate (OP), pyrethroid, and select herbicides during pregnancy, and to explore exposure determinants. In 2014, 17 pregnant women from rural Ghana were surveyed about household pesticide use and provided weekly first morning urine voids during three visits (n = 51 samples). A total of 90.1% (46/51) of samples had detectable OP metabolites [geometric mean, GM (95% CI): 3,5,6 trichloro-2-pyridinol 0.54 ug/L (0.36-0.81), para-nitrophenol 0.71 ug/L (0.51 1.00)], 75.5% (37/49) had detectable pyrethroid metabolites [GM: 3-phenoxybenzoic acid 0.23 ug/L (0.17, 0.32)], and 70.5% (36/51) had detectable 2,4 dichlorophenoxyacetic acid levels, a herbicide [GM: 0.46 ug/L (0.29-0.73)]. Concentrations of para-nitrophenol and 2,4-dichlorophenoxyacetic acid in Ghanaian pregnant women appear higher when compared to nonpregnant reproductive-aged women in a reference U.S. POPULATION: Larger studies are necessary to more fully explore predictors of exposure in this population. PMID- 28353658 TI - Development of a Glycosaminoglycan Derived, Selectin Targeting Anti-Adhesive Coating to Treat Endothelial Cell Dysfunction. AB - Endothelial cell (EC) dysfunction is associated with many disease states including deep vein thrombosis (DVT), chronic kidney disease, sepsis and diabetes. Loss of the glycocalyx, a thin glycosaminoglycan (GAG)-rich layer on the EC surface, is a key feature of endothelial dysfunction and increases exposure of EC adhesion molecules such as selectins, which are involved in platelet binding to ECs. Once bound, platelets cause thrombus formation and an increased inflammatory response. We have developed a GAG derived, selectin targeting anti-adhesive coating (termed EC-SEAL) consisting of a dermatan sulfate backbone and multiple selectin-binding peptides designed to bind to inflamed endothelium and prevent platelet binding to create a more quiescent endothelial state. Multiple EC-SEAL variants were evaluated and the lead variant was found to preferentially bind to selectin-expressing ECs and smooth muscle cells (SMCs) and inhibit platelet binding and activation in a dose-dependent manner. In an in vivo model of DVT, treatment with the lead variant resulted in reduced thrombus formation. These results indicate that EC-SEAL has promise as a potential therapeutic in the treatment of endothelial dysfunction. PMID- 28353659 TI - A Pharmacological Examination of the Cardiovascular Effects of Malayan Krait (Bungarus candidus) Venoms. AB - Cardiovascular effects (e.g., tachycardia, hypo- and/or hypertension) are often clinical outcomes of snake envenoming. Malayan krait (Bungarus candidus) envenoming has been reported to cause cardiovascular effects that may be related to abnormalities in parasympathetic activity. However, the exact mechanism for this effect has yet to be determined. In the present study, we investigated the in vivo and in vitro cardiovascular effects of B. candidus venoms from Southern (BC-S) and Northeastern (BC-NE) Thailand. SDS-PAGE analysis of venoms showed some differences in the protein profile of the venoms. B. candidus venoms (50 ug/kg 100 ug/kg, i.v.) caused dose-dependent hypotension in anaesthetised rats. The highest dose caused sudden hypotension (phase I) followed by a return of mean arterial pressure to baseline levels and a decrease in heart rate with transient hypertension (phase II) prior to a small decrease in blood pressure (phase III). Prior administration of monovalent antivenom significantly attenuated the hypotension induced by venoms (100 ug/kg, i.v.). The sudden hypotensive effect of BC-NE venom was abolished by prior administration of hexamethonium (10 mg/kg, i.v.) or atropine (5 mg/kg, i.v.). BC-S and BC-NE venoms (0.1 ug/kg-100 ug/ml) induced concentration-dependent relaxation (EC50 = 8 +/- 1 and 13 +/- 3 ug/mL, respectively) in endothelium-intact aorta. The concentration-response curves were markedly shifted to the right by pre-incubation with L-NAME (0.2 mM), or removal of the endothelium, suggesting that endothelium-derived nitric oxide (NO) is likely to be responsible for venom-induced aortic relaxation. Our data indicate that the cardiovascular effects caused by B. candidus venoms may be due to a combination of vascular mediators (i.e., NO) and autonomic adaptation via nicotinic and muscarinic acetylcholine receptors. PMID- 28353660 TI - Extensive Evolution of Cereal Ribosome-Inactivating Proteins Translates into Unique Structural Features, Activation Mechanisms, and Physiological Roles. AB - Ribosome-inactivating proteins (RIPs) are a class of cytotoxic enzymes that can depurinate rRNAs thereby inhibiting protein translation. Although these proteins have also been detected in bacteria, fungi, and even some insects, they are especially prevalent in the plant kingdom. This review focuses on the RIPs from cereals. Studies on the taxonomical distribution and evolution of plant RIPs suggest that cereal RIPs have evolved at an enhanced rate giving rise to a large and heterogeneous RIP gene family. Furthermore, several cereal RIP genes are characterized by a unique domain architecture and the lack of a signal peptide. This advanced evolution of cereal RIPs translates into distinct structures, activation mechanisms, and physiological roles. Several cereal RIPs are characterized by activation mechanisms that include the proteolytic removal of internal peptides from the N-glycosidase domain, a feature not documented for non cereal RIPs. Besides their role in defense against pathogenic fungi or herbivorous insects, cereal RIPs are also involved in endogenous functions such as adaptation to abiotic stress, storage, induction of senescence, and reprogramming of the translational machinery. The unique properties of cereal RIPs are discussed in this review paper. PMID- 28353661 TI - The Neutrophil/Lymphocyte Ratio at Diagnosis Is Significantly Associated with Survival in Metastatic Pancreatic Cancer Patients. AB - Different inflammation-based scores such as the neutrophil/lymphocyte ratio (NLR), the Odonera Prognostic Nutritional Index (PNI), the Glasgow Prognostic Score, the platelet/lymphocyte ratio, and the C-reactive protein/albumin ratio have been found to be significantly associated with pancreatic cancer (PDAC) prognosis. However, most studies have investigated patients undergoing surgery, and few of them have compared these scores. We aimed at evaluating the association between inflammatory-based scores and PDAC prognosis. In a single center cohort study, inflammatory-based scores were assessed at diagnosis and their prognostic relevance as well as that of clinic-pathological variables were evaluated through multiple logistic regression and survival probability analysis. In 206 patients, age, male sex, tumor size, presence of distant metastasis, access to chemotherapy, and an NLR > 5 but not other scores were associated with overall survival (OS) at multivariate analysis. Patients with an NLR < 5 had a median survival of 12 months compared to 4 months in those with an NLR > 5. In the 81 patients with distant metastasis at diagnosis, an NLR > 5 resulted in the only variable significantly associated with survival. Among patients with metastatic disease who received chemotherapy, the median survival was 3 months in patients with an NLR > 5 and 7 months in those with an NLR < 5. The NLR might drive therapeutic options in PDAC patients, especially in the setting of metastatic disease. PMID- 28353663 TI - Use of Carabids for the Post-Market Environmental Monitoring of Genetically Modified Crops. AB - Post-market environmental monitoring (PMEM) of genetically modified (GM) crops is required by EU legislation and has been a subject of debate for many years; however, no consensus on the methodology to be used has been reached. We explored the suitability of carabid beetles as surrogates for the detection of unintended effects of GM crops in general PMEM surveillance. Our study combines data on carabid communities from five maize field trials in Central Europe. Altogether, 86 species and 58,304 individuals were collected. Modeling based on the gradual elimination of the least abundant species, or of the fewest categories of functional traits, showed that a trait-based analysis of the most common species may be suitable for PMEM. Species represented by fewer than 230 individuals (all localities combined) should be excluded and species with an abundance higher than 600 should be preserved for statistical analyses. Sixteen species, representing 15 categories of functional traits fulfill these criteria, are typical dominant inhabitants of agroecocoenoses in Central Europe, are easy to determine, and their functional classification is well known. The effect of sampling year is negligible when at least four samples are collected during maize development beginning from 1 April. The recommended methodology fulfills PMEM requirements, including applicability to large-scale use. However, suggested thresholds of carabid comparability should be verified before definitive conclusions are drawn. PMID- 28353664 TI - Modeling and Density Estimation of an Urban Freeway Network Based on Dynamic Graph Hybrid Automata. AB - In this paper, in order to describe complex network systems, we firstly propose a general modeling framework by combining a dynamic graph with hybrid automata and thus name it Dynamic Graph Hybrid Automata (DGHA). Then we apply this framework to model traffic flow over an urban freeway network by embedding the Cell Transmission Model (CTM) into the DGHA. With a modeling procedure, we adopt a dual digraph of road network structure to describe the road topology, use linear hybrid automata to describe multi-modes of dynamic densities in road segments and transform the nonlinear expressions of the transmitted traffic flow between two road segments into piecewise linear functions in terms of multi-mode switchings. This modeling procedure is modularized and rule-based, and thus is easily extensible with the help of a combination algorithm for the dynamics of traffic flow. It can describe the dynamics of traffic flow over an urban freeway network with arbitrary topology structures and sizes. Next we analyze mode types and number in the model of the whole freeway network, and deduce a Piecewise Affine Linear System (PWALS) model. Furthermore, based on the PWALS model, a multi-mode switched state observer is designed to estimate the traffic densities of the freeway network, where a set of observer gain matrices are computed by using the Lyapunov function approach. As an example, we utilize the PWALS model and the corresponding switched state observer to traffic flow over Beijing third ring road. In order to clearly interpret the principle of the proposed method and avoid computational complexity, we adopt a simplified version of Beijing third ring road. Practical application for a large-scale road network will be implemented by decentralized modeling approach and distributed observer designing in the future research. PMID- 28353662 TI - Black Tea High-Molecular-Weight Polyphenol-Rich Fraction Promotes Hypertrophy during Functional Overload in Mice. AB - Mitochondria activation factor (MAF) is a high-molecular-weight polyphenol extracted from black tea that stimulates training-induced 5' adenosine monophosphate-activated protein kinase (AMPK) activation and improves endurance capacity. Originally, MAF was purified from black tea using butanol and acetone, making it unsuitable for food preparation. Hence, we extracted a MAF-rich sample "E80" from black tea, using ethanol and water only. Here, we examined the effects of E80 on resistance training. Eight-week old C57BL/6 mice were fed with a normal diet or a diet containing 0.5% E80 for 4, 7 and 14 days under conditions of functional overload. It was found that E80 administration promoted overload induced hypertrophy and induced phosphorylation of the Akt/mammalian target of rapamycin (mTOR) pathway proteins, such as Akt, P70 ribosomal protein S6 kinase (p70S6K), and S6 in the plantaris muscle. Therefore, functional overload and E80 administration accelerated mTOR signaling and increased protein synthesis in the muscle, thereby inducing hypertrophy. PMID- 28353665 TI - Does a 4-6 Week Shoeing Interval Promote Optimal Foot Balance in the Working Equine? AB - Variation in equine hoof conformation between farriery interventions lacks research, despite associations with distal limb injuries. This study aimed to determine linear and angular hoof variations pre- and post-farriery within a four to six week shoeing/trimming interval. Seventeen hoof and distal limb measurements were drawn from lateral and anterior digital photographs from 26 horses pre- and post-farriery. Most lateral view variables changed significantly. Reductions of the dorsal wall, and weight bearing and coronary band lengths resulted in an increased vertical orientation of the hoof. The increased dorsal hoof wall angle, heel angle, and heel height illustrated this further, improving dorsopalmar alignment. Mediolateral measurements of coronary band and weight bearing lengths reduced, whilst medial and lateral wall lengths from the 2D images increased, indicating an increased vertical hoof alignment. Additionally, dorsopalmar balance improved. However, the results demonstrated that a four to six week interval is sufficient for a palmer shift in the centre of pressure, increasing the loading on acutely inclined heels, altering DIP angulation, and increasing the load on susceptible structures (e.g., DDFT). Mediolateral variable asymmetries suit the lateral hoof landing and unrollment pattern of the foot during landing. The results support regular (four to six week) farriery intervals for the optimal prevention of excess loading of palmar limb structures, reducing long-term injury risks through cumulative, excessive loading. PMID- 28353666 TI - Potentials of Long Noncoding RNAs (LncRNAs) in Sarcoma: From Biomarkers to Therapeutic Targets. AB - Sarcoma includes some of the most heterogeneous tumors, which make the diagnosis, prognosis and treatment of these rare yet diverse neoplasms especially challenging. Long noncoding RNAs (lncRNAs) are important regulators of cancer initiation and progression, which implies their potential as neoteric prognostic and diagnostic markers in cancer, including sarcoma. A relationship between lncRNAs and sarcoma pathogenesis and progression is emerging. Recent studies demonstrate that lncRNAs influence sarcoma cell proliferation, metastasis, and drug resistance. Additionally, lncRNA expression profiles are predictive of sarcoma prognosis. In this review, we summarize contemporary advances in the research of lncRNA biogenesis and functions in sarcoma. We also highlight the potential for lncRNAs to become innovative diagnostic and prognostic biomarkers as well as therapeutic targets in sarcoma. PMID- 28353667 TI - Incidence of Breast, Prostate, Testicular, and Thyroid Cancer in Italian Contaminated Sites with Presence of Substances with Endocrine Disrupting Properties. AB - The aim of the present study was to investigate the incidence of breast (females), prostate, testicular, and thyroid cancer in the Italian National Priority Contaminated Sites (NPCSs), served by cancer registries, where the presence of endocrine disruptors (EDs), reported to be linked to these tumours, was documented. Evidence of carcinogenicity of EDs present in NPCSs was assessed based on evaluation by international scientific institutions and committees. Standardized Incidence Ratios (SIRs) were computed for each NPCS and cancer site between 1996 and 2005. Excess incidence of one or more cancer site studied was found in twelve out of fourteen NPCSs. Significantly increased SIRs were found for breast cancer in eight NPCSs, for prostate cancer in six, for thyroid cancer (both gender) in four, and for testicular cancer in two. Non-significantly increased SIRs were found in five NPCSs for testicular cancer and in two for thyroid cancer (males). In a small number of instances a significant deficit was reported, mainly for thyroid and prostate cancer. Although increased incidence of one or more cancer sites studied were found in several NPCSs, the ecological study design and the multifactorial aetiology of the considered tumours do not permit concluding causal links with environmental contamination. Regarding the observation of some excesses in SIRs, continuing epidemiological surveillance is warranted. PMID- 28353668 TI - Bevacizumab for Patients with Recurrent Gliomas Presenting with a Gliomatosis Cerebri Growth Pattern. AB - Bevacizumab has been shown to improve progression-free survival and neurologic function, but failed to improve overall survival in newly diagnosed glioblastoma and at first recurrence. Nonetheless, bevacizumab is widely used in patients with recurrent glioma. However, its use in patients with gliomas showing a gliomatosis cerebri growth pattern is contentious. Due to the marked diffuse and infiltrative growth with less angiogenic tumor growth, it may appear questionable whether bevacizumab can have a therapeutic effect in those patients. However, the development of nodular, necrotic, and/or contrast-enhancing lesions in patients with a gliomatosis cerebri growth pattern is not uncommon and may indicate focal neo-angiogenesis. Therefore, control of growth of these lesions as well as control of edema and reduction of steroid use may be regarded as rationales for the use of bevacizumab in these patients. In this retrospective patient series, we report on 17 patients with primary brain tumors displaying a gliomatosis cerebri growth pattern (including seven glioblastomas, two anaplastic astrocytomas, one anaplastic oligodendroglioma, and seven diffuse astrocytomas). Patients have been treated with bevacizumab alone or in combination with lomustine or irinotecan. Seventeen matched patients treated with bevacizumab for gliomas with a classical growth pattern served as a control cohort. Response rate, progression-free survival, and overall survival were similar in both groups. Based on these results, anti-angiogenic therapy with bevacizumab should also be considered in patients suffering from gliomas with a mainly infiltrative phenotype. PMID- 28353671 TI - Facial Expression Recognition with Fusion Features Extracted from Salient Facial Areas. AB - In the pattern recognition domain, deep architectures are currently widely used and they have achieved fine results. However, these deep architectures make particular demands, especially in terms of their requirement for big datasets and GPU. Aiming to gain better results without deep networks, we propose a simplified algorithm framework using fusion features extracted from the salient areas of faces. Furthermore, the proposed algorithm has achieved a better result than some deep architectures. For extracting more effective features, this paper firstly defines the salient areas on the faces. This paper normalizes the salient areas of the same location in the faces to the same size; therefore, it can extracts more similar features from different subjects. LBP and HOG features are extracted from the salient areas, fusion features' dimensions are reduced by Principal Component Analysis (PCA) and we apply several classifiers to classify the six basic expressions at once. This paper proposes a salient areas definitude method which uses peak expressions frames compared with neutral faces. This paper also proposes and applies the idea of normalizing the salient areas to align the specific areas which express the different expressions. As a result, the salient areas found from different subjects are the same size. In addition, the gamma correction method is firstly applied on LBP features in our algorithm framework which improves our recognition rates significantly. By applying this algorithm framework, our research has gained state-of-the-art performances on CK+ database and JAFFE database. PMID- 28353669 TI - MIP-Based Sensors: Promising New Tools for Cancer Biomarker Determination. AB - Detecting cancer disease at an early stage is one of the most important issues for increasing the survival rate of patients. Cancer biomarker detection helps to provide a diagnosis before the disease becomes incurable in later stages. Biomarkers can also be used to evaluate the progression of therapies and surgery treatments. In recent years, molecularly imprinted polymer (MIP) based sensors have been intensely investigated as promising analytical devices in several fields, including clinical analysis, offering desired portability, fast response, specificity, and low cost. The aim of this review is to provide readers with an overview on recent important achievements in MIP-based sensors coupled to various transducers (e.g., electrochemical, optical, and piezoelectric) for the determination of cancer biomarkers by selected publications from 2012 to 2016. PMID- 28353672 TI - Gas Sensor Based on 3-D WO3 Inverse Opal: Design and Applications. AB - A three-dimensional inverse opal (3DIO) WO3 architecture has been synthesized via a simple sacrificial template method. Morphology features of the 3DIO were characterized by scanning electron microscope (SEM) and its structure was characterized by X-ray diffraction (XRD). The shrinking ratio of the PMMA spheres was ~28.2% through measuring the distribution of the PMMA spheres and 3DIO WO3 center-to-center distance between the spheres and macropores, respectively. Beyond that, the 3DIO gas sensing properties were investigated systematically and the sensing mechanism of 3DIO WO3 was proposed. The results indicated that the response of the 3DIO sensor possessed excellent sensitivity to acetone gas, especially at trace levels. The 3DIO gas sensor response was ~7 to 5 ppm of acetone and could detect acetone low to 0.2 ppm effectively, which was in close proximity to the theoretical low detection limit of 0.14 ppm when Ra/Rg >= 1.2 was used as the criterion for reliable gas sensing. All in all, the obvious satisfaction of the gas-sensing properties was ascribed to the structure of the 3DIO, and the sensor could be a promising novel device in the future. PMID- 28353670 TI - Demand and Signing of General Practitioner Contract Service among the Urban Elderly: A Population-Based Analysis in Zhejiang Province, China. AB - This study aims to examine whether the urban elderly in the Zhejiang Province of China signed contracts with their general practitioner (GP) based on their health service needs, and to further identify the determinants of their demand and signing decisions. A community-based cross-sectional study was conducted in 16 community health service (CHS) institutions in Zhejiang Province, China. The urban elderly over 60 years of age were enrolled when visiting the sampled CHS. Baseline characteristics were compared between participants using Chi-Square tests for categorical variables. Univariate and multivariable logistic regression analyses were used to identify determinants of the GP contract service demand and signing decisions, respectively. Among the 1440 urban elderly, 56.67% had signed contracts with their GP, and 55.35% had a demand of the GP contract service. The influencing factors of demand were a history of diabetes or cardiovascular disease (OR = 1.33, 95% CI, 1.05-1.68); urban resident basic medical insurance (URBMI) vs. urban employee basic medical insurance (UEBMI) (OR = 1.96, 95% CI, 1.46-2.61); and middle-income vs. low-income (OR = 0.67, 95% CI, 0.50-0.90 for RMB 1001-3000; OR = 0.59, 95% CI, 0.39-0.90 for RMB 3001-5000). Having a demand for the GP contract service was the strongest determinant of signing decisions (OR = 13.20, 95% CI, 10.09-17.27). Other factors also contributed to these decisions, including gender, caregiver, and income. The urban elderly who had signed contracts with GPs were mainly based on their health care needs. Elderly people with a history of diabetes or cardiovascular disease, as well as those with URBMI, were found to have stronger needs of a GP contract service. It is believed that the high-income elderly should be given equal priority to those of low-income. PMID- 28353673 TI - Metal Oxide Gas Sensors, a Survey of Selectivity Issues Addressed at the SENSOR Lab, Brescia (Italy). AB - This work reports the recent results achieved at the SENSOR Lab, Brescia (Italy) to address the selectivity of metal oxide based gas sensors. In particular, two main strategies are being developed for this purpose: (i) investigating different sensing mechanisms featuring different response spectra that may be potentially integrated in a single device; (ii) exploiting the electronic nose (EN) approach. The former has been addressed only recently and activities are mainly focused on determining the most suitable configuration and measurements to exploit the novel mechanism. Devices suitable to exploit optical (photoluminescence), magnetic (magneto-optical Kerr effect) and surface ionization in addition to the traditional chemiresistor device are here discussed together with the sensing performance measured so far. The electronic nose is a much more consolidated technology, and results are shown concerning its suitability to respond to industrial and societal needs in the fields of food quality control and detection of microbial activity in human sweat. PMID- 28353674 TI - Optimization of an Optical Test Bench for Tire Properties Measurement and Tread Defects Characterization. AB - Tire characteristics and behavior are of great importance in vehicle dynamics since the forces transmitted in the tire-road contact are the main contributors to global vehicle performance. Several research groups have focused on the study and modeling of tires. Some of the most important factors that need to be known are tread characteristics and pressure distribution in the tire-ground contact patch. In this work, a test bench has been used to adequately determine the aforementioned factors. The measurement principle of the test bench is the frustration of total internal reflection (FTIR) of light. It makes use of a laterally illuminated glass on which the tire leans. An interposed plastic interface between them causes the reflection of light. Finally, a video camera captures the bright image formed through the glass. The brightness level in each pixel of the image is related to existing normal pressure. A study of the parameters that affect the test bench calibration such as type of interface material used, diffuse light, hysteresis, creep and transverse light absorption is performed. Experimental tests are conducted to relate tire inflation pressure and camber angle to the pressure distribution. Furthermore, the test bench is used to detect and evaluate the influence of defects in the tire on the contact pressures. PMID- 28353675 TI - NMR and IR Investigations of Strong Intramolecular Hydrogen Bonds. AB - For the purpose of this review, strong hydrogen bonds have been defined on the basis of experimental data, such as OH stretching wavenumbers, nuOH, and OH chemical shifts, deltaOH (in the latter case, after correction for ring current effects). Limits for O-H...Y systems are taken as 2800 > nuOH > 1800 cm-1, and 19 ppm > deltaOH > 15 ppm. Recent results as well as an account of theoretical advances are presented for a series of important classes of compounds such as beta-diketone enols, beta-thioxoketone enols, Mannich bases, proton sponges, quinoline N-oxides and diacid anions. The O...O distance has long been used as a parameter for hydrogen bond strength in O-H...O systems. On a broad scale, a correlation between OH stretching wavenumbers and O...O distances is observed, as demonstrated experimentally as well as theoretically, but for substituted beta diketone enols this correlation is relatively weak. PMID- 28353676 TI - An Improved Approach for RSSI-Based only Calibration-Free Real-Time Indoor Localization on IEEE 802.11 and 802.15.4 Wireless Networks. AB - Assuming a reliable and responsive spatial contextualization service is a must have in IEEE 802.11 and 802.15.4 wireless networks, a suitable approach consists of the implementation of localization capabilities, as an additional application layer to the communication protocol stack. Considering the applicative scenario where satellite-based positioning applications are denied, such as indoor environments, and excluding data packet arrivals time measurements due to lack of time resolution, received signal strength indicator (RSSI) measurements, obtained according to IEEE 802.11 and 802.15.4 data access technologies, are the unique data sources suitable for indoor geo-referencing using COTS devices. In the existing literature, many RSSI based localization systems are introduced and experimentally validated, nevertheless they require periodic calibrations and significant information fusion from different sensors that dramatically decrease overall systems reliability and their effective availability. This motivates the work presented in this paper, which introduces an approach for an RSSI-based calibration-free and real-time indoor localization. While switched-beam array based hardware (compliant with IEEE 802.15.4 router functionality) has already been presented by the author, the focus of this paper is the creation of an algorithmic layer for use with the pre-existing hardware capable to enable full localization and data contextualization over a standard 802.15.4 wireless sensor network using only RSSI information without the need of lengthy offline calibration phase. System validation reports the localization results in a typical indoor site, where the system has shown high accuracy, leading to a sub metrical overall mean error and an almost 100% site coverage within 1 m localization error. PMID- 28353677 TI - Physicochemical Properties of Jatropha Oil-Based Polyol Produced by a Two Steps Method. AB - A low cost, abundant, and renewable vegetable oil source has been gaining increasing attention due to its potential to be chemically modified to polyol and thence to become an alternative replacement for the petroleum-based polyol in polyurethane production. In this study, jatropha oil-based polyol (JOL) was synthesised from non-edible jatropha oil by a two steps process, namely epoxidation and oxirane ring opening. In the first step, the effect of the reaction temperature, the molar ratio of the oil double bond to formic acid, and the reaction time on the oxirane oxygen content (OOC) of the epoxidised jatropha oil (EJO) were investigated. It was found that 4.3% OOC could be achieved with a molar ratio of 1:0.6, a reaction temperature of 60 degrees C, and 4 h of reaction. Consequently, a series of polyols with hydroxyl numbers in the range of 138-217 mgKOH/g were produced by oxirane ring opening of EJOs, and the physicochemical and rheological properties were studied. Both the EJOs and the JOLs are liquid and have a number average molecular weight (Mn) in the range of 834 to 1457 g/mol and 1349 to 2129 g/mol, respectively. The JOLs exhibited Newtonian behaviour, with a low viscosity of 430-970 mPas. Finally, the JOL with a hydroxyl number of 161 mgKOH/g was further used to synthesise aqueous polyurethane dispersion, and the urethane formation was successfully monitored by Fourier Transform Infrared (FTIR). PMID- 28353679 TI - Metal-Free alpha-C(sp3)-H Functionalized Oxidative Cyclization of Tertiary N,N Diaryl Amino Alcohols: Theoretical Approach for Mechanistic Pathway. AB - The mechanistic pathway of TEMPO/I2-mediated oxidative cyclization of N,N-diaryl amino alcohols 1 was investigated. Based on direct empirical experiments, three key intermediates (aminium radical cation 3, alpha-aminoalkyl radical 4, and iminium 5), four types of reactive species (radical TEMPO, cationic TEMPO, TEMPO I, and iodo radical), and three types of pathways ((1) SET/PCET mechanism; (2) HAT/1,6-H transfer mechanism; (3) ionic mechanism) were assumed. Under the assumption, nine free energy diagrams were acquired through density functional theory calculations. From the comparison of solution-phase free energy, some possible mechanisms were excluded, and then the chosen plausible mechanisms were concretized using the more stable intermediate 7. PMID- 28353678 TI - Assessment of Lipophilicity Indices Derived from Retention Behavior of Antioxidant Compounds in RP-HPLC. AB - Reverse phase high pressure liquid chromatography was employed in order to evaluate the lipophilicity of antioxidant compounds from different classes, such as phenolic acids, flavanones, flavanols, flavones, anthocyanins, stilbenes, xantonoids, and proanthocyanidins. The retention time of each compound was measured using five different HPLC columns: RP18 (LiChroCART, Purosphere RP-18e), C8 (Zorbax, Eclipse XDBC8), C16-Amide (Discovery RP-Amide C16), CN100 (Saulentechnik, Lichrosphere), and pentafluorophenyl (Phenomenex, Kinetex PFP), and the mobile phase consisted of methanol and water (0.1% formic acid) in different proportions. The measurements were conducted at two different column temperatures, room temperature (22 degrees C) and, in order to mimic the environment from the human body, 37 degrees C. Furthermore, principal component analysis (PCA) was used to obtain new lipophilicity indices and holistic lipophilicity charts. Additionally, highly representative depictions of the chromatographic behavior of the investigated compounds and stationary phases at different temperatures were obtained using two new chemometric approaches, namely two-way joining cluster analysis and sum of ranking differences. PMID- 28353680 TI - A Self-Sustained Wireless Multi-Sensor Platform Integrated with Printable Organic Sensors for Indoor Environmental Monitoring. AB - A self-sustained multi-sensor platform for indoor environmental monitoring is proposed in this paper. To reduce the cost and power consumption of the sensing platform, in the developed platform, organic materials of PEDOT:PSS and PEDOT:PSS/EB-PANI are used as the sensing films for humidity and CO2 detection, respectively. Different from traditional gas sensors, these organic sensing films can operate at room temperature without heating processes or infrared transceivers so that the power consumption of the developed humidity and the CO2 sensors can be as low as 10 MUW and 5 MUW, respectively. To cooperate with these low-power sensors, a Complementary Metal-Oxide-Semiconductor (CMOS) system-on chip (SoC) is designed to amplify and to read out multiple sensor signals with low power consumption. The developed SoC includes an analog-front-end interface circuit (AFE), an analog-to-digital convertor (ADC), a digital controller and a power management unit (PMU). Scheduled by the digital controller, the sensing circuits are power gated with a small duty-cycle to reduce the average power consumption to 3.2 MUW. The designed PMU converts the power scavenged from a dye sensitized solar cell (DSSC) module into required supply voltages for SoC circuits operation under typical indoor illuminance conditions. To our knowledge, this is the first multiple environmental parameters (Temperature/CO2/Humidity) sensing platform that demonstrates a true self-powering functionality for long term operations. PMID- 28353681 TI - A Cardiac Early Warning System with Multi Channel SCG and ECG Monitoring for Mobile Health. AB - Use of information and communication technology such as smart phone, smart watch, smart glass and portable health monitoring devices for healthcare services has made Mobile Health (mHealth) an emerging research area. Coronary Heart Disease (CHD) is considered as a leading cause of death world wide and an increasing number of people die prematurely due to CHD. Under such circumstances, there is a growing demand for a reliable cardiac monitoring system to catch the intermittent abnormalities and detect critical cardiac behaviors which lead to sudden death. Use of mobile devices to collect Electrocardiography (ECG), Seismocardiography (SCG) data and efficient analysis of those data can monitor a patient's cardiac activities for early warning. This paper presents a novel cardiac data acquisition method and combined analysis of Electrocardiography (ECG) and multi channel Seismocardiography (SCG) data. An early warning system is implemented to monitor the cardiac activities of a person and accuracy assessment of the early warning system is conducted for the ECG data only. The assessment shows 88% accuracy and effectiveness of our proposed analysis, which implies the viability and applicability of the proposed early warning system. PMID- 28353682 TI - A Coarse Alignment Method Based on Digital Filters and Reconstructed Observation Vectors. AB - In this paper, a coarse alignment method based on apparent gravitational motion is proposed. Due to the interference of the complex situations, the true observation vectors, which are calculated by the apparent gravity, are contaminated. The sources of the interference are analyzed in detail, and then a low-pass digital filter is designed in this paper for eliminating the high frequency noise of the measurement observation vectors. To extract the effective observation vectors from the inertial sensors' outputs, a parameter recognition and vector reconstruction method are designed, where an adaptive Kalman filter is employed to estimate the unknown parameters. Furthermore, a robust filter, which is based on Huber's M-estimation theory, is developed for addressing the outliers of the measurement observation vectors due to the maneuver of the vehicle. A comprehensive experiment, which contains a simulation test and physical test, is designed to verify the performance of the proposed method, and the results show that the proposed method is equivalent to the popular apparent velocity method in swaying mode, but it is superior to the current methods while in moving mode when the strapdown inertial navigation system (SINS) is under entirely self-contained conditions. PMID- 28353684 TI - Posture Detection Based on Smart Cushion for Wheelchair Users. AB - The postures of wheelchair users can reveal their sitting habit, mood, and even predict health risks such as pressure ulcers or lower back pain. Mining the hidden information of the postures can reveal their wellness and general health conditions. In this paper, a cushion-based posture recognition system is used to process pressure sensor signals for the detection of user's posture in the wheelchair. The proposed posture detection method is composed of three main steps: data level classification for posture detection, backward selection of sensor configuration, and recognition results compared with previous literature. Five supervised classification techniques-Decision Tree (J48), Support Vector Machines (SVM), Multilayer Perceptron (MLP), Naive Bayes, and k-Nearest Neighbor (k-NN)-are compared in terms of classification accuracy, precision, recall, and F measure. Results indicate that the J48 classifier provides the highest accuracy compared to other techniques. The backward selection method was used to determine the best sensor deployment configuration of the wheelchair. Several kinds of pressure sensor deployments are compared and our new method of deployment is shown to better detect postures of the wheelchair users. Performance analysis also took into account the Body Mass Index (BMI), useful for evaluating the robustness of the method across individual physical differences. Results show that our proposed sensor deployment is effective, achieving 99.47% posture recognition accuracy. Our proposed method is very competitive for posture recognition and robust in comparison with other former research. Accurate posture detection represents a fundamental basic block to develop several applications, including fatigue estimation and activity level assessment. PMID- 28353683 TI - Model-Based Estimation of Ankle Joint Stiffness. AB - We address the estimation of biomechanical parameters with wearable measurement technologies. In particular, we focus on the estimation of sagittal plane ankle joint stiffness in dorsiflexion/plantar flexion. For this estimation, a novel nonlinear biomechanical model of the lower leg was formulated that is driven by electromyographic signals. The model incorporates a two-dimensional kinematic description in the sagittal plane for the calculation of muscle lever arms and torques. To reduce estimation errors due to model uncertainties, a filtering algorithm is necessary that employs segmental orientation sensor measurements. Because of the model's inherent nonlinearities and nonsmooth dynamics, a square root cubature Kalman filter was developed. The performance of the novel estimation approach was evaluated in silico and in an experimental procedure. The experimental study was conducted with body-worn sensors and a test-bench that was specifically designed to obtain reference angle and torque measurements for a single joint. Results show that the filter is able to reconstruct joint angle positions, velocities and torque, as well as, joint stiffness during experimental test bench movements. PMID- 28353685 TI - Strong population structure in a species manipulated by humans since the Neolithic: the European fallow deer (Dama dama dama). AB - Species that have been translocated and otherwise manipulated by humans may show patterns of population structure that reflect those interactions. At the same time, natural processes shape populations, including behavioural characteristics like dispersal potential and breeding system. In Europe, a key factor is the geography and history of climate change through the Pleistocene. During glacial maxima throughout that period, species in Europe with temperate distributions were forced south, becoming distributed among the isolated peninsulas represented by Anatolia, Italy and Iberia. Understanding modern patterns of diversity depends on understanding these historical population dynamics. Traditionally, European fallow deer (Dama dama dama) are thought to have been restricted to refugia in Anatolia and possibly Sicily and the Balkans. However, the distribution of this species was also greatly influenced by human-mediated translocations. We focus on fallow deer to better understand the relative influence of these natural and anthropogenic processes. We compared modern fallow deer putative populations across a broad geographic range using microsatellite and mitochondrial DNA loci. The results revealed highly insular populations, depauperate of genetic variation and significantly differentiated from each other. This is consistent with the expectations of drift acting on populations founded by small numbers of individuals, and reflects known founder populations in the north. However, there was also evidence for differentiation among (but not within) physically isolated regions in the south, including Iberia. In those regions we find evidence for a stronger influence from natural processes than may be expected for a species with such strong, known anthropogenic influence. PMID- 28353686 TI - Genetic structure and invasion history of the house mouse (Mus musculus domesticus) in Senegal, West Africa: a legacy of colonial and contemporary times. AB - Knowledge of the genetic make-up and demographic history of invasive populations is critical to understand invasion mechanisms. Commensal rodents are ideal models to study whether complex invasion histories are typical of introductions involving human activities. The house mouse Mus musculus domesticus is a major invasive synanthropic rodent originating from South-West Asia. It has been largely studied in Europe and on several remote islands, but the genetic structure and invasion history of this taxon have been little investigated in several continental areas, including West Africa. In this study, we focussed on invasive populations of M. m. domesticus in Senegal. In this focal area for European settlers, the distribution area and invasion spread of the house mouse is documented by decades of data on commensal rodent communities. Genetic variation at one mitochondrial locus and 16 nuclear microsatellite markers was analysed from individuals sampled in 36 sites distributed across the country. A combination of phylogeographic and population genetics methods showed that there was a single introduction event on the northern coast of Senegal, from an exogenous (probably West European) source, followed by a secondary introduction from northern Senegal into a coastal site further south. The geographic locations of these introduction sites were consistent with the colonial history of Senegal. Overall, the marked microsatellite genetic structure observed in Senegal, even between sites located close together, revealed a complex interplay of different demographic processes occurring during house mouse spatial expansion, including sequential founder effects and stratified dispersal due to human transport along major roads. PMID- 28353688 TI - Quantitative method for gait pattern detection based on fiber Bragg grating sensors. AB - This paper presents a method that uses fiber Bragg grating (FBG) sensors to distinguish the temporal gait patterns in gait cycles. Unlike most conventional methods that focus on electronic sensors to collect those physical quantities (i.e., strains, forces, pressure, displacements, velocity, and accelerations), the proposed method utilizes the backreflected peak wavelength from FBG sensors to describe the motion characteristics in human walking. Specifically, the FBG sensors are sensitive to external strain with the result that their backreflected peak wavelength will be shifted according to the extent of the influence of external strain. Therefore, when subjects walk in different gait patterns, the strains on FBG sensors will be different such that the magnitude of the backreflected peak wavelength varies. To test the reliability of the FBG sensor platform for gait pattern detection, the gold standard method using force sensitive resistors (FSRs) for defining gait patterns is introduced as a reference platform. The reliability of the FBG sensor platform is determined by comparing the detection results between the FBG sensors and FSRs platforms. The experimental results show that the FBG sensor platform is reliable in gait pattern detection and gains high reliability when compared with the reference platform. PMID- 28353689 TI - Robust phase unwrapping for phase images in Fourier domain Doppler optical coherence tomography. AB - To solve the 2 ? phase ambiguity for phase-resolved Doppler images in Doppler optical coherence tomography, we present a modified network programming technique for the first time to the best of our knowledge. The proposed method assumes that error of the discrete derivatives between unwrapped phase image and wrapped phase image can be arbitrary values instead of integer-multiple of 2 ? , which makes the real-phase restoration accurate and robust against noise. We compared our proposed method with the network programming method. Parameters including root mean-square-error and noise amplification degree were adopted for comparison. The experimental study on simulated images, phantom, and real-vessel OCT images were performed. The proposed method consistently achieves optimal results. PMID- 28353687 TI - Harnessing endogenous signals from hepatocytes using a low volume multi-well plate. AB - Hepatocytes are highly differentiated epithelial cells that lose their phenotype and function when removed from the in vivo environment. Given the importance of hepatic cultures for drug toxicity, bioartificial liver assist devices and basic biology studies, considerable efforts have been focused on the maintenance of hepatic function in vitro. The methods used to date include co-cultivation of hepatocytes with stromal cells, organizing these cells into spheroids and imbedding them into bioactive gels. Our team has recently demonstrated that primary rat hepatocytes confined to microfluidic channels in the absence of convection maintained the epithelial phenotype through upregulation of endogenous signals including hepatocyte growth factor (HGF). The objective of the present study was to transition from microfluidic devices, which are somewhat specialized and challenging to use, towards low volume multiwell plates ubiquitous in biology laboratories. Using a combination of 3D printing and micromolding we have constructed inserts that can be placed into standard 12-well plates and can be used to create low volume culture conditions under which primary hepatocytes maintained a differentiated phenotype. This phenotype enhancement was confirmed by hepatic function assays including albumin synthesis and expression. Importantly we confirmed upregulation of HGF inside the low volume culture plates and demonstrated that inhibition of HGF signaling degraded the hepatic phenotype in our cell culture platform. Overall, this study outlines a new cell culture system that leverages the low volume effects of microfluidic channels in a multiwell plate format. Beyond hepatocytes, such a system may be of use in the maintenance of other difficult-to-culture cells including stem cells and primary cancer cells. PMID- 28353691 TI - ? PMID- 28353690 TI - Impact of Rates of Change of Lamina Cribrosa and Optic Nerve Head Surface Depths on Visual Field Progression in Glaucoma. AB - Purpose: To investigate the impact of the rates of change of anterior lamina cribrosa surface depth (ALCSD) and optic nerve head surface depth (ONHSD) on visual field (VF) progression in glaucoma. Methods: One hundred forty-six eyes of 95 glaucoma patients had optical coherence tomography ONH imaging and VF testing at approximately 4-month intervals for greater than or equal to 5 years. Anterior lamina cribrosa surface depth and ONHSD were measured with reference to (1) Bruch's membrane opening (BMO), and (2) choroid-sclera interface (CSI). The rates of change of ALCSD and ONHSD of individual eyes were measured with linear regression analysis. The hazard ratios (HRs) of the rates of change of ALCSD/ONHSD for prediction of VF progression as per Early Manifest Glaucoma Trial criteria were determined by joint longitudinal and survival models. Results: Using the BMO reference, 23.3% and 28.1% of eyes showed a significant positive trend (posterior displacement), whereas 29.5% and 24.0% showed a significant negative trend (anterior displacement) of ALCSD and ONHSD, respectively. Using the CSI reference, the proportions with a significant negative trend decreased to 11.6% and 14.4%, respectively; and the proportions with a significant positive trend increased to 37.7% and 38.4%, respectively. The HRs of VF progression were 1.06 and 1.11 for each micrometer per year increase in the rates of change of ALCSDBMO and ONHSDBMO, respectively; and 1.07 and 1.09 for each micrometer per year increase in the rates of change of ALCSDCSI and ONHSDCSI, respectively. Conclusions: Identifying fast progressors of posterior ALCS/ONHS displacement is relevant to the management of glaucoma patients as they have a higher risk of VF progression. PMID- 28353692 TI - ? PMID- 28353693 TI - ? PMID- 28353694 TI - ? PMID- 28353695 TI - ? PMID- 28353696 TI - ? PMID- 28353697 TI - ? PMID- 28353698 TI - ? PMID- 28353699 TI - ? PMID- 28353701 TI - ? PMID- 28353700 TI - ? PMID- 28353702 TI - ? PMID- 28353703 TI - ? PMID- 28353705 TI - ? PMID- 28353704 TI - ? PMID- 28353706 TI - ? PMID- 28353707 TI - ? PMID- 28353708 TI - ? PMID- 28353709 TI - ? PMID- 28353710 TI - ? PMID- 28353711 TI - ? PMID- 28353712 TI - ? PMID- 28353713 TI - ? PMID- 28353714 TI - ? PMID- 28353716 TI - ? PMID- 28353715 TI - ? PMID- 28353717 TI - ? PMID- 28353718 TI - ? PMID- 28353719 TI - ? PMID- 28353720 TI - ? PMID- 28353721 TI - ? PMID- 28353722 TI - ? PMID- 28353723 TI - ? PMID- 28353724 TI - ? PMID- 28353725 TI - ? PMID- 28353726 TI - ? PMID- 28353727 TI - ? PMID- 28353728 TI - ? PMID- 28353729 TI - ? PMID- 28353730 TI - ? PMID- 28353731 TI - ? PMID- 28353732 TI - ? PMID- 28353733 TI - ? PMID- 28353734 TI - ? PMID- 28353735 TI - ? PMID- 28353736 TI - ? PMID- 28353737 TI - ? PMID- 28353739 TI - ? PMID- 28353738 TI - ? PMID- 28353740 TI - ? PMID- 28353741 TI - ? PMID- 28353742 TI - ? PMID- 28353743 TI - ? PMID- 28353744 TI - ? PMID- 28353745 TI - ? PMID- 28353746 TI - ? PMID- 28353747 TI - ? PMID- 28353748 TI - ? PMID- 28353749 TI - ? PMID- 28353750 TI - ? PMID- 28353751 TI - ? PMID- 28353752 TI - ? PMID- 28353753 TI - ? PMID- 28353754 TI - ? PMID- 28353755 TI - ? PMID- 28353756 TI - ? PMID- 28353757 TI - ? PMID- 28353758 TI - ? PMID- 28353760 TI - ? PMID- 28353759 TI - ? PMID- 28353761 TI - ? PMID- 28353762 TI - The occurrence of chondrodystrophy in chick embryos II. The genetic evidence. PMID- 28353763 TI - ? PMID- 28353764 TI - ? PMID- 28353765 TI - ? PMID- 28353766 TI - ? PMID- 28353767 TI - ? PMID- 28353768 TI - ? PMID- 28353769 TI - ? PMID- 28353770 TI - ? PMID- 28353771 TI - ? PMID- 28353772 TI - ? PMID- 28353774 TI - ? PMID- 28353773 TI - ? PMID- 28353775 TI - ? PMID- 28353776 TI - ? PMID- 28353777 TI - ? PMID- 28353778 TI - ? PMID- 28353779 TI - ? PMID- 28353780 TI - ? PMID- 28353781 TI - ? PMID- 28353782 TI - ? PMID- 28353783 TI - ? PMID- 28353784 TI - ? PMID- 28353785 TI - ? PMID- 28353786 TI - ? PMID- 28353787 TI - ? PMID- 28353788 TI - ? PMID- 28353789 TI - ? PMID- 28353790 TI - ? PMID- 28353791 TI - ? PMID- 28353792 TI - ? PMID- 28353793 TI - ? PMID- 28353794 TI - ? PMID- 28353795 TI - ? PMID- 28353796 TI - ? PMID- 28353797 TI - ? PMID- 28353798 TI - ? PMID- 28353799 TI - ? PMID- 28353800 TI - ? PMID- 28353802 TI - ? PMID- 28353801 TI - ? PMID- 28353803 TI - ? PMID- 28353804 TI - ? PMID- 28353805 TI - ? PMID- 28353806 TI - ? PMID- 28353807 TI - ? PMID- 28353809 TI - ? PMID- 28353808 TI - ? PMID- 28353810 TI - ? PMID- 28353811 TI - ? PMID- 28353812 TI - ? PMID- 28353813 TI - ? PMID- 28353815 TI - Asymmetry and relative growth of parts in the two sexes of the hermit-crab, eupagurus priedeauxi. PMID- 28353814 TI - ? PMID- 28353816 TI - ? PMID- 28353817 TI - ? PMID- 28353818 TI - ? PMID- 28353819 TI - ? PMID- 28353820 TI - ? PMID- 28353821 TI - ? PMID- 28353822 TI - ? PMID- 28353823 TI - ? PMID- 28353824 TI - ? PMID- 28353825 TI - ? PMID- 28353826 TI - ? PMID- 28353827 TI - The effect of yolk injections on the plumage of an ovariotomised brown leghron hen. PMID- 28353828 TI - ? PMID- 28353829 TI - ? PMID- 28353830 TI - Effect of thyroxin upon the thyroid gland and the regeneration and pigmentation of hair in Peromyscus. AB - 1. Thyroxin distended the follicles of the thyroid gland of Peromyscus. 2. Thyroxin increased the rapidity and extent of hair regeneration in mice from which half the hair on the back was removed. 3. The regenerated portion of the pelage contained fewer hairs than were removed; the smaller the type of hair the less complete was its regeneration. 4. Thyroxin did not affect the pigmentation of regenerated hairs. PMID- 28353832 TI - ? PMID- 28353831 TI - ? PMID- 28353833 TI - ? PMID- 28353834 TI - ? PMID- 28353835 TI - ? PMID- 28353836 TI - ? PMID- 28353837 TI - ? PMID- 28353839 TI - ? PMID- 28353838 TI - ? PMID- 28353840 TI - ? PMID- 28353841 TI - ? PMID- 28353843 TI - ? PMID- 28353842 TI - ? PMID- 28353844 TI - Spermatogenesis following early ovariotomy in the brown leghorn fowl. PMID- 28353845 TI - ? PMID- 28353846 TI - ? PMID- 28353847 TI - ? PMID- 28353848 TI - ? PMID- 28353849 TI - ? PMID- 28353851 TI - ? PMID- 28353850 TI - ? PMID- 28353852 TI - ? PMID- 28353853 TI - ? PMID- 28353854 TI - ? PMID- 28353855 TI - ? PMID- 28353856 TI - ? PMID- 28353857 TI - ? PMID- 28353858 TI - ? AB - ZUSAMMENFASSUNG: Wenn wir die Ausbildung der sekundaren Geschlechtsmerkmale in der postembryonalen Entwicklung des Ch. parallelus und der Wirbeltiere vergleichen, so beobachten wir eine grobetae Analogie zwischen denselben. 1. Die sekundaren Geschlechtsmerkmale erscheinen bei Ch. parallelus erst allmahlich, mit fortschreitendem Alter; sie fehlen in der 1. Altersstufe und fehlen auch ganz oder teilweise in der 2. Altersstufe. Sie sind in der 3. Altersstufe angedeutet und in der 4. klar zu erkennen, aber ihr Maximum erreichen sie erst beim Ubergang des Insekts zur erwachsenen Form. 2. Von besonderer Wichtigkeit ist es, dabeta bei der Entwicklung der sekundaren Geschlechtsmerkmale des Ch. parallelus ein deutlicher Sprung beim Ubergang zur erwachsenen Form beobachtet wird. Hier beobachten wir eine im Vergleich zu den vorhergehenden Altersstufen unverhaltnismabetaige Vergrobetaerung der sekundaren Geschlechtsunterschiede. 3. Die unverhaltnismabetaig starke Entwicklung der sekundaren Geschlechtsmerkmale beim Ubergang zum erwachsenen Zustand kann mit einer Entwicklungshemmung der einen und einer Entwicklungsstimulierung der anderen Merkmale bei den verschiedenen Geschlechtern erklart werden. 4. Nur die aubetaeren Geschlechtsorgane, zu welchen die letzten veranderten Hinterleibsegmente gehoren, unterscheiden sich deutlich (ohne Transgression) bei den Mannchen und Weibchen in der 1. Altersstufe, und zwar schon beim Ausschlupfen derselben aus dem Ei. Diese Unterschiede werden aber mit dem Alter grobetaer. Auf diese Weise entwickeln sich die Unterschiede im Bau der aubetaeren Geschlechtsteile viel fruher als die anderen Geschlechtsmerkmale. PMID- 28353859 TI - Intrinsic and extrinsic factors in the primary development of the skeleton. PMID- 28353860 TI - ? PMID- 28353861 TI - ? PMID- 28353863 TI - ? PMID- 28353862 TI - ? PMID- 28353864 TI - The influence of the quantity and quality of chromosomal material on the size of the cells in drosophila melanogaster. AB - 1. The small bristles on the surface of the wing ofDrosophila correspond each to a single cell. This fact makes possible the measurement of the size of the cells by counting the number of bristles within a known area of the wing surface. 2. Comparison of the cell size in male, female, superfemale, supermale, intersex and triploid female showed that the size of the cells increases with the increase of the total volume of the chromosomes contained in their nuclei. 3. The presence or absence of the Y-chromosome does not affect the size of the cells in spite of the considerable volume of the chromosome. 4. The loss of one fourth chromosome reduces the size of the cells considerably in spite of the smallness of the volume of this chromosome. 5. The mutant gene miniature alters the size of the cells strikingly. The epidermal cells of the wing membrane are apparent in miniature during the whole imaginal life of the fly; in wild-type and in all other mutants studied the epidermal cells degenerate soon after the emergence of the fly from the pupa. 6. The size of the cells in different races of the same species is determined by the quality as well as by the quantity of the chromosomal material contained in their nuclei. PMID- 28353865 TI - Determination of skeleton forming material at the time of the first cleavage in the eggs of echinus and paracentrotus. PMID- 28353866 TI - ? PMID- 28353867 TI - ? PMID- 28353868 TI - ? PMID- 28353869 TI - ? PMID- 28353870 TI - ? PMID- 28353871 TI - ? PMID- 28353872 TI - ? PMID- 28353873 TI - ? PMID- 28353874 TI - Regeneration and fragmentation in the Syllidian Polychaetes : Studies on the Syllidae II. PMID- 28353875 TI - ? PMID- 28353876 TI - ? PMID- 28353877 TI - ? PMID- 28353878 TI - Regeneration and reorganization in sabella. PMID- 28353879 TI - ? PMID- 28353880 TI - ? PMID- 28353881 TI - ? PMID- 28353882 TI - ? PMID- 28353883 TI - ? PMID- 28353885 TI - ? PMID- 28353884 TI - ? PMID- 28353886 TI - ? PMID- 28353887 TI - ? PMID- 28353888 TI - ? PMID- 28353889 TI - ? PMID- 28353890 TI - ? PMID- 28353891 TI - ? PMID- 28353892 TI - ? PMID- 28353893 TI - ? PMID- 28353894 TI - ? PMID- 28353895 TI - ? PMID- 28353896 TI - ? PMID- 28353897 TI - ? PMID- 28353898 TI - ? PMID- 28353900 TI - The effect of intensity and duration of light and of duration of darkness, partly modified by temperature, upon wing-production in aphids. PMID- 28353899 TI - ? PMID- 28353901 TI - ? PMID- 28353903 TI - ? PMID- 28353902 TI - ? PMID- 28353904 TI - ? PMID- 28353905 TI - ? PMID- 28353906 TI - ? PMID- 28353908 TI - ? PMID- 28353907 TI - ? PMID- 28353909 TI - ? PMID- 28353910 TI - ? PMID- 28353911 TI - ? PMID- 28353912 TI - ? PMID- 28353913 TI - ? PMID- 28353915 TI - ? PMID- 28353914 TI - ? PMID- 28353916 TI - ? PMID- 28353917 TI - ? PMID- 28353918 TI - ? PMID- 28353919 TI - ? PMID- 28353920 TI - ? PMID- 28353922 TI - ? PMID- 28353921 TI - The influence of temperature on egg size and variation in Drosophila melanogaster. PMID- 28353923 TI - ? PMID- 28353924 TI - ? PMID- 28353925 TI - ? PMID- 28353926 TI - ? PMID- 28353927 TI - ? PMID- 28353928 TI - ? PMID- 28353929 TI - ? PMID- 28353930 TI - ? PMID- 28353931 TI - ? PMID- 28353932 TI - A study of normal and regenerative growth in the pistol-crab, alpheus dentipes (Guer.), with special reference to the phenomenon of chela reversal. AB - An analysis has been made of the normal growth of the thoracic appendages in the pistol-crab,Alpheus dentipes. The chelae are the only asymmetrical appendages and, within an extensive size range, the growth-coefficient of the large chela (crusher) is smaller than that of the small chela (nipper), even in the most rapidly growing dimensions of the segment containing the growth-centre.The partition coefficient for growth in certain dimensions of the chelae is not constant but is reduced progressively during the growthperiod, due (it is suggested) to the impracticability of maintaining the intensive heterogony developed during the early stages of growth.Regenerative growth of the chelae has been studied quantitatively after autotomy of one, the other, or both normal chelae, effected once only or repeatedly as new chelae appeared at moulting. New chelae are regenerated repeatedly with little or no waning of growth intensity but in continuously growing chelae, growth intensity is substantially reduced at the end of the instar of autotomy. The amount of growth is not correlated with thenumber of days available for regeneration. When both chelae regenerate simultaneously the larger one grows relatively slower than the smaller one to the end of the instar of autotomy but afterwards this condition is reversed. When the nipper alone is autotomised, growth of the crusher is inhibited and shrinkage may occur. Crusher autotomy, on the other hand, stimulates nipper growth and to an extent which varies with the dimension.The problem of chela reversal has been discussed and certain suggestions have been preferred. PMID- 28353933 TI - ? PMID- 28353934 TI - ? PMID- 28353935 TI - ? PMID- 28353936 TI - ? PMID- 28353938 TI - ? PMID- 28353937 TI - ? PMID- 28353939 TI - ? PMID- 28353941 TI - ? PMID- 28353942 TI - ? PMID- 28353940 TI - ? PMID- 28353943 TI - ? PMID- 28353944 TI - ? PMID- 28353945 TI - ? PMID- 28353946 TI - ? PMID- 28353947 TI - ? PMID- 28353948 TI - ? PMID- 28353949 TI - ? PMID- 28353950 TI - ? PMID- 28353951 TI - Observations on limb development in Rana sylvatica following unilateral eye extirpation. AB - 1. The eye extirpation experiment ofDuRKEN (1913) has been repeated over a period of years with larvae ofRana sylvatica, and conflicting results have been obtained. 2. In the experiments herein reported, larvae have been reared under varied conditions of illumination and of temperature. The few defective cases obtained (0.7% of the whole) were distributed equally between the operated individuals and the controls, and were independent of the influences of darkness or of light, and of varying temperatures. 3. The results of these experiments strongly indicate that there is no causal relationship between the early removal of an eye and the later development of the limbs. 4. The occurrence of cases with defective limbs among museum specimens and among material collected in the field suggests that abnormal limb formation may be due to an instability of the individual. PMID- 28353952 TI - ? PMID- 28353953 TI - ? PMID- 28353954 TI - ? PMID- 28353955 TI - ? PMID- 28353956 TI - ? PMID- 28353957 TI - ? PMID- 28353958 TI - The development in vivo and in vitro of the avian patella. PMID- 28353959 TI - Induction by the endoderm in birds. AB - 1. The endoderm was separated from the epiblast in chick and duck embryos of young primitive streak stages, and then the two layers of tissue were replaced so that their longitudinal axes were diametrically opposed: i. e. the anterior part of the endoderm lay under the posterior region of the epiblast, and the posterior part of the endoderm under the anterior region of the epiblast. The combination was then cultivatedin vitro by the watch-glass technique. 2. The displaced endoderm had in most cases an effect on the development of the epiblast. It either (1) hindered the normal growth in length of the primitive streak, or (2) caused the development of a new primitive streak. In some cases the secondary (induced) streak disappeared on further cultivation, in some cases both streaks persisted and gave rise to a double monster, and in still other cases the secondary streak persisted and the primary disappeared. In two cases primary and secondary united to form a single semicircular embryo. 3. It is argued that the endoderm does not induce the differentiation of a definite tissue, but that it induces the form-building movements which lead to the development of the primitive streak. PMID- 28353960 TI - Induction by heteroplastic grafts of the primitive streak in birds. PMID- 28353961 TI - ? PMID- 28353962 TI - ? PMID- 28353963 TI - The influence of temperature on variation and inheritance of bodily dimensions inDrosophila melanogaster. PMID- 28353964 TI - ? PMID- 28353966 TI - ? PMID- 28353965 TI - ? PMID- 28353967 TI - ? PMID- 28353968 TI - ? PMID- 28353969 TI - ? PMID- 28353970 TI - ? PMID- 28353971 TI - ? PMID- 28353972 TI - ? PMID- 28353973 TI - ? PMID- 28353974 TI - ? PMID- 28353975 TI - Regional determination in the development of the trout. PMID- 28353976 TI - ? PMID- 28353977 TI - ? PMID- 28353978 TI - ? PMID- 28353980 TI - ? PMID- 28353979 TI - ? PMID- 28353981 TI - ? PMID- 28353982 TI - ? PMID- 28353983 TI - ? PMID- 28353984 TI - ? PMID- 28353985 TI - ? PMID- 28353986 TI - ? PMID- 28353987 TI - ? PMID- 28353988 TI - ? PMID- 28353989 TI - ? PMID- 28353990 TI - ? PMID- 28353992 TI - ? PMID- 28353991 TI - ? PMID- 28353993 TI - Experiments with direct currents on chick embryos. PMID- 28353994 TI - ? PMID- 28353996 TI - ? PMID- 28353995 TI - ? PMID- 28353997 TI - ? PMID- 28353998 TI - ? PMID- 28353999 TI - ? PMID- 28354000 TI - ? PMID- 28354001 TI - ? PMID- 28354002 TI - ? PMID- 28354003 TI - ? PMID- 28354004 TI - ? PMID- 28354005 TI - ? PMID- 28354006 TI - ? PMID- 28354007 TI - ? PMID- 28354008 TI - ? PMID- 28354009 TI - ? PMID- 28354010 TI - ? PMID- 28354011 TI - ? PMID- 28354012 TI - ? PMID- 28354013 TI - ? PMID- 28354014 TI - ? PMID- 28354015 TI - ? PMID- 28354016 TI - ? PMID- 28354017 TI - ? PMID- 28354018 TI - Studies on the effects of some genetic lethal factors on the embryonic development ofDrosophila melanogaster : V. An analysis of the mutantX 10. AB - 1. The development of the embryonic lethal mutantX 10 was studied by means of serial sections and by observations on living embryos. 2. The factor varies in its expression; three distinct types of abnormal embryos are produced, and in some the lethality does not occur until the larval stage. 3. Intype I embryos development stops after the formation of a cap of undifferentiated cells; intype II, differentiation is extremely limited, often giving nervous tissue exclusively, and no organ formation occurs;type III embryos reach a late stage of development, and the main features of morphogenesis are undisturbed, but cellular differentiation is retarded and abnormal. 4. Type III embryos provide some evidence that the pole cells invaginated with the posterior mid-gut rudiment give rise to both the germ cells and to the middle mid-gut cells, and also that the mesodermal parts of the gonads do not develop in the absence of the germ cells. 5. The origin of distinct types of embryonic lethal abnormalities, and of a larval lethality, from a single mutant factor, is discussed in terms of general developmental concepts. PMID- 28354019 TI - Studies on the effects of some genetic lethal factors on the embryonic development ofDrosophila melanogaster : VI. An analysis of the mutantS9. AB - 1. The development of the embryonic lethal mutantS9 was studied by means of serial sections and by observations on living embryos. 2. Lethality does not occur in the embryonic stage in all cases; a variable proportion of individuals of the lethal genotype dies in the pupal or larval stages. 3. The primary abnormality in the affected embryos is a disturbance of the distribution of the cleavage nuclei, which causes the blastoderm to be fragile at its anterior end, and consequently to lead to deformations in the later development of this region. 4. In the later stages of development, morphogenetic movements and cellular differentiation are disturbed in ways which differ greatly in individual cases, so that a wide variety of abnormalities is found in late embryos. PMID- 28354020 TI - ? PMID- 28354021 TI - ? PMID- 28354022 TI - ? PMID- 28354023 TI - ? PMID- 28354024 TI - ? PMID- 28354025 TI - ? PMID- 28354026 TI - ? PMID- 28354027 TI - ? PMID- 28354028 TI - ? PMID- 28354029 TI - ? PMID- 28354030 TI - ? PMID- 28354031 TI - ? PMID- 28354033 TI - ? PMID- 28354034 TI - ? PMID- 28354032 TI - ? PMID- 28354035 TI - ? PMID- 28354036 TI - ? PMID- 28354037 TI - ? PMID- 28354039 TI - ? PMID- 28354038 TI - ? PMID- 28354040 TI - ? PMID- 28354041 TI - Interaction between female and male parts in gynandromorphs of Drosophila simulans. PMID- 28354042 TI - ? PMID- 28354043 TI - ? PMID- 28354044 TI - ? PMID- 28354045 TI - ? PMID- 28354046 TI - ? PMID- 28354047 TI - ? PMID- 28354048 TI - ? PMID- 28354049 TI - ? PMID- 28354050 TI - ? PMID- 28354051 TI - ? PMID- 28354052 TI - ? PMID- 28354053 TI - ? PMID- 28354054 TI - ? PMID- 28354055 TI - ? PMID- 28354056 TI - ? PMID- 28354058 TI - ? PMID- 28354057 TI - ? PMID- 28354059 TI - ? PMID- 28354060 TI - The structure of the lymph glands ofDrosophila larvae. AB - 1. A detailed morphological and histological description is given of the lymph glands of late third instar wild type larvae. 2. In the late second instar of the wild type the lymph glands release some or their cells and these form the imaginal disc mesoderm, the lymph hearts, and other structures. The formation and the functioning of the lymph hearts are described. 3. It is argued that blood cells do not exist in theDrosophila larva. PMID- 28354061 TI - A genetically controlled malignant tumour inDrosophila. PMID- 28354062 TI - Lethal no-differentiation and the development of the imaginal discs during the larval stage inDrosophilia. AB - 1. Lethal no-differentiation, symboll-nd, is characterised by the failure of some or all of the imaginal buds to continue differentiation during the larval third instar. This is due to abnormal proliferation of the imaginal disc mesoderm. 2. There is a well-defined sequence in the sensitivity of the different organs to the lethal effect, the legs being the most commonly affected, and the genital disc the least commonly. 3. The abnormal proliferation of the mesoderm is preceded by degenerative changes in the lymph glands. 4. The mechanism of differentiation of the imaginal buds is discussed and it is argued that the organisation of the imaginal organs is determined primarily by the mesoderm. 5. It is suggested that the proliferation of the imaginal bud mesoderm is normally inhibited by a "bud-differentiation hormone" secreted by the lymph glands. The requirements of the different imaginal discs from this postulated hormone were represented by a histogram, in fig. 14. PMID- 28354063 TI - Regulation capacities of the wing- and halterediscs of wild type and bithoraxDrosophila. AB - 1. On removal of one dorsal mesothoracic disc from third-instar larvae ofDrosophila melanogaster (wild stock), regulation took place in one fourth of the cases, by the activity of the corresponding disc of the intact side. 2. In larvae of abithorax stock, regulation took place in the majority of cases, but it was due to the activity of thebx dorsal metathoracic disc of the operated side. 3. The sternopleura is present after extirpation of the wing disc but absent after extirpation of the ventral mesothoracic disc. 4. The findings under 1 and 2 are discussed in connection with previous work on regulation in larval discs. PMID- 28354064 TI - ? PMID- 28354065 TI - ? PMID- 28354066 TI - ? PMID- 28354067 TI - ? PMID- 28354068 TI - ? PMID- 28354069 TI - ? PMID- 28354070 TI - ? PMID- 28354071 TI - ? PMID- 28354072 TI - ? PMID- 28354073 TI - ? PMID- 28354074 TI - ? PMID- 28354075 TI - ? PMID- 28354076 TI - ? PMID- 28354077 TI - ? PMID- 28354078 TI - ? PMID- 28354079 TI - The morphogenetic action of follicle-stimulating hormone on post-nodal fragments of early chick blastoderms. AB - The morphogenetic action of ovine follicle-stimulating hormone has been studied. The hormone is incorporated in known concentrations in agar-albumen-compton base and post-nodal fragments of primitivestreak stage chick blastoderms 0.7 mm behind theHENSEN'S node are cultured on the base for 35-45 hours. The hormone is found to induce the formation of neural tissue, notochord-like tissue and mesodermal aggregations resembling somites. PMID- 28354080 TI - ? PMID- 28354081 TI - RNA and protein distribution during the development of axial mesodermal structures in the ascidian,Clavelina picta. PMID- 28354082 TI - Influence of the endoderm on heart differentiation during the early stages of development of the chicken embryo. AB - 1. In stages +4, 5 and +5 in the chick embryo, the bilateral extirpation of the endoderm in the entire extension of the P.H.M. region detains heart differentiation, giving rise to acardiac embryos. 2. The unilateral extirpation of the endoderm in the entire extension of the P.H.M. region detains heart differentiation of the primordium of the side operated on, forming a typical beating heart from the heterolateral primordium. 3. If the extirpation of the endoderm is partial, a small beating vesicle is formed on the side operated on, which has the characters of the ventricle bulb or atrium, according to which region of the endoderm was extirpated. 4. It is not possible to demonstrate a difference between right side and left side extirpations of the endoderm. 5. The formation of the fore-gut is detained completely or unilateraly due to the absence of the morphogenetic movements of the endoderm in the extirpated region. Neither are the fore-gut fissures formed. 6. The embryos which form are abnormal in the encephalic extremity, observing platyneuria and vascular dilatations with great frequency. 7. In the stages in which these experiments have been carried out, the P.H.M. is not found to be determined as yet and still needs the influence or induction of the endoderm in order to initiate its differentiation. PMID- 28354083 TI - ? PMID- 28354084 TI - The genetic control of developmental competence and morphogenetic tissue interactions in genetic mosaics. AB - 1. InDrosophila melanogaster the genotype Theta causes the development of an interalar bristle-organ which is not formed in the wild type. The genotype Minute n causes, in Theta flies, a strong reduction in the frequency of the occurrence of the interalar bristle. 2. By means of genetic mosaics, produced by somatic crossing over and segregation, a developmental analysis was applied to the differences in interalar differentiation between the wild-type, the Theta and the Minute-n genotype. 3. Loss of Minute-n in segregated tissues of Minute-n Theta flies leads to differentiation of the interalar bristle. Loss of Minute-n and Theta in segregates of such flies may also lead to differentiation of the bristle, particularly in spots of small area. 4. In the neighborhood of the border between the genetically different tissues of mosaics extra bristles may be formed. 5. The data furnish evidence for interactions between the genetically different tissues of mosaics: inhibition of bristle formation in the surroundings of differentiating bristles, and spread of gene-dependent substances concerned with differentiation. 6. The results can be interpreted in terms of a constant prepattern for the interalar bristle in wild-type, Theta and Minute Theta genotypes, but of different competence of cells with the three genotypes to respond to the prepattern by differentiation of the interalar bristle. PMID- 28354085 TI - ? PMID- 28354086 TI - ? PMID- 28354087 TI - ? PMID- 28354088 TI - Studies on the effects of some genetic lethal factors on the embryonic development ofDrosophila melanogaster : III. An analysis op the mutantX 27. AB - 1. The development of the embryonic lethal mutantX 27 was studied by means of serial sections and by observations on living embryos. 2. The embryos reaches a late stage of development, and survives after the time at which normal embryos hatch. 3. The earliest observable effect of the factor is upon the first stage of gastrulation, in which the formation of the ventral furrow is disturbed. 4. Some abnormalities of the final embryo, especially certain deformations of the hind gut and the nervous system, originate in mechanical disturbances arising from the abnormalities in gastrulation. 5. Other abnormalities do not originate in this way, but are due to defective cell differentiation: the gut remains sac-like, the ectoderm remains unsegmented, and the musculature of the body wall is undeveloped. 6. It is probable that the failure of the musculature of the body wall to develop follows from the absence of segmentation in the hypoderm, and that a type of inductive mechanism is involved. PMID- 28354089 TI - Studies on the effects of some genetic lethal factors on the embryonic development ofDrosophila melanogaster : IV. An analysis op the mutantX 20. AB - 1. The development of the embryonic lethal mutantX 20 was studied by means of serial sections and by observations on living embryos. 2. There is considerable variation in the expression of the lethality in the embryo. Four types of abnormal embryos are produced:I andII, in which there are certain abnormalities in various organ systems;III, in which there is an irregular blastoderm, and no development after gastrulation; andIV, in which cell proliferation occurs, but not differentiation. 3. Intypes I andII, the chief abnormality is in the differentiation of the ectoderm, but the disturbances in it are of contrary kinds in the two types. Intype I, a complete nervous system is produced, but the hypoderm is absent ventrally; whereas intype II, the nervous system is nearly or quite absent, and the hypoderm is complete. 4. The abnormal embryos oftype I are identical with some of those which previous workers have obtained by treating normal embryos with ultrasonics during blastoderm formation. 5. It is suggested that the primary effect of the factor is upon some sub-microscopic cellular factor in an early developmental stage, which has an effect upon ectodermal differentiation. PMID- 28354090 TI - ? PMID- 28354091 TI - ? PMID- 28354092 TI - ? AB - EDTA and ethylurethan specifically interferes with the formation of normalDictyostelium fruiting bodies without inhibiting the cellular differentiation into spores and stalk cells. Thus differentiation is largely independent from the normal culmination process.On the other hand a preferential inhibition of the differentiation has been observed with 2-mercaptoethanol, the spores being more sensitive than the stalk cells. PMID- 28354093 TI - ? PMID- 28354094 TI - ? PMID- 28354095 TI - ? PMID- 28354096 TI - ? PMID- 28354097 TI - ? PMID- 28354098 TI - ? PMID- 28354099 TI - ? PMID- 28354100 TI - ? PMID- 28354101 TI - ? PMID- 28354102 TI - ? PMID- 28354103 TI - ? PMID- 28354104 TI - ? PMID- 28354105 TI - ? PMID- 28354106 TI - ? PMID- 28354107 TI - ? PMID- 28354108 TI - ? PMID- 28354109 TI - Formation of the shell about the embryo of Hydra. PMID- 28354111 TI - ? PMID- 28354110 TI - ? PMID- 28354112 TI - ? PMID- 28354113 TI - ? PMID- 28354114 TI - ? PMID- 28354115 TI - ? PMID- 28354116 TI - ? PMID- 28354117 TI - Interactions between the endocrine system and the developing tissue inEphestia kuhniella. PMID- 28354118 TI - ? PMID- 28354119 TI - ? AB - 1. In a young larva ofRana esculenta, the budding fourth digit of a hind limb is cut off unilaterally. After 4 days, before regeneration has proceeded appreciably, the hind limbs are removed on both sides, fixed and compared with limbs of control larvae of identical stage. 2. It is found that one phalanx of the fourth digit is significantly shorter on the unoperated side than the corresponding phalanx of the controls. 3. The second and third digit, adjacent to the amputated fourth, lag behind in their growth compared with the controls. PMID- 28354120 TI - ? AB - 1. For the experiments larvae ofPeriplaneta americana (25-28 mm) were used. The antennae were amputated: (a) at different levels immediately after molting; (b) at the same level at different times after the molt. The rate of metamorphosis was observed at the first molt after the operation. 2. The proportion of adult molts increases with the length of the stump of the antennae if symmetrical amputations were carried out at different levels on the first day after the larval molt. There is a negative linear relation between the percentage of adult molts (probit values) and the calculated intensity of the regeneration processes which decreases with the length of the stump. 3. If the proportion of adult molts (probits) is plotted against the logarithm of the time of amputation a straight line relation to time is obtained provided the amputation was carried out during the growth and differentiation period of the antenna. The rate of metamorphosis increases with time. 4. The observed behavior is discussed in terms of a mutual relationship between the endocrine system and the developing tissue. It is suggested that the intensity of the developmental processes is the essential variable controlling the level of prothoracic gland hormone which controls the activity of the corpora allata. PMID- 28354121 TI - ? PMID- 28354122 TI - ? PMID- 28354123 TI - ? PMID- 28354124 TI - ? PMID- 28354126 TI - ? PMID- 28354125 TI - ? PMID- 28354127 TI - ? PMID- 28354128 TI - ? PMID- 28354129 TI - ? PMID- 28354130 TI - ? PMID- 28354131 TI - ? PMID- 28354132 TI - ? PMID- 28354133 TI - ? PMID- 28354134 TI - ? PMID- 28354135 TI - ? PMID- 28354136 TI - ? PMID- 28354137 TI - Selective fertilization in the rat. PMID- 28354138 TI - ? PMID- 28354139 TI - The effect of foreign skin on feather pattern in the common fowl (Gallus domesticus). AB - Experiments with skin grafting in the fowl have shown that a large measure of success is obtainable by means of a very simple technique. When a graft is placed on the back of a newly hatched chick the feathers subsequently developed conform very strictly in color and pattern to the type characteristic of the breed from which the graft was derived, except that occasionally some abnormally colored feathers are produced. These feathers are found to belong to two classes, one of which can be duplicated in unoperated birds, while the other is distinctive and represents a combination of the characteristics of donor and host. The data at hand do not justify anything more than a tentative hypothesis as to the exact mode of interaction in this case, but the fact that such an interaction does occur places the bird in line with some of the lower forms, and opens a new field for the study of regulatory processes in warm blooded animals. PMID- 28354140 TI - ? PMID- 28354141 TI - ? PMID- 28354142 TI - Differentiation versus cleavage in chorio-allantoic grafts. AB - A considerable amount of data obtained in the course of a large series of experiments upon the embryo of the fowl has lead to the conclusion that there is a great amount of independence between the processes involved in cell division and those concerned with differentiation in ontogeny. The conclusions are based upon the fact that when parts of the embryo are grafted at early stages, the size of the resulting organ is much smaller than that of organ segregates grafted at later stages. There is a direct relationship expressed in the series studied. Mention is made of the development of a number of organs in grafts and controls. The eye is selected for detailed discussion because of the fact that the differentiation of the subordinate parts is clear-cut, and models may easily be made of such organs for subsequent weighing and comparison. While there is a marked discrepancy between the sizes of the organs arising in grafts made at different developmental stages, the differentiation of the subordinate parts is essentially similar to that in the controls. The behavior in the chick is, therefore, similar to that already observed in some of the invertebrate groups. Such a method of attack may yield valuable information concerning the intimate nature of the processes involved in each event, viz. cell division, and cell differentiation, which may, very conceivably aid in their interpretation of these events. PMID- 28354143 TI - ? PMID- 28354144 TI - ? PMID- 28354145 TI - ? PMID- 28354146 TI - ? PMID- 28354147 TI - ? PMID- 28354148 TI - ? PMID- 28354149 TI - Some observations upon grafted eyes of frog larvae. PMID- 28354150 TI - ? PMID- 28354151 TI - ? PMID- 28354152 TI - ? PMID- 28354153 TI - ? PMID- 28354154 TI - ? PMID- 28354155 TI - ? PMID- 28354156 TI - ? PMID- 28354157 TI - ? PMID- 28354158 TI - ? PMID- 28354159 TI - ? PMID- 28354160 TI - ? PMID- 28354161 TI - ? PMID- 28354162 TI - ? PMID- 28354163 TI - ? PMID- 28354164 TI - ? PMID- 28354165 TI - ? PMID- 28354167 TI - ? PMID- 28354168 TI - ? PMID- 28354166 TI - ? PMID- 28354169 TI - ? PMID- 28354170 TI - ? PMID- 28354171 TI - ? PMID- 28354172 TI - ? PMID- 28354173 TI - ? PMID- 28354174 TI - ? PMID- 28354175 TI - ? PMID- 28354176 TI - ? AB - 1. Cells ofDictyostelium discoideum grow exponentially when cultivated in suspension. The generation time is 3,3 hrs (20 degrees C). 2. In all stages of their development the cells can agglutinate spontaneously. Agglutinates in a certain developmental stage undergo immediate transformation into fruiting bodies, if they can make contact with the liquid/air interphase. This contact induces the polarity of the fruiting bodies. Autonomous polarization does not occur. Bilateral interphase contact induces twin fruiting bodies pointing in opposite directions. 3. Weakening of intercellular contacts results in a reduction of the average size of the agglutinates and can thus be recognized easily under standardized conditions. This was shown to be the case for two morphologically deficient mutants. PMID- 28354177 TI - ? PMID- 28354178 TI - ? PMID- 28354179 TI - ? PMID- 28354180 TI - ? PMID- 28354181 TI - ? PMID- 28354182 TI - Experiments showing the role of migrating neural crest (mesectoderm) in the formation of head skeleton and loose connective tissue in Rana palustris. PMID- 28354183 TI - An analysis of the responses of isolated portions of the amphibian nervous system. PMID- 28354184 TI - ? PMID- 28354185 TI - ? PMID- 28354186 TI - ? PMID- 28354187 TI - ? PMID- 28354188 TI - ? PMID- 28354189 TI - ? PMID- 28354190 TI - ? PMID- 28354191 TI - ? PMID- 28354192 TI - Embryonic segregation and its role in the life history. PMID- 28354193 TI - ? PMID- 28354194 TI - ? PMID- 28354195 TI - ? PMID- 28354196 TI - Studies on some aspects of regeneration inPelmatohydra oligactis. AB - 1. A histological and experimental study undertaken to elucidate the mechanism of regeneration ofPelmatohydra oligactis has shown that there is no significant mitotic activity in regeneration. 2. Chloroacetophenone (CAP) caused inhibition of regeneration but cystine and cysteine were ineffective. 3. The results are discussed from the point of view of the importance of -SH? -SS- equilibrium in regeneration. It is suggested that CAP might be acting on enzymatic -SH groups that are vitally concerned in some energy system. PMID- 28354197 TI - ? PMID- 28354199 TI - ? PMID- 28354198 TI - ? PMID- 28354200 TI - ? PMID- 28354201 TI - ? PMID- 28354202 TI - ? PMID- 28354203 TI - ? PMID- 28354204 TI - ? PMID- 28354205 TI - ? PMID- 28354206 TI - ? PMID- 28354207 TI - ? PMID- 28354208 TI - The genetic control of genital morphology inDrosophila : A study of the external genitalia of sex mosaics. PMID- 28354209 TI - ? PMID- 28354210 TI - ? PMID- 28354211 TI - ? PMID- 28354212 TI - ? PMID- 28354213 TI - ? PMID- 28354214 TI - ? PMID- 28354215 TI - ? PMID- 28354216 TI - ? PMID- 28354217 TI - ? PMID- 28354219 TI - ? PMID- 28354218 TI - ? PMID- 28354220 TI - ? PMID- 28354221 TI - ? PMID- 28354222 TI - ? PMID- 28354223 TI - ? PMID- 28354224 TI - ? PMID- 28354225 TI - ? PMID- 28354226 TI - ? PMID- 28354227 TI - ? PMID- 28354228 TI - ? PMID- 28354229 TI - ? PMID- 28354230 TI - ? PMID- 28354231 TI - ? PMID- 28354233 TI - Mitotic complex in the cardiac field of chick embryos. AB - 1. The mitotic peculiarity of the ventricle has been studied. 2. Diffused mitotic activity is noticed throughout the tissue matrix. No definite mitotic zone is seen. The total mitotic activity varies in the different regions as well as in different times of growth. 3. Except in 3 day heart, the rate of cell division is always more in the central area. 4. The ratio of dividing nuclei to resting nuclei in the peripheral region of 3 day heart is higher than that in the central region. 5. The most important item in the individuation of this organ is that the total percentage of dividing nuclei in the different stages, always present a slender figure. However, the cell increase is continuous. 6. The frequency is at its maximum. (11.03%) in 13 day heart, and the minimum (3.09%) in 21 day heart. The percentage of divisional figures in other stages fluctuates in between them. The cell increase in the heart continues even after hatching. PMID- 28354232 TI - ? PMID- 28354234 TI - ? PMID- 28354235 TI - ? PMID- 28354236 TI - ? PMID- 28354237 TI - ? PMID- 28354238 TI - ? PMID- 28354239 TI - ? PMID- 28354240 TI - ? PMID- 28354241 TI - ? PMID- 28354242 TI - ? PMID- 28354243 TI - ? PMID- 28354244 TI - ? PMID- 28354245 TI - ? PMID- 28354246 TI - ? PMID- 28354247 TI - ? PMID- 28354248 TI - ? PMID- 28354249 TI - ? PMID- 28354250 TI - ? PMID- 28354251 TI - ? PMID- 28354252 TI - ? PMID- 28354253 TI - ? PMID- 28354254 TI - ? PMID- 28354255 TI - ? PMID- 28354256 TI - ? PMID- 28354257 TI - ? PMID- 28354258 TI - ? PMID- 28354259 TI - ? PMID- 28354260 TI - ? PMID- 28354261 TI - ? PMID- 28354262 TI - Growth and development of flesh flies as influenced by the feeding of hypophysis (Pituitary gland). AB - 1. Flesh fly larvae of the speciesSarcophaga saracena andCalliphora erythrocephala were used. Different groups of larvae from the same parent, the same litter and under approximately the same meteorological conditions were fed exclusively on an abundant diet of the anterior lobe, posterior lobe and whole gland of the hypophysis of the pig. The controls were fed on an abundant diet of brain and muscle, obtained from the same animal. 2. A method for obtaining quickly the first stage larvae of a larviparous fly by cesarotomy was developed. 3. When fed to flesh fly larvae under the conditions described, anterior lobe of the hypophysis exercises no growth promoting influence; neither was the rate of metamorphosis accelerated over that of the control animals. 4. The differences in growth that do occur may be conveniently accounted for by the normal variation in growth development occurring in the species. 5. No toxic effect or any observable retardation of growth was produced on the larvae as a result of an exclusive and abundant diet of the gland substance. 6. The larvae ingesting muscle showed an increased larval period ranging from 25 to 40 hours over that of the maggots feeding on the other substances and this factor is dependent on a slower rate of liquefaction of this tissue, for the pupal period in all groups of larvae of the same parentage was approximately of the same duration. 7. The chemical make up of the different substances fed, as well as any resulting bacterial action on them does not appear to be of any great significance in these experiments, since the larvae feeding on them developed into healthy adult flies. 8. Since the injection of extracts of hypophysis (anterior lobe) is usually effective and in most cases non-effective when the gland substance is fed by mouth, it becomes necessary to make a distinction between the effects produced by the feeding of the hypophysis and those resulting from the injection of its extracts. PMID- 28354263 TI - ? PMID- 28354264 TI - ? PMID- 28354265 TI - ? PMID- 28354266 TI - ? PMID- 28354267 TI - ? PMID- 28354268 TI - ? PMID- 28354270 TI - ? PMID- 28354271 TI - ? PMID- 28354269 TI - ? PMID- 28354272 TI - ? PMID- 28354273 TI - ? PMID- 28354274 TI - ? PMID- 28354275 TI - ? PMID- 28354276 TI - Effects of feeding silkworms on extract of the anterior lobe of the pituitary gland. AB - Silk worms have been fed upon extract of the anterior lobe of the pituitary gland, special precautions being taken to ensure that the insects actually ingest the active principle.Marked retardation of growth is described. Metamorphosis was delayed likewise, and the mortality at the various metamorphological stages much greater than in the control group of worms.Normal movements were unaffected but definite slowing of the circulation was observed.Reasons are advanced for the belief that the retardatory effect was caused by a failure of metabolism, and it is suggested that this may relate to carbohydrate metabolism in particular. A distinction between vertebrates and invertebrates is noted, the former exhibiting an initial retardatory effect followed by an acceleration of growth whilst the latter only show retardation. PMID- 28354277 TI - ? PMID- 28354278 TI - ? PMID- 28354279 TI - ? PMID- 28354280 TI - ? PMID- 28354281 TI - ? PMID- 28354282 TI - ? PMID- 28354283 TI - ? PMID- 28354284 TI - ? PMID- 28354285 TI - ? PMID- 28354286 TI - The formation of lenses from the margin of the optic cup in eyes implanted in the belly wall of Triton and the possibility of the formation of lenses from belly ectoderm. PMID- 28354287 TI - ? PMID- 28354288 TI - ? PMID- 28354289 TI - ? PMID- 28354290 TI - ? PMID- 28354291 TI - ? PMID- 28354292 TI - ? PMID- 28354293 TI - ? PMID- 28354294 TI - ? PMID- 28354295 TI - ? PMID- 28354296 TI - ? PMID- 28354297 TI - ? PMID- 28354298 TI - ? PMID- 28354299 TI - ? PMID- 28354300 TI - ? PMID- 28354301 TI - ? PMID- 28354302 TI - ? PMID- 28354303 TI - ? PMID- 28354304 TI - ? PMID- 28354306 TI - ? PMID- 28354305 TI - ? PMID- 28354307 TI - ? PMID- 28354308 TI - ? PMID- 28354309 TI - ? PMID- 28354310 TI - ? PMID- 28354311 TI - ? PMID- 28354312 TI - ? PMID- 28354313 TI - ? PMID- 28354314 TI - ? PMID- 28354315 TI - ? PMID- 28354316 TI - ? PMID- 28354317 TI - ? PMID- 28354318 TI - ? PMID- 28354320 TI - ? PMID- 28354319 TI - ? PMID- 28354321 TI - ? PMID- 28354322 TI - ? PMID- 28354323 TI - ? PMID- 28354324 TI - ? PMID- 28354325 TI - ? PMID- 28354327 TI - ? PMID- 28354326 TI - ? PMID- 28354328 TI - ? PMID- 28354329 TI - The effect of reversing the medio-lateral or transverse axis of the fore-limb bud in the salamander embryo (Amblystoma punctatum Linn.). PMID- 28354330 TI - ? PMID- 28354331 TI - ? PMID- 28354332 TI - ? PMID- 28354333 TI - On the coherence of the blastomeres of sea urchin eggs. AB - 1. The formation of the hyaline substance is prevented by the action of a solution of non-electrolyte. 2. Cell division does not depend upon the presence of hyaline substance or a hyaline layer. 3. The cell bridges arise independently of the hyaline layer. 4. The size and tensile strength of the cell bridges depend upon the concentration of calcium-ion. 5. Although both the hyaline layer and the cell bridges are affected in the same fashion by the lack of calcium-ion, they react differently to a medium slightly hypertonic. PMID- 28354334 TI - ? PMID- 28354335 TI - ? PMID- 28354336 TI - ? PMID- 28354337 TI - ? AB - 1. Chemically pure thyroxin solution was used to study the effect on the metamorphic rate, fecundity, sex ratio, size and crossing-over ofDrosophila melanogaster. 2. The data obtained show thatDrosophila does not respond to thyroxin in the same way as do the Vertebrates. 3. Some small alteration (e. g. in the egg-laying period) was due to the secondary effect of thyroxin; i. e. the altered pH of the food. 4. The negative results obtained byDOBKIEWICZ with dried thyroid gland were confirmed when pure thyroxin was used. PMID- 28354338 TI - ? PMID- 28354339 TI - ? PMID- 28354340 TI - ? PMID- 28354341 TI - ? PMID- 28354342 TI - ? PMID- 28354343 TI - ? PMID- 28354344 TI - The mutant "proboscipedia" in Drosophila melanogaster - A case of hereditary homoosis. AB - The recessive mutant "proboscipedia", found byBRIDGES April 27, 1931, has its locus in the third chromosome at approximately 5.3 units to the right of Dichaete, or at 45.7.In proboscipedia the oral lobes are converted into a labium like organ, which also resembles a pair of antenna-like or tarsus-like appendages. This change, as well as the modifications of the labrum, maxillae, maxillary palpi, and other structures give to the mouth parts of proboscipedia a resemblance to those of the biting type found in insects of lower orders.The four fold resemblance of the modified oral lobes in proboscipedia to the labrum, the maxillary palpi, the antenae and the tarsi is comprehensible in view of the homology of these three head-appendages with each other and with the walking legs. PMID- 28354345 TI - ? PMID- 28354346 TI - ? PMID- 28354347 TI - ? PMID- 28354348 TI - ? PMID- 28354349 TI - ? PMID- 28354350 TI - ? PMID- 28354351 TI - ? PMID- 28354352 TI - ? PMID- 28354353 TI - ? PMID- 28354354 TI - ? PMID- 28354355 TI - ? PMID- 28354356 TI - ? PMID- 28354357 TI - ? PMID- 28354358 TI - ? PMID- 28354359 TI - Observations on physiological factors influencing the genetic coloration of fowl plumage. AB - 1. Evidence is given that there is in the Brown Leghorn Fowl (light brown variety) a direct correlation between the rate of growth of the feathers and the amount of black pigment deposited in them. 2. The effect of hormones (male, female, thyroid and anterior pituitary extracts) on growth rates and on pigmentation is considered. 3. Tests are described to discover whether female hormone has an effect on the production of melanin by the tyrosine - tyrosinase reaction. 4. A suggestion is made regarding the previously known fact that there are in urine unidentified substances affecting (inhibiting) the tyrosine - tyrosinase reaction. PMID- 28354360 TI - ? PMID- 28354361 TI - ? PMID- 28354362 TI - ? PMID- 28354363 TI - ? PMID- 28354364 TI - Observations on effects of ultra-violet rays upon living eggs of Nereis limbata exposed before insemination. AB - A. Eggs ofNereis exposed to ultra-violet light before insemination exhibit threee marked effects: 1. They extrude jelly equally from all parts of the cortex. 2. The first cleavage plane passes through that area of the egg from which the membrane is farthest removed-the site of maximum effect of the exposure. This sharply localized cortical injury can be traced throughout the egg's development into the worm of three segments. The majority of these worms exhibit a blister on the side of the first segment behind the head. 3. Polar body formation is suppressed. B. These effects are due to a sharply localized cortical injury. PMID- 28354366 TI - ? PMID- 28354365 TI - ? PMID- 28354367 TI - Potencies of the gonad-forming area in the chick as tested in chorio-allantoic grafts. AB - 1. This report deals with an analysis by chorio-allantoic grafting of the developmental potentialities of the gonad-forming areas of stages prior to the genital ridge in the chick embryo. The stages tested include a) those prior to the formation of the germinal epithelium (donors having from 29 to 34 somites) and b) those in which a germinal epithelium is visibly differentiated (donors having from 35 to 41 somites). In all of these stages germ-cells are present in the gonadforming areas. 2. a) In 34% of the 77 grafts histologically examined a gonad of specific sex has differentiated. Prior to the origin of the germinal epithelium such a gonad arises in 23.9% of the grafts whereas after its formation in 48.4% of the grafts; according to a former report (WILLIER '27) when the genital ridge stage is reached it forms in approximately 100% of the grafts. b) A gonad-like body of undetermined sex forms commonly (60%) in the grafts of the gonad-forming area whereas it rarely does so in grafts of the genital ridge. Prior to the 31-somite stage this type of gonad only has thus far formed. Several grades of organization of these bodies are recognized. c) The gonad-forming area yields somewhat frequently multiple gonads whereas a well-defined genital ridge gives as a rule a single gonad. d) The size of the gonad of specific sex which arises from the gonad-forming area is smaller than one from the genital ridge. It is thus evident that a progressive change in the developmental potentialities of the gonad-forming area occurs as it transforms into a genital ridge. This is interpreted as indicating that the gonad-forming area during its initial development exhibits an ascending organization which finally attains at the genital ridge stage a fully "determined" condition. 3. In the majority of the grafts of the gonad-forming area masses of germinal-cells are found external to the gonad in the mesenchyme or spaces within it. In such positions the germ-cells merely undergo repeated multiplication, exhibiting no tendency to form a gonad. If by chance germ-cells come to be situated in the wall of either the Wolffian or Mullerian duct, the overlying coelomic epithelium thickens into a layer simulating a germinal epithelium, yet the essential components of an avian gonad, namely, the sexual cords, fail completely to invaginate. The origin and differentiation of the germinal epithelium, on the contrary, is apparently independent of primordial germ-cells since a sterile gonad forms in grafts of whole blastoderms of early somite stages following the removal of the "germ-cell crescent" ofSWIFT. 4. Germ-cells in the mesenchyme remain cytologically undifferentiated, like the primordial germ-cells, whereas those which come to be situated in the sexual cords undergo specific differentiation. The conclusion is reached, therefore, that the germ-cell is dependent upon the specific tissue environment of the sexual cord for its sexual differentiation. PMID- 28354368 TI - Gradients of normal and regenerative growth in the pistol-crab, alpheus dentipes. AB - 1. During normal growth of the pistol-crab,Alpheus dentipes, the distribution of growth potential along the antero-posterior axis of the body takes the form of a growth gradient with its high point in the chelae-bearing segment. Values of k are presented in the text. 2. During regenerative growth of the thoracic appendages the normal growth gradient is maintained, with slight modification; the relative rate of growth in length of the chelae is reduced. 3. The absolute and relative rate of regeneration of thoracic appendages is exceedingly rapid (see text for values) and varies with body size. Large males used in these experiments regenerate roughly twice the absolute length of appendage regenerated by small males, during the mean day, but form smaller fractions of normal appendage length. 4. Logarithmic plots of carapace length against appendage length at the end of the period of regeneration yield approximations to straight lines in every instance.HUXLEY's idea of growth partition receives support and is shown to apply in regeneration as in normal growth. 5. The partition coefficients for regenerative growth are smaller than those for normal growth, in general. The constant fractional factor kR/kN is considerably less than unity in the male crusher and its propus and it is suggested that small values of this constant are correlated with high normal growth coefficients. PMID- 28354369 TI - ? PMID- 28354370 TI - ? PMID- 28354371 TI - ? PMID- 28354372 TI - ? PMID- 28354373 TI - ? PMID- 28354374 TI - ? PMID- 28354375 TI - ? PMID- 28354376 TI - ? PMID- 28354377 TI - ? PMID- 28354378 TI - ? PMID- 28354379 TI - ? PMID- 28354380 TI - ? PMID- 28354381 TI - ? PMID- 28354382 TI - ? PMID- 28354383 TI - ? PMID- 28354384 TI - ? PMID- 28354385 TI - ? PMID- 28354386 TI - ? PMID- 28354387 TI - ? PMID- 28354388 TI - ? PMID- 28354389 TI - ? PMID- 28354390 TI - ? PMID- 28354391 TI - ? PMID- 28354392 TI - ? PMID- 28354393 TI - ? PMID- 28354394 TI - ? PMID- 28354395 TI - ? PMID- 28354396 TI - ? PMID- 28354397 TI - ? PMID- 28354398 TI - ? PMID- 28354399 TI - ? PMID- 28354400 TI - ? PMID- 28354401 TI - ? PMID- 28354402 TI - ? PMID- 28354403 TI - ? PMID- 28354405 TI - ? PMID- 28354404 TI - ? PMID- 28354406 TI - ? PMID- 28354407 TI - ? PMID- 28354408 TI - ? PMID- 28354409 TI - ? PMID- 28354410 TI - ? PMID- 28354411 TI - ? PMID- 28354412 TI - ? PMID- 28354413 TI - ? PMID- 28354414 TI - ? PMID- 28354415 TI - ? PMID- 28354416 TI - ? PMID- 28354417 TI - ? PMID- 28354418 TI - ? PMID- 28354419 TI - ? PMID- 28354420 TI - ? PMID- 28354421 TI - ? PMID- 28354422 TI - The antigenicity of regenerating tail tissue in the newt Diemictylus viridescens. AB - Young adult male rabbits were inoculated with antigens prepared from regenerating (blastema stage) and nonregenerating tail tissues of the newtDiemictylus viridescens. Blood was collected from these rabbits after six weeks of semiweekly injection, two weeks of respite, and two more weeks of injections. A Freund adjuvant was added to the antigen preparations at the time of injection in order to elicit the anamnestic effect.Ouchterlony agar diffusions of the newt antigen preparations vs. the rabbit antisera were carried out. The resulting patterns of precipitation bands were compared and photographed.The strongest precipitation reactions of a given series were those between the antigen preparations made from nonregenerating tissue and their homologous antisera. The weakest reactions occurred between regenerating tissue antigens and regenerating tissue antisera. The strength of the antigen-antibody reactions was judged by the number of bands appearing in the diffusion plate and by the distinctness of these bands. Reactions of intermediate strength occurred between regenerating antigens and nonregenerating antisera, between nonregenerating antigens and regenerating antisera, and between antigens and antisera of different series.The loss of antigenicity during the blastemal period was considered to be related to the destruction of tissue in the wound areas at this time, and to indicate a quantitative rather than a qualitative loss of protein in regenerating tissue. PMID- 28354423 TI - ? PMID- 28354424 TI - ? PMID- 28354425 TI - ? PMID- 28354426 TI - ? PMID- 28354427 TI - ? PMID- 28354428 TI - ? PMID- 28354429 TI - ? PMID- 28354430 TI - ? PMID- 28354431 TI - Correlation in the development and growth of the eye studied by means of heteroplastic transplantation. PMID- 28354432 TI - ? PMID- 28354433 TI - ? PMID- 28354434 TI - ? PMID- 28354435 TI - ? PMID- 28354436 TI - ? PMID- 28354437 TI - ? PMID- 28354438 TI - ? PMID- 28354439 TI - ? PMID- 28354440 TI - ? PMID- 28354441 TI - ? PMID- 28354442 TI - ? PMID- 28354443 TI - ? PMID- 28354444 TI - ? PMID- 28354445 TI - ? PMID- 28354446 TI - ? AB - The morphogenetic capacities of cells inDictyostelium discoideum, as well as of groups (agglutinates) of these cells are changed in a constant time course after food consumption has been stopped.Two questions were posed: 1. When is the capacity of aggregation at its maximum level in a culture of single suspended cells. 2. At what time do agglutinates answer an external stimulus immediately by establishing polarity.The maximum of aggregation capacity lies 8-10 hours after complete food exhaustion. This functional stage is cytologically characterized by accumulation of metachromatic granules in the cells [seeBONNER et al. (1955)]. - The polarization capacity of agglutinates depends primarily on the functional age of the cells (this means that the age of the cells is related to the time of complete food exhaustion), and secondly it depends on the age of the agglutinates. In the most favorable case the maximum response is reached 12 hours after complete food exhaustion.A difference of about 2 hours lies between the beginning of aggregation and polarization. This difference in time could explain the centerless aggregation patterns of a well synchronized cell population as well as the appearance of primary aggregation centers in non-synchronized cultures. PMID- 28354448 TI - ? PMID- 28354447 TI - ? PMID- 28354449 TI - ? PMID- 28354450 TI - ? PMID- 28354451 TI - ? PMID- 28354452 TI - ? PMID- 28354453 TI - ? PMID- 28354454 TI - ? PMID- 28354455 TI - ? PMID- 28354456 TI - ? PMID- 28354457 TI - ? PMID- 28354458 TI - ? PMID- 28354459 TI - ? PMID- 28354460 TI - ? PMID- 28354461 TI - ? PMID- 28354462 TI - ? PMID- 28354463 TI - ? PMID- 28354464 TI - ? PMID- 28354465 TI - ? PMID- 28354466 TI - ? PMID- 28354468 TI - ? PMID- 28354467 TI - A study of the physiological value of alpha-amino acids during the early periods of growth and differentiation. PMID- 28354469 TI - Mitosis in hydra : Mitosis in the indifferent interstitial cells of hydra. AB - 1. The indifferent interstitial cells divide by mitosis. 2. This mitosis occurs within the nuclear area but not inside the nuclear membrane. 3. Centrioles are present and appear to be enclosed within the nuclear membrane during the early telephase. 4. Various fixing agents have great effect upon the chromosomes, causing them to shrink from their V-shape to rather rod-like structures. 5. The indifferent cells of the endoderm divide in a manner similar to the indifferent cells of the ectoderm. PMID- 28354470 TI - ? PMID- 28354471 TI - ? PMID- 28354472 TI - ? PMID- 28354473 TI - Regional differences in the action of the organization center. PMID- 28354474 TI - ? PMID- 28354475 TI - ? PMID- 28354476 TI - ? PMID- 28354477 TI - ? PMID- 28354478 TI - ? PMID- 28354479 TI - ? PMID- 28354480 TI - ? PMID- 28354481 TI - ? PMID- 28354482 TI - ? PMID- 28354483 TI - ? PMID- 28354484 TI - ? PMID- 28354485 TI - Differential reduction of vital dyes in the early development of echinoderms. PMID- 28354486 TI - A contribution to the physiology of exogastrulation in echinoderms. PMID- 28354487 TI - ? PMID- 28354488 TI - Studies on the creeper fowl X. A study of the mode of action of a lethal factor by explantation methods. PMID- 28354490 TI - ? PMID- 28354489 TI - ? PMID- 28354492 TI - ? PMID- 28354491 TI - ? PMID- 28354493 TI - ? PMID- 28354494 TI - ? PMID- 28354495 TI - ? PMID- 28354496 TI - ? PMID- 28354497 TI - ? PMID- 28354498 TI - ? PMID- 28354499 TI - ? PMID- 28354500 TI - ? PMID- 28354501 TI - ? PMID- 28354502 TI - ? PMID- 28354503 TI - ? PMID- 28354504 TI - ? PMID- 28354505 TI - ? PMID- 28354506 TI - ? PMID- 28354507 TI - ? PMID- 28354508 TI - ? PMID- 28354509 TI - ? PMID- 28354510 TI - ? PMID- 28354511 TI - ? PMID- 28354512 TI - ? PMID- 28354513 TI - ? PMID- 28354514 TI - ? PMID- 28354516 TI - ? PMID- 28354515 TI - ? PMID- 28354517 TI - ? PMID- 28354518 TI - ? PMID- 28354519 TI - ? PMID- 28354520 TI - ? PMID- 28354521 TI - ? PMID- 28354522 TI - ? PMID- 28354523 TI - ? PMID- 28354524 TI - ? PMID- 28354525 TI - The production of pigment in vitro by chick neural crest. AB - 1. Neural crest, or regions containing presumptive neural crest, from chick embryos between late primitive streak stage and 20 somites, was explanted in plasma clot cultures on depression slides, and grown for periods ranging from 3 to 14 days. 2. During the first four days in vitro, differentiation of pigment occurs, the colorless refractile granules of the cells gradually deepening in tone from yellow to deep brown or black, until large numbers of typical melanophores are present. 3. The most intense pigmentation occurred in cultures from embryos of dominant black breeds. There is an apparent positive correlation between the presence of the genetic factor for black and the capacity for pigment production, since hybrids carrying the black factor, and dominant white in which the presence of the black factor is masked by an inhibitor, also produce pigment in cultures of neural crest, while cultures of recessive white which lack the genetic factor for pigment were negative. 4. Pigment production is related to the stage of the embryo at the time of explantation. A very low percentage of positives was obtained from embryos prior to the formation of the neural folds, the highest percentage of strongly positive cultures being obtained from embryos of from one to 7 somites, when the neural crest material is most concentrated. The lower percentages obtained in early stages are probably due to the undetermined nature of the explant, in the older stages to the increasing diffuseness of the neural crest as a result of cellular migration. 5. Control cultures, made from other regions of the embryo, were invariably negative when taken in stages prior to migration of the neural crest, except in cases where the whole embryo was explanted after removal of the pre-otic crest. Here a few black cells occurred as probable derivatives of the post-otic section of the crest. PMID- 28354526 TI - ? PMID- 28354527 TI - ? PMID- 28354528 TI - ? PMID- 28354529 TI - ? PMID- 28354530 TI - ? PMID- 28354531 TI - ? PMID- 28354532 TI - ? PMID- 28354534 TI - ? PMID- 28354533 TI - ? PMID- 28354535 TI - ? PMID- 28354536 TI - ? PMID- 28354538 TI - ? PMID- 28354537 TI - ? PMID- 28354539 TI - Genes that affect early developmental stages of Drosophila melanogaster. PMID- 28354540 TI - ? PMID- 28354541 TI - ? PMID- 28354542 TI - ? PMID- 28354543 TI - ? PMID- 28354544 TI - ? PMID- 28354545 TI - ? PMID- 28354546 TI - ? PMID- 28354547 TI - ? PMID- 28354548 TI - ? PMID- 28354549 TI - ? PMID- 28354550 TI - ? PMID- 28354551 TI - ? PMID- 28354552 TI - ? PMID- 28354553 TI - ? PMID- 28354554 TI - ? PMID- 28354555 TI - ? PMID- 28354556 TI - ? PMID- 28354557 TI - ? PMID- 28354558 TI - ? PMID- 28354559 TI - ? PMID- 28354560 TI - ? PMID- 28354561 TI - ? PMID- 28354562 TI - ? PMID- 28354563 TI - ? PMID- 28354564 TI - ? PMID- 28354565 TI - ? PMID- 28354566 TI - ? PMID- 28354567 TI - ? PMID- 28354568 TI - ? PMID- 28354569 TI - Responses of the genital system and the urinogenital papilla of the female catfish,Heteropneustes fossilis (Bloch) to sex hormones. AB - Intraperitoneal injections of diethylstilbestrol and testosterone propionate into the catfish,Heteropneustes fossilis (BLOCH) elicited pronounced changes in the female reproductive system and the urinogenital papilla. Considerable gonadal and oviducal hypotrophy occurred in the hormone recipients. Marked histological alterations were also encountered in the genital system of the experimental females. Another interesting response was the inhibition of the urinogenital papilla of the treated fishes. It is suggested that the changes in the ovary and the oviduct were induced by the sex hormones throught the inhibition of the gonadotrophic activity of the anterior hypophysis. The changes in the urinogenital papilla proved that this structure in the female catfish is a true secondary sexual character and is under the estrogenic control of the ovary. PMID- 28354570 TI - ? PMID- 28354571 TI - ? PMID- 28354572 TI - ? PMID- 28354573 TI - ? PMID- 28354574 TI - ? PMID- 28354575 TI - ? PMID- 28354576 TI - ? PMID- 28354577 TI - ? PMID- 28354578 TI - ? PMID- 28354579 TI - ? PMID- 28354580 TI - ? PMID- 28354581 TI - ? PMID- 28354582 TI - ? PMID- 28354583 TI - ? PMID- 28354584 TI - ? PMID- 28354585 TI - ? PMID- 28354586 TI - ? PMID- 28354587 TI - ? PMID- 28354588 TI - ? PMID- 28354589 TI - ? PMID- 28354590 TI - ? PMID- 28354591 TI - ? PMID- 28354592 TI - ? PMID- 28354593 TI - ? PMID- 28354594 TI - ? PMID- 28354595 TI - ? PMID- 28354596 TI - ? PMID- 28354597 TI - ? PMID- 28354598 TI - ? PMID- 28354599 TI - Autonomy in the regionalisation of branchial endoderm in amphibia. AB - 1. The branchial endoderm taken from late neurula or tail bud embryos developed into typical pharynx, when left to develop with head-mesenchyme, while in a purely ectodermal environment lacking mesodermal elements, it did not give rise to any identifiable structure. 2. The same endodermal piece was explanted together with lateral mesoderm. In this combination, the frequency of the occurrence of intestine decreased with increasing age of the donor, and the appearance of "pharyngoid" (the amorphous assemblage of pharyngeal cells) increased. 3. The piece of branchial endoderm was removed from an early neurula, and was isolated alone or together with cranial ectomesoderm for 24 or 48 hours, until the synchronous control had reached early or late tail bud stage; then pre isolated piece of endoderm was combined with lateral mesoderm and cultivated further in an epidermal envelope. A decreased production of intestine and increased production of "pharyngoid" were obtained, according to the duration of the pre-isolation. 4. In the discussion, the establishment of regionalisation of endoderm in normal embryo was interpreted as anautonomous process, which can be accerelated by contact with head mesenchyme but which does not require it, while for the individuation of pharyngeal organisation, the presence of mesenchyme was considered to be indispensable. PMID- 28354600 TI - Induction of bone, cartilage and hemopoietic tissue by subcutaneously implanted tissue diaphragms. AB - The subcutaneous implantation of appropriate tissue diaphragms (short, broad glass cylinders) rather regularly induces the formation of bones provided with marrow cavities and junction cartilage plates, in the rat.Bone formation, unlike the development of hemopoietic tissue, can be prevented, under these circumstances, by topical blockade of the phagocyte system with carbon particles.The role of nonspecific topical stress factors, in the induction of such highly specific structural transformations, has been discussed. PMID- 28354601 TI - ? PMID- 28354602 TI - ? PMID- 28354603 TI - ? PMID- 28354604 TI - ? PMID- 28354605 TI - ? PMID- 28354606 TI - ? PMID- 28354607 TI - ? PMID- 28354608 TI - ? PMID- 28354609 TI - ? PMID- 28354610 TI - ? PMID- 28354611 TI - ? PMID- 28354612 TI - ? PMID- 28354613 TI - ? PMID- 28354614 TI - ? PMID- 28354615 TI - ? PMID- 28354616 TI - ? PMID- 28354617 TI - ? PMID- 28354618 TI - Morphogenesis studies by means of X-rays : II. Note on an inherited cuticular tumor in Drosophila. PMID- 28354619 TI - Morphogenesis studies by means of X-rays : III. X-ray induced persistence of a larval character in Drosophila. AB - A peculiar x-ray induced localized growth inDrosophila imagos is described and provisionally identified as a persistent larval spiracle. The view is expressed that a chromosomal upset changes the cell chemistry in such a way as to make them impervious to normal destruction during metamorphosis. PMID- 28354620 TI - ? PMID- 28354622 TI - ? PMID- 28354621 TI - ? PMID- 28354623 TI - Effects of temperature-fasting on the structural organisation of chick embryos. AB - 1. The progressive effects of temperature fasting on the blastoderms of chick have been studied. 2. The blastoderms do not show any morphogenetic change up to the 7th day of delay prior to incubation. Embryological changes in form of suppression arise in the organisation of blastoderms delayed over 12 days or more. The axes of the embryos tend to be more shortened in the further delayed embryos. 3. The axial structures of the blastoderms suffer reduction in shape and size until they disappear in the blastoderms kept waiting for 15 to 20 days. The blastoderms enlarge into a sheet-like structure without any mark of organisation. 4. The blastoderms become gradually incapacitated beyond the temperature-fasting for over 20 days. 5. The probable mechanism of these morphogenetic features have been sought in the denaturation of "Cell substances" by dehydration, suppression of mitotic activities and morphogenetic movements of cells of the blastoderms. PMID- 28354624 TI - ? PMID- 28354625 TI - ? PMID- 28354626 TI - ? PMID- 28354627 TI - Experimental dissociation of cells from hydra. AB - 1. The cellular configuration of a hydra is dissociated under the pressure of a cover-glass and the different cell types are isolated and observed in hanging drop chamber. 2. With the exception of certain cnidoblasts, all the cells are rounded after dissociation of which only the nutritive muscular cells of the endoderm show amoeboid movement. 3. Pseudopodium originates as ectoplasmic out pushing in which endoplasm flows in afterwards. Pseudopodia are thrown from all sides of the cell. 4. The details of intra-cellular contents in the different cell-types are described. 5. The nature of surface rigidity, attachment and cell shape before and after dissociation have been discussed in relation to the animal form and morphallactic power of hydra. PMID- 28354628 TI - ? PMID- 28354629 TI - Transport of thermal energy across the organization centre of chick embryo. AB - 1. Transit of heat from three selected points across the blastoderm has been analysed. 2. The shock at the differentiating centre is more drastic than that at a point away from it. 3. The posterior and the middle portion of the embryo are more susceptible than the anterior portion of the same to the thermal shock. 4. Graded types of ontogenesis have been observed after thermal treatment. 5. The epiblast is the most susceptible layer to heat treatment than the other two. 6. Different aspects of the abnormal morphogenesis have been explained from the point of view of morphogenetic movement of cells. PMID- 28354630 TI - ? PMID- 28354631 TI - ? PMID- 28354632 TI - ? PMID- 28354633 TI - ? PMID- 28354634 TI - ? PMID- 28354635 TI - ? PMID- 28354636 TI - ? PMID- 28354637 TI - ? PMID- 28354638 TI - ? PMID- 28354639 TI - ? PMID- 28354640 TI - ? PMID- 28354642 TI - ? PMID- 28354641 TI - ? PMID- 28354643 TI - ? PMID- 28354644 TI - ? PMID- 28354645 TI - ? PMID- 28354646 TI - ? PMID- 28354647 TI - Duration of light and the wings op the aphid macrosiphum solanifolii. PMID- 28354648 TI - ? PMID- 28354649 TI - ? PMID- 28354650 TI - Physiological dominance and physiological isolation in development and reconstitution. PMID- 28354651 TI - Genetic rate-factors in gammarus. PMID- 28354652 TI - ? PMID- 28354653 TI - ? PMID- 28354654 TI - ? PMID- 28354655 TI - The development of egg-fragments in annelids. AB - 1. The unfertilized eggs ofChatopterus, taken near the beginning of the maturation-period, may readily, by strong centrifuging, be broken into fragments of varying size and contents. Both nucleated and non-nucleated fragments of various sizes may be fertilized, and may develop into actively swimming dwarf larvae, some of which approach the normal whole larvae in form, structure and movements. 2. The fragments may contain varying combinations of the three main zones produced by centrifuging, including those derived from the hyaline mid dle zone whicharealmost entirely composed of hyaloplasm. Any of the fragments irrespective of their contents may develop if of sufficient size. 3. The cleavage pattern of the fragments, irrespective of their contents, closely follows that of the whole eggs, including the size-relations, the alternation of spiral cleavages and the arrangement of the blastomeres. The first cleavage may or may not be accompanied by the formation of a polar lobe, the fragments being probably derived in the first case from the lower hemisphere, in the second from the upper one. In both cases the cleavage is unequal in the normal proportions, and there seems to be only one type of regular cleavage. 4. Since hyaline fragments may segment normally and may produce actively swimming dwarf larvae of nearly normal appearance, it seems probable that the basis of localization, cleavage-patterns, and differentiation must be sought in some kind of internalstructure in the apparently structureless hyoplasm or ground-substance. 5. Some review and discussion is offered of the evidence that the ooplasmic structure is progressively developed and transformed before, during and after cleavage. 6. The relation between mosaic development and embryonic induction or organizing activities is discussed, including some consideration of the question of organizing centers in the "mosaic" types of cleavage. PMID- 28354656 TI - ? PMID- 28354657 TI - ? PMID- 28354658 TI - ? PMID- 28354660 TI - ? PMID- 28354659 TI - ? PMID- 28354661 TI - ? PMID- 28354662 TI - ? PMID- 28354663 TI - ? PMID- 28354664 TI - ? PMID- 28354665 TI - Seasonal variations in fertility and in the sex ratio of mammals, with special reference to the rat. PMID- 28354666 TI - ? PMID- 28354667 TI - ? PMID- 28354668 TI - ? PMID- 28354669 TI - ? PMID- 28354670 TI - ? PMID- 28354671 TI - ? PMID- 28354672 TI - ? PMID- 28354673 TI - ? PMID- 28354674 TI - ? PMID- 28354675 TI - ? PMID- 28354676 TI - ? PMID- 28354677 TI - ? PMID- 28354678 TI - ? PMID- 28354679 TI - ? PMID- 28354680 TI - ? PMID- 28354681 TI - ? PMID- 28354682 TI - ? PMID- 28354683 TI - ? PMID- 28354684 TI - ? PMID- 28354685 TI - ? PMID- 28354686 TI - ? PMID- 28354687 TI - ? PMID- 28354689 TI - ? PMID- 28354688 TI - ? PMID- 28354690 TI - ? PMID- 28354691 TI - ? PMID- 28354692 TI - The modification of development by means of temperature gradients. PMID- 28354693 TI - ? PMID- 28354694 TI - ? PMID- 28354695 TI - ? PMID- 28354696 TI - ? PMID- 28354697 TI - ? PMID- 28354698 TI - ? PMID- 28354699 TI - ? PMID- 28354700 TI - ? PMID- 28354701 TI - ? PMID- 28354703 TI - ? PMID- 28354702 TI - ? PMID- 28354704 TI - ? PMID- 28354705 TI - ? PMID- 28354706 TI - Reproduction in alcoholic mice: II. Treated males : A study of prenatal mortality and sex ratios. PMID- 28354707 TI - ? PMID- 28354708 TI - ? PMID- 28354709 TI - ? PMID- 28354710 TI - ? PMID- 28354711 TI - ? PMID- 28354712 TI - ? PMID- 28354713 TI - ? PMID- 28354714 TI - ? PMID- 28354715 TI - ? PMID- 28354716 TI - Influence of the antimitotic phenanthrenequinone on the cleavage of the eggs of the mollusc,Mytilus edulis L. AB - 1. Phenanthrenequinone, in concentrations above 1?2 M, produces cytolysis. 2. It causes blockage in the single cell stage in concentrations down to 1?200 M. 3. The main area of antimitotic activity lies in between 1?2 M to 1?20 M. 4. Most of the abnormal forms are like those produced by naphthoquinone. 5. A new and so far unobserved "linear type of cleavage" is found at the three- and four-cell stages. 6. Phenanthrenequinone is relatively more toxic than naphthoquinone. 7. Phenanthrenequinone can also affect the nuclear apparatus, producing pyenosis. 8. It can also inhibit the cell cortex in the same manner as naphthoquinone: there is no evidence that in Mytilus one quinone stimulates cortical expansion and the other cortical contraction. PMID- 28354717 TI - ? PMID- 28354718 TI - ? PMID- 28354719 TI - ? PMID- 28354720 TI - ? PMID- 28354721 TI - ? PMID- 28354722 TI - ? PMID- 28354723 TI - ? PMID- 28354724 TI - ? PMID- 28354725 TI - ? PMID- 28354726 TI - An electronmicroscopic study of developing amphibian ectoderm. AB - 1. Small pieces of ectoderm were excised from gastrulae, neurulae, and tailbud embryos ofXenopus laevis andTriturus alpestris, preserved inLEHMANN's fixatives, sectioned at 0.025-0.75MU, and photographed with a Trub-Tauber electron microscope. 2. The following features characterize the early gastrular ectoderm: endoplasmic reticulum coarse, vesicular, and predominantly loose; mitochondria mostly globular and irregular; lipoid droplets and yolk-platelets with investing plasma membranes; pigment granules ofTriturns, but not ofXenopus, composed of subunits; nuclei polymorphic, especially inTriturus, with deep infoldings of nuclear membrane; cells frequently connected only by cytoplasmic bridges which may be anastomosed, cells otherwise separated by spaces or canals. 3. Presumptive medullary plate from the very early neurula shows certain differences from the above features: endoplasmic and nuclear reticula considerably more dense; cytoplasmic vesicles, fibers, and granules more delicate; mitochondria smooth and rod-like with increased number of cristae; intercellular spaces less prominent, except between presumptive neural plate and chordamesoderm, the cytoplasmic processes of which may anastomose. 4. Presumptive epidermis of the very early neurula shows a wide meshed fibrous reticulum and distally situated mitochondria, foreshadowing the development of highly differentiated outer zones in the epidermal cells of the tailbud embryo. 5. Mitochondria of neural cells of the late tailbud embryo are predominantly perinuclear, quite elongate, relatively narrow, and possess many thin longitudinally or diagonally placed cristae. 6. Mitochondria of the tailbud epidermis are shorter and thicker than those of the neural tube cells, exhibit pores and swollen tubules, and occur in large numbers below a distal zone of dense cytoplasmic reticulum and secretory vesicles, which seem to form in waves and to discharge periodically their secretion to the surface of the skin. 7. The concept of mitochondrial "differentiation" is further developed and the function of epidermal mitochondria and the importance of intercellular contacts, especially in relation to neural induction, are discussed. PMID- 28354727 TI - ? PMID- 28354728 TI - ? PMID- 28354729 TI - ? PMID- 28354730 TI - ? PMID- 28354731 TI - ? PMID- 28354732 TI - ? PMID- 28354733 TI - ? PMID- 28354734 TI - ? PMID- 28354735 TI - ? PMID- 28354737 TI - ? PMID- 28354736 TI - ? PMID- 28354738 TI - ? PMID- 28354740 TI - ? PMID- 28354741 TI - ? PMID- 28354739 TI - ? PMID- 28354742 TI - ? PMID- 28354743 TI - Factors inhibiting metamorphosis inBugula andAmaroecium larvae. PMID- 28354744 TI - Studies on the process of lens induction inXenopus laevis (Daudin). AB - 1. Optic vesicle from stage 24 (NIEUWKOOP andFABER 1956) can induce lens in the ectoderm from early to mid grastrula, and even from ventral ectoderm of a tail bud stage. 2. Lenses were induced from early ectoderm cultured over night before grafting even though it remained thick. 3. For lens formation and its differentiation, prolonged contact with the optic vesicle seems essential. 4. Lens anlage removed from the influence of the optic vesicle as late as the stage 24 (NIEUWKOOP andFABER 1956) and cultured as an explant attached to the head region failed to differentiate. 5. The environment offered by the head region and the headmesoderm plays an important role in determining the lens competence. 6. Xenopus optic vesicle can induce lens from Axolotl ectoderm. 7. There was no instance of retinal regeneration. PMID- 28354745 TI - ? PMID- 28354746 TI - ? PMID- 28354747 TI - ? PMID- 28354748 TI - An analysis of the early development ofPlanorbis exustus using barbituric acid. AB - 1. The effect of barbituric acid (BA), which is a structural analogue of uracil, has been studied on the development ofPlanorbis exustus. 2. Cleavage is not affected by BA at any concentration that has been tried. At 0.06 M, BA is found to stop development of the embryos at the early gastrula stage. Some of the arrested embryos subsequently exogastrulated. The block of development cannot be removed by transferiing them to normal medium. The chemical at concentrations ranging from 0.005 to 0.04 M cause a general retardation in development. It conspicuously prolongs the duration of development between the trochophore and the veliger stages. Reduction or absence of shell occurs when animals metamorphose in the presence of BA. 3. The results seem to indicate that in the molluscan species studied there is no RNA synthesis during the cleavage phase, that morphogenesis stops when the synthesis of RNA is blocked by the use of BA, that catabolism is predominant in the pre-trochophore phase. The irreversible block imposed by BA (0.06 M) at gastrulation is interpreted to suggest that the inhibitor acts on some nuclear RNA. PMID- 28354749 TI - ? PMID- 28354750 TI - Influence of the ectoderm on heart differentiation and placement in the chicken embryo. AB - 1. The unilateral or bilateral extirpation of the ectoderm of the P.H.M. region in stages 5 to 8 in the chicken embryo exerts no influence in heart determination and differentiation, since in all the cases a morphological and structurally typical heart is formed. 2. Neither does the extirpation of the ectoderm interfere in the migratory process of the cells of the P.H.M., since, with the exception of one case of cardia bifida, a unique heart is formed in a unique pericardial cavity. 3. The extirpation of the ectoderm exerts a clear influence over the situation of the heart and over its curvatures since when the ablation of the ectoderm is unilateral, the heart is displaced toward the side opposite that of the extirpation. It is, therefore, normal in the extirpations of the left ectoderm and inverted in those of the right. 4. The primary fore-gut pocket does not form on the side where the ectoderm has been extirpated. This, therefore, exerts a clear influence on the formation of the fore-gut pockets and in the form the fore-gut takes. 5. The extirpation of the ectoderm in stages 6 and 7 constantly inhibits the process of the closing of the neural canal in the encephalic region (mesencephalon and anterior part of the rhombencephalon), the neural differentiation normally continuing its process. This suggests that the force of the neural folds during the formation of the neural tube is transmitted to them through the ectoderm. PMID- 28354751 TI - ? PMID- 28354752 TI - ? PMID- 28354753 TI - ? PMID- 28354754 TI - ? PMID- 28354755 TI - ? PMID- 28354756 TI - ? PMID- 28354757 TI - ? PMID- 28354758 TI - ? PMID- 28354759 TI - A critical analysis of excretory products as sex controlling agents in cladocera. AB - Conditions seem to exist under which the sex of the young to be produced by a Cladoceran mother is not determined by the animal's immediate environment. In such mothers a sex determining mechanism appears to have been inherited, and such mothers have been called "Sex Fast".Laboratory stock cultures of Cladocera not infrequently pass through periods of depression. While in such periods the mothers are for the most part "Sex Fast". Whether this can be termed sex control by inherent sexual cycles is questionable.The contention that many factors in the external environment of Cladocera may under suitable conditions act as sex controlling factors has been conclusively proven by numerous investigators. For the most part these are factors which affect the mother's metabolism, presumably accelerating or retarding the mother's development, acceleration being associated with female production, retardation with male production.Food, temperature and excretory substances are the external environmental factors most often associated with sex control in Cladocera. The evidence supporting the role of food and temperature in this reaction appears to be adequate but further experimental evidence supporting excretory substances in the control of sex is needed before a specific role in sex control in Cladocera can be assigned to this factor. PMID- 28354760 TI - ? PMID- 28354761 TI - ? PMID- 28354762 TI - ? PMID- 28354763 TI - ? PMID- 28354764 TI - A note on the asymmetry of male fiddler-crabs (UCA pugilator). PMID- 28354765 TI - A study of relative growth in UCA pugnax. AB - 1. 50 males and 43 females were divided into classes according to carapace breadth. The relative growth rates of certain parts of the body were investigated by analysis of linear measurements carried out on the carapace and appendages. 2. The increased growth rate of pereiopods immediately posterior to the strongly heterogonic cheliped was concluded to be due, in part at all events, to the rapid growth of the cheliped, since the increase is considerably smaller on the small cheliped side in the male. 3. There seems to be, in addition, a sexual difference, the growth in the corresponding pereiopods in the female differing from that found in the male on the small cheliped side. 4. In the female the growth of the last two pereiopods is greater than that in the male; it is suggested that this is possibly due to the influence of the region of rapid growth present in the abdomen in the female. 5. The appendages anterior to the large cheliped in the male are apparently not inhibited. In this respect Uca pugnax differs from other forms which have been investigated. 6. The growth rate of the carapace breadth is greater than that of its length throughout the period investigated in the male, but only throughout the earlier part of the development of the female. PMID- 28354766 TI - A further study of the growth of parts in palaemon carcinus. AB - Male and female prawns (Palaemon carcinus) were classed into groups according to carapace length, which was the standard adopted.The lengths of separate segments of pereiopods 1, 2, 3 and 5 were measured and their means calculated for the different classes.In the second pereiopod, the cheliped, the growth centre is in the dactylus in the female and in the propus in the male. But in young females it appears that the growth centre is in the propus and in young males in the dactylus.The difference between the rates of growth of the various segments in both males and females was slight in most cases, those in the male being consistently higher than those in the female.The lengths of the second and last abdominal segments were also measured. In both males and females growth was found to be negatively heterogonic, but growth was in each case more rapid in the female than in the male. PMID- 28354768 TI - ? PMID- 28354767 TI - ? PMID- 28354769 TI - ? PMID- 28354770 TI - ? PMID- 28354771 TI - ? PMID- 28354772 TI - ? PMID- 28354773 TI - ? PMID- 28354774 TI - ? PMID- 28354775 TI - ? PMID- 28354776 TI - ? PMID- 28354777 TI - ? PMID- 28354778 TI - ? PMID- 28354779 TI - ? PMID- 28354780 TI - ? AB - 1. Closely packed cells ofDictyostelium discoideum, grown in a suspension culture, form aggregation patterns whose specific structures reflect the functional states of the cells. 2. Prior to the development of these structures, waves of excitation appear which propagate with a velocity of about 40MU/min. If functioning rhythmically as a whole, the wave-propagating center gives rise to a system of separate, concentric waves. If, on the contrary, parts of the center become active successively, a continuous spiralshaped excitation front is formed. 3. It is proposed, that the propagated waves associated with an autorhythmic center inhibit the formation of similar centers in its vicinity ("spacing effect"). 4. The aggregates formed by the closely packed cells are often too large to give rise to a single sorocarp. In this case a mechanism becomes active which divides the cell mass; each of the resulting parts transforms itself into a sorocarp. PMID- 28354781 TI - ? PMID- 28354782 TI - ? PMID- 28354784 TI - ? PMID- 28354783 TI - Morphogenesis in the amphibian embryo fertilization and blastula formation. AB - The morphology of the cortex of the amphibian egg is discussed, with special reference to the hyaline membrane.The physical properties of the cortex are reviewed, especially those evidenced by the wound healing reaction. The participation of the hyaline membrane in this process is particularly emphasized.An analysis of the activation processes normally associated with fertilization indicates that they may be accounted for by three cortical contractions, two radially symmetrical, with center at the animal pole, and one asymmetrical (or bilaterally symmetrical) originating at the point of sperm entrance. The contractions may be spatially correlated with three wounds normally afflicted on the cortex, viz., the expulsion of the polar bodies and penetration of the sperm. The first cortical contraction leads to separation between egg surface and vitelline membrane, and consequently to rotation of orientation, the second leads to formation of the perivitelline space, and the third to grey crescent formation.The mechanisms of blastula formation and of volume regulation are finally discussed. The strong adhesion between the cells and the hyaline membrane are of special importance in the former process. The hydrostatic pressure exerted through the cortex tension of the individual cells is suggested to account for the transport of water against the osmotic pressure difference from cells to blastocoele. The tension in the hyaline membrane developing in the late blastula and early gastrula is suggested to control the volume of the embryo. PMID- 28354785 TI - ? PMID- 28354786 TI - ? PMID- 28354787 TI - ? PMID- 28354788 TI - ? PMID- 28354789 TI - ? PMID- 28354790 TI - ? PMID- 28354791 TI - ? PMID- 28354792 TI - ? PMID- 28354793 TI - ? PMID- 28354794 TI - ? PMID- 28354795 TI - ? PMID- 28354796 TI - ? PMID- 28354797 TI - ? PMID- 28354798 TI - ? AB - A growth-regulation-system is defined in mathematical terms in order to interpret the observed behavior of regenerating and growing imaginal disks of the wings inEphestia kuhniella.It is assumed that the growth-rate of an imaginal disk depends upon two variables, a variablek which is interpreted as the concentration of the moulting hormone and a second variablez representing the size of the disk measured by the number of cells. A rising hormone concentration tends to increase and a rising number of cells tends to decrease the growth-rate of a disk. If two imaginal disks of different size are present in one larva and the concentration of the moulting hormone is the same for both, then the growth-rate of the smaller imaginal disk can only be greater than or equal to the growth-rate of the larger one. The model contains the possibility that a small imaginal disk grows independently of the hormone level with a maximum and constant rate.On the basis of that model some theorems are derived in order to simplify the interpretation of the empirical data which consist of daily counts of cell divisions on the upper side of the imaginal disks after successive extirpation or one, two of three imaginal disks. The data do not contradict the model and suggest that before reaching a critical size the regenerating imaginal disk grows independently of the hormone level while afterwards the growth-rate depends upon the two variables mentioned above.Some ideas are discussed about the control of the hormone level and the conditions under which the time for the regulation of size differences is minimized. PMID- 28354799 TI - ? PMID- 28354800 TI - ? PMID- 28354801 TI - ? PMID- 28354802 TI - ? AB - Studied is the establishment during oogenesis of the bilateral symmetry in the banana-shapedGryllus domesticus egg. Follicular length of the panoistic egg follicle is used for classification of oogenetic stages.External rotation symmetry of oocyte and follicle changes to the bilateral symmetric banana form at about 500MUm of follicular length.Internal bilateral symmetry is already visible at this and younger stages with regard to the eccentric position of the oocyte nucleus. In the banana form of the oocyte the oocyte nucleus is located presumptive dorso-caudally. In the cylindric form it lies in the posterior half of the oocyte.The germinal vesicle itself exhibits a marked polarity: oocyte nucleolus and a crescent of granular material are always eccentrically located in the presumptive dorso-caudal quarter of the nucleus.Germinal vesicle's polarization and its slightly eccentric location become simultaneously visible in follicles 60 to 100MUm of length. Thus at this time one can anticipate in a very early stage of oogenesis on the oocyte nucleus the future poles and axes of the coming embryo.Oocyte nucleus polarization and location appear to be uniform in all follicles of an ovariole and may presumably be due to external orientating factors. PMID- 28354803 TI - ? PMID- 28354804 TI - ? PMID- 28354805 TI - Contact reaction of cells in sponge aggregation. PMID- 28354806 TI - ? PMID- 28354807 TI - ? PMID- 28354808 TI - ? AB - A count-chamber like methodes enables us to estimate the number of cysts corresponding to each developmental stage of the spermatogenesis.The multiplication of the germ cells depends upon the physiological conditions of the host: it is stopped in isolated larval abdomina, and is low in larvae of a crowded culture where pupation is delayed. In implants of 48 h old testis in. virgin adult females the multiplication rate is lower than in males and in mated females; it is as high as in situ in castrated females or in pupal hosts.The time required for the oldest cysts with spermatocytes to enter the meiotic divisions is with one exception for all these experiments the same as in situ; only in pupal hosts it will be accelerated. The subsequent spermatid differentiation in sperm also takes the same time as in situ. Thereby the premeiotic growth and postmeiotic differentiation is as efficient in all tested milieus as in situ, even when the hosts have not attained or already bypassed the metamorphosis. This autonomy is also valid for germ cells under insufficient multiplying conditions, provided that the spermatocytes have reached a certain stage in the premeiotic growth.When the first cysts reach the postmeiotic stages the further multiplication of cysts is stopped. This regulative mechanism is attributed to a specific inhibition operated by the spermatids.The autonomy of the spermatocyte differentiation and the unified behaviour of all the cells within a cyst are discussed. PMID- 28354809 TI - ? AB - 48 h old testis were implanted into different adult hosts. In virgin females the germ cell multiplication is lower than in both mated females or in males. However in all host types the differentiation into spermatids beginns at the same time as in situ.The role of the different adult host glands in male germ cell development was investigated. Through inactivation of such glands in mated females or implantation of extra glands in virgin hosts was demonstrated, that not the adult Corpus allatum but the Median Neurosecretory Brain Cells (MNBC) are responsable for this germ cell multiplication.Adult host provided with larval Ring gland or pupal host accelerate the germ cell differentiation but not the germ cell multiplication of implanted testis. This acceleration would be much higher if the normal development of the germ cells in adult hosts were due to rests of pupal hormons in this milieu.The nutritive conditions of the host play a very important role in germ cell multiplication. The testis implanted in castrated females or females injected with casein hydrolisate show a higher number of developing germ cells. The MNBC controll the protein metabolism (assimilation) but are only indirectly responsable for the germ cell multiplication; the multiplication is a consequence of the autonomous protein synthesis of the germ cells themself.The growth of other imaginal discs in adult hosts are discussed in the light of these results. PMID- 28354810 TI - ? PMID- 28354811 TI - ? PMID- 28354812 TI - ? PMID- 28354813 TI - ? PMID- 28354814 TI - ? PMID- 28354815 TI - ? PMID- 28354816 TI - ? PMID- 28354817 TI - ? PMID- 28354818 TI - ? PMID- 28354819 TI - ? PMID- 28354820 TI - ? PMID- 28354821 TI - ? PMID- 28354822 TI - ? PMID- 28354823 TI - ? PMID- 28354824 TI - ? PMID- 28354825 TI - ? PMID- 28354826 TI - ? PMID- 28354827 TI - ? PMID- 28354828 TI - A study of the inductive capacity of post-nodal primitive-streak pieces after treatment with follicle-stimulating hormone. AB - Chick embryos at the primitive-streak stage were treatedin vitro with 0.002 and 0.008% follicle-stimulating hormone (FSH)(NIH-FSH-S1) for 24 hours. Post-nodal primitive-streak pieces 0.8 mm behind the node level were grafted into host chick embryos at the primitive-streak stage to assess the capacity of the grafted pieces to produce inductions.Control grafts from donors maintained under identical conditions were unable to cause induction; all of them were resorbed into the host embryo. The post-nodal pieces treated with FSH acquired capacity to induce neural tissue. The grafts seemed to induce foregut formation also. FSH appeared to have supported differentiation of the grafts into somites and mesenchyme. PMID- 28354829 TI - ? PMID- 28354830 TI - Action of the rhombencephalon on the differentiation of the auditive placodes. Chronology of its influence. AB - 1. In order to establish the influence of the rhombencephalon on the differentiation of the auditive placode in the embryo of the chicken, and the chronology of this influence, we have extirpated the abovementioned encephalic vesicle in different stages of the embryonic development. We have also carried out transplants of the recently formed auditive vesicle to other embryonic regions. 2. The rhombencephalon is indispensable for the initiation of differentiation of the auditive placode until the pre-somitic phase of the embryonic development. 3. Once the somitic segmentation has begun, the influence of the rhombencephalon is no longer necessary for the formation of the auditive placode, fossa, and vesicle. PMID- 28354831 TI - Influence of the endoderm on heart differentiation. PMID- 28354832 TI - ? PMID- 28354833 TI - ? PMID- 28354834 TI - ? PMID- 28354835 TI - ? PMID- 28354836 TI - ? PMID- 28354837 TI - ? PMID- 28354838 TI - ? PMID- 28354839 TI - ? PMID- 28354840 TI - ? PMID- 28354842 TI - ? PMID- 28354841 TI - ? PMID- 28354843 TI - ? PMID- 28354845 TI - ? PMID- 28354846 TI - ? PMID- 28354844 TI - ? PMID- 28354847 TI - Physical investigation on the origin of coloured patches of some kidney beans, Phaseolus vulgaris L. AB - 1. The geometrical configuration of the coloured patches of a certain species of kidney bean,Phaseolus vulgaris L., is explained satisfactorily by the combination of two sets of boundary lines on the surface of seed. 2. It is shown experimentally that these two sets of lines have a close relationship to the crack-figures developed on enamel layer upon rubber ball when it is allowed to expand under suitable conditions. 3. The process of embryonal growth of the seed is investigated microscopically. An enormous expansion of ovule in comparison with funicular part is verified to take place m an early stage of ovular growth. 4. From the above evidences it may be assumed that some kind of cracks or latent cracks are made on the outer layer of ovule at a certain stage of growth, which may mark the boundaries of areas with different kind of properties with respect to pigment formation. This latent crackfigure may be developed into the coloured pattern in the well-grown state of seed. Nearly the same mechanism is assumed to hold for the formation of albino in Toraudura Kidney Bean, one of the varieties of the species. 5. Coloured patches of some mammals are discussed also in connection with the phenomenon of rupture of the surface of embryo. PMID- 28354848 TI - ? PMID- 28354849 TI - ? PMID- 28354850 TI - ? PMID- 28354851 TI - ? PMID- 28354852 TI - ? PMID- 28354853 TI - ? PMID- 28354854 TI - ? PMID- 28354855 TI - ? PMID- 28354856 TI - ? PMID- 28354857 TI - ? PMID- 28354858 TI - ? PMID- 28354859 TI - ? PMID- 28354860 TI - ? PMID- 28354861 TI - Relation between the grey crescent and the organizer center of a urodele egg (Triturus torosus). PMID- 28354862 TI - ? PMID- 28354863 TI - ? PMID- 28354864 TI - ? PMID- 28354865 TI - ? AB - In the Lepidoptera the different cuticles of the caterpillar, of the pupa and of the adult are produced by the same epidermis, without regard to increase and polyploidisation of epidermis cells.By histological and morphological investigations it could be shown, which parts of the skin on an abdominal segment ofGalleria mellonella correspond to eachother in these three stages of development. A skin graft, heterotoply transplanted from one caterpillar to another as well as the experimental surroundings of that graft, do not develop corresponding to their normal prospective fate during metamorphosis. In grafting experiments a kind of regulating development takes place. The skin of the graft and its surroundings always develop by locally producing a succession of skin types which is normally to be found along the main axis of an adult segment: Morphological polarity is locally altered in grafting experiments. In the skin regions where morphological polarity is altered experimentally, the scales are no longer orientated parallel to the main axis of the body nor do they show an orientation parallel to the experimentally evoked "new segment axes". The scales show intermediate orientations. From the manner of morphological differentiation and scale orientation in the graft experiments a relationship may be concluded between the morphogenetic systems of the segmental epidermis inGalleria and of the early germ of the sea urchin. PMID- 28354866 TI - Separation of cell layers in hydra. AB - The mesolamella of hydra is dissociable by means of divalent metal chelation with EDTA and is more susceptible to this treatment than the intercellular cements of each layer. Uncontaminated gastrodermal and epidermal cells may be obtained by this treatment. PMID- 28354867 TI - ? PMID- 28354868 TI - ? PMID- 28354869 TI - Concerning the mechanism of hydrocephalus in the progeny of Trypan Blue treated rats. AB - 1. Seven foetal rats aged 19-21 days were examined in serial section to investigate the lesion responsible for the hydrocephalus in the offsprings of Trypan Blue injected mothers. 2. In four, lesions of the aqueduct were found. Three were examples of atresia which extended into the third ventricle. The fourth showed stenosis. 3. The obstruction in one of the remainder was probably due to impaction of the cerebellum and medulla oblongata in the foramen magnum associated with a spinal myelocele. 4. No satisfactory explanation for the hydrocephalus could be offered in the other two animals. PMID- 28354870 TI - ? PMID- 28354871 TI - ? PMID- 28354872 TI - ? PMID- 28354873 TI - ? PMID- 28354874 TI - ? PMID- 28354875 TI - ? PMID- 28354876 TI - ? PMID- 28354877 TI - ? PMID- 28354878 TI - ? PMID- 28354879 TI - ? PMID- 28354880 TI - ? PMID- 28354881 TI - ? PMID- 28354882 TI - ? PMID- 28354883 TI - ? PMID- 28354884 TI - ? PMID- 28354885 TI - ? PMID- 28354886 TI - ? PMID- 28354887 TI - ? PMID- 28354888 TI - ? PMID- 28354889 TI - ? PMID- 28354891 TI - ? PMID- 28354890 TI - ? PMID- 28354892 TI - ? PMID- 28354893 TI - Experimental studies on the induction of the sucker in Bombinator pachypus (homoplastic and xenoplastic transplantations). PMID- 28354894 TI - ? PMID- 28354895 TI - ? PMID- 28354896 TI - ? PMID- 28354897 TI - ? PMID- 28354898 TI - ? PMID- 28354899 TI - ? PMID- 28354900 TI - ? PMID- 28354901 TI - ? PMID- 28354902 TI - ? PMID- 28354903 TI - ? PMID- 28354904 TI - ? PMID- 28354905 TI - ? PMID- 28354906 TI - ? PMID- 28354907 TI - ? PMID- 28354908 TI - ? PMID- 28354909 TI - ? PMID- 28354911 TI - ? PMID- 28354910 TI - ? PMID- 28354912 TI - ? PMID- 28354913 TI - ? PMID- 28354914 TI - ? PMID- 28354915 TI - Epithelio-mesenchymal relationships in the regional differentiation of the digestive tract in the amphibian embryo. AB - 1. Endodermal pieces taken out of the presumptive gastric and intestinal regions of the early neurula were explanted together with ecto- or endomesodermal fragments removed from various regions of neurula ofTriturus pyrrhogaster. 2. The future development of the endodermal piece was found to be shifted anteriorwards to produce branchial and/or oesophago-gastric epithelium when the endoderm was left to develop within a mesenchymal environment. The endodermal piece showed predominantly a development into intestinal structures when it was combined with lateral mesoderm and left to develop within a mesenchyme-free environment. 3. The anteriorward shift of the future development of the explanted endoderm by niesenchyme occurred with different grades, according to the source from which the mesenchyme was derived. The mesenchyme derived from the cranial mesectoderm was found to be most effective, and the efficiency falls gradually in the mesenchyme derived from more lateral or posterior regions. 4. Considerable differences were noted between the endodermal pieces tested, in their reactivity to the effect from mesenchyme. The explanted gastric piece can be shifted anteriorwards more easily than can the explanted intestinal piece. 5. The developmental paths of the undetermined endoderm, in the explantation condition, appeared to be decided by two factors, one residing in the mesenchyme and another in the endoderm. PMID- 28354916 TI - The differentiating capacity of dissociated sponge cells. AB - 1. The intricacy of regeneration depends largely on the behaviour of cells during early hours of contact. 2. Cellular contact is a necessary prerequisite to bring about the phenomenon of regeneration. 3. Cells dedifferentiate and attain a generalized state before regeneration. 4. Certain unipotent cells can only redifferentiate into original fate e.g., pinacocytes, scleroblasts, choanocytes. 5. Other types of cells completely lose their original characteristics and become totipotent i.e. redifferentiate into other types of cells. These are called pluripotent cells e.g. amoeboid cells. 6. Definite orientation of cells are observed from the beginning of cell aggregation. Archeocytes remain in the periphery and other cells in the middle of the mass. 7. Redifferentiation begins from 4-6 hours stage of reaggregation. PMID- 28354917 TI - ? PMID- 28354918 TI - ? PMID- 28354919 TI - The effects of chloro-acetophenone onXenopus laevis embryos. AB - The effects on Xenopus embryos of treatment for short periods with the sulphydryl inhibitor chlorocoetophenone (CAP) have been investigated. Abnormalities of the central nervous system and eyes are described, and compared with those obtained by other workers using various inhibitory treatments on amphibian embryos. PMID- 28354920 TI - ? PMID- 28354921 TI - ? PMID- 28354922 TI - ? PMID- 28354923 TI - Influence of the antimitotic naphthoquinone on the cleavage of the eggs of the mollusc,Mytilus edulis L. AB - 1. A brief account is given of the cleavage ofMytilus edulis L.2.Naphthoquinone in concentrations above 1? million produces cytolysis of the newly fertilised eggs. It causes some blockage of cleavage at the single cell stage in concentrations down to 1?40 M. The main area of its antimitotic activity is in the range between 1? M and 1?6 M. Resistance to the substance increases as cleavage proceeds. 3. Some abnormalities of cleavage are found at all antimitotic concentrations. The types of abnormality are described. They do not appear to fit easily into the hypothesis of Huber (1947) that the effect of this substance is to enhance the contraction and inhibit the expansion of the cell cortex. PMID- 28354924 TI - ? PMID- 28354925 TI - ? PMID- 28354926 TI - ? PMID- 28354928 TI - ? PMID- 28354927 TI - ? PMID- 28354929 TI - Behaviour op lethal-no-imaginal-bud larvae towards imaginal bud and lymph gland transplants. AB - 1. Lethal-no-imaginal-bud larvae become phenotypically normal if early third instar lymph glands or imaginal buds are transplanted into them before they develop the lethal phenotype. Both tissues were thrown down as melanised black bodies at the end of the third instar. 2. It was argued that the lymph gland transplant has inhibited the development of cell hypertrophy through its secretion, while the imaginal bud transplant seems to have stimulated the production of corresponding antibodies. The imaginal buds are thought to behave as isoantigens in the bud-free haemolymph ofl-nib larvae. 3. Early third instar wild type buds, or even saline solution, caused the melanisation of the cells of the lymph glands if injected into early third instar wild type larvae. PMID- 28354930 TI - ? PMID- 28354931 TI - ? PMID- 28354932 TI - ? PMID- 28354934 TI - ? PMID- 28354933 TI - ? PMID- 28354935 TI - ? PMID- 28354936 TI - ? PMID- 28354937 TI - ? PMID- 28354939 TI - ? PMID- 28354938 TI - ? PMID- 28354940 TI - ? AB - 1. Two imaginai discs of different mutants, sexes and species respectively of different segments (wing and genital disc) fromDrosophila larvae ready to pupate were mixed in order to get a homogeneous aggregate. Before mixing the two discs were partially dissociated either enzymatically or only mechanically. 2. The aggregates were implanted into larval hosts. Their differentiated structures were studied after metamorphosis. 3. Dissociated cells and groups of cells find together and form organized genital or wing structures. 4. Homoplastic-homonome homosexual aggregates of male genital discs form mosaics in all plates both donors taking part in building up one plate. The same cooperation is observed in the heteroplastic-homonome-homosexual combination. 5. The homoplastic-homonome heterosexual combination yields mosaics only in the anal plates and in the region of peripheral bristles. 6. In a heteronome combination the wing and genital cells separate completely so that no mosaic can be formed. 7. Mosaic plates are not randomly composed of different bristle types, but carry only those bristles which occur alsoin situ on one common plate. To form a mosaic, obviously, cells of the same field quality unite (isotypic association), whereby field specificity overrides species, sex and pattern specific differences. 8. In rare cases the rule of isotypic association is broken and "faulty" mosaics are formed. 9. The integration effect and the pattern formation are discussed and interpreted as a result of affinities and movements of determined cells. PMID- 28354941 TI - ? PMID- 28354942 TI - ? PMID- 28354943 TI - ? AB - The aggregation centers ofDictyostelium minutum have three functions: 1. they cause a chemotactic reaction, 2. they induce a change of the cells' functional state which enables the cells to establish intercellular contacts, 3. in some strains, they induce the foundation of further centers.Cells of this species, before being included in a center, are unable to join each other. From this results en exceptionally simple and clearly arranged aggregation pattern, because the assembling of aggregating cells into streams is omitted. PMID- 28354944 TI - ? PMID- 28354945 TI - ? PMID- 28354946 TI - ? PMID- 28354947 TI - ? PMID- 28354948 TI - A study of the effects of trypan blue injected into amphibian zygotes. AB - Trypan blue was injected (0.001-0.002 mg/egg) into zygotes ofRana. The trypan blue-injected series showed much greater mortality than the controls. A probable suppression of gastrulation was seen. 29.7% of the dye-injected and 50.3% of the control embryos developed beyond stage 14. Abnormalities seemed to appear only after neurulation began. Microcephaly, trunk and tail abnormalities occurred though in a small number. Sections of a few embryos revealed disorganized brain and degeneration of the neural tissue. There were no cases of mesodermalization of the notochord.The results are discussed from the view point that trypan blue alters the physical state of proteins in the cytoplasm of the egg. PMID- 28354949 TI - Inhibition of development ofPlanorbis exustus by chloramphenicol. AB - The effect of chloramphenicol (CP) on the development ofPlanorbis exustus has been studied. The antibiotic is found to inhibit cleavage at high concentrations. At low concentrations development is blocked at early gastrulation. There are indications that the effect cannot be reversed by mere transfer of the embryos into normal medium, if they have been treated for 48 hours. If transfer into normal medium is made 24 hours after commencement of treatment, development is resumed.Gastrulae developed normally even in the presence of CP. In low concentrations of CP a characteristic delay in development is observed between the trochophore and hippo stages.The significance of this developmental inhibition has been discussed in relation to synthetic processes occurring in the various phases of development.The antilytic property of CP is evident in these experiments. PMID- 28354950 TI - What are the factors which lead to the fusion of the two heart primordia ? An experimental analysis. AB - 1. In stages 5 and 6 ofHAMBURGER andHAMILTON, the presumptive heart primordia of both sides, placed in contact, Fig. 1, originate two hearts in many cases instead of joining and originating a unique heart, as happens during normogenesis. 2. The two hearts are independent and are found to be very close in the same pericardial cavity, Figs. 7 and 8. 3. The heart formed, from the primordium left "in situ", is a complete and normal heart, Figs. 7 and 8. 4. The heart formed from the transplant is much smaller and consists of a bulb, ventricle, and in some cases atrium, but its curvatures are typical and normal, Figs. 7 and 8. 5. The heart formed of the transplant organizes itself in contact with a small foregut formed from the endoderm of the transplant, Figs. 4 and 9. 6. The endoderm ist not only important in order for the P.H.M. to begin its differentiation in a heart direction but also organizes the P.H.M in such a way that the result is not only heart tissue but a heart, i.e. an organ with typical form and structure. PMID- 28354951 TI - ? PMID- 28354952 TI - ? PMID- 28354953 TI - ? PMID- 28354954 TI - ? PMID- 28354955 TI - ? PMID- 28354956 TI - ? PMID- 28354957 TI - ? PMID- 28354958 TI - ? PMID- 28354959 TI - ? PMID- 28354960 TI - ? PMID- 28354961 TI - ? PMID- 28354962 TI - ? PMID- 28354963 TI - ? PMID- 28354964 TI - ? PMID- 28354965 TI - ? PMID- 28354966 TI - ? PMID- 28354967 TI - ? PMID- 28354968 TI - ? PMID- 28354969 TI - ? PMID- 28354970 TI - ? PMID- 28354971 TI - ? PMID- 28354972 TI - Reproduction in alcoholic mice: I. Treated females. A study of the influence of alcohol on ovarian activity, prenatal mortality and sex ratio. AB - 1. When female mice are treated with light doses of alcohol fumes, (45 minutes a day starting at four weeks) and compared with their untreated sisters from the same litter of inbred lines: a) the time between mating and birth of a litter tends to be lengthened; b) the age at the opening of the vaginal orifice and at the first oestrous shown by smears, is questionably increased; c) the length of the oestrous cycle, the number of corpora lutea, size of litter (father untreated), natal and prenatal mortality, show no modification. 2. In isolated cases when the oestrous cycles were recorded before treatment began, the alcohol was associated with cycles whose length' was roughly doubled; this effect was more frequent when the heavy treatment was used. When female mice are treated with completely anesthetizing doses of alcohol fumes (five days a week starting at four weeks), are mated with normal males, and are compared with their untreated sisters from the same litter and mated with the same normal male: a) the treatment tends to delay the birth of the first litter and increases the intervals of time between successive births, when all young are killed at birth and the mothers remated at once; b) the number of corpora lutea per pregnancy is slightly increased without regard to whether the treatments are suspended during the last week of each pregnancy (series A) or not (series B); c) litter size is reduced by 0,5 mice in series A and 0,7 mice in series B; d) pregnancies yielding no full term young ("zero" litters) are slightly more frequent; e) the proportion of young found dead at birth is increased, in series A by 4,5%, in series B by 9,4%; and in both test and control litters, the proportion of females dead is slightly higher than the males; f) the prenatal mortality is increased by from one to two embryos per litter; g) the sex ratios show no modification: the combined totals give 51,2% males in 2857 mice; h) the occurrence of abnormalities among the young is not influenced. PMID- 28354973 TI - ? PMID- 28354974 TI - ? PMID- 28354975 TI - ? PMID- 28354976 TI - ? PMID- 28354977 TI - ? PMID- 28354978 TI - ? PMID- 28354979 TI - ? PMID- 28354980 TI - ? PMID- 28354981 TI - ? PMID- 28354982 TI - ? PMID- 28354983 TI - ? PMID- 28354984 TI - ? PMID- 28354985 TI - ? PMID- 28354986 TI - The origin of independent and of conjoined twins in fresh-water snails. PMID- 28354987 TI - ? PMID- 28354988 TI - ? PMID- 28354989 TI - ? PMID- 28354990 TI - ? PMID- 28354991 TI - ? PMID- 28354992 TI - ? PMID- 28354993 TI - ? PMID- 28354994 TI - ? PMID- 28354995 TI - ? PMID- 28354997 TI - ? PMID- 28354996 TI - ? PMID- 28354998 TI - ? PMID- 28354999 TI - ? PMID- 28355000 TI - ? PMID- 28355001 TI - ? PMID- 28355002 TI - ? PMID- 28355003 TI - ? PMID- 28355005 TI - ? PMID- 28355004 TI - ? PMID- 28355006 TI - ? PMID- 28355007 TI - An immunological hypothesis of tumour development inDrosophila. PMID- 28355008 TI - A cinematographic study of the embryology ofDrosophila melanogaster. AB - In connection with studies on the effect of genetic abnormalities on development, a film was made of the normal development of theDrosophila embryo. Time-lapse motion technique was used, and this made it possible to make new observations on those phases of the development which involve large re-arrangements of the embryonic material, in particular on blastoderm formation, gastrulation and involution of the head. These new observations have been incorporated in an account of the complete development of the embryo up to the time of hatching. PMID- 28355009 TI - Studies on the effects of some genetic lethal factors on the embryonic development ofDrosophila melanogaster : I. A preliminary survey of some sex linked lethal stocks, and an analysis of the mutantLff 11. AB - 1. Out of seventy sex-linked lethal mutants examined, twelve were found to cause death in the embryonic stage. 2. In six of the embryonic lethals, no visible abnormalities occurred, but the embryos failed to hatch. 3. In the other six cases there were obvious morphogenetic disturbances. Detailed developmental studies were made of these, of which the mutantLff 11 is reported in the present paper. 4. The embryo of the mutantLff 11 reaches a late stage of development, and lives beyond the normal time of hatching, but it is abnormal in many respects. Differentiation of the tissues is relatively normal, but the organ systems are extremely disorganized. 5. The disorganization of the late embryo arises from abnormalities in gastrulation, which have two major effects:- 1) the invagination of the posterior mid-gut rudiment and the germband posteriorly; 2) the formation of a constriction behind the head region. 6. It seems likely that these abnormalities arise from disturbances in the relative timing of certain developmental events, in particular in the precocious formation of the embryonic membrane material. 7. The abnormalities in gastrulation are discussed with respect to the light they throw upon the mechanism of gastrulation in normal embryos, and especially upon the significance of the cephalic furrow. 8. Certain resemblances between the mutant development and that of coleopteran embryos are pointed out, and their evolutionary significance is discussed. PMID- 28355010 TI - Studies on the effects of some genetic lethal factors on the embryonic development ofDrosophila melanogaster : II. An analysis op the mutantX 2. AB - 1. The development of the embryonic lethal mutantX 2 was studied by means of serial sections and by time-lapse cine-photography of the complete development. 2. The embryo reaches a late stage of development, and survives for several hours after the time at which normal embryos hatch. Differentiation of all the tissues occurs, but the organ systems are extremely disorganized. 3. The most distinctive characteristic of the late embryo is the absence of gut in the middle region, and its partial external development at the anterior and posterior ends. 4. The abnormalities of the late embryo result from the disorganization resulting from two effects which appear at the end of gastrulation:- 1) the partial or complete failure of the endoderm and proctodaeal and stomodaeal rudiments to invaginate; 2) the presence of deep furrows over the surface of the embryo. 5. The primary effect of the factor appears to be upon the control of nuclear and cell division in blastoderm formation or in early gastrulation. This results in an excessive number of surface cells in the germ band, which causes it to become furrowed at the time of its extension. This in turn probably causes mechanical interference with the invagination of the gut rudiments. PMID- 28355011 TI - ? PMID- 28355012 TI - ? PMID- 28355013 TI - ? PMID- 28355014 TI - Tracing morphogenetic movements by means of labelled cells. AB - A technique involving the use of labelled grafts, detectable by autoradiographs, is proposed for mapping embryonic presumptive areas and cell migrations. It permits identification of isolated graft cells. It has been applied to reinvestigate the localization of presumptive endoderm in early gastrulae ofXenopus, originally described byNIEUWKOOP andFLORSCHUTZ. PMID- 28355015 TI - ? PMID- 28355016 TI - ? PMID- 28355017 TI - ? PMID- 28355018 TI - ? PMID- 28355019 TI - ? PMID- 28355020 TI - ? PMID- 28355021 TI - ? PMID- 28355022 TI - ? PMID- 28355023 TI - ? PMID- 28355024 TI - ? PMID- 28355025 TI - ? PMID- 28355026 TI - ? PMID- 28355027 TI - ? PMID- 28355028 TI - ? PMID- 28355029 TI - ? PMID- 28355030 TI - Preliminary evaluation of a novel bladder-liner for facilitating residual limb fluid volume recovery without doffing. AB - For people who wear a prosthetic limb, residual-limb fluid volume loss during the day may be problematic and detrimentally affect socket fit. The purpose of this research was to test the capability of a novel liner with adjustable bladders positioned within its wall to mitigate volume loss and facilitate limb fluid volume recovery and retention. Bioimpedance analysis was used to monitor fluid volume changes in the anterior and posterior residual limb of participants with transtibial amputation. Participants underwent six cycles of sitting for 90 s, standing for 90 s, and walking for 5 min with liquid within the bladder-liners. Between the third and fourth cycles, participants sat for 10 min with liquid left within the bladders (Liquid-In) or removed (Liquid-Out). Results showed that participants recovered more fluid volume during the 10 min of sitting with Liquid Out than Liquid-In (p = 0.09 for anterior and p = 0.04 for posterior). However, those fluid volume recoveries were not well retained in the short term (after the fourth cycle) or the long term (after the sixth cycle). Physiologic differences between sessions, reflected in the rates of fluid volume change at the outset of the session, and excessive stiffness of the bladder-liners may have affected fluid volume retentions. PMID- 28355031 TI - Metabolic effects of using a variable impedance prosthetic knee. AB - A transfemoral amputation has a significant effect on walking. Though current prosthetic knee options serve to restore mobility, as do purely passive devices, they do not fully restore nondisabled gait. Persons with transfemoral amputation incur a higher metabolic cost during walking than persons without amputation and as a result walk slower and for a shorter distance before tiring. An original variable-impedance transmission prosthetic knee (VI Knee) was tested with five study participants with unilateral transfemoral amputation at two steady-state walking speeds, one below and one above their preferred walking speed. While walking with the VI Knee, participants with shorter limbs showed a reduction in metabolic cost compared with their conventional C-Leg prosthesis, while those with longer limbs exhibited an increase. Though differences were observed between speeds, overall, the difference in metabolic cost (reduction or increase) was found to correlate significantly with rise in the center of mass, with those with shorter residual limbs exhibiting less overall lifting of the body during gait. PMID- 28355033 TI - Transtibial amputee gait efficiency: Energy storage and return versus solid ankle cushioned heel prosthetic feet. AB - Energy storage and return (ESR) feet have long been assumed to promote metabolically efficient amputee gait. However, despite being prescribed for approximately 30 yr, there is limited evidence that they achieve this desired function. Here, we report a meta-analysis of data from 10 studies that met our selection criteria to determine whether amputee walking with ESR feet is more efficient than with conventional solid ankle cushioned heel (SACH) feet. Additionally, the data were tested for a relationship with walking speed since it has been suggested ESR feet might perform better at higher speeds. The raw data are highly variable because of differences in study protocols; therefore, we normalized the data and found a statistically significant difference (p < 0.001) between ESR and SACH feet. However, the magnitude of this difference is small, with the cost of transport (COT) with ESR feet being 97.3% of the cost with SACH feet. No relationship between ESR COT and speed was found (p = 0.19). We hypothesize that the small but statistically significant difference between ESR and SACH feet may not constitute a functionally significant improvement in COT, possibly related to the limited push-off power provided by ESR feed compared with nondisabled ankles. PMID- 28355032 TI - Physical activity, ambulation, and comorbidities in people with diabetes and lower-limb amputation. AB - We characterized physical activity (PA) and its relation to physical function and number of comorbidities in people with diabetes and transtibial amputation (AMP), people with diabetes without AMP, and nondisabled adults without diabetes or AMP. Twenty-two individuals with type 2 diabetes mellitus (DM) and transtibial amputation (DM+AMP), 11 people with DM, and 13 nondisabled participants were recruited for this cross-sectional cohort study. Measures included PA volume and intensity, a Timed Up and Go test, a 2-min walk test, and number of comorbidities. The nondisabled group performed greater amounts of PA than the DM group, who performed greater amounts of PA than the DM+AMP group. PA was related to physical function in the DM group and in the DM+AMP group, whereas no such relationship existed in the nondisabled group. PA was not related to number of comorbidities in any group. These findings suggest the ability to walk may affect overall performance of PA. Alternately, PA may alleviate walking problems. This possibility is of interest because issues with walking may be modifiable by improved levels and intensity of PA. PA's lack of relation to number of comorbidities suggests that factors beyond multiple morbidities account for group differences in PA. PMID- 28355036 TI - Rehabilitation and multiple limb amputations: A clinical report of patients injured in combat. AB - This clinical report describes the outpatient rehabilitation program for patients with multiple limb amputations enrolled in the Comprehensive Combat and Complex Casualty Care facility at the Naval Medical Center San Diego. Injury-specific data for 29 of these patients wounded by blast weaponry in Afghanistan in 2010 or 2011 were captured by the Expeditionary Medical Encounter Database at the Naval Health Research Center and were reviewed for this report. Their median Injury Severity Score was 27 (N = 29; range, 11-54). Patients averaged seven moderate to serious injuries (Abbreviated Injury Scale scores >=2), including multiple injuries to lower limbs and injuries to the torso and/or upper limbs. All patients received care from numerous clinics, particularly physical therapy during the first 6 mo postinjury. Clinic use generally declined after the first 6 mo with the exception of prosthetic devices and repairs. The clinical team implemented the Mayo-Portland Adaptability Inventory, 4th Revision (MPAI-4) to assess functioning at outpatient program initiation and discharge (n = 23). At program discharge, most patients had improved scores for the MPAI-4 items assessing mobility, pain, and transportation, but not employment. Case reports described rehabilitation for two patients with triple amputations and illustrated multispecialty care and contrasting solutions for limb prostheses. PMID- 28355034 TI - The biomechanical response of persons with transfemoral amputation to variations in prosthetic knee alignment during level walking. AB - Prosthetic alignment is an important factor in the overall fit and performance of a lower-limb prosthesis. However, the association between prosthetic alignment and control strategies used by persons with transfemoral amputation to coordinate the movement of a passive prosthetic knee is poorly understood. This study investigated the biomechanical response of persons with transfemoral amputation to systematic perturbations in knee joint alignment during a level walking task. Quantitative gait data were collected for three alignment conditions: bench alignment, 2 cm anterior knee translation (ANT), and 2 cm posterior knee translation (POST). In response to a destabilizing alignment perturbation (i.e., the ANT condition), participants significantly increased their early-stance hip extension moment, confirming that persons with transfemoral amputation rely on a hip extensor strategy to maintain knee joint stability. However, participants also decreased the rate at which they loaded their prosthesis, decreased their affected-side step length, increased their trunk flexion, and maintained their prosthesis in a more vertical posture at the time of opposite toe off. Collectively, these results suggest that persons with transfemoral amputation rely on a combination of strategies to coordinate stance-phase knee flexion. Further, comparatively few significant changes were observed in response to the POST condition, suggesting that a bias toward posterior alignment may have fewer implications in terms of stance-phase, knee joint control. PMID- 28355035 TI - Explaining modified 2-min walk test outcomes in male Veterans with traumatic or nontraumatic lower-limb amputation. AB - Little evidence exists to support the presence of differences in spatiotemporal gait parameters and ambulation ability between those individuals with traumatic and nontraumatic lower-limb amputation (LLA). We conducted an exploratory study of 81 male Veterans with unilateral amputation to quantify differences in spatiotemporal gait parameters and ambulatory mobility between Veterans with traumatic and nontraumatic LLA. Furthermore, we identified variables that significantly contributed to the explanation of variability in modified 2-min walk test distance. All participants completed the modified 2-min walk test and a spatiotemporal gait analysis using an instrumented walkway during a routine physical therapy visit. Veterans with nontraumatic LLA walked significantly shorter mean distances during a modified 2-min walk test than Veterans with traumatic LLA. Variables identified as significant contributors to modified 2-min walk test variability were amputated limb stance time, amputated limb step length, and percentage of the gait cycle spent in double support. These findings demonstrate that differences in spatiotemporal gait parameters and ambulatory mobility exist between Veterans with traumatic and nontraumatic LLA and identify important spatiotemporal parameters of gait contributing to this decline. These parameters should be considered as targets for intervention and future investigation. PMID- 28355038 TI - The perceived functional benefit of dynamic arm supports in daily life. AB - Dynamic arm supports are provided to assist with activities of daily living (ADLs) in people with limited upper-limb function. However, the perceived functional benefit of these devices in daily life is unknown. Insight into the functional benefit may give direction to the development of new devices and may affect the factors that patients and their health care providers consider during the selection process of a device. A cross-sectional study involving 23 Dutch experienced dynamic arm support users was performed in the Netherlands. The study included a questionnaire, an interview, and an observation of ADL task performance in the domestic setting. Twenty participants completed this study. Five users had a large perceived functional benefit, nine a moderate benefit, and five no benefit (one was unable to indicate the benefit). People with limited functional abilities benefited most. Participants varied in the amount of device use, activities the device is used for, and reasons for using (or not using) the device. On an individual level, selection using a selection tool and a good evaluation of the prescription could improve user-device matches. PMID- 28355037 TI - The effect of common wrist orthoses on the stiffness of wrist rotations. AB - Wrist orthoses (also known as splints, braces, or supports) are commonly used to support or restrict the motion of a weak or injured wrist. These orthoses generally function by stiffening the wrist joint. Therefore, choosing the proper orthosis (or improving orthoses) requires that we understand their stiffness properties. In this study, we present a method for measuring the stiffness of wrist orthoses, and we apply this method to 12 of the most common wrist orthoses. We found similarities and differences between these orthoses, indicating that different orthoses have different effects on the wrist joint and, presumably, on wrist behavior. In particular, all six orthoses with a stay on the volar side or the volar and dorsal sides added a significant amount of stiffness to the wrist joint. In contrast, only one of three orthoses with a stay on the dorsal side and none of the three orthoses without stays exhibited a significant amount of stiffness, calling into question their ability to support the wrist joint. This work lays a foundation for future studies investigating the effect of wrist orthosis stiffness on wrist behavior and how wrist orthosis stiffness can be designed to produce behavior that facilitates healing. PMID- 28355039 TI - Elevated vacuum suspension preserves residual-limb skin health in people with lower-limb amputation: Randomized clinical trial. AB - : A growing number of clinical trials and case reports support qualitative claims that use of an elevated vacuum suspension (EVS) prosthesis improves residual-limb health on the basis of self-reported questionnaires, clinical outcomes scales, and wound closure studies. Here, we report first efforts to quantitatively assess residual-limb circulation in response to EVS. Residual-limb skin health and perfusion of people with lower-limb amputation (N = 10) were assessed during a randomized crossover study comparing EVS with nonelevated vacuum suspension (control) over a 32 wk period using noninvasive probes (transepidermal water loss, laser speckle imaging, transcutaneous oxygen measurement) and functional hyperspectral imaging approaches. Regardless of the suspension system, prosthesis donning decreased perfusion in the residual limb under resting conditions. After 16 wk of use, EVS improved residual-limb oxygenation during treadmill walking. Likewise, prosthesis-induced reactive hyperemia was attenuated with EVS following 16 wk of use. Skin barrier function was preserved with EVS but disrupted after control socket use. Taken together, outcomes suggest chronic EVS use improves perfusion and preserves skin barrier function in people with lower-limb amputation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; "Evaluation of limb health associated with a prosthetic vacuum socket system": NCT01839123; https://clinicaltrials.gov/ct2/show/NCT01839123?term=NCT01839123&rank=1. PMID- 28355040 TI - Barriers to outcome measure administration and completion at discharge from inpatient rehabilitation of people with amputation. AB - We performed a retrospective chart review of consecutive patients discharged from an inpatient amputee rehabilitation program over a 2 yr period (January 2010 December 2011). Our objective was to determine barriers to the completion of a standardized maximum walk test (MWT) at discharge. Over the study period, there were 190 discharges. The sample had a mean age of 63.5 yr (standard deviation [SD] +/- 14.2 yr), was 71.6% male, and had a majority of transtibial amputation (67%). The average length of inpatient stay was 28.1 d (SD +/- 13.2 d). MWT including distance and time was completed in 149 (78%) of the discharges; the main factors limiting patient performance on this measure were cardiorespiratory fatigue (53%), lower-limb pain (24%), back pain (12%), and skin problems (6%). Among those patients who completed the MWT, in 31% no limiting factor was identified. Forty-one discharge MWTs were not completed as a result of nonambulatory status (34%), acute illness (17%), limb pain (7%), skin problems (12%), or other reasons. Knowing these limitations may direct care from a clinical standpoint and provides valuable data for research planning to further examine outcome measures in this population. PMID- 28355041 TI - Clozapine Augmentation With Antiepileptic Drugs for Treatment-Resistant Schizophrenia: A Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVE: To meta-analyze randomized controlled trials (RCTs) for the efficacy and safety of adjunctive antiepileptic drugs (AEDs) to augment clozapine therapy for treatment-resistant schizophrenia. DATA SOURCES: The search included databases in English (PubMed, PsycINFO, Embase, and Cochrane Library databases and the Cochrane Controlled Trials Register) and in Chinese (China Journal Net [CJN], WanFang, and China Biology Medicine [CBM]) and references from retrieved articles. The databases were searched using dates inclusive from their onset until January 1, 2016, for terms reflecting (a) schizophrenia, (b) clozapine, and (c) adjunctive drugs. STUDY SELECTION: From 1,969 potentially relevant articles, 21 articles describing 22 RCTs were selected. DATA EXTRACTION: Two independent investigators extracted data for a random-effects meta-analysis and assessed the quality of the studies using risk of bias and the Jadad scale. Standard mean difference, risk ratio (RR) +/- 95% confidence intervals (CIs), and the number needed to harm (NNH) were used. RESULTS: A total of 22 RCTs (N = 1,227) with 4 AEDs (topiramate [5 RCTs, n = 270], lamotrigine [8 RCTs, n = 299], sodium valproate [6 RCTs, n = 430], and magnesium valproate [3 RCTs, n = 228]) were analyzed. The means weighted by sample size were 12.1 weeks for treatment duration, 36.2 years for age, and 61% for male frequency. Significant superiority in total psychopathology was observed for topiramate (P < .0001), lamotrigine (P = .05), and sodium valproate (P = .002), compared to clozapine monotherapy. After removing outliers, the positive effect of sodium valproate remained, but the positive effect of lamotrigine disappeared (P = .40). Significantly improved efficacy in positive and general symptom severity was observed for topiramate (P = .04 and P = .02, respectively) and sodium valproate (P = .009 and P = .003, respectively). There were no significant differences regarding adverse drug reactions and all-cause discontinuations except for topiramate, which was associated with more all-cause discontinuations (RR = 1.99; 95% CI, 1.16 to 3.39; P = .01; I2 = 0%; NNH = 7). CONCLUSIONS: Sodium valproate augmentation was efficacious and safe. Topiramate augmentation had a too-high discontinuation rate. High-quality RCTs are needed to inform clinical recommendations. PMID- 28355042 TI - Contributing Factors and Mental Health Outcomes of First Suicide Attempt During Childhood and Adolescence: Results From a Nationally Representative Study. AB - OBJECTIVE: To investigate whether risk factors for suicide attempts differ in children and adolescents and to categorize adulthood mental health outcomes of child and adolescent suicide attempters in the general population. METHODS: Using a large (N = 34,653), nationally representative US adult sample, the 2004-2005 National Epidemiologic Survey on Alcohol and Related Conditions, we examined whether individuals who first attempted suicide during childhood (under the age of 13 years) differ from those who first attempted suicide during adolescence (13 through 17 years) in (1) contributing factors for first suicide attempt, including mental disorders and traumatic experiences that occurred before the first suicide attempt, parental history of mental disorders, and family poverty and (2) adulthood mental health outcomes, including lifetime and current prevalence of DSM-IV psychiatric disorders and quality of life measures. RESULTS: Suicide attempts during childhood (n = 104) were more strongly related to childhood maltreatment, while suicide attempts during adolescence (n = 415) were more strongly associated with major depressive episode. Compared to first suicide attempts during adolescence, first attempts during childhood were associated with increased risk for multiple suicide attempts (61.3% vs 32.6%), several psychiatric disorders (mania, hypomania, and panic disorder), and poorer social functioning during adulthood (all P values < .05). CONCLUSIONS: Suicide attempts in children and adolescents substantially differ in contributing factors and adulthood mental health outcomes. Preventing childhood maltreatment and early intervention for psychiatric disorders may have broad benefits to reduce not only the suffering of these children and adolescents, but also the burden of suicide. PMID- 28355043 TI - Gastroenterology-Urology Devices; Manual Gastroenterology-Urology Surgical Instruments and Accessories. Final rule; technical amendment. AB - The Food and Drug Administration (FDA) is amending the identification of manual gastroenterology-urology surgical instruments and accessories to reflect that the device does not include specialized surgical instrumentation for use with urogyencologic surgical mesh specifically intended for use as an aid in the insertion, placement, fixation, or anchoring of surgical mesh during urogynecologic procedures ("specialized surgical instrumentation for use with urogynecologic surgical mesh"). These amendments are being made to reflect changes made in the recently issued final reclassification order for specialized surgical instrumentation for use with urogynecologic surgical mesh. PMID- 28355044 TI - Schedules of Controlled Substances: Placement of 10 Synthetic Cathinones Into Schedule I. Final rule. AB - With the issuance of this final rule, the Drug Enforcement Administration places 10 synthetic cathinones: 4-methyl-N-ethylcathinone (4-MEC); 4-methyl-alpha pyrrolidinopropiophenone (4-MePPP); alpha-pyrrolidinopentiophenone ([alpha]-PVP); 1-(1,3-benzodioxol-5-yl)-2-(methylamino)butan-1-one (butylone, bk-MBDB e); 2 (methylamino)-1-phenylpentan-1-one (pentedrone); 1-(1,3-benzodioxol-5-yl)-2 (methylamino)pentan-1-one (pentylone, bk-MBDP); 4-fluoro-N-methylcathinone (4 FMC, flephedrone); 3-fluoro-N-methylcathinone (3-FMC); 1-(naphthalen-2-yl)-2 (pyrrolidin-1-yl)pentan-1-one (naphyrone); alpha-pyrrolidinobutiophenone ([alpha] PBP) and their optical, positional, and geometric isomers, salts and salts of isomers, whenever the existence of such salts, isomers, and salts of isomers is possible, into schedule I of the Controlled Substances Act. This scheduling action is pursuant to the Controlled Substances Act which requires that such actions be made on the record after opportunity for a hearing through formal rulemaking. This rule continues the imposition of the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances on persons who handle (manufacture, distribute, reverse distribute, import, export, engage in research, conduct instructional activities or chemical analysis, or possess), or propose to handle 4-MEC, 4-MePPP, [alpha]-PVP, butylone, pentedrone, pentylone, 4-FMC, 3-FMC, naphyrone, or [alpha]-PBP. PMID- 28355045 TI - Schedules of Controlled Substances: Placement of Brivaracetam Into Schedule V. Final rule. AB - This final rule adopts without change an interim final rule with request for comments published in the Federal Register on May 12, 2016. The Drug Enforcement Administration is placing the substance brivaracetam ((2S)-2-[(4R)-2-oxo-4 propylpyrrolidin-1-yl] butanamide) (also referred to as BRV; UCB-34714; Briviact) (including its salts) into schedule V of the Controlled Substances Act. This scheduling action is pursuant to the Controlled Substances Act, as revised by the Improving Regulatory Transparency for New Medical Therapies Act which was signed into law on November 25, 2015. PMID- 28355046 TI - Medical Devices; Clinical Chemistry and Clinical Toxicology Devices; Classification of the Continuous Glucose Monitor Secondary Display. Final order. AB - The Food and Drug Administration (FDA) is classifying the continuous glucose monitor secondary display into class II (special controls). The special controls that will apply to the device are identified in this order and will be part of the codified languagefor the continuous glucose monitor secondary display's classification. The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 28355047 TI - Medical Devices; Clinical Chemistry and Clinical Toxicology Devices; Classification of the High Throughput Genomic Sequence Analyzer for Clinical Use. Final order. AB - The Food and Drug Administration (FDA) is classifying the high throughput genomic sequence analyzer for clinical use into class II (special controls). The special controls that will apply to the device are identified in this order and will be part of the codified language for the classification of the high throughput genomic sequence analyzer for clinical use device. The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 28355048 TI - Medical Devices; Neurological Devices, Classification of the Vibratory Counter Stimulation Device. Final order. AB - The Food and Drug Administration (FDA) is classifying the vibratory counter stimulation device into class II (special controls). The special controls that will apply to the device are identified in this order and will be part of the codified language for the vibratory counter-stimulation device's classification. The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 28355049 TI - Schedules of Controlled Substances: Placement of FDA-Approved Products of Oral Solutions Containing Dronabinol [(-)-delta-9-transtetrahydrocannabinol (delta-9 THC)] in Schedule II. Interim final rule, with request for comments. AB - On July 1, 2016, the U.S. Food and Drug Administration (FDA) approved a new drug application for Syndros, a drug product consisting of dronabinol [(-)-delta-9 trans-tetrahydrocannabinol (delta-9-THC)] oral solution. Thereafter, the Department of Health and Human Services (HHS) provided the Drug Enforcement Administration (DEA) with a scheduling recommendation that would result in Syndros (and other oral solutions containing dronabinol) being placed in schedule II of the Controlled Substances Act (CSA). In accordance with the CSA, as revised by the Improving Regulatory Transparency for New Medical Therapies Act, DEA is hereby issuing an interim final rule placing FDA-approved products of oral solutions containing dronabinol in schedule II of the CSA. PMID- 28355050 TI - Release of VA Records Relating to HIV. Final rule. AB - The Department of Veterans Affairs (VA) is amending its medical regulations governing the release of VA medical records. Specifically, VA is eliminating the restriction on sharing a negative test result for the human immunodeficiency virus (HIV) with veterans' outside providers. HIV testing is a common practice today in healthcare and the stigma of testing that may have been seen in the 1980s when HIV was first discovered is no longer prevalent. Continuing to protect negative HIV tests causes delays and an unnecessary burden on veterans when VA tries to share electronic medical information with the veterans' outside providers through electronic health information exchanges. For this same reason, VA will also eliminate restrictions on negative test results of sickle cell anemia. This final rule eliminates the current barriers to electronic medical information exchange. PMID- 28355051 TI - MOFabric: Electrospun Nanofiber Mats from PVDF/UiO-66-NH2 for Chemical Protection and Decontamination. AB - Textiles capable of capture and detoxification of toxic chemicals, such as chemical-warfare agents (CWAs), are of high interest. Some metal-organic frameworks (MOFs) exhibit superior reactivity toward CWAs. However, it remains a challenge to integrate powder MOFs into engineered materials like textiles, while retaining functionalities like crystallinity, adsorptivity, and reactivity. Here, we present a simple method of electrospinning UiO-66-NH2, a zirconium MOF, with polyvinylidene fluoride (PVDF). The electrospun composite, which we refer to as "MOFabric", exhibits comparable crystal patterns, surface area, chlorine uptake, and simulant hydrolysis to powder UiO-66-NH2. The MOFabric is also capable of breaking down GD (O-pinacolyl methylphosphonofluoridae) faster than powder UiO-66 NH2. Half-life of GD monitored by solid-state NMR for MOFabric is 131 min versus 315 min on powder UiO-66-NH2. PMID- 28355052 TI - Design, Synthesis, and Experimental Validation of Peptide Ligands Targeting Mycobacterium tuberculosis sigma Factors. AB - Transcription in prokaryotes is a multistep process and is primarily regulated at the initiation stage. sigma factors are involved in promoter recognition and thus govern prokaryotic gene expression. Mycobacterium tuberculosis (Mtb) sigma factors have been previously suggested as important drug targets through large scale genome analyses. Here we demonstrate the feasibility of specific targeting of Mtb sigma factors using designed peptides. A peptide library was generated using three-dimensional structural features corresponding to the interface regions of sigma factors and the RNA polymerase. In silico optimization of the peptides, employing structural as well as sequence features, aided specific targeting of sigmaA and sigmaB. We synthesized and characterized the best hit peptide from the peptide library along with other control peptides and studied the interaction of these peptides with sigmaB using biolayer interferometry. The experimental data validate the design strategy. These studies suggest the feasibility of designing specific peptides via in silico methods that bind sigmaB with nanomolar affinity. We note that this strategy can be broadly applied to modulate prokaryotic transcription by designed peptides, thereby providing a tool for studying bacterial adaptation as well as host-pathogen interactions in infectious bacteria. PMID- 28355053 TI - Experimental Study on the Role of Sedimentation and Degradation Processes on Atmospheric Deposition of Persistent Organic Pollutants in a Subtropical Water Column. AB - The goal of this study is to experimentally assess the role of vertical sinking and degradation processes of persistent organic pollutants (POPs) in a subtropical water column. This was done by measuring the concentrations of selected typical organochlorine pesticides, including hexachlorocyclohexanes (HCHs), hexachlorobenzene (HCB), dichlorodiphenyltrichloroethanes (DDTs), trans chlordane (TC), and cis-chlordane (CC), in atmosphere (gas phase), water (dissolved and particulate phases), and sedimentation samples simultaneously from October 2011 to April 2013 in a subtropical lake. The fugacity ratios suggested net deposition for alpha-HCH, gamma-HCH, p,p'-DDT, p,p'-DDD, p,p'-DDE, o,p'-DDT, TC, and CC, indicating that the subtropical lake was acting as a "sink" for these chemicals. The enantiomer fractions of alpha-HCH, o,p'-DDT, TC, and CC in the dissolved phase samples were much more deviated from the racemic values than were those in the air samples, suggesting that these chemicals have suffered microbial degradation in the subtropical lake. In fact, 99% to 100% of atmospheric input of alpha-HCH and gamma-HCH to the subtropical lake was estimated to be depleted via microbial degradation, while the role of hydrolysis and vertical sinking was very small. For more hydrophobic p,p'-DDT, o,p'-DDT, TC, and CC, the role of vertical sinking was 2 to 3 orders of magnitude larger than that for alpha-HCH and gamma HCH. Microbial degradation was also very important for removing p,p'-DDT, o,p' DDT, TC, and CC from the water column. PMID- 28355054 TI - Secondary Organic Aerosol Formation over Coastal Ocean: Inferences from Atmospheric Water-Soluble Low Molecular Weight Organic Compounds. AB - A lack of consensus on the distributions and formation pathways of secondary organic aerosols (SOA) over oceanic regions downwind of pollution sources limits our ability to assess their climate impact globally. As a case study, we report here on water-soluble SOA components such as dicarboxylic acids, oxocarboxylic acids, and alpha-dicarbonyls in the continental outflows from the Indo-Gangetic Plain (IGP) and Southeast Asia (SEA) to the Bay of Bengal. Oxalic acid (C2) is the dominant species followed by succinic (C4) and glyoxylic acids (omegaC2) in the outflow. Nonsea-salt SO42- also dominates (~70%) total water-soluble inorganic constituents and correlates well with aerosol liquid water content (LWC) and C2, indicating their production through aqueous phase photochemical reactions. Furthermore, mass ratios of dicarboxylic acids (C2/C4, C2/omegaC2), and their relative abundances in water-soluble organic carbon and total organic carbon are quite similar between the two continental (IGP and SEA) outflows, indicating the formation of SOA through aqueous phase photochemical reactions in LWC-enriched aerosols, largely controlled by anthropogenic SO42-. PMID- 28355055 TI - Layered Metal Thiophosphite Materials: Magnetic, Electrochemical, and Electronic Properties. AB - Beyond graphene, transitional metal dichalcogenides, and black phosphorus, there are other layered materials called metal thiophosphites (MPSx), which are recently attracting the attention of scientists. Here we present the synthesis, structural and morphological characterization, magnetic properties, electrochemical performance, and the calculated density of states of different layered metal thiophosphite materials with a general formula MPSx, and as a result of varying the metal component, we obtain CrPS4, MnPS3, FePS3, CoPS3, NiPS3, ZnPS3, CdPS3, GaPS4, SnPS3, and BiPS4. SnPS3, ZnPS3, CdPS3, GaPS4, and BiPS4 exhibit only diamagnetic behavior due to core electrons. By contrast, trisulfides with M = Mn, Fe, Co, and Ni, as well as CrPS4, are paramagnetic at high temperatures and undergo a transition to antiferromagnetic state on cooling. Within the trisulfides series the Neel temperature characterizing the transition from paramagnetic to antiferromagnetic phase increases with the increasing atomic number and the orbital component enhancing the total effective magnetic moment. Interestingly, in terms of catalysis NiPS3, CoPS3, and BiPS4 show the highest efficiency for hydrogen evolution reaction (HER), while for the oxygen evolution reaction (OER) the highest performance is observed for CoPS3. Finally, MnPS3 presents the highest oxygen reduction reaction (ORR) activity compared to the other MPSx studied here. This great catalytic performance reported for these MPSx demonstrates their promising capabilities in energy applications. PMID- 28355056 TI - Deconvolution of Gene Expression Noise into Spatial Dynamics of Transcription Factor-Promoter Interplay. AB - Gene expression noise is not only the mere consequence of stochasticity, but also a signal that reflects the upstream physical dynamics of the cognate molecular machinery. Soil bacteria facing recalcitrant pollutants exploit noise of catabolic promoters to deploy beneficial phenotypes such as metabolic bet-hedging and/or division of biochemical labor. Although the role of upstream promoter regulator interplay in the origin of this noise is little understood, its specifications are probably ciphered in flow cytometry data patterns. We studied Pm promoter activity of the environmental bacterium Pseudomonas putida and its cognate regulator XylS by following expression of Pm-gfp fusions in single cells. Using mathematical modeling and computational simulations, we determined the kinetic properties of the system and used them as a baseline code to interpret promoter activity in terms of upstream regulator dynamics. Transcriptional noise was predicted to depend on the intracellular physical distance between regulator source (where XylS is produced) and the target promoter. Experiments with engineered bacteria in which this distance is minimized or enlarged confirmed the predicted effects of source/target proximity on noise patterns. This approach allowed deconvolution of cytometry data into mechanistic information on gene expression flow. It also provided a basis for selecting programmable noise levels in synthetic regulatory circuits. PMID- 28355057 TI - Trichloramine Removal with Activated Carbon Is Governed by Two Reductive Reactions: A Theoretical Approach with Diffusion-Reaction Models. AB - Mechanisms underlying trichloramine removal with activated carbon treatment were proven by batch experiments and theoretical analysis with diffusion-reaction models. The observed values of trichloramine and free chlorine were explained only by the model in which (1) both trichloramine and free chlorine were involved as reactants, (2) the removals of reactants were affected both by the intraparticle diffusion and by the reaction with activated carbon, and (3) trichloramine decomposition was governed by two distinct reductive reactions. One reductive reaction was expressed as a first-order reaction: the reductive reaction of trichloramine with the basal plane of PAC, which consists of graphene sheets. The other reaction was expressed as a second-order reaction: the reductive reaction of trichloramine with active functional groups located on the edge of the basal plane. Free chlorine competitively reacted with both the basal plane and the active functional groups. The fact that the model prediction succeeded even in experiments with different activated carbon doses, with different initial trichloramine concentrations, and with different sizes of activated carbon particles clearly proved that the mechanisms described in the model were reasonable for explaining trichloramine removal with activated carbon treatment. PMID- 28355058 TI - Real-Time Dissection of Distinct Dynamin-Dependent Endocytic Routes of Influenza A Virus by Quantum Dot-Based Single-Virus Tracking. AB - Entry is the first critical step for the infection of influenza A virus and of great significance for the research and development of antiflu drugs. Influenza A virus depends on exploitation of cellular endocytosis to enter its host cells, and its entry behaviors in distinct routes still need further investigation. With the aid of a single-virus tracking technique and quantum dots, we have realized real-time and multicolor visualization of the endocytic process of individual viruses and comprehensive dissection of two distinct dynamin-dependent endocytic pathways of influenza A virus, either dependent on clathrin or not. Based on the sequential progression of protein recruitment and viral motility, we have revealed the asynchronization in the recruitments of clathrin and dynamin during clathrin-dependent entry of the virus, with a large population of events for short-lived recruitments of these two proteins being abortive. In addition, the differentiated durations of dynamin recruitment and responses to inhibitors in these two routes have evidenced somewhat different roles of dynamin. Besides promoting membrane fission in both entry routes, dynamin also participates in the maturation of a clathrin-coated pit in the clathrin-dependent route. Collectively, the current study displays a dynamic and precise image of the entry process of influenza A virus and elucidates the mechanisms of distinct entry routes. This quantum dot-based single-virus tracking technique is proven to be well-suited for investigating the choreographed interactions between virus and cellular proteins. PMID- 28355060 TI - Phage-Based Structural Color Sensors and Their Pattern Recognition Sensing System. AB - The mammalian olfactory system provides great inspiration for the design of intelligent sensors. To this end, we have developed a bioinspired phage nanostructure-based color sensor array and a smartphone-based sensing network system. Using a M13 bacteriophage (phage) as a basic building block, we created structural color matrices that are composed of liquid-crystalline bundled nanofibers from self-assembled phages. The phages were engineered to express cross-responsive receptors on their major coat protein (pVIII), leading to rapid, detectable color changes upon exposure to various target chemicals, resulting in chemical- and concentration-dependent color fingerprints. Using these sensors, we have successfully detected 5-90% relative humidity with 0.2% sensitivity. In addition, after modification with aromatic receptors, we were able to distinguish between various structurally similar toxic chemicals including benzene, toluene, xylene, and aniline. Furthermore, we have developed a method of interpreting and disseminating results from these sensors using smartphones to establish a wireless system. Our phage-based sensor system has the potential to be very useful in improving national security and monitoring the environment and human health. PMID- 28355061 TI - Apo E-Functionalization of Solid Lipid Nanoparticles Enhances Brain Drug Delivery: Uptake Mechanism and Transport Pathways. AB - Several strategies have been implemented to enhance brain drug delivery, and herein solid lipid nanoparticles functionalized with apolipoprotein E were tested in hCMEC/D3 cell monolayers. The mean diameter of 160 nm, negative charge of -12 mV, and their lipophilic characteristics make these nanosystems suitable for brain delivery. Confocal images and flow cytometry data showed a cellular uptake increase of 1.8-fold for SLN-Palmitate-ApoE and 1.9-fold for SLN-DSPE-ApoE when compared with the non-functionalized SLNs. Clathrin-mediated endocytosis was distinguished as the preferential internalization pathway involved in cellular uptake and nanoparticles could cross the blood-brain barrier predominantly by a transcellular pathway. The understanding of the mechanisms involved in the transport of these nanosystems through the blood-brain barrier may potentiate their application on brain drug delivery. PMID- 28355059 TI - Membrane Oxidation in Cell Delivery and Cell Killing Applications. AB - Cell delivery or cell killing processes often involve the crossing or disruption of cellular membranes. We review how, by modifying the composition and properties of membranes, membrane oxidation can be exploited to enhance the delivery of macromolecular cargoes into live human cells. We also describe how membrane oxidation can be utilized to achieve efficient killing of bacteria by antimicrobial peptides. Finally, we present recent evidence highlighting how membrane oxidation is intimately engaged in natural biological processes such as antigen delivery in dendritic cells and in the killing of bacteria by antimicrobial peptides. Overall, the insights that have been recently gained in this area should facilitate the development of more effective delivery technologies and antimicrobial therapeutic approaches. PMID- 28355062 TI - Impact of Pore Size on Fenton Oxidation of Methyl Orange Adsorbed on Magnetic Carbon Materials: Trade-Off between Capacity and Regenerability. AB - The economic cleanup of wastewater continues to be an active area of research. In this study, the influence of pore size on regeneration by Fenton oxidation for carbon materials with adsorbed methyl orange (MO) was investigated. More specifically three carbon supports, with pore sizes ranging from mainly microporous to half microporous-half mesoporous to mainly mesoporous, were impregnated with gamma-Fe2O3 to make them magnetic and easy to separate from solution. The carbon samples were characterized before adsorption and after regeneration with hydrogen peroxide at 20 degrees C. In addition, adsorption kinetics and isotherms were collected, and the Weber-Morris intraparticle diffusion model and Freundlich isotherm model fit to the data. The adsorption capacity increased with increasing microporosity while the regeneration efficiency increased with increasing mesoporosity. Further experiments with varying regeneration and adsorption conditions suggested that the regeneration process may be kinetically limited. The MO adsorbed in the micropores was strongly adsorbed and difficult to remove unlike the MO adsorbed in the mesopores, which could be reacted under relatively mild conditions. Thus, there was a trade-off between adsorption capacity and regeneration. PMID- 28355063 TI - Quantitative Adverse Outcome Pathways and Their Application to Predictive Toxicology. AB - A quantitative adverse outcome pathway (qAOP) consists of one or more biologically based, computational models describing key event relationships linking a molecular initiating event (MIE) to an adverse outcome. A qAOP provides quantitative, dose-response, and time-course predictions that can support regulatory decision-making. Herein we describe several facets of qAOPs, including (a) motivation for development, (b) technical considerations, (c) evaluation of confidence, and (d) potential applications. The qAOP used as an illustrative example for these points describes the linkage between inhibition of cytochrome P450 19A aromatase (the MIE) and population-level decreases in the fathead minnow (FHM; Pimephales promelas). The qAOP consists of three linked computational models for the following: (a) the hypothalamic-pitutitary-gonadal axis in female FHMs, where aromatase inhibition decreases the conversion of testosterone to 17beta-estradiol (E2), thereby reducing E2-dependent vitellogenin (VTG; egg yolk protein precursor) synthesis, (b) VTG-dependent egg development and spawning (fecundity), and (c) fecundity-dependent population trajectory. While development of the example qAOP was based on experiments with FHMs exposed to the aromatase inhibitor fadrozole, we also show how a toxic equivalence (TEQ) calculation allows use of the qAOP to predict effects of another, untested aromatase inhibitor, iprodione. While qAOP development can be resource-intensive, the quantitative predictions obtained, and TEQ-based application to multiple chemicals, may be sufficient to justify the cost for some applications in regulatory decision-making. PMID- 28355064 TI - Plastic Bag Derived-Microplastics as a Vector for Metal Exposure in Terrestrial Invertebrates. AB - Microplastics are widespread contaminants in terrestrial environments but comparatively little is known about interactions between microplastics and common terrestrial contaminants such as zinc (Zn). In adsorption experiments fragmented HDPE bags c. one mm2 in size showed similar sorption characteristics to soil. However, when present in combination with soil, concentrations of adsorbed Zn on a per mass basis were over an order of magnitude lower on microplastics. Desorption of the Zn was minimal from both microplastics and soil in synthetic soil solution (0.01 M CaCl2), but in synthetic earthworm guts desorption was higher from microplastics (40-60%) than soil (2-15%), suggesting microplastics could increase Zn bioavailability. Individual Lumbricus terrestris earthworms exposed for 28 days in mesocosms of 260 g moist soil containing 0.35 wt % of Zn bearing microplastic (236-4505 mg kg-1) ingested the microplastics, but there was no evidence of Zn accumulation, mortality, or weight change. Digestion of the earthworms showed that they did not retain microplastics in their gut. These findings indicate that microplastics could act as vectors to increase metal exposure in earthworms, but that the associated risk is unlikely to be significant for essential metals such as Zn that are well regulated by metabolic processes. PMID- 28355066 TI - Thermodynamics of Protein Folding Studied by Umbrella Sampling along a Reaction Coordinate of Native Contacts. AB - Spontaneous transitions between the native and non-native protein conformations are normally rare events that hardly take place in typical unbiased molecular dynamics simulations. It was recently demonstrated that such transitions can be well described by a reaction coordinate, Q, that represents the collective fraction of the native contacts between the protein atoms. Here we attempt to use this reaction coordinate to enhance the conformational sampling. We perform umbrella sampling simulations with biasing potentials on Q for two model proteins, Trp-Cage and BBA, using the CHARMM force field. Hamiltonian replica exchange is implemented in these simulations to further facilitate the sampling. The simulations appear to have reached satisfactory convergence, resulting in unbiased free energies as a function of Q. In addition to the native structure, multiple folded conformations are identified in the reconstructed equilibrium ensemble. Some conformations without any native contacts nonetheless have rather compact geometries and are stabilized by hydrogen bonds not present in the native structure. Whereas the enhanced sampling along Q reasonably reproduces the equilibrium conformational space, we also find that the folding of an alpha-helix in Trp-Cage is a slow degree of freedom orthogonal to Q and therefore cannot be accelerated by biasing the reaction coordinate. Overall, we conclude that whereas Q is an excellent parameter to analyze the simulations, it is not necessarily a perfect reaction coordinate for enhanced sampling, and better incorporation of other slow degrees of freedom may further improve this reaction coordinate. PMID- 28355065 TI - Haze in Apple-Based Beverages: Detailed Polyphenol, Polysaccharide, Protein, and Mineral Compositions. AB - Producers of apple-based beverages are confronted with colloidal instability. Haze is caused by interactions between molecules that lead to the formation of aggregates. Haze composition in three apple-based beverages, namely, French sparkling cider, apple juice, and pommeau, was studied. Phenolic compounds, proteins, polysaccharides, and minerals were analyzed using global and detailed analytical methods. The results explained <75% (w/w) of haze dry mass. Polyphenols, represented mainly by procyanidins, were the main compounds identified and accounted for 10-31% of haze. However, oxidized phenolic compounds were probably underestimated and may represent a high proportion of haze. Proteins were present in all of the samples in proportions of <6% of haze except in two apple juice hazes, where they were the main constituents (18 and 24%). Polysaccharides accounted for 0-30% of haze. Potassium and calcium were the main minerals. PMID- 28355067 TI - Chemical Properties of Dialkyl Halonium Ions (R2Hal+) and Their Neutral Analogues, Methyl Carboranes, CH3-(CHB11Hal11), Where Hal = F, Cl. AB - Chloronium cations in their salts (CnH2n+1)2Cl+{CHB11Cl11-}, with n = 1 to 3 and exceptionally stable carborane anions, are stable at ambient and elevated temperatures. The temperature at which they decompose to carbocations with HCl elimination (below 150 degrees C) decreases with the increasing n from 1 to 3 because of increasing ionicity of C-Cl bonds in the C-Cl+-C bridge. At room temperature, the salts of cations with n >= 4 [starting from t-Bu2Cl+ or (cyclo C5H11)2Cl+] are unstable and decompose. With decreasing chloronium ion stability, their ability to interact with chloroalkanes to form oligomeric cations increases. It was shown indirectly that unstable salt of fluoronium ions (CH3)2F+(CHB11F11-) must exist at low temperatures. The proposed (CH3)2F+ cation is much more reactive than the corresponding chloronium, showing at room temperature chemical properties expected of (CH3)2Cl+ at elevated temperatures. PMID- 28355068 TI - Rh2(II)-Catalyzed Ring Expansion of Cyclobutanol-Substituted Aryl Azides To Access Medium-Sized N-Heterocycles. AB - A new reactivity pattern of Rh2(II)-N-arylnitrenes was discovered that facilitates the synthesis of medium-sized N-heterocycles from ortho-cyclobutanol substituted aryl azides. The key ring-expansion step of the catalytic cycle is both chemoselective and stereospecific. Our mechanistic experiments implicate the formation of a rhodium N-arylnitrene catalytic intermediate and reveal that sp3 C H bond amination of this electrophilic species is competitive with the ring expansion process. PMID- 28355069 TI - Design, Synthesis, and Pharmacological Characterization of N-(4-(2 (6,7-Dimethoxy 3,4-dihydroisoquinolin-2(1H)yl)ethyl)phenyl)quinazolin-4-amine Derivatives: Novel Inhibitors Reversing P-Glycoprotein-Mediated Multidrug Resistance. AB - P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a principal obstacle for successful cancer chemotherapy. A novel P-gp inhibitor with a quinazoline scaffold, 12k, was considered to be the most promising for in-depth study. 12k possessed high potency (EC50 = 57.9 +/- 3.5 nM), low cytotoxicity, and long duration of activity in reversing doxorubicin (DOX) resistance in K562/A02 cells. 12k also boosted the potency of other MDR-related cytotoxic agents with different structures, increased accumulation of DOX, blocked P-gp-mediated Rh123 efflux, and suppressed P-gp ATPase activity in K562/A02 MDR cells. However, 12k did not have any effects on CYP3A4 activity or P-gp expression. In particular, 12k had a good half-life and oral bioavailability and displayed no influence on DOX metabolism to obviate the side effects closely related to increased plasma concentrations of cytotoxic agents in vivo. PMID- 28355070 TI - Actinomycete Metabolome Induction/Suppression with N-Acetylglucosamine. AB - The metabolite profiles of three sponge-derived actinomycetes, namely, Micromonospora sp. RV43, Rhodococcus sp. RV157, and Actinokineospora sp. EG49 were investigated after elicitation with N-acetyl-d-glucosamine. 1H NMR fingerprint methodology was utilized to study the differences in the metabolic profiles of the bacterial extracts before and after elicitation. Our study found that the addition of N-acetyl-d-glucosamine modified the secondary metabolite profiles of the three investigated actinomycete isolates. N-Acetyl-d-glucosamine induced the production of 3-formylindole (11) and guaymasol (12) in Micromonospora sp. RV43, the siderophore bacillibactin 16, and surfactin antibiotic 17 in Rhodococcus sp. RV157 and increased the production of minor metabolites actinosporins E-H (21-24) in Actinokineospora sp. EG49. These results highlight the use of NMR fingerprinting to detect changes in metabolism following addition of N-acetyl-d-glucosamine. N-Acetyl-d-glucosamine was shown to have multiple effects including suppression of metabolites, induction of new metabolites, and increased production of minor compounds. PMID- 28355072 TI - Spontaneous Amino-yne Click Polymerization: A Powerful Tool toward Regio- and Stereospecific Poly(beta-aminoacrylate)s. AB - Efficient synthesis of poly(enamine)s has been a great challenge because of their poor stability, poor solubility, and low molecular weights. In this work, a spontaneous amino-yne click polymerization for the efficient preparation of poly(enamine)s was established, which could proceed with 100% atom efficiency under very mild conditions without any external catalyst. Through systematic optimization of the reaction conditions, several soluble and thermally stable poly(beta-aminoacrylate)s with high molecular weights (Mw up to 64400) and well defined structures were obtained in excellent yields (up to 99%). Moreover, the polymerization can perform in a regio- and stereospecific fashion. Nuclear magnetic resonance spectra analysis revealed that solely anti-Markovnikov additive products with 100% E-isomer were obtained. The reaction mechanism was well demonstrated with the assistance of density functional theory calculations. In addition, by introducing the tetraphenylethene moiety, the resulting polymers exhibit unique aggregation-induced emission characteristics and could be applied in explosives detection and bioimaging. This polyhydroamination is a new type of click polymerization and opens up enormous opportunities for preparing functional polymeric materials. PMID- 28355073 TI - Enantiospecific Total Synthesis of the Highly Strained (-)-Presilphiperfolan-8-ol via a Pd-Catalyzed Tandem Cyclization. AB - A rare element of high strain in molecules of natural origin is a 1,2-trans fusion of 5-membered rings within a [3.3.0]-bicycle, a motif present in (-) presilphiperfolan-8-ol. This molecule also possesses a 1,3-trans stereochemical arrangement of substituents on one of its 5-membered rings, a pattern shared by a number of other terpenes. Herein, we disclose the first total synthesis of this highly strained target in 13 steps. The key operation is a Pd-catalyzed tandem cyclization that directly establishes the requisite 1,3-trans stereochemical arrangement on one ring while concurrently setting the stage for the controlled generation of the highly strained 1,2-trans ring fusion of the final architecture. PMID- 28355074 TI - Ion Distribution and Hydration Structure in the Stern Layer on Muscovite Surface. AB - Based on molecular dynamics simulations of eight ions (Na+, K+, Rb+, Cs+, Mg2+, Ca2+, Sr2+, and Ba2+) on muscovite mica surfaces in water, we demonstrate that experimental data on the muscovite mica surface can be rationalized through a unified picture of adsorption structures including the hydration structure, cation heights from the muscovite surface, and state stability. These simulations enable us to categorize the inner-sphere surface complex into two different species: an inner-sphere surface complex in a ditrigonal cavity (IS1) and that on top of Al (IS2). By considering the presence of the two inner-sphere surface complexes, the experimental finding that the heights of adsorbed cations from the muscovite surface are proportional to the ionic radius for K+ and Cs+ but inversely proportional to the ionic radius for Ca2+ and Ba2+ was explained. We find that Na+, Ca2+, Sr2+, and Ba2+ can form both IS1 and IS2; K+, Rb+, and Cs+ can form only IS1; and Mg2+ can form only IS2. It is suggested that the formation of IS1 and IS2 is governed by the charge density of the ions. Among the eight ions, we also find that the hydration structure for the outer-sphere surface complexes of divalent cations differs from that of the monovalent cations by one adsorbed water molecule (i.e., a water molecule located in a ditrigonal cavity). PMID- 28355075 TI - Two-Dimensional Heterostructure as a Platform for Surface-Enhanced Raman Scattering. AB - Raman enhancement on a flat nonmetallic surface has attracted increasing attention, ever since the discovery of graphene enhanced Raman scattering. Recently, diverse two-dimensional layered materials have been applied as a flat surface for the Raman enhancement, attributed to different mechanisms. Looking beyond these isolated materials, atomic layers can be reassembled to design a heterostructure stacked layer by layer with an arbitrary chosen sequence, which allows the flow of charge carriers between neighboring layers and offers novel functionalities. Here, we demonstrate the heterostructure as a novel Raman enhancement platform. The WSe2 (W) monolayer and graphene (G) were stacked together to form a heterostructure with an area of 10 mm * 10 mm. Heterostructures with different stacked structuress are used as platforms for the enhanced Raman scattering, including G/W, W/G, G/W/G/W, and W/G/G/W. On the surface of the heterostructure, the intensity of the Raman scattering is much stronger compared with isolated layers, using the copper phthalocyanine (CuPc) molecule as a probe. It is found that the Raman enhancement effect on heterostructures depends on stacked methods. Phonon modes of CuPc have the strongest enhancement on G/W. W/G and W/G/G/W have a stronger enhancement than that on the isolated WSe2 monolayer, while lower than the graphene monolayer. The G/W/G/W/substrate demonstrated a comparable Raman enhancement effect than the G/W/substrate. These differences are due to the different interlayer couplings in heterostructures related to electron transition probability rates, which are further proved by first-principle calculations and probe-pump measurements. PMID- 28355071 TI - Ecdysone Receptor Agonism Leading to Lethal Molting Disruption in Arthropods: Review and Adverse Outcome Pathway Development. AB - Molting is critical for growth, development, reproduction, and survival in arthropods. Complex neuroendocrine pathways are involved in the regulation of molting and may potentially become targets of environmental endocrine disrupting chemicals (EDCs). Based on several known ED mechanisms, a wide range of pesticides has been developed to combat unwanted organisms in food production activities such as agriculture and aquaculture. Meanwhile, these chemicals may also pose hazards to nontarget species by causing molting defects, and thus potentially affecting the health of the ecosystems. The present review summarizes the available knowledge on molting-related endocrine regulation and chemically mediated disruption in arthropods (with special focus on insects and crustaceans), to identify research gaps and develop a mechanistic model for assessing environmental hazards of these compounds. Based on the review, multiple targets of EDCs in the molting processes were identified and the link between mode of action (MoA) and adverse effects characterized to inform future studies. An adverse outcome pathway (AOP) describing ecdysone receptor agonism leading to incomplete ecdysis associated mortality was developed according to the OECD guideline and subjected to weight of evidence considerations by evolved Bradford Hill Criteria. This review proposes the first invertebrate ED AOP and may serve as a knowledge foundation for future environmental studies and AOP development. PMID- 28355076 TI - Complementary Metal Oxide Semiconductor-Compatible, High-Mobility, ?111?-Oriented GaSb Nanowires Enabled by Vapor-Solid-Solid Chemical Vapor Deposition. AB - Using CMOS-compatible Pd catalysts, we demonstrated the formation of high mobility ?111?-oriented GaSb nanowires (NWs) via vapor-solid-solid (VSS) growth by surfactant-assisted chemical vapor deposition through a complementary experimental and theoretical approach. In contrast to NWs formed by the conventional vapor-liquid-solid (VLS) mechanism, cylindrical-shaped Pd5Ga4 catalytic seeds were present in our Pd-catalyzed VSS-NWs. As solid catalysts, stoichiometric Pd5Ga4 was found to have the lowest crystal surface energy and thus giving rise to a minimal surface diffusion as well as an optimal in-plane interface orientation at the seed/NW interface for efficient epitaxial NW nucleation. These VSS characteristics led to the growth of slender NWs with diameters down to 26.9 +/- 3.5 nm. Over 95% high crystalline quality NWs were grown in ?111? orientation for a wide diameter range of between 10 and 70 nm. Back-gated field-effect transistors (FETs) fabricated using the Pd-catalyzed GaSb NWs exhibit a superior peak hole mobility of ~330 cm2 V-1 s-1, close to the mobility limit for a NW channel diameter of ~30 nm with a free carrier concentration of ~1018 cm-3. This suggests that the NWs have excellent homogeneity in phase purity, growth orientation, surface morphology and electrical characteristics. Contact printing process was also used to fabricate large-scale assembly of Pd-catalyzed GaSb NW parallel arrays, confirming the potential constructions and applications of these high-performance electronic devices. PMID- 28355077 TI - Isothermal Amplification for MicroRNA Detection: From the Test Tube to the Cell. AB - MicroRNAs (miRNAs) are a class of small noncoding RNAs that act as pivotal post transcriptional regulators of gene expression, thus involving in many fundamental cellular processes such as cell proliferation, migration, and canceration. The detection of miRNAs has attracted significant interest, as abnormal miRNA expression is identified to contribute to serious human diseases such as cancers. Particularly, miRNAs in peripheral blood have recently been recognized as important biomarkers potential for liquid biopsy. Furthermore, as miRNAs are expressed heterogeneously in different cells, investigations into single-cell miRNA expression will be of great value for resolving miRNA-mediated regulatory circuits and the complexity and heterogeneity of miRNA-related diseases. Thus, the development of miRNA detection methods, especially for complex clinic samples and single cells is in great demand. In this Account, we will present recent progress in the design and application of isothermal amplification enabling miRNA detection transition from the test tube to the clinical sample and single cell, which will significantly advance our knowledge of miRNA functions and disease associations, as well as its translation in clinical diagnostics. miRNAs present a huge challenge in detection because of their extremely short length (~22 nucleotides) and sequence homology (even with only single-nucleotide variation). The conventional golden method for nucleic acid detection, quantitative PCR (qPCR), is not amenable to directly detecting short RNAs and hardly enables distinguishing between miRNA family members with very similar sequences. Alternatively, isothermal amplification has emerged as a powerful method for quantification of nucleic acids and attracts broad interest for utilization in developing miRNA assays. Compared to PCR, isothermal amplification can be performed without precise control of temperature cycling and is well fit for detecting short RNA or DNA. We and other groups are seeking methods based on isothermal amplification for detecting miRNA with high specificity (single nucleotide resolution) and sensitivity (detection limit reaching femtomolar or even attomolar level). These methods have recently been demonstrated to quantify miRNA in clinical samples (tissues, serum, and plasma). Remarkably, attributed to the mild reaction conditions, isothermal amplification can be performed inside cells, which has recently enabled miRNA detection in single cells. The localized in situ amplification even enables imaging of miRNA at the single-molecule level. The single-cell miRNA profiling data clearly shows that genetically identical cells exhibit significant cell-to-cell variation in miRNA expression. The leap of miRNA detection achievements will significantly contribute to its full clinical adoption and translation and give us new insights into miRNA cellular functions and disease associations. PMID- 28355078 TI - Discovery of Novel Indazole Derivatives as Orally Available beta3-Adrenergic Receptor Agonists Lacking Off-Target-Based Cardiovascular Side Effects. AB - We previously discovered that indazole derivative 8 was a highly selective beta3 adrenergic receptor (beta3-AR) agonist, but it appeared to be metabolically unstable. To improve metabolic stability, further optimization of this scaffold was carried out. We focused on the sulfonamide moiety of this scaffold, which resulted in the discovery of compound 15 as a highly potent beta3-AR agonist (EC50 = 18 nM) being inactive to beta1-, beta2-, and alpha1A-AR (beta1/beta3, beta2/beta3, and alpha1A/beta3 > 556-fold). Compound 15 showed dose-dependent beta3-AR-mediated responses in marmoset urinary bladder smooth muscle, had a desirable metabolic stability and pharmacokinetic profile (Cmax and AUC), and did not obviously affect heart rate or mean blood pressure when administered intravenously (3 mg/kg) to anesthetized rats. Thus, compound 15 is a highly potent, selective, and orally available beta3-AR agonist, which may serve as a candidate drug for the treatment of overactive bladder without off-target-based cardiovascular side effects. PMID- 28355079 TI - Ultrafast Charge Transfer between Light Absorber and Co3O4 Water Oxidation Catalyst across Molecular Wires Embedded in Silica Membrane. AB - The mechanism of visible light-induced hole transfer from a molecular light absorber, in the form of a free-base porphyrin, coupled to a Co3O4 nanoparticle catalyst for water oxidation by a molecular wire (p-oligo(phenylenevinylene) featuring three aryl units) is investigated by transient absorption spectroscopy. The wires are covalently anchored on the Co3O4 surface and embedded in a dense, yet ultrathin (2 nm), silica layer that separates light absorber and catalyst. The porphyrin is electrostatically adsorbed on the silica surface, and aqueous colloidal solutions of the core-shell particles are used for transient optical measurements. Pulsed optical excitation of the porphyrin results in rapid injection of the photogenerated hole onto the molecular wire and concurrent formation of reduced light absorber in less than 1 picosecond (ps). Ultrafast charge separation was monitored by transient absorption of the wire radical cation, which is given by bands in the 500 to 600 nm region and at 1130 nm, while formation of reduced porphyrin was characterized by absorption at 700 nm. Forward transfer of the hole to Co3O4 catalyst proceeds in 255 +/- 23 ps. Ultrafast transfer of positive charge from the molecular assembly to a metal oxide nanoparticle catalyst for water oxidation is unprecedented. Holes on Co3O4 recombined with electrons of the reduced sensitizer with biphasic kinetics on a much longer time scale of ten to several hundred nanoseconds. The unusually efficient hole transfer coupling of a molecular light absorber with an Earth abundant metal oxide catalyst by silica-embedded p-oligo(phenylenevinylene) offers an approach for integrated artificial photosystems featuring product separation on the nanoscale. PMID- 28355081 TI - Synthesis of cis,syndiotactic-A-alt-B Copolymers from Enantiomerically Pure Endo 2-Substituted-5,6-Norbornenes. AB - Cis,syndiotactic A-alt-B copolymers, where A and B are two enantiomerically pure endo-2-substituted-5,6-norbornenes with "opposite" chiralities of the endo-2 substituted-5,6-norbornene skeleton, can be prepared using Mo(N-2,6 Me2C6H3)(CHCMe2Ph)(OHMT)(pyrrolide) (1) as the initiator (OHMT = O-2,6 Mesityl2C6H3). Formation of a high percentage of A-alt-B dyads is proposed to rely on an inversion of chirality at the metal with each propagating step and a kinetically preferred diastereomeric relationship between a given chirality at the metal in propagating species and the chirality of the endo-2-substituted-5,6 norbornene skeleton. We also demonstrate that A-alt-B copolymers can be modified to give new variations which may not be accessible through direct copolymerization. PMID- 28355080 TI - Synthesis of Ring-Fused Pyridinium Salts by Intramolecular Nucleophilic Aromatic Substitution Reaction and Their Optoelectronic Properties. AB - The synthesis of nitrogen cation-doped polycyclic aromatic hydrocarbons (PAHs) having a variety of counteranions is reported via the trimethylsilyl (TMS) promoted intramolecular aromatic nucleophilic substitution (SNAr) reaction of fluoroarenes and pyridine groups. The electrochemical properties and optical properties of the obtained nitrogen cation-doped PAHs were studied in detail, clarifying that they have low-lying LUMO levels and good emission properties derived from the incorporation of planar N-arylpyridinium moieties. PMID- 28355083 TI - Systematic Review of Outcomes Reporting in Professional Baseball: A Call for Increased Validation and Consistency. AB - BACKGROUND: Historically, treatment efficacy of professional baseball injuries has been determined by assessing the return-to-play (RTP) rate or using patient reported functional outcomes scores; however, these methods may not be sensitive and specific enough for elite athletes. As a consequence, performance-based statistics are increasingly being reported in the medical literature. PURPOSE: To (1) assess how treatment efficacy is currently reported in professional baseball players; (2) examine the variability in the reporting of these measures in terms of frequency, length of time followed, and units of measure; and (3) identify any attempts to validate these performance-based statistics. STUDY DESIGN: Systematic review. METHODS: All studies reporting treatment efficacy in professional baseball in PubMed, Embase, and Cochrane were identified. Data collected included frequency and method of reporting: RTP, functional outcomes, and performance based statistics. RESULTS: Fifty-four studies met all inclusion criteria. Of these, 51 (94%) reported RTP, 12 (22%) utilized functional outcomes, and 18 (33%) provided baseball-specific performance-based statistics to assess treatment efficacy. Great variability was seen in how follow-up was defined (games, seasons, months), duration of follow-up, and which performance-based statistics were utilized. None of the studies validated these performance-based statistics, determined minimal time of follow-up needed, or assessed the baseline variability in these statistics among noninjured players. CONCLUSION: Most studies reported RTP to determine treatment efficacy, but significant variability was seen in how players were followed. Similarly, great variability was noted in the type and number of performance-based statistics utilized. Additional studies are necessary to validate these measures and determine the appropriate length of time that they should be followed. CLINICAL RELEVANCE: This study provides a clear overview of the current methods that are used to determine treatment efficacy in professional baseball players. PMID- 28355084 TI - Effect of NSAIDs on Recovery From Acute Skeletal Muscle Injury: A Systematic Review and Meta-analysis. AB - BACKGROUND: There is debate as to whether the use of nonsteroidal anti inflammatory drugs (NSAIDs) is beneficial after acute skeletal muscle injury. Some studies have suggested that NSAID use may be detrimental to injured muscle. PURPOSE: To determine whether NSAID use affects recovery from skeletal muscle injury as assessed by strength loss, soreness, and/or blood creatine kinase level. STUDY DESIGN: Systematic review and meta-analysis. METHODS: An extensive systematic review was completed searching 16 databases (eg, PubMed, Cochrane Library, EMBASE). Inclusion criteria were (1) acute injury to skeletal muscle, (2) use of a control condition, (3) certainty of the NSAID dose administered, and (4) use of 1 or more of the 3 desired outcome measures. A total of 5343 study reports were screened, of which 41 studies were deemed suitable for inclusion. The standardized mean difference was used as the effect size (ES) and was calculated such that a positive ES indicated NSAID efficacy. Meta-analyses were run using a random-effects model. RESULTS: For all studies, time points after injury, and injury markers combined, NSAID use was found to elicit a small to medium, significant decrease in the markers of injury (overall ES = +0.34; P = .0001). Because heterogeneity in study ES was apparent (ie, Q- df = 52.4, P = .000005; I2 = 57%), subgroup meta-analyses and meta-regressions were run in an attempt to explain the heterogeneity. In human studies, study ESs were higher when lower body muscles were injured ( P = .045). In animal studies, study ESs were lower with longer NSAID administration durations ( P = .023) and at longer follow-up times after injury ( P = .010). CONCLUSION: Overall, our analysis supports NSAID use for reducing strength loss, soreness, and blood creatine kinase level after an acute muscle injury, at least for humans and in the short term. Additional research is required to determine why NSAID use appears to be more effective when lower-body muscles in humans are injured. It would also be important to determine why NSAID use appears detrimental at later times after injury in animals but not humans. PMID- 28355082 TI - Mindfulness-Based Interventions in Clinical Samples of Adolescents with Chronic Illness: A Systematic Review. AB - BACKGROUND: Mindfulness-based interventions (MBIs) have emerged as a promising strategy for individuals with a chronic illness, given their versatility in targeting both physical and mental health outcomes. However, research to date has focused on adult or community-based populations. OBJECTIVES: To systematically review and critically appraise MBIs in clinical pediatric samples living with chronic physical illness. DATA SOURCES: Electronic searches were conducted by a Library Information Specialist familiar with the field by using EMBASE, PsycINFO, MEDLINE, CINAHL, Web of Science, and EBM Reviews databases. Study Eligibility, Participants, and Interventions: Published English peer-reviewed articles of MBIs in clinical samples of children and adolescents (3-18 years) with chronic physical illness. STUDY APPRAISAL AND SYNTHESIS METHODS: Two reviewers independently selected articles for review and extracted data. Results are narratively described, and the reporting quality of each study was assessed via the STROBE Checklist. RESULTS: Of a total 4710 articles, 8 articles met inclusion criteria. All studies were small (n < 20, except 1 study of n = 59), included only outpatient adolescent samples, and focused on feasibility and acceptability of MBI; only 1 study included a comparison group (n = 1). No studies included online components or remote attendance. All studies found that MBI was acceptable to adolescents, whereas feasibility and implementation outcomes were mixed. Many studies were underpowered to detect significant differences post-MBI, but MBI did demonstrate improvements in emotional distress in several studies. Conclusions and Implications of Key Findings: The literature on MBIs is preliminary in nature, focusing on adapting and developing MBI for adolescents. Although MBIs appear to be a promising approach to coping with symptoms related to chronic illness in adolescents, future research with adequate sample sizes and rigorous research designs is warranted. PMID- 28355085 TI - Validation of a Dry Model for Assessing the Performance of Arthroscopic Hip Labral Repair. AB - BACKGROUND: Arthroscopic hip labral repair is a technically challenging and demanding surgical technique with a steep learning curve. Arthroscopic simulation allows trainees to develop these skills in a safe environment. PURPOSE: The purpose of this study was to evaluate the use of a combination of assessment ratings for the performance of arthroscopic hip labral repair on a dry model. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A total of 47 participants including orthopaedic surgery residents (n = 37), sports medicine fellows (n = 5), and staff surgeons (n = 5) performed arthroscopic hip labral repair on a dry model. Prior arthroscopic experience was noted. Participants were evaluated by 2 orthopaedic surgeons using a task-specific checklist, the Arthroscopic Surgical Skill Evaluation Tool (ASSET), task completion time, and a final global rating scale. All procedures were video-recorded and scored by an orthopaedic fellow blinded to the level of training of each participant. RESULTS: The internal consistency/reliability (Cronbach alpha) using the total ASSET score for the procedure was high (intraclass correlation coefficient > 0.9). One-way analysis of variance for the total ASSET score demonstrated a difference between participants based on the level of training ( F3,43 = 27.8, P < .001). A good correlation was seen between the ASSET score and previous exposure to arthroscopic procedures ( r = 0.52-0.73, P < .001). The interrater reliability for the ASSET score was excellent (>0.9). CONCLUSION: The results of this study demonstrate that the use of dry models to assess the performance of arthroscopic hip labral repair by trainees is both valid and reliable. Further research will be required to demonstrate a correlation with performance on cadaveric specimens or in the operating room. PMID- 28355086 TI - Presence of Bacteria in Spontaneous Achilles Tendon Ruptures. AB - BACKGROUND: The structural pathology of Achilles tendon (AT) ruptures resembles tendinopathy, but the causes remain unknown. Recently, a number of diseases were found to be attributed to bacterial infections, resulting in low-grade inflammation and progressive matrix disturbance. The authors speculate that spontaneous AT ruptures may also be influenced by the presence of bacteria. HYPOTHESIS: Bacteria are present in ruptured ATs but not in healthy tendons. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Patients with spontaneous AT ruptures and patients undergoing anterior cruciate ligament (ACL) reconstruction were recruited for this study. During AT surgical repair, excised tendinopathic tissue was collected, and healthy tendon samples were obtained as controls from hamstring tendon grafts used in ACL reconstruction. Half of every sample was reserved for DNA extraction and the other half for histology. Polymerase chain reaction (PCR) was conducted using 16S rRNA gene universal primers, and the PCR products were sequenced for the identification of bacterial species. A histological examination was performed to compare tendinopathic changes in the case and control samples. RESULTS: Five of 20 AT rupture samples were positive for the presence of bacterial DNA, while none of the 23 hamstring tendon samples were positive. Sterile operating and experimental conditions and tests on samples, controlling for harvesting and processing procedures, ruled out the chance of postoperative bacterial contamination. The species identified predominantly belonged to the Staphylococcus genus. AT rupture samples exhibited histopathological features characteristic of tendinopathy, and most healthy hamstring tendon samples displayed normal tendon features. There were no apparent differences in histopathology between the bacterial DNA-positive and bacterial DNA-negative AT rupture samples. CONCLUSION: The authors have demonstrated the presence of bacterial DNA in ruptured AT samples. It may suggest the potential involvement of bacteria in spontaneous AT ruptures. PMID- 28355087 TI - Reply: Validity of the Posttraumatic Stress Symptoms-14 Instrument in Acute Respiratory Failure Survivors. PMID- 28355088 TI - Temozolomide-Mediated Apoptotic Death Is Improved by Thymoquinone in U87MG Cell Line. AB - Apoptosis induction of cancer cells can be an appropriate strategy by which chemotherapeutic agents kill tumor cells. The aim of the present study was to investigate the effect of temozolomide and thymoquinone combination on apoptotic pathway of human glioblastoma multiforme cell line (U87MG). U87MG cells were cultured, treated with temozolomide and thymoquinone, and cell proliferation was measured. Apoptosis cell death and its possible mechanism were investigated by various methods. Combination of temozolomide and thymoquinone had a synergistic effect on cells viability. Thymoquinone intensified the temozolomide-induced apoptosis. Combination of temozolomide and thymoquinone can be a good strategy for treatment of glioblastoma. PMID- 28355089 TI - CT vaginography: a new CT technique for imaging of upper and middle vaginal fistulas. AB - OBJECTIVE: Different types of vaginal fistulas is a relatively uncommon condition in the Western world but very frequent in developing countries. In the past, conventional vaginography was the radiological examination of choice for exploring this condition. CT and MRI are now both used for this purpose. Our objective was to test the feasibility and to explore the potential role of a new CT imaging technique implementing vaginal introitus obstruction and opacification of the vagina with iodine contrast agent, to show patency of a fistula. METHODS: We describe the technical protocol of CT-vaginography as performed in Geneva University Hospitals, including vaginal catheterization with a Foley catheter and obstruction of the introitus by inflating the balloon of the catheter. We also report three cases of patients with suspected vaginal fistula who underwent CT vaginography. RESULTS: The examinations were technically successful. In one patient, it revealed the presence of fistulous pathways from the vaginal fornix along the bilateral infected surgical prostheses. In a second patient, it showed a fistula between the vagina and the necrotic cavity of a recurrent cervical cancer. In a third patient, it proved the absence of a suspected vaginal fistula. CONCLUSION: CT-vaginography is a technically feasible CT protocol that provides anatomical and functional information on clinically suspected vaginal fistulas. Advances in knowledge: After the abandon of conventional vaginography in the era of transaxial imaging, the current modalities of imaging vaginal fistulas provide excellent anatomical detail but less functional information concerning the permeability of a vaginal fistulous pathway. We propose the use of CT vaginography, a technical protocol that we describe in detail. PMID- 28355090 TI - Consistency of Effect with a Low-Dose, Estradiol Vaginal Capsule (TX-004HR): Evaluating Improvement in Vaginal Physiology and Moderate-to-Severe Dyspareunia in Subgroups of Postmenopausal Women. AB - BACKGROUND: The 12-week, randomized, double-blind, placebo-controlled, multicenter, phase 3 REJOICE trial demonstrated that TX-004HR, an investigational, applicator-free, low-dose vaginal softgel capsule containing solubilized 17beta-estradiol, effectively and rapidly treats symptoms of vulvar and vaginal atrophy (VVA) with negligible to very low systemic absorption. The aim of this analysis was to assess whether the efficacy of TX-004HR varies with age, body mass index (BMI), uterine status, pregnancy status, and vaginal delivery. METHODS: The REJOICE trial evaluated the efficacy of 4-, 10-, and 25 MUg doses of TX-004HR in postmenopausal women (40-75 years) with VVA and a self identified most bothersome symptom of moderate-to-severe dyspareunia. Prespecified subgroup analyses of the four co-primary endpoints (percentages of superficial cells and parabasal cells, vaginal pH, and severity of dyspareunia) were analyzed with respect to age, BMI, uterine status, pregnancy status, and vaginal births. Each dose was compared with placebo for change from baseline to week 2 through week 12, respectively. RESULTS: TX-004HR significantly improved superficial cells, parabasal cells, and vaginal pH from baseline to weeks 2 and 12 in most subgroups. All TX-004HR doses numerically reduced the severity of dyspareunia by 2 weeks and maintained efficacy over 12 weeks, with many of the subgroups having statistically significant improvement relative to placebo. CONCLUSIONS: TX-004HR was efficacious for treating symptomatic VVA, and it demonstrated a consistency of effect when women's age, BMI, uterine status, pregnancy status, and vaginal births were evaluated. Clinical Trial Identifier: NCT02253173. PMID- 28355091 TI - Cytomegalovirus Retinitis: A Review. AB - Cytomegalovirus (CMV) is a ubiquitous DNA herpes virus that causes significant morbidity and mortality in immunocompromised individuals. CMV retinitis is a potentially blinding manifestation of CMV infection that was commonly seen in advanced acquired immunodeficiency syndrome (AIDS) in the era before modern combination antiretroviral therapy era, but is also recognized in patients with immune deficiency from multiple causes. The advent of and advances in antiretroviral therapies for human immunodeficiency virus have decreased the incidence of CMV retinitis by over 90% among AIDS patients, and improved visual outcomes in those affected. The diagnosis is generally a clinical one, and treatment modalities include systemic and intravitreal antiviral medications. Retinal detachment and immune recovery uveitis are sight-threatening complications of CMV retinitis that require specific treatments. PMID- 28355092 TI - Acute Toxicity and Cytotoxicity of Pereskia aculeata, a Highly Nutritious Cactaceae Plant. AB - Pereskia aculeata is a Cactaceae plant with valuable nutritional properties, including terrific amounts of protein, minerals, vitamins, and fiber. However, P. aculeata is reported to contain antinutrients and alkaloids in its leaves. In addition, in a study on growth and development, Wistar rats fed with P. aculeata and casein as protein source grew less than the control group (fed with casein only). Therefore, in this study, we evaluated, for the first time, the oral acute toxicity of P. aculeata in rats and also the cytotoxicity behavior of the plant on lettuce seeds. The acute toxicity research was carried out using dried P. aculeata ethanolic extract, in three different doses, administered by gavage to 24 female Wistar rats. The rats were then examined for signs of toxicity, food intake, body weight, and fecal excretion fluctuations, as well as histopathological alterations, using eight different body tissues. The acute toxicity study did not show any difference among the groups in either clinical evaluation or histopathological analyses. For the cytotoxicity study, dried P. aculeata ethanolic extract was applied on lettuce seeds in five different concentrations. These seeds were evaluated for germination, root and shoot length, and mitotic index. The results show that P. aculeata extract affects lettuce root and shoot growth, but not germination or mitotic index. In conclusion, the acute toxicity on rats and the cytogenotoxicity on lettuce of P. aculeata are neglectable, validating the potential of this plant to be used as a functional food. PMID- 28355093 TI - A Multi-Institutional Study of Struvite Stones: Patterns of Infection and Colonization. AB - OBJECTIVE: To examine urine and stone bacteriology of struvite stone formers in a large cohort of patients undergoing percutaneous nephrolithotomy (PCNL). MATERIALS AND METHODS: A total of 1191 patients, with stone and urine cultures, treated with PCNL for renal calculi were included in the study. Statistical differences were assessed using Mann-Whitney U and T-tests. RESULTS: Stone cultures were positive in 72% of patients with struvite stones. Urea-splitting organisms accounted for only half of the positive stone cultures. Enterococcus (9/50, 18%), Proteus (9/50, 18%), and Escherichia coli (6/50, 12%) were the most commonly identified organisms. Notably, two-thirds of struvite formers with negative stone culture had at least one positive culture for a urea-splitting organism on urine culture going back 1 year from the time of surgery. A majority (67%) of struvite stone cultures were found to be resistant to first- and second generation cephalosporins. CONCLUSIONS: The bacteriology of struvite stones has shifted away from traditional urea-splitting organisms and antibiotic coverage must be expanded to include organisms such as Enterococcus that do not respond to cephalosporins. Causative organisms may be found by going back in time to identify the initial organism that could have induced struvite stone formation to inform preventative therapy. PMID- 28355094 TI - Advances in treatment of pulmonary arterial hypertension: patent review. AB - INTRODUCTION: Current therapeutic approaches for pulmonary arterial hypertension (PAH) commonly include use of prostacyclins, endothelin pathway antagonists or NO (nitric oxide) pathway modulators. These agents are non-specific and suffer from several important shortcomings including short half-lives, invasive routes of administration, higher dose and frequency requirements, and several dose-related systemic side effects. Hence, discovery of novel agents with improved therapeutic efficacy with respect to survival benefits and the development of non-invasive routes of administration are in critical need. Current research aimed at developing more selective therapies for PAH are focused both on agents acting on novel molecular targets, as well as, novel compounds acting on conventional pathways with improved characteristics. Area covered: The present review covers recently filed (issued/application) patents (2010-2016) describing novel agents acting on investigational targets as well as novel compounds with improved characteristics acting on established targets. Patents describing combinations of conventional and investigational compounds are also discussed. Expert opinion: PAH has recently been considered as cancer-like disease with over-proliferation of pulmonary arterial smooth muscle cells and endothelial cells. New cellular and molecular biological advances have revealed novel target/pathways involved in the pathogenesis and progression of PAH. Thus, discovery of agents that act on these novel pathways provides a promising avenue of research for improving therapeutic approaches for PAH. PMID- 28355095 TI - Postpartum Health of Women with Intellectual and Developmental Disabilities: A Call to Action. PMID- 28355096 TI - Antimicrobial Resistance Profiles of Listeria monocytogenes and Listeria innocua Isolated from Ready-to-Eat Products of Animal Origin in Spain. AB - The objective of this work was to investigate the antimicrobial resistance in Listeria spp. isolated from food of animal origin. A total of 50 Listeria strains isolated from meat and dairy products, consisting of 7 Listeria monocytogenes and 43 Listeria innocua strains, were characterized for antimicrobial susceptibility against nine antimicrobials. The strains were screened by real-time PCR for the presence of antimicrobial resistance genes: tet M, tet L, mef A, msr A, erm A, erm B, lnu A, and lnu B. Multidrug resistance was identified in 27 Listeria strains, 4 belonging to L. monocytogenes. Resistance to clindamycin was the most common resistance phenotype and was identified in 45 Listeria strains; the mechanisms of resistance are still unknown. A medium prevalence of resistance to tetracycline (15 and 9 resistant and intermediate strains) and ciprofloxacin (13 resistant strains) was also found. Tet M was detected in Listeria strains with reduced susceptibility to tetracycline, providing evidence that both L. innocua and L. monocytogenes displayed acquired resistance. The presence of antimicrobial resistance genes in L. innocua and L. monocytogenes indicates that these genes may be transferred to commensal and pathogenic bacteria via the food chain; besides this, antibiotic resistance in L. monocytogenes could compromise the effective treatment of listeriosis in humans. PMID- 28355098 TI - Meniscus beyond mechanics: Using biology to advance our understanding of meniscus injury and treatment. PMID- 28355097 TI - Sex-Related 30-Day and Long-Term Mortality in Acute Myocardial Infarction Patients Treated with Percutaneous Coronary Intervention. AB - BACKGROUND: The data on sex as an independent risk factor for death in acute myocardial infarction (MI) patients are still contrasting. The aim was to assess how sex influences 30-day and long-term all-cause mortality in MI patients undergoing percutaneous coronary intervention (PCI). MATERIALS AND METHODS: Data from 3624 MI patients undergoing PCI at our institution from January 2009 to December 2014, 30.6% were women, were analyzed. A propensity-matched analysis was performed to adjust for differences in the baseline characteristics between men and women. The effect of sex on 30-day and long-term mortality was observed. Multivariate logistic regression modeling was used for 30-day mortality and Cox regression analysis for long-term mortality. The median follow-up time was 27 months (25th, 75th percentile: 9, 48). RESULTS: Women had a significantly higher unadjusted 30-day (5.9% in men vs. 9.5% in women; p < 0.0001) and long-term mortality (13.5% in men vs. 19.0% in women; p < 0.0001). In a propensity-matched analysis, female sex was not associated with a higher 30-day (adjusted odds ratio: 1.46; 95% confidence interval: 0.97-2.19) or long-term mortality (hazard ratio 1.02; 95% CI 0.81-1.28). Age older than 77 years, cardiogenic shock, PCI of left anterior descending artery (LAD), thrombolysis in myocardial infarction (TIMI) flow less than 3 after PCI, hypertension, dyslipidemia, and P2Y12 receptor antagonists were identified as independent predictors of 30-day and long-term mortality. In addition, renal failure requiring dialysis predicted long-term mortality. CONCLUSION: Older age, comorbidities, worse clinical presentation, and adjunctive pharmacotherapy rather than sex may explain the higher mortality rate in women with MI undergoing PCI. PMID- 28355099 TI - Validity of the Posttraumatic Stress Symptoms-14 Instrument in Acute Respiratory Failure Survivors. PMID- 28355100 TI - Primary SWL Is an Efficient and Cost-Effective Treatment for Lower Pole Renal Stones Between 10 and 20 mm in Size: A Large Single Center Study. AB - INTRODUCTION: To assess the clinical features, outcomes, complications, and cost effectiveness of shockwave lithotripsy (SWL), flexible ureterorenoscopy (FURS), and percutaneous nephrolithotomy (PCNL) in the treatment of lower pole (LP) stones (10-20 mm) in a large tertiary referral center. PATIENTS AND METHODS: Consecutive patients treated for solitary LP stones (10-20 mm) between 2008 and 2013 were identified from a prospective database. SWL was used as primary treatment in all cases (following a stone multidisciplinary team assessment), with FURS and PCNL reserved for SWL contraindications, failure, or patient choice. "Success" was defined as stone free and/or clinically insignificant stone fragments (<=3 mm) at 1 and 3 months follow-up. Effect of anatomy on SWL success was determined from using CT images and regression analysis. Average cost per treatment modality (including additional second-line treatments) was calculated for each group using the National Health Service England 2014/15 National Tariff Healthcare Resource Group codes. RESULTS: Two hundred twenty-five patients were included (mean age 54.9; median stone size 12 mm). One hundred ninety-eight (88%), 21 (9.3%), and 6 (2.7%) patients underwent SWL, FURS, and PCNL as primary treatments, respectively, for median stone sizes of 12, 12, and 20 mm. Overall success rates were 82.8%, 76.1%, and 66.7%, respectively (p < 0.05). Sixty-three percent of patients undergoing primary SWL were effectively treated after one session. Anatomical analysis determined infundibulopelvic angle and infundibular length to be significantly different in patients effectively treated with SWL (p = 0.04). The average cost per treatment modality was also significantly lower for SWL (L750) than for FURS (L1261) or PCNL (L2658) (p < 0.01). CONCLUSION: SWL is both an efficacious and cost-effective primary treatment for patients with solitary LP stones (10-20 mm). The majority of patients can be effectively treated with primary SWL in a dedicated stone center, with the benefits of a short length of stay, low complication, and auxiliary treatment rates. The referral of such patients to high-volume lithotripsy centers with demonstrable outcomes should be given due consideration. PMID- 28355101 TI - Pioneer Robotic Serra-Doria Operation for Recurrent Achalasia After Heller's Cardiomyotomy: A "New Quondam" Procedure. AB - INTRODUCTION: Recurrence of achalasia may occur in 10%-20% of cases operated by Heller's cardiomyotomy. Most of these patients will require further surgery to relieve symptoms. Major technical difficulties can be found in these reoperations. CASE REPORT: A 50-year-old female patient with relapsed idiopathic achalasia after Heller's technique was treated with an unusual procedure, for the first time in the literature, by minimally invasive access with robotic assistance. CONCLUSIONS: The Serra-Doria operation allows preserving the esophagus and alleviating dysphagic symptoms with low rates of postoperative complications. The use of robotic technology is perfectly feasible and allows minimally invasive access in complex cases and reoperations. PMID- 28355102 TI - Suppressive roles of A3AR and TMIGD3 i1 in osteosarcoma malignancy. PMID- 28355103 TI - Homeopathic Treatment for Postpartum Depression: A Case Report. AB - Postpartum psychosis has long-lasting consequences for mother and child. Beside depression, sleep and eating disturbances, exhaustion, social withdrawal, and anxiety, postpartum depression can also interfere with normal maternal-infant bonding and adversely affect child development. Recent reports show that most affected pregnant women are hesitant about taking antidepressant drugs, with a high percentage discontinuing their use. Some authors suggest that the reluctance of pregnant women to take antidepressant drugs should encourage clinicians to discuss with their patients the use of psychological interventions or alternative forms of treatment. In this article, a case of severe postpartum depression, treated successfully with homeopathic therapy, is presented. Considering the high noncompliance of women suffering from postpartum depression with conventional antidepressant medication, research in safe complementary medical methods is justified. One of these methods should be homeopathy. PMID- 28355104 TI - Laparoscopic Colectomy Versus Open Colectomy for Treatment of Transverse Colon Cancer: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The surgical management of transverse colon cancer (TCC) is still not standardized. The aim of this meta-analysis was to evaluate the effect of laparoscopic colectomy (LC) for treatment of TCC in terms of short-term and long term outcomes compared with open colectomy. METHOD: A systematic literature search with no limits was performed in PubMed and Embase. The last search was performed on September 15, 2016. The short-term outcomes included intraoperative outcomes, postoperative outcomes, and oncological surgical quality. The long-term outcomes included overall survival (OS) and disease-free survival (DFS). RESULTS: Thirteen articles and one conference abstract published between 2010 and 2016 with a total of 1728 patients were enrolled in this meta-analysis. LC was associated with significant less estimated blood loss, fewer total postoperative complications, and shorter time to first flatus, time to liquid diet, length of hospital stay, and length of postoperative hospital stay. However, longer operative time was needed in LC. There was no statistically significant difference between the groups concerning the intraoperative complications, mortality, ileus, anastomotic leakage, bleeding, wound infection, abdominal infection, lymph nodes harvested, proximal resection margin, distal resection margin, OS, or DFS. CONCLUSION: Our meta-analysis suggests that LC is a safe and feasible technique for TCC associated with less estimated blood loss, fewer total postoperative complications, quicker recovery of intestinal function, shorter length of hospital stay, and equivalent long-term outcomes. Furthermore, a large scaled, prospective randomized controlled study is warranted to verify those results. PMID- 28355105 TI - JOSD1 Negatively Regulates Type-I Interferon Antiviral Activity by Deubiquitinating and Stabilizing SOCS1. AB - The Josephin domain-containing (JOSD) protein 1 (JOSD1) is recognized as one member of deubiquitinases (DUBs) due to its catalytic "Josephin" domain. However, the in vivo deubiquitinating activity of JOSD1 remains unidentified, and the biological functions of JOSD1 are largely unknown. In this study, we report that JOSD1 plays an important role in regulating type-I interferon (IFN-I)-mediated antiviral activity. JOSD1 physically interacts with SOCS1, which is an essential negative regulator of many cytokines signaling, and enhances SOCS1 stability by deubiquitinating K48-linked polyubiquitination of SOCS1. Furthermore, JOSD1 inhibits IFN-I-induced signaling pathway and antiviral response. Interestingly, during the early stage of viral infections, the levels of JOSD1 and SOCS1 undergo downregulation, which may facilitate activation of IFN-I signaling and efficient antiviral activity. Thus, our finding identified the first deubiquitinating substrate of JOSD1 and a novel biological function of JOSD1 and may provide a potential target for IFNs-based antiviral therapy. PMID- 28355106 TI - Chromosomal Mapping of Repetitive DNA Sequences in the Genus Bryconamericus (Characidae) and DNA Barcoding to Differentiate Populations. AB - The mapping of repetitive DNA sites by fluorescence in situ hybridization has been widely used for karyotype studies in different species of fish, especially when dealing with related species or even genera presenting high chromosome variability. This study analyzed three populations of Bryconamericus, with diploid number preserved, but with different karyotype formulae. Bryconamericus ecai, from the Forquetinha river/RS, presented three new cytotypes, increasing the number of karyotype forms to seven in this population. Other two populations of Bryconamericus sp. from the Vermelho stream/PR and Cambuta river/PR exhibited interpopulation variation. The chromosome mapping of rDNA sites revealed unique markings among the three populations, showing inter- and intrapopulation variability located in the terminal region. The molecular analysis using DNA barcoding complementing the cytogenetic analysis also showed differentiation among the three populations. The U2 small nuclear DNA repetitive sequence exhibited conserved features, being located in the interstitial region of a single chromosome pair. This is the first report on its occurrence in the genus Bryconamericus. Data obtained revealed a karyotype variability already assigned to the genus, along with polymorphism of ribosomal sites, demonstrating that this group of fish can be undergoing a divergent evolutionary process, constituting a substantive model for studies of chromosomal evolution. PMID- 28355107 TI - Pathology of Aging in NOD scid gamma Female Mice. AB - In the past decade, NOD.Cg- Prkdcscid Il2rgtm1Wjl/SzJ (NSG, NOD scid gamma) mice have become a model of choice in several areas of biomedical research; however, comprehensive data on their spontaneous age-related pathology are not currently available in the literature. The prevalence of spontaneous morbidity affecting aged NSG female breeders enrolled in a parasitology study was documented with classification of neoplastic and non-neoplastic (inflammatory, metabolic, degenerative) lesions. Malignant mammary neoplasms were most commonly diagnosed, often accompanied by pulmonary metastases, while a low frequency of lymphoma and histiocytic sarcoma was documented. The major inflammatory conditions were suppurative pleuropneumonia and bronchopneumonia with abscess formation, from which Pasteurella pneumotropica was commonly isolated, followed by otitis media. Both inflammatory and degenerative lesions of the genital tract were identified, along with neoplasms such as endometrial yolk sac carcinomas and granulosa cell tumors. Novel conditions identified included renal tubular degeneration and necrosis associated with 2 concurrent types of intranuclear inclusions, focal or multifocal hyperostosis of the skull, and neuroendocrine tumors of the mesometrium. The majority of degenerative lesions that affected the genital tract, endocrine, and skeletal systems did not represent the actual underlying cause of death but rather were considered incidental findings. This study indicates that both inflammatory and neoplastic conditions contribute to morbidity and mortality in experimentally manipulated aged female NSG mice. PMID- 28355108 TI - Prognostic Significance of Canine Mammary Tumor Histologic Subtypes: An Observational Cohort Study of 229 Cases. AB - Histopathology is considered the gold standard diagnostic method for canine mammary tumors. In 2011, a new histologic classification for canine mammary tumors was proposed. The present study was a 2-year prospective study that validated the 2011 classification as an independent prognostic indicator with multivariate analysis in a population of 229 female dogs, identifying subtype specific median survival times (MST) and local recurrence/distant metastasis rates. Dogs with benign tumors and carcinoma arising in benign mixed tumors all had an excellent prognosis. Dogs with complex carcinoma and simple tubular carcinoma also experienced prolonged survival. Those with simple tubulopapillary carcinoma, intraductal papillary carcinoma, and carcinoma and malignant myoepithelioma had a more than 10-fold higher risk of tumor-related death. The prognosis was even worse for adenosquamous carcinoma (MST = 18 months), comedocarcinoma (MST = 14 months), and solid carcinoma (MST = 8 months). The most unfavorable outcome was for anaplastic carcinoma (MST = 3 months) and carcinosarcoma (MST = 3 months), which also had the highest metastatic rates (89% and 100%, respectively). Adenosquamous carcinoma exhibited the highest local recurrence rate (50%). In the same canine population, the tumor diameter was recognized as a strong predictor of local recurrence/distant metastasis and an independent prognosticator of survival in the multivariate analysis. Excision margins were predictive only of local recurrence, whereas lymphatic invasion and histologic grade were predictive of local recurrence/distant metastasis and survival, although only in univariate analyses. In conclusion, this study validated the 2011 classification scheme and provided information to be used in the clinical setting and as the basis for future prognostic studies. PMID- 28355109 TI - Identification of 12 Piroplasms Infecting Ten Tick Species in China Using Reverse Line Blot Hybridization. AB - Piroplasmosis, a disease of domestic and wild animals, is caused by tick-borne protozoa in the genera of Theileria and Babesia. There is limited information available about the prevalence of piroplasmosis in ticks in China, and to assess the potential threat of piroplasmosis in China, we investigated the infections of ovine and bovine Babesia and Theileria species in ticks collected from cattle, yaks, sheep, horses, and camels in several regions of China where tick-borne diseases have been reported. In total, 652 ticks were collected from the animals in 6 provinces of China. Babesia spp. and Theileria spp. were detected with a PCR RLB method and identified by sequencing. Overall, 157 ticks (24.1%) were infected with 5 Babesia and 4 Theileria species. Among tested tick samples, 134 (20.6%) were single infections with 1 of 7 piroplasm species, with Theileria annulata (118/652, 18.1%) being dominant. Only 23 (3.5%) tick samples were double or triple infected, Theileria luwenshuni and Theileria sinensis (18/652, 2.8%) were frequently observed in co-infections. Some piroplasm species were carried by ticks that were not previously reported to be vectors. PMID- 28355111 TI - The Missing Fellow: First Description of the Trypanoxyuris pigrae Male (Nematoda: Oxyuridae), a Parasite of the Black Howler Monkey (Alouatta pigra) in Mexico. AB - The first morphological description of the male of Trypanoxyuris pigrae Solorzano Garcia, Nadler, and Perez-Ponce de Leon, 2016 , is presented in this study. Morphological data are supported by molecular data. Specimens of T. pigrae were recovered after the necropsy of a roadkill black howler monkey (Alouatta pigra) in southeastern Mexico. Males of T. pigrae are characterized by having 3 notched lips and a long esophagus with a posterior bulb; they also show a single crested lateral alae, a single spicule, and 4 caudal papillae. Morphological features coincide with those of the previously described T. pigrae females, and molecular profiles confirmed species identification. Males of T. pigrae are very similar to those of Trypanoxyuris minutus, another species of pinworm that also parasitizes the black howler monkey, A. pigra; however, the shape of the lips represents a very reliable diagnostic feature. Because of this, detailed en face observations are recommended to discriminate between these pinworm species. PMID- 28355114 TI - Hypofractionated Radiotherapy for Prostate Cancer: Further Evidence to Tip the Scales. PMID- 28355113 TI - Moderate Hypofractionation in High-Risk, Organ-Confined Prostate Cancer: Final Results of a Phase III Randomized Trial. AB - Purpose To report the final results on treatment outcomes of a randomized trial comparing conventional and hypofractionated radiotherapy in high-risk, organ confined prostate cancer (PCa). Patients and Methods This single-institution, randomized clinical trial, conducted from January 2003 to December 2007, enrolled 168 patients with high-risk PCa who were randomly assigned in a 1:1 ratio to conventional (80 Gy in 40 fractions in 8 weeks) or hypofractionated radiotherapy (62 Gy in 20 fractions in 5 weeks) to prostate and seminal vesicles. The primary outcome measure was late toxicity. Additional outcomes were freedom from biochemical failure (FFBF), prostate cancer-specific survival (PCaSS), and overall survival (OS), evaluated on an intention-to-treat basis. Results A total of 85 patients were assigned to conventional and 83 to hypofractionated radiotherapy. At a median follow-up of 9 years (interquartile range, 7.5 to 10.1 years), no differences was observed in physician-assessed late gastro intestinal and genitourinary toxicity greater than or equal to grade 2 ( P = .68 and .57, respectively) were found between the two arms. The 10-year FFBF rate was 72% in the hypofractionation group and 65% in the conventional fractionation group ( P = .148). Ten-year OS rates were 75% in the hypofractionation group and 64% in the conventional group, respectively ( P = .22). The same features for 10-year PCaSS were 95% and 88%, respectively ( P = .066). Hypofractionation, pretreatment prostate-specific antigen level, Gleason score, and clinical tumor stage for FFBF, and hypofractionation and Gleason score for PCaSS were significant prognostic variables on the multivariate analysis. Conclusion Long-term findings showed that hypofractionated radiotherapy failed the intent of either reducing physician-assessed late toxicity or maintaining the same efficacy. A postrandomization analysis, however, revealed that hypofractionation was a significant prognostic factor for FFBF and PCaSS, when adjusted for clinical prognostic variables. PMID- 28355112 TI - Final Results of the IELSG-19 Randomized Trial of Mucosa-Associated Lymphoid Tissue Lymphoma: Improved Event-Free and Progression-Free Survival With Rituximab Plus Chlorambucil Versus Either Chlorambucil or Rituximab Monotherapy. AB - Purpose There is no consensus on the optimal systemic treatment of patients with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. The IELSG 19 phase III study, to our knowledge, was the first such study to address the question of first-line treatment in a randomized trial. Patients and Methods Eligible patients were initially randomly assigned (1:1 ratio) to receive either chlorambucil monotherapy (6 mg/m2/d orally on weeks 1 to 6, 9 to 10, 13 to 14, 17 to 18, and 21 to 22) or a combination of chlorambucil (same schedule as above) and rituximab (375 mg/m2 intravenously on day 1 of weeks 1, 2, 3, 4, 9, 13, 17, and 21). After the planned enrollment of 252 patients, the protocol was amended to continue with a three-arm design (1:1:6 ratio), with a new arm that included rituximab alone (same schedule as the combination arm) and with a final sample size of 454 patients. The main end point was event-free survival (EFS). Analysis of chlorambucil versus the combination arm was performed and reported separately before any analysis of the third arm. Results At a median follow-up of 7.4 years, addition of rituximab to chlorambucil led to significantly better EFS (hazard ratio, 0.54; 95% CI, 0.38 to 0.77). EFS at 5 years was 51% (95% CI, 42 to 60) with chlorambucil alone, 50% (95% CI, 42 to 59) with rituximab alone, and 68% (95% CI, 60 to 76) with the combination ( P = .0009). Progression-free survival was also significantly better with the combination ( P = .0119). Five-year overall survival was approximately 90% in each arm. All treatments were well tolerated. No unexpected toxicities were recorded. Conclusion Rituximab in combination with chlorambucil demonstrated superior efficacy in mucosa-associated lymphoid tissue lymphoma; however, improvements in EFS and progression-free survival did not translate into longer overall survival. PMID- 28355116 TI - Quality of Survivorship in a Rare Disease: Clinicofunctional Outcome and Physical Activity in an Observational Cohort Study of 618 Long-Term Survivors of Ewing Sarcoma. AB - Purpose Significantly improved survival rates in patients with Ewing sarcoma have raised interest in accessing the quality of long-term survivorship. In this study, subjective and objective measurement tools, preclassified as physical or mental scores, were used to assess clinicofunctional outcome and physical activity after intensive bone tumor treatment. Methods Long-term outcome of 618 survivors from consecutive Ewing sarcoma trials was assessed by the Toronto Extremity Salvage Score, Short-Form Health Survey (SF-36), Brief Symptom Inventory (BSI), and Rosenberg Self-Esteem Scale questionnaires and by the accelerometric StepWatch 3 Activity Monitor. Prospective measurements were correlated retrospectively with standardized primary trial data. Results were compared with 316 nonrandom healthy peers by using effect sizes ( d). Median observation time was 12.9 years from primary diagnosis (range, 3.7 to 31.2 years). Results Absolute subjective scores were moderate to good for survivors. Compared with control subjects, unfavorable outcome was shown on physical Toronto Extremity Salvage Score, SF-36 Physical Component Summary, and BSI-Somatization scales (| d| >= 0.50; P < .01), in contrast to SF-36 Mental Component Summary, BSI-Anxiety, BSI-Depression, and Rosenberg Self-Esteem Scale mental scales (| d| <= 0.31). Survivors were less active than control subjects, as demonstrated by a step count difference of 1,742 steps per day ( d = -0.43; P < .01); however, on average, the recommended level for an active lifestyle was achieved (>= 10,000 steps). Location of pelvic tumor was the major inferior disease-specific prognostic factor in physical scores ( P < .01), whereas nondisease-specific inferior factors in questionnaires were older age and female sex ( P < .01). Conclusion Survivors of Ewing sarcoma apparently returned to a normal life with minor limitations. Observed reductions in physical scores should be a focus in future research to optimize treatment strategies to reduce a negative impact on the quality of survivorship. PMID- 28355115 TI - Complete Hematologic and Molecular Response in Adult Patients With Relapsed/Refractory Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment With Blinatumomab: Results From a Phase II, Single-Arm, Multicenter Study. AB - Purpose Few therapeutic options are available for patients with Philadelphia chromosome-positive (Ph+) B-precursor acute lymphoblastic leukemia (ALL) who progress after failure of tyrosine kinase inhibitor (TKI) -based therapy. Here, we evaluated the efficacy and tolerability of blinatumomab in patients with relapsed or refractory Ph+ ALL. Patients and Methods This open-label phase II study enrolled adults with Ph+ ALL who had relapsed after or were refractory to at least one second-generation or later TKI or were intolerant to second generation or later TKIs and intolerant or refractory to imatinib. Blinatumomab was administered in 28-day cycles by continuous intravenous infusion. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh) during the first two cycles. Major secondary end points included minimal residual disease response, rate of allogeneic hematopoietic stem-cell transplantation, relapse-free survival, overall survival, and adverse events (AEs). Results Of 45 patients, 16 (36%; 95% CI, 22% to 51%) achieved CR/CRh during the first two cycles, including four of 10 patients with the T315I mutation; 88% of CR/CRh responders achieved a complete minimal residual disease response. Seven responders (44%) proceeded to allogeneic hematopoietic stem-cell transplantation, including 55% (six of 11) of transplantation-naive responders. Median relapse-free survival and overall survival were 6.7 and 7.1 months, respectively. The most frequent AEs were pyrexia (58%), febrile neutropenia (40%), and headache (31%). Three patients had cytokine release syndrome (all grade 1 or 2), and three patients had grade 3 neurologic events, one of which (aphasia) required temporary treatment interruption. There were no grade 4 or 5 neurologic events. Conclusion Single-agent blinatumomab showed antileukemia activity in high-risk patients with Ph+ ALL who had relapsed or were refractory to TKIs. AEs were consistent with previous experience in Ph- ALL. PMID- 28355117 TI - Molecular Cloning, Identification, and Expression Patterns of Myostatin Gene in Water Buffalo (Bubalus Bubalis). AB - : Myostatin (MSTN), also named growth differentiation factor 8 (GDF8), is a transforming growth factor-beta (TGF-beta) family member with a key role in the negative regulation of skeletal muscle growth. However, its role in ovarian folliculogenesis remains unclear. To provide us with a basis for understanding this role, we cloned MSTN and examined its expression patterns in water buffalo (Bubalus bubalis). The complete ORF of the water buffalo MSTN gene is 1,128 nucleotides, which encode a 375 amino acid protein and sharing 99% identity at the deducted amino acid level with that of Bos taurus. Protein sequence analysis showed that MSTN is a weakly acerbic extracellular protein, consisting of signal peptides at 18-19 sites, a TGF-beta propeptide, and a TGF-beta domain. RT-PCR analyses demonstrated that water buffalo MSTN was expressed in multiple tissues but not limited to muscle. Immunohistochemistry staining confirmed the presence of MSTN in oocytes and granulosal cells. To our knowledge, this is the first study to confirm the expression of MSTN in the water buffalo ovary, suggesting an additional role of MSTN in water buffalo folliculogenesis, along with its role in skeletal muscle growth regulation. Further study of the regulatory mechanism of MSTN in water buffalo reproduction is warranted. ABBREVIATIONS: MSTN, myostatin; ORF, open reading frame. PMID- 28355118 TI - Carbonyl Compounds Produced by Vaporizing Cannabis Oil Thinning Agents. AB - OBJECTIVE: Cannabis use has increased in the United States, particularly the use of vaporized cannabis oil, which is often mixed with thinning agents for use in vaporizing devices. E-cigarette research shows that heated thinning agents produce potentially harmful carbonyls; however, similar studies have not been conducted (1) with agents that are commonly used in the cannabis industry and (2) at temperatures that are appropriate for cannabis oil vaporization. The goal of this study was to determine whether thinning agents used in the cannabis industry produce potentially harmful carbonyls when heated to a temperature that is appropriate for cannabis oil vaporization. DESIGN: Four thinning agents (propylene glycol [PG], vegetable glycerin [VG], polyethylene glycol 400 [PEG 400], and medium chain triglycerides [MCT]) were heated to 230 degrees C and the resulting vapors were tested for acetaldehyde, acrolein, and formaldehyde. Each agent was tested three times. SETTING/LOCATION: Testing was conducted in a smoking laboratory. OUTCOME MEASURES: Carbonyl levels were measured in micrograms per puff block. RESULTS: Analyses showed that PEG 400 produced significantly higher levels of acetaldehyde and formaldehyde than PG, MCT, and VG. Formaldehyde production was also significantly greater in PG compared with MCT and VG. Acrolein production did not differ significantly across the agents. CONCLUSIONS: PG and PEG 400 produced high levels of acetaldehyde and formaldehyde when heated to 230 degrees C. Formaldehyde production from PEG 400 isolate was particularly high, with one inhalation accounting for 1.12% of the daily exposure limit, nearly the same exposure as smoking one cigarette. Because PG and PEG 400 are often mixed with cannabis oil, individuals who vaporize cannabis oil products may risk exposure to harmful formaldehyde levels. Although more research is needed, consumers and policy makers should consider these potential health effects before use and when drafting cannabis-related legislation. PMID- 28355119 TI - High-Intensity Focused Ultrasound for the Treatment of Prostate Cancer: A Review. AB - Over the past 25 years, the average life expectancy for men has increased almost 4 years, and the age of prostate cancer detection has decreased an average of 10 years with diagnosis increasingly made at early-stage disease where curative therapy is possible. These changing trends in the age and extent of malignancy at diagnosis have revealed limitations in conventional curative therapies for prostate cancer, including a significant risk of aggressive cancer recurrence, and the risk of long-term genitourinary morbidity and its detrimental impact on patient's quality of life (QOL). Greater awareness of the shortcomings in radical prostatectomy, external radiotherapy, and brachytherapy has prompted the search for alternative curative therapies that offer comparable rates of cancer control and less treatment-related morbidity to better preserve QOL. High-intensity focused ultrasound (HIFU) possesses characteristics that make it an attractive curative therapy option. HIFU is a noninvasive approach that uses precisely delivered ultrasound energy to achieve tumor cell necrosis without radiation or surgical excision. In current urologic oncology, HIFU is used clinically in the treatment of prostate cancer and is under experimental investigation for therapeutic use in multiple malignancies. Clinical research on HIFU therapy for localized prostate cancer began in the 1990s, and there have now been ~65,000 prostate cancer patients treated with HIFU, predominantly with the Ablatherm (EDAP TMS, Lyon, France) device. Neoadjuvant transurethral resection of the prostate has been combined with HIFU since 2000 to reduce prostate size, facilitate tissue destruction, and to minimize side effects. Advances in imaging technologies are expected to further improve the already superior efficacy and morbidity outcomes, and ongoing investigation of HIFU as a focal therapy in salvage and palliative indications is serving to expand the role of HIFU as a highly versatile noninvasive therapy for prostate cancer. PMID- 28355120 TI - Monitoring the World Health Organization Global Target 2025 for Exclusive Breastfeeding: Experience From the United States. AB - BACKGROUND: Exclusive breastfeeding under 6 months, calculated from a single 24 hour recall among mothers of children 0 to 5 months of age, is a World Health Organization (WHO) indicator used to monitor progress on the 2025 global breastfeeding target. Many upper-middle-income and high-income countries, including the United States, do not have estimates for this indicator. Research aim: To describe the prevalence of exclusive breastfeeding under 6 months in the United States. METHODS: We used a single 24-hour dietary recall from the National Health and Nutrition Examination Survey 2009-2012 to calculate the prevalence of exclusive breastfeeding under 6 months. We discuss our results in the context of routine breastfeeding surveillance, which is reported from a national survey with different methodology. RESULTS: Among children younger than 6 months, 24.4%, 95% confidence interval [17.6, 31.1], were exclusively breastfed the previous day. CONCLUSION: To our knowledge, this is the first estimate of the WHO indicator of exclusive breastfeeding under 6 months for the United States. This study supports the global surveillance and data strategy for reporting to the WHO on the 2025 target for exclusive breastfeeding. PMID- 28355121 TI - Airway Resistance in Patients with Obstructive Sleep Apnea Syndrome Following Robotic Prostatectomy. AB - BACKGROUND: Because minimally invasive surgery can improve postoperative recovery, it became the preferred technique for patients with significant comorbidities. However, steep Trendelenburg position and abdominal CO2 insufflation can lead to a significant increase in upper airway resistance and an alteration of overall lung function. In particular, patients who already suffer from an obstructive airway disease like obstructive sleep apnea syndrome (OSAS) might be at risk for postoperative airway complications. Therefore, we perioperatively performed spirometric tests in patients with OSAS undergoing robotic surgery in steep Trendelenburg position. METHODS: Twenty patients with OSAS were enrolled in the study. A day before surgery lung function measurements were performed and repeated preoperatively, 40, 120, and 240 minutes and 1 and 5 days postoperatively. We measured vital capacity (VC), forced expiratory volume in 1 second (FEV1), maximal mid expiratory and inspiratory flow (MEF50, MIF50), arterial oxygen saturation, and nasal flow. RESULTS: The ratio of MEF50 to MIF50, as an indicator of upper airway resistance, was increased significantly postoperatively and normalized within 24 hours (p < 0.0001), while FEV1 and VC were significantly reduced and recovered only partially as much as the fifth postoperative day (p < 0.0001). CONCLUSION: Airway resistance increased following robotic radical prostatectomy in Trendelenburg position in patients with OSAS. Two separate major effects can be observed. A significant increase of the upper airway resistance, which improved to preoperative conditions within 24 hours, and a reduction in FEV1 and VC, which recovered only partially as much as the fifth postoperative day. PMID- 28355122 TI - The platelets' perspective to pathogen reduction technologies. AB - A wide variety of clinical conditions, associated with low circulating platelet counts, require platelet transfusion in order to normalize hemostatic function. Although single-donor apheresis platelets bear the lowest risk of transfusion transmitted infections, pathogen reduction technologies (PRT) are being implemented worldwide to reduce this risk further through inactivation of known, emergent and as yet to be discovered nucleic acid-based pathogens. Human blood platelets are now known to harbor a diverse transcriptome, important to their function and comprised of >5000 protein-coding messenger RNAs and different classes of non-coding RNAs, including microRNAs. Our appreciation of the nucleic acid-dependent functions of platelets is likely to increase. On the other hand, the side effects of PRT on platelet function are underappreciated. Recent evidences suggest that PRT may compromise platelets' responsiveness to agonists, and induce platelet activation. For instance, platelets have the propensity to release proinflammatory microparticles (MPs) upon activation, and the possibility that PRT may enhance the production of platelet MPs in platelet concentrates (PCs) appears likely. With this in mind, it would be timely and appropriate to investigate other means to inactivate pathogens more specifically, or to modify the currently available PRT so to better preserve the platelet function and improve the safety of PCs; platelets' perspective to PRT deserves to be considered. PMID- 28355123 TI - GFFview: A Web Server for Parsing and Visualizing Annotation Information of Eukaryotic Genome. AB - Owing to wide application of RNA sequencing (RNA-seq) technology, more and more eukaryotic genomes have been extensively annotated, such as the gene structure, alternative splicing, and noncoding loci. Annotation information of genome is prevalently stored as plain text in General Feature Format (GFF), which could be hundreds or thousands Mb in size. Therefore, it is a challenge for manipulating GFF file for biologists who have no bioinformatic skill. In this study, we provide a web server (GFFview) for parsing the annotation information of eukaryotic genome and then generating statistical description of six indices for visualization. GFFview is very useful for investigating quality and difference of the de novo assembled transcriptome in RNA-seq studies. PMID- 28355124 TI - Ocular Pharmacology for Scleritis: Review of Treatment and a Practical Perspective. AB - Scleritis is defined as an infectious or noninfectious inflammation of the sclera that can be broadly categorized according to anatomic location (ie, anterior or posterior) and whether the process is necrotizing or non-necrotizing. Treatment for scleritis is dictated by the etiology of the inflammation, with infectious forms requiring treatment of the inciting agent and noninfectious forms requiring treatment of the underlying inflammation with immunosuppression. Pharmacotherapy for noninfectious scleritis can be classified according to delivery route (eg, local or systemic) and mechanism of action (eg, biologic or nonbiologic). This review will briefly summarize the classification scheme for scleritis before reviewing in depth both systemic and local pharmacotherapies that can be used to effectively treat an eye afflicted by either infectious or noninfectious scleritis. Traditional anti-inflammatory agents such as nonsteroidal anti inflammatory drugs, steroids, and immunomodulatory therapy will be discussed, as well as newer biologic therapies such as antitumor necrosis factor alpha and anti CD20 agents. PMID- 28355125 TI - Epitope Mapping of the Antibody Response Against the Envelope Proteins of the Feline Foamy Virus. AB - Foamy viruses (FV) are retroviruses that infect several species without pathological signs, but induce substantial antibody responses in the infected host. In the case of feline FV (FFV), antibodies against Gag, Bet, and Env have been used to indicate infection; however, it is unclear whether the response to specific epitopes correlates with immunity. Here, we investigated the epitope specificity of antibodies targeting the Env protein using peptide microarrays. Sera from naturally and experimentally FFV-infected cats and pumas and from rats immunized with FFV Env expression plasmids were analyzed. An immunodominant epitope was identified in the Env leader protein (Elp), and a strong reactivity to two epitope clusters in the transmembrane (TM) subunit of Env was observed. Moreover, a short stretch of residues in the C-terminal part of the surface (SU) protein was found to be significantly associated with FFV serotype FUV-mediated neutralization. Taken together, our results add a new level of detail on the B cell epitope repertoire induced during FFV infection. Furthermore, our results provide a basis for current attempts to modify FV vectors to express and present vaccine epitopes for the directed induction of humoral immunity. PMID- 28355126 TI - Plasma protein binding monitoring of therapeutic drugs in patients using single set of hollow fiber centrifugal ultrafiltration. AB - AIM: Plasma protein binding (PPB), as a significant influenced factor of pharmacokinetic and pharmacodynamic properties of a medicine, is a suitable index for therapeutic drug monitoring (TDM) strategies. A suitable measurement technique of PPB of patients is in urgent need and attracts many analysts' attention. Results & methodology: In this study, a novel method was proposed to analyze free drug concentration and total drug concentration (Ct) successively in one unit with a sample. All RSDs were less than 3%. The absolute recovery of Ct ranged from 98.1 to 101.2%. DISCUSSION & CONCLUSION: It is extremely valuable to consider PPB as an important index for TDM, perfecting information of medication, reflecting the disease condition more comprehensively, providing assistance for doctors to adjust the dose regimen. The proposed technique, convenience, accuracy and without the influence of plasma condition, provides a feasible method to monitor PPB of various patients, facilitating the popularization of monitoring PPB in TDM. PMID- 28355127 TI - Being Spontaneous: The Future of Telehealth Implementation? AB - INTRODUCTION: The smartphone simplifies interprofessional communication, and smartphone applications can facilitate telemedicine activity. Much has been written about the steps that need to be followed to implement and establish a successful telemedicine service that is integrated into everyday clinical practice. A traditional and systematic approach has evolved incorporating activities such as strategy development, needs assessment, business cases and plans, readiness assessment, implementation plans, change management interventions, and ongoing monitoring and evaluation. This "best practice" has been promoted in the telehealth literature for many years. In contrast, several recent initiatives have arisen without any such formal undertakings. This article describes the strengths and weaknesses of two "spontaneous" telemedicine services in dermatology and burn management that have evolved in South Africa. METHODS: Two spontaneous services were identified and reviewed. RESULTS: In one unsolicited service, doctors at rural referring hospitals have been taking photographs of skin lesions and sending them with a brief text message history to dermatologists using the instant messaging smartphone app, WhatsApp. In the other, burns service, admissions to the burns unit or the clinic were triaged by telephonic description of the case and completion of a preadmission questionnaire. More recently, management and referral decisions are made only after completion of the questionnaire and subsequent submission of photographs of the burn sent by WhatsApp, with the decision transmitted by text message. DISCUSSION: Although efficient and effective, potential legal and ethical shortcomings have been identified. CONCLUSION: These "spontaneous" telehealth services challenge traditional best practice, yet appear to lead to truly integrated practice and, therefore, are successful and warrant further study. PMID- 28355128 TI - Concurrent Examination of Bobcats and Ticks Reveals High Prevalence of Cytauxzoon felis in Southern Illinois. AB - Cytauxzoon felis is an intraerythrocytic apicomplexan of felids enzootic in the southeastern United States. In domestic cats (Felis catus), this parasite can result in the highly fatal disease cytauxzoonosis or bobcat fever. Bobcats (Lynx rufus) are the wild animal reservoir host. To date, the characterization of prevalence of C. felis in bobcats is mostly based on broad-scale surveys from hunter-harvested specimens collected across large geographic areas, usually consisting of multiple states. Detailed studies on the development, transmission, distribution, effects, and prevalence of C. felis in the tick vectors are scarce. To fill some of these gaps in the literature, such as prevalence in ticks and bobcats in a discrete region, we examined bobcats and ticks in an 8,000-km2 portion of southern Illinois. We screened for C. felis using a nested polymerase chain reaction that amplifies a fragment of the nuclear small subunit (SSU) 18S rRNA. We screened 125 individual bobcats collected in southern Illinois from 2003 to 2015; of these, 70.6% were positive for C. felis. In addition, we screened 214 ticks of both vector species (Amblyomma americanum and Dermacentor variabilis) and detected C. felis in 15.6% of them; this prevalence is higher than reported by previous surveys. Our study reports the prevalence of C. felis in ticks and bobcats from south Illinois. We found that 70.6% of bobcats and 15.6% of ticks were infected with C. felis, which suggests risk of transmission to domestic cats. PMID- 28355129 TI - Sudden water pollution accidents and reservoir emergency operations: impact analysis at Danjiangkou Reservoir. AB - Danjiangkou Reservoir is the source reservoir of the Middle Route of the South-to North Water Diversion Project (MRP). Any sudden water pollution accident in the reservoir would threaten the water supply of the MRP. We established a 3-D hydrodynamic and water quality model for the Danjiangkou Reservoir, and proposed scientific suggestions on the prevention and emergency management for sudden water pollution accidents based on simulated results. Simulations were performed on 20 hypothetical pollutant discharge locations and 3 assumed amounts, in order to model the effect of pollutant spreading under different reservoir operation types. The results showed that both the location and mass of pollution affected water quality; however, different reservoir operation types had little effect. Five joint regulation scenarios, which altered the hydrodynamic processes of water conveyance for the Danjiangkou and Taocha dams, were considered for controlling pollution dispersion. The results showed that the spread of a pollutant could be effectively controlled through the joint regulation of the two dams and that the collaborative operation of the Danjiangkou and Taocha dams is critical for ensuring the security of water quality along the MRP. PMID- 28355130 TI - Value of whole-body magnetic resonance imaging for screening multifocal osteonecrosis in patients with polymyositis/dermatomyositis. AB - OBJECTIVE: To assess the value of coronal short-tau inversion recovery whole-body MRI (STIR-WBMRI) for screening osteonecrosis in patients with polymyositis (PM)/dermatomyositis (DM). METHODS: The imaging and medical records of 129 patients with PM/DM who met the Bohan and Peter diagnostic criteria were retrospectively analyzed. STIR-WBMRI was performed in all patients. 18 patients had follow-up STIR-WBMRI. 12 patients underwent regional knee and/or hip MRI while 25 patients underwent radiography of the lower extremities. RESULTS: STIR WBMRI detected osteonecrosis in 15 (11.6%) patients. 38 joints were affected (mean, 2.5 per patient; range, 1-5 joints). Of the 38 joints affected by osteonecrosis, 33 had no clinical symptoms. Among the 12 patients who underwent regional MRI, STIR-WBMRI detected all 10 osteonecrotic sites seen on the regional MRI. The location, shape and size of the osteonecrotic lesions revealed on regional MRI were in accordance with those displayed on STIR-WBMRI. Of the 15 patients with osteonecrosis, 6 performed routine radiography of the affected joints and revealed no osteonecrotic lesions. Follow-up WBMRI detected new osteonecrosis in two patients whose first WBMRI revealed that there was no osteonecrosis in any skeleton. CONCLUSION: In addition to displaying muscle inflammation, STIR-WBMRI can efficiently detect early multifocal osteonecrosis in the whole bodies of patients with PM/DM. Advances in knowledge: In patients with PM/DM, WBMRI which takes 12-15 min can display muscular involvement and detect early multisite osteonecrosis in the whole body at the same time. Osteonecrotic lesions revealed by WBMRI are in accordance with those displayed on regional WBMRI. PMID- 28355131 TI - Silencing of BCR/ABL Chimeric Gene in Human Chronic Myelogenous Leukemia Cell Line K562 by siRNA-Nuclear Export Signal Peptide Conjugates. AB - Herein we described the synthesis of siRNA-NES (nuclear export signal) peptide conjugates by solid phase fragment coupling and the application of them to silencing of bcr/abl chimeric gene in human chronic myelogenous leukemia cell line K562. Two types of siRNA-NES conjugates were prepared, and both sense strands at 5' ends were covalently linked to a NES peptide derived from TFIIIA and HIV-1 REV, respectively. Significant enhancement of silencing efficiency was observed for both of them. siRNA-TFIIIA NES conjugate suppressed the expression of BCR/ABL gene to 8.3% at 200 nM and 11.6% at 50 nM, and siRNA-HIV-1REV NES conjugate suppressed to 4.0% at 200 nM and 6.3% at 50 nM, whereas native siRNA suppressed to 36.3% at 200 nM and 30.2% at 50 nM. We could also show complex of siRNA-NES conjugate and designed amphiphilic peptide peptidebeta7 could be taken up into cells with no cytotoxicity and showed excellent silencing efficiency. We believe that the complex siRNA-NES conjugate and peptidebeta7 is a promising candidate for in vivo use and therapeutic applications. PMID- 28355132 TI - Angiopoietin-2 in white adipose tissue improves metabolic homeostasis through enhanced angiogenesis. AB - Despite many angiogenic factors playing crucial roles in metabolic homeostasis, effects of angiopoietin-2 (ANG-2) in adipose tissue (AT) remain unclear. Utilizing a doxycycline-inducible AT-specific ANG-2 overexpression mouse model, we assessed the effects of ANG-2 in AT expansion upon a high-fat diet (HFD) challenge. ANG-2 is significantly induced, with subcutaneous white AT (sWAT) displaying the highest ANG-2 expression. ANG-2 overexpressing mice show increased sWAT vascularization and are resistant to HFD-induced obesity. In addition, improved glucose and lipid metabolism are observed. Mechanistically, the sWAT displays a healthier expansion pattern with increased anti-inflammatory macrophage infiltration. Conversely, ANG-2 neutralization in HFD-challenged wild type mice shows reduced vascularization in sWAT, associated with impaired glucose tolerance and lipid clearance. Blocking ANG-2 causes significant pro-inflammatory and pro-fibrotic changes, hallmarks of an unhealthy AT expansion. In contrast to other pro-angiogenic factors, such as vascular endothelial growth factor-A (VEGF A), this is achieved without any enhanced beiging of white AT. PMID- 28355133 TI - An allosteric transport mechanism for the AcrAB-TolC multidrug efflux pump. AB - Bacterial efflux pumps confer multidrug resistance by transporting diverse antibiotics from the cell. In Gram-negative bacteria, some of these pumps form multi-protein assemblies that span the cell envelope. Here, we report the near atomic resolution cryoEM structures of the Escherichia coli AcrAB-TolC multidrug efflux pump in resting and drug transport states, revealing a quaternary structural switch that allosterically couples and synchronizes initial ligand binding with channel opening. Within the transport-activated state, the channel remains open even though the pump cycles through three distinct conformations. Collectively, our data provide a dynamic mechanism for the assembly and operation of the AcrAB-TolC pump. PMID- 28355136 TI - Pharmacologic Impact (aka "Breaking Bad") of Medications on Wound Healing and Wound Development: A Literature-based Overview. AB - Patients with wounds often are provided pharmacologic interventions for their wounds as well as for their acute or chronic illnesses. Drugs can promote wound healing or substantively hinder it; some medications cause wound or skin reactions. A comprehensive review of extant literature was conducted to examine the impact of drug therapy on wound healing and skin health. MEDLINE and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched for English-language articles published between 2000 and 2016 using the terms drugs, medications, drug skin eruptions, adverse skin reactions, wound healing, delayed wound healing, nonhealing wound, herbals, and herbal supplements. The search yielded 140 articles (CINAHL) and 240 articles (MEDLINE) for medications and wound healing. For medications and adverse skin effects, the search identified 256 articles (CINAHL) and 259 articles (MEDLINE). The articles included mostly narrative reviews, some clinical trials, and animal studies. Notable findings were synthesized in a table per pharmacological class and/or agent focusing on wound healing impact and drug-induced adverse skin reactions. The medications most likely to impair wound healing and damage skin integrity include antibiotics, anticonvulsants, angiogenesis inhibitors, steroids, and nonsteroidal anti-inflammatory drugs. Conversely, drugs such as ferrous sulfate, insulin, thyroid hormones, and vitamins may facilitate wound healing. Selected clinical practices, including obtaining a detailed medication history that encompasses herbal supplements use; assessing nutrition status especially protein blood levels affecting drug protein binding; and scrutinizing patient history and physical characteristics for risk factors (eg, atopy history) can help diminish and/or eliminate adverse integumentary outcomes. "Deprescribing" (discontinuing unnecessary medications) should be utilized when possible. Contemporary wound care clinicians must be cognizant of these mitigating clinical approaches. PMID- 28355137 TI - A Retrospective Study of Pilonidal Sinus Healing by Secondary Intention Using Negative Pressure Wound Therapy Versus Alginate or Gauze Dressings. AB - Pilonidal sinus (PS) disease is an inflammatory skin and subcutaneous tissue condition that presents with infection, acute abscess, chronic discharging wounds, and/or pain. Surgery with open healing by secondary intention typically is used to achieve the fastest healing time with minimal recurrence rates. A retrospective analysis was conducted of data extracted from the medical records of 73 consecutive patients who had symptomatic natal cleft PS over a 10-year period to compare use of NPWT to alginate-based/gauze daily dressing (DD) changes in terms of healing time and recurrence. Variables extracted included age, gender, PS wound diameter (small <1 cm, medium 1 cm to 3 cm, large >3 cm), and time in weeks to achieving the endpoint (epithelialization). Risk factors examined that can affect healing or recurrence of previously operated PS disease included initial drainage before excision and risk factors for impaired healing (morbid obesity as determined by body mass index [BMI] >=35, chronic infective skin conditions, and ongoing therapy with immuno-modulating drugs or chemotherapy), and loss to follow-up. Data were collected and analyzed using the chi-squared statistic, Kaplan-Meier curves, and Cox regression models. The total time of follow-up was 390 weeks for the DD group and 311 weeks for NPWT group. Patient mean age was 26.5 +/- 10.7 years, most (53, 72.6%) were male, and 12 (16.4%) had comorbidities potentially affecting healing. Nine (9) were treated with primary closure and 62 patients were treated with open healing by secondary intention (2 additional patients receiving DD were excluded from the analysis because they had small sinuses that made NPWT unfeasible). Among participants, 30 (48%) received DD and 32 had NPWT. The median time to healing was 10 weeks (95% CI: 7-17) in the DD group and 8 weeks (95% CI: 7-9) in the NPWT group (not significantly different). In patients who healed, the average time to healing was 15.0 +/- 18.1 and 9.8 +/- 6.3 weeks in the DD and NPWT groups, respectively (not significantly different). The PS wound recurred in 5 patients - 4 (12.5%) in the DD group and 1 (3.1%) in the NPWT group (P = .355). In univariate analysis, only the presence of comorbidities was found to significantly affect time to healing (HR 95%, CI: 0.40 [0.17-0.93]; P = .033]. Prospective, randomized controlled clinical studies are warranted. PMID- 28355134 TI - The interactome of the copper transporter ATP7A belongs to a network of neurodevelopmental and neurodegeneration factors. AB - Genetic and environmental factors, such as metals, interact to determine neurological traits. We reasoned that interactomes of molecules handling metals in neurons should include novel metal homeostasis pathways. We focused on copper and its transporter ATP7A because ATP7A null mutations cause neurodegeneration. We performed ATP7A immunoaffinity chromatography and identified 541 proteins co isolating with ATP7A. The ATP7A interactome concentrated gene products implicated in neurodegeneration and neurodevelopmental disorders, including subunits of the Golgi-localized conserved oligomeric Golgi (COG) complex. COG null cells possess altered content and subcellular localization of ATP7A and CTR1 (SLC31A1), the transporter required for copper uptake, as well as decreased total cellular copper, and impaired copper-dependent metabolic responses. Changes in the expression of ATP7A and COG subunits in Drosophila neurons altered synapse development in larvae and copper-induced mortality of adult flies. We conclude that the ATP7A interactome encompasses a novel COG-dependent mechanism to specify neuronal development and survival. PMID- 28355135 TI - Dynamic transcriptional signature and cell fate analysis reveals plasticity of individual neural plate border cells. AB - The 'neural plate border' of vertebrate embryos contains precursors of neural crest and placode cells, both defining vertebrate characteristics. How these lineages segregate from neural and epidermal fates has been a matter of debate. We address this by performing a fine-scale quantitative temporal analysis of transcription factor expression in the neural plate border of chick embryos. The results reveal significant overlap of transcription factors characteristic of multiple lineages in individual border cells from gastrula through neurula stages. Cell fate analysis using a Sox2 (neural) enhancer reveals that cells that are initially Sox2+ cells can contribute not only to neural tube but also to neural crest and epidermis. Moreover, modulating levels of Sox2 or Pax7 alters the apportionment of neural tube versus neural crest fates. Our results resolve a long-standing question and suggest that many individual border cells maintain ability to contribute to multiple ectodermal lineages until or beyond neural tube closure. PMID- 28355138 TI - Ultrasound to Detect Pressure-related Deep Tissue Injuries in Adults Admitted via the Emergency Department: A Prospective, Descriptive, Pilot Study. AB - Stage 4 pressure ulcers (PUs) start with tissue death at the level of the bone, also known as deep tissue injury (DTI). Studies have shown the appearance of DTI on the skin is delayed for several days after the original pressure-related injury to the deep soft tissues. Studies also suggest DTI can be seen using ultrasound (US) technology. A prospective, descriptive, correlational pilot study was conducted to evaluate the use of US technology to detect DTI in the soft tissues that are not visible on the skin upon hospital admission. Study participants included a convenience sample of 33 persons at risk for PUs (ie, Braden score <18) admitted through the emergency department. Each participant had US scans of 13 common PU body sites. All scans were documented in the radiologist report in the electronic medical record. Creatinine phosphokinase, calcium levels, and urine myoglobin levels also were assessed upon enrollment. Skin failure risk factors (SFRFs), including fever, hypotension, weight loss, coagulopathy, and acidosis/respiratory failure, also were documented. Patients were examined for skin PUs every day for 7 days after US scan. Twenty-three (23) patients completed the study. US scans identified pressure necrosis at 2 levels: bone (54 positive [US+]) and subcutaneous (SC); 79 US+, respectively). US+ bone sites resulted in 5 PUs appearing 6 to 7 days post-admission (sensitivity = 100%, specificity 84.7%, positive predictive value 10%, and negative predictive value 100%), indicating all DTI that later became purple skin DTI were detected by the US. US+ SC sites, located immediately under the skin, yielded 5 PUs appearing on day 2 after admission (sensitivity 100%, specificity 74.8%, positive predictive value 6.3%, and negative predictive value 100%). The participants with PU occurrence in both bone and SC groups had low Braden scores (bone group mean = 13.25, SC group mean = 11.2). Study patients who were positive for PU also had >4 SFRFs. Creatinine phosphokinase, calcium, and myoglobin levels were inconsistent and did not correlate with US+ scans. These observations warrant larger studies to confirm findings and optimize the validity of US screening for DTI in select populations, which may help improve protocols of care and PU admission documentation. The preliminary results suggest inclusion of the Braden Scale score and known PU risk factors may improve the positive predictive value of this test. PMID- 28355139 TI - Levamisole-induced Necrosis Syndrome: Presentation and Management. AB - Levamisole is an antihelminthic drug with immunomod- ulatory properties. Recent estimates suggest the majority of the cocaine in the United States is adulterated with levamisole. Le- vamisole-induced necrosis syndrome (LINES) is characterized by vasculitis, neutropenia, and purpura that progresses to skin necro- sis. Diagnosis relies on physical examination ndings and history of previous cocaine use. The purpose of this case series is to describe the pathophysiology, diagnosis, and management of LINES. The au- thors' institutional database was reviewed from 2008 to 2015, and they found 3 patients with LINES. Subsequent management and outcomes data are discussed. Patients had a variety of outcomes ranging from local wound care to necrosis and amputation of pha- langes. Patients with LINES can have a wide variety of outcomes; thus, this syndrome must be aggressively managed. Psychotherapy should also be utilized to help patients with further cocaine use. Levamisole-induced necrosis syndrome incidence is expected to in- crease, and all providers should be aware of this patient population. PMID- 28355140 TI - Pretibial Myxedema Masquerading as a Venous Leg Ulcer. AB - The authors report a case of pretibial myxedema (PTM) masquerading as a venous leg ulcer to alert wound care clinicians to this diagnostic possibility. Pretibial myxedema is a localized form of mucin cutaneous deposition characterized by indurated plaques most commonly on anterior legs. It is more likely to present in patients with Graves' disease, but it can be found in euthyroid patients as well. The physiopathology of PTM is complex, and there is an accumulation of highly hydrophilic glycosaminoglycans in the dermis. Minimal morbidity is associated with PTM, but the pruritus related to mucin deposition can be intense. The skin around venous leg ulcers and the skin changes related to PTM can have a similar clinical presentation, which may be a reason PTM is under recognized. PMID- 28355143 TI - An Experience of an Individual With a Chronic Wound in an Open Abdomen: A Grounded Theory. AB - : The open abdomen (OA) surgical technique has become an option for treating complex abdominal injuries; however, complications leading to late closure conditions might arise. In these cases the wound must be left open, which greatly impacts the patient's life. OBJECTIVE: The author aims to describe the experiences of individuals with a chronic OA wound. METHODS: Qualitative design using grounded theory was utilized. This study was carried out with a group of 28 adults who were treated with OA technique and whose wound had remained open for more than a month in duration and only received outpatient wound care. Data were collected through open interviews and examined under continuous comparison. The average age of the respondents was 45 years, and their wound, treated with OA due to severe abdominal infection, remained open between 2 months and 8 years. RESULTS: An emergent theory was developed to describe how people facing this experience undergo a process of 4 stages: 1) finding an OA wound upon waking, 2) feeling desperate about the healing process and the limitations involved, 3) regaining control of their life, and 4) taking advantage of their second chance at life with an OA wound. CONCLUSION: This study provides insight for nurses and other health care professionals into the experiences of patients with a chronic OA wound and proposes an emerging theory based on the conceptualization of these experiences. PMID- 28355142 TI - Effects of Adrenomedullin and Glucagon-like Peptide on Distal Flap Necrosis and Vascularity: The Role of Receptor Systems and Nitric Oxide. AB - OBJECTIVE: Flap necrosis in the distal area due to the deficiency of blood circulation is a major complication in flap treatment. In many previous studies, some natural substances such as chlorogenic acid, adrenomedullin (ADM), and glucagon-like peptide-1 (GLP-1) have been used to improve flap viability via their vasodilator, angiogenic, and antioxidant effects. The aim of this study is to clarify the mechanism through the use of selective antagonists for calcitonin gene-related peptide (CGRP) receptors and GLP-1 receptors such as CGRP-(8-37), exendin-(9-39), respectively, in the flap healing effects of ADM and GLP-1. The role of nitric oxide (NO) was investigated in the mechanism as well. MATERIALS AND METHODS: Seventy adult female Wistar rats (200 g-250 g) were used in the study. The cutaneous skin flap (8 cm x 3 cm) on the abdominal wall was raised based on the superficial inferior epigastric artery (SIEA). Single-dose substance injections were administered into the SIEA. Necrosis in the flap area was evaluated on postoperative day 7. The proportion of the necrosis area (necrosis area % = [necrosis area/flap area] x 100) and vascularity (vascular number/cm2) in the distal area were calculated. RESULTS: The administrations of ADM or GLP-1 increased the vascularity and decreased the necrosis area in the distal flap region. The ADM receptor antagonist, CGRP-(8-37), did not prevent the positive effects of ADM on flap healing and vascularity. A GLP-1 receptor antagonist, exendin-(9-39), prevented the effect of GLP-1 on flap healing and vascularity. Nitric oxide mediated the beneficial effects of both peptides on flap healing. CONCLUSION: The CGRP receptors have no direct role, but NO acts as a mediator in the beneficial effect of ADM on flap healing. The GLP-1 specific receptors and NO act as important interagents for the effects of GLP-1 on flap healing. PMID- 28355144 TI - The Effect of Negative Pressure Wound Therapy With Antiseptic Instillation on Biofilm Formation in a Porcine Model of Infected Spinal Instrumentation. AB - OBJECTIVE: This study evaluates the effect of negative pressure wound therapy with antiseptic instillation (NPWTi) in the clearance of infection and biofilm formation in an in vivo model of infected spinal implants compared to traditional treatment modalities. MATERIALS AND METHODS: Five pigs underwent titanium rod implantation of their spinous processes followed by injection of 1 x 106 CFUs/100MUL of methicillin-resistant Staphylococcus aureus through the fascia at each site. At 1 week postoperatively, an experimental arm of 3 pigs received NPWTi, and a control arm of 2 pigs received wet-to-dry dressings. The persistence of local infection in the experimental group was compared to the control group using tissue cultures. Biofilm development on spinal implants was evaluated using scanning electron microscopy. RESULTS: Mean bacterial count showed a statistical difference between the experimental and the control groups (P < .05). Scanning electron microscopy revealed the presence of uniform biofilm formation across the surface of control group instrumentation, whereas the experimental group showed interrupted areas between biofilm formations. CONCLUSION: The authors concluded that NPWTi is associated with decreased bacterial load and biofilm formation compared to wet-to-dry dressings in an in vivo porcine model of infected spinal instrumentation. PMID- 28355145 TI - Histopathological and biochemical assessments of Costus afer stem on alloxan induced diabetic rats. AB - BACKGROUND: In continuation of our study of the biological activity of the aqueous extract of Costus afer stem used in tradomedicare in Nigeria, this work has investigated the biochemical, nephroprotective, hepatoprotective and protective effects of aqueous extract of C. afer stem on alloxan-induced hyperglycaemic albino Wistar rats. METHODS: Thirty male albino Wistar rats (150 200 g) were weight-matched into six groups of five rats each. Groups 1 and 2 were the normal (non-induced) and toxic (alloxan-induced) controls, respectively. Groups 3-6 were induced and treated with 1, 2 and 3 g/kg of the aqueous extract of C. afer stem and glibenclamide (5 mg/kg), respectively. Food and fluid intake, body weight, absolute and relative weight of organs (liver, pancreas, and kidneys) and biochemical parameters were measured. RESULTS: There was a significant reduction in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin triglyceride, creatinine, urea and electrolyte when compared with toxic control group. The liver marker enzymes were restored in all the treated groups. The aqueous stem extract possessed hypoglycaemic effect and reversed the histopathological damage in alloxan-induced diabetic rats. CONCLUSIONS: This study suggests that aqueous stem extract of C. afer possesses both hypoglycaemic and organ protective properties. PMID- 28355146 TI - IB2d: a Python and MATLAB implementation of the immersed boundary method. AB - The development of fluid-structure interaction (FSI) software involves trade-offs between ease of use, generality, performance, and cost. Typically there are large learning curves when using low-level software to model the interaction of an elastic structure immersed in a uniform density fluid. Many existing codes are not publicly available, and the commercial software that exists usually requires expensive licenses and may not be as robust or allow the necessary flexibility that in house codes can provide. We present an open source immersed boundary software package, IB2d, with full implementations in both MATLAB and Python, that is capable of running a vast range of biomechanics models and is accessible to scientists who have experience in high-level programming environments. IB2d contains multiple options for constructing material properties of the fiber structure, as well as the advection-diffusion of a chemical gradient, muscle mechanics models, and artificial forcing to drive boundaries with a preferred motion. PMID- 28355147 TI - GLIMPSE: Google Glass interface for sensory feedback in myoelectric hand prostheses. AB - OBJECTIVE: Providing sensory feedback to the user of the prosthesis is an important challenge. The common approach is to use tactile stimulation, which is easy to implement but requires training and has limited information bandwidth. In this study, we propose an alternative approach based on augmented reality. APPROACH: We have developed the GLIMPSE, a Google Glass application which connects to the prosthesis via a Bluetooth interface and renders the prosthesis states (EMG signals, aperture, force and contact) using augmented reality (see through display) and sound (bone conduction transducer). The interface was tested in healthy subjects that used the prosthesis with (FB group) and without (NFB group) feedback during a modified clothespins test that allowed us to vary the difficulty of the task. The outcome measures were the number of unsuccessful trials, the time to accomplish the task, and the subjective ratings of the relevance of the feedback. MAIN RESULTS: There was no difference in performance between FB and NFB groups in the case of a simple task (basic, same-color clothespins test), but the feedback significantly improved the performance in a more complex task (pins of different resistances). Importantly, the GLIMPSE feedback did not increase the time to accomplish the task. Therefore, the supplemental feedback might be useful in the tasks which are more demanding, and thereby less likely to benefit from learning and feedforward control. The subjects integrated the supplemental feedback with the intrinsic sources (vision and muscle proprioception), developing their own idiosyncratic strategies to accomplish the task. SIGNIFICANCE: The present study demonstrates a novel self contained, ready-to-deploy, wearable feedback interface. The interface was successfully tested and was proven to be feasible and functionally beneficial. The GLIMPSE can be used as a practical solution but also as a general and flexible instrument to investigate closed-loop prosthesis control. PMID- 28355148 TI - The unusual solvatochromism and solvatofluorochromism of longwave absorbing and emitting barbiturate merocyanine dyes. AB - Spectral-fluorescent properties of a series of merocyanine dyes comprising the barbituric acid residue as the electron-accepting terminal group are investigated in comparison with those of their N,N-methylated analogues in media of various polarity. It is revealed that in polar aprotic solvents the electronic absorption spectra of the studied compounds are influenced dramatically by the formation of hydrogen bonds between the NH-groups of barbituric residue and solvent molecules. An effect of such nucleophilic solvation on the electronic structure of the studied dyes is analysed using both the spectral data obtained and the DFT/B3LYP quantum chemical simulation. It is found also, that solvation has comparatively weak influence on the shape and position of the fluorescence bands of the studied merocyanines while the fluorescence quantum yield changes substantially in solvents of various polarity. PMID- 28355149 TI - Fluorescence of aminofluoresceins as an indicative process allowing one to distinguish between micelles of cationic surfactants and micelle-like aggregates. AB - Among the vast set of fluorescein derivatives, the double charged R2- anions of aminofluoresceins are known to exhibit only low quantum yields of fluorescence, [Formula: see text]. The [Formula: see text] value becomes as high as that of the fluorescein dianion when the lone electron pair of the amino group is involved in a covalent bond. According to Munkholm et al (1990 J. Am. Chem. Soc. 112 2608 12), a much smaller increase in the emission intensity can be observed in the presence of surfactant micelles. However, all these observations refer to aqueous or alcoholic solvents. In this paper, we show that in the non-hydrogen bond donor (or 'aprotic') solvents DMSO and acetone, the quantum yields, phi, of the 4'- (or 5')-aminofluorescein R2- species amount to 61-67% and approach that of fluorescein (phi = 87%), whereas in water phi is only 0.6-0.8%. In glycerol, a solvent with an extremely high viscosity, the phi value is only 6-10%. We report on the enhancement of the fluorescence of the aminofluorescein dianions as an indicative process, which allows us to distinguish between the micelle-like aggregates of cationic dendrimers of low generation, common spherical surfactant micelles, and surfactant bilayers. Some of these colloidal aggregates partly restore the fluorescence of aminofluoresceins in aqueous media. By contrast, other positively charged micellar-like aggregates do not enhance the quantum yield of aminofluorescein R2- species. Results for several related systems, such as CTAB-coated SiO2 particles and reverse microemulsions, are briefly described, and the possible reasons for the observed phenomena are discussed. PMID- 28355150 TI - Spatiotemporal mapping of diffusion dynamics and organization in plasma membranes. AB - Imaging fluorescence correlation spectroscopy (FCS) and the related FCS diffusion law have been applied in recent years to investigate the diffusion modes of lipids and proteins in membranes. These efforts have provided new insights into the membrane structure below the optical diffraction limit, new information on the existence of lipid domains, and on the influence of the cytoskeleton on membrane dynamics. However, there has been no systematic study to evaluate how domain size, domain density, and the probe partition coefficient affect the resulting imaging FCS diffusion law parameters. Here, we characterize the effects of these factors on the FCS diffusion law through simulations and experiments on lipid bilayers and live cells. By segmenting images into smaller 7 * 7 pixel areas, we can evaluate the FCS diffusion law on areas smaller than 2 um and thus provide detailed maps of information on the membrane structure and heterogeneity at this length scale. We support and extend this analysis by deriving a mathematical expression to calculate the mean squared displacement (MSDACF) from the autocorrelation function of imaging FCS, and demonstrate that the MSDACF plots depend on the existence of nanoscopic domains. Based on the results, we derive limits for the detection of domains depending on their size, density, and relative viscosity in comparison to the surroundings. Finally, we apply these measurements to bilayers and live cells using imaging total internal reflection FCS and single plane illumination microscopy FCS. PMID- 28355151 TI - Interaction of a tricationic meso-substituted porphyrin with guanine-containing polyribonucleotides of various structures. AB - The interaction of a tricationic water-soluble meso-(N-methylpyridinium) substituted porphyrin, TMPyP3+, derived from classic TMPyP4, with double-stranded poly(G) ? poly(C) and four-stranded poly(G) polyribonucleotides has been studied in aqueous buffered solutions, pH 6.9, of low and near-physiological ionic strengths in a wide range of molar phosphate-to-dye ratios (P/D). To clarify the binding modes of TMPyP3+ to biopolymers various spectroscopic techniques, including absorption and polarized fluorescence spectroscopy, Raman spectroscopy, and resonance light scattering, were used. As a result, two competitive binding modes were revealed. In solution of low ionic strength outside binding of the porphyrin to the polynucleotide backbone with self stacking prevailed at low P/D ratios (P/D < 3.5). It manifested itself by the substantial quenching of porphyrin fluorescence. Also the formation of large scale porphyrin aggregates was observed near the stoichiometric binding ratio. The spectral changes observed at P/D > 30 including emission enhancement were supposed to be caused by the embedding of partially stacked porphyrin J-dimers into the polymer groove. TMPyP3+ binding to poly(G) induced a fluorescence increase 2.5 times as large as that observed for poly(G) ? poly(C). In solution of near-physiological ionic strength the efficiency of external porphyrin binding was reduced substantially due to the competitive binding of Na+ ions with the polymer backbone. The spectroscopic characteristics of porphyrin bound to polynucleotides at different conditions were compared with those for free porphyrin. PMID- 28355152 TI - Fluorescence of carbonyl-containing intraionic polymethines. AB - Electronic structure and spectral-fluorescent properties of four related indole based intraionic polymethines are discussed. They all comprise at least one carbonyl group in the acceptor part of their molecule but the effects of the carbonyls upon their UV/Vis and fluorescence spectra depend substantially on its position within the polymethine chromophore. At that, solvation of the carbonyls with highly electrophilic protic solvents can, as a function of dye structure, cause both a rise and decrease of fluorescence quantum yield of a dye or have no tangible effect at all. To get insight into the regularities of such behaviour, the dyes were examined closely using both their absorption and fluorescence spectral data and the (TD) DFT quantum chemical simulation. PMID- 28355153 TI - Novel benzanthrone probes for membrane and protein studies. AB - The applicability of a series of novel benzanthrone dyes to monitoring the changes in physicochemical properties of lipid bilayer and to differentiating between the native and aggregated protein states has been evaluated. Based on the quantitative parameters of the dye-membrane and dye-protein binding derived from the fluorimetric titration data, the most prospective membrane probes and amyloid tracers have been selected from the group of examined compounds. Analysis of the red edge excitation shifts of the membrane- and amyloid-bound dyes provided information on the properties of benzanthrone binding sites within the lipid and protein matrixes. To understand how amyloid specificity of benzanthrones correlates with their structure, quantitative structure activity relationship (QSAR) analysis was performed involving a range of quantum chemical molecular descriptors. A statistically significant model was obtained for predicting the sensitivity of novel benzanthrone dyes to amyloid fibrils. PMID- 28355155 TI - Dispersed dynamics of solvation in G-quadruplex DNA: comparison of dynamic Stokes shifts of probes in parallel and antiparallel quadruplex structures. AB - G-quadruplex DNA (GqDNA) structures play an important role in many specific cellular functions and are promising anti-tumor targets for small molecules (ligands). Here, we measured the dynamic Stokes shift of a ligand (Hoechst) bound to parallel c-Myc (mPu22) GqDNA over five decades of time from 100 fs to 10 ns, and compared it with the previously reported dynamics of DAPI bound to antiparallel human telomeric (hTelo22) GqDNA (Pal et al 2015 J. Phys. Chem. Lett. 6 1754). Stokes shift data from fluorescence up-conversion and time-correlated single photon counting experiments was combined to cover the broad dynamic range. The results show that the solvation dynamics of Hoechst in parallel mPu22 GqDNA follow a power law relaxation, added to fast 2 ps exponential relaxation, from 100 fs to 10 ns, with only a subtle difference of power law exponents in the two ligand-GqDNA systems (0.06 in Hoechst-mPu22 compared to 0.16 in DAPI-hTelo22). We measured steady-state fluorescence spectra and time-resolved anisotropy decays which confirm the tight binding of Hoechst to parallel mPu22 with a binding constant of ~1 * 105 M-1. The molecular docking of Hoechst in parallel GqDNA followed by a 50 ns molecular dynamics (MD) simulation on a Hoechst-GqDNA complex reveals that Hoechst binds to one of the outer G-tetrads by end-stacking near G13 and G4, which is different from the binding site of DAPI inside a groove of antiparallel hTelo22 GqDNA. Reconciling previous experimental and simulation results, we assign the 2 ps component to the hydration dynamics of only weakly perturbed water near mPu22 and the power law relaxation to the coupled motion of water and DNA (i.e. DNA backbone, unpaired bases and loops connecting G-tetrads) which come near the Hoechst inside parallel GqDNA. PMID- 28355154 TI - Fluorescence monitoring of the effect of oxidized lipids on the process of protein fibrillization. AB - The kinetics of lysozyme and insulin amyloid formation in the presence of the oxidized phospholipids (oxPLs) was investigated using Thioflavin T fluorescence assay. The kinetic parameters of fibrillization process (lag time and apparent rate constant) have been determined upon varying the following experimental parameters: the type of lipid assemblies (premicellar aggregates and lipid bilayer vesicles), pH, temperature and lipid-to-protein molar ratio. It was found that oxPLs premicellar aggregates induced the more pronounced increase of the maximum Thioflavin T fluorescence, which is proportional to the extent of fibril formation, compared to the vesicles composed of the oxidized and unoxidized lipids. In contrast, the oxPLs, used as dispersions or included into vesicles, inhibited fibril nucleation and elongation under near-physiological conditions in vitro compared to liposomes containing unoxidized lipids. The results obtained provide deeper insight into the molecular mechanisms of the oxidative stress modulated conformational diseases, and could be employed for the anti-amyloid drug development. PMID- 28355156 TI - Combined thioflavin T-Congo red fluorescence assay for amyloid fibril detection. AB - Fluorescence represents one of the most powerful tools for the detection and structural characterization of the pathogenic protein aggregates, amyloid fibrils. The traditional approaches to the identification and quantification of amyloid fibrils are based on monitoring the fluorescence changes of the benzothiazole dye thioflavin T (ThT) and absorbance changes of the azo dye Congo red (CR). In routine screening it is usually sufficient to perform only the ThT and CR assays, but both of them, when used separately, could give false results. Moreover, fibrillization kinetics can be measured only by ThT fluorescence, while the characteristic absorption spectra and birefringence of CR represent more rigid criteria for the presence of amyloid fibrils. Therefore, it seemed reasonable to use both these dyes simultaneously, combining the advantages of each technique. To this end, we undertook a detailed analysis of the fluorescence spectral behavior of these unique amyloid tracers upon their binding to amyloid fibrils from lysozyme, insulin and an N-terminal fragment of apolipoprotein A-I with Iowa mutation. The fluorescence measurements revealed several criteria for distinguishing between fibrillar and monomeric protein states: (i) a common drastic increase in ThT fluorescence intensity; (ii) a sharp decrease in ThT fluorescence upon addition of CR; (iii) an appearance of the maximum at 535-540 nm in the CR excitation spectra; (iv) increase in CR fluorescence intensity at 610 nm. Based on these findings we designed a novel combined ThT-CR fluorescence assay for amyloid identification. Such an approach not only strengthens the reliability of the ThT assay, but also provides new opportunities for structural characterization of amyloid fibrils. PMID- 28355157 TI - Luminescence study of nanosized Al2O3:Tb3+ obtained by gas-dispersed synthesis. AB - Terbium-doped Al2O3 samples were obtained by gas-dispersed synthesis. It was shown that the resulting powders, with particle sizes of 10-70 nm, consist of a mixture of transition aluminas, among which the delta *-polymorph is dominant. The luminescence properties of Al2O3:Tb3+ have been studied upon excitation in the UV-visible range of the spectrum. It was found that Tb3+ ions cause several groups of inhomogeneously broadened emission bands in the range of 470-640 nm, which are characteristic for disordered materials. In addition, the emission spectra contain a broad band at about 450 nm and several narrower ones in the 680 720 nm region. These features are attributed to surface defects and impurity Cr3+ ions occupying Al3+ octahedral positions, respectively. PMID- 28355158 TI - Study on the interaction of 6-(2-morpholin-4-yl-ethyl)-6H-indolo [2,3 b]quinoxaline hydrochloride with human serum albumin by fluorescence spectroscopy. AB - Under physiological conditions, in vitro interaction between the bio-active substance 6-(2-morpholin-4-yl-ethyl)-6H-indolo[2,3-b]quinoxaline hydrochloride (MIQ) and human serum albumin (HSA) was investigated at an excitation wavelength 260 nm and at different temperatures (298 K, 308 K and 313 K) by fluorescence emission spectroscopy. From spectral analysis, MIQ showed a strong ability to quench the intrinsic fluorescence of HSA through a static quenching procedure. The binding constant is estimated asK A = 2.55 * 10-4 l . mol-1 at 298 K. Based on the thermodynamic parameters evaluated from the van 't Hoff equation, the enthalpy change (DeltaH degrees ) and entropy change (DeltaS degrees ) were derived to be negative values. A value of 2.37 nm for the average distance r between MIQ (acceptor) and tryptophan residues of HSA (donor) was derived from the fluorescence resonance energy transfer. UV/vis absorption spectra were used to confirm the quenching mechanism. PMID- 28355159 TI - Fluorescent probes sensitive to changes in the cholesterol-to-phospholipids molar ratio in human platelet membranes during atherosclerosis. AB - Environment-sensitive fluorescent probes were used for the spectroscopic visualization of pathological changes in human platelet membranes during cerebral atherosclerosis. It has been estimated that the ratiometric probes 2-(2' hydroxyphenyl)-5-phenyl-1,3,4-oxadiazole and 2-phenyl-phenanthr[9,10]oxazole can detect changes in the cholesterol-to-phospholipids molar ratio in human platelet membranes during the disease. PMID- 28355160 TI - Probing protein-lipid interactions by FRET between membrane fluorophores. AB - Forster resonance energy transfer (FRET) is a powerful fluorescence technique that has found numerous applications in medicine and biology. One area where FRET proved to be especially informative involves the intermolecular interactions in biological membranes. The present study was focused on developing and verifying a Monte-Carlo approach to analyzing the results of FRET between the membrane-bound fluorophores. This approach was employed to quantify FRET from benzanthrone dye ABM to squaraine dye SQ-1 in the model protein-lipid system containing a polycationic globular protein lysozyme and negatively charged lipid vesicles composed of phosphatidylcholine and phosphatidylglycerol. It was found that acceptor redistribution between the lipid bilayer and protein binding sites resulted in the decrease of FRET efficiency. Quantification of this effect in terms of the proposed methodology yielded both structural and binding parameters of lysozyme-lipid complexes. PMID- 28355161 TI - Sensitive detection of PDT-induced cell damages with luminescent oxygen nanosensors. AB - In this work luminescent nanosensors specifically created for intracellular oxygen (ic-O2) were utilized to assess photodynamic therapy (PDT) -induced cell damages. Firstly, ic-O2 was demonstrated to be consumed much faster than extracellular O2 with respective O2 nanosensors. Using the ic-O2 nanosensors, PDT treated cells with different degree of impairment were then resolved according to the oxygen consumption rate (OCR). The evolving trend of cytotoxicity derived from OCRs was in agreement with cell viability obtained from 3-(4,5 cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Moreover, the direct damage of PDT on cell mitochondria was successfully detected by monitoring respiration instantly after PDT treatment, which is actually beyond the scope of MTT assay. These results suggest that fluorescence sensing of ic-O2-associated cell respiration is promising and even may become a standardized method, complementary to MTT assay, to evaluate PDT-induced cytotoxicity. PMID- 28355162 TI - GFP as potential cellular viscosimeter. AB - The molecular dimensions of proteins such as green fluorescent protein (GFP) are large as compared to the ones of solvents like water or glycerol. The microscopic viscosity, which determines the resistance to diffusion of, e.g. GFP, is then the same as that determined from the resistance of the solvent to flow, which is known as macroscopic viscosity. GFP in water/glycerol mixtures senses this macroscopic viscosity, because the translational and rotational diffusion coefficients are proportional to the reciprocal value of the viscosity as predicted by the Stokes-Einstein equations. To test this hypothesis, we have performed time-resolved fluorescence anisotropy (reporting on rotational diffusion) and fluorescence correlation spectroscopy (reporting on translational diffusion) experiments of GFP in water/glycerol mixtures. When the solvent also contains macromolecules of similar or larger dimensions as GFP, the microscopic and macroscopic viscosities can be markedly different and the Stokes-Einstein relations must be adapted. It was established from previous dynamic fluorescence spectroscopy observations of diffusing proteins with dextran polysaccharides as co-solvents (Lavalette et al 2006 Eur. Biophys. J. 35 517-22), that rotation and translation sense a different microscopic viscosity, in which the one arising from rotation is always less than that from translation. A microscopic viscosity parameter is defined that depends on scaling factors between GFP and its immediate environment. The direct consequence is discussed for two reported diffusion coefficients of GFP in living cells. PMID- 28355163 TI - Self-assisted optothermal trapping of gold nanorods under two-photon excitation. AB - We report a self-assisted optothermal trapping and patterning of gold nanorods (GNRs) on glass surfaces with a femtosecond laser. We show that GNRs are not only the trapping targets, but also can enhance the optothermal trapping of other particles. This trapping phenomenon is the net result of thermophoresis and a convective flow caused by localized heating. The heating is due to the conversion of absorbed photons into heat at GNR's longitudinal surface plasmon resonance (LSPR) wavelength. First, we investigated the optothermal trapping of GNRs at their LSPR wavelength on the glass surface with as low as 0.5 mW laser power. The trapping range was observed to be larger than a typical field of view, e.g. 210 um * 210 um here. Second, by adjusting the distance between the laser focus and the glass surface, ring patterns of GNRs on the glass surface were obtained. These patterns could be controlled by the laser power and the numerical aperture of the microscope objective. Moreover, we examined the spectral emission of GNRs under different trapping conditions using the spectral phasor approach to reveal the temperature and association status of GNRs. Our study will help understanding manipulation of flows in solution and in biological systems that can be applied in future investigations of GNR-induced heating and flows. PMID- 28355164 TI - Bose-Einstein condensation and indirect excitons: a review. AB - We review recent progress on Bose-Einstein condensation (BEC) of semiconductor excitons. The first part deals with theory, the second part with experiments. This Review is written at a time where the problem of exciton Bose-Einstein condensation has just been revived by the understanding that the exciton condensate must be dark because the exciton ground state is not coupled to light. Here, we theoretically discuss this missed understanding before providing its experimental support through experiments that scrutinize indirect excitons made of spatially separated electrons and holes. The theoretical part first discusses condensation of elementary bosons. In particular, the necessary inhibition of condensate fragmentation by exchange interaction is stressed, before extending the discussion to interacting bosons with spin degrees of freedom. The theoretical part then considers composite bosons made of two fermions like semiconductor excitons. The spin structure of the excitons is detailed, with emphasis on the crucial fact that ground-state excitons are dark: indeed, this imposes the exciton Bose-Einstein condensate to be not coupled to light in the dilute regime. Condensate fragmentations are then reconsidered. In particular, it is shown that while at low density, the exciton condensate is fully dark, it acquires a bright component, coherent with the dark one, beyond a density threshold: in this regime, the exciton condensate is 'gray'. The experimental part first discusses optical creation of indirect excitons in quantum wells, and the detection of their photoluminescence. Exciton thermalisation is also addressed, as well as available approaches to estimate the exciton density. We then switch to specific experiments where indirect excitons form a macroscopic fragmented ring. We show that such ring provides efficient electrostatic trapping in the region of the fragments where an essentially-dark exciton Bose-Einstein condensate is formed at sub-Kelvin bath temperatures. The macroscopic spatial coherence of the photoluminescence observed in this essentially dark region confirms this conclusion. PMID- 28355165 TI - Environment-sensitive quinolone demonstrating long-lived fluorescence and unusually slow excited-state intramolecular proton transfer kinetics. AB - A new small fluorescent dye based on 3-hydroxybenzo[g]quinolone, a benzo-analogue of Pseudomonas quinolone signal species, has been synthesized. The dye demonstrates interesting optical properties, with absorption in the visible region, two band emission due to an excited-state intramolecular proton transfer (ESIPT) reaction and high fluorescence quantum yield in both protic and aprotic media. Time-resolved fluorescence spectroscopy shows that the ESIPT reaction time is unusually long (up to 8 ns), indicating that both forward and backward ESIPT reactions are very slow in comparison to other 3-hydroxyquinolones. In spite of these slow rate constants, the ESIPT reaction was found to show a reversible character as a result of the very long lifetimes of both N* and T* forms (up to 16 ns). The ESIPT reaction rate is mainly controlled by the hydrogen bond donor ability in protic solvents and the polarity in aprotic solvents. Using large unilamellar vesicles and giant unilamellar vesicles of different lipid compositions, the probe was shown to preferentially label liquid disordered phases. PMID- 28355166 TI - Synchronisation through learning for two self-propelled swimmers. AB - The coordinated motion by multiple swimmers is a fundamental component in fish schooling. The flow field induced by the motion of each self-propelled swimmer implies non-linear hydrodynamic interactions among the members of a group. How do swimmers compensate for such hydrodynamic interactions in coordinated patterns? We provide an answer to this riddle though simulations of two, self-propelled, fish-like bodies that employ a learning algorithm to synchronise their swimming patterns. We distinguish between learned motion patterns and the commonly used a priori specified movements, that are imposed on the swimmers without feedback from their hydrodynamic interactions. First, we demonstrate that two rigid bodies executing pre-specified motions, with an alternating leader and follower, can result in substantial drag-reduction and intermittent thrust generation. In turn, we study two self-propelled swimmers arranged in a leader-follower configuration, with a-priori specified body-deformations. These two self-propelled swimmers do not sustain their tandem configuration. The follower experiences either an increase or decrease in swimming speed, depending on the initial conditions, while the swimming of the leader remains largely unaffected. This indicates that a-priori specified patterns are not sufficient to sustain synchronised swimming. We then examine a tandem of swimmers where the leader has a steady gait and the follower learns to synchronize its motion, to overcome the forces induced by the leader's vortex wake. The follower employs reinforcement learning to adapt its swimming-kinematics so as to minimize its lateral deviations from the leader's path. Swimming in such a sustained synchronised tandem yields up to [Formula: see text] reduction in energy expenditure for the follower, in addition to a [Formula: see text] increase in its swimming-efficiency. The present results show that two self-propelled swimmers can be synchronised by adapting their motion patterns to compensate for flow-structure interactions. Moreover, swimmers can exploit the vortical structures of their flow field so that synchronised swimming is energetically beneficial. PMID- 28355167 TI - Microvascular structure as a prognostically relevant endpoint. AB - Remodelling of subcutaneous small resistance arteries, as indicated by an increased media-to-lumen ratio, is frequently present in hypertensive, obese, or diabetic patients. The increased media-to-lumen ratio may impair organ flow reserve. This may be important in the maintenance and, probably, also in the progressive worsening of hypertensive disease. The presence of structural alterations represents a prognostically relevant factor, in terms of development of target organ damage or cardiovascular events, thus allowing us a prediction of complications in hypertension. In fact, media-to-lumen ratio of small arteries at baseline, and possibly their changes during treatment may have a strong prognostic significance. However, new, non-invasive techniques are needed before suggesting extensive application of the evaluation of remodelling of small arteries for the cardiovascular risk stratification in hypertensive patients. Some new techniques for the evaluation of microvascular morphology in the retina, currently under clinical investigation, seem to represent a promising and interesting future perspective. The evaluation of microvascular structure is progressively moving from bench to bedside, and it could represent, in the near future, an evaluation to be performed in all hypertensive patients, to obtain a better stratification of cardiovascular risk, and, possibly, it might be considered as an intermediate endpoint in the evaluation of the effects of antihypertensive therapy, provided that a demonstration of a prognostic value of non-invasive measures of microvascular structure is made available. PMID- 28355168 TI - Associations of plasma uric acid and purine metabolites with blood pressure in children: the KOALA Birth Cohort Study. AB - OBJECTIVE: Elevated serum uric acid concentration has been associated with high blood pressure (BP) and hypertension. A putative underlying mechanism is the accumulation of reactive oxygen species when uric acid is generated by an increased enzyme activity of xanthine oxidase (XO). The aims of the present study were to investigate the associations between plasma uric acid concentration, purine metabolite ratios, as proxies for increased XO activity, and SBP and DBP in school-age children. METHODS: Cross-sectional analyses were performed in 246 children (46% boys; mean age 7.1 years) from the Dutch KOALA Birth Cohort Study. Purine metabolites were determined with ultra-performance liquid chromatography tandem mass spectrometry. During a home visit, a nurse collected a blood sample and measured BP three times; in addition, parents measured their child's BP on three consecutive days, in the morning and evening. Generalized estimating equations were used for analyses while controlling for variables such as sex, age, BMI, physical activity, and dietary intake. RESULTS: In multivariable analysis, uric acid (per SD of 38 MUmol/l) was associated with DBP z-scores [sbeta 0.07; confidence interval (CI), 0.01-1.14], but not with SBP z-scores. Higher ratios of uric acid/xanthine (per SD of 138) (sbeta 0.09; CI, 0.01-0.17) and xanthine/hypoxanthine (per SD of 321) (sbeta 0.08; CI, 0.02-0.17) were associated with higher DBP z-scores, but not with SBP z-scores. CONCLUSION: In school-age children, uric acid and the ratios of uric acid/xanthine and xanthine/hypoxanthine were significantly associated with DBP z-scores. Suggesting that, both uric acid concentration and increased XO activity are associated with BP. PMID- 28355169 TI - The systolic-diastolic difference in carotid stiffness is increased in type 2 diabetes: The Maastricht Study. AB - OBJECTIVE: In type 2 diabetes (T2D), increased arterial stiffening results from accelerated arterial wall matrix remodeling. The associated structural alterations modify the pressure dependency of arterial stiffness, which can be quantified by the systolic-diastolic difference in carotid pulse wave velocity (deltaPWV). We evaluated the association between T2D and deltaPWV as marker for matrix remodeling and whether deltaPWV may contain additional information beyond carotid stiffness (cPWV). METHODS: In 746 individuals from The Maastricht Study, 415 with normal glucose metabolism; 126 with prediabetes; and 205 with T2D, carotid pulse wave velocity (cPWV) and deltaPWV were determined by ultrasonography and tonometry. Multiple linear regression analyses were used to investigate associations of glucose metabolism status (with normal glucose metabolism as reference) with cPWV and deltaPWV, adjusting for age, sex, mean arterial pressure, prior cardiovascular disease, estimated glomerular filtration rate and smoking, and deltaPWV or cPWV as appropriate. RESULTS: After adjustment for age, sex, mean arterial pressure, prior cardiovascular disease, estimated glomerular filtration rate and smoking, T2D was associated with greater cPWV [beta (95% confidence interval) 0.376 (0.119; 0.632)] and deltaPWV [0.301 (0.013; 0.589)]. After additional adjustment for deltaPWV or cPWV, associations of T2D with cPWV and deltaPWV were attenuated [0.294 (0.048; 0.539) and 0.173 (-0.103; 0.449), respectively]. Prediabetes was not associated with either cPWV or deltaPWV. CONCLUSION: The systolic-diastolic difference in carotid stiffness is increased in T2D, but not prediabetes. Importantly, the association was not abolished by carotid stiffness, which suggests that systolic-diastolic difference in carotid stiffness carries additional information regarding arterial matrix remodeling. PMID- 28355170 TI - Comparing Practice Patterns Between Pediatric and General Emergency Medicine Physicians: A Scoping Review. AB - OBJECTIVE: Acutely ill infants and children presenting to the emergency department are treated by either physicians with pediatric emergency medicine (PEM) training or physicians without PEM training, a good proportion of which are general emergency medicine-trained physicians (GEDPs). This scoping review identified published literature comparing the care provided to infants and children (<=21 years of age) by PEM-trained physicians to that provided by GEDPs. METHODS: The search was conducted in 2 main steps as follows: (1) initial literature search to identify available literature with evolving feedback from the group while simultaneously deciding search concepts as well as inclusion and exclusion criteria and (2) modification of search concepts and conduction of search using finalized concepts as well as review and selection of articles for final analysis using set inclusion criteria. Each study was independently assessed by 2 reviewers for eligibility and quality. Data were independently abstracted by reviewers, and authors were contacted for missing data. RESULTS: Our search yielded 3137 titles and abstracts. Twenty articles reporting 19 studies were included in the final analysis. The studies were grouped under type of care, diagnostic studies, medication administration, and process of care. The studies addressed differences in the management of fever, croup, bronchiolitis, asthma, urticaria, febrile seizures, and diabetic ketoacidosis. CONCLUSIONS: This review highlights the lack of robust studies and heterogeneity of literature comparing practice patterns of PEM-trained physicians with GEDPs. We have outlined a systematic approach to reviewing a body of literature for topics that lack clear terms of comparison across studies. PMID- 28355171 TI - Glaucoma Mini-Shunt Implantation After Keratoplasty. AB - PURPOSE: To report the outcomes of patients who underwent miniature glaucoma shunt implantation after secondary glaucoma due to keratoplasty. MATERIALS AND METHODS: Prospective study of consecutive clinical cases who underwent mini glaucoma shunt implantation following keratoplasty. In brief, a fornix-based conjunctival flap was performed, approximately 50% thickness scleral flap. Mitomycin C 0.025% placed under Tenon's capsule. A 25-G needle created entry for mini-shunt. Ex-PRESS model P-50 was inserted. Scleral flap and conjunctiva were closed with 10-0 Nylon. STATA 8.0 and SPSS software were used for statistical analysis. RESULTS: Seventeen eyes of 17 patients with a mean age of 39.70 years (SD=18.33, range: 18 to 76). A total of 64.70% were male and 35.30% female. Eleven cases after penetrating keratoplasty, 3 cases after triple procedure, 2 after deep anterior lamellar keratoplasty, and 1 following endothelial keratoplasty. Most of the indications for keratoplasty were keratoconus in 9 cases (52.94%), 4 due to endothelial failure (23.52%), 3 cases of herpetic keratitis (17.64%), and 1 case of post-LASIK ectasia (5.88%). Mean preoperative intraocular pressure was 35.94 mm Hg with maximal medical therapy (SD=9.65, range: 18 to 55). Decreasing intraocular pressure to 12.76 mm Hg postoperatively (SD=2.51, range 10 to 18) (P=0.001). Mean follow-up after mini-glaucoma shunt implantation was 23.76 months (SD=8.73, range: 10 to 35 mo). Preoperative mean uncorrected distance visual acuity (UDVA) was 1.31+/-0.63 (20/408 Snellen) and postoperative mean UDVA was 0.85+/-0.40 (20/141 Snellen) (P=0.001). Preoperative mean corrected distance visual acuity (CDVA) was 0.83+/-0.76 (20/135 Snellen) and postoperative mean CDVA was 0.56+/-0.44 (20/72 Snellen) (P=0.032). CONCLUSIONS: Ex-PRESS miniature glaucoma shunt could be an alternative treatment in postkeratoplasty glaucoma resistant to medical treatment. This technique may be helpful, in trying to avoid corneal damage produced by conventional glaucoma procedures. PMID- 28355172 TI - Eyepass Glaucoma Implant in Open-Angle Glaucoma After Failed Conventional Medical Therapy: Clinical Results of a 5-Year-Follow-up. AB - PURPOSE OF THE STUDY: The purpose of the study was to evaluate the long-term safety and intraocular pressure (IOP) lowering effect of the Eyepass glaucoma implant (GMP Vision Solutions, Inc.). PATIENTS AND METHODS: The prospective study included 15 patients (16 eyes) with primary open-angle glaucoma who underwent an implantation of the Y-shaped Eyepass glaucoma implant. This shunt diverts aqueous from the anterior chamber directly into Schlemm's canal to increase outflow and to lower the IOP. IOP, visual acuity, potential complications and the number of antiglaucomatous medications were monitored over a period of 5 years. RESULTS: The implant was successfully inserted in 14 of 16 eyes. Mean IOP was reduced from 26.4+/-8.1 mm Hg (SD) to 16.4+/-5.3 mm Hg (P=0.032) at the end of the follow-up. Mean number of antiglaucomatous medications dropped from 2.1+/-1.2 (SD) to 0.9+/ 1.2 (SD). In 5 cases, no pressure-lowering medications were necessary 5 years after surgery. Mean best-corrected visual acuity did not change significantly (P>0.05). In all cases, filtering blebs were observed and sustained using antimetabolites. The most common complication was temporary ocular hypotony. Two patients required a revision surgery due to implant malposition. CONCLUSIONS: The Eyepass glaucoma implant seems to be a safe and effective treatment option for patients with primary open-angle glaucoma. The use of this device resulted in a significant decrease of IOP. PMID- 28355173 TI - Glaucoma Diagnostic Capability of Circumpapillary Retinal Nerve Fiber Layer Thickness in Circle Scans With Different Diameters. AB - PURPOSE: To compare varying circumpapillary optical coherence tomographic (OCT) scan diameters for glaucoma diagnosis. MATERIALS AND METHODS: Prospective, cross sectional, observational study. Circumpapillary retinal nerve fiber layer thickness (RNFLT) was measured using spectral-domain OCT in 1 randomly selected eye. Scans with diameters of 3.5, 4.1, and 4.7 mm were obtained, each with 7 parameters: mean global (G) RNFLT and mean RNFLT for the temporal-inferior (TI), nasal-inferior (NI), temporal-superior (TS), nasal-superior (NS), nasal (N), and temporal (T) sectors. Areas under the receiver operating characteristic curve (AUCs) were calculated. RESULTS: Mean age was 55+/-18 years in 68 healthy eyes and 59+/-15 years in 95 glaucomatous eyes (P=0.12). Visual field mean deviation was -7.55+/-6.61 dB in glaucomatous eyes. In all 3 circle scans, mean TI RNFLT had the greatest AUC (0.974 to 0.983), followed by mean G RNFLT (0.949 to 0.956). The AUC of mean TI RNFLT in the 4.1-mm scan (0.983) was greater than the AUCs of mean TI RNFLTs in the 4.7- (0.978; P=0.128) and 3.5-mm (0.974; P=0.049) scans. The AUC of mean TI RNFLT in the 4.1-mm scan (0.983) was greater than the AUCs of mean G RNFLTs in the 3.5- (0.954; P=0.011), 4.1- (0.956; P=0.016), and 4.7-mm (0.949; P=0.011) scans. In 2 eyes with large parapapillary atrophy, RNFL segmentation error was noted only in the 3.5-mm scan in the area of parapapillary atrophy. CONCLUSIONS: Further investigations to find the spectral-domain OCT circle scan diameter with the best diagnostic capability and the least artifacts are warranted, especially focusing on larger-than-conventional circle scans. PMID- 28355174 TI - Nonmedical Out-of-Pocket Patient and Companion Expenditures Associated With Glaucoma Care. AB - PURPOSE: Nonmedical out-of-pocket cost to both patients and their companions of office visits for routine glaucoma care has not been extensively studied in the United States. We evaluate potential key predictors of patient expenditures that are critical to assessing the cost-effectiveness of glaucoma health care delivery. MATERIALS AND METHODS: In total, 300 patients responded to the survey in 3 clinics in 2 clinical practice settings. Main outcome measures included both average visit and yearly expenditures. RESULTS: Of the 300 patients, the majority were female (n=187, 62.3%) and African American (n=171, 57.0%). The median age was 66 years. The median [range; mean (SD)] expenditure per patient visit was $22.10 ($11.1, $42.9; $44.1 (72.8)). Patients with companions paid $38.77 more in average visit expenditure (beta: 0.87, P<0.001). The average visit expenditure for retired patients was $17.37 less when compared with nonretired patients (beta: -0.4, P=0.004). Patients living in a rural or suburban area paid $43.91 and $14.13 more per visit, respectively (beta: 0.73, P=0.0004; beta: 0.31, P=0.03), compared with patients living in an urban area. Patients with noncommercial insurance paid $24.01 less in average visit expenditure (beta: 0.66, P=0.0008). The median yearly patient expenditure was $96.70 [$44.6, $222.7; $210.4 (333.9)]. Patients with companions paid $192.37 more in yearly expenditure (beta: 0.9, P<0.001) than those without companions, whereas retired patients paid $80.83 less in yearly expenditure (beta: -0.39, P=0.03) than nonretirees. Patients with noncommercial insurance paid $109.34 less in yearly expenditure (beta: -0.63, P=0.01). CONCLUSIONS: Although a small part of the total cost of glaucoma care, nonmedical out-of-pocket costs constitute a substantial noncovered medical expense to most patients in the United States. Patients who are employed, come with companions, live in nonurban areas, or are on Medicare have greater expenditures. PMID- 28355175 TI - Synergistic Cytotoxicity of beta-Elemene and Cisplatin in Gingival Squamous Cell Carcinoma by Inhibition of STAT3 Signaling Pathway. AB - BACKGROUND Cisplatin remains one of the most active agents and is the mainstay of combination chemotherapy regimens against gingival squamous cell carcinoma. However, the efficacy of cisplatin is limited by its high toxicity and the development of drug resistance. beta-elemene, isolated from the Chinese herb Rhizoma zedoariahas, is highly effective against malignancies and has low toxicity, but the development of beta-elemene sensitizing chemotherapy in targeting the STAT3 signaling pathway remains unexplored in gingival squamous cell carcinoma. The present study was conducted to assess the chemosensitizing effects of b-elemene for enhancing the cytotoxicity of cisplatin in gingival squamous cell carcinoma. MATERIAL AND METHODS The gingival squamous cell carcinoma YD-38 cell line was used. MTT assay, clonogenic assay, annexin V/PI apoptosis assay, Western blot analysis, and xenograft model treatment were carried out in vitro and in vivo. RESULTS beta-elemene significantly enhanced proliferative inhibition and cisplatin induced apoptosis in gingival squamous cell carcinoma. Cisplatin combined with beta-elemene decreased the expressions of p-STAT3, p-JAK2, and Bcl-2, and increased the expressions of Bax and caspase-3 significantly compared to cisplatin only treatment, as well as in the xenograft model. CONCLUSIONS The results indicated that beta-elemene promoted the anti proliferative and apoptotic effect of cisplatin by inhibiting STAT3 and blocking the JAK2-STAT3 signaling pathway in GSCC in vitro and in vivo. PMID- 28355176 TI - Visualization and targeting of LGR5+ human colon cancer stem cells. AB - The cancer stem cell (CSC) theory highlights a self-renewing subpopulation of cancer cells that fuels tumour growth. The existence of human CSCs is mainly supported by xenotransplantation of prospectively isolated cells, but their clonal dynamics and plasticity remain unclear. Here, we show that human LGR5+ colorectal cancer cells serve as CSCs in growing cancer tissues. Lineage-tracing experiments with a tamoxifen-inducible Cre knock-in allele of LGR5 reveal the self-renewal and differentiation capacity of LGR5+ tumour cells. Selective ablation of LGR5+ CSCs in LGR5-iCaspase9 knock-in organoids leads to tumour regression, followed by tumour regrowth driven by re-emerging LGR5+ CSCs. KRT20 knock-in reporter marks differentiated cancer cells that constantly diminish in tumour tissues, while reverting to LGR5+ CSCs and contributing to tumour regrowth after LGR5+ CSC ablation. We also show that combined chemotherapy potentiates targeting of LGR5+ CSCs. These data provide insights into the plasticity of CSCs and their potential as a therapeutic target in human colorectal cancer. PMID- 28355177 TI - Optically excited structural transition in atomic wires on surfaces at the quantum limit. AB - Transient control over the atomic potential-energy landscapes of solids could lead to new states of matter and to quantum control of nuclear motion on the timescale of lattice vibrations. Recently developed ultrafast time-resolved diffraction techniques combine ultrafast temporal manipulation with atomic-scale spatial resolution and femtosecond temporal resolution. These advances have enabled investigations of photo-induced structural changes in bulk solids that often occur on timescales as short as a few hundred femtoseconds. In contrast, experiments at surfaces and on single atomic layers such as graphene report timescales of structural changes that are orders of magnitude longer. This raises the question of whether the structural response of low-dimensional materials to femtosecond laser excitation is, in general, limited. Here we show that a photo induced transition from the low- to high-symmetry state of a charge density wave in atomic indium (In) wires supported by a silicon (Si) surface takes place within 350 femtoseconds. The optical excitation breaks and creates In-In bonds, leading to the non-thermal excitation of soft phonon modes, and drives the structural transition in the limit of critically damped nuclear motion through coupling of these soft phonon modes to a manifold of surface and interface phonons that arise from the symmetry breaking at the silicon surface. This finding demonstrates that carefully tuned electronic excitations can create non equilibrium potential energy surfaces that drive structural dynamics at interfaces in the quantum limit (that is, in a regime in which the nuclear motion is directed and deterministic). This technique could potentially be used to tune the dynamic response of a solid to optical excitation, and has widespread potential application, for example in ultrafast detectors. PMID- 28355178 TI - Corrigendum: Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. PMID- 28355179 TI - CRISPR-Cas systems exploit viral DNA injection to establish and maintain adaptive immunity. AB - Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas systems provide protection against viral and plasmid infection by capturing short DNA sequences from these invaders and integrating them into the CRISPR locus of the prokaryotic host. These sequences, known as spacers, are transcribed into short CRISPR RNA guides that specify the cleavage site of Cas nucleases in the genome of the invader. It is not known when spacer sequences are acquired during viral infection. Here, to investigate this, we tracked spacer acquisition in Staphylococcus aureus cells harbouring a type II CRISPR-Cas9 system after infection with the staphylococcal bacteriophage phi12. We found that new spacers were acquired immediately after infection preferentially from the cos site, the viral free DNA end that is first injected into the cell. Analysis of spacer acquisition after infection with mutant phages demonstrated that most spacers are acquired during DNA injection, but not during other stages of the viral cycle that produce free DNA ends, such as DNA replication or packaging. Finally, we showed that spacers acquired from early-injected genomic regions, which direct Cas9 cleavage of the viral DNA immediately after infection, provide better immunity than spacers acquired from late-injected regions. Our results reveal that CRISPR-Cas systems exploit the phage life cycle to generate a pattern of spacer acquisition that ensures a successful CRISPR immune response. PMID- 28355180 TI - DHX9 suppresses RNA processing defects originating from the Alu invasion of the human genome. AB - Transposable elements are viewed as 'selfish genetic elements', yet they contribute to gene regulation and genome evolution in diverse ways. More than half of the human genome consists of transposable elements. Alu elements belong to the short interspersed nuclear element (SINE) family of repetitive elements, and with over 1 million insertions they make up more than 10% of the human genome. Despite their abundance and the potential evolutionary advantages they confer, Alu elements can be mutagenic to the host as they can act as splice acceptors, inhibit translation of mRNAs and cause genomic instability. Alu elements are the main targets of the RNA-editing enzyme ADAR and the formation of Alu exons is suppressed by the nuclear ribonucleoprotein HNRNPC, but the broad effect of massive secondary structures formed by inverted-repeat Alu elements on RNA processing in the nucleus remains unknown. Here we show that DHX9, an abundant nuclear RNA helicase, binds specifically to inverted-repeat Alu elements that are transcribed as parts of genes. Loss of DHX9 leads to an increase in the number of circular-RNA-producing genes and amount of circular RNAs, translational repression of reporters containing inverted-repeat Alu elements, and transcriptional rewiring (the creation of mostly nonsensical novel connections between exons) of susceptible loci. Biochemical purifications of DHX9 identify the interferon-inducible isoform of ADAR (p150), but not the constitutively expressed ADAR isoform (p110), as an RNA-independent interaction partner. Co depletion of ADAR and DHX9 augments the double-stranded RNA accumulation defects, leading to increased circular RNA production, revealing a functional link between these two enzymes. Our work uncovers an evolutionarily conserved function of DHX9. We propose that it acts as a nuclear RNA resolvase that neutralizes the immediate threat posed by transposon insertions and allows these elements to evolve as tools for the post-transcriptional regulation of gene expression. PMID- 28355181 TI - Evolutionary dynamics on any population structure. AB - Evolution occurs in populations of reproducing individuals. The structure of a population can affect which traits evolve. Understanding evolutionary game dynamics in structured populations remains difficult. Mathematical results are known for special structures in which all individuals have the same number of neighbours. The general case, in which the number of neighbours can vary, has remained open. For arbitrary selection intensity, the problem is in a computational complexity class that suggests there is no efficient algorithm. Whether a simple solution for weak selection exists has remained unanswered. Here we provide a solution for weak selection that applies to any graph or network. Our method relies on calculating the coalescence times of random walks. We evaluate large numbers of diverse population structures for their propensity to favour cooperation. We study how small changes in population structure-graph surgery-affect evolutionary outcomes. We find that cooperation flourishes most in societies that are based on strong pairwise ties. PMID- 28355182 TI - Postsynaptic synaptotagmins mediate AMPA receptor exocytosis during LTP. AB - Strengthening of synaptic connections by NMDA (N-methyl-d-aspartate) receptor dependent long-term potentiation (LTP) shapes neural circuits and mediates learning and memory. During the induction of NMDA-receptor-dependent LTP, Ca2+ influx stimulates recruitment of synaptic AMPA (alpha-amino-3-hydroxy-5-methyl-4 isoxazole propionic acid) receptors, thereby strengthening synapses. How Ca2+ induces the recruitment of AMPA receptors remains unclear. Here we show that, in the pyramidal neurons of the hippocampal CA1 region in mice, blocking postsynaptic expression of both synaptotagmin-1 (Syt1) and synaptotagmin-7 (Syt7), but not of either alone, abolished LTP. LTP was restored by expression of wild-type Syt7 but not of a Ca2+-binding-deficient mutant Syt7. Blocking postsynaptic expression of Syt1 and Syt7 did not impair basal synaptic transmission, reduce levels of synaptic or extrasynaptic AMPA receptors, or alter other AMPA receptor trafficking events. Moreover, expression of dominant-negative mutant Syt1 which inhibits Ca2+-dependent presynaptic vesicle exocytosis, also blocked Ca2+-dependent postsynaptic AMPA receptor exocytosis, thereby abolishing LTP. Our results suggest that postsynaptic Syt1 and Syt7 act as redundant Ca2+ sensors for Ca2+-dependent exocytosis of AMPA receptors during LTP, and thereby delineate a simple mechanism for the recruitment of AMPA receptors that mediates LTP. PMID- 28355183 TI - Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition. AB - Chromatin is reprogrammed after fertilization to produce a totipotent zygote with the potential to generate a new organism. The maternal genome inherited from the oocyte and the paternal genome provided by sperm coexist as separate haploid nuclei in the zygote. How these two epigenetically distinct genomes are spatially organized is poorly understood. Existing chromosome conformation capture-based methods are not applicable to oocytes and zygotes owing to a paucity of material. To study three-dimensional chromatin organization in rare cell types, we developed a single-nucleus Hi-C (high-resolution chromosome conformation capture) protocol that provides greater than tenfold more contacts per cell than the previous method. Here we show that chromatin architecture is uniquely reorganized during the oocyte-to-zygote transition in mice and is distinct in paternal and maternal nuclei within single-cell zygotes. Features of genomic organization including compartments, topologically associating domains (TADs) and loops are present in individual oocytes when averaged over the genome, but the presence of each feature at a locus varies between cells. At the sub-megabase level, we observed stochastic clusters of contacts that can occur across TAD boundaries but average into TADs. Notably, we found that TADs and loops, but not compartments, are present in zygotic maternal chromatin, suggesting that these are generated by different mechanisms. Our results demonstrate that the global chromatin organization of zygote nuclei is fundamentally different from that of other interphase cells. An understanding of this zygotic chromatin 'ground state' could potentially provide insights into reprogramming cells to a state of totipotency. PMID- 28355184 TI - Smart wing rotation and trailing-edge vortices enable high frequency mosquito flight. AB - Mosquitoes exhibit unusual wing kinematics; their long, slender wings flap at remarkably high frequencies for their size (>800 Hz)and with lower stroke amplitudes than any other insect group. This shifts weight support away from the translation-dominated, aerodynamic mechanisms used by most insects, as well as by helicopters and aeroplanes, towards poorly understood rotational mechanisms that occur when pitching at the end of each half-stroke. Here we report free-flight mosquito wing kinematics, solve the full Navier-Stokes equations using computational fluid dynamics with overset grids, and validate our results with in vivo flow measurements. We show that, although mosquitoes use familiar separated flow patterns, much of the aerodynamic force that supports their weight is generated in a manner unlike any previously described for a flying animal. There are three key features: leading-edge vortices (a well-known mechanism that appears to be almost ubiquitous in insect flight), trailing-edge vortices caused by a form of wake capture at stroke reversal, and rotational drag. The two new elements are largely independent of the wing velocity, instead relying on rapid changes in the pitch angle (wing rotation) at the end of each half-stroke, and they are therefore relatively immune to the shallow flapping amplitude. Moreover, these mechanisms are particularly well suited to high aspect ratio mosquito wings. PMID- 28355186 TI - Ebola: The great ape gamble. PMID- 28355187 TI - Environment: Hothouse of disease. PMID- 28355188 TI - Perspective: The one-health way. PMID- 28355185 TI - Myeloid progenitor cluster formation drives emergency and leukaemic myelopoiesis. AB - Although many aspects of blood production are well understood, the spatial organization of myeloid differentiation in the bone marrow remains unknown. Here we use imaging to track granulocyte/macrophage progenitor (GMP) behaviour in mice during emergency and leukaemic myelopoiesis. In the steady state, we find individual GMPs scattered throughout the bone marrow. During regeneration, we observe expanding GMP patches forming defined GMP clusters, which, in turn, locally differentiate into granulocytes. The timed release of important bone marrow niche signals (SCF, IL-1beta, G-CSF, TGFbeta and CXCL4) and activation of an inducible Irf8 and beta-catenin progenitor self-renewal network control the transient formation of regenerating GMP clusters. In leukaemia, we show that GMP clusters are constantly produced owing to persistent activation of the self renewal network and a lack of termination cytokines that normally restore haematopoietic stem-cell quiescence. Our results uncover a previously unrecognized dynamic behaviour of GMPs in situ, which tunes emergency myelopoiesis and is hijacked in leukaemia. PMID- 28355189 TI - Parasites: Kitty carriers. PMID- 28355190 TI - Microbiome: Puppy power. PMID- 28355191 TI - Climate change: As the ice melts. PMID- 28355192 TI - Animal health. PMID- 28355193 TI - Pets: Millennia together. PMID- 28355194 TI - Dogs: The riddle of resistance. PMID- 28355196 TI - Response to Sabour. PMID- 28355195 TI - The relationship of human milk leptin and macronutrients with gastric emptying in term breastfed infants. AB - BackgroundInfants breastfed on demand exhibit a variety of feeding patterns and self-regulate their nutrient intake, but factors influencing their gastric emptying (GE) are poorly understood. Despite research into appetite regulation properties of leptin, there is limited information about relationships between human milk leptin and infant GE.MethodsGastric volumes were calculated from ultrasound scans of infants' stomachs (n=20) taken before and after breastfeeding, and then every 12.5 min (median; range: 3-45 min) until the next feed. Skim milk leptin and macronutrient concentrations were measured and doses were calculated.ResultsThe leptin concentration was (mean+/-SD) 0.51+/-0.16 ng/ml; the leptin dose was 45.5+/-20.5 ng per feed. No relationships between both concentration and dose of leptin and time between the feeds (P=0.57; P=1, respectively) or residual stomach volumes before the subsequent feed (P=0.20; P=0.050) were found. Post-feed stomach volumes (GE rate) were not associated with leptin concentration (P=0.77) or dose (P=0.85).ConclusionGE in term breastfed infants was not associated with either skim milk leptin concentration or dose. Further investigation with inclusion of whole-milk leptin and other hormones that affect gastrointestinal activity is warranted. PMID- 28355197 TI - Response to "Commentary on identity of fibroblast pneumocyte factor: rat vs. human". PMID- 28355198 TI - Effects of osteopontin-enriched formula on lymphocyte subsets in the first 6 months of life: a randomized controlled trial. AB - BackgroundHuman milk is rich in osteopontin (OPN), which has immunomodulatory functions.MethodsIn a randomized controlled trial, standard formula (SF) and the same formula with 65 mg of OPN/L (F65) or 130 mg of OPN/L (F130), representing ~50 and 100% of the OPN concentration in human milk, were compared. We examined frequencies and composition of peripheral blood immune cells by four-color immunoflow cytometry of formula-fed infants at ages 1, 4, and 6 months, and compared them with a breastfed (BF) reference group.ResultsThe F130 group had increased T-cell proportions compared with the SF (P=0.036, average effect size 0.51) and F65 groups (P=0.008, average effect size 0.65). Compared with the BF group, the monocyte proportions were increased in the F65 (P=0.001, average effect size 0.59) and F130 (P=0.006, average effect size 0.50) groups, but were comparable among the formula groups.ConclusionOPN in an infant formula at a concentration close to that of human milk increased the proportion of circulating T cells compared with both SF and formula with added OPN at ~50% of the concentration in human milk. This suggests that OPN may favorably influence immune ontogeny in infancy and that the effects appear to be dose-dependent. PMID- 28355199 TI - Commentary on the identity of fibroblast pneumocyte factor: rat vs. human. PMID- 28355200 TI - Electronic cigarette use is not associated with quitting of conventional cigarettes in youth smokers. AB - BackgroundTo investigate the association between electronic cigarette (e-cig) use and smoking cessation among smokers who called the Youth Quitline in Hong Kong.MethodsThis longitudinal study collected data on youth smokers' (N=189) use and perception of e-cigs, conventional cigarette smoking behavior, and sociodemographic characteristics at baseline. Self-reported past 7-day point prevalence of abstinence (PPA) was assessed in the 6-month telephone follow-up. Linear and logistic regressions were used to estimate the association of e-cig use with quitting cigarette smoking and other cessation-related outcomes.ResultsE cig users were younger, more addicted to nicotine, and less ready to quit (all P<0.05) at baseline. The PPA rate was lower in e-cig users (13.4% vs. 20.8%) at follow-up. E-cig use was not associated with PPA at the 6-month follow-up (odds ratio (OR): 0.56, 95% CI: 0.24 to 1.35), but it was nonsignificantly related to more cessation attempts (raw coefficient (b): 1.26, 95% CI: -0.13 to 2.66). Among those who still smoked, e-cig use was nonsignificantly associated with intention to quit smoking (OR: 0.55, 95% CI: 0.15 to 2.05), nicotine dependence (Fagerstrom score, b: 0.75, 95% CI: -0.39 to 1.90), and perceptions on quitting cigarette smoking.ConclusionE-cig use was not associated with successful smoking cessation among Youth Quitline smokers. PMID- 28355201 TI - Sex and age differences in phenylephrine mechanisms and outcomes after piglet brain injury. AB - BackgroundTraumatic brain injury (TBI) is the leading cause of injury-related death in children, with boys and children under 4 years of age having particularly poor outcomes. Cerebral autoregulation is often impaired after TBI, contributing to poor outcome. In prior studies on newborn pigs, phenylephrine (Phe) preferentially protected cerebral autoregulation in female but not in male subjects after TBI. We hypothesized that, in contrast to the newborn, Phe prevents impairment of autoregulation and tissue injury following TBI in both sexes of older pigs.MethodsCerebral autoregulation, cerebrospinal fluid (CSF) extracellular signal-related kinase (ERK) and endothelin, and histopathology were determined after moderate fluid percussion brain injury (FPI) in male and female juvenile pigs after Phe.ResultsAutoregulation was more impaired in male than in female subjects. Phe protects autoregulation in both sexes after FPI, blocks ERK and endothelin, and decreases the number of necrotic neurons in male and female subjects after FPI.ConclusionsThese data indicate that Phe protects autoregulation and limits neuronal necrosis via blockage of ERK and endothelin after FPI in male and female subjects. Together with prior observations in newborn pigs where Phe protected autoregulation in female but not in male subjects, these data suggest that use of Phe to improve outcomes after TBI is both sex- and age-dependent. PMID- 28355203 TI - Response to Torday. PMID- 28355202 TI - MicroRNA-155 modulates bile duct inflammation by targeting the suppressor of cytokine signaling 1 in biliary atresia. AB - BackgroundBiliary atresia (BA) is an etiologically perplexing disease, manifested by neonatal cholestasis, repeated cholangitis, and progressive biliary fibrosis. MiR-155 has been implicated to modulate the immune response, which contributes to biliary injury. However, its potential role in the pathogenesis of BA has not been addressed so far.MethodsThe microRNA changes from BA patients and controls were identified via microarray. The immunomodulatory function of miR-155 was investigated via cell transfection and reporter assay. The lentiviral vector pL miR-155 inhibitor was transfected into a mouse model to investigate its role in BA.ResultsThe expression of miR-155 in livers of BA patients was significantly increased, and an inverse correlation between miR-155 and suppressor of cytokine signaling 1 (SOCS1) was detected. MiR-155 overexpression promoted expressions of major histocompatibility complex (MHC) I, MHC II, Chemokine (C-X-C motif) ligand (CXCL) 9, CXCL10, monocyte chemotactic protein 1, and CXCL1 after IFN-gamma stimulation, which could be suppressed by SOCS1 overexpression. Moreover, miR-155 overexpression activated JAK2/STAT3, thus enhancing the pro-inflammatory effect. Downregulating miR-155 reduced the incidence of BA in a rhesus monkey rotavirus induced BA model.ConclusionOur results reveal a vital contribution of miR-155 upregulation and consequent SOCS1 downregulation to an immune response triggered via IFN-gamma in BA. PMID- 28355204 TI - Characterization of CD31 expression on murine and human neonatal T lymphocytes during development and activation. AB - BackgroundCD31, expressed by the majority of the neonatal T-cell pool, is involved in modulation of T-cell receptor signaling by increasing the threshold for T-cell activation. Therefore, CD31 could modulate neonatal tolerance and adaptive immune responses.MethodsLymphocytes were harvested from murine neonates at different ages, human late preterm and term cord blood, and adult peripheral blood. Human samples were activated over a 5-day period to simulate acute inflammation. Mice were infected with influenza; lungs and spleens were harvested at days 6 and 9 post infection and analyzed by flow cytometry.ResultsCD31 expressing neonatal murine CD4+ and CD8a+ T cells increase over the first week of life. Upon in vitro stimulation, human infants' CD4+ and CD8a+ T cells shed CD31 faster in comparison with adults. In the context of acute infection, mice infected at 3 days of age have an increased number of naive and activated CD31+ T lymphocytes at the site of infection at days 6 and 9 post infection, as compared with those infected at 7 days of age; however, the opposite is true in the periphery.ConclusionDifferences in trafficking of CD31+ cytotoxic T lymphocytes (CTLs) during acute influenza infection could modulate tolerance and contribute to a dampened adaptive immune response in neonates. PMID- 28355205 TI - Interaction between maternal caffeine intake during pregnancy and CYP1A2 C164A polymorphism affects infant birth size in the Hokkaido study. AB - BackgroundCaffeine, 1,3,7-trimethylxanthine, is widely consumed by women of reproductive age. Although caffeine has been proposed to inhibit fetal growth, previous studies on the effects of caffeine on infant birth size have yielded inconsistent findings. This inconsistency may result from failure to account for individual differences in caffeine metabolism related to polymorphisms in the gene for CYP1A2, the major caffeine-metabolizing enzyme.MethodsFive hundred fourteen Japanese women participated in a prospective cohort study in Sapporo, Japan, from 2002 to 2005, and 476 mother-child pairs were included for final analysis.ResultsCaffeine intake was not significantly associated with mean infant birth size. When caffeine intake and CYP1A2 C164A genotype were considered together, women with the AA genotype and caffeine intake of >=300 mg per day had a mean reduction in infant birth head circumference of 0.8 cm relative to the reference group after adjusting for confounding factors. In a subgroup analysis, only nonsmokers with the AA genotype and caffeine intake of >=300 mg per day had infants with decreased birth weight (mean reduction, 277 g) and birth head circumference (mean reduction, 1.0 cm).ConclusionNonsmokers who rapidly metabolize caffeine may be at increased risk for having infants with decreased birth size when consuming >=300 mg of caffeine per day. PMID- 28355206 TI - Hepatic MDR3 expression impacts lipid homeostasis and susceptibility to inflammatory bile duct obstruction in neonates. AB - BackgroundHeterozygous mutations in the gene ABCB4, encoding the phospholipid floppase MDR3 (Mdr2 in mice), are associated with various chronic liver diseases. Here we hypothesize that reduced ABCB4 expression predisposes to extrahepatic biliary atresia (EHBA).MethodsLivers from neonatal wild-type (wt) and heterozygous Mdr2-deficient mice were subjected to mass spectrometry-based lipidomics and RNA sequencing studies. Following postnatal infection with rhesus rotavirus (RRV), liver immune responses and EHBA phenotype were assessed. Hepatic microarray data from 40 infants with EHBA were mined for expression levels of ABCB4.ResultsPhosphatidylcholine (PC) and phosphatidylethanolamine (PE) were increased, whereas the PC/PE ratio was decreased in neonatal Mdr2+/- mice compared with wt mice. Following RRV challenge, hepatic expression of IFNgamma and infiltration with CD8+ and NK+ lymphocytes were increased in Mdr2+/- mice. Plasma total bilirubin levels and prevalence of complete ductal obstruction were higher in these mice. In infants with EHBA, hepatic gene expression of ABCB4 was downregulated in those with an inflammatory compared with a fibrosing molecular phenotype.ConclusionDecreased expression of ABCB4 causes dysregulation in (phospho)lipid homeostasis, and predisposes to aberrant pro-inflammatory lymphocyte responses and an aggravated phenotype of EHBA in neonatal mice. Downregulated ABCB4 is associated with an inflammatory transcriptome signature in infants with EHBA. PMID- 28355207 TI - An integrated overview of the midgut bacterial flora composition of Phlebotomus perniciosus, a vector of zoonotic visceral leishmaniasis in the Western Mediterranean Basin. AB - BACKGROUND: The Leishmania developmental life cycle within its sand fly vector occurs exclusively in the lumen of the insect's digestive tract in the presence of symbiotic bacteria. The composition of the gut microbiota and the factors that influence its composition are currently poorly understood. A set of factors, including the host and its environment, may influence this composition. It has been demonstrated that the insect gut microbiota influences the development of several human pathogens, such as Plasmodium falciparum. For sand flies and Leishmania, understanding the interactions between the parasite and the microbial environment of the vector midgut can provide new tools to control Leishmania transmission. METHODOLOGY/PRINCIPAL FINDINGS: The midguts of female Phlebotomus perniciosus from laboratory colonies or from the field were collected during the months of July, September and October 2011 and dissected. The midguts were analyzed by culture-dependent and culture-independent methods. A total of 441 and 115 cultivable isolates were assigned to 30 and 11 phylotypes from field collected and colonized P. perniciosus, respectively. Analysis of monthly variations in microbiota composition shows a species diversity decline in October, which is to the end of the Leishmania infantum transmission period. In parallel, a compilation and a meta-analysis of all available data concerning the microbiota of two Psychodidae genera, namely Phlebotomus and Lutzomyia, was performed and compared to P. perniciosus, data obtained herein. This integrated analysis did not reveal any substantial divergences between Old and New world sand flies with regards to the midgut bacterial phyla and genera diversity. But clearly, most bacterial species (>76%) are sparsely distributed between Phlebotominae species. CONCLUSION/SIGNIFICANCE: Our results pinpoint the need for a more exhaustive understanding of the bacterial richness and abundance at the species level in Phlebotominae sand flies in order to capture the role of midgut bacteria during Leishmania development and transmission. The occurrence of Bacillus subtilis in P. perniciosus and at least two other sand fly species studied so far suggests that this bacterial species is a potential candidate for paratransgenic or biolological approaches for the control of sand fly populations in order to prevent Leishmania transmission. PMID- 28355209 TI - Coefficients of variation of ground reaction force measurement in cats. AB - Gait analysis has been extensively performed in dogs and horses; however, very little is known about feline biomechanics. It was, therefore, the aim of this study to determine the coefficient of variation (CV) among three ground reaction force (GRF) measurements taken for 15 client-owned European shorthaired cats without a training period and a short acclimatisation time. Gait was measured as each cat walked across a pressure-sensitive walkway, and measurements were made three times over a multi-week period (range: 2 to 17 weeks). The parameters evaluated were peak vertical force (PFz), vertical impulse (IFz), stance phase duration (SPD), step length (SL), paw contact area (PCA) and symmetry index (SI%) of the front and hind limbs. After averaging each of the values from the three measurements, the CV and 95% confidence interval (CI) were calculated for all parameters. PFz showed the lowest CV (~ 3%), while IFz showed the highest CV (~11%) when normalised to body mass. When the GRFs were normalised to total force, the CV of PFz dropped to ~2% and that of IFz dropped to ~3%. The CV of SL and PCA were lower (~6% respectively ~5%) compared to the CV for SPD (~10%). The SI% for both PFz and IFz were comparable to the values reported in the gait analysis literature for dogs. Results of the current study indicate that gait analysis of cats using pressure-sensitive walkways produces reliable data and is a promising approach for evaluation of lameness. The results also suggest that PFz may be a more reliable parameter than IFz and that normalisation to percent of total force may aid in interpretation of the evaluated data. PMID- 28355208 TI - CLAVATA1 controls distinct signaling outputs that buffer shoot stem cell proliferation through a two-step transcriptional compensation loop. AB - The regulation of stem cell proliferation in plants is controlled by intercellular signaling pathways driven by the diffusible CLAVATA3 (CLV3p) peptide. CLV3p perception is thought to be mediated by an overlapping array of receptors in the stem cell niche including the transmembrane receptor kinase CLV1, Receptor-Like Protein Kinase 2 (RPK2), and a dimer of the receptor-like protein CLV2 and the CORYNE (CRN) pseudokinase. Mutations in these receptors have qualitatively similar effects on stem cell function but it is unclear if this represents common or divergent signaling outputs. Previous work in heterologous systems has suggested that CLV1, RPK2 and CLV2/CRN could form higher order complexes but it is also unclear what relevance these putative complexes have to in vivo receptor functions. Here I use the in vivo regulation of a specific transcriptional target of CLV1 signaling in Arabidopsis to demonstrate that, despite the phenotypic similarities between the different receptor mutants, CLV1 controls distinct signaling outputs in living stem cell niches independent of other receptors. This regulation is separable from stem cell proliferation driven by WUSCHEL, a proposed common transcriptional target of CLV3p signaling. In addition, in the absence of CLV1, CLV1-related receptor kinases are ectopically expressed but also buffer stem cell proliferation through the auto-repression of their own expression. Collectively these data reveal a unique in vivo role for CLV1 separable from other stem cell receptors and provides a framework for dissecting the signaling outputs in stem cell regulation. PMID- 28355213 TI - The role of noise in self-organized decision making by the true slime mold Physarum polycephalum. AB - Self-organized mechanisms are frequently encountered in nature and known to achieve flexible, adaptive control and decision-making. Noise plays a crucial role in such systems: It can enable a self-organized system to reliably adapt to short-term changes in the environment while maintaining a generally stable behavior. This is fundamental in biological systems because they must strike a delicate balance between stable and flexible behavior. In the present paper we analyse the role of noise in the decision-making of the true slime mold Physarum polycephalum, an important model species for the investigation of computational abilities in simple organisms. We propose a simple biological experiment to investigate the reaction of P. polycephalum to time-variant risk factors and present a stochastic extension of an established mathematical model for P. polycephalum to analyze this experiment. It predicts that-due to the mechanism of stochastic resonance-noise can enable P. polycephalum to correctly assess time variant risk factors, while the corresponding noise-free system fails to do so. Beyond the study of P. polycephalum we demonstrate that the influence of noise on self-organized decision-making is not tied to a specific organism. Rather it is a general property of the underlying process dynamics, which appears to be universal across a wide range of systems. Our study thus provides further evidence that stochastic resonance is a fundamental component of the decision making in self-organized macroscopic and microscopic groups and organisms. PMID- 28355210 TI - Helicobacter pylori infection and low dietary iron alter behavior, induce iron deficiency anemia, and modulate hippocampal gene expression in female C57BL/6 mice. AB - Helicobacter pylori (H.pylori), a bacterial pathogen, is a causative agent of gastritis and peptic ulcer disease and is a strong risk factor for development of gastric cancer. Environmental conditions, such as poor dietary iron resulting in iron deficiency anemia (IDA), enhance H.pylori virulence and increases risk for gastric cancer. IDA affects billions of people worldwide, and there is considerable overlap between regions of high IDA and high H.pylori prevalence. The primary aims of our study were to evaluate the effect of H.pylori infection on behavior, iron metabolism, red blood cell indices, and behavioral outcomes following comorbid H. pylori infection and dietary iron deficiency in a mouse model. C57BL/6 female mice (n = 40) were used; half were placed on a moderately iron deficient (ID) diet immediately post-weaning, and the other half were maintained on an iron replete (IR) diet. Half were dosed with H.pylori SS1 at 5 weeks of age, and the remaining mice were sham-dosed. There were 4 study groups: a control group (-Hp, IR diet) as well as 3 experimental groups (-Hp, ID diet; +Hp, IR diet; +Hp,ID diet). All mice were tested in an open field apparatus at 8 weeks postinfection. Independent of dietary iron status, H.pylori -infected mice performed fewer exploratory behaviors in the open field chamber than uninfected mice (p<0.001). Hippocampal gene expression of myelination markers and dopamine receptor 1 was significantly downregulated in mice on an ID diet (both p<0.05), independent of infection status. At 12 months postinfection, hematocrit (Hct) and hemoglobin (Hgb) concentration were significantly lower in +Hp, ID diet mice compared to all other study groups. H.pylori infection caused IDA in mice maintained on a marginal iron diet. The mouse model developed in this study is a useful model to study the neurologic, behavioral, and hematologic impact of the common human co-morbidity of H. pylori infection and IDA. PMID- 28355212 TI - Is music enriching for group-housed captive chimpanzees (Pan troglodytes)? AB - Many facilities that house captive primates play music for animal enrichment or for caregiver enjoyment. However, the impact on primates is unknown as previous studies have been inconclusive. We conducted three studies with zoo-housed chimpanzees (Pan troglodytes) and one with group-housed chimpanzees at the National Centre for Chimpanzee Care to investigate the effects of classical and pop/rock music on various variables that may be indicative of increased welfare. Study one compared the behaviour and use of space of 18 animals when silence, classical or pop/rock music was played into one of several indoor areas. Overall, chimpanzees did not actively avoid the area when music was playing but were more likely to exit the area when songs with higher beats per minute were broadcast. Chimpanzees showed significantly fewer active social behaviours when music, rather than silence, was playing. They also tended to be more active and engage in less abnormal behaviour during the music but there was no change to either self-grooming or aggression between music and silent conditions. The genre of music had no differential effects on the chimpanzees' use of space and behaviour. In the second study, continuous focal observations were carried out on three individuals with relatively high levels of abnormal behaviour. No differences in behaviour between music and silence periods were found in any of the individuals. The final two studies used devices that allowed chimpanzees to choose if they wanted to listen to music of various types or silence. Both studies showed that there were no persistent preferences for any type of music or silence. When taken together, our results do not suggest music is enriching for group-housed captive chimpanzees, but they also do not suggest that music has a negative effect on welfare. PMID- 28355211 TI - Transcriptome-wide analysis of alternative routes for RNA substrates into the exosome complex. AB - The RNA exosome complex functions in both the accurate processing and rapid degradation of many classes of RNA. Functional and structural analyses indicate that RNA can either be threaded through the central channel of the exosome or more directly access the active sites of the ribonucleases Rrp44 and Rrp6, but it was unclear how many substrates follow each pathway in vivo. We used CRAC (UV crosslinking and analysis of cDNA) in growing cells to identify transcriptome wide interactions of RNAs with the major nuclear exosome-cofactor Mtr4 and with individual exosome subunits (Rrp6, Csl4, Rrp41 and Rrp44) along the threaded RNA path. We compared exosome complexes lacking Rrp44 exonuclease activity, carrying a mutation in the Rrp44 S1 RNA-binding domain predicted to disfavor direct access, or with multiple mutations in Rrp41 reported to impede RNA access to the central channel in vitro. Preferential use of channel-threading was seen for mRNAs, 5S rRNA, scR1 (SRP) and aborted tRNAs transcripts. Conversely, pre-tRNAs preferentially accessed Rrp44 directly. Both routes participated in degradation and maturation of RNAPI transcripts, with hand-over during processing. Rrp41 mutations blocked substrate passage through the channel to Rrp44 only for cytoplasmic mRNAs, supporting the predicted widening of the lumen in the Rrp6 associated, nuclear complex. Many exosome substrates exhibited clear preferences for a specific path to Rrp44. Other targets showed redundancy, possibly allowing the efficient handling of highly diverse RNA-protein complexes and RNA structures. Both threading and direct access routes involve the RNA helicase Mtr4. mRNAs that are predominately nuclear or cytoplasmic exosome substrates can be distinguished in vivo. PMID- 28355214 TI - A new paramutation-like example at the Delta gene of Drosophila. AB - The hereditary transmission of a phenotype independent from DNA sequence implies epigenetic effects. Paramutation is a heritable epigenetic phenomenon observed in plants and animals. To investigate paramutation in Drosophila, we used the P{ry+t7.2 = PZ}Dl05151 P-element insertion in the Drosophila melanogaster genome that causes a dominant visible phenotype: the presence of characteristic extra veins in the fly wings. This extra-vein phenotype presents variable expressivity and incomplete penetrance. The insert is a PZ element located 680 bp upstream from the ATG of the Delta (Dl) gene, encoding the Notch ligand involved in wing vein development, and acts as a null allele. In the G2 offspring from a cross between the heterozygous transgenic stock and wild-type flies, we observed the transmission of the extra-vein phenotype to wild-type flies without the transgene, independently of gender and across many generations. This is a "paramutation-like" example in the fly: the heritable transmission of a phenotypic change not linked to a classical genetic mutation. A "paramutagenic" allele in heterozygotes transmits the phenotype of the heterozygotes to the wild type allele ("paramutant") in a stable manner through generations. Distinct from paramutation events so far described in Drosophila, here we deal with a dominant effect on a single gene involving variable hereditary signals. PMID- 28355215 TI - Salmonella genomic island 1 (SGI1) reshapes the mating apparatus of IncC conjugative plasmids to promote self-propagation. AB - IncC conjugative plasmids and Salmonella genomic island 1 (SGI1) and relatives are frequently associated with multidrug resistance of clinical isolates of pathogenic Enterobacteriaceae. SGI1 is specifically mobilized in trans by IncA and IncC plasmids (commonly referred to as A/C plasmids) following its excision from the chromosome, an event triggered by the transcriptional activator complex AcaCD encoded by these helper plasmids. Although SGI1 is not self-transmissible, it carries three genes, traNS, traHS and traGS, coding for distant homologs of the predicted mating pore subunits TraNC, TraHC and TraGC, respectively, encoded by A/C plasmids. Here we investigated the regulation of traNS and traHGS and the role of these three genes in the transmissibility of SGI1. Transcriptional fusion of the promoter sequences of traNS and traHGS to the reporter gene lacZ confirmed that expression of these genes is inducible by AcaCD. Mating experiments using combinations of deletion mutants of SGI1 and the helper IncC plasmid pVCR94 revealed complex interactions between these two mobile genetic elements. Whereas traNC and traHGC are essential for IncC plasmid transfer, SGI1 could rescue null mutants of each individual gene revealing that TraNS, TraHS and TraGS are functional proteins. Complementation assays of individual traC and traS mutants showed that not only do TraNS/HS/GS replace TraNC/HC/GC in the mating pore encoded by IncC plasmids but also that traGS and traHS are both required for SGI1 optimal transfer. In fact, remodeling of the IncC-encoded mating pore by SGI1 was found to be essential to enhance transfer rate of SGI1 over the helper plasmid. Furthermore, traGS was found to be crucial to allow DNA transfer between cells bearing IncC helper plasmids, thereby suggesting that by remodeling the mating pore SGI1 disables an IncC-encoded entry exclusion mechanism. Hence traS genes facilitate the invasion by SGI1 of cell populations bearing IncC plasmids. PMID- 28355216 TI - Chirosurveillance: The use of native bats to detect invasive agricultural pests. AB - Invasive insect pests cost the agricultural industry billions of dollars annually in crop losses. Timely detection of pests is critical for management efficiency. Innovative pest detection strategies, such as environmental DNA (eDNA) techniques, combined with efficient predators, maximize sampling resolution across space and time and may improve surveillance. We tested the hypothesis that temperate insectivorous bats can be important sentinels of agricultural insect pest surveillance. Specifically, we used a new high-sensitivity molecular assay for invasive brown marmorated stink bugs (Halyomorpha halys) to examine the extent to which big brown bats (Eptesicus fuscus) detect agricultural pests in the landscape. We documented consistent seasonal predation of stink bugs by big brown bats. Importantly, bats detected brown marmorated stink bugs 3-4 weeks earlier than the current standard monitoring tool, blacklight traps, across all sites. We highlight here the previously unrecognized potential ecosystem service of bats as agents of pest surveillance (or chirosurveillance). Additional studies examining interactions between other bat and insect pest species, coupled with comparisons of detectability among various conventional monitoring methods, are needed to verify the patterns extracted from this study. Ultimately, robust economic analyses will be needed to assess the cost-effectiveness of chirosurveillance as a standard strategy for integrated pest management. PMID- 28355217 TI - Correction: Transcriptional Orchestration of the Global Cellular Response of a Model Pennate Diatom to Diel Light Cycling under Iron Limitation. AB - [This corrects the article DOI: 10.1371/journal.pgen.1006490.]. PMID- 28355218 TI - sCD163 levels as a biomarker of disease severity in leprosy and visceral leishmaniasis. AB - BACKGROUND: CD163, receptor for the haptoglobin-hemoglobin complex, is expressed on monocytes/macrophages and neutrophils. A soluble form of CD163 (sCD163) has been associated with the M2 macrophage phenotype, and M2 macrophages have been shown to down-modulate inflammatory responses. In particular, previous studies have shown that M2 is closely associated with the most severe clinical presentation of leprosy (i.e. lepromatous leprosy (LL)), as well as tuberculosis. We hypothesized that sCD163 correlates with severity of diseases caused by intracellular pathogens. METHODOLOGY/PRINCIPAL FINDINGS: To assess this hypothesis, sCD163 levels were measured in the serum of leprosy and visceral leishmaniasis (VL) patients stratified by severity of the clinical presentation. sCD163 levels were significantly higher in patients with these diseases than those observed in healthy control individuals. Further analyses on infection and disease status of leprosy and VL patients revealed a clear association of sCD163 levels with clinical parameters of disease severity. In vitro culture assays revealed that Leishmania infection induced CD163 expression on the surface of both monocyte/macrophages and neutrophils, suggesting these cells as possible sources of sCD163. FACS analyses shows that the cells expressing CD163 produces both TNF-alpha and IL-4. CONCLUSIONS/SIGNIFICANCE: Taken together, our results reveal sCD163 as a potential biomarker of severity of diseases caused by intracellular pathogens M. leprae and Leishmania spp. and have a modulatory role, with a mix of an inflammatory property induced by TNF-alpha release, but that potentially induces an anti-inflammatory T cell response, related to IL-4 release. PMID- 28355219 TI - Discovery of temporal and disease association patterns in condition-specific hospital utilization rates. AB - Identifying temporal variation in hospitalization rates may provide insights about disease patterns and thereby inform research, policy, and clinical care. However, the majority of medical conditions have not been studied for their potential seasonal variation. The objective of this study was to apply a data driven approach to characterize temporal variation in condition-specific hospitalizations. Using a dataset of 34 million inpatient discharges gathered from hospitals in New York State from 2008-2011, we grouped all discharges into 263 clinical conditions based on the principal discharge diagnosis using Clinical Classification Software in order to mitigate the limitation that administrative claims data reflect clinical conditions to varying specificity. After applying Seasonal-Trend Decomposition by LOESS, we estimated the periodicity of the seasonal component using spectral analysis and applied harmonic regression to calculate the amplitude and phase of the condition's seasonal utilization pattern. We also introduced four new indices of temporal variation: mean oscillation width, seasonal coefficient, trend coefficient, and linearity of the trend. Finally, K-means clustering was used to group conditions across these four indices to identify common temporal variation patterns. Of all 263 clinical conditions considered, 164 demonstrated statistically significant seasonality. Notably, we identified conditions for which seasonal variation has not been previously described such as ovarian cancer, tuberculosis, and schizophrenia. Clustering analysis yielded three distinct groups of conditions based on multiple measures of seasonal variation. Our study was limited to New York State and results may not directly apply to other regions with distinct climates and health burden. A substantial proportion of medical conditions, larger than previously described, exhibit seasonal variation in hospital utilization. Moreover, the application of clustering tools yields groups of clinically heterogeneous conditions with similar seasonal phenotypes. Further investigation is necessary to uncover common etiologies underlying these shared seasonal phenotypes. PMID- 28355220 TI - High GC content causes orphan proteins to be intrinsically disordered. AB - De novo creation of protein coding genes involves the formation of short ORFs from noncoding regions; some of these ORFs might then become fixed in the population. These orphan proteins need to, at the bare minimum, not cause serious harm to the organism, meaning that they should for instance not aggregate. Therefore, although the creation of short ORFs could be truly random, the fixation should be subjected to some selective pressure. The selective forces acting on orphan proteins have been elusive, and contradictory results have been reported. In Drosophila young proteins are more disordered than ancient ones, while the opposite trend is present in yeast. To the best of our knowledge no valid explanation for this difference has been proposed. To solve this riddle we studied structural properties and age of proteins in 187 eukaryotic organisms. We find that, with the exception of length, there are only small differences in the properties between proteins of different ages. However, when we take the GC content into account we noted that it could explain the opposite trends observed for orphans in yeast (low GC) and Drosophila (high GC). GC content is correlated with codons coding for disorder promoting amino acids. This leads us to propose that intrinsic disorder is not a strong determining factor for fixation of orphan proteins. Instead these proteins largely resemble random proteins given a particular GC level. During evolution the properties of a protein change faster than the GC level causing the relationship between disorder and GC to gradually weaken. PMID- 28355221 TI - Acute juvenile Paracoccidioidomycosis: A 9-year cohort study in the endemic area of Rio de Janeiro, Brazil. AB - BACKGROUND: Paracoccidioidomycosis (PCM) is a systemic mycosis caused by pathogenic dimorphic fungi of the genus Paracoccidioides. It is the most important systemic mycosis in Latin America and the leading cause of hospitalizations and death among them in Brazil. Acute PCM is less frequent but relevant because vulnerable young patients are affected and the severity is usually higher than that of the chronic type. METHODS: The authors performed a retrospective cohort study from 2001 to 2009 including acute juvenile PCM patients from a reference center in Rio de Janeiro, Brazil. Clinical, epidemiological, diagnostic, therapeutic, and prognostic data were reported. RESULTS: Twenty-nine patients were included. The average age was 23 years old and the male to female ratio was 1:1.07. All cases were referred from 3 of 9 existing health areas in the state of Rio de Janeiro, predominantly from urban areas (96.5%). Lymph nodes were the most affected organs (100%), followed by the skin and the spleen (31% each). Twenty-eight patients completed treatment (median 25 months) and progressed to clinical and serological cure; 1 death occurred. Twenty four patients completed 48-month median follow-up. Four patients abandoned follow up after the end of treatment. The most frequent sequela was low adrenal reserve. Paracoccidioides brasiliensis S1 was identified by partial sequencing of the arf and gp43 genes from 4 patients who presented a viable fungal culture. CONCLUSION: Acute juvenile PCM is a severe disease with a high rate of complications. There are few cohort clinical studies of acute PCM in the literature. More studies should be developed to promote improvement in patients' healthcare. PMID- 28355223 TI - Pre-control relationship of onchocercal skin disease with onchocercal infection in Guinea Savanna, Northern Nigeria. AB - BACKGROUND: Onchocerca volvulus infection can result in blindness, itching and skin lesions. Previous research concentrated on blindness. METHODS: A clinical classification system of the cutaneous changes in onchocerciasis was used for the first time in this study within the context of an early ivermectin drug trial in the savanna region of Kaduna State, northern Nigeria. Skin examinations were performed in 6,790 individuals aged 5+ years in endemic communities and 1,343 individuals in nonendemic communities. RESULTS / DISCUSSION: There was increased risk for all forms of onchocercal skin disease in endemic communities with the most common finding being the presence of nodules (1,438 individuals, 21.2%), followed by atrophy (367, 6.1% of those < 50 years), acute papular onchodermatitis, APOD (233, 3.4%), depigmentation (216, 3.2%) and chronic papular onchodermatitis, CPOD (155, 2.3%). A further 645 individuals (9.5%) complained of pruritus but had completely normal skin. APOD was more common in males whereas atrophy, hanging groin and nodules were more common in females. After controlling for age and sex, microfilarial positivity was a risk factor for CPOD, depigmentation, hanging groin and nodules (OR 1.54, p = 0.046; OR 2.29, p = 0.002; OR 2.18, p = 0.002 and OR 3.80, p <0.001 respectively). Comparable results were found using presence of nodules as the marker for infection. Microfilarial load showed similar, though weaker, results. A total of 2621(38.6%) endemic residents had itching with normal skin, or had one or more types of onchocercal skin disease including nodules, which may be considered as a composite index of the overall prevalence of onchocercal skin disease. CONCLUSION: Significant levels of onchocercal skin disease were documented in this savanna area, which subsequently resulted in a reassessment of the true burden of skin disease in onchocerciasis. This paper represents the first detailed report of the association of onchocercal skin disease with markers for onchocercal infection. PMID- 28355224 TI - Generation of infectious recombinant Adeno-associated virus in Saccharomyces cerevisiae. AB - The yeast Saccharomyces cerevisiae has been successfully employed to establish model systems for a number of viruses. Such model systems are powerful tools to study the virus biology and in particular for the identification and characterization of host factors playing a role in the viral infection cycle. Adeno-associated viruses (AAV) are heavily studied due to their use as gene delivery vectors. AAV relies on other helper viruses for successful replication and on host factors for several aspects of the viral life cycle. However the role of host and helper viral factors is only partially known. Production of recombinant AAV (rAAV) vectors for gene delivery applications depends on knowledge of AAV biology and the limited understanding of host and helper viral factors may be precluding efficient production, particularly in heterologous systems. Model systems in simpler eukaryotes like the yeast S. cerevisiae would be useful tools to identify and study the role of host factors in AAV biology. Here we show that expression of AAV2 viral proteins VP1, VP2, VP3, AAP, Rep78, Rep52 and an ITR-flanked DNA in yeast leads to capsid formation, DNA replication and encapsidation, resulting in formation of infectious particles. Many of the AAV characteristics observed in yeast resemble those in other systems, making it a suitable model system. Future findings in the yeast system could be translatable to other AAV host systems and aid in more efficient production of rAAV vectors. PMID- 28355222 TI - Transaldolase inhibition impairs mitochondrial respiration and induces a starvation-like longevity response in Caenorhabditis elegans. AB - Mitochondrial dysfunction can increase oxidative stress and extend lifespan in Caenorhabditis elegans. Homeostatic mechanisms exist to cope with disruptions to mitochondrial function that promote cellular health and organismal longevity. Previously, we determined that decreased expression of the cytosolic pentose phosphate pathway (PPP) enzyme transaldolase activates the mitochondrial unfolded protein response (UPRmt) and extends lifespan. Here we report that transaldolase (tald-1) deficiency impairs mitochondrial function in vivo, as evidenced by altered mitochondrial morphology, decreased respiration, and increased cellular H2O2 levels. Lifespan extension from knockdown of tald-1 is associated with an oxidative stress response involving p38 and c-Jun N-terminal kinase (JNK) MAPKs and a starvation-like response regulated by the transcription factor EB (TFEB) homolog HLH-30. The latter response promotes autophagy and increases expression of the flavin-containing monooxygenase 2 (fmo-2). We conclude that cytosolic redox established through the PPP is a key regulator of mitochondrial function and defines a new mechanism for mitochondrial regulation of longevity. PMID- 28355225 TI - Aridity influences the recovery of vegetation and shrubland birds after wildfire. AB - Wildfires play a determining role in the composition and structure of many plant and animal communities. On the other hand, climate change is considered to be a major driver of current and future fire regime changes. Despite increases in drought in many areas of the world, the effects of aridity on post-fire colonization by animals have been rarely addressed. This study aims to analyse how a regional aridity gradient affects post-fire recovery of vegetation, bird species richness and the numbers of four early to middle-successional warbler species associated with the shrub cover. The database contains bird relative abundance and environmental variables from 3072 censuses in 695 transects located in 70 recently burnt areas (1 to 11 years after wildfire) in Catalonia (Spain), which were sampled between 2006 and 2013. Generalized linear mixed models (GLMMs) showed that plant cover was affected by time since fire, aridity and forest management. However, only the highest vegetation height layer (>100 cm) recovered slower in arid areas after fire. Time since fire positively influenced bird species richness and the relative abundance of the four focal species. The post fire recovery of Melodious (Hippolais polyglotta) and Subalpine warblers (Sylvia cantillans) was hampered by aridity. Although this was not demonstrated for Dartford (S. undata) and Sardinian warblers (S. melanocephala), their occurrence was low in the driest areas during the first three years after fire. Overall, this study suggests that future increases in aridity can affect plant regeneration after fire and slow down the recovery of animal populations that depend on understorey and shrublands. Given the recently highlighted increases in aridity and fire frequency in Mediterranean-climate regions, improved knowledge on how aridity affects ecological succession is especially necessary. PMID- 28355226 TI - Considering medical risk information and communicating values: A mixed-method study of women's choice in prenatal testing. AB - INTRODUCTION: Nowadays, an important decision for pregnant women is whether to undergo prenatal testing for aneuploidies and which tests to uptake. We investigate the factors influencing women's choices between non-invasive prenatal testing (NIPT) and invasive prenatal tests in pregnancies with elevated a priori risk of fetal aneuploidies. METHODOLOGY: This is a mixed-method study. We used medical data (1st Jan 2015-31st Dec 2015) about women participating in further testing at Fetomaternal Medical Center at Helsinki University Hospital and employed Chi-square tests and ANOVA to compare the groups of women choosing different methods. Multinomial logistic regressions revealed the significant clinical factors influencing women's choice. We explored the underlying values, beliefs, attitudes and other psychosocial factors that affect women's choice by interviewing women with the Theory of Planned Behavior framework. The semi structured interview data were processed by thematic analysis. RESULTS: Statistical data indicated that gestational age and counseling day were strong factors influencing women's choice. Interview data revealed that women's values and moral principles on pregnancy and childbirth chiefly determined the choices. Behavioral beliefs (e.g. safety and accuracy) and perceived choice control (e.g. easiness, rapidness and convenience) were also important and the major trade-offs happened between these constructs. DISCUSSION: Values are the determinants of women's choice. Service availability and convenience are strong factors. Medical risk status in this choice context is not highly influential. Choice aids can be developed by helping women to identify their leading values in prenatal testing and by providing lists of value-matching test options and attributes. PMID- 28355227 TI - When music is salty: The crossmodal associations between sound and taste. AB - Here we investigate associations between complex auditory and complex taste stimuli. A novel piece of music was composed and recorded in four different styles of musical articulation to reflect the four basic tastes groups (sweet, sour, salty, bitter). In Experiment 1, participants performed above chance at pairing the music clips with corresponding taste words. Experiment 2 uses multidimensional scaling to interpret how participants categorize these musical stimuli, and to show that auditory categories can be organized in a similar manner as taste categories. Experiment 3 introduces four different flavors of custom-made chocolate ganache and shows that participants can match music clips with the corresponding taste stimuli with above-chance accuracy. Experiment 4 demonstrates the partial role of pleasantness in crossmodal mappings between sound and taste. The present findings confirm that individuals are able to make crossmodal associations between complex auditory and gustatory stimuli, and that valence may mediate multisensory integration in the general population. PMID- 28355228 TI - Indo-Pacific humpback dolphins (Sousa chinensis) in Hong Kong: Modelling demographic parameters with mark-recapture techniques. AB - Indo-Pacific humpback dolphins (Sousa chinensis) inhabiting Hong Kong waters are thought to be among the world's most anthropogenically impacted coastal delphinids. We have conducted a 5-year (2010-2014) photo-ID study and performed the first in this region comprehensive mark-recapture analysis applying a suite of open population models and robust design models. Cormack-Jolly-Seber (CJS) models suggested a significant transient effect and seasonal variation in apparent survival probabilities as result of a fluid movement beyond the study area. Given the spatial restrictions of our study, limited by an administrative border, if emigration was to be considered negligible the estimated survival rate of adults was 0.980. Super-population estimates indicated that at least 368 dolphins used Hong Kong waters as part of their range. Closed robust design models suggested an influx of dolphins from winter to summer and increased site fidelity in summer; and outflux, although less prominent, during summer-winter intervals. Abundance estimates in summer (N = 144-231) were higher than that in winter (N = 87-111), corresponding to the availability of prey resources which in Hong Kong waters peaks during summer months. We point out that the current population monitoring strategy used by the Hong Kong authorities is ill-suited for a timely detection of a population change and should be revised. PMID- 28355229 TI - Surgery increases cell death and induces changes in gene expression compared with anesthesia alone in the developing piglet brain. AB - In a range of animal species, exposure of the brain to general anaesthesia without surgery during early infancy may adversely affect its neural and cognitive development. The mechanisms mediating this are complex but include an increase in brain cell death. In humans, attempts to link adverse cognitive development to infantile anaesthesia exposure have yielded ambiguous results. One caveat that may influence the interpretation of human studies is that infants are not exposed to general anaesthesia without surgery, raising the possibility that surgery itself, may contribute to adverse cognitive development. Using piglets, we investigated whether a minor surgical procedure increases cell death and disrupts neuro-developmental and cognitively salient gene transcription in the neonatal brain. We randomly assigned neonatal male piglets to a group who received 6h of 2% isoflurane anaesthesia or a group who received an identical anaesthesia plus 15 mins of surgery designed to replicate an inguinal hernia repair. Compared to anesthesia alone, surgery-induced significant increases in cell death in eight areas of the brain. Using RNAseq data derived from all 12 piglets per group we also identified significant changes in the expression of 181 gene transcripts induced by surgery in the cingulate cortex, pathway analysis of these changes suggests that surgery influences the thrombin, aldosterone, axonal guidance, B cell, ERK-5, eNOS and GABAA signalling pathways. This suggests a number of novel mechanisms by which surgery may influence neural and cognitive development independently or synergistically with the effects of anaesthesia. PMID- 28355231 TI - A systematic review of economic evaluations of population-based sodium reduction interventions. AB - OBJECTIVE: To summarise evidence describing the cost-effectiveness of population based interventions targeting sodium reduction. METHODS: A systematic search of published and grey literature databases and websites was conducted using specified key words. Characteristics of identified economic evaluations were recorded, and included studies were appraised for reporting quality using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. RESULTS: Twenty studies met the study inclusion criteria and received a full paper review. Fourteen studies were identified as full economic evaluations in that they included both costs and benefits associated with an intervention measured against a comparator. Most studies were modelling exercises based on scenarios for achieving salt reduction and assumed effects on health outcomes. All 14 studies concluded that their specified intervention(s) targeting reductions in population sodium consumption were cost-effective, and in the majority of cases, were cost saving. Just over half the studies (8/14) were assessed as being of 'excellent' reporting quality, five studies fell into the 'very good' quality category and one into the 'good' category. All of the identified evaluations were based on modelling, whereby inputs for all the key parameters including the effect size were either drawn from published datasets, existing literature or based on expert advice. CONCLUSION: Despite a clear increase in evaluations of salt reduction programs in recent years, this review identified relatively few economic evaluations of population salt reduction interventions. None of the studies were based on actual implementation of intervention(s) and the associated collection of new empirical data. The studies universally showed that population-based salt reduction strategies are likely to be cost effective or cost saving. However, given the reliance on modelling, there is a need for the effectiveness of new interventions to be evaluated in the field using strong study designs and parallel economic evaluations. PMID- 28355230 TI - A blood-based biomarker panel to risk-stratify mild traumatic brain injury. AB - Mild traumatic brain injury (TBI) accounts for the vast majority of the nearly two million brain injuries suffered in the United States each year. Mild TBI is commonly classified as complicated (radiographic evidence of intracranial injury) or uncomplicated (radiographically negative). Such a distinction is important because it helps to determine the need for further neuroimaging, potential admission, or neurosurgical intervention. Unfortunately, imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) are costly and not without some risk. The purpose of this study was to screen 87 serum biomarkers to identify a select panel of biomarkers that would predict the presence of intracranial injury as determined by initial brain CT. Serum was collected from 110 patients who sustained a mild TBI within 24 hours of blood draw. Two models were created. In the broad inclusive model, 72kDa type IV collagenase (MMP-2), C-reactive protein (CRP), creatine kinase B type (CKBB), fatty acid binding protein-heart (hFABP), granulocyte-macrophage colony stimulating factor (GM-CSF) and malondialdehyde modified low density lipoprotein (MDA-LDL) significantly predicted injury visualized on CT, yielding an overall c statistic of 0.975 and a negative predictive value (NPV) of 98.6. In the parsimonious model, MMP-2, CRP, and CKBB type significantly predicted injury visualized on CT, yielding an overall c-statistic of 0.964 and a negative predictive value (NPV) of 97.2. These results suggest that a serum based biomarker panel can accurately differentiate patients with complicated mild TBI from those with uncomplicated mild TBI. Such a panel could be useful to guide early triage decisions, including the need for further evaluation or admission, especially in those environments in which resources are limited. PMID- 28355232 TI - A genome-wide trans-ethnic interaction study links the PIGR-FCAMR locus to coronary atherosclerosis via interactions between genetic variants and residential exposure to traffic. AB - Air pollution is a worldwide contributor to cardiovascular disease mortality and morbidity. Traffic-related air pollution is a widespread environmental exposure and is associated with multiple cardiovascular outcomes such as coronary atherosclerosis, peripheral arterial disease, and myocardial infarction. Despite the recognition of the importance of both genetic and environmental exposures to the pathogenesis of cardiovascular disease, studies of how these two contributors operate jointly are rare. We performed a genome-wide interaction study (GWIS) to examine gene-traffic exposure interactions associated with coronary atherosclerosis. Using race-stratified cohorts of 538 African-Americans (AA) and 1562 European-Americans (EA) from a cardiac catheterization cohort (CATHGEN), we identify gene-by-traffic exposure interactions associated with the number of significantly diseased coronary vessels as a measure of chronic atherosclerosis. We found five suggestive (P<1x10-5) interactions in the AA GWIS, of which two (rs1856746 and rs2791713) replicated in the EA cohort (P < 0.05). Both SNPs are in the PIGR-FCAMR locus and are eQTLs in lymphocytes. The protein products of both PIGR and FCAMR are implicated in inflammatory processes. In the EA GWIS, there were three suggestive interactions; none of these replicated in the AA GWIS. All three were intergenic; the most significant interaction was in a regulatory region associated with SAMSN1, a gene previously associated with atherosclerosis and B cell activation. In conclusion, we have uncovered several novel genes associated with coronary atherosclerosis in individuals chronically exposed to increased ambient concentrations of traffic air pollution. These genes point towards inflammatory pathways that may modify the effects of air pollution on cardiovascular disease risk. PMID- 28355233 TI - Coding and non-coding gene regulatory networks underlie the immune response in liver cirrhosis. AB - Liver cirrhosis is recognized as being the consequence of immune-mediated hepatocyte damage and repair processes. However, the regulation of these immune responses underlying liver cirrhosis has not been elucidated. In this study, we used GEO datasets and bioinformatics methods to established coding and non-coding gene regulatory networks including transcription factor-/lncRNA-microRNA-mRNA, and competing endogenous RNA interaction networks. Our results identified 2224 mRNAs, 70 lncRNAs and 46 microRNAs were differentially expressed in liver cirrhosis. The transcription factor -/lncRNA- microRNA-mRNA network we uncovered that results in immune-mediated liver cirrhosis is comprised of 5 core microRNAs (e.g., miR-203; miR-219-5p), 3 transcription factors (i.e., FOXP3, ETS1 and FOS) and 7 lncRNAs (e.g., ENTS00000671336, ENST00000575137). The competing endogenous RNA interaction network we identified includes a complex immune response regulatory subnetwork that controls the entire liver cirrhosis network. Additionally, we found 10 overlapping GO terms shared by both liver cirrhosis and hepatocellular carcinoma including "immune response" as well. Interestingly, the overlapping differentially expressed genes in liver cirrhosis and hepatocellular carcinoma were enriched in immune response-related functional terms. In summary, a complex gene regulatory network underlying immune response processes may play an important role in the development and progression of liver cirrhosis, and its development into hepatocellular carcinoma. PMID- 28355234 TI - Deltoid muscle volume affects clinical outcome of reverse total shoulder arthroplasty in patients with cuff tear arthropathy or irreparable cuff tears. AB - We aimed to estimate the interrelation between preoperative deltoid muscle status by measuring the 3-dimensional deltoid muscle volume and postoperative functional outcomes after reverse total shoulder arthroplasty(RTSA). Thirty-five patients who underwent RTSA participated in this study. All patients underwent preoperative magnetic resonance imaging(MRI) as well as pre- and postoperative radiography and various functional outcome evaluations at least 1 year. The primary outcome parameter was set as age- and sex-matched Constant scores. The 3 dimensional deltoid muscle model was generated using a medical image processing software and in-house code, and the deltoid muscle volume was calculated automatically. Various clinical and radiographic factors comprising the deltoid muscle volume adjusted for body mass index(BMI) were analyzed, and their interrelation with the outcome parameters was appraised using a multivariate analysis. As a result, all practical consequences considerably improved following surgery(all p<0.01). Overall, 20 and 15 indicated a higher and a lower practical consequence than the average, respectively, which was assessed by the matched Constant scores. The deltoid muscle volume adjusted for BMI(p = 0.009), absence of a subscapularis complete tear (p = 0.040), and greater change in acromion deltoid tuberosity distance(p = 0.013) were associated with higher matched Constant scores. Multivariate analysis indicated that the deltoid muscle volume was the single independent prognostic factor for practical consequences(p = 0.011). In conclusion, the preoperative deltoid muscle volume significantly affected the functional outcome following RTSA in patients with cuff tear arthropathy or irreparable cuff tears. Therefore, more attention should be paid to patients with severe atrophied deltoid muscle who are at a high risk for poor practical consequences subsequent to RTSA. PMID- 28355235 TI - Heat-induced symmetry breaking in ant (Hymenoptera: Formicidae) escape behavior. AB - The collective egress of social insects is important in dangerous situations such as natural disasters or enemy attacks. Some studies have described the phenomenon of symmetry breaking in ants, with two exits induced by a repellent. However, whether symmetry breaking occurs under high temperature conditions, which are a common abiotic stress, remains unknown. In our study, we deposited a group of Polyrhachis dives ants on a heated platform and counted the number of escaping ants with two identical exits. We discovered that ants asymmetrically escaped through two exits when the temperature of the heated platform was >32.75 degrees C. The degree of asymmetry increased linearly with the temperature of the platform. Furthermore, the higher the temperature of heated platform was, the more ants escaped from the heated platform. However, the number of escaping ants decreased for 3 min when the temperature was higher than the critical thermal limit (39.46 degrees C), which is the threshold for ants to endure high temperature without a loss of performance. Moreover, the ants tended to form small groups to escape from the thermal stress. A preparatory formation of ant grouping was observed before they reached the exit, indicating that the ants actively clustered rather than accidentally gathered at the exits to escape. We suggest that a combination of individual and grouping ants may help to optimize the likelihood of survival during evacuation. PMID- 28355236 TI - Environmental and biological cues for spawning in the crown-of-thorns starfish. AB - Sporadic outbreaks of the coral-eating crown-of-thorns starfish are likely to be due, at least in part, to spatial and temporal variation in reproductive and settlement success. For gonochoric and broadcast spawning species such as crown of-thorns starfish, spawning synchrony is fundamental for achieving high rates of fertilization. Highly synchronized gamete release within and among distinct populations is typically the result of the entrainment of neurohormonal endogenous rhythms by cues from the environment. In this study, we conducted multiple spawning assays to test the effects of temperature change, reduced salinity and nutrient enrichment of seawater, phytoplankton, gametes (sperm and eggs), and the combined effect of sperm and phytoplankton on the likelihood of spawning in male and female crown-of-thorns starfish. We also investigated sex specific responses to each of these potential spawning cues. We found that (1) abrupt temperature change (an increase of 4 degrees C) induced spawning in males, but less so in females; (2) males often spawned in response to the presence of phytoplankton, but none of the females spawned in response to these cues; (3) the presence of sperm in the water column induced males and females to spawn, although additive and synergistic effects of sperm and phytoplankton were not significant; and (4) males are more sensitive to the spawning cues tested and most likely spawn prior to females. We propose that environmental cues act as spawning 'inducers' by causing the release of hormones (gonad stimulating substance) in sensitive males, while biological cues (pheromones) from released sperm, in turn, act as spawning 'synchronizers' by triggering a hormonal cascade resulting in gamete shedding by conspecifics. Given the immediate temporal linkage between the timing of spawning and fertilization events, variability in the extent and synchronicity of gamete release will significantly influence reproductive success and may account for fluctuations in the abundance of crown of-thorns starfish. PMID- 28355237 TI - Identifying the effects of education on the ability to cope with a disability among individuals with disabilities. AB - The literature on disability has suggested that an educated individual with a disability is more likely to better cope with her/his disability than those without education. However, few published studies explore whether the relationship between education and ability to cope with a disability is anything more than an association. Using data on disability and accommodation from a large Danish survey from 2012-13 and exploiting a major Danish schooling reform as a natural experiment, we identified a potential causal effect of education on both economic (holding a job) as well as social (cultural activities, visiting clubs/associations, etc.) dimensions of coping among individuals with a disability, controlling for background factors, functioning, and disability characteristics. We found that endogeneity bias was only present in the case of economic participation and more educated individuals with a disability indeed had higher levels of both economic and social coping. To some extent, having more knowledge of public support systems and higher motivation explained the better coping among the group of individuals with disabilities who were educated. Our results indicated, however, that a large part of the effect of education on the ability to cope with a disability among individuals with disabilities was suggestive of a causal relationship. PMID- 28355239 TI - Temporal and spatial comparisons of the reproductive biology of northern Gulf of Mexico (USA) red snapper (Lutjanus campechanus) collected a decade apart. AB - In studies done a decade apart, we provide evidence of a recent shift toward a slower progression to sexual maturity as well as reduced egg production, especially among young, small female red snapper, in the Gulf of Mexico (Gulf). Slower maturation rates (among fish <=6 years old), lower GSI values and decreased spawning frequency were observed, and were especially pronounced in the northwestern Gulf. Furthermore, an Index of Reproductive Importance showed that young fish (ages 2-7) are contributing far less to the spawning stock in recent years, while older fish (>8 years) are contributing more, when compared to fish from the same age groups sampled in the previous decade. Coincident with these changes in reproductive output, fishing pressure has steadily declined gulf-wide, and spawning stock biomass and spawning potential ratio have increased. Thus, it is possible that the age structure of the red snapper stock is becoming less truncated, or that reproductive effort observed is due to the temporary influence of recent strong year classes produced in 2004 and 2006 as they begin to reach full reproductive potential. If the latter is true, careful documentation of the stock's reproductive dynamics during a time of population growth provides new understanding at the meta-population spatial and decadal temporal scales. In contrast, if the former is true, a truncated age structure due to overharvest can limit the productivity of the Gulf red snapper stock. In addition, we have learned that red snapper females in the northwestern Gulf collected on natural reefs and banks have much higher reproductive output than those on artificial reefs in the form of standing and toppled oil and gas platforms, thus making the need to know the relative abundance of females found on these disparate habitats an important next step toward better-understanding factors impacting the reproductive dynamics of this species. PMID- 28355238 TI - Terpene synthases from Cannabis sativa. AB - Cannabis (Cannabis sativa) plants produce and accumulate a terpene-rich resin in glandular trichomes, which are abundant on the surface of the female inflorescence. Bouquets of different monoterpenes and sesquiterpenes are important components of cannabis resin as they define some of the unique organoleptic properties and may also influence medicinal qualities of different cannabis strains and varieties. Transcriptome analysis of trichomes of the cannabis hemp variety 'Finola' revealed sequences of all stages of terpene biosynthesis. Nine cannabis terpene synthases (CsTPS) were identified in subfamilies TPS-a and TPS-b. Functional characterization identified mono- and sesqui-TPS, whose products collectively comprise most of the terpenes of 'Finola' resin, including major compounds such as beta-myrcene, (E)-beta-ocimene, (-) limonene, (+)-alpha-pinene, beta-caryophyllene, and alpha-humulene. Transcripts associated with terpene biosynthesis are highly expressed in trichomes compared to non-resin producing tissues. Knowledge of the CsTPS gene family may offer opportunities for selection and improvement of terpene profiles of interest in different cannabis strains and varieties. PMID- 28355240 TI - Optimized Triton X-114 assisted lipopolysaccharide (LPS) removal method reveals the immunomodulatory effect of food proteins. AB - SCOPE: Investigations into the immunological response of proteins is often masked by lipopolysaccharide (LPS) contamination. We report an optimized Triton X-114 (TX-114) based LPS extraction method for beta-lactoglobulin (BLG) and soy protein extract suitable for cell-based immunological assays. METHODS AND RESULTS: Optimization of an existing TX-114 based phase LPS extraction method resulted in >99% reduction of LPS levels. However, remaining TX-114 was found to interfere with LPS and protein concentration assays and decreased viability of THP-1 macrophages and HEK-Blue 293 cells. Upon screening a range of TX-114 extraction procedures, TX-114-binding beads were found to most effectively lower TX-114 levels without affecting protein structural properties. LPS-purified proteins showed reduced capacity to activate TLR4 compared to non-treated proteins. LPS purified BLG did not induce secretion of pro-inflammatory cytokines from THP-1 macrophages, as non-treated protein did, showing that LPS contamination masks the immunomodulatory effect of BLG. Both HEK293 cells expressing TLR4 and differentiated THP-1 macrophages were shown as a relevant model to screen the protein preparations for biological effects of LPS contamination. CONCLUSION: The reported TX-114 assisted LPS-removal from protein preparations followed by bead based removal of TX-114 allows evaluation of natively folded protein preparations for their immunological potential in cell-based studies. PMID- 28355241 TI - Effects of shallow natural gas well structures and associated roads on grassland songbird reproductive success in Alberta, Canada. AB - Grassland songbird populations across North America have experienced dramatic population declines due to habitat loss and degradation. In Canada, energy development continues to fragment and disturb prairie habitat, but effects of oil and gas development on reproductive success of songbirds in North American mixed grass prairies remains largely unknown. From 2010-2012, in southeastern Alberta, Canada, we monitored 257 nests of two ground-nesting grassland songbird species, Savannah sparrow (Passerculus sandwichensis) and chestnut-collared longspur (Calcarius ornatus). Nest locations varied with proximity to and density of conventional shallow gas well structures and associated roads in forty-two 258-ha mixed-grass prairie sites. We estimated the probabilities of nest success and clutch size relative to gas well structures and roads. There was little effect of distance to or density of gas well structure on nest success; however, Savannah sparrow experienced lower nest success near roads. Clutch sizes were lower near gas well structures and cattle water sources. Minimizing habitat disturbance surrounding gas well structures, and reducing abundance of roads and trails, would help minimize impacts on reproductive success for some grassland songbirds. PMID- 28355242 TI - Fluoroscopy-free Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) for controlling life threatening postpartum hemorrhage. AB - BACKGROUND: Severe postpartum hemorrhage occurs in 1/1000 women giving birth. This condition is often dramatic and may be life threatening. Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) has in recent years been introduced as a novel treatment for hemorrhagic shock. We present a series of fluoroscopy-free REBOA for controlling life threatening postpartum hemorrhage. METHODS: In 2008 an 'aortic occlusion kit' was assembled and used in three Norwegian university hospitals. The on-call interventional radiologist (IR) was to be contacted with a response time < 30 minutes in case of life threatening PPH. Demographics and characteristics were noted from the medical records. RESULTS: This retrospective study includes 36 patients treated with fluoroscopy free REBOA for controlling severe postpartum hemorrhage in the years 2008-2015. The REBOA success rate was 100% and no patients died from REBOA related complications. Uterine artery embolization was performed in 17 (47%) patients and a hysterectomy in 16 (44%) patients. A short (11cm) introducer length was strongly associated with iliac artery thrombus formation (rho = 0.50, P = 0.002). In addition, there was a strong negative correlation between uterine artery embolization and hysterectomy (rho = -0.50, P = 0.002). CONCLUSIONS: Our Norwegian experience indicates the clinical safety and feasibility of REBOA in life threatening PPH. Also, REBOA can be used in an emergency situation without the use of fluoroscopy with a high degree of technical success. It is important that safety implementation of REBOA is established, especially through limited aortic balloon occlusion time and a thorough balloon deflation regime. PMID- 28355243 TI - Ketogenic diet improves the spatial memory impairment caused by exposure to hypobaric hypoxia through increased acetylation of histones in rats. AB - Exposure to hypobaric hypoxia causes neuron cell damage, resulting in impaired cognitive function. Effective interventions to antagonize hypobaric hypoxia induced memory impairment are in urgent need. Ketogenic diet (KD) has been successfully used to treat drug-resistant epilepsy and improves cognitive behaviors in epilepsy patients and other pathophysiological animal models. In the present study, we aimed to explore the potential beneficial effects of a KD on memory impairment caused by hypobaric hypoxia and the underlying possible mechanisms. We showed that the KD recipe used was ketogenic and increased plasma levels of ketone bodies, especially beta-hydroxybutyrate. The results of the behavior tests showed that the KD did not affect general locomotor activity but obviously promoted spatial learning. Moreover, the KD significantly improved the spatial memory impairment caused by hypobaric hypoxia (simulated altitude of 6000 m, 24 h). In addition, the improving-effect of KD was mimicked by intraperitoneal injection of BHB. The western blot and immunohistochemistry results showed that KD treatment not only increased the acetylated levels of histone H3 and histone H4 compared to that of the control group but also antagonized the decrease in the acetylated histone H3 and H4 when exposed to hypobaric hypoxia. Furthermore, KD hypoxia treatment also promoted PKA/CREB activation and BDNF protein expression compared to the effects of hypoxia alone. These results demonstrated that KD is a promising strategy to improve spatial memory impairment caused by hypobaric hypoxia, in which increased modification of histone acetylation plays an important role. PMID- 28355245 TI - Correction: Biting Midges (Diptera: Ceratopogonidae) from Cambay Amber Indicate that the Eocene Fauna of the Indian Subcontinent Was Not Isolated. AB - [This corrects the article DOI: 10.1371/journal.pone.0169144.]. PMID- 28355244 TI - Does personality affect health-related quality of life? A systematic review. AB - BACKGROUND: Health-related quality of life (HRQOL) is increasingly measured as an outcome for clinical and health services research. However, relatively little is known about how non-health factors affect HRQOL. Personality is a potentially important factor, yet evidence regarding the effects of personality on HRQOL measures is unclear. METHODS: This systematic review examined the relationships among aspects of personality and HRQOL. Eligible studies were identified from Medline and PsycINFO. The review included 76 English-language studies with HRQOL as a primary outcome and that assessed personality from the psychological perspective. Individuals with various health states, including ill (e.g., cancer, cardiovascular disorders), aging, and healthy, were included in this review study. RESULTS: Some personality characteristics were consistently related to psychosocial aspects more often than physical aspects of HRQOL. Personality characteristics, especially neuroticism, mastery, optimism, and sense of coherence were most likely to be associated with psychosocial HRQOL. Personality explained varying proportions of variance in different domains of HRQOL. The range of variance explained in psychosocial HRQOL was 0 to 45% and the range of explained variance in physical HRQOL was 0 to 39%. CONCLUSIONS: Personality characteristics are related to HRQOL. Systematic collection and analysis of personality data alongside HRQOL measures may be helpful in medical research, clinical practice, and health policy evaluation. PMID- 28355246 TI - SEARCH 8Es: A novel point of care ultrasound protocol for patients with chest pain, dyspnea or symptomatic hypotension in the emergency department. AB - OBJECTIVE: This study was conducted to evaluate a problem-oriented focused torso bedside ultrasound protocol termed "Sonographic Evaluation of Aetiology for Respiratory difficulty, Chest pain, and/or Hypotension" (SEARCH 8Es) for its ability to narrow differential diagnoses and increase physicians' diagnostic confidence, and its diagnostic accuracy, for patients presenting with dyspnea, chest pain, or symptomatic hypotension. METHODS: This single-center prospective observational study was conducted over 12 months in an emergency department and included 308 patients (184 men and 124 women; mean age, 67.7 +/- 19.1 years) with emergent cardiopulmonary symptoms. The paired t-test was used to compare the number of differential diagnoses and physician's level of confidence before and after SEARCH 8Es. The overall accuracy of the SEARCH 8Es protocol in differentiating 13 diagnostic entities was evaluated based on concordance (kappa coefficient) with the diagnosis made by the inpatient specialists. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated. RESULTS: SEARCH 8Es narrows the number of differential diagnoses (2.5 +/- 1.5 vs. 1.4 +/- 0.7; p < 0.001) and improves physicians' diagnostic confidence (2.8 +/- 0.8 vs. 4.3 +/- 0.9; p < 0.001) significantly. The overall kappa coefficient value was 0.870 (p < 0.001), with the overall sensitivity, specificity, positive predictive value, and negative predictive value at 90.9%, 99.0%, 89.7%, and 99.0%, respectively. CONCLUSION: The SEARCH 8Es protocol helps emergency physicians to narrow the differential diagnoses, increase diagnostic confidence and provide accurate assessment of patients with dyspnea, chest pain, or symptomatic hypotension. PMID- 28355247 TI - Effects of photocoagulation on ocular blood flow in patients with severe non proliferative diabetic retinopathy. AB - PURPOSE: To investigate ocular blood flow and correlations between ocular blood flow and variables in patients with severe non-proliferative diabetic retinopathy (S-NPDR) following panretinal photocoagulation (PRP). METHODS: In this retrospective, cross-sectional study, the blood flow on the optic nerve head (ONH) and choroid was assessed with laser speckle flowgraphy (LSFG) using the mean blur rate (MBR) in 76 eyes of 76 patients with S-NPDR who underwent PRP, 39 eyes of 39 patients with S-NPDR who did not undergo PRP, and 71 eyes of 71 normal subjects. The correlation between MBR and variables, including visual acuity (VA) and choroidal area determined by binarization method, was analyzed. RESULTS: The mean age was 62.9 +/- 11.9 years in the S-NPDR with PRP eyes, 55.6 +/- 11.4 years in the S-NPDR without PRP eyes, and 60.3 +/- 11.1 years in the normal subject eyes. The ONH MBR in vessel and tissue areas and the choroidal MBR were significantly lower in the S-NDR with PRP group than in the other groups (p < 0.001, p < 0.001, and p < 0.001, respectively). The luminal and the stromal areas were significantly smaller in the S-NDR with PRP group than in the other groups (p < 0.001 and p < 0.001, respectively). LogMAR best corrected visual acuity (BCVA) exhibited significant negative correlation with the ONH MBR in vessel (r = -0.386, p < 0.001), tissue (r = -0.348, p < 0.001), and the choroid MBR (r = 0.339, p = 0.002) in the S-NDR with PRP group. Stepwise multiple regression analysis demonstrated that BCVA was a common independent factor associated with the ONH MBR in vessel, tissue, and the choroidal MBR in the S-NDR with PRP group. CONCLUSIONS: ONH and choroid MBR in addition to choroidal component, including the luminal area, were significantly lower in eyes of patients with S-NPDR after PRP compared with no PRP and normal subjects group. This could suggest that the significantly reduced ocular blood flow in PRP-treated S-NPDR eyes correlated with long-term decreased post-PRP luminal area and visual acuity. PMID- 28355248 TI - Searching for new strategies against biofilm infections: Colistin-AMP combinations against Pseudomonas aeruginosa and Staphylococcus aureus single- and double-species biofilms. AB - Antimicrobial research is being pressured to look for more effective therapeutics for the ever-growing antibiotic-resistant infections, and antimicrobial peptides (AMP) and antimicrobial combinations are promising solutions. This work evaluates colistin-AMP combinations against two major pathogens, Pseudomonas aeruginosa and Staphylococcus aureus, encompassing non- and resistant strains. Colistin (CST) combined with the AMP temporin A (TEMP-A), citropin 1.1 (CIT-1.1) and tachyplesin I linear analogue (TP-I-L) was tested against planktonic, single- and double species biofilm cultures. Overall synergy for planktonic P. aeruginosa and synergy/additiveness for planktonic S. aureus were observed. Biofilm growth prevention was achieved with synergy and additiveness. Pre-established 24 h-old biofilms were harder to eradicate, especially for S. aureus and double-species biofilms; still, some synergy and addictiveness was observed for higher concentrations, including for the biofilms of resistant strains. Different treatment times and growth media did not greatly influence AMP activity. CST revealed low toxicity compared with the other AMP but its combinations were toxic for high concentrations. Overall, combinations reduced effective AMP concentrations, mainly in prevention scenarios. Improvement of effectiveness and toxicity of therapeutic strategies will be further investigated. PMID- 28355249 TI - Barley (Hordeum vulgare) in the Okhotsk culture (5th-10th century AD) of northern Japan and the role of cultivated plants in hunter-gatherer economies. AB - This paper discusses archaeobotanical remains of naked barley recovered from the Okhotsk cultural layers of the Hamanaka 2 archaeological site on Rebun Island, northern Japan. Calibrated ages (68% confidence interval) of the directly dated barley remains suggest that the crop was used at the site ca. 440-890 cal yr AD. Together with the finds from the Oumu site (north-eastern Hokkaido Island), the recovered seed assemblage marks the oldest well-documented evidence for the use of barley in the Hokkaido Region. The archaeobotanical data together with the results of a detailed pollen analysis of contemporaneous sediment layers from the bottom of nearby Lake Kushu point to low-level food production, including cultivation of barley and possible management of wild plants that complemented a wide range of foods derived from hunting, fishing, and gathering. This qualifies the people of the Okhotsk culture as one element of the long-term and spatially broader Holocene hunter-gatherer cultural complex (including also Jomon, Epi Jomon, Satsumon, and Ainu cultures) of the Japanese archipelago, which may be placed somewhere between the traditionally accepted boundaries between foraging and agriculture. To our knowledge, the archaeobotanical assemblages from the Hokkaido Okhotsk culture sites highlight the north-eastern limit of prehistoric barley dispersal. Seed morphological characteristics identify two different barley phenotypes in the Hokkaido Region. One compact type (naked barley) associated with the Okhotsk culture and a less compact type (hulled barley) associated with Early-Middle Satsumon culture sites. This supports earlier suggestions that the "Satsumon type" barley was likely propagated by the expansion of the Yayoi culture via south-western Japan, while the "Okhotsk type" spread from the continental Russian Far East region, across the Sea of Japan. After the two phenotypes were independently introduced to Hokkaido, the boundary between both barley domains possibly existed ca. 600-1000 cal yr AD across the island region. Despite a large body of studies and numerous theoretical and conceptual debates, the question of how to differentiate between hunter-gatherer and farming economies persists reflecting the wide range of dynamic subsistence strategies used by humans through the Holocene. Our current study contributes to the ongoing discussion of this important issue. PMID- 28355250 TI - Avian binocular vision: It's not just about what birds can see, it's also about what they can't. AB - With the exception of primates, most vertebrates have laterally placed eyes. Binocular vision in vertebrates has been implicated in several functions, including depth perception, contrast discrimination, etc. However, the blind area in front of the head that is proximal to the binocular visual field is often neglected. This anterior blind area is important when discussing the evolution of binocular vision because its relative length is inversely correlated with the width of the binocular field. Therefore, species with wider binocular fields also have shorter anterior blind areas and objects along the mid-sagittal plane can be imaged at closer distances. Additionally, the anterior blind area is of functional significance for birds because the beak falls within this blind area. We tested for the first time some specific predictions about the functional role of the anterior blind area in birds controlling for phylogenetic effects. We used published data on visual field configuration in 40 species of birds and measured beak and skull parameters from museum specimens. We found that birds with proportionally longer beaks have longer anterior blind areas and thus narrower binocular fields. This result suggests that the anterior blind area and beak visibility do play a role in shaping binocular fields, and that binocular field width is not solely determined by the need for stereoscopic vision. In visually guided foragers, the ability to see the beak-and how much of the beak can be seen varies predictably with foraging habits. For example, fish- and insect-eating specialists can see more of their own beak than birds eating immobile food can. But in non-visually guided foragers, there is no consistent relationship between the beak and anterior blind area. We discuss different strategies-wide binocular fields, large eye movements, and long beaks-that minimize the potential negative effects of the anterior blind area. Overall, we argue that there is more to avian binocularity than meets the eye. PMID- 28355253 TI - Three-party authenticated key agreements for optimal communication. AB - Authenticated key agreements enable users to determine session keys, and to securely communicate with others over an insecure channel via the session keys. This study investigates the lower bounds on communications for three-party authenticated key agreements and considers whether or not the sub-keys for generating a session key can be revealed in the channel. Since two clients do not share any common secret key, they require the help of the server to authenticate their identities and exchange confidential and authenticated information over insecure networks. However, if the session key security is based on asymmetric cryptosystems, then revealing the sub-keys cannot compromise the session key. The clients can directly exchange the sub-keys and reduce the transmissions. In addition, authenticated key agreements were developed by using the derived results of the lower bounds on communications. Compared with related approaches, the proposed protocols had fewer transmissions and realized the lower bounds on communications. PMID- 28355251 TI - Immunization with a streptococcal multiple-epitope recombinant protein protects mice against invasive group A streptococcal infection. AB - Streptococcus pyogenes (group A Streptococcus; GAS) causes clinical diseases, including pharyngitis, scarlet fever, impetigo, necrotizing fasciitis and streptococcal toxic shock syndrome. A number of group A streptococcus vaccine candidates have been developed, but only one 26-valent recombinant M protein vaccine has entered clinical trials. Differing from the design of a 26-valent recombinant M protein vaccine, we provide here a vaccination using the polyvalence epitope recombinant FSBM protein (rFSBM), which contains four different epitopes, including the fibronectin-binding repeats domain of streptococcal fibronectin binding protein Sfb1, the C-terminal immunogenic segment of streptolysin S, the C3-binding motif of streptococcal pyrogenic exotoxin B, and the C-terminal conserved segment of M protein. Vaccination with the rFSBM protein successfully prevented mortality and skin lesions caused by several emm strains of GAS infection. Anti-FSBM antibodies collected from the rFSBM-immunized mice were able to opsonize at least six emm strains and can neutralize the hemolytic activity of streptolysin S. Furthermore, the internalization of GAS into nonphagocytic cells is also reduced by anti-FSBM serum. These findings suggest that rFSBM can be applied as a vaccine candidate to prevent different emm strains of GAS infection. PMID- 28355252 TI - Factors associated with early mycological clearance in HIV-associated cryptococcal meningitis. AB - INTRODUCTION: The first-line combination therapy for HIV-associated cryptococcal meningitis (CM), a condition of high mortality particularly in the first two weeks of treatment, consists of amphotericin B plus flucytosine (5-FC). Given that 5-FC remains unavailable in many countries, the knowledge of factors influencing mycological clearance in patients treated with second-line therapy could contribute to effective management. OBJECTIVES: To determine the factors associated with the clearance of Cryptococcus sp. from the cerebrospinal fluid by the second week of effective antifungal therapy (early mycological clearance) in HIV-associated CM. METHODS: Retrospective cohort study based on secondary data corresponding to HIV-associated CM cases hospitalized at a tertiary health care center in Lima, Peru where 5-FC remains unavailable. Risk factors associated with early mycological clearance were analyzed by generalized linear regression models. RESULTS: From January 2000 to December 2013, 234 individuals were discharged with a diagnosis of HIV-associated CM; in 215 we retrieved the required data. The inpatient mortality was 20% (43/215), 15 of them in the first two weeks of treatment. In the final model (157 cases), adjusted for age, previous episode of CM, ART use, type of antifungal treatment, raised intracranial pressure, frequency of therapeutic lumbar punctures, baseline fungal burden and treatment period, the factors associated with early mycological clearance were: Amphotericin B deoxycholate plus fluconazole as combination therapy (RR, 1.56; 95% CI, 1.14-2.14); severe baseline intracranial pressure (>=35 cm H2O) (RR, 0.57; 95% CI, 0.33-0.99); and baseline fungal burden over 4.5 log10 CFU/mL (RR, 0.61 95% CI: 0.39-0.95). CONCLUSIONS: In a setting without access to first-line therapy for CM, the combination therapy with amphotericin B deoxycholate plus fluconazole was positively associated with early mycological clearance, while high fungal burden and severe baseline intracranial pressure were negatively associated, and thus related to failure. PMID- 28355254 TI - Annexin A1 can inhibit the in vitro invasive ability of nasopharyngeal carcinoma cells possibly through Annexin A1/S100A9/Vimentin interaction. AB - Annexin A1 is a member of a large superfamily of glucocorticoid-regulated, calcium- and phospholipid-binding proteins. Our previous studies have shown that the abnormal expression of Annexin A1 is related to the occurrence and development of nasopharyngeal carcinoma (NPC). To understand the roles of Annexin A1 in the tumorigenesis of NPC, targeted proteomic analysis was performed on Annexin A1-associated proteins from NPC cells. We identified 436 proteins associated with Annexin A1, as well as two Annexin A1-interacted key proteins, S100A9 and Vimentin, which were confirmed by co-immunoprecipitation. Gene function classification revealed that the Annexin A1-associated proteins can be grouped into 21 clusters based on their molecular functions. Protein-protein interaction analysis indicated that Annexin A1 /S100A9/Vimentin interactions may be involved in the invasion and metastasis of NPC because they can form complexes in NPC cells. The down-regulation of Annexin A1 in NPC may lead to the overexpression of S100A9/Vimentin, which may increase the possibility of the invasion ability of NPC cells by adjusting the function of cytoskeleton proteins. Results suggested that the biological functions of Annexin A1 in NPC were diverse, and that Annexin A1 can inhibit the in vitro invasive ability of NPC cells through Annexin A1 /S100A9/Vimentin interaction. PMID- 28355255 TI - Efficiency and optimal size of hospitals: Results of a systematic search. AB - BACKGROUND: National Health Systems managers have been subject in recent years to considerable pressure to increase concentration and allow mergers. This pressure has been justified by a belief that larger hospitals lead to lower average costs and better clinical outcomes through the exploitation of economies of scale. In this context, the opportunity to measure scale efficiency is crucial to address the question of optimal productive size and to manage a fair allocation of resources. METHODS AND FINDINGS: This paper analyses the stance of existing research on scale efficiency and optimal size of the hospital sector. We performed a systematic search of 45 past years (1969-2014) of research published in peer-reviewed scientific journals recorded by the Social Sciences Citation Index concerning this topic. We classified articles by the journal's category, research topic, hospital setting, method and primary data analysis technique. Results showed that most of the studies were focussed on the analysis of technical and scale efficiency or on input / output ratio using Data Envelopment Analysis. We also find increasing interest concerning the effect of possible changes in hospital size on quality of care. CONCLUSIONS: Studies analysed in this review showed that economies of scale are present for merging hospitals. Results supported the current policy of expanding larger hospitals and restructuring/closing smaller hospitals. In terms of beds, studies reported consistent evidence of economies of scale for hospitals with 200-300 beds. Diseconomies of scale can be expected to occur below 200 beds and above 600 beds. PMID- 28355257 TI - Lithic technological responses to Late Pleistocene glacial cycling at Pinnacle Point Site 5-6, South Africa. AB - There are multiple hypotheses for human responses to glacial cycling in the Late Pleistocene, including changes in population size, interconnectedness, and mobility. Lithic technological analysis informs us of human responses to environmental change because lithic assemblage characteristics are a reflection of raw material transport, reduction, and discard behaviors that depend on hunter gatherer social and economic decisions. Pinnacle Point Site 5-6 (PP5-6), Western Cape, South Africa is an ideal locality for examining the influence of glacial cycling on early modern human behaviors because it preserves a long sequence spanning marine isotope stages (MIS) 5, 4, and 3 and is associated with robust records of paleoenvironmental change. The analysis presented here addresses the question, what, if any, lithic assemblage traits at PP5-6 represent changing behavioral responses to the MIS 5-4-3 interglacial-glacial cycle? It statistically evaluates changes in 93 traits with no a priori assumptions about which traits may significantly associate with MIS. In contrast to other studies that claim that there is little relationship between broad-scale patterns of climate change and lithic technology, we identified the following characteristics that are associated with MIS 4: increased use of quartz, increased evidence for outcrop sources of quartzite and silcrete, increased evidence for earlier stages of reduction in silcrete, evidence for increased flaking efficiency in all raw material types, and changes in tool types and function for silcrete. Based on these results, we suggest that foragers responded to MIS 4 glacial environmental conditions at PP5-6 with increased population or group sizes, 'place provisioning', longer and/or more intense site occupations, and decreased residential mobility. Several other traits, including silcrete frequency, do not exhibit an association with MIS. Backed pieces, once they appear in the PP5-6 record during MIS 4, persist through MIS 3. Changing paleoenvironments explain some, but not all temporal technological variability at PP5-6. PMID- 28355258 TI - The value of Gd-EOB-DTPA-enhanced MR imaging in characterizing cirrhotic nodules with atypical enhancement on Gd-DTPA-enhanced MR images. AB - PURPOSE: To evaluate the utility of Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) in characterizing atypically enhanced cirrhotic nodules detected on conventional Gd-DTPA-enhanced MR images. MATERIALS AND METHODS: We enrolled 61 consecutive patients with 88 atypical nodules seen on conventional Gd-DTPA enhanced MR images who underwent Gd-EOB-DTPA-enhanced MRI within a 3-month period. Using a reference standard, we determined that 58 of the nodules were hepatocellular carcinoma (HCC) and 30 were dysplastic nodules (DNs). Tumor size, signal intensity on precontrast T1-weighted images (T1WI), T2-weighted images (T2WI) and diffusion-weighted images (DWI), and the enhancement patterns seen on dynamic phase and hepatocyte phase images were determined. RESULTS: There were significant differences between DNs and HCC in hyperintensity on T2WI, hypointensity on T1WI, hypervascularity on arterial phase images, typical HCC enhancement patterns on dynamic MR images, hypointensity on hepatocyte phase images, and hyperintensity on DWI. The sensitivity and specificity were 79.3% and 83.3% for T2WI, 50.0% and 80.0% for T1WI, 82.8% and 76.7% for DWI, 17.2% and 100% for dynamic MR imaging, 93.1% and 83.3% for hepatocyte phase imaging, and 46.8% and 100% when arterial hypervascularity was combined with hypointensity on hepatocyte-phase imaging. CONCLUSION: Gd-EOB-DTPA-enhanced hepatocyte phase imaging is recommended for patients at high risk for HCC who present with atypical lesions on conventional Gd-DTPA-enhanced MR images. PMID- 28355256 TI - The usefulness of monomeric periostin as a biomarker for idiopathic pulmonary fibrosis. AB - The natural course of idiopathic pulmonary fibrosis (IPF) is variable. Predicting disease progression and survival in IPF is important for treatment. We previously demonstrated that serum periostin has the potential to be a prognostic biomarker for IPF. Our aim was to use monomeric periostin in a multicenter study to evaluate its efficacy in diagnosing IPF and predicting its progression. To do so, we developed a new periostin kit to detect only monomeric periostin. The subjects consisted of 60 IPF patients in a multicenter cohort study. We applied monomeric periostin, total periostin detected by a conventional kit, and the conventional biomarkers-KL-6, SP-D, and LDH-to diagnose IPF and to predict its short-term progression as estimated by short-term changes of %VC and % DL, CO. Moreover, we compared the fraction ratios of monomeric periostin to total periostin in IPF with those in other periostin-high diseases: atopic dermatitis, systemic scleroderma, and asthma. Monomeric periostin showed the greatest ability to identify IPF comparable with KL-6 and SP-D. Both monomeric and total periostin were well correlated with the decline of %VC and % DL, CO. Clustering of IPF patients into high and low periostin groups proved useful for predicting the short-term progression of IPF. Moreover, the relative ratio of monomeric periostin was higher in IPF than in other periostin-high diseases. Measuring monomeric periostin is useful for diagnosing IPF and predicting its short-term progression. Moreover, the ratio of monomeric periostin to total periostin is elevated in IPF compared to other periostin-high diseases. PMID- 28355259 TI - To evaluate efficacy and safety of amphotericin B in two different doses in the treatment of post kala-azar dermal leishmaniasis (PKDL). AB - BACKGROUND: Post kala-azar dermal leishmaniasis (PKDL) is a skin disorder that usually occurs among patients with a past history of visceral leishmaniasis (VL). Cases are also reported without a history of VL. There is no satisfactory treatment regimen available at present. We aimed to compare the efficacy and safety of amphotericin B in two different doses (0.5mg/kg vs 1mg/kg) in a prospective randomized trial in 50 PKDL patients. METHODS: In this open label study 50 patients with PKDL, aged between 5-60 years were randomized in two groups. Group A received amphotericin B in the dose of 0.5 mg/kg in 5% dextrose, daily for 20 infusions for 3 courses at an interval of 15 days between each course and Group B received amphotericin B in the dose of 1mg/kg in 5% dextrose on alternate days, 20 infusions for 3 courses an interval of 15 days between each course and followed up for one year. RESULTS: A total of 50 patients were enrolled, 25 in each of group A and group B. Two patients lost to follow up and three patients withdrew consent due to adverse events. The initial cure rate was 92% in group A and 88% in group B by intention to treat analysis and final cure rate by per protocol analysis was 95.65% and 95.45% in group A and group B respectively. Two patients each from either group relapsed. Nephrotoxicity was the most common adverse event occurring in both the groups. CONCLUSION: The lower dose appears to have fewer adverse events however, nephrotoxicity remains a problem in both regimens. The 0.5mg/kg regimen may be considered instead of the higher dosage however safer treatments remain critical for PKDL treatment. PMID- 28355260 TI - Increased trefoil factor 2 levels in patients with chronic kidney disease. AB - In chronically damaged tissue, trefoil factor family (TFF) peptides ensure epithelial protection and restitution. In chronic kidney disease (CKD), TFF1 and TFF2 are reported to be upregulated. Especially in the early phase, CKD is associated with silently ongoing renal damage and inflammation. Moreover, many patients are diagnosed late during disease progression. We therefore sought to investigate the potential of TFF2 as biomarker for CKD. We followed 118 patients suffering from predialysis CKD and 23 healthy volunteers. TFF2 concentrations were measured using ELISA. Our results showed, that median TFF2 serum levels were significantly higher in patients with later CKD stages as compared to healthy controls (p < 0.001) or early stages (p < 0.001). In patients with mid CKD stages TFF2 serum levels were significantly higher than in healthy controls (p = 0.002). Patients with early or mid CKD stages had significantly higher TFF2 urine concentrations than later CKD stages (p < 0.001 and p = 0.009, respectively). Fractional TFF2 excretion differed significantly between early CKD stages and healthy controls (p = 0.01). ROC curve showed that TFF2 levels can predict different CKD stages (AUC > 0.75). In conclusion, urine and serum TFF2 levels of CKD patients show a different profile dependent on CKD stages. Whereas TFF2 urine levels continuously decreased with disease progression, TFF2 serum concentrations progressively increased from the early to later CKD stages, indicating changes in renal function and offering the potential to examine the course of CKD. PMID- 28355262 TI - Correction: Accuracy of optical biometry combined with Placido disc corneal topography for intraocular lens power calculation. AB - [This corrects the article DOI: 10.1371/journal.pone.0172634.]. PMID- 28355261 TI - Preclinical mouse model to monitor live Muc5b-producing conjunctival goblet cell density under pharmacological treatments. AB - PURPOSE: Modification of mucous cell density and gel-forming mucin production are established hallmarks of mucosal diseases. Our aim was to develop and validate a mouse model to study live goblet cell density in pathological situations and under pharmacological treatments. METHODS: We created a reporter mouse for the gel-forming mucin gene Muc5b. Muc5b-positive goblet cells were studied in the eye conjunctiva by immunohistochemistry and probe-based confocal laser endomicroscopy (pCLE) in living mice. Dry eye syndrome (DES) model was induced by topical application of benzalkonium chloride (BAK) and recombinant interleukine (rIL) 13 was administered to reverse the goblet cell loss in the DES model. RESULTS: Almost 50% of the total of conjunctival goblet cells are Muc5b+ in unchallenged mice. The decrease density of Muc5b+ conjunctival goblet cell population in the DES model reflects the whole conjunctival goblet cell loss. Ten days of BAK in one eye followed by 4 days without any treatment induced a -18.3% decrease in conjunctival goblet cell density. A four days of rIL13 application in the DES model restored the normal goblet cell density. CONCLUSION: Muc5b is a biological marker of DES mouse models. We bring the proof of concept that our model is unique and allows a better understanding of the mechanisms that regulate gel forming mucin production/secretion and mucous cell differentiation in the conjunctiva of living mice and can be used to test treatment compounds in mucosal disease models. PMID- 28355263 TI - The effect of a sequential structure of practice for the training of perceptual cognitive skills in tennis. AB - OBJECTIVE: Anticipation of opponent actions, through the use of advanced (i.e., pre-event) kinematic information, can be trained using video-based temporal occlusion. Typically, this involves isolated opponent skills/shots presented as trials in a random order. However, two different areas of research concerning representative task design and contextual (non-kinematic) information, suggest this structure of practice restricts expert performance. The aim of this study was to examine the effect of a sequential structure of practice during video based training of anticipatory behavior in tennis, as well as the transfer of these skills to the performance environment. METHODS: In a pre-practice-retention transfer design, participants viewed life-sized video of tennis rallies across practice in either a sequential order (sequential group), in which participants were exposed to opponent skills/shots in the order they occur in the sport, or a non-sequential (non-sequential group) random order. RESULTS: In the video-based retention test, the sequential group was significantly more accurate in their anticipatory judgments when the retention condition replicated the sequential structure compared to the non-sequential group. In the non-sequential retention condition, the non-sequential group was more accurate than the sequential group. In the field-based transfer test, overall decision time was significantly faster in the sequential group compared to the non-sequential group. CONCLUSION: Findings highlight the benefits of a sequential structure of practice for the transfer of anticipatory behavior in tennis. We discuss the role of contextual information, and the importance of representative task design, for the testing and training of perceptual-cognitive skills in sport. PMID- 28355264 TI - Epidemiology and outcomes of hypoglycemia in patients with advanced diabetic kidney disease on dialysis: A national cohort study. AB - BACKGROUND: Patients with advanced diabetic kidney disease (DKD) behave differently to diabetic patients without kidney disease. We aimed to investigate the associations of hypoglycemia and outcomes after initiation of dialysis in patients with advanced DKD on dialysis. METHODS: Using National Health Insurance Research Database, 20,845 advanced DKD patients beginning long-term dialysis between 2002 and 2006 were enrolled. We investigated the incidence of severe hypoglycemia episodes before initiation of dialysis. Patients were followed from date of first dialysis to death, end of dialysis, or 2008. Main outcomes measured were all-cause mortality, myocardial infarction (MI), and subsequent severe hypoglycemic episodes after dialysis. RESULTS: 19.18% patients had at least one hypoglycemia episode during 1-year period before initiation of dialysis. Advanced DKD patients with higher adapted Diabetes Complications Severity Index (aDCSI) scores were associated with more frequent hypoglycemia (P for trend < 0.001). Mortality and subsequent severe hypoglycemia after dialysis both increased with number of hypoglycemic episodes. Compared to those who had no hypoglycemic episodes, those who had one had a 15% higher risk of death and a 2.3-fold higher risk of subsequent severe hypoglycemia. Those with two or more episodes had a 19% higher risk of death and a 3.9-fold higher risk of subsequent severe hypoglycemia. However, previous severe hypoglycemia was not correlated with risk of MI after dialysis. CONCLUSIONS: The rate of severe hypoglycemia was high in advanced DKD patients. Patients with higher aDCSI scores tended to have more hypoglycemic episodes. Hypoglycemic episodes were associated with subsequent hypoglycemia and mortality after initiation of dialysis. We studied the associations and further study is needed to establish cause. In addition, more attention is needed for hypoglycemia prevention in advanced DKD patients, especially for those at risk patients. PMID- 28355265 TI - Effects of different lower-limb sensory stimulation strategies on postural regulation-A systematic review and meta-analysis. AB - Systematic reviews of balance control have tended to only focus on the effects of single lower-limb stimulation strategies, and a current limitation is the lack of comparison between different relevant stimulation strategies. The aim of this systematic review and meta-analysis was to examine evidence of effects of different lower-limb sensory stimulation strategies on postural regulation and stability. Moderate- to high- pooled effect sizes (Unbiased (Hedges' g) standardized mean differences (SMD) = 0.31-0.66) were observed with the addition of noise in a Stochastic Resonance Stimulation Strategy (SRSS), in three populations (i.e., healthy young adults, older adults, and individuals with lower limb injuries), and under different task constraints (i.e., unipedal, bipedal, and eyes open). A Textured Material Stimulation Strategy (TMSS) enhanced postural control in the most challenging condition-eyes-closed on a stable surface (SMD = 0.61), and in older adults (SMD = 0.30). The Wearable Garments Stimulation Strategy (WGSS) showed no or adverse effects (SMD = -0.68-0.05) under all task constraints and in all populations, except in individuals with lower-limb injuries (SMD = 0.20). Results of our systematic review and meta-analysis revealed that future research could consider combining two or more stimulation strategies in intervention treatments for postural regulation and balance problems, depending on individual needs. PMID- 28355266 TI - Molecular epidemiology and antimicrobial susceptibility of Clostridium difficile isolates from two Korean hospitals. AB - Clostridium difficile is one of the main etiological agents causing antibiotic associated diarrhea. This study investigated the genetic diversity of 70 toxigenic C. difficile isolates from two Korean hospitals by employing toxinotyping, ribotyping, multilocus sequence typing (MLST), and pulsed-field gel electrophoresis (PFGE). Toxin gene amplification resulted in 68 A+B+ and two A-B+ isolates. Most isolates (95.7-100%) were susceptible to daptomycin, metronidazole, and vancomycin. Seventy C. difficile isolates were classified into five toxinotypes, 19 ribotypes, 16 sequence types (STs), and 33 arbitrary pulsotypes. All C. difficile isolates of ribotype 018 (n = 38) were classified into ST17, which was the most prevalent ST in both hospitals. However, C. difficile isolates of ST17 (ribotype 018) exhibited pulsotypes that differed by hospital. ST2 (ribotype 014/020), 8 (ribotypes 002), 17 (ribotype 018), and 35 (ribotypes 015) were detected in both hospitals, whereas other STs were unique to each hospital. Statistical comparison of the different typing methods revealed that ribotyping and PFGE were highly predictive of STs. In conclusion, our epidemiological study indicates that C. difficile infections in both hospitals are associated with the persistence of endemic clones coupled with the emergence of many unique clones. A combination of MLST with PFGE or ribotyping could be useful for monitoring epidemic C. difficile strains and the emergence of new clones in hospitals. PMID- 28355267 TI - Food consumption and food exchange of caged honey bees using a radioactive labelled sugar solution. AB - We measured the distribution of sugar solution within groups of caged honey bees (Apis mellifera) under standard in vitro laboratory conditions using 14C polyethylene glycol as a radioactive marker to analyze ingestion by individual bees after group feeding. We studied the impact of different experimental setups by varying the number of bees, age of bees, origin of bees, duration of experiment, the amount of available diet, and the influence of the neurotoxic pesticide imidacloprid in the diet on the feeding and food sharing behavior (trophallaxis). Sugar solution was non-uniformly distributed in bees in 36 out of 135 cages. As a measure of the extent to which the sugar diet was equally distributed between caged bees, we calculated the (inner 80%) intake ratio by dividing the intake of the 90th percentile bee by the intake of the 10th percentile bee. This intake ratio ranged from 1.3 to 94.8 in 133 individual cages, further supporting a non-uniform distribution of food among caged bees. We can expect a cage with 10 or 30 bees containing one bee that ingests, on average, the 8.8-fold of the bee in the same cage ingesting the smallest quantity of food. Inner 80% intake ratios were lower in experiments with a permanent or chronic offering of labelled sugar solution compared to temporary or acute feedings. After pooling the data of replicates to achieve a higher statistical power we compared different experimental setups. We found that uniform food distribution is best approached with 10 newly emerged bees per cage, which originate from a brood comb from a single colony. We also investigated the trophallaxis between caged honey bees which originally consumed the diet and newly added bees. Color marked bees were starved and added to the cages in a ratio of 10:5 or 20:20 after the initial set of bees consumed all the labelled sugar solution. The distribution of the labelled sugar solution by trophallaxis within 48 hours to added bees was 25% (10:5) or 45% (20:20) of the initial sugar solution. Imidacloprid at its median lethal dose (LD50) in the sugar solution reduced this post-feeding food transmission to 27% (20:20). Our results show that differences in food intake exist within caged bees that may lead to differential exposure that can influence the interpretation of toxicity tests. PMID- 28355268 TI - Signs of current suicidality in men: A systematic review. AB - Suicide signs have been identified by expert consensus and are relied on by service providers, community helpers' and family members to identify suicidal men. Whether signs that are reported in suicide literature accurately describe male presentations of suicidality is unclear. A systematic review of the literature was conducted to identify male-specific signs of current suicidality and identify gaps in the literature for future research. Searches through Medline, CINAHL, PsychInfo and the Behavioral Sciences Collection, guided by the PRISMA-P statement, identified 12 studies that met the study eligibility criteria. Although the results generally reflected suicide signs identified by expert consensus, there is little research that has examined male-specific signs of the current suicidal state. This review highlights the need for scientific research to clarify male presentation of suicidality. Implications for future research to improve the prompt identification of suicidal men are discussed. PMID- 28355269 TI - Use of a counterfactual approach to evaluate the effect of area closures on fishing location in a tropical tuna fishery. AB - Spatial closures are widely used in marine conservation and fisheries management and it is important to understand their contribution to achieving management objectives. Many previous evaluations of closed area effects have used before after comparisons, which, without controlling for a full range of factors, cannot ascribe changes in fleet behaviour to area closures per se. In this study we used a counterfactual approach to disentangle the effect of two closed areas on fishing location from other competing effects on the behaviour of the Indian Ocean tuna purse seine fishery. Our results revealed an inconsistent effect of the one of the closed areas between years, after taking into account the influence of environmental conditions on fleet behaviour. This suggests that the policy of closing the area per se was not the main driver for the fleet allocating its effort elsewhere. We also showed a marked difference in effect between the two closed areas resulting from their different locations in the fishery area. These findings highlight the need to account for other key fleet behavioural drivers when predicting or evaluating the contribution of area closures to achieving conservation and fishery management objectives. PMID- 28355270 TI - The NF-kappaB-dependent and -independent transcriptome and chromatin landscapes of human coronavirus 229E-infected cells. AB - Coronavirus replication takes place in the host cell cytoplasm and triggers inflammatory gene expression by poorly characterized mechanisms. To obtain more insight into the signals and molecular events that coordinate global host responses in the nucleus of coronavirus-infected cells, first, transcriptome dynamics was studied in human coronavirus 229E (HCoV-229E)-infected A549 and HuH7 cells, respectively, revealing a core signature of upregulated genes in these cells. Compared to treatment with the prototypical inflammatory cytokine interleukin(IL)-1, HCoV-229E replication was found to attenuate the inducible activity of the transcription factor (TF) NF-kappaB and to restrict the nuclear concentration of NF-kappaB subunits by (i) an unusual mechanism involving partial degradation of IKKbeta, NEMO and IkappaBalpha and (ii) upregulation of TNFAIP3 (A20), although constitutive IKK activity and basal TNFAIP3 expression levels were shown to be required for efficient virus replication. Second, we characterized actively transcribed genomic regions and enhancers in HCoV-229E infected cells and systematically correlated the genome-wide gene expression changes with the recruitment of Ser5-phosphorylated RNA polymerase II and prototypical histone modifications (H3K9ac, H3K36ac, H4K5ac, H3K27ac, H3K4me1). The data revealed that, in HCoV-infected (but not IL-1-treated) cells, an extensive set of genes was activated without inducible p65 NF-kappaB being recruited. Furthermore, both HCoV-229E replication and IL-1 were shown to upregulate a small set of genes encoding immunomodulatory factors that bind p65 at promoters and require IKKbeta activity and p65 for expression. Also, HCoV-229E and IL-1 activated a common set of 440 p65-bound enhancers that differed from another 992 HCoV-229E-specific enhancer regions by distinct TF-binding motif combinations. Taken together, the study shows that cytoplasmic RNA viruses fine tune NF-kappaB signaling at multiple levels and profoundly reprogram the host cellular chromatin landscape, thereby orchestrating the timely coordinated expression of genes involved in multiple signaling, immunoregulatory and metabolic processes. PMID- 28355271 TI - Transient helicity in intrinsically disordered Axin-1 studied by NMR spectroscopy and molecular dynamics simulations. AB - Many natural proteins are, as a whole or in part, intrinsically disordered. Frequently, such intrinsically disordered regions (IDRs) undergo a transition to a defined and often helical conformation upon binding to partner molecules. The intrinsic propensity of an IDR sequence to fold into a helical conformation already in the absence of a binding partner can have a decisive influence on the binding process and affinity. Using a combination of NMR spectroscopy and molecular dynamics (MD) simulations we have investigated the tendency of regions of Axin-1, an intrinsically disordered scaffolding protein of the WNT signaling pathway, to form helices in segments interacting with binding partners. Secondary chemical shifts from NMR measurements show an increased helical population in these regions. Systematic application of MD advanced sampling approaches on peptide segments of Axin-1 reproduces the experimentally observed tendency and allows insights into the distribution of segment conformations and free energies of helix formation. The results, however, were found to dependent on the force field water model. Recent water models specifically designed for IDRs significantly reduce the predicted helical content and do not improve the agreement with experiment. PMID- 28355272 TI - Vitamin D receptor gene is epigenetically altered and transcriptionally up regulated in multiple sclerosis. AB - OBJECTIVE: Vitamin D deficiency has been linked to increased risk of multiple sclerosis (MS) and poor outcome. However, the specific role that vitamin D plays in MS still remains unknown. In order to identify potential mechanisms underlying vitamin D effects in MS, we profiled epigenetic changes in vitamin D receptor (VDR) gene to identify genomic regulatory elements relevant to MS pathogenesis. METHODS: Human T cells derived from whole blood by negative selection were isolated in a set of 23 relapsing-remitting MS (RRMS) patients and 12 controls matched by age and gender. DNA methylation levels were assessed by bisulfite cloning sequencing in two regulatory elements of VDR. mRNA levels were measured by RT-qPCR to assess changes in VDR expression between patients and controls. RESULTS: An alternative VDR promoter placed at exon 1c showed increased DNA methylation levels in RRMS patients (median 30.08%, interquartile range 19.2%) compared to controls (18.75%, 9.5%), p-value<0.05. Moreover, a 6.5-fold increase in VDR mRNA levels was found in RRMS patients compared to controls (p value<0.001). CONCLUSIONS: An alternative promoter of the VDR gene shows altered DNA methylation levels in patients with multiple sclerosis, and it is associated with VDR mRNA upregulation. This locus may represent a candidate regulatory element in the genome relevant to MS pathogenesis. PMID- 28355273 TI - Synthesis, characterization, and debromination reactivity of cellulose-stabilized Pd/Fe nanoparticles for 2,2',4,4'-tretrabromodiphenyl ether. AB - In this study, two kinds of cellulose derivatives (polyanionic cellulose (PAC) and hydroxypropylmethyl cellulose (HPMC)) were selected as stabilizers of Pd/Fe nanoparticles (NPs) to investigate their influences on the debromination performances of 2,2',4,4'-tretrabromodiphenyl ether (BDE47). Field emission scanning electron microscope (FE-SEM) images revealed that the cellulose stabilized Pd/Fe NPs were smaller and more uniform than the bare-Pd/Fe NPs. X-ray diffractometer (XRD) and X-ray photoelectron spectroscopy (XPS) results suggested that cellulose coatings found on Pd/Fe NPs surfaces featured some antioxidation abilities, which followed the order of HPMC < PAC. Sedimentation tests demonstrated that the stabilizing power of PAC for Pd/Fe NPs was higher than that of HPMC. Fourier transfer infrared spectrometer (FTIR) results indicated that PAC molecules were bound to the Pd/Fe NPs surfaces by polar covalent bonds and hydrogen bonds, while HPMC molecules interacted with the nanoparticles by hydrogen bonds. Batch debromination test for BDE47 demonstrated that the catalytic debromination rate with cellulose-stabilized Pd/Fe NPs was higher than that with bare-Pd/Fe NPs during reaction period of 15 min. Overall, this study indicated that both celluloses are beneficial to forming smaller, more regular, stable and antioxidative Pd/Fe NPs, leading to higher debromination reactivity for BDE47 compared with the bare-Pd/Fe NPs. Therefore Pd/Fe NPs can be utilized as a promising remediation technology for the contaminated groundwater and soils. PMID- 28355275 TI - Investigating time-efficiency of forward masking paradigms for estimating basilar membrane input-output characteristics. AB - It is well known that pure-tone audiometry does not sufficiently describe individual hearing loss (HL) and that additional measures beyond pure-tone sensitivity might improve the diagnostics of hearing deficits. Specifically, forward masking experiments to estimate basilar-membrane (BM) input-output (I/O) function have been proposed. However, such measures are very time consuming. The present study investigated possible modifications of the temporal masking curve (TMC) paradigm to improve time and measurement efficiency. In experiment 1, estimates of knee point (KP) and compression ratio (CR) of individual BM I/Os were derived without considering the corresponding individual "off-frequency" TMC. While accurate estimation of KPs was possible, it is difficult to ensure that the tested dynamic range is sufficient. Therefore, in experiment 2, a TMC based paradigm, referred to as the "gap method", was tested. In contrast to the standard TMC paradigm, the maker level was kept fixed and the "gap threshold" was obtained, such that the masker just masks a low-level (12 dB sensation level) signal. It is argued that this modification allows for better control of the tested stimulus level range, which appears to be the main drawback of the conventional TMC method. The results from the present study were consistent with the literature when estimating KP levels, but showed some limitations regarding the estimation of the CR values. Perspectives and limitations of both approaches are discussed. PMID- 28355274 TI - PrPSc formation and clearance as determinants of prion tropism. AB - Prion strains are characterized by strain-specific differences in neuropathology but can also differ in incubation period, clinical disease, host-range and tissue tropism. The hyper (HY) and drowsy (DY) strains of hamster-adapted transmissible mink encephalopathy (TME) differ in tissue tropism and susceptibility to infection by extraneural routes of infection. Notably, DY TME is not detected in the secondary lymphoreticular system (LRS) tissues of infected hosts regardless of the route of inoculation. We found that similar to the lymphotropic strain HY TME, DY TME crosses mucosal epithelia, enters draining lymphatic vessels in underlying laminae propriae, and is transported to LRS tissues. Since DY TME causes disease once it enters the peripheral nervous system, the restriction in DY TME pathogenesis is due to its inability to establish infection in LRS tissues, not a failure of transport. To determine if LRS tissues can support DY TME formation, we performed protein misfolding cyclic amplification using DY PrPSc as the seed and spleen homogenate as the source of PrPC. We found that the spleen environment can support DY PrPSc formation, although at lower rates compared to lymphotropic strains, suggesting that the failure of DY TME to establish infection in the spleen is not due to the absence of a strain-specific conversion cofactor. Finally, we provide evidence that DY PrPSc is more susceptible to degradation when compared to PrPSc from other lymphotrophic strains. We hypothesize that the relative rates of PrPSc formation and clearance can influence prion tropism. PMID- 28355276 TI - Rituximab maintenance therapy for patients with diffuse large B-cell lymphoma: A meta-analysis. AB - PURPOSE: The addition of rituximab to standard chemotherapy has significantly improved survival in patients with lymphoma. Recently, maintenance therapy with rituximab has been shown to prevent relapse and provide survival benefits for patients with follicular or mantle cell lymphoma. However, the effects of rituximab in patients with diffuse large B-cell lymphoma (DLBCL) remain unclear. Two new studies involving rituximab in the treatment of DLBCL were performed this past year. We performed a meta analysis to evaluate the effects of rituximab maintenance treatment of patients with DLBCL. METHODS: Several databases (PubMed, MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials) databases were reviewed for relevant randomized controlled trials published prior to May, 2016. Two reviewers assessed the quality of the included studies and extracted data independently. The hazard ratios (HRs) for time-to-event data and relative risks (RRs) for the other data were pooled and estimated. RESULTS: Totally 5 studies including 1740 patients were eligible for the meta-analysis. Compared to the observation group, patients who received rituximab maintenance therapy had significantly improved event-free survival (EFS) (HR = 0.80, 95% CI: 0.65-0.98) and progression-free survival (PFS) (HR = 0.72, 95% CI: 0.54-0.94). However, there was no statistically significant difference in overall survival (OS) (HR = 0.66, 95% CI: 0.27-1.29). A subgroup analysis suggested that male patients may benefit from rituximab maintenance therapy with a better EFS (HR = 0.53, 95% CI: 0.34-0.82-), while this advantage was not observed in female patients (HR = 0.99, 95% CI: 0.64-1.52). CONCLUSIONS: Rituximab maintenance may provide survival benefits beyond that afforded by first- and second-line chemotherapy alone, especially in male patients. However, maintenance rituximab treatment may cause more adverse events. It is recommended that both survival benefits and adverse events should be taken into consideration when making treatment decisions. PMID- 28355278 TI - Analysis using national databases reveals a positive association between dietary polyunsaturated fatty acids with TV watching and diabetes in European females. AB - In recent years, dietary polyunsaturated fatty acids (PUFA) have increased in parallel to sedentary behavior and diabetes across the world. To test any putative association between dietary PUFA and sedentary behavior or diabetes in females, we obtained country-specific, cross-sectional data on sedentary activity and diabetes prevalence from European Cardiovascular Statistics 2012. Age and gender-specific, nutritional data from each country were obtained from nutritional surveys as well. Socioeconomic (GDP), physical environment (urbanization index) and climatic confounders were accounted for each country. Upon analysis, we found a strong, positive association between sedentary lifestyle in 11-yr old girls (> = 2 hours of TV/ weekday) and dietary PUFA across 21 European countries. Further, a weak association of dietary PUFA and a strong relationship of per-capita GDP was established with elevated fasting blood glucose [(> = 7.0 mmol/L; or on medication] among 25+ year old adult females across 23 countries in Europe. In summary, we present novel ecological evidence that dietary PUFA is strongly associated with sedentary behavior among pre-teen girls and weakly associated with diabetes among adult women across Europe. In the latter group, per-capita GDP was a significant predictor for diabetes as well. Therefore, we recommend that prospective randomized controlled trials (RCTs) be implemented to evaluate if ubiquitous presence of dietary PUFA and low socioeconomic status are possible confounders when intervening to treat/prevent sedentary lifestyle or diabetes in female subjects in Western nations. PMID- 28355277 TI - Modulation of the immune response by Fonsecaea pedrosoi morphotypes in the course of experimental chromoblastomycosis and their role on inflammatory response chronicity. AB - A common theme across multiple fungal pathogens is their ability to impair the establishment of a protective immune response. Although early inflammation is beneficial in containing the infection, an uncontrolled inflammatory response is detrimental and may eventually oppose disease eradication. Chromoblastomycosis (CBM), a cutaneous and subcutaneous mycosis, caused by dematiaceous fungi, is capable of inducing a chronic inflammatory response. Muriform cells, the parasitic form of Fonsecaea pedrosoi, are highly prevalent in infected tissues, especially in long-standing lesions. In this study we show that hyphae and muriform cells are able to establish a murine CBM with skin lesions and histopathological aspects similar to that found in humans, with muriform cells being the most persistent fungal form, whereas mice infected with conidia do not reach the chronic phase of the disease. Moreover, in injured tissue the presence of hyphae and especially muriform cells, but not conidia, is correlated with intense production of pro-inflammatory cytokines in vivo. High-throughput RNA sequencing analysis (RNA-Seq) performed at early time points showed a strong up regulation of genes related to fungal recognition, cell migration, inflammation, apoptosis and phagocytosis in macrophages exposed in vitro to muriform cells, but not conidia. We also demonstrate that only muriform cells required FcgammaR and Dectin-1 recognition to be internalized in vitro, and this is the main fungal form responsible for the intense inflammatory pattern observed in CBM, clarifying the chronic inflammatory reaction observed in most patients. Furthermore, our findings reveal two different fungal-host interaction strategies according to fungal morphotype, highlighting fungal dimorphism as an important key in understanding the bipolar nature of inflammatory response in fungal infections. PMID- 28355280 TI - The effect of social group size on feather corticosterone in the co-operatively breeding Smooth-billed Ani (Crotophaga ani): An assay validation and analysis of extreme social living. AB - Living closely with others can provide a myriad of fitness benefits, from shared territory defense to co-operative resource acquisition. Costs of social aggregation are not absent, however, and likely influence optimal and observed groups' sizes in a social species. Here, we explored optimal group size in a joint-nesting cuckoo species (the Smooth-billed Ani, Crotophaga ani) using endocrine markers of stress physiology (corticosterone, or CORT). Smooth-billed Anis exhibit intense reproductive competition that is exacerbated in atypically large groups. We therefore hypothesized that intra-group competition (measured by social group size) mediates the desirability and physiological cost of social group membership in this species. To test this hypothesis, we captured 47 adult Smooth-billed Anis (31 males, 16 females) during the breeding seasons of 2012 2014 in south-western Puerto Rico, and documented social group sizes. Tail feathers were sampled and used to quantify CORT (pg/mg) in enzyme-linked immunosorbent assays (ELISAs) (n = 50). Our analyses show significant differences in feather-CORT of adults between categorical group sizes, with individuals from atypically large social groups (>= x + 1SD) having highest mean concentrations (33.319 pg/mg), and individuals from atypically small social groups (<= x - 1SD) having lowest mean concentrations (8.969 pg/mg). Whether reproductive competition or effort is responsible for elevated CORT in atypically large social groups, however, remains unclear. Our results suggest that living in atypically large groups is physiologically expensive and may represent an evolutionarily unstable strategy. To our knowledge, this is the first study to explore a correlation between stress physiology and group size in a joint-nesting species. PMID- 28355279 TI - Highly sensitive measurements of disease progression in rare disorders: Developing and validating a multimodal model of retinal degeneration in Stargardt disease. AB - BACKGROUND: Each inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options-including gene therapy-are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (> 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients. To accommodate this problem, we developed and validated a sensitive and reliable composite clinical trial endpoint for disease progression based on structural measurements of retinal degeneration. METHODS AND FINDINGS: We used longitudinal data from early-onset Stargardt patients from the Netherlands (development cohort, n = 14) and the United Kingdom (external validation cohort, n = 18). The composite endpoint was derived from best-corrected visual acuity, fundus autofluorescence, and spectral domain optical coherence tomography. Weighting optimization techniques excluded visual acuity from the composite endpoint. After optimization, the endpoint outperformed each univariable outcome, and showed an average progression of 0.41 degrees retinal eccentricity per year (95% confidence interval, 0.30-0.52). Comparing with actual longitudinal values, the model accurately predicted progression (R2, 0.904). These properties were largely preserved in the validation cohort (0.43 degrees /year [0.33-0.53]; prediction: R2, 0.872). We subsequently ran a two-year trial simulation with the composite endpoint, which detected a 25% decrease in disease progression with 80% statistical power using only 14 patients. CONCLUSIONS: These results suggest that a multimodal endpoint, reflecting structural macular changes, provides a sensitive measurement of disease progression in Stargardt disease. It can be very useful in the evaluation of novel therapeutic modalities in rare disorders. PMID- 28355281 TI - Toward a phenological mismatch in estuarine pelagic food web? AB - Alterations of species phenology in response to climate change are now unquestionable. Until now, most studies have reported precocious occurrence of life cycle events as a major phenological response. Desynchronizations of biotic interactions, in particular predator-prey relationships, are however assumed to strongly impact ecosystems' functioning, as formalized by the Match-Mismatch Hypothesis (MMH). Temporal synchronicity between juvenile fish and zooplankton in estuaries is therefore of essential interest since estuaries are major nursery grounds for many commercial fish species. The Gironde estuary (SW France) has suffered significant alterations over the last three decades, including two Abrupt Ecosystem Shifts (AES), and three contrasted intershift periods. The main objective of this study was to depict modifications in fish and zooplankton phenology among inter-shift periods and discuss the potential effects of the resulting mismatches at a community scale. A flexible Bayesian method was used to estimate and compare yearly patterns of species abundance in the estuary among the three pre-defined periods. Results highlighted (1) an earlier peak of zooplankton production and entrance of fish species in the estuary and (2) a decrease in residence time of both groups in the estuary. Such species-specific phenological changes led to changes in temporal overlap between juvenile fish and their zooplanktonic prey. This situation questions the efficiency and potentially the viability of nursery function of the Gironde estuary, with potential implications for coastal marine fisheries of the Bay of Biscay. PMID- 28355282 TI - Breeding success of a marine central place forager in the context of climate change: A modeling approach. AB - In response to climate warming, a southward shift in productive frontal systems serving as the main foraging sites for many top predator species is likely to occur in Subantarctic areas. Central place foragers, such as seabirds and pinnipeds, are thus likely to cope with an increase in the distance between foraging locations and their land-based breeding colonies. Understanding how central place foragers should modify their foraging behavior in response to changes in prey accessibility appears crucial. A spatially explicit individual based simulation model (Marine Central Place Forager Simulator (MarCPFS)), including bio-energetic components, was built to evaluate effects of possible changes in prey resources accessibility on individual performances and breeding success. The study was calibrated on a particular example: the Antarctic fur seal (Arctocephalus gazella), which alternates between oceanic areas in which females feed and the land-based colony in which they suckle their young over a 120 days rearing period. Our model shows the importance of the distance covered to feed and prey aggregation which appeared to be key factors to which animals are highly sensitive. Memorization and learning abilities also appear to be essential breeding success traits. Females were found to be most successful for intermediate levels of prey aggregation and short distance to the resource, resulting in optimal female body length. Increased distance to resources due to climate warming should hinder pups' growth and survival while female body length should increase. PMID- 28355283 TI - Streptococcus gallolyticus infection in colorectal cancer and association with biological and clinical factors. AB - There is an unambiguous association of Streptococcus gallolyticus infection with colorectal cancer, although there is limited information about epidemiology or interaction between molecular and environmental factors. We performed an original quantitative analysis of S. gallolyticus in unselected colorectal cancer patients (n = 190) and their association with clinical, pathological tumor molecular profiles (microsatellite instability, hypermethylator phenotype and chromosomal instability pathways), and other biological factors in colorectal tumor and normal tissues (cytomegalovirus and Epstein-Barr virus infection). We developed a new quantitative method to assess bacterial load. Analytical validation was reached with a very high sensitivity and specificity. Our results showed a 3.2% prevalence of S. gallolyticus infection in our unselected cohort of colorectal cancer cases (6/190). The average S. gallolyticus copy number was 7,018 (range 44 34,585). No previous reports relating to S. gallolyticus infection have been published for unselected cohorts of patients. Finally, and despite a low prevalence of S. gallolyticus in this study, we were able to define a specific association with tumor tissue (p = 0.03) and with coinfection with Epstein-Barr virus (p = 0.042; OR: 9.49; 95% IC: 1.1-82.9). The prevalence data provided will be very useful in the design of future studies, and will make it possible to estimate the sample size needed to assess precise objectives. In conclusion, our results show a low prevalence of S. gallolyticus infection in unselected colorectal cancer patients and an association of positive S. gallolyticus infection with tumor tissue and Epstein-Barr virus coinfection. Further studies will be needed to definitively assess the prevalence of S. gallolyticus in colorectal cancer and the associated clinicopathological and molecular profiles. PMID- 28355285 TI - Characteristics of women obtaining induced abortions in selected low- and middle income countries. AB - BACKGROUND: In 2010-2014, approximately 86% of abortions took place in low- and middle-income countries (LMICs). Although abortion incidence varies minimally across geographical regions, it varies widely by subregion and within countries by subgroups of women. Differential abortion levels stem from variation in the level of unintended pregnancies and in the likelihood that women with unintended pregnancies obtain abortions. OBJECTIVES: To examine the characteristics of women obtaining induced abortions in LMICs. METHODS: We use data from official statistics, population-based surveys, and abortion patient surveys to examine variation in the percentage distribution of abortions and abortion rates by age at abortion, marital status, parity, wealth, education, and residence. We analyze data from five countries in Africa, 13 in Asia, eight in Europe, and two in Latin America and the Caribbean (LAC). RESULTS: Women across all sociodemographic subgroups obtain abortions. In most countries, women aged 20-29 obtained the highest proportion of abortions, and while adolescents obtained a substantial fraction of abortions, they do not make up a disproportionate share. Region specific patterns were observed in the distribution of abortions by parity. In many countries, a higher fraction of abortions occurred among women of high socioeconomic status, as measured by wealth status, educational attainment, and urban residence. Due to limited data on marital status, it is unknown whether married or unmarried women make up a larger share of abortions. CONCLUSIONS: These findings help to identify subgroups of women with disproportionate levels of abortion, and can inform policies and programs to reduce the incidence of unintended pregnancies; and in LMICs that have restrictive abortion laws, these findings can also inform policies to minimize the consequences of unsafe abortion and motivate liberalization of abortion laws. Program planners, policymakers, and advocates can use this information to improve access to safe abortion services, postabortion care, and contraceptive services. PMID- 28355284 TI - Differential action of glucocorticoids on apolipoprotein E gene expression in macrophages and hepatocytes. AB - Apolipoprotein E (apoE) has anti-atherosclerotic properties, being involved in the transport and clearance of cholesterol-rich lipoproteins as well as in cholesterol efflux from cells. We hypothesized that glucocorticoids may exert anti-inflammatory properties by increasing the level of macrophage-derived apoE. Our data showed that glucocorticoids increased apoE expression in macrophages in vitro as well as in vivo. Dexamethasone increased ~6 fold apoE mRNA levels in cultured peritoneal macrophages and RAW 264.7 cells. Administered to C57BL/6J mice, dexamethasone induced a two-fold increase in apoE expression in peritoneal macrophages. By contrast, glucocorticoids did not influence apoE expression in hepatocytes, in vitro and in vivo. Moreover, dexamethasone enhanced apoE promoter transcriptional activity in RAW 264.7 macrophages, but not in HepG2 cells, as tested by transient transfections. Analysis of apoE proximal promoter deletion mutants, complemented by protein-DNA interaction assays demonstrated the functionality of a putative glucocorticoid receptors (GR) binding site predicted by in silico analysis in the -111/-104 region of the human apoE promoter. In hepatocytes, GR can bind to their specific site within apoE promoter but are not able to modulate the gene expression. The modulatory blockade in hepatocytes is a consequence of partial involvement of transcription factors and other signaling molecules activated through MEK1/2 and PLA2/PLC pathways. In conclusion, our study indicates that glucocorticoids (1) differentially target apoE gene expression; (2) induce a significant increase in apoE level specifically in macrophages. The local increase of apoE gene expression in macrophages at the level of the atheromatous plaque may have therapeutic implications in atherosclerosis. PMID- 28355286 TI - Gender preference and perinatal depression in Turkey: A cohort study. AB - BACKGROUND: Child gender preference is important in some cultures and has been found to modify risk for antenatal and postnatal depression. We investigated discrepancies in the child gender preference between participating women and other key family members and the extent to which these predicted perinatal depression. METHODS: In a large cohort study of perinatal depression in urban and rural Turkey, participants had been asked about child gender preferences: their own, and those of their husband, parents, and parents in-law. Of 730 participants recruited in their third trimester (94.6% participation), 578 (79.2%) were reassessed at a mean (SD) 4.1 (3.3) months after childbirth, and 488 (66.8%) were reassessed at 13.7 (2.9) months. RESULTS: No associations were found between any gender preference reported in the antenatal period and depression at any examination. On the other hand, we found associations of antenatal depression with differences in participant-reported gender preference and that reported for their mother-in-law (OR 1.81, 1.08-3.04). This non-agreement also predicted depression at the 4 month (OR 2.24, 1.24-4.03) and 14 month (OR 2.07, 1.05-4.04) post-natal examinations. These associations with postnatal depression persisted after adjustment for a range of covariates (ORs 3.19 (1.54-6.59) and 3.30 (1.49 7.33) respectively). CONCLUSIONS: Reported disagreement in child gender preferences between a woman and her mother-in-law was a predictor of post-natal depression and may reflect wider family disharmony as an underlying factor. PMID- 28355287 TI - The Sirt6 gene: Does it play a role in tooth development? AB - Dental Mesenchymal Cells (DMCs) are known to play a role in tooth development as well as in the repair and regeneration of dental tissue. A large number of signaling molecules regulate the proliferation and differentiation of DMC, though the underlying mechanisms are still not fully understood. Sirtuin-6 (SIRT6), a key regulator of aging, can exert an impact on embryonic stem cell (ESC) differentiation. The experimental deletion of Sirt6 in mouse bone marrow cells has been found to have an inhibiting impact on the bone mineral density and the osteogenic differentiation of these cells. The possible role of Sirt6 in tooth development, however, has at present remained largely unexplored. In the present study, we found that SIRT6 had no effect on tooth development before birth. However, Sirt6 gene deletion in knockout mice did have two post-natal impacts: a delay in tooth eruption and sluggishness in the development of dental roots. We propose an explanation of the possible molecular basis of the changes observed in Sirt6-/- mice. SIRT6 is expressed in mouse odontoblasts. Sirt6 deletion enhanced the proliferation of DMCs, as well as their capacity for adipogenic differentiation. On the other hand, it inhibited their capacity for in vitro osteogenic/chondrogenic differentiation. Further studies suggested that other factors may mediate the role of Sirt6 in odontogenesis. These include the nuclear factor kappa B (NF-kappaB), p38 mitogen-activated protein kinase (p38-MAPK), extracellular regulated MAP kinase (ERK) pathways and the mitochondrial energy. We demonstrated that Sirt6 plays a role in tooth root formation and confirmed that SIRT6 is necessary for DMC differentiation as well as for the development of the tooth root and for eventual tooth eruption. These results establish a new link between SIRT6 and tooth development. PMID- 28355288 TI - Theory and associated phenomenology for intrinsic mortality arising from natural selection. AB - Standard evolutionary theories of aging and mortality, implicitly based on assumptions of spatial averaging, hold that natural selection cannot favor shorter lifespan without direct compensating benefit to individual reproductive success. However, a number of empirical observations appear as exceptions to or are difficult to reconcile with this view, suggesting explicit lifespan control or programmed death mechanisms inconsistent with the classic understanding. Moreover, evolutionary models that take into account the spatial distributions of populations have been shown to exhibit a variety of self-limiting behaviors, maintained through environmental feedback. Here we extend recent work on spatial modeling of lifespan evolution, showing that both theory and phenomenology are consistent with programmed death. Spatial models show that self-limited lifespan robustly results in long-term benefit to a lineage; longer-lived variants may have a reproductive advantage for many generations, but shorter lifespan ultimately confers long-term reproductive advantage through environmental feedback acting on much longer time scales. Numerous model variations produce the same qualitative result, demonstrating insensitivity to detailed assumptions; the key conditions under which self-limited lifespan is favored are spatial extent and locally exhaustible resources. Factors including lower resource availability, higher consumption, and lower dispersal range are associated with evolution of shorter lifespan. A variety of empirical observations can parsimoniously be explained in terms of long-term selective advantage for intrinsic mortality. Classically anomalous empirical data on natural lifespans and intrinsic mortality, including observations of longer lifespan associated with increased predation, and evidence of programmed death in both unicellular and multicellular organisms, are consistent with specific model predictions. The generic nature of the spatial model conditions under which intrinsic mortality is favored suggests a firm theoretical basis for the idea that evolution can quite generally select for shorter lifespan directly. PMID- 28355289 TI - Increased expression of protein kinase CK2alpha correlates with poor patient prognosis in epithelial ovarian cancer. AB - Epithelial ovarian cancer (EOC) is one of the deadly gynecological malignancies. The function of protein kinase CK2alpha (CK2alpha) in EOC is still unknown. Our study aimed to investigate the relationship between the protein expression of CK2alpha and the tumor progression, the prognosis of human EOC. In this study, we analyzed the expression levels of CK2alpha through Western blot, using EOC cell lines like A2780, HO8910, COV644, OVCAR3, SKOV3, and the primary normal ovarian surface epithelial (NOSE) cells. Furthermore, OVCAR3 and SKOV3 EOC cells were employed as a cellular model to study the role of CK2alpha on cell growth, migration, invasion, apoptosis, and cell cycle distribution. In addition, we investigated CK2alpha protein expression in tumor tissues from patients with EOC by immunohistochemistry and analyzed the association between CK2alpha expression and clinicopathologic parameters and prognosis of EOC patients. And we found that compared with NOSE cells, CK2alpha protein expression was increased in A2780, HO8910, OVCAR3, and SKOV3 ovarian cancer cell lines. Decreased CK2alpha expression suppressed OVCAR3 and SKOV3 cell growth and induced more apoptosis. CK2alpha knockdown using specific siRNAs inhibited migration and invasion ability of OVCAR3 and SKOV3 cells. In addition, high CK2alpha protein expression was found in 68.4% (80/117) of EOC patients. Increased CK2alpha expression of was significantly correlated with FIGO staging and peritoneal cytology. Patients with higher CK2alpha expression had a significantly poorer overall survival compared with those with lower CK2alpha expression. Multi-variate Cox regression analysis proved that increased CK2alpha expression was an independent prognostic marker for EOC. Taken together, our data displayed that CK2alpha may play a role in tumor aggressive behavior of EOC and could be used as a marker for predicting prognosis of EOC patient. High CK2alpha expression might predict poor patient survival. PMID- 28355290 TI - Prevalence of valvular heart diseases and associated risk factors in Han, Uygur and Kazak population in Xinjiang, China. AB - BACKGROUND: Valvular heart diseases (VHD) is very common in clinical practice and has became the subject of growing attention in the field of cardiovascular medicine. Our aim was to assess the prevalence and correlates of VHD in the general population in Xinjiang, China. METHODS: Using a 4-stage stratified cluster random sampling method, a total of 14618 participants were recruited in the Cardiovascular Risk Survey (CRS) study. The participants' personal information, medical history were assessed by questionnaire. VHD was diagnosed by transthoracic echocardiography. We carried out the statistical analysis utilizing SPSS Statistics version 19.0. RESULTS: In the total study group, VHD was observed in 1397 (9.65%) individuals. The prevalence rates of VHD in Han, Uygur and Kazak group are 13.51%, 2.71% and 12.29% respectively. The prevalence rates of VHD increased strikingly with age (all P < 0.001). The results of multinomial regression analysis indicated that VHD were related to age in Han group, to age smoking and hypertension in Uygur group, to age and hypertension in Kazak group. CONCLUSION: Our research provides a unique prevalence rate of VHD in Xinjiang natural population. The result suggests that VHD are notably common in this population (9.65%) and increase with age. There exists significant difference of prevalence rate between ethnics. The main risk factors of VHD are age, hypertension and smoking. Valvular heart diseases should be regarded as a serious and growing public-health problem. PMID- 28355291 TI - Site-specific variation in gene expression from Symbiodinium spp. associated with offshore and inshore Porites astreoides in the lower Florida Keys is lost with bleaching and disease stress. AB - Scleractinian coral are experiencing unprecedented rates of mortality due to increases in sea surface temperatures in response to global climate change. Some coral species however, survive high temperature events due to a reduced susceptibility to bleaching. We investigated the relationship between bleaching susceptibility and expression of five metabolically related genes of Symbiodinium spp. from the coral Porites astreoides originating from an inshore and offshore reef in the Florida Keys. The acclimatization potential of Symbiodinium spp. to changing temperature regimes was also measured via a two-year reciprocal transplant between the sites. Offshore coral fragments displayed significantly higher expression in Symbiodinium spp. genes PCNA, SCP2, G3PDH, PCP and psaE than their inshore counterparts (p<0.05), a pattern consistent with increased bleaching susceptibility in offshore corals. Additionally, gene expression patterns in Symbiodinium spp. from site of origin were conserved throughout the two-year reciprocal transplant, indicating acclimatization did not occur within this multi-season time frame. Further, laboratory experiments were used to investigate the influence of acute high temperature (32 degrees C for eight hours) and disease (lipopolysaccharide of Serratia marcescens) on the five metabolically related symbiont genes from the same offshore and inshore P. astreoides fragments. Gene expression did not differ between reef fragments, or as a consequence of acute exposure to heat or heat and disease, contrasting to results found in the field. Gene expression reported here indicates functional variation in populations of Symbiodinium spp. associated with P. astreoides in the Florida Keys, and is likely a result of localized adaptation. However, gene expression patterns observed in the lab imply that functional variation in zooxanthellae observed under conditions of chronic moderate stress is lost under the acute extreme conditions studied here. PMID- 28355292 TI - A decorated raven bone from the Zaskalnaya VI (Kolosovskaya) Neanderthal site, Crimea. AB - We analyze a radius bone fragment of a raven (Corvus corax) from Zaskalnaya VI rock shelter, Crimea. The object bears seven notches and comes from an archaeological level attributed to a Micoquian industry dated to between 38 and 43 cal kyr BP. Our study aims to examine the degree of regularity and intentionality of this set of notches through their technological and morphometric analysis, complemented by comparative experimental work. Microscopic analysis of the notches indicate that they were produced by the to-and-fro movement of a lithic cutting edge and that two notches were added to fill in the gap left between previously cut notches, probably to increase the visual consistency of the pattern. Multivariate analysis of morphometric data recorded on the archaeological notches and sets of notches cut by nine modern experimenters on radii of domestic turkeys shows that the variations recorded on the Zaskalnaya set are comparable to experimental sets made with the aim of producing similar, parallel, equidistant notches. Identification of the Weber Fraction, the constant that accounts for error in human perception, for equidistant notches cut on bone rods and its application to the Zaskalnaya set of notches and thirty-six sets of notches incised on seventeen Upper Palaeolithic bone objects from seven sites indicate that the Zaskalnaya set falls within the range of variation of regularly spaced experimental and Upper Palaeolithic sets of notches. This suggests that even if the production of the notches may have had a utilitarian reason the notches were made with the goal of producing a visually consistent pattern. This object represents the first instance of a bird bone from a Neanderthal site bearing modifications that cannot be explained as the result of butchery activities and for which a symbolic argument can be built on direct rather than circumstantial evidence. PMID- 28355293 TI - Understanding the genetic diversity and population structure of yam (Dioscorea alata L.) using microsatellite markers. AB - Yams (Dioscorea sp.) are staple food crops for millions of people in tropical and subtropical regions. Dioscorea alata, also known as greater yam, is one of the major cultivated species and most widely distributed throughout the tropics. Despite its economic and cultural importance, very little is known about its origin, diversity and genetics. As a consequence, breeding efforts for resistance to its main disease, anthracnose, have been fairly limited. The objective of this study was to contribute to the understanding of D. alata genetic diversity by genotyping 384 accessions from different geographical regions (South Pacific, Asia, Africa and the Caribbean), using 24 microsatellite markers. Diversity structuration was assessed via Principal Coordinate Analysis, UPGMA analysis and the Bayesian approach implemented in STRUCTURE. Our results revealed the existence of a wide genetic diversity and a significant structuring associated with geographic origin, ploidy levels and morpho-agronomic characteristics. Seventeen major groups of genetically close cultivars have been identified, including eleven groups of diploid cultivars, four groups of triploids and two groups of tetraploids. STRUCTURE revealed the existence of six populations in the diploid genetic pool and a few admixed cultivars. These results will be very useful for rationalizing D. alata genetic resources in breeding programs across different regions and for improving germplasm conservation methods. PMID- 28355294 TI - Mining expression and prognosis of topoisomerase isoforms in non-small-cell lung cancer by using Oncomine and Kaplan-Meier plotter. AB - DNA topoisomerases are essential to modulate DNA topology during various cellular genetic processes. The expression and distinct prognostic value of topoisomerase isoforms in non-small-cell lung cancer (NSCLC) is not well established. In the current study, we have examined the mRNA expression of topoisomerase isoforms by using Oncomine analysis and investigated their prognostic value via the Kaplan Meier plotter database in NSCLC patients. Our analysis indicated that the expression level of topoisomerases in lung cancer was higher compared with normal tissues. Especially, high expression of two topoisomerase isoforms, TOP2A and TOP3A, was found to be correlated to worse overall survival (OS) in all NSCLC and lung adenocarcinoma (Ade) patients, but not in lung squamous cell carcinoma (SCC) patients. In a contrast, high expression of isoforms TOP1 and TOP2B indicated better OS in all NSCLC and Ade, but not in SCC patients. Meanwhile, high expression of TOP1MT and TOP3B was not correlated with OS in NSCLC patients. Furthermore, we also demonstrated a relationship between topoisomerase isoforms and the clinicopathological features for the NSCLC patients, such as grades, clinical stages, lymph node status, smoking status, gender, chemotherapy and radiotherapy. These results support that TOP2A and TOP3A are associated with worse prognosis in NSCLC patients. In addition, our study also shows that TOP1 and TOP2B contribute to favorable prognosis in NSCLC patients. The exact prognostic significance of TOP1MT and TOP3B need to be further elucidated. Comprehensive evaluation of expression and prognosis of topoisomerase isoforms will be a benefit for the better understanding of heterogeneity and complexity in the molecular biology of NSCLC, paving a way for more accurate prediction of prognosis and discovery of potential drug targets for NSCLC patients. PMID- 28355295 TI - Risk prediction of pulmonary tuberculosis using genetic and conventional risk factors in adult Korean population. AB - A complex interplay among host, pathogen, and environmental factors is believed to contribute to the risk of developing pulmonary tuberculosis (PTB). The lack of replication of published genome-wide association study (GWAS) findings limits the clinical utility of reported single nucleotide polymorphisms (SNPs). We conducted a GWAS using 467 PTB cases and 1,313 healthy controls obtained from two community based cohorts in Korea. We evaluated the performance of PTB risk models based on different combinations of genetic and nongenetic factors and validated the results in an independent Korean population comprised of 179 PTB cases and 500 healthy controls. We demonstrated the polygenic nature of PTB and nongenetic factors such as age, sex, and body mass index (BMI) were strongly associated with PTB risk. None of the SNPs achieved genome-wide significance; instead, we were able to replicate the associations between PTB and ten SNPs near or in the genes, CDCA7, GBE1, GADL1, SPATA16, C6orf118, KIAA1432, DMRT2, CTR9, CCDC67, and CDH13, which may play roles in the immune and inflammatory pathways. Among the replicated SNPs, an intergenic SNP, rs9365798, located downstream of the C6orf118 gene showed the most significant association under the dominant model (OR = 1.59, 95% CI 1.32-1.92, P = 2.1*10-6). The performance of a risk model combining the effects of ten replicated SNPs and six nongenetic factors (i.e., age, sex, BMI, cigarette smoking, systolic blood pressure, and hemoglobin) were validated in the replication set (AUC = 0.80, 95% CI 0.76-0.84). The strategy of combining genetic and nongenetic risk factors ultimately resulted in better risk prediction for PTB in the adult Korean population. PMID- 28355296 TI - Tetraarsenic hexoxide induces G2/M arrest, apoptosis, and autophagy via PI3K/Akt suppression and p38 MAPK activation in SW620 human colon cancer cells. AB - Tetraarsenic hexoxide (As4O6) has been used in Korean folk medicines for the treatment of cancer, however its anti-cancer mechanisms remain obscured. Here, this study investigated the anti-cancer effect of As4O6 on SW620 human colon cancer cells. As4O6 has showed a dose-dependent inhibition of SW620 cells proliferation. As4O6 significantly increased the sub-G1 and G2/M phase population, and Annexin V-positive cells in a dose-dependent manner. G2/M arrest was concomitant with augment of p21 and reduction in cyclin B1, cell division cycle 2 (cdc 2) expressions. Nuclear condensation, cleaved nuclei and poly (adenosine diphosphate-ribose) polymerase (PARP) activation were also observed in As4O6-treated SW620 cells. As4O6 induced depolarization of mitochondrial membrane potential (MMP, DeltaPsim) but not reactive oxygen species (ROS) generation. Further, As4O6 increased death receptor 5 (DR5), not DR4 and suppressed the B cell lymphoma-2 (Bcl-2) and X-linked inhibitor of apoptosis protein (XIAP) family proteins. As4O6 increased the formation of AVOs (lysosomes and autophagolysosomes) and promoted the conversion of microtubule-associated protein 1A/1B-light chain 3 (LC3)-I to LC3-II in a dose- and time- dependent manner. Interestingly, a specific phosphoinositide 3-kinase (PI3K)/Akt inhibitor (LY294002) augmented the As4O6 induced cell death; whereas p38 mitogen-activated protein kinases (p38 MAPK) inhibitor (SB203580) abrogated the cell death. Thus, the present study provides the first evidence that As4O6 induced G2/M arrest, apoptosis and autophagic cell death through PI3K/Akt and p38 MAPK pathways alteration in SW620 cells. PMID- 28355297 TI - Transcription factor-induced activation of cardiac gene expression in human c kit+ cardiac progenitor cells. AB - Although transplantation of c-kit+ cardiac progenitor cells (CPCs) significantly alleviates post-myocardial infarction left ventricular dysfunction, generation of cardiomyocytes by exogenous CPCs in the recipient heart has often been limited. Inducing robust differentiation would be necessary for improving the efficacy of the regenerative cardiac cell therapy. We assessed the hypothesis that differentiation of human c-kit+ CPCs can be enhanced by priming them with cardiac transcription factors (TFs). We introduced five different TFs (Gata4, MEF2C, NKX2.5, TBX5, and BAF60C) into CPCs, either alone or in combination, and then examined the expression of marker genes associated with the major cardiac cell types using quantitative RT-PCR. When introduced individually, Gata4 and TBX5 induced a subset of myocyte markers. Moreover, Gata4 alone significantly induced smooth muscle cell and fibroblast markers. Interestingly, these gene expression changes brought by Gata4 were also accompanied by morphological changes. In contrast, MEF2C and NKX2.5 were largely ineffective in initiating cardiac gene expression in CPCs. Surprisingly, introduction of multiple TFs in different combinations mostly failed to act synergistically. Likewise, addition of BAF60C to Gata4 and/or TBX5 did not further potentiate their effects on cardiac gene expression. Based on our results, it appears that GATA4 is able to potentiate gene expression programs associated with multiple cardiovascular lineages in CPCs, suggesting that GATA4 may be effective in priming CPCs for enhanced differentiation in the setting of stem cell therapy. PMID- 28355298 TI - An alternative reference space for H&E color normalization. AB - Digital imaging of H&E stained slides has enabled the application of image processing to support pathology workflows. Potential applications include computer-aided diagnostics, advanced quantification tools, and innovative visualization platforms. However, the intrinsic variability of biological tissue and the vast differences in tissue preparation protocols often lead to significant image variability that can hamper the effectiveness of these computational tools. We developed an alternative representation for H&E images that operates within a space that is more amenable to many of these image processing tools. The algorithm to derive this representation operates by exploiting the correlation between color and the spatial properties of the biological structures present in most H&E images. In this way, images are transformed into a structure-centric space in which images are segregated into tissue structure channels. We demonstrate that this framework can be extended to achieve color normalization, effectively reducing inter-slide variability. PMID- 28355299 TI - Mild hypothermia alleviates brain oedema and blood-brain barrier disruption by attenuating tight junction and adherens junction breakdown in a swine model of cardiopulmonary resuscitation. AB - Mild hypothermia improves survival and neurological recovery after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). However, the mechanism underlying this phenomenon is not fully elucidated. The aim of this study was to determine whether mild hypothermia alleviates early blood-brain barrier (BBB) disruption. We investigated the effects of mild hypothermia on neurologic outcome, survival rate, brain water content, BBB permeability and changes in tight junctions (TJs) and adherens junctions (AJs) after CA and CPR. Pigs were subjected to 8 min of untreated ventricular fibrillation followed by CPR. Mild hypothermia (33 degrees C) was intravascularly induced and maintained at this temperature for 12 h, followed by active rewarming. Mild hypothermia significantly reduced cortical water content, decreased BBB permeability and attenuated TJ ultrastructural and basement membrane breakdown in brain cortical microvessels. Mild hypothermia also attenuated the CPR-induced decreases in TJ (occludin, claudin-5, ZO-1) and AJ (VE cadherin) protein and mRNA expression. Furthermore, mild hypothermia decreased the CA- and CPR-induced increases in matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) expression and increased angiogenin-1 (Ang-1) expression. Our findings suggest that mild hypothermia attenuates the CA- and resuscitation-induced early brain oedema and BBB disruption, and this improvement might be at least partially associated with attenuation of the breakdown of TJ and AJ, suppression of MMP-9 and VEGF expression, and upregulation of Ang-1 expression. PMID- 28355301 TI - Variations of pterygium prevalence by age, gender and geographic characteristics in China: A systematic review and meta-analysis. AB - BACKGROUND: Pterygium is a common chronic ophthalmic condition, which may result in significant visual morbidity or lead to blindness in extreme cases. The prevalence of pterygium in China has not been reported at the sub-national level. METHODS: In this study, we conducted a systematic review and meta-analysis to estimate the prevalence of pterygium in China. China National Knowledge Infrastructure (CNKI), Wanfang, Chinese Biomedicine Literature Database (CBM SinoMed), PubMed, Embase and Medline were searched before September 2016. We performed a multilevel mixed-effect meta-regression based on the included studies, our results showed that age, gender and latitude were significantly associated with pterygium prevalence. Based on the final model, the age and gender-specific prevalence of pterygium in 31 Chinese provinces (except Hongkong, Macau and Taiwan) and the whole country was generated. RESULTS: In 2010, the overall prevalence of pterygium in Chinese people aged 15-84 years was 9.84% (95% CI: 6.72-14.14), and the number of pterygium cases in China was 108.65 million (95% CI: 74.23-156.13). CONCLUSIONS: In conclusion, the prevalence of pterygium in Chinese population in 2010 was estimated at both the national and provincial levels. The higher burden of pterygium across the country calls for efforts to advocate public health education encouraging people to take appropriate protective measures. PMID- 28355300 TI - Evaluation of synthetic vascular grafts in a mouse carotid grafting model. AB - Current animal models for the evaluation of synthetic grafts are lacking many of the molecular tools and transgenic studies available to other branches of biology. A mouse model of vascular grafting would allow for the study of molecular mechanisms of graft failure, including in the context of clinically relevant disease states. In this study, we comprehensively characterise a sutureless grafting model which facilitates the evaluation of synthetic grafts in the mouse carotid artery. Using conduits electrospun from polycaprolactone (PCL) we show the gradual development of a significant neointima within 28 days, found to be greatest at the anastomoses. Histological analysis showed temporal increases in smooth muscle cell and collagen content within the neointima, demonstrating its maturation. Endothelialisation of the PCL grafts, assessed by scanning electron microscopy (SEM) analysis and CD31 staining, was near complete within 28 days, together replicating two critical aspects of graft performance. To further demonstrate the potential of this mouse model, we used longitudinal non-invasive tracking of bone-marrow mononuclear cells from a transgenic mouse strain with a dual reporter construct encoding both luciferase and green fluorescent protein (GFP). This enabled characterisation of mononuclear cell homing and engraftment to PCL using bioluminescence imaging and histological staining over time (7, 14 and 28 days). We observed peak luminescence at 7 days post-graft implantation that persisted until sacrifice at 28 days. Collectively, we have established and characterised a high-throughput model of grafting that allows for the evaluation of key clinical drivers of graft performance. PMID- 28355303 TI - Correction: Plant species classification using flower images-A comparative study of local feature representations. AB - [This corrects the article DOI: 10.1371/journal.pone.0170629.]. PMID- 28355302 TI - Prevalence of Caesarean sections in Enugu, southeast Nigeria: Analysis of data from the Healthy Beginning Initiative. AB - BACKGROUND: In order to meet the Sustainable Development Goal to decrease maternal mortality, increased access to obstetric interventions such as Caesarean sections (CS) is of critical importance. As a result of women's limited access to routine and emergency obstetric services in Nigeria, the country is a major contributor to the global burden of maternal mortality. In this analysis, we aim to establish rates of CS and determine socioeconomic or medical risk factors associated with having a CS in Enugu, southeast Nigeria. METHODS: Data for this study originated from the Healthy Beginning Initiative study. Participant characteristics were obtained from 2300 women at baseline via a semi-structured questionnaire. Only women between the ages of 17-45 who had singleton deliveries were retained for this analysis. Post-delivery questionnaires were used to ascertain mode-of-delivery. Crude and adjusted logistic regressions with Caesarean as the main outcome are presented. RESULTS: In this sample, 7.22% women had a CS. Compared to women who lived in an urban setting, those who lived in a rural setting had a significant reduction in the odds of having a CS (aOR: 0.58; 0.38-0.89). Significantly higher odds of having a CS were seen among those with high peripheral malaria parasitemia compared to those with low parasitemia (aOR: 1.54; 1.04-2.28). CONCLUSION: This study revealed that contrary to the increasing trend in use of CS in low-income countries, women in this region of Nigeria had limited access to this intervention. Increasing age and socioeconomic proxies for income and access to care (e.g., having a tertiary-level education, full-time employment, and urban residence) were shown to be key determinants of access to CS. Further research is needed to ascertain the obstetric conditions under which women in this region receive CS, and to further elucidate the role of socioeconomic factors in accessing CS. PMID- 28355304 TI - Isolation and characterization of the TaSnRK2.10 gene and its association with agronomic traits in wheat (Triticum aestivum L.). AB - Sucrose non-fermenting 1-related protein kinases (SnRKs) comprise a major family of signaling genes in plants and are associated with metabolic regulation, nutrient utilization and stress responses. This gene family has been proposed to be involved in sucrose signaling. In the present study, we cloned three copies of the TaSnRK2.10 gene from bread wheat on chromosomes 4A, 4B and 4D. The coding sequence (CDS) is 1086 bp in length and encodes a protein of 361 amino acids that exhibits functional domains shared with SnRK2s. Based on the haplotypes of TaSnRK2.10-4A (Hap-4A-H and Hap-4A-L), a cleaved amplified polymorphic sequence (CAPS) marker designated TaSnRK2.10-4A-CAPS was developed and mapped between the markers D-1092101 and D-100014232 using a set of recombinant inbred lines (RILs). The TaSnRK2.10-4B alleles (Hap-4B-G and Hap-4B-A) were transformed into allele specific PCR (AS-PCR) markers TaSnRK2.10-4B-AS1 and TaSnRK2.10-4B-AS2, which were located between the markers D-1281577 and S-1862758. No diversity was found for TaSnRK2.10-4D. An association analysis using a natural population consisting of 128 winter wheat varieties in multiple environments showed that the thousand grain weight (TGW) and spike length (SL) of Hap-4A-H were significantly higher than those of Hap-4A-L, but pant height (PH) was significantly lower. PMID- 28355305 TI - Inflammation scores predict the survival of patients with hepatocellular carcinoma who were treated with transarterial chemoembolization and recombinant human type-5 adenovirus H101. AB - BACKGROUND: The systemic inflammatory response plays an important role in cancer development and progression. An original inflammation-based staging system for predicting survival in patients undergoing transarterial chemoembolization (TACE) combined with recombinant human type-5 adenovirus H101 is not available. This study aimed to validate the prognostic value of inflammation scores for patients with hepatocellular carcinoma (HCC) who were treated with TACE combined with H101. METHODS: The data from 216 patients with HCC who underwent TACE combined with H101 from January 2007 to July 2015 were retrospectively collected, and the association of the inflammation scores with overall survival (OS) was analyzed. Univariate and multivariate analyses were performed to identify variables associated with OS. The prognostic value of the inflammation scores, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), neutrophil/ platelet-to-lymphocyte ratio (NLR-PLR), modified Glasgow Prognostic Score (mGPS), prognostic nutritional index (PNI), prognostic index (PI), tumor node-metastasis (TNM), Barcelona Clinic Liver Cancer (BCLC) and Cancer of the Liver Italian Program (CLIP) staging systems were analyzed and compared using the areas under the receiver operating characteristic curves (AUROCs). RESULTS: The estimated 1-, 2-, and 3-year OS rates were 61.3%, 44.2%, and 40.5% for the entire study cohort, respectively; the median OS was 17 months. According to the multivariate Cox proportional hazards model, the pretreatment NLR, tumor diameter and pretreatment alpha-fetoprotein (AFP) levels were independent predictors of OS. The CLIP score had superior discriminative abilities compared with other staging systems, and the NLR-PLR score consistently displayed a higher AUROC value than the other inflammation-based prognostic scores. The combination of the NLR-PLR and CLIP scores exhibited a superior prognostic ability for OS compared to the NLR-PLR or CLIP scores alone. CONCLUSIONS: The NLR-PLR score is a more powerful predictive system than the other inflammation-based scores for patients with HCC who were treated with TACE and H101. The predictive ability may be improved by utilizing a combination of the NLR-PLR and CLIP scores. PMID- 28355306 TI - Genome-wide association analysis identifies resistance loci for bacterial blight in a diverse collection of indica rice germplasm. AB - Bacterial blight, which is caused by Xanthomonas oryzae pv. oryzae (Xoo), is one of the most devastating rice diseases worldwide. The development and use of disease-resistant cultivars have been the most effective strategy to control bacterial blight. Identifying the genes mediating bacterial blight resistance is a prerequisite for breeding cultivars with broad-spectrum and durable resistance. We herein describe a genome-wide association study involving 172 diverse Oryza sativa ssp. indica accessions to identify loci influencing the resistance to representative strains of six Xoo races. Twelve resistance loci containing 121 significantly associated signals were identified using 317,894 single nucleotide polymorphisms, which explained 13.3-59.9% of the variability in lesion length caused by Xoo races P1, P6, and P9a. Two hotspot regions (L11 and L12) were located within or nearby two cloned R genes (xa25 and Xa26) and one fine-mapped R gene (Xa4). Our results confirmed the relatively high resolution of genome-wide association studies. Moreover, we detected novel significant associations on chromosomes 2, 3, and 6-10. Haplotype analyses of xa25, the Xa26 paralog (MRKc; LOC_Os11g47290), and a Xa4 candidate gene (LOC_11g46870) revealed differences in bacterial blight resistance among indica subgroups. These differences were responsible for the observed variations in lesion lengths resulting from infections by Xoo races P1 and P9a. Our findings may be relevant for future studies involving bacterial blight resistance gene cloning, and provide insights into the genetic basis for bacterial blight resistance in indica rice, which may be useful for knowledge-based crop improvement. PMID- 28355307 TI - Mediterranean spotted fever in Spain, 1997-2014: Epidemiological situation based on hospitalization records. AB - INTRODUCTION: Mediterranean spotted fever (MSF) is a zoonotic disease caused by Rickettsia conorii. In Spain, deficiencies in the official reporting result in misreporting of this disease. This study aims to describe the clinical and temporal-spatial characteristics of MSF hospitalizations between 1997 and 2014. MATERIALS AND METHODS: We performed a retrospective descriptive study using the Hospitalization Minimum Data Set (CMBD). All CMBD's hospital discharges with ICD 9 CM code 082.1 were analyzed. Hospitalization rates were calculated and clinical characteristics were described. Spatial distribution of cases and their temporal behavior were also assessed. RESULTS: A total of 4,735 hospitalizations with MSF diagnosis were recorded during the study period, out of which 62.2% were male, mean age of 48. Diabetes mellitus, alcohol dependence syndrome, and chronic liver disease occurred in 10.8%, 2.4% and 2.8% hospitalizations, respectively. The median annual hospitalization rate showed a decreasing trend from a maximum of 12.9 in 1997 to a minimum rate of 3.1 in 2014. Most admissions occurred during the summer, showing a significant annual seasonal behavior. Important regional differences were found. DISCUSSION: Although MSF hospitalization rates have decreased considerably, it remains a public health problem due to its severity and economic impact. Therefore, it would be desirable to improve its oversight and surveillance. PMID- 28355308 TI - Structural basis for non-genuine phenolic acceptor substrate specificity of Streptomyces roseochromogenes prenyltransferase CloQ from the ABBA/PT-barrel superfamily. AB - Acceptor substrate specificity of Streptomyces roseochromogenes prenyltransferase SrCloQ was investigated using different non-genuine phenolic compounds. RP-UHPLC UV-MSn was used for the tentative annotation and quantification of the prenylated products. Flavonoids, isoflavonoids and stilbenoids with different types of substitution were prenylated by SrCloQ, although with less efficiency than the genuine substrate 4-hydroxyphenylpyruvate. The isoflavan equol, followed by the flavone 7,4'-dihydroxyflavone, were the best non-genuine acceptor substrates. B ring C-prenylation was in general preferred over A-ring C-prenylation (ratio 5:1). Docking studies of non-genuine acceptor substrates with the B-ring oriented towards the donor substrate dimethylallyl pyrophosphate, showed that the carbonyl group of the C-ring was able to make stabilizing interactions with the residue Arg160, which might determine the preference observed for B-ring prenylation. No reaction products were formed when the acceptor substrate had no phenolic hydroxyl groups. This preference can be explained by the essential hydrogen bond needed between a phenolic hydroxyl group and the residue Glu281. Acceptor substrates with an additional hydroxyl group at the C3' position (B-ring), were mainly O3'-prenylated (> 80% of the reaction products). This can be explained by the proximity of the C3' hydroxyl group to the donor substrate at the catalytic site. Flavones were preferred over isoflavones by SrCloQ. Docking studies suggested that the orientation of the B-ring and of the phenolic hydroxyl group at position C7 (A-ring) of flavones towards the residue Tyr233 plays an important role in this observed preference. Finally, the insights obtained on acceptor substrate specificity and regioselectivity for SrCloQ were extended to other prenyltransferases from the CloQ/NhpB family. PMID- 28355311 TI - Enhancing Root Eminence and Papilla Contour Using Single, Contoured, Subepithelial Connective Tissue Autografts for Recession Coverage. AB - Current techniques using autogenous soft tissue in periodontal plastic surgery have limitations in the number of teeth that can be treated and may result in suboptimal esthetic results. The innovative use of single, contoured grafts reported in this article overcomes the drawbacks associated with these techniques by more efficient use of available donor tissue. Autogenous tissue is used to graft each individual tooth, leaving the interdental areas uncovered. Multiple teeth-in some cases an entire arch-can be treated in one session, providing consistent and predictable reestablishment of the normal scalloped gingival architecture and convex root eminence. PMID- 28355309 TI - The differential expression of MC1R regulators in dorsal and ventral quail plumages during embryogenesis: Implications for plumage pattern formation. AB - Melanin pigmentation patterns are ubiquitous in animals and function in crypsis, physical protection, thermoregulation and signalling. In vertebrates, pigmentation patterns formed over large body regions as well as within appendages (hair/feathers) may be due to the differential distribution of pigment producing cells (melanocytes) and/or regulation of the melanin synthesis pathway. We took advantage of the pigmentation patterns of Japanese quail embryos (pale ventrum and patterned feathers dorsally) to explore the role of genes and their transcripts in regulating the function of the melanocortin-1-receptor (MC1R) via 1. activation: pro-opiomelanocortin (POMC), endoproteases prohormone convertase 1 (PC1) and 2 (PC2), and 2. inhibition-agouti signaling and agouti-related protein (ASIP and AGRP, respectively). Melanocytes are present in all feather follicles at both 8 and 12 days post-fertilisation (E8/E12), so differential deposition of melanocytes is not responsible for pigmentation patterns in embryonic quail. POMC transcripts expressed were a subset of those found in chicken and POMC expression within feather follicles was strong. PC1 was not expressed in feather follicles. PC2 was strongly expressed in all feather follicles at E12. ASIP transcript expression was variable and we report four novel ASIP transcripts. ASIP is strongly expressed in ventral feather follicles, but not dorsally. AGRP expression within feather follicles was weak. These results demonstrate that the pale-bellied quail phenotype probably involves inhibition of MC1R, as found previously. However, quail may require MC1R activation for eumelanogenesis in dorsal feathers which may have important implications for an understanding of colour pattern formation in vertebrates. PMID- 28355310 TI - Tangent screen perimetry in the evaluation of visual field defects associated with ptosis and dermatochalasis. AB - PURPOSE: To determine if tangent visual fields gathered during assessment of superior visual field deficits caused by blepharoptosis and dermatochalasis offer good correlation to clinical exam in a time and cost efficient manner. METHODS: Prospective, observational case series. Subjects included all patients referred to a single surgeon (CCN) who underwent surgical correction of blepharoptosis and/or dermatochalasis. Preoperatively and postoperatively, upper margin-to reflex distances were assessed. Tangent visual fields were performed in a timed fashion and analyzed for degrees of intact vision in the vertical meridian and degrees squared of area under the curve. Data were compared by Student t-tests and Pearson correlation coefficients. RESULTS: Mean preoperative superior visual fields with the eyelid in the natural position measured 8 degrees in the vertical meridian. Measurements in the vertical meridian and area under the curve showed excellent correlation (r = 0.87). Patients with ptosis showed strong correlation between margin-to-reflex distance and superior visual fields. Patients completed field testing faster than reported times for automated or Goldmann testing. Finally, tangent screens were the least expensive type of equipment to purchase. CONCLUSIONS: Tangent visual fields are a rapid and inexpensive way to test for functional loss of superior visual field in patients with upper eyelid malposition. Our data revealed potential differences between tangent screen results and published results for automated or Goldmann visual field testing which warrants further studies. PMID- 28355312 TI - Oral Rehabilitation of a Severe Periodontally Involved Patient with Mucous Membrane Pemphigoid: A 15-Year Follow-Up Case Report. AB - Mucous membrane pemphigoid (MMP) refers to a group of chronic autoimmune subepithelial diseases distinguished by erosive lesions of the mucous membranes and skin. Its treatment consists of inhibition of the inflammatory reaction by means of corticosteroids and symptomatic medication. This is a report of a patient suffering from a combination of MMP and severe generalized chronic periodontitis. The patient has been treated with oral corticosteroids, initial phase therapy, extraction with immediate implant placement, and periodontal surgery where the prognosis was questionable. The case has been followed up for 15 years. Periodontal therapy with immediate implant placement was determined to be a viable modality to achieve a total rehabilitation of a case suffering from MMP combined with severe generalized chronic periodontitis. PMID- 28355314 TI - Ideology, science, and people in Amilcar Cabral. AB - The present article contributes to the debate on how historians and social scientists perceive and understand relations between ideology and science, which are often seen as realms belonging to rival kingdoms. Following an analysis and critical positioning vis-a-vis Cabralian studies, the text examines how scholars of Cabral have portrayed his agronomic activities. It then undertakes a genealogical analysis of the Cabralian concept of people and suggests that the emergence of this concept in Cabral's discourse derives from the intersection of the development of anti-colonial nationalist thought in the former Portuguese Empire and the development of agrarian studies in metropolitan Portugal. PMID- 28355315 TI - Bodies in motion: spaces, emotions and representations that (de)construct realities. AB - OBJECTIVE To analyze the social representations of the body among Brazilian and Costa Rican transsexual people through their life stories. METHOD Qualitative and descriptive multicenter research. The study population consisted of 70 participants. Two organizations cooperated to collect the information, one in Florianopolis, SC-Brazil and one in San Jose, the capital of Costa Rica. Content Analysis was used to analyze the data. RESULTS Based on the results, a single social representation of corporeality was unveiled: "Modeled bodies: about the elasticity of corporeality". This representation described two clear elementary context units (discourse matrices). The first associates the body with an inconclusive, transitory, volatile, pliable, moldable and fluid object, while the second relates the body with a separate institution, but regulated and controlled by others. CONCLUSION In conclusion, the transsexual body is a volatile, transient, transformable institution, crossed by the marks of a historicizing and historicizable time, which comes within the scope not only of what can be named by means of linguistic signs, but also of what belongs to the unnamable in terms of sociocultural perceptions and feelings. PMID- 28355313 TI - Short-term quality of life change perceived by patients after transition to mandibular overdentures AB - The aim of this longitudinal observational study was to evaluate the oral health related quality of life (OHRQoL) following patient rehabilitation with implant retained mandibular overdentures (IMO) and to identify the contribution of the different domains to OHRQoL. The Oral Health Impact Profile (OHIP-EDENT), Dental Impact on Daily Living (DIDL), and Geriatric Oral Health Assessment Index (GOHAI) questionnaires were completed twice by 25 patients: after 3 months of rehabilitation with complete dentures (CD) and after 3 months of IMO loading using stud abutments. The evaluation after IMO rehabilitation showed significant improvement in three DIDL domains: appearance (p = 0.011), eating and chewing (p = 0.003), and general performance (p = 0.003). The GOHAI results showed significant differences in two domains: psychosocial (p = 0.005) and pain and discomfort (p = 0.0004). The OHIP-EDENT outcomes showed significant improvements in five domains: functional limitation (p = 0.0001), physical pain (p = 0.0002), physical disability (p = 0.0010), and psychological disability and handicap (p = 0.032). The largest observed effect sizes were close to one standard deviation and were observed in the eating and chewing domain (0.93) of the DIDL; the pain and discomfort domain (0.83) of the GOHAI, and the functional limitation (0.89), physical pain (1.02), physical disability (0.84) domains of the OHIP-EDENT. The percentage of satisfied patients increased in all domains. Self-reported OHRQoL of CD wearers was significantly improved after 3 months of treatment with IMO, especially concerning the functional and pain-related aspects. PMID- 28355316 TI - Proposal of nursing care plan in people hospitalized with AIDS. AB - OBJECTIVE to elaborate and validate a proposal for a nursing care plan in people hospitalized with AIDS, in an infectious disease unit, using ICNP(r) version 2015. METHODS A cross-sectional study, followed by validation of content, performed with 20 nurses and 120 people, living with AIDS in an infectious disease unit of a hospital of infectious diseases in Northeast Brazil. The methodological trajectory was carried out in the following stages: elaboration of the diagnosis, nursing outcomes; Initial proposal of nursing interventions; Preparation of a care plan; And validation of the plan by field experts. RESULTS 42 diagnoses were elaborated and validated, 33 presented CVI > 0.80 (55.42%) among field experts. From this quantitative, 228 interventions were elaborated and 41 obtained a CVI > 0.80 (44.78%), considered validated. CONCLUSION The study allowed us to identify and validate nursing diagnoses, outcomes and interventions for the use in clinical practice, aiming to subsidize the process of care for people with AIDS. PMID- 28355317 TI - Control of anxiety through music in a head and neckoutpatient clinic: a randomized clinical trial. AB - OBJECTIVE Evaluating the effectiveness of a musical intervention in reducing anxiety and vital parameters in people suffering from head and neck cancer. METHOD A randomized controlled clinical trial, performed in a head and neck outpatient clinic with 40 participants, subdivided into two groups (intervention and control).The classicalmusic"Spring" from The Four Seasons by Vivaldi was used as an intervention.The State-Trait Anxiety Inventory (STAI) was used as the data collectioninstrument,along with an inventory of socio-demographic and clinical data. Student'st-test was used to verify intragroup and intergroup statistical significance. RESULTS Participants presented a statistically significant reduction in levels of perceived anxiety (t= 12.68; p<0.001),as well as blood pressure levels (t = 4.56; p<0.001); pulse (t = 6.15; p<0.001) and respiratory rate (t = 5.10; p<0.001). CONCLUSION Music has proven to be an effective non pharmacological therapeutic resource in managinganxiety in an outpatient setting for people with cancer, as well as in reducing blood pressure, pulse and respiratory rate. Brazilian Registry of Clinical Trials: RBR-7W4YJJ. PMID- 28355318 TI - Cerebellar ataxia associated with anti-glutamic acid decarboxylase (anti-GAD) autoantibodies: a rare and puzzling disease. PMID- 28355319 TI - Malignant multiple sclerosis: clinical and demographic prognostic factors. AB - Patients with malignant multiple sclerosis (MMS) reach a significant level of disability within a short period of time (Expanded Disability Status Scale score of 6 within five years). The clinical profile and progression of the disease were analyzed in a Brazilian cohort of 293 patients. Twenty-five (8,53%) patients were found to have MMS and were compared with the remaining 268 (91,47%). Women, non white patients, older age at disease onset, shorter intervals between the first attacks, and more attacks in the first two years of the disease were all more common in the MMS group. These findings could serve as prognostic factors when making therapeutic decisions. PMID- 28355320 TI - Clinical characteristics of patients with cerebellar ataxia associated with anti GAD antibodies. AB - Methods: This retrospective and descriptive study evaluated the clinical characteristics and outcomes of patients with CA-GAD-ab. Result: Three patients with cerebellar ataxia, high GAD-ab titers and autoimmune endocrine disease were identified. Patients 1 and 2 had classic stiff person syndrome and insidious onset cerebellar ataxia, while Patient 3 had pure cerebellar ataxia with subacute onset. Patients received intravenous immunoglobulin therapy with no response in Patients 1 and 3 and partial recovery in Patient 2. Conclusion: CA-GAD-ab is rare and its clinical presentation may hamper diagnosis. Clinicians should be able to recognize this potentially treatable autoimmune cerebellar ataxia. PMID- 28355321 TI - Assessment of energy expenditure in individuals with post-poliomyelitis syndrome. AB - Methods: The Baecke questionnaire for the evaluation of habitual physical activity (HPA), assessment of quality of life (WHOQOL-Bref), and the Fatigue Severity Scale were administered to patients with PPS, poliomyelitis sequelae (PS) and to a control group (CG). Participated in the study 116 individuals (PPS=52,PS= 28,CG=36). Results: Patients with PPS tended to increase their HPA from 10 to 20 years of age, compared with those in the PS group and the CG. In the period from 21 to 30 years of age, there was significant increase in the PPS group's occupational physical activity compared to the PS group, and the occupational physical activity (21-30 years of age) correlated with the onset of symptoms of PPS. Conclusion: Patients with PPS had a higher energy expenditure during life, especially in occupational physical activity at ages 21-30 years, suggesting this decade is critical for the development of PPS. PMID- 28355322 TI - Cutaneous allodynia is more frequent in chronic migraine, and its presence and severity seems to be more associated with the duration of the disease. AB - Objective: To evaluate cutaneous allodynia among patients with chronic and episodic migraine in a tertiary headache clinic. Methods: 80 subjects with episodic migraine and 80 with chronic migraine were assessed in a tertiary hospital. The 12-item Allodynia Symptom Checklist/Brazil questionnaire was applied to classify subjects according to the presence and severity of cutaneous allodynia. Results: Cutaneous allodynia was identified in 81.3% of the episodic migraine group and 92.5% of the chronic migraine group (p = 0.03). No increased association could be attributed to chronic migraine when adjusted by years with disease (PR = 1.12; 95%CI = 0.99 to 1.27; p = 0.06). The groups also did not differ in the severity of allodynia, and severe presentation was the most frequent. Discussion: Both groups seemed to be similarly affected in the cephalic and extracephalic regions, with the same severity. Conclusion: Cutaneous allodynia is more frequent in chronic migraine, and its presence and severity seems to be more associated with the duration of the disease. PMID- 28355323 TI - Conventional physical therapy and physical therapy based on reflex stimulation showed similar results in children with myelomeningocele. AB - We aimed to investigate whether infants with myelomeningocele would improve their motor ability and functional independence after ten sessions of physical therapy and compare the outcomes of conventional physical therapy (CPT) to a physical therapy program based on reflex stimulation (RPT). Twelve children were allocated to CPT (n = 6, age 18.3 months) or RPT (n = 6, age 18.2 months). The RPT involved proprioceptive neuromuscular facilitation. Children were assessed with the Gross Motor Function Measure and the Pediatric Evaluation of Disability Inventory before and after treatment. Mann-Whitney tests compared the improvement on the two scales of CPT versus RPT and the Wilcoxon test compared CPT to RPT (before vs. after treatment). Possible correlations between the two scales were tested with Spearman correlation coefficients. Both groups showed improvement on self care and mobility domains of both scales. There were no differences between the groups, before, or after intervention. The CPT and RPT showed similar results after ten weeks of treatment. PMID- 28355324 TI - Validation of the Frenchay activity index on stroke victims. AB - Purpose: To evaluate the inter-rater reliability and predictive validity of the Frenchay Activities Index (FAI) in patients after stroke. Methods: One hundred sixty-one patients were selected for consecutive application of the FAI and National Institutes of Health Stroke Scale (NIHSS). Spearman's test was used for correlation between different scales. The FAI and NIHSS association was evaluated using ordinal logistic regression. Additionally, 36 patients underwent FAI rating on the same day by two independent evaluators. Results: A negative correlation between the FAI and the NIHSS scores (p = 0.017 r = -0.22) was found. Adjusting all variables with possible association with the NIHSS, ordinal logistic regression showed that the FAI had a significant association with NIHSS scores (OR 0.93, 95% CI 0.87 to 0.99, p: 0.033). The inter-rater agreement was considered good, k = 0.66 (0.54 to 0.78), p < 0.001. Conclusions: The FAI is a valid and useful method to assess instrumental activities before acute stroke in a Brazilian population. PMID- 28355326 TI - Soul, butterfly, mythological nymph: psyche in philosophy and neuroscience. AB - The term "psyche" and its derivatives - including "Psychology" and "Psychiatry" - are rooted in classical philosophy and in mythology. Over the centuries, psyche has been the subject of discourse and contemplation, and of fable; it has also come to signify, in entomology, the order of Lepidoptera. In the current surge of research on brain and mind, there is a gradual transition from the psyche (or the "soul") to the specified descriptors defined by the fields of Behavioral, Cognitive and Integrative Neuroscience. PMID- 28355325 TI - Estrogen receptor-alpha gene XbaI A > G polymorphism influences short-term cognitive decline in healthy oldest-old individuals. AB - Methods: The individuals were categorized in two groups according to the presence or absence of cognitive decline. Cognitive data were related to genetic information. Results: The XbaI -351 AA genotype was more common among cognitive decliners, while -351G allele carriers showed cognitive stability or improvement. Conclusion: These results suggest that ESR-1 could be associated with one-year cognitive decline in healthy oldest-old individuals, since the estrogen pathway may be involved with neuroprotection, even in healthy brain aging. PMID- 28355327 TI - Traumatic brain lesions in newborns. AB - Methods: A literature review using the PubMed data base, MEDLINE, EMBASE, Science Direct, The Cochrane Database, Google Scholar, and clinical trials. Selected papers from 1922 to 2016 were studied. We selected 109 papers, through key-words, with inclusion and exclusion criteria. Discussion: This paper discusses the risk factors for birth trauma, the anatomy of the occipito-anterior and vertex presentation, and traumatic brain lesions. Conclusion: Birth-related traumatic brain injury may cause serious complications in newborn infants. Its successful management includes special training, teamwork, and an individual approach. PMID- 28355328 TI - Georges Simenon, Inspector Maigret and his relevance to the practice of Neurology. AB - Georges Simenon's work, including his famous 'romans durs' novels and the forensic investigations carried out by his artistic creation, Inspector Maigret, bear many similarities to some of the diagnostic methods of the founders of Neurology, particularly Jean-Martin Charcot. PMID- 28355330 TI - Charcot and vascular Parkinsonism. AB - Jean-Martin Charcot (1825-1893), recognized as the founder of Neurology and the first formal teacher of nervous system diseases, died on August 16, 1893, from acute pulmonary edema secondary to myocardial infarction. In his last years, there were several descriptions of his gait and posture disorders, suggesting the diagnosis of "lower-half parkinsonism" due to cerebrovascular disease. PMID- 28355329 TI - Parkinson's disease - 200 years: the outstanding contribution of "Old Hubert". AB - Two hundred years after the publication, of "An Essay on the Shaking Palsy", this indisputable landmark in our understanding of the nature of Parkinson's disease still remains. What is frequently overlooked, however, is the originality of James Parkinson's ideas about how clinical observations could be segregated into diagnostic entities. Parkinson was a surgeon apothecary with wide ranging interests outside medicine including geology and paleontology. He was also a strong campaigner for social change and a political pamphleteer, writing under the nom de plume of "Old Hubert". PMID- 28355331 TI - Facial and bulbar muscle atrophy in acetylcholine receptor antibody-positive myasthenia gravis. PMID- 28355332 TI - Late radiation therapy brain abnormalities that mimic leukoencephalopathy with anterior temporal lobe cysts. PMID- 28355333 TI - Intracranial hypotension secondary to spontaneous spinal cerebrospinal fluid leaks. PMID- 28355334 TI - Social inequality in health: revisiting moments and trends in 50 years of publication of RSP. AB - This study describes the frequency and types of articles on social inequalities in health published in 50 years of the Revista de Saude Publica, taking as reference some milestones that were used as guidelines to develop the research on this theme. Checking titles, keywords and abstracts or full texts, we identified 288 articles whose central or secondary focus was social inequalities in health. Corresponding to just 1.8% in the initial years, articles on social inequalities in health have represent 10.1% of the articles published in the last decade. The designs used were mainly cross-sectional (58.0%) and ecological (18.1%). The most analyzed themes were: food/nutrition (20.8%), mortality (13.5%), infectious diseases (10.1%), oral health (9.0%), and health services (8.7%). Articles focused on the analysis of racial inequalities in health amounted to 6.9%. Few articles monitored the trends of social inequalities in health, essential enterprise to assess and support interventions, and an even smaller number evaluated the impact of policies and programs on the reduction of social inequalities in health. RESUMO Este estudo descreve a frequencia e os tipos de artigos sobre desigualdades sociais em saude publicados nos 50 anos da Revista de Saude Publica, tomando por referencia alguns marcos que balizaram o desenvolvimento das investigacoes nessa tematica. Checando titulos, palavras chave e resumos ou textos completos, foram identificados 288 artigos cujo foco central ou secundario era desigualdades sociais em saude. Correspondendo a apenas 1,8% nos anos iniciais, artigos sobre desigualdades sociais em saude chegaram a representar 10,1% dos publicados na ultima decada. Os desenhos utilizados foram principalmente transversais (58,0%) e ecologicos espaciais (18,1%). Os temas mais analisados foram: alimentacao/nutricao (20,8%), mortalidade (13,5%), doencas infecciosas (10,1%), saude bucal (9,0%) e servicos de saude (8,7%). Artigos voltados a analise de desigualdades raciais em saude somaram 6,9%. Poucos artigos monitoraram as tendencias das desigualdades sociais em saude, empreendimento essencial para avaliar e subsidiar intervencoes, e um numero ainda menor avaliou o impacto de politicas e programas na reducao das desigualdades sociais em saude. PMID- 28355335 TI - The mental health care model in Brazil: analyses of the funding, governance processes, and mechanisms of assessment. AB - OBJECTIVE: This study aims to analyze the current status of the mental health care model of the Brazilian Unified Health System, according to its funding, governance processes, and mechanisms of assessment. METHODS: We have carried out a documentary analysis of the ordinances, technical reports, conference reports, normative resolutions, and decrees from 2009 to 2014. RESULTS: This is a time of consolidation of the psychosocial model, with expansion of the health care network and inversion of the funding for community services with a strong emphasis on the area of crack cocaine and other drugs. Mental health is an underfunded area within the chronically underfunded Brazilian Unified Health System. The governance model constrains the progress of essential services, which creates the need for the incorporation of a process of regionalization of the management. The mechanisms of assessment are not incorporated into the health policy in the bureaucratic field. CONCLUSIONS: There is a need to expand the global funding of the area of health, specifically mental health, which has been shown to be a successful policy. The current focus of the policy seems to be archaic in relation to the precepts of the psychosocial model. Mechanisms of assessment need to be expanded. OBJETIVO: Analisar o estagio atual do modelo de atencao a saude mental do Sistema Unico de Saude, segundo seu financiamento, processos de governanca e mecanismos de avaliacao. METODOS: Foi realizada uma analise documental de portarias, informes tecnicos, relatorios de conferencia, resolucoes e decretos de 2009 a 2014. RESULTADOS: Trata-se de um momento de consolidacao do modelo psicossocial, com ampliacao da rede assistencial, inversao de financiamento para servicos comunitarios com forte enfase na area de crack e outras drogas. A saude mental e uma area subfinanciada dentro do subfinanciamento cronico do Sistema Unico de Saude. O modelo de governanca constrange o avanco de servicos essenciais, havendo a necessidade da incorporacao de um processo de regionalizacao da gestao. Os mecanismos avaliativos no campo burocratico se mostram pouco incorporados a politica de saude. CONCLUSOES: E necessario ampliar o financiamento global da saude e especifico da saude mental, que vem se constituindo como uma politica exitosa. O foco atual da politica se mostra anacronico aos preceitos do modelo psicossocial. Aponta-se a necessidade de ampliacao de mecanismos avaliativos. PMID- 28355336 TI - The relationship between indicators of socioeconomic status and cesarean section in public hospitals. AB - OBJECTIVE: To assess the relationship between indicators of socioeconomic status and cesarean section in public hospitals that adopt standardized protocols of obstetrical care. METHODS: This was a prospective cohort study conducted between May 2005 and January 2006 with 831 pregnant women recruited from 10 public primary care clinics in Sao Paulo, Brazil. Demographic and clinical characteristics were collected during pregnancy. The three main exposures were schooling, monthly family income per capita, and residential crowding. The main outcome was cesarean section at three public hospitals located in the area. Crude and adjusted risk ratios (RR), with 95% confidence intervals were calculated using Poisson regression with robust variance. We examined the effects of each exposure variable on cesarean section accounting for potential confounders by using four different models: crude, adjusted by mother's characteristics, by obstetrical complications, and by the other two indicators of socioeconomic status. RESULTS: Among the 757 deliveries performed in the public hospitals, 215 (28.4%) were by cesarean section. In the bivariate analysis, cesarean section was associated with higher family income per capita, higher education, lower residential crowding, pregnancy planning, white skin color, having a partner, and advanced maternal age. In the multivariate analysis, after adjustment for covariates, none of the socioeconomic status variables remained associated with cesarean section. CONCLUSIONS: In this group, the chance of women undergoing cesarean section was not associated with indicators of socioeconomic status only, but was defined in accordance with major obstetric and clinical conditions. PMID- 28355337 TI - Translation, cross-cultural adaptation and validation of the Diabetes Empowerment Scale - Short Form. AB - OBJECTIVE: To translate, cross-culturally adapt and validate the Diabetes Empowerment Scale - Short Form for assessment of psychosocial self-efficacy in diabetes care within the Brazilian cultural context. METHODS: Assessment of the instrument's conceptual equivalence, as well as its translation and cross cultural adaptation were performed following international standards. The Expert Committee's assessment of the translated version was conducted through a web questionnaire developed and applied via the web tool e-Surv. The cross-culturally adapted version was used for the pre-test, which was carried out via phone call in a group of eleven health care service users diagnosed with type 2 diabetes mellitus. The pre-test results were examined by a group of experts, composed by health care consultants, applied linguists and statisticians, aiming at an adequate version of the instrument, which was subsequently used for test and retest in a sample of 100 users diagnosed with type 2 diabetes mellitus via phone call, their answers being recorded by the web tool e-Surv. Internal consistency and reproducibility of analysis were carried out within the statistical programming environment R. RESULTS: Face and content validity were attained and the Brazilian Portuguese version, entitled Escala de Autoeficacia em Diabetes - Versao Curta, was established. The scale had acceptable internal consistency with Cronbach's alpha of 0.634 (95%CI 0.494- 0.737), while the correlation of the total score in the two periods was considered moderate (0.47). The intraclass correlation coefficient was 0.50. CONCLUSIONS: The translated and cross culturally adapted version of the instrument to spoken Brazilian Portuguese was considered valid and reliable to be used for assessment within the Brazilian population diagnosed with type 2 diabetes mellitus. The use of a web tool (e Surv) for recording the Expert Committee responses as well as the responses in the validation tests proved to be a reliable, safe and innovative method. OBJETIVO: Traduzir, adaptar culturalmente e validar o Diabetes Empowerment Scale Short Form para aplicacao no contexto cultural brasileiro. METODOS: A analise do instrumento, para avaliar a equivalencia conceitual e de itens, bem como sua traducao e adaptacao cultural, foram realizadas de acordo com a metodologia padrao. A etapa de avaliacao pelo comite de juizes foi conduzida por meio de questionario eletronico, desenvolvido e aplicado pela ferramenta web e-Surv. A versao adaptada foi utilizada durante o pre-teste, aplicado via ligacao telefonica, a um grupo de 11 usuarios com diabetes melito tipo 2. Os resultados do pre-teste foram examinados por profissionais da area da saude, linguistica aplicada e estatistica, para obtencao de uma versao adequada do instrumento. Em seguida, foi aplicada no teste e reteste em amostra de 100 usuarios com diabetes, por ligacao telefonica, com registro das respostas dos usuarios por meio da ferramenta e-Surv. As analises de consistencia interna e reprodutibilidade foram realizadas no ambiente de programacao estatistica R. RESULTADOS: Foi possivel obter validade de face e de conteudo do instrumento, que resultou na versao em portugues, intitulada Escala de Autoeficacia em Diabetes - Versao Curta. A escala apresentou consistencia interna aceitavel, com alfa de Cronbach igual a 0,634 (IC95% 0,494-0,737), enquanto a concordancia do escore total nos dois momentos foi considerada moderada (0,47). O coeficiente de correlacao intraclasse teve o valor de 0,50. CONCLUSOES: O processo de traducao e de adaptacao para a lingua portuguesa falada no Brasil gerou uma versao do instrumento considerada valida e confiavel para a populacao brasileira. A utilizacao do e-Surv para o registro dos dados coletados do comite de juizes, assim como das respostas dos testes de validacao, mostrou-se uma metodologia confiavel, segura e inovadora. PMID- 28355338 TI - Social and behavior change communication in the fight against malaria in Mozambique. AB - Long-lasting insecticide-treated nets and/or indoor residual spraying, associated with case management, are key interventions in the control of malaria in Africa. The objective of this study is to comment on the role of social and behavior change communication as a potential key intervention in the control of malaria in Mozambique. RESUMO As redes mosquiteiras impregnadas com insecticidade de longa duracao e/ou pulverizacao intra-domiciliaria, associada ao manejo de casos sao intervencoes-chave no controlo da malaria em Africa. O objetivo deste estudo foi comentar o papel da comunicacao para a mudanca social e de comportamento como intervencao potencialmente chave no controlo da malaria em Mocambique. PMID- 28355340 TI - Erratum. PMID- 28355339 TI - Food consumed outside the home in Brazil according to places of purchase. AB - OBJECTIVE: This study aims to describe the places of purchase of food consumed outside the home, characterize consumers according to the places of consumption, and identify the food purchased by place of consumption in Brazil. METHODS: We have used data from the Pesquisa de Orcamento Familiar (Household Budget Survey) of 2008-2009 with a sample of 152,895 subjects over 10 years of age. The purchase of food outside the home was collected from the records of all expenditures made in seven days. The places of purchase were grouped according to their characteristics: supermarket, bakery, street food, restaurant, snack bar, fruit shop, and other places. The types of food were grouped into nine categories, considering the nutritional aspects and the marketing characteristics of the item. We have estimated the frequency of purchase in the seven groups of places in Brazil and according to gender and type of food purchased per place. We have calculated the average age, income and years of education, as well as the per capita expenditure according to places of purchase of food consumed outside the home. RESULTS: The purchase of food outside the home was reported by 41.2% of the subjects, being it greater among men than women (44% versus 38.5%). Adults had a higher frequency (46%) than teenagers (37.7%) and older adults (24.2%). The highest frequency of places of purchase were snack bar (16.9%) and restaurant (16.4%), while the fruit shop (1.2%) presented the lowest frequency. Sweets, snack chips and soft drinks were the most purchased items in most places. Average expenditure was higher for restaurant (R$33.20) and lower for fruit shop (R$4.10) and street food (R$5.00). CONCLUSIONS: The highest percentage of food consumed outside the home comes from snack bars and restaurants, pointing to important places for the development of public policies focused on promoting healthy eating. OBJETIVO: Descrever os locais de aquisicao dos alimentos consumidos fora do lar, caracterizar os consumidores de acordo com os locais de consumo e identificar os alimentos adquiridos por local de consumo no Brasil. METODOS: Utilizaram-se dados da Pesquisa de Orcamento Familiar 2008-2009 em uma amostra de 152.895 individuos acima de 10 anos. A aquisicao de alimentos para consumo fora do lar foi coletada por registros de todos os gastos realizados no periodo de sete dias. Os locais de aquisicao de alimentos foram agrupados de acordo com suas caracteristicas: supermercado, padaria, comida de rua, restaurante, lanchonete, frutaria e outros. Os tipos de alimentos adquiridos foram alocados em nove categorias de alimentos, considerando os aspectos nutricionais e as caracteristicas de comercializacao do item. Estimou-se a frequencia de aquisicao de alimentos nos sete grupos de locais no Brasil e por sexo e o tipo de alimento adquirido por local. Calculou-se a media de idade, de renda e de anos de escolaridade, bem como da despesa per capita segundo locais de aquisicao de alimentos consumidos fora do lar. RESULTADOS: A aquisicao de alimentos fora do lar foi reportada por 41,2% dos individuos, sendo maior entre os homens do que nas mulheres (44% versus 38,5%). Os adultos apresentaram maior frequencia de aquisicao (46%) do que os adolescentes (37,7%) e os idosos (24,2%). Os locais com maiores frequencias de consumo de alimentos fora do lar foram lanchonete (16,9%) e restaurante (16,4%), enquanto frutaria (1,2%) apresentou a menor frequencia. Doces, salgadinhos e refrigerante foram os alimentos mais adquiridos na maioria dos locais. Os gastos medios com alimentos foram maiores para restaurante (R$33,20) e menores para frutaria (R$4,10) e comida de rua (R$5,00). CONCLUSOES: O maior percentual de consumo de alimentos fora do lar e proveniente de lanchonete e restaurante, apontando importantes locais para o desenvolvimento de politicas publicas com foco na promocao da alimentacao saudavel. PMID- 28355341 TI - Erratum. AB - [This corrects the article doi: 10.1590/1519-6984.12015]. PMID- 28355342 TI - Association of weight control behaviors with body mass index and weight-based self-evaluation. AB - Objective:: To determine the frequency of weight control behaviors (WCBs) and their correlation with body mass index (BMI) and weight-based self-evaluation. Methods:: Data were collected by the Brazilian Internet Study on Temperament and Psychopathology (BRAINSTEP) from 27,501 volunteers (30.4% men, mean age 28.9+/ 8.7 years). Results:: The most prevalent WCBs for men and women were exhaustive physical exercise and prolonged fasting, respectively. Frequent exhaustive physical exercise was the only behavior more often adopted by men. BMI was positively associated with WCBs, which were very frequent in obese subjects. About 15% of normal-weight women reported using diuretics and laxatives, and 12.2% reported vomiting as a WCB at least occasionally. Among subjects who regarded body weight highly in their self-evaluation, there was a strong positive association with all WCBs, at similar degrees, in both genders. Compared to those who never base their intrinsic personal value on body weight, those who frequently base intrinsic value on body weight were at 25-30 times higher risk of inducing vomiting. Conclusion:: The prevalence of participants adopting WCBs was high, especially in women and obese subjects. Weight-based self-evaluation was more strongly associated with WCBs than BMI. PMID- 28355343 TI - Association between body image dissatisfaction and depressive symptoms in adolescents. AB - OBJECTIVE: To determine the association between body image dissatisfaction (BID) and depressive symptoms in adolescents from a school in Lima, Peru. METHODS: A cross-sectional study was performed through a census of 875 high-school students, aged 13 to 17 years, from a school in Lima. Participants completed a survey containing the Body Shape Questionnaire (BSQ) and the Patient Health Questionnaire-9 (PHQ-9). Data regarding demographics, alcohol and tobacco use, self-esteem, and family history of depression were also obtained. To identify associated factors, Poisson regression with robust variance was used. Prevalence ratios with 95% confidence intervals were calculated. RESULTS: Of the 875 adolescents, 55.8% were male. The mean age was 14.1+/-1.5 years. Depressive symptoms were observed in 19.9% of participants. An association between BID and depressive symptoms was found. Alcohol and tobacco use were also associated with the outcome of interest. CONCLUSIONS: Teens who had BID were 3.7 times more likely to report depressive symptoms. Additionally, those who used tobacco or alcohol were 1.5 and 1.4 times more likely to have depressive symptoms, respectively. Further studies targeting other populations and using longitudinal designs are recommended. PMID- 28355344 TI - Psychiatric event in multiple sclerosis: could it be the tip of the iceberg? AB - Multiple sclerosis (MS) is a chronic progressive inflammatory disease of the central nervous system. Psychiatric comorbidities are highly prevalent in patients with MS, and can have drastic impact on quality of life and interpersonal relationships. Despite this high prevalence, whether psychiatric manifestations may represent the first signs of MS is still debatable. This constitutes an important issue, since early diagnosis of "psychiatric-onset MS" would result in prompt management, which usually ameliorates long-term prognosis. Here, we discuss clinical and radiological hints that suggest a diagnosis of psychiatric-onset MS. Briefly, this entity should be considered in healthy patients presenting with late-onset psychiatric symptoms, with or without cognitive decline, and with negative family history of psychiatric diseases. A thorough neurological exam is crucial to detect any subtle neurological signs. Brain magnetic resonance imaging is recommended to rule out frontotemporal lesions that might explain the clinical picture. Poor response to standard psychiatric treatments provides additional evidence for the diagnosis of an organic disease (e.g., MS). Combining psychopharmaceuticals with intravenous corticosteroids would result in good outcomes, but patients should be monitored carefully for possible psychiatric exacerbation, a common side effect of steroids. PMID- 28355345 TI - Chronic dosing with mirtazapine does not produce sedation in rats. AB - Objective:: Sedation/somnolence are major side effects of pharmacotherapies for depression, and negatively affect long-term treatment compliance in depressed patients. Use of mirtazapine (MIR), an atypical antidepressant approved for the treatment of moderate to severe depression with comorbid anxiety disorders, is associated with significant sedation/somnolence, especially in short-term therapy. Nonetheless, studies with human subjects suggest that MIR-induced sedation is transient, especially when high and repeated doses are used. The purpose of this study was to explore the effects of acute and chronic administration of different doses of MIR on sedation in the rat. Methods:: Assessment of sedation was carried out behaviorally using the rotarod, spontaneous locomotor activity, and fixed-bar tests. Results:: A 15-mg/kg dose of MIR induced sedative effects for up to 60 minutes, whereas 30 mg/kg or more produced sedation within minutes and only in the first few days of administration. Conclusion:: These results suggest that 30 mg/kg is a safe, well tolerated dose of MIR which generates only temporary sedative effects. PMID- 28355346 TI - Association between dietary patterns and mental disorders in pregnant women in Southern Brazil. AB - Objective:: To evaluate the association between dietary patterns and mental disorders among pregnant women in southern Brazil. Methods:: Cross-sectional study with 712 pregnant women recruited from the Study of Food Intake and Eating Behaviors in Pregnancy (ECCAGe). Food intake assessment was performed using the Food Frequency Questionnaire. Dietary patterns were identified by cluster analysis. The Primary Care Evaluation of Mental Disorders (PRIME-MD) was used to evaluate participants' mental health. Poisson regression models with robust variance were fitted to estimate prevalence ratios (PR). Results:: In the adjusted models, there was a high prevalence of major depressive disorder among women with low fruit intake (43%, PR 1.43, 95%CI 1.04-1.95) and high sweets and sugars intake (91%, PR 1.91, 95%CI 1.19-3.07). Women with a common-Brazilian dietary pattern had higher prevalence of major depressive disorder compared to those with a varied consumption pattern (PR 1.43, 95%CI 1.01-2.02). Low intake of beans was significantly associated with generalized anxiety disorder (PR 1.40, 95%CI 1.01-1.93). Conclusions:: Low consumption of fruits and beans and intake of the common-Brazilian dietary pattern during pregnancy were associated with higher prevalence of mental disorders. These results reinforce the importance of an adequate dietary intake to ensure better mental health in pregnancy. PMID- 28355347 TI - Mortality in traffic accidents with older adults in Colombia. AB - OBJECTIVE To analyze the traffic accident mortality in the Colombian older adults during the 1998-2012 period and show the loss of productive years and mortality from this cause. METHODS Quantitative study of the trend analysis of deaths in Colombia in traffic accidents, from 1998 to 2012, according to death records and population projected by the Colombian National Administrative Department of Statistics. Frequency distribution profile of the deceased, death rates per hundred thousand inhabitants, potential years of life lost and calculation of excess mortality by age in the over 60 were made. RESULTS In the study period 100,758 deaths occurred in traffic accidents, 6,717 annual average, of which 18.5% occurred in people aged 60 years and over. The predominated deaths were men; the risk of dying was 32.15 per hundred thousand people in this age range, with double risk of dying those under 60 years. CONCLUSIONS The young population has a higher proportion of deaths, but those over 60 years are at increased risk of death, leading to the need to turn our gaze to the improvement of road infrastructure and standards, to educate the population in self-care and compliance with safety measures and prepare society for an ever more adult population, more numerous and more prone to take risks. PMID- 28355348 TI - Validation of self-reported diabetes in a representative sample of Sao Paulo city. AB - OBJECTIVE To validate the self-reported diabetes mellitus in adults and older adults living in the city of Sao Paulo, Brazil. METHODS We have used data of 569 subjects (284 adults and 285 older adults), participants of the population-based cross-sectional study Inquerito de Saude do Municipio de Sao Paulo (Health Survey of Sao Paulo). Fasting glucose >= 7.0 mmol/L (126 mg/dL) and/or use of drugs (oral hypoglycemic and/or insulin) defined the diagnosis of diabetes mellitus. We have validated the self-reported diabetes mellitus by calculating the sensitivity, specificity, positive predictive values, and negative predictive values. We have used Poisson regression with robust variance to verify the factors associated with the sensitivity of the self-reported datum. For all analyses, we have considered the sample design of the study. RESULTS The sensitivity of self-reported diabetes mellitus was 63.8% (95%CI 49.2-76.3), specificity was 99.7% (95%CI 99.1-99.9), positive predictive value was 95.5% (95%CI 84.4-98.8), and negative predictive value was 96.9% (95%CI 94.9-98.2). The correct reporting of diabetes mellitus was more prevalent among older adults (PR = 2.0; 95%CI 1.2-3.5) than among adults. CONCLUSIONS The use of the datum of self reported diabetes mellitus is valid, especially among older adults living in the city of Sao Paulo. The results highlight the need to track diabetes mellitus in asymptomatic subjects who have one or more risk factors for it, mainly in the adult population of this city. PMID- 28355349 TI - Overexpression of ezrin and galectin-3 as predictors of poor prognosis of cervical cancer. AB - The aim of this study was to explore the correlation of ezrin and galectin-3 expressions with prognosis in cervical cancer. The immunohistochemical method was applied to detect ezrin and galectin-3 expressions in normal cervix tissues (n=30), cervicitis tissues (n=28), cervical intraepithelial neoplasia (CIN) tissues (classified as I-III, n=89), and cervical carcinoma tissues (n=84). Follow-up was conducted for 5 to 78 months to analyze the correlation of protein expressions with prognosis. Ezrin and galectin-3 expressions in cervical cancer were significantly higher than in normal cervix, cervicitis and CIN (all P<0.05), and expressions in CIN were significantly higher than in normal cervix and cervicitis (both P<0.05). The expressions of ezrin and galectin-3 were both related with histological grade, deep myometrial invasion and lymph node metastasis (all P<0.05). Spearman analysis showed that ezrin expression was positively correlated with galectin-3 expression in cervical cancer (r=0.355, P<0.05). The survival rate of patients with high expressions of ezrin and galectin-3 was significantly lower than those with low expressions of proteins (both P<0.05). The expressions of ezrin and galectin-3, histological grade, depth of stromal invasion, and lymph node metastasis are risk factors affecting the survival rate of patients with cervical cancer. The expressions of ezrin and galectin-3 were correlated with the development of cervical cancer, and overexpressions of those proteins were indicative of poor prognosis in patients with cervical cancer. PMID- 28355350 TI - Influence of antihypertensive drugs on aortic and coronary effects of Ang-(1-7) in pressure-overloaded rats. AB - This study investigated the influence of antihypertensive drugs, such as angiotensin-converting enzyme inhibitors (ACEIs), AT1 receptor blockers (ARBs), voltage-gated L-type calcium channel blockers, and mineralocorticoid receptor antagonists (MRAs), on the effects of angiotensin-(1-7) [Ang-(1-7)] on aorta and coronary arteries from pressure-overloaded rats. Pressure overload was induced by abdominal aortic banding (AB). To evaluate the role of antihypertensive drugs on the effect of Ang-(1-7), AB male Wistar rats weighing 250-300 g were treated with vehicle or low doses (5 mg.kg-1.day-1, gavage) of losartan, captopril, amlodipine, or spironolactone. Isolated aortic rings and isolated perfused hearts under constant flow were used to evaluate the effect of Ang-(1-7) in thoracic aorta and coronary arteries, respectively. Ang-(1-7) induced a significant relaxation in the aorta of sham animals, but this effect was reduced in the aortas of AB rats. Chronic treatments with losartan, captopril or amlodipine, but not with spironolactone, restored the Ang-(1-7)-induced aorta relaxation in AB rats. The coronary vasodilatation evoked by Ang-(1-7) in sham rats was blunted in hypertrophic rats. Only the treatment with losartan restored the coronary vasodilatory effect of Ang-(1-7) in AB rat hearts. These data support a beneficial vascular effect of an association of Ang-(1-7) and some antihypertensive drugs. Thus, this association may have potential as a new therapeutic strategy for cardiovascular diseases. PMID- 28355352 TI - A novel frameshift mutation of Chediak-Higashi syndrome and treatment in the accelerated phase. AB - Chediak-Higashi syndrome (CHS) is a rare autosomal recessive immunodeficiency disease characterized by frequent infections, hypopigmentation, progressive neurologic deterioration and hemophagocytic lymphohistiocytosis (HLH), known as the accelerated phase. There is little experience in the accelerated phase of CHS treatment worldwide. Here, we present a case of a 9-month-old boy with continuous high fever, hypopigmentation of the skin, enlarged lymph nodes, hepatosplenomegaly and lung infection. He was diagnosed with CHS by gene sequencing, and had entered the accelerated phase. After 8 weeks of therapy, the boy had remission and was prepared for allogenic stem cell transplantation. PMID- 28355351 TI - Naringenin regulates production of matrix metalloproteinases in the knee-joint and primary cultured articular chondrocytes and alleviates pain in rat osteoarthritis model. AB - Inflammation of cartilage is a primary symptom for knee-joint osteoarthritis. Matrix metalloproteinases (MMPs) are known to play an important role in the articular cartilage destruction related to osteoarthritis. Naringenin is a plant derived flavonoid known for its anti-inflammatory properties. We studied the effect of naringenin on the transcriptional expression, secretion and enzymatic activity of MMP-3 in vivo in the murine monosodium iodoacetate (MIA) osteoarthritis model. The assessment of pain behavior was also performed in the MIA rats. The destruction of knee-joint tissues was analyzed microscopically. Moreover, the effect of naringenin was also studied in vitro in IL-1beta activated articular chondrocytes. The transcriptional expression of MMP-3, MMP-1, MMP-13, thrombospondin motifs (ADAMTS-4) and ADAMTS-5 was also studied in primary cultured chondrocytes of rats. Naringenin caused significant reduction in pain behavior and showed marked improvement in the tissue morphology of MIA rats. Moreover, a significant inhibition of MMP-3 expression in MIA rats was observed upon treatment with naringenin. In the in vitro tests, naringenin caused a significant reduction in the transcriptional expression, secretion and enzymatic activity of the studied degradative enzymes. The NF-kappaB pathway was also found to be inhibited upon treatment with naringenin in vitro. Overall, the study suggests that naringenin alleviated pain and regulated the production of matrix metalloproteinases via regulation of NF-kappaB pathway. Thus, naringenin could be a potent therapeutic option for the treatment of osteoarthritis. PMID- 28355353 TI - Influence of schooling and age on cognitive performance in healthy older adults. AB - Few studies have examined the influence of a low level of schooling on age related cognitive decline in countries with wide social and economic inequalities by using the Cambridge Automated Neuropsychological Test Battery (CANTAB). The aim of the present study was to assess the influence of schooling on age-related cognitive decline using unbiased cognitive tests. CANTAB allows cognitive assessment across cultures and education levels with reduced interference of the examiner during data acquisition. Using two-way ANOVA, we assessed the influences of age and education on test scores of old adults (61-84 years of age). CANTAB tests included: Visual Sustained Attention, Reaction Time, Spatial Working Memory, Learning and Episodic Memory. All subjects had a minimum visual acuity of 20/30 (Snellen Test), no previous or current history of traumatic brain/head trauma, stroke, language impairment, chronic alcoholism, neurological diseases, memory problems or depressive symptoms, and normal scores on the Mini Mental State Examination (MMSE). Subjects were grouped according to education level (1 to 7 and >=8 years of schooling) and age (60-69 and >=70 years). Low schooling level was associated with significantly lower performance on visual sustained attention, learning and episodic memory, reaction time, and spatial working memory. Although reaction time was influenced by age, no significant results on post hoc analysis were detected. Our findings showed a significantly worse cognitive performance in volunteers with lower levels of schooling and suggested that formal education in early life must be included in the preventive public health agenda. In addition, we suggest that CANTAB may be useful to detect subtle cognitive changes in healthy aging. PMID- 28355354 TI - Cerebral blood flow and vasoreactivity in aging: an arterial spin labeling study. AB - Regional cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) in young and elderly participants were assessed using pulsed arterial spin labeling (ASL) and blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) techniques in combination with inhalation of CO2. Pulsed ASL and BOLD-MRI were acquired in seventeen asymptomatic volunteers (10 young adults, age: 30+/-7 years; 7 elderly adults, age: 64+/-8 years) with no history of diabetes, hypertension, and neurological diseases. Data from one elderly participant was excluded due to the incorrigible head motion. Average baseline CBF in gray matter was significantly reduced in elderly (46+/-9 mL.100 g-1.min-1) compared to young adults (57+/-8 mL.100 g-1.min-1; P=0.02). Decreased pulsed ASL-CVR and BOLD-CVR in gray matter were also observed in elderly (2.12+/-1.30 and 0.13+/-0.06 %/mmHg, respectively) compared to young adults (3.28+/-1.43 and 0.28+/-0.11 %/mmHg, respectively; P<0.05), suggesting some degree of vascular impairment with aging. Moreover, age-related decrease in baseline CBF was observed in different brain regions (inferior, middle and superior frontal gyri; precentral and postcentral gyri; superior temporal gyrus; cingulate gyri; insula, putamen, caudate, and supramarginal gyrus). In conclusion, CBF and CVR were successfully investigated using a protocol that causes minimal or no discomfort for the participants. Age related decreases in baseline CBF and CVR were observed in the cerebral cortex, which may be related to the vulnerability for neurological disorders in aging. PMID- 28355355 TI - CIRBP protects H9C2 cells against myocardial ischemia through inhibition of NF kappaB pathway. AB - Myocardial ischemia is a major cause of death and remains a disease with extremely deficient clinical therapies and a major problem worldwide. Cold inducible RNA-binding protein (CIRBP) is reported to be involved in multiple pathological processes, including myocardial ischemia. However, the molecular mechanisms of myocardial ischemia remain elusive. Here, we first overexpressed CIRBP by transfection of pc-CIRBP (pcDNA3.1 containing coding sequenced for CIRBP) and silenced CIRBP by transfection of small interfering RNA targeting CIRBP (siCIRBP). pcDNA3.1 and the negative control of siCIRBP (siNC) were transfected into H9C2 cells to act as controls. We then constructed a cell model of myocardial ischemia through culturing cells in serum-free medium with hypoxia in H9C2 cells. Subsequently, AlamarBlue assay, flow cytometry and western blot analysis were used, respectively, to assess cell viability, reactive oxygen species (ROS) level and apoptosis, and expression levels of IkappaBalpha, p65 and Bcl-3. We demonstrated that CIRBP overexpression promoted cell proliferation (P<0.001), inhibited cell apoptosis (P<0.05), reduced ROS level (P<0.001), down regulated phosphorylated levels of IkappaBalpha and p65 (P<0.01 or P<0.001), and up-regulated expression of Bcl-3 (P<0.001) in H9C2 cells with myocardial ischemia. The influence of CIRBP knockdown yielded opposite results. Our study revealed that CIRBP could protect H9C2 cells against myocardial ischemia through inhibition of NF-kappaB pathway. PMID- 28355356 TI - Therapy of tacrolimus combined with corticosteroids in idiopathic membranous nephropathy. AB - We evaluated the efficacy and safety of tacrolimus (TAC) combined with corticosteroids in treating patients with idiopathic membranous nephropathy (IMN). One hundred seventy-seven biopsy-proven IMN patients were recruited in this retrospective clinical study. Sixty patients received TAC (target blood concentration of 4-8 ng/mL) and 117 patients received daily cyclophosphamide (CYC, 100 mg) combined with prednisone. Remission rates at the end of the first, second and third month in the TAC group were significantly higher than that in the CYC group (1st: 35.0 vs 19.7%, P<0.05; 2nd: 56.7 vs 38.5%, P<0.05; 3rd: 76.7 vs 59.0%, P<0.05). In the first 3 months, daily urinary protein and serum albumin in the TAC group obtained a better improvement than that in the CYC group (P<0.05). At the end of the sixth and the twelfth month, the remission rates, daily urinary protein and serum albumin were all comparable between the two groups (P>0.05). No significant difference of relapse rate between the groups was found (16.3 vs 12.0%, P>0.05). Patients were more likely to develop glucose intolerance in the TAC group. The TAC regimen obtained more benefits in treating IMN patients, especially in the first 3 months, than the CYC regimen. PMID- 28355357 TI - The influence of body image on surgical decisions in adolescent idiopathic scoliosis patients. AB - OBJECTIVES:: The objective of this study was to evaluate whether the severity of deformities in patients with adolescent idiopathic scoliosis contributes to patients' decision regarding whether to undergo an operation. METHODS:: We evaluated body image factors in adolescent idiopathic scoliosis patients. We evaluated the magnitude of the main scoliotic curve, gibbosity (magnitude and location), shoulder height asymmetry and patient's age. We analyzed the correlation of these data with the number of years the patient was willing to trade for surgery, as measured by the time-trade-off method. RESULTS:: A total of 52 patients were studied. We did not find a correlation between any of the parameters that were studied and the number of years that the patient would trade for the surgery. CONCLUSIONS:: The magnitude of body deformities in patients with adolescent idiopathic scoliosis does not interfere with the decision to undertake surgical treatment. PMID- 28355358 TI - Breast-conserving surgery in locally advanced breast cancer submitted to neoadjuvant chemotherapy. Safety and effectiveness based on ipsilateral breast tumor recurrence and long-term follow-up. AB - OBJECTIVE:: To evaluate ipsilateral breast tumor recurrence after breast conserving surgery for locally advanced breast cancer. METHODS:: A retrospective observational cohort study was performed in patients with locally advanced breast cancer submitted to breast-conserving surgery after neoadjuvant chemotherapy based on an adriamycin-cyclophosphamide-paclitaxel regimen. We evaluated the clinical, pathologic, immunohistochemistry, and surgical factors that contribute to ipsilateral breast tumor recurrence and locoregional recurrence. A Kaplan Meier analysis and Cox model were used to evaluate the main factors related to disease-free survival. RESULTS:: Of the 449 patients who received neoadjuvant chemotherapy, 98 underwent breast-conserving surgery. The average diameter of the tumors was 5.3 cm, and 87.2% reached a size of up to 3 cm. Moreover, 86.7% were classified as clinical stage III, 74.5% had T3-T4 tumors, 80.5% had N1-N2 axilla, and 89.8% had invasive ductal carcinoma. A pathologic complete response was observed in 27.6% of the tumors, and 100.0% of samples had free margins. The 5 year actuarial overall survival rate was 81.2%, and the mean follow-up was 72.8 months. The rates of ipsilateral breast tumor recurrence and locoregional recurrence were 11.2% and 15.3%, respectively. Multifocal morphology response was the only factor related to ipsilateral breast tumor recurrence disease-free survival (p=0.04). A multivariate analysis showed that the pathologic response evaluation criteria in solid tumors (RECIST)-breast cutoff was the only factor related to locoregional recurrence disease-free survival (p=0.01). CONCLUSIONS:: Breast-conserving surgery is a safe and effective therapy for selected locally advanced breast tumors. PMID- 28355359 TI - Oxidative stress and immune system analysis after cycle ergometer use in critical patients. AB - OBJECTIVE:: The passive cycle ergometer aims to prevent hypotrophy and improve muscle strength, with a consequent reduction in hospitalization time in the intensive care unit and functional improvement. However, its effects on oxidative stress and immune system parameters remain unknown. The aim of this study is to analyze the effects of a passive cycle ergometer on the immune system and oxidative stress in critical patients. METHODS:: This paper describes a randomized controlled trial in a sample of 19 patients of both genders who were on mechanical ventilation and hospitalized in the intensive care unit of the Hospital Agamenom Magalhaes. The patients were divided into two groups: one group underwent cycle ergometer passive exercise for 30 cycles/min on the lower limbs for 20 minutes; the other group did not undergo any therapeutic intervention during the study and served as the control group. A total of 20 ml of blood was analysed, in which nitric oxide levels and some specific inflammatory cytokines (tumour necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma) and interleukins 6 (IL-6) and 10 (IL-10)) were evaluated before and after the study protocol. RESULTS:: Regarding the demographic and clinical variables, the groups were homogeneous in the early phases of the study. The nitric oxide analysis revealed a reduction in nitric oxide variation in stimulated cells (p=0.0021) and those stimulated (p=0.0076) after passive cycle ergometer use compared to the control group. No differences in the evaluated inflammatory cytokines were observed between the two groups. CONCLUSION:: We can conclude that the passive cycle ergometer promoted reduced levels of nitric oxide, showing beneficial effects on oxidative stress reduction. As assessed by inflammatory cytokines, the treatment was not associated with changes in the immune system. However, further research in a larger population is necessary for more conclusive results. PMID- 28355360 TI - Helicobacter Pylory infection in patients with esophageal squamous cell carcinoma. AB - OBJECTIVE:: Esophageal squamous cell carcinoma is one of the most common esophageal diseases in the developing world, but the relationship between esophageal squamous cell carcinoma and Helicobacter pylori infection remains a neglected topic. The primary objective of this study was to determine the association between Helicobacter pylori infection and esophageal squamous cell carcinoma. A second purpose was to determine the incidence and factors associated with Helicobacter pylori infection following esophagectomy. METHOD:: The microorganism was identified by testing the gastric biopsy materials from 95 esophageal squamous cell carcinoma patients (66 females; 39 were esophagectomized) for urease activity in a medium containing urea and a power of hydrogen detection reagent and comparing the results with those from a healthy population. Differences in patient characteristics were assessed with chi-square tests and t-tests for categorical and continuous factors, respectively. RESULTS:: The patients with esophageal squamous cell carcinoma had a significantly lower prevalence of Helicobacter pylori compared with the healthy population (p<0.001). The naive and esophagectomized patients, in contrast, showed no significant differences in Helicobacter pylori infection (p>0.005). Patients with esophageal squamous cell carcinoma showed a significant association between leukocytosis and hypoglobulinemia and the presence of Helicobacter pylori infection (p=0.023 and p=0.045, respectively). CONCLUSION:: These results suggest that Helicobacter pylori is not an etiological factor in patients with esophageal squamous cell carcinoma. We found a statistically significant negative correlation between esophageal squamous cell cancer and Helicobacter pylori infection. These findings may guide new strategies for esophageal squamous cell carcinoma therapy. PMID- 28355361 TI - Anaerobic bacteria in the intestinal microbiota of Brazilian children. AB - OBJECTIVE:: Changes in the neonatal gut environment allow for the colonization of the mucin layer and lumen by anaerobic bacteria. The aim of the present study was to evaluate Bifidobacterium, Lactobacillus and Lactococcus colonization through the first year of life in a group of 12 Brazilian infants and to correlate these data with the levels of Escherichia coli. The presence of anaerobic members of the adult intestinal microbiota, including Eubacterium limosum and Faecalibacterium prausnitzii, was also evaluated. METHODS:: Fecal samples were collected during the first year of life, and 16S rRNA from anaerobic and facultative bacteria was detected by real-time PCR. RESULTS:: Bifidobacterium was present at the highest levels at all of the studied time points, followed by E. coli and Lactobacillus. E. limosum was rarely detected, and F. prausnitzii was detected only in the samples from the latest time points. CONCLUSION:: These results are consistent with reports throughout the world on the community structure of the intestinal microbiota in infants fed a milk diet. Our findings also provide evidence for the influence of the environment on intestinal colonization due to the high abundance of E. coli. The presence of important anaerobic genera was observed in Brazilian infants living at a low socioeconomic level, a result that has already been well established for infants living in developed countries. PMID- 28355362 TI - Controlled clinical trial addressing teeth whitening with hydrogen peroxide in adolescents: a 12-month follow-up. AB - OBJECTIVES:: To evaluate the colorimetric change in incisors and canines of adolescents aged 12 to 20 years submitted to at-home whitening and to evaluate satisfaction, sensitivity and discomfort during the procedures through a questionnaire. METHOD:: Thirty adolescents were randomly assigned to the following groups: 1) 6.0% hydrogen peroxide (White Class with calcium - FGM); 2) 7.5% hydrogen peroxide (White Class with calcium - FGM); 3) 10% hydrogen peroxide (Oral B 3D White - Oral-B); 4) Control group - placebo. Assessments were performed prior to treatment as well as at 7, 30, 180 and 360 days after treatment. Friedman's ANOVA was used to analyze color. The Kruskal-Wallis test followed by Dunn's post hoc test was used to compare the groups at the different evaluation times. Answers on the questionnaires were ranked, and non-parametrical tests were employed. The groups were compared in each period using the Kruskal Wallis test followed by the Student-Newman-Keuls test. Categorical data were analyzed using Fisher's exact test, and the Wilcoxon test was used for the analysis of different periods. P-values were corrected using the Hyan-Holm step down Bonferroni procedure. Clinicaltrials.gov: NCT01998386. RESULTS:: Similar results were obtained one month after treatment with both tooth whitening gels and whitening strips. Patients were partially satisfied with the treatment after the first and second weeks and would recommend it. All products demonstrated color stability after 12 months of follow-up. CONCLUSIONS:: The bleaching procedure was efficient, and the patients could perceive its result. Further investigations are needed to determine the effects of bleaching on young teeth. PMID- 28355363 TI - The effects of individually ventilated cages on the respiratory systems of male and female Wistar rats from birth until adulthood. AB - OBJECTIVE:: To evaluate the respiratory systems of male and female rats maintained in individually ventilated cages (IVCs) from birth until adulthood. METHODS:: Female Wistar rats were housed in individually ventilated cages or conventional cages (CCs) and mated with male Wistar rats. After birth and weaning, the male offspring were separated from the females and kept in cages of the same type until 12 weeks of age. RESULTS:: The level of food consumption was lower in male offspring (IVC=171.7+/-9; CC=193.1+/-20) than in female offspring (IVC=100.6+/-7; CC=123.4+/-0.4), whereas the water intake was higher in female offspring (IVC=149.8+/-11; CC=99.2+/-0) than in male offspring (IVC=302.5+/-25; CC=249.7+/-22) at 11 weeks of age when housed in IVCs. The cage temperature was higher in individually ventilated cages than in conventional cages for both male (IVCs=25.9+/-0.5; CCs=22.95+/-0.3) and female (IVCs=26.2+/-0.3; CCs=23.1+/-0.3) offspring. The respiratory resistance (IVC=68.8+/-2.8; CC=50.6+/-3.0) and elastance (IVC=42.0+/-3.9; CC=32.4+/-2.0) at 300 um/kg were higher in the female offspring housed in ventilated cages. The ciliary beat values were lower in both the male (IVCs=13.4+/-0.2; CC=15+/-0.4) and female (IVC=13.5+/-0.4; CC=15.9+/ 0.6) offspring housed in individually ventilated cages than in those housed in conventional cages. The total cell (IVC=117.5+/-9.7; CC=285.0+/-22.8), neutrophil (IVC=13.1+/-4.8; CC=75.6+/-4.1) and macrophage (IVC=95.2+/-11.8; CC=170.0+/-18.8) counts in the bronchoalveolar lavage fluid were lower in the female offspring housed in individually ventilated cages than in those housed in conventional cages. CONCLUSIONS:: The environmental conditions that exist in individually ventilated cages should be considered when interpreting the results of studies involving laboratory animals. In this study, we observed gender dimorphism in both the water consumption and respiratory mechanics of rats kept in ventilated cages. PMID- 28355364 TI - Sheep Model for Uterine Transplantation: The Best Option Before Starting a Human Program. AB - OBJECTIVE:: This study reports the first four cases of a uterine transplant procedure conducted in sheep in Latin America. The aim of this study was to evaluate the success of uterine transplantation in sheep. METHOD:: The study was conducted at Laboratory of Medical Investigation 37 (LIM 37) at the University of Sao Paulo School of Medicine. Four healthy mature ewes weighing 40-60 kg were used as both the donor and recipient for a transplant within the same animal (auto-transplant). Institutional guidelines for the care of experimental animals were followed. RESULTS:: The first two cases of auto-transplant were performed to standardize the technique. After complete uterine mobilization and isolation of the blood supply, the unilateral vascular pedicle was sectioned and anastomosed on the external iliac vessels. After standardization, the protocol was implemented. Procurement surgery was performed without complications or bleeding. After isolation of uterine arteries and veins as well as full mobilization of the uterus, ligation of the distal portion of the internal iliac vessels was performed with subsequent division and end-to-side anastomosis of the external iliac vessels. After vaginal anastomosis, the final case presented with arterial thrombosis in the left uterine artery. The left uterine artery anastomosis was re opened and flushed with saline solution to remove the clot from the artery lumen. Anastomosis was repeated with restoration of blood flow for a few minutes before another uterine artery thrombosis appeared on the same side. All four animals were alive after the surgical procedure and were euthanized after the experimental period. CONCLUSION:: We describe the success of four uterine auto transplants in sheep models. PMID- 28355365 TI - The acceptability of vaginal smear self-collection for screening for cervical cancer: a systematic review. AB - Cervical cancer is a major cause of death in adult women. However, many women do not undergo cervical cancer screening for the following reasons: fear, shame, physical limitations, cultural or religious considerations and lack of access to health care services. Self-collected vaginal smears maybe an alternative means of including more women in cervical cancer screening programs. The objective of this systematic review was to evaluate the acceptability of vaginal smear self collection for cervical cancer screening. We selected articles from PubMed, the Cochrane Library and Embase that were published between January 1995 and April 2016. Studies written in English, French, Italian, Portuguese or Spanish that involved women between 18 and 69 years of age who had engaged in sexual intercourse were included in this review. The review was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta Analyses) statement. Nineteen studies were ultimately evaluated in this review. Most of the included studies (n=17) demonstrated that the self-collection method exhibited outstanding acceptability among women with respect to cervical cancer screening, and only two studies indicated that self-collection exhibited low acceptability among women in this context. The acceptability of self-collection was determined subjectively (without standardized questionnaires) in 10 studies (53%) and via structured and validated questionnaires in the remaining studies. The results of our review suggest that the self-collection method is well accepted and may therefore encourage greater participation in cervical cancer screening programs. However, additional studies are required to verify these results. PMID- 28355367 TI - Radiotherapy and the SUS: A collapse foretold. PMID- 28355366 TI - Diagnostic models of the pre-test probability of stable coronary artery disease: A systematic review. AB - A comprehensive search of PubMed and Embase was performed in January 2015 to examine the available literature on validated diagnostic models of the pre-test probability of stable coronary artery disease and to describe the characteristics of the models. Studies that were designed to develop and validate diagnostic models of pre-test probability for stable coronary artery disease were included. Data regarding baseline patient characteristics, procedural characteristics, modeling methods, metrics of model performance, risk of bias, and clinical usefulness were extracted. Ten studies involving the development of 12 models and two studies focusing on external validation were identified. Seven models were validated internally, and seven models were validated externally. Discrimination varied between studies that were validated internally (C statistic 0.66-0.81) and externally (0.49-0.87). Only one study presented reclassification indices. The majority of better performing models included sex, age, symptoms, diabetes, smoking, and hyperlipidemia as variables. Only two diagnostic models evaluated the effects on clinical decision making processes or patient outcomes. Most diagnostic models of the pre-test probability of stable coronary artery disease have had modest success, and very few present data regarding the effects of these models on clinical decision making processes or patient outcomes. PMID- 28355368 TI - Treatment of benign prostatic hyperplasia. PMID- 28355369 TI - Therapeutic use of the rebound effect of modern drugs: "New homeopathic medicines". AB - The homeopathic treatment is based on the principle of therapeutic similitude, employing medicines that cause certain disorders to treat similar manifestations, stimulating a reaction of the organism against its own ailments. The occurrence of this secondary reaction of the organism, opposite in nature to the primary action of the medicines, is evidenced in the study of the rebound (paradoxical) effect of several classes of modern drugs. In this work, in addition to substantiate the principle of similitude before the experimental and clinical pharmacology, we suggest a proposal to employ hundreds of conventional drugs according to homeopathic method, applying the therapeutic similitude between the adverse events of medicines and the clinical manifestations of patients. Describing existing lines of research and a specific method for the therapeutic use of the rebound effect of modern drugs (http://www.newhomeopathicmedicines.com), we hope to minimize prejudices related to the homeopathy and contribute to a broadening of the healing art. PMID- 28355370 TI - Targeting personalized medicine in a non-Hodgkin lymphoma patient with 18F-FDG and 18F-choline PET/CT. AB - Early diagnosis and staging of non-Hodgkin lymphoma (NHL) is essential for therapeutic strategy decision. Positron emission tomography/computed tomography (PET/CT) with fluordeoxyglucose (FDG), a glucose analogue, labeled with fluor-18 (18F-FDG) has been used to evaluate staging, therapy response and prognosis in NHL patients. However, in some cases, 18F-FDG has shown false-positive uptake due to inflammatory reaction after chemo and/or radiation therapy. In this case report, we present a NHL patient evaluated with 18F-FDG and 18F-choline PET/CT scan imaging pre- and post-therapy. 18F-FDG and 18F-choline PET/CT were performed for the purpose of tumor staging and have shown intense uptake in infiltrative tissue as well as in the lymph node, but with some mismatching in the tumor. Post treatment 18F-FDG and 18F-choline PET/ CT scans revealed no signs of radiotracer uptake, suggesting complete remission of the tumor. 18F-choline may be a complimentary tool for staging and assessment of therapeutic response in non Hodgkin lymphoma, while non-18F-FDG tracer can be used for targeted therapy and patient management. PMID- 28355371 TI - Characteristics of training and motivation of physicians working in emergency medicine. AB - Introduction:: Emergency medicine is an area in which correct decisions often need to be made fast, thus requiring a well-prepared medical team. There is little information regarding the profile of physicians working at emergency departments in Brazil. Objective:: To describe general characteristics of training and motivation of physicians working in the emergency departments of medium and large hospitals in Salvador, Brazil. Method:: A cross-sectional study with standardized interviews applied to physicians who work in emergency units in 25 medium and large hospitals in Salvador. At least 75% of the professionals at each hospital were interviewed. One hospital refused to participate in the study. Results:: A total of 659 physicians were interviewed, with a median age of 34 years (interquartile interval: 29-44 years), 329 (49.9%) were female and 96 (14.6%) were medical residents working at off hours. The percentage of physicians who had been trained with Basic Life Support, Advanced Cardiovascular Life Support and Advanced Trauma Life Support courses was 5.2, 18.4 and 11.0%, respectively, with a greater frequency of Advanced Cardiovascular Life Support training among younger individuals (23.6% versus 13.9%; p<0.001). Thirteen percent said they were completely satisfied with the activity, while 81.3% expressed a desire to stop working in emergency units in the next 15 years, mentioning stress levels as the main reason. Conclusion:: The physicians interviewed had taken few emergency immersion courses. A low motivational level was registered in physicians who work in the emergency departments of medium and large hospitals in Salvador. PMID- 28355372 TI - A prospective randomized trial comparing patent blue and methylene blue for the detection of the sentinel lymph node in breast cancer patients. AB - Introduction:: Methylene blue is more widely available and less expensive than patent blue, with an apparently lower risk of anaphylaxis. Objective:: The two dyes were compared regarding detection of the sentinel lymph node (SLN). Method:: A prospective, randomized trial involved 142 patients with invasive breast carcinoma. Sixty-nine (49.3%) assigned to patent blue (group A) and 71 (50.70%) to methylene blue (group B). Thirty-five patients (25.0%) were clinical stage III or IV; 55 (38.7%) had axillary lymph nodes affected; and 69 (49.3%) underwent neoadjuvant chemotherapy. Two patients were excluded because the dye type was not recorded. Results:: Patients and tumor characteristics were similar in both groups. SLNs were identified in 47 women (68.1%) in group A and 43 (60.6%) in group B (p=0.35). SLNs were affected in 22 cases (51.2%) in group A and 21 (48.8%) in group B (p=0.62). The SLN was the only node affected in 12 cases (54.5%) in group A and six (33.3%) in group B (p=0.18). The time and degree of difficulty involved in identifying the SLN were similar in both groups. There were no complications or allergies. Conclusion:: Methylene blue performed as well as patent blue in identifying the SLN in breast cancer patients. PMID- 28355373 TI - Overweight and obesity in preschoolers: Prevalence and relation to food consumption. AB - Objective:: To determine overweight and obesity prevalence in preschool children from public education, and to determine their relation to food consumption. Method:: Cross-sectional study with children aged between 2 and 5 years, of both sexes, enrolled at municipal day care centers. Socioeconomic, demographic and anthropometric data were collected, in order to calculate the body mass index (BMI) for age. Data on food consumption were assessed using a Food Frequency Questionnaire. chi2 test, Kruskal-Wallis test, Student's t-test and Pearson's correlation were used at a significance level of 5%. Results:: Of 548 children, 52% were male, with mean age of 4.2 years old. Most families had incomes between 1 and 2 minimum wages (59.7%), in addition to 10 years (mothers) of education. Anthropometric parameters did not differ significantly between sexes. According to the BMI-for-age, it was found that most of children were well-nourished (85.2%), 8.2% had the risk of becoming overweight, and 4.2% were overweight. The most consumed foods were: rice (100%), beans (99.4%), bread (98.5%), fruit (98.5%), red meat (97.1%), butter and margarine (95.4%), biscuits, cakes and sweet pies (94.1%), dairy products (94.1%), chocolate milk (91.7%), and soft drinks (90.2%). Consumed foods that were strongly correlated (r > 0.7) to the risk of/excess weight were, as follows: bread; biscuits, cakes, sweet pies; dairy products; chocolate milk; sausages. Conclusion:: There was low prevalence of overweight and absence of obesity among the population assessed. The risk of overweight was greater among girls. Data from the study showed deviations in food consumption. PMID- 28355374 TI - Qualitative and quantitative ultrasound assessment of gastric content. AB - Objective:: Pulmonary aspiration of the gastric contents is one of the most feared complications in anesthesia. Its prevention depends on preoperative fasting as well as identification of risky patients. A reliable diagnostic tool to assess gastric volume is currently lacking. The aim of this study performed on volunteers was to evaluate the feasibility of ultrasonography to identify qualitative and quantitative gastric content. Method:: A standardized gastric scanning protocol was applied on 67 healthy volunteers to assess the gastric antrum in four different situations: fasting, after ingesting clear fluid, milk and a solid meal. A qualitative and quantitative assessment of the gastric content in the antrum was performed by a blinded sonographer. The antrum was considered either as empty, or containing clear or thick fluid, or solids. Total gastric volume was predicted based on a cross-sectional area of the antrum. A p value less than 0.05 was considered statistically significant. Results:: For each type of gastric content, the sonographic characteristics of the antrum and its content were described and illustrated. Sonographic qualitative assessment allowed to distinguish between an empty stomach and one with different kinds of meal. The predicted gastric volume was significantly larger after the consumption of any food source compared to fasting. Conclusion:: Bedside sonography can determine the nature of gastric content. It is also possible to estimate the difference between an empty gastric antrum and one that has some food in it. Such information may be useful to estimate the risk of aspiration, particularly in situations when prandial status is unknown or uncertain. PMID- 28355375 TI - Influence of morbid obesity on physical capacity, knee-related symptoms and overall quality of life: A cross-sectional study. AB - Objective:: To evaluate the impact of morbid obesity on physical capacity, joint related symptoms, and on the overall quality of life. Method:: Cross-sectional study carried out at a university hospital, enrolling 39 individuals admitted to a bariatric surgery service. Physical capacity was assessed by Six-Minute Walk Test (SMWT) and the Borg rating of perceived exertion (RPE). Knee-related symptoms were evaluated by Knee Injury and Osteoarthritis Outcome Score (KOOS) and the Lysholm Score. Quality of life was evaluated by Short Form 36 Health Questionnaire (SF-36). Results:: On SMWT, the mean distance walked was 374.1+/ 107.5 m. The mean Borg score was 12.9+/-2.4. KOOS questionnaire found the following scores: pain (64.3+/-24), other symptoms (67.2+/-25.5), function in daily living (60.4+/-26.8), function in sport and recreation (28.5+/-32.2), knee related quality of life (35.9+/-33.5), mean Lysholm scale score (55.3+/-25.4). SF 36 provided the following scores: physical functioning (41+/-27.4), physical role functioning (34.6+/-39.2), bodily pain (45.7+/-23.6), general health perceptions (63.1+/-26.2), vitality (53.5+/-12.1), social role functioning (52.6+/-29.3), emotional role functioning (41+/-44.9), mental health (55+/-27.7). Conclusion:: Obesity led to significant loss of physical capacity, gait impairment, knee related symptoms, and a negative impact on the overall quality of life. PMID- 28355376 TI - Regulation of muscle plasticity and trophism by fatty acids: A short review. AB - The skeletal muscle tissue has a remarkable ability to alter its plastic structural and functional properties after a harmful stimulus, regulating the expression of proteins in complex events such as muscle regeneration. In this context, considering that potential therapeutic agents have been widely studied, nutritional strategies have been investigated in order to improve the regenerative capacity of skeletal muscle. There is evidence of the modulatory action of fatty acids, such that oleic and linoleic acids, that are abundant in Western diets, on muscle function and trophism. Thus, fatty acids appear to be potential candidates to promote or impair the recovery of muscle mass and function during regeneration, since they modulate intracellular pathways that regulate myogenesis. This study is the first to describe and discuss the effect of fatty acids on muscle plasticity and trophism, with emphasis on skeletal muscle regeneration and in vitro differentiation of muscle cells. PMID- 28355377 TI - Hypomagnesemia and its relation with chronic low-grade inflammation in obesity. AB - Introduction:: The accumulation of visceral fat in obesity is associated with excessive production of proinflammatory adipokines, which contributes to low grade chronic inflammation state. Moreover, the literature has shown that mineral deficiency, in particular of magnesium, has important role in the pathogenesis of this metabolic disorder with relevant clinical repercussions. Objective:: To bring updated information about the participation of hypomagnesemia in the manifestation of low-grade chronic inflammation in obese individuals. Method:: Articles published in PubMed, SciELO, LILACS and ScienceDirect, using the following keywords: "obesity," "magnesium" and "low grade inflammation." Results:: Scientific evidence suggests that magnesium deficiency favors the manifestation of low-grade chronic inflammation in obese subjects. Conclusion:: From literature data, it is evident the participation of magnesium through biochemical and metabolic reactions in protecting against this metabolic disorder present in obesity. PMID- 28355378 TI - Systematic review of the synergist muscle ablation model for compensatory hypertrophy. AB - Objective:: The aim was to evaluate the effectiveness of the experimental synergists muscle ablation model to promote muscle hypertrophy, determine the period of greatest hypertrophy and its influence on muscle fiber types and determine differences in bilateral and unilateral removal to reduce the number of animals used in this model. Method:: Following the application of the eligibility criteria for the mechanical overload of the plantar muscle in rats, nineteen papers were included in the review. Results:: The results reveal a greatest hypertrophy occurring between days 12 and 15, and based on the findings, synergist muscle ablation is an efficient model for achieving rapid hypertrophy and the contralateral limb can be used as there was no difference between unilateral and bilateral surgery, which reduces the number of animals used in this model. Conclusion:: This model differs from other overload models (exercise and training) regarding the characteristics involved in the hypertrophy process (acute) and result in a chronic muscle adaptation with selective regulation and modification of fast-twitch fibers in skeletal muscle. This is an efficient and rapid model for compensatory hypertrophy. PMID- 28355379 TI - Osteoporosis and autophagy: What is the relationship? AB - Autophagy is a survival pathway wherein non-functional proteins and organelles are degraded in lysosomes for recycling and energy production. Therefore, autophagy is fundamental for the maintenance of cell viability, acting as a quality control process that prevents the accumulation of unnecessary structures and oxidative stress. Increasing evidence has shown that autophagy dysfunction is related to several pathologies including neurodegenerative diseases and cancer. Moreover, recent studies have shown that autophagy plays an important role for the maintenance of bone homeostasis. For instance, in vitro and animal and human studies indicate that autophagy dysfunction in bone cells is associated with the onset of bone diseases such as osteoporosis. This review had the purpose of discussing the issue to confirm whether a relationship between autophagy dysfunction and osteoporosis exits. PMID- 28355380 TI - Induced pluripotent stem cells reprogramming: Epigenetics and applications in the regenerative medicine. AB - Induced pluripotent stem cells (iPSCs) are somatic cells reprogrammed into an embryonic-like pluripotent state by the expression of specific transcription factors. iPSC technology is expected to revolutionize regenerative medicine in the near future. Despite the fact that these cells have the capacity to self renew, they present low efficiency of reprogramming. Recent studies have demonstrated that the previous somatic epigenetic signature is a limiting factor in iPSC performance. Indeed, the process of effective reprogramming involves a complete remodeling of the existing somatic epigenetic memory, followed by the establishment of a "new epigenetic signature" that complies with the new type of cell to be differentiated. Therefore, further investigations of epigenetic modifications associated with iPSC reprogramming are required in an attempt to improve their self-renew capacity and potency, as well as their application in regenerative medicine, with a new strategy to reduce the damage in degenerative diseases. Our review aimed to summarize the most recent findings on epigenetics and iPSC, focusing on DNA methylation, histone modifications and microRNAs, highlighting their potential in translating cell therapy into clinics. PMID- 28355381 TI - Bariatric surgery in individuals with liver cirrhosis: A narrative review. AB - Introduction:: Bariatric surgery has become the gold standard treatment for morbid obesity, but there is no consensus regarding its safety and efficacy among individuals with chronic liver diseases. Objective:: To critically evaluate the existing evidence on literature about bariatric surgery in individuals with liver cirrhosis. Method:: Narrative review performed by means of an online search in the MEDLINE and LILACS databases. Results:: Bariatric surgery is safe and effective in individuals with chronic liver disease without clinical decompensation or significant portal hypertension. Individuals with severe liver function impairment present significantly higher surgical morbidity and mortality. Among candidates to liver transplantation, surgery may be performed before, after and even during transplantation, and there is a predominant trend to perform it after. Vertical sleeve gastrectomy seems to be the most adequate technique in this group of subjects. Conclusion:: Bariatric surgery is safe and effective in individuals with compensated cirrhosis without significant portal hypertension, but presents higher morbidity. Among candidates to liver transplantation and/or individuals with severe portal hypertension, morbidity and mortality are significantly higher. PMID- 28355382 TI - Satisfaction and quality of life in users of auditory brainstem implant. AB - Purpose To evaluate satisfaction and quality of life of users of Auditory Implant Brainstem. Methods This is a cross-sectional and descriptive study conducted at Divisao de Clinica Otorrinolaringologica of Hospital das Clinicas of Faculdade de Medicina da Universidade de Sao Paulo, Brazil. For the research, 19 users of an Auditory Brainstem Implant answered the following questionnaires: KINDLR (Questionnaire for Measuring Health-Related Quality of Life in Children and Adolescents), for children and adolescents, their parents and/or caregivers; WHOQOL-BREF questionnaire, for adult participants; and the Satisfaction with Amplification in Daily Life (SADL) questionnaire culturally adapted to Brazilian Portuguese. Results The quality of life of children using Auditory Brainstem Implant from the perspective of their parents showed global results above average, as for most domains, except for the emotional well-being domain. Adults showed results above average for all domains. Regarding satisfaction with the device, the adult users of auditory brainstem implant were satisfied in general, except with regard to personal image. The parents of the children showed dissatisfaction in all subscales, except for the subscale of services and cost. Conclusion The results indicated that although patients are dissatisfied with the device in some aspects, overall the quality of life was rated as good for most of the aspects assessed. PMID- 28355383 TI - The relevance of syllable per minute measuring at the assessment of reading rate. AB - Purpose To verify whether there are differences in the assessment of reading rate of children at 3rd and 4th grade from elementary school using the measures of words read per minute and syllables read per minute. Methods This research counted on 29 children from 3rd grade and 28 from the 4th grade of elementary school without reading and writing disorders. All children were asked to read aloud a text according to their schooling level. The procedure was recorded and the reading rate was calculated both in words and syllables read per minute. Results Data indicated that syllable read per minute measure was more effective to calculate reading rate of children from different schooling levels since it provides a more reliable profile of reading rate. Conclusion The present study showed evidences that syllable per minute measure is more precise to characterize children's performance since it considers linguistic and textual features. PMID- 28355384 TI - Creation of a list of homonyms in Brazilian Portuguese for linguistic processing tasks. AB - Purpose This paper presents procedures and steps to create a list of homonyms, their meanings and representative images. Methods One hundred and three homonyms in Brazilian Portuguese were secluded through searches in text books and dictionaries and the meanings were verified. The homonyms were analyzed and selected according pre-established criteria. Twenty-six homonyms with two meanings were selected and one image was used to represent each meaning. To test the instrument, twenty elementary school children in 4th (n = 10) and 5ht (n = 10) grades were selected from a private school in Sao Paulo. To identify the meanings of major and minor occurrence, the students gave their understanding of the words presented to them orally. The students were also asked to name the fifty-two images to determine the degree of recognition. Percentages of accuracy were calculated. Results Among the 26 homonyms, two were excluded because the students were unable to name them. Two images were little recognized and, therefore, replaced with others that better represented the homonyms. Conclusion A list of 24 homonyms and 48 images (one for each meaning) was developed. The results of the presentation of these items to elementary school children in the 4th and 5th grades proved the adequacy of the list. The material is seen as efficient for use in recognition tasks and can be applied in semantic priming tasks. PMID- 28355386 TI - Biological invasion at an early stage? First record of the banjo catfish Pseudobunocephalus iheringii (Siluriformes: Aspredinidae) in the Tramandai river basin, Brazil and the potential invasion pathway to this system. PMID- 28355385 TI - Vocal tract discomfort in teachers after teaching activity. AB - Purpose To evaluate the vocal tract discomfort (VTD) reported by teachers, comparing their vocal self-assessment at three different times: before teaching, after four hours of teaching, and after eight hours of teaching. Methods The study sample was composed of 50 teachers: 42 women and eight men. The participating teachers were divided into two groups according to the cutoff value of the Voice Symptom Scale (VoiSS): Vocal Risk Group (VRG) and Vocally Healthy Group (VHG). The List of Vocal Signs and Symptoms (LVSS) was used to identify the number of vocal symptoms in each group. The groups were evaluated at three specific moments (before (BT) and after four (4HT) and eight (8HT) hours of teaching) by means of the Vocal Tract Discomfort Scale (VTD scale) and vocal self assessment. Results The VRG presented more vocal signs and symptoms of the LVSS than the VHG (total: VHG=0.56/VRG=1.60, p<0.001; work-related VHG=0.79/VRG=2.49, p<0.001). The VHG did not report change in discomfort for both frequency (p=1.132) and severity (p=0.431) and showed better vocal self-assessment (BT=0.67; 4HT=0.96; 8HT=0.96, p=0.007). However, the VRG presented vocal tract discomfort after four and eight hours of teaching for both frequency (BT=1.60; 4HT=2.49; 8HT=2.95, p<0.001) and severity (BT=1.79; 4HT=2.52; 8HT=3.12, p<0.001) and worse voice self-assessment (BT=2.00; 4HT=2.42; 8HT=3.00, p<0.001). Conclusion Teachers at vocal risk present worse vocal self-assessment and increased vocal tract discomfort throughout the teaching working day. PMID- 28355387 TI - Effects of soil and space on the woody species composition and vegetation structure of three Cerrado phytophysiognomies in the Cerrado-Amazon transition. AB - The Cerrado Biome is considered one of the world's biodiversity hotspots because of its rich biodiversity, the high level of endemism and the increasing threat. The Cerrado is composed by a mosaic of different vegetation types, including physiognomies that vary from grasslands (campo limpo) to savannas (typical cerrado or cerrado sensu stricto) and cerrado woodlands (cerradao). However, the factors that determine the composition of the Cerrado's flora and the structure of the physiognomies that compose this biome are still poorly understood. Here, we investigate the influence of the chemical and granulometric properties of the soil and the effect of geographic distance on the occurrence and abundance of woody species in three Cerrado phytophysiognomies - cerrado woodland (cerradao), dense cerrado savanna and typical cerrado savanna - in the Cerrado-Amazon transition. We tested the hypothesis that the edaphic characteristics and geographic space determine the species composition and the structure of the woody vegetation of these three phytophysiognomies. We demonstrate that the dissimilarities in the structure and composition of the three sites were determined more by space (13% of explanation) than edaphic properties (1%), but primarily by the interaction between these two factors (26%). We conclude that, in situations where the chemical and granulometric properties of the soil are relatively homogeneous, as we found in the present study, geographic distance between sites has a greater influence than variation in the substrate's properties on modelling the occurrence and abundance of the woody plant species in the Cerrado. PMID- 28355389 TI - Leptodactylus chaquensis Cei, 1950 (Leptodactylidae, Leptodactylinae): extension of the distribution in state of Rio Grande do Sul, southern Brazil. PMID- 28355388 TI - "In vitro" evaluation of the bacterivore potential of three Cladoceran species occurring in tropical and subtropical regions. AB - Cladocerans occupy an important position among the bacterial consumers in freshwater food webs, being relatively non-selective filter feeders that can exert a strong impact on microbial populations. We evaluated the bacterivory potential of three cladocerans species of subtropical and tropical occurrence (Ceriodaphnia silvestrii, Daphnia gessneri and Ceriodaphnia cornuta) at different life stages, by scanning electron microscopy (SEM) and by the quantification of their bacterial consumption rates using fluorescently labeled bacteria (FLB). All species showed filter mesh sizes sufficiently narrow to retain bacteria. The largest distance between setules was found in primiparous C. cornuta, and the smallest in neonate D. gessneri. The lowest ingestion (IR) and removal (RR) rates were observed in primiparous C. silvestrii and the highest values were observed in adults of D. gessneri. We conclude that bacteria may be considered an important food supplement, particularly for neonates who presented smaller intersetular distances and higher filtration rates than the other life stages. PMID- 28355390 TI - Could Fidicina mannifera (Hemiptera: Cicadoidea: Fidicinini) promote a resource pulse in two Brazilian Cerrado vegetation classes? AB - Cicadas are usually studied regarding their importance in agriculture. However, the possibility of this group to represent a pulse of nutrients can also imply on the success of a given species in the biome. The aim of this study was to assess the level of total soluble proteins and lipids of Fidicina mannifera (Fabricius, 1803), and to determine whether the species can promote a pulse of nutrients in two vegetation classes of the Brazilian Cerrado. To assess the pulse of nutrients, it was concluded the determination of total soluble proteins and lipids from samples of males and adult females of F. mannifera, and the spatial distribution of exuviae of this species was also calculated in two vegetation classes of the Brazilian Cerrado. The amount of protein provided by each individual did not differ between males and females (p = 0.66) but females had 40% more lipids than males (p = 0.05). Regarding F. mannifera the gallery forest offered 11.75 g/ha of protein, 3.91 g/ha of lipids, and the Cerrado stricto sensu offered 4.25 g/ha of protein, and 1.41 g/ha of lipid. The male cicadas have a hollow abdomen, which houses a resonance chamber for sound production in order to attract females to mate, and females store larger amounts of lipids, mainly located in the abdominal cavity, where the body fat is directly linked to the reproductive system for the development of the ovaries and egg production after emergence. The mass occurrence of F. mannifera in the Brazilian Cerrado and the fast availability of proteins and lipids make this species a food resource that can directly impact the diet of secondary consumers and scavengers, although the amount of nutrients available by F. mannifera does not promote a pulse of nutrients in the study site. PMID- 28355391 TI - Nesting of Morelet's crocodile, Crocodylus moreletii (Dumeril and Bibron), in Los Tuxtlas, Mexico. AB - We evaluated the nesting by Crocodylus moreletii in Lago de Catemaco, Veracruz, southeastern, Mexico. During the nesting and hatching seasons, we searched for nests along the northern margins of the lake and small associated streams. We investigated egg mortality by weekly monitoring each of the nests found, recording sign of predation (tracks and holes dug into the nest) and the effect of water level fluctuations. We not found differences to nest between inland or flooded zones. However, we found that egg size varied among nests. In nests built inland, predation was the major cause of egg mortality whereas flooding resulted in more deaths of eggs in the flooding zone. Flooding killed 25% of eggs monitored in this study. We suggest that to increase nest success in the Morelet's crocodile it is necessary to promote conservation of nesting areas around the lake, recently occupied by urban or tourist developments. PMID- 28355393 TI - Seed removal of Dipteryx alata Vog. (Leguminosae: Faboidae) in the edge and interior of Cerrado. AB - Post-dispersal seed agents of mortality include pathogens, invertebrates, and vertebrates, which may shape tropical tree populations and communities. In this study I experimentally evaluated Dipteryx alata endocarp removal both in the interior and edge of Cerrado vegetation. Specifically, I simulated primary dispersion of endocarps by bats and evaluated secondary removal intensity according to habitat, season, and endocarp number. This study was developed in the Pombo Natural Municipal Park, a large Cerrado remnant with an area of 9,000 ha, located in the Western Brazil. In each of the two habitat types, I set down 45 points in which D. alata piles of 1, 3, 7, 15, and 40 endocarps were positioned. On average, endocarp removal in the interior was higher than in the edge, so that the intensity of removal varied from positive density-dependent (interior: rains), to negative density-dependent (edge: both seasons). Also, at both habitat types and seasons non removed endocarps were intensely attacked by fungus. Indeed, seed mortality by fungus infestation was positive density dependent. The results indicate high propensity of endocarps to escape from removal in the edge, in principle, a defaunated area. As Dipteryx species strongly rely on caviomorph rodents for their dispersal, the scarcity of these vectors might reduce recruitment chances of D. alata in remnants of Cerrado. This imply in future changes in the vegetation structure from the edge to the interior towards low tree diversity. PMID- 28355392 TI - Insect diversity in organic rice fields under two management systems of levees vegetation. AB - Simplified environments characterize agroecosystems, reducing the diversity of associated plants, which are not cultivated for economic purposes, causing unbalances that can promote the emergence of cultivated plants pests, as well as the reduction of their natural enemies. Management systems that increase diversity in agroecosystems can extend the action of natural enemies of pests. Studies to understand the diversity of insects associated with rice cultivation and determine their ecological guilds can provide information about the composition and structure of such ecosystems, which can be applied to integrated pest management. Therefore, the study aimed to describe and compare groups of insects in irrigated rice fields, with organic management using two different systems of levees vegetation management, and relate them to the phenological states of rice cultivation (seedling, vegetative, and reproductive). Samples were taken in a plantation located in Aguas Claras district of Viamao, RS. The total area of 18 ha was divided into two. A subarea called not cut (NC), where wild vegetation of levees was maintained, and the subarea named cut (C), where monthly cuts were made to levees vegetation, from the beginning of soil preparation until the harvest. From October 2012 to March 2013 were held weekly collections in quadrats randomly located in both the rice fields and the levees. A total of 800 insects were collected, 429 in the C subarea and 371 in the NC. There were identified 97 morphospecies in the C and 108 in NC, being 54 shared between the subareas. The captured insects were grouped into guilds: saprophages (C = 38.2%; NC = 27.5%), phytophagous (C = 28.5%; NC = 33.2%), entomophagous (grouping parasitoids and predators) (C = 29.4%; NC = 35%) and finally other insects (C = 4 %; NC = 4.3%). The peak abundance of phytophagous and entomophagous was registered in the vegetative stage of rice. At the same stage the UPGMA analysis showed that similarity in species composition was greater than 90% in the groups obtained in the paddy fields of C and NC subareas. The vegetation of levees can positively influence the presence of entomophagous in the field. Although the abundance did not change clearly, the greatest diversity in the NC areas of all the groups, may contribute to the maintenance of ecological services expanding the system resilience. PMID- 28355394 TI - Severe sepsis from a Ciprofloxacin resistant salmonellosis in a kidney transplant recipient. AB - INTRODUCTION: Salmonellosis is a relatively rare complication in kidney transplant recipients that cannot be clinically distinguished from other forms of enteritis. Among kidney transplant patients, it varies broadly in intensity, and is highly associated with extra-intestinal disease, bacteremia, and, in this case, a high mortality rate. CASE REPORT: Here we describe a clinical case of ciprofloxacin resistant salmonellosis in a kidney transplant patient. CONCLUSION: This case illustrates how immunosuppressed patients can be exposed to rare forms of infection, often clinically difficult to identify, and possibly with severe clinical courses and poor outcomes despite evidence-based empiric antibiotic therapy. PMID- 28355395 TI - Obesity and kidney disease. AB - Obesity has been pointed out as an important cause of kidney diseases. Due to its close association with diabetes and hypertension, excess weight and obesity are important risk factors for chronic kidney disease (CKD). Obesity influences CKD development, among other factors, because it predisposes to diabetic nephropathy, hypertensive nephrosclerosis and focal and segmental glomerulosclerosis. Excess weight and obesity are associated with hemodynamic, structural and histological renal changes, in addition to metabolic and biochemical alterations that lead to kidney disease. Adipose tissue is dynamic and it is involved in the production of "adipokines", such as leptin, adiponectin, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, transforming growth factor-beta and angiotensin-II. A series of events is triggered by obesity, including insulin resistance, glucose intolerance, dyslipidemia, atherosclerosis and hypertension. There is evidence that obesity itself can lead to kidney disease development. Further studies are required to better understand the association between obesity and kidney disease. PMID- 28355396 TI - Formula to detect high sodium excretion from spot urine in chronic kidney disease patients. AB - INTRODUCTION: Excessive sodium intake is related to adverse renal and cardiovascular outcomes in patients with chronic kidney disease (CKD) and assessment of sodium intake is complex and not evaluated very often in clinical practice. OBJECTIVE: To develop a new formula to estimate 24h sodium excretion from urine sample (second void) of patients with CKD. METHODS: We included 51 participants with CKD who provided 24-hour urine collection and a sample of the second urine of the day to determine the sodium excretion. A formula to estimate the 24-hour sodium excretion was developed from a multivariate regression equation coefficients. The accuracy of the formula was tested by calculating the P30 (proportion of estimates within 30% of measured sodium exection) and the ability of the formula to discriminate sodium intake higher than 3.6 g/day was evaluated by ROC curve. RESULTS: Correlation test between measured and estimated sodium was significant (r = 0.57; p < 0.001), but P30 test identified a low accuracy (61%) of the formula. Different cutoff points were tested by performance tests and a ROC curve was generated with the cutoff that showed better performance (3.6 g/day). An area under the curve of 0.69 with a sensitivity of 0.91 and specificity of 0.53 was obtained. CONCLUSION: A simple formula with high sensitivity in detecting patients with sodium consumption higher than 3.6 g/day from isolated urine sample was developed. Studies with a higher number of participants and with different populations are necessary to test formula's validity. PMID- 28355397 TI - 90-kDa N-domain angiotensin I-converting enzyme (ACE): possible marker for hypertension in a renal transplant model. AB - INTRODUCTION: Hypertension is nearly universal in kidney transplant and several factors are associated with post transplant hypertension, including immunosuppressive medications and genetic predisposition. OBJECTIVE: The aims were to evaluate the effects of spontaneously hypertensive rats (SHR) kidney transplantation in Wistar rats and the possible transference of 80/90-kDa N domain ACE. METHODS: To do so, the data from Wistar recipients of kidney from SHR were compared to data from transplanted Wistar submitted to CsA treatment and, to Wistar Sham. RESULTS AND DISCUSSION: Despite the unaltered blood pressure observed at early stages, 80/90-kDa ACE was found expressed in the urine of rats 7 and 15 days after transplantation, which was intense when rats became hypertensive 30 days post-surgery. CONCLUSION: Our data show that this enzyme is associated with the development of hypertension, and this marker appears in the urine before any substantial blood pressure alteration. PMID- 28355398 TI - Cinacalcet in peritoneal dialysis patients: one-center experience. AB - INTRODUCTION: Secondary hyperparathyroidism is the target of several therapeutic strategies, including the use of cinacalcet. Most studies were done only in hemodialysis patients, with few data from peritoneal dialysis patients. OBJECTIVE: The aim of our work was to evaluate the effectiveness of cinacalcet in secondary hyperparathyroidism in a one-center peritoneal dialysis patients. METHODS: A retrospective study was performed in 27 peritoneal dialysis patients with moderate to severe secondary hyperparathyroidism (PTHi > 500 pg/mL with normal or elevated serum calcium levels) treated with cinacalcet. Demographic, clinical and laboratory parameters at the beginning of cinacalcet therapy, second, fourth, sixth months after and at the time it was finished were analyzed. RESULTS: Patients were under peritoneal dialysis at 30.99 +/- 16.58 months and were treated with cinacalcet for 15.6 +/- 13.4 months; 21 (77.8%) patients showed adverse gastrointestinal effects; PTHi levels at the beginning of cinacalcet therapy were 1145 +/- 449 pg/mL. The last PTHi levels under cinacalcet therapy was 1131 +/- 642 pg/mL. PTHi reduction was statistically significant at 2 months after the beginning of cinacalcet (p = 0.007) but not in the following evaluations. CONCLUSION: It is necessary the development of new forms of cinacalcet presentation, in order to avoid gastrointestinal effects adverse factors and to improve therapeutic adherence. PMID- 28355399 TI - Comparative analysis of primary and secondary glomerulopathies in the northeast of Brazil: data from the Pernambuco Registry of Glomerulopathies - REPEG. AB - INTRODUCTION: In Brazil, glomerulopathies are the third leading cause of chronic renal disease, accounting for 11% of dialysis patients. Studies on the prevalence of this disease in Northeastern Brazil are scarce. OBJECTIVE: The aim was to describe the findings of biopsies and to conduct a comparative analysis on the clinical laboratory presentation of primary glomerulopathies (PG) and secondary glomerulopathies (SG). METHODS: This was a retrospective study conducted at two public teaching hospitals in the state of Pernambuco, Northeastern Brazil. RESULTS: A total of 1151 biopsies performed between 1998 and 2016 were analyzed. The sample consisted of 670 biopsies of native kidneys, after excluding extra glomerular diseases and unsuitable material. PG were more frequent than SG (58% vs. 42%). There was a prevalence among PG of focal segmental glomerulosclerosis (43%). Membranoproliferative glomerulonephritis and collapsing glomerulopathy, accounted for 9% and 3% of the PG, respectively. For SG, the main etiologies were lupus nephritis (67%) and infections (10%). Female sex, hematuria and an elevated level of creatinine were related to a greater chance of SG, at multivariate analysis. An increase of proteinuria reduced this chance. Nephrotic syndrome was more common among the PG, while urinary abnormalities and nephritic syndrome prevailed in patients with SG. CONCLUSION: This is the first registry of glomerulopathies in Northeastern Brazil. It also presents a comparative analysis of the main clinical laboratory abnormalities of PG and SG, and includes the current classifications of glomerular diseases. PMID- 28355400 TI - Acute kidney injury diagnosis in Intensive Care Units: biomarkers or Information? AB - In recent years, the diagnosis of acute kidney injury (AKI) has been based on classifications such as RIFLE, AKIN and KDIGO, which has the goal of world standardization and timely recognition of the disease. It is essential that intensivists be aware about these classifications, because most of the time, they will have the first opportunity to diagnose AKI. However, it is still very common that the nephrologist consultation be performed in advanced stages of the AKI, when the interventions to halt the progression are very limited. We recently assessed intensivist on AKI diagnostic criteria, with emphasis on RIFLE, and observed a very low level of knowledge and lack of use in daily practice. Faced with the constant search for new biomarkers of kidney injury, these and other evidences, highlights the urgency of simple actions, such as the beginning of educational interventions in order to familiarize the intensivist with the latest clinical tools for AKI diagnosis. PMID- 28355401 TI - Schistosoma mansoni associated glomerulopathy with IgA mesangial deposits: case report. AB - INTRODUCTION: Renal involvement is a severe form of schistosomiasis and occurs in 10% to 15% of patients with the hepatosplenic form of the disease. Nephrotic syndrome is the most common clinical presentation. It is a complication caused by immune complexes (IC), it is rare to appear in the Brazilian context with a immunoglobulin A (IgA) deposits. When installed the renal injury by Schistosoma mansoni, classically presents as membranoproliferative glomerulonephritis (mesangiocapillary) with lobular accentuation. OBJECTIVE: To report a case of schistosomiasis nephropathy that appeared 7 years after treatment of hepatosplenic schistosomiasis with histologic pattern of mesangial proliferative glomerulonephritis with IgA deposits in mesangium. Clinically developed with progressive decrease of proteinuria with angiotensin receptor blocker (ARB). METHOD: It was reported a case of a 36 years old patient, brown, with classical sintoms of nephrotic syndrome (proteinuria > 3.5 g/24h, hypoalbuminemia and hypercholesterolemia), however with hepatosplenic schistosomiasis history 7 years ago and portal hypertension. Patient underwent renal biopsy which showed IgA deposits in mesangial, being more intense than immunoglobulin G (IgG), accompanied by C1q and C3, with 4/13 glomeruli sclerotic, standard light mesangial glomerulonephritis renal injury with IgA deposits. Patient began taking ARB with progressive improvement in proteinuria. CONCLUSION: Patients with glomerulonephritis by schistosoma don't show improvement of disease progression with antiparasitic treatment. However the anti-proteinuric treatment can slow the progression of end stage kidney disease. PMID- 28355402 TI - Budd-Chiari syndrome secondary to catheter-associated inferior vena cava thrombosis. AB - INTRODUCTION: Patients with chronic kidney disease (CKD) are at increased risk for thrombotic complications. The use of central venous catheters as dialysis vascular access additionally increases this risk. We describe the first case of Budd-Chiari syndrome (BCS) secondary to central venous catheter misplacement in a patient with CKD. CASE REPORT: A 30-year-old female patient with HIV/AIDS and CKD on hemodialysis was admitted to the emergency room for complaints of fever, prostration, and headache in the last six days. She had a tunneled dialysis catheter placed at the left jugular vein. The diagnosis of BCS was established by abdominal computed tomography that showed a partial thrombus within the inferior vena cava which extended from the right atrium to medium hepatic vein, and continuing along the left hepatic vein. Patient was treated with anticoagulants and discharged asymptomatic. DISCUSSION: Budd-Chiari syndrome is a rare medical condition caused by hepatic veins thrombosis. It can involve one, two, or all three of the major hepatic veins. It is usually related to myeloproliferative disorders, malignancy and hypercoagulable states. This case calls attention for inadvertent catheter tip placement into hepatic vein leading to this rare complication. CONCLUSION: Assessment of catheter dialysis tip location with radiological image seems to be a prudent measure after each procedure even if the tunneled dialysis catheter has been introduced with fluoroscopy image. PMID- 28355403 TI - When kidneys get old: an essay on nephro-geriatrics. AB - Aging is a nearly universal phenomenon in biology only partially controlled by genetic endowment. Individuals and their organs age at varying rates. The kidneys manifest the aging process by steady loss of nephrons and a corresponding decrease in glomerular filtration rate (GFR) beginning about age 30 years. The mechanisms responsible for this observation is are elusive. However, defining chronic kidney disease based on arbitrary, fixed thresholds of GFR in the later phases of life can be problematical as it may over-diagnosis CKD in the elderly. A modest, persisting reduction of GFR (around 45-59 ml/min/1.73m2) without abnormal proteinuria does not seem to confer much of an adverse effect on mortality and remaining life expectancy in older adults and the development of end-stage renal disease in such subjects is very uncommon. Old kidneys should not be equated with "diseased" kidneys. PMID- 28355404 TI - Daily variability of resting energy expenditure in acute kidney injury patients on dialysis. AB - INTRODUCTION: It is needed for nutrition prescription correct estimate of resting energy expenditure (REE), which is a challenge given the possible daily variation in critically ill patients with acute kidney injury (AKI). OBJECTIVE: To evaluate the daily variability of REE measured by indirect calorimetry (IC) in patients with AKI and dialysis indication and identify clinical variables associated with REE. METHODS: The REE was measured on the time of dialysis indication and the subsequent four days. We also evaluated parameters that can influence the REE. The daily differences were analyzed by generalized linear model for repeated measures. We also used Spearman correlation and multiple linear regression. RESULTS: There were 301 IC measurements in 114 patients, mean age of 60.65 +/- 16.9 years and 68.4% were male. The average REE was 2081 +/- 645 kcal, rising on day 5 (2270 +/- 556 kcal) compared to the days 2 and 3 (2022 +/- 754; 2022 +/- 660 kcal, respectively, p = 0,04). When normalized to weight, there was no significant difference in REE (kcal/kg/day) during follow-up. REE was positively correlated with total leukocyte count, C-reactive protein, minute volume (MV), fraction of inspired oxygen (FiO2) urea nitrogen appearance (UNA), weight and height and inversely with age. After multiple regression, MV, FiO2, weight and age are correlated independently with REE. CONCLUSION: Patients with AKI have REE stable. The REE was associated independently with FiO2, MV, body weight and age. Thus, ventilatory parameters should be evaluated each day for the necessary dietary changes may be made. PMID- 28355405 TI - Developing educational material on chronic kidney disease using best practices in health literacy. AB - Based in the precepts of Health Literacy (HL), an educational booklet "Do you know the Chronic Kidney Disease?" was written. It was used as a basic text for development of a Brazilian instrument for Assessment of Health Literacy (Teste de Avaliacao de Letramento em Saude or TALES). The guideline used to create the TALES obeyed four steps: systematization of content; creation and drawing of images by an expert designer; submission to a Committee of Experts on nephrology and linguistics; and editing and printing of the content. The content covering six aspects of chronic kidney disease (definition, diagnosis, signs and symptoms, prevention, risk factors and treatment) was developed utilizing multimodality techniques such as: creation of personages; verbal and visual metaphors; metonymy; personifications; direct dialogue; and plain language avoided of technicalities. During the development of TALES, the booklet proved to be useful in translating complicated scientific concepts on kidney disease into meaningfuly health messages. In conclusion, besides of being used as basic text for the development of TALES, the booklet "Do you know chronic kidney disease?", based in best practices in HL, can assist health professionals in communicating to patients using consumer-friendly educational materials that might impact positive health-related behaviors and results. PMID- 28355406 TI - Syndrome of inappropriate antidiuretic hormone secretion induced by the phytotherapy Harpagophytum procumbers: case report. AB - INTRODUCTION: The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the inability of antidiuretic hormone (ADH) suppression, compromising the mechanisms of water excretion and urinary concentration. It manifests as hyponatremia and its symptoms, especially neurological. There are many causes that trigger such disease, notably: central nervous system disorders, malignant neoplasm, drugs and others. CASE REPORT: A 65 years female hypertensive patient presented clinical and laboratory manifestations of hyponatremia due to SIADH. It happened twice under use of herbal medication for osteoarthritis treatment. DISCUSSION: The drug-related hyponatremia can be triggered by direct effect of the drug or by association with SIADH. The clinical manifestations presented could have been related to psychiatric condition and may have severe outcome if not properly diagnosed. The association of an herbal medicine to SIADH could be confirmed after a new episode of hyponatremia related to Harpagophytum procumbers reintroduction. Our literature review did not find this herbal medicine associated with SIADH, so far. CONCLUSION: SIADH may be caused by herbal medicine described from now on their association in the literature. PMID- 28355407 TI - Critical analysis of graft loss and death in kidney transplant recipients treated with mTOR inhibitors. AB - Registry studies and systematic reviews have shown higher risk for mortality and graft loss in patients in use of mTOR inhibitors (mTORi) compared to calcineurin based (CNI) immunosuppressive regimens. The majority of these studies pooled data from early trials using different strategies such as "de novo" combination of the high dose mTOR inhibitors with standard dose of CNI or high dose mTORi combined with mycophenolate. The large heterogeneity of these initial exploratory studies, many of them no longer in use, turns difficult any comparison with a well-defined standard of care regimen. The new strategies using concentration controlled reduced exposure of mTORi and CNI or early conversion from CNI to mTORi use have shown comparable patient and graft survival. Nevertheless, considering the central role of mTOR in health and disease states, more research is necessary to mitigate the adverse events and to explore further the potential beneficial effects of mTOR inhibitors. PMID- 28355408 TI - Evaluation of diagnostic tests for cytomegalovirus active infection in renal transplant recipients. AB - INTRODUCTION: Cytomegalovirus (CMV) infection is a main viral infection after kidney transplantation. The diagnostic methods currently employed are pp65 antigenemia and nucleic acid amplification by polymerase chain reaction (PCR) and aim at detecting viral replication. OBJECTIVE: The goal of this study was to evaluate and compare by both methods the incidence of CMV active infection in kidney transplant patients and to establishthe best clinical-laboratory correlation. METHODS: Thirty sequential kidney transplant recipients were enrolled in a single center prospective cohort study. Peripheral blood samples were drawn from day 15 until the 6th month after transplantation and tested for CMV replication by pp65 antigenemia and quantitative PCR assays (qPCR). RESULTS: Two hundred forty samples were analyzed and the incidence of active infection was similar by both methods. Time elapsed to the first positive test was almost identical but more samples tested positive by qPCR than by antigenemia in a behavior that was almost evenly distributed overtime. Agreement between tests was observed in 217 samples (90.4%; kappa = 0.529; p < 0.001) and in 25 patients the tests were concordant (83.3%; kappa = 0.667; p < 0.001). The evaluation of the diagnostic parameters for CMV replication revealed higher sensitivity for the qPCR test (82.1%) against antigenemia (59.0%). Quantitative PCR was also slightly more accurate than antigenemia. CONCLUSION: Our data demonstrate that both methods are suitable and have almost equivalent accuracy for the detection of post-transplant cytomegalovirus replication. The choice for either test must take in consideration the demand, execution capability and cost-effectiveness at each institution. PMID- 28355409 TI - Life-saving vascular access in vascular capital exhaustion: single center experience in intra-atrial catheters for hemodialysis. AB - INTRODUCTION: Intra-atrial catheter (IAC) placement through an open surgical approach has emerged as a life-saving technique in hemodialysis (HD) patients with vascular access exhaustion. OBJECTIVE: To assess the complications of IAC placement, as well as patient and vascular access survival after this procedure. METHODS: The authors retrospectively analyzed all seven patients with vascular capital exhaustion, without immediate alternative renal replacement therapy (RRT), who underwent IAC placement between January 2004 and December 2015 at a single center. RESULTS: Seven patients were submitted to twelve IAC placements. Bleeding (6/7) and infections (3/7) were the main complications in the early postoperative period. Two (2/7, 29%) patients died from early complications and 5/7 were discharged with a properly functioning IAC. The most frequent late complication was catheter accidental dislodgement in all remaining five patients, followed by catheter thrombosis and catheter-related infections in the same proportion (2/5). During follow-up, two of five patients died from vascular accesses complications. After IAC failure, one patient was transferred to peritoneal dialysis and a kidney transplant was performed in the other. Only one patient remains on HD after the third IAC, with a survival of 50 months. The mean patient survival after IAC placement was 19 +/- 25 (0-60) months and the mean IAC patency was 8 +/- 11 (0-34) months. CONCLUSION: Placing an IAC to perform HD is associated to significant risks and high mortality. However, when alternative RRT are exhausted, or as a bridge to others modalities, this option should be considered. PMID- 28355410 TI - Obesity and kidney disease: hidden consequences of the epidemic. AB - Obesity has become a worldwide epidemic, and its prevalence has been projected to grow by 40% in the next decade. This increasing prevalence has implications for the risk of diabetes, cardiovascular disease and also for Chronic Kidney Disease. A high body mass index is one of the strongest risk factors for new-onset Chronic Kidney Disease. In individuals affected by obesity, a compensatory hyperfiltration occurs to meet the heightened metabolic demands of the increased body weight. The increase in intraglomerular pressure can damage the kidneys and raise the risk of developing Chronic Kidney Disease in the long-term. The incidence of obesity-related glomerulopathy has increased ten-fold in recent years. Obesity has also been shown to be a risk factor for nephrolithiasis, and for a number of malignancies including kidney cancer. This year the World Kidney Day promotes education on the harmful consequences of obesity and its association with kidney disease, advocating healthy lifestyle and health policy measures that makes preventive behaviors an affordable option. PMID- 28355411 TI - Evaluating the Effectiveness of Cooling Vest in a Hot and Humid Environment. AB - Objective: This study aims to evaluate the effectiveness of a newly designed hybrid cooling vest for construction workers in alleviating heat stress. Method: Two types of cooling vests, namely, a commonly worn Vest A and a newly designed Vest B, were tested in a climatic chamber environment (34.0 degrees C temperature, 60% relative humidity, and 0.4 m s-1 air velocity) using a sweating thermal manikin. Four test scenarios were included: fan off with no phase change materials (PCMs) (Fan-off), fan on with no PCMs (Fan-on), fan off with completely solidified PCMs (PCM + Fan-off), and fan on with completely solidified PCMs (PCM + Fan-on). Result: Test results showed that Vests A and B provided a continuous cooling effect during the 3-h test. The average cooling power for the torso region of Vest B was 67 W, which was higher than that of Vest A (56 W). The addition of PCMs offered a cooling effect of approximately 60 min. Ventilation fans considerably improved the evaporative heat loss compared with the Fan-off condition. Conclusion: The newly designed hybrid cooling vest (Vest B) may be an effective means to reduce heat strain and enhance work performance in a hot and humid environment. PMID- 28355412 TI - Influence of Work Pace on Upper Extremity Kinematics and Muscle Activity in a Short-Cycle Repetitive Pick-and-Place Task. AB - Objectives: This study investigated the extent to which controlled changes in work pace in a cyclic pick-and-place task influence upper extremity kinematics and muscle activity, and whether an effect depends on working height. Methods: Thirteen participants performed the task for 4 min at each of five work paces ranging from 8 to 12 cycles.min-1 in each of two experimental conditions where the hand was moved horizontally with an average upper arm elevation of 30 degrees and 50 degrees , respectively. For each work cycle, we calculated the average and standard deviation of the upper arm elevation angle and the activity of the trapezius and deltoid muscles, as well as the angular peak velocity. We summarized these seven variables by calculating averages across cycles and cycle to-cycle variabilities. Results: At 30 degrees arm elevation, pace significantly influenced within-cycle angle variation, cycle-to-cycle variability of the average angle, angular peak velocity, and cycle-to-cycle variability of peak velocity. However, only angular peak velocity increased monotonically across all paces from 8 to 12 cycles.min-1). Average activity in the trapezius and the deltoid were the only muscle activity variables to increase consistently with pace. These effects of work pace did not change with working height. Conclusion: The present study did not find any consistent work pace effect on upper extremity kinematics and muscle activity, in spite of a comprehensive empirical basis compared to previous literature. While our results suggest that work pace may not be of critical concern in an occupational health context, we encourage further studies verifying or disproving this notion. PMID- 28355413 TI - Maintenance of Low-Pressure Carburising Furnaces: A Source of PAH Exposure. AB - Objectives: Low-pressure carburising is a new technology used to harden steel; the process has been shown to be a source of considerable polycyclic aromatic hydrocarbons (PAH) pollution. Some PAH are carcinogenic, and activities such as furnace maintenance may thus represent a risk to workers. Occupational exposure during these operations should therefore be assessed. Methods: In this study, the PAH-related carcinogenic risk associated with furnace maintenance was assessed by monitoring atmospheric levels of benzo[a]pyrene (BaP), a representative marker, alongside urinary levels of 3-hydroxybenzo[a]pyrene (3-OHBaP), one of its metabolites. PAH exposure levels were monitored during seven sampling campaigns in four different factories specialized in heat-treatment of mechanical workpieces for the automotive and helicopter industries. Two types of furnace were studied, and 37 individuals were monitored. Results: Values up to 20-fold the French regulatory value of 150 ng/m3 for atmospheric BaP, and, for urinary 3 OHBaP values up to 40-fold the French biological limit value (BLV) of 0.35 nmol/mol of creatinine were detected. Very high concentrations of BaP, close to or even exceeding those found in coal-tar pitch (up to about 20 g/kg), were measured in residues (tars, dusts) deposited inside the furnace. Even when adequate and suitable personal protective equipment was used, urinary 3-OHBaP values often exceeded the BLV. We hypothesize that this exposure is linked to insidious and fortuitous dermal contamination through contact with factory equipment and staining. PMID- 28355414 TI - Retrospective Assessment of Occupational Exposures for the GENEVA Study of ALS among Military Veterans. AB - Objective: This paper describes the retrospective exposure assessment conducted to assess occupational exposures for the Genes and Environmental Exposures in Veterans (GENEVA) study, a case-control study investigating the joint contribution of genetics and environmental exposures to the risk of amyotrophic lateral sclerosis (ALS) among military veterans. Methods: Occupational histories for 1597 study participants collected as part of the GENEVA study were the basis for this retrospective exposure assessment. The data set included 15528 jobs held from 1924 to 2010, representing 4539 unique industry and occupation (I&O) combinations. Three industrial hygiene experts were recruited to independently rate occupational exposures to specific agents previously associated with an increased risk of ALS. Utilizing information on industry, job title, tasks performed, and materials used for each job held, raters assigned exposures associated with each I&O for the 'current time' defined as the period after 1995 (post-1995). The exposure assessment targeted agents identified as potential occupational risk factors for ALS. Experts rated semi-quantitatively exposure intensity in five exposure categories (0-4) for Group A agents (lead, formaldehyde, hydrocarbon solvents, and chlorinated solvents) and qualitatively as yes/no (1/0) exposed for Group B agents (mercury, selenium, arsenic, polychlorinated biphenyls, electromagnetic field, pesticides, and viral agents). Confidence scores (0-3) were reported for every I&O rated based on raters' experience with that industry and/or job. Each I&O was assigned an average exposure score of the raters and an alternative exposure rating was developed for each I&O by excluding low confidence (<2) scores before averaging. Exposure reconstruction for jobs held pre-1995 was done by comparing exposure data extracted from the OSHA Chemical Exposure and Health Database (CEHD) during pre 1995 and post-1995. For agents with limited exposure data in the CEHD, pre-1995 exposures were determined based on raters' judgment. Results: The proportion of I&O combinations determined to be 'exposed' ranged from 0.1 to 26% across different agents, with the highest values corresponding to hydrocarbon solvents and the lowest to selenium. Industries with the highest proportion of exposed records include manufacturing, utilities, healthcare, and military with non combat jobs. Analyses for raters' reliability showed the best agreement between the raters when rating exposure to viral agents (kappa = 0.67), hydrocarbon solvents (kappa = 0.53), and lead (kappa = 0.50). The proportion of 'exposed' I&O combinations increased for hydrocarbon solvents, chlorinated solvents, and pesticides when exposure ratings were adjusted by raters' confidence. Compared to post-1995, exposures in the earlier period (pre-1995) were deemed higher or the same for most of the agents and lower for formaldehyde and electromagnetic field exposures. Conclusions: Our results indicate that using raters' confidence assessment in determining exposure scores increases both the proportion of I&O combinations regarded as exposed and the intensity scores, suggesting raters tend to be conservative in their assessment when they lack detailed knowledge of an industry or job. PMID- 28355415 TI - Exposure to Inhalable Dust, Endotoxin, and Total Volatile Organic Carbons on Dairy Farms Using Manual and Automated Feeding Systems. AB - Introduction: Agricultural workers tend to have high exposures to organic dusts which may induce or exacerbate respiratory disorders. Studies investigating the effect of work tasks and farm characteristics on organic dust exposures among farm workers suggest that handling of animal feed is an important exposure determinant; however, the effect of the animal feeding system has not been explored in any detail. Objectives: To measure the exposure of Irish dairy farmers to inhalable dust, endotoxin, and total volatile organic compounds (TVOCs) during parlour work and to explore whether levels of exposure to these agents depend on the applied feeding system in the farms. Methods: Thirty-eight personal exposure measurements were collected from farmers across seven dairy farms. The farms used manual, loft, or semi-automated feeding systems. Information on worker tasks and farm characteristics was collected during the surveys. Associations between exposure concentrations and feeding systems, worker tasks, and other farm characteristics were explored in linear mixed-effect regression models with farmer identity treated as a random effect. Results: Exposure concentrations were variable and had a geometric mean (GM; geometric standard deviation) of 1.5 mg m-3 (1.8) for inhalable dust and 128 EU m-3 (2.5) for endotoxin. More than 50% of the exposure measurements for endotoxin, and organic dust exceeded recommended health-based occupational exposure limits. Endotoxin levels were somewhat lower in farms using semi-automatic feeding systems when compared to those using manual feeding systems but in multivariate regression analysis associations were not statistically significant (beta = 0.54, P = 0.4). Performance of activities related to handling and spreading of hay or straw was the strongest determinant for both inhalable dust and endotoxin exposure (beta = 0.78, P <= 0.001; beta = 0.72, P = 0.02, respectively). The level of dust exposure increased also as a consequence of a lower outdoor temperature, and higher ratio of distributed feed per cow (P = 0.01). Stationary measurements of TVOC and CO2 concentrations inside the dairy parlours had a GM of 180 ppb (1.9) and 589 ppb (1.3), respectively. The use of cow teat disinfectants and building ventilation were both strong predictors of TVOC concentrations within parlours. Conclusions: Dairy farm workers can be exposed to high and variable levels of inhalable dust and endotoxin and may be at risk of respiratory disease. Results from this study suggest that exposure control strategies for organic dusts and TVOCs exposures should consider building ventilation and work tasks such as spreading of bedding material, using spray disinfectants and animal feeding. Until effective permanent engineering controls are established farm workers should be encouraged to wear respiratory protective equipment during these tasks. PMID- 28355416 TI - Accuracy Evaluation of Three Modelling Tools for Occupational Exposure Assessment. AB - Objectives: The objective of this study is to evaluate the accuracy and robustness of three exposure-modelling tools [STOFFENMANAGER(r) v.6, European Centre for Ecotoxicology and Toxicology of Chemical Target Risk Assessment v.3.1 (ECETOC TRA v.3.1), and Advanced REACH Tool (ART v.1.5)], by comparing available measured data for exposure to organic solvents and pesticides in occupational exposure scenarios (ESs). Methods: Model accuracy was evaluated by comparing the predicted and the measured values, expressed as an underestimation or overestimation factor (PRED/EXP), and by regression analysis. Robustness was quantitatively described by the so-called variable 'Uncertainty Factor' (UF), which was attributed to each model's input: a higher UF score indicates greater model uncertainty and poorer robustness. Results: ART was the most accurate model, with median PRED/EXP factors of 1.3 and 0.15 for organic solvent and pesticide ESs, respectively, and a significant correlation (P < 0.05) among estimated and measured data. As expected, Tier 1 model ECETOC TRA demonstrated the worst performance in terms of accuracy, with median PRED/EXP factors of 2.0 for organic solvent ESs and 3545 for pesticide ESs. Simultaneously, STOFFENMANAGER(r) showed a median UF equal to 2.0, resulting in the most robust model. Discussion: ECETOC TRA was not considered acceptable in terms of accuracy, confirming that this model is not appropriate for the evaluation of the selected ESs for pesticides. Conversely, STOFFENMANAGER(r) was the best choice, and ART tended to underestimate the exposure to pesticides. For organic solvent ESs, there were no cases of strong underestimation, and all models presented overall acceptable results; for the selected ESs, ART showed the best accuracy. Stoffenmanager was the most robust model overall, indicating that even with a mistake in ES interpretation, predicted values would remain acceptable. Conclusion: ART may lead to more accurate results when well-documented ESs are available. In other situations, Stoffenmanager appears to be a safer alternative because of its greater robustness, particularly when entry data uncertainty is difficult to assess. ECETOC TRA cannot be directly compared to higher tiered models because of its simplistic nature: the use of this tool should be limited only to exceptional cases in which a strong conservative and worst-case evaluation is necessary. PMID- 28355418 TI - Characterization of Particulate Fume and Oxides Emission from Stainless Steel Plasma Cutting. AB - Plasma cutting is a metal fabrication process that employs an electrically conductive plasma arc to cut metals. The metal fume emitted from stainless steel plasma cutting may consist of hexavalent chromium (Cr6+), which is a carcinogen, and other toxicants. Overexposure to plasma cutting fume may cause pulmonary toxicity and other health effects. This study was to evaluate the effects of operation parameters (arc current and arc time) on the fume formation rates, Cr6+ and other oxides concentrations, particle size distributions (PSD), and particle morphology. A fume chamber and high-volume pump were used to collect fume produced from cutting ER308L stainless steel plates with arc currents varying between 20 and 50 A. The amount of fume collected on glass fiber filters was gravimetrically determined and normalized to arc time. Cr6+ and other oxides in the fume were analyzed using ion chromatography. PSD of the fume was examined using a scanning mobility particle sizer and an aerodynamic particle sizer for fine and coarse fractions, respectively. The particle morphology was imaged through a transmission electron microscope (TEM). Total fume generation rate increased with arc current and ranged from 16.5 mg min-1 at 20 A to 119.0 mg min 1 at 50 A. Cr6+ emissions (219.8-480.0 ug min-1) from the plasma cutting were higher than welding fume in a previous study. Nitrogen oxides level can be an indicator of oxidation level and Cr6+ formation (R = 0.93). Both PSD measurement and TEM images confirmed a multimodal size distribution. A high concentration of a fine fraction of particles with geometric mean sizes from 96 to 235 nm was observed. Higher arc current yielded more particles, while lower arc current was not able to penetrate the metal plates. Hence, the worker should optimize the arc current to balance cut performance and fume emission. The findings indicated that arc current was the dominant factor in fume emission from plasma cutting. Appropriate ventilation and respiratory protection should be used to reduce workers' exposure. PMID- 28355417 TI - Organosilane-Based Coating of Quartz Species from the Traditional Ceramics Industry: Evidence of Hazard Reduction Using In Vitro and In Vivo Tests. AB - The exposure to respirable crystalline silica (RCS), e.g. quartz, in industrial settings can induce silicosis and may cause tumours in chronic periods. Consequently, RCS in the form of quartz and cristobalite has been classified as human lung carcinogen category 1 by the International Agency for Research on Cancer in 1997, acknowledging differences in hazardous potential depending on source as well as chemical, thermal, and mechanical history. The physico-chemical determinants of quartz toxicity are well understood and are linked to density and abundance of surface silanol groups/radicals. Hence, poly-2-vinylpyridine-N-oxide and aluminium lactate, which effectively block highly reactive silanol groups at the quartz surface, have formerly been introduced as therapeutic approaches in the occupational field. In the traditional ceramics industry, quartz-containing raw materials are indispensable for the manufacturing process, and workers are potentially at risk of developing quartz-related lung diseases. Therefore, in the present study, two organosilanes, i.e. Dynasylan(r) PTMO and Dynasylan(r) SIVO 160, were tested as preventive, covalent quartz-coating agents to render ceramics production safer without loss in product quality. Coating effectiveness and coating stability (up to 1 week) in artificial alveolar and lysosomal fluids were first analysed in vitro, using the industrially relevant quartz Q1 as RCS model, quartz DQ12 as a positive control, primary rat alveolar macrophages as cellular model system (75 ug cm-2; 4 h of incubation +/- aluminium lactate to verify quartz-related effects), and lactate dehydrogenase release and DNA strand break induction (alkaline comet assay) as biological endpoints. In vitro results with coated quartz were confirmed in a 90-day intratracheal instillation study in rats with inflammatory parameters as most relevant readouts. The results of the present study indicate that in particular Dynasylan(r) SIVO 160 (0.2% w/w of quartz) was able to effectively and stably block toxicity of biologically active quartz species without interfering with technical process quality of certain ceramic products. In conclusion, covalent organosilane coatings of quartz might represent a promising strategy to increase workers' safety in the traditional ceramics industry. PMID- 28355419 TI - Farewell to Corbett, but Not to His Contributions. PMID- 28355420 TI - Kaizen. PMID- 28355422 TI - How We Evaluate Biomarker Studies. PMID- 28355421 TI - An Assessment of the Robustness of the COSHH-Essentials (C-E) Target Airborne Concentration Ranges 15 Years on, and Their Usefulness for Determining Control Measures. AB - The Health and Safety Executive (HSE) in Great Britain (GB), in association with its stakeholders, developed the Control of Substances Hazardous to Health (COSHH) Essentials (C-E) control banding tool in 1998. The objective was to provide a simple tool for employers, particularly small and medium-sized enterprises (SMEs), to help select and apply appropriate measures for the adequate control of exposure to hazardous substances. The tool used hazard classification information (R-phrases) to assign substances to one of five health hazard groups, each with its respective 'target airborne concentration range'. The validity of the allocation of substances to a target airborne concentration range was demonstrated at the time using 111 substances that had a current health-based Occupational Exposure Limit (OEL) in GB. The C-E control banding approach remains an important tool to complement exposure assessment/monitoring and the selection and use of suitable control measures for hazardous substances. These include engineering controls and personal protective equipment (PPE). The C-E based control banding approach has been adopted around the world. This paper extends the original validation exercise, using a greater number of chemical substances, to establish whether the target airborne concentration ranges remain appropriate. This is of particular interest in light of the introduction of the Globally Harmonized System (GHS) for classification, in which R-phrases have now been replaced by hazard-statements (H-statements). The validation exercise includes substances with OELs published by nine bodies internationally; and the Derived No Effect Levels (DNELs) assigned by registrants under the European Union Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) Regulations. When compared against 8-hour TWA OELs for 850 substances drawn from nine bodies and a limited number of DNELS, the C-E target airborne concentration ranges remain valid. This comparative work also informs a wider consideration around the practicality and the applicability of the C-E generic approach to facilitate the implementation of good practice control for a wide range of substances (more than 95%) which do not have any recognized OEL. PMID- 28355423 TI - Phototherapy for Vitiligo: A Systematic Review and Meta-analysis. AB - Importance: References to the expected treatment response to phototherapy would be helpful in the management of vitiligo because phototherapy requires long treatment durations over several months. Objective: To estimate the treatment response of vitiligo to phototherapy. Data Sources: A comprehensive database search of MEDLINE, EMBASE, and the Cochrane library from inception to January 26, 2016, was performed for all prospective studies. The main keywords used were vitiligo, phototherapy, psoralen, PUVA, ultraviolet, NBUVB, and narrowband. Study Selection: All prospective studies reporting phototherapy outcome for at least 10 participants with generalized vitiligo were included. Of 319 studies initially identified, the full texts of 141 studies were assessed for eligibility, and 35 were finally included in the analysis. Of these, 29 studies included 1201 patients undergoing narrowband UV-B (NBUVB) phototherapy, and 9 included 227 patients undergoing psoralen-UV-A (PUVA) phototherapy. Data Extraction and Synthesis: Two reviewers independently extracted the following data: study design, number and characteristics of the participants, phototherapy protocol, and rate of repigmentation based on the quartile scale. Single-arm meta-analyses were performed for the NBUVB and PUVA groups. Sample size-weighted means were calculated using a random-effects model for the repigmentation rates of the included studies. Main Outcomes and Measures: The primary outcomes were at least mild (>=25%), at least moderate (>=50%), and marked (>=75%) responses on a quartile scale. Response rates were calculated as the number of participants who showed the corresponding repigmentation divided by the number of all participants enrolled in the individual studies. Results: The meta-analysis included 35 unique studies (1428 unique patients). For NBUVB phototherapy, an at least mild response occurred in 62.1% (95% CI, 46.9%-77.3%) of 130 patients in 3 studies at 3 months, 74.2% (95% CI, 68.5%-79.8%) of 232 patients in 11 studies at 6 months, and 75.0% (95% CI, 60.9%-89.2%) of 512 patients in 8 studies at 12 months. A marked response was achieved in 13.0% (95% CI, 2.1%-23.9%) of 106 patients in 2 studies at 3 months, 19.2% (95% CI, 11.4%-27.0%) of 266 patients in 13 studies at 6 months, and 35.7% (95% CI, 21.5%-49.9%) of 540 patients in 9 studies at 12 months. For PUVA phototherapy, an at least mild response occurred in 51.4% (95% CI, 28.1%-74.7%) of 103 patients in 4 studies at 6 months and 61.6% (95% CI, 20.2%-100%) of 72 patients in 3 studies at 12 months. In the subgroup analyses, marked responses were achieved on the face and neck in 44.2% (95% CI, 24.2% 64.2%), on the trunk in 26.1% (95% CI, 8.7%-43.5%), on the extremities in 17.3% (95% CI, 8.2%-26.5%), and on the hands and feet in none after at least 6 months of NBUVB phototherapy. Conclusions and Relevance: Long-duration phototherapy should be encouraged to enhance the treatment response in vitiligo. The greatest response is anticipated on the face and neck. PMID- 28355425 TI - Rituximab Treatment of Nivolumab-Induced Bullous Pemphigoid. PMID- 28355424 TI - Development and Validation of a Clinically Based Risk Calculator for the Transdiagnostic Prediction of Psychosis. AB - Importance: The overall effect of At Risk Mental State (ARMS) services for the detection of individuals who will develop psychosis in secondary mental health care is undetermined. Objective: To measure the proportion of individuals with a first episode of psychosis detected by ARMS services in secondary mental health services, and to develop and externally validate a practical web-based individualized risk calculator tool for the transdiagnostic prediction of psychosis in secondary mental health care. Design, Setting, and Participants: Clinical register-based cohort study. Patients were drawn from electronic, real world, real-time clinical records relating to 2008 to 2015 routine secondary mental health care in the South London and the Maudsley National Health Service Foundation Trust. The study included all patients receiving a first index diagnosis of nonorganic and nonpsychotic mental disorder within the South London and the Maudsley National Health Service Foundation Trust in the period between January 1, 2008, and December 31, 2015. Data analysis began on September 1, 2016. Main Outcomes and Measures: Risk of development of nonorganic International Statistical Classification of Diseases and Related Health Problems, Tenth Revision psychotic disorders. Results: A total of 91 199 patients receiving a first index diagnosis of nonorganic and nonpsychotic mental disorder within South London and the Maudsley National Health Service Foundation Trust were included in the derivation (n = 33 820) or external validation (n = 54 716) data sets. The mean age was 32.97 years, 50.88% were men, and 61.05% were white race/ethnicity. The mean follow-up was 1588 days. The overall 6-year risk of psychosis in secondary mental health care was 3.02 (95% CI, 2.88-3.15), which is higher than the 6-year risk in the local general population (0.62). Compared with the ARMS designation, all of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses showed a lower risk of psychosis, with the exception of bipolar mood disorders (similar risk) and brief psychotic episodes (higher risk). The ARMS designation accounted only for a small proportion of transitions to psychosis (n = 52 of 1001; 5.19% in the derivation data set), indicating the need for transdiagnostic prediction of psychosis in secondary mental health care. A prognostic risk stratification model based on preselected variables, including index diagnosis, age, sex, age by sex, and race/ethnicity, was developed and externally validated, showing good performance and potential clinical usefulness. Conclusions and Relevance: This online individualized risk calculator can be of clinical usefulness for the transdiagnostic prediction of psychosis in secondary mental health care. The risk calculator can help to identify those patients at risk of developing psychosis who require an ARMS assessment and specialized care. The use of this calculator may eventually facilitate the implementation of an individualized provision of preventive focused interventions and improve outcomes of first episode psychosis. PMID- 28355426 TI - Focal Pegylated Liposomal Doxorubicin-Induced Urticarialike Reaction at Cutaneous Transformed Sezary Lesions. PMID- 28355427 TI - Reply to the Letter by Dr Peter Griffin and Prof. Andrew Curran, "Response to Article by Prof. Hans Kromhout, Hygiene Without Numbers". PMID- 28355429 TI - Corrections to Text, Tables, and Figure. PMID- 28355428 TI - Health Disparities and Triple-Negative Breast Cancer in African American Women: A Review. AB - Importance: Variation in cancer incidence and outcome has well-documented correlations with racial/ethnic identity. In the United States, the possible genetic and ancestral hereditary explanations for these associations are confounded by socioeconomic, cultural, and lifestyle patterns. Differences in the breast cancer burden of African American compared with European/white American women represent one of the most notable examples of disparities in oncology related to racial/ethnic identity. Elucidating the source of these associations is imperative in achieving the promise of the national Precision Medicine Initiative. Observations: Population-based breast cancer mortality rates have been higher for African American compared with white American women since the early 1980s, largely reflecting declines in mortality that have been disproportionately experienced among white American patients and at least partly explained by the advent of endocrine therapy that is less effective in African American women because of the higher prevalence of estrogen receptor-negative disease. The increased risk of triple-negative breast cancer in African American women as well as western, sub-Saharan African women compared with white American, European, and east African women furthermore suggests that selected genetic components of geographically defined African ancestry are associated with hereditary susceptibility for specific patterns of mammary carcinogenesis. Disentangling health care access barriers, as well as reproductive, lifestyle, and dietary factors from genetic contributions to breast cancer disparities remains challenging. Epigenetics and experiences of societal inequality (allostatic load) increase the complexity of studying breast cancer risk related to racial/ethnic identity. Conclusions and Relevance: Oncologic anthropology represents a transdisciplinary field of research that can combine the expertise of population geneticists, multispecialty oncologists, molecular epidemiologists, and behavioral scientists to eliminate breast cancer disparities related to racial/ethnic identity and advance knowledge related to the pathogenesis of triple-negative breast cancer. PMID- 28355430 TI - Association Between Elements of Electronic Health Record Systems and the Weekend Effect in Urgent General Surgery. PMID- 28355432 TI - Primary Prevention Implantable Cardioverter Defibrillators in Patients With Nonischemic Cardiomyopathy: A Meta-analysis. AB - Importance: Conflicting data have emerged on the efficacy of implantable cardioverter defibrillators (ICDs) for primary prevention of sudden cardiac death (primary prevention ICDs) in patients with nonischemic cardiomyopathy. Objective: To investigate the association of primary prevention ICDs with all-cause mortality in patients with nonischemic cardiomyopathy. Data Sources: PubMed was searched from January 1, 2000, through October 31, 2016, for the terms implantable defibrillator OR implantable cardioverter defibrillator AND non ischemic cardiomyopathy. Additional references were identified from bibliographies of pertinent articles and queries to experts in this field. Study Selection: Inclusion criteria consisted of a randomized clinical trial design and comparison of the ICD with medical therapy (control) in at least 100 patients with nonischemic cardiomyopathy. In addition, studies had to report on all-cause mortality during a follow-up period of at least 12 months and be published in English. The search yielded 10 studies, of which only 1 met the inclusion criteria. A search of bibliographies of pertinent articles and queries of experts in this field led to 3 additional studies. Data Extraction and Synthesis: The PRISMA guidelines were used to abstract data and assess data quality and validity. Data were pooled using fixed- and random-effects models. Main Outcomes and Measures: The primary end point was all-cause mortality. Before data collection started, primary prevention ICDs were hypothesized to reduce all-cause mortality among patients with nonischemic cardiomyopathy. Results: Four randomized clinical trials met the selection criteria and included 1874 unique patients; 937 were in the ICD group and 937 in the control group. Pooling data from these trials showed a significant reduction in all-cause mortality with an ICD (hazard ratio, 0.75; 95% CI, 0.61-0.93; P = .008; P = .87 for heterogeneity). Conclusions and Relevance: Primary prevention ICDs are efficacious at reducing all-cause mortality among patients with nonischemic cardiomyopathy. These findings support professional guidelines that recommend the use of ICDs in such patients. PMID- 28355433 TI - Proteomics of Atrial Fibrillation: Evolving From a Coarse Understanding to a Fine Phenotype. PMID- 28355431 TI - State Variation in the Receipt of a Contralateral Prophylactic Mastectomy Among Women Who Received a Diagnosis of Invasive Unilateral Early-Stage Breast Cancer in the United States, 2004-2012. AB - Importance: The use of contralateral prophylactic mastectomies (CPMs) among patients with invasive unilateral breast cancer has increased substantially during the past decade in the United States despite the lack of evidence for survival benefit. However, whether this trend varies by state or whether it is correlated with changes in proportions of reconstructive surgery among these patients is unclear. Objective: To determine state variation in the temporal trend and in the proportion of CPMs among women with early-stage unilateral breast cancer treated with surgery. Design, Setting, and Participants: A retrospective cohort study of 1.2 million women 20 years of age or older diagnosed with invasive unilateral early-stage breast cancer and treated with surgery from January 1, 2004, through December 31, 2012, in 45 states and the District of Columbia as compiled by the North American Association of Central Cancer Registries. Data analysis was performed from August 1, 2015, to August 31, 2016. Exposure: Contralateral prophylactic mastectomy. Main Outcomes and Measures: Temporal changes in the proportion of CPMs among women with early-stage unilateral breast cancer treated with surgery by age and state, overall and in relation to changes in the proportions of those who underwent reconstructive surgery. Results: Among the 1 224 947 women with early-stage breast cancer treated with surgery, the proportion who underwent a CPM nationally increased between 2004 and 2012 from 3.6% (4013 of 113 001) to 10.4% (12 890 of 124 231) for those 45 years or older and from 10.5% (1879 of 17 862) to 33.3% (5237 of 15 745) for those aged 20 to 44 years. The increase was evident in all states, although the magnitude of the increase varied substantially across states. For example, among women 20 to 44 years of age, the proportion who underwent a CPM from 2004-2006 to 2010-2012 increased from 14.9% (317 of 2121) to 24.8% (436 of 1755) (prevalence ratio [PR], 1.66; 95% CI, 1.46-1.89) in New Jersey compared with an increase from 9.8% (162 of 1657) to 32.2% (495 of 1538) (PR, 3.29; 95% CI, 2.80-3.88) in Virginia. In this age group, CPM proportions for the period from 2010 to 2012 were over 42% in the contiguous states of Nebraska, Missouri, Colorado, Iowa, and South Dakota. From 2004 to 2012, the proportion of reconstructive surgical procedures among women aged 20 to 44 years who were diagnosed with early-stage breast cancer and received a CPM increased in many states; however, it did not correlate with the proportion of women who received a CPM. Conclusions and Relevance: The increase in the proportion of CPMs among women with early-stage unilateral breast cancer treated with surgery varied substantially across states. Notably, in 5 contiguous Midwest states, nearly half of young women with invasive early-stage breast cancer underwent a CPM from 2010 to 2012. Future studies should examine the reasons for the geographic variation and increasing trend in the use of CPMs. PMID- 28355434 TI - Economic Analysis of Apixaban Therapy for Patients With Atrial Fibrillation From a US Perspective: Results From the ARISTOTLE Randomized Clinical Trial. AB - Importance: The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial reported that apixaban therapy was superior to warfarin therapy in preventing stroke and all-cause death while causing significantly fewer major bleeds. To establish the value proposition of substituting apixiban therapy for warfarin therapy in patients with atrial fibrillation, we performed a cost-effectiveness analysis using patient-level data from the ARISTOTLE trial. Objective: To assess the cost and cost-effectiveness of apixaban therapy compared with warfarin therapy in patients with atrial fibrillation from the perspective of the US health care system. Design, Setting, and Participants: This economic analysis uses patient-level resource use and clinical data collected in the ARISTOTLE trial, a multinational randomized clinical trial that observed 18 201 patients (3417 US patients) for a median of 1.8 years between 2006 and 2011. Interventions: Apixaban therapy vs warfarin therapy. Main Outcomes and Measures: Within-trial resource use and cost were compared between treatments, using externally derived US cost weights. Life expectancies for US patients were estimated according to their baseline risk and treatment using time-based and age-based survival models developed using the overall ARISTOTLE population. Quality-of-life adjustment factors were obtained from external sources. Cost-effectiveness (incremental cost per quality-adjusted life-year gained) was evaluated from a US perspective, and extensive sensitivity analyses were performed. Results: Of the 3417 US patients enrolled in ARISTOTLE, the mean (SD) age was 71 (10) years; 2329 (68.2%) were male and 3264 (95.5%) were white. After 2 years of anticoagulation therapy, health care costs (excluding the study drug) of patients treated with apixaban therapy and warfarin therapy were not statistically different (difference, -$60; 95% CI, -$2728 to $2608). Life expectancy, modeled from ARISTOTLE outcomes, was significantly longer with apixaban therapy vs warfarin therapy (7.94 vs 7.54 quality-adjusted life years). The incremental cost, including cost of anticoagulant and monitoring, of achieving these benefits was within accepted US norms ($53 925 per quality adjusted life year, with 98% likelihood of meeting a $100 000 willingness-to-pay threshold). Results were generally consistent when model assumptions were varied, with lifetime cost-effectiveness most affected by the price of apixaban and the time horizon. Conclusions and Relevance: Apixaban therapy for ARISTOTLE-eligible patients with atrial fibrillation provides clinical benefits at an incremental cost that represents reasonable value for money judged using US benchmarks for cost-effectiveness. Trial Registration: clinicaltrials.gov Identifier: NCT00412984. PMID- 28355435 TI - Do Patterns of Breast Cancer Surgical Care Reflect National Voting Records? PMID- 28355436 TI - Error in Byline and Results Section and Other Typographical Errors. PMID- 28355437 TI - Radiofrequency Exposures of Workers on Low-Power FM Radio Transmitters. AB - Low-power radio transmitters are one of the most common radio frequency sources and the exposure limit values (ELVs) for occupational exposure may be exceeded close to them. Therefore, a detailed analysis and assessment of occupational exposure in their vicinity is presented in the paper. For 20 different exposure scenarios, electric field strength and specific absorption rate (SAR) values were computed to determine whether the action levels (ALs) and ELVs of the European directive 2013/35/EU are exceeded for different 500 W radio transmitters. The results show that the ALs are very conservative for such exposure situations. Even when the ALs are greatly exceeded, the SAR values are not necessarily above the limit. However, in some situations, the ELVs were also exceeded. The local 10 g averaged value of the SAR can be exceeded if the worker is grounded (in direct contact with the steel structure), while the whole body ELVs can be exceeded for exposures at distances of <1 m from the transmitting dipole array antennas. PMID- 28355438 TI - Exposure to Diisocyanates and Their Corresponding Diamines in Seven Different Workplaces. AB - Biological monitoring to assess exposure to diisocyanates in the workplace is becoming increasingly widespread due to its relative ease of use and ability to look at all exposure routes. Currently, biological monitoring measures the corresponding isocyanate-derived diamine in urine, after hydrolysis. Because of this, any exposure to the diamines themselves released during the industrial process could confound the assessment of diisocyanate exposure. This paper reports an initial assessment of the extent of diamine formation and exposure during different processes involving diisocyanates including casting, grouting, core making, spray painting, foam blowing, and floor screeding. Air monitoring and glove analysis were conducted for both the relevant diisocyanate (measured as total NCO) and its corresponding diamine; urine samples were analysed (after hydrolysis) for the isocyanate-derived diamine. Processes that generated aerosols (as demonstrated by impinger analysis) such as spray painting and foam blowing were associated with the detection of diamines. Those processes that did not generate aerosols (casting, grouting, core making, and screeding) had no diamines detected, either in air or on gloves. In spray-painting tasks, diamines were a minor component (<15%) of the ambient concentration whereas in the foam blowing processes, where water is added to the process, diamine generation is more marked (up to eight times the airborne NCO concentration). Some non-aerosol processes gave rise to substantial diamine levels in urine (in exceedance of international guidance values, >5 umol mol-1 creatinine) despite airborne levels being well within occupational exposure limits (20 ug m-3 total NCO in Great Britain); measurement data and statistical modelling indicated that skin absorption was the most likely exposure route. Foam blowing exposures were more complex, but urinary levels were greater than those expected from diisocyanate inhalation alone (measured as total NCO). This study provides evidence that biological monitoring for diisocyanates based on measuring the corresponding diamine in urine is valid, although any co-exposure to diamines themselves should be considered when interpreting results. It also demonstrates the potential for substantial skin absorption of diisocyanates in certain processes such as floor screeding and foam production. PMID- 28355439 TI - Constructing a Database of Similar Exposure Groups: The Application of the Exporisq-HAP Database from 1995 to 2015. AB - Background: Similar exposure groups (SEGs) are needed to reliably assess occupational exposures and health risks. However, the construction of SEGs can turn out to be rather challenging because of the multifactorial variability of exposures. Objectives: The objective of this study is to put forward a semi empirical approach developed to construct and implement a SEG database for exposure assessments. An occupational database of airborne levels of polycyclic aromatic hydrocarbons (PAHs) was used as an illustrative and working example. Methods: The approach that was developed consisted of four steps. The first three steps addressed the construction and implementation of the occupational Exporisq HAP database (E-HAP). E-HAP was structured into three hierarchical levels of exposure groups, each of which was based on exposure determinants, along 16 dimensions that represented the sampled PAHs. A fourth step was implemented to identify and generate SEGs using the geometric standard deviation (GSD) of PAH concentrations. Results: E-HAP was restructured into 16 (for 16 sampled PAHs) 3 * 3 matrices: three hierarchical levels of description versus three degrees of dispersion, which included low (the SEG database: GSD <= 3), medium (3 < GSD <= 6), and high (GSD > 6). Benzo[a]pyrene (BaP) was the least dispersed particulate PAH with 41.5% of groups that could be considered as SEGs, 48.5% of groups of medium dispersion, and only 8% with high dispersion. These results were comparable for BaP, BaP equivalent toxic, or the sum of all carcinogenic PAHs but were different when individual gaseous PAHs or ?PAHG were chosen. Conclusion: Within the framework of risk assessment, such an approach, based on groundwork studies, allows for both the construction of an SEG database and the identification of exposure groups that require improvements in either the description level or the homogeneity degree toward SEG. PMID- 28355440 TI - Interventions for Hidradenitis Suppurativa: Updated Summary of an Original Cochrane Review. AB - Clinical Question: Which treatments have been shown to be effective in randomized clinical trials (RCTs) for hidradenitis suppurativa (HS) in adults? Bottom Line: There is high-quality evidence of benefit from adalimumab given weekly, while every other week dosing is ineffective, with reductions in Dermatology Life Quality Index (DLQI) scores compared with placebo of 2.8 points (95% CI, -3.7 to 2.0 points) and 1.6 points (95% CI, -3.9 to 0.6 points), respectively. Moderate quality evidence suggests that infliximab is beneficial; RCT evidence for other interventions was lower in quality or absent, limiting further conclusions. PMID- 28355441 TI - Annals of Occupational Hygiene Performance, 2016. PMID- 28355442 TI - Association Between Vascular Cell Adhesion Molecule 1 and Atrial Fibrillation. AB - Importance: Accumulating evidence links inflammation and atrial fibrillation (AF). Objective: To assess whether markers of systemic and atrial inflammation are associated with incident AF in the general population. Design, Setting, and Participants: The Bruneck Study is a prospective, population-based cohort study with a 20-year follow-up (n = 909). The population included a random sample of the general community aged 40 to 79 years. Levels of 13 inflammation markers were measured at baseline in 1990. Findings were replicated in a case-control sample nested within the prospective Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR) study (n = 1770). Data analysis was performed from February to May 2016. Exposures: Levels of 13 inflammation markers. Main Outcomes and Measures: Incident AF over a 20-year follow-up period in the Bruneck Study. Results: Of the 909 participants included in the Bruneck Study, mean [SD] age was 58.8 (11.4) years and 448 (49.3%) were women. Among the 880 participants free of prevalent AF (n = 29) at baseline, 117 developed AF during the 20-year follow-up period (incidence rate, 8.2; 95% CI, 6.8-9.6 per 1000 person-years). The levels of soluble vascular cell adhesion molecule 1 (VCAM 1) and osteoprotegerin were significantly associated with incident AF (hazard ratio [HR], 1.49; 95% CI, 1.26-1.78; and 1.46; 95% CI, 1.25-1.69, respectively; P < .001 with Bonferroni correction for both), but osteoprotegerin lost significance after age and sex adjustment (HR, 1.05; 95% CI, 0.87-1.27; P > .99 with Bonferroni correction). Matrix metalloproteinase 9, metalloproteinase inhibitor 1, monocyte chemoattractant protein-1, P-selectin, fibrinogen, receptor activator of nuclear factor-kappaB ligand, high-sensitivity C-reactive protein, adiponectin, leptin, soluble intercellular adhesion molecule 1, and E-selectin all fell short of significance (after Bonferroni correction in unadjusted and age and sex-adjusted analyses). The HR for a 1-SD higher soluble VCAM-1 level was 1.34 (95% CI, 1.11-1.62; Bonferroni-corrected P = .03) in a multivariable model. The association was of a dose-response type, at least as strong as that obtained for N-terminal pro-B-type natriuretic peptide (multivariable HR for a 1-SD higher N-terminal pro-B-type natriuretic peptide level, 1.15; 95% CI, 1.04-1.26), internally consistent in various subgroups, and successfully replicated in the SAPHIR Study (age- and sex-adjusted, and multivariable odds ratios for a 1-SD higher soluble VCAM-1 level, 1.91; 95% CI, 1.24-2.96, P = .003; and 2.59; 95% CI, 1.45-4.60; P = .001). Conclusions and Relevance: Levels of soluble VCAM-1, but not other inflammation markers, are significantly associated with new-onset AF in the general community. Future studies should address whether soluble VCAM-1 is capable of improving AF risk classification beyond the information provided by standard risk scores. PMID- 28355444 TI - Use of the Novel Derivatizing Agent 1,8-Diaminonapthalene With the CIP10 Sampler to Measure 4,4'-Methylene Diphenyl Diisocyanate Atmospheres. AB - DAN is a novel derivatizing agent for isocyanate sampling which targets total reactive isocyanate group (TRIG). Field evaluations have been conducted for 4,4' Methylene diphenyl diisocyanate (MDI) sampling using DAN as the derivatizing agent in a CIP10. The perimidone formed, selective of TRIG, was analyzed in laboratory by liquid chromatography coupled to tandem mass spectrometry. Workplaces using MDI-based polyurethane spray foam and MDI wood product binder were studied. Each study compared the data obtained between the CIP10/DAN, the CIP10/MP, and a reference method. As a first evaluation, the CIP10/DAN sampled simulated MDI spray foam atmosphere in parallel with impingers (reference method) and CIP10/MP. The mean of the TRIG concentration values measured was 16% (95% confidence interval [CI], [1, 31]) higher for the CIP10/MP samples as compared to the impinger samples, while the mean TRIG concentrations found were 98% (95% CI [63, 133]) higher for the CIP10/DAN samples as compared to the impinger samples. For sampling done in a real workplace using MDI-based spray foam, the CIP10/DAN method showed lower results than the CIP10/MP method. The presence of hygroscopic DMSO used in the DAN approach is a limitation and may prevent obtaining accurate results in the spray foam atmosphere. CIP10/DAN was also studied in MDI wood product binder atmosphere. Mean TRIG concentrations found were 80% (95% CI [51, 110]) and 79% (95% CI [50, 108]) lower for the CIP10/MP and CIP10/DAN method, respectively, as compared to the reference method (a 13-mm filter coated with MP). In this case, the CIP10 may have reached its limit in this last evaluation where vapors and particles below 1 um were not collected as efficiently as they were with the reference method. PMID- 28355445 TI - Reducing the Margins of Error During Breast-Conserving Surgery: Disruptive Technologies or Traditional Disruptions? PMID- 28355443 TI - The Use of Metabolomics to Identify Biological Signatures of Manganese Exposure. AB - Objectives: Manganese (Mn) is a known neurotoxicant, and given its health effects and ubiquitous nature in metal-working settings, identification of a valid and reproducible biomarker of Mn exposure is of interest. Here, global metabolomics is utilized to determine metabolites that differ between groups defined by Mn exposure status, with the goal being to help inform a potential metabolite biomarker of Mn exposure. Methods: Mn exposed subjects were recruited from a Mn steel foundry and Mn unexposed subjects were recruited from crane operators at a metal recycling facility. Over the course of a work day, each subject wore a personal inhalable dust sampler (IOM), and provided an end of shift urine sample that underwent global metabolomics profiling. Both exposed and unexposed subjects were divided into a training set and demographically similar validation set. Using a two-sided adjusted t-test, relative abundances of all metabolites found were compared between Mn exposed and unexposed training sets, and those with a false discovery rates (FDR) <0.1 were further tested in the validation sets. Results: Fifteen ions were found to be significantly different (FDR < 0.1) between the exposed and unexposed training sets, and nine of these ions remained significantly different between the exposed and unexposed validation set as well. When further dividing exposure status into 'lower exposure' and 'higher exposure', several of these nine ions exhibited an apparent exposure-response relationship. Conclusions: This is the first time that metabolomics has been used to distinguish between Mn exposure status in an occupational cohort, though additional work should be done to replicate these findings with a larger cohort. With metabolite identification by name, empirical formula, or pathway, a better understanding of the relationship between Mn exposure and neurotoxic effects could be elucidated, and a potential metabolite biomarker of Mn exposure could be determined. PMID- 28355447 TI - US Public Opinion on Health Care Reform, 2017. PMID- 28355446 TI - Wood Dust in Joineries and Furniture Manufacturing: An Exposure Determinant and Intervention Study. AB - Objectives: To assess wood dust exposures and determinants in joineries and furniture manufacturing and to evaluate the efficacy of specific interventions on dust emissions under laboratory conditions. Also, in a subsequent follow-up study in a small sample of joinery workshops, we aimed to develop, implement, and evaluate a cost-effective and practicable intervention to reduce dust exposures. Methods: Personal inhalable dust (n = 201) was measured in 99 workers from 10 joineries and 3 furniture-making factories. To assess exposure determinants, full shift video exposure monitoring (VEM) was conducted in 19 workers and task-based VEM in 32 workers (in 7 joineries and 3 furniture factories). We assessed the efficacy of vacuum extraction on hand tools and the use of vacuum cleaners instead of sweeping and dry wiping under laboratory conditions. These measures were subsequently implemented in three joinery workshops with 'high' (>4 mg m-3) and one with 'low' (<2 mg m-3) baseline exposures. We also included two control workshops (one 'low' and one 'high' exposure workshop) in which no interventions were implemented. Exposures were measured 4 months prior and 4 months following the intervention. Results: Average (geometric means) exposures in joinery and furniture making were 2.5 mg m-3 [geometric standard deviations (GSD) 2.5] and 0.6 mg m-3 (GSD 2.3), respectively. In joinery workers cleaning was associated with a 3.0-fold higher (P < 0.001) dust concentration compared to low exposure tasks (e.g. gluing), while the use of hand tools showed 3.0- to 11.0-fold higher (P < 0.001) exposures. In furniture makers, we found a 5.4-fold higher exposure (P < 0.001) with using a table/circular saw. Laboratory efficiency experiments showed a 10-fold decrease in exposure (P < 0.001) when using a vacuum cleaner. Vacuum extraction on hand tools combined with a downdraft table reduced exposures by 42.5% for routing (P < 0.1) and 85.5% for orbital sanding (P < 0.001). Following intervention measures in joineries, a borderline statistically significant (P < 0.10) reduction in exposure of 30% was found in workshops with 'high' baseline exposures, but no reduction was shown in the workshop with 'low' baseline exposures. Conclusions: Wood dust exposure is high in joinery workers and (to a lesser extent) furniture makers with frequent use of hand tools and cleaning being key drivers of exposure. Vacuum extraction on hand tools and alternative cleaning methods reduced workplace exposures substantially, but may be insufficient to achieve compliance with current occupational exposure limits. PMID- 28355448 TI - Urinary 8-Oxo-7,8-Dihydro-2'-Deoxyguanosine in Tunisian Electric Steel Foundry Workers Exposed to Polycyclic Aromatic Hydrocarbons. AB - In this study, urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), as biomarker of oxidative DNA damage, was evaluated in Tunisian electric steel foundry workers and was associated with polycyclic aromatic hydrocarbon (PAH) exposure. Ninety-three healthy male workers were enrolled in the study; 8-oxodG was assessed by liquid chromatography-triple quadrupole mass spectrometry. Exposure to PAHs was evaluated by measuring 16 urinary PAHs (U-PAHs) and 8 monohydroxylated metabolites (OHPAHs). The median 8-oxodG level for all subjects was 3.20 ug l-1 (1.85 ug g-1 creatinine). No correlation between 8-oxodG and 1 hydroxypyrene or any other OHPAH was found. Significant linear correlations between 8-oxodG and some U-PAHs were found, particularly urinary acenaphthylene (r = 0.249), phenanthrene (r = 0.327), anthracene (r = 0.357), fluoranthene (r = 0.248), and pyrene (r = 0.244). Multiple regression analyses confirmed that urinary phenanthrene, anthracene, and naphthalene (the latter with a non-linear relationship) were predictors of 8-oxodG; job title, but not smoking, was a determinant of 8-oxodG; the variance explained by these models was up to 20%. The oxidative DNA damage assessed by urinary 8-oxodG was moderate and in the range of values reported in other occupational fields or in the general population. The results of this study indicate that the investigated biomarkers of PAH exposure were only minor contributors to urinary 8-oxodG. PMID- 28355449 TI - Rebuilding Consensus on Valid Criteria for Disordered Grief. PMID- 28355450 TI - Are Novel Anticoagulants Worth Their Cost? PMID- 28355451 TI - Treatment of Alopecia Areata With Tofacitinib. PMID- 28355452 TI - Low-Density Lipoprotein Measurement Discordance: When 2 Wrongs Lead to the Right Answer-Elevated Lipoprotein (a). PMID- 28355454 TI - A Study of the Validity of Two Exposure Assessment Tools: Stoffenmanager and the Advanced REACH Tool. AB - The use of exposure modelling tools for estimating chemical airborne exposure has increased since the European Union's REACH legislation for safe use of industrial chemicals came into force. Two tools that European Chemicals Agency recommends are Stoffenmanager(r) and the Advanced REACH Tool (ART). The aim of this study was to investigate the validity of these two exposure modelling tools by comparing the lack of agreement between estimated and measured exposure. We examined the airborne chemical exposure at companies in seven different types of industries: wood, printing, foundry, spray painting, flour milling, chemical industry, and plastic moulding industry. The inhalable exposure of liquids or powders at two to three situations at each company was modelled with both tools and measured. To study the validity of the tools, the mean differences and precisions (lack of agreement) of exposures from both situations handling liquids and powders were calculated by using the 50th percentile outcome of the tools and the geometric mean of the measured exposure (all data were ln transformed). For Stoffenmanager, the mean difference and precision of the situations concerning liquids were 0.22 +/- 1.0 and for powders -0.024 +/- 0.66. It was also shown that Stoffenmanager overestimated low exposures and underestimated high exposures. Stoffenmanager showed higher agreement with the measured exposure in the wood and flour mill industries than in foundry and the plastic moulding industry. For ART, the mean difference and precision of liquids were -0.55 +/- 0.88 and for powders 1.4 +/- 1.6. ART showed lower agreement with the measured exposure in the wood industry. PMID- 28355453 TI - Dermoscopic Clues for Diagnosing Melanomas That Resemble Seborrheic Keratosis. AB - Importance: Melanomas that clinically mimic seborrheic keratosis (SK) can delay diagnosis and adequate treatment. However, little is known about the value of dermoscopy in recognizing these difficult-to-diagnose melanomas. Objective: To describe the dermoscopic features of SK-like melanomas to understand their clinical morphology. Design, Setting, and Participants: This observational retrospective study used 134 clinical and dermoscopic images of histopathologically proven melanomas in 134 patients treated in 9 skin cancer centers in Spain, France, Italy, and Austria. Without knowledge that the definite diagnosis for all the lesions was melanoma, 2 dermoscopy-trained observers evaluated the clinical descriptions and 48 dermoscopic features (including all melanocytic and nonmelanocytic criteria) of all 134 images and classified each dermoscopically as SK or not SK. The total dermoscopy score and the 7-point checklist score were assessed. Images of the lesions and patient data were collected from July 15, 2013, through July 31, 2014. Main Outcomes and Measures: Frequencies of specific morphologic patterns of (clinically and dermoscopically) SK-like melanomas, patient demographics, and interobserver agreement of criteria were evaluated. Results: Of the 134 cases collected from 72 men and 61 women, all of whom were white and who had a mean (SD) age of 55.6 (17.5) years, 110 (82.1%) revealed dermoscopic features suggestive of melanoma, including pigment network (74 [55.2%]), blue-white veil (72 [53.7%]), globules and dots (68 [50.7%]), pseudopods or streaks (47 [35.1%]), and blue-black sign (43 [32.3%]). The remaining 24 cases (17.9%) were considered likely SKs, even by dermoscopy. Overall, lesions showed a scaly and hyperkeratotic surface (45 [33.6%]), yellowish keratin (42 [31.3%]), comedo-like openings (41 [30.5%]), and milia-like cysts (30 [22.4%]). The entire sample achieved a mean (SD) total dermoscopy score of 4.7 (1.6) and a 7-point checklist score of 4.4 (2.3), while dermoscopically SK like melanomas achieved a total dermoscopy score of only 4.2 (1.3) and a 7-point checklist score of 2.0 (1.9), both in the range of benignity. The most helpful criteria in correctly diagnosing SK-like melanomas were the presence of blue white veil, pseudopods or streaks, and pigment network. Multivariate analysis found only the blue-black sign to be significantly associated with a correct diagnosis, while hyperkeratosis and fissures and ridges were independent risk markers of dermoscopically SK-like melanomas. Conclusions and Relevance: Seborrheic keratosis-like melanomas can be dermoscopically challenging, but the presence of the blue-black sign, pigment network, pseudopods or streaks, and/or blue-white veil, despite the presence of other SK features, allows the correct diagnosis of most of the difficult melanoma cases. PMID- 28355455 TI - The Effects of Trivialization of Workplace Violence on Its Victims: Profession and Sex Differences in a Cross-Sectional Study among Healthcare and Law Enforcement Workers. AB - Background: Workers from the law enforcement and healthcare sectors tend to normalize or mute their victimization from workplace violence (WPV). Objectives: This study aims to assess the impact of the trivialization of WPV on psychological consequences for workers who have been affected by a WPV incident. The second aim is to assess the moderating effect of sex on the trivialization of WPV. The third and overarching aim is to assess the moderating effect of professional identity on the relations between individual and organizational factors and psychological consequences following a WPV incident. Methods: The findings are based on a convenience sample of 377 (204 female and 173 male) workers from the law enforcement and healthcare sectors. Individual factors (sex, age, professional identity, prior victimization, witnessing WPV, injuries, and trivialization of violence) and perceived support factors (colleagues' support and employer's support) were used as predictor variables of psychological consequences in hierarchical linear regression models. Sex was used as a moderator of trivialization while professional identity was used as a moderator of all predictors. Findings: When individual and social support factors were controlled for, normalizing violence was negatively associated with psychological consequences while perceiving a taboo associated with complaining about WPV was positively associated for all participants. When these relations were moderated by the sex of the participants and then by their professional identity, normalization was found to decrease psychological consequences only for male healthcare workers. Implications: To help employees cope with WPV, organizations should promote strategies adapted to profession and sex differences. For male healthcare workers, normalization as a cognitive coping strategy should be formally recognized. For both professions and sexes, organizational strategies that counter the perceived taboo of complaining about violence should be reinforced. PMID- 28355456 TI - The Surge of Opioid Use, Addiction, and Overdoses: Responsibility and Response of the US Health Care System. PMID- 28355457 TI - Clinically Relevant Diagnostic Criteria for a Persistent Impairing Grief Disorder: Putting Patients First. PMID- 28355459 TI - Laboratory Monitoring of Non-Vitamin K Antagonist Oral Anticoagulant Use in Patients With Atrial Fibrillation: A Review. AB - Importance: The non-vitamin K antagonist oral anticoagulants (NOACs) apixaban, dabigatran, edoxaban, and rivaroxaban are administered in fixed doses without anticoagulant monitoring. Randomized trials show that unmonitored NOAC therapy is at least as effective as and safer than dose-adjusted warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. Subgroup analyses indicate that plasma drug levels or anticoagulant activity of the NOACs predict stroke and bleeding. This review examines the historical basis for anticoagulant monitoring, discusses methods to measure and interpret drug levels, and critically assesses the role of routine laboratory monitoring in the management of NOAC therapy. Observations: The predictable anticoagulant response of NOACs has provided the pharmacological basis for their administration in fixed doses without routine coagulation monitoring. Although it is possible to accurately measure NOAC drug levels, within-patient variability complicates interpretation of these results. Furthermore, patient characteristics, such as age and renal function, confound the association between NOAC drug levels and clinical outcomes. Information is lacking on the optimal drug level in particular patient groups (eg, elderly, the renally impaired, and those with high bleeding risk), the appropriate dose adjustment to achieve expected levels, and whether routine laboratory monitoring and dose adjustment will improve clinical outcomes. A benefit of a management strategy that incorporates routine therapeutic drug monitoring and dose adjustment over current standard-of-care metrics without such monitoring remains unproven. Conclusions and Relevance: Robust evidence from patients with atrial fibrillation randomized to NOACs or warfarin demonstrates that unmonitored NOAC therapy is at least as effective and safe as monitored warfarin, with lower rates of intracranial hemorrhage and reduced mortality. Further research is required to determine whether routine laboratory monitoring might provide a net benefit for patients. Until such data are available, clinicians should continue to prescribe NOACs in fixed doses without routine monitoring. PMID- 28355458 TI - Changes in US Lifetime Heroin Use and Heroin Use Disorder: Prevalence From the 2001-2002 to 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions. AB - Importance: Heroin use is an urgent concern in the United States. Little is know about the course of heroin use, heroin use disorder, and associated factors. Objective: To examine changes in the lifetime prevalence, patterns, and associated demographics of heroin use and use disorder from 2001-2002 to 2012 2013 in 2 nationally representative samples of the US adult general population. Design, Setting, and Participants: This survey study included data from 43 093 respondents of the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) and 36 309 respondents of the 2012-2013 NESARC-III. Data were analyzed from February 2 to September 15, 2016. Main Outcomes and Measures: Lifetime heroin use and DSM-IV heroin use disorder. Results: Among the 79 402 respondents (43.3% men; 56.7% women; mean [SD] age, 46.1 [17.9] years), prevalence of heroin use and heroin use disorder significantly increased from 2001-2002 to 2012-2013 (use: 0.33% [SE, 0.03%] vs 1.6% [SE, 0.08%]; disorder: 0.21% [SE, 0.03%] vs 0.69% [SE, 0.06%]; P < .001). The increase in the prevalence of heroin use was significantly pronounced among white (0.34% [SE, 0.04%] in 2001 2002 vs 1.90% [SE, 0.12%] in 2012-2013) compared with nonwhite (0.32% [SE, 0.05%] in 2001-2002 vs 1.05% [SE, 0.10%] in 2012-2013; P < .001) individuals. The increase in the prevalence of heroin use disorder was more pronounced among white individuals (0.19% [SE, 0.03%] in 2001-2002 vs 0.82% [SE, 0.08%] in 2012-2013; P < .001) and those aged 18 to 29 (0.21% [SE, 0.06%] in 2001-2002 vs 1.0% [0.17%] in 2012-2013; P = .01) and 30 to 44 (0.20% [SE, 0.04%] in 2001-2002 vs 0.77% [0.10%] in 2012-2013; P = .03) years than among nonwhite individuals (0.25% [SE, 0.04%] in 2001-2002 vs 0.43% [0.07%] in 2012-2013) and older adults (0.22% [SE, 0.04%] in 2001-2002 vs 0.51% [SE, 0.07%] in 2012-2013). Among users, significant differences were found across time in the proportion of respondents meeting DSM IV heroin use disorder criteria (63.35% [SE, 4.79%] in 2001-2001 vs 42.69% [SE, 2.87%] in 2012-2013; P < .001). DSM-IV heroin abuse was significantly more prevalent among users in 2001-2002 (37.02% [SE, 4.67%]) than in 2012-2013 (19.19% [SE, 2.34%]; P = .001). DSM-IV heroin dependence among users was similar in 2001 2002 (28.22% [SE, 3.95%]) and in 2012-2013 (25.02% [SE, 2.20%]; P = .48). The proportion of those reporting initiation of nonmedical use of prescription opioids before initiating heroin use increased across time among white individuals (35.83% [SE, 6.03%] in 2001-2002 to 52.83% [SE, 2.88%] in 2012-2013; P = .01). Conclusions and Relevance: The prevalence of heroin use and heroin use disorder increased significantly, with greater increases among white individuals. The nonmedical use of prescription opioids preceding heroin use increased among white individuals, supporting a link between the prescription opioid epidemic and heroin use in this population. Findings highlight the need for educational campaigns regarding harms related to heroin use and the need to expand access to treatment in populations at increased risk for heroin use and heroin use disorder. PMID- 28355460 TI - Temporal Trend in Wood Dust Exposure During the Production of Wood Pellets. AB - Objective: Wood dust data collected in the production of wood pellets during 2001 to 2013 were evaluated to study a temporal trend in inhalation exposure. Methods: A linear mixed effects model of natural ln-transformed data was used to express the relative annual difference in inhalation wood dust exposure. Results: There was an annual decrease of -20.5% of the geometric mean wood dust exposure during 2001 until 2013. The results were based on 617 inhalable dust samples collected at 14 different production units. The exposure to wood dust at the industrial premises investigated has decreased from a relatively high level of 6.4 mg m-3 in 2001 to 1.0 mg-3 in 2013. The Swedish Occupational Exposure Limit (SOEL) of 2 mg m-3 may still be exceeded. Conclusion: Analysis of the temporal trend in soft wood production units revealed declines in exposure of 20.5% per annum. It is important that precautions are taken to protect workers from a hazardous exposure to wood dust at the premises as the SOEL of 2 mg m-3 at some occasions is still exceeded. Additional measurements of wood dust exposure should be carried out on a regular basis in wood pellet production units in Sweden as well in other countries. PMID- 28355461 TI - Isavuconazole: is there a need for a new antifungal? PMID- 28355462 TI - Changes in the epidemiological landscape of invasive mould infections and disease. AB - Although a wide variety of pathogens are associated with invasive mould diseases, Aspergillus spp. have historically been one of the most common causative organisms. Most invasive mould infections are caused by members of the Aspergillus fumigatus species complex and an emerging issue is the occurrence of azole resistance in A. fumigatus, with resistance to amphotericin B documented in other Aspergillus spp. The epidemiology of invasive fungal disease has shifted in recent years as non-A. fumigatus Aspergillus spp. and other moulds have become progressively more important, although there are no consolidated data on the prevalence of less common species of moulds. The incidence of mucormycosis may have been underestimated, which is a potential concern since species belonging to the order Mucorales are more resistant to antifungal agents than Aspergillus spp. All species of Mucorales are unaffected by voriconazole and most show moderate resistance in vitro to echinocandins. Fusarium spp. may be the second most common nosocomial fungal pathogen after Aspergillus in some tertiary hospitals, and show a susceptibility profile marked by a higher level of resistance than that of Aspergillus spp. Recently, Scedosporium aurantiacum has been reported as an emerging opportunistic pathogen, against which voriconazole is the most active antifungal agent. Other mould species can infect humans, although invasive fungal disease occurs less frequently. Since uncommon mould species exhibit individual susceptibility profiles and require tailored clinical management, accurate classification at species level of the aetiological agent in any invasive fungal disease should be regarded as the standard of care. PMID- 28355463 TI - Therapeutic drug monitoring for invasive mould infections and disease: pharmacokinetic and pharmacodynamic considerations. AB - Therapeutic drug monitoring (TDM) may be required to achieve optimal clinical outcomes in the setting of significant pharmacokinetic variability, a situation that applies to a number of anti-mould therapies. The majority of patients receiving itraconazole should routinely be managed with TDM. Voriconazole exhibits highly variable inter-individual pharmacokinetics, and a trough concentration of 1.0-5.5 mg/L is widely accepted although it is derived from relatively low-quality evidence. The case for TDM of posaconazole is currently in a state of flux following the introduction of a newer tablet formulation with improved oral bioavailability, but it may be indicated when used for either prophylaxis or treatment of established disease. The novel broad-spectrum azole drug isavuconazole does not currently appear to require TDM but 'real-world' data are awaited and TDM could be considered in selected clinical cases. For both polyene and echinocandin agents, there are insufficient data regarding the relationship between serum concentrations and therapeutic outcomes to support the routine use of TDM. A number of practical challenges to the implementation of TDM in the treatment of invasive mould infections remain unsolved. The delivery of TDM as a future standard of care will require real-time measurement of drug concentrations at the bedside and algorithms for dosage adjustment. Finally, measures of pharmacodynamic effect are required to deliver therapy that is truly individualized. PMID- 28355464 TI - Early diagnosis of invasive mould infections and disease. AB - Invasive mould infections (IMIs), such as invasive aspergillosis or mucormycosis, are a major cause of death in patients with haematological cancer and in patients receiving long-term immunosuppressive therapy. Early diagnosis and prompt initiation of antifungal therapy are crucial steps in the management of patients with IMI. The diagnosis of IMI remains a major challenge, with an increased spectrum of fungal pathogens and a diversity of clinical and radiological presentations within the expanding spectrum of immunocompromised hosts. Diagnosis is difficult to establish and is expressed on a scale of probability (proven, probable and possible). Imaging (CT scan), microbiological tools (direct examination, culture, PCR, fungal biomarkers) and histopathology are the pillars of the diagnostic work-up of IMI. None of the currently available diagnostic tests provides sufficient sensitivity and specificity alone, so the optimal approach relies on a combination of multiple diagnostic strategies, including imaging, fungal biomarkers (galactomannan and 1,3-beta-d-glucan) and molecular tools. In recent years, the development of PCR for filamentous fungi (primarily Aspergillus or Mucorales) and the progress made in the standardization of fungal PCR technology, may lead to future advances in the field. The appropriate diagnostic approach for IMI should be individualized to each centre, taking into account the local epidemiology of IMI and the availability of diagnostic tests. PMID- 28355465 TI - Clinical considerations in the early treatment of invasive mould infections and disease. AB - Different therapeutic strategies for invasive fungal diseases have been explored, each with particular strengths and weaknesses. Broad-spectrum antifungal prophylaxis seems logical, but selective use is important due to its substantial disadvantages, including interference with diagnostic assays, selection for resistance, drug toxicity and drug-drug interactions. Antimould prophylaxis should be restricted to high-risk groups, such as patients undergoing intensive chemotherapy for acute myeloid leukaemia or myelodysplastic syndrome, allogeneic HSCT patients with prior invasive fungal infection, graft-versus-host-disease or extended neutropenia, recipients of a solid organ transplant, or patients with a high-risk inherited immunodeficiency. An empirical approach, whereby mould-active therapy is started in neutropenic patients with fever unresponsive to broad spectrum antibiotics, is widely applied but incurs the clinical and cost penalties associated with overtreatment. A benefit for all-cause mortality using empirical therapy has not been shown, but it is recommended for high-risk patients who remain febrile after 4-7 days of broad-spectrum antibiotics and in whom extended neutropenia is anticipated. There is growing interest in delaying antifungal treatment until an invasive fungal infection is confirmed ('pre emptive' or 'diagnostics-driven' management), prompted by the development of more sensitive diagnostic techniques. Comparisons of empirical versus pre-emptive regimens are sparse, particularly with modern triazole agents, but treatment costs are lower with pre-emptive therapy and the available evidence has not indicated reduced efficacy. Pre-emptive treatment may be appropriate in neutropenic patients who remain febrile after administration of broad-spectrum antibiotics but who are clinically stable. Further work is required to define accurately the specific patient subgroups in which each management approach is optimal. PMID- 28355466 TI - Invasive mould infections in the ICU setting: complexities and solutions. AB - Infections caused by filamentous fungi represent a major burden in the ICU. Invasive aspergillosis is emerging in non-neutropenic individuals with predisposing conditions, e.g. corticosteroid treatment, chronic obstructive pulmonary disease, liver cirrhosis, solid organ cancer, HIV infection and transplantation. Diagnosis is challenging because the signs and symptoms are non specific, and initiation of additional diagnostic examinations is often delayed because clinical suspicion is low. Isolation of an Aspergillus species from the respiratory tract in critically ill patients, and tests such as serum galactomannan, bronchoalveolar lavage 1-3-beta-d-glucan and specific PCR should be interpreted with caution. ICU patients should start adequate antifungal therapy upon suspicion of invasive aspergillosis, without awaiting definitive proof. Voriconazole, and now isavuconazole, are the drugs of choice. Mucormycosis is a rare, but increasingly prevalent disease that occurs mainly in patients with uncontrolled diabetes mellitus, immunocompromised individuals or previously healthy patients with open wounds contaminated with Mucorales. A high proportion of cases are diagnosed in the ICU. Rapidly progressing necrotizing lesions in the rhino-sinusal area, the lungs or skin and soft tissues are the characteristic presentation. Confirmation of diagnosis is based on demonstration of tissue invasion by non-septate hyphae, and by new promising molecular techniques. Control of underlying predisposing conditions, rapid surgical resection and administration of liposomal amphotericin B are the main therapeutic actions, but new agents such as isavuconazole are a promising alternative. Patients with mucormycosis receive a substantial part of their care in ICUs and, despite advances in diagnosis and treatment, mortality remains very high. PMID- 28355467 TI - New pharmacological opportunities for the treatment of invasive mould diseases. AB - Recently, several randomized studies have been published that will shape treatment decisions in the prevention and management of invasive mould infections. Liposomal amphotericin B is an option for empirical or targeted treatment of invasive aspergillosis or mucormycosis, but for prophylaxis therapy, the triazole class now predominates. The triazole voriconazole is currently regarded as a drug of choice for the treatment of proven or probable invasive aspergillosis, and has shown significantly higher response rates than amphotericin B deoxycholate in this setting, with fewer severe drug-related adverse events. Isavuconazole, the newest triazole agent, offers the advantages of once-daily dosing, a wider spectrum of antifungal activity than voriconazole, predictable pharmacokinetics and fewer CYP enzyme-mediated drug interactions. A recent large randomized clinical trial showed mortality to be similar under isavuconazole or voriconazole in patients with invasive mould disease, with fewer drug-related adverse events in isavuconazole-treated patients. Another study has indicated that isavuconazole is also effective in mucormycosis infections but patient numbers were small and confirmation is awaited. Experimental studies combining different drug classes with antimould activity have been promising, but the clinical database is limited. A large randomized trial of combination therapy compared voriconazole plus the echinocandin anidulafungin versus voriconazole monotherapy in patients with invasive aspergillosis. Results showed the overall response rate to be similar, but combination therapy improved survival for the subpopulation of patients in whom the diagnosis was confirmed by serum and/or bronchoalveolar lavage fluid galactomannan positivity. This active field of research is likely to continue evolving rapidly in the coming years. PMID- 28355471 TI - Moving From Static to Dynamic Models of the Onset of Mental Disorder: A Review. AB - Importance: In recent years, there has been increased focus on subthreshold stages of mental disorders, with attempts to model and predict which individuals will progress to full-threshold disorder. Given this research attention and the clinical significance of the issue, this article analyzes the assumptions of the theoretical models in the field. Observations: Psychiatric research into predicting the onset of mental disorder has shown an overreliance on one-off sampling of cross-sectional data (ie, a snapshot of clinical state and other risk markers) and may benefit from taking dynamic changes into account in predictive modeling. Cross-disciplinary approaches to complex system structures and changes, such as dynamical systems theory, network theory, instability mechanisms, chaos theory, and catastrophe theory, offer potent models that can be applied to the emergence (or decline) of psychopathology, including psychosis prediction, as well as to transdiagnostic emergence of symptoms. Conclusions and Relevance: Psychiatric research may benefit from approaching psychopathology as a system rather than as a category, identifying dynamics of system change (eg, abrupt vs gradual psychosis onset), and determining the factors to which these systems are most sensitive (eg, interpersonal dynamics and neurochemical change) and the individual variability in system architecture and change. These goals can be advanced by testing hypotheses that emerge from cross-disciplinary models of complex systems. Future studies require repeated longitudinal assessment of relevant variables through either (or a combination of) micro-level (momentary and day-to-day) and macro-level (month and year) assessments. Ecological momentary assessment is a data collection technique appropriate for micro-level assessment. Relevant statistical approaches are joint modeling and time series analysis, including metric-based and model-based methods that draw on the mathematical principles of dynamical systems. This next generation of prediction studies may more accurately model the dynamic nature of psychopathology and system change as well as have treatment implications, such as introducing a means of identifying critical periods of risk for mental state deterioration. PMID- 28355472 TI - Drag Reduction in a Natural High-Frequency Swinging Micro-Articulation: Mouthparts of the Honey Bee. AB - Worker-bee mouthparts consist of the glossa, the galeae and the vestigial labial palp, and it is these structures that enable bees to feed themselves. The articulation joints, 60~70 um in diameter, are present on the tip of the labial palp and are covered with olfactory sensilla, allowing movements between the segments. Using a specially designed high-speed camera system, we discovered that the articulation joint could swing in the nectar at a frequency of ~50 Hz, considerably higher than the usual motion frequency of mammalian joints. To understand the potential drag reduction in this tiny organ, we examined its microstructure and also its surface wettability. We found that chitinous semispherical protuberances (4~6 um in diameter) are uniformly scattered on the surface of the joint and, moreover, that the surface is hydrophobic. We proposed a hydrodynamic model and revealed that the specialized surface can effectively reduce the mean equivalent friction (Ff) by ~10%, through the use of protuberances immersed in the liquid feed. Theoretical results indicated that the dimensions of such protuberances are the predominant factor in minimizing Ff, and that the natural dimensions of the protuberances are close to the theoretical optimum at which friction is at a minimum. These discoveries may inspire the design of high-frequency micro-joints for engineering applications, such as in micro-stirrers. PMID- 28355473 TI - Response of Chrysoperla nipponensis (Okamoto) (Neuroptera: Chrysopidae) Under Long and Short Photoperiods. AB - C. nipponensis: Photoperiod is an important factor influencing many biological processes including population dynamics of many insect species in temperate zones. To determine the population response of Chrysoperla nipponensis under altered conditions (high temperature and short photoperiod) and to test whether the short photoperiod was suitable for artificial storage, the life table data of were collected at 25 degrees C under a long photoperiod, 15:9 h (L:D), and a short photoperiod, 9:15 h (L:D) and analyzed using the age-stage, two-sex life table approach. We found that developed faster under long photoperiod than under the short photoperiod. The shorter developmental time, higher fecundity, and higher proportion of females found during the long photoperiod resulted in higher intrinsic and net reproductive rates, but a shorter mean generation time and life expectancy compared to those reared during the short photoperiod. Individuals reared under the short photoperiod also had a high reproductive value. Population projection demonstrated that reared at long photoperiod would complete four generations in 150 d, while reared under short photoperiod would just be entering the second generation. Our results demonstrated that the different fitness values obtained for individuals by varying photoperiod lengths, were readily distinguishable when using the age-stage, two-sex life table. PMID- 28355474 TI - Geographical Distribution Patterns and Niche Modeling of the Iconic Leafcutter Ant Acromyrmex striatus (Hymenoptera: Formicidae). AB - Ants are considered one of the most successful groups in the planet's evolutionary history. Among them highlights the fungus-farming ants of the genera Atta and Acromyrmex that occur throughout most of the Americas. Within the Acromyrmex genus, the species A. striatus distinguishes from other Acromyrmex species as its morphology and karyotype differ from its congeners. This species is found in open environments of dry climate in the southern States of Brazil, Argentina, Paraguay and Uruguay; however, little is known about the current distribution of the species. This article aimed to investigate the current distribution of the species by compiling its known distribution and discussing its distributional range. To achieve this, published and unpublished data obtained through a literature search and active collections in various locations were compiled. Published and unpublished data revealed that 386 colonies were recorded, distributed across four countries where its occurrence is known. Environmental factors, such as temperature, humidity, soil type and vegetation, as well as historical geological and climate events that have modified Earth's surface may have influenced species distribution patterns. In the Neotropics, the environmental factors that most impacted the distribution of species were the glaciation periods that occurred in the Quaternary, leading to a great migratory process. These factors may have contributed to the current geographical distribution of A. striatus. PMID- 28355476 TI - Illustrated Key to Species of Genus Dendroctonus (Coleoptera: Curculionidae) Occurring in Mexico and Central America. AB - We provide an illustrated key of species of Dendroctonus Erichson from Mexico and Central America based on characters of the male genitalia and external morphology. The key incorporates newly identified diagnostic characters for this genus that enhance discrimination of particularly difficult sibling species. PMID- 28355475 TI - Identification and Evaluation of Suitable Reference Genes for Normalization of MicroRNA Expression in Helicoverpa armigera (Lepidoptera: Noctuidae) Using Quantitative Real-Time PCR. AB - More and more studies have focused on microRNAs (miRNAs) expression in the pest Helicoverpa armigera (Lepidoptera: Noctuidae) recently. Quantitative real-time PCR (qRT-PCR) is being widely used in miRNA expression studies. Suitable reference genes are necessary for the correct analysis of results. In this study, 10 candidate genes of H. armigera were selected and analyzed for their expression stability under different biotic and abiotic conditions with 3 statistical methods, including geNorm, NormFinder, and Bestkeeper. Combination the best number of reference genes was calculated by geNorm. One target gene, let-7, was used to validate the selection of reference genes. The suitable candidate reference genes were shown as follows: miR-9 and U6 snRNA for developmental stages, miR-100 and U6 snRNA for larval tissues, miR-100 and miR-305 for adult tissues, miR-9 and miR-279 for parasitic treatment, miR-998 and U6 snRNA for nuclear polyhedrosis virus infection, miR-9 and U6 snRNA for insecticide treatment, miR-92a, miR-100, and miR-279 for temperature treatment, miR-92a, miR 305, and miR-998 for starvation treatment, miR-9 and miR-279 for light treatment, miR-305 and miR-998 for hormone treatment, and there was not one reference gene suitable for all samples. This study could promote future research on miRNAs expression in H. armigera with optimal reference genes under different experimental conditions. PMID- 28355477 TI - Population Growth Parameters of Tuta absoluta (Lepidoptera: Gelechiidae) on Tomato Plant Using Organic Substrate and Biofertilizers. AB - The tomato leafminer, Tuta absoluta (Meyrick) is a devastating pest associated with tomato. In this study, effects of tomato plants treated with vermicompost (20, 40, and 60%), humic fertilizer (2, 4 and 6 g/kg soil) and plant growth promoting rhizobacteria (Pseudomonas fluorescens and Bacillus subtilis) were investigated on the life table parameters of T. absoluta in a growth chamber at 25 +/- 2 degrees C, 65 +/- 5% RH, and 16:8 (L:D) h. Significant differences were found for the total developmental time, fecundity, and oviposition period of T. absoluta on the treatments tested. The net reproductive rate (R0), intrinsic rate of natural increase (rm), finite rate of increase (lambda), mean generation time (T), and doubling time (DT) of T. absoluta were significantly different among treatments tested. We found that in all vermicompost, humic fertilizer and plant growth promoting rhizobacteria treatments, values of R0, rm, and lambda were lower than control treatment. However, the lowest values of these parameters were obtained on 2 g/kg humic fertilizer and 40% vermicompost. Furthermore, T. absoluta had longest T and DT values on 2 g/kg humic fertilizer treatment. Data obtained showed that the addition of 2 g/kg humic fertilizer and 40% vermicompost to the growing soil reduced T. absoluta populations in tomato cultures. In addition, these levels of fertilizers improved growth parameters of tomato seedlings (plant height, wet weight, and dry weight) compared with other treatments. These results could be useful in improving the sustainable management of the moth. PMID- 28355478 TI - Local and Landscape Constraints on Coffee Leafhopper (Hemiptera: Cicadellidae) Diversity. AB - The intensification of agriculture drives many ecological and environmental consequences including impacts on crop pest populations and communities. These changes are manifested at multiple scales including small-scale management practices and changes to the composition of land-use types in the surrounding landscape. In this study, we sought to examine the influence of local and landscape-scale agricultural factors on a leafhopper herbivore community in Mexican coffee plantations. We sampled leafhopper (Hemiptera: Cicadellidae) diversity in 38 sites from 9 coffee plantations of the Soconusco region of Chiapas, Mexico. While local management factors such as coffee density, branches per coffee bush, tree species, and density were not important in explaining leafhopper abundance and richness, shade management at the landscape level and elevation significantly affected leafhoppers. Specifically, the percentage of low shade coffee in the landscape (1,000-m radius surrounding sites) increased total leafhopper abundance. In addition, Shannon's diversity of leafhoppers was increased with coffee density. Our results show that abundance and diversity of leafhoppers are greater in simplified landscapes, thereby suggesting that these landscapes will have higher pest pressure and may be more at-risk for diseases vectored by these species in an economically important crop. PMID- 28355480 TI - Orientation Inside Linear Nests by Male and Female Osmia bicornis (Megachilidae). AB - Numerous species of solitary bees and wasps build linear nests with only one entrance. Developing insects must orient themselves inside their nest to choose the correct direction in which to emerge. Misorientation and chewing towards the dead end of the nest can result in significant mortality. Most insects position themselves towards the nest entrance during cocoon construction; however, some individuals are misoriented. We tested whether imagines can examine and possibly correct their orientation after emerging from their cocoons. Males were usually able to correct their misoriented position based on the shape of the cell wall and emerged through the correct entrance, whereas most females pursued the direction that they faced in their cocoons. We suggest that there can be more than one time point during development when bees can control their position in relation to the nest entrance and that the importance of these time points varies between sexes. PMID- 28355479 TI - A General Approach to Test for Interaction Among Mixtures of Insecticidal Proteins Which Target Different Orders of Insect Pests. AB - A shift toward transgenic crops which produce combinations of insecticidal proteins has increased the interest (Syngenta Seeds, Inc., Minnetonka, MN) in studying the potential for interactions amongst those proteins. We present a general testing method which accommodates proteins with nonoverlapping spectrums of activity. Our sequential testing approach first investigates groups of the proteins with overlapping activity; e.g., proteins active against Lepidoptera or Coleoptera, respectively. The Colby method is used to test for interactions within each respective group. Subsequently, the mixture of proteins within each group is regarded as a single entity and tests for interactions between the groups (when combined) is conducted using analysis of variance. We illustrate the method using Cry1Ab, Vip3Aa20, and Cry1F (a mixture of proteins active against Lepidoptera), and mCry3A and eCry3.1Ab (a mixture of proteins active against Coleoptera). These insecticidal proteins are produced by Bt11 * MIR162 * TC1507 * MIR604 * 5307 maize. We detected no interactions between Cry1Ab, Vip3Aa20, and Cry1F in tests using larvae of two different lepidopteran species, and possible slight antagonism between mCry3A and eCry3.1Ab with a coleopteran test species. We detected no effect of (eCry3.1Ab + mCry3A) on the potency of (Cry1Ab + Vip3Aa20 + Cry1F) to lepidopteran larvae, and no effect of (Cry1Ab + Vip3Aa20 + Cry1F) on the potency of (mCry3A + eCry3.1Ab) to coleopteran larvae. We discuss implications of these results for characterization of Bt11 * MIR162 * TC1507 * MIR604 * 5307 maize, and the value of the method for characterizing other transgenic crops that produce several insecticidal proteins. PMID- 28355482 TI - gamma-Aminobutyric Acid (GABA) Accumulation in Tea (Camellia sinensis L.) through the GABA Shunt and Polyamine Degradation Pathways under Anoxia. AB - gamma-Aminobutyric acid (GABA) is an important bioactive component of tea (Camellia sinensis) providing various health benefits. We studied GABA accumulation via the GABA shunt and polyamine degradation pathways under anoxia in tea leaves. Anoxia caused a ~20-fold increment in GABA concentration, relative to fresh tea leaves. This increment was due to the increase of glutamate decarboxylase and diamine oxidase activities. Genes involved in GABA formation, such as CsGAD1 and CsGAD2, were significantly up-regulated by anoxia. The concentrations of putrescine and spermine, two substrates for GABA production, were also increased by anoxia. Treating tea leaves with aminoguanidine completely inhibited diamine oxidase activity during anoxia, but the concentration of GABA decreased by only ~25%. We infer that about one-fourth of GABA formed in tea leaves under anoxia comes from the polyamine degradation pathway, opening the possibility of producing GABA tea based through the regulation of metabolism. PMID- 28355481 TI - Mechanistic Studies of an Amine Oxidase Derived from d-Amino Acid Oxidase. AB - The flavoprotein d-amino acid oxidase has long served as a paradigm for understanding the mechanism of oxidation of amino acids by flavoproteins. Recently, a mutant d-amino acid oxidase (Y228L/R283G) that catalyzed the oxidation of amines rather than amino acids was described [Yasukawa, K., et al. (2014) Angew. Chem., Int. Ed. 53, 4428-4431]. We describe here the use of pH and kinetic isotope effects with (R)-alpha-methylbenzylamine as a substrate to determine whether the mutant enzyme utilizes the same catalytic mechanism as the wild-type enzyme. The effects of pH on the steady-state and rapid-reaction kinetics establish that the neutral amine is the substrate, while an active-site residue, likely Tyr224, must be uncharged for productive binding. There is no solvent isotope effect on the kcat/Km value for the amine, consistent with the neutral amine being the substrate. The deuterium isotope effect on the kcat/Km value is pH-independent, with an average value of 5.3, similar to values found with amino acids as substrates for the wild-type enzyme and establishing that there is no commitment to catalysis with this substrate. The kcat/KO2 value is similar to that seen with amino acids as the substrate, consistent with the oxidative half-reaction being unperturbed by the mutation and with flavin oxidation preceding product release. All of the data are consistent with the mutant enzyme utilizing the same mechanism as the wild-type enzyme, transfer of hydride from the neutral amine to the flavin. PMID- 28355483 TI - Gas-Phase Conformations and N-Glycosidic Bond Stabilities of Sodium Cationized 2' Deoxyguanosine and Guanosine: Sodium Cations Preferentially Bind to the Guanine Residue. AB - 2'-Deoxyguanosine (dGuo) and guanosine (Guo) are fundamental building blocks of DNA and RNA nucleic acids. In order to understand the effects of sodium cationization on the gas-phase conformations and stabilities of dGuo and Guo, infrared multiple photon dissociation (IRMPD) action spectroscopy experiments and complementary electronic structure calculations are performed. The measured IRMPD spectra of [dGuo+Na]+ and [Guo+Na]+ are compared to calculated IR spectra predicted for the stable low-energy structures computed for these species to determine the most favorable sodium cation binding sites, identify the structures populated in the experiments, and elucidate the influence of the 2'-hydroxyl substituent on the structures and IRMPD spectral features. These results are compared with those from a previous IRMPD study of the protonated guanine nucleosides to elucidate the differences between sodium cationization and protonation on structure. Energy-resolved collision-induced dissociation (ER-CID) experiments and survival yield analyses of protonated and sodium cationized dGuo and Guo are performed to compare the effects of these cations toward activating the N-glycosidic bonds of these nucleosides. For both [dGuo+Na]+ and [Guo+Na]+, the gas-phase structures populated in the experiments are found to involve bidentate binding of the sodium cation to the O6 and N7 atoms of guanine, forming a 5-membered chelation ring, with guanine found in both anti and syn orientations and C2'-endo (2T3 or 3T2) puckering of the sugar. The ER-CID results, IRMPD yields and the computed C1'-N9 bond lengths indicate that sodium cationization activates the N-glycosidic bond less effectively than protonation for both dGuo and Guo. The 2'-hydroxyl substituent of Guo is found to impact the preferred structures very little except that it enables a 2'OH...3'OH hydrogen bond to be formed, and stabilizes the N-glycosidic bond relative to that of dGuo in both the sodium cationized and protonated complexes. PMID- 28355484 TI - Podosome Force Generation Machinery: A Local Balance between Protrusion at the Core and Traction at the Ring. AB - Determining how cells generate and transduce mechanical forces at the nanoscale is a major technical challenge for the understanding of numerous physiological and pathological processes. Podosomes are submicrometer cell structures with a columnar F-actin core surrounded by a ring of adhesion proteins, which possess the singular ability to protrude into and probe the extracellular matrix. Using protrusion force microscopy, we have previously shown that single podosomes produce local nanoscale protrusions on the extracellular environment. However, how cellular forces are distributed to allow this protruding mechanism is still unknown. To investigate the molecular machinery of protrusion force generation, we performed mechanical simulations and developed quantitative image analyses of nanoscale architectural and mechanical measurements. First, in silico modeling showed that the deformations of the substrate made by podosomes require protrusion forces to be balanced by local traction forces at the immediate core periphery where the adhesion ring is located. Second, we showed that three-ring proteins are required for actin polymerization and protrusion force generation. Third, using DONALD, a 3D nanoscopy technique that provides 20 nm isotropic localization precision, we related force generation to the molecular extension of talin within the podosome ring, which requires vinculin and paxillin, indicating that the ring sustains mechanical tension. Our work demonstrates that the ring is a site of tension, balancing protrusion at the core. This local coupling of opposing forces forms the basis of protrusion and reveals the podosome as a nanoscale autonomous force generator. PMID- 28355485 TI - Rigidity Theory-Based Approximation of Vibrational Entropy Changes upon Binding to Biomolecules. AB - We introduce a computationally efficient approximation of vibrational entropy changes (DeltaSvib) upon binding to biomolecules based on rigidity theory. From constraint network representations of the binding partners, DeltaSvib is estimated from changes in the number of low frequency ("spongy") modes with respect to changes in the networks' coordination number. Compared to DeltaSvib computed by normal-mode analysis (NMA), our approach yields significant and good to fair correlations for data sets of protein-protein and protein-ligand complexes. Our approach could be a valuable alternative to NMA-based DeltaSvib computation in end-point (free) energy methods. PMID- 28355487 TI - Comparison of QM/MM Methods To Obtain Ligand-Binding Free Energies. AB - We have compared two approaches to calculate relative binding free energies employing molecular dynamics simulations at the combined quantum mechanical/molecular mechanics (QM/MM) level. As a test case, we study the binding of nine cyclic carboxylate ligands to the octa-acid deep-cavitand host system. The ligand is treated with the semiempirical PM6-DH+ QM method. In the first approach, we perform direct alchemical QM/MM free energy perturbation (FEP). In the second, reference-potential approach, we convert the ligands with FEP at the molecular mechanics (MM) level and then perform also MM -> QM/MM FEP for each ligand. We show that the two approaches give identical results within statistical uncertainty. For the reference-potential approach, the MM -> QM/MM perturbation converges in terms of energies, uncertainties, and overlap measures with two intermediate states, giving a precision of 0.5-0.9 kJ/mol for all eight transformations considered. On the other hand, the QM/MM-FEP approach requires 17 18 intermediate states, showing that the reference-potential approach is more effective. Previous calculations with single-step exponential averaging (i.e., entirely avoiding QM/MM simulations) required fewer QM/MM energy calculations, but they gave worse precision and involved approximations with an unclear effect on the results. PMID- 28355486 TI - Molecular Recognition in Mitochondrial Cytochromes P450 That Catalyze the Terminal Steps of Corticosteroid Biosynthesis. AB - The mitochondrial cytochromes P450 11B1 and P450 11B2 are responsible for the final stages of cortisol and aldosterone synthesis, respectively. Dysregulation of both enzymes has been implicated in secondary forms of hypertension. Molecular recognition of the cytochromes P450 with their corresponding redox partner is a key step in the catalytic cycle, yet the precise nature of the interaction of P450 11B1 or P450 11B2 with their proximal partner, adrenodoxin (Adx), is still unknown. Here, we obtained P450 11B1.Adx2 and P450 11B2.Adx2 complexes using the zero-length cross-linker ethyl-3-[3-(dimethylamino)propyl]carbodiimide, which formed best under low-ionic strength conditions. R-to-K mutations were introduced into the P450s at residues predicted to form salt bridges with Adx and allow cross-linking with the carbodiimide reagent. Mass spectrometric analysis of the chymotrypsin-digested ternary complexes identified seven cross-linked peptide pairs. Consistent with the electrostatic interaction of K370 in P450 11B1-WT and K366 in P450 11B2-R366K with D79 of Adx, Adx mutation L80K abolished complex formation. Using these sites of interaction as constraints, protein docking calculations based on the crystal structures of the two proteins yielded a structural model of the P450 11B1.Adx2 complex. The appositional surfaces include R/K366, K370, and K357 of P450 11B1, which interact with D79, D76, and D113 (second molecule) of Adx, respectively. Similar to P450 11B1, P450 11B2 also forms a complex with the Adx dimer via three lysine residues. We describe similarities and differences in our models of the P450 11B1.Adx2 and P450 11B2.Adx2 complexes with the structure of the P450 11A1-Adx fusion protein. PMID- 28355488 TI - Spectrophotometry of Thin Films of Light-Absorbing Particles. AB - Thin films of dispersions of light-absorbing solid particles or emulsions containing a light-absorbing solute all have a nonuniform distribution of light absorbing species throughout the sample volume. This results in nonuniform light absorption over the illuminated area, which causes the optical absorbance, as measured using a conventional specular UV-vis spectrophotometer, to deviate from the Beer-Lambert relationship. We have developed a theoretical model to account for the absorbance properties of such films, which are shown to depend on the size and volume fraction of the light-absorbing particles plus other sample variables. We have compared model predictions with measured spectra for samples consisting of emulsions containing a dissolved light-absorbing solute. Using no adjustable parameters, the model successfully predicts the behavior of nonuniform, light-absorbing emulsion films with varying values of droplet size, volume fraction, and other parameters. PMID- 28355489 TI - Encapsulation of Ibuprofen in CD-MOF and Related Bioavailability Studies. AB - Although ibuprofen is one of the most widely used nonsteroidal anti-inflammatory drugs (NSAIDs), it exhibits poor solubility in aqueous and physiological environments as a free acid. In order to improve its oral bioavailability and rate of uptake, extensive research into the development of new formulations of ibuprofen has been undertaken, including the use of excipients as well as ibuprofen salts, such as ibuprofen lysinate and ibuprofen, sodium salt. The ultimate goals of these studies are to reduce the time required for maximum uptake of ibuprofen, as this period of time is directly proportional to the rate of onset of analgesic/anti-inflammatory effects, and to increase the half-life of the drug within the body; that is, the duration of action of the effects of the drug. Herein, we present a pharmaceutical cocrystal of ibuprofen and the biocompatible metal-organic framework called CD-MOF. This metal-organic framework (MOF) is based upon gamma-cyclodextrin (gamma-CD) tori that are coordinated to alkali metal cations (e.g., K+ ions) on both their primary and secondary faces in an alternating manner to form a porous framework built up from (gamma-CD)6 cubes. We show that ibuprofen can be incorporated within CD-MOF-1 either by (i) a crystallization process using the potassium salt of ibuprofen as the alkali cation source for production of the MOF or by (ii) absorption and deprotonation of the free-acid, leading to an uptake of 23-26 wt % of ibuprofen within the CD MOF. In vitro viability studies revealed that the CD-MOF is inherently not affecting the viability of the cells with no IC50 value determined up to a concentration of 100 MUM. Bioavailability investigations were conducted on mice, and the ibuprofen/CD-MOF pharmaceutical cocrystal was compared to control samples of the potassium salt of ibuprofen in the presence and absence of gamma-CD. From these animal studies, we observed that the ibuprofen/CD-MOF-1 cocrystal exhibits the same rapid uptake of ibuprofen as the ibuprofen potassium salt control sample with a peak plasma concentration observed within 20 min, and the cocrystal has the added benefit of a 100% longer half-life in blood plasma samples and is intrinsically less hygroscopic than the pure salt form. PMID- 28355490 TI - Phylogenomic inferences from reference-mapped and de novo assembled short-read sequence data using RADseq sequencing of California white oaks (Quercus section Quercus). AB - The emergence of next generation sequencing has increased by several orders of magnitude the amount of data available for phylogenetics. Reduced representation approaches, such as restriction-sited associated DNA sequencing (RADseq), have proven useful for phylogenetic studies of non-model species at a wide range of phylogenetic depths. However, analysis of these datasets is not uniform and we know little about the potential benefits and drawbacks of de novo assembly versus assembly by mapping to a reference genome. Using RADseq data for 83 oak samples representing 16 taxa, we identified variants via three pipelines: mapping sequence reads to a recently published draft genome of Quercus lobata, and de novo assembly under two sets of locus filters. For each pipeline, we inferred the maximum likelihood phylogeny. All pipelines produced similar trees, with minor shifts in relationships within well-supported clades, despite the fact that they yielded different numbers of loci (68 000 - 111 000 loci) and different degrees of overlap with the reference genome. We conclude that both the reference-aligned and de novo assembly pipelines yield reliable results, and that advantages and disadvantages of these approaches pertain mainly to downstream uses of RADseq data, not to phylogenetic inference per se. PMID- 28355492 TI - Longitudinal Bone Mineralization Assessment in Children Treated With Long-Term Parenteral Nutrition for Severe Intestinal Failure. AB - BACKGROUND: Metabolic bone disease is common in children receiving home parenteral nutrition (HPN) for intestinal failure (IF). Long-term evolution of bone mass in pediatric IF is poorly documented. The aims of this study were (1) to determine the prevalence of low bone mass (LBM) in children receiving HPN for IF, (2) to evaluate the evolution of total bone mineral content (TBMC) during HPN with dual-energy x-ray absorptiometry (DXA), and (3) to identify related factors. METHODS: All children referred in our HPN center from 2004 to 2014 were eligible. Inclusion criteria were HPN dependence due to noninflammatory IF, at least 2 TBMC assessments, and HPN duration of at least 2 years at last DXA. TBMC was expressed in z score for ideal weight for height (WFH). LBM was defined by a TBMC WFH z score <=-2 standard deviations (SD). RESULTS: A total of 175 DXAs for 31 children were performed, mean of 5.6 +/- 2.9 assessments per child. The median time between first and last DXA recorded was 6.2 years (0.7-16.6). At the first DXA, 14 children (45%) had a LBM. TBMC increased by +0.1 +/- 0.04 SD per year of HPN ( P = .012). The risk of LBM decreased with an odds ratio of 0.9 per year of HPN (95% confidence interval, 0.92-0.99; P = .018). Lean mass z score and calcium parenteral intakes were related to the TBMC improvement. CONCLUSION: LBM is common in pediatric IF, but bone status could improve during HPN in these children. PMID- 28355491 TI - Suicide Ideation and Attempts among First Nations Peoples Living On-Reserve in Canada: The Intergenerational and Cumulative Effects of Indian Residential Schools. AB - OBJECTIVE: Suicide rates among Indigenous peoples in Canada are at least twice that of their non-Indigenous counterparts. Although contemporary stressors contribute to this increased risk, historical experiences such as the Indian Residential School (IRS) system may also have continuing links with the risk for suicidal thoughts and behaviors. The current investigation examined the intergenerational and cumulative links between familial IRS attendance in relation to lifetime suicide ideation and attempts among First Nations adults living on-reserve. METHOD: Data from the 2008-2010 First Nations Regional Health Survey were analyzed, and participants comprised a representative sample of First Nations adults older than 18 years (weighted N = 127,338; IRS attendees were excluded). Of those who knew their familial IRS history, 38.0% had no history of attendance, 19.3% had a grandparent who attended, 16.2% had a parent who attended, and 26.5% had a parent and grandparent who attended. RESULTS: Exposure of one previous familial generation to the IRS experience was associated with increased risk for lifetime suicide ideation (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.16 to 1.84; P = 0.001) and attempts (OR, 1.44; 95% CI, 1.07 to 1.94; P < 0.016) compared with those with no IRS history. Having 2 generations of IRS familial history was associated with greater odds of reporting a suicide attempt compared with having one generation (OR, 1.35; 95% CI, 1.05 to 1.75; P = 0.022), which was reduced when current levels of distress and ideation were accounted for. CONCLUSION: Findings support the existence of linkages between intergenerational exposure to IRS and risk for suicidal ideation and attempts and for a potential cumulative risk in relation to suicide attempts across generations. PMID- 28355493 TI - pfmdr1 (Plasmodium falciparum multidrug drug resistance gene 1): a pivotal factor in malaria resistance to artemisinin combination therapies. AB - INTRODUCTION: Plasmodium falciparum, the deadly agent of malaria, is notorious for its capacity to develop drug resistance. Treatment failures of artemisinin therapy regimens (ACTc), the present mainstay, is emerging. The transporter coding pfmdr1 gene is a central node in this process, having been associated with in vitro and in vivo parasite response to a broad range of ACT antimalarials. Areas covered: The review covers the historical origins of the pfmdr1 discovery, followed by a detailed description of its sequence and expression characteristics, as well as the structural and functional characteristics of its coded transmembrane protein. pfmdr1 association with ACT drugs response in vivo and in vitro is thoroughly reviewed. A reference is made to significant compounds presently in the development pipeline. The literature search was focused on Pubmed based searches with occasional resource to edited books, World Health Organization documentation and conference reports for adding valuable details. Expert commentary: Pfmdr1 has emerged as the central gene in P. falciparum ACT resistance. Understanding the basis of this role is critical for epidemiologic surveillance and design of improved resistance-refractory antimalarials. Specifically, unveiling situations of drug collateral sensitivity associated with specific pfmdr1 genetic variation will provide opportunities for personalized optimal therapy options. PMID- 28355494 TI - Potential methane emission reductions for two manure treatment technologies. AB - The effect of two dairy manure treatments, solid-liquid separation (SLS) and anaerobic digestion (AD), on methane potential and the speed of production was evaluated. Assays were performed in the lab to measure methane (CH4) production over 202 d from dairy manure samples taken before and after each treatment. Compared to raw manure, CH4 emissions on a per-L basis were reduced 81% by SLS and 59% by AD, on average. The mean (SD) ultimate CH4 emission potential (B0) per kg of volatile solids (VS) was 247 (8) L CH4 kg-1 VS for raw manure, 221 (9) L CH4 kg-1 VS for separated liquid, and 160 (4) L CH4 kg-1 VS for anaerobic digestate. Thus, SLS reduced the B0 of the liquid fraction by 11% and AD reduced B0 by up to 35% compared to raw manure. Manure treatment affected the speed of CH4 production: SLS increased the CH4 production rate and thus separated liquid manure was the fastest to produce 90% of the ultimate CH4 production. Therefore, both the speed of degradation and B0 should be considered when assessing these techniques for farm-scale manure storages, because actual emission reductions will depend on storage conditions. PMID- 28355495 TI - A novel polyaspartic acid derivative with multifunctional groups for scale inhibition application. AB - Polyaspartic acid is a green biodegradable antiscalant and widely applied in water treatment field. However, its scale inhibition efficiency is not prominent, especially for calcium orthophosphate. So we introduced acylamino and hydroxyl groups simultaneously to prepare a novel polyaspartic-acid derivative (PASPTU) with multifunctional groups by the reaction of polysuccinimide with threonine and urea. The graft copolymer was analyzed by using nuclear magnetic resonance, gel permeation chromatography, thermogravimetric analyzer and Fourier transform infrared spectroscopy. Its scale inhibition performance for calcium orthophosphate, calcium sulfate and calcium carbonate was evaluated. The findings showed that the scale inhibition rates of the graft copolymer reached up to 100% for calcium orthophosphate, 100% for calcium sulfate and 91% for calcium carbonate at certain dosages. The findings above showed that the copolymer had excellent scale inhibition efficiency for calcium salts in water treatment processes. PMID- 28355496 TI - Recovery of ammonia through struvite production using anaerobic digestate of piggery wastewater and leachate of sewage sludge ash. AB - Anaerobic digestate of piggery wastewater (ADPW) contains high concentrations of ammonia and phosphorus with unbalanced molar ratio. Thus, ammonia remains at a high level even after phosphorus is completely removed through struvite formation. In this study, both ammonia and phosphorus were recovered by adding leachate of sewage sludge ash (SSA) into ADPW. It was demonstrated that 11,600 mg L-1 of total phosphorus and 7266.7 mg L-1 of [Formula: see text]-P were extracted from SSA by using sulfuric acid at the H2SO4/SSA mass ratio of 0.35. ADPW and the leachate of SSA were mixed at the volumetric ratio of 1:1.29, and then struvite was formed at the molar ratio of 1.2 (Mg2+):1.0 ([Formula: see text]-P):1.0 (NH3 N). Removal efficiencies of ammonia and phosphorus were 91.95% and 99.65%, respectively. The obtained struvite was analyzed by various methods and was found to meet the Korean fertilizer standards, except for copper. PMID- 28355497 TI - Molecular characterization of dihydroneopterin aldolase and aminodeoxychorismate synthase in common bean-genes coding for enzymes in the folate synthesis pathway. AB - Common beans (Phaseolus vulgaris) are excellent sources of dietary folates, but different varieties contain different amounts of these compounds. Genes coding for dihydroneopterin aldolase (DHNA) and aminodeoxychorismate synthase (ADCS) of the folate synthesis pathway were characterized by PCR amplification, BAC clone sequencing, and whole genome sequencing. All DHNA and ADCS genes in the Mesoamerican cultivar OAC Rex were isolated and compared with those genes in the genome of Andean genotype G19833. Both genotypes have two functional DHNA genes and one pseudo gene. PvDHNA1 and PvDHNA2 proteins have similar secondary structures and conserved residues as DHNA homologs in Staphylococcus aureus and Arabidopsis. Sequence analysis and synteny mapping indicated that PvDHNA1 might be a duplicated and transposed copy of PvDHNA2. There is only one ADCS gene (PvADCS) identified in the bean genome and it is identical in OAC Rex and G19833. PvADCS has the conserved motifs required for catalytic activity similar to other plant ADCS homologs. DHNA and ADCS gene-specific markers were developed, mapped, and compared to their physical locations on chromosomes 1 and 7, respectively. The gene-specific markers developed in this study should be useful for detection and selection of varieties with enhanced folate contents in bean breeding programs. PMID- 28355498 TI - Multispectral Optoacoustic Tomography for Assessment of Crohn's Disease Activity. PMID- 28355499 TI - Quadrivalent HPV Vaccination and the Risk of Adverse Pregnancy Outcomes. AB - BACKGROUND: The quadrivalent human papillomavirus (HPV) vaccine is recommended for all girls and women 9 to 26 years of age. Some women will have inadvertent exposure to vaccination during early pregnancy, but few data exist regarding the safety of the quadrivalent HPV vaccine in this context. METHODS: We assessed a cohort that included all the women in Denmark who had a pregnancy ending between October 1, 2006, and November 30, 2013. Using nationwide registers, we linked information on vaccination, adverse pregnancy outcomes, and potential confounders among women in the cohort. Women who had vaccine exposure during the prespecified time windows were matched for propensity score in a 1:4 ratio with women who did not have vaccine exposure during the same time windows. Outcomes included spontaneous abortion, stillbirth, major birth defect, small size for gestational age, low birth weight, and preterm birth. RESULTS: In matched analyses, exposure to the quadrivalent HPV vaccine was not associated with significantly higher risks than no exposure for major birth defect (65 cases among 1665 exposed pregnancies and 220 cases among 6660 unexposed pregnancies; prevalence odds ratio, 1.19; 95% confidence interval [CI], 0.90 to 1.58), spontaneous abortion (20 cases among 463 exposed pregnancies and 131 cases among 1852 unexposed pregnancies; hazard ratio, 0.71; 95% CI, 0.45 to 1.14), preterm birth (116 cases among 1774 exposed pregnancies and 407 cases among 7096 unexposed pregnancies; prevalence odds ratio, 1.15; 95% CI, 0.93 to 1.42), low birth weight (76 cases among 1768 exposed pregnancies and 277 cases among 7072 unexposed pregnancies; prevalence odds ratio, 1.10; 95% CI, 0.85 to 1.43), small size for gestational age (171 cases among 1768 exposed pregnancies and 783 cases among 7072 unexposed pregnancies; prevalence odds ratio, 0.86; 95% CI, 0.72 to 1.02), or stillbirth (2 cases among 501 exposed pregnancies and 4 cases among 2004 unexposed pregnancies; hazard ratio, 2.43; 95% CI, 0.45 to 13.21). CONCLUSIONS: Quadrivalent HPV vaccination during pregnancy was not associated with a significantly higher risk of adverse pregnancy outcomes than no such exposure. (Funded by the Novo Nordisk Foundation and the Danish Medical Research Council.). PMID- 28355500 TI - Case 10-2017 - A 6-Month-Old Boy with Gastrointestinal Bleeding and Abdominal Pain. PMID- 28355501 TI - U.S. Nutrition Assistance, 2018 - Modifying SNAP to Promote Population Health. PMID- 28355502 TI - Motorcycle-Helmet Laws and Public Health. PMID- 28355503 TI - From Trial to Target Populations - Calibrating Real-World Data. PMID- 28355504 TI - Acute Kidney Injury in Critically Ill Children and Young Adults. PMID- 28355505 TI - Acute Kidney Injury in Critically Ill Children and Young Adults. PMID- 28355506 TI - Convalescent Plasma and the Dose of Ebola Virus Antibodies. PMID- 28355507 TI - Convalescent Plasma and the Dose of Ebola Virus Antibodies. PMID- 28355508 TI - Myasthenia Gravis. PMID- 28355510 TI - Tumbu Fly Larvae. PMID- 28355509 TI - Prostate Cancer Screening - A Perspective on the Current State of the Evidence. PMID- 28355512 TI - Under Pressure. PMID- 28355511 TI - Docosahexaenoic Acid and Bronchopulmonary Dysplasia in Preterm Infants. AB - BACKGROUND: Studies in animals and in humans have suggested that docosahexaenoic acid (DHA), an n-3 long-chain polyunsaturated fatty acid, might reduce the risk of bronchopulmonary dysplasia, but appropriately designed trials are lacking. METHODS: We randomly assigned 1273 infants born before 29 weeks of gestation (stratified according to sex, gestational age [<27 weeks or 27 to <29 weeks], and center) within 3 days after their first enteral feeding to receive either an enteral emulsion providing DHA at a dose of 60 mg per kilogram of body weight per day or a control (soy) emulsion without DHA until 36 weeks of postmenstrual age. The primary outcome was bronchopulmonary dysplasia, defined on a physiological basis (with the use of oxygen-saturation monitoring in selected infants), at 36 weeks of postmenstrual age or discharge home, whichever occurred first. RESULTS: A total of 1205 infants survived to the primary outcome assessment. Of the 592 infants assigned to the DHA group, 291 (49.1% by multiple imputation) were classified as having physiological bronchopulmonary dysplasia, as compared with 269 (43.9%) of the 613 infants assigned to the control group (relative risk adjusted for randomization strata, 1.13; 95% confidence interval [CI], 1.02 to 1.25; P=0.02). The composite outcome of physiological bronchopulmonary dysplasia or death before 36 weeks of postmenstrual age occurred in 52.3% of the infants in the DHA group and in 46.4% of the infants in the control group (adjusted relative risk, 1.11; 95% CI, 1.00 to 1.23; P=0.045). There were no significant differences between the two groups in the rates of death or any other neonatal illnesses. Bronchopulmonary dysplasia based on a clinical definition occurred in 53.2% of the infants in the DHA group and in 49.7% of the infants in the control group (P=0.06). CONCLUSIONS: Enteral DHA supplementation at a dose of 60 mg per kilogram per day did not result in a lower risk of physiological bronchopulmonary dysplasia than a control emulsion among preterm infants born before 29 weeks of gestation and may have resulted in a greater risk. (Funded by the Australian National Health and Medical Research Council and others; Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820 .). PMID- 28355513 TI - Ensuring Vaccine Safety in Pregnant Women. PMID- 28355514 TI - Maternal Immunization. PMID- 28355515 TI - Shortened Antimicrobial Treatment for Acute Otitis Media. PMID- 28355516 TI - Kaposi's Sarcoma of the Oral Cavity. PMID- 28355517 TI - Repurposing a Bacterial Immune System to Discover Antiviral Targets. PMID- 28355519 TI - Errata. PMID- 28355518 TI - Code-based Diagnostic Algorithms for Idiopathic Pulmonary Fibrosis. Case Validation and Improvement. AB - RATIONALE: Population-based studies of idiopathic pulmonary fibrosis (IPF) in the United States have been limited by reliance on diagnostic code-based algorithms that lack clinical validation. OBJECTIVES: To validate a well-accepted International Classification of Diseases, Ninth Revision, code-based algorithm for IPF using patient-level information and to develop a modified algorithm for IPF with enhanced predictive value. METHODS: The traditional IPF algorithm was used to identify potential cases of IPF in the Kaiser Permanente Northern California adult population from 2000 to 2014. Incidence and prevalence were determined overall and by age, sex, and race/ethnicity. A validation subset of cases (n = 150) underwent expert medical record and chest computed tomography review. A modified IPF algorithm was then derived and validated to optimize positive predictive value. RESULTS: From 2000 to 2014, the traditional IPF algorithm identified 2,608 cases among 5,389,627 at-risk adults in the Kaiser Permanente Northern California population. Annual incidence was 6.8/100,000 person-years (95% confidence interval [CI], 6.1-7.7) and was higher in patients with older age, male sex, and white race. The positive predictive value of the IPF algorithm was only 42.2% (95% CI, 30.6 to 54.6%); sensitivity was 55.6% (95% CI, 21.2 to 86.3%). The corrected incidence was estimated at 5.6/100,000 person years (95% CI, 2.6-10.3). A modified IPF algorithm had improved positive predictive value but reduced sensitivity compared with the traditional algorithm. CONCLUSIONS: A well-accepted International Classification of Diseases, Ninth Revision, code-based IPF algorithm performs poorly, falsely classifying many non IPF cases as IPF and missing a substantial proportion of IPF cases. A modification of the IPF algorithm may be useful for future population-based studies of IPF. PMID- 28355520 TI - Errata. PMID- 28355521 TI - Errata. PMID- 28355522 TI - Errata. PMID- 28355523 TI - Errata. PMID- 28355524 TI - Ten years on: a review of medical terminations of pregnancy performed in a sexual health clinic. AB - : Background Access to medical termination of pregnancy (MToP) services in regional Queensland remains inadequate and it is still possible for women and providers to be criminally prosecuted for accessing or providing abortion. Cairns Sexual Health Service (CSHS) has been providing medical terminations of pregnancy for 10 years, demonstrating that this service can be safely and successfully integrated into a primary healthcare setting. METHODS: A retrospective audit of MToPs performed between 2011 and 2015 was conducted to follow on from our previously reported audit covering 2006-09. RESULTS: In total, 1859 MToPs have been performed by CHSH since 2006, with 1712 within the 5-year period of 2011-15. Changes in clinical practice over this time have streamlined the service and reduced unsuccessful outcomes from 12.2% between 2006 and 2009 to 0.9% between 2011 and 2015. CONCLUSION: The initial provision of MToP through CSHS was anticipated to be a short-term arrangement; however, 10 years on, this service continues with strong community demand. Provision of MToP services through primary healthcare settings can help improve access for women living outside of major metropolitan areas. If moves to decriminalise abortion in Queensland are successful, there is potential for even greater access. PMID- 28355525 TI - Time to wait: a systematic review of strategies that affect out-patient waiting times. AB - Objective Out-patient waiting times pose a significant challenge for public patients in need of specialist evaluation and intervention. The aim of the present study was to identify and categorise effective strategies to reduce waiting times for specialist out-patient services with a focus on the Australian healthcare system. Methods A systematic review of major health databases was conducted using the key terms 'outpatient*' AND 'waiting time', 'process*' AND 'improvement in outpatient clinics'. Identified articles were assessed for their relevance by sequential review of the title, abstract and full text. References of the selected manuscripts were scanned for additional relevant articles. Selected articles were evaluated for consistent and emerging themes. Results In all, 152 articles were screened, of which 38 were included in the present review. Numerous strategies identified in the articles were consolidated into 26 consistent approaches. Three overarching themes were identified as significantly affecting waiting times: resource realignment, operational efficiency and process improvement. Conclusions Strategies to align resources, increase operational efficiency and improve processes provide a comprehensive approach that may reduce out-patient waiting times. What is known about the topic? Out-patient waiting times are a challenge in most countries that seek to provide universal access to health care for all citizens. Although there has been extensive research in this area, many patients still experience extensive delays accessing specialist care, particularly in the public health sector. The multiple factors that contribute to bottlenecks and inefficiencies in the referral process and affect patient waiting times are often poorly understood. What does this paper add? This paper reviews the published healthcare literature to identify strategies that affect specialist out-patient waiting times for patients. The findings suggest that there are numerous operational strategies that affect waiting times. These strategies may be categorised into three overarching themes (resource alignment, operational efficiencies and out-patient processes) that, when actioned in a coordinated approach, have the potential to significantly reduce out-patient waiting times. What are the implications for practitioners? This paper identifies evidence-based strategies for aligning resources, improving operational efficiency and streamlining processes, which may provide improvements to specialist out-patient waiting times for patients. Addressing the identified organisational, person related, cultural and attitudinal factors will assist health system managers and health practitioners target the most appropriate improvement activities to reduce waiting times. PMID- 28355526 TI - Community knowledge of law at the end of life: availability and accessibility of web-based resources. AB - Objective The aim of the present study was to identify online resources community members may access to inform themselves about their legal duties and rights in end-of-life decision making. Methods Resource mapping identified online resources that members of the public in New South Wales, Victoria and Queensland are likely to identify, and assessed the ease or difficulty in locating them. Resources were then critically analysed for accessibility of language and format using the Patient Education Materials Assessment Tool (PEMAT). Results Identified resources differed considerably based on whether search terms identified by community members or experts were used. Most resources focused on advance directives, enduring powers of attorney and substitute decision making. Relatively few provided information about legal duties (e.g. powers and responsibilities of substitute decision makers) or resolving conflict with health practitioners. Accessibility (understandability and actionability) of resource content varied. Conclusions Although numerous resources on end-of-life law are available online, community members may not be able to identify relevant resources or find resource content accessible. What is known about the topic? Research on participation by patients in decision making about their treatment has focused primarily on medical rather than legal knowledge. What does this paper add? The present study investigated which online resources community members may access to inform themselves about the law on end-of-life decision making. The resources identified were analysed for ease of location and content accessibility. What are the implications for practitioners? Authors of online resources on end-of-life decision making should consider whether their resources can be: (1) identified by search terms used by the public; (2) understood by a general audience; and (3) readily used to promote reader action. PMID- 28355527 TI - Feasibility evaluation of a pilot scribe-training program in an Australian emergency department. AB - Objective Medical scribes have an emerging and expanding role in health, particularly in Emergency Medicine in the US. Scribes assist physicians with documentation and clerical tasks at the bedside while the physician consults with his or her patient. Scribes increase medical productivity. The aim of the present study was to examine the feasibility of a pilot hospital-administered scribe training program in Australia and to evaluate the ability of an American training course (Medical Scribe Training Systems) to prepare trainee scribes for clinical training in an emergency department in Australia. Methods The present study was a pilot, prospective, observational cohort study from September 2015 to February 2016 at Cabrini Emergency Department, Melbourne. Scribe trainees were enrolled in the pre-work course and then trained clinically. Feasibility of training scribes and limited efficacy testing of the course was undertaken. Results The course was acceptable to users and demand for training exists. There were many implementation tasks and issues experienced and resources were required to prepare the site for scribe implementation. Ten trainees were enrolled for preclinical training. Six candidates undertook clinical training, five achieved competency (required seven to 16 clinical shifts after the preclinical course). The training course was helpful and provided a good introduction to the scribe role. The course required adaptation to a non-US setting and the specific hospital setting. In addition, it needed more detail in some common emergency department topics. Conclusion Training scribes at a hospital in Australia is feasible. The US training course used can assist with preclinical training. Course modification is required. What is known about the topic? Scribes increase emergency physician productivity in Australia. There is no previous work on how to train scribes in Australia. What does this paper add? We show that implementing a scribe-training program is feasible and that a training package can be purchased from the US to train scribes in Australia and that it is useful. We also show the adaptation that the course may require to meet Australian emergency department needs. What are the implications for practitioners? Scribes could become an additional member of the emergency department team in Australia and can be trained locally. PMID- 28355528 TI - Making every Australian count: challenges for the National Disability Insurance Scheme (NDIS) and the equal inclusion of homeless Aboriginal and Torres Strait Islander Peoples with neurocognitive disability. AB - This article highlights the dearth of accurate evidence available to inform the National Disability Insurance Scheme (NDIS) regarding the extent and nature of neurocognitive disability amongst homeless Aboriginal and Torres Strait Islander people. Without accurate prevalence rates of neurocognitive disability, homeless Aboriginal and Torres Strait Islander people are in danger of not being counted by the NDIS and not receiving supports to which they are entitled. Addressing this knowledge gap is challenged by a range of factors, including: (1) the long term effect of profound intergenerational disenfranchisement of Aboriginal and Torres Strait Islander people; (2) Aboriginal and Torres Strait Islander cultural perspectives around disability; (3) the generally unrecognised and poorly understood nature of neurocognitive disability; (4) the use of research methods that are not culturally safe; (5) research logistics; and (6) the absence of culturally appropriate assessment tools to identify prevalence. It is argued that an accurate evidence base that is informed by culturally safe research methods and assessment tools is needed to accurately guide the Commonwealth government and the National Disability Insurance Agency about the expected level of need for the NDIS. Research within this framework will contribute to the realisation of a truly inclusive NDIS. PMID- 28355529 TI - Allied health leadership in New South Wales: a study of perceptions and priorities of allied health leaders. AB - Objective The aim of the present study was to investigate the opinions and perceptions of senior allied health (AH) leaders in relation to AH leadership, governance and organisation from an Australian public health perspective. The target group was the New South Wales (NSW) Health AH directors or advisors, the most senior public AH professionals in NSW. Methods The study was conducted over a 6-month period in 2014-15 and comprised two parts: (1) data collection through a 46-question online survey that sought the views of AH leaders about the field of AH in NSW; and (2) two confirmatory focus groups with members of the NSW Health Allied Health Directors Committee. Results The online questionnaire generated novel information about the field of AH in the public sector of NSW, including the current organisation, governance and culture of AH. Focus group participants explored key findings in greater depth, including the effects of AH on and value of AH to the health system as a whole, as well as the attributes and competencies required by AH leaders. Participants identified the need to build and grow their influence, to more clearly demonstrate AH's contribution and to realign efforts towards more strategic issues influencing governance, performance, professional standards and advocacy. This entailed broadening the vision and scope of AH Directors as well as across discipline leaders. Conclusion The results provide new information about Australian AH leadership, governance, culture and organisation, and highlight potential priorities for future leadership activities. What is known about this topic? Although leadership is considered an essential element in the provision of high-quality health care, leadership across AH remains underexamined. What does this paper add? There is a paucity of literature pertaining to AH leadership nationally and internationally. This paper describes the issues affecting AH leaders and leadership in NSW, as reported by senior AH leaders. What are the implications for practitioners? This study identifies key elements related to AH leadership and governance. Health systems and services can use this information to implement strategies that enhance AH leadership capability. PMID- 28355530 TI - Effects of benzo[a]pyrene dietary intake to antioxidative enzymes of Lymantria dispar (Lepidoptera: Lymantriidae) larvae from unpolluted and polluted forests. AB - Anthropogenic activity in industrial development has imposed great threats to the environment and wildlife in the form of persistent organic pollutants. Polycyclic aromatic hydrocarbons (PAH) tend to accumulate in vegetation foliage which is the main food source of polyphagous insect species Lymantria dispar L. Origin and multigenerational adaptation of L. dispar population to environmental challenges strongly condition the enzymes' sensitivity to pollutants. In this study, our aim was to investigate response of the superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST) to the chronic dietary exposure of benzo[a]pyrene in the midgut tissues and hemolymph of two L. dispar populations originating from unpolluted and polluted forest habitat. Midgut tissue of the larvae from the polluted forest showed significant increase in SOD, CAT and GST activity, while in unpolluted forest's larvae SOD and CAT showed elevated activities in hemolymph. L. dispar populations adapted to different level of pollution in their environment and expressed distinct tissue-dependent antioxidative enzyme sensitivity to benzo[a]pyrene diet, implying high potential for further elucidation of these enzymes as molecular biomarkers. PMID- 28355532 TI - FISHing Out the Details of CRISPR Genome Tracks. PMID- 28355533 TI - If Life Keeps Throwing Curveballs, You've Probably Reached a Wall. PMID- 28355531 TI - Using a genome-scale metabolic network model to elucidate the mechanism of chloroquine action in Plasmodium falciparum. AB - Chloroquine, long the default first-line treatment against malaria, is now abandoned in large parts of the world because of widespread drug-resistance in Plasmodium falciparum. In spite of its importance as a cost-effective and efficient drug, a coherent understanding of the cellular mechanisms affected by chloroquine and how they influence the fitness and survival of the parasite remains elusive. Here, we used a systems biology approach to integrate genome scale transcriptomics to map out the effects of chloroquine, identify targeted metabolic pathways, and translate these findings into mechanistic insights. Specifically, we first developed a method that integrates transcriptomic and metabolomic data, which we independently validated against a recently published set of such data for Krebs-cycle mutants of P. falciparum. We then used the method to calculate the effect of chloroquine treatment on the metabolic flux profiles of P. falciparum during the intraerythrocytic developmental cycle. The model predicted dose-dependent inhibition of DNA replication, in agreement with earlier experimental results for both drug-sensitive and drug-resistant P. falciparum strains. Our simulations also corroborated experimental findings that suggest differences in chloroquine sensitivity between ring- and schizont-stage P. falciparum. Our analysis also suggests that metabolic fluxes that govern reduced thioredoxin and phosphoenolpyruvate synthesis are significantly decreased and are pivotal to chloroquine-based inhibition of P. falciparum DNA replication. The consequences of impaired phosphoenolpyruvate synthesis and redox metabolism are reduced carbon fixation and increased oxidative stress, respectively, both of which eventually facilitate killing of the parasite. Our analysis suggests that a combination of chloroquine (or an analogue) and another drug, which inhibits carbon fixation and/or increases oxidative stress, should increase the clearance of P. falciparum from the host system. PMID- 28355534 TI - Synthetic Biology: Engineering Living Systems from Biophysical Principles. AB - Synthetic biology was founded as a biophysical discipline that sought explanations for the origins of life from chemical and physical first principles. Modern synthetic biology has been reinvented as an engineering discipline to design new organisms as well as to better understand fundamental biological mechanisms. However, success is still largely limited to the laboratory and transformative applications of synthetic biology are still in their infancy. Here, we review six principles of living systems and how they compare and contrast with engineered systems. We cite specific examples from the synthetic biology literature that illustrate these principles and speculate on their implications for further study. To fully realize the promise of synthetic biology, we must be aware of life's unique properties. PMID- 28355535 TI - Volume Transitions of Isolated Cell Nuclei Induced by Rapid Temperature Increase. AB - Understanding the physical mechanisms governing nuclear mechanics is important as it can impact gene expression and development. However, how cell nuclei respond to external cues such as heat is not well understood. Here, we studied the material properties of isolated nuclei in suspension using an optical stretcher. We demonstrate that isolated nuclei regulate their volume in a highly temperature sensitive manner. At constant temperature, isolated nuclei behaved like passive, elastic and incompressible objects, whose volume depended on the pH and ionic conditions. When the temperature was increased suddenly by even a few degrees Kelvin, nuclei displayed a repeatable and reversible temperature-induced volume transition, whose sign depended on the valency of the solvent. Such phenomenon is not observed for nuclei subjected to slow heating. The transition temperature could be shifted by adiabatic changes of the ambient temperature, and the magnitude of temperature-induced volume transition could be modulated by modifying the chromatin compaction state and remodeling processes. Our findings reveal that the cell nucleus can be viewed as a highly charged polymer gel with intriguing thermoresponsive properties, which might play a role in nuclear volume regulation and thermosensing in living cells. PMID- 28355536 TI - Tracking Multiple Genomic Elements Using Correlative CRISPR Imaging and Sequential DNA FISH. AB - Live imaging of genome has offered important insights into the dynamics of the genome organization and gene expression. The demand to image simultaneously multiple genomic loci has prompted a flurry of exciting advances in multicolor CRISPR imaging, although color-based multiplexing is limited by the need for spectrally distinct fluorophores. Here we introduce an approach to achieve highly multiplexed live recording via correlative CRISPR imaging and sequential DNA fluorescence in situ hybridization (FISH). This approach first performs one-color live imaging of multiple genomic loci and then uses sequential rounds of DNA FISH to determine the loci identity. We have optimized the FISH protocol so that each round is complete in 1 min, demonstrating the identification of seven genomic elements and the capability to sustain reversible staining and washing for up to 20 rounds. We have also developed a correlation-based algorithm to faithfully register live and FISH images. Our approach keeps the rest of the color palette open to image other cellular phenomena of interest, as demonstrated by our simultaneous live imaging of genomic loci together with a cell cycle reporter. Furthermore, the algorithm to register faithfully between live and fixed imaging is directly transferrable to other systems such as multiplex RNA imaging with RNA FISH and multiplex protein imaging with antibody-staining. PMID- 28355537 TI - Ephemeral Protein Binding to DNA Shapes Stable Nuclear Bodies and Chromatin Domains. AB - Fluorescence microscopy reveals that the contents of many (membrane-free) nuclear bodies exchange rapidly with the soluble pool while the underlying structure persists; such observations await a satisfactory biophysical explanation. To shed light on this, we perform large-scale Brownian dynamics simulations of a chromatin fiber interacting with an ensemble of (multivalent) DNA-binding proteins able to switch between an "on" (binding) and an "off" (nonbinding) state. This system provides a model for any DNA-binding protein that can be posttranslationally modified to change its affinity for DNA (e.g., through phosphorylation). Protein switching is a nonequilibrium process, and it leads to the formation of clusters of self-limiting size, where individual proteins in a cluster exchange with the soluble pool with kinetics similar to those seen in photobleaching experiments. This behavior contrasts sharply with that exhibited by nonswitching proteins, which are permanently in the on-state; when these bind to DNA nonspecifically, they form clusters that grow indefinitely in size. To explain these findings, we propose a mean-field theory from which we obtain a scaling relation between the typical cluster size and the protein switching rate. Protein switching also reshapes intrachromatin contacts to give networks resembling those seen in topologically associating domains, as switching markedly favors local (short-range) contacts over distant ones. Our results point to posttranslational modification of chromatin-bridging proteins as a generic mechanism driving the self-assembly of highly dynamic, nonequilibrium, protein clusters with the properties of nuclear bodies. PMID- 28355538 TI - Understanding the Relative Flexibility of RNA and DNA Duplexes: Stretching and Twist-Stretch Coupling. AB - The flexibility of double-stranded (ds) RNA and dsDNA is crucial for their biological functions. Recent experiments have shown that the flexibility of dsRNA and dsDNA can be distinctively different in the aspects of stretching and twist stretch coupling. Although various studies have been performed to understand the flexibility of dsRNA and dsDNA, there is still a lack of deep understanding of the distinctive differences in the flexibility of dsRNA and dsDNA helices as pertains to their stretching and twist-stretch coupling. In this work, we have explored the relative flexibility in stretching and twist-stretch coupling between dsRNA and dsDNA by all-atom molecular dynamics simulations. The calculated stretch modulus and twist-stretch coupling are in good accordance with the existing experiments. Our analyses show that the differences in stretching and twist-stretch coupling between dsRNA and dsDNA helices are mainly attributed to their different (A- and B-form) helical structures. Stronger basepair inclination and slide in dsRNA is responsible for the apparently weaker stretching rigidity versus that of dsDNA, and the opposite twist-stretch coupling for dsRNA and dsDNA is also attributed to the stronger basepair inclination in dsRNA than in dsDNA. Our calculated macroscopic elastic parameters and microscopic analyses are tested and validated by different force fields for both dsRNA and dsDNA. PMID- 28355540 TI - Arginase of Helicobacter Gastric Pathogens Uses a Unique Set of Non-catalytic Residues for Catalysis. AB - Helicobacter pylori arginase, a bimetallic enzyme, is crucial for pathogenesis of the bacterium in human stomach. Despite conservation of the signature motifs in all arginases, the H. pylori homolog has a non-conserved motif (153ESEEKAWQKLCSL165), whose role was recently shown to be critical for its stability and function. The sequence analysis also reveals the presence of this motif with critical residues in the homolog of other Helicobacter gastric pathogens. However, the underlying mechanism for its significance in catalytic function is not clearly understood. Using H. pylori arginase, our studies reveal that the interactions of His122 and Tyr125 with Trp159 are indispensable for tertiary structural intactness through optimal positioning of the motif and thus for the catalytic function. The single and double mutants of His122 and Tyr125 not only enhanced the solvent accessibility and conformational flexibility of Trp159 in the holo protein, but also showed complete loss of catalytic activity. An intact bimetallic center and unaltered substrate binding indicate that proper positioning of the motif by aromatic-aromatic contact is vital for the generation of a catalytically active conformation. Additionally, the metal ions provide higher stability to the holo protein. We also identified the presence of these two residues exclusively in arginase of other Helicobacter gastric pathogens, which may have similar function. Therefore, to the best of our knowledge, these findings highlight for the first time that arginase of all Helicobacter gastric pathogens utilizes a unique non-catalytic triad for catalysis, which could be exploited for therapeutics. PMID- 28355539 TI - Opposing Intermolecular Tuning of Ca2+ Affinity for Calmodulin by Neurogranin and CaMKII Peptides. AB - We investigated the impact of bound calmodulin (CaM)-target compound structure on the affinity of calcium (Ca2+) by integrating coarse-grained models and all atomistic simulations with nonequilibrium physics. We focused on binding between CaM and two specific targets, Ca2+/CaM-dependent protein kinase II (CaMKII) and neurogranin (Ng), as they both regulate CaM-dependent Ca2+ signaling pathways in neurons. It was shown experimentally that Ca2+/CaM (holoCaM) binds to the CaMKII peptide with overwhelmingly higher affinity than Ca2+-free CaM (apoCaM); the binding of CaMKII peptide to CaM in return increases the Ca2+ affinity for CaM. However, this reciprocal relation was not observed in the Ng peptide (Ng13-49), which binds to apoCaM or holoCaM with binding affinities of the same order of magnitude. Unlike the holoCaM-CaMKII peptide, whose structure can be determined by crystallography, the structural description of the apoCaM-Ng13-49 is unknown due to low binding affinity, therefore we computationally generated an ensemble of apoCaM-Ng13-49 structures by matching the changes in the chemical shifts of CaM upon Ng13-49 binding from nuclear magnetic resonance experiments. Next, we computed the changes in Ca2+ affinity for CaM with and without binding targets in atomistic models using Jarzynski's equality. We discovered the molecular underpinnings of lowered affinity of Ca2+ for CaM in the presence of Ng13-49 by showing that the N-terminal acidic region of Ng peptide pries open the beta-sheet structure between the Ca2+ binding loops particularly at C-domain of CaM, enabling Ca2+ release. In contrast, CaMKII peptide increases Ca2+ affinity for the C-domain of CaM by stabilizing the two Ca2+ binding loops. We speculate that the distinctive structural difference in the bound complexes of apoCaM-Ng13-49 and holoCaM-CaMKII delineates the importance of CaM's progressive mechanism of target binding on its Ca2+ binding affinities. PMID- 28355542 TI - Exploring Binding Mechanisms in Nuclear Hormone Receptors by Monte Carlo and X ray-derived Motions. AB - In this study, we performed an extensive exploration of the ligand entry mechanism for members of the steroid nuclear hormone receptor family (androgen receptor, estrogen receptor alpha, glucocorticoid receptor, mineralocorticoid receptor, and progesterone receptor) and their endogenous ligands. The exploration revealed a shared entry path through the helix 3, 7, and 11 regions. Examination of the x-ray structures of the receptor-ligand complexes further showed two distinct folds of the helix 6-7 region, classified as "open" and "closed", which could potentially affect ligand binding. To improve sampling of the helix 6-7 loop, we incorporated motion modes based on principal component analysis of existing crystal structures of the receptors and applied them to the protein-ligand sampling. A detailed comparison with the anisotropic network model (an elastic network model) highlights the importance of flexibility in the entrance region. While the binding (interaction) energy of individual simulations can be used to score different ligands, extensive sampling further allows us to predict absolute binding free energies and analyze reaction kinetics using Markov state models and Perron-cluster cluster analysis, respectively. The predicted relative binding free energies for three ligands binding to the progesterone receptor are in very good agreement with experimental results and the Perron cluster cluster analysis highlighted the importance of a peripheral binding site. Our analysis revealed that the flexibility of the helix 3, 7, and 11 regions represents the most important factor for ligand binding. Furthermore, the hydrophobicity of the ligand influences the transition between the peripheral and the active binding site. PMID- 28355541 TI - A Combined NMR and SAXS Analysis of the Partially Folded Cataract-Associated V75D gammaD-Crystallin. AB - A cataract is a pathological condition characterized by the clouding of the normally clear eye lens brought about by deposition of crystallin proteins in the lens fiber cells. These protein aggregates reduce visual acuity by scattering or blocking incoming light. Chemical damage to proteins of the crystallin family, accumulated over a lifetime, leads to age-related cataract, whereas inherited mutations are associated with congenital or early-onset cataract. The V75D mutant of gammaD-crystallin is associated with congenital cataract in mice and was previously shown to un/fold via a partially folded intermediate. Here, we structurally characterized the stable equilibrium urea unfolding intermediate of V75D at the ensemble level using solution NMR and small-angle x-ray scattering. Our data show that, in the intermediate, the C-terminal domain retains a folded conformation that is similar to the native wild-type protein, whereas the N terminal domain is unfolded and comprises an ensemble of random conformers, without any detectable residual structural propensities. PMID- 28355543 TI - Structural Analysis of a Temperature-Induced Transition in a Viral Capsid Probed by HDX-MS. AB - Icosahedral viral capsids are made of a large number of symmetrically organized protein subunits whose local movements can be essential for infection. In the capsid of the minute virus of mice, events required for infection that involve translocation of peptides through capsid pores are associated with a subtle conformational change. In vitro, this change can be reversibly induced by overcoming the energy barrier through mild heating of the capsid, but little is known about the capsid regions involved in the process. Here, we use hydrogen deuterium exchange coupled to mass spectrometry to analyze the dynamics of the minute virus of mice capsid at increasing temperatures. Our results indicate that the transition associated with peptide translocation involves the structural rearrangement of regions distant from the capsid pores. These alterations are reflected in an increased dynamics of some secondary-structure elements in the capsid shell from which spikes protrude, and a decreased dynamics in the long intertwined loops that form the large capsid spikes. Thus, the translocation events through capsid pores involve a global conformational rearrangement of the capsid and a complex alteration of its equilibrium dynamics. This study additionally demonstrates the potential of hydrogen-deuterium exchange coupled to mass spectrometry to explore in detail temperature-dependent structural dynamics in large macromolecular protein assemblies. Most importantly, it paves the way for undertaking novel studies of the relationship between structure, dynamics, and biological function in virus particles and other large protein cages. PMID- 28355545 TI - Membrane Phase-Dependent Occlusion of Intramolecular GLUT1 Cavities Demonstrated by Simulations. AB - Experimental evidence has shown a close correlation between the composition and physical state of the membrane bilayer and glucose transport activity via the glucose transporter GLUT1. Cooling alters the membrane lipids from the fluid to gel phase, and also causes a large decrease in the net glucose transport rate. The goal of this study is to investigate how the physical phase of the membrane alters glucose transporter structural dynamics using molecular-dynamics simulations. Simulations from an initial fluid to gel phase reduce the size of the cavities and tunnels traversing the protein and connecting the external regions of the transporter and the central binding site. These effects can be ascribed solely to membrane structural changes since in silico cooling of the membrane alone, while maintaining the higher protein temperature, shows protein structural and dynamic changes very similar to those observed with uniform cooling. These results demonstrate that the protein structure is sensitive to the membrane phase, and have implications for how transmembrane protein structures respond to their physical environment. PMID- 28355544 TI - Complex Photochemistry within the Green-Absorbing Channelrhodopsin ReaChR. AB - Channelrhodopsins (ChRs) are light-activated ion channels widely employed for photostimulation of excitable cells. This study focuses on ReaChR, a chimeric ChR variant with optimal properties for optogenetic applications. We combined electrophysiological recordings with infrared and UV-visible spectroscopic measurements to investigate photocurrents and photochemical properties of ReaChR. Our data imply that ReaChR is green-light activated (lambdamax = 532 nm) with a non-rhodopsin-like action spectrum peaking at 610 nm for stationary photocurrents. This unusual spectral feature is associated with photoconversion of a previously unknown light-sensitive, blue-shifted photocycle intermediate L (lambdamax = 495 nm), which is accumulated under continuous illumination. To explain the complex photochemical reactions, we propose a symmetrical two-cycle model based on the two C15=N isomers of the retinal cofactor with either syn- or anti-configuration, each comprising six consecutive states D, K, L, M, N, and O. Ion conduction involves two states per cycle, the late M- (M2) with a deprotonated retinal Schiff base and the consecutive green-absorbing N-state that both equilibrate via reversible reprotonation. In our model, a fraction of the deprotonated M-intermediate of the anti-cycle may be photoconverted-as the L state-back to its inherent dark state, or to its M-state pendant (M') of the syn cycle. The latter reaction pathway requires a C13=C14, C15=N double-isomerization of the retinal chromophore, whereas the intracircular photoconversion of M back to D involves only one C13=C14 double-bond isomerization. PMID- 28355546 TI - Gramicidin A Channel Formation Induces Local Lipid Redistribution I: Experiment and Simulation. AB - Integral membrane protein function can be modulated by the host bilayer. Because biological membranes are diverse and nonuniform, we explore the consequences of lipid diversity using gramicidin A channels embedded in phosphatidylcholine (PC) bilayers composed of equimolar mixtures of di-oleoyl-PC and di-erucoyl-PC (dC18:1+dC22:1, respectively), di-palmitoleoyl-PC and di-nervonoyl-PC (dC16:1+dC24:1, respectively), and di-eicosenoyl-PC (pure dC20:1), all of which have the same average bilayer chain length. Single-channel lifetime experiments, molecular dynamics simulations, and a simple lipid compression model are used in tandem to gain insight into lipid redistribution around the channel, which partially alleviates the bilayer deformation energy associated with channel formation. The average single-channel lifetimes in the two-component bilayers (95 +/- 10 ms for dC18:1+dC22:1 and 195 +/- 20 ms for dC16:1+dC24:1) were increased relative to the single-component dC20:1 control bilayer (65 +/- 10 ms), implying lipid redistribution. Using a theoretical treatment of thickness-dependent changes in channel lifetimes, the effective local enrichment of lipids around the channel was estimated to be 58 +/- 4% dC18:1 and 66 +/- 2% dC16:1 in the dC18:1+dC22:1 and dC16:1+dC24:1 bilayers, respectively. 3.5-MUs molecular dynamics simulations show 66 +/- 2% dC16:1 in the first lipid shell around the channel in the dC16:1+dC24:1 bilayer, but no significant redistribution (50 +/- 4% dC18:1) in the dC18:1+dC22:1 bilayer; these simulated values are within the 95% confidence intervals of the experimental averages. The strong preference for the better matching lipid (dC16:1) near the channel in the dC16:1+dC24:1 mixture and lesser redistribution in the dC18:1+dC22:1 mixture can be explained by the energetic cost associated with compressing the lipids to match the channel's hydrophobic length. PMID- 28355547 TI - Gramicidin A Channel Formation Induces Local Lipid Redistribution II: A 3D Continuum Elastic Model. AB - To change conformation, a protein must deform the surrounding bilayer. In this work, a three-dimensional continuum elastic model for gramicidin A in a lipid bilayer is shown to describe the sensitivity to thickness, curvature stress, and the mechanical properties of the lipid bilayer. A method is demonstrated to extract the gramicidin-lipid boundary condition from all-atom simulations that can be used in the three-dimensional continuum model. The boundary condition affects the deformation dramatically, potentially much more than typical variations in the material stiffness do as lipid composition is changed. Moreover, it directly controls the sensitivity to curvature stress. The curvature stress and hydrophobic surfaces of the all-atom and continuum models are found to be in excellent agreement. The continuum model is applied to estimate the enrichment of hydrophobically matched lipids near the channel in a mixture, and the results agree with single-channel experiments and extended molecular dynamics simulations from the companion article by Beaven et al. in this issue of Biophysical Journal. PMID- 28355548 TI - Deconvolution of Camera Instrument Response Functions. AB - Temporal sequences of fluorescence intensities in single-molecule experiments are often obtained from stacks of camera images. The dwell times of different macromolecular structural or functional states, correlated with characteristic fluorescence intensities, are extracted from the images and combined into dwell time distributions that are fitted by kinetic functions to extract corresponding rate constants. The frame rate of the camera limits the time resolution of the experiment and thus the fastest rate processes that can be reliably detected and quantified. However, including the influence of discrete sampling (framing) on the detected time series in the fitted model enables rate processes near to the frame rate to be reliably estimated. This influence, similar to the instrument response function in other types of instruments, such as pulsed emission decay fluorometers, is easily incorporated into the fitted model. The same concept applies to any temporal data that is low-pass filtered or decimated to improve signal to noise ratio. PMID- 28355549 TI - A Sigmoid Functional Response Emerges When Cytotoxic T Lymphocytes Start Killing Fresh Target Cells. AB - Cytotoxic T lymphocyte (CTL)-mediated killing involves the formation of a synapse with a target cell, followed by delivery of perforin and granzymes. Previously, we derived a general functional response for CTL killing while considering that CTLs form stable synapses (i.e., single-stage) and that the number of conjugates remains at steady state. However, the killing of target cells sometimes requires multiple engagements (i.e., multistage). To study how multistage killing and a lack of steady state influence the functional response, we here analyze a set of differential equations as well as simulations employing the cellular Potts model, in both cases describing CTLs that kill target cells. We find that at steady state the total killing rate (i.e., the number of target cells killed by all CTLs) is well described by the previously derived double saturation function. Compared to single-stage killing, the total killing rate during multistage killing saturates at higher CTL and target cell densities. Importantly, when the killing is measured before the steady state is approached, a qualitatively different functional response emerges for two reasons: First, the killing signal of each CTL gets diluted over several targets and because this dilution effect is strongest at high target cell densities; this can result in a peak in the dependence of the total killing rate on the target cell density. Second, the total killing rate exhibits a sigmoid dependence on the CTL density when killing is a multistage process, because it takes typically more than one CTL to kill a target. In conclusion, a sigmoid dependence of the killing rate on the CTLs during initial phases of killing may be indicative of a multistage killing process. Observation of a sigmoid functional response may thus arise from a dilution effect and is not necessarily due to cooperative behavior of the CTLs. PMID- 28355550 TI - Mechanotransduction-Induced Reversible Phenotypic Switching in Prostate Cancer Cells. AB - Phenotypic plasticity is posed to be a vital trait of cancer cells such as circulating tumor cells, allowing them to undergo reversible or irreversible switching between phenotypic states important for tumorigenesis and metastasis. While irreversible phenotypic switching can be detected by studying the genome, reversible phenotypic switching is often difficult to examine due to its dynamic nature and the lack of knowledge about its contributing factors. In this study, we demonstrate that culturing cells in different physical environments, stiff, soft, or suspension, induced a phenotypic switch in prostate cancer cells via mechanotransduction. The mechanosensitive phenotypic switching in prostate cancer cells was sustainable yet reversible even after long-term culture, demonstrating the impact of mechanical signals on prostate cancer cell phenotypes. Importantly, such a mechanotransduction-mediated phenotypic switch in prostate cancer cells was accompanied by decreased sensitivity of the cells to paclitaxel, suggesting a role of mechanotransduction in the evolution of drug resistance. Multiple signaling pathways such as p38MAPK, ERK, and Wnt were found to be involved in the mechanotransduction-induced phenotypic switching of prostate cancer cells. Given that cancer cells experience different physical environments during disease progression, this study provides useful information about the important role of mechanotransduction in cancer, and how circulating tumor cells may be capable of continuously changing their phenotypes throughout the disease process. PMID- 28355551 TI - Unraveling the Receptor-Ligand Interactions between Bladder Cancer Cells and the Endothelium Using AFM. AB - Adhesion of cancer cells to endothelial cells is a key step in cancer metastasis; therefore, identifying the key molecules involved during this process promises to aid in efforts to block the metastatic cascade. We have previously shown that intercellular adhesion molecule-1 (ICAM-1) expressed by endothelial cells is involved in the interactions of bladder cancer cells (BCs) with the endothelium. However, the ICAM-1 ligands have never been investigated. In this study, we combined adhesion assays and atomic force microscopy (AFM) to identify the ligands involved and to quantify the forces relevant in such interactions. We report the expression of MUC1 and CD43 on BCs, and demonstrate that these ligands interact with ICAM-1 to mediate cancer cell-endothelial cell adhesion in the case of the more invasive BCs. This was achieved with the use of adhesion assays, which showed a strong decrease in the attachment of BCs to endothelial cells when MUC1 and CD43 were blocked by antibodies. In addition, AFM measurements showed a similar decrease, by up to 70%, in the number of rupture events that occurred when MUC1 and CD43 were blocked. When we applied a Gaussian mixture model to the AFM data, we observed a distinct force range for receptor-ligand bonds, which allowed us to precisely identify the interactions of ICAM-1 with MUC1 or CD43. Furthermore, a detailed analysis of the rupture events suggested that CD43 is strongly connected to the cytoskeleton and that its interaction with ICAM-1 mainly corresponds to force ramps followed by sudden jumps. In contrast, MUC1 seems to be weakly connected to the cytoskeleton, as its interactions with ICAM-1 are mainly associated with the formation of tethers. This analysis is quite promising and may also be applied to other types of cancer cells. PMID- 28355552 TI - Energy Transfer Mechanisms during Molecular Delivery to Cells by Laser-Activated Carbon Nanoparticles. AB - Previous studies have shown that exposure of carbon black nanoparticles to nanosecond pulsed near-infrared laser causes intracellular delivery of molecules through hypothesized transient breaks in the cell membrane. The goal of this study is to determine the underlying mechanisms of sequential energy transfer from laser light to nanoparticle to fluid medium to cell. We found that laser pulses on a timescale of 10 ns rapidly heat carbon nanoparticles to temperatures on the order of 1200 K. Heat is transferred from the nanoparticles to the surrounding aqueous medium on a similar timescale, causing vaporization of the surrounding water and generation of acoustic emissions. Nearby cells can be impacted thermally by the hot bubbles and mechanically by fluid mechanical forces to transiently increase cell membrane permeability. The experimental and theoretical results indicate that transfer of momentum and/or heat from the bubbles to the cells are the dominant mechanisms of energy transfer that results in intracellular uptake of molecules. We further conclude that neither thermal expansion of the nanoparticles nor a carbon-steam chemical reaction play a significant role in the observed effects on cells, and that acoustic pressure appears to be concurrent with, but not essential to, the observed bioeffects. PMID- 28355553 TI - Deciphering CaMKII Multimerization Using Fluorescence Correlation Spectroscopy and Homo-FRET Analysis. AB - While kinases are typically composed of one or two subunits, calcium-calmodulin (CaM)-dependent protein kinase II (CaMKII) is composed of 8-14 subunits arranged as pairs around a central core. It is not clear if the CaMKII holoenzyme functions as an assembly of independent subunits, as catalytic pairs, or as a single unit. One strategy to address this question is to genetically engineer monomeric and dimeric CaMKII and evaluate how their activity compares to the wild type (WT) holoenzyme. Here a technique that combines fluorescence correlation spectroscopy and homo-FRET analysis was used to characterize assembly mutants of Venus-tagged CaMKIIalpha to identify a dimeric CaMKII. Spectroscopy was then used to compare how holoenzyme structure and function changes in response to activation with CaM in the dimeric mutant, WT-holoenzyme, and a monomeric CaMKII oligomerization-domain deletion mutant control. CaM triggered an increase in hydrodynamic volume in both WT and dimeric CaMKII without altering subunit stoichiometry or the net homo-FRET between Venus-tagged catalytic domains. Biochemical analysis revealed that the dimeric mutant also functioned like WT holoenzyme in terms of its kinase activity with an exogenous substrate, and for endogenous T286 autophosphorylation. We conclude that the fundamental functional units of CaMKII holoenzyme are paired catalytic-domains. PMID- 28355555 TI - Experimental Estimation of Membrane Tension Induced by Osmotic Pressure. PMID- 28355554 TI - Hydrodynamic Hunters. AB - The Gram-negative Bdellovibrio bacteriovorus (BV) is a model bacterial predator that hunts other bacteria and may serve as a living antibiotic. Despite over 50 years since its discovery, it is suggested that BV probably collides into its prey at random. It remains unclear to what degree, if any, BV uses chemical cues to target its prey. The targeted search problem by the predator for its prey in three dimensions is a difficult problem: it requires the predator to sensitively detect prey and forecast its mobile prey's future position on the basis of previously detected signal. Here instead we find that rather than chemically detecting prey, hydrodynamics forces BV into regions high in prey density, thereby improving its odds of a chance collision with prey and ultimately reducing BV's search space for prey. We do so by showing that BV's dynamics are strongly influenced by self-generated hydrodynamic flow fields forcing BV onto surfaces and, for large enough defects on surfaces, forcing BV in orbital motion around these defects. Key experimental controls and calculations recapitulate the hydrodynamic origin of these behaviors. While BV's prey (Escherichia coli) are too small to trap BV in hydrodynamic orbit, the prey are also susceptible to their own hydrodynamic fields, substantially confining them to surfaces and defects where mobile predator and prey density is now dramatically enhanced. Colocalization, driven by hydrodynamics, ultimately reduces BV's search space for prey from three to two dimensions (on surfaces) even down to a single dimension (around defects). We conclude that BV's search for individual prey remains random, as suggested in the literature, but confined, however-by generic hydrodynamic forces-to reduced dimensionality. PMID- 28355556 TI - Ufd1-Npl4 Recruit Cdc48 for Disassembly of Ubiquitylated CMG Helicase at the End of Chromosome Replication. AB - Disassembly of the Cdc45-MCM-GINS (CMG) DNA helicase is the key regulated step during DNA replication termination in eukaryotes, involving ubiquitylation of the Mcm7 helicase subunit, leading to a disassembly process that requires the Cdc48 "segregase". Here, we employ a screen to identify partners of budding yeast Cdc48 that are important for disassembly of ubiquitylated CMG helicase at the end of chromosome replication. We demonstrate that the ubiquitin-binding Ufd1-Npl4 complex recruits Cdc48 to ubiquitylated CMG. Ubiquitylation of CMG in yeast cell extracts is dependent upon lysine 29 of Mcm7, which is the only detectable site of ubiquitylation both in vitro and in vivo (though in vivo other sites can be modified when K29 is mutated). Mutation of K29 abrogates in vitro recruitment of Ufd1-Npl4-Cdc48 to the CMG helicase, supporting a model whereby Ufd1-Npl4 recruits Cdc48 to ubiquitylated CMG at the end of chromosome replication, thereby driving the disassembly reaction. PMID- 28355557 TI - Liver-Specific Activation of AMPK Prevents Steatosis on a High-Fructose Diet. AB - AMP-activated protein kinase (AMPK) plays a key role in integrating metabolic pathways in response to energy demand. We identified a mutation in the gamma1 subunit (gamma1D316A) that leads to activation of AMPK. We generated mice with this mutation to study the effect of chronic liver-specific activation of AMPK in vivo. Primary hepatocytes isolated from these mice have reduced gluconeogenesis and fatty acid synthesis, but there is no effect on fatty acid oxidation compared to cells from wild-type mice. Liver-specific activation of AMPK decreases lipogenesis in vivo and completely protects against hepatic steatosis when mice are fed a high-fructose diet. Our findings demonstrate that liver-specific activation of AMPK is sufficient to protect against hepatic triglyceride accumulation, a hallmark of non-alcoholic fatty liver disease (NAFLD). These results emphasize the clinical relevance of activating AMPK in the liver to combat NAFLD and potentially other associated complications (e.g., cirrhosis and hepatocellular carcinoma). PMID- 28355559 TI - Altered Synapse Stability in the Early Stages of Tauopathy. AB - Synapse loss is a key feature of dementia, but it is unclear whether synaptic dysfunction precedes degenerative phases of the disease. Here, we show that even before any decrease in synapse density, there is abnormal turnover of cortical axonal boutons and dendritic spines in a mouse model of tauopathy-associated dementia. Strikingly, tauopathy drives a mismatch in synapse turnover; postsynaptic spines turn over more rapidly, whereas presynaptic boutons are stabilized. This imbalance between pre- and post-synaptic stability coincides with reduced synaptically driven neuronal activity in pre-degenerative stages of the disease. PMID- 28355558 TI - Neuroprotective Functions for the Histone Deacetylase SIRT6. AB - The histone deacetylase SIRT6 promotes DNA repair, but its activity declines with age with a concomitant accumulation of DNA damage. Furthermore, SIRT6 knockout mice exhibit an accelerated aging phenotype and die prematurely. Here, we report that brain-specific SIRT6-deficient mice survive but present behavioral defects with major learning impairments by 4 months of age. Moreover, the brains of these mice show increased signs of DNA damage, cell death, and hyperphosphorylated Tau a critical mark in several neurodegenerative diseases. Mechanistically, SIRT6 regulates Tau protein stability and phosphorylation through increased activation of the kinase GSK3alpha/beta. Finally, SIRT6 mRNA and protein levels are reduced in patients with Alzheimer's disease. Taken together, our results suggest that SIRT6 is critical to maintain genomic stability in the brain and that its loss leads to toxic Tau stability and phosphorylation. Therefore, SIRT6 and its downstream signaling could be targeted in Alzheimer's disease and age-related neurodegeneration. PMID- 28355560 TI - Identification of a Tissue-Restricted Isoform of SIRT1 Defines a Regulatory Domain that Encodes Specificity. AB - The conserved NAD+-dependent deacylase SIRT1 plays pivotal, sometimes contrasting, roles in diverse physiological and pathophysiological conditions. In this study, we uncover a tissue-restricted isoform of SIRT1 (SIRT1-DeltaE2) that lacks exon 2 (E2). Candidate-based screening of SIRT1 substrates demonstrated that the domain encoded by this exon plays a key role in specifying SIRT1 protein protein interactions. The E2 domain of SIRT1 was both necessary and sufficient for PGC1alpha binding, enhanced interaction with p53, and thus downstream functions. Since SIRT1-FL and SIRT1-DeltaE2 were found to have similar intrinsic catalytic activities, we propose that the E2 domain tethers specific substrate proteins. Given the absence of SIRT1-DeltaE2 in liver, our findings provide insight into the role of the E2 domain in specifying "metabolic functions" of SIRT1-FL. Identification of SIRT1-DeltaE2 and the conserved specificity domain will enhance our understanding of SIRT1 and guide the development of therapeutic interventions. PMID- 28355561 TI - Pneumocystis-Driven Inducible Bronchus-Associated Lymphoid Tissue Formation Requires Th2 and Th17 Immunity. AB - Inducible bronchus-associated lymphoid tissue (iBALT) is an ectopic lymphoid structure composed of highly organized T cell and B cell zones that forms in the lung in response to infectious or inflammatory stimuli. Here, we develop a model for fungal-mediated iBALT formation, using infection with Pneumocystis that induces development of pulmonary lymphoid follicles. Pneumocystis-dependent iBALT structure formation and organization required CXCL13 signaling. Cxcl13 expression was regulated by interleukin (IL)-17 family members, as Il17ra-/-, Il17rb-/-, and Il17rc-/- mice failed to develop iBALT. Interestingly, Il17rb-/- mice have intact Th17 responses, but failed to generate an anti-Pneumocystis Th2 response. Given a role for Th2 and Th17 immunity in iBALT formation, we demonstrated that primary pulmonary fibroblasts synergistically upregulated Cxcl13 transcription following dual stimulation with IL-13 and IL-17A in a STAT3/GATA3-dependent manner. Together, these findings uncover a role for Th2/Th17 cells in regulating Cxcl13 expression and provide an experimental model for fungal-driven iBALT formation. PMID- 28355562 TI - Th1 Differentiation Drives the Accumulation of Intravascular, Non-protective CD4 T Cells during Tuberculosis. AB - Recent data indicate that the differentiation state of Th1 cells determines their protective capacity against tuberculosis. Therefore, we examined the role of Th1 polarizing factors in the generation of protective and non-protective subsets of Mtb-specific Th1 cells. We find that IL-12/23p40 promotes Th1 cell expansion and maturation beyond the CD73+CXCR3+T-betdim stage, and T-bet prevents deviation of Th1 cells into Th17 cells. Nevertheless, IL- 12/23p40 and T-bet are also essential for the production of a prominent subset of intravascular CX3CR1+KLRG1+ Th1 cells that persists poorly and can neither migrate into the lung parenchyma nor control Mtb growth. Furthermore, T-bet suppresses development of CD69+CD103+ tissue resident phenotype effectors in lung. In contrast, Th1-cell-derived IFN gamma inhibits the accumulation of intravascular CX3CR1+KLRG1+ Th1 cells. Thus, although IL-12 and T-bet are essential host survival factors, they simultaneously oppose lung CD4 T cell responses at several levels, demonstrating the dual nature of Th1 polarization in tuberculosis. PMID- 28355563 TI - Cell Traversal Activity Is Important for Plasmodium falciparum Liver Infection in Humanized Mice. AB - Malaria sporozoites are deposited into the skin by mosquitoes and infect hepatocytes. The molecular basis of how Plasmodium falciparum sporozoites migrate through host cells is poorly understood, and direct evidence of its importance in vivo is lacking. Here, we generated traversal-deficient sporozoites by genetic disruption of sporozoite microneme protein essential for cell traversal (PfSPECT) or perforin-like protein 1 (PfPLP1). Loss of either gene did not affect P. falciparum growth in erythrocytes, in contrast with a previous report that PfPLP1 is essential for merozoite egress. However, although traversal-deficient sporozoites could invade hepatocytes in vitro, they could not establish normal liver infection in humanized mice. This is in contrast with NF54 sporozoites, which infected the humanized mice and developed into exoerythrocytic forms. This study demonstrates that SPECT and perforin-like protein 1 (PLP1) are critical for transcellular migration by P. falciparum sporozoites and demonstrates the importance of cell traversal for liver infection by this human pathogen. PMID- 28355564 TI - SMARCAD1 Contributes to the Regulation of Naive Pluripotency by Interacting with Histone Citrullination. AB - Histone citrullination regulates diverse cellular processes. Here, we report that SMARCAD1 preferentially associates with H3 arginine 26 citrullination (H3R26Cit) peptides present on arrays composed of 384 histone peptides harboring distinct post-transcriptional modifications. Among ten histone modifications assayed by ChIP-seq, H3R26Cit exhibited the most extensive genomewide co-localization with SMARCAD1 binding. Increased Smarcad1 expression correlated with naive pluripotency in pre-implantation embryos. In the presence of LIF, Smarcad1 knockdown (KD) embryonic stem cells lost naive state phenotypes but remained pluripotent, as suggested by morphology, gene expression, histone modifications, alkaline phosphatase activity, energy metabolism, embryoid bodies, teratoma, and chimeras. The majority of H3R26Cit ChIP-seq peaks occupied by SMARCAD1 were associated with increased levels of H3K9me3 in Smarcad1 KD cells. Inhibition of H3Cit induced H3K9me3 at the overlapping regions of H3R26Cit peaks and SMARCAD1 peaks. These data suggest a model in which SMARCAD1 regulates naive pluripotency by interacting with H3R26Cit and suppressing heterochromatin formation. PMID- 28355565 TI - Coordinated Pulses of mRNA and of Protein Translation or Degradation Produce EGF Induced Protein Bursts. AB - Protein responses to extracellular cues are governed by gene transcription, mRNA degradation and translation, and protein degradation. In order to understand how these time-dependent processes cooperate to generate dynamic responses, we analyzed the response of human mammary cells to the epidermal growth factor (EGF). Integrating time-dependent transcript and protein data into a mathematical model, we inferred for several proteins their pre-and post-stimulus translation and degradation coefficients and found that they exhibit complex, time-dependent variation. Specifically, we identified strategies of protein production and degradation acting in concert to generate rapid, transient protein bursts in response to EGF. Remarkably, for some proteins, for which the response necessitates rapidly decreased abundance, cells exhibit a transient increase in the corresponding degradation coefficient. Our model and analysis allow inference of the kinetics of mRNA translation and protein degradation, without perturbing cells, and open a way to understanding the fundamental processes governing time dependent protein abundance profiles. PMID- 28355566 TI - Enhanced Degradation of Misfolded Proteins Promotes Tumorigenesis. AB - An adequate cellular capacity to degrade misfolded proteins is critical for cell survival and organismal health. A diminished capacity is associated with aging and neurodegenerative diseases; however, the consequences of an enhanced capacity remain undefined. Here, we report that the ability to clear misfolded proteins is increased during oncogenic transformation and is reduced upon tumor cell differentiation. The augmented capacity mitigates oxidative stress associated with oncogenic growth and is required for both the initiation and maintenance of malignant phenotypes. We show that tripartite motif-containing (TRIM) proteins select misfolded proteins for proteasomal degradation. The higher degradation power in tumor cells is attributed to the upregulation of the proteasome and especially TRIM proteins, both mediated by the antioxidant transcription factor Nrf2. These findings establish a critical role of TRIMs in protein quality control, connect the clearance of misfolded proteins to antioxidant defense, and suggest an intrinsic characteristic of tumor cells. PMID- 28355567 TI - SIRT6 Is Essential for Adipocyte Differentiation by Regulating Mitotic Clonal Expansion. AB - Preadipocytes initiate differentiation into adipocytes through a cascade of events. Mitotic clonal expansion, as one of the earliest events, is essential for adipogenesis. However, the underlying mechanisms that regulate mitotic clonal expansion remain elusive. SIRT6 is a member of the evolutionarily conserved sirtuin family of nicotinamide adenine dinucleotide (NAD)+-dependent protein deacetylases. Here, we show that SIRT6 deficiency in preadipocytes blocks their adipogenesis. Analysis of gene expression during adipogenesis reveals that KIF5C, which belongs to the kinesin family, is negatively regulated by SIRT6. Furthermore, we show that KIF5C is a negative factor for adipogenesis through interacting with CK2alpha', a catalytic subunit of CK2. This interaction blocks CK2alpha' nuclear translocation and CK2 kinase activity and inhibits mitotic clonal expansion during adipogenesis. These findings reveal a crucial role of SIRT6 in adipogenesis and provide potential therapeutic targets for obesity. PMID- 28355568 TI - A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2. AB - During development of the vertebrate CNS, the basic helix-loop-helix (bHLH) transcription factor Olig2 sustains replication competence of progenitor cells that give rise to neurons and oligodendrocytes. A pathological counterpart of this developmental function is seen in human glioma, wherein Olig2 is required for maintenance of stem-like cells that drive tumor growth. The mitogenic/gliomagenic functions of Olig2 are regulated by phosphorylation of a triple serine motif (S10, S13, and S14) in the amino terminus. Here, we identify a set of three serine/threonine protein kinases (glycogen synthase kinase 3alpha/beta [GSK3alpha/beta], casein kinase 2 [CK2], and cyclin-dependent kinases 1/2 [CDK1/2]) that are, collectively, both necessary and sufficient to phosphorylate the triple serine motif. We show that phosphorylation of the motif itself serves as a template to prime phosphorylation of additional serines and creates a highly charged "acid blob" in the amino terminus of Olig2. Finally, we show that small molecule inhibitors of this forward-feeding phosphorylation cascade have potential as glioma therapeutics. PMID- 28355569 TI - Severity of Demyelinating and Axonal Neuropathy Mouse Models Is Modified by Genes Affecting Structure and Function of Peripheral Nodes. AB - Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited polyneuropathies. Mutations in 80 genetic loci can cause forms of CMT, resulting in demyelination and axonal dysfunction. The clinical presentation, including sensory deficits, distal muscle weakness, and atrophy, can vary greatly in severity and progression. Here, we used mouse models of CMT to demonstrate genetic interactions that result in a more severe neuropathy phenotype. The cell adhesion molecule Nrcam and the Na+ channel Scn8a (NaV1.6) are important components of nodes. Homozygous Nrcam and heterozygous Scn8a mutations synergized with both an Sh3tc2 mutation, modeling recessive demyelinating Charcot-Marie-Tooth type 4C, and mutations in Gars, modeling dominant axonal Charcot-Marie-Tooth type 2D. We conclude that genetic variants perturbing the structure and function of nodes interact with mutations affecting the cable properties of axons by thinning myelin or reducing axon diameter. Therefore, genes integral to peripheral nodes are candidate modifiers of peripheral neuropathy. PMID- 28355570 TI - Pancreatic alpha Cell-Derived Glucagon-Related Peptides Are Required for beta Cell Adaptation and Glucose Homeostasis. AB - Pancreatic alpha cells may process proglucagon not only to glucagon but also to glucagon-like peptide-1 (GLP-1). However, the biological relevance of paracrine GLP-1 for beta cell function remains unclear. We studied effects of locally derived insulin secretagogues on beta cell function and glucose homeostasis using mice with alpha cell ablation and with alpha cell-specific GLP-1 deficiency. Normally, intestinal GLP-1 compensates for the lack of alpha cell-derived GLP-1. However, upon aging and metabolic stress, glucose tolerance is impaired. This was partly rescued with the DPP-4 inhibitor sitagliptin, but not with glucagon administration. In isolated islets from these mice, glucose-stimulated insulin secretion was heavily impaired and exogenous GLP-1 or glucagon rescued insulin secretion. These data highlight the importance of alpha cell-derived GLP-1 for glucose homeostasis during metabolic stress and may impact on the clinical use of systemic GLP-1 agonists versus stabilizing local alpha cell-derived GLP-1 by DPP 4 inhibitors in type 2 diabetes. PMID- 28355571 TI - Identification of Interleukin-1 by Functional Screening as a Key Mediator of Cellular Expansion and Disease Progression in Acute Myeloid Leukemia. AB - Secreted proteins in the bone marrow microenvironment play critical roles in acute myeloid leukemia (AML). Through an ex vivo functional screen of 94 cytokines, we identified that the pro-inflammatory cytokine interleukin-1 (IL-1) elicited profound expansion of myeloid progenitors in ~67% of AML patients while suppressing the growth of normal progenitors. Levels of IL-1beta and IL-1 receptors were increased in AML patients, and silencing of the IL-1 receptor led to significant suppression of clonogenicity and in vivo disease progression. IL-1 promoted AML cell growth by enhancing p38MAPK phosphorylation and promoting secretion of various other growth factors and inflammatory cytokines. Treatment with p38MAPK inhibitors reversed these effects and recovered normal CD34+ cells from IL-1-mediated growth suppression. These results highlight the importance of ex vivo functional screening to identify common and actionable extrinsic pathways in genetically heterogeneous malignancies and provide impetus for clinical development of IL-1/IL1R1/p38MAPK pathway-targeted therapies in AML. PMID- 28355572 TI - Precise Temporal Profiling of Signaling Complexes in Primary Cells Using SWATH Mass Spectrometry. AB - Spatiotemporal organization of protein interactions in cell signaling is a fundamental process that drives cellular functions. Given differential protein expression across tissues and developmental stages, the architecture and dynamics of signaling interaction proteomes is, likely, highly context dependent. However, current interaction information has been almost exclusively obtained from transformed cells. In this study, we applied an advanced and robust workflow combining mouse genetics and affinity purification (AP)-SWATH mass spectrometry to profile the dynamics of 53 high-confidence protein interactions in primary T cells, using the scaffold protein GRB2 as a model. The workflow also provided a sufficient level of robustness to pinpoint differential interaction dynamics between two similar, but functionally distinct, primary T cell populations. Altogether, we demonstrated that precise and reproducible quantitative measurements of protein interaction dynamics can be achieved in primary cells isolated from mammalian tissues, allowing resolution of the tissue-specific context of cell-signaling events. PMID- 28355573 TI - Single-Cell RNA-Seq Reveals Hypothalamic Cell Diversity. AB - The hypothalamus is one of the most complex brain structures involved in homeostatic regulation. Defining cell composition and identifying cell-type specific transcriptional features of the hypothalamus is essential for understanding its functions and related disorders. Here, we report single-cell RNA sequencing results of adult mouse hypothalamus, which defines 11 non-neuronal and 34 neuronal cell clusters with distinct transcriptional signatures. Analyses of cell-type-specific transcriptomes reveal gene expression dynamics underlying oligodendrocyte differentiation and tanycyte subtypes. Additionally, data analysis provides a comprehensive view of neuropeptide expression across hypothalamic neuronal subtypes and uncover Crabp1+ and Pax6+ neuronal populations in specific hypothalamic sub-regions. Furthermore, we found food deprivation exhibited differential transcriptional effects among the different neuronal subtypes, suggesting functional specification of various neuronal subtypes. Thus, the work provides a comprehensive transcriptional perspective of adult hypothalamus, which serves as a valuable resource for dissecting cell-type specific functions of this complex brain region. PMID- 28355575 TI - Mechanism study of humic acid functional groups for Cr(VI) retention: Two dimensional FTIR and 13C CP/MAS NMR correlation spectroscopic analysis. AB - Undissolved humic acid (HA) is known to substantially effect the migration and transformation of hexavalent chromium [Cr(VI)] in soils. The mechanisms of Cr(VI) retention in soils by undissolved HA have been reported; however, past studies are inconclusive about the types of HA functional groups that are involved in Cr(VI) retention and the retention mechanisms. Utilizing a two-dimensional correlation spectroscopy (2DCOS) analysis for FTIR and 13C CP/MAS NMR, this study investigated the variations of HA function groups and molecular structures after reactions with aqueous Cr(VI) under different pH conditions. Based on the changing sequence of functional groups interpreted from the 2DCOS results, a four step mechanism for Cr(VI) retention was determined as follows: (1) electrostatic adsorption of Cr(VI) to HA surface, (2) complexation of adsorbed Cr(VI) by carboxyl and ester, (3) reduction of complexed Cr(VI) to Cr(III) by phenol and polysaccharide, and (4) complexation of reduced Cr(III) by carboxylic groups. These functional groups that are involved in Cr(VI) retention were determined to occur in aromatic domains. PMID- 28355574 TI - Phosphoproteomics of Primary Cells Reveals Druggable Kinase Signatures in Ovarian Cancer. AB - Our understanding of the molecular determinants of cancer is still inadequate because of cancer heterogeneity. Here, using epithelial ovarian cancer (EOC) as a model system, we analyzed a minute amount of patient-derived epithelial cells from either healthy or cancerous tissues by single-shot mass-spectrometry-based phosphoproteomics. Using a multi-disciplinary approach, we demonstrated that primary cells recapitulate tissue complexity and represent a valuable source of differentially expressed proteins and phosphorylation sites that discriminate cancer from healthy cells. Furthermore, we uncovered kinase signatures associated with EOC. In particular, CDK7 targets were characterized in both EOC primary cells and ovarian cancer cell lines. We showed that CDK7 controls cell proliferation and that pharmacological inhibition of CDK7 selectively represses EOC cell proliferation. Our approach defines the molecular landscape of EOC, paving the way for efficient therapeutic approaches for patients. Finally, we highlight the potential of phosphoproteomics to identify clinically relevant and druggable pathways in cancer. PMID- 28355577 TI - A novel perceptual discrimination training task: Reducing fear overgeneralization in the context of fear learning. AB - Generalization is an adaptive learning mechanism, but it can be maladaptive when it occurs in excess. A novel perceptual discrimination training task was therefore designed to moderate fear overgeneralization. We hypothesized that improvement in basic perceptual discrimination would translate into lower fear overgeneralization in affective cues. Seventy adults completed a fear conditioning task prior to being allocated into training or placebo groups. Predesignated geometric shape pairs were constructed for the training task. A target shape from each pair was presented. Thereafter, participants in the training group were shown both shapes and asked to identify the image that differed from the target. Placebo task participants only indicated the location of each shape on the screen. All participants then viewed new geometric pairs and indicated whether they were identical or different. Finally, participants completed a fear generalization test consisting of perceptual morphs ranging from the CS + to the CS-. Fear-conditioning was observed through physiological and behavioural measures. Furthermore, the training group performed better than the placebo group on the assessment task and exhibited decreased fear generalization in response to threat/safety cues. The findings offer evidence for the effectiveness of the novel discrimination training task, setting the stage for future research with clinical populations. PMID- 28355576 TI - Role of germinal centers for the induction of broadly-reactive memory B cells. AB - Virus-specific memory B cells (Bmem) play a crucial role in protecting against variant viruses. The ability to recognize these variant viruses, defined as antibody breadth, is achieved in Bmem populations by two very different pathways, germline-encoded cross-reactivity and affinity-driven, somatic evolution in germinal centers (GCs) for conserved viral epitopes. The latter class of broadly reactive Bmem cells are not cross-reactive per se, but bind epitopes crucial for viral fitness. Although these conserved epitopes are often weakly immunogenic, the GC reaction is surprisingly permissive for the continued survival/proliferation of B cells that bind with low affinity or react to cryptic epitopes, increasing their chance of memory recruitment. In this review, we discuss the adaptive strategies of B-cell memory to viral antigenic variations. PMID- 28355578 TI - Self-perception of readiness for clinical practice: A survey of accelerated Masters program graduate registered nurses. AB - Accelerated nursing programs are gaining momentum as a means of career transition into the nursing profession for mature age learners in an attempt to meet future healthcare workforce demands in Australia. With a gap in the literature on readiness for practice of graduates from accelerated nursing programs at the Masters level the purpose of this study was to evaluate the effectiveness of the program based on graduates' preparedness for practice and graduate outcomes. Using a descriptive, exploratory design an online survey was used to explore the perception of graduate nurses' readiness for clinical practice. Forty-nine graduates from a nursing Masters program at an Australian university completed the survey defining readiness for practice as knowledge of self-limitations and seeking help, autonomy in basic clinical procedures, exhibiting confidence, possessing theoretical knowledge and practicing safe care. Graduates perceived themselves as adequately prepared to work as a beginner practitioner with their perception of readiness for clinical practice largely positive. The majority of participants agreed that the program had prepared them for work as a beginner practitioner with respondents stating that they felt adequately prepared in most areas relating to clinical practice. This would suggest that educational preparation was adequate and effective in achieving program objectives. PMID- 28355579 TI - Stability of BK polyomavirus IgG seroreactivity and its correlation with preceding viremia. AB - BACKGROUND: Recently we showed that the level of BK polyomavirus (BKPyV) IgG seroreactivity in kidney donors predicted viremia and BKPyV-associated nephropathy in kidney transplant recipients (KTRs). This observation could be explained by assuming a direct association between BKPyV seroreactivity and the amount of persistent infectious virus in the renal allograft. OBJECTIVES: Since the renal BKPyV reservoir is probably sowed by viremia during primary BKPyV infection, we systematically analysed the dynamics of BKPyV IgG seroreactivity in relation to preceding BKPyV viremia in KTRs and healthy individuals. STUDY DESIGN: A cohort of 85 KTRs consisting of BKPyV viremic and nonviremic subjects was analysed for BKPyV IgG seroreactivity at five fixed time points until one year after transplantation. A cohort of 87 healthy blood donors (HBDs) was used as controls. RESULTS: Baseline BKPyV seropositivity was high in both KTRs and HBDs, and the baseline mean BKPyV IgG level comparable. BKPyV IgG levels in nonviremic KTRs and HBDs remained stable during follow-up, while a considerable increase was observed in viremic KTRs (p=0.015). The increase of BKPyV seroreactivity in viremic KTRs was associated with the duration and peak level of BKPyV viremia. CONCLUSIONS: BKPyV IgG seroreactivity was stable over time in immunocompetent subjects, which enables the use of this potential pretransplantation biomarker in kidney donors. The observed dose-dependent relationship of BKPyV IgG seroreactivity with preceding BKPyV replication is in agreement with the assumption that BKPyV seroreactivity reflects past BKPyV activity and correlates with the amount of latent BKPyV residing within a kidney allograft. PMID- 28355580 TI - Rapid determination of some psychotropic drugs in complex matrices by tandem dispersive liquid-liquid microextraction followed by high performance liquid chromatography. AB - Simple and rapid determinations of some psychotropic drugs in some pharmaceutical wastewater and human plasma samples were successfully accomplished via the tandem dispersive liquid-liquid microextraction combined with high performance liquid chromatography-ultraviolet detection (TDLLME-HPLC-UV). TDLLME of the three psychotropic drugs clozapine, chlorpromazine, and thioridazine was easily performed through two consecutive dispersive liquid-liquid microextractions. By performing this convenient method, proper sample preconcentrations and clean-ups were achieved in just about 7min. In order to achieve the best extraction efficiency, the effective parameters involved were optimized. The optimal experimental conditions consisted of 100MUL of CCl4 (as the extraction organic solvent), and the pH values of 13 and 2 for the donor and acceptor phases, respectively. Under these optimum experimental conditions, the proposed TDLLME HPLC-UV technique provided a good linearity in the range of 5-3000ngmL-1 for the three psychotropic drugs with the correlation of determinations (R2s) higher than 0.996. The limits of quantification (LOQs) and limits of detection (LODs) obtained were 5.0ngmL-1 and 1.0-1.5ngmL-1, respectively. Also the proper enrichment factors (EFs) of 96, 99, and 88 for clozapine, chlorpromazine, and thioridazine, respectively, and good extraction repeatabilities (relative standard deviations below 9.3%, n=5) were obtained. PMID- 28355581 TI - Capecitabine in early breast cancer: A meta-analysis of randomised controlled trials. AB - PURPOSE: Capecitabine is an effective therapy for metastatic breast cancer. Its role in early breast cancer is uncertain due to conflicting data from randomised controlled trials (RCTs). METHODS: PubMed and major conference proceedings were searched to identify RCTs comparing standard chemotherapy with or without capecitabine in the neoadjuvant or adjuvant setting. Hazard ratios (HRs) for disease-free survival (DFS) and overall survival (OS), as well as odds ratios (ORs) for toxicities were extracted or calculated and pooled in a meta-analysis. Subgroup analysis compared triple-negative breast cancer (TNBC) to non-TNBC and whether capecitabine was given in addition to or in place of standard chemotherapy. Meta-regression was used to explore the influence of TNBC on OS. RESULTS: Eight studies comprising 9302 patients were included. In unselected patients, capecitabine did not influence DFS (hazard ratio [HR] 0.99, p = 0.93) or OS (HR 0.90, p = 0.36). There was a significant difference in DFS when capecitabine was given in addition to standard treatment compared with in place of standard treatment (HR 0.92 versus 1.62, interaction p = 0.002). Addition of capecitabine to standard chemotherapy was associated with significantly improved DFS in TNBC versus non-TNBC (HR 0.72 versus 1.01, interaction p = 0.02). Meta regression showed that adding capecitabine to standard chemotherapy was associated with improved OS in studies with higher proportions of patients with TNBC (R = -0.967, p = 0.007). Capecitabine increased grade 3/4 diarrhoea (odds ratio [OR] 2.33, p < 0.001) and hand-foot syndrome (OR 8.08, p < 0.001), and resulted in more frequent treatment discontinuation (OR 3.80, p < 0.001). CONCLUSION: Adding capecitabine to standard chemotherapy appears to improve DFS and OS in TNBC, but increases adverse events in keeping with its known toxicity profile. PMID- 28355583 TI - Structure of the O-specific polysaccharide from a marine bacterium Cellulophaga algicola. AB - The O-polysaccharide was isolated from the lipopolysaccharide of Cellulophaga algicola and studied by chemical analyses along with 1H and 13C NMR spectroscopy, including 2D 1H, 1H COSY, TOCSY, ROESY, 1N, 13S HSQC, HMBC experiments. It was found that the polysaccharide is built up of branched pentasaccharide repeating units, containing D-mannose (Man), D-glucuronic acid (GlcA), N-acetyl-D glucosamine (GlcNAc), two L-rhamnose (Rha) residues and O-acetyl groups in a non stoichiometric amount and has the following structure. PMID- 28355582 TI - Synthesis of beta-galactosylamides as ligands of the peanut lectin. Insights into the recognition process. AB - The synthesis of mono and divalent beta-galactosylamides linked to a hydroxylated chain having a C2 symmetry axis derived from l-tartaric anhydride is reported. Reference compounds devoid of hydroxyl groups in the linker were also prepared from beta-galactosylamine and succinic anhydride. After functionalization with an alkynyl residue, the resulting building blocks were grafted onto different azide equipped scaffolds through the copper catalyzed azide-alkyne cycloaddition. Thus, a family of structurally related mono and divalent beta-N-galactopyranosylamides was obtained and fully characterized. The binding affinities of the ligands towards the model lectin PNA were measured by the enzyme-linked lectin assay (ELLA). The IC50 values were significantly higher than that of galactose but the presence of hydroxyl groups in the aglycone chain improved lectin recognition. Docking and molecular dynamics experiments were in accordance with the hypothesis that a hydroxyl group properly disposed in the linker could mimic the Glc O3 in the recognition process. On the other hand, divalent presentation of the ligands led to lectin affinity enhancements. PMID- 28355584 TI - Ambulatory urodynamic monitoring of women with overactive bladder syndrome during single voiding cycle. AB - OBJECTIVE(S): To present data of standardized ambulatory urodynamic monitoring (AUM) performed in women with overactive bladder syndrome (OAB) and to evaluate the relevance of AUM data with clinical findings of the patients. STUDY DESIGN: Records of women with symptoms of OAB were retrospectively reviewed (n=249). Of women fulfilling the Overactive Bladder Awareness Tool (OAB-V8) with a score >=8 and the 3-day voiding diary (VD) with a frequency >7/day (n=167), those who underwent urodynamic investigation were selected (n=76). The data of this study were retrieved from the records of Ankara University Cebeci Hospital and based on the AUM findings of single voiding cycle of women with OAB. AUM, which is among the institutionally approved primary urodynamic investigation methods, is performed with LUNA ambulatory monitoring recorder (MMSTM) in the clinical setting with a standardized technique, in reproducing lower urinary tract symptoms of women since 2011. The relationship of the urodynamic data with the clinical findings were evaluated. RESULTS: AUM traces of women (n=76) with OAB revealed 63.1% DO, 64.4% urgency and 77.7% urinary incontinence of which were 14.4% urgency urinary incontinence (UUI), 25% stress urinary incontinence (SUI) and 38.1% mixed urinary incontinence (MUI). OAB patients with DO reported more urinary incontinence episodes/day, nocturia and mixed urinary incontinence in the voiding diary (p<0.04) and had significantly higher irritative symptom bother reflected by the questionnaires (p<0.04). Women with DO were more likely to be postmenopausal (p=0.02) and were found to have more urgency (p<0.001), urgency episodes (p=0.05) and incontinence (urge and mixed) (p<0.001). However, no association was found between the extent of pelvic organ prolapse and the presence of DO. CONCLUSIONS: AUM performed with a standardized technique during single voiding cycle seems to be a reliable method in reproducing symptoms of women with OAB. It provides both clinically relevant findings and objective documentation of urgency which is the main symptom for OAB. The detection of DO according to the ICS definition were also found to be concordant with urodynamicaly observed urgency and urinary incontinence. Objective and subjective clinical findings of OAB were found to be more severe in women with DO. PMID- 28355585 TI - Isolation and characterization of a novel chalcone synthase gene family from mulberry. AB - Chalcone synthase (CHS) is the pivotal enzyme that catalyzes the first committed step of the phenylpropanoid pathway leading to flavonoids. Here, five CHS genes were determined in mulberry (Morus atropurpurea Roxb.). Interestingly, phylogenetic analysis tended to group three MaCHSs in the stilbene synthase (STS) family and initially annotated these as MaSTSs. A co-expression system that harbored a 4-coumarate:CoA ligase gene and one of the candidate genes was established to determine the functions of this novel gene family. The fermentation result demonstrated that MaSTS in fact encoded a CHS enzyme, and was consequently retermed MaCHS. Tissue-specific expression analysis indicated that MaCHS1/MaCHS2 was highly abundant in fruit, and MaCHS4 had significant expression in root bark, stem bark and old leaves, while MaCHS3 and MaCHS5 were more expressed in old leaves. Subcellular localization experiments showed that MaCHS was localized to the cytoplasm. Transcription levels suggested MaCHS genes were involved in a series of defense responses. Over-expression of MaCHS in transgenic tobacco modified the metabolite profile, and resulted in elevated tolerance to a series of environmental stresses. This study comprehensively evaluated the function of MaCHS genes and laid the foundation for future research on MaCHS in mulberry. PMID- 28355586 TI - Simultaneous removal of thallium and chloride from a highly saline industrial wastewater using modified anion exchange resins. AB - Simultaneous removal of thallium (Tl) and chloride from a highly saline industrial wastewater was investigated using modified anion ion exchange resins. The removal of thallium was mainly driven by the exchange of Tl-chlorocomplex (TlCl4-) formed in the oxidation of thallous (Tl (I)) to thallic ion (Tl (III)) by hydrogen peroxide (H2O2) under saline conditions. Over 97% of thallium and chloride removal was achieved using the modified resins, with a wide optimal conditions found to be H2O2 dosage 1.0-25.0mL/L, pH 1.6-4.3, and flow rate 0.5 4.7mL/L. The modified resins had an exchange capacity of 4.771mg Tl/g dry resins for thallium and 1800mg Cl/g dry resins for chloride. Stable regeneration could be achieved with the modified resins: over 97% of thallium and 90% of chloride can be eluted using Na2SO3 solution and alternating hot (60 degrees C) H2SO4 and cold (25 degrees C) water, and over 98% removal of thallium and chloride was achieved after five consecutive regeneration cycles. PMID- 28355587 TI - Exopolymeric substances from drinking water biofilms: Dynamics of production and relation with disinfection by products. AB - Exopolymeric substances (EPS) as an external matrix of biofilm could react with disinfectants in drinking water networks forming disinfection by-products (DBP). Based on an experimental setup using two chlorine conditions-biofilm 1 (2.6 +/- 0.8 mgCl/L) and biofilm 2 (0.7 +/- 0.2 mg Cl/L)-samples of biofilms were recovered during 9 campaigns and EPS were extracted. Analyses of SUVA, fluorescence and amino acid (AA) content were carried out on the EPS to observe variation over time and correlations with DBP formation potential (DBPfp) after chlorination. SUVA values were under 2 L/mgC*m showing that both EPS were hydrophilic. Slightly higher SUVA in biofilm 2 with low variation over time was observed. Fluorescence showed that aromatic proteins and fulvic like substances were the principal components and increased in biofilm 1 over time. AA decreased with time, and higher values of alanine, threonine, proline and isoleucine were observed in biofilm 2. Based on general associations, the SUVA of biofilm 2 correlated well with chloroform (CF) (r = 0.80). Generally, in both biofilms, tryptophan-like substances were negatively correlated with DBP while humic acid like substances correlated positively, but with low indexes (r = 0.3-0.6). Correlations of data from individual sampling increased the indices (r over 0.8), suggesting a temporal influence of other factors on DBPfp such as inorganics, filtered water and the structural composition of EPS. In biofilm 1, Br-haloacetic acids (Br-HAA), dibromoacetonitrile and bromochloro acetonitrile were inversely associated with arginine and valine, as were di and trichloropropanone to arginine. On the contrary, in biofilm 2, the following amino acids correlated positively with DBP: alanine with Br-HAA, alanine with CF, alanine with N-DBP (chloropicrin, di and tri-chloro acetonitrile), and valine with CF. As this is the first report about the relation between temporal variation of EPS and DBPfp of biofilms in two different chlorinated conditions, it provides new evidence about the function of these complex substances in drinking water systems. PMID- 28355588 TI - Dihydropyrazole and dihydropyrrole structures based design of Kif15 inhibitors as novel therapeutic agents for cancer. AB - Mitotic Kinesin motors, Eg5 and Kif15, have recently emerged as good targets for cancer as they play an inevitable role during mitosis. But, most of the Eg5 inhibitors were found ineffective when the cancer cells develop resistance to them by escalating the expression of Kif15 as alternative to Eg5. Therefore, the drugs that target Kif15 became necessary to be used either as a single or in combination with Eg5 inhibitors. The present study used 39 dihydropyrazole and 13 dihydropyrrole derivatives that were having in vitro inhibitory potential against kinesin motors to develop a common pharmacophore hypothesis AHRR and atom-based QSAR model. The model was used for virtual screening of ZINC database and the resultant hits were docked against Kif15. The four drug candidates with high docking score were examined for their activity and pharmacokinetic behaviour. Based on the results these drugs could be considered as lead candidates in further drug development for cancer. PMID- 28355589 TI - Fluorescence resonance energy transfer usage to track the sequence promoter changes in CGB5 gene in ovarian cancer patients. AB - PURPOSE: The survival rates for ovarian cancer patients remain very low, often as a result of late diagnosis due to the asymptomatic course of the early stage disease. Based on the important biological contribution of human chorionic gonadotropin to various key processes including; cell cycle control, DNA repair, cellular differentiation and developmental processes, we hypothesized that genetic polymorphisms in the genes promoter could be associated with ovarian cancer risk. Thus, the purpose of the study was to determine whether particular polymorphisms occur in the promoter region of the human chorionic gonadotropin polypeptide 5 encoding gene, and if so, are they associated with ovarian cancer outcome. PATIENTS AND METHODS: We analyzed Central European females diagnosed with ovarian cancer (n=95) and controls (n=76) for the occurrence of at least one of three polymorphisms (rs7260002, rs7246045, rs540432391) and their impact on cancer risk. The fluorescence resonance energy transfer technique was used in order to conduct single nucleotide polymorphisms genotyping. RESULTS: The occurrence of two studied polymorphisms, rs7260002 and rs540432391 present in the 5' upstream region of the chorionic gonadotropin (CG) gene were associated with an increased risk of ovarian cancer. The former polymorphism had a minor impact on cancer risk (P=0.049; OR=1.95; 95% CI=0.97-3.92), while the latter had a much larger impact and may be of great importance in the evaluation of cancer development in the analyzed population (p<0.001; OR 8.5; 95% CI 3.59-20.23). CONCLUSIONS: The fluorescence resonance energy transfer application used in tracking the sequence promoter variations of genes expressed during tumorigenesis may be an important factor in early prediction of ovarian cancer. Taking under consideration the elevated CG expression associated with several different cancer types it seems reasonable to estimate if the analyzed polymorphisms could affect cancer outcome. PMID- 28355590 TI - Physicochemical characterization of the oolong tea polysaccharides with high molecular weight and their synergistic effects in combination with polyphenols on hepatocellular carcinoma. AB - This study was to investigate the synergistic effects of polysaccharides with the molecular weight more than 80kDa (OTPS1) and polyphenols (OTP) isolated from oolong tea on hepatocellular carcinoma (HCC) in vitro and in vivo. The physicochemical properties of OTPS fractions were characterized. The synergistic effects of OTPS1 and OTP were evaluated based on the combination index (CI). Results showed that the highest uronic acid contents (32.96%) and viscosity (239.56mLg-1), multicavity structure of OTPS1 were contributed to the synergistic effects with OTP (52.17% content of epigallocatechin-3-gallate (EGCG)). OTPS1 and OTP showed the strongest synergism ability on SMMC7721 cells (CI<0.2). Co administrated with OTPS1 and OTP exhibited the synergistic effects on the tumor proliferation and growth with the CI values of 0.34 and 0.39, respectively. Antioxidative and immune levels of the mice were obviously increased after combination administration. These results suggested that OTPS1 in combination with OTP might be functional supplements for the treatment of HCC. PMID- 28355591 TI - Effect of aquo-alchoholic extract of Glycyrrhiza glabra against Pseudomonas aeruginosa in Mice Lung Infection Model. AB - The prevalence of lung infection caused by Pseudomonas aeruginosa strains that are classified as multi-drug resistant has increased considerably and is mainly attributed to relative insufficiency of potent chemotherapeutic modalities. The present study was conducted to evaluate the antimicrobial activity of aquo alcoholic extract of Glycyrrhiza glabra against the P. aeruginosa causing lung infection in Swiss albino mice. The study involves evaluation of lethal dose of P. aeruginosa in Swiss albino mice and analysis of disease manifestation that includes bacteremia, hypothermia, reduction in body weight and other parameters for 48h of infection. Physical manifestations of infected mice showed a significant decline in body temperature that is 29+/-0.57 degrees C (at 48th h) from 38.81+/-0.33 degrees C (0h) and 30% weight loss was observed at the end of the study. Further the efficacy of G. glabra extract against lung infection induced with the calculated lethal dose was evaluated by employing bacteremia, histopathology and radiological analysis. Bacterial burden showed that 2.30+/ 0.02 Log10CFU/mL at day 7, a significant decline in the bacterial load as compared to day 1 when the bacterial burden was found to be 3.32+/-0.1 Log10CFU/mL. Histopathological results showed more diffuse and patchy accumulation of inflammatory cells within the alveolar space also the infiltrates were noted in all the lung section of infected mice. In treated animal group improved lung histology was seen with the exudates were less seen in D1 dose (20mg/kg) and disappeared in D2 dose (80mg/kg). The study clearly declares that the G. glabra extract is effective against lung infection caused by P. aeruginosa at dose of 80mg/kg. The LCMS results revealed that the extract contains Glycyrrhizin, Stigmasterol and Ergosterol, Licochalcone and Glabridin. The current study expected to further exploit the biomedical properties of this extract in the preparation of a potent regimen against such threatening pathogen. PMID- 28355592 TI - Primary particulate emissions and secondary organic aerosol (SOA) formation from idling diesel vehicle exhaust in China. AB - In China diesel vehicles dominate the primary emission of particulate matters from on-road vehicles, and they might also contribute substantially to the formation of secondary organic aerosols (SOA). In this study tailpipe exhaust of three typical in-use diesel vehicles under warm idling conditions was introduced directly into an indoor smog chamber with a 30m3 Teflon reactor to characterize primary emissions and SOA formation during photo-oxidation. The emission factors of primary organic aerosol (POA) and black carbon (BC) for the three types of Chinese diesel vehicles ranged 0.18-0.91 and 0.15-0.51gkg-fuel-1, respectively; and the SOA production factors ranged 0.50-1.8gkg-fuel-1 and SOA/POA ratios ranged 0.7-3.7 with an average of 2.2. The fuel-based POA emission factors and SOA production factors from this study for idling diesel vehicle exhaust were 1-3 orders of magnitude higher than those reported in previous studies for idling gasoline vehicle exhaust. The emission factors for total particle numbers were 0.65-4.0*1015particleskg-fuel-1, and particles with diameters less than 50nm dominated in total particle numbers. Traditional C2-C12 precursor non-methane hydrocarbons (NMHCs) could only explain less than 3% of the SOA formed during aging and contribution from other precursors including intermediate volatile organic compounds (IVOC) needs further investigation. PMID- 28355593 TI - Blasted copper slag as fine aggregate in Portland cement concrete. AB - The present work focuses on assessing the viability of applying blasted copper slag, produced during abrasive blasting, as fine aggregate for Portland cement concrete manufacturing, resulting in an alternative and safe disposal method. Leaching assays showed no toxicity for this material. Concrete mixtures were produced, with high aggregate replacement ratios, varying from 0% to 100%. Axial compressive strength, diametrical compressive strength, elastic modulus, physical indexes and durability were evaluated. Assays showed a significant improvement in workability, with the increase in substitution of fine aggregate. With 80% of replacement, the concrete presented lower levels of water absorption capacity. Axial compressive strength and diametrical compressive strength decreased, with the increase of residue replacement content. The greatest reductions of compressive strength were found when the replacement was over 40%. For tensile strength by diametrical compression, the greatest reduction occurred for the concrete with 80% of replacement. After the accelerated aging, results of mechanic properties showed a small reduction of the concrete with blasted copper slag performance, when compared with the reference mixture. Results indicated that the blasted copper slag is a technically viable material for application as fine aggregate for concrete mixtures. PMID- 28355594 TI - Does teaching non-technical skills to medical students improve those skills and simulated patient outcome? AB - Objectives: The purpose of this study is to evaluate the effects of a tailor made, non-technical skills seminar on medical student's behaviour, attitudes, and performance during simulated patient treatment. Methods: Seventy-seven students were randomized to either a non-technical skills seminar (NTS group, n=43) or a medical seminar (control group, n=34). The human patient simulation was used as an evaluation tool. Before the seminars, all students performed the same simulated emergency scenario to provide baseline measurements. After the seminars, all students were exposed to a second scenario, and behavioural markers for evaluating their non-technical skills were rated. Furthermore, teamwork relevant attitudes were measured before and after the scenarios, and perceived stress was measured following each simulation. All simulations were also evaluated for various medical endpoints. Results: Non-technical skills concerning situation awareness (p<.01, r=0.5) and teamwork (p<.01, r=0.45) improved from simulation I to II in the NTS group. Decision making improved in both groups (NTS: p<.01, r=0.39; control: p<.01, r=0.46). The attitude 'handling errors' improved significantly in the NTS group (p<.05, r=0.34). Perceived stress decreased from simulation I to II in both groups. Medical endpoints and patients' outcome did not differ significantly between the groups in simulation II. Conclusions: This study highlights the effectiveness of a single brief seminar on non-technical skills to improve student's non-technical skills. In a next step, to improve student's handling of emergencies and patient outcomes, non-technical skills seminars should be accompanied by exercises and more broadly embedded in the medical school curriculum. PMID- 28355595 TI - Use of Hemoadsorption in a Case of Severe Hepatic Failure and Hyperbilirubinemia. PMID- 28355596 TI - ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Radiological, Nuclear Medicine & Hybrid Imaging. PMID- 28355598 TI - Two Novel TEX15 Mutations in a Family with Nonobstructive Azoospermia. AB - AIM: Genetic investigations explain only a small percentage of cases of nonobstructive azoospermia (NOA), a condition that affects up to 2% of infertile couples. This study aimed to identify further genomic variants that are associated with primary spermatogenic failure within the testis. METHODS: One family with 2 infertile siblings affected by NOA was genotyped by whole-exome sequencing. DNA variants were filtered based on quality score, allele frequency, and functional roles of genes in spermatogenesis. RESULTS: Both NOA males were compound heterozygotes for a nonsense mutation and a single nucleotide deletion leading to premature stop codons in the TEX15 gene (c.2419A>T, p.Lys807*, and c.3040delT, p.Ser1014Leufs*5, respectively). The single mutations were identified only on one allele in 6 family members, including 3 fertile males who conceived naturally. CONCLUSION: This is the second reported case of a TEX15 deleterious mutation cosegregating with NOA in a family in which the infertile phenotype is reminiscent of the one observed in the TEX15-knockout mouse, confirming that TEX15 plays a critical role in normal spermatogenesis and its defects may be responsible for a number of NOA cases. PMID- 28355597 TI - Endobronchial Valve Used as Salvage Therapy in a Mechanically Ventilated Patient with Intractable Life-Threatening Haemoptysis. AB - Treatment options for intractable life-threatening haemoptysis in mechanically ventilated patients with structural lung disease who do not respond to bronchial artery embolisation (BAE) and who are deemed unfit for surgery are limited. A 26 year-old HIV-positive male with a poorly preserved CD4 count and active pulmonary tuberculosis was intubated and mechanically ventilated for persistent life threatening haemoptysis. Two attempts at BAE failed, and life-threatening haemoptysis recurred daily for 14 days despite antituberculous therapy. He was deemed unfit for surgery during that period. We proceeded to identify the source of bleeding endoscopically and implanted an endobronchial valve in the left upper lobe bronchus. Following the collapse of the affected lobe, haemoptysis ceased and the patient was promptly liberated from mechanical ventilation. He remained haemoptysis free for the duration of his hospitalisation. Endobronchial valves, therefore, may be a viable option in patients mechanically ventilated with persistent life-threatening haemoptysis in whom all other conventional measures fail and who are considered unfit for surgery. PMID- 28355599 TI - Urinary Infections in Patients with Catheters in the Upper Urinary Tract: Microbiological Study. AB - BACKGROUND: Infections related to catheters in the upper urinary tract (CUUT) are associated with specific characteristics. METHODS: A prospective observational study was carried out from 2012 to 2015 to evaluate infections in patients with CUUT. RESULTS: A total of 209 infections were included (99 with double-J, 81 with nephrostomy, and 29 with internal/external nephroureteral stents). Among nephrostomy tube carriers, the most frequently isolated microorganisms were Pseudomonas and Enterococcus. In those with an internal/external nephroureteral stent, Klebsiella was the most common, and 57.1% were extended-spectrum beta lactamase-producing Klebsiella. In double-J carriers, Escherichia coli and Enterococcus were the most common microorganisms. Multiple-drug resistance (MDR) microorganisms were isolated in 28.6, 47.1, and 58.3% of patients with double-J, nephrostomy, and internal-external nephroureteral stents. A percutaneous CUUT (p = 0.005) and immunosuppression (p = 0.034) were risk factors for MDR microorganisms. CONCLUSIONS: Non-E. coli bacteria are commonly isolated in patients with CUUT. MDR microorganisms are frequent, mainly in percutaneous approach or immunosuppression. PMID- 28355600 TI - Usefulness of Endobronchial Ultrasound in Patients with Human Immunodeficiency Virus Infection and Mediastinal Lymphadenopathy. AB - BACKGROUND: There are few published studies about the usefulness of endobronchial ultrasound (EBUS) in patients infected with human immunodeficiency virus (HIV). The clinical spectrum of likely diseases in this population is varied and differs from patients not infected with HIV. OBJECTIVE: The aim of this study was to measure the usefulness of EBUS-guided transbronchial needle aspiration (EBUS TBNA) in HIV-infected patients with mediastinal lymphadenopathy. MATERIALS AND METHODS: We conducted an observational, cross-sectional, retrospective, descriptive study on patients with HIV infection and mediastinal lymphadenopathy who underwent EBUS-TBNA between September 2014 and April 2016. The patients' final diagnosis, regardless of the sample from which it was obtained, was considered the positive gold standard, and the absence of diagnosis was the negative. The study measured diagnostic accuracy of bronchoalveolar lavage (BAL), transbronchial biopsy (TBB), and EBUS-TBNA. RESULTS: A total of 43 procedures were performed; 79.1% (34/43) of the patients were male, and the median age was 35 years (range, 22-66). The overall diagnostic yield including all types of samples was 90.7% (39/43); the yield of BAL was 50% (21), that of TBB 61.9% (26), and that of EBUS-TBNA was 60.5% (26). The combined yield of BAL with TBB was 69.8% (30); the yield of BAL with EBUS-TBNA was 86% (37) and that of TBB with EBUS-TBNA was 88.4% (38). The highest diagnostic accuracy was 97.7% for the combination of TBB and EBUS-TBNA. CONCLUSIONS: The most common infectious diagnoses were tuberculosis, with a higher diagnostic accuracy using EBUS-TBNA than BAL. With malignancies, both EBUS-TBNA and TBB were useful. EBUS-TBNA is a minimally invasive diagnostic tool that should be considered in these patients. PMID- 28355601 TI - A Revised Fibrinogen Cutoff Value in the Chinese Disseminated Intravascular Coagulation Scoring System May Provide a Better Prognostic Value for Hematological Malignancies. AB - To retrospectively validate the prognostic value of the latest Chinese disseminated intravascular coagulation (DIC) scoring system (CDSS) in hematological malignancies, 260 patients with confirmed hematological malignancies and suspected DIC in West China Hospital between 2011 and 2015 were included in this study. We evaluated via univariate and multivariate analyses the diagnostic biomarkers, and the cutoff levels used in the CDSS, except those for fibrinogen, were found to be valid. In subgroup analyses, the value of fibrinogen was found to be mainly unfit for the acute promyelocytic leukemia group. Forty six patients (17.7%) had elevated fibrinogen levels (>4 g/L) and tended to have a poor prognosis, and thus we redetermined the cutoff value of fibrinogen (<1 g/L or >4 g/L was defined as abnormal). As a result, all of the markers used in the CDSS had prognostic value (including for the promyelocytic leukemia group); meanwhile, this modification also resulted in a larger area under the receiver operating characteristic curve compared to the CDSS and the International Society on Thrombosis and Haemostasis score. We believe that, with regard to prognosis prediction, this cutoff value modification for fibrinogen is preferable for DIC patients with a tendency toward severe hypofibrinogenemia. However, a multicenter, prospective study is needed to validate this possibility. PMID- 28355602 TI - Results from Two Consecutive Studies of Consolidation Therapy after Autologous Transplant for Multiple Myeloma: Thalidomide, Dexamethasone, and Clarithromycin or Lenalidomide, Dexamethasone, and Clarithromycin. AB - BACKGROUND: In multiple myeloma (MM), relapse is a problem after autologous hematopoietic stem cell transplantation (ASCT). In the nontransplant setting, thalidomide/dexamethasone/clarithromycin (BLT-D) and lenalidomide/dexamethasone/clarithromycin (BiRd) achieve responses with acceptable toxicity. Both regimens are reasonable objects of study in the post ASCT setting. PATIENTS AND METHODS: We report on BLT-D and BiRd given post-ASCT. Studies were conducted consecutively. After recovery from ASCT, therapy was started. All 3 drugs were given for 1 year, and then immunomodulatory drugs alone were given as long as tolerated or until disease progression. RESULTS: For BLT-D, the most common toxicity was peripheral neuropathy (PN). For BiRd, infection, PN, and neutropenia were the most common adverse events. BiRd was associated with a higher frequency of secondary cancers. The median follow-up for BLT-D was 10.2 years (range 8.6-10.7) and for BiRd it was 7.5 years (range 6.4-8.4). After BLT D, 18 patients (67%) were alive and 10 (37%) were alive without disease progression, and after BiRd, 18 patients (58%) were alive and 10 (32%) were alive without disease progression. CONCLUSIONS: BLT-D and BiRd can be given post-ASCT with different toxicity profiles and comparable disease-free and overall survival rates. A randomized study comparing these regimens to single-agent lenalidomide is needed to determine which approach is superior. Key Message: Relapse of MM is a major problem after ASCT. Strategies are needed post-ASCT to improve outcomes. In the nontransplant setting, thalidomide or lenalidomide/dexamethasone/clarithromycin treat MM with acceptable toxicity. We, thus, studied both regimens post- ASCT. They can be given with different toxicity profiles and result in good disease control. PMID- 28355603 TI - Glomerular Morphology and Renal Function after Warm Ischemia by Main Artery or Selective Clamping in a Porcine Model. AB - OBJECTIVE: The study aimed to evaluate the ischemic and non-ischemic areas after selective arterial occlusion by using stereological analysis of glomeruli, and to compare them with main arterial clamping and sham-operated animals. MATERIALS AND METHODS: Twenty-four male pigs were used in the study. The animals were divided into 3 groups with 8 animals in each as follows: group sham, submitted to laparoscopic dissection of the renal pedicle but not submitted to ischemia; group arterial (A), submitted to left renal artery clamping; and group selective (S), submitted to left renal artery caudal branch occlusion. Groups A and S underwent 30 min of warm ischemia. Left and right kidneys were collected after 21 days and renal fragments were processed for stereological evaluation. Glomerular volume density (Vv[glom]), mean glomerular volume (MGV), and glomerular density were measured. Serum creatinine and urea were assessed preoperatively, 10 days after surgery, and before euthanasia. RESULTS: There was no significant difference among groups with regard to renal function. Renal weight and volume were similar among groups. Also, no difference was observed between the groups with regard to Vv[glom], MGV, and glomerular density, both when compared to its right control or when left kidneys were compared. CONCLUSIONS: Selective arterial clamping technique was neither superior nor inferior to main artery clamping. PMID- 28355605 TI - The Use of a Software-Assisted Method to Estimate Fetal Weight at and Near Term Using Magnetic Resonance Imaging. AB - OBJECTIVE: The aim of this study was to apply a semi-automated calculation method of fetal body volume and, thus, of magnetic resonance-estimated fetal weight (MR EFW) prior to planned delivery and to evaluate whether the technique of measurement could be simplified while remaining accurate. METHODS: MR-EFW was calculated using a semi-automated method at 38.6 weeks of gestation in 36 patients and compared to the picture archiving and communication system (PACS). Per patient, 8 sequences were acquired with a slice thickness of 4-8 mm and an intersection gap of 0, 4, 8, 12, 16, or 20 mm. The median absolute relative errors for MR-EFW and the time of planimetric measurements were calculated for all 8 sequences and for each method (assisted vs. PACS), and the difference between the methods was calculated. RESULTS: The median delivery weight was 3,280 g. The overall median relative error for all 288 MR-EFW calculations was 2.4% using the semi-automated method and 2.2% for the PACS method. Measurements did not differ between the 8 sequences using the assisted method (p = 0.313) or the PACS (p = 0.118), while the time of planimetric measurement decreased significantly with a larger gap (p < 0.001) and in the assisted method compared to the PACS method (p < 0.01). CONCLUSION: Our simplified MR-EFW measurement showed a dramatic decrease in time of planimetric measurement without a decrease in the accuracy of weight estimates. PMID- 28355604 TI - Cutoff Pepsinogen Level for Predicting Unintendedly Eradicated Cases of Helicobacter pylori Infection in Subjects with Seemingly Normal Pepsinogen Levels. AB - BACKGROUNDS/AIMS: In the ABC method, which is a method for risk stratification of gastric cancer using serum anti-Helicobacter pylori antibody and pepsinogen (PG) test, subjects with normal PG and seronegative for H. pylori are named as "Group A" and are regarded as having a low risk of gastric cancer. These "Group A" subjects include unintentionally eradicated cases at relatively high risk, and this study aimed to identify these subjects. METHODS: Of the 109 subjects, 76 were classified as uninfected Group A subjects with negative histologic H. pylori infection and no histologic and endoscopic atrophy, and 33 subjects were classified serologically as Group A after successful eradication, which are serologically equal to the unintendedly eradicated cases in Group A. The usefulness of measuring PG levels to detect post-eradication cases was validated by using a receiver operating characteristic (ROC) curve analysis. RESULTS: The area under the ROC curve for PGI level was 0.736 +/- 0.06 (p < 0.01; cutoff value, 37.0 ng/mL; sensitivity, 77.6%; specificity, 72.7%), and that for the PGI/II ratio was 0.660 +/- 0.06 (p < 0.01; cutoff value, 5.1; sensitivity, 84.2%; specificity, 43.4%). CONCLUSION: PGI levels of <=37 ng/mL and PGI/II ratios of <=5.1 effectively identified unintendedly eradicated cases in Group A. PMID- 28355606 TI - Use of an Osteoblast Overload Damage Model to Probe the Effect of Icariin on the Proliferation, Differentiation and Mineralization of MC3T3-E1 Cells through the Wnt/beta-Catenin Signalling Pathway. AB - BACKGROUND/AIMS: Mechanical loading plays an important role in the regulation of bone mass. However, bone cells are not always under physiological stress. In some cases, bone tissue is subjected to an overloaded mechanical environment. For example, a person who is weight training and a stevedore often experience bone pain, inflammation and other bone fatigue damage symptoms. Icariin is the major ingredient of Herba epimedii, which has been widely used for the treatment of bone injury in traditional Chinese medicine, but its mechanism remains unknown. The aim of this study was to probe the effect of icariin on the proliferation and differentiation of osteoblasts exposed to overload and to determine whether the Wnt/beta-catenin signalling pathway is involved in the drug response in osteoblasts. METHODS: Mouse MC3T3-E1 cells were exposed to mechanical tensile strain using a four- point bending device to create an overload damage model. An MTT assay was performed to determine the effects of icariin on MC3T3-E1 cell proliferation. The mRNA and protein levels of ALP, COL-I, OCN, RUNX2 and beta catenin were assessed using RT-PCR and immunoblotting. The protein levels of beta catenin in the MC3T3-E1 cells were also determined using fluorescence microscopy. The mineralization of osteoblasts was assessed using Alizarin Red S staining. RESULTS: We found that icariin enhanced the proliferation of osteoblasts exposed to overload and promoted MC3T3-E1 cell differentiation and mineralization. Furthermore, the gene and protein expression levels of beta-catenin and RUNX2 all increased with icariin treatment compared with those in the damage group. CONCLUSION: Our study suggested that icariin promotes proliferation and differentiation in osteoblasts exposed to overload. The effect of icariin on osteoblastic differentiation acted by activating the RUNX2 promoter and the Wnt/beta- catenin pathway. PMID- 28355607 TI - Superagonistic CD28 Protects against Renal Ischemic Injury by Expansion of Regulatory T-Cell. AB - BACKGROUND: Regulatory T (Treg) cells are a highly suppressive subset of CD4+ lymphocytes and have recently been proved to be crucial to suppress the inflammatory responses of ischemic kidney injury. CD28 superagonists (CD28sa) are monoclonal antibodies that preferentially expand Treg cells without a T-cell receptor and a costimulatory signal. This study aims to test the protection and discover the mechanisms of CD28sa treatment against renal ischemia-reperfusion (IR) injury (IRI). METHODS: Male C57BL/6N mice were treated with CD28sa via peritoneal injection (0.1 mg) 6 days before the induction of IRI, or with 18-min ischemic precondition (IPC). IRI was induced by bilateral clamping of renal pedicles for 35 min followed by reperfusion. The role of Treg expansion in renal protection conferred by CD28sa treatment was examined using anti-CD25 antibody. RESULTS: CD28sa treatment alone significantly increased the percentage of Treg cells in the spleen (18.10 +/- 2.00 vs. 6.64 +/- 0.86%, p < 0.01), peripheral blood (16.43 +/- 5.94 vs. 2.57 +/- 1.09%, p < 0.01), and kidney (2.69 +/- 0.90 vs. 0.53 +/- 0.14%, p < 0.01) of C57BL/6N mice 6 days after the administration. Mice pretreated with CD28sa or IPC had less renal injury at 24 h after IRI with attenuation of renal tubular damage and lower serum creatinine compared with the mice that underwent renal IRI alone. The number of infiltrating macrophages in the kidney and IFN-gamma secreting CD4+ T cells in peripheral blood were diminished in the CD28sa-IR group and the IPC-IR group. The renal protection bestowed by CD28sa or IPC was abolished by anti-CD25 antibody administration. CONCLUSIONS: Treg expansion induced by CD28sa ameliorated renal IRI. PMID- 28355609 TI - Emerging Role of CaV1.2 Channels in Proliferation and Migration in Distinct Cancer Cell Lines. AB - Extensive research is currently underway, seeking better diagnostic methods and treatments and a better understanding of the molecular mechanisms involved in cancer, from the role of specific genetic mutations to the intricate biochemical and molecular pathways involved. Because of their role in regulating relevant physiological events such as cell proliferation, migration, and invasion, ion channels have recently been recognized as important elements in cancer initiation and progression. Moreover, it has been reported that pharmacological intervention in ion channel activity might provide protection against diverse types of cancer, and that ion channels could be used as targets to counteract tumor growth, prevent metastasis, and overcome the therapy resistance of tumor cells. In this context, Ca2+ channels have been found to play a role in tumorigenesis and tumor progression. Specifically, L-type Ca2+ channel inhibition may affect cell proliferation, differentiation, and apoptosis. This review aims to provide insights into the potential role of these channels in cancer cell lines, emphasizing their participation in cell proliferation, migration, and autophagy induction, as well as their potential as rational targets for new cancer therapeutics. PMID- 28355608 TI - New Wavelet Neurovascular Bundle for Bedside Evaluation of Cerebral Autoregulation and Neurovascular Coupling in Newborns with Hypoxic-Ischemic Encephalopathy. AB - Neonatal encephalopathy (NE) resulting from birth asphyxia constitutes a major global public health burden for millions of infants every year, and despite therapeutic hypothermia, half of these neonates have poor neurological outcomes. As new neuroprotective interventions are being studied in clinical trials, there is a critical need to establish physiological surrogate markers of therapeutic efficacy, to guide patient selection and/or to modify the therapeutic intervention. The challenge in the field of neonatal brain injury has been the difficulty of clinically discerning NE severity within the short therapeutic window after birth or of analyzing the dynamic aspects of the cerebral circulation in sick NE newborns. To address this roadblock, we have recently developed a new "wavelet neurovascular bundle" analytical system that can measure cerebral autoregulation (CA) and neurovascular coupling (NVC) at multiple time scales under dynamic, nonstationary clinical conditions. This wavelet analysis may allow noninvasive quantification at the bedside of (1) CA (combining metrics of blood pressure and cerebral near-infrared spectroscopy, NIRS) and (2) NVC (combining metrics obtained from NIRS and EEG) in newborns with encephalopathy without mathematical assumptions of linear and stationary systems. In this concept paper, we present case examples of NE using the proposed physiological wavelet metrics of CA and NVC. The new approach, once validated in large NE studies, has the potential to optimize the selection of candidates for therapeutic decision-making, and the prediction of neurocognitive outcomes. PMID- 28355610 TI - Thymic Neuroendocrine Neoplasms: Biological Behaviour and Therapy. AB - Thymic neuroendocrine neoplasms are rare tumours, but their management can often be highly problematic. While previously assumed to be essentially variants of bronchopulmonary (lung) carcinoids, they are generally more aggressive and more difficult to treat. Some 25% are associated with multiple endocrine neoplasia-1, while a higher proportion are associated with the ectopic ACTH syndrome, and occasionally both. We discuss the classification of these tumours, their biology as far as is known, and their clinical, biochemical and imaging features. We also review possible management options and suggest stratagems to optimise their treatment, which even today is far from optimal. PMID- 28355611 TI - The Effects of miR-136-5p-Mediated Regulation of A20 in Astrocytes from Cultured Spinal Cord Cultured Cells In Vitro. AB - BACKGROUND/AIMS: This study focused on investigating the regulatory mechanism of miR-136-5p in mouse astrocytes stimulated with interleukin-17(IL-17). METHODS: C57BL/6 mouse astrocytes were stimulated with IL-17 (100ng/ml) for various periods of time (0-48 hours) and at various doses (0-200 ng), and the expression levels of inflammatory cytokine and chemokine genes (IL-6, TNF-alpha, MCP-1, MCP 5 and MIP-2) were then detected by real-time PCR. The expression of the A20 gene was measured with real-time PCR in cells that were stimulated with IL-17 (50 ng/ml) for various periods of time (0-48 hours). C57BL/6 mouse astrocytes were transfected with Ctrl-anti-miR-136-5p or LNA -anti-miR-136-5p for 48 h. Thereafter, the cells were stimulated with or without IL-17 (50ng/ml) for 6 h. The level of A20 protein (TNFalpha-induced protein 3, TNFAIP3) was detected by Western blot analysis. RESULTS: (1) Compared with the DMEM control group, within six hours, IL-17 stimulation significantly increased the expression levels of inflammatory cytokine and chemokine genes and clearly decreased the expression level of the A20 protein. (2) Without IL-17 stimulation, the expression level of the miR-136-5p gene was significantly decreased, whereas in the miR-136-5p inhibition group, the A20 protein expression was elevated. IL-17 stimulation slightly decreased the expression of the A20 protein in the miR-136-5p-inhibition group, but it was still slightly higher than in the control group. CONCLUSION: This study demonstrated that miR-136-5p affected the expression of A20 in IL-17 stimulated astrocytes. PMID- 28355612 TI - Strengthening health security at the Hajj mass gatherings: characteristics of the infectious diseases surveillance systems operational during the 2015 Hajj. AB - Background: Hajj is one of the largest and the most ethnically and culturally diverse mass gatherings worldwide. The use of appropriate surveillance systems ensures timely information management for effective planning and response to infectious diseases threats during the pilgrimage. The literature describes infectious diseases prevention and control strategies for Hajj but with limited information on the operations and characteristics of the existing Hajj infectious diseases surveillance systems. Method: We reviewed documents, including guidelines and reports from the Saudi Ministry of Health's database, to describe the characteristics of the infectious diseases surveillance systems that were operational during the 2015 Hajj, highlighting best practices and gaps and proposing strategies for strengthening and improvement. Using Pubmed and Embase online search engines and a combination of search terms including, 'mass gatherings' 'Olympics' 'surveillance' 'Hajj' 'health security', we explored the existing literature and highlighted some lessons learnt from other international mass gatherings. Results: A regular indicator-based infectious disease surveillance system generates routine reports from health facilities within the Kingdom to the regional and central public health directorates all year round. During Hajj, enhanced indicator-based notifiable diseases surveillance systems complement the existing surveillance tool to ensure timely reporting of event information for appropriate action by public health officials. Conclusion: There is need to integrate the existing Hajj surveillance data management systems and to implement syndromic surveillance as an early warning system for infectious disease control during Hajj. International engagement is important to strengthen Hajj infectious diseases surveillance and to prevent disease transmission and globalization of infectious agents which could undermine global health security. PMID- 28355614 TI - Silent killer-the dangers of carbon monoxide poisoning during international travel. PMID- 28355613 TI - Clostridium difficile infection in returning travellers. AB - Background: There is increasing recognition of the contribution of community acquired cases to the global burden of Clostridium difficile infection (CDI). The epidemiology of CDI among international travellers is poorly understood, and factors associated with international travel, such as antibiotic use and changes in gut microbiota, could potentially put travellers at higher risk. Methods: We summarized demographic, travel-associated and geographic characteristics of travellers with CDI in the GeoSentinel database from 1997 to 2015. We also surveyed GeoSentinel sites to compare various testing indications, approaches, and diagnostic modalities. Results: We identified 260 GeoSentinel records, including 187 that satisfied criteria for analysis (confirmed cases in non immigrant travellers aged >2 years, seen <12 weeks post-travel). CDI was reported in all age groups and in travellers to all world regions; the largest proportions of cases having destinations in Asia (31%), Central/South America or the Caribbean (30%) and Africa (24%). Our site survey revealed substantial heterogeneity of testing approaches between sites; the most commonly used test was the C. difficile toxin gene PCR. Conclusions: CDI is encountered in returning international travellers, although there is considerable variability in testing practices. These data underscore the importance of awareness of C. difficile as a potential cause of travel-associated diarrhoea. PMID- 28355615 TI - Bordetella pertussis infections in travelers: data from the GeoSentinel global network. AB - Background: Pertussis is a highly contagious, vaccine-preventable respiratory infection that is endemic worldwide. There are limited data regarding the occurrence of pertussis in travelers. The objective of this study is to identify travel-related pertussis cases reported to the GeoSentinel Surveillance Network. Methods: This is a descriptive, retrospective analysis of GeoSentinel records from 25 travel/tropical medicine clinics in 16 countries. Frequencies of demographic and travel-related characteristics and symptoms of 74 cases of pertussis in travelers and new immigrants from 1999 to 2015 were analysed. Results: There were 74 probable and confirmed cases of pertussis in the GeoSentinel database; median age was 44 years, and 38 (51%) patients were female. Tourism was the most common reason for travel (41; 55%). Country of exposure was determined in 66 cases with travelers returning from India and China constituting the highest number of cases (10 cases each; 15% each). Seventy of 74 (95%) patients had respiratory symptoms, while fatigue and fever were reported by 21 (28%) and 20 (27%), respectively. Immunization status against pertussis was unknown. Most cases were reported after 2005 (69; 93%). Conclusions: Our study describes 74 cases of pertussis acquired during travel and reported to the GeoSentinel Network. Pertussis should be considered in returned travelers who present with respiratory symptoms. Surveillance and detection of imported cases are important to prevent onward transmission in the community. The pre-travel consultation provides an opportunity to verify immunization status and provide routine vaccinations such as pertussis. PMID- 28355616 TI - Medical evacuations in the oil and gas industry: a retrospective review with implications for future evacuation and preventative strategies. AB - Background: Businesses increasingly conduct operations in remote areas where medical evacuation [Medevac(s)] carries more risk. Royal Dutch Shell developed a remote healthcare strategy whereby enhanced remote healthcare is made available to the patient through use of telemedicine and telemetry. To evaluate that strategy, a review of Medevacs of Shell International employees [i.e. expatriate employees (EEs) and frequent business travellers (FBTs)] was undertaken. Method: A retrospective review of Medevac data (period 2008-12) that were similar in operational constraints and population profile was conducted. Employee records and Human Resource data were used as a denominator for the population. Analogous Medevac data from specific locations were used to compare patterns of diagnoses. Results: A total of 130 Medevacs were conducted during the study period, resulting in a Medevac rate of 4 per 1000 of population with 16 per 1000 for females and 3 per 1000 for males, respectively. The youngest and oldest age groups required Medevacs in larger proportions. The evacuation rates were highest for countries classified as 'high' or 'extreme risk'. The most frequent diagnostic categories for Medevac were: trauma, digestive, musculoskeletal, cardiac and neurological. In 9% of the total, a strong to moderate link could be made between the pre-existing medical condition and diagnosis leading to Medevac. Conclusion: This study uniquely provides a benchmark Medevac rate (4 per 1000) for EEs and FBTs and demonstrates that Medevac rates are highest from countries identified as 'high risk'; there is an age and gender bias, and pre-existing medical conditions are of notable relevance. It confirms a change in the trend from injury to illness as a reason for Medevac in the oil and gas industry and demonstrates that diagnoses of a digestive and traumatic nature are the most frequent. A holistic approach to health (as opposed to a predominant focus on fitness to work), more attention to female travellers, and the application of modern technology and communication will reduce the need for Medevacs. PMID- 28355617 TI - Fasten your seatbelts: preventing injury from air turbulence in travellers. PMID- 28355618 TI - Avoiding the rough: travel health risks facing golf tourists. PMID- 28355620 TI - Imported dengue fever in East London: a 6-year retrospective observational study. AB - Background: Dengue fever (DF) is a frequently imported arthropod-borne infection in the United Kingdom but its broad range of clinical presentations makes it potentially unrecognized by clinicians. Methods: We conducted a 6-year retrospective case note review of laboratory confirmed DF patients in East London in the period from 1 January 2010 through 31 December 2015. Epidemiological, clinical and laboratory features of imported DF were described. Risk factors associated with viraemic DF presentations were assessed. Results: Forty-four patients (4 from primary care clinics and 40 from three acute hospitals) were confirmed to have DF through RNA and/or IgM detection. In total, 86.4% (38/44) had primary infection compared to 13.6% (6/44) with secondary infection. Viraemic DF presentations accounted for 59.1% (26/44) of cases. The median age was 34 years (IQR 25-43). Most patients were males (68.2%, 30/44) and of non-white ethnicity (81.8%, 36/44). South Asia was the most frequent travel destination (52.3%, 23/44) followed by Southeast Asia (20.5%, 9/44). July-September was the peak season of presentation (43.2%, 19/44). The median interval between arrival in the UK and laboratory testing was 7 days (IQR 4-13). Arriving from abroad <= 7 days before molecular testing (age-adjusted odds ratios [OR] 16.98, 95% CI 2.43 118.75, P = 0.004) and travel to South or Southeast Asia regions (age-adjusted OR 4.41, 95% CI 1.07-18.21, P = 0.040) were associated with detectable viraemia at presentation. Only one DF patient met the WHO severity criteria. HIV serostatus was determined in 61.4% (27/44) of cases. Conclusion: Clinicians need to improve DF recognition as well as rates of HIV testing in tropical travellers. Region of travel and time since arrival from DF endemic settings may help clinicians optimize requests for molecular testing. Further research on the clinical and public health aspects of imported DF is needed. PMID- 28355619 TI - Infection burden among medical events onboard cargo ships: a four-year study. AB - Background: . Cargo ships are medically isolated, yet neglected environments. We aimed to know about medical events onboard cargo ships. Methods: We reviewed all the medical events onboard a large commercial 471-cargo ship company for 4 years. Medical events were recorded within 20 categories as routinely used by Medical Maritime Consulting Centers, using a 4-level medical gravity score. The chi 2 test and logistic regression and correspondence analyses were used for the analysis of qualitative variables. Results: Excluding wounds and burns, a total of 322 illness events were notified by onboard health officers for 471 ships totalizing 46 navigation/months. 250 non-infectious events and 72 cases of infection yielded an incidence of 7.75 medical events for 1000 person-years. Infections comprised 25 digestive tract infections, 17 skin infections, 8 urinary tract infections, 5 dental infections, 4 isolated fevers, 3 Ear-Nose-Throat and respiratory tract infections, 2 ocular infections, myalgia and orchitis and 1 case of mediastinal infection. The mean age for sailors diagnosed with infection (37.7 +/- 10.5 years) was significantly younger than the mean age of sailors diagnosed with non-infectious disease (40.8 +/- 11.2 years) ( P = 0.04). In affected sailors, the proportion of death and hospitalization among infectious disease cases (26/69, 37.7%) was significantly higher than the proportion of death and hospitalization for non-infectious disease cases (48/242, 19.8%) ( P = 0.02). The correspondence analysis showed that the routes may be classified according to two main independent risks, digestive infections and skin infections. We observed a statistically significant correlation between the severity of medical events and the maritime route "North Europe-OI-Australia India-North Europe". Conclusions: These data illustrate a previously underreported variability of the medical risks in various maritime routes; and help promoting targeted medical interventions including the implementation of onboard point-of-care laboratories, to further increase the rapidity of the diagnosis and the medical management onboard cargo ships. PMID- 28355621 TI - Use of pre-travel vaccine-preventable disease serology as a screening tool to identify patients in need of pre-travel vaccination: a retrospective audit. AB - Background: Vaccination is a safe and effective public health intervention that not only protects individual travellers from vaccine-preventable diseases (VPDs), but prevents them from becoming a source of disease in their destination and on their return. Obtaining an accurate vaccination history from travellers during a pre-travel review can be difficult; serology may be used to identify patients who are non-immune to specific diseases in order to guide vaccination requirements. Clinically relevant data about the usefulness of serology in this setting are lacking. We performed a retrospective audit of pre-travel VPD serology requested by practitioners of a busy community-based travel clinic. Methods: All serological results for measles, mumps, rubella, varicella zoster virus, hepatitis A and B requested over a 5-year period were extracted and analysed. Results were stratified by gender and year of birth and compared using Stata. Results: Four thousand four hundred and fifty-one serological assays from 1445 individual were assessed. Overall, 47% of patients tested had at least one negative serological result. High rates of seropositivity for measles, mumps and rubella were seen in those born prior to 1966 but >10% of travellers born after 1966 lacked serological evidence of protection against these diseases. Hepatitis A and B serological results revealed broadly lower rates of immunity in our community likely reflecting the absence of these vaccines from historical vaccine protocols. Conclusions: Serology can be a useful tool in the identification of non-immune travellers to enable targeted vaccination prior to travel. We recommend that travel health clinicians assess patients' vaccination and infection histories, and strongly consider serology or vaccination where there is doubt about immunity. This will help protect the traveller and prevent importation of disease into destination or home communities. PMID- 28355622 TI - Climate change, emerging infections and blood donations. PMID- 28355623 TI - QUEST+: A general multidimensional Bayesian adaptive psychometric method. AB - QUEST+ is a Bayesian adaptive psychometric testing method that allows an arbitrary number of stimulus dimensions, psychometric function parameters, and trial outcomes. It is a generalization and extension of the original QUEST procedure and incorporates many subsequent developments in the area of parametric adaptive testing. With a single procedure, it is possible to implement a wide variety of experimental designs, including conventional threshold measurement; measurement of psychometric function parameters, such as slope and lapse; estimation of the contrast sensitivity function; measurement of increment threshold functions; measurement of noise-masking functions; Thurstone scale estimation using pair comparisons; and categorical ratings on linear and circular stimulus dimensions. QUEST+ provides a general method to accelerate data collection in many areas of cognitive and perceptual science. PMID- 28355624 TI - Corrections. PMID- 28355626 TI - Color contributes to object-contour perception in natural scenes. AB - The magnitudes of chromatic and achromatic edge contrast are statistically independent and thus provide independent information, which can be used for object-contour perception. However, it is unclear if and how much object-contour perception benefits from chromatic edge contrast. To address this question, we investigated how well human-marked object contours can be predicted from achromatic and chromatic edge contrast. We used four data sets of human-marked object contours with a total of 824 images. We converted the images to the Derrington-Krauskopf-Lennie color space to separate chromatic from achromatic information in a physiologically meaningful way. Edges were detected in the three dimensions of the color space (one achromatic and two chromatic) and compared to human-marked object contours using receiver operating-characteristic (ROC) analysis for a threshold-independent evaluation. Performance was quantified by the difference of the area under the ROC curves (DeltaAUC). Results were consistent across different data sets and edge-detection methods. If chromatic edges were used in addition to achromatic edges, predictions were better for 83% of the images, with a prediction advantage of 3.5% DeltaAUC, averaged across all data sets and edge detectors. For some images the prediction advantage was considerably higher, up to 52% DeltaAUC. Interestingly, if achromatic edges were used in addition to chromatic edges, the average prediction advantage was smaller (2.4% DeltaAUC). We interpret our results such that chromatic information is important for object-contour perception. PMID- 28355625 TI - Predicting rhesus monkey eye movements during natural-image search. AB - There are three prominent factors that can predict human visual-search behavior in natural scenes: the distinctiveness of a location (salience), similarity to the target (relevance), and features of the environment that predict where the object might be (context). We do not currently know how well these factors are able to predict macaque visual search, which matters because it is arguably the most popular model for asking how the brain controls eye movements. Here we trained monkeys to perform the pedestrian search task previously used for human subjects. Salience, relevance, and context models were all predictive of monkey eye fixations and jointly about as precise as for humans. We attempted to disrupt the influence of scene context on search by testing the monkeys with an inverted set of the same images. Surprisingly, the monkeys were able to locate the pedestrian at a rate similar to that for upright images. The best predictions of monkey fixations in searching inverted images were obtained by rotating the results of the model predictions for the original image. The fact that the same models can predict human and monkey search behavior suggests that the monkey can be used as a good model for understanding how the human brain enables natural scene search. PMID- 28355627 TI - The role of one-shot learning in #TheDress. AB - #TheDress is remarkable in two aspects. First, there is a bimodal split of the population in the perception of the dress's colors (white/gold vs. black/blue). Second, whereas interobserver variance is high, intra-observer variance is low, i.e., the percept rarely switches in a given individual. There are two plausible routes of explanations: either one-shot learning during the first presentation of the image splits observers into two different, stable populations, or the differences are caused by stable traits of observers, such as different visual systems. Here, we hid large parts of the image by white occluders. The majority of naive participants perceived the dress as black and blue. With black occluders, the majority of observers perceived the dress as white and gold. The percept did not change when we subsequently presented the full image, arguing for a crucial role of one-shot learning. Next, we investigated whether the first fixation determines the perceived color in naive observers. We found no such effect. It remains thus a puzzling question where the source of variability in the different percepts comes from. PMID- 28355628 TI - Taking a(c)count of eye movements: Multiple mechanisms underlie fixations during enumeration. AB - We habitually move our eyes when we enumerate sets of objects. It remains unclear whether saccades are directed for numerosity processing as distinct from object oriented visual processing (e.g., object saliency, scanning heuristics). Here we investigated the extent to which enumeration eye movements are contingent upon the location of objects in an array, and whether fixation patterns vary with enumeration demands. Twenty adults enumerated random dot arrays twice: first to report the set cardinality and second to judge the perceived number of subsets. We manipulated the spatial location of dots by presenting arrays at 0 degrees , 90 degrees , 180 degrees , and 270 degrees orientations. Participants required a similar time to enumerate the set or the perceived number of subsets in the same array. Fixation patterns were systematically shifted in the direction of array rotation, and distributed across similar locations when the same array was shown on multiple occasions. We modeled fixation patterns and dot saliency using a simple filtering model and show participants judged groups of dots in close proximity (2 degrees -2.5 degrees visual angle) as distinct subsets. Modeling results are consistent with the suggestion that enumeration involves visual grouping mechanisms based on object saliency, and specific enumeration demands affect spatial distribution of fixations. Our findings highlight the importance of set computation, rather than object processing per se, for models of numerosity processing. PMID- 28355629 TI - Translucency and the perception of shape. AB - Previous studies have shown that the perceived three-dimensional (3D) shape of objects depends on their material composition. The majority of this work has focused on glossy, flat-matte, or velvety materials. Here, we studied perceived 3D shape of translucent materials. We manipulated the spatial frequency of surface relief perturbations of translucent and opaque objects. Observers indicated which of two surfaces appeared to have more bumps. They also judged local surface orientation using gauge probe figures. We found that translucent surfaces appeared to have fewer bumps than opaque surfaces with the same 3D shape (Experiment 1), particularly when self-occluding contours were hidden from view (Experiment 2). We also found that perceived local curvature was underestimated for translucent objects relative to opaque objects, and that estimates of perceived local surface orientation were similarly correlated with luminance for images of both opaque and translucent objects (Experiment 3). These findings suggest that the perceived mesoscopic shape of completely matte translucent objects can be underestimated due to a decline in the steepness of luminance gradients relative to those of opaque objects. PMID- 28355630 TI - Inferring the stiffness of unfamiliar objects from optical, shape, and motion cues. AB - Visually inferring the stiffness of objects is important for many tasks but is challenging because, unlike optical properties (e.g., gloss), mechanical properties do not directly affect image values. Stiffness must be inferred either (a) by recognizing materials and recalling their properties (associative approach) or (b) from shape and motion cues when the material is deformed (estimation approach). Here, we investigated interactions between these two inference types. Participants viewed renderings of unfamiliar shapes with 28 materials (e.g., nickel, wax, cork). In Experiment 1, they viewed nondeformed, static versions of the objects and rated 11 material attributes (e.g., soft, fragile, heavy). The results confirm that the optical materials elicited a wide range of apparent properties. In Experiment 2, using a blue plastic material with intermediate apparent softness, the objects were subjected to physical simulations of 12 shape-transforming processes (e.g., twisting, crushing, stretching). Participants rated softness and extent of deformation. Both correlated with the physical magnitude of deformation. Experiment 3 combined variations in optical cues with shape cues. We find that optical cues completely dominate. Experiment 4 included the entire motion sequence of the deformation, yielding significant contributions of optical as well as motion cues. Our findings suggest participants integrate shape, motion, and optical cues to infer stiffness, with optical cues playing a major role for our range of stimuli. PMID- 28355631 TI - Persistent illusory apparent motion in sequences of uncorrelated random dots. AB - We report a novel phenomenon in which long sequences of random dot arrays refreshing at 2.5 Hz lead to persistent illusory percepts of coherent apparent motion. We term this effect illusory apparent motion (IAM). To quantify this illusion, we devised a persistence task in which observers are primed with a particular motion pattern and must indicate when the motion pattern ends. In Experiment 1 (N = 119), we induced translational apparent motion patterns and show that both drifting motion (e.g., up-up-up-up) and rebounding motion (e.g., up-down-up-down) persists throughout many frames of uncorrelated random dots, although rebounding motion tends to persist for longer (a rebounding bias). In Experiment 2 (N = 60), we induced rotational IAM on an annulus-shaped display, and show that the topology of the display (whether the annulus is complete or has a gap) determines whether or not the rebounding bias is present. Based on our findings, we argue that IAM provides a powerful tool to study the mechanisms, constraints, and individual differences in the perception of illusory motion. PMID- 28355632 TI - Cross-modal attention influences auditory contrast sensitivity: Decreasing visual load improves auditory thresholds for amplitude- and frequency-modulated sounds. AB - We used a cross-modal dual task to examine how changing visual-task demands influenced auditory processing, namely auditory thresholds for amplitude- and frequency-modulated sounds. Observers had to attend to two consecutive intervals of sounds and report which interval contained the auditory stimulus that was modulated in amplitude (Experiment 1) or frequency (Experiment 2). During auditory-stimulus presentation, observers simultaneously attended to a rapid sequential visual presentation-two consecutive intervals of streams of visual letters-and had to report which interval contained a particular color (low load, demanding less attentional resources) or, in separate blocks of trials, which interval contained more of a target letter (high load, demanding more attentional resources). We hypothesized that if attention is a shared resource across vision and audition, an easier visual task should free up more attentional resources for auditory processing on an unrelated task, hence improving auditory thresholds. Auditory detection thresholds were lower-that is, auditory sensitivity was improved-for both amplitude- and frequency-modulated sounds when observers engaged in a less demanding (compared to a more demanding) visual task. In accord with previous work, our findings suggest that visual-task demands can influence the processing of auditory information on an unrelated concurrent task, providing support for shared attentional resources. More importantly, our results suggest that attending to information in a different modality, cross-modal attention, can influence basic auditory contrast sensitivity functions, highlighting potential similarities between basic mechanisms for visual and auditory attention. PMID- 28355633 TI - Combining 1-D components to extract pattern information: It is about more than component similarity. AB - At least under some conditions, plaid stimuli are processed by combining information first extracted in orientation and scale-selective channels. The rules that govern this combination across channels are only partially understood. Although the available data suggests that only components having similar spatial frequency and contrast are combined, the extent to which this holds has not been firmly established. To address this question, we measured, in human subjects, the short-latency reflexive vergence eye movements induced by stereo plaids in which spatial frequency and contrast of the components are independently varied. We found that, although similarity in component spatial frequency and contrast matter, they interact in a nonseparable way. One way in which this relationship might arise is if the internal estimate of contrast is not a faithful representation of stimulus contrast but is instead spatial frequency-dependent (with higher spatial frequencies being boosted). We propose that such weighting might have been put in place by a mechanism that, in an effort of achieve contrast constancy and/or coding efficiency, regulates the gain of detectors in early visual cortex to equalize their long-term average response to natural images. PMID- 28355634 TI - The social determinants of inequalities in self-reported health in Europe: findings from the European social survey (2014) special module on the social determinants of health. AB - Background: Health inequalities persist between and within European countries. Such inequalities are usually explained by health behaviours and according to the conditions in which people work and live. However, little is known about the relative contribution of these factors to health inequalities in European countries. This paper aims to investigate the independent and joint contribution of a comprehensive set of behavioural, occupational and living conditions factors in explaining social inequalities in self-rated health (SRH). Method: Data from 21 countries was obtained from the 2014 European Social Survey and examined for respondents aged 25-75. Adjusted rate differences (ARD) and adjusted rate risks (ARR), generated from binary logistic regression models, were used to measure health inequalities in SRH and the contribution of behavioural, occupational and living conditions factors. Result: Absolute and relative inequalities in SRH were found in all countries and the magnitude of socio-economic inequalities varied considerably between countries. While factors were found to differentially contribute to the explanation of educational inequalities in different European countries, occupational and living conditions factors emerged as the leading causes of inequalities across most of the countries, contributing both independently and jointly with behavioural factors. Conclusion: The observed shared effects of different factors to health inequalities points to the interdependent nature of occupational, behavioural and living conditions factors. Tackling health inequalities should be a concentred effort that goes beyond interventions focused on single factors. PMID- 28355635 TI - Subjective perceptions of unmet need for health care in Europe among social groups: Findings from the European social survey (2014) special module on the social determinants of health. AB - Background: Unmet need can be defined as the individually perceived subjective differences between services judged necessary to deal with health problems and the services actually received. This study examines what factors are associated with unmet need, as well as how reasons for unmet need are distributed across socioeconomic and demographic groups in Europe. Methods: Multilevel logistic regression models were employed using data from the 7th round of the European Social Survey, on people aged 25-75. Self-reported unmet need measured whether respondents had been unable to get medical consultation or treatment in the last 12 months. Reasons for unmet need were grouped into three categories: availability, accessibility and acceptability. Health status was measured by self reported health, non-communicable diseases and depressive symptoms. Results: Two thirds of all unmet need were due waiting lists and appointment availability. Females and young age groups reported more unmet need. We found no educational inequalities, while financial strain was found to be an important factor for all types of unmet need for health care in Europe. All types of health care use and poor health were associated with unmet need. Low physician density and high out of-pocket payments were found to be associated with unmet need due to availability. Conclusion: Even though health care coverage is universal in many European welfare states, financial strain appeared as a major determinant for European citizens' access to health care. This may suggest that higher income groups are able to bypass waiting lists. European welfare states should, therefore, intensify their efforts in reducing barriers for receiving care. PMID- 28355636 TI - Educational inequalities in risky health behaviours in 21 European countries: findings from the European social survey (2014) special module on the social determinants of health. AB - Background: It has been suggested that cross-national variation in educational inequalities in health outcomes (e.g. NCDs) is due to cross-national variation in risky health behaviour. In this paper we aim to use highly recent data (2014) to examine educational inequalities in risky health behaviour in 21 European countries from all regions of the continent to map cross-national variation in the extent to which educational level is associated with risky health behaviour. We focus on four dimensions of risky health behaviour: smoking, alcohol use, lack of physical activity and lack of fruit and vegetable consumption. Methods: We make use of recent data from the 7th wave of the European Social Survey (2014), which contains a special rotating module on the social determinants of health. We performed logistic regression analyses to examine the associations between educational level and the risky health behaviour indicators. Educational level was measured through a three-category version of the harmonized International Standard Classification of Education (ISCED). Results: Our findings show substantial and mostly significant inequalities in risky health behaviour between educational groups in most of the 21 European countries examined in this paper. The risk of being a daily smoker is higher as respondents' level of education is lower (Low education (L): OR = 4.24 (95% CI: 3.83-4.68); Middle education (M): OR = 2.91 (95% CI: 2.65-3.19)). Respondents have a lower risk of consuming alcohol frequently if they have a low level of education (L: OR = 0.59 (95% CI: 0.54 0.64); M: OR = 0.70 (95% CI: 0.65-0.76)), but a higher risk of binge drinking frequently (L: OR = 1.29 (95% CI: 1.16-1.44); M: OR = 1.15 (95% CI: 1.04-1.27)). People are more likely to be physically active at least 3 days in the past week when they have a higher level of education (M: OR = 1.42 (95% CI: 1.34-1.50); H: OR = 1.67 (95% CI: 1.55-1.80)). Finally, people are more likely to consume fruit and vegetables at least daily if they have a higher level of education (fruit: M: OR = 1.09 (95% CI: 1.03-1.16); H: OR = 1.77 (95% CI: 1.63-1.92); vegetables: M: OR = 1.34 (95% CI: 1.26-1.42); H: OR = 2.35 (95% CI: 2.16-2.55)). However, we also found considerable cross-national variation in the associations between education and risky health behaviour. Conclusions: Our results yield a complex picture: the lowest educational groups are more likely to smoke and less likely to engage in physical activity and to eat fruit and vegetables, but the highest educational groups are at greater risk of frequent alcohol consumption. Additionally, inequalities in risky health behaviour do not appear to be systematically weakest in the South or strongest in the North and West of Europe. PMID- 28355637 TI - Self-rated health and wellbeing among the working-age immigrant population in Western Europe: findings from the European social survey (2014) special module on the social determinants of health. AB - Background: The aim is to study the difference in self-rated health and wellbeing between native non-migrants and different immigrant groups: new (defined as having lived in the host country for 10 years or less), old (living in the host country for more than 10 years) and second-generation immigrants living in Western European countries. Methods: We use the European Social Survey Round 7, collected in 2014/15, to study the working-age population aged 20-64. We separate between first (new and old) and second-generation immigrants. Self-rated health was dichotomised as very good and good versus less than good health. Wellbeing was measured by constructing a continuous scale from eight 4-point Likert scale items (CES-D8). Data for 14 Western European countries were pooled together (N = 18 577). Men and women were analyzed separately using binary logistic and OLS regression. Results: For self-rated health, we found support among both men and women for the healthy migrant hypothesis. Among men only, second-generation immigrants had more deteriorating self-rated health by age, and old immigrants were similar to the natives. The four groups differed in wellbeing only among those with primary education, and more so among men than among women. Second generation immigrants were worse and new immigrants better than natives and old immigrants. Conclusion: This study supports the healthy migrant hypothesis among both men and women. Among men, old and second-generation immigrants' predicted health falls more steeply by age. There was some variation between migrant groups in wellbeing among those with low education. PMID- 28355638 TI - The socioeconomic distribution of non-communicable diseases in Europe: findings from the European Social Survey (2014) special module on the social determinants of health. AB - Background: A range of non-communicable diseases (NCDs) has been found to follow a social pattern whereby socioeconomic status predicts either a higher or lower risk of disease. Comprehensive evidence on the socioeconomic distribution of NCDs across Europe, however, has been limited. Methods: Using cross-sectional 2014 European Social Survey data from 20 countries, this paper examines socioeconomic inequalities in 14 self-reported NCDs separately for women and men: heart/circulatory problems, high blood pressure, back pain, arm/hand pain, foot/leg pain, allergies, breathing problems, stomach/digestion problems, skin conditions, diabetes, severe headaches, cancer, obesity and depression. Using education to measure socioeconomic status, age-controlled adjusted risk ratios were calculated and separately compared a lower and medium education group with a high education group. Results: At the pooled European level, a social gradient in health was observed for 10 NCDs: depression, diabetes, obesity, heart/circulation problems, hand/arm pain, high blood pressure, breathing problems, severe headaches, foot/leg pain and cancer. An inverse social gradient was observed for allergies. Social gradients were observed among both genders, but a greater number of inequalities were observed among women. Country-specific analyses show that inequalities in NCDs are present everywhere across Europe and that inequalities exist to different extents for each of the conditions. Conclusion: This study provides the most up-to-date overview of socioeconomic inequalities for a large number of NCDs across 20 European countries for both women and men. Future investigations should further consider the diseases, and their associated determinants, for which socioeconomic differences are the greatest. PMID- 28355639 TI - Occupational inequalities in self-rated health and non-communicable diseases in different regions of Europe: findings from the European Social Survey (2014) special module on the social determinants of health. AB - Background: Socioeconomic inequalities in the prevalence of non-communicable diseases (NCDs) are evident across European populations. Several previous studies have addressed the question of whether occupational inequalities in health differ across European regions. It is uncertain however, the degree to which occupational inequalities in NCDs are similar or dissimilar across different European regions. Methods: Using 2014 European Social Survey data from 20 countries, this article examines occupational inequalities in poor self-rated health (SRH) and 14 self-reported NCDs separately for women and men, by European region: heart/circulatory problems, high blood pressure, back pain, arm/hand pain, foot/leg pain, allergies, breathing problems, stomach/digestion problems, skin conditions, diabetes, severe headaches, cancer, obesity and depression. Age controlled adjusted risk ratios were calculated and separately compared a working class and intermediate occupational group with a salariat group. Results: Working class Europeans appear to have the highest risk of reporting poor SRH and a number of NCDs. We find inequalities in some NCDS to be the largest in the Northern region, suggesting further evidence of a Nordic paradox. Like some previous work, we did not find larger inequalities in poor SRH in the Central/East region. However, we did find the largest inequalities in this region for some NCDs. Our results do not align completely with previous work which finds smaller health inequalities in Southern Europe. Conclusions: This work provides a first look at occupational inequalities across a range of NCDs for European men and women by region. Future work is needed to identify the underlying determinants behind regional differences. PMID- 28355640 TI - The contribution of housing and neighbourhood conditions to educational inequalities in non-communicable diseases in Europe: findings from the European Social Survey (2014) special module on the social determinants of health. AB - Background: Social gradients have been found across European populations, where less affluent groups are more often affected by poor housing and neighbourhood conditions. While poor housing and neighbourhood quality have been associated with a range of non-communicable diseases (NCDs), these conditions have rarely been applied to the examination of socioeconomic differences in NCDs. This study therefore asks 'to what extent does adjusting for poor housing and neighbourhood conditions reduce inequalities in NCDs among men and women in Europe'? Methods: Our analysis used pooled-data from 20 European countries for women (n= 12 794) and men (n= 11 974), aged 25-75, from round 7 of the European Social Survey. Fourteen NCDs were investigated: heart/circulatory problems, high blood pressure, back pain, arm/hand pain, foot/leg pain, allergies, breathing problems, stomach/digestion problems, skin conditions, diabetes, severe headaches, cancer, obesity and depression. We used binary logistic regression models, stratified by gender, and adjusted rate ratios to examine whether educational inequalities in NCDs were reduced after controlling for poor housing and neighbourhood quality. Results: Overall, we find that adjusting for poor housing and neighbourhood quality reduces inequalities in NCDs. While reductions were relatively small for some NCDs-for high blood pressure, reductions were found in the range of 0-4.27% among women-for other conditions reductions were more considerable. Controlling for both housing and neighbourhood conditions for example, reduced inequalities by 16-24% for severe headaches and 14-30% for breathing problems. Conclusions: Social gradients in poor housing and neighbourhood quality could be an important contributor to educational inequalities in some NCDs. PMID- 28355641 TI - Depressed during the depression: has the economic crisis affected mental health inequalities in Europe? Findings from the European Social Survey (2014) special module on the determinants of health. AB - Background: Economic crises constitute a shock to societies with potentially harmful effects to the mental health status of the population, including depressive symptoms, and existing health inequalities. Methods: With recent data from the European Social Survey (2006-14), this study investigates how the economic recession in Europe starting in 2007 has affected health inequalities in 21 European nations. Depressive feelings were measured with the CES-D eight-item depression scale. We tested for measurement invariance across different socio economic groups. Results: Overall, depressive feelings have decreased between 2006 and 2014 except for Cyprus and Spain. Inequalities between persons whose household income depends mainly on public benefits and those who do not have decreased, while the development of depressive feelings was less favorable among the precariously employed and the inactive than among the persons employed with an unlimited work contract. There are no robust effects of the crisis measure on health inequalities. Conclusion: Negative implications for mental health (in terms of depressive feelings) have been limited to some of the most strongly affected countries, while in the majority of Europe persons have felt less depressed over the course of the recession. Health inequalities have persisted in most countries during this time with little influence of the recession. Particular attention should be paid to the mental health of the inactive and the precariously employed. PMID- 28355642 TI - Quality of life and living with cancer: findings from the European social survey (2014) special module on the social determinants of health. AB - Background: This study is a comparison of quality of life (QOL) of current and previous cancer victims with people who never had experienced cancer in samples from the general population from the 19 countries in the European Social Survey (ESS) 2014. Methods: The study was based on the ESS 2014 with representative samples from 19 countries. QOL was measured by combining two questions on happiness and life satisfaction into a QOL scale. Multilevel modelling was used to examine whether the relationship between cancer status and QOL varies between countries in general and by welfare state regimes in particular. Results: People with cancer at the time of the interview, showed lower general QOL than both people who previously have had cancer and people who never have experienced cancer. The unadjusted and the adjusted odds ratios (ORs) for poor QOL were respectively, OR = 2.38, (2.07, 2.74) and OR = 1.98, (1.71, 2.30). The difference between the 'Never' and the 'Previously' groups was minor but statistical significant. The welfare state classification was a strong predictor of country differences in QOL, but there was no significant statistical interaction effect between cancer status and the welfare state classification. The study also replicated well-documented findings on differences in QOL by education and social support. Conclusion: The QOL of people with a cancer disease is significantly impaired. People who previously have had cancer, scored only slightly lower on the QOL scale than people who never had experienced cancer. We found evidence indicating that these differences may vary between the countries, but this variation cannot be explained by the welfare state classification. PMID- 28355643 TI - Regional inequalities in self-reported conditions and non-communicable diseases in European countries: Findings from the European Social Survey (2014) special module on the social determinants of health. AB - Background: Within the European Union (EU), substantial efforts are being made to achieve economic and social cohesion, and the reduction of health inequalities between EU regions is integral to this process. This paper is the first to examine how self-reported conditions and non-communicable diseases (NCDs) vary spatially between and within countries. Methods: Using 2014 European Social Survey (ESS) data from 20 countries, this paper examines how regional inequalities in self-reported conditions and NCDs vary for men and women in 174 regions (levels 1 and 2 Nomenclature of Statistical Territorial Units, 'NUTS'). We document absolute and relative inequalities across Europe in the prevalence of eight conditions: general health, overweight/obesity, mental health, heart or circulation problems, high blood pressure, back, neck, muscular or joint pain, diabetes and cancer. Results: There is considerable inequality in self-reported conditions and NCDs between the regions of Europe, with rates highest in the regions of continental Europe, some Scandinavian regions and parts of the UK and lowest around regions bordering the Alps, in Ireland and France. However, for mental health and cancer, rates are highest in regions of Eastern European and lowest in some Nordic regions, Ireland and isolated regions in continental Europe. There are also widespread and consistent absolute and relative regional inequalities in all conditions within countries. These are largest in France, Germany and the UK, and smallest in Denmark, Sweden and Norway. There were higher inequalities amongst women. Conclusion: Using newly available harmonized morbidity data from across Europe, this paper shows that there are considerable regional inequalities within and between European countries in the distribution of self-reported conditions and NCDs. PMID- 28355644 TI - Does the pattern of occupational class inequalities in self-reported health depend on the choice of survey? A comparative analysis of four surveys and 35 European countries. AB - Background: Despite increasing overall life expectancy, substantial differences in health between socioeconomic groups persist. Research on inequalities in health often draws on data from different, single surveys. An important question that arises is whether these surveys reflect health and inequalities in the same way. When occupational class is utilized, data are often not analysed for women. The aim of this study therefore is to investigate whether patterns of occupational class inequalities in self-reported health differ across sex and country, between four major European surveys. Methods: Data on self-reported health and occupational class are taken from the European Social Survey (ESS), the EU Statistics on Income and Living Conditions (EU-SILC), the European Working Conditions Survey (EWCS) and the International Social Survey Programme (ISSP). Data from 35 countries for men and women aged 25-65 years are analysed. Occupational class is measured according to manual and non-manual workers. Age standardized prevalence rates, and prevalence ratios (PR) between non-manual and manual workers and likelihood ratio (LR) tests are estimated to determine occupational class inequalities in self-rated health in Europe. Results: Results show that prevalence rates of less than good health differ noticeably between countries and surveys. Furthermore, occupational class inequalities in health differ between countries. In some countries inequalities are larger for women than for men. This is especially true in Eastern, Central and Baltic European countries. Besides that no regional patterns, consistent over all surveys, in inequalities could be detected. Inequalities differed significantly between surveys. Conclusion: The magnitude of inequalities in all countries depend on the survey used in the analysis. When undertaking a comparative analysis of inequalities in health, or other determinants, these differences have to be taken into account, as results might differ according to the data source used. PMID- 28355645 TI - Informal care in Europe: findings from the European Social Survey (2014) special module on the social determinants of health. AB - Background: Against the background of a rising demand for informal care in European societies, this study sets out to provide descriptive information by gender on (i) prevalence rates of (intensive) informal caregiving, (ii) characteristics of (intensive) informal caregivers and (iii) consequences of (intensive) informal caregiving in terms of mental well-being. Results: On average, 34.3% of the population in 20 European countries were informal caregivers and 7.6% were intensive caregivers (providing care for minimum 11 h a week). Countries with high numbers of caregivers had low numbers of intensive caregivers. Caregiving was most prevalent among women, 50-59 year olds, non employed-especially those doing housework-and religious persons. Determinants of providing care hardly differed by gender. Caregivers, especially female and intensive caregivers, reported lower mental well-being than non-caregivers. Conclusions: Our results suggest support for both crowding-in and crowding-out effects of the welfare state. Middle-aged women may become increasingly time squeezed as they are likely to be the first to respond to higher demands for informal care, while they are also the major target groups in employment policies aiming for increased labour market participation. Caregivers, and especially female and intensive caregivers, report lower levels of mental well-being. Supportive policies such as respite care or training and counselling may therefore be needed in order to sustain informal care as an important resource of our health care systems. PMID- 28355646 TI - The social and behavioural determinants of health in Europe: findings from the European Social Survey (2014) special module on the social determinants of health. AB - Background: Previous studies comparing the social and behavioural determinants of health in Europe have largely focused on individual countries or combined data from various national surveys. In this article, we present the findings from the new rotating module on social determinants of health in the European Social Survey (ESS) (2014) to obtain the first comprehensive comparison of estimates on the prevalence of the following social and behavioural determinants of health: working conditions, access to healthcare, housing quality, unpaid care, childhood conditions and health behaviours. Methods: We used the 7th round of the ESS. We present separate results for men and women. All estimates were age-standardized in each separate country using a consistent metric. We show country-specific results as well as pooled estimates for the combined cross-national sample. Results: We found that social and behavioural factors that have a clear impact on physical and mental health, such as lack of healthcare access, risk behaviour and poor working conditions, are reported by substantial numbers of people in most European countries. Furthermore, our results highlight considerable cross national variation in social and behavioural determinants of health across European countries. Conclusions: Substantial numbers of Europeans are exposed to social and behavioural determinants of health problems. Moreover, the extent to which people experience these social and behavioural factors varies cross nationally. Future research should examine in more detail how these factors are associated with physical and mental health outcomes, and how these associations vary across countries. PMID- 28355647 TI - Prevalence of physical and mental non-communicable diseases in Europe: findings from the European Social Survey (2014) special module on the social determinants of health. AB - Background: Previous studies examining physical and mental non-communicable diseases (NCDs) in Europe have so far largely either focused on limited numbers of countries or on fairly limited ranges of NCDs, with mental health in particular often being ignored. This article has three aims: (i) To provide a recent, comprehensive overview of a broad range of NCDs across a range of countries in all European regions; (ii) To give an overview of measures of physical and mental health in the new special rotating module in the European Social Survey (ESS); and (iii) To offer the first comprehensive comparison of estimates on physical and mental NCDs across European countries in this new promising data source. We use data from the 7th wave of the ESS. Results are presented separately for men and women. All results were age-standardized by weighting up or down the unstandardized (crude) prevalence rates for 5-year age groups in each country to a common standard. We present pooled estimates for the combined cross-national sample as well as country-specific results. Overall, 74.1% of men and 79.7% of women reported at least one physical NCD. Across the 21 countries were observed that these percentages varied between 45.2% (for men in Hungary) and 91.6% (women in Finland). Serious depressive symptoms were reported by 10.2% of men and 18.8% of women, with percentages ranging between 6.2% (men in Ireland) and 30.9% (women in Portugal). A substantial share of Europeans experience the burden of NCDs, and the extent to which people report these conditions varies across countries. However, all physical and mental NCDs in this rotating module are reported by considerable percentages in each of the 21 country samples, which emphasizes that these conditions are not marginal phenomena but public health concerns. PMID- 28355648 TI - The health of European populations: introduction to the special supplement on the 2014 European Social Survey (ESS) rotating module on the social determinants of health. AB - This introduction summarizes the main findings of the Supplement 'Social inequalities in health and their determinants' to the European Journal of Public Health. The 16 articles that constitute this supplement use the new ESS (2014) health module data to analyze the distribution of health across European populations. Three main themes run across these articles: documentation of cross national variation in the magnitude and patterning of health inequalities; assessment of health determinants variation across populations and in their contribution to health inequalities; and the examination of the effects of health outcomes across social groups. Social inequalities in health are investigated from an intersectional stance providing ample evidence of inequalities based on socioeconomic status (occupation, education, income), gender, age, geographical location, migrant status and their interactions. Comparison of results across these articles, which employ a wide range of health outcomes, social determinants and social stratification measures, is facilitated by a shared theoretical and analytical approach developed by the authors in this supplement. PMID- 28355649 TI - Financial difficulties in childhood and adult depression in Europe. AB - Background: Financial difficulties in childhood may be associated with immediate and long-term consequences for mental health. The aim of the current paper is to investigate the association between childhood financial difficulties and adult depression, and assess the relative contribution of financial difficulties in childhood to symptoms of adult depression across different age groups. Methods: Using three age cohorts (25-40, 41-59, 60-75) from 19 countries in the European Social Survey Round 7 (N =18 401), multi-level and country-wise OLS regression analyses were used to investigate the association between financial difficulties in childhood and adult depression, while adjusting for age, education, gender, highest education in family, level of family conflict, number of social meetings and marital status. Results: Financial difficulties in childhood was found to be influential predictors of depression scores for 25-40 year olds in 10 out of 19 countries in fully adjusted models. In older participants, depression scores were mostly influenced by frequency of social meetings and marital status. There was great variation in the pattern of influential risk factors across countries, and the predicted effect childhood financial difficulties had on adult depression scores. Conclusion: Childhood financial difficulties as predictors of depression appear to, by themselves, exert the strongest influence in younger adults. There was, however, large variation between countries in the magnitude of associated risk, and in the pattern of risk factors contributing to adult depression, which underscores the need to account for country-level factors when aiming to gain knowledge about mental health. PMID- 28355650 TI - Exploring the differences in general practitioner and health care specialist utilization according to education, occupation, income and social networks across Europe: findings from the European social survey (2014) special module on the social determinants of health. AB - Background: Low socioeconomic position (SEP) tends to be linked to higher use of general practitioners (GPs), while the use of health care specialists is more common in higher SEPs. Despite extensive literature in this area, previous studies have, however, only studied health care use by income or education. The aim of this study is, therefore, to examine inequalities in GP and health care specialist use by four social markers that may be linked to health care utilization (educational level, occupational status, level of financial strain and size and frequency of social networks) across 20 European countries and Israel. Methods: Logistic regression models were employed using data from the seventh round of the European Social Survey; this study focused upon people aged 25-75 years, across 21 countries. Health care utilization was measured according to self-reported use of GP or specialist care within 12 months. Analyses tested four social markers: income (financial strain), occupational status, education and social networks. Results: We observed a cross-national tendency that countries with higher or equal probability of GP utilization by lower SEP groups had a more consistent probability of specialist use among high SEP groups. Moreover, countries with inequalities in GP use in favour of high SEP groups had comparable levels of inequalities in specialist care utilization. This was the case for three social markers (education, occupational class and social networks), while the pattern was less pronounced for income (financial strain). Conclusion: There are significant inequalities associated with GP and specialist health care use across Europe-with higher SEP groups more likely to use health care specialists, compared with lower SEP groups. In the context of health care specialist use, education and occupation appear to be particularly important factors. PMID- 28355651 TI - [Perception of the Emergency Department for Outpatient Care in a Rural Region in Saxony-Anhalt: A Qualitative Survey of Patients and General Practitioners]. AB - Background The increasing number of low-acuity visits to Emergency Departments (ED) is an important issue in Germany and contributes to ED crowding. A sustainable solution needs deeper knowledge of patients' underlying rationales. Methods To explore patients' motives we conducted 31 semi-structured face-to-face interviews with low-acuity ED patients in a rural region in Saxony-Anhalt. Subsequently we interviewed 12 General Practitioners (GP)s about their perspectives on patients visiting ED with low-acuity conditions and referring patients to ED. A qualitative content analysis approach was used for data analysis. Results All patients were connected to a GP. One third had visited ED because of 24/7 availability when consultation hours and working times overlapped. Another third had addressed EDs full range of laboratory and imaging technology with a subjective need for fast diagnosis. One group reported that they had been referred to the ED by their GP. The interviewed GPs classified patients' ED usage for time-constraints as impatience and growing demand, while they expressed greater understanding for patients striving to ED for anxiety reasons. Most GPs sometimes referred patients to ED for diagnostic reasons. Conclusion The findings demonstrate that ED usage with non-urgent conditions takes place for different reasons. Therefore, ED plays a pivotal role not only in emergency care, but also in ambulant care. The growing demand for ambulant care indicates a need for changed health care structures. PMID- 28355652 TI - Endoscopic dissection of a symptomatic giant gastric leiomyoma arising from the muscularis propria. PMID- 28355653 TI - A rare etiology of idiopathic recurrent acute pancreatitis. PMID- 28355654 TI - Experience of Point-of-Care Devices in Obstetrical Care. AB - During pregnancy and puerperium, there are pronounced hemostatic changes characterized by increased coagulability and decreased fibrinolysis. In addition, hemostasis can change dramatically during obstetric complications. Several reports have described substandard management of hemostatic defects in this setting and state the need for guidelines and better care. Point-of-care devices can assess hemostatic status and are especially suitable in perioperative settings. Using point-of-care devices, no time is required for transportation, allowing faster availability of results and providing potential for better care of the patient. This article will demonstrate the use of a viscoelastic method in six different patients; five with impaired hemostasis, and where the use of viscoelastic method contributes or should have contributed to better care. The cases represent patients with normal delivery; postpartum hemorrhage (PPH); PPH with low fibrinogen; placental abruption; preeclampsia with hemolysis, elevated liver enzymes, low platelet count syndrome; and finally, one patient with sepsis. This article also shows the need for good practices and good supervision to implement the devices in patient care. PMID- 28355657 TI - [Editorial Ophthalmic Genetics: Insights Into Actual Methods of Diagnostics, Phenotyping and Therapy]. PMID- 28355655 TI - Coronary Artery Bypass Surgery in Diffuse Advanced Coronary Artery Disease: 1 Year Clinical and Angiographic Results. AB - BACKGROUND: Proper treatment of patients with diffuse, severe coronary artery disease (CAD) is a challenge due to its complexity. Thus, data on the outcomes after coronary artery bypass graft (CABG) in this population is scarce. In this study, we aimed to determine the impact of CABG on the clinical and functional status, as well as graft patency in those individuals. METHODS: Patients with severe and diffuse CAD who underwent incomplete CABG due to complex anatomy or extensive distal coronary involvement were evaluated preoperatively and 1 year after surgery. Postoperative coronary angiography was performed to evaluate graft patency. Graft occlusion was defined as the complete absence of opacification of the target vessel. Stratified analysis of graft occlusion was performed by graft type and territories, defined as left anterior descending artery (LAD), the left circumflex branch, and the right coronary artery territories; the latter two, grouped, were further classified as non-LAD territory. RESULTS: A total of 57 patients were included, in whom 131 grafts were placed. There was a significant improvement in Canadian Cardiovascular Society angina symptom severity (Z = -6.1; p < 0.001) and maximum oxygen uptake (p < 0.001), with a corresponding decrease in the use of long-acting nitrates (p < 0.001). The overall graft occlusion rate was 19.1%, with no significant difference between LAD and non-LAD territories (p = 0.08). However, a significantly lower occlusion rate was noted for the internal mammary artery (IMA) grafts when compared with saphenous vein grafts (p = 0.01), though this difference was only significant in the LAD territory (p = 0.04). Overall, the use of venous graft was the only predictor occlusion at 1 year (odds ratio: 4.03; p = 0.016). CONCLUSION: In patients with diffuse CAD, incomplete CABG surgery resulted in a significant clinical improvement, with acceptable graft occlusion rates at 1 year, particularly for IMA grafts to the LAD territory. PMID- 28355658 TI - [Next-Generation Sequencing: A Quantum Leap in Ophthalmology Research and Diagnostics]. AB - Many eye diseases have a genetic basis, and most can be caused by mutations in many different genes (extensive genetic heterogeneity). The retinal dystrophies are a good example: More than 200 genes have been identified for the isolated forms (Leber's congenital amaurosis, retinitis pigmentosa, cone-rod dystrophy, congenital stationary night blindness), and for syndromes that comprise additional dysfunctions or malformations of extraocular tissues and organs. Selecting genes for diagnostic testing has been difficult, and their analysis with the hitherto predominant DNA sequencing method (Sanger sequencing) has been extremely laborious: The phenotype rarely indicates the affected gene, and the contributions of the particular genes to the disease (e.g., to LCA) were largely unknown. Consequently, comprehensive genetic analyses were impossible in most cases. In the recent years, high-throughput sequencing technologies, summarized as next-generation sequencing (NGS), have revolutionized genetic research and, subsequently, genetic diagnostics. The latter has far-reaching implications for the individual management of patients with genetic eye diseases and their families. PMID- 28355659 TI - [Potential of fMRI for the Functional Assessment of the Pathological Visual System]. AB - Current developments in functional magnetic resonance imaging (fMRI) of the human visual system have generated a set of powerful approaches that are of great promise for modern ophthalmology. These make it possible to perform an objective spatially resolved test of visual function in patients with strong visual impairment and even to investigate the functional organisation of the visual cortex in the blind. As a consequence, they open a broad field of applications for functional assessment in ophthalmology and provide fundamental insights into the interplay of pathology and plasticity in the human visual system. This is highlighted by current studies investigating patients with acquired or congenital defects of the macula, or with visual pathway abnormalities, extended retinal damage, and complete blindness. Therapeutic approaches targeting the restoration of visual input are expected to benefit from these fMRI applications, either for the estimation of the success rate of a planned retinal therapy or as an objective high-level biomarker for the readout of therapy success. PMID- 28355660 TI - [Potential of Adaptive Optics for the Diagnostic Evaluation of Hereditary Retinal Diseases]. AB - The use of adaptive optics in ophthalmoscopy is a breakthrough technological achievement. With AO ophthalmoscopes, the microscopic retinal structure can be visualised non-invasively and on a cellular level, allowing for cellular scale imaging of the retinal nerve fibre layer, the smallest retinal capillaries, rod and cone photoreceptors, and the retinal pigment epithelium mosaic in the living subject. Regarding the diagnostic evaluation of retinal diseases, the current research focuses on monogenetic retinal diseases, which - when better understood may allow for conclusions to be drawn about other multifactorial diseases and their underlying mechanisms (model disease). For disease monitoring and current and future pharmacological intervention (e.g. gene therapy), they will help to better establish novel and reliable clinical endpoints. New AO imaging devices have just become commercially available, and the number of retinal pathologies visualised with AO is increasing. Recently, an AO-based microstimulation technique has been introduced, which offers the possibility to directly correlate retinal structure with visual function on a cellular level. PMID- 28355661 TI - [Gene Replacement Therapy for Inherited Retinal Dystrophies]. AB - Characteristics of inherited retinal dystrophies include deficiencies in light perception and nervous conduction within the retina, leading to reduced vision or even blindness. In this context, the loss of function of photoreceptor-specific genes causes a variety of clinically and aetiologically distinct syndromes - each of them belonging to the group of rare diseases. With a prevalence of 1 in 2500, however, inherited retinal diseases are clinically significant and important - especially since these diseases lead to restrictions of a patient's fitness for work and overall quality of life. More than 250 genetic mutations causing the various types of inherited retinal dystrophies have been identified by now (https://sph.uth.tmc.edu/Retnet). In recent years, preclinical research on suitable animal models has yielded important progress in the understanding of the mutations underlying the pathological and molecular biological processes of these diseases. These findings have led to the development of novel and innovative therapeutic strategies for the treatment of inherited retinal dysfunctions, which are still incurable. Meanwhile, many of the successful preclinical studies have led to translational research projects aiming to find treatment options for human patients. However, some preliminary results of these human translational studies indicate the need to optimise and refine the underlying therapeutic concepts. PMID- 28355662 TI - [Photoreceptor Transplantation into the Degenerative Retina]. AB - Vision impairment and blindness due to photoreceptor loss represents one of the major causes for disability in industrialized societies. Whereas rod photoreceptors allow vision under dim light conditions, cone photoreceptors provide high-acuity vision in daylight conditions and color detection. Several therapeutic strategies are currently developed to repair vision loss, including cell-based interventions. Within the last decade, major progress regarding the replacement of photoreceptors by transplantation has been made in pre-clinical animal models. This includes defining the necessary conditions, like the optimal ontogenetic stage of transplantable donor photoreceptors, cell-specific enrichment procedures and robust transplantation technologies. Moreover, first studies provided evidence for functional improvements by photoreceptor transplantation in mouse models of retinal dysfunction. Furthermore, advances in cell culture technology were made by introducing methods to generate photoreceptor-containing retinal organoids, derived from pluripotent stem cells, that provide theoretically unlimited sources for the production of photoreceptor transplants. Interestingly, the recently identified transfer of cytoplasmic material between donor and host photoreceptors might represent an additional treatment option for cell transplantation approaches. Within this review, we focus on the main developments within the photoreceptor transplantation field and discuss important achievements, challenges and hurdles to develop photoreceptor transplantation towards clinical applications. PMID- 28355664 TI - ? PMID- 28355663 TI - [Genotype-Phenotype Correlations in Patients with CRB1 Mutations]. AB - Background Mutations in the CRB1 gene were identified in patients with early onset severe retinal dystrophy (EOSRD), childhood-onset and juvenile-onset rod cone dystrophy. This study describes the phenotypic spectrum of disease-causing CRB1-mutations in the first two decades of life. Materials and Methods Eight patients, aged three months to 20 years, underwent a full comprehensive ophthalmological examination including best corrected visual acuity testing (BCVA), color vision testing, funduscopy, spectral-domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) recording. Automated and manual retinal layer segmentation of SD-OCT recordings was performed using DIOCTA software. A full-field electroretinography (ffERG, ISCEV Standard) and visual fields were performed in cooperative patients. Results Five patients carried mutations causing a loss of the corresponding gene product (splice-mutation, nonsense-mutation, frame-shifting mutation). These patients presented with generally reduced vision in the first months of life that never exceeded 0.04 during the observational period. The sixth patient carried a homozygous missense mutation and reached maximal BCVA 0.05 at the age of 6 years. Two further patients, carrying at least one hypomorphic missense-mutation, presented with better preserved visual function with up to 0.5 at the age of 20 years. The recorded ffERG was below threshold in the majority of patients. Visual fields were severely restricted. The photoreceptor layers were significantly reduced in SD-OCT whenever stratification of retinal layers was possible. The inner nuclear layer thickness increased with progressing retinal degeneration. A-Scan analysis revealed better preservation of the retinal stratification in patients with missense mutations. Conclusions Patients with CRB1-mutations presented with a severe phenotype with severely reduced visual acuity from birth. Missense mutations with predicted residual function of the gene product were associated with moderate expression of the disease. Severe and progressive restriction of visual fields occurred in the first decade of life. The reduced retinal stratification indicates a general loss of structural integrity of the retinal layers. PMID- 28355665 TI - ? PMID- 28355666 TI - ? PMID- 28355667 TI - Pancreas Divisum in Children and Duodenum-Preserving Resection of the Pancreatic Head. AB - INTRODUCTION: A retrospective study was performed to evaluate the clinical features, diagnostic methods, and treatment alternatives in children with pancreas divisum (PD). MATERIALS AND METHODS: Patients who underwent treatment for PD between 1999 and 2014 at our department were evaluated for sex, age, presenting symptoms, physical examination findings, biochemical markers, diagnostic methods, treatment modalities, and results of treatment during follow up. RESULTS: Seven patients who underwent treatment of symptomatic PD were included in the study. The median for follow-up period was 8 years (from 26 months to 16 years). Male-to-female ratio was 4:3 and the median age at presentation was 11 years (2-14 years). Presenting symptoms were recurrent episodic epigastric pain. Pancreatitis was documented by elevated amylase or lipase levels. Endoscopic retrograde cholangiopancreatography (ERCP) was the method of diagnosis of PD in all patients. Five patients had complete PD and two had incomplete variants. Three patients improved after ERCP papillotomy. In three patients, papillotomy was unsuccessful but they have only mild episodes of pancreatitis. One patient presented at the age of 4 years with recurrent pancreatitis. She was treated surgically by duodenum-preserving resection of the pancreatic head (DPRPH) because of severe recurrent pancreatitis occurring even after ERCP papillotomy. The patient is 26 months after operation without any reported problems. CONCLUSION: Patients with symptomatic PD are indicated for ERCP papillotomy attempt. If there is not improvement after ERCP, then recurrent bouts of severe pancreatitis are considered as an indication for surgical procedure. DPRPH is a safe and feasible surgical alternative. PMID- 28355669 TI - The Knee: Update on Imaging and Intervention. PMID- 28355670 TI - Update on MRI Pulse Sequences for the Knee: Imaging of Cartilage, Meniscus, Tendon, and Hardware. AB - Magnetic resonance imaging (MRI) is widely used in the clinical setting as well as for research applications. Since its inception, technical development has broadly progressed as a response to challenges in both the clinical and research settings. Higher magnetic field strength and advances in hardware and software have revolutionized the diagnostic potential of MRI and moved well beyond diagnosis to characterization of tissue metabolism, biochemistry, disease pathogenesis, and material property, to name a few. This article focuses on state of-the-art clinical and cutting-edge novel pulse sequences applied to knee MRI. PMID- 28355671 TI - Multiligamentous Injury of the Knee: MRI Diagnosis and Injury Patterns. AB - Anterior cruciate and posterior cruciate injuries rarely occur in isolation and are often associated with injuries to the secondary or supporting structures that provide stability against rotational forces. These structures include the posterolateral and posteromedial corner ligaments and tendons, as well as the anterolateral ligament. If injuries to these secondary structures are not appreciated at the time of cruciate ligament reconstruction, an isolated cruciate ligament reconstruction may be predisposed to early failure. Thus it is crucial for radiologists interpreting knee magnetic resonance imaging to understand and report on injury to these ligaments and tendons at the time of initial injury to help the orthopaedic surgeon plan a comprehensive approach to ligament reconstruction. This strategy will ultimately result in improved patient outcomes. PMID- 28355672 TI - Ligamentous Reconstruction of the Knee: What Orthopaedic Surgeons Want Radiologists to Know. AB - Knee ligament injuries are common, and treatment methods are continually evolving. Accurate clinical diagnosis with imaging confirmation is critical to support appropriate treatment. Several imaging pearls allow for improved recognition of injuries. Stress radiographs may be obtained to quantify knee laxity. Magnetic resonance imaging allows assessment of the complex anatomy of the knee and has excellent sensitivity and specificity for many injuries. PMID- 28355673 TI - The Extensor Mechanism: Imaging and Intervention. AB - We present an overview of imaging and intervention of the extensor mechanism of the knee. Particular focus is placed on the evaluation of patellofemoral tracking disorders, patellar and quadriceps tendinosis and tears, patellar fracture, lateral patellar condyle patellar friction syndrome, and prepatellar bursitis. Anatomical and biomechanical factors contributing to these disorders are considered. Imaging evaluation is presented in a clinical context, and therapeutic options for these disorders are discussed. Image-guided therapy options for symptomatic patellar tendinosis are also described and illustrated. PMID- 28355674 TI - Ultrasound of the Knee: Common Pathology Excluding Extensor Mechanism. AB - Ultrasound can be used to diagnose many types of pathology and guide various diagnostic or therapeutic procedures. The most common applications for musculoskeletal ultrasound of the knee include evaluation of the joint recesses, the extensor mechanism, and bursae including Baker's cyst. However, a role exists for ultrasound in the evaluation of cartilage, other tendons, ligaments, peripheral nerves, osseous structures, and vasculature. This article reviews common pathologies of these structures as seen with ultrasound. In addition, various ultrasound-guided procedures pertaining to these pathologies are introduced. The importance of a comprehensive evaluation is also emphasized as a method to maximize information gained from the ultrasound examination. PMID- 28355675 TI - Magnetic Resonance Imaging of Arthritis of the Knee. AB - The knee joint is involved in a wide variety of arthritides, and imaging has always played a major role in both aiding diagnosis and assessing the severity of such diseases. Plain film radiography has traditionally been used as the primary imaging modality for radiographic diagnosis of arthritis. However, magnetic resonance imaging (MRI) shows a greater sensitivity to both the bone and soft tissue features of this group of conditions. This article reviews the imaging features of osteoarthritis (OA) of the knee shown on MRI and the criteria used to diagnose this condition. It also discusses imaging features that suggest the underlying arthropathy is not OA. PMID- 28355676 TI - Imaging Nerve Pathology of the Knee: Magnetic Resonance Imaging and Ultrasound. AB - Peripheral neuropathies are not uncommon, and the diagnostic evaluation includes a clinical assessment and electrophysiologic studies as well as diagnostic imaging. Magnetic resonance imaging (MRI) and high-resolution ultrasound (HRUS) are of special importance in providing the surgeon with information in the context of nerve trauma, entrapment, and nerve involvement by tumors. Peripheral neuropathy about the knee can occur in the context of associated knee pathology such as trauma, as part of a systemic disease, or as an isolated finding. In this review, we discuss the role of MRI and HRUS in the evaluation of peripheral neuropathy and present imaging examples of peripheral neuropathy involving the knee. PMID- 28355677 TI - Imaging of the Pediatric Knee. AB - The knee joint is commonly injured in the young athlete. This article discusses the common injury patterns around the knee that are unique to this patient population. Pediatric patients have relative weak points at their physes and apophyses that result in different forces on ligaments and bones during injury compared with adults. Common pathologic findings seen on imaging include patellar and patellar tendon injury, physeal fractures, osteochondral abnormality, ligament tears, and meniscal injury. Imaging studies are also performed to evaluate pediatric patients after surgical knee injury repair, and radiologists should be familiar with certain pediatric-specific knee repair techniques and their imaging appearances. A thorough knowledge of normal and pathologic imaging findings of the pediatric knee allows the radiologist to make important diagnostic and management contributions. PMID- 28355678 TI - Surgical Correction of Articular Damage in the Knee: Osteoarticular Transplantation to Joint Reconstruction. AB - Injuries of the articular cartilage remain difficult to treat and can range from small articular cartilage defects to end-stage severe osteoarthritis. In this review, we discuss various surgical treatment options including imaging features and associated complications. Specifically, we review microfracture, acellular matrix-induced microfracture, autologous osteochondral transplantation, osteochondral allograft transplantation, autologous chondrocyte implantation, along with various forms of knee arthroplasties. PMID- 28355679 TI - A Simple Technique to Prevent Early or Late EndoButton Deployment in Anterior Cruciate Ligament Reconstructions: A Technical Note. AB - The use of suspensory graft fixation methods in arthroscopic reconstruction of the anterior cruciate ligament has become increasingly popular with the more frequent use of tendon grafts and anatomical techniques involving the creation of bone tunnels. An important technical step to ensure adequate fixation of the graft when using EndoButton-type implants, particularly in the femur, involves flipping the EndoButton plate at the correct length to avoid performing this maneuver before the appropriate time or leaving soft tissue between the plate and lateral cortex of the femur. In the present study, we describe a simple arthroscopic technique for indicating the correct time to flip/deploy the EndoButton plate. PMID- 28355680 TI - Function of the Anterior Intermeniscal Ligament. AB - The function and importance of the anterior intermeniscal ligament (AIML) of the knee are not fully known. The purpose of this study was to evaluate the biomechanical and sensorimotor function of the AIML. Computational analysis was used to assess AIML and tibiomeniscofemoral biomechanics under combined translational and rotational loading applied during dynamic knee flexion extension. Histologic and immunohistochemical examination was used to identify and characterize neural elements in the tissue. The computational models were created from anatomy and passive motion of two female subjects and histologic examinations were conducted on AIMLs retrieved from 10 fresh-frozen cadaveric knees. It was found that AIML strain increased with compressive knee loading and that external rotation of the tibia unloads the AIML, suppressing the relationship between AIML strain and compressive knee loads. Extensive neural elements were located throughout the AIML tissue and these elements were distributed across the three AIML anatomical types. The AIMLs have a beneficial influence on knee biomechanics with decreased meniscal load sharing with AIML loss. The AIML plays a significant biomechanical and neurologic role in the sensorimotor functions of the knee. The major role for the AIML may primarily involve its neurologic function. PMID- 28355681 TI - A Biomechanical Study of Two Distinct Methods of Anterior Cruciate Ligament Rupture, and a Novel Surgical Reconstruction Technique, in a Small Animal Model of Posttraumatic Osteoarthritis. AB - Small animal models are critical for studies of sports-related knee injury and disease such as posttraumatic osteoarthritis (PTOA) following anterior cruciate ligament (ACL) rupture. In such models, ACL damage can be achieved by surgical transection or, using a more recent innovation, by noninvasive biomechanical means. Whether these approaches differentially alter normal mechanics is unknown. Furthermore, while surgical reconstruction of ruptured ACL can greatly improve joint stability, its effect on PTOA development is also unclear. Our primary purpose was to characterize rodent knee joint mechanics in two models of ACL rupture using a novel quantitative laxity mechanical test. Our secondary aim was to characterize a new reconstruction technique using autograft tail tendon, and to assess its effect on joint mechanics. Our hypothesis was that surgical ACL transection would have a greater effect on joint mechanics. A total of 24 rat knee specimens underwent surgical or biomechanical ACL rupture and were stabilized using a new reconstruction technique using autograft tail tendon. Joint mechanics were assessed three times; preinjury, postinjury, and again after reconstruction, using quantitative joint laxity testing. Primary test readouts were maximum anteroposterior (AP) laxity, loading curve slope, and energy absorption. Student's t-tests were performed to identify intragroup differences. All surgical transections were completed successfully; maximum load in the biomechanical model was 67 +/- 7.7 N, with a coefficient of variation of 11.43%. Surgical transection caused increased AP laxity, while biomechanical injury nonsignificantly increased this parameter. In both cases, these changes recovered to baseline by reconstruction. Loading curve slope was reduced in both models and was also returned to baseline by repair. Energy absorption followed the same pattern except it remained significantly different from baseline postreconstruction in the surgical group. This study supports our hypothesis knee joint mechanics is differentially affected by injury mechanism in a small animal model. We also report a novel reconstruction technique in this model, using autograft tail tendon. PMID- 28355683 TI - [Patients with endometriosis need long term management]. PMID- 28355682 TI - Efficacy of Tranexamic Acid for Hemostasis in Patients Undergoing High Tibial Osteotomy. AB - Extensive bone bleeding and an uncomfortable hematoma can develop due to the opening gap and space during a medial open high tibial osteotomy (HTO). Tranexamic acid (TXA) has been used in various orthopaedic surgeries to reduce bleeding and wound complications. However, no study has investigated the effect of TXA during HTO. Therefore, the purpose of this study is to evaluate the efficacy of TXA in reducing postoperative blood loss in patients undergoing HTO. The hypothesis is that topical TXA administration will reduce postoperative bleeding in patients undergoing medial opening HTO. Topical TXA (2 g in 20 mL saline) was administered at the osteotomy site in patients (n = 15) who underwent medial open HTO from November 2015 to March 2016. Patients (n = 15) who underwent medial open wedge HTO by the same surgeon from October 2014 to October 2015 were enrolled as a control group for comparison. Drainage volumes on postoperative days (PODs) 1, 2, and 3 as well as hemoglobin (Hb) level on PODs 1, 6, and 13 were measured and compared. Mean total postoperative drainage volume was 246 mL in the TXA group and 377 mL in the control group. Mean drainage volume on POD 1 was 138 mL in the TXA group and 277 mL in the control group (p < 0.05). No differences in drainage volume were detected between the groups on POD 2 or 3. Preoperative Hb levels were 13.0 g/dL in the TXA group and 12.9 g/dL in the control group, which decreased to 11.9 g/dL in the TXA group and 11.2 g/dL in the control group on POD 1. These postoperative Hb differences were significant (p < 0.05). Also, Hb levels were 11.7 and 12.0 g/dL in the TXA group and 11.4 and 11.6 g/dL in the control group on PODs 6 and 13, respectively (p > 0.05). An extensive hematoma requiring additional surgery developed in one case in the control group. No wound complications were detected in the TXA group. Topical TXA was effective for reducing postoperative bleeding after medial open HTO. The level of evidence of the study is Level 3. PMID- 28355684 TI - [Reference ranges of gestational weight gain in Chinese population on the incidence of macrosomia: a multi-center cross-sectional survey]. AB - Objective: To investigate the influence of gestational weight gain (GWG) on the incidence of macrosomia, and to establish the reference ranges of GWG based on the incidence of macrosomia. Methods: A multicenter, cross-sectional study was conducted. Totally, 112 485 women were recruited from 39 hospitals in 14 provinces in China. Totally, 61 149 cases were eligible with singleton pregnancies and non-premature deliveries. The associations of pre-pregnancy body mass index (BMI), GWG, newborn gender and gestational diabetes with macrosomia were analyzed with logistic regression. The normal GWG ranges were calculated in all maternal BMI subgroups, based on the normal incidence of macrosomia was set as the range of 5.0% to 10.0%. Results: In this study, the incidence of macrosomia was 7.46% (4 563/611 149). The macrosociam was positive related with maternal height, delivery week, pre-pregnancy BMI, GWG, gestational diabetes, primipara, and male babies significantly (P<0.05), based on unadjusted and adjusted logestic regression. The normal range of GWG 20.0-25.0, 10.0-20.0, 0 10.0 and 0-5.0 kg in subgroups of underweight (pre-pregnancy BMI<18.5 kg/m(2)), normal (18.5-24.9 kg/m(2)), overweight (25.0-29.9 kg/m(2)) and obese (>=30.0 kg/m(2)), respectively. Conclusion: The reference range of GWG in China based on the incidence of macrosomia is established. PMID- 28355685 TI - [Clinical outcome and placenta characteristics of spontaneous twin anemia polycythemia sequence]. AB - Objective: To investigate the clinical outcome and placental characteristics of spontaneous twin anemia-polycythemia sequence (sTAPS). Methods: Twelve cases with sTAPS delivered in Peking University Third Hospital from May 2013 to August 2016. The data of ultrasound characteristics, gestational age at delivery, and 1 minute Apgar score were analyzed, retrospectively. Placental superficial vascular anastomoses, placental territory discordance and the ratio of umbilical cords insertion distance to the longest placental diameter were also analyzed. Results: (1) Only 1 case of sTAPS was diagnosed prenatally, the others were diagnosed postnatally because the fetal middle cerebral artery(MCA) doppler was not measured regularly. Five cases were complicated with selective intrauterine growth restriction (sIUGR). The median gestational age at delivery was 32.8 weeks (31-37 weeks) . The pregnancies were terminated because 3 cases were sIUGR type I, 1 case was sIUGR type II, 1 case was sIUGR type III, 2 cases were fetal distress, 2 cases were severe pre-eclampsia, 2 cases were premature rupture of membrane, 1 case was fetal hydrops with abnormal doppler waveforms of ductus venouses. (2) When 5 sIUGR cases were excluded, there was no difference between the twins in birth weight [1 797 g (940-2 620 g) , 1 648 g (980-2 500 g) ; P=0.688]. The hemoglobin (Hb) level in all donor was significantly lower than recipient (P=0.000) and the inter-twin Hb difference was 147.6 g/L (84.0-216.0 g/L). While the reticulocyte percentage in donor was significantly higher than recipient (P=0.013) and reticulocyte percentage ratio was 3.60 (1.04-7.50). Five donor newborns had neonatal asphyxia, including 1 severe asphyxia, while no asphyxia happened in the recipient twins. (3) Arterio-arterial (A-A) anastomoses, veno-venous (V-V) anastomoses, arterio-venous (A-V) anastomoses were found in 3, 1 and 11 placentas, respectively. The total number of anastomoses was 2 (1-5) and the total diameter was 1.1 mm (0.4-2.1 mm), including 0 (0-1) A-A anastomoses with 0.2 mm (0.0-0.9 mm) in diameter and 2 (0-5) A-V anastomoses with 0.7 mm (0.0 2.1 mm) in diameter. The placental territory discordance was 0.17 (0.02-0.40) and the ratio of umbilical cords insertion to the longest placental diameter was 0.82 (0.34-0.99). Conclusions: The pathogenesis of sTAPS might result from slow and chronic blood transfusion from donor to recipient through a few minuscule vascular anastomoses in the placenta. In all monochorionic twins, especially sIUGR cases, MCA doppler should be monitored closely in the second and third trimester, in order to diagnose and manage sTAPS in time. PMID- 28355686 TI - [Retrospective analysis of outcomes of selectively or spontaneously reduced multiple pregnancies out of 6 917 in vitro fertilization-embryo transfer pregnancy cycles]. AB - Objective: To analyze the effects of fetal reduction in early pregnancy on obstetric and neonatal outcomes of spontaneously or selectively reduced multiple pregnancies produced by in vitro fertilization-embryo transfer (IVF-ET). Methods: Retrospective study of 6 917 clinical pregnancies from IVF-ET cycles, including 754 multiple pregnancies divided into two groups according to the remaining fetus number: reduced singleton group (n=599) and reduced twin group (n=155); and maternal and neonatal outcomes of two groups were compared to primary singleton group (n=3 589) and primary twin group (n=2 574). Results: The rate of pregnancy complication [9.85%(59/599) versus 6.21%(223/3 589)], preterm birth [19.37%(116/599) versus 10.73%(385/3 589)], low birth weight [9.71%(56/577) versus 4.57% (152/3 324)], perinatal death [0.69%(4/577) versus 0.12%(4/3 324)] and malformation [2.95%(17/577) versus 1.02%(34/3 324)] in reduced singleton group were significantly higher than those in primary singleton group (all P<0.01). There were no significant differences between reduced twin group and primary twin group (all P>0.05). In reduced singleton group, birth defect rate was 2.95%, which was higher than those of the other three groups (P<0.05), in this group spontaneous pregnancy reduction accounted for 89.3% (535/599). Conclusions: (1) The rate of pregnancy complication, preterm birth, low birth weight, perinatal death and malformation in reduced singleton group are still higher than primary singletons, suggesting embryo reduction only is a compensated method in multiple pregnancies. Limiting the number of embryos transferred is the essential solution. (2) The rate of birth defect in spontaneous pregnancy reduction group is higher, so prenatal examination should be reinforced in this group. PMID- 28355687 TI - [Clinical analysis of pelvic abscess with endometriosis]. AB - Objective: To investigate the clinical features, diagnosis and treatments of pelvic abscess with endometriosis. Methods: A retrospective analysis was performed on 129 cases of pelvic abscess in Peking Union Medical College Hospital from January 2000 to January 2016. Among them, 34 women with endometriosis were divided into the study group and the others were in the control group. The clinical characteristics, therapeutic regimens and outcomes were compared. Results: (1) General conditions: there were no statistic differences between the two groups in age, WBC, serum CA(125), intrauterine device in use, pelvic inflammatory disease history; while incidence rates of dysmenorrhea (65%, 22/34) and infertility (21%, 7/34) in the study group were higher than those in the control group (all P<0.05). (2) Clinical manifestations: fever, abdominal pain and pelvic mass were the main symptoms in two groups. The incidence rates of septic shock were 12% (4/34) in the study group and 2% (2/95) in the control group (P<0.05). (3) Treatment: treatment with puncture all failed in the study group (7/7) and surgeries were required. In contrast, there was only 1/19 treatment failure with puncture in the control group. The puncture failure rates were statistically significant (P<0.05). Compared with the study group and the control group, there were significant differences (P<0.05) in the operation time of laparoscopic surgery [(76+/-41) versus (53+/-21) minutes] and of laparotomy [(168+/-58) versus (116+/-35) minutes], intra-operative blood loss of laparoscopic surgery [(216+/-296) versus (43+/-36) ml] and of laparotomy [(448+/ 431) versus (145+/-24) ml]. Conclusions: Pelvic abscess in women with endometriosis is more severe and refractory to antibiotics and puncture treatment. Active surgical intervention is required. Although surgical procedures are often difficult, prognosis is comparatively satisfied. PMID- 28355688 TI - [A randomized study of intensity-modulated radiation therapy versus three dimensional conformal radiation therapy for pelvic radiation in patients of post operative treatment with gynecologic malignant tumor]. AB - Objective: To study the difference between intensity-modulated radiation therapy (IMRT) and three dimensional conformal radiation therapy (3D-CRT) for pelvic radiation of post-operative treatment with gynecologic malignant tumor. Methods: A prospective investigation study was conducted on 183 patients of post-operative patients with whole pelvic radiation therapy of cervical cancer or endometrial cancer in Zhejiang Cancer Hospital [IMRT group (n=85) and 3D-CRT group (n=98)] from Oct. 2015 to Oct. 2016. The two groups received same dose (45 Gy in 25 fractions). Comparison of two groups with radiation dosimetry:the score according to the Radiation Therapy Oncology Group (RTOG) acute radiation injury grading standards before and after radiotherapy reaction, the score from functional assessment of cancer therapy scale-cervix (FACT-Cx) scale and expanded prostate cancer index composite for clinical practice (EPIC-CP) scale were also analyzed. Results: (1) There were no significant effect with age, culture level, family economic condition and ratio of radiochemotherapy between two groups (all P>0.05). (2) Dosimetric comparison for IMRT vs 3D-CRT: the average dose of planning target volume (PTV) decreased (46.1+/-0.4) vs (46.4+/-0.5) Gy, V(45) dose percentage increased (95.2+/-1.0) % vs (93.3+/-2.0) %, intestinal bag dose of V(4)0 decreased (24.4+/-6.8) % vs (36.5+/-15.9) %, rectal V(40) dose percentage decreased (73.9+/-12.3) % vs (85.4+/-8.4) %, and lower rectal V(45) dose percentage (32.8+/-13.4) % vs (71.5+/-13.7) %, bladder V(40) dose percentage decreased (55.5+/-13.0) % vs (84.4+/-13.0) %. Bone marrow V(20) lower: (67.9+/ 5.4) % vs (79.5+/-6.6) %, V(1)0 lower: (82.1+/-6.0) % vs (86.3+/-6.6) %; there were significant differences (all P<0.05). There was no significant difference between the dose of V(45) in the intestinal pouch and bladder (P>0.05). (3) Acute radiation injury classification for IMRT vs 3D-CRT: big or small intestine: II III reaction [13% (11/85) vs 24% (24/98); chi(2)=3.925, P=0.048], there was significant difference. Bladder: III reaction [19% (16/85) vs 26% (25/98); chi(2)=1.171, P=0.279], there was no significant difference. Radiochemotherapy of bone marrow suppression: III-IV reaction (14/20), the incidence rate [26% (14/54) vs 31% (20/65); chi(2)=0.339, P=0.562], the difference was not statistically significant. (4) Quality of life scale by FACT-Cx scale in IMRT vs 3D-CRT: there were no significant difference before radiotherapy (82+/-16 vs 85+/-16; t=1.279, P=0.203), while there was significant difference after radiotherapy (76+/-14 vs 71+/-18; t=-2.160, P=0.032). EPIC-CP scale score: before radiotherapy they were (16+/-7 vs 15+/-6; t=-0.174, P=0.862),but after radiotherapy (18+/-7 vs 22+/-7; t=3.158, P=0.002), there was significant difference between them. Before and after radiotherapy, the increased EPIC-CP scale of the IMRT group vs 3D-CRT group were 3+/-4 and 6+/-4, the 3D-CRT group was significantly higher, the difference was statistically significant (t=5.500, P=0.000). Conclusion: IMRT has shown that there are a significant benefit for the post-operative patients with cervical cancer and endometrial cancer compared to 3D-CRT. PMID- 28355690 TI - [Supporting treatment for bereavement in pregnancy loss]. PMID- 28355691 TI - [How to improve the quality of cytologic sampling of uterine cervix: princixal points and difficulties]. PMID- 28355689 TI - [Comparison of robotic surgery with laparoscopy for surgical staging of endometrial cancer: a meta-analysis]. AB - Objective: To evaluate the safety and effectiveness of robotic surgery in surgical staging of endometrial cancer. Methods: Searched English and Chinese databases, including Cochrane library, PubMed, Embase, Web of Science, China National Knowledge Internet, data base of Wanfang, China Science and Technology Journal (CSTJ) , and relevant journals and magazines by hand from Jan. 2000 to Oct. 2016. (1) In accordance with the inclusion criteria, two independent investigators screened databases and extracted the relevant data respectively, then evaluated the quality of including studies in Newcastle-Ottawa Scale (NOS) . (2) Meta-analysis was performed with RevMan 5.3 software. Heterogeneity inspection was done for each study and different effect model included the random effect model and fixed effect model was chose according to the results: of the inspection. At last, the related parameters of the robotic surgery and laparoscopic surgery was analysed. Results (1) Thirteen articles were ultimately included. All of them were written in English and included a total of 1 554 patients, included 739 cases of robotic surgery and 815 cases of laparoscopic surgery. Thirteen articles were all cohort study, four of them were prospective cohort study, while others were retrospective cohort study. After quality assessment, all studies had more than 5 stars and illustrated the higher quality. (2) Meta-analysis results showed: compared with laparoscopic surgery in surgical staging of endometrial cancer, robotic surgery had less estimated blood loss [standard deviation (SD)=-72.31 ml, 95%CI:-107.29 to-37.33, P<0.01], less time for hospital stay (SD=-0.29 days, 95%CI:-0.46 to-0.13, P=0.001), less need for blood transfusion [risk ratio (RR)=0.57, 95%CI: 0.33 to 0.97, P=0.040], and conversion to open surgery (RR=0.41, 95%CI: 0.26 to 0.65, P=0.000), less intraoperative complications (RR=0.43, 95%CI: 0.24 to 0.76, P=0.004) in surgical staging of endometrial cancer. There was no statistically significant difference in aspects of operative time (SD=10.26 minutes, 95% CI:-13.62 to 34.13, P=0.400), postoperative complications (RR=0.87, 95% CI: 0.67 to 1.12, P=0.280), the total number of lymph nodes removed (SD=-0.04, 95% CI:-3.99 to 3.91, P=0.980), the number of pelvic lymph node dissection (SD=0.48, 95%CI:-1.76 to 2.71, P=0.680) and the number of para-aortic lymph node dissection (SD=0.46, 95%CI:-1.42 to 2.34, P=0.630). Conclusions: Compared the robotic surgery with laparoscopic surgery in surgical staging of endometrial cancer, robotic surgery has less estimated blood loss, less need for blood transfusion and conversion to open surgery, less intraoperative complications and other advantages. While its cost is so expensive that restrict clinical application. PMID- 28355692 TI - [Influence of aluminum on microRNA29 and beta-site amyloid precursor protein cleaving enzyme 1 in the brain of rats]. AB - Objective: To investigate the influence of aluminum on microRNA29 (miR29) subtypes miR29a, miR29a*, miR29b1, miR29b2, miR29c1, and miR29c2 and beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) in the brain of rats. Methods: A total of 40 Sprague-Dawley rats were randomly divided into control group and 15, 30, and 45 MUmol/kg groups according to the body weight, with 10 rats in each group. The rats were exposed to aluminum (at a dose of 0.1 ml/100 g body weight) by intraperitoneal injection for 8 weeks. The rats in control group were given 0.9% normal saline, and those in exposure groups were given aluminum maltolate (equivalent volumesof maltolate and aluminum solution were mixed before exposure) . The cerebral cortex and hippocampus were isolated after exposure ended; Western blotting was used to measure the change in BACE1 expression, and real-time reverse transcription polymerase chain reaction was used to measure the mRNA expression of miR29 subtypes in the cerebral cortex and hippocampus. Results: Compared with the control group, the 45 MUmol/kg group had a significant increase in BACE1 expression in the cerebral cortex, and the 30 and 45 MUmol/kg groups had significant increases in BACE1 expression in the hippocampus (all P<0.05) . Compared with the control group, the 15, 30, and 45 MUmol/kg groups had significant reductions in the mRNA expression of miR29a*, miR29b2, miR29c1, and miR29c2 in the cerebral cortex and hippocampus (all P<0.01) , and the 45 MUmol/kg group had significant reductions in the mRNA expression of miR29a and miR29b1 in the cerebral cortex and hippocampus (all P<0.05) . The results of correlation analysis showed that there was no correlation between the mRNA expression of miR29a*, miR29b2, miR29c1, and miR29c2 and BACE1 expression in the cerebral cortex and hippocampus (all P>0.05) , while the mRNA expression of miR29a and miR29b1 was negatively correlated with BACE1 expression (cerebral cortex: r= 0.987 and -0.981, P<0.05; hippocampus: r=-0.992 and -0.991, P<0.05) . Conclusion: Aluminum can reduce the expression of miR29 subtypes and increase BACE1 expression in the brain, and the expression of miR29a and miR29b1 is negatively correlated with BACE1 expression. PMID- 28355693 TI - [Influence of occupational aluminum exposure on cognitive function and glutamate receptor protein expression in workers]. AB - Objective: To investigate the influence of occupational aluminum exposure on cognitive function and glutamate receptor protein expression in peripheral blood lymphocytes in workers and the possibility of glutamate receptor being used as a biomarker for cognitive impairment in aluminum workers. Methods: From October to December, 2014, cluster sampling was performed to select 121 workers in aluminum electrolysis workshop as exposure group and 231 workers in thermoelectric workshop and logistics department as control group. Mini-Mental State Examination, clock drawing test, digit span test (DST) , verbal fluency test (VFT) , and Fuld Object-Memory (FOM) Evaluation were used to analyze cognitive function. Graphite furnace atomic absorption spectrophotometry was used to measure plasma aluminum level as an exposure indicator. Enzyme-linked immunosorbent assay was used to measure the content of glutamate receptor proteins in peripheral blood lymphocytes, including the subunits of N-methyl-D aspartate receptor NR1, NR2A, and NR2B and metabotropic glutamate receptor 1 (mGluR1) . The correlation between cognitive function indices and the content of glutamate receptor proteins was analyzed. Results: There was no significant difference in plasma aluminum level between the control group and the exposure group (132.52+/-80.40 MUg/L vs 182.88+/-72.32 MUg/L, P>0.05) . According to the plasma aluminum level, the study subjects were divided into control group and low , medium-, and high-level plasma aluminum groups, and there were significant differences in plasma aluminum level between these groups (all P<0.01) . The high level plasma aluminum group had a significantly lower memory ability score than the control group and the low- and medium-level plasma aluminum groups (all P<0.05) . The high-level plasma aluminum group had lower DST and digital span forward (DSF) scores than the control group and the low-and medium-level plasma aluminum groups. The low-, medium-, and high-level plasma aluminum groups had lower digital span backward (DSB) scores than the control group. The medium-and high-level plasma aluminum groups had lower VFT scores than the control group and the low-level plasma aluminum group. The high-level plasma aluminum group had significantly lower expression of NR1 and NR2A proteins than the control group and the low-and medium-level plasma aluminum groups, and the medium- and high level plasma aluminum groups had significantly higher expression of mGluR1 protein than the control group and the low-level plasma aluminum group (all P<0.05) . The expression of NR1 and NR2A proteins was negatively correlated with plasma aluminum level (r=-0.475 and -0.692, both P<0.05) , andthe expression of mGluR1 protein was positively correlated with plasma aluminum level (r=0.756, P<0.05) . The expression of NR1 protein was positively correlated with DSF, DSB, DST, and VFT scores (r(s)=0.213, 0.249, 0.271, and 0.228, all P<0.05) , and the expression of NR2A protein was positively correlated with VFT score (r(s)=0.206, P<0.05) . Conclusion: Occupational aluminum exposure may affect workers' memory function, and the expression of NR1 and NR2A in peripheral blood lymphocytes is correlated with cognitive function indices and can be used as biomarkers for cognitive impairment in aluminum workers. PMID- 28355694 TI - [Effect of the mediation of the taurine on striatum tissue Ca(2+) homeostasis in manganese exposed rats]. AB - Objective: To elucidate the effect of taurine on neurotoxicity induced by Mn by investigating activities of Na(+)-K(+)-ATPase and Ca(2+)-Mg(2+)-ATPase and content of Mn and active calmodulin in manganese exposed rats. Methods: 156 male SD rats were randomly divided into 1 control group, 3 manganese exposed groups (10, 15, and 20 mg/kg respectively) , and 9 taurine intervened groups based on orthogonal design (doses of taurine intervention were 100, 150, and 200 mg/kg respectively) , with 12 rats in each group. After 12 weeks of exposure, all rats were decapitated and corpus striatums were removed, activities of Na(+)-K(+) ATPase and Ca(2+)-Mg(2+)-ATPase and content of Mn and active calmodulin were analyzed. Results: The corpus striatum Mn content of the 3 dose groups exposed to Mn and 9 taurine intervened groups were significantly higher than that of the control group (P<0.05) . Active calmodulin content in 10 mg/kg manganese exposed group was significantly higher than that of the control group (P<0.05) . 150 and 200 mg/kg of taurine could decrease active calmodulin content of the group exposed to 10 mg/kg of Mn (P<0.05) . The corpus striatum activities of Na(+)-K(+) ATPase and Ca(2+)-Mg(2+)-ATPase of the 3 dose groups exposed to Mn were significantly lower than that of the control group (P<0.05) . 150 mg/kg of taurine could increase activities of Na(+)-K(+)-ATPase of the group exposed to 10 mg/kg of Mn (P<0.05) . 150 and 200 mg/kg of taurine could respectively improve activities of Ca(2+)-Mg(2+)-ATPase of the group exposed to 15, 10 mg/kg of Mn (P<0.05) . Conclusion: Mn can decrease the rats corpus striatum activities of Na(+)-K(+)-ATPase and Ca(2+)-Mg(2+)-ATPase, effect level of active calmodulin in relation to dose of Mn, to a certain extent, taurine could regulate activities of Na(+)-K(+)-ATPase and Ca(2+)-Mg(2+)-ATPase and improve the level of active calmodulin. PMID- 28355695 TI - [Oxidative stress and autophagy in SK-N-SH cells induced by manganese chloride or 1-methyl-4-phenylpyridinium: a comparative analysis]. AB - Objective: To investigate the effect of manganese chloride (MnCl(2)) or 1-methyl 4-phenylpyridinium (MPP (+)) on oxidative stress and autophagy in human neuroblastomaSK-N-SH cells and the mechanism of the neurotoxicity of manganese. Methods: SK-N-SH cells were treated with MnCl(2) or MPP(+) at doses of 0.062 5, 0.125, 0.25, 0.5, 1.0, and 2.0 mmol/L for 24 hours, and MTT assay was used to measure cell viability. The cells weretreated with MnCl(2) or MPP(+) at doses of 0.125, 0.25, and 0.5 mmol/L for 24 hours, and flow cytometry was used to measure the content of reactive oxygen species (ROS) in cells, a laser scanning confocal microscope was used to observe autophagosome in cells, and Western blot was used to measure the expression of autophagy-related proteins P62 and LC3-II/LC3-I. Results: Compared with the control group, the 0.0625-2.0 mmol/L MnCl(2) and 0.125 2.0 mmol/L MPP (+) treatment groups had significant reductions in the viability of SK-N-SH cells, and the 0.25-2.0 mmol/L MnCl(2) treatment groups had significantly lower viability than the groups treated with the same doses of MPP(+) (all P<0.05) . Compared with the control group, the 0.125-0.25 mmol/L MnCl(2) and 0.125-0.5 mmol/L MPP(+) treatment groups had significant increases in the content of ROS, and the 0.25-0.5 mmol/L MPP(+) treatment groups had significantly higher content of ROS than the groups treated with the same doses of MnCl(2) (all P<0.05) . Compared with the control group, the 0.25-0.5 mmol/L MnCl(2) andMPP(+) treatment groups had significant increases in autophagy-related proteins LC3-II/LC3-I and significant reductions in P62 expression; the 0.125-0.5 mmol/L MPP(+) treatment groups had significantly higher LC3-II/LC3-I than the groups treated with the same doses of MnCl(2), and the 0.125 and 0.25 mmol/L MPP (+) treatment groups had significantly lower P62 expression than the groups treated with the same doses of MnCl(2) (all P<0.05) . Conclusion: Both MnCl(2) and MPP(+) can induce oxidative stress and autophagy in SK-N-SH cells, and MPP(+) has a significantly greater inductive effect on autophagy of SK-N-SH cells than MnCl(2). PMID- 28355696 TI - [Effects of bisphenol A on the expression of N-cadherin, Vimentin and FSHR in rat Sertoli cells]. AB - Objective: To explore the effects of BPA on the expression of N-cadherin, Vimentin and FSHR in rat Sertoli cells. Methods: Primary Sertoli cells collected from prepuberty rats (18-21 d) were cultured for 48 h, and then they were treated with 0, 30, 50, 70 MUmol/L BPA respectively for 24 h. The methods of MTT, real time quantitative PCR and Western blotting were utilized to measure the cell ability of Sertoli cells, the mRNA and protein expression levels of N-cadherin, Vimentin and FSHR respectively. Results: Compared with control, the cell abilities of Sertoli cells in 50 MUmol/L BPA group and 70 MUmol/L BPA group increased significantly (P<0.05) . The cell abilities of Sertoli cells decreased with the increases of exposure doses of BPA. Compared with control, the expression of N-cadherin mRNA only increased in 30 MUmol/L BPA group (P<0.05) , the expression of Vimentin mRNA decreased significantly in all doses group of BPA (P<0.05) , the expression of FSHR mRNA increased in all doses group of BPA (P<0.05) . Compared with the control, the protein levels of N-cadherin increased significantly in 50 MUmol/L BPA group (P<0.05) , the protein levels of Vimentin decreased significantly in all doses group of BPA (P<0.05) , the protein levels of FSHR decreased significantly in 50 MUmol/L BPA group and 70 MUmol/L BPA group (P<0.05) . Conclusion: The mechanism of testicular toxicity from BPA might be the alterations of N-cadherin, Vimentin and FSHR by disturbing normal spermatogenesis. PMID- 28355697 TI - [Study on apoptosis mechanism of H9c2 cardiomyocytes induced by N, N dimethylformamide]. AB - Objective: To observe the change levels of nuclear factor-kappa B (NF-kappaB) p65 protein in cytoplasm and nuclear, phosphorylation of inhibitor of kappa B (p IkappaB) protein and cytochrome C (Cyt-c) , cleaved cysteinyl aspartate specific proteinase-3 (Cleaved caspase-3) , B-cell lymphoma/leukemia-2 (Bcl-2) in cytoplasm in the process of N, N-dimethylformamide (DMF) -induced apoptosis in H9c2 cardiomyocytes, and explore the tentative mechanism of apoptosis. Methods: H9c2 cardiomyocytes were exposed to 200 mmol/L DMF. Western blotting was used to detect the protein expression levels of p65 in cytoplasm and nuclear, p-IkappaB after exposure for 0, 2, 4, 6, 8, 12 h, and the protein expression levels of Cyt c, Cleaved caspase-3, Bcl-2 in cytoplasm after exposure for 0, 2, 4, 8, 12, 24 h. Immunofluorescencecytochemistry (IFC) was used to observe the location of Cyt-c after 200 mmol/L DMF exposure for different times. Results: The levels of p65 in cytoplasm and nuclear and p-IkappaB among groups were statistically significant (F were 7.79, 33.11, 90.25, respectively, all P<0.01) . Compared with the control group, the levels of p65 in cytoplasm of 2, 4, 6 h group were significantly decreased (all P<0.01) ; the levels of p65 in nuclear of 2, 4, 6, 8 h were significantly increased (all P<0.01) ; the levels of p-IkappaB of 2, 4, 6 h group were significantly increased (all P<0.01) . The levels of Cyt-c, Cleaved caspase 3 and Bcl-2 among groups were statistically significant (F were 51.42, 503.68, 73.37, respectively, all P<0.01) . Compared with the control group, the levels of Cyt-c of 8, 12 h group were significantly increased (both P<0.01) ; the levels of Cleaved caspase-3 of 2, 4, 8, 12, 24 h were significantly increased (all P<0.01) ; the levels of Bcl-2 of 2, 4, 8, 12, 24 h group were significantly decreased (all P<0.01) . IFC showed that Cyt-c was released from the mitochondria to the cytoplasm gradually as the extension of the exposure time. Conclusion: NF-kappaB signaling pathway and mitochondrial pathway are involved in the mechanism of DMF induced apoptosis in H9c2 cardiomyocytes. PMID- 28355698 TI - [Workplace social capital and intention to stay among Chinese nurses: a structural equation model]. AB - Objective: To explore a model that workplace social capital is associated with intention to stay (ITS) in the nursing profession and that this association is partially mediated by organizational commitment, job satisfaction, and job stress among Chinese nurses. Methods: A cross-sectional, observationalstudy was conducted in Shanghai, China between September and December 2014. Two thousandforty-two nurses from 23 healthcare organizations were recruited for the current study using a two-stage sampling process.Intention to stay, workplace social capital, job satisfaction, organizational commitment, and job stress was measured by validated scale. Measured variable path analysis (MVPA) was used to test their hypothesized relationships. Results: There were significant positive direct effects from workplace social capital (beta=0.11, P<0.01) , organizational commitment (beta=0.81, P<0.01) and job satisfaction (beta=0.03, P<0.01) to ITS, and a negative direct effects from job strain to ITS (beta=-0.03, P<0.01) . The model explained 84% of the variability in ITS. Additionally, workplace social capital had significant positive direct effects on organizational commitment (beta=0.65, P<0.01) , job satisfaction (beta=0.44, P<0.01) and negative direct effects on job strain (beta=-0.35, P<0.01) . The indirect effect of social capital to ITS was 0.55. Job satisfaction was positively associated with organizational commitment (r=0.47, P<0.01) , and negtively associated with job stress (r=-0.12, P<0.01) . Job stress was negtively associated with organizational commitment (r=-0.20, P<0.01) . Conclusion: This study suggests that greater workplace social capital may lead to higher ITS in nursing primarily by increasing commitment to the nursing occupation and their job satisfaction and by reducing their sense of job stress. PMID- 28355699 TI - [Study on the health effect of the occupational stress in aircrew]. AB - Objective: To explore the relationship between occupational stress and physiological and biochemical indexes, to research the health effect of the occupational stress in aircrew. Methods: 450 aircrews were conducted with the OSI R questionnaire survey, examine the level of blood pressure, blood routine, ALT and UA. Results: The concentration of HB was positively related with task conflict and entertainment and leisure (beta=0.262 and 0.106, both P<0.05) , while heavy task, task discomfort and psychological stress reactions were negatively related with HB (beta=-0.163, -0.102, and -0.137, all P<0.05) ; task conflict and self-care were positively related with RBC (beta=0.221 and 0.159, both P<0.01) , heavy task, psychological stress reactions and social support were negatively related with RBC (beta=-0.157, -0.119, and -0.113, all P<0.05) ; task ambiguity and self-care had a positive relationship with ALT (beta=0.144 and 0.159, both P<0.01) while heavy task, psychological stress reactions and social support had a negative relationship with ALT (beta=-0.176, -0.096, and -0.102, all P<0.05) ; self-care was positively related with SBP (beta=0.170, P<0.01) , task discomfort, interpersonal stress reactions and social support were negatively related with SBP (beta=-0.093, -0.103, and -0.111, all P<0.05) ; while self-care was positively related with DBP (beta=0.139, P<0.01) , social support was negatively related with DBP (beta=-0.114, P<0.05) . Conclusion: Occupational stress of the aircrew is significantly related with blood pressure, RBC, ALT and UA, occupational stress can make effects on the health of aircrew. PMID- 28355700 TI - [Effects of video work on the ocular vascular hemodynamic and visual of the operators]. AB - Objective: To investigate the effects of long time video display terminal (VDT) operation on the ocular vascular hemodynamic and visual acuity. Methods: During March and October 2015, 120 cases of video monitoring warriors were selected as study group, another 155 cases of logistics personnel as the control group. The low vision of the two groups was calculated and compared, and the color Doppler flow imaging was used to measure the central retinal artery (CRA) , short posterior ciliary artery (SPCA) , anterior ciliary artery (ACA) , (peak systolic velocity, PSV) , end diastolic velocity (EDV) and (resistance index (RI) . The differences of hemodynamic parameters between these two groups were evaluated, and the relationship between the visual acuity and each hemodynamic parameter was analyzed. Results: The visual acuity of the study group was[0.8 (0.4-1.2) ], much lower than the control group, and the rate of low version in the study group was 40.00%, much higher than that of the control group. Compared with the control group, both of ACA and CRA of SPCA, PSV and EDV in the study group were decreased, while RI of CRA, ACA were increased (P<0.05) ; Compared with the control group, no statistical significance was found in the RI of SPCA in the study group (P>0.05) . The PSV and EDV were negatively correlated with visual acuity (r value of PSV and visual acuity were -0.352, -0.265 and -0.304; r value of EDV and visual acuity were -0.324, -0.348 and -0.365, while RI was positively correlated with visual acuity (r value were 0.363, 0.326 and 0.344) . Conclusion: Our data suggest that long time video operation may be associated with changes of ocular vascular hemodynamic parameters and raise the incidence of low vision. PMID- 28355701 TI - [Incidence and trend of occupational diseases in Ningbo, China, from 2006 to 2015]. AB - Objective: To investigate the incidence, distribution features, and incidence trend of occupational diseases in Ningbo, China, from 2006 to 2015. Methods: In February 2016, the data on occupational disease report cards in the occupational disease and occupational health information system from 2006 to 2015 were collected to perform a comprehensive analysis of the types, incidence trend, population characteristics, and enterprise characteristics of occupational diseases. Results: There were 845 new cases of occupational diseases in Ningbo from 2006 to 2015, among which 596 (70.53%) were pneumoconiosis; there were 445 (74.66%) cases of stage I pneumoconiosis, 73 (12.25%) cases of stage II pneumoconiosis, and 78 (13.09%) cases of stage III pneumoconiosis; silicosis (59.76%) was the most common type of pneumoconiosis. Of all patients with occupational diseases, 84.97% were male, 64.50%were aged 35-55 years, and 63.67% had 5-20 working years. Most of the patients with occupational diseases worked in small and medium-sized private (or foreign) enterprises; the most common industries were black metal smelting and rolling (38.76%) , construction (17.11%) , and non-metallic ore mining (13.09%) . A total of 51.28%, 10.26%, and 7.69% of the patients with occupational poisoning worked in the electric apparatus manufacturing industry, furniture manufacturing industry, and chemical raw material and chemical product manufacturing industry, respectively. The cases of occupational diseases are mainly distributed in Yuyao City (24.62%) , Yinzhou District (23.91%) , and Ninghai County (15.62%) . Conclusion: Pneumoconiosis is the most common type of occupational disease in Ningbo and most of these patients work in small and medium-sized private (or foreign) enterprises. The supervision of small and medium-sized private enterprises should be enhanced to protect workers' health. PMID- 28355702 TI - [Prevalence of breast and gynecological diseases in female workers in the administrative office and workshop of an automobile part factory]. AB - Objective: To investigate the prevalence of breast and gynecological diseases in female workers in the administrative office and workshop of an automobile part factory, and to provide a basis for promoting the health of female workers. Methods: In March 2015, color ultrasound examination of the breast, uterus, and bilateral adnexa was performed for all female workers, and routine gynecological examination, routine leucorrhea examination, and thinprep liquid-based cytology test were performed for married female workers. The detection rates of breast and gynecological diseases in female workers in the administrative office and workshop were analyzed. Results: In the 314 female workers, the overall detection rate of breast and gynecological diseases was 86.31%; the detection rate of abnormal breast ultrasound results was 72.93%, mainly breast hyperplasia; the detection rate of abnormal gynecological ultrasound results was 12.14%, mainly hysteromyoma, pelvic effusion, and uterus-rectum fossa effusion. The overall detection rate of cervicitis or vaginitis in married female workers was 66.86%. The univariate analysis showed that compared with those in the administrative office, the female workers in the workshop had significantly higher detection rates of breast hyperplasia and grade 2 breast lesions on the Breast Imaging Reporting and Data System (BI-RADS) and significantly lower detection rates of hysteromyoma and grade 3 breast lesions on the BI-RADS (all P <0.05) . The multivariate analysis showed that age was a risk factor for hysteromyoma (OR=1.261) , age and working in the workshop were risk factors for breast hyperplasia (OR=1.065 and 1.834) , married status was a protective factor against breast hyperplasia and grade 2 breast lesions on the BI-RADS (OR=0.334 and 0.450) , and working in workshop was a risk factor for grade 2 breast lesions on the BI RADS (OR=1.890) and a protective factor against grade 3 breast lesions on the BI RADS (OR=0.355) . Conclusion: Female workers in an automobile part factory have high prevalence rates of breast and gynecological diseases. Night shifts for female workers in the workshop should be reduced as much as possible, and female workers, especially those in the administrative office, should be guided to release pressure and take a balanced diet. PMID- 28355703 TI - [Comparison and application of two risk assessment methods for occupational lead exposure risk classification in a lead-acid battery enterprise]. AB - Objective: To apply and compare two risk assessment methods for occupational lead exposure risk classification in a lead-acid battery enterprise. Methods: In April 2013, an occupational health survey was carried out in a lead-acid battery enterprise. Lead smoke and lead dust were tested in the workplace. The risk assessment index system for occupational chemical hazards that was established and optimized by the research group (referred to as "optimized index system" ) , as well as the Singapore semi-quantitative risk assessment model, was used for occupational lead exposure risk classification in the lead-acid battery enterprise. The two risk classification results were analyzed and compared. Results: In the lead smoke risk classification results, the optimized index system classified the raw material group and foundry group workshops as Class I hazardous and the assembling group workshop as Class II hazardous. The Singapore semi-quantitative risk assessment model classified the raw material group workshop as high risk and foundry group and assembling group workshops as extremely high risk. In the lead dust risk classification results, the optimized index system classified the raw material group workshop as Class I hazardous, while the plate painting group, plate cutting group, and assembling group workshops were classified as Class II hazardous. The Singapore semi-quantitative risk assessment model classified the raw material group workshop as medium risk, the plate painting group and plate cutting group workshops as high risk, and the assembling group workshop as extremely high risk. Conclusion: There are some differences in risk assessment of occupational lead exposure between the two risk assessment methods. The optimized index system is comparably more reasonable and feasible, and is highly operable. PMID- 28355705 TI - [Occupational mental health and job satisfaction in university teachers in Shenyang, China]. AB - Objective: To investigate the current status of occupational mental health and job satisfaction in university teachers in Shenyang, China and related influencing factors. Methods: A total of 1500 teachers from 6 universities in Shenyang were randomly selected as study subjects from November 2013 to January 2014. Self-administered questionnaires were used to investigate mental health, including effort-reward imbalance questionnaire, Minnesota Satisfaction Questionnaire, Center for Epidemiological Survey-Depression Scale, and Psychological Capital Questionnaire. Results: Of all teachers, 58.9% had depressive symptoms. Depressive symptoms in university teachers were negatively correlated with the scores of psychological capital, supervisory commitment, and perceived organizational support (r=-0.461, -0.306, and -0.366, all P<0.01) and were positively correlated with the score of occupational stress (r=0.414, P<0.01) . Job satisfaction was positively correlated with psychological capital, perceived organizational support, and supervisory commitment (r=0.650, 0.715, and 0.636, all P<0.01) and negatively correlated with occupational stress (r=-0.475, P<0.01) . The direct effects of occupational stress, perceived organizational support, and supervisory commitment on job satisfaction were -0.30, 0.26, and 0.14, respectively, and their indirect effects were -0.0176, 0.0656, and 0.0368, respectively. The direct effects of occupational stress, perceived organizational support, and supervisory commitment on depressive symptoms were 0.20, -0.08, and 0.05, respectively, and their indirect effects was 0.033, -0.123, and -0.069, respectively. Conclusion: Occupational mental health is closely associated with job satisfaction in university teachers in Shenyang, and psychological capital has a mediating effect on perceived organizational support, supervisory commitment, occupational stress, job satisfaction, and depressive symptoms. PMID- 28355704 TI - [A trend analysis of the incidence of occupational diseases in Chongqing, China, from 2006 to 2014]. AB - Objective: To investigate the incidence of occupational diseases in Chongqing, China, from 2006 to 2014, and to analyze the harm, features, and trend of occupational diseases in Chongqing. Methods: The data of new cases of occupational diseases from 2006 to 2014 were collected, and the patients with a confirmed diagnosis of occupational diseases were selected as study subjects to analyze the incidence of occupational diseases in Chongqing. Results: There were 17499 cases of occupational diseases in total in Chongqing from 2006 to 2014. Among these patients, 17124 (97.86%) were male, most of whom (95.40%) had occupational pneumoconiosis, and 375 (2.14%) were female, most of whom (72.80%) had occupational chemical poisoning. There were 16400 cases (93.72%) of occupational pneumoconiosis in total, mainly coal workers' pneumoconiosis (55.87%) and silicosis (43.02%) , and the main industries involved were coal mining and washing, railway transport equipment manufacturing, and mining and washing of bituminous coal and anthracite. There were 724 cases of occupational poisoning in total; there were 281 cases of acute occupational poisoning, mainly gas poisoning (39.86%) and carbon monoxide poisoning (33.10%) ; there were 443 cases of chronic occupational poisoning, mainly poisoning caused by benzene (47.63%) , mercury and its inorganic compounds (32.74%) , and lead and its inorganic compounds (9.03%) . Conclusion: Occupational diseases in Chongqing are mainly occupational pneumoconiosis, and occupational health supervision should be enhanced in the industries of coal mining and washing and railway transport equipment manufacturing to protect workers' health. PMID- 28355706 TI - [Clinical effect of rock salt aerosol therapy in treatment of occupational allergic contact dermatitis]. AB - Objective: To investigate the clinical effect and safety of rock salt aerosol therapy in the treatment of occupational allergic contact dermatitis. Methods: A total of 65 patients with acute exacerbation of occupational allergic contact dermatitis who were treated in the Outpatient Service and Inpatient Department of our hospital from March 2013 to December 2015 were enrolled and randomly divided into observation group and control group using a random number table. Both groups were givensymptomatic treatment including desensitization, and the patients in the observation group were given rock salt aerosol therapy for 2 courses in addition to the symptomatic treatment. The changes in symptoms, signs, blood eosinophil count, and IgE were observed. Results: There were significant changes in symptom score at the first and second courses of the treatment (P<0.05) , and there was an interaction between time of therapy and grouping (P<0.05) . There was no significant difference in symptom score before treatment between the two groups (P>0.05) , while there were differences at the first and second courses of the treatment (P<0.05) . After the second course of treatment, the observation group had a significantly higher overall response rate than the control group (P<0.05) ; both groups had significant reductions in blood eosinophil count and the observation group had a significantly greater reduction than the control group (P<0.05) . After two courses of treatment, both groups had significant increases in the number of patients with normal IgE (both P<0.05) , and after the second course of treatment, the observation group had a significantly higher number than the control group (P<0.05) . Both groups had mild adverse events, which did not affect the treatment. Conclusion: In the treatment of occupational allergic contact dermatitis, rock salt aerosol therapy has a certain effect on the recovery of symptoms, signs, blood eosinophil count, and IgE. PMID- 28355707 TI - [A case of severe poisoning with paint thinner]. PMID- 28355708 TI - [Effects of extract of Ginkgo biloba on magnetic resonance imaging and electroencephalography in patients with delayed encephalopathy after acute carbon monoxide poisoning]. AB - Objective: To observe the effects of extract of Ginkgo biloba (Ginaton) on magnetic resonance imaging (MRI) and electroencephalography (EEG) in patients with delayed encephalopathy after acute carbon monoxide poisoning. Methods: The 84 patients with delayed encephalopathy after acute carbon monoxide poisoning treated in our hospital from Jan. 2011 to Apr. 2016 were randomly divied into therapy group and observation group. The therapy group received routine treatments of hyperbaric oxygen, cure cerebral edema and promote brain cell metabolism, and observation group was given intravenous injection (intravenous drip) Ginaton 70 mg (adding 0.9% sodium chloride injection 250 ml) , once a day, 2 weeks for one therapeutic course. The changes of MRI and EEG before and after treatment between therapy group and observation group were observed. Results: In the observation group, the white matter and globus pallidus lesions of 14 d after treatment were smaller than those in the treatment group, and the abnormal signal intensity was decreased. At 14 days after treatment the improvement of EEG in observation group were better than therapy group (P<0.05) . Conclusion: Early treatment of extract of Ginkgo biloba (Ginaton) in delayed encephalopathy after acute carbon monoxide poisoning can effectively improve lesion and signal on MRI and abnormal rate on EEG. It has a certain therapeutic effect in clinical. PMID- 28355709 TI - [A long-term follow-up of a patient with occupational chronic lead poisoning]. PMID- 28355710 TI - [Determination of glycidyl methacrylate in the air of workplace captured adsorbent tube by gas chromatography]. AB - Objective: To develop a new solid sorbent tube for capturing glycidyl methacrylate (GMA) in workplace air, and establish a complete set of method. Methods: GMA in workplace air was captured by the new solid sorbent tube filled with carbon aerogel adsorbent, desorbed with solution of 50% (V/V) dimethylformamide-carbon disulfide, separated through capillary chromatographic column, and then analyzed by gas chromatography-flame ionization detector. Results: The linear range of GMA was 0.38-604.80 mg/L, and the related coefficient was 0.999 82. The within-run and the between-run precision were 1.11% 2.80% and 2.53%-4.84% respectively. The average desorption efficiency was 93.20% 94.97%. The minimum quantification concentration and The minimum quantification concentration were 0.02 and 0.07 mg/m(3) respectively (3.00 L sample) . Samples could be stored for at least 8 days at room temperature. Conclusion: The newly developed solid sorbent tube and its complete set of gas chromatography method is simple, and has high sensitivity and precision, so it can be used for sampling and quantitative detection of GMA in workplace air. PMID- 28355711 TI - [Determination of dimethyl sulfate in the air of workplace by GC-MS]. AB - Objective: To establish a method to detect the concentrations of dimethyl sulfate in the air of workplace by GC-MS. Methods: DMS in the air of workplace adsorpted by Silicone tube, then desorped by acetone, add 1.0 ml of acetone, shake 1 min, placed after 30 min, the desorption solution qualitative and quantitative determination by gas chromatography-mass. Results: The calibration curves were liner in the range of 0.1-200.0 MUg/ml. The within-run and between-run precisions were 2.6%-4.7% and 4.0%-9.0% respectively. The method detection limit is 0.1 MUg/ml, the minimum detectable concentration is 0.02 mg/m(3) (in terms of sampling 4.5 L) . Add 1 ml of desorption liquid, place 30 min, the average desorption efficiency of more than 90%. Conclusion: This method has simple pretreatment, short analysis period, and optimized linear rage and limit of detection, and is suitable for the determination of DMS in workplace air. PMID- 28355712 TI - [The occupational disease hazards prevention and control status survey of tertiary hospitals in Shandong province]. PMID- 28355713 TI - [Health protection zone standards for industrial enterprises in China and their application]. PMID- 28355714 TI - [Focus on insomnia complicating cardiovascular disease]. PMID- 28355715 TI - [Reappraisal of lipid management in patient with acute coronary syndrome]. PMID- 28355716 TI - [A retrospective analysis of clinical characteristics and outcomes of heart failure patients with different left ventricular ejection fractions]. AB - Objective: To compare the clinical characteristics, and outcomes of patients with heart failure with different left ventricular ejection fractions (LVEF). Methods: A total of 1 182 hospitalized patients with heart failure (HF) were enrolled and retrospectively studied in the present study. The patients were stratified by LVEF as reduced (HFrEF, LVEF<40%, n=313), mid-range (HFmrEF, 40% <=LVEF <50%, n=287) and preserved (HFpEF, LVEF>=50%, n=582) ejection fraction groups. Among the 1 182 cases, 941 of them (81.3%, 84.9%, and 84.0% inHFrEF, HFmrEF and HFpEF groups, respectively) were followed up for an median duration of 27.3 months. Results: (1) Among the study patients, 26.5% were in HFrEF, 24.3% in HFmrEF, and 49.2% in HFpEF groups. (2) Ischemic heart disease with HFmrEF was more frequent than that in patients with HFrEF. The average age, percentage of female subjects, systolic blood pressure, uric acid, N terminal B-type natriuretic peptide precursor (NT-proBNP), hemoglobin, and the incidence of hypertensive heart disease, anemia, atrial fibrillation in patients with HFmrEF were higher than those in patients with HFrEF, but lower than those in patients with HFpEF (all P<0.01). (3) The all-cause cumulative mortality was 10.8% at 1 year, 20.6% at 2 years and 35.9% at 5 years. No difference was observed in the all-cause cumulative mortality at 1 year, 2 years, 5 years among the three groups (all P>0.05). Conclusions: The HFmrEF patients, as a new and distinct group, were with many intermediate characteristics compared with HFrEF and HFpEF subjects. However, the all-cause mortality was not significantly different among HF patients with different LVEF. PMID- 28355717 TI - [The relationship between LDL-C and ischemic stroke in 2 470 patients with nonvalvular atrial fibrillation in Xinjiang region]. AB - Objective: To evaluate the association between LDL-C and ischemic stroke in patients with nonvalvular atrial fibrillation (AF). Method: A total of 2 470 patients with nonvalvular AF were included in the present study. The clinical data and laboratory examination results of the patients in the hospital were collected. The subjects were either divided into the ischemic stroke history (n=560), and non- ischemic stroke history groups (n=1 910), or divided into the low-middle risk (n=566) and high risk groups (n=1 904) based on CHA(2)DS(2) - VASc score. Results: There were significant differences in the proportion of Han, the ratio of gender, age, hemoglobin, hematocrit, ALT, serum uric acid, HDL-C and LDL-C between the patients with ischemic stroke history and without (all P<0.05). Similarly, there were significant differences in the proportion of Han, the ratio of gender, age, white blood cell count, hemoglobin, hematocrit, platelet count, ALT, albumin, TG and LDL-C between subjects in the low-middle risk group and those in the high risk group (all P<0.05). A logistical regression analysis showed that LDL-C was an independent risk factor for both the ischemic stroke history (OR 2.089, 95% CI 1.860-2.347, P<0.05), and future ischemic stroke risk (OR 1.270, 95% CI 1.079-1.494, P<0.05) in patients with nonvalvular AF. Conclusion: LDL-C is associated with ischemic stroke in patients with nonvalvular AF, and it is also an independent risk factor for future ischemic stroke in these patients. PMID- 28355718 TI - [The clinical characteristics of stroke in young patients with cardiac myxoma]. AB - Objective: To investigate the clinical characteristics of stroke in young patients with cardiac myxoma. Methods: Medical records of young patients (aged between 18-44 years) diagnosed with cardiac myxoma in Beijing Anzhen Hospital affiliated to Capital Medical University from January 2005 to March 2016 were retrospective reviewed. Results: A total of 117 cases were included (85 female and 32 male)with the average age (36+/-7)years old. Most myxomas (83.8%) were located in the left atrium, 7.7% were in the right atrium, 3.5% were in the both atriums, 2.6% were in the left ventricle, and a few were in the left atrium plus left ventricle and in the right ventricle. Of all the patients, 24 (20.5%) (16 women and 8 men) were complicated with cerebral infarction. Among them, 3 patients were with lower extremity arterial embolisms. Two patients were with cerebral hemorrhage. The cerebral infarction mainly involved in the distribution area of the internal carotid artery. Infarctions involving 2 or more cerebral vessels were found in 4 cases. Most subjects (58.3%) manifested with hemiplegia, and some (18.2%) with syncope. The proportion of the left atrial myxoma in patients with cerebral infarction (100.0%) was significantly higher than those in patients without cerebral infarction (85.1%, P=0.044). Subjects with tumor diameter less than 3 cm were more frequently complicated with cerebral infarction (37.5% vs 13.8%, P= 0.009). A logistic analysis showed that the odds ratio of myxoma with tumor diameter less than 3 cm for cerebral infarction was 3.750(95%CI 1.343-10.470). Conclusions: Cardiac myxoma is more common in young women, and often complicated with cerebral infarction. The infarctions are mainly distributed in internal carotid artery system, and some are involved in multiple vascular systems. The incidence of stroke is associated with the position of the myxoma. Smail-size myxoma cannot be ignored for its risk of stroke. PMID- 28355719 TI - [A clinical analysis of 123 cases of primary empty sella]. AB - Objective: This study was conducted to analyze the clinical characteristics and pituitary function of patients with primary empty sella (PES). Methods: The clinical data from 123 hospitalized adult patients with PES from January 2010 to May 2016 were retrospectively studied. Results: (1) The average age of the 123 (male 43, female 80) PES patients was (59.2+/-13.6) years (ranging 24-92 years), among whom 61% patients were in the age group between 50-69 years. (2) The symptoms of the patients included fatigue (56.1%), headache (34.1%), nausea and vomiting (17.9%), gonadal dysfunction (17.1%), visual disturbance (5.7%) and hypopituitarism crisis (3.3%). (3) Hypopituitarism was found in 66 of the 123 patients. Among them, 36.6%, 31.7% and 17.1% were central hypoadrenalism, hypogonadism, and hypothyroidism, respectively.The percentage of hypopituitarism in complete PES was significantly higher than that in partial PES (P<0.05). (4) Sixteen patients were concomitant with other autoimmune diseases including 11 patients with Graves' disease and 2 with Cushing's syndrome due to adrenal adenoma. Conclusions: The incidence of hypopituitarism in PES was 53.7%, in which the pituitary-adrenal axis hypofunction was more common. An overall evaluation of the pituitary function was essential for the patients who had headache and fatigue, or with suspected PES. The patients with hypopituitarism should be given hormone replacement therapy in time and followed up afterword. PMID- 28355720 TI - [The clinical characteristics of adult hemophagocytic lymphohistiocytosis treated with haploidentical donor hematopoietic stem cell transplantation]. AB - Objective: To analyze the clinical characteristics of adult patients with hemophagocytic lymphohistiocytosis (HLH) receiving haploidentical donor hematopoietic stem cell transplantation (HID HSCT). Method: We retrospectively reviewed 20 adult patients with HLH from August 2009 to August 2014.The clinical features and outcome were analyzed. Results: Conditioning regimens consisted of total body irradiation/etoposide/cyclophosphamide (TBI/VP-16/CTX) and busulfan (Bu)/VP-16/CTX in HLH with anti-thymocyte globulin (ATG) 8 mg/kg.The stem cells were mobilized from donors' peripheral blood.Median time to white blood cell engraftment was 13 (9-27) days.Median time to platelet engraftment was 14 (10-28) days.Mixed chimerism after transplantation developed in 4 patients and no patient presented graft failure.Eight patients developed grade II to III acute graft versus-host disease (GVHD), while as chronic GVHD occurred in 9 patients.Among 12 patients with EB virus(EBV) reactivation, 2 patients developed post-transplant lymphoproliferative disorder (PTLD), 7 were suspected as PTLD and 3 were considered as relapse of primary disease.With a median follow-up of 20 months (range: 0.5-108 months) after transplantation, the estimated 2-year overall survival (OS) rate was (60.0+/-11.0)% in all patients.During the follow-up, 12 patients survived, 8 died including 5 within 100 days after HSCT.Among 5 non remission patients before HSCT, 4 patients died within 100 days after HCT. Conclusions: HID HSCT is an effective treatment for adult patients with HLH to achieve remission and long-term survival. High proportion of mixed chimerism has been seen at early stage after transplantation.EBV reactivation and early transplant-related mortality are common. PMID- 28355721 TI - [The efficacy of cyclosporine A as salvage therapy for severe active ulcerative colitis refractory to glucocorticoid]. AB - Objective: To clarify the efficacy and safety of cyclosporine A (CsA) as salvage therapy in patients with severe active ulcerative colitis (UC) and refractory to steroids. Methods: A total of 24 severe active UC patients refractory to steroids and hospitalized from 2006 to 2012, were retrospectively enrolled.Data including demographic features, clinical manifestations, laboratory tests and medications were collected. Results: CsA was effective in 15(62.5%) patients, who did not receive colectomy during 12-week administration. This regimen was tolerable in most patients.Twelve (50.0%) patients reported 16 adverse events, but only one patient withdrew CsA due to intolerance.The rates of adverse events in initial intravenous CsA including 4 mg.kg(-1).d(-1,) 3 mg.kg(-1).d(-1) and 2 mg.kg(-1).d( 1) were 2/2, 9/17 and 1/5 respectively.Responders had higher white blood cell count compared with non-responders (P= 0.045). Conclusions: CsA could be an effective alternative regimen to colectomy in severe active UC patients who are refractory to steroids. PMID- 28355723 TI - [A cross-sectional study on application of glucocorticoid in systemic lupus erythematosus patients]. AB - Objective: To explore the status of glucocorticoid application in patients with systemic lupus erythematosus (SLE) in China. Methods: Epidemiological survey was used. The SLE patients who met the 1997 classification criteria of American College of Rheumatology were enrolled. The usage of glucocorticoid and related adverse reactions were recorded and analyzed. Results: A total of 400 SLE patients were enrolled, including 35 men and 365 women. The average age was (37.4+/-14.0) years old, and the average duration of disease was (6.7+/-5.8) years. There were 310 patients using glucocorticoid as maintenance. Sixty-one percent (n=244) patients started using medium dose (prednisone 30-<60 mg/d) as the initial treatment of glucocorticoid, which lasted for(37+/-11)days.The time of drug duration in patients with low dose prednisone (7.5-<30 mg/d)and high dose (60-100 mg/d) was(92+/-20)and(17+/-3)days respectively (P<0.05 between 3 groups). However, patients receiving different initial dosage were of no discrepancy in the maintenance therapy. During maintenance, even though 51.0% (n=158) patients were on prednisone 2.5-5 mg/d, the duration of drug use in >5-10 mg/d groupwas longer[(29.9+/-3.3) months]. Patients with involvement of internal organs had a higher tendency to use 60-100 mg/d prednisone or pulse-dose therapy in the initial treatment, nevertheless these two groups had no difference of maintenance dosage. Among all 400 patients, 62 patients withdrew glucocorticoid, including 17 patients with disease remission (4.3%), 44 by self-withdrawal and one with adverse reaction. Conclusion: In China, the medium dosage of glucocorticoid is the most common initial treatment in patients with SLE.Prednisone 2.5-5 mg/d was the most common choicefor maintenance therapy. Currently, the proportion of glucocorticoid withdrawal remains low in SLE patients achieving remission. PMID- 28355722 TI - [A clinical analysis of 5 patients with infratentorial primary angiitis of central nervous system]. AB - Objective: To explore the clinical characteristics of infratentorial primary angiitis in central nervous system(PACNS). Methods: A total of 5 cases diagnosed as infratentorial PACNS in the neurology department of Navy General Hospital of PLA in 2015 were enrolled in the study. The clinical, imaging and pathological data were collected and analyzed. Results: All the 5 cases were male with the median onset age of thirty-four. Five cases presented with dizziness, two with headache, three with walking unstable, two with facial numbness and one with dysarthria. Rising pressure of cerebrospinal fluid (CSF) (190-245 cmH(2)O, 1 cmH(2)O=0.098 kPa) was found in 4 cases by the lumbar puncture, mildly increased number of leukocyte in 2 cases [(12-28)*10(6)/L], increased CSF protein in 3 cases(540-979 mg/L) and increased IgG index in 3 cases(0.84-1.45). Pons lesions were revealed by magnetic resonance imaging(MRI)in 4 cases, brachium pontis lesions in 2 cases, cerebellum lesions in 2 cases, one with midbrain lesion in 1 case, unilateral lesions in 4 cases and bilateral lesion in 1 case. Different degree of edema and mass effect were shown in all lesions by MRI. Patch like enhancement was found by contrast MRI in 5 cases and meningeal enhancement in 2 cases. Elevation of choline(Cho)peak was found by magnetic resonance spectroscopy(MRS)in 4 cases, reduction of N-acetyl aspartate(NAA) peak in 3 cases, appearance of lactate peak in 1 case and lipid peak in another case. Arterial spin labeling(ASL) was performed in 4 cases and no hyperperfusion was found. Susceptibility weighted imaging(SWI) was performed in 3 cases and microhemorrhage in the lesions was found in 2 cases and normal in 1 case. Magnetic resonance arteriography(MRA) was performed in 1 case and no stenosis was found. Digital subtraction arteriography(DSA) was performed in 1 case and multiple stenosis of the intracranial arteries was showed. Two cases had taken the stereotactic brain biopsy and the histopathologic diagnosis was angiitis. Five cases were treated with methylprednisolone and cyclophosphamide was added on in 1 case. Good prognosis was found in all cases. Conclusions: Infratentorial PACNS mostly attacks middle-aged males. The lesions tend to locate in unilateral pons, brachium pontis, cerebellum and midbrain. Hemorrhage or microhemorrhage in lesions is often found by SWI and no hyperperfusion is shown by ASL, which would be useful to distinguish PACNS from malignant tumors. Given the limitations of brain biopsy in clinical practice, clinical and imaging features would be helpful to diagnose PACNS. PMID- 28355724 TI - [A clinical analysis on fever of unknown origin in in-patients with systemic lupus erythematosus]. AB - To investigate the etiology and differential diagnoses of patients with systemic lupus erythematosus (SLE) and fever of unknown origin (FUO). From January 2012 to December 2014, a total of 928 SLE patients were admitted to Peking Union Medical College Hospital.Only 50 patients were combined with FUO (5.4%). The most common reason of fever was caused by infections(33 cases, 66.0%), including bacterial infection in 17 cases with 5 tuberculosis, viral infection in 11 cases, and fungal infection in 5 cases.The second reason offever was due to poor disease control or recurrence in 17 patients (34.0%). No fever was caused by malignant tumor.When clinical data was compared between 17 non-infected patients versus 33 infected patients, C reactive protein and procalcitonin in the infected group were significantly higher than those in the non-infected group.In SLE patients combined with FUO, infection is the most common etiology which is necessary to be paid attention to. PMID- 28355725 TI - [A case report of immunoglonulin lambda light chain amyloidosis combined with leukocyte cell-derived chemotaxin-2 amyloidosis]. PMID- 28355726 TI - [A case report of secondary hypoadrenocorticism caused by the intake of glycyrrhiza]. PMID- 28355727 TI - [A case of renal cysts and diabetes syndrome presenting with gout as initial symptom]. PMID- 28355728 TI - [The diagnosis and treatment of diabetic ketoacidosis]. PMID- 28355729 TI - [An update of the application and mechanism of mesenchymal stem cells for treatment of systemic sclerosis]. PMID- 28355730 TI - [A consensus statement on the diagnosis and treatment of cardiovascular diseases combined with insomnia from Chinese experts]. AB - Recent years have seen a large amount of research indicating a high morbidity and mortality of cardiovascular disease (CVD) combined with insomnia, which leads to increasing attentions in studying the association between insomnia and CVD, such as coronary heart diseases, hypertension, heart failure, psycho-cardiology diseases and so on. Sufficient evidence shows that patients suffering from CVD are much more likely to get involved in insomnia than healthy persons. Furthermore, causing great troubles to patients with CVD, insomnia seriously influences the treatment process and prognosis of CVD. However, there is a lack of pragmatic direction for the diagnosis and treatment of this comorbidity. As a result, a specialized consensus statement offering guidance in diagnosing and treating CVD combined with insomnia, is in exigent need. This consensus, which is made by experienced experts from various relevant professional fields including cardiology, psychiatry, neurology, psychology and so forth, has summarized the recommendations for the concepts, epidemiology, pathophysiology mechanisms, diagnosis, management and the special approaches of traditional Chinese medicine in this comorbid conditions. In conclusion, it's certain that this consensus will contribute to the practitioners in managing CVD accompanied with insomnia. PMID- 28355732 TI - [Hybrid operation for cerebral vascular disease:status and prospect clinical application]. PMID- 28355731 TI - [The 455th case: swollen leg, jaundice and mental disturbance]. AB - A 17-year-old young man with a history of swollen leg and intermittent jaundice was presented to Peking Union Medical College Hospital with acute fever and mental disturbance. He developed deep venous thrombosis, acute myocardial infarction and plantar skin necrosis during the past four years, and was presented with an acute episode of fever, thrombocytopenia, acute kidney injury, acute myocardial infarction, mental disturbance, and obstructive jaundice. Laboratory tests showed schistocytes on peripheral blood smear.High titer of antiphospholipid antibodies was detected.Strikingly, the activity of a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS13)was significantly decreased without the production of inhibitors. Images indicated stenosis of the common bile duct, common hepatic duct, and cystic duct, which caused dilation of bile ducts and the gall bladder. Corticosteroids and anticoagulation therapy were effective at first, but the disease relapsedonce the corticosteroids tapered down. Plasma exchange was administrated for 17 times, which was effective temporarily during this episode. Methylprednisolone pulse therapy, intravenous immunoglobulin, rituximab, anticoagulation therapy, and bile drainage, were all tried but still could not control the disease. The patient's family agreed to withdraw treatment after he developed septic shock. PMID- 28355733 TI - [Management of 42 complex intracranial aneurysms in hybrid operating room]. AB - Objective: To analyze the efficacy and methods of hybrid operation in the treatment of complex intracranial aneurysms. Methods: Fourty-two patients with complex intracranial aneurysms were treated in hybrid operation room of Qilu Hospital of Shandong University between July 2011 and October 2016. Twenty-one cases of aneurysm clipping guided by intraoperative angiography, 10 cases of aneurysm clipping assisted by endovascular therapy, and 11 cases of aneurysm occlusion assisted by bypass surgery. Results: Thirty-five patients were followed up 6-36 months.Thirty-three (94.3%) cases were completely occlusion, 2 (5.7%) cases were recurrent in follow-up.One of the recurrence case was performed interventional embolization treatment, and the other was continuous follow-up. Conclusion: Hybrid operating room is beneficial to evaluate the surgical curative effect immediately. It could increase the occlusion rate of complicated aneurysms, and could provide an ideal platform for complicated intracranial aneurysm treatment. PMID- 28355734 TI - [Application of hybrid operating room in the treatment of spinal dural arteriovenous fistulas]. AB - Objective: To explore the experience in the treatment of spinal dural arteriovenous fistulas with application of hybrid operating room. Method: A retrospective analysis was performed among 22 patients with spinal dural arteriovenous fistulas admitted to Department of Neurosurgery of Tianjin Medical University General Hospital who received operation in the hybrid operating room from March 2011 to February 2016. Modified Aminoff-Logue scores (ALS) for myelopathy was used to evaluate the spinal function.All the 22 patients were followed up 6-12 months after the operation. Result: All the patients were diagnosed by spinal digital subtraction angiography (DSA). The modified ALS pre operation and post-operation 6 months were (4.7+/-1.8) and (2.0+/-1.5), respectively, with significant difference (P<0.01). There were 15 cases with mild dysfunction, 6 cases with moderate dysfunction, severe dysfunction in 1 case before operation.Fifteen cases were cured, 4 cases improved, 1 case had no change after 6 months follow-up.The improvement rate was 95.45%. Conclusion: The application of hybrid operating room in the treatment of spinal dural arteriovenous fistulas achieves good outcome and provides a convenient and effective approach, which embodies the idea of precision medicine. PMID- 28355735 TI - [Clinical application of hybrid surgery for the treatment of cerebral arteriovenous malformations]. AB - Objective: To investigate the application of hybrid technique for the treatment of cerebral arteriovenous malformations (CAVMs) and to assess the value of hybrid technique. Methods: The cases of CAVMs treated in Qilu hospital and People's Hospital of Xinjiang Uygur Autonomous Region from July 2011 to July 2016 were analyzed retrospectively.Two modes of hybrid surgery, "angiographic diagnosis craniotomy lesion resection or/and hematoma clearance-intraoperative angiography evaluation" and "angiographic diagnosis-intraoperative embolization-craniotomy lesion resection or/and hematoma clearance-intraoperative angiography evaluation" were applied for all the cases.We placed an aneurysm clip as marker in surgery field during real-time angiography.If CAVMs residues occurred during surgery, we re-resected the residue according to the guidance of the marker (clip) and DSA imaging. Intra-operative angiography evaluated the results of CAVMs resection one more time.Postoperatively, follow-up CT scan was performed for all the patients. Results: Of all the cases with CAVMs, there were 8 cases of scale I, 13 cases of scale II, 10 cases of scale III and 6 cases of scale IV according to Spetzler Martin Scale.There were 28 cases of acute hemorrhagic CAVMs and 9 cases of chronic hemorrhagic CAVMs or no-hemorrhagic CAVMs.Intra-operative angiography showed CAVMs residues in 6 cases of acute hemorrhagic CAVMs and only one in chronic group.About 18.92% residual rate of CAVMs were found for the first time intra-operative assessment angiography.With the guidance of intra-operative angiography and aneurysm clip as Marker, all residues of CAVMs were resected totally.Follow up CT showed the hematomas disappeared in all the cases of acute hemorrhagic cases.The cure rate of CAVMs with hybrid surgery was 100% according to the final intra-operative assessment angiography. Conclusions: (1)Hybrid surgery for the treatment of CAVMs in one session could evaluate the results of CAVMs resection and instruct the surgical procedure according to real-time angiography.This model could improve the treatment safety and efficacy for patients with CAVMs.(2)Patients with higher Spetzler-Martin Scale (III-IV) who need intra-operative embolization and patients with hemorrhagic CAVMs are more suitable for hybrid surgery. PMID- 28355736 TI - [Hybrid surgery for complex symptomatic intracranial fistulas: a technical note]. AB - Objective: To explore the efficacy of hybrid management of complex symptomatic intracranial fistulas in neurovascular hybrid operating room. Methods: From March 2014 to January 2015, 2 complex dural arteriovenous fistulas and 1 carotid cavernous fistulas were managed by hybrid surgeries in the PLA Rocket Force General Hospital.With first attempts with endovascular treatment failed, all cases were finally managed by hybrid surgery.Dural arteriovenous fistulas were approached via meningeal artery followed craniotomy.The carotid cavernous fistulas were treated by direct puncture into the left cavernous sinus after craniotomy. Results: Post-operative angiography demonstrated complete occlusion for 2 cases and nearly complete occlusion for 1 case.All 3 cases had no complications.On discharge 2 patients presented no symptoms and 1 greatly improved.Within the follow-up (1-33 months), 1 patient had recurrence after 21 months and received re-embolization with complete occlusion. Conclusion: Hybrid surgery is a promising method to manage complex intracranial fistulas. PMID- 28355737 TI - [Clinical features and prognostic analysis of neuromyelitisoptica spectrum disease with sjogrensyndrome]. AB - Objective: To explore the clinical features and conduct prognostic analysis about visual recovery and relapse of neuromyelitisoptica (NMO) spectrum disease (NMOSD) with sjogren syndrome (SS). Methods: A retrospective and prospective observational study was conducted.Between July 2013 and June 2016, 172 patients with NMOSD (NMOSD-non SS: 116/172, 67.4%; NMOSD-SS: 56/172, 32.6%) were assessed at Beijing Tongren Hospital, Capital Medical University, Beijing, China.The prognostic factors of NMOSD-SS patients were also analyzed. Results: As compared with NMOSD-non SS patients, NMOSD-SS patients had worse visual impairment (percentage of patients with visual acuity less than 0.1, 83.9% vs 69.8%, P<0.05), higher positive rate of SSA (92.9% vs 0.0%, P<0.05), higher proportion of dryness of mouth and eye (66.1% vs 5.2%, P<0.05) as well as higher percentage of reduced visual evoked potential (VEP) amplitude (60.7% vs 43.1%, P<0.05). NMOSD-SS patients had a significantly higher average year recurrent frequency (0.58 vs 0.53) and significantly shorter mean recurrence time (6.7 months vs 12.4 months, P<0.05). The results showed that recurrent eyes, the worst visual acuities of onset less than 0.1 were independent risk factors of visual impairment (visual activity <0.1), according to at least six months' follow-up of all NMOSD-SS patients (OR=6.410 and 9.434, respectively, P<0.05). Meanwhile, immunosuppressive drugs were protective factors of relapse in NMOSD-SS patients (OR=0.107, P<0.05). Conclusions: NMOSD-SS patients have worse visual impairment, and they are more vulnerable to relapse than NMOSD-non SS patients, and the vision is lack of recovery for NMOSD-SS with recurrent eyes or the worst vision of onset less than 0.1.Immunosuppressive drugs can reduce the recurrence of NMOSD SS relapse. PMID- 28355738 TI - [Research on risk factors of short-term outcome in AIDS patients with pneumocystis pneumonia]. AB - Objective: To investigate the prognostic risk factors of acquired immunodeficiency syndrome (AIDS) patients with pneumocystis pneumonia (PCP), and to establish risk models for predicting early outcome. Methods: The clinical data of 418 AIDS patients with PCP admitted to Department of Infectious Diseases, Beijing You'an Hospital, Capital Medical University from January 2008 to May 2016 were retrospectively analyzed.The patients were divided into death group and survival group according to clinical outcome during hospitalization.Data of the two groups were collected including general information and laboratory test results.Multivariate Logistic regression was used to analyze risk factors affecting prognosis of patients, establish prognostic models and evaluate predictive value of the model. Results: Of the 418 AIDS patients with PCP, 388 cases were male and 30 cases were female, aged from 5 to 82 years, mean age was (40+/-12) years.There were 82 patients in the death group and 336 patients in the survival group.Disease course, bacterial infection and alveolar-arterial oxygen pressure difference(P(A-a)O(2)), serum lactate dehydrogenase(LDH), white blood cell (WBC), neutrophil (N), alanine aminotransferase (AST), urea nitrogen (BUN) and serum potassium (K) were significantly higher in the death group than those in the survival group (all P<0.05), and arterial oxygen pressure (PaO(2)), blood oxygen saturation (SpO(2)), CD4(+) T lymphocyte count, lymphocyte (L) , hemoglobin (Hb), platelet (PLT), albumin (ALB), prealbumin (PALB), cholinesterase (CHE), cholesterol (CHO), serum chlorine (Cl) and serum sodium (Na) were significantly lower in the death group than those in the survival group (all P<0.05). Multivariate Logistic regression analysis showed that P(A-a)O(2, )ALB, LDH, N and CD4(+) T lymphocyte count were prognostic factors of AIDS complicated with PCP.Prognostic index=9.736+ 0.112*P(A-a)O(2)-0.719*ALB+ 0.006*LDH+ 0.355*N 0.021*CD4.ROC curve of the short-term prognostic model was 0.985 (95%CI 0.977 0.994), with P value 0.000, cut-off value 0.907, sensitivity 92.0% and specificity 98.8%.The mortality rate increased with the increase of equation value. Conclusions: P(A-a)O(2, )ALB, LDH, N and CD4(+) T lymphocyte count are independent risk factors to predict short-term prognosis in these patients.The short-term prognostic model based on independent risk factors is useful in guiding clinical treatment. PMID- 28355739 TI - [Value of multi-slice spiral CT in preoperative diagnosis of pancreatic cancer]. AB - Objective: To analyze the diagnostic value of multi-slice spiral computed tomography (MSCT) in preoperative tumor staging, lymphatic metastasis, vascular invasion and perineural invasion. Methods: From January 2013 to December 2015, MSCT images of 87 patients from the Second Hospital of Harbin Medical University who were examined by contrast-enhanced MSCT and diagnosed as pancreatic cancer by surgical pathology within 2 weeks were collected.MSCT images were retrospectively analyzed to evaluate the tumor staging, lymphatic metastasis, vascular invasion and perineural invasion and then compared with surgical pathology.Kappa test and receiver operation characteristic (ROC) curve were used to evaluate the diagnostic value of MSCT in pancreatic cancer. Results: The overall accuracy of MSCT in T staging of pancreatic cancer was 85.1% (kappa =0.67, P<0.01); the accuracy of T1, T2, T3 and T4 staging were 75.0%, 57.1%, 95.0% and 66.7%; the sensitivity were 75.0%, 80.0%, 87.7% and 75.0%; the specificity were 98.8%, 92.2%, 86.4% and 96.2%; the positive predictive value (PPV) were 75.0%, 57.1%, 95.0% and 66.7%; the negative predictive value (NPV) were 98.8%, 97.3%, 70.4% and 97.4%.The accuracy, sensitivity, specificity, PPV and NPV of MSCT in diagnosing lymphatic metastasis were 62.1%, 62.3%, 61.5%, 79.2% and 41.0%.The accuracy, sensitivity, specificity, PPV and NPV of MSCT in diagnosing vascular invasion were 94.3%, 78.6%, 97.3%, 84.6% and 95.9%.The accuracy, sensitivity, specificity, PPV and NPV of MSCT in diagnosing MSCT perineural invasion were 80.5%, 81.1%, 76.9%, 95.2% and 41.7%.The area under curve (AUC) was 0.79(95%CI 0.68-0.90, P=0.001). Conclusion: Contrast-enhanced MSCT plays important roles in evaluation of preoperative tumor staging, vascular invasion and perineural invasion of pancreatic cancer while it has little value on diagnosis of lymphatic metastasis. PMID- 28355740 TI - [A comparison between 3.0 T MRI and histopathology for preoperative T staging of potentially resectable esophageal cancer]. AB - Objective: To explore the value of 3.0 T MRI using multiple sequences (star VIBE+ BLADE) in evaluating the preoperative T staging for potentially resectable esophageal cancer (EC). Methods: Between April 2015 and March 2016, a total of 66 consecutive patients with endoscopically proven resectable EC underwent 3.0T MRI in the Affiliated Cancer Hospital of Zhengzhou University.Two independent readers were assigned a T staging on MRI according to the 7th edition of UICC-AJCC TNM Classification, the results of preoperative T staging were compared and analyzed with post-operative pathologic confirmation. Results: The MRI T staging of two readers were highly consistent with histopathological findings, and the sensitivity, specificity and accuracy of preoperative T staging MR imaging were also very high. Conclusion: 3.0 T MRI using multiple sequences is with high accuracy for patients of potentially resectable EC in T staging. The staging accuracy of T1, T2 and T3 is better than that of T4a. 3.0T MRI using multiple sequences could be used as a noninvasive imaging method for pre-operative T staging of EC. PMID- 28355741 TI - [MRI of the finger ligament and tendon injuries: imaging technique and clinical application]. AB - Objective: To explore the MRI technique and the clinical application in ligament and tendons of fingers. Methods: The study was reviewed and approved by an institutional review board of hospital.A total of 20 normal volunteers and 50 patients from Beijing Jishuitan Hospital between May 2012 and May 2015 with finger injuries were chosen to undergo magnetic resonance examination by using Achieva 3.0 T MR produced by Philips.Scanning from coronal, sagittal and axial view in T(1)-weighted and proton fat saturation sequence (PD-FS), choosing suitable parameters, in order to get clear images of finger tendons and ligaments. Results: Twenty normal volunteers without tendons or ligament injuries showed homogeneous low-signal-intensity on T(1)-weighted and proton fat saturation sequence (PD-FS) images.In the 50 patients with finger injuries, there were 33 cases of ligament injuries, 10 cases of extensor tendon injuries and 7 cases of flexor tendon injuries. There were 8 cases of all the 50 cases combined with bone fracture.The injured ligaments and tendons became thicker and discontinued in T(1)WI and demonstrated heterogeneously increased signal intensity with edema in the soft tissues surrounding the injured sites in PD-FS. Conclusion: MRI can demonstrate the anatomy and injuries features of ligament and tendons in fingers accurately.It is significance for the early diagnosis and treatment protocols of the ligament and tendons injuries. PMID- 28355742 TI - [Lumbosacral nerve bowstring disease]. AB - Objective: To define a novel disease-lumbosacral nerve bowstring disease, and propose the diagnostic criteria, while capsule surgery was performed and evaluated in the preliminary study. Methods: From June 2016 to December 2016, a total of 30 patients (22 male and 8 female; mean age of 55.1+/-9.7 years) with lumbosacral nerve bowstring disease were included in Department of Spine Surgery, Changzheng Hospital, the Second Military Medical University.Lumbosacral nerve bowstring disease was defined as axial hypertension of nerve root and spinal cord caused by congenital anomalies, which could be accompanied by other lesions as lumbar disc herniation, spinal cord stenosis or spondylolisthesis, or aggravated by iatrogenic lesions, resulting in neurological symptoms.This phenomenon is similar to a stretched string, the higher tension on each end the louder sound.Meanwhile, the shape of lumbosacral spine looks like a bow, thus, the disease is nominated as lumbosacral nerve bowstring disease.All the patients underwent capsule surgery and filled out Owestry disability index (ODI) and Tempa scale for kinesiophobia (TSK) before and after surgery. Results: The mean surgery time was (155+/-36) min, (4.3+/-0.4) segments were performed surgery.The pre operative VAS, TSK and ODI scores were (7.6+/-0.8), (52.0+/-10.3) and (68.4+/ 12.7), respectively.The post-operative VAS, TSK and ODI scores were (3.3+/-0.4), ( 24.6+/-5.2) and (32.1+/-7.4)(P<0.05, respectively), respectively. Conclusion: The definition and diagnostic criteria of lumbosacral nerve bowstring disease was proposed.Capsule surgery was an effective strategy with most patients acquired excellent outcomes as symptoms relieved and quality of life improved. PMID- 28355743 TI - [Topping-off surgery versus double-segment fusion for treatment of lumbar degenerative disease with mid-long term follow-up]. AB - Objective: To compare the mid-long term clinical effect of Topping-off surgery and lumbar fusion surgery for two-segmental lumbar degenerative disease. Methods: From March 2009 to March 2012, one hundred and twenty-six consecutive patients (Topping-off surgery and two-segment PLIF surgery) were studied in Orthopedics Department, Beijing Chao-Yang Hospital, Capital Medical University.The VAS and ODI were used to assess clinical symptoms.All patients underwent flexion/extension radiographs examinations before surgery, 1, 2 years and last follow-up postoperatively.Lumbar lordosis, sacral slop, data of Coflex segment and adjacent segment (disc height index, range of motion, foraminal height, foraminal width and Pfirrmann classification of intervertebral disc in MRI) were recorded.The paired double-tailed t test was used to analyze the differences in the results from baseline to each postoperative time point.The paired double tailed t test was used in both groups to analyze the differences in the results from baseline to each postoperative time point.The Chi-square test was used to evaluate the differences between the incidences of adjacent segment degeneration(ASD) in the groups. Logistic regression analysis was used to analyze risk factors for developing radiographic ASD. Results: In topping-off group, 60 patients, average operation time was (134.5+/-10.2) min. The average blood loss was (301.5+/-64.6) ml.In fusion group, 68 patients, average age (58.3+/-4.6) years.The average follow-up time was (47.5+/-5.1) months.The average operation time was (158.6+/-19.3) min (P=0.000). The average blood loss was (413.6+/-131.3) ml (P=0.000). Sex, age, body mass index and intervertebral disc grading were matched between the two groups.Better improvement in VAS back pain score was noted in the topping-off group over the fusion group (P=0.030). Both groups achieved good recovery in ODI and improvement in VAS leg pain and back pain scores at last follow-up postoperatively.In the Topping-off group, FH increased from 10.5 mm at baseline to 11.8 mm at 1 year after surgery (P=0.000) and then decreased mildly in the third postoperative year, while in the fusion group, showed no significant change at all postoperative time points.In the fusion group, the disc height and FW at the same segment were no significant change after first year follow-up, while ROM was significantly decreased after surgery (P=0.000). Foraminal height, foraminal width and intervertebral disc height of adjacent segment of Coflex implant level were found decreased at the end of the postoperative follow-up, while compared with preoperative data no significant difference (P>0.05). At last follow-up, eight patients (13.3%) in the Topping-off group and eighteen patients (26.5%) in the fusion group developed ASD (P=0.033). Conclusions: Topping-off surgery compared with two-segment lumbar fusion surgery can achieve a good result in cases with pre-existing mild or moderate adjacent segment degeneration, restrict the adjacent segment's range of motion and reduce the adjacent segment degeneration. Under strict indications, Topping-off surgery is an acceptable alternative to fusion surgery for the treatment of two-segment lumbar disease. PMID- 28355744 TI - [Clinical effect of minimally-Invasive surgical-transforaminal lumbar interbody fusion technique associated with percutaneous pedicle screws in micro endoscopy discectomy]. AB - Objective: To evaluate the clinical efficacy between the minimally-Invasive surgical (MIS)-transforaminal lumbar interbody fusion (TLIF) technique associated with percutaneous pedicle screws in micro endoscopy discectomyand MIS-TLIF technique associated with both sides of the lower lumbar spine Wiltse approach in Quadrant channel with treatment of single segment herniation associated with lumbar instability syndrome. Methods: From January 2012 to January 2015, 75 cases that meet the inclusion and exclusion criteria were treated by retrospective study method, which were divided into two groups in Department of Orthopedics, the Affiliated Hospital of Putian University.Experimental group(30 patients) were treated with MIS-TLIF technique associated with percutaneous pedicle screws in microendoscopy discectomy, control group were treated with MIS-TLIF technique associated with both sides of the lower lumbar spine Wiltse approach in Quadrant Chanel.Compare operation time, blood loss, postoperativehospital stay, clinical efficacy, nailing accuracy, fusion rate, postoperative pain scoring of two groups. Results: The blood loss[(102.1+/-5.5) min vs(103.7+/-7.7) min, t=-0.586, P>0.05], postoperative blood loss, hospital stay[(44.6+/-5.2) ml and(57.2+/-5.3) ml, (7.3+/-1.6) d and(9.3+/-1.9) d; t=-5.813, -2.774, P<0.05], JOA score before and after surgery in same group were statistically significant(P<0.05), respectively.Patients of two groups compared with operation time, clinical efficacy, nailing accuracy[group A: 97.5%, group B: 95.7%; chi(2)=3.00, P>0.05.Postoperative 3 month , group A: 96.7%(29/30), group B: 94.3%(33/35; chi(2)=0.79, P>0.05], fusion rate[group A: 96.7%(29/30), group B: 94.3%(33/35), chi(2)=0.79, P>0.05], preoperative JOA score[(20.4+/-2.4)score and(7.9+/-1.0), (19.1+/-2.7)score and(7.8+/-1.2)score], postoperative JOA score were no statistically significant respectively, P>0.05. JOA score of both groups were statistically significant respectively Before and after operate.Excellent rate: group A; 84.4%(25/30), group B: 80.0%(28/35), chi(2)=0.43, P>0.05. Conclusion: MIS-TLIF technique associated with percutaneous pedicle screws in micro endoscopy discectomy relative to conventional minimally invasive spine surgery had many advantages: minimal damage, operation conveniently, precisely clinical effect, that is a kind of feasible and reliable minimally invasive surgery which is worth promoting. PMID- 28355746 TI - [A journey of a thousand miles begins with a single step: the impact of case report on medical literature]. PMID- 28355745 TI - [Cinnamaldehyde attenuates pressure overload-induced cardiac fibrosis via inhibition of endothelial mesenchymal transition]. AB - Objective: The aim of this study is to investigate the underlying mechanism of cinnamaldehyde attenuating pressure overload-induced cardiac fibrosis. Methods: The mice were randomly divided into control group, model group and treatment group by random number table and each group had 8 mice.Cardiac hypertrophy was induced by aortic banding. Heart vascular density was detected by immunohistochemical staining of CD31.The expression level of stromal cells marker alpha-smooth muscle actin (alpha-SMA) was detected by immunofluorescence staining in different groups.The expression levels of endothelial cell associated markers and stromal cell associated markers were detected by using Western blotting.The possible molecular pathway was also screened by using Western blotting. Human umbilical vein endothelial cell (HUVECs) were stimulated with TGFbeta1 and cultured with 10 nmol/L cinnamomum for 24 hour to further confirm the mechanism. Results: Eight weeks after operation, the vascular density was significantly decreased in model group mice heart.The expressions of stromal cells markers were increased (alpha-SMA: 2.57+/-0.38; Vimentin: 0.58+/-0.02) and endothelial cell markers were reduced (CD31: 0.58+/-0.29; CD34: 0.62+/-0.21). While cinnamicaldehyde treatment significantly increased the mouse heart vascular density, increased endothelial cell markers expression (CD31: 1.51+/-0.11; CD34: 2.37+/-0.44; P<0.05), and reduced stromal cells marker expression (alpha-SMA: 1.22+/-0.14; Vimentin: 0.35+/-0.03; P<0.05). Further studies showed that the anti fibrosis effect of cinnamicaldehyde was mainly through the TGFbeta /smad signaling pathway.10 nmol/L cinnamomum attenuated TGFbeta1 induced endothelial mesenchymal transition in HUVECs. Conclusion: Cinnamaldehyde may be able to retard the progression of cardiac fibrosis, via blocking endothelial to mesenchymal transition, which, in verse, is through regulating TGFbeta /smad signaling pathway. PMID- 28355747 TI - [Discussions of case studies in patients with sleep disorders]. PMID- 28355748 TI - [The comment on clinical research for coordinative research]. PMID- 28355749 TI - [Application of information intelligence technology in hospital operation decision analysis]. PMID- 28355750 TI - [Association between subjective and objective sleepiness in obstructive sleep apnea hypopnea syndrome patients]. AB - Objective: To examine the association between subjective sleepiness and objective sleepiness in Chinese obstructive sleep apnea hypopnea syndrome (OSAHS) patients. Methods: A total of 1 660 patients meeting the diagnostic criteria of OSAHS based on overnight polysomnography from West China Hospital, Sichuan University in the period from Jul 2010 to Jul 2014 were enrolled in the study. The Epworth Sleepiness Scale (ESS) and Multiple Sleep Latency Test (MSLT) were to evaluate subjective and objective sleepiness, respectively. The subjects were categorized into quartiles [A (0-4) (n=406), B (5-7) (n=325), C (8-12) (n=443), D(13-24) (n=486) groups] based on the ESS score distribution. Survival analysis was used to characterize the association between the ESS score and the mean sleep latency (MSL). Results: The apnea hypopnea index (AHI) in D group was higher than other three groups [(58.7+/-26.1) vs (36.8+/-24.2), (42.6+/-26.7), (45.7+/-26.6) events/h, all P<0.05]. The mean sleep latency in D group was shorter than other three groups [(8.0+/-4.6) vs (10.9+/-4.4), (10.3+/-4.8), (9.4+/-4.5) min, all P<0.05]. The Kaplan-Meier survivor functions across the ESS score quartiles were distinct and fourth quartiles were progressively associated with a greater tendency for falling asleep (chi(2)=77.76, P<0.001 by Log-rank test) in the daytime (The percentages of awaking patients in fourth quartiles were progressively lower at the same time). The adjusted hazard ratios for sleep onset during the MSLT for the group B, C and D were 1.05 (95%CI: 0.90-1.22), 1.22 (95%CI: 1.07-1.40), and 1.38 (95%CI: 1.20-1.60), respectively, comparing to group A. Conclusion: Subjective report of daytime sleepiness is consistent with the objective sleepiness in OSAHS patients. PMID- 28355751 TI - [Accuracy of Berlin questionnaire with different body mass index cutoff values in the screening of patients with obstructive sleep apnea]. AB - Objective: To evaluate the accuracy of Berlin questionnaire in the screening of patients with obstructive sleep apnea (OSA), after using different body mass index (BMI) cutoff values. Methods: The data were collected from September, 2011 to May, 2012 at the Sleep Medicine Center of West China Hospital, Sichuan University (Chengdu, China). A total of 350 consecutive patients (302 males and 48 females, 19-68 years old, average (42.9+/-11.0) years old) with suspected OSA who underwent an overnight polysomnography (PSG) were recruited into this study. Berlin questionnaire was completed. Based on the severity of OSA which were determined by apnea-hypopnea index (AHI), the patients were classified into four groups of primary snoring (<5 events/h), mild (5-<15 events/h), moderate (15-<30 events/h) and severe OSA (>=30 events/h). Sensitivity, specificity, positive predictive values, negative predictive values and the area under the receiver operating characteristics curve of Berlin questionnaire with different BMI cutoff values were calculated. Results: In patients with BMI>=30 kg/m(2,) to diagnose mild-moderate-severe (AHI>=5 events/h), moderate-severe (AHI>=15 events/h), and severe (AHI>=30 events/h) OSA, the sensitivity of Berlin questionnaire were 69.2%, 71.6%, and 76.6%; the negative predictive values were 15.7%, 33.0%, and 56.5%, respectively. In patients with BMI>=24 kg/m(2,) questionnaire had the highest sensitivity (94.3%, 94.8%, and 96.7%, respectively) and negative predictive values (28.0%, 44.0%, and 72.0%, respectively). Conclusions: When BMI cutoff values gradually declines, the sensitivity and negative predictive values of Berlin questionnaire increase, but the specificity and positive predictive values decline. The accuracy of Berlin questionnaire possibly is related to BMI cutoff values. PMID- 28355752 TI - [Incidence and influencing factors of continuous positive airway pressure treatment-emergent central sleep apnea in the patients with obstructive sleep apnea syndrome at high altitude]. AB - Objective: To investigate the incidence of treatment-emergent central sleep apnea (TE-CSA), the characteristics of demography and the influencing factors in patients with obstructive sleep apnea syndrome (OSAS) after initial continuous positive airway pressure (CPAP) titration at high altitude. Methods: Clinical data of 297 patients with OSAS which living in plateau areas (1 000 meters or more above sea level) were retrospectively analyzed in this study from January to December, 2015. All of these patients taken an overnight CPAP titration in the Sleep Medicine Center of First People's Hospital of Yunnan Province. They were classified as with TE-CSA group and non TE-CSA group according to the outcome of CPAP titration. Comparisons of demographic characteristic, parameters of polysomnography in CPAP titration night, lung function test and blood gas analysis were made between the two groups, respectively, and statistical analysis was carried. Results: The incidence of TE-CSA was 16.5% (49/297) after initial CPAP titration at high altitude, which was higher in male patients (18.2% vs 6.8%, P=0.061). The incidence of TE-CSA decreased with the increase of age and body mass index (BMI), and the decrease of resident altitude. Multivariate Logistic regression analysis showed that the resident altitude, mixed apnea index (MAI), forced expiratory volume in 1 second (FEV(1)) and forced vital capacity (FVC) ratio, functional residual capacity (RV) and total lung capacity (TLC) ratio were the main factors affecting the occurrence of TE-CSA. Among them, the increase of resident altitude and MAI were risk factors [OR=1.16(1.02, 1.32), 1.05(1.01, 1.09)]. The increase of FEV(1)/FVC and RV/TLC were protective factors [OR=0.94(0.89, 0.98), 0.94(0.88, 0.99)]. Conclusion: The incidence of TE-CSA is high at high altitude area, and the increase of resident altitude and MAI are the risk factors for TE-CSA. PMID- 28355753 TI - [Effect of obstructive sleep apnea on sleep architecture of acute ischemic stroke patients]. AB - Objective: To investigate the effect of obstructive sleep apnea (OSA) on sleep architecture in acute ischemic stroke (AIS) patients. Methods: Seventy AIS patients with polysomnography examination from June 2014 to April 2016 were included in the Second Affiliated Hospital of Soochow University. Twenty-seven healthy controls during the same period were chosen as control group. According to apnea-hypopnea index (AHI), AIS patients were divided into AIS group (AHI<5/h) and AIS+ OSA group (AHI>=5/h). Their general conditions, Neurological function defect (national institutes of health stroke scale, NIHSS) on admission and at discharge and self-care ability (modified Rankin Scale, mRS) at discharge and 3 months later (mRS score <2 reflected good prognosis, and mRS score>=2 reflected unfavorable prognosis) were collected. Results: Fifty-two patients (74.3%) had OSA in total seventy AIS patients. Total sleep time (TST) was significantly shorter and sleep efficiency (SE) was lower in AIS group than the control group (P=0.007, 0.008, respectively). AIS+ OSA group had longer non-rapid eye movement (NREM)1 than control group [24.9(21.3) vs 14.3(10.6), P=0.044]. Compared with AIS group, AIS+ OSA group had shorter NREM3 [13.0(13.2) vs 19.6(12.8), P=0.039]. There was no significant difference between the infarct location of AIS group and AIS+ OSA group. However, AIS+ OSA group had higher mRS score observed at 3 months through follow-up visit than AIS group (P=0.027). Spearman correlation analysis showed a positive correlation between unfavorable prognosis of stroke at 3 months and atrial fibrillation, the oxygen desaturation index (ODI), percentage of oxygen saturation <90% of total recording time (TS90%), AHI, the longest time of apnea and hypopnea, respiratory related microarousal and NIHSS, while a negative correlation between unfavorable prognosis of stroke and NREM3, lowest nocturnal oxygen saturation (L-SaO(2)). On Logistic analysis, the unfavorable prognosis was independently predicted by AHI and NIHSS. Conclusions: Sleep architecture of cerebral infarction patients are disturbed with its characteristic of shorter total sleep time and lower sleep efficiency. Cerebral infarction patients with OSA have longer NREM1 and shorter NREM3. PMID- 28355754 TI - [Colorectal resection combined with simultaneous radiofrequency ablation in the treatment of synchronous colorectal liver metastases: a retrospective analysis]. AB - Objective: To compare the efficacy and safety of colorectal resection combined with simultaneous radiofrequency ablation (RFA) in the treatment of synchronous colorectal liver metastases(SCRLM). Methods: This retrospective study involved the patients admitted between January 1st 2010 and September 1st 2013. A total of 20 patients who underwent colorectal resection combined with simultaneous RFA of SCRLM were enrolled. Those patients (RFA group) were matched with 20 patients (Resection group) who underwent simultaneous resections of colorectal cancer and SCRLM based on the propensity scores. Perioperative parameters and survival outcomes were compared between the two groups. Results: The RFA and Resection groups were comparable in demographics, cancer characteristics and chemotherapy treatment (all P>0.05). The estimated blood loss and intraoperative blood transfusions in the RFA group were significantly lower than those in the resection group [150.00(100.00-200.00) vs 200.00(112.50-650.00), 1 vs 7, all P>0.05]. The postoperative stay in the RFA group was significantly shorter than that in laparoscopic group [8.50(8.00-10.75) vs 11.00(8.25-14.25), P=0.043]. There was no significant difference in postoperative complications (P>0.05). The 3-year disease free survival rate was 14.00% in the RFA group, and 31.20% in the Resection group (P=0.047). However, the 3-year overall rates were similar between the two groups (P>0.05). Conclusions: Compared with simultaneous resections of colorectal cancer and SCRLM resections, colorectal resection combined with simultaneous RFA of SCRLM was associated with less surgical blood loss and shorter hospitalization. Although inferior to simultaneous resections of colorectal cancer and SCRLM resections in survival outcomes, this approach extends the capability of delivering potentially curative treatment for colorectal cancer patients with unresectable SCRLM. PMID- 28355755 TI - [Predictors of in-hospital mortality in adult postcardiotomy cardiacgenic shock patients successfully weaned from venoarterial extracorporeal membrane oxygenation]. AB - Objective: To assess the factors associated with outcome of patients undergoing extracorporeal membrane oxygenation (ECMO) in a large ECMO center. Methods: Patients aged >18 years who received ECMO support for postcardiotomy cardiogenic shock were identified between January 2011 and December 2015. One hundred and seventy-seven patients (64.8%) successfully weaned from ECMO. These patients were divided into two groups depending on whether they could survive to hospital discharge: the survival group (group S, n=119) and death group (group D, n=58). Multivariate logistic regression was performed to identify risk factors independently associated with in-hospital mortality. Results: Compared to those from group D, patients in group S exhibited a younger age[(53.4+/-11.7) vs (58.9+/-11.5) years], a lower inotrope score at the beginning of ECMO [25(15, 60) vs 35.0(23, 60)], a lower average platelets transfusion [4.0(2.0, 5.2) vs 5.0(3.0, 7.2)U] (all P<0.05). There were shorter duration of ECMO support [95.0(73.0, 131.0) vs 120.0(95.8, 160.2) h], shorter ventilation time [137.0(70.0, 236.8) vs 215.0(164.0, 305.0) h], shorter stay in ICU [182.0(140.0, 236.0) vs 259.0(207.0, 382.0) h] and longer hospital stay after weaned from ECMO [14(11, 24) vs 8(4, 16) d] in group S patients compared to those in group D (all P<0.05). Age>65 years (P=0.046), neurologic complications (P<0.001) and lower extremity ischemia (P<0.001) during ECMO support, left ventricular ejection fraction<35% (P=0.011) and central venous pressure (CVP)>12 cmH(2)O(P=0.018) when weaned from ECMO, and the multi-organ function failure (P<0.001) after weaned from ECMO were independently associated with in-hospital mortality. Conclusions: Neurologic complications and lower extremity ischemia that occurred during ECMO, multi-organ function failure after weaned from ECMO had a significant impact on in-hospital mortality. Further studies are needed to prevent neurologic complications and lower extremity ischemia in these patients. Interventions that could reduce these complications may improve outcome. PMID- 28355756 TI - [Effect of intravenous infusion with lidocaine on rapid recovery of laparoscopic cholecystectomy]. AB - Objective: To investigate the effect of intravenous infusion with lidocaine on rapid recovery of laparoscopic cholecystectomy. Methods: This study was a prospective randomized controlled trial. From February to August 2016 in Affiliated Yiwu Hospital of Wenzhou Medical University, 60 patients scheduled for laparoscopic cholecystectomy under general anesthesia were involved and randomly divided into control group (n=30) and lidocaine group (n=30). Patients in lidocaine group received lidocaine 1.5 mg/kg intravenously before induction and followed by 2.0 mg.kg(-1).h(-1) to the end of surgery. Patients in control group received equal volumes of saline intravenously. Anesthesia induction in both groups were given intravenous midazolam 0.03 mg/kg, sufentanil 0.2 MUg/kg, propofol 2.0 mg/kg and cisatracuium 0.2 mg/kg. Anesthesia was maintained with propofol 0.05-0.20 mg.kg(-1).min(-1) and remifentanil 0.1-0.5 MUg.kg(-1).min(-1) for laryngeal mask airway which bispectral index (BIS) value maintained at 40-60. BIS, heart rate(HR) and mean arterial pressure(MAP) were recorded before anesthesia induction, before and immediately after laryngeal mask implantation, intraoperative 30 min and anesthesia awake. Pain scores were assessed using visual analogue scales (VAS) at postoperation immediately, 30 min during postanesthesia care unit (PACU), 2, 6, 12, and 24 h after surgery. The time of PACU retention, postoperative ambulation, first intestine venting and discharge were recorded. The dosage of propofol and remifentanil, the frequency of sufentanil used, the incidence of postoperative nausea and vomiting were also recorded. Patient satisfaction was evaluated by using Simple Restoration Quality Score (QoR-9). Results: BIS values before and after laryngeal mask implantation in lidocaine group were 50.50+/-3.47 and 54.63+/-1.25 respectively, which was lower than those in control group(54.30+/-4.78, 55.80+/-2.33; t=3.542, 2.423, all P<0.05). The VAS score at postoperation immediately, PACU 30 min, postoperative 2, 6, 12 h in lidocaine group were 2.76+/-0.97, 2.37+/-0.93, 2.10+/-1.12, 1.76+/ 0.97, 1.20+/-0.76 respectively, which was lower than those in control group (3.83+/-1.34, 3.27+/-1.26, 3.06+/-1.20, 2.63+/-0.88, 1.90+/-0.84; t=3.528, 3.154, 3.217, 3.603, 3.372, all P<0.05 ). The frequency of additional sufentanil at postoperation immediately and PACU 30 min in lidocaine group was 5(17%), 3(10%), which were less than those in control group(12(40%), 9(30%); chi(2)=4.022, 3.950, all P<0.05). The dosage of propofol and remifentanil in lidocaine group were (4.33+/-0.75) mg.kg(-1).h(-1) and (9.00+/-1.66) MUg.kg(-1).h(-1) respectively, which were less than those in control group ((5.20+/-1.39) mg.kg(-1).h(-1) and (10.43+/-2.20) MUg.kg(-1).h(-1;) t= 2.982, 2.842, all P<0.05). The time of PACU retention, postoperative ambulation and first intestine venting were (39.90 +/- 8.06) min, (11.93+/-1.68) h and (10.16+/-1.05) h respectively in lidocaine group, which were shorter than those in control group ((48.23+/-10.04) min, (13.16+/ 1.58) h and (11.13+/-1.30) h; t=3.514, 2.931, 3.156, all P<0.05). The QoR-9 score in lidocaine group was 15.60+/-1.07, which was higher than that in control group(14.73+/-0.74, t=-3.649, P<0.05). There was no significant difference in the incidence of postoperative nausea/vomiting and the discharge time between two groups (all P>0.05). Conclusion: Intravenous infusion of lidocaine can effectively reduce the dosages of propofol and remifentanil, postoperative early VAS score, postoperative ambulation time and first intestine venting time which could improve the satisfaction of patients. PMID- 28355757 TI - [Concurrent renal cell carcinoma and urothelial carcinoma: long-term follow-up study of 24 cases]. AB - Objective: To investigate the clinical manifestation, diagnosis, treatment and outcome of simultaneous occurrence of renal cell carcinoma and urothelial carcinoma. Methods: Twenty-four consecutive patients with synchronous renal cell carcinoma and urothelial carcinoma treated in our center from March 2005 to December 2015 were retrospectively reviewed. Their clinical, pathological and prognostic features were evaluated. Kaplan-Meier curves were used to estimate overall survival. Results: Patient' age was range from 48 to 79 yrs (median 69.5). Fourteen patients presented with macroscopic hematuria, and 10 patients were asymptomatic. B-ultrasound, computed tomography (CT) and cystoscopy initially indicated renal cell carcinoma concurrent with ipsilateral upper urinary tract urothelial carcinoma (UTUC) in 4 cases, renal cell carcinoma concurrent with bladder tumor in 16 cases, renal cell carcinoma concurrent with both ipsilateral UTUC and bladder tumor in 1 case, renal cell carcinoma in 2 cases and ureter carcinoma in 1 case. Different treatments were performed. The median follow-up time after surgery was 22.5 months. For patients with synchronous renal cell carcinoma and bladder tumor, there was no significant survival difference between patients treated with partial nephrectomy or radical nephrectomy. During follow up, 3 patients died of renal cell carcinoma, 3 patients died of non-oncological disease and 1 patient died of ureter carcinoma. The 3-year overall survival rate was 82.7%. For patients with synchronous renal cell carcinoma and bladder tumor, there was no significant survival difference between patients treated with partial nephrectomy or radical nephrectomy (P=0.874). Conclusions: Concurrence of renal cell carcinoma and urothelial carcinoma is clinically rare. Treatments should be individualized. The prognosis for a patient with synchronous renal cell carcinoma and urothelial carcinoma is associated with the more aggressive one. PMID- 28355758 TI - [Progress and challenge of Stanford type A aortic dissection in China]. AB - In recent 20 years, the rapid development of acute Stanford type A aortic dissection in China has been mainly due to three aspects: (1) the refined classification of aortic dissection based on Stanford classification, (2) right axillary artery canal and selective cerebral perfusion technology become basic cardiopulmonary bypass strategy for Stanford type A aortic dissection, and (3) total aortic arch replacement and descending aortic stent graft surgery (Sun's surgery) become the standard treatment of Stanford type A aortic dissection. However, there are still many problems in the diagnosis and treatment of aortic dissection in China, such as: (1) unstandardized, lack of comprehensive guidelines of aortic dissection, (2) immature, perioperative organ protection and intraoperative blood protection technology remains a big flaw, and (3) it takes a long time to get patient prepared for surgery. In conclusion, as to the issue of the management of acute Stanford type A aortic dissection, there will be a long way for Chinese doctors to go. Peers should pay more attention to this problem and take more efforts, so that the outcome of acute Stanford type A aortic dissection surgical patients can be improved. PMID- 28355759 TI - [Clinical practice and thoughts on the strategy of root reconstruction for Stanford type A aortic dissection]. AB - The strategy of root reconstruction for Stanford type A aortic dissection (AAD) includes resection of the intimal tear site, correction of concomitant aortic valve dysfunction and amendment of coronary lesion. Supracommissural tube graft replacement is a well-adopted and convenient procedure for most patients, although its application is limited when distinct sinus expansion and severe intimal damage is present. Composite valve conduit replacement (Bentall procedure) is suitable for patients with overt sinus damage. However, a fraction of patients with functional aortic valve will be unnecessarily put into risks for prosthetic complications. Valve-sparing aortic root replacement (VSRR), which includes aortic root remodeling (Yacoub procedure) and reimplantation (David procedure) techniques, has the advantage of retaining autologous aortic valve while guaranteeing resection of damaged vessel segments.The Yacoub procedure is relatively convenient but harbors long-term risk for annulus expansion, while the David procedure demonstrates long-term benefit but may be too demanding to be operated in emergent scenario as AAD. The last decade has witnessed worldwide endeavors to investigate the treatment strategy for aortic root, especially the VSRR approach. The preliminary results are encouraging and demonstrating improvements for both mid- and long-term outcomes of AAD, which enables standardized and personalized surgical management for these patients. PMID- 28355760 TI - [Treatment strategies of complex lesions in patients with acute Stanford type A dissection of important branches involvement]. AB - Acute Stanford type A aortic dissection with important branches involved is more complex, could lead to organ malperfusion syndrome even organ failure. The understanding of pathological anatomy, classification, staging, and the pathophysiological change has increasingly mature, but not complete. In addition, the treatment strategy for complex lesions is diversified, some questions may not reach consensus. Fully understanding of the anatomical and pathophysiology is very important for surgeons to choose reasonable treatment strategy. As the rapid development of the basic research, imaging techniques and the concept of surgery procedures, the manage technique of Stanfrod type A dissection and branch vessels at the same time is getting seriously, the related issues also need further discussions. PMID- 28355761 TI - [Factor analysis and method exploring for lymph nodes harvest in gastric cancer]. AB - The number of lymph node dissection and positive lymph nodes are the necessary guarantees for patients to achieve accurate staging after gastric cancer surgery. On the basis of the minimum number of lymph nodes dissection recommended by the NCCN guidelines, as many as possible lymph node yields will be most likely to benefit patients. Many factors can influence the number of lymph node yields including surgery, patient, tumor pathology and postoperative sorting factors. Compared with traditional manual nodal dissection method, fat-clearing technique and methylene blue staining method can improve the number of lymph nodes detection, while lymphatic tracers, such as carbon nanoparticles, are conducive to show lymphatic vessels, contributing to the dissection of small lymph nodes. The initial results from People's Liberation Army General Hospital show that lymph node packet submission after isolation by surgeon yields more lymph nodes. For the establishment of standards, lymph node retrieval-related procedures need further in-depth exploration and investigation. PMID- 28355762 TI - [Clinical analysis of different root treatment methods in acute Stanford type A aortic dissection]. AB - Objective: To discuss the perioperative and follow-up results of different surgical methods for acute Stanford type A aortic dissection patients and analyzed the results. Methods: The clinic data of 351 acute Stanford type A aortic dissection patients received surgical therapy at Department of Thoracic and Cardiovascular Surgery, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital from January 2008 to December 2015 were analyzed retrospectively. There were 272 male and 79 female patients, aging from 22 to 83 years with a mean age of (52+/-13) years. According to root size, aortic valve structure and the status of dissection involvement, these patients were devided into three major groups: 218 cases with root reconstruction using Dacron felts, 34 cases with root reconstruction concomitant with aortic valve resuspension repair and 99 cases in with Bentall procedure. Proper shape based on the status of dissection involvement of Dacron patch was cut and put between the middle and outerlayer of aorta, then inside the inner layerone band Dacron felt was sutured with the aorta and the new middle layer with Dacron patch as mentioned above. In some cases the prolapsed aortic valve was re-suspended to the aortic cusp. Clinical outcomes among the 3 procedures were compared by chi(2) test, Fisher's exact test, t test and analysis of variance. Results: Cardiopulmonary bypass, cross-clamp, and circulatory arrest times of all the patients were (250+/-78), (171+/-70) and (31+/-10) minutes, respectively. The 30-day mortality was 9.2%(33/351), while no difference among the 3 procedures (9.6%, 8.8% and 9.1%). In the average follow-up time of (26.0+/-23.0) months (range from 0.5 to 90.0 months), survival rates were similar among the 3 procedures (77.7%, 77.4% and 77.8%). Only one patient received redo Bentall procedure because of severe aortic regurgitation and dilated aortic root (diameter of 50 mm). Conclusions: The indication of root management of acute Stanford type A aortic dissection is based on the diameter of aortic root, structure of aortic leaflets, and the dissection involvement. For most acute Stanford type A aortic dissection patients, aortic root reconstruction is a feasible and safe method. PMID- 28355763 TI - [Late reoperations after repaired Stanford type A aortic dissection]. AB - Objective: To summarize the experience of reoperations on patients who had late complications related to previous aortic surgery for Stanford type A dissection. Methods: From August 2008 to October 2016, 14 patients (10 male and 4 female patients) who underwent previous cardiac surgery for Stanford type A aortic dissection accepted reoperations on the late complications at Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University. The range of age was from 41 to 76 years, the mean age was (57+/-12) years. In these patients, first time operations were ascending aorta replacement procedure in 3 patients, ascending aorta combined with partial aortic arch replacement in 4 patients, aortic root replacement (Bentall) associated with Marfan syndrome in 3 patients, aortic valve combined with ascending aorta replacement (Wheat) in 1 patient, ascending aorta combined with Sun's procedure in 1 patient, Wheat combined with Sun's procedure in 1 patient, Bentall combined with Sun's procedure in 1 patient. The interval between two operations averaged 0.3 to 10.0 years with a mean of (4.8+/-3.1) years. The reasons for reoperations included part anastomotic split, aortic valve insufficiency, false aneurysm formation, enlargement of remant aortal and false cavity. The selection of reoperation included anastomotic repair, aortic valve replacement, total arch replacement and Sun's procedure. Results: Of the 14 patients, the cardiopulmonary bypass times were 107 to 409 minutes with a mean of (204+/-51) minutes, cross clamp times were 60 to 212 minutes with a mean of (108+/-35) minutes, selective cerebral perfusion times were 16 to 38 minutes with a mean of (21+/-11) minutes. All patients survived from the operation, one patient died from severe pulmonary infection 50 days after operation. Three patients had postoperative complications, including acute renal failure of 2 patients and pulmonary infection of 1 patient, and these patients were recovered after treatment. Thirteen patients were finally recovered from hospital. The patients were followed up for 16 to 45 months, and no aortic rupture, paraplegia and death were observed in the follow-up. Conclusions: Patients for residual aortic dissection after initial operations on Stanford type A aortic dissection should be attached great importance and always need emergency surgery, but the technique is demanding and risk is great for surgeons and patients, which need enough specification and accurate on aortic operation. More importantly, the Sun's procedure also should be performed on the treatment of residual aortic dissection or distal arch expansion, and obtains the short- and long-term results in the future. PMID- 28355764 TI - [Prognostic factors for in-hospital mortality in patients with acute kidney injury requiring continuous renal replacement therapy undergoing surgery for acute Stanford type A aortic dissection]. AB - Objective: To evaluate prognostic factors for in-hospital mortality in patients with acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) undergoing surgery for acute Stanford type A aortic dissection. Methods: Retrospective analysis were conducted for 60 patients diagnosed with AKI requiring CRRT undergoing surgery for acute Stanford type A aortic dissection at Beijing Anzhen Hospital, Capital Medical University from March 2015 to September 2016. There were 43 male and 17 female patients with an mean age of (50+/-14) years. Demographic characteristics, diagnosis, perioperative periodrelated data, clinical parameters during CRRT were collected to set up a database. The patients were divided into survival group and non-survival group according to in-hospital mortality. The prognostic factors of mortality in-hospital after AKI requiring CRRT were analyzed by multivariate Logistic regression analysis regression. Results: In the 60 adult patients who had received CRRT, 21 patients (35.0%) died. There were significant differences between died and survival patients on proportion of age>60 years (chi(2)=6.851, P=0.003), lactic acid levels at 12-hour after CRRT (t=-3.631, P=0.004), lactic acid levels at 24 hours after CRRT (t= 2.986, P=0.032), proportion of body mass index >25 kg/m(2) (chi(2)=5.660, P=0.041), cardiopulmonary bypass time (t=-2.720, P=0.001). Multivariate Logistic regression analysis revealed that age>=60 years (OR=16.450, 95% CI: 2.172 to 84.589); high lactic acid levels at 12-hour after CRRT (OR=1.719, 95% CI: 1.998 to 2.960) and long cardiopulmonary bypass time (OR=1.028, 95% CI: 1.004 to 1.052) (all P<0.05) were independent prognostic factors of in-hospital mortality. Conclusions: Age >=60 years, high lactic acid levels at 12-hour after CRRT and long cardiopulmonary bypass time were independent prognostic factors of patients with AKI requiring CRRT after aortic surgery. Proper identification and management shall improve the prognosis of patients. PMID- 28355765 TI - [Liposuction combined with lymphatico-venous anastomosis for treatment of secondary lymphedema of the lower limbs: a report of 49 cases]. AB - Objective: To study the clinical effects of liposuction combined with lymphatico venous anastomosis for treatment of secondary lymphedema of the lower limbs. Methods: A retrospective analysis was performed for 49 patients who had undergone liposuction combined with lymphatico-venous anastomosis to treat secondary lymphedema of the lower limbs at Department of Lymph Surgery, Beijing Shijitan Hospital from November 2013 to February 2015.All patients were female aging from 31 to 70 years with median age of (52+/-10)years.All patients had history of pelvic surgery.There were 32 cases with cervical carcinoma, 11 cases with endometrial cancer, 1 case with ovarian cancer who accepted radical hysterectomy, 2 cases with benign tumor who accepted resection, 2 cases accepted inguinal lymph node dissection, 1 case with rectal cancer accepted radical resection.There were 30 cases with history of radiation therapy and 23 cases with history of erysipelas recurrent((2.1+/-3.9)/year). The limb swelling degree in preoperative and postoperative patients was explored using one-way analysis of variance with replicate measures and paired sample t-test. Meanwhile the incidence of lymphogenous infection was used as an evaluation of operation efficacy. Results: The mean lower limb circumference difference at 7 days, 6 months and 12 months was (0.17+/-1.36)cm, (1.25+/-1.62)cm and(1.58+/-1.56)cm, respectively, which was significantly decreased compared with preoperative((4.92+/-2.16)cm) (t=-5.712, 5.777, -5.765; all P<0.01). The mean lower limb volume difference at 7 days, 6 months and 12 months was (522+/-799)ml, (726+/-973)ml and (889+/-895)ml, respectively, which was significantly decreased compared with preoperative((2 729+/-1 335) ml)(t=-5.905, -6.093, -5.777; all P<0.01). The incidence of erysipelas was 0.0(0.0, 0.0)/6 months within 6 months after operation and 0.0(0.0, 0.0)/6 months within 6-12 months after operation, which was significantly lower than that before operation(0.0(0.0, 2.0)/year). The feeling of tightness and heaviness of the limb was significantly improved compared with preoperative. Conclusion: Liposuction combined with lymphatico-venous anastomosis is an effective method for the treatment of secondary lymphedema of the lower limbs. PMID- 28355766 TI - [Clinical outcomes of single-level lumbar spondylolisthesis by minimally invasive transforaminal lumbar interbody fusion with bilateral tubular channels]. AB - Objective: To evaluate the clinical effectiveness of minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) for single-level lumbar spondylolisthesis treatment with bilateral Spotlight tubular channels. Methods: A total of 21 patients with lumbar spondylolisthesis whom underwent MIS-TLIF via bilateral Spotlight tubular channels were retrospectively analyzed from October 2014 to November 2015. The 21 patients included 11 males and 10 females ranged from 35 to 82 years (average aged 60.7 years). In term of spondylolisthesis category, there were 18 cases of degenerative spondylolisthesis and 3 cases of isthmic spondylolisthesis. With respect to spondylolisthesis degree, 17 cases were grade I degrees and 4 cases were grade II degrees . Besides, 17 cases at L(4-5) and 4 cases at L(5)-S(1)were categorized by spondylolisthesis levels. Operation duration, blood loss, postoperative drainage and intraoperative exposure time were recorded, functional improvement was defined as an improvement in the Oswestry Disability Index (ODI), Visual Analog Scale (VAS) was also employed at pre and post-operation (3 months and the last follow-up), to evaluate low back and leg pain. Furthermore, to evaluate the recovery of the intervertebral foramen and of lumbar sagittal curvature, average height of intervertebral space, Cobb angles of lumbar vertebrae and operative segments, spondylolisthesis index were measured. At the last follow-up, intervertebral fusion was assessed using Siepe evaluation criteria and the clinical outcome was assessed using the MacNab scale. Radiographic and functional outcomes were compared pre- and post-operation using the paired T test to determine the effectiveness of MIS-TLIF. Statistical significance was defined as P<0.05. Results: All patients underwent a successful MIS-TLIF surgery. The operation time (235.2+/-30.2) mins, intraoperative blood loss (238.1+/-130.3) ml, postoperative drainage (95.7+/-57.1) ml and intraoperative radiation exposure (47.1+/-8.8) were recorded. Different significance between 3 months post-operative follow-up and pre-operation was exhibited (P<0.01) in respects of lumbar VAS (t=11.1, P<0.01) and leg VAS (t=17.8, P<0.01). Moreover, final follow-up compared with pre operation, and final follow-up compared with 3 months post-operative follow-up, VAS scores were also statistical difference (P<0.01). At the final follow-up, there were significant differences compared with pre-operation in ODI scores (t=30.1, P<0.01). Comparison between 3 months post-operative follow-up and pre operation, statistical distinctions were demonstrated (P<0.05) in terms of mean height of intervertebral space (t=-10.9, P<0.01), the Cobb angles of lumbar vertebrae (t=-2.4, P<0.05), operative segments Cobb angles (t=-5.2, P<0.01) and Lumbar spondylolisthesis incidence (t=17.1, P<0.01). In addition, there was statistical difference between final follow-up and pre-operation (P<0.05) as well. For instance, mean height of intervertebral space (t=-10.5, P<0.01), the Cobb angles of lumbar vertebrae (t=-2.7, P<0.05), operative segments Cobb angles (t=-4.2, P<0.01) and Lumbar spondylolisthesis incidence (t=18.6, P<0.01) were involved. All spondylolisthesis vertebrae were restored completely. Lastly, at the last follow-up, 12 cases of grade 1 and 7 cases of grade 2 fusion were present as determined by the Siepe evaluation criteria. McNab scale assessment classified 17 patients having excellent clinical outcome, 3 patients in good and 1 patient having a better clinical outcome. Conclusion: MIS-TLIF with bilateral Spotlight tubular channels is a safe and effective approach for single segment lumbar spondylolisthesis. PMID- 28355767 TI - [Effects of reconstruction with unicondylar osteoarticular allografts with or without prosthesis for bone tumors around knee joint]. AB - Objective: To investigate the survival rate, function outcomes, and complications after using unicondylar osteoarticular allografts with or without prosthesis to reconstruct the knee joint for tumors located in distal femoral or proximal tibial uni-condyle. Methods: Twenty-two patients who underwent unicondylar osteoarticular allografts with or without prosthesis composite reconstructions from January 2007 to December 2015 in Department of Orthopaedic Surgery of Xi Jing Hospital, the Fourth Military Medical University were retrospectively reviewed. There were 14 males and 8 females and the mean age was 35 years(8-65 years). There were 12 malignent tumors and 10 aggressive benign tumors. The tumors were located in distal femur in 14 cases and proximal tibia in 8 cases. After tumor excision, the distal femur was reconstructed with unicondylar osteoallograft-prosthesis composite, and proximal tibial plate was reconstructed with unicondylar osteoarticular allograft with the help of computer-assisted navigation system. Function and radiograph were documented according to the Musculoskeletal Tumor Society (MSTS) functional scoring system and the International Society of Limb Salvage (ISOLS) radiographic scoring system. The median follow-up time was 60 months (5-116 months). Results: At the latest follow up, 2 patients had amputation owing to local recurrence in 12 malignant tumors. Three patients had pulmonary metastasis and 1 patient died another 2 alive with disease. Kaplan-Meier analysis indicated that the disease-free survival rate was 73%. There was no recurrence and metastasis in 10 patients with giant cell tumor. The average MSTS score was 26 points and the radiographic score was 78% 94%(average 90%). The complications included superficial infection in 1 patient and screw broken in 1 patient. There was no broken or collapse allograft in all composite reconstruction patients but 6 cases in allograft reconstruction. Conclusions: Unicondylar osteoarticular allografts or prosthesis composite was feasible reconstruction for tumors in distal femoral uni-condyle. It could provide good functional outcomes and also prevent joint degeneration. Similarly, allograft reconstruction was also a reliable technique for proximal tibial defect. PMID- 28355768 TI - [Prognostic analysis of patients with myasthenia gravis after extended thymectomy]. AB - Objective: To identify the long-term outcome of patients with myasthenia gravis (MG) after extended thymectomy, and to analyze the prognostic factors. Methods: The medical data and follow-up results in 72 patients with MG who underwent extended thymectomy in Department of Thoracic Surgery, Anhui Provincial Hospital Affiliated with Anhui Medical University from January 2006 to October 2015 were retrospectively reviewed and analyzed. There were 32 male and 40 female patients, aging from 10 to 70 years with a mean age of 39.5 years. The outcome-related factors including gender, age while being operated on, duration of preoperative period, whether taking steroid before operation, modified Osserman classification, pathology type of thymus were analyzed by chi(2) test and multivariate regression analysis. Results: All patients were followed up from 6 to 75 months (median 37 months). Among them, 21 patients (29.2%) achieved complete stable remission, 18 patients (25.0%) experienced pharmacological remission, 20 patients (27.8%) improved, 9 patients (12.5%) reminded stable and 4 patients (5.6%) deteriorated. Both univariate and multicariate analysis revealed that duration of preoperative period (OR=22.871, 95% CI: 2.813 to 185.917, P=0.003) and Osserman classification (OR=0.103, 95% CI: 0.014 to 0.774, P=0.027) showed significantly associated with the surgical curative effect. Conclusions: Extended thymectomy is an efective measure for MG. The duration of preoperative period and Osserman classification are prognostic factors for thymectomized MG. Those patients with generalized MG or whose duration of preperative period is less than 6 months are likely to have better prognosis. PMID- 28355769 TI - [Changes in nutritional status of patients with different diseases during hospitalization]. AB - Objective: To evaluate changes in nutritional status of hospitalized patients with different diseases by subjective global assessment (SGA) and nutritional risk screening (NRS-2002). Methods: A prospective and parallel research done by multi-center collaboration from 34 hospitals in China from June to September 2014. Hospitalized patients with the following diseases were investigated: malignant tumor (2 487 cases), benign disease of the digestive system (1 358 cases), benign disease of the nervous system (1 043 cases), benign bone disease (451 cases), benign disease of the respiratory system(395 cases), cardiovascular disease (227 cases), benign thyroid and breast disease (179 cases), and endocrine disease (149 cases). Patients above the age of 18 and hospitalization time between 7-30 days were included. Physical indexes were measured, the NRS-2002 and SGA scores were recorded, the nutritional support were recorded during hospitalization and 24 hours after discharge from hospital. Measurement data between groups were analyzed using t test or Wilcoxon rank sum test, enumeration data and ranked data between groups were analyzed using chi-square test or Fisher exact test. Results: There were 6 638 cases of hospitalized patients, 3 861 cases were males and 2 777 were females, the male/female ratio was 1.4?1.0; the median age was 60 years; the median height was 1.66 m; the median weight was 62 kg; the median body mass index (BMI)was 22.89 kg/m(2). At discharge, compared with that of admission, the body weight, BMI, grip strength, upper arm and calf circumferences of patients with malignant tumor were significantly decreased (t=20.15-259.67, all P<0.01); the body weight and calf circumference were significantly decreased (t=35.27, 60.40, P<0.01)of patients with digestive benign disease; the body weight of patients with benign bone diseases was decreased (t=2.12, P=0.033); the body weight, grip strength and upper arm circumference were decreased in patients with benign thyroid and breast disease (t=2.79-10.18, all P<0.01); nutritional risk incidence rate (from NRS-2002) of patients with malignant tumor was significantly higher(chi(2)=21.275, P=0.000); moderate malnutrition (from SGA) incidence rate was significantly higher(chi(2)=62.318, P=0.000; chi(2)=11.312, P<0.01) in patients with malignant tumor and with orthopedics diseases. Compared with that of admission, records of the patients with other diseases had no statistically difference at discharge, no more than 50% of the patients under risk of nutritional deficiency(except those with digestive benign diseases )received nutritional support, while the proportion of non-parenteral nutrition application was higher. Conclusion: The patients with malignant tumor have higher incidence rate of malnutrition on admission and at discharge. Doctors should pay more attention to the nutritional status(screening and evaluation) of patients before discharge and use appropriate and adequate nutrition support in order to prevent the weight loss and improve the life quality of patients. PMID- 28355770 TI - [Effects and mechanism of allogeneic platelet rich plasma on collagen synthesis in wound healing]. AB - Objective: To investigate the effects and mechanism of allogeneic platelet rich plasma (PRP) on collagen in wound surface at different time. Methods: A total of 50 clean 7-week rats were selected for this study, including 10 rats for platelet rich blood plasma preparation, 20 rats for PRP group and 20 rats for control group, 0.1 ml allogenic PRP and 0.1 ml saline were smeared respectively on wound surfaces of PRP and control group, wound regeneration and healing were examined. Cellular and histological morphology alteration was observed via Masson staining, type I and type III collagen protein and mRNA expression level were detected by Western blot and real-time PCR. T test was applied for comparison between two samples and one-way ANOVA was utilized for comparison between two groups. Results: The wound healing rate of PRP group was higher than that of control group on 3(rd,) 6(th,) 10(th) and 15(th) day (30.33+/-3.35 vs.18.35+/-2.04, 55.51+/-2.74 vs.36.83+/-2.34, 79.64+/-1.40 vs.56.92+/-1.44, 86.88+/-2.12 vs.65.80+/-1.76) after wound surface formation, there were statistic differences (t=13.66-50.48, all P<0.05). The wound collagen of PRP group form faster and coarser, and the fibers arrayed more densely in Masson staining. The protein expression of type I collagen(1.92+/-0.09 vs.1.18+/-0.11) and type III collagen(1.16+/-0.05 vs.0.74+/-0.11) of PRP group were higher than that of control group (t=22.99, P<0.01; t=17.62, P<0.05); the mRNA expression of type I collagen(5.17+/-0.11 vs.1.79+/-0.18, 6.97+/-0.09 vs.1.96+/-0.08, 6.00+/-0.26 vs.2.10+/-0.05, 4.95+/-0.11 vs.3.58+/-0.09)and type III collagen(2.35+/-0.08 vs.1.44+/-0.05, 3.08+/-0.05 vs.1.84+/-0.06, 3.48+/-0.07 vs.2.36+/-0.09, 4.42+/ 0.07 vs.2.77+/-0.10) were higher than that of control group on 3(rd,) 6(th,) 10(th) and 15(th) day after wound surface formation, there were significant differences (t=43.37-188.37, all P<0.05). Conclusion: The allogeneic platelet rich plasma may promote fibroblasts secreted collagen by activated and releasing all kinds of growth factors, especially type I and type III collagen to accelerate the wound healing. PMID- 28355771 TI - [Progress of problems related to the reconstruction of aortic arch in acute type A aortic dissection]. AB - Aortic arch reconstruction is one of the most challenging operations in aortic surgery. Anatomical abnormalities of the aortic arch, including bovine aortic arch, aberrant right subclavian artery, and single vertebral artery have direct impact on the choice of surgical procedures and methods of brain protection.The risk of aortic arch reconstruction and the difficulty of operation, it is possible to avoid the injury of patients by strictly grasping the indication of operation. Intraoperative arterial cannulation and brain protection strategies are directly related to the success of the operation. This article makes a brief review of the above problems in the reconstruction of the aortic arch, hoping to be helpful to the cardiovascular surgeon. PMID- 28355772 TI - [Progress in application of three-dimensional imaging technique in complex hepatobiliary surgery]. AB - Hepatobiliary surgery is considered to be technically challenging because of complex intrahepatic and perihilar anatomical structures and variations.Nowadays, three-dimensional imaging technique plays an important role in the time of precise liver surgery.Three-dimensional images depict the spatial location of tumor, and the course, confluence pattern and variation of portal vein, hepatic artery, biliary system and hepatic vein distinctly while showing involved hepatic segments and the relationship with adjacent vessels from omnidirectional view, measuring the length of margin and future remnant liver.With the help of surgical simulation, surgeons can determine the significant vessels preoperatively.The application of three-dimensional imaging technique may improve the resectability and safety of complex hepatobiliary surgery, such as hilar cholangiocarcinoma, centrally located liver tumor, hepatolithiasis and living donor liver transplantation.Meanwhile, three-dimensional visualization facilitates the understanding of two-dimensional images and complicated surgical anatomy for surgeons. PMID- 28355773 TI - The cooperative breeding perspective helps in pinning down when uniquely human evolutionary processes are necessary-CORRIGENDUM. PMID- 28355774 TI - Identity matters to individuals: Group assessment cannot be reduced to collective performance. AB - Although we agree that both identification and differentiation play a key role in explaining individual behaviour in groups, we suggest that (1) cohesion and differentiation should be better articulated, (2) the proposal carries implicit value choices that are not necessarily universal, and (3) the success of a group in shaping individual behaviour should refer to the values of individual members. PMID- 28355775 TI - The hows and whys of "we" (and "I") in groups. AB - Informed by our interdisciplinary research program on collaborative recall, we argue that Baumeister et al. should consider: (1) group success as a balance between differentiation and integration (not differentiation alone); (2) variation in constellations of people and processes within and across groups; and (3) nuanced measurement of what people bring to, do in, and get out of groups. PMID- 28355776 TI - The unique role of the agent within the romantic group. AB - In this commentary, we apply the authors' view to small groups consisting of two people who are in a committed romantic relationship. Our focus is on the circumstances that make it more likely that people will stay within such a group and minimize the chances that they will replace their partner. In our restless society, such ongoing replacement is a pressing issue. PMID- 28355777 TI - The subtle effects of incentives and competition on group performance. AB - We show that, under some circumstances, identification and differentiation in the form of competition and individual rewards may undermine, rather than improve, group performance. The key factor for successful group performance seems to be whether or not group members share common goals and whether or not they have aligned incentives. PMID- 28355778 TI - Solved paradoxes and old hats? The research needed on differentiated selves. AB - The idea that differentiated selves almost always improve group outcomes is overly simplistic. We argue that it is essential to distinguish between two distinct elements of differentiated selves - identifiability and specialization - and to identify conditions under which they influence group outcomes. Adopting a group-by-situation perspective, in which group and situation variables are considered jointly, is recommended to generate novel hypotheses. PMID- 28355779 TI - Group and individual as complementary conceptual categories. AB - Baumeister et al. depart from self-theories that contrast the psychology of the group with the psychology of the individual by considering how differentiated identities further collective interests. In concert with Deviance Regulation Theory, their framework offers a foundation for predicting the reward and punishment contingencies that will help groups function as more than the sum of their parts. PMID- 28355780 TI - But is it social? How to tell when groups are more than the sum of their members. AB - Failure to distinguish between statistical effects and genuine social interaction may lead to unwarranted conclusions about the role of self-differentiation in group function. We offer an introduction to these issues from the perspective of recent research on collaborative cognition. PMID- 28355781 TI - Social, not individual, identification is the key to understanding group phenomena. AB - Baumeister and colleagues argue for the indispensability of groups in human life. Yet, in positing individual differentiation as the key to effective group functioning, they adopt a Western-centric view of the relationship of the individual to the group and overlook an alternative social identity account in which depersonalisation, not individuation, is central to understanding many group phenomena. PMID- 28355782 TI - Considering the role of ecology on individual differentiation. AB - Our commentary articulates some of the commonalities between Baumeister et al.'s theory of socially differentiated roles and Strategic Differentiation-Integration Effort. We expand upon the target article's position by arguing that differentiating social roles is contextual and driven by varying ecological pressures, producing character displacement not only among individuals within complex societies, but also across social systems and multiple levels of organization. PMID- 28355783 TI - Reputational concerns as a general determinant of group functioning. AB - To understand a group's (dys)functionality, we propose focusing on its members' concerns for their reputation. The examples of prosocial behavior and information exchange in decision-making groups illustrate that empirical evidence directly or indirectly suggests that reputational concerns play a central role in groups. We argue that our conceptualization fulfills criteria for a good theory: enhancing understanding, abstraction, testability, and applicability. PMID- 28355784 TI - Social identification is generally a prerequisite for group success and does not preclude intragroup differentiation. AB - On the basis of research in the social identity tradition, we contend (a) that identification and differentiation are not mutually exclusive, (b) that a sequence in which identification gives way to differentiation is not necessarily associated with superior organizational outcomes, and PMID- 28355785 TI - How group members contribute to group performance: Evidence from agent-based simulations. AB - The authors argue that group performance depends on the degree to which group members identify with the group as well as on their degree of differentiation. In this commentary, I discuss results from agent-based simulations, suggesting that group performance depends, at least in part, on features orthogonal to agents' caring about group performance or about how they are perceived by other group members. PMID- 28355786 TI - Humans are not the Borg: Personal and social selves function as components in a unified self-system. AB - Does joining groups trigger a cascade of psychological processes that can result in a loss of individuality and lead to such outcomes as social loafing and poor decision-making? Rather than privileging the self comprising primarily individual qualities as the "true self," a multilevel, multicomponent approach suggests that, in most cases, personal and collective identities are integrated and mutually sustaining. PMID- 28355787 TI - Groups need selves, but which selves? Dual selves in groups and the downsides of individuation. AB - It may be true that "groups need selves," as Baumeister et al. contend. However, certain types of selfhood and too much selfhood can both be detrimental to group functioning. I draw on theory and research on dual selves in work groups and teams to outline boundary conditions to the hypothesis that emphasizing individual selves yields positive effects for groups. PMID- 28355788 TI - We agree and we disagree, which is exactly what most people do most of the time. AB - Humans are continually diverging and converging with respect to each other. Research across many domains suggests that differentiation and integration are aspects of a more complex set of dynamics, and are not step-wise but interdependent and continuous. Research on conformity in particular reveals that divergence and dissent are forms of cooperation, reflecting concerns for both individual and group integrity. PMID- 28355789 TI - Beyond old dichotomies: Individual differentiation can occur through group commitment, not despite it. AB - The target article resuscitates an old but outdated dichotomy: a theoretical dualism between group belonging and intragroup differentiation. A convergence of evidence - including that within the social identity tradition - shows that intragroup differentiation is not incompatible with strong group identity. Indeed, when norms encourage autonomy, dissent, and individual freedom, intragroup differentiation occurs through group commitment, not despite it. PMID- 28355790 TI - Member differentiation and group tasks: More than meets the eye. AB - Analyzing how various forms of member similarity and difference affect group performance is a worthwhile task. I argue that the authors' analysis would be improved by distinguishing between subjective and objective forms of member differentiation and by utilizing a different typology of group tasks. PMID- 28355791 TI - Group behavior in the military may provide a unique case. AB - The optimal functioning of male coalitionary behavior in a military context may run contrary to some of the arguments about the importance of individual differentiation in Baumeister et al. Incentives become institutionally inverted within military contexts. Because the history of combat exerted powerful and sustained selection pressures on male groups, individual identification can work against the successful completion of collective action problems surrounding in group defense in military contexts. PMID- 28355792 TI - Group members differ in relative prototypicality: Effects on the individual and the group. AB - All groups are differentiated into more or less group-prototypical members. Central members readily influence and lead the group, and they define its identity. Peripheral members can feel voiceless and marginalized, as well as uncertain about their membership status - they may engage in extreme behaviors to try to win acceptance. These relative prototypicality dynamics sometimes benefit group performance but sometimes compromise performance. PMID- 28355793 TI - Group membership: Who gets to decide? AB - In this commentary, I focus on several problems that the authors' understanding of group identity raises: the legality of avoiding background diversity, the problem of effectively unshareable knowledge, the practical quality of some outcomes arrived at by groups with homogeneous backgrounds, and moral issues about fairness. I note also that much recent research challenges the view that background diversity is more likely to be a detriment than a benefit. PMID- 28355794 TI - Task specificity and the impact on both the individual and group during the formation of groups. AB - We agree with aspects of Baumeister et al.'s view that shared identities are necessary during initial stages of group formation. In contrast to their analysis, however, we provide evidence that the value of self-differentiation depends more on the task itself than on the stage of group development and challenge the authors to focus on the functions of the group. PMID- 28355795 TI - Differentiated selves help only when identification is strong and tasks are complex. AB - Whereas differentiation is overestimated - it more often hurts than helps group performance - identification is underestimated. A more viable perspective sees identification and cooperative motivation as the sine qua non of group functioning, with differentiation helping in a relatively narrow set of cognitively complex tasks that require creativity and deep and deliberate information processing by individual members. PMID- 28355796 TI - Vicarious contagion decreases differentiation - and comes with costs. AB - Baumeister et al. propose that individual differentiation is a crucial determinant of group success. We apply their model to processes lying in between the individual and the group - vicarious processes. We review literature in four domains - attitudes, emotions, moral behavior, and self-regulation - showing that group identification can lead to vicarious contagion, reducing individual differentiation and inducing negative consequences. PMID- 28355797 TI - Group effort in resuscitation teams. AB - Baumeister and colleagues underline that individual identification and differentiation of selves are important characteristics for group performance. They name specialization, moral responsibility, and efficiency as vital components of well-functioning groups. In my commentary, I transfer their framework to the group effort within resuscitation teams to discuss for the first time how these components determine teamwork during resuscitation. PMID- 28355798 TI - Differentiation of selves: Differentiating a fuzzy concept. AB - Notwithstanding the appeal of the "one size fits all" approach that Baumeister et al. propose, we argue that there is no panacea for improving group performance. The concept of "differentiation of selves" constitutes an umbrella term for similar seeming but actually different constructs. Even the same type of "differentiation of selves" can be beneficial for some and harmful for other tasks. PMID- 28355799 TI - Disputing deindividuation: Why negative group behaviours derive from group norms, not group immersion. AB - Strong social identity does not lead to lack of accountability and "bad" behavior in groups and crowds but rather causes group behavior to be driven by group norms. The solution to problematic group behavior is therefore not to individualize the group but rather to change group norms, as underlined by the relational dynamics widely studied in the SIDE tradition. PMID- 28355800 TI - Not even wrong: Imprecision perpetuates the illusion of understanding at the cost of actual understanding. AB - The target article is plagued by imprecision, making it largely impossible to evaluate the authors' theory in a scientific manner. PMID- 28355801 TI - Differentiated selves can surely be good for the group, but let's get clear about why. AB - We applaud the goal of reconciling the self and group literatures and agree that a differentiated self may sometimes improve group outcomes. Nevertheless, greater precision regarding the underlying mechanisms is needed. Specifically, differentiated selves improve outcomes by overriding selfishness when they allow for personal regulation (being personally recognized and valued) rather than social regulation (specialization of labor). PMID- 28355803 TI - Differentiating selves facilitates group outcomes. AB - The target article proposed that differentiation of selves is a crucial moderator of group outcomes, such that differentiation of selves contributes to beneficial outcomes of groups while limiting undesirable outcomes. In this response, we aim to complement the target article by refining and expanding several aspects of the theory. We address our conceptualization of optimal group functioning, clarify the term differentiation of selves, comment on the two-step nature of our model, offer theoretical connections and extensions, and discuss applications and opportunities for future research. PMID- 28355802 TI - Roles and ranks: The importance of hierarchy for group functioning. AB - Baumeister et al. propose that role differentiation is critical for group functioning. We propose that effective groups require rank differentiation in addition to role differentiation. We suggest that rank differentiation supports division of labor by incentivizing group members, satisfying fundamental human needs, and organizing and integrating the contributions of differentiated group members. PMID- 28355804 TI - Heavy objects and small children: Developmental data extend the passive frame theory. AB - Passive frame theory is compatible with modern complexity theory and the idea that conflict drives the emergence of a novel structural organization. After describing new developmental data, we suggest that this conflict needs to be expanded to include not only conflict between action options, but also between action and perception. PMID- 28355805 TI - Infer yourself: Interoception and internal "action" in conscious selfhood. AB - Can consciousness be understood through an association with voluntary skeletomotor action selection? Although flexible and integrated action selection is a plausible function for consciousness, a narrow focus on skeletomotor control neglects the contributions to conscious selfhood and subjectivity that rest on interoception and autonomic regulation (internal "action"). I consider these issues from the perspective of predictive processing. PMID- 28355806 TI - Can skeletomotor action integration occur without consciousness? Evidence from unconscious action inhibition. AB - Morsella et al. claim that consciousness functions to integrate incompatible skeletal muscle intentions. Their primary cases of conscious skeletomotor integration involve action suppression, such as holding one's breath underwater, which requires suppressing the urge to inhale. This indicates that the authors seem to think action inhibition counts as the relevant kind of integration. I suggest that there is reason to think this kind of inhibition can occur unconsciously via unconscious inhibitory mechanisms. Unconscious inhibition therefore potentially undermines the authors' thesis. If cases of unconscious inhibition are not instances of integration, then the authors should clarify exactly what counts as integration. PMID- 28355807 TI - The chemosensory brain requires a distributed cellular mechanism to harness information and resolve conflicts - is consciousness the forum? AB - The central nervous system (CNS) evolved from a chemosensory epithelium, but a simple epithelium has limited means to resolve conflicts between early drives (e.g., approach vs. avoid). Understanding the role of "consciousness" as a resolution device, with specific focus on chemosensation and the olfactory system, is of appeal. I argue that consciousness is not the adjudicator, but is instead the forum that brings conflicting (conscious) inputs into a form that allows them to be (unconsciously) compared/contrasted, guiding rational action. PMID- 28355808 TI - Conscious olfaction: Content, function, and localization. AB - The target article's emphasis on olfaction is a welcome reminder of the multimodal nature of conscious experience. Here, I explore the distinctive and even unique attributes of our sense of smell from the point of view of their bearing on and fit with a subcortical locus of sensory experience. PMID- 28355809 TI - Action-based synthesis of parental brain consciousness. AB - Parenting consciousness, in line with passive frame theory, may be considered inseparable from action. With combined brain-imaging and cognitive-behavioral analyses, we are in the early phases of understanding how parental brain circuits regulate parental thoughts and behavior. Furthermore, work on parental consciousness confirms the importance of motor outputs and outlines related circuits that inform consciousness across generations. PMID- 28355810 TI - Content encapsulation in consciousness is likely to be incomplete. AB - Although the passive frame theory (PST) seems to be very plausible, the encapsulation of content generation deserves further elaboration. Many concepts and data considering the capacity theory, perception, and higher cognitive processes seem to contradict this principle. In general, PST can be suitable in many cases, but it needs to be completed by other mechanisms. PMID- 28355811 TI - Consciousness around the time of saccadic eye movements. AB - During saccadic eye movements, the job of the nervous system is not to perceive a change in stimulation from the receptors, but to prevent a change from reaching consciousness. These movements occupy an intermediate range between actions that are almost always conscious, such as finger movements, and those that are never conscious, such as the smooth-muscle actions of the digestive system. Consciousness in this context requires attention to the consequences of an action. PMID- 28355812 TI - Calling for a developmental perspective on action-based consciousness. AB - Human newborns can resolve some response conflicts in order to adapt their behaviour, suggesting that the newborn has consciousness according to Morsella et al.'s framework. However, we pose a range of developmental questions regarding Morsella et al.'s account, especially concerning the role of consciousness in the development of action. PMID- 28355813 TI - Getting back from the basics: What is the role for attention and fronto-parietal circuits in consciousness? AB - Morsella et al. present a novel theory of consciousness which is more "low-level, circumscribed, counterintuitive, and passive" than previous accounts. There is much to like about this approach. However, what are the explanatory costs associated with these characteristics? In particular, how does this low-level and passive theory accommodate evidence for top-down attention being necessary (but not sufficient) for visual consciousness? PMID- 28355814 TI - Consciousness of emotions and action selection. AB - The domain of emotions corresponds to the consciousness model proposed by Morsella et al. The action schemata unconsciously activated by spontaneous emotions are indeed automatically selected from a small number of innate operative patterns, whereas behavioral responses selected at the cognitive level of emotional processing consist of strategic plans, leading to a conscious integration of goal-directed actions. PMID- 28355815 TI - At what timescale does consciousness operate? AB - While applauding Morsella et al. for linking consciousness to action control, we ask what their theory implies regarding the exact functionality of consciousness and the timescale at which it operates. Does consciousness operate on, and resolve the conflict it emerges from (despite its slowness), or does it operate on future conflicts that it might resolve by externalizing/socializing cognitive control? PMID- 28355816 TI - Locating consciousness: We are conflicted by the role of conflict. AB - What is consciousness for? Consciousness allows us to handle conflict, a promising proposal by Morsella et al. However, they provide little evidence as to why consciousness is particularly valuable in resolving conflict, nor do they limit the role of consciousness to only conflicting experiences. We attempt to clarify their possible positions and offer several solutions for how these might be formulated and tested. PMID- 28355817 TI - How does consciousness for action relate to attention for action? AB - The interesting target article by Morsella et al. addresses critical issues that impact our understanding of consciousness. It is surprising, however, to see no treatment of the relationship between attention and consciousness, particularly given available models. Whether olfaction is most suitable as a model system to study consciousness for action also seems questionable. These issues are elaborated in the present commentary. PMID- 28355818 TI - Insights on consciousness from taste memory research. AB - Taste research in rodents supports the relevance of memory in order to determine the content of consciousness by modifying both taste perception and later action. Associated with this issue is the fact that taste and visual modalities share anatomical circuits traditionally related to conscious memory. This challenges the view of taste memory as a type of non-declarative unconscious memory. PMID- 28355819 TI - Conflicts everywhere! Perceptions, actions, and cognition all entail memory and reflect conflict. AB - Morsella et al. assert that the function of consciousness is to determine which of many competing action options is expressed through the skeletomuscular system at any given moment. The present commentary addresses this issue from the first person perspective and agrees with Morsella and colleagues, yet further proposes that the option-selection function of consciousness plays out in cognition as well. PMID- 28355820 TI - Origins of emotional consciousness. AB - While the field of emotions research has benefited from new developments in neuroscience, many theoretical questions remain unsolved. We propose that integrating our iterative reprocessing (IR) framework with the passive frame theory (PFT) may help unify competing theoretical perspectives of emotion. Specifically, we propose that PFT and the IR framework offer a point of origin for emotional experience. PMID- 28355821 TI - Homing in on consciousness: Why is a dream conscious? AB - Morsella et al. argue convincingly that consciousness is for adaptive voluntary action. What, then, is consciousness in a dream for? Two prior questions present themselves. In a dream, how do contents get into the conscious field? What are the properties of consciousness in a dream? PMID- 28355822 TI - Metacognition and conscious experience. AB - Morsella et al. focus on the conscious nature of sensation. However, also critical to an understanding of consciousness is the role of internally generated experience, such as the content of autobiographical memory or metacognitive experiences. For example, tip-of-the-tongue states are conscious feelings that arise when recall fails. Internally driven experiences drive us to action and therefore are consistent with the current approach. PMID- 28355824 TI - Four questions for passive frame theory. AB - Four questions are raised about the passive frame theory of Morsella et al.: (1) What is the relation of the theory to the response-selection-bottleneck view of attention? (2) Does the theory accommodate the contents of consciousness? (3) What about animals without skeletal muscles? (4) How do the contents of consciousness change with the development of automaticity? PMID- 28355823 TI - Passive frame theory: A new synthesis. AB - Passive frame theory attempts to illuminate what consciousness is, in mechanistic and functional terms; it does not address the "implementation" level of analysis (how neurons instantiate conscious states), an enigma for various disciplines. However, in response to the commentaries, we discuss how our framework provides clues regarding this enigma. In the framework, consciousness is passive albeit essential. Without consciousness, there would not be adaptive skeletomotor action. PMID- 28355825 TI - The science of consciousness must include its more advanced forms. AB - Morsella et al. argue that science should not focus on high forms of consciousness. We disagree. An understanding of high forms of consciousness is invaluable to the scientific study of consciousness. Moreover, it poses challenges to the passive frame theory. Specifically, it challenges the notions that conscious thoughts are not connected and that consciousness serves skeletomotor conflict only. PMID- 28355826 TI - What if consciousness has no function? AB - An implicitly dualist or Cartesian materialist theory of consciousness is proposed without citing the many well-known problems with such theories. A function for consciousness is proposed with no reference to the possibility that "consciousness itself" has no function of its own. The theory builds on proposed "subset consensus" and "integration consensus" when in the literature there is no such consensus on these issues. PMID- 28355827 TI - Consciousness weaves our internal view of the outside world. AB - Low-level consciousness is fundamental to our understanding of the world. Within the conscious field, the constantly changing external visual information is transformed into stable, object-based percepts. Remarkably, holistic objects are perceived while we are cognizant of all of the spatial details comprising the objects and of the relationship between individual elements. This parallel conscious association is unique to the brain. Conscious contributions to motor activity come after our understanding of the world has been established. PMID- 28355828 TI - Consciousness for perception and for action: A perspective from unconscious binding. AB - I argue that the scope and strength of unconscious perception have been overestimated in extant theories. I describe an unconscious binding perspective, and how in conjunction with rigorous methodology it can guide the delineation of unconscious processing. Under this perspective, the function of consciousness is to increase the saliency of conscious contents by facilitating the deployment of focal attention. PMID- 28355829 TI - An "ecological" action-based synthesis. AB - We expand upon Morsella et al.'s synthesis in the direction of what Gibson (1979) called an ecological approach to perception. Morsella et al. describe consciousness as a director of voluntary action, but they understate the role of the environment in its evolution as well as in directing behavior. We elaborate these roles in the context of the concept of affordances. PMID- 28355830 TI - Is conscious content available only to the skeletal muscle system? AB - I applaud Morsella et al.'s approach to investigate consciousness in terms of behavioral control. After all, the function of the brain is to control behavior, and consciousness contributes to the function of the brain. However, I question whether conscious content is available only to the skeletal muscle system, as the principle of parallel responses into skeletal muscle (PRISM) (Morsella 2005) proposes. PMID- 28355831 TI - The primary (dis)function of consciousness: (Non)Integration. AB - Morsella et al. put forward an interesting theory about the functions of consciousness. However, I argue that this theory is more about showing what is not the function of consciousness, and claiming that it does not integrate, than vice versa - as opposed to its proclaimed goal. In addition, the question of phenomenality and its relations with integration is still left open. PMID- 28355832 TI - Human consciousness is fundamental for perception and highest emotions. AB - Have Morsella et al. examined the fundamentals of consciousness? An experiment by Bar et al. (2006) has demonstrated the fundamental aspects of conscious and unconscious mechanisms of perception. The mental representations are not crisp and conscious like the perceived objects are, but vague and unconscious. This experiment points to the fundamental function of the neural mechanisms of consciousness in perception. Consciousness is also fundamental for the highest emotions. PMID- 28355833 TI - Explaining consciousness: From correlations to foundations. AB - What does it take to explain the roles of consciousness for action and action for consciousness? This commentary claims that efficient functional explanations must meet two epistemological requirements: independent description of explanandum and explanans, and foundational explanation of their mutual relationship. It is argued that Morsella et al.'s target articledoes not fully meet these requirements. PMID- 28355834 TI - Conscious content generated by unconscious action-related adjustments. AB - As mentioned in the target article by Morsella et al., the motor program's contents as a whole do not influence each other in the conscious field; however, research shows that some of their generated aspects could be sensitive to the context of the behavior. Such motivational "context-contamination" leads to voluntarily "turn off" of negative states. Taking place out of the conscious field, these adjustments would have critical influence on behavior, such as aggression. PMID- 28355835 TI - Bidirectional synaptic plasticity can explain bidirectional retrograde effects of emotion on memory. AB - Emotional events can either impair or enhance memory for immediately preceding items. The GANE model explains this bidirectional effect as a glutamate "priority" signal that modulates noradrenaline release depending on arousal state. We argue for an alternative explanation: that priority itself evokes phasic noradrenaline release. Thus, contrasting E-1 memory effects are explained by a mechanism based on the Bienenstock-Cooper-Munro theory. PMID- 28355837 TI - Firestone & Scholl conflate two distinct issues. AB - Firestone & Scholl (F&S) seem to believe that the viability of a distinction between perception and cognition depends on perception being encapsulated from top-down information. We criticize this assumption and argue that top-down effects can leave the distinction between perception and cognition fully intact. Individuating the visual system is one thing; the question of encapsulation is quite another. PMID- 28355838 TI - Acting is perceiving! AB - We challenge Firestone & Scholl's (F&S's) narrow conceptualization of what perception is and - most important - what it is for. Perception guides our (inter)actions with the environment, with attention ensuring that the actor is attuned to information relevant for action. We dispute F&S's misconceived (and counterfactual) view of perception as a module that functions independently from cognition, attention, and action. PMID- 28355839 TI - Attention alters predictive processing. AB - Firestone & Scholl (F&S) bracket many attentional effects as "peripheral," altering the inputs to a cognitive process without altering the processing itself. By way of contrast, I highlight an emerging class of neurocomputational models that imply profound, pervasive, nonperipheral influences of attention on perception. This transforms the landscape for empirical debates concerning possible top-down effects on perception. PMID- 28355836 TI - GANEing traction: The broad applicability of NE hotspots to diverse cognitive and arousal phenomena. AB - The GANE (glutamate amplifies noradrenergic effects) model proposes that local glutamate-norepinephrine interactions enable "winner-take-more" effects in perception and memory under arousal. A diverse range of commentaries addressed both the nature of this "hotspot" feedback mechanism and its implications in a variety of psychological domains, inspiring exciting avenues for future research. PMID- 28355840 TI - Studies on cognitively driven attention suggest that late vision is cognitively penetrated, whereas early vision is not. AB - Firestone & Scholl (F&S) examine, among other possible cognitive influences on perception, the effects of peripheral attention and conclude that these effects do not entail cognition directly affecting perception. Studies in neuroscience with other forms of attention, however, suggest that a stage of vision, namely late vision, is cognitively penetrated mainly through the effects of cognitively driven spatial and object-centered attention. PMID- 28355841 TI - Hallucinations and mental imagery demonstrate top-down effects on visual perception. AB - In this commentary, we present two examples where perception is not only influenced by, but also in fact driven by, top-down effects: hallucinations and mental imagery. Crucially, both examples avoid all six of the potential confounds that Firestone & Scholl (F&S) raised as arguments against previous studies claiming to demonstrate the influence of top-down effects on perception. PMID- 28355842 TI - Fundamental differences between perception and cognition aside from cognitive penetrability. AB - Fundamental differences between perception and cognition argue that the distinction can be maintained independently of cognitive penetrability. The core processes of cognition can be integrated under the theory of relational knowledge. The distinguishing properties include symbols and an operating system, structure-consistent mapping between representations, construction of representations in working memory that enable generation of inferences, and different developmental time courses. PMID- 28355843 TI - Gaining knowledge mediates changes in perception (without differences in attention): A case for perceptual learning. AB - Firestone & Scholl (F&S) assert that perceptual learning is not a top-down effect, because experience-mediated changes arise from familiarity with the features of the object through simple repetition and not knowledge about the environment. Emberson and Amso (2012) provide a clear example of perceptual learning that bypasses the authors' "pitfalls" and in which knowledge, not repeated experience, results in changes in perception. PMID- 28355844 TI - Beyond perceptual judgment: Categorization and emotion shape what we see. AB - By limiting their review largely to studies measuring perceptual judgment, Firestone & Scholl (F&S) overstate their case. Evidence from inattentional blindness and emotion-induced blindness suggests that categorization and emotion shape what we perceive in the first place, not just the qualities that we judge them to have. The role of attention in such cases is not easily dismissed as "peripheral." PMID- 28355845 TI - Attention and memory-driven effects in action studies. AB - We provide empirical examples to conceptually clarify some items on Firestone & Scholl's (F&S's) checklist, and to explain perceptual effects from an attentional and memory perspective. We also note that action and embodied cognition studies seem to be most susceptible to misattributing attentional and memory effects as perceptual, and identify four characteristics unique to action studies and possibly responsible for misattributions. PMID- 28355846 TI - Convergent evidence for top-down effects from the "predictive brain". AB - Modern conceptions of brain function consider the brain as a "predictive organ," where learned regularities about the world are utilised to facilitate perception of incoming sensory input. Critically, this process hinges on a role for cognitive penetrability. We review a mechanism to explain this process and expand our previous proposals of cognitive penetrability in visual recognition to social vision and visual hallucinations. PMID- 28355847 TI - Task demand not so damning: Improved techniques that mitigate demand in studies that support top-down effects. AB - Firestone & Scholl's (F&S's) techniques to combat task demand by manipulating expectations and offering alternative cover stories are fundamentally flawed because they introduce new forms of demand. We review five superior techniques to mitigate demand used in confirmatory studies of top-down effects. We encourage researchers to apply the same standards when evaluating evidence on both sides of the debate. PMID- 28355848 TI - Attention and multisensory modulation argue against total encapsulation. AB - Firestone & Scholl (F&S) postulate that vision proceeds without any direct interference from cognition. We argue that this view is extreme and not in line with the available evidence. Specifically, we discuss two well-established counterexamples: Attention directly affects core aspects of visual processing, and multisensory modulations of vision originate on multiple levels, some of which are unlikely to fall "within perception." PMID- 28355849 TI - The myth of pure perception. AB - Firestone & Scholl (F&S) assume that pure perception is unaffected by cognition. This assumption is untenable for definitional, anatomical, and empirical reasons. They discount research showing nonoptical influences on visual perception, pointing out possible methodological "pitfalls." Results generated in multiple labs are immune to these "pitfalls," suggesting that perceptions of physical layout do indeed reflect bioenergetic resources. PMID- 28355850 TI - An action-specific effect on perception that avoids all pitfalls. AB - The visual system is influenced by action. Objects that are easier to reach or catch look closer and slower, respectively. Here, we describe evidence for one action-specific effect, and show that none of the six pitfalls can account for the results. Vision is not an isolate module, as shown by this top-down effect of action on perception. PMID- 28355851 TI - Memory colours affect colour appearance. AB - Memory colour effects show that colour perception is affected by memory and prior knowledge and hence by cognition. None of Firestone & Scholl's (F&S's) potential pitfalls apply to our work on memory colours. We present a Bayesian model of colour appearance to illustrate that an interaction between perception and memory is plausible from the perspective of vision science. PMID- 28355852 TI - Action valence and affective perception. AB - Respecting all constraints proposed by Firestone & Scholl (F&S), we have shown that perceived facial expressions of emotion depend on the congruency between bodily action (comfort/discomfort) and target emotion (happiness/anger) valence. Our studies challenge any bold claim against penetrability of perception and suggest that perceptual theory can benefit from demonstrations of how - under controlled circumstances - observer's states can mold expressive qualities. PMID- 28355853 TI - What draws the line between perception and cognition? AB - The investigation of top-down effects on perception requires a rigorous definition of what qualifies as perceptual to begin with. Whereas Firestone & Scholl's (F&S's) phenomenological demarcation of perception from cognition appeals to intuition, we argue that the dividing line is best attained at the functional level. We exemplify how this approach facilitates scrutinizing putative interactions between judging and perceiving. PMID- 28355854 TI - The anatomical and physiological properties of the visual cortex argue against cognitive penetration. AB - We are consciously aware of visual objects together with the minute details that characterize each object. Those details are perceived instantaneously and in parallel. V1 is the only visual area with spatial resolution and topographical exactitude matching perceptual abilities. For cognition to penetrate perception, it needs to affect V1 image representation. That is unlikely because of the detailed parallel V1 organization and the nature of top-down connections, which can influence only large parts of the visual field. PMID- 28355856 TI - The folly of boxology. AB - Although the authors do a valuable service by elucidating the pitfalls of inferring top-down effects, they overreach by claiming that vision is cognitively impenetrable. Their argument, and the entire question of cognitive penetrability, seems rooted in a discrete, stage-like model of the mind that is unsupported by neural data. PMID- 28355855 TI - The El Greco fallacy and pupillometry: Pupillary evidence for top-down effects on perception. AB - In this commentary, we address the El Greco fallacy by reviewing some recent pupillary evidence supporting top-down modulation of perception. Furthermore, we give justification for including perceptual effects of attention in tests of cognitive penetrability. Together, these exhibits suggest that cognition can affect perception (i.e., they support cognitive penetrability). PMID- 28355857 TI - Cognition can affect perception: Restating the evidence of a top-down effect. AB - We argue that Firestone & Scholl (F&S) provide worthwhile recommendations but that their critique of research by Levin and Banaji (2006) is unfounded. In addition, we argue that F&S apply unjustified level of skepticism about top-down effects relative to other broad hypotheses about the sources of perceptual intelligence. PMID- 28355858 TI - Oh the irony: Perceptual stability is important for action. AB - I review experiments in which drinking a sugarless drink causes some participants who have low blood sugar from fasting to give lower slant estimates. Ironically, this only occurs to the extent that they believe that they have received sugar and that the sugar was meant to make the hill look shallower; those who received sugar showed no similar effect. These findings support the hypothesis that low blood sugar causes greater participant cooperation - which, in combination with other experimental details, can lead participants to make judgments that can either seem to support the effort hypothesis or contradict it. I also emphasize the importance of perceptual stability in the perception of spatial layout. PMID- 28355859 TI - Crossmodal processing and sensory substitution: Is "seeing" with sound and touch a form of perception or cognition? AB - The brain has evolved in this multisensory context to perceive the world in an integrated fashion. Although there are good reasons to be skeptical of the influence of cognition on perception, here we argue that the study of sensory substitution devices might reveal that perception and cognition are not necessarily distinct, but rather continuous aspects of our information processing capacities. PMID- 28355860 TI - Perception, as you make it. AB - The main question that Firestone & Scholl (F&S) pose is whether "what and how we see is functionally independent from what and how we think, know, desire, act, and so forth" (sect. 2, para. 1). We synthesize a collection of concerns from an interdisciplinary set of coauthors regarding F&S's assumptions and appeals to intuition, resulting in their treatment of visual perception as context-free. PMID- 28355861 TI - Perception, cognition, and delusion. AB - Firestone & Scholl's (F&S) critique of putative empirical evidence for the cognitive penetrability of perception focuses on studies of neurologically normal populations. We suggest that a comprehensive exploration of the cognition perception relationship also incorporate work on abnormal perception and cognition. We highlight the prominence of these issues in contemporary debates about the formation and maintenance of delusions. PMID- 28355862 TI - Carving nature at its joints or cutting its effective loops? On the dangers of trying to disentangle intertwined mental processes. AB - Attention is often inextricably intertwined with perception, and it is deployed not only to spatial regions, but also to sensory dimensions, learned dimensions, and learned complex configurations. Firestone & Scholl's (F&S)'s tactic of isolating visual perceptual processes from attention and action has the negative consequence of neglecting interactions that are critically important for allowing people to perceive their world in efficient and useful ways. PMID- 28355863 TI - Representation of affect in sensory cortex. AB - Contemporary neuroscience suggests that perception is perhaps best understood as a dynamically iterative process that does not honor cleanly segregated "bottom up" or "top-down" streams. We argue that there is substantial empirical support for the idea that affective influences infiltrate the earliest reaches of sensory processing and even that primitive internal affective dimensions (e.g., goodness to-badness) are represented alongside physical dimensions of the external world. PMID- 28355864 TI - Not even wrong: The "it's just X" fallacy. AB - I applaud Firestone & Scholl (F&S) in calling for more rigor. But, although F&S are correct that some published work on top-down effects suffers from confounds, their sweeping claim that there are no top-down effects on perception is premised on incorrect assumptions. F&S's thesis is wrong. Perception is richly and interestingly influenced by cognition. PMID- 28355865 TI - Tweaking the concepts of perception and cognition. AB - One approach to the issue of a joint in nature between perception and cognition is to investigate whether the concepts of perception and cognition can be tweaked to avoid direct, content-specific effects of cognition on perception. PMID- 28355866 TI - How cognition affects perception: Brain activity modelling to unravel top-down dynamics. AB - In this commentary on Firestone & Scholl's (F&S's) article, we argue that researchers should use brain-activity modelling to investigate top-down mechanisms. Using functional brain imaging and a specific cognitive paradigm, modelling the BOLD signal provided new insight into the dynamic causalities involved in the influence of cognitions on perceptions. PMID- 28355867 TI - On the neural implausibility of the modular mind: Evidence for distributed construction dissolves boundaries between perception, cognition, and emotion. AB - Firestone & Scholl (F&S) rely on three problematic assumptions about the mind (modularity, reflexiveness, and context-insensitivity) to argue cognition does not fundamentally influence perception. We highlight evidence indicating that perception, cognition, and emotion are constructed through overlapping, distributed brain networks characterized by top-down activity and context sensitivity. This evidence undermines F&S's ability to generalize from case studies to the nature of perception. PMID- 28355868 TI - Seeing and thinking: Foundational issues and empirical horizons. AB - The spectacularly varied responses to our target article raised big-picture questions about the nature of seeing and thinking, nitty-gritty experimental design details, and everything in between. We grapple with these issues, including the ready falsifiability of our view, neuroscientific theories that allow everything but demand nothing, cases where seeing and thinking conflict, mental imagery, the free press, an El Greco fallacy fallacy, hallucinogenic drugs, blue bananas, subatomic particles, Boeing 787s, and the racial identities of geometric shapes. PMID- 28355869 TI - Bottoms up! How top-down pitfalls ensnare speech perception researchers, too. AB - Not only can the pitfalls that Firestone & Scholl (F&S) identify be generalised across multiple studies within the field of visual perception, but also they have general application outside the field wherever perceptual and cognitive processing are compared. We call attention to the widespread susceptibility of research on the perception of speech to versions of the same pitfalls. PMID- 28355870 TI - The distinction between perception and judgment, if there is one, is not clear and intuitive. AB - Firestone & Scholl (F&S) consider the distinction between judgment and perception to be clear and intuitive. Their intuition is based on considerations about visual perception. That such a distinction is clear, or even existent, is less obvious in nonvisual modalities. Failing to distinguish between perception and judgment is therefore not a flaw in investigating top-down effects of cognition on perception, as the authors suggest. Instead, it is the result of considering the variety of human perception. PMID- 28355871 TI - Behavior is multiply determined, and perception has multiple components: The case of moral perception. AB - We introduce two propositions for understanding top-down effects on perception. First, perception is not a unitary construct but is composed of multiple components. Second, behavior is multiply determined by cognitive processes. We call for a process-oriented research approach to perception and use our own research on moral perception as a "case study of case studies" to examine these issues. PMID- 28355872 TI - Epitaxial Growth of SrTiO3 Films on Cube-Textured Cu-Clad Substrates by PLD at Low Temperature Under Reducing Atmosphere. AB - The growth of epitaxial {001}<100> SrTiO3 (STO) on low-cost cube-textured Cu based clad substrate at low temperature was carried out by means of pulsed laser deposition (PLD). STO film was deposited in one step under a reducing atmosphere (5% H2 and 95% Ar mixture) to prevent the oxidation of the metal surface. The optimization of PLD parameters leads to a sharpest biaxial texture at a temperature as low as 500 degrees C and a thickness of 500 nm with a (100) STO layer. The upper limit of highly textured STO thickness was also investigated. The maximum thickness which retains the best quality {001}<100> texture is 800 nm, since the texture is preserved not only through the layer but also on the surface. Atomic force microscopy (AFM) and scanning electron microscopy (SEM) measurements showed that STO films are continuous, dense, and smooth with very low roughness (between 5 and 7 nm). This paper describes the development of STO layer by means of PLD in absence of oxygen throughout the process, suggesting an alternative and effective method for growing highly {001}<100> textured STO layer on low-cost metal substrates. PMID- 28355873 TI - Role of Vacancy Condensation in the Formation of Voids in Rutile TiO2 Nanowires. AB - Titanium dioxide nanowire (NW) arrays are incorporated in many devices for energy conversion, energy storage, and catalysis. A common approach to fabricate these NWs is based on hydrothermal synthesis strategies. A drawback of this low temperature method is that the NWs have a high density of defects, such as stacking faults, dislocations, and oxygen vacancies. These defects compromise the performance of devices. Here, we report a postgrowth thermal annealing procedure to remove these lattice defects and propose a mechanism to explain the underlying changes in the structure of the NWs. A detailed transmission electron microscopy study including in situ observation at elevated temperatures reveals a two-stage process. Additional spectroscopic analyses and X-ray diffraction experiments clarify the underlying mechanisms. In an early, low-temperature stage, the as grown mesocrystalline NW converts to a single crystal by the dehydration of surface-bound OH groups. At temperatures above 500 degrees C, condensation of oxygen vacancies takes place, which leads to the fabrication of NWs with internal voids. These voids are faceted and covered with Ti3+-rich amorphous TiOx. PMID- 28355875 TI - Insights on Water Dynamics in the Hygromorphic Phenomenon of Biopolymer Films. AB - Water-responsive biopolymer thin films with engineered matrix characteristics can accomplish desirable shape changing properties such as self-folding. Self-folding response of chitosan film is experimentally characterized by its total folding time and rate of folding. Here, atomistic simulation is employed to investigate the molecular mechanism responsible for modified self-folding behavior observed in nanoparticle reinforced chitosan films. The nanocomposite system is solvated with water content varying from 10% to 100% of total mass of the system. The free volume available for diffusion of water molecules is affected by the flexibility of glycosidic linkages present in chitosan chains. The increase in mobility of water molecules with increase in water content decides the rate of folding. A separate molecular system is modeled with confined region between nanoparticles densified with chitosan chains and water molecules. The thickness of confined region is determined from the critical distance of influence of nanoparticles on water molecules. The adsorption of water on nanoparticle surface and relaxation of chitosan chains are responsible for increased total folding time with nanoparticle concentration. This simulation study, complemented with experimental observations provides a useful insight into the designing of actuators and sensors based on the phenomenon of hygromorphism. PMID- 28355874 TI - Targeted Diazotransfer Reagents Enable Selective Modification of Proteins with Azides. AB - In chemical biology, azides are used to chemically manipulate target structures in a bioorthogonal manner for a plethora of applications ranging from target identification to the synthesis of homogeneously modified protein conjugates. While a variety of methods have been established to introduce the azido group into recombinant proteins, a method that directly converts specific amino groups in endogenous proteins is lacking. Here, we report the first biotin-tethered diazotransfer reagent DtBio and demonstrate that it selectively modifies the model proteins streptavidin and avidin and the membrane protein BioY on cell surface. The reagent converts amines in the proximity of the binding pocket to azides and leaves the remaining amino groups in streptavidin untouched. Reagents of this novel class will find use in target identification as well as the selective functionalization and bioorthogonal protection of proteins. PMID- 28355876 TI - Diverse Redoxome Reactivity Profiles of Carbon Nucleophiles. AB - Targeted covalent inhibitors have emerged as a powerful approach in the drug discovery pipeline. Key to this process is the identification of signaling pathways (or receptors) specific to (or overexpressed in) disease cells. In this context, fragment-based ligand discovery (FBLD) has significantly expanded our view of the ligandable proteome and affords tool compounds for biological inquiry. To date, such covalent ligand discovery has almost exclusively employed cysteine-reactive small-molecule fragments. However, functional cysteine residues in proteins are often redox-sensitive and can undergo oxidation in cells. Such reactions are particularly relevant in diseases, like cancer, which are linked to excessive production of reactive oxygen species. Once oxidized, the sulfur atom of cysteine is much less reactive toward electrophilic groups used in the traditional FBLD paradigm. To address this limitation, we recently developed a novel library of diverse carbon-based nucleophile fragments that react selectively with cysteine sulfenic acid formed in proteins via oxidation or hydrolysis reactions. Here, we report analysis of sulfenic acid-reactive C nucleophile fragments screened against a colon cancer cell proteome. Covalent ligands were identified for >1280 S-sulfenylated cysteines present in "druggable" proteins and orphan targets, revealing disparate reactivity profiles and target preferences. Among the unique ligand-protein interactions identified was that of a pyrrolidinedione nucleophile that reacted preferentially with protein tyrosine phosphatases. Fragment-based covalent ligand discovery with C-nucleophiles affords an expansive snapshot of the ligandable "redoxome" with significant implications for covalent inhibitor pharmacology and also affords new chemical tools to investigate redox-regulation of protein function. PMID- 28355877 TI - Hard Superconducting Gap in InSb Nanowires. AB - Topological superconductivity is a state of matter that can host Majorana modes, the building blocks of a topological quantum computer. Many experimental platforms predicted to show such a topological state rely on proximity-induced superconductivity. However, accessing the topological properties requires an induced hard superconducting gap, which is challenging to achieve for most material systems. We have systematically studied how the interface between an InSb semiconductor nanowire and a NbTiN superconductor affects the induced superconducting properties. Step by step, we improve the homogeneity of the interface while ensuring a barrier-free electrical contact to the superconductor and obtain a hard gap in the InSb nanowire. The magnetic field stability of NbTiN allows the InSb nanowire to maintain a hard gap and a supercurrent in the presence of magnetic fields (~0.5 T), a requirement for topological superconductivity in one-dimensional systems. Our study provides a guideline to induce superconductivity in various experimental platforms such as semiconductor nanowires, two-dimensional electron gases, and topological insulators and holds relevance for topological superconductivity and quantum computation. PMID- 28355878 TI - Promoting colorectal cancer screening through a new model of delivering rural primary care in the USA: a qualitative study. AB - INTRODUCTION: Despite the known benefits of colorectal cancer (CRC) screening, rural areas have consistently reported lower screening rates than their urban counterparts. Alternative healthcare delivery models, such as accountable care organizations (ACOs), have the potential to increase CRC rates through collaboration among healthcare providers with the aim of improving quality and decreasing cost. However, researchers have not sufficiently explored how this innovative model could influence the promotion of cancer screening. The purpose of the study was to explore the mechanism of how CRC screening can be promoted in ACO-participating rural primary care clinics. METHODS: The study collected qualitative data from in-depth interviews with 21 healthcare professionals employed in ACO-participating primary care clinics in rural Nebraska. Participants were asked about their views on opportunities and challenges to promote CRC screening in an ACO context. Data were analyzed using a grounded theory approach. RESULTS: The study found that the new healthcare delivery model can offer opportunities to promote cancer screening in rural areas through enhanced electronic health record use, information sharing and collaborative learning within ACO networks, use of standardized quality measures and performance feedback, a shift to preventive/comprehensive care, adoption of team based care, and empowered care coordinators. The perceived challenges were found in financial instability, increased staff workload, lack of provider training/education, and lack of resources in rural areas. CONCLUSIONS: This study found that the innovative care delivery model, ACO, could provide a well-designed platform for promoting CRC screening in rural areas, if sustainable resources (eg finance, health providers, and education) are provided. This study provides 'practical' information to identify effective and sustainable intervention programs to promote preventive screening. Further efforts are needed to facilitate delivery system reforms in rural primary care, such as improving performance evaluation measures and methods. PMID- 28355879 TI - Developing a grounded theory for interprofessional collaboration acquisition using facilitator and actor perspectives in simulated wilderness medical emergencies. AB - CONTEXT: Interprofessional collaboration is a complex process that has the potential to transform patient care for the better in urban, rural and remote healthcare settings. Simulation has been found to improve participants' interprofessional competencies, but the mechanisms by which interprofessionalism is learned have yet to be understood. A rural wilderness medicine conference (WildER Med) in northern Ontario, Canada with simulated medical scenarios has been demonstrated to be effective in improving participants' collaboration without formal interprofessional education (IPE) curriculum. ISSUES: Interprofessionalism may be taught through rural and remote medical simulation, as done in WildER Med where participants' interprofessional competencies improved without any formal IPE curriculum. This learning may be attributed to the informal and hidden curriculum. Understanding the mechanism by which this rural educational experience contributed to participants' learning to collaborate requires insight into the events before, during and after the simulations. The authors drew upon feedback from facilitators and patient actors in one-on-one interviews to develop a grounded theory for how collaboration is taught and learned. LESSONS LEARNED: Sharing emerged as the core concept of a grounded theory to explain how team members acquired interprofessional collaboration competencies. Sharing was enacted through the strategies of developing common goals, sharing leadership, and developing mutual respect and understanding. Further analysis of the data and literature suggests that the social wilderness environment was foundational in enabling sharing to occur. Medical simulations in other rural and remote settings may offer an environment conducive to collaboration and be effective in teaching collaboration. When designing interprofessional education, health educators should consider using emergency response teams or rural community health teams to optimize the informal and hidden curriculum contributing to interprofessional learning. PMID- 28355882 TI - Corrigendum. AB - Duschinsky, R., & Solomon, J. (2017) Infant Disorganized Attachment: Clarifying Levels of Analysis. Clinical Child Psychology and Psychiatry. DOI: 10.1177/1359104516685602 . PMID- 28355881 TI - Delineating Characteristics of Maladaptive Repetitive Thought. AB - Worry, rumination, and obsessive thinking are theorized to differ on temporal orientation, positive perceived function, degree of intrusiveness, and discordance with one's self-concept. However, prior findings with respect to such differences may be due to method variance of the measures used and/or inclusion of items confounded by diagnostic symptoms. Accurately capturing differences between types of perseverative thought linked to psychopathology and understanding whether such aspects are common across disorders or specific to some may be important to designing effective treatments for them. Two studies are presented detailing the development and validation of the Perseverative Cognitions Questionnaire (PCQ). The PCQ is a 45-item self-report measure that assesses six dimensional characteristics of worry, rumination, and obsessive thinking previously found to discriminate these thought styles: Lack of Controllability, Preparing for the Future, Expecting the Worst, Searching for Causes/Meaning, Dwelling on the Past, and Thinking Discordant with Ideal Self. Factor structure of the PCQ was established using principal components, exploratory factor, and confirmatory factor analyses. PCQ scales exhibited differential convergence with measures of perseverative thought and psychopathology. The PCQ also demonstrated acceptable retest correlations across 1- and 2-week periods, and incremental validity when predicting symptoms of anxiety, depression, and obsessive compulsive disorder. PMID- 28355880 TI - Current Treatment Strategies for Intracranial Aneurysms: An Overview. AB - Intracranial aneurysm is a leading cause of stroke. Its treatment has evolved over the past 2 decades. This review summarizes the treatment strategies for intracranial aneurysms from 3 different perspectives: open surgery approach, transluminal treatment approach, and new technologies being used or trialed. We introduce most of the available treatment techniques in detail, including contralateral clipping, wrapping and clipping, double catheters assisting coiling and waffle-cone technique, and so on. Data from major trials such as Analysis of Treatment by Endovascular approach of Non-ruptured Aneurysms (ATENA), Internal Subarachnoid Trial (ISAT), Clinical and Anatomical Results in the Treatment of Ruptured Intracranial Aneurysms (CLARITY), and Barrow Ruptured Aneurysm Trial (BRAT) as well as information from other clinical reports and local experience are reviewed to suggest a clinical pathway for treating different types of intracranial aneurysms. It will be a valuable supplement to the current existing guidelines. We hope it could help assisting real-time decision-making in clinical practices and also encourage advancements in managing the disease. PMID- 28355883 TI - Thalassiolin D: a new flavone O-glucoside Sulphate from the seagrass Thalassia hemprichii. AB - Thalassiolin D, a new flavone O-glucoside sulphate along with three flavonoids, two steroids, p-hydroxybenzoic acid, 4,4'-dihydroxybenzophenone and nitrogen compound, octopamine were isolated from the seagrass Thalassia hemprichii, collected from the Saudi Red Sea coast. By extensive spectroscopic analysis including 1D and 2D NMR and MS data, the structure of the new compound was elucidated as diosmetin 7-O-beta-glucosyl-2"-sulphate. The new compound displayed moderately in vitro antiviral HCV protease activity with IC50 value 16 MUM. PMID- 28355884 TI - Does the CATCH Early Childhood Program Increase Physical Activity Among Low Income Preschoolers?-Results From a Pilot Study. AB - PURPOSE: To explore whether the physical activity (PA) component of the Coordinated Approach to Child Health Early Childhood (CATCH EC) program helps increasing preschoolers' PA during active times at preschool. DESIGN: Nonrandomized controlled experimental study. SETTING: Head Start centers in Houston, Texas, 2009 to 2010 school year. PARTICIPANTS: A total of 439 preschoolers aged 3 to 5 years (3 intervention centers, n = 220; 3 comparison centers, n = 219). INTERVENTION: The CATCH EC preschool-based teacher-led nutrition and PA program. MEASURES: Preschoolers' PA was measured at baseline and postintervention using the System for Observing Fitness Instruction Time Preschool version, a direct observation method measuring PA at the classroom level. Parent surveys provided demographic data. ANALYSIS: Pre-to-post changes in preschoolers' PA were examined using the Mann-Whitney U test. RESULTS: Results show a significant decrease in the percentage time preschoolers spent in level 2 PA (low activity) at intervention ( P = .005) and comparison ( P = .041) centers. Indoor vigorous activity increased significantly on an average by +6.04% pre-to post intervention among preschoolers in the intervention group ( P = .049); no significant change was found in the comparison group. CONCLUSION: The CATCH EC favorably increased indoor vigorous PA level among low-income children attending Head Start. PMID- 28355886 TI - The diagnostic utility of patient-report and speech-language pathologists' ratings for detecting the early onset of bulbar symptoms due to ALS. AB - OBJECTIVE: This study aimed to determine the diagnostic utility of clinician speech ratings and patient self-report for detecting early bulbar changes associated with amyotrophic lateral sclerosis (ALS), compared to instrumentation based speech measures. METHODS: Thirty-six individuals with ALS and 17 healthy control participants were included. Patients' awareness of early bulbar motor involvement was assessed using self-reported scores on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). Clinicians' detection of early bulbar motor involvement was assessed through perceptual speech ratings by two experienced speech-language pathologists. Participants with ALS were grouped as 'bulbar pre-symptomatic' or 'bulbar symptomatic' based on self-report and clinician ratings, and compared to healthy controls on six instrumentation-based speech measures. ROC analysis was used to compare the sensitivity and specificity of perceptual and instrumentation-based measures for detecting bulbar changes in pre-symptomatic individuals. RESULTS: Early bulbar changes that were documented using instrumentation-based measures were undetected by both patients and clinicians. ROC analyses indicated that instrumentation-based measures outperformed clinicians' scaled severity ratings, and that percent pause time was the best measure for differentiating healthy controls from bulbar pre-symptomatic individuals with ALS. CONCLUSIONS: Findings suggested that instrumentation-based measures of speech may be necessary for early detection of bulbar changes due to ALS. PMID- 28355888 TI - Diagnosing lung cancer using etoposide microparticles labeled with 99mTc. AB - The diagnosis of lung cancer mostly occurs when the cancer is already in an advanced stage. In this situation, there are few options for the treatment and most of them have few chances of success. In this study, we developed and tested etoposide microparticles as a diagnostic agent for imaging lung cancer at early stages of development. We tested etoposide microparticles labeled with technetium 99m in inducted mice. The results demonstrated that over 10% of the total dose used was uptake by the tumor site. Also, the results showed that the microparticles had a good renal clearance and low uptake by liver and spleen. The data suggest that these micro-radiopharmaceuticals may be used for lung cancer imaging exam, especially single-photo emission computed tomography (SPECT).[Formula: see text]. PMID- 28355887 TI - Micro to nanoneedles: a trend of modernized transepidermal drug delivery system. AB - The transdermal route of drug delivery is convenient, pain-free and follows controlled rate release pattern. However, many therapeutically active drugs cannot cross the stratum corneum effectively. Lipophilic drugs like nifedipine cross the outer skin barrier easily and polar drugs, such as epinephrine are ineffective in showing the same effect. Due to these reasons, advancements in drug delivery have taken place to deliver a wide range of drugs, especially macromolecules through the transdermal route and directly into systemic circulation bypassing hepatic metabolism and GIT degradation. So there is a need for advanced drug delivery systems like microneedles and nanoneedles through transdermal route. These tiny needles will also serve as non-toxic, safe and stable systems for advanced drug delivery. Thus, macro to nanoformulation is the fast emerging fields nowadays. These have additional advantages to transdermal patches, such as better penetration, permeation, controlled release and direct delivery to the cytoplasm. PMID- 28355889 TI - Polyarginine and PEG-AEYLR comodified nanostructured lipid carrier: 10mol% uncleavable PEG-AEYLR showed no shielding effect to polyarginine in vitro while maintaining good tumor targeting in vivo. AB - We constructed a dual ligands-modified nanostructured lipid carrier (NLC) called PAR-NLC, in which the epidermal growth factor receptor (EGFR)-targeted small peptide AEYLR was attached to the distal end of PEG2000 anchored on the NLC surface naming PEG-AEYLR, and poly-arginine (R8) as a classic cell-penetrating peptide was attached directly to the NLC surface. PAR-NLC was near-spherical particle with average size ~50 nm and zeta potential at +14.09 mV; the cellular uptake of PAR-NLC showed synergistic effect of the two peptides, presented as significant superior cellular uptake in EGFR-positive cells NCI-H1299 and S180 over EGFR-negative cell K562. In the animal optical imaging study, 2 h after the administration of the Dir-loaded PAR-NLC, maximum Dir signal appeared in tumor tissue, indicating prompt tumor targeting effect, as time prolonged to 48 h, the Dir signal attenuated in the organs except tumor, suggesting constant clearance from the body. In the in vivo antitumor study, in premise of the same dose, paclitaxel-loaded PAR-NLC exhibited better antitumor and safety effect than Taxol, the body weight of the mice was more stable and tumor size was smaller. In summary, PAR-NLC was a potential drug carrier to deliver anticancer drugs safely and effectively. PMID- 28355890 TI - A randomized controlled trial of expressive writing in breast cancer survivors with lymphedema. AB - OBJECTIVE: Breast cancer survivors who develop lymphedema report poorer quality of life (QoL) than those without lymphedema. Expressive writing is a potential intervention to address QoL. DESIGN: Adult women (N = 107) with breast cancer and chronic Stage II lymphedema were randomised to writing about thoughts and feelings specific to lymphedema and its treatment (intervention) or about daily activities (control) for four, 20-min sessions. MAIN OUTCOME MEASURES: Outcome measures were several indicators of QoL assessed at baseline, one, three, and six months post-intervention (total scores and subscales of Upper Limb Lymphedema 27 and Functional Assessment of Cancer Therapy-Breast). Hypothesised moderators of change in QoL were dispositional optimism, avoidant behaviours, and time since lymphedema diagnosis. RESULTS: There was no statistically significant intent-to treat main effects of expressive writing on QoL. Statistically significant moderating effects on change in different indicators of QoL were observed for all three moderators. Expressive writing was more effective for improving QoL in women who were higher on optimism, lower on avoidance and had less time since a lymphedema diagnosis. CONCLUSION: These results provide further evidence that there are subsets of individuals for whom expressive writing is more effective. Future research may investigate targeting expressive writing based on identified moderators. PMID- 28355892 TI - Cardiac Rehabilitation. PMID- 28355891 TI - Assessing the Factor Structure of the Integrative Hope Scale. AB - While some researchers contend that hope is unidimensional, other researchers regard hope to be multidimensional. Schrank, Woppmann, Sibitz, and Lauber's exploratory factor analysis of their Integrative Hope Scale (IHS) found subscales of Trust, Future Orientation, Social Relations, and Lack of Perspective. However, subsequent articles have utilized only the total IHS score. To resolve this issue, a community sample of 288 participants completed the IHS as well as two measures of hedonic well-being (Positive and Negative Affect Schedule; Temporal Satisfaction With Life Scale), a measure of eudemonic well-being (Measure of Actualization of Potential), and a measure of time orientation (the Zimbardo Time Perspective Inventory). One-factor, four-factor oblique, higher order, and bifactor models were compared through confirmatory factor analysis and interpreted using Omega reliability coefficients. While the poorest model fit was for the one-factor model, little reliable variance was found in subscale scores after controlling for a general hope factor with the exception of the Lack of Perspective factor. IHS total and subscale scores were associated with measures of well-being and time orientation. We suggest researchers continue to focus on using the IHS total score, but also report subscale scores, especially for the Lack of Perspective subscale. PMID- 28355893 TI - Physical activity/Sports Cardiology. PMID- 28355894 TI - Diabetes/ Lipids/Obesity/Nutrition. PMID- 28355895 TI - Physical activity/Sports cardiology. PMID- 28355896 TI - Exercise testing/ training/ Cardiac Rehabilitation. PMID- 28355897 TI - Prevention, Epidemiology & Population Science (PEP). PMID- 28355900 TI - Other. PMID- 28355898 TI - Exercise testing/ training/ Cardiac rehabilitation. PMID- 28355902 TI - Risk factors: others. PMID- 28355901 TI - New frontiers in Sports Cardiology: quantifying risk in master athletes. PMID- 28355903 TI - Exercise Basic & Translational Research (EBTR). PMID- 28355904 TI - Update on the athlete's ECG; International criteria 2017. PMID- 28355905 TI - Diabetes/Lipids/Obesity. PMID- 28355906 TI - Diabetes/ Lipids/Obesity/Nutrition. PMID- 28355907 TI - Sport Cardiology. PMID- 28355908 TI - Exercise testing/ training/ Cardiac Rehabilitation. PMID- 28355909 TI - Risk factors: others. PMID- 28355910 TI - Exercise testing/ training/ Cardiac Rehabilitation. PMID- 28355911 TI - Physical activity/Sports Cardiology. PMID- 28355913 TI - Investigating and managing challenging cases in sports cardiology. PMID- 28355912 TI - Epidemiology/ Public health. PMID- 28355914 TI - Epidemiology. PMID- 28355915 TI - Epidemiology/ Public health. PMID- 28355916 TI - Other. PMID- 28355917 TI - Risk factors: others. PMID- 28355918 TI - Physical activity/Sports Cardiology. PMID- 28355919 TI - Innovations in preventing sudden death in athletes. PMID- 28355920 TI - Epidemiology/ Public health. PMID- 28355921 TI - Diabetes/ Lipids/Obesity/Nutrition. PMID- 28355923 TI - Diabetic ulcer regeneration: stem cells, biomaterials, growth factors. AB - The impairment of ulcer wound healing in diabetic patients is a vital clinical problem affecting millions of patients. Several clinical and basic science studies have demonstrated that stem cell therapy, to be effective in healing diabetic ulcer. Furthermore, these ulcer wounds may be healed from molecular maneuvering of growth factors to improve microcirculation within the ulcer wound. In addition, ulcer wound dressings may be employed as medicated systems, through the delivery of drugs, growth factors, peptides and stem cells. These dressing materials can include natural, modified and synthetic polymers, as well as their mixtures or combinations. This review paper will give a summary of some of the recent advances on the application of stem cells, biomaterials and growth factors in the treatment of diabetic ulcer wound. PMID- 28355924 TI - Insulin Pump Occlusions: For Patients Who Have Been Around the (Infusion) Block. PMID- 28355925 TI - Exploring change in a group-based psychological intervention for multiple sclerosis patients. AB - PURPOSE: The study is focused on a group-based cognitive behavioral intervention aimed at promoting the quality of life and psychological well-being of multiple sclerosis patients. The study investigates how the group intervention promoted change among participants and fostered their adjustment to the illness. MATERIALS AND METHODS: The intervention involved six groups of patients (a total of 41 patients) and included four consecutive sessions and a 6-month follow-up. To explore change, verbatim transcripts of the intervention sessions were analyzed using a mixed-methods content analysis with qualitative data combined with descriptive statistics. The categories of resistance and openness to change were used to describe the process of change. RESULTS: Resistance and openness to change coexisted during the intervention. Only in the first session did resistance prevail over openness to change; thereafter, openness to change gradually increased and stabilized over time, and openness to change was then always stronger than resistance. CONCLUSIONS: The study builds on previous research on the effectiveness of group-based psychological interventions for multiple sclerosis patients and gives methodological and clinical suggestions to health care professionals working with multiple sclerosis patients. Implications for rehabilitation The study suggests that a group-based cognitive behavioral intervention for multiple sclerosis patients focused on the promotion of identity redefinition, a sense of coherence and self-efficacy in dealing with multiple sclerosis fosters the process of change and may be effective in promoting patients' adjustment to their illness. Health care professionals leading group based psychological interventions for multiple sclerosis patients should be aware that resistance and openness to change coexist in the process of change. The study suggests that the duration of the intervention is a crucial factor: a minimum of three sessions appears to be necessary for group participants to develop greater openness to change and follow-up sessions should be implemented to maintain positive changes among participants. The use of qualitative instruments to evaluate group interventions captures the complexity of processes and gives useful indications to health professionals to improve rehabilitation programs. PMID- 28355927 TI - Permutation Disalignment Index as an Indirect, EEG-Based, Measure of Brain Connectivity in MCI and AD Patients. AB - OBJECTIVE: In this work, we introduce Permutation Disalignment Index (PDI) as a novel nonlinear, amplitude independent, robust to noise metric of coupling strength between time series, with the aim of applying it to electroencephalographic (EEG) signals recorded longitudinally from Alzheimer's Disease (AD) and Mild Cognitive Impaired (MCI) patients. The goal is to indirectly estimate the connectivity between the cortical areas, through the quantification of the coupling strength between the corresponding EEG signals, in order to find a possible matching with the disease's progression. METHOD: PDI is first defined and tested on simulated interacting dynamic systems. PDI is then applied to real EEG recorded from 8 amnestic MCI subjects and 7 AD patients, who were longitudinally evaluated at time [Formula: see text]0 and 3 months later (time [Formula: see text]1). At time [Formula: see text]1, 5 out of 8 MCI patients were still diagnosed MCI (stable MCI) whereas the remaining 3 exhibited a conversion from MCI to AD (prodromal AD). PDI was compared to the Spectral Coherence and the Dissimilarity Index. RESULTS: Limited to the size of the analyzed dataset, both Coherence and PDI resulted sensitive to the conversion from MCI to AD, even though only PDI resulted specific. In particular, the intrasubject variability study showed that the three patients who converted to AD exhibited a significantly ([Formula: see text]) increased PDI (reduced coupling strength) in delta and theta bands. As regards Coherence, even though it significantly decreased in the three converted patients, in delta and theta bands, such a behavior was also detectable in one stable MCI patient, in delta band, thus making Coherence not specific. From the Dissimilarity Index point of view, the converted MCI showed no peculiar behavior. CONCLUSIONS: PDI significantly increased, in delta and theta bands, specifically in the MCI subjects who converted to AD. The increase of PDI reflects a reduced coupling strength among the brain areas, which is consistent with the expected connectivity reduction associated to AD progression. PMID- 28355926 TI - Role of male partner involvement in ART retention and adherence in Malawi's Option B+ program. AB - Malawi's Option B+ program provides all HIV-infected pregnant women free lifelong antiretroviral therapy (ART), but challenges remain regarding retention and ART adherence, potentially due to male partner barriers. We explored relationships between male partner involvement and Option B+ retention and adherence. In 2014, a randomized controlled trial in Malawi compared male recruitment strategies for couple HIV testing and counseling (cHTC) at an antenatal clinic. This secondary analysis was conducted among the entire cohort (N = 200) of women, irrespective of randomization status. We assessed whether cHTC attendance, early disclosure of HIV-positive status, and partner ART reminders were associated with retention and adherence at one month after starting treatment. Retention was defined as attending HIV clinic follow-up within one day of running out of pills. Adherence was defined as taking >=95% of ARTs by pill count. We used binomial regression to calculate adjusted risk ratios (aRR) and 95% confidence intervals (CI). Median female age was 26 years. Most women (79%) were retained; of these, 68% were adherent. Receiving cHTC was associated with improved retention (aRR 1.33, 95% CI 1.12, 1.59). Receiving male partner ART reminders was weakly associated with retention (aRR 1.16, 95% CI 0.96, 1.39). Disclosure within one day was not associated with retention (aRR 1.08, 95% CI: 0.91, 1.28). Among those who were retained, these three behaviors were not associated with improved 95% adherence. CHTC could play an important role in improving Option B+ retention. Increasing cHTC participation and enhancing adherence-related messages within cHTC are important. PMID- 28355929 TI - Teasing Apart Overclaiming, Overconfidence, and Socially Desirable Responding. AB - Contamination with positivity bias is a potential problem in virtually all areas of psychological assessment. To determine the impact of positivity bias, one common approach is to embed special indicators within one's assessment battery. Such tools range from social desirability scales to overconfidence measures to the so-called overclaiming technique. Despite the large literature on these different approaches and underlying theoretical notions, little is known about the overall nomological network-in particular, the degree to which these constructs overlap. To this end, a broad spectrum of positivity bias detection tools was administered in low-stakes settings ( N = 798) along with measures of the Big Five, grandiose narcissism, and cognitive ability. Exploratory factor analyses revealed six first-order and two second-order factors. Overclaiming was not loaded by any of the six first-order factors and overconfidence was not explained by either of the two second-order factors. All other measures were confounded with personality and/or cognitive ability. Based on our findings, overclaiming is the most distinct potential indicator of positivity bias and independent of known personality measures. PMID- 28355928 TI - Measurement properties of mental health literacy tools measuring help-seeking: a systematic review. AB - BACKGROUND: Mental health literacy is important to improve help-seeking behaviors. However, the quality of mental health help-seeking tools remains unknown. AIMS: We conducted a systematic review to appraise the quality of such tools. METHODS: We searched databases for English publications addressing psychometrics of help-seeking tools. We included help-seeking tools addressing mental health in general and tools on four mental disorders: anxiety, depression, attention deficit hyperactivity disorder (ADHD) and schizophrenia. We determined the methodological quality of studies as "excellent", "good", "fair", or "indeterminate". We ranked the level of evidence of each measurement property as "strong", "moderate", "limited", "conflicting" or "unknown". RESULTS: We found 12 help-seeking tools in 24 studies that assessed related psychometrics. The methodological quality of included studies ranged from "poor" to "excellent" with four studies on the content validity, structural validity or internal consistency demonstrating "excellent" quality. Three tools demonstrated overall strong evidence (content or structural validity); eight tools demonstrated moderate evidence (internal consistency, structural or construct validity); and eight tools demonstrated limited evidence (reliability, construct validity or internal consistency). CONCLUSIONS: We recommend the application of tools with strong or moderate evidence for their psychometric properties. Future research may focus on the generalizability of the tools across diverse settings. PMID- 28355930 TI - Use of voriconazole in non-meningeal cryptococcosis. PMID- 28355931 TI - A Brief Measure of Narcissism Among Female Juvenile Delinquents and Community Youths: The Narcissistic Personality Inventory-13. AB - Research on narcissism has a long tradition, but there is limited knowledge regarding its application among female youth, especially for forensic samples of incarcerated female youth. Drawing on 377 female adolescents (103 selected from forensic settings and 274 selected from school settings) from Portugal, the current study is the first to examine simultaneously the psychometric properties of a brief version of the Narcissistic Personality Inventory (NPI-13) among females drawn from incarcerated and community settings. The results support the three-factor structure model of narcissism after the removal of one item due to its low factor loading. Internal consistency, convergent validity, and discriminant validity showed promising results. In terms of criterion-related validity, significant associations were found with criterion-related variables such as age of criminal onset, conduct disorder, crime severity, violent crimes, and alcohol and drug use. The findings provide support for use of the NPI-13 among female juveniles. PMID- 28355932 TI - How Danish dentists and dental hygienists handle their role in child abuse and neglect matters. AB - OBJECTIVE: The objective of this study was to identify how the dental team perceives its role in safeguarding children, to identify barriers to referral to social services, to compare data with data previously reported from Denmark, and to assess if increased focus on safeguarding children has had an effect on how the dental team handles its responsibility to refer to social services. MATERIAL AND METHODS: The study is based on a Danish version of a questionnaire previously used in Scotland and Denmark. The questionnaire was sent to a random sample of the Danish dental team. RESULTS: The number of returned questionnaires was 964 (67.0%) with valid data. Of these, 40.8% had had a suspicion of child abuse or neglect and 50.0% had referred their concern to social services. Frequently reported barriers to referral were uncertainty about observations, signs, and symptoms of abuse and neglect, and uncertainty about referral procedures. A total of 84 (8.9%) of the respondents had received both undergraduate and postgraduate training on the topic, and 64.4% of the respondents found that the dental staff could recognize signs and symptoms of abuse and neglect. CONCLUSION: Findings suggest a continuous need for a focus on the awareness and training of the Danish dental staff on the important topic of child abuse and neglect. PMID- 28355933 TI - Interprofessional Survey of Perceived Barriers and Facilitators to Early Mobilization of Critically Ill Patients in Montreal, Canada. AB - OBJECTIVE: Early mobilization is safe, feasible, and associated with better outcomes in patients with critical illness. However, barriers to mobilization in clinical practice still exist. The objective of this study was to assess the knowledge and practice patterns of intensive care unit (ICU) clinicians, as well as the barriers and facilitators to early mobilization. DESIGN: Cross-sectional survey. SETTING: Intensive care units of 3 university-affiliated hospitals in Montreal, Canada. PARTICIPANTS: One hundred and thirty-eight ICU clinicians, including nurses, physicians, respiratory therapists, and physiotherapists. INTERVENTIONS: None. MEASUREMENTS: Perceived barriers, facilitators, knowledge, and practice patterns of early mobilization were assessed using a previously validated mobility survey tool. MAIN RESULTS: The overall response rate was 50.0% (138 of 274). Early mobilization was not perceived as a top priority in 49% of respondents. Results showed that clinicians were not fully aware of the benefits of early mobilization as per the current literature. About 58% of clinicians did not feel well trained and informed to mobilize mechanically ventilated patients. Perceptions on patient-level barriers varied with clinicians' professional training, but there was a high degree of interprofessional and intraprofessional disagreement on the permissible maximal level activity in different scenarios of critically ill patients. CONCLUSIONS: Our survey shows limited awareness, among our respondents, of the clinical benefits of early mobilization and high level of disagreement on the permissible maximal level of activity in the critically ill patients. Future studies should evaluate the role of knowledge translation in modifying these barriers and improving early mobilization. PMID- 28355934 TI - Simulation-based trauma education for medical students: A review of literature. AB - BACKGROUND: Medical students often do not feel prepared to manage emergency situations after graduation. They experience a lack of practical skills and show significant deficits in cognitive performance to assess and stabilize trauma patients. Most reports in the literature about simulation-based education pertain to postgraduate training. Simulation-based trauma education (SBTE) in undergraduate medical education could improve confidence and performance of recently graduated doctors in trauma resuscitation. We reviewed the literature in search of SBTE effectiveness for medical students. METHODS: A PubMed, Embase and CINAHL literature search was performed to identify all studies that reported on the effectiveness of SBTE for medical students, on student perception on SBTE or on the effectiveness of different simulation modalities. RESULTS: Eight studies were included. Three out of four studies reporting on the effectiveness of SBTE demonstrated an increase in performance of students after SBTE. SBTE is generally highly appreciated by medical students. Only one study directly compared two modalities of SBTE and reported favorable results for the mechanical model rather than the standardized live patient model. CONCLUSION: SBTE appears to be an effective method to prepare medical students for trauma resuscitation. Furthermore, students enjoy SBTE and they perceive SBTE as a very useful learning method. PMID- 28355936 TI - Assessment of Adult ADHD With College Students. AB - OBJECTIVE: When assessing adult ADHD, self-report measures are commonly used to guide clinical diagnosis. Self-report measures may be broadband covering a range of behaviors or narrowband and specific to symptoms associated with ADHD. METHOD: This study examined the results of broadband and narrowband measures for college students referred for evaluation of ADHD at a university clinic. RESULTS: With consideration of diagnosis, which included additional information, the group of students who received a diagnosis of ADHD differed significantly from those who did not receive an ADHD diagnosis only on the symptom sets associated with ADHD for both the broadband and narrowband. At the same time, for the total sample, significant correlations emerged for ADHD symptoms with social stress, anxiety, and sense of inadequacy. CONCLUSION: This suggests the need for consideration of alternative or co-occurring factors influencing symptom presentation and functional impairment. PMID- 28355935 TI - Proof-of-Concept Evaluation of the SailValve Self-Expanding Deep Venous Valve System in a Porcine Model. AB - PURPOSE: To evaluate the SailValve, a new self-expanding deep venous valve concept based on a single polytetrafluoroethylene cusp floating up and down in the bloodstream like a sail, acting as a flow regulator and allowing minimal reflux to reduce thrombogenicity. METHODS: Both iliac veins of 5 pigs were implanted with SailValve devices; the first animal was an acute pilot experiment to show the feasibility of accurately positioning the SailValve via a femoral access. The other 4 animals were followed for 2 weeks (n=2) or 4 weeks (n=2) under a chronic implantation protocol. Patency and valve function were evaluated directly in all animals using ascending and descending phlebography after device placement and at termination in the chronic implant animals. For reasons of clinical relevance, a regimen of clopidogrel and calcium carbasalate was administered. Histological analysis was performed according to a predefined protocol by an independent pathologist. RESULTS: Deployment was technically feasible in all 10 iliac veins, and all were patent directly after placement. No perioperative or postoperative complications occurred. Ascending phlebograms in the follow-up animals confirmed the patency of all valves after 2 or 4 weeks. Descending phlebograms showed full function in 5 of 8 valves. Limited reflux was seen in 1 valve (4-week group), and the function in the remaining 2 valves (2 week group) was insufficient because of malpositioning. No macroscopic thrombosis was noted on histology. Histology in the follow-up groups revealed a progressive inflammatory reaction to the valves. CONCLUSION: This animal study shows the potential of the SailValve concept with sufficient valve function after adequate positioning and no (thrombogenic) occlusions after short-term follow-up. Future research is essential to optimize valve material and long-term patency. PMID- 28355937 TI - Treatment and outcomes of endoscopic surgery and traditional open resection in sinonasal mucosal melanoma. AB - OBJECTIVE: The optimal surgical approach for sinonasal mucosal melanoma (SNM) remains under debate. We aimed to compare the therapeutic efficacy of traditional open resection and endoscopic surgery for patients with SNM treated at a single center. METHODS: Thirty-three patients diagnosed with SNM who underwent surgery between January 1995 and June 2014 at a single institution were retrospectively analyzed; 18 patients were treated using an open resection approach and 15 using an endoscopic resection approach for the primary tumor. The associations between open resection and endoscopic resection with treatment-related survival outcomes were assessed using the Kaplan-Meier method and log-rank test. RESULTS: The most common presenting symptoms were epistaxis and abstraction; the nasal cavity was the most common anatomic location. The open resection and endoscopic resection groups did not have significantly different demographic or tumor characteristics. Overall survival (p = .66) and disease-free survival (p = .73) were modest and did not differ significantly between the open resection and endoscopic resection groups. CONCLUSIONS: This retrospective study indicates that the endoscopic endonasal approach is an effective treatment for SNM in selected cases and, when performed by a skilled surgeon, can enable successful radical resection with a similar efficacy as traditional open resection. PMID- 28355938 TI - Extrapolation of Survival Data in Cost-effectiveness Analyses: The Need for Causal Clarity. PMID- 28355939 TI - Comparison of four electronic root canal length measurement devices. AB - OBJECTIVE: The objective of this study is to evaluate the performance of four electronic root canal length measurement devices (ERCLMDs) [Root ZX, Raypex 6, ProPex II, and VDW Gold with ERCLMD] in wet and dry root canals with different major foramen diameters, in association with three file positions within the final 1 mm of canals. MATERIALS AND METHODS: Fifty roots were divided into five groups that were instrumented apically to the terminus diameter using K-files 15, 20, 30, 40, and 60. ERCLMD measurements were made when the file tip was at major foramen, 0.5 mm and 1.0 mm short of the foramen, when the apex touched to the surface of saline or was immersed 3 mm into saline, and when the canal was dry or was irrigated with saline. The differences between the electronic lengths and the actual lengths were calculated. The data were analyzed using the three-, two-, and one-way ANOVA and the LSD test (p < .05). RESULTS: Overall, the four ERCLMDs demonstrated 12.8% unstable and beyond the foramen measurements (11.3%). About 85% of the beyond the foramen measurements had foramen diameters 0.40 and 0.60. ERCLMD comparisons related to the file positions in the foramen diameters showed significant differences between ERCLMDs in each foramen diameter (p < .05). CONCLUSIONS: All ERCLMDs provided highly accurate measurements within the final 1 mm of the foramen. Wet or dry canals and apex conditions did not adversely affect the accuracy of the ERCLMDs' readings. ProPex II located the file positions in the teeth with different foramen diameters more accurately than the other ERCLMDs. PMID- 28355940 TI - Immunohistochemical analysis of EGFR and hyaluronan in tongue cancer and the development of regional recurrence in patients initially diagnosed N0. AB - OBJECTIVE: To investigate whether the extent of expression of hyaluronan (HA) and epidermal growth factor receptor (EGFR) in squamous cell carcinoma of the mobile tongue can predict the risk of cervical metastasis and survival. STUDY DESIGN: Retrospective histopathologic study. METHODS: Surgical specimens from 64 patients who had undergone surgery for squamous cell carcinoma of the mobile tongue were assessed using immunohistochemistry to investigate the expression of HA and EGFR in the primary tumours, and the data were then correlated to cervical metastasis and survival. RESULTS: There was a significant correlation between the intensity of HA staining and patient survival (p .024), and a weak correlation between the staining proportion of EGFR and the risk for regional recurrence (AUC 66). CONCLUSIONS: This study indicates that immunoscoring using HA could be used to provide prognostic tools for tongue cancer, and that it might be of interest to study the prognostic properties of EGFR further concerning the risk for regional recurrence after the primary treatment. PMID- 28355941 TI - P.S. for post-Soviet: A glimpse to a life of persons with intellectual disabilities. AB - This article focuses on the situation of persons with intellectual disabilities in the developing post-Soviet countries and aims to review the extent to which services offered to them promote values of the Convention on the Rights of Persons with Disabilities and empower these persons to lead fulfilling lives. Interviews with experts revealed that post-Soviet countries form a peculiar cluster among other developing countries, which has specific attributes. First of all, there prevails a strong stigmatization, which consequently leads to the predominant silent mandate to isolate those with intellectual disabilities in big residential care institutions. Second, the governments' lack political will to start the reforms and initiatives of nongovernmental organizations which they do not sustain (or, assumingly, are even suppressed). As a result, persons with intellectual disabilities find themselves stuck between the Soviet tradition of exclusion and simulated superficial reforms. PMID- 28355942 TI - A preliminary investigation of a school-based musical theater intervention program for children with intellectual disabilities. AB - The presence of an intellectual disability may cause a child to have significant deficits in social skills and emotion regulation abilities across development. A vital next step is to find interventions that can be delivered in the school environment and across disability categories that target socioemotional factors. The current study investigated the feasibility of delivering a school-based musical theater program to students with intellectual disability across a range of school settings. A within-group repeated-measures design was used to analyze pre- and post-video recordings of the intervention program, which were coded for six domains of socioemotional ability across all participants ( n = 47). Results showed that significant gains across all domains were observed. However, these gains related to school- and individual-level student factors, such as grade level, severity of disability, and baseline social skill ability. PMID- 28355944 TI - Commissurorraphy in the Dog. AB - Commissurorraphy is a surgical procedure designed to move the lip commissure rostrally. This procedure may be helpful as a unilateral procedure in cases of unilateral mandibulectomy to support tongue function and improve esthetics. Bilateral commissurorraphy is utilized in cases of radical bilateral mandibulectomy and as a salvage procedure for support of bilateral mandibular fractures in cases where rigid surgical fixation is not feasible. Dehiscence is the most likely complication of commissurorraphy. Tension can be reduced at the rostral extent of the incision by utilizing mattress sutures, intravenous fluid tubing, and/or buttons to prevent tearing through sutures. PMID- 28355943 TI - Atopic Eczema: Genetic Associations and Potential Links to Developmental Exposures. AB - Atopic eczema (AE), or atopic dermatitis (AD), is a common inflammatory skin disease with a disrupted epidermal barrier and an allergic immune response. AD/AE is prominently characterized by a symptomatic itch and transient skin lesions. Infants compose a significant percentage affected. Two models have been proposed to explain AD/AE skin pathology: the gut microbiome-focused inside-outside model and the outside-inside model concentrating on the disrupted skin barrier/skin microbiome. Gene disruptions contributing to epidermal structure, as well as those in immune system genes, are implicated. Over 30 genes have been linked to AD/AE with Flg and Tmem79/Matt alterations being common. Other linked disruptions are in the interleukin-1 family of cytokines/receptors and the TH2 gene family of cytokines. Inheritable epigenetic modifications of the genes or associated proteins may also be involved. Skin barrier disruption and the allergic immune response have been the main foci in mechanistic studies of AD/AE, but the role of the environment is becoming more apparent. Thus, an examination of in utero exposures could be very helpful in understanding the heterogeneity of AD/AE. Although research is limited, there is evidence that developmental exposure to environmental tobacco smoke or phthalates may impact disease. Management for AD/AE includes topical corticosteroids and calcineurin inhibitors, which safely facilitate improvements in select individuals. Disease heterogeneity warrants continued research not only into elucidating disease mechanism(s), via identification of contributing genetic alterations, but also research to understand how/when these genetic alterations occur. This may lead to the cure that those affected by AD/AE eagerly await. PMID- 28355946 TI - Dysexecutive Symptoms in Primary Progressive Aphasia: Beyond Diagnostic Criteria. AB - Primary progressive aphasia (PPA) is a heterogeneous neurodegenerative condition in which the most prominent clinical feature is language difficulties. Other cognitive domains have been described to remain unaffected at the early stages of the disease and, therefore, excluded from diagnostic criteria. However, we show in this article that executive function (EF) disorders may be present in the 3 variants (nonfluent/agrammatic, logopenic, and semantic) of PPA. We also illustrate changes in language and EF by means of a 3-year behavioral and neuroimaging longitudinal study of a patient suffering from the semantic variant of PPA. This review provides an update on current knowledge of PPA, suggesting that dysexecutive symptoms may be encountered in the 3 PPA variants, in their early phases and/or in more advanced stages, when atrophy extends to adjacent brain areas. PMID- 28355947 TI - Evaluation of combined dynamic compression and single channel noise reduction for hearing aid applications. AB - OBJECTIVE: Single-channel noise reduction (SCNR) and dynamic range compression (DRC) are important elements in hearing aids. Only relatively few studies have addressed interaction effects and typically used real hearing aids with limited knowledge about the integrated algorithms. Here the potential benefit of different combinations and integration of SCNR and DRC was systematically assessed. DESIGN: Ten different systems combining SCNR and DRC were implemented, including five serial arrangements, a parallel and two multiplicative approaches. In an instrumental evaluation, signal-to-noise ratio (SNR) improvement and spectral contrast enhancement (SCE) were assessed. Quality ratings at 0 and +6 dB SNR, and speech reception thresholds (SRTs) in noise were measured using stationary and babble noise. STUDY SAMPLE: Thirteen young normal-hearing (NH) listeners and 12 hearing-impaired (HI) listeners participated. RESULTS: In line with an increased segmental SNR and spectral contrast compared to a serial concatenation, the parallel approach significantly reduced the perceived noise annoyance for both subject groups. The proposed multiplicative approaches could partly counteract increased speech distortions introduced by DRC and achieved the best overall quality for the HI listeners. CONCLUSIONS: For high SNRs well above the individual SRT, the specific combination of SCNR and DRC is perceptually relevant and the integrative approaches were preferred. PMID- 28355945 TI - Late-Life Depression: Modifications of Brain Resting State Activity. AB - Late-life depression (LLD) is a common emotional and mental disability in the elderly population characterized by the presence of depressed mood, the loss of interest or pleasure in daily activities, and other depression symptoms. It has a serious effect on the quality of life of elderly individuals and increases their risk of developing physical and mental diseases. It is an important area of research, given the growing elderly population. Brain functional connectivity modifications represent one of the neurobiological biomarker for LLD even if to date remains poorly understood. In our study, we enrolled 10 elderly patients with depressive symptoms compared to 11 age-matched healthy controls. All participants were evaluated by means of neuropsychological tests and underwent the same functional magnetic resonance imaging (fMRI) protocol to evaluate modifications of brain resting state functional connectivity. Between-group differences were observed for the Geriatric Depression Scale and Hamilton Depression Rating Scale, with higher scores for patients with LLD. Voxel-wise, 1 way analysis of variance revealed between-group differences in left frontoparietal network (lFPN) and sensory motor network (SMN): Increased intrinsic connectivity in the LLD group was observed in the left dorsolateral prefrontal cortex and in the left superior parietal lobule of the lFPN and increased intrinsic connectivity in the LLD group was observed in the bilateral primary somatosensory cortex of the SMN. Our findings support the use of resting state fMRI as a potential biomarker for LLD; even if to confirm the relationship between brain changes and the pathophysiology of LLD, longitudinal neuroimaging studies are required. PMID- 28355948 TI - Sequential endoscopic ultrasound identifies predictive variables for relapse-free follow-up after neoadjuvant chemotherapy in gastric cancer. AB - BACKGROUND: The accuracy of endosonographic tumor staging after neoadjuvant therapy is less reliable than in primary staging. Therefore, the value of sequential endosonographic examinations after neaodjuvant chemotherapy in gastro esophageal cancer is discussed controversially. Previous data suggest, that endoscopic ultrasound (EUS) after neoadjuvant treatment using other variables than classic uTN-criteria may identify patients with a better prognosis. METHODS: In 67 patients with locally advanced gastric cancer treated in curative intent, we performed EUS before and after neoadjuvant chemotherapy. Endosonographic yTN stage was compared to pathohistological yTN-stage after curative resection. The uTN-stage, yuTN-stage, maximal tumor thickness and maximal lymph node diameter as well as the shift of these variables after neoadjuvant therapy were analyzed for their usefulness to predict recurrence-free follow-up. RESULTS: Accuracy of EUS for yTN-staging after neoadjuvant therapy was poor, especially in lower tumor stages. However, three heavily correlated variables analyzed by sequential EUS could be used for the prediction of prognosis: low endosonographic tumor stage (yuT0-2) after neoadjuvant chemotherapy, a decrease of two or more steps in uT stage and a maximal tumor thickness of <15 mm after chemotherapy were significantly associated with recurrence-free follow-up. Endosonographic T-stage before neoadjuvant therapy, as well as lymph node variables before or after chemotherapy, were of no predictive value. CONCLUSION: In spite of poor concordance between endosonographic and pathohistological TN-stage after neoadjuvant treatment, sequential EUS, performed before and after neoadjuvant therapy, possibly identify patients at risk for tumor relapse after multimodal treatment in gastric cancer. This finding should be validated in a larger patient cohort. PMID- 28355949 TI - Differences in the suppression of distortion product otoacoustic emissions by contralateral white noise between patients with acute or chronic tinnitus. AB - OBJECTIVE: The mechanisms underlying the shift from acute tinnitus to chronic remain obscure. An association between tinnitus and medial olivocochlear bundle (MOCB) reflex dysfunction has been hypothesised by several studies. The differences between participants with acute and chronic tinnitus have not yet been investigated. DESIGN: Participants were examined with distortion product otoacoustic emissions (DPOAEs) suppression elicited by contralateral white noise. They were compared in terms of frequency regions with non-recordable DPOAEs, suppression amplitudes and the presence of DPOAE enhancement. STUDY SAMPLE: Eighteen participants with acute tinnitus, 40 age-matched adults with chronic tinnitus and 17 controls were included. All participants (aged 34.7 +/- 9.6years; mean +/- Standard deviation) had normal hearing. Tinnitus was bilateral in 22 participants and unilateral in 36. RESULTS: Ears with chronic tinnitus presented significantly lower DPOAE suppression amplitudes than ears with acute tinnitus (p < 0.0001). Both acute and chronic tinnitus ears present a high prevalence of enhancement, significantly different from controls (p < 0.0001, p = 0.0002, respectively). Non-recordable DPOAEs were significantly more frequent in the chronic than in the acute tinnitus and control groups (p < 0.0001). CONCLUSIONS: The differences between study groups indicate that when tinnitus becomes chronic, DPOAEs suppression presents changes that might reveal corresponding steps in tinnitus pathophysiology. Treatment implications are discussed. PMID- 28355950 TI - Caregiving roles: when will they be routinely recognized and supported? PMID- 28355952 TI - Is there evidence to support serum antinuclear antibodies testing in women with recurrent implantation failure undergoing in vitro fertilization? AB - One of the most challenging aspects of reproductive medicine is the management of recurrent implantation failure. Various investigations, including antinuclear antibodies testing, are performed to seek an explanation and guide treatment. However, is there sufficient evidence or available therapeutic options to support antinuclear antibodies testing? We present a short review on the current literature and an attempt at a systematic review evaluating the association between antinuclear antibodies and recurrent implantation failure to address this question. PMID- 28355951 TI - Output signal-to-noise ratio and speech perception in noise: effects of algorithm. AB - OBJECTIVE: The aims of this study were to: 1) quantify the amount of change in signal-to-noise ratio (SNR) as a result of compression and noise reduction (NR) processing in devices from three hearing aid (HA) manufacturers and 2) use the SNR changes to predict changes in speech perception. We hypothesised that the SNR change would differ across processing type and manufacturer, and that improvements in SNR would relate to improvements in performance. DESIGN: SNR at the output of the HAs was quantified using a phase-inversion technique. A linear mixed model was used to determine whether changes in SNR across HA conditions were predictive of changes in aided speech perception in noise. STUDY SAMPLE: Two groups participated: 25 participants had normal-hearing and 25 participants had mild to moderately severe sensorineural hearing loss. RESULTS: The HAs programmed for both groups changed the SNR by a small, but statistically significant amount. Significant interactions in SNR changes were observed between HA devices and processing types. However, the change in SNR was not predictive of changes in speech perception. CONCLUSION: Although observed significant changes in SNR resulting from compression and NR did not convert to changes in speech perception, these algorithms may serve other purposes. PMID- 28355953 TI - Novel fork-tip needles versus standard needles for EUS-guided tissue acquisition from solid masses of the upper GI tract: a matched cohort study. AB - BACKGROUND: There are very few available data on the novel SharkCoreTM needles for EUS-FNB. AIM: Comparison of the performance of the SharkCoreTM needles with the standard EUS-FNA needles for the diagnosis of solid upper GI masses. PATIENTS AND METHODS: Single-center, retrospective cohort study in an academic tertiary referral hospital. Patients were matched 1:1 for the site of the lesion and the presence or absence of rapid on-site evaluation (ROSE). RESULTS: A total of 102 patients were included. There was no statistically significant difference in the mean number of passes (3.3 +/- 1.3 versus 3.4 +/- 1.5; p = .89). Similar results were observed at the subgroup with ROSE (4.3 +/- 1.3 versus 3.7 +/- 1.5; p = .26). More histological specimens were obtained with the SharkCoreTM needles compared to standard needles (59 versus 5%; p < .001). Diagnostic test characteristics were not significantly different (sensitivity: 91.5 versus 85.7; specificity: 100 versus 100%; accuracy: 92.2 versus 85.4% for SharkCoreTM versus standard needles, p > .05 in all cases). At multivariable analysis, there was no statistically significant difference in the mean number of passes in all patients (p = .23) and in the ROSE subgroup (p = .66). However, the SharkCoreTM needle obtained significantly more histological material than the standard needle (odds ratio 66; 95% confidence interval: 11.8, 375.8, p < .001). There was no significant difference in complication rates (p = .5). LIMITATIONS: Retrospective study, single-center. CONCLUSION: The SharkCore needles were similar to standard FNA needles in terms of the number of passes to reach diagnosis, but obtained significantly more histological specimen. PMID- 28355954 TI - Evaluation of an automated enzyme-linked fluorescent assay for thyroxine measurement in cat and dog sera. AB - Measurement of total thyroxine (T4) is the first testing step in the work-up of thyroid disease in small animals. We evaluated an enzyme-linked fluorescent assay (ELFA) as an in-house method to measure T4 in cats and dogs. We compared the T4 concentration in sera of 122 cats and 176 dogs measured by the ELFA with an enzyme immunoassay (EIA) to assess the concordance of the 2 methods. Bias of the ELFA in cats was -11.4% and in dogs 1.4%. Using Bland-Altman plots, limits of agreement were -81.5 to 58.7% in cats and -71.4 to 74.4% in dogs. Imprecision was calculated for both methods. Intra- and interassay coefficients of variation (CVs) of the ELFA in feline sera were 0.7 and 3.4% and of the EIA 7.6 and 15.7%, respectively. Intra- and interassay CVs of both ELFA and EIA in canine sera were <9.5%. Reference intervals for the ELFA method were established and were 13.3 49.5 nmol/L for cats and 10.1-42.9 nmol/L for dogs. Accuracy of the EIA and ELFA was scored by assessing if the measured T4 value would identify the expected T4 range (low, normal, or elevated) of patients, based on history, clinical presentation, other diagnostic means, and response to therapy. This was possible for 75 cats and 50 dogs. Both methods yielded acceptable results, but the EIA was more accurate compared to the ELFA (percentage of true-positives in cats and dogs: EIA: 97% and 100%; ELFA: 92% and 94%). PMID- 28355955 TI - Helicobacter pylori infection in Icelandic children. AB - OBJECTIVE: The prevalence of Helicobacter pylori (HP) infection is decreasing in the western world. The seroprevalence among 25-50-year-old Icelandic adults was recently shown to be 30-40%. Information on the seroprevalence in Nordic children is limited. We aimed at ascertaining the infection prevalence among healthy Icelandic children. METHODS: The infection status in stored frozen blood samples from two cross-sectional studies on the health of 7-9-year-old children (n = 125) and 16-18-year-old adolescents (n = 80) was determined by enzyme-linked immunosorbent assay (ELISA). Information on family demographics and GI symptoms was obtained by standardized questionnaires. RESULTS: Overall, 3.4% (7/205) of the children were infected with H. pylori. The prevalence was 2.6% (5/190), missing data n = 3, among children with both parents born in a low prevalence country compared to 17% (2/12) among those with at least one parent born in a high prevalence area (p = .026). When at least one parent was born in a high prevalence country, the odds ratio for being H. pylori seropositive was 2.2 (95% CI, 1.02-54.67), when adjusted for the educational status of the mother. There was no significant association between H. pylori infection and gastrointestinal symptoms. CONCLUSION: Prevalence of H. pylori infection in Iceland has become very low, suggesting a great reduction in transmission from older generations. There was an association between H. pylori infection and origin from high prevalence areas but not with gastrointestinal symptoms. The results mirror recent studies of children of Scandinavian ancestry. PMID- 28355956 TI - Hepatocellular carcinoma in Danish patients: a single Copenhagen center experience. AB - OBJECTIVE: Hepatocellular carcinoma (HCC) is a common cause of cancer, and most HCC patients have underlying cirrhosis. Retrospectively, we aimed to characterize patients with newly diagnosed HCC at a Danish hospital and to investigate survival and identify predictive factors for survival. METHODS: All patients diagnosed with HCC from January 2008 to December 2014 were retrospectively enrolled in this study. Overall survival was estimated by using the Kaplan-Meier method. A multivariate Cox regression analysis was performed to identify predictive factors for survival. RESULTS: Sixty-seven patients were diagnosed with HCC (incidence rate 3.55/100,000 people/year). Ninety-three percent had underlying cirrhosis. Alcohol-related liver disease and chronic viral hepatitis B or C were responsible for 55 and 31% of cases, respectively. Median survival was 81 days and 1-month, 3-months and 1-year cumulative survival rates were 74, 40 and 17%, respectively. We identified the presence of portal vein thrombosis, high Child-Pugh score, high MELD score and high AST as independent negative prognostic factors for survival. Survival was poorer in patients seen for the first time when the diagnosis of HCC was made than in patients followed in the outpatient clinic (p = .06) indicating a substantial delay in diagnosis. CONCLUSIONS: Survival was poor in this cohort of patients, almost exclusively caused by delay in diagnosis and admittance to hospital. An increased general information about HCC and the possibilities of therapy seems warranted. PMID- 28355957 TI - Adolescent brain activation: dependence on sex, dietary satiation, and restraint. AB - The study aimed to explore how both sex and dietary restraint impacts brain activation in response to visual food stimuli in young adolescents (12-13 years) under fed and fasted conditions. Food and non-food images were viewed by 15 boys and 14 girls, while functional magnetic resonance images were acquired. The adolescents were either fasted or in a satiated (fed) state following a randomized crossover study design. When satiation state was not considered, girls showed significantly greater brain activity than boys in regions associated with executive function and decision making, working memory, and self-awareness. In contrast, when either fasted or fed states were considered separately, boys showed significantly increased brain activity in regions linked to executive function, self-awareness, and decision making than the girls. When fasted, compared to unrestrained eaters, restrained individuals showed heightened activation in regions connected to executive function and decision making, with areas associated with self-assessment showing increased activity for unrestrained eaters relative to restrained under fed conditions. These findings highlight important differences in adolescent brain activity and support further investigations to gain greater insight into how these differences might evolve with age. PMID- 28355958 TI - The Patient Health Questionnaire depression screener in spinal cord injury. AB - CONTEXT: Although depression is not inevitable following spinal cord injury/dysfunction (SCI/D), it can have a negative impact on rehabilitation. Evidence-based assessment of depression utilizing self-report instruments, such as the Patient Health Questionnaire-9 (PHQ-9), is considered good clinical practice. Although the PHQ-9 has been studied in individuals with SCI/D, little is known about the clinical utility of the Patient Health Questionnaire-2 (PHQ 2). Traditional cutoff scores for the PHQ-2 were examined to explore their operating characteristics as related to PHQ-9 results. METHODS: Archival data were collected for 116 Veterans with SCI/D who completed the PHQ-2 and PHQ-9 as one component of their routine, comprehensive SCI annual evaluation at a Veterans Affairs Medical Center. Logistic regressions were performed to determine the impact of different cutoff scores for the PHQ-2 on the likelihood that participants would endorse clinically significant levels of depressive symptoms on the PHQ-9 (>=10). RESULTS: Using a cutoff score of 3 or greater correctly classified 94.8% of the cases, outperforming the other cutoff scores. A cutoff score of 3 or greater had a sensitivity of 83.3% and specificity of 97.8%, and yielded a positive predictive value of 90.9% and a negative predictive value of 95.7%. CONCLUSION: The PHQ-2 shows promise as a clinically useful screener in the community-residing SCI/D population. Findings regarding the presence of suicidal ideation emphasize the importance of routine screening for depressive symptomatology in the SCI/D population. Future research should investigate the role of the PHQ-2 in clinical decision-making and treatment monitoring. PMID- 28355959 TI - Does national expenditure on research and development influence stroke outcomes? AB - Background Expenditure on research and development is a macroeconomic indicator representative of national investment. International organizations use this indicator to compare international research and development activities. Aim We investigated whether differences in expenditures on research and development at the country level may influence the incidence of stroke and stroke mortality. Methods We compared stroke metrics with absolute amount of gross domestic expenditure on R&D (GERD) per-capita adjusted for purchasing power parity (aGERD) and relative amount of GERD as percent of gross domestic product (rGERD). Sources included official data from the UNESCO, the World Health Organization, the World Bank, and population-based studies. We used correlation analysis and multivariable linear regression modeling. Results Overall, data on stroke mortality rate and GERD were available from 66 countries for two periods (2002 and 2008). Age-standardized stroke mortality rate was associated with aGERD (r = 0.708 in 2002 and r = -0.730 in 2008) or rGERD (r = -0.545 in 2002 and r = -0.657 in 2008) (all p < 0.001). Multivariable analysis showed a lower aGERD and rGERD were independently and inversely associated with higher stroke mortality (all p < 0.05). The estimated prevalence of hypertension, diabetes, or obesity was higher in countries with lower aGERD. The analysis of 27 population-based studies showed consistent inverse associations between aGERD or rGERD and incident risk of stroke and 30-day case fatality. Conclusions There is higher stroke mortality among countries with lower expenditures in research and development. While this study does not prove causality, it suggests a potential area to focus efforts to improve global stroke outcomes. PMID- 28355961 TI - Stress, sense of coherence and subjective health in adolescents aged 13-18 years. AB - BACKGROUND: This study investigated the relationships between sex, age, stress and sense of coherence (SOC) and each of self-rated health (SRH) and subjective health complaints (SHCs) in adolescents. METHODS: The study was based on a cross sectional sample of 1239 adolescents aged 13-18 years. The participants reported scores on a questionnaire, including 12 items assessing SHC, the 13-item version of the Orientation to Life Questionnaire and the 30-item Adolescent Stress Questionnaire. Data were analysed with descriptive, comparative and hierarchical multiple regression analyses. RESULTS: Boys scored significantly higher on SRH than girls, whereas girls scored higher on SHCs. In the multivariate model, stress was significantly associated with SHCs, but not with SRH. SOC was significantly positively related to SRH and negatively related to SHC; the associations were significantly stronger for girls than for boys. A significant moderation effect (protective role) of SOC was found on the relation between stress and SHC. CONCLUSIONS: No causal conclusion was possible, but the findings may be used as a basis for further investigation of the role of stress and SOC in longitudinal studies and intervention studies. PMID- 28355960 TI - Preventive effects of multiple domain interventions on lifestyle and risk factor changes in stroke survivors: Evidence from a two-year randomized trial. AB - Background and aim Behavioral and lifestyle interventions in stroke patients need to be intense enough to result in sustainable treatment differences among groups of a randomized trial. Therefore, we report the effects of multidomain interventions on lifestyle and laboratory parameters after 12 and 24 months from a trial that examined whether intensive risk factor management can prevent cognitive decline in ischemic stroke patients. Methods This prospective randomized, open-label, blinded endpoint trial recruited patients within three months after acute stroke in five Austrian neurological clinics during June 2010 and November 2012. One hundred and one patients were randomized into multidomain intervention and 101 into standard care. Lifestyle interventions were individualized to match predefined targets of regular physical activity, healthy diet, and adequate physiological risk factor control. Results A total of 167 participants (80 intervention, 87 control) completed the 12-month visit and 155 (76 intervention, 79 control) the 24-month visit. During the first 12 months, adherence to healthy lifestyle and adequately controlled physiological parameters (measured by summary scores) improved significantly in the intervention group compared to controls (p < 0.01). The consumption of reduced-fat milk (p = 0.031), reduced-fat spreads (p = 0.007), and fish (p = 0.021) increased in the intervention group from baseline to 12 months but not in controls. After 24 months, the group difference was significant for the lifestyle summary score but no longer for the combined laboratory lifestyle score. Conclusions These results demonstrate that intensified individualized multidomain lifestyle interventions in stroke patients are effective in promoting healthy lifestyle in stroke care. PMID- 28355962 TI - Indications and Outcomes From 32 Consecutive Patients for the Treatment of Rectal Lesions by Transanal Minimally Invasive Surgery. AB - BACKGROUND: The aim of this study was to evaluate the feasibility, safety, perioperative morbidity, and short-term outcomes of the transanal minimally invasive surgery (TAMIS) technique. METHODS: This is a descriptive review of prospectively collected data from 32 consecutive patients who underwent TAMIS procedures in our colorectal unit over a 40-month period. GelPOINT Path port was used in all cases. Demographic data, indications, tumor characteristics, morbidity, and follow-up data were collected. Primary endpoints included feasibility, safety, perioperative morbidity, and resection quality. RESULTS: Fifteen adenomas, 12 carcinomas, 1 gastrointestinal stromal tumor, and 1 neuroendocrine tumor were locally excised. Additionally, 3 pelvic abscesses were drained transanally using the TAMIS port. Mean distance from the anal verge was 5.6 +/- 1.5 cm. Early postoperative complications occurred in 22%, with only one case of major complication (3.1%) requiring reoperation, and no postoperative mortality. Four carcinomas were understaged (33.3%) and 1 adenoma overstaged (6.7%) preoperatively. Three carcinomas were not suspected preoperatively (25%). Microscopic positive lateral margin was found in one case, and no affected deep margin was found. Fragmentation rate was 6.9%, 2 cases, both lesions over 20 cm2. In cases of fit patients with high-risk carcinomas, 2 underwent immediate salvage surgery and another 2 refused and were treated with adjuvant radiotherapy. With a median follow-up of 26 months, the overall recurrence rate was 10.3%, 1 adenoma and 2 carcinomas. CONCLUSION: TAMIS seems to be a safe and reproducible procedure for local excision of well-selected rectal lesions with low morbidity and good functional outcomes. PMID- 28355963 TI - Risk factors for infant mortality in rural and urban Nigeria: evidence from the national household survey. AB - AIMS: This study investigates the rural-urban differences in infant mortality rates (IMRs) and the associated risk factors in Nigeria. METHODS: The dataset from the 2013 Nigeria demographic and health survey (NDHS), disaggregated by rural-urban residence, was analyzed using complex samples statistics. A multivariable logistic regression analysis was computed to explore the adjusted relationship and identify risk factors for infant mortality. RESULTS: In rural and urban Nigeria, IMRs were 70 and 49 deaths per 1000 live births, respectively. Risk factors in rural residence were past maternal marital union (adjusted odds ratio (AOR): 1.625, p = 0.020), small birth size (AOR: 1.550, p < 0.001), birth interval <24 months (AOR: 2.057, p < 0.001), residence in North-East (AOR: 1.346, p = 0.038) and North-West (AOR: 1.653, p < 0.001) regions, and cesarean delivery (AOR: 2.922, p = 0.001). Risk factors in urban residence were poor wealth index (AOR: 2.292, p < 0.001), small birth size (AOR: 2.276, p < 0.001), male gender (AOR: 1.416, p = 0.022), birth interval <24 months (AOR: 1.605, p = 0.002), maternal obesity (AOR: 1.641, p = 0.008), and cesarean delivery (AOR: 1.947, p = 0.032). CONCLUSIONS: Infants in rural residence had higher rates of mortality than their urban counterparts and disparities in risk factors exist between the residences. PMID- 28355964 TI - Study of Image Qualities From 6D Robot-Based CBCT Imaging System of Small Animal Irradiator. AB - PURPOSE: To assess the quality of cone beam computed tomography images obtained by a robotic arm-based and image-guided small animal conformal radiation therapy device. METHOD AND MATERIALS: The small animal conformal radiation therapy device is equipped with a 40 to 225 kV X-ray tube mounted on a custom made gantry, a 1024 * 1024 pixels flat panel detector (200 MUm resolution), a programmable 6 degrees of freedom robot for cone beam computed tomography imaging and conformal delivery of radiation doses. A series of 2-dimensional radiographic projection images were recorded in cone beam mode by placing and rotating microcomputed tomography phantoms on the "palm' of the robotic arm. Reconstructed images were studied for image quality (spatial resolution, image uniformity, computed tomography number linearity, voxel noise, and artifacts). RESULTS: Geometric accuracy was measured to be 2% corresponding to 0.7 mm accuracy on a Shelley microcomputed tomography QA phantom. Qualitative resolution of reconstructed axial computed tomography slices using the resolution coils was within 200 MUm. Quantitative spatial resolution was found to be 3.16 lp/mm. Uniformity of the system was measured within 34 Hounsfield unit on a QRM microcomputed tomography water phantom. Computed tomography numbers measured using the linearity plate were linear with material density ( R2 > 0.995). Cone beam computed tomography images of the QRM multidisk phantom had minimal artifacts. CONCLUSION: Results showed that the small animal conformal radiation therapy device is capable of producing high-quality cone beam computed tomography images for precise and conformal small animal dose delivery. With its high-caliber imaging capabilities, the small animal conformal radiation therapy device is a powerful tool for small animal research. PMID- 28355967 TI - Joint power generation differentiates young and adult sprinters during the transition from block start into acceleration: a cross-sectional study. AB - The aim of this study was to investigate differences in joint power generation between well-trained adult athletes and young sprinters from block clearance to initial contact of second stance. Eleven under 16 (U16) and 18 under 18 (U18) promising sprinters executed an explosive start action. Fourteen well-trained adult sprinters completed the exact same protocol. All athletes were equipped with 74 spherical reflective markers, while an opto-electronic motion analysis system consisting of 12 infrared cameras (250 Hz, MX3, Vicon, Oxford Metrics, UK) and 2 Kistler force plates (1,000 Hz) was used to collect the three-dimensional marker trajectories and ground reaction forces (Nexus, Vicon). Three-dimensional kinematics, kinetics, and power were calculated (Opensim) and time normalised from the first action after gunshot until initial contact of second stance after block clearance. This study showed that adult athletes rely on higher knee power generation during the first stance to induce longer step length and therefore higher velocity. In younger athletes, power generation of hip was more dominant. PMID- 28355965 TI - Long Noncoding RNA PVT1 Promotes EMT and Cell Proliferation and Migration Through Downregulating p21 in Pancreatic Cancer Cells. AB - BACKGROUND AND AIM: Long noncoding RNA-plasmacytoma variant translocation 1 is identified to be highly expressed and exhibits oncogenic activity in a variety of human malignancies, including pancreatic cancer. However, little is known about the overall biological role and mechanism of plasmacytoma variant translocation 1 in pancreatic cancer so far. In this study, we investigated the effect of plasmacytoma variant translocation 1 on pancreatic cancer cell proliferation and migration as well as epithelial-mesenchymal transition. METHODS: Pancreatic cancer tissue specimens and cell line were used in this study, with normal tissue and cell line acting as control. RESULTS: It showed that plasmacytoma variant translocation 1 expression was significantly upregulated in pancreatic cancer tissues or cell line compared to normal groups. Plasmacytoma variant translocation 1 downregulation significantly inhibited zinc finger E-box-binding protein 1/Snail expression but promoted p21 expression, and it also inhibited the cell proliferation and migration. Additionally, p21 downregulation enhanced, and p21 overexpression repressed, zinc finger E-box-binding protein 1/Snail expression and cells proliferation in PANC-1 cells. However, p21 downregulation reversed the effect of plasmacytoma variant translocation 1 downregulation on zinc finger E-box-binding protein 1/Snail expression and cell proliferation and migration. CONCLUSION: Plasmacytoma variant translocation 1 promoted epithelial mesenchymal transition and cell proliferation and migration through downregulating p21 in pancreatic cancer cells. PMID- 28355968 TI - Abiraterone-induced rhabdomyolysis resulting in acute kidney injury: A case report and review of the literature. AB - Abiraterone, a CYP17 inhibitor, blocks androgen biosynthesis in multiple tissue types. In combination with prednisone, it is approved as a first-line treatment for metastatic castration-resistant prostate cancer. We present a case of rhabdomyolysis associated with abiraterone therapy resulting in acute on chronic kidney injury in a patient with metastatic castration-resistant prostate cancer. Strict monitoring should be employed in patients started on abiraterone who have additional risk factors for developing rhabdomyolysis. PMID- 28355969 TI - Incidence of asparaginase-related hepatotoxicity, pancreatitis, and thrombotic events in adults with acute lymphoblastic leukemia treated with a pediatric inspired regimen. AB - Asparaginase is a critical component of acute lymphoblastic leukemia (ALL) treatment in children; however, its use in adults is often avoided as a result of toxicities including hepatotoxicity, thrombosis, and pancreatitis which have been reported more commonly in adults than in children. In this retrospective analysis, short-acting L-asparaginase (L-ASP) and long-acting polyethylene glycol (PEG)-asparaginase (PEG-ASP) were compared for grade 3-4 toxicities and characterized by patient and drug-related factors to identify strategies for toxicity avoidance in adults with ALL. Asparaginase was administered during sequential courses of chemotherapy using a pediatric-inspired treatment regimen. Forty-eight patients who received PEG-ASP and nine patients who received L-ASP were identified. The rates of toxicity were as follows for the PEG-ASP and L-ASP groups, respectively: hepatotoxicity (60% vs. 33%, P = 0.275), pancreatitis (17% vs. 22%, P = 0.650), thrombosis (19.0% vs. 0%, P = 0.328), or any grade 3-4 toxicity (71% vs. 44%, P = 0.143). Toxicity did not correlate with dose, either by individual dose based on flat or BSA-based measures. Logistic regression identified obesity as a risk factor for heptatotoxicity (OR = 8.44, 95% CI: 1.395 51.117). Hypofibrinogenemia was identified as a pharmacodynamic marker for predicting hepatotoxicity. In conclusion, grade 3-4 toxicity was not statistically different between adult ALL patients receiving PEG-ASP and L-ASP, but toxicity was strongly associated with obesity and hypofibrinogenemia, not dose. PMID- 28355970 TI - Clinical impact and management of fluconazole discontinuation on sirolimus levels in bone marrow transplant patients. AB - Sirolimus, an immunosuppressant, is indicated post-allogeneic stem cell transplant to reduce the risk of graft-versus-host-disease. Sirolimus is metabolized by cytochrome P450 3A4 and is a substrate of the P-glycoprotein (P gp) drug efflux pump. Interactions with known inhibitors of the CYP3A4 enzyme and P-glycoprotein, such as fluconazole, are anticipated. Co-administration of fluconazole leads to an increase in sirolimus blood concentrations due to an inhibition of metabolism. The discontinuation of fluconazole will likely result in a decline in sirolimus blood concentrations, leaving patients at risk of graft versus-host-disease. We report on three patients managed by the Hematology, Oncology Blood and Marrow Transplant Program at the Alberta Children's Hospital. The discontinuation of fluconazole showed a marked reduction in sirolimus trough levels, requiring >200% increase in sirolimus dose to achieve therapeutic levels. PMID- 28355971 TI - Could knee inflammatory synovitis be induced by pembrolizumab? AB - Pembrolizumab, a selective anti-PD-1 humanized monoclonal antibody, reactivates T cells to fight cancer. Immune-related adverse events such as autoimmune colitis, pneumonitis, hepatitis, nephritis, hypophysitis, and thyroiditis may occur during, or weeks to months after therapy. Pemprolizumab-induced synovitis is rarely reported. With the wide use of immunotherapy to treat cancers, physicians need to be aware of this rare immune-related adverse event and provide immediate treatment to avoid permanent joint damage. PMID- 28355973 TI - Patient-therapist convergence in alliance ratings as a predictor of outcome in psychotherapy for generalized anxiety disorder. AB - OBJECTIVE: Although patients and therapists aligning over time on their perceptions of alliance quality is regarded as clinically important, few studies have examined the influence of such dyadic convergence on psychotherapy outcomes. This study tested whether early treatment convergence in patient-therapist alliance ratings was associated with subsequent worry and distress reduction in psychotherapy for generalized anxiety disorder (GAD), and whether treatment type and the dyad members' initial alliance perceptions moderated these associations. METHOD: Data derived from a randomized trial for which patients with severe GAD received either 15 sessions of standard cognitive-behavioral therapy (CBT; n = 43) or CBT integrated with motivational interviewing (n = 42). Patients and therapists rated the alliance after each session. Patients rated worry after each session, and their distress multiple times. RESULTS: As predicted, dyadic multilevel modeling revealed that early alliance convergence was associated with greater subsequent worry (p = .03) and distress (p = .01) reduction, and the combination of low initial patient-rated alliance and low convergence was associated with the worst outcome for the distress variable (p = .04). CONCLUSIONS: Results suggest that alliance convergence may be an important clinical process that bears on outcome, rendering it an important marker for therapist responsiveness. PMID- 28355974 TI - Microbial alginate dressings show improved binding capacity for pathophysiological factors in chronic wounds compared to commercial alginate dressings of marine origin. AB - Marine alginates are well established in wound management. Compared with different modern wound dressings, marine alginates cannot prove superior effects on wound healing. Alginates from bacteria have never been studied for medical applications so far, although the microbial polymer raises expectations for improved binding of wound factors because of its unique O-acetylation. Due to its possible positive effects on wound healing, alginates from bacteria might be a superior future medical product for clinical use. To prove the binding capacity of microbial alginates to pathophysiological factors in chronic wounds, we processed microbial alginate fibres, produced from fermentation of the soil bacterium Azotobacter vinelandii ATCC 9046, into needle web dressings and compared them with commercial dressings made of marine alginate. Four dressings were assessed: Marine alginate dressings containing either ionic silver or zinc/manganese/calcium, and microbial alginate dressings with and without nanosilver. All dressings were tested in an in vitro approach for influence on chronic wound parameters such as elastase, matrix metalloproteases-2, tumour necrosis factor-alpha, interleukin-8, and free radical formation. Despite the alginate origin or addition of antimicrobials, all dressings were able to reduce the concentration of the proinflammatory cytokines TNF-alpha and IL-8. However, microbial alginate was found to bind considerable larger amounts of elastase and matrix metalloproteases-2 in contrast to the marine alginate dressings. The incorporation of zinc, silver or nanosilver into alginate fibres did not improve their binding capacity for proteases or cytokines. The addition of nanosilver slightly enhanced the antioxidant capacity of microbial alginate dressings, whereas the marine alginate dressing containing zinc/manganese/calcium was unable to inhibit the formation of free radicals. The enhanced binding affinity by microbial alginate of Azotobacter vinelandii to pathophysiological factors may be interesting to support optimal conditions for wound healing. PMID- 28355975 TI - The Potential of Collective Intelligence in Emergency Medicine: Pooling Medical Students' Independent Decisions Improves Diagnostic Performance. AB - BACKGROUND: Evidence suggests that pooling multiple independent diagnoses can improve diagnostic accuracy in well-defined tasks. We investigated whether this is also the case for diagnostics in emergency medicine, an ill-defined task environment where diagnostic errors are rife. METHODS: A computer simulation study was conducted based on empirical data from 2 published experimental studies. In the computer experiments, 285 medical students independently diagnosed 6 simulated patients arriving at the emergency room with dyspnea. Participants' diagnoses (n = 1,710), confidence ratings, and expertise levels were entered into a computer simulation. Virtual groups of different sizes were randomly created, and 3 collective intelligence rules (follow-the-plurality rule, follow-the-most-confident rule, and follow-the-most-senior rule) were applied to combine the independent decisions into a final diagnosis. For different group sizes, the performance levels (i.e., percentage of correct diagnoses) of the 3 collective intelligence rules were compared with each other and against the average individual accuracy. RESULTS: For all collective intelligence rules, combining independent decisions substantially increased performance relative to average individual performance. For groups of 4 or fewer, the follow-the-most confident rule outperformed the other rules; for larger groups, the follow-the plurality rule performed best. For example, combining 5 independent decisions using the follow-the-plurality rule increased diagnostic accuracy by 22 percentage points. These results were robust across case difficulty and expertise level. Limitations of the study include the use of simulated patients diagnosed by medical students. Whether results generalize to clinical practice is currently unknown. CONCLUSION: Combining independent decisions may substantially improve the quality of diagnoses in emergency medicine and may thus enhance patient safety. PMID- 28355977 TI - Physical Therapist Clinical Reasoning and Action for Individuals With Undiagnosed Lower Extremity Tumors: A Report of 3 Cases. AB - Study Design Resident's case problem. Background Although rare in the general population, bone and soft tissue tumors may be more frequently encountered in patients seeking physical therapy because of the propensity of their initial symptoms to mimic those of commonly treated musculoskeletal disorders. Screening for tumors requires the physical therapist to be attentive to unexpected findings. The purpose of this paper was to describe the clinical-reasoning and screening processes of physical therapists who facilitated the timely recognition of bone and soft tissue tumors in 3 patients referred through medical channels. Diagnosis The referral diagnoses were lumbar spinal stenosis, calcaneal bursitis, and postexcisional quadriceps weakness. When comprehensively examined, each of the patients had either atypical examination findings or failed to respond to physical therapy treatment. After the physical therapists alerted the appropriate medical providers of the examination findings, diagnoses of high-grade osteosarcoma of the pelvis, chondroma of the knee, and liposarcoma of the thigh followed. Discussion Tumors of the lower extremity can initially mimic common musculoskeletal pathology. Physical therapists must remain alert for red flags, atypical signs and symptoms, and poor responses to treatment, even when patients are referred through medical channels. Particular attention is necessary in the case of unusual symptoms in the lower extremity, where over half of primary malignant tumors occur. Level of Evidence Differential diagnosis, level 5. J Orthop Sports Phys Ther 2017;47(5):359-366. Epub 29 Mar 2017. doi:10.2519/jospt.2017.7037. PMID- 28355976 TI - On-Ice Return-to-Hockey Progression After Anterior Cruciate Ligament Reconstruction. AB - Synopsis The literature pertaining to the rehabilitation of ice hockey players seeking to return to sport after anterior cruciate ligament reconstruction (ACLR) is currently limited. The purpose of this clinical commentary was to present a criterion-based progression for return to ice hockey for athletes after ACLR. First, we review pertinent literature and provide previously published guidelines on general rehabilitation after ACLR. Then, we present a 4-phase, on-ice skating progression with objective criteria to initiate each phase. During the early on ice phase, the athlete is reintroduced to specific demands, including graded exposure to forward, backward, and crossover skating. In the intermediate on-ice phase, the emphasis shifts to developing power and introducing anticipated changes of direction within a controlled environment. During the late on-ice phase, the focus progresses to developing anaerobic endurance and introducing unanticipated changes of direction, but still without other players or contact. Finally, once objective return-to-sport criteria are met, noncontact team drills, outnumbered and even-numbered drills, practices, scrimmages, and games are progressively reintroduced during the return-to-sport phase. Recommendations for off-ice strength and conditioning exercises complement the on-ice progression. Additionally, we apply the return-to-hockey progression framework to a case report of a female collegiate defensive ice hockey player who returned to sport successfully after ACLR. This criterion-based return-to-hockey progression may guide rehabilitation specialists managing athletes returning to ice hockey after ACLR. J Orthop Sports Phys Ther 2017;47(5):324-333. Epub 29 Mar 2017. doi:10.2519/jospt.2017.7245. PMID- 28355978 TI - Limb Symmetry Indexes Can Overestimate Knee Function After Anterior Cruciate Ligament Injury. AB - Study Design Prospective cohort. Background The high risk of second anterior cruciate ligament (ACL) injuries after return to sport highlights the importance of return-to-sport decision making. Objective return-to-sport criteria frequently use limb symmetry indexes (LSIs) to quantify quadriceps strength and hop scores. Whether using the uninvolved limb in LSIs is optimal is unknown. Objectives To evaluate the uninvolved limb as a reference standard for LSIs utilized in return to-sport testing and its relationship with second ACL injury rates. Methods Seventy athletes completed quadriceps strength and 4 single-leg hop tests before anterior cruciate ligament reconstruction (ACLR) and 6 months after ACLR. Limb symmetry indexes for each test compared involved-limb measures at 6 months to uninvolved-limb measures at 6 months. Estimated preinjury capacity (EPIC) levels for each test compared involved-limb measures at 6 months to uninvolved-limb measures before ACLR. Second ACL injuries were tracked for a minimum follow-up of 2 years after ACLR. Results Forty (57.1%) patients achieved 90% LSIs for quadriceps strength and all hop tests. Only 20 (28.6%) patients met 90% EPIC levels (comparing the involved limb at 6 months after ACLR to the uninvolved limb before ACLR) for quadriceps strength and all hop tests. Twenty-four (34.3%) patients who achieved 90% LSIs for all measures 6 months after ACLR did not achieve 90% EPIC levels for all measures. Estimated preinjury capacity levels were more sensitive than LSIs in predicting second ACL injuries (LSIs, 0.273; 95% confidence interval [CI]: 0.010, 0.566 and EPIC, 0.818; 95% CI: 0.523, 0.949). Conclusion Limb symmetry indexes frequently overestimate knee function after ACLR and may be related to second ACL injury risk. These findings raise concern about whether the variable ACL return-to-sport criteria utilized in current clinical practice are stringent enough to achieve safe and successful return to sport. Level of Evidence Prognosis, 2b. J Orthop Sports Phys Ther 2017;47(5):334-338. Epub 29 Mar 2017. doi:10.2519/jospt.2017.7285. PMID- 28355979 TI - Longitudinal Monitoring of Patients With Chronic Low Back Pain During Physical Therapy Treatment Using the STarT Back Screening Tool. AB - Study Design Preplanned secondary analysis of a randomized clinical trial. Background The STarT Back Screening Tool (SBST) was developed to screen and to classify patients with low back pain into subgroups for the risk of having a poor prognosis. However, this classification at baseline does not take into account variables that can influence the prognosis during treatment or over time. Objectives (1) To investigate the changes in risk subgroup measured by the SBST over a period of 6 months, and (2) to assess the long-term predictive ability of the SBST when administered at different time points. Methods Patients with chronic nonspecific low back pain (n = 148) receiving physical therapy care as part of a randomized trial were analyzed. Pain intensity, disability, global perceived effect, and the SBST were collected at baseline, 5 weeks, 3 months, and 6 months. Changes in SBST risk classification were calculated. Hierarchical linear regression models adjusted for potential confounders were built to analyze the predictive capabilities of the SBST when administered at different time points. Results A large proportion of patients (60.8%) changed their risk subgroup after receiving physical therapy care. The SBST improved the prediction for all 6-month outcomes when using the 5-week risk subgroup and the difference between baseline and 5-week subgroup, after controlling for potential confounders. The SBST at baseline did not improve the predictive ability of the models after adjusting for confounders. Conclusion This study shows that many patients change SBST risk subgroup after receiving physical therapy care, and that the predictive ability of the SBST in patients with chronic low back pain increases when administered at different time points. Level of Evidence Prognosis, 2b. J Orthop Sports Phys Ther 2017;47(5):314-323. Epub 29 Mar 2017. doi:10.2519/jospt.2017.7199. PMID- 28355980 TI - Star Excursion Balance Test Anterior Asymmetry Is Associated With Injury Status in Division I Collegiate Athletes. AB - Study Design Retrospective cohort. Background Star Excursion Balance Test (SEBT) performance differs by sport in healthy collegiate athletes, and lower extremity injury rates also vary by sport, sex, and athletic exposure. The relationship between SEBT performance and injury risk has not been evaluated with consideration of these additional variables, which may be necessary to fully describe the relationship between SEBT performance and injury risk. Objectives To assess the association between preseason SEBT performance and noncontact injury occurrence to the knee or ankle in Division I collegiate athletes when controlling for sport, sex, and athletic exposure. Methods Star Excursion Balance Test performance, starting status, and injury status were reviewed retrospectively in National Collegiate Athletic Association Division I collegiate athletes from a single institution. A total of 147 athletes were healthy at the time of preseason SEBT testing and either remained healthy (n = 118) or sustained a noncontact injury to the knee or ankle (n = 29) during their sport's subsequent competitive season. Side-to-side asymmetries were calculated in each direction as the absolute difference in reach distance between limbs. Star Excursion Balance Test reach distances and asymmetries were compared between groups using multivariable regression, controlling for sport, sex, and athletic exposure (starter, nonstarter). Receiver operating characteristic curves were used to determine optimal sensitivity and specificity for significant models. Results When controlling for sport, sex, and athletic exposure, SEBT side-to-side asymmetry in the anterior direction, expressed as an absolute or normalized to limb length, discriminated between injured and noninjured athletes (area under the curve greater than 0.82). Conclusion Assessing side-to-side reach asymmetry in the anterior direction of the SEBT may assist in identifying collegiate athletes who are at risk for sustaining noncontact injuries to the knee or ankle. Level of Evidence Prognosis, level 2b. J Orthop Sports Phys Ther 2017;47(5):339 346. Epub 29 Mar 2017. doi:10.2519/jospt.2017.6974. PMID- 28355981 TI - Risk of Recurrence of Low Back Pain: A Systematic Review. AB - Study Design Systematic review. Background While most people with acute low back pain (LBP) recover quickly, recurrences are believed to be common. To our knowledge, no published high-quality systematic review has assessed the risk of recurrent LBP or the factors that would predict LBP recurrence. Objectives The aim of this study was to investigate the risk of, and prognostic factors for, a recurrence of LBP in patients who have recovered from a previous episode of LBP within the last year. Methods Systematic searches were conducted in the MEDLINE, Embase, and CINAHL databases. We included longitudinal studies of adults who had recovered from a previous episode of LBP within 12 months. The primary outcome was a new episode of LBP. Secondary outcomes were other types of recurrence (eg, episodes causing care seeking). Results Eight studies were included in the review: 7 observational studies and 1 randomized trial (2 publications). Six studies reported recurrence proportions for the primary outcome of an episode of LBP. Meta-analysis was not conducted due to the low quality and heterogeneity of studies. Only 1 study was considered an inception cohort study; it reported a 1 year recurrence proportion of 33%. A history of previous episodes of LBP prior to the most recent episode was the only factor that consistently predicted recurrence of LBP. Conclusion The available research does not provide robust estimates of the risk of LBP recurrence and provides little information about factors that predict recurrence in people recently recovered from an episode of LBP. Level of Evidence Prognosis, 1a-. Prospectively registered in PROSPERO on February 9, 2016 (CRD42016030220). J Orthop Sports Phys Ther 2017;47(5):305-313. Epub 29 Mar 2017. doi:10.2519/jospt.2017.7415. PMID- 28355982 TI - Low copy numbers of FCGR3A and FCGR3B associated with Chinese patients with SLE and AASV. AB - Low-affinity Fcgamma receptors (FcgammaR) act as key mediators of the pathogenic effects of autoantibodies. In this study, we aimed to determine whether copy number variations (CNVs) in FCGR3A and FCGR3B were associated with systemic lupus nephritis (SLE) and ANCA-associated systemic vasculitis (AASV) in Chinese individuals. A total of 1118 individuals were enrolled, including 415 SLE patients, 139 AASV patients, and 564 healthy controls. FCGR3A and FCGR3B copy numbers (CNs) were determined by both a paralogue ratio test and TaqMan quantitative PCR assay. In the susceptibility associations, a low FCGR3B CN was significantly associated with SLE ( p = 5.01 * 10-3; odds ratio (OR) 1.71; 95% confidence interval (CI) 1.17-2.48) and AASV ( p = 0.04; OR = 1.72; 95% CI 1.02 2.88). A low FCGR3A CN was also significantly associated with SLE ( p = 6.02 * 10 3; OR 2.72; 95% CI 1.30-5.71) and AASV ( p = 0.042; OR 2.64; 95% CI 1.00-6.93). Further subphenotype analysis revealed that low CNs of FCGR3A and FCGR3B were significantly associated with clinical manifestations in SLE and AASV patients. Therefore, in this case-control study, we identified low CNs of FCGR2A and FCGR3B to be common risk factors for SLE and AASV. PMID- 28355983 TI - Mesenteric inflammatory veno-occlusive disease of the spleen metasynchronous with two arterial thrombotic events in systemic lupus erythematosus. AB - Vasculitides, particularly those affecting small vessels, are known to complicate systemic lupus erythematosus (SLE); however, isolated venulitis of the mesenteric bed has rarely been reported. Here we relate the case of a 46-year-old woman with SLE who presented with acute abdominal pain due to artery thrombosis and extended splenic ischemia requiring splenectomy. The histological examination revealed diffuse venulitis in the absence of arterial vasculitis consistent with the definition of mesenteric inflammatory veno-occlusive disease (MIVOD). Furthermore, arterial wall thickening suggestive of uncomplicated atherosclerosis was observed. Two months later, the patient suffered of severe myocardial infarction (MI) resulting from thrombosis of the anterior interventricular coronary artery with otherwise no signs of coronary disease at coronarography. Extensive work-up to establish the cause of MI was negative, with the exception of marginal, isolated and transient elevation of cardiolipin IgG (14.5 GPL, n.v. 0-5 GPL). This patient's SLE history is dramatically marked by the previously non described association of MIVOD and two arterial thrombotic events (splenic and coronary) occurring within a two months period, and stresses the need of better understanding and prevention of vascular complications in SLE. PMID- 28355984 TI - Hydroxychloroquine-induced hyperpigmentation in systemic diseases: prevalence, clinical features and risk factors: a cross-sectional study of 41 cases. AB - Introduction Hydroxychloroquine is an antimalarial agent widely prescribed in internal medicine, rheumatology and dermatology. Its use can be complicated by various side effects including skin pigmentation. Objectives The aim of the study is to review epidemiological, clinical features and risk factors of hydroxychloroquine-induced pigmentation. Materials and methods We performed a cross-sectional study conducted over a period of 5 months. During this period, patients who had been treated with hydroxychloroquine for over 6 months, in the internal medicine department, underwent a complete dermatological examination. All patients completed a structured questionnaire to collect demographic data, dosage and treatment duration of hydroxychloroquine, other drug intake, hydroxychloroquine indication, and presence of pigmentary changes on the skin, nail, hair, and mucosa. Results A total of 41 patients (38 women and 3 men) were included in the study. The mean age was 39.2 +/- 15.4 years. The hydroxychloroquine was indicated for systemic lupus erythematosus in 73.2%, dermatomyositis in 12.2%, rheumatoid arthritis in 9.8%, actinic lichen and sarcoidosis each in 2.4%. Cutaneous pigmented lesions were found in 21 cases (51%), mucous pigmentation in 5 cases (12%) and nail pigmentation in 1 case (2.5%). In 12 of 41 (29%) of the hydroxychloroquine users, we conclude a hydroxychloroquine-induced pigmentation. There were 11 women and one man with a mean age of 43 years and all of them were systemic lupus erythematosus patients. Pigmented lesions were located on the lower limbs in seven cases, the face in two cases, lips in two cases and the gum in two cases. Pigmentation appeared after a median duration of hydroxychloroquine treatment of 32 months with a median cumulative dose of 361 g. Overall, two patients reported that the appearance of pigmented lesions was preceded by the occurrence of ecchymotic areas following microtrauma. Significant association was found between hydroxychloroquine-induced pigmentation and treatment with oral anticoagulants and/or antiplatelet agents ( p = 0.03). Conclusion Our systematic examination of patients demonstrated that hydroxychloroquine-induced pigmentation is not rare. The imputability of hydroxychloroquine in the genesis of this discoloration is difficult to establish. Our study supports the hypothesis that ecchymosis, platelet antiaggregants and oral anticoagulants may be the main predisposing factors to hydroxychloroquine-induced pigmentation. PMID- 28355985 TI - Cessation of oral anticoagulants in antiphospholipid syndrome. AB - Objective To study the outcome of patients with antiphospholipid syndrome (APS) after oral anticoagulant treatment cessation. Methods We performed a retrospective study of patients with APS experiencing cessation of oral anticoagulant and enrolled in a French multicentre observational cohort between January 2014 and January 2016. The main outcome was the occurrence of recurrent thrombotic event after oral anticoagulation cessation. Results Forty four APS patients interrupted oral anticoagulation. The median age was 43 (27-56) years. The median duration of anticoagulation was 21 (9-118) months. Main causes of oral anticoagulant treatment cessation were switch from vitamin K antagonists to aspirin in 15 patients, prolonged disappearance of antiphospholipid antibodies in ten, bleeding complications in nine and a poor therapeutic adherence in six. Eleven (25%) patients developed a recurrent thrombotic event after oral anticoagulation cessation, including three catastrophic APS and one death due to lower limb ischemia. Antihypertensive treatment required at time of oral anticoagulants cessation seems to be an important factor associated with recurrent thrombosis after oral anticoagulant cessation (15.2% in patients with no relapse versus 45.5% in patients with recurrent thrombosis, p = 0.038). Oral anticoagulant treatment was re-started in 18 (40.9%) patients. Conclusion The risk of a new thrombotic event in APS patients who stopped their anticoagulation is high, even in those who showed a long lasting disappearance of antiphospholipid antibodies. Except for the presence of treated hypertension, this study did not find a particular clinical or biological phenotype for APS patients who relapsed after anticoagulation cessation. Any stopping of anticoagulant in such patients should be done with caution. PMID- 28355986 TI - Retinal vasculopathy in patients with systemic lupus erythematosus. AB - A retrospective case control study was conducted in the Peking Union Medical College Hospital. Medical records were reviewed for demographic data, clinical features, laboratory results, systemic lupus erythematosus (SLE) disease activity evaluations, and ophthalmic examinations to investigate the clinical characteristics and significance of retinal vasculopathy (RV) in Chinese patients with systemic lupus erythematosus. The prevalence of RV was approximately 0.66% (35/5298) in SLE patients. A total of 60 eyes were involved. The ocular presentations included decrease of visual acuity (48/60, 80%), visual field loss (7/60, 11.7%), and diplopia (3/60, 5%). Ophthalmic fundoscopic examination revealed cotton-wool spots (30/60, 50%), retinal vascular attenuation (31/60, 51.6%), and hemorrhages (41/60, 68.3%). Retinal angiogram showed that 72.7% (16/22) eyes had vaso-occlusion. The ophthalmic episodes could occur at any stage of SLE duration, with a median of 12 months (0-168 months) following SLE onset. Twenty-one (35%) eyes did not recover, or even worsened, during hospital stay. RV was found to be significantly associated with neuropsychiatric lesions (51.4% vs. 21.3%, p = .005) and hematological disturbance (62.9% vs. 34.3%, p = .005). SLE patients with RV had significantly higher SLE disease activity index scores than controls (19.9 +/- 0.9 vs. 10.2 +/- 0.7, p < .001). An inverse association of anti-SSA antibody with RV was detected (34.3% vs. 67.1%, p = .001). Nervous system disturbance (odds ratio (OR) = 4.340, 95% confidence interval (CI) 1.438, 13.094, p = .009) and leukocytopenia (OR = 6.385, 95% CI 1.916, 21.278, p = .003) were independent risk factors, while anti-SSA antibody positivity (OR = 0.249, 95% CI 0.087, 0.710, p = .009) was a protective factor for RV in SLE patients. In certain cases, RV is a threatening condition for SLE patients presenting with clinical ocular manifestations. Ophthalmo-fundoscopic detection is recommended as soon as SLE is diagnosed. PMID- 28355987 TI - Acute acalculous cholecystitis in patients with systemic lupus erythematosus: A unique form of disease flare. AB - Objective We aimed to investigate the clinical features of acute acalculous cholecystitis (AAC) in patients with systemic lupus erythematosus (SLE). Methods SLE patients with AAC hospitalized in the Peking Union Medical College Hospital (PUMCH) from January 2001 to September 2015 were retrospectively analyzed. Their medical records were systematically reviewed. The diagnosis of AAC was based on clinical manifestations and confirmed by radiologic findings including a distended gallbladder with thickened wall, pericholecystic fluid and absence of gallstones. Results Among the 8411 hospitalized SLE patients in PUMCH, 13 (0.15%) were identified to have SLE-AAC. Eleven (84.6%) of them were female, with a mean age of 30.1 +/- 8.6 years. AAC was the initial manifestation of SLE in four (30.8%) cases. Eleven (84.6%) patients complained of fever and abdominal pain, four (30.8%) had positive Murphy's sign and six (46.2%) had elevated liver enzymes. The median SLE Disease Activity Index was 8.0 (range 0-20.0) at the time of AAC. Other affected organs in SLE-AAC included kidney (11, 84.6%) and hematologic system (11, 84.6%), followed by mucocutaneous (seven, 53.8%), musculoskeletal (seven, 53.8%) and neuropsychiatric (two, 15.4%) systems. All patients received treatment of glucocorticoids and immunosuppressants but none underwent surgical intervention. During a median follow-up of 28 months (range, 2 320 months), 12 cases (92.4%) responded to treatment with no relapse and one patient (7.6%) died of septic shock. Conclusion Our study suggests that AAC is a relatively uncommon and underestimated gastrointestinal involvement of SLE that is often associated with active disease. For patients with AAC in SLE, treatment with aggressive glucocorticoids could result in a good prognosis. PMID- 28355988 TI - Direct oral anticoagulants: an alternative treatment for thrombotic antiphospholipid syndrome? AB - Background Direct oral anticoagulants (DOACs) demonstrate a lower risk-benefit ratio than vitamin K antagonists (VKAs) for secondary thromboprophylaxis of thrombotic events. But there are no data on the efficacy of DOACs for the prevention of thrombotic recurrence in patients with antiphospholipid syndrome (APS). In this study, we evaluated the efficacy of DOACs to prevent recurrences of thrombotic events in patients with APS. Methods This was a single-center pilot, using a multi-step Fleming design. If seven or fewer patients presented treatment failure with rivaroxaban, the study could conclude efficacy. Results A total of 23 patients were included. APS involved the veins only ( n = 19), arteries only ( n = 2) or both ( n = 1) and 1 patient exhibited catastrophic antiphospholipid syndrome (CAPS). Overall, two patients were positive for lupus anticoagulant, anti-beta-2 glycoprotein I antibodies and anticardiolipid antibodies (triple positivity). The mean duration of follow up was 35.6 (range, 29-40) months. A total of six treatment failures were reported: one patient, with triple positivity, developed bilateral distal pulmonary embolism (PE) after 20 months of treatment with rivaroxaban, two patients refused to take rivaroxaban, the treatment was stopped in three other patients: two with adverse effects and one with chronic iron-deficiency anemia. Conclusions Rivaroxaban may represent an alternative for secondary thromboprophylaxis for thrombo-embolism in patients with APS, in particular, those with poor international normalized ratio (INR) control and those who are not at the highest risk of recurrent thrombosis, such as those with triple positivity. PMID- 28355989 TI - Reduced volumes of the CA1 and CA4-dentate gyrus hippocampal subfields in systemic lupus erythematosus. AB - Introduction There is evidence for hippocampal dysfunctions in systemic lupus erythematosus (SLE), which may contribute to neuropsychiatric impairments. However, fine structural alterations of the hippocampus have not been investigated in SLE. Methods We measured the volume of hippocampal subfields in 18 SLE patients and 20 healthy control individuals matched for age, gender, and education. The MRI protocol included structural T1 volumes (Philips Achieva 3T scanner, magnetization-prepared rapid acquisition gradient echo (MPRAGE)). For image processing, we used the neuGRID platform and the longitudinal pipeline of FreeSurfer v6.0 with the "hipposubfields" flag. Results Patients with SLE showed reduced volumes of CA1 (Cornu Ammonis 1) and CA4-dentate gyrus subfields relative to the control individuals. Smaller CA1 volumes were associated with worse performance on the Addenbrooke's Cognitive Examination. Conclusions These preliminary results indicate a prominent vulnerability and functional relevance of the CA1 hippocampal subfield in SLE. PMID- 28355990 TI - Active elbow flexion is possible in C4 quadriplegia using hybrid assistive limb (HAL(r)) technology: A case study. AB - CONTEXT: Patients with complete quadriplegia after high cervical spinal cord injury are fully dependent with activities of daily living. Assistive technology can improve their quality of life. We examined the use of a hybrid assistive limb for single joints (HAL-SJ) in a 19-year-old man with complete C4 quadriplegia due to chronic spinal cord injury to restore function of active elbow flexion. This is the first report on the use of the HAL-SJ in a patient with spinal cord injury. FINDINGS: The HAL-SJ intervention for each elbow was administered in 10 sessions. Clinical assessment using surface EMG was conducted to evaluate muscle activity of the trapezius, biceps brachii, infraspinatus, and triceps brachii muscle before, and during the 2nd, 3rd, 6th, and 9th interventions. Surface electromyography (EMG) before intervention showed no contraction in the upper arms, but in the bilateral trapezius. The HAL-SJ used motion intention from the right trapezius for activation. After the 6th and 7th session, respectively, biceps EMG showed that voluntary contraction and right elbow flexion could be performed by motion intention from the right biceps. After the 10th session, voluntary bicep contraction was possible. HAL-SJ treatment on the left elbow was performed using the same protocol with a similar outcome. After completing treatment on both upper extremities, both biceps contracted voluntarily, and he could operate a standard wheelchair for a short distance independently. CONCLUSION: HAL-SJ intervention is feasible and effective in restoring elbow flexor function in a patient with C4 chronic spinal cord injury and complete quadriplegia. PMID- 28355992 TI - A Qualitative Systematic Review of the Bereavement Process Following Suicide. AB - Despite the fact that a large number of people are bereaved by suicide each year, the experiences of those bereaved by suicide are poorly understood. It has been suggested that a contributing factor in relation to this lack of understanding has been the use of quantitative methods, which may not be sensitive to the bereavement process and its thematic content. Therefore, the current article outlines a systematic review of 11 qualitative studies that address issues related to the bereavement process following suicide. The results indicate that those bereaved by suicide encounter a range of difficult feelings following suicide including blame, guilt, and emptiness and that these feelings are affected by participants' ability to make meaning of the event. The meaning making process is a complex one that occurs within a difficult social context in which both those bereaved by suicide and members of the wider community struggle to interact with each other in a beneficial way. Clinical implications of these findings are discussed. PMID- 28355991 TI - Cautioning Health-Care Professionals. AB - Science and practice seem deeply stuck in the so-called stage theory of grief. Health-care professionals continue to "prescribe" stages. Basically, this perspective endorses the idea that bereaved people go through a set pattern of specific reactions over time following the death of a loved one. It has frequently been interpreted prescriptively, as a progression that bereaved persons must follow in order to adapt to loss. It is of paramount importance to assess stage theory, not least in view of the current status of the maladaptive "persistent complex bereavement-related disorder" as a category for further research in DSM-5. We therefore review the status and value of this approach. It has remained hugely influential among researchers as well as practitioners across recent decades, but there has also been forceful opposition. Major concerns include the absence of sound empirical evidence, conceptual clarity, or explanatory potential. It lacks practical utility for the design or allocation of treatment services, and it does not help identification of those at risk or with complications in the grieving process. Most disturbingly, the expectation that bereaved persons will, even should, go through stages of grieving can be harmful to those who do not. Following such lines of reasoning, we argue that stage theory should be discarded by all concerned (including bereaved persons themselves); at best, it should be relegated to the realms of history. There are alternative models that better represent grieving processes. We develop guidelines to enhance such a move beyond the stage approach in both theory and practice. PMID- 28355993 TI - "Our Only Child Has Died"-A Study of Bereaved Older Chinese Parents. AB - Long and complicated grief is a relevant factor contributing to the deterioration of the older adults' later life quality. In China, the unintentional consequence of the one-child policy has emerged. There, the group of older adults who lost their only child is called shiduers. The current study compared 42 older adults who lost their only child to 33 older adults who have a child, in term of their physical and mental health, and social support. The results confirmed the general deteriorating trend in those aspects of the bereaved Chinese parents' life after their only child's death. The results also revealed the impairments on the shiduers' physical, mental, and social aspects were significant, compared to the clinical diagnosis cutoff points used in Western countries. Unique policy and cultural characteristics are the main factors contributing to the severe impairment of shiduers. Results have implications for policy advocacy and practice intervention in specific cultural environments. PMID- 28355995 TI - New Advances in Infant Feeding: New Products and Novel Technologies. AB - BACKGROUND: Breastfeeding is the best way to provide ideal food for infants. However, there are many situations in which breastfeeding is unviable (maternal illness, hygiene problems, intravenous feeding requirement, storage). Safe, efficient, and nutritious products should be offered by the industry to mothers and healthcare professionals as an alternative. OBJECTIVE: The present review aims to update the state of the art regarding the most innovative developments in infant feeding formulation and, the promising novel technologies that are being investigated to achieve a balance between the microbiological stability, organoleptic and nutritional value of baby food. METHODS: The research lines included in the present systematic review are focused on both, the most innovative ingredients and emergent technologies applied increasing the offer of tailor-made nutritional profiled products with improved quality and safety. RESULTS: According to the reviewed research and recently published patents the current emergence of a new generation of infant products is remarkable, with specific product lines aimed at infants at different stages of development and affected by several disorders (low-weight babies, premature neonates, allergenic patients), with special emphasis on the application of novel technologies (e.g. High Hydrostatic Pressure (HHP) and microencapsulation) as potential techniques to ensure the microbiological safety of developed products, and the improvement of their nutritional value, complementary to the addition of functional ingredients, such as omega 3 and 6 fatty acids, amino acids, prebiotics and probiotics, and medicinal herb supplementation (e.g. lemon balm, royal jelly). CONCLUSION: The present research work provides a general view of recent advances in infant products processing and formulation focusing on the technological effects and quality/safety developments. PMID- 28355994 TI - College Student Adjustment and Coping. AB - The present study examined the coping-related predictors of four domains of college adjustment (i.e., academic, social, personal or emotional, and institutional attachment) for bereaved and nonbereaved students ( N = 225). Findings indicated that support from friends was positively associated with academic and social adjustment and institutional attachment and that avoidant emotional-focused coping was negatively associated with all domains of adjustment for both bereaved and nonbereaved students. Interaction effects indicated that institutional attachment was lower at high levels of problem-focused coping for bereaved students and that bereaved students exhibited lower levels of both social adjustment and institutional attachment at low levels of family support, whereas nonbereaved students exhibited lower social adjustment at high levels of family support. Directions for future research and implications for practice and higher education policy are offered. PMID- 28355996 TI - Environmentally Responsive Systems for Drug Delivery. AB - BACKGROUND: In recent decades, the development of the environmentally responsive systems for drug delivery has been well regarded, with enormous potential in different applications.

Methods: These environmentally sensitive, smart, intelligent formulations have the ability to alter their physical properties in response to small changes in physical or chemical conditions, such as temperature, glucose, pH, ultrasound, light, electric field and redox potential with a huge potential in drug delivery systems. The use of formulations containing smart materials enables to carry the drug to the target tissue, cells and release in a triggered way. Consequently, they have demonstrated several advantages like decreased dose frequency, ease of preparation and administration, prolonged release with reduced side effects, as well as, reduced costs when compared to conventional processes for industrial applications. In this sense, many patents have deposited, displaying different pharmaceutical devices using responsive systems.

Results: There are more than twenty-five patents deposited about thermoresponsive systems. Furthermore, a few number of patents within glucose responsive, ultrasound responsive and light responsive deposited. There also are about eight patents that are pH-responsive, four as electric-field responsive. Most of them cover more than one type of stimuli.

Conclusion: Therefore, in this review, since 1975 to 2016, we have categorized, reviewed and discussed the patents, applications, pharmaceutical dosage forms, the importance and perspectives of this environmentally responsive approach as potentially useful therapeutic modality. PMID- 28355997 TI - Magnetic Nanoparticles: A Review on Stratagems of Fabrication an d its Biomedical Applications. AB - BACKGROUND: The aim of this review is to provide an insight to the underlying biomedical applications of magnetic nanoparticles (MNPs). METHODS: The most specific characteristic of MNPs is their response to an applied magnetic force, and this property of MNPs has been utilized in applications such as diagnosis of diseases, drug delivery and drug targeting. Currently, MNPs have attracted great attention because of their potential as contrast agents for magnetic resonance imaging (MRI) and heat mediators for cancer therapy (hyperthermia). RESULTS: Furthermore, the MNPs are also being used to achieve targeted delivery of biological molecules. Nowadays cancer is one of the biggest challenges and our goal is not only to improve the therapeutic outcome, but also to improve the methods of treatment along with the minimum adverse effect. Some suitable conclusions have been quoted on the precise synthesis approaches by focusing the mechanism of MNPs and new modification made on the production of these nanoparticles. CONCLUSION: In this review diverse biomedical application of MNPs were also addressed and patents related remarks also made from the literature. PMID- 28355999 TI - Can Ligands of Different Functional Types Induce Distinct Dynamics in G Protein Coupled Receptors? AB - G Protein-Coupled Receptors (GPCRs) are the most common therapeutic targets for drug discovery by the pharmaceutical industries. Since 2007, several three dimensional X-ray crystallographic structures of ligand-activated GPCRs have been determined in their agonist-bound or inverse agonist-bound states, providing a wealth of fundamental resources for the investigation of the atomic-level mechanism of receptor activation and deactivation. A number of computational methods, such as conventional and enhanced sampling Molecular Dynamic (MD) simulations have been applied to investigate the receptor dynamics bound with ligands of different functional types (i.e., agonist and inverse agonist). In this article, we reviewed recent efforts in characterizing the dynamical activation and deactivation mechanisms of GPCRs induced by different functional types of ligands. PMID- 28355998 TI - Bioactive Molecule-loaded Drug Delivery Systems to Optimize Bone Tissue Repair. AB - Bioactive molecules such as peptides and proteins can optimize the repair of bone tissue; however, the results are often unpredictable when administered alone, owing to their short biological half-life and instability. Thus, the development of bioactive molecule-loaded drug delivery systems (DDS) to repair bone tissue has been the subject of intense research. DDS can optimize the repair of bone tissue owing to their physicochemical properties, which improve cellular interactions and enable the incorporation and prolonged release of bioactive molecules. These characteristics are fundamental to favor bone tissue homeostasis, since the biological activity of these factors depends on how accessible they are to the cell. Considering the importance of these DDS, this review aims to present relevant information on DDS when loaded with osteogenic growth peptide and bone morphogenetic protein. These are bioactive molecules that are capable of modulating the differentiation and proliferation of mesenchymal cells in bone tissue cells. Moreover, we will present different approaches using these peptide and protein-loaded DDS, such as synthetic membranes and scaffolds for bone regeneration, synthetic grafts, bone cements, liposomes, and micelles, which aim at improving the therapeutic effectiveness, and we will compare their advantages with commercial systems. PMID- 28356000 TI - New Achievements in Bioinformatics Prediction of Post Translational Modification of Proteins. AB - Post translational modification (PTM) is one of the critical levels in regulation of gene expression that determines the fate of proteins after translation in eukaryotic cells. Since the detection of PTM sites in proteins is useful for diagnosis and prevention of diseases, numerous web-tool predictors are introduced to predict various types of PTMs. In this paper, an attempt is made to summarize a number of server predictors for the prediction of PTM sites. PMID- 28356001 TI - Atomoxetine Protects Against NMDA Receptor-mediated Hippocampal Neuronal Death Following Transient Global Cerebral Ischemia. AB - BACKGROUND: Atomoxetine has been widely used for the treatment of attention deficit/ hyperactivity disorder. ATX has additional abilities such as antagonistic effects on the N-methyl-Daspartate receptors (NMDARs) and benefit effects in some animal models of neurological disorders. However, there were few studies regarding protective effects and related mechanisms of ATX against cerebral ischemic insults. OBJECTIVE: The objective of this study is to investigate neuroprotection of ATX pretreatment and its mechanisms in the hippocampal cornu ammonis 1 (CA1) region following transient global cerebral ischemia in gerbils. METHOD: Gerbils were subjected to transient global cerebral ischemia induced by the occlusion of common carotid arteries for 5 min. Thirty mg/kg of ATX was administrated intraperitoneally once daily for 3 days before ischemic surgery. To examine neuroprotective effects of ATX, we carried out neuronal nuclear antigen immunohistochemistry and Fluoro-Jade B histofluorescence staining. In addition, immunoreactivities of NMDAR1, NMDAR2A/B, B-cell lymphoma 2 (Bcl-2) and Bcl-2- associated X protein (Bax) are closely related with neuroexcitotoxicity. RESULTS: ATX pretreatment reduced ischemia-induced hyperactivity and protected CA1 pyramidal neurons from ischemia. Pretreatment with ATX significantly attenuated ischemia-induced increases of NMDAR1 and NMDAR2A/B immunoreactivities in the CA1 pyramidal neurons at early time following ischemia. In addition, significant ischemia-induced alterations of Bcl-2 and Bax immunoreactivities were not observed in the ATX-treated group following ischemia. CONCLUSION: These results show that pretreatment with ATX protected against ischemic neuronal via inhibition of ischemia-induced excitotoxicity at early time following transient global cerebral ischemia. PMID- 28356003 TI - Young Stroke Patients Treated with Intravenous Thrombolysis have a More Favorable Outcome and Mortality Compared with Older Patients. AB - BACKGROUND: Previous clinical studies suggest that intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator benefits stroke patients, but the efficacy of IVT in young stroke patients is not well-studied in China. OBJECTIVE: We compared the safety and efficacy of IVT with recombinant tissue plasminogen activator between Chinese young stroke patients (18-50 years old) and older patients (51-80 years old). METHOD: We analyzed data from the Soochow Stroke Registry for 373 stroke patients (18-50 years, n=74 vs. 51-80 years, n=299) who received IVT between May 2009 and January 2016. Main outcomes included symptomatic intracerebral hemorrhage (sICH) within 7 days, and mortality and favorable outcome (modified Rankin scale 0-2) at 3 months. Associations between baseline characteristics and outcomes for the two groups were analyzed by logistic regression. RESULTS: Favorable outcome at 3 months was significantly higher in young adults (adjusted odds ratio 2.09; 95% confidence interval 1.09 3.99, p=0.026). The incidence of sICH and mortality was low for young adults compared with older patients, but there were no statistically significant differences between the two groups. Multivariable analysis showed that baseline National Institutes of Health Stroke Score was associated with favorable outcome (p=0.026) in young adults. CONCLUSION: Our analysis indicated that young stroke patients treated with IVT had a more favorable outcome without an increased risk of sICH and mortality compared with older patients. We conclude that IVT is safe and at least as beneficial for Chinese young adults with acute ischemic stroke compared with older patients. PMID- 28356004 TI - Post-Transcriptional and Post-translational Regulation of Central Carbon Metabolic Enzymes in Cancer. AB - Malignant transformation of cells requires specific adaptations of cellular metabolism to support growth and survival. Alterations in cancer central carbon metabolism including aerobic glycolysis, elevated glutaminolysis, dysregulated tricarboxylic acid cycle and pentose phosphate pathway, facilitate cancer development by maintaining viability and building new biomass. Although a variety of oncogenes or tumor suppressors contribute to these rewiring, accumulating evidence suggests that both post-transcriptional and post-translational modifications (PTMs) also orchestrate the tightly controlled regulation of cancer metabolic adaptations, broadening the biological mechanisms of cancer metabolic reprogramming. Micro RNA, one kind of posttranscriptional modification, mediates transcriptional silencing of various metabolic enzymes. Additional, different kinds of PTMs play important roles in cancer metabolic rewiring by affecting the function, interaction or stability of target proteins. We survey recent studies demonstrating PTMs at lysine residues and microRNAs that are involved in reprogramming of cancer central carbon metabolism, and summarize the effect of these modifications according to different parts of central carbon metabolic pathway. Moreover, we provide an updated overview of the compounds or agents targeting central carbon metabolism in cancer. Given that the heterogeneity of cancer biology, a combination of these novel therapeutics and standard chemotherapeutic agents may obtain better benefit and overcome drug resistance. Finally, this review discusses the challenges and some new steps that may further advance this field. PMID- 28356002 TI - Prognostic Parameters for Symptomatic Intracranial Hemorrhage after Intravenous Thrombolysis in Acute Ischemic Stroke in an Asian Population. AB - BACKGROUND: Symptomatic intracranial hemorrhage (sICH) is a major complication after intravenous thrombolysis leading to severe disability and death. The incidence was higher in Asian than in western countries. Prognostic factors across ethnicities are presumably different. Studies in Asian populations are limited. METHOD: Clinical data from January 2008 to September 2016 in one provincial and four regional hospitals in the northern part of Thailand were retrospectively reviewed. Patients were those with acute ischemic stroke, to whom recombinant tissue plasminogen activator (rt-PA) had been prescribed. They were classified into 3 groups; no intracranial hemorrhage (no ICH), asymptomatic intracranial hemorrhage (asICH) and symptomatic intracranial hemorrhage (sICH), based on clinical and brain imaging (computed tomography or CT). Prognostic parameters were investigated using a multi-level, multivariable ordinal logistic model. RESULTS: After exclusion of ineligible patients, the remaining 1,172 patients were classified into no ICH (n=923, 78.8%), asICH (n=154, 13.1%) and sICH (n=95, 8.1%). Independent prognostic parameters for intracranial hemorrhage were the National Institutes of Health Stroke Scale (NIHSS) >20 (OR, 3.51; 95% CI, 2.18-5.65; p<0.001), NIHSS >10 (OR, 2.02; 95% CI, 1.42-2.87; p<0.001), use of nicardipine during rt-PA (OR, 1.61; 95% CI, 1.09-2.40; p=0.018), systolic blood pressure (SBP) prior to thrombolysis >= 140 mmHg (OR, 1.47; 95% CI, 1.06-2.04; p=0.021), and platelet count <250,000 cell/mm3 (OR, 1.45; 95% CI, 1.04-2.01; p=0.029). CONCLUSION: Patients with these parameters should be closely monitored. Information should be provided to the patients and their relatives. PMID- 28356005 TI - The Oxime Derivatives of 1-R-1H-Naphtho[2,3-d][1,2,3]triazole-4,9-dione 2-oxides: Synthesis and Properties. AB - OBJECTIVE: To synthesize a novel chemotype based on the naphthoquinone scaffold with retained cytotoxicity and provisionally low intracellular oxidation potential. BACKGROUND: Derivatives of naphthoquinone, although potent anticancer agents, can exert heart toxicity due to generation of free oxygen species. METHODS: In this study, we modified the scaffold by replacing one carbonyl group with the oxime moiety. Interestingly, only one carbonyl group in 1-R-1H naphtho[2,3-d][1,2,3]triazole-4,9-dione 2-oxides reacted with hydroxylamine. The spatial structure was determined by X-ray analysis. New compounds were tested for the ability to form stable complexes with double stranded DNA by spectroscopy and molecular docking and to induce death of tumor cell lines and non-malignant counterparts. RESULTS: The resulting 1-R-1H-naphtho[2,3-d][1,2,3]triazole-4,9 dione 4-oxime 2-oxides were further acylated to produce a series of 1-R-1H naphtho[2,3-d][1,2,3]triazole-4,9-dione 4-(O-acyloxime) 2-oxides. Newly synthesized compounds demonstrated a higher (in submicromolar or low micromolar range) cytotoxic potency against human colon and breast adenocarcinoma cell lines than to non-malignant skin fibroblasts. Spectroscopic measurements revealed that, unlike other classes of quinone derivatives, new naphthotriazoledione oxides did not form stable complexes with double stranded DNA regardless of their fitting to the DNA minor groove (as determined by molecular modeling). CONCLUSION: Thus, our chemical modifications yielded a new chemotype with good cytotoxic properties and yet-to-be-identified intracellular target(s). PMID- 28356006 TI - Body Fluids-Derived Exosomes: Paving the Novel Road to Lung Cancer Diagnosis and Therapy. AB - Lung cancer is a major human malignancy. Nowadays, the lack of specific diagnostic markers of lung cancer restricts the early diagnosis and therapy of patients. Exosomes, as spherical 30-100 nm microvesicles, are released by normal and cancer cells in both physiological and pathological circumstances. Exosomes carry various molecular cargos such as miRNA, proteins, mRNA, DNA and lipids. Therefore, analysis of the molecular profiles of exosomes may provide beneficial biomarkers for disease diagnosis. Exosomes can be transported by body fluids. The molecules (miRNAs and proteins) detected in body fluid exosomes may contribute to lung cancer diagnosis. In this review, we summarize typical molecules (miRNAs and proteins) in body fluids-derived exosomes to reveal the potential biomarkers in lung cancer. Besides, the role and the application of exosomes in chemotherapy and radiotherapy of lung cancer patients have also been discussed in this review. PMID- 28356008 TI - The Evolutionary Tale and Future Directions of Aromatase Inhibitors in Breast Carcinoma. AB - Aromatase inhibitors have often been likened to that of 'medical scalpels' for the treatment of breast carcinoma. By inhibiting the singular step of aromatisation, they have proven to be extremely effective allies in the treatment of breast cancer among postmenopausal women. However, their relevance soon may not be limited to the post-menopausal age group alone. Recent studies have hinted at their utility amongst the premenopausal women; combined with ovarian ablation techniques, aromatase inhibitors may prove to be equally effective and more, as compared to tamoxifen in this age-group. Additionally, explorations aimed at ascertaining their potential utility as an effective preventive strategy against breast carcinoma have yielded encouraging results. However, for aromatase inhibitors to be able to attain their full potential, further strategic fine tuning aimed at maximising their efficacy and minimising their potentially far reaching adverse effects, is the need of the hour. Despite the recent diversification, the issue of resistance to aromatase inhibitors in breast cancer threatens to derail the advances so gained till date. Fortunately, a few novel ploys have come to the fore, for instance combining aromatase inhibitors with HER 2 antibodies that could potentially help circumvent the menace of resistance in the near future. Till date, the utility of aromatase inhibitors can at best be described as onedimensional. However, with the unearthing of potential new avenues for its application, this assortment of molecules today stands on the precipice of ushering in a new revolution in the treatment of breast carcinoma. PMID- 28356007 TI - Fluorescent Immortalized Human Adipose Derived Stromal Cells (hASCs-TS/GFP+) for Studying Cell Drug Delivery Mediated by Microvesicles. AB - BACKGROUND: A new tool for the drug delivery is based on the use of Mesenchymal Stromal Cells (MSCs) loaded in vitro with anti-cancer drugs. Unfortunately, the restricted lifespan of MSCs represents a significant limitation to produce them in high amounts and for long time studies. Immortalized MSCs from adipose tissue (hASCs) have been generated as good source of cells with stable features. These cells could improve the development of standardized procedures for both in vitro and preclinical studies. Furthermore they facilitate procedures for preparing large amounts of secretome containing microvesicles (MVs). METHOD: We used human adipose tissue derived MSCs immortalized with hTERT+SV40 (TS) genes and transfected with GFP (hASCs-TS/GFP+). This line was investigated for its ability to uptake and release anticancer drugs. Microvesicles associated to paclitaxel (MVs/PTX) were isolated, quantified, and tested on pancreatic cancer cells. RESULTS: The line hASCs-TS/GFP+ maintained the main mesenchymal characters and was able to uptake and release, in active form, both paclitaxel and gemcitabine. From paclitaxel loaded hASCs-TS/GFP+ cells were isolated microvesicles in sufficient amount to inhibit "in vitro" the proliferation of pancreatic tumor cells. CONCLUSION: Our study suggests that human immortalized MSCs could be used for a large scale production of cells for mediated drug delivery. Moreover, the secretion of drug-associated MVs could represent a new way for producing new drug formulation by "biogenesis". In the context of the "advanced cell therapy procedure", the MVs/PTX production would use less resource and time and it could possibly contribute to simplification of GMP procedures. PMID- 28356009 TI - ECPIRM, a Potential Therapeutic Agent for Cutaneous T-Cell Lymphoma, Inhibits Cell Proliferation and Promotes Apoptosis via a JAK/STAT Pathway. AB - BACKGROUND: Retinoids are important agents for the treatment of cutaneous T-cell lymphomas (CTCL). But side effects and drug resistance caused by activation of RAR/RXR limited their clinical application. Therefore, it is urgent to develop new agents to fight against CTCL. ECPIRM, a 13-cis retinoic acid derivative, was reported that it inhibited proliferation and induced apoptosis of SCL-1 cells. OBJECTIVE: The aim of this study was to evaluate the biological activities and mechanisms of ECPIEM. METHODS: The effect of ECPIRM on cell proliferation was determined by MTT assay and Trypan blue exclusion assay while FACS analysis was used to detect changes in cell cycle and apoptosis in HUT78 cells. The influence of ECPIRM on RAR/RXR and JAK/STAT signaling was evaluated by western blot analysis. RESULTS: ECPIRM, better than other agents (all-trans retinoic acid,13 cis-retinoic acid or bexarotene), inhibited proliferation and induced apoptosis significantly in HUT78 cells, but with little cytotoxicity on normal lymphocytes. Then ECPIRM induced G0/G1 phase arrest by decreasing the expression of cyclinD1, cyclinE, CDK2 and CDK4 while increasing p21. Furthermore, the unaffected expression of RAR and RXR members suggested that ECPIRM acted independently of RAR/RXR pathway in HUT78 cells. But decreased phosphorylation of JAK1, STAT3, STAT5 and downregulated Bcl-xL, Cyclin D1 and c-Myc indicated that ECPIRM inhibited the activation of JAK/STAT signaling. CONCLUSION: ECPIRM inhibited proliferation, induced apoptosis and G0/G1 phase arrest in HUT78 cells through inhibiting JAK/STAT pathway but not RAR/RXR pathway, which presented ECPIRM as a promising candidate for the treatment of CTCL patients. PMID- 28356010 TI - The Emerging Roles of RASSF5 in Human Malignancy. AB - Ras association domain family member 5 (RASSF5, also named NORE1) is an identified member of the RASSF gene family which could bind selectively to activate Ras and function as an antineoplastic effector in multiple cellular regulations. While highly expressed in majority of normal tissues, RASSF5 is epigenetically inactivated by promoter hypermethylation in numerous cancer cell lines and primary cancers, suggesting it as a potential tumor suppressor. Nevertheless, the physiologic significance of RASSF5 in tumorigenesis remains unclear. We performed a systematic literature review and assessment from PUBMED and MEDLINE databases in this article. RASSF5 is involved in a series of cellular responses including apoptosis, senescence, cell cycle regulation, differentiation and cell proliferation and the inactivation of RASSF5 has been implicated to participate in the oncogenesis, progression and poor prognosis of human cancers. In this review, we mainly elucidate the acknowledged structure, progress in the verified functions and research advances of RASSF5 and the probably relevant signaling pathways. Based on these evidences, potentiality of RASSF5 as a new therapeutic target for human cancers may play a significant role in future oncotherapy. PMID- 28356011 TI - Thymol Elicits HCT-116 Colorectal Carcinoma Cell Death Through Induction of Oxidative Stress. AB - BACKGROUND: Colon cancer is one of the most deadly and common carcinomas occurring worldwide and there have been many attempts to treat this cancer. The present work was designed in order to evaluate thymol as a potent drug against colon cancer. MATERIALS AND METHODS: Cytotoxicity of thymol at different concentrations was evaluated against a human colon carcinoma cell line (HCT-116 cells). Fluorescent staining was carried out to evaluate the level of ROS as well as mitochondrial and DNA fragmentation and immunoblot analysis were performed to confirm apoptosis and mitoptosis. RESULTS AND CONCLUSION: Results of the study demonstrated that thymol efficiently created an oxidative stress environment inside HCT-116 cells, a colorectal carcinoma cell line, through induction of ROS production along with intense damage to DNA and mitochondria, as observed through Hoechst and rhodamine 123 staining, respectively. Moreover, expression of PARP-1, p-JNK, cytochrome-C and caspase-3 proteins was up-regulated, suggesting HCT-116 cells underwent mitoptotic cell death. Therefore, thymol could be used as a potent drug against colon cancer due to its lower toxicity and prevalence in natural medicinal plants. PMID- 28356012 TI - Synthesis of Novel Imine Stilbene Analogs Exhibiting Potent Anticancer Activity. AB - BACKGROUND: Resveratrol (RV) and its analogues Aza-stilbenes were found effective in exhibiting anticancer activity. OBJECTIVE: The present study mainly focused on the green synthesis of novel imine stilbene analogues and evaluation of their anticancer activity besides their influence on hypoxia-induced gene expression in cancer cells. METHOD: Novel imine stilbenes, differing in number and/or position of hydroxyl and methoxy functional groups, have been synthesized using green chemistry mediated condensation reaction between aldehydes and amines in the ethanolic extract of Psoralea corylifolia hairy roots and tested for their anticancer potential. RESULTS: Ethanol containing 1% hairy root extract facilitated instant reaction and yielded more than 99% product( s). MTT assay on HeLa cells treated with imine stilbene analogues revealed an increase in the inhibition of cell proliferation as compared to RV. Treatment of nontumor HEK293 cells with these compounds disclosed minimal toxicity implying the selective advantage of these compounds for cervical cancer therapy. Scratch assay on HeLa cells displayed inhibition of directional cell motility by these analogues and compound 3e [4-((E)-(4- hydroxyphenylimino)methyl)-2-methoxyphenol] recorded maximum inhibition. In reporter assay, as compared to untreated N-(2-Methoxy-2 oxoacetyl) glycine methyl ester (DMOG) induced cells, hypoxia response element- directed transcriptional activity has been significantly reduced in DMOG induced cells treated with imine stilbene analogues. CONCLUSION: Overall results indicated that four of the five imine stilbene analogues exhibited enhanced anticancer activity than that of the RV. As such, the novel synthetic compounds 3d, 3e and 3b endowed with potent anticancer activity than RV can serve as drug lead molecules. PMID- 28356013 TI - Synthesis and Cytotoxic Activities of Difluoro-Dimethoxy Chalcones. AB - BACKGROUND: Although anticancer chemotherapeutics are available in markets, side effects related to the drugs in clinical use lead to researchers to investigate new drug candidates which are more safe, potent and selective than others. Chalcones are popular with their anticancer activities with the several reported mechanisms including inhibition of angiogenesis, inhibition of tubulin polymerization, and induction of apoptosis etc. OBJECTIVE: This study was focused on to synthesize of 1-(2,4/2,6-difluorophenyl)-3-(2,3/2,4/2,5/3,4- dimethoxyphenyl)-2-propen-1-ones (1-8) and investigate their cytotoxic properties with possible mechanism of action. METHOD: The compounds were synthesized by Claisen-Schmidt condensation. The chemical structures were confirmed by 1H NMR, 13C NMR, DEPT, COSY, HMQC, HMBC, 19F NMR and HRMS. In vitro cytotoxic effects of the compounds against human tumour cell lines [gingival carcinoma (Ca9-22), oral squamous cell carcinoma (HSC-2)] and human normal oral cells [gingival fibroblasts (HGF), periodontal ligament fibroblasts (HPLF)] were evaluated via MTT test. RESULTS: All compounds had higher cytotoxicity than reference compound 5-Fluorouracil (5-FU). The compounds 3-7 had higher potency selectivity expression values (PSE) than 5-FU and PSE values of the compounds were over 100. All chalcone derivatives seem good candidates for further studies according to very remarkable and high PSE values. CONCLUSION: It was clearly demonstrated that compound 7 can induce early apoptosis at a concentration of 10 uM and dose dependent late apoptosis starting at 10 uM. Compound 7 induced cleavage of the apoptosis marker PARP. The results indicate that new chalcones reported here can promote apoptosis in human tumour cell lines. PMID- 28356014 TI - Inhibition of EGFR Signaling by N-cyclohexyl-2-(1-(phenylsulfonyl)piperidin-4-yl) acetamide. AB - BACKGROUND: The epidermal growth factor receptor (EGFR) is a driver oncogene and specific blockade of EGFR has been shown to be an effective therapeutic approach against multiple human cancers. AIMS: Here we employed the homogeneous time resolved fluorescence (HTRF) technology to screen new EGFR mediators. METHOD: 4 hits (NDS-41107, NDS-41119, NDS-41111 and NDS-41126) were confirmed in a compound library of 8000 compounds, and the IC50 values were determined to be 15.45+/ 2.25uM (NDS-41107), 6.16+/-0.88 uM (NDS-41119), 11.33+/-3.31 uM (NDS-41111) and 11.19+/-1.67uM (NDS-41126), respectively. We then showed that NDS-41119 (N cyclohexyl-2-(1-(phenylsulfonyl) piperidin-4-yl) acetamide) significantly inhibited EGFR signaling in human lung cancer cells, as evidenced by decreased phosphorylation of EGFR,ERK and Akt. NDS-41119 also attenuated EGF-induced cell proliferation and migration in a dose-dependent manner. We finally demonstrated that NDS-41119 inhibited the T790M mutation in NCI-H1975 cells and potentiated the effect of gefitinib against resistant cells. RESULT: Our results will contribute to the development of novel EGFR-targeted anti-cancer drugs. PMID- 28356015 TI - Synthesis of Phenol-derivatives and Biological Screening for Anticancer Activity. AB - BACKGROUND: Phenolic compounds are known for their cytotoxic properties against cancer cells despite their still unclear general mechanism of action. Herein is reported the evaluation of the cytotoxic effects of on human osteosarcoma cells of nine phenol derivatives against osteosarcoma cells, and some insights on their mechanism. METHOD AND RESULTS: The cytotoxicity was characterized by cell viability, scratch assay, cellular DNA content measurement, Annexin V apoptosis, mitochondrial calcium and caspase 3/7 assays. The study shows that out of the nine compounds used in this study, a tetrahydroquinoline derivative, 2-((1,2,3,4 tetrahydroquinolin-1-yl)(4- methoxyphenyl)methyl) phenol, was found to exhibit strong inhibitory response with IC50 of 50.5 +/- 3.8 uM, and therefore can be a potential chemotherapeutic agent. Further experiments revealed that this compound induces cell death by apoptosis and also act as a migration inhibitor. Analysis of the mitochondrial calcium following treatment with the compound on U2OS cells showed a significant reduction in the level of mitochondrial calcium concentration suggesting a mitochondrial calcium-independent mechanism in triggering apoptosis. Treatment of HEK293 cells with the compound confirmed the cytotoxic effects of the compound, however, an increase in the level of mitochondrial calcium was observed. Moreover, the caspase 3/7 mediated cell death was also observed in both cell types. CONCLUSION: Overall, the study suggests that the derivatives of this compound can be used for development of new therapeutics for osteosarcoma and other cancers. PMID- 28356016 TI - Tetrazole Derivatives as Promising Anticancer Agents. AB - Tetrazole cycle is a promising pharmacophore fragment frequently used in the development of novel drugs. This moiety is a stable, practically non-metabolized bioisosteric analog of carboxylic, cis-amide, and other functional groups. Over recent 10-15 years, various isomeric forms of tetrazole (NH-unsubstituted, 1H-1- substituted, and 2H-2-substituted tetrazoles) have been successfully used in the design of promising anticancer drugs. Coordination compounds of transition metals containing tetrazoles as ligands, semisynthetic tetrazolyl derivatives of natural compounds (biogenic acids, peptides, steroids, combretastatin, etc.), 5-oxo and 5 thiotetrazoles, and some other related compounds have been recognized as promising antineoplastic agents. This review presents a comprehensive analysis of modern approaches to synthesis of these tetrazole derivatives as well as their biological (anticancer) properties. The most promising structure types of tetrazoles to be used as anticancer agents have been picked out. PMID- 28356017 TI - Antitumor Activity of Copper (I)-Nicotinate Complex and Autophagy Modulation in HCC1806 Breast Cancer Cells. AB - BACKGROUND: Squamous cell cancer is a heterogeneous aggressive disease, therefore, its treatment is challenging. Increased attention has been paid to metal complexes as anticancer drugs. However, new insights towards autophagy have been recognized due to its role in tumor cell death or survival. OBJECTIVE: To clarify the antitumor activity of copper (I) nicotinate complex (CNC) as new therapeutic agent and understand the role of autophagy modulation as a prospective target for the advancement of efficient therapeutic agent for treatment. METHOD: Viability of MDA-MB-231 and HCC1806 cells and IC50 values of CNC for both cell lines were assessed by MTT assay. Also, the viability and IC50 values of Torin1 and Chloroquine (CQ) were assessed only in HCC1806 cells by MTT assay. The level of microtubule-associated protein 1 light chain 3 (LC3) was assessed by ELISA. Real time PCR was used to detect the changes in NBR1 gene expression. Cell cycle distribution and quantitative detection of acid vesicular organelles (AVOs) were determined by flow cytometry. Fluorescence microscope was used for qualitative detection of AVOs. Modulation of autophagy was carried out by Torin1 as inducer and CQ as inhibitor. RESULTS: CNC restrained the growth, in a dose-dependent manner, and induced cell death in human HCC1806 cell line. In addition, the CNC treated cells displayed inhibition of autophagy, as indicated by reduction of AVOs, decrease in LC3 protein level and up regulation of NBR1 gene expression. CONCLUSION: CNC, as an autophagy inhibitor and pro-apoptotic agent, could be a promising anti-cancer agent either alone or in combination with other therapeutic drugs. PMID- 28356019 TI - Biological Activity Evaluation of Novel 1,2,4-Triazine Derivatives Containing Thiazole/Benzothiazole Rings. AB - BACKGROUND: Triazine ring is a prominent structural motif found in some azanucleosides whose efficiency improved many times in the research area of antitumor agents. OBJECTIVE: In this study, we have designed and synthesized novel 2-[(5,6-diphenyl-1,2,4-triazin-3-yl)thio]-N-(6- substituted benzo/(thiazol) 2-yl)acetamide (2a-d, 3a-f) derivatives using 1,2,4-triazine core along with two important heterocyles, thiazole and benzothiazole rings. METHOD: The acquired ten final compounds were screened to investigate their antitumor activity against lung adenocarcinoma cell line, A549 and mouse fibroblast cell line, NIH/3T3. Five compounds with higher antiproliferative activity have been further studied to evaluate whether the cell death due to necrosis or apoptosis using flow cytometry. RESULTS AND CONCLUSION: Compound 3b bearing 6-methylbenzothiazole moiety has been established as the most active antitumor compound with a selective profile and higher apoptotic cell level. All final componds were also screened against acetylcholine/butyrylcholinesterase enzymes to state their anticholinesterase activity. PMID- 28356018 TI - Enhancement of the Effect of Methyl Pyropheophorbide-a-Mediated Photodynamic Therapy was Achieved by Increasing ROS through Inhibition of Nrf2-HO-1 or Nrf2 ABCG2 Signaling. AB - BACKGROUND: Emerging evidence indicates that the transcription factor nuclear factor-E2-related factor 2 (Nrf2) plays an essential role in cellular defense against oxidative stress; its activation has been related to cytoprotection. OBJECTIVE: Here, we investigated the role of Nrf2 in improving the efficacy of methyl pyropheophorbide-amediated photodynamic therapy (Mppa-PDT) via the downregulation of Nrf2. METHOD: Human ovarian cancer A2780 cells and SKOV3 cells were treated with Mppa-PDT and siRNA transfection was performed to inhibit Nrf2. After treated with siRNA and Mppa-PDT, the cell viability was examined with CCK-8 assay; cell apoptosis was detected tested by flow cytometry with Annexin V FITC/PI; the celluar reactive oxygen species (ROS) and mitochondrial membrane potential were measured with DCFHDA and JC-1 staining; expression of protein was assessed by western blot analysis. RESULTS: We found that Nrf2 translocated from the cytoplasm to the nucleus in vitro and in vivo, and the expression of Nrf2 and P-Nrf2 increased through a possible mechanism regulated by mitogen-activated protein kinase (MAPK) after Mppa-PDT treatment. Furthermore, cytotoxicity and apoptosis induced by Mppa-PDT increased after Nrf2down-regulation. Nrf2 down regulation increased reactive oxygen species (ROS) levels by attenuating antioxidants or pumping Mppa out of cells,which resulted from the inhibition of Nrf2-HO-1 or Nrf2- ABCG2 signaling. In addition, SKOV3 cells exhibited increased resistance to Mppa-PDT, and the expression levels of P-Nrf2 and ABCG2 were higher in SKOV3 cells than in A2780 cells, suggesting that Nrf2-ABCG2 signaling might be involved in the intrinsic resistanceto Mppa-PDT. CONCLUSION: These results provided evidence that Nrf2 down-regulation can enhance the effect of Mppa-PDT. PMID- 28356021 TI - Novel Thiourea Derivatives Bearing Sulfonamide Moiety as Anticancer Agents Through COX-2 Inhibition. AB - BACKGROUND: Thiourea derivatives bearing sulfonamide moiety are well known for their anticancer activity. OBJECTIVE: The anticancer activity of the target compounds was studied, via inhibition of COX-2 enzyme. METHOD: A series of novel thioureas 5a-n, 8, quinazoline 6, benzo[g]quinazoline 7 and benzo[1,3] dioxole 10, bearing a sulfonamide moiety was synthesized from the starting compound N (2,6-dimethoxypyrimidin-4-yl)-4- isothiocyanatobenzenesulfonamide 2. The target compounds were screened against HepG2, MCF-7, Caco-2, HCT-116, PC-3 cancer cell lines and VERO-B normal cell line. RESULTS: Out of all the tested compounds, compound 5c showed a broad selective cytotoxicity against HepG2, MCF-7, Caco-2 and PC-3 cancer cells. Moreover, a sensitization assay was performed on Caco-2 cells, and compound 5c proved to act as a chemosensitizer for cisplatin on colon cancer (Caco-2) cells. The target compounds were further screened in vitro for their anti COX1/COX2 activity and investigated in vivo as antiinflammatory agents against carrageenan-induced rat paw oedema model. CONCLUSION: Compound 5g showed the most selective inhibitory activity against COX-2. While, compounds 5a, 6, 5m, 5n, 5g and 5i revealed significant anti-inflammatory effect as presented in carrageenan-induced oedema assay. Molecular docking of the tested compounds disclosed important binding modes which may be responsible for their anticancer activity via inhibition of the COX-2 enzyme. PMID- 28356020 TI - Anti-cancer Effect of Cyanidin-3-glucoside from Mulberry via Caspase-3 Cleavage and DNA Fragmentation in vitro and in vivo. AB - BACKGROUND: Fruits of Morus alba L. (mulberry) have various bioactive compounds such as polyphenols and anthocyanins and used as a herbal medicine. However, the anti-cancer effects and molecular basis have not been elucidated. METHODS: We isolated the cyanidin-3-glucoside in various cultivar of mulberry by acidified methanol extraction methods. This molecule were compared mass spectroscopic properties by LC-MS/MS and analyzed by 1H and 13C NMR. We examined the anti cancer effect with molecular mechanisms of the cyanidin-3-glucoside on MDA-MB-453 human breast cancer cells and xenograft animal model. RESULTS: The treatment with the mulberry cyanidin-3-glucoside decreased cell viability in a dose-dependent manner with alteration of apoptotic protein contents, and DNA fragmentation, suggesting that cells undergo apoptosis. Supporting the observations, Treatment with the cyanidin-3-glucoside showed active apoptosis by caspase-3 cleavage and DNA fragmentation through Bcl-2 and Bax pathway. Indeed, cyanidin-3-glucoside inhibits tumor growth in MDA-MB-453 cells-inoculated nude mice. Tumor growth of xenograft nude mouse was significantly reduced compared to the control group by the cyanidin-3-glucoside. CONCLUSION: The data demonstrate that cyanidin-3 glucoside isolated from mulberry induced apoptosis in breast cancer (MDA-MB-453) cells, and therefore, has a potential as an anti-cancer agent. These results show that mulberry cyanidin-3-glucoside inhibit the proliferation and growth in vitro and in vivo model and, indicating the inhibition of tumor progression. PMID- 28356022 TI - Synthesis and Evaluation of Some Dibromoquinazoline-sulphonamide Hybrids and some Schiff's Base Analogs for their Cytotoxic Activity. AB - BACKGROUND: Cancer is one of the most dangerous diseases with quite a high mortality rate. Many quinazoline derivatives show potent anticancer activity. OBJECTIVE: In this work our aim is to develop novel, safe and effective anticancer agents. METHOD: New 6,8-dibromo-2-(4-chlorophenyl)-quinazoline sulphonamide hybrids and some Schiff's base analogs were synthesized, and their structures were confirmed by spectral and elemental analysis. Cytotoxicity of all synthesized compounds was evaluated on three cancer cell lines MCF7, HCT116 and HEPG2 using sulpharodamine- B assay method and doxorubicin as a reference drug. All tested compounds show promising cytotoxic activities on the three cell lines. RESULTS: Compound IXd was 2 times more active than doxorubicin on MCF7 cancer cells, while it was 3 times more potent than doxorubicin on HCT116 cancer cells. Compound IV was 2 times more active than doxorubicin while compound VI exhibited similar activity to doxorubicin on HEPG2 cell line. The most active compounds were tested against epidermal growth factor receptor tyrosine kinase (EGFR TK). Compounds IV, IXd, IXf show the most potent inhibitory percent 62.3, 91.1, 91.6 respectively. Compounds IV, V, VII, IXd, IXf caused a significant increase of CASP3 activity with range 86.5-37.6 %. CONCLUSION: The present work led to the discovery of new cytotoxic compounds having quinazoline pharmacophore. PMID- 28356023 TI - The Cross-talk between Tristetraprolin and Cytokines in Cancer. AB - Cytokines are small secreted proteins serving as vital mediators that mediate the host immune responses. Transcription and post-transcription play a critical role in cytokine expression through the regulation of message RNA (mRNA) cytoplasmic localization, translation initiation and decay. Researches have been conducted to reveal regulatory mechanisms of cytokines production in cells involved in cancer. AU-rich element (ARE) can regulate the degradation and translation of mRNA by connecting with specific ARE binding proteins. It is now clear that tristetraprolin (TTP), as the most common ARE binding protein, negatively regulates many aspects of the cytokines through binding to the AREs in the 3' untranslated region (3'UTR) of mRNA. Furthermore, some certain cytokines have an impact on TTP expression and function. Therefore, the cross-regulation between cytokines and TTP has come into sight. The complicated regulatory networks between cytokines and TTP are closely related to tumorigenesis. In this review, we summarize specific regulatory mechanisms of cytokine mRNAs. We focus on how TTP negatively regulates inflammatory and oncogenic cytokines expression after combining with AREs, we also pay attention to some cytokines mediating the expression of TTP and their cross-talk in various cancers in detail. PMID- 28356026 TI - Volatile Inhibitors of Phosphatidylinositol-3-Kinase (PI3K) Pathway: Anticancer Potential of Aroma Compounds of Plant Essential Oils. AB - BACKGROUND: Cancer is a grave health problem for the world as the global cancer burden rises to 14 million new cases with 8.2 million deaths every year which is expected to rise by 70% in the next 2 decades as reported by the WHO.These steady rises in death demand for rapid developments in anti-cancer agents. Essential oils, being natural and multi-component complex systems have recently attracted a lot of attention in this search for novel anti-cancer agents. MATERIALS AND METHODS: The pharmaceutical attributes of essential oil components, specifically focusing on their affinity towards COX, 5-LOX, AKT, MDM2, PDK1 and mTOR which defines the phosphatidylinositol-3- kinase (PI3K) pathway, were assessed. 123 compounds present in essential oils of different plants were analyzed for their drug like attributes which were then allowed to dock with PI3K dependent receptors crucial for the development of cancer malignancies. Among them, 21 compounds were filtered possessing high druglikeness with favourable metabolism offered by major cytochromeP450 isoforms. Finally, the best docked compounds with highest binding affinities were employed for building a ligand based pharmacophore. Being inhibitors of P-glycoproteins, these molecules also exhibited good absorption profiles and noncarcinogenic properties. Further from these 21, six compounds were evaluated against A549 lung cancer cells. RESULTS: The pharmacophoric feature obtained can be applied for both designing and screening moieties for active inhibitors of the phosphatidylinositol-3-kinase pathway specifically from essential oil compounds and these final 21 compounds can be further promoted to studies for anti-cancer drug development. Among these, six compounds exhibited promising inhibitory results against A549 lung cancer cells. Furthermore, immunoblotting assay confirmed the efficacy of the compounds for inhibiting mTOR and AKT enzymes which are bandmasters for downstream signaling of thePI3K pathway. CONCLUSION: Methyl nonanoate, (R)-citronellol, cis carveol (L-carveol), 3-methyl-Cyclohexanone, 4-carene and thujopsene were finally screened for PI3K targeted anti-cancer therapies which may find direct application as inhalers or sprays against lung cancer as these compounds are highly volatile. PMID- 28356025 TI - Regulation of Apoptosis by SYB in HepG2 Liver Cancer Cells is Mediated by the P53/Caspase 9 Axis. AB - OBJECTIVE: To explore the function of miR-34a in promotion of apoptosis by SYB. METHODS: In this study, the most effective concentration of SYB was determined by measuring cell proliferation. Relative miR-34a mRNA levels were detected by quantitative RT-PCR. Apoptosis was assessed using Annexin- V/PI assays, whereas protein levels of p53, caspase 3, caspase 9, caspase 8 and Bcl2 were evaluated by western blotting. RESULTS: Minimum HepG2 cell growth was observed after 36h of exposure to 150 nmol/L SYB. miR-34a expression was highest 40min after the addition of SYB. SYB slightly decreased the abundance of Bcl-2, but increased the abundance of p53, caspase 3, caspase 9 and caspase 8. SYB failed to alter miR-34a expression when p53 was inhibited. Bcl-2 abundance remained low over time, whereas the abundance of caspase 3, caspase 9 and caspase 8 gradually increased. Inhibition of p53 promoted HepG2 cell growth in comparison with that of the control group. miR-34a was silenced to assess the role of miR-34a in the inhibitory effect of SYB on HepG2 cell growth. When p53 was silenced, protein abundance of Bcl2, caspase 3, caspase 8 and caspase 9 remained unchanged following the addition of SYB; moreover, HepG2 cell growth was increased. Conlusion: SYB represents a promising therapeutic approach for liver cancer patients. PMID- 28356024 TI - Anti-Cancer Effects of Citalopram on Hepatocellular Carcinoma Cells Occur via Cytochrome C Release and the Activation of NF-kB. AB - BACKGROUND: Evidence has been provided of the anti-proliferative activity of citalopram against some cancer cells. OBJECTIVE: The apoptotic impact of citalopram, an antidepressant, against liver hepatocellular carcinoma cell line HepG2 was investigated in relation to the oxidative pathway and nuclear factor (NF)kappaB activation. METHOD: The cytotoxic effects of citalopram on HepG2 cells were determined by MTT assay. Reactive oxygen species (ROS) formation and cytochrome c release were measured following treatment with citalopram. Apoptosis analysis and Bax and Bcl--2 mRNA and protein levels were also determined. RESULTS: The cytotoxic effects of different concentrations of citalopram on HepG2 cells were observed as a reduction in cell viability and an increase in ROS formation. Citalopram caused an increase in mitochondrial Bax levels and a decrease in Bcl2 levels and also caused cytochrome c release. Moreover, DAPI staining and flow cytometry assays revealed citalopram-induced apoptosis in HepG2 cells. Oxidant scavengers and Bay 11-7082 (an irreversible inhibitor of NFkappaB activation) prevented the citalopram-associated cell death, increased BAX and decreased Bcl2. CONCLUSION: Outcomes from current study suggest that citalopram might exhibit apoptotic effect against hepatocellular carcinoma cell line by induction of cell death through cytochrome c release and ROS-dependent activation of NFkappaB. PMID- 28356027 TI - Natural Polyphenols in the Treatment of Alzheimer's Disease. AB - Neurodegenerative disease is an incurable disease which involves the degeneration or death of the nerve cells. Alzheimer's Disease (AD) is a neurodegenerative disease discovered in 1906 by Alois Alzheimer, a German clinical psychiatrist and neuroanatomist. The main pathological hallmarks of this disease are the formation of extracellular amyloid beta (Abeta) plaques and intracellular neurofibrillary tangle (NFT). The accumulation of the amyloid protein aggregates in the brain of AD patients leads to oxidative stress and inflammation. Other postulated reasons for the development of this disease are cholinergic depletion and excessive glutamatergic neurotransmission. The current drugs approved and marketed for the treatment of AD are cholinesterase inhibitors (ChEIs) and N-methyl-Daspartate (NMDA) receptor antagonists. The function of ChEIs is to avoid cholinergic depletion; whereas the function of NMDA receptor antagonist is to block excessive glutamatergic neurotransmission. Unfortunately, the current drugs prescribed for AD show only modest improvement in terms of symptomatic relief and delay the progression of the disease. This review will discuss about several polyphenolic compounds as potential natural treatment options for AD. Three compounds are highlighted in this review - Curcumin (Cur), Resveratrol (Rsv) and Epigallocatechin-3- gallate (EGCG). These compounds have huge potential for AD treatment, especially due to their low frequency of adverse events. However, the current conventional pharmaceutical drugs remain as the mainstay of treatment for AD. PMID- 28356028 TI - The Application of Nanomaterials in Stem Cell Therapy for Some Neurological Diseases. AB - BACKGROUND: Stem cell therapy provides great promising therapeutic benefits for various neurological disorders. Cell transplantation has emerged as cell replacement application for nerve damage. Recently, nanomaterials obtain wide development in various industrial and medical fields, and nanoparticles have been applied in the neurological field for tracking and treating nervous system diseases. Combining stem cells with nanotechnology has raised more and more attentions; and it has demonstrated that the combination has huge effects on clinical diagnosis and therapeutics in multiple central nervous system diseases, meanwhile, improves prognosis. OBJECTIVE: The aim of this review was to give a brief overview of the application of nanomaterials in stem cell therapy for neurological diseases. RESULTS: Nanoparticles not only promote stem cell proliferation and differentiation in vitro or in vivo, but also play dominant roles on stem cell imaging and tracking. Furthermore, via delivering genes or drugs, nanoparticles can participate in stem cell therapeutic applications for various neurological diseases, such as ischemic stroke, spinal cord injury (SCI), multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD) and gliomas. However, nanoparticles have potential cytotoxic effects on nerve cells, which are related to their physicochemical properties. CONCLUSION: Nano-stem cell based therapy as a promising strategy has the ability to affect neuronal repair and regeneration in the central nervous system. PMID- 28356029 TI - Oncogenic Role of SET/I2PP2A for Gynecologic Cancers. AB - SET (SE translocation, SET) is an evolutionarily conserved gene broadly expressed in various human tissues, especially in the gonadal and neural system. As a multitasking protein, SET is involved in essential cell processes such as histone modification, chromatin remodeling, DNA repair, gene transcription, and androgen synthesis. Recent studies showed that SET is overexpressed in breast cancers, ovary cancers and a variety of other malignancies. The strong correlation between SET expression levels and survival of ovarian cancer patients, and SET-mediated activation of androgen synthesis, strongly indicated that this factor may play a significant role in gynecologic cancers. Here, we summarized data pertaining to the pathological implications of SET in tumorigenesis and cancer progression. We analyzed how SET, through the PP2A-dependent and PP2A-independent pathways, may regulate different cell functions. Potential interactions among these pathways and future studies on SET's oncogenic activities are also discussed. PMID- 28356030 TI - Comparison the Effect of Fish-Oil and Calcium Supplementation on Treatment of Primary Dysmenorrhea. AB - BACKGROUND: Primary dysmenorrhea is common among young girls and childbearing women. Dysmenorrhea is a painful contraction of uterus which occurs in the beginning of bleeding or before the menstrual cycle begins. Regarding the mechanism of calcium in response to hormonal change and the role of fish oil on reducing prostaglandins, we compared the effectiveness of fish-oil and calcium supplementation in treating primary dysmenorrheal. METHODS: This randomized double-blinded clinical trial was conducted on women aged 18 to 45 years with moderate to severe primary dysmenorrhea symptoms from January 2015 to March 2015. The women were randomly divided to two groups (fish oil and calcium). The drugs were given every day in the first cycle and from 8 days before till 2 days after initiation of menstruation for the second and third cycles. The intensity of pain and other symptoms of dysmenorreha were recorded and data were analyzed in SPSS 16 using T-test and X2 tests. Significant level was considered to be less than 0.05. RESULTS: The mean +/- SD age of the patients in the fish oil group was 25.0+/-4.3 and in calcium group was 25.48+/-6.6 years. According to this result, there was no statistically significant difference in the intensity of pain between fish-oil group and calcium group before and 1 month after the study (P>0.05). However, there was statistically significant difference between fish oil group and calcium group before the study and 2 months (P=0.001) and 3 months after study (p<0.001). Besides, the fishoil patients needed less analgesic as compared to the calcium patients. CONCLUSION: It is concluded that omega-3 is more effective than calcium, what can be justified by pain mechanisms and symptoms pathology in dysmenorrheal. PMID- 28356031 TI - Old But Good: Modified-Release Prednisone in Rheumatoid Arthritis. AB - BACKGROUND: Since more than 50 years glucocorticoids represent the milestone in the treatment of inflammatory diseases, including rheumatoid arthritis (RA). However, many patients with RA present a circadian rhythm in symptoms severity with a significant worsening in the morning, that correlates with cyclic changes in circulating hormones and cytokines. Classical steroid therapy given in the morning fails to intercept this pathophysiological phenomenon. In the last years, a novel formulation of prednisone has been developed in order to better fit these variations, improve efficacy and minimize adverse events (chronotherapy). This modified-release (MR) prednisone is administered in the evening at 10.00 p.m. and absorbed after about 4 hours. METHODS: In this article, we reviewed the recent clinical trials evaluating the efficacy of MR prednisone in RA patients, including two randomized controlled double-blind clinical trials Circadian Administration of Prednisone in Rheumatoid Arthritis - 1 (CAPRA-1) and CAPRA-2 and other nonrandomized observational studies. RESULTS: According to the available evidence, MR prednisone seems effective in ameliorating morning stiffness in RA patients. CONCLUSION: In conclusion, the use of MR prednisone in the treatment regimen could be a costeffective choice in a significant proportion of RA patients, particularly in those with a clinical phenotype characterized by morning stiffness or morning recrudescence of pain. With regards to the safety, MR prednisone adverse events profile does not differ from that of IR glucocorticoids. PMID- 28356032 TI - Impact of Percutaneous Closure of Interatrial Shunts on Migraine Attacks: Single Operator Series and Review of the Literature. AB - BACKGROUND: The association of migraine with intracardiac communications and a resultant improvement with their closure has been a matter of controversy. Mostly observational and retrospective studies indicate a significant improvement in migraine attacks in patients undergoing percutaneous closure procedures. However, there is a paucity of randomized trials on this topic and prospective data provide little evidence that the device closure approach has any significant effect on migrainous attacks. OBJECTIVE: The aim of this study is to further examine this important controversial topic by presenting our own prospective findings from a single-operator series of 110 patients with patent foramen ovale (PFO) or atrial septal defect (ASD) undergoing percutaneous device closure and also by conducting an in-depth literature review, amply discussing the data on this topic and finally proposing a practical strategy for migraineurs. METHODS: A prospective analysis of our own data was conducted among 110 patients undergoing percutaneous closure of either a patent foramen ovale (PFO) (n=75) or an atrial septal defect (ASD) (n=35), investigating the impact of PFO/ASD closure on migraine symptoms. Closure was effected with use of an Amplatzer occluder in a simplified procedure, performed under local anesthesia with use of plain fluoroscopy alone without intra-procedural echocardiographic guidance. Complete sealing was obtained in 98.7% of PFO patients and 94.3% of ASD patients. All patients were questioned about migraine symptomatology and were followed-up long term for their clinical outcome. They all received dual antiplatelet therapy for 6 months. RESULTS: Great improvement in migraine symptomatology was observed after the closure procedures. Specifically, 54 (49%) patients suffered from migraine before the procedures, 45 PFO and 9 ASD patients. Improvement (50%) or abolition (33.3%) of migraine symptoms occurred in 45 patients, 37 (82.2%) PFO and 8 (88.9%) ASD patients, yielding an overall favorable effect of 83.3%. An atrial septal aneurysm was present in 44 (58.7%) PFO patients, which has recently been considered an important predictor of the occurrence of migraine in PFO patients. Importantly, the favorable effect extended beyond the 6-month period when dual antiplatelet therapy was discontinued. A recent comprehensive meta analysis of 20 studies, comprising patients with unexplained stroke and migraine undergoing transcatheter PFO closure, showed that resolution of migraine occurred in a majority of patients with aura and for a smaller proportion of patients without aura. On the other hand, another recent review maintains that closure of PFO for migraine prevention does not significantly reduce the intensity and severity of migraine. CONCLUSION: A high percentage (49%) of PFO/ASD patients in this series were also migraine sufferers. Percutaneous closure offered migraine relief in 83% of patients, 82% in PFO patients and 89% in ASD patients. Thus, based on this experience and on literature review, a strategic approach for device closure is proposed for migraineurs with a PFO or ASD. PMID- 28356033 TI - A Glycation Angle to Look into the Diabetic Vasculopathy: Cause and Cure. AB - In diabetic patients, accelerated glycation process causes increased oxidative stress and chronic hyperglycaemia that play a vital role in the diabetic complications. Extensive intracellular and extracellular generation of these glycated products finally form advanced glycation end products (AGEs). The accumulation of AGEs is related with the intensive risk for microvascular and macrovascular injuries for diabetic patients. Therefore, formation of AGEs results from the condensation of reducing sugars with biomolecules like nucleic acids, proteins, and lipids which potentially alter their function. Effect of AGEs formation is also related with the cross-linking that promotes vascular stiffness which modifies the vascular structure and long-life function of proteins. Formation of AGEs may also activate specific receptors, like receptor for AGEs (RAGEs) that induce the intracellular signaling which enhance the oxidative stress and also the amplification of key pro-sclerotic and pro inflammatory cytokines. From last few decades, a huge number of pre-clinical studies related with the AGEs formation in the diabetic patients have been performed. The target for such trials was the formation and degradation of AGEs, and its interaction with RAGEs. This review focuses on the mechanism how these AGEs exert detrimental nuisance in the diabetes, as well as deal with existing strategies to disrupt the action or formation of AGEs. Therefore, the unseen role of both the early and advanced stage glycation in the diabetic Vasculopathy is described. We have also illustrated how the glycation inhibition results in the delay of the development of vascular complications in diabetic patients. PMID- 28356034 TI - The Role of Redox Dysregulation in the Inflammatory Response to Acute Myocardial Ischaemia-reperfusion Injury - Adding Fuel to the Fire. AB - BACKGROUND: The inflammatory response to acute myocardial ischaemia/ reperfusion injury (IRI) plays a critical role in determining myocardial infarct (MI) size, and subsequent post-MI left ventricular (LV) remodelling, making it a potential therapeutic target for improving clinical outcomes in patients presenting with an acute myocardial infarction (AMI). Recent experimental studies using advanced imaging and molecular techniques, have yielded new insights into the mechanisms through which reactive oxygen species (ROS) contribute to the inflammatory response induced by acute myocardial IRI - "adding fuel to the fire". The infiltration of inflammatory cells into the MI zone, leads to elevated myocardial concentrations of ROS, cytokine release, and activation of apoptotic and necrotic death pathways. Anti-oxidant and anti-inflammatory therapies have failed to protect the heart against acute myocardial IRI. This may be, in part, due to a lack of understanding of the time course, nature and mechanisms of the inflammation and redox dysregulation, which occur in the setting of acute myocardial IRI. CONCLUSION: In this article, we examine the inflammatory response and redox dysregulation induced by acute myocardial IRI, and highlight potential therapeutic options for targeting redox dysregulation, in order to attenuate the detrimental effects of the inflammatory response following an AMI, so as to reduce MI size and prevent heart failure. PMID- 28356035 TI - Environmental Factors and Hypertension. AB - BACKGROUND: Environmental factors are a major cause of poor health worldwide. The most solid evidence is for air pollution, leading to increased disability adjusted life years. Outdoor temperature and other seasonal climate changes may also influence cardiovascular health, according to their direct modulation of air pollution. Moreover, an increasing body of evidence associates environmental exposure to noise with poor cardiovascular outcome, and in particular with hypertension. METHODS: This review is aimed at reviewing current evidence about the role of these environmental factors in cardiovascular disease and specifically hypertension. In particular, the impact of air pollution, with its short-term and long-term effects, the outdoor temperature and noise pollution will be investigated. CONCLUSIONS: People belonging to low social classes, as well as children, women, older people and those with established cardiovascular diseases, seem to have a greater susceptibility to the effects of environmental stressors, recalling the concept of "environmental justice". The accumulating strong scientific evidence may thus support public health policies aimed at reducing social inequalities in cardiovascular health. PMID- 28356036 TI - New Imaging Frontiers in Cardiology: Fast and Quantitative Maps from Raw Data. AB - BACKGROUND: Among the novelties in the field of cardiovascular imaging, the construction of quantitative maps in a fast and efficient way is one of the most interesting aspects of the clinical research. Quantitative parametric maps are typically obtained by post processing dynamic images, that is, sets of images usually acquired in different temporal intervals, where several images with different contrasts are obtained. Magnetic resonance imaging, and emission tomography (positron emission and single photon emission) are the imaging techniques best suited for the formation of quantitative maps. METHODS: In this review article we present several methods that can be used for obtaining parametric maps, in a fast way, starting from the acquired raw data. We describe both methods commonly used in clinical research, and more innovative methods that build maps directly from the raw data, without going through the image reconstruction. RESULTS: We briefly described recently developed methods in magnetic resonance imaging that accelerate further the MR raw data generation, based on appropriate sub-sampling of k-space; then, we described recently developed methods for generating MR parametric maps. With regard to the emission tomography techniques, we gave an overview of both conventional methods, and more recently developed direct estimation algorithms for parametric image reconstruction from dynamic positron emission tomography data. CONCLUSION: We have provided an overview of the possible approaches that can be followed to realize useful parametric maps from imaging raw data. We moved from the conventional approaches to more recent and efficient methods for accelerating the raw data generation and the of parametric maps formation. PMID- 28356037 TI - Markers of Early Vascular Ageing. AB - BACKGROUND: Cardiovascular damage is clinically manifested as coronary artery disease, heart failure, stroke and peripheral artery disease. The prevalence of these adverse conditions is higher with advancing age. Although many patients present cardiovascular damage late in their life, it is common to see patients with early atherosclerosis in cardiovascular intensive care units at ages lower than 50 years in men and 55 for women. METHODS AND RESULTS: In this review of the literature we identified risk factors of early vascular damage. The classic risk factors such as age, gender, diabetes mellitus, dyslipidemia, smoking, alcohol, hypertension, obesity, family history and newer biomarkers such as hs-CRP, folic acid, homocysteine, fibrinogen are neither strong nor predictive of the individual patient's risk to present early cardiovascular disease. All these risk factors have been used to propose risk scores for possible future events but we still lack a single strong marker indicating new onset of disease that will predict the future independently of the classical factors. The role of vascular imaging techniques to identify patients with subclinical atherosclerotic vascular damage before clinical disease, including the effect of known and unknown risk factors on the vascular tree, seems to be very important for intensifying preventive measures in high risk patients. Early arteriosclerosis measured from pulse wave velocity is associated with reduced arterial elasticity and is associated with future cardiovascular events. CONCLUSIONS: Vascular measurements may better represent the continuum of cardiovascular disease from a young healthy to an aged diseased vessel that is going to produce adverse clinical events. PMID- 28356038 TI - Factors Associated with HIV Testing and HIV Treatment Adherence: A Systematic Review. AB - BACKGROUND: The impact of the global economic crisis on HIV-related access and care remains unclear. The objective of this systematic review of the literature was to evaluate the association between socioeconomic factors and HIV diagnosis, and adherence to treatment, following the 2008 global economic crisis. METHOD: A systematic search of PubMed and Scopus for studies published between January 2008 and October 2016 was conducted. Studies providing data on social, demographic, economic and cultural barriers associated with HIV diagnosis and treatment were included. RESULTS: Of 33 studies included, 22 evaluated HIV testing and 11 evaluated treatment adherence. Medical history of a sexually transmitted disease, knowledge of HIV-related risks, and age, were significantly associated with HIV testing in most of the included studies. Absence of social support, and alcohol or substance use, were the most common factors associated with adherence. Financial factors were not as commonly found to be related to access to HIV diagnosis and HIV treatment adherence, compared to knowledge of HIV-related risks and social support. CONCLUSION: The identification of persons who are less likely to test for HIV, and to adhere to HIV treatment, may serve as a guide for public health interventions, especially in resource-limited areas. PMID- 28356039 TI - The Potential Protective Effects of Phenolic Compounds against Low-density Lipoprotein Oxidation. AB - BACKGROUND: The exact mechanism(s) of atherosclerosis in humans remains elusive, but one theory hypothesizes that this deleterious process results from the oxidative modification of low-density lipoprotein (LDL). Research suggests that foods rich in dietary phenolic compounds with antioxidant activity can mitigate the extent of LDL oxidation in vivo. With regard to the different classes of flavonoids, there appears to be a structurefunction relationship between the various moieties/constituents attached to the flavonoids' three ring system and their impact at retarding LDL oxidation. METHODS: This article summarizes the findings to date of both in vitro and in vivo studies using foods or phenolic extracts isolated from foodstuffs at inhibiting the incidence of LDL oxidation. Three bases: SCOPUS, Web Science, and PubMed were used for search. RESULTS: An often used method for the determination of antioxidant properties of natural phenolic compounds is the LDL oxidation assay. LDLs are isolated from human plasma and their oxidation is induced by Cu2+ ions or 2,2'-azobis(2 methylpropionamidine) dihydrochloride (AAPH). The sample is incubated with a phenolic extract or individual/isolated phenolic compounds. LDL oxidation is then monitored by various chemical methods (e.g., measurement of the generation of conjugated dienes and trienes). This technique confirmed the antioxidant properties of several extracts as obtained from plant material (e.g., grapes, berries, orange, grapefruit, coffee, tea, chocolate, olives, nuts) as well as the individual phenolic compounds (e.g., luteolinidin, apigenidin, caffeic acid, chlorogenic acid, catechin, quercetin, rutin). Several studies in vivo confirmed protective effects of phenolic compounds against LDL oxidation. They covered the healthy subjects with hyperlipidaemia, overweight, obesity, metabolic syndrome, heavy smokers, patients receiving haemodialysis, patients with peripheral vascular disease, and subjects at high cardiovascular risk. The studies comprise individuals of all ages, and the number of participants in the different experiments varied widely. CONCLUSION: Properly designed double-blind, placebo controlled randomised clinical trials offer stronger evidence as to the impact of dietary phenolics consumption at retarding LDL oxidation. More such clinical trials are needed to strengthen the hypothesis that foods rich in dietary phenolic compounds with antioxidant activity can mitigate the extent of LDL oxidation in vivo. PMID- 28356040 TI - The Relevance of Dietary Polyphenols in Cardiovascular Protection. AB - The chemical structure of polyphenols consisting of aromatic rings, capable of quenching free radicals, makes them ideal candidates to protect against oxidation. Polyphenols are present in a variety of foods including grapes, berries, dark chocolate, coffee and tea to mention a few. A number of studies have shown that dietary polyphenols exert a protective effect against hypertension, dyslipidemias, inflammation, endothelial function and atherosclerosis, conditions associated with increased risk for cardiovascular disease. Studies indicate that by decreasing cholesterol absorption, polyphenols alter hepatic cholesterol homeostasis resulting in decreases in plasma lipids and reduction in atherogenic lipoproteins thus having a protective effect against atherosclerosis; polyphenols have also been shown to decrease the activity of enzymes involved in the renin-angiotensinaldosterone system and improve blood pressure. Further, they have been recognized to increase nitric oxide production and to improve endothelial function. In this review we will present some of the evidence derived from epidemiological studies, clinical interventions as well as animal and cell studies supporting the cardioprotective effects of dietary polyphenols. PMID- 28356041 TI - Recent Advances in Antiretroviral Agents: Potent Integrase Inhibitors. AB - Integrase strand transfer inhibitors (INSTIs) belong to a novel class of antiretroviral agents that have emerged as the new first-line treatments. Three such compounds are currently available, raltegravir, elvitegravir, dolutegravir and two more under development, bictegravir and cabotegravir. These compounds share the same mode of action but exhibit different pharmacokinetic/ pharmacodynamic properties, and drug-drug interactions. A series of studies in the past decade have established their efficacy compared to previous regimens, both in treatment- naive and experienced patients. INSTIs have demonstrated a favorable safety profile with fewer adverse events and low rates of virological failure. Emergence of resistance to these agents, however, is a worrying concern, particularly for elvitegravir and raltegravir that display a lower genetic barrier than dolutegravir. On-going trials aim at establishing INSTIs as part of dual-drug HIV treatments or even monotherapy. New long-acting, injectable formulations are under investigation for treatment or prevention. PMID- 28356042 TI - Recent Advances in Oncological Submissions of Dendrimer. AB - BACKGROUND: Disseminated metastatic cancer requires insistent management owing to its reduced responsiveness for chemotherapeutic agents, toxicity to normal cells consequently lower survival rate and hampered quality of life of patients. METHODS: Dendrimer mediated cancer therapy is advantageous over conventional chemotherapy, radiotherapy and surgical resection due to reduced systemic toxicity, and molecular level cell injury to cancerous mass, for an appreciable survival of the subject. Recently used dendrimer mediated nanotechnology for oncology aims to conquer these challenges. Dendrimers based nano-constructs are having architectures comparable to that of biological vesicles present in the human body. RESULTS: Operating with dendrimer technology, proffers the exclusive and novel strategies with numerous applications in cancer management involving diagnostics, therapeutics, imaging, and prognostics by sub-molecular interactions. Dendrimers are designed to acquire the benefits of the malignant tumor morphology and characteristics, i.e. leaky vasculature of tumor, expression of specific cell surface antigen, and rapid proliferation. CONCLUSION: Dendrimers mediated targeted therapy recommends innovatory function equally in diagnostics (imaging, immune-detection) as well as chemotherapy. Currently, dendrimers as nanomedicine has offered a strong assurance and advancement in drastically varying approaches towards cancer imaging and treatment. The present review discusses different approaches for cancer diagnosis and treatment such as, targeted and control therapy, photodynamic therapy, photo-thermal therapy, gene therapy, antiangiogenics therapy, radiotherapy etc. PMID- 28356044 TI - An Updated Portrait of Pathogenesis, Molecular Markers and Signaling Pathways of Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is the vital cause of cancer -related death throughout the world. At present, the exact mechanism responsible for the formation of HCC and its maintenance remains suspicious. Hepatocarcinogenesis involves a multistep activity involving several genetic aberrations which result in malignant transformation of the liver cells. The prevalence and occurrence of this disease are kept on increasing and an increase in the liver transplantation cases are vital indications for it. In the past decades, significant progress has been achieved toward the better elucidation of molecular pathways of oncogenic processes. Several, cell signaling mechanisms involved in tumor pathogenesis have been identified, leading to the production of new tumor markers and to set targets for therapy, including cytokines, enzymes, proteantigens. However, more tumor markers are in need for the effective early diagnosis of the disease condition and monitor the treatment efficacy. This review updates the recent findings in key molecular markers, pathways involved, animal models and treatment strategies in HCC and the advances obtained from basic research and clinical studies. PMID- 28356043 TI - Pre-Exposure Prophylaxis for HIV: Evidence and Perspectives. AB - HIV remains an important public health issue worldwide. However, new prevention approaches have recently been developed and are very promising. Antiretroviral treatment as prevention, or as a prophylaxis after exposure to HIV, has been shown to reduce the likelihood of HIV acquisition. Over the last years, animal studies and randomized clinical trials in humans showed that antiretrovirals can also be efficacious and safe if used once daily, or intermittently, as prophylaxis before an individual is exposed to HIV (Pre-exposure Prophylaxis - PrEP). Fears about development of resistant strains have not been justified insofar given the accumulated evidence from research studies. Demonstration projects are ongoing and first results indicate that interests in the uptake of PrEP are high and adherence is satisfactory. Models suggest that PrEP could be a cost-effective or cost-saving approach under certain provisions including delivery to people at high risk of HIV infection, using less expensive medications, delivery in high HIV prevalence settings, short-term use for periods of higher risk, and evaluation in a longer-term period. The current review summarizes evidence on efficacy, safety and effectiveness of PrEP, and discusses future challenges and perspectives. PMID- 28356045 TI - Pathophysiological Implications of Dipeptidyl Peptidases. AB - Dipeptidyl peptidases (DPPs) belong to one of the protease families classified under EC 3.4.14 in the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology. DPPs family consists of eight members in the mammalian species. They play a role in oligopeptide N-terminal processing and degradation of bioactive peptides. Over the past 20 years, most of the studies have been focused on DPP 4 that has important roles in metabolism and immunity. A large number of pharmacological inhibitors against DPP 4 have been tested rigorously and some of them are now used in the treatment of type 2 diabetes and obesity. In addition, current researches cast a spotlight on other physiological and pathological functions of DPP family members such as DPP 3 for the purpose of investigating their application as novel therapeutic compounds. In this review, we provide an update about the pathophysiological functions of DPPs, and discuss the future potential of the DPP family as pharmacological and therapeutic agents and targets. PMID- 28356046 TI - White Matter Integrity in Subcortical Vascular Cognitive Impairment: A Multimodal Structural MRI Study. AB - OBJECTIVE: To investigate the disruption of white matter (WM) integrity in patients with subcortical vascular cognitive impairment (SVCI) with multimodal structural magnetic resonance imaging (MRI), and to explore the relationships between WM damage, structural network disruptions, and general cognitive function decline. METHODS: Twenty-eight patients with SVCI and twenty control subjects underwent structural MRI scans and neuropsychological assessment. WM volume (WMV), WM hyperintensities (WMH), lacunar infarcts (LI), diffusion tensor imaging parameters and structural network characteristics were compared between two groups. Correlations between these parameters and general cognitive function were calculated. RESULTS: WMV, WMH load, LI number, mean fractional anisotropy (FA), peak height and peak location of mean diffusivity (MD) of normal-appearing WM (NAWM) and structural network characteristics were significantly different between the two groups. Disruption of WM microstructure and network characteristics was widespread. WMV, WMH load, mean FA and peak location of MD of NAWM explained about 70% of the variance in structural network characteristics. Shortest path length with LI number explained 47.5% of the variance in z-scores. CONCLUSION: SVCI was associated with widespread disruptions of WM integrity in the brain. Network characteristics may be a comprehensive reflection of WM integrity and a superior predictor of general cognitive function, while LI was an independent predictor of cognitive impairment. PMID- 28356047 TI - Is VEGF a Key Target of Cotinine and Other Potential Therapies Against Alzheimer Disease? AB - BACKGROUND: The vascular endothelial growth factor (VEGF) is a neuroprotective cytokine that promotes neurogenesis and angiogenesis in the brain. In animal models, it has been shown that environmental enrichment and exercise, two non pharmacological interventions that are beneficial decreasing the progression of Alzheimer disease (AD) and depressive-like behavior, enhance hippocampal VEGF expression and neurogenesis. Furthermore, the stimulation of VEGF expression promotes neurotransmission and synaptic plasticity processes such as neurogenesis. It is thought that these VEGF actions in the brain, may underly its beneficial therapeutic effects against psychiatric and other neurological conditions. CONCLUSION: In this review, evidence linking VEGF deficit with the development of AD as well as the potential role of VEGF signaling as a therapeutic target for cotinine and other interventions in neurodegenerative conditions are discussed. PMID- 28356048 TI - Diagnostic and Prognostic Potential of Retinal Biomarkers in Early On-Set Alzheimer's Disease. AB - OBJECTIVE: Accumulating evidence suggests that the eye can be used in the assessment of early on-set Alzheimer's disease (AD). The eye offers a natural window to the brain through the retina. The retina and brain share common developmental origins and patho-physiological origins and mechanisms, having been sequestered from it during early development, but retaining its connections with the brain via the optic nerve. Therefore, it is well understood that neurological abnormalities have a direct profound impact on the retina. Recent studies suggest an array of physiological and pathological changes in the retina in dementia and specifically in AD. There are also reports on imaging the two hallmark proteins of the disease, extracellular amyloid beta peptides and intracellular hyper phosphorylated tau protein, as a proxy to neuroimaging. RESULTS: In this review, we summarise retinal structural, functional and vascular changes reported to be associated with AD. We also review techniques employed to image these two major hall mark proteins of AD and their relevance for early detection of AD. PMID- 28356052 TI - The Limitations of Gram-stain Microscopy of Synovial Fluid in Concomitant Septic and Crystal Arthritis. AB - BACKGROUND: Rapid diagnosis of septic arthritis from Gram-stain microscopy is limited by an inherent false-negative rate of 25-78%. The presence of concomitant crystal arthritis in 5% of cases represents a particular diagnostic challenge. OBJECTIVES: This study aims to investigate the effects that a concomitant crystal arthropathy has on the ability of Gram-stain microscopy of synovial fluid to diagnose a septic arthritis. METHODS: This is a 22-year retrospective cohort study. Inclusion criteria were a positive synovial fluid culture result with a positive clinical diagnosis of septic arthritis. Results were correlated with the presence or absence of urate and calcium pyrophosphate crystals, and Gram-stain result. During this time our collection and analysis methods remained unchanged. All samples were collected in Lithium Heparin containers. Chi-squared test with a p value < 0.05 was considered significant. RESULTS: 602 synovial fluid samples were included. 162 cases of concomitant crystal arthritis were identified (27%). Of these, 16 (10%) had an initial negative Gram-stain. Out of the 440 samples with no crystals detected, 18 (4%) had an initial negative Gram-stain microscopy result (p < 0.05). CONCLUSION: The incidence of concurrent septic and crystal arthritis may be higher than previously thought. Synovial fluid samples in concomitant septic and crystal arthritis are significantly less likely to have a positive Gram-stain at microscopy than in cases of an isolated septic arthritis. We would advise the clinician to maintain a high index of suspicion for septic arthritis in these patients. PMID- 28356051 TI - The Frequency of HLA-B27 in a Colombian Population with Signs of Spondyloarthritis. AB - BACKGROUND: The strong association between HLA-B27 and spondyloarthritis (SpA) has demonstrated that typing the HLA-B27 antigen is a crucial step in diagnosis and aids in defining the progression and severity of disease. OBJECTIVE: To describe the frequency of HLA-B27 in Colombian individuals with clinical manifestations associated with SpA. MATERIALS AND METHODOLOGY: We retrospectively analyzed 4109 HLA-B27 typing requests to the Hospital Militar Central and the Instituto de Referencia Andino from Colombian individuals with clinical signs suggestive of SpA between 2009 and 2012. We used basic digital cytometry followed by Polymerase Chain Reaction with sequence specific primers when confirmation was needed. We determined the frequency of HLA-B27 in the population and levels of association of HLA-B27 with SpA. RESULTS: Our population included 1585 men (36.8%) and 2524 women (61.4%). The predominant age range was between 19 and 45 years (49.9%). The majority (95.4%) of the study population came from the Andean region and eastern plains. The most frequent clinical manifestations were peripheral. Only a small fraction (12.1%) of the 4109 subjects was HLA-B27 positive. Of those, 56.9% were male, and 54.7% were between 19 and 45 years old. In contrast, when rheumatologists referred the HLA B27, 64% were found to be positive. CONCLUSION: The frequency of the HLA-B27 allele in individuals with clinical signs suggestive of SpA was low, in accordance with the lower prevalence found in Colombian patients diagnosed with SpA compared to American and European population. PMID- 28356049 TI - Calcium-engaged Mechanisms of Nongenomic Action of Neurosteroids. AB - BACKGROUND: Neurosteroids form the unique group because of their dual mechanism of action. Classically, they bind to specific intracellular and/or nuclear receptors, and next modify genes transcription. Another mode of action is linked with the rapid effects induced at the plasma membrane level within seconds or milliseconds. The key molecules in neurotransmission are calcium ions, thereby we focus on the recent advances in understanding of complex signaling crosstalk between action of neurosteroids and calcium-engaged events. METHODS: Short-time effects of neurosteroids action have been reviewed for GABAA receptor complex, glycine receptor, NMDA receptor, AMPA receptor, G protein-coupled receptors and sigma-1 receptor, as well as for several membrane ion channels and plasma membrane enzymes, based on available published research. RESULTS: The physiological relevance of neurosteroids results from the fact that they can be synthesized and accumulated in the central nervous system, independently from peripheral sources. Fast action of neurosteroids is a prerequisite for genomic effects and these early events can significantly modify intracellular downstream signaling pathways. Since they may exert either positive or negative effects on calcium homeostasis, their role in monitoring of spatio-temporal Ca2+ dynamics, and subsequently, Ca2+-dependent physiological processes or initiation of pathological events, is evident. CONCLUSION: Neurosteroids and calcium appear to be the integrated elements of signaling systems in neuronal cells under physiological and pathological conditions. A better understanding of cellular and molecular mechanisms of nongenomic, calcium-engaged neurosteroids action could open new ways for therapeutic interventions aimed to restore neuronal function in many neurological and psychiatric diseases. PMID- 28356053 TI - Levetiracetam in Compare to Sodium Valproate for Prophylaxis in Chronic Migraine Headache: A Randomized Double-Blind Clinical Trial. AB - BACKGROUND: Migraine is not curable, but preventive treatments are usually used to decrease the intensity and frequency of headache attacks. Different therapeutic options are widely studied for chronic migraine (CM), but all of them have different inefficacies. OBJECTIVE: The aim of this study was to compare the efficacy of levetiracetam versus sodium valproate in the treatment of CM. METHODS: A randomized controlled clinical trial was conducted on 62 patients with chronic migraine (30 patients in intervention group-treated with levetiracetam and 32 patients in control group- treated with sodium valproate). The treatment regimen consisted of initial dose of levetiracetam or sodium valproate 500 mg daily which increased to 500 mg two times a day after two weeks. The treatment response was evaluated by measuring pain frequency, pain severity, and the MIDAS (migraine disability assessment) score over three months follow-up. RESULTS: During a three-month follow-up, the mean of headache frequency, severity, and MIDAS score were changed significantly. The rate of decrease in headache frequency was higher in control group than intervention group ((6.7+/-2.7 and 14.4+/-5.3 day/month, respectively) (P<0.001). Also, headache severity and MIDAS score significantly decreased in the control group than intervention group (3.4+/ 1.1 and 5.7+/-1.6, respectively P<0.001, 16.7 +/- 6.1 and 30.2+/-9.8, respectively (P<0.001). CONCLUSIONS: According to our findings, levetiracetam offered improvement in headache frequency, severity, and MIDAS score in patients with CM. However, levetiracetam was not effective enough for chronic migraine as valproate, despite some significant effect. Thus levetiracetam can be one of the choices for limited chronic migraine subjects who are in contraindication of Valproate. PMID- 28356054 TI - Role of Chirality in Drugs: An Overview. AB - Stereochemistry has occupied a great role in the manufacture and development of pharmaceuticals. Chiral properties play an important role in the determination of pharmacological actions of the drug. In recent years, there is a considerable interest in chiral separation to isolate and examine both enantiomers. This article provides an overview about the stereochemistry and its role in drugs, and also, offers approved isolation methods for enantiomeric pairs. PMID- 28356055 TI - A genome-wide association study reveals a locus for bilateral iridal hypopigmentation in Holstein Friesian cattle. AB - BACKGROUND: Eye pigmentation abnormalities in cattle are often related to albinism, Chediak-Higashi or Tietz like syndrome. However, mutations only affecting pigmentation of coat color and eye have also been described. Herein 18 Holstein Friesian cattle affected by bicolored and hypopigmented irises have been investigated. RESULTS: Affected animals did not reveal any ophthalmological or neurological abnormalities besides the specific iris color differences. Coat color of affected cattle did not differ from controls. Histological examination revealed a reduction of melanin pigment in the iridal anterior border layer and stroma in cases as cause of iris hypopigmentation. To analyze the genetics of the iris pigmentation differences, a genome-wide association study was performed using Illumina BovineSNP50 BeadChip genotypes of the 18 cases and 172 randomly chosen control animals. A significant association on bovine chromosome 8 (BTA8) was identified at position 60,990,733 with a -log10(p) = 9.17. Analysis of genotypic and allelic dependences between cases of iridal hypopigmentation and an additional set of 316 randomly selected Holstein Friesian cattle controls showed that allele A at position 60,990,733 on BTA8 (P = 4.0e-08, odds ratio = 6.3, 95% confidence interval 3.02-13.17) significantly increased the chance of iridal hypopigmentation. CONCLUSIONS: The clinical appearance of the iridal hypopigmentation differed from previously reported cases of pigmentation abnormalities in syndromes like Chediak-Higashi or Tietz and seems to be mainly of cosmetic character. Iridal hypopigmentation is caused by a reduced content of melanin pigment in the anterior border layer and iridal stroma. A single genomic position on BTA8 was detected to be significantly associated with iridal hypopigmentation in examined cattle. To our knowledge this is the first report about this phenotype in Holstein Friesian cattle. PMID- 28356057 TI - Erratum to: What impact do assumptions about missing data have on conclusions? a practical sensitivity analysis for a cancer survival registry. PMID- 28356056 TI - M-AMST: an automatic 3D neuron tracing method based on mean shift and adapted minimum spanning tree. AB - BACKGROUND: Understanding the working mechanism of the brain is one of the grandest challenges for modern science. Toward this end, the BigNeuron project was launched to gather a worldwide community to establish a big data resource and a set of the state-of-the-art of single neuron reconstruction algorithms. Many groups contributed their own algorithms for the project, including our mean shift and minimum spanning tree (M-MST). Although M-MST is intuitive and easy to implement, the MST just considers spatial information of single neuron and ignores the shape information, which might lead to less precise connections between some neuron segments. In this paper, we propose an improved algorithm, namely M-AMST, in which a rotating sphere model based on coordinate transformation is used to improve the weight calculation method in M-MST. RESULTS: Two experiments are designed to illustrate the effect of adapted minimum spanning tree algorithm and the adoptability of M-AMST in reconstructing variety of neuron image datasets respectively. In the experiment 1, taking the reconstruction of APP2 as reference, we produce the four difference scores (entire structure average (ESA), different structure average (DSA), percentage of different structure (PDS) and max distance of neurons' nodes (MDNN)) by comparing the neuron reconstruction of the APP2 and the other 5 competing algorithm. The result shows that M-AMST gets lower difference scores than M-MST in ESA, PDS and MDNN. Meanwhile, M-AMST is better than N-MST in ESA and MDNN. It indicates that utilizing the adapted minimum spanning tree algorithm which took the shape information of neuron into account can achieve better neuron reconstructions. In the experiment 2, 7 neuron image datasets are reconstructed and the four difference scores are calculated by comparing the gold standard reconstruction and the reconstructions produced by 6 competing algorithms. Comparing the four difference scores of M-AMST and the other 5 algorithm, we can conclude that M AMST is able to achieve the best difference score in 3 datasets and get the second-best difference score in the other 2 datasets. CONCLUSIONS: We develop a pathway extraction method using a rotating sphere model based on coordinate transformation to improve the weight calculation approach in MST. The experimental results show that M-AMST utilizes the adapted minimum spanning tree algorithm which takes the shape information of neuron into account can achieve better neuron reconstructions. Moreover, M-AMST is able to get good neuron reconstruction in variety of image datasets. PMID- 28356058 TI - HIV-infected persons with type 2 diabetes show evidence of endothelial dysfunction and increased inflammation. AB - BACKGROUND: Increased incidence of cardiovascular diseases (CVD) in both HIV infection and type 2 diabetes (T2D) compared to the general population has been described. Little is known about the combined effect of HIV infection and T2D on inflammation and endothelial function, both of which may contribute to elevated risk of CVD. METHODS: Cross-sectional study including 50 HIV-infected persons on combination anti-retroviral therapy (cART), with HIV RNA <200 copies/mL (n = 25 with T2D (HIV + T2D+), n = 25 without T2D (HIV + T2D-)) and 50 uninfected persons (n = 22 with T2D (HIV-T2D+) and n = 28 without T2D (HIV-T2D-)). Groups were matched on age and sex. High sensitive C-reactive protein (hsCRP) was used to determine inflammation (cut-off 3 mg/L). The marker of endothelial dysfunction asymmetric dimethylarginine (ADMA) was measured using high performance liquid chromatography. Trimethylamine-N-oxide (TMAO), a microbiota-dependent, pro atherogenic marker was measured using stable isotope dilution LC/MS/MS. RESULTS: The percentage of HIV + T2D+, HIV + T2D-, HIV-T2D+, and HIV-T2D- with hsCRP above cut-off was 50%, 19%, 47%, and 11%, respectively. HIV + T2D+ had elevated ADMA (0.67 MUM (0.63-0.72) compared to HIV + T2D- (0.60 MUM (0.57-0.64) p = 0.017), HIV-T2D+ (0.57 MUM (0.51-63) p = 0.008), and HIV-T2D- (0.55 MUM (0.52-0.58) p < 0.001). No differences in TMAO between groups were found. However, a positive correlation between ADMA and TMAO was found in the total population (rs = 0.32, p = 0.001), which was mainly driven by a close correlation in HIV + T2D+ (rs = 0.63, p = 0.001). CONCLUSION: Elevated inflammation and evidence of endothelial dysfunction was found in HIV-infected persons with T2D. The effect on inflammation was mainly driven by T2D, while both HIV infection and T2D may contribute to endothelial dysfunction. Whether gut microbiota is a contributing factor to this remains to be determined. PMID- 28356059 TI - Association between acute gastrointestinal injury and biomarkers of intestinal barrier function in critically ill patients. AB - BACKGROUND: To assess the associations of biomarkers of intestinal barrier function and other clinical variables with acute gastrointestinal injury (AGI) grade, and of these clinical variables with mortality in critically ill patients. METHODS: This was a single-center, observational, prospective study. Patients were included if they were diagnosed with AGI and underwent tests for the measurement of plasma levels of intestinal fatty acid-binding protein (i-FABP), D lactate (D-la), and lipopolysaccharide. General characteristics, AGI grades, Acute Physiology and Chronic Health Evaluation (APACHE) II scores, Sepsis-related Organ Failure Assessment (SOFA) scores, intra-abdominal pressure (IAP), and 28 day mortality were recorded and compared among patients with different AGI grades. RESULTS: Among the 90 included patients, the APACHE II score, IAP, and LPS and D-la levels significantly differed between the four AGI grades. Multinomial logistic regression analysis with grade I as the reference for grades II, III, and IV revealed that high APACHE II scores increased the odds of AGI grade III (odds ratio [OR], 1.754; 95% confidence interval [CI], 1.225-2.511) and grade IV (OR, 1.493; 95% CI, 1.079-2.066). Similarly, IAP increased the odds of AGI grade III (OR, 1.622; 95% CI, 1.111-2.369) and grade IV (OR, 1.518; 95% CI, 1.066-2.162). Elevated D-la increased the odds of AGI grades II (OR, 1.059; 95% CI, 1.005-1.117), III (OR, 1.155; 95% CI, 1.052-2.268), and IV (OR, 1.088; 95% CI, 1.013-1.168). In contrast, i-FABP and LPS did not increase the odds of any AGI grade. SOFA scores could independently predict the odds of death in AGI patients (OR, 1.223; 95% CI, 1.007-1.485). CONCLUSION: AGI patients exhibit loss of gastrointestinal barrier function, and D-la could serve as a better marker of AGI grade than i-FABP or lipopolysaccharide. PMID- 28356060 TI - Genetic variation in the microsomal triglyceride transfer protein (-493G/T) is associated with hepatic steatosis in patients infected with hepatitis C virus. AB - BACKGROUND: In chronic hepatitis C, the fibrosis progression rates are extremely variable and can be influenced by factors associated with the host, virus and environment. Among the associated metabolic factors, hepatic steatosis is characterized by an accumulation of triglycerides in hepatocytes. In the host, genetic determinants of hepatic steatosis are observed, such as single-nucleotide polymorphisms (SNPs) in the microsomal triglyceride transfer protein (MTTP) gene. The MTTP -493G/T SNP appears to play an important role in the regulation of gene expression and influences the plasma concentration of circulating low-density lipoprotein (LDL). The present study investigated the influence of this SNP in the development of hepatic steatosis in patients with chronic hepatitis C and evaluated the association of hepatic steatosis with certain characteristics of these patients and the hepatitis C virus (HCV). METHODS: Two hundred thirty-nine patients with chronic hepatitis C were genotyped for the MTTP -493G/T SNP by a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The association between hepatic steatosis and selected characteristics of the patient and virus was evaluated using bivariate and multivariate analyses. RESULTS: The most prevalent MTTP -493G/T genotype was GG (46%) followed by GT (43.5%) and TT (10.5%). Multivariate analysis of the total cohort revealed associations between the presence of hepatic steatosis and inflammatory activity of moderate to high intensity (P < 0.001), advanced age (P = 0.010), elevated gamma glutamyl transpeptidase (GGT) levels (P = 0.010) and low LDL levels (P = 0.022). Hepatic steatosis was also associated with the TT/GT genotype of the MTTP -493G/T SNP in patients infected with HCV genotype 3 (P < 0.001). CONCLUSIONS: In chronic hepatitis C patients infected with HCV genotype 3 and with the TT/GT genotype of the MTTP -493G/T SNP, a significant increase in hepatic steatosis was observed, which may indicate that this SNP has a significant influence on the accumulation of triglycerides in hepatocytes. Furthermore, associations were observed between hepatic steatosis and inflammatory activity of moderate to high intensity, advanced age, elevated GGT and low LDL levels. PMID- 28356061 TI - Distribution of Ki-67 values within HER2 & ER/PgR expression variants of ductal breast cancers as a potential link between IHC features and breast cancer biology. AB - BACKGROUND: Unexpected differences in Ki-67 values among HER2 & ER/PgR defined subgroups were found. This study aims to detect possible subdivisions beyond the conventional breast cancer types. METHODS: One thousand one hundred eighty consecutive patients with invasive ductal breast carcinoma were included and distributed in 16 subgroups (four HER2 phenotypes (0+, 1+, 2+ and 3+) times four ER/PgR phenotypes). Complex distributions of Ki-67 values were tested by expectation maximization (EM) clustering. RESULTS: Pooled Ki67 values of all patients showed the presence of three EM clusters (defined as LMA-low mitotic activity, IMA-intermediate mitotic activity and HMA-high mitotic activity) with expected mean Ki-67 values of 1.17%, 40.45% and 77.79%, respectively. Only ER-PgR tumors significantly dispersed in three clusters (29.75% tumors in LMA, 46.95% in IMA and 23.30% in the HMA cluster), while almost no detected HMA tumors were of ER + PgR+ or ER + PgR- phenotypes. Among 799 ER + PgR+ patients distribution in clusters was HER2 dependent (p = 0.000243), due to increased number of IMA HER2 3+ tumors on the expense of LMA HER2 3+ tumors (52 IMA out of 162 HER2 3+ patients versus113 IMA out of 637 HER2 < 3+ patients). This was not found among ER + PgR- patients (p = 0.186968). Among ER-PgR- patients, HER2 overexpression also increased number of IMA tumor, but by reducing the number of HMA tumors (p < 0.000001). Here, difference between HER2 absent (0+) and HER2 3+ patients was evident (10 HMA out of 125 HER2 3+ patients versus 42 HMA out of 103 HER2 0+ patients). CONCLUSIONS: Results suggest that distributions of breast cancers in three clusters of mitotic activity depend on different mechanisms for ER + PgR+ and ER negative tumors. Although HER2 overexpression increases number of IMA tumors in both settings, in the former it is done by reducing number of LMA tumors, while in the latter it reduces the number of HMA tumors. Mitotic activity of ER + PgR- tumors seems unrelated to the HER2 status, possibly as an indicator that ER dysfunctionality in cancers that lack PgR expression. Among ER negative tumors, the absence of HER2 (0+) might be as important as the HER2 overexpression. PMID- 28356062 TI - Successful multigravid pregnancy in a 42-year-old patient on continuous ambulatory peritoneal dialysis and a review of the literature. AB - BACKGROUND: For peritoneal dialysis patients, the likelihood of conception is low and the probability of getting through the pregnancy successfully is even lower. Almost 60 years after the first reported case of a successful pregnancy in a dialysis patient, many issues concerning pregnancy in dialysis patients remain unresolved. Our patient's pregnancy is considered high risk as she has end stage renal failure and falls in the category of advance maternal age for pregnancy. We describe here the course of her uneventful pregnancy which we hope will contribute to the overall knowledge and management of pregnancy in elderly patients receiving peritoneal dialysis. CASE PRESENTATION: We report a successful elderly multigravid pregnancy, in a patient undergoing continuous ambulatory peritoneal dialysis (CAPD). Her pregnancy was detected early and she was closely managed by the nephrologist and obstetrician. She tolerated the same PD prescription throughout 36 weeks of pregnancy with daily ultrafiltration of 500 1500mls. Her blood pressure remained well controlled without the need of any antihypertensive medication. Her total Kt/V ranged from 1.93 to 2.73. Her blood parameters remained stable and she was electively admitted at 36 weeks for a trans-peritoneal lower segment caesarian section and bilateral tubal ligation. CONCLUSIONS: At the age of 42, our case is the oldest reported successful pregnancy in a patient on peritoneal dialysis. With careful counselling and meticulous follow up, we have shown that woman in the early stage of end stage renal failure can successfully deliver a full term baby without any complications. Therefore, these women should not be discourage from conceiving even if they are in advanced maternal age for pregnancy. PMID- 28356063 TI - Daclatasvir/asunaprevir based direct-acting antiviral therapy ameliorate hepatitis C virus-associated cryoglobulinemic membranoproliferative glomerulonephritis: a case report. AB - BACKGROUND: Direct-acting antivirals (DAAs) dramatically improve the treatment of hepatitis C virus (HCV) infections. However, the effects of DAAs on extra-hepatic manifestations such as HCV-associated glomerulonephritis, especially in cases with renal dysfunction, are not well elucidated. CASE PRESENTATION: A 69-year-old Japanese woman was diagnosed as having chronic hepatitis C, genotype 1b at the age of 55. She presented with hypertension, microscopic hematuria, proteinuria, renal dysfunction, purpura, and arthralgia at the age of 61. She also had hypocomplementemia and cryoglobulinemia. Renal biopsy revealed membranoproliferative glomerulonephritis (MPGN), and she was diagnosed as having HCV-associated cryoglobulinemic MPGN. She declined interferon therapy at the time and was treated with antihypertensive medications as well as oral corticosteroid that were effective in reducing proteinuria. However, when the corticosteroid dose was reduced, proteinuria worsened. She began antiviral treatment with daclatasvir/asunaprevir (DCV/ASV). Clearance of HCV-RNA was obtained by 2 weeks and sustained, and liver function was normalized. In addition, microhematuria turned negative, proteinuria decreased, hypocomplementemia and estimated glomerular filtration rate were improved, whereas cryoglobulinemia persisted. She completed 24 weeks of therapy without significant adverse effects. CONCLUSION: In a case of HCV-associated cryoglobulinemic MPGN with renal dysfunction, DCV/ASV based DAAs ameliorated microhematuria, proteinuria and renal function without significant side effects. PMID- 28356064 TI - Protocol of the PANCALYZE trial: a multicenter, prospective study investigating the tumor biomarkers CXCR4, SMAD4, SOX9 and IFIT3 in patients with resected pancreatic adenocarcinoma to predict the pattern of recurrence of the disease. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies today with an urgent need for novel therapeutic strategies. Biomarker analysis helps to better understand tumor biology and might emerge as a tool to develop personalized therapies. The aim of the study is to investigate four promising biomarkers to predict the clinical course and particularly the pattern of tumor recurrence after surgical resection. DESIGN: Patients undergoing surgery for PDAC can be enrolled into the PANCALYZE trial. Biomarker expression of CXCR4, SMAD4, SOX9 and IFIT3 will be prospectively assessed by immunohistochemistry and verified by rt.-PCR from tumor and adjacent healthy pancreatic tissue of surgical specimen. Immunohistochemistry expression pattern of all four biomarkers will be combined into a single score. Beginning with the hospital stay clinical data from enrolled patients will be collected and followed. Different adjuvant chemotherapy protocols will be used to create subgroups. The combined biomarker expression score will be correlated with the further clinical course of the patients to test the hypothesis if CXCR4 positive, SMAD4 negative, SOX9 positive, IFIT3 positive tumors will predominantly develop metastatic spread. DISCUSSION: Pancreatic cancer is associated with different patterns of progression requiring personalized therapeutic strategies. Biomarker expression analysis might be a tool to predict the pattern of tumor recurrence and discriminate patients that develop systemic metastatic disease from those with tumors that rather develop local recurrence over time. This data might lead to personalized adjuvant treatment decisions as patients with tumors that stay localized might benefit from adjuvant local therapies like radiochemotherapy as compared to those with systemic recurrence who would benefit exclusively from chemotherapy. Moreover, the pattern of propagation might be a predefined characteristic of pancreatic cancer determined by the genetic signature of the tumor. In the future, biomarker expression analysis could be performed on tumor biopsies to develop personalized therapeutic pathways right after diagnosis of cancer. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00006179 . PMID- 28356065 TI - Purification, characterization and amino acid content of cholesterol oxidase produced by Streptomyces aegyptia NEAE 102. AB - BACKGROUND: There is an increasing demand on cholesterol oxidase for its various industrial and clinical applications. The current research was focused on extracellular cholesterol oxidase production under submerged fermentation by a local isolate previously identified as Streptomyces aegyptia NEAE 102. The crude enzyme extract was purified by two purification steps, protein precipitation using ammonium sulfate followed by ion exchange chromatography using DEAE Sepharose CL-6B. The kinetic parameters of purified cholesterol oxidase from Streptomyces aegyptia NEAE 102 were studied. RESULTS: The best conditions for maximum cholesterol oxidase activity were found to be 105 min of incubation time, an initial pH of 7 and temperature of 37 degrees C. The optimum substrate concentration was found to be 0.4 mM. The higher thermal stability behavior of cholesterol oxidase was at 50 degrees C. Around 63.86% of the initial activity was retained by the enzyme after 20 min of incubation at 50 degrees C. The apparent molecular weight of the purified enzyme as sized by sodium dodecyl sulphate-polyacryalamide gel electrophoresis was approximately 46 KDa. On DEAE Sepharose CL-6B column cholesterol oxidase was purified to homogeneity with final specific activity of 16.08 U/mg protein and 3.14-fold enhancement. The amino acid analysis of the purified enzyme produced by Streptomyces aegyptia NEAE 102 illustrated that, cholesterol oxidase is composed of 361 residues with glutamic acid as the most represented amino acid with concentration of 11.49 MUg/mL. CONCLUSIONS: Taking into account the extracellular production, wide pH tolerance, thermal stability and shelf life, cholesterol oxidase produced by Streptomyces aegyptia NEAE 102 suggested that the enzyme could be industrially useful. PMID- 28356066 TI - Effectiveness of conservative interventions for sickness and pain behaviors induced by a high repetition high force upper extremity task. AB - BACKGROUND: Systemic inflammation is known to induce sickness behaviors, including decreased social interaction and pain. We have reported increased serum inflammatory cytokines in a rat model of repetitive strain injury (rats perform an upper extremity reaching task for prolonged periods). Here, we sought to determine if sickness behaviors are induced in this model and the effectiveness of conservative treatments. METHODS: Experimental rats underwent initial training to learn a high force reaching task (10 min/day, 5 days/week for 6 weeks), with or without ibuprofen treatment (TRHF vs. TRHF + IBU rats). Subsets of trained animals went on to perform a high repetition high force (HRHF) task for 6 or 12 weeks (2 h/day, 3 days/week) without treatment, or received two secondary interventions: ibuprofen (HRHF + IBU) or a move to a lower demand low repetition low force task (HRHF-to-LRLF), beginning in task week 5. Mixed-effects models with repeated measures assays were used to assay duration of social interaction, aggression, forepaw withdrawal thresholds and reach performance abilities. One way and two-way ANOVAs were used to assay tissue responses. Corrections for multiple comparisons were made. RESULTS: TRHF + IBU rats did not develop behavioral declines or systemic increases in IL-1beta and IL-6, observed in untreated TRHF rats. Untreated HRHF rats showed social interaction declines, difficulties performing the operant task and forepaw mechanical allodynia. Untreated HRHF rats also had increased serum levels of several inflammatory cytokines and chemokines, neuroinflammatory responses (e.g., increased TNFalpha) in the brain, median nerve and spinal cord, and Substance P and neurokinin 1 immunoexpression in the spinal cord. HRHF + IBU and HRHF-to-LRLF rats showed improved social interaction and reduced inflammatory serum, nerve and brain changes. However, neither secondary treatment rescued HRHF-task induced forepaw allodynia, or completely attenuated task performance declines or spinal cord responses. CONCLUSIONS: These results suggest that inflammatory mechanisms induced by prolonged performance of high physical demand tasks mediate the development of social interaction declines and aggression. However, persistent spinal cord sensitization was associated with persistent behavioral indices of discomfort, despite use of conservative secondary interventions indicating the need for prevention or more effective interventions. PMID- 28356067 TI - Probiotic bacteria prevent Salmonella - induced suppression of lymphoproliferation in mice by an immunomodulatory mechanism. AB - BACKGROUND: Salmonella enterica infections often exhibit a form of immune evasion. We previously observed that probiotic bacteria could prevent inhibition of lymphoproliferation and apoptosis responses of T cells associated with S. enterica infections in orally challenged mice. RESULTS: In this study, changes in expression of genes related to lymphocyte activation in mucosa-associated lymphoid tissues (MALT) of mice orally infected with S. enterica with and without treatment with probiotic bacteria were evaluated. Probiotic bacteria increased expression of mRNA for clusters of differentiation antigen 2 (Cd2), protein tyrosine phosphatase receptor type C (Ptprc), and Toll-like receptor 6 (Tlr6) genes related to T and B cell activation in mouse intestinal tissue. The probiotic bacteria were also associated with reduced mRNA expression of a group of genes (RelB, Myd88, Ikappakappaa, Jun, Irak2) related to nuclear factor of kappa light chains enhancer in B cells (NF-kappaB) signal transduction pathway regulated cytokine responses. Probiotic bacteria were also associated with reduced mRNA expression of apoptotic genes (Casp2, Casp12, Dad1, Akt1, Bad) that suggest high avidity lymphocyte sparing. Reduced CD2 immunostaining in mesenteric lymph nodes (MLN) was suggestive of reduced lymphocyte activation in probiotic treated mice. Reduced immunostaining of TLR6 in MALT of probiotic-treated, S. enterica-infected mice suggests that diminished innate immune sensitivity to S. enterica antigens is associated with preventing lymphocyte deletion. CONCLUSIONS: The results of this study are consistent with prevention of S. enterica-induced deletion of lymphocytes by the influence of probiotic bacteria in mucosal lymphoid tissues of mice. PMID- 28356068 TI - A randomized trial of remote ischemic preconditioning and control treatment for cardioprotection in sevoflurane-anesthetized CABG patients. AB - BACKGROUND: Remote ischemic preconditioning (RIPC) efficacy is debated. Possibly, because propofol, which has a RIPC-inhibiting action, is used in most RIPC trials. It has been suggested that clinical efficacy is, however, present with volatile anesthesia in the absence of propofol, although this is based on one phase 1 trial only. Therefore, in the present study we further explore the relation between RIPC and cardioprotection with perioperative anesthesia restricted to sevoflurane and fentanyl, in CABG patients without concomitant procedures. METHODS: In a single-center study, we aimed to randomize 46 patients to either RIPC (3x5 min inflation of a blood pressure cuff around the arm) or control treatment (deflated cuff around the arm). Blood samples were obtained before and after RIPC to evaluate potential RIPC-induced mediators (Interleukin (IL)-6, IL-10, Tumor Necrosis Factor-alpha, Macrophage Inhibitory Factor). An atrial tissue sample was obtained at cannulation of the appendix of the right atrium for determination of mitochondrial bound hexokinase II (mtHKII) and other survival proteins (Akt and AMP-activated protein kinase alpha). In blood samples taken before and 6, 12 and 24 h after surgery cardiac troponin T (cTnT) and C reactive protein (CRP) were determined. Surgery was strictly performed under sevoflurane anesthesia (no propofol). RESULTS: We actually randomized 16 patients to control treatment and 13 patients to RIPC. The mean 24 h area under the curve (AUC) cTnT was 11.44 (standard deviation 4.66) in the control group and 10.90 (standard deviation 4.73) in the RIPC group (mean difference 0.54, 95% CI -3.06 to 4.13; p = 0.76). The mean 24 h AUC CRP was 1319 (standard deviation 92) in the control group and 1273 (standard deviation 141) in the RIPC group (mean difference 46.2, 95% CI -288 to 380; p = 0.78). RIPC was without effect on survival proteins in atrial tissue samples obtained before surgery (mitochondrial hexokinase, Akt and AMPK) and inflammatory mediators obtained before and immediately after RIPC (IL-6, IL-10, TNF-alpha, macrophage migration inhibitory factor). CONCLUSION: Many factors can interfere with the outcome of RIPC. Trying to correct for this led to strict inclusion criteria, which, in combination with a decreased institutional frequency of CABG without concomitant procedures and a change in institutional anesthetic regimen away from volatile anesthetics towards total intravenous anesthesia, caused slow inclusion and halting of this trial after 3 years, before target inclusion could be reached. Therefore this study is underpowered to prove its primary goal that RIPC reduced AUC cTnT by < 25%. Nevertheless, we have shown that the effect of RIPC on 24 h AUC cTnT, in cardiac surgery with anesthesia during surgery restricted to sevoflurane/fentanyl (no propofol), was between a decrease of 27% and an increase of 36%. These findings are not in line with previous studies in this field. TRIAL REGISTRATION: The Netherlands Trial Register: NTR2915 ; Registered 25 Mei 2011. PMID- 28356069 TI - Broad induction of immunoregulatory mechanisms after a short course of anti-IL 7Ralpha antibodies in NOD mice. AB - BACKGROUND: Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of the insulin-producing beta-cells in the pancreas. Therefore, approaches that effectively halt the pathogenic T cell response are predicted to have preventive or therapeutic benefit for type 1 diabetes patients. We previously demonstrated that long-term blocking of IL-7 signaling, which is critical for the survival and function of T cells, prevented and reversed type 1 diabetes in non-obese diabetic mice. However, such persistent inhibition of T cell responses raises concerns about causing immunodeficiency. Here, we asked whether a reduced duration of the treatment with anti-IL-7Ralpha antibodies retained efficacy in preventing diabetes. Moreover, we sought to identify immunoregulatory mechanisms induced by anti-IL-7Ralpha administration. RESULTS: Anti-IL-7Ralpha antibodies were administered to prediabetic NOD mice for 3 weeks and blood samples were taken at the end of treatment and 2 weeks later to analyze changes in T cell phenotypes in response to IL-7Ralpha blockade. We found that the co-inhibitory receptors LAG-3, Tim-3 and PD-1 were increased on peripheral blood CD4+ and CD8+ T cells from anti-IL-7Ralpha-treated mice. Expression of these receptors contributed to reduced T cell cytokine production in response to TCR stimulation. In addition, the frequency of Tregs within the circulating CD4+ T cells was increased at the end of anti-IL-7Ralpha antibody treatment and these Tregs showed a more activated phenotype. In vitro restimulation assays revealed that effector T cells from anti-IL-7Ralpha-treated mice were more sensitive to co inhibitory receptor induction after TCR stimulation. Importantly, these changes were accompanied by delayed type 1 diabetes disease kinetics. CONCLUSIONS: Together, our data show that short-term blockade of IL-7Ralpha induces detectable changes in co-inhibitory receptor expression and Treg frequencies in peripheral blood of NOD mice. These changes appear to have long-lasting effects by delaying or preventing type 1 diabetes incidence. Hence, our study provides further support for using anti-IL-7Ralpha antibodies to modulate autoreactive T cell responses. PMID- 28356070 TI - Core-genome scaffold comparison reveals the prevalence that inversion events are associated with pairs of inverted repeats. AB - BACKGROUND: Genome rearrangement describes gross changes of chromosomal regions, plays an important role in evolutionary biology and has profound impacts on phenotype in organisms ranging from microbes to humans. With more and more complete genomes accomplished, lots of genomic comparisons have been conducted in order to find genome rearrangements and the mechanisms which underlie the rearrangement events. In our opinion, genomic comparison of different individuals/strains within the same species (pan-genome) is more helpful to reveal the mechanisms for genome rearrangements since genomes of the same species are much closer to each other. RESULTS: We study the mechanism for inversion events via core-genome scaffold comparison of different strains within the same species. We focus on two kinds of bacteria, Pseudomonas aeruginosa and Escherichia coli, and investigate the inversion events among different strains of the same species. We find an interesting phenomenon that long (larger than 10,000 bp) inversion regions are flanked by a pair of Inverted Repeats (IRs). This mechanism can also explain why the breakpoint reuses for inversion events happen. We study the prevalence of the phenomenon and find that it is a major mechanism for inversions. The other observation is that for different rearrangement events such as transposition and inverted block interchange, the two ends of the swapped regions are also associated with repeats so that after the rearrangement operations the two ends of the swapped regions remain unchanged. To our knowledge, this is the first time such a phenomenon is reported for transposition event. CONCLUSIONS: In both Pseudomonas aeruginosa and Escherichia coli strains, IRs were found at the two ends of long sequence inversions. The two ends of the inversion remained unchanged before and after the inversion event. The existence of IRs can explain the breakpoint reuse phenomenon. We also observed that other rearrangement operations such as transposition, inverted transposition, and inverted block interchange, had repeats (not necessarily inverted) at the ends of each segment, where the ends remained unchanged before and after the rearrangement operations. This suggests that the conservation of ends could possibly be a popular phenomenon in many types of chromosome rearrangement events. PMID- 28356072 TI - Comparative and functional genomics of the Lactococcus lactis taxon; insights into evolution and niche adaptation. AB - BACKGROUND: Lactococcus lactis is among the most widely studied lactic acid bacterial species due to its long history of safe use and economic importance to the dairy industry, where it is exploited as a starter culture in cheese production. RESULTS: In the current study, we report on the complete sequencing of 16 L. lactis subsp. lactis and L. lactis subsp. cremoris genomes. The chromosomal features of these 16 L. lactis strains in conjunction with 14 completely sequenced, publicly available lactococcal chromosomes were assessed with particular emphasis on discerning the L. lactis subspecies division, evolution and niche adaptation. The deduced pan-genome of L. lactis was found to be closed, indicating that the representative data sets employed for this analysis are sufficient to fully describe the genetic diversity of the taxon. CONCLUSIONS: Niche adaptation appears to play a significant role in governing the genetic content of each L. lactis subspecies, while (differential) genome decay and redundancy in the dairy niche is also highlighted. PMID- 28356073 TI - Practical partnered research to improve weight loss among overweight/obese veterans: lessons from the trenches. AB - BACKGROUND: Obesity and obesity-related conditions, such as type 2 diabetes, are a major issue for Veteran health. Veterans Health Administration (VA) researchers and health systems leaders have worked separately and together to provide more effective weight management programs for Veterans. Although randomized clinical trials are often considered the gold standard for establishing efficacy of interventions in controlled circumstances, pragmatic clinical trials (PCTs) provide agility for translation. MAIN TEXT: VA researchers and health system leaders collaboratively designed a PCT to compare the Diabetes Prevention Program (VA-DPP) to usual care (MOVE!(r)) in promoting weight loss and glycemic control among overweight/obese Veterans with prediabetes. Together, they navigated the tensions that exist between quality improvement and research activities, facing challenges but reaping significant rewards. Early findings led to updated national guidance for delivering obesity treatment in VA. SHORT CONCLUSION: Partnered research and the use of PCTs can be powerful strategies for accelerating evidence-based findings into practice. Collaborative partnerships between researchers and health systems leaders can help enhance and sustain translation in real-world settings. PMID- 28356074 TI - A deletion in the intergenic region upstream of Ednrb causes head spot in the rat strain KFRS4/Kyo. AB - BACKGROUND: Head spot is one of the phenotypes identified in the KFRS4/Kyo rat strain. Although previous linkage analysis suggested that Ednrb, which is frequently involved in coat color variations in various animals, could be the gene responsible for this phenotype, no mutations have been identified in its coding region. RESULTS: To identify mutations causative of this phenotype in KFRS4/Kyo, we analyzed target capture sequencing data that we recently generated. Our target capture method has a unique feature, i.e., it covers not only exonic regions but also conserved non-coding sequences (CNSs) among vertebrates; therefore, it has the potential to detect regulatory mutations. We identified a deletion of approximately 50 kb in length approximately 50 kb upstream of Ednrb. A comparative analysis with the epigenomic data in the corresponding region in humans and mice showed that one of the CNSs might be an enhancer. Further comparison with Hi-C data, which provide information about chromosome conformation, indicated that the putative enhancer is spatially close to the promoter of Ednrb, suggesting that it acts as an enhancer of Ednrb. CONCLUSIONS: These in silico data analyses strongly suggest that the identified deletion in the intergenic region upstream of Ednrb, which might contain a melanocyte specific enhancer, is the mutation causative of the head spot phenotype in the KFRS4/Kyo rat strain. PMID- 28356071 TI - Changes in the Sclerotinia sclerotiorum transcriptome during infection of Brassica napus. AB - BACKGROUND: Sclerotinia sclerotiorum causes stem rot in Brassica napus, which leads to lodging and severe yield losses. Although recent studies have explored significant progress in the characterization of individual S. sclerotiorum pathogenicity factors, a gap exists in profiling gene expression throughout the course of S. sclerotiorum infection on a host plant. In this study, RNA-Seq analysis was performed with focus on the events occurring through the early (1 h) to the middle (48 h) stages of infection. RESULTS: Transcript analysis revealed the temporal pattern and amplitude of the deployment of genes associated with aspects of pathogenicity or virulence during the course of S. sclerotiorum infection on Brassica napus. These genes were categorized into eight functional groups: hydrolytic enzymes, secondary metabolites, detoxification, signaling, development, secreted effectors, oxalic acid and reactive oxygen species production. The induction patterns of nearly all of these genes agreed with their predicted functions. Principal component analysis delineated gene expression patterns that signified transitions between pathogenic phases, namely host penetration, ramification and necrotic stages, and provided evidence for the occurrence of a brief biotrophic phase soon after host penetration. CONCLUSIONS: The current observations support the notion that S. sclerotiorum deploys an array of factors and complex strategies to facilitate host colonization and mitigate host defenses. This investigation provides a broad overview of the sequential expression of virulence/pathogenicity-associated genes during infection of B. napus by S. sclerotiorum and provides information for further characterization of genes involved in the S. sclerotiorum-host plant interactions. PMID- 28356075 TI - Genome-wide association study and accuracy of genomic prediction for teat number in Duroc pigs using genotyping-by-sequencing. AB - BACKGROUND: The number of teats in pigs is related to a sow's ability to rear piglets to weaning age. Several studies have identified genes and genomic regions that affect teat number in swine but few common results were reported. The objective of this study was to identify genetic factors that affect teat number in pigs, evaluate the accuracy of genomic prediction, and evaluate the contribution of significant genes and genomic regions to genomic broad-sense heritability and prediction accuracy using 41,108 autosomal single nucleotide polymorphisms (SNPs) from genotyping-by-sequencing on 2936 Duroc boars. RESULTS: Narrow-sense heritability and dominance heritability of teat number estimated by genomic restricted maximum likelihood were 0.365 +/- 0.030 and 0.035 +/- 0.019, respectively. The accuracy of genomic predictions, calculated as the average correlation between the genomic best linear unbiased prediction and phenotype in a tenfold validation study, was 0.437 +/- 0.064 for the model with additive and dominance effects and 0.435 +/- 0.064 for the model with additive effects only. Genome-wide association studies (GWAS) using three methods of analysis identified 85 significant SNP effects for teat number on chromosomes 1, 6, 7, 10, 11, 12 and 14. The region between 102.9 and 106.0 Mb on chromosome 7, which was reported in several studies, had the most significant SNP effects in or near the PTGR2, FAM161B, LIN52, VRTN, FCF1, AREL1 and LRRC74A genes. This region accounted for 10.0% of the genomic additive heritability and 8.0% of the accuracy of prediction. The second most significant chromosome region not reported by previous GWAS was the region between 77.7 and 79.7 Mb on chromosome 11, where SNPs in the FGF14 gene had the most significant effect and accounted for 5.1% of the genomic additive heritability and 5.2% of the accuracy of prediction. The 85 significant SNPs accounted for 28.5 to 28.8% of the genomic additive heritability and 35.8 to 36.8% of the accuracy of prediction. CONCLUSIONS: The three methods used for the GWAS identified 85 significant SNPs with additive effects on teat number, including SNPs in a previously reported chromosomal region and SNPs in novel chromosomal regions. Most significant SNPs with larger estimated effects also had larger contributions to the total genomic heritability and accuracy of prediction than other SNPs. PMID- 28356076 TI - Dexmedetomidine's inhibitory effects on acetylcholine release from cholinergic nerves in guinea pig trachea: a mechanism that accounts for its clinical benefit during airway irritation. AB - BACKGROUND: Airway instrumentation can evoke upper airway reflexes including bronchoconstriction and cough which can cause serious complications including airway trauma, laryngospasm or bronchospasm which may in turn lead to difficulty with ventilation and hypoxemia. These airway events are mediated in part by irritant-induced neuronal modulation of airway tone and cough responses. We investigated whether the commonly used anesthetic agents dexmedetomidine, lidocaine or remifentanil attenuated neuronal and airway smooth muscle responses in the upper airways of guinea pigs. METHODS: The ability of dexmedetomidine, lidocaine or remifentanil to attenuate direct cholinergic nerve stimulation, C fiber stimulation or direct smooth muscle contraction were studied using isolated tracheal rings from male guinea pigs under four paradigms; (1) the magnitude of contractile force elicited by cholinergic electrical field stimulation (EFS); (2) the amount of acetylcholine released during cholinergic EFS; (3) the direct airway smooth muscle relaxation of a sustained acetylcholine-induced contraction and (4) the magnitude of C-fiber mediated contraction. RESULTS: Dexmedetomidine (1-100 MUM) and lidocaine (1 mM) attenuated cholinergic 30Hz EFS-induced tracheal ring contraction while remifentanil (10 MUM) had no effect. Dexmedetomidine at 10 MUM (p = 0.0047) and 100 MUM (p = 0.01) reduced cholinergic EFS-induced acetylcholine release while lidocaine (10 MUM-1 mM) and remifentanil (0.1-10 MUM) did not. Tracheal ring muscle force induced by the exogenous addition of the contractile agonist acetylcholine or by a prototypical C-fiber analogue of capsaicin were also attenuated by 100 MUM dexmedetomidine (p = 0.0061 and p = 0.01, respectively). The actual tracheal tissue concentrations of dexmedetomidine achieved (0.54-26 nM) following buffer application of 1-100 MUM of dexmedetomidine were within the range of clinically achieved plasma concentrations (12 nM). CONCLUSIONS: The alpha2 adrenoceptor agonist dexmedetomidine reduced cholinergic EFS-induced contractions and acetylcholine release consistent with the presence of inhibitory alpha2 adrenoceptors on the prejunctional side of the postganglionic cholinergic nerve-smooth muscle junction. Dexmedetomidine also attenuated both exogenous acetylcholine-induced contraction and C-fiber mediated contraction, suggesting a direct airway smooth muscle effect and an underlying mechanism for cough suppression, respectively. PMID- 28356078 TI - Calcium oxalate crystal related kidney injury in a patient receiving Roux-en Y hepaticojejunostomy due to gall bladder cancer. AB - BACKGROUND: Calcium oxalate nephropathy is rare in current practice. It was a common complication during jejunoileal bypass, but much less seen in modern gastric bypass surgery for morbid obesity. The major cause of it is enteric hyperoxaluria. CASE PRESENTATION: We report on a patient here with acute kidney disease due to calcium oxalate nephropathy, rather than the conditions mentioned above. The male patient received a Roux-en Y hepaticojejunostomy and common bile duct drainage. In addition to enteric hyperoxaluria, chronic kidney disease related metabolic acidosis, chronic diarrhea related volume depletion, a high oxalate and low potassium diet, long term ascorbic acid intake and long term exposure to antibiotics, all predisposed him to having oxalate nephropathy. CONCLUSION: This is the first case with such conditions and we recommend that similarly diagnosed patients avoid all these predisposing factors, in order to avoid this rare disease and its undesired outcome. PMID- 28356077 TI - Evolutionary origin and function of NOX4-art, an arthropod specific NADPH oxidase. AB - BACKGROUND: NADPH oxidases (NOX) are ROS producing enzymes that perform essential roles in cell physiology, including cell signaling and antimicrobial defense. This gene family is present in most eukaryotes, suggesting a common ancestor. To date, only a limited number of phylogenetic studies of metazoan NOXes have been performed, with few arthropod genes. In arthropods, only NOX5 and DUOX genes have been found and a gene called NOXm was found in mosquitoes but its origin and function has not been examined. In this study, we analyzed the evolution of this gene family in arthropods. A thorough search of genomes and transcriptomes was performed enabling us to browse most branches of arthropod phylogeny. RESULTS: We have found that the subfamilies NOX5 and DUOX are present in all arthropod groups. We also show that a NOX gene, closely related to NOX4 and previously found only in mosquitoes (NOXm), can also be found in other taxonomic groups, leading us to rename it as NOX4-art. Although the accessory protein p22-phox, essential for NOX1-4 activation, was not found in any of the arthropods studied, NOX4-art of Aedes aegypti encodes an active protein that produces H2O2. Although NOX4-art has been lost in a number of arthropod lineages, it has all the domains and many signature residues and motifs necessary for ROS production and, when silenced, H2O2 production is considerably diminished in A. aegypti cells. CONCLUSIONS: Combining all bioinformatic analyses and laboratory work we have reached interesting conclusions regarding arthropod NOX gene family evolution. NOX5 and DUOX are present in all arthropod lineages but it seems that a NOX2-like gene was lost in the ancestral lineage leading to Ecdysozoa. The NOX4-art gene originated from a NOX4-like ancestor and is functional. Although no p22-phox was observed in arthropods, there was no evidence of neo-functionalization and this gene probably produces H2O2 as in other metazoan NOX4 genes. Although functional and present in the genomes of many species, NOX4-art was lost in a number of arthropod lineages. PMID- 28356079 TI - Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBLs) colonization as a risk factor for developing ESBL infections in pediatric cardiac surgery patients: "retrospective cohort study". AB - BACKGROUND: Children with cardiac defects need many hospitalizations and repetitive antibiotic therapies, with an increasing risk of colonization with multidrug-resistant bacteria (MDRB) such as extended-spectrum beta-lactamase producing Enterobacteriaceae (ESBL-E) Post-operative infections with these bacteria in paediatric cardiac surgery are life threatening. This article aims to study the prevalence of ESBL colonization among paediatric cardiac surgery patients, and to compare occurrence of post-operative infections with and without ESBL colonization. We also aim to study the correlation between the onset of postoperative infection and other parameters such as age, length of stay and preoperative antibiotic therapy. METHODS: A retrospective cohort study included paediatric cardiac surgery patients in Cheikh Zaid hospital in Rabat, Morocco, between the 1st of January 2011 and 31 December 2014. A screening for ESBL colonization was requested for children who had a risk factor (previous hospitalization and/or taking antibiotics) at admission. Swabs were collected from three sites (throat, nose and anus). Two groups were compared - patients colonized and not colonized with ESBLs. Statistical analysis was performed using R software. RESULTS: ESBL colonization screening was performed in 111 patients. Positive colonization was detected in 17 cases (15%). Klebsiella pneumoniae (KP): 9 (53%) was the most frequently isolated species. Among the 17 patients, 23.5% (4/17) developed a postoperative infection due to ESBLs versus only one patient without colonization (1%). There was a statically significant difference in terms of occurrence of postoperative infection between the two groups (p = 0.001). Relative risk of developing a postoperative infection with positive colonization was 22 (95% CI, 8.37-58.5). CONCLUSIONS: The analysis of colonization with multidrug-resistant bacteria and the prevention of nosocomial infections appear to be important challenges for paediatric cardiac surgery. Systematic screening of ESBL colonization for cardiac surgery could have a significant contribution, on one hand to guide prophylactic antibiotic therapy of patients, and on the other, to prevent spread of those infections. PMID- 28356080 TI - Patient-reported non-adherence and immunosuppressant trough levels are associated with rejection after renal transplantation. AB - BACKGROUND: Different measures of non-adherence to immunosuppressant (IS) medication have been found to be associated with rejection episodes after successful transplantation. The aim of the current study was to investigate whether graft rejection after renal transplantation is associated with patient reported IS medication non-adherence and IS trough level variables (IS trough level variability and percentage of sub-therapeutic IS trough levels). METHODS: Patient-reported non-adherence, IS trough level variability, percentage of sub therapeutic IS trough levels, and acute biopsy-proven late allograft rejections were assessed in 267 adult renal transplant recipients who were >=12 months post transplantation. RESULTS: The rate of rejection was 13.5%. IS trough level variability, percentage of sub-therapeutic IS trough levels as well as patient reported non-adherence were all significantly and positively associated with rejection, but not with each other. Logistic regression analyses revealed that only the percentage of sub-therapeutic IS trough levels and age at transplantation remained significantly associated with rejection. CONCLUSIONS: Particularly, the percentage of sub-therapeutic IS trough levels is associated with acute rejections after kidney transplantation whereas IS trough level variability and patient-reported non-adherence seem to be of subordinate importance. Patient-reported non-adherence and IS trough level variables were not correlated; thus, non-adherence should always be measured in a multi methodological approach. Further research concerning the best combination of non adherence measures is needed. PMID- 28356081 TI - The prevalence of HIV among adults with pulmonary TB at a population level in Zambia. AB - BACKGROUND: Tuberculosis and HIV co-infection is one of the main drivers of poor outcome for both diseases in Zambia. HIV infection has been found to predict TB infection/disease and TB has been reported as a major cause of death among individuals with HIV. Improving case detection of TB/HIV co-infection has the potential to lead to early treatment of both conditions and can impact positively on treatment outcomes. This study was conducted in order to determine the HIV prevalence among adults with tuberculosis in a national prevalence survey setting in Zambia, 2013-2014. METHODS: A countrywide cross sectional survey was conducted in 2013/2014 using stratified cluster sampling, proportional to population size for rural and urban populations. Each of the 66 countrywide clusters represented one census supervisory area with cluster size averaging 825 individuals. Socio demographic characteristics were collected during a household visit by trained survey staff. A standard symptom-screening questionnaire was administered to 46,099 eligible individuals across all clusters, followed by chest x-ray reading for all eligible. Those symptomatic or with x-ray abnormalities were confirmed or ruled out as TB case by either liquid culture or Xpert MTBRif performed at the three central reference laboratories. HIV testing was offered to all participants at the survey site following the national testing algorithm with rapid tests. The prevalence was expressed as the proportion of HIV among TB cases with 95% confidence limits. RESULTS: A total of 265/6123 (4.3%) participants were confirmed of having tuberculosis. Thirty-six of 151 TB survey cases who accepted HIV testing were HIV-seropositive (23.8%; 95% CI 17.2-31.4). The mean age of the TB/HIV cases was 37.6 years (range 24-70). The majority of the TB/HIV cases had some chest x-ray abnormality (88.9%); were smear positive (50.0%), and/or had a positive culture result (94.4%). None of the 36 detected TB/HIV cases were already on TB treatment, and 5/36 (13.9%) had a previous history of TB treatment. The proportion of TB/HIV was higher in urban than in the rural clusters. The HIV status was unknown for 114/265 (43.0%) of the TB cases. CONCLUSIONS: The TB/HIV prevalence in the general population was found to be lower than what is routinely reported as incident TB/HIV cases at facility level. However; the TB/HIV co infection was higher in areas with higher TB prevalence. Innovative and effective strategies for ensuring TB/HIV co-infected individuals are detected and treated early are required. PMID- 28356082 TI - Anti-tumor effects of everolimus and metformin are complementary and glucose dependent in breast cancer cells. AB - BACKGROUND: Clinical efficacy of the mTOR inhibitor everolimus is limited in breast cancer and regularly leads to side-effects including hyperglycemia. The AMPK inhibitor and anti-diabetic drug metformin may counteract everolimus-induced hyperglycemia, as well as enhancing anti-cancer efficacy. We investigated the glucose-dependent growth-inhibitory properties of everolimus, metformin and the combination in breast cancer cell lines. METHODS: The breast cancer cell lines MCF-7, MDA-MB-231 and T47D were cultured in media containing 11 mM or 2.75 mM glucose with 21% or 1% oxygen. Everolimus and metformin treated cells were subjected to cytotoxicity and clonogenic assays, western blotting, FACS and metabolic measurements. RESULTS: Everolimus was less effective in MCF7 cells under low glucose conditions compared to high glucose conditions (IC50 of >50 nM vs 29.1 +/- 1.4 nM) in a short-term survival assay, while sensitivity of MDA-MB 231 and T47D cells to everolimus was lost under low glucose conditions. In contrast, metformin was more effective in low than in high glucose conditions in MCF7 (IC50 of 1.8 +/- 1.2 mM vs >5 mM) and MDA-MB231 cells (1.5 +/- 1.3 mM vs 2.6 +/- 1.2 mM). Metformin sensitivity of T47D cells was independent of glucose concentrations. Everolimus combined with metformin additively inhibited cell survival, clonogenicity, mTOR signaling activity and mitochondrial respiration. These effects were not the result of enhanced autophagy or apoptosis induction. Similar results were observed under hypoxic conditions. CONCLUSION: Metformin induced effects are additive to the anti-proliferative and colony inhibitory properties of everolimus through inhibition of mitochondrial respiration and mTOR signaling. These results warrant further in vivo investigation of everolimus combined with metformin as a putative anti-cancer therapy. PMID- 28356083 TI - Limitations and opportunities of whole blood bilirubin measurements by GEM premier 4000(r). AB - BACKGROUND: Neonatal hyperbilirubinemia has traditionally been screened by either total serum bilirubin or transcutaneous bilirubin. Whole blood bilirubin (TwB) by the GEM Premier 4000(r) blood gas analyzer (GEM) is a relatively new technology and it provides fast bilirubin results with a small sample volume and can measure co-oximetry and other analytes. Our clinical study was to evaluate the reliability of TwB measured by the GEM and identify analytical and clinical factors that may contribute to possible bias. METHODS: 440 consecutive healthy newborn samples that had plasma bilirubin ordered for neonatal hyperbilirubinemia screening were included. TwB was first measured using the GEM, after which the remainder of the blood was spun and plasma neonatal bilirubin was measured using the VITROS 5600(r) (VITROS). RESULTS: 62 samples (14%) were excluded from analysis due to failure in obtaining GEM results. Passing-Bablok regression suggested that the GEM results were negatively biased at low concentrations of bilirubin and positively biased at higher concentrations relative to the VITROS results (y = 1.43x-61.13). Bland-Altman plots showed an overall negative bias of the GEM bilirubin with a wide range of differences compared to VITROS. Both hemoglobin concentration and hemolysis affected the accuracy of the GEM results. Clinically, male infants had higher mean bilirubin levels, and infants delivered by caesarean section had lower hemoglobin levels. When comparing the number of results below the 40th percentile and above the 95th percentile cut-offs in the Bhutani nomogram which would trigger discharge or treatment, GEM bilirubin exhibited poor sensitivity and poor specificity in contrast to VITROS bilirubin. CONCLUSIONS: An imperfect correlation was observed between whole blood bilirubin measured on the GEM4000(r) and plasma bilirubin on the VITROS 5600(r). The contributors to the observed differences between the two instruments were specimen hemolysis and the accuracy of hemoglobin measurements, the latter of which affects the calculation of plasma-equivalent bilirubin. Additionally, the lack of standardization of total bilirubin calibration particularly in newborn specimens, may also account for some of the disagreement in results. PMID- 28356084 TI - Conjugal amyotrophic lateral sclerosis: a case report from Scotland. AB - BACKGROUND: Conjugal amyotrophic lateral sclerosis is rare, with significant effects on psychological and care needs. We report a case of conjugal amyotrophic lateral sclerosis disease from central Scotland. This case is particularly unusual as both patients were diagnosed within an 18-month period and experienced the disease simultaneously, with similar symptomatology and progression. CASE PRESENTATION: Patient A was a 71-year-old man who presented with unilateral arm weakness and wasting. Patient B was a 68-year-old woman who presented with unilateral shoulder and elbow weakness. Diagnosis of amyotrophic lateral sclerosis was made within a few months of presentation in both cases, based on typical clinical symptomatology together with supportive neurophysiological testing. Interventions included enteral feeding and non-invasive ventilation. The time period between symptom onset and death was 5 years for Patient A and 3.5 years for Patient B. CONCLUSION: This case illustrates two main points: the care issues surrounding cases of conjugal neurological disease, and the psychological issues in these patients. There are significant care issues arising when co habiting couples both develop severe functionally limiting neurological diseases at the same time. The more slowly progressive nature of Patient A's disease may be at least partially explained by the support he was able to receive from Patient B before she developed symptoms. Secondly, there are important psychological effects of living with someone with the same - but more advanced - progressive and incurable neurological disease. Thus, Patient B was reluctant to have certain interventions that she had observed being given to her husband. Lastly, no plausible shared environmental risk factors were identified, implying that the co-occurrence of ALS in this couple was a random association. PMID- 28356088 TI - Erratum to: SWITCH: Highlighting consensus among medical scientists increases public support for vaccines: evidence from a randomized experiment. PMID- 28356086 TI - Characterization of calcineurin from Cryptococcus humicola and the application of calcineurin in aluminum tolerance. AB - BACKGROUND: Calcineurin (CaN) is a Ca2+- and calmodulin (CaM)-dependent serine/threonine phosphatase. Previous studies have found that CaN is involved in the regulation of the stress responses. RESULTS: In this study, the growth of Cryptococcus humicola was inhibited by the CaN inhibitor tacrolimus (FK506) under aluminum (Al) stress. The expression of CNA encoding a catalytic subunit A (CNA) and its interaction with CaM were upregulated when the concentration of Al was increased. A CaM-binding domain and key amino acids responsible for interaction with CaM were identified. ?CNAb with a deletion from S454 to A639 was detected to bind to CaM, while ?CNAa with a deletion from R436 to A639 showed no binding to CaM. The binding affinities of CNA1 and CNA2, in which I439 or I443 were replaced by Ala, were decreased relative to wild-type CNA. The phosphatase activities of ?CNAa, CNA1 and CNA2 were lower than the wild-type protein. These results suggest that the region between R436 and S454 is essential for the interaction with CaM and I439, I443 are key amino acids in this region. The ability of the CNA transgenic yeast to develop resistance to Al was significantly higher than that of control yeast. Residual Al in the CNA transgenic yeast culture media was significantly lower than the amount of Al originally added to the media or the residual Al remaining in the control yeast culture media. These findings suggest that CNA confers Al tolerance, and the mechanism of Al tolerance may involve absorption of active Al. CONCLUSIONS: Al stress up-regulated the expression of CNA. CaM-binding domain and key amino acids responsible for interaction with CaM were identified and both are required for phosphatase activities. CNA conferred yeast Al resistance indicating that the gene has a potential to improve Al tolerance through gene engineering. PMID- 28356085 TI - CNV discovery for milk composition traits in dairy cattle using whole genome resequencing. AB - BACKGROUND: Copy number variations (CNVs) are important and widely distributed in the genome. CNV detection opens a new avenue for exploring genes associated with complex traits in humans, animals and plants. Herein, we present a genome-wide assessment of CNVs that are potentially associated with milk composition traits in dairy cattle. RESULTS: In this study, CNVs were detected based on whole genome re-sequencing data of eight Holstein bulls from four half- and/or full-sib families, with extremely high and low estimated breeding values (EBVs) of milk protein percentage and fat percentage. The range of coverage depth per individual was 8.2-11.9*. Using CNVnator, we identified a total of 14,821 CNVs, including 5025 duplications and 9796 deletions. Among them, 487 differential CNV regions (CNVRs) comprising ~8.23 Mb of the cattle genome were observed between the high and low groups. Annotation of these differential CNVRs were performed based on the cattle genome reference assembly (UMD3.1) and totally 235 functional genes were found within the CNVRs. By Gene Ontology and KEGG pathway analyses, we found that genes were significantly enriched for specific biological functions related to protein and lipid metabolism, insulin/IGF pathway-protein kinase B signaling cascade, prolactin signaling pathway and AMPK signaling pathways. These genes included INS, IGF2, FOXO3, TH, SCD5, GALNT18, GALNT16, ART3, SNCA and WNT7A, implying their potential association with milk protein and fat traits. In addition, 95 CNVRs were overlapped with 75 known QTLs that are associated with milk protein and fat traits of dairy cattle (Cattle QTLdb). CONCLUSIONS: In conclusion, based on NGS of 8 Holstein bulls with extremely high and low EBVs for milk PP and FP, we identified a total of 14,821 CNVs, 487 differential CNVRs between groups, and 10 genes, which were suggested as promising candidate genes for milk protein and fat traits. PMID- 28356087 TI - Evaluation of ocular pulse amplitude in non-arteritic anterior ischaemic optic neuropathy. AB - BACKGROUND: To evaluate the ocular pulse amplitude (OPA) in patients with chronic non-arteritic anterior ischaemic optic neuropathy (NAION). METHODS: This cross sectional study comprised a study group of 30 eyes from 30 patients with NAION and a control group of 31 eyes from 31 age and gender-matched healthy subjects. Bilateral OPA was measured with dynamic contour tonometry (DCT) and was compared between the study and control groups. RESULTS: No statistically significant difference was found between the study and control groups in terms of hypertension, diabetes mellitus, ischaemic heart disease and hyperlipidemia. The mean intraocular pressure (IOP) measured with Goldmann Applanation Tonometry and DCT in the study and control groups was not statistically different (p1 = 0.094, p2 = 0.240). The mean OPA in the study group and the control group were 2.01 +/- 0.69 mmHg and 1.97 +/- 0.68 mmHg (p = 0.839). CONCLUSION: No significant difference was determined in the OPA levels of eyes with NAION at the chronic stage and eyes in the control group. PMID- 28356089 TI - Sedentary behaviour is associated with increased long-term cardiovascular risk in patients with rheumatoid arthritis independently of moderate-to-vigorous physical activity. AB - BACKGROUND: Rheumatoid Arthritis (RA) is associated with an increased risk of cardiovascular disease (CVD). The physical dysfunction symptomatic of RA means people living with this disease spend large periods of the day sedentary, which may further elevate their risk of CVD. The primary aim of this study was to investigate relationships between objectively assessed sedentary behaviour patterns and light physical activity (LPA) with 10-year risk of CVD. Secondary aims were to explore the role of sedentary behaviour patterns and LPA for individual CVD risk factors and functional disability in RA. The extent to which associations were independent of moderate-to-vigorous physical activity (MVPA) engagement was also examined. METHODS: Baseline data from a subsample of participants recruited to the Physical Activity in Rheumatoid Arthritis (PARA) study were used to answer current research questions. Sixty-one patients with RA (mean age (+/- SD) = 54.92 +/- 12.39 years) provided a fasted blood sample and underwent physical assessments to evaluate factors associated with their cardiovascular health. Sedentary behaviour patterns (sedentary time, sedentary bouts, sedentary breaks), LPA and MVPA were measured via 7-days of accelerometry. Ten-year CVD risk was computed (Q-risk-score2), and functional disability determined via questionnaire. RESULTS: Regressions revealed significant positive associations between sedentary time and the number of sedentary bouts per day >=20 min with 10-year CVD risk, with the reverse true for LPA participation. Associations were independent of MVPA engagement. CONCLUSIONS: Promoting LPA participation and restricting sedentary bouts to <20 min may attenuate long-term CVD risk in RA, independent of MVPA engagement. TRIAL REGISTRATION: ISRCTN04121489 (retrospectively registered 19/10/2012). PMID- 28356090 TI - ANCA vasculitis in a patient with Alport syndrome: a difficult diagnosis but a treatable disease! AB - BACKGROUND: Alport syndrome and ANCA-associated vasculitis are both rare diseases. The co-existence of these two conditions has never been reported. There is no obvious pathogenic link between these two glomerular diseases. The management of this case highlights the importance of a systematic approach when investigating the unexpected unfavourable evolution of a known glomerulopathy. CASE PRESENTATION: A-17 year old caucasian boy with a genetically proven X-linked Alport syndrome presented with progressive dyspnea, fatigue and pallor. His blood tests showed a severe anemia (Hb 6.9 g/dl) with acute worsening of kidney function (serum creatinine, normal 9 months earlier, was now 3.6 mg/dl). Microscopic hematuria and proteinuria also worsened. He soon developed signs of alveolar hemorrhage. Serological tests showed the presence of perinuclear ANCA with anti MPO specificity. Kidney biopsy showed a necrotizing and crescentic glomerulonephritis. Pulses of methylprednisolone were given in combination with plasmapheresis. The patient further received 6 pulses of cyclophosphamide, followed by maintenance oral azathioprine. During the 15-months follow up he remained well with serum creatinine back to normal, and some residual proteinuria and hematuria ascribed to Alport syndrome. CONCLUSION: We report a young patient with the coexistence of Alport syndrome and ANCA associated vasculitis. Clinicians should be aware of the possibility of a second acquired disease in a patient with a known kidney disease, genetic in this case. This coexistence is very rare, but should be considered even if both diseases are rare, if the evolution is atypical for the single (known) primary disease. The diagnosis of the added vasculitis prompted in our case the initiation of immunosuppressive drugs, with a favourable outcome. PMID- 28356091 TI - Effects of yoga, strength training and advice on back pain: a randomized controlled trial. AB - BACKGROUND: Among the working population, non-specific low-back pain and neck pain are one of the most common reasons for sickness absenteeism. The aim was to evaluate the effects of an early intervention of yoga - compared with strength training or evidence-based advice - on sickness absenteeism, sickness presenteeism, back and neck pain and disability among a working population. METHODS: A randomized controlled trial was conducted on 159 participants with predominantly (90%) chronic back and neck pain. After screening, the participants were randomized to kundalini yoga, strength training or evidence-based advice. Primary outcome was sickness absenteeism. Secondary outcomes were sickness presenteeism, back and neck pain and disability. Self-reported questionnaires and SMS text messages were completed at baseline, 6 weeks, 6 and 12 months. RESULTS: The results did not indicate that kundalini yoga and strength training had any statistically significant effects on the primary outcome compared with evidence based advice. An interaction effect was found between adherence to recommendations and sickness absenteeism, indicating larger significant effects among the adherers to kundalini yoga versus evidence-based advice: RR = 0.47 (CI 0.30; 0.74, p = 0.001), strength training versus evidence-based advice: RR = 0.60 (CI 0.38; 0.96, p = 0.032). Some significant differences were also found for the secondary outcomes to the advantage of kundalini yoga and strength training. CONCLUSIONS: Guided exercise in the forms of kundalini yoga or strength training does not reduce sickness absenteeism more than evidence-based advice alone. However, secondary analyses reveal that among those who pursue kundalini yoga or strength training at least two times a week, a significantly reduction in sickness absenteeism was found. Methods to increase adherence to treatment recommendations should be further developed and applied in exercise interventions. TRIAL REGISTRATION: Clinicaltrials.gov NCT01653782, date of registration: June, 28, 2012, retrospectively registered. PMID- 28356092 TI - The educational gradient in cardiovascular risk factors: impact of shared family factors in 228,346 Norwegian siblings. AB - BACKGROUND: Various indicators of childhood socioeconomic position have been related to cardiovascular disease (CVD) risk in adulthood. We investigated the impact of shared family factors on the educational gradient in midlife CVD risk factors by assessing within sibling similarities in the gradient using a discordant sibling design. METHODS: Norwegian health survey data (1980-2003) was linked to educational and generational data. Participants with a full sibling in the health surveys (228,346 individuals in 98,046 sibships) were included. Associations between attained educational level (7-9 years, 10-11 years, 12 years, 13-16 years, or >16 years) and CVD risk factor levels in the study population was compared with the corresponding associations within siblings. RESULTS: Educational gradients in risk factors were attenuated when factors shared by siblings was taken into account: A one category lower educational level was associated with 0.7 (95% confidence interval 0.6 to 0.8) mm Hg higher systolic blood pressure (27% attenuation), 0.4 (0.4 to 0.5) mmHg higher diastolic blood pressure (30%), 1.0 (1.0 to 1.1) more beats per minute higher heart rate (21%), 0.07 (0.06 to 0.07) mmol/l higher serum total cholesterol (32%), 0.2 (0.2 to 0.2) higher smoking level (5 categories) (30%), 0.15 (0.13 to 0.17) kg/m2 higher BMI (43%), and 0.2 (0.2 to 0.2) cm lower height (52%). Attenuation increased with shorter age-difference between siblings. CONCLUSION: About one third of the educational gradients in modifiable CVD risk factors may be explained by factors that siblings share. This implies that childhood environment is important for the prevention of CVD. PMID- 28356093 TI - Conflict-related trauma and bereavement: exploring differential symptom profiles of prolonged grief and posttraumatic stress disorder. AB - BACKGROUND: Exposure to trauma and bereavement is common in conflict-affected regions. Previous research suggests considerable heterogeneity in responses to trauma and loss with varying symptom representations. The purpose of the current study was to (1) identify classes of prolonged grief disorder (PGD) and posttraumatic stress disorder (PTSD) symptom profiles among individuals who were exposed to both trauma and loss due to the Colombian armed conflict and (2) to examine whether sociodemographic, loss and trauma-related characteristics could predict class membership. METHODS: Three hundred eight victims of internal displacement who had experienced trauma and loss were assessed through measures of PGD (PG-13), PTSD (PCL-C), and social support (DUKE-UNC). Latent class analysis (LCA) was performed to analyze differential profiles by symptoms of PGD and PTSD and multinomial logistic regression was used to analyze predictors of class membership. RESULTS: LCA revealed a four-class solution: a resilient class (23.6%), a PTSD-class (23.3%), a predominately PGD class (25.3%) and a high distress-class with overall high values of PGD and PTSD (27.8%). Relative to the resilient class, membership to the PGD class was predicted by the loss of a close family member and the exposure to a higher number of assaultive traumatic events, whereas membership to the PTSD class was predicted by the perception of less social support. Compared to the resilient class, participants in the high distress-class were more likely to be female, to have lost a close relative, experienced more accidental and assaultive traumatic events, and perceived less social support. DISCUSSION: Specific symptom profiles emerged following exposure to trauma and loss within the context of the Colombian armed conflict. Profiles were associated with distinct types of traumatic experiences, the degree of closeness to the person lost, the amount of social support perceived, and gender. The results have implications for identifying distressed subgroups and informing interventions in accordance with the patient's symptom profile. PMID- 28356094 TI - Do the correlates of screen time and sedentary time differ in preschool children? AB - BACKGROUND: Preschool children can spend up to 12 h a day in sedentary time and few meet current recommendations for screen time. Little is known about ecological correlates that could be targeted to decrease specific versus total sedentary behaviour. This study examined whether the correlates of screen time and sedentary time differ in preschool boys and girls. METHODS: Parents participating in the HAPPY Study in 2008/09 in Melbourne, Australia reported their child's usual screen time and potential individual, social and physical environment correlates. Children wore ActiGraph GT1M accelerometers for eight days to objectively assess sedentary time (<100 counts.min-1). Multivariable linear regression analyses were performed, stratified by sex and controlling for child age, preschool/childcare attendance and clustering by centre of recruitment. Correlates significantly associated with screen time or sedentary time in individual models (p < 0.05) were included in final combined models. RESULTS: Children were sedentary for 301.1 (SD 34.1) minutes/day and spent 108.5 (SD 69.6) minutes/day in screen time. There were no sex differences in screen or sedentary time. In the final models, sleep duration was inversely associated with girls' sedentary time and boys' screen time. The only other consistent correlates for boys and girls were parental self-efficacy to limit screen time and screen time rules, which were inversely associated with screen time for both sexes. Parents reporting that they get bored watching their child play was inversely associated and maternal television viewing was positively associated with boys' screen time. Paternal age was positively associated with boys' sedentary time. Maternal ethnicity was inversely associated and paternal education, child preferences for sedentary behaviour, and parental concerns about child's physical activity and sedentary behaviour were positively associated with girls' screen time. CONCLUSIONS: The modifiable correlates of total sedentary and screen time identified in this study could be targeted in interventions to reduce these behaviours. With correlates differing for screen and sedentary time, and between boys and girls, interventions may also benefit from including behaviour- and sex specific strategies. PMID- 28356095 TI - Methylphenidate use and school performance among primary school children: a descriptive study. AB - BACKGROUND: There is no conclusive evidence that stimulants have beneficial effects on major associated outcome parameters, particularly school performance. We assessed the differences in school performance among children using methylphenidate at the end of primary school in relation to various parameters of methylphenidate use. METHODS: We linked children from a pharmacy prescription database with standardized achievement test results at the end of primary school. We explored differences in test scores between current methylphenidate users versus never users and methylphenidate users who stopped treatment at least 6 months before the test, early versus late starters, different dosage of methylphenidate, and concurrent antipsychotic or asthma treatment. RESULTS: Out of the 7736 children, 377 (4.9%) children were treated with methylphenidate at the time of the test. After adjusting for confounders the methylphenidate users (532.58 +/- .48) performed significantly lower on the test than never users (534.72 +/- .11). Compared with late starters of methylphenidate treatment (536.94 +/- 1.51) we found significantly lower test scores for the early starters (532.33 +/- .50). CONCLUSION: Our study indicates that children using methylphenidate still perform less at school compared to their peers. Our study also suggests that earlier start of methylphenidate treatment is associated with a lower school performance compared to children starting later with the treatment. This result could either indicate a limited effect of long term treatment or a more strongly affected group of early starters. PMID- 28356096 TI - beta-Cell protection and antidiabetic activities of Crassocephalum crepidioides (Asteraceae) Benth. S. Moore extract against alloxan-induced oxidative stress via regulation of apoptosis and reactive oxygen species (ROS). AB - BACKGROUND: Medicinal plants are becoming more popular in the treatment of various diseases because of the adverse effects of the current therapy, especially antioxidant plant components such as phenols and flavonoids have a protective role against oxidative stress-induced degenerative diseases like diabetes. Thus, the purpose of this study was to investigate beta-cell protection and antidiabetic activities of Crassocephalum crepidioides (Asteraceae) Benth. S. Moore. METHOD: The in-vitro study was conducted by the pancreatic beta-cell culture and alpha-amylase inhibition technique which includes two methods, namely starch-iodine method and 3,5-dinitrosalicylic acid (DNSA) method. On the other hand, the in-vivo study was performed by oral glucose tolerance test (OGTT) method and alloxan-induced diabetes method by using Wistar albino rat. At the end pancreatic specimens were removed and processed for histopathological study. RESULT: The plant extract showed significant (*p < 0.05, **p < 0.01) effect on hyperglycemia as compared to standard (Gliclazide) in OGTT. The plant extract showed efficient protection activity of pancreatic beta-cell from cell death in INS-1 cell line by significantly reduced (*p < 0.05, **p < 0.01) the levels alloxan-induced apoptosis and intracellular reactive oxygen species (ROS) accumulation. In addition, the plant extract showed a significant (*p < 0.05, **p < 0.01) effect on hyperglycemia by increases in percent of beta-cells present in each islet (45% - 60%) compared to the diabetic group. CONCLUSION: The result showed that C. crepidioides had beta-cell protection and antidiabetic activities in pancreatic beta-cell culture and Wistar albino rat. PMID- 28356098 TI - Bitterness and antibacterial activities of constituents from Evodia rutaecarpa. AB - BACKGROUND: Bitter herbs are important in Traditional Chinese Medicine and the Electronic Tongue (e-Tongue) is an instrument that can be trained to evaluate bitterness of bitter herbs and their constituents. The aim of this research was to evaluate bitterness of limonoids and alkaloids from Evodia rutaecarpa to demonstrate that they are main bitter material basic of E. rutaecarpa. METHODS: Nine compounds, including limonoids, indoloquinazoline alkaloids and quinolone alkaloids, were isolated, identified and analyzed by the e-Tongue. Additionally, the antibacterial activities of the nine compounds were evaluated against E. coli and S. aureus. RESULTS: All the nine compounds had bitter taste and antibacterial activities to some extent. Among them, limonoids, which were the bitterest compounds, had greater antibacterial activities than alkaloids. And there is a positive correlation between bitter taste and antibacterial activities. CONCLUSIONS: It was confirmed in our study that limonoids, indoloquinazoline alkaloids and quinolone alkaloids are main bitter material basic of E. rutaecarpa based on two evaluation methods of e-Tongue and antibacterial experiment. In addition, the e-Tongue technique is a suitable new method to measure bitter degree in herbs. PMID- 28356097 TI - Adaptive goal setting and financial incentives: a 2 * 2 factorial randomized controlled trial to increase adults' physical activity. AB - BACKGROUND: Emerging interventions that rely on and harness variability in behavior to adapt to individual performance over time may outperform interventions that prescribe static goals (e.g., 10,000 steps/day). The purpose of this factorial trial was to compare adaptive vs. static goal setting and immediate vs. delayed, non-contingent financial rewards for increasing free living physical activity (PA). METHODS: A 4-month 2 * 2 factorial randomized controlled trial tested main effects for goal setting (adaptive vs. static goals) and rewards (immediate vs. delayed) and interactions between factors to increase steps/day as measured by a Fitbit Zip. Moderate-to-vigorous PA (MVPA) minutes/day was examined as a secondary outcome. RESULTS: Participants (N = 96) were mainly female (77%), aged 41 +/- 9.5 years, and all were insufficiently active and overweight/obese (mean BMI = 34.1 +/- 6.2). Participants across all groups increased by 2389 steps/day on average from baseline to intervention phase (p < .001). Participants receiving static goals showed a stronger increase in steps per day from baseline phase to intervention phase (2630 steps/day) than those receiving adaptive goals (2149 steps/day; difference = 482 steps/day, p = .095). Participants receiving immediate rewards showed stronger improvement (2762 step/day increase) from baseline to intervention phase than those receiving delayed rewards (2016 steps/day increase; difference = 746 steps/day, p = .009). However, the adaptive goals group showed a slower decrease in steps/day from the beginning of the intervention phase to the end of the intervention phase (i.e. less than half the rate) compared to the static goals group (-7.7 steps vs. -18.3 steps each day; difference = 10.7 steps/day, p < .001) resulting in better improvements for the adaptive goals group by study end. Rate of change over the intervention phase did not differ between reward groups. Significant goal phase x goal setting x reward interactions were observed. CONCLUSIONS: Adaptive goals outperformed static goals (i.e., 10,000 steps) over a 4-month period. Small immediate rewards outperformed larger, delayed rewards. Adaptive goals with either immediate or delayed rewards should be preferred for promoting PA. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02053259 registered prospectively on January 31, 2014. PMID- 28356099 TI - Corneal densitometry changes in a patient with interface fluid syndrome after small incision lenticule extraction. AB - BACKGROUND: To report a case of interface fluid syndrome (IFS) following small incision lenticule extraction (SMILE) evaluated with corneal densitometry and optical coherence tomography (OCT). CASE PRESENTATION: An 18-year-old man reported sudden vision loss 24 days after SMILE procedure. Intraocular pressure (IOP) was 36.3 mmHg (OD) and 36.7 mmHg (OS) by noncontact tonometry. Moderate corneal edema, interface fluid pocket and haze were observed by OCT and confirmed by corneal densitometry values. Discontinuation of steroids and addition of hypotensive medication were offered immediately. The symptoms were cured after the medication. Changes of corneal densitometry were consistent with the clinical course of IFS. CONCLUSION: This case illustrates that it is crucial to be aware that a history of SMILE can also cause IFS. Both OCT and corneal densitometry can serve as auxiliary means to evaluate the clinical course of IFS, and appropriate IOP management is an effective approach. PMID- 28356101 TI - Erratum to: Reference intervals for thyroid stimulating hormone and free thyroxine derived from neonates undergoing routine screening for congenital hypothyroidism at a university teaching hospital in Nairobi, Kenya: a cross sectional study. PMID- 28356100 TI - Bioactivity of arid region honey: an in vitro study. AB - BACKGROUND: Antioxidant and anti-inflammatory properties of honey have been largely recognized by various studies. Almost all of the potential benefits are associated with polyphenol content. Honey varieties from the arid region are reported to be rich in polyphenols, but data related to its bioactivity in vitro is greatly lacking. This study aimed at establishing the antioxidant and anti inflammatory properties of arid region honey. Four honey varieties from arid region (H1, H2, H3, and H4) and two popular non-arid region honey (H5 and H6) were tested in vitro in this study. METHODS: The erythrocyte membrane protection effect of honey varieties were measured by hemolysis assay after exposing erythrocytes to a peroxide generator. The subsequent production of MDA (malondialdehyde) content in erythrocytes was measured. Immunomodulatory effect of the honey varieties was tested in prostate cancer cells PC-3 and PBMC (peripheral blood mononuclear cells) by measuring the IL-6 (interleukin 6) and NO (nitric oxide) levels in cell culture supernatant after incubation with the honey varieties. PC-3 cell viability was assessed after incubation with honey varieties for 24 h. RESULTS: Arid region honey exhibited superior erythrocyte membrane protection effect with H4 measuring 1.3 +/- 0.042mMTE/g and H2 measuring 1.122 +/ 0.018mMTE/g. MDA levels were significantly reduced by honey samples, especially H4 (20.819 +/- 0.63 nmol/mg protein). We observed a significant decrease in cell population in PC-3 after 24 h in culture on treatment with honey. A moderate increase in NO levels was observed in both cultures after 24 h at the same time levels of IL-6 were remarkably reduced by honey varieties. CONCLUSION: The results demonstrate the antioxidant effect of arid region honey due to its erythrocyte membrane protection effect and subsequent lowering of oxidative damage as evident from lower levels of lipid peroxidation byproduct MDA. Arid region honey varieties were as good as non-arid region types at decreasing cell viability of prostate cancer cells. The moderate increase in NO levels in PC-3 and PBMCs were not significant enough to elicit any pro-inflammatory response. However, IL-6 secretion was remarkably reduced by all honey varieties in a comparable level indicating the potential anti-inflammatory property of arid region honey. PMID- 28356103 TI - Erratum to: Unraveling the associations of age and menopause with cardiovascular risk factors in a large population-based study. PMID- 28356102 TI - Methods for analyzing observational longitudinal prognosis studies for rheumatic diseases: a review & worked example using a clinic-based cohort of juvenile dermatomyositis patients. AB - Most outcome studies of rheumatic diseases report outcomes ascertained on a single occasion. While single assessments are sufficient for terminal or irreversible outcomes, they may not be sufficiently informative if outcomes change or fluctuate over time. Consequently, longitudinal studies that measure non-terminal outcomes repeatedly afford a better understanding of disease evolution.Longitudinal studies require special analytic methods. Newer longitudinal analytic methods have evolved tremendously to deal with common challenges in longitudinal observational studies. In recent years, an increasing number of studies have used longitudinal design. This review aims to help readers understand and apply the findings from longitudinal studies. Using a cohort of children with juvenile dermatomyositis (JDM), we illustrate how to study evolution of disease activity in JDM using longitudinal methods. PMID- 28356104 TI - Heterologous biosynthesis and manipulation of crocetin in Saccharomyces cerevisiae. AB - BACKGROUND: Due to excellent performance in antitumor, antioxidation, antihypertension, antiatherosclerotic and antidepressant activities, crocetin, naturally exists in Crocus sativus L., has great potential applications in medical and food fields. Microbial production of crocetin has received increasing concern in recent years. However, only a patent from EVOVA Inc. and a report from Lou et al. have illustrated the feasibility of microbial biosynthesis of crocetin, but there was no specific titer data reported so far. Saccharomyces cerevisiae is generally regarded as food safety and productive host, and manipulation of key enzymes is critical to balance metabolic flux, consequently improve output. Therefore, to promote crocetin production in S. cerevisiae, all the key enzymes, such as CrtZ, CCD and ALD should be engineered combinatorially. RESULTS: By introduction of heterologous CrtZ and CCD in existing beta-carotene producing strain, crocetin biosynthesis was achieved successfully in S. cerevisiae. Compared to culturing at 30 degrees C, the crocetin production was improved to 223 MUg/L at 20 degrees C. Moreover, an optimal CrtZ/CCD combination and a titer of 351 MUg/L crocetin were obtained by combinatorial screening of CrtZs from nine species and four CCDs from Crocus. Then through screening of heterologous ALDs from Bixa orellana (Bix_ALD) and Synechocystis sp. PCC6803 (Syn_ALD) as well as endogenous ALD6, the crocetin titer was further enhanced by 1.8-folds after incorporating Syn_ALD. Finally a highest reported titer of 1219 MUg/L at shake flask level was achieved by overexpression of CCD2 and Syn_ALD. Eventually, through fed-batch fermentation, the production of crocetin in 5-L bioreactor reached to 6278 MUg/L, which is the highest crocetin titer reported in eukaryotic cell. CONCLUSIONS: Saccharomyces cerevisiae was engineered to achieve crocetin production in this study. Through combinatorial manipulation of three key enzymes CrtZ, CCD and ALD in terms of screening enzymes sources and regulating protein expression level (reaction temperature and copy number), crocetin titer was stepwise improved by 129.4-fold (from 9.42 to 1219 MUg/L) as compared to the starting strain. The highest crocetin titer (6278 MUg/L) reported in microbes was achieved in 5-L bioreactors. This study provides a good insight into key enzyme manipulation involved in serial reactions for microbial overproduction of desired compounds with complex structure. PMID- 28356105 TI - First clinical case report of Cytauxzoon sp. infection in a domestic cat in France. AB - BACKGROUND: Feline cytauxzoonosis is an emerging infection caused by tick transmitted apicomplexan parasites of the genus Cytauxzoon. The association of clinical disease with Cytauxzoon infection appears to be limited to C. felis infections in the Americas. Sporadic infections of wild and domestic felids with Cytauxzoon sp. were recently described in European countries but clinical reports of the infection are rare and incomplete. This case report brings new interesting information on cytauxzoonosis expression in Europe. CASE PRESENTATION: A 9-years old castrated European shorthair cat living in rural area of north-eastern France (Saint Sauveur, Bourgogne-Franche-Comte region), without any travel history was presented for consultation due to hyperthermia, anorexia, depression and prolonged fever that didn't respond to antibiotic therapy. The cat had outdoor access with a history of vagrancy and was adequately vaccinated (core vaccines and FeLV vaccine). During biological investigations, intraerythrocytic inclusions were observed on blood smear and were further investigated by PCR analysis and sequencing. Molecular analyses confirmed Cytauxzoon sp. infection. The cat was treated with a subcutaneous injection of imidocarb dipropionate (3.5 mg/kg). One week after treatment, the cat improved clinically, although parasitic inclusions within erythrocytes persisted, and only a mild lymphocytosis was found. Two weeks after treatment, the cat appeared in excellent health, appetite was normal and parasitemia was negative. However, one month after treatment the cat relapsed with hyperthermia, anorexia, and depression. Blood smears and PCR were once again positive. Subsequently, the cat received an additional dose of imidocarb dipropionate (3.5 mg/kg SC) and recovered rapidly without other clinical signs. Two weeks after the second imidocarb injection, the cat was hit by a car and died. CONCLUSION: This case provides the first clinical description of infection by Cytauxzoon sp. in a domestic cat in France. These findings support the fact that cytauxzoonosis should be considered in the differential diagnosis of acute febrile illness which does not respond to antibiotic in cats with outdoor access especially in areas where populations of wild felids are present. PMID- 28356106 TI - Protective effects of various ratios of DHA/EPA supplementation on high-fat diet induced liver damage in mice. AB - BACKGROUND: A sedentary lifestyle and poor diet are risk factors for the progression of non-alcoholic fatty liver disease. However, the pathogenesis of hepatic lipid accumulation is not completely understood. Therefore, the present study explored the effects of dietary supplementation of various ratios of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on a high-fat diet induced lipid metabolism disorder and the concurrent liver damage. METHODS: Using high-fat diet-fed C57BL/6 J mice as the animal model, diets of various ratios of DHA/EPA (2:1, 1:1, and 1:2) with an n-6/n-3 ratio of 4:1 were prepared using fish and algae oils enriched in DHA and/or EPA and sunflower seed oils to a small extent instead of the high-fat diet. RESULTS: Significantly decreased hepatic lipid deposition, body weight, serum lipid profile, inflammatory reactions, lipid peroxidation, and expression of adipogenesis-related proteins and inflammatory factors were observed for mice that were on a diet supplemented with DHA/EPA compared to those in the high-fat control group. The DHA/EPA 1:2 group showed lower serum triglycerides (TG), total cholesterol (TC), and low-density lipoprotein-cholesterol levels, lower SREBP-1C, FAS, and ACC-1 relative mRNA expression, and higher Fra1 mRNA expression, with higher relative mRNA expression of enzymes such as AMPK, PPARalpha, and HSL observed in the DHA/EPA 1:1 group. Lower liver TC and TG levels and higher superoxide dismutase levels were found in the DHA/EPA 2:1 group. Nonetheless, no other notable effects were observed on the biomarkers mentioned above in the groups treated with DHA/EPA compared with the DHA group. CONCLUSIONS: The results showed that supplementation with a lower DHA/EPA ratio seems to be more effective at alleviating high-fat diet-induced liver damage in mice, and a DHA/EPA ratio of 1:2 mitigated inflammatory risk factors. These effects of n-3 polyunsaturated fatty acids (PUFA) on lipid metabolism may be linked to the upregulation of Fra1 and attenuated activity of c Jun and c-Fos, thus ultimately reducing the severity of the lipid metabolism disorder and liver damage to some extent. PMID- 28356107 TI - Parental separation in childhood as a risk factor for depression in adulthood: a community-based study of adolescents screened for depression and followed up after 15 years. AB - BACKGROUND: Earlier research has investigated the association between parental separation and long-term health outcomes among offspring, but few studies have assessed the potentially moderating role of mental health status in adolescence. The aim of this study was to analyze whether parental separation in childhood predicts depression in adulthood and whether the pattern differs between individuals with and without earlier depression. METHODS: A community-based sample of individuals with adolescent depression in 1991-93 and matched non depressed peers were followed up using a structured diagnostic interview after 15 years. The participation rate was 65% (depressed n = 227; non-depressed controls n = 155). Information on parental separation and conditions in childhood and adolescence was collected at baseline. The outcome was depression between the ages 19-31 years; information on depression was collected at the follow-up diagnostic interview. The statistical method used was binary logistic regression. RESULTS: Our analyses showed that depressed adolescents with separated parents had an excess risk of recurrence of depression in adulthood, compared with depressed adolescents with non-separated parents. In addition, among adolescents with depression, parental separation was associated with an increased risk of a switch to bipolar disorder in adulthood. Among the matched non-depressed peers, no associations between parental separation and adult depression or bipolar disorder were found. CONCLUSIONS: Parental separation may have long-lasting health consequences for vulnerable individuals who suffer from mental illness already in adolescence. PMID- 28356108 TI - Amelioration of experimental autoimmune encephalomyelitis by clozapine is not associated with defective CD4 T cell responses. AB - Atypical antipsychotic agents, such as clozapine, are used for treating psychosis and depression and have recently been found to modulate neuroinflammation. We have shown previously that treatment of mice with the atypical antipsychotic agents, clozapine or risperidone, attenuates disease severity in experimental autoimmune encephalomyelitis (EAE); however, the mechanism by which they are protective is unknown. In this study, we investigated the effects of clozapine on CD4+ T cell responses and found that clozapine did not significantly affect the expansion of myelin-specific T cells, their differentiation into pathogenic subsets, or their encephalitogenic capacity to induce EAE. Interestingly, although clozapine enhanced differentiation of regulatory T (Treg) cells, in vivo neutralization of Tregs indicated that Tregs were not responsible for the protective effects of clozapine during the induction and effector phase of EAE. Taken together, our studies indicate that clozapine does not mediate its protective effects by directly altering CD4 T cells. PMID- 28356109 TI - Systematic review and meta-analysis of mortality of patients infected with carbapenem-resistant Klebsiella pneumoniae. AB - PURPOSE: Carbapenem resistant K. pneumoniae (CRKP) has aroused widespread attention owing to its very limited therapeutic options, and this strain has increased rapidly in recent years. Although it is accepted that drug resistance is associated with increased mortality in general, but some other studies found no such relationship. To estimate mortality of patients infected with CRKP in general and analyze factors for mortality of this infection, thus, we conducted this systematic review and meta-analysis. METHODS: A systematic literature review of relevant studies published until December 2015 was conducted. We selected and assessed articles reporting mortality of patients infected with CRKP. RESULTS: Pooled mortality was 42.14% among 2462 patients infected with CRKP versus 21.16% in those infected with carbapenem-susceptible K. pneumoniae (CSKP). The mortality of patients with bloodstream infection (BSI) or urinary tract infection was 54.30 and 13.52%, respectively, and 48.9 and 43.13% in patients admitted to the intensive care unit (ICU) or who underwent solid organ transplantation (SOT). Mortality was 47.66% in patients infected with K. pneumoniae carbapenemase producing K. pneumoniae and 46.71% in those infected with VIM-producing K. pneumoniae. Geographically, mortality reported in studies from North America, South America, Europe, and Asia was 33.24, 46.71, 50.06, and 44.82%, respectively. CONCLUSIONS: Our study suggests that patients infected with CRKP have higher mortality than those infected with CSKP, especially in association with BSI, ICU admission, or SOT. We also considered that patients' survival has a close relationship with their physical condition. Our results imply that attention should be paid to CRKP infection, and that strict infection control measures and new antibiotics are required to protect against CRKP infection. PMID- 28356112 TI - Predictors of breath alcohol concentrations in college parties. AB - BACKGROUND: Alcohol use and subsequent consequences are harmful for individual college students. Other students and the university can also be negatively impacted by the consequences of alcohol use. METHOD: A field-based study was used to assess the alcohol use environment at college parties. Researchers replicated a previous study by driving and walking a route to identify parties primarily on Thursday, Friday, and Saturday evenings between 9:00 PM and 1:00 AM across an academic year. Parties were randomly sampled. Hosts were asked for permission to enter the party at each sampled location. A census of partygoers was attempted at each party. Participants were asked to complete a brief survey and give a breath sample. All participants were recruited into a follow-up survey. Bivariate and multivariate analyses of individual-level and party-level factors associated with intoxication are presented. RESULTS: The research team identified 29 parties: 16 were approached, and 12 were surveyed. Overall, 112 participants were surveyed for a response rate of approximately 28.7% of partygoers. Controlling for demographic characteristics, consumption of shots of liquor/spirits was significantly associated with a five times greater risk for intoxication. Notably, drinking games were protective of breath alcohol concentration (BrAC) risk in this model. Individuals who reported engaging in drinking games were 74% less likely to report a BrAC above the U.S. legal limit, while controlling for underage drinking in the model. Several party characteristics were identified that increased overall BrAC at the parties, including whether the party was themed, if it was a Greek life party, and whether there were illicit drugs present. Notably, when intoxication is examined by gender and party theme, women are significantly more likely to be intoxicated at themed parties: 75% were above 0.08 at themed parties compared to 35% above 0.08 at non-themed parties. CONCLUSIONS: Field-based data collection methods can, and should, be modified to conduct needs assessment and evaluation of prevention programs on college campuses. The findings on this campus were different than the originally sampled campus. Prevention programs should target unique risks identified on each campus, and to respond to problematic party behaviors with comprehensive programming rather than policy-level bans. PMID- 28356110 TI - Understanding cell signaling in cancer stem cells for targeted therapy - can phosphoproteomics help to reveal the secrets? AB - BACKGROUND: Cancer represents heterogeneous and aberrantly proliferative manifestations composed of (epi)genetically and phenotypically distinct cells with a common clonal origin. Cancer stem cells (CSC) make up a rare subpopulation with the remarkable capacity to initiate, propagate and spread a malignant disease. Furthermore, CSC show increased therapy resistance, thereby contributing to disease relapse. Elimination of CSC, therefore, is a crucial aim to design efficacious treatments for long-term survival of cancer patients. In this article, we highlight the nature of CSC and propose that phosphoproteomics based on unbiased high-performance liquid chromatography-mass spectrometry provides a powerful tool to decipher the molecular CSC programs. Detailed knowledge about the regulation of signaling processes in CSC is a prerequisite for the development of patient-tailored multi-modal treatments including the elimination of rare CSC. MAIN BODY: Phosphorylation is a crucial post-translational modification regulating a plethora of both intra- and intercellular communication processes in normal and malignant cells. Small-molecule targeting of kinases has proven successful in the therapy, but the high rates of relapse and failure to stem malignant spread suggest that these kinase inhibitors largely spare CSC. Studying the kinetics of global phosphorylation patterns in an unbiased manner is, therefore, required to improve strategies and successful treatments within multi-modal therapeutic regimens by targeting the malignant behavior of CSC. The phosphoproteome comprises all phosphoproteins within a cell population that can be analyzed by phosphoproteomics, allowing the investigation of thousands of phosphorylation events. One major aspect is the perception of events underlying the activation and deactivation of kinases and phosphatases in oncogenic signaling pathways. Thus, not only can this tool be harnessed to better understand cellular processes such as those controlling CSC, but also applied to identify novel drug targets for targeted anti-CSC therapy. CONCLUSION: State-of the-art phosphoproteomics approaches focusing on single cell analysis have the potential to better understand oncogenic signaling in heterogeneous cell populations including rare, yet highly malignant CSC. By eliminating the influence of heterogeneity of populations, single-cell studies will reveal novel insights also into the inter- and intratumoral communication processes controlling malignant CSC and disease progression, laying the basis for improved rational combination treatments. PMID- 28356111 TI - Tumor-derived CXCL5 promotes human colorectal cancer metastasis through activation of the ERK/Elk-1/Snail and AKT/GSK3beta/beta-catenin pathways. AB - BACKGROUND: Metastasis is a major cause of death in human colorectal cancer patients. However, the contribution of chemokines in the tumor microenvironment to tumor metastasis is not fully understood. METHODS: Herein, we examinined several chemokines in colorectal cancer patients using chemokine ELISA array. Immunohistochemistry was used to detect expression of CXCL5 in colorectal cancer patients tissues. Human HCT116 and SW480 cell lines stably transfected with CXCL5, shCXCL5 and shCXCR2 lentivirus plasmids were used in our in vitro study. Immunoblot, immunofluorescence and transwell assay were used to examine the molecular biology and morphological changes in these cells. In addition, we used nude mice to detect the influence of CXCL5 on tumor metastasis in vivo. RESULTS: We found that CXCL5 was overexpressed in tumor tissues and associated with advanced tumor stage as well as poor prognosis in colorectal cancer patients. We also demonstrated that CXCL5 was primarily expressed in the tumor cell cytoplasm and cell membranes, which may indicate that the CXCL5 was predominantly produced by cancer epithelial cells instead of fibroblasts in the tumor mesenchyme. Additionally, overexpression of CXCL5 enhanced the migration and invasion of colorectal cancer cells by inducing the epithelial-mesenchymal transition (EMT) through activation of the ERK/Elk-1/Snail pathway and the AKT/GSK3beta/beta catenin pathway in a CXCR2-dependent manner. The silencing of Snail and beta catenin attenuated CXCL5/CXCR2-enhanced cell migration and invasion in vitro. The elevated expression of CXCL5 can also potentiate the metastasis of colorectal cancer cells to the liver in vivo in nude mice intrasplenic injection model. CONCLUSION: In conclusion, our findings support CXCL5 as a promoter of colorectal cancer metastasis and a predictor of poor clinical outcomes in colorectal cancer patients. PMID- 28356113 TI - Killing of Serratia marcescens biofilms with chloramphenicol. AB - Serratia marcescens is a Gram-negative bacterium with proven resistance to multiple antibiotics and causative of catheter-associated infections. Bacterial colonization of catheters mainly involves the formation of biofilm. The objectives of this study were to explore the susceptibility of S. marcescens biofilms to high doses of common antibiotics and non-antimicrobial agents. Biofilms formed by a clinical isolate of S. marcescens were treated with ceftriaxone, kanamycin, gentamicin, and chloramphenicol at doses corresponding to 10, 100 and 1000 times their planktonic minimum inhibitory concentration. In addition, biofilms were also treated with chemical compounds such as polysorbate 80 and ursolic acid. S. marcescens demonstrated susceptibility to ceftriaxone, kanamycin, gentamicin, and chloramphenicol in its planktonic form, however, only chloramphenicol reduced both biofilm biomass and biofilm viability. Polysorbate 80 and ursolic acid had minimal to no effect on either planktonic and biofilm grown S. marcescens. Our results suggest that supratherapeutic doses of chloramphenicol can be used effectively against established S. marcescens biofilms. PMID- 28356114 TI - Effectiveness of multi-drug regimen chemotherapy treatment in osteosarcoma patients: a network meta-analysis of randomized controlled trials. AB - BACKGROUND: Osteosarcoma is the most common malignant bone tumour. Due to the high metastasis rate and drug resistance of this disease, multi-drug regimens are necessary to control tumour cells at various stages of the cell cycle, eliminate local or distant micrometastases, and reduce the emergence of drug-resistant cells. Many adjuvant chemotherapy protocols have shown different efficacies and controversial results. Therefore, we classified the types of drugs used for adjuvant chemotherapy and evaluated the differences between single- and multi drug chemotherapy regimens using network meta-analysis. METHODS: We searched electronic databases, including PubMed (MEDLINE), EmBase, and the Cochrane Library, through November 2016 using the keywords "osteosarcoma", "osteogenic sarcoma", "chemotherapy", and "random*" without language restrictions. The major outcome in the present analysis was progression-free survival (PFS), and the secondary outcome was overall survival (OS). We used a random effect network meta analysis for mixed multiple treatment comparisons. RESULTS: We included 23 articles assessing a total of 5742 patients in the present systematic review. The analysis of PFS indicated that the T12 protocol (including adriamycin, bleomycin, cyclophosphamide, dactinomycin, methotrexate, cisplatin) plays a more critical role in osteosarcoma treatment (surface under the cumulative ranking (SUCRA) probability 76.9%), with a better effect on prolonging the PFS of patients when combined with ifosfamide (94.1%) or vincristine (81.9%). For the analysis of OS, we separated the regimens to two groups, reflecting the disconnection. The T12 protocol plus vincristine (94.7%) or the removal of cisplatinum (89.4%) is most likely the best regimen. CONCLUSIONS: We concluded that multi-drug regimens have a better effect on prolonging the PFS and OS of osteosarcoma patients, and the T12 protocol has a better effect on prolonging the PFS of osteosarcoma patients, particularly in combination with ifosfamide or vincristine. The OS analysis showed that the T12 protocol plus vincristine or the T12 protocol with the removal of cisplatinum might be a better regimen for improving the OS of patients. However, well-designed randomized controlled trials of chemotherapeutic protocols are still necessary. PMID- 28356115 TI - Integrating ethnobiological knowledge into biodiversity conservation in the Eastern Himalayas. AB - Biocultural knowledge provides valuable insight into ecological processes, and can guide conservation practitioners in local contexts. In many regions, however, such knowledge is underutilized due to its often-fragmented record in disparate sources. In this article, we review and apply ethnobiological knowledge to biodiversity conservation in the Eastern Himalayas. Using Sikkim, India as a case study, we: (i) traced the history and trends of ethnobiological documentation; (ii) identified priority species and habitat types; and, (iii) analyzed within and among community differences pertaining to species use and management. Our results revealed that Sikkim is a biocultural hotspot, where six ethnic communities and 1128 species engage in biocultural relationships. Since the mid 1800s, the number of ethnobiological publications from Sikkim has exponentially increased; however, our results also indicate that much of this knowledge is both unwritten and partitioned within an aging, gendered, and caste or ethnic group specific stratum of society. Reviewed species were primarily wild or wild cultivated, native to subtropical and temperate forests, and pend IUCN Red List of Threatened Species assessment. Our results demonstrate the value of engaging local knowledge holders as active participants in conservation, and suggest the need for further ethnobiological research in the Eastern Himalayas. Our interdisciplinary approach, which included rank indices and geospatial modelling, can help integrate diverse datasets into evidence-based policy. PMID- 28356116 TI - Occupational exposures and determinants of ultrafine particle concentrations during laser hair removal procedures. AB - BACKGROUND: Occupational exposures to ultrafine particles in the plume generated during laser hair removal procedures, the most commonly performed light based cosmetic procedure, have not been thoroughly characterized. Acute and chronic exposures to ambient ultrafine particles have been associated with a number of negative respiratory and cardiovascular health effects. Thus, the aim of this study was to measure airborne concentrations of particles in a diameter size range of 10 nm to 1 MUm in procedure rooms during laser hair removal procedures. METHODS: TSI Model 3007 Condensation Particle Counters were used to quantify the particle count concentrations in the waiting and procedure rooms of a dermatology office. Particle concentrations were sampled before, during, and after laser hair removal procedures, and characteristics of each procedure were noted by the performing dermatologist. RESULTS: Twelve procedures were sampled over 4 days. Mean ultrafine particle concentrations in the waiting and procedure rooms were 14,957.4 particles/cm3 and 22,916.8 particles/cm3 (p < 0.0001), respectively. Compared to background ultrafine particle concentrations before the procedure, the mean concentration in the procedure room was 2.89 times greater during the procedure (p = 0.009) and 2.09 times greater after the procedure (p = 0.007). Duration of procedure (p = 0.006), body part (p = 0.013), and the use of pre laser lotion/type of laser (p = 0.039), were the most important predictors of ultrafine particle concentrations. Use of a smoke evacuator (a recommended form of local exhaust ventilation) positioned at 30.5 cm from the source, as opposed to the recommended 1-2 in., lowered particle concentrations, but was not a statistically significant predictor (p = 0.49). CONCLUSIONS: Laser hair removal procedures can generate high exposures to ultrafine particles for dermatologists and other individuals performing laser hair removal, with exposure varying based on multiple determinants. PMID- 28356117 TI - Association of traditional Chinese medicine therapy and the risk of dementia in patients with hypertension: a nationwide population-based cohort study. AB - BACKGROUND: Patients with hypertension (HTN) reportedly have a higher risk of developing dementia. However, it remains unclear if use of Traditional Chinese Medicine (TCM), the most common form of complementary and alternative medicine, can help lower the risk of dementia for these patients. So the aim of the study was to investigate the effects of TCM on dementia risk among patients with hypertension. METHODS: This longitudinal cohort study used the Taiwanese National Health Insurance Research Database (NHIRD) to identify 143,382 newly diagnosed hypertension patients aged 20-90 years who received treatment between 1998 and 2007. Among them, 52,365 (36.52%) had received TCM after the onset of hypertension (TCM users), and the remaining 91,017 patients (63.48%) were designated as a control group (non-TCM users). All enrollees were followed until the end of 2012 to record the incidence of dementia. A Cox proportional hazards regression model was used to compute the hazard ratio (HR) of dementia in patients who received TCM. RESULTS: During the 15-year follow-up, 3933 TCM users and 10,316 non-TCM users developed dementia, representing an incidence rate of 8.41 and 11.55%, respectively, per 1000 person-years. TCM users had a significantly reduced risk of dementia compared to non-TCM users (adjusted HR = 0.76; 95% confidence interval [CI] = 0.74-0.81). The predominant effect was observed among those treated with TCM longer than 180 days (adjusted HR = 0.65; 95% CI = 0.62-0.69). Among the commonly used TCM products, Tian-Ma-Gou-Teng-Yin, Dan-Shen (Radix Salviae Miltiorrhizae), Chuan-Niu-Xi (Radix Cyathulae), Ge-Gen (Radix Puerariae), Jia-Wei-Xiao-Yao-San, and Jue-Ming-Zi (Semen Cassiae) were significantly associated with a lower risk of dementia. CONCLUSIONS: Results from this population-based study support the effects of TCM on reducing dementia risk, which may provide a reference for dementia prevention strategies. PMID- 28356118 TI - Algometry to measure pain threshold in the horse's back - An in vivo and in vitro study. AB - BACKGROUND: The aim of this study was to provide information on algometric transmission of pressure through the dorsal thoracolumbar tissues of the equine back. Using a commercially available algometer, measurements were carried out with six different tips (hemispheric and cylindrical surfaces, contact areas 0.5 cm2, 1 cm2, and 2 cm2). In nine live horses the threshold of pressure that lead to any reaction was documented. In postmortem specimens of five euthanized horses the transmission of algometer pressure onto a pressure sensor placed underneath the dorsal thoracolumbar tissues at the level of the ribs or the transverse lumbar processes respectively was measured. RESULTS: Algometer tips with a contact area of 1 cm2 led to widely similar results irrespective of the surface shape; these measurements also had the lowest variance. Contact areas of 0.5 cm2 resulted in a lower pressure threshold, and those of 2 cm2 resulted in a higher pressure threshold. The hemispheric shape of the contact area resulted in a higher pressure threshold, than the cylindrical contact area. Compared to the thoracic region, a significantly higher pressure threshold was found in the lumbar region in the live horses. This result corresponds to the increased tissue thickness in the lumbar region compared to the thoracic region, also documented as less pressure transmission in the lumbar region on the in vitro specimens. CONCLUSIONS: Algometry is an easily practicable and well tolerated method to quantify pain but it is important to consider the many factors influencing the results obtained. PMID- 28356119 TI - Erratum to: Cross-border movement of older patients: a descriptive study on health service use of Japanese retirees in Thailand. PMID- 28356121 TI - A survey of the impact of owning a service dog on quality of life for individuals with physical and hearing disability: a pilot study. AB - BACKGROUND: Quality of life refers to a person's experienced standard of health, comfort and happiness and is typically measured using subjective self-report scales. Despite increasing scientific interest in the value of dogs to human health and the growing demand for trained service dogs, to date no research has reported how service dogs may affect client perceptions of quality of life. METHOD: We compared quality of life scores on the 16 item Flanagan quality of life scale from individuals who owned a trained service dog with those who were eligible to receive a dog, but did not yet have one (waiting list control). Data were analysed separately from two groups; those with a service dog trained for individuals with physical disabilities (with physical service dog: n = 72; waiting for a service dog: n = 24; recruited from Dogs for Good database) and those with a hearing service dog (with hearing service dog = 111; waiting for a service dog = 30; recruited from Hearing Dogs for Deaf People database). RESULTS: When controlling for age and gender individuals scored higher on total quality of life scores if they owned a service dog or a hearing service dog, but this was only statistically significant for those with a service dog. Both groups (physical service dog and hearing service dog) scored significantly higher on items relating to health, working, learning and independence if they owned a service dog, in comparison to those on the waiting list. Those with a physical service dog also scored significantly higher on items relating to recreational activities (including items relating to reading/listening to music, socialising, creative expression), and those involving social interactions (including items relating to participating in organisations, socialising, relationship with relatives). Additionally, those with a physical service dog scored higher on understanding yourself and material comforts than those on the waiting list control. In contrast, those with a hearing service dog appeared to receive fewer benefits on items relating to social activities. CONCLUSIONS: Owning a service dog can bring significant specific and potentially general benefits to the quality of life of individuals with physical disabilities and hearing impairments. These benefits may have considerable implications for individuals with disabilities, society and the economy by promoting independence, learning and working abilities. PMID- 28356120 TI - In vivo TSPO and cannabinoid receptor type 2 availability early in post-stroke neuroinflammation in rats: a positron emission tomography study. AB - BACKGROUND: Upregulated levels of 18-kDa translocator proteins (TSPO) and type 2 endocannabinoid receptors (CB2) are considered to reflect different aspects of microglia-related neuroinflammatory responses in the brain. Relative to the increase in the TSPO expression that occurs slightly later during neuroinflammation in a proinflammatory fashion, CB2 activation is considered to relate to the neuroprotective responses that occurs predominantly at an early stage of brain disorders. These findings, however, were deduced from studies with different animal samples under different experimental settings. Here, we aimed to examined the differences in TSPO binding and CB2 availability at an early stage of stroke in the same animal using positron emission tomography (PET). METHODS: We used a total of eight Sprague-Dawley rats that underwent photothrombotic stroke surgery. The binding levels of a TSPO tracer [11C](R)PK11195 and a CB2 tracer [11C]NE40 were measured at 24 h after the surgery in the same animal using PET in combination with immunohistochemistry for CB2 and several other markers. A morphological inspection was also performed with X-ray computed tomography for small animals. RESULTS: The levels of [11C]NE40 binding potential (BPND) were significantly higher in the cerebral cortical region on the lesion side than those on the non-lesion side, whereas no difference was found in the levels of [11C](R)PK11195 BPND between hemispheres. The tracer influx index (R1) data were all reduced on the lesion side irrespective of tracers. This increase in [11C]NE40 BPND was concomitant with an elevation in CB2 expression mainly within the microglia in the peri-infarct area, as shown by immunohistochemical examinations with Iba-1, CD11b/c+, and NG2+ staining. CONCLUSIONS: The present results provide in vivo evidence of different responses of microglia occurring in the acute state of stroke. The use of the CB2 tracer [11C]NE40 allows us to evaluate the roles played by the neuroprotective aspect of microglia in acute neuroinflammatory processes. PMID- 28356122 TI - Integrated analysis identifies microRNA-195 as a suppressor of Hippo-YAP pathway in colorectal cancer. AB - BACKGROUND: With persistent inconsistencies in colorectal cancer (CRC) miRNAs expression data, it is crucial to shift toward inclusion of a "pre-laboratory" integrated analysis to expedite effective precision medicine and translational research. Aberrant expression of hsa-miRNA-195 (miR-195) which is distinguished as a clinically noteworthy miRNA has previously been observed in multiple cancers, yet its role in CRC remains unclear. METHODS: In this study, we performed an integrated analysis of seven CRC miRNAs expression datasets. The expression of miR-195 was validated in The Cancer Genome Atlas (TCGA) datasets, and an independent validation sample cohort. Colon cancer cells were transfected with miR-195 mimic and inhibitor, after which cell proliferation, colony formation, migration, invasion, and dual luciferase reporter were assayed. Xenograft mouse models were used to determine the role of miR-195 in CRC tumorigenicity in vivo. RESULTS: Four downregulated miRNAs (hsa-let-7a, hsa-miR 125b, hsa-miR-145, and hsa-miR-195) were demonstrated to be potentially useful diagnostic markers in the clinical setting. CRC patients with a decreased level of miR-195-5p in tumor tissues had significantly shortened survival as revealed by the TCGA colon adenocarcinoma (COAD) dataset and our CRC cohort. Overexpression of miR-195-5p in DLD1 and HCT116 cells repressed cell growth, colony formation, invasion, and migration. Inhibition of miR-195-5p function contributed to aberrant cell proliferation, migration, invasion, and epithelial mesenchymal transition (EMT). We identified miR-195-5p binding sites within the 3'-untranslated region (3'-UTR) of the human yes-associated protein (YAP) mRNA. YAP1 expression was downregulated after miR-195-5p treatment by qRT-PCR analysis and western blot. CONCLUSIONS: Four downregulated miRNAs were shown to be prime candidates for a panel of biomarkers with sufficient diagnostic accuracy for CRC in a clinical setting. Our integrated microRNA profiling approach identified miR 195-5p independently associated with prognosis in CRC. Our results demonstrated that miR-195-5p was a potent suppressor of YAP1, and miR-195-5p-mediated downregulation of YAP1 significantly reduced tumor development in a mouse CRC xenograft model. In the clinic, miR-195-5p can serve as a prognostic marker to predict the outcome of the CRC patients. PMID- 28356123 TI - Epidemiology of chronic obstructive pulmonary disease in the global HIV-infected population: a systematic review and meta-analysis protocol. AB - BACKGROUND: Evidence suggests a relationship between human immunodeficiency virus (HIV) infection and chronic obstructive pulmonary disease (COPD). Although the high burden of COPD and the HIV disease is clearly demonstrated, to the best of our knowledge, there is a lack of summary and meta-analysis data on the epidemiology of COPD in the global HIV-infected population to date. The present protocol for a systematic review and meta-analysis intends to summarize existing data on the prevalence, incidence, and risk factors of COPD in the global HIV infected population. METHODS AND DESIGN: The present review will include cohort, cross-sectional, and case-control studies conducted among HIV infected people, which report prevalence, incidence, and factors associated with COPD or enough data for their estimation. We will consider published and unpublished studies in English and French language, regardless of geographical location. Relevant records will be searched using PubMed/Medline, and Scopus from inception to December 31st, 2016. Reference lists of eligible papers and relevant review articles will be screened. Two investigators will independently screen, select studies, and extract data, with discrepancies resolved by consensus or arbitrarily by a third investigator. Risk of bias and methodological quality of the included studies will be assessed using the Newcastle-Ottawa Scale. Funnel plots and Egger's test will be used to determine publication bias. The study specific estimates will be pooled through a random-effects meta-analysis model to obtain an overall summary estimate. To keep the effect of studies with extremely small or extremely large estimates on the overall estimate to a minimum, the variance of the study-specific prevalence/incidence will be stabilized with the Freeman-Tukey single arc-sine transformation. The heterogeneity will be evaluated by the chi2 test on Cochrane's Q statistic. Results will be presented by geographic region and by antiretroviral therapy status. We plan to summarize data on factors associated with COPD in narrative format. DISCUSSION: This systematic review and meta-analysis will give an overview of the epidemiology of COPD in the global HIV population to inform policy-makers and to provide accurate data that can underpin effective interventions for optimizing their detection and management. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016052639 . PMID- 28356124 TI - Denosumab treatment for progressive skull base giant cell tumor of bone in a 14 year old female - a case report and literature review. AB - BACKGROUND: Giant cell tumor of bone (GCT) is a rare primary bone tumor, which can metastasize and undergo malignant transformation. The standard treatment of GCT is surgery. In patients with unresectable or metastatic disease, additional therapeutic options are available. These include blocking of the receptor activator of NF-kappa B ligand (RANKL) signaling pathway, which plays a role in the pathogenesis of GCT of bone, via the anti-RANKL monoclonal antibody denosumab. CASE PRESENTATION: Herein we report on a female teenager who presented in a very poor clinical condition (cachexia, diplopia, strabismus, dysphonia with palsy of cranial nerves V, VI, VIII, IX, X, XI and XII) due to progressive disease, after incomplete resection and adjuvant radiotherapy, of a GCT which affected the cervical spine (C1 and C2) as well as the skull base; and who had an impressive clinical response to denosumab therapy. To the best of our knowledge, this is the youngest patient ever reported with a skull base tumor treated with denosumab. CONCLUSION: In situations when surgery can be postponed and local aggressiveness of the tumor does not urge for acute surgical intervention, upfront use of denosumab in order to reduce the tumor size might be considered. Principally, the goal of denosumab therapy is to reduce tumor size as much as possible, with the ultimate goal to make local surgery (or as in our case re surgery) amenable. However, improvement in quality of life, as demonstrated in our patient, is also an important aspect of such targeted therapies. PMID- 28356125 TI - Feasibility and acceptability of group music therapy vs wait-list control for treatment of patients with long-term depression (the SYNCHRONY trial): study protocol for a randomised controlled trial. AB - BACKGROUND: Depression is of significant global concern. Despite a range of effective treatment options it is estimated that around one in five diagnosed with an acute depressive episode continue to experience enduring symptoms for more than 2 years. There is evidence for effectiveness of individual music therapy for depression. However, no studies have as yet looked at a group intervention within an NHS context. This study aims to assess the feasibility of conducting a randomised controlled trial of group music therapy for patients with long-term depression (symptom durations of 1 year or longer) within the community. METHODS: This is a single-centre randomised controlled feasibility trial of group music therapy versus wait-list control with a nested process evaluation. Thirty participants will be randomised with unbalanced allocation (20 to receive the intervention immediately, 10 as wait-list controls). Group music therapy will be offered three times per week in a community centre with a focus on songwriting. Data will be collected post-intervention, 3 and 6 months after the intervention finishes. We will examine the feasibility of recruitment processes including identifying the number of eligible participants, participation and retention rates and the intervention in terms of testing components, measuring adherence and estimation of the likely intervention effect. A nested process evaluation will consist of treatment fidelity analysis, exploratory analysis of process measures and end-of-participation interviews with participants and referring staff. DISCUSSION: Whilst group music therapy is an option in some community mental health settings, this will be the first study to examine group music therapy for this particular patient group. We will assess symptoms of depression, acceptability of the intervention and quality of life. We anticipate potential challenges in the recruitment and retention of participants. It is unclear whether offering the intervention three times per week will be acceptable to participants, particularly given participants' enduring symptoms and impact upon motivation. This study will provide data to inform both development of the intervention and to assess and inform the design of a full trial. TRIAL REGISTRATION: ISRCTN.com, ISRCTN18164037 . Registered on 26 September 2016. PMID- 28356127 TI - Photon irradiation using a water bath technique for treatment of confluent carcinoma in situ of the hand, digits, and nail bed: a case report. AB - BACKGROUND: Confluent squamous cell carcinoma in situ, or Bowen's disease, involving the hand, digit, and nail bed is rare and represents a significant therapeutic challenge. Surgical excision is recommended as first-line treatment but in cases of extensive disease can lead to unacceptable functional morbidity or cosmetic outcomes. Radiation therapy has been shown to be equally efficacious to surgery in the treatment of carcinoma in situ but its use has historically been limited due to concerns regarding toxicity. In this case report we present a novel therapeutic technique that may enable radiotherapy to be employed as a definitive treatment option in these challenging cases. CASE PRESENTATION: A 75 year-old white man with a previous history of carcinoma in situ of his right hand previously treated with 5-fluorouracil presented with recurrent biopsy-proven confluent squamous cell carcinoma in situ of multiple surfaces of his right hand and digits with involvement of nail beds. To avoid extensive resection and possible amputation he was offered definitive external beam radiation therapy utilizing a water bath as a tissue-equivalent bolus material. This protocol enabled improved dose homogeneity to the target volume while minimizing acute toxicity. He experienced complete clinical resolution of the disease with only minimal acute edema and hyperpigmentation. Twenty months following treatment completion he remains disease-free with normal function and excellent cosmesis. CONCLUSIONS: Therapeutic radiation utilizing water as a tissue-equivalent bolus in this complicated case enabled definitive treatment of disease without compromising functional or cosmetic outcomes. Radiotherapy may therefore be an alternative and under-utilized approach to surgical excision in difficult-to treat cases of carcinoma in situ. PMID- 28356126 TI - Starch/PCL composite nanofibers by co-axial electrospinning technique for biomedical applications. AB - BACKGROUND: In this study, starch and polycaprolactone (PCL), composite nanofibers were fabricated by co-axial needle electrospinning technique. Processing parameters such as polymer concentration, flow rate and voltage had a marked influence on the composite fiber diameter. Fourier transform infrared spectroscopy, scanning electron microscopy (SEM), mechanical and physical properties (such as density, viscosity and electrical conductivity) of the composite fibres were evaluated. Moreover, a cell culture test was performed in order to determine their cytotoxicity for wound dressing application. RESULTS: The effect of starch ratio in the solution on the properties and morphological structure of the fibers produced was presented. With lower starch concentration values, the fibers have greater ultimate tensile strength characteristic (mostly 4 and 5 wt%). According to SEM results, it can be figured out that the nanofibers fabricated have good spinnability and morphology. The mean diameter of the fibers is about 150 nm. According to results of cell culture study, the finding can be determined that the increase of starch in the fiber also increases the cell viability. CONCLUSIONS: Composite nanofibers of starch/PCL have been prepared using a co-axial needle electrospinning technique. PCL was successfully encapsulated within starch. Fiber formation was observed for different ratio of starch. With several test, analysis and measurement performed, some important parameters such as quality and effectuality of each fiber obtained for wound dressing applications were discussed in detail. PMID- 28356128 TI - The impact of conscientiousness, mastery, and work circumstances on subsequent absenteeism in employees with and without affective disorders. AB - BACKGROUND: High numbers of employees are coping with affective disorders. At the same time, ambitiousness, achievement striving and a strong sense of personal control and responsibility are personality characteristics that are nowadays regarded as key to good work functioning, whereas social work circumstances tend to be neglected. However, it is largely unkown how personality characteristics and work circumstances affect work functioning when facing an affective disorder. Given the high burden of affective disorders on occupational health, we investigate these issues in the context of affective disorders and absenteeism from work. The principal aim of this paper is to examine whether particular personality characteristics that reflect self-governance (conscientiousness and mastery) and work circumstances (demands, control, support) influence the impact of affective disorders on long-term absenteeism (>10 working days). METHODS: Baseline and 1-year follow-up data from 1249 participants in the Netherlands Study of Depression and Anxiety (NESDA) in 2004-2006 was employed. Multivariate logistic regression analyses were performed, including interaction effects between depressive, anxiety, and comorbid disorders and personality and work circumstances. RESULTS: In general, mastery and conscientiousness increased nor diminished odds of subsequent long-term absenteeism, whereas higher job support significantly decreased these odds. Interaction effects showed that the impact of affective disorders on absenteeism was stronger for highly conscientious employees and for employees who experienced high job demands. CONCLUSIONS: Affective disorders may particularly severely affect work functioning of employees who are highly conscientious or face high psychological job demands. Adjusting working conditions to their individual needs may prevent excessive work absence. PMID- 28356129 TI - The effects of probiotic and synbiotic supplementation on metabolic syndrome indices in adults at risk of type 2 diabetes: study protocol for a randomized controlled trial. AB - BACKGROUND: The incidence of type 2 diabetes, cardiovascular diseases, and obesity has been rising dramatically; however, their pathogenesis is particularly intriguing. Recently, dysbiosis of the intestinal microbiota has emerged as a new candidate that may be linked to metabolic diseases. We hypothesize that selective modulation of the intestinal microbiota by probiotic or synbiotic supplementation may improve metabolic dysfunction and prevent diabetes in prediabetics. In this study, a synthesis and study of synbiotics will be carried out for the first time in Iran. METHODS/DESIGN: In a randomized triple-blind controlled clinical trial, 120 adults with impaired glucose tolerance based on the inclusion criteria will be selected by a simple random sampling method and will be randomly allocated to 6 months of 6 g/d probiotic, synbiotic or placebo. The fecal abundance of bacteria, blood pressure, height, weight, and waist and hip circumferences will be measured at baseline and following treatment. Also, plasma lipid profiles, HbA1C, fasting plasma glucose, and insulin levels, will be measured and insulin resistance (HOMA-IR) and beta-cell function (HOMA-B) will be calculated at baseline and will be repeated at months 3, 6, 12, and 18. The data will be compared within and between groups using statistical methods. DISCUSSION: The results of this trial could contribute to the evidence-based clinical guidelines that address gut microbiota manipulation to maximize health benefits in prevention and management of metabolic syndrome in prediabetes. TRIAL REGISTRATION: Iranian Registry of Clinical Trials: IRCT201511032321N2 . Registered on 27 February 2016. PMID- 28356130 TI - Parecoxib reduced ventilation induced lung injury in acute respiratory distress syndrome. AB - BACKGROUND: Cyclooxygenase-2 (COX-2) contributes to ventilation induced lung injury (VILI) and acute respiratory distress syndrome (ARDS). The objective of present study was to observe the therapeutic effect of parecoxib on VILI in ARDS. METHODS: In this parallel controlled study performed at Harbin Medical University, China between January 2016 and March 2016, 24 rats were randomly allocated into sham group (S), volume ventilation group/ARDS (VA), parecoxib/volume ventilation group/ARDS (PVA). Rats in the S group only received anesthesia; rats in the VA and PVA group received intravenous injection of endotoxin to induce ARDS, and then received ventilation. Rats in the VA and PVA groups were treated with intravenous injection of saline or parecoxib. The ratio of arterial oxygen pressure to fractional inspired oxygen (PaO2/FiO2), the wet to dry weight ratio of lung tissue, inflammatory factors in serum and bronchoalveolar lavage fluid (BALF), and histopathologic analyses of lung tissue were examined. In addition, survival was calculated at 24 h after VILI. RESULTS: Compared to the VA group, in the PVA group, PaO2/FiO2 was significantly increased; lung tissue wet to dry weight ratio; macrophage and neutrophil counts, total protein and neutrophil elastase levels in BALF; tumor necrosis factor alpha, interleukin-1beta, and prostaglandin E2 levels in BALF and serum; and myeloperoxidase (MPO) activity, malondialdehyde levels, and Bax and COX-2 protein levels in lung tissue were significantly decreased, while Bcl-2 protein levels were significantly increased. Lung histopathogical changes and apoptosis were reduced by parecpxib in the PVA group. Survival was increased in the PVA group. CONCLUSIONS: Parecoxib improves gas exchange and epithelial permeability, decreases edema, reduces local and systemic inflammation, ameliorates lung injury and apoptosis, and increases survival in a rat model of VILI. PMID- 28356131 TI - Treatment of infants with Syndromic Robin sequence with modified palatal plates: a minimally invasive treatment option. AB - BACKGROUND: Infants with Robin sequence (RS) suffer from upper airway obstruction (UAO) and feeding problems. We developed an oral appliance with a velar extension in combination with functional treatment and appropriate feeding techniques, which was proven effective in isolated RS. As the above problems are particularly challenging in syndromic RS, we set out to evaluate our treatment concept also in these patients. METHODS: We searched our electronic departmental database to identify all children admitted to our department between 01/01/2003 and 31/12/2009 because of syndromic RS. UAO was quantified by cardiorespiratory sleep studies performed before and during treatment with a modified palatal plate. This appliance consists of a palatal part, covering the hard palate as well as the alveolar ridges and the potential cleft, and a velar extension shifting the tongue in a more anterior position, thereby opening the pharyngeal airway. It is adjusted by fiberoptic nasopharyngoscopy and controlled by cardiorespiratory sleep studies. Obstructive sleep apnea was defined as a mixed obstructive sleep apnea index (MOAI) >3/h. Feeding modalities before and after treatment and weight gain, determined as standard deviation score, were also evaluated. RESULTS: Of 68 children meeting inclusion criteria, 56 completed treatment (46 of these being infants). Underlying diagnoses included craniofacial dysostosis (N = 13) and synostosis syndromes (N = 5), unspecified dysmorphic syndromes (N = 23) and miscellaneous rare conditions (N = 27). Median MOAI decreased from 8.5 (range 0.3 76.0) at admission to 1.1 (0.0-5.2) at discharge (p < 0.001). 51 children received only a TPP and 5 additionally continuous positive airway pressure (CPAP) or high-flow nasal cannula during sleep for mild residual OSA. Three children ultimately required tracheostomy. The number of exclusively gavage fed infants was reduced from 23 to 7. Conversely, the number of children fed exclusively by mouth increased from 18 to 30. Median SDS for weight decreased from -1.6 (-3.5 1.7) to -1.3 (-4.1-2.5). Twelve children had their treatment prematurely discontinued, e.g. due to laryngeal collapse/laryngomalacia. No patient died during treatment. CONCLUSION: Treatment of UAO and feeding problems in these children with syndromic RS by a modified palatal plate with a velar extension was shown to be effective and safe. If confirmed in prospective studies, it may help to avoid more invasive interventions. PMID- 28356132 TI - Down-regulation of E-cadherin enhances prostate cancer chemoresistance via Notch signaling. AB - BACKGROUND: The chemoresistance of prostate cancer (PCa) is invariably associated with the aggressiveness and metastasis of this disease. New emerging evidence indicates that the epithelial-to-mesenchymal transition (EMT) may play pivotal roles in the development of chemoresistance and metastasis. As a hallmark of EMT, E-cadherin is suggested to be a key marker in the development of chemoresistance. However, the molecular mechanisms underlying PCa chemoresistance remain unclear. The current study aimed to explore the association between EMT and chemoresistance in PCa as well as whether changing the expression of E-cadherin would affect PCa chemoresistance. METHODS: Parental PC3 and DU145 cells and their chemoresistant PC3-TxR and DU145-TxR cells were analyzed. PC3-TxR and DU145-TxR cells were transfected with E-cadherin-expressing lentivirus to overexpress E cadherin; PC3 and DU145 cells were transfected with small interfering RNA to silence E-cadherin. Changes of EMT phenotype-related markers and signaling pathways were assessed by Western blotting and quantitative real-time polymerase chain reaction. Tumor cell migration, invasion, and colony formation were then evaluated by wound healing, transwell, and colony formation assays, respectively. The drug sensitivity was evaluated using MTS assay. RESULTS: Chemoresistant PC3 TxR and DU145-TxR cells exhibited an invasive and metastatic phenotype that associated with EMT, including the down-regulation of E-cadherin and up regulation of Vimentin, Snail, and N-cadherin, comparing with that of parental PC3 and DU145 cells. When E-cadherin was overexpressed in PC3-TxR and DU145-TxR cells, the expression of Vimentin and Claudin-1 was down-regulated, and tumor cell migration and invasion were inhibited. In particular, the sensitivity to paclitaxel was reactivated in E-cadherin-overexpressing PC3-TxR and DU145-TxR cells. When E-cadherin expression was silenced in parental PC3 and DU145 cells, the expression of Vimentin and Snail was up-regulated, and, particularly, the sensitivity to paclitaxel was decreased. Interestingly, Notch-1 expression was up regulated in PC3-TxR and DU145-TxR cells, whereas the E-cadherin expression was down-regulated in these cells comparing with their parental cells. The use of gamma-secretase inhibitor, a Notch signaling pathway inhibitor, significantly increased the sensitivity of chemoresistant cells to paclitaxel. CONCLUSION: The down-regulation of E-cadherin enhances PCa chemoresistance via Notch signaling, and inhibiting the Notch signaling pathway may reverse PCa chemoresistance. PMID- 28356133 TI - Abdominal massage for neurogenic bowel dysfunction in people with multiple sclerosis (AMBER - Abdominal Massage for Bowel Dysfunction Effectiveness Research): study protocol for a randomised controlled trial. AB - BACKGROUND: Multiple sclerosis (MS) is a life-long condition primarily affecting younger adults. Neurogenic bowel dysfunction (NBD) occurs in 50-80% of these patients and is the term used to describe constipation and faecal incontinence, which often co-exist. Data from a pilot study suggested feasibility of using abdominal massage for the relief of constipation, but the effectiveness remains uncertain. METHODS/DESIGN: This is a multi-centred patient randomised superiority trial comparing an experimental strategy of once daily abdominal massage for 6 weeks against a control strategy of no massage in people with MS who have stated that their constipation is bothersome. The primary outcome is the Neurogenic Bowel Dysfunction Score at 24 weeks. Both groups will receive optimised advice plus the MS Society booklet on bowel management in MS, and will continue to receive usual care. Participants and their clinicians will not be blinded to the allocated intervention. Outcome measures are primarily self-reported and submitted anonymously. Central trial staff who will manage and analyse the trial data will be unaware of participant allocations. Analysis will follow intention to-treat principles. DISCUSSION: This pragmatic randomised controlled trial will demonstrate if abdominal massage is an effective, cost-effective and viable addition to the treatment of NBD in people with MS. TRIAL REGISTRATION: ClinicalTrials.gov, ISRCTN85007023 . Registered on 10 June 2014. PMID- 28356134 TI - External validation of the ROSC after cardiac arrest (RACA) score in a physician staffed emergency medical service system. AB - BACKGROUND: The return of spontaneous circulation (ROSC) after cardiac arrest (RACA) score may have implications as a quality indicator for the emergency medical services (EMS) system. We aimed to validate this score externally in a physician staffed urban EMS system. METHODS: We conducted a retrospective cohort study. Data on resuscitation attempts from the Helsinki EMS cardiac arrest registry from 1.1.2008 to 31.12.2010 were collected and analyzed. For each attempted resuscitation the RACA score variables were collected and the score calculated. The endpoint was ROSC defined as palpable pulse over 30 s. Calibration was assessed by comparing predicted and observed ROSC rates in the whole sample, separately for shockable and non-shockable rhythm, and separately for resuscitations lead by a specialist, registrar or medical supervisor (i.e., senior paramedic). Data are presented as medians and interquartile ranges. Statistical testing included chi-square test, the Mann-Whitney U test, Hosmer Lemeshow goodness of fit test and calculation of 95% confidence intervals (CI) for proportions. RESULTS: A total of 680 patients were included of whom 340 attained ROSC. The RACA score was higher in patients with ROSC (0.62 [0.46-0.69] than in those without (0.46 [0.36-0.57]) (p < 0.001). Observed against predicted ROSC indicated reasonable calibration overall (p = 0.30), with better calibration in patients with a shockable initial rhythm (p = 0.75) than in patients with a non-shockable rhythm (p = 0.04). There was no statistical difference between observed and predicted ROSC rates in resuscitations attended by a specialist (50% vs 53%, 95% CI 45-55) or registrar (55% vs 53%, 95% CI 48-62), but rates were lower than predicted in resuscitations lead by a medical supervisor (36% vs 49%, 95% CI 25-47). DISCUSSION: Developing a practical severity-of-illness scoring system for out-of-hospital cardiac arrest patients would allow patient heterogeneity adjustment and measurement of quality of care in analogy to commoly used severity-of-illness- scores developed for the similar purposes for the general intensive care unit population. However, transferring RACA score to another country with different population and EMS system might affect the performance and generalizability of the score. CONCLUSIONS: This study found a good overall calibration and moderate discrimination of the RACA score in a physician staffed urban EMS system which suggests external validity of the score. Calibration was suboptimal in patients with a non-shockable rhythm which may due to a local do-not-attempt-resuscitation policy. The lower than expected overall ROSC rate in resuscitations attended by medical supervisors requires further study. PMID- 28356135 TI - DNA methylation mediates genotype and smoking interaction in the development of anti-citrullinated peptide antibody-positive rheumatoid arthritis. AB - BACKGROUND: Multiple factors, including interactions between genetic and environmental risks, are important in susceptibility to rheumatoid arthritis (RA). However, the underlying mechanism is not fully understood. This study was undertaken to evaluate whether DNA methylation can mediate the interaction between genotype and smoking in the development of anti-citrullinated peptide antibody (ACPA)-positive RA. METHODS: We investigated the gene-smoking interactions in DNA methylation using 393 individuals from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA). The interaction between rs6933349 and smoking in the risk of developing ACPA-positive RA was further evaluated in a larger portion of the EIRA (1119 controls and 944 ACPA-positive patients with RA), and in the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) (1556 controls and 792 ACPA-positive patients with RA). Finally, mediation analysis was performed to investigate whether DNA methylation of cg21325723 mediates this gene-environment interaction on the risk of developing of ACPA-positive RA. RESULTS: We identified and replicated one significant gene environment interaction between rs6933349 and smoking in DNA methylation of cg21325723. This gene-smoking interaction is a novel interaction in the risk of developing ACPA-positive in both Caucasian (multiplicative P value = 0.056; additive P value = 0.016) and Asian populations (multiplicative P value = 0.035; additive P value = 0.00027), and it is mediated through DNA methylation of cg21325723. CONCLUSIONS: We showed that DNA methylation of cg21325723 can mediate the gene-environment interaction between rs6933349 and smoking, impacting the risk of developing ACPA-positive RA, thus being a potential regulator that integrates both internal genetic and external environmental risk factors. PMID- 28356136 TI - Efficacy and safety of rapid intermittent correction compared with slow continuous correction with hypertonic saline in patients with moderately severe or severe symptomatic hyponatremia: study protocol for a randomized controlled trial (SALSA trial). AB - BACKGROUND: Hyponatremia is the most common electrolyte imbalance encountered in clinical practice, associated with increased mortality and length of hospital stay. However, no high-quality evidence regarding whether hypertonic saline is best administered as a continuous infusion or a bolus injection has been found to date. Therefore, in the current study, we will evaluate the efficacy and safety of rapid intermittent correction compared with slow continuous correction with hypertonic saline in patients with moderately severe or severe symptomatic hyponatremia. METHODS/DESIGN: This is a prospective, investigator-initiated, multicenter, open-label, randomized controlled study with two experimental therapy groups. A total of 178 patients with severe symptomatic hyponatremia will be enrolled and randomly assigned to receive either rapid intermittent bolus or slow continuous infusion management with hypertonic saline. The primary outcome is the incidence of overcorrection at any given period over 2 days. The secondary outcomes will include the efficacy and safety of two other approaches to the treatment of hyponatremia with 3% hypertonic saline. DISCUSSION: This is the first clinical trial to investigate the efficacy and safety of rapid intermittent correction compared with slow continuous correction with hypertonic saline in patients with moderately severe or severe hyponatremia. TRIAL REGISTRATION: ClinicalTrials.gov, identifier number: NCT02887469 . Registered on 1 August 2016. PMID- 28356138 TI - Can flosealTM be applied safely during otologic surgery? Assessment of ototoxicity in a chinchilla animal model. AB - BACKGROUND: In otologic surgery good visualization is paramount, and patients with bleeding diatheses or who need to be anti-coagulated can present a significant challenge. Here, we determine whether FlosealTM, a hemostatic matrix, is ototoxic in a validated animal model. METHODS: Nine chinchillas housed in the animal care facilities of the Montreal Children's Hospital Research Institute were used for the study. After a myringotomy incision was made in each tympanic membrane, baseline auditory brainstem response measurements were performed at 8, 20, and 25 kHz. In each animal one ear was randomized to receive FlosealTM to the middle ear cavity, whereas the other ear served as the control and received 0.9% sodium chloride. Outcome measures included early (day 7) and late (day 30) auditory brainstem response, clinical evidence of facial nerve or vestibular disturbance and histological evidence of ototoxity. RESULTS: There was no significant hearing threshold shift on auditory brainstem response across all tested frequencies for both experimental and control ear. No animals receiving FlosealTM developed facial or vestibular nerve dysfunction and there was no histological evidence of ototoxicity. CONCLUSION: Based on the preliminary ototoxicity assessment on nine chinchillas, transtympanic FlosealTM does not appear to be ototoxic. More studies are warranted to assess the safety and applicability of the product in humans. PMID- 28356137 TI - Ethnic and diet-related differences in the healthy infant microbiome. AB - BACKGROUND: The infant gut is rapidly colonized by microorganisms soon after birth, and the composition of the microbiota is dynamic in the first year of life. Although a stable microbiome may not be established until 1 to 3 years after birth, the infant gut microbiota appears to be an important predictor of health outcomes in later life. METHODS: We obtained stool at one year of age from 173 white Caucasian and 182 South Asian infants from two Canadian birth cohorts to gain insight into how maternal and early infancy exposures influence the development of the gut microbiota. We investigated whether the infant gut microbiota differed by ethnicity (referring to groups of people who have certain racial, cultural, religious, or other traits in common) and by breastfeeding status, while accounting for variations in maternal and infant exposures (such as maternal antibiotic use, gestational diabetes, vegetarianism, infant milk diet, time of introduction of solid food, infant birth weight, and weight gain in the first year). RESULTS: We demonstrate that ethnicity and infant feeding practices independently influence the infant gut microbiome at 1 year, and that ethnic differences can be mapped to alpha diversity as well as a higher abundance of lactic acid bacteria in South Asians and a higher abundance of genera within the order Clostridiales in white Caucasians. CONCLUSIONS: The infant gut microbiome is influenced by ethnicity and breastfeeding in the first year of life. Ethnic differences in the gut microbiome may reflect maternal/infant dietary differences and whether these differences are associated with future cardiometabolic outcomes can only be determined after prospective follow-up. PMID- 28356139 TI - Tumor microenvironment: driving forces and potential therapeutic targets for breast cancer metastasis. AB - Distant metastasis to specific target organs is responsible for over 90% of breast cancer-related deaths, but the underlying molecular mechanism is unclear. Mounting evidence suggests that the interplay between breast cancer cells and the target organ microenvironment is the key determinant of organ-specific metastasis of this lethal disease. Here, we highlight new findings and concepts concerning the emerging role of the tumor microenvironment in breast cancer metastasis; we also discuss potential therapeutic intervention strategies aimed at targeting components of the tumor microenvironment. PMID- 28356140 TI - Clinical course and prognosis of musculoskeletal pain in patients referred for physiotherapy: does pain site matter? AB - BACKGROUND: Danish patients with musculoskeletal disorders are commonly referred for primary care physiotherapy treatment but little is known about their general health status, pain diagnoses, clinical course and prognosis. The objectives of this study were to 1) describe the clinical course of patients with musculoskeletal disorders referred to physiotherapy, 2) identify predictors associated with a satisfactory outcome, and 3) determine the influence of the primary pain site diagnosis relative to those predictors. METHODS: This was a prospective cohort study of patients (n = 2,706) newly referred because of musculoskeletal pain to 30 physiotherapy practices from January 2012 to May 2012. Data were collected via a web-based questionnaire 1-2 days prior to the first physiotherapy consultation and at 6 weeks, 3 and 6 months, from clinical records (including primary musculoskeletal symptom diagnosis based on the ICPC-2 classification system), and from national registry data. The main outcome was the Patient Acceptable Symptom State. Potential predictors were analysed using backwards step-wise selection during longitudinal Generalised Estimating Equation regression modelling. To assess the influence of pain site on these associations, primary pain site diagnosis was added to the model. RESULTS: Of the patients included, 66% were female and the mean age was 48 (SD 15). The percentage of patients reporting their symptoms as acceptable was 32% at 6 weeks, 43% at 3 months and 52% at 6 months. A higher probability of satisfactory outcome was associated with place of residence, being retired, no compensation claim, less frequent pain, shorter duration of pain, lower levels of disability and fear avoidance, better mental health and being a non-smoker. Primary pain site diagnosis had little influence on these associations, and was not predictive of a satisfactory outcome. CONCLUSION: Only half of the patients rated their symptoms as acceptable at 6 months. Although satisfactory outcome was difficult to predict at an individual patient level, there were a number of prognostic factors that were associated with this outcome. These factors should be considered when developing generic prediction tools to assess the probability of satisfactory outcome in musculoskeletal physiotherapy patients, because the site of pain did not affect that prognostic association. PMID- 28356141 TI - Genomic history of the origin and domestication of common bean unveils its closest sister species. AB - BACKGROUND: Modern civilization depends on only a few plant species for its nourishment. These crops were derived via several thousands of years of human selection that transformed wild ancestors into high-yielding domesticated descendants. Among cultivated plants, common bean (Phaseolus vulgaris L.) is the most important grain legume. Yet, our understanding of the origins and concurrent shaping of the genome of this crop plant is limited. RESULTS: We sequenced the genomes of 29 accessions representing 12 Phaseolus species. Single nucleotide polymorphism-based phylogenomic analyses, using both the nuclear and chloroplast genomes, allowed us to detect a speciation event, a finding further supported by metabolite profiling. In addition, we identified ~1200 protein coding genes (PCGs) and ~100 long non-coding RNAs with domestication-associated haplotypes. Finally, we describe asymmetric introgression events occurring among common bean subpopulations in Mesoamerica and across hemispheres. CONCLUSIONS: We uncover an unpredicted speciation event in the tropical Andes that gave rise to a sibling species, formerly considered the "wild ancestor" of P. vulgaris, which diverged before the split of the Mesoamerican and Andean P. vulgaris gene pools. Further, we identify haplotypes strongly associated with genes underlying the emergence of domestication traits. Our findings also reveal the capacity of a predominantly autogamous plant to outcross and fix loci from different populations, even from distant species, which led to the acquisition by domesticated beans of adaptive traits from wild relatives. The occurrence of such adaptive introgressions should be exploited to accelerate breeding programs in the near future. PMID- 28356143 TI - Reverse pupillary block after implantation of a scleral-sutured posterior chamber intraocular lens: a retrospective, open study. AB - BACKGROUND: To report the clinical features of patients with reverse pupillary block (RPB) after scleral-sutured posterior chamber intraocular lens (PC IOL) implantation and biometric changes after laser peripheral iridotomy (LPI). METHODS: Eight patients attending our hospital's ophthalmology outpatient clinic, who developed RPB after implantation of a scleral-sutured PC IOL due to subluxation of the crystalline lens or IOL, were investigated in this retrospective, observational study. RESULTS: Preoperative evaluations showed angle pigmentation in all cases and iridodonesis in 2 cases. Two subjects had used an alpha1A-adrenoceptor antagonist for benign prostatic hyperplasia. Pars plana or anterior partial vitrectomy was performed in all cases. All eyes showed an extremely deep anterior chamber, a concave iris configuration, and contact between the IOL optic and the iris at the pupillary margin. Pupil capture was detected in 2 cases. The mean (+/- SD) anterior chamber angle (ACA) was 89.91 +/- 10.06 degrees , and the anterior chamber depth (ACD) was 4.42 +/- 0.16 mm before LPI. After LPI, the iris immediately became flat with a decreased ACA (51.70 +/- 2.59 degrees ; P = 0.018) and ACD (4.14 +/- 0.15 mm; P = 0.012). After LPI, the intraocular pressure decreased from 19.75 +/- 3.77 mmHg to 15.63 +/- 4.30 mmHg (P = 0.011), and the spherical equivalent decreased from -0.643 +/- 0.385 D to - 0.875 +/- 0.505 D (P = 0.016). CONCLUSION: Concomitant vitrectomy, angle pigmentation, and iridodonesis may be risk factors for RPB after scleral-sutured PC IOL implantation. LPI is effective for relieving the RPB. PMID- 28356142 TI - Towards evidence-based vitamin D supplementation in infants: vitamin D intervention in infants (VIDI) - study design and methods of a randomised controlled double-blinded intervention study. AB - BACKGROUND: Vitamin D is important for bone mass accrual during growth. Additionally, it is considered a requirement for a multitude of processes associated with, for example, the development of immunity. Many countries apply vitamin D supplementation strategies in infants, but the guidelines are not based on scientific evidence and aim at prevention of rickets. It remains unclear whether the recommended doses are sufficient for the wide array of other effects of vitamin D. The VIDI trial performed in Finland is the first large randomised controlled study for evaluation of the effects of different vitamin D supplemental doses in infancy on: 1. bone strength 2. infections and immunity 3. allergy, atopy and asthma 4. cognitive development 5. genetic regulation of mineral homeostasis METHODS/DESIGN: VIDI, a randomised controlled double-blinded single-centre intervention study is conducted in infants from the age of 2 weeks to 24 months. Participants, recruited at Helsinki Maternity Hospital, are randomised to receive daily either 10 MUg (400 IU) or 30 MUg (1 200 IU) of vitamin D3 supplementation. Both groups are assessed at 6 months of age for calcium homeostasis, and at 12 and 24 months of age for parameters associated with bone strength, growth, developmental milestones, infections, immunity, atopy related diseases, and genetic factors involved in these functions. DISCUSSION: The study enables evaluation of short and long term effects of supplemental vitamin D on growth, immune functions and skeletal and developmental parameters in infants, and the effects of genetic factors therein. The results enable institution of evidence-based guidelines for vitamin D supplementation in infancy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01723852 , registration date 6.11.2012. PMID- 28356145 TI - Adoption of innovative and evidence-based practices for children and adolescents in state-supported mental health clinics: a qualitative study. AB - BACKGROUND: This study examined how mental health clinic administrators decided whether or not to adopt evidence-based and other innovative practices by exploring their views of implementation barriers and facilitators and operation of these views in assessment of implementation costs and benefits. METHODS: Semi structured interviews were conducted with 75 agency chief executive officers and program directors of 34 New York State-licensed mental health clinics serving children and adolescents. RESULTS: Three interconnected themes relating to barriers and facilitators were identified, namely costs and benefits associated with adoption, capacity for adoption, and acceptability of new practices. The highest percentage of participants (86.7%) mentioned costs as a barrier, followed by limited capacity (55.9%) and lack of acceptability (52.9%). The highest percentage (82.3%) of participants identified available capacity as a facilitator, followed by acceptability (41.2%) and benefits or limited costs (24.0%). Assessment of costs and benefits exhibited several principles of behavioural economics, including loss aversion, temporal discounting use of heuristics, sensitivity to monetary incentives, decision fatigue, framing, and environmental influences. CONCLUSIONS: The results point to opportunities for using agency leader models to develop strategies to facilitate implementation of evidence-based and innovative practices for children and adolescents. PMID- 28356144 TI - Amplification and up-regulation of MIR30D was associated with disease progression of cervical squamous cell carcinomas. AB - BACKGROUND: Cervical squamous cell carcinoma (CSCC) is the most frequent type among cervical cancers. Although the altered miRNA miR-30d expression and the amplified chromosome locus of MIR30D, 8q24, have been reported in somatic cancers, the definitive functional impact of such region especially in CSCC remains under-investigated. METHODS: One hundred thirty-six cases of CSCC tissues and matched adjacent normal ovarian epithelial tissues were assessed in this study. FISH and qPCR were performed to detect the copy number and microRNA expression of MIR30D gene in the collected samples. In in-vitro study, proliferation of CSCC cells were analyzed using WST-1 assay and invasion abilities of CSCC cells were evaluated by transwell assay. In-vivo study using a model of nude mice bearing tumor was also performed. RESULTS: Copy number gains of MIR30D were detected in 22.8% (31 out of 136) of CSCC samples. Copy number of MIR30D was positively correlated with tumor progression. CSCCs with lymph node metastases (LNM) also showed more frequencies (36.4%) of MIR30D amplification than those without LNM (18.4%, p < 0.05). CSCCs with increased copy number of MIR30D also showed a positive correlation with miR-30d up-regulation. Inhibition of miR-30d in CSCC cells led to impaired tumor growth and migration. CONCLUSIONS: Copy number amplifications of MIR30D gene and enhanced expression of miR-30d were positively correlated with tumor progression in CSCCs, indicating miR-30d might play an oncomiric role in the progression of CSCC. PMID- 28356146 TI - Do the disc degeneration and osteophyte contribute to the curve rigidity of degenerative scoliosis? AB - BACKGROUND: The factors associated with lateral curve flexibility in degenerative scoliosis have not been well documented. Disc degeneration could result in significant change in stiffness and range of motion in lateral bending films. The osteophytes could be commonly observed in degenerative spine but the relationship between osteophyte formation and curve flexibility remains controversial. The aim of the current study is to clarify if the disc degeneration and osteophyte formation were both associated with curve flexibility of degenerative scoliosis. METHODS: A total of 85 patients were retrospectively analyzed. The inclusion criteria were as follow: age greater than 45 years, diagnosed as degenerative scoliosis and coronal Cobb angle greater than 20 degrees . Curve flexibility was calculated based on Cobb angle, and range of motion (ROM) was based on disc angle evaluation. Regional disc degeneration score (RDS) was obtained according to Pfirrmann classification and osteophyte formation score (OFS) was based on Nanthan classification. Spearman correlation was performed to analyze the relationship between curve flexibility and RDS as well as OFS. RESULTS: Moderate correlation was found between RDS and curve flexibility with a Spearman coefficient of -0.487 (P = 0.009). Similarly, moderate correlation was observed between curve flexibility and OFS with a Spearman coefficient of -0.429 (P = 0.012). Strong correlation was found between apical ROM and OFS compared to the relationship between curve flexibility and OFS with a Spearman coefficient of 0.627 (P < 0.001). CONCLUSIONS: Both disc degeneration and osteophytes formation correlated with curve rigidity. The pre-operative evaluation of both features may aid in the surgical decision-making in degenerative scoliosis patients. PMID- 28356147 TI - Genotypic and phenotypic characterization of G6PD deficiency in Bengali adults with severe and uncomplicated malaria. AB - BACKGROUND: Control of malaria increasingly involves administration of 8 aminoquinolines, with accompanying risk of haemolysis in individuals with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Few data on the prevalence and genotypic basis of G6PD deficiency are available from Bangladesh, where malaria remains a major problem in the South (Chittagong Division). The aim of this study was to determine the prevalence of G6PD deficiency, and associated G6PD genotypes, in adults with falciparum malaria in southern Bangladesh. METHODS: G6PD status was assessed via a combination of fluorescent spot testing (FST) and genotyping in 141 Bengali patients admitted with falciparum malaria to two centres in Chittagong Division from 2012 to 2014. In addition, an analysis of genomic data from 1000 Genomes Project was carried out among five healthy Indian subcontinent populations. RESULTS: One male patient with uncomplicated malaria was found to have G6PD deficiency on FST and a genotype associated with deficiency (hemizygous Orissa variant). In addition, there were two female patients heterozygous for deficiency variants (Orissa and Kerala-Kalyan). These three patients had a relatively long duration of symptoms prior to admission compared to G6PD normal cases, possibly suggesting an interaction with parasite multiplication rate. In addition, one of 27 healthy local controls was deficient on FST and hemizygous for the Mahidol variant of G6PD deficiency. Examination of 1000 Genomes Project sequencing data across the Indian subcontinent showed that 19/723 chromosomes (2.63%) carried a variant associated with deficiency. In the Bengali from Bangladesh 1000 Genomes population, three of 130 chromosomes (2.31%) carried deficient alleles; this included single chromosomes carrying the Kerala Kalyan and Orissa variants. CONCLUSIONS: In line with other recent work, G6PD deficiency is uncommon in Bengalis in Bangladesh. Further studies of particular ethnic groups are needed to evaluate the potential risk of wide deployment of primaquine in malaria control efforts in Bangladesh. PMID- 28356149 TI - Disparities in receipt of recommended care among younger versus older medicare beneficiaries: a cohort study. AB - BACKGROUND: Although health disparities have been documented between Medicare beneficiaries based on age (<65 years vs. older age groups), underuse of recommended medical care in younger beneficiaries has not been thoroughly investigated. In this study, we aim to identify and characterize vulnerabilities of the younger Medicare age group (aged <65 years) in relation to older age groups (aged 65-74 years and >=75 years) and to explore age group as a determinant of use of recommended care among Medicare beneficiaries. METHODS: We conducted a cohort study of community-dwelling Medicare beneficiaries who participated in the Medicare Current Beneficiary Survey between 2001 and 2008 (N = 30,117). Age group characteristics were compared using cross-sectional data at baseline. During follow-up, we assessed the association between age and receipt of recommended care on 38 recommended care indicators, adjusting for sociodemographic and clinical characteristics. Follow-up periods differed by component indicator. RESULTS: At baseline, a higher proportion of younger beneficiaries experienced social disadvantage, disability and certain morbidities than older age groups. During follow-up, younger beneficiaries were significantly less likely to receive overall recommended care compared to those 65-74 years of age (adjusted odds ratio and 95% confidence interval: 0.75, 0.70-0.80). In addition, male gender, non-Hispanic black race, less than high school education, living alone, with children or with others, psychiatric disorders and higher activity limitation stages were all associated with underuse of recommended care. CONCLUSIONS: Younger Medicare beneficiary status appears to be an independent risk factor for underuse of appropriate care. Support to ameliorate disparities in different social and health aspects may be warranted. PMID- 28356148 TI - Prediction of complications in early-onset pre-eclampsia (PREP): development and external multinational validation of prognostic models. AB - BACKGROUND: Unexpected clinical deterioration before 34 weeks gestation is an undesired course in early-onset pre-eclampsia. To safely prolong preterm gestation, accurate and timely prediction of complications is required. METHOD: Women with confirmed early onset pre-eclampsia were recruited from 53 maternity units in the UK to a large prospective cohort study (PREP-946) for development of prognostic models for the overall risk of experiencing a complication using logistic regression (PREP-L), and for predicting the time to adverse maternal outcome using a survival model (PREP-S). External validation of the models were carried out in a multinational cohort (PIERS-634) and another cohort from the Netherlands (PETRA-216). Main outcome measures were C-statistics to summarise discrimination of the models and calibration plots and calibration slopes. RESULTS: A total of 169 mothers (18%) in the PREP dataset had adverse outcomes by 48 hours, and 633 (67%) by discharge. The C-statistics of the models for predicting complications by 48 hours and by discharge were 0.84 (95% CI, 0.81 0.87; PREP-S) and 0.82 (0.80-0.84; PREP-L), respectively. The PREP-S model included maternal age, gestation, medical history, systolic blood pressure, deep tendon reflexes, urine protein creatinine ratio, platelets, serum alanine amino transaminase, urea, creatinine, oxygen saturation and treatment with antihypertensives or magnesium sulfate. The PREP-L model included the above except deep tendon reflexes, serum alanine amino transaminase and creatinine. On validation in the external PIERS dataset, the reduced PREP-S model showed reasonable calibration (slope 0.80) and discrimination (C-statistic 0.75) for predicting adverse outcome by 48 hours. Reduced PREP-L model showed excellent calibration (slope: 0.93 PIERS, 0.90 PETRA) and discrimination (0.81 PIERS, 0.75 PETRA) for predicting risk by discharge in the two external datasets. CONCLUSIONS: PREP models can be used to obtain predictions of adverse maternal outcome risk, including early preterm delivery, by 48 hours (PREP-S) and by discharge (PREP-L), in women with early onset pre-eclampsia in the context of current care. They have a potential role in triaging high-risk mothers who may need transfer to tertiary units for intensive maternal and neonatal care. TRIAL REGISTRATION: ISRCTN40384046 , retrospectively registered. PMID- 28356150 TI - Pregnane X receptor is associated with unfavorable survival and induces chemotherapeutic resistance by transcriptional activating multidrug resistance related protein 3 in colorectal cancer. AB - BACKGROUND: Although chemotherapy represents a predominant anti-cancer therapeutic modality, drug treatment efficacy is often limited due to the development of resistant tumor cells. The pregnane X receptor (PXR) affects chemotherapeutic effects by regulating targets involved in drug metabolism and transportation, but the regulatory mechanism is poorly understood. METHODS: Oxaliplatin (L-OHP) content in tumor cells was analyzed by mass cytometry. The roles of PXR on cancer cell proliferation, apoptosis and tumor growth with L-OHP treated were investigated by MTS, colony formation, flow cytometry and xenograft tumor assays. Luciferase reporter, Chromatin-immunoprecipitation and Site directed mutagenesis were evaluated the mechanisms. The PXR and multidrug resistance-related protein 3 (MRP3) expressions were examined by western blot, RT PCR or immunohistochemistry of TMA. Kaplan-Meier and Cox regression were adopted to analyze the prognostic value of PXR in colorectal cancer (CRC). RESULTS: PXR over-expression significantly increased oxaliplatin (L-OHP) transport capacity with a reduction of its content and repressed the effects of L-OHP on tumour cell proliferation and apoptosis. Conversely, PXR knockdown augments L-OHP-mediated cellular proliferation and apoptosis. Moreover, PXR significantly reduced the therapeutic effects of L-OHP on tumor growth in nude mice. Further studies indicated a positive correlation between PXR and MRP3 expression and this finding was confirmed in two independent cohorts. Significantly increased MRP3 expression was also found in PXR over-expressing cell lines. Mechanistically, PXR could directly bind to the MRP3 promoter, activating its transcription. The PXR binding sites were determined to be at -796 to -782bp (CTGAAGCAGAGGGAA) and the key binding sites were the "AGGGA" (-787 to -783bp) on the MRP3 promoter. Accordingly, blockade of MRP3 diminishes the effects on drug resistance of PXR. In addition, PXR expression is significantly associated with poor overall survival and represents an unfavorable and independent factor for male or stage I + II CRC patient prognosis. CONCLUSIONS: PXR is a potential biomarker for predicting outcome and activates MRP3 transcription by directly binding to its promoter resulting in an increased L-OHP efflux capacity, and resistance to L-OHP or platinum drugs in CRC. Our work reveals a novel and unique mechanism of drug resistance in CRC. PMID- 28356152 TI - Mid-term outcome following revision surgery of clavicular non- and malunion using anatomic locking compression plate and iliac crest bone graft. AB - BACKGROUND: Treatment of clavicular non- and malunion is still challenging. Current surgical procedures often result in frustrating functional outcome along with high-grade subjective impairment and increased rates of revision surgery. However, the combination of biological augmentation with vital bone graft and a biomechanically sufficient fixation system seems to be a promising concept of treatment. METHODS: In this retrospective study, 14 patients with a mean age of 44 years (26-67 years) suffering from non-union (n = 11) and/or malunion (n = 3) of the clavicle were enrolled. All patients were surgically treated using an anatomical precontoured locking compression plate (LCP) and autologous iliac crest bone graft. Functional outcome was assessed using the age- and sex-specific relative Constant Score. RESULTS: Mean follow-up was 27 months (range 12-44 months). The relative Constant Score significantly improved from preoperative 61 +/- 8 (43-72) to 82 +/- 10 (65-100) points at the final follow-up examination (p < 0.05). All patients showed bony union radiographically. One patient presented with a re-fracture of the clavicle nearly 3 years after revision surgery and 5 weeks after implant removal. Secondary fractures at the donor site of the anterior superior iliac spine were recorded in two patients. CONCLUSIONS: Iliac crest bone graft and anatomic locking plate fixation allow for a safe and adequate stabilization and radiographical bony union in non- and malunions of the clavicle with a high degree of patient satisfaction. However, secondary fractures of the anterior superior iliac spine constitute relevant complications and the time of hardware removal should be considered carefully. PMID- 28356151 TI - Endothelial dysfunction in the pathogenesis of pre-eclampsia in Ghanaian women. AB - BACKGROUND: Pre-eclampsia (PE) remains a disease of theories despite extensive research into its etiology. Alteration in the production of vascular endothelial growth factor (VEGF), a biomarker of endothelial dysfunction, is associated with pre-eclampsia although conflicting reports have been reported. The aim of the study was to determine and compare maternal serum levels of VEGF among pre eclamptics, normotensive non pregnant and pregnant women. This was a cross sectional study involving 100 women with pre-eclampsia, 102 women with normotensive pregnancy and 75 normotensives who were not pregnant. The study was carried out at Korle Bu Teaching Hospital (KBTH) from April to June in 2011. Basic socio-demographic and obstetric data were obtained by means of structured questionnaire. Following venesection, about 5mls of blood was sampled from the participants for the various tests. Enzyme Linked Immunosorbent Assay was used to determine the maternal serum levels of free VEGF. Data analysis was performed using SPSS version 20. RESULTS: Significant reduction in median serum levels of free VEGF was seen in both, normal pregnant [84.06 pg/ml (IQR: 78.90-99.67)] and pre-eclamptic women [4.71 pg/ml, (IQR: 3.41-7.93)] compared to the non-pregnant (395.85 pg/ml, IQR 234.93-625) with p < 0.001; the reduction was far greater in the pre-eclamptic group compared to that of normotensive pregnant group (p < 0.001). Early-onset pre-eclampsia had significantly more severe reduction in free VEGF levels (3.89, IQR: 2.60-5.67 pg/ml) compared to that of late onset PE (5.23, IQR: 3.78-16.97 pg/ml) with p<0.001 indicating a severer endothelial damage in former. CONCLUSIONS: Endothelial dysfunction contributes significantly to the pathogenesis of pre-eclampsia as demonstrated by profound decrease in maternal serum VEGF levels in PE compared to normotensive pregnancy and non-pregnancy state. The pathophysiology of early-onset pre-eclampsia may be partly explained by marked reduction in free serum VEGF levels with resultant severe endothelial dysfunction. PMID- 28356153 TI - Scrotal granulomatous aspergillosis in a dromedary camel (Camelus dromedarius). AB - BACKGROUND: This report describes a case of primary subcutaneous aspergillosis in a 7-year-old neutered male dromedary camel (Camelus dromedarius). CASE PRESENTATION: The animal developed a large nodular lesion in the right scrotum two years after surgical intervention for neutering. The mass had a firm consistency and was painful at palpation. Histopathology revealed dermal granulomatous inflammation with a necrotic centre, surrounded by plasma cells, macrophages, neutrophils, and sparse fungal hyphae characterised by parallel cell walls, distinct septa, and dichotomous branching. Fungal culture was not performed, but a panel of mono- and polyclonal antibodies specific for different fungal genera identified the hyphae as Aspergillus sp. CONCLUSIONS: The occurrence of subcutaneous lesions is a rare manifestation of aspergillosis in animals, and this appears to be the first case reported in the dromedary camel. PMID- 28356154 TI - Patterns of cross-contamination in a multispecies population genomic project: detection, quantification, impact, and solutions. AB - BACKGROUND: Contamination is a well-known but often neglected problem in molecular biology. Here, we investigated the prevalence of cross-contamination among 446 samples from 116 distinct species of animals, which were processed in the same laboratory and subjected to subcontracted transcriptome sequencing. RESULTS: Using cytochrome oxidase 1 as a barcode, we identified a minimum of 782 events of between-species contamination, with approximately 80% of our samples being affected. An analysis of laboratory metadata revealed a strong effect of the sequencing center: nearly all the detected events of between-species contamination involved species that were sent the same day to the same company. We introduce new methods to address the amount of within-species, between individual contamination, and to correct for this problem when calling genotypes from base read counts. CONCLUSIONS: We report evidence for pervasive within species contamination in this data set, and show that classical population genomic statistics, such as synonymous diversity, the ratio of non-synonymous to synonymous diversity, inbreeding coefficient FIT, and Tajima's D, are sensitive to this problem to various extents. Control analyses suggest that our published results are probably robust to the problem of contamination. Recommendations on how to prevent or avoid contamination in large-scale population genomics/molecular ecology are provided based on this analysis. PMID- 28356155 TI - Minimal disease activity and impact of disease in psoriatic arthritis: a Spanish cross-sectional multicenter study. AB - BACKGROUND: Patients with psoriatic arthritis (PsA) experience functional impairment and reduced quality of life, and thus patient global assessment in PsA is explained mainly by the physical, but also by the psychological, aspect of the disease. To assess the prevalence of minimal disease activity (MDA) in Spanish patients with PsA, we examined their characteristics and the association between MDA and the impact of the disease as assessed by the PsA Impact of Disease (PsAID) questionnaire. METHODS: A cross-sectional multicenter study was carried out in patients who fulfilled the Classification for Psoriatic Arthritis (CASPAR) criteria with at least 1 year of disease duration, and who were treated with biological or conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs) according to routine clinical practice in Spain. Patients were considered in MDA if they met at least 5/7 of the MDA criteria. The association between MDA and the recently developed PsAID questionnaire was also recorded. RESULTS: Of 227 patients included, 133 (58.6%) were in the MDA state (52% with antitumor necrosis factor (anti-TNF)alpha monotherapy, 24% with csDMARD monotherapy, and 24% with anti-TNFalpha in combination with csDMARD). Using multivariate logistic regression analysis, male gender (odds ratio (OR) 2.74, p = 0.001), a sedentary lifestyle (OR 3.13, p = 0.002), familial history of PsA (OR 0.38, p = 0.036), C-reactive protein (CRP) level (OR 0.92, p = 0.010), and use of corticoids (OR 0.33, p = 0.007) were considered features related to MDA. MDA patients had a significantly lower impact of the disease according to PsAID (mean total score (SD): MDA 3.3 (3.1) vs. non-MDA 7.1 (5.2); p < 0.001). CONCLUSIONS: Nearly 60% of Spanish PsA patients achieve MDA in routine clinical practice. MDA remains one of the most useful therapeutic targets for PsA since patients who reached this state also had a significantly lower impact of disease according to PsAID. PMID- 28356156 TI - Chimeric antigen receptor T cells: a novel therapy for solid tumors. AB - The chimeric antigen receptor T (CAR-T) cell therapy is a newly developed adoptive antitumor treatment. Theoretically, CAR-T cells can specifically localize and eliminate tumor cells by interacting with the tumor-associated antigens (TAAs) expressing on tumor cell surface. Current studies demonstrated that various TAAs could act as target antigens for CAR-T cells, for instance, the type III variant epidermal growth factor receptor (EGFRvIII) was considered as an ideal target for its aberrant expression on the cell surface of several tumor types. CAR-T cell therapy has achieved gratifying breakthrough in hematological malignancies and promising outcome in solid tumor as showed in various clinical trials. The third generation of CAR-T demonstrates increased antitumor cytotoxicity and persistence through modification of CAR structure. In this review, we summarized the preclinical and clinical progress of CAR-T cells targeting EGFR, human epidermal growth factor receptor 2 (HER2), and mesothelin (MSLN), as well as the challenges for CAR-T cell therapy. PMID- 28356158 TI - Interactions between Sirt1 and MAPKs regulate astrocyte activation induced by brain injury in vitro and in vivo. AB - BACKGROUND: Astrocyte activation is a hallmark of traumatic brain injury resulting in neurological dysfunction or death for an overproduction of inflammatory cytokines and glial scar formation. Both the silent mating type information (Sirt1) expression and mitogen-activated protein kinase (MAPK) signal pathway activation represent a promising therapeutic target for several models of neurodegenerative diseases. We investigated the potential effects of Sirt1 upregulation and MAPK pathway pharmacological inhibition on astrocyte activation in vitro and in vivo. Moreover, we attempted to confirm the underlying interactions between Sirt1 and MAPK pathways in astrocyte activation after brain injury. METHODS: The present study employs an interleukin-1beta (IL-1beta) stimulated primary cortical astrocyte model in vitro and a nigrostriatal pathway injury model in vivo to mimic the astrocyte activation induced by traumatic brain injury. The activation of GFAP, Sirt1, and MAPK pathways were detected by Western blot; astrocyte morphological hypertrophy was assessed using immunofluorescence staining; in order to explore the neuroprotective effect of regulation Sirt1 expression and MAPK pathway activation, the motor and neurological function tests were assessed after injury. RESULTS: GFAP level and morphological hypertrophy of astrocytes are elevated after injury in vitro or in vivo. Furthermore, the expressions of phosphorylated extracellular regulated protein kinases (p-ERK), phosphorylated c-Jun N-terminal kinase (p-JNK), and phosphorylated p38 activation (p-p38) are upregulated, but the Sirt1 expression is downregulated. Overexpression of Sirt1 significantly increases the p-ERK expression and reduces the p-JNK and p-p38 expressions. Inhibition of ERK, JNK, or p38 activation respectively with their inhibitors significantly elevated the Sirt1 expression and attenuated the astrocyte activation. Both the overproduction of Sirt1 and inhibition of ERK, JNK, or p38 activation can alleviate the astrocyte activation, thereby improving the neurobehavioral function according to the modified neurological severity scores (mNSS) and balance latency test. CONCLUSIONS: Thus, Sirt1 plays a protective role against astrocyte activation, which may be associated with the regulation of the MAPK pathway activation induced by brain injury in vitro and in vivo. PMID- 28356157 TI - Migration of mitochondrial DNA in the nuclear genome of colorectal adenocarcinoma. AB - BACKGROUND: Colorectal adenocarcinomas are characterized by abnormal mitochondrial DNA (mtDNA) copy number and genomic instability, but a molecular interaction between mitochondrial and nuclear genome remains unknown. Here we report the discovery of increased copies of nuclear mtDNA (NUMT) in colorectal adenocarcinomas, which supports link between mtDNA and genomic instability in the nucleus. We name this phenomenon of nuclear occurrence of mitochondrial component as numtogenesis. We provide a description of NUMT abundance and distribution in tumor versus matched blood-derived normal genomes. METHODS: Whole-genome sequence data were obtained for colon adenocarcinoma and rectum adenocarcinoma patients participating in The Cancer Genome Atlas, via the Cancer Genomics Hub, using the GeneTorrent file acquisition tool. Data were analyzed to determine NUMT proportion and distribution on a genome-wide scale. A NUMT suppressor gene was identified by comparing numtogenesis in other organisms. RESULTS: Our study reveals that colorectal adenocarcinoma genomes, on average, contains up to 4.2 fold more somatic NUMTs than matched normal genomes. Women colorectal tumors contained more NUMT than men. NUMT abundance in tumor predicted parallel abundance in blood. NUMT abundance positively correlated with GC content and gene density. Increased numtogenesis was observed with higher mortality. We identified YME1L1, a human homolog of yeast YME1 (yeast mitochondrial DNA escape 1) to be frequently mutated in colorectal tumors. YME1L1 was also mutated in tumors derived from other tissues. We show that inactivation of YME1L1 results in increased transfer of mtDNA in the nuclear genome. CONCLUSIONS: Our study demonstrates increased somatic transfer of mtDNA in colorectal tumors. Our study also reveals sex-based differences in frequency of NUMT occurrence and that NUMT in blood reflects NUMT in tumors, suggesting NUMT may be used as a biomarker for tumorigenesis. We identify YME1L1 as the first NUMT suppressor gene in human and demonstrate that inactivation of YME1L1 induces migration of mtDNA to the nuclear genome. Our study reveals that numtogenesis plays an important role in the development of cancer. PMID- 28356159 TI - Prevalence and risk factors for anemia severity and type in Malawian men and women: urban and rural differences. AB - BACKGROUND: The global burden of anemia is large especially in sub-Saharan Africa, where HIV is common and lifestyles are changing rapidly with urbanization. The effects of these changes are unknown. Studies of anemia usually focus on pregnant women or children, among whom the burden is greatest. We describe prevalence and risk factors for anemia among rural and urban men and women of all ages in Malawi. METHODS: We analyzed data from a population-wide cross-sectional survey of adults conducted in two sites, Karonga (rural) and Lilongwe (urban), commencing in May 2013. We used multinomial logistic regression models, stratified by sex to identify risk factors for mild and moderate-to severe anemia. RESULTS: Anemia prevalence was assessed among 8,926 men (age range 18-100 years) and 14,978 women (age range: 18-103 years). Weighted prevalence levels for all, mild, and moderate-to-severe anemia were 8.2, 6.7 and 1.2% in rural men; 19.4, 12.0 and 7.4% in rural women; 5.9, 5.1 and 0.8% in urban men; and 23.4, 13.6 and 10.1% in urban women. Among women, the odds of anemia were higher among urban residents and those with higher socioeconomic status. Increasing age was associated with higher anemia prevalence in men. Among both men and women, HIV infection was a consistent risk factor for severity of anemia, though its relative effect was stronger on moderate-to-severe anemia. CONCLUSIONS: The drivers of anemia in this population are complex, include both socioeconomic and biological factors and are affecting men and women differently. The associations with urban lifestyle and HIV indicate opportunities for targeted intervention. PMID- 28356160 TI - Optimizing conditions for labeling of mesenchymal stromal cells (MSCs) with gold nanoparticles: a prerequisite for in vivo tracking of MSCs. AB - BACKGROUND: Mesenchymal stromal cells (MSCs) have an inherent migratory capacity towards tumor tissue in vivo. With the future objective to quantify the tumor homing efficacy of MSCs, as first step in this direction we investigated the use of inorganic nanoparticles (NPs), in particular ca. 4 nm-sized Au NPs, for MSC labeling. Time dependent uptake efficiencies of NPs at different exposure concentrations and times were determined via inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: The labeling efficiency of the MSCs was determined in terms of the amount of exocytosed NPs versus the amount of initially endocytosed NPs, demonstrating that at high concentrations the internalized Au NPs were exocytosed over time, leading to continuous exhaustion. While exposure to NPs did not significantly impair cell viability or expression of surface markers, even at high dose levels, MSCs were significantly affected in their proliferation and migration potential. These results demonstrate that proliferation or migration assays are more suitable to evaluate whether labeling of MSCs with certain amounts of NPs exerts distress on cells. However, despite optimized conditions the labeling efficiency varied considerably in MSC lots from different donors, indicating cell specific loading capacities for NPs. Finally, we determined the detection limits of Au NP-labeled MSCs within murine tissue employing ICP-MS and demonstrate the distribution and homing of NP labeled MSCs in vivo. CONCLUSION: Although large amounts of NPs improve contrast for imaging, duration and extend of labeling needs to be adjusted carefully to avoid functional deficits in MSCs. We established an optimized labeling strategy for human MSCs with Au NPs that preserves their migratory capacity in vivo. PMID- 28356162 TI - Blood transfusion and coagulopathy in geriatric trauma patients. AB - BACKGROUND: Trauma resuscitation has undergone a paradigm shift with new emphasis on the early use of blood products and increased proportions of plasma and platelets. However, it is unclear how this strategy is applied or how effective it is in the elderly population. The study aim is to identify differences in transfusion practices and the coagulopathy of trauma in the elderly. METHODS: Data was prospectively collected on all consecutive patients that met trauma activation criteria at a Level I trauma centre. Data fields included patient demographics, co-morbidities, injury and resuscitation data, laboratory values, thromboelastography (TEG) results, and outcome measures. Elderly patients were defined as those 55 and older. Propensity-score matched analysis was completed for patients receiving blood product transfusion. Patients were matched by gender, mechanism, injury severity score (ISS), head injury, and time from injury. RESULTS: Total of 628 patients were included, of which 142 (23%) were elderly. Elderly patients were more likely to be female (41% vs. 24%), suffer blunt mechanism of trauma (96% vs. 80%), have higher ISS scores (mean 25.4 vs. 21.6) and mortality (19% vs. 8%). Elderly patients were significantly more likely to receive a blood transfusion (42% vs. 30%), specifically for red cells and plasma. Propensity-matched analysis resulted in no difference in red cell transfusion or mortality. Despite the broad similarities between the matched cohorts, trauma coagulopathy as measured by TEG was less commonly observed in the elderly. DISCUSSION: Our results suggest that elderly trauma patients are more likely to receive blood products when admitted to a trauma centre, though this may be attributed to under-triage. The results also suggest an altered coagulopathic response to traumatic injury which is partially influenced by increased anticoagulant and antiplatelet medication use in the geriatric population. CONCLUSION: It is not clear whether the acute coagulopathy of trauma is equivalent in geriatric patients, and further study is therefore warranted. PMID- 28356163 TI - A novel system for continuous, real-time monitoring of heart motion signals. AB - BACKGROUND: Understanding cardiac mechanics is important for developing cardiac therapies. Current modalities for assessing cardiac mechanics sample patient's heart at specific heart rate, contractility, preload, and afterload. The objective of this study was to test the feasibility of a novel system composed of intra-cardiac leads equipped with an inertial module chip (3D accelerometers and 3D gyroscopes) in monitoring continuous heart motion. METHODS: In this descriptive study, four healthy pigs were anesthetized and instrumented with motion-sensitive intra-cardiac leads; the temporal correlation between signals from motion sensors and tissue Doppler from the chest wall were studied; changes in real-time heart accelerations (ACC) and angular velocity (ANGV) were reported as percentages of change from baseline. RESULTS: Heart motion signals were sensed continuously from the right ventricular apex (RVa) and coronary sinus (CS). Volume expansion did not produce significant changes in the ACC and ANGV signals. Increasing heart rate increased the peak systolic ACC signal recorded from RVa and CS by 94 and 76%, respectively, and increased both peak systolic (61% RVa and 27% CS) and diastolic ANGV (200% CS vs. 31% RVa). Epinephrine administration increased peak systolic ACC signals at both sites (246% RVa; 331% CS). Peak systolic and diastolic ANGV increased in response to epinephrine (systolic: 198% RVa and 175% CS; diastolic: 723% CS and 89% RVa) (p = 0.125 for all changes expressed in percent). Temporal correlation between the ANGV signal and tissue Doppler signal was detected throughout all interventions. CONCLUSIONS: A novel system for continuously monitoring heart motion signals from within the heart was presented. Heart motion signals in response to physiologic manipulations were characterized. PMID- 28356161 TI - The cell cycle checkpoint inhibitors in the treatment of leukemias. AB - The inhibition of the DNA damage response (DDR) pathway in the treatment of cancers has recently reached an exciting stage with several cell cycle checkpoint inhibitors that are now being tested in several clinical trials in cancer patients. Although the great amount of pre-clinical and clinical data are from the solid tumor experience, only few studies have been done on leukemias using specific cell cycle checkpoint inhibitors. This review aims to summarize the most recent data found on the biological mechanisms of the response to DNA damages highlighting the role of the different elements of the DDR pathway in normal and cancer cells and focusing on the main genetic alteration or aberrant gene expression that has been found on acute and chronic leukemias. This review, for the first time, outlines the most important pre-clinical and clinical data available on the efficacy of cell cycle checkpoint inhibitors in single agent and in combination with different agents normally used for the treatment of acute and chronic leukemias. PMID- 28356164 TI - Excessive activation of the TLR9/TGF-beta1/PDGF-B pathway in the peripheral blood of patients with systemic lupus erythematosus. AB - BACKGROUND: Our aim is to study the existence of the TLR9/TGF-beta1/PDGF-B pathway in healthy humans and patients with systemic lupus erythematosus (SLE), and to explore its possible involvement in the pathogenesis of lupus nephritis (LN). METHODS: Protein levels of the cytokines were detected by ELISA. mRNA levels of the cytokines were analyzed by real-time PCR. MTT assay was used to test the proliferation of mesangial cells under different treatments. RESULTS: Compared to healthy controls (N Control = 56), levels of Toll-like receptor (TLR)9, transforming growth factor (TGF)-beta1, and platelet-derived growth factor B (PDGF-B) were increased significantly in the peripheral blood of SLE patients (N SLE = 112). Significant correlations between the levels of TLR9, TGF beta1, and PDGF-B were observed in both healthy controls and SLE patients. The levels of TGF-beta1 and PDGF-B were greatly enhanced by TLR9 activation in primary cell cultures. The proliferation of mesangial cells induced by the plasma of SLE patients was significantly higher than that induced by healthy controls; PDGF-B was involved in this process. The protein levels of PDGF-B homodimer correlated with the levels of urine protein in SLE patients with LN (N LN =38). CONCLUSIONS: The TLR9/TGF-beta1/PDGF-B pathway exists in humans and can be excessively activated in SLE patients. High levels of PDGF-B may result in overproliferation of mesangial cells in the kidney that are involved in the development of glomerulonephritis and LN. Further studies are necessary to identify TLR9, TGF-beta1, and PDGF-B as new therapeutic targets to prevent the development of glomerulonephritis and LN. PMID- 28356165 TI - Relationship between hyperglycemia, antioxidant capacity and some enzymatic and non-enzymatic antioxidants in African patients with type 2 diabetes. AB - BACKGROUND AND PURPOSE: Studies demonstrate that free radicals are involved in the pathogenesis of diabetic complications. The aim of this study was to determine the implication of total antioxidant capacity (TAC) and some enzymatic and non-enzymatic antioxidants as suitable biomarkers of diabetic complications risk factors. METHODS: A total of 90 patients (70 patients with or without diabetic complications +20 normal healthy) were examined by evaluating the level of lipid peroxidation, nitrogen monoxide (NO), fasting blood glucose, glycated haemoglobin (HbA1c), enzymatic and non-enzymatic antioxidants using standard spectrophotometric methods. RESULTS: The fasting blood glucose and HbA1c levels were respectively 2.05 and 2.32 times higher in the group of patients with diabetes and complications (DPWC) compared to those of healthy persons. A statistically higher level of malondialdehyde (MDA), NO and TAC was observed in a group of patients with diabetes and complications compared to those without complications (DPNC). A significant positive correlation was found between catalase (CAT) and fasting blood glucose while a significant and negative correlation was noted between reduced glutathione (GSH) and fasting blood glucose. Also was noted a significant relationship between HbA1c and other markers of oxidative stress. CONCLUSIONS: The results suggest that the plasma levels of CAT, TAC and reduced glutathione could give information on the risk of developing complications of diabetes, considering that the modification of these biomarkers levels were associated with oxidative stress. PMID- 28356167 TI - SGEM Hot Off the Press: Computer provider order entry (CPOE) and emergency department flow. PMID- 28356170 TI - Oenococcus oeni: Queen of the cellar, nightmare of geneticists. AB - Oenococcus oeni is a wine-associated lactic acid bacterium (LAB) responsible mostly for wine malolactic fermentation (MLF). This fastidious bacterium (auxotrophic for many amino acids and slow growing) possesses remarkable adaptability to harsh physicochemical conditions and can reprogramme its metabolic pathways to enhance its survival in wine. Thus, O. oeni is an instructive bacterial model for investigating stress response mechanisms in LAB. However, the lack of appropriate techniques to modify the O. oeni genome has hampered molecular studies of this species. The application of recent advances in molecular genetics promises to provide a better understanding of the regulation of stress responses in this species in the future. PMID- 28356169 TI - The KL24 gene cluster and a genomic island encoding a Wzy polymerase contribute genes needed for synthesis of the K24 capsular polysaccharide by the multiply antibiotic resistant Acinetobacter baumannii isolate RCH51. AB - The whole-genome sequence of the multiply antibiotic resistant Acinetobacter baumannii isolate RCH51 belonging to sequence type ST103 (Institut Pasteur scheme) revealed that the set of genes at the capsule locus, KL24, includes four genes predicted to direct the synthesis of 3-acetamido-3,6-dideoxy-d-galactose (d Fuc3NAc), and this sugar was found in the capsular polysaccharide (CPS). One of these genes, fdtE, encodes a novel bifunctional protein with an N-terminal FdtA 3,4-ketoisomerase domain and a C-terminal acetyltransferase domain. KL24 lacks a gene encoding a Wzy polymerase to link the oligosaccharide K units to form the CPS found associated with isolate RCH51, and a wzy gene was found in a small genomic island (GI) near the cpn60 gene. This GI is in precisely the same location as another GI carrying wzy and atr genes recently found in several A. baumannii isolates, but it does not otherwise resemble it. The CPS isolated from RCH51, studied by sugar analysis and 1D and 2D 1H and 13C NMR spectroscopy, revealed that the K unit has a branched pentasaccharide structure made up of Gal, GalNAc and GlcNAc residues with d-Fuc3NAc as a side branch, and the K units are linked via a beta-d-GlcpNAc-(1->3)-beta-d-Galp linkage formed by the Wzy encoded by the GI. The functions of the glycosyltransferases encoded by KL24 were assigned to formation of specific bonds. A correspondence between the order of the genes in KL24 and other KL and the order of the linkages they form was noted, and this may be useful in future predictions of glycosyltransferase specificities. PMID- 28356166 TI - Integrative clustering reveals a novel split in the luminal A subtype of breast cancer with impact on outcome. AB - BACKGROUND: Breast cancer is a heterogeneous disease at the clinical and molecular level. In this study we integrate classifications extracted from five different molecular levels in order to identify integrated subtypes. METHODS: Tumor tissue from 425 patients with primary breast cancer from the Oslo2 study was cut and blended, and divided into fractions for DNA, RNA and protein isolation and metabolomics, allowing the acquisition of representative and comparable molecular data. Patients were stratified into groups based on their tumor characteristics from five different molecular levels, using various clustering methods. Finally, all previously identified and newly determined subgroups were combined in a multilevel classification using a "cluster-of clusters" approach with consensus clustering. RESULTS: Based on DNA copy number data, tumors were categorized into three groups according to the complex arm aberration index. mRNA expression profiles divided tumors into five molecular subgroups according to PAM50 subtyping, and clustering based on microRNA expression revealed four subgroups. Reverse-phase protein array data divided tumors into five subgroups. Hierarchical clustering of tumor metabolic profiles revealed three clusters. Combining DNA copy number and mRNA expression classified tumors into seven clusters based on pathway activity levels, and tumors were classified into ten subtypes using integrative clustering. The final consensus clustering that incorporated all aforementioned subtypes revealed six major groups. Five corresponded well with the mRNA subtypes, while a sixth group resulted from a split of the luminal A subtype; these tumors belonged to distinct microRNA clusters. Gain-of-function studies using MCF-7 cells showed that microRNAs differentially expressed between the luminal A clusters were important for cancer cell survival. These microRNAs were used to validate the split in luminal A tumors in four independent breast cancer cohorts. In two cohorts the microRNAs divided tumors into subgroups with significantly different outcomes, and in another a trend was observed. CONCLUSIONS: The six integrated subtypes identified confirm the heterogeneity of breast cancer and show that finer subdivisions of subtypes are evident. Increasing knowledge of the heterogeneity of the luminal A subtype may add pivotal information to guide therapeutic choices, evidently bringing us closer to improved treatment for this largest subgroup of breast cancer. PMID- 28356171 TI - A Case of "Abnormally Abnormal" Hypoxic Ventilatory Responses: A Novel NPARM PHOX 2B Gene Mutation. AB - ABSTRACT: Congenital central hypoventilation syndrome (CCHS) is a rare disorder associated with dysregulation of the autonomic ventilatory response to hypoxia and hypercarbia usually caused by polyalanine repeat expansion mutations in the PHOX 2B gene. Non-polyalanine repeat mutations (NPARM) represent approximately 10% of cases, and usually require continuous ventilation during sleep, although our knowledge of disease progression is limited. Here we present a case with a novel NPARM CCHS mutation associated with a premature stop codon for the PHOX 2B protein. Despite the type of the mutation, patient management with supplementary oxygen has been sufficient. Experience from our case may help when counseling parents. PMID- 28356172 TI - Severe Obstructive Sleep Apnea in a Child With Goldenhar Syndrome and Nasal Obstruction. AB - ABSTRACT: A 4-year-old boy with Goldenhar syndrome and severe obstructive sleep apnea does not tolerate nasal continuous positive airway pressure. Evaluation with imaging showed nasal obstruction with an inverted tooth. This case illustrates the importance of personalized evaluation and treatment plan in a child with Goldenhar syndrome. PMID- 28356174 TI - Next Steps for the Premier Clinical Journal in the Sleep Field. PMID- 28356175 TI - Transparency and Partnership. PMID- 28356173 TI - Management of Obstructive Sleep Apnea in Commercial Motor Vehicle Operators: Recommendations of the AASM Sleep and Transportation Safety Awareness Task Force. AB - ABSTRACT: The American Academy of Sleep Medicine Sleep and Transportation Safety Awareness Task Force responded to the Federal Motor Carrier Safety Administration and Federal Railroad Administration Advance Notice of Proposed Rulemaking and request for public comments regarding the evaluation of safety-sensitive personnel for moderate-to-severe obstructive sleep apnea (OSA). The following document represents this response. The most salient points provided in our comments are that (1) moderate-to-severe OSA is common among commercial motor vehicle operators (CMVOs) and contributes to an increased risk of crashes; (2) objective screening methods are available and preferred for identifying at-risk drivers, with the most commonly used indicator being body mass index; (3) treatment in the form of continuous positive airway pressure (CPAP) is effective and reduces crashes; (4) CPAP is economically viable; (5) guidelines are available to assist medical examiners in determining whether CMVOs with moderate to-severe OSA should continue to work without restrictions, with conditional certification, or be disqualified from operating commercial motor vehicles. PMID- 28356176 TI - Underestimation of Sleep Apnea With Home Sleep Apnea Testing Compared to In Laboratory Sleep Testing. PMID- 28356177 TI - Automated Screening of Children With Obstructive Sleep Apnea Using Nocturnal Oximetry: An Alternative to Respiratory Polygraphy in Unattended Settings. AB - STUDY OBJECTIVES: Nocturnal oximetry has become known as a simple, readily available, and potentially useful diagnostic tool of childhood obstructive sleep apnea (OSA). However, at-home respiratory polygraphy (HRP) remains the preferred alternative to polysomnography (PSG) in unattended settings. The aim of this study was twofold: (1) to design and assess a novel methodology for pediatric OSA screening based on automated analysis of at-home oxyhemoglobin saturation (SpO2), and (2) to compare its diagnostic performance with HRP. METHODS: SpO2 recordings were parameterized by means of time, frequency, and conventional oximetric measures. Logistic regression models were optimized using genetic algorithms (GAs) for three cutoffs for OSA: 1, 3, and 5 events/h. The diagnostic performance of logistic regression models, manual obstructive apnea-hypopnea index (OAHI) from HRP, and the conventional oxygen desaturation index >= 3% (ODI3) were assessed. RESULTS: For a cutoff of 1 event/h, the optimal logistic regression model significantly outperformed both conventional HRP-derived ODI3 and OAHI: 85.5% accuracy (HRP 74.6%; ODI3 65.9%) and 0.97 area under the receiver operating characteristics curve (AUC) (HRP 0.78; ODI3 0.75) were reached. For a cutoff of 3 events/h, the logistic regression model achieved 83.4% accuracy (HRP 85.0%; ODI3 74.5%) and 0.96 AUC (HRP 0.93; ODI3 0.85) whereas using a cutoff of 5 events/h, oximetry reached 82.8% accuracy (HRP 85.1%; ODI3 76.7) and 0.97 AUC (HRP 0.95; ODI3 0.84). CONCLUSIONS: Automated analysis of at-home SpO2 recordings provide accurate detection of children with high pretest probability of OSA. Thus, unsupervised nocturnal oximetry may enable a simple and effective alternative to HRP and PSG in unattended settings. PMID- 28356178 TI - Autotitrating CPAP as a Tool for CPAP Initiation for Children. AB - STUDY OBJECTIVES: Few studies have assessed autotitrating positive airway pressure (autoPAP) for treatment of obstructive sleep apnea (OSA) in children. We aimed to review our use of autoPAP for initiation of continuous positive airway pressure (CPAP) therapy in children, and compare autoPAP-derived treatment pressures to CPAP treatment pressure determined by attended polysomnography (PSG). METHODS: Retrospective review of children initiated on autoPAP from 2013 to 2015. Mean autoPAP pressure (AutoMean pressure) and average device pressure <= 90% of time (Auto90 pressure) were taken from downloaded data and compared to the recommended treatment pressure following titration PSG (PSG pressure). RESULTS: Fifty-two children started CPAP, of whom 26 (age +/- standard deviation 11.9 +/- 3.4 years) used autoPAP and had titration PSG. AutoPAP was used on average 84% of nights (standard deviation 20%) in the first month, with a mean +/- standard deviation 6.3 +/- 2.0 hours of use on nights used. The median (interquartile range) obstructive apnea-hypopnea index decreased from 16.6 (11, 35) events/h before treatment to 2.2 (0.4, 3.8) events/h on the titration PSG. Median (interquartile range) PSG pressure was 9.0 cm H2O (7.0, 10.0), AutoMean pressure was 6.3 cm H2O (5.3, 7.5), and Auto90 pressure was 8.1 cm H2O (7.1, 9.5). These were significantly different (P < .001), with the significant difference lying between AutoMean and the other two pressures. PSG pressure was greater than or equal to the AutoMean pressure in all cases, and greater than or equal to the Auto90 pressure in 20 out of 26 cases (77%). CONCLUSIONS: AutoPAP is a safe and effective means of initiating CPAP in children. AutoMean and Auto90 pressures are usually below treatment pressure determined by titration PSG. PMID- 28356179 TI - Upper Airway Reflexes are Preserved During Dexmedetomidine Sedation in Children With Down Syndrome and Obstructive Sleep Apnea. AB - STUDY OBJECTIVES: The assessment of pharyngeal collapsibility is difficult to perform in children under normal sleep. An alternative is to perform the assessment under an anesthetic, such as dexmedetomidine (DEX), that induces non rapid eye movement (NREM) sleep. The objectives of this study were to compare critical closing airway pressure (Pcrit) obtained during natural sleep to that obtained under DEX in patients with Down syndrome (DS) and persistent obstructive sleep apnea (OSA) and determine whether Pcrit measured under sedation predicts the severity of OSA. METHODS: The passive and active Pcrit, which represent airway passive mechanical properties and active dynamic responses to airway obstruction, respectively, were measured. Upper airway reflex activity was estimated by calculating the difference between active and passive Pcrit. Subjects underwent overnight polysomnography during which Pcrit was measured during normal sleep. Pcrit was also measured during DEX sedation at a dose of 2 MUg/kg/h. RESULTS: The study included 50 patients with median age of 11.4 years (interquartile range: 7.0-13.9) and median body mass index of 23.0 kg/m2 (interquartile range: 18.4-29.1), 66% male and 80% Caucasian. Passive Pcrit was significantly higher than active Pcrit when measured during normal sleep and DEX induced sleep. There was a positive association between apnea-hypopnea index and passive Pcrit (Spearman r = 0.53, P = .0001) and active Pcrit (r = 0.55, P = .0002) under DEX-induced sleep. There were no significant differences between the Pcrit measurements during natural sleep and during DEX sedation. CONCLUSION: Patients with OSA can compensate for airway obstruction under DEX-induced sleep. The close association between Pcrit and apnea-hypopnea index suggests that airway responses with DEX sedation parallel those seen during natural sleep. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01902407. PMID- 28356180 TI - Nocturnal Desaturation is Associated With Atrial Fibrillation in Patients With Ischemic Stroke and Obstructive Sleep Apnea. AB - STUDY OBJECTIVES: Both atrial fibrillation (AF) and obstructive sleep apnea (OSA) are risk factors for ischemic stroke. Previous studies suggested that OSA is associated with AF in individuals who have not had a stroke. For better secondary prevention of stroke, this study determined the association between OSA and AF among patients with ischemic stroke. METHODS: This cross-sectional study recruited consecutive patients with subacute ischemic stroke admitted for neurorehabilitation. The baseline and clinical data were collected, and standard polysomnography was performed in a sleep center. RESULTS: The 47 women and 111 men enrolled in this study were divided into two groups according to the presence of AF. The AF group (n = 26) had a significantly older age (72.2 versus 60.1 years, P = .016), significantly more disability (Barthel index: 35 versus 45, P = .045), and marginally higher mean oxygen desaturation (6.7% versus 5.6%, P = .079) compared to the non-AF group. The two groups did not significantly differ in sex, body mass index, prevalence of hyperthyroidism, and other parameters of OSA. The multivariate logistic regression analysis revealed that mean desaturation was significantly associated with AF after adjusting for age, neck circumference, Barthel index and high-density lipoprotein level (odds ratio = 1.19 (95% confidence interval 1.05-1.35), P = .008). CONCLUSIONS: Nocturnal hypoxia due to OSA is an independent predictor of AF in patients with subacute ischemic stroke. The use of overnight pulse oximeter to assess nocturnal hypoxia and predict paroxysmal AF in patients with cryptogenic stroke needs further evaluation. COMMENTARY: A commentary on this article appears in this issue on page 667. PMID- 28356181 TI - Validation of the Nox-T3 Portable Monitor for Diagnosis of Obstructive Sleep Apnea in Chinese Adults. AB - STUDY OBJECTIVES: To evaluate the performance of a portable monitor (Nox-T3, Nox Medical Inc. Reykjavik, Iceland) used to diagnose obstructive sleep apnea in Chinese adults. METHODS: Eighty Chinese adults (mean +/- standard deviation age 47.6 +/- 14.0 years, 77.5% males, body mass index 27.5 +/- 5.4 kg/m2) underwent overnight, unattended home sleep apnea testing (HSAT) with the Nox-T3 portable monitor followed by an overnight in-laboratory polysomnogram (PSG) with simultaneous portable monitor recording. The portable monitor recordings were scored using automated analysis and then manually edited using different criteria for scoring hypopneas. Polysomnography was scored based on recommended guidelines. RESULTS: When scoring of hypopneas required a >= 4% oxygen desaturation event, the mean +/- standard deviation apnea-hypopnea index (AHI) was 24.4 +/- 20.8 events/h on HSAT, 28.0 +/- 22.9 events/h on in-laboratory portable monitor recording, and 28.6 +/- 23.9 events/h on PSG (P < .0001). Bland Altman analysis of AHI on PSG versus HSAT showed a mean difference (95% confidence interval) of -4.64 (-7.15, -2.13); limits of agreement (equal to +/- 2 standard deviations) was -26.62 to 17.35 events/h. Based on a threshold of AHI >= 5 events/h, HSAT had 95% sensitivity, 69% specificity, 94% positive predictive value, and 75% negative predictive value compared to PSG. Using an AHI >= 15 events/h, HSAT had 93% sensitivity, 85% specificity, 89% positive predictive value, and 91% negative predictive value. Closer agreements were present when comparing the simultaneous recordings. Similar results were obtained using different scoring criteria for hypopneas. CONCLUSIONS: Despite known differences between HSAT and PSG, the results show close agreement between the two diagnostic tests in Chinese adults, especially when controlling for night-to-night variability and changes in sleeping environment. PMID- 28356183 TI - Cryopreservation of saltwater crocodile (Crocodylus porosus) spermatozoa. AB - The aim of the present study was to develop a protocol for the successful cryopreservation of Saltwater crocodile spermatozoa. Sperm cells were frozen above liquid nitrogen vapour in phosphate-buffered saline (PBS) containing either 0.3M trehalose, 0.3M raffinose or 0.3M sucrose and compared with glycerol (0.3 2.7M). Although the highest levels of mean post-thaw motility were observed following cryopreservation in 0.3M trehalose (7.6%) and 0.3M sucrose (7.3%), plasma membrane integrity (PI) was best following cryopreservation in 2.7M glycerol (52.5%). A pilot study then assessed the cytotoxicity of glycerol and sucrose prior to cryopreservation and revealed no loss of survival when spermatozoa were diluted in 0.68M glycerol or 0.2-0.3M sucrose once cryoprotectants were washed out with PBS or Biggers, Whitten and Whittingham medium containing sperm capacitation agents (BWWCAP). A final study refined the combined use of permeating (0.68 or 1.35M glycerol) and non-permeating (0.2 or 0.3M sucrose) cryoprotectants. Spermatozoa were cryopreserved in liquid nitrogen vapour at rates of approximately -21 degrees Cmin-1 (fast freeze) or -6.0 degrees Cmin-1 (slow freeze). Post-thaw survival was highest with a combination of 0.2M sucrose and 0.68M glycerol and when these cryoprotectants were washed out with BWWCAP, regardless of whether spermatozoa were frozen using a fast (motility 14.2+/-4.7%; PI 20.7+/-2.0%) or slow (motility 12.0+/-2.7%; PI 22+/-4%) cryopreservation rate. PMID- 28356184 TI - Placentation in the plains zebra (Equus quagga). AB - The placenta and fetal gonads of 12 pregnant plains zebra (Equus quagga), estimated to be between 81 and 239 days of gestation, were examined. The diffuse, microcotyledonary zebra placenta appeared, developmentally, to be 3-4 weeks behind its counterpart in horse pregnancy and this, together with the presence of small and long-lived endometrial cups, low levels of zebra chorionic gonadotrophin in maternal serum and few accessory corpora lutea in the maternal ovaries during the first half of gestation, made zebra pregnancy more similar to donkey than horse pregnancy. Zebra fetal gonads enlarged after 80 days of gestation and their interstitial cells stained positively for 3beta hydroxysteroid dehydrogenase and 17,20 lyase steroid enzymes while the trophoblast stained for aromatase. This confirmed that zebra fetal gonads, like those of the horse and donkey, can synthesise C19 androgens, which can then be aromatised by the placenta to C18 oestrogens. It is remarkable that such unusual feto-placental mechanisms of production of gonadotrophic and steroid hormones has persisted unchanged within the genus Equus despite the many physical adaptations and the considerable loss of chromosomes that have occurred during the evolution of its member species. PMID- 28356182 TI - The Efficacy of Low-Level Continuous Positive Airway Pressure for the Treatment of Snoring. AB - STUDY OBJECTIVES: To assess effects of low-level continuous positive airway pressure (CPAP) on snoring in habitual snorers without obstructive sleep apnea (OSA). METHODS: A multicenter prospective in-laboratory reversal crossover intervention trial was conducted between September 2013 and August 2014. Habitual snorers were included if they snored (inspiratory sound pressure level >= 40 dBA) for >= 30% all sleep breaths on a baseline sleep study (Night 1), and if significant OSA and daytime somnolence were absent. Included participants then underwent a CPAP titration study at 2, 4, or 6 cm H2O (Night 2) to examine snoring responses to step-increases in nasal pressure, a treatment night at optimal pressure (Night 3), followed by baseline night (Night 4). At each pressure, snoring intensity was measured on each breath. Snoring frequency was quantified as a percentage of sleep breaths at thresholds of 40, 45, 50, and 55 dBA. Sleep architecture and OSA severity were characterized using standard measurements. RESULTS: On baseline sleep studies, participants demonstrated snoring at >= 40 dBA on 53 +/- 3% and >= 45 dBA on 35 +/- 4% of breaths. Snoring frequency decreased progressively as nasal pressure increased from 0 to 4 cm H2O at each threshold, and plateaued thereafter. CPAP decreased snoring frequency by 67% and 85% at 40 and 45 dBA, respectively. Intervention did not alter sleep architecture and sleep apnea decreased minimally. CONCLUSIONS: Low-level CPAP below the range required to treat OSA diminished nocturnal snoring, and produced uniform reduction in nightly noise production below the World Health Organization's limit of 45 dBA. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT01949584. PMID- 28356186 TI - Welcome Message. PMID- 28356185 TI - Steroid hormones interact with natriuretic peptide C to delay nuclear maturation, to maintain oocyte-cumulus communication and to improve the quality of in vitro produced embryos in cattle. AB - In vivo, oocyte maturation is triggered by the ovulatory LH surge, whereas in vitro it is precociously induced when the cumulus-oocyte complex is removed from the follicle. Natriuretic peptide C (NPPC) delays germinal vesicle breakdown (GVBD) while increasing oocyte-cumulus communication during in vitro maturation (IVM) in cattle. In the present study we first tested the hypothesis that steroids secreted by the follicle (17beta-oestradiol, progesterone and androstenedione) interact with NPPC to delay GVBD and to maintain oocyte-cumulus communication as assessed by transfer of a dye (Lucifer Yellow) from the oocyte to cumulus cells. Then, we assessed the effects of steroid hormones and NPPC, alone and in combination in a pre-IVM culture, on embryo production. The combination of NPPC with steroids delayed GVDB, increased natriuretic peptide receptor 2 (NPR2) mRNA abundance in cumulus cells during culture, and maintained oocyte-cumulus communication at levels not different from non-cultured controls. The addition of steroids and/or NPPC to a pre-IVM culture did not alter blastocyst rates after IVF, but supplementation with steroids increased blastocyst total cell number. The present study provides evidence, for the first time in cattle, that steroids interact with NPPC to regulate oocyte nuclear maturation and oocyte-cumulus communication, and improve oocyte developmental competence. PMID- 28356187 TI - Vulvar carcinoma in Norway: A 50-year perspective on trends in incidence, treatment and survival. AB - OBJECTIVE: To explore trends in vulvar squamous cell carcinoma (SCC) incidence, age and stage at diagnosis, treatment and survival in Norway from 1961 to 2010. METHODS: From 1961 to 2010, 2233 cases of vulvar SCC were extracted from the Cancer Registry of Norway. Data on age at diagnosis, tumor morphology, stage of the disease and treatment were analyzed. Age-standardized incidence rates, adjusted to the Norwegian standard population, were computed. Relative survival was calculated as a ratio of the observed survival in the study population over the expected survival in the background population. Multivariate Cox model was fitted to estimate hazard ratios. RESULTS: The overall incidence of vulvar SCC increased >2.5 fold (from 1.70 to 4.66 per 100,000 women/year; P<0.01). Age specific incidence rates increased among women aged <=60years (by 150% in age group 0-39years, 175% in age group 40-49years and 68% in age group 50-59years). From 1971 to 2010, the percentage of patients receiving surgery as only treatment decreased from 81% to 61%, whereas the use of radiation and combination therapy (surgery and radiation) increased from 3% to 11% and 6% to 20%, respectively. 5 year relative survival increased significantly among women <=80years (from 72% to 83% among women aged <=60years and from 60% to 65% among women aged 61-80years). CONCLUSIONS: The incidence of vulvar SCC has increased since the sixties, particularly among women younger than 60years. Despite less aggressive surgical treatment, survival has improved. PMID- 28356188 TI - An index of the ratio of inflammatory to antiviral cell types mediates the effects of social adversity and age on chronic illness. AB - BACKGROUND: It is assumed that both social stress and chronological age increase the risk of chronic illness, in part, through their effect on systemic inflammation. Unfortunately, observational studies usually employ single-marker measures of inflammation (e.g., Interleukin-6, C-reactive protein) that preclude strong tests for mediational effects. OBJECTIVE: The present study investigated the extent to which the effects of socioeconomic disadvantage and age on onset of chronic illness is mediated by dominance of the innate (inflammatory) over the acquired (antiviral) components of the immune system. METHODS: We assessed inflammation using the ratio of inflammatory to antiviral cell types (ITACT Ratio). This approach provided a stronger test of evolutionary arguments regarding the effect of social stress on chronic inflammation than is the case with cytokine measures, and afforded an opportunity to replicate findings obtained utilizing mRNA. We used structural equation modeling and longitudinal data from a sample of 100 middle-age African American women to perform our analyses. RESULTS: Dominance of inflammatory over antiviral cell activity was associated with each of the eight illnesses included in our chronic illness measure. Both socioeconomic disadvantage and age were also associated with inflammatory dominance. Pursuant to the central focus of the study, the effects of socioeconomic adversity and age on increased illness were mediated by our measure of inflammatory dominance. The indirect effect of these variables through inflammatory cell profile was significant, with neither socioeconomic disadvantage nor age showing a significant association with illness once the impact of inflammatory cell profile was taken into account. CONCLUSIONS: First, the analysis provides preliminary validation of a new measure of inflammation that is calculated based on the ratio of inflammatory to antiviral white blood cells. Second, our results support the hypothesis that socioeconomic disadvantage and chronological age increase risk for chronic illness in part through their effect on inflammatory processes. PMID- 28356189 TI - Longevity of fiber-reinforced composite fixed partial dentures (FRC FPD) Systematic review. AB - OBJECTIVES: to assess FRC FPDs longevity through systematically reviewing contemporary clinical evidence. Population investigated comprised patients requiring replacement of a single missing anterior/posterior tooth. Intervention was FRC FPDs. No control/comparison selected. Outcome was longevity of FRC FPDs. The focus question was: 'What is the longevity of FRC FPDs used to replace one anterior or posterior tooth in patients?' DATA: Randomised, non-randomised, controlled, prospective and retrospective clinical studies were included. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses were applied. The Overall Strength of Clinical Recommendation (OSCR) was assessed using the Strength of Recommendation Taxonomy system. Survival of FPDs was assessed using the Kaplan-Meier method. Analysis of FPD-survival according to location and occurrence of different failures was performed using Logrank and Chi-square testing. SOURCES: PubMed, MEDLINE, and Web of Science databases were searched between January 2007 and December 2015. STUDY SELECTION: Nine studies were included, involving placement of 592 FRC FPDs in 463 patients. Follow-up periods ranged between 2 months and 8 years. Kaplan-Meier overall survival probability was 94.5% (95%C.I: 92.5%-96.5%) at 4.8 years. There was no significant difference in survival probability of anterior versus posterior FRC FPDs (P=0.278). Veneering material fracture/delamination occurred significantly more than other types of failures (Ps<0.05). A meta-analysis could not be performed. OSCR was moderate. CONCLUSIONS: FRC FPDs demonstrated high overall survival with predictable performance outcomes. However, long-term performance remains unclear. CLINICAL SIGNIFICANCE: FRC FPDs are viable medium-term management alternatives for replacing single anterior or posterior teeth in patients. PMID- 28356190 TI - Plug-plug kinetic capillary electrophoresis for in-capillary exoglycosidase digestion as a profiling tool for the analysis of glycoprotein glycans. AB - An online exoglycosidase digestion was combined with a plug-plug kinetic mode of capillary electrophoresis (CE) for the analysis of glycoprotein-derived oligosaccharides. An exoglycosidase solution and a solution of glycoprotein glycans derivatized with 8-aminopyrene-1,3,6-trisulfonic acid (APTS) were introduced to a neutrally coated capillary previously filled with electrophoresis buffer solution containing 0.5w/v% hydroxypropylcellulose. After immersion of both ends of the capillary in the buffer solutions, a negative voltage was applied for analysis. An APTS group of an oligosaccharide derivative has triply negative charges, which forced saccharide derivatives to anode with fast mobility and pass through the enzyme plug, which are detected at the anodic end. If the terminal monosaccharides of APTS-labeled oligosaccharides are released by the action of an exoglycosidase, the migration times of the oligosaccharides shift to those of digested oligosaccharides. We examined beta-galactosidase, alpha mannosidase, beta-N-acetylhexosaminidase, alpha-neuraminidase, and alpha fucosidase, and found only beta-galactosidase and alpha-neuraminidase showed good reactivity toward APTS-labeled oligosaccharides; the reaction was completed by injecting a 3.6cm long plug of 200 and 50mU/mL concentration of exoglycosidases. In contrast, other exoglycosidases could not react with APTS labeled oligosaccharides at a concentration up to 5U/mL. The beta-N-acetylhexosaminidase reaction was successively followed by the electrophoretic mobility of APTS oligosaccharides and stopped for 10min when saccharide derivatives were achieved in the enzyme plug. The reaction of alpha-fucosidase and alpha-mannosidase was completed by decreasing the electrophoretic voltage to -2kV when the APTS oligosaccharides were passing through an exoglycosidase plug. We established the CE conditions for all of the glycosidic linkage analysis of glycoprotein glycans. PMID- 28356191 TI - Performance of permethyl pillar[5]arene stationary phase for high-resolution gas chromatography. AB - This work presents the investigation of permethyl pillar[5]arene (MP5) as stationary phase for capillary gas chromatographic (GC) separations. The MP5 capillary column fabricated by the sol-gel coating method exhibited weak polarity and high column efficiency over 4200 plates/m for n-dodecane, n-octanol and naphthalene. Particularly, the MP5 stationary phase displays unique retention for dibromoalkanes, which was found to be closely related with the linker length, and shows high resolving capability for a wide range of positional and structural isomers, including alkylbenzenes, chlorobenzenes and chloronitrobenzenes, naphthalene derivatives, phenols and anilines. Moreover, the MP5 column showed good thermal stability and repeatability and reproducibility with the relative standard deviation in the range of 0.02-0.04% for intra-day, 0.32-0.46% for inter day and 1.5-3.4% for between-column, respectively. This work demonstrates an promising future of pillar[n]arenes as a new type of stationary phase in chromatographic separations. PMID- 28356192 TI - Empirically based assessment and taxonomy of psychopathology for ages 11/2-90+ years: Developmental, multi-informant, and multicultural findings. AB - BACKGROUND: Originating in the 1960s, the Achenbach System of Empirically Based Assessment (ASEBA) comprises a family of instruments for assessing problems and strengths for ages 11/2-90+ years. PURPOSE: To provide an overview of the ASEBA, related research, and future directions for empirically based assessment and taxonomy. CONTENT: Standardized, multi-informant ratings of transdiagnostic dimensions of behavioral, emotional, social, and thought problems are hierarchically scored on narrow-spectrum syndrome scales, broad-spectrum internalizing and externalizing scales, and a total problems (general psychopathology) scale. DSM-oriented and strengths scales are also scored. The instruments and scales have been iteratively developed from assessments of clinical and population samples of hundreds of thousands of individuals. Items, instruments, scales, and norms are tailored to different kinds of informants for ages 11/2-5, 6-18, 18-59, and 60-90+ years. To take account of differences between informants' ratings, parallel instruments are completed by parents, teachers, youths, adult probands, and adult collaterals. Syndromes and Internalizing/Externalizing scales derived from factor analyses of each instrument capture variations in patterns of problems that reflect different informants' perspectives. Confirmatory factor analyses have supported the syndrome structures in dozens of societies. Software displays scale scores in relation to user-selected multicultural norms for the age and gender of the person being assessed, according to ratings by each type of informant. Multicultural norms are derived from population samples in 57 societies on every inhabited continent. Ongoing and future research includes multicultural assessment of elders; advancing transdiagnostic progress and outcomes assessment; and testing higher order structures of psychopathology. PMID- 28356193 TI - Cell Calcium special issue: Preface. PMID- 28356194 TI - Assessment of TRPM7 functions by drug-like small molecules. AB - Transient receptor potential cation channel subfamily M member 7 (TRPM7) is a plasma membrane ion channel linked to a cytosolic protein kinase domain. Genetic inactivation of this bi-functional protein revealed its crucial role in Ca2+ signalling, Mg2+ metabolism, immune responses, cell motility, proliferation and differentiation. Malfunctions of TRPM7 are associated with anoxic neuronal death, cardiac fibrosis, tumour progression and macrothrombocytopenia. Recently, several groups have identified small organic compounds acting as inhibitors or activators of the TRPM7 channel. In follow-up studies, the identified TRPM7 modulators were successfully used to uncover new cellular functions of TRPM7 in situ including a crucial role of TRPM7 in Ca2+ signaling and Ca2+ dependent cellular processes. Hence, TRPM7 has been defined as a promising drug target. Here, we summarize the progress in this quickly developing field. PMID- 28356195 TI - Age-related changes and distribution of T cell markers (CD3 and CD4) and toll like receptors(TLR2, TLR3,TLR4 and TLR7) in the duck lymphoid organs. AB - T lymphocytes and Toll-like receptors have been confirmed to have correlation with the ability to resistance to pathogenic challenges and play an important role in duck immune system. However, the information of ontogeny of T lymphocytes and Toll-like receptors is scarcely in duck. Therefore, to address these questions, we report the development and distribution of CD3 and CD4 by immunocytochemistry and the age-related mRNA level of duck T cell markers (CD3 and CD4) and Toll-like receptors (TLR2, TLR3, TLR4 and TLR7) by real time quantitative PCR in duck lymphoid organs (thymus, bursa of Fabricius and spleen). Results indicated that CD3 and CD4 positive cells can be observed in all test organs and partly change in an age-related way. CD4 positive T cell of duck spleen mainly distributed in periarterial lymphatic sheaths and red pulp, not in white pulp. Both of CD3 and CD4 were experienced significant increased wave twice in duck lymphoid organs and T cell dependent cellular immunity of duck may well established until 5 weeks old. The mRNA expression levels of duck TLRs were age and organ dependent, and duck TLR3 and TLR7 were significantly lower abundance in the spleen but higher in thymus and bursa of Fabricius, respectively. This study provide the essential knowledge of the ontogeny of T cells and Toll-like receptors in duck, which may shed lights on the T-cell mediate immunity and innate immunity in duck. PMID- 28356196 TI - Facile preparation of fibrin coated open tubular column for characterization of monoclonal antibody variants by capillary electrochromatography. AB - Monoclonal antibodies (mAbs) are one of the most promising classes of therapeutic protein biopharmaceuticals. However, the complexity of mAbs poses a daunting analytical challenge for heterogeneity characterization of mAbs. In this study, inspired by blood coagulation, we adopted a fibrin coating as a novel stationary phase in open tubular (OT) column for the separation of the mAbs variants by capillary electrochromatography. The fibrin coating was prepared by in situ polymerization of fibrin in the presence of thrombin as a catalyst inside a fused silica capillary. Scanning electron microscopy and electroosmotic flow measurement were carried out to characterize the fibrin coated OT columns. The average thickness of the fibrin coating was about 1.13MUm. And the EOF of the column was pH-dependent. The electrochromatographic performance of the prepared columns was evaluated by characterization of the variants of three mAbs (cetuximab, trastuzumab and rituximab). The columns demonstrated good repeatability with the run-to-run, day-to-day and column-to-column relative standard deviations of migration times less than 2.42%. The study highlighted the potential of adsorbed proteins as stationary phases for the separation of mAbs variants. Furthermore, the study provided a new platform for characterization of heterogeneity of mAbs in pharmaceutical industry. PMID- 28356197 TI - Risk factors for depression following traumatic injury: An epidemiological study from a scandinavian trauma center. AB - INTRODUCTION: A significant proportion of patients suffer depression following traumatic injuries. Once manifested, major depression is challenging to overcome and its presence risks impairing the potential for physical rehabilitation and functional recovery. Risk stratification for early detection and intervention in these instances is important. This study aims to investigate patient and injury characteristics associated with an increased risk for depression. METHODS: All patients with traumatic injuries were recruited from the trauma registry of an urban university hospital between 2007 and 2012. Patient and injury characteristics as well as outcomes were collected for analysis. Patients under the age of eighteen, prescribed antidepressants within one year of admission, in hospital deaths and deaths within 30days of trauma were excluded. Pre- and post admission antidepressant data was requested from the national drugs registry. Post-traumatic depression was defined as the prescription of antidepressants within one year of trauma. To isolate independent risk factors for depression a multivariable forward stepwise logistic regression model was deployed. RESULTS: A total of 5981 patients met the inclusion criteria of whom 9.2% (n=551) developed post-traumatic depression. The mean age of the cohort was 42 [standard deviation (SD) 18] years and 27.1% (n=1620) were females. The mean injury severity score was 9 (SD 9) with 18.4% (n=1100) of the patients assigned a score of at least 16. Six variables were identified as independent predictors for post-traumatic depression. Factors relating to the patient were female gender and age. Injury specific variables were penetrating trauma and GCS score of<=8 on admission. Furthermore, intensive care admission and increasing hospital length of stay were predictors of depression. CONCLUSION: Several risk factors associated with the development of post-traumatic depression were identified. A better targeted in hospital screening and patient-centered follow up can be offered taking these risk factors into consideration. PMID- 28356198 TI - Prevalence of Unanticipated Events Associated With MRI Examinations: A Benchmark for MRI Quality, Safety, and Patient Experience. AB - PURPOSE: To determine the prevalence of unanticipated events (UE) associated with MRI examinations in a multicenter academic radiology department. METHODS: UE reported by MRI technologists for examinations performed between June 2013 and November 2014 on 17 scanners in a university- and community-affiliated single health system were retrospectively reviewed. Events were categorized into the following categories: (1) problems with orders and scheduling; (2) scan delays; (3) unanticipated foreign bodies; (4) non-contrast-related patient events (eg, patient motion, discomfort, claustrophobia, need for sedation); (5) contrast related patient events; and (6) technical acquisition issues. Logistic regression analysis of UE was performed after adjusting based on scanner site (university- vs community-affiliated hospital), hospital setting (outpatient [OP] vs mixed outpatient and inpatient [OP/IP]), and timing of the scan (business days vs weekends/holidays). RESULTS: A total of 34,587 MRI examinations were assessed (87% university-affiliated; 58% OP) with 5775 (16.7%) UE (1.9% of patients had more than one category event). Rates of UE for each category were as follows: 1.9% orders and scheduling, 3.3% delays in scan, 0.5% foreign bodies, 10.4% non contrast-related patient events, 1.3% contrast-related patient events, and 1.5% technical issues. After adjustment for location of scanner, clinical setting, and timing of the scan, the rate of overall UE was significantly higher in university affiliated sites (coefficient, 0.09 [95% confidence interval (CI), 0.07-0.10]; P < .001), in scans performed in the mixed OP/IP setting (coefficient, 0.09 [95% CI, 0.08-0.09]; P < .001), and in scans performed during weekends/holidays (coefficient, 0.02 [95% CI, 0.01-0.04]; P < .001). CONCLUSIONS: UE associated with MRI examinations are common (16.7%), with the majority being patient-related issues unrelated to contrast administration. PMID- 28356199 TI - R-SCAN: Appropriate Imaging for Low-Risk Prostate Cancer. PMID- 28356200 TI - Both qSOFA score and bedside plasma lactate are the predictors of mortality for patients with infections in ED. PMID- 28356201 TI - The risk of level IB nodal involvement in oropharynx cancer: Guidance for submandibular gland sparing irradiation. AB - PURPOSE: Xerostomia remains a common side effect of head and neck irradiation. Conflicting data exist regarding the likelihood of level IB involvement for patients with oropharyngeal squamous cell cancer (OPSCC), and data are limited on this risk in patients with human papillomavirus-positive disease. This study examined surgically treated OPSCC to determine the risk of pathologic level IB nodal involvement and to identify a cohort of patients in whom ipsilateral level IB radiation therapy may be safely omitted. METHODS AND MATERIALS: A total of 102 submandibular nodal dissections were identified (92 ipsilateral and 10 contralateral) in 92 patients from 2010 to 2016 in those undergoing primary surgical treatment and dissection of ipsilateral level IB lymph nodes. Radiographically positive cases were excluded. Retrospective chart review was used for data collection, and the rate of pathologic level IB involvement was determined. RESULTS: The ipsilateral level IB nodal station had negative imaging and pathologically positive nodes at rates of 4.3% in OPSCC and 5.3% in human papillomavirus-positive OPSCC. Positive node burden in the ipsilateral neck at stations other than IB appeared to correlate with the risk of pathologic positive IB (pIB+) nodes: 50% of pathologically IB-negative patients had 2 or more positive nodes versus 75% of pIB+ patients who had 4 or more positive nodes. CONCLUSIONS: Our data indicate a low risk of pathologic level IB involvement in early-stage OPSCC. High positive node burden in stations near level IB may be associated with a higher chance of pathologic level IB involvement. PMID- 28356202 TI - Role of tissue expansion in abdominal wall reconstruction: A systematic evidence based review. AB - BACKGROUND: Tissue expanders (TEs) can be used to assist primary closure of complicated hernias and large abdominal wall defects. However, there is no consensus regarding the optimal technique, use, or associated risk of TE in abdominal wall reconstruction. METHODS: A systematic search of PubMed and Embase databases was conducted to identify articles reporting abdominal wall reconstruction with TE techniques. English articles published between 1980 and 2016 were included on the basis of the following inclusion criteria: two-stage TE surgical technique, >3 cases, reporting of postoperative complications, hernia recurrence, and patient-based clinical data. RESULTS: Fourteen studies containing 103 patients (85 adults and 18 children) were identified for analysis. Most patients presented with a skin-grafted ventral hernia (n = 86). The etiology of the hernia was from trauma or prior abdominal surgery. The remaining patients had TE placed before organ transplantation (n = 12) or for congenital abdominal wall defects (n = 5). The location for expander placement was subcutaneous (n = 74), between the internal and external obliques (n = 26), posterior to the rectus sheath (n = 2), and intra-peritoneal (n = 1). Postoperative infections and implant-related problems were the most commonly reported complications after Stage I. The most common complication after Stage II was recurrent hernia, which was observed in 12 patients (11.7%). Five patients with TE died. Complications and mortality were more prevalent in children, immunosuppressed patients, and those with chronic illnesses. CONCLUSIONS: Tissue expansion for abdominal wall reconstruction can be successfully used for a variety of carefully selected patients with an acceptable complication and risk profile. PMID- 28356204 TI - What Is the Utility of Thrombolytic Therapy for Acute Deep Venous Thrombosis? PMID- 28356203 TI - Variation in Patients' Travel Times among Imaging Examination Types at a Large Academic Health System. AB - RATIONALE AND OBJECTIVES: Patients' willingness to travel farther distances for certain imaging services may reflect their perceptions of the degree of differentiation of such services. We compare patients' travel times for a range of imaging examinations performed across a large academic health system. MATERIALS AND METHODS: We searched the NYU Langone Medical Center Enterprise Data Warehouse to identify 442,990 adult outpatient imaging examinations performed over a recent 3.5-year period. Geocoding software was used to estimate typical driving times from patients' residences to imaging facilities. Variation in travel times was assessed among examination types. RESULTS: The mean expected travel time was 29.2 +/- 20.6 minutes, but this varied significantly (p < 0.001) among examination types. By modality, travel times were shortest for ultrasound (26.8 +/- 18.9) and longest for positron emission tomography-computed tomography (31.9 +/- 21.5). For magnetic resonance imaging, travel times were shortest for musculoskeletal extremity (26.4 +/- 19.2) and spine (28.6 +/- 21.0) examinations and longest for prostate (35.9 +/- 25.6) and breast (32.4 +/- 22.3) examinations. For computed tomography, travel times were shortest for a range of screening examinations [colonography (25.5 +/- 20.8), coronary artery calcium scoring (26.1 +/- 19.2), and lung cancer screening (26.4 +/- 14.9)] and longest for angiography (32.0 +/- 22.6). For ultrasound, travel times were shortest for aortic aneurysm screening (22.3 +/- 18.4) and longest for breast (30.1 +/- 19.2) examinations. Overall, men (29.9 +/- 21.6) had longer (p < 0.001) travel times than women (27.8 +/- 20.3); this difference persisted for each modality individually (p <= 0.006). CONCLUSIONS: Patients' willingness to travel longer times for certain imaging examination types (particularly breast and prostate imaging) supports the role of specialized services in combating potential commoditization of imaging services. Disparities in travel times by gender warrant further investigation. PMID- 28356205 TI - Hospital Emergency Care as a Public Good and Community Health Benefit. PMID- 28356206 TI - Lung-Protective Ventilation in the Emergency Department. PMID- 28356207 TI - The US Emergency Care Coordination Center. PMID- 28356208 TI - Paraclinical findings in Iranian veterans exposed to sulfur mustard gas: A literature review. AB - OBJECTIVE: Sulfur mustard (SM) causes various systemic disturbances in human beings. This study aimed to assess paraclinical changes caused by exposure to SM gas in Iranian veterans during the war between Iraq and Iran. METHODS: A literature review was carried out in international and national medical databases including ISI, Medline, Scopus, Iranmedex and Irandoc. Both Farsi and English literature were searched. RESULTS: Search of the literature yielded 422 medical articles related to SM poisoning. Among them, 30 relevant articles were thoroughly reviewed. The most important reported complications were leukopenia, neutropenia, lymphopenia, eosinophilia, thrombocytopenia, increased bleeding time, positive C-reactive protein (CRP), rheumatoid factor (RF), antinuclear antibody (ANA), decreased T helper cells, natural killer cells, IL6, and IL8 levels, elevation of serum immunoglobulins, decreased levels of T3, T4 and cortisol, increased level of adrenocorticotropic hormone (ACTH), proteinuria, hematuria, and elevated liver enzymes. Also, there were some changes in chest assessments. CONCLUSIONS: SM causes profound systemic complications in victims, even years after exposure. The paraclinical changes can be observed in hematology, immune system, biochemistry, hormonal profile and some imaging studies. PMID- 28356209 TI - Nutcracker Syndrome: An Update on Current Diagnostic Criteria and Management Guidelines. AB - BACKGROUND: Nutcracker syndrome (NCS) describes left renal vein compression between the superior mesenteric artery and the aorta. Although uncommon, it is an important diagnosis due to the important morbidity associated with it, including the risk of chronic kidney disease from long-term left renal vein (LRV) hypertension and the risk of LRV thrombosis. METHODS: This article reviews the literature on NCS, particularly with respect to the diagnostic accuracy of different imaging modalities and the success rates, complications, and long-term follow-up data associated with various surgical interventions. RESULTS AND DISCUSSION: The diagnosis of this condition is based on a stepwise work-up with history and clinical examination, followed by Doppler ultrasonography, computed tomography, magnetic resonance imaging, intravascular ultrasound (IVUS) and phlebography with measurement of the renocaval pressure gradient. Management is determined by symptom severity; often symptom resolution occurs following a conservative approach. However, in some cases, surgical management is required, particularly when conservative management is unsuccessful. When it comes to the surgical management of NCS three main pathways exist: open surgery, laparoscopic surgery and endovascular approaches, with the latter 2 becoming increasingly popular due to their minimal invasiveness. Additionally, cases involving the use of robotic surgery in the management of NCS have been reported. CONCLUSION: Despite the rarity of NCS, its recognition and management are important. This article has explored the evidence basis for conservative, medical and surgical options. PMID- 28356210 TI - Outcome After Ruptured AAA Repair in Octo- and Nonagenarians in Sweden 1994-2014. AB - OBJECTIVE: To report the outcome after ruptured abdominal aortic aneurysm (rAAA) repair in octo- and nonagenarians from the Swedish Vascular Registry 1994-2014. MATERIAL AND METHODS: 2335 intact AAA (iAAA) and 1538 rAAA were identified in patients aged 80 years and older. Crude, long-term, and relative survival data were analysed using the Kaplan-Meier method. Crude survival was calculated including all deaths. Long-term survival was analysed excluding AAA repair related mortality, defined as death within 90 days of surgery. Relative survival was assessed by comparing the observed long-term survival after AAA repair with the expected survival of a Swedish population adjusted for age, gender, and operation year. Differences were compared using log-rank tests. The multivariate Cox model was used for adjusting for confounding factors between open repair (OR) and endovascular aneurysm repair (EVAR). RESULTS: Crude survival after rAAA repair was 30 days (55%), 90 days (50%), 1 year (45%), 5 years (26%), and 10 years (9%). Long-term survival was 1 year (90%), 5 years (53%), and 10 years (18%). When individuals with rAAA were categorized into males and females, crude and long-term survival showed no significant differences (p = .204 and p = .134). When rAAA patients were categorized into age groups (80-84 years, 85-89 years, 90+) crude survival diminished with increasing age, but long-term survival was not (p = .009 and p = .368). Compared with the general population, rAAA patients showed only a minor decrease in relative survival. Crude survival after rAAA was better for EVAR compared with OR (p = .007), hazard ratio 1.3 (95% CI 1.1-1.6, p < .012). CONCLUSIONS: There is a high (50%) peri-operative mortality after surgery for rAAA in octo- and nonagenarians, with no significant differences between the sexes and worse survival with increasing age. However, if a patient has survived the initial 90 days, long-term survival in this very old cohort is surprisingly good at more than 50% after 5 years, only slightly less than the general population. PMID- 28356212 TI - The use of think-aloud protocols to identify a decision-making process of community pharmacists aimed at improving CMS Star Ratings scores. AB - BACKGROUND: The Center for Medicare and Medicaid Services (CMS) created the Star Rating system based on multiple measures that indicate the overall quality of health plans. Community pharmacists can impact certain Star Ratings measure scores through medication adherence and patient safety interventions. OBJECTIVE: To explore methods, needs, and workflow issues of community pharmacists to improve CMS Star Ratings measures. METHODS: Think-aloud protocols (TAPs) were conducted with active community retail pharmacists in Oklahoma. Each TAP was audio recorded and transcribed to documents for analysis. Analysts agreed on common themes, illuminated differences in findings, and saturation of the data gathered. Methods, needs, and workflow themes of community pharmacists associated with improving Star Ratings measures were compiled and organized to exhibit a decision-making process. Five TAPs were performed among three independent pharmacy owners, one multi-store owner, and one chain-store administrator. RESULTS: A thematically common 4-step process to monitor and improve CMS Star Ratings scores among participants was identified. To improve Star Ratings measures, pharmacists: 1) used technology to access scores, 2) analyzed data to strategically set goals, 3) assessed individual patient information for comprehensive assessment, and 4) decided on interventions to best impact Star Ratings scores. Participants also shared common needs, workflow issues, and benefits associated with methods used in improving Star Ratings. CONCLUSION: TAPs were useful in exploring processes of pharmacists who improve CMS Star Ratings scores. Pharmacists demonstrated and verbalized their methods, workflow issues, needs, and benefits related to performing the task. The themes and decision making process identified to improving CMS Star Ratings scores will assist in the development of training and education programs for pharmacists in the community setting. PMID- 28356213 TI - Organizational readiness for change: Preceptor perceptions regarding early immersion of student pharmacists in health-system practice. AB - PURPOSE: To examine preceptors' perceptions regarding readiness for change pre- and post-implementation of a pilot early immersion program engaging student pharmacists in direct patient care. METHODS: Student pharmacists enrolled in the second professional year of a Doctor of Pharmacy degree program completed a four week health-system introductory pharmacy practice experience (IPPE) which was modified to include direct patient care roles in operational (drug preparation and dispensing) and clinical (comprehensive medication management) pharmacy environments. Pharmacy preceptors with direct oversight for program implementation completed a pre/post Organizational Readiness for Implementing Change (ORIC) survey and a 50-min interview or focus group post-experience. The ORIC survey evaluates two dimensions of organizational readiness for change - change commitment and change efficacy. Additional items assessed included implementation needs, support, and perceived value of the change. ORIC survey constructs were compared before and after the experience. Interviews and focus groups were audio recorded, transcribed, and evaluated by constant comparative analysis. A mixed methods approach was used to triangulate findings and develop greater understanding of the ORIC survey results. RESULTS: Twenty pharmacy preceptors (37 +/- 8 years of age, 60% female, 65% clinical pharmacist position, 70% prior preceptor experience) participated in the study. There were no significant changes in pre/post survey constructs, except for a decline in the perception of organizational change commitment (p < 0.001). Sub-analyses indicated the decline was associated with items assessing individual dedication and individual commitment to the change (p < 0.05 for both). Primary emerging themes from interviews included concerns about implementation requirements, contextual factors of the experience that affected implementation, and varying perceptions about the value of early immersion across preceptor roles. CONCLUSION: As pharmacy curricula immerse student pharmacists in practice earlier in their education, pharmacy departments can utilize the ORIC survey to identify preceptors' commitment and concerns to support the necessary changes for student pharmacist engagement. PMID- 28356211 TI - PKD2-Related Autosomal Dominant Polycystic Kidney Disease: Prevalence, Clinical Presentation, Mutation Spectrum, and Prognosis. AB - BACKGROUND: PKD2-related autosomal dominant polycystic kidney disease (ADPKD) is widely acknowledged to be of milder severity than PKD1-related disease, but population-based studies depicting the exact burden of the disease are lacking. We aimed to revisit PKD2 prevalence, clinical presentation, mutation spectrum, and prognosis through the Genkyst cohort. STUDY DESIGN: Case series, January 2010 to March 2016. SETTINGS & PARTICIPANTS: Genkyst study participants are individuals older than 18 years from 22 nephrology centers from western France with a diagnosis of ADPKD based on Pei criteria or at least 10 bilateral kidney cysts in the absence of a familial history. Publicly available whole-exome sequencing data from the ExAC database were used to provide an estimate of the genetic prevalence of the disease. OUTCOMES: Molecular analysis of PKD1 and PKD2 genes. Renal survival, age- and sex-adjusted estimated glomerular filtration rate. RESULTS: The Genkyst cohort included 293 patients with PKD2 mutations (203 pedigrees). PKD2 patients with a nephrology follow-up corresponded to 0.63 (95% CI, 0.54-0.72)/10,000 in Brittany, while PKD2 genetic prevalence was calculated at 1.64 (95% CI, 1.10-3.51)/10,000 inhabitants in the European population. Median age at diagnosis was 42 years. Flank pain was reported in 38.9%; macroscopic hematuria, in 31.1%; and cyst infections, in 15.3% of patients. At age 60 years, the cumulative probability of end-stage renal disease (ESRD) was 9.8% (95% CI, 5.2%-14.4%), whereas the probability of hypertension was 75.2% (95% CI, 68.5% 81.9%). Although there was no sex influence on renal survival, men had lower kidney function than women. Nontruncating mutations (n=36) were associated with higher age-adjusted estimated glomerular filtration rates. Among the 18 patients with more severe outcomes (ESRD before age 60), 44% had associated conditions or nephropathies likely to account for the early progression to ESRD. LIMITATIONS: Younger patients and patients presenting with milder forms of PKD2-related disease may not be diagnosed or referred to nephrology centers. CONCLUSIONS: Patients with PKD2-related ADPKD typically present with mild disease. In case of accelerated degradation of kidney function, a concomitant nephropathy should be ruled out. PMID- 28356214 TI - Global Forum of the World Federation of Hemophilia, September 26-27, 2005, Montreal, Quebec, Canada. PMID- 28356215 TI - Successful treatment of adult pleomorphic rhabdomyosarcoma with bone invasion in the lower leg by chemotherapy and biological reconstruction: A case report. PMID- 28356216 TI - Novel dental adhesive with triple benefits of calcium phosphate recharge, protein repellent and antibacterial functions. AB - OBJECTIVE: A new adhesive containing nanoparticles of amorphous calcium phosphate (NACP) with calcium (Ca) and phosphate (P) ion rechargeability was recently developed; however, it was not antibacterial. The objectives of this study were to: (1) develop a novel adhesive with triple benefits of Ca and P ion recharge, protein-repellent and antibacterial functions via dimethylaminohexadecyl methacrylate (DMAHDM) and 2-methacryloyloxyethyl phosphorylcholine (MPC); and (2) investigate dentin bond strength, protein adsorption, Ca and P ion concentration, microcosm biofilm response and pH properties. METHODS: MPC, DMAHDM and NACP were mixed into a resin consisting of ethoxylated bisphenol A dimethacrylate (EBPADMA), pyromellitic glycerol dimethacrylate (PMGDM), 2-hydroxyethyl methacrylate (HEMA) and bisphenol A glycidyl dimethacrylate (BisGMA). Protein adsorption was measured using a micro bicinchoninic acid method. A human saliva microcosm biofilm model was tested on resins. Colony-forming units (CFU), live/dead assay, metabolic activity, Ca and P ion concentration and biofilm culture medium pH were determined. RESULTS: The adhesive with 5% MPC+5% DMAHDM+30% NACP inhibited biofilm growth, reducing biofilm CFU by 4 log, compared to control (p<0.05). Dentin shear bond strengths were similar (p>0.1). Biofilm medium became a Ca and P ion reservoir having ion concentration increasing with NACP filler level. The adhesive with 5% MPC+5% DMAHDM+30% NACP maintained a safe pH>6, while commercial adhesive had a cariogenic pH of 4. SIGNIFICANCE: The new adhesive with triple benefits of Ca and P ion recharge, protein-repellent and antibacterial functions substantially reduced biofilm growth, reducing biofilm CFU by 4 orders of magnitude, and yielding a much higher pH than commercial adhesive. This novel adhesive is promising to protect tooth structures from biofilm acids. The method of using NACP, MPC and DMAHDM is promising for application to other dental materials to combat caries. PMID- 28356217 TI - Growth and accelerated differentiation of mesenchymal stem cells on graphene oxide-coated titanate with dexamethasone on surface of titanium implants. AB - OBJECTIVE: In this study, the objective is to construct graphene-oxide-coated titanate on titanium foils as drug vehicle to enhance cell proliferation and osteo-differentiation of rat bone mesenchymal stem cells (rBMSCs). METHODS: Graphene oxide (GO) sheets obtained using the modified Hummer's method and characterized by AFM were coupled with bioactive titanate on Ti implants (GO-Ti) pretreated by alkali, followed by reduction (rGO-Ti). They were characterized by Raman spectroscopy, XPS, SEM, FTIR and contact angle. After dexamethasone (DEX) was loaded onto them (DEX-GO-Ti and DEX-rGO-Ti), cell proliferation of rBMSCs on them was evaluated by CCK-8 and F-actin staining, and differentiation through alkaline phosphatase activity, mRNA expression, and calcium nodules. RESULTS: The obtained GO sheets were monolayers from AFM. Raman spectra exhibited two prominent peaks at D and G bands, and the I(D)/I(G) ratios increased from 0.96 to 1.68 after reduction. XPS proved the existence of oxygenated functional groups for GO-Ti and the reduction of their intensity for rGO-Ti. From SEM, GO and rGO were evenly coated on nanostructures. DEX-GO-Ti absorbed most amount of DEX and released in a sustained manner. CCK-8 results showed that DEX-GO-Ti showed excellent performance on promoting cell proliferation. RMBSCs on DEX-GO-Ti presented greatly high expression of calcium, proteins and mRNA related to osteogenic differentiation. SIGNIFICANCE: GO coated titanate nanostructrues on surfaces of Ti foils by a simple self-assembly method, showed excellent vechiles for DEX. The construct promoted proliferation and accelerated osteogenic differentiation of rBMSCs, and would be prosperous for their further applications. PMID- 28356218 TI - Efficient antibody production in the methylotrophic yeast Ogataea minuta by overexpression of chaperones. AB - A production system for a therapeutic monoclonal antibody was developed using the methylotrophic yeast Ogataea minuta IFO10746. The genetically engineered O. minuta secreted a detectable amount of anti-TRAIL receptor antibody into the culture supernatant, and the secreted antibody was purified by multiple column chromatography steps. In the purification process, both fully and partially assembled antibodies were detected and isolated. The fully assembled antibody from O. minuta showed almost the same biological activity as that derived from mammalian cells despite the distinct glycosylation profile, whereas the partially assembled antibody showed no cytotoxic activity. To increase the production of active antibody in O. minuta, we overexpressed selected chaperone proteins (included protein disulfide isomerase (OmPDI1), thiol oxidase (OmERO1), and immunoglobulin heavy chain binding protein (OmKAR2)) known to assist in the proper folding (in the endoplasmic reticulum) of proteins destined for secretion. Each of these chaperones enhanced antibody secretion, and together these three factors yielded 16-fold higher antibody accumulation while increasing the ratio of the fully assembled antibody compared to that from the parental strain. Supplementation of a rhodanine-3-acetic acid derivative (R3AD_1c), an inhibitor of O-mannosylation, further increased the secretion of the correctly assembled antibody. These results indicated that the co-overexpression of chaperones is an effective way to produce the correctly assembled antibody in O. minuta. PMID- 28356219 TI - Cell wall alpha-1,3-glucan prevents alpha-amylase adsorption onto fungal cell in submerged culture of Aspergillus oryzae. AB - We have previously reported that alpha-amylase (Taka-amylase A, TAA) activity disappears in the later stage of submerged Aspergillus oryzae culture as a result of TAA adsorption onto the cell wall. Chitin, one of the major components of the cell wall, was identified as a potential factor that facilitates TAA adsorption. However, TAA adsorption only occurred in the later stage of cultivation, although chitin was assumed to be sufficiently abundant in the cell wall regardless of the submerged culture period. This suggested the presence a factor that inhibits TAA adsorption to the cell wall in the early stage of cultivation. In the current study, we identified alpha-1,3-glucan as a potential inhibiting factor for TAA adsorption. We constructed single, double, and triple disruption mutants of three alpha-1,3-glucan synthase genes (agsA, agsB, and agsC) in A. oryzae. Growth characteristics and cell wall component analysis of these disruption strains showed that AgsB plays a major role in alpha-1,3-glucan synthesis. In the DeltaagsB mutant, TAA was adsorbed onto the mycelium in all stages of cultivation (early and later), and the DeltaagsB mutant cell walls had a significantly high capacity for TAA adsorption. Moreover, the alpha-1,3-glucan content of the cell wall prepared from the wild-type strain in the later stage of cultivation was markedly reduced compared with that in the early stage. These results suggest that alpha-1,3-glucan is a potential inhibiting factor for TAA adsorption onto the cell wall component, chitin, in the early stage of submerged culture in A. oryzae. PMID- 28356220 TI - Ethyl acetate production by the elusive alcohol acetyltransferase from yeast. AB - Ethyl acetate is an industrially relevant ester that is currently produced exclusively through unsustainable processes. Many yeasts are able to produce ethyl acetate, but the main responsible enzyme has remained elusive, hampering the engineering of novel production strains. Here we describe the discovery of a new enzyme (Eat1) from the yeast Wickerhamomyces anomalus that resulted in high ethyl acetate production when expressed in Saccharomyces cerevisiae and Escherichia coli. Purified Eat1 showed alcohol acetyltransferase activity with ethanol and acetyl-CoA. Homologs of eat1 are responsible for most ethyl acetate synthesis in known ethyl acetate-producing yeasts, including S. cerevisiae, and are only distantly related to known alcohol acetyltransferases. Eat1 is therefore proposed to compose a novel alcohol acetyltransferase family within the alpha/beta hydrolase superfamily. The discovery of this novel enzyme family is a crucial step towards the development of biobased ethyl acetate production and will also help in selecting improved S. cerevisiae brewing strains. PMID- 28356221 TI - Rapid detection of all known ebolavirus species by reverse transcription-loop mediated isothermal amplification (RT-LAMP). AB - Ebola virus disease (EVD), a highly virulent infectious disease caused by ebolaviruses, has a fatality rate of 25-90%. Without a licensed chemotherapeutic agent or vaccine for the treatment and prevention of EVD, control of outbreaks requires accurate and rapid diagnosis of cases. In this study, five sets of six oligonucleotide primers targeting the nucleoprotein gene were designed for specific identification of each of the five ebolavirus species using reverse transcription-loop mediated isothermal amplification (RT-LAMP) assay. The detection limits of the ebolavirus species-specific primer sets were evaluated using in vitro transcribed RNAs. The detection limit of species-specific RT-LAMP assays for Zaire ebolavirus, Sudan ebolavirus, Tai Forest ebolavirus, and Bundibugyo ebolavirus was 256 copies/reaction, while the detection limit for Reston ebolavirus was 64 copies/reaction, and the detection time for each of the RT-LAMP assays was 13.3+/-3.0, 19.8+/-4.6, 14.3+/-0.6, 16.1+/-4.7, and 19.8+/ 2.4min (mean+/-SD), respectively. The sensitivity of the species-specific RT-LAMP assays were similar to that of the established RT-PCR and quantitative RT-PCR assays for diagnosis of EVD and are suitable for field or point-of-care diagnosis. The RT-LAMP assays were specific for the detection of the respective species of ebolavirus with no cross reaction with other species of ebolavirus and other viral hemorrhagic fever viruses such as Marburg virus, Lassa fever virus, and Dengue virus. The species-specific RT-LAMP assays developed in this study are rapid, sensitive, and specific and could be useful in case of an EVD outbreak. PMID- 28356222 TI - Neutrophil to Lymphocyte Ratio is Associated With Outcome During Ipilimumab Treatment. AB - BACKGROUND: Ipilimumab (IPI) and BRAF inhibitors (BRAFi) improve survival in melanoma, but not all patients will benefit and toxicity can be significant. Pretreatment neutrophil to lymphocyte ratio (NLR) has been associated with outcome in IPI-treated patients, but has not been studied during treatment or in BRAFi-treated patients. METHODS: Using a prospectively maintained database, patients with unresectable stage III or IV melanoma treated with IPI or a BRAFi (vemurafenib or dabrafenib as monotherapy) from 2006 to 2011 were identified. NLR was calculated before treatment and at 3-week intervals after treatment initiation until 9weeks. Baseline NLR was tested for association with overall survival (OS), progression free survival (PFS), and clinical response to treatment. On-treatment NLRs were tested for association with the same outcomes using landmark survival analyses and time-dependent Cox regression models. The association of relative change of NLR from baseline with outcomes was also examined. A multivariate model tested the association of NLR and OS/PFS with additional clinical factors. RESULTS: There were 197 IPI patients and 65 BRAFi patients. In multivariable analysis adjusting for M stage, and disease type (in OS)/gender (in PFS), an NLR value of 5 or above at every timepoint was associated with worse OS (HR 2.03-3.37, p<0.001), PFS (HR 1.81-2.51, p<0.001), and response to therapy (OR 3.92-9.18, p<0.007), in the IPI cohort. In addition, a >30% increase in NLR above baseline at any timepoint was associated with a worse OS and PFS (HR 1.81 and 1.66, p<0.004). In BRAFi patients, NLR was not consistently associated with outcomes. CONCLUSIONS: A high NLR, whether measured prior to or during treatment with IPI, is associated with worse OS, PFS, and clinical response in patients with advanced melanoma. An increasing NLR from baseline during treatment was correlated with worse OS and PFS in IPI-treated patients. In comparison, as NLR was not associated with outcomes in BRAFi patients, NLR may have a uniquely predictive value in patients treated with immunotherapy. PMID- 28356224 TI - Socially-induced variation in physiological mediators of parental care in a colonial bird. AB - Social facilitation of reproduction occurs in humans and animals, and may represent one of the bases of reproduction in groups. However, its underlying physiological mechanisms remain largely unexplored. Here, we found in a colonial bird, the Adelie penguin (Pygoscelis adeliae), that the number of parental interactions (nest relief ceremonies) performed by breeding individuals on the colony was positively related to prolactin levels in other breeding individuals exposed to these interactions (i.e. focal individuals). As prolactin is typically involved in the expression of parental behaviour in birds, this suggests that parental interactions by conspecifics represent social cues that might increase parental motivation in focal individuals. Moreover, parental interactions were not related to corticosterone levels in focal individuals, suggesting that these social cues were not stressful for penguins. However, social stimulation still had a cost for focal individuals, as it was negatively related to their antioxidant defences (a component of self-maintenance). As social stimulation was also positively related to prolactin levels, this highlights the fact that social stimulation acts on the trade-off between reproduction and self-maintenance. For the first time, the results of the current study shed light on the physiological factors potentially underlying social facilitation of parental care. Importantly, they suggest that, even though social facilitation of parental care may increase breeding performance, it can also negatively affect other fitness components. PMID- 28356223 TI - The role of the PI(3,5)P2 kinase TbFab1 in endo/lysosomal trafficking in Trypanosoma brucei. AB - Protein trafficking through endo/lysosomal compartments is critically important to the biology of the protozoan parasite Trypanosoma brucei, but the routes material may take to the lysosome, as well as the molecular factors regulating those routes, remain incompletely understood. Phosphoinositides are signaling phospholipids that regulate many trafficking events by recruiting specific effector proteins to discrete membrane subdomains. In this study, we investigate the role of one phosphoinositide, PI(3,5)P2 in T. brucei. We find a low steady state level of PI(3,5)P2 in bloodstream form parasites comparable to that of other organisms. RNAi knockdown of the putative PI(3)P-5 kinase TbFab1 decreases the PI(3,5)P2 pool leading to rapid cell death. TbFab1 and PI(3,5)P2 both localize strongly to late endo/lysosomes. While most trafficking functions were intact in TbFab1 deficient cells, including both endocytic and biosynthetic trafficking to the lysosome, lysosomal turnover of an endogenous ubiquitinylated membrane protein, ISG65, was completely blocked suggesting that TbFab1 plays a role in the ESCRT-mediated late endosomal/multivesicular body degradative pathways. Knockdown of a second component of PI(3,5)P2 metabolism, the PI(3,5)P2 phosphatase TbFig4, also resulted in delayed turnover of ISG65. Together, these results demonstrate an essential role for PI(3,5)P2 in the turnover of ubiquitinylated membrane proteins and in trypanosome endomembrane biology. PMID- 28356225 TI - miR-532 promoted gastric cancer migration and invasion by targeting NKD1. AB - Gastric cancer is one of the most common human malignant neoplasms, especially in China, its regulatory mechanism is important to develop new therapy approaches. miRNAs have been demonstrated to regulate gastric cancer progression. We found miR-532 was overexpressed in gastric cancer tissues and cells. Wound healing and transwell assay revealed that its overexpression promoted gastric cancer cell migration and invasion, its knockdown inhibited gastric cancer cell migration and invasion. Wnt/beta-catenin antagonist naked cuticle homolog 1 (NKD1) was the target of miR-532, miR-532 inhibited NKD1 expression. TOP/FOP luciferase activity analysis suggested miR-532 also increased Wnt/beta-catenin pathway activity. Overexpression miR-532 and NKD1 inhibited gastric cancer cell migration and invasion, consistent with miR-532 knockdown. These findings revealed miR-532 promoted gastric cancer cell migration and invasion through inhibiting NKD1 and activated Wnt/beta-catenin pathway. We provide a potential target for gastric cancer therapy. PMID- 28356226 TI - Surfactants from itaconic acid: Toxicity to HaCaT keratinocytes in vitro, micellar solubilization, and skin permeation enhancement of hydrocortisone. AB - One of the most widely used approaches for improving drug permeation across the stratum corneum barrier of the skin is the use of chemical penetration enhancers, such as surfactants. In this study, two anionic surfactants, named C12-OPK and C18-OPK, were synthesized via condensation of itaconic acid and fatty amines, with C12 and C18 alkyl chains, respectively. Assessment of impacts on HaCaT keratinocyte cell viability was used as indicator of their potential to cause skin irritation 24h post exposure (Alamar Blue assay). The LC50 values of C12-OPK and C18-OPK (144 and 85mg/L, respectively) were lower than LC50 values of the most used commercial surfactants (e.g. SDS). The effect of different surfactant concentrations (up to ten times the critical micellar concentration, CMC) on hydrocortisone (HC) solubility and permeation through porcine skin was also evaluated. Results showed that drug solubility increased linearly with increasing concentrations of both surfactants, as a consequence of the association between drug and micelles. In vitro permeation results showed that the permeability coefficient increased at surfactant concentrations lower than the CMC. In particular, a higher enhancement effect on drug permeation was obtained with C18 OPK, due to its hydrophobic properties that ensured a more effective HC permeation in comparison to C12-OPK. PMID- 28356227 TI - Production and characterization of a PEGylated derivative of recombinant human deoxyribonuclease I for cystic fibrosis therapy. AB - Recombinant human deoxyribonuclease I (rhDNase) is the mucolytic agent most widely used for the treatment of respiratory disease in cystic fibrosis. However, rhDNase is rapidly cleared from the lungs which implies a high dosing frequency and limited patient adherence. The aim of this study was to produce a long-acting PEGylated derivative of rhDNase presenting a preserved enzymatic activity. Site specific PEGylation on the N-terminal (N-ter) leucine residue of rhDNase was achieved by reductive alkylation at acidic pH using linear 20kDa, linear 30kDa or two-arm 40kDa polyethylene glycol (PEG) propionaldehydes. Yields of mono PEGylated products ranged between 45% and 61%. Conjugation to PEG fully preserved the secondary structure and the in vitro enzymatic activity of the native protein. These properties offer interesting perspectives for in vivo inhalation studies of the PEGylated enzyme. PMID- 28356228 TI - Co-injection of Abeta1-40 and ApoE4 impaired spatial memory and hippocampal long term potentiation in rats. AB - Apolipoprotein E4 (APOE4) allele located on chromosome 19 is a major genetic risk factor for developing Alzheimer's disease (AD). However, the direct effects of ApoE4 on the cognitive function and long-term synaptic plasticity have not fully investigated. At the same time, although amyloid beta protein (Abeta)-ApoE complexes are principal components of AD-associated brain damage, there is still lack of in vivo study on the effects of co-existed Abeta1-40 and ApoE4. In the present study, we examined the effects of ApoE4 on the spatial memory and hippocampal long term potentiation (LTP) by using Morris water maze test and in vivo field potential recording, compared the neurotoxicity of Abeta1-40 and ApoE4, and investigated the effects of co-application of Abeta1-40 and ApoE4 on cognitive behavior and synaptic plasticity. The results showed that intracerebrovenrticular (i.c.v.) injection of Abeta1-40 or ApoE4 significantly and similarly impaired spatial learning and memory, and depressed the high frequency stimulus (HFS) induced LTP. Importantly, compared to the effects of Abeta1-40 or ApoE4 alone, co-injection of Abeta1-40 and ApoE4 produced much heavier damages in cognitive behaviors and long term synaptic plasticity. These results demonstrated that ApoE4 not only exerted direct neurotoxicity but also enhanced the neurotoxicity of Abeta1-40 on spatial cognitive function and hippocampal LTP, which maybe partly elucidates the mechanism by which APOE4 allele exerted negative effects as a major genetic risk factor for developing AD. PMID- 28356229 TI - Association of rs1738074 polymorphism of TAGAP gene with susceptibility to multiple sclerosis in the Iranian population. AB - Multiple sclerosis (MS) is one of the most common diseases of the central nervous system (CNS) in the Iranian population. To date, association of many genes with the prevalence and progression of the disease have been investigated. In the present study, the impact of rs1738074 single nucleotide polymorphism (SNP) in the TAGAP gene (TAGAP rs1738074) on the risk of MS was evaluated in a sample of the Iranian population. In a case control study, genotyping was performed on 300 patients and normal individuals. The data were analyzed using Pearson's chi square test. The results showed a significant difference in the SNP frequency between case and control groups (p-value=0.049). The genotype frequencies of TT, TC and CC in patients were 10.67%, 51.33% and 38%, respectively, and in normal individuals were 20.66%, 42.67% and 36.67%, respectively. The results showed a significant difference in the genotype frequency of T/T between the patient and control groups (p<0.05). Interestingly, individuals with T/T genotype were estimated to be less susceptible to MS ((p-value=0.025), Fisher's exact test), odd ratio was 2.18 (controls versus MS patients) with 95% CI: 1.137-4.187. The results suggested that TAGAP rs1738074 polymorphism could be considered as a risk factor in the prevalence of MS in the Iranian population. PMID- 28356232 TI - Detection of high Leishmania infantum loads in Phlebotomus perniciosus captured in the leishmaniasis focus of southwestern Madrid region (Spain) by real time PCR. AB - Since 2010 a human leishmaniasis outbreak has been notified in southwestern Madrid region that still remains active. Entomological surveys have been carried out in the affected area in order to obtain information about species diversity, distribution, and density of sand flies. Moreover, molecular identification of blood meal preferences of sand flies and molecular detection of Leishmania infantum has been performed. In this work, we optimized a real time PCR assay in order to determine parasite loads in unfed and blood-fed Phlebotomus perniciosus female sand flies caught in the focus area. Results showed elevated parasite loads in nearly 70% of the studied positive sand flies. Furthermore, significantly higher parasite loads were observed in females without blood in their guts. In conclusion, high L. infantum loads found in P. perniciosus sand flies from the Madrid focus support the exceptional characteristics of this outbreak. PMID- 28356230 TI - Effect of 7,8-dihydroneopterin mediated CD36 down regulation and oxidant scavenging on oxidised low-density lipoprotein induced cell death in human macrophages. AB - The role of CD36 in oxidised low-density lipoprotein (oxLDL) mediated cell death was examined by down regulating the receptor level with the macrophage generated antioxidant 7,8-dihydroneopterin. Down regulation of CD36 protein levels in human monocyte derived macrophages by 7,8-dihydroneopterin corresponded to a decrease in CD36-mRNA. The oxidation products of 7,8-dihydroneopterin, dihydroxanthopterin and neopterin did not significantly down regulate CD36. The CD36 down regulation resulted in a decrease in oxLDL uptake measured as 7-ketocholesterol accumulation. Though less oxLDL was taken up by the macrophages as a result of the 7,8-dihydroneopterin induced down regulation in CD36 levels, the cytotoxicity of the oxLDL was not decreased. Addition of 7,8-dihydroneopterin to oxLDL treated macrophages decreased the concentration of intracellular oxidants. In the presence of oxLDL, 7,8-dihydroneopterin was oxidised to neopterin showing that the 7,8-dihydroneopterin was scavenging intracellular oxidants generated in response to the oxLDL. The results show CD36 down regulation does not protect human macrophages form oxLDL cytotoxicity but 7,8-dihydroneopterin intracellular oxidant scavenging is protective. PMID- 28356231 TI - Malaria overdiagnosis and subsequent overconsumption of antimalarial drugs in Angola: Consequences and effects on human health. AB - Microscopic blood smear examinations done in health centers of Angola demonstrated a large overdiagnosis of malaria cases with an average rate of errors as high as 85%. Overall 83% of patients who received Coartem(r) had an inappropriate treatment. Overestimated malaria diagnosis was noticed even when specific symptoms were part of the clinical observation, antimalarial treatments being subsequently given. Then, malaria overdiagnosis has three main consequences, (i) the lack of data reliability is of great concern, impeding epidemiological records and evaluation of the actual influence of operations as scheduled by the National Malaria Control Programme; (ii) the large misuse of antimalarial drug can increase the selective pressure for resistant strain and can make a false consideration of drug resistant P. falciparum crisis; and (iii) the need of strengthening national health centers in term of human, with training in microscopy, and equipment resources to improve malaria diagnosis with a large scale use of rapid diagnostic tests associated with thick blood smears, backed up by a "quality control" developed by the national health authorities. Monitoring of malaria cases was done in three Angolan health centers of Alto Liro (Lobito town) and neighbor villages of Cambambi and Asseque (Benguela Province) to evaluate the real burden of malaria. Carriers of Plasmodium among patients of newly-borne to 14 years old, with or without fever, were analyzed and compared to presumptive malaria cases diagnosed in these health centers. Presumptive malaria cases were diagnosed six times more than the positive thick blood smears done on the same children. In Alto Liro health center, the percentage of diagnosis error reached 98%, while in Cambambi and Asseque it was of 79% and 78% respectively. The percentage of confirmed malaria cases was significantly higher during the dry (20.2%) than the rainy (13.2%) season. These observations in three peripheral health centers confirmed what has already been noticed in other malaria endemic regions, and highlight the need for an accurate evaluation of the Malaria control programme implemented in Angola. PMID- 28356233 TI - Pine processionary caterpillar Thaumetopoea pityocampa envenomation in 109 dogs: A retrospective study. AB - Contact with the caterpillars of the pine processionary moth (CPPM) Thaumetopoea pityocampa induces severe local allergic reactions. The purpose of this large scale retrospective cohort-study was to describe the clinical manifestations and related risk factors of CPPM exposure. This cohort-study included 109 dogs between the years of 2000 and 2016. Tongue lesions ranging from oedema to severe necrosis were observed in 94/109 dogs (86%). The following systemic signs were observed in 60/109 dogs (55%): vomiting (52/109, 48%), dyspnoea (6/109, 5%), hypovolemia (4/109, 4%) and diarrhoea (2/109, 2%). Based on the time elapsed from CPPM contact to the first oral flushing, three groups were defined: <2 h (group 1, 37/105, 35%), 2 h-6 h (group 2, 39/105, 37%) and >6 h (group 3, 29/105, 28%). Tongue necrosis (TN) at admission was significantly more common in the dogs in group 3 than those in groups 1 and 2 (45% vs. 5% and 5% respectively, p = 0.0002). In addition, the development of TN during hospitalisation was significantly more common in the dogs in group 3 (65%) than in those in the other groups (21% in group 1, p = 0.02) and 31% in group 2, p = 0.001). The dogs in group 3 presented a 14.63-fold higher risk of TN at admission and a 3.78-fold higher risk of developing necrosis during hospitalisation compared with the other groups. The survival rate after exposure was 97%. Long-term follow-up data were available for 69/109 dogs (63%). Twenty-three dogs (37%) had persistent, definitive TN without major consequences on quality of life. Elapsed time between contact and first oral flushing appears to be a key determinant for the progression of necrotic lesions, and the best results were observed when flushing occurred within 6 h of contact. The prognosis of CPPM envenomation is excellent, with a short hospitalisation duration. PMID- 28356235 TI - Engineering a xylanase from Streptomyce rochei L10904 by mutation to improve its catalytic characteristics. AB - Protein engineering was performed by N-terminal region replacement and site directed mutagenesis in the cord of a xylanase (Srxyn) from Streptomyce rochei L10904 to improve its catalytic characteristics. Three mutants SrxynF, SrxynM and SrxynFM displayed 2.1-fold, 3.2-fold and 5.3-fold higher specific activities than that of Srxyn, respectively. Moreover, all of the mutants showed greater substrate affinity and kcat/Km than the native Srxyn. In addition, the enzymes showed improved hydrolysis characteristics, of which the most noteworthy is the enhanced ability of producing xylobiose (X2) and xylotriose (X3) from polymeric substrates. The engineered xylanases have greater potential for applications in oligosaccharide preparation industry. PMID- 28356236 TI - Characterization of the groove binding between di-(2-ethylhexyl) phthalate and calf thymus DNA. AB - In this study, the interaction between di-(2-ethylhexyl) phthalate (DEHP) and calf thymus DNA (ctDNA) was investigated by a combination of multispectroscopic methods, chemometrics algorithm, cyclic voltammetry and molecular simulation. The concentration profiles of the components obtained from resolving the UV-vis absorption data by multivariate curve resolution-alternating least-squares (MCR ALS) provided a basic evidence for the formation of DEHP-ctDNA complex. Furthermore, the groove binding of DEHP to ctDNA was evidenced by the results from iodide quenching effect, single-stranded DNA quenching effect, melting studies, viscosity measurements and cyclic voltammetry. The binding constant of the complex was in the order of magnitudes of 104Lmol-1, and hydrophobic forces were inferred to drive the binding process. Analysis of Fourier transform infrared spectra suggested that DEHP preferentially bound to A-T rich region of ctDNA in the minor groove, and these results further confirmed by molecular docking. The circular dichroism spectra indicated that DEHP induced a decrease in base stacking degree and an increase in right-handed helicity of ctDNA, but did not cause a significant damage in DNA. This study may improve the understanding of interaction between DEHP and ctDNA and help evaluate the toxicological effect of DEHP. PMID- 28356238 TI - Hepatic effects of tartrazine (E 102) after systemic exposure are independent of oestrogen receptor interactions in the mouse. AB - Tartrazine is a food colour that activates the transcriptional function of the human oestrogen receptor alpha in an in vitro cell model. Since oestrogens are cholestatic, we hypothesised tartrazine will cause periportal injury to the liver in vivo. To test this hypothesis, tartrazine was initially administered systemically to mice resulting in a periportal recruitment of inflammatory cells, increased serum alkaline phosphatase activity and mild periportal fibrosis. To determine whether an oestrogenic effect may be a key event in this response, tartrazine, sulphonated metabolites and a food additive contaminant were screened for their ability to interact with murine oestrogen receptors. In all cases, there were no interactions as agonists or antagonists and further, no oestrogenicity was observed with tartrazine in an in vivo uterine growth assay. To examine the relevance of the hepatic effects of tartrazine to its use as a food additive, tartrazine was orally administered to transgenic NF-kappaB-Luc mice. Pre- and concurrent oral treatment with alcohol was incorporated given its potential to promote gut permeability and hepatic inflammation. Tartrazine alone induced NF- kappaB activities in the colon and liver but there was no periportal recruitment of inflammatory cells or fibrosis. Tartrazine, its sulphonated metabolites and the contaminant inhibited sulphotransferase activities in murine hepatic S9 extracts. Given the role of sulfotransferases in bile acid excretion, the initiating event giving rise to periportal inflammation and subsequent hepatic pathology through systemic tartrazine exposure is therefore potentially associated an inhibition of bile acid sulphation and excretion and not on oestrogen receptor-mediated transcriptional function. However, these effects were restricted to systemic exposures to tartrazine and did not occur to any significant effect after oral exposure. PMID- 28356234 TI - Efficacy of novel antibody-based drugs against rhinovirus infection: In vitro and in vivo results. AB - Rhinoviruses (RVs) cause the common cold and are associated with exacerbations of chronic inflammatory respiratory diseases, especially asthma and chronic obstructive pulmonary disease (COPD). We have assessed the antiviral drugs Anaferon for Children (AC) and Ergoferon (containing AC as one of the active pharmaceutical ingredients) in in vitro and in vivo experimental models, in order to evaluate their anti-rhinoviral and immunomodulatory potential. HeLa cells were pretreated with AC, and levels of the interferon-stimulated gene (ISG), 2'-5' oligoadenylate synthetase 1 (OAS1-A) and viral replication were analyzed. In a mouse model of RV-induced exacerbation of allergic airway inflammation we administered Ergoferon and analyzed its effect on type I (IFN-beta), type II (IFN gamma) and type III (IFN-lambda) IFNs induction, cell counts in bronchoalveolar lavage (BAL), cytokine (interleukin (IL)-4; IL-6) and chemokine (CXCL10/IP-10; CXCL1/KC) levels. It was shown that AC increased OAS1-A production and significantly decreased viral replication in vitro. Increased IFNs expression together with reduced neutrophils/lymphocytes recruitment and correlated IL-4/IL 6 declination was demonstrated for Ergoferon in vivo. However, there was no effect on examined chemokines. We conclude that AC and Ergoferon possess effects against RV infection and may have potential as novel therapies against RV-induced exacerbations of asthma. PMID- 28356240 TI - The Annual American Men's Internet Survey of Behaviors of Men Who Have Sex With Men in the United States: 2015 Key Indicators Report. AB - The American Men's Internet Survey (AMIS) is an annual Web-based behavioral survey of men who have sex with men (MSM) living in the United States. This Rapid Surveillance Report describes the third cycle of data collection (September 2015 through April 2016; AMIS-2015). The key indicators are the same as previously reported for AMIS (December 2013-May 2014, AMIS-2013; November 2014-April 2015, AMIS-2014). The AMIS survey methodology has not substantively changed since AMIS 2014. MSM were recruited from a variety of websites using banner advertisements and email blasts. Additionally, participants from AMIS-2014 who agreed to be recontacted for future research were emailed a link to the AMIS-2015 survey. Men were eligible to participate if they were age 15 years and older, resided in the United States, provided a valid US ZIP code, and reported ever having sex with a man. We examined demographic and recruitment characteristics using multivariable regression modeling (P<.05) stratified by participants' self-reported human immunodeficiency virus (HIV) status. The AMIS-2015 round of data collection resulted in 10,217 completed surveys from MSM representing every US state and Puerto Rico. Participants were mainly non-Hispanic white, older than 40 years, living in the US South, living in urban areas, and recruited from general social networking websites. Self-reported HIV prevalence was 9.35% (955/10,217). Compared to HIV-negative/unknown status participants, HIV-positive participants were more likely to have had anal sex without a condom with any male partner in the past 12 months (75.50%, 721/955 vs 63.09%, 5843/9262, P<.001) and more likely to have had anal sex without a condom with a serodiscordant or unknown status partner (34.45%, 329/955 vs 17.07%, 1581/9262, P<.001). The reported use of marijuana and other illicit substances in the past 12 months was higher among HIV positive participants than HIV-negative/unknown status participants (marijuana use: 24.61%, 235/955 vs 22.96%, 2127/9262; other illicit substance use: 28.59%, 273/955 vs 17.51%, 1622/9262, respectively; both P<.001). Most HIV negative/unknown status participants (79.11%, 7327/9262) reported ever having a previous HIV test, and 55.69% (5158/9262) reported HIV testing in the past 12 months. HIV-positive participants were more likely to report sexually transmitted infection (STI) testing and diagnosis compared to HIV-negative/unknown status participants (STI testing: 71.73%, 685/955 vs 38.52%, 3568/9262; STI diagnosis: 25.65%, 245/955 vs 8.12%, 752/9262, respectively; both P<.001). PMID- 28356239 TI - "Fitspiration" on Social Media: A Content Analysis of Gendered Images. AB - BACKGROUND: "Fitspiration" (also known as "fitspo") aims to inspire individuals to exercise and be healthy, but emerging research indicates exposure can negatively impact female body image. Fitspiration is frequently accessed on social media; however, it is currently unclear the degree to which messages about body image and exercise differ by gender of the subject. OBJECTIVE: The aim of our study was to conduct a content analysis to identify the characteristics of fitspiration content posted across social media and whether this differs according to subject gender. METHODS: Content tagged with #fitspo across Instagram, Facebook, Twitter, and Tumblr was extracted over a composite 30-minute period. All posts were analyzed by 2 independent coders according to a codebook. RESULTS: Of the 415/476 (87.2%) relevant posts extracted, most posts were on Instagram (360/415, 86.8%). Most posts (308/415, 74.2%) related thematically to exercise, and 81/415 (19.6%) related thematically to food. In total, 151 (36.4%) posts depicted only female subjects and 114/415 (27.5%) depicted only male subjects. Female subjects were typically thin but toned; male subjects were often muscular or hypermuscular. Within the images, female subjects were significantly more likely to be aged under 25 years (P<.001) than the male subjects, to have their full body visible (P=.001), and to have their buttocks emphasized (P<.001). Male subjects were more likely to have their face visible in the post (P=.005) than the female subjects. Female subjects were more likely to be sexualized than the male subjects (P=.002). CONCLUSIONS: Female #fitspo subjects typically adhered to the thin or athletic ideal, and male subjects typically adhered to the muscular ideal. Future research and interventional efforts should consider the potential objectifying messages in fitspiration, as it relates to both female and male body image. PMID- 28356241 TI - Virtual Reality for Management of Pain in Hospitalized Patients: Results of a Controlled Trial. AB - BACKGROUND: Improvements in software and design and reduction in cost have made virtual reality (VR) a practical tool for immersive, three-dimensional (3D), multisensory experiences that distract patients from painful stimuli. OBJECTIVE: The objective of the study was to measure the impact of a onetime 3D VR intervention versus a two-dimensional (2D) distraction video for pain in hospitalized patients. METHODS: We conducted a comparative cohort study in a large, urban teaching hospital in medical inpatients with an average pain score of >=3/10 from any cause. Patients with nausea, vomiting, dementia, motion sickness, stroke, seizure, and epilepsy and those placed in isolation were excluded. Patients in the intervention cohort viewed a 3D VR experience designed to reduce pain using the Samsung Gear Oculus VR headset; control patients viewed a high-definition, 2D nature video on a 14-inch bedside screen. Pre- and postintervention pain scores were recorded. Difference-in-difference scores and the proportion achieving a half standard deviation pain response were compared between groups. RESULTS: There were 50 subjects per cohort (N=100). The mean pain reduction in the VR cohort was greater than in controls (-1.3 vs -0.6 points, respectively; P=.008). A total of 35 (65%) patients in the VR cohort achieved a pain response versus 40% of controls (P=.01; number needed to treat=4). No adverse events were reported from VR. CONCLUSIONS: Use of VR in hospitalized patients significantly reduces pain versus a control distraction condition. These results indicate that VR is an effective and safe adjunctive therapy for pain management in the acute inpatient setting; future randomized trials should confirm benefit with different visualizations and exposure periods. TRIAL REGISTRATION: Clinicaltrials.gov NCT02456987; https://clinicaltrials.gov/ct2/show/NCT02456987 (Archived by WebCite at http://www.webcitation.org/6pJ1P644S). PMID- 28356242 TI - Indian doctors take to streets to demand better security. PMID- 28356237 TI - Preparation, characterization and antibacterial applications of carboxymethyl chitosan/CuO nanocomposite hydrogels. AB - In this study, a series of antibacterial carboxymethyl chitosan/CuO nanocomposites were prepared by treating the carboxymethyl chitosan (CMCh) hydrogel with copper (II) chloride (CuCl2) solution followed by the oxidation of copper ions in the presence of sodium hydroxide. The resulting nanocomposite hydrogels were characterized by using FTIR, XRD and SEM techniques. The SEM micrographs revealed the uniform distribution of CuO nanoparticles in the hydrogel matrix with the size ranging from 20nm to 50nm, while XRD patterns confirmed the formation of monoclinic crystalline structures of CuO nanoparticles. The swelling behavior of the nanocomposite hydrogels were studied at a varied pH range. CMCh/CuO nanocomposite hydrogels showed rather higher swelling as compared to pure CMCh hydrogel. The antibacterial properties of the nanocomposite hydrogels were studied against Staphylococcus aureus and Escherichia coli. The results showed excellent antibacterial behavior of the nanocomposite hydrogels. Therefore, the developed CMCh/CuO nanocomposite hydrogels might be used effectively in numerous biomedical fields. PMID- 28356243 TI - Efficacy of glucocorticoids, conventional and targeted synthetic disease modifying antirheumatic drugs: a systematic literature review informing the 2016 update of the EULAR recommendations for the management of rheumatoid arthritis. AB - OBJECTIVES: To perform a systematic literature review (SLR) informing the 2016 update of the recommendations for the management of rheumatoid arthritis (RA). METHODS: An SLR for the period between 2013 and 2016 was undertaken to assess the efficacy of glucocorticoids (GCs), conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and targeted synthetic DMARDs (tsDMARDs) (tofacitinib and baricitinib) in randomised clinical trials. RESULTS: For GCs, four studies were included in the SLR. Patients without poor prognostic factors experienced benefit when GCs were added to methotrexate (MTX). Lower doses of GCs were similar to higher doses. For csDMARDs, two new studies comparing MTX monotherapy with combination csDMARD were included in the SLR. In the tREACH trial at the end of 12 months no difference between the groups in disease activity, functional ability and radiographic progression was seen, using principles of tight control (treat-to-target). In the CareRA trial, combination therapy with csDMARDs was not superior to MTX monotherapy and monotherapy was better tolerated.For tsDMARDs, tofacitinib and baricitinib were shown to be more effective than placebo (MTX) in different patient populations. CONCLUSIONS: Addition of GCs to csDMARD therapy may be beneficial but the benefits should be balanced against the risk of toxicity. Under tight control conditions MTX monotherapy is not less effective than combination csDMARDs, but better tolerated. Tofacitinib and baricitinib are efficacious in patients with RA, including those with refractory disease. PMID- 28356245 TI - Exercise prescription and the doctor's duty of non-maleficence. PMID- 28356246 TI - Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation therapy. AB - We investigated the frequency and characteristics of intracranial hemorrhage (ICH), the factors associated with the risk of ICH, and outcomes post-ICH overall and by randomized treatment. We identified patients with ICH from the overall trial population enrolled in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial who received >=1 dose of the study drug (n = 18 140). ICH was adjudicated by a central committee. Cox regression models were used to identify factors associated with ICH. ICH occurred in 174 patients; most ICH events were spontaneous (71.7%) versus traumatic (28.3%). Apixaban resulted in significantly less ICH (0.33% per year), regardless of type and location, than warfarin (0.80% per year). Independent factors associated with increased risk of ICH were enrollment in Asia or Latin America, older age, prior stroke/transient ischemic attack, and aspirin use at baseline. Among warfarin-treated patients, the median (25th, 75th percentiles) time from most recent international normalized ratio (INR) to ICH was 13 days (6, 21 days). Median INR prior to ICH was 2.6 (2.1, 3.0); 78.5% of patients had a pre-ICH INR <3.0. After ICH, the modified Rankin scale score at discharge was >=4 in 55.7% of patients, and the overall mortality rate at 30 days was 43.3% with no difference between apixaban- and warfarin-treated patients. ICH occurred at a rate of 0.80% per year with warfarin regardless of INR control and at a rate of 0.33% per year with apixaban and was associated with high short-term morbidity and mortality. This highlights the clinical relevance of reducing ICH by using apixaban rather than warfarin and avoiding concomitant aspirin, especially in patients of older age. This trial was registered at www.clinicaltrials.gov as #NCT00412984. PMID- 28356247 TI - PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. AB - Primary central nervous system (CNS) lymphoma (PCNSL) and primary testicular lymphoma (PTL) are rare extranodal large B-cell lymphomas with similar genetic signatures. There are no standard-of-care treatment options for patients with relapsed and refractory PCNSL and PTL, and the overall prognosis is poor. PCNSLs and PTLs exhibit frequent 9p24.1 copy-number alterations and infrequent translocations of 9p24.1 and associated increased expression of the programmed cell death protein 1 (PD-1) ligands, PD-L1 and PD-L2. The activity of PD-1 blockade in other lymphomas with 9p24.1 alterations prompted us to test the efficacy of the anti-PD1 antibody, nivolumab, in 4 patients with relapsed/refractory PCNSL and 1 patient with CNS relapse of PTL. All 5 patients had clinical and radiographic responses to PD-1 blockade, and 3 patients remain progression-free at 13+ to 17+ months. Our data suggest that nivolumab is active in relapsed/refractory PCNSL and PTL and support further investigation of PD-1 blockade in these diseases. PMID- 28356248 TI - How productive are NHS consultants? PMID- 28356249 TI - A rare clavicular lump in a baby: congenital pseudarthrosis. PMID- 28356250 TI - Pseudotumor cerebri syndrome in childhood: incidence, clinical profile and risk factors in a national prospective population-based cohort study. AB - AIM: To investigate the epidemiology, clinical profile and risk factors of pseudotumor cerebri syndrome (PTCS) in children aged 1-16 years. METHODS: A national prospective population-based cohort study over 25 months. Newly diagnosed PTCS cases notified via British Paediatric Surveillance Unit were ascertained using classical diagnostic criteria and categorised according to 2013 revised diagnostic criteria. We derived national age, sex and weight-specific annual incidence rates and assessed effects of sex and weight categories. RESULTS: We identified 185 PTCS cases of which 166 also fulfilled revised diagnostic criteria. The national annual incidence (95% CI) of PTCS in children aged 1-16 years was 0.71 (0.57 to 0.87) per 100 000 population increasing with age and weight to 4.18 and 10.7 per 100 000 in obese boys and girls aged 12-15 years, respectively. Incidence rates under 7 years were similar in both sexes. From 7 years onwards, the incidence in girls was double that in boys, but only in overweight (including obese) children. In children aged 12-15 years, an estimated 82% of the incidence of PTCS was attributable to obesity. Two subgroups of PTCS were apparent: 168 (91%) cases aged from 7 years frequently presented on medication and with headache and were predominantly female and obese. The remaining 17 (9%) cases under 7 years often lacked these risk factors and commonly presented with paralytic squint. CONCLUSIONS: This uniquely large population-based study of childhood PTCS will inform the design of future intervention studies. It suggests that weight reduction is central to the prevention of PTCS. PMID- 28356252 TI - Palliative care doctors should be included in treatment discussions. PMID- 28356253 TI - Adrenocortical carcinoma masquerading as Cushing's disease. AB - Cushing's syndrome (CS) can be classified as adrenocorticotropic hormone (ACTH) dependent or ACTH-independent depending on the ACTH levels. However, 30% of the patients with CS have ACTH levels in the 'grey zone' (5-20 pg/mL), thereby posing a challenge in establishing the aetiological diagnosis. In a patient with full blown features of Cushing's syndrome with equivocal ACTH levels, and a pituitary microadenoma on contrast-enhanced MRI sella, can falsely lead to a diagnosis of Cushing's disease. Pituitary microadenoma, if <6 mm in size, may be an incidental finding (incidentaloma) in this scenario and can be present in ~3-27% of the healthy population. Therefore, in a patient with CS with equivocal ACTH levels and a pituitary microadenoma, multiple samplings for ACTH and adrenal imaging should be performed to exclude ACTH-independent CS and if required, bilateral inferior petrosal sinus sampling to determine the source of ACTH excess. PMID- 28356254 TI - Haemophagocytic lymphohistiocytosis associated with fulminant hepatitis and multiorgan failure following primary Epstein-Barr virus and herpes simplex virus type 1 infection. AB - We present a case of severe fatal hepatitis in a young patient presumably triggered by two ubiquitous viral diseases which occurred in close succession. This case is unusual because of the exceptional chronological sequence of primary Epstein-Barr virus and herpes simplex virus type 1 infection causing systemic immune dysregulation associated with rapidly developing liver failure and consecutive multiorgan failure. Clinical, laboratory and histopathological findings indicated the development of secondary haemophagocytic lymphohistiocytosis triggered by these closely succeeding viral primary infections. PMID- 28356258 TI - A boy with fever and arthralgia. PMID- 28356257 TI - Exploring Human Antimicrobial Antibody Responses on a Single B Cell Level. AB - Analysis of monoclonal antibodies (MAbs) derived from single B cell cloning has been highly beneficial for antimicrobial immunotherapy, vaccine design, and advancing our understanding of pathogen-triggered effects on the human immunoglobulin repertoire. Sequencing of variable domains of single B cells, and characterization of binding and functional activities of MAbs derived from those sequences, provides in-depth insight not only into sites of susceptibility for antibody-mediated neutralization or opsonization of the pathogen but also into the dynamics of protective antibody evolution during infection. This information can be utilized to rapidly develop novel immunotherapies of completely human origin and provides a roadmap for structure-based vaccine design that aims to elicit similar protective antibody responses. Here, we summarize recent aspects of the single B cell cloning approach. PMID- 28356260 TI - QOFerrendum. PMID- 28356261 TI - Ribociclib Approved for Advanced Breast Cancer. AB - The FDA has approved ribociclib combined with aromatase inhibitor therapy for women with metastatic HR-positive, HER2-negative breast cancer. It is the second CDK 4/6 inhibitor approved for these patients, behind palbociclib; a third is under investigation. PMID- 28356262 TI - Of Cancer and Random Mutations. AB - In an expanded analysis that includes data from 69 countries, researchers at Johns Hopkins School of Medicine in Baltimore, MD, once again report a strong correlation between stem-cell division rates and lifetime cancer risk. They have also calculated, for the first time, the respective contributions of random replication errors, environmental factors, and heredity to mutations that drive cancer. PMID- 28356256 TI - Recent Progress in the Prevention of Serogroup B Meningococcal Disease. AB - The widespread use of meningococcal polysaccharide conjugate vaccines has highlighted the challenge of providing protection against serogroup B disease. Over a period of 4 decades, vaccine development has focused on subcapsular protein antigens, first with outer membrane vesicle (OMV) vaccines against epidemic outbreaks, and more recently on new multicomponent vaccines designed to offer better cross-protection against the antigenically diverse strains responsible for endemic disease. Because of the low incidence of meningococcal disease, the protective efficacy of these vaccines has not been determined in clinical studies, and their licensure has been based on serological data; however, the serological assays used to predict protective coverage have limitations. As a result, evidence of the effectiveness of these vaccines against different strains and the contribution of specific antigens to protection can only be provided by epidemiological analyses following their implementation in sufficiently large populations. The recent inclusion of the four-component meningococcal serogroup B (4CMenB) vaccine, Bexsero, in the infant immunization program in the UK has provided preliminary evidence that the vaccine is effective. Ongoing surveillance will provide valuable data on its longer-term impact and antigenic coverage. Further development of protein-based vaccines against meningococcal disease is anticipated to improve antigenic coverage and adjust to changes in circulating strains. At the same time, alternative immunization strategies may be explored to improve overall vaccine effectiveness by, for example, protecting the youngest infants or providing herd protection. PMID- 28356263 TI - Profiling Response, Resistance to Immunotherapy. AB - In a longitudinal analysis of patients with metastatic melanoma who received sequential therapies targeting CTLA-4, then PD-1 upon disease progression, researchers have discovered that high copy-number loss in recurrent regions of the tumor genome is associated with resistance to immune checkpoint blockade. PMID- 28356266 TI - Nurse led clinics can improve secondary prevention after coronary events. PMID- 28356264 TI - Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients. AB - BACKGROUND: Recent exome sequencing studies identified filamin C (FLNC) as a candidate gene for hypertrophic cardiomyopathy (HCM). Our aim was to determine the rate of FLNC candidate variants in a large cohort of HCM patients who were also sequenced for the main sarcomere genes. METHODS AND RESULTS: A total of 448 HCM patients were next generation-sequenced (semiconductor chip technology) for the MYH7, MYBPC3, TNNT2, TNNI3, ACTC1, TNNC1, MYL2, MYL3, TPM1, and FLNC genes. We also sequenced 450 healthy controls from the same population. Based on the reported population frequencies, bioinformatic criteria, and familial segregation, we identified 20 FLNC candidate variants (13 new; 1 nonsense; and 19 missense) in 22 patients. Compared with the patients, only 1 of the control's missense variants was nonreported (P=0.007; Fisher exact probability test). Based on the familial segregation and the reported functional studies, 6 of the candidate variants (in 7 patients) were finally classified as likely pathogenic, 10 as variants of uncertain significance, and 4 as likely benign. CONCLUSIONS: We provide a compelling evidence of the involvement of FLNC in the development of HCM. Most of the FLNC variants were associated with mild forms of HCM and a reduced penetrance, with few affected in the families to confirm the segregation. Our work, together with others who found FLNC variants among patients with dilated and restrictive cardiomyopathies, pointed to this gene as an important cause of structural cardiomyopathies. PMID- 28356265 TI - Programmatic Approach to Management of Tetralogy of Fallot With Major Aortopulmonary Collateral Arteries: A 15-Year Experience With 458 Patients. AB - BACKGROUND: Tetralogy of Fallot with major aortopulmonary collateral arteries is a complex and heterogeneous condition. Our institutional approach to this lesion emphasizes early complete repair with the incorporation of all lung segments and extensive lobar and segmental pulmonary artery reconstruction. METHODS AND RESULTS: We reviewed all patients who underwent surgical intervention for tetralogy of Fallot and major aortopulmonary collateral arteries at Lucile Packard Children's Hospital Stanford (LPCHS) since November 2001. A total of 458 patients underwent surgery, 291 (64%) of whom underwent their initial procedure at LPCHS. Patients were followed for a median of 2.7 years (mean 4.3 years) after the first LPCHS surgery, with an estimated survival of 85% at 5 years after first surgical intervention. Factors associated with worse survival included first LPCHS surgery type other than complete repair and Alagille syndrome. Of the overall cohort, 402 patients achieved complete unifocalization and repair, either as a single-stage procedure (n=186), after initial palliation at our center (n=74), or after surgery elsewhere followed by repair/revision at LPCHS (n=142). The median right ventricle:aortic pressure ratio after repair was 0.35. Estimated survival after repair was 92.5% at 10 years and was shorter in patients with chromosomal anomalies, older age, a greater number of collaterals unifocalized, and higher postrepair right ventricle pressure. CONCLUSIONS: Using an approach that emphasizes early complete unifocalization and repair with incorporation of all pulmonary vascular supply, we have achieved excellent results in patients with both native and previously operated tetralogy of Fallot and major aortopulmonary collateral arteries. PMID- 28356267 TI - Hemoglobin inhibits albumin uptake by proximal tubule cells: implications for sickle cell disease. AB - Proximal tubule (PT) dysfunction, including tubular proteinuria, is a significant complication in young sickle cell disease (SCD) that can eventually lead to chronic kidney disease. Hemoglobin (Hb) dimers released from red blood cells upon hemolysis are filtered into the kidney and internalized by megalin/cubilin receptors into PT cells. The PT is especially sensitive to heme toxicity, and tubular dysfunction in SCD is thought to result from prolonged exposure to filtered Hb. Here we show that concentrations of Hb predicted to enter the tubule lumen during hemolytic crisis competitively inhibit the uptake of another megalin/cubilin ligand (albumin) by PT cells. These effects were independent of heme reduction state. The Glu7Val mutant of Hb that causes SCD was equally effective at inhibiting albumin uptake compared with wild-type Hb. Addition of the Hb scavenger haptoglobin (Hpt) restored albumin uptake in the presence of Hb, suggesting that Hpt binding to the Hb alphabeta dimer-dimer interface interferes with Hb binding to megalin/cubilin. BLAST searches and structural modeling analyses revealed regions of similarity between Hb and albumin that map to this region and may represent sites of Hb interaction with megalin/cubilin. Our studies suggest that impaired endocytosis of megalin/cubilin ligands, rather than heme toxicity, may be the cause of tubular proteinuria in SCD patients. Additionally, loss of these filtered proteins into the urine may contribute to the extra-renal pathogenesis of SCD. PMID- 28356268 TI - Neurotrophin 3 upregulates proliferation and collagen production in human aortic valve interstitial cells: a potential role in aortic valve sclerosis. AB - Calcific aortic valve disease (CAVD) is a leading cardiovascular disorder in the elderly. Diseased aortic valves are characterized by sclerosis (fibrosis) and nodular calcification. Sclerosis, an early pathological change, is caused by aortic valve interstitial cell (AVIC) proliferation and overproduction of extracellular matrix (ECM) proteins. However, the mechanism of aortic valve sclerosis remains unclear. Recently, we observed that diseased human aortic valves overexpress growth factor neurotrophin 3 (NT3). In the present study, we tested the hypothesis that NT3 is a profibrogenic factor to human AVICs. AVICs isolated from normal human aortic valves were cultured in M199 growth medium and treated with recombinant human NT3 (0.10 ug/ml). An exposure to NT3 induced AVIC proliferation, upregulated the production of collagen and matrix metalloproteinase (MMP), and augmented collagen deposition. These changes were abolished by inhibition of the Trk receptors. NT3 induced Akt phosphorylation and increased cyclin D1 protein levels in a Trk receptor-dependent fashion. Inhibition of Akt abrogated the effect of NT3 on cyclin D1 production. Furthermore, inhibition of either Akt or cyclin D1 suppressed NT3-induced cellular proliferation and MMP-9 and collagen production, as well as collagen deposition. Thus, NT3 upregulates cellular proliferation, ECM protein production, and collagen deposition in human AVICs. It exerts these effects through the Trk Akt-cyclin D1 cascade. NT3 is a profibrogenic mediator in human aortic valve, and overproduction of NT3 by aortic valve tissue may contribute to the mechanism of valvular sclerosis. PMID- 28356269 TI - miR-375 negatively regulates the synthesis and secretion of catecholamines by targeting Sp1 in rat adrenal medulla. AB - The adrenal gland is an important endocrine gland in balancing homeostasis and the response to stress by synthesizing and secreting catecholamines (CATs), and it has been confirmed that microRNA-375 (miR-375) is highly expressed in adrenal medulla. However, up to now there are few reports about the functions and related mechanisms in adrenal medulla. The present study was thus designed to study the roles and related mechanisms in rat adrenal medulla. Our results showed that miR 375 was specifically expressed in rat adrenal medulla chromaffin cells, and its expression was downregulated when rats were exposed to stress. The further functional studies demonstrated that the inhibition of endogenous miR-375 induced the secretion of CATs in primary rat medulla chromaffin cells and PC12 cells, whereas miR-375 overexpression resulted in a decline of CAT secretion. In addition, our results showed that miR-375 negatively regulated tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH) and mediated adrenomedullary CAT biosynthesis. These functions of miR-375 were accomplished by its binding to the 3'-untranslated region of Sp1, which was involved in the regulation of TH and DBH expressions. These novel findings suggest that miR-375 acts as a potent negative mediator in regulating the synthesis and secretion of CATs in the adrenal medulla during the maintenance of homeostasis under stress. PMID- 28356271 TI - Cashew consumption reduces total and LDL cholesterol: a randomized, crossover, controlled-feeding trial. AB - Background: Cashews are the third most-consumed tree nut in the United States and are abundant with monounsaturated fatty acids and polyunsaturated fatty acids, which are associated with reduced cardiovascular disease risk. Although a qualified Food and Drug Administration health claim exists for nuts and heart health, cashews have been exempt from its use because cashews exceed the disqualifying amount of saturated fatty acids. Approximately one-third of the saturated fat in cashews is stearic acid, which is relatively neutral on blood lipids, thereby suggesting that cashews could have effects that are similar to those of other nuts. However, clinical data on cashews and blood lipids have been limited.Objective: We investigated the effect of reasonable intakes of cashews on serum lipids in adults with or at risk of high LDL cholesterol.Design: In a randomized, crossover, isocaloric, controlled-feeding study, 51 men and women (aged 21-73 y) with a median LDL-cholesterol concentration of 159 mg/dL (95% CI: 146, 165 mg/dL) at screening consumed typical American diets with cashews (28-64 g/d; 50% of kilocalories from carbohydrate, 18% of kilocalories from protein, and 32% of kilocalories from total fat) or potato chips (control; 54% of kilocalories from carbohydrate, 18% of kilocalories from protein, and 29% of kilocalories from total fat) for 28 d with a >=2-wk washout period.Results: Consumption of the cashew diet resulted in a significantly greater median change from baseline (compared with the control, all P < 0.05) in total cholesterol [-3.9% (95% CI: 9.3%, 1.7%) compared with 0.8% (95% CI: -1.5%, 4.5%), respectively], LDL cholesterol [-4.8% (95% CI: -12.6%, 3.1%) compared with 1.2% (95% CI: -2.3%, 7.8%), respectively], non-HDL cholesterol [-5.3% (95% CI: -8.6%, 2.1%) compared with 1.7% (95% CI: -0.9%, 5.6%), respectively], and the total-cholesterol:HDL cholesterol ratio [-0.0% (95% CI: -4.3%, 4.8%) compared with 3.4% (95% CI: 0.6%, 5.2%), respectively]. There were no significant differences between diets for HDL cholesterol and triglyceride.Conclusions: In comparison with a control diet, the incorporation of cashews into typical American diets decreases total cholesterol and LDL cholesterol. Results from this study provide support that the daily consumption of cashews, when substituted for a high-carbohydrate snack, may be a simple dietary strategy to help manage total cholesterol and LDL cholesterol. This study was registered at clinicaltrials.gov as NCT02769741. PMID- 28356270 TI - Ulk1-mediated autophagy plays an essential role in mitochondrial remodeling and functional regeneration of skeletal muscle. AB - Autophagy is a conserved cellular process for degrading aggregate proteins and dysfunctional organelle. It is still debatable if autophagy and mitophagy (a specific process of autophagy of mitochondria) play important roles in myogenic differentiation and functional regeneration of skeletal muscle. We tested the hypothesis that autophagy is critical for functional regeneration of skeletal muscle. We first observed time-dependent increases (3- to 6-fold) of autophagy related proteins (Atgs), including Ulk1, Beclin1, and LC3, along with reduced p62 expression during C2C12 differentiation, suggesting increased autophagy capacity and flux during myogenic differentiation. We then used cardiotoxin (Ctx) or ischemia-reperfusion (I/R) to induce muscle injury and regeneration and observed increases in Atgs between days 2 and 7 in adult skeletal muscle followed by increased autophagy flux after day 7 Since Ulk1 has been shown to be essential for mitophagy, we asked if Ulk1 is critical for functional regeneration in skeletal muscle. We subjected skeletal muscle-specific Ulk1 knockout mice (MKO) to Ctx or I/R. MKO mice had significantly impaired recovery of muscle strength and mitochondrial protein content post-Ctx or I/R. Imaging analysis showed that MKO mice have significantly attenuated recovery of mitochondrial network at 7 and 14 days post-Ctx. These findings suggest that increased autophagy protein and flux occur during muscle regeneration and Ulk1-mediated mitophagy is critical for recovery for the mitochondrial network and hence functional regeneration. PMID- 28356272 TI - Choline and its metabolites are differently associated with cardiometabolic risk factors, history of cardiovascular disease, and MRI-documented cerebrovascular disease in older adults. AB - Background: There is a potential role of choline in cardiovascular and cerebrovascular disease through its involvement in lipid and one-carbon metabolism.Objective: We evaluated the associations of plasma choline and choline related compounds with cardiometabolic risk factors, history of cardiovascular disease, and cerebrovascular pathology.Design: A cross-sectional subset of the Nutrition, Aging, and Memory in Elders cohort who had undergone MRI of the brain (n = 296; mean +/- SD age: 73 +/- 8.1 y) was assessed. Plasma concentrations of free choline, betaine, and phosphatidylcholine were measured with the use of liquid-chromatography-stable-isotope dilution-multiple-reaction monitoring-mass spectrometry. A volumetric analysis of MRI was used to determine the cerebrovascular pathology (white-matter hyperintensities and small- and large vessel infarcts). Multiple linear and logistic regression models were used to examine relations of plasma measures with cardiometabolic risk factors, history of cardiovascular disease, and radiologic evidence of cerebrovascular pathology.Results: Higher concentrations of plasma choline were associated with an unfavorable cardiometabolic risk-factor profile [lower high-density lipoprotein (HDL) cholesterol, higher total homocysteine, and higher body mass index (BMI)] and greater odds of large-vessel cerebral vascular disease or history of cardiovascular disease but lower odds of small-vessel cerebral vascular disease. Conversely, higher concentrations of plasma betaine were associated with a favorable cardiometabolic risk-factor profile [lower low density lipoprotein (LDL) cholesterol and triglycerides] and lower odds of diabetes. Higher concentrations of plasma phosphatidylcholine were associated with characteristics of both a favorable cardiometabolic risk-factor profile (higher HDL cholesterol, lower BMI, lower C-reactive protein, lower waist circumference, and lower odds of hypertension and diabetes) and an unfavorable profile (higher LDL cholesterol and triglycerides).Conclusion: Choline and its metabolites have differential associations with cardiometabolic risk factors and subtypes of vascular disease, thereby suggesting differing roles in the pathogenesis of cardiovascular and cerebral large-vessel disease compared with that of small-vessel disease. PMID- 28356273 TI - Nutrition label use is associated with lower longer-term diabetes risk in US adults. AB - Background: Regular nutrition label use may have important long-term health implications. To our knowledge, the role of nutrition label use in protecting against the development of chronic diseases was unexplored prospectively before this study.Objective: We tested the association between nutrition label use and risk of a future diabetes diagnosis in a multiethnic US cohort.Design: Data from the ongoing National Longitudinal Survey of Youth-1979 (NLSY79) were analyzed. From 2002 (baseline) to 5 follow-up time points (2004-2012), 7150 diabetes-free, multiethnic young adults were prospectively followed for a diagnosis of incident diabetes. Nutrition label use, diabetes diagnosis, time to diabetes diagnosis, and all covariates were self-reported.Results: Between January 2002 and September 2013, 430 participants (6.0%) were diagnosed with diabetes. A weighted, multivariable, extended Cox regression was conducted, which suggested that in nutrition label users, the HR of diabetes diagnosis risk decreased significantly with time (P-nutrition label use * time interaction < 0.05) compared with risk in nutrition label nonusers.Conclusions: There is an association between nutrition label use and diabetes risk in the longer term. However, additional longitudinal research with a robust dietary intake assessment is needed to test this hypothesis. PMID- 28356274 TI - Relation between hypermetabolism, cachexia, and survival in cancer patients: a prospective study in 390 cancer patients before initiation of anticancer therapy. AB - Background: Cachexia is a major cause of death in cancer patients. The role of hypermetabolism in cancer cachexia remains unclear.Objective: We studied the relation between resting energy expenditure (REE), the estimated energy balance, clinical and biological markers of cachexia, and survival.Design: REE was measured with the use of indirect calorimetry in cancer patients before the initiation of anticancer therapies. Hypermetabolic, normometabolic, and hypometabolic patients were identified with the use of Boothby's standard. Weight loss, performance status (PS), C-reactive protein (CRP), albumin, the nutritional risk index, daily energy intake, energy balance (equal to daily energy intakes minus the REE), and survival were recorded.Results: Of 390 enrolled patients, 49% of subjects were hypermetabolic, 30% of subjects were normometabolic, and 21% of subjects were hypometabolic. Mean daily energy intakes did not differ significantly between the 3 groups. Hypermetabolic patients, compared with normometabolic patients, were more likely to have a negative energy balance [45% compared with 32%, respectively; OR: 1.74 (95% CI: 1.05, 2.91); P = 0.024], weight loss >5% [48% compared with 34%, respectively; OR: 1.83 (95% CI: 1.11, 3.04); P = 0.013], PS >=2 [40% compared with 29%, respectively; OR: 1.70 (95% CI: 1.01, 2.88); P = 0.038], and CRP concentrations >=10 mg/L [52% compared with 33%, respectively; OR: 2.2 (95% CI: 1.33, 3.66); P = 0.001]. In metastatic patients, compared with normometabolism, hypermetabolism was associated with a reduced median survival [14.6 compared with 21.4 mo, respectively; OR: 1.48 (95% CI: 1.01, 2.17); P = 0.044].Conclusions: Hypermetabolism is correlated with clinical and biological markers of cancer cachexia and is associated with a shorter survival in metastatic cancer patients. The development of therapeutic strategies that aim to blunt hypermetabolism appears warranted. This trial was registered at www.controlled-trials.com as ISRCTN46152275. PMID- 28356276 TI - Dietary intake and adipose tissue content of long-chain n-3 PUFAs and subsequent 5-y change in body weight and waist circumference. AB - Background: Adding long-chain n-3 (omega-3) polyunsaturated fatty acids (PUFAs) to a rodent diet reduces fat mass and prevents the development of obesity, but evidence of a similar effect in humans is rather limited.Objectives: We investigated the associations between dietary intake and adipose tissue content of long-chain n-3 PUFAs and subsequent 5-y change in body weight and waist circumference in humans. Effect modification by the carbohydrate:protein ratio and glycemic index was also investigated.Design: A total of 29,152 participants included in the Diet, Cancer, and Health cohort were followed. Dietary intake was assessed with the use of a validated 192-item semiquantitative food-frequency questionnaire. Adipose tissue content of fatty acids was determined by gas chromatography in a random sample of the cohort (n = 1660). Anthropometric measurements were taken at baseline and 5 y later. Associations were investigated with the use of a linear regression model.Results: For high (1.22 g/d) compared with low (0.28 g/d) total n-3 PUFA intake, the difference in 5-y weight change was 147.6 g (95% CI: -42.3, 337.5 g); P-trend = 0.088. No associations between the individual n-3 PUFAs eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid were observed. Intake of n-3 PUFAs was not associated with a 5-y change in waist circumference. For high (0.16%) compared with low (0.06%) adipose tissue content of EPA, the difference in 5-y weight change was -649.6 g (95% CI: -1254.2, -44.9 g); P-trend = 0.027. No associations between total n-3 PUFA, docosapentaenoic acid, and docosahexaenoic acid and 5-y weight change were observed. Adipose tissue content of n-3 PUFAs was not associated with 5-y change in waist circumference. No effect modification by carbohydrate:protein ratio or glycemic index was found.Conclusion: Dietary intake and adipose tissue content of long-chain n-3 PUFAs were neither consistently nor appreciably associated with change in body weight or waist circumference. PMID- 28356275 TI - A systematic review and meta-analysis of randomized controlled trials of the effect of konjac glucomannan, a viscous soluble fiber, on LDL cholesterol and the new lipid targets non-HDL cholesterol and apolipoprotein B. AB - Background: Evidence from randomized controlled trials (RCTs) suggests the consumption of konjac glucomannan (KJM), a viscous soluble fiber, for improving LDL-cholesterol concentrations. It has also been suggested that the cholesterol lowering potential of KJM may be greater than that of other fibers. However, trials have been relatively scarce and limited in sample size and duration, and the effect estimates have been inconsistent. The effect of KJM on new lipid targets of cardiovascular disease (CVD) risk is also unknown.Objective: This systematic review and meta-analysis aimed to assess the effect of KJM on LDL cholesterol, non-HDL cholesterol, and apolipoprotein B.Design: Medline, Embase, CINAHL, and the Cochrane Central databases were searched. We included RCTs with a follow-up of >=3 wk that assessed the effect of KJM on LDL cholesterol, non-HDL cholesterol, or apolipoprotein B. Data were pooled by using the generic inverse variance method with random-effects models and expressed as mean differences (MDs) with 95% CIs. Heterogeneity was assessed by the Cochran Q statistic and quantified by the I2 statistic.Results: Twelve studies (n = 370), 8 in adults and 4 in children, met the inclusion criteria. KJM significantly lowered LDL cholesterol (MD: -0.35 mmol/L; 95% CI: -0.46, -0.25 mmol/L) and non-HDL cholesterol (MD: -0.32 mmol/L; 95% CI: -0.46, -0.19 mmol/L). Data from 6 trials suggested no impact of KJM on apolipoprotein B.Conclusions: Our findings support the intake of ~3 g KJM/d for reductions in LDL cholesterol and non-HDL cholesterol of 10% and 7%, respectively. The information may be of interest to health agencies in crafting future dietary recommendations related to reduction in CVD risk. This study was registered at clinicaltrials.gov as NCT02068248. PMID- 28356277 TI - Validation of spot urine in predicting 24-h sodium excretion at the individual level. AB - Background: Evidence for the effect of dietary sodium intake on the risk of cardiovascular disease has been controversial. One of the main explanations for the conflicting results lies in the great variability associated with measurement methods for sodium intake. Spot urine collection is a convenient method commonly used for sodium estimation, but its validity for predicting 24-h urinary sodium excretion at the individual level has not been well evaluated among the general population.Objective: The aim of this study was to evaluate the validity of the Kawasaki, the International Cooperative Study on Salt, Other Factors, and Blood Pressure (INTERSALT), and the Tanaka formulas in predicting 24-h urinary sodium excretion by using spot urine samples in Chinese adults.Design: We analyzed the relative and absolute differences and misclassification at the individual level from 3 commonly used methods for estimating sodium intake among 141 Chinese community residents.Results: The mean measured 24-h sodium excretion was 220.8 mmol/d. The median (95% CIs) differences between measured sodium and those estimated from the Kawasaki, INTERSALT, and Tanaka methods were 6.4 mmol/d ( 17.5, 36.8 mmol/d), -67.3 mmol/d (-96.5, -46.9 mmol/d), and -42.9 mmol/d (-59.1, 24.8 mmol/d), respectively. The proportions of relative differences >40% with the Kawasaki, INTERSALT, and Tanaka methods were 31.2%, 41.1%, and 22.0%, respectively; and the absolute difference for the 3 methods was >51.3 mmol/d (3 g salt) in approximately half of the participants. The misclassification rate was 63.1% for the Kawasaki method, 78.7% for the INTERSALT method, and 66.0% for the Tanaka method at the individual level.Conclusion: The results from our study do not support the use of spot urine to estimate 24-h urinary sodium excretion at the individual level because of its poor performance with respect to misclassification. This trial was registered at www.chictr.org.cn as ChiCTR-IOR 16010278. PMID- 28356278 TI - What's normal? Oligosaccharide concentrations and profiles in milk produced by healthy women vary geographically. AB - Background: Human milk is a complex fluid comprised of myriad substances, with one of the most abundant substances being a group of complex carbohydrates referred to as human milk oligosaccharides (HMOs). There has been some evidence that HMO profiles differ in populations, but few studies have rigorously explored this variability.Objectives: We tested the hypothesis that HMO profiles differ in diverse populations of healthy women. Next, we examined relations between HMO and maternal anthropometric and reproductive indexes and indirectly examined whether differences were likely related to genetic or environmental variations.Design: In this cross-sectional, observational study, milk was collected from a total of 410 healthy, breastfeeding women in 11 international cohorts and analyzed for HMOs by using high-performance liquid chromatography.Results: There was an effect of the cohort (P < 0.05) on concentrations of almost all HMOs. For instance, the mean 3 fucosyllactose concentration was >4 times higher in milk collected in Sweden than in milk collected in rural Gambia (mean +/- SEM: 473 +/- 55 compared with 103 +/- 16 nmol/mL, respectively; P < 0.05), and disialyllacto-N-tetraose (DSLNT) concentrations ranged from 216 +/- 14 nmol/mL (in Sweden) to 870 +/- 68 nmol/mL (in rural Gambia) (P < 0.05). Maternal age, time postpartum, weight, and body mass index were all correlated with several HMOs, and multiple differences in HMOs [e.g., lacto-N-neotetrose and DSLNT] were shown between ethnically similar (and likely genetically similar) populations who were living in different locations, which suggests that the environment may play a role in regulating the synthesis of HMOs.Conclusions: The results of this study support our hypothesis that normal HMO concentrations and profiles vary geographically, even in healthy women. Targeted genomic analyses are required to determine whether these differences are due at least in part to genetic variation. A careful examination of sociocultural, behavioral, and environmental factors is needed to determine their roles in this regard. This study was registered at clinicaltrials.gov as NCT02670278. PMID- 28356280 TI - Sex-Specific Relationship Between Serum Uric Acid and Risk of Stroke: A Dose Response Meta-Analysis of Prospective Studies. AB - BACKGROUND: Conflicting findings of the association between serum uric acid (UA) and stroke have been reported in both men and women, and it is unclear whether this association was different between men and women. We preformed this meta analysis to assess the sex-specific effect of serum UA on the risk of stroke and its subtypes. METHODS AND RESULTS: Prospective studies that reported sex-specific association of UA levels with stroke or reported in a certain sex were included. Dose-response relationships were assessed by the generalized least squares trend estimation, and summary effect estimates were evaluated with random-effect models. Subgroup and sensitivity analyses were performed to assess the potential sources of heterogeneity and the robustness of the pooled estimation. Altogether, 13 prospective studies were identified in this study. The summary of relative risks (95% CIs) of stroke for a 1-mg/dL increase in serum UA levels were 1.10 (1.05-1.14) for men and 1.11 (1.09-1.13) for women. There is no significant difference in the effect of UA on future stroke risk between men and women (Pinteraction=0.736). Subgroup analyses showed that the significant associations persisted in most stratifications, and sensitivity analyses according to various inclusion criteria yielded similar results. A nonlinear relationship was observed in men (Pnon-linearity<0.001), with risk increasing significantly from a UA of 6 mg/dL and more steeply at higher UA levels. CONCLUSIONS: Elevated serum UA levels were significantly associated with modestly increased risk of stroke in both men and women and have similar adverse effects on development of stroke in both sexes. PMID- 28356281 TI - Sex- and Race-Related Differences in Characteristics and Outcomes of Hospitalizations for Heart Failure With Preserved Ejection Fraction. AB - BACKGROUND: Sex and race have emerged as important contributors to the phenotypic heterogeneity of heart failure with preserved ejection fraction (HFpEF). However, there remains a need to identify important sex- and race-related differences in characteristics and outcomes using a nationally representative cohort. METHODS AND RESULTS: Data were obtained from the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project-Nationwide Inpatient Sample files between 2008 and 2012. Hospitalizations with a diagnosis of HFpEF were included for analysis. Demographics, hospital characteristics, and age-adjusted comorbidity prevalence rates were compared between men and women and whites and blacks. In-hospital mortality was determined and compared for each subgroup. Multivariable regression analyses were used to identify and compare correlates of in-hospital mortality for each subgroup. A sample of 1 889 608 hospitalizations was analyzed. Men with HFpEF were slightly younger than women with HFpEF and had a higher Elixhauser comorbidity score. Men experienced higher in-hospital mortality compared with women, a finding that was attenuated after adjusting for comorbidity. Blacks with HFpEF were younger than whites with HFpEF, with lower rates of most comorbidities. Hypertension, diabetes, anemia, and chronic renal failure were more common among blacks. Blacks experienced lower in-hospital mortality compared with whites, even after adjusting for age and comorbidity. Important correlates of mortality among all 4 subgroups included pulmonary circulation disorders, liver disease, and chronic renal failure. Atrial fibrillation was an important correlate of mortality only among women and blacks. CONCLUSIONS: Differences in patient characteristics and outcomes reinforce the notion that sex and race contribute to the phenotypic heterogeneity of HFpEF. PMID- 28356279 TI - History of Periodontitis Diagnosis and Edentulism as Predictors of Cardiovascular Disease, Stroke, and Mortality in Postmenopausal Women. AB - BACKGROUND: Few studies have reported associations between periodontitis and cardiovascular disease (CVD) risk in older women, which is the objective of the present investigation. METHODS AND RESULTS: Participants were 57 001 postmenopausal women ages 55 to 89 years (mean 68 years; >85% 60 and older) who were enrolled (1993-1998) in the Women's Health Initiative Observational Study, and were without known CVD when history of periodontitis and edentulism was assessed by questionnaire at study Year-5 (1998-2003). There were 3589 incident CVD events and 3816 total deaths during a mean follow-up of 6.7 years. In multivariable analysis, periodontitis was not associated with CVD events, but was associated with higher total mortality (hazard ratio (HR)=1.12, 95% CI: 1.05 1.21). Edentulism was associated with higher age- and smoking-adjusted risks of CVD (HR=1.42, 95% CI: 1.27-1.59) and mortality (HR=1.47, 95% CI: 1.32-1.63). Further adjustment eliminated the association with CVD, but mortality remained significantly increased (HR=1.17, 95% CI: 1.02-1.33). Stratification on age, race ethnicity, smoking, and diabetes mellitus yielded comparable results; however, edentulism was more strongly associated with CVD in women reporting >=1 dental visit (HR=1.57) compared with <1 visit (HR 1.03, interaction P=0.004) annually. CONCLUSIONS: In community-dwelling older women, edentulism was associated with increased risks of CVD and total mortality, and presence of periodontitis, which is more prevalent than edentulism, was associated with 17% higher mortality rate. These findings suggest that improving periodontal condition of the general population could reduce overall mortality. PMID- 28356282 TI - Impact of Diabetes Mellitus on the Pharmacodynamic Effects of Ticagrelor Versus Clopidogrel in Troponin-Negative Acute Coronary Syndrome Patients Undergoing Ad Hoc Percutaneous Coronary Intervention. AB - BACKGROUND: Diabetes mellitus (DM) is associated with enhanced platelet reactivity and impaired response to oral antiplatelet therapy, including clopidogrel. This post hoc analysis investigated the pharmacodynamic effects of ticagrelor versus clopidogrel loading dose (LD) in troponin-negative acute coronary syndrome patients with or without DM undergoing percutaneous coronary intervention in the Ad Hoc PCI study. METHODS AND RESULTS: Patients randomized (1:1) to receive ticagrelor 180 mg LD or clopidogrel 600 mg LD were assessed by diabetic status. Platelet reactivity (P2Y12 reaction units [PRU] on VerifyNow(r) assay) was measured pre-LD, at 0.5, 2, and 8 hours post-LD, and at the end of the percutaneous coronary intervention. The primary endpoint was PRU levels 2 hours post-LD; secondary endpoints included rates of high on-treatment platelet reactivity (PRU>=208). Of 100 randomized patients, 51 received ticagrelor (DM, n=20; non-DM, n=31) and 49 clopidogrel (DM, n=16; non-DM, n=33). At 2 hours post LD, mean (SD) PRU levels in DM patients were 130.1 (111.7) with ticagrelor versus 287.6 (71.9) with clopidogrel (mean [95%CI] difference -157.5 [-225.3, -89.8]; P<0.001); in non-DM patients, they were 75.3 (75.7) versus 243.0 (72.4) (mean difference -167.7 [-207.1, -128.3]; P<0.001). High on-treatment platelet reactivity rates at 2 hours post-LD were also significantly (P<0.001) reduced with ticagrelor versus clopidogrel in DM and non-DM patients. Between-treatment differences for PRU and high on-treatment platelet reactivity were not significant at earlier time points but were at 8 hours post-LD (P<0.001). CONCLUSIONS: Compared with clopidogrel, ticagrelor achieved faster, enhanced platelet inhibition and reduced high on-treatment platelet reactivity rates, in DM and non-DM patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01603082. PMID- 28356286 TI - Early, but not late, treatment with human umbilical cord blood-derived mesenchymal stem cells attenuates cisplatin nephrotoxicity through immunomodulation. AB - Preemptive treatment with mesenchymal stem cells (MSCs) can attenuate cisplatin induced acute kidney injury (AKI). However, it is uncertain whether MSC treatment after the development of renal dysfunction prevents AKI progression or if MSC immunomodulatory properties contribute to MSC therapy. In this study, human umbilical cord blood (hUCB)-derived MSCs were used to compare the effects and mechanisms of early and late MSC therapy in a murine model. After cisplatin injection into C57BL/6 mice, hUCB-MSCs were administered on day 1 (early treatment) or day 3 (late treatment). With early treatment, cisplatin nephrotoxicity was attenuated as evidenced by decreased blood urea nitrogen (BUN) and reduced apoptosis and tubular injury scores on day 3 Early treatment resulted in downregulation of intrarenal monocyte chemotactic protein-1 and IL-6 expression and upregulation of IL-10 and VEGF expression. Flow cytometric analysis showed similar populations of infiltrated immune cells in both groups; however, regulatory T-cell (Treg) infiltration was 2.5-fold higher in the early treatment group. The role of Tregs was confirmed by the blunted effect of early treatment on renal injury after Treg depletion. In contrast, late treatment (at a time when BUN levels were 2-fold higher than baseline levels) showed no renoprotective effects on day 6 Neither the populations of intrarenal infiltrating immune cells (including Tregs) nor cytokine expression levels were affected by late treatment. Our results suggest that early MSC treatment attenuates renal injury by Treg induction and immunomodulation, whereas a late treatment (i.e., after the development of renal dysfunction) does not prevent AKI progression or alter the intrarenal inflammatory micromilieu. PMID- 28356288 TI - 2017 Robert W. Berliner Award for Excellence in Renal Physiology. PMID- 28356283 TI - Saving the sweetness: renal glucose handling in health and disease. AB - Glucose homeostasis is highly controlled, and the function of the kidney plays an integral role in this process. The exquisite control of blood glucose relies, in part, on renal glucose filtration, renal glucose reabsorption, and renal gluconeogenesis. Particularly critical to maintaining glucose homeostasis is the renal reabsorption of glucose; with ~162 g of glucose filtered by the kidney per day, it is imperative that the kidney have the ability to efficiently reabsorb nearly 100% of this glucose back in the bloodstream. In this review, we focus on this central process, highlighting the renal transporters and regulators involved in both the physiology and pathophysiology of glucose reabsorption. PMID- 28356284 TI - Monophosphoryl lipid A induces protection against LPS in medullary thick ascending limb through a TLR4-TRIF-PI3K signaling pathway. AB - Monophosphoryl lipid A (MPLA) is a detoxified derivative of LPS that induces tolerance to LPS and augments host resistance to bacterial infections. Previously, we demonstrated that LPS inhibits [Formula: see text] absorption in the medullary thick ascending limb (MTAL) through a basolateral Toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-ERK pathway. Here we examined whether pretreatment with MPLA would attenuate LPS inhibition. MTALs from rats were perfused in vitro with MPLA (1 ug/ml) in bath and lumen or bath alone for 2 h, and then LPS was added to (and MPLA removed from) the bath solution. Pretreatment with MPLA eliminated LPS-induced inhibition of [Formula: see text] absorption. In MTALs pretreated with MPLA plus a phosphatidylinositol 3 kinase (PI3K) or Akt inhibitor, LPS decreased [Formula: see text] absorption. MPLA increased Akt phosphorylation in dissected MTALs. The Akt activation was eliminated by a PI3K inhibitor and in MTALs from TLR4-/- or Toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-/- mice. The effect of MPLA to prevent LPS inhibition of [Formula: see text] absorption also was TRIF dependent. Pretreatment with MPLA prevented LPS-induced ERK activation; this effect was dependent on PI3K. MPLA alone had no effect on [Formula: see text] absorption, and MPLA pretreatment did not prevent ERK-mediated inhibition of [Formula: see text] absorption by aldosterone, consistent with MPLA's low toxicity profile. These results demonstrate that pretreatment with MPLA prevents the effect of LPS to inhibit [Formula: see text] absorption in the MTAL. This protective effect is mediated directly through MPLA stimulation of a TLR4-TRIF-PI3K-Akt pathway that prevents LPS-induced ERK activation. These studies identify detoxified TLR4-based immunomodulators as novel potential therapeutic agents to prevent or treat renal tubule dysfunction in response to bacterial infections. PMID- 28356290 TI - Novel contrast mixture improves bladder wall contrast for visualizing bladder injury. AB - Here, we tested whether combined contrast-enhanced magnetic resonance imaging (CCE-MRI), using a mixture of gadolinium- and iron oxide-based contrast agents, can segment the bladder wall from the bladder lumen. CCE-MRI relies on the differences in particle size and contrast mechanisms of two agents for improved image contrast. Under isoflurane anesthesia, T1-weighted imaging of adult female Sprague-Dawley rat bladder was performed using standard turbospin echo sequences at 7 Tesla, before and after transurethral instillation of 0.3 ml of single contrast MRI or CCE-MRI composed of 0.4-64 mM of gadolinium chelate (Gd DTPA/Gadavist) and 5 mM ferumoxytol. Bladder wall contrast was assessed in the control group exposed to saline and in the bladder injury group exposed to 0.5 ml of protamine sulfate (10 mg/ml) for 30 min. CCE-MRI following instillation of 0.4 4 mM Gd-DTPA and 5 mM ferumoxytol mixture achieved segmentation between the bladder lumen and bladder wall. Hyperintensity in the bladder wall combined with hypointensity in the lumen is consistent with the increased diffusion of the dissolved Gd-DTPA and simultaneous localization of the larger nanoparticles of ferumoxytol in the lumen. The normalized hyperintense signal in the bladder wall increased from 0.46 +/- 0.07 in control group to 0.73 +/- 0.14 in the protamine sulfate-exposed group (P < 0.0001). CCE-MRI following instillation of contrast mixture identifies bladder wall changes likely associated with bladder injury with improved image contrast. PMID- 28356285 TI - Exosome production and its regulation of EGFR during wound healing in renal tubular cells. AB - Kidney repair following injury involves the reconstitution of a structurally and functionally intact tubular epithelium. Growth factors and their receptors, such as EGFR, are important in the repair of renal tubules. Exosomes are cell-produced small (~100 nm in diameter) vesicles that contain and transfer proteins, lipids, RNAs, and DNAs between cells. In this study, we examined the relationship between exosome production and EGFR activation and the potential role of exosome in wound healing. EGFR activation occurred shortly after scratch wounding in renal tubular cells. Wound repair after scratching was significantly promoted by EGF and suppressed by EGFR inhibitor gefitinib. Interestingly, scratch wounding induced a significant increase of exosome production. The exosome production was decreased by EGF and increased by gefitinib, suggesting a suppressive role of EGFR signaling in exosome production. Conversely, inhibition of exosome release by GW4869 and manumycin A markedly increased EGFR activation and promoted wound healing. Moreover, exosomes derived from scratch-wounding cells could inhibit wound healing. Collectively, the results indicate that wound healing in renal tubular cells is associated with EGFR activation and exosome production. Although EGFR activation promotes wound healing, released exosomes may antagonize EGFR activation and wound healing. PMID- 28356287 TI - PGF2alpha regulates the basolateral K channels in the distal convoluted tubule. AB - Our aim is to examine the role of PGF2alpha receptor (FP), a highly expressed prostaglandin receptor in the distal convoluted tubule (DCT) in regulating the basolateral 40-pS K channel. The single-channel studies demonstrated that PGF2alpha had a biphasic effect on the 40-pS K channel in the DCT-PGF2alpha stimulated at low concentrations (less than 500 nM), while at high concentrations (above 1 uM), it inhibited the 40-pS K channels. Moreover, neither 13,14-dihydro 15-keto-PGF2alpha (a metabolite of PGF2alpha) nor PGE2 was able to mimic the effect of PGF2alpha on the 40-pS K channel in the DCT. The inhibition of PKC had no significant effect on the 40-pS K channel; however, it abrogated the inhibitory effect of 5 uM PGF2alpha on the K channel. Moreover, stimulation of PKC inhibited the 40-pS K channel in the DCT, suggesting that PKC mediates the inhibitory effect of PGF2alpha on the 40-pS K channel. Conversely, the stimulatory effect of PGF2alpha on the 40-pS K channel was absent in the DCT treated with DPI, a NADPH oxidase (NOX) inhibitor. Also, adding 100 uM H2O2 mimicked the stimulatory effect of PGF2alpha and increased the 40-pS K channel activity in DCT. Moreover, the stimulatory effect of 500 nM PGF2alpha and H2O2 was not additive, suggesting the role of superoxide-related species in mediating the stimulatory effect of PGF2alpha on the 40-pS K channel. The inhibition of Src family tyrosine protein kinase (SFK) not only inhibited the 40-pS K channel in the DCT but also completely abolished the stimulatory effects of PGF2alpha and H2O2 on the 40-pS K channel. We conclude that PGF2alpha at low doses stimulates the basolateral 40-pS K channel by a NOX- and SFK-dependent mechanism, while at high concentrations, it inhibits the K channel by a PKC-dependent pathway. PMID- 28356291 TI - Slowly cycling Rho kinase-dependent actomyosin cross-bridge "slippage" explains intrinsic high compliance of detrusor smooth muscle. AB - Biological soft tissues are viscoelastic because they display time-independent pseudoelasticity and time-dependent viscosity. However, there is evidence that the bladder may also display plasticity, defined as an increase in strain that is unrecoverable unless work is done by the muscle. In the present study, an electronic lever was used to induce controlled changes in stress and strain to determine whether rabbit detrusor smooth muscle (rDSM) is best described as viscoelastic or viscoelastic plastic. Using sequential ramp loading and unloading cycles, stress-strain and stiffness-stress analyses revealed that rDSM displayed reversible viscoelasticity, and that the viscous component was responsible for establishing a high stiffness at low stresses that increased only modestly with increasing stress compared with the large increase produced when the viscosity was absent and only pseudoelasticity governed tissue behavior. The study also revealed that rDSM underwent softening correlating with plastic deformation and creep that was reversed slowly when tissues were incubated in a Ca2+-containing solution. Together, the data support a model of DSM as a viscoelastic-plastic material, with the plasticity resulting from motor protein activation. This model explains the mechanism of intrinsic bladder compliance as "slipping" cross bridges, predicts that wall tension is dependent not only on vesicle pressure and radius but also on actomyosin cross-bridge activity, and identifies a novel molecular target for compliance regulation, both physiologically and therapeutically. PMID- 28356289 TI - Sex-specific computational models of the spontaneously hypertensive rat kidneys: factors affecting nitric oxide bioavailability. AB - The goals of this study were to 1) develop a computational model of solute transport and oxygenation in the kidney of the female spontaneously hypertensive rat (SHR), and 2) apply that model to investigate sex differences in nitric oxide (NO) levels in SHR and their effects on medullary oxygenation and oxidative stress. To accomplish these goals, we first measured NO synthase (NOS) 1 and NOS3 protein expression levels in total renal microvessels of male and female SHR. We found that the expression of both NOS1 and NOS3 is higher in the renal vasculature of females compared with males. To predict the implications of that finding on medullary oxygenation and oxidative stress levels, we developed a detailed computational model of the female SHR kidney. The model was based on a published male kidney model and represents solute transport and the biochemical reactions among O2, NO, and superoxide ([Formula: see text]) in the renal medulla. Model simulations conducted using both male and female SHR kidney models predicted significant radial gradients in interstitial fluid oxygen tension (Po2) and NO and [Formula: see text] concentration in the outer medulla and upper inner medulla. The models also predicted that increases in endothelial NO-generating capacity, even when limited to specific vascular segments, may substantially raise medullary NO and Po2 levels. Other potential sex differences in SHR, including [Formula: see text] production rate, are predicted to significantly impact oxidative stress levels, but effects on NO concentration and Po2 are limited. PMID- 28356295 TI - Role of leptin in energy expenditure: the hypothalamic perspective. AB - The adipocyte-derived hormone leptin is a peripheral signal that informs the brain about the metabolic status of an organism. Although traditionally viewed as an appetite-suppressing hormone, studies in the past decade have highlighted the role of leptin in energy expenditure. Leptin has been shown to increase energy expenditure in particular through its effects on the cardiovascular system and brown adipose tissue (BAT) thermogenesis via the hypothalamus. The current review summarizes the role of leptin signaling in various hypothalamic nuclei and its effects on the sympathetic nervous system to influence blood pressure, heart rate, and BAT thermogenesis. Specifically, the role of leptin signaling on three different hypothalamic nuclei, the dorsomedial hypothalamus, the ventromedial hypothalamus, and the arcuate nucleus, is reviewed. It is known that all of these brain regions influence the sympathetic nervous system activity and thereby regulate BAT thermogenesis and the cardiovascular system. Thus the current work focuses on how leptin signaling in specific neuronal populations within these hypothalamic nuclei influences certain aspects of energy expenditure. PMID- 28356293 TI - Urinary DcR2 is a novel biomarker for tubulointerstitial injury in patients with diabetic nephropathy. AB - Tubulointerstitial injury (TII) plays a crucial role in the progression of diabetic nephropathy (DN), but lack of specific and sensitive biomarkers for monitoring TII in DN management. This study is to investigate whether urinary decoy receptor 2 (uDcR2) could serve as a novel noninvasive biomarker for assessing TII in DN. We recruited 311 type 2 diabetics and 139 DN patients who were diagnosed by renal biopsy. uDcR2 levels were measured by ELISA, and renal DcR2 expression was detected immunohistochemically. Associations between uDcR2 and renal DcR2 and renal functional parameters were evaluated. Receiver operating characteristics (ROC) curve analyzed area under the curve (AUC) of uDcR2 for assessing TII. Double staining was undertaken for renal DcR2 with proximal and distal tubular markers; senescent markers p16, p21, and senescence-associated beta-galactosidase (SA-beta-gal); and fibrotic markers collagen I and IV. We found DcR2 was primarily expressed in renal proximal tubules; uDcR2 levels were elevated per albuminuria stratum and correlated with renal functional parameters in diabetics and were associated with percentage of tubular DcR2 and TII score in DN. The uDcR2 had an AUC of 0.909 for assessing TII in DN by ROC analysis. Almost all tubular DcR2 was coexpressed with p16 and p21, and nearly more than one-half of tubular DcR2 was positive for SA-beta-gal, primarily in collagen I- and IV positive regions of DN. Our results indicate uDcR2 could potentially serve as a novel biomarker for TII and may reflect senescence of renal proximal tubular cells in DN pathogenesis. PMID- 28356297 TI - Nitric oxide-sensitive guanylyl cyclase signaling affects CO2-dependent but not pressure-dependent regulation of cerebral blood flow. AB - Cerebrovascular CO2 reactivity is affected by nitric oxide (NO). We tested the hypothesis that sildenafil selectively potentiates NO-cGMP signaling, which affects CO2 reactivity. Fourteen healthy males (34 +/- 2 yr) were enrolled in the study. Blood pressure (BP), ECG, velocity of cerebral blood flow (CBF; measured by transcranial Doppler), and end-tidal CO2 (EtCO2) were assessed at baseline (CO2 ~39 mmHg), during hyperventilation (CO2 ~24 mmHg), during hypercapnia (CO2 ~46 mmHg), during boluses of phenylephrine (25-200 ug), and during graded head-up tilting (HUT). Measurements were repeated 1 h after 100 mg sildenafil were taken. Results showed that sildenafil did not affect resting BP, heart rate, CBF peak and mean velocities, estimated regional cerebrovascular resistance (eCVR; mean BP/mean CBF), breath/min, and EtCO2: 117 +/- 2/67 +/- 3 mmHg, 69 +/- 3 beats/min, 84 +/- 5 and 57 +/- 4 cm/s, 1.56 +/- 0.1 mmHg.cm-1.s-1, 14 +/- 0.5 breaths/min, and 39 +/- 0.9 mmHg, respectively. Sildenafil increased and decreased the hypercapnia induced in CBF and eCVR, respectively. Sildenafil also attenuated the decrease in peak velocity of CBF, 25 +/- 2 vs. 20 +/- 2% (P < 0.05) and increased the eCVR, 2.5 +/- 0.2 vs. 2 +/- 0.2% (P < 0.03) during hyperventilation. Sildenafil did not affect CBF despite significant increases in the eCVRs that were elicited by phenylephrine and HUT. This investigation suggests that sildenafil, which potentiates the NO-cGMP signaling, seems to affect the cerebrovascular CO2 reactivity without affecting the static and dynamic pressure dependent mechanisms of cerebrovascular autoregulation. PMID- 28356298 TI - Activation of CB1 receptors by 2-arachidonoylglycerol attenuates vasoconstriction induced by U46619 and angiotensin II in human and rat pulmonary arteries. AB - Recent evidence suggests that endocannabinoids acting via cannabinoid CB1 receptors may modulate vascular responses of various vasoconstrictors in the rodent systemic vasculature. The aim of the study was to investigate whether endocannabinoids modulate the contractile responses evoked by a thromboxane A2 analog (U46619), angiotensin II (ANG II), serotonin (5-HT), and phenylephrine, which stimulate distinct Gq/11 protein-coupled receptors (thromboxane, ANG II type 1, 5-HT2, and alpha1-adrenergic receptors) in isolated endothelium-intact human and rat pulmonary arteries (hPAs and rPAs, respectively). The CB1 receptor antagonist AM251 (1 MUM) and diacylglycerol lipase (2-arachidonoylglycerol synthesis enzyme) inhibitor RHC80267 (40 MUM) enhanced contractions induced by U46619 in hPAs and rPAs and by ANG II in rPAs in an endothelium-dependent manner. AM251 did not influence vasoconstrictions induced by 5-HT or phenylephrine in rPAs. The monoacylglycerol lipase (2-arachidonoylglycerol degradation enzyme) inhibitor JZL184 (1 MUM), but not the fatty acid amide hydrolase (anandamide degradation enzyme) inhibitor URB597 (1 MUM), attenuated contractions evoked by U46619 in hPAs and rPAs and ANG II in rPAs. 2-Arachidonoylglycerol concentration dependently induced relaxation of hPAs, which was inhibited by endothelium denudation or AM251 and enhanced by JZL184. Expression of CB1 receptors was confirmed in hPAs and rPAs using Western blotting and immunohistochemistry. The present study shows the protective interaction between the endocannabinoid system and vasoconstriction in response to U46619 and ANG II in the human and rat pulmonary circulation. U46619 and ANG II may stimulate rapid endothelial release of endocannabinoids (mainly 2-arachidonoylglycerol), leading to CB1 receptor dependent and/or CB1 receptor-independent vasorelaxation, which in the negative feedback mechanism reduces later agonist-induced vasoconstriction. PMID- 28356292 TI - Responses of distal nephron Na+ transporters to acute volume depletion and hyperkalemia. AB - We assessed effects of acute volume reductions induced by administration of diuretics in rats. Direct block of Na+ transport produced changes in urinary electrolyte excretion. Adaptations to these effects appeared as alterations in the expression of protein for the distal nephron Na+ transporters NCC and ENaC. Two hours after a single injection of furosemide (6 mg/kg) or hydrochlorothiazide (HCTZ; 30 mg/kg) Na+ and K+ excretion increased but no changes in the content of activated forms of NCC (phosphorylated on residue T53) or ENaC (cleaved gamma subunit) were detected. In contrast, amiloride (0.6 mg/kg) evoked a similar natriuresis that coincided with decreased pT53NCC and increased cleaved gammaENaC. Alterations in posttranslational membrane protein processing correlated with an increase in plasma K+ of 0.6-0.8 mM. Decreased pT53NCC occurred within 1 h after amiloride injection, whereas changes in gammaENaC were slower and were blocked by the mineralocorticoid receptor antagonist spironolactone. Increased gammaENaC cleavage correlated with elevation of the surface expression of the subunit as assessed by in situ biotinylation. Na depletion induced by 2 h of furosemide or HCTZ treatment increases total NCC expression without affecting ENaC protein. However, restriction of Na intake for 10 h (during the day) or 18 h (overnight) increased the abundance of both total NCC and of cleaved alpha- and gammaENaC. We conclude that the kidneys respond acutely to hyperkalemic challenges by decreasing the activity of NCC while increasing that of ENaC. They respond to hypovolemia more slowly, increasing Na+ reabsorptive capacities of both of these transporters. PMID- 28356303 TI - Devi Sridhar: Governing global health. PMID- 28356296 TI - Sex-dependent effects of antenatal glucocorticoids on insulin sensitivity in adult sheep: role of the adipose tissue renin angiotensin system. AB - Exposure to glucocorticoids in utero is associated with changes in organ function and structure in the adult. The aims of this study were to characterize the effects of antenatal exposure to glucocorticoids on glucose handling and the role of adipose tissue. Pregnant sheep received betamethasone (Beta, 0.17 mg/kg) or vehicle 24 h apart at 80 days of gestation and allowed to deliver at term. At 9 mo, male and female offspring were fed at either 100% of nutritional allowance (lean) or ad libitum for 3 mo (obese). At 1 yr, they were chronically instrumented under general anesthesia. Glucose tolerance was evaluated using a bolus of glucose (0.25 g/kg). Adipose tissue was harvested after death to determine mRNA expression levels of angiotensinogen (AGT), angiotensin-converting enzyme (ACE) 1, ACE2, and peroxisome proliferator-activated receptor gamma (PPAR gamma). Data are expressed as means +/- SE and analyzed by ANOVA. Sex, obesity, and Beta exposure had significant effects on glucose tolerance and mRNA expression. Beta impaired glucose tolerance in lean females but not males. Superimposed obesity worsened the impairment in females and unmasked the defect in males. Beta increased ACE1 mRNA in females and males and AGT in females only (P < 0.05 by three-way ANOVA). Obesity increased AGT in females but had no effect on ACE1 in either males or females. PPAR-gamma mRNA exhibited a significant sex (F = 42.8; P < 0.01) and obesity (F = 6.9; P < 0.05) effect and was significantly higher in males (P < 0.01 by three-way ANOVA). We conclude that adipose tissue may play an important role in the sexually dimorphic response to antenatal glucocorticoids. PMID- 28356299 TI - Well patient, worrying thoracic magnetic resonance aortogram. PMID- 28356305 TI - Sixty seconds on . . . happiness. PMID- 28356306 TI - Effect of Age and Sex on the QTc Interval in Children and Adolescents With Type 1 and 2 Long-QT Syndrome. AB - BACKGROUND: In congenital long-QT syndrome, age, sex, and genotype have been associated with cardiac events, but their effect on the trend in QTc interval has never been established. We, therefore, aimed to assess the effect of age and sex on the QTc interval in children and adolescents with type 1 (LQT1) and type 2 (LQT2) long-QT syndrome. METHODS AND RESULTS: QTc intervals of 12-lead resting electrocardiograms were determined, and trends over time were analyzed using a linear mixed-effects model. The study included 278 patients with a median follow up of 4 years (interquartile range, 1-9) and a median number of 6 (interquartile range, 2-10) electrocardiograms per patient. Both LQT1 and LQT2 male patients showed QTc interval shortening after the onset of puberty. In LQT2 male patients, this was preceded by a progressive QTc interval prolongation. In LQT1, after the age of 12 years, male patients had a significantly shorter QTc interval than female patients. In LQT2, during the first years of life and from 14 to 26 years, male patients had a significantly shorter QTc interval than female patients. On the contrary, between 5 and 14 years, LQT2 male patients had significantly longer QTc interval than LQT2 female patients. CONCLUSIONS: There is a significant effect of age and sex on the QTc interval in long-QT syndrome, with a unique pattern per genotype. The age of 12 to 14 years is an important transitional period. In the risk stratification and management of long-QT syndrome patients, clinicians should be aware of these age-, sex-, and genotype-related trends in QTc interval and especially the important role of the onset of puberty. PMID- 28356304 TI - Erythromycin: prophylaxis against recurrent small bowel obstruction. AB - We describe three cases where erythromycin suspension has been used successfully in preventing recurrence of small bowel obstruction in patients with terminal illness and for whom it proved more effective than standard preparations such as metoclopramide and domperidone. These patients also experienced a longer term benefit over some months. With recent alerts over longer term use of metoclopramide and domperidone, we demonstrate that erythromycin is a viable alternative prokinetic in patients with terminal illness at risk of small bowel obstruction instead of or alongside metoclopramide and domperidone. More research is required to establish the point at which erythromycin should be considered in the management of symptoms. In addition, research into the possibility of a viable alternative to erythromycin is needed. PMID- 28356308 TI - What Is the Best Age for Diagnostic Prediction of Pediatric Long-QT Syndrome With a Borderline QT Interval? PMID- 28356300 TI - Reassessing Phase II Heart Failure Clinical Trials: Consensus Recommendations. AB - The increasing burden and the continued suboptimal outcomes for patients with heart failure underlines the importance of continued research to develop novel therapeutics for this disorder. This can only be accomplished with successful translation of basic science discoveries into direct human application through effective clinical trial design and execution that results in a substantially improved clinical course and outcomes. In this respect, phase II clinical trials play a pivotal role in determining which of the multitude of potential basic science discoveries should move to the large and expansive registration trials in humans. A critical examination of the phase II trials in heart failure reveals multiple shortcomings in their concept, design, execution, and interpretation. To further a dialogue on the challenges and potential for improvement and the role of phase II trials in patients with heart failure, the Food and Drug Administration facilitated a meeting on October 17, 2016, represented by clinicians, researchers, industry members, and regulators. This document summarizes the discussion from this meeting and provides key recommendations for future directions. PMID- 28356302 TI - Impact of introduction of rapid diagnostic tests for malaria on antibiotic prescribing: analysis of observational and randomised studies in public and private healthcare settings. AB - Objectives To examine the impact of use of rapid diagnostic tests for malaria on prescribing of antimicrobials, specifically antibiotics, for acute febrile illness in Africa and Asia.Design Analysisof nine preselected linked and codesigned observational and randomised studies (eight cluster or individually randomised trials and one observational study).Setting Public and private healthcare settings, 2007-13, in Afghanistan, Cameroon, Ghana, Nigeria, Tanzania, and Uganda.Participants 522 480 children and adults with acute febrile illness.Interventions Rapid diagnostic tests for malaria.Main outcome measures Proportions of patients for whom an antibiotic was prescribed in trial groups who had undergone rapid diagnostic testing compared with controls and in patients with negative test results compared with patients with positive results. A secondary aim compared classes of antibiotics prescribed in different settings.Results Antibiotics were prescribed to 127 052/238 797 (53%) patients in control groups and 167 714/283 683 (59%) patients in intervention groups. Antibiotics were prescribed to 40% (35 505/89 719) of patients with a positive test result for malaria and to 69% (39 400/57 080) of those with a negative result. All but one study showed a trend toward more antibiotic prescribing in groups who underwent rapid diagnostic tests. Random effects meta-analysis of the trials showed that the overall risk of antibiotic prescription was 21% higher (95% confidence interval 7% to 36%) in intervention settings. In most intervention settings, patients with negative test results received more antibiotic prescriptions than patients with positive results for all the most commonly used classes: penicillins, trimethoprim-sulfamethoxazole (one exception), tetracyclines, and metronidazole.Conclusions Introduction of rapid diagnostic tests for malaria to reduce unnecessary use of antimalarials-a beneficial public health outcome-could drive up untargeted use of antibiotics. That 69% of patients were prescribed antibiotics when test results were negative probably represents overprescription.This included antibiotics from several classes, including those like metronidazole that are seldom appropriate for febrile illness, across varied clinical, health system, and epidemiological settings. It is often assumed that better disease specific diagnostics will reduce antimicrobial overuse, but they might simply shift it from one antimicrobial class to another. Current global implementation of malaria testing might increase untargeted antibiotic use and must be examined. PMID- 28356294 TI - Exocytosis proteins as novel targets for diabetes prevention and/or remediation? AB - Diabetes remains one of the leading causes of morbidity and mortality worldwide, affecting an estimated 422 million adults. In the US, it is predicted that one in every three children born as of 2000 will suffer from diabetes in their lifetime. Type 2 diabetes results from combinatorial defects in pancreatic beta-cell glucose-stimulated insulin secretion and in peripheral glucose uptake. Both processes, insulin secretion and glucose uptake, are mediated by exocytosis proteins, SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complexes, Sec1/Munc18 (SM), and double C2-domain protein B (DOC2B). Increasing evidence links deficiencies in these exocytosis proteins to diabetes in rodents and humans. Given this, emerging studies aimed at restoring and/or enhancing cellular levels of certain exocytosis proteins point to promising outcomes in maintaining functional beta-cell mass and enhancing insulin sensitivity. In doing so, new evidence also shows that enhancing exocytosis protein levels may promote health span and longevity and may also harbor anti cancer and anti-Alzheimer's disease capabilities. Herein, we present a comprehensive review of the described capabilities of certain exocytosis proteins and how these might be targeted for improving metabolic dysregulation. PMID- 28356307 TI - Visualizing Localized Reentry With Ultra-High Density Mapping in Iatrogenic Atrial Tachycardia: Beware Pseudo-Reentry. AB - BACKGROUND: The activation pattern of localized reentry (LR) in atrial tachycardia remains incompletely understood. We used the ultra-high density Rhythmia mapping system to study activation patterns in LR. METHODS AND RESULTS: LR was suggested by small rotatory activations (carousels) containing the full spectrum of the color-coded map. Twenty-three left-sided atrial tachycardias were mapped in 15 patients (age: 64+/-11 years). 16 253+/-9192 points were displayed per map, collected over 26+/-14 minutes. A total of 50 carousels were identified (median 2; quartiles 1-3 per map), although this represented LR in only n=7 out of 50 (14%): here, rotation occurred around a small area of scar (<0.03 mV; 12+/ 6 mm diameter). In LR, electrograms along the carousel encompassed the full tachycardia cycle length, and surrounding activation moved away from the carousel in all directions. Ablating fractionated electrograms (117+/-18 ms; 44+/-13% of tachycardia cycle length) within the carousel interrupted the tachycardia in every LR case. All remaining carousels were pseudo-reentrant (n=43/50 [86%]) occurring in areas of wavefront collision (n=21; median 0.5; quartiles 0-2 per map) or as artifact because of annotation of noise or interpolation in areas of incomplete mapping (n=22; median 1, quartiles 0-2 per map). Pseudo-reentrant carousels were incorrectly ablated in 5 cases having been misinterpreted as LR. CONCLUSIONS: The activation pattern of LR is of small stable rotational activations (carousels), and this drove 30% (7/23) of our postablation atrial tachycardias. However, this appearance is most often pseudo-reentrant and must be differentiated by interpretation of electrograms in the candidate circuit and activation in the wider surrounding region. PMID- 28356309 TI - Arginase-II Promotes Tumor Necrosis Factor-alpha Release From Pancreatic Acinar Cells Causing beta-Cell Apoptosis in Aging. AB - Aging is associated with glucose intolerance. Arginase-II (Arg-II), the type-II L arginine-ureahydrolase, is highly expressed in pancreas. However, its role in regulation of pancreatic beta-cell function is not known. Here we show that female (not male) mice deficient in Arg-II (Arg-II-/-) are protected from age associated glucose intolerance and reveal greater glucose induced-insulin release, larger islet size and beta-cell mass, and more proliferative and less apoptotic beta-cells compared with the age-matched wild-type (WT) controls. Moreover, Arg-II is mainly expressed in acinar cells and is upregulated with aging, which enhances p38 mitogen-activated protein kinase (p38 MAPK) activation and release of tumor necrosis factor-alpha (TNF-alpha). Accordingly, conditioned medium of isolated acinar cells from old WT (not Arg-II-/-) mice contains higher TNF-alpha levels than the young mice and stimulates beta-cell apoptosis and dysfunction, which are prevented by a neutralizing anti-TNF-alpha antibody. In acinar cells, our study demonstrates an age-associated Arg-II upregulation, which promotes TNF-alpha release through p38 MAPK leading to beta-cell apoptosis, insufficient insulin secretion, and glucose intolerance in female rather than male mice. PMID- 28356310 TI - Statement of Retraction. Transcription Factor 7-Like 2 Regulates beta-Cell Survival and Function in Human Pancreatic Islets. PMID- 28356315 TI - Reporting of professional misconduct is influenced by nurses' level of education and managerial experience. PMID- 28356317 TI - Conduct and reporting of a vertebroplasty trial warrants critical examination. PMID- 28356316 TI - Targeted psychological interventions may prevent depression in children and adolescents. PMID- 28356313 TI - Phenobarbital Meets Phosphorylation of Nuclear Receptors. AB - Phenobarbital was the first therapeutic drug to be characterized for its induction of hepatic drug metabolism. Essentially at the same time, cytochrome P450, an enzyme that metabolizes drugs, was discovered. After nearly 50 years of investigation, the molecular target of phenobarbital induction has now been delineated to phosphorylation at threonine 38 of the constitutive androstane receptor (NR1I3), a member of the nuclear receptor superfamily. Determining this mechanism has provided us with the molecular basis to understand drug induction of drug metabolism and disposition. Threonine 38 is conserved as a phosphorylation motif in the majority of both mouse and human nuclear receptors, providing us with an opportunity to integrate diverse functions of nuclear receptors. Here, I review the works and accomplishments of my laboratory at the National Institutes of Health National Institute of Environmental Health Sciences and the future research directions of where our study of the constitutive androstane receptor might take us. PMID- 28356318 TI - Early invasive strategy in patients with non-ST segment elevation acute coronary syndrome delays death or MI by 18 months. PMID- 28356314 TI - High-Throughput and Reliable Isotope Label-free Approach for Profiling 24 Metabolic Enzymes in FVB Mice and Sex Differences. AB - FVB mice are extensively used in transgenic and pharmacokinetic research. In this study, a validated isotope label-free method was constructed using ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) to quantify 24 drug-metabolizing enzymes (DMEs) in FVB mice. The DMEs include cytochrome P450s (CYP450s/Cyp450s), UDP-glucuronsyltransferases (UGTs/Ugts), and sulfotransferases (SULTs/Sults), which catalyze a variety of reactions to detoxify xenobiotics and endobiotics. The proposed UHPLC-MS/MS method exhibited good range and high sensitivity for signature peptides, as well as acceptable accuracy, precision, and recovery. The protein expression profiles of the DMEs were determined in male and female mice. Overall, the major Cyps, Ugts, and Sults were expressed in male mice followed the rank order: Cyp2c29 > 2e1 > 3a11 > 1a2 > 2d22 > 27a1 > 2c39; Ugt2b5 > 2b1 > 1a6a > 1a9 > 1a1 > 2a3 > 1a2 > 1a5; and Sult1a1 > 3a > 1d1. In contrast, the rank order in female mice was Cyp2c29 > 2e1 > 2c39 > 2d22 > 3a11 > 1a2 > 27a1; Ugt1a6a > 2b5 > 1a1 > 2b1 > 2a3 > 1a9 > 1a5 > 1a2; and Sult1a1 > 3a1 > 1d1. Cyp2c29, Cyp1a2, Cyp27a1, Ugt2b1, Ugt2b5 and Ugt2b36 were male predominant, whereas Cyp2c39, Cyp2d22, Cyp7a1, Ugt1a1, Ugt1a5, Sult1a1, Sult3a1, and Sult1d1 were female predominant. This work could serve as a useful reference for the metabolic study of new drugs and for elucidating the effectiveness and toxicity of drugs. The method is stable, simple, and rapid for determining the expression of DMEs in animals. PMID- 28356319 TI - Fast-Acting Insulin Aspart Improves Glycemic Control in Basal-Bolus Treatment for Type 1 Diabetes: Results of a 26-Week Multicenter, Active-Controlled, Treat-to Target, Randomized, Parallel-Group Trial (onset 1). AB - OBJECTIVE: This multicenter, treat-to-target, phase 3 trial evaluated the efficacy and safety of fast-acting insulin aspart (faster aspart) versus conventional insulin aspart (IAsp) in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS: The primary end point was change from baseline in HbA1c after 26 weeks. After an 8-week run-in, subjects were randomized (1:1:1) to double blind mealtime faster aspart (n = 381), IAsp (n = 380), or open-label postmeal faster aspart (n = 382)-each with insulin detemir. RESULTS: HbA1c was reduced in both treatment groups, and noninferiority to IAsp was confirmed for both mealtime and postmeal faster aspart (estimated treatment difference [ETD] faster aspart IAsp, mealtime, -0.15% [95% CI -0.23; -0.07], and postmeal, 0.04% [-0.04; 0.12]); mealtime faster aspart statistically significantly reduced HbA1c versus IAsp (P = 0.0003). Postprandial plasma glucose (PPG) increments were statistically significantly lower with mealtime faster aspart at 1 h (ETD -1.18 mmol/L [95% CI 1.65; -0.71], -21.21 mg/dL [-29.65; -12.77]; P < 0.0001) and 2 h (-0.67 mmol/L [ 1.29; -0.04], -12.01 mg/dL [-23.33; -0.70]; P = 0.0375) after the meal test; superiority to IAsp for the 2-h PPG increment was confirmed. The overall rate of severe or blood glucose-confirmed (plasma glucose <3.1 mmol/L [56 mg/dL]) hypoglycemic episodes and safety profiles were similar between treatments. CONCLUSIONS: Faster aspart effectively improved HbA1c, and noninferiority to IAsp was confirmed, with superior PPG control for mealtime faster aspart versus IAsp. Subjects randomized to postmeal faster aspart for all meals maintained HbA1c noninferior to that obtained with mealtime IAsp. PMID- 28356320 TI - Risk Adjustment, Reinsurance Improved Financial Outcomes For Individual Market Insurers With The Highest Claims. AB - The Affordable Care Act (ACA) reformed the individual health insurance market. Because insurers can no longer vary their offers of coverage based on applicants' health status, the ACA established a risk adjustment program to equalize health related cost differences across plans. The ACA also established a temporary reinsurance program to subsidize high-cost claims. To assess the impact of these programs, we compared revenues to claims costs for insurers in the individual market during the first two years of ACA implementation (2014 and 2015), before and after the inclusion of risk adjustment and reinsurance payments. Before these payments were included, for the 30 percent of insurers with the highest claims costs, claims (not including administrative expenses) exceeded premium revenues by $90-$397 per enrollee per month. The effect was reversed after these payments were included, with revenues exceeding claims costs by $0-$49 per month. The risk adjustment and reinsurance programs were relatively well targeted in the first two years. While there is ongoing discussion regarding the future of the ACA, our findings can shed light on how risk-sharing programs can address risk selection among insurers-a pervasive issue in all health insurance markets. PMID- 28356312 TI - An intranasally delivered peptide drug ameliorates cognitive decline in Alzheimer transgenic mice. AB - Alzheimer's disease (AD) is the most common neurodegenerative disease. Imbalance between the production and clearance of amyloid beta (Abeta) peptides is considered to be the primary mechanism of AD pathogenesis. This amyloid hypothesis is supported by the recent success of the human anti-amyloid antibody aducanumab, in clearing plaque and slowing clinical impairment in prodromal or mild patients in a phase Ib trial. Here, a peptide combining polyarginines (polyR) (for charge repulsion) and a segment derived from the core region of Abeta amyloid (for sequence recognition) was designed. The efficacy of the designed peptide, R8-Abeta(25-35), on amyloid reduction and the improvement of cognitive functions were evaluated using APP/PS1 double transgenic mice. Daily intranasal administration of PEI-conjugated R8-Abeta(25-35) peptide significantly reduced Abeta amyloid accumulation and ameliorated the memory deficits of the transgenic mice. Intranasal administration is a feasible route for peptide delivery. The modular design combining polyR and aggregate-forming segments produced a desirable therapeutic effect and could be easily adopted to design therapeutic peptides for other proteinaceous aggregate-associated diseases. PMID- 28356311 TI - Regulation of Brn3b by DLX1 and DLX2 is required for retinal ganglion cell differentiation in the vertebrate retina. AB - Regulated retinal ganglion cell (RGC) differentiation and axonal guidance is required for a functional visual system. Homeodomain and basic helix-loop-helix transcription factors are required for retinogenesis, as well as patterning, differentiation and maintenance of specific retinal cell types. We hypothesized that Dlx1, Dlx2 and Brn3b homeobox genes function in parallel intrinsic pathways to determine RGC fate and therefore generated Dlx1/Dlx2/Brn3b triple-knockout mice. A more severe retinal phenotype was found in the Dlx1/Dlx2/Brn3b-null retinas than was predicted by combining features of the Brn3b single- and Dlx1/Dlx2 double-knockout retinas, including near total RGC loss with a marked increase in amacrine cells in the ganglion cell layer. Furthermore, we discovered that DLX1 and DLX2 function as direct transcriptional activators of Brn3b expression. Knockdown of Dlx2 expression in primary embryonic retinal cultures and Dlx2 gain of function in utero strongly support that DLX2 is both necessary and sufficient for Brn3b expression in vivo We suggest that ATOH7 specifies RGC committed progenitors and that Dlx1 and Dlx2 function both downstream of ATOH7 and in parallel, but cooperative, pathways that involve regulation of Brn3b expression to determine RGC fate. PMID- 28356323 TI - Bacterial and Fungal Endophthalmitis. AB - Endophthalmitis is a severe eye infection that may result in permanent loss of useful vision in the affected eye. Most cases are exogenous and occur as a complication of cataract surgery, an intravitreal injection, or penetrating ocular trauma. Endogenous endophthalmitis results from hematogenous seeding of the eye by bacteria or fungi, but bacteremia or fungemia may be transient and patients may present without symptoms of systemic infection. Nearly all endophthalmitis patients present with decreased vision, and some also have eye pain. Eye examination usually reveals a hypopyon and intraocular inflammation. Diagnosis is clinical, supported by cultures of the vitreous and/or aqueous or by blood cultures in some endogenous cases. Molecular diagnostic techniques have been used in research laboratories for pathogen identification in endophthalmitis and offer the possibility of rapid diagnosis, including in culture-negative cases. Intravitreal injection of antibiotics is the most important component of treatment; some cases also benefit from surgical debridement of the vitreous by a vitrectomy. The visual outcome depends partly on the pathogen: coagulase-negative staphylococcal endophthalmitis has a better prognosis than does streptococcal endophthalmitis, for example. Endophthalmitis is a medical emergency, and prompt diagnosis and treatment are essential for saving vision. PMID- 28356322 TI - Mechanisms of precise genome editing using oligonucleotide donors. AB - The use of programmable meganucleases is transforming genome editing and functional genomics. CRISPR/Cas9 was developed such that targeted genomic lesions could be introduced in vivo with unprecedented ease. In the presence of homology donors, these lesions facilitate high-efficiency precise genome editing (PGE) via homology-directed repair (HDR) pathways. However, the identity and hierarchy of the HDR (sub)pathways leading to the formation of PGE products remain elusive. Here, we established a green to blue fluorescent protein conversion system to systematically characterize oligodeoxynucleotide (ODN)-mediated PGE using Cas9 and its nickase variants in human cells. We demonstrate that, unlike double stranded DNA (dsDNA) donors with central heterologies, ODNs generated short conversion tracts with Gaussian-like distributions. Interestingly, single-nick induced PGE using ODN donors produced conversion tracts biased either mostly uni- or bidirectional depending on the relative strandedness of the ODNs and the nick. Moreover, the ODNs were physically incorporated into the genome only in the bidirectional, but not in the unidirectional, conversion pathway. In the presence of double-stranded genomic lesions, the unidirectional conversion pathway was preferentially utilized even though the knock-in mutation could theoretically have been converted by both pathways. Collectively, our results suggest that ODN mediated PGE utilizes synthesis-dependent strand annealing and single-stranded DNA incorporation pathways. Both of these pathways generate short conversion tracts with Gaussian-like distributions. Although synthesis-dependent strand annealing is preferentially utilized, our work unequivocally establishes the existence of a single-stranded DNA incorporation pathway in human cells. This work extends the paradigms of HDR-mediated gene conversion and establishes guidelines for PGE in human cells. PMID- 28356328 TI - Technology versus biology: the limits of pre-implantation genetic screening: Better methods to detect the origin of aneuploidy in pre-implantation embryos could improve the success rate of artificial reproduction. PMID- 28356326 TI - Caenorhabditis elegans oocytes detect meiotic errors in the absence of canonical end-on kinetochore attachments. AB - Mitotically dividing cells use a surveillance mechanism, the spindle assembly checkpoint, that monitors the attachment of spindle microtubules to kinetochores as a means of detecting errors. However, end-on kinetochore attachments have not been observed in Caenorhabditis elegans oocytes and chromosomes instead associate with lateral microtubule bundles; whether errors can be sensed in this context is not known. Here, we show that C. elegans oocytes delay key events in anaphase, including AIR-2/Aurora B relocalization to the microtubules, in response to a variety of meiotic defects, demonstrating that errors can be detected in these cells and revealing a mechanism that regulates anaphase progression. This mechanism does not appear to rely on several components of the spindle assembly checkpoint but does require the kinetochore, as depleting kinetochore components prevents the error-induced anaphase delays. These findings therefore suggest that in this system, kinetochores could be involved in sensing meiotic errors using an unconventional mechanism that does not use canonical end-on attachments. PMID- 28356324 TI - Insulin-regulated aminopeptidase inhibitors do not alter glucose handling in normal and diabetic rats. AB - Insulin-regulated aminopeptidase (IRAP) co-localizes with the glucose transporter 4 (GLUT4) in GLUT4 storage vesicles (GSV) in insulin-responsive cells. In response to insulin, IRAP is the only transmembrane enzyme known to translocate together with GLUT4 to the plasma membrane in adipocytes and muscle cells. Although the intracellular region of IRAP is associated with GLUT4 vesicle trafficking, the role of the aminopeptidase activity in insulin-responsive cells has not been elucidated. The aim of this study was to investigate whether the inhibition of the aminopeptidase activity of IRAP facilitates glucose uptake in insulin-responsive cells. In both in vitro and in vivo studies, inhibition of IRAP aminopeptidase activity with the specific inhibitor, HFI-419, did not modulate glucose uptake. IRAP inhibition in the L6GLUT4myc cell line did not alter glucose uptake in both basal and insulin-stimulated state. In keeping with these results, HFI419 did not affect peripheral, whole-body glucose handling after an oral glucose challenge, neither in normal rats nor in the streptozotocin (STZ)-induced experimental rat model of diabetes mellitus (DM). Therefore, acute inhibition of IRAP aminopeptidase activity does not affect glucose homeostasis. PMID- 28356321 TI - Transcriptional regulatory dynamics drive coordinated metabolic and neural response to social challenge in mice. AB - Agonistic encounters are powerful effectors of future behavior, and the ability to learn from this type of social challenge is an essential adaptive trait. We recently identified a conserved transcriptional program defining the response to social challenge across animal species, highly enriched in transcription factor (TF), energy metabolism, and developmental signaling genes. To understand the trajectory of this program and to uncover the most important regulatory influences controlling this response, we integrated gene expression data with the chromatin landscape in the hypothalamus, frontal cortex, and amygdala of socially challenged mice over time. The expression data revealed a complex spatiotemporal patterning of events starting with neural signaling molecules in the frontal cortex and ending in the modulation of developmental factors in the amygdala and hypothalamus, underpinned by a systems-wide shift in expression of energy metabolism-related genes. The transcriptional signals were correlated with significant shifts in chromatin accessibility and a network of challenge associated TFs. Among these, the conserved metabolic and developmental regulator ESRRA was highlighted for an especially early and important regulatory role. Cell type deconvolution analysis attributed the differential metabolic and developmental signals in this social context primarily to oligodendrocytes and neurons, respectively, and we show that ESRRA is expressed in both cell types. Localizing ESRRA binding sites in cortical chromatin, we show that this nuclear receptor binds both differentially expressed energy-related and neurodevelopmental TF genes. These data link metabolic and neurodevelopmental signaling to social challenge, and identify key regulatory drivers of this process with unprecedented tissue and temporal resolution. PMID- 28356325 TI - Return on investment of public health interventions: a systematic review. AB - BACKGROUND: Public sector austerity measures in many high-income countries mean that public health budgets are reducing year on year. To help inform the potential impact of these proposed disinvestments in public health, we set out to determine the return on investment (ROI) from a range of existing public health interventions. METHODS: We conducted systematic searches on all relevant databases (including MEDLINE; EMBASE; CINAHL; AMED; PubMed, Cochrane and Scopus) to identify studies that calculated a ROI or cost-benefit ratio (CBR) for public health interventions in high-income countries. RESULTS: We identified 2957 titles, and included 52 studies. The median ROI for public health interventions was 14.3 to 1, and median CBR was 8.3. The median ROI for all 29 local public health interventions was 4.1 to 1, and median CBR was 10.3. Even larger benefits were reported in 28 studies analysing nationwide public health interventions; the median ROI was 27.2, and median CBR was 17.5. CONCLUSIONS: This systematic review suggests that local and national public health interventions are highly cost saving. Cuts to public health budgets in high income countries therefore represent a false economy, and are likely to generate billions of pounds of additional costs to health services and the wider economy. PMID- 28356327 TI - The crossover conformational shift of the GTPase atlastin provides the energy driving ER fusion. AB - The homotypic fusion of endoplasmic reticulum membranes is catalyzed by the atlastin GTPase. The mechanism involves trans-dimerization between GTPase heads and a favorable crossover conformational shift, catalyzed by GTP hydrolysis, that converts the dimer from a "prefusion" to "postfusion" state. However, whether crossover formation actually energizes fusion remains unclear, as do the sequence of events surrounding it. Here, we made mutations in atlastin to selectively destabilize the crossover conformation and used fluorescence-based kinetic assays to analyze the variants. All variants underwent dimerization and crossover concurrently, and at wild-type rates. However, certain variants were unstable once in the crossover dimer conformation, and crossover dimer stability closely paralleled lipid-mixing activity. Tethering, however, appeared to be unimpaired in all mutant variants. The results suggest that tethering and lipid mixing are catalyzed concurrently by GTP hydrolysis but that the energy requirement for lipid mixing exceeds that for tethering, and the full energy released through crossover formation is necessary for fusion. PMID- 28356329 TI - Effectors of Filamentous Plant Pathogens: Commonalities amid Diversity. AB - Fungi and oomycetes are filamentous microorganisms that include a diversity of highly developed pathogens of plants. These are sophisticated modulators of plant processes that secrete an arsenal of effector proteins to target multiple host cell compartments and enable parasitic infection. Genome sequencing revealed complex catalogues of effectors of filamentous pathogens, with some species harboring hundreds of effector genes. Although a large fraction of these effector genes encode secreted proteins with weak or no sequence similarity to known proteins, structural studies have revealed unexpected similarities amid the diversity. This article reviews progress in our understanding of effector structure and function in light of these new insights. We conclude that there is emerging evidence for multiple pathways of evolution of effectors of filamentous plant pathogens but that some families have probably expanded from a common ancestor by duplication and diversification. Conserved folds, such as the oomycete WY and the fungal MAX domains, are not predictive of the precise function of the effectors but serve as a chassis to support protein structural integrity while providing enough plasticity for the effectors to bind different host proteins and evolve unrelated activities inside host cells. Further effector evolution and diversification arise via short linear motifs, domain integration and duplications, and oligomerization. PMID- 28356334 TI - Clinical Applications of Circulating Tumor Cells in Pharmacotherapy: Challenges and Perspectives. AB - Screening for circulating tumor cells (CTCs) has been identified as one approach to ultrasensitive liquid biopsy in real-time monitoring of cancer patients. The detection of CTCs in peripheral blood from cancer patients is promising as a diagnostic tool; however, the application of CTCs in therapeutic treatment still faces serious challenges with respect to specificity and sensitivity. Here, we review the significant roles of CTCs in metastasis and the strengths and weaknesses of the currently available methods for CTC detection and characterization. Moreover, we discuss the clinical application of CTCs as markers for patient prognosis, and we specifically focus on the application of CTCs as indicators in cancer pharmacotherapy. Characterization of the detected CTCs will provide new biologic perspectives and clinical applications for the treatment of cancer patients with metastasis. PMID- 28356333 TI - Patients' reports of adverse events: a data linkage study of Australian adults aged 45 years and over. AB - BACKGROUND: Understanding a patient's hospital experience is fundamental to improving health services and policy, yet, little is known about their experiences of adverse events (AEs). This study redresses this deficit by investigating the experiences of patients in New South Wales hospitals who suffered an AE. METHODS: Data linkage was used to identify a random sample of 20 000 participants in the 45 and Up Cohort Study, out of 267 153 adults aged 45 years and over, who had been hospitalised in the prior 6 months. A cross sectional survey was administered to these patients to capture their experiences, including whether they had an AE and received honest communication about it. RESULTS: Of the 18 993 eligible participants, 7661 completed surveys were received (40% response rate) and 474 (7%) reported having an AE. Most AEs related to clinical processes and procedures (33%), or medications and intravenous fluids (21%). Country of birth and admission through emergency were significant predictors of the occurrence of an event. An earlier admission in the prior 6 months or a transfer to another healthcare facility was also associated with more AEs. Of those who suffered an AE, 58% reported serious or moderate effects. CONCLUSIONS: Given the exclusions in our sample population (under 45 years), the AE rate reported by patients of 7% is similar to the approximately 10% rate reported in the general population by retrospective medical record reviews. AE data that include patient experience may provide contextual information currently missing. Capturing and using patient experience data more effectively is critical; there may be opportunities for applying co-design methodology to improve the management of AEs and be more responsive to patients' concerns. PMID- 28356332 TI - Occupational exposure and amyotrophic lateral sclerosis in a prospective cohort. AB - OBJECTIVE: To prospectively study suspected occupational risk factors for amyotrophic lateral sclerosis (ALS). METHODS: For this case-cohort analysis within the prospective Netherlands Cohort Study, 58 279 men and 62 573 women aged 55-69 years at enrolment in 1986 were followed up for 17.3 years on ALS mortality. Information on occupational history and potential confounders were collected at baseline through a self-administered questionnaire and entered for a random subcohort (2092 men and 2074 women) and ALS deaths (76 men and 60 women). Occupational exposure to solvents, pesticides, metals, extremely low frequency magnetic fields (ELF-MFs) and electrical shocks was estimated by means of job exposure matrices (JEMs). Associations between ever/never occupationally exposed and cumulative exposure and ALS mortality were analysed by gender using Cox regression. RESULTS: Occupational exposure to ELF-MF showed a possible association with ALS mortality among men: HR for ever holding a job with high exposure versus background 2.19 (95% (CI): 1.02 to 4.73) and HR for the highest tertile of cumulative exposure versus background 1.93 (95% CI 1.05 to 3.55). INTERPRETATION: These results strengthen the evidence suggesting a positive association between ELF-MF exposure and ALS. We did not replicate earlier positive findings for other occupational exposures. PMID- 28356331 TI - DNA Damage Induces a Secretory Program in the Quiescent TME that Fosters Adverse Cancer Phenotypes. AB - Carcinomas develop in complex environments that include a diverse spectrum of cell types that influence tumor cell behavior. These microenvironments represent dynamic systems that contribute to pathologic processes. Damage to DNA is a notable inducer of both transient and permanent alterations in cellular phenotypes. Induction of a DNA damage secretory program is known to promote adverse tumor cell behaviors such as proliferation, invasion, metastasis, and treatment resistance. However, prior studies designed to identify genotoxic stress-induced factors evaluated actively proliferating in vitro cultures of cells such as fibroblasts as experimental models. Conversely, the vast majority of benign cells in a typical tumor microenvironment (TME) are not proliferating but rather exist in quiescent (i.e., G0) or in terminally differentiated states. In this study, the diversity and magnitude of transcriptional responses to genotoxic damage in quiescent prostate fibroblasts were assessed using gene expression profiling. The secretory damage response in quiescent cells was highly concordant with that of actively dividing cells. Quiescent human prostate stroma exposed to genotoxic agents (e.g., mitoxantrone) in vivo resulted in significant upregulation (2.7- to 5.7-fold; P <= 0.01) of growth factors and cytokines including IL1beta, MMP3, IL6, and IL8. The paracrine effects of damaged quiescent cells consistently increased the proliferation and invasion of prostate cancer cells and promoted cell survival and resistance to apoptosis following exposure to chemotherapy.Implications: Benign quiescent cells in the TME respond to genotoxic stress by inducing a secretory program capable of promoting therapy resistance. Developing approaches to suppress the secretory program may improve treatment responses. Mol Cancer Res; 15(7); 842-51. (c)2017 AACR. PMID- 28356336 TI - Near-Infrared Fluorescence Lymphatic Imaging of a Toddler With Congenital Lymphedema. AB - Primary lymphedema in the pediatric population remains poorly diagnosed and misunderstood due to a lack of information on the causation and underlying anatomy of the lymphatic system. Consequently, therapeutic protocols for pediatric patients remain sparse and with little evidence to support them. In an effort to better understand the causation of primary pediatric lymphedema and to better inform clinical care, we report the use of near-infrared fluorescence lymphatic imaging on the extremities of an alert, 21-month-old boy who presented with unilateral right arm and hand lymphedema at birth. The imaging results indicated an intact, apparently normal lymphatic anatomy with no obvious malformation, but with decreased lymphatic contractile function of the affected upper extremity relative to the contralateral and lower extremities. We hypothesized that the lack of contraction of the lymphatic vessels rather than an anatomic malformation was the source of the unilateral extremity swelling, and that compression and manual lymphatic drainage could be effective treatments. PMID- 28356335 TI - Childhood Adiposity and Nonalcoholic Fatty Liver Disease in Adulthood. AB - OBJECTIVE: To investigate the association of childhood adiposity and change in adiposity status from childhood to adulthood with nonalcoholic fatty liver disease (NAFLD) and abnormal liver enzyme levels in adulthood. METHODS: Data were obtained from a population-based cohort of children aged 6 to 18 years started in 1987. From 2010 to 2014, 1350 subjects (aged 28-45 years) from the original cohort were followed. Childhood overweight and obesity were defined using BMI and subscapular skinfold thickness, respectively. In adulthood, ultrasound-based NAFLD, abnormal liver enzymes, and related risk factors were assessed. RESULTS: Overweight or obese children were more likely to have adult NAFLD (males: odds ratio [OR] = 2.49 for BMI and 2.78 for subscapular skinfold thickness; females: OR = 3.34 and 3.61; all Ps < .001) and alanine aminotransferase (ALT) elevation (males: OR = 1.64 and 1.66; females: OR = 2.12 and 3.01; all Ps < .05) than children with normal weight for both sexes. Compared with subjects who had normal weight in childhood and were nonobese in adulthood, subjects who were obese in adulthood, irrespective of their childhood adiposity status, were more likely to have NAFLD and ALT elevation in adulthood for both sexes. However, subjects who were overweight or obese in childhood but became nonobese in adulthood had similar likelihood of having NAFLD and ALT elevation in adulthood for both sexes. CONCLUSIONS: Overweight or obese children are more likely to have NAFLD and ALT elevation in adulthood. However, the risk associated with increased weight during childhood can be mitigated by becoming nonobese in adulthood. PMID- 28356330 TI - Cancer Immunotherapy: Whence and Whither. AB - The current concepts and practice of cancer immunotherapy evolved from classical experiments that distinguished "self" from "non-self" and the finding that humoral immunity is complemented by cellular immunity. Elucidation of the biology underlying immune checkpoints and interactions between ligands and ligand receptors that govern the immune system's ability to recognize tumor cells as foreign has led to the emergence of new strategies that mobilize the immune system to reverse this apparent tolerance. Some of these approaches have led to new therapies such as the use of mAbs to interfere with the immune checkpoint. Others have exploited molecular technologies to reengineer a subset of T cells to directly engage and kill tumor cells, particularly those of B-cell malignancies. However, before immunotherapy can become a more effective method of cancer care, there are many challenges that remain to be addressed and hurdles to overcome. Included are manipulation of tumor microenvironment (TME) to enhance T effector cell infiltration and access to the tumor, augmentation of tumor MHC expression for adequate presentation of tumor associated antigens, regulation of cytokines and their potential adverse effects, and reduced risk of secondary malignancies as a consequence of mutations generated by the various forms of genetic engineering of immune cells. Despite these challenges, the future of immunotherapy as a standard anticancer therapy is encouraging. Mol Cancer Res; 15(6); 635-50. (c)2017 AACR. PMID- 28356338 TI - Time-Varying Association of Individual BP Components with eGFR in Late-Stage CKD. AB - BACKGROUND AND OBJECTIVES: The association of individual BP components with changes in eGFR in patients with late-stage CKD is unknown. The objectives of our study were to examine the associations of systolic BP, diastolic BP, and pulse pressure with continuous temporal changes in eGFR and an eGFR decline >=30% in late-stage CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a retrospective cohort study (2010-2015) of patients with CKD in a multidisciplinary CKD clinic with an eGFR<=30. The associations of repeat measures of BP (systolic BP, diastolic BP, and pulse pressure) with eGFR were examined using general linear mixed models. The associations of BP components and eGFR decline >=30% were examined with time-varying Cox models. RESULTS: In total, 1203 patients were followed for a median of 548 days (interquartile range, 292 913), with an average of 6.7 visits and BP measures per patient. Mean baseline systolic BP, diastolic BP, pulse pressure, and eGFR were 139.2 mmHg, 73.2 mmHg, 64.9 mmHg, and 16.8 ml/min, respectively. Systolic BP and diastolic BP measures over time were statistically significantly associated with changes in eGFR (P<0.001), whereas pulse pressure was not. Patients with extremes of systolic BP (<105 or >170) and high diastolic BP (>90) measures were at a higher risk of GFR decline >=30% (systolic BP <105: hazard ratio, 1.51; 95% confidence interval, 0.98 to 2.34; systolic BP >170: hazard ratio, 1.62; 95% confidence interval, 1.05 to 2.49; referent systolic BP =121-130; diastolic BP =81-90: hazard ratio, 1.40; 95% confidence interval, 0.99 to 1.86; diastolic BP >90: hazard ratio, 1.83; 95% confidence interval, 1.21 to 2.77; referent diastolic BP =61-70). The findings were consistent after multiple sensitivity analyses. Pulse pressure was not significantly associated with risk of eGFR decline. CONCLUSIONS: In patients referred to a multidisciplinary care clinic with late-stage CKD, only extremes of systolic BP and elevations of diastolic BP were associated with eGFR decline. PMID- 28356342 TI - Widespread changes in nucleosome accessibility without changes in nucleosome occupancy during a rapid transcriptional induction. AB - Activation of transcription requires alteration of chromatin by complexes that increase the accessibility of nucleosomal DNA. Removing nucleosomes from regulatory sequences has been proposed to play a significant role in activation. We tested whether changes in nucleosome occupancy occurred on the set of genes that is activated by the unfolded protein response (UPR). We observed no decrease in occupancy on most promoters, gene bodies, and enhancers. Instead, there was an increase in the accessibility of nucleosomes, as measured by micrococcal nuclease (MNase) digestion and ATAC-seq (assay for transposase-accessible chromatin [ATAC] using sequencing), that did not result from removal of the nucleosome. Thus, changes in nucleosome accessibility predominate over changes in nucleosome occupancy during rapid transcriptional induction during the UPR. PMID- 28356337 TI - "Maybe They Don't Even Know That I Exist": Challenges Faced by Family Members and Friends of Patients with Advanced Kidney Disease. AB - BACKGROUND AND OBJECTIVES: Family members and friends of patients with advanced chronic illness are increasingly called on to assist with ever more complex medical care and treatment decisions arising late in the course of illness. Our goal was to learn about the experiences of family members and friends of patients with advanced kidney disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: As part of a study intended to identify opportunities to enhance advance care planning, we conducted semistructured interviews at the Veterans Affairs Puget Sound Health Care System with 17 family members and friends of patients with advanced kidney disease. Interviews were conducted between April of 2014 and May of 2016 and were audiotaped, transcribed, and analyzed inductively using grounded theory to identify emergent themes. RESULTS: The following three themes emerged from interviews with patients' family members and friends: (1) their roles in care and planning were fluid over the course of the patient's illness, shaped by the patients' changing needs and their readiness to involve those close to them; (2) their involvement in patients' care was strongly shaped by health care system needs. Family and friends described filling gaps left by the health care system and how their involvement in care and decision-making was at times constrained and at other times expected by providers, depending on system needs; and (3) they described multiple sources of tension and conflict in their interactions with patients and the health care system, including instances of being pitted against the patient. CONCLUSIONS: Interviews with family members and friends of patients with advanced kidney disease provide a window on the complex dynamics shaping their engagement in patients' care, and highlight the potential value of offering opportunities for engagement throughout the course of illness. PMID- 28356340 TI - Analysis of Cardiac Myocyte Maturation Using CASAAV, a Platform for Rapid Dissection of Cardiac Myocyte Gene Function In Vivo. AB - RATIONALE: Loss-of-function studies in cardiac myocytes (CMs) are currently limited by the need for appropriate conditional knockout alleles. The factors that regulate CM maturation are poorly understood. Previous studies on CM maturation have been confounded by heart dysfunction caused by whole organ gene inactivation. OBJECTIVE: To develop a new technical platform to rapidly characterize cell-autonomous gene function in postnatal murine CMs and apply it to identify genes that regulate transverse tubules (T-tubules), a hallmark of mature CMs. METHODS AND RESULTS: We developed CRISPR/Cas9/AAV9-based somatic mutagenesis, a platform in which AAV9 delivers tandem guide RNAs targeting a gene of interest and cardiac troponin-T promoter-driven Cre to RosaCas9GFP/Cas9GFP neonatal mice. When directed against junctophilin-2 (Jph2), a gene previously implicated in T-tubule maturation, we achieved efficient, rapid, and CM-specific JPH2 depletion. High-dose AAV9 ablated JPH2 in 64% CMs and caused lethal heart failure, whereas low-dose AAV9 ablated JPH2 in 22% CMs and preserved normal heart function. In the context of preserved heart function, CMs lacking JPH2 developed T-tubules that were nearly morphologically normal, indicating that JPH2 does not have a major, cell-autonomous role in T-tubule maturation. However, in hearts with severe dysfunction, both adeno-associated virus-transduced and nontransduced CMs exhibited T-tubule disruption, which was more severe in the transduced subset. These data indicate that cardiac dysfunction disrupts T-tubule structure and that JPH2 protects T-tubules in this context. We then used CRISPR/Cas9/AAV9 based somatic mutagenesis to screen 8 additional genes for required, cell autonomous roles in T-tubule formation. We identified RYR2 (Ryanodine Receptor-2) as a novel, cell-autonomously required T-tubule maturation factor. CONCLUSIONS: CRISPR/Cas9/AAV9-based somatic mutagenesis is a powerful tool to study cell autonomous gene functions. Genetic mosaics are invaluable to accurately define cell-autonomous gene function. JPH2 has a minor role in normal T-tubule maturation but is required to stabilize T-tubules in the failing heart. RYR2 is a novel T-tubule maturation factor. PMID- 28356343 TI - Targeted deletion of Kcne3 impairs skeletal muscle function in mice. AB - KCNE3 (MiRP2) forms heteromeric voltage-gated K+ channels with the skeletal muscle-expressed KCNC4 (Kv3.4) alpha subunit. KCNE3 was the first reported skeletal muscle K+ channel disease gene, but the requirement for KCNE3 in skeletal muscle has been questioned. Here, we confirmed KCNE3 transcript and protein expression in mouse skeletal muscle using Kcne3-/- tissue as a negative control. Whole-transcript microarray analysis (770,317 probes, interrogating 28,853 transcripts) findings were consistent with Kcne3 deletion increasing gastrocnemius oxidative metabolic gene expression and the proportion of type IIa fast-twitch oxidative muscle fibers, which was verified using immunofluorescence. The down-regulated transcript set overlapped with muscle unloading gene expression profiles (>=1.5-fold change; P < 0.05). Gastrocnemius K+ channel alpha subunit remodeling arising from Kcne3 deletion was highly specific, involving just 3 of 69 alpha subunit genes probed: known KCNE3 partners KCNC4 and KCNH2 (mERG) were down-regulated, and KCNK4 (TRAAK) was up-regulated (P < 0.05). Functionally, Kcne3-/- mice exhibited abnormal hind-limb clasping upon tail suspension (63% of Kcne3-/- mice >=10-mo-old vs. 0% age-matched Kcne3+/+ littermates). Whereas 5 of 5 Kcne3+/+ mice exhibited the typical biphasic decline in contractile force with repetitive stimuli of hind-limb muscle, both in vivo and in vitro, this was absent in 6 of 6 Kcne3-/- mice tested. Finally, myoblasts isolated from Kcne3-/- mice exhibit faster-inactivating and smaller sustained outward currents than those from Kcne3+/+ mice. Thus, Kcne3 deletion impairs skeletal muscle function in mice.-King, E. C., Patel, V., Anand, M., Zhao, X., Crump, S. M., Hu, Z., Weisleder, N., Abbott, G. W. Targeted deletion of Kcne3 impairs skeletal muscle function in mice. PMID- 28356339 TI - Nicotinamide Phosphoribosyltransferase in Smooth Muscle Cells Maintains Genome Integrity, Resists Aortic Medial Degeneration, and Is Suppressed in Human Thoracic Aortic Aneurysm Disease. AB - RATIONALE: The thoracic aortic wall can degenerate over time with catastrophic consequences. Vascular smooth muscle cells (SMCs) can resist and repair artery damage, but their capacities decline with age and stress. Recently, cellular production of nicotinamide adenine dinucleotide (NAD+) via nicotinamide phosphoribosyltransferase (Nampt) has emerged as a mediator of cell vitality. However, a role for Nampt in aortic SMCs in vivo is unknown. OBJECTIVES: To determine whether a Nampt-NAD+ control system exists within the aortic media and is required for aortic health. METHODS AND RESULTS: Ascending aortas from patients with dilated aortopathy were immunostained for NAMPT, revealing an inverse relationship between SMC NAMPT content and aortic diameter. To determine whether a Nampt-NAD+ control system in SMCs impacts aortic integrity, mice with Nampt-deficient SMCs were generated. SMC-Nampt knockout mice were viable but with mildly dilated aortas that had a 43% reduction in NAD+ in the media. Infusion of angiotensin II led to aortic medial hemorrhage and dissection. SMCs were not apoptotic but displayed senescence associated-beta-galactosidase activity and upregulated p16, indicating premature senescence. Furthermore, there was evidence for oxidized DNA lesions, double-strand DNA strand breaks, and pronounced susceptibility to single-strand breakage. This was linked to suppressed poly(ADP ribose) polymerase-1 activity and was reversible on resupplying NAD+ with nicotinamide riboside. Remarkably, we discovered unrepaired DNA strand breaks in SMCs within the human ascending aorta, which were specifically enriched in SMCs with low NAMPT. NAMPT promoter analysis revealed CpG hypermethylation within the dilated human thoracic aorta and in SMCs cultured from these tissues, which inversely correlated with NAMPT expression. CONCLUSIONS: The aortic media depends on an intrinsic NAD+ fueling system to protect against DNA damage and premature SMC senescence, with relevance to human thoracic aortopathy. PMID- 28356344 TI - YAP promotes myogenic differentiation via the MEK5-ERK5 pathway. AB - Yes-associated protein (YAP) is a transcriptional coactivator in the Hippo pathway that regulates cell proliferation, differentiation, and apoptosis. The MEK5/ERK5 MAPK cascade is essential for the early step of myogenesis. In this study, we generated C2C12 stable cell lines that expressed YAP (C2C12-YAP cells) and found that ERK5 and MEK5 were activated in C2C12-YAP cells compared with control C2C12 (C2C12-vector) cells. C2C12-YAP stable cells also differentiated into myotubes better than C2C12-vector cells, and expressed elevated levels of myogenin, a transcription factor that regulates myogenesis, as well as elevated levels of myosin heavy chain, a skeletal muscle marker. Western blot analysis revealed that Src and c-Abl (Abelson murine leukemia viral oncogene homolog 1) activation were enhanced in C2C12-YAP cells. Conversely, treatment of inhibitors of c-Abl, Src, or MEK5 inhibited activation of MEK5 and ERK5 and myogenesis of C2C12 myoblasts. Specific interactions between YAP and proteins in the ERK5 pathway, such as MEK kinase 3 (MEKK3) and ERK5, were illustrated by coimmunoprecipitation experiments. MEKK3 contains the PPGY motif (aa 178-181), which may interact with YAP. Site-directed mutagenesis experiments revealed that expression of MEKK3 Y181F mutant inhibited MEK5/ERK5 activation and myogenic differentiation. These results suggest that YAP promotes muscle differentiation by activating the Abl/Src/MEKK3/MEK5/ERK5 kinase cascade.-Chen, T.-H., Chen, C. Y., Wen, H.-C., Chang, C.-C., Wang, H.-D., Chuu, C.-P., Chang, C.-H. YAP promotes myogenic differentiation via the MEK5-ERK5 pathway. PMID- 28356341 TI - Essential role for centromeric factors following p53 loss and oncogenic transformation. AB - In mammals, centromere definition involves the histone variant CENP-A (centromere protein A), deposited by its chaperone, HJURP (Holliday junction recognition protein). Alterations in this process impair chromosome segregation and genome stability, which are also compromised by p53 inactivation in cancer. Here we found that CENP-A and HJURP are transcriptionally up-regulated in p53-null human tumors. Using an established mouse embryonic fibroblast (MEF) model combining p53 inactivation with E1A or HRas-V12 oncogene expression, we reproduced a similar up regulation of HJURP and CENP-A. We delineate functional CDE/CHR motifs within the Hjurp and Cenpa promoters and demonstrate their roles in p53-mediated repression. To assess the importance of HJURP up-regulation in transformed murine and human cells, we used a CRISPR/Cas9 approach. Remarkably, depletion of HJURP leads to distinct outcomes depending on their p53 status. Functional p53 elicits a cell cycle arrest response, whereas, in p53-null transformed cells, the absence of arrest enables the loss of HJURP to induce severe aneuploidy and, ultimately, apoptotic cell death. We thus tested the impact of HJURP depletion in pre established allograft tumors in mice and revealed a major block of tumor progression in vivo. We discuss a model in which an "epigenetic addiction" to the HJURP chaperone represents an Achilles' heel in p53-deficient transformed cells. PMID- 28356346 TI - Biophysical characterization of the Varroa destructor NaV1 sodium channel and its affinity for tau-fluvalinate insecticide. AB - The decline of the western honeybee (Apis mellifera) has been reported to be due to parasitism by Varroa destructor mites and to colony collapse disorder in which these mites may be involved. In-hive chemicals such as tau-fluvalinate are being used to control Vdestructor populations. This approach may lead to the chronic exposure of bees to this liposoluble chemical, which tends to accumulate in hives. We cloned a variant of the V. destructor voltage-dependent sodium (VdNaV1) channel and studied its biophysical characteristics and sensitivity to tau fluvalinate using the Xenopus oocyte expression system and the 2-microelectrode voltage-clamp technique. We compared the affinity of VdNaV1 for tau-fluvalinate with the honeybee voltage-dependent sodium ortholog. Our results showed that the honeybee sodium channel is more sensitive to tau-fluvalinate than the V. destructor channel, suggesting that care must be taken when treating hives with this chemical.-Gosselin-Badaroudine, P., Chahine, M. Biophysical characterization of the Varroa destructor NaV1 sodium channel and its affinity for tau-fluvalinate insecticide. PMID- 28356347 TI - Leukocyte phosphodiesterase expression after lipopolysaccharide and during sepsis and its relationship with HLA-DR expression. AB - Phosphodiesterases (PDEs) may modulate inflammatory pathways, but PDE expression is poorly documented in humans with sepsis. Using quantitative PCR on whole blood leukocytes, we characterized PDE mRNA expression in healthy volunteers (n = 20), healthy volunteers given lipopolysaccharide (LPS; n = 18), and critically ill patients with (n = 20) and without (n = 20) sepsis. PDE4B protein expression was also studied in magnetic-activated cell sorting (MACS)-isolated CD15+ neutrophils (from 7 healthy volunteers, 5 patients without and 5 with sepsis). We studied relationships between PDE expression, HLA-DR (mRNA and expression on CD14+ monocytes), tumor necrosis factor (TNF)-alpha, and interleukin (IL)-10 levels. LPS administration in volunteers was associated with increases in PDE4B and PDE4D and decreases in PDE4A and PDE7A mRNAs. The observed global down-regulation of the HLA-DR complex was correlated with PDE7A. Critically ill patients had lower TNF-alpha/IL-10 mRNA ratios than the volunteers had and global down-regulation of the HLA-DR complex. Septic patients had persistently lower mRNA levels of PDE7A, PDE4A, and 4B (also at a protein level) and decreasing levels of PDE4D over time. Low PDE4D mRNA levels correlated negatively with HLA-DMA and HLA-DMB. LPS administration and sepsis are, therefore, associated with different PDE mRNA expression patterns. The effect of PDE changes on immune dysfunction and HLA-DR expression requires further investigation. PMID- 28356345 TI - mTOR activation protects liver from ischemia/reperfusion-induced injury through NF-kappaB pathway. AB - Hepatic steatosis renders liver more vulnerable to ischemia/reperfusion injury (IRI), which commonly occurs in transplantation, trauma, and liver resection. The underlying mechanism is not fully characterized. We aimed to clarify the role of mechanistic target of rapamycin (mTOR) signaling in hepatic ischemia/reperfusion injury (HIRI) in normal and steatotic liver using Alb-TSC1-/- (AT) and Alb-mTOR-/ (Am) transgenic mice. Steatotic liver induced by high-fat diet was more vulnerable to IRI. Activation of hepatic mTOR in AT mice decreased lipid accumulation attenuated HIRI as measured by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, circulating levels of alanine aminotransferase and lactate dehydrogenase, and inflammatory mediators such as monocyte chemoattractant protein 1 (MCP-1), TNF-alpha, and IL-6 and hepatic cleaved caspase 3 in mice fed either a normal chow diet or a high-fat diet. The effects of mTOR activation on hepatic cleaved caspase 3 were reversed by rapamycin, an inhibitor of mTOR signaling. Inhibition of hepatic mTOR in Am mice increased hepatic lipid deposition and HIRI. The increment in hepatic susceptibility to IRI was significantly attenuated by pretreatment with IKKbeta inhibitor. Further, suppression of mTOR facilitated nuclear translocation of NF kappaB p65. In conclusion, our study suggests that mTOR activity in hepatocytes decreases hepatic vulnerability to injury through a mechanism dependent on NF kappaB proinflammatory cytokine signaling pathway in both normal and steatotic liver.-Li, Z., Zhang, J., Mulholland, M., Zhang, W. mTOR activation protects liver from ischemia/reperfusion-induced injury through NF-kappaB pathway. PMID- 28356349 TI - cAMP: a multifaceted modulator of immune synapse assembly and T cell activation. AB - T Lymphocyte activation involves a substantial reorganization of the membranous and intracellular compartments. Signaling complexes assemble and dismantle in a highly ordered fashion in both compartments and orchestrate the activation of T cells with high sensitivity and specificity. TCR ligation leads to a short burst of cAMP production, which is centrally required for T cell activation; however, sustained elevations in intracellular cAMP concentrations are immunosuppressive. Emerging evidence of the existence of local cAMP pools gleaned from studies on other cell types suggests that cAMP compartmentalization may account, in part, for these opposing effects. Whereas cAMP compartmentalization has been identified as a central factor in the control of the cAMP-dependent processes in other cell types, this has, as yet, not been addressed in T lymphocytes. In this review, we discuss the role of cAMP in T cell activation and differentiation, with an emphasis on the effects mediated by the cAMP effectors, protein kinase A (PKA) and exchange protein activated by cAMP (EPAC)1, and on the regulatory proteins that may control the generation of local cAMP pools in T cells. We also present an overview of the available tools to image cAMP production at the subcellular level and discuss how bacterial adenylate cyclase (AC) toxins that are known to generate local cAMP pools can be exploited to address the role of cAMP compartmentalization in T cell activation. PMID- 28356348 TI - Tpl2 promotes neutrophil trafficking, oxidative burst, and bacterial killing. AB - Tumor progression locus 2 (Tpl2) is a serine/threonine kinase that promotes inflammatory cytokine production by activating the MEK/ERK pathway. Tpl2 has been shown to be important for eliciting the inflammatory properties of macrophages; however, there is relatively little known about the contribution of Tpl2 to neutrophil effector functions. This is an important consideration, as neutrophils provide the first line of defense against infection in the innate immune system. We found that Tpl2 is expressed in both human and murine neutrophils, suggesting a potential function for Tpl2 in this lineage. Despite significantly higher proportions of bone marrow (BM) neutrophils in Tpl2-deficient (Tpl2-/- ) mice compared with wild-type (WT) mice, Tpl2-/- mice have significantly reduced proportions of circulating neutrophils. Tpl2-/- neutrophils show impaired recruitment to thioglycollate, which was primarily a result of neutrophil extrinsic factors in the host. In response to infection, neutrophils secrete inflammatory cytokines and produce reactive oxygen species (ROS), which promote bacterial killing. Tpl2 ablation impaired neutrophil TNF secretion in response to LPS stimulation, superoxide generation in response to the chemotactic peptide fMLP, and killing of the extracellular bacterium, Citrobacter rodentium, despite normal bacterial phagocytosis. These results implicate Tpl2 in the regulation of multiple neutrophil antimicrobial pathways, including inflammatory cytokine secretion and oxidative burst. Furthermore, they indicate that Tpl2 functions early during infection to bolster neutrophil-mediated innate immunity against extracellular bacteria. PMID- 28356350 TI - From top to bottom: midkine and pleiotrophin as emerging players in immune regulation. AB - Cytokines are pivotal in the generation and resolution of the inflammatory response. The midkine/pleiotrophin (MK/PTN) family of cytokines, composed of just two members, was discovered as heparin-binding neurite outgrowth-promoting factors. Since their discovery, expression of this cytokine family has been reported in a wide array of inflammatory diseases and cancer. In this minireview, we will discuss the emerging appreciation of the functions of the MK/PTN family in the immune system, which include promoting lymphocyte survival, sculpting myeloid cell phenotype, driving immune cell chemotaxis, and maintaining hematopoiesis. PMID- 28356351 TI - Juvenile hormone differentially regulates two Grp78 genes encoding protein chaperones required for insect fat body cell homeostasis and vitellogenesis. AB - Juvenile hormone (JH) has a well known role in stimulating insect vitellogenesis (i.e. yolk deposition) and oocyte maturation, but the molecular mechanisms of JH action in insect reproduction are unclear. The 78-kDa glucose-regulated protein (Grp78) is a heat shock protein 70-kDa family member and one of the most abundant chaperones in the endoplasmic reticulum (ER) where it helps fold newly synthesized peptides. Because of its prominent role in protein folding, and also ER stress, we hypothesized that Grp78 might be involved in fat body cell homeostasis and vitellogenesis and a regulatory target of JH. We report here that the migratory locust Locusta migratoria possesses two Grp78 genes that are differentially regulated by JH. We found that Grp78-1 is regulated by JH through Mcm4/7-dependent DNA replication and polyploidization, whereas Grp78-2 expression is directly activated by the JH-receptor complex comprising methoprene-tolerant and Taiman proteins. Interestingly, Grp78-2 expression in the fat body is about 10-fold higher than that of Grp78-1 Knockdown of either Grp78-1 or Grp78-2 significantly reduced levels of vitellogenin (Vg) protein, accompanied by retarded maturation of oocytes. Depletion of both Grp78-1 and Grp78-2 resulted in ER stress and apoptosis in the fat body and in severely defective Vg synthesis and oocyte maturation. These results indicate a crucial role of Grp78 in JH dependent vitellogenesis and egg production. The presence and differential regulation of two Grp78 genes in L. migratoria likely help accelerate the production of this chaperone in the fat body to facilitate folding of massively synthesized Vg and other proteins. PMID- 28356353 TI - A ternary membrane protein complex anchors the spindle pole body in the nuclear envelope in budding yeast. AB - In budding yeast (Saccharomyces cerevisiae) the multilayered spindle pole body (SPB) is embedded in the nuclear envelope (NE) at fusion sites of the inner and outer nuclear membrane. The SPB is built from 18 different proteins, including the three integral membrane proteins Mps3, Ndc1, and Mps2. These membrane proteins play an essential role in the insertion of the new SPB into the NE. How the huge core structure of the SPB is anchored in the NE has not been investigated thoroughly until now. The present model suggests that the NE protein Mps2 interacts via Bbp1 with Spc29, one of the coiled-coil proteins forming the central plaque of the SPB. To test this model, we purified and reconstituted the Mps2-Bbp1 complex from yeast and incorporated the complex into liposomes. We also demonstrated that Mps2-Bbp1 directly interacts with Mps3 and Ndc1. We then purified Spc29 and reconstituted the ternary Mps2-Bbp1-Spc29 complex, proving that Bbp1 can simultaneously interact with Mps2 and Spc29 and in this way link the central plaque of the SPB to the nuclear envelope. Interestingly, Bbp1 induced oligomerization of Spc29, which may represent an early step in SPB duplication. Together, this analysis provides important insights into the interaction network that inserts the new SPB into the NE and indicates that the Mps2-Bbp1 complex is the central unit of the SPB membrane anchor. PMID- 28356356 TI - Web stickiness optimised to humidity. PMID- 28356352 TI - Rearrangement of a polar core provides a conserved mechanism for constitutive activation of class B G protein-coupled receptors. AB - The glucagon receptor (GCGR) belongs to the secretin-like (class B) family of G protein-coupled receptors (GPCRs) and is activated by the peptide hormone glucagon. The structures of an activated class B GPCR have remained unsolved, preventing a mechanistic understanding of how these receptors are activated. Using a combination of structural modeling and mutagenesis studies, we present here two modes of ligand-independent activation of GCGR. First, we identified a GCGR-specific hydrophobic lock comprising Met-338 and Phe-345 within the IC3 loop and transmembrane helix 6 (TM6) and found that this lock stabilizes the TM6 helix in the inactive conformation. Disruption of this hydrophobic lock led to constitutive G protein and arrestin signaling. Second, we discovered a polar core comprising conserved residues in TM2, TM3, TM6, and TM7, and mutations that disrupt this polar core led to constitutive GCGR activity. On the basis of these results, we propose a mechanistic model of GCGR activation in which TM6 is held in an inactive conformation by the conserved polar core and the hydrophobic lock. Mutations that disrupt these inhibitory elements allow TM6 to swing outward to adopt an active TM6 conformation similar to that of the canonical beta2 adrenergic receptor complexed with G protein and to that of rhodopsin complexed with arrestin. Importantly, mutations in the corresponding polar core of several other members of class B GPCRs, including PTH1R, PAC1R, VIP1R, and CRFR1, also induce constitutive G protein signaling, suggesting that the rearrangement of the polar core is a conserved mechanism for class B GPCR activation. PMID- 28356358 TI - Chilly white-browed babblers huddle to avoid torpor. PMID- 28356357 TI - For Heliconius' eyes only. PMID- 28356354 TI - N-terminal half of transportin SR2 interacts with HIV integrase. AB - The karyopherin transportin SR2 (TRN-SR2, TNPO3) is responsible for shuttling specific cargoes such as serine/arginine-rich splicing factors from the cytoplasm to the nucleus. This protein plays a key role in HIV infection by facilitating the nuclear import of the pre-integration complex (PIC) that contains the viral DNA as well as several cellular and HIV proteins, including the integrase. The process of nuclear import is considered to be the bottleneck of the viral replication cycle and therefore represents a promising target for anti-HIV drug design. Previous studies have demonstrated that the direct interaction between TRN-SR2 and HIV integrase predominantly involves the catalytic core domain (CCD) and the C-terminal domain (CTD) of the integrase. We aimed at providing a detailed molecular view of this interaction through a biochemical characterization of the respective protein complex. Size-exclusion chromatography was used to characterize the interaction of TRN-SR2 with a truncated variant of the HIV-1 integrase, including both the CCD and CTD. These experiments indicate that one TRN-SR2 molecule can specifically bind one CCD-CTD dimer. Next, the regions of the solenoid-like TRN-SR2 molecule that are involved in the interaction with integrase were identified using AlphaScreen binding assays, revealing that the integrase interacts with the N-terminal half of TRN-SR2 principally through the HEAT repeats 4, 10, and 11. Combining these results with small-angle X-ray scattering data for the complex of TRN-SR2 with truncated integrase, we propose a molecular model of the complex. We speculate that nuclear import of the PIC may proceed concurrently with the normal nuclear transport. PMID- 28356359 TI - Stay-at-home zebra finches use magnetic compasses too. PMID- 28356355 TI - Metabolomic profiling reveals a finely tuned, starvation-induced metabolic switch in Trypanosoma cruzi epimastigotes. AB - Trypanosoma cruzi, the etiological agent of Chagas disease, is a protozoan parasite with a complex life cycle involving a triatomine insect and mammals. Throughout its life cycle, the T. cruzi parasite faces several alternating events of cell division and cell differentiation in which exponential and stationary growth phases play key biological roles. It is well accepted that arrest of the cell division in the epimastigote stage, both in the midgut of the triatomine insect and in vitro, is required for metacyclogenesis, and it has been previously shown that the parasites change the expression profile of several proteins when entering this quiescent stage. However, little is known about the metabolic changes that epimastigotes undergo before they develop into the metacyclic trypomastigote stage. We applied targeted metabolomics to measure the metabolic intermediates in the most relevant pathways for energy metabolism and oxidative imbalance in exponentially growing and stationary growth-arrested epimastigote parasites. We show for the first time that T. cruzi epimastigotes transitioning from the exponential to the stationary phase exhibit a finely tuned adaptive metabolic mechanism that enables switching from glucose to amino acid consumption, which is more abundant in the stationary phase. This metabolic plasticity appears to be crucial for survival of the T. cruzi parasite in the myriad different environmental conditions to which it is exposed during its life cycle. PMID- 28356360 TI - Slime molds transfer knowledge through fusion. PMID- 28356361 TI - [Cardiac] Pressure's on for thirsty trout. PMID- 28356362 TI - Too much hibernation isn't always good for you. PMID- 28356363 TI - Bumblebees adapt for turbulence. PMID- 28356364 TI - Feisty fish from anoxic waters. PMID- 28356365 TI - A radical shift in perspective: mitochondria as regulators of reactive oxygen species. AB - Mitochondria are widely recognized as a source of reactive oxygen species (ROS) in animal cells, where it is assumed that over-production of ROS leads to an overwhelmed antioxidant system and oxidative stress. In this Commentary, we describe a more nuanced model of mitochondrial ROS metabolism, where integration of ROS production with consumption by the mitochondrial antioxidant pathways may lead to the regulation of ROS levels. Superoxide and hydrogen peroxide (H2O2) are the main ROS formed by mitochondria. However, superoxide, a free radical, is converted to the non-radical, membrane-permeant H2O2; consequently, ROS may readily cross cellular compartments. By combining measurements of production and consumption of H2O2, it can be shown that isolated mitochondria can intrinsically approach a steady-state concentration of H2O2 in the medium. The central hypothesis here is that mitochondria regulate the concentration of H2O2 to a value set by the balance between production and consumption. In this context, the consumers of ROS are not simply a passive safeguard against oxidative stress; instead, they control the established steady-state concentration of H2O2 By considering the response of rat skeletal muscle mitochondria to high levels of ADP, we demonstrate that H2O2 production by mitochondria is far more sensitive to changes in mitochondrial energetics than is H2O2 consumption; this concept is further extended to evaluate how the muscle mitochondrial H2O2 balance should respond to changes in aerobic work load. We conclude by considering how differences in the ROS consumption pathways may lead to important distinctions amongst tissues, along with briefly examining implications for differing levels of activity, temperature change and metabolic depression. PMID- 28356366 TI - Zebra finches have a light-dependent magnetic compass similar to migratory birds. AB - Birds have a light-dependent magnetic compass that provides information about the spatial alignment of the geomagnetic field. It is proposed to be located in the avian retina and mediated by a light-induced, radical-pair mechanism involving cryptochromes as sensory receptor molecules. To investigate how the behavioural responses of birds under different light spectra match with cryptochromes as the primary magnetoreceptor, we examined the spectral properties of the magnetic compass in zebra finches. We trained birds to relocate a food reward in a spatial orientation task using magnetic compass cues. The birds were well oriented along the trained magnetic compass axis when trained and tested under low-irradiance 521 nm green light. In the presence of a 1.4 MHz radio-frequency electromagnetic (RF)-field, the birds were disoriented, which supports the involvement of radical pair reactions in the primary magnetoreception process. Birds trained and tested under 638 nm red light showed a weak tendency to orient ~45 deg clockwise of the trained magnetic direction. Under low-irradiance 460 nm blue light, they tended to orient along the trained magnetic compass axis, but were disoriented under higher irradiance light. Zebra finches trained and tested under high-irradiance 430 nm indigo light were well oriented along the trained magnetic compass axis, but disoriented in the presence of a RF-field. We conclude that magnetic compass responses of zebra finches are similar to those observed in nocturnally migrating birds and agree with cryptochromes as the primary magnetoreceptor, suggesting that light-dependent, radical-pair-mediated magnetoreception is a common property for all birds, including non-migratory species. PMID- 28356367 TI - Humidity-mediated changes in an orb spider's glycoprotein adhesive impact prey retention time. AB - Properties of the viscous prey capture threads of araneoid orb spiders change in response to their environment. Relative humidity (RH) affects the performance of the thread's hygroscopic droplets by altering the viscoelasticity of each droplet's adhesive glycoprotein core. Studies that have characterized this performance used smooth glass and steel surfaces and uniform forces. In this study, we tested the hypothesis that these changes in performance translate into differences in prey retention times. We first characterized the glycoprotein contact surface areas and maximum extension lengths of Araneus marmoreus droplets at 20%, 37%, 55%, 72% and 90% RH and then modeled the relative work required to initiate pull-off of a 4 mm thread span, concluding that this species' droplets and threads performed optimally at 72% RH. Next, we evaluated the ability of three equally spaced capture thread strands to retain a house fly at 37%, 55% and 72% RH. Each fly's struggle was captured in a video and bouts of active escape behavior were summed. House flies were retained 11 s longer at 72% RH than at 37% and 55% RH. This difference is ecologically significant because the short time after an insect strikes a web and before a spider begins wrapping it is an insect's only opportunity to escape from the web. Moreover, these results validate the mechanism by which natural selection can tune the performance of an orb spider's capture threads to the humidity of its habitat. PMID- 28356368 TI - Avian torpor or alternative thermoregulatory strategies for overwintering? AB - It is unclear whether torpor really is uncommon amongst passerine birds. We therefore examined body temperature and thermoregulatory strategies of an Austral passerine, the white-browed babbler (Pomatostomus superciliosus), which has characteristics related to a high probability of torpor use; it is a sedentary, insectivorous, cooperative breeding species, which we studied during winter in a temperate habitat. Wild, free-living babblers maintained normothermy overnight, even at sub-zero ambient temperatures, with a mean minimum body temperature of 38.5+/-0.04 degrees C that was independent of minimum black bulb temperature. Physiological variables measured in the laboratory revealed that babblers had a low basal metabolic rate and evaporative water loss, but their body temperature and thermal conductance were typical of those of other birds and they had a typical endothermic response to low ambient temperature. Huddling yielded significant energy savings at low temperatures and a roost nest created a microclimate that buffered against low temperatures. Low basal energy requirements, communal roosting and the insulation of a roost nest confer sufficient energetic benefits, allowing babblers to meet energy requirements without resorting to heterothermia, even in their depauperate, low-productivity landscape, suggesting that passerine birds use alternatives to torpor to balance their energy budgets when possible. PMID- 28356369 TI - The independence of eye movements in a stomatopod crustacean is task dependent. AB - Stomatopods have an extraordinary visual system, incorporating independent movement of their eyes in all three degrees of rotational freedom. In this work, we demonstrate that in the peacock mantis shrimp, Odontodactylus scyllarus, the level of ocular independence is task dependent. During gaze stabilization in the context of optokinesis, there is weak but significant correlation between the left and right eyes in the yaw degree of rotational freedom, but not in pitch and torsion. When one eye is completely occluded, the uncovered eye does not drive the covered eye during gaze stabilization. However, occluding one eye does significantly affect the uncovered eye, lowering its gaze stabilization performance. There is a lateral asymmetry, with the magnitude of the effect depending on the eye (left or right) combined with the direction of motion of the visual field. In contrast, during a startle saccade, the uncovered eye does drive a covered eye. Such disparate levels of independence between the two eyes suggest that responses to individual visual tasks are likely to follow different neural pathways. PMID- 28356370 TI - Comorbidities in the management of patients with lung cancer. AB - Lung cancer represents a major public health issue worldwide. Unfortunately, more than half of them are diagnosed at an advanced stage. Moreover, even if diagnosed early, diagnosis procedures and treatment can be difficult due to the frequent comorbidities observed in these patients. Some of these comorbidities have a common major risk factor, i.e. smoking, whereas others are unrelated to smoking but frequently observed in the general population. These comorbidities must be carefully assessed before any diagnostic and/or therapeutic decisions are made regarding the lung cancer. For example, in a patient with severe emphysema or with diffuse lung fibrosis, transthoracic needle biopsy can be contraindicated, meaning that in some instances a precise diagnosis cannot be obtained; in a patient with chronic obstructive pulmonary disease, surgery may be impossible or should be preceded by intensive rehabilitation; patients with interstitial lung disease are at risk of radiation pneumonitis and should not receive drugs which can worsen the respiratory insufficiency. Patients who belong to what are called "special populations", e.g. elderly or HIV infected, should be treated specifically, especially regarding systemic treatment. Last but not least, psychosocial factors are of great importance and can vary from one country to another according to health insurance coverage. PMID- 28356372 TI - Pulmonary complications and survival after autologous stem cell transplantation: predictive role of pulmonary function and pneumotoxic medications. PMID- 28356371 TI - Metabolomics analysis identifies different metabotypes of asthma severity. AB - In this study, we sought to determine whether asthma has a metabolic profile and whether this profile is related to disease severity.We characterised the serum from 22 healthy individuals and 54 asthmatics (12 mild, 20 moderate, 22 severe) using liquid chromatography-high-resolution mass spectrometry-based metabolomics. Selected metabolites were confirmed by targeted mass spectrometry assays of eicosanoids, sphingolipids and free fatty acids.We conclusively identified 66 metabolites; 15 were significantly altered with asthma (p<=0.05). Levels of dehydroepiandrosterone sulfate, cortisone, cortisol, prolylhydroxyproline, pipecolate and N-palmitoyltaurine correlated significantly (p<0.05) with inhaled corticosteroid dose, and were further shifted in individuals treated with oral corticosteroids. Oleoylethanolamide increased with asthma severity independently of steroid treatment (p<0.001). Multivariate analysis revealed two patterns: 1) a mean difference between controls and patients with mild asthma (p=0.025), and 2) a mean difference between patients with severe asthma and all other groups (p=1.7*10-4). Metabolic shifts in mild asthma, relative to controls, were associated with exogenous metabolites (e.g. dietary lipids), while those in moderate and severe asthma (e.g. oleoylethanolamide, sphingosine-1-phosphate, N palmitoyltaurine) were postulated to be involved in activating the transient receptor potential vanilloid type 1 (TRPV1) receptor, driving TRPV1-dependent pathogenesis in asthma.Our findings suggest that asthma is characterised by a modest systemic metabolic shift in a disease severity-dependent manner, and that steroid treatment significantly affects metabolism. PMID- 28356373 TI - Maximal mid-expiratory flow detects early lung disease in alpha1-antitrypsin deficiency. AB - Pathological studies suggest that loss of small airways precedes airflow obstruction and emphysema in chronic obstructive pulmonary disease (COPD). Not all alpha1-antitrypsin deficiency (AATD) patients develop COPD, and measures of small airways function might be able to detect those at risk.Maximal mid expiratory flow (MMEF), forced expiratory volume in 1 s (FEV1), ratio of FEV1/forced vital capacity (FVC), health status, presence of emphysema (computed tomography (CT) densitometry) and subsequent decline in FEV1 were assessed in 196 AATD patients.FEV1/FVC, FEV1 % predicted and lung densitometry related to MMEF % pred (r2=0.778, p<0.0001; r2=0.787, p<0.0001; r2=0.594, p<0.0001, respectively) in a curvilinear fashion. Patients could be divided into those with normal FEV1/FVC and MMEF (group 1), normal FEV1/FVC and reduced MMEF (group 2) and those with spirometrically defined COPD (group 3). Patients in group 2 had worse health status than group 1 (median total St George's Respiratory Questionnaire (SGRQ) 23.15 (interquartile range (IQR) 7.09-39.63) versus 9.67 (IQR 1.83-22.35); p=0.006) and had a greater subsequent decline in FEV1 (median change in FEV1 1.09% pred per year (IQR -1.91-0.04% pred per year) versus -0.04% pred per year (IQR -0.67-0.03% pred per year); p=0.007).A reduction in MMEF is an early feature of lung disease in AATD and is associated with impaired health status and a faster decline in FEV1. PMID- 28356374 TI - Concordance between upper and lower airway microbiota in infants with cystic fibrosis. AB - Nasopharyngeal and oropharyngeal samples are commonly used to direct therapy for lower respiratory tract infections in non-expectorating infants with cystic fibrosis (CF).We aimed to investigate the concordance between the bacterial community compositions of 25 sets of nasopharyngeal, oropharyngeal and bronchoalveolar lavage (BAL) samples from 17 infants with CF aged ~5 months (n=13) and ~12 months (n=12) using conventional culturing and 16S-rRNA sequencing.Clustering analyses demonstrated that BAL microbiota profiles were in general characterised by a mixture of oral and nasopharyngeal bacteria, including commensals like Streptococcus, Neisseria, Veillonella and Rothia spp. and potential pathogens like Staphylococcus aureus, Haemophilus influenzae and Moraxella spp. Within each individual, however, the degree of concordance differed between microbiota of both upper respiratory tract niches and the corresponding BAL.The inconsistent intra-individual concordance between microbiota of the upper and lower respiratory niches suggests that the lungs of infants with CF may have their own microbiome that seems seeded by, but is not identical to, the upper respiratory tract microbiome. PMID- 28356375 TI - IFN-alpha/IFN-lambda responses to respiratory viruses in paediatric asthma. PMID- 28356376 TI - A good asthma catch by professional fishing. PMID- 28356377 TI - "Baseline characteristics of idiopathic pulmonary fibrosis: analysis from the Australian Idiopathic Pulmonary Fibrosis Registry." Helen E. Jo, Ian Glaspole, Christopher Grainge, Nicole Goh, Peter M.A. Hopkins, Yuben Moodley, Paul N. Reynolds, Sally Chapman, E. Haydn Walters, Christopher Zappala, Heather Allan, Gregory J. Keir, Andrew Hayen, Wendy A. Cooper, Annabelle M. Mahar, Samantha Ellis, Sacha Macansh and Tamera J. Corte. Eur Respir J 2017; 49: 1651592. PMID- 28356378 TI - IFN-alpha/IFN-lambda responses to respiratory viruses in paediatric asthma. PMID- 28356379 TI - Rhinovirus species/genotypes and interferon-lambda: subtypes, receptor and polymorphisms - missing pieces of the puzzle of childhood asthma? PMID- 28356380 TI - Understanding at-risk subgroups for lung function impairment in life-long nonsmokers with alpha1-antitrypsin deficiency. PMID- 28356381 TI - Rhinovirus species/genotypes and interferon-lambda: subtypes, receptor and polymorphisms - missing pieces of the puzzle of childhood asthma? PMID- 28356382 TI - Limited Presence of IL-22 Binding Protein, a Natural IL-22 Inhibitor, Strengthens Psoriatic Skin Inflammation. AB - Psoriasis is a chronic inflammatory disease resulting from dysregulated immune activation associated with a large local secretion of cytokines. Among them, IL 22 largely contributes to epithelial remodeling and inflammation through inhibiting the terminal differentiation of keratinocytes and inducing antimicrobial peptides and selected chemokines. The activity of IL-22 is regulated by IL-22 binding protein (IL-22BP); however, the expression and role of IL-22BP in psoriatic skin has remained unknown so far. Here we showed that nonaffected skin of psoriasis patients displayed lower expression of IL-22BP than skin of healthy controls. Furthermore, the strong IL-22 increase in lesional psoriatic skin was accompanied by a moderate induction of IL-22BP. To investigate the role of IL-22BP in controlling IL-22 during skin inflammation, we used imiquimod-induced skin disease in rodents and showed that rats with genetic IL 22BP deficiency (Il22ra2-/-) displayed exacerbated disease that associated with enhanced expression of IL-22-inducible antimicrobial peptides. We further recapitulated these findings in mice injected with an anti-IL-22BP neutralizing Ab. Hypothesizing that the IL-22/IL-22BP expression ratio reflects the level of bioactive IL-22 in psoriasis skin, we found positive correlations with the expression of IL-22-inducible molecules (IL-20, IL-24, IL-36gamma, CXCL1, and BD2) in keratinocytes. Finally, we observed that serum IL-22/IL-22BP protein ratio strongly correlated with psoriasis severity. In conclusion, we propose that although IL-22BP can control deleterious actions of IL-22 in the skin, its limited production prevents a sufficient neutralization of IL-22 and contributes to the development and maintenance of epidermal alterations in psoriasis. PMID- 28356383 TI - Vigilin Regulates the Expression of the Stress-Induced Ligand MICB by Interacting with Its 5' Untranslated Region. AB - NK cells are part of the innate immune system, and are able to identify and kill hazardous cells. The discrimination between normal and hazardous cells is possible due to an array of inhibitory and activating receptors. NKG2D is one of the prominent activating receptors expressed by all human NK cells. This receptor binds stress-induced ligands, including human MICA, MICB, and UL16-binding proteins 1-6. The interaction between NKG2D and its ligands facilitates the elimination of cells under cellular stress, such as tumor transformation. However, the mechanisms regulating the expression of these ligands are still not well understood. Under normal conditions, the NKG2D ligands were shown to be posttranscriptionally regulated by cellular microRNAs and RNA-binding proteins (RBPs). Thus far, only the 3' untranslated regions (UTRs) of MICA, MICB, and UL16 binding protein 2 were shown to be regulated by RBPs and microRNAs, usually resulting in their downregulation. In this study we investigated whether MICB expression is controlled by RBPs through its 5'UTR. We used an RNA pull-down assay followed by mass spectrometry and identified vigilin, a ubiquitously expressed multifunctional RNA-binding protein. We demonstrated that vigilin binds and negatively regulates MICB expression through its 5'UTR. Additionally, vigilin downregulation in target cells led to a significant increase in NK cell activation against said target cells. Taken together, we have discovered a novel mode of MICB regulation. PMID- 28356384 TI - IL-26 Confers Proinflammatory Properties to Extracellular DNA. AB - In physiological conditions, self-DNA released by dying cells is not detected by intracellular DNA sensors. In chronic inflammatory disorders, unabated inflammation has been associated with a break in innate immune tolerance to self DNA. However, extracellular DNA has to complex with DNA-binding molecules to gain access to intracellular DNA sensors. IL-26 is a member of the IL-10 cytokine family, overexpressed in numerous chronic inflammatory diseases, in which biological activity remains unclear. We demonstrate in this study that IL-26 binds to genomic DNA, mitochondrial DNA, and neutrophil extracellular traps, and shuttles them in the cytosol of human myeloid cells. As a consequence, IL-26 allows extracellular DNA to trigger proinflammatory cytokine secretion by monocytes, in a STING- and inflammasome-dependent manner. Supporting these biological properties, IL-10-based modeling predicts two DNA-binding domains, two amphipathic helices, and an in-plane membrane anchor in IL-26, which are structural features of cationic amphipathic cell-penetrating peptides. In line with these properties, patients with active autoantibody-associated vasculitis, a chronic relapsing autoimmune inflammatory disease associated with extensive cell death, exhibit high levels of both circulating IL-26 and IL-26-DNA complexes. Moreover, in patients with crescentic glomerulonephritis, IL-26 is expressed by renal arterial smooth muscle cells and deposits in necrotizing lesions. Accordingly, human primary smooth cells secrete IL-26 in response to proinflammatory cytokines. In conclusion, IL-26 is a unique cationic protein more similar to a soluble pattern recognition receptor than to conventional cytokines. IL-26 expressed in inflammatory lesions confers proinflammatory properties to DNA released by dying cells, setting up a positive amplification loop between extensive cell death and unabated inflammation. PMID- 28356387 TI - Inducible TAP1 Negatively Regulates the Antiviral Innate Immune Response by Targeting the TAK1 Complex. AB - The innate immune response is critical for host defense and must be tightly controlled, but the molecular mechanisms responsible for its negative regulation are not yet completely understood. In this study, we report that transporter 1, ATP-binding cassette, subfamily B (TAP1), a virus-inducible endoplasmic reticulum associated protein, negatively regulated the virus-triggered immune response. In this study, we observed upregulated expression of TAP1 following virus infection in human lung epithelial cells (A549), THP-1 monocytes, HeLa cells, and Vero cells. The overexpression of TAP1 enhanced virus replication by inhibiting the virus-triggered activation of NF-kappaB signaling and the production of IFNs, IFN stimulated genes, and proinflammatory cytokines. TAP1 depletion had the opposite effect. In response to virus infection, TAP1 interacted with the TGF-beta activated kinase (TAK)1 complex and impaired the phosphorylation of TAK1, subsequently suppressing the phosphorylation of the IkappaB kinase complex and NF kappaB inhibitor alpha (IkappaBalpha) as well as NF-kappaB nuclear translocation. Our findings collectively suggest that TAP1 plays a novel role in the negative regulation of virus-triggered NF-kappaB signaling and the innate immune response by targeting the TAK1 complex. PMID- 28356385 TI - RGC-32 Promotes Th17 Cell Differentiation and Enhances Experimental Autoimmune Encephalomyelitis. AB - Th17 cells play a critical role in autoimmune diseases, including multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Response gene to complement (RGC)-32 is a cell cycle regulator and a downstream target of TGF-beta that mediates its profibrotic activity. In this study, we report that RGC-32 is preferentially upregulated during Th17 cell differentiation. RGC-32-/- mice have normal Th1, Th2, and regulatory T cell differentiation but show defective Th17 differentiation in vitro. The impaired Th17 differentiation is associated with defects in IFN regulatory factor 4, B cell-activating transcription factor, retinoic acid-related orphan receptor gammat, and SMAD2 activation. In vivo, RGC-32-/- mice display an attenuated experimental autoimmune encephalomyelitis phenotype accompanied by decreased CNS inflammation and reduced frequency of IL-17- and GM-CSF-producing CD4+ T cells. Collectively, our results identify RGC-32 as a novel regulator of Th17 cell differentiation in vitro and in vivo and suggest that RGC-32 is a potential therapeutic target in multiple sclerosis and other Th17-mediated autoimmune diseases. PMID- 28356388 TI - Emergency medicine: what keeps me, what might lose me? A narrative study of consultant views in Wales. AB - : EDs are currently under intense pressure due to increased patient demand. There are major issues with retention of senior personnel, making the specialty a less attractive choice for junior doctors. This study aims to explore what attracted EM consultants to their career and keeps them there. It is hoped this can inform recruitment strategies to increase the popularity of EM to medical students and junior doctors, many of whom have very limited EM exposure. METHODS: Semistructured interviews were conducted with 10 consultants from Welsh EDs using a narrative approach. RESULTS: Three main themes emerged that influenced the career choice of the consultants interviewed: (1) early exposure to positive EM role models; (2) non-hierarchical team structure; (3) suitability of EM for flexible working. The main reason for consultants leaving was the pressure of work impacting on patient care. CONCLUSION: The study findings suggest that EM consultants in post are positive about their careers despite the high volume of consultant attrition. This study reinforces the need for dedicated undergraduate EM placements to stimulate interest and encourage medical student EM aspirations. Consultants identified that improving the physical working environment, including organisation, would increase their effectiveness and the attractiveness of EM as a long-term career. PMID- 28356386 TI - The Granulocyte Progenitor Stage Is a Key Target of IRF8-Mediated Regulation of Myeloid-Derived Suppressor Cell Production. AB - Alterations in myelopoiesis are common across various tumor types, resulting in immature populations termed myeloid-derived suppressor cells (MDSCs). MDSC burden correlates with poorer clinical outcomes, credited to their ability to suppress antitumor immunity. MDSCs consist of two major subsets, monocytic and polymorphonuclear (PMN). Intriguingly, the latter subset predominates in many patients and tumor models, although the mechanisms favoring PMN-MDSC responses remain poorly understood. Ordinarily, lineage-restricted transcription factors regulate myelopoiesis that collectively dictate cell fate. One integral player is IFN regulatory factor (IRF)-8, which promotes monocyte/dendritic cell differentiation while limiting granulocyte development. We recently showed that IRF8 inversely controls MDSC burden in tumor models, particularly the PMN-MDSC subset. However, where IRF8 acts in the pathway of myeloid differentiation to influence PMN-MDSC production has remained unknown. In this study, we showed that: 1) tumor growth was associated with a selective expansion of newly defined IRF8lo granulocyte progenitors (GPs); 2) tumor-derived GPs had an increased ability to form PMN-MDSCs; 3) tumor-derived GPs shared gene expression patterns with IRF8-/- GPs, suggesting that IRF8 loss underlies GP expansion; and 4) enforced IRF8 overexpression in vivo selectively constrained tumor-induced GP expansion. These findings support the hypothesis that PMN-MDSCs result from selective expansion of IRF8lo GPs, and that strategies targeting IRF8 expression may limit their load to improve immunotherapy efficacy. PMID- 28356389 TI - Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation. AB - Human hepatocellular carcinomas (HCCs), which arise on a background of chronic liver damage and inflammation, express c-Fos, a component of the AP-1 transcription factor. Using mouse models, we show that hepatocyte-specific deletion of c-Fos protects against diethylnitrosamine (DEN)-induced HCCs, whereas liver-specific c-Fos expression leads to reversible premalignant hepatocyte transformation and enhanced DEN-carcinogenesis. c-Fos-expressing livers display necrotic foci, immune cell infiltration, and altered hepatocyte morphology. Furthermore, increased proliferation, dedifferentiation, activation of the DNA damage response, and gene signatures of aggressive HCCs are observed. Mechanistically, c-Fos decreases expression and activity of the nuclear receptor LXRalpha, leading to increased hepatic cholesterol and accumulation of toxic oxysterols and bile acids. The phenotypic consequences of c-Fos expression are partially ameliorated by the anti-inflammatory drug sulindac and largely prevented by statin treatment. An inverse correlation between c-FOS and the LXRalpha pathway was also observed in human HCC cell lines and datasets. These findings provide a novel link between chronic inflammation and metabolic pathways important in liver cancer. PMID- 28356391 TI - TLR4 signals in B lymphocytes are transduced via the B cell antigen receptor and SYK. AB - Toll-like receptors (TLRs) play an important role in immune responses to pathogens by transducing signals in innate immune cells in response to microbial products. TLRs are also expressed on B cells, and TLR signaling in B cells contributes to antibody-mediated immunity and autoimmunity. The SYK tyrosine kinase is essential for signaling from the B cell antigen receptor (BCR), and thus for antibody responses. Surprisingly, we find that it is also required for B cell survival, proliferation, and cytokine secretion in response to signaling through several TLRs. We show that treatment of B cells with lipopolysaccharide, the ligand for TLR4, results in SYK activation and that this is dependent on the BCR. Furthermore, we show that B cells lacking the BCR are also defective in TLR induced B cell activation. Our results demonstrate that TLR4 signals through two distinct pathways, one via the BCR leading to activation of SYK, ERK, and AKT and the other through MYD88 leading to activation of NF-kappaB. PMID- 28356390 TI - The kinase TBK1 functions in dendritic cells to regulate T cell homeostasis, autoimmunity, and antitumor immunity. AB - Dendritic cells (DCs) are crucial for mediating immune responses but, when deregulated, also contribute to immunological disorders, such as autoimmunity. The molecular mechanism underlying the function of DCs is incompletely understood. In this study, we have identified TANK-binding kinase 1 (TBK1), a master innate immune kinase, as an important regulator of DC function. DC specific deletion of Tbk1 causes T cell activation and autoimmune symptoms and also enhances antitumor immunity in animal models of cancer immunotherapy. The TBK1-deficient DCs have up-regulated expression of co-stimulatory molecules and increased T cell-priming activity. We further demonstrate that TBK1 negatively regulates the induction of a subset of genes by type I interferon receptor (IFNAR). Deletion of IFNAR1 could largely prevent aberrant T cell activation and autoimmunity in DC-conditional Tbk1 knockout mice. These findings identify a DC specific function of TBK1 in the maintenance of immune homeostasis and tolerance. PMID- 28356393 TI - JNeurosci Manuscripts May Now Include Extended Datasets. PMID- 28356394 TI - Age-Related Changes in Frontal, Striatal, and Medial Temporal Activity during Expected Value Evaluation. PMID- 28356392 TI - BATF2 inhibits immunopathological Th17 responses by suppressing Il23a expression during Trypanosoma cruzi infection. AB - Inappropriate IL-17 responses are implicated in chronic tissue inflammation. IL 23 contributes to Trypanosoma cruzi-specific IL-17 production, but the molecular mechanisms underlying regulation of the IL-23-IL-17 axis during T. cruzi infection are poorly understood. Here, we demonstrate a novel function of BATF2 as a negative regulator of Il23a in innate immune cells. IL-17, but not IFN gamma, was more highly produced by CD4+ T cells from spleens and livers of T. cruzi-infected Batf2-/- mice than by those of wild-type mice. In this context, Batf2-/- mice showed severe multiorgan pathology despite reduced parasite burden. T. cruzi-induced IL-23 production was increased in Batf2-/- innate immune cells. The T. cruzi-induced enhanced Th17 response was abrogated in Batf2-/-Il23a-/- mice. The interaction of BATF2 with c-JUN prevented c-JUN-ATF-2 complex formation, inhibiting Il23a expression. These results demonstrate that IFN-gamma inducible BATF2 in innate immune cells controls Th17-mediated immunopathology by suppressing IL-23 production during T. cruzi infection. PMID- 28356395 TI - The Dorsolateral Prefrontal Cortex, a Dynamic Cortical Area to Enhance Top-Down Attentional Control. PMID- 28356396 TI - Correction: Liu et al., "Vectored Intracerebral Immunization with the Anti-Tau Monoclonal Antibody PHF1 Markedly Reduces Tau Pathology in Mutant Tau Transgenic Mice". PMID- 28356397 TI - Correction: Favero and Castro-Alamancos, "Synaptic Cooperativity Regulates Persistent Network Activity in Neocortex". PMID- 28356398 TI - Erratum: de la Vega et al., "Large-Scale Meta-Analysis of Human Medial Frontal Cortex Reveals Tripartite Functional Organization". PMID- 28356400 TI - Phospho-ERK and sex steroids in the mPOA: involvement in male mouse sexual behaviour. AB - This paper aimed to investigate the mechanisms triggering ERK phosphorylation and its functional role in male sexual behaviour. ERK1/2-phosphorylated form was detected in the medial preoptic area of the hypothalamus (mPOA) during the sexual stimulation of naive and sexually experienced males who were killed 5 min after the first intromission. This mating-induced ERK phosphorylation was increased in sexually experienced males compared to that in naive mice. The functional role of the ERK1/2 pathway activation during sexual behaviour was explored with the administration of a MEK inhibitor, SL-327 (30 mg/kg, i.p.), 45 min before the contact with a receptive female. Inhibition of ERK phosphorylation was found to decrease sexual motivation in both naive and experienced males without altering their copulatory ability. The mechanisms potentially involved in this rapid ERK1/2 pathway activation were specified ex vivo on hypothalamic slices. A thirty minute incubation with 100 nM of testosterone (T), dihydrotestosterone (DHT) or oestradiol (E2) led to ERK phosphorylation. No changes were observed after incubation with testosterone 3-(O-carboxymethyl)oxime-BSA (T-BSA), an impermeable to the plasma membrane form of testosterone. All these results indicate that ERK phosphorylation within the mPOA could be a key player in the motivational signalling pathway and considered as an index of sexual motivation. They also demonstrate the involvement of oestrogen receptor (ER) and androgen receptor (AR) transduction pathways in steroid-dependent ERK activation. PMID- 28356403 TI - Short- and long-term effects of diving on pulmonary function. AB - The diving environment provides a challenge to the lung, including exposure to high ambient pressure, altered gas characteristics and cardiovascular effects on the pulmonary circulation. Several factors associated with diving affect pulmonary function acutely and can potentially cause prolonged effects that may accumulate gradually with repeated diving exposure. Evidence from experimental deep dives and longitudinal studies suggests long-term adverse effects of diving on the lungs in commercial deep divers, such as the development of small airways disease and accelerated loss of lung function. In addition, there is an accumulating body of evidence that diving with self-contained underwater breathing apparatus (scuba) may not be associated with deleterious effects on pulmonary function. Although changes in pulmonary function after single scuba dives have been found to be associated with immersion, ambient cold temperatures and decompression stress, changes in lung function were small and suggest a low likelihood of clinical significance. Recent evidence points to no accelerated loss of lung function in military or recreational scuba divers over time. Thus, the impact of diving on pulmonary function largely depends on factors associated with the individual diving exposure. However, in susceptible subjects clinically relevant worsening of lung function may occur even after single shallow-water scuba dives. PMID- 28356404 TI - Medical management of chronic thromboembolic pulmonary hypertension. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) results from incomplete resolution of acute pulmonary emboli, organised into fibrotic material that obstructs large pulmonary arteries, and distal small-vessel arteriopathy. Pulmonary endarterectomy (PEA) is the treatment of choice for eligible patients with CTEPH; in expert centres, PEA has low in-hospital mortality rates and excellent long-term survival. Supportive medical therapy consists of lifelong anticoagulation plus diuretics and oxygen, as needed.An important recent advance in medical therapy for CTEPH is the arrival of medical therapies for patients with inoperable disease or persistent/recurrent pulmonary hypertension after PEA. The soluble guanylate cyclase stimulator riociguat is licensed for the treatment of CTEPH in patients with inoperable disease or with recurrent/persistent pulmonary hypertension after PEA. Clinical trials of this agent have shown improvements in patients' haemodynamics and exercise capacity. Phosphodiesterase 5 inhibitors, endothelin receptor antagonists and prostanoids have been used in the treatment of CTEPH, but evidence of benefit is limited. Challenges in the future development of medical therapy for CTEPH include better understanding of the underlying pathology, end-points to monitor the condition's progress, and the optimisation of pulmonary arterial hypertension therapies in relation to diverse patient characteristics and emerging options such as balloon pulmonary angioplasty. PMID- 28356401 TI - Exposure to endocrine disruptors during adulthood: consequences for female fertility. AB - Endocrine disrupting chemicals are ubiquitous chemicals that exhibit endocrine disrupting properties in both humans and animals. Female reproduction is an important process, which is regulated by hormones and is susceptible to the effects of exposure to endocrine disrupting chemicals. Disruptions in female reproductive functions by endocrine disrupting chemicals may result in subfertility, infertility, improper hormone production, estrous and menstrual cycle abnormalities, anovulation, and early reproductive senescence. This review summarizes the effects of a variety of synthetic endocrine disrupting chemicals on fertility during adult life. The chemicals covered in this review are pesticides (organochlorines, organophosphates, carbamates, pyrethroids, and triazines), heavy metals (arsenic, lead, and mercury), diethylstilbesterol, plasticizer alternatives (di-(2-ethylhexyl) phthalate and bisphenol A alternatives), 2,3,7,8-tetrachlorodibenzo-p-dioxin, nonylphenol, polychlorinated biphenyls, triclosan, and parabens. This review focuses on the hypothalamus, pituitary, ovary, and uterus because together they regulate normal female fertility and the onset of reproductive senescence. The literature shows that several endocrine disrupting chemicals have endocrine disrupting abilities in females during adult life, causing fertility abnormalities in both humans and animals. PMID- 28356402 TI - The biochemical properties of the two Arabidopsis thaliana isochorismate synthases. AB - The important plant hormone salicylic acid (SA; 2-hydroxybenzoic acid) regulates several key plant responses including, most notably, defence against pathogens. A key enzyme for SA biosynthesis is isochorismate synthase (ICS), which converts chorismate into isochorismate, and for which there are two genes in Arabidopsis thaliana One (AtICS1) has been shown to be required for increased SA biosynthesis in response to pathogens and its expression can be stimulated throughout the leaf by virus infection and exogenous SA. The other (AtICS2) appears to be expressed constitutively, predominantly in the plant vasculature. Here, we characterise the enzymatic activity of both isozymes expressed as hexahistidine fusion proteins in Escherichia coli. We show for the first time that recombinant AtICS2 is enzymatically active. Both isozymes are Mg2+-dependent with similar temperature optima (ca. 33 degrees C) and similar Km values for chorismate of 34.3 +/- 3.7 and 28.8 +/- 6.9 uM for ICS1 and ICS2, respectively, but reaction rates were greater for ICS1 than for ICS2, with respective values for Vmax of 63.5 +/- 2.4 and 28.3 +/- 2.0 nM s-1 and for kcat of 38.1 +/- 1.5 and 17.0 +/- 1.2 min-1 However, neither enzyme displayed isochorismate pyruvate lyase (IPL) activity, which would enable these proteins to act as bifunctional SA synthases, i.e. to convert chorismate into SA. These results show that although Arabidopsis has two functional ICS enzymes, it must possess one or more IPL enzymes to complete biosynthesis of SA starting from chorismate. PMID- 28356405 TI - The pathophysiology of chronic thromboembolic pulmonary hypertension. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, progressive pulmonary vascular disease that is usually a consequence of prior acute pulmonary embolism. CTEPH usually begins with persistent obstruction of large and/or middle sized pulmonary arteries by organised thrombi. Failure of thrombi to resolve may be related to abnormal fibrinolysis or underlying haematological or autoimmune disorders. It is now known that small-vessel abnormalities also contribute to haemodynamic compromise, functional impairment and disease progression in CTEPH. Small-vessel disease can occur in obstructed areas, possibly triggered by unresolved thrombotic material, and downstream from occlusions, possibly because of excessive collateral blood supply from high-pressure bronchial and systemic arteries. The molecular processes underlying small-vessel disease are not completely understood and further research is needed in this area. The degree of small-vessel disease has a substantial impact on the severity of CTEPH and postsurgical outcomes. Interventional and medical treatment of CTEPH should aim to restore normal flow distribution within the pulmonary vasculature, unload the right ventricle and prevent or treat small-vessel disease. It requires early, reliable identification of patients with CTEPH and use of optimal treatment modalities in expert centres. PMID- 28356406 TI - Balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is thought to result from incomplete resolution of pulmonary thromboemboli that undergo organisation into fibrous tissue within pulmonary arterial branches, filling pulmonary arterial lumina with collagenous obstructions. The treatment of choice is pulmonary endarterectomy (PEA) in CTEPH centres, which has low post-operative mortality and good long-term survival. For patients ineligible for PEA or who have recurrent or persistent pulmonary hypertension after surgery, medical treatment with riociguat is beneficial. In addition, percutaneous balloon pulmonary angioplasty (BPA) is an emerging option, and promises haemodynamic and functional benefits for inoperable patients. In contrast to conventional angioplasty, BPA with undersized balloons over guide wires exclusively breaks intraluminal webs and bands, without dissecting medial vessel layers, and repeat sessions are generally required. Observational studies report that BPA improves haemodynamics, symptoms and functional capacity in patients with CTEPH, but controlled trials with long-term follow-up are needed. Complications include haemoptysis, wire injury, vessel dissection, vessel rupture, reperfusion pulmonary oedema, pulmonary parenchymal bleeding and haemorrhagic pleural effusions. This review summarises the available evidence for BPA, patient selection, recent technical refinements and periprocedural imaging, and discusses the potential future role of BPA in the management of CTEPH. PMID- 28356407 TI - An epidemiological analysis of the burden of chronic thromboembolic pulmonary hypertension in the USA, Europe and Japan. AB - Epidemiological data for chronic thromboembolic pulmonary hypertension (CTEPH) are limited and there are conflicting reports regarding its pathogenesis.A literature review was conducted to identify CTEPH epidemiological data up to June 2014. Data were analysed to provide estimates of the incidence of CTEPH in the USA, Europe and Japan. An epidemiological projection model derived country specific estimates of future incidence and diagnosis rates of CTEPH.Overall, 25 publications and 14 databases provided quantitative epidemiological data. In the USA and Europe, the crude annual incidence of diagnosed pulmonary embolism and crude annual full (i.e. diagnosed and undiagnosed) incidence of CTEPH were 66-104 and 3-5 cases per 100 000 population, respectively, while in Japan these rates were lower at 6.7 and 1.9 per 100 000 population, respectively. In 2013, 7-29% of CTEPH cases in Europe and the USA were diagnosed, and the majority of patients were in New York Heart Association functional class III/IV at diagnosis. The projection model indicated that incidence of CTEPH will continue to increase over the next decade.These data suggest that CTEPH is underdiagnosed and undertreated, and there is an urgent need to increase awareness of CTEPH. High-quality epidemiological studies are required to increase understanding of CTEPH. PMID- 28356408 TI - Biological responses of sharks to ocean acidification. AB - Sharks play a key role in the structure of marine food webs, but are facing major threats due to overfishing and habitat degradation. Although sharks are also assumed to be at relatively high risk from climate change due to a low intrinsic rate of population growth and slow rates of evolution, ocean acidification (OA) has not, until recently, been considered a direct threat. New studies have been evaluating the potential effects of end-of-century elevated CO2 levels on sharks and their relatives' early development, physiology and behaviour. Here, we review those findings and use a meta-analysis approach to quantify the overall direction and magnitude of biological responses to OA in the species of sharks that have been investigated to date. While embryo survival and development time are mostly unaffected by elevated CO2, there are clear effects on body condition, growth, aerobic potential and behaviour (e.g. lateralization, hunting and prey detection). Furthermore, studies to date suggest that the effects of OA could be as substantial as those due to warming in some species. A major limitation is that all past studies have involved relatively sedentary, benthic sharks that are capable of buccal ventilation-no studies have investigated pelagic sharks that depend on ram ventilation. Future research should focus on species with different life strategies (e.g. pelagic, ram ventilators), climate zones (e.g. polar regions), habitats (e.g. open ocean), and distinct phases of ontogeny in order to fully predict how OA and climate change will impact higher-order predators and therefore marine ecosystem dynamics. PMID- 28356409 TI - Embracing interactions in ocean acidification research: confronting multiple stressor scenarios and context dependence. AB - Changes in the Earth's environment are now sufficiently complex that our ability to forecast the emergent ecological consequences of ocean acidification (OA) is limited. Such projections are challenging because the effects of OA may be enhanced, reduced or even reversed by other environmental stressors or interactions among species. Despite an increasing emphasis on multifactor and multispecies studies in global change biology, our ability to forecast outcomes at higher levels of organization remains low. Much of our failure lies in a poor mechanistic understanding of nonlinear responses, a lack of specificity regarding the levels of organization at which interactions can arise, and an incomplete appreciation for linkages across these levels. To move forward, we need to fully embrace interactions. Mechanistic studies on physiological processes and individual performance in response to OA must be complemented by work on population and community dynamics. We must also increase our understanding of how linkages and feedback among multiple environmental stressors and levels of organization can generate nonlinear responses to OA. This will not be a simple undertaking, but advances are of the utmost importance as we attempt to mitigate the effects of ongoing global change. PMID- 28356410 TI - Why men trophy hunt. PMID- 28356411 TI - Jewelled spiders manipulate colour-lure geometry to deceive prey. AB - Selection is expected to favour the evolution of efficacy in visual communication. This extends to deceptive systems, and predicts functional links between the structure of visual signals and their behavioural presentation. Work to date has primarily focused on colour, however, thereby understating the multicomponent nature of visual signals. Here I examined the relationship between signal structure, presentation behaviour, and efficacy in the context of colour based prey luring. I used the polymorphic orb-web spider Gasteracantha fornicata, whose yellow- or white-and-black striped dorsal colours have been broadly implicated in prey attraction. In a manipulative assay, I found that spiders actively control the orientation of their conspicuous banded signals in the web, with a distinct preference for near-diagonal bearings. Further field-based study identified a predictive relationship between pattern orientation and prey interception rates, with a local maximum at the spiders' preferred orientation. There were no morph-specific effects on capture success, either singularly or via an interaction with pattern orientation. These results reveal a dynamic element in a traditionally 'static' signalling context, and imply differential functions for chromatic and geometric signal components across visual contexts. More broadly, they underscore how multicomponent signal designs and display behaviours may coevolve to enhance efficacy in visual deception. PMID- 28356412 TI - Dynamic masquerade with morphing three-dimensional skin in cuttlefish. AB - Masquerade is a defence tactic in which a prey resembles an inedible or inanimate object thus causing predators to misclassify it. Most masquerade colour patterns are static although some species adopt postures or behaviours to enhance the effect. Dynamic masquerade in which the colour pattern can be changed is rare. Here we report a two-step sensory process that enables an additional novel capability known only in cuttlefish and octopus: morphing three-dimensional physical skin texture that further enhances the optical illusions created by coloured skin patterns. Our experimental design incorporated sequential sensory processes: addition of a three-dimensional rock to the testing arena, which attracted the cuttlefish to settle next to it; then visual processing by the cuttlefish of physical textures on the rock to guide expression of the skin papillae, which can range from fully relaxed (smooth skin) to fully expressed (bumpy skin). When a uniformly white smooth rock was presented, cuttlefish moved to the rock and deployed a uniform body pattern with mostly smooth skin. When a rock with small-scale fragments of contrasting shells was presented, the cuttlefish deployed mottled body patterns with strong papillae expression. These robust and reversible responses indicate a sophisticated visual sensorimotor system for dynamic masquerade. PMID- 28356414 TI - Prospective Evaluation of Light Scatter Technology Paired with Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry for Rapid Diagnosis of Urinary Tract Infections. AB - Urinary tract infections are one of the most common reasons for health care visits. Diagnosis and optimal treatment often require a urine culture, which takes an average of 1.5 to 2 days from urine collection to results, delaying optimal therapy. Faster, but accurate, alternatives are needed. Light scatter technology has been proposed for several years as a rapid screening tool, whereby negative specimens are excluded from culture. A commercially available light scatter device, BacterioScan 216Dx (BacterioScan, Inc.), has recently been advertised for this application. Paired use of mass spectrometry (MS) for bacterial identification and automated-system-based susceptibility testing straight from the light scatter suspension might provide dramatic improvement in times to a result. The present study prospectively evaluated the BacterioScan device, with culture as the reference standard. Positive light scatter specimens were used for downstream rapid matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) MS organism identification and automated-system-based antimicrobial susceptibility testing. Prospective evaluation of 439 urine samples showed a sensitivity of 96.5%, a specificity of 71.4%, and positive and negative predictive values of 45.1% and 98.8%, respectively. MALDI-TOF MS analysis of the suspension after density-based selection yielded a sensitivity of 72.1% and a specificity of 96.9%. Antimicrobial susceptibility testing of the samples identified by MALDI-TOF MS produced an overall categorical agreement of 99.2%. Given the high sensitivity and negative predictive value of results obtained, BacterioScan 216Dx is a reasonable approach for urine screening and might produce negative results in as few as 3 h, with no downstream workup. Paired rapid identification and susceptibility testing might be useful when MALDI-TOF MS results in an organism identification, and it might decrease the time to a result by more than 24 h. PMID- 28356413 TI - Epidemiological and Molecular Characterization of an Invasive Group A Streptococcus emm32.2 Outbreak. AB - An emm32.2 invasive group A streptococcus (iGAS) outbreak occurred in Liverpool from January 2010 to September 2012. This genotype had not previously been identified in Liverpool, but was responsible for 32% (14/44) of all iGAS cases reported during this time period. We performed a case-case comparison of emm32.2 iGAS cases with non-emm32.2 control iGAS cases identified in the Liverpool population over the same time period to assess patient risk factors for emm32.2 iGAS infection. The emm32.2 iGAS cases were confined to the adult population. We show that homelessness, intravenous drug use, and alcohol abuse predisposed patients to emm32.2 iGAS disease; however, no obvious epidemiological linkage between the patients with emm32.2 iGAS could be identified. Comparative whole genome sequencing analysis of emm32.2 iGAS and non-emm32.2 control isolates was also performed to identify pathogen factors which might have driven the outbreak. We identified 19 genes, five of which had previously been implicated in virulence, which were present in all of the emm32.2 iGAS isolates but not present in any of the non-emm32.2 control isolates. We report that a novel emm32.2 genotype emerged in Liverpool in 2010 and identified a specific subset of genes, which could have allowed this novel emm32.2 genotype to persist in a disadvantaged population in the region over a 3-year period. PMID- 28356415 TI - Evaluation of GenoType NTM-DR Assay for Identification of Mycobacterium chimaera. AB - Identification of species within the Mycobacterium avium complex (MAC) is difficult, and most current diagnostic laboratory tests cannot distinguish between species included in the complex. Differentiation of species within the MAC is important, as Mycobacterium chimaera has recently emerged as a major cause of invasive cardiovascular infections following open heart surgery. A new commercial diagnostic assay, GenoType NTM-DR ver. 1.0, is intended to differentiate between three species within the MAC, namely, Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium chimaera In this study, we investigated an archival collection of 173 MAC isolates using 16S rRNA and 16S 23S internal transcribed spacer (ITS) gene sequencing, and GenoType NTM-DR was evaluated for identifying M. chimaera and other species belonging to the MAC. Species identification of 157/173 (91%) isolates with the GenoType NTM-DR assay was in agreement with 16S rRNA and 16S-23S ITS gene sequencing results. Misidentification occurred with 16 isolates which belonged to four species included in the MAC that are rarely encountered in clinical specimens. Despite some limitations of this assay, GenoType NTM-DR had 100% specificity for identifying M. chimaera This novel assay will enable diagnostic laboratories to differentiate species belonging to the Mycobacterium avium complex and to accurately identify M. chimaera It can produce rapid results and is also more cost efficient than gene sequencing methods. PMID- 28356416 TI - In Vitro Antifungal Susceptibility of Yeast and Mold Phases of Isolates of Dimorphic Fungal Pathogen Emergomyces africanus (Formerly Emmonsia sp.) from HIV Infected South African Patients. AB - Disseminated emmonsiosis is an important AIDS-related mycosis in South Africa that is caused by Emergomycesafricanus, a newly described and renamed dimorphic fungal pathogen. In vitro antifungal susceptibility data can guide management. Identification of invasive clinical isolates was confirmed phenotypically and by sequencing of the internal transcribed spacer region. Yeast and mold phase MICs of fluconazole, voriconazole, itraconazole, posaconazole, caspofungin, anidulafungin, micafungin, and flucytosine were determined with custom-made frozen broth microdilution (BMD) panels in accordance with Clinical and Laboratory Standards Institute recommendations. MICs of amphotericin B, itraconazole, posaconazole, and voriconazole were determined by Etest. Fifty unique E. africanus isolates were tested. The yeast and mold phase geometric mean (GM) BMD and Etest MICs of itraconazole were 0.01 mg/liter. The voriconazole and posaconazole GM BMD MICs were 0.01 mg/liter for both phases, while the GM Etest MICs were 0.001 and 0.002 mg/liter, respectively. The fluconazole GM BMD MICs were 0.18 mg/liter for both phases. The GM Etest MICs of amphotericin B, for the yeast and mold phases were 0.03 and 0.01 mg/liter. The echinocandins and flucytosine had very limited in vitro activity. Treatment and outcome data were available for 37 patients; in a multivariable model including MIC data, only isolation from blood (odds ratio [OR], 8.6; 95% confidence interval [CI], 1.3 to 54.4; P = 0.02) or bone marrow (OR, 12.1; 95% CI, 1.2 to 120.2; P = 0.03) (versus skin biopsy) was associated with death. In vitro susceptibility data support the management of disseminated emmonsiosis with amphotericin B, followed by itraconazole, voriconazole, or posaconazole. Fluconazole was a relatively less potent agent. PMID- 28356417 TI - Use of Ancillary Carbapenemase Tests To Improve Specificity of Phenotypic Definitions for Carbapenemase-Producing Enterobacteriaceae. AB - Carbapenemase-producing Enterobacteriaceae (CPE) are a significant threat to public health. In 2015, CDC revised the surveillance definition for CPE to include all Enterobacteriaceae resistant to any carbapenem tested. However, this definition is associated with poor specificity. We evaluated the performance of this definition, compared to carbapenemase PCR, for a collection of 125 Enterobacteriaceae We also investigated the impact of ancillary testing for carbapenemase of isolates that met the CDC CPE surveillance definition. The two ancillary tests evaluated were the Xpert Carba-R assay, a molecular test, and the carbapenem inactivation method (CIM). Two variables were evaluated for the CIM: suspension of organisms in double-distilled water (ddH2O) versus tryptic soy broth (TSB) to incubate disks, and incubation of plates for 6 h versus 18 to 20 h. The sensitivity and specificity of the Carba-R assay were 100% compared to the results of in-house PCR. The sensitivities of the CIM performed with TSB were 94.6% when read at 6 h and 97.7% when read at 18 to 20 h; the sensitivities with ddH2O were 88.0% when read at 6 h and 93.0% when incubated for 18 to 20 h. The specificity was 100% for all variables tested. Without ancillary testing, the sensitivity of the CDC definition was 98.9% for CPE, and the specificity was 6.1%. Testing isolates that screened positive by the CDC definition with the Xpert Carba-R did not change the sensitivity, and it improved the specificity to 100%. Similarly, the use of the CIM (TSB and 18 to 20 h of incubation) to confirm screen-positive isolates resulted in a sensitivity of 95.6% and specificity of 100%. PMID- 28356419 TI - Chronic breathlessness associated with poorer physical and mental health-related quality of life (SF-12) across all adult age groups. AB - Little is known about the impact of chronic breathlessness (modified Medical Research Council (mMRC) score >=2 for most days, at least three of the last six months) on health-related quality of life (Short Form-12 (SF-12)). 3005 adults from randomly selected households were interviewed face-to-face in South Australia. mMRC >=2 community prevalence was 2.9%. Adjusted analyses showed clinically meaningful and statistically significant decrements of physical and mental components of SF-12 (mean SF-12 summary scores in physical (-13.0 (-16.0 to -10.2)) and mental (-10.7 (-13.7 to -7.8)) components compared with people with mMRC=0) as chronic breathlessness severity increased, across five age groupings. PMID- 28356418 TI - Impact of Contaminating DNA in Whole-Genome Amplification Kits Used for Metagenomic Shotgun Sequencing for Infection Diagnosis. AB - Whole-genome amplification (WGA) is a useful tool for amplification of very small quantities of DNA for many uses, including metagenomic shotgun sequencing for infection diagnosis. Depending on the application, background DNA from WGA kits can be problematic. Three WGA kits were tested for their utility in a metagenomics approach to identify the pathogens in sonicate fluid comprised of biofilms and other materials dislodged from the surfaces of explanted prosthetic joints using sonication. The Illustra V2 Genomiphi, Illustra single cell Genomiphi, and Qiagen REPLI-g single cell kits were used to test identical sonicate fluid samples. Variations in the number of background reads, the genera identified in the background, and the number of reads from known pathogens known to be present in the samples were observed between kits. These results were then compared to those obtained with a library preparation without prior WGA using an NEBNext Ultra II paired-end kit, which requires a very small amount of input DNA. This approach also resulted in the presence of contaminant bacterial DNA and yielded fewer reads from the known pathogens. These findings highlight the impact that WGA kit selection can have on metagenomic analysis of low-biomass samples and the importance of the careful selection and consideration of the implications of using these tools. PMID- 28356420 TI - PKC-mediated phosphorylation of nuclear lamins at a single serine residue regulates interphase nuclear size in Xenopus and mammalian cells. AB - How nuclear size is regulated is a fundamental cell-biological question with relevance to cancers, which often exhibit enlarged nuclei. We previously reported that conventional protein kinase C (cPKC) contributes to nuclear size reductions that occur during early Xenopus development. Here we report that PKC-mediated phosphorylation of lamin B3 (LB3) contributes to this mechanism of nuclear size regulation. By mapping PKC phosphorylation sites on LB3 and testing the effects of phosphomutants in Xenopus laevis embryos, we identify the novel site S267 as being an important determinant of nuclear size. Furthermore, FRAP studies demonstrate that phosphorylation at this site increases lamina dynamics, providing a mechanistic explanation for how PKC activity influences nuclear size. We subsequently map this X. laevis LB3 phosphorylation site to a conserved site in mammalian lamin A (LA), S268. Manipulating PKC activity in cultured mammalian cells alters nuclear size, as does expression of LA-S268 phosphomutants. Taken together, these data demonstrate that PKC-mediated lamin phosphorylation is a conserved mechanism of nuclear size regulation. PMID- 28356421 TI - UNC-45A is required for neurite extension via controlling NMII activation. AB - UNC-45A is a highly conserved member of the UNC-45/CRO1/She4p family of proteins, which act as chaperones for conventional and nonconventional myosins. NMII mediates contractility and actin-based motility, which are fundamental for proper growth cone motility and neurite extension. The presence and role of UNC-45A in neuronal differentiation have been largely unknown. Here we demonstrate that UNC 45A is a novel growth cone--localized, NMII-associated component of the multiprotein complex regulating growth cone dynamics. We show that UNC-45A is dispensable for neuron survival but required for neurite elongation. Mechanistically, loss of UNC-45A results in increased levels of NMII activation. Collectively our results provide novel insights into the molecular mechanisms of neurite growth and define UNC-45A as a novel and master regulator of NMII mediated cellular processes in neurons. PMID- 28356422 TI - Clustering of integrin alpha5 at the lateral membrane restores epithelial polarity in invasive colorectal cancer cells. AB - Apicobasolateral polarity is a fundamental property of epithelial cells, and its loss is a hallmark of cancer. Integrin-mediated contact with the extracellular matrix defines the basal surface, setting in motion E-cadherin-mediated cell-cell contact, which establishes apicobasolateral polarity. Role(s) for lateral integrins in this polarization process and the consequences of their disruption are incompletely understood. We show that addition of an integrin beta1 activating monoclonal antibody, P4G11, to invasive colorectal cancer cells in three-dimensional type 1 collagen reverts the invasive phenotype and restores apicobasolateral polarity. P4G11 induces clustering of integrin alpha5beta1 at lateral, intercellular surfaces. This leads to deposition and polymerization of fibronectin and recruitment of paxillin to sites of lateral integrin alpha5beta1 clustering and is followed by tight junction formation, as determined by ZO-1 localization. Inducible elimination of integrin alpha5 abrogates the epithelial organizing effects of P4G11. In addition, polymerization of fibronectin is required for the effects of P4G11, and addition of polymerized superfibronectin is sufficient to induce tight junction formation and apicobasolateral polarization. In the normal human colon, we show that integrin alpha5 localizes to the lateral membrane of terminally differentiated colonocytes and that integrin alpha5 staining may be reduced in colorectal cancer. Thus we propose a novel role for integrin alpha5beta1 in regulating epithelial morphogenesis. PMID- 28356423 TI - Phosphorylated cortactin recruits Vav2 guanine nucleotide exchange factor to activate Rac3 and promote invadopodial function in invasive breast cancer cells. AB - Breast carcinoma cells use specialized, actin-rich protrusions called invadopodia to degrade and invade through the extracellular matrix. Phosphorylation of the actin nucleation-promoting factor and actin-stabilizing protein cortactin downstream of the epidermal growth factor receptor-Src-Arg kinase cascade is known to be a critical trigger for invadopodium maturation and subsequent cell invasion in breast cancer cells. The functions of cortactin phosphorylation in this process, however, are not completely understood. We identify the Rho-family guanine nucleotide exchange factor Vav2 in a comprehensive screen for human SH2 domains that bind selectively to phosphorylated cortactin. We demonstrate that the Vav2 SH2 domain binds selectively to phosphotyrosine-containing peptides corresponding to cortactin tyrosines Y421 and Y466 but not to Y482. Mutation of the Vav2 SH2 domain disrupts its recruitment to invadopodia, and an SH2-domain mutant form of Vav2 cannot support efficient matrix degradation in invasive MDA MB-231 breast cancer cells. We show that Vav2 function is required for promoting invadopodium maturation and consequent actin polymerization, matrix degradation, and invasive migratory behavior. Using biochemical assays and a novel Rac3 biosensor, we show that Vav2 promotes Rac3 activation at invadopodia. Rac3 knockdown reduces matrix degradation by invadopodia, whereas a constitutively active Rac3 can rescue the deficits in invadopodium function in Vav2-knockdown cells. Together these data indicate that phosphorylated cortactin recruits Vav2 to activate Rac3 and promote invadopodial maturation in invasive breast cancer cells. PMID- 28356424 TI - Bridging length scales to measure polymer assembly. AB - Time-resolvable quantitative measurements of polymer concentration are very useful to elucidate protein polymerization pathways. There are numerous techniques to measure polymer concentrations in purified protein solutions, but few are applicable in vivo. Here we develop a methodology combining microscopy and spectroscopy to overcome the limitations of both approaches for measuring polymer concentration in cells and cell extracts. This technique is based on quantifying the relationship between microscopy and spectroscopy measurements at many locations. We apply this methodology to measure microtubule assembly in tissue culture cells and Xenopus egg extracts using two-photon microscopy with FLIM measurements of FRET. We find that the relationship between FRET and two photon intensity quantitatively agrees with predictions. Furthermore, FRET and intensity measurements change as expected with changes in acquisition time, labeling ratios, and polymer concentration. Taken together, these results demonstrate that this approach can quantitatively measure microtubule assembly in complex environments. This methodology should be broadly useful for studying microtubule nucleation and assembly pathways of other polymers. PMID- 28356425 TI - Efficacy of the PARP Inhibitor Veliparib with Carboplatin or as a Single Agent in Patients with Germline BRCA1- or BRCA2-Associated Metastatic Breast Cancer: California Cancer Consortium Trial NCT01149083. AB - Purpose: We aimed to establish the MTD of the poly (ADP-ribose) (PAR) polymerase inhibitor, veliparib, in combination with carboplatin in germline BRCA1- and BRCA2- (BRCA)-associated metastatic breast cancer (MBC), to assess the efficacy of single-agent veliparib, and of the combination treatment after progression, and to correlate PAR levels with clinical outcome.Experimental Design: Phase I patients received carboplatin (AUC of 5-6, every 21 days), with escalating doses (50-20 mg) of oral twice-daily (BID) veliparib. In a companion phase II trial, patients received single-agent veliparib (400 mg BID), and upon progression, received the combination at MTD. Peripheral blood mononuclear cell PAR and serum veliparib levels were assessed and correlated with outcome.Results: Twenty-seven phase I trial patients were evaluable. Dose-limiting toxicities were nausea, dehydration, and thrombocytopenia [MTD: veliparib 150 mg po BID and carboplatin (AUC of 5)]. Response rate (RR) was 56%; 3 patients remain in complete response (CR) beyond 3 years. Progression-free survival (PFS) and overall survival (OS) were 8.7 and 18.8 months. The PFS and OS were 5.2 and 14.5 months in the 44 patients in the phase II trial, with a 14% RR in BRCA1 (n = 22) and 36% in BRCA2 (n = 22). One of 30 patients responded to the combination therapy after progression on veliparib. Higher baseline PAR was associated with clinical benefit.Conclusions: Safety and efficacy are encouraging with veliparib alone and in combination with carboplatin in BRCA-associated MBC. Lasting CRs were observed when the combination was administered first in the phase I trial. Further investigation of PAR level association with clinical outcomes is warranted. Clin Cancer Res; 23(15); 4066-76. (c)2017 AACR. PMID- 28356426 TI - Whole-Grain Intake, Reflected by Dietary Records and Biomarkers, Is Inversely Associated with Circulating Insulin and Other Cardiometabolic Markers in 8- to 11 Year-Old Children. AB - Background: Whole-grain consumption seems to be cardioprotective in adults, but evidence in children is limited.Objective: We investigated whether intakes of total whole grain and dietary fiber as well as specific whole grains were associated with fat mass and cardiometabolic risk profile in children.Methods: We collected cross-sectional data on parental education, puberty, diet by 7-d records, and physical activity by accelerometry and measured anthropometry, fat mass index by dual-energy X-ray absorptiometry, and blood pressure in 713 Danish children aged 8-11 y. Fasting blood samples were obtained and analyzed for alkylresorcinols, biomarkers of whole-grain wheat and rye intake, HDL and LDL cholesterol, triacylglycerols, insulin, and glucose. Linear mixed models included puberty, parental education, physical activity, and intakes of energy, fruit and vegetables, saturated fat, and n-3 (omega-3) polyunsaturated fatty acids.Results: Median (IQR) whole-grain and dietary fiber intakes were 52 g/d (35-72 g/d) and 17 g/d (14-22 g/d), respectively. Fourteen percent of children were overweight or obese and most had low-risk cardiometabolic profiles. Dietary whole-grain and fiber intakes were not associated with fat mass index but were inversely associated with serum insulin [both P < 0.01; e.g., with 0.68 pmol/L (95% CI: 0.26, 1.10 pmol/L) lower insulin . g whole grain-1 . MJ-1]. Whole-grain oat intake was inversely associated with fat mass index, systolic blood pressure, and LDL cholesterol (all P < 0.05) as well as insulin (P = 0.003), which also tended to be inversely associated with whole-grain rye intake (P = 0.11). Adjustment for fat mass index did not change the associations. The C17-to-C21 alkylresorcinol ratio, reflecting whole-grain rye to wheat intake, was inversely associated with insulin (P < 0.001).Conclusions: Higher whole-grain intake was associated with lower serum insulin independently of fat mass in 8- to 11-y-old Danish children. Whole-grain oat intake was linked to an overall protective cardiometabolic profile, and whole-grain rye intake was marginally associated with lower serum insulin. This supports whole grains as healthy dietary components in childhood. This trial was registered at clinicaltrials.gov as NCT01577277. PMID- 28356427 TI - Microbiota-Gut-Brain Axis: Modulator of Host Metabolism and Appetite. AB - The gut harbors an enormous diversity of microbes that are essential for the maintenance of homeostasis in health and disease. A growing body of evidence supports the role of this microbiota in influencing host appetite and food intake. Individual species within the gut microbiota are under selective pressure arising from nutrients available and other bacterial species present. Each bacterial species within the gut aims to increase its own fitness, habitat, and survival via specific fermentation of dietary nutrients and secretion of metabolites, many of which can influence host appetite and eating behavior by directly affecting nutrient sensing and appetite and satiety-regulating systems. These include microbiota-produced neuroactives and short-chain fatty acids. In addition, the gut microbiota is able to manipulate intestinal barrier function, interact with bile acid metabolism, modulate the immune system, and influence host antigen production, thus indirectly affecting eating behavior. A growing body of evidence indicates that there is a crucial role for the microbiota in regulating different aspects of eating-related behavior, as well as behavioral comorbidities of eating and metabolic disorders. The importance of intestinal microbiota composition has now been shown in obesity, anorexia nervosa, and forms of severe acute malnutrition. Understanding the mechanisms in which the gut microbiota can influence host appetite and metabolism will provide a better understanding of conditions wherein appetite is dysregulated, such as obesity and other metabolic or eating disorders, leading to novel biotherapeutic strategies. PMID- 28356428 TI - Avanelle Kirksey, PhD (1926-2016). PMID- 28356429 TI - Enrichment of Triglyceride-Rich Lipoproteins with Apolipoprotein C-I Is Positively Associated with Their Delayed Plasma Clearance Independently of Other Transferable Apolipoproteins in Postmenopausal Overweight and Obese Women. AB - Background: The role of plasma apolipoprotein (apo) C-I in cardiometabolic risk in humans is unclear. However, in vitro studies showed a dual role for apoC-I, both protective and harmful, depending on the carrier lipoprotein.Objective: We tested the hypothesis that triglyceride (TG)-rich lipoprotein (TRL) apoC-I, not total or HDL apoC-I, is associated with delayed postprandial plasma clearance of TRLs, independently of apoC-II, apoC-III, and apoE.Methods: This cross-sectional study examines the plasma clearance of a 13C-triolein-labeled high-fat meal (68% fat energy) in 20 postmenopausal overweight and obese women [body mass index (in kg/m2) >=27; aged 45-74 y] as the increment change in area under the 6-h postprandial curves (iAUC6h) of TRL parameters. Lipoproteins were fractionated by fast-protein LC. Transferable apolipoproteins were measured by ELISA. TRL enrichment with apolipoproteins was calculated by dividing their TRL concentrations by TRL apoB. The effects of human apoC-I and apoC-III on the hydrolysis and storage of 3H-triolein-labeled TRLs were tested in 3T3-L1 adipocytes.Results: TRL apoC-I was positively associated with plasma apo B-48 and total and non-HDL TGs, cholesterol, and apoB (r = 0.52-0.97) and negatively with HDL cholesterol (r = -0.52) and LDL diameter (r = -0.91) (P < 0.05). Total and HDL apoC-I were correlated only with total (r = 0.62) and HDL (r = 0.75) cholesterol. Women with high fasting TRL enrichment with apoC-I (99-365 MUmol apoC-I/MUmol apoB), but not apoC-II, apoC-III, or apoE, had higher iAUC6h for TGs (+195%), 13C-TGs (+319%), and apo B-48 (+186%) than those with low enrichment (14 97 MUmol apoC-I/MUmol apoB). The 4-h postprandial increase in TRL apoC-I was associated with a 4-h increase in TRL TGs and iAUC6h for TGs, 13C-TGs, and apo B 48 (r = 0.74-0.86, P < 0.001), independently of 4-h changes in TRL apoB, apoC-II, apoC-III, or apoE. ApoC-I and apoC-III inhibited 3H-TRL clearance by adipocytes by >75% (P < 0.001).Conclusions: TRL enrichment with apoC-I is positively associated with postprandial hypertriglyceridemia and remnant accumulation in postmenopausal overweight and obese women, independently of apoC-II, apoC-III, or apoE, which may be due to inhibiting TRL clearance by adipocytes. Reducing TRL apoC-I may ameliorate delayed postprandial plasma clearance of TRLs and associated risks in humans. PMID- 28356430 TI - A Novel Organic Selenium Compound Exerts Unique Regulation of Selenium Speciation, Selenogenome, and Selenoproteins in Broiler Chicks. AB - Background: A new organic selenium compound, 2-hydroxy-4-methylselenobutanoic acid (SeO), displayed a greater bioavailability than sodium selenite (SeNa) or seleno-yeast (SeY) in several species.Objective: This study sought to determine the regulation of the speciation of selenium, expression of selenogenome and selenocysteine biosynthesis and degradation-related genes, and production of selenoproteins by the 3 forms of selenium in the tissues of broiler chicks.Methods: Day-old male chicks (n = 6 cages/diet, 6 chicks/cage) were fed a selenium-deficient, corn and soy-based diet [base diet (BD), 0.05 mg Se/kg] or the BD + SeNa, SeY, or SeO at 0.2 mg Se/kg for 6 wk. Plasma, livers, and pectoral and thigh muscles were collected at weeks 3 and 6 to assay for total selenium, selenomethionine, selenocysteine, redox status, and selected genes, proteins, and enzymes.Results: Although both SeY and SeO produced greater concentrations (P < 0.05) of total selenium (20-172%) and of selenomethionine (<=15-fold) in the liver, pectoral muscle, and thigh than those of SeNa, SeO further raised (P < 0.05) these concentrations by 13-37% and 43-87%, respectively, compared with SeY. Compared with the BD, only SeO enhanced (P < 0.05) the mRNA of selenoprotein (Seleno) s and methionine sulfoxide reductase B1 (Msrb1) in the liver and thigh (62-98%) and thioredoxin reductase (TXRND) activity in the pectoral and thigh muscles (20-37%) at week 3. Furthermore, SeO increased (P < 0.05) the expression of glutathione peroxidase (Gpx) 3, GPX4, SELENOP, and SELENOU relative to the SeNa group by 26-207%, and the expression of Selenop, O-phosphoseryl-transfer RNA (tRNA):selenocysteinyl-tRNA synthase, GPX4, and SELENOP relative to the SeY group by 23-55% in various tissues.Conclusions: Compared with SeNa or SeY, SeO demonstrated a unique ability to enrich selenomethionine and total selenium depositions, to induce the early expression of Selenos and Mrsb1 mRNA and TXRND activity, and to enhance the protein production of GPX4, SELENOP, and SELENOU in the tissues of chicks. PMID- 28356431 TI - Acute Peanut Consumption Alters Postprandial Lipids and Vascular Responses in Healthy Overweight or Obese Men. AB - Background: Postprandial hyperlipidemia is associated with impaired endothelial function. Peanut consumption favorably affects the lipid and lipoprotein profile; however, the effects on endothelial function remain unclear.Objective: The purpose of the study was to evaluate the effects of acute peanut consumption as part of a high-fat meal on postprandial endothelial function.Methods: We conducted a randomized, controlled, crossover postprandial study to evaluate the effect of acute peanut consumption on postprandial lipids and endothelial function as assessed by flow-mediated dilatation (FMD) of the brachial artery in 15 healthy overweight or obese men [mean age: 26.7 y; mean body mass index (in kg/m2): 31.4]. Participants consumed, in a randomized order, a peanut meal containing 3 ounces (85 g) ground peanuts (1198 kcal; 40.0% carbohydrate, 47.7% fat, 19.4% saturated fat, 13.2% protein) and a control meal matched for energy and macronutrient content. Meals were in the form of a shake, scheduled >=1 wk apart. Lipids, lipoproteins, glucose, and insulin were measured at baseline (0 min) and at 30, 60, 120, and 240 min after shake consumption. FMD was measured at baseline and at 240 min.Results: Acute peanut consumption blunted the serum triglyceride (TG) response 120 and 240 min after consumption compared with the control meal (means +/- SEMs-120 min: 188.9 +/- 19.4 compared with 197.5 +/- 20.7 mg/dL; 240 min: 189.9 +/- 24.3 compared with 197.3 +/- 18.4 mg/dL; P < 0.05 for both). Total, LDL, and HDL cholesterol and glucose and insulin responses were similar between the test meals. Compared with baseline, only the control meal significantly decreased FMD at 240 min (control: -1.2% +/- 0.5%; P = 0.029; peanut: -0.6% +/- 0.5%; P = 0.3). Participants with higher baseline total (>150 mg/dL) and LDL (>100 mg/dL)-cholesterol concentrations showed a significant decrease in FMD after the control meal (-1.8%, P = 0.017; -2.0%, P = 0.038), whereas the peanut meal maintained endothelial function in all participants irrespective of total- and LDL-cholesterol concentrations.Conclusion: The inclusion of 85 g peanuts (3 ounces) as part of a high-fat meal improved the postprandial TG response and preserved endothelial function in healthy overweight or obese men. This trial was registered at clinicaltrials.gov as NCT01405300. PMID- 28356432 TI - The Inflammatory Potential of the Diet Is Associated with Depressive Symptoms in Different Subgroups of the General Population. AB - Background: Low-grade chronic inflammation, which can be modulated by diet, has been suggested as an important risk factor for depression, but few studies have investigated the association between the inflammatory potential of the diet and depression.Objective: We investigated the prospective association between the inflammatory potential of the diet, measured by the Dietary Inflammatory Index (DII), and incident depressive symptoms and tested the potential modulating effect of sex, age, physical activity, and smoking status.Methods: This study included 3523 participants (aged 35-60 y) from the SU.VI.MAX (Supplementation en Vitamines et Mineraux Antioxydants) cohort, who were initially free of depressive symptoms. Baseline DII (1994-1996) was computed by using repeated 24-h dietary records. Incident depressive symptoms were defined by a Center for Epidemiologic Studies-Depression Scale score >=17 for men and >=23 for women in 2007-2009. We used multivariable logistic regression models to estimate ORs and 95% CIs, and modeled the DII as a continuous variable and as sex-specific quartiles.Results: A total of 172 cases of incident depressive symptoms were identified over a mean follow-up of 12.6 y. The DII was not associated with incident depressive symptoms in the full sample. In sex-specific models, men with a higher DII had a higher risk of incident depressive symptoms (quartile 4 compared with quartile 1-OR: 2.32; 95% CI: 1.01, 5.35), but the association was only marginally significant (P trend = 0.06). When analyses were performed across smoking status, current and former smokers with a higher DII had a higher risk of incident depressive symptoms (quartile 4 compared with quartile 1-OR: 2.21; 95% CI: 1.08, 4.52). A positive association was also observed among less physically active participants (quartile 4 compared with quartile 1-OR: 2.07; 95% CI: 1.05, 4.07).Conclusion: The promotion of a healthy diet with anti-inflammatory properties may help to prevent depressive symptoms, particularly among men, smokers, or physically inactive individuals. This trial was registered at clinicaltrials.gov as NCT0027242. PMID- 28356434 TI - The Growth-Promoting Effect of Dietary Nucleotides in Fish Is Associated with an Intestinal Microbiota-Mediated Reduction in Energy Expenditure. AB - Background: Nucleotides have been used as functional nutrients to improve the growth and health of animals, including fish. The mechanism involved in the growth-promotion effect of nucleotides is still unclear.Objective: We investigated the bioenergetic mechanism underlying the growth-promotion effect of nucleotides in zebrafish and the associated roles played by the intestinal microbiota.Methods: Larval zebrafish were fed a control or a 0.1% mixed nucleotides-supplemented diet for 2 wk. Standard metabolic rate, the minimal rate of energy expenditure by animals at rest, was evaluated by oxygen consumption with the use of a respirometer. The expressions of fasting-induced adipose factor (Fiaf), inflammatory cytokines, and genes involved in fatty acid (FA) oxidation were tested by quantitative reverse transcriptase-polymerase chain reaction. The intestinal microbiota from the nucleotide-fed fish (NT fish) or control fish was transferred to 3-d postfertilization germ-free zebrafish in which oxygen consumption and expression of cytokines and fiaf were evaluated.Results: Compared with controls, nucleotide supplementation at 0.1% increased the weight and energy gains of zebrafish by 10% and 25%, respectively (P < 0.01). Standard metabolic rate was 28% lower in NT fish than in controls (P < 0.001). Nucleotide supplementation downregulated the inflammatory tone in the head kidney of the fish. Moreover, NT fish had a 51% lower intestinal expression of fiaf than did controls (P < 0.05), which was consistent with decreased expression of key genes involved in FA oxidation [carnitine:palmitoyl transferase 1a (cpt1a) and medium chain acyl coenzyme A dehydrogenase (mcad)] in liver and muscle. Germ-free zebrafish colonized with microbiota from NT fish had a 25% lower standard metabolic rate than did those colonized by control microbiota (P < 0.01), whereas direct nucleotide feeding of germ-free zebrafish did not affect standard metabolic rate relative to germ-free controls that were not fed nucleotides. Furthermore, germ-free zebrafish colonized with nucleotide microbiota exhibited downregulated inflammatory tone and 33% lower fiaf expression compared with their control microbiota-colonized counterparts.Conclusions: The growth-promoting effect of dietary nucleotides in zebrafish involves 2 intestinal microbiota mediated mechanisms that result in reduced standard metabolic rate: 1) lower inflammatory tone and 2) reduced FA oxidation associated with increased microbial suppression of intestinal fiaf. PMID- 28356435 TI - Robert Proulx Heaney, MD (1927-2016). PMID- 28356433 TI - Circulating Vitamin K Is Inversely Associated with Incident Cardiovascular Disease Risk among Those Treated for Hypertension in the Health, Aging, and Body Composition Study (Health ABC). AB - Background: A role for vitamin K in coronary artery calcification (CAC), a subclinical manifestation of cardiovascular disease (CVD), has been proposed because vitamin K-dependent proteins, including the calcification inhibitor matrix Gla protein (MGP), are present in vascular tissue. Observational studies found that low circulating phylloquinone (vitamin K-1) was associated with increased CAC progression, especially in persons treated for hypertension. It is unknown whether hypertension treatment modifies this putative role of vitamin K in clinical CVD risk.Objective: We determined the association between vitamin K status and incident clinical CVD in older adults in the Health ABC (Health, Aging, and Body Composition Study) and whether the association differed by hypertension treatment status.Methods: Plasma phylloquinone was measured in 1061 participants free of CVD (70-79 y of age, 58% women, 39% black). Plasma uncarboxylated MGP [(dp)ucMGP] was measured in a subset of 635 participants. Multivariate Cox models estimated the HR for incident CVD over 12.1 follow-up years. Effect modification by hypertension was tested with the use of interaction terms.Results: Neither low plasma phylloquinone (<0.2 nmol/L) nor elevated (dp)ucMGP (>=574 pmol/L) was significantly associated with incident CVD [respective HRs (95% CIs): 1.27 (0.75, 2.13) and 1.02 (0.72, 1.45)]. In participants treated for hypertension (n = 489; 135 events), low plasma phylloquinone was associated with higher CVD risk overall (HR: 2.94; 95% CI: 1.41, 6.13). In those with untreated hypertension (n = 153; 48 events) and without hypertension (n = 418; 92 events), low plasma phylloquinone was not associated with incident CVD. The association between high (dp)ucMGP did not differ by hypertension treatment status (P-interaction = 0.72).Conclusions: Vitamin K status was not significantly associated with CVD risk overall, but low plasma phylloquinone was associated with a higher CVD risk in older adults treated for hypertension. Additional evidence from larger clinical studies is needed to clarify the importance of vitamin K to CVD in persons treated for hypertension, a segment of the population at high risk of clinical CVD events. PMID- 28356436 TI - Intestinal Barrier Function and the Gut Microbiome Are Differentially Affected in Mice Fed a Western-Style Diet or Drinking Water Supplemented with Fructose. AB - Background: The consumption of a Western-style diet (WSD) and high fructose intake are risk factors for metabolic diseases. The underlying mechanisms are largely unclear.Objective: To unravel the mechanisms by which a WSD and fructose promote metabolic disease, we investigated their effects on the gut microbiome and barrier function.Methods: Adult female C57BL/6J mice were fed a sugar- and fat-rich WSD or control diet (CD) for 12 wk and given access to tap water or fructose-supplemented water. The microbiota was analyzed with the use of 16S rRNA gene sequencing. Barrier function was studied with the use of permeability tests, and endotoxin, mucus thickness, and gene expressions were measured.Results: The WSD increased body weight gain but not endotoxin translocation compared with the CD. In contrast, high fructose intake increased endotoxin translocation 2.6- and 3.8-fold in the groups fed the CD + fructose and WSD + fructose, respectively, compared with the CD group. The WSD + fructose treatment also induced a loss of mucus thickness in the colon (-46%) and reduced defensin expression in the ileum and colon. The lactulose:mannitol ratio in the WSD + fructose mice was 1.8-fold higher than in the CD mice. Microbiota analysis revealed that fructose, but not the WSD, increased the Firmicutes:Bacteroidetes ratio by 88% for CD + fructose and 63% for WSD + fructose compared with the CD group. Bifidobacterium abundance was greater in the WSD mice than in the CD mice (63-fold) and in the WSD + fructose mice than in the CD + fructose mice (330-fold).Conclusions: The consumption of a WSD or high fructose intake differentially affects gut permeability and the microbiome. Whether these differences are related to the distinct clinical outcomes, whereby the WSD primarily promotes weight gain and high fructose intake causes barrier dysfunction, needs to be investigated in future studies. PMID- 28356437 TI - Getting the terminology right in sexual health research: the importance of accurately classifying fuck buddies among men who have sex with men. AB - OBJECTIVE: The aim of this report was to raise the issue of the definition and classification of partner terminology in men who have sex with men (MSM) research, particularly in regards to 'fuck buddies'. If definitions in research differ from general consensus in the MSM population, it is possible that public health strategies will be ineffective as the target population may be inaccurate. METHODS: Thirty semistructured interviews with MSM attending the Melbourne Sexual Health Centre were conducted, focusing on the willingness to change sexual practices to reduce the risk of pharyngeal gonorrhoea. As part of these interviews, men were also asked their views on the terminology they used to describe their relationships and sexual partners. RESULTS: The degree of emotional attachment often defined the type or classification of relationships. There was a consensus among men that partners they engaged with for 'sex only' were classified as casual partners and partners with whom there was an emotional attachment or formalisation of the relationship were classified as 'regular partners'. However, the classification of 'fuck buddy' as a regular or casual partner was less clear. CONCLUSIONS: Further research is needed to ascertain the ways in which men conceptualise sexual relationships and define or classify partner types, particularly 'fuck buddy' relationships. A third category for sexual relationships should be considered to encapsulate fuck buddy relationships. PMID- 28356438 TI - Googling Service Boundaries for Endovascular Clot Retrieval Hub Hospitals in a Metropolitan Setting: Proof-of-Concept Study. AB - BACKGROUND AND PURPOSE: There is great interest in how endovascular clot retrieval hubs provide services to a population. We applied a computational method to objectively generate service boundaries for such endovascular clot retrieval hubs, defined by traveling time to hub. METHODS: Stroke incidence data merged with population census to estimate numbers of stroke in metropolitan Melbourne, Australia. Traveling time from randomly generated addresses to 4 endovascular clot retrieval-capable hubs (Royal Melbourne Hospital [RMH], Monash Medical Center [MMC], Alfred Hospital [ALF], and Austin Hospital [AUS]) estimated using Google Map application program interface. Boundary maps generated based on traveling time at various times of day for combinations of hubs. RESULTS: In a 2 hub model, catchment was best distributed when RMH was paired with MMC (model 1a, RMH 1765 km2 and MMC 1164 km2) or with AUS (model 1c, RMH 1244 km2 and AUS 1685 km2), with no statistical difference between models (P=0.20). Catchment was poorly distributed when RMH was paired with ALF (model 1b, RMH 2252 km2 and ALF 676 km2), significantly different from both models 1a and 1c (both P<0.05). Model 1a had the greatest proportion of patients arriving within ideal time of 30 minutes followed by model 1c (P<0.001). In a 3-hub model, the combination of RMH, MMC, and AUS was superior to that of RMH, MMC, and ALF in catchment distribution and travel time. The method was also successfully applied to the city of Adelaide demonstrating wider applicability. CONCLUSIONS: We provide proof of concept for a novel computational method to objectively designate service boundaries for endovascular clot retrieval hubs. PMID- 28356440 TI - Fractional Flow Reserve and Cardiac Events in Coronary Artery Disease: Data From a Prospective IRIS-FFR Registry (Interventional Cardiology Research Incooperation Society Fractional Flow Reserve). AB - BACKGROUND: We evaluated the prognosis of deferred and revascularized coronary stenoses after fractional flow reserve (FFR) measurement to assess its revascularization threshold in clinical practice. METHODS: The IRIS-FFR registry (Interventional Cardiology Research In-cooperation Society Fractional Flow Reserve) prospectively enrolled 5846 patients with >=1coronary lesion with FFR measurement. Revascularization was deferred in 6468 lesions and performed in 2165 lesions after FFR assessment. The primary end point was major adverse cardiac events (cardiac death, myocardial infarction, and repeat revascularization) at a median follow-up of 1.9 years and analyzed on a per-lesion basis. A marginal Cox model accounted for correlated data in patients with multiple lesions, and a model to predict per-lesion outcomes was adjusted for confounding factors. RESULTS: For deferred lesions, the risk of major adverse cardiac events demonstrated a significant, inverse relationship with FFR (adjusted hazard ratio, 1.06; 95% confidence interval, 1.05-1.08; P<0.001). However, this relationship was not observed in revascularized lesions (adjusted hazard ratio, 1.00; 95% confidence interval, 0.98-1.02; P=0.70). For lesions with FFR >=0.76, the risk of major adverse cardiac events was not significantly different between deferred and revascularized lesions. Conversely, in lesions with FFR <=0.75, the risk of major adverse cardiac events was significantly lower in revascularized lesions than in deferred lesions (for FFR 0.71-0.75, adjusted hazard ratio, 0.47; 95% confidence interval, 0.24-0.89; P=0.021; for FFR <=0.70, adjusted hazard ratio 0.47; 95% confidence interval, 0.26-0.84; P=0.012). CONCLUSIONS: This large, prospective registry showed that the FFR value was linearly associated with the risk of cardiac events in deferred lesions. In addition, revascularization for coronary artery stenosis with a low FFR (<=0.75) was associated with better outcomes than the deferral, whereas for a stenosis with a high FFR (>=0.76), medical treatment would be a reasonable and safe treatment strategy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01366404. PMID- 28356441 TI - Left Ventricular Dysfunction Switches Mesenchymal Stromal Cells Toward an Inflammatory Phenotype and Impairs Their Reparative Properties Via Toll-Like Receptor-4. AB - BACKGROUND: Little is known about the potentially unfavorable effects of mesenchymal stromal cell (MSC) activation on the heart. MSCs can respond to tissue injury by anti- or proinflammatory activation. We aimed to study the potential negative interaction between left ventricular dysfunction (LVD) and MSC activation. METHODS: We isolated MSCs from cardiac and subcutaneous fat tissues of mice with LVD 28 days after myocardial infarction or sham operation. To evaluate the effect of LVD on MSCs, we characterized cardiac MSCs and subcutaneous MSCs in vitro. Subsequently, we injected MSCs or saline into the infarcted myocardium of mice and evaluated LV remodeling and function 28 days after myocardial infarction. To test the hypothesis that toll-like receptor 4 (TLR4) mediates proinflammatory polarization of MSCs, we characterized cardiac MSCs from TLR4-/- and wild-type (WT) mice after inflammatory stimulation in vitro. Next, we transplanted cardiac MSCs from TLR4-/- and WT male mice into the infarcted myocardium of female WT mice and evaluated infarct size, MSC retention, inflammation, remodeling, and function after 7 days. RESULTS: LVD switched cardiac MSCs toward an inflammatory phenotype, with increased secretion of inflammatory cytokines as well as chemokines. The effect of LVD on subcutaneous MSCs was less remarkable. Although transplantation of cardiac MSCs and subcutaneous MSCs from LVD and sham hearts did not improve LV remodeling and function, cardiac MSCs from LVD exacerbated anterior wall thinning 28 days after myocardial infarction. The inflammatory polarization of cardiac MSCs by LVD was mediated by TLR4, as we found less secretion of inflammatory cytokines and higher secretion of anti-inflammatory cytokines from activated cardiac MSCs of TLR4 deficient mice, compared with WT cardiac MSCs. Significantly, TLR4 deficiency preserved the expression of CD47 (don't eat me signal) on cardiac MSCs after both TLR4 stimulation in vitro and transplantation into the infarcted heart. Compared with WT cardiac MSCs and saline, TLR4-/- cardiac MSCs survived in the cardiac tissue and maintained their reparative properties, reduced infarct size, increased scar thickness, and attenuated LV dilatation 7 days after myocardial infarction. CONCLUSIONS: The environment of the failing and infarcted myocardium drives resident and transplanted MSCs toward a proinflammatory phenotype and restricts their survival and reparative effects in a mechanism mediated by TLR4. PMID- 28356442 TI - Modulation of Endothelial Bone Morphogenetic Protein Receptor Type 2 Activity by Vascular Endothelial Growth Factor Receptor 3 in Pulmonary Arterial Hypertension. AB - BACKGROUND: Bone morphogenetic protein (BMP) signaling has multiple roles in the development and function of the blood vessels. In humans, mutations in BMP receptor type 2 (BMPR2), a key component of BMP signaling, have been identified in the majority of patients with familial pulmonary arterial hypertension (PAH). However, only a small subset of individuals with BMPR2 mutation develops PAH, suggesting that additional modifiers of BMPR2 function play an important role in the onset and progression of PAH. METHODS: We used a combination of studies in zebrafish embryos and genetically engineered mice lacking endothelial expression of Vegfr3 to determine the interaction between vascular endothelial growth factor receptor 3 (VEGFR3) and BMPR2. Additional in vitro studies were performed by using human endothelial cells, including primary lung endothelial cells from subjects with PAH. RESULTS: Attenuation of Vegfr3 in zebrafish embryos abrogated Bmp2b-induced ectopic angiogenesis. Endothelial cells with disrupted VEGFR3 expression failed to respond to exogenous BMP stimulation. Mechanistically, VEGFR3 is physically associated with BMPR2 and facilitates ligand-induced endocytosis of BMPR2 to promote phosphorylation of SMADs and transcription of ID genes. Conditional, endothelial-specific deletion of Vegfr3 in mice resulted in impaired BMP signaling responses, and significantly worsened hypoxia-induced pulmonary hypertension. Consistent with these data, we found significant decrease in VEGFR3 expression in pulmonary arterial endothelial cells from human PAH subjects, and reconstitution of VEGFR3 expression in PAH pulmonary arterial endothelial cells restored BMP signaling responses. CONCLUSIONS: Our findings identify VEGFR3 as a key regulator of endothelial BMPR2 signaling and a potential determinant of PAH penetrance in humans. PMID- 28356443 TI - A MicroRNA93-Interferon Regulatory Factor-9-Immunoresponsive Gene-1-Itaconic Acid Pathway Modulates M2-Like Macrophage Polarization to Revascularize Ischemic Muscle. AB - BACKGROUND: Currently, no therapies exist for treating and improving outcomes in patients with severe peripheral artery disease (PAD). MicroRNA93 (miR93) has been shown to favorably modulate angiogenesis and to reduce tissue loss in genetic PAD models. However, the cell-specific function, downstream mechanisms, or signaling involved in miR93-mediated ischemic muscle neovascularization is not clear. Macrophages were best known to modulate arteriogenic response in PAD, and the extent of arteriogenic response induced by macrophages is dependent on greater M2 to M1 activation/polarization state. In the present study, we identified a novel mechanism by which miR93 regulates macrophage polarization to promote angiogenesis and arteriogenesis to revascularize ischemic muscle in experimental PAD. METHODS: In vitro (macrophages, endothelial cells, skeletal muscle cells under normal and hypoxia serum starvation conditions) and in vivo experiments in preclinical PAD models (unilateral femoral artery ligation and resection) were conducted to examine the role of miR93-interferon regulatory factor-9 immunoresponsive gene-1 (IRG1)-itaconic acid pathway in macrophage polarization, angiogenesis, arteriogenesis, and perfusion recovery. RESULTS: In vivo, compared with wild-type controls, miR106b-93-25 cluster-deficient mice (miR106b-93-25-/-) showed decreased angiogenesis and arteriogenesis correlating with increased M1 like macrophages after experimental PAD. Intramuscular delivery of miR93 in miR106b-93-25-/- PAD mice increased angiogenesis, arteriogenesis, and the extent of perfusion, which correlated with more M2-like macrophages in the proximal and distal hind-limb muscles. In vitro, miR93 promotes and sustains M2-like polarization even under M1-like polarizing conditions (hypoxia serum starvation). Delivery of bone marrow-derived macrophages from miR106b-93-25-/- to wild-type ischemic muscle decreased angiogenesis, arteriogenesis, and perfusion, whereas transfer of wild-type macrophages to miR106b-93-25-/- had the opposite effect. Systematic analysis of top differentially upregulated genes from RNA sequencing between miR106b-93-25-/- and wild-type ischemic muscle showed that miR93 regulates IRG1 function to modulate itaconic acid production and macrophage polarization. The 3' untranslated region luciferase assays performed to determine whether IRG1 is a direct target of miR93 revealed that IRG1 is not an miR93 target but that interferon regulatory factor-9, which can regulate IRG1 expression, is an miR93 target. In vitro, increased expression of interferon regulatory factor-9 and IRG1 and itaconic acid treatment significantly decreased endothelial angiogenic potential. CONCLUSIONS: miR93 inhibits interferon regulatory factor-9 to decrease IRG1-itaconic acid production to induce M2-like polarization in ischemic muscle to enhance angiogenesis, arteriogenesis, and perfusion recovery in experimental PAD. PMID- 28356444 TI - Antibody-Mediated Inhibition of Tspan12 Ameliorates Vasoproliferative Retinopathy Through Suppression of beta-Catenin Signaling. AB - BACKGROUND: Anti-angiogenic biologicals represent an important concept for the treatment of vasoproliferative diseases. However, the need for continued treatment, the presence of nonresponders, and the risk of long-term side effects limit the success of existing therapeutic agents. Although Tspan12 has been shown to regulate retinal vascular development, nothing is known about its involvement in neovascular disease and its potential as a novel therapeutic target for the treatment of vasoproliferative diseases. METHODS: Rodent models of retinal neovascular disease, including the mouse model of oxygen-induced retinopathy and the very low density lipoprotein receptor knockout mouse model were analyzed for Tspan/beta-catenin regulation. Screening of a phage display of a human combinatorial antibody (Ab) library was used for the development of a high affinity Ab against Tspan12. Therapeutic effects of the newly developed Ab on vascular endothelial cells were tested in vitro and in vivo in the oxygen-induced retinopathy and very low density lipoprotein receptor knockout mouse model. RESULTS: The newly developed anti-Tspan12 Ab exhibited potent inhibitory effects on endothelial cell migration and tube formation. Mechanistic studies confirmed that the Ab inhibited the interaction between Tspan12 and Frizzled-4 and effectively modulates beta-catenin levels and target genes in vascular endothelial cells. Tspan12/beta-catenin signaling was activated in response to acute and chronic stress in the oxygen-induced retinopathy and very low density lipoprotein receptor mouse model of proliferative retinopathy. Intravitreal application of the Ab showed significant therapeutic effects in both models without inducing negative side effects on retina function. Moreover, combined intravitreal injection of the Ab with a known vascular endothelial growth factor inhibitor, Aflibercept, resulted in significant enhancement of the therapeutic efficacy of each monotherapy. Combination therapy with the Tspan12 blocking antibody can be used to reduce anti-vascular endothelial growth factor doses, thus decreasing the risk of long-term off-target effects. CONCLUSIONS: Tspan12/beta-catenin signaling is critical for the progression of vasoproliferative disease. The newly developed anti-Tspan12 antibody has therapeutic effects in vasoproliferative retinopathy and can enhance the potency of existing anti- vascular endothelial growth factor agents. PMID- 28356445 TI - Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. AB - BACKGROUND: Kawasaki disease is an acute vasculitis of childhood that leads to coronary artery aneurysms in ~25% of untreated cases. It has been reported worldwide and is the leading cause of acquired heart disease in children in developed countries. METHODS AND RESULTS: To revise the previous American Heart Association guidelines, a multidisciplinary writing group of experts was convened to review and appraise available evidence and practice-based opinion, as well as to provide updated recommendations for diagnosis, treatment of the acute illness, and long-term management. Although the cause remains unknown, discussion sections highlight new insights into the epidemiology, genetics, pathogenesis, pathology, natural history, and long-term outcomes. Prompt diagnosis is essential, and an updated algorithm defines supplemental information to be used to assist the diagnosis when classic clinical criteria are incomplete. Although intravenous immune globulin is the mainstay of initial treatment, the role for additional primary therapy in selected patients is discussed. Approximately 10% to 20% of patients do not respond to initial intravenous immune globulin, and recommendations for additional therapies are provided. Careful initial management of evolving coronary artery abnormalities is essential, necessitating an increased frequency of assessments and escalation of thromboprophylaxis. Risk stratification for long-term management is based primarily on maximal coronary artery luminal dimensions, normalized as Z scores, and is calibrated to both past and current involvement. Patients with aneurysms require life-long and uninterrupted cardiology follow-up. CONCLUSIONS: These recommendations provide updated and best evidence-based guidance to healthcare providers who diagnose and manage Kawasaki disease, but clinical decision making should be individualized to specific patient circumstances. PMID- 28356446 TI - Fibroblast-Specific Genetic Manipulation of p38 Mitogen-Activated Protein Kinase In Vivo Reveals Its Central Regulatory Role in Fibrosis. AB - BACKGROUND: In the heart, acute injury induces a fibrotic healing response that generates collagen-rich scarring that is at first protective but if inappropriately sustained can worsen heart disease. The fibrotic process is initiated by cytokines, neuroendocrine effectors, and mechanical strain that promote resident fibroblast differentiation into contractile and extracellular matrix-producing myofibroblasts. The mitogen-activated protein kinase p38alpha (Mapk14 gene) is known to influence the cardiac injury response, but its direct role in orchestrating programmed fibroblast differentiation and fibrosis in vivo is unknown. METHODS: A conditional Mapk14 allele was used to delete the p38alpha encoding gene specifically in cardiac fibroblasts or myofibroblasts with 2 different tamoxifen-inducible Cre recombinase-expressing gene-targeted mouse lines. Mice were subjected to ischemic injury or chronic neurohumoral stimulation and monitored for survival, cardiac function, and fibrotic remodeling. Antithetically, mice with fibroblast-specific transgenic overexpression of activated mitogen-activated protein kinase kinase 6, a direct inducer of p38, were generated to investigate whether this pathway can directly drive myofibroblast formation and the cardiac fibrotic response. RESULTS: In mice, loss of Mapk14 blocked cardiac fibroblast differentiation into myofibroblasts and ensuing fibrosis in response to ischemic injury or chronic neurohumoral stimulation. A similar inhibition of myofibroblast formation and healing was also observed in a dermal wounding model with deletion of Mapk14. Transgenic mice with fibroblast-specific activation of mitogen-activated protein kinase kinase 6-p38 developed interstitial and perivascular fibrosis in the heart, lung, and kidney as a result of enhanced myofibroblast numbers. Mechanistic experiments show that p38 transduces cytokine and mechanical signals into myofibroblast differentiation through the transcription factor serum response factor and the signaling effector calcineurin. CONCLUSIONS: These findings suggest that signals from diverse modes of injury converge on p38alpha mitogen-activated protein kinase within the fibroblast to program the fibrotic response and myofibroblast formation in vivo, suggesting a novel therapeutic approach with p38 inhibitors for future clinical application. PMID- 28356439 TI - Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology. AB - The study of botulinum neurotoxins (BoNT) is rapidly progressing in many aspects. Novel BoNTs are being discovered owing to next generation sequencing, but their biologic and pharmacological properties remain largely unknown. The molecular structure of the large protein complexes that the toxin forms with accessory proteins, which are included in some BoNT type A1 and B1 pharmacological preparations, have been determined. By far the largest effort has been dedicated to the testing and validation of BoNTs as therapeutic agents in an ever increasing number of applications, including pain therapy. BoNT type A1 has been also exploited in a variety of cosmetic treatments, alone or in combination with other agents, and this specific market has reached the size of the one dedicated to the treatment of medical syndromes. The pharmacological properties and mode of action of BoNTs have shed light on general principles of neuronal transport and protein-protein interactions and are stimulating basic science studies. Moreover, the wide array of BoNTs discovered and to be discovered and the production of recombinant BoNTs endowed with specific properties suggest novel uses in therapeutics with increasing disease/symptom specifity. These recent developments are reviewed here to provide an updated picture of the biologic mechanism of action of BoNTs, of their increasing use in pharmacology and in cosmetics, and of their toxicology. PMID- 28356448 TI - Broad-scale trophic shift in the pelagic North Pacific revealed by an oceanic seabird. AB - Human-induced ecological change in the open oceans appears to be accelerating. Fisheries, climate change and elevated nutrient inputs are variously blamed, at least in part, for altering oceanic ecosystems. Yet it is challenging to assess the extent of anthropogenic change in the open oceans, where historical records of ecological conditions are sparse, and the geographical scale is immense. We developed millennial-scale amino acid nitrogen isotope records preserved in ancient animal remains to understand changes in food web structure and nutrient regimes in the oceanic realm of the North Pacific Ocean (NPO). Our millennial scale isotope records of amino acids in bone collagen in a wide-ranging oceanic seabird, the Hawaiian petrel (Pterodroma sandwichensis), showed that trophic level declined over time. The amino acid records do not support a broad-scale increase in nitrogen fixation in the North Pacific subtropical gyre, rejecting an earlier interpretation based on bulk and amino acid specific delta15N chronologies for Hawaiian deep-sea corals and bulk delta15N chronologies for the Hawaiian petrel. Rather, our work suggests that the food web structure in the NPO has shifted at a broad geographical scale, a phenomenon potentially related to industrial fishing. PMID- 28356447 TI - Exposure to dairy manure leads to greater antibiotic resistance and increased mass-specific respiration in soil microbial communities. AB - Intensifying livestock production to meet the demands of a growing global population coincides with increases in both the administration of veterinary antibiotics and manure inputs to soils. These trends have the potential to increase antibiotic resistance in soil microbial communities. The effect of maintaining increased antibiotic resistance on soil microbial communities and the ecosystem processes they regulate is unknown. We compare soil microbial communities from paired reference and dairy manure-exposed sites across the USA. Given that manure exposure has been shown to elicit increased antibiotic resistance in soil microbial communities, we expect that manure-exposed sites will exhibit (i) compositionally different soil microbial communities, with shifts toward taxa known to exhibit resistance; (ii) greater abundance of antibiotic resistance genes; and (iii) corresponding maintenance of antibiotic resistance would lead to decreased microbial efficiency. We found that bacterial and fungal communities differed between reference and manure-exposed sites. Additionally, the beta-lactam resistance gene ampC was 5.2-fold greater under manure exposure, potentially due to the use of cephalosporin antibiotics in dairy herds. Finally, ampC abundance was positively correlated with indicators of microbial stress, and microbial mass-specific respiration, which increased 2.1 fold under manure exposure. These findings demonstrate that the maintenance of antibiotic resistance associated with manure inputs alters soil microbial communities and ecosystem function. PMID- 28356450 TI - Terrestrial reproduction as an adaptation to steep terrain in African toads. AB - How evolutionary novelties evolve is a major question in evolutionary biology. It is widely accepted that changes in environmental conditions shift the position of selective optima, and advancements in phylogenetic comparative approaches allow the rigorous testing of such correlated transitions. A longstanding question in vertebrate biology has been the evolution of terrestrial life histories in amphibians and here, by investigating African bufonids, we test whether terrestrial modes of reproduction have evolved as adaptations to particular abiotic habitat parameters. We reconstruct and date the most complete species level molecular phylogeny and estimate ancestral states for reproductive modes. By correlating continuous habitat measurements from remote sensing data and locality records with life-history transitions, we discover that terrestrial modes of reproduction, including viviparity evolved multiple times in this group, most often directly from fully aquatic modes. Terrestrial modes of reproduction are strongly correlated with steep terrain and low availability of accumulated water sources. Evolutionary transitions to terrestrial modes of reproduction occurred synchronously with or after transitions in habitat, and we, therefore, interpret terrestrial breeding as an adaptation to these abiotic conditions, rather than an exaptation that facilitated the colonization of montane habitats. PMID- 28356449 TI - Why does drug resistance readily evolve but vaccine resistance does not? AB - Why is drug resistance common and vaccine resistance rare? Drugs and vaccines both impose substantial pressure on pathogen populations to evolve resistance and indeed, drug resistance typically emerges soon after the introduction of a drug. But vaccine resistance has only rarely emerged. Using well-established principles of population genetics and evolutionary ecology, we argue that two key differences between vaccines and drugs explain why vaccines have so far proved more robust against evolution than drugs. First, vaccines tend to work prophylactically while drugs tend to work therapeutically. Second, vaccines tend to induce immune responses against multiple targets on a pathogen while drugs tend to target very few. Consequently, pathogen populations generate less variation for vaccine resistance than they do for drug resistance, and selection has fewer opportunities to act on that variation. When vaccine resistance has evolved, these generalities have been violated. With careful forethought, it may be possible to identify vaccines at risk of failure even before they are introduced. PMID- 28356451 TI - Warming magnifies predation and reduces prey coexistence in a model litter arthropod system. AB - Climate warming can destabilize interactions between competitors as smaller organisms gain advantages in warmer environments. Whether and how warming-induced effects on competitive interactions are modified by predation remains unknown. We hypothesized that predation will offset the competitive advantage of smaller prey species in warmer environments because of their greater vulnerability to predation. To test this, we assembled a litter arthropod community with two Collembola species (Folsomia candida and Proisotoma minuta) of different body sizes across a temperature gradient (three thermal environments) and in the presence and absence of predatory mites. Predatory mites reduced Collembola coexistence with increasing temperatures. Contradicting our hypothesis, the larger prey species always outperformed the smaller prey species in warmer environments with predators. Larger prey probably benefited as they expressed a greater trait (body length) plasticity to warming. Warming can thus magnify predation effects and reduce the probability of prey coexistence. PMID- 28356452 TI - The dynamic association between ovariole loss and sterility in adult honeybee workers. AB - In the social insects, ovary state (the presence or absence of mature oocytes) and ovary size (the number of ovarioles) are often used as proxies for the reproductive capacity of an individual worker. Ovary size is assumed to be fixed post-eclosion whereas ovary state is demonstrably plastic post-eclosion. Here, we show that in fact ovary size declines as honeybee workers age. This finding is robust across two honeybee species: Apis mellifera and A. cerana The ovariole loss is likely to be due to the regression of particular ovarioles via programmed cell death. We also provide further support for the observation that honeybee workers with activated ovaries (mature oocytes present) most commonly have five ovarioles rather than a greater or smaller number. This result suggests that workers with more than five ovarioles are unable to physiologically support more than five activated ovarioles and that workers with fewer than five ovarioles are below a threshold necessary for ovary activation. As a worker's ovariole number declines with age, studies on worker ovariole number need to take this plasticity into account. PMID- 28356454 TI - First macrobiota biomineralization was environmentally triggered. AB - Why large and diverse skeletons first appeared ca 550 Ma is not well understood. Many Ediacaran skeletal biota show evidence of flexibility, and bear notably thin skeletal walls with simple, non-hierarchical microstructures of either aragonite or high-Mg calcite. We present evidence that the earliest skeletal macrobiota, found only in carbonate rocks, had close soft-bodied counterparts hosted in contemporary clastic rocks. This includes the calcareous discoidal fossil Suvorovella, similar to holdfasts of Ediacaran biota taxa previously known only as casts and moulds, as well as tubular and vase-shaped fossils. In sum, these probably represent taxa of diverse affinity including unicellular eukaryotes, total group cnidarians and problematica. Our findings support the assertion that the calcification was an independent and derived feature that appeared in diverse groups where an organic scaffold was the primitive character, which provided the framework for interactions between the extracellular matrix and mineral ions. We conclude that such skeletons may have been acquired with relative ease in the highly saturated, high alkalinity carbonate settings of the Ediacaran, where carbonate polymorph was further controlled by seawater chemistry. The trigger for Ediacaran biomineralization may have been either changing seawater Mg/Ca and/or increasing oxygen levels. By the Early Cambrian, however, biomineralization styles and the range of biominerals had significantly diversified, perhaps as an escalating defensive response to increasing predation pressure. Indeed skeletal hardparts had appeared in clastic settings by Cambrian Stage 1, suggesting independence from ambient seawater chemistry where genetic and molecular mechanisms controlled biomineralization and mineralogy had become evolutionarily constrained. PMID- 28356453 TI - The melanocortin system regulates body pigmentation and social behaviour in a colour polymorphic cichlid fish. AB - The melanocortin system is a neuroendocrine system that regulates a range of physiological and behavioural processes. We examined the extent to which the melanocortin system simultaneously regulates colour and behaviour in the cichlid fish Astatotilapia burtoni We found that yellow males are more aggressive than blue males, in line with previous studies. We then found that exogenous alpha melanocyte-stimulating hormone (alpha-MSH) increases yellowness of the body and dispersal of xanthophore pigments in both morphs. However, alpha-MSH had a morph specific effect on aggression, with only blue males showing an increase in the rate of aggression. Exogenous agouti signalling peptide (ASIP), a melanocortin antagonist, did not affect coloration but reduced the rate of aggression in both colour morphs. Blue males had higher cortisol levels than yellow males. Neural gene expression of melanocortin receptors (mcr) and ligands was not differentially regulated between colour morphs. In the skin, however, mc1r and pro-opiomelanocortin (pomc) beta were upregulated in blue males, while asip 1 was upregulated in yellow males. The effects of alpha-MSH on behaviour and body coloration, combined with morph-specific regulation of the stress response and the melanocortin system, suggest that the melanocortin system contributes to the polymorphism in behaviour and coloration in A. burtoni. PMID- 28356455 TI - Seasonal body size reductions with warming covary with major body size gradients in arthropod species. AB - Major biological and biogeographical rules link body size variation with latitude or environmental temperature, and these rules are often studied in isolation. Within multivoltine species, seasonal temperature variation can cause substantial changes in adult body size, as subsequent generations experience different developmental conditions. Yet, unlike other size patterns, these common seasonal temperature-size gradients have never been collectively analysed. We undertake the largest analysis to date of seasonal temperature-size gradients in multivoltine arthropods, including 102 aquatic and terrestrial species from 71 global locations. Adult size declines in warmer seasons in 86% of the species examined. Aquatic species show approximately 2.5-fold greater reduction in size per degrees C of warming than terrestrial species, supporting the hypothesis that greater oxygen limitation in water than in air forces aquatic species to exhibit greater plasticity in body size with temperature. Total percentage change in size over the annual cycle appears relatively constant with annual temperature range but varies between environments, such that the overall size reduction in aquatic-developing species (approx. 31%) is almost threefold greater than in terrestrial species (approx. 11%). For the first time, we show that strong correlations exist between seasonal temperature-size gradients, laboratory responses and latitudinal-size clines, suggesting that these patterns share common drivers. PMID- 28356456 TI - Field study suggests that sex determination in sea lamprey is directly influenced by larval growth rate. AB - Sex determination mechanisms in fishes lie along a genetic-environmental continuum and thereby offer opportunities to understand how physiology and environment interact to determine sex. Mechanisms and ecological consequences of sex determination in fishes are primarily garnered from teleosts, with little investigation into basal fishes. We tagged and released larval sea lamprey (Petromyzon marinus) into unproductive lake and productive stream environments. Sex ratios produced from these environments were quantified by recapturing tagged individuals as adults. Sex ratios from unproductive and productive environments were initially similar. However, sex ratios soon diverged, with unproductive environments becoming increasingly male-skewed and productive environments becoming less male-skewed with time. We hypothesize that slower growth in unproductive environments contributed to the sex ratio differences by directly influencing sex determination. To the best of our knowledge, this is the first study suggesting that growth rate in a fish species directly influences sex determination; other studies have suggested that the environmental variables to which sex determination is sensitive (e.g. density, temperature) act as cues for favourable or unfavourable growth conditions. Understanding mechanisms of sex determination in lampreys may provide unique insight into the underlying principles of sex determination in other vertebrates and provide innovative approaches for their management where valued and invasive. PMID- 28356457 TI - Speed dependency in alpha-motoneuron activity and locomotor modules in human locomotion: indirect evidence for phylogenetically conserved spinal circuits. AB - Coordinated locomotor muscle activity is generated by the spinal central pattern generators (CPGs). Vertebrate studies have demonstrated the following two characteristics of the speed control mechanisms of the spinal CPGs: (i) rostral segment activation is indispensable for achieving high-speed locomotion; and (ii) specific combinations between spinal interneuronal modules and motoneuron (MN) pools are sequentially activated with increasing speed. Here, to investigate whether similar control mechanisms exist in humans, we examined spinal neural activity during varied-speed locomotion by mapping the distribution of MN activity in the spinal cord and extracting locomotor modules, which generate basic MN activation patterns. The MN activation patterns and the locomotor modules were analysed from multi-muscle electromyographic recordings. The reconstructed MN activity patterns were divided into the following three patterns depending on the speed of locomotion: slow walking, fast walking and running. During these three activation patterns, the proportion of the activity in rostral segments to that in caudal segments increased as locomotion speed increased. Additionally, the different MN activation patterns were generated by distinct combinations of locomotor modules. These results are consistent with the speed control mechanisms observed in vertebrates, suggesting phylogenetically conserved spinal mechanisms of neural control of locomotion. PMID- 28356459 TI - Viral hepatitis and the risk of Parkinson disease. PMID- 28356458 TI - Cortical superficial siderosis and first-ever cerebral hemorrhage in cerebral amyloid angiopathy. AB - OBJECTIVE: To investigate whether cortical superficial siderosis (cSS) is associated with increased risk of future first-ever symptomatic lobar intracerebral hemorrhage (ICH) in patients with cerebral amyloid angiopathy (CAA) presenting with neurologic symptoms and without ICH. METHODS: Consecutive patients meeting modified Boston criteria for probable CAA in the absence of ICH from a single-center cohort were analyzed. cSS and other small vessel disease MRI markers were assessed according to recent consensus recommendations. Patients were followed prospectively for future incident symptomatic lobar ICH. Prespecified Cox proportional hazard models were used to investigate cSS and first-ever lobar ICH risk adjusting for potential confounders. RESULTS: The cohort included 236 patients with probable CAA without lobar ICH at baseline. cSS prevalence was 34%. During a median follow-up of 3.26 years (interquartile range 1.42-5.50 years), 27 of 236 patients (11.4%) experienced a first-ever symptomatic lobar ICH. cSS was a predictor of time until first ICH (p = 0.0007, log-rank test). The risk of symptomatic ICH at 5 years of follow-up was 19% (95% confidence interval [CI] 11%-32%) for patients with cSS at baseline vs 6% (95% CI 3%-12%) for patients without cSS. In multivariable Cox regression models, cSS presence was the only independent predictor of increased symptomatic ICH risk during follow-up (HR 4.04; 95% CI 1.73-9.44, p = 0.001), after adjusting for age, lobar cerebral microbleeds burden, and white matter hyperintensities. CONCLUSIONS: cSS is consistently associated with an increased risk of future lobar ICH in CAA with potentially important clinical implications for patient care decisions such as antithrombotic use. PMID- 28356460 TI - Impaired intracortical inhibition demonstrated in vivo in people with Dravet syndrome. AB - OBJECTIVE: Dravet syndrome is a rare neurodevelopmental disorder characterized by seizures and other neurologic problems. SCN1A mutations account for ~80% of cases. Animal studies have implicated mutation-related dysregulated cortical inhibitory networks in its pathophysiology. We investigated such networks in people with the condition. METHODS: Transcranial magnetic stimulation using single and paired pulse paradigms was applied to people with Dravet syndrome and to 2 control groups to study motor cortex excitability. RESULTS: Short interval intracortical inhibition (SICI), which measures GABAergic inhibitory network behavior, was undetectable in Dravet syndrome, but detectable in all controls. Other paradigms, including those testing excitatory networks, showed no difference between Dravet and control groups. CONCLUSIONS: There were marked differences in inhibitory networks, detected using SICI paradigms, while other inhibitory and excitatory paradigms yielded normal results. These human data showing reduced GABAergic inhibition in vivo in people with Dravet syndrome support established animal models. PMID- 28356461 TI - Parental family history of dementia in relation to subclinical brain disease and dementia risk. AB - OBJECTIVE: To determine the association of parental family history with risk of dementia by age at onset and sex of affected parent in a population-based cohort. METHODS: From 2000 to 2002, we assessed parental history of dementia in participants without dementia of the Rotterdam Study. We investigated associations of parental history with risk of dementia until 2015, adjusting for demographics, cardiovascular risk factors, and known genetic risk variants. Furthermore, we determined the association between parental history and markers of neurodegeneration and vascular disease on MRI. RESULTS: Of 2,087 participants (mean age 64 years, 55% female), 407 (19.6%) reported a history of dementia in either parent (mean age at diagnosis 79 years). During a mean follow-up of 12.2 years, 142 participants developed dementia. Parental history was associated with risk of dementia independently of known genetic risk factors (hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.12-2.48), in particular when parents were diagnosed at younger age (<80 years: HR 2.58, 95% CI 1.61-4.15; >=80 years: HR 1.01, 95% CI 0.58-1.77). Accordingly, age at diagnosis in probands was highly correlated with age at diagnosis in their parents <80 years (r = 0.57, p = 0.001) but not thereafter (r = 0.17, p = 0.55). Among 1,161 participants without dementia with brain MRI, parental history was related to lower cerebral perfusion and higher burden of white matter lesions and microbleeds. Dementia risk and MRI markers were similar for paternal and maternal history. CONCLUSIONS: Parental history of dementia increases risk of dementia, primarily when age at parental diagnosis is <80 years. Unexplained heredity may be attributed in part to cerebral hypoperfusion and small vessel disease. We found no evidence of preferential maternal compared to paternal transmission. PMID- 28356462 TI - Diagnostic errors in cerebrovascular disease: What are we missing? PMID- 28356463 TI - Dopamine D2/D3 imbalance during migraine attack and allodynia in vivo. AB - OBJECTIVE: To evaluate in vivo the dynamics of endogenous dopamine (DA) neurotransmission during migraine ictus with allodynia. METHODS: We examined 8 episodic migraineurs and 8 healthy controls (HC) using PET with [11C]raclopride. The uptake measure of [11C]raclopride, nondisplaceable binding potential (BPND), would increase when there was a reduction in endogenous DA release. The opposite is true for a decrease in [11C]raclopride BPND. Patients were scanned twice: one PET session was during a spontaneous migraine ictus at rest, followed by a sustained thermal pain threshold (STPT) challenge on the trigeminal region, eliciting an allodynia experience; another was during interictal phase. RESULTS: Striatal BPND of [11C]raclopride in migraineurs did not differ from HC. We found a significant increase in [11C]raclopride BPND in the striatum region of migraineurs during both headache attack and allodynia relative to interictal phase. However, when compared to the migraine attack at rest, migraineurs during the STPT challenge had a significant sudden reduction in [11C]raclopride BPND in the insula. Such directional change was also observed in the caudate of HC relative to the interictal phase during challenge. Furthermore, ictal changes in [11C]raclopride BPND in migraineurs at rest were positively correlated with the chronicity of migraine attacks, and negatively correlated with the frequency during challenge. CONCLUSIONS: Our findings demonstrate that there is an imbalanced uptake of [11C]raclopride during the headache attack and ictal allodynia, which indicates reduction and fluctuation in ictal endogenous DA release in migraineurs. Moreover, the longer the history and recurrence of migraine attacks, the lower the ictal endogenous DA release. PMID- 28356464 TI - ED misdiagnosis of cerebrovascular events in the era of modern neuroimaging: A meta-analysis. AB - OBJECTIVE: With the emergency department (ED) being a high-risk site for diagnostic errors, we sought to estimate ED diagnostic accuracy for identifying acute cerebrovascular events. METHODS: MEDLINE and Embase were searched for studies (1995-2016) reporting ED diagnostic accuracy for ischemic stroke, TIA, or subarachnoid hemorrhage (SAH). Two independent reviewers determined inclusion. We identified 1,693 unique citations, examined 214 full articles, and analyzed 23 studies. Studies were rated on risk of bias (QUADAS-2). Diagnostic data were extracted. We prospectively defined clinical presentation subgroups to compare odds of misdiagnosis. RESULTS: Included studies reported on 15,721 patients. Studies were at low risk of bias. Overall sensitivity (91.3% [95% confidence interval (CI) 90.7-92.0]) and specificity (92.7% [91.7-93.7]) for a cerebrovascular etiology was high, but there was significant variation based on clinical presentation. Misdiagnosis was more frequent among subgroups with milder (SAH with normal vs abnormal mental state; false-negative rate 23.8% vs 4.2%, odds ratio [OR] 7.03 [4.80-10.31]), nonspecific (dizziness vs motor findings; false-negative rate 39.4% vs 4.4%, OR 14.22 [9.76-20.74]), or transient (TIA vs ischemic stroke; false discovery rate 59.7% vs 11.7%, OR 11.21 [6.66-18.89]) symptoms. CONCLUSIONS: Roughly 9% of cerebrovascular events are missed at initial ED presentation. Risk of misdiagnosis is much greater when presenting neurologic complaints are mild, nonspecific, or transient (range 24%-60%). This difference suggests that many misdiagnoses relate to symptom-specific factors. Future research should emphasize studying causes and designing error-reduction strategies in symptom-specific subgroups at greatest risk of misdiagnosis. PMID- 28356465 TI - Viral hepatitis and Parkinson disease: A national record-linkage study. AB - OBJECTIVE: To study associations between viral hepatitis and Parkinson disease (PD). METHODS: A retrospective cohort study was done by analyzing linked English National Hospital Episode Statistics and mortality data (1999-2011). Cohorts of individuals with hepatitis B, hepatitis C, autoimmune hepatitis, chronic active hepatitis, and HIV were constructed, and compared to a reference cohort for subsequent rates of PD. RESULTS: The standardized rate ratio (RR) of PD following hepatitis B was 1.76 (95% confidence interval [CI] 1.28-2.37) (p < 0.001), based on 44 observed compared with 25 expected cases. The RR of PD following hepatitis C was 1.51 (95% CI, 1.18-1.9) (p < 0.001), based on 48.5 expected and 73 observed cases. There was no significant association between autoimmune hepatitis, chronic active hepatitis or HIV, and subsequent PD. When including only those episodes of care for PD that occurred first at least 1 year following each exposure condition, the RR for hepatitis B and hepatitis C were 1.82 (1.29-2.5) and 1.43 (1.09-1.84), respectively. CONCLUSIONS: We report strong evidence in favor of an elevation of rates of subsequent PD in patients with hepatitis B and hepatitis C. These findings may be explained by factors peculiar to viral hepatitis, but whether it reflects consequences of infection, shared disease mechanisms, or the result of antiviral treatment remains to be elucidated. Further work is needed to confirm this association and to investigate pathophysiologic pathways, potentially advancing etiologic understanding of PD more broadly. PMID- 28356468 TI - Strategies for obstacle avoidance during walking in the cat. AB - Avoiding obstacles is essential for successful navigation through complex environments. This study aimed to clarify what strategies are used by a typical quadruped, the cat, to avoid obstacles during walking. Four cats walked along a corridor 2.5 m long and 25 or 15 cm wide. Obstacles, small round objects 2.5 cm in diameter and 1 cm in height, were placed on the floor in various locations. Movements of the paw were recorded with a motion capture and analysis system (Visualeyez, PTI). During walking in the wide corridor, cats' preferred strategy for avoiding a single obstacle was circumvention, during which the stride direction changed while stride duration and swing-to-stride duration ratio were preserved. Another strategy, stepping over the obstacle, was used during walking in the narrow corridor, when lateral deviations of walking trajectory were restricted. Stepping over the obstacle involved changes in two consecutive strides. The stride preceding the obstacle was shortened, and swing-to-stride ratio was reduced. The obstacle was negotiated in the next stride of increased height and normal duration and swing-to-stride ratio. During walking on a surface with multiple obstacles, both strategies were used. To avoid contact with the obstacle, cats placed the paw away from the object at a distance roughly equal to the diameter of the paw. During obstacle avoidance cats prefer to alter muscle activities without altering the locomotor rhythm. We hypothesize that a choice of the strategy for obstacle avoidance is determined by minimizing the complexity of neuro-motor processes required to achieve the behavioral goal.NEW & NOTEWORTHY In a study of feline locomotor behavior we found that the preferred strategy to avoid a small obstacle is circumvention. During circumvention, stride direction changes but length and temporal structure are preserved. Another strategy, stepping over the obstacle, is used in narrow walkways. During overstepping, two strides adjust. A stride preceding the obstacle decreases in length and duration. The following stride negotiating the obstacle increases in height while retaining normal temporal structure and nearly normal length. PMID- 28356467 TI - The potential for understanding the synaptic organization of human motor commands via the firing patterns of motoneurons. AB - Motoneurons are unique in being the only neurons in the CNS whose firing patterns can be easily recorded in human subjects. This is because of the one-to-one relationship between the motoneuron and muscle cell behavior. It has long been appreciated that the connection of motoneurons to their muscle fibers allows their action potentials to be amplified and recorded, but only recently has it become possible to simultaneously record the firing pattern of many motoneurons via array electrodes placed on the skin. These firing patterns contain detailed information about the synaptic organization of motor commands to the motoneurons. This review focuses on parameters in these firing patterns that are directly linked to specific features of this organization. It is now well established that motor commands consist of three components, excitation, inhibition, and neuromodulation; the importance of the third component has become increasingly evident. Firing parameters linked to each of the three components are discussed, along with consideration of potential limitations in their utility for understanding the underlying organization of motor commands. Future work based on realistic computer simulations of motoneurons may allow quantitative "reverse engineering" of human motoneuron firing patterns to provide good estimates of the relative amplitudes and temporal patterns of all three components of motor commands. PMID- 28356466 TI - Evidence for a causal relationship between low vitamin D, high BMI, and pediatric onset MS. AB - OBJECTIVE: To utilize Mendelian randomization to estimate the causal association between low serum vitamin D concentrations, increased body mass index (BMI), and pediatric-onset multiple sclerosis (MS) using genetic risk scores (GRS). METHODS: We constructed an instrumental variable for vitamin D (vitD GRS) by computing a GRS for 3 genetic variants associated with levels of 25(OH)D in serum using the estimated effect of each risk variant. A BMI GRS was also created that incorporates the cumulative effect of 97 variants associated with BMI. Participants included non-Hispanic white individuals recruited from over 15 sites across the United States (n = 394 cases, 10,875 controls) and Sweden (n = 175 cases, 5,376 controls; total n = 16,820). RESULTS: Meta-analysis findings demonstrated that a vitD GRS associated with increasing levels of 25(OH)D in serum decreased the odds of pediatric-onset MS (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.55, 0.94; p = 0.02) after controlling for sex, genetic ancestry, HLA-DRB1*15:01, and over 100 non-human leukocyte antigen MS risk variants. A significant association between BMI GRS and pediatric disease onset was also demonstrated (OR 1.17, 95% CI 1.05, 1.30; p = 0.01) after adjusting for covariates. Estimates for each GRS were unchanged when considered together in a multivariable model. CONCLUSIONS: We provide evidence supporting independent and causal effects of decreased vitamin D levels and increased BMI on susceptibility to pediatric-onset MS. PMID- 28356470 TI - Development and long-term integration of MGE-lineage cortical interneurons in the heterochronic environment. AB - Interneuron precursors transplanted into visual cortex induce network plasticity during their heterochronic maturation. Such plasticity can have a significant impact on the function of the animal and is normally present only during a brief critical period in early postnatal development. Elucidating the synaptic and physiological properties of interneuron precursors as they mature is key to understanding how long-term circuit changes are induced by transplants. We studied the development of transplant-derived interneurons and compared it to endogenously developing interneurons (those that are born and develop in the same animal) at parallel developmental time points, using patch-clamp recordings in acute cortical slices. We found that transplant-derived interneurons develop into fast-spiking and non-fast-spiking neurons characteristic of the medial ganglionic eminence (MGE) lineage. Transplant-derived interneurons matured more rapidly than endogenously developing interneurons, as shown by more hyperpolarized membrane potentials, smaller input resistances, and narrower action potentials at a juvenile age. In addition, transplant-derived fast-spiking interneurons have more quickly saturating input-output relationships and lower maximal firing rates in adulthood, indicating a possible divergence in function. Transplant-derived interneurons both form inhibitory synapses onto host excitatory neurons and receive excitatory synapses from host pyramidal cells. Unitary connection properties are similar to those of host interneurons. These transplant-derived interneurons, however, were less densely functionally connected onto host pyramidal cells than were host interneurons and received fewer spontaneous excitatory inputs from host cells. These findings suggest that many physiological characteristics of interneurons are autonomously determined, while some factors impacting their circuit function may be influenced by the environment in which they develop.NEW & NOTEWORTHY Transplanting embryonic interneurons into older brains induces a period of plasticity in the recipient animal. We find that these interneurons develop typical fast-spiking and non-fast-spiking phenotypes by the end of adolescence. However, the input-output characteristics of transplant derived neurons diverged from endogenously developing interneurons during adulthood, and they showed lower connection rates to local pyramidal cells at all time points. This suggests a unique and ongoing role of transplant-derived interneurons in host circuits, enabling interneuron transplant therapies. PMID- 28356469 TI - PICs in motoneurons do not scale with the size of the animal: a possible mechanism for faster speed of muscle contraction in smaller species. AB - The majority of studies on the electrical properties of neurons are carried out in rodents, and in particular in mice. However, the minute size of this animal compared with humans potentially limits the relevance of the resulting insights. To be able to extrapolate results obtained in a small animal such as a rodent, one needs to have proper knowledge of the rules governing how electrical properties of neurons scale with the size of the animal. Generally speaking, electrical resistances of neurons increase as cell size decreases, and thus maintenance of equal depolarization across cells of different sizes requires the underlying currents to decrease in proportion to the size decrease. Thus it would generally be expected that voltage-sensitive currents are smaller in smaller animals. In this study, we used in vivo preparations to record electrical properties of spinal motoneurons in deeply anesthetized adult mice and cats. We found that PICs do not scale with size, but instead are constant in their amplitudes across these species. This constancy, coupled with the threefold differences in electrical resistances, means that PICs contribute a threefold larger depolarization in the mouse than in the cat. As a consequence, motoneuronal firing rate sharply increases as animal size decreases. These differences in firing rates are likely essential in allowing different species to control muscles with widely different contraction speeds (smaller animals have faster muscle fibers). Thus from our results we have identified a possible new mechanism for how electrical properties are tuned to match mechanical properties within the motor output system.NEW & NOTEWORTHY The small size of the mouse warrants concern over whether the properties of their neurons are a scaled version of those in larger animals or instead have unique features. Comparison of spinal motoneurons in mice to cats showed unique features. Firing rates in the mouse were much higher, in large part due to relatively larger persistent inward currents. These differences likely reflect adaptations for controlling much faster muscle fibers in mouse than cat. PMID- 28356471 TI - Contributions of space-clamp errors to apparent time-dependent loss of Mg2+ block induced by NMDA. AB - N-methyl-d-aspartate receptors (NMDARs) govern synaptic plasticity, development, and neuronal response to insult. Prolonged activation of NMDARs such as during an insult may activate secondary currents or modulate Mg2+ sensitivity, but the conditions under which these occur are not fully defined. We reexamined the effect of prolonged NMDAR activation in juvenile mouse hippocampal slices. NMDA (10 MUM) elicited current with the expected negative-slope conductance in the presence of 1.2 mM Mg2+ However, several minutes of continued NMDA exposure elicited additional inward current at -70 mV. A higher concentration of NMDA (100 uM) elicited the current more rapidly. The additional current was not dependent on Ca2+, network activity, or metabotropic NMDAR function and did not persist on agonist removal. Voltage ramps revealed no alteration of either reversal potential or NMDA-elicited conductance between -30 mV and +50 mV. The result was a more linear NMDA current-voltage relationship. The current linearization was also induced in interneurons and in mature dentate granule neurons but not immature dentate granule cells, dissociated cultured hippocampal neurons, or nucleated patches excised from CA1 pyramidal neurons. Comparative simulations of NMDA application to a CA1 pyramidal neuron and to a cultured neuron revealed that linearization can be explained by space-clamp errors arising from gradual recruitment of distal dendritic NMDARs. We conclude that persistent secondary currents do not strongly contribute to NMDAR responses in juvenile mouse hippocampus and careful discernment is needed to exclude contributions of clamp artifacts to apparent secondary currents.NEW & NOTEWORTHY We report that upon sustained activation of NMDARs in juvenile mouse hippocampal neurons there is apparent loss of Mg2+ block at negative membrane potentials. However, the phenomenon is explained by loss of dendritic voltage clamp, leading to a linear current-voltage relationship. Our results give a specific example of how spatial voltage errors in voltage-clamp recordings can readily be misinterpreted as biological modulation. PMID- 28356472 TI - Task-dependent vestibular feedback responses in reaching. AB - When reaching for an earth-fixed object during self-rotation, the motor system should appropriately integrate vestibular signals and sensory predictions to compensate for the intervening motion and its induced inertial forces. While it is well established that this integration occurs rapidly, it is unknown whether vestibular feedback is specifically processed dependent on the behavioral goal. Here, we studied whether vestibular signals evoke fixed responses with the aim to preserve the hand trajectory in space or are processed more flexibly, correcting trajectories only in task-relevant spatial dimensions. We used galvanic vestibular stimulation to perturb reaching movements toward a narrow or a wide target. Results show that the same vestibular stimulation led to smaller trajectory corrections to the wide than the narrow target. We interpret this reduced compensation as a task-dependent modulation of vestibular feedback responses, tuned to minimally intervene with the task-irrelevant dimension of the reach. These task-dependent vestibular feedback corrections are in accordance with a central prediction of optimal feedback control theory and mirror the sophistication seen in feedback responses to mechanical and visual perturbations of the upper limb.NEW & NOTEWORTHY Correcting limb movements for external perturbations is a hallmark of flexible sensorimotor behavior. While visual and mechanical perturbations are corrected in a task-dependent manner, it is unclear whether a vestibular perturbation, naturally arising when the body moves, is selectively processed in reach control. We show, using galvanic vestibular stimulation, that reach corrections to vestibular perturbations are task dependent, consistent with a prediction of optimal feedback control theory. PMID- 28356473 TI - Density of available striatal dopamine receptors predicts trait impulsiveness during performance of an attention-demanding task. AB - The density (measured at binding potential) of available striatal D2/D3 receptors has been shown to predict trait impulsiveness. This relationship is highly robust and well replicated. In each case, however, the availability of dopamine receptors was measured at rest. More broadly, the extent to which relationships between dopamine receptor availability and behavioral traits hold when participants perform a cognitive task is unclear. Furthermore, the performance of a cognitive task engages fundamentally different neural networks than are maximally engaged during the resting state. This complicates interpretation of previously observed correlations, which could be influenced by two distinct factors. The first is variation in available receptor density, which reflects a stable trait of the individual. The second is variation in context-specific dopamine release, which differentially displaces some dopamine radiotracers (such as raclopride) across individuals. Using an existing data set, we related trait impulsiveness, as measured using the Barratt Impulsiveness Scale (BIS-11), to the density (binding potential) of available striatal D2/D3 receptors as measured using positron emission tomography (PET) with [11C]raclopride. Importantly, the PET scan was completed while participants performed an attention-demanding visual search task. We replicate robust correlations between this measure of receptor availability and trait impulsiveness previously demonstrated during the resting state, extending this relationship to periods of active task engagement. Our results support the idea that this relationship depends on striatal D2/D3 receptor density and not on context-dependent dopamine release.NEW & NOTEWORTHY Several studies have demonstrated a relationship between the density of available striatal D2/D3 receptors and trait impulsiveness. However, in each case, the availability of dopamine receptors was measured during the resting state. This complicates interpretation of previously observed correlations, which could be influenced by either stable variation in receptor density or context-dependent dopamine release. We present evidence uniquely consistent with the former interpretation, providing clarity to the nature of this brain-behavior relationship. PMID- 28356475 TI - Afferent motor feedback determines the perceived location of tactile stimuli in the external space presented to the moving arm. AB - People make systematic errors when localizing a brief tactile stimulus in the external space presented on the index finger while moving the arm. Although these errors likely arise in the spatiotemporal integration of the tactile input and information about arm position, the underlying arm position information used in this process is not known. In this study, we tested the contributions of afferent proprioceptive feedback and predictive arm position signals by comparing localization errors during passive vs. active arm movements. In the active trials, participants were instructed to localize a tactile stimulus in the external space that was presented to the index finger near the time of a self generated arm movement. In the passive trials, each of the active trials was passively replayed in randomized order, using a robotic device. Our results provide evidence that the localization error patterns of the passive trials are similar to the active trials and, moreover, did not lag but rather led the active trials, which suggests that proprioceptive feedback makes an important contribution to tactile localization. To further test which kinematic property of this afferent feedback signal drives the underlying computations, we examined the localization errors with movements that had differently skewed velocity profiles but overall the same displacement. This revealed a difference in the localization patterns, which we explain by a probabilistic model in which temporal uncertainty about the stimulus is converted into a spatial likelihood, depending on the actual velocity of the arm rather than involving an efferent, preprogrammed movement.NEW & NOTEWORTHY We show that proprioceptive feedback of arm motion rather than efferent motor signals contributes to tactile localization during an arm movement. Data further show that localization errors depend on arm velocity, not displacement per se, suggesting that instantaneous velocity feedback plays a role in the underlying computations. Model simulation using Bayesian inference suggests that these errors depend not only on spatial but also on temporal uncertainties of sensory and motor signals. PMID- 28356474 TI - Functional remodeling of subtype-specific markers surrounding implanted neuroprostheses. AB - Microelectrode arrays implanted in the brain are increasingly used for the research and treatment of intractable neurological disease. However, local neuronal loss and glial encapsulation are known to interfere with effective integration and communication between implanted devices and brain tissue, where these observations are typically based on assessments of broad neuronal and astroglial markers. However, both neurons and astrocytes comprise heterogeneous cellular populations that can be further divided into subclasses based on unique functional and morphological characteristics. In this study, we investigated whether or not device insertion causes alterations in specific subtypes of these cells. We assessed the expression of both excitatory and inhibitory markers of neurotransmission (vesicular glutamate and GABA transporters, VGLUT1 and VGAT, respectively) surrounding single-shank Michigan-style microelectrode arrays implanted in the motor cortex of adult rats by use of quantitative immunohistochemistry. We found a pronounced shift from significantly elevated VGLUT1 within the initial days following implantation to relatively heightened VGAT by the end of the 4-wk observation period. Unexpectedly, we observed VGAT positivity in a subset of reactive astrocytes during the first week of implantation, indicating heterogeneity in early-responding encapsulating glial cells. We coupled our VGLUT1 data with the evaluation of a second marker of excitatory neurons (CamKiialpha); the results closely paralleled each other and underscored a progression from initially heightened to subsequently weakened excitatory tone in the neural tissue proximal to the implanted electrode interface (within 40 MUm). Our results provide new evidence for subtype-specific remodeling surrounding brain implants that inform observations of suboptimal integration and performance.NEW & NOTEWORTHY We report novel changes in the local expression of excitatory and inhibitory synaptic markers surrounding microelectrode arrays implanted in the motor cortex of rats, where a progressive shift toward increased inhibitory tone was observed over the 4-wk observation period. The result was driven by declining glutamate transporter expression (VGLUT1) in parallel with increasing GABA transporter expression (VGAT) over time, where a reactive VGAT+ astroglial subtype made an unexpected contribution to our findings. PMID- 28356476 TI - Transfer of dynamic motor skills acquired during isometric training to free motion. AB - Recent studies have explored the prospects of learning to move without moving, by displaying virtual arm movement related to exerted force. However, it has yet to be tested whether learning the dynamics of moving can transfer to the corresponding movement. Here we present a series of experiments that investigate this isometric training paradigm. Subjects were asked to hold a handle and generate forces as their arms were constrained to a static position. A precise simulation of reaching was used to make a graphic rendering of an arm moving realistically in response to the measured interaction forces and simulated environmental forces. Such graphic rendering was displayed on a horizontal display that blocked their view to their actual (statically constrained) arm and encouraged them to believe they were moving. We studied adaptation of horizontal, planar, goal-directed arm movements in a velocity-dependent force field. Our results show that individuals can learn to compensate for such a force field in a virtual environment and transfer their new skills to the actual free motion condition, with performance comparable to practice while moving. Such nonmoving techniques should impact various training conditions when moving may not be possible.NEW & NOTEWORTHY This study provided early evidence supporting that training movement skills without moving is possible. In contrast to previous studies, our study involves 1) exploiting cross-modal sensory interactions between vision and proprioception in a motionless setting to teach motor skills that could be transferable to a corresponding physical task, and 2) evaluates the movement skill of controlling muscle-generated forces to execute arm movements in the presence of external forces that were only virtually present during training. PMID- 28356477 TI - Moving slowly is hard for humans: limitations of dynamic primitives. AB - Mounting evidence suggests that human motor control uses dynamic primitives, attractors of dynamic neuromechanical systems that require minimal central supervision. However, advantages for control may be offset by compromised versatility. Extending recent results showing that humans could not sustain discrete movements as duration decreased, this study tested whether smoothly rhythmic movements could be maintained as duration increased. Participants performed horizontal movements between two targets, paced by sounds with intervals that increased from 1 to 6 s by 200 ms per cycle and then decreased again. The instruction emphasized smooth rhythmic movements without interspersed dwell times. We hypothesized that 1) when oscillatory motions slow down, smoothness decreases; 2) slower oscillatory motions are executed as submovements or even discrete movements; and 3) the transition between smooth oscillations and submovements shows hysteresis. An alternative hypothesis was that 4) removing visual feedback restores smoothness, indicative of visually evoked corrections causing the irregularity. Results showed that humans could not perform slow and smooth oscillatory movements. Harmonicity decreased with longer intervals, and dwell times between cycles appeared and became prominent at slower speeds. Velocity profiles showed an increase with cycle duration of the number of overlapping submovements. There was weak evidence of hysteresis in the transition between these two types of movement. Eliminating vision had no effect, suggesting that intermittent visually evoked corrections did not underlie this phenomenon. These results show that it is hard for humans to execute smooth rhythmic motions very slowly. Instead, they "default" to another dynamic primitive and compose motion as a sequence of overlapping submovements.NEW & NOTEWORTHY Complementing a large body of prior work showing advantages of composing primitives to manage the complexity of motor control, this paper uncovers a limitation due to composition of behavior from dynamic primitives: while slower execution frequently makes a task easier, there is a limit and it is hard for humans to move very slowly. We suggest that this remarkable limitation is not due to inadequacies of muscle, nor to slow neural communication, but is a consequence of how the control of movement is organized. PMID- 28356478 TI - Spatial attention during saccade decisions. AB - Behavioral measures of decision making are usually limited to observations of decision outcomes. In the present study, we made use of the fact that oculomotor and sensory selection are closely linked to track oculomotor decision making before oculomotor responses are made. We asked participants to make a saccadic eye movement to one of two memorized target locations and observed that visual sensitivity increased at both the chosen and the nonchosen saccade target locations, with a clear bias toward the chosen target. The time course of changes in visual sensitivity was related to saccadic latency, with the competition between the chosen and nonchosen targets resolved faster before short-latency saccades. On error trials, we observed an increased competition between the chosen and nonchosen targets. Moreover, oculomotor selection and visual sensitivity were influenced by top-down and bottom-up factors as well as by selection history and predicted the direction of saccades. Our findings demonstrate that saccade decisions have direct visual consequences and show that decision making can be traced in the human oculomotor system well before choices are made. Our results also indicate a strong association between decision making, saccade target selection, and visual sensitivity.NEW & NOTEWORTHY We show that saccadic decisions can be tracked by measuring spatial attention. Spatial attention is allocated in parallel to the two competing saccade targets, and the time course of spatial attention differs for fast-slow and for correct-erroneous decisions. Saccade decisions take the form of a competition between potential saccade goals, which is associated with spatial attention allocation to those locations. PMID- 28356480 TI - Estimating the implicit component of visuomotor rotation learning by constraining movement preparation time. AB - When sensory feedback is perturbed, accurate movement is restored by a combination of implicit processes and deliberate reaiming to strategically compensate for errors. Here, we directly compare two methods used previously to dissociate implicit from explicit learning on a trial-by-trial basis: 1) asking participants to report the direction that they aim their movements, and contrasting this with the directions of the target and the movement that they actually produce, and 2) manipulating movement preparation time. By instructing participants to reaim without a sensory perturbation, we show that reaiming is possible even with the shortest possible preparation times, particularly when targets are narrowly distributed. Nonetheless, reaiming is effortful and comes at the cost of increased variability, so we tested whether constraining preparation time is sufficient to suppress strategic reaiming during adaptation to visuomotor rotation with a broad target distribution. The rate and extent of error reduction under preparation time constraints were similar to estimates of implicit learning obtained from self-report without time pressure, suggesting that participants chose not to apply a reaiming strategy to correct visual errors under time pressure. Surprisingly, participants who reported aiming directions showed less implicit learning according to an alternative measure, obtained during trials performed without visual feedback. This suggests that the process of reporting can affect the extent or persistence of implicit learning. The data extend existing evidence that restricting preparation time can suppress explicit reaiming and provide an estimate of implicit visuomotor rotation learning that does not require participants to report their aiming directions.NEW & NOTEWORTHY During sensorimotor adaptation, implicit error-driven learning can be isolated from explicit strategy-driven reaiming by subtracting self-reported aiming directions from movement directions, or by restricting movement preparation time. Here, we compared the two methods. Restricting preparation times did not eliminate reaiming but was sufficient to suppress reaiming during adaptation with widely distributed targets. The self-report method produced a discrepancy in implicit learning estimated by subtracting aiming directions and implicit learning measured in no-feedback trials. PMID- 28356479 TI - Dynamical signatures of isometric force control as a function of age, expertise, and task constraints. AB - From the conceptual and methodological framework of the dynamical systems approach, force control results from complex interactions of various subsystems yielding observable behavioral fluctuations, which comprise both deterministic (predictable) and stochastic (noise-like) dynamical components. Here, we investigated these components contributing to the observed variability in force control in groups of participants differing in age and expertise level. To this aim, young (18-25 yr) as well as late middle-aged (55-65 yr) novices and experts (precision mechanics) performed a force maintenance and a force modulation task. Results showed that whereas the amplitude of force variability did not differ across groups in the maintenance tasks, in the modulation task it was higher for late middle-aged novices than for experts and higher for both these groups than for young participants. Within both tasks and for all groups, stochastic fluctuations were lowest where the deterministic influence was smallest. However, although all groups showed similar dynamics underlying force control in the maintenance task, a group effect was found for deterministic and stochastic fluctuations in the modulation task. The latter findings imply that both components were involved in the observed group differences in the variability of force fluctuations in the modulation task. These findings suggest that between groups the general characteristics of the dynamics do not differ in either task and that force control is more affected by age than by expertise. However, expertise seems to counteract some of the age effects.NEW & NOTEWORTHY Stochastic and deterministic dynamical components contribute to force production. Dynamical signatures differ between force maintenance and cyclic force modulation tasks but hardly between age and expertise groups. Differences in both stochastic and deterministic components are associated with group differences in behavioral variability, and observed behavioral variability is more strongly task dependent than person dependent. PMID- 28356482 TI - Representation of individual forelimb muscles in primary motor cortex. AB - Stimulus-triggered averaging (StTA) of forelimb muscle electromyographic (EMG) activity was used to investigate individual forelimb muscle representation within the primary motor cortex (M1) of rhesus macaques with the objective of determining the extent of intra-areal somatotopic organization. Two monkeys were trained to perform a reach-to-grasp task requiring multijoint coordination of the forelimb. EMG activity was simultaneously recorded from 24 forelimb muscles including 5 shoulder, 7 elbow, 5 wrist, 5 digit, and 2 intrinsic hand muscles. Microstimulation (15 uA at 15 Hz) was delivered throughout the movement task and individual stimuli were used as triggers for generating StTAs of EMG activity. StTAs were used to map the cortical representations of individual forelimb muscles. As reported previously (Park et al. 2001), cortical maps revealed a central core of distal muscle (wrist, digit, and intrinsic hand) representation surrounded by a horseshoe-shaped proximal (shoulder and elbow) muscle representation. In the present study, we found that shoulder and elbow flexor muscles were predominantly represented in the lateral branch of the horseshoe whereas extensors were predominantly represented in the medial branch. Distal muscles were represented within the core distal forelimb representation and showed extensive overlap. For the first time, we also show maps of inhibitory output from motor cortex, which follow many of the same organizational features as the maps of excitatory output.NEW & NOTEWORTHY While the orderly representation of major body parts along the precentral gyrus has been known for decades, questions have been raised about the possible existence of additional more detailed aspects of somatotopy. In this study, we have investigated this question with respect to muscles of the arm and show consistent features of within-arm (intra-areal) somatotopic organization. For the first time we also show maps of how inhibitory output from motor cortex is organized. PMID- 28356481 TI - SK channel inhibition mediates the initiation and amplitude modulation of synchronized burst firing in the spinal cord. AB - Burst firing in motoneurons represents the basis for generating meaningful movements. Neuromodulators and inhibitory receptor blocker cocktails have been used for years to induce burst firing in vitro; however, the ionic mechanisms in the motoneuron membrane that contribute to burst initiation and amplitude modulation are not fully understood. Small conductance Ca2+-activated potassium (SK) channels regulate excitatory inputs and firing output of motoneurons and interneurons and therefore, are a candidate for mediating bursting behavior. The present study examines the role of SK channels in the generation of synchronized bursting using an in vitro spinal cord preparation from adult mice. Our results show that SK channel inhibition is required for both initiation and amplitude modulation of burst firing. Specifically, administration of the synaptic inhibition blockers strychnine and picrotoxin amplified the spinal circuit excitatory drive but not enough to evoke bursting. However, when SK channels were inhibited using various approaches, the excitatory drive was further amplified, and synchronized bursting was always evoked. Furthermore, graded SK channel inhibition modulated the amplitude of the burst in a dose-dependent manner, which was reversed using SK channel activators. Importantly, modulation of neuronal excitability using multiple approaches failed to mimic the effects of SK modulators, suggesting a specific role for SK channel inhibition in generating bursting. Both NMDA (N-methyl-d-aspartate) and AMPA (alpha-amino-3-hydroxy-5 methylisoxazole-4-propionate) receptors were found to drive the synchronized bursts. The blocking of gap junctions did not disturb the burst synchrony. These results demonstrate a novel mechanistic role for SK channels in initiating and modulating burst firing of spinal motoneurons.NEW & NOTEWORTHY This study demonstrates that cholinergic inhibition or direct blockade of small conductance Ca2+-activated potassium (SK) channels facilitates burst firing in spinal motoneurons. The data provide a novel mechanistic explanation for synchronized bursting initiation and amplitude modulation through SK channel inhibition. Evidence also shows that synchronized bursting is driven by NMDA (N-methyl-d aspartate) and AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate) receptors and that gap junctions do not mediate motoneuron synchronization in this behavior. PMID- 28356483 TI - Depletion of the human N-terminal acetyltransferase hNaa30 disrupts Golgi integrity and ARFRP1 localization. AB - The organization of the Golgi apparatus (GA) is tightly regulated. Golgi stack scattering is observed in cellular processes such as apoptosis and mitosis, and has also been associated with disruption of cellular lipid metabolism and neurodegenerative diseases. Our studies show that depletion of the human N-alpha acetyltransferase 30 (hNaa30) induces fragmentation of the Golgi stack in HeLa and CAL-62 cell lines. The GA associated GTPase ADP ribosylation factor related protein 1 (ARFRP1) was previously shown to require N-terminal acetylation for membrane association and based on its N-terminal sequence, it is likely to be a substrate of hNaa30. ARFRP1 is involved in endosome-to-trans-Golgi network (TGN) traffic. We observed that ARFRP1 shifted from a predominantly cis-Golgi and TGN localization to localizing both Golgi and non-Golgi vesicular structures in hNaa30-depleted cells. However, we did not observe loss of membrane association of ARFRP1. We conclude that hNaa30 depletion induces Golgi scattering and induces aberrant ARFRP1 Golgi localization. PMID- 28356484 TI - A randomized placebo-controlled clinical study of nab-paclitaxel as second-line chemotherapy for patients with advanced non-small cell lung cancer in China. AB - We performed a randomized and placebo-controlled clinical study to investigate whether nab-paclitaxel can improve survival in patients with advanced non-small cell lung cancer (NSCLC) after unsuccessful first-line chemotherapy. Patients with stages III to IV advanced NSCLC after first-line platinum-based chemotherapy failure were randomly assigned in a 1:1 ratio to receive second-line treatment of nab-paclitaxel or placebo. Ninety two eligible patients were enrolled in the study. The median progression-free survival (PFS) was 4.6 months (95% confidence interval (CI): 3.4-6.7 months) for nab-paclitaxel, compared with 2.0 months (95% CI: 0.9-4.3 months) for placebo, representing a 56% reduction in disease progression (hazard ratio: 0.62; 95% CI: 0.33-0.81; P<0.001). The median overall survival (OS) was 6.3 months (95% CI: 3.9-8.2 months) for nab-paclitaxel, compared with 4.9 months (95% CI: 2.1-5.9 months) for placebo, representing a 22% reduction in disease progression (hazard ratio: 0.71; 95% CI: 0.33-0.85; P<0.001). Adverse events (AEs) were also observed for nab-paclitaxel. Nab paclitaxel can improve survival in patients with advanced NSCLC after unsuccessful first-line chemotherapy. PMID- 28356485 TI - Down-regulation of microRNA-216b inhibits IL-1beta-induced chondrocyte injury by up-regulation of Smad3. AB - Osteoarthritis (OA) is the most common type of joint disease, leading to a major cause of pain and disability. OA is characterized by the continuous degradation of articular cartilage, mainly resulting in an imbalance between synthesis and degradation of articular chondrocyte extracellular matrix (ECM). Aberrant miR 216b expression has been found in multiple cancers. However, the level of miR 216b in OA cartilage and its role in progression of this disease are still unknown. In the present study, the functional roles of miR-216b and its expression in OA tissues and interleukin-1beta (IL-1beta)-induced chondrocytes were examined. We found that the level of miR-216b was significantly higher and Smad3 expression was obviously lower in OA cartilage and IL-1beta-induced chondrocytes than in normal tissues and cells. Furthermore, a bioinformatics analysis and luciferase reporter assay identified Smad3 as a direct target gene of miR-216b, and Smad3 expression was reduced by miR-216b overexpression at both the mRNA and protein levels. A functional analysis demonstrated that miR-216b down-regulation obviously alleviated the IL-1beta-induced inhibition in cell proliferation, type II collagen, and aggrecan down-regulation and matrix metalloproteinase-13 (MMP-13) up-regulation, while miR-216b overexpression had the opposite effects. Knockdown of Smad3 by siRNA reversed the effects of the miR 216b inhibitor on cell proliferation, the expressions of type II collagen, aggrecan, and MMP-13. Our results suggested that miR-216b contributes to progression of OA by directly targeting Smad3, providing a potential therapeutic target for treatment of OA. PMID- 28356486 TI - Caveat emptor: for researchers, a rose will not smell sweet unless we know its composition. AB - In a recent publication in Bioscience Reports "Contaminants in commercial preparations of 'purified' small leucine-rich proteoglycans may distort mechanistic studies", Brown et al. identified by mass spectrometry and immunoblotting that certain commercial preparations of the small leucine-rich proteoglycans (SLRPs) decorin and biglycan, in fact, contained a mix of several proteoglycans that also included fibromodulin and aggrecan. The preparations were thus not suitable to study specific activities of decorin or biglycan. Decorin and biglycan are widely studied SLRPs that are considered to have highly multi functional effects on cells. Decorin is of interest as a transforming growth factor-beta antagonist and is also finding use in tissue engineering materials. This Commentary discusses Brown et al.'s findings and general issues raised for researchers who work with commercially sourced purified proteoglycans. PMID- 28356488 TI - The opinions and experiences of Irish obstetric and gynaecology trainee doctors in relation to abortion services in Ireland. AB - INTRODUCTION: The provision of abortion services in the Republic of Ireland is legally restricted. Recent legislation that has been implemented allows for abortion if there is a real and substantial risk to the woman's life, but in general Irish women must travel abroad for abortion services. The aims of this study were to investigate the clinical experiences of Irish obstetric non consultant hospital doctors (NCHDs) that work in this environment and to assess their attitudes towards termination of pregnancy (ToP). METHODS: We conducted an online cross-sectional descriptive survey of 184 Irish obstetric NCHDs. Quantitate and qualitative analysis was performed. RESULTS: There was a 28% response rate. 88% of respondents thought that ToP should be permitted for fatal fetal abnormality if the parents choose, 96% if the woman's health is severely affected and 86% in cases of rape and incest. Over 90% of respondents believed a woman's health suffers because of the need to travel abroad to undergo a ToP. Physical, psychological and social reasons were explored. The research also highlights that obstetric trainees are actively involved in the provision of preabortion and postabortion care. CONCLUSIONS: The clinical experiences and opinions of the respondents suggest that the current legal availability of abortion in Ireland is insufficient to guide best clinical practice and does not represent the views of those that provide obstetric care. PMID- 28356489 TI - How shared is shared decision-making? A care-ethical view on the role of partner and family. AB - The aim of shared decision-making (SDM) is to provide information to patients in order to enable them to decide autonomously and freely about treatment together with the doctor, without interference, force or coercion by others. Relatives may be considered as hindering or impeding a patient's own decision. Qualitative empirical research into lived experience of SDM of patients with cancer, however, problematises the patient's autonomy when facing terminal illness and the need to make decisions regarding treatment. Confronted with this difficulty, this contribution tries to think through patients' dependency of others, and make their autonomy more relational, drawing on care-ethical critics of a one-sided view of autonomy and on Ricoeur's view of the fundamentally intersubjective, relational self. We aim to conceptualise relatives not as a third party next to the doctor and the patient, but as co-constituents of the patient's identity and as such present in the decision-making process from the outset. What is more, partners and the family may be of inestimable help in retrieving the patient's identity in line with the past, present and possible future. PMID- 28356487 TI - A structural and functional analogue of a Bowman-Birk-type protease inhibitor from Odorrana schmackeri. AB - Frog skin secretions contain complex peptidomes and peptidic protease inhibitors that are one of the biologically and structurally described groups of components. In the present study, by use of molecular 'shotgun' cloning and LC MS/MS fractionation sequencing, a novel Bowman-Birk-type heptadecapeptide (AALKGCWTKSIPPKPCF-amide), named Odorrana schmackeriTrypsin Inhibitor (OSTI), with a canonical Cys6-Cys16 disulfide bridge, was isolated and identified in piebald odorous frog (O. schmackeri) skin secretion. A synthetic replicate of OSTI-exhibited trypsin inhibitory activity with a Ki value of 0.3 +/- 0.04 nM and also a tryptase inhibitory effect with a Ki of 2.5 +/- 0.6 MUM. This is the first time that this property has been reported for a peptide originating from amphibian sources. In addition, substituting lysine (K) with phenylalanine (F) at the presumed P1 position, completely abrogated the trypsin and tryptase inhibition, but produced a strong chymotrypsin inhibition with a Ki of 1.0 +/- 0.1 MUM. Thus, the specificity of this peptidic protease inhibitor could be optimized through modifying the amino acid residue at the presumed P1 position and this novel native OSTI, along with its analogue, [Phe9]-OSTI, have expanded the potential drug discovery and development pipeline directed towards alleviation of serine protease-mediated pathologies. PMID- 28356491 TI - Should gratitude be a requirement for access to live organ donation? AB - Gratitude is both expected and problematic in live organ donation. Are there grounds to require it, and to forbid access to live donor transplantation to a recipient who fails to signal that he feels any form of gratitude? Recipient gratitude is not currently required for organ donation, but it is expected and may be a moral requirement. Despite this, we argue that making it a condition for live organ transplantation would be unjustified. It would constitute a problematic and disproportionate punishment for perceived immoral behaviour on the part of the recipient. It would also bar the donor from positive aspects of organ donation that remain even in the absence of recipient gratitude. A potential recipient's lack of gratitude should be explored as a possible symptom of other morally problematic issues and integrated into the information provided to the potential donor. Recognition of the donor's gift and gratitude for it may also need to be expressed in part by others. This last aspect is relevant even in cases where the recipient feels and expresses gratitude. PMID- 28356490 TI - The deadly business of an unregulated global stem cell industry. AB - In 2016, the Office of the State Coroner of New South Wales released its report into the death of an Australian woman, Sheila Drysdale, who had died from complications of an autologous stem cell procedure at a Sydney clinic. In this report, we argue that Mrs Drysdale's death was avoidable, and it was the result of a pernicious global problem of an industry exploiting regulatory systems to sell unproven and unjustified interventions with stem cells. PMID- 28356492 TI - The moral bioenhancement of psychopaths. AB - We argue that the mandatory moral bioenhancement of psychopaths is justified as a prescription of social morality. Moral bioenhancement is legitimate when it is justified on the basis of the reasons of the recipients. Psychopaths expect and prefer that the agents with whom they interact do not have certain psychopathic traits. Particularly, they have reasons to require the moral bioenhancement of psychopaths with whom they must cooperate. By adopting a public reason and a Kantian argument, we conclude that we can justify to a psychopath being the recipient of mandatory moral bioenhancement because he has a reason to require the application of this prescription to other psychopaths. PMID- 28356493 TI - The psychological health and well-being experiences of female military veterans: a systematic review of the qualitative literature. AB - INTRODUCTION: Women in the military are a minority group who, in addition to facing exposure to traumatic events due to the nature of the work, face additional stressors while deployed. It is argued that these exposures and experiences place individuals at a significantly higher risk of finding it difficult adjusting post deployment. This paper focuses on the psychological health and well-being of female veterans post-deployment. METHODS: A systematic review of the literature related to female veterans' experiences upon returning home from deployment was conducted. RESULTS: Eight in-depth qualitative studies met the inclusion criteria for the study and were analysed using thematic analysis. Five key themes were identified in the papers: (1) bringing the war home, (2) post-deployment adjustment, (3) loss, (4) failed belongingness and (5) post-traumatic growth. CONCLUSIONS: These studies provide a useful insight into the different psychological health and well-being experiences that female veterans encounter. Additionally, the associated effects upon the individual and their families and communities are considered. PMID- 28356495 TI - Classic Spotlight, 1982 and 1983: Articles of Significant Interest Selected from the Journal of Virology Archives by the Editors. PMID- 28356496 TI - Erratum for Weger-Lucarelli et al., "Development and Characterization of Recombinant Virus Generated from a New World Zika Virus Infectious Clone". PMID- 28356494 TI - Soluble Epoxide Hydrolase Pharmacological Inhibition Decreases Alveolar Bone Loss by Modulating Host Inflammatory Response, RANK-Related Signaling, Endoplasmic Reticulum Stress, and Apoptosis. AB - Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid derived from the cytochrome P450 enzymes, are mainly metabolized by soluble epoxide hydrolase (sEH) to their corresponding diols. EETs but not their diols, have anti inflammatory properties, and inhibition of sEH might provide protective effects against inflammatory bone loss. Thus, in the present study, we tested the selective sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), in a mouse model of periodontitis induced by infection with Aggregatibacter actinomycetemcomitans Oral treatment of wild-type mice with TPPU and sEH knockout (KO) animals showed reduced bone loss induced by A. actinomycetemcomitans This was associated with decreased expression of key osteoclastogenic molecules, receptor activator of nuclear factor-kappaB/RANK ligand/osteoprotegerin, and the chemokine monocyte chemotactic protein 1 in the gingival tissue without affecting bacterial counts. In addition, downstream kinases p38 and c-Jun N-terminal kinase known to be activated in response to inflammatory signals were abrogated after TPPU treatment or in sEH KO mice. Moreover, endoplasmic reticulum stress was elevated in periodontal disease but was abrogated after TPPU treatment and in sEH knockout mice. Together, these results demonstrated that sEH pharmacological inhibition may be of therapeutic value in periodontitis. PMID- 28356498 TI - In vivo targets of human placental micro-vesicles vary with exposure time and pregnancy. AB - Throughout human gestation, the placenta extrudes vast quantities of extracellular vesicles (EVs) of different sizes into the maternal circulation. Although multinucleated macro-vesicles are known to become trapped in the maternal lungs and do not enter the peripheral circulation, the maternal organs and cells that smaller placental micro-vesicles interact with in vivo remain unknown. This study aimed to characterise the interaction between placental micro vesicles and endothelial cells in vitro and to elucidate which organs placental micro-vesicles localise to in vivo Placental macro- and micro-vesicles were isolated from cultured human first trimester placental explants by sequential centrifugation and exposed to human microvascular endothelial cells for up to 72 h. In vivo, placental macro- and micro-vesicles were administered to both non pregnant and pregnant CD1 mice, and after two or 30 min or 24 h, organs were imaged on an IVIS Kinetic Imager. Placental EVs rapidly interacted with endothelial cells via phagocytic and clathrin-mediated endocytic processes in vitro, with over 60% of maximal interaction being achieved by 30 min of exposure. In vivo, placental macro-vesicles were localised exclusively to the lungs regardless of time of exposure, whereas micro-vesicles were localised to the lungs, liver and kidneys, with different distribution patterns depending on the length of exposure and whether the mouse was pregnant or not. The fact that placental EVs can rapidly interact with endothelial cells and localise to different organs in vivo supports that different size fractions of placental EVs are likely to have different downstream effects on foeto-maternal communication. PMID- 28356499 TI - Relationship of DNA integrity to HRG C633T SNP and ART outcome in infertile couples. AB - The status of sperm DNA fragmentation, protamine deficiency, free thiols and disulphide bonds in colloid-selected samples and its relationship to ART outcome or HRG C633T SNP is not known. The objective of this study was to determine these relationships in spermatozoa from men with male factor or unknown factor infertility (n = 118) undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). Sperm DNA integrity was analysed by flow cytometry using three fluorescent probes (acridine orange, monobromobimane and chromomycin A3). Principal component analysis (PCA) was used to identify the parameters that most influenced fertility. The relationships of sperm DNA integrity with seminal parameters, HRG C633T SNP and ART outcome were established using ANOVA and t test. Sperm concentration and yield after preparation accounted for 27% of the total variance; sperm DNA integrity (%DFI and disulphide bonds) accounted for 16% of the variance in men from infertile couples. Sperm %DFI was significantly higher (P < 0.05) in older men than in younger men. A significant difference (P < 0.01) was observed in %DFI between smokers and non-smokers. Sperm %DFI was significantly higher (P < 0.01) in male factor infertility compared to either female factor or unknown factor infertility while free thiols were significantly higher (P < 0.01) in unknown infertility factor. No significant difference was observed between IVF success/failure in any of the seminal parameters studied. There was a tendency for protamine deficiency to be higher and disulphide concentration to be lower in men with HRG 633T. Such assessments may provide additional useful information about the prognosis for ART outcome, although more research is needed before clinical guidelines can be provided. PMID- 28356500 TI - A novel testis-specific protein, PRAMEY, is involved in spermatogenesis in cattle. AB - Preferentially expressed antigen in melanoma (PRAME) is a cancer/testis antigen that is predominantly expressed in normal testicular tissues and a variety of tumors. The function of the PRAME family in spermatogenesis remains unknown. This study was designed to characterize the Y-linked PRAME (PRAMEY) protein during spermatogenesis in cattle. We found that PRAMEY is a novel male germ cell specific, and a germinal granule-associated protein that is expressed in spermatogenic cells during spermatogenesis. The intact PRAMEY protein (58 kDa) was detected in different ages of testes but not in epididymal spermatozoa. A PRAMEY isoform (30 kDa) was highly expressed only in testes after puberty and in epididymal spermatozoa. This isoform interacts with PP1gamma2 and is likely the mature protein present in the testes and sperm. Immunofluorescent staining demonstrated that PRAMEY was located predominantly in the acrosome granule of spermatids, and in acrosome and flagellum of spermatozoa. Immunogold electron microscopy further localized the PRAMEY protein complex to the nucleus and several cytoplasmic organelles, including the rough endoplasmic reticulum, some small vesicles, the intermitochondrial cement, the chromatoid body and the centrioles, in spermatogonia, spermatocytes, spermatids and/or spermatozoa. PRAMEY was highly enriched in and structurally associated with the matrix of the acrosomal granule (AG) in round spermatids, and migrated with the expansion of the AG during acrosomal biogenesis. While the function of PRAMEY remains unclear during spermatogenesis, our results suggest that PRAMEY may play an essential role in acrosome biogenesis and spermatogenesis.Free Chinese abstract: A Chinese translation of this abstract is freely available at http://www.reproduction online.org/content/153/6/847/suppl/DC1.FreeSpanish abstract: A Spanish translation of this abstract is freely available at http://www.reproduction online.org/content/153/6/847/suppl/DC2. PMID- 28356501 TI - Anti-Mullerian Hormone (AMH) and fertility management in agricultural species. AB - A reliable, easy to assess marker for fertility in agricultural species would be highly desirable and Anti-Mullerian Hormone (AMH) is a promising candidate. This review summarizes recent findings concerning AMH and its role in fertility management, mainly in cattle. It focuses on (1) alterations in circulating AMH concentrations from birth to puberty and during estrous cycles; (2) correlation of circulating AMH concentrations with ovarian follicle numbers and ovarian reserve; (3) factors that impact circulating AMH concentrations; (4) use of AMH as a predictor of fertility. Circulating AMH concentrations can be easily and reliably measured with a single blood sample in adult cattle because AMH varies minimally during the estrous cycle and is repeatable across multiple cycles. Circulating AMH concentrations are positively associated with several measures of fertility. Dairy heifers with low compared with higher AMH concentrations subsequently had lower pregnancy rates, higher probability of being culled after birth of their first calf and shorter herd longevity. Also, AMH is predictive of response to superovulation in cattle and sheep. Several factors contribute to the variability in AMH concentrations among individuals; for example, beef cattle have higher AMH than dairy cattle. Nutritional imbalances, disease and endocrine disruptors during fetal life may negatively program the size of the ovarian reserve and consequently serum AMH concentrations and potential fertility in adulthood. We conclude that AMH may be a predictor of fertility and herd longevity in cattle, whereas in sheep and other farm species, the potential association between AMH and reproductive performance remains largely unexplored.Free Italian abstract: An Italian translation of this abstract is freely available at http://www.reproduction online.org/content/154/1/R1/suppl/DC1. PMID- 28356502 TI - Origins and Evolution of Stomatal Development. AB - The fossil record suggests stomata-like pores were present on the surfaces of land plants over 400 million years ago. Whether stomata arose once or whether they arose independently across newly evolving land plant lineages has long been a matter of debate. In Arabidopsis, a genetic toolbox has been identified that tightly controls stomatal development and patterning. This includes the basic helix-loop-helix (bHLH) transcription factors SPEECHLESS (SPCH), MUTE, FAMA, and ICE/SCREAMs (SCRMs), which promote stomatal formation. These factors are regulated via a signaling cascade, which includes mobile EPIDERMAL PATTERNING FACTOR (EPF) peptides to enforce stomatal spacing. Mosses and hornworts, the most ancient extant lineages to possess stomata, possess orthologs of these Arabidopsis (Arabidopsis thaliana) stomatal toolbox genes, and manipulation in the model bryophyte Physcomitrella patens has shown that the bHLH and EPF components are also required for moss stomatal development and patterning. This supports an ancient and tightly conserved genetic origin of stomata. Here, we review recent discoveries and, by interrogating newly available plant genomes, we advance the story of stomatal development and patterning across land plant evolution. Furthermore, we identify potential orthologs of the key toolbox genes in a hornwort, further supporting a single ancient genetic origin of stomata in the ancestor to all stomatous land plants. PMID- 28356505 TI - Target practice in severe asthma. AB - The NLRP3 inflammasome/caspase-1/IL-1beta axis may be a therapeutic target in severe steroid-resistant asthma. PMID- 28356504 TI - Using geospatial mapping to design HIV elimination strategies for sub-Saharan Africa. AB - Treatment as prevention (TasP) has been proposed by the World Health Organization and the Joint United Nations Programme on HIV/AIDS (UNAIDS) as a global strategy for eliminating HIV. The rationale is that treating individuals reduces their infectivity. We present a geostatistical framework for designing TasP-based HIV elimination strategies in sub-Saharan Africa. We focused on Lesotho, where ~25% of the population is infected. We constructed a density of infection map by gridding high-resolution demographic data and spatially smoothing georeferenced HIV testing data. The map revealed the countrywide geographic dispersion pattern of HIV-infected individuals. We found that ~20% of the HIV-infected population lives in urban areas and that almost all rural communities have at least one HIV infected individual. We used the map to design an optimal elimination strategy and identified which communities should use TasP. This strategy minimized the area that needed to be covered to find and treat HIV-infected individuals. We show that UNAIDS's elimination strategy would not be feasible in Lesotho because it would require deploying treatment in areas where there are ~4 infected individuals/km2 Our results show that the spatial dispersion of Lesotho's population hinders, and may even prevent, the elimination of HIV. PMID- 28356506 TI - The neural substrates of super memory. AB - Specific neural networks support superior memory in world-class memory athletes. PMID- 28356507 TI - How to straighten out that which bends up. AB - Chikungunya virus requires host granzyme A to drive joint inflammation. PMID- 28356503 TI - EXO70C2 Is a Key Regulatory Factor for Optimal Tip Growth of Pollen. AB - The exocyst, a eukaryotic tethering complex, coregulates targeted exocytosis as an effector of small GTPases in polarized cell growth. In land plants, several exocyst subunits are encoded by double or triple paralogs, culminating in tens of EXO70 paralogs. Out of 23 Arabidopsis thaliana EXO70 isoforms, we analyzed seven isoforms expressed in pollen. Genetic and microscopic analyses of single mutants in EXO70A2, EXO70C1, EXO70C2, EXO70F1, EXO70H3, EXO70H5, and EXO70H6 genes revealed that only a loss-of-function EXO70C2 allele resulted in a significant male-specific transmission defect (segregation 40%:51%:9%) due to aberrant pollen tube growth. Mutant pollen tubes grown in vitro exhibited an enhanced growth rate and a decreased thickness of the tip cell wall, causing tip bursts. However, exo70C2 pollen tubes could frequently recover and restart their speedy elongation, resulting in a repetitive stop-and-go growth dynamics. A pollen specific depletion of the closest paralog, EXO70C1, using artificial microRNA in the exo70C2 mutant background, resulted in a complete pollen-specific transmission defect, suggesting redundant functions of EXO70C1 and EXO70C2. Both EXO70C1 and EXO70C2, GFP tagged and expressed under the control of their native promoters, localized in the cytoplasm of pollen grains, pollen tubes, and also root trichoblast cells. The expression of EXO70C2-GFP complemented the aberrant growth of exo70C2 pollen tubes. The absent EXO70C2 interactions with core exocyst subunits in the yeast two-hybrid assay, cytoplasmic localization, and genetic effect suggest an unconventional EXO70 function possibly as a regulator of exocytosis outside the exocyst complex. In conclusion, EXO70C2 is a novel factor contributing to the regulation of optimal tip growth of Arabidopsis pollen tubes. PMID- 28356509 TI - Macrophages take rheumatoid arthritis up a "Notch". AB - Notch signaling in bone marrow-derived inflammatory macrophages is central to synovial inflammation seen in rheumatoid arthritis, representing a promising future therapeutic target. PMID- 28356508 TI - The druggable genome and support for target identification and validation in drug development. AB - Target identification (determining the correct drug targets for a disease) and target validation (demonstrating an effect of target perturbation on disease biomarkers and disease end points) are important steps in drug development. Clinically relevant associations of variants in genes encoding drug targets model the effect of modifying the same targets pharmacologically. To delineate drug development (including repurposing) opportunities arising from this paradigm, we connected complex disease- and biomarker-associated loci from genome-wide association studies to an updated set of genes encoding druggable human proteins, to agents with bioactivity against these targets, and, where there were licensed drugs, to clinical indications. We used this set of genes to inform the design of a new genotyping array, which will enable association studies of druggable genes for drug target selection and validation in human disease. PMID- 28356510 TI - Estimation of polio infection prevalence from environmental surveillance data. AB - A major obstacle to eradicating polio is that poliovirus from endemic countries can be reintroduced to polio-free countries. Environmental surveillance (ES) can detect poliovirus from sewage or wastewaters samples, even in the absence of patients with paralysis. ES is underused, in part because its sensitivity is unknown. We used two unique data sets collected during a natural experiment provided by the 2013 polio outbreak in Israel: ES data from different locations and records of supplemental immunization with the live vaccine. Data from the intersecting population between the two data sets (covering more than 63,000 people) yielded a dose-dependent relationship between the number of poliovirus shedders and the amount of poliovirus in sewage. Using a mixed-effects linear regression analysis of these data, we developed several quantitative tools, such as (i) ascertainment of the number of infected individuals from ES data for application during future epidemics elsewhere, (ii) evaluation of the sensitivity of ES, and (iii) determination of the confidence level of the termination of poliovirus circulation after an outbreak. These results will be valuable in monitoring future outbreaks with ES, and this approach could be used to certify poliovirus elimination or to validate the need for more containment efforts. PMID- 28356512 TI - Cardiac regeneration: All work and no repair? AB - Structural changes in the developing heart may influence the limited regenerative capacity of the adult heart. We examine how the workload exerted on the adult mammalian heart may limit regenerative capability and discuss recent therapies that demonstrate beneficial effects through unloading the heart. PMID- 28356513 TI - The Devil is in the details for DNA mismatch repair. PMID- 28356511 TI - Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis. AB - There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2 RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G4C2 RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic C9ORF72 mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G4C2 RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G4C2 RNA and downstream G4C2 RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2 RNA-based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention. PMID- 28356514 TI - Cytokine receptor signaling is required for the survival of ALK- anaplastic large cell lymphoma, even in the presence of JAK1/STAT3 mutations. AB - Activating Janus kinase (JAK) and signal transducer and activator of transcription (STAT) mutations have been discovered in many T-cell malignancies, including anaplastic lymphoma kinase (ALK)- anaplastic large cell lymphomas (ALCLs). However, such mutations occur in a minority of patients. To investigate the clinical application of targeting JAK for ALK- ALCL, we treated ALK- cell lines of various histological origins with JAK inhibitors. Interestingly, most exogenous cytokine-independent cell lines responded to JAK inhibition regardless of JAK mutation status. JAK inhibitor sensitivity correlated with the STAT3 phosphorylation status of tumor cells. Using retroviral shRNA knockdown, we have demonstrated that these JAK inhibitor-sensitive cells are dependent on both JAK1 and STAT3 for survival. JAK1 and STAT3 gain-of-function mutations were found in some, but not all, JAK inhibitor-sensitive cells. Moreover, the mutations alone cannot explain the JAK1/STAT3 dependency, given that wild-type JAK1 or STAT3 was sufficient to promote cell survival in the cells that had either JAK1or STAT3 mutations. To investigate whether other mechanisms were involved, we knocked down upstream receptors GP130 or IL-2Rgamma. Knockdown of GP130 or IL-2Rgamma induced cell death in selected JAK inhibitor-sensitive cells. High expression levels of cytokines, including IL-6, were demonstrated in cell lines as well as in primary ALK- ALCL tumors. Finally, ruxolitinib, a JAK1/2 inhibitor, was effective in vivo in a xenograft ALK- ALCL model. Our data suggest that cytokine receptor signaling is required for tumor cell survival in diverse forms of ALK- ALCL, even in the presence of JAK1/STAT3 mutations. Therefore, JAK inhibitor therapy might benefit patients with ALK- ALCL who are phosphorylated STAT3. PMID- 28356515 TI - Identification of targets of tumor suppressor microRNA-34a using a reporter library system. AB - miRNAs play critical roles in various biological processes by targeting specific mRNAs. Current approaches to identifying miRNA targets are insufficient for elucidation of a miRNA regulatory network. Here, we created a cell-based screening system using a luciferase reporter library composed of 4,891 full length cDNAs, each of which was integrated into the 3' UTR of a luciferase gene. Using this reporter library system, we conducted a screening for targets of miR 34a, a tumor-suppressor miRNA. We identified both previously characterized and previously uncharacterized targets. miR-34a overexpression in MDA-MB-231 breast cancer cells repressed the expression of these previously unrecognized targets. Among these targets, GFRA3 is crucial for MDA-MB-231 cell growth, and its expression correlated with the overall survival of patients with breast cancer. Furthermore, GFRA3 was found to be directly regulated by miR-34a via its coding region. These data show that this system is useful for elucidating miRNA functions and networks. PMID- 28356516 TI - Efficacy, long-term toxicity, and mechanistic studies of gold nanorods photothermal therapy of cancer in xenograft mice. AB - Gold nanorods (AuNRs)-assisted plasmonic photothermal therapy (AuNRs-PPTT) is a promising strategy for combating cancer in which AuNRs absorb near-infrared light and convert it into heat, causing cell death mainly by apoptosis and/or necrosis. Developing a valid PPTT that induces cancer cell apoptosis and avoids necrosis in vivo and exploring its molecular mechanism of action is of great importance. Furthermore, assessment of the long-term fate of the AuNRs after treatment is critical for clinical use. We first optimized the size, surface modification [rifampicin (RF) conjugation], and concentration (2.5 nM) of AuNRs and the PPTT laser power (2 W/cm2) to achieve maximal induction of apoptosis. Second, we studied the potential mechanism of action of AuNRs-PPTT using quantitative proteomic analysis in mouse tumor tissues. Several death pathways were identified, mainly involving apoptosis and cell death by releasing neutrophil extracellular traps (NETs) (NETosis), which were more obvious upon PPTT using RF conjugated AuNRs (AuNRs@RF) than with polyethylene glycol thiol-conjugated AuNRs. Cytochrome c and p53-related apoptosis mechanisms were identified as contributing to the enhanced effect of PPTT with AuNRs@RF. Furthermore, Pin1 and IL18-related signaling contributed to the observed perturbation of the NETosis pathway by PPTT with AuNRs@RF. Third, we report a 15-month toxicity study that showed no long term toxicity of AuNRs in vivo. Together, these data demonstrate that our AuNRs PPTT platform is effective and safe for cancer therapy in mouse models. These findings provide a strong framework for the translation of PPTT to the clinic. PMID- 28356517 TI - Protectin D1n-3 DPA and resolvin D5n-3 DPA are effectors of intestinal protection. AB - The resolution of inflammation is an active process orchestrated by specialized proresolving lipid mediators (SPM) that limit the host response within the affected tissue; failure of effective resolution may lead to tissue injury. Because persistence of inflammatory signals is a main feature of chronic inflammatory conditions, including inflammatory bowel diseases (IBDs), herein we investigate expression and functions of SPM in intestinal inflammation. Targeted liquid chromatography-tandem mass spectrometry-based metabololipidomics was used to identify SPMs from n-3 polyunsaturated fatty acids in human IBD colon biopsies, quantifying a significant up-regulation of the resolvin and protectin pathway compared with normal gut tissue. Systemic treatment with protectin (PD)1n 3 DPA or resolvin (Rv)D5n-3 DPA protected against colitis and intestinal ischemia/reperfusion-induced inflammation in mice. Inhibition of 15-lipoxygenase activity reduced PD1n-3 DPA and augmented intestinal inflammation in experimental colitis. Intravital microscopy of mouse mesenteric venules demonstrated that PD1n 3 DPA and RvD5n-3 DPA decreased the extent of leukocyte adhesion and emigration following ischemia-reperfusion. These data were translated by assessing human neutrophil-endothelial interactions under flow: PD1n-3 DPA and RvD5n-3 DPA reduced cell adhesion onto TNF-alpha-activated human endothelial monolayers. In conclusion, we propose that innovative therapies based on n-3 DPA-derived mediators could be developed to enable antiinflammatory and tissue protective effects in inflammatory pathologies of the gut. PMID- 28356520 TI - Consistent and powerful graph-based change-point test for high-dimensional data. AB - A change-point detection is proposed by using a Bayesian-type statistic based on the shortest Hamiltonian path, and the change-point is estimated by using ratio cut. A permutation procedure is applied to approximate the significance of Bayesian-type statistics. The change-point test is proven to be consistent, and an error probability in change-point estimation is provided. The test is very powerful against alternatives with a shift in variance and is accurate in change point estimation, as shown in simulation studies. Its applicability in tracking cell division is illustrated. PMID- 28356518 TI - BCL6 promotes glioma and serves as a therapeutic target. AB - ZBTB transcription factors orchestrate gene transcription during tissue development. However, their roles in glioblastoma (GBM) remain unexplored. Here, through a functional screening of ZBTB genes, we identify that BCL6 is required for GBM cell viability and that BCL6 overexpression is associated with worse prognosis. In a somatic transgenic mouse model, depletion of Bcl6 inhibits the progression of KrasG12V-driven high-grade glioma. Transcriptome analysis demonstrates the involvement of BCL6 in tumor protein p53 (TP53), erythroblastic leukemia viral oncogene homolog (ErbB), and MAPK signaling pathways. Indeed, BCL6 represses the expression of wild-type p53 and its target genes in GBM cells. Knockdown of BCL6 augments the activation of TP53 pathway in response to radiation. Importantly, we discover that receptor tyrosine kinase AXL is a transcriptional target of BCL6 in GBM and mediates partially the regulatory effects of BCL6 on both MEK-ERK (mitogen-activated protein/extracellular signal regulated kinase kinase-extracellular signal-regulated kinase) and S6K-RPS6 (ribosomal protein S6 kinase-ribosomal protein S6) axes. Similar to BCL6 silencing, depletion of AXL profoundly attenuates GBM proliferation both in vitro and in vivo. Moreover, targeted inhibition of BCL6/nuclear receptor corepressor 1 (NCoR) complex by peptidomimetic inhibitor not only significantly decreases AXL expression and the activity of MEK-ERK and S6K-RPS6 cascades but also displays a potent antiproliferative effect against GBM cells. Together, these findings uncover a glioma-promoting role of BCL6 and provide the rationale of targeting BCL6 as a potential therapeutic approach. PMID- 28356519 TI - Structural reconstruction of protein ancestry. AB - Ancestral protein reconstruction allows the resurrection and characterization of ancient proteins based on computational analyses of sequences of modern-day proteins. Unfortunately, many protein families are highly divergent and not suitable for sequence-based reconstruction approaches. This limitation is exemplified by the antigen receptors of jawed vertebrates (B- and T-cell receptors), heterodimers formed by pairs of Ig domains. These receptors are believed to have evolved from an extinct homodimeric ancestor through a process of gene duplication and diversification; however molecular evidence has so far remained elusive. Here, we use a structural approach and laboratory evolution to reconstruct such molecules and characterize their interaction with antigen. High resolution crystal structures of reconstructed homodimeric receptors in complex with hen-egg white lysozyme demonstrate how nanomolar affinity binding of asymmetrical antigen is enabled through selective recruitment and structural plasticity within the receptor-binding site. Our results provide structural evidence in support of long-held theories concerning the evolution of antigen receptors, and provide a blueprint for the experimental reconstruction of protein ancestry in the absence of phylogenetic evidence. PMID- 28356521 TI - Hot spot of N2 fixation in the western tropical South Pacific pleads for a spatial decoupling between N2 fixation and denitrification. PMID- 28356522 TI - Minute Virus of Canines NP1 Protein Governs the Expression of a Subset of Essential Nonstructural Proteins via Its Role in RNA Processing. AB - Parvoviruses use a variety of means to control the expression of their compact genomes. The bocaparvovirus minute virus of canines (MVC) encodes a small, genus specific protein, NP1, which governs access to the viral capsid gene via its role in alternative polyadenylation and alternative splicing of the single MVC pre mRNA. In addition to NP1, MVC encodes five additional nonstructural proteins (NS) that share an initiation codon at the left end of the genome and which are individually encoded by alternative multiply spliced mRNAs. We found that three of these proteins were encoded by mRNAs that excise the NP1-regulated MVC intron immediately upstream of the internal polyadenylation site, (pA)p, and that generation of these proteins was thus regulated by NP1. Splicing of their progenitor mRNAs joined the amino termini of these proteins to the NP1 open reading frame, and splice site mutations that prevented their expression inhibited virus replication in a host cell-dependent manner. Thus, in addition to controlling capsid gene access, NP1 also controls the expression of three of the five identified NS proteins via its role in governing MVC pre-mRNA splicing.IMPORTANCE The Parvovirinae are small nonenveloped icosahedral viruses that are important pathogens in many animal species, including humans. Minute virus of canine (MVC) is an autonomous parvovirus in the genus Bocaparvovirus It has a single promoter that generates a single pre-mRNA. NP1, a small genus specific MVC protein, participates in the processing of this pre-mRNA and so controls capsid gene access via its role in alternative internal polyadenylation and splicing. We show that NP1 also controls the expression of three of the five identified NS proteins via its role in governing MVC pre-mRNA splicing. These NS proteins together are required for virus replication in a host cell-dependent manner. PMID- 28356523 TI - ORF7 of Varicella-Zoster Virus Is Required for Viral Cytoplasmic Envelopment in Differentiated Neuronal Cells. AB - Although a varicella-zoster virus (VZV) vaccine has been used for many years, the neuropathy caused by VZV infection is still a major health concern. Open reading frame 7 (ORF7) of VZV has been recognized as a neurotropic gene in vivo, but its neurovirulent role remains unclear. In the present study, we investigated the effect of ORF7 deletion on VZV replication cycle at virus entry, genome replication, gene expression, capsid assembly and cytoplasmic envelopment, and transcellular transmission in differentiated neural progenitor cells (dNPCs) and neuroblastoma SH-SY5Y (dSY5Y) cells. Our results demonstrate that the ORF7 protein is a component of the tegument layer of VZV virions. Deleting ORF7 did not affect viral entry, viral genome replication, or the expression of typical viral genes but clearly impacted cytoplasmic envelopment of VZV capsids, resulting in a dramatic increase of envelope-defective particles and a decrease in intact virions. The defect was more severe in differentiated neuronal cells of dNPCs and dSY5Y. ORF7 deletion also impaired transmission of ORF7-deficient virus among the neuronal cells. These results indicate that ORF7 is required for cytoplasmic envelopment of VZV capsids, virus transmission among neuronal cells, and probably the neuropathy induced by VZV infection.IMPORTANCE The neurological damage caused by varicella-zoster virus (VZV) reactivation is commonly manifested as clinical problems. Thus, identifying viral neurovirulent genes and characterizing their functions are important for relieving VZV related neurological complications. ORF7 has been previously identified as a potential neurotropic gene, but its involvement in VZV replication is unclear. In this study, we found that ORF7 is required for VZV cytoplasmic envelopment in differentiated neuronal cells, and the envelopment deficiency caused by ORF7 deletion results in poor dissemination of VZV among neuronal cells. These findings imply that ORF7 plays a role in neuropathy, highlighting a potential strategy to develop a neurovirulence-attenuated vaccine against chickenpox and herpes zoster and providing a new target for intervention of neuropathy induced by VZV. PMID- 28356524 TI - SGTA-Dependent Regulation of Hsc70 Promotes Cytosol Entry of Simian Virus 40 from the Endoplasmic Reticulum. AB - Membrane penetration by nonenveloped viruses remains enigmatic. In the case of the nonenveloped polyomavirus simian virus 40 (SV40), the virus penetrates the endoplasmic reticulum (ER) membrane to reach the cytosol and then traffics to the nucleus to cause infection. We previously demonstrated that the cytosolic Hsc70 SGTA-Hsp105 complex is tethered to the ER membrane, where Hsp105 and SGTA facilitate the extraction of SV40 from the ER and transport of the virus into the cytosol. We now find that Hsc70 also ejects SV40 from the ER into the cytosol in a step regulated by SGTA. Although SGTA's N-terminal domain, which mediates homodimerization and recruits cellular adaptors, is dispensable during ER-to cytosol transport of SV40, this domain appears to exert an unexpected post-ER membrane translocation function during SV40 entry. Our study thus establishes a critical function of Hsc70 within the Hsc70-SGTA-Hsp105 complex in promoting SV40 ER-to-cytosol membrane penetration and unveils a role of SGTA in controlling this step.IMPORTANCE How a nonenveloped virus transports across a biological membrane to cause infection remains mysterious. One enigmatic step is whether host cytosolic components are co-opted to transport the viral particle into the cytosol. During ER-to-cytosol membrane transport of the nonenveloped polyomavirus SV40, a decisive infection step, a cytosolic complex composed of Hsc70-SGTA Hsp105 was previously shown to associate with the ER membrane. SGTA and Hsp105 have been shown to extract SV40 from the ER and transport the virus into the cytosol. We demonstrate here a critical role of Hsc70 in SV40 ER-to-cytosol penetration and reveal how SGTA controls Hsc70 to impact this process. PMID- 28356525 TI - MicroRNA miR-27 Inhibits Adenovirus Infection by Suppressing the Expression of SNAP25 and TXN2. AB - Recent studies have reported that host microRNAs (miRNAs) regulate infections by several types of viruses via various mechanisms and that inhibition of the miRNA processing factors enhances or prevents viral infection. However, it has not been clarified whether these effects of miRNAs extend to adenovirus (Ad) infection. Here we show that miR-27a and -b efficiently inhibit infection with an Ad via the downregulation of SNAP25 and TXN2, which are members of the SNARE proteins and the thioredoxin family, respectively. Approximately 80% reductions in Ad genomic copy number were found in cells transfected with miR-27a/b mimics, whereas there were approximately 2.5- to 5-fold larger copy numbers of the Ad genome following transfection with miR-27a/b inhibitors. Microarray gene expression analysis and in silico analysis demonstrated that SNAP25 and TXN2 are target genes of miR 27a/b. A reporter assay using plasmids containing the 3' untranslated regions of the SNAP25 and TXN2 genes showed that miR-27a/b directly suppressed SNAP25 and TXN2 expression through posttranscriptional gene silencing. Knockdown of SNAP25 led to a significant inhibition of Ad entry into cells. Knockdown of TXN2 induced cell cycle arrest at G1 phase, leading to a reduction in Ad replication. In addition, overexpression of Ad-encoded small noncoding RNAs (VA-RNAs) restored the miR-27a/b-mediated reduction in infection level with a VA-RNA-lacking Ad mutant due to the VA-RNA-mediated inhibition of miR-27a/b expression. These results indicate that miR-27a and -b suppress SNAP25 and TXN2 expression via posttranscriptional gene silencing, leading to efficient suppression of Ad infection.IMPORTANCE Adenovirus (Ad) is widely used as a platform for replication incompetent Ad vectors (Adv) and replication-competent oncolytic Ad (OAd) in gene therapy and virotherapy. Regulation of Ad infection is highly important for efficient gene therapies using both Adv and OAd. In this study, we demonstrate that miR-27a and -b, which are widely expressed in host cells, suppress SNAP25 and TXN2 expression through posttranscriptional gene silencing. Suppression of SNAP25 and TXN2 expression leads to inhibition of Ad entry into cells and to cell cycle arrest, respectively, leading to efficient suppression of Ad infection. Our findings provide important clues to the improvement of gene therapies using both Adv and OAd. PMID- 28356526 TI - Chimeric Hemagglutinin Constructs Induce Broad Protection against Influenza B Virus Challenge in the Mouse Model. AB - Seasonal influenza virus epidemics represent a significant public health burden. Approximately 25% of all influenza virus infections are caused by type B viruses, and these infections can be severe, especially in children. Current influenza virus vaccines are an effective prophylaxis against infection but are impacted by rapid antigenic drift, which can lead to mismatches between vaccine strains and circulating strains. Here, we describe a broadly protective vaccine candidate based on chimeric hemagglutinins, consisting of globular head domains from exotic influenza A viruses and stalk domains from influenza B viruses. Sequential vaccination with these constructs in mice leads to the induction of broadly reactive antibodies that bind to the conserved stalk domain of influenza B virus hemagglutinin. Vaccinated mice are protected from lethal challenge with diverse influenza B viruses. Results from serum transfer experiments and antibody dependent cell-mediated cytotoxicity (ADCC) assays indicate that this protection is antibody mediated and based on Fc effector functions. The present data suggest that chimeric hemagglutinin-based vaccination is a viable strategy to broadly protect against influenza B virus infection.IMPORTANCE While current influenza virus vaccines are effective, they are affected by mismatches between vaccine strains and circulating strains. Furthermore, the antiviral drug oseltamivir is less effective for treating influenza B virus infections than for treating influenza A virus infections. A vaccine that induces broad and long-lasting protection against influenza B viruses is therefore urgently needed. PMID- 28356528 TI - Interactions between the Dengue Virus Polymerase NS5 and Stem-Loop A. AB - The process of RNA replication by dengue virus is still not completely understood despite the significant progress made in the last few years. Stem-loop A (SLA), a part of the viral 5' untranslated region (UTR), is critical for the initiation of dengue virus replication, but quantitative analysis of the interactions between the dengue virus polymerase NS5 and SLA in solution has not been performed. Here, we examine how solution conditions affect the size and shape of SLA and the formation of the NS5-SLA complex. We show that dengue virus NS5 binds SLA with a 1:1 stoichiometry and that the association reaction is primarily entropy driven. We also observe that the NS5-SLA interaction is influenced by the magnesium concentration in a complex manner. Binding is optimal with 1 mM MgCl2 but decreases with both lower and higher magnesium concentrations. Additionally, data from a competition assay between SLA and single-stranded RNA (ssRNA) indicate that SLA competes with ssRNA for the same binding site on the NS5 polymerase. SLA70 and SLA80, which contain the first 70 and 80 nucleotides (nt), respectively, bind NS5 with similar binding affinities. Dengue virus NS5 also binds SLAs from different serotypes, indicating that NS5 recognizes the overall shape of SLA as well as specific nucleotides.IMPORTANCE Dengue virus is an important human pathogen responsible for dengue hemorrhagic fever, whose global incidence has increased dramatically over the last several decades. Despite the clear medical importance of dengue virus infection, the mechanism of viral replication, a process commonly targeted by antiviral therapeutics, is not well understood. In particular, stem-loop A (SLA) and stem-loop B (SLB) located in the 5' untranslated region (UTR) are critical for binding the viral polymerase NS5 to initiate minus-strand RNA synthesis. However, little is known regarding the kinetic and thermodynamic parameters driving these interactions. Here, we quantitatively examine the energetics of intrinsic affinities, characterize the stoichiometry of the complex of NS5 and SLA, and determine how solution conditions such as magnesium and sodium concentrations and temperature influence NS5-SLA interactions in solution. Quantitatively characterizing dengue virus NS5 SLA interactions will facilitate the design and assessment of antiviral therapeutics that target this essential step of the dengue virus life cycle. PMID- 28356527 TI - Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis. AB - West Nile virus (WNV) is a mosquito-transmitted flavivirus that can cause debilitating encephalitis. To delineate the mechanisms behind this pathology, we studied Ccr7-deficient mice, which afforded us the capacity to study infection in mice with disrupted peripheral cellular trafficking events. The loss of Ccr7 resulted in an immediate pan-leukocytosis that remained elevated throughout the infection. This leukocytosis resulted in a significant enhancement of leukocyte accumulation within the central nervous system (CNS). Despite an excess of virus specific T cells in the CNS, Ccr7-deficient mice had significantly higher CNS viral loads and mortality rates than wild-type animals. Mechanistically, the elevated trafficking of infected myeloid cells into the brain in Ccr7-deficient mice resulted in increased levels of WNV in the CNS, thereby effectively contributing to neuroinflammation and lowering viral clearance. Combined, our experiments suggest that during WNV infection, Ccr7 is a gatekeeper for nonspecific viral transference to the brain.IMPORTANCE In this study, we show that Ccr7 is required for the sufficient migration of dendritic cells and T cells into the draining lymph node immediately following infection and for the restriction of leukocyte migration into the brain. Further, the severe loss of dendritic cells in the draining lymph node had no impact on viral replication in this organ, suggesting that WNV may migrate from the skin into the lymph node through another mechanism. Most importantly, we found that the loss of Ccr7 results in a significant leukocytosis, leading to hypercellularity within the CNS, where monocytes/macrophages contribute to CNS viremia, neuroinflammation, and increased mortality. Together, our data point to Ccr7 as a critical host defense restriction factor limiting neuroinflammation during acute viral infection. PMID- 28356530 TI - Role of Neuraminidase in Influenza A(H7N9) Virus Receptor Binding. AB - Influenza A(H7N9) viruses have caused a large number of zoonotic infections since their emergence in 2013. They remain a public health concern due to the repeated high levels of infection with these viruses and their perceived pandemic potential. A major factor that determines influenza A virus fitness and therefore transmissibility is the interaction of the surface glycoproteins hemagglutinin (HA) and neuraminidase (NA) with the cell surface receptor sialic acid. Typically, the HA is responsible for binding to the sialic acid to allow virus internalization and the NA is a sialidase responsible for cleaving sialic acid to aid virus spread and release. N9 NA has previously been shown to have receptor binding properties mediated by a sialic acid binding site, termed the hemadsorption (Hb) site, which is discrete from the enzymatically active sialidase site. This study investigated the N9 NA from a zoonotic H7N9 virus strain in order to determine its possible role in virus receptor binding. We demonstrate that this N9 NA has an active Hb site which binds to sialic acid, which enhances overall virus binding to sialic acid receptor analogues. We also show that the N9 NA can also contribute to receptor binding due to unusual kinetic characteristics of the sialidase site which specifically enhance binding to human-like alpha2,6-linked sialic acid receptors.IMPORTANCE The interaction of influenza A virus glycoproteins with cell surface receptors is a major determinant of infectivity and therefore transmissibility. Understanding these interactions is important for understanding which factors are necessary to determine pandemic potential. Influenza A viruses generally mediate binding to cell surface sialic acid receptors via the hemagglutinin (HA) glycoprotein, with the neuraminidase (NA) glycoprotein being responsible for cleaving the receptor to allow virus release. Previous studies showed that the NA proteins of the N9 subtype can bind sialic acid via a separate binding site distinct from the sialidase active site. This study demonstrates for purified protein and virus that the NA of the zoonotic H7N9 viruses has a binding capacity via both the secondary binding site and unusual kinetic properties of the sialidase site which promote receptor binding via this site and which enhance binding to human-like receptors. This could have implications for understanding human-to-human transmission of these viruses. PMID- 28356531 TI - Homologous Capsid Proteins Testify to the Common Ancestry of Retroviruses, Caulimoviruses, Pseudoviruses, and Metaviruses. PMID- 28356529 TI - Antigenic Drift Defines a New D4 Subgenotype of Measles Virus. AB - The measles virus hemagglutinin (MeV-H) protein is the main target of protective neutralizing antibodies. Using a panel of monoclonal antibodies (MAbs) that recognize known major antigenic sites in MeV-H, we identified a D4 genotype variant that escapes neutralization by MAbs targeting the neutralizing epitope (NE) antigenic site. By site-directed mutagenesis, L249P was identified as the critical mutation disrupting the NE in this genotype D4 variant. Forty-two available D4 genotype gene sequences were subsequently analyzed and divided into 2 groups according to the presence or absence of the L249P MeV-H mutation. Further analysis of the MeV-N gene sequences of these 2 groups confirmed that they represent clearly definable, sequence-divergent D4 subgenotypes, which we named subgenotypes D4.1 and D4.2. The subgenotype D4.1 MeVs were isolated predominantly in Kenya and Ethiopia, whereas the MAb-resistant subgenotype D4.2 MeVs were isolated predominantly in France and Great Britain, countries with higher vaccine coverage rates. Interestingly, D4.2 subgenotype viruses showed a trend toward diminished susceptibility to neutralization by human sera pooled from approximately 60 to 80 North American donors. Escape from MAb neutralization may be a powerful epidemiological surveillance tool to monitor the evolution of new MeV subgenotypes.IMPORTANCE Measles virus is a paradigmatic RNA virus, as the antigenic composition of the vaccination has not needed to be updated since its discovery. The vaccine confers protection by inducing neutralizing antibodies that interfere with the function of the hemagglutinin protein. Viral strains are indistinguishable serologically, although characteristic nucleotide sequences differentiate 24 genotypes. In this work, we describe a distant evolutionary branch within genotype D4. Designated subgenotype D4.2, this virus is distinguishable by neutralization with vaccine-induced monoclonal antibodies that target the neutralizing epitope (NE). The subgenotype D4.2 viruses have a higher predominance in countries with intermediary levels of vaccine coverage. Our studies demonstrate that subgenotype D4.2 lacks epitopes associated with half of the known antigenic sites, which significantly impacts our understanding of measles virus evolution. PMID- 28356532 TI - pH Optimum of Hemagglutinin-Mediated Membrane Fusion Determines Sensitivity of Influenza A Viruses to the Interferon-Induced Antiviral State and IFITMs. AB - The replication and pathogenicity of influenza A viruses (IAVs) critically depend on their ability to tolerate the antiviral interferon (IFN) response. To determine a potential role for the IAV hemagglutinin (HA) in viral sensitivity to IFN, we studied the restriction of IAV infection in IFN-beta-treated human epithelial cells by using 2:6 recombinant IAVs that shared six gene segments of A/Puerto Rico/8/1934 virus (PR8) and contained HAs and neuraminidases of representative avian, human, and zoonotic H5N1 and H7N9 viruses. In A549 and Calu 3 cells, viruses displaying a higher pH optimum of HA-mediated membrane fusion, H5N1-PR8 and H7N9-PR8, were less sensitive to the IFN-induced antiviral state than their counterparts with HAs from duck and human viruses, which fused at a lower pH. The association between a high pH optimum of fusion and reduced IFN sensitivity was confirmed by using HA point mutants of A/Hong Kong/1/1968-PR8 that differed solely by their fusion properties. Furthermore, similar effects of the viral fusion pH on IFN sensitivity were observed in experiments with (i) primary human type II alveolar epithelial cells and differentiated cultures of human airway epithelial cells, (ii) nonrecombinant zoonotic and pandemic IAVs, and (iii) preparations of IFN-alpha and IFN-lambda1. A higher pH of membrane fusion and reduced sensitivity to IFN correlated with lower restriction of the viruses in MDCK cells stably expressing the IFN-inducible transmembrane proteins IFITM2 and IFITM3, which are known to inhibit viral fusion. Our results reveal that the pH optimum of HA-driven membrane fusion of IAVs is a determinant of their sensitivity to IFN and IFITM proteins.IMPORTANCE The IFN system constitutes an important innate defense against viral infection. Substantial information is available on how IAVs avoid detection by sensors of the IFN system and disable IFN signaling pathways. Much less is known about the ability of IAVs to tolerate the antiviral activity of IFN-induced cellular proteins. The IFN-induced proteins of the IFITM family block IAV entry into target cells and can restrict viral spread and pathogenicity. Here we show for the first time that the sensitivity of IAVs to the IFN-induced antiviral state and IFITM2 and IFITM3 proteins depends on the pH value at which the viral HA undergoes a conformational transition and mediates membrane fusion. Our data imply that the high pH optimum of membrane fusion typical of zoonotic IAVs of gallinaceous poultry, such as H5N1 and H7N9, may contribute to their enhanced virulence in humans. PMID- 28356533 TI - A Lipopeptide HIV-1/2 Fusion Inhibitor with Highly Potent In Vitro, Ex Vivo, and In Vivo Antiviral Activity. AB - Peptides derived from the C-terminal heptad repeat (CHR) region of the human immunodeficiency virus type 1 (HIV-1) fusogenic protein gp41 are potent viral entry inhibitors, and currently, enfuvirtide (T-20) is the only one approved for clinical use; however, emerging drug resistance largely limits its efficacy. In this study, we generated a novel lipopeptide inhibitor, named LP-19, by integrating multiple design strategies, including an N-terminal M-T hook structure, an HIV-2 sequence, intrahelical salt bridges, and a membrane-anchoring lipid tail. LP-19 showed stable binding affinity and highly potent, broad, and long-lasting antiviral activity. In in vitro studies, LP-19 efficiently inhibited HIV-1-, HIV-2-, and simian immunodeficiency virus (SIV)-mediated cell fusion, viral entry, and infection, and it was highly active against diverse subtypes of primary HIV-1 isolates and inhibitor-resistant mutants. Ex vivo studies demonstrated that LP-19 exhibited dramatically increased anti-HIV activity and an extended half-life in rhesus macaques. In short-term monotherapy, LP-19 reduced viral loads to undetectable levels in acutely and chronically simian-human immunodeficiency virus (SHIV)-infected monkeys. Therefore, this study offers an ideal HIV-1/2 fusion inhibitor for clinical development and emphasizes the importance of the viral fusion step as a drug target.IMPORTANCE The peptide drug T-20 is the only viral fusion inhibitor in the clinic, which is used for combination therapy of HIV-1 infection; however, it requires a high dosage and easily induces drug resistance, calling for a new drug with significantly improved pharmaceutical profiles. Here, we have developed a short-lipopeptide based fusion inhibitor, termed LP-19, which mainly targets the conserved gp41 pocket site and shows highly potent inhibitory activity against HIV-1, HIV-2, and even SIV isolates. LP-19 exhibits dramatically increased antiviral activity and an extended half-life in rhesus macaques, and it has potent therapeutic efficacy in SHIV-infected monkeys, highlighting its high potential as a new viral fusion inhibitor for clinical use. PMID- 28356534 TI - Mutual Interplay between the Human Cytomegalovirus Terminase Subunits pUL51, pUL56, and pUL89 Promotes Terminase Complex Formation. AB - Human cytomegalovirus (HCMV) genome encapsidation requires several essential viral proteins, among them pUL56, pUL89, and the recently described pUL51, which constitute the viral terminase. To gain insight into terminase complex assembly, we investigated interactions between the individual subunits. For analysis in the viral context, HCMV bacterial artificial chromosomes carrying deletions in the open reading frames encoding the terminase proteins were used. These experiments were complemented by transient-transfection assays with plasmids expressing the terminase components. We found that if one terminase protein was missing, the levels of the other terminase proteins were markedly diminished, which could be overcome by proteasome inhibition or providing the missing subunit in trans These data imply that sequestration of the individual subunits within the terminase complex protects them from proteasomal turnover. The finding that efficient interactions among the terminase proteins occurred only when all three were present together is reminiscent of a folding-upon-binding principle leading to cooperative stability. Furthermore, whereas pUL56 was translocated into the nucleus on its own, correct nuclear localization of pUL51 and pUL89 again required all three terminase constituents. Altogether, these features point to a model of the HCMV terminase as a multiprotein complex in which the three players regulate each other concerning stability, subcellular localization, and assembly into the functional tripartite holoenzyme.IMPORTANCE HCMV is a major risk factor in immunocompromised individuals, and congenital CMV infection is the leading viral cause for long-term sequelae, including deafness and mental retardation. The current treatment of CMV disease is based on drugs sharing the same mechanism, namely, inhibiting viral DNA replication, and often results in adverse side effects and the appearance of resistant virus strains. Recently, the HCMV terminase has emerged as an auspicious target for novel antiviral drugs. A new drug candidate inhibiting the HCMV terminase, Letermovir, displayed excellent potency in clinical trials; however, its precise mode of action is not understood yet. Here, we describe the mutual dependence of the HCMV terminase constituents for their assembly into a functional terminase complex. Besides providing new basic insights into terminase formation, these results will be valuable when studying the mechanism of action for drugs targeting the HCMV terminase and developing additional substances interfering with viral genome encapsidation. PMID- 28356535 TI - Phosphatidylserine Lateral Organization Influences the Interaction of Influenza Virus Matrix Protein 1 with Lipid Membranes. AB - Influenza A virus matrix protein 1 (M1) is an essential component involved in the structural stability of the virus and in the budding of new virions from infected cells. A deeper understanding of the molecular basis of virion formation and the budding process is required in order to devise new therapeutic approaches. We performed a detailed investigation of the interaction between M1 and phosphatidylserine (PS) (i.e., its main binding target at the plasma membrane [PM]), as well as the distribution of PS itself, both in model membranes and in living cells. To this end, we used a combination of techniques, including Forster resonance energy transfer (FRET), confocal microscopy imaging, raster image correlation spectroscopy, and number and brightness (N&B) analysis. Our results show that PS can cluster in segregated regions in the plane of the lipid bilayer, both in model bilayers constituted of PS and phosphatidylcholine and in living cells. The viral protein M1 interacts specifically with PS-enriched domains, and such interaction in turn affects its oligomerization process. Furthermore, M1 can stabilize PS domains, as observed in model membranes. For living cells, the presence of PS clusters is suggested by N&B experiments monitoring the clustering of the PS sensor lactadherin. Also, colocalization between M1 and a fluorescent PS probe suggest that, in infected cells, the matrix protein can specifically bind to the regions of PM in which PS is clustered. Taken together, our observations provide novel evidence regarding the role of PS-rich domains in tuning M1-lipid and M1-M1 interactions at the PM of infected cells.IMPORTANCE Influenza virus particles assemble at the plasma membranes (PM) of infected cells. This process is orchestrated by the matrix protein M1, which interacts with membrane lipids while binding to the other proteins and genetic material of the virus. Despite its importance, the initial step in virus assembly (i.e., M1 lipid interaction) is still not well understood. In this work, we show that phosphatidylserine can form lipid domains in physical models of the inner leaflet of the PM. Furthermore, the spatial organization of PS in the plane of the bilayer modulates M1-M1 interactions. Finally, we show that PS domains appear to be present in the PM of living cells and that M1 seems to display a high affinity for them. PMID- 28356537 TI - Pathogenic Events in a Nonhuman Primate Model of Oral Poliovirus Infection Leading to Paralytic Poliomyelitis. AB - Despite a great deal of prior research, the early pathogenic events in natural oral poliovirus infection remain poorly defined. To establish a model for study, we infected 39 macaques by feeding them single high doses of the virulent Mahoney strain of wild type 1 poliovirus. Doses ranging from 107 to 109 50% tissue culture infective doses (TCID50) consistently infected all the animals, and many monkeys receiving 108 or 109 TCID50 developed paralysis. There was no apparent difference in the susceptibilities of the three macaque species (rhesus, cynomolgus, and bonnet) used. Virus excretion in stool and nasopharynges was consistently observed, with occasional viremia, and virus was isolated from tonsils, gut mucosa, and draining lymph nodes. Viral replication proteins were detected in both epithelial and lymphoid cell populations expressing CD155 in the tonsil and intestine, as well as in spinal cord neurons. Necrosis was observed in these three cell types, and viral replication in the tonsil/gut was associated with histopathologic destruction and inflammation. The sustained response of neutralizing antibody correlated temporally with resolution of viremia and termination of virus shedding in oropharynges and feces. For the first time, this model demonstrates that early in the infectious process, poliovirus replication occurs in both epithelial cells (explaining virus shedding in the gastrointestinal tract) and lymphoid/monocytic cells in tonsils and Peyer's patches (explaining viremia), extending previous studies of poliovirus pathogenesis in humans. Because the model recapitulates human poliovirus infection and poliomyelitis, it can be used to study polio pathogenesis and to assess the efficacy of candidate antiviral drugs and new vaccines.IMPORTANCE Early pathogenic events of poliovirus infection remain largely undefined, and there is a lack of animal models mimicking natural oral human infection leading to paralytic poliomyelitis. All 39 macaques fed with single high doses ranging from 107 to 109 TCID50 Mahoney type 1 virus were infected, and many of the monkeys developed paralysis. Virus excretion in stool and nasopharynges was consistently observed, with occasional viremia; tonsil, mesentery lymph nodes, and intestinal mucosa served as major target sites of viral replication. For the first time, this model demonstrates that early in the infectious process, poliovirus replication occurs in both epithelial cells (explaining virus shedding in the gastrointestinal tract) and lymphoid/monocytic cells in tonsils and Peyer's patches (explaining viremia), thereby supplementing historical reconstructions of poliovirus pathogenesis. Because the model recapitulates human poliovirus infection and poliomyelitis, it can be used to study polio pathogenesis, candidate antiviral drugs, and the efficacy of new vaccines. PMID- 28356538 TI - Automated tracking and classification of the settlement behaviour of barnacle cyprids. AB - A focus on the development of nontoxic coatings to control marine biofouling has led to increasing interest in the settlement behaviour of fouling organisms. Barnacles pose a significant fouling challenge and accordingly the behaviour of their settlement-stage cypris larva (cyprid) has attracted much attention, yet remains poorly understood. Tracking technologies have been developed that quantify cyprid movement, but none have successfully automated data acquisition over the prolonged periods necessary to capture and identify the full repertoire of behaviours, from alighting on a surface to permanent attachment. Here we outline a new tracking system and a novel classification system for identifying and quantifying the exploratory behaviour of cyprids. The combined system enables, for the first time, tracking of multiple larvae, simultaneously, over long periods (hours), followed by automatic classification of typical cyprid behaviours into swimming, wide search, close search and inspection events. The system has been evaluated by comparing settlement behaviour in the light and dark (infrared illumination) and tracking one of a group of 25 cyprids from the water column to settlement over the course of 5 h. Having removed a significant technical barrier to progress in the field, it is anticipated that the system will accelerate our understanding of the process of surface selection and settlement by barnacles. PMID- 28356536 TI - Herpes Simplex Virus 1 UL34 Protein Regulates the Global Architecture of the Endoplasmic Reticulum in Infected Cells. AB - Upon herpes simplex virus 1 (HSV-1) infection, the CD98 heavy chain (CD98hc) is redistributed around the nuclear membrane (NM), where it promotes viral de envelopment during the nuclear egress of nucleocapsids. In this study, we attempted to identify the factor(s) involved in CD98hc accumulation and demonstrated the following: (i) the null mutation of HSV-1 UL34 caused specific dispersion throughout the cytoplasm of CD98hc and the HSV-1 de-envelopment regulators, glycoproteins B and H (gB and gH); (ii) as observed with CD98hc, gB, and gH, wild-type HSV-1 infection caused redistribution of the endoplasmic reticulum (ER) markers calnexin and ERp57 around the NM, whereas the UL34-null mutation caused cytoplasmic dispersion of these markers; (iii) the ER markers colocalized efficiently with CD98hc, gB, and gH in the presence and absence of UL34 in HSV-1-infected cells; (iv) at the ultrastructural level, wild-type HSV-1 infection caused ER compression around the NM, whereas the UL34-null mutation caused cytoplasmic dispersion of the ER; and (v) the UL34-null mutation significantly decreased the colocalization efficiency of lamin protein markers of the NM with CD98hc and gB. Collectively, these results indicate that HSV-1 infection causes redistribution of the ER around the NM, with resulting accumulation of ER-associated CD98hc, gB, and gH around the NM and that UL34 is required for ER redistribution, as well as for efficient recruitment to the NM of the ER-associated de-envelopment factors. Our study suggests that HSV-1 induces remodeling of the global ER architecture for recruitment of regulators mediating viral nuclear egress to the NM.IMPORTANCE The ER is an important cellular organelle that exists as a complex network extending throughout the cytoplasm. Although viruses often remodel the ER to facilitate viral replication, information on the effects of herpesvirus infections on ER morphological integrity is limited. Here, we showed that HSV-1 infection led to compression of the global ER architecture around the NM, resulting in accumulation of ER associated regulators associated with nuclear egress of HSV-1 nucleocapsids. We also identified HSV-1 UL34 as a viral factor that mediated ER remodeling. Furthermore, we demonstrated that UL34 was required for efficient targeting of these regulators to the NM. To our knowledge, this is the first report showing that a herpesvirus remodels ER global architecture. Our study also provides insight into the mechanism by which the regulators for HSV-1 nuclear egress are recruited to the NM, where this viral event occurs. PMID- 28356539 TI - Mechanisms of stochastic onset and termination of atrial fibrillation studied with a cellular automaton model. AB - Mathematical models of cardiac electrical excitation are increasingly complex, with multiscale models seeking to represent and bridge physiological behaviours across temporal and spatial scales. The increasing complexity of these models makes it computationally expensive to both evaluate long term (more than 60 s) behaviour and determine sensitivity of model outputs to inputs. This is particularly relevant in models of atrial fibrillation (AF), where individual episodes last from seconds to days, and interepisode waiting times can be minutes to months. Potential mechanisms of transition between sinus rhythm and AF have been identified but are not well understood, and it is difficult to simulate AF for long periods of time using state-of-the-art models. In this study, we implemented a Moe-type cellular automaton on a novel, topologically equivalent surface geometry of the left atrium. We used the model to simulate stochastic initiation and spontaneous termination of AF, arising from bursts of spontaneous activation near pulmonary veins. The simplified representation of atrial electrical activity reduced computational cost, and so permitted us to investigate AF mechanisms in a probabilistic setting. We computed large numbers (approx. 105) of sample paths of the model, to infer stochastic initiation and termination rates of AF episodes using different model parameters. By generating statistical distributions of model outputs, we demonstrated how to propagate uncertainties of inputs within our microscopic level model up to a macroscopic level. Lastly, we investigated spontaneous termination in the model and found a complex dependence on its past AF trajectory, the mechanism of which merits future investigation. PMID- 28356541 TI - On the Inside. PMID- 28356542 TI - The First Broad-Spectrum Abscisic Acid Antagonist. PMID- 28356543 TI - ADDENDUM: Vol. 167: 481-492, 2015. PMID- 28356540 TI - Population genetics of immune-related multilocus copy number variation in Native Americans. AB - While multiallelic copy number variation (mCNV) loci are a major component of genomic variation, quantifying the individual copy number of a locus and defining genotypes is challenging. Few methods exist to study how mCNV genetic diversity is apportioned within and between populations (i.e. to define the population genetic structure of mCNV). These inferences are critical in populations with a small effective size, such as Amerindians, that may not fit the Hardy-Weinberg model due to inbreeding, assortative mating, population subdivision, natural selection or a combination of these evolutionary factors. We propose a likelihood based method that simultaneously infers mCNV allele frequencies and the population structure parameter f, which quantifies the departure of homozygosity from the Hardy-Weinberg expectation. This method is implemented in the freely available software CNVice, which also infers individual genotypes using information from both the population and from trios, if available. We studied the population genetics of five immune-related mCNV loci associated with complex diseases (beta-defensins, CCL3L1/CCL4L1, FCGR3A, FCGR3B and FCGR2C) in 12 traditional Native American populations and found that the population structure parameters inferred for these mCNVs are comparable to but lower than those for single nucleotide polymorphisms studied in the same populations. PMID- 28356545 TI - CORRECTION: Vol. 169: 2761-2773, 2015. PMID- 28356544 TI - CORRECTION: Vol. 173: 998-1016, 2017. PMID- 28356546 TI - RETRACTION: Vol. 153: 1321-1331, 2010. PMID- 28356547 TI - Mechanisms of iPS cell generation and beyond. AB - The generation of induced pluripotent stem cells (iPSCs) achieved by overexpression of Oct4, Sox2, Klf4 and c-Myc, transformed our classical views of the cellular epigenetic landscape and delivered a new concept for cell and tissue engineering. In addition to iPSCs, several other cell types have also been generated by master transcription factor (TF)-mediated transdifferentiation. However, the critical molecular mechanisms amongst diverse cellular identity changes are not well understood. Through the investigation of reprogramming mechanisms, we recently revealed that over-expression of constitutive active Smad3 boosted not only iPSC generation, but also 3 other master TF-mediated conversions, from B cells to macrophages, myoblasts to adipocytes, and human fibroblasts to neurons. This demonstrated that there were common mechanisms underlying different master TF-mediated cell conversions. To illuminate such mechanisms further, we have recently performed CRISPR/Cas9-mediated genome-wide knockout screening during reprogramming with a lentiviral gRNA library containing 90,000 gRNAs. This screening provided us with ~15 novel reprogramming roadblock genes as well as ~20 candidate genes essential for the reprogramming process but not for ES cell self-renewal. This data set will be a valuable resource to further understand how overexpression of master TFs alters cellular identity, and to achieve more faithful, efficient cell conversions for regenerative medicine.(Presented at the 1934th Meeting, March 17, 2017). PMID- 28356548 TI - Linking Pathogen Virulence, Host Immunity and The Microbiota at the Intestinal Barrier. AB - The mechanisms that allow enteric pathogens to colonize the intestine and host immunity as well as the indigenous microbiota to inhibit pathogen colonization remain poorly understood. Our laboratory is using Citrobacter rodentium, a mouse pathogen that models human infections by enteropathogenic E. coli, to understand the mechanisms that regulate the colonization and clearance of the pathogen in the gut. These studies have revealed how the pathogen colonizes and replicates successfully early during infection and how host immunity and the indigenous microbiota cooperate to eradicate the pathogen in the later stage of the infection. The impairment of the immune system to control the barrier function of the intestine leads to pathogen invasion and the induction of a second layer of host protective immunity to limit the systemic spread of the pathogen.(Presented at the 1931st Meeting, January 17, 2017). PMID- 28356550 TI - A Blast of Mistakes: Undiagnosed Cervical Spondylolisthesis Following a Bomb Explosion. AB - BACKGROUND A case of spinal trauma had an unusual clinical course due to medical mistakes, from which we can learn some important lessons. CASE REPORT We report a case of spondylolisthesis following a bomb explosion, which went undiagnosed for a long time because of a series of mistakes that are highlighted in this article. What makes this case unique is that the spondylolisthesis developed during hospital stay, but the patient had no loss of mobility, strength, or sensitivity. CONCLUSIONS This case shows that establishing the conditions of an organ or a body part upon admission to hospital may not be enough when a patient has suffered extensive and serious trauma, and that it is necessary to carry out more checkups over time, especially if there are new clues and symptoms. PMID- 28356549 TI - Expression of Adiponectin Receptor-1 and Prognosis of Epithelial Ovarian Cancer Patients. AB - BACKGROUND Adiponectin receptor-1 (AdipoR1) has been reported to be associated with the risk of obesity-associated malignancies, including epithelial ovarian cancer (EOC). The aim of this study was to determine if AdipoR1 could serve as a prognosis indicator for patients with EOC. MATERIAL AND METHODS In this study, expression of AdipoR1 in 73 EOC patients consecutively admitted to our hospital was detected by immunohistochemical staining. Univariate and multivariate analyses were performed to assess the relationship between AdipoR1 expression level and progression-free survival (PFS) and overall survival (OS) rates in patients. RESULTS A relatively lower expression of AdipoR1 in the cancerous tissues was detected compared to normal ovarian tissues, but the difference was not significant (p>0.05). AdipoR1 expression level in EOC patients was negatively correlated with advanced FIGO stages in patients and tumor differentiation, but had no correlation with pathological types, presenting of ascites, shorter platinum-free interval (PFI), diabetes, preoperative and postoperative body mass index (BMI), or platelet counts (p>0.05). Moreover, patients with AdipoR1 expression had a significantly longer PFS and OS compared to the negative expression group (p<0.001). CONCLUSIONS Our findings suggest that AdipoR1 expression level in cancerous tissues might serve as an independent prognostic indicator in EOC patients and is associated with longer PFS and OS. PMID- 28356551 TI - [Epidemiology of Campylobacteriosis in Castile and Leon, Spain,during the period 2008-2015]. AB - OBJECTIVE: Campylobacter is considered the most frequent agent of gastroenteritis in humans all around the world. The aim of this study was to know the incidence, trend and seasonality of notified campylobacteriosis cases in Castile and Leon, Spain, from 2008 to 2015. In addition, to describe the type of case and source of notification, and study the influence of age, sex and Campylobacter species on the hospitalization of cases. METHODS: Retrospective cross-sectional study with a time series analysis. Data on notified campylobacteriosis cases were collected from the Epidemiological Surveillance System of Castile and Leon (2008-2015). Incidence rates and incidence rate ratios by age, sex and year of notification were calculated. In order to estimate trend and seasonality, a time series analysis was performed using a multiplicative method and adjusted to a linear and exponential model. RESULTS: From 4,330 cases analyzed, 49.4% of children aged under 5 were affected. The ratio of men to women was 1.43 and 61.8% of cases were notified from secondary care. C. jejuni was isolated from 72.3% of samples (n=2,593). Incidence rate ranged from 11.42 cases per 100,000 inhabitants in 2008 to 33.53 in 2015. The seasonality range was from 71.97% (13th four-week period) to 125.54% (9th four-week period). Hospitalization reached 62.5% for people aged 60 or over. CONCLUSIONS: A growing trend of notified campylobacteriosis cases is observed in Castile and Leon (2008-2015), mainly in children aged under 5, with a peak in summer months. Males are more affected than females and hospitalization increases with age. PMID- 28356553 TI - Altering the coffee-ring effect by adding a surfactant-like viscous polymer solution. AB - A uniform deposition of the suspended particles in an evaporating droplet is necessary in many research fields. Such deposition is difficult to achieve, because the coffee-ring effect dominates the internal flow in a droplet. The present study adopts a biocompatible, surfactant-like polymer (Polyethylene glycol, PEG) to break the coffee-ring effect and obtain a relatively uniform deposition of the microparticles with yielding multi-ring pattern over a droplet area. Movements of the suspended particles in evaporating droplets and deposition patterns of them on a glass substrate were analyzed with microscopic images and video files. The PEG in the droplets successfully altered the coffee-ring effect because of the surface tension variation, which induced a centripetal Marangoni flow. Balancing these two phenomena apparently generated the Marangoni vortex. For PEG solution droplets, the pinning-depinning process during evaporation was periodically repeated and multiple rings were regularly formed. In conclusion, adding a surfactant-like viscous polymer in a droplet could provide a uniform coating of suspended particles, such as cells and various biomaterials, which would be essentially required for droplet assays of biomedical applications. PMID- 28356552 TI - Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration. AB - Tuberculosis (TB) treatment is long and complex, typically involving a combination of drugs taken for 6 months. Improved drug regimens to shorten and simplify treatment are urgently required, however a major challenge to TB drug development is the lack of predictive pre-clinical tools. To address this deficiency, we have adopted a new high-content imaging-based approach capable of defining the killing kinetics of first line anti-TB drugs against intracellular Mycobacterium tuberculosis (Mtb) residing inside macrophages. Through use of this pharmacokinetic-pharmacodynamic (PK-PD) approach we demonstrate that the killing dynamics of the intracellular Mtb sub-population is critical to predicting clinical TB treatment duration. Integrated modelling of intracellular Mtb killing alongside conventional extracellular Mtb killing data, generates the biphasic responses typical of those described clinically. Our model supports the hypothesis that the use of higher doses of rifampicin (35 mg/kg) will significantly reduce treatment duration. Our described PK-PD approach offers a much needed decision making tool for the identification and prioritisation of new therapies which have the potential to reduce TB treatment duration. PMID- 28356554 TI - A simple technique to overcome self-focusing, filamentation, supercontinuum generation, aberrations, depth dependence and waveguide interface roughness using fs laser processing. AB - Several detrimental effects limit the use of ultrafast lasers in multi-photon processing and the direct manufacture of integrated photonics devices, not least, dispersion, aberrations, depth dependence, undesirable ablation at a surface, limited depth of writing, nonlinear optical effects such as supercontinuum generation and filamentation due to Kerr self-focusing. We show that all these effects can be significantly reduced if not eliminated using two coherent, ultrafast laser-beams through a single lens - which we call the Dual-Beam technique. Simulations and experimental measurements at the focus are used to understand how the Dual-Beam technique can mitigate these problems. The high peak laser intensity is only formed at the aberration-free tightly localised focal spot, simultaneously, suppressing unwanted nonlinear side effects for any intensity or processing depth. Therefore, we believe this simple and innovative technique makes the fs laser capable of much more at even higher intensities than previously possible, allowing applications in multi-photon processing, bio medical imaging, laser surgery of cells, tissue and in ophthalmology, along with laser writing of waveguides. PMID- 28356555 TI - Prevalence of polymorphisms in OPG, RANKL and RANK as potential markers for Charcot arthropathy development. AB - Charcot arthropathy is one of the most serious complications of diabetic foot syndrome that leads to amputation of the affected limb. Since there is no cure for Charcot arthropathy, early diagnosis and implementation preventive care are the best available treatment. However, diagnosis is hindered by obscure clinical picture of the disease and lack of molecular markers for its early detection. Results of recent research suggest that OPG-RANKL-RANK axis regulating bone metabolism can be associated with Charcot arthropathy and that SNPs in OPG gene are associated with the disease. Here we report the results of comprehensive analysis of ten SNPs in OPG, RANKL and RANK genes in 260 subjects divided into diabetes, neuropathy and Charcot arthropathy groups. Besides genotype analysis we performed linkage disequilibrium and hierarchical clustering to obtain information about correlation between SNPs. Our results show that OPG 245T/G (rs3134069) and OPG 1217C/T (rs3102734) polymorphisms co-occur in patients with Charcot arthropathy (r2 = 0.99). Moreover, hierarchical clustering revealed a characteristic profile of all SNPs in Charcot arthropathy and neuropathy, which is distinct from control group. Our results suggest that analysis of multiple SNPs can be used as potential marker of Charcot arthropathy and provide insight into possible molecular mechanisms of its development. PMID- 28356556 TI - Spin-dependent thermoelectric effects in Fe-C6 doped monolayer MoS2. AB - By using the non-equilibrium Green's function with density functional theory, we have studied the thermal spin transport properties of Fe-C6 cluster doped monolayer MoS2. The results show that the device has a perfect Seebeck effect under temperature difference without gate voltage or bias voltage. Moreover, we also find the thermal colossal magnetoresistance effect, which is as high as 107%. The competition between spin up electrons and spin down holes of the parallel spin configuration leads to peculiar behavior of colossal magnetoresistance and thermo-current, which is essential for the design of thermal transistors. These results are useful in future MoS2-based multifunctional spin caloritronic devices. PMID- 28356559 TI - Reinterpretation of oceanic 230Th profiles based on decadal export productivity (2003-2010). AB - Understanding 230Th distributions in the global ocean is important to support and guide the use of this important radioactive nuclide in multiple aspects of oceanographic research, and this issue is now revisited. Based on estimates of export productivity (EP) over 2003-2010 and assuming 230Th scavenging at equilibrium at seven Pacific stations where linear 230Th profiles are found, an empirical equilibrium-state 230Th-scavenging versus EP correlation is established. This correlation demonstrates the relationship between 230Th scavenging intensity and EP in the absence of advection. With this correlation, other 230Th profiles from global oceans are reinterpreted. My findings provide alternative explanations of signals carried by 230Th distributions with regard to advection, by a reassessment of the 230Th deficits in deep waters. Such an equilibrium-state 230Th-scavenging versus EP correlation provides a basis for convenient parameterization for use in 3D modeling studies of the 230Th distributions. PMID- 28356558 TI - Rising fluoroquinolone resistance in Campylobacter isolated from feedlot cattle in the United States. AB - Antibiotic resistance, particularly to fluoroquinolones and macrolides, in the major foodborne pathogen Campylobacter is considered a serious threat to public health. Although ruminant animals serve as a significant reservoir for Campylobacter, limited information is available on antibiotic-resistant Campylobacter of bovine origin. Here, we analyzed the antimicrobial susceptibilities of 320 C. jejuni and 115 C. coli isolates obtained from feedlot cattle farms in multiple states in the U.S. The results indicate that fluoroquinolone resistance reached to 35.4% in C. jejuni and 74.4% in C. coli, which are significantly higher than those previously reported in the U.S. While all fluoroquinolone resistant (FQR) C. coli isolates examined in this study harbored the single Thr-86-Ile mutation in GyrA, FQR C. jejuni isolates had other mutations in GyrA in addition to the Thr-86-Ile change. Notably, most of the analyzed FQR C. coli isolates had similar PFGE (pulsed field gel electrophoresis) patterns and the same MLST (multilocus sequence typing) sequence type (ST-1068) regardless of their geographic sources and time of isolation, while the analyzed C. jejuni isolates were genetically diverse, suggesting that clonal expansion is involved in dissemination of FQR C. coli but not C. jejuni. These findings reveal the rising prevalence of FQR Campylobacter in the U.S. and provide novel information on the epidemiology of antibiotic-resistant Campylobacter in the ruminant reservoir. PMID- 28356560 TI - Brain activity in the right-frontal pole and lateral occipital cortex predicts successful post-operatory outcome after surgery for anterior glenoumeral instability. AB - Shoulder apprehension is more complex than a pure mechanical problem of the shoulder, creating a scar at the brain level that prevents the performance of specific movements. Surgery corrects for shoulder instability at the physical level, but a re-dislocation within the first year is rather common. Predicting which patient will be likely to have re-dislocation is therefore crucial. We hypothesized that the assessment of neural activity at baseline and follow-up is the key factor to predict the post-operatory outcome. 13 patients with shoulder apprehension (30.03 +/- 7.64 years) underwent clinical and fMRI examination before and one year after surgery for shoulder dislocation contrasting apprehension cue videos and control videos. Data analyses included task-related general linear model (GLM) and correlations imaging results with clinical scores. Clinical examination showed decreased pain and increased shoulder functions for post-op vs. pre-op. Coherently, GLM results show decreased activation of the left pre-motor cortex for post-surgery vs. pre-surgery. Right-frontal pole and right occipital cortex activity predicts good recovery of shoulder function measured by STT. Our findings demonstrate that beside physical changes, changes at the brain level also occur one year after surgery. In particular, decreased activity in pre motor and orbito-frontal cortex is key factor for a successful post-operatory outcome. PMID- 28356561 TI - Myeloperoxidase-positive cell infiltration of normal colorectal mucosa is related to body fatness and is predictive of adenoma occurrence. AB - Body fatness is a risk factor for colorectal cancer, and promotes an inflammatory environment. Indeed, inflammation in normal colorectal mucosa may be a factor linking body fatness to colorectal carcinogenesis. In this study, we evaluated myeloperoxidase (MPO)-positive cells infiltration of normal colorectal mucosa as a marker of cancer-promoting inflammation in overweight and obese subjects. One hundred and three subjects with normal colonoscopy entered the study. Waist circumference (WC) and body mass index (BMI) were measured, and MPO-positive cells on histological sections of biopsies of normal colorectal mucosa were counted under a light microscope. The occurrence of adenomas was then evaluated on follow-up colonoscopies. Mean MPO-positive cell count (+/-s.e.m.) was higher in subject with a WC equal or above the obesity cutoff values according to gender (2.63+/-0.20 vs 2.06+/-0.18, P=0.03), and in subjects with BMI equal or above 25 kg m-2 (2.54+/-0.18 vs 1.97+/-0.20, P=0.03). A Cox proportional hazard model showed that mean MPO-positive cell count in normal colorectal mucosa was the only factor independently related to occurrence of adenomas in follow-up colonoscopies. Though preliminary, these results show that MPO-positive cell infiltration in normal colorectal mucosa is related with body fatness, as evaluated by WC and BMI, and it may be considered a useful and simple marker to estimate adenoma occurrence risk. PMID- 28356562 TI - Proteomic analysis reveals a role of melatonin in promoting cucumber seed germination under high salinity by regulating energy production. AB - Seed germination is a critical and complex process in the plant life cycle. Although previous studies have found that melatonin can promote seed germination under salt stress, the involvement of melatonin in the regulation of proteomic changes remains poorly understood. In this study, a total of 157 proteins were significantly influenced (ratio >= 2 or <= -2) by melatonin during seed germination under salt stress using a label-free quantitative technique. Our GO analysis revealed that several pathways were obviously regulated by melatonin, including ribosome biosynthesis, lipid metabolism, carbohydrate metabolism, and storage protein degradation. Not only stress-tolerant proteins but also proteins that produce ATP as part of glycolysis, the citric acid cycle, and the glyoxylate cycle were upregulated by melatonin. Overall, this study provides new evidence that melatonin alleviates the inhibitory effects of NaCl stress on seed germination by promoting energy production. This study is the first to provide insights at the proteomic level into the molecular mechanism of melatonin in response to salt stress in cucumber seeds. This may be helpful to further understand the role of melatonin in cucumber seed germination under stress conditions. PMID- 28356563 TI - Homozygous p.(Glu87Lys) variant in ISCA1 is associated with a multiple mitochondrial dysfunctions syndrome. AB - The iron-sulfur (Fe-S) cluster (ISC) biogenesis pathway is indispensable for many fundamental biological processes and pathogenic variations in genes encoding several components of the Fe-S biogenesis machinery, such as NFU1, BOLA3, IBA57 and ISCA2 are already implicated in causing four types of multiple mitochondrial dysfunctions syndromes (MMDS). We report on two unrelated families, with two affected children each with early onset neurological deterioration, seizures, extensive white matter abnormalities, cortical migrational abnormalities, lactic acidosis and early demise. Exome sequencing of two affected individuals, one from each family, revealed a homozygous c.259G>A [p.(Glu87Lys)] variant in ISCA1 and Mendelian segregation was confirmed in both families. The ISCA1 variant lies in the only shared region of homozygosity between the two families suggesting the possibility of a founder effect. In silico functional analyses and structural modeling of the protein predict the identified ISCA1 variant to be detrimental to protein stability and function. Notably the phenotype observed in all affected subjects with the ISCA1 pathogenic variant is similar to that previously described in all four types of MMDS. Our findings suggest association of a pathogenic variant in ISCA1 with another MMDS. PMID- 28356564 TI - Combined pituitary hormone deficiency due to gross deletions in the POU1F1 (PIT 1) and PROP1 genes. AB - Pituitary development depends on a complex cascade of interacting transcription factors and signaling molecules. Lesions in this cascade lead to isolated or combined pituitary hormone deficiency (CPHD). The aim of this study was to identify copy number variants (CNVs) in genes known to cause CPHD and to determine their structure. We analyzed 70 CPHD patients from 64 families. Deletions were found in three Turkish families and one family from northern Iraq. In one family we identified a 4.96 kb deletion that comprises the first two exons of POU1F1. In three families a homozygous 15.9 kb deletion including complete PROP1 was discovered. Breakpoints map within highly homologous AluY sequences. Haplotype analysis revealed a shared haplotype of 350 kb among PROP1 deletion carriers. For the first time we were able to assign the boundaries of a previously reported PROP1 deletion. This gross deletion shows strong evidence to originate from a common ancestor in patients with Kurdish descent. No CNVs within LHX3, LHX4, HESX1, GH1 and GHRHR were found. Our data prove multiplex ligation dependent probe amplification to be a valuable tool for the detection of CNVs as cause of pituitary insufficiencies and should be considered as an analytical method particularly in Kurdish patients. PMID- 28356565 TI - Functional analysis of a nonstop mutation in MITF gene identified in a patient with Waardenburg syndrome type 2. AB - Waardenburg syndrome (WS) is an autosomal dominant inherited neurogenic disorder with the combination of various degrees of sensorineural deafness and pigmentary abnormalities affecting the skin, hair and eye. The four subtypes of WS were defined on the basis of the presence or absence of additional symptoms. Mutation of human microphthalmia-associated transcription factor (MITF) gene gives rise to WS2. Here, we identified a novel WS-associated mutation at the stop codon of MITF (p.X420Y) in a Chinese WS2 patient. This mutation resulted in an extension of extra 33 amino-acid residues in MITF. The mutant MITF appeared in both the nucleus and the cytoplasm, whereas the wild-type MITF was localized in the nucleus exclusively. The mutation led to a reduction in the transcriptional activities, whereas the DNA-binding activity was not altered. We show that the foremost mechanism was haploinsufficiency for the mild phenotypes of WS2 induced in X420Y MITF. PMID- 28356566 TI - Successful newborn screening for Gaucher disease using fluorometric assay in China. AB - Gaucher disease (GD) is an inherited metabolic disorder that involves accumulation of glycolipid glucocerebroside in monocyte-macrophage cells, which can result in multiple organ damage. Enzyme replacement and substrate reduction therapies have improved the potential for early diagnosis and treatment. Determining the true incidence of this rare disease is critical for relevant policy establishment. Newborn screening allows for early diagnosis and an comparatively accurate incidence of GD. A fluorometric method to detect acid beta glucocerebrosidase (GBA) activity on a dried blood spot punch was developed. Validity and feasibility of the fluorometric method was demonstrated by examining 116 healthy controls, 19 confirmed GD patients and 19 obligate carriers. GBA activity was measured on dried blood spots of 80 855 newborns. Samples from positively screened newborns were reanalyzed by a leukocyte GBA activity test and GBA gene analysis. Plasma glucosylsphingosine level was determined as a biomarker of the pathophysiology of GD. GD patients were distinguished from healthy controls and obligate carriers using the fluorometric method. Mean GBA activity in newborn screening specimens was 145.69+/-44.76 MUmol l-1 h-1 (n=80 844). Three children had low GBA activity, of which one child had low GBA activity on the second dried blood spot specimen. Leukocyte, genetic and biomarker analysis confirmed the diagnosis and indicated that this child was in the early stages of GD. In conclusion, the incidence of GD in Shanghai of China is approximately 1 in 80 855. Screening for GD by fluorometric analysis of GBA activity is an efficient and feasible technology in newborns. PMID- 28356567 TI - Fast learning in free-foraging bumble bees is negatively correlated with lifetime resource collection. AB - Despite widespread interest in the potential adaptive value of individual differences in cognition, few studies have attempted to address the question of how variation in learning and memory impacts their performance in natural environments. Using a novel split-colony experimental design we evaluated visual learning performance of foraging naive bumble bees (Bombus terrestris) in an ecologically relevant associative learning task under controlled laboratory conditions, before monitoring the lifetime foraging performance of the same individual bees in the field. We found appreciable variation among the 85 workers tested in both their learning and foraging performance, which was not predicted by colony membership. However, rather than finding that foragers benefited from enhanced learning performance, we found that fast and slow learners collected food at comparable rates and completed a similar number of foraging bouts per day in the field. Furthermore, bees with better learning abilities foraged for fewer days; suggesting a cost of enhanced learning performance in the wild. As a result, slower learning individuals collected more resources for their colony over the course of their foraging career. These results demonstrate that enhanced cognitive traits are not necessarily beneficial to the foraging performance of individuals or colonies in all environments. PMID- 28356568 TI - Negative regulators and their mechanisms in NLRP3 inflammasome activation and signaling. AB - Inflammasomes are cytosolic multiprotein complexes that cause the release of biologically active interleukin-1beta. The best-characterized inflammasome is the NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain containing-3 or Nod-like receptor protein 3) inflammasome. The NLRP3 inflammasome forms an assembly consisting of the ASC (apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain) adaptor protein and the effector, caspase-1 (cysteine-dependent aspartate-directed protease-1). Numerous agents and ligands derived from pathogens, modified self-cells and the environment induce NLRP3 inflammasome complex formation. NLRP3 inflammasome activation is tightly controlled at the transcriptional and post-translational levels to prevent unwanted excessive inflammation. Recent studies have highlighted the roles and mechanisms of several negative regulators that inhibit the assembly of NLRP3 inflammasome complexes and suppress inflammatory responses. The identification and characterization of new players in the regulation of NLRP3 inflammasome may lead to the development of inflammasome-targeting therapeutics against various inflammatory diseases related to NLRP3 inflammasome-associated pathogenesis. PMID- 28356569 TI - Synergistic targeting of breast cancer stem-like cells by human gammadelta T cells and CD8+ T cells. AB - The inherent resistance of cancer stem cells (CSCs) to existing therapies has largely hampered the development of effective treatments for advanced malignancy. To help develop novel immunotherapy approaches that efficiently target CSCs, an experimental model allowing reliable distinction of CSCs and non-CSCs was set up to study their interaction with non-MHC-restricted gammadelta T cells and antigen specific CD8+ T cells. Stable lines with characteristics of breast CSC-like cells were generated from ras-transformed human mammary epithelial (HMLER) cells as confirmed by their CD44hi CD24lo GD2+ phenotype, their mesenchymal morphology in culture and their capacity to form mammospheres under non-adherent conditions, as well as their potent tumorigenicity, self-renewal and differentiation in xenografted mice. The resistance of CSC-like cells to gammadelta T cells could be overcome by inhibition of farnesyl pyrophosphate synthase (FPPS) through pretreatment with zoledronate or with FPPS-targeting short hairpin RNA. gammadelta T cells induced upregulation of MHC class I and CD54/ICAM-1 on CSC like cells and thereby increased the susceptibility to antigen-specific killing by CD8+ T cells. Alternatively, gammadelta T-cell responses could be specifically directed against CSC-like cells using the humanised anti-GD2 monoclonal antibody hu14.18K322A. Our findings identify a powerful synergism between MHC-restricted and non-MHC-restricted T cells in the eradication of cancer cells including breast CSCs. Our research suggests that novel immunotherapies may benefit from a two-pronged approach combining gammadelta T-cell and CD8+ T-cell targeting strategies that triggers effective innate-like and tumour-specific adaptive responses. PMID- 28356572 TI - Coming to grips with cell surface polarity. PMID- 28356570 TI - Idiopathic pulmonary fibrosis and a role for autoimmunity. AB - Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias. It is typically associated with extensive and progressive fibrosis, and is fatal and has limited treatment options. Characteristically IPF patients display large lymphocyte aggregates composed of CD3+ T cells and CD20+ B cells within the lung tissue that are located near sites of active fibrosis. In addition, IPF patients can have autoantibodies to a range of host antigens, suggesting a breakdown in immunological tolerance. In this review, we examine the role of T and B cells in IPF pathogenesis and discuss how loss of self-tolerance to lung-specific proteins could exacerbate disease progression in IPF. We discuss what these results mean in terms of future prospects for immunotherapy of IPF. PMID- 28356573 TI - Plant cell development: Forcing cell polarity. PMID- 28356574 TI - Comments on the associations of systolic and diastolic blood pressure night-to day ratios with atherosclerotic cardiovascular diseases. PMID- 28356571 TI - The mystery of membrane organization: composition, regulation and roles of lipid rafts. AB - Cellular plasma membranes are laterally heterogeneous, featuring a variety of distinct subcompartments that differ in their biophysical properties and composition. A large number of studies have focused on understanding the basis for this heterogeneity and its physiological relevance. The membrane raft hypothesis formalized a physicochemical principle for a subtype of such lateral membrane heterogeneity, in which the preferential associations between cholesterol and saturated lipids drive the formation of relatively packed (or ordered) membrane domains that selectively recruit certain lipids and proteins. Recent studies have yielded new insights into this mechanism and its relevance in vivo, owing primarily to the development of improved biochemical and biophysical technologies. PMID- 28356576 TI - Pade resummation of many-body perturbation theories. AB - In a typical scenario the diagrammatic many-body perturbation theory generates asymptotic series. Despite non-convergence, the asymptotic expansions are useful when truncated to a finite number of terms. This is the reason for the popularity of leading-order methods such as the GW approximation in condensed matter, molecular and atomic physics. Appropriate truncation order required for the accurate description of strongly correlated materials is, however, not known a priori. Here an efficient method based on the Pade approximation is introduced for the regularization of perturbative series allowing to perform higher-order self-consistent calculations and to make quantitative predictions on the convergence of many-body perturbation theories. The theory is extended towards excited states where the Wick theorem is not directly applicable. Focusing on the plasmon-assisted photoemission from graphene, we treat diagrammatically electrons coupled to the excited state plasmons and predict new spectral features that can be observed in the time-resolved measurements. PMID- 28356577 TI - The powerful advantages of extracellular electrical recording. PMID- 28356575 TI - Ejection time: influence of hemodynamics and site of measurement in the arterial tree. AB - The left ventricular ejection time is routinely measured from a peripheral arterial waveform. However, the arterial waveform undergoes constant transformation as the pulse wave propagates along the arterial tree. Our goal was to determine if the left ventricular ejection time measured peripherally in the arterial tree accurately reflected the ejection time measured through the aortic valve. Moreover, we examined/accessed the modulating influence of hemodynamics on ejection time measurements. Continuous wave Doppler waveform images through the aortic valve and the simultaneously obtained radial artery pressure waveforms were analyzed to determine central and peripheral ejection times, respectively. The peripheral ejection time was significantly longer than the simultaneously measured central ejection time (174.5+/-25.2 ms vs. 120.7+/-14.4 ms; P<0.0001; 17.4+/-8.7% increase). Moreover, the ejection time prolongation was accentuated at lower blood pressures, lower heart rate and lower pulse wave velocity. The time difference between centrally and peripherally measured ejection times likely reflects intrinsic vascular characteristics. Moreover, given that the ejection time also depends on blood pressure, heart rate and pulse wave velocity, peripherally measured ejection times might need to be adjusted to account for changes in these variables. PMID- 28356578 TI - Stem cells: A case of metabolic identity in the intestinal crypt. PMID- 28356579 TI - Power comes from technical fidelity, not from ease of use. PMID- 28356580 TI - Extracellular gastrointestinal electrical recordings: movement not electrophysiology. PMID- 28356582 TI - Gut microbiota: NLRP12 regulates gut microbiota to suppress intestinal inflammation. PMID- 28356581 TI - Gut microbiome as a clinical tool in gastrointestinal disease management: are we there yet? AB - Spurred on by ever-evolving developments in analytical methodology, the microbiome, and the gut microbiome in particular, has become the hot topic in biomedical research. Ingenious experiments in animal models have revealed the extent to which the gut microbiota sustains health and how its disruption might contribute to disease pathogenesis. Not surprisingly, associations between the microbiota and disease states in humans have been the subject of considerable interest and many links proposed. However, with rare exceptions, the incrimination of an altered microbiota in disease pathogenesis seems premature at this time given our incomplete understanding of the composition of the gut microbiota in health and the effect of many confounding factors in the interpretation of supposedly abnormal microbial signatures. Future studies must account for these variables and the bidirectionality of host-microorganism interactions in health and disease. In this Perspectives, the status of microbiota signatures in the clinical arena (for facilitating diagnosis or refining prognosis) will be critically assessed and guidance toward future progress provided. PMID- 28356584 TI - Hearing loss: Vector overcomes barrier to gene therapy delivery. PMID- 28356583 TI - Correct techniques for extracellular recordings of electrical activity in gastrointestinal muscle. PMID- 28356585 TI - Drug toxicity: Cardiac safety index for TKIs. PMID- 28356586 TI - TransCelerate makes progress. PMID- 28356587 TI - Fragment-based phenotypic screening is a hit. PMID- 28356588 TI - Viral infections: Reinvigorating exhausted T cells in hepatitis B infection. PMID- 28356589 TI - Jay Bradner. PMID- 28356590 TI - Cancer: Bacterium-based immunotherapy. PMID- 28356591 TI - PRIME time at the EMA. PMID- 28356592 TI - Infectious diseases: Targeting T cells to treat Chikungunya virus infections. PMID- 28356593 TI - Liver disease: Conscious uncoupling in NASH. PMID- 28356594 TI - Ocular disorders: Vitamin B3 blocks glaucoma. PMID- 28356595 TI - Anticancer drugs: All roads lead to EZH2 inhibition. PMID- 28356596 TI - FDA approves Novartis's CDK4/6 inhibitor. PMID- 28356597 TI - Cardiovascular disease: Thioredoxin lowers hypertension. PMID- 28356598 TI - PARP inhibitors plough on. PMID- 28356601 TI - Prospects for RNA delivery with nanotechnologies. PMID- 28356600 TI - Double TALEN-edited T-cells kick B-ALL into touch. PMID- 28356599 TI - Towards Personalized Medicine in Melanoma: Implementation of a Clinical Next Generation Sequencing Panel. AB - Molecular diagnostics are increasingly performed routinely in the diagnosis and management of patients with melanoma due to the development of novel therapies that target specific genetic mutations. The development of next-generation sequencing (NGS) technologies has enabled to sequence multiple cancer-driving genes in a single assay, with improved sensitivity in mutation detection. The main objective of this study was the design and implementation of a melanoma specific sequencing panel, and the identification of the spectrum of somatic mutations in a series of primary melanoma samples. A custom panel was designed to cover the coding regions of 35 melanoma-related genes. Panel average coverage was 2,575.5 reads per amplicon, with 92,8% of targeted bases covered >=500*. Deep coverage enabled sensitive discovery of mutations in as low as 0.5% mutant allele frequency. Eighty-five percent (85/100) of the melanomas had at least one somatic mutation. The most prevalent mutated genes were BRAF (50%;50/199), NRAS (15%;15/100), PREX2 (14%;14/100), GRIN2A (13%;13/100), and ERBB4 (12%;12/100). Turn-around-time and costs for NGS-based analysis was reduced in comparison to conventional molecular approaches. The results of this study demonstrate the cost effectiveness and feasibility of a custom-designed targeted NGS panel, and suggest the implementation of targeted NGS into daily routine practice. PMID- 28356602 TI - Does Quality Affect Patients' Choice of Doctor? Evidence from England. AB - Reforms giving users of public services choice of provider aim to improve quality. But such reforms will work only if quality affects choice of provider. We test this crucial prerequisite in the English health care market by examining the choice of 3.4 million individuals of family doctor. Family doctor practices provide primary care and control access to non-emergency hospital care, the quality of their clinical care is measured and published and care is free. In this setting, clinical quality should affect choice. We find that a 1 standard deviation increase in clinical quality would increase practice size by around 17%. PMID- 28356603 TI - Photocatalytic performance of Cu2O-loaded TiO2/rGO nanoheterojunctions obtained by UV reduction. AB - A novel dot-like Cu2O-loaded TiO2/reduced graphene oxide (rGO) nanoheterojunction was synthesized via UV light reduction for the first time. Cu2O with size of ca. 5 nm was deposited on rGO sheet and TiO2 nanosheets. The products were characterized by infrared spectroscopy, Raman spectrum, UV-Vis diffuse reflectance spectra, XPS techniques, photoluminescence spectra. The results demonstrated that Cu2O and rGO enhanced the absorption for solar light, separation efficiency of electron-hole pairs, charge shuttle and transfer, and eventually improved photoelectrochemical and photocatalytic performance for contaminants degradation. The reaction time and anion precursor could affect the final copper-containing phase. As extending UV irradiation time, Cu2+ was be first reduced to Cu2O and then transformed to metal Cu. In comparison with CH3COO (copper acetate), NO3- (copper nitrate) and Cl- (copper chloride), SO42- (copper sulfate) was the optimum for synthesizing pure Cu2O phase. PMID- 28356604 TI - Early molecular signatures of responses of wheat to Zymoseptoria tritici in compatible and incompatible interactions. AB - Zymoseptoria tritici, the causal agent of septoria tritici blotch, a serious foliar disease of wheat, is a necrotrophic pathogen that undergoes a long latent period. Emergence of insensitivity to fungicides, and pesticide reduction policies, mean there is a pressing need to understand septoria and control it through greater varietal resistance. Stb6 and Stb15, the most common qualitative resistance genes in modern wheat cultivars, determine specific resistance to avirulent fungal genotypes following a gene-for-gene relationship. This study investigated compatible and incompatible interactions of wheat with Z. tritici using eight combinations of cultivars and isolates, with the aim of identifying molecular responses that could be used as markers for disease resistance during the early, symptomless phase of colonization. The accumulation of TaMPK3 was estimated using western blotting, and the expression of genes implicated in gene for-gene interactions of plants with a wide range of other pathogens was measured by qRT-PCR during the presymptomatic stages of infection. Production of TaMPK3 and expression of most of the genes responded to inoculation with Z. tritici but varied considerably between experimental replicates. However, there was no significant difference between compatible and incompatible interactions in any of the responses tested. These results demonstrate that the molecular biology of the gene-for-gene interaction between wheat and Zymoseptoria is unlike that in many other plant diseases, indicate that environmental conditions may strongly influence early responses of wheat to infection by Z. tritici, and emphasize the importance of including both compatible and incompatible interactions when investigating the biology of this complex pathosystem. PMID- 28356605 TI - Assessing Historical Mining and Smelting Effects on Heavy Metal Pollution of River Systems over Span of Two Decades. AB - Research was conducted on the most polluted river system in Poland, impacted by active and historical mining. Bottom sediment, suspended particulate matter and river water were collected in 2014 from Przemsza river and its tributaries. Sampling points remained the same as those chosen in a 1995 study. This allowed the comparison of heavy metal accumulation in bottom sediment over a span of almost two decades. It was concluded that Przemsza river water and its tributaries are heavily contaminated with the following (in MUg/dm3): Pb (0.99 145.7), Zn (48-5020), and Cd 0.12-12.72). Concentrations of metals in bottom sediment exceeded the background values by a factor of several hundred (100 times for Zn, 150 times for Pb, and 240 times for Cd). The arithmetic mean for metal concentration in fractions <63 MUm sampled in 2014 has remained comparable to the level found in 1995 (in mg/kg): Zn 16,918 and 13,505, Pb 4177 and 4758, and Cd 92 and 134. It was determined that 20-50% more metals have accumulated in suspended matter, rather than in bottom sediment (in mg/kg): 20,498 Zn, Pb 5170, and 164 Cd. This exceeds the limits of the most polluted LAWA Class IV classification. Since the concentrations of Zn, Pb, and Cd increase drastically after the outlet of the Przemsza into the Vistula, it was concluded that river Przemsza is the cause of significant degradation of Vistula's bottom sediment and suspended matter. A two-decade legacy of extremely high contamination of the Przemsza river sediments has persisted despite decreasing mining and smelting activity in the vicinity. PMID- 28356606 TI - Stratospheric variability contributed to and sustained the recent hiatus in Eurasian winter warming. AB - The recent hiatus in global-mean surface temperature warming was characterized by a Eurasian winter cooling trend, and the cause(s) for this cooling is unclear. Here we show that the observed hiatus in Eurasian warming was associated with a recent trend toward weakened stratospheric polar vortices. Specifically, by calculating the change in Eurasian surface air temperature associated with a given vortex weakening, we demonstrate that the recent trend toward weakened polar vortices reduced the anticipated Eurasian warming due to increasing greenhouse gas concentrations. Those model integrations whose stratospheric vortex evolution most closely matches that in reanalysis data also simulate a hiatus. While it is unclear whether the recent weakening of the midwinter stratospheric polar vortex was forced, a properly configured model can simulate substantial deviations of the polar vortex on decadal timescales and hence such hiatus events, implying that similar hiatus events may recur even as greenhouse gas concentrations rise. PMID- 28356607 TI - Output-Sensitive Filtering of Streaming Volume Data. AB - Real-time volume data acquisition poses substantial challenges for the traditional visualization pipeline where data enhancement is typically seen as a pre-processing step. In the case of 4D ultrasound data, for instance, costly processing operations to reduce noise and to remove artefacts need to be executed for every frame. To enable the use of high-quality filtering operations in such scenarios, we propose an output-sensitive approach to the visualization of streaming volume data. Our method evaluates the potential contribution of all voxels to the final image, allowing us to skip expensive processing operations that have little or no effect on the visualization. As filtering operations modify the data values which may affect the visibility, our main contribution is a fast scheme to predict their maximum effect on the final image. Our approach prioritizes filtering of voxels with high contribution to the final visualization based on a maximal permissible error per pixel. With zero permissible error, the optimized filtering will yield a result that is identical to filtering of the entire volume. We provide a thorough technical evaluation of the approach and demonstrate it on several typical scenarios that require on-the-fly processing. PMID- 28356608 TI - BIOPHYSICAL PROPERTIES OF SUBTHRESHOLD RESONANCE OSCILLATIONS AND SUBTHRESHOLD MEMBRANE OSCILLATIONS IN NEURONS. AB - Subthreshold-level activities in neurons play a crucial role in neuronal oscillations. These small-amplitude oscillations have been suggested to be involved in synaptic plasticity and in determining the frequency of network oscillations. Subthreshold membrane oscillations (STOs) and subthreshold resonance oscillations (SROs) are the main constituents of subthreshold-level activities in neurons. In this study, a general theoretical framework for analyzing the mechanisms underlying STOs and SROs in neurons is presented. Results showed that the resting membrane potential and the hyperpolarization activated potassium channel (h-channel) affect the subthreshold-level activities in stellate cells. The contribution of h-channel on resonance is attributed to its large time constant, which produces the time lag between Ih and the membrane potential. Conversely, the persistent sodium channels (Nap-channels) only play an amplifying role in these neurons. PMID- 28356609 TI - Ischemia-Modified Albumin as a Marker of Acute Coronary Syndrome: The Case for Revising the Concept of "N-Terminal Modification" to "Fatty Acid Occupation" of Albumin. AB - Ischemia-modified albumin (IMA) is assumed "N-terminal modified" albumin which is generated immediately following myocardial ischemia. The diagnosis of IMA is based on reduced cobalt binding affinity to albumin which is attributed mainly to incapability of cobalt to bind at albumin's modified N-terminus. Although the albumin cobalt binding test was accepted as a potentially powerful marker for discriminating acute coronary syndrome from nonischemic chest pain, its usefulness has been brought into question in recent years. Patients with acutely ischemic myocardium exhibit a rapid increase in serum levels of fatty acids (FAs). Almost all released FAs are strongly bound to albumin which create conformational changes in the protein with resultant reduced cobalt binding affinity. There is a clear metabolic and temporal relationship between IMA measured via albumin cobalt binding testing and serum levels of FAs. In line with what has been suggested recently in the literature, we conclude that a shift from the concept of "N-terminal modified" to "FA-occupied" albumin is required, as this better describes IMA in patients with acute coronary syndrome. We also offer "oxidation modified albumin, OMA," which is conceptually different from the "FA occupied" IMA, to describe modification of albumin in chronic disease associated with increased oxidative stress. PMID- 28356610 TI - A Panel of CA19-9, Ca125, and Ca15-3 as the Enhanced Test for the Differential Diagnosis of the Pancreatic Lesion. AB - Background. Proper diagnosis of pancreatic lesion etiology is a challenging clinical dilemma. Studies suggest that surgery for suspected pancreatic ductal adenocarcinoma (PDAC) reveals a benign lesion in 5% to 13% of cases. The aim of our study was to assess whether routinely used biomarkers such as CA19-9, Ca125, Ca15-3, and CEA, when combined, can potentially yield an accurate test predicting pancreatic lesion etiology. Methods. We retrospectively analyzed data of 326 patients who underwent a diagnostic process due to pancreatic lesions of unknown etiology. Results. We found statistically significant differences in mean levels of all biomarkers. In logistic regression model, we applied levels CA19-9, Ca125, and Ca15-3 as variables. Two validation methods were used, namely, random data split into training and validation groups and bootstrapping. Afterward, we built ROC curve using the model that we had created, reaching AUC = 0,801. With an optimal cut-off point, it achieved specificity of 81,2% and sensitivity of 63,10%. Our proposed model has superior diagnostic accuracy to both CA19-9 (p = 0,0194) and CA125 (p = 0,0026). Conclusion. We propose a test that is superior to CA19-9 in a differential diagnosis of pancreatic lesion etiology. Although our test fails to reach exceptionally high accuracy, its feasibility and cost effectiveness make it clinically useful. PMID- 28356611 TI - Predatory interactions between prey affect patch selection by predators. AB - ABSTRACT: When predators can use several prey species as food sources, they are known to select prey according to foraging efficiency and food quality. However, interactions between the prey species may also affect prey choice, and this has received limited attention. The effect of one such interaction, intraguild predation between prey, on patch selection by predators was studied here. The predatory mite Neoseiulus californicus preys on young larvae of the western flower thrips Frankliniella occidentalis and on all stages of the two-spotted spider mite Tetranychus urticae. The two prey species co-occur on several plant species, on which they compete for resources, and western flower thrips feed on eggs of the spider mites. A further complicating factor is that the thrips can also feed on the eggs of the predator. We found that performance of the predatory mite was highest on patches with spider mites, intermediate on patches with spider mites plus thrips larvae and lowest on patches with thrips larvae alone. Patch selection and oviposition preference of predators matched performance: predators preferred patches with spider mites over patches with spider mites plus thrips. Patches with thrips only were not significantly more attractive than empty patches. We also investigated the cues involved in patch selection and found that the attractiveness of patches with spider mites was significantly reduced by the presence of cues associated with killed spider mite eggs. This explains the reduced attractiveness of patches with both prey. Our results point at the importance of predatory interactions among prey species for patch selection by predators. SIGNIFICANCE STATEMENT: Patch selection by predators is known to be affected by factors such as prey quality, the presence of competitors and predators, but little is known on the effects of interactions among prey species present on patch selection. In this paper, we show that patch selection by a predator is affected by such interactions, specifically by the feeding of one prey species on eggs of the other. PMID- 28356612 TI - Contact with Counter-Stereotypical Women Predicts Less Sexism, Less Rape Myth Acceptance, Less Intention to Rape (in Men) and Less Projected Enjoyment of Rape (in Women). AB - Intergroup contact-(positive) interactions with people from different social groups-is a widely researched and strongly supported prejudice-reducing mechanism shown to reduce prejudice against a wide variety of outgroups. However, no known previous research has investigated whether intergroup contact can also reduce sexism against women. Sexism has an array of negative outcomes. One of the most detrimental and violent ones is rape, which is both justified and downplayed by rape myth acceptance. We hypothesised that more frequent, higher quality contact with counter-stereotypical women would predict lower levels of sexism and thus less rape myth acceptance (in men) and less sexualised projected responses to rape (in women). Two studies using online surveys with community samples supported these hypotheses. In Study 1, 170 male participants who experienced more positive contact with counter-stereotypical women reported less intention to rape. Similarly, in Study 2, 280 female participants who experienced more positive contact with counter-stereotypical women reported less projected sexual arousal at the thought of being raped. Thus, the present research is the first known to show that contact could be a potential tool to combat sexism, rape myth acceptance, intentions to rape in men, and sexualisation of rape by women. PMID- 28356613 TI - Atomic Layer Deposition of Titanium Oxide on Single-Layer Graphene: An Atomic Scale Study toward Understanding Nucleation and Growth. AB - Controlled synthesis of a hybrid nanomaterial based on titanium oxide and single layer graphene (SLG) using atomic layer deposition (ALD) is reported here. The morphology and crystallinity of the oxide layer on SLG can be tuned mainly with the deposition temperature, achieving either a uniform amorphous layer at 60 degrees C or ~2 nm individual nanocrystals on the SLG at 200 degrees C after only 20 ALD cycles. A continuous and uniform amorphous layer formed on the SLG after 180 cycles at 60 degrees C can be converted to a polycrystalline layer containing domains of anatase TiO2 after a postdeposition annealing at 400 degrees C under vacuum. Using aberration-corrected transmission electron microscopy (AC-TEM), characterization of the structure and chemistry was performed on an atomic scale and provided insight into understanding the nucleation and growth. AC-TEM imaging and electron energy loss spectroscopy revealed that rocksalt TiO nanocrystals were occasionally formed at the early stage of nucleation after only 20 ALD cycles. Understanding and controlling nucleation and growth of the hybrid nanomaterial are crucial to achieving novel properties and enhanced performance for a wide range of applications that exploit the synergetic functionalities of the ensemble. PMID- 28356614 TI - A study on the physical fitness of children with juvenile rheumatoid arthritis. AB - [Purpose] This study was conducted to assess the physical fitness of children with juvenile rheumatoid arthritis (JRA). [Subjects and Methods] In total, 26 children with juvenile rheumatoid arthritis (JRA) and 25 healthy controls participated in this study. Using the physical fitness measurement instruments, the Inbody 720 and Quark b2, the elements of physical fitness that were assessed included muscular strength, muscular endurance, flexibility, lung capacity, and body composition. [Results] The results revealed significant differences in muscular strength, muscular endurance, lung capacity, body composition, functional ability, and health-related quality of life between the children with juvenile rheumatoid arthritis (JRA) and the control group. [Conclusion] These results suggested that children with juvenile rheumatoid arthritis (JRA) have inferior physical fitness when compared to healthy children. The present study was conducted to develop an accurate evaluation standard to assess the physical fitness of children with juvenile rheumatoid arthritis (JRA). PMID- 28356615 TI - Effect of belly dancing on urinary incontinence-related muscles and vaginal pressure in middle-aged women. AB - [Purpose] This study examined the effect of belly dancing on the urinary incontinence-related muscles and vaginal pressure in middle-aged women to provide fundamental data for establishing an effective training program focusing on mitigating and preventing urinary incontinence. [Subjects and Methods] The subjects included 24 middle-aged women, who have been diagnosed with urinary incontinence. The subjects were randomly divided into two groups, viz. the experimental group (N=12) and control group (N=12). The experimental group underwent a belly dancing program focusing on pelvis moves. [Results] In the experimental group, the urinary incontinence-related muscle strength and vaginal pressure were increased, while the control group showed no significant change. [Conclusion] Belly dancing focusing on pelvis moves had a positive effect on the urinary incontinence-related muscle strength and vaginal pressure, suggesting that a recreational dance program focusing on pelvic exercise can be used to prevent and relieve the symptoms of urinary incontinence as a non-surgical treatment. PMID- 28356616 TI - The effects of horse-riding simulator exercise on balance in elderly with knee osteoarthritis. AB - [Purpose] The aim of this study was to examine the effects of horse-riding simulator exercise on balance in elderly with knee osteoarthritis. [Subjects and Methods] Fifty elderly patients with knee osteoarthritis were recruited, a horse riding simulator group performed exercise three times a week for eight weeks. And each exercise was performed for 30 minutes. [Results] The horse-riding simulator group showed significant differences after the intervention in Short Form Berg Balance Scale, Functional reaching test. [Conclusion] The results of this study indicate that horse-riding simulator exercise is effective on knee osteoarthritis. Therefore, horse-riding simulator exercise can be used balance training for knee osteoarthritis. PMID- 28356617 TI - Effects on sitting pressure distribution during the application of different cushions and anterior height wedges. AB - [Purpose] The purpose of this study was to investigate interface pressure redistribution in healthy volunteers when applying different cushions and anterior wedge heights. [Subjects and Methods] This study included 36 healthy individuals in their 20s. The peak and mean pressures were measured by applying different cushions and anterior wedge heights. The results were analyzed by using a one-way analysis of variance and post-hoc analysis. [Results] The peak and mean pressures were statistically significant based on the cushion types and anterior wedge height. The peak pressure was at its highest and lowest when sitting on a 6 cm anterior wedge and a foam cushion, respectively. The mean pressure was greatest when sitting on a 6-cm anterior wedge of a firm surface and smallest when sitting on a 5 cm foam cushion. [Conclusion] This study shows that the most effective method for pressure redistribution was sitting on a 5 cm foam cushion without an anterior wedge. PMID- 28356618 TI - Affective temperament profile in ankylosing spondylitis patients using TEMPS-A. AB - [Purpose] This study aimed to compare the most common dominant affective temperaments in Ankylosing Spondylitis patients and investigate the relationship between the dominant affective temperaments and pain levels, disease activity, quality of life, current depression, and anxiety level in Ankylosing Spondylitis patients. [Subjects and Methods] Fifty-one patients diagnosed with axial spondiloartropathy and forty-two age- and gender-matched control subjects were included in this study. Disease duration, erythrocyte sedimentation rate, serum C reactive protein, pain by the Visual Analog Scale, disease activity by the Bath Ankylosing Spondylitis Disease Activity Index, functional status by the Bath Ankylosing Spondylitis Functional Index; psychological status by the Beck Depression Inventory, Beck Anxiety Inventory and overall health assessment by the Ankylosing Spondylitis Quality of Life Scale were assessed in patients. The Turkish version of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego Auto Questionnaire was used to determine the dominant affective temperament. [Results] There was no statistical difference in the distribution of temperament subtypes between patients with Ankylosing Spondylitis and the controls. Depressive, anxious, and cyclothymic temperament scores were higher in patients with high values on the Bath Ankylosing Spondylitis Functional Index and Visual Analog Scale. There was a correlation between anxious subtypes of affective temperament scores and the value of Ankylosing Spondylitis Quality of Life Scale. Correlation analysis also found depressive, cyclothymic, irritable, and anxious temperament and psychiatric symptoms to be significantly related. [Conclusion] Affective temperament may contribute to symptoms of depression and anxiety in patients with Ankylosing Spondylitis and may increase disease activity and may reduce their quality of life. PMID- 28356619 TI - Cognitive basis about risk level classifications for the self-assessment of older drivers. AB - [Purpose] This study analyzed the cognitive functions according to risk level for the Driver 65 Plus measure, and examined the cognitive basis of self-assessment for screening the driving risk of elderly drivers. [Subjects and Methods] A total of 46 older drivers with a driver's license participated in this study. All participants were evaluated with Driver 65 Plus. They were classified into three groups of "safe," "caution" and "stop," and examined for cognitive functions with Trail Making Test and Montreal Cognitive Assessment-K. The cognitive test results of the three groups were compared. [Results] Trail Making Test-A, Trail Making Test-B, and Montreal Cognitive Assessment-K showed a significant difference between the three groups. The safe group showed significantly higher ability than the caution and stop groups in the three cognitive tests. In addition, cognitive functions of naming, attention, language, and delayed recall were significantly different between the three groups. [Conclusion] Self-assessment of older drivers is a useful tool for screening the cognitive aspects of driving risk. The cognitive functions, such as attention and recall, are the critical factors for screening the driving risk of elderly drivers. PMID- 28356620 TI - Effect of a modified grip angle of a walker on the wrist deviation angle, muscle activation and palmar load during walker-assisted gait in elderly people. AB - [Purpose] The aim of this study was to develop a new handle holder by modifying the inclination of the existing handle holder to reduce load on the wrist joints. [Subjects and Methods] The subjects of this study consisted of 25 elderly people aged 65 years or older accustomed to a walker-assisted gait. Two types of handle holders ((1) standard handle holder (2) inclination handle holder) were applied to all subjects and their wrist joint movement and muscle activity were measured while they conducted 10 cycle walker-assisted gait. [Results] The use of an inclination handle holder during the walker-assisted gait decreased considerably the extensor carpi radialis longus activity and angles of the ulnar deviation and wrist extension. [Conclusion] Improvements in the overall structure of a walker may be a new tool for improving existing walker users but the replacement cost will be expensive. The inclination handle holder presented in this study decreases the burden on the wrist joints of walker users without any overall structural changes in the walker, thereby reducing the occurrence of musculoskeletal diseases of the wrist joint during the walker-assisted gait of elderly people. PMID- 28356621 TI - Changes in T2-weighted MRI of supinator muscle, pronator teres muscle, and extensor indicis muscle with manual muscle testing. AB - [Purpose] In order to detect muscle activity with manual muscle testing, T2 weighted magnetic resonance (T2w-MR) images were detected by a 0.2 T compact MRI system. [Subjects and Methods] The subjects were 3 adult males. Transverse T2 weighted multi-slice spin-echo images of the left forearm were measured by a 39 ms echo-time with a 2,000 ms repetition time, a 9.5 mm slice thickness, 1 accumulation and a total image acquisition time of 4 min 16 s. First, T2w-MR images in the resting condition were measured. Then, manipulative isometric contraction exercise (5 sec duration) to the supinator muscle, the pronator teres muscle or the extensor indicis muscle was performed using Borg's rating of perceived exertion (RPE) scale of 15-17. The T2w-MR images were measured immediately after the exercise. [Results] T2w-MR image intensities increased significantly in the supinator muscle, the pronator teres muscle and the extensor indicis muscle after the exercise. However, the image intensities in the rest of the muscle did not change. [Conclusion] Using T2w-MR images, we could detect muscle activity in a deep muscle, the supinator muscle, and a small muscle, the extensor indicis muscle. These results also support the reliability of the manual muscle testing method. PMID- 28356622 TI - Evaluation of the relationship between the static measurement of transverse arch flexibility of the forefoot and gait parameters in healthy subjects. AB - [Purpose] To investigate the relationship between the static measurement of the transverse arch of the forefoot, using a 3-dimensional (3D) foot scanner, and kinetics and kinematics of gait parameters in the sagittal plane. [Subjects and Methods] Twenty healthy subjects participated in this study. The transverse arch of the forefoot was measured under three conditions as follows: condition 1, sitting; condition 2, standing; and condition 3, foot forward and lower leg tilting anteriorly to the maximum position with heel contact. Gait parameters were recorded using a 3D motion analysis system and force plate. Correlation coefficients between TAF for each comparison of conditions and gait parameters were calculated using the Spearman correlation analysis. [Results] Rates of the transverse arch of the forefoot width and height between condition 2 and condition 3 were significantly correlated with the anterior and posterior component of ground reaction forces, the hip joint extension angle, and the ankle plantar flexion moment. [Conclusion] Our study's findings indicated that increased stiffness of the transverse arch of the forefoot was related to the increase in ankle plantar moment, and decreased stiffness of the transverse arch of the forefoot was related to the increase in hip joint extension angle during gait. PMID- 28356623 TI - "Slow walking with turns" increases quadriceps and erector spinae muscle activity. AB - [Purpose] To maintain an independent lifestyle, older adults should improve muscle strength and mass, or aerobic capacity. A new exercise pattern, called slow walking with turns, which incorporates turning as an extra load additional to walking. The purpose of this study was to measure oxygen consumption during exercise and muscle activity while turning. [Subjects and Methods] Recreationally active volunteers participated. The participants performed 20 turns per minute while walking back and forth over distances of 1.5 to 3.5 m. We measured oxygen consumption, heart rate, and rating of perceived exertion and performed electromyography during the exercise. [Results] The metabolic equivalents of the exercise were 4.0 +/- 0.4 to 6.3 +/- 4.0 Mets. Activity was significantly greater in the vastus medialis, vastus lateralis, and erector spinae during the turn phase of slow walking with turns than during the stance phase of treadmill walking. [Conclusion] These findings suggest that slow walking with turns may help to preserve the muscle strength and mass of the trunk and lower limbs that are needed to maintain an independent lifestyle. Slow walking can be performed easily by older people, and in slow walking with turns, the exercise intensity can be adjusted as required for each individual. PMID- 28356624 TI - Relation between change in exercise capacity and change in blood amino acids in patients with chronic heart failure. AB - [Purpose] Although cardiac rehabilitation (CR) is recommended for patients with chronic heart failure (CHF), adequate exercise effect cannot be obtained in elderly patients. Administration of amino acids (AA) to CHF patients has been reported to improve exercise capacity, but the changes in AA composition in plasma before and after CR had not been reported. This study aimed to measure plasma levels of AA in CHF patients and compare with values of normal range. In addition the relationship between the change of exercise capacity and AA were examined. [Subjects and Methods] Twelve CHF patients (60% males, aged 68 +/- 12 years) were studied. The correction between the rates of changes in exercise capacity parameters and in plasma AA levels was investigated. [Results] Anaerobic threshold (AT) and peak oxygen uptake (VO2) improved significantly after CR. The AA profile showed no specific pattern, and citrulline (Cit) was the amino acid showing a significant positive correlation with exercise capacity (?Cit vs. ?AT: r=0.602, ?Cit vs. ?AT-work rate (WR): r=0.681, ?Cit vs. ?VO2/WR: r=0.635). A tendency of positive correlation was observed between ?Cit and ?peak VO2 (r=0.456). [Conclusion] The AA profile showed no specific pattern, but a relationship between change in exercise capacity and Cit were found. PMID- 28356626 TI - Effects of wearing functional foot orthotic on pelvic angle among college students in their 20s with flatfoot. AB - [Purpose] This study examined the impact of wearing a functional foot orthotic on the pelvic angle of young adults who have flatfoot. [Subjects and Methods] A total of 15 college students diagnosed with flatfoot were included in the study. Changes in the pelvic angle in the stance period during walking before and after orthotic use were measured using a VICON Motion System (VICON, Hansung, Korea). The data were analyzed using SPSS 12.0 for Windows. [Results] In the experimental group, the pelvic angle during the mid-stance and mid-swing periods of the gait cycle significantly decreased on the left and right sides after wearing the orthotic, compared to the measurements taken before orthotic usage. The pelvic angle change on the left and right sides also decreased after wearing the orthotic, though this difference was not significant. [Conclusion] The pelvic angle of college students with flatfoot decreased after they wore orthotics. This implies that wearing orthotic shoes can greatly benefit individuals during normal walking by promoting passive changes that decrease the pelvic angle. PMID- 28356625 TI - Instantaneous changes in respiratory function induced by passive pelvic suspension in the supine position in relation to increased diaphragm excursion. AB - [Purpose] This study aimed to introduce an approach of pelvic suspension (PS) using sling cords and to obtain evidence for changes in respiratory function of healthy subjects. [Subjects and Methods] Subjects were 25 healthy men. In the supine position, with hip and knee joints flexed at 90 degrees , the subjects' pelvises were suspended with sling belts. Diaphragm excursion, respiratory function, and respiratory comfort in these postures were measured using ultrasonography, respirometry, and visual analog scale (VAS), respectively. [Results] When the pelvis was passively suspended with sling cords, the diaphragm moved 5 mm cranially and diaphragm excursion showed an instantaneous increase compared with the control. The tidal volume (VT) showed an increase and the respiration rate (RR) showed a decrease. The extent of diaphragm excursion was correlated with changes in VT under the control and PS conditions. Independent measurements of pulmonary function revealed that PS reduced the expiratory reserve volume, being correlated positively and negatively to increases in vital and inspiratory capacities, respectively. Furthermore, VAS values for respiratory ease were greater with PS than with the control. [Conclusion] These results suggest that PS effectively changed diaphragm excursion and respiratory function, leading to ease of breathing (i.e., deep and slow respiration). PMID- 28356627 TI - Examination of center of pressure displacement and muscle activity of the hip girdle muscles on lateral movement in the sitting position, focusing on kinematic features before and after the start of exercise. AB - [Purpose] This study aimed to evaluate the kinematic characteristics at the start of lateral movement in the sitting position, for application in physical therapy. [Subjects and Methods] Eleven healthy male subjects (mean age, 24.8 +/- 3.7 years) were included in the study after they provided informed consent. The electromyographic activities of the tensor fascia lata, gluteus medius, and rectus femoris, and the center of pressure (COP) displacement during lateral reach in the sitting position were measured. The task was recorded on video for analysis. [Results] In almost all subjects, before the beginning of the task, the electromyographic activity in the opposite side of each studied muscle was recorded, and the opposite and anterior displacement of the COP was observed. The video analysis revealed that all subjects showed lateral displacement of the thoracic part of the trunk after the start of the task. However, the lumbar region and pelvis maintained their starting positions. [Conclusion] COP displacement occurred in the reverse reaction before the task, and this involved the hip girdle muscles of the opposite side. A reverse reaction displaced the pelvis to the opposite side to ensure instability of posture through side tilting of the trunk at the beginning of the task. PMID- 28356628 TI - Factors inducing falling in schizophrenia patients. AB - [Purpose] The purpose of this study is to investigate the factors causing falling among patients with schizophrenia hospitalized in psychiatric hospitals. [Subjects and Methods] The study subjects were divided into either those having experienced a fall within the past one year (Fall group, 12 patients) and those not having experienced a fall (Non-fall group, 7 patients), and we examined differences between the two groups. Assessment items measured included muscle strength, balance ability, flexibility, body composition assessment, Global Assessment of Functioning scale (GAF), the antipsychotic drug intake, and Drug Induced Extra-Pyramidal Symptoms Scale (DIEPSS). [Results] As a result, significant differences were observed in regard to One leg standing time with eyes open, Time Up and Go Test (TUGT), and DIEPSS Sialorrhea between the Fall group and the Non-fall group. [Conclusion] These results suggest that a decrease in balance ability was significantly correlated with falling in schizophrenia patients. PMID- 28356629 TI - The effects of posterior talar glide with dorsiflexion of the ankle on mobility, muscle strength and balance in stroke patients: a randomised controlled trial. AB - [Purpose] The purpose of this study was to examine the effectiveness of posterior talar glide (PTG) with dorsiflexion of the ankle on stroke patients ankle mobility, muscle strength, and balance ability. [Subjects and Methods] Thirty four subjects were randomly assigned to either a PTG with dorsiflexion group (PTG; n=17), or a weight-bearing with placebo PTG group (control; n=17). Subjects in the PTG group performed PTG with dorsiflexion, designed to improve ankle mobility, muscle strength and balance ability with proprioceptive control of the ankle, for 10 glides of 5 sets/day, 5 days/week, for 4 weeks. [Results] The experimental group showed significant improvement on the Ankle Dorsiflexion Range of Motion assessment, Ankle Dorsiflexor Manual Muscle Test, Functional Reach Test, Time Up and Go test, and Functional Gait Assessment compared to the control group. However, regarding Ankle Plantarflexion Range of Motion assessment and the Ankle Plantarflexor Manual Muscle Test, no significant differences were found between the two groups. [Conclusion] The results of this study show that PTG with dorsiflexion can improve ankle mobility, muscle strength and balance ability in patients recovering from stroke. This exercise may prove useful in clinical rehabilitation. Further research on the long-term effectiveness of PTG on gait ability is suggested. PMID- 28356630 TI - Activities of daily living and manual hand dexterity in persons with idiopathic parkinson disease. AB - [Purpose] The purpose of this study was to evaluate the relationship between daily activities and manual dexterity in persons with Parkinson disease. [Subjects and Methods] The study participants were 25 patients with idiopathic Parkinson disease. This study used two clinical tools, the box-and-block test and Schwab and England Activities of Daily Living scale, to investigate the relationship between manual dexterity and Schwab and England Activities of Daily Living score. [Results] A positive correlation was observed between the Schwab and England Activities of Daily Living and the box-and-block test scores on the more and less affected sides. Moreover, the Schwab and England Activities of Daily Living score had a greater correlation with the box-and-block test score on the less affected side than that on the more affected side. [Conclusion] Manual dexterity and activities of daily living showed a positive correlation in individuals with Parkinson disease. The results of this study suggest that manual dexterity is an important factor for predicting physical performance in daily living in persons with Parkinson disease. PMID- 28356631 TI - Associations of knee muscle force, bone malalignment, and knee-joint laxity with osteoarthritis in elderly people. AB - [Purpose] From the viewpoint of prevention of knee osteoarthritis, the aim of this study was to verify how muscle strength and joint laxity are related to knee osteoarthritis. [Subjects and Methods] The study subjects consisted of 90 community-dwelling elderly people aged more than 60 years (22 males, 68 females). Femorotibial angle alignment, knee joint laxity, knee extensors and flexor muscle strengths were measured in all subjects. In addition, the subjects were divided into four groups based on the presence of laxity and knee joint deformation, and the muscle strength values were compared. [Results] There was no significant difference in knee extensor muscle strength among the four groups. However, there was significant weakness of the knee flexor muscle in the group with deformation and laxity was compared with the group without deformation and laxity. [Conclusion] Decreased knee flexor muscle strengths may be involved in knee joint deformation. The importance of muscle strength balance was also considered. PMID- 28356632 TI - The effects of inspiratory diaphragm breathing exercise and expiratory pursed-lip breathing exercise on chronic stroke patients' respiratory muscle activation. AB - [Purpose] The purpose of this study is to examine the effects of inspiratory diaphragm breathing exercise and expiratory pursed-lip breathing exercise on chronic stroke patients' respiratory muscle activation. [Subjects and Methods] All experimental subjects performed exercises five times per week for four weeks. Thirty chronic stroke patients were randomly assign to an experimental group of 15 patients and a control group of 15 patients. The experimental group underwent exercises consisting of basic exercise treatment for 15 minutes and inspiratory diaphragm breathing exercise and expiratory pursed-lip breathing exercise for 15 minutes and the control group underwent exercises consisting of basic exercise treatment for 15 minutes and auto-med exercise for 15 minutes. The activation levels of respiratory muscles were measured before and after the experiment using MP 150WSW to obtain the results of the experiment. [Results] In the present study, when the pulmonary functions of the experimental group and the control group before and after the experiment were compared, whereas the experimental group showed significant differences in all sections. In the verification of intergroup differences between the experimental group and the control group before and after the experiment. [Conclusion] The respiratory rehabilitation exercise is considered to be capable of inducing positive effects on stroke patients' respiratory muscles through diaphragm breathing exercise and lip puckering breathing exercise. PMID- 28356634 TI - Comparison of anterior gluteus medius fiber activation during general exercises and PNF exercises. AB - [Purpose] This study compared the activation of anterior gluteus medius fibers during general exercises and proprioceptive neuromuscular facilitation exercises. [Subjects and Methods] The study enrolled 15 healthy adults. The participants performed general hip abductor strengthening exercises and proprioceptive neuromuscular facilitation exercises; during both types of exercise, electromyography activity was recorded. [Results] Greater anterior gluteus medius fiber activation was observed during the proprioceptive neuromuscular facilitation exercises compared with the general hip abductor strengthening exercises. The anterior gluteus medius fibers exhibited greater activity during pattern 2 exercises compared with any other type of exercise. [Conclusion] The results suggest that pattern 2 exercises can selectively activate anterior gluteus medius fibers. PMID- 28356633 TI - Factors influencing executive function by physical activity level among young adults: a near-infrared spectroscopy study. AB - [Purpose] Prevention of dementia requires early intervention against it. To ensure that early interventions are effective it is crucial to study the cognitive functions related to dementia in young adulthood. Moreover, it is needed not only to verify the cognitive function test but also to elucidate the actual brain activity and the influence of related factors on the brain activity. To investigate the factors influencing cognitive function among young adults and examine the differences in executive function by physical activity level. [Subjects and Methods] Forty healthy university students (mean age, 20.4 years) were classified into two groups by cognitive function score (HIGH and LOW), determined according to Trail Making Test performance and Stroop task processing time. We then assessed what factors were related to cognitive function by logistic regression analysis. Executive function was determined by brain blood flow using near-infrared spectroscopy during the Stroop task, and was then compared by physical activity levels (determined according to number of steps per hour). [Results] Full-scale Intelligence Quotient according to the 3rd Wechsler Adult Intelligent Scale and number of steps per hour influenced cognitive function score, with odds ratios of 1.104 and 1.012, respectively. Oxy-hemoglobin concentrations in areas related to executive function during the Stroop task were significantly higher among those in the high physical activity group than among those in the low physical activity group. [Conclusion] The study revealed that Full-scale Intelligence Quotient and a number of steps per hour are factors associated with the cognitive functions in young adulthood. In addition, activity in execution function related area was found to be significantly higher in the high physical activity group than in the low physical activity group, suggesting the importance of physical activity for enhancing young adulthood cognitive functions. PMID- 28356635 TI - Effects of a standard transfer exercise program on transfer quality and activities of daily living for transfer-dependent spinal cord injury patients. AB - [Purpose] The objective of this study was to analyze the effect of a standard transfer exercise program on the transfer quality and activities of daily living (ADL) in wheelchair-dependent spinal cord injury patients. [Subjects and Methods] We randomly divided 22 patients into 2 groups. During the intervention period, one group received treatment with both conventional physical therapy and a standard sitting pivot transfer exercise program (experimental group, n=12) and the other group was managed solely with conventional physical therapy (control group, n=10). The standard transfer exercise program comprised of an independent and a dependent program. Exercises were conducted 30 minutes daily, 3 times per week, over a period of 6 weeks. All subjects were tested using a transfer assessment instrument (TAI) and spinal cord independence measure (SCIM) before and after the intervention. [Results] Compared to the control group, the intervention group scored higher on both the transfer assessment instrument (TAI Part 1, Part 2, TAI total score) and spinal cord independence measure tests (SCIM mobility room and toilet score; SCIM total score). [Conclusion] In conclusion, the standard transfer exercise program is an effective tool which improves transfer quality and the ability of wheelchair-dependent spinal cord injury patients to carry out their ADLs. PMID- 28356636 TI - Functional electrical stimulation to the abdominal wall muscles synchronized with the expiratory flow does not induce muscle fatigue. AB - [Purpose] Continuous electrical stimulation of abdominal wall muscles is known to induce mild muscle fatigue. However, it is not clear whether this is also true for functional electrical stimulation delivered only during the expiratory phase of breathing. This study aimed to examine whether or not intermittent electrical stimulation delivered to abdominal wall muscles induces muscle fatigue. [Subjects and Methods] The subjects were nine healthy adults. Abdominal electrical stimulation was applied for 1.5 seconds from the start of expiration and then turned off during inspiration. The electrodes were attached to both sides of the abdomen at the lower margin of the 12th rib. Abdominal electrical stimulation was delivered for 15 minutes with the subject in a seated position. Expiratory flow was measured during stimulus. Trunk flexor torque and electromyography activity were measured to evaluate abdominal muscle fatigue. [Results] The mean stimulation on/off ratio was 1:2.3. The declining rate of abdominal muscle torque was 61.1 +/- 19.1% before stimulus and 56.5 +/- 20.9% after stimulus, not significantly different. The declining rate of mean power frequency was 47.8 +/- 11.7% before stimulus and 47.9 +/- 10.2% after stimulus, not significantly different. [Conclusion] It was found that intermittent electrical stimulation to abdominal muscles synchronized with the expiratory would not induce muscle fatigue. PMID- 28356637 TI - Rate of oral intake and effects of mechanical insufflation-exsufflation on pulmonary complications in patients with duchenne muscular dystrophy. AB - [Purpose] In Duchenne muscular dystrophy, it increases risks of difficulties of expectoration of secretion, asphyxia, aspiration pneumonia because of decreased cough function. The aim of this study is to prove that manually assisted coughing or mechanical insufflation-exsufflation prevents pulmonary complication and contribute to continue oral intake safely and continue rate of oral intake in Duchenne muscular dystrophy. [Subjects and Methods] We investigated the status of using ventilator, manually assisted coughing or mechanical insufflation exsufflation, and oral intake or not. In addition, we inspected the frequency of fever (over 37 degrees C) needed antibiotics from medical records for index of respiratory tract infection, and compared with every period of using mechanical insufflation-exsufflation from respiratory evaluation on cough peak flow. [Results] Fifty-eight patients participated in this study. There were 45 Full time noninvasive positive pressure ventilation patients. Forty-three in 45 Full time noninvasive positive pressure ventilation patients (95.6%) avoided tracheostomy and continued noninvasive positive pressure ventilation because they continued oral intake without tracheal intubation due to the respiratory acute exacerbation by asphyxia or aspiration pneumonia. [Conclusion] Duchenne muscular dystrophy patients can continue oral intake safely while preventing pulmonary complication by using manually assisted coughing or mechanical insufflation exsufflation. PMID- 28356638 TI - Effects of manual lymph drainage for abdomen on the brain activity of subjects with psychological stress. AB - [Purpose] The present study investigated the effects of manual lymph drainage for abdomen on electroencephalography in subjects with psychological stress. [Subjects and Methods] Twenty-eight subjects were randomly allocated to undergo a 20-min session of either manual lymph drainage or abdominal massage on a bed. [Results] Analysis of electroencephalograms from the manual lymph drainage group showed a significant increase in relaxation, manifested as an increase in average absolute, relative alpha activity and a decrease in relative gamma activity. [Conclusion] Our results suggest that the application of manual lymph drainage from the abdomen provides acute neural effects that increase relaxation in subjects with psychological stress. PMID- 28356639 TI - The effects of upper extremity task training with symmetric abdominal muscle contraction on trunk stability and balance in chronic stroke patients. AB - [Purpose] The purpose of this study is to examine the effects of upper extremity task training employing the bracing method on the trunk control and balance of stroke patients. [Subjects and Methods] The subjects were 46 stroke patients whose strokes had occurred six months or more prior to the study. The subjects were divided into two groups. One group underwent upper extremity task training with symmetric abdominal muscle contraction (bracing) applied. The other group simply underwent upper extremity task training, without bracing. [Results] The experimental group's Trunk Impairment Scale (TIS) significantly increased after the intervention, whereas the control group did not see any significant difference. There was significant improvement in balance after the intervention in both the experimental group and the control group. According to the between group comparisons, the improvements in the experimental group were significantly greater in the control group, except in the Postural Assessment Scale (PASS). [Conclusion] Based on the results of this study, upper extremity task exercises with symmetric abdominal muscle contraction, conducted as part of adult hemiplegic patients' trunk stabilization exercises, can be applied to a diverse range of hemiplegic patients and implemented as an exercise program after discharge from hospital. PMID- 28356641 TI - Effect of transcranial direct current stimulation of stroke patients on depression and quality of life. AB - [Purpose] The aim of this study was to assess the effects of transcranial direct current stimulation (tDCS) on depression and quality of life (QOL) in patients with stroke, by conducting conventional occupational therapy with and without tDCS on 20 patients each. [Subjects and Methods] The experimental group (N=20) received both tDCS and conventional occupational therapy, while the control group (N=20) received false tDCS and conventional occupational therapy. The treatment was conducted 20 times over a four-week period; each session was 30 minutes long. The Beck Depression Inventory (BDI) was administered to score the depression levels in patients before and after the intervention, while the stroke-specific quality of life (SS-QOL) was measured to compare the QOL. [Result] Following the intervention, the patients in the experimental group showed a significant decrease in depression and an increase in the QOL. In contrast, the control group showed no significant changes in depression or QOL. Our findings indicate that tDCS decreased depression while increasing QOL in patients with stroke. [Conclusion] In other words, our study confirmed that the application of tDCS during stroke rehabilitation improves the depression symptoms and QOL in patients. PMID- 28356640 TI - Fatigue influences lower extremity angular velocities during a single-leg drop vertical jump. AB - [Purpose] Fatigue alters lower extremity landing strategies and decreases the ability to attenuate impact during landing. The purpose of this study was to reveal the influence of fatigue on dynamic alignment and joint angular velocities in the lower extremities during a single leg landing. [Subjects and Methods] The 34 female college students were randomly assigned to either the fatigue or control group. The fatigue group performed single-leg drop vertical jumps before, and after, the fatigue protocol, which was performed using a bike ergometer. Lower extremity kinematic data were acquired using a three-dimensional motion analysis system. The ratio of each variable (%), for the pre-fatigue to post fatigue protocols, were calculated to compare differences between each group. [Results] Peak hip and knee flexion angular velocities increased significantly in the fatigue group compared with the control group. Furthermore, hip flexion angular velocity increased significantly between each group at 40 milliseconds after initial ground contact. [Conclusion] Fatigue reduced the ability to attenuate impact by increasing angular velocities in the direction of hip and knee flexion during landings. These findings indicate a requirement to evaluate movement quality over time by measuring hip and knee flexion angular velocities in landings during fatigue conditions. PMID- 28356642 TI - The effects of preceding exercise on myocardial damage in rats. AB - [Purpose] The purpose of this study was to investigate the effects of exercise on myocardial injury in male Sprague-Dawley rats. Two groups of rats were trained with either moderate- or high-intensity treadmill running for four weeks. Subsequently, the concentrations of cardiac troponin and the N-terminal of prohormone brain natriuretic peptide (NT-proBNP) were examined following a single bout of prolonged intensive exercise (lasting 3 h). [Subjects and Methods] The study included 40 six-week-old male Sprague-Dawley rats weighing 150-180 g each. The aerobic exercise group was divided into high-intensity (28 m/min) and moderate-intensity (15 m/min) subgroups. Both subgroups were trained for 35 min daily for six days per week (excluding Sunday) over a four-week period. Following training, the high- and moderate-intensity exercise groups and a nonexercise group performed one bout of prolonged treadmill exercise for 3 h at a speed of 15 m/min. [Results] The cardiac troponin and NT-proBNP levels differed significantly between the groups. [Conclusion] The exercise groups showed lower levels of cardiac troponin and NT-proBNP than the nonexercise group after the bout of prolonged intensive exercise. PMID- 28356643 TI - Effects of friction massage of the popliteal fossa on blood flow velocity of the popliteal vein. AB - [Purpose] Friction massage (friction) of the popliteal fossa is provided for the purpose of relieving pain related to circulatory disorders by improving venous flow in the lower legs. The purpose of this study is to verify the effects of enhancing the venous flow based on measuring the blood flow velocity of the popliteal vein before and after providing friction to the patients. [Subjects and Methods] Fifteen healthy male university students participated in the study. The Doppler ultrasonography (DU) was used to measure the blood flow velocity of the popliteal vein, in order to verify the effects of enhancing the venous flow by comparing the measured values before and after a friction massage. [Results] The result of comparing the blood flow velocity before and after providing friction showed that there was a significant increase after friction. [Conclusion] This study proved that friction to the popliteal fossa is effectively enhances venous flow by increasing the blood flow velocity in the popliteal vein. PMID- 28356645 TI - The study of elbow injury in male adult kendo players. AB - [Purpose] Elbow injury in male adult kendo players was investigated and examined in order to obtain an indicator of prophylaxis of injury. [Subjects and Methods] The subjects were 22 male adult kendo players aged 25 to 60 years old, and presence or absence of pain, range of motion, and muscle strength in the elbow joints were investigated. In addition, among athletes with limited range of motion (ROM) in the elbow joints, three athletes who had received an explanation and had provided informed consent underwent CT, and the images were examined. [Result] As a result, posterior pain and decreased range of extension motion in the right elbow were noted in 86% of the subjects, and the CT images showed free bone fragments and osteophytes in the olecranon. Also, characteristics were noted that extension muscle strength was stronger than flexion muscle strength in elbow muscle strength. [Conclusion] Based on these results, characteristic disorders in male adult kendo players include an impingement disorder in the posterior region of the right elbow. PMID- 28356644 TI - Maximal respiratory pressure in healthy Japanese children. AB - [Purpose] Normal values for respiratory muscle pressures during development in Japanese children have not been reported. The purpose of this study was to investigate respiratory muscle pressures in Japanese children aged 3-12 years. [Subjects and Methods] We measured respiratory muscle pressure values using a manovacuometer without a nose clip, with subjects in a sitting position. Data were collected for ages 3-6 (Group I: 68 subjects), 7-9 (Group II: 86 subjects), and 10-12 (Group III: 64 subjects) years. [Results] The values for respiratory muscle pressures in children were significantly higher with age in both sexes, and were higher in boys than in girls. Correlation coefficients were significant at values of 0.279 to 0.471 for each gender relationship between maximal respiratory pressure and age, height, and weight, respectively. [Conclusion] In this study, we showed pediatric respiratory muscle pressure reference value for each age. In the present study, values for respiratory muscle pressures were lower than Brazilian studies. This suggests that differences in respiratory muscle pressures vary with ethnicity. PMID- 28356646 TI - The effects of action observation training and mirror therapy on gait and balance in stroke patients. AB - [Purpose] The aim of this study was to evaluate the effects of action observation training and mirror therapy to improve on balance and gait function of stroke patients. [Subjects and Methods] The participants were randomly allocated to one of three groups: The action observation training with activity group practiced additional action observation training with activity for three 30-minute session for six weeks (n=12). The mirror therapy with activity group practiced additional mirror therapy with activity for three 30-minute sessions for six weeks (n=11). The only action observation training group practiced additional action observation training for three 30-minute sessions for weeks (n=12). All groups received conventional therapy for five 60-minute sessions over a six-week period. [Results] There were significant improvements in balance and gait function. The action observation training with activity group significantly improved subjects' static balance. The action observation training with activity group and the mirror therapy with activity group significantly improved subjects' gait ability. [Conclusion] The activation of mirror neurons combined with a conventional stroke physiotherapy program enhances lower-extremity motor recovery and motor functioning in stroke patients. PMID- 28356647 TI - The effects of exercise training using transcranial direct current stimulation (tDCS) on breathing in patients with chronic stroke patients. AB - [Purpose] This study was conducted to investigate the effect of exercise training using transcranial direct current stimulation (tDCS) on breathing in patients with chronic stroke patients. [Subjects and Methods] Thirty chronic stroke patients who do not show abnormal response to electric stimulation were enrolled in this study and each 15 subjects were randomized either into the study group and the sham-controlled group. The subjects performed diaphragmatic breathing exercise for 20 minutes while tDCS device was attached to them (for study group, the device was on while for the sham-controlled group, the device was turned off 30 seconds later) [Results] The results of FVC, FEF1 and FEV1/FVC in the study group and those of FVC and FEV1 in the sham-controlled group were significantly increased after the breathing exercise. The independent comparison result between the groups showed that the breathing performance of study group significantly improved based on the results of FVC and FEV1. [Conclusion] In conclusion, the results of this study confirmed that breathing exercise effectively improved FVC and FEV1 in chronic stroke patients. Also, the breathing exercise using tDCS was more effective in improving FVC and FEV1. PMID- 28356648 TI - Effect of maitland mobilization in cervical and thoracic spine and therapeutic exercise on functional impairment in individuals with chronic neck pain. AB - [Purpose] This study evaluated joint mobilization and therapeutic exercise applied to the cervical spine and upper thoracic spine for functional impairment caused by chronic neck pain. [Subjects and Methods] Eighteen study subjects were randomly assigned to two groups of nine people each. Therapeutic exercise only was applied to the cervical and upper thoracic spine for Group I, while both therapeutic exercise and joint mobilization were applied to Group II. The visual analog scale, neck disability index, active cervical range of motion, static balance capacity, and muscle tone were assessed with a pre-test. The intervention was carried out for 60 minutes a day, three times a week, for two weeks for each group, followed by a post-test using the same protocol as the pre-test. [Results] The visual analog scale, neck disability index, and active cervical range of motion improved significantly in both groups. Group II improved significantly more on right lateral flexion and rightward rotation. Muscle tone improved significantly in the upper trapezius in both groups. [Conclusion] The joint mobilization and therapeutic exercise for functional impairments caused by chronic neck pain had a significant effect on several types of functional impairment. PMID- 28356649 TI - The effects of extracorporeal shock wave therapy on the pain and function of patients with degenerative knee arthritis. AB - [Purpose] The purpose of this study was to identify the effects of extracorporeal shock wave therapy on the pain and function of patients with degenerative knee arthritis. [Subjects and Methods] Twenty patients with degenerative knee arthritis were divided into a conservative physical therapy group (n=10) and an extracorporeal shock wave therapy group (n=10). Both groups received general conservative physical therapy, and the extracorporeal shock wave therapy was additionally treated with extracorporeal shock wave therapy after receiving conservative physical therapy. Both groups were treated three times a week over a four-week period. The visual analogue scale was used to evaluate pain in the knee joints of the subjects, and the Korean Western Ontario and McMaster Universities Osteoarthritis Index was used to evaluate the function of the subjects. [Results] The comparison of the visual analogue scale and Korean Western Ontario and McMaster Universities Osteoarthritis Index scores within each group before and after the treatment showed statistically significant declines in scores in both the conservative physical therapy group and extracorporeal shock wave therapy group. A group comparison after the treatment showed statistically significant differences in these scores in the extracorporeal shock wave therapy group and the conservative physical therapy group. [Conclusion] extracorporeal shock wave therapy may be a useful nonsurgical intervention for reducing the pain of patients with degenerative knee arthritis and improving these patients' function. PMID- 28356650 TI - The effects of pelvic diagonal movements and resistance on the lumbar multifidus. AB - [Purpose] The purpose of this study was to compare the effects of pelvic diagonal movements, made with and without resistance, on the thickness of lumbar multifidus muscles. [Subjects and Methods] Participants in this study were healthy subjects who had no musculoskeletal disorders or lumbar-related pain. Participants were positioned on their side and instructed to lie with their hip flexor at 40 degrees. Ultrasonography was used for measurement, and the values of two calculations were averaged. [Results] The thickness of ipsilateral lumbar multifidus muscles showed a significant difference following the exercise of pelvic diagonal movements. The results of anterior elevation movements and posterior depression movements also demonstrated significant difference. There was no significant difference in lumbar multifidus muscles thickness between movements made with and without resistance. [Conclusion] These findings suggest that pelvic diagonal movements can be an effective method to promote muscular activation of the ipsilateral multifidus. Furthermore, researchers have concluded that resistance is not required during pelvic diagonal movements to selectively activate the core muscles. PMID- 28356651 TI - A comparison of outcomes of asymmetry in infants with congenital muscular torticollis according to age upon starting treatment. AB - [Purpose] The purpose of this study was to compare the outcomes of asymmetry in infants with congenital muscular torticollis (CMT) according to the age when treatment was started. [Subjects and Methods] 102 infant CMT patients under the age of 6 months were selected. The subjects were divided into a group that started treatment before six weeks (n=55) and a group that started treatment after six weeks (n=47). Asymmety was evaluated by determining the difference in the thickness of the two sternocleidomastoid muscles (DTSM) using ultrasonography, head tilt (HT) based on a physical examination, and the torticollis overall assessment (TOA). Patients received ultrasound and massage therapy for 30 minutes, in conjunction with passive stretching exercises, 3 times a week. [Results] Following the intervention, the DTSM, HT and TOA showed significant differences in the two groups. The DTSM of the group that started treatment before six weeks was significantly better than that of the group that started treatment after six weeks. [Conclusion] The results of this study suggest that early intervention is more effective than later intervention. PMID- 28356652 TI - The Canadian occupational performance measure for patients with stroke: a systematic review. AB - [Purpose] This study investigated whether the Canadian Occupational Performance Measure is a suitable outcome measure for assessing patients with stroke in research and clinical settings. [Subjects and Methods] The study included into two parts: (1) an investigation of the reliability and validity of the Canadian Occupational Performance Measure for patients with stroke and (2) an exploration of Canadian Occupational Performance Measure results in randomized controlled trials of patients with stroke. For this review, the study searched the MEDLINE, PubMed, and CINAHL Plus with Full Text databases for articles published before September 2015. [Results] Finally, three eligible articles were collected in part 1, and ten randomized controlled trials studies were collected in part 2. The findings of part 1 revealed that the Canadian Occupational Performance Measure had efficient test-retest reliability, however, the Canadian Occupational Performance Measure revealed weak associations with other assessment tools such as Barthel Index used for patients with stroke. Six of the randomized controlled trials studies used the Canadian Occupational Performance Measure as a primary outcome and two as a secondary outcome, while the other two as a goal-setting instrument. [Conclusion] This review indicates that the Canadian Occupational Performance Measure is appropriate for clinicians, including physiotherapists, in assessing outcome for patients with stroke. The Canadian Occupational Performance Measure can assist patients in identifying their outcome performance and provide therapists with directions on interventions. PMID- 28356653 TI - Effects of electrical stimulation combined with dysphagia therapy in elderly individual with oropharyngeal dysphagia: a case study. AB - [Purpose] The purpose of the present study was to investigate the effects of dysphagia therapy in an old man with difficulty swallowing in the oral and pharyngeal phases. [Subjects and Methods] The subject was a 72-year-old man with no history of neurological disorders. He was admitted to local hospital because of the complaint of swallowing difficulty. The interventions performed were electrical stimulation and conventional dysphagia therapy. We assessed the tongue and lip muscle strengths. Swallowing function was evaluated by using the videofluoroscopic dysphagia and penetration-aspiration scales. [Results] After the intervention, the tongue and lip muscle strengths increased from 35 to 39 kPa and from 18 to 23 kPa, respectively. Moreover, the oral and pharyngeal phases of the videofluoroscopic dysphagia scale were improved. Furthermore, aspiration decreased from 4 to 2 points in the penetration-aspiration scale. [Conclusion] Our results suggest that electrical stimulation and conventional dysphagia therapy were effective in improving the swallowing function in an elderly individual with dysphagia. PMID- 28356654 TI - Disordered voluntary cough as freezing phenomenon in parkinsonism. AB - [Purpose] In patients with parkinsonism, the precise mechanism of impaired voluntary cough remains poorly understood. This study used the flow-volume curve to clarify whether disordered voluntary cough reflects the freezing phenomenon. [Subjects and Methods] Case 1 was a 58-year-old female who had been suffering from progressive supranuclear palsy-pure akinesia with gait freezing. Case 2 was a 59-year-old female who had advanced juvenile parkinsonism. The subjects were asked to take a deep inspiration to the total lung capacity and then cough more than five times through the face mask into the spirometer without intervening inspirations between the coughing efforts. [Results] Hesitation in cough initiation (case 2), decreased peak cough flow (case 1), and rounding of the first spike (cases 1 and 2) were observed. In addition, movements of the spike wave at a lower lung volume became progressively smaller and faster (cases 1 and 2). [Conclusion] These clinical manifestations in our patients are similar to those observed in the freezing phenomenon. However, to date, the concept of cough freezing has been underrecognized in clinical practice. From the present study, it could be hypothesized that the freezing phenomenon can occur in voluntary cough as well as in gait, speech, and writing. PMID- 28356655 TI - Early literacy and comprehension skills in children learning English as an additional language and monolingual children with language weaknesses. AB - Many children learning English as an additional language (EAL) show reading comprehension difficulties despite adequate decoding. However, the relationship between early language and reading comprehension in this group is not fully understood. The language and literacy skills of 80 children learning English from diverse language backgrounds and 80 monolingual English-speaking peers with language weaknesses were assessed at school entry (mean age = 4 years, 7 months) and after 2 years of schooling in the UK (mean age = 6 years, 3 months). The EAL group showed weaker language skills and stronger word reading than the monolingual group but no difference in reading comprehension. Individual differences in reading comprehension were predicted by variations in decoding and language comprehension in both groups to a similar degree. PMID- 28356656 TI - CpG Type A Induction of an Early Protective Environment in Experimental Multiple Sclerosis. AB - Experimental autoimmune encephalomyelitis (EAE) is an inflammatory, demyelinating disease of the CNS that mimics human multiple sclerosis (MS), and it is thought to be driven by Th1 and Th17 myelin-reactive cells. Although adaptive immunity is clearly pivotal in the pathogenesis of EAE, with an essential role of CD4+ T cells, little is known of early, innate responses in this experimental setting. CpG-rich oligodeoxynucleotides (ODNs), typically found in microbial genomes, are potent activators of TLR9 in plasmacytoid dendritic cells (pDCs). In this study, we compared the effects of two types of CpG, namely, type A and type B, on EAE. We found that treatment with CpG type A ODN (CpG-A), known to induce high amounts of IFN-alpha in pDCs, significantly reduced disease severity in EAE, relative to controls (12.63 +/- 1.86 versus 23.49 +/- 1.46, resp.; p = 0.001). Treatment also delayed onset of neurological deficits and reduced spinal cord demyelination, while increasing the percentage of splenic regulatory (Foxp3+ CD4+) T cells. CpG A likewise reduced the levels of IL-17 and IFN-gamma in the CNS. Mechanistic insight into those events showed that CpG-A promoted a regulatory phenotype in pDCs. Moreover, adoptive transfer of pDCs isolated from CpG-A-treated mice inhibited CNS inflammation and induced disease remission in acute-phase EAE. Our data thus identify a link between TLR9 activation by specific ligands and the induction of tolerance via innate immunity mechanisms. PMID- 28356658 TI - N-acetyl cysteine versus allopurinol in the prevention of contrast nephropathy in patients with chronic kidney disease: A randomized controlled trial. AB - Contrast media administration can lead to acute deterioration in renal function particularly in patients with pre-existing chronic kidney disease. This prospective, randomized controlled open-label parallel group study was undertaken at Nizam's Institute of Medical Sciences, Hyderabad, from June to December 2015. A total of 95 patients were included, of which 35 received n-acetylcysteine (NAC) + normal saline (NS), 30 patients received allopurinol (ALL) + NS, and 30 patients received placebo. In our study, the overall incidence of CIN was 24%. Incidence of CIN in NAC + NS, ALL + NS, and placebo group were 20%, 16%, and 36%, respectively. The major finding of this study was there was no significant difference between NAC and allopurinol in the prevention of contrast nephropathy. However, only allopurinol was superior to placebo. In our study, hyperuricemia and baseline serum creatinine were the only risk factors associated with CIN. PMID- 28356657 TI - Obesity and kidney disease: Hidden consequences of the epidemic. PMID- 28356659 TI - The effect of resolution time of acute kidney injury on clinical outcomes. AB - Acute kidney injury (AKI) is a frequent and complex disease. It is not clearly defined whether its duration is related to adverse outcomes. We determined the effect of AKI resolution time on patient's clinical outcomes. A prospective cohort of hospitalized patients with AKI by AKI network (AKIN) creatinine criteria was included. Variables for prognosis and follow-up were analyzed. One hundred and thirteen patients were included in the study. Seventy-seven (68.1%) were males, mean age 55 years (range, 16-76 years), and 48 (42.5%) were diabetic. The most common cause of AKI was sepsis (31%). AKI resolution time <=2 days and >2 days was seen in 47 (41.6%) and 66 (58.4%) of the cases, respectively. AKI resolution time >2 days was common in older patients (66.24 +/- 17.6 year vs. 47.16 +/- 12.32 year, P = 0.004), with the use of mechanical ventilation (27% vs. 4%, P = 0.02) and vasopressors (41% vs. 11%, P <= 0.01); it was associated with increased mortality (47% vs. 4%, P <= 0.01), and a discharge estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 (52% vs. 2%, P = 0.01), than in patients with resolution time <=2 days. Survival rate was significantly worse in patients with a resolution time >2 days. By multivariate logistic step-wise regression analysis, AKI >2days, vasopressor use, and AKIN stage 2-3 were independently associated with higher mortality. AKI >2 days and vasopressor utilization were independently associated to an eGFR <60 ml/min/1.73 m2 at the time of discharge. We conclude that AKI resolution time >2 days is linked to adverse clinical outcomes. PMID- 28356660 TI - Prevalence of hypothyroidism in nondiabetic chronic kidney disease and effect of thyroxine replacement on estimated glomerular filtration rate. AB - Reduced T3 and free T4, elevated thyroid stimulating hormone, and hyporesponsiveness to thyrotropin releasing hormone raise questions about the presence of hypothyroidism in chronic kidney disease (CKD) and raise the possibility of benefit from thyroxine supplementation. A prospective cohort study was conducted on 73 nondiabetic CKD cases. Hypothyroid patients were started on levothyroxine and were reviewed after 3 and 6 months. The mean age of study population was 42.3 +/- 16.8 years. Of the total population, 32 (43.8%) cases had hypothyroidism, among whom 2 (2.7%) had overt hypothyroidism and 30 (41.1%) had subclinical hypothyroidism. Prevalence of hypothyroidism increased with increasing severity of CKD. There were 1 (3.1%) case with hypothyroidism in stage 3b, 8 (25%) cases in stage 4, and 23 (71.9%) cases in stage 5. The mean estimated glomerular filtration rate (ml/min/1.73 m2) at baseline was 13.7 +/- 8.9 which increased to 17.5 +/- 6.8 and 22.4 +/- 9.3 after 3 and 6 months of thyroid hormone replacement therapy (THRT), respectively (P < 0.001). Hypothyroidism is commonly associated with nondiabetic CKD and its prevalence increases with declining renal function. THRT significantly improves renal function in nondiabetic CKD with hypothyroidism. PMID- 28356661 TI - Anti-glomerular basement membrane disease: Case series from a tertiary center in North India. AB - Anti-glomerular basement (anti-GBM) disease is an uncommon disorder with a bimodal age of presentation. Patients presenting with dialysis-dependent renal failure have poor renal outcomes. There is limited data regarding the clinical presentation and outcomes of anti-GBM disease from India. We conducted this prospective study to analyze the clinical presentation and outcomes of anti-GBM disease at a large tertiary care hospital in North India over 11/2 years. Subjects with a biopsy proven anti-GBM disease (light microscopic examination showing crescents and immunofluorescence examination showing linear deposition of IgG) with or without positive anti-GBM antibodies in serum were included in the study and followed-up for at least 12 months. All the patients were treated with steroids, cyclophosphamide, and plasma exchange. A total of 17 patients (nine males) were included. The mean age at presentation was 39.11 +/- 16.58 (range 11 72) years. Twelve patients (70%) presented with rapidly progressive glomerulonephritis (RPGN), 4 (23.5%) presented with Goodpasture syndrome, while 1 (5.8%) had nephritic syndrome, 7 (41%) were hypertensive, and 14 (82.3%) required dialysis at the time of presentation. Four patients (23.5%) had associated anti neutrophil cytoplasmic antibody positivity (anti-myeloperoxidase antibodies in all). Fourteen (87.5%) patients had crescentic glomerulonephritis, while 5 (31.25%) showed necrotizing (n = 4) or granulomatous (n = 1) in the vasculitis. Of 16 patients who received treatment, four (23.25%) achieved complete remission. In this single-center study, the majority of anti-GBM disease patients presented with RPGN and had crescentic glomerulonephritis on biopsy with poor treatment outcome. PMID- 28356662 TI - Pregnancy-related acute kidney injury: An analysis of 165 cases. AB - Pregnancy-related acute kidney injury (PRAKI) contributes to 3-7% of overall acute kidney injury (AKI) cases in Indian subcontinent. The aim of this study was to determine the outcomes of PRAKI and risk factors associated with renal injury and maternal mortality. One hundred and sixty-five patients with PRAKI, seen at M. S. Ramaiah Medical College between 2005 and 2014, were included in this, observational study. AKI was analyzed in terms of maximal stage of renal injury attained as per Risk, Injury, Failure, Loss of function, and End-stage renal disease (RIFLE) criteria. Outcomes included requirement for renal replacement therapy (RRT), maternal, and fetal mortality. Incidence of PRAKI was 1.56%, and the mean age of the study population was 25 years. Fifty percent of the patients were diagnosed with PRAKI during their first pregnancy. PRAKI was observed most commonly in the postpartum period (60%), followed by third trimester (32%); as per RIFLE criteria, failure was seen in 36% and injury in 34%. Thirty percent of cases required RRT. Sepsis (59%), pre-eclampsia, and eclampsia (56%) were the leading causes of PRAKI, while sepsis was the leading cause of maternal mortality. Maternal and fetal mortality were 20% and 22%, respectively. In univariate analysis, shock, hemorrhage requiring transfusion of >5 units packed red blood cells, oliguria, and "Loss" category of RIFLE were significantly associated with mortality. Majority of the patients (57%) required Intensive Care Unit care with a mean duration of admission at 7.3 days, and 75% was diagnosed with AKI at the time of admission. We report the lowest incidence of PRAKI in contemporary Indian literature. PRAKI was associated with high maternal and fetal mortality, with sepsis being the leading cause. No association was noted between mortality and initial stages of RIFLE criteria. PMID- 28356663 TI - Safety and effectiveness of transjugular renal biopsy: A single center study. AB - Although percutaneous renal biopsy remains the preferred method, there are several scenarios where transjugular approach is more suitable. We hereby describe our technique of transjugular renal biopsy (TJRB) and evaluate its safety and efficacy. We retrospectively collected data regarding indication for the transjugular route of biopsy, its complications, clinical and laboratory data, and adequacy of samples from patients' records. TJRB was performed when the patients were at a high risk for bleeding from percutaneous renal biopsy. Tissue samples were assessed by a pathologist for adequacy. All patients were followed up with ultrasonographic scan 3 h after the procedure and on day 3. Nine patients (age 41.5 +/- 15.4 years; 8 men) underwent 9 TJRB procedures. The procedure was technically successful in all patients. Six patients (66.67%) had a platelet count of <50,000/mcL, 2 (33.3%) had an elevated International Normalized Ratio of more than 1.4, and 1 had both. 3.2 +/- 0.4 cores were obtained, with median (range) number of glomeruli being ten (7-11). Adequate renal tissue sample was obtained in all the patients. Though capsular perforation developed in 5 patients, none had major complication requiring management (endovascular treatment or blood transfusion). TJRB is a safe and effective in patients with contraindications to percutaneous biopsy. PMID- 28356664 TI - Comparison of serum creatinine-based estimating equations with gates protocol for predicting glomerular filtration rate in indian population. AB - In clinical practice, serum creatinine-based predicting equations and Gates protocol based on gamma camera imaging of kidneys after injection of Tc99m diethylenetriaminepentaacetic acid (DTPA) are commonly used to assess glomerular filtration rate (GFR). Comparison of these methods, especially the chronic kidney disease-epidemiology collaboration (CKD-EPI) equation with gold standard method of assessment of GFR by plasma clearance of Tc-99mDTPA is not well-studied in Indian population. We conducted this study to compare GFR estimation by gamma camera-based Gates protocol and serum creatinine-based predicting equations with GFR measured by plasma clearance of Tc-99mDTPA. One hundred and five patients (65 male and 40 female) underwent Tc-99m DTPA renal scan followed by withdrawal of venous blood samples at 2, 3, and 4 h as per predefined protocol. Gates method GFR (GFRs) was assessed using standard protocol. GFR by plasma sampling (GFRp) was calculated by slope-intercept method with provision for corrections. Estimated GFR was calculated by Cockroft-Gault formula, four variable modification of diet in renal disease (MDRD) equation, and CKD-EPI equation (GFRCG, GFRMDRD, GFRCKD-EPI, respectively). GFR measured by gold standard method (GFRp) was compared with that estimated by other methods by calculating correlation coefficient, bias, precision, and accuracy. GFR estimated by all three estimating equations correlated better than GFRs with GFRp. For estimating GFRp, GFRCKD-EPI had highest correlation with GFRp with least bias and highest precision. Gamma camera-based Gates protocol was the least precise and least accurate method for estimating GFRp. To conclude, all three estimating equations based on serum creatinine are superior to Tc-99m DTPA scintigraphy for estimating GFR; CKD-EPI equation being the most accurate and precise. PMID- 28356665 TI - Renal allograft eosinophilia: An unusual presentation of sudden graft dysfunction. AB - We present a case of sudden allograft dysfunction 11 months after renal transplantation which presented as severe peripheral and allograft eosinophilia and was managed as a case of an acute cellular rejection with significant interstitial graft eosinophilic infiltration. Patient had partial response to antirejection therapy and eventually ended up in a chronic allograft dysfunction. PMID- 28356667 TI - Hemophagocytic lymphohistiocytosis secondary to hemodialysis catheter-related blood stream infection. AB - A 57-year-old man on dialysis presented with fever due to Pseudomonas septicemia. Workup revealed very high triglycerides and serum ferritin levels. A bone marrow examination showed hemophagocytosis. A diagnosis of hemophagocytic lymphohistiocytosis (HLH) was made and steroids were started. He was put on automated peritoneal dialysis. Patients' condition continued to deteriorate and he succumbed to his illness. This case illustrates the development of HLH secondary to infections which are increasingly being recognized in the literature. Often this diagnosis is missed as it becomes difficult to differentiate between sepsis and HLH. The presence of high ferritin, hypertriglyceridemia, and hemophagocytosis in the bone marrow confirms the diagnosis. PMID- 28356666 TI - Acyclovir-induced thrombotic microangiopathy. AB - Acyclovir is a commonly used antiviral drug. Acute kidney injury (AKI) due to intratubular crystal precipitation and interstitial nephritis is well known. Here we present a case of acyclovir induced AKI in a 61 year old male with herpes zoster, which presented like thrombotic microangiopathy with acute interstitial nephritis. This is the first case report on acyclovir causing thrombotic microaniopathy with partial improvement in renal function after plasmapharesis. PMID- 28356668 TI - Targeting renin-angiotensin system in malignant hypertension in atypical hemolytic uremic syndrome. AB - Hypertension is common in hemolytic uremic syndrome (HUS) and often difficult to control. Local renin-angiotensin activation is believed to be an important part of thrombotic microangiopathy, leading to a vicious cycle of progressive renal injury and intractable hypertension. This has been demonstrated in vitro via enhanced tissue factor expression on glomerular endothelial cells which is enhanced by angiotensin II. We report two pediatric cases of atypical HUS with severe refractory malignant hypertension, in which we targeted the renin angiotensin system by using intravenous (IV) enalaprilat, oral aliskiren, and oral enalapril with quick and dramatic response of blood pressure. Both drugs, aliskiren and IV enalaprilat, were effective in controlling hypertension refractory to multiple antihypertensive medications. These appear to be promising alternatives in the treatment of severe atypical HUS-induced hypertension and hypertensive emergency. PMID- 28356669 TI - C3 glomerulopathy associated to multiple myeloma successfully treated by autologous stem cell transplant. AB - A 32-year-old male presented with advanced renal failure and nephrotic proteinuria due to lambda light chain multiple myeloma. Renal biopsy showed a proliferative glomerulonephritis with isolated C3 deposits. Renal recovery was obtained after chemotherapy and autologous stem cell transplant. We review previously described cases of C3 glomerulopathy associated with monoclonal gammopathy. PMID- 28356670 TI - An unusual case of gastrointestinal mucormycosis in a patient with nephrotic syndrome. AB - Immunosuppression predisposes to a variety of infections, some of which occur at unusual sites. Of all the forms of mucormycosis, involvement of the intestines is rare. High degree of suspicion along with the use of invasive procedures can facilitate the diagnosis of these infections. We report a rare case of gastrointestinal Mucor in a patient with nephrotic syndrome. PMID- 28356671 TI - Brachial plexus compression due to subclavian artery pseudoaneurysm from internal jugular vein catheterization. AB - Internal jugular vein (IJV) catheterization has become the preferred approach for temporary vascular access for hemodialysis. However, complications such as internal carotid artery puncture, vessel erosion, thrombosis, and infection may occur. We report a case of brachial plexus palsy due to compression by right subclavian artery pseudoaneurysm as a result of IJV catheterization in a patient who was under maintenance hemodialysis. PMID- 28356672 TI - Scrub typhus meningitis in a renal transplant recipient. AB - Scrub typhus is a rickettsial infection commonly seen in Asia. The clinical presentation ranges from nonspecific febrile illness to potentially fatal multiorgan involvement such as liver, kidney, or lung. Central nervous system involvement is uncommon. We report a 45-year-old female renal transplant recipient who presented with fever, headache, meningeal signs, graft dysfunction, and eschar. IgM antibodies against Orientia tsutsugamushi were positive by enzyme linked immunosorbent assay. Despite oral doxycycline therapy for 5 days, she did not improve but responded well to intravenous azithromycin. To the best of our knowledge, scrub typhus as a cause of meningitis in a renal transplant recipient has not been reported so far. PMID- 28356673 TI - Remission of post-transplant focal segmental glomerulosclerosis with angiotensin receptor blockers. AB - Recurrence of focal segmental glomerulosclerosis (FSGS) is common after kidney transplantation. Plasmapheresis (PP) is considered to be the most effective treatment; however, results are variable and relapse is common after stopping plasmapheresis. Here, we report an unusual case of recurrent FSGS, who achieved complete remission with angiotensin receptor blocker therapy. PMID- 28356674 TI - Fibrillary glomerulonephritis presenting as crescentic glomerulonephritis. AB - Fibrillary glomerulonephritis (FGN) is a rare primary glomerular disease that commonly presents clinically with hypertension, proteinuria, microscopic hematuria, and varying degree of renal insufficiency. Histologically, FGN can present with different patterns of glomerular injury, more commonly mesangioproliferative, membranoproliferative, and membranous nephropathy. While crescent formation has been described in some kidney biopsy series of FGN, crescentic glomerulonephritis pattern of glomerular injury has been rarely described. Optimal therapy and outcomes in FGN presenting with crescentic GN is not currently known. We report an adult patient who presented with massive proteinuria and severe renal failure. The kidney biopsy revealed crescentic FGN (C-FGN). The patient remained dialysis dependent despite immunosuppressive therapy. We also briefly review FGN, and the few reported cases of C-FGN that presented as rapidly progressive or advanced renal failure in the literature. PMID- 28356675 TI - Thrombotic microangiopathy due to Viperidae bite: Two case reports. AB - Snake bite is mainly an occupational hazard and causes serious health problems in rural India. Acute kidney injury (AKI) occurs in 5-30% cases. Renal pathologic findings include acute tubular necrosis, cortical necrosis, interstitial nephritis, glomerulonephritis, and vasculitis. Thrombotic microangiopathy (TMA) occurrence after a snake bite is reported rarely. Here, we present two patients who developed TMA after viper bite treated with hemodialysis and plasmapheresis. Renal biopsy showed fibrin thrombi in glomeruli and arterioles with cortical necrosis. One patient progressed to end-stage renal disease and other was lost to follow-up. TMA should be considered as a possible pathogenesis of AKI after snake bite. The role of plasma exchanges in snake bite TMA is yet to be defined. PMID- 28356676 TI - Brief report: Fungal balls in the urinary tract of an infant. PMID- 28356678 TI - Net2Align: An Algorithm For Pairwise Global Alignment of Biological Networks. AB - The amount of data on molecular interactions is growing at an enormous pace, whereas the progress of methods for analysing this data is still lacking behind. Particularly, in the area of comparative analysis of biological networks, where one wishes to explore the similarity between two biological networks, this holds a potential problem. In consideration that the functionality primarily runs at the network level, it advocates the need for robust comparison methods. In this paper, we describe Net2Align, an algorithm for pairwise global alignment that can perform node-to-node correspondences as well as edge-to-edge correspondences into consideration. The uniqueness of our algorithm is in the fact that it is also able to detect the type of interaction, which is essential in case of directed graphs. The existing algorithm is only able to identify the common nodes but not the common edges. Another striking feature of the algorithm is that it is able to remove duplicate entries in case of variable datasets being aligned. This is achieved through creation of a local database which helps exclude duplicate links. In a pervasive computational study on gene regulatory network, we establish that our algorithm surpasses its counterparts in its results. Net2Align has been implemented in Java 7 and the source code is available as supplementary files. PMID- 28356679 TI - Identification and analysis of insulin like peptides in nematode secretomes provide targets for parasite control. AB - Insulin-like (ins) peptides play an important role in development and metabolism across the metazoa. In nematodes, these are also required for dauer formation and longevity and are expressed in different types of neurons across various life stages which demonstrate their role in parasites and could become possible targets for parasite control. To date, many nematode genomes are publically available. However, a systematic screening of ins peptides across different nematode group has not been reported. In the present study, we systematically identified ins peptides in the secretomes of 73 nematodes with fully sequenced genomes covering five different groups viz. plant parasitic, animal parasitic, human parasitic, entomopathogenic and free living nematodes. From the total of 93,949 secretory proteins, 176 proteins were uniquely mapped to 40 identified C. elegans ins families. The obtained result showed that 74.15% of the identified ins proteins were represented in free living nematodes only and remaining 25.84% were combinedly identified in all other nematode groups. The ins-1, ins-17 and ins-18 were the only ins families which were detected in all the studied nematode groups. Out of 176 proteins, 96 of ins proteins were predicted as hydrophilic in nature and 39 proteins were found stable using ProtParam analysis. Our study provides insight into the distribution of ins peptides across different group of nematodes and this information could be useful for further experimental study. PMID- 28356680 TI - Micro surgery - need of the hour. PMID- 28356677 TI - The role of metabolic reprogramming in T cell fate and function. AB - T lymphocytes undergo extensive changes in their metabolic properties during their transition through various differentiation states, from naive to effector to memory or regulatory roles. The cause and effect relationship between metabolism and differentiation is a field of intense investigation. Many recent studies demonstrate the dependency of T cell functional outcomes on metabolic pathways and the possibility of metabolic intervention to modify these functions. In this review, we describe the basic metabolic features of T cells and new findings on how these correlate with various differentiation fates and functions. We also highlight the latest information regarding the main factors that affect T cell metabolic reprogramming. PMID- 28356681 TI - Complications in the use of bilateral inferiorly based nasolabial flaps for advanced oral submucous fibrosis. AB - Surgical management of advanced oral submucous fibrosis (OSMF) using bilateral inferiorly based nasolabial flaps is becoming increasingly popular. However no comprehensive analysis of delayed complications using this technique is available in the literature. The authors have conducted a retrospective study to examine the delayed complications of bilateral inferiorly based nasolabial flaps used in advanced oral submucous fibrosis at their institute along with a detailed review of literature on the subject. Thirty-two patients from January 2004 to December 2015 with OSMF and an interincisal distance less than 15 mm were included. All patients were treated with bilateral inferiorly based nasolabial flaps for correction of the restricted mouth opening. All patients had postoperative physiotherapy and were followed up for a minimum period of 6 months. All complaints of patients during the follow up phase were included in this study. In this series, complications such as partial necrosis, intra-oral hair growth, unacceptable extra-oral scar, wound dehiscence, orocutaneous fistula, and pincushioning effect were observed. Numerous complications can occur with the use of nasolabial flaps for the management of advanced oral submucous fibrosis. Although most complications are of inconsequential nature the surgeon must observe due diligence when using this flap. PMID- 28356682 TI - Dental implants in children: A multidisciplinary perspective for long-term success. AB - Congenital hypodontia or trauma is a frequent cause of loss of teeth in children. The absence of teeth leads to loss of function and lack of normal alveolar growth, along with unpleasant esthetics that hamper the psychosocial development of the young child. Traditionally, the management of tooth loss in the young child is done by conservative means. None of those methods of treatment are completely satisfactory and have their own drawbacks. Dental implants in a young child would be an ideal mode of treatment for the absence of teeth. One of the main deterring factors for implant placement in children is the impending growth. Growth in the maxilla and mandible does not happen uniformly in one plane. It is multidirectional, occurring in sagittal, vertical, and transverse planes. It does not happen at a fixed pace, slow periods of growth are followed by phases of accelerated growth called the growth spurts. Successful implant treatment in children has been achieved by several clinicians when they incorporated a multidisciplinary approach in their treatment plan. The design and type of implant system used in pediatric patients is also responsible for successful treatment outcome. The purpose of this review is to understand the implications of growth and growth assessment and recommendations for the formulation of the treatment plan in pediatric dental implant patients. PMID- 28356684 TI - Effects of honey in the management of alveolar osteitis: A study. AB - INTRODUCTION: Alveolar osteitis (AO) is a complication of tooth extraction which indicates inflammation of alveolar bone of either maxilla or mandible. This study uses Apitherapy where honey catalyses biological reactions to improve immune system, makes local environment unbearable for microorganisms in the affected socket and enhances healing. MATERIALS AND METHODS: 50 patients of AO were included in the study. After cleansing of the affected socket, honey dressing was applied. Dressings were changed daily for first 2 days and then altenatively. In biochemical investigations, CRP levels in the body were measured using Nephelometry method. Microbiological examination was done for the identification of microorganism and semi quantitative count of colony forming units. RESULT: Results were assessed from clinical, microbiological, biochemical and radiological findings at 1st, 2nd, 3rd, 5th, 7th day based on VAS score, erythema, pus discharge, swelling, lymphadenitis, fever, bleeding on probing, exposed bone and necrotic debris. Pre-Treatment CRP was 2.08 +/- 1.62 which significantly (P = 0.0001) decreased to 0.82 +/- 0.48. Mean change and average percentage change were 1.25 +/- 1.51 and 44.1% respectively. CONCLUSION: Majority of the patients with exposed bone got healed socket with evidance of granulation tissue and healing gingiva in about one week. CRP levels at the completion of treatment of AO with honey dressing showed a significant decrease from the pre treatment values indicating fast recovery. Microbiological examination showed presence of normal commensal flora at AO sites like Streptococcus, Staphyloccocus and Enterococcus. So, the role of bacteria in the genesis of AO, if any, appears unclear. PMID- 28356683 TI - A study on total intravenous anesthesia in orthognathic surgical procedures. AB - AIMS AND OBJECTIVE: To assess the use of propofol for induction and maintenance of anaesthesia among patients undergoing various combinations of orthognathic surgical procedures. MATERIALS AND METHODS: Following Preoperative evaluation, patients were given Fentanyl (2 micrograms/kg) intravenously. Induction (2 mg/kg) and maintenance (10 mg/kg/hr) of anaesthesia was achieved by Propofol infusion. Blood Pressure and heart rate were maintained at >70 or 80 mm Hg and >50 respectively and were monitored continuously. Infusion was stopped approximately 30 to 40 minutes before the end of surgery. Immediate recovery recorded and was assessed. RESULTS: The average duration of anaesthesia and surgery were found to be 4 hrs 28 min (SD= 1 hr. 35 min) and 4 hrs 3 min (SD=1 hr 38 min). None of the patients experienced pain on injection of induction agent. No significant change was observed in the mean heart rate and mean BP at different time intervals from baseline value to 30 minutes after the recovery. The average time taken to obey simple commands after stopping Propofol infusion was 42.60 +/- 9.09 min. Time taken for spontaneous eye opening, full orientation and to count backwards was 43.45 +/- 9.11, 47.85 +/- 8.18 and 50.9 +/- 9.14 respectively. Face-Hand test performed at 15 min after extubation was positive in all the patients. The mean Aldrete score at 15 min after extubation was 11.65 +/- 0.75. The mean value of unaided sitting time for at least 2 min was after 119.00 +/- 20.56 min. The average score of picture card test, time taken in "picking up matches" test, Ball bearing test, time taken to walk and to void urine were 5.80 +/- 1.47, 67.95 +/- 5.72, 9.80 +/- 2.57, 172.75 +/- 39.25 and 163.75 +/- 55.96 respectively. Ninety percent of the patients were amenable for a repeat of this anaesthetic using the same regime but 10% of them did not answer anything. Seven patients (35%) had chills post-operatively. CONCLUSION: Propofol is an excellent anaesthetic for day care procedures. PMID- 28356685 TI - Treatment modalities for surgical management of anterior palatal fistula: Comparison of various techniques, their outcomes, and the factors governing treatment plan: A retrospective study. AB - AIM: Aim of this retrospective study was to access the various surgical treatment options available for repair of Anterior palatal fistula depending upon their size and presenting age, and also to anticipate the treatment outcome. MATERIALS AND METHODS: The series include study report of forty patients with secondary anterior palatal fistula post cleft palate repair, reported in a single unit during a duration of 3 years. All the cases were managed surgically under general anesthesia. The patients were classified depending upon the location of anterior palatal fistula (APF), the quality of tissue and age of patients to chalk out a justified treatment option outlay. RESULTS: Forty cases were split for surgical correction into various options depending on their size, site, and quality of the tissue. Most of the cases were operated with a Bardach's Redo for fistula closure (n = 16) (40%) and crevicular flap technique (n = 13) (32.5%). Our overall success (satisfactory results) was 77.5% as observed in 31 out of 40 cases with individual success rates for Bardach's and crevicular being 75% and 77%, respectively. There was reduction in size of fistula in three cases (7.5%) and a remnant pinpoint hole in four cases (10%) among all the operated cases. CONCLUSION: Management of post palatoplasty fistulas of the hard palate presents a challenging situation for a clinician following the surgical correction of cleft palate. Current paper describes the diagnosis and clinical management of forty cases reporting with unilateral APF following cleft palate surgery, over 3 years. Authors have attempted to propose different treatment modalities for surgical management of unilateral APF. It was concluded in the primary review that the size of fistula was irrelevant in determining the clinical outcome. Instead, the quality and condition of the adjacent tissue appear to be the major governing factors for selecting treatment modality as well as the surgical consequences. PMID- 28356687 TI - Evaluation of two socket healing procedures with and without mesenchymal stem cells: A comparative study. AB - AIMS AND OBJECTIVES: Successful preservation of the edentulous ridge after extraction may eliminate or reduce the need for ridge augmentation procedures. It is proved that grafting of fresh extraction sockets with bone grafts promotes ridge preservation. An objective method of maintaining height and width of alveolar ridge using mesenchymal stem cells (MSCs) seeded on collagen membrane was implemented in this study. METHODOLOGY: Ten bilaterally symmetrical extraction sockets scheduled for extraction were selected for this study. Involved teeth were extracted atraumatically and the sockets were curetted. MSCs seeded on collagen membrane were placed in the extracted socket on one side. On the other side, only collagen membrane was placed inside the socket. Both the sockets were closed primarily with nonresorbable sutures. Buccolingual and mesiodistal widths of the ridges at three different levels (2 mm below cementoenamel junction [CEJ], 5 mm below CEJ, and 8 mm below CEJ) were assessed immediately after extraction and postoperatively at 3 and 6 months. RESULTS: There was statistically significant observation in maintaining the alveolar ridge width in the grafted site when compared to the nongrafted site. CONCLUSION: Socket healing procedure using MSCs and collagen membrane was successful in maintaining width of alveolar socket. PMID- 28356686 TI - Evaluating the use of octyl-2-cyanoacrylate in unilateral cleft lip repair. AB - BACKGROUND: Facial cosmetic results are one of the most concerning issues for the parents who get their children operated for cleft lip. Moreover, the postoperative care of the surgical site, the discomfort associated with the suture removal, and additional visit for suture removal are other reasons which encourages one to use any new technologies that may replace the need for suture placement. In this study, we used octyl-2-cyanoacrylate, a tissue adhesive which offers a viable alternative to traditional techniques without compromising optimal wound closure. OBJECTIVE: To perform a comprehensive comparison of the outcomes from the use of Dermabond in patients undergoing primary repair of congenital cleft lip +/- palate anomalies. MATERIALS AND METHODS: Twenty patients, in the age group of 3-18 months were treated surgically for unilateral cleft lip deformity using Millard rotation-advancement flap. Pre- and post operative photographs of the patients were taken at 1 week, 2 week, 1 month, 6 months, and 1 year postoperatively and were evaluated using Vancouver scar scale which was given by Sullivan in 1990. Paired t-test was used for statistical analysis. RESULTS: Increased vascularity (hyperemia) was seen in the 1st and 2nd week in 35% and 30% patients, respectively which gradually reduced to normal in subsequent follow-ups. The scar was flat in 85% of patients in 1st week, and the number decreased to 10% at the end of 1 year. No wound dehiscence was found in any patients. Statistical analysis showed that among all the follow-ups, only the difference between the first and second follow-ups. Comparison of the results of 1 week with all other follow-ups yielded no significant results. CONCLUSION: Octyl-2-cyanoacrylate can be used for cleft lip closure effectively. The procedure is relatively painless and quick. Added to this are benefits of protection from wound infection since the material is bacteriostatic. PMID- 28356688 TI - Comparing hemodynamic and glycemic response to local anesthesia with epinephrine and without epinephrine in patients undergoing tooth extractions. AB - INTRODUCTION: Lignocaine with epinephrine as local anesthetic (LA) provides hemostasis and decreases the risk of systemic toxicity. The purpose of the present study was to investigate and compare the response of lignocaine with and without epinephrine to evaluate hemodynamic and metabolic response in normotensive and type II controlled diabetic patients. MATERIAL AND METHODS: A total of 50 patients (25 healthy and 25 controlled type II diabetics) undergoing multiple tooth extractions (age group of 20-80 years) were included in this prospective, randomised, clinical study. On their first visit, the patients were given 2% lignocaine HCl with 1:200,000 epinephrine, and 2% lignocaine HCl was given on the second visit, to carry out tooth extractions. Blood pressure (BP), pulse rate, oxygen saturation, and blood glucose estimations were done at definite intervals (before, immediately after, and 20 min after the administration of LA) on both the visits. RESULTS: The increase in blood glucose concentration following the administration of 2% lignocaine HCl with 1:200,000 epinephrine was statistically significant (P < 0.05) in controlled diabetic patients. Statistically significant variability in diastolic BP (DBP) was also noted in controlled diabetic patients. Both systolic BP and DBPs were statistically significantly elevated after the administration of 2% lignocaine HCl. CONCLUSION: 2% lignocaine HCl with 1:200,000 epinephrine in type II diabetics and 2% lignocaine HCl should be used with caution in normotensive as well as type II controlled diabetic patients. PMID- 28356689 TI - An epidemiological survey in hospital setup in Lucknow district: A cross sectional study. AB - INTRODUCTION: Oral cancer is the sixth most common form of cancer reported globally which includes lip, tongue, mouth, and throat. Developing countries face several challenges to identify and remove potential risk factors. Chewing tobacco/pan masala is considered to be the most potential risk factor for oral precancerous lesions and oral cancer. OBJECTIVE: To study the clinical epidemiological profile of oral cancer cases and potential risk factor associated with it. MATERIALS AND METHODS: This is cross-sectional study which includes all major tertiary hospital in Lucknow district. Five hundred and eight cases of oral cancer reported in all major tertiary hospitals in Lucknow district during 2013 2016. STUDY VARIABLE: Clinicoepidemiological characteristics of oral cancer cases. STATISTICAL ANALYSIS: percentages, proportions. RESULTS: Out of 508 cases, majority of the subjects included in the study belonged to 18-75 years age group. Reported cases of oral cancer in males were higher as compared to females. Most of the subjects belonged to lower middle and upper lower socioeconomic group. It was found that 199 (39.2%) subjects consumed smokeless tobacco. Buccal mucosa was the common site of oral cancer being present in 50.4% of the subjects. Histopathologically, 256 cases of buccal mucosa, 17 cases of lip, 33 cases of alveolar region, 16 cases of mandible region, 156 cases of tongue region, 7 cases of gingival buccal sulcus region, and 23 cases of palate were diagnosed as oral squamous cell carcinoma. CONCLUSION: In the present study, the most affected site was buccal mucosa (50.4%), tongue (30.7%), and other diagnosis was <10%. PMID- 28356692 TI - Ameloblastic fibroma or fibrosarcoma: A dilemma of oral surgeon. AB - Ameloblastic fibroma (AF) is an uncommon true mixed odontogenic tumor, with a relative frequency between 1.5% and 4.5% of all odontogenic tumors. It may behave either as a true neoplasm or as a hamartomatous proliferation of odontogenic epithelium of the enamel organ and odontogenic mesenchyme of the primitive dental pulp. Frequently diagnosed between the first and second decades of life with 75% of cases was diagnosed before the age of 20 and present with a well-defined unilocular or multilocular radiolucencies. A conservative approach, enucleation with curettage, and long-term follow-up are absolutely necessary for any recurrence or change to fibrosarcoma. We report a case of AF in a 10-year-old male patient who presented with a chief complaint of swelling in the right mandibular posterior region. Enucleation and curettage were done under general anesthesia, followed by immunohistochemical markers (Ki-67, Mib-1) to assess the sarcomatous changes and aggressiveness of the tumor. PMID- 28356691 TI - Preoperative evaluation of cervical lymph nodes for metastasis in patients with oral squamous cell carcinoma: A comparative study of efficacy of palpation, ultrasonography and computed tomography. AB - INTRODUCTION: Oral cancer is a major health threat in a country like India, where patients frequently present with advanced disease with regional dissemination to cervical lymph nodes. The management and prognosis depend on the status of cervical lymph nodes. Thus, it becomes imperative to diagnose and evaluate them preoperatively. AIM: This study aims to compare the efficacy of palpation, ultrasonography (USG) and computed tomography (CT) in the preoperative evaluation of cervical lymph node for metastasis in patients with oral squamous cell carcinoma. SETTINGS: Department of Oral and Maxillofacial Surgery, SCB Dental College and Hospital, Cuttack, Odisha, India. METHODOLOGY: A total of thirty patients of either sex of age group 20-70 years, diagnosed with oral cancer were randomly selected for the study and subjected to palpation, USG and computer tomography followed by histopathology for confirmation. The results were evaluate statistically by sensitivity, specificity, positive predictive value, and negative predictive value and accuracy. RESULTS: For level IA palpation, USG and CT were equally sensitive (100%) and specific (100%). Although palpation, USG and CT were equally sensitive (80%) for level IB, the specificity of palpation (70%) =28 mmHg not responding to medical treatment were retrospectively analyzed. All patients had poor visual acuity and underwent Alahmady ring implantation. The ring was designed from fenestrated silicon tube used in lacrimal surgeries and was implanted subsclerally after passing it through the anterior chamber. Patients were followed up for at least 24 months. Success in this study was defined based on IOP >=8 mmHg and <21 mmHg, with not more than 1 glaucoma drug, and improvement of patient symptoms and signs with maximum use of beta blocker as antiglaucoma drug. RESULTS: A total of 15 eyes of 15 patients (9 males [60%] and 6 females [40%]) were analyzed in this study. The mean IOP before surgery was 38.6 mmHg (standard deviation [SD]: 6.98) and it was 14.05 mmHg (SD =7.57) after surgery. The follow-up range was 24-36 months. Success of silicon drainage device was defined as an IOP <21 mmHg on the last follow-up visit. Medications included only beta-blockers and topical steroids for those who were without severe complications or for those who were not in a condition to undergo a further glaucoma surgery. CONCLUSION: Alahmady ring implantation proves to be a good surgical option for neovascular glaucoma; however, a longer follow-up period is recommended. PMID- 28356710 TI - Switching to preservative-free latanoprost: impact on tolerability and patient satisfaction. AB - Patient satisfaction with glaucoma treatment has been poorly studied to date. Because glaucoma is a chronic condition in which the therapeutic response is dependent on adherence to treatment, patient acceptability is an important factor in achieving satisfactory outcomes. This multicenter, international (Belgium, the Netherlands, and Spain), epidemiological convenience sample survey among patients commencing treatment with preservative-free latanoprost collected data on patient satisfaction with particular regard to tolerability. A total of 1,541 patients were recruited who were predominantly elderly (74% were over 60 years of age) and female (61%). Most of the patients had previously received preserved topical glaucoma medication (69%), 6.7% had previously received preservative-free medication, whereas 24% had not previously been treated for glaucoma. The great majority of patients (>95%) were satisfied with the preservative-free latanoprost treatment. Among the patients who had previously received preserved medication, 73% of patients found preservative-free latanoprost to be better tolerated and 89% found it at least as easy to use as their prior treatment. Patient satisfaction (determined by a 0-100 mm visual analog scale) was improved by 47% on a switch from preserved treatment to preservative-free latanoprost. Intraocular pressure was similar in patients who had previously received preserved (18.3 mmHg), preservative-free (17.8 mmHg) glaucoma medication or who were naive to treatment (20.3 mmHg). Preservative-free latanoprost provided effective reduction of intraocular pressure with better tolerability and patient satisfaction than preserved glaucoma medication. This tolerability profile can be expected to improve adherence to treatment in glaucoma patients. PMID- 28356707 TI - Epigenetic intervention with a BET inhibitor ameliorates acute retinal ganglion cell death in mice. AB - PURPOSE: The bromo and extraterminal (BET) epigenetic "reader" family is becoming an appealing new therapeutic target for several common diseases, yet little is known of its role in retinal neurodegeneration. We explored the potential of BET inhibition in the protection of retinal ganglion cells (RGCs). METHODS: To test the therapeutic effect of JQ1, an inhibitor highly selective for the BET family of proteins, we used an acute RGC damage model induced by N-methyl-D-aspartic acid (NMDA) excitotoxicity. Adult C57BL/6 mice received an intravitreal injection of NMDA with (or without) JQ1 in one eye and vehicle control in the contralateral eye; RGC loss was assessed on retinal sections and whole mounts. Gene expression and apoptosis were analyzed by quantitative real time (RT)-PCR and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), respectively. For counting RGCs, immunostaining of the marker protein BRN3A was performed on whole mounts. RESULTS: NMDA treatment eliminated RGCs (day 7 and day 14 post injection) and diminished the expression (mRNAs) of RGC-selective genes, including Thy1, Nrn1, Sncg, and Nfl (day 3 and day 7). In contrast, co-injection with JQ1 maintained the number and gene expression of RGCs at ~2 fold of the control (NMDA only, no JQ1), and it decreased NMDA-induced TUNEL-positive cells in the RGC layer by 35%. While NMDA treatment dramatically upregulated mRNAs of inflammatory cytokines (TNFalpha, IL-1beta, MCP-1, RANTES) in retinal homogenates, co injection with JQ1 suppressed their upregulation by ~50%. CONCLUSIONS: Intravitreal injection of a BET inhibitor (JQ1) ameliorates NMDA-induced RGC death, revealing the RGC-protective potential of pharmacological blockage of the BET family. This new strategy of epigenetic intervention may be extended to other retinal degenerative conditions. PMID- 28356711 TI - Intravitreal aflibercept versus intravitreal ranibizumab for the treatment of diabetic macular edema. AB - PURPOSE: The purpose of this study was to compare the efficacy of intravitreal aflibercept and ranibizumab in the treatment of diabetic macular edema (DME) in eyes with moderate visual loss. PATIENTS AND METHODS: This study is a randomized prospective study. Seventy eyes with DME were divided into two groups (each containing 35 eyes). Eyes in group I were treated with intravitreal injection of 2 mg/0.05 mL aflibercept and eyes in group II were treated with intravitreal injection of 0.5 mg/0.1 mL ranibizumab. All the eyes had three successive injections as a loading dose (with 1 month interval), and then the patients were followed up monthly for 12 months. The outcomes of the study were visual acuity, central macular thickness (CMT), and the number of re-injections of the drug. RESULTS: Mean age of the patients in group I was 55.05+/-4.7 years and in group II was 56.64+/-5.8 years (P=0.17). The mean baseline best corrected visual acuity (BCVA) of eyes treated with aflibercept was 0.17+/-0.05 and with ranibizumab was 0.18+/-0.04 (P=0.9). BCVA was improved in both the groups at the end of the follow-up period and was found to be 0.42+/-0.28 and 0.37+/-0.23, respectively (P=0.27). The mean baseline CMT of eyes in group I was 465.29+/-33.7 um and in group II was 471.5+/-34.4 um (P=0.65). CMT decreased in both the groups to 360.8+/-85.7 um and 387.3+/-87.8 um, respectively (P=0.2). The mean number of drug re-injection was 2.62+/-0.68 and 3.03+/-0.95 in both the groups, respectively (P=0.02). CONCLUSION: Aflibercept and ranibizumab have the same efficacy in the treatment of DME in eyes with moderate visual loss but with less number of drug re-injection and less treatment burden with aflibercept (2.62+/ 0.68 versus 3.03+/-0.95). PMID- 28356709 TI - The SPARC-related modular calcium binding protein 2 (SMOC2) gene polymorphism in primary glaucoma: a case-control study. AB - Primary glaucomas are among the most common eye diseases that may potentially result in bilateral blindness. Both genetics and environmental factors are reported to be involved in the etiology of primary glaucomas. Secreted protein acidic and rich in cysteine (SPARC)-related modular calcium binding protein 2 (SMOC2) is a matricellular glycoprotein encoded by the SMOC2 gene and known to regulate the expression of extracellular matrix (ECM) proteins and matrix metalloproteinases (MMPs), which play an important role in the pathogenesis of primary glaucomas. The frequencies of alleles and genotypes of SMOC2 variants were examined in 406 Saudi subjects, including primary open angle glaucoma (POAG, n=140) and primary angle closure glaucoma (PACG, n=64) patients and 202 matched healthy controls using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Genotyping of SMOC2 polymorphism (rs13208776) revealed a significantly higher frequency of the heterozygous genotype GA (P<0.01) and a lower frequency of wild type GG genotype (P=0.05) in glaucoma patients compared to the controls. Upon stratification of the patients on the basis of types of glaucoma, PACG patients had a significantly higher frequency of GA genotype as compared to the controls (P<0.01), whereas there was no significant difference between the POAG patient and control groups in frequencies of SMOC2 alleles and genotypes. Further, there was no significant difference in frequency distribution of alleles and genotypes between male and female patients. This study indicates that the GA genotype of SMOC2 (G>A) polymorphism is significantly associated with PACG and may be a risk factor. However, further large-scale studies in the Saudi population as well as in other ethnic populations are needed to confirm this association. PMID- 28356712 TI - A protocol for topographic-guided corneal repair utilizing the US Food and Drug Administration-approved Wavelight Contoura. AB - PURPOSE: To demonstrate how Wavelight Contoura can be used to repair corneas damaged by trauma and prior poor surgical outcomes. METHODS: Four representative eyes are presented that show different scenarios in which highly irregular corneas can be corrected with Wavelight Contoura using a protocol (named the San Diego Protocol) designed to use the information in Contoura processing. Both laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) were used. RESULTS: Highly aberrant corneas with large amounts of warpage can be corrected safely with the Wavelight Contoura system. The San Diego Protocol requires individual analysis of each case with decisions based on the level of warpage and the level of epithelial hyperplastic compensation. The need for a second refractive power equalization procedure should be planned for. CONCLUSION: Contoura measured refraction can be integrally used as part of the San Diego Protocol to safely repair highly warped corneas. The refractive outcomes show dramatic improvement in vision, best-corrected visual acuity (BCVA), refraction, and topographic uniformity. PMID- 28356715 TI - Clinical potential of SLAMF7 antibodies - focus on elotuzumab in multiple myeloma. AB - Elotuzumab is one of the first monoclonal antibodies to be approved for the treatment of multiple myeloma. It is a humanized immunoglobulin G kappa (IgGkappa) antibody that targets signaling lymphocytic activation molecule family member 7 (SLAMF7), a surface marker that is highly expressed on normal and malignant plasma cells. This review summarizes the preclinical and clinical data that led to the approval of elotuzumab, along with a discussion on the ongoing and future clinical investigations. PMID- 28356714 TI - Delafloxacin: design, development and potential place in therapy. AB - Delafloxacin (DLX) is a new fluoroquinolone pending approval, which has shown a good in vitro and in vivo activity against major pathogens associated with skin and soft tissue infections and community-acquired respiratory tract infections. DLX also shows good activity against a broad spectrum of microorganisms, including those resistant to other fluoroquinolones, as methicillin-resistant Staphylococcus aureus. Its pharmacokinetic properties and excellent activity in acidic environments make DLX an alternative in the treatment of these and other infections. In this manuscript, a detailed analysis of this new fluoroquinolone is performed, from its chemical structure to its in vivo activity in recently published clinical trials. Its possible place in the current antimicrobial outlook and in other infectious models is also discussed. PMID- 28356713 TI - Artonin E induces p53-independent G1 cell cycle arrest and apoptosis through ROS mediated mitochondrial pathway and livin suppression in MCF-7 cells. AB - Artonin E is a prenylated flavonoid compound isolated from the stem bark of Artocarpus elasticus. This phytochemical has been previously reported to be drug like with full compliance to Lipinski's rule of five and good physicochemical properties when compared with 95% of orally available drugs. It has also been shown to possess unique medicinal properties that can be utilized in view of alleviating most human disease conditions. In this study, we investigated the cytotoxic mechanism of Artonin E in MCF-7 breast cancer cells, which has so far not been reported. In this context, Artonin E significantly suppressed the breast cancer cell's viability while inducing apoptosis in a dose-dependent manner. This apoptosis induction was caspase dependent, and it is mediated mainly through the intrinsic pathway with the elevation of total reactive oxygen species. Gene and protein expression studies revealed significant upregulation of cytochrome c, Bax, caspases 7 and 9, and p21 in Artonin E-treated MCF-7 cells, while MAPK and cyclin D were downregulated. Livin, a member of the inhibitors of apoptosis, whose upregulation has been noted to precede chemotherapeutic resistance and apoptosis evasion was remarkably repressed. In all, Artonin E stood high as a potential agent in the treatment of breast cancer. PMID- 28356716 TI - Synergistic protective effect of N-acetylcysteine and taurine against cisplatin induced nephrotoxicity in rats. AB - Cisplatin (cis-diaminedichloroplatinum II; CDDP) is an effective anticancer drug, but it has limitations because of its nephrotoxicity. This study investigates the protective effect of N-acetylcysteine (NAC) and taurine (TAU), both individually and in combination, against CDDP nephrotoxicity in rats. For this purpose, 48 male rats were assigned into eight groups (n=6) as follows: 1) control group, 2) NAC group, 3) TAU group, 4) NAC-TAU group, 5) CDDP group, 6) CDDP-NAC group, 7) CDDP-TAU group, and 8) CDDP-NAC-TAU group. Cisplatin was administered as a single intraperitoneal injection at a concentration of 6 mg/kg. Three days after CDDP administration, NAC (50 mg/kg) and/or TAU (50 mg/kg) were administered three times weekly for four consecutive weeks. Kidney function markers in serum, urinary glucose and protein, as well as oxidant and antioxidant parameters in renal tissue were assessed. Administration of CDDP significantly elevated urinary glucose and protein, as well as serum creatinine, urea, and uric acid. Moreover, CDDP enhanced lipid peroxidation and suppressed the major enzymatic antioxidants in the kidney tissue. Treatment with NAC or TAU protected against the alterations in the serum, urine, and renal tissue when used individually along with CDDP. Furthermore, a combined therapy of both was more effective in ameliorating CDDP induced nephrotoxicity, which points out to their synergistic effect. PMID- 28356717 TI - Nanostructured lipid carriers for incorporation of copper(II) complexes to be used against Mycobacterium tuberculosis. AB - Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis. Cessation of treatment before the recommended conclusion may lead to the emergence of multidrug-resistant strains. The aim of this study was to develop nanostructured lipid carriers (NLCs) for use in the treatment of M. tuberculosis. The NLCs comprised the following lipid phase: 2.07% polyoxyethylene 40 stearate, 2.05% caprylic/capric triglyceride, and 0.88% polyoxyl 40 hydrogenated castor oil; the following aqueous phase: 3.50% poloxamer 407 (F1-F6), and 0.50% cetyltrimethylammonium bromide (F7-F12); and incorporated the copper(II) complexes [CuCl2(INH)2].H2O (1), [Cu(NCS)2(INH)2].5H2O (2), and [Cu(NCO)2(INH)2].4H2O (3) to form compounds F11.1, F11.2, and F11.3, respectively. The mean diameter of F11, F11.1, F11.2, and F11.3 ranged from 111.27+/-21.86 to 134.25+/-22.72 nm, 90.27+/-12.97 to 116.46+/-9.17 nm, 112.4+/ 10.22 to 149.3+/-15.82 nm, and 78.65+/-6.00 to 122.00+/-8.70 nm, respectively. The polydispersity index values for the NLCs ranged from 0.13+/-0.01 to 0.30+/ 0.09. The NLCs showed significant changes in zeta potential, except for F11.2, with F11, F11.1, F11.2, and F11.3 ranging from 18.87+/-4.04 to 23.25+/-1.13 mV, 17.03+/-1.77 to 21.42+/-1.87 mV, 20.51+/-1.88 to 22.60+/-3.44 mV, and 17.80+/ 1.96 to 25.25+/-7.78 mV, respectively. Atomic force microscopy confirmed the formation of nanoscale spherical particle dispersions by the NLCs. Differential scanning calorimetry determined the melting points of the constituents of the NLCs. The in vitro activity of copper(II) complex-loaded NLCs against M. tuberculosis H37Rv showed an improvement in the anti-TB activity of 55.4, 27.1, and 41.1 times the activity for complexes 1, 2, and 3, respectively. An in vivo acute toxicity study of complex-loaded NLCs demonstrated their reduced toxicity. The results suggest that NLCs may be a powerful tool to optimize the activity of copper(II) complexes against M. tuberculosis. PMID- 28356719 TI - Synergistic effects of antimicrobial peptide DP7 combined with antibiotics against multidrug-resistant bacteria. AB - Antibiotic-resistant bacteria present a great threat to public health. In this study, the synergistic effects of antimicrobial peptides (AMPs) and antibiotics on several multidrug-resistant bacterial strains were studied, and their synergistic effects on azithromycin (AZT)-resistance genes were analyzed to determine the relationships between antimicrobial resistance and these synergistic effects. A checkerboard method was used to evaluate the synergistic effects of AMPs (DP7 and CLS001) and several antibiotics (gentamicin, vancomycin [VAN], AZT, and amoxicillin) on clinical bacterial strains (Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, and Escherichia coli). The AZT-resistance genes (ermA, ermB, ermC, mefA, and msrA) were identified in the resistant strains using quantitative polymerase chain reaction. For all the clinical isolates tested that were resistant to different antibiotics, DP7 had high antimicrobial activity (<=32 mg/L). When DP7 was combined with VAN or AZT, the effect was most frequently synergistic. When we studied the resistance genes of the AZT-resistant isolates, the synergistic effect of DP7-AZT occurred most frequently in highly resistant strains or strains carrying more than two AZT resistance genes. A transmission electron microscopic analysis of the S. aureus strain synergistically affected by DP7-AZT showed no noteworthy morphological changes, suggesting that a molecular-level mechanism plays an important role in the synergistic action of DP7-AZT. AMP DP7 plus the antibiotic AZT or VAN is more effective, especially against highly antibiotic-resistant strains. PMID- 28356720 TI - mHealth intervention to support asthma self-management in adolescents: the ADAPT study. AB - PURPOSE: Poor medication adherence in adolescents with asthma results in poorly controlled disease and increased morbidity. The aim of the ADolescent Adherence Patient Tool (ADAPT) study is to develop an mHealth intervention to support self management and to evaluate the effectiveness in improving medication adherence and asthma control. INTERVENTION: The ADAPT intervention consists of an interactive smartphone application (app) connected to a desktop application for health care providers, in this study, the community pharmacist. The app contains several functions to improve adherence as follows: 1) a questionnaire function to rate asthma symptoms and monitor these over time; 2) short movie clips with medication and disease information; 3) a medication reminder; 4) a chat function with peers; and 5) a chat function with the pharmacist. The pharmacist receives data from the patient's app through the desktop application, which enables the pharmacist to send information and feedback to the patient. STUDY DESIGN: The ADAPT intervention is tested in a community pharmacy-based cluster randomized controlled trial in the Netherlands, aiming to include 352 adolescents with asthma. The main outcome is adherence, measured by patient's self-report and refill adherence calculated from pharmacy dispensing records. In addition, asthma control, illness perceptions, medication beliefs, and asthma-related quality of life are measured. CONCLUSION: This study will provide in-depth knowledge on the effectiveness of an mHealth intervention to support asthma self-management in adolescents. These insights will also be useful for adolescents with other chronic diseases. PMID- 28356718 TI - Sodium-glucose cotransporter 2 inhibitors combined with dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes: a review of current clinical evidence and rationale. AB - Type 2 diabetes mellitus (T2DM) is a progressive and multifactorial cardiometabolic disorder. Almost half of adults with diabetes fail to achieve their recommended glucose control target. This has prompted some clinicians to advocate the use of more intensive initial therapy, including the use of combination therapy to target multiple physiologic defects in diabetes with the goal of achieving and sustaining glucose control. Numerous options exist for combining the various classes of glucose-lowering agents in the treatment of T2DM. This report reviews the mechanism, rationale, and evidence from clinical trials for combining two of the newer drug classes, namely, dipeptidyl peptidase 4 inhibitors and sodium-glucose cotransporter 2 inhibitors, and considers the possible role of such dual therapy in the management of T2DM. PMID- 28356721 TI - The influence of wearing schemes and supportive telephone calls on adherence in accelerometry measurement: results of a randomized controlled trial. AB - BACKGROUND: Physical activity (PA) can be assessed by accelerometer monitors. However, a high adherence to wearing this device is essential to obtain valid data. In this study, the influence of different wearing schemes and additional supportive phone calls (SPCs) on adherence was examined. METHODS: A randomized study with four groups was conducted in the context of a health examination program among participants aged 40-75 years without a history of cardiovascular diseases. Participants were recruited in different settings (general medical practices, job center, and health insurance). The participants were asked to wear an accelerometer for 7 consecutive days according to the wearing scheme "day and night" or "day only" and received or did not receive SPCs. Full adherence was defined as a total wearing time of 98 hours (between 8 am and 10 pm during 7 days). A generalized linear model was used to calculate the difference between the maximum possible and the observed adherence. RESULTS: Adherence could be assessed for 249 participants (mean age: 56.40 years; standard deviation [SD] 9.83, 40% males). The mean wearing time was 84.04 hours (SD 20.75). Participants with the wearing scheme day and night were significantly more adherent than participants with the wearing scheme day only (incidence rate ratio [IRR] 0.63; P=0.005). SPCs had no additional effect on adherence (IRR 0.80; P=0.168). CONCLUSION: To assess PA, the wearing scheme day and night provides the best possible adherence in this group of participants. Further studies are necessary to examine adherence and the effects of additional SPCs in other samples or settings. PMID- 28356722 TI - From therapeutic patient education principles to educative attitude: the perceptions of health care professionals - a pragmatic approach for defining competencies and resources. AB - Educative attitude is an essential, if implicit, aspect of training to acquire competency in therapeutic patient education (TPE). With multiple (or nonexistent) definitions in the literature, however, the concept needs clarification. The primary aim of this study was to analyze the representations and transformations experienced by health care professionals in the course of TPE training in order to characterize educative attitude. We conducted an exploratory qualitative study using several narrative research-based tools with participants of two TPE continuing education courses. We then performed an inductive thematic analysis. Thirty-three people participated in the study; the majority were women (n=29), nurses (n=17) working in a hospital setting (n=28). Seven categories of statements were identified: time-related ("the right moment, how much time it takes"), the benefits of TPE (to health care professionals' personal well-being), emotions and feelings (quality of exchanges, sharing), the professional nature of TPE (educational competencies required), the holistic, interdisciplinary approach (complexity of the person and value of teamwork), the educational nature of the care relationship (education an integral part of care) and the ethical dimension (introspection essential). The first three components appear fairly innovative, at least in formulation. The study's originality rests primarily in its choice of participants - highly motivated novices who expressed themselves in a completely nontheoretical way. Health models see attitude as critical for adopting a behavior. Best TPE practices should encourage personal work on this, opening professionals to the social, experiential and emotional aspects of managing chronic illness. PMID- 28356724 TI - Evaluation of the association between subconjunctival orbital fat prolapse and thyroid-associated orbitopathy. PMID- 28356723 TI - Treatment patterns in Medicaid patients with schizophrenia initiated on a first- or second-generation long-acting injectable versus oral antipsychotic. AB - BACKGROUND: Poor antipsychotic (AP) adherence is a key issue in patients with schizophrenia. First-generation antipsychotic (FGA) and second-generation antipsychotic (SGA) long-acting injectable therapies (LAI) may improve adherence compared to oral antipsychotics (OAP). The objective of the study was to compare treatment adherence and persistence in Medicaid patients with schizophrenia initiated on first-generation long-acting injectable therapies (FGA-LAI) or second-generation long-acting injectable therapies (SGA-LAI) versus OAP. METHODS: Adults with schizophrenia initiated on FGA-LAI, SGA-LAI, or OAP on or after January 2010 were identified using a six-state Medicaid database (January 2009 March 2015). Outcomes were assessed during the 12 months following treatment initiation. Index medication adherence was assessed using the proportion of days covered >=80%, while persistence was assessed as no gap of >=30, >=60, or >=90 days between days of supply. Outcomes were compared between FGA/SGA-LAI and OAP cohorts using chi-squared tests and adjusted odds ratios (OR). RESULTS: During follow-up, AP polypharmacy was more common in FGA-LAI patients (N=1,089; 36%; P=0.029) and less common in SGA-LAI patients (N=2,209; 27%; P<0.001) versus OAP patients (N=20,478; 33%). After adjustment, SGA-LAI patients had 24% higher odds of adherence at 12 months (OR: 1.24; P<0.001), in contrast to FGA-LAI patients who had 48% lower odds of adherence (OR: 0.52; P<0.001) relative to OAP patients. SGA-LAI patients were more likely to be persistent (no gap >=60 days) at 12 months than OAP patients (37% vs 30%; P<0.001), but not FGA-LAI patients (31% vs 30%; P=0.776). In comparison to OAP patients, SGA-LAI patients had 46% higher adjusted odds of persistence (no gap >=60 days; OR: 1.46; P<0.001), while FGA-LAI patients were not significantly different (OR: 0.95; P=0.501). CONCLUSION: Medicaid patients initiated on SGA-LAI demonstrated better treatment adherence and persistence compared to OAP patients, while those initiated on FGA-LAI did not show significant improvement in adherence or persistence and had more AP polypharmacy relative to OAP patients. These findings suggest the potential value of SGA-LAI in the treatment of schizophrenia. PMID- 28356725 TI - Is diabetes mellitus associated with clinical outcomes in aging males treated with transurethral resection of prostate for bladder outlet obstruction: implications from Taiwan Nationwide Population-Based Cohort Study. AB - PURPOSE: We assessed the lower urinary tract symptoms (LUTSs) and clinical outcomes between diabetes mellitus (DM) patients and non-diabetic (non-DM) patients receiving transurethral resection of prostate (TUR-P). METHODS: This analysis was a retrospective cohort study using 13 years (2000-2012) of claims data from Taiwan's National Health Insurance Research Database (NHIRD). A total of 4,887 patients who had persistent LUTSs and underwent TUR-P for prostate enlargement (benign prostate enlargement [BPE]) were enrolled and divided into two groups: DM and non-DM groups. The patients' characteristics, postoperative clinical outcomes, and the medication records after TUR-P were compared. Chi square test was used for categorical variables and independent samples t-test for continuous variables. Multivariable logistic regression analysis was used to compare the risk of postoperative outcomes. Finally, we estimated the medication free survival rate after TUR-P using Kaplan-Meier method and compared it between study groups using log-rank test. RESULTS: DM group patients had a higher prevalence of comorbidities. Postoperatively, the DM group had lower rates of urinary tract infection (UTI; odds ratio [OR], 0.78; P=0.009) and higher rates of urinary retention requiring catheterization (OR, 1.35; P=0.01) within 1 month after TUR-P. A higher proportion of patients with DM took anti-muscarinics (OR, 1.23; P=0.032) within the first 3 months and alpha-blockers (OR, 1.18; P=0.049) during 3-12 months after receiving TUR-P. Overall, the DM group patients had a worse postoperative medication-free survival compared to that of non-DM group patients (95% confidence interval [95% CI], 1.14; P=0.005). CONCLUSION: DM patients require higher rates of continuing medication after TUR-P, especially anti-muscarinics in 3 months postoperatively and alpha-blocker after 3 months postoperatively. DM patients also had higher incidence of urine retention after surgery. DM patients had relatively poor treatment outcomes compared to DM-free patients. PMID- 28356726 TI - Searching for the relationship between the parameters of metabolic syndrome and the rs17782313 (T>C) polymorphism of the MC4R gene in postmenopausal women. AB - Metabolic syndrome (MS) is widespread in the human population, and its incidence is continuously increasing, generating serious health problems. The purpose of this study was to find the relationship between the parameters of MS and the melanocortin type 4 receptor (MC4R) gene polymorphism in postmenopausal women. The study involved 344 healthy Polish women, who had their last menstrual cycle 1 year ago or earlier. The study included blood analysis, survey, and body measurements. The mean age was 58.5+/-6.6 years. An increased body mass index was observed in 65.7% and abdominal obesity in 80.3% of the study population. MS was diagnosed in 40.7% of all participants, including 39.3% of women with the T/T genotype and 44.7% of those with the C/X genotype (chi2 test; P>0.05). A logistic regression model showed that the probability of MS was higher in patients with the C/X genotype (odds ratio =1.25) (chi2 test; P>0.05). The study concluded that MS is a very common condition among postmenopausal women. The C/X genotype of the MC4R gene seems to predispose postmenopausal women to developing some MS symptoms. PMID- 28356727 TI - Effects of dual tasks and dual-task training on postural stability: a systematic review and meta-analysis. AB - The use of dual-task training paradigm to enhance postural stability in patients with balance impairments is an emerging area of interest. The differential effects of dual tasks and dual-task training on postural stability still remain unclear. A systematic review and meta-analysis were conducted to analyze the effects of dual task and training application on static and dynamic postural stability among various population groups. Systematic identification of published literature was performed adhering to Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines, from inception until June 2016, on the online databases Scopus, PEDro, MEDLINE, EMBASE, and SportDiscus. Experimental studies analyzing the effects of dual task and dual-task training on postural stability were extracted, critically appraised using PEDro scale, and then summarized according to modified PEDro level of evidence. Of 1,284 records, 42 studies involving 1,480 participants met the review's inclusion criteria. Of the studies evaluating the effects of dual-task training on postural stability, 87.5% of the studies reported significant enhancements, whereas 30% of the studies evaluating acute effects of dual tasks on posture reported significant enhancements, 50% reported significant decrements, and 20% reported no effects. Meta-analysis of the pooled studies revealed moderate but significant enhancements of dual-task training in elderly participants (95% CI: 1.16-2.10) and in patients suffering from chronic stroke (-0.22 to 0.86). The adverse effects of complexity of dual tasks on postural stability were also revealed among patients with multiple sclerosis (-0.74 to 0.05). The review also discusses the significance of verbalization in a dual-task setting for increasing cognitive motor interference. Clinical implications are discussed with respect to practical applications in rehabilitation settings. PMID- 28356728 TI - Impact of a COPD comprehensive case management program on hospital length of stay and readmission rates. AB - BACKGROUND: COPD accounts for the highest rate of hospital admissions among major chronic diseases. COPD hospitalizations are associated with impaired quality of life, high health care utilization, and poor prognosis and result in an economic and a social burden that is both substantial and increasing. AIM: The aim of this study is to determine the efficacy of a comprehensive case management program (CCMP) in reducing length of stay (LOS) and risk of hospital admissions and readmissions in patients with COPD. MATERIALS AND METHODOLOGY: We retrospectively compared outcomes across five large hospitals in Vancouver, BC, Canada, following the implementation of a systems approach to the management of COPD patients who were identified in the hospital and followed up in the community for 90 days. We compared numbers, rates, and intervals of readmission and LOS during 2 years of active program delivery compared to 1 year prior to program implementation. RESULTS: A total of 1,564 patients with a clinical diagnosis of COPD were identified from 2,719 hospital admissions during the 3 years of study. The disease management program reduced COPD-related hospitalizations by 30% and hospitalizations for all causes by 13.6%. Similarly, the rate of readmission for all causes showed a significant decline, with hazard ratios (HRs) of 0.55 (year 1) and 0.51 (year 2) of intervention (P<0.001). In addition, patients' mean LOS (days) for COPD-related admissions declined significantly from 10.8 to 6.8 (P<0.05). CONCLUSION: A comprehensive disease management program for COPD patients, including education, case management, and follow-up, was associated with significant reduction in hospital admissions and LOS. PMID- 28356729 TI - Measures of bronchodilator response of FEV1, FVC and SVC in a Swedish general population sample aged 50-64 years, the SCAPIS Pilot Study. AB - BACKGROUND: Data are lacking from general population studies on how to define changes in lung function after bronchodilation. This study aimed to analyze different measures of bronchodilator response of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and slow vital capacity (SVC). MATERIALS AND METHODS: Data were derived from the Swedish Cardiopulmonary Bioimage Study (SCAPIS) Pilot study. This analysis comprised 1,050 participants aged 50-64 years from the general population. Participants were investigated using a questionnaire, and FEV1, FVC and SVC were recorded before and 15 minutes after inhalation of 400 ug of salbutamol. A bronchodilator response was defined as the relative change from baseline value expressed as the difference in units of percent predicted normal. Predictors of bronchodilator responses were assessed using multiple linear regression models. Airway obstruction was defined as FEV1/FVC ratio below lower limit of normal (LLN) before bronchodilation, and COPD was defined as an FEV1/FVC ratio below LLN after bronchodilation. Physician diagnosed asthma was defined as an affirmative answer to "Have you ever had asthma diagnosed by a physician?". Asymptomatic never-smokers were defined as those not reporting physician-diagnosed asthma, physician-diagnosed COPD or emphysema, current wheeze or chronic bronchitis and being a lifelong never smoker. RESULTS: Among all subjects, the greatest bronchodilator responses (FEV1, FVC and SVC) were found in subjects with asthma or COPD. The upper 95th percentile of bronchodilator responses in asymptomatic never-smokers was 8.7% for FEV1, 4.2% for FVC and 5.0% for SVC. The bronchodilator responses were similar between men and women. In a multiple linear regression model comprising all asymptomatic never-smokers, the bronchodilator response of FEV1 was significantly associated with airway obstruction and height. CONCLUSION: When the bronchodilator response in asymptomatic never-smokers is reported as the difference in units of predicted normal, significant reversibility of FEV1, FVC and SVC to bronchodilators is ~9%, 4% and 5%, respectively. PMID- 28356730 TI - Plasminogen activator inhibitor-1 is elevated in patients with COPD independent of metabolic and cardiovascular function. AB - INTRODUCTION: Plasminogen activator inhibitor-1 (PAI-1), a major inhibitor of fibrinolysis, is associated with thrombosis, obesity, insulin resistance, dyslipidemia, and premature aging, which all are coexisting conditions of chronic obstructive pulmonary disease (COPD). The role of PAI-1 in COPD with respect to metabolic and cardiovascular functions is unclear. METHODS: In this study, which was nested within a prospective cohort study, the serum levels of PAI-1 were cross-sectionally measured in 74 stable COPD patients (Global Initiative for Chronic Obstructive Lung Disease [GOLD] Stages I-IV) and 18 controls without lung disease. In addition, triglycerides, high-density lipoprotein cholesterol, fasting plasma glucose, waist circumference, blood pressure, smoking status, high sensitive C-reactive protein (hs-CRP), adiponectin, ankle-brachial index, N terminal pro-B-type natriuretic peptide, and history of comorbidities were also determined. RESULTS: The serum levels of PAI-1 were significantly higher in COPD patients than in controls, independent of a broad spectrum of possible confounders including metabolic and cardiovascular dysfunction. A multivariate regression analysis revealed triglyceride and hs-CRP levels to be the best predictors of PAI-1 within COPD. GOLD Stages II and III remained independently associated with higher PAI-1 levels in a final regression analysis. CONCLUSION: The data from the present study showed that the serum levels of PAI-1 are higher in patients with COPD and that moderate-to-severe airflow limitation, hypertriglyceridemia, and systemic inflammation are independent predictors of an elevated PAI-1 level. PAI-1 may be a potential biomarker candidate for COPD specific and extra-pulmonary manifestations. PMID- 28356731 TI - Co-delivery nanoparticles with characteristics of intracellular precision release drugs for overcoming multidrug resistance. AB - Combination chemotherapy in clinical practice has been generally accepted as a feasible strategy for overcoming multidrug resistance (MDR). Here, we designed and successfully prepared a co-delivery system named S-D1@L-D2 NPs, where denoted some smaller nanoparticles (NPs) carrying a drug doxorubicin (DOX) were loaded into a larger NP containing another drug (vincristine [VCR]) via water-in-oil-in water double-emulsion solvent diffusion-evaporation method. Chitosan-alginate nanoparticles carrying DOX (CS-ALG-DOX NPs) with a smaller diameter of about 20 nm formed S-D1 NPs; vitamin E D-alpha-tocopheryl polyethylene glycol 1000 succinate-modified poly(lactic-co-glycolic acid) nanoparticles carrying VCR (TPGS PLGA-VCR NPs) with a larger diameter of about 200 nm constituted L-D2 NPs. Some CS-ALG-DOX NPs loaded into TPGS-PLGA-VCR NPs formed CS-ALG-DOX@TPGS-PLGA-VCR NPs. Under the acidic environment of cytosol and endosome or lysosome in MDR cell, CS ALG-DOX@TPGS-PLGA-VCR NPs released VCR and CS-ALG-DOX NPs. VCR could arrest cell cycles at metaphase by inhibiting microtubule polymerization in the cytoplasm. After CS-ALG-DOX NPs escaped from endosome, they entered the nucleus through the nuclear pore and released DOX in the intra-nuclear alkaline environment, which interacted with DNA to stop the replication of MDR cells. These results indicated that S-D1@L-D2 NPs was a co-delivery system of intracellular precision release loaded drugs with pH-sensitive characteristics. S-D1@L-D2 NPs could obviously enhance the in vitro cytotoxicity and the in vivo anticancer efficiency of co delivery drugs, while reducing their adverse effects. Overall, S-D1@L-D2 NPs can be considered an innovative platform for the co-delivery drugs of clinical combination chemotherapy for the treatment of MDR tumor. PMID- 28356732 TI - Angiopep-2-conjugated poly(ethylene glycol)-co- poly(epsilon-caprolactone) polymersomes for dual-targeting drug delivery to glioma in rats. AB - The blood-brain barrier is a formidable obstacle for glioma chemotherapy due to its compact structure and drug efflux ability. In this study, a dual-targeting drug delivery system involving Angiopep-2-conjugated biodegradable polymersomes loaded with doxorubicin (Ang-PS-DOX) was developed to exploit transport by the low-density lipoprotein receptor-related protein 1 (LRP1), which is overexpressed in both blood-brain barrier and glioma cells. The polymersomes (PS) were prepared using a thin-film hydration method. The PS were loaded with doxorubicin using the pH gradient method (Ang-PS-DOX). The resulting PS were uniformly spherical, with diameters of ~135 nm and with ~159.9 Angiopep-2 molecules on the surface of each PS. The drug-loading capacity and the encapsulation efficiency for doxorubicin were 7.94%+/-0.17% and 95.0%+/-1.6%, respectively. Permeability tests demonstrated that the proton diffusion coefficient across the PS membrane was far slower than that across the liposome membrane, and the common logarithm value was linearly dependent on the dioxane content in the external phase. Compared with PS DOX, Ang-PS-DOX demonstrated significantly higher cellular uptake and stronger cytotoxicity in C6 cells. In vivo pharmacokinetics and brain distribution experiments revealed that Ang-PS-DOX achieved a more extensive distribution and more abundant accumulation in glioma cells than PS-DOX. Moreover, the survival time of glioma-bearing rats treated with Ang-PS-DOX was significantly prolonged compared with those treated with PS-DOX or a solution of free doxorubicin. These results suggested that Ang-PS-DOX can target glioma cells and enhance chemotherapeutic efficacy. PMID- 28356734 TI - Therapeutic effects of proteoliposomes on X-linked chronic granulomatous disease: proof of concept using macrophages differentiated from patient-specific induced pluripotent stem cells. AB - Chronic granulomatous disease (CGD) is a rare inherited immunodeficiency due to dysfunction of the phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex leading to severe and recurrent infections in early childhood. The main genetic form is the X-linked CGD leading to the absence of cytochrome b558 composed of NOX2 and p22 phox , the membrane partners of the NADPH oxidase complex. The first cause of death of CGD patients is pulmonary infections. Recombinant proteoliposome-based therapy is an emerging and innovative approach for membrane protein delivery, which could be an alternative local, targeted treatment to fight lung infections in CGD patients. We developed an enzyme therapy using recombinant NOX2/p22 phox liposomes to supply the NADPH oxidase activity in X0-linked CGD (X0-CGD) macrophages. Using an optimized prokaryotic cell-free protein synthesis system, a recombinant cytochrome b558 containing functional hemes was produced and directly inserted into the lipid bilayer of specific liposomes. The size of the NOX2/p22 phox liposomes was estimated to be around 700 nm. These proteoliposomes were able to generate reactive oxygen species (ROS) in an activated reconstituted cell-free NADPH oxidase activation assay in the presence of recombinant p47 phox , p67 phox and Rac, the cytosolic components of the NADPH oxidase complex. Furthermore, using flow cytometry and fluorescence microscopy, we demonstrated that cytochrome b558 was successfully delivered to the plasma membrane of X0-CGD-induced pluripotent stem cell (iPSC) derived macrophages. In addition, NADPH oxidase activity was restored in X0-CGD iPSC-derived macrophages treated with NOX2/p22 phox liposomes for 8 h without any toxicity. In conclusion, we confirmed that proteoliposomes provide a new promising technology for the delivery of functional proteins to the membrane of targeted cells. This efficient liposomal enzyme replacement therapy will be useful for future treatment of pulmonary infections in CGD patients refractory to conventional anti-infectious treatments. PMID- 28356733 TI - A novel selective VPAC2 agonist peptide-conjugated chitosan modified selenium nanoparticles with enhanced anti-type 2 diabetes synergy effects. AB - A novel neuroendocrine peptide, pituitary adenylate cyclase activating peptide (PACAP), was found to have an important role in carbohydrate or lipid metabolism and was susceptible to dipeptidyl peptidase IV degradation. It can not only mediate glucose-dependent insulin secretion and lower blood glucose by activating VPAC2 receptor, but also raise blood glucose by promoting glucagon production by VPAC1 receptor activation. Therefore, its therapeutic application is restricted by the exceedingly short-acting half-life and the stimulatory function for glycogenolysis. Herein, we generated novel peptide-conjugated selenium nanoparticles (SeNPs; named as SCD), comprising a 32-amino acid PACAP-derived peptide DBAYL that selectively binds to VPAC2, and chitosan-modified SeNPs (SeNPs CTS, SC) as slow-release carrier. The circulating half-life of SCD is 14.12 h in mice, which is 168.4-and 7.1-fold longer than wild PACAP (~5 min) and DBAYL (~1.98 h), respectively. SCD (10 nmol/L) significantly promotes INS-1 cell proliferation, glucose uptake, insulin secretion, insulin receptor expression and also obviously reduces intracellular reactive oxygen species levels in H2O2 injured INS-1 cells. Furthermore, the biological effects of SCD are stronger than Exendin-4 (a clinically approved drug through its insulinotropic effect), DBAYL, SeNPs or SC. A single injection of SCD (20 nmol/kg) into db/db mice with type 2 diabetes leads to enhanced insulin secretion and sustained hypoglycemic effect, and the effectiveness and duration of SCD in enhancing insulin secretion and reducing blood glucose levels are much stronger than Exendin-4, SeNPs or SC. In db/db mice, chronic administration of SCD by daily injection for 12 weeks markedly improved glucose and lipid profiles, insulin sensitivity and the structures of pancreatic and adipose tissue. The results indicate that SC can play a role as a carrier for the slow release of bioactive peptides and SCD could be a hopeful therapeutic against type 2 diabetes through the synergy effects of DBAYL and SeNPs. PMID- 28356735 TI - Inhibition of gap junction intercellular communication is involved in silica nanoparticles-induced H9c2 cardiomyocytes apoptosis via the mitochondrial pathway. AB - Gap junction intercellular communication (GJIC) between cardiomyocytes is essential for synchronous heart contraction and relies on connexin-containing channels. Connexin 43 (Cx43) is a major component involved in GJIC in heart tissue, and its abnormal expression is closely associated with various cardiac diseases. Silica nanoparticles (SNPs) are known to induce cardiovascular toxicity. However, the mechanisms through which GJIC plays a role in cardiomyocytes apoptosis induced by SNPs remain unknown. The aim of the present study is to determine whether SNPs-decreased GJIC promotes apoptosis in rat cardiomyocytes cell line (H9c2 cells) via the mitochondrial pathway using CCK-8 Kit, scrape-loading dye transfer technique, Annexin V/PI double-staining assays, and Western blot analysis. The results showed that SNPs elicited cytotoxicity in H9c2 cells in a time- and concentration-dependent manner. SNPs also reduced GJIC in H9c2 cells in a concentration-dependent manner through downregulation of Cx43 and upregulation of P-Cx43. Inhibition of gap junctions by gap junction blocker carbenoxolone disodium resulted in decreased survival and increased apoptosis, whereas enhancement of the gap junctions by retinoic acid led to enhanced survival but decreased apoptosis. Furthermore, SNPs-induced apoptosis through the disrupted functional gap junction was correlated with abnormal expressions of the proteins involved in the mitochondrial pathway-related apoptosis such as Bcl 2/Bax, cytochrome C, Caspase-9, and Caspase-3. Taken together, our results provide the first evidence that SNPs-decreased GJIC promotes apoptosis in cardiomyocytes via the mitochondrial pathway. In addition, downregulation of GJIC by SNPs in cardiomyocytes is mediated through downregulation of Cx43 and upregulation of P-Cx43. These results suggest that in rat cardiomyocytes cell line, GJIC plays a protective role in SNPs-induced apoptosis and that GJIC may be one of the targets for SNPs-induced biological effects. PMID- 28356736 TI - Nanoliposomal artemisinin for the treatment of murine visceral leishmaniasis. AB - Visceral leishmaniasis (VL) is a fatal, vector-borne disease caused by the intracellular protozoa of the genus Leishmania. Most of the therapeutics for VL are toxic, expensive, or ineffective. Sesquiterpenes are a new class of drugs with proven antimicrobial and antiviral activities. Artemisinin is a sesquiterpene lactone with potent antileishmanial activity, but with limited access to infected cells, being a highly lipophilic molecule. Association of artemisinin with liposome is a desirable strategy to circumvent the problem of poor accessibility, thereby improving its efficacy, as demonstrated in a murine model of experimental VL. Nanoliposomal artemisinin (NLA) was prepared by thin film hydration method and optimized using Box-Behnken design with a mean particle diameter of 83+/-16 nm, polydispersity index of 0.2+/-0.03, zeta potential of 27.4+/-5.7 mV, and drug loading of 33.2%+/-2.1%. Morphological study of these nanoliposomes by microscopy showed a smooth and spherical surface. The mechanism of release of artemisinin from the liposomes followed the Higuchi model in vitro. NLA was free from concomitant signs of toxicity, both ex vivo in murine macrophages and in vivo in healthy BALB/c mice. NLA significantly denigrated the intracellular infection of Leishmania donovani amastigotes and the number of infected macrophages ex vivo with an IC50 of 6.0+/-1.4 ug/mL and 5.1+/-0.9 ug/mL, respectively. Following treatment in a murine model of VL, NLA demonstrated superior efficacy compared to artemisinin with a percentage inhibition of 82.4%+/ 3.8% in the liver and 77.6%+/-5.5% in spleen at the highest dose of 20 mg/kg body weight with modulation of cell-mediated immunity towards protective Th1 type. This study is the first report on the use of a liposomal drug delivery system for artemisinin as a promising alternative intervention against VL. PMID- 28356737 TI - Synthesis, characterization, and antimicrobial properties of novel double layer nanocomposite electrospun fibers for wound dressing applications. AB - Herein, novel hybrid nanomaterials were developed for wound dressing applications with antimicrobial properties. Electrospinning was used to fabricate a double layer nanocomposite nanofibrous mat consisting of an upper layer of poly(vinyl alcohol) and chitosan loaded with silver nanoparticles (AgNPs) and a lower layer of polyethylene oxide (PEO) or polyvinylpyrrolidone (PVP) nanofibers loaded with chlorhexidine (as an antiseptic). The top layer containing AgNPs, whose purpose was to protect the wound site against environmental germ invasion, was prepared by reducing silver nitrate to its nanoparticulate form through interaction with chitosan. The lower layer, which would be in direct contact with the injured site, contained the antibiotic drug needed to avoid wound infections which would otherwise interfere with the healing process. Initially, the upper layer was electrospun, followed sequentially by electrospinning the second layer, creating a bilayer nanofibrous mat. The morphology of the nanofibrous mats was studied by scanning electron microscopy and transmission electron microscopy, showing successful nanofiber production. X-ray diffraction confirmed the reduction of silver nitrate to AgNPs. Fourier transform infrared spectroscopy showed a successful incorporation of the material used in the produced nanofibrous mats. Thermal studies carried out by thermogravimetric analysis indicated that the PVP drug-loaded layer had the highest thermal stability in comparison to other fabricated nanofibrous mats. Antimicrobial activities of the as-synthesized nanofibrous mats against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans were determined using disk diffusion method. The results indicated that the PEO-drug-loaded mat had the highest antibacterial activity, warranting further attention for numerous wound-healing applications. PMID- 28356738 TI - pH-sensitive micelles self-assembled from polymer brush (PAE-g-cholesterol)-b-PEG b-(PAE-g-cholesterol) for anticancer drug delivery and controlled release. AB - A novel amphiphilic pH-sensitive triblock polymer brush (poly(beta-amino esters) g-cholesterol)-b-poly(ethylene glycol)-b-(poly(beta-amino esters)-g-cholesterol) ((PAE-g-Chol)-b-PEG-b-(PAE-g-Chol)) was designed and synthesized successfully through a three-step reaction, and their self-assembled polymeric micelles were used as hydrophobic anticancer drug delivery carriers to realize effectively controlled release. The critical micelle concentrations were 6.8 MUg/mL, 12.6 MUg/mL, 17.4 MUg/mL, and 26.6 MUg/mL at pH values of 7.4, 6.5, 6.0, and 5.0, respectively. The trend of critical micelle concentrations indicated that the polymer had high stability that could prolong the circulation time in the body. The hydrodynamic diameter and zeta potential of the polymeric micelles were influenced significantly by the pH values. As pH decreased from 7.4 to 5.0, the particle size and zeta potential increased from 205.4 nm to 285.7 nm and from +12.7 mV to +47.0 mV, respectively. The pKb of the polymer was confirmed to be approximately 6.5 by the acid-base titration method. The results showed that the polymer had sharp pH-sensitivity because of the protonation of the amino groups, resulting in transformation of the PAE segment from hydrophobic to hydrophilic. Doxorubicin-loaded polymeric micelles were prepared with a high loading content (20%) and entrapment efficiency (60%) using the dialysis method. The in vitro results demonstrated that drug release rate and cumulative release were obviously dependent on pH values. Furthermore, the drug release mechanism was also controlled by the pH values. The polymer had barely any cytotoxicity, whereas the doxorubicin-loaded system showed high toxicity for HepG2 cells as free drugs. All the results proved that the pH-sensitive triblock polymer brush and its self assembled micelle might be a potential delivery carrier for anticancer drugs with sustained release. PMID- 28356739 TI - A pH-responsive prodrug delivery system of 10-HCPT for controlled release and tumor targeting. AB - We synthesized a pH-responsive conjugate of 10-hydroxycamptothecin thiosemicarbazide-linear polyethylene glycol 2000 (PEG2000). The conjugate was confirmed by matrix-assisted laser desorption time of flight mass spectrometry, 1H NMR, and 13C NMR. The water solubility of the prodrug was increased by over 3,000 times; much longer body circulation time, higher tumor-targeting ability, and reduced toxicity were observed, compared with commercial 10-HCPT injection. The linker contains a pH-sensitive hydrazone bond, which breaks under low pH conditions in the tumor microenvironment. The conjugates showed good stability in phosphate-buffered saline (pH 7.4) and rat plasma. This amphiphilic conjugate could self-assemble into nanosized micelles of 80-100 nm. Cytotoxicity assay results indicate significantly higher efficacy of the conjugate (IC50 [half maximal inhibitory concentration] =0.117 uM on SW180 cells) than 10-HCPT solution (IC50 =0.241 uM on SW480 cells). Cellular uptake analysis suggested its rapid internalization and nuclear transport. Pharmacokinetic analysis of the conjugates demonstrated that the conjugate circulated for a longer time in the blood circulation system (T2/1 =10.516+/-1.158 h) than did 10-HCPT solution (T2/1 =1.859+/-1.385 h), and that it also enhanced the targeting and mean residence time (MRT0-inf =39.873+/-4.549 h) in the tumor site, compared with 10-HCPT (MRT0 inf =9.247+/-1.026 h). Finally, the conjugate demonstrated an increased tumor growth inhibition effect (TIR =82.66%+/-7.175%) in vivo and lower side effects than 10-HCPT (TIR =63.85%+/-5.233%). This prodrug holds great promise in improving therapeutic efficacy and overcoming multidrug resistance. PMID- 28356741 TI - Laser thermal ablation of multidrug-resistant bacteria using functionalized gold nanoparticles. AB - The issue of multidrug resistance (MDR) has become an increasing threat to public health. One alternative strategy against MDR bacteria would be to construct therapeutic vectors capable of physically damaging these microorganisms. Gold nanoparticles hold great promise for the development of such therapeutic agents, since the nanoparticles exhibit impressive properties, of which the most important is the ability to convert light into heat. This property has scientific significance since is exploited to develop nano-photothermal vectors to destroy bacteria at a molecular level. The present paper summarizes the latest advancements in the field of nanotargeted laser hyperthermia of MDR bacteria mediated by gold nanoparticles. PMID- 28356742 TI - Some children with autism have latent social skills that can be tested. AB - BACKGROUND: The idea of latent social skills in autism emerged as a possible interpretation of the rapid (but temporary) improvement of autistic subjects in oxytocin studies. We tested a hypothesis that a normal response to Item No 59 "Secure Base" from the third version of the Autism Diagnostic Interview - Revised (ADIR-59) could indicate the presence of latent social skills in autism. METHODS: We examined 110 autistic children (88 boys and 22 girls) with a mean age of 6.0+/ 2.5 years (range: 2.2-14.8 years) using the Autism Diagnostic Observation Schedule (ADOS) - Generic. A diagnosis of mental retardation was established in 68 autistic children (62%). RESULTS: The difference in the ADOS social domain between children aged <=5 years on one side and children older than 5 years on the other side was significant in subjects with normal responses to ADIR-59 (9.60 vs 6.47; P=0.031) but not in those with abnormal responses to ADIR-59 (10.62 vs 9.63; P=0.537). In a predictive model, lower ADOS social domain scores were predicted by older age (P=0.001), lower scores on the ADIR-59 (P=0.01), and the absence of mental retardation (P=0.049). CONCLUSION: The results support the hypothesis that the normal response to item ADIR-59 "Secure Base" indicates the presence of latent social skills in autism that might foretell further social growth in older autistic subjects. PMID- 28356740 TI - PEG-b-(PELG-g-PLL) nanoparticles as TNF-alpha nanocarriers: potential cerebral ischemia/reperfusion injury therapeutic applications. AB - Brain ischemia/reperfusion (I/R) injury (BI/RI) is a leading cause of death and disability worldwide. However, the outcome of pharmacotherapy for BI/RI remains unsatisfactory. Innovative approaches for enhancing drug sensitivity and recovering neuronal activity in BI/RI treatment are urgently needed. The purpose of this study was to evaluate the protective effects of tumor necrosis factor (TNF)-alpha-loaded poly(ethylene glycol)-b-(poly(ethylenediamine L-glutamate)-g poly(L-lysine)) (TNF-alpha/PEG-b-(PELG-g-PLL)) nanoparticles on BI/RI. The particle size of PEG-b-(PELG-g-PLL) and the loading and release rates of TNF alpha were determined. The nanoparticle cytotoxicity was evaluated in vitro using rat cortical neurons. Sprague Dawley rats were preconditioned with free TNF-alpha or TNF-alpha/PEG-b-(PELG-g-PLL) polyplexes and then subjected to 2 hours ischemia and 22 hours reperfusion. Brain edema was assessed using the brain edema ratio, and the antioxidative activity was assessed by measuring the superoxide dismutase (SOD) activity and the malondialdehyde (MDA) content in the brain tissue. We further estimated the inflammatory activity and apoptosis level by determining the levels of interleukin-4 (IL-4), IL-6, IL-8, IL-10, and nitric oxide (NO), as well as the expression of glial fibrillary acidic protein (GFAP), intercellular adhesion molecule-1 (ICAM-1), and cysteine aspartase-3 (caspase-3), in the brain tissue. We provide evidence that TNF-alpha preconditioning attenuated the oxidative stress injury, the inflammatory activity, and the apoptosis level in I/R-induced cerebral injury, while the application of block copolymer PEG-b-(PELG g-PLL) as a potential TNF-alpha nanocarrier with sustained release significantly enhanced the bioavailability of TNF-alpha. We propose that the block copolymer PEG-b-(PELG-g-PLL) may function as a potent nanocarrier for augmenting BI/RI pharmacotherapy, with unprecedented clinical benefits. Further studies are needed to better clarify the underlying mechanisms. PMID- 28356743 TI - Dynamic balance in children with attention-deficit hyperactivity disorder and its relationship with cognitive functions and cerebellum. AB - BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is linked to the presence of motor deficiencies, including balance deficits. The cerebellum serves as an integrative structure for balance control and is also involved in cognition, including timing and anticipatory regulation. Cerebellar development may be delayed in children and adolescents with ADHD, and inconsistent reaction time is commonly seen in ADHD. We hypothesized that dynamic balance deficits would be present in children with ADHD and they would correlate with attention and cerebellar functions. METHODS: Sixty-two children with ADHD and no other neurological conditions and 62 typically developing (TD) children were examined with five trials of the Phyaction Balance Board, an electronic balancing platform. Cerebellar clinical symptoms were evaluated using an international ataxia rating scale. Conners' Continuous Performance Test was used to evaluate patterns of reaction. RESULTS: Children with ADHD had poorer performance on balancing tasks, compared to TD children (P<0.001). They exhibited significantly greater sway amplitudes than TD children (P<0.001) in all of the five balancing trials. The effect size of the difference between the groups increased continuously from the first to the last trial. Balance score in both groups was related to the variation in the reaction time, including reaction time standard error (r =0.25; P=0.0409, respectively, r =0.31; P=0.0131) and Variability of Standard Error (r =0.28; P=0.0252, respectively, r =0.41; P<0.001). The burden of cerebellar symptoms was strongly related to balance performance in both groups (r =0.50, P<0.001; r =0.49, P=0.001). CONCLUSION: This study showed that ADHD may be associated with poor dynamic balance control. Furthermore, we showed that maintaining balance correlates with neuropsychological measures of consistency of reaction time. Balance deficits and impaired cognitive functioning could reflect a common cerebellar dysfunction in ADHD children. PMID- 28356744 TI - The influence of depression, level of functioning in everyday life, and illness acceptance on quality of life in patients with Parkinson's disease: a preliminary study. AB - BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, and its incidence will increase as the global population ages. Due to the multitude of symptoms, this disease clearly has a significant impact on decreasing quality of life for those with PD. We aimed to evaluate the effect of selected variables on quality of life in people with idiopathic PD treated pharmacologically. MATERIALS AND METHODS: This study was conducted among 50 patients with PD aged 47-85 years. The diagnostic survey method was applied to collect data with the use of the authors' questionnaire and standardized questionnaires, including, Parkinson's Disease Questionnaire (PDQ), Beck Depression Inventory, Instrumental Activities of Daily Living Scale, and Acceptance of Illness Scale. The results were statistically analyzed. RESULTS: Analysis of the study material showed that people who were more self-reliant were characterized by lower intensity of depressive symptoms (rho=-0.567, P=0), were more likely to accept their illness (rho=0.611, P=0), and assessed quality of life better in each of the studied domains of the PDQ. Illness acceptance correlated with the occurrence of depressive symptoms (rho=-0.567, P=0) and significantly affected quality of life. CONCLUSION: Factors such as depression, disease acceptance, and functional capacity have a significant impact on the subjective assessment of quality of life in patients with PD. Evaluation of these factors should be taken into account in the therapeutic process, to minimize their negative impact on quality of life in patients with PD. PMID- 28356745 TI - Illness denial questionnaire for patients and caregivers. AB - PURPOSE: Interest in assessing denial is still present, despite the criticisms concerning its definition and measurement. We tried to develop a questionnaire (Illness Denial Questionnaire, IDQ) assessing patients' and caregivers' denial in relation to their illness/disturbance. PATIENTS AND METHODS: After a preliminary study, a final version of 24 dichotomous items (true/false) was selected. We hypothesized a theoretical model with three dimensions: denial of negative emotions, resistance to change, and conscious avoidance, the first two composing the actual Denial and the last representing an independent component of the illness denial behavior. The IDQ was administered to 400 subjects (219 patients and 181 caregivers) together with the Anxiety-Depression Questionnaire - Reduced form (AD-R), in order to assess concurrent validity. Confirmatory factor analysis (CFA), internal consistency indices (Cronbach's alpha and McDonald's omega), and test-retest analysis were performed. RESULTS: CFA and internal consistency indices (Cronbach's alpha: 0.87-0.96) indicated a clear and meaningful three factor structure of IDQ, for both patients and caregivers. Further analyses showed good concurrent validity, with Denial and its subscale negatively associated with anxiety and depression and avoidance positively associated with anxiety and depression. The IDQ also showed a good stability (r from 0.71 to 0.87). CONCLUSION: The IDQ demonstrated good psychometric properties. Denial of negative emotions and resistance to change seem to contribute to a real expression of denial, and conscious avoidance seems to constitute a further step in the process of cognitive-affective elaboration of the illness. PMID- 28356746 TI - An estimate of the cost of administering intravenous biological agents in Spanish day hospitals. AB - OBJECTIVE: To estimate the unit costs of administering intravenous (IV) biological agents in day hospitals (DHs) in the Spanish National Health System. PATIENTS AND METHODS: Data were obtained from 188 patients with rheumatoid arthritis, collected from nine DHs, receiving one of the following IV therapies: infliximab (n=48), rituximab (n=38), abatacept (n=41), or tocilizumab (n=61). The fieldwork was carried out between March 2013 and March 2014. The following three groups of costs were considered: 1) structural costs, 2) material costs, and 3) staff costs. Staff costs were considered a fixed cost and were estimated according to the DH theoretical level of activity, which includes, as well as personal care of each patient, the DH general activities (complete imputation method, CIM). In addition, an alternative calculation was performed, in which the staff costs were considered a variable cost imputed according to the time spent on direct care (partial imputation method, PIM). All costs were expressed in euros for the reference year 2014. RESULTS: The average total cost was ?146.12 per infusion (standard deviation [SD] +/-87.11; CIM) and ?29.70 per infusion (SD +/-11.42; PIM). The structure-related costs per infusion varied between ?2.23 and ?62.35 per patient and DH; the cost of consumables oscillated between ?3.48 and ?20.34 per patient and DH. In terms of the care process, the average difference between the shortest and the longest time taken by different hospitals to administer an IV biological therapy was 113 minutes. CONCLUSION: The average total cost of infusion was less than that normally used in models of economic evaluation coming from secondary sources. This cost is even less when the staff costs are imputed according to the PIM. A high degree of variability was observed between different DHs in the cost of the consumables, in the structure-related costs, and in those of the care process. PMID- 28356747 TI - Second-line afatinib administration in an elderly patient with squamous cell carcinoma. AB - INTRODUCTION: The majority of cases of lung cancer are still diagnosed at a late stage. At this stage, palliative therapeutic options including nonspecific cytotoxic drugs, targeted therapy, or immunotherapy can be utilized. In 2016, immunotherapy was approved in Europe for squamous cell carcinoma and adenocarcinoma. Moreover, afatinib was also approved as second-line therapy for squamous cell carcinoma. CASE REPORT: This article presents a case of a 76-year old male with squamous cell carcinoma who received nab-paclitaxel as first-line therapy, and his treatment was switched to the tyrosine kinase inhibitor afatinib (40 mg) after disease progression with left lung atelectasis. After receiving afatinib for only 28 days, the atelectasis resolved. No adverse effects were observed from the afatinib therapy. DISCUSSION: In this case, afatinib 40 mg proved to be an effective alternative treatment for an elderly patient. Treatment choice should be based on the performance status of the patient, cost effectiveness, and drug treatment guidelines. PMID- 28356749 TI - Adrenalectomy does not improve survival rates of patients with solitary adrenal metastasis from non-small cell lung cancer. AB - BACKGROUND AND PURPOSE: Several case reports and studies have suggested that there is an increased survival rate for patients who undergo resection of solitary adrenal metastasis from non-small cell lung cancer (NSCLC). This study aimed to investigate whether NSCLC patients with solitary adrenal metastasis could gain a higher survival rate after adrenalectomy (ADX) when compared with those patients undergoing nonsurgical treatment, and to investigate the potential prognostic factors. PATIENTS AND METHODS: A total of 1,302 NSCLC inpatients' data from 2001 to 2015 were retrospectively reviewed to identify those with solitary adrenal metastasis. Overall survival for those who underwent both primary resection and ADX was compared to those patients with conservative treatment using the log-rank test. Potential prognostic variables were evaluated with univariate and multivariate analyses including clinical, therapeutic, pathologic, primary and metastatic data. RESULTS: A total of 22 NSCLC patients with solitary adrenal metastasis were identified, with an overall median survival of 11 months (95% confidence interval: 9.4-12.6 months) and a 1-year survival rate of 51.4% (95% confidence interval: 29.6%-73.2%). All of the patients had died by 30 months. There was no significant survival difference between patients who underwent primary and metastasis resection (n=10) and those treated conservatively (n=12), (P=0.209). Univariate analysis identified Eastern Cooperative Oncology Group performance status (ECOG PS) as the significant predictor of survival (P=0.024). Age (<65 vs >=65 years), sex, pathologic type, mediastinal lymph node stage (N2 vs N0/N1), primary tumor size (<5 vs >=5 cm), primary location (central vs peripheral), metastatic tumor size (<5 vs >=5 cm), metastasis laterality, synchronous metastasis, and metastatic field radiotherapy were not identified as potential prognostic factors in relation to survival rate. In multivariate analysis, a stepwise selection procedure allowed both ECOG PS (P=0.007, relative risk =3.57) and pathologic type (P=0.069) to enter the Cox's hazard function. CONCLUSION: Primary and metastatic radical resection may not prolong the survival of NSCLC patients with solitary adrenal metastasis. ECOG PS and pathologic type might be the prognostic factors for these patients. PMID- 28356748 TI - Effects of sharing information on drug administration errors in pediatric wards: a pre-post intervention study. AB - BACKGROUND AND PURPOSE: Drug administration errors are more likely to reach the patient than other medication errors. The main aim of this study was to determine whether the sharing of information on drug administration errors among health care providers would reduce such problems. PATIENTS AND METHODS: This study involved direct, undisguised observations of drug administrations in two pediatric wards of a major teaching hospital in Kuala Lumpur, Malaysia. This study consisted of two phases: Phase 1 (pre-intervention) and Phase 2 (post intervention). Data were collected by two observers over a 40-day period in both Phase 1 and Phase 2 of the study. Both observers were pharmacy graduates: Observer 1 just completed her undergraduate pharmacy degree, whereas Observer 2 was doing her one-year internship as a provisionally registered pharmacist in the hospital under study. A drug administration error was defined as a discrepancy between the drug regimen received by the patient and that intended by the prescriber and also drug administration procedures that did not follow standard hospital policies and procedures. Results from Phase 1 of the study were analyzed, presented and discussed with the ward staff before commencement of data collection in Phase 2. RESULTS: A total of 1,284 and 1,401 doses of drugs were administered in Phase 1 and Phase 2, respectively. The rate of drug administration errors reduced significantly from Phase 1 to Phase 2 (44.3% versus 28.6%, respectively; P<0.001). Logistic regression analysis showed that the adjusted odds of drug administration errors in Phase 1 of the study were almost three times that in Phase 2 (P<0.001). The most common types of errors were incorrect administration technique and incorrect drug preparation. Nasogastric and intravenous routes of drug administration contributed significantly to the rate of drug administration errors. CONCLUSION: This study showed that sharing of the types of errors that had occurred was significantly associated with a reduction in drug administration errors. PMID- 28356750 TI - Early discharge compared with ordinary discharge after percutaneous coronary intervention - a systematic review and meta-analysis of safety and cost. AB - AIM: We aimed to summarize the pooled effect of early discharge compared with ordinary discharge after percutaneous coronary intervention (PCI) on the composite endpoint of re-infarction, revascularization, stroke, death, and incidence of rehospitalization. We also aimed to compare costs for the two strategies. METHODS: The study was a systematic review and a meta-analysis of 12 randomized controlled trials including 2962 patients, followed by trial sequential analysis. An estimation of cost was considered. Follow-up time was 30 days. RESULTS: For early discharge, pooled effect for the composite endpoint was relative risk of efficacy (RRe)=0.65, 95% confidence interval (CI) (0.52-0.81). Rehospitalization had a pooled effect of RRe=1.10, 95% CI (0.88-1.38). Early discharge had an increasing risk of rehospitalization with increasing frequency of hypertension for all populations, except those with stable angina, where a decreasing risk was noted. Advancing age gave increased risk of revascularization. Early discharge had a cost reduction of 655 Euros per patient compared with ordinary discharge. CONCLUSION: The pooled effect supports the safe use of early discharge after PCI in the treatment of a heterogeneous population of patients with coronary artery disease. There was an increased risk of rehospitalization for all subpopulations, except patients with stable angina. Clinical trials with homogeneous populations of acute coronary syndrome are needed to be conclusive on this issue. PMID- 28356752 TI - Value as the key concept in the health care system: how it has influenced medical practice and clinical decision-making processes. AB - In the last 10 years, value has played a key role in the health care system. In this concept, innovations in medical practice and the increasing importance of patient centeredness have contributed to draw the attention of the medical community. Nonetheless, a large consensus on the meaning of "value" is still lacking: patients, physicians, policy makers, and other health care professionals have different ideas on which component of value may play a prominent role. Yet, shared clinical decision-making and patient empowerment have been recognized as fundamental features of the concept of value. Different paradigms of health care system embrace different meanings of value, and the absence of common and widely accepted definition does not help to identify a unique model of care in health care system. Our aim is to provide an overview of those paradigms that have considered value as a key theoretical concept and to investigate how the presence of value can influence the medical practice. This article may contribute to draw attention toward patients and propose a possible link between health care system based on "value" and new paradigms such as patient-centered system (PCS), patient empowerment, and P5 medicine, in order to create a predictive, personalized, preventive, participatory, and psycho-cognitive model to treat patients. Indeed, patient empowerment, value-based system, and P5 medicine seem to shed light on different aspects of a PCS, and this allows a better understanding of people under care. PMID- 28356751 TI - New pharmacological and technological management strategies in heart failure. AB - Heart failure is a complex clinical syndrome resulting from impairment of ventricular filling or ejection of blood associated with symptoms of dyspnea, fatigue, as well as peripheral and/or pulmonary edema. This syndrome is progressive and characterized by worsening quality of life despite escalating levels of care, affecting 5.7 million Americans with an annual cost of over >=30 billion US dollars. Treatment for this syndrome has evolved over three distinct eras: the nonpharmacological era, the pharmacological era, and the device era, with the focus shifting from symptomatic relief to decreasing morbidity and mortality. Over the past 10 years, the field has undergone a renaissance, with the development of new pharmacologic, hemodynamic monitoring, and device therapies proven to improve outcomes in patients with heart failure. This article will review several recent innovations in the management of patients with heart failure. PMID- 28356753 TI - Mental resilience, perceived immune functioning, and health. AB - BACKGROUND: Mental resilience can be seen as a trait that enables an individual to recover from stress and to face the next stressor with optimism. People with resilient traits are considered to have a better mental and physical health. However, there are limited data available assessing the relationship between resilient individuals and their perspective of their health and immune status. Therefore, this study was conducted to examine the relationship between mental resilience, perceived health, and perceived immune status. METHODS: A total of 779 participants recruited at Utrecht University completed a questionnaire consisting of demographic characteristics, the brief resilience scale for the assessment of mental resilience, the immune function questionnaire (IFQ), and questions regarding their perceived health and immune status. RESULTS: When correcting for gender, age, height, weight, smoker status, amount of cigarettes smoked per week, alcohol consumption status, amount of drinks consumed per week, drug use, and frequency of past year drug use, mental resilience was significantly correlated with perceived health (r=0.233, p=0.0001), perceived immune functioning (r=0.124, p=0.002), and IFQ score (r=-0.185, p=0.0001). CONCLUSION: A significant, albeit modest, relationship was found between mental resilience and perceived immune functioning and health. PMID- 28356755 TI - Primary pancreatic lymphoma: two case reports and a literature review. AB - Primary pancreatic lymphoma (PPL) is an extremely rare disease, with only a few cases reported in the literature. Clinical manifestations of PPL are often nonspecific and may mimic other pancreatic diseases. Because of the limited experience of PPL, clinicopathological features, differential diagnosis, optimal therapy, and outcomes are not well defined. We described two cases diagnosed as PPL and confirmed by histological examination and immunohistochemical analysis. Case 1 was a young man with obstructive jaundice and upper abdominal malaise mimicking a pancreatic adenocarcinoma. A computed tomography (CT) scan revealed a diffuse heterogeneous mass in the head of the pancreas along with dilated bile ducts, no dilated pancreatic duct, no liver or splenic involvement, or evident retroperitoneal adenopathies. The patient underwent a pancreatico-duodenectomy, and the postoperative histopathology confirmed diffuse large B-cell non-Hodgkin lymphoma. Postoperatively, he received six courses of the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisolone). Case 2 was an older man with left flank pain. A CT confirmed a mass with irregular margins at the tail of the pancreas and the hilum of the spleen. The mass was heterogeneous, with no clear boundary between lesions, spleen, stomach, and pancreas, with nearby blood vessels wrapped around it, and multiple enlarged lymph nodes in the abdominal cavity. A CT-guided biopsy was performed. The immunohistological findings of the specimen revealed a diffuse large B-cell lymphoma. The size of the tumor was significantly reduced after four cycles of the CHOP chemotherapy regimen. These two cases were different in clinical manifestation, location, and treatment. We reviewed the literature and discussed the clinicopathological features, differential diagnosis, optimal therapy, and outcomes of this neoplasm. PMID- 28356754 TI - Identification of key pathways and genes influencing prognosis in bladder urothelial carcinoma. AB - BACKGROUND: Genomic profiling can be used to identify the predictive effect of genomic subsets for determining prognosis in bladder urothelial carcinoma (BUC) after radical cystectomy. This study aimed to investigate potential gene and pathway markers associated with prognosis in BUC. METHODS: A microarray dataset of BUC was obtained from The Cancer Genome Atlas database. Differentially expressed genes (DEGs) were identified by DESeq of the R platform. Kaplan-Meier analysis was applied for prognostic markers. Key pathways and genes were identified using bioinformatics tools, such as gene set enrichment analysis, gene ontology, the Kyoto Encyclopedia of Genes and Genomes, gene multiple association network integration algorithm (GeneMANIA), Search Tool for the Retrieval of Interacting Genes/Proteins, and Molecular Complex Detection. RESULTS: A comparative gene set enrichment analysis of tumor and adjacent normal tissues suggested BUC tumorigenesis resulted mainly from enrichment of cell cycle and DNA damage and repair-related biological processes and pathways, including TP53 and mitotic recombination. Two hundred and fifty-six genes were identified as potential prognosis-related DEGs. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that the potential prognosis-related DEGs were enriched in angiogenesis, including the cyclic adenosine monophosphate biosynthetic process, cyclic guanosine monophosphate-protein kinase G, mitogen activated protein kinase, Rap1, and phosphoinositide-3-kinase-AKT signaling pathway. Nine hub genes, TAGLN, ACTA2, MYH11, CALD1, MYLK, GEM, PRELP, TPM2, and OGN, were identified from the intersection of protein-protein interaction and GeneMANIA networks. Module analysis of protein-protein interaction and GeneMANIA networks mainly showed enrichment of the cyclic guanosine monophosphate-protein kinase G signaling pathway, angiogenesis, cell proliferation, and differentiation, which are associated with tumor angiogenesis and cancer prognosis. CONCLUSION: Genes and pathways related to cell cycle and DNA damage and repair may play a crucial role in BUC pathogenesis, whereas those pertaining to tumor angiogenesis may be key factors in influencing BUC prognosis, especially in advanced disease stages. PMID- 28356756 TI - Suppression of microRNA-629 enhances sensitivity of cervical cancer cells to 1'S 1'-acetoxychavicol acetate via regulating RSU1. AB - BACKGROUND: Cervical cancer is the fourth most frequent malignancy affecting women worldwide, but drug resistance and toxicities remain a major challenge in chemotherapy. The use of natural compounds is promising because they are less toxic and able to target multiple signaling pathways. The 1'S-1'-acetoxychavicol acetate (ACA), a natural compound isolated from wild ginger Alpinia conchigera, induced cytotoxicity on various cancer cells including cervical cancer. MicroRNAs (miRNAs) are short noncoding RNAs that regulate numerous biological processes, such as apoptosis and chemosensitivity. Past studies reported that miR-629 is upregulated in many cancers, and its expression was altered in ACA-treated cervical cancer cells. However, the role of miR-629 in regulating sensitivity toward ACA or other anticancer agents has not been reported. Hence, this study aims to investigate the role of miR-629 in regulating response toward ACA on cervical cancer cells. METHODS: The miR-629 expression following transfection with miR-629 hairpin inhibitor and hairpin inhibitor negative control was measured using quantitative real-time polymerase chain reaction (RT-qPCR). The 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to investigate sensitivity toward ACA. Apoptosis was detected using Annexin V/propidium iodide and Caspase 3/7 assays. The gene target for miR-629 was identified using miRNA target prediction programs, luciferase reporter assay and Western blots. Gene overexpression studies were performed to evaluate its role in regulating response toward ACA. RESULTS: Transfection with miR-629 hairpin inhibitor downregulated its expression in both cervical cancer cell lines. Suppression of miR-629 increased sensitivity toward ACA by reducing cell proliferation and inducing apoptosis. Luciferase reporter assay confirmed RSU1 as a direct target of miR-629. Overexpression of miR-629 decreased RSU1 protein expression, while inhibition of miR-629 increased RSU1 protein expression. Overexpression of RSU1 augmented antiproliferative and apoptosis-inducing effects of ACA. CONCLUSION: Our findings showed that combination of ACA with miR-629 and RSU1 may provide a potential strategy in treating cervical cancer. PMID- 28356757 TI - Erratum: Primary neuroendocrine breast carcinomas: a retrospective analysis and review of literature [Corrigendum]. AB - [This corrects the article on p. 397 in vol. 10, PMID: 28176908.]. PMID- 28356758 TI - Erratum: Efficacy and safety of icotinib in patients with brain metastases from lung adenocarcinoma [Corrigendum]. AB - [This corrects the article on p. 2911 in vol. 9, PMID: 27274284.]. PMID- 28356759 TI - Diagnostic and prognostic roles of IRAK1 in hepatocellular carcinoma tissues: an analysis of immunohistochemistry and RNA-sequencing data from the cancer genome atlas. AB - BACKGROUND: IRAK1 has been repoted to play an essential role in the development of multiple cancers. However, the clinical significance of IRAK1 in hepatocellular carcinoma (HCC) and the underlying molecular mechanism remain unclear. Therefore, we aimed to investigate the role of IRAK1 in the pathogenesis of HCC in this study. MATERIALS AND METHODS: HCC tissues and para-carcinoma tissues were collected for immunohistochemistry (IHC) analysis to evaluate IRAK1 expression. Data of IRAK1 expression were downloaded from the cancer genome atlas (TCGA) for analyzing the clinical significance of IRAK1. Receiver operating characteristic (ROC) curve and survival analyses were carried out to assess the diagnostic and prognostic significance of IRAK1 in IHC and TCGA data. Additionally, we investigated the alteration of IRAK1 gene in HCC from cBioPortal to generate a network of the interaction between IRAK1 and the neighboring genes. The influence of IRAK1 gene alteration on the prognosis of HCC patients was evaluated by survival analysis. RESULTS: Analysis of both IHC and TCGA data revealed a significant upregulation of IRAK1 in HCC tissues. The IHC analysis revealed there was an increasing trend in IRAK1 expression among normal liver tissues, liver cirrhosis tissues, para-carcinoma tissues and HCC tissues. The ROC curves for IHC and TCGA data demonstrated that IRAK1 exhibited a significant diagnostic value for HCC. Moreover, IRAK1 expression was observed to be associated with tumor size, metastasis and T-stage. The survival analysis indicated that the upregulation of IRAK1 predicted a worse overall survival of HCC. Additionally, data from cBioPortal confirmed that 29% of HCC tissues possessed an alteration of the IRAK1 gene. CONCLUSION: IRAK1 may act as an oncogene in the development of HCC with its overexpression in HCC. Moreover, IRAK1 might serve as a promising diagnostic and therapeutic target for HCC. PMID- 28356760 TI - The associations between five polymorphisms of vascular endothelial growth factor and renal cell carcinoma risk: an updated meta-analysis. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is a key mediator that plays an important role in angiogenesis, tumor growth, and tumor metastasis. The associations between five polymorphisms of VEGF (rs3025039, rs699947, rs10434, rs1570360, and rs2010963) and renal cell carcinoma (RCC) risk have been extensively investigated, but the currently available results are inconsistent and inconclusive. To obtain a more accurate assessment of the associations, we conducted a meta-analysis in this study. MATERIALS AND METHODS: Relevant studies were collected systemically from the following three electronic databases: MEDLINE, Web of Science, and CNKI (Chinese National Knowledge Infrastructure). Statistical analyses were performed using Review Manager 5.2 in a fixed- or random-effects model. Pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to establish the strength of associations. RESULTS: A total of eight case-control studies with 1,936 RCC cases and 2,770 controls fulfilling the inclusion criteria were selected for this meta-analysis. The pooled OR indicated that rs699947 polymorphism was significantly associated with RCC risk in all genetic models. A significant association was also found between the rs3025039 polymorphism and RCC risk in a homozygous model (TT vs CC: OR =1.38, 95% CI =1.11-1.72, P=0.004), a dominant model (CT+TT vs CC: OR =1.21, 95% CI =1.05-1.39, P=0.01), and a recessive model (TT vs CC+CT: OR =1.28, 95% CI =1.04 1.57, P=0.02). After a subgroup analysis of ethnicity in the allele contrast model of rs3025039 polymorphism, we found a significant relationship in the allele contrast model (T vs C: OR =1.21, 95% CI =1.05-1.40, P=0.007) in the Asian population. With regard to rs10434 polymorphism, significant association was observed only in a homozygous model (GG vs AA: OR =0.75, 95% CI =0.57-0.98, P=0.03). As to rs1570360 or rs2010963, we did not observe any relationship between the two polymorphisms and RCC risk in our study. CONCLUSION: Our meta analysis confirmed the fact that rs699947, rs3025039, and rs10434 polymorphisms were significantly relevant to elevated RCC risk. In the meanwhile, this study also demonstrated that the allele contrast model of rs3025039 polymorphism was likely to be associated with risk of RCC in the Asian population. PMID- 28356761 TI - The coexpression of EphB4 and EphrinB2 is associated with poor prognosis in HER2 positive breast cancer. AB - OBJECTIVE: HER2 overexpression is associated with aggressive phenotypes in breast cancer, including increased tumor proliferation, greater invasiveness, and reduced overall survival. The overall response rate to HER2-targeted therapies remains <30%. There is an urgent need for the identification of efficient markers to predict patients with a poor prognosis. This study was designed to investigate the correlation between EphB4 and EphrinB2 expression and the clinicopathological characteristics of HER2-positive breast cancer. MATERIALS AND METHODS: A total of 111 primary HER2-positive breast cancer patients were enrolled in this study (diagnosed since December 2005 to November 2010 from the Second Hospital of Dalian Medical University). The protein expression of EphB4 and EphrinB2 was examined by immunohistochemistry using paraffin-embedded tumor tissues. RESULTS: There was a significant correlation between EphB4 and EphrinB2 expression (P=0.013, r=0.255). Kaplan-Meier analysis showed that the prognosis of patients with a high expression of both EphB4 and EphrinB2 was significantly worse than the prognosis of patients with either EphB4 or EphrinB2 expression and patients with negative expression (hazard ratio [HR] =1.935, P=0.0224). However, high expression of EphB4 or EphrinB2 alone was not an independent prognostic factor to predict worse overall survival. To summarize, HER2-positive breast cancer patients with overexpression of both EphB4 and EphrinB2 were associated with the worst prognosis. CONCLUSION: High expression of EphB4 and EphrinB2 correlated with poor overall survival, which can serve as an independent prognostic indicator in primary HER2-positive breast cancer patients. PMID- 28356763 TI - The US Food and Drug Administration's drug safety recommendations and long-acting beta2-agonist dispensing pattern changes in adult asthma patients: 2003-2012. AB - BACKGROUND: Emerging safety issues associated with long-acting beta2-agonist (LABA) have led to multiple regulatory activities by the US Food and Drug Administration (FDA) since 2003, including Drug Safety Communications (DSCs) in 2010. These DSCs had three specific recommendations for the safe use of LABA products in adult asthma treatment. METHODS: We examined the initiation of LABA containing products for adult asthma treatment using an intermittent time series approach in a claims database from 2003 to 2012. We assessed the alignment of dispensing patterns with the following 2010 FDA recommendations: 1) contraindicated use of single-ingredient (SI)-LABA without an asthma controller medication (ACM); 2) a LABA should only be used when asthma is not adequately controlled on inhaled corticosteroids (ICSs) or ACM; and 3) step-down asthma therapy (e.g., discontinue LABA) when asthma control is achieved. RESULTS: There were 477,922 adults (18-64 years old) dispensed a new LABA during 2003-2012. Among LABA initiators, patients who initiated an SI-LABA and who did "not" have an ACM dispensed on the same date decreased from >9% in 2003 (the initial labeling change) to <2% post 2010 DSCs (p-value <0.0001 in the segmented regression model). The proportion of asthma patients dispensed an ICS in 6 months prior to initiating LABA treatment did not increase. The proportion of patients with longer than 4 months of continuous treatment did not decrease over the study period. CONCLUSION: Although the decrease in SI-LABA initiation is consistent with FDA's recommendations, low ICS dispensing before initiating a LABA and LABA continuation practices require further efforts to move toward the recommended safe practices. PMID- 28356762 TI - In silico-based vaccine design against Ebola virus glycoprotein. AB - Ebola virus (EBOV) is one of the lethal viruses, causing more than 24 epidemic outbreaks to date. Despite having available molecular knowledge of this virus, no definite vaccine or other remedial agents have been developed yet for the management and avoidance of EBOV infections in humans. Disclosing this, the present study described an epitope-based peptide vaccine against EBOV, using a combination of B-cell and T-cell epitope predictions, followed by molecular docking and molecular dynamics simulation approach. Here, protein sequences of all glycoproteins of EBOV were collected and examined via in silico methods to determine the most immunogenic protein. From the identified antigenic protein, the peptide region ranging from 186 to 220 and the sequence HKEGAFFLY from the positions of 154-162 were considered the most potential B-cell and T-cell epitopes, correspondingly. Moreover, this peptide (HKEGAFFLY) interacted with HLA A*32:15 with the highest binding energy and stability, and also a good conservancy of 83.85% with maximum population coverage. The results imply that the designed epitopes could manifest vigorous enduring defensive immunity against EBOV. PMID- 28356765 TI - Erratum: Reduced butyrylcholinesterase activity is an early indicator of trauma induced acute systemic inflammatory response [Corrigendum]. AB - [This corrects the article on p. 221 in vol. 9, PMID: 27920568.]. PMID- 28356764 TI - Study of nasal exhaled nitric oxide levels in diagnosis of allergic rhinitis in subjects with and without asthma. AB - BACKGROUND: The measure of fractional exhaled nitric oxide (FENO) in the airways is a useful tool to guide the diagnosis and titration of inhaled corticosteroids in patients with asthma. However, its role in diagnosis of allergic rhinitis (AR), especially in subjects with asthma, is not well established. OBJECTIVE: To study the cutoff of nasal FENO in the diagnosis of subjects with AR and AR-asthma compared to age-matched subjects without AR or asthma and its correlations with the clinical and functional characteristics. METHODS: The study was cross sectional and descriptive. Subjects were grouped into control subjects, AR, and AR-asthma, based on the inclusion criteria. Exhaled NO (nasal FENO, bronchial FENO, and alveolar concentration of NO) was measured by multiple flow electro luminescence device. RESULTS: Six hundred twenty-eight subjects were included: 217 control subjects (children: n=98, 10+/-4 years; adults: n=119, 50+/-16 years), 168 subjects with AR (children: n=54, 10+/-3 years; adults: n=114, 49+/ 15 years), and 243 subjects with AR-asthma (children: n=115, 10+/-3 years; adults: n=128, 51+/-14 years). Nasal peak inspiratory flow and peak expiratory flow were lower in subjects with AR and AR-asthma than in control subjects (P<0.01 and P<0.01; and P<0.05 and P<0.01, respectively). Nasal FENO levels were significantly higher in subjects with AR and AR-asthma than in control subjects (1614+/-629 and 1686+/-614 ppb vs 582+/-161 ppb; P<0.001 and P<0.001, respectively). In subjects with AR non-asthma, the cutoffs of nasal FENO for those diagnosed with AR were 775 ppb in children, 799 ppb in adults, and 799 in the general population (sensitivity: 92.68%, 92.63%, and 92.65%, respectively; specificity: 91.67%, 95.00%, and 96.87%, respectively). In subjects with AR asthma, the cutoffs of nasal FENO were higher, especially in asthma children (1458 ppb; sensitivity: 72.97% and specificity: 95.83%). CONCLUSION: Nasal FENO measurement is a useful technique for the diagnosis of AR in subjects with and without asthma. PMID- 28356767 TI - Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel group study. AB - BACKGROUND/OBJECTIVE: Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. METHODS: This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID) in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0=not present to 10=unbearable) recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. RESULTS: A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. CONCLUSION: Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of this preliminary result in a larger, adequately powered study is needed. PMID- 28356766 TI - Post-thoracotomy pain syndrome and sensory disturbances following thoracotomy at 6- and 12-month follow-ups. AB - BACKGROUND: Persistent pain affects a large proportion of patients after thoracotomy and is associated with sensory disturbances. The objective of this prospective study was to investigate the time course of pain and sensory disturbances over a 12-month period. METHODS: Patients scheduled for thoracotomy were recruited. Data were collected on the day before surgery, including baseline characteristics and the presence of any preoperative pain. At 6- and 12-month follow-ups, data on pain were collected using the Brief Pain Inventory-Short Form, and perceived sensory disturbances around the thoracotomy scar were recorded from a self-exploration test. RESULTS: At 12 months after surgery, 97 patients had complete data including baseline and 6-and 12-month measurements. Almost half of the patients reported post-thoracotomy pain at the follow-ups. However, 20% of the patients not reporting post-thoracotomy pain at 6 months did report it at 12 months. Between 40% and 60% of patients experienced some kind of sensory disturbance at 6 months. A small decline in some kind of sensory disturbance was reported by 20%-50% of patients at 12 months. CONCLUSION: A proportion of patients experienced either resolved or delayed onset of pain. Sensory changes were strongly associated with post-thoracotomy pain syndrome, but were also present in a large proportion of patients without it. PMID- 28356768 TI - Drug-screening and genomic analyses of HER2-positive breast cancer cell lines reveal predictors for treatment response. AB - BACKGROUND: Approximately 15%-20% of all diagnosed breast cancers are characterized by amplified and overexpressed HER2 (= ErbB2). These breast cancers are aggressive and have a poor prognosis. Although improvements in treatment have been achieved after the introduction of trastuzumab and lapatinib, many patients do not benefit from these drugs. Therefore, in-depth understanding of the mechanisms behind the treatment responses is essential to find alternative therapeutic strategies. MATERIALS AND METHODS: Thirteen HER2 positive breast cancer cell lines were screened with 22 commercially available compounds, mainly targeting proteins in the ErbB2-signaling pathway, and molecular mechanisms related to treatment sensitivity were sought. Cell viability was measured, and treatment responses between the cell lines were compared. To search for response predictors and genomic and transcriptomic profiling, PIK3CA mutations and PTEN status were explored and molecular features associated with drug sensitivity sought. RESULTS: The cell lines were divided into three groups according to the growth-retarding effect induced by trastuzumab and lapatinib. Interestingly, two cell lines insensitive to trastuzumab (KPL4 and SUM190PT) showed sensitivity to an Akt1/2 kinase inhibitor. These cell lines had mutation in PIK3CA and loss of PTEN, suggesting an activated and druggable Akt-signaling pathway. Expression levels of five genes (CDC42, MAPK8, PLCG1, PTK6, and PAK6) were suggested as predictors for the Akt1/2 kinase-inhibitor response. CONCLUSION: Targeting the Akt-signaling pathway shows promise in cell lines that do not respond to trastuzumab. In addition, our results indicate that several molecular features determine the growth-retarding effects induced by the drugs, suggesting that parameters other than HER2 amplification/expression should be included as markers for therapy decisions. PMID- 28356769 TI - Validation of Health Behavior and Stages of Change Questionnaire. AB - BACKGROUND: The transtheoretical model (TTM) has been widely used to promote healthy behaviors in different groups. However, a questionnaire has not yet been developed to evaluate the health behaviors that medical practitioners often consider in individuals with cancer or at a high risk of developing cancer. PURPOSE: The aim of this study was to construct and validate the Health Behavior and Stages of Change Questionnaire (HBSCQ), which is based on the TTM and health recommendations related to risk and factors that protect against cancer. METHODS: Content validity was conducted in two phases (qualitative and quantitative). Item difficulty index, item discrimination index, and discrimination coefficient were obtained based on the classical test theory. Finally, Cronbach's alpha was used. RESULTS: Measure of concordance showed scores considered adequate and excellent. The item discrimination index obtained a rating of "excellent" and suggested the preservation of all items. The discrimination coefficient scores are >0.74. The global internal consistency of the HBSCQ was 0.384. HBSCQ specification between groups of internal consistency for the sample of men was 0.712 and that for the sample of women was 0.378. CONCLUSION/IMPLICATIONS FOR PRACTICE: The HBSCQ represents a proposal for a fast, simple, and innovative screening test, which aims to identify persons who may benefit from interventions to promote health behaviors delimited to the stage of change. PMID- 28356770 TI - Breast cancer in patients with Li-Fraumeni syndrome - a case-series study and review of literature. AB - BACKGROUND: Li-Fraumeni Syndrome (LFS) is a rare disease with autosomal dominant inheritance linked to germline mutations of tumor suppressor gene TP53. These patients are predisposed to malignancies such as sarcoma, breast cancer, leukemia, and other malignancies. Breast cancer, the most common malignancy in adult patients with LFS, has an early-onset presentation and is usually treated as per the guidelines for the general population due to the limited literature about breast cancer in LFS. We aimed to describe our institutional experience treating patients with breast cancer and LFS to contribute to literature about this entity. DESIGN: Retrospective single-institution case-series study. We searched for cases with LFS and breast cancer from 01/01/2000 to 12/31/2015 with treatment received at our institution. RESULTS: We identified 4 cases (2 African Americans, 1 Indian, and 1 Hispanic) in 4 different families, who were diagnosed with LFS after presenting with breast cancer. Three cases were triple-negative disease and 1 case was ER+, HER2 positive disease. They were treated with mastectomy and a third-generation breast chemotherapy regimen and/or trastuzumab containing regimen. Radiation therapy was used in 2 patients. Breast cancer recurrence was seen in 1 patient, while three other malignancies were identified after breast cancer treatment (1 breast sarcoma, 1 leiomyosarcoma, and 1 myelodysplastic syndrome). A patient, who underwent surveillance with a positron emission tomography-computed tomography scan, was found to have a stage I leiomyosarcoma and was treated with surgical resection, but then developed metastatic disease requiring cytotoxic chemotherapy. CONCLUSION: Breast cancer among patients with LFS needs a multidisciplinary treatment approach. Surgical management follows the guidelines for the general population. Risk-benefit assessment of chemotherapy and radiotherapy needs to be performed carefully in a case-by-case approach. Patients should undergo multimodality cancer surveillance, preferably in the context of a clinical trial. PMID- 28356771 TI - nab-Paclitaxel for the treatment of pancreatic cancer. AB - BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-P) plus gemcitabine (Gem) became a standard treatment option for metastatic pancreatic cancer (MPC) following positive results from a global phase III trial (MPACT). A large number of studies have now published results on the use of nab-P/Gem to treat advanced and early-stage disease, warranting a comprehensive review. The main goal of this systematic review is to summarize the efficacy and safety data of nab-P/Gem for the treatment of pancreatic cancer (PC). METHODS: This systematic review includes results from studies that either published results in a peer-reviewed journal or presented the results at a major oncology conference. RESULTS: Sixty-two studies were included (50 in the advanced/metastatic setting and 12 in the locally advanced setting). Most studies on the treatment of MPC were exclusively first line (33/50). Nevertheless, the studies in this review comprised a broad spectrum of patients, including those <65 and >=65 years of age and those with a Karnofsky performance status of 70-100. Median overall survival (OS) in studies of nab P/Gem in the advanced/metastatic setting ranged from 8.7 to 13.5 months. In addition, 15 studies of patients with advanced/metastatic PC examined nab-P/Gem as a backbone on which to add a variety of agents, including cancer stem cell inhibitors, stromal disrupting agents, and immune-modulating agents (median OS, 6.9-17 months). Ongoing trials are investigating nab-P/Gem with or without other agents across disease settings. DISCUSSION: Studies conducted after MPACT have demonstrated that nab-P/Gem is an effective regimen for the first-line treatment of MPC for a wide range of patients. Regimens using nab-P/Gem as a backbone on which to combine additional agents are being studied actively, particularly in the advanced disease setting. Ongoing studies will yield valuable insights on the utility of nab-P-containing regimens to improve patient outcomes in PC in both earlier-stage and advanced disease. PMID- 28356772 TI - Chinese health care system and clinical epidemiology. AB - China has gone through a comprehensive health care insurance reform since 2003 and achieved universal health insurance coverage in 2011. The new health care insurance system provides China with a huge opportunity for the development of health care and medical research when its rich medical resources are fully unfolded. In this study, we review the Chinese health care system and its implication for medical research, especially within clinical epidemiology. First, we briefly review the population register system, the distribution of the urban and rural population in China, and the development of the Chinese health care system after 1949. In the following sections, we describe the current Chinese health care delivery system and the current health insurance system. We then focus on the construction of the Chinese health information system as well as several existing registers and research projects on health data. Finally, we discuss the opportunities and challenges of the health care system in regard to clinical epidemiology research. China now has three main insurance schemes. The Urban Employee Basic Medical Insurance (UEBMI) covers urban employees and retired employees. The Urban Residence Basic Medical Insurance (URBMI) covers urban residents, including children, students, elderly people without previous employment, and unemployed people. The New Rural Cooperative Medical Scheme (NRCMS) covers rural residents. The Chinese Government has made efforts to build up health information data, including electronic medical records. The establishment of universal health care insurance with linkage to medical records will provide potentially huge research opportunities in the future. However, constructing a complete register system at a nationwide level is challenging. In the future, China will demand increased capacity of researchers and data managers, in particular within clinical epidemiology, to explore the rich resources. PMID- 28356773 TI - Update on the usage and safety of epinephrine auto-injectors, 2017. AB - Anaphylaxis is a serious, potentially fatal allergic reaction. Guidelines recommend prompt intramuscular injections of epinephrine as the first-line therapy for anaphylaxis. Delayed epinephrine treatment may cause undesirable clinical outcomes, including death. In the community, epinephrine auto-injectors (EAIs) are commonly used to treat anaphylaxis. This literature review examines several recent concerns regarding the safety of EAIs that may prevent the timely administration of epinephrine. Reports of cardiovascular complications are linked with epinephrine administration, although recent studies suggest that these events are much more commonly associated with intravenous epinephrine rather than with EAIs. Recent studies have also highlighted accidental injections of EAIs in patients' or caregivers' fingers and lacerations associated with the use of EAI in children. However, the data suggest that both accidental injections and lacerations are rare and require limited medical intervention. In addition, patients may receive conflicting information on the safety and efficacy of using expired EAIs. Overall, it is believed that the benefits of using EAIs far outweigh the potential risks of not administering an EAI. Although legitimate safety concerns are associated with EAIs, adverse events are rare. Continued training of medical providers, caregivers, and patients may be beneficial to address these concerns and reduce EAI-associated injuries while ensuring that patients receive necessary medical care. PMID- 28356775 TI - Alternative surgical methods for ptosis in patients with 18p deletion syndrome. PMID- 28356774 TI - Robotic-assisted hysterectomy: patient selection and perspectives. AB - Minimally invasive hysterectomy via the laparoscopic or vaginal approach is beneficial to patients when compared with laparotomy, but has not been offered in the past to all women because of the technical difficulties and the long learning curve required for laparoscopic hysterectomy. Robotic-assisted hysterectomy for benign indications may allow for a shorter learning curve but does not offer clear advantages over conventional laparoscopic hysterectomy in terms of surgical outcomes. In addition, robotic hysterectomy is invariably associated with increased costs. Nevertheless, this surgical approach has been widely adopted by gynecologic surgeons. The aim of this review is to describe specific indications and patients who may benefit from robotic-assisted hysterectomy. These include hysterectomy for benign conditions in cases with high surgical complexity (such as pelvic adhesive disease and endometriosis), hysterectomy and lymphadenectomy for treatment of endometrial carcinoma, and obese patients. In the future, additional evidence regarding the benefits of single-site robotic hysterectomy may further modify the indications for robotic-assisted hysterectomy. PMID- 28356776 TI - Diabetic papillopathy treated with intravitreal ranibizumab. AB - In this report, we present a case of diabetic papillopathy that resolved after a single dose of intravitreal ranibizumab injection. A 50-year-old male presented with painless visual loss in his right eye. His visual acuity was 1/10 in the right eye and 10/10 in the left eye. Anterior segment examination of both eyes was unremarkable. Posterior segment of the right eye showed nonproliferative diabetic retinopathy with a swollen optic disc. Fluorescein angiography and optical coherence tomography were performed. There was dye leakage from the right optic disc. Optical coherence tomography revealed a significant increase in retinal nerve fiber layer thickness. Magnetic resonance imaging of the brain and orbit were normal. The patient received a single intravitreal ranibizumab (0.5 mg) injection. Two weeks after the injection, there was a marked regression of the disc swelling. Three months after the injection the optic disc was pallor and visual acuity was 6/10. PMID- 28356777 TI - Intraocular eyelashes and iris cyst in anterior chamber following penetrating eye injury: a case report. AB - BACKGROUND: The presence of intraocular eyelashes following penetrating eye injury or ocular surgery is relatively uncommon. The response of the eye to intraocular eyelashes is variable. The eyelash may be symptomatic or may remain asymptomatic for long periods. OBJECTIVE: We report a case with two intraocular eyelashes and an iris cyst after 2 years of asymptomatic period following penetrating eye injury. CASE PRESENTATION: A 24-year-old male presented with decreased vision in the left eye which he had noticed for the previous 2 weeks. His visual acuity was 6/6 in the right eye and 6/18 in the left eye, improving to 6/9 with -2.5 DC * 140 degrees correction. The intraocular pressure was 12 mmHg in both eyes. On slit-lamp examination, the left eye showed 8 mm linear peripheral corneal opacity nasally, two eyelashes in the superior anterior chamber, and an iris cyst measuring 4 mm * 4 mm in the superior iris. The right eye was normal. Dilated fundus examination of both eyes was normal. The eyelashes and cyst were removed surgically. There were no complications during the 3-month follow-up period. CONCLUSION: Intraocular implantation of eyelashes following penetrating eye injury can remain asymptomatic for long periods; however, late development of iris cyst may occur. PMID- 28356778 TI - Decreasing racial disparity with the combination of ledipasvir-sofosbuvir for the treatment of chronic hepatitis C. AB - African Americans (AA) in the US are twice as likely to be infected with hepatitis C virus (HCV) compared to the non-Hispanic-white US population (Cau). They are also more likely to be infected with HCV genotype 1, more likely to develop hepatocellular carcinoma, and, in addition, have a lower response rate to interferon-based therapies. With the increase in response rates reported for combinations of direct-acting antivirals, the possibility that racial disparity would be eliminated by agents that directly inhibit virus replication has become a reality. The objective of this review is to evaluate the literature from clinical studies and retrospective analysis with respect to the response of AA to the most prescribed antiviral combination sofosbuvir plus ledipasvir. While few studies have focused on AA patients, sufficient information is availed from the literature and studies in our predominately AA clinic population to confirm that ledipasvir-sofosbuvir has a similar effectiveness in AA as compared to Cau. PMID- 28356780 TI - Views on group simulation in an integrated medical curriculum. PMID- 28356779 TI - Potential use of mesenchymal stem cells in human meniscal repair: current insights. AB - The menisci of the human knee play an important role in maintaining normal functions to provide stability and nutrition to the articular cartilage, and to absorb shock. Once injured, these important structures have very limited natural healing potential. Unfortunately, the traditional arthroscopic meniscectomy performed on these damaged menisci may predispose the joint toward early development of osteoarthritis. Although a very limited number of studies are available, mesenchymal stem cells (MSCs) have been investigated as an alternative therapeutic modality to repair human knee meniscal tears. This review summarizes the results of published applications of MSCs in human patients, which showed that the patients who received MSCs (autologous adipose tissue-derived stem cells or culture-expanded bone marrow-derived stem cells) presented symptomatic improvements, along with magnetic resonance imaging evidences of the meniscal repair. PMID- 28356781 TI - The importance of feedback for medical students' development. PMID- 28356782 TI - An evaluation of exact matching and propensity score methods as applied in a comparative effectiveness study of inhaled corticosteroids in asthma. AB - BACKGROUND: Cohort matching and regression modeling are used in observational studies to control for confounding factors when estimating treatment effects. Our objective was to evaluate exact matching and propensity score methods by applying them in a 1-year pre-post historical database study to investigate asthma-related outcomes by treatment. METHODS: We drew on longitudinal medical record data in the PHARMO database for asthma patients prescribed the treatments to be compared (ciclesonide and fine-particle inhaled corticosteroid [ICS]). Propensity score methods that we evaluated were propensity score matching (PSM) using two different algorithms, the inverse probability of treatment weighting (IPTW), covariate adjustment using the propensity score, and propensity score stratification. We defined balance, using standardized differences, as differences of <10% between cohorts. RESULTS: Of 4064 eligible patients, 1382 (34%) were prescribed ciclesonide and 2682 (66%) fine-particle ICS. The IPTW and propensity score-based methods retained more patients (96%-100%) than exact matching (90%); exact matching selected less severe patients. Standardized differences were >10% for four variables in the exact-matched dataset and <10% for both PSM algorithms and the weighted pseudo-dataset used in the IPTW method. With all methods, ciclesonide was associated with better 1-year asthma-related outcomes, at one-third the prescribed dose, than fine-particle ICS; results varied slightly by method, but direction and statistical significance remained the same. CONCLUSION: We found that each method has its particular strengths, and we recommend at least two methods be applied for each matched cohort study to evaluate the robustness of the findings. Balance diagnostics should be applied with all methods to check the balance of confounders between treatment cohorts. If exact matching is used, the calculation of a propensity score could be useful to identify variables that require balancing, thereby informing the choice of matching criteria together with clinical considerations. PMID- 28356783 TI - High-resolution mapping of genes involved in plant stage-specific partial resistance of barley to leaf rust. AB - Partial resistance quantitative trait loci (QTLs) Rphq11 and rphq16 against Puccinia hordei isolate 1.2.1 were previously mapped in seedlings of the mapping populations Steptoe/Morex and Oregon Wolfe Barleys, respectively. In this study, QTL mapping was performed at adult plant stage for the two mapping populations challenged with the same rust isolate. The results suggest that Rphq11 and rphq16 are effective only at seedling stage, and not at adult plant stage. The cloning of several genes responsible for partial resistance of barley to P. hordei will allow elucidation of the molecular basis of this type of plant defence. A map based cloning approach requires to fine-map the QTL in a narrow genetic window. In this study, Rphq11 and rphq16 were fine-mapped using an approach aiming at speeding up the development of plant material and simplifying its evaluation. The plant materials for fine-mapping were identified from early plant materials developed to produce QTL-NILs. The material was first selected to carry the targeted QTL in heterozygous condition and susceptibility alleles at other resistance QTLs in homozygous condition. This strategy took four to five generations to obtain fixed QTL recombinants (i.e., homozygous resistant at the Rphq11 or rphq16 QTL alleles, homozygous susceptible at the non-targeted QTL alleles). In less than 2 years, Rphq11 was fine-mapped into a 0.2-cM genetic interval and a 1.4-cM genetic interval for rphq16. The strongest candidate gene for Rphq11 is a phospholipid hydroperoxide glutathione peroxidase. Thus far, no candidate gene was identified for rphq16. PMID- 28356784 TI - Synthesis of beta-cyclodextrin-lysozyme conjugates and their physicochemical and biochemical properties. AB - Recently a great interest in the field of protein engineering and the design of innovative drug delivery systems employing specific ligands such as cyclodextrins is observed. The paper reports the solid state, thermal method for protein coupling with beta-cyclodextrin and the physicochemical and biological properties of the obtained conjugates. The structure of the obtained conjugates was investigated via liquid chromatography-mass spectrometry, dynamic light scattering and circular dichroism analysis. The presented conjugates were biologically active and covalently bound beta-cyclodextrin preserved the ability to form inclusion complexes with the model compound. This report demonstrates the great potential of cyclodextrin as a modifying unit that can be used to modulate the properties of therapeutic proteins, additionally giving such conjugates the possibility to transport many therapeutic substances in the form of inclusion complexes. In addition, the paper presents the potential of protein-cyclodextrin conjugates to construct innovative bioactive molecules for biological and medical applications. PMID- 28356785 TI - Successful application of thrombolysis and angioplasty in case of mechanical aortic valve and coronary graft thrombosis. AB - Prosthetic valve thrombosis (PVT) is a rare and fatal complication requiring immediate treatment. Optimal management of the left-sided obstructive PVT is still controversial and depends on patient's status, estimated risk of surgery, thrombus location and size, and clinician's experience. We report a case of a 71 year-old woman, presenting with signs of cardiogenic shock. Transesophageal echoscopy was used to diagnose acute obstructive thrombosis of the mechanical aortic valve. Concomitant coronary graft thrombosis was suspected due to signs of acute myocardial infarction. Thrombolysis with alteplase and subsequent stenting of the venous graft lead to successful resolution of the thrombotic lesions and a favourable patient outcome. Fibrinolytic therapy followed by angioplasty is a rational treatment alternative for inoperable or high risk patients in the case of concomitant mechanical valve and graft thrombosis. PMID- 28356786 TI - FFR guided PCI on long coronary lesions: 2-year clinical results with 2nd or newer generation DES. AB - Background. Despite improvements in drug-eluting stent (DES) technology, treatment strategies for long coronary artery lesions remain a controversial issue. The aim of our study was to evaluate the long-term clinical results after FFR guided PCI on long coronary lesions. Materials and methods. A total of 74 consecutive patients with significant (mean FFR 0.61 +/- 0.11) coronary artery lesions >=30 mm in length were included in the prospective study. All patients were treated with FFR guided PCI implanting newer generation Biolimus, Everolimus or Zotarolimus eluting stents. Clinical endpoints - target vessel revascularization (TVR) and major adverse cardiac events (MACE) - were recorded at 1 and 2 years. Results. 100% angiographic procedure success was achieved, the mean post procedural FFR was 0.88 +/- 0.06. At 2-year follow-up, 6 (8.1%) patients had ischemia driven TVR, all within the first 12 months. There were no target vessel related acute coronary syndromes and definite stent thromboses in the study group. At 2 years, the total MACE rate was 29.7%. There was a trend towards a higher TVR rate in patients with overlapping DES vs single DES implanted (9.6 vs 4.5%, p = 0.6). On regression analysis, the total stent length had no influence on the TVR rate. Conclusions. At 2 years after stenting long coronary lesions with newer generation DES the TVR rate was 8.1%, which is acceptable in the high cardiovascular risk population with diffuse coronary artery disease. The total stent length did not affect the long-term clinical outcomes. PMID- 28356787 TI - Vasa praevia: a case report and literature review. AB - Background. The aim of this article is to present a rare clinical case of vasa praevia as well as to assess the relevance of the problem by reviewing the latest literature sources. Materials and methods. In this report we present a case of a 33-year-old woman diagnosed with vasa praevia at 33 weeks of pregnancy, after hospitalisation with preterm rupture of membranes following the delivery of a live healthy baby through a lower segment Caesarean section during 33rd week of gestation at Vilnius University Hospital Santariskiu Clinics. We investigated all the documentation of the patient before and after delivery. Results and conclusions. Vasa praevia is a rather rare pathology which is likely to occur during pregnancy, may result in heavy bleeding and be particularly threatening to the fetus life. A timely diagnosis for these women is essential. The gold standard for vasa praevia diagnosis is the fetal ultrasound scan. Vasa praevia pathology is found during the routine second trimester ultrasound check-up. The selection of proper tactics applied during pregnancy care is essential. At the gestational age of 28-32, it is advisable to mature fetal lungs as well as the fetus condition should be investigated by a perinatologist. The mode of delivery is the C-section which tends to reduce the frequency of possible complications. PMID- 28356788 TI - The changes of radiotherapy in Lithuania: infrastructure, utilization rate, and cost. AB - Background. The aim of this study was to evaluate radiation therapy (RT) productivity, capacity, and cost in Lithuania. Materials and methods. An electronic questionnaire was prepared and sent to the country's RT centres. The data was collected for the years 2011-2014. The early data of the RT infrastructure was obtained from the QUARTS Project (2001). Results. In Lithuania the external beam RT was applied to 32.6% of new cancer cases (non-melanomatous skin cancer and benign conditions were excluded). In 2014, RT was more frequently applied for breast and prostate carcinomas, 23 and 20%, respectively. The country owned 11 units of linear accelerators (linacs) and this accounts for 3.7 linacs per one million population. 3D conformal RT is the standard approach in all four RT centres in Lithuania. IMRT practices were established in three centers and VMAT or stereotactic RT in two of them. 73% of linacs were capable of IGRT, while only 27% were equipped with CBCT. The average linac workload was 567 patients per year and showed a 10% decrease compared with the 2011 data. During a ten-year period, the average cost per patient for RT treatment increased 7.6 times - from EUR 129 to 974. The reimbursement system in Lithuania is not favourable for application of RT. Conclusions. During the recent thirteen years, RT services in Lithuania have dramatically improved, but we are still behind the average of European countries and benchmark rates. It is important to continue optimising the efficiency of RT services, and further evidence-based studies on RT infrastructure assessment and planning are needed. PMID- 28356789 TI - Significance of KRAS, NRAS, BRAF and PIK3CA mutations in metastatic colorectal cancer patients receiving Bevacizumab: a single institution experience. AB - Background. KRAS mutation is an important predictive and prognostic factor for patients receiving anti-EGFR therapy. An expanded KRAS, NRAS, BRAF, PIK3CA mutation analysis provides additional prognostic information, but its role in predicting bevacizumab efficacy is unclear. The aim of our study was to evaluate the incidence of KRAS, NRAS, BRAF and PIK3CA mutations in metastatic colorectal cancer patients receiving first line oxaliplatin based chemotherapy with or without bevacizumab and to evaluate their prognostic and predictive significance. Methods. 55 patients with the first-time diagnosed CRC receiving FOLFOX +/- bevacizumab were involved in the study. Tumour blocks were tested for KRAS mutations in exons 2, 3 and 4, NRAS mutations in exons 2, 3 and 4, BRAF mutation in exon 15 and PIK3CA mutations in exons 9 and 20. The association between mutations and clinico-pathological factors, treatment outcomes and survival was analyzed. Results. KRAS mutations were detected in 67.3% of the patients, BRAF in 1.8%, PIK3CA in 5.5% and there were no NRAS mutations. A significant association between the high CA 19-9 level and KRAS mutation was detected (mean CA 19-9 levels were 276 and 87 kIU/l, respectively, p = 0.019). There was a significantly higher response rate in the KRAS, NRAS, BRAF and PIK3CA wild type cohort receiving bevacizumab compared to any gene mutant type (100 and 60%, respectively, p = 0.030). The univariate Cox regression analysis did not confirm KRAS and other tested mutations as prognostic factors for PFS or OS. Conclusions. Our study revealed higher KRAS and lower NRAS, BRAF and PIK3CA mutation rates in the Lithuanian population than those reported in the literature. KRAS mutation was associated with the high CA 19-9 level and mucinous histology type, but did not show any predictive or prognostic significance. The expanded KRAS, NRAS, BRAF and PIK3CA mutation analysis provided additional significant predictive information. PMID- 28356790 TI - Response preparation and intra-individual reaction time variability in schizophrenia. AB - Background. It is important to prepare response in advance to increase the efficiency of its execution. The process of response preparation is usually studied using the precueing paradigm. In this paradigm subjects have to employ the preceding information about further imperative stimulus to perform proper response preparation, which shortens the reaction time of subsequent response execution. Previous studies detected the impairment of response preparation in schizophrenia only with the help of electroencephalographic parameters, but not with the assessing of reaction time. Therefore, in this study we attempted to find a behavioural parameter that could detect impairment in response preparation of schizophrenia patients. It was recently found that appropriate response preparation not only shortens the reaction time but also increases its stability, which is measured with the intra-individual reaction time variability. It was also revealed that response stability could better find cognitive dysfunction in some studies of schizophrenia disorder than classical behavioural parameters. Hence, the main goal of this study was to verify if intra-individual reaction time variability could detect the impairment of response preparation in schizophrenia patients. Materials and methods. In order to achieve the main purpose, we carried out a study with 14 schizophrenia patients and 14 control group subjects. We used precueing paradigm in our research, in which participants had to employ information about stimulus probability for the proper response preparation. Results. Our main result showed that despite the responses of schizophrenia patients were faster to the high-probability stimulus than to the low-probability one (F (1, 13) = 30.9, p < 0.001), intra-individual reaction time variability did not differ in this group between the responses to more and less probable stimuli (F (1, 13) = 0.64, p = 0.44). Conclusions. Results of the study suggest that people with schizophrenia were able to use precueing probabilistic information only to shorten their reaction time, but not to increase response stability. Therefore, it was found that intra-individual reaction time variability parameter could detect response preparation impairment in schizophrenia, and could be used in clinical purposes. PMID- 28356791 TI - ? AB - ELECTRONIC CIGARETTES A NEW WAY TO QUIT SMOKING OR A NEW THREAT?: The use of e cigarettes in adults and adolescents has increased since 2010. Most e-cigarette users are cigarette smokers. A majority of e-cigarette users perceive them to be a tool to quit or reduce smoking. E-cigarette devices consist of a cartridge containing a liquid, an atomizer (vaporization chamber with a heating element), and a battery. The user activates the atomizer, which heats the liquid and produces a vapour to inhale. Across all brands, the main components in e cigarette liquids are propylene glycol or glycerol, in addition, nicotine and/or flavourings can be added. A variety of other compounds have also been identified. Long-term health consequences of e-cigarette use are unknown but are likely to be less than continuing to smoke conventional cigarettes. The toxicity of chronic exposure to these and other components of e-cigarettes is uncertain. The safety and efficacy of e-cigarette use for smoking cessation is unknown. Clinicians should encourage smokers seeking to quit smoking to use US Food and Drug Administration (FDA)-approved smoking cessation aids as a first choice and make sure that newer approved strategies for smoking cessation pharmacotherapy are offered. If a smoker is not willing to use these evidence-based approaches and asks about using e-cigarettes, the clinician should not discourage e-cigarette use as long as the smoker is informed about the uncertainties of the device safety and efficacy. Public health concerns regarding e-cigarettes include their potential to increase youth initiation of tobacco products and to re-normalize tobacco use in places where cigarette smoking is not acceptable. The health effects of second-hand vapour exposure are unknown. Regulation for e-cigarettes varies worldwide and is changing. Keywords: electronic cigarettes, smoking, vapour. PMID- 28356792 TI - A fast and fatal course of bronchiectasis: an unusual rare expression of chronic graft versus host disease. A case report. AB - Introduction. We report a case of a patient with acute myeloid leukaemia whose treatment with bone marrow transplantation (BMT) was followed by chronic graft versus host disease (GVHD) with lung involvement and bronchiectasis. This report illustrates an unusual course of a fast progression of the bronchiectasis due to BMT. Case description. A 33-year-old female was diagnosed with acute myeloid leukaemia. An allogeneic BMT was performed. One month after the transplantation, acute GVHD with skin involvement occurred. Treatment with prednisolone and mycophenolate mofetil (MMF) has been started. Nine months later, the patient was examined by a pulmonologist due to progressive dyspnoea. A pulmonary computed tomography (CT) scan showed normal parenchyma of the lungs and no changes to the bronchi. A CT scan performed 7 months later revealed bronchiectasis for the first time. No clinical response was associated with the treatment and the patient's respiratory status progressively deteriorated. During the final hospitalization, a CT scan performed 1 year later revealed huge cystic bronchiectasis in both lungs. Despite the prophylaxis and treatment of GVHD and aggressive antimicrobial therapy, the patient died one year after the diagnosis of bronchiectasis. Conclusions. This case demonstrates that a fast and fatal course of bronchiectasis, that occurs after BMT, should always be considered as a possible manifestation of chronic graft versus host disease (cGVHD) following allogeneic BMT. PMID- 28356793 TI - Heterogeneity of nutritional habits of Lithuanian ethnolinguistic groups: population-based study. AB - BACKGROUND: Lithuania is a Northern European country consisting of two main ethnolinguistic groups: Samogitians and Highlanders. The objective of the paper is to investigate differences in nutritional habits of 18-65-year-old Lithuanians living in different ethnolinguistic regions. MATERIALS AND METHODS: A representative, population-based, random sample of the 18-65-year-old ethnic Lithuanian population was interviewed from 17 December 2008 to 20 May 2013. Lithuanians living in their ethnolinguistic region for at least three generations were included (n = 1,133). We analysed responses to 12 questions about nutritional habits of respondents. For the univariate analysis, we applied the chi-squared test. For the clusterisation of the survey questions, we employed a multiple correspondence analysis (MCA). RESULTS: Comparing Samogitians' and Highlanders' responses according to their gender, education, and place of residence, we observed more often significant differences (p < 0.05) for the urban population, respondents without higher education, and women. The nutrition of Highlanders was more consistent with national and WHO nutritional recommendations. Significant differences were obtained in the consumption of fish (p = 1.9 . 10-12), milk (p = 1.8 . 10-4) and grain products (p = 0.01). MCA revealed that all questions fall into three groups with a different composition for Samogitians and Highlanders. We failed to demonstrate the impact of different nutritional habits on the body mass index. CONCLUSIONS: According to the univariate and multivariate analysis, the nutritional habits of Lithuanian ethnolinguistic regions are heterogeneous. Dependency on an ethnolinguistic region might be considered an important factor for the preparation of appropriate health and nutrition education and disease prevention programmes. The issue of excess weight remains equally important for both ethnolinguistic groups. PMID- 28356794 TI - Identification of genetic causes of congenital neurodevelopmental disorders using genome wide molecular technologies. AB - BACKGROUND: Intellectual disability affects about 1-2% of the general population worldwide, and this is the leading socio-economic problem of health care. The evaluation of the genetic causes of intellectual disability is challenging because these conditions are genetically heterogeneous with many different genetic alterations resulting in clinically indistinguishable phenotypes. Genome wide molecular technologies are effective in a research setting for establishing the new genetic basis of a disease. We describe the first Lithuanian experience in genome-wide CNV detection and whole exome sequencing, presenting the results obtained in the research project UNIGENE. MATERIALS AND METHODS: The patients with developmental delay/intellectual disability have been investigated (n = 66). Diagnostic screening was performed using array-CGH technology. FISH and real time PCR were used for the confirmation of gene-dose imbalances and investigation of parental samples. Whole exome sequencing using the next generation high throughput NGS technique was used to sequence the samples of 12 selected families. RESULTS: 14 out of 66 patients had pathogenic copy number variants, and one patient had novel likely pathogenic aberration (microdeletion at 4p15.2). Twelve families have been processed for whole exome sequencing. Two identified sequence variants could be classified as pathogenic (in MECP2, CREBBP genes). The other families had several candidate intellectual disability gene variants that are of unclear clinical significance and must be further investigated for possible effect on the molecular pathways of intellectual disability. CONCLUSIONS: The genetic heterogeneity of intellectual disability requires genome wide approaches, including detection of chromosomal aberrations by chromosomal microarrays and whole exome sequencing capable of uncovering single gene mutations. This study demonstrates the benefits and challenges that accompany the use of genome wide molecular technologies and provides genotype-phenotype information on 32 patients with chromosomal imbalances and ID candidate sequence variants. PMID- 28356795 TI - Hypoplastic left heart syndrome: a review. AB - BACKGROUND: Hypoplastic left heart syndrome (HLHS) is an etiologically multifactorial congenital heart disease affecting one in 5,000 newborns. Thirty years ago there were no treatment options for this pathology and the natural course of the disease led to death, usually within the first weeks of life. Recently surgical palliative techniques have been developed allowing for a five year survival in more than half the cases. MATERIALS AND METHODS: We reviewed literature available on HLHS, specifically its anatomy, embryology and pathophysiology, and treatment. The Pubmed and ClinicalKey databases were searched using the key words hypoplastic left heart syndrome, foetal aortic valvuloplasty, foetal septoplasty, Norwood procedure, bidirectional Glenn procedure, Fontan procedure, hybrid procedure. The relevant literature was reviewed and included in the article. We reported a case from Children's Clinical University Hospital, Riga, to illustrate treatment tactics in Latvia. RESULTS: There are three possible directions for therapy in newborns with HLHS: orthotopic heart transplantation, staged surgical palliation and palliative non-surgical treatment or comfort care. Another treatment mode - foetal therapy - has arisen. Staged palliation and full Fontan circulation is a temporary solution, however, the only means for survival until heart transplantation. Fifty to 70% of patients who have gone through all three stages of palliation live to the age of five years. CONCLUSIONS: The superior mode of treatment is not yet clear and the management must be based on each individual case, the experience of each clinic, as well as the financial aspects and will of the patient's parents. PMID- 28356798 TI - Trends in maternal health in Lithuania 1995-2014. AB - BACKGROUND: The Lithuanian Perinatology Program, orders issued by the Ministry of Health, regulating the care and treatment of mothers and their infants, and the well-running perinatal care system helped to improve the diagnostics and treatment of pregnancy pathology. Over the last 20 years, Lithuania has experienced significant improvements in the maternal and perinatal health. MATERIALS AND METHODS: Data was collected from the official statistics database, Medical Data of Births, provided by the Institute of Hygiene Health Information Centre, Vilnius University Faculty of Medicine, and the Vilnius University Centre of Neonatology in 1995-2014. RESULTS: The average maternal age at delivery ranged from 25.8 years in 1995 to 28.8 years in 2014. The comparison of 2001 and 2014 data shows that the incidence of gestational diabetes increased by 6.7 times due to the improved diagnosis. The percentage of hypertensive disorders decreased from 6.1% in 1997 to 3.2% in 2014. Between 1995 and 2014, the prevalence of anemia among pregnant women declined by half. The marked decrease in respiratory, urinary, genital and other diseases was observed among pregnant women. From 1995 to 2014, in Lithuania there were 67 maternal deaths related to pregnancy and childbirth. Hemorrhage and infections during pregnancy, delivery and the postpartum period are considered the most common causes of maternal death. PMID- 28356796 TI - Preoperative risk factors of malnutrition for cardiac surgery patients. AB - BACKGROUND: Malnutrition (MN) is prevalent in cardiac surgery, but there are no specific preoperative risk factors of MN. The aim of this study is to assess the clinically relevant risk factors of MN for cardiac surgery patients. MATERIALS AND METHODS: The nutritional state of the patients was evaluated one day prior to surgery using a bioelectrical impedance analysis phase angle (PA). Two groups of patients were generated according to low PA: malnourished and well nourished. Risk factors of MN were divided into three clinically relevant groups: psychosocial and lifestyle factors, laboratory findings and disease-associated factors. Variables in each different group were entered into separate multivariate logistic regression models. RESULTS: A total of 712 patients were included in the study. The majority of them were 65-year old men after a CABG procedure. Low PA was present in 22.9% (163) of patients. The analysis of disease related factors of MN revealed the importance of heart functions (NYHA IV class OR: 3.073, CI95%: 1.416-6.668, p = 0.007), valve pathology (OR: 1.825, CI95%: 1.182-2.819, p = 0.007), renal insufficiency (OR: 4.091, CI95%: 1.995-8.389, p < 0.001) and body mass index (OR: 0.928, CI95%: 0.890-0.968, p < 0.001). Laboratory values related to MN were levels of haemoglobin (OR: 0.967, CI95%: 0.951-0.983, p < 0.001) and C-reactive protein (OR: 1.015, CI95%: 1.002-1.028, p = 0.0279). The lifestyle variables that qualified as risk factors concerned the intake of food (OR: 3.030, CI95%: 1.353-6.757, p = 0.007) and mobility (OR: 2.770, CI95%: 1.067 7.194, p = 0.036). CONCLUSIONS: MN risk factors comprise three different clinical groups: psychosocial and lifestyle factors, laboratory findings and disease associated factors. The patients who are most likely to be malnourished are those with valve pathology, severe imparted heart function, insufficient renal function and high inflammatory markers. Also these patients have decreased mobility and food intake. PMID- 28356797 TI - Successful treatment of advanced stage yolk sac tumour of extragonadal origin: a case report and review of literature. AB - BACKGROUND: Yolk sac tumour diagnosis should be considered for young age patients admitted to the hospital with non-specific complaints of widespread disease. Correct diagnosis and carefully planned treatment is the key to a successful outcome. METHODS AND MATERIALS: We present a rare case of a widespread yolk sack tumour of a uterine broad ligament. Our team directed a special attention towards the patient's young age, advanced disease, and fertility sparing strategy of treatment. RESULTS AND CONCLUSIONS: Stage IV yolk sac tumours of extragonadal origin are rarely reported in the literature. Hence, diagnosis and treatment often pose a challenge for emergency care unit doctors, gynaecologists, and oncologists. However, it can be a potentially curable disease. Moreover, patients' fertility can also be preserved. We believe that further analysis of similar cases is necessary to study outcomes and evaluate patients' responses to a sequence of medical decisions taken for this specific case. PMID- 28356800 TI - Inappropriate habits of antibiotic use among medical specialists and students in Vilnius. AB - INTRODUCTION: The resistance to antibacterial drugs is an emerging worldwide problem. Numbers of inappropriate ways to use antibiotics contribute to this issue. Self-medication is one of them. This study seeks to find out how prevalent the self-medication with antibiotics, their storage at home and the inappropriate acquisition of antibacterial drugs are among medical specialists in Vilnius, Lithuania. METHODS: A cross-sectional survey was conducted. To better identify the potential target groups, the respondents were classified according to their relation to medical care: physicians, other medical personnel, medical students and people, directly not related to medical care. RESULTS: The overall actual self-medication with antibiotics rate was 4.0%. And, although the actual self medication rate might seem rather low, the intended self-medication rate was 51.4%. Also, a prevalent antibacterial drugs storage at home (45.8%) with a wide variety of preparations was reported. Only 61.9% respondents received prescriptions for antibiotics from their treating physician. 7.6% used the non prescribed medicines and 22.0% received a prescription from a physician, who was either their colleague or a familiar person. CONCLUSIONS: Inappropriate habits of antibiotic use are prevalent. While there were some differences between the research groups, most of them were not statistically significant. It means that measures should be taken targeting health care givers as well as the general population. Educational programs about the rational use of antibiotics may help reducing the improper habits of antibacterial drugs usage, including self medication. Encouraging the electronic drug prescription may be beneficial while reducing the prevalent inappropriate acquisition of antibiotics. PMID- 28356799 TI - Quality of diabetes care at the largest outpatient clinics in Vilnius. AB - BACKGROUND: Essential data on the quality of diabetes care needed for the development of National Diabetes Programme in Lithuania are lacking. The aim of the study was to assess the quality of diabetes care compared to the local guidelines in Vilnius, Lithuania. MATERIALS AND METHODS: Retrospective data collection covering the period from 2012 to 2013 was performed in 5 Vilnius outpatient clinics assessing process and outcome indicators in type 1 (T1DM) and type 2 diabetes mellitus (T2DM) subjects. RESULTS: In a sample of 1,719 patients (58.9% women, 92.6% T2DM) the annual HbA1c assessment rate was 88.6%. Glycaemic control was significantly better in T2DM compared to T1DM patients: average HbA1c was 7.0 +/- 1.4% vs 9.1 +/- 1.8% and HbA1c <= 7% in 59 vs 9.4%, respectively (p < 0.001); referrals to an endocrinologist were recommended in 56.3% of cases. Annual screening for diabetic foot, retinopathy, nephropathy, renal function and lipids was performed in 4.6, 24.4, 2.3, 29.3 and 13.2% of patients, respectively, with higher performance rate of retinal screening and urinary microalbumin in T1DM; BMI and blood pressure were recorded for 50.2 and 97.2% of patients, respectively. Prevalence of nephropathy, polyneuropathy, retinopathy, and angiopathy was 8.4, 36.2, 10.7 and 7.7%, respectively, with the higher prevalence in T1DM. CONCLUSIONS: The analysis revealed good glycaemic control in T2DM, but insufficient in T1DM. Continuous monitoring of diabetes complications and cardiovascular risk factors did not meet the local Diabetes Care Guidelines. PMID- 28356801 TI - Fatal pulmonary complication during induction therapy in a patient with ANCA associated vasculitis. AB - ANCA-associated vasculitis (AAV) is an inflammatory systemic disorder affecting small to medium sized vessels and likely leading to any organ dysfunction. Adequate treatment is important to avoid mortality or severe organ damage. In most cases initial treatment (induction therapy) allows to achieve remission. Induction therapy leads to immunosuppression and may cause severe infections. However, in vasculitis patients even an intensive immunosuppressive therapy is rarely complicated by an invasive fungal infection. We present a case in a 29 year old male patient with newly diagnosed AAV. He suffered a fatal pulmonary complication of the induction immunosuppressive treatment. Pathological (infectious) changes in the lungs were misinterpreted as progression of the vasculitis and he died due to disseminated angioinvasive aspergillosis. A clinical course, imaging and histopathology of this case are described and discussed. PMID- 28356802 TI - ? AB - ECTOPIC HETEROTOPIC PANCREAS IN THE MESENTERY OF THE JEJUNUM CASE REPORT AND LITERATURE REVIEW: Ectopic pancreas is a rare congenital disorder characterized by the presence of the normal pancreatic tissue located outside the pancreas. The heterotopic pancreatic tissue in the mesentery of the jejunum is an entity that is seen very rarely. It is often found incidentally at different sites in the gastrointestinal (GI) tract. Although it is usually a silent anomaly, an ectopic pancreas may become clinically evident when complicated by inflammation, bleeding, obstruction or malignant transformation. However, the development of clinical symptoms depends on the size, location, and pathological changes similar to those observed in the case of the normal pancreas. Surgery is not indicated unless complications occur, so diagnosis is very important for prevention of unnecessary surgery. We present a case that had the ectopic pancreatic tissue in the mesentery of the jejunum. We show the computed tomography imaging findings of this patient. The presented case report demonstrated that heterotopic pancreas should always be considered in the differential diagnosis of gastric tumours. Keywords: ectopic heterotopic pancreas, jejunum, mesentery. PMID- 28356803 TI - Superior mesenteric artery syndrome. AB - BACKGROUND: An obstruction of the distal part of the duodenum can occur because of the superior mesenteric artery syndrome (SMAS) after a surgical correction of scoliosis. It is essential to evaluate the risk factors and diagnose the SMAS in time because complications of this condition are life-threatening and it is associated with a high rate of morbidity. Diagnostics of the SMAS is challenging, because it is rare and its symptoms are non-specific. Therefore, in order to better understand the essence of this pathology and to make diagnosis easier we present a rare clinical case of the superior mesenteric artery syndrome after a surgical correction of neuromuscular scoliosis. THE CLINICAL CASE: A 12-year-old girl with a specific development disorder, sensory neuropathy and progressive kypho-scoliosis was admitted to Vilnius University Children's Hospital. The patient had right side 50-degree thoracic scoliosis and an 80-degree thoracic kyphosis. She underwent posterior spinal fusion with hooks and screws from Th1 to L2. On the fourth day after the surgery the patient developed nausea and began to vomit each day 1-2 times per day, especially after meals. The SMAS was suspected and a nasogastric tube was inserted, stomach decompression and the correction of electrolytes disbalance were made. After the treatment, the symptoms did not recur and a satisfactory correction and balance of the spine were made in coronal and sagittal planes. CONCLUSIONS: It is extremely important to identify the risk factors of the SMAS and begin preoperative diet supplements before surgical correction of scoliosis for patients with a low body mass index. After the first episode of vomiting following the surgery, we recommend to investigate these patients for a gastrointestinal obstruction as soon as possible. Decompression of the stomach, enteral or parenteral nutrition, and fluid therapy are essential in treating the SMAS. PMID- 28356804 TI - Aorto-duodenal fistula: a rare but serious complication of gastrointestinal hemorrhage. A case report. AB - A primary aortoduodenal fistula (PADF) is a rare cause of gastrointestinal bleeding that is difficult to diagnose (and sometimes not diagnosed until a laparotomy.) A PADF is associated with high mortality if undiagnosed and untreated (the mortality rate of nearly 100% in the absence of a surgical intervention). While this condition is extremely rare with an incidence rate at autopsy of 0.04% to 0.07%, a secondary ADF occurs much more commonly (the post operative incidence of 0.5% to 2.3%) and is due to prior aortic surgery and/or the placement of a synthetic aortic graft. It should be considered in any elderly patient who presents with upper gastrointestinal bleeding in the context of a known abdominal aortic aneurysm or without it when no identifiable source of bleeding is found. We present an autopsy case of a 59-year-old man with no history of an abdominal aortic aneurysm who presented with intermittent massive gastrointestinal bleeding. The autopsy revealed a pinhole fistula. It was identified between an atherosclerotic abdominal aortic aneurysm and the lower horizontal part of the duodenum. Our case indicates that the aortoenteric fistula can result in fatal gastrointestinal bleeding. This case is unique in that the fistula formed as a result of a complex atherosclerotic abdominal aorta and a localized necrotizing granulomatous aortitis the etiology of which was not clear. PMID- 28356805 TI - Successful management of gastropulmonary fistula due to invasive fungal infection after chemotherapy and autologous stem cell transplantation: a case report. AB - BACKGROUND: Invasive fungal infections (IFI) contribute significantly to mortality and morbidity in patients receiving myelosuppressive chemotherapy for hematologic malignancies. Acquired gastropulmonary fistula is a rare complication of IFI. MATERIAL AND METHODS: We present a case history of a patient with malignant myeloma. She was treated with autologous stem cell transplantation and chemotherapy for three years. She had been treated with antifungal agents as well. Following a specific treatment, she developed an invasive fungal infection (IFI) of the left lung which had been complicated with left gastropulmonary fistula. The patient's general condition was deteriorating, so it was decided to perform a surgical intervention. At the first procedure, open-window thoracostomy was created in order to facilitate treatment by daily packing of the cavity. Four weeks after the thoracostomy, a thoracomyoplasty was performed to repair a gastropleural fistula. During the laparotomy, the gastric fundus was freed from adjacent tissues and repaired. Intrathoracic transposition of the latissimus dorsi and anterior serratus muscle flaps was performed simultaneously to create a new diaphragm. The open-window thoracostomy was left open due to some small bronchial fistulas. The thoracostomy opening healed spontaneously during the following six months. CONCLUSION: We report what is, to the best of our knowledge, the first case of an invasive fungal infection (Geotrichum capitatum) successfully treated with intravenous amphotericin B, voriconazole, and surgery on infected soft tissues (organs) for a patient with multiple myeloma in prolonged neutropenia. The efficacy and safety of the surgery for infected soft tissues requires further evaluation. PMID- 28356806 TI - Mental hygiene movement as a (r)evolutionary trend in public health in interwar Kaunas and Vilnius from 1918 to 1939. AB - OBJECTIVE: The health care system of the interwar period is distinguished by its revolutionary attempts to overcome social diseases and social hardships in general. In the researches published after the Second World War, different and in some cases even contradicting ideas on mental hygiene and eugenics were mixed together and were associated - almost exclusively - with the Nazi's racist ideology, totalitarian, or authoritarian regimes. The assessments of social medical policy of the interwar period in the Baltic region also became rather one sided. Felder's recent study (1) gives the impression that changes in psychiatry in Lithuania were caused by the Nazi's eugenics as a single agent. However, there were other factors. One of the most significant ones was the mental hygiene movement that will be discussed in this paper. METHODS: In this research we used descriptive and comparative methods. RESULTS: After the First World War, the problem of treatment of the mentally ill was a medical and a social issue that required a completely new approach both in Lithuania and in Vilnius. The most notable manifestation of such a new attitude in psychiatry was a mental hygiene movement. University scientists in Vilnius and Kaunas were discussing issues of mental hygiene. CONCLUSIONS: The mental hygiene movement of the early 20th century played an important role in the later development in psychiatry and medical sciences. The ideas published by the medical doctors in Kaunas and Vilnius were partly characteristic of the interwar period, although some of them went far ahead of their times. PMID- 28356808 TI - The Impact of Event Scale - Revised: psychometric properties of the Lithuanian version in a sample of employees exposed to workplace bullying. AB - BACKGROUND: The Impact of Event Scale-Revised (IES-R) is often used as a self report instrument for symptoms of post-traumatic stress (PTS). The objective of this study was to explore the reliability and validity of the Lithuanian IES-R in a sample of employees with exposure to workplace bullying in different occupations. MATERIALS AND METHODS: The original IES-R was translated into Lithuanian, and the comparability of content was verified through back translation procedures. 294 employees with exposure to workplace bullying (52 teachers from the secondary schools of Kaunas, 56 family physicians, 101 nurses of internal medicine departments, 40 waiters, and 45 seafarers) were administered the Lithuanian IES-R and the General Health Questionnaire - 12 (GHQ-12) in order to verify some aspects of convergent validity. The exploratory factor analysis was used to verify the construct validity of the IES-R. RESULTS: The reliability of the Lithuanian version of the IES-R was verified. Cronbach's alpha of the total scale was 0.95. Exploratory factor analysis showed a clear factor structure with three independent dimensions: intrusion, avoidance and hyperarousal. Cronbach's alpha for subscales of intrusion, avoidance and hyperarousal were 0.89, 0.85, and 0.88, respectively. The convergent validity was supported by positive correlations between the subscales (intrusion, avoidance, hyperarousal) and the GHQ-12. CONCLUSIONS: The results suggest that the self-reported Lithuanian IES-R is a valid instrument for assessing the dimensions of post traumatic stress, has good psychometric properties, and may be applied in prolonged trauma-exposed populations. PMID- 28356807 TI - Increasing attendance in a cervical cancer screening programme by personal invitation: experience of a Lithuanian primary health care centre. AB - BACKGROUND: High participation rates are an essential component of an effective screening programme and many approaches were introduced as being successful for enhancing compliance to screening guidelines. The aim of this study was to evaluate to which extent a personal invitation by mail increases the rate of attendance in a cervical cancer screening programme in a primary health care centre. MATERIALS AND METHODS: The study was carried out as a pilot project to gain insight into feasibility of applying a well-known compliance increasing measure in Lithuanian population. The study included a sample of women registered at the primary health care centre in Panevezys who had not participated in the cervical cancer screening programme for six and more years. Personal registered invitation letters to attend the primary health care centre for a Pap smear were sent out to 1789 women by mail. RESULTS: In total, 2195 women were tested during 2011 at the primary health care centre. 487 (22.2%) of them attended the screening programme after receiving a personal invitation letter. Response rate for attending screening after receiving a personal invitation letter was 27.3%. CONCLUSIONS: Our study demonstrated that personal invitation letters addressed to long-term non-attendees could markedly increase participation in cervical cancer screening in Lithuania. PMID- 28356809 TI - A series of cases of rhabdomyolysis after ingestion of Tricholoma equestre. AB - Tricholoma equestre (hereinafter - T. equestre) is a common edible fungus that is considered to be toxic under certain conditions. Here, we report four cases of acute poisoning caused by T. equestre, including one lethal outcome in Lithuania between 2004 and 2013. In the severe case, fatigue, nausea without vomiting and muscle pain, profuse sweating without fever, and respiratory insufficiency occurred. Laboratory tests showed an elevation of creatine kinase (CK), aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Although clinical findings and laboratory tests support evidence of rhabdomyolysis, no renal insufficiency was observed. Significance of T. equestre in cardiac changes is feasible but remains unclear. PMID- 28356810 TI - Perinatal injury of the central nervous system in Lithuania from 1997 to 2014. AB - BACKGROUND: Perinatal CNS injuries are significant for the health of neonates and for child development at a later period. The aim of this study was to evaluate the dynamics of the frequency of perinatal CNS lesions (corresponding to ICD 10 code P91) over a 20-year period, using the data collected from the Lithuanian Medical Data of Births (Registry of Births). MATERIAL AND METHODS: In total, data of 559,164 newborns were analyzed. RESULTS: During the period from 1997 to 2014, the frequency of term newborns with perinatal CNS injury decreased almost two times, from 20.4/1000 live births in 1997 to 15.5/1000 live births in 2014, or from 3.12% (95% CI 2.95; 3.31) to 1.46% (95% CI 1.32; 1.61). In 18 years, the rate of infant mortality from perinatal CNS injury decreased by more than four times and in 2014 it was 0.3/1000 births; it accounts for 11% of neonatal mortality (2.6/1000 live births). The largest decrease of CNS injury was seen after a caesarean birth (from 13.7% in 1999 to 1.7% in 2014) and breech delivery (from 9.7% in 1999 to 0.8% in 2014). Analysis of the dynamics of perinatal CNS injury in preterm births in selected groups did not identify a significant positive shift during the period. When evaluating the level of childbirth services in different-level maternity hospitals, CNS injury is undoubtedly diminished in 2B-level maternity hospitals (regional). Also, positive dynamics was observed in the data of 2A-level maternity hospitals, while in 3-level maternity hospitals (university hospitals), which deal with the most complicated obstetrical pathology and preterm newborns, positive dynamics was not observed. It is estimated that the frequency of hypoxic-ischemic encephalopathy was 0.63/1000 live births in Lithuania in 1993. CONCLUSIONS: The frequency of perinatal CNS injury and its positive dynamics in over 18 years shows a progressive and scientifically-based perinatal health care organization in Lithuania. PMID- 28356811 TI - ? AB - A COMPARATIVE STUDY OF BREAST VOLUME BODY SIZE AND PASSIVE BODY MASS IN PREGNANT AND YOUNG NULLIPAROUS WOMEN: The aim. To compare the relation between the changes in the body and breast size in pregnant and young nulliparous women. Materials and methods. In 2008-2009, 82 young nulliparous nineteen-year-old women were examined in Siauliai (Study I). Their body mass and breast size data were compared with the findings obtained from the examination of pregnant women during their first trimester in Vilnius from 2013 to 2015 (Study II). These findings involved longitudinal and transverse dimensions, the volume of various parts of the body, skin folds, breast dimensions, waist, hips, body mass indices, breast volume, and passive body mass. Both studies used standard anthropometric techniques and Martin instruments. The breast volume was calculated according to the formula of Kramer and Dexler (1981). The percentage of the passive body mass (fat tissue) were determined from the skin folds and the subcutaneous adipose tissue according to the formulae of Wilmore and Behnke (1970), and of Siri (1961). The differences between the groups were assessed by Student's t test. The selected reliability level was p < 0.05. Results. The following indicators were found to be statistically significantly higher in the group of pregnant women: chest, waist, hips, breast volume and the waist-hip index. The adipose tissue in pregnant women increased in the upper part of the body, although the relative and absolute passive body weight between the groups differed insignificantly. a comparison of the measurements of primiparous and multiparous young women with the measurements of the nulliparous subjects shows that the multiparous women had a larger amount of fat tissue, while in primiparous and young nulliparous women these indicators were not significantly different. Body size indices of the subgroups of pregnant women with small, medium, and large breasts were higher than those of the young nulliparous with similar measurements. The body size of lean women (below 25 percentile) was higher than that of young nulliparous women in the group of pregnant women. Differences in the body size indices of medium obese women (between 25 and 75 percentiles) were similar to the indicators of medium-sized female breasts in the group of pregnant women. The differences found in obese women (above 75 percentile) were similar to the indices recorded in the women of medium obesity. Conclusions. The passive body mass of pregnant women was accumulating in the upper part of the body. The body mass index in pregnant women was higher than that in nulliparous young women. Over the course of time (the age difference between the studied groups was ~10 years), the female body increases, the topography of the distribution of the adipose tissue changes. Pregnant women's breast volume was significantly higher than that of young nulliparous women. This phenomenon can be explained by pregnant women's higher passive body mass and older age. Keywords: anthropometry, passive body mass, pregnancy, breasts. PMID- 28356812 TI - Antenatal diagnostic aspects of placenta percreta and its influence on the perinatal outcome: a clinical case and literature review. AB - BACKGROUND: Placenta percreta is a very rare, but extremely life-threatening obstetrical pathology for the mother and the child, especially in the cases when it is not diagnosed before the birth and when it results in massive bleeding and a dramatic deterioration of condition. It is extremely important to diagnose this pathology as early as possible and plan further optimal care of patients in order to minimize life-threatening complications. CASE REPORT: The paper presents an illustrated clinical case of placenta percreta determined before the birth. Features of visual diagnostics are discussed. A 32-year-old pregnant woman with a history of two caesarean deliveries arrived at the tertiary level hospital at 22 weeks of gestation due to abdomen pain. Placenta previa was diagnosed and ultrasound, magnetic resonance imaging suggesting placenta percreta were seen. On the 32nd week, the planned caesarean hysterectomy was performed. The balloon catheters to occlude the internal iliac arteries and minimize bleeding during the surgery were used. CONCLUSIONS: Antenatal diagnosis of placenta percreta is especially important. Methods of visual diagnostics are complementary. The optimal surgical approach during caesarean hysterectomy remains controversial. In the case of the slow oozing without a clearly identified source of bleeding after hysterectomy and internal iliac arteries balloons deflation, ligation of one of the internal iliac arteriescan be reasonable to avoid residual haemorrhage and relaparotomy. PMID- 28356813 TI - Laparoscopic repair of the uterine scar defect - successful treatment of secondary infertility: a case report and literature review. AB - BACKGROUND: The aim of this paper is to present a clinical case of laparoscopic repair of a uterine scar defect, to assess the effectiveness of treatment reviewing the latest literature sources, and to provide recommendations of uterine scar defect management. MATERIALS AND METHODS: We report the case of a 33 year-old woman with an insufficient uterine scar and one-year history of secondary infertility. Following this, she underwent corrective laparoscopic repair, successfully got pregnant two months later and carried pregnancy to full term. We discuss the prevalence of caesarean scar defects, their clinical symptoms, diagnostic methods, various treatment techniques, and their outcomes. RESULTS AND CONCLUSION: Caesarean scar defects, insufficient uterine scars, isthmocele or scar dehiscence following a caesarean section involve myometrial discontinuity at the site of a scar previous caesarean section. These anatomical defects associated with prolonged menstrual bleeding, chronic pelvic pain, dysmenorrhea, dyspareunia and secondary infertility. Laparoscopic repair of the uterine scar defect is an effective method of treatment of secondary infertility. Patients with a previous history of caesarean section who present complaints of secondary infertility, need a detailed evaluation of the uterine scar before planning future pregnancies. PMID- 28356814 TI - Chronobiological types, duration of sleeping and psycho-emotional condition of teenagers. AB - Sleep is a biological process that operates according to day and night cycles. This self-regulatory system is universal in all organisms, including humans and mammals. For this reason, the topic is widely analysed in the existing literature; however, no studies about chronobiological types of teenagers have been conducted in Lithuania before. 253 schoolchildren, 13 to 18 years of age, were surveyed in schools of Vilnius and Panevezys, Lithuania. Responses were gathered during the period from September 2013 to February 2014. The survey consists of four parts: demographical data, Morningness-Eveningness Questionnaire, PedsQL 4.0 survey of life quality, and HADS - Hospital Anxiety and Depression Survey. In total, 115 (45.5%) boys and 138 (54.5%) girls participated in the survey. On average, boys sleep 7.10 (+/-1.27) hours, compared to 6.79 (+/ 1.20) (p = 0.05) hours for girls. 94 (37.2%) survey participants feel sleepy and/or very sleepy at school. 133 (52.6%) respondents find it difficult/very difficult to wake up in the morning. 218 (86.2%) respondents use the computer before going to sleep: 96 (83.5%) boys and 122 (88.4%) girls. Based on a subjective evaluation, 187 (73.9%) respondents categorize themselves as the evening type and 66 (26.1%) as the morning type. 13 (5.1%) respondents exhibit symptoms of depression. The majority of the respondents categorize themselves as evening/middle chronotypes. The average duration of sleep is 6.93 (+/-1.24) hours. 86.2% of the respondents use the computer before going to sleep. Half of the children may have difficulties waking up in the morning. One out of three children feels sleepy at school. PMID- 28356816 TI - Pediatric Laboratory Medicine: Some Aspects of Obesity, Metabolic Syndrome, Neonatal Screening, Reference and Critical Values. PMID- 28356815 TI - A higher-level classification of the Pannonian and western Pontic steppe grasslands (Central and Eastern Europe). AB - QUESTIONS: What are the main floristic patterns in the Pannonian and western Pontic steppe grasslands? What are the diagnostic species of the major subdivisions of the class Festuco-Brometea (temperate Euro-Siberian dry and semi dry grasslands)? LOCATION: Carpathian Basin (E Austria, SE Czech Republic, Slovakia, Hungary, Romania, Slovenia, N Croatia and N Serbia), Ukraine, S Poland and the Bryansk region of W Russia. METHODS: We applied a geographically stratified resampling to a large set of releves containing at least one indicator species of steppe grasslands. The resulting data set of 17 993 releves was classified using the TWINSPAN algorithm. We identified groups of clusters that corresponded to the class Festuco-Brometea. After excluding releves not belonging to our target class, we applied a consensus of three fidelity measures, also taking into account external knowledge, to establish the diagnostic species of the orders of the class. The original TWINSPAN divisions were revised on the basis of these diagnostic species. RESULTS: The TWINSPAN classification revealed soil moisture as the most important environmental factor. Eight out of 16 TWINSPAN groups corresponded to Festuco-Brometea. A total of 80, 32 and 58 species were accepted as diagnostic for the orders Brometalia erecti, Festucetalia valesiacae and Stipo-Festucetalia pallentis, respectively. In the further subdivision of the orders, soil conditions, geographic distribution and altitude could be identified as factors driving the major floristic patterns. CONCLUSIONS: We propose the following classification of the Festuco-Brometea in our study area: (1) Brometalia erecti (semi-dry grasslands) with Scabioso ochroleucae-Poion angustifoliae (steppe meadows of the forest zone of E Europe) and Cirsio-Brachypodion pinnati (meadow steppes on deep soils in the forest steppe zone of E Central and E Europe); (2) Festucetalia valesiacae (grass steppes) with Festucion valesiacae (grass steppes on less developed soils in the forest-steppe zone of E Central and E Europe) and Stipion lessingianae (grass steppes in the steppe zone); (3) Stipo-Festucetalia pallentis (rocky steppes) with Asplenio septentrionalis-Festucion pallentis (rocky steppes on siliceous and intermediate soils), Bromo-Festucion pallentis (thermophilous rocky steppes on calcareous soils), Diantho-Seslerion (dealpine Sesleria caerulea grasslands of the Western Carpathians) and Seslerion rigidae (dealpine Sesleria rigida grasslands of the Romanian Carpathians). PMID- 28356818 TI - Epidemiology and Natural History of NAFLD. AB - Paralleling the growing prevalence of obesity and metabolic syndrome, nonalcoholic fatty liver disease (NAFLD) is emerging as the most frequent hepatopathy in adults and children. The true prevalence of pediatric NAFLD is still unknown, because of the heterogeneity of diagnostic methods used for diagnosis in the available studies and the different characteristics of the populations evaluated. Pediatric NAFLD is typically of primary origin and it is strongly associated with several features of the metabolic syndrome. Age, gender and race/ethnicity are significant determinants of risk, and sex hormones, insulin sensitivity and adipocytokines are implicated in the pathogenesis of pediatric NAFLD. The natural history of NAFLD in children is still poorly understood, because of its complex nature and the scarcity of prospective studies, especially in pediatric populations. Both genetic and environmental factors seem to be implicated in the development and progression of the disease via multiple mechanisms that involve liver crosstalk with other organs and tissues, especially gut and adipose tissue. To evaluate and effectively treat pediatric NAFLD, the pathophysiology and natural history of the disease should be clarified and noninvasive methods for screening, diagnosis, and longitudinal assessment developed. PMID- 28356819 TI - Different Viewpoints: International Perspectives on Newborn Screening. AB - Newborn blood-spot screening to detect potentially treatable disorders is widely practiced across the globe. However, there are great variations in practice, both in terms of disorders covered, screening technologies, disease definition, information provision, parental informed consent, and storage and disposal of residual specimens, partly reflecting the degree to which screening is the subject of explicit legislation (and thus public and media pressure) or is embedded in a general health care system and managed at an executive level. It is generally accepted that disorders to be screened for should comply with the ten Wilson and Jungner criteria, but the way that compliance is assessed ranges from broadly-based opinion surveys to detailed analysis of quantitative data. Consequently, even countries with comparable levels of economic development and health care show large differences in the number of disorders screened for. There are several areas on which there are no generally accepted guidelines: how should parents be informed about screening and to what extent should they be encouraged to regard screening as an option to choose to refuse? Is DNA mutation analysis acceptable as part of a screening protocol? How soon should the blood samples be destroyed once screening has been completed? As technology advances and the potential scope of screening expands at both the metabolite and genome level, challenging policy issues will have to be faced. PMID- 28356817 TI - Pediatric Non-Alcoholic Fatty Liver Disease. AB - The rapidly increasing prevalence of childhood obesity and its associated co morbidities such as hypertriglyceridemia, hyper-insulinemia, hypertension, early atherosclerosis, metabolic syndrome, and non-alcoholic fatty liver disease are major public health concerns in many countries. Therefore the trends in child and adolescent obesity should be closely monitored over time, as in the near future, we may anticipate a major increase of young adults with the stigmata of the metabolic syndrome, and of the related non-alcoholic fatty liver disease (NAFLD), that may lead to non-alcoholic steatohepatitis. PMID- 28356820 TI - Advances in Pediatric Reference Intervals for Biochemical Markers: Establishment of the Caliper Database in Healthy Children and Adolescents. AB - Clinical laboratory reference intervals provide valuable information to medical practitioners in their interpretation of quantitative laboratory test results, and therefore are critical in the assessment of patient health and in clinical decision-making. The reference interval serves as a health-associated benchmark with which to compare an individual test result. Unfortunately, critical gaps currently exist in accurate and up-to-date pediatric reference intervals for accurate interpretation of laboratory tests performed in children and adolescents. These critical gaps in the available laboratory reference intervals have the clear potential of contributing to erroneous diagnosis or misdiagnosis of many diseases. To address these important gaps, several initiatives have begun internationally by a number of bodies including the KiGGS initiative in Germany, the Aussie Normals in Australia, the AACC-National Children Study in USA, the NORICHILD Initiative in Scandinavia, and the CALIPER study in Canada. In the present article, we will review the gaps in pediatric reference intervals, challenges in establishing pediatric norms in healthy children and adolescents, and the major contributions of the CALIPER program to closing the gaps in this crucial area of pediatric laboratory medicine. We will also discuss the recently published CALIPER reference interval database (www.caliperdatabase.com) developed to provide comprehensive age and gender specific pediatric reference intervals for a larger number of biochemical markers, based on a large and diverse healthy children cohort. The CALIPER database is based on a multiethnic population examining the influence of ethnicity on laboratory reference intervals. Thus the database has proved to be of global benefit and is being adopted by hospital laboratories worldwide. PMID- 28356821 TI - Metabolic Setup and Risks in Obese Children. AB - BACKGROUND: In the past decades, the obesity epidemic in children of all ages has been an important research field for detecting the metabolic causes and consequences of obesity, the major focus being on insulin and adipocytokine levels. Metabolic work-up in obese children is recommended in the age group as young as 2-6 years. There is evidence that birth weight can be a factor causing obesity later in life accompanied by metabolic complications. METHODS: Insulin, leptin, and adiponectin levels were analyzed in 269 obese children and 60 controls, as well as 110 newborn children with different birth weight and different length of gestation, using standard methods. RESULTS: In 53.6% of the obese children, complications of obesity such as diabetes mellitus, obesity, hyperlipidemia, heart attack or stroke were found in family members. The peak insulinemia on OGTT was significantly higher in the pubertal compared to the prepubertal group (110.5+/- 75.9 MUU/mL versus 72.2+/-62.7 MUU/mL) (p<0.005). Glucose intolerance was confirmed in 24%. The leptin level was significantly higher and the adiponectin level was lower in pubertal obese children compared to the prepubertal children and controls (p<0.05). In newborns the leptin and adiponectin levels were in correlation with anthropometric parameters: body weight (BW), body length (BL), BW/BL, BMI, and the pondered index (p<0.05). CONCLUSION: Obese children have high insulinemia in all ages, reaching its peak towards puberty. The leptin and adiponectin levels might be indicators of the metabolic syndrome. Our findings in newborns might influence the nutritional approach in the future in order to prevent complications of obesity. PMID- 28356822 TI - The Diagnosis of Prediabetes in Adolescents. AB - BACKGROUND: Prediabetes is characterized by isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), and combined IFG/IGT. This study aimed to establish the prevalence of prediabetes and examine possible contributory factors in a cohort of obese adolescents. METHODS: In this prospective study, we recruited 85 obese patients from the Obesity Clinic at the University Children's Hospital and 17 normal weight controls. All patients were of Caucasian origin, 60 males/42 females, aged 7.4-18.3 years, with at least Tanner 2 stage of puberty. RESULTS: Depending on criteria we used, insulin resistance was confirmed in 62-100% of obese patients, predominantly in the group with BMI SDS > 3. oGTT revealed isolated impaired fasting glucose (IFG) in 13.9%, impaired glucose tolerance (IGT) in 20.8% and combined IFG and IGT only in 2.8% of the obese patients. Patients in the prediabetes group were older (14+/-2.4 vs 12.8+/-2.5 p=0.04) and had higher glucose levels (p<0.001) during the whole oGTT compared to normal glucose tolerance (NGT) group. There was no difference between groups in respect to family history, BMI, lipids and fasting insulin. Insulinogenic index, WBISI and HOMA%B were significantly lower in the prediabetes group compared to the NGT group (p=0.07, 0.01 and 0.04 respectively). HbA1c level was measured in 58% of patients and was significantly higher in the prediabetes group (5.4+/-0.3 vs 5.7+/-0.4, p=0.002). CONCLUSION: Prediabetes occurrence was fairly high in our obese adolescents. Further studies should establish what would be the most appropriate screening test to diagnose these patients at risk for type 2 diabetes and initiate treatment without delay. PMID- 28356823 TI - Molecular Analysis of Cystic Fibrosis Patients in Hungary - An Update to the Mutational Spectrum. AB - BACKGROUND: In this study the authors present an update to the CFTR mutation profile in Hungary, utilizing data from a selected cohort of 45 cystic fibrosis (CF) patients from different regions of the country. METHODS: Depending on the preceding analysis, four different mutation detection methods were used. A commercial assay targeting the most common CF-causing mutations was performed as the first test followed by an allele specific PCR for CFTRdele2,3(21kb), Sanger sequencing and MLPA analysis of the coding region of the CFTR gene. RESULTS: In our recent study 27 different mutations were detected, including 2 novel ones (c.1037_1038insA and c.1394C>T). Besides F508del (c.1521_1523delCTT), the following mutations were found at a frequency of >= 4.0%: W1282X (c.3846G>A), N1303K (c.3909C>G), CFTRdele2,3(21kb) (c.54-5940_273+10250del21kb) and 2184insA (c.2052_2053insA). In addition, four mutations (G542X, Y1092X, 621+1G>T, and 2143delT) were found in more than one allele. CONCLUSIONS: The updated database of Hungarian mutations not only enables to increase the efficiency of the existing diagnostic approach, but also provides a further refined basis for the introduction of the molecular newborn screening (NBS) program in Hungary. PMID- 28356826 TI - Population-Based Pediatric Reference Intervals in General Clinical Chemistry: A Swedish Survey. AB - Very few high quality studies on pediatric reference intervals for general clinical chemistry and hematology analytes have been performed. Three recent prospective community-based projects utilising blood samples from healthy children in Sweden, Denmark and Canada have substantially improved the situation. The Swedish survey included 701 healthy children. Reference intervals for general clinical chemistry and hematology were defined. PMID- 28356824 TI - Direct Molecular Diagnosis of CYP21A2 Point Mutations in Macedonian and Serbian Patients with 21-Hydroxylase Deficiency. AB - BACKGROUND: Steroid 21-hydroxylase deficiency is present in 90-95% of all cases with congenital adrenal hyperplasia (CAH), an autosomal recessive disorder. It can present as the severe classical salt wasting (SW) or simple virilising (SV) form, or the milder, nonclassical form. Nine pseudogene-derived point mutations account for about 80% of all defects in the CYP21A2 gene coding the 21 hydroxylase enzyme. METHODS: We have studied nine CYP21A2 point mutations in 61 Macedonian and 24 Serbian patients with different clinical presentations of CAH, using the PCR/ACRS method. RESULTS: Six different mutations were detected in 71.3% of alleles of the Macedonian patients. The most prevalent mutation was IVS2. Mutations were detected in 85.4% of the SW, 83.4% SV and 47.7% LO alleles. In the Macedonian patients the most common genotype was IVS2/IVS2. Five different mutations were detected in 64.6% of alleles of the Serbian patients. The most prevalent was P30L. Mutations were present in 83.3% SW, 80% SV and 50% of the LO alleles. In the Serbian patients, the P30L/P30L genotype was the most frequent. CONCLUSIONS: Specific CYP21A2 mutations are involved in different clinical forms of CAH. High frequency of P30L was found in both populations. Also, high prevalence of the mild P30L mutation was found in both the Macedonian and Serbian classical SV patients. Our findings support the role of the P30L mutation in pronounced virilisation. An unusual finding is the low frequency of V281L in the Macedonian non-classical patients and its absence in the ones from Serbia. PMID- 28356825 TI - Selective Screening for Metabolic Disorders in the Slovenian Pediatric Population. AB - BACKGROUND: Inborn errors of metabolism (IEM) are disorders with a block in the metabolic pathway caused by a genetic defect of a specific enzyme. Although each of these diseases is quite rare, as a group they account for a significant proportion of newborn and childhood morbidity and mortality. Early diagnosis is important to prevent complications or even death of the child. Selective screening is an important diagnostic tool for the diagnosis of IEM. METHODS: In Slovenia, symptomatic patients with suspected IEM are referred to the University Children's Hospital Ljubljana. Techniques used for selective screening are gas chromatography-mass spectrometry, ion exchange chromatography-post-column derivatization, liquid chromatography-tandem mass spectrometry and isoelectric focusing. Fluorimetric method is used for enzyme activity measurement. RESULTS: There are 168 patients with amino and organic acidemias, 5 patients with disorders in fatty acids metabolism, 1 patient with a congenital disorder of glycosylation, 42 patients with Fabry disease (of which 37 are adult) and 20 patients with Gaucher disease (of which 18 are adult) in the Slovenian Register for Rare Diseases. CONCLUSIONS: In Slovenia, management of patients with IEM is centralized at the University Children's Hospital, with the exception of adult patients with Fabry and Gaucher disease. The team work is well organized with close cooperation between the laboratory and pediatricians specialized in metabolic disorders. According to the known frequencies of IEM from the literature, we would expect more positive results than obtained. To evaluate these results, we are planning to perform a pilot study on expanded newborn screening. PMID- 28356827 TI - Effect of L-carnitine Supplementation on Circulating C-reactive Protein Levels: A Systematic Review and Meta-Analysis. AB - BACKGROUND: C-reactive protein (CRP) has been proposed as a risk marker and risk factor of cardiovascular disease. There have been a number of clinical reports suggesting that supplementation with L-carnitine can modulate systemic inflammation and lower circulating CRP concentrations, but the results have not been consistent. METHODS: A comprehensive literature search in Medline, Scopus and Cochrane Central Register of Controlled Trials was performed in December 2012 to identify clinical trials investigating the impact of oral L-carnitine supplementation on serum/plasma CRP concentration. A random effect method was used to calculate the combined effect size. RESULTS: Six studies comprising 541 cases and 546 controls met the inclusion criteria. Meta-analysis of included trials revealed a significant reduction of circulating CRP concentrations in subjects under L-carnitine intervention compared to the control treatment. The calculated combined weighted mean reduction in CRP concentrations was -0.39 mg/L [95% CI (-0.62 - -0.16)]. This effect size estimate was found to be robust and remained unaffected by the removal of each single study. CONCLUSIONS: The overall findings of the present meta-analysis support the clinically relevant benefit of L-carnitine supplementation in lowering the circulating levels of CRP. PMID- 28356828 TI - Oxidized Low Density Lipoprotein and High Sensitive C-Reactive Protein in Non Diabetic, Pre-Diabetic and Diabetic Patients in the Acute Phase of the First Myocardial Infarction Treated by Primary Percutaneous Coronary Intervention. AB - BACKGROUND: Oxidized low density lipoprotein (ox-LDL) and high-sensitive C reactive protein (hs-CRP) are elevated in diabetes mellitus (DM) and associated with accelerated atherosclerosis. Little is known about their dynamics in the acute phase of ST segment elevation myocardial infarction (STEMI), especially in relation to the presence of DM and pre-diabetes (pre-DM). This study aimed to analyze time-dependent changes in ox-LDL and hs-CRP regarding the presence of pre DM and DM in STEMI patients treated by primary percutaneous coronary intervention (pPCI). METHODS: In 103 consecutive patients with the first anterior STEMI ox-LDL and hs-CRP were measured before pPCI, on day 2 and day 7 after pPCI. RESULTS: Patients were classified into: non-diabetics, pre-diabetics and diabetics. In each group the maximal ox-LDL concentration was found on admission, decreased on day 2 and reached the lowest values on day 7 (p<0.001). Diabetics had the highest ox-LDL concentrations compared to pre-diabetics and non-diabetics (on admission: p=0.028, on day 2: p=0.056, on day 7: p=0.004). hs-CRP concentration rose from admission, reached its peak on day 2 and decreased on day 7, in each group (p<0.001). Significant differences in hs-CRP concentrations were found between non-diabetics and pre-diabetics on admission (p=0.018) and day 2 (p=0.026). In a multivariate analysis DM was an independent determinant of high ox-LDL concentrations. Both ox-LDL and hs-CRP significantly correlated with Killip class, left ventricular ejection fraction, NT-proBNP and peak troponin I. CONCLUSIONS: In patients with the first STEMI treated by pPCI there were significant differences in ox-LDL and hs-CRP concentrations between non diabetics, pre-diabetics and diabetics. Ox-LDL and hs-CRP concentrations were related to heart failure parameters. PMID- 28356829 TI - Associations of Resistin Levels with Resistin Gene Polymorphism and Metabolic Syndrome in Thais. AB - BACKGROUND: Metabolic syndrome (MS) is a clinical constellation comprising risk factors associated with developing cardiovascular disease and type 2 diabetes. Resistin has been suggested as a linkage between obesity, inflammation and type 2 diabetes. This study aimed to investigate resistin concentrations and hematological-biochemical parameters in MS subjects and controls, and to determine whether two resistin gene (RETN) polymorphisms (-420C>G & +299G>A) are linked to resistin levels and MS among Thais. METHODS: This case-control study was performed with 322 Thai volunteers: 160 MS subjects and 162 controls. Anthropometric parameters and hematological-biochemical variables were determined. The RETN -420C>G (rs1862513) and +299G>A (rs3745367) polymorphisms were genotyped by PCR-RFLP technique. RESULTS: The resistin levels of the MS group were significantly higher than those of the control group. Resistin levels were positively correlated with anthropometric parameters and WBC count in the MS group. According to RETN -420C>G polymorphism, MS subjects with the G allele (CG/GG) (3.9 MUg/L) had significantly higher resistin concentrations than in subjects with the CC genotype (2.4 MUg/L); with regard to RETN +299G>A polymorphism, carriers with the A allele (GA/AA) (3.8 MUg/L) had significantly higher resistin levels than subjects with the GG genotype (2.7 MUg/L), after adjusting for potential covariates. However, the RETN -420C>G and +299G>A polymorphisms were not found to be associated with MS, hematological-biochemical parameters and anthropometric variables. CONCLUSIONS: These findings suggest resistin levels are linked with MS and the RETN -420C>G and +299G>A polymorphisms have impacted the circulating resistin concentrations. However, these two RETN polymorphisms probably do not influence susceptibility to MS among Thais. PMID- 28356830 TI - Post-Effort Changes in Activity of Traditional Diagnostic Enzymatic Markers in Football Players' Blood. AB - BACKGROUND: Long-term and intensive physical effort causes metabolic and biochemical adaptations for both athletic and non-athletic objectives. Knowing the importance of aerobic training in football players, the aim of this study was to evaluate changes in the activity of: creatinine kinase (CK), creatine kinase MB (CKMB), lactate dehydrogenase (LDH), alpha-hydroxybutyrate dehydrogenase (HBDH), cholinesterase (ChE) and alkaline phosphatase (ALP) in response to a semi long distance outdoor run under aerobic conditions among both female and male football players. METHODS: Sixteen participants aged 21.9+/-2 years (women) and 18.4+/-0.5 years (men), all of them voluntarily recruited football players, took part in an outdoor run, the women covering a distance of 7.4+/-0.3 km while men covered a distance of 10.7+/-1.0 km. Plasma activities of the studied enzymes were determined using an appropriate diagnostic assay kit. RESULTS: Our results indicate that total LDH activity could be a useful tool in evaluating physical fitness among athletes. We simultaneously established that ChE could not be a marker useful in assessing metabolic response to physical effort in athletes. Moreover, our results suggest that post-effort changes in ALP activity might be used to estimate early symptoms of certain vitamin deficiencies in an athlete's diet. CONCLUSIONS: We confirmed that the assessment of activity of selected traditional diagnostic enzymatic markers provides information about muscle state after physical effort. PMID- 28356831 TI - Correlation Between Glycated Hemoglobin and Homa Indices in Type 2 Diabetes Mellitus: Prediction of Beta-Cell Function from Glycated Hemoglobin. AB - BACKGROUND: The present study aimed to determine the most efficient insulin resistance function related to glycemic control expressed as glycated hemoglobin (HbA1c) in type 2 diabetes mellitus patients (T2DM). The other aim is to derive equations for the prediction of beta cell functions containing HbA1c as a parameter in addition to fasting glucose and insulin. METHODS: T2DM Patients were grouped according to the following: (1) degree of control (good, fair, and poor control) and (2) insulin resistance as observed in obtained data and significant differences revealed by the homeostasis model assessment (HOMA) of related parameters (insulin resistance = HOMA2IR, beta-cell function = HOMA%B, and insulin sensitivity = HOMA%S) among groups. Correlations and forecasting regression analysis were calculated. RESULTS: HbA1c was found to be correlated with insulin resistance parameters in T2DM subgroups. This correlation was also significantly correlated with HOMA%B and the quantitative insulin sensitivity check index (QUICKI) in fair and poor control groups. Regression analysis was used to predict the forecasting equations for HOMA%B. The best applicable equations were derived for healthy control (HOMA2%B= 1.76*FBG+5.00*Insulin+4.69*HbA1c+189.84) and poor control groups (HOMA2%B=0.001* FBG+0.5*Insulin-8.67*HbA1c+101.96). These equations could be used to predict beta cell function (HOMA%B) after FBG, insulin and HbA1c values were obtained for healthy and poor control groups. In the good and fair control groups, the applicability of the HOMA model fails to yield appropriate results. CONCLUSIONS: Beta-cell function is correlated with QUICKI and HbA1c and could be predicted properly from HbA1c, insulin, and glucose in the healthy and poor control groups. New regression equations were established that involve HbA1c. PMID- 28356832 TI - Homologous Recombination Repair Polymorphisms and the Risk for Osteosarcoma. AB - BACKGROUND: DNA repair mechanisms are essential for maintaining genome stability, and genetic variability in DNA repair genes may contribute to cancer susceptibility. Our aim was to evaluate the influence of polymorphisms in the homologous recombination repair genes XRCC3, RAD51, and NBN on the risk for osteosarcoma. METHODS: In total, 79 osteosarcoma cases and 373 controls were genotyped for eight single nucleotide polymorphisms (SNPs) in XRCC3, RAD51, and NBN. Logistic regression was used to determine the association of these SNPs with risk for osteosarcoma. RESULTS: None of the investigated SNPs was associated with risk for osteosarcoma in the whole cohort of patients, however, in patients diagnosed before the age of thirty years XRCC3 rs861539 C>T and NBN rs1805794 G>C were associated with significantly decreased risk for osteosarcoma (P=0.047, OR=0.54, 95% CI=0.30-0.99 and P=0.036, OR=0.42, 95% CI=0.19-0.94, respectively). Moreover, in the carriers of a combination of polymorphic alleles in both SNPs risk for osteosarcoma was decreased even more significantly (Ptrend=0.007). The risk for developing osteosarcoma was the lowest in patients with no wild-type alleles for both SNPs (P=0.039, OR=0.31, 95% CI=0.10-0.94). CONCLUSIONS: Our results suggest that polymorphisms in homologous recombination repair genes might contribute to risk for osteosarcoma in patients diagnosed below the age of thirty years. PMID- 28356833 TI - Association of Functional Variants of Phase I and II Genes with Chronic Obstructive Pulmonary Disease in a Serbian Population. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a complex disorder characterized by increased oxidative stress. Functional genetic variants of phase I and II genes are implicated in oxidants-antioxidants imbalance and may be involved in COPD development. In this study, we aimed to investigate the role of cytochrome P450 (CYP), glutathione S-transferase (GST) and microsomal epoxide hydrolase (mEH) functional variants in the pathogenesis of COPD in a Serbian population. METHODS: The genotypes of 122 COPD patients and 100 controls with normal lung function were determined for CYP1A1 *1A/*2A, CYP2E1 *1A/*5B, GSTM1 null, GSTT1 null GSTP1 Ile105Val, mEH Tyr113His and mEH His139Arg gene variants. RESULTS: Results obtained showed that GSTM1 null variant was significantly more represented in COPD patients than in controls (61.5% vs. 47.0%; OR=1.80; p=0.042). Also, a significant difference was observed for combinations of GSTM1 null and GSTP1 105Val/(Val) (38.5% vs. 24.0%; OR=1.98; p=0.029), as well as for CYP1A1 *1A/*2A, GSTM1 null and mEH 113His/(His) genotypes (7.4% vs. 1.0%; OR=7.88; p=0.025). CONCLUSIONS: These are the first data concerning the analysis of the variants of phase I and II genes in the pathogenesis of COPD in a Serbian population. Results obtained in this study open up the possibility for thorough analyses of the role of genetic factors in COPD on larger cohorts. Also, they implicate the importance of previously described genetic associations with COPD in our population, as well as reveal a new one, not reported so far. PMID- 28356835 TI - "Treatment Resistance" Enigma Resolved by Pharmacogenomics - A Case Study of Clozapine Therapy in Schizophrenia. AB - The introduction of antipsychotic medication in the 1950s forever changed the outlook on the treatment of schizophrenia, although there is still a large proportion of patients who do not reach functional recovery. At least 30% of patients do not respond to clozapine, the tricyclic dibenzodiazepine with complex pharmacological actions, which was proven to be more effective than any other antipsychotic in the treatment of schizophrenia. According to most of the therapeutic guidelines for schizophrenia, clozapine is the third line therapy for patients who did not respond to other antipsychotics. Large inter-individual variability exists for clozapine bioavailability and plasma steady-state concentrations and clearance. Clozapine is metabolized by the cytochrome P450 oxidase enzyme family (CYP450). Cytochrome P450 1A2 (CYP1A2), which is polymorphically expressed in humans, is the main enzyme of clozapine metabolism. This case report addresses the influence of CYP1A2*1F genetic polymorphism on clozapine metabolism, explains the primary non-response of a young patient with schizophrenia due to increased gene expression in homozygous genotype *1F/*1F (increased metabolism of clozapine) and underlies the importance of personalizing schizophrenia treatment by means of genetic and other molecular tools, at least in the cases of "treatment resistance". PMID- 28356834 TI - Brain Injury Alters Ectonucleotidase Activities and Adenine Nucleotide Levels in Rat Serum. AB - BACKGROUND: Cortical stab injury (CSI) induces changes in the activity, expression and cellular distribution of specific ectonucleotidases at the injury site. Also, several experimentally induced neuropathologies are associated with changes in soluble ectonucleotidase activities in the plasma and serum, whilst various insults to the brain alter purine compounds levels in cerebrospinal fluid, but also in serum, indicating that insults to the brain may induce alterations in nucleotides release and rate of their hydrolysis in the vascular system. Since adenine nucleotides and adenosine regulate diverse cellular functions in the vascular system, including vascular tone, platelet aggregation and inflammatory responses of lymphocytes and macrophages, alterations of ectonucleotidase activities in the vascular system may be relevant for the clinical outcome of the primary insult. METHODS: We explored ectonucleotidase activities using specific enzyme assays and determined adenine nucleotides concentrations by the UPLC method in the rat serum after cortical stab injury. RESULTS: At 4-h post-injury, ATP and AMP hydrolysis increased by about 60% and 40%, respectively, while phosphodiesterase activity remained unchanged. Also, at 4-h post-injury a marked decrease in ATP concentration and more than 2-fold increase in AMP concentration were recorded. CONCLUSIONS: CSI induces rapid up regulation of nucleotide catabolizing soluble ectonucleotidases in rat serum, which leads to the observed shift in serum nucleotide levels. The results obtained imply that ectonucleotidases and adenine nucleotides participate in the communication between the brain and the vascular system in physiological and pathological conditions and thereby may be involved in the development of various human neuropathologies. PMID- 28356836 TI - Laryngeal Granuloma - Benefit in Treatment with Zinc Supplementation? AB - Laryngeal granulomas present as contact and postintubation ulcers and granulomas. Essentially, a contact granuloma is a pseudotumor of the lateral wall of the posterior glottis. The most common etiological factor is voice abuse, with predisponing factors such as reflux disease. Postintubation ulcers and granulomas, although of different etiology, according to all the other traits belong to this clinical entity. The therapy of choice is conservative treatment. Surgical laser excision is indicated for resistant cases and those whose size is causing respiratory distress. Treatment of laryngeal granulomas with zinc supplementation is reported in the literature as one of the forms of conservative treatment, and we wanted to consider it in this review. Zinc is an essential mineral that plays a vital role in many biochemical reactions and is considered very important for wound healing. PMID- 28356837 TI - Curious Cases of the Enzymes. AB - Life as we know it heavily relies on biological catalysis, in fact, in a very nonromantic version of it, life could be considered as a series of chemical reactions, regulated by the guarding principles of thermodynamics. In ancient times, a beating heart was a good sign of vitality, however, to me, it is actually the presence of active enzymes that counts... Though we do not usually pay attention, the history of enzymology is as old as humanity itself, and dates back to the ancient times. This paper is dedicated to these early moments of this remarkable science that touched our lives in the past and will make life a lot more efficient for humanity in the future. There was almost always a delicate, fundamentally essential relationship between mankind and the enzymes. Challenged by a very alien and hostile Nature full of predators, prehistoric men soon discovered the medicinal properties of the plants, through trial and error. In fact, they accidently discovered the enzyme inhibitors and thus, in crude terms, kindled a sparkling area of research. These plant-derivatives that acted as enzyme inhibitors helped prehistoric men in their pursuit of survival and protection from predators; in hunting and fishing... Later in history, while the underlying purposes of survival and increasing the quality of life stayed intact, the ways and means of enzymology experienced a massive transformation, as the 'trial and error' methodology of the ancients is now replaced with rational scientific theories. PMID- 28356838 TI - Role and Responsibilities of Laboratory Medicine Specialists in the Verification OF Metrological Traceability of in vitro Medical Diagnostics. AB - To be accurate and equivalent, laboratory results should be traceable to higher order references. Furthermore, their quality should fulfill acceptable measurement uncertainty as defined to fit the intended clinical use. With this aim, in vitro diagnostics (IVD) manufacturers should define a calibration hierarchy to assign traceable values to their system calibrators and to fulfill during this process uncertainty limits for calibrators, which should represent a proportion of the uncertainty budget allowed for clinical laboratory results. It is therefore important that, on one hand, the laboratory profession clearly defines the clinically acceptable uncertainty for relevant tests and, on the other hand, end-users may know and verify how manufacturers have implemented the traceability of their calibrators and estimated the corresponding uncertainty. Important tools for IVD traceability surveillance are quality control programmes through the daily verification by clinical laboratories that control materials of analytical systems are in the manufacturer's declared validation range [Internal Quality Control (IQC) component I] and the organization of External Quality Assessment Schemes meeting metrological criteria. In a separate way, clinical laboratories should also monitor the reliability of employed commercial systems through the IQC component II, devoted to estimation of the measurement uncertainty due to random effects, which includes analytical system imprecision together with individual laboratory performance in terms of variability. PMID- 28356839 TI - Laboratory Diagnostics and Quality of Blood Collection. AB - Diagnostic blood samples collected by phlebotomy are the most common type of biological specimens drawn and sent to laboratory medicine facilities for being analyzed, thus supporting caring physicians in patient diagnosis, follow-up and/or therapeutic monitoring. Phlebotomy, a relatively invasive medical procedure, is indeed critical for the downstream procedures accomplished either in the analytical phase made in the laboratory or in the interpretive process done by the physicians. Diagnosis, management, treatment of patients and ultimately patient safety itself can be compromised by poor phlebotomy quality. We have read with interest a recent article where the authors addressed important aspects of venous blood collection for laboratory medicine analysis. The authors conducted a phlebotomy survey based on the Clinical and Laboratory Standard Institute (CLSI) H03-A6 document (presently replaced by the GP41-A6 document) in three government hospitals in Ethiopia to evaluate 120 professionals (101 non laboratory professionals vs. 19 laboratory professionals) as regards the venous blood collection practice. The aim of this mini (non-systematic) review is to both take a cue from the above article and from current practices we had already observed in other laboratory settings, and discuss four questionable activities performed by health care professionals during venous blood collection. We refer to: i) diet restriction assessment; ii) puncture site cleansing; iii) timing of tourniquet removal and; iv) mixing specimen with additives. PMID- 28356841 TI - Effect of Nutritionally Relevant Doses of Long-Chain N-3 Pufa on Lipid Status, Oxidative Stress and Inflammatory Markers in an Average Middle-Aged Serbian Population. AB - BACKGROUND: This study investigated the effects of a nutritionally relevant intake of eicosapentaenoic (EPA) and docosahexaenoic (DHA) fatty acids derived from oily fish or a fish oil supplement on selected cardiovascular risk factors in average middle-aged individuals. METHODS: Thirty-three participants were randomized to receive salmon (oily fish) providing 274 mg EPA + 671 mg DHA/day or a commercial fish oil supplement providing 396 mg EPA + 250 mg DHA/day in a cross over trial over an 8-week period separated by a 6-month washout period. Blood samples were collected before and after each intervention and lipids, inflammatory and oxidative stress parameters were determined. RESULTS: Plasma levels of EPA, DHA and total n-3 fatty acids significantly increased after both interventions. A decreasing trend in triglycerides was more pronounced with salmon than with the fish oil supplement, but the changes noticed were not significant. Although there were no relevant changes in inflammatory marker concentrations at the end of both interventions, significant negative correlations were noticed between total plasma n-3 fatty acids and soluble intercellular adhesion molecule and C-reactive protein throughout the whole intervention period (p<0.05). Among the oxidative stress parameters, intervention with salmon showed a prooxidative effect through a superoxide anion increase (p=0.025). A relevant positive correlation was also found between its concentration and total plasma n-3 fatty acids (p<0.05). Other oxidative stress markers were not significantly influenced by the dietary interventions applied. CONCLUSIONS: Following two sets of recommendations for n-3 fatty acids intake aimed at the general public had only a moderate effect on the selected cardiovascular risk factors in average healthy middle-aged subjects over a short term period. PMID- 28356842 TI - The Pleiotropic Effects of Atorvastatin on Stable Angina Patients: Evidence by Analysis of High-Density Lipoprotein Size and Subclasses, and Plasma mRNA. AB - BACKGROUND: High-density lipoproteins (HDL) have athero-protective biological properties: antioxidative, anti-apoptotic, anti-inflammatory, and they have the efflux capacity of cellular cholesterol. Plasma mRNA analysis can be used to investigate statin pleiotropy in vivo as a new analytical tool for non-invasive assessment of gene expression in vascular beds. The aim of this study was to assess the pleiotropic effects of atorvastatin in stable angina patients with high-risk values (group A) as compared with patients who had borderline and desirable HDL-cholesterol (HDL-C) values (group B). METHODS: The atorvastatin therapy (20 mg/day) was given to forty-three patients with stable angina for 10 weeks. We investigated three statin pleiotropy-targeted genes: inter-cellular adhesion molecule-1, chemokine (C-C motif) ligand 2 and cathepsin S and assessed by gel electrophoresis gradient the effects of atorvastatin on HDL size and subclasses. RESULTS: In group A, after therapy, HDL-C concentration was significantly increased but not in group B. Atorvastatin lowered plasma chemokine (C-C motif) ligand 2 and intercellular adhesion molecule-1 mRNA levels in both groups, but did not change the plasma cathepsin S mRNA levels. In group A only, baseline total bilirubin showed negative correlations with the genes of cathepsin S (r=-0.506; p=0.023) and significantly increased after therapy. CONCLUSIONS: HDL C and bilirubin can be promising therapeutic targets in the treatment of cardiovascular diseases. Analysis of cell-free mRNA in plasma might become a useful tool for estimating statin pleiotropy. PMID- 28356840 TI - Oxidative and Nitrosative Stress in Stable Renal Transplant Recipients with Respect to the Immunosuppression Protocol - Differences or Similarities? AB - BACKGROUND: The aim of the study was to evaluate parameters of oxidative and nitrosative stress as well as antioxidative parameters in a group of renal transplant recipients with stable graft function and no clinical signs of cardiovascular disease. We also aimed to determine the correlations among these parameters and to evaluate potential differences in all the biomarkers with regard to the immunosuppression protocol. METHODS: We enrolled 57 renal transplant recipients and 31 controls who were age and sex matched with the renal transplant recipients. All of the patients included in this study had post-renal transplant surgery at least 12 months earlier and were on standard immunosuppressive therapy. In this study, we determined thiobarbituric acid reactive substances in plasma and red blood cells and advanced oxidation protein products, nitrosative stress parameters (asymmetric and symmetric dimethylarginine - ADMA and SDMA), and antioxidative parameters (total SH groups and catalase activity). RESULTS: The results of our study demonstrated that the levels of oxidative and nitrosative stress were significantly increased compared to the healthy population (p<0.01 except for plasma catalase activity p<0.05). Correlation analysis showed significant positive correlations between: ADMA and SDMA (p<0.01); ADMA and nitrates (p<0.05); SDMA and nitrates (p<0.05); between OS parameters in the experimental group; AOPP and SH groups (p<0.05) and TBARS in plasma and SH groups (p<0.01), SDMA and AOPP (p< 0.05); SDMA and TBARS in plasma (p<0.05); SDMA and SH groups (p<0.01); nitrates and SH groups (p<0.05). CONCLUSION: There was no significant difference in oxidative and nitrosative stress parameters with respect to the immunosuppressive protocol. PMID- 28356844 TI - High False Positives and False Negatives in Yeast Parameter in an Automated Urine Sediment Analyzer. AB - BACKGROUND: Automated urine sediment analyzers have proven their feasibility in medical laboratories. However, editing manual microscopic review of some specimens severely limits the usefulness of such systems. This study aims to give feedback on the practical experience on "Yeast", which is one of the parameters that compel frequent manual reviews. METHODS: 5448 freshly collected urine specimens submitted from various departments of our hospital for diagnostic urinalysis were studied by the UriSed(r) (77 Elektronika, Hungary). A specialist medical doctor inspected every image on-board, and reviewed the ones with a "Yeast" alarm by traditional manual microscopy. RESULTS: UriSed alarmed in 491 samples (9%) for yeast. In 59 samples (1%) the number of particles exceeded the cut-off and a "positive for yeast" was set. A false positive report of yeast +1 to 3+/HPF was found in 51 samples (0.9%). There were 8 cases with positive for yeast from both microscopic methods. Thirty-three "negative for yeast" samples were corrected as positive after the manual microscopic review. CONCLUSIONS: We report a high percentage of false positives and negatives in the yeast parameter, in line with other studies on UriSed as well as on other instruments in the market. As an important feedback, our observations showed that the major concern in false results was "the focusing problem". We believe in the necessity of a focus check and comparison of alarms between images on board. PMID- 28356843 TI - Association Between Thyroid Hormones, Lipids and Oxidative Stress Markers in Subclinical Hypothyroidism. AB - BACKGROUND: Oxidative stress plays a role in the pathogenesis of many chronic diseases. It is recognized in overt hypothyroidism while its existence in subclinical hypothyroidism (SCH) is not well established. The aim of this study was to determine whether there was increased oxidation of lipids and proteins in SCH, and examine their association with lipids and thyroid hormones. METHODS: Male adults (35-59 years) with SCH (n=467) and euthyroid controls (n=190) were studied. Anthropometric measurements, plasma lipids, thyroid stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), total antioxidant capacity (T-AOC), lipid peroxidation products, malondialdehyde (MDA), advanced oxidation protein products (AOPP) and dityrosine concentrations were measured. RESULTS: Plasma concentrations of MDA were significantly higher (p<0.05) in SCH (8.11+/-1.39 nmol/mL) compared with euthyroid controls (7.34+/-1.31 nmol/mL) while AOPP, dityrosine and T-AOC levels were not different. MDA was not associated with TSH (beta=-0.019, P=0.759), FT4 (beta=-0.062, P=0.323) and FT3 (beta=-0.018, P=0.780) in SCH while levels increased with elevated total cholesterol (beta=0.229, P=0.001), LDL (beta=0.203, P=0.009) and triglycerides (beta=0.159, P=0.036) after adjustment for age and body mass index. T-AOC reduced (beta=-0.327, P=0.030) with increased MDA in euthyroid controls and not in SCH (beta=-0.068, P=0.349), while levels increased with elevated triglycerides in both groups. CONCLUSIONS: Oxidative stress was increased in subclinical hypothyroidism as evidenced by the elevated lipid peroxidation product, malondialdehyde, while protein oxidation was absent. Thus, reduction of oxidative stress may be beneficial in patients with subclinical hypothyroidism. PMID- 28356845 TI - HMGA2 Expression in Renal Carcinoma and its Clinical Significance. AB - BACKGROUND: The objective of this study is to detect HMGA2 expression in renal carcinoma to explore its relationship with clinicopathology and its significance in prognosis. METHODS: Expressions of HMGA2 mRNA and protein were detected in 50 renal carcinoma specimens, 50 corresponding adjacent normal kidney tissue samples and 40 renal benign tumour specimens via reverse transcription polymerase chain reaction and immunohistochemical assay. Expression analysis was performed along with clinical data analysis. RESULTS: The relative expression levels of HMGA2 mRNA in renal carcinoma, renal benign tumour tissues and adjacent normal renal tissues were 0.84+/-0.23, 0.19+/-0.06 and 0.08+/-0.04, respectively. HMGA2 protein positive rates were 68.0%, 7.5% and 2.0%, with a significant difference (P<0.05). HMGA2 expression was not significantly correlated with gender, age, tumour size and histological type (P>0.05), but was significantly correlated with TNM stages and lymph node metastasis (P<0.05). CONCLUSIONS: The expressions of HMGA2 gene and protein in renal carcinoma were closely correlated with tumour formation, progression and metastasis. HMGA2 may become a powerful new pathological marker and prognostic factor for renal carcinoma. PMID- 28356846 TI - Multicenter Comparison of Seven 25OH Vitamin D Automated Immunoassays. AB - BACKGROUND: The measurement of 25OH vitamin D continues to grow in clinical laboratories. The aim of this multi-center study was to compare the results of seven automated commercial immunoassays with a reference HPLC technique. METHODS: One hundred and twenty consecutive outpatient serum samples were centrifuged, divided in aliquots, frozen and shipped to the participating laboratories. 25OH Vitamin D was measured with a reference HPLC system and with seven automated commercial immunoassays (Roche Cobas E601, Beckman Coulter Unicel DXI 800, Ortho Vitros ES, DiaSorin Liaison, Siemens Advia Centaur, Abbott Architect i System and IDS iSYS). RESULTS: Compared to the reference method, the regression coefficients ranged from 0.923 to 0.961 (all p<0.001). The slope of Deming fit ranged from 0.95 to 1.06, whereas the intercept was comprised between -15.2 and 9.2 nmol/L. The bias from the reference HPLC technique varied from -14.5 to 8.7 nmol/L. The minimum performance goal for bias was slightly exceeded by only one immunoassay. The agreement between HPLC and the different immunoassays at 50 nmol/L 25OH Vitamin D varied between 0.61 and 0.85 (all p<0.001). The percentage of samples below this cut-off was significantly different with only one immunoassay. CONCLUSIONS: The excellent correlation with the reference HPLC technique attests that all seven automated immunoassays may be reliably used for routine assessment of 25OH-D in clinical laboratories. The significant bias among the different methods seems mostly attributable to the lack of standardization and calls for additional efforts for improving harmonization of 25OH-D immunoassays. PMID- 28356847 TI - LAPTM4B Gene Expression and Polymorphism as Diagnostic Markers of Breast Cancer in Egyptian Patients. AB - BACKGROUND: The aim of this study was to investigate the association between LAPTM4B gene polymorphism and the risk of breast cancer among Egyptian female patients. Also, measurement was done of its serum level to evaluate its significance as a diagnostic marker for breast cancer. METHODS: This case control study was done on 88 breast cancer patients, 40 with fibroadenoma and 80 healthy subjects. Genotyping of the LAPTM4B polymorphism was determined by PCR. Serum LAPTM4B level was measured using ELISA. RESULTS: There was a significant difference in the (*1/2+ *2/2) genotypes in breast cancer patients (59.1) compared to the control subjects (43.8%) (P=0.047; OR=1.86; 95% CI =1.01-3.43). The frequency of the allele 2* of the LAPTM4B gene was significantly higher in breast cancer patients (36.4%) than in the control (25.6%) (p=0.034; OR=1.66; 95% CI =1.04-2.65). Genotypes (*1/2+*2/2) were significantly associated with the differential classification of TNM. Serum level of LAPTM4B was significantly higher in breast cancer patients than in control and fibroadenoma and in fibroadenoma patients than in control. In breast cancer patients, serum LAPTM4B was significantly higher in stage III and in large tumor size. Serum LAPTM4B was significantly higher in the cancer patients' genotypes (*1/2+*2/2). CONCLUSIONS: Genetic polymorphism of LAPTM4B is a potential risk factor for the development of breast cancer. Serum LAPTM4B may be used as a diagnostic and prognostic marker for breast cancer. PMID- 28356848 TI - Genetic Variants of Cytochrome b-245, Alpha Polypeptide Gene and Premature Acute Myocardial Infarction Risk in an Iranian Population. AB - BACKGROUND: Oxidative stress induced by superoxide anion plays critical roles in the pathogenesis of coronary artery disease (CAD) and hence acute myocardial infarction (AMI). The major source of superoxide production in vascular smooth muscle and endothelial cells is the NADPH oxidase complex. An essential component of this complex is p22phox, that is encoded by the cytochrome b-245, alpha polypeptide (CYBA) gene. The aim of this study was to investigate the association of CYBA variants (rs1049255 and rs4673) and premature acute myocardial infarction risk in an Iranian population. METHODS: The study population consisted of 158 patients under the age of 50 years, with a diagnosis of premature AMI, and 168 age-matched controls with normal coronary angiograms. Genotyping of the polymorphisms was performed by the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). RESULTS: There was no association between the genotypes and allele frequencies of rs4673 polymorphism and premature acute myocardial infarction (P>0.05). A significant statistical association was observed between the genotypes distribution of rs1049255 polymorphism and AMI risk (P=0.037). Furthermore, the distribution of AA+AG/GG genotypes was found to be statistically significant between the two groups (P=0.011). CONCLUSIONS: Our findings indicated that rs1049255 but not rs4673 polymorphism is associated with premature AMI. PMID- 28356849 TI - Susceptibility to Breast Cancer and Intron 3 Ins/Del Genetic Polymorphism of DNA Double-Strand Break Repair Gene XRCC4. AB - BACKGROUND: Since genetic variations in X-ray cross-complementing group 4 (XRCC4; OMIM: 194363) repair gene might be associated with a reduction in cellular DNA repair capacity, it is hypothesized that XRCC4 Ins/Del (I/D) polymorphism (in intron 3 of the gene; rs28360071) may be a risk factor for breast cancer. Therefore, the present case-control study was carried out. METHODS: The present case-control study included 407 females with breast cancer and a total of 394 healthy females from the general population matched with patients according to age. Genotypic analysis for the XRCC4 I/D polymorphism was performed by PCR. In order to investigate the effect of XRCC4 I/D polymorphism on age at diagnosis of breast cancer, the Kaplan-Meier survival analysis and the Cox proportional hazards regression model were used. RESULTS: Based on the present case-control study, the ID (OR=0.95, 95% CI: 0.69-1.31, P=0.781) and DD (OR=1.24, 95% CI: 0.84 1.83, P=0.274) genotypes were not associated with breast cancer risk compared with the II genotype. Based on the Cox regression model, there was significant association between genotypes of I/D polymorphism and age at diagnosis of breast cancer (ID+DD vs II; HR=0.79, 95% CI: 0.64-0.98, P=0.036). CONCLUSION: Although there was no significant association between XRCC4 I/D polymorphism and risk of breast cancer, patients having the II genotype have lower age at diagnosis in comparison with patients having ID+DD genotypes. PMID- 28356850 TI - Influence of Promoter Polymorphisms of the TNF-alpha (-308G/A) and IL-6 (-174G/C) Genes on Therapeutic Response to Etanercept in Rheumatoid Arthritis. AB - BACKGROUND: The study was undertaken to assess the influence of functional 308G/A TNF-alpha (rs 1800629) and -174G/C IL-6 (rs1800795) promoter polymorphisms on the therapeutic response to etanercept, a TNF-alpha blocker, in patients with rheumatoid arthritis (RA). METHODS: Seventy-three patients suffering from active RA were studied, at baseline and 6 and 12 months after therapy. The therapeutic response was estimated according to the European League Against Rheumatism response criteria. Patients were genotyped for -308G/A TNF-alpha and -174G/C IL-6 polymorphisms by the PCR-RFLP method, and the influence of genotype on etanercept response was assessed. RESULTS: No difference in the percentage of responders (patients who had DAS28 improvement > 1.2) between patients with the TNF-alpha 308GG and GA and AA genotype was detected after 6 and 12 months of treatment. After 12 months of treatment the percentage of responders was significantly increased in patients with the IL-6 -174GG genotype compared with those with the GC or CC genotype (p=0.006 by Chi-square test). Evaluation of the patients according to their combined IL-6/TNF-alpha genotypes showed that patients with the IL-6 -174GG / TNF-alpha-308GG genotype were more frequent among the responders compared to those with other combined genotypes (p=0.022 by Chi-square test). More precisely, all patients with the combined IL-6 -174GG / TNF-alpha 308GG genotype were responders after 12 months of etanercept treatment. CONCLUSIONS: The study suggests that patients who are genetically low TNF-alpha and IL-6 producers are the best responders to etanercept therapy. PMID- 28356851 TI - Pharmacogenetics may Influence Tacrolimus Daily Dose, but not Urinary Tubular Damage Markers in the Long-Term Period after Renal Transplantation. AB - BACKGROUND: The primary goal of this study was to evaluate the influence of cytochrome P450 (CYP) 3A5 (6986A>G) and ABCB1 (3435C>T) polymorphisms on tacrolimus (TAC) dosage regimen and exposure. Second, we evaluated the influence of TAC dosage regimen and the tested polymorphisms on renal oxidative injury, as well as the urinary activities of tubular ectoenzymes in a long-term period after transplantation. Also, we aimed to determine the association between renal oxidative stress and tubular damage markers in the renal transplant patients. METHODS: The study included 72 patients who were on TAC based immunosuppression. Allele-specific PCR was used for polymorphism determination. We measured the urinary thiobarbituric acid reactive substances (TBARS) and reactive carbonyl derivates (RCD) in order to evaluate oxidative injury, as well as the urinary activities of ectoenzymes (N-acetyl-beta-D-glucosaminidase, aminopeptidase N and dipeptidyl peptidase IV) to evaluate tubular damage. RESULTS: The carriers of CYP 3A5*1 allele required statistically higher daily doses of TAC than CYP *3/*3 carriers, as well as the carriers of C allele of ABCB1 gene compared to those with TT genotype. Also, there were no differences in TBARS, RCD and the activities of ectoenzymes between the patients' genotypes. Our results showed significant correlations between urinary TBARS and RCD and the ectoenzymes' activities. CONCLUSIONS: Our findings suggest that CYP 3A5 and ABCB1 3435 polymorphism may affect TAC daily doses, but not the drug's tubular toxicity. Furthermore, tubular damage may be associated with increased renal oxidative stress. PMID- 28356852 TI - Prognostic Value and Daily Trend of Interleukin-6, Neutrophil CD64 Expression, C Reactive Protein and Lipopolysaccharide-Binding Protein in Critically Ill Patients: Reliable Predictors of Outcome or Not? AB - BACKGROUND: Severe sepsis and/or trauma complicated by multiple organ dysfunction syndrome are the leading causes of death in critically ill patients. The aim of this prospective single-centre study was to assess the prognostic value and daily trend of interleukin-6 (IL-6), neutrophil CD64 expression, C-reactive protein (CRP) and lipopolysaccharide-binding protein (LBP) regarding outcome in critically ill patients with severe trauma and/or severe sepsis. Outcome measure was hospital mortality. METHODS: One hundred and two critically ill patients admitted to the intensive care unit of a tertiary university hospital were enrolled in this prospective study. Blood samples were collected on admission (day 1), days 2 and 3. RESULTS: CD64 index was 1.6-fold higher on day 1 and 1.78 fold higher on day 2 in non-survivors (p<0.05). The area under the curve (AUC) for the CD64 index on day 1 for outcome was 0.727. At a cut-off level of 2.80 sensitivity was 75% and specificity was 65%. Patients with CD64 index level on day 1 higher than 2.80 had 2.4-fold higher probability of dying. Odds ratio is 2.40; 95% CI 0.60-9.67. CONCLUSIONS: CD64 index on day 1 is a fairly good predictor of outcome. AUCs for IL-6, CRP and LBP were < 0.55, suggesting these biomarkers failed to predict outcome. PMID- 28356853 TI - Association of Serum Pentraxin-3 and High-Sensitivity C-Reactive Protein with the Extent of Coronary Stenosis in Patients Undergoing Coronary Angiography. AB - BACKGROUND: We compared factors of inflammation - high sensitivity C-reactive protein (hsCRP) and pentraxin-3 (PTX3), and we explored their relationship with coronary artery disease (CAD). Also, we tested the usefulness of hsCRP and PTX3 in the risk assessment of coronary stenosis development and the diagnostic ability of these biomarkers to detect disease severity. METHODS: The study group consisted of 93 CAD patients undergoing coronary angiography. Patients were divided into CAD(0), representing subclinical stenosis, and CAD (1-3), representing significant stenosis in one, two or three vessels. RESULTS: We determined the concentration of lipid status parameters, hsCRP and PTX3. We found significantly lower PTX3 and hsCRP concentrations in CAD(0) than in CAD(1-3) group. Concentration of PTX3 showed an increasing trend with the increasing number of vessels affected. The area under ROC curve (AUC) for the combinations of hsCRP and PTX3 with lipid parameters had useful accuracy for detecting CAD(1 3) patients (AUC=0.770, p<0.001). CONCLUSION: PTX3 is a promising independent diagnostic marker for identifying patients with CAD, and a useful indicator of disease progression. In all the analyses PTX3 showed better performance than hsCRP. A combination of PTX3, hsCRP with the lipid status parameters provides risk stratification of the development of coronary stenosis and better classification than their individual application. PMID- 28356854 TI - Association of Hyponatremia and Hypovitaminosis D in Ambulatory Adults. AB - BACKGROUND: Hyponatremia and vitamin D deficiency are frequent disorders, and both have been associated with gait disturbances, falls and fractures. The aim of this study was to evaluate the existence of an association between serum sodium and vitamin D serum levels. METHODS: We performed a retrospective investigation to establish whether hyponatremia and vitamin D deficiency may be associated in a general population of unselected outpatients. An electronic search was performed in the laboratory information systems of the Hospital of Verona and the Hospital of Parma (Italy), to retrieve combined results for total vitamin D and sodium obtained in all outpatients referred for health check-up in the year 2013. RESULTS: Combined results of vitamin D and sodium could be retrieved for 5097 outpatients (3859 females and 1238 males; mean age 64+/-17 years). Vitamin D deficient subjects displayed significantly lower levels of serum sodium (140 versus 141 mmol/L; p<0.001), along with a significantly higher rate of hyponatremia (6.3% versus 5.1%; p=0.037). Accordingly, hyponatremic subjects had significantly lower levels of serum vitamin D (55 versus 60 nmol/L; p=0.015), along with a significantly higher rate of vitamin D deficiency (41.8% versus 36.1%; p=0.030). A highly significant correlation was found between sodium and total vitamin D after adjustment for age and gender (p<0.001). CONCLUSIONS: The results of this study demonstrate for the first time the existence of a significant correlation between the serum levels of sodium and total vitamin D in a general population of unselected outpatients. PMID- 28356855 TI - Increased Antioxidant Quality Versus Lower Quantity of High Density Lipoprotein in Benign Prostatic Hyperplasia. AB - BACKGROUND: Oxidative stress may be involved in the pathogenesis of every human disease. To understand its possible role in benign prostatic hyperplasia (BPH), we measured the overall oxidative status of patients with BPH and the serum activity of the high density lipoprotein (HDL)-related antioxidant enzymes paraoxonase 1 (PON1) and arylesterase (ARE). METHODS: Fifty-six urology outpatient clinic patients with BPH (mean age 64+/-8.6 years) were prospectively included in the study. Forty volunteer healthy controls from the laboratory staff (mean age 62+/-10 years) were enrolled for comparison. Serum total antioxidant status (TAS), total oxidant status (TOS), PON1, ARE, and HDL levels were measured by commercially available, ready-to-use kits. RESULTS: Serum TAS and HDL levels were significantly lower in the BPH group than in the control group (P=0.004 and P=0.02, respectively). No significant between-group differences were observed for TOS levels or PON1 and ARE enzyme activities (P=0.30, P=0.89, and P=0.74, respectively). In the BPH group, the calculated parameters PON1/HDL and ARE/HDL were significantly higher (P=0.02 and P=0.04, respectively). CONCLUSIONS: Our findings agree with the previous reports of impaired oxidant/antioxidant balance in BPH patients. The activities of HDL-related enzymes between groups with significantly different HDL levels may be deceptive; adjusted values may help to reach more accurate conclusions. PMID- 28356856 TI - Hematological and Biochemical Parameters in Elite Soccer Players During A Competitive Half Season. AB - BACKGROUND: The purpose of the present study was to report and discuss the hematological and biochemical behavior of elite soccer players, in order to get more insight in the physiological characteristics of these sportsmen and to provide trainers and sports doctors with useful indicators. METHODS: Nineteen male soccer players volunteered to participate in this study. We followed the young elite soccer players during a competitive half season. Venous blood samples were collected between 9:00 and 10:00 a.m. after an overnight fast (10 h) at baseline, after 45 and 90 days and hematological and biochemical parameters were measured. RESULTS: Hemoglobin and hematocrit levels were significantly reduced over the observational period (p<0.05), but erythrocyte count and iron levels remained unchanged. Bilirubin and ferritin levels significantly increased in response to regular soccer training (p<0.05). We observed a significant decrease in muscle enzyme plasma activity during the 90 days study period. ANOVA analysis revealed a significant increase in the leukocyte and neutrophil counts (p<0.05), in parallel with a significant decrease in the lymphocyte count (p<0.05) after the observational period of 90 days. CONCLUSIONS: Elite soccer players are characterized by significant changes in biochemical and hematological parameters over the half season, which are linked to training workload, as well as adaptation induced by the soccer training. Although the values of the measured parameters fell within the reference range, regular monitoring of the biochemical and hematological parameters is fundamental for the identification of a healthy status and related optimal performances by sport doctors and trainers and selection of a correct workload by trainers. PMID- 28356857 TI - Questionable Reliability of Homocysteine as the Metabolic Marker for Folate and Vitamin B12 Deficiency in Patients with Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: An increased homocysteine (Hcy) concentration may represent a metabolic marker of folate and vitamin B12 deficiency, both significant public health problems. For different reasons, patients with chronic obstructive pulmonary disease (COPD) are prone to these deficiencies. The study evaluates the reliability of Hcy concentration in predicting folate or vitamin B12 deficiency in these patients. METHODS: A group of 50 COPD patients (28 males/22 females, age (chi+/-SD=49.0+/-14.5) years was enrolled. A chemiluminescent microparticle immunoassay was applied for homocysteine, folate and vitamin B12 concentration. Kolmogorov-Smirnov, Mann-Whitney U and chi2 tests, Spearman's correlation and ROC analysis were included in the statistical analysis, with the level of significance set at 0.05. RESULTS: Average (SD) concentrations of folate and vitamin B12 were 4.13 (2.16) MUg/L and 463.6 (271.0) ng/L, whereas only vitamin B12 correlated with the Hcy level (P=-0.310 (R=0.029)). Gender related differences were not significant and only a borderline significant correlation between age and folate was confirmed (R=0.279 (P=0.047)). The incidence of folate and vitamin B12 deficiency differed significantly (P=0.000 and P<0.000 for folate and vitamin B12 respectively), depending on the cutoff used for classification (4.4, 6.6 and 8.0 MUg/L - folate; 203 and 473 ng/L - vitamin B12). ROC analyses failed to show any significance of hyperhomocysteinemia as a predictor of folate or vitamin B12 deficiency. CONCLUSION: Reliability of the Hcy concentration as a biomarker of folate or vitamin B12 depletion in COPD patients is not satisfactory, so their deficiency cannot be predicted by the occurrence of HHcy. PMID- 28356858 TI - Greater Efficiency Observed 12 Months Post-Implementation of an Automatic Tube Sorting and Registration System in a Core Laboratory. AB - BACKGROUND: Sample classification and registration have been recognized as important and time-consuming processes in laboratories. There is increasing pressure on laboratories to automate processes due to intense workload and reduce manual procedures and errors. The aim of the present study was to evaluate the positive effects of an automatic tube registration and sorting system on specimen processing. METHODS: An automatic tube registration and sorting system (HCTS2000 MK2, m-u-t AG, Wedel, Germany) was evaluated. Turnaround time (TAT), rate of sample rejection and unrealized tests were examined 12 months pre- and post implementation of the automatic tube sorting and registration system. RESULTS: The mean TAT of routine chemistry immunoassay, complete blood cell count (CBC) and coagulation samples were significantly improved (P<0.001). The number of rejected samples and unrealized tests was insignificantly decreased post implementation of the system (0.4% to 0.2% and 4.5% to 1.4%, respectively) (P>0.05). CONCLUSIONS: By reducing delays and errors in the preanalytical processing and sorting of samples, significant improvements in specimen processing were observed after implementation of the system. These results suggest that an automatic tube registration and sorting system may also be used to improve specimen processing in a higher-volume core laboratory. PMID- 28356859 TI - Diagnostic Accuracy of Brain-derived Neurotrophic Factor and Nitric Oxide in Patients with Schizophrenia: A pilot study. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) and nitric oxide (NO) play multiple roles in the developing and adult CNS. Since BDNF and NO metabolisms are dysregulated in schizophrenia, we measured these markers simultaneously in the blood of schizophrenics and assessed their diagnostic accuracy. METHODS: Thirty eight patients with schizophrenia classified according to demographic characteristics, symptomatologyand therapy and 39 age- and gender-matched healthy controls were enrolled. BDNF was determined by the ELISA technique while the concentration of nitrite/nitrate ([Formula: see text]) was measured by the colorimetric method. RESULTS: Serum BDNF levels were significantly lower (20.38+/ 3.73 ng/mL, P = 1.339E-05), whilst plasma [Formula: see text] concentrations were significantly higher (84.3 (72-121) MUmol/L, P=4.357E-08) in patients with schizophrenia than in healthy controls (25.65+/-4.32 ng/mL; 60.9 (50-76) MUmol/L, respectively). The lowest value of BDNF (18.14+/-3.26 ng/mL) and the highest [Formula: see text] concentration (115.3 (80-138) MUmol/L) were found in patients treated with second-generation antipsychotics (SGA). The patients diseased before the age of 24 and the patients suffering for up to one year had significantly lower serum BDNF levels than those diseased after the age of 24 and the patients who were ill longer than one year. Both BDNF and [Formula: see text] showed good diagnostic accuracy, but BDNF had better ROC curve characteristics, especially in patients with negative symptomatology. CONCLUSIONS: BDNF and nitrite/nitrate showed inverse changes in schizophrenic patients. The most pronounced changes were found in patients treated with second-generation antipsychotics. Although BDNF is not specific of schizophrenia, it may be a clinically useful biomarker for the diagnosis of patients expressing predominantly negative symptoms. PMID- 28356860 TI - Regulation of Insulin and Insulin-Like Activity in Malnourished Patients with Carcinoma Ventriculi Subjected to Total Gastrectomy and Personalized Nutritional Support. AB - BACKGROUND: Insulin and insulin-like growth factor (IGF) activities are disturbed during critical illness. Time-course changes in the concentrations of insulin, IGF-I and IGF-binding proteins (IGFBPs) were monitored in this study and their correlation with interleukin (IL)-6 was assessed in patients subjected to total gastrectomy and specific nutritional regime. METHODS: Patients were fed post operatively according to the following scheme: parenteral nutrition on day 1, enteral nutrition combined with parenteral form from day 2 to 7, peroral nutrition from day 8 and full oral nutrition from day 14. Blood samples were taken periodically and the levels of IL-6, insulin, IGF-I and IGFBP-1 to -4 were determined. RESULTS: On day 1 post-operatively, the concentration of IL-6 reached its maximum and decreased afterwards. The concentration of insulin increased until day 3 and then started to fall. The concentration of IGF-I, already low preoperatively, continued to decrease. The concentration of IGFBP-1 peaked on day 1 post-operatively, whereas the concentration of IGFBP-3 decreased on that day. The concentration of IL-6 correlated positively with the concentration of IGFBP-1 and negatively with IGFBP-3. On day 14, the concentrations of IL-6, insulin and IGFBP-1 returned to or were close to their basal levels, whereas the concentrations of IGF-I and IGFBP-3 remained reduced. CONCLUSIONS: A 14-day post operative recovery, which included specific nutritional support, was suitable to restore insulin concentration and re-establish IGFBP-1 regulation primarily by nutrition. Very low IGF-I level on day 14 after surgery and IGFBP-3 concentration still lower than before surgery indicated that the catabolic condition was not compensated. PMID- 28356862 TI - CTX Correlation to Disease Duration and Adiponectin in Egyptian Children with T1DM. AB - BACKGROUND: In this study, we investigated the relationship of adiponectin with bone marker changes in Egyptian children and adolescents with T1DM and the effect of disease duration on these markers, as well as the possible correlations between adiponectin and bone markers in these patients. METHODS: Sixty Egyptian children and adolescent patients with T1DM were studied. Serum adiponectin and collagen breakdown products (cross-linked C-terminal telopeptide of collagen type l "CTX") were measured and compared to the results of 20 age-matched healthy controls. RESULTS: After adjustment for age, BMI, Tanner stage and gender; (total) adiponectin was significantly higher in all T1DM patients. Serum level of CTX and 25(OH)D showed a marked decrease in diabetics with disease duration > 5 years. Serum level of (total) calcium and inorganic phosphorus (Pi) did not show significant difference from control. CTX was inversely correlated to FBG and T1DM duration. Pi was inversely, while 25(OH)D was directly correlated to FBG. Total calcium showed an inverse correlation with HbA1c. FBG, TC, TAG, LDL-C were independent predictors of CTX in T1DM. CONCLUSIONS: Adiponectin showed no correlation with either CTX or bone homeostatic indices. FBG, TC, TAG, LDL-C were independent predictors of CTX in T1DM. We recommend further investigation of adiponectin isoforms in a population-based study, to establish a good age- and sex-related reference. PMID- 28356861 TI - Influence of Cyp2c19*2 Gene Variant on Therapeutic Response During Clopidogrel Treatment in Patients with Carotid Artery Stenosis. AB - BACKGROUND: Despite the proven clinical effect of oral antiplatelet drugs, a considerable number of patients do not have an adequate response to clopidogrel. The aim of our study was to determine the influence of CYP2C19*2 loss-of-function variant allele on clopidogrel responsiveness in patients with carotid artery stenosis. METHODS: One hundred and twelve patients with carotid artery stenosis undergoing endarterectomy were included in this one-year prospective study. All of them received clopidogrel (75 mg daily) for at least 30 days after the intervention. They were followed from the moment of hospital admission. CYP2C19*2 genotyping was performed by TaqMan Assay. The influence of CYP2C19*2 variant allele on clopidogrel platelet reactivity was determined using multiple-electrode aggregometry (MEA). RESULTS: Genotyping results showed that 82 (73.2%) patients were homozygous for wild type, 29 (25.9%) were heterozygous for the CYP2C19*2 allele and 1 (0.9%) was CYP2C19*2 homozygous. After 24 hours, among those with the wild type 29.3% were clopidogrel responders, and in those with the CYP2C19*2 alleles 10%. In the wild type group, 74.4% were clopidogrel responders after 7 days of taking the drug; 82.9% after 30 days of clopidogrel introduction, respectively. In patients with the CYP2C19*2 alleles the number of responders increased up to 46.7% after 7 days; 53.3% after 30 days of taking the drug, respectively. The risk for being a low-responder is higher for the patients heterozygous for the CYP2C19*2 allele vs. wild-type (OR 4.250, 95% CI 1.695 10.658, P<0.01). CONCLUSIONS: The CYP2C19*2 loss-of-function variant allele has significant influence on clopidogrel response in patients with carotid artery stenosis undergoing endarterectomy. PMID- 28356863 TI - NO-Synthase Activity in Patients with Coronary Heart Disease Associated with Hypertension of Different Age Groups. AB - BACKGROUND: Coronary heart disease is the leading cause of death and disability worldwide. Hypertension is a major independent risk factor for the development of CHD. Abnormalities in NO generation or activity have been proposed as a major mechanism of CHD. The purpose of this article is to determine the activity of eNOS and iNOS in patients with isolated CHD and CHD associated with HT of different age groups. METHODS: Fifty patients with isolated CHD and 42 patients with CHD associated with HT were enrolled in this study. NOS activity was determined by nitrite anion formed in the reaction. RESULTS: A statistically significant increase in iNOS activity is observed in elderly donors. In patients with isolated coronary heart disease cNOS activity is statistically significantly reduced with respect to the control group. The reduction of enzymatic activity of cNOS is more expressed in elderly patients than in middle-aged patients with coronary heart disease. Alterations in eNOS activity are more expressed in patients with coronary heart disease associated with hypertension than in patients with isolated coronary heart disease. Against the background of cNOS inhibition in the patients, a sharp increase in iNOS activity is observed. CONCLUSIONS: It has been shown that disturbance of endothelial function in patients with coronary heart disease associated with hypertension is characterized by reduced endothelial NO synthesis by cNOS and increased systemic NO synthesis due to increased iNOS activity. It has been found that the lack of endothelial NO and hyperproduction of "harmful" NO by iNOS are more expressed in elderly patients. PMID- 28356864 TI - Increased Monoclonal Components: Prevalence in an Italian Population of 44 474 Outpatients Detected by Capillary Electrophoresis. AB - BACKGROUND: Identification, quantification and typing of M-Proteins (MP) play an important role in the diagnosis, classification and monitoring of monoclonal gammopathies both of malignant origin (eg. Multiple Myeloma) and of unknown origin. Previous evidence attests that MGUS (Monoclonal Gammopathy of Undetermined Significance) detected by agarose gel electrophoresis has a prevalence of 3.2% in the general population. Therefore, our study aimed to verify this data by means of capillary zone electrophoresis (CZE). METHODS: CZE was performed to evaluate the prevalence of M-Protein (MP) in 44.474 consecutive outpatients of all ages with a prescription for serum protein electrophoresis over a 2-year period (2008 and 2009). All MPs that were identified were then typed by immunofixation electrophoresis on agarose gel (IFE). RESULTS: In subjects aged over 50 (23.408, i.e., 52.6% of the whole cohort) MP <=30 g/L (MGUS) was identified in 6.0% of cases, with a frequency nearly double than that previously reported. The population was then divided into ten-year age groups: the 71-80 age group had the highest percentage of MP (29%), followed by 61-70 (27%), 51-60 (18%), 81-90 (12%), 41-50 (8%), 31-40 (3%), >90 (2%) and <30 (1%). The frequency of MP types (IFE) was the same in each age group, with IgG Kappa being the most represented class. CONCLUSIONS: According to the high MGUS prevalence observed in this study, these results may be useful especially for general practitioners, because the identification even of small MP (analytical sensitivity: 0.5 g/L) may help optimize clinical management. PMID- 28356865 TI - Evaluation of Systemic Antioxidant Level and Oxidative Stress in Relation to Lifestyle and Disease Progression in Asthmatic Patients. AB - BACKGROUND: Asthma is a chronic disorder of the airways. Oxidative stress is an important part of asthma pathogenesis. It plays a crucial role in exacerbating the disease, as well as an important consequence of airways inflammation. AIM: The present study was undertaken to investigate the lipid peroxidation and catalase activity in serum and antioxidant level in plasma of asthmatic patients and their association with lifestyle and severity of the disease. METHODS: A total of 210 subjects, 120 asthmatics and 90 healthy controls matched in respect to age, sex, lifestyle and socioeconomic status, were chosen randomly for the present study. The samples were analyzed for MDA concentration and catalase activity in serum and ferric reducing ability of plasma (FRAP). Statistical analysis was done using unpaired Student's t-test, ANOVA with Duncan post hoc test and Pearson coefficient of correlation. RESULTS: The serum MDA was found to be significantly higher in the asthmatics as compared to healthy individuals (p<0.01) while catalase activity in serum and antioxidant level of the plasma were markedly lower in the asthmatics as compared to healthy individuals (p<0.01). A significant difference was observed in serum MDA, catalase activity and plasma antioxidant level among the patients in relation to the severity of disease. There was a marked increase in the serum MDA in the patients with longer duration of the disease (p<0.05). CONCLUSIONS: The oxidant-antioxidant imbalance occurs in asthma leading to oxidative stress and is an important part of the asthma pathogenesis. PMID- 28356866 TI - Survivin and VEGF as Novel Biomarkers in Diagnosis of Endometriosis. AB - BACKGROUND: The aim of this study was to investigate the role of peripheral blood markers as additional diagnostic tools to transvaginal ultrasound (TVU) findings in the diagnosis of endometriosis. METHODS: This study included 40 patients undergoing laparoscopy for suspected endometriosis from January to December 2012. Preoperative levels of serum CA125, CA19-9, CEA and mRNA expression levels for survivin and VEGF were obtained. Real-time PCR was used to determine relative gene expression. A new diagnostic score was obtained by deploying the peripheral blood markers to the TVU findings. Statistical methods used were Chi-square, Fisher's, Student's t-test or the Mann - Whitney test. RESULTS: There was a statistically significant difference in serum CA125, survivin and VEGF levels in patients with endometriosis and those without endometriosis (p<0.001, p=0.025 and p=0.009, respectively). False negative TVU findings were noted in 3/13 patients (23.1%) with peritoneal endometriosis without ovaries involvement. High sensitivity (93.3%), specificity (90.0%), PPV (96.6%), NPV (81.8%) and accuracy (92.5%) were obtained for a diagnostic score based on TVU and significant peripheral blood markers (CA125, survivin and VEGF). CONCLUSIONS: Determination of serum CA125, mRNA expression levels for survivin and VEGF along with TVU can contribute to higher accuracy of the noninvasive diagnostic tools for endometriosis. PMID- 28356867 TI - Seventy Years of Biochemical Subjects' Development in Pharmacy Curricula: Experience from Serbia. AB - INTRODUCTION: The pharmacists played an important role in the development of biochemistry as applied chemistry in Serbia. What is more, the first seven state chemists in Serbia were pharmacists. State chemists performed the chemical toxicological analysis as well as some medical and biochemical ones. When it comes to the education of medical biochemists as health workers, the period after the beginning of the second half of the twentieth century should be taken into account because that is when the training of pharmaceutical staff of the Faculty of Pharmacy, University of Belgrade, begins on the territory of Serbia. This paper presents the development of medical biochemistry through the development of curriculum, personnel and literature since the foundation of the Faculty of Pharmacy in Serbia until today. OBJECTIVE: The aim of this paper is to present the historical development of biochemistry at the Faculty of Pharmacy, University of Belgrade, through analysis of three indicators: undergraduate and postgraduate education of medical biochemists, teaching literature and professional associations and trade associations. METHOD: The method of direct data was applied in this paper. Also, desktop analysis was used for analyzing of secondary data, regulations, curricula, documents and bibliographic material. Desktop research was conducted and based on the following sources: Archives of the University of Belgrade-Faculty of Pharmacy, Museum of the History of Pharmacy at the University of Belgrade-Faculty of Pharmacy, the Society of Medical Biochemists of Serbia and the Serbian Chamber of Biochemists. RESULTS AND CONCLUSION: The curricula, the Bologna process of improving education, the expansion of the range of subjects, the number of students, professional literature for teaching biochemistry, as well as professional associations and trade associations are presented through the results. PMID- 28356868 TI - Quality Assurance in Clinical Chemistry: A Touch of Statistics and A Lot of Common Sense. AB - Working in laboratories of clinical chemistry, we risk feeling that our personal contribution to quality is small and that statistical models and manufacturers play the major roles. It is seldom sufficiently acknowledged that personal knowledge, skills and common sense are crucial for quality assurance in the interest of patients. The employees, environment and procedures inherent to the laboratory including its interactions with the clients are crucial for the overall result of the total testing chain. As the measurement systems, reagents and procedures are gradually improved, work on the preanalytical, postanalytical and clinical phases is likely to pay the most substantial dividends in accomplishing further quality improvements. This means changing attitudes and behaviour, especially of the users of the laboratory. It requires understanding people and how to engage them in joint improvement processes. We need to use our knowledge and common sense expanded with new skills e.g. from the humanities, management, business and change sciences in order to bring this about together with the users of the laboratory. PMID- 28356869 TI - Blood Sampling Seasonality as an Important Preanalytical Factor for Assessment of Vitamin D Status. AB - BACKGROUND: The measurement of vitamin D is now commonplace for preventing osteoporosis and restoring an appropriate concentration that would be effective to counteract the occurrence of other human disorders. The aim of this study was to establish whether blood sampling seasonality may influence total vitamin D concentration in a general population of Italian unselected outpatients. METHODS: We performed a retrospective search in the laboratory information system of the University Hospital of Parma (Italy, temperate climate), to identify the values of total serum vitamin D (25-hydroxyvitamin D) measured in outpatients aged 18 years and older, who were referred for routine health check-up during the entire year 2014. RESULTS: The study population consisted in 11,150 outpatients (median age 62 years; 8592 women and 2558 men). The concentration of vitamin D was consistently lower in samples collected in Winter than in the other three seasons. The frequency of subjects with vitamin D deficiency was approximately double in samples drawn in Winter and Spring than in Summer and Autumn. In the multivariate analysis, the concentration of total vitamin D was found to be independently associated with sex and season of blood testing, but not with the age of the patients. CONCLUSIONS: According to these findings, blood sampling seasonality should be regarded as an important preanalytical factor in vitamin D assessment. It is also reasonable to suggest that the amount of total vitamin D synthesized during the summer should be high enough to maintain the levels > 50 nmol/L throughout the remaining part of the year. PMID- 28356870 TI - Salivary Cortisol as a Biomarker of Stress in Mothers and their Low Birth Weight Infants and Sample Collecting Challenges. AB - BACKGROUND: Salivary cortisol measurement is a non-invasive method suitable for use in neonatal research. Mother-infant separation after birth represents stress and skin-to-skin contact (SSC) has numerous benefits. The aim of the study was to measure salivary cortisol in mothers and newborns before and after SSC in order to assess the effect of SSC on mothers' and infants' stress and to estimate the efficacy of collecting small saliva samples in newborns. METHODS: Salivary cortisol was measured in 35 mother-infant pairs before and after the first and the fifth SSC in small saliva samples (50 MUL) using the high sensitivity Quantitative ELISA-Kit (0.0828 nmol/L) for low cortisol levels detection. Samples were collected with eye sponge during 3 to 5 minutes. RESULTS: Cortisol level in mothers decreased after SSC: the highest levels were measured before and the lowest after SSC and the differences in values were significant during both the first (p<0.001) and the fifth SSC (p<0.001). During the first SSC the cortisol level decrease was detected in 14 (40%) and an increase in 21 (60%) newborns, and during the fifth SSC a decrease was detected in 16 (45.7%) and an increase in 19 (54.3%) newborns, without confirmed significance of the difference. Saliva sampling efficacy using eye sponge was 75%. CONCLUSIONS: Cortisol level decrease in mothers proves the stress reduction during SSC, while variable cortisol levels in infants do not indicate stress reduction and imply the need for further research. The used sampling method appeared to be one of the most optimal considering the sample volume, sampling time and efficacy. PMID- 28356871 TI - Comparison of Spectrophotometric and Fluorimetric Methods in Evaluation of Biotinidase Deficiency. AB - BACKGROUND: Biotin, a water-soluble vitamin, is used as a co-factor by enzymes involved in carboxylation reactions. Biotinidase (BTD) catalyzes the recycling of biotin from endogenous and dietary sources. Biotinidase deficiency (BD) is an autosomal recessively inherited disorder of biotin recycling that is associated with neurologic and cutaneous consequences when untreated. The aim of the study was to compare the results of spectrophotometric and fluorimetric methods, as well as to evaluate the advantages and disadvantages of both methods in current research practices. METHODS: Study group was chosen among the BD suspected newborn, children and parents (n = 52) who applied to Hacettepe University Pediatric Metabolism Unit. RESULTS: BTD activity is stable for 2 hours at room temperature and at 4 degrees C, and for 4 months at -20 degrees C and -80 degrees C. Genetic and clinical results showed that 25% of the total number of patients had complete BD which was treated with 10 mg/day biotin, while 15.38% of the patients had partial BD, and they were prescribed biotin 5 mg/day. The area under the ROC curve was 0.960+/-0.25 and 0.927+/- 0.41 for the fluorimetric and spectrophotometric method, respectively. Fluorimetric method showed 100% sensitivity and 97% specificity, whereas spectrophotometric method showed 90.5% sensitivity and 93.7% specificity. CONCLUSIONS: Fluorimetric method is superior to the spectrophotometric method due to higher sensitivity and specificity. PMID- 28356872 TI - The Relationship of Myocardial Collagen Metabolism and Reverse Remodeling after Cardiac Resynchronization Therapy. AB - BACKGROUND: In the majority of patients with a wide QRS complex and heart failure resistant to optimal medical therapy, cardiac resynchronization therapy (CRT) leads to reverse ventricular remodeling and possibly to changes in cardiac collagen synthesis and degradation. We investigated the relationship of biomarkers of myocardial collagen metabolism and volumetric response to CRT. METHODS: We prospectively studied 46 heart failure patients (mean age 61+/-9 years, 87% male) who underwent CRT implantation. Plasma concentrations of amino terminal propeptide type I (PINP), a marker of collagen synthesis, and carboxy terminal collagen telopeptide (CITP), a marker of collagen degradation, were measured before and 6 months after CRT. Response to CRT was defined as 15% or greater reduction in left ventricular end-systolic volume at 6-month follow-up. RESULTS: Baseline PINP levels showed a negative correlation with both left ventricular end-diastolic volume (r=-0.51; p=0.032), and end-systolic diameter (r=-0.47; p=0.049). After 6 months of device implantation, 28 patients (61%) responded to CRT. No significant differences in the baseline levels of PINP and CITP between responders and nonresponders were observed (p>0.05 for both). During follow-up, responders demonstrated a significant increase in serum PINP level from 31.37+/-18.40 to 39.2+/-19.19 MUg/L (p=0.049), whereas in non-responders serum PINP levels did not significantly change (from 28.12+/-21.55 to 34.47+/- 18.64 MUg/L; p=0.125). There were no significant changes in CITP levels in both responders and non-responders (p>0.05). CONCLUSIONS: Left ventricular reverse remodeling induced by CRT is associated with an increased collagen synthesis in the first 6 months of CRT implantation. PMID- 28356873 TI - Silencing of LncRNA HULC Enhances Chemotherapy Induced Apoptosis in Human Gastric Cancer. AB - BACKGROUND: Gastric cancer (GC) is one of the most common cancers in the world; however, chemoresistance greatly decreases the efficacy of therapy in gastric cancer. Long noncoding RNAs (IncRNAs) participate in a variety of biological processes, and we hypothesize that lncRNA HULC regulates the multidrug resistance in GC treatment. METHODS: We obtained GC tissue samples from 42 GC patients and detected the expression level of HULC in the plasma and tissues via qRT-PCR. The relationship between HULC expression and survival rate was confirmed by Kaplan Meier survival analysis. We verified the expression of HULC in GC cell lines via qRT-PCR, and the function of HULC was detected via flow cytometry assay and CCK-8 assay. RESULTS: HULC was highly expressed in the plasma and tissues of the GC patients compared with controls, with HULC high expression indicating lower survival rate. HULC knockdown enhanced cisplatin-induced apoptosis in GC cells. CONCLUSIONS: Our results suggest that silencing lncRNA HULC could enhance chemotherapy induced apoptosis in GC cells, which could provide a novel approach for therapeutic strategies. PMID- 28356874 TI - Transcriptional Activity of Gene Encoding Subunits R1 and R2 of Interferon Gamma Receptor in Peripheral Blood Mononuclear Cells in Patients with Slow Coronary Flow. AB - BACKGROUND: Slow coronary flow (SCF) is a coronary artery disorder characterized with delayed opacification of epicardial coronary arteries without obstructive coronary disease. The pathophysiological mechanisms of SCF remain unclear. One of the possible mechanisms that may participate in the pathology of SCF is endothelial dysfunction related to the inflammatory process. Interferon gamma (IFN-gamma) is an inflammatory cytokine that acts through its specific receptor composed of two subunits, IFN-gammaR1 and IFN-gammaR2. Transcriptional activity of the gene encoding these subunits influences IFN-gamma activity. This study aimed to investigate the gene expression of IFN-gamma receptor subunits in peripheral blood mononuclear cells (PBMC) from patients with SCF. METHODS: The study was performed with 30 patients (22 male/8 female) aged 35-76 (52.8+/-11.7 years) with SCF and 15 sex- (11 male/4 female), Body Max Index (BMI)- and age matched (54.73+/-9.42 years) healthy subjects. Total mRNA was extracted from PBMC and was determined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). The relative expression values (2-DeltaDeltaCt) between control and case groups were determined and the Mann-Whitney U test was used for statistical analysis. RESULTS: There was a significant increase in the gene expression of IFN-gammaR1 in PBMC from SCF patients vs. controls (P< 0.0001); but the differences in IFN-gammaR2 gene expression were statistically insignificant between patient and control groups (P= 0.853). CONCLUSIONS: It can be concluded that IFN-gamma gene expression may influence the function of microvasculature and thereby contribute to the pathophysiology of SCF. PMID- 28356876 TI - Usefulness of NT-proBNP in the Follow-Up of Patients after Myocardial Infarction. AB - BACKGROUND: Since serial analyses of NT-proBNP in patients with acute coronary syndromes have shown that levels measured during a chronic, later phase are a better predictor of prognosis and indicator of left ventricular function than the levels measured during an acute phase, we sought to assess the association of NT proBNP, measured 6 months after acute myocardial infarction (AMI), with traditional risk factors, characteristics of in-hospital and early postinfarction course, as well as its prognostic value and optimal cut-points in the ensuing 1 year follow-up. METHODS: Fasting venous blood samples were drawn from 100 ambulatory patients and NT-proBNP concentrations in lithium-heparin plasma were determined using a one-step enzyme immunoassay based on the "sandwich" principle on a Dimension RxL clinical chemistry system (DADE Behring-Siemens). Patients were followed-up for the next 1 year, for the occurrence of new cardiac events. RESULTS: Median (IQR) level of NT-proBNP was 521 (335-1095) pg/mL. Highest values were mostly associated with cardiac events during the first 6 months after AMI. Negative association with reperfusion therapy for index infarction confirmed its long-term beneficial effect. In the next one-year follow-up of stable patients, multivariate Cox regression analysis revealed the independent prognostic value of NT-proBNP for new-onset heart failure prediction (p=0.014), as well as for new coronary events prediction (p=0.035). Calculation of the AUCs revealed the optimal NT-proBNP cut-points of 800 pg/mL and 516 pg/mL, respectively. CONCLUSIONS: NT-proBNP values 6 months after AMI are mainly associated with the characteristics of early infarction and postinfarction course and can predict new cardiac events in the next one-year follow-up. PMID- 28356875 TI - Association of Bax Expression and Bcl2/Bax Ratio with Clinical and Molecular Prognostic Markers in Chronic Lymphocytic Leukemia. AB - BACKGROUND: In chronic lymphocytic leukemia (CLL), in vivo apoptotic resistance of malignant B lymphocytes results, in part, from the intrinsic defects of their apoptotic machinery. These include genetic alterations and aberrant expression of many apoptosis regulators, among which the Bcl2 family members play a central role. AIM: The aim of this study was to investigate the association of pro apoptotic Bax gene expression and Bcl2/Bax ratio with the clinical features of CLL patients as well as with molecular prognostic markers, namely the mutational status of rearranged immunoglobulin heavy variable (IGHV) genes and lipoprotein lipase (LPL) gene expression. METHODS: We analyzed the expression of Bax mRNA and Bcl2/Bax mRNA ratio in the peripheral blood mononuclear cells of 58 unselected CLL patients and 10 healthy controls by the quantitative reverse-transcriptase polymerase chain reaction. RESULTS: We detected significant Bax gene overexpression in CLL samples compared to non-leukemic samples (p=0.003), as well as an elevated Bcl2/Bax ratio (p=<0.001). Regarding the association with prognostic markers, the Bcl2/Bax ratio showed a negative correlation to lymphocyte doubling time (r=-0.307; p=0.0451), while high-level Bax expression was associated with LPL-positive status (p=0.035). Both the expression of Bax and Bcl2/Bax ratio were higher in patients with unmutated vs. mutated IGHV rearrangements, but this difference did not reach statistical significance. CONCLUSIONS: Our results suggest that dysregulated expression of Bcl2 and Bax, which leads to a high Bcl2/Bax ratio in leukemic cells, contributes to the pathogenesis and clinical course of CLL. PMID- 28356877 TI - Lack of Association between Angiotensin Converting Enzyme I/D Polymorphism and Unexplained Recurrent Miscarriage in Saudi Arabia. AB - BACKGROUND: An insertion/deletion (I/D) polymorphism in the angiotensin converting enzyme (ACE) gene has been associated with recurrent miscarriage (RM) in several populations. We initiated this study to determine the association, if any, between the I/D polymorphism of ACE gene and RM in Saudi females. METHOD: This study was conducted on 61 Saudi females suffering from RM (mean age: 34.1+/ 6.2 years; range 15-45) attending clinics at King Khalid University Hospital, and 59 age matched females who had at least 2 children, as controls. Blood samples were drawn in EDTA tubes by venipuncture. DNA was extracted using the Puregene DNA purification kits. Insertion/Deletion (I/D) polymorphism of ACE gene was investigated by amplifying the genomic DNA by PCR using gene-specific primers. A single 190 bp or 490 bp band was obtained in the homozygous cases for the D allele or I allele, respectively, while the presence of both 190 and 490 bp bands indicated heterozygosity (ID). STATISTICAL ANALYSIS: Deviation from Hardy Weinberg equilibrium was determined (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl). A standard chi-square (chi2) test was used for comparing the genotype and allele frequencies in the two groups and Students't' test and chi2 test were employed to compare values between the two groups. P<0.05 was considered statistically significant. RESULTS: The frequencies of DD, ID, and II genotypes were 56.7%, 29.5% and 4.9%, respectively, in females with RM and 54.2%, 42.3% and 3.3% respectively in the control group, but the difference was not statistically significant. CONCLUSION: In some populations, meta-analyses showed an association between I/D polymorphism and RM risk, and the D allele was implicated as an increased risk factor for RM. However, this association was not apparent in the Saudi females. PMID- 28356878 TI - Cardiac Troponin I is Increased in Patients with Polytrauma and Chest or Head Trauma. Results of A Retrospective Case-Control Study. AB - BACKGROUND: We performed a retrospective case-control study to assess the values of cardiac troponin I (cTnI) in a large number of patients admitted to the emergency department (ED) with different types of trauma. METHODS: The study population consisted of all patients aged 18 years or older admitted to the local ED with all types of traumas over a 1-year period. Results of cTnI were compared with those of 125 consecutive blood donors and 25 non-cardiac chest pain ED patients. RESULTS: The final study population consisted of 380 trauma patients, 10 with isolated abdominal trauma, 99 with isolated trauma of the limbs, 49 with isolated chest trauma, 145 with isolated head trauma and 77 with polytrauma. The concentration of cTnI did not differ among the three study populations, but the frequency of measurable values was substantially higher in patients with trauma (63%) than in blood donors and non-cardiac chest pain ED patients (both 20%). The frequency of cTnI values above the 99th percentile of the reference range was significantly higher in trauma patients (20%) than in blood donors (0%) and noncardiac chest pain ED patients (8%). Increased cTnI values were more frequent after head trauma (21%), chest trauma (27%) and polytrauma (29%) compared to patients with abdominal (0%) or limbs trauma (8%). CONCLUSIONS: These results suggest that the measurement of cardiac troponin may be advisable to identify potential cardiac involvement in trauma patients, especially in those with polytrauma and head or chest trauma. PMID- 28356879 TI - Relationship between Cardiovascular Risk Score and Traditional and Nontraditional Cardiometabolic Parameters in Obese Adolescent Girls. AB - BACKGROUND: Since the cardiovascular (CV) risk score in the young population, children and adolescents, is underestimated, especially in developing countries such as Montenegro, where a strong interaction exists between the genetically conditioned CV risk and environmental factors, the purpose of this study was to estimate CV risk in apparently healthy adolescent girls. Moreover, we aimed to test some new, emerging CV risk factors and their interaction with the traditional ones, such as obesity. Precisely, we aimed to assess the impact of low bilirubin levels, as a routine biochemical parameter, as an additional risk factor for atherosclerotic disease in the adult phase. METHODS: Forty-five obese adolescent girls (mean age 17.8+/-1.22 years) and forty-five age- and sex-matched normal weight controls, all nonsmokers, were included. Anthropometric and biochemical parameters were measured. Cardiovascular Risk Score (CVRS) was calculated by adding the points for each risk factor (e.g. sex, HDL-c, non-HDL-c, blood pressure and fasting glycemia). RESULTS: A significant positive relationship between CVRS and ALT, hsCRP and TG/HDL-c, but an opposite relationship between CVRS and total bilirubin were found (P<0.001). Multiple linear regression analysis showed that higher waist circumference (WC) and LDL-c, but lower HDL-c were independent predictors of lower bilirubin values (adjusted R2=0.603, P<0.001). CONCLUSIONS: Obese adolescent girls are at an increased risk of cardiovascular disease late in life. In addition to the traditional risk factors, total bilirubin may have the potential to discriminate between low and higher risk for cardiovascular disturbances in healthy adolescent girls. PMID- 28356880 TI - Cardiovascular Risk Factors in 7-13 Years Old Children from Vojvodina (Serbia). AB - BACKGROUND: Atherosclerosis is a chronic inflammatory disease which starts early in life and depends on many factors, an important one being dyslipoproteinemia. According to several studies, atherosclerotic plaques or their precursors could be seen in children younger than 10 years. During later life, interaction with a sedentary way of life, as well as unhealthy nutrition, smoking, alcohol consumption, obesity and family history of cardiovascular disease cause the burden of atherosclerotic disease. METHODS: Study included 624 children (316 boys, 308 girls), aged from 7-13 years. We analysed socio-demographic data (BMI, blood pressure, cardiovascular family history, smoking status), as well as lipid status with lipoprotein little a-Lp(a), and apolipoproteins: Apo AI, Apo B-100 for all children. This enabled us to calculate new atherogenic indices Tg/HDL-c, lipid tetrad index (LTI) and lipid pentad index (LPI). Cardiovascular risk for later life was estimated by using modified Risk Score for Young Individuals (RS), which divided the subjects according to the score level: low, medium and higher risk. RESULTS: The older children (13 y) had better lipid status than the younger children, i.e. significantly lower total cholesterol, LDL-C, triglycerides and non-HDL-C concentration and significantly higher HDL-C concentration than the younger children and this was in accordance with the RS level. Children with a positive family history of CV disease had significantly higher Lp(a) concentration and blood pressure. LPI was significantly higher in children with a higher RS. CONCLUSIONS: The results of our work could be used for cardiovascular risk assessment in apparently healthy children to provide preventive measures which could control the changeable risk factors. PMID- 28356882 TI - Protective Role of Maternal P.VAL158MET Catechol-O-Methyltransferase Polymorphism against Early-Onset Preeclampsia and its Complications. AB - BACKGROUND: Up until now there have been contradictory data about the association between p.Val158Met catechol-O-methyltransferase (COMT) polymorphism and risk of preeclampsia (PE). The goal of this study was to assess the potential correlation between p.Val158Met COMT polymorphism and risk of early-onset PE, risk of a severe form of early-onset PE, as well as risk of small-for-gestational-age (SGA) complicating PE. METHODS: The study included 47 early-onset PE patients and 47 control cases. Forty-seven early-onset PE patients were grouped by disease severity (33 patients with a severe form and 14 patients without severe features) and secondly by size for gestational age (12 patients with appropriate-for gestational-age (AGA) and 35 patients with SGA size). p.Val158Met polymorphism was genotyped by PCR-RFLP analysis. RESULTS: Allele analysis showed significant difference in COMT allele distribution between early-onset PE and control group as well as early-onset PE SGA and controls (p=0.04057 and p=0.0411 respectively). A statistically significant distribution difference between the severe form and form without severe features of early-onset PE patients was not observed (p>0.05). The highest difference observed was in the allele recessive model where COMT MetMet genotype was associated with decreased risk of early-onset PE (OR=0.281; 95%CI = 0.092-0.7836) and PE complications including severe early onset PE (OR= 0.304; 95%CI=0.086-0.944) and SGA early-onset PE (OR=0.284; 95%CI=0.081-0.874). CONCLUSIONS: COMT may be used as a candidate gene for early onset PE and its severe form and SGA complications. PMID- 28356883 TI - NLRP3 and CARD8 Polymorphisms Influence Higher Disease Activity in Rheumatoid Arthritis. AB - BACKGROUND: The activation of NLRP3-inflammasome may contribute to inflammatory processes in rheumatoid arthritis (RA). Functional polymorphisms in the genes coding for its components NLRP3 and CARD8 were associated with a proinflammatory phenotype. Our aim was to investigate the influence of these polymorphisms on RA susceptibility and disease activity at the time of diagnosis and after six months of treatment. METHODS: A group of 128 RA patients treated with methotrexate and 122 healthy controls were genotyped for NLRP3 rs35829419 (p. Q705K) and CARD8 rs2043211 (p. C10X) polymorphisms. RESULTS: RA susceptibility was not influenced by the investigated polymorphisms or their interaction. The investigated polymorphisms explained 8% of variability in DAS28 at the time of diagnosis. Carriers of NLRP3 rs35829419 or CARD8 rs2043211 polymorphisms had significantly higher DAS28 at the time of diagnosis (p=0.003; p=0.022; respectively). Polymorphic CARD8 rs2043211 TT genotype was also associated with higher DAS28 after six months of treatment (p=0.033). CONCLUSIONS: Genetic variability of inflammasome components may contribute to higher disease activity at the time of diagnosis and after 6 months of methotrexate treatment in RA patients. Better understanding of the immunological mechanisms behind a more active course of RA may suggest novel treatment approaches in a subset of patients with a proinflammatory phenotype. PMID- 28356881 TI - Association of GSTO1 and GSTO2 Polymorphism with Risk of End-Stage Renal Disease Development and Patient Survival. AB - BACKGROUND: Oxidative stress in patients with end-stage renal disease (ESRD) is associated with long-term cardiovascular complications. The cytosolic family of glutathione S-transferases (GSTs) is involved in the detoxication of various toxic compounds and antioxidant protection. GST omega class members, GSTO1 and GSTO2 possess, unlike other GSTs, dehydroascorbate reductase and deglutathionylation activities. The aim of this study was to clarify the role of genetic polymorphisms of GSTO1 (rs4925) and GSTO2 (rs156697) as risk determinants for ESRD development, as well as in the survival of these patients. METHODS: A total of 199 patients and 199 healthy subjects were included in the study and genotyped for both GSTO1 and GSTO2 polymorphism. Protein thiol and carbonyl groups as markers of protein oxidative damage were determined spectrophotometrically. Cox proportional hazard model and Kaplan-Meier analysis were performed to investigate the role of GSTO1 and GSTO2 genetic polymorphism on mortality of ESRD patients during the follow-up period (36 month). RESULTS: Individuals carrying the variant GSTO2 GG genotype were at 2.45-fold higher risk of ESRD development compared to the wild type GSTO2 AA genotype (OR=2.45; 95%CI=1.18-5.07; p=0.016). The results of GSTO1/GSTO2 haplotype analysis showed that the haplotype combination of GSTO1 (*A)/GSTO2 (*A) (GSTO1 variant/GSTO2 wild type allele) was protective for ESRD (OR=0.23 95%CI=0.12-0.44, p=0.001). Patients carrying at least one GSTO1 reference allele have shorter mean overall (Log rank=2.844, p =0.241) and cardiovascular survival probability (Log rank=4.211, p=0.122). CONCLUSIONS: GSTO polymorphisms have been shown to act as significant markers in assessing the risk of ESRD development and patients' survival. PMID- 28356884 TI - Predictive Value of Carcinoembryonic and Carbohydrate Antigen 19-9 Related to Some Clinical, Endoscopic and Histological Colorectal Cancer Characteristics. AB - BACKGROUND: Colorectal cancer (CRC) is an important oncological and public health problem worldwide, including Serbia. Unfortunately, half of the patients are recognized in an advanced stage of the disease, therefore, early detection through specific tumor biomarkers, such as carcinoembryonic (CEA) and carbohydrate antigen 19-9 (CA 19-9), is the only way to cope with CRC expansion. METHODS: Our cross-sectional study evaluated the influence of some clinical, endoscopic and histological characteristics of CRC on CEA and CA 19-9 serum levels, to determine whether these biomarkers could be related to CRC detection. The study included 372 participants: 181 suffered from CRC and 191 participants were controls. Endoscopic and histological examinations were used for CRC diagnosis, while additional ultrasound and abdominal computerised tomography imaging were used for staging the disease. Measurement of CEA and CA 19-9 was performed after CRC confirmation. RESULTS: Age, gender, tumor localization, macro morphological and histological characteristics did not influence biomarkers serum levels. Both were significantly higher (p<0.01) in patients with Dukes D stage of CRC compared with controls. Sensitivity (76.8%) and specificity (76.6%) of CEA alone were higher than for CA 19-9, but with no statistical significance. Furthermore, sensitivity of CEA alone in the Dukes A/B group was similar to the entire CRC patient group. CONCLUSIONS: Although not recommended as a screening method for the general population, elevated values of each biomarker indicate further diagnostic procedures and their simultaneous testing can improve the diagnostic sensitivity in early detection of CRC, as shown by the united analysis (AUC 0.842). PMID- 28356885 TI - Susceptibility to Ulcerative Colitis and Genetic Polymorphisms of A251G SOD1 and C-262T CAT. AB - BACKGROUND: Reactive oxygen species can attack and damage almost every molecule found in living cells, including proteins, carbohydrates, lipids, and DNA. For this reason, their production is normally tightly controlled. Among the most important defenses against these radicals are the superoxide dismutase (SOD) enzymes and catalase (CAT). Increasing attention has been given to the role of reactive oxygen metabolites in the pathogenesis of ulcerative colitis (UC), which is defined as an idiopathic and chronic intestinal inflammation. Accordingly, we hypothesized a relation between genetic polymorphisms in the two antioxidant enzymes SOD1 A251G (rs2070424) and CAT C-262T (rs1001179) and the risk of UC. METHODS: The present case-control study included 109 UC patients (46 males and 50 females) and 186 (67 males and 119 females) gender-matched healthy controls. Genotyping was done by the PCR-RFLP method. RESULTS: After adjusting for age and gender, a significant association was observed between the AG+GG genotypes of SOD1 A251G polymorphism (vs. AA genotype) and risk of UC (OR=0.29, 95% CI: 0.10 0.86, P= 0.025) after adjusting for age and gender. Our statistical analysis revealed that the CAT C-262T polymorphism did not associate with the risk of UC before and/or after adjusting for age and gender. CONCLUSIONS: Based on the present statistical analysis, the G allele of the SOD1 A251G polymorphism decreases the risk of UC, thus it might be assumed that the G allele has a protective role. PMID- 28356886 TI - Analysis of the Variability of Epstein-Barr Virus Genes in Infectious Mononucleosis: Investigation of the Potential Correlation with Biochemical Parameters of Hepatic Involvement. AB - BACKGROUND: Primary Epstein-Barr virus (EBV) infection is usually asymptomatic, although at times it results in the benign lymphoproliferative disease, infectious mononucleosis (IM), during which almost half of patients develop hepatitis. The aims of the present study are to evaluate polymorphisms of EBV genes circulating in IM isolates from this geographic region and to investigate the correlation of viral sequence patterns with the available IM biochemical parameters. METHODS: The study included plasma samples from 128 IM patients. The genes EBNA2, LMP1, and EBNA1 were amplified using nested-PCR. EBNA2 genotyping was performed by visualization of PCR products using gel electrophoresis. Investigation of LMP1 and EBNA1 included sequence, phylogenetic, and statistical analyses. RESULTS: The presence of EBV DNA in plasma samples showed correlation with patients' necessity for hospitalization (p=0.034). The majority of EBV isolates was genotype 1. LMP1 variability showed 4 known variants, and two new deletions (27-bp and 147-bp). Of the 3 analyzed attributes of LMP1 isolates, the number of 33-bp repeats less than the reference 4.5 was the only one that absolutely correlated with the elevated levels of transaminases. EBNA1 variability was presented by prototype subtypes. A particular combination of EBNA2, LMP1, and EBNA1 polymorphisms, deleted LMP1/P-thr and non-deleted LMP1/P ala, as well as genotype 1/ 4.5 33-bp LMP1 repeats or genotype 2/ 4.5 33-bp LMP1 repeats showed correlation with elevated AST (aspartate aminotransferase) and ALT (alanine transaminase). CONCLUSIONS: This is the first study which identified the association between EBV variability and biochemical parameters in IM patients. These results showed a possibility for the identification of hepatic related diagnostic EBV markers. PMID- 28356887 TI - Pre-Test and Post-Test Applications to Shape the Education of Phlebotomists in A Quality Management Program: An Experience in a Training Hospital. AB - BACKGROUND: After the introduction of modern laboratory instruments and information systems, preanalytic phase is the new field of battle. Errors in preanalytical phase account for approximately half of total errors in clinical laboratory. The objective of this study was to share an experience of an education program that was believed to be successful in decreasing the number of rejected samples received from the Emergency Department (ED). METHODS: An education program about laboratory procedures, quality requirements in the laboratory, patient and health-care worker safety was planned by the quality team to be performed on 36 people who were responsible for sample collection in the ED. A questionary which included 11 questions about the preanalytic phase was applied to all the attendees before and after training. The number of rejected samples per million was discovered with right proportion account over the number of accepted and rejected samples to laboratory after and before the training period. RESULTS: Most of the attendees were nurses (n: 22/55%), with over 12 years of experience in general and 2-4 years experience in the ED. Knowledge level of the attendees was calculated before training as 58.9% and after training as 91.8%. While the total rate of sample rejection before training was 2.35% (sigma value 3.37-3.50), the rate after training was 1.56% (sigma value 3.62 3.75). CONCLUSIONS: Increasing the knowledge of staff has a direct positive impact on the preanalytic phase. The application of a pre-test was observed to be a feasible tool to shape group specific education programs. PMID- 28356888 TI - Mothers' Mobility after Separation: Do Grandmothers Matter? AB - Starting from a life course perspective, this study aims to gain more insight into mobility patterns of recently separated mothers, focusing especially on moves to the location of their own mother: the maternal grandmother. Separated mothers, having linked lives with their own mothers, may benefit from their practical and emotional support. Additionally, the grandparents' home can be a (temporary) place to stay shortly after divorce. Data come from the System of social statistical datasets (Statistics Netherlands). This unique dataset combines longitudinal data from a vast number of administrative registers. It covers the complete Dutch population, making it exceptionally well suited for life course and mobility research. We studied mothers with minor children between 1/1/2008 and 31/12/2010. Our study included 579,500 mothers, of whom about 8,800 (1.5%) experienced a separation in 2008. Separated mothers moved to the grandmother's municipality more often than non-separated mothers, which might be partially motivated by the need for childcare. They also coresided with the grandmother more than non-separated movers, mostly because of a vulnerable socio economic position. Although often temporary, coresidence appears to have a prolonged impact on the mothers' location choice; mothers frequently stayed in the grandmother's municipality after moving out. Finally, our results indicated that some mothers seemed to use the parental home as a stepping stone to cohabit with a new partner. (c) 2016 The Authors. Population, Space and Place published by John Wiley & Sons Ltd. PMID- 28356889 TI - The Effects of Different Intensities of Exercise on Behavioral and Molecular Pain Related Reactions in Rats: Implications for Medication Development. AB - Drug discovery for pain management is an important area of research given current limitations in medications for pain, including the addictive potential of opiates. While exercise may help worsen or lessen pain, the precise molecular mechanisms involved are incompletely understood. Thus, in the present study, we evaluated the effects of exercise intensity on pain via assessment of behavior and c-Fos expression. An animal model of moderate and high-intensity treadmill exercise was established. The specific nociceptive behaviors, such as flinches, favoring, lifting, and licking, were observed within 60 min following intraplantar injection of formalin. Lifting and licking times in the 1 h following formalin injection were shorter in the moderate/high-intensity exercise groups than the control group. The common pain scores in the exercise groups were significantly lower than those in the control group. There was no significant difference between the exercise groups. There was no significant difference in flinches among the three groups. Moderate/high-intensity exercise decreased c-Fos expression in the ipsilateral dorsal horn. These results suggest that different intensities of exercise may substantially influence pain-related responses. Exercise may reduce c-Fos expression and attenuate pain-related behaviors and provide insight into how exercise may reduce pain. Further research is needed to understand the precise mechanisms by which exercise may reduce c-Fos expression as the mediating entities may represent suitable targets for medication development for pain management, including medications that might be used in lieu of or in conjunction with exercise. PMID- 28356890 TI - Evaluation and Optimization of in silico designed Sphingosine-1-Phosphate (S1P) Receptor Subtype 1 Modulators for the Management of Multiple Sclerosis. AB - Multiple Sclerosis (MS) is a chronic autoimmune disorder affecting the Central Nervous System (CNS) through inflammation, demyelination and neurodegeneration. Sphingosine-1-phosphate receptor (S1PR1) modulators have been approved for the management of MS. Phosphorylated fingolimod mimics endogenous sphingosine-1 phosphate (S1P), a bioactive lipid that regulates remyelination and cell injury. Amiselimod was developed as a successor of fingolimod, with more specificity for S1PR1, and showed promising results until phase 2 clinical trials. This study utilized the fingolimod and amiselimod scaffolds, together with their critical binding interactions for the S1PR1 Ligand Binding Pocket, as templates for the in silico de novo design of high efficiency binding Lipinski rule-compliant molecules. A rigorous selection process identified two molecules, Molecules 003 and 019, deriving from fingolimod and amiselimod, respectively, which were deemed most suitable for further optimization. PMID- 28356891 TI - Variable Effects of Autophagy Induction by Trehalose on Herpesviruses Depending on Conditions of Infection. AB - Trehalose is a non-reducing sugar formed from two glucose units. Trehalose induces abundant autophagy in cultured cells and also reduces the rate of aggregation of the huntingtin protein in the animal model of Huntington disease, a chronic neurological disease in humans. The mechanism of this effect on autophagy is now known to be caused by starvation secondary to inhibition of a family of glucose transporters known as the solute carrier 2 or the glucose transporter family. Variable effects of trehalose treatment have been observed during infections with two herpesviruses-human cytomegalovirus and varicella zoster virus. The reasons for differing results have now been delineated. These differences are caused by two variables in conditions of infection: timing of addition of trehalose and type of inoculum (cell-free virus vs. infected cells). When monolayers pretreated with trehalose were inoculated with cell-free virus, there was a decline in virus spread by as much as 93 percent when compared with untreated monolayers. However, when monolayers were inoculated with infected cells rather than cell-free virus, there was no decline in virus spread. These results demonstrated that the effect of trehalose was limited to monolayers that were starved when inoculated with cell-free virus. In contrast, sufficient virus was already present in infected cell inocula so as to minimize any inhibitory effect of a starved monolayer. These results also showed that trehalose did not specifically inhibit a herpesvirus; rather, addition of trehalose to cell culture media altered the intracellular environment. PMID- 28356892 TI - Discovery of a Structurally Unique Small Molecule that Inhibits Protein Synthesis. AB - Identifying and characterizing natural products and synthetic small molecules that inhibit biochemical processes such as ribosomal translation can lead to novel sources of molecular probes and therapeutics. The search for new antibiotics has been invigorated by the increasing burden of drug-resistant bacteria and has identified many clinically essential prokaryote-specific ribosome inhibitors. However, the current cohort of antibiotics is limited with regards to bacterial resistance mechanisms because of structural similarity within classes. From a high-throughput screen for translation inhibitors, we discovered a new compound, T6102, which inhibits bacterial protein synthesis in vitro, inhibits bacterial growth of Bacillus subtilis in vivo, and has a chemical structure that appears to be unique among known classes of translation-inhibiting antibiotics. T6102's unique structure compared to current clinically-utilized antibiotics makes it an exciting new candidate for the development of next generation antibiotics. PMID- 28356893 TI - Alzheimer's Toxic Amyloid Beta Oligomers: Unwelcome Visitors to the Na/K ATPase alpha3 Docking Station. AB - Toxic amyloid beta oligomers (AbetaOs) are known to accumulate in Alzheimer's disease (AD) and in animal models of AD. Their structure is heterogeneous, and they are found in both intracellular and extracellular milieu. When given to CNS cultures or injected ICV into non-human primates and other non-transgenic animals, AbetaOs have been found to cause impaired synaptic plasticity, loss of memory function, tau hyperphosphorylation and tangle formation, synapse elimination, oxidative and ER stress, inflammatory microglial activation, and selective nerve cell death. Memory loss and pathology in transgenic models are prevented by AbetaO antibodies, while Aducanumab, an antibody that targets AbetaOs as well as fibrillar Abeta, has provided cognitive benefit to humans in early clinical trials. AbetaOs have now been investigated in more than 3000 studies and are widely thought to be the major toxic form of Abeta. Although much has been learned about the downstream mechanisms of AbetaO action, a major gap concerns the earliest steps: How do AbetaOs initially interact with surface membranes to generate neuron-damaging transmembrane events? Findings from Ohnishi et al (PNAS 2005) combined with new results presented here are consistent with the hypothesis that AbetaOs act as neurotoxins because they attach to particular membrane protein docks containing Na/K ATPase-alpha3, where they inhibit ATPase activity and pathologically restructure dock composition and topology in a manner leading to excessive Ca++ build-up. Better understanding of the mechanism that makes attachment of AbetaOs to vulnerable neurons a neurotoxic phenomenon should open the door to therapeutics and diagnostics targeting the first step of a complex pathway that leads to neural damage and dementia. PMID- 28356894 TI - A Novel Epi-drug Therapy Based on the Suppression of BET Family Epigenetic Readers. AB - Recent progress in epigenetic research has made a profound influence on pharmacoepigenomics, one of the fastest growing disciplines promising to provide new epi-drugs for the treatment of a broad range of diseases. Histone acetylation is among the most essential chromatin modifications underlying the dynamics of transcriptional activation. The acetylated genomic regions recruit the BET (bromodomain and extra-terminal) family of bromodomains (BRDs), thereby serving as a molecular scaffold in establishing RNA polymerase II specificity. Over the past several years, the BET epigenetic readers have become the main targets for drug therapy. The discovery of selective small-molecule compounds with capacity to inhibit BET proteins has paved a path for developing novel strategies against cancer, cardiovascular, skeletal, and inflammatory diseases. Therefore, further research into small chemicals impeding the regulatory activity of BRDs could offer therapeutic benefits for many health problems including tumor growth, heart disease, oral, and bone disorders. PMID- 28356895 TI - Exploiting Long Noncoding RNAs as Pharmacological Targets to Modulate Epigenetic Diseases. AB - Long non-coding RNAs (lncRNAs) constitute the largest class of non-coding transcripts in the human genome. Results from next-generation sequencing and bioinformatics advances indicate that the human genome contains more non-coding RNA genes than protein-coding genes. Validated functions of lncRNAs suggest that they are master regulators of gene expression and often exert their influences via epigenetic mechanisms by modulating chromatin structure. Specific lncRNAs can regulate transcription in gene clusters. Since the functions of protein-coding genes in clusters are often tied to specific pathways, lncRNAs constitute attractive pharmacological targets. Here we review the current knowledge of lncRNA functions in human cells and their roles in disease processes. We also present forward-looking perspectives on how they might be manipulated pharmacologically for the treatment of a variety of human diseases, in which regulation of gene expression by epigenetic mechanisms plays a major role. PMID- 28356896 TI - A Cell-Based Assay to Assess Hemichannel Function. AB - Activation of connexin hemichannels is involved in the pathophysiology of disorders that include deafness, stroke, and cardiac infarct. This aspect makes hemichannels an attractive therapeutic target. Unfortunately, most available inhibitors are not selective or isoform specific, which hampers their translational application. The absence of a battery of useful inhibitors is due in part to the absence of simple screening assays for the discovery of hemichannel-active drugs. Here, we present an assay that we have recently developed to assess hemichannel function. The assay is based on the expression of functional human connexins in a genetically modified bacterial strain deficient in K+ uptake. These modified cells do not grow in low-K+ medium, but functional expression of connexin hemichannels allows K+ uptake and growth. This cell-growth based assay is simple, robust, and easily scalable to high-throughput multi-well platforms. PMID- 28356898 TI - Novel Pharmacologic Candidates for Treatment of Primary Open-Angle Glaucoma. AB - Primary open-angle glaucoma (OAG) affects approximately 45 million people worldwide and more than 2.5 million people aged 40 years or older in the United States. Pharmacologic treatment for glaucoma is directed towards lowering intraocular pressure (IOP) to slow disease progression and delay visual field loss. Current medical treatment options for the lowering of IOP include the following classes of topical medications: beta-adrenergic antagonists, alpha adrenergic agonists, cholinergic agonists, carbonic anhydrase inhibitors, and prostaglandin analogs. Issues with existing drugs include failure to achieve target IOP with monotherapy, drug-related side effects, and low patient compliance with multiple daily administration of eye drops. In recent years, the scientific and medical community has seen encouraging development of novel classes of drugs for primary OAG, the majority of which lower IOP by targeting the trabecular meshwork outflow pathway to increase aqueous humor outflow. Among the most promising new pharmacologic candidates are rho kinase inhibitors including ripasudil (K-115), netarsudil (AR-13324), and AMA0076; adenosine receptor agonists including trabodenoson (INO-8875); and modified prostaglandin analogs including latanoprostene bunod (LBN, BOL-303259-X) and ONO-9054. This study aims to systematically review and summarize the most recent developments in clinical trials for new pharmacologic options for the treatment of primary open angle glaucoma. PMID- 28356900 TI - Medication Safety in Clinical Trials: Role of the Pharmacist in Optimizing Practice, Collaboration, and Education to Reduce Errors. AB - Standardized safety practices for investigational drugs in clinical research protocols are limited and the vast majority of research pharmacists have concerns regarding its safety. Identified areas for medication safety risks include protocol complexity, medication ordering, and the processes for packaging, storage, and dispensing investigational medications. Inclusion of a pharmacist creates multiple mechanisms to promote safety and improve the quality of clinical research. This is accomplished through collaborating in the development of a research protocol, reviewing as a member of an advisory committee, developing mechanisms that contribute to safety, and assuring compliance with local and national regulations and standards. Ultimately, the profession of pharmacy has foundational responsibility for assuring the safe and effective use of medications, including investigational drugs in clinical research. It is through multidisciplinary collaboration that a research study will attain the highest standards for safety and maximize the quality and effectiveness of the data obtained in the clinical trial. PMID- 28356899 TI - Drug Development Against Metastatic Cancers. AB - While combinational diagnostic and treatment strategies over the past decades have significantly improved the overall survival of cancer patients, metastatic cancer remains a leading cause of death in developed countries. The lack of successful treatment strategies for the disease is in large part due to the complexity of the metastatic transformation, which embodies extensive cellular and extracellular alterations, enabling metastatic cancer cells to reach and colonize other organs. The mode of action for the majority of anti-cancer drugs used in clinics today is primarily tumor growth inhibition. While they are effective in destroying cancer cells, they fall short in blocking metastasis. Here we discuss the evolution of past and current anti-cancer drug development, the limits of current strategies, and possible alternative approaches for future drug development against metastatic cancers. PMID- 28356897 TI - Novel Molecular Strategies and Targets for Opioid Drug Discovery for the Treatment of Chronic Pain. AB - Opioid drugs like morphine and fentanyl are the gold standard for treating moderate to severe acute and chronic pain. However, opioid drug use can be limited by serious side effects, including constipation, tolerance, respiratory suppression, and addiction. For more than 100 years, we have tried to develop opioids that decrease or eliminate these liabilities, with little success. Recent advances in understanding opioid receptor signal transduction have suggested new possibilities to activate the opioid receptors to cause analgesia, while reducing or eliminating unwanted side effects. These new approaches include designing functionally selective ligands, which activate desired signaling cascades while avoiding signaling cascades that are thought to provoke side effects. It may also be possible to directly modulate downstream signaling through the use of selective activators and inhibitors. Separate from downstream signal transduction, it has also been found that when the opioid system is stimulated, various negative feedback systems are upregulated to compensate, which can drive side effects. This has led to the development of multi-functional molecules that simultaneously activate the opioid receptor while blocking various negative feedback receptor systems including cholecystokinin and neurokinin-1. Other novel approaches include targeting heterodimers of the opioid and other receptor systems which may drive side effects, and making endogenous opioid peptides druggable, which may also reduce opioid mediated side effects. Taken together, these advances in our molecular understanding provide a path forward to break the barrier in producing an opioid with reduced or eliminated side effects, especially addiction, which may provide relief for millions of patients. PMID- 28356903 TI - Biomarkers, Translational Medicine, and Drug Development: An Interview with Chirag R. Parikh, MD, PhD. PMID- 28356901 TI - Penicillin's Discovery and Antibiotic Resistance: Lessons for the Future? AB - Undoubtedly, the discovery of penicillin is one of the greatest milestones in modern medicine. 2016 marks the 75th anniversary of the first systemic administration of penicillin in humans, and is therefore an occasion to reflect upon the extraordinary impact that penicillin has had on the lives of millions of people since. This perspective presents a historical account of the discovery of the wonder drug, describes the biological nature of penicillin, and considers lessons that can be learned from the golden era of antibiotic research, which took place between the 1940s and 1960s. Looking back at the history of penicillin might help us to relive this journey to find new treatments and antimicrobial agents. This is particularly relevant today as the emergence of multiple drug resistant bacteria poses a global threat, and joint efforts are needed to combat the rise and spread of resistance. PMID- 28356902 TI - Is Open Science the Future of Drug Development? AB - Traditional drug development models are widely perceived as opaque and inefficient, with the cost of research and development continuing to rise even as production of new drugs stays constant. Searching for strategies to improve the drug discovery process, the biomedical research field has begun to embrace open strategies. The resulting changes are starting to reshape the industry. Open science-an umbrella term for diverse strategies that seek external input and public engagement-has become an essential tool with researchers, who are increasingly turning to collaboration, crowdsourcing, data sharing, and open sourcing to tackle some of the most pressing problems in medicine. Notable examples of such open drug development include initiatives formed around malaria and tropical disease. Open practices have found their way into the drug discovery process, from target identification and compound screening to clinical trials. This perspective argues that while open science poses some risks-which include the management of collaboration and the protection of proprietary data-these strategies are, in many cases, the more efficient and ethical way to conduct biomedical research. PMID- 28356904 TI - Clinical utility of patiromer, sodium zirconium cyclosilicate, and sodium polystyrene sulfonate for the treatment of hyperkalemia: an evidence-based review. AB - INTRODUCTION: Hyperkalemia is a serious medical condition that often manifests in patients with chronic kidney disease and heart failure. Renin-angiotensin aldosterone system inhibitors are known to improve outcomes in these disease states but can also cause drug-induced hyperkalemia. New therapeutic options exist for managing hyperkalemia in these patients which warrant evidence-based evaluation. AIM: The objective of this article was to review the efficacy and safety evidence for patiromer, sodium zirconium cyclosilicate (ZS9), and sodium polystyrene sulfonate (SPS) for the treatment of hyperkalemia. EVIDENCE REVIEW: Current treatment options to enhance potassium excretion are SPS and loop diuretics, which are complicated by ambiguous efficacy and known toxicities. Patiromer and ZS9 are new agents designed to address this treatment gap. Both unabsorbable compounds bind potassium in the gastrointestinal (GI) tract to facilitate fecal excretion. The capacity to bind other medications in the GI tract infers high drug-drug interaction potential, which has been demonstrated with patiromer but not yet investigated with ZS9 or SPS. Phase II and III clinical trials of patiromer and ZS9 demonstrated clear evidence of a dose dependent potassium-lowering effect and the ability to initiate, maintain, or titrate renin-angiotensin-aldosterone system inhibitors. There is limited evidence base for SPS: two small clinical trials indicated potassium reduction in chronic hyperkalemia. All agents may cause adverse GI effects, although they are less frequent with ZS9. Concerns remain for SPS to cause rare GI damage. Electrolyte abnormalities occurred with patiromer and SPS, whereas urinary tract infections, edema, and corrected QT-interval prolongations were reported with ZS9. CONCLUSION: Patiromer and ZS9 have improved upon the age-old standard SPS for the treatment of hyperkalemia. Additional research should focus on drug-drug interactions in patients on multiple medications, incidence of rare adverse events, and use in high-risk populations. PMID- 28356905 TI - Corrigendum: Matrix Metalloproteinase-7 and Kidney Fibrosis. AB - [This corrects the article on p. 21 in vol. 8, PMID: 28239354.]. PMID- 28356906 TI - Corrigendum: Failing to get the gist of what's being said: background noise impairs higher-order cognitive processing. AB - [This corrects the article on p. 548 in vol. 6, PMID: 26052289.]. PMID- 28356907 TI - Neuroprotective Effect and Mechanism of Thiazolidinedione on Dopaminergic Neurons In Vivo and In Vitro in Parkinson's Disease. AB - The aim of the present study was to gain insight into the neuroprotection effects and mechanism of thiazolidinedione pioglitazone in both in vitro and in vivo MPP+/MPTP induced PD models. In vivo experimental results showed that oral treatment of pioglitazone resulted in significant improvements in behavior symptoms damaged by MPTP and increase in the survival of TH positive neurons in the pioglitazone intervention groups. In addition, oral treatment of pioglitazone increased the expression of peroxisome proliferator-activated receptor-gamma coactivator of 1alpha (PGC-1alpha) and increased the number of mitochondria, along with an observed improvement in mitochondrial ultrastructure. From in vitro studies, 2,4-thiazolidinedione resulted in increased levels of molecules regulated function of mitochondria, including PGC-1alpha, nuclear respiratory factor 1 (NRF1), NRF2, and mitochondria fusion 2 (Mfn2), and inhibited mitochondria fission 1 (Fis1). We show that protein levels of Bcl-2 and ERK were reduced in the MPP+-treated group compared with the control group. This effect was observed to be reversed upon treatment with 2,4-thiazolidinedione, as Bcl-2 and ERK expression levels were increased. We also observed that levels of the apoptotic protein Bax showed opposite changes compared to Bcl-2 and ERK levels. The results from this study confirm that pioglitazone/2,4-thiazolidinedione is able to activate PGC-1alpha and prevent damage of dopaminergic neurons and restore mitochondria ultrastructure through the regulation of mitochondria function. PMID- 28356908 TI - Random Deep Belief Networks for Recognizing Emotions from Speech Signals. AB - Now the human emotions can be recognized from speech signals using machine learning methods; however, they are challenged by the lower recognition accuracies in real applications due to lack of the rich representation ability. Deep belief networks (DBN) can automatically discover the multiple levels of representations in speech signals. To make full of its advantages, this paper presents an ensemble of random deep belief networks (RDBN) method for speech emotion recognition. It firstly extracts the low level features of the input speech signal and then applies them to construct lots of random subspaces. Each random subspace is then provided for DBN to yield the higher level features as the input of the classifier to output an emotion label. All outputted emotion labels are then fused through the majority voting to decide the final emotion label for the input speech signal. The conducted experimental results on benchmark speech emotion databases show that RDBN has better accuracy than the compared methods for speech emotion recognition. PMID- 28356909 TI - Treatment of Prolapsing Hemorrhoids in HIV-Infected Patients with Tissue Selecting Technique. AB - The aim of this retrospective study was to evaluate the outcome of a tissue selecting therapy stapler (TST) for prolapsing hemorrhoids in HIV-infected patients. Sixty-two patients with stage III-IV hemorrhoidal prolapse were treated with TST by a single surgeon between June and November 2014. The TST group comprised 32 patients (4 females), and the TST + HIV group comprised 30 HIV infected patients (3 females). Age, gender, and preoperative examination as well as intraoperative and postoperative features were assessed. There was no marked difference in hemorrhoidal prolapse between the TST and HIV + TST groups, except for patient satisfaction at 12 months. TST is an effective and safe technique for treatment of prolapsing hemorrhoids in HIV-infected patients. PMID- 28356910 TI - Clinicopathological Characteristics and Prognosis of Papillary Thyroid Carcinoma in Naturally Menopausal Women with Various Durations of Premenarche, Reproductive Periods, and Postmenopausal Stages. AB - Background. Papillary thyroid cancer (PTC) exhibits a higher incidence in women. Due to various ages at menarche and menopause, estrogen levels vary, which may account for the differences in the occurrence, development, and prognosis of female patients with PTC. Objective. The aim of this study was to investigate the association between various durations in different estrogen levels and PTC and to provide important information to guide clinical management and treatment of this disease. Methods. First, we selected naturally menopausal female study subjects diagnosed with PTC at Zhejiang Cancer Hospital from 2007 to 2012 and then compared the differences in clinicopathological characteristics and prognosis among subjects with various lengths of premenarche, reproductive periods, and postmenopausal stages. Results. We found that all patients showed a significantly higher incidence of tumor multicentricity and intrathyroidal dissemination as the time after menopause increased. Additionally, women with shorter (<30) or longer (>38) reproductive lives had increased recurrence rates of PTC. Conclusions. In this study, we did not find any relationship of self-reported menarche and menopausal ages with the prognosis of PTC patients. More importantly, natural postmenopausal PTC patients with shorter or longer reproductive life, compared to the normal groups, had a higher rate of cancer recurrence and the patients with these characteristics could be recommended a more aggressive surgical treatment. PMID- 28356911 TI - Factors Associated with the Prevalence of Thyroid Nodules and Goiter in Middle Aged Euthyroid Subjects. AB - The aim of the present study was to determine associations of thyroid hormone levels and different metabolic parameters and anthropometric measurements with volume of nodular and nonnodular thyroid as well as with prevalence of goiter and thyroid nodules in middle-aged euthyroid subjects. Methods. The study consisted of 317 euthyroid subjects aged 48-49 from the Kaunas Cardiovascular Risk Cohort study. Thyroid-stimulating hormone (TSH), free thyroxine (FT4), and antithyroid peroxidase antibody (ATPO) levels, as well as anthropometric and metabolic parameters and smoking information, were evaluated. Results. In subjects with and without thyroid nodules, thyroid volume correlated with components of metabolic syndrome, body mass index (BMI), smoking, and TSH levels. In the nonnodular thyroid group, thyroid volume was also positively related to serum insulin and HOMA-IR, whereas a negative correlation between thyroid volume and leptin was identified in the nodular thyroid group. The goiter was identified in 12.3% of subjects. Female gender, thyroid nodules, smoking, BMI, and levels of TSH were independent predictors for goiter. Thyroid nodules were found in 31.2% of participants. Female gender, higher TSH levels, and thyroid volume were independent risk factors for thyroid nodules. Conclusions. Female gender, thyroid nodules, smoking, BMI, and TSH levels were identified as potential predictors of goiter. Female gender, TSH levels, and thyroid volume predicted the presence of thyroid nodules. PMID- 28356912 TI - Toothpick inside the Common Bile Duct: A Case Report and Literature Review. AB - The incidence and prevalence of foreign body (FB) ingestion are difficult to estimate. Unlike other foreign bodies, the ingestion of a toothpick is very uncommon and carries high morbidity and mortality rates. We report a case of a 73 year-old female patient presenting mid-term epigastric pain. Abdominal ultrasound revealed a slightly dilated common bile duct (CBD) and magnetic resonance showed an irregular filling failure in distal CBD and gallstones. Endoscopic Retrograde Cholangiopancreatography revealed major papilla on the edge of a diverticulum and confirmed the distal filling failure. After sphincterotomy, a partially intact toothpick was extracted from the CBD. Neither fistulas nor perforation signs were found. Literature related to foreign bodies and toothpick ingestion was reviewed and some hypotheses to explain the reported case were created. To our knowledge, this is the first report of a toothpick lodged inside the biliary tract. PMID- 28356913 TI - Posterior Cord Syndrome and Trace Elements Deficiency as an Uncommon Presentation of Common Variable Immunodeficiency. AB - Diarrhea is one of the most common symptoms in common variable immunodeficiency, but neurologic manifestations are rare. We presented a 50-year-old woman with recurrent diarrhea and severe weight loss that developed a posterior cord syndrome. Endoscopy found a duodenal villous blunting, intraepithelial lymphocytosis, and lack of plasma cells and magnetic resonance imaging of the spine was normal. Laboratory assays confirmed common variable immunodeficiency syndrome and showed low levels of trace elements (copper and zinc). Treatment was initiated with parenteral replacement of trace elements and intravenous human immunoglobulin and the patient improved clinically. In conclusion, physicians must be aware that gastrointestinal and neurologic disorders may be related to each other and remember to request trace elements laboratory assessment. PMID- 28356915 TI - Role of Parental Smoking in Severe Bronchiolitis: A Hospital Based Case-Control Study. AB - Objective. Bronchiolitis is one of the commonest causes of hospitalization of infants and young children in Bangladesh. About 21% of under 5 children attending different hospitals of Bangladesh have bronchiolitis. Fifty percent (50%) men and three percent (3%) women of Bangladesh are smokers. Parental smoking is an important risk factor for both susceptibility and severity of bronchiolitis. The aim of this study was to find out the role of parental smoking in severe bronchiolitis. Design. Case-control study. Place and Duration of Study. The study was conducted in the Department of Paediatrics, Sylhet MAG Osmani Medical College Hospital, Bangladesh, from July 2013 to December 2015. Patients and Methods. Sixty-four patients admitted into the ward with severe bronchiolitis were enrolled as cases and sixty-four suitably matched apparently healthy children attending EPI centre and outpatient department presenting with nonrespiratory illness were enrolled as controls. Sample size was calculated using Guilford and Frucher formula. The technique was systematic random sampling. Every second case satisfying the inclusion and exclusion criteria was enrolled in the study. Results. The mean age of the patients was 7.53 (SD +/- 4.75) months. Forty (62.5%) patients were male and twenty four (37.5%) patients were female. Male-to female ratio was 1.7 : 1. Most of the cases (60.95%) came from low socioeconomic background. More than half of the cases (53.13%) were not exclusively breastfed babies. Mean length of hospital stay was 6.41 (SD +/- 2.82) days. Thirty eight (59%) cases and twenty six (34%) controls were exposed to parental smoking. Result was highly significant (p = 0.005). Odds ratio was 2.8 (95% CI from 1.36 to 5.72). Conclusion. Exposure to parental smoking causes a statistically significant (p = 0.005, odds ratio = 2.8) increase in the risk of developing severe bronchiolitis in the first year of life. PMID- 28356914 TI - Targeting Signaling Pathways in Cancer Stem Cells for Cancer Treatment. AB - The Wnt, Hedgehog, and Notch pathways are inherent signaling pathways in normal embryogenesis, development, and hemostasis. However, dysfunctions of these pathways are evident in multiple tumor types and malignancies. Specifically, aberrant activation of these pathways is implicated in modulation of cancer stem cells (CSCs), a small subset of cancer cells capable of self-renewal and differentiation into heterogeneous tumor cells. The CSCs are accountable for tumor initiation, growth, and recurrence. In this review, we focus on roles of Wnt, Hedgehog, and Notch pathways in CSCs' stemness and functions and summarize therapeutic studies targeting these pathways to eliminate CSCs and improve overall cancer treatment outcomes. PMID- 28356916 TI - Spasmolytic and Antibacterial Activity of Two Citrus sinensis Osbeck Varieties Cultivated in Mexico. AB - Antibacterial activity on ATCC strains of Escherichia coli, Salmonella enterica, Salmonella enteritidis, and Salmonella choleraesuis and spasmolytic effect on contraction on rat ileum trips were determinate. Eight organic extracts (hexanic and methanolic) of albedo (mesocarp) and flavedo (pericarp) of two varieties (Valencian and National) of Citrus sinensis (L.) Osbeck of Yucatan, Mexico, were studied. Additionally, chromatographic fingerprints were obtained and correlated with their pharmacological effects. MAN, MAV, and HFN extract caused inhibition against S. choleraesuis (MIC: 1000 ug/mL) and S. enteritidis (MIC: 1000 ug/mL). Regarding the spasmolytic effect, the Valencian extracts variety was more efficient on spontaneous contraction, HAV (Emax = 51.98 +/- 1.98%), MAV (Emax = 35.98 +/- 1.42%), HFV (Emax = 68.91 +/- 4.14%), and MFV (Emax = 51.28 +/- 2.59%), versus National variety, HAN (Emax = 43.80 +/- 6.32%), MAN (Emax = 14.62 +/- 1.69%), HFN (Emax = 64.87 +/- 3.04%), and MFN (Emax = 31.01 +/- 3.92%). Chromatographic fingerprints of HFV and HFN were found to have some similar signals that belong to monoterpenes, whereas for HAN and HAV similar signals were found belonging to fatty acids and triterpenoids. Methanolic extracts showed signals of (1) furfural, (2) furfural acetone (3) furfuraldehyde and (4) beta sitosterol compounds. Flavedo portion of C. sinensis possessed spasmolytic effect on rat ileum strips and antibacterial activity against Salmonella strains. This species is source for obtaining bioactive compounds with therapeutic potential in the treatment of infectious diarrhea. PMID- 28356917 TI - Introduction to LJPC issue 9.1. PMID- 28356918 TI - Collaborating sites for community-oriented integrated care and health promotion. AB - London Journal of Primary Care wishes to develop a network of collaborating sites to better understand how to achieve community-oriented integrated care and health promotion in different contexts. A collaborating site can do more than submit papers. It can develop its own domain on the LJPC website, contribute to the development of LJPC policy, and stimulate discussions with other collaborating sites. At any time a collaborating site can opt out. In addition to securing papers for publication, a site might nurture a network of supporters, teach people to use multiple research and quality improvement methods, develop a system of governance for locally led inquiries, develop case studies of community oriented integrated care and health promotion and facilitate within-site and between-site learning and change. PMID- 28356919 TI - The use of case studies to drive bottom-up leadership in community-oriented integrated care and health promotion (COIC). AB - London Journal of Primary Care is supporting a collaborative network of multidisciplinary colleagues with an interest in community-oriented health care and health promotion (COIC). Case study methodology is well suited to generating knowledge from the frontline of health and social care service delivery and is a much under-developed resource. It is most effective when dealing with wicked problems, namely, the sort of complex, entangled and multi-faceted problems that successful COIC programmes must overcome. Used collaboratively, it supports effective networking across professional and community boundaries. PMID- 28356920 TI - General practice nursing: who is cherishing this workforce? AB - The remodelling of the NHS requires a strong general practice nurse (GPN) workforce within general practice. The challenges facing general practice nursing are set within the current policy context and recent available evidence and illustrated by drawing upon the experience of a current GPN working in London. It is argued that there is a need to support the professional development of GPNs and nurture the next generation of potential GPNs if the current shortage of GPNs is to be addressed. PMID- 28356921 TI - Henri de Toulouse-Lautrec's talent - and troubles - were larger than life. PMID- 28356922 TI - New Care Models revisited. PMID- 28356923 TI - The Guy's and St Thomas's NHS Foundation Trust @home service: an overview of a new service. AB - Hospital in the home is a relatively new concept within the UK healthcare system. The Guy's and St Thomas's NHS Foundation Trust (GSTT) @home service 'Bringing hospital care to your home' was commissioned by Lambeth and Southwark CCG in 2014 to provide acute care in the patients' place of residence by facilitating rapid discharge from hospital. The service is designed for 260-280 referrals each month from local hospitals, London Ambulance Service, GPs, district nurses and palliative care services. The GSTT@home provides intensive care for a short episode through multidisciplinary team work with the aim of returning the patient to their prior health status following an acute episode of ill health. The main criteria for referrals are adults, living within Lambeth or Southwark with an acute onset of illness often with acute exacerbations of chronic conditions. Care is delivered using 25 clinical pathways using integrated care teams, including those for respiratory disease, heart failure and palliative care services. Recently, the service extended to include overnight palliative care. As care shifts from hospital to the community, it is envisaged that these types of programmes will become an essential component of care provision. This paper describes the service and presents initial service evaluation data. PMID- 28356924 TI - Whole system quality: local benchmarking to improve workforce planning. PMID- 28356925 TI - IkappaB-alpha: At the crossroad between oncogenic and tumor-suppressive signals. AB - Nuclear factor kappaB (NF-kappaB) is an essential component of tumorigenesis and resistance to cancer treatments. NFKB inhibitor alpha (IkappaB-alpha) acts as a negative regulator of the classical NF-kappaB pathway through its ability to maintain the presence of NF-kappaB in the cytoplasm. However, IkappaB-alpha is also able to form a complex with tumor protein p53, promoting its inactivation. Recently, we demonstrated that IkappaB-alpha is able to mediate p53 nuclear exclusion and inactivation in chronic myeloid leukemia, indicating that IkappaB alpha can modulate either oncogenic or tumor-suppressive functions, with important implications for cancer treatment. The present review describes the role of IkappaB-alpha in cancer pathogenesis, with particular attention to hematological cancers, and highlights the involvement of IkappaB-alpha in the regulation of p53 tumor-suppressive functions. PMID- 28356926 TI - Familial risk for lung cancer. AB - Lung cancer, which has a low survival rate, is a leading cause of cancer associated mortality worldwide. Smoking and air pollution are the major causes of lung cancer; however, numerous studies have demonstrated that genetic factors also contribute to the development of lung cancer. A family history of lung cancer increases the risk for the disease in both smokers and never-smokers. This review focuses on familial lung cancer, in particular on the familial aggregation of lung cancer. The development of familial lung cancer involves shared environmental and genetic factors among family members. Familial lung cancer represents a good model for investigating the association between environmental and genetic factors, as well as for identifying susceptibility genes for lung cancer. In addition, studies on familial lung cancer may help to elucidate the etiology and mechanism of lung cancer, and may identify novel biomarkers for early detection and diagnosis, targeted therapy and improved prevention strategies. This review presents the aetiology and molecular biology of lung cancer and then systematically introduces and discusses several aspects of familial lung cancer, including the characteristics of familial lung cancer, population-based studies on familial lung cancer and the genetics of familial lung cancer. PMID- 28356928 TI - A novel hysteroscopic approach for ovarian cancer screening/early diagnosis. AB - The lethality of epithelial ovarian cancer (EOC) may be due to common misconceptions regarding etiology and the absence of effective screening and early diagnostic tools. Reviews of histopathological surveys performed on the resected fallopian tubes of breast cancer (BRCA) mutation carriers, who underwent risk-reducing salpingo-oophorectomy, unexpectedly revealed the presence of occult carcinomas of the fallopian tubes. This finding prompted studies that demonstrated the most accredited theory of type II EOC development, which suggests that a large proportion of these tumors are derived from the fallopian tube. At present, no diagnostic tools or screening programs have been demonstrated to be effective or cost-effective in improving the outcome of EOC; it is therefore imperative that the scientific community unite its efforts in the identification of a valid screening and/or early diagnostic method for the treatment of this lethal gynecological malignancy. To this end, the present paper proposes a novel tool for the screening/early diagnosis of EOC: The 'Tuba-check'. This novel approach is based on the possibility of acquiring specimens for tubal lumen cytology via hysteroscopy in a minimally-invasive outpatient setting. The present study protocol aimed to validate the technical feasibility and oncological accuracy of the proposed approach, commencing with a cohort of patients with an expected increased oncological risk, including BRCA mutation carriers or those with a gene expression profile of 'BRCA-ness'. If the data collected by the present study protocol validates this approach, the 'Tuba-check' may, in the near future, be extended for the treatment of all women, therefore reducing the number of victims of epithelial ovarian carcinoma. PMID- 28356927 TI - From inflammation to gastric cancer: Role of Helicobacter pylori. AB - Gastric cancer is a multifactorial disease and a leading cause of mortality and the risk factors for this include environmental factors and factors that influence host-pathogen interaction and complex interplay between these factors. Gastric adenocarcinomas are of two types, namely intestinal and diffuse type, and Helicobacter pylori (H. pylori) infection has been suspected of being causally linked to the initiation of chronic active gastritis, which leads to adenocarcinoma of the intestinal type. Even though most individuals with H. pylori infection do not show any clinical symptoms, long-term infection leads to inflammation of gastric epithelium and approximately 10% of infected patients develop peptic ulcers and 1-3% of patients develop gastric adenocarcinoma. Among the several mechanisms involved in tumorigenesis, CagA and peptidoglycan of H. pylori, which enter the infected gastric epithelial cells play an important role by triggering oncogenic pathways. Inflammation induced by H. pylori in gastric epithelium, which involves the cyclooxygenase-2/prostaglandin E2 pathway and IL 1beta, is also an important factor that triggers chronic active gastritis and adenocarcinoma. H. pylori infection induced oxidative stress and dysregulated E cadherin/beta-catenin/p120 interactions and function also play a critical role in tumorigenesis. Environmental and dietary factors, in particular salt intake, are known to modify the pathogenesis induced by H. pylori. Gastric cancer induced by H. pylori appears to involve several mechanisms, making this mode of tumorigenesis a highly complicated process. Nevertheless, there are many events in this tumorigenesis that remain to be clarified and investigated. PMID- 28356929 TI - Anti-tumor effects of metformin on head and neck carcinoma cell lines: A systematic review. AB - Metformin is commonly used for treating type 2 diabetes, and may also reduce cancer risk. Previous studies have demonstrated the association between metformin use and a decreased risk of head and neck cancer. Therefore, the aim of the present systematic review was to summarize the available literature on the in vitro anti-tumor effects of metformin on head and neck squamous cell carcinoma (HNSCC). Research studies were obtained from Cochrane Library, Embase, LILACS, MEDLINE and PubMed databases, without time or language restrictions. Only in vitro studies analyzing the effects of metformin on HNSCC cell lines were included. The authors methodically appraised all the selected studies according to the Grading of Recommendations Assessment, Development and Evaluation method to make a judgment of the evidence quality. Of the 388 identified reports, 11 studies met the inclusion criteria and were used for qualitative analysis. These studies demonstrated that metformin is important in inhibiting cell proliferation, inducing G0/G1 cell cycle arrest and apoptosis, and in regulating proteins involved in carcinogenesis pathways, which corroborates its potential in vitro anti-tumor effects. The present systematic review highlights the biological mechanisms of metformin used alone or together with traditional therapies for cancer. Though very limited, currently available preclinical evidence shows that metformin exerts a potential effect on head and neck carcinoma. PMID- 28356930 TI - Effect of targeted silencing of IL-8 on in vitro migration and invasion of SKOV3 ovarian cancer cells. AB - The aim of the study was to determine whether interleukin-8 (IL-8) affects human SKOV3 ovarian cancer cell migration and invasion by targeting silencing of IL-8 expression. Silencing small-interfering RNA (siRNA) targeting IL-8 gene was constructed to infect SKOV3 cells by lentiviral vector. The expression of IL-8 and p-nuclear factor (NF)-kappaB protein was detected by western blot analysis. The wound scratch and Transwell tests were used to assay the cell migration and invasiveness of SKOV3 cells infected with lentiviral vector targeting IL-8 gene siRNA. The levels of IL-8 protein expressed by SKOV3 cells infected by lentiviral vector targeting IL-8 gene siRNA decreased by 72.3%. IL-8 (50 ng/ml) increased the ability of SKOV3 cells to suppress cell migration (p<0.01). Cisplatin and silencing of IL-8 achieved the ability to inhibit SKOV3 cell invasion (p<0.01), and 100 ng/ml concentration of IL-8 enhanced the ability of SKOV3 invasion (p<0.01). Silencing of IL-8 to a certain extent reduced the expression of p-NF kappaB proteins, but it was not statistically significant. In conclusion, silencing of IL-8 may inhibit the migration and invasion of SKOV3 cells, which may be independent of the p-NF-kappaB protein. PMID- 28356931 TI - MicroRNA-320a downregulation mediates human liver cancer cell proliferation through the Wnt/beta-catenin signaling pathway. AB - MicroRNAs (miRs) have emerged as key epigenetic regulators involved in cancer progression. miR-320a has been demonstrated to be a novel tumor suppressive microRNA in several types of cancers. In the present study, the role of miR-320a in human hepatocellular carcinoma (HCC) was investigated. The expression levels of miR-320a and messenger RNA were determined by reverse transcription quantitative polymerase chain reaction, while cell cycle and cell apoptosis were analyzed by flow cytometry. The cell proliferative ability was determined by Cell Counting Kit-8 assay and colony formation assay. The downstream target of miR 320a was confirmed by luciferase reporter assay, while the protein levels were measured by western blotting. The results revealed that miR-320a was inversely associated with HCC proliferation in HCC cell lines. Functional studies demonstrated that miR-320a significantly decreased the capability of cell proliferation and induced G0/G1 growth arrest in vitro. In addition, beta-catenin was identified as one of the direct targets of miR-320a, downregulating the expression level of beta-catenin, c-myc, cyclin D1 and dickkopf-1. In conclusion, miR-320a may act as a tumor-suppressive microRNA through targeting beta-catenin in HCC. PMID- 28356932 TI - Human serum albumin-mediated apoptin delivery suppresses breast cancer cell growth in vitro and in vivo. AB - Gene therapy is one of the most promising potential therapeutic strategies for many types of cancer. Cell apoptosis is an active, programmed physiological process of the body, and its disruption has been closely associated with the occurrence of tumor development. Apoptin is known to induce tumor cell apoptosis. In the present study, the MCF-7 breast cancer cell line was transfected with a human serum albumin (HSA) and apoptin expressing plasmid [HSA-polyethylenimine (PEI)-pcDNA-Apoptin]. Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to detect the expression of apoptin in the transfected MCF-7 cells, while MTT assays and flow cytometry were conducted to detect cell viability and apoptosis. Furthermore, hematoxylin and eosin staining was used to observe the morphology of xenografts from mice injected with MCF-7 cells. It was demonstrated that the HSA-PEI-pcDNA-Apoptin expression plasmid resulted in the upregulation of apoptin in MCF-7 cells, and efficiently suppressed breast tumor growth in vivo. These findings indicated that the use of HSA as an apoptin expression vector has potential therapeutic benefits for cancer and confirms the requirement for the further evaluation of apoptin in clinical trials. PMID- 28356933 TI - DKK4 enhances resistance to chemotherapeutics 5-Fu and YN968D1 in colorectal cancer cells. AB - Dickkopf-related protein 4 (DKK4) is a target of the beta-catenin/transcription factor 4 complex in colorectal cancer. Previous research has demonstrated that its expression level may vary and has indicated that it may have a role in the development of resistance to chemotherapy in colorectal cancer cells. In the present study, DKK4 was over expressed in several colorectal cancer cell lines. The DKK4 over-expressing cell lines were screened using reverse transcription quantitative polymerase chain reaction analysis and western blotting. Analysis of cell viability in the control and DKK4 over-expressing cell lines, following treatment with 5-fluorouracil (5-Fu), YN968D1 or both, indicated that DKK4 over expressing cells exhibit increased drug resistance. The results of Transwell chamber assays suggested that DKK4 had an effect on cell migration. Furthermore, the results from flow cytometric analysis showed that the percentage of apoptotic cells was reduced in the DKK4 over-expressing cell lines, following drug treatment, compared with the control. The present data suggested that DKK4 may enhance the resistance of colorectal cancer cells to 5-Fu and YN968D1 treatment, when used alone or in combination. PMID- 28356934 TI - A malignant inflammatory myofibroblastic tumor of the hypopharynx harboring the 3a/b variants of the EML4-ALK fusion gene. AB - Inflammatory myofibroblastic tumors (IMT) in the head and neck region are rare neoplasms that generally mimic benign/low-grade neoplasms. Overexpression of anaplastic lymphoma kinase (ALK) has been reported in 50% of IMT cases, secondary to ALK activation by structural rearrangements in the ALK gene, which results in a fusion protein with echinoderm microtubule associated protein like 4 (EML4) in ~20% of cases. The present study describes a case of a 74-year-old woman with a malignant IMT in the right posterior hypopharynx harboring a previously unreported chromosomal rearrangement resulting in EML4 and ALK gene fusion. Strong ALK immunoreactivity was observed in neoplastic cells, while fluorescent in situ hybridization combined with fluorescent fragment analysis and direct sequencing identified the first case of the 3a/b variants of the EML4-ALK fusion gene in IMT. The results of the current study highlight the uncommon occurrence of ALK-positive IMT in the head/neck region and demonstrate the importance of integrating different molecular methodologies to identify unequivocal gene fusion characterization. PMID- 28356935 TI - Melittin inhibits the invasion of MCF-7 cells by downregulating CD147 and MMP-9 expression. AB - Tumor invasion and metastasis are the critical steps in determining the aggressive phenotype of human cancers. Melittin, a major component of bee venom, has been reported to induce apoptosis in several cancer cells. However, the mechanisms of melittin involvement in cancer invasion and metastasis remain unclear. Our previous study indicated that melittin inhibits cyclophilin A (CypA), a ubiquitously distributed peptidylprolyl cis-trans isomerase, in macrophage cells. In the present study, the Transwell assay results showed that melittin may downregulate the invasion level of MCF-7 cells in a dose-dependent manner. Additionally, it was also found, using flow cytometry and reverse transcription-polymerase chain reaction, that melittin decreased the expression of cluster of differentiation (CD)147 and matrix metallopeptidase-9 (MMP-9), whereas CypA upregulated the expression of CD147 and MMP-9. Overall, the present study indicated that melittin decreased the invasion level of MCF-7 cells by downregulating CD147 and MMP-9 by inhibiting CypA expression. The results of the present study provide an evidence for melittin in anticancer therapy and mechanisms. PMID- 28356936 TI - Danshensu, a major water-soluble component of Salvia miltiorrhiza, enhances the radioresponse for Lewis Lung Carcinoma xenografts in mice. AB - The molecule 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoic acid (danshensu), a herbal preparation used in traditional Chinese medicine, has been found to possess potential antitumor and anti-angiogenesis effects. The aim of the present study was to investigate the efficacy of the combination of radiation therapy (RT) with danshensu in the treatment of Lewis lung carcinoma (LLC) xenografts, whilst exploring and evaluating the mechanism involved. In total, 8-week old female C57BL/6J mice were randomly assigned into 3 groups to receive: RT, RT + cisplatin and RT + danshensu, respectively, when LLC reached 100-150 mm3. Each group was divided into 7 subgroups according to the different irradiation doses that were administered. Tumor growth curves were created and the sensitization enhancement ratios of the drugs were calculated. The experiment was then repeated, and the 4 groups of tumor-bearing mice were treated with natural saline, danshensu, RT + danshensu and RT, respectively. The mice were sacrificed on day 7, and tumor tissue and blood were collected to determine microvessel density, the expression of proangiogenic factors, and the levels of blood thromboxane B2 and 6-keto-prostaglandin-F1alpha. Tumor hypoxia was also detected using in vivo fluorescence imaging. With respect to LLC xenografts, treatment with danshensu + RT significantly enhanced the effects of tumor growth inhibition (P<0.05). Furthermore, tumor vasculature was remodeled and microcirculation was improved, which significantly reduced tumor hypoxia (P<0.05). The present study demonstrated that danshensu significantly enhanced the radioresponse of LLC xenografts in mice. The mechanism involved may be associated with the alleviation of tumor cell hypoxia following treatment with danshensu + RT, caused by the improvement of tumor microcirculation and the remodeling of tumor vasculature. PMID- 28356937 TI - Resveratrol promotes regression of renal carcinoma cells via a renin-angiotensin system suppression-dependent mechanism. AB - The aim of the present study was to investigate the effect of resveratrol on renal carcinoma cells and explore possible renin-angiotensin system-associated mechanisms. Subsequent to resveratrol treatment, the cell viability, apoptosis rate, cytotoxicity levels, caspase 3/7 activity and the levels of angiotensin II (AngII), AngII type 1 receptor (AT1R), vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) were evaluated in renal carcinoma cells. The effects of AngII, AT1R, VEGF and COX-2 on resveratrol-induced cell growth inhibition and apoptosis were also examined. The results indicated that resveratrol treatment may suppress growth, induce apoptosis, and decrease AngII, AT1R, VEGF and COX-2 levels in renal carcinoma ACHN and A498 cells. In addition, resveratrol-induced cell growth suppression and apoptosis were reversed when co-culturing with AT1R or VEGF. Thus, resveratrol may suppress renal carcinoma cell proliferation and induce apoptosis via an AT1R/VEGF pathway. PMID- 28356938 TI - Expression of Axl and its prognostic significance in human breast cancer. AB - Breast cancer is the most common malignant cancer and second leading cause of cancer-related death among women, and its prevalence continues to increase. Axl overexpression has been identified in the many types of human cancer, and it has been demonstrated to participate in signaling pathways related to carcinogenesis and cancer development. In the present study, Axl expression was examined by performing immunohistochemical staining in 60 breast cancer tumors and 40 benign breast lesions (25 mammary dysplasia and 15 breast fibroadenoma). In total, 34 (56.67%) cancer tissues and 13 (32.5%) benign breast lesions were classified as exhibiting high levels of Axl expression, indicating a significant association between malignancy and high Axl expression. High Axl expression was also associated with estrogen receptor (ER) positivity (P=0.028), progesterone receptor (PR) positivity (P=0.007), and poor tumor differentiation (P=0.033). No significant associations were observed between Axl expression and age, tumor size, lymph node metastasis, tumor node metastasis staging, human epidermal growth factor receptor 2 and Ki67 antigen. The Kaplan-Meier survival analysis and Cox proportional hazard model both demonstrated that there was no statistical difference between Axl expression and breast cancer prognosis. However, it remains unclear whether the expression of Axl is correlated with the prognosis of luminal type breast cancer patients. PMID- 28356939 TI - Identification of genes associated with tongue cancer in patients with a history of tobacco and/or alcohol use. AB - The present study aimed to identify genes associated with tongue cancer in patients with a history of tobacco and/or alcohol use. Microarray dataset GSE42023, including 10 tissue samples of tongue cancer from patients with a history of tobacco and/or alcohol use (habit group) and 11 tissue samples of non habit-associated tongue cancer (non-habit group), were downloaded from the Gene Expression Omnibus database. Differentially-expressed genes (DEGs) between the habit and non-habit groups were identified using the Linear Models for Microarray Data software package. The enrichment functions and pathways of these genes were subsequently predicted using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Transcription factors (TFs) and tumor-associated genes (TAGs) were selected from the DEGs using the Encyclopedia of DNA Elements database and the TAG database, respectively. Protein-protein interaction (PPI) networks for DEGs were constructed using Cytoscape. In addition, functional module analysis was performed using BioNet. This analysis identified 642 DEGs between the habit and non-habit groups, including 200 upregulated and 442 downregulated genes. The majority of upregulated DEGs were functionally enriched in the regulation of apoptosis and the calcium signaling pathway. The majority of downregulated DEGs were functionally enriched in fat cell differentiation and the adipocytokine signaling pathway. In addition, 31 TFs and 42 TAGs were identified from the DEGs. Furthermore, this analysis demonstrated that certain DEGs, including AKT serine/threonine kinase 1 (AKT1), E1A binding protein p300 (EP300), erb-b2 receptor tyrosine kinase 2 (ERBB2) and epiregulin (EREG), had high connectivity degrees in the PPI networks and/or functional modules. Overall, DEGs in a functional module, such as AKT1, EP300, ERBB2 and EREG, may serve important roles in the development of tongue cancer in patients with a history of tobacco and/or alcohol use. These DEGs are potential therapeutic targets for the treatment of tongue cancer in these groups. PMID- 28356940 TI - Imbalanced adaptive responses associated with microsatellite instability in cholangiocarcinoma. AB - The adaptive response of the genome protection mechanism occurs in cells when exposed to genotoxic stress due to the overproduction of free radicals via inflammation and infection. In such circumstances, cells attempt to maintain health via several genome protection mechanisms. However, evidence is increasing that this adaptive response may have deleterious effect; a reduction of antioxidant enzymes and/or imbalance in the DNA repair system generates microsatellite instability (MSI), which has procarcinogenic implications. Therefore, the present study hypothesized that MSI caused by imbalanced responses of antioxidant enzymes and/or DNA repair enzymes as a result of oxidative/nitrative stress arising from the inflammatory response is involved in liver fluke-associated cholangiocarcinogenesis. The present study investigated this hypothesis by identifying the expression patterns of antioxidant enzymes, including superoxide dismutase 2 (SOD2) and catalase (CAT), and DNA repair enzymes, including alkyladenine DNA glycosylase (AAG), apurinic endonuclease (APE) and DNA polymerase beta (DNA pol beta). In addition, the activities of the antioxidant enzymes, SOD2 and CAT, were examined in human cholangiocarcinoma (CCA) tissues using immunohistochemical staining. MSI was also analyzed in human CCA tissues. The resulting data demonstrated that the expression levels of the SOD2 and CAT enzymes decreased. The activities of SOD2 and CAT decreased significantly in the CCA tissues, compared with the hepatic tissue of cadaveric donors. In the DNA repairing enzymes, it was found that the expression levels of AAG and DNA pol beta enzymes increased, whereas the expression of APE decreased. In addition, it was found that MSI-high was present in 69% of patients, whereas MSI-low was present in 31% of patients, with no patients classified as having microsatellite stability. In the patients, a MSI-high was correlated with poor prognosis, indicated by a shorter survival rate. These results indicated that the reduction of antioxidant enzymes and adaptive imbalance of base excision repair enzymes in human CCA caused MSI, and may be associated with the progression of cancer. PMID- 28356941 TI - Aspirin enhances the cytotoxic activity of bortezomib against myeloma cells via suppression of Bcl-2, survivin and phosphorylation of AKT. AB - In our previous study, it was found that aspirin (ASA) exerted antimyeloma actions in vivo and in vitro. The resistance to bortezomib (BTZ) in multiple myeloma (MM) is partly due to AKT activation and the upregulation of survivin induced by BTZ, which are the targets of ASA in gastric and ovarian cancer, respectively. Thus, the present study investigated the interaction between ASA and BTZ in MM and further clarified the underlying mechanisms. MM1.S and RPMI 8226 cell lines harboring the N- and K-Ras mutations, respectively, were treated with 2.5 mM ASA, 10 nM BTZ and ASA+BTZ for different durations. The proliferation and apoptosis of the cells were determined, and the underlying mechanisms governing the interaction of ASA and BTZ were examined in the MM cells. Treatment with ASA+BTZ caused higher rates of proliferative inhibition and apoptosis in the MM1.S and RPMI-8226 cells in time-dependent manner, compared with either agent alone. A drug interaction assay revealed the additive effect of ASA and BTZ on the myeloma cells. ASA alone inhibited the levels of phosphorylated AKT (p-AKT) and survivin, whereas BTZ alone augmented the levels of p-AKT and survivin. Of note, ASA markedly decreased the upregulation of p-AKT and survivin induced by BTZ. Treatment with ASA+BTZ significantly suppressed the level of Bcl-2, compared with either agent alone. ASA may potentiate the antimyeloma activity of BTZ against myeloma cells via suppression of AKT phosphorylation, survivin and Bcl-2, indicating the potential of ASA+BTZ in treating MM, particularly for cases of BTZ refractory/relapsed MM. PMID- 28356942 TI - Anti-metastatic activity of fangchinoline in human gastric cancer AGS cells. AB - Fangchinoline (FCL) is an active component isolated from the traditional medicinal plant Stephania tetrandra S. Moore, and has been reported to possess anti-cancer functions in several types of cancers; however, the effect of FCL on gastric cancer metastasis and its underlying molecular mechanisms remain unknown. The current study aimed to investigate the effect of FCL on the cell migration and invasion of human metastatic gastric cancer AGS cells and its mechanisms. Our study demonstrates that FCL dosage dependently suppressed the adhesion, migration and invasion capacities of human gastric cancer AGS cells without obvious cytotoxic effects. Reverse transcription-polymerase chain reaction and western blot assays demonstrated that FCL greatly inhibited the expression of matrix metalloproteinase (MMP)-2 and MMP-9 at both the mRNA and protein levels, while it significantly increased the expression of tissue inhibitor of metalloproteinase (TIMP) 1 and TIMP2 messenger RNAs. Our results also indicated that FCL repressed the phosphorylation of AKT in gastric cancer AGS cells. In summary, FCL may exert its anti-metastatic property in human gastric cancer cells in vitro by suppression of MMP-2 and MMP-9, increase of TIMP1 and TIMP2 genes, and inhibition of AKT phosphorylation. FCL may be a drug candidate for the treatment of gastric cancer metastasis. PMID- 28356943 TI - LASS2 inhibits growth and invasion of bladder cancer by regulating ATPase activity. AB - Homo sapiens longevity assurance homolog 2 of yeast LAG1 (LASS2) is a novel suppressor of human cancer metastasis, and downregulation of LASS2 has been associated with a poor prognosis in patients with bladder cancer (BC). However, the molecular mechanism underlying LASS2-mediated inhibition of tumor invasion and metastasis in BC remains unclear. LASS2 has been reported to directly bind to subunit C of vacuolar H+-ATPase (V-ATPase) in various types of cancer, suggesting that LASS2 may inhibit cancer invasion and metastasis by regulating the function of V-ATPase. The present study investigated the effect of LASS2-specific small interfering (si)RNA on the invasion and metastasis of the RT4 human BC cell line, which has a low metastatic potential, and its functional interaction with V ATPase. Silencing of LASS2 in RT4 cells was able to increase V-ATPase activity, the extracellular hydrogen ion concentration and, in turn, the activation of secreted matrix metalloproteinase (MMP)-2 and MMP-9, which occurred simultaneously with enhanced cell proliferation, cell survival and cell invasion in vitro, as well as acceleration of BC growth in vivo. In this process, it was found that siRNA-LASS2 treatment was able to suppress cell apoptosis induced by doxorubicin. These findings suggest that silencing of LASS2 may enhance the growth, invasion and metastasis of BC by regulating ATPase activity. PMID- 28356944 TI - Plasma miR-145, miR-20a, miR-21 and miR-223 as novel biomarkers for screening early-stage non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality in the world. Late diagnosis is one of the most significant reasons for the high mortality rate of lung cancer. The identification of microRNAs (miRNAs) has opened a new field for molecular diagnosis of cancer. The purpose of the present study was to investigate whether plasma miRNAs may be used as biomarkers for early-stage NSCLC. A total of 232 participants, including 149 NSCLC patients and 83 healthy controls, were recruited between July 2012 and May 2014. We measured the levels of 10 miRNAs (miR-30d, miR-383, miR-20a, miR-145, miR-221, miR-25, miR-223, miR-21, miR-126 and miR-210) in plasma samples of 40 individuals (20 patients and 20 matched healthy controls) at the point of identification of disease, and 129 NSCLC patients and 83 healthy controls at the validation stage using reverse transcription-quantitative polymerase chain reaction. Receiver operating characteristics (ROC) curves were generated for each possible combination of the miRNAs. We observed that the expression of plasma miR-145, miR 20a, miR-21 and miR-223 was significantly increased in the early-stage NSCLC samples compared with controls. miRNAs have significant diagnostic value for early-stage NSCLC. Combined ROC analyses using these four miRNAs revealed an elevated area under the ROC curve (AUC) of 0.897, with a sensitivity and specificity of 81.8 and 90.1%, respectively. This AUC helped in distinguishing early-stage NSCLC. Furthermore, the levels of the four plasma miRNAs were significantly decreased following surgery (P<0.05). Altered expression of miR 145, miR-20a, miR-21 and miR-223 in plasma are of tumor origin, and the four miRNAs may represent potential novel non-invasive biomarkers for early-stage NSCLC. PMID- 28356945 TI - Evaluation of nano-magnetic fluid on malignant glioma cells. AB - The temperature variation rule of nano-magnetic fluid in the specific magnetic field and the effect on the treatment of malignant glioma were examined. The temperature variation of nano-magnetic fluid in the specific magnetic field was investigated by heating in vitro, and cell morphology was observed through optical microscopy and electron microscopy. MTT detection also was used to detect the effect of Fe3O4 nanometer magnetic fluid hyperthermia (MFH) on the proliferation of human U251 glioma cell line. The Fe3O4 nano MFH experiment was used to detect the inhibition rate of the tumor volume in nude mice with tumors. The results of the experiment showed that the heating ability of magnetic fluid was positively correlated with its concentration at the same intensity of the magnetic field. The results also indicated the prominent inhibitory effect of nanometer MFH on the proliferation of glioma cells, which was a dose-dependent relationship with nanometer magnetic fluid concentration. The hyperthermia experiment of nude mice with tumors displayed a significant inhibiting effect of Fe3O4 nanometer magnetic fluid in glioma volume. These results explain that iron (II, III) oxide (Fe3O4) nanometer MFH can inhibit the proliferation of U251 glioma cells, and has an obvious inhibitory effect on glioma volume, which plays a certain role in the treatment of brain glioma. PMID- 28356946 TI - Ginsenoside Rh2 enhances the antitumor immunological response of a melanoma mice model. AB - The treatment of malignant tumors following surgery is important in preventing relapse. Among all the post-surgery treatments, immunomodulators have demonstrated satisfactory effects on preventing recurrence according to recent studies. Ginsenoside is a compound isolated from panax ginseng, which is a famous traditional Chinese medicine. Ginsenoside aids in killing tumor cells through numerous processes, including the antitumor processes of ginsenoside Rh2 and Rg1, and also affects the inflammatory processes of the immune system. However, the role that ginsenoside serves in antitumor immunological activity remains to be elucidated. Therefore, the present study aimed to analyze the effect of ginsenoside Rh2 on the antitumor immunological response. With a melanoma mice model, ginsenoside Rh2 was demonstrated to inhibit tumor growth and improved the survival time of the mice. Ginsenoside Rh2 enhanced T-lymphocyte infiltration in the tumor and triggered cytotoxicity in spleen lymphocytes. In addition, the immunological response triggered by ginsenoside Rh2 could be transferred to other mice. In conclusion, the present study provides evidence that ginsenoside Rh2 treatment enhanced the antitumor immunological response, which may be a potential therapy for melanoma. PMID- 28356947 TI - Downregulation of feline sarcoma-related protein inhibits cell migration, invasion and epithelial-mesenchymal transition via the ERK/AP-1 pathway in bladder urothelial cell carcinoma. AB - Feline sarcoma-related protein (Fer) is a nuclear and cytoplasmic non-receptor protein tyrosine kinase and Fer overexpression is associated with various biological processes. However, the clinicopathological characteristics and molecular mechanisms of Fer expression in bladder urothelial cell carcinoma (UCC) have yet to be elucidated. The present study demonstrated that Fer was significantly upregulated in bladder UCC tissues and cell lines. A clinicopathological analysis suggested that Fer expression was significantly associated with tumor stage, histological grade and lymph node status, and Fer expression was a prognostic factor for overall survival in a multivariate analysis. Furthermore, small interfering RNA (siRNA) was used to silence the expression of the Fer gene in human bladder UCC T24 cells, and was shown to significantly reduce the migration and invasion of the cells. It was also observed that Fer-siRNA caused the T24 cells to acquire an epithelial cobblestone phenotype, and was able to reverse the epithelial-mesenchymal transition of the cells. Subsequently, Fer-knockdown was shown to deactivate the extracellular signal-regulated kinase/activator protein-1 signaling pathway in T24 cells. These results indicated, for the first time, that Fer has a critical role in bladder UCC progression and may be a potential therapeutic target for bladder UCC metastasis. PMID- 28356948 TI - EGFR expression is associated with cytoplasmic staining of CXCR4 and predicts poor prognosis in triple-negative breast carcinomas. AB - The purpose of the present study was to investigate the significance of C-X-C motif chemokine receptor type 4 (CXCR4) and epidermal growth factor receptors (EGFRs) in triple-negative breast cancer (TNBC). CXCR4 and EGFR expression levels were immunohistochemically determined in 207 primary breast cancer specimens. The associations between receptor expression and clinicopathological characteristics were analyzed, and receptor expression was also assessed as a prognostic factor. In the human MDA-MB-231 TNBC cell line, CXCR4 or EGFR was stably knocked down by short hairpin RNA, and the biological behavior of the cells, including migration, invasion and tumorigenesis, was investigated. The results revealed that TNBC was associated with younger age, higher histological grade and an aggressive phenotype. CXCR4 and EGFR were highly expressed in patients with TNBC, and those with high CXCR4 or EGFR expression exhibited an unfavorable prognosis in terms of disease-free survival and overall survival. In MDA-MB-231 cells, the expression of CXCR4 protein was decreased following EGFR silencing, while CXCR4 knockdown also caused a decrease in EGFR protein levels. The migratory and invasive capabilities of MDA-MB-231 cells were decreased following the knockdown of CXCR4 or EGFR expression. A strong correlation between CXCR4 and EGFR expression was identified in patients with TNBC. The results suggest that elevated expression levels of these two receptors may serve as predictive factors for poor prognosis in patients with TNBC. In addition, tumor proliferation, migration, invasion and tumorigenesis are weakened in MDA-MB-231 cells following suppression of CXCR4 or EGFR expression. Therefore, EGFR and CXCR4 may be potential therapeutic targets for TNBC. PMID- 28356950 TI - Expression of CHODL in hepatocellular carcinoma affects invasion and migration of liver cancer cells. AB - Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated death. Due to rapid progression and metastasis, the long-term survival remains poor for most patients. Thus, it is important to discover and develop novel preventive strategies and therapeutic approaches for HCC. Recent data show that chondrolectin (CHODL) is commonly overexpressed in the majority of lung cancers, indicating a possible correlation between CHODL and metastasis of lung cancer cells. Our investigation shows that the expression of CHODL is significantly decreased in HCC clinical samples and in HCC cell lines. Overexpression of CHODL in SMMC7721 cells with a lentiviral vector increased SMMC7721 cell migration and invasion. Our findings establish for the first time an association between human CHODL and HCC metastasis. PMID- 28356949 TI - Association between XRCC1 and ERCC1 single-nucleotide polymorphisms and the efficacy of concurrent radiochemotherapy in patients with esophageal squamous cell carcinoma. AB - The aim of the present study was to investigate the association between single nucleotide polymorphisms (SNPs) in X-ray repair cross-complementing 1-399 (XRCC1 399) or excision repair cross-complementation group 1-118 (ERCC1-118) and the short-term efficacy of radiochemotherapy, tumor metastasis and relapse, as well as the survival time in patients with esophageal squamous cell carcinoma (ESCC). TaqMan probe-based quantitative polymerase chain reaction (qPCR) was conducted to examine the levels of XRCC1-399 and ERCC1-118 SNPs in the peripheral blood of 50 patients with pathologically confirmed ESCC. In addition, the associations between different genotypes and short-term therapeutic efficacy [the complete remission (CR) rate], tumor metastasis and relapse, as well as the survival time following concurrent radiochemotherapy, were determined. A total of 50 ESCC patients who received concurrent radiochemotherapy were enrolled. It was found that the short-term therapeutic efficacy (CR rate) was higher in the group of patients carrying the homozygous mutation of XRCC1-399 (A/A genotype) than in the group of patients without the XRCC1-399 mutation (G/G genotype). In addition, the CR rate was significantly increased in patients carrying one or two ERCC1-118 C alleles (C/C or C/T genotype) compared with patients lacking the C allele (T/T genotype). The differences were statistically significant (A/A vs. G/G, P=0.014; TT vs. C/T+C/C, P=0.040). During the follow-up period, the group of patients carrying the homozygous mutation of XRCC1-399 (A/A genotype) exhibited a markedly reduced risk of metastasis and relapse compared with the group of patients carrying non-mutated XRCC1-399 (G/G genotype; P=0.031). By contrast, ERCC1-118 SNP was not associated with the risk of metastasis and recurrence (P>0.05). The combined results of univariate and multivariate Cox regression analysis showed that the SNP in ERCC1-118 was closely associated with survival time. The mean survival time was significantly prolonged in patients carrying 1 or 2 C alleles (C/C or C/T genotype) compared with patients lacking the C allele (T/T genotype) [T/T vs. C/C, HR=12.96, 95% confidence interval (CI)=3.08-54.61, P<0.001; TT vs. C/T+C/C, HR=11.71, 95% CI=3.06-44.83, P<0.001]. However, XRCC1-399SNP had no effect on survival time (P>0.05). XRCCl-399 SNP was associated with the short term therapeutic efficacy (the CR rate) and tumor metastasis/relapse in ESCC patients who received the docetaxel plus cisplatin (TP) regimen-based concurrent radiochemotherapy. By contrast, ERCC1-118 SNP was significantly associated with the short-term therapeutic efficacy (the CR rate) and survival time in ESCC patients who received TP regimen-based concurrent radiochemotherapy. PMID- 28356951 TI - MicroRNA-93-5p increases multidrug resistance in human colorectal carcinoma cells by downregulating cyclin dependent kinase inhibitor 1A gene expression. AB - Multidrug resistance (MDR) impedes successful chemotherapy in colorectal carcinoma (CRC) and emerging evidence suggests that microRNAs (miRs) are involved in the development of MDR. In the present study, the role of miR-93-5p in the modulation of drug resistance in CRC was investigated using HCT-8 and MDR HCT 8/vincristine (VCR) cell lines. The results demonstrated upregulated expression of miR-93-5p and MDR protein 1 (MDR1) in HCT-8/VCR cells, compared with the parental HCT-8 cells. Furthermore, cyclin-dependent kinase inhibitor 1A (CDKN1A) was identified as a potential target of miR-93-5p using miR target analysis tools, including PicTar, TargetScan and miRanda. In addition, inhibition of miR 93-5p expression in HCT-8/VCR cells markedly downregulated MDR1 gene expression, upregulated CDKN1A gene expression and induced cell cycle arrest in G1. Conversely, the overexpression of miR-93-5p in HCT-8/VCR cells upregulated MDR1 gene expression, downregulated CDKN1A gene expression and promoted G1/S transition. Furthermore, the in vitro drug sensitivity assay performed suggested that downregulation of miR-93-5p enhanced the sensitivity of HCT-8/VCR cells to VCR, while the upregulation of miR-93-5p decreased the sensitivity of HCT-8 cells to VCR. In conclusion, the results of the present study suggest that miR-93-5p serves a role in the development of MDR through downregulating CDKN1A gene expression in CRC. PMID- 28356952 TI - Forkhead transcription factor 1 inhibits endometrial cancer cell proliferation via sterol regulatory element-binding protein 1. AB - The morbidity and mortality associated with endometrial cancer (EC) has increased in recent years. Regarded as a tumor suppressor, forkhead transcription factor 1 (FOXO1) has various biological activities and participates in cell cycle progression, apoptosis and differentiation. Notably, FOXO1 also functions in the regulation of lipogenesis and energy metabolism. Lipogenesis is a feature of cancer and is upregulated in EC. Sterol regulatory element-binding protein 1 (SREBP1) is a transcription factor that is also able to regulate lipogenesis. Increased expression of SREBP1 is directly correlated with malignant transformation of tumors. A previous study demonstrated that SREBP1 was highly expressed in EC and directly resulted in tumorigenesis. However, the association between FOXO1 and SREBP1 in EC is not clear. In the present study, lentiviruses overexpressing FOXO1 were used in cell transfection and transduction. Cell viability assays demonstrated that the overexpression of FOXO1 was able to suppress cell proliferation significantly in Ishikawa and AN3 CA cell lines. In addition, FOXO1 overexpression significantly inhibited cell migration and invasion ability in vitro. In xenograft models, overexpression of FOXO1 suppressed cell tumorigenesis, and western blot analysis demonstrated that SREBP1 expression was markedly reduced in the FOXO1-overexpressing cells. It may therefore be concluded that FOXO1 is able to inhibit the proliferative capacity of cells in vitro and in vivo, in addition to the migratory and invasive capacities in vitro by directly targeting SREBP1. PMID- 28356953 TI - Alkaloids of fascaplysin are effective conventional chemotherapeutic drugs, inhibiting the proliferation of C6 glioma cells and causing their death in vitro. AB - Glioblastoma multiforme is an invasive malignant glial brain tumor with a poor prognosis for patients. The primary reasons that lead to the development of treatment resistance are associated with tumor cells infiltrating the brain parenchyma and the specific properties of tumor stem cells. A crucial research area in medical science is the search for effective agents that are able to act on these targets. Fascaplysin alkaloids possess potent antitumor activity. Modern methods for the targeted delivery of drugs reveal extensive possibilities in terms of the clinical use of these compounds. The aim of the present study was to establish effective concentrations of fascaplysin that inhibit the growth and kill the cells of glial tumors, as well as to perform a comparative analysis of fascaplysin's effectiveness in relation to other chemotherapy drugs. C6 glioma cells were utilized as an optimal model of glioblastoma. It was established that fascaplysin at 0.5 uM has a strong cytotoxic effect, which is subsequently replaced by tumor cell death via apoptosis as the length of drug exposure time is increased. Fascaplysin kills glioma cells at a dose higher than 0.5 uM. The efficiency of fascaplysin was observed to significantly exceed that of temozolomide. Therefore, a significant feature of fascaplysin is its ability to inhibit the growth of and kill multipotent tumor cells. PMID- 28356954 TI - Multicenter phase II study of infusional 5-fluorouracil (5-FU), leucovorin, and oxaliplatin, plus biweekly cetuximab as first-line treatment in patients with metastatic colorectal cancer (CELINE trial). AB - The current phase II study investigated the efficacy and safety of biweekly cetuximab combined with standard oxaliplatin-based chemotherapy [infusional 5 fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX-6)] in the first-line treatment of KRAS wild-type metastatic colorectal cancer (mCRC). Sixty patients with a median age of 64 years (range, 38-82 syears) received a biweekly intravenous infusion of cetuximab (500 mg/m2 on day 1) followed by FOLFOX-6 (2 hour oxaliplatin 85 mg/m2 infusion on day 1 in tandem with a 2-h leucovorin 200 mg/m2 infusion on days 1 and 2, and 5-FU as a 400 mg/m2 bolus followed by a 46 hour 2,400 mg/m2 infusion on days 1-3). Patient response rate was 70%, with 95% disease control rates. The median progression-free survival was 13.8 months. Thirteen patients (21.7%) were able to undergo resection of previously unresectable metastases, with the aim of curing them. The median follow-up was 22.7 months, and median overall survival was 31.0 months. Cetuximab did not increase FOLFOX-6 toxicity and was generally well tolerated. The results of the current study demonstrate that the combination of biweekly cetuximab with FOLFOX 6 was well tolerated and had a manageable safety profile for the first-line treatment of KRAS wild-type metastatic colorectal cancer. Efficacy was comparable to other treatment regimens. The results support the administration of biweekly cetuximab in combination with FOLFOX-6, which may be more convenient and provide treatment flexibility in this setting for patients with metastatic colorectal cancers. PMID- 28356956 TI - P300 promotes migration, invasion and epithelial-mesenchymal transition in a nasopharyngeal carcinoma cell line. AB - A previous study demonstrated that p300 is overexpressed in nasopharyngeal carcinoma (NPC), and that its expression is an independent prognostic factor. The aim of the present study is to investigate the role of p300 in human NPC development. A small hairpin (sh) RNA lentiviral expression vector targeting the p300 gene was constructed to suppress the expression of p300 in NPC cells. Knockdown of p300 was verified by reverse transcription-quantitative polymerase chain reaction and western blotting. Wound-healing, invasion, immunofluorescence and immunoprecipitation assays were performed to assess the influence of p300 on nasopharyngeal tumorigenesis and metastasis in vitro. The expression of p300 was upregulated in NPC cell lines. After knockdown of p300, the migration and invasion ability of shp300 cells were significantly inhibited (P<0.05). Furthermore, the depletion of p300 expression in NPC cell lines resulted in the upregulation of epithelial phenotype marker E-cadherin and alpha-catenin, and downregulation of mesenchymal phenotype markers N-cadherin and vimentin. p300 promotes epithelial-mesenchymal transition (EMT) through the acetylation of Smad2 and Smad3 in the tumor growth factor-beta signaling pathway. In conclusion, p300 may be involved in the invasion and metastasis of NPC through the induction of EMT. PMID- 28356955 TI - Ursolic acid sensitizes radioresistant NSCLC cells expressing HIF-1alpha through reducing endogenous GSH and inhibiting HIF-1alpha. AB - In previous studies, the present authors demonstrated that effective sensitization of ionizing radiation-induced death of tumor cells, including non small cell lung cancer (NSCLC) cells, could be produced by oleanolic acid (OA), a pentacyclic triterpenoid present in plants. In the present study, it was investigated whether ursolic acid (UA), an isomer of OA, had also the capacity of sensitizing radioresistant NSCLC cells. The radioresistant cell line H1299/M hypoxia inducible factor-1alpha (HIF-1alpha) was established by transfection with a recombinant plasmid expressing mutant HIF-1alpha (M-HIF-1alpha). Compared with parental H1299 cells and H1299 cells transfected with empty plasmid, H1299/M-HIF 1alpha cells had lower radiosensitivity. Following the use of UA to treat NSCLC cells, elevation of the radiosensitivity of cells was observed by MTT assay. The irradiated H1299/M-HIF-1alpha cells were more sensitive to UA pretreatment than the irradiated cells with empty plasmid and control. The alteration of DNA damage in the irradiated cells was further measured using micronucleus (MN) assay. The combination of UA treatment with radiation could induce the increase of cellular MN frequencies, in agreement with the change in the tendency observed in the cell viability assay. It was further shown that the endogenous glutathione (GSH) contents were markedly attenuated in the differently irradiated NSCLC cells with UA (80 umol/l) pretreatment through glutathione reductase/5,5'-dithiobis-(2 nitrob-enzoic acid) (DTNB) recycling assay. The results revealed that UA treatment alone could effectively decrease the GSH content in H1299/M-HIF-1alpha cells. In addition, the inhibition of HIF-1alpha expression in radioresistant cells was confirmed by western blotting. It was then concluded that UA could upregulate the radiosensitivity of NSCLC cells, and in particular reduce the refractory response of cells expressing HIF-1alpha to ionizing radiation. The primary mechanism is associated with reduction of endogenous GSH and inhibition of high expression of intracellular HIF-1alpha. UA should therefore be deeply studied as a potential radiosensitizing reagent for NSCLC radiotherapy. PMID- 28356957 TI - Autophagy impacts on oxaliplatin-induced hepatocarcinoma apoptosis via the IL 17/IL-17R-JAK2/STAT3 signaling pathway. AB - The interleukin (IL)-17/IL-17 receptor (IL-17R) complex has been shown to be important for the regulation of inflammation; however, its role in the regulation of tumor processes has recently emerged as a research focus. The present study demonstrated that oxaliplatin was able to increase the levels of IL-17/IL-17R in hepatocellular carcinoma (HCC) patients and cells lines, and that it had important roles in reducing the susceptibility of the cells to oxaliplatin induced apoptosis. Furthermore, the expression of autophagy-related proteins was induced by IL-17/IL-17R and autophagy was shown to induce resistance to oxaliplatin in HCC. In addition, the janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway was shown to be an important pathway in the induction of autophagy in response to oxaliplatin. Autopjhagy was inhibited by 3-methyladenine and JAK2/STAT3 signaling was blocked by AG490, which induced apoptosis in SMMC7721 cells treated with oxaliplatin. The results of the present study may help to elucidate the mechanism underlying the role of IL-17/IL 17R-induced autophagy in the chemoresistance of HCC, as well as help to establish and develop measures to overcome chemoresistance in HCC. PMID- 28356958 TI - Bioinformatic identification of candidate genes induced by trichostatin A in BGC 823 gastric cancer cells. AB - The aim of the present study was to identify the candidate genes induced by trichostatin A (TSA) in BGC-823 gastric cancer (GC) cells and to explore the possible inhibition mechanism of TSA in GC. Gene expression data were obtained through chip detection, and differentially expressed genes (DEGs) between GC cells treated with TSA and untreated GC cells (control group) were identified. Gene ontology analysis of the DEGs was performed using the database for annotation, visualization and integrated discovery. Then sub-pathway enrichment analysis was performed and a microRNA (miRNA) regulatory network was constructed. We selected 76 DEGs, among which 43 were downregulated genes and 33 were upregulated genes. By sub-pathway enrichment analysis of the DEGs, the propanoate metabolism pathway was selected as the sub-pathway. By constructing a miRNA regulatory network, we identified that DKK1 and KLF13 were the top hub nodes. The propanoate metabolism pathway and the genes DKK1 and KLF13 may play significant roles in the inhibition of GC induced by TSA. These genes may be potential therapeutic targets for GC. However, further experiments are still required to confirm our results. PMID- 28356959 TI - Effect of cancer/testis antigen NY-SAR-35 on the proliferation, migration and invasion of cancer cells. AB - NY-SAR-35 is a cancer/testis (CT) antigen that was identified by serological analysis of recombinant complementary DNA expression libraries. The gene encoding NY-SAR-35 is located on the * chromosome and is aberrantly expressed in a number of cancer types and germ cells, such as those in the testes, but not in normal tissue. It has been reported that treatment with a demethylating agent induced the expression of NY-SAR-35 in several types of cancer cells. However, the function of NY-SAR-35 in cancer remains undetermined. In present study, the role of NY-SAR-35 in human lung adenocarcinoma (SK-LC-14) and hepatocellular carcinoma (SNU-449) cells was investigated following stable transfection of the NY-SAR-35 gene. NY-SAR-35 was observed to be expressed in the cytoplasm of the cells. In addition, the bromodeoxyuridine incorporation assay and immunofluorescence staining for proliferating cell nuclear antigen and Ki-67 demonstrated that proliferation was increased in cells transfected with NY-SAR-35. In addition, the trypan blue exclusion assay indicated that NY-SAR-35 increased cancer cell viability. Furthermore, NY-SAR-35 increased the migration and invasion of the cells. These results indicate that NY-SAR-35 increases cancer cell viability, proliferation, migration and invasion. PMID- 28356960 TI - Induction of apoptosis by FFJ-5, a novel naphthoquinone compound, occurs via downregulation of PKM2 in A549 and HepG2 cells. AB - Pyruvate kinase isoenzyme M2 (PKM2) has previously been identified as a tumor biomarker and as a potential target for cancer therapy. In this study, FSFJ-5, a characterized naphthoquinone modifier of mollugin, was synthesized in order to investigate its anticancer activity and the potential mechanisms. It was observed that FFJ-5 inhibited the cell growth of human lung adenocarcinoma cells A549 and human hepatoma cells HepG2 by MTT assays. FFJ-5 arrested cell cycle at the G2/M phase. Further analyses demonstrated that FFJ-5 attenuated the expression of PKM2 and reduced the production of adenosine triphosphate (ATP). Reduced expression and activity of epidermal growth factor receptor (EGFR) and Akt were observed in A549 and HepG2 cells exposed to FFJ-5. FFJ-5 exposure also resulted in cell apoptosis, in association with decreased intracellular pH level and mitochondrial membrane potential. In addition, FFJ-5 activated the caspase-3 cascade. In conclusion, FFJ-5 inhibited cancer cell growth via the blocking the EGFR-Akt-PKM2 pathway or through the synergistic action of EGFR, Akt and PKM2 proteins, alongside a decrease in ATP production. In addition, FFJ-5 induced cancer cell apoptosis by decreasing the intracellular pH level and the mitochondrial apoptosis pathway. The present results suggest a potential role of FFJ-5 on the therapy of human cancer. PMID- 28356961 TI - 2-Deoxyglucose and sorafenib synergistically suppress the proliferation and motility of hepatocellular carcinoma cells. AB - Cancer cells consume more glucose than normal cells, mainly due to their increased rate of glycolysis. 2-Deoxy-d-glucose (2DG) is an analogue of glucose, and sorafenib is a kinase inhibitor and molecular agent used to treat hepatocellular carcinoma (HCC). The present study aimed to demonstrate whether combining 2DG and sorafenib suppresses tumor cell proliferation and motility more effectively than either drug alone. HLF and PLC/PRF/5 HCC cells were incubated with sorafenib with or without 1 uM 2DG, and subjected to a proliferation assay. A scratch assay was then performed to analyze cell motility following the addition of 2DG and sorafenib in combination, and each agent alone. RNA was isolated and subjected to reverse transcription-quantitative polymerase chain reaction to analyze the expression of cyclin D1 and matrix metalloproteinase-9 (MMP9) following the addition of 2DG and sorafenib in combination and each agent alone. Proliferation was markedly suppressed in cells cultured with 1 uM 2DG and 30 uM sorafenib compared with cells cultured with either agent alone (P<0.05). In addition, levels of Cyclin D1 expression decreased in cells exposed to 3 uM sorafenib and 1 uM 2DG compared with cells exposed to 2DG or sorafenib alone (P<0.05). Scratch assay demonstrated that the distance between the growing edge of the cell sheet and the scratched line was shorter in cells cultured with sorafenib and 2DG than in cells cultured with 2DG or sorafenib alone (P<0.05). Levels of MMP9 expression decreased more in cells treated with both sorafenib and 2DG than in cells treated with 2DG or sorafenib alone (P<0.05). Therefore, 2DG and sorafenib in combination suppressed the proliferation and motility of HCC cells more effectively than 2DG or sorafenib alone, and a cancer treatment combining both drugs may be more effective than sorafenib alone. PMID- 28356962 TI - Comparative clinicopathological characteristics of colon and rectal T1 carcinoma. AB - Lymph node metastasis significantly influences the management of patients with colorectal carcinoma. It has been observed that the biology of colorectal carcinoma differs by location. The aim of the current study was to retrospectively compare the clinicopathological characteristics of patients with colon and rectal T1 carcinomas, particularly their rates of lymph node metastasis. Of the 19,864 patients who underwent endoscopic or surgical resection of colorectal neoplasms at Showa University Northern Yokohama Hospital, 557 had T1 surgically resected carcinomas, including 457 patients with colon T1 carcinomas and 100 patients with rectal T1 carcinomas. Analysed clinicopathological features included patient age, gender, tumor size, morphology, tumor budding, invasion depth, vascular invasion, histological grade, lymphatic invasion and lymph node metastasis. Rectal T1 carcinomas were significantly larger than colon T1 carcinomas (mean +/- standard deviation: 23.7+/-13.1 mm vs. 19.9+/-11.0 mm, P<0.01) and were accompanied by significantly higher rates of vascular invasion (48.0% vs. 30.2%, P<0.01). Significant differences were not observed among any other clinicopathological factors. In conclusion, tumor location itself was not a risk factor for lymph node metastasis in colorectal T1 carcinomas, even though on average, rectal T1 carcinomas were larger and accompanied by a significantly higher rate of vascular invasion than colon T1 carcinomas. PMID- 28356963 TI - Human antigen R as a predictive marker for response to gemcitabine-based chemotherapy in advanced cisplatin-resistant urothelial cancer. AB - In patients with advanced urothelial cancer (UC), a combination of cisplatin (CDDP) and gemcitabine (GEM) is the most commonly used first-line systematic chemotherapy regimen. Although no standard regime for the treatment of CDDP resistant UC has been established, GEM-based regimens are frequently used in these patients. In other types of cancer, human antigen R (HuR) status in cancer cells is closely associated with patient response to GEM. The aim of the present study was to establish the predictive potential of HuR expression for disease progression and survival in patients with UC who were treated with GEM-based regimens as a first or second-line chemotherapy. A total of 50 patients with advanced UC were enrolled in the current study. As first-line chemotherapy, methotrexate, vinblastine, epirubicin and CDDP (MVEC) combination therapy and GEM and CDDP combination therapy were administered in 34 (68.0%) and 16 patients (32.0%), respectively. Following progression, 45 patients (90.0%) were treated with combined GEM and paclitaxel therapy, and 5 patients (10.0%) were treated with GEM monotherapy. Cytoplasmic and nuclear HuR expression was evaluated using immunohistochemical techniques. The associations between HuR expression levels and local tumor response and treatment outcomes were analyzed. In first-line chemotherapy, no anticancer effects were observed to be significantly associated with nuclear or cytoplasmic HuR expression. In second-line chemotherapy nuclear HuR expression also exhibited no significant association with anticancer effects; however, the local tumor response was significantly improved if positive cytoplasmic HuR expression was present (P=0.002). Multivariate analyses revealed that cytoplasmic HuR expression levels were a significant predictive marker for longer OS (hazard ratio, 0.22; 95% confidence interval, 0.09-0.56; P=0.001). No significant association was observed between nuclear HuR expression levels and the overall survival. Therefore, cytoplasmic HuR expression is a significant predictive marker of response to GEM-based chemotherapy in patients with CDDP resistant UC. Despite the limitations of a small and retrospective study, the results of the present study may facilitate the development of novel treatment strategies and provide a focus for additional basic and clinical studies. PMID- 28356964 TI - Prognostic significance of KLF4 expression in gastric cancer. AB - To understand the roles of pluripotent stem cell-inducing genes in gastric cancer, the expression of Kruppel-like factor 4 (KLF4), Nanog, octamer-binding transcription factor 4 (Oct4), avian myelocytomatosis viral oncogene homolog (c Myc) and sex-determining region Y-box 2 (SOX2) was examined using the newly developed gastric carcinoma tissue microarray. The associations between the immunohistochemical expression levels of the pluripotency-inducing factors and the clinicopathological data of 108 patients with gastric cancer were analyzed. No associations were identified between the expression levels of the five pluripotency-inducing factors and the tumor-node-metastasis (TNM) classification or clinicopathological characteristics of the patients. In addition, multivariate analysis revealed no association of Nanog, Oct4, SOX2 or c-Myc with the prognosis of the gastric cancer patients; however, low expression of KLF4 was determined to be an independent negative prognostic factor (P=0.0331), particularly in patients who underwent R0 resection (TNM stages 2 and 3; P=0.0048). In summary, low KLF4 expression was found to be negatively associated with overall survival, and may therefore be a useful prognostic marker in gastric cancer patients. PMID- 28356966 TI - Stromal expression of Fer suppresses tumor progression in renal cell carcinoma and is a predictor of survival. AB - Fps/Fes related (Fer) is a non-receptor tyrosine kinase that is expressed in fibroblasts, immune cells and endothelial cells. Fer serves an important pathological role in cell survival, angiogenesis and the immune system. However, the pathological role of Fer expression in the stromal cells surrounding renal cell carcinoma (RCC) has not been previously investigated. In the present study, immunohistochemical analysis of Fer was performed using the formalin-fixed tissue samples of 152 patients with RCC. The proliferative and apoptotic indices were used to represent the percentage of proliferation marker protein Ki-67- and cleaved caspase-3-positive cells, respectively. The microvessel density was defined as the number of cluster of differentiation (CD) 31-positively stained vessels/mm2. In addition, CD57+ and CD68+ cells were counted using semi quantification of natural killer (NK) cells and macrophages. Fer expression in stromal cells was negatively associated with Fuhrman grade, pathological tumor stage and metastasis (P<0.001). Fer expression in stromal cells was negatively associated with CD68+ macrophage density, whereas it was positively associated with CD57+ NK cell density. Kaplan-Meier estimators indicated that decreased stromal Fer expression was a predictive marker of decreased cause-specific survival rate (P<0.001). Furthermore, low expression of Fer was identified as being an independent marker of decreased cause-specific survival using multivariate analysis (hazard ratio, 7.4; 95% confidence interval, 1.7-33.0; P<0.001). The results of the present study suggested that low Fer expression in stromal cells is associated with increased malignant aggressiveness and decreased survival in patients with RCC. CD57+ NK cell and CD68+ macrophage regulation in cancer-stromal tissue is considered to affect RCC pathology. PMID- 28356965 TI - Overexpression of KAI1 inhibits retinoblastoma metastasis in vitro. AB - The present study aimed to investigate the expression of cluster of differentiation 82 (KAI1), a gene involved in the suppression of tumor metastasis, in human retinoblastoma (RB) tissue and to study the effect of KAI1 expression on RB cell migration and invasion. KAI1 expression was examined in 26 patients with non-invasive and invasive retinoblastoma using reverse transcription-quantitative polymerase chain reaction and western blot analysis. A lentiviral vector containing KAI1 cDNA was used to transfect the two RB cell lines, HXO-Rb44-Gl and Y79. Following successful transfection, the migratory and invasive capacity of the two RB cell lines was evaluated using a Transwell(r) migration assay. KAI1 expression was observed to be downregulated in invasive RB compared to non-invasive RB. The migratory and invasive capacities of KAI1 transfected cell lines were significantly decreased compared to those of the control cells. KAI1 may be involved in retinoblastoma metastasis, and increased expression of KAI1 significantly inhibits the metastatic ability of RB cells in vitro. PMID- 28356967 TI - Trametes robiniophila may induce apoptosis and inhibit MMPs expression in the human gastric carcinoma cell line MKN-45. AB - Gastric carcinoma (GC) is one of the most common malignant tumors and is mainly treated by invasive surgeries. The present study aimed to investigate the treatment potential of Trametes robiniophila on GC using the human GC cell line MKN-45. Cells were incubated with Trametes robiniophila at a concentration of 0, 5 and 10 mg/ml for 24 h. The apoptosis of the cell line was examined with acridine orange/ethidium bromide staining and flow cytometry. The expression of B cell lymphoma (Bcl)-2, Fas, caspase-3, matrix metalloproteinase (MMP)-2 and MMP-9 was analyzed using reverse transcription-polymerase chain reaction and western blotting. With increasing drug concentrations, the proportion of apoptotic and necrotic cells increased. For a certain concentration, the apoptotic ratio also increased with increasing response times. Compared with the control group, the Bcl-2, MMP-2 and MMP-9 expression levels in the MKN-45 cell line decreased, while the expression levels of Fas and caspase-3 increased (P<0.05), and the expression patterns were strengthened with increasing drug concentrations. The present study revealed that Trametes robiniophila had treatment potential on GC, and it may act on gastric cells through apoptotic induction and MMPs expression inhibition. Based on the present results, Trametes robiniophila may be considered as an alternative approach for noninvasive therapy of GC. However, future studies should be performed to clarify this further. PMID- 28356968 TI - Bone metastasis from lung cancer identified by genetic profiling. AB - Cancer metastasis remains responsible for the vast majority of cases of cancer related morbidity and mortality. Metastasis, by its definition, is the spread of cancer from the primary site to the distant tissues. Advancing the scientific and clinical understanding of cancer metastasis is a high priority. The prerequisite requirement for pathological consistency may be compromised during metastasis. The present study reports the case of a cancer patient with different pathological types. The patient presented with pain in the neck and right hip, as well as weight loss. He underwent whole-body positron emission tomography computed tomography, which identified a mass in the lung and abnormal metabolism of the bone. Biopsies of the ilium and lung were performed and he was shown to have lung adenocarcinoma and bone squamous carcinoma. The morphology and immunohistochemical patterns were completely different, while each lesion harbored an identical genetic profile. The bone lesion was identified to be a metastasis from the lung cancer. The patient was prescribed an epithelial growth factor receptor inhibitor, which resulted in a partial response in the lung mass and alleviation of the patient's bone pain. Through this case study, we advocate the importance of using genetic testing in addition to pathological assessment. PMID- 28356969 TI - MicroRNA-149 targets specificity protein 1 to suppress human tongue squamous cell carcinoma cell proliferation and motility. AB - The expression and function of microRNA-149 have been studied in numerous types of cancer. However, thus far, there are no studies of microRNA-149 in tongue squamous cell carcinoma (TSCC). The present study investigated the expression, biological function and molecular mechanism of microRNA-149 in TSCC in vitro, discussing whether it may be a therapeutic biomarker of TSCC in the future. In the present study, microRNA-149 expression in TSCC tissues, matched normal adjacent tissues, TSCC cell lines and normal gingival epithelial cells were analyzed using quantitative polymerase chain reaction. Following transfection with microRNA-149 mimics, cell proliferation, migration and invasion assays, a luciferase assay and western blotting were performed. The present study found that the expression of microRNA-149 was significantly decreased in TSCC tissues and cell lines compared with matched normal tissue and normal gingival epithelial cells, respectively. In addition, it was also demonstrated that microRNA-149 inhibited cell proliferation, migration and invasion by directly targeting specificity protein 1. Therefore, the results suggested that microRNA-149 may be a novel target for TSCC therapy in the future. PMID- 28356970 TI - Influence of gap junction intercellular communication composed of connexin 43 on the antineoplastic effect of adriamycin in breast cancer cells. AB - Gap junctions (GJs) serve the principal role in the antineoplastic (cytotoxicity and induced apoptosis) effect of chemical drugs. The aim of the present study was to determine the effect of GJ intercellular communication (GJIC) composed of connexin 43 (Cx43) on adriamycin cytotoxicity in breast cancer cells. Four cell lines (Hs578T, MCF-7, MDA-MB-231 and SK-BR-3) with different degree of malignancy were used in the study. The results of western blotting and immunofluorescence revealed that, in Hs578T and MCF-7 cells, which have a low degree of malignancy, the expression levels of Cx43 and GJIC were higher than those in MDA-MB-231 and SK-BR-3 cells (which have a high degree of malignancy). In Hs578T and MCF-7 cells, where GJ could be formed, the function of GJ was modulated by a pharmacological potentiators [retinoid acid (RA)]/inhibitors [oleamide and 18 alpha-glycyrrhetinic acid (18-alpha-GA)] and small interfering RNA (siRNA). In high-density cells (where GJ was formed), enhancement of GJ function by RA increased the cytotoxicity of adriamycin, while inhibition of GJ function by oleamide/18-alpha-GA and siRNA decreased the cytotoxicity caused by adriamycin. Notably, the modulation of GJ did not affect the survival of cells treated with adriamycin when cells were in low density (no GJ was formed). The present study illustrated the association between GJIC and the antitumor effect of adriamycin in breast cancer cells. The cytotoxicity of adriamycin on breast cancer cells was increased when the function of gap junctions was enhanced. PMID- 28356972 TI - Wild-type p53-induced phosphatase 1 is a prognostic marker and therapeutic target in bladder transitional cell carcinoma. AB - Wild-type p53-induced phosphatase (Wip1) is an established oncogene and is associated with development of multiple forms of human cancer. However, the expression and role of Wip1 in human bladder transitional cell carcinoma (TCC) remains to be elucidated. In the present study, immunohistochemistry demonstrated that Wip1 was overexpressed in bladder TCC tissues compared with corresponding normal bladder tissues in 106 bladder TCC cases (P<0.0001). Furthermore, high expression levels of Wip1 were significantly associated with increasing tumor size (P=0.002), pathological grade (P=0.025), clinical T stage (P=0.001) and lymph nodal metastasis (P=0.003). Kaplan-Meier survival analysis identified that patients with high Wip1 expression levels exhibited a lower overall survival time (P<0.0001), and Cox proportional hazards regression model analysis demonstrated that Wip1 expression was an independent prognostic factor in patients with bladder TCC (P=0.025). In addition, downregulation of Wip1 expression by transfection with small interfering RNA in bladder cancer cells inhibited cell proliferation, invasion and migration (P<0.05), along with the upregulation of p53 protein levels (P<0.05). These findings suggest that Wip1 may function as a potential prognostic marker and therapeutic target in bladder cancer. PMID- 28356971 TI - Elevated microRNA-125b levels predict a worse prognosis in HER2-positive breast cancer patients. AB - Breast cancer, the second most common cancer worldwide, is the leading cause of cancer-associated mortality in women, accounting for ~15% of all cancer associated mortalities in women. The development, local invasion and metastasis of breast cancer are associated with the dysregulation and mutation of numerous genes and epigenetic mechanisms, including coding RNA and non-coding RNA, such as microRNAs (miRs/miRNAs). Previous studies have shown a dual-faced role of miR 125b in breast cancer. In the present study, a total of 221 paraffin-embedded breast cancer and 49 paraffin-embedded non-cancerous breast tissue samples were collected. In situ hybridization was used to analyze the expression of miR-125b in the breast cancer tissues. Spearman's rank correlation analysis was used to analyze the expression correlation between miR-125b and human epidermal growth factor 2 (HER2). The overall survival estimates over time were calculated using the Kaplan-Meier method with log-rank test. It was found that miR-125b expression was significantly increased in the breast cancer tissues compared with that in the non-cancerous tissues, and high miR-125b expression indicated a poor prognosis in the breast cancer patients. In addition, miR-125b expression was positively correlated with HER2, but not with progesterone receptor and estrogen receptor. Notably, high miR-125b expression was significantly correlated with tumor size and Tumor-Node-Metastasis stage in the HER2-positive breast cancer patients, along with a poor prognosis. The present study provides clinical data to confirm the oncogenic potential of miR-125b, particularly in HER2-positive human breast cancer. Thus, identification of miR-125b may be a potential molecular biomarker for the prediction of clinical outcomes in breast cancer patients, particularly HER2-positive cases that will receive paclitaxel-based neoadjuvant chemotherapy. PMID- 28356973 TI - Patients with normal-range CA19-9 levels represent a distinct subgroup of pancreatic cancer patients. AB - Pancreatic cancer remains a lethal disease that responds poorly to multiple types of treatment. Therefore, the identification of distinct subgroups that exhibit unique therapeutic responses is an urgent requirement. In the present multicenter study (1,912 cases), the differences between the therapeutic responses and clinical characteristics of two subgroups of pancreatic cancer, carbohydrate antigen 19-9 (CA19-9)-normal (baseline serum level, <=37 U/ml) and CA19-9 elevated (baseline serum level, >37 U/ml), were analyzed. CA19-9-normal expression was identified to be an independent prognostic factor for patients with stage I-II [hazard ratio (HR)=0.77; P=0.037] and stage III-IV (HR=0.68; P<0.001) pancreatic cancer. The 5-year survival rate of the stage III-IV CA19-9 normal subgroup was increased compared with the stage I-II CA19-9-elevated subgroup (15.4 vs. 13.8%). In the stage I-II CA19-9-normal and CA19-9-elevated subgroups, gemcitabine-based chemotherapy was a significant positive prognostic factor for survival (CA19-9-normal, HR=0.54, P=0.013; CA19-9-elevated, HR=0.55, P<0.001). However, among stage III-IV patients, the CA19-9-normal subgroup exhibited a poor response to gemcitabine-based chemotherapy (HR=0.77; P=0.165), while the CA19-9-elevated subgroup exhibited a favorable response, resulting in a lower rate of mortality (HR=0.70; P<0.001) compared with no chemotherapy. It was concluded that CA19-9-normal pancreatic cancer is a less aggressive subgroup; however, advanced CA19-9-normal pancreatic cancer exhibits a poorer response to gemcitabine-based chemotherapy. PMID- 28356974 TI - Gastrointestinal stromal tumor with a PDGFRA mutation masquerading as gastric plexiform fibromyxoma: A comparative clinicopathological study of two cases. AB - Gastric plexiform fibromyxoma (PF) is a rare mesenchymal tumor with a histologically distinctive multinodular pattern, dissimilar to conventional gastrointestinal stromal tumor (GIST). The current study presents one case of gastric PF, and one case of GIST with a platelet-derived growth factor receptor alpha (PDGFRA) mutation mimicking PF, and discusses their differential diagnoses. The two patients were a 51-year-old male with PF and a 47-year-old female with GIST, each of whom presented with an occupying lesion in the gastric antrum. Histologically, the two cases shared a rare and approximately unanimous morphological pattern of a prominent multinodular and plexiform figuration in the gastric wall, including mucoid matrix, short spindle cells and small caliber vascular elements, and areas of stromal tumor cells exhibited an epithelioid appearance. Immunohistochemistry revealed that the PF tumor cells were positive for smooth muscle actin (SMA), but negative for mast/stem cell growth factor receptor (KIT), GIST-1 (DOG1), cluster of differentiation (CD) 34, S-100, desmin and cytokeratin AE1/AE3. The case of GIST expressed KIT and DOG1, but was negative for SMA, CD34, S-100, desmin and AE1/AE3. In addition, the GIST case, which was observed to harbor a D842V mutation in exon 18 of PDGFRA, was demonstrated to be genetically distinct from PF. The cases presented in the current study were uncommon in that GIST exhibited a plexiform appearance that mimicked the histology of the rare PF tumor; therefore, GIST must be considered and discounted first when determining a differential diagnosis for a gastrointestinal mesenchymal neoplasm. PMID- 28356975 TI - Potential regulation of glioma through the induction of apoptosis signaling via Egl-9 family hypoxia-inducible factor 3. AB - Glioma is an aggressive form of brain cancer that occurs following the abnormal proliferation of glial cells. Although glioma cannot spread to other organs, the morbidity and mortality rates of the disease are high, even following surgery, radiotherapy and chemotherapy. The function of Egl-9 family hypoxia-inducible factor 3 (Egln3) in cancer is controversial, and it is debated as to whether Egln3 positively or negatively regulates tumors. In the present study, a mouse model of low-grade glioma was successfully established. Through the use of immunohistochemical and western blot analyses, it was demonstrated that Egln3 expression in glioma tissue performed an important role in regulation by amplifying the signals for apoptosis, as determined by an increase in DNA fragments. Furthermore, Egln3 expression was inhibited by the administration of dimethyloxalylglycine, and the downregulated expression of Egln3 had marked effects on the regulation of glioma through apoptosis. The present study therefore provides evidence of an association between Egln3 expression and apoptosis in low-grade glioma. PMID- 28356976 TI - CD147 promotes the proliferation, invasiveness, migration and angiogenesis of human lung carcinoma cells. AB - Cluster of differentiation (CD) 147 is a transmembrane glycoprotein that is highly expressed at the tumor cell surface, which stimulates fibroblasts to produce a large number of matrix metalloproteinases and promotes tumor invasion and metastasis and tumor-induced angiogenesis. The present study investigated the functions and the role of CD147 in the human lung carcinoma A549 cell line. The present study constructed expression and interference [small interfering (si) RNA] lentiviral vectors of CD147, which established stable overexpression and low expression of CD147 in the A549 cell line, named A549-CD147 and A549-siCD147, respectively. The differences in biological features between various levels of CD147 expression in A549 cells was investigated by cell counting kit-8 (CCK-8), Transwell, scratch and lumen formation assays. The results of the CCK-8 assay revealed that A549-CD147 cell proliferation was significantly increased and A549 siCD147 cell proliferation was decreased compared with the control groups. The A549-CD147 cells had the largest number of cells penetrating the Matrigel in the Transwell assay, which indicates that upregulation of CD147 expression increases the infiltration capacity of cells. The scratch assay revealed that A549-CD147 cells have the highest capacity for migration, while A549-siCD147 cells have the lowest. Quantitative polymerase chain reaction and western blot analysis demonstrated that vascular endothelial growth factor (VEGF) expression was proportional to the expression level of CD147 at the mRNA and protein level. The lumen formation assay revealed that the number of vessel lumens that human umbilical vein endothelial cells formed in the A549-CD147 cell supernatant was increased compared with the A549-siCD147 cells. Collectively, the present results suggest that CD147 is important in the promotion of lung carcinoma cell proliferation, invasion and metastasis and the upregulation of VEGF, which stimulates the angiogenesis of lung carcinoma. In conclusion, CD147 may be a potential target in the treatment of lung carcinoma. PMID- 28356977 TI - Clinical significance of platelet-derived growth factor receptor-beta gene expression in stage II/III gastric cancer with S-1 adjuvant chemotherapy. AB - Overall survival remains unsatisfactory in stage II/III gastric cancer, even after curative surgery and adjuvant chemotherapy. Platelet-derived growth factor receptor-beta (PDGFR-beta) is associated with the proliferation of cancer cells. The present study therefore investigated the association of PDGFR-beta gene expression with patient outcome in 134 stage II/III gastric cancer patients who received adjuvant chemotherapy with S-1. Relative PDGFR-beta gene expression was measured in surgical cancer tissue and adjacent normal mucosa specimens by reverse transcription-quantitative polymerase chain reaction. The PDGFR-beta gene expression levels were found to be significantly higher in the cancer tissues compared with the adjacent normal mucosa. A high level of PDGFR-beta gene expression was associated with a significantly poorer 5-year overall survival rate compared with a low level of PDGFR-beta expression. Upon multivariate analysis, PDGFR-beta gene expression was found to be an independent predictor of survival. Overall, the study indicates that PDGFR-beta overexpression in gastric cancer tissues is a useful independent predictor of outcome in patients with stage II/III gastric cancer who receive adjuvant chemotherapy with S-1. PMID- 28356978 TI - Reproducibility of the EGFR immunohistochemistry scores for tumor samples from patients with advanced non-small cell lung cancer. AB - Epidermal growth factor receptor (EGFR) is overexpressed in >60% of non-small cell lung cancer (NSCLC) cases. In combination with radiotherapy or chemotherapy, first-line treatments with antibodies against EGFR, including cetuximab and necitumumab, have demonstrated benefits by increasing overall survival (OS), particularly in patients who overexpress EGFR. The present study evaluated the interobserver agreement among three senior pathologists, who were blinded to the clinical outcomes and assessed tumor samples from 85 patients with NSCLC using the H-score method. EGFR immunohistochemistry was performed using a qualitative immunohistochemical kit. The reported (mean +/- standard deviation) H-scores from each pathologist were 111+/-102, 127+/-103 and 128.53+/-104.03. The patients with average H-scores >=1, >=100, >=200 and between 250-300 were 85.9, 54.1, 28.2 and 12.9, respectively. Patients who had an average H-score >100 had a shorter OS time compared with those with lower scores. Furthermore, patients with EGFR mutations who were treated with EGFR-tyrosine kinase inhibitors (TKIs) and had an average H-score >100 had a longer OS time compared with those with an average H score <100. The interobserver concordance for the total H-scores were 0.982, 0.980 and 0.988, and for a positive H-score >=200, the interobserver concordance was 0.773, 0.710 and 0.675, respectively. The determination of EGFR expression by the H-score method is highly reproducible among pathologists and is a prognostic factor associated with a poor OS in all patients. Additionally, the results of the present study suggest that patients with EGFR mutations that are treated with EGFR-TKIs and present with a high H-score have a longer OS time. PMID- 28356979 TI - Inhibition of store-operated Ca2+ entry counteracts the apoptosis of nasopharyngeal carcinoma cells induced by sodium butyrate. AB - Sodium butyrate (NaBu), a histone deacetylase inhibitor, has demonstrated anti tumor effects in several cancers, and is a promising candidate chemotherapeutic agent. However, its roles in nasopharyngeal carcinoma (NPC), an endemic malignant disease in Southern China and Southeast Asia, has rarely been studied. In the present study, MTT assay, colony formation assay, flow cytometry analysis and western blotting were performed to explore the influence of NaBu on NPC cells and its underlying mechanism. NaBu induced morphological changes and inhibited proliferation in 5-8F and 6-10B cells. MTT assay revealed that NaBu was cytotoxic to 5-8F and 6-10B cells in a dose- and time-dependent manner. Furthermore, flow cytometry analysis revealed that NaBu induced obvious cell apoptosis in 5-8F and 6-10B cells due to the activation of the mitochondrial apoptosis axis. In addition, flow cytometry analysis and western blotting demonstrated that NaBu could enhance the Ca2+ influx by promoting store-operated Ca2+ entry (SOCE) in 5 8F and 6-10B cells. Inhibition of SOCE by specific inhibitors or downregulated expression of calcium release-activated calcium channel protein 1 and stromal interaction molecule 1 could counteract the apoptosis of NPC cells induced by NaBu. Thus, the current study revealed that enhanced SOCE and activated mitochondrial apoptosis axis may account for the mechanisms of cytotoxicity of NaBu in NPC cells, and that NaBu serves as a promising chemotherapeutic agent in NPC therapy. PMID- 28356980 TI - Regulation of cell migration via the EGFR signaling pathway in oral squamous cell carcinoma cells. AB - Cell migration potency is essential in cancer metastasis and is often regulated by extracellular stimuli. Oral squamous cell carcinoma cell lines include those that are sensitive, as well as resistant, to the effects of the epidermal growth factor receptor (EGFR) inhibitor cetuximab on cell migration. In the present study, the molecular differences in the EGFR response to cell migration between the SAS cetuximab-sensitive and HSC4 cetuximab-resistant cell lines was examined. Treatment with the EGFR inhibitors AG1478 and cetuximab reduced the migration potency of SAS cells, but not HSC4 cells. The migration of the two cell lines was inhibited under serum-free culture conditions, and the addition of EGF to the serum-free medium promoted the migration of SAS cells, but not HSC4 cells. In addition, SAS cell migration was reduced by the mitogen-activated protein kinase kinase and protein kinase B (Akt) inhibitors PD98059 and MK2206, whereas HSC4 cell migration was only inhibited by MK2206. EGF induced an increase in extracellular signal-regulated kinase phosphorylation levels in HSC4 cells, and stimulated Akt phosphorylation levels in SAS cells. Furthermore, the staining of actin filaments with phalloidin was significantly increased by the inhibition of EGFR in SAS cells, but was not observed as altered in HSC4 cells. Conversely, the addition of EGF to the culture medium decreased the accumulation of actin filaments in SAS cells. The results suggest that the EGF-EGFR signaling pathway has an important role in SAS cell migration via the modulation of actin dynamics, and that HSC4 cell migration is regulated by a serum component other than EGFR. PMID- 28356981 TI - Characteristic expression of fukutin in gastric cancer among atomic bomb survivors. AB - Approximately 70 years have passed since the atomic bombs were dropped on Nagasaki and Hiroshima. To elucidate potential biomarkers and possible mechanisms of radiation-induced cancer, the expression of FKTN, which encodes fukutin protein and causes Fukuyama-type congenital muscular dystrophy, was analyzed in gastric cancer (GC) tissue samples from atomic bomb survivors. Expression of cluster of differentiation (CD) 10 was also evaluated, as it has previously been observed that positive fukutin expression was frequently noted in CD10-positive GC cases. In the first cohort from Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital (Hiroshima, Japan; n=92), 102 (53%) of the GC cases were positive for fukutin. Expression of fukutin was not associated with exposure status, but was associated with CD10 expression (P=0.0001). The second cohort was from Hiroshima University Hospital (Hiroshima, Japan; n=86), and these patients were also in the Life Span Study cohort, in which atomic bomb radiation doses were precisely estimated using the DS02 system. Expression of fukutin was detected in 58 (67%) of GC cases. GC cases positive for fukutin were observed more frequently in the low dose-exposed group than in the high dose-exposed group (P=0.0001). Further studies with a larger cohort, including precise radiation dose estimation, may aid in clarifying whether fukutin could serve as a potential biomarker to define radiation-induced GC in atomic-bomb survivors. PMID- 28356982 TI - DHX32 expression is an indicator of poor breast cancer prognosis. AB - Emerging evidence suggests that DEAH-box polypeptide 32 (DHX32) serves an important role in the progression and metastasis of cancer. However, the role of DHX32 in breast cancer remains to be completely elucidated. The aim of the present study was to evaluate the expression and clinical significance of DHX32 in breast cancer. The reverse transcription-quantitative polymerase chain reaction was performed to analyze DHX32 messenger (m)RNA expression, and western blotting and immunohistochemistry were performed to examine DHX32 protein expression in breast cancer and adjacent non-cancerous tissues. The association in breast cancer between DHX32 expression, clinicopathological features and prognosis was analyzed using 193 breast cancer tissue samples. The results of the present study demonstrated that breast cancer tissues exhibited increased DHX32 mRNA and protein expression compared with adjacent non-cancerous tissues (P<0.001). In addition, DHX32 expression was significantly associated with breast cancer clinical stage (P=0.006), histological grade (P=0.029), lymph node metastasis (P<0.001) and expression of the proliferation marker Ki-67 (P=0.004). Kaplan-Meier estimator analysis indicated that increased DHX32 expression is associated with poor prognosis in patients with breast cancer. Furthermore, the Cox proportional hazards model indicated that DHX32 expression is an independent prognostic factor for decreased overall survival and disease-free survival in patients with breast cancer. In conclusion, the results of the present study suggest that DHX32 overexpression is an unfavorable prognostic biomarker in breast cancer and a potential therapeutic target of future breast cancer treatments. PMID- 28356983 TI - TCN, an AKT inhibitor, exhibits potent antitumor activity and enhances radiosensitivity in hypoxic esophageal squamous cell carcinoma in vitro and in vivo. AB - The aim of the present study was to investigate the radiosensitization effect of triciribine (TCN) on human esophageal squamous cell carcinoma (ESCC) in normoxia or hypoxia and its mechanism. The cytotoxicity and radiosensitization mechanism of TCN were investigated by Cell Counting Kit 8, clonogenic assay, flow cytometry, western blotting (WB) and immunofluorescence staining of phospho histone H2A.X, Ser139 (gamma-H2AX) in ESCC in vitro, while the protein expression levels of AKT, phosphorylated (p)-AKT, hypoxia-inducible factor (HIF)-1alpha and vascular endothelial growth factor (VEGF) were evaluated by WB in vivo. The cytotoxicity of TCN was dose dependent. Upon exposure to TCN, ESCC cells in hypoxia treated with 4-Gy radiotherapy exhibited an evidently higher apoptotic rate than cells subjected to other treatments. TCN could significantly inhibit the protein expression of p-AKT, HIF-1alpha and VEGF in vitro and in vivo. The present results suggested that TCN can effectively inhibit AKT, p-AKT, HIF-1alpha and VEGF, thus conferring radiosensitivity to ESCC in vitro and vivo. TCN is considered as an adjuvant in radiotherapy of ESCC in clinical application. PMID- 28356984 TI - Interleukin-1beta activates focal adhesion kinase and Src to induce matrix metalloproteinase-9 production and invasion of MCF-7 breast cancer cells. AB - Interleukin-1beta (IL-1b) is a pleiotropic cytokine that is important in tumor progression and invasion. Matrix metalloproteinase-9 (MMP-9), which is a secreted matrix-degrading enzyme, is one of the key regulators of tumor invasion and metastasis. The current report indicated that IL-1b promotes MMP-9 production and cell invasion in non-metastatic MCF-7 breast cancer cells. IL-1b activated focal adhesion kinase (FAK) and proto-oncogene tyrosine-protein kinase Src (Src). Moreover, inhibiting the Src/FAK pathway reduced the IL-1b-induced production of MMP-9 and cell invasion. To investigate the functional role of FAK in MMP-9 production cell lines expressing mutant FAK in FAK knock-out mouse fibroblasts were generated. In wild-type FAK-expressing cells, MMP-9 production was induced by IL-1b stimulation. By contrast, IL-1b-induced MMP-9 production was abrogated in FAK knock-out, FAK Y397F, FAK Y925F, and kinase dead mutant-expressing cells. Therefore the results of the current study indicate that FAK and Src kinases are activated by IL-1b and play a critical role in MMP-9 production and tumor cell invasion. PMID- 28356985 TI - Molecular mechanisms of cholangiocarcinoma cell inhibition by medicinal plants. AB - Cholangiocarcinoma (CCA) is one of the most common causes of cancer-associated mortality in Thailand. Certain phytochemicals have been demonstrated to modulate apoptotic signaling pathways, which may be targeted for the prevention and treatment of cancer. Therefore, the aim of the present study was to investigate the effect of specific medicinal plants on the inhibition of CCA cell proliferation, and to identify the molecular mechanisms underlying this. A WST-1 cell proliferation assay was performed using an RMCCA1 cell line, and apoptotic signaling pathways were also investigated using a PathScan Stress and Apoptosis Signaling Antibody Array Kit. The cell proliferation assay indicated that extracts from the Phyllanthus emblica fruit pulp (PEf), Phyllanthus emblica seed (PEs), Terminalia chebula fruit pulp (TCf), Terminalia chebula seed (TCs), Areca catechu seed (ACs), Curcuma longa (CL) and Moringa oleifera seed (MOs) exerted anti-proliferative activity in RMCCA1 cells. In addition, the PathScan assay revealed that certain pro-apoptotic molecules, including caspase-3, poly (ADP ribose) polymerase, checkpoint kinase 2 and tumor protein 53, exhibited increased activity in RMCCA1 cells treated with the aforementioned selected plant extracts, with the exception of PEf. The mitogen-activated protein kinase (MAPK) pathways (including ERK1/2 and p38 MAPK) expression level was significantly increased in RMCCA1 cells pre-treated with extracts of PEs, TCf, CL and MOs. The activation of protein kinase B (Akt) was significantly demonstrated in RMCCA1 cells pre-treated with extracts of TCf, ACs and MOs. In summary, the present study demonstrated that extracts of PEs, TCf, TCs, ACs, CL and MOs exhibited anti-proliferative effects in CCA cells by inducing pro-apoptotic signals and modulating signal transduction molecules. Further studies in vivo are required to demonstrate the potential applications of specific plant extracts for the treatment of human cancer. PMID- 28356986 TI - Hypoxia regulates CD44 expression via hypoxia-inducible factor-1alpha in human gastric cancer cells. AB - Hypoxia induces proliferation and invasion in cancer cells via hypoxia-inducible factor (HIF)-1alpha. The cell adhesion molecule cluster of differentiation (CD) 44 has been associated with increased cell invasion and metastasis. Whether hypoxia regulates the expression of CD44 in gastric cancer cells remains to be established. In the current study, the effects of hypoxia on HIF-1alpha and CD44 expression levels in human gastric cell lines SGC-7901 and BGC-823 were evaluated. The cells were cultured in 1% O2 for 1 week and then treated with 20 nM rapamycin for 72 h. Cell viability was evaluated using the Cell Counting kit-8 assay, and cell invasion was detected by the Transwell invasion assay. The protein and messenger (m) RNA expression levels of HIF-1alpha and CD44 were detected using western blotting and reverse transcription-quantitative polymerase chain reaction, respectively. The results revealed that cell viability and invasion increased under hypoxic conditions, but decreased following rapamycin treatment in SGC-7901 and BGC-823 cells. Hypoxia also increased the protein and mRNA expression levels of HIF-1alpha and CD44 in these two cell lines. However, this hypoxia-induced increase in HIF-1alpha and CD44 protein and mRNA expression levels was inhibited by rapamycin. These findings suggest that hypoxia induced the proliferation and invasion of SGC-7901 and BGC-823 cells. Furthermore, CD44 expression levels were potentially associated with HIF-1alpha expression levels. Therefore, in gastric cancer cells, hypoxia may regulate CD44 expression via HIF 1alpha in order to promote cell proliferation and invasion. PMID- 28356987 TI - Pro-apoptotic and anti-proliferative effects of corn silk extract on human colon cancer cell lines. AB - Corn silk is an economically and nutritionally significant natural product as it represents a staple food for a large proportion of the world population. This study investigated the anticancer activity of corn silk extract in human colon cancer cells and human gastric cancer cells. Following treatment with corn silk extract, certain apoptosis-related events were observed, including inhibition of cell proliferation, loss of mitochondrial membrane potential (DeltaPsim), release of Ca2+ and release of cytochrome c from the mitochondria into the cytosol. Our results revealed that corn silk extract inhibited the proliferation of cancer cells and increased the level of apoptosis in a concentration-dependent manner. Western blot analysis revealed that corn silk extract upregulated the levels of Bax, cytochrome c, caspase-3 and caspase-9, but downregulated the levels of B cell lymphoma 2. These results suggest that corn silk extract may induce apoptosis through the mitochondria-mediated pathway. PMID- 28356988 TI - Complete response to capecitabine in a frail, elderly patient with metastatic colorectal cancer: A case report. AB - The clinical management of frail, elderly patients affected by colorectal cancer (CRC) remains a subject of debate. The present study reports the case of an elderly man with metastatic CRC (mCRC) who was successfully treated with capecitabine. The patient survived for 29 months, thus highlighting its potential activity in terms of obtaining a complete response and high efficacy. A 77-year old man presented with adenocarcinoma of the rectum with multiple and synchronous liver metastases, in addition to several comorbidities. The patient received single-agent capecitabine chemotherapy (825 mg/mq twice a day) on days 1-14 of a 21-day cycle. Following 12 cycles of well-tolerated therapy, a computed tomography scan revealed a complete response with no evidence of liver metastases. An overall survival of 29 months was documented, and the patient eventually succumbed to a diabetes-related complication. In compromised patients with mCRC, reduced-dose capecitabine is an excellent therapeutic option due to its positive safety profile, activity and efficacy. PMID- 28356990 TI - Single nucleotide polymorphisms of the haptoglobin gene in non-small cell lung cancer treated with personalized peptide vaccination. AB - The present study analyzed polymorphisms of the 5' flanking region (from nt -840 to +151) of the haptoglobin gene in 120 patients with advanced non-small cell lung cancer (NSCLC) receiving personalized peptide vaccinations. In the region, six single nucleotide polymorphisms (SNPs) were confirmed, of which two, rs5472 and rs9927981, were completely linked to each other. The minor allele frequencies of rs5472/rs9927981 and rs4788458 were higher than those of the other three SNPs. The genotype frequencies of rs5472 or rs9927981 were A/A or C/C (42.5%, n=51), A/G or C/T (40.8%, n=49), and G/G or T/T (16.7%, n=20), respectively; and those of rs4788458 were T/T (34.2%, n=41), T/C (40.0%, n=48), and C/C (25.8%, n=31). The association between polymorphism rs5472/rs9927981 and prognosis, or between rs4788458 and prognosis, was analyzed further. However, no correlation was found between these SNPs and overall survival, regardless of subgroup analysis of gender, histology or concurrent therapy. These results suggest that the polymorphisms rs5472/rs9927981 and rs4788458 are not useful prognostic tools for patients with NSCLC treated with personalized peptide vaccination. PMID- 28356991 TI - Prognostic significance of the preoperative lymphocyte-to-monocyte ratio in patients with colorectal cancer. AB - A correlation between the lymphocyte-to-monocyte ratio (LMR) and the survival of patients with hematological malignancies has been reported previously. However, there have been few studies investigating the prognostic significance of LMR in patients with solid tumors. The aim of the present study was to evaluate the prognostic significance of preoperative LMR in patients with colorectal cancer (CRC). A total of 189 patients undergoing potentially curative surgery for CRC were enrolled. The LMR was calculated from preoperative blood samples by dividing absolute lymphocyte count by absolute monocyte count. A cut-off value of 4.8 was set based on the receiver operating characteristic curve; 116 patients were classified as high-LMR, and 73 patients classified as low-LMR. The high-LMR group exhibited significantly better relapse-free survival (P=0.0018) and overall survival (P=0.0127) rates than the low-LMR group. According to the multivariate analysis of survival, preoperative LMR was identified as an independent prognostic factor for relapse-free survival (P=0.041) and overall survival (P=0.031). Therefore, preoperative LMR is a useful prognostic marker in patients with CRC. PMID- 28356992 TI - Arctigenin, a natural lignan compound, induces G0/G1 cell cycle arrest and apoptosis in human glioma cells. AB - The aim of the current study was to investigate the anticancer potential of arctigenin, a natural lignan compound, in malignant gliomas. The U87MG and T98G human glioma cell lines were treated with various concentrations of arctigenin for 48 h and the effects of arctigenin on the aggressive phenotypes of glioma cells were assessed. The results demonstrated that arctigenin dose-dependently inhibited the growth of U87MG and T98G cells, as determined using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and bromodeoxyuridine incorporation assays. Arctigenin exposure also induced a 60-75% reduction in colony formation compared with vehicle-treated control cells. However, arctigenin was not observed to affect the invasiveness of glioma cells. Arctigenin significantly increased the proportion of cells in the G0/G1 phase and reduced the number of cells in the S phase, as compared with the control group (P<0.05). Western blot analysis demonstrated that arctigenin increased the expression levels of p21, retinoblastoma and p53 proteins, and significantly decreased the expression levels of cyclin D1 and cyclin-dependent kinase 4 proteins. Additionally, arctigenin was able to induce apoptosis in glioma cells, coupled with increased expression levels of cleaved caspase-3 and the pro-apoptotic BCL2 associated X protein. Furthermore, arctigenin-induced apoptosis was significantly suppressed by the pretreatment of cells with Z-DEVD-FMK, a caspase-3 inhibitor. In conclusion, the results suggest that arctigenin is able to inhibit cell proliferation and may induce apoptosis and cell cycle arrest at the G0/G1 phase in glioma cells. These results warrant further investigation of the anticancer effects of arctigenin in animal models of gliomas. PMID- 28356993 TI - Primary breast lymphoma: A single center study. AB - The aim of the present study was to summarize the clinical characteristics of primary breast lymphoma (PBL) and evaluate its management approaches. A total of 29 patients newly diagnosed with PBL, and treated between April 2006 and May 2013, were analyzed retrospectively. The median survival follow-up time for all patients was 66.8 (range, 25.4-110.0) months. The results of the follow-up revealed 22 living lymphoma-free patients and 7 patients who had succumbed to PBL. Of the 7 deceased patients, 6 had succumbed to lymphoma and 1 to chemotherapy-associated hepatic failure. In total, 1 patient who presented with bilateral breast lymphoma developed left breast relapse following lumpectomy and chemotherapy, 2 patients developed a bone marrow relapse, 1 patient developed lung and mediastinal lymph node relapses, and 1 patient developed a skin relapse. The Kaplan-Meier estimator predicted 5-year overall survival and progression-free survival rates for all patients of 74.4 and 74.6%, respectively. PBL appears to be a rare disease with a good overall prognosis and low incidence of local relapse, following chemotherapy alone or in combination with other treatments. Further studies investigating the development of effective agents for use in treatment-resistant patients are required. PMID- 28356989 TI - Sorafenib therapy following resection prolongs disease-free survival in patients with advanced hepatocellular carcinoma at a high risk of recurrence. AB - Sorafenib is the standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC); however, its therapeutic value in patients with HCC following resection remains controversial. The current retrospective study was undertaken to assess the effects of sorafenib treatment following surgical resection in patients with advanced HCC disease who were at a high risk for recurrence. Between July 2010 and July 2013, a consecutive cohort of 42 patients with advanced HCC and at a high risk of recurrence (i.e., those with portal vein tumor thrombosis, adjacent organ involvement or tumor rupture) who underwent resection were analyzed. The patients were categorized into the sorafenib group (n=14) or the best supportive care (BSC) group (n=28). Although the histological grade, Barcelona Clinic Liver Cancer Stage, tumor size, nodule number and proportion of patients with high serum alpha-fetoprotein levels were comparable between the sorafenib and BSC groups, those receiving sorafenib following resection had significantly longer disease-free survival (DFS) of 5.2 months [95% confidence interval (CI), 1.2-9.2 months] compared with the BSC group [1.8 months (95% CI, 0.6-3.0 months)]. No differences in overall survival were noted between the groups. Furthermore, no drug-related adverse events resulted in discontinuation of sorafenib therapy. Univariate log-rank analysis revealed that sorafenib treatment (P=0.002) and treatment prior to resection (P=0.012) were significantly associated with longer DFS; however, sorafenib therapy (P=0.027) and tumor size (P=0.028) were associated with longer DFS by multivariate analysis. Furthermore, sorafenib was well-tolerated and improved DFS in patients with advanced HCC who underwent hepatic resection. Thus, tumor resection followed by sorafenib therapy may represent an effective therapeutic strategy for patients with advanced HCC. This possibility should be confirmed in larger, multicenter studies. PMID- 28356994 TI - Pinus massoniana bark extract inhibits migration of the lung cancer A549 cell line. AB - The bark of Pinus massoniana is a traditional Chinese medicine for the treatment of various health disorders. Previous studies have demonstrated that P. massoniana bark extract (PMBE) may induce the apoptosis of hepatoma and cervical cancer cells. However, whether PMBE is able to inhibit the migration of lung cancer cells requires further investigation. In the current study, the effects of PMBE on the viability of human lung cancer A549 cells were detected using an MTT assay. The migration of lung cancer cells following exposure to PMBE were quantified using wound healing and Transwell assays, respectively. The expression levels of matrix metalloproteinase (MMP)-9 were determined using western blotting. The results revealed that PMBE significantly inhibited the growth of the lung cancer cells. In addition, the wound closure rate and the migration of the lung cancer cells were suppressed by PMBE. Furthermore, the expression levels of MMP-9 were reduced. These findings indicated that PMBE is able to restrict the migration and invasion of lung cancer cells, and that PMBE may serve as a novel therapeutic agent for patients with metastatic lung cancer in the future. PMID- 28356995 TI - Apigenin enhances the cisplatin cytotoxic effect through p53-modulated apoptosis. AB - Epidemiological and experimental evidence suggests that dietary flavonoids, including apigenin, have anticancer roles. Apigenin has been reported to elevate p53, a critical molecule in the induction of apoptosis. The present study aimed to investigate whether apigenin, a dietary flavonoid, improves the cytotoxic effect of cisplatin in a cancer cell culture system, and to elucidate the mechanism of this effect. Multiple tumor cell types were treated with apigenin, cisplatin or both drugs. Cell viability was evaluated, and the cytotoxic effect was determined biochemically and microscopically. Treatment with apigenin increased cisplatin-induced DNA damage and the apoptosis of tumor cells in a p53 dependent manner. Apigenin, when used with cisplatin, inhibited cell proliferation and promoted mitogen-activated protein kinase activation and subsequent p53 phosphorylation, leading to p53 accumulation and upregulation of proapoptotic proteins. Cisplatin is one of the most commonly used chemotherapeutic drugs for malignant tumors, but resistance to this drug occurs. The current results therefore demonstrate that dietary flavonoids may diminish the resistance of cancers to cisplatin. PMID- 28356997 TI - Variations in the structure of airborne bacterial communities in Tsogt-Ovoo of Gobi desert area during dust events. AB - Asian dust events transport the airborne bacteria in Chinese desert regions as well as mineral particles and influence downwind area varying biological ecosystems and climate changes. However, the airborne bacterial dynamics were rarely investigated in the Gobi desert area, where dust events are highly frequent. In this study, air samplings were sequentially performed at a 2-m high above the ground at the sampling site located in desert area (Tsogt-Ovoo of Gobi desert; Mongolia 44.2304 degrees N, 105.1700 degrees E). During the dust event days, the bacterial cells and mineral particles increased to more than tenfold of concentrations. MiSeq sequencing targeting 16S ribosomal DNA revealed that the airborne bacteria in desert area mainly belonged to the classes Acidobacteria, Actinobacteria, Bacteroidetes, Chloroflexi, Bacilli, Alpha-proteobacteria, Beta proteobacteria, and Gamma-proteobacteria. The bacterial community structures were different between dust events and non-dust events. The air samples collected at the dust events indicated high abundance rates of Alpha-proteobacteria, which were reported to dominate on the leaf surfaces of plants or in the saline lake environments. After the dust events, the members of Firmicutes (Bacilli) and Bacteroidetes, which are known to form endospore and attach with coarse particles, respectively, increased their relative abundances in the air samples. Presumably, the bacterial compositions and diversities in atmosphere significantly vary during dust events, which carry some particles from grassland (phyllo-sphere), dry lake, and sand surfaces, as well as some bacterial populations such as Firmicutes and Bacteroidetes maintain in the atmosphere for longer time. PMID- 28356996 TI - Methods for 20S Immunoproteasome and 20S Constitutive Proteasome Determination Based on SPRI Biosensors. AB - The 20S proteasome, released into the circulation, is a novel cancer biomarker. It exists in two forms: the constitutive proteasome (20Sc) and the immunoproteasome (20Si), which both have separate diagnostic significance. The aim of this work was to develop new methods for 20Si and 20Sc determination. Five alternative specific biosensors usable with the surface plasmon resonance imaging (SPRI) technique for 20Si determination have been developed. Specific 20Si entrapment on the biosensor surface from an analyzed solution was achieved by means of an immobilized specific 20Si receptor. Four of the biosensors contain newly synthesized specific 20Si receptors, while the fifth contains the inhibitor ONX 0914. A method for 20Sc determination using an SPRI biosensor containing PSI inhibitor has been developed. By the introduction of an inhibitor blocking 20Si, 20Sc is selectively determined. All of the methods developed for 20Si and 20Sc determination exhibit good selectivity and satisfactory precision, recoveries and dynamic response ranges. 20Si and 20Sc were determined in blood plasma samples from healthy donors and patients with acute leukemia. In the case of these patients 20Si was the major component, and its level was more than one order of magnitude higher than in the healthy donors. PMID- 28356998 TI - Polycyclic aromatic hydrocarbons bound to outdoor and indoor airborne particles (PM2.5) and their mutagenicity and carcinogenicity in Silesian kindergartens, Poland. AB - Assessment of exposure to polycyclic aromatic hydrocarbons (PAHs) is important due to the widespread presence of PAHs in the environment and their toxicological relevance, especially to susceptible populations such as children and their health. The aim of this study is to compare indoor and outdoor concentrations of particulate matter with a diameter of 2.5 MUm or less (PM2.5) and 15 individual PAHs, as well as contribution of the analyzed PAHs to mutagenic and carcinogenic activity. Samples were collected during spring season in two sites in southern Poland (Silesia) representing urban and rural areas. Indoor samples of PM2.5 were sampled in kindergartens. At the same time, in the vicinity of the kindergarten buildings, the collection of the outdoor PM2.5 samples was carried out. Mutagenic (MEQ) and carcinogenic (TEQ) equivalents related to BaP and the percentage share expressed as mutagenic (MP) and carcinogenic (CP) potential of each individual compound to the total mutagenic/carcinogenic potential of the PAH mixture were calculated. The obtained results show that high concentrations of PM2.5 (above 25 MUg/m3) and 15 PM2.5-bound PAHs in outdoor and indoor air were similar in the two studied areas. In overall PAHs mutagenic and carcinogenic potential, the percentage share of benzo(a)pyrene (BaP) was dominant and varied from 49.0-54.5% to 62.5-70.0%, respectively. The carried out study indicates the necessity of reducing PAH emission from solid fuel combustion, which is reflected in PM2.5 bound PAHs concentrations and their diagnostic ratios. In the recent years, health effects on children resulting from their activity pattern and air quality in the public places have been a serious problem. PMID- 28356999 TI - Ozone Treatment on Dentin Hypersensitivity Surfaces - A Pilot Study. AB - BACKGROUND: Dentin hypersensitivity (DH) is a frequent condition in adults and difficult to treat. The aim of this single-blind, randomised controlled clinical trial was to investigate immediate and long-term effect of ozone treatment (Prozone, W&H NORDIC AB) for 12 seconds on hypersensitive teeth compared to placebo treatment, using a split-mouth design. METHODS: 26 patients (12 M, 14 F, mean age 44+ 2) were included in the study having at least two teeth with confirmed DH in different quadrants of the dentition (each subject had one test and one control tooth). A visual analogue scale (VAS) was used to measure the patients' pain perception immediately and at a long-term follow-up three months later. RESULTS: Significant reduction in pain perception from DH surfaces was demonstrated from ozone treated test teeth as well as in placebo treated control teeth. We found a moderate (16.2%) but significant pain relief (p< 0.012) over time in 57.7% of all treated teeth. CONCLUSION: Results from this study confirm previously published results showing no significant effect of ozone treatment on hypersensitive teeth compared to placebo treatment. PMID- 28357001 TI - Laser Assisted Non-surgical Periodontal Therapy: A Double Blind, Randomized Clinical Trial. AB - The objective of this study was to examine potential benefits of using laser therapy for secular decontamination in conjunction with scaling and root planing in the treatment of chronic periodontitis. The study was performed on 173 teeth in 14 patients in a split-mouth design, one side received scaling and root planing followed by laser therapy using a carbon dioxide (CO2) laser with an ablative handpiece (test group); the contralateral side received scaling and root planing without laser (control group). Clinical and laboratory parameters were evaluated prior to treatment and at 3 and 6 months following therapy; clinical measurements were performed by two blinded examiners. The clinical parameters included measurement of gingival recession (REC), bleeding on probing (BOP), clinical attachment level (CAL), pocket depth (PD), furcation involvement (FUR), and tooth mobility (MOB). Laboratory testing to determine the levels of periodontal pathogens was performed using PCR techniques. The results of the study revealed statistically significant differences in clinical and laboratory parameters at 3 and 6 months after therapy for both test and control groups, but no significant difference was observed between the two groups. However, sites receiving laser therapy tended to show a greater decrease in probing depths, gain in clinical attachment level, and reduced bacterial levels. In conclusion, the overall results of the study suggest a potential benefit of using laser therapy in conjunction with scaling and root planing for the treatment of chronic periodontitis. PMID- 28357000 TI - Root Canal Transportation and Centering Ability of Nickel-Titanium Rotary Instruments in Mandibular Premolars Assessed Using Cone-Beam Computed Tomography. AB - INTRODUCTION: The aim of this study was to evaluate, using cone-beam computed tomography (CBCT), transportation and centralization of different nickel-titanium (NiTi) rotary instruments. METHODS: One hundred and twenty eight mandibular premolars were selected and instrumented using the following brands of NiTi files: WaveOne, WaveOne Gold, Reciproc, ProTaper Next, ProTaper Gold, Mtwo, BioRaCe and RaCe. CBCT imaging was performed before and after root canal preparation to obtain measurements of mesial and distal dentin walls and calculations of root canal transportation and centralization. A normal distribution of data was confirmed by the Kolmogorov-Smirnov and Levene tests, and results were assessed using the Kruskal-Wallis test. Statistical significance was set at 5%. RESULTS: ProTaper Gold produced the lowest canal transportation values, and RaCe, the highest. ProTaper Gold files also showed the highest values for centering ability, whereas BioRaCe showed the lowest. No significant differences were found across the different instruments in terms of canal transportation and centering ability (P > 0.05). CONCLUSION: Based on the methodology employed, all instruments used for root canal preparation of mandibular premolars performed similarly with regard to canal transportation and centering ability. PMID- 28357003 TI - Alveolar Ridge Preservation After Tooth Extraction with DFDBA and Platelet Concentrates: A Radiographic Retrospective Study. AB - OBJECTIVES: The purpose of this study was to evaluate vertical alveolar bone loss 3 months after tooth extraction when a technique of ridge preservation was applied using a particulate demineralized freeze-dried bone allograft 300 - 500 um associated with platelet concentrates (platelet-rich-fibrin) in the form of gel and membranes. MATERIAL AND METHODS: A retrospective radiological clinical study was conducted on 56 patients for whom 95 extractions had been performed immediately followed by alveolar filling. Among the patients, 17 were smokers and 16 were provided with an immediate removable temporary prosthesis after extractions. Vertical bone loss was measured radiologically by panoramic X-ray before extractions and by a computed tomography scan 3 months after, at the level of mid-buccal bone wall, by two independent observers. For statistical analysis, Student's t-test was performed to compare the mean bone loss between mono- and pluri-radicular teeth and to compare the mean bone loss between tobacco users versus non users and finally to compare the mean bone loss between individuals that had provisional removable prosthesis and those that had not. RESULTS: Three months after tooth extraction, the mean of vertical loss of the mid-buccal bone wall was 0.72 (SD 0.71) mm (5.53% SD 5.19). No significant difference between bone loss at mono-radicular and pluri-radicular teeth (P = 0.982) was observed. There was no significant correlation between tobacco habits and bone loss (P = 0.2), nor between provisional removable prosthesis and bone loss (P = 0.786). CONCLUSION: These results indicate a good potential for the technique using Demineralized Freeze-Dried Bone Allograft 300 - 500 um and platelet concentrates in alveolar bone preservation. PMID- 28357002 TI - Evidence of Signs and Symptoms of Craniomandibular Disorders in Fibromyalgia Patients. AB - OBJECTIVE: The purpose of this study is to highlight the evidence of signs and symptoms of craniomandibular disorders (CMD) in patients suffering from fibromyalgia. MATERIALS AND METHOD: The study has been carried out from May 2011 to May 2015, recruiting a sample of fibromyalgia patients at the Department of Neurophysiopathology at the hospital Policlinico in Bari. Among the 150 examined patients, 60 of them have been diagnosed to suffer from fibromyalgia and 27 accepted to be investigated with a gnathologic examination at the Dental School at the University of Bari. RESULTS: 24 patients (88.9%) were women and 3 (11.1%) men; from 26 to 66 years old (average age, 39). 14 patients (51.9%) were affected by primary fibromyalgia, the remaining 13 (48.1%) by secondary fibromyalgia, mainly associated with hypothyroidism (29.6%). VAS average score was about 8 +/- 1.85. The frequency of pain was daily in 15 patients (55.6%); twice a week in 10 patients (37.03%) and a few times a month in 2 patients (7.4%). 11 patients (40.7%) attributed the onset of fibromyalgia to a specific instigating event. In addition, from the gnathologic anamnesis, 11 patients (40,7%) reported a painful symptom in the head-neck region, especially in the frontal region, in the neck, in the masseter muscle and ATM. VAS average score was 3.4 +/- 2.8, significantly lower than the one referring to the fibromyalgia pain. The gnathological examination found CMD signs and symptoms in 18 patients (66.7%). Concerning the prevalence of CMD, in type I fibromyalgia, myofascial pain was more frequent (5 patients), whereas in type II fibromyalgia, what was more frequent was a dislocation with reduction (3 patients). CONCLUSION: Based on clinic experience, we can affirm that some patients with CMD report pain in other regions. It is difficult to distinguish the CMD forms directly correlated to fibromyalgia from those engendered by parafunctional activities; hence the need is to resolve the fibromyalgia syndrome adopting a multidisciplinary approach. PMID- 28357004 TI - Perceptions of Teaching Methods for Preclinical Oral Surgery: A Comparison with Learning Styles. AB - PURPOSE: Dental extraction is a routine part of clinical dental practice. For this reason, understanding the way how students' extraction knowledge and skills development are important. PROBLEM STATEMENT AND OBJECTIVES: To date, there is no accredited statement about the most effective method for the teaching of exodontia to dental students. Students have different abilities and preferences regarding how they learn and process information. This is defined as learning style. In this study, the effectiveness of active learning in the teaching of preclinical oral surgery was examined. The personality type of the groups involved in this study was determined, and the possible effect of personality type on learning style was investigated. METHOD: This study was undertaken over five years from 2011 to 2015. The sample consisted of 115 students and eight staff members. Questionnaires were submitted by 68 students and all eight staff members involved. Three measures were used in the study: The Index of Learning Styles (Felder and Soloman, 1991), the Myers-Briggs Type Indicator (MBTI), and the styles of learning typology (Grasha and Hruska-Riechmann). RESULTS AND DISCUSSION: Findings indicated that demonstration and minimal clinical exposure give students personal validation. Frequent feedback on their work is strongly indicated to build the cognitive, psychomotor, and interpersonal skills needed from preclinical oral surgery courses. CONCLUSION: Small group cooperative active learning in the form of demonstration and minimal clinical exposure that gives frequent feedback and students' personal validation on their work is strongly indicated to build the skills needed for preclinical oral surgery courses. PMID- 28357005 TI - Peripheral Solitary Osteoma of the Zygomatic Arch: A Case Report and Literature Review. AB - Osteoma is a benign slow-growing osteogenic neoplasm commonly occurring in the craniofacial skeleton, characterized by the proliferation of compact and/or cancellous bone. Osteomas may be peripheral, central, or extraskeletal. Peripheral osteomas arise from the periosteum and are quite uncommon in the jaw bones. The exact aetiology and pathogenesis of peripheral osteoma are unknown. Clinically, peripheral osteomas are usually asymptomatic, but depending on the location and size of the lesion, it may cause swelling, pain, esthetic disfigurement and functional impairment. On radiological imaging, a peripheral osteoma appears often as well-circumscribed, round to oval, pedunculated radiopaque mass attached to the cortex by a broad base or a pedicle. Asymptomatic osteomas are treated conservatively, while surgical excision is indicated when the lesion is symptomatic, actively growing, or for cosmetic reasons. Histologically, osteomas are composed of a normal-appearing, dense mass of lamellar bone. Recurrence of peripheral osteoma after surgical removal is extremely rare and there are no reports of malignant transformation. A review of the literature disclosed only 7 well-documented cases of peripheral osteoma located at the zygomatic bone. The purpose of this article is to present the clinical, radiographic, surgical and histological features of a solitary peripheral osteoma of the left zygomatic arch in a 55-year-old woman and to review the literature about this uncommon pathologic entity. PMID- 28357006 TI - Comparison of Three types of Tooth Brushes on Plaque and Gingival Indices: A Randomized Clinical Trial. AB - OBJECTIVE: To compare clinical results of three types of manual tooth brushes on plaque removal efficacy and gingivitis. METHOD: This study is a single blind randomized trial with crossover design which involved 30 periodontaly healthy individuals. Professional plaque removal and oral hygiene instruction were performed for all the participants in the first step of our study followed by asking them to avoid brushing for 2 days. Thereafter plaque and gingivitis scores were measured using plaque and gingival indices (PI and GI). Then subjects were instructed to use Pulsar tooth brush for a two-week period and then, GI and PI indices were assessed again. After passing one-week period for wash out, subjects didn't brush for 2 days and indices were recorded again. The same procedure was done for CrossAction, and Butler 411 tooth brushes respectively and at the end of the study these variables were analyzed using SPSS software ver.16. Repeated measurement ANOVA test was used to compare the scores between different brushes. RESULT: Finding of this study reveals that using all three types of tooth brushes resulted in significant plaque and gingivitis reduction compared to baseline levels. Pulsar tooth brush was significantly more effective in diminishing PI and GI than Butler tooth brush (p=0.044 and 0.031 respectively). CONCLUSION: According to our findings all 3 types of tooth brushes are effective in reduction of plaque and gingivitis and this reduction is significantly greater for Pulsar tooth brush compared to Butler and CrossAction tooth brushes. PMID- 28357007 TI - Maze Procedures for Atrial Fibrillation, From History to Practice. AB - Atrial fibrillation may result in significant symptoms, (systemic) thrombo embolism, as well as tachycardia-induced cardiomyopathy with cardiac failure, and consequently be associated with significant morbidity and mortality. Nowadays symptomatic atrial fibrillation can be treated with catheter-based ablation, surgical ablation or hybrid approaches. In this setting a fairly large number of surgical approaches and procedures are described and being practised. It should be clear that the Cox-maze procedure resulted from building up evidence and experience in different steps, while some of the present surgical approaches and techniques are being based only on technical feasibility with limited experience, rather than on a process of consequent methodology. Some of the issues still under debate are whether or not the maze procedure can be limited to the left atrium or even to isolation of the pulmonary veins or that bi-atrial procedures are indicated, whether or not cardiopulmonary bypass is to be applied and which route of exposure facilitates an optimal result. In addition, maze procedures are not procedures guide by electrophysiological mapping. At least in theory not in all patients all lesions of the maze procedures are necessary. A history and aspects of current practise in surgical treatment of atrial fibrillation is presented. PMID- 28357008 TI - Rotational Atherectomy and Stent Implantation for Calcified Left Main Lesions. AB - BACKGROUND: Left main coronary artery (LMCA) bifurcation and heavily calcified lesions are common and challenging to treat percutaneously. Rotational atherectomy (RA) may be beneficial in this setting to facilitate stent placement though direct supporting evidence is lacking. This study sought to analyze patients who underwent RA of the LMCA. METHODS: Consecutive cases involving RA of the LMCA between 1/1/2004 and 12/31/2009 at a private, tertiary referral hospital were reviewed retrospectively. Medical records, angiograms and clinically driven follow-up were reviewed. RESULTS: Thirty-one cases were identified (20 protected, 11 unprotected), including 23 with stent implantation (21 drug-eluting, 2 bare metal). All 31 lesions had moderate to severe calcification, 84% involved the distal segment. Mean burr-to-vessel ratio was 0.43. Overall angiographic success was 90% (28/31) and was higher with a drug-eluting stent versus no stent (100% vs. 62%; P = 0.0153). In-hospital major adverse cardiovascular events (MACE) occurred in 1 patient (3%). Mid-term MACE occurred in 6 patients (26%) and tended to occur less frequently in patients with protected LMCAs (P = 0.0697). At final follow-up, patients were more likely to be alive and free from angina with a protected LMCA (94% vs. 57% unprotected; P = 0.0564) and with a drug-eluting stent (89% vs. 50% with no stent; P = 0.0281). CONCLUSIONS: RA of the LMCA to facilitate stent implantation appears to be safe and effective with favorable mid term outcomes. In the setting of severe calcification and distal LMCA involvement RA and drug-eluting stent implantation should be considered. PMID- 28357010 TI - Do We Need Premedication Before Coronary Angiography? A Controlled Clinical Trial. AB - BACKGROUND: Premedication with benzodiazepines has been thought to reduce patient anxiety, pain perception, and non-catheter-induced coronary spasms and may increase procedure-related complications. We used to routinely provide premedication with diazepam and chlorpheniramine before cardiac catheterization procedures. However the benefits of such a treatment are not well established here. Therefore, we designed this study to test whether the routine use of premedication during coronary angiography is needed. METHODS: A total of 200 consecutive patients scheduled to undergo either diagnostic or therapeutic coronary angiographic procedures were randomized to receive either premedication with diazepam (5 mg) and chlorpheniramine (4 mg) 60 minutes prior to their procedures (n = 100) or no premedication (n = 100). The administration of intravenous midazolam during the procedures was permitted at the operator's discretion. The primary endpoints were anxiety and pain perception during the procedure. RESULTS: A total of 200 patients with similar baseline characteristics were randomized into two groups. The first group received oral premedication with diazepam (5 mg) and chlorphenamine (4 mg) 60 minutes prior to their procedures, and the other group did not receive premedication. We observed no differences in periprocedural pain perception (31% in the premedicated group versus 29% in the non-premedicated group; P = 0.75) or anxiety (59% in the premedicated group versus 50% in the non-premedicated group; P = 0.2). Interestingly, local pain was more pronounced in the premedicated patients than in the non-premedicated patients (30% versus 16%, respectively; P = 0.018). There were no contrast related reactions reported in either group. CONCLUSION: Treatment with oral diazepam and chlorphenamine prior to cardiac catheterization and percutaneous coronary intervention does not alter rates of anxiety, periprocedural pain. PMID- 28357011 TI - Short-Term Left Ventricular Remodeling After Revascularization in Subacute Total and Subtotal Occlusion With the Infarct-Related Left Anterior Descending Artery. AB - BACKGROUND: Large randomized studies revealed that percutaneous coronary intervention has no clinical benefit in patients with total occlusion. The purpose of this study is to evaluate left ventricular remodelling after PCI for total and subtotal infarct-related left anterior desending artery in stable patients who have not received trombolytic theraphy. METHODS: Sixty stable patients with subacute anterior myocardial infarction who have total or subtotal occlusion in the infarct-related left anterior descending artery were enrolled the study (20 patient in the total-medical group, 20 patient in the total-PCI group and 20 patient in the subtotal-PCI group). All patients' left ventricular diameters, volumes and ejection fractions measured at admission and after a month. RESULTS: The necrotic segment number in scintigraphy were similar in three groups. In the total-PCI group, there were significant increases in left ventricular diastolic diameter, left ventricular end-diastolic volume and left ventricular end-systolic volume at first month. A borderline significant increase was observed in LVEDV in the total-medical group at first month. No significant difference was seen in all echocardiographic parameters in the subtotal-PCI group at a month after discharge. The percentage of increase in LVEDV was significantly higher and the percentage of increase in LVESV was borderline significantly higher in the total-PCI group than the other groups. CONCLUSIONS: In stable patients, PCI for total occlusion in the subacute phase of anterior MI causes an increase in LV remodeling. Nevertheless PCI for subtotal occlusion in the subacute phase of anterior MI may prevent LV remodeling. PMID- 28357009 TI - Peripheral Augmentation Index is Associated With the Ambulatory Arterial Stiffness Index in Patients With Hypertension. AB - BACKGROUND: Vascular dysfunction is highly prevalent if not ubiquitous in patients with hypertension. We compared two different measures of vascular function obtained from digital volume waveforms with measures of ventricular vascular load derived from 24-hour blood pressure (BP) recordings in patients with hypertension. METHODS: Digital pulsatile volume waveforms were captured via plethysmography (peripheral arterial tone, PAT) and used to derive augmentation index (a measure of ventricular-vascular coupling) and the pulse wave amplitude reactive hyperemia index (a measure of microvascular reactivity). Ambulatory arterial stiffness index (AASI) and the BP variability ratio (BPVR) were derived from 24-hour ambulatory BP recordings. RESULTS: There was a positive association between PAT-AIx and AASI (r = 0.52, P < 0.05). There was also a positive association between PAT-AIx and BPVR (r = 0.37, P < 0.05). PAT-AIx was not associated with PWA-RHI (r = -0.14, P > 0.05). PWA-RHI was not associated with AASI or BPVR (P > 0.05). CONCLUSIONS: PAT-AIx is associated with ambulatory measures of vascular function and may offer clinical insight into vascular burden and cardiovascular disease risk in patients with hypertension independent of information obtained from PWA-RHI. PMID- 28357013 TI - Late Atrio-ventricular Block After Arterial Switch for D-transposition of the Great Vessels With Intact Interventricular Septum. AB - Arterial switch operation for transposition of the great arteries without ventricular septal defect usually does not lead to atrio-ventricular conduction disturbances. We discuss the case of a young boy presenting with first and second degree supra hisian atrio-ventricular block late after switch operation. PMID- 28357012 TI - Bovine Intestinal Alkaline Phosphatase Reduces Inflammation After Induction of Acute Myocardial Infarction in Mice. AB - BACKGROUND: There has been increasing evidence suggesting that lipopolysaccharide or endotoxin may be an important activator of the innate immune system after acute myocardial infarction. Bovine intestinal alkaline phosphatase reduces inflammation in several endotoxin mediated diseases by dephosphorylation of the lipid A moiety of lipopolysaccharide. The aim of this study was to investigate the effect of bovine intestinal alkaline phosphatase on reducing inflammation after acute myocardial infarction. METHODS: Just before permanent ligation of the left anterior descending coronary (LAD) artery to induce acute myocardial infarction in Balb/c mice, bovine intestinal alkaline phosphatase (bIAP) was administrated intravenously. After 4 hours, mice were sacrificed and the inflammatory response was assessed. Acute myocardial infarction induced the production of different cytokines, which were measured in blood. RESULTS: Treatment with bovine intestinal alkaline phosphatase resulted in a significant reduction of the pro-inflammatory cytokines IL-6, IL-1beta and the chymase mouse mast cell protease-1. No difference in the production of the anti-inflammatory cytokine IL-10 was observed between the control group and the bovine intestinal alkaline phosphatase treated group. CONCLUSION: In a mouse model of permanent LAD coronary artery ligation, bIAP diminishes the pro-inflammatory responses but does not have an effect on the anti-inflammatory response in the acute phase after acute myocardial infarction. PMID- 28357014 TI - Giant Left Atrial Myxoma Causing Mitral Valve Obstruction and Concomitant Coronary Artery Disease. AB - We describe a 56-year old male patient who presented with congestive heart failure and had undergone echocardiography that showed a mobile, giant left atrial mass which caused obstruction in the left ventricular outflow tract. The patient underwent a coronary angiography before operation that showed severe stenosis in the left anterior descending and circumflex artery. The patient underwent resection of the mass and coronary artery bypass grafting. The pathology of the mass was myxoma and patient had a satisfactory outcome. PMID- 28357015 TI - Persistent Left Superior Vena Cava Draining into the Coronary Sinus: A Case Report. AB - Persistent left superior vena cava (PLSVC) is a congenital anomaly of the thoracic venous system resulting from the abnormal persistence of an embryological vessel that normally regresses during early fetal life. This anomaly is often discovered incidentally during surgery, cardiovascular imaging or invasive cardiovascular procedures. In most cases, a PLSVC drains into the right atrium through the coronary sinus. In the remainder of cases, it enters directly or through the pulmonary veins into the left atrium. A dilated coronary sinus on echocardiography should always raise the suspicion of a PLSVC as it has important clinical implications. The diagnosis should be confirmed by saline contrast echocardiography. We report a patient with persistent left superior vena cava with an enlarged coronary sinus and normal right superior vena cava. PMID- 28357016 TI - Isolated Pericardial Hydatid Cyst: A Case Report. AB - Cardiac echinococcosis is extremely rare, and cysts are found mostly within the myocardium. Most cardiac hydatid cysts are located in the left ventricular wall. Only a few cases of isolated pericardial hydatid cysts have been reported. Echocardiography, computed tomography and magnetic resonance imaging are important diagnostic tools for the diagnosis of echinococcosis. Herein, we report a rare case of isolated pericardial hydatid cyst who presented to our emergency department with complaints of mid-sternal chest pain and shortness of breath. PMID- 28357017 TI - Temporary Transvenous Cardiac Pacing in Patients With Acute Myocardial Infarction Predicts Increased Mortality. AB - BACKGROUND: Temporary pacemakers (TP) are used in emergency situations for severe bradyarrhythmias secondary to acute myocardial infarction (AMI) and to non-AMI related cardiac disorders. TP have been studied previously in AMI patients treated with thrombolytic therapy; limited information is available on current outcomes in AMI patients treated with percutaneous coronary intervention. METHODS: We reviewed the indications, complications, and mortality associated with TP insertion over a four year period (2003 - 2007) at a university hospital. RESULTS: Seventy-three temporary pacemakers were inserted (47 men, 26 women) during this period. The mean age was 65.2 years. TP were used in 29 AMI patients (39.7 % of total) and 44 non-AMI patients (60.3% of total). The duration of TP use was 2.6 +/- 0.4 days in the whole cohort, 2.46 % of all AMI patients (29/1180) admitted during this period required a TP. Six of these patients requiring a TP required a permanent pacemaker. Eight patients with AMI and a TP died (27.6%). In contrast 8.9 % of AMI patients not requiring a TP died (P < 0.01). There were no statistically significant differences between the AMI and non-AMI groups in the duration of temporary pacing (2.4 +/- 0.6 days vs. 2.8 +/- 0.4 days), in complications (27.6% vs. 29.5%), or in mortality (27.6% vs. 15.9%). The need for a permanent pacemaker (PPM) differed significantly between the AMI and non-AMI patients (20.7% vs. 54.5%; P < 0.05). CONCLUSION: Our results indicate that AMI patients infrequently require a TP and that approximately 20% of these patients require a PPM. These results suggest that early revascularization of the conduction system with current interventional techniques has decreased the need for TP in AMI patients. However, this group requires more intensive monitoring as the mortality rate in this group of patients is significantly higher than the other AMI patients not requiring TP. PMID- 28357018 TI - New Guidelines for the Management of Chest Pain: Lessons From a Recent Audit in Tauranga, New Zealand. AB - BACKGROUND: Protocol based care is known to improve the outcomes of patients admitted with recent onset chest pain. The aim of this clinical review was to investigate chest pain management, using newly published guidance from NICE, in the emergency department of a regional hospital in New Zealand. METHODS: All admissions with chest pain during the period of September-October 2010 were identified retrospectively (n = 599), and a sufficiently powered random sample (n = 120) taken. Relevant data was identified from patient notes, including basic demographics and specific management details. RESULTS: One hundred and eighteen patients were analysed (M = 65, F = 53), 99.2% received an ECG on admission, yet only 59.3% of patients had documented evidence of a repeat ECG, with admissions during the day less likely to receive one compared to those admitted overnight (51.5% vs 69.2%, P = 0.04). Younger patients (< 39 years) appeared less likely to receive aspirin than older patients (38.9% vs 80.0%, P = 0.06), 21.3% of patients failed to receive 300 mg aspirin, and 45.6% of patients received oxygen despite normal saturations. CONCLUSIONS: Despite good performance in a number of areas, this clinical review has highlighted that some standards, such as repeat ECGs, administration of aspirin therapy and appropriate use of oxygen are not being met in all patients with chest pain. A chest pain management pathway is to be implemented for all relevant admissions, to ensure that essential aspects of care are not missed. Timely dissemination and implementation of new clinical guidelines remains a challenge in clinical practice. PMID- 28357019 TI - Effectiveness of Telemetry Guidelines in Predicting Clinically Significant Arrhythmias in Hospitalized Patients. AB - BACKGROUND: Cardiac rhythm monitoring is widely applied on hospitalized patients. However, its value has not been evaluated systematically. METHODS: This study considered the utility of our institutional telemetry guidelines in predicting clinically significant arrhythmias. A retrospective analysis was performed of 562 patients admitted to the telemetry unit. A total of 1932 monitoring days were evaluated. Patients were divided into 2 groups based on telemetry guidelines: "telemetry indicated" and "telemetry not indicated". RESULTS: Differences in arrhythmia event rates and pre-defined clinical significance were determined. One hundred and forty-four (34%) vs. 16 (11%) patients had at least one arrhythmic event in the "telemetry indicated" group compared with the "telemetry not indicated" group, respectively (P = 0.001). No patient in the "telemetry not indicated" group had a clinically significant arrhythmia. In contrast, of patients in the "telemetry indicated" group who had at least one arrhythmic event, 36% were considered clinically significant (P < 0.05). CONCLUSION: In conclusion, this study validates and supports the use of our institutional telemetry guidelines to allocate this resource appropriately and predict clinically significant arrhythmias. PMID- 28357020 TI - Long Term Outcomes in Stress Echocardiography: Ten Year Follow up of a Cohort in a Single Centre. AB - BACKGROUD: The high service burden for acute admissions and referrals via rapid access chest pain clinics for evaluation of possible coronary artery disease means that many patients are now undergoing an investigation such as stress echocardiography as part of their evaluation. We aimed to see if the reassurance provided by negative stress echocardiography correlates with long-term event free survival. METHODS: A cohort of all patients who were referred at a single centre for stress echocardiography for diagnosis of coronary artery disease between January 1st 1999 and December 31st 2000 were followed up at least 10 years following theirs stress echocardiogram for further major cardiovascular events and mortality. RESULTS: A total of 64 patients were identified where records could be obtained for analysis. There were 16 positive scans, 37 negative scans and 11 inconclusive scans. The indeterminacy rate of scans was 17%, the sensitivity rate for detecting significant disease as indexed to invasive angiography was 88 % and the specificity rate compared with angiography was 75%. There were no myocardial infarctions or new diagnoses of heart failure in the negative echocardiogram group. There were seven deaths in the total population and only one death from cardiovascular causes in the negative echocardiogram group. CONCLUSION: Stress echocardiography even in this small group predicts long term outcomes as well as invasive coronary angiography. PMID- 28357021 TI - Choice and Utility of Pacing Maneuver in Establishing the Mechanism of Supraventricular Tachycardia: A Single Center Experience. AB - BACKGROUND: To evaluate the choice and utility of pacing maneuvers in the electrophysiology (EP) laboratory in establishing supraventricular tachycardia (SVT) mechanism. METHODS: We retrospectively examined a cohort of 160 consecutive patients with SVT presenting for invasive EP evaluation to a single center with 8 electrophysiologists. We analyzed the utility of the two most commonly used pacing maneuvers: (1) ventricular entrainment (VE) and (2) His-refractory premature ventricular stimuli (HRPVC) during SVT. RESULTS: VE was performed in 96 patients: atrial tachycardia (AT) 12, atrioventricular nodal reentrant tachycardia (AVNRT) 66, and orthodromic reciprocating tachycardia (ORT) 18. During VE, AT patients were most likely to have ventriculo-atrial (VA) dissociation (AT 58%, AVNRT 18%, ORT 0%, P < 0.001) and had a tendency towards less SVT termination (AT 0%, AVNRT 9%, ORT 11%, P = 0.19). HRPVCs were delivered in 39 patients: AT 1, AVNRT 24, and ORT 14. Advancement of atrial signal with HRPVC was only observed in ORT (AT 0%, AVNRT 0%, ORT 79%, P < 0.001) and SVT termination was also mostly observed in ORT (AT 0%, AVNRT 4%, ORT 21%, P = 0.33). The overall diagnostic utility of VE was lowest in AT (AT 42%, AVNRT 71%, ORT 83%, P = 0.04), while HRPVC was rarely used in AT. Furthermore, the utilization of maneuvers varied extensively (0% to100%) among the 8 electrophysiologists. CONCLUSION: There is great variation in the utilization of pacing maneuvers and their utility in ascertaining the mechanism of SVT. Our results support the fact that discerning AT from AVNRT mechanism remains the most challenging task in SVT diagnosis. PMID- 28357022 TI - Failure to Treat Torsades de Pointes. AB - A healthy 22 year old male with no history of cardiac disease was admitted with severe community acquired pneumonia that was initially treated with moxifloxacin and azithromycin. At admission, he was found to be hypokalemic and hypomagnesemic. Two days after admission, he experienced several episodes of Torsades de Pointes (TdP). He was initially treated with isoproterenol. A temporary transvenous pacemaker was inserted and set at a rate of 100 bpm. After correction of electrolytes, withdrawal of QT-prolonging medications and ventricular pacing at the mentioned heart rate, another episode of TdP ensued.We report and discuss a case of recurrent TdP in spite of conventional acute management for this condition. PMID- 28357023 TI - Acute Stroke and Limb Ischemia Secondary to Catastrophic Massive Intracardiac Thrombus in a 40-Year-Old Patient With Dilated Cardiomyopathy. AB - Dilated cardiomyopathy has been associated with left ventricular (LV) thrombosis which leads to substantial morbidity and mortality as a site for systemic emboli. We report an interesting case of a stroke and acute limb ischemia secondary to a large mobile pedunculated LV thrombus in 40-year-old patient with dilated cardiomyopathy. PMID- 28357025 TI - A Rare Case of Non-Obstructive Membrane of the Body of Left Atrial Appendage Incidentally Found in Asymptomatic Adult Woman. AB - The membranes of the left atrial appendage cavity are very rare entity and their clinical significance is not clear. We reported a rare case of a non-obstructive membrane traversing the body of the left atrial appendage incidentally found in asymptomatic adult woman. PMID- 28357024 TI - Atrial Myxoma: A Case Presentation and Review. AB - Myxomas are the most common primary cardiac tumors, most frequently found in the left atrium. We present a case of an atrial myxoma. An in-depth review of atrial myxoma is presented, examining the important clinical symptoms and diagnostic indicators. The treatment of atrial myxoma is then discussed, with an emphasis on current therapies. An extensive literature review has been performed to present a comprehensive review of the causes, pathophysiology of atrial myxoma. PMID- 28357028 TI - Limitations and opportunities of non-invasive liver stiffness measurement in children. AB - Changes in liver structure are an important issue in chronic hepatopathies. Until the end of the 20th century, these changes could only be determined by histological analyses of a liver specimen obtained via biopsy. The well-known limitations of this technique (i.e., pain, bleeding and the need for sedation) have precluded its routine use in follow-up of patients with liver diseases. However, the introduction of non-invasive technologies, such as ultrasound and magnetic resonance imaging, for measurement of liver stiffness as an indirect marker of fibroses has changed this situation. Today, several non-invasive tools are available to physicians to estimate the degree of liver fibrosis by analysing liver stiffness. This review describes the currently available tools for liver stiffness determination that are applicable to follow-up of liver fibrosis/cirrhosis with established clinical use in children, and discusses their features in comparison to the "historical" tools. PMID- 28357027 TI - Exercise Modifies the Gut Microbiota with Positive Health Effects. AB - The human gastrointestinal tract (GIT) is inhabited by a wide cluster of microorganisms that play protective, structural, and metabolic functions for the intestinal mucosa. Gut microbiota is involved in the barrier functions and in the maintenance of its homeostasis. It provides nutrients, participates in the signaling network, regulates the epithelial development, and affects the immune system. Considering the microbiota ability to respond to homeostatic and physiological changes, some researchers proposed that it can be seen as an endocrine organ. Evidence suggests that different factors can determine changes in the gut microbiota. These changes can be both quantitative and qualitative resulting in variations of the composition and metabolic activity of the gut microbiota which, in turn, can affect health and different disease processes. Recent studies suggest that exercise can enhance the number of beneficial microbial species, enrich the microflora diversity, and improve the development of commensal bacteria. All these effects are beneficial for the host, improving its health status. In this paper, we intend to shed some light over the recent knowledge of the role played by exercise as an environmental factor in determining changes in microbial composition and how these effects could provide benefits to health and disease prevention. PMID- 28357029 TI - Chronic exposure to ethanol causes steatosis and inflammation in zebrafish liver. AB - AIM: To evaluate the effects of chronic exposure to ethanol in the liver and the expression of inflammatory genes in zebrafish. METHODS: Zebrafish (n = 104), wild type, adult, male and female, were divided into two groups: Control and ethanol (0.05 v/v). The ethanol was directly added into water; tanks water were changed every two days and the ethanol replaced. The animals were fed twice a day with fish food until satiety. After two and four weeks of trial, livers were dissected, histological analysis (hematoxilin-eosin and Oil Red staining) and gene expression assessment of adiponectin, adiponectin receptor 2 (adipor2), sirtuin-1 (sirt-1), tumor necrosis factor-alpha (tnf-a), interleukin-1b (il-1b) and interleukin-10 (il-10) were performed. Ultrastructural evaluations were conducted at fourth week. RESULTS: Exposing zebrafish to 0.5% ethanol developed intense liver steatosis after four weeks, as demonstrated by oil red staining. In ethanol-treated animals, the main ultrastructural changes were related to cytoplasmic lipid particles and droplets, increased number of rough endoplasmic reticulum cisterns and glycogen particles. Between two and four weeks, hepatic mRNA expression of il-1b, sirt-1 and adipor2 were upregulated, indicating that ethanol triggered signaling molecules which are key elements in both hepatic inflammatory and protective responses. Adiponectin was not detected in the liver of animals exposed and not exposed to ethanol, and il-10 did not show significant difference. CONCLUSION: Data suggest that inflammatory signaling and ultrastructural alterations play a significant role during hepatic steatosis in zebrafish chronically exposed to ethanol. PMID- 28357026 TI - Novel Noninvasive Nuclear Medicine Imaging Techniques for Cardiac Inflammation. AB - PURPOSE OF REVIEW: Inflammation is a key player in a wide range of cardiovascular and myocardial diseases. Given the numerous implications of inflammatory processes in disease initiation and progression, functional imaging modalities including positron emission tomography (PET) represent valuable diagnostic, prognostic, and monitoring tools in patient management. Since increased glucose metabolism is a hallmark of inflammation, PET using the radiolabeled glucose analog [18F]-2-deoxy-2-fluoro-d-glucose (FDG) is the mainstay diagnostic test for nuclear imaging of (cardiac) inflammation. Recently, new approaches using more specific tracers to overcome the limited specificity of FDG have emerged. RECENT FINDINGS: PET imaging has proven its value in a number of inflammatory conditions of the heart including myocarditis, endocarditis, sarcoidosis, or reactive changes after myocardial infarction. In infection-related endocarditis, FDG-PET and white blood cell scintigraphy have been implemented in current guidelines. FDG-PET is considered as nuclear medical gold standard in myocarditis, pericarditis, or sarcoidosis. Novel strategies, including targeting of somatostatin receptors or C-X-C motif chemokine receptor CXCR4, have shown promising results in first studies. SUMMARY: Nuclear medicine techniques offer valuable information in the assessment of myocardial inflammation. Given the possibility to directly visualize inflammatory activity, they represent useful tools for diagnosis, risk stratification, and therapy monitoring. PMID- 28357031 TI - Concordance of non-invasive mechanical and serum tests for liver fibrosis evaluation in chronic hepatitis C. AB - AIM: To determine the sensitivity and specificity of liver stiffness measurement (LSM) and serum markers (SM) for liver fibrosis evaluation in chronic hepatitis C. METHODS: Between 2012 and 2014, 81 consecutive hepatitis C virus (HCV) patients had METAVIR score from liver biopsy compared with concurrent results from LSM [transient elastography (TE) [FibroScan(r)/ARFI technology (Virtual Touch(r))] and SM [FIB-4/aspartate aminotransferase-to-platelet ratio index (APRI)]. The diagnostic performance of these tests was assessed using receiver operating characteristic curves. The optimal cut-off levels of each test were chosen to define fibrosis stages F >= 2, F >= 3 and F = 4. The Kappa index set the concordance analysis. RESULTS: Fifty point six percent were female and the median age was 51 years (30-78). Fifty-six patients (70%) were treatment-naive. The optimal cut-off values for predicting F >= 2 stage fibrosis assessed by TE were 6.6 kPa, for acoustic radiation force impulse (ARFI) 1.22 m/s, for APRI 0.75 and for FIB-4 1.47. For F >= 3 TE was 8.9 kPa, ARFI was 1.48 m/s, APRI was 0.75, and FIB-4 was 2. For F = 4, TE was 12.2 kPa, ARFI was 1.77 m/s, APRI was 1.46, and FIB-4 was 3.91. The APRI could not distinguish between F2 and F3, P = 0.92. The negative predictive value for F = 4 for TE and ARFI was 100%. Kappa index values for F >= 3 METAVIR score for TE, ARFI and FIB-4 were 0.687, 0.606 and 0.654, respectively. This demonstrates strong concordance between all three screening methods, and moderate to strong concordance between them and APRI (Kappa index = 0.507). CONCLUSION: Given the costs and accessibility of LSM methods, and the similarity with the outcomes of SM, we suggest that FIB-4 as well as TE and ARFI may be useful indicators of the degree of liver fibrosis. This is of particular importance to developing countries. PMID- 28357030 TI - Factors associated with long-term survival after liver transplantation: A retrospective cohort study. AB - AIM: To identify predictive factors associated with long-term patient and graft survival (> 15 years) in liver transplant recipients. METHODS: Medical charts of all de novo adult liver transplant recipients (n = 140) who were transplanted in Hamburg between 1997 and 1999 were retrospectively reviewed. In total, 155 transplantations were identified in this time period (15 re-transplantations). Twenty-six orthotopic liver transplant (OLT) recipients were early lost to follow up due to moving to other places within 1 year after transplantation. All remaining 114 patients were included in the analysis. The following recipient factors were analysed: Age, sex, underlying liver disease, pre-OLT body mass index (BMI), and levels of alanine aminotransferase (ALT), bilirubin, creatinine and gamma-glutamyltransferase (gamma-GT), as well as warm and cold ischemia times. Furthermore, the following donor factors were assessed: Age, BMI, cold ischemia time and warm ischemia time. All surviving patients were followed until December 2014. We divided patients into groups according to their underlying diagnosis: (1) hepatocellular carcinoma (n = 5, 4%); (2) alcohol toxic liver disease (n = 25, 22.0%); (3) primary sclerosing cholangitis (n = 6, 5%); (4) autoimmune liver diseases (n = 7, 6%); (5) hepatitis C virus cirrhosis (n = 15, 13%); (6) hepatitis B virus cirrhosis (n = 21, 19%); and (7) other (n = 35, 31%). The group "other" included rare diagnoses, such as acute liver failure, unknown liver failure, stenosis and thrombosis of the arteria hepatica, polycystic liver disease, Morbus Osler and Caroli disease. RESULTS: The majority of patients were male (n = 70, 61%). Age and BMI at the time point of transplantation ranged from 16 years to 69 years (median: 53 years) and from 15 kg/m2 to 33 kg/m2 (median: 24), respectively. Sixty-six OLT recipients (58%) experienced a follow-up of 15 years after transplantation. Recipient's age (P = 0.009) and BMI (P = 0.029) were identified as risk factors for death by chi2-test. Kaplan-Meier analysis confirmed BMI or age above the median as predictors of decreased long-term survival (P = 0.008 and P = 0.020). Hepatitis B as underlying disease showed a trend for improved long-term survival (P = 0.049, chi2-test, P = 0.055; Kaplan Meier analysis, Log rank). Pre-transplant bilirubin, creatinine, ALT and gamma-GT levels were not associated with survival in these patients of the pre-era of the model of end stage liver disease. CONCLUSION: The recipients' age and BMI were predictors of long-term survival after OLT, as well as hepatitis B as underlying disease. In contrast, donors' age and BMI were not associated with decreased survival. These findings indicate that recipient factors especially have a high impact on long-term outcome after liver transplantation. PMID- 28357032 TI - Meta-analysis reveals up-regulation of cholesterol processes in non-alcoholic and down-regulation in alcoholic fatty liver disease. AB - AIM: To compare transcriptomes of non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) in a meta-analysis of liver biopsies. METHODS: Employing transcriptome data from patient liver biopsies retrieved from several public repositories we performed a meta-analysis comparing ALD and NAFLD. RESULTS: We observed predominating commonalities at the transcriptome level between ALD and NAFLD, most prominently numerous down-regulated metabolic pathways and cytochrome-related pathways and a few up-regulated pathways which include ECM-receptor interaction, phagosome and lysosome. However some pathways were regulated in opposite directions in ALD and NAFLD, for example, glycolysis was down-regulated in ALD and up-regulated in NAFLD. Interestingly, we found rate limiting genes such as HMGCR, SQLE and CYP7A1 which are associated with cholesterol processes adversely regulated between ALD (down-regulated) and NAFLD (up-regulated). We propose that similar phenotypes in both diseases may be due to a lower level of the enzyme CYP7A1 compared to the cholesterol synthesis enzymes HMGCR and SQLE. Additionally, we provide a compendium of comparative KEGG pathways regulation in ALD and NAFLD. CONCLUSION: Our finding of adversely regulated cholesterol processes in ALD and NAFLD draws the focus to regulation of cholesterol secretion into bile. Thus, it will be interesting to further investigate CYP7A1-mediated cholesterol secretion into bile - also as possible drug targets. The list of potential novel biomarkers may assist differential diagnosis of ALD and NAFLD. PMID- 28357034 TI - An adaptable toolkit to assess commercial fishery costs and benefits related to marine protected area network design. AB - Around the world, governments are establishing Marine Protected Area (MPA) networks to meet their commitments to the United Nations Convention on Biological Diversity. MPAs are often used in an effort to conserve biodiversity and manage fisheries stocks. However, their efficacy and effect on fisheries yields remain unclear. We conducted a case-study on the economic impact of different MPA network design strategies on the Atlantic cod ( Gadus morhua) fisheries in Canada. The open-source R toolbox that we developed to analyze this case study can be customized to conduct similar analyses for other systems. We used a spatially-explicit individual-based model of population growth and dispersal coupled with a fisheries management and harvesting component. We found that MPA networks that both protect the target species' habitat (particularly the spawning grounds), and were spatially optimized to improve population connectivity had the highest net present value (i.e., were most profitable for the fishing industry). These higher profits were achieved primarily by reducing the distance travelled for fishing and reducing the probability of a moratorium event. These findings add to a growing body of knowledge demonstrating the importance of incorporating population connectivity in the MPA planning process, as well as the ability of this R toolbox to explore ecological and economic consequences of alternative MPA network designs. PMID- 28357033 TI - A double blinded, placebo-controlled pilot study to examine reduction of CD34 +/CD117 +/CD133 + lymphoma progenitor cells and duration of remission induced by neoadjuvant valspodar in dogs with large B-cell lymphoma. AB - We previously described a population of lymphoid progenitor cells (LPCs) in canine B-cell lymphoma defined by retention of the early progenitor markers CD34 and CD117 and "slow proliferation" molecular signatures that persist in the xenotransplantation setting. We examined whether valspodar, a selective inhibitor of the ATP binding cassette B1 transporter (ABCB1, a.k.a., p glycoprotein/multidrug resistance protein-1) used in the neoadjuvant setting would sensitize LPCs to doxorubicin and extend the length of remission in dogs with therapy naive large B-cell lymphoma. Twenty dogs were enrolled into a double blinded, placebo controlled study where experimental and control groups received oral valspodar (7.5 mg/kg) or placebo, respectively, twice daily for five days followed by five treatments with doxorubicin 21 days apart with a reduction in the first dose to mitigate the potential side effects of ABCB1 inhibition. Lymph node and blood LPCs were quantified at diagnosis, on the fourth day of neoadjuvant period, and 1-week after the first chemotherapy dose. Valspodar therapy was well tolerated. There were no differences between groups in total LPCs in lymph nodes or peripheral blood, nor in event-free survival or overall survival. Overall, we conclude that valspodar can be administered safely in the neoadjuvant setting for canine B-cell lymphoma; however, its use to attenuate ABCB1 + cells does not alter the composition of lymph node or blood LPCs, and it does not appear to be sufficient to prolong doxorubicin-dependent remissions in this setting. PMID- 28357035 TI - dbVar structural variant cluster set for data analysis and variant comparison. AB - dbVar houses over 3 million submitted structural variants (SSV) from 120 human studies including copy number variations (CNV), insertions, deletions, inversions, translocations, and complex chromosomal rearrangements. Users can submit multiple SSVs to dbVAR that are presumably identical, but were ascertained by different platforms and samples, to calculate whether the variant is rare or common in the population and allow for cross validation. However, because SSV genomic location reporting can vary - including fuzzy locations where the start and/or end points are not precisely known - analysis, comparison, annotation, and reporting of SSVs across studies can be difficult. This project was initiated by the Structural Variant Comparison Group for the purpose of generating a non-redundant set of genomic regions defined by counts of concordance for all human SSVs placed on RefSeq assembly GRCh38 (RefSeq accession GCF_000001405.26). We intend that the availability of these regions, called structural variant clusters (SVCs), will facilitate the analysis, annotation, and exchange of SV data and allow for simplified display in genomic sequence viewers for improved variant interpretation. Sets of SVCs were generated by variant type for each of the 120 studies as well as for a combined set across all studies. Starting from 3.64 million SSVs, 2.5 million and 3.4 million non-redundant SVCs with count >=1 were generated by variant type for each study and across all studies, respectively. In addition, we have developed utilities for annotating, searching, and filtering SVC data in GVF format for computing summary statistics, exporting data for genomic viewers, and annotating the SVC using external data sources. PMID- 28357036 TI - Finger stick blood collection for gene expression profiling and storage of tempus blood RNA tubes. AB - With this report we aim to make available a standard operating procedure (SOP) developed for RNA stabilization of small blood volumes collected via a finger stick. The anticipation that this procedure may be improved through peer-review and/or readers public comments is another element motivating the publication of this SOP. Procuring blood samples from human subjects can, among other uses, enable assessment of the immune status of an individual subject via the profiling of RNA abundance using technologies such as real time PCR, NanoString, microarrays or RNA-sequencing. It is often desirable to minimize blood volumes and employ methods that are the least invasive and can be practically implemented outside of clinical settings. Finger-stick blood samples are increasingly used for measurement of levels of pharmacological drugs and biological analytes. It is a simple and convenient procedure amenable for instance to field use or self collection at home using a blood sample collection kit. Such methodologies should also enable the procurement of blood samples at high frequency for health or disease monitoring applications. PMID- 28357037 TI - Electronic medical records in humanitarian emergencies - the development of an Ebola clinical information and patient management system. AB - By November 2015, the West Africa Ebola epidemic had caused 28598 infections and 11299 deaths in the three countries most affected. The outbreak required rapid innovation and adaptation. Medecins sans Frontieres (MSF) scaled up its usual 20 30 bed Ebola management centres (EMCs) to 100-300 beds with over 300 workers in some settings. This brought challenges in patient and clinical data management resulting from the difficulties of working safely with high numbers of Ebola patients. We describe a project MSF established with software developers and the Google Social Impact Team to develop context-adapted tools to address the challenges of recording Ebola clinical information. We share the outcomes and key lessons learned in innovating rapidly under pressure in difficult environmental conditions. Information on adoption, maintenance, and data quality was gathered through review of project documentation, discussions with field staff and key project stakeholders, and analysis of tablet data. In March 2015, a full prototype was deployed in Magburaka EMC, Sierra Leone. Inpatient data were captured on 204 clinical interactions with 34 patients from 5 March until 10 April 2015. 85 record "pairs" for 32 patients with 26 data items (temperature and symptoms) per pair were analysed. The average agreement between sources was 85%, ranging from 69% to 95% for individual variables. The time taken to deliver the product was more than that anticipated by MSF (7 months versus 6 weeks). Deployment of the tablet coincided with a dramatic drop in patient numbers and thus had little impact on patient care. We have identified lessons specific to humanitarian-technology collaborative projects and propose a framework for emergency humanitarian innovation. Time and effort is required to bridge differences in organisational culture between the technology and humanitarian worlds. This investment is essential for establishing a shared vision on deliverables, urgency, and ownership of product. PMID- 28357039 TI - Predictors and brain connectivity changes associated with arm motor function improvement from intensive robotic practice in chronic stroke. AB - Background and Purpose: The brain changes that underlie therapy-induced improvement in motor function after stroke remain obscure. This study sought to demonstrate the feasibility and utility of measuring motor system physiology in a clinical trial of intensive upper extremity rehabilitation in chronic stroke related hemiparesis. Methods: This was a substudy of two multi-center clinical trials of intensive robotic arm therapy in chronic, significantly hemiparetic, stroke patients. Transcranial magnetic stimulation was used to measure motor cortical output to the biceps and extensor digitorum communus muscles. Magnetic resonance imaging (MRI) was used to determine the cortical anatomy, as well as to measure fractional anisotropy, and blood oxygenation (BOLD) during an eyes-closed rest state. Region-of-interest time-series correlation analysis was performed on the BOLD signal to determine interregional connectivity. Functional status was measured with the upper extremity Fugl-Meyer and Wolf Motor Function Test. Results: Motor evoked potential (MEP) presence was associated with better functional outcomes, but the effect was not significant when considering baseline impairment. Affected side internal capsule fractional anisotropy was associated with better function at baseline. Affected side primary motor cortex (M1) activity became more correlated with other frontal motor regions after treatment. Resting state connectivity between affected hemisphere M1 and dorsal premotor area (PMAd) predicted recovery. Conclusions: Presence of motor evoked potentials in the affected motor cortex and its functional connectivity with PMAd may be useful in predicting recovery. Functional connectivity in the motor network shows a trends towards increasing after intensive robotic or non-robotic arm therapy. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifiers: CT00372411 & NCT00333983. PMID- 28357040 TI - Simple and adaptable R implementation of WHO/ISH cardiovascular risk charts for all epidemiological subregions of the world. AB - The World Health Organisation and International Society of Hypertension (WHO/ISH) cardiovascular disease (CVD) risk assessment charts have been implemented in many low- and middle-income countries as part of the WHO Package of Essential Non Communicable Disease (PEN) Interventions for Primary Health Care in Low-Resource settings. Evaluation of the WHO/ISH cardiovascular risk charts and their use is a key priority and since they only exist in paper or PDF formats, we developed a simple R implementation of the charts for all epidemiological subregions of the world. The main strengths of this implementation are that it is built in a free, open-source, coding language with simple syntax, can be modified by the user, and can be used with a standard computer. PMID- 28357041 TI - Improving data transparency in clinical trials using blockchain smart contracts. AB - The scientific credibility of findings from clinical trials can be undermined by a range of problems including missing data, endpoint switching, data dredging, and selective publication. Together, these issues have contributed to systematically distorted perceptions regarding the benefits and risks of treatments. While these issues have been well documented and widely discussed within the profession, legislative intervention has seen limited success. Recently, a method was described for using a blockchain to prove the existence of documents describing pre-specified endpoints in clinical trials. Here, we extend the idea by using smart contracts - code, and data, that resides at a specific address in a blockchain, and whose execution is cryptographically validated by the network - to demonstrate how trust in clinical trials can be enforced and data manipulation eliminated. We show that blockchain smart contracts provide a novel technological solution to the data manipulation problem, by acting as trusted administrators and providing an immutable record of trial history. PMID- 28357038 TI - Neurosteroids are reduced in diabetic neuropathy and may be associated with the development of neuropathic pain. AB - INTRODUCTION: Peripheral and central sensitisation are implicated in the development of neuropathic pain. Hypersensitivity of pain pathway neurons has been described in animal models of diabetic neuropathy, which is postulated to be related to an imbalance between inhibitory and excitatory signals within the spinal cord. GABAergic neurons within the pain pathway are vital for the transmission of painful stimuli to higher centres. A developmental change in the rate of exponential decay of GABAergic synaptic events has been observed in other types of neurons and this may be associated with fluctuations in endogenous neurosteroid tone. Methods: The whole-cell patch-clamp technique was used on slices of neural tissue. Electrophysiological recordings were obtained from wild type mice between the ages of 6 and 80 days in the spinal cord, the nucleus reticularis of the thalamus and the cerebral cortex. Recordings were also obtained from mice with diabetic neuropathy (ob/ob and db/db) between the ages of 60 and 80 days. Behavioural experiments were performed to examine mechanical and thermal nociception. RESULTS: Electrophysiological recordings from cortical pain pathway neurons from mature type-2 diabetic mice revealed that the endogenous neurosteroid tone is reduced compared to control. However, selected neurosteroid compounds had a more pronounced effect on the GABA A receptors of these diabetic mice. ob/ob mice exhibit mechanical hyperalgesia and allodynia, which was reduced by neurosteroids applied exogenously. CONCLUSIONS: The reduced endogenous neurosteroid tone in ob/ob mice may be linked to their hypersensitivity. Neurosteroids may exert analgesic effects in pathological pain states by attempting to restore the physiological GABAergic inhibitory tone. PMID- 28357042 TI - Low-cost, rapidly-developed, 3D printed in vitro corpus callosum model for mucopolysaccharidosis type I. AB - The rising prevalence of high throughput screening and the general inability of (1) two dimensional (2D) cell culture and (2) in vitro release studies to predict in vivo neurobiological and pharmacokinetic responses in humans has led to greater interest in more realistic three dimensional (3D) benchtop platforms. Advantages of 3D human cell culture over its 2D analogue, or even animal models, include taking the effects of microgeometry and long-range topological features into consideration. In the era of personalized medicine, it has become increasingly valuable to screen candidate molecules and synergistic therapeutics at a patient-specific level, in particular for diseases that manifest in highly variable ways. The lack of established standards and the relatively arbitrary choice of probing conditions has limited in vitro drug release to a largely qualitative assessment as opposed to a predictive, quantitative measure of pharmacokinetics and pharmacodynamics in tissue. Here we report the methods used in the rapid, low-cost development of a 3D model of a mucopolysaccharidosis type I patient's corpus callosum, which may be used for cell culture and drug release. The CAD model is developed from in vivo brain MRI tracing of the corpus callosum using open-source software, printed with poly (lactic-acid) on a Makerbot Replicator 5X, UV-sterilized, and coated with poly (lysine) for cellular adhesion. Adaptations of material and 3D printer for expanded applications are also discussed. PMID- 28357045 TI - Growth performance and feed utilization of keureling fish Tor tambra (Cyprinidae) fed formulated diet supplemented with enhanced probiotic. AB - Background The objective of the present study was to determine the optimum dosage of probiotic in the diet of keureling fish ( Tor tambra) fry. MethodsLactobacillus casei from Yakult(r) was used as a starter, and enhanced with Curcuma xanthorrhiza, Kaempferia galanga and molasses. The mixture was fermented for 7 days prior to use as probiotic in a formulated diet containing 30% crude protein. Four levels of probiotic dosage; 0 ml kg -1 (control), 5 ml kg -1, 10 ml kg -1 and 15 ml kg -1 were tested in this study. The fish was fed twice a day at 08.00 AM and 06.00 PM at the ration of 5% body weight for 80 days. Results The results showed that growth performance and feed efficiency increased with increasing probiotic dosage in the diet from control (no probiotic) to 10 ml kg -1 of probiotic dosage and then decreased when the dosage was increased up to 15 ml kg -1. Conclusions The best values for all measured parameters were recorded at the dosage of 10 ml kg -1. Therefore, it was concluded that the optimum dosage of enhanced probiotic for T. tambra fry was 10 ml kg -1 of feed. PMID- 28357046 TI - Surgical education and adult learning: Integrating theory into practice. AB - Surgical education continues to evolve from the master-apprentice model. Newer methods of the process need to be used to manage the dual challenges of educating while providing safe surgical care. This requires integrating adult learning concepts into delivery of practical training and education in busy clinical environments. A narrative review aimed at outlining and integrating adult learning and surgical education theory was undertaken. Additionally, this information was used to relate the practical delivery of surgical training and education in day-to-day surgical practice. Concepts were sourced from reference material. Additional material was found using a PubMed search of the words: 'surgical education theory' and 'adult learning theory medical'. This yielded 1351 abstracts, of which 43 articles with a focus on key concepts in adult education theory were used. Key papers were used to formulate structure and additional cross-referenced papers were included where appropriate. Current concepts within adult learning have a lot to offer when considering how to better deliver surgical education and training. Better integration of adult learning theory can be fruitful. Individual teaching surgical units need to rethink their paradigms and consider how each individual can contribute to the education experience. Up skilling courses for trainers can do much to improve the delivery of surgical education. Understanding adult learning concepts and integrating these into day-to-day teaching can be valuable. PMID- 28357044 TI - Characterization of BRCA1/2 mutations in patients with family history of breast cancer in Armenia. AB - Background. Breast cancer is one of the most common cancers in women worldwide. The germline mutations of the BRCA1 and BRCA2 genes are the most significant and well characterized genetic risk factors for hereditary breast cancer. Intensive research in the last decades has demonstrated that the incidence of mutations varies widely among different populations. In this study we attempted to perform a pilot study for identification and characterization of mutations in BRCA1 and BRCA2 genes among Armenian patients with family history of breast cancer and their healthy relatives. Methods. We performed targeted exome sequencing for BRCA1 and BRCA2 genes in 6 patients and their healthy relatives. After alignment of short reads to the reference genome, germline single nucleotide variation and indel discovery was performed using GATK software. Functional implications of identified variants were assessed using ENSEMBL Variant Effect Predictor tool. Results. In total, 39 single nucleotide variations and 4 indels were identified, from which 15 SNPs and 3 indels were novel. No known pathogenic mutations were identified, but 2 SNPs causing missense amino acid mutations had significantly increased frequencies in the study group compared to the 1000 Genome populations. Conclusions. Our results demonstrate the importance of screening of BRCA1 and BRCA2 gene variants in the Armenian population in order to identity specifics of mutation spectrum and frequencies and enable accurate risk assessment of hereditary breast cancers. PMID- 28357047 TI - The challenges with the validation of research antibodies. AB - This article further discusses the reproducibility crisis in biomedical science and how poor conduct of commercial antibodies contribute to this. In addition, the way quality data are presented on product sheets by antibody vendors is scrutinized. The article proposes that there is a distinction between testing data and validation data, and special attention is asked for consistency between batches and aliquots. Moreover, the article separates the specifics, such as formulation, antigen and price, from the specifics on performance. Finally, a two tier approach is discussed, enabling scientists to anticipate how an antibody is likely to perform when repeated purchases are required. PMID- 28357043 TI - Recent advances in understanding and preventing human papillomavirus-related disease. AB - High-risk human papillomaviruses (hrHPV) are responsible for anogenital and oropharyngeal cancers, which together account for at least 5% of cancers worldwide. Industrialised nations have benefitted from highly effective screening for the prevention of cervical cancer in recent decades, yet this vital intervention remains inaccessible to millions of women in low- and middle-income countries (LMICs), who bear the greatest burden of HPV disease. While there is an urgent need to increase investment in basic health infrastructure and rollout of prophylactic vaccination, there are now unprecedented opportunities to exploit recent scientific and technological advances in screening and treatment of pre invasive hrHPV lesions and to adapt them for delivery at scale in resource limited settings. In addition, non-surgical approaches to the treatment of cervical intraepithelial neoplasia and other hrHPV lesions are showing encouraging results in clinical trials of therapeutic vaccines and antiviral agents. Finally, the use of next-generation sequencing to characterise the vaginal microbial environment is beginning to shed light on host factors that may influence the natural history of HPV infections. In this article, we focus on recent advances in these areas and discuss their potential for impact on HPV disease. PMID- 28357048 TI - Bibliometric analysis of Oropouche research: impact on the surveillance of emerging arboviruses in Latin America. AB - Given the emergence and reemergence of viral diseases, particularly in Latin America, we would like to provide an analysis of the patterns of research and publication on Oropouche virus (OROV). We also discuss the implications of recent epidemics in certain areas of South America, and how more clinical and epidemiological information regarding OROV is urgently needed. PMID- 28357050 TI - Heat remains unaccounted for in thermal physiology and climate change research. AB - In the aftermath of the Paris Agreement, there is a crucial need for scientists in both thermal physiology and climate change research to develop the integrated approaches necessary to evaluate the health, economic, technological, social, and cultural impacts of 1.5 degrees C warming. Our aim was to explore the fidelity of remote temperature measurements for quantitatively identifying the continuous redistribution of heat within both the Earth and the human body. Not accounting for the regional distribution of warming and heat storage patterns can undermine the results of thermal physiology and climate change research. These concepts are discussed herein using two parallel examples: the so-called slowdown of the Earth's surface temperature warming in the period 1998-2013; and the controversial results in thermal physiology, arising from relying heavily on core temperature measurements. In total, the concept of heat is of major importance for the integrity of systems, such as the Earth and human body. At present, our understanding about the interplay of key factors modulating the heat distribution on the surface of the Earth and in the human body remains incomplete. Identifying and accounting for the interconnections among these factors will be instrumental in improving the accuracy of both climate models and health guidelines. PMID- 28357051 TI - The cyanobacterial nitrogen fixation paradox in natural waters. AB - Nitrogen fixation, the enzymatic conversion of atmospheric N (N 2) to ammonia (NH 3), is a microbially mediated process by which "new" N is supplied to N-deficient water bodies. Certain bloom-forming cyanobacterial species are capable of conducting N 2 fixation; hence, they are able to circumvent N limitation in these waters. However, this anaerobic process is highly sensitive to oxygen, and since cyanobacteria produce oxygen in photosynthesis, they are faced with a paradoxical situation, where one critically important (for supporting growth) biochemical process is inhibited by another. N 2-fixing cyanobacterial taxa have developed an array of biochemical, morphological, and ecological adaptations to minimize the "oxygen problem"; however, none of these allows N 2 fixation to function at a high enough efficiency so that it can supply N needs at the ecosystem scale, where N losses via denitrification, burial, and advection often exceed the inputs of "new" N by N 2 fixation. As a result, most marine and freshwater ecosystems exhibit chronic N limitation of primary production. Under conditions of perpetual N limitation, external inputs of N from human sources (agricultural, urban, and industrial) play a central role in determining ecosystem fertility and, in the case of N overenrichment, excessive primary production or eutrophication. This points to the importance of controlling external N inputs (in addition to traditional phosphorus controls) as a means of ensuring acceptable water quality and safe water supplies. Nitrogen fixation, the enzymatic conversion of atmospheric N 2 to ammonia (NH 3) is a microbially-mediated process by which "new" nitrogen is supplied to N-deficient water bodies. Certain bloom-forming cyanobacterial species are capable of conducting N 2 fixation; hence they are able to circumvent nitrogen limitation in these waters. However, this anaerobic process is highly sensitive to oxygen, and since cyanobacteria produce oxygen in photosynthesis, they are faced with a paradoxical situation, where one critically important (for supporting growth) biochemical process is inhibited by another. Diazotrophic cyanobacterial taxa have developed an array of biochemical, morphological and ecological adaptations to minimize the "oxygen problem"; however, none of these allows N 2 fixation to function at a high enough efficiency so that it can supply N needs at the ecosystem scale, where N losses via denitrification, burial and advection often exceed the inputs of "new" N by N 2 fixation. As a result, most marine and freshwater ecosystems exhibit chronic N limitation of primary production. Under conditions of perpetual N limitation, external inputs of N from human sources (agricultural, urban, industrial) play a central role in determining ecosystem fertility and in the case of N overenrichment, excessive primary production, or eutrophication. This points to the importance of controlling external N inputs (in addition to traditional phosphorus controls) as a means of ensuring acceptable water quality and safe water supplies. PMID- 28357049 TI - Neuronal substrates for initiation, maintenance, and structural organization of sleep/wake states. AB - Animals continuously alternate between sleep and wake states throughout their life. The daily organization of sleep and wakefulness is orchestrated by circadian, homeostatic, and motivational processes. Over the last decades, much progress has been made toward determining the neuronal populations involved in sleep/wake regulation. Here, we will discuss how the application of advanced in vivo tools for cell type-specific manipulations now permits the functional interrogation of different features of sleep/wake state regulation: initiation, maintenance, and structural organization. We will specifically focus on recent studies examining the roles of wake-promoting neuronal populations. PMID- 28357053 TI - C3 glomerulopathy. AB - C3 glomerulopathy is a recently defined entity that encompasses a group of kidney diseases caused by abnormal control of complement activation with deposition of complement component C3 in glomeruli leading to variable glomerular inflammation. Before the recognition of the unique pathogenesis of these cases, they were variably classified according to their morphological features. C3 glomerulopathy accounts for roughly 1% of all renal biopsies. Clear definition of this entity has allowed a better understanding of its pathogenesis and clinical course and is likely to lead to the design of rational therapies over the next few years. PMID- 28357052 TI - Recent advances in understanding and managing gout. AB - Gout is the most common crystal arthropathy and the leading cause of inflammatory arthritis. It is associated with functional impairment and, for many, a diminished health-related quality of life. Numerous studies have demonstrated the impact of gout and its associated conditions on patient morbidity and mortality. Unfortunately, gout remains under-diagnosed and under-treated in the general community. Despite major advances in treatment strategies, as many as 90% of patients with gout are poorly controlled or improperly managed and their hyperuricemia and recurrent flares continue. The introduction of novel urate lowering therapies, new imaging modalities, and a deeper understanding of the pathogenesis of gout raise the possibility of better gout care and improved patient outcomes. Here, we spotlight recent advances in the diagnosis and management of gout and discuss novel therapeutics in gout treatment. PMID- 28357054 TI - Recent advances in Japanese encephalitis. AB - Japanese encephalitis is a flaviviral disease that is endemic to the South, Southeast Asia, and Asia Oceania regions. Given that about 60% of the world's population (about 7.4 billion) resides in this region (about 4.4 billion), this disease poses a significant threat to global health. Active vaccination campaigns conducted in endemic countries have led to a decrease in the number of reported cases over the years. In this article, we strive to briefly highlight recent advances in understanding the role of microRNAs in disease pathology, focus on providing brief summaries of recent clinical trials in the field of Japanese encephalitis therapeutics, and review the current prophylactic strategies. PMID- 28357056 TI - What serial homologs can tell us about the origin of insect wings. AB - Although the insect wing is a textbook example of morphological novelty, the origin of insect wings remains a mystery and is regarded as a chief conundrum in biology. Centuries of debates have culminated into two prominent hypotheses: the tergal origin hypothesis and the pleural origin hypothesis. However, between these two hypotheses, there is little consensus in regard to the origin tissue of the wing as well as the evolutionary route from the origin tissue to the functional flight device. Recent evolutionary developmental (evo-devo) studies have shed new light on the origin of insect wings. A key concept in these studies is "serial homology". In this review, we discuss how the wing serial homologs identified in recent evo-devo studies have provided a new angle through which this century-old conundrum can be explored. We also review what we have learned so far from wing serial homologs and discuss what we can do to go beyond simply identifying wing serial homologs and delve further into the developmental and genetic mechanisms that have facilitated the evolution of insect wings. PMID- 28357055 TI - Recent advances in treating Parkinson's disease. AB - This article summarizes (1) the recent achievements to further improve symptomatic therapy of motor Parkinson's disease (PD) symptoms, (2) the still-few attempts to systematically search for symptomatic therapy of non-motor symptoms in PD, and (3) the advances in the development and clinical testing of compounds which promise to offer disease modification in already-manifest PD. However, prevention (that is, slowing or stopping PD in a prodromal stage) is still a dream and one reason for this is that we have no consensus on primary endpoints for clinical trials which reflect the progression in prodromal stages of PD, such as in rapid eye movement sleep behavior disorder (RBD) -a methodological challenge to be met in the future. PMID- 28357058 TI - How are base excision DNA repair pathways deployed in vivo? AB - Since the discovery of the base excision repair (BER) system for DNA more than 40 years ago, new branches of the pathway have been revealed at the biochemical level by in vitro studies. Largely for technical reasons, however, the confirmation of these subpathways in vivo has been elusive. We review methods that have been used to explore BER in mammalian cells, indicate where there are important knowledge gaps to fill, and suggest a way to address them. PMID- 28357057 TI - Cell-cell adhesion interface: rise of the lateral membrane. AB - The lateral membrane plays an important role in the mechanical stability of epithelial cell sheet in steady state. In addition, the lateral membrane is continuously remodeled during dynamic processes such as cell extrusion, cytokinesis, and intercellular cell movement. In wound healing, the lateral membrane must be built from flat and spread cells that had crawled into the area of the wound. Thus, forming the lateral membrane is a phenomenon that occurs not only in development but also during homeostatic maintenance and regeneration of differentiated epithelial tissues. PMID- 28357060 TI - Visceral scalloping on abdominal computed tomography due to abdominal tuberculosis. AB - OBJECTIVE: Scalloping of visceral organs is described in pseudomyxoma peritonei, malignant ascites, among other conditions, but not tuberculosis. METHODS: We report findings from a retrospective study of patients with abdominal tuberculosis who had visceral scalloping on abdominal computed tomography (CT). Diagnosis of abdominal tuberculosis was made on the basis of combination of clinical, biochemical, radiological and microbiological criteria. The clinical data, hematological and biochemical parameters, and findings of chest X-ray, CT, Mantoux test, and HIV serology were recorded. RESULTS: Of 72 patients with abdominal tuberculosis whose CT scans were included, seven patients had visceral scalloping. The mean age of these patients was 32.14 +/- 8.43 years and four were men. While six patients had scalloping of liver, one had splenic scalloping. The patients presented with abdominal pain (all), abdominal distension (five patients), loss of weight or appetite (all), and fever (four patients). Mantoux test was positive in five, while none had HIV infection. The diagnosis was based on fluid (ascitic or collections) evaluation in four patients, ileo-cecal biopsy in one patient, fine needle aspiration from omental thickening in one patient, and sputum positivity for acid fast bacilli (AFB) in one patient. On CT examination, four patients had ascites, five had collections, one had lymphadenopathy, four had peritoneal involvement, three had pleural effusion, and two had ileo-cecal thickening. All except one patient received standard ATT for 6 months or 9 months (one patient). Pigtail drainage for collections was needed for two patients. DISCUSSION: This report is the first description of visceral scalloping of liver and spleen in patients with abdominal tuberculosis. Previously, this finding has been reported primarily with pseudomyxoma peritonei and peritoneal carcinomatosis. CONCLUSION: Visceral scalloping may not conclusively distinguish peritoneal tuberculosis from peritoneal carcinomatosis or pseudomyxoma peritonei. PMID- 28357059 TI - Recent advances in managing and understanding uveitis. AB - Uveitis is a sight-threatening disease entity with intraocular inflammation that arises from various causes. It mainly affects working-age individuals and may lead to irreversible visual loss if not treated properly in a timely manner. This article reviews recent advances in the management and understanding of uveitis since 2014, including treatment with new immunosuppressive therapies that use biological agents, local therapy with steroid implants, and imaging studies for the evaluation of uveitis. PMID- 28357061 TI - Oral mucositis caused by Candida glabrata biofilms: failure of the concomitant use of fluconazole and ascorbic acid. AB - OBJECTIVES: Candida glabrata is becoming one of the most prevalent pathogenic yeasts in cases of oral diseases. Mucositis is an recurrent oral infection in immunocompromised patients, and the actual guidelines recommend the use of fluconazole (Flu) for many cases. However, the azole resistance by C. glabrata is renowned, causing a reduced therapeutic response, especially when it occurs in biofilms. In this study, we performed an in vitro evaluation of an alternative pharmacotherapy for C. glabrata biofilm infections, combining ascorbic acid (AA) with Flu. AA is recognized for degrading beta-glucans, an important compound of the biofilm matrices, which prevent drug diffusion. MATERIALS AND METHODS: Routine clinical 30 or 40 mg/l doses of Flu were applied to C. glabrata biofilms simultaneously with 200 or 300 mg/l of AA. RESULTS: The results showed that this combination effectively promoted the degradation of the biofilm network, but unfortunately, also stimulated the growth of the yeasts population due to release of several glucose monomers during beta-glucans hydrolysis. DISCUSSION: AA lead to the hydrolysis of the beta-glucans of the matrix, liberating glucose molecules which are used as carbon souce by the yeasts, thus suppressing the desired antifungal effect of the drug combination with Flu. CONCLUSIONS: Unlike to what happens in treatment of bacterial infection, AA should not be used together with Flu in the treating oral mucositis caused by Candida. PMID- 28357062 TI - Treatment optimization for HIV/HCV co-infected patients. AB - Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections affect millions of persons around the globe and cause profound morbidity and mortality. A major intersection exists between these two epidemics, with HCV infection being more common in persons with HIV than in the general population, largely due to shared routes of transmission. HCV co-infection increases risk for liver- and non liver-related morbidity and mortality, making HCV treatment a priority in HIV co infected persons, but the treatment of HCV in co-infected patients has been daunting for multiple reasons. Until recently, HCV treatment has frequently been deferred due to the low rates of cure, significant adverse effects, burdensome duration of therapy and drug-drug interactions with HIV antiretroviral medications. Untreated HCV has resulted in significant health consequences for the millions of those infected and has led to multiple downstream impacts on our healthcare systems around the world. The development of a remarkable number of new HCV direct-acting agents (DAAs) that are significantly more efficacious and tolerable than the previous interferon-based regimens has transformed this important field of medicine, with the potential to dramatically reduce the burden of infection and improve health outcomes in this population. This review will summarize the epidemiology and clinical impact of HIV/HCV co-infection and current approaches to the treatment of HCV in HIV/HCV co-infected patients. PMID- 28357064 TI - Key proteins involved in insulin vesicle exocytosis and secretion. AB - In vivo insulin secretion is predominantly affected by blood glucose concentration, blood concentration of amino acids, gastrointestinal hormones and free nerve functional status, in addition to other factors. Insulin is one of the most important hormones in the body, and its secretion is precisely controlled by nutrients, neurotransmitters and hormones. The insulin exocytosis process is similar to the neurotransmitter release mechanism. There are various types of proteins and lipids that participate in the insulin secretory vesicle fusion process, such as soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein, Ras-related proteins and vacuolar-type H+-ATPase (V ATPase). Notably, the SNARE protein is the molecular basis of exocytotic activity. In the current review, the role of the vesicle membrane proteins (synaptobrevins, vesicle associated membrane proteins and target membrane proteins) and auxiliary proteins (Rab proteins and Munc-18 proteins) in vesicle fusion activity were summarized. A summary of these key proteins involved in insulin granule secretion will facilitate understanding of the pathogenesis of diabetes. PMID- 28357063 TI - Protein kinase CK2 in development and differentiation. AB - Among the human kinomes, protein kinase CK2 (formerly termed casein kinase II) is considered to be essential, as it is implicated in the regulation of various cellular processes. Experiments with pharmacological inhibitors of the kinase activity of CK2 provide evidence that CK2 is essential for development and differentiation. Therefore, the present review addresses the role of CK2 during embryogenesis, neuronal, adipogenic, osteogenic and myogenic differentiation in established model cell lines, and in embryonic, neural and mesenchymal stem cells. CK2 kinase activity appears to be essential in the early stages of differentiation, as CK2 inhibition at early time points generally prevents differentiation. In addition, the present review reports on target proteins of CK2 in embryogenesis and differentiation. PMID- 28357065 TI - Role of microRNAs in the pathogenesis of diabetic cardiomyopathy. AB - The morbidity of diabetes mellitus has been increasing annually. As a progressive metabolic disorder, chronic complications occur in the late stage of diabetes. In addition, cardiovascular diseases account for the major cause of morbidity and mortality among the diabetic population worldwide. Diabetic cardiomyopathy (DCM) is a type of diabetic heart disease. Patients with DCM show symptoms and signs of heart failure while no specific cause, such as coronary disease, hypertension, alcohol consumption, or other structural heart diseases has been identified. The pathogenesis of DCM is complex and has not been well understood until recently. MicroRNAs (miRs) belong to a novel family of highly conserved, short, non-coding, single-stranded RNA molecules that regulate transcriptional and post transcriptional gene expression. Furthermore, recent studies have demonstrated an association between miRs and DCM. In the current review, the role of miRs in the pathogenesis of DCM is summarized. It was concluded that miRs contribute to the regulation of cardiomyocyte hypertrophy, myocardial fibrosis, cardiomyocyte apoptosis, mitochondrial dysfunction, myocardial electrical remodeling, epigenetic modification and various other pathophysiological processes of DCM. These studies may provide novel insights into targets for prevention and treatment of the disease. PMID- 28357066 TI - Association of two synonymous splicing-associated CpG single nucleotide polymorphisms in calpain 10 and solute carrier family 2 member 2 with type 2 diabetes. AB - Coding synonymous single nucleotide polymorphisms (SNPs) have attracted little attention until recently. However, such SNPs located in epigenetic, CpG sites modifying exonic splicing enhancers (ESEs) can be informative with regards to the recently verified association of intragenic methylation and splicing. The present study describes the association of type 2 diabetes (T2D) with the exonic, synonymous, epigenetic SNPs, rs3749166 in calpain 10 (CAPN10) glucose transporter (GLUT4) translocator and rs5404 in solute carrier family 2, member 2 (SLC2A2), also termed GLUT2, which, according to prior bioinformatic analysis, strongly modify the splicing potential of glucose transport-associated genes. Previous association studies reveal that only rs5404 exhibits a strong negative T2D association, while data on the CAPN10 polymorphism are contradictory. In the present study DNA from blood samples of 99 Greek non-diabetic control subjects and 71 T2D patients was analyzed. In addition, relevant publicly available cases (40) resulting from examination of 110 Personal Genome Project data files were analyzed. The frequency of the rs3749166 A allele, was similar in the patients and non-diabetic control subjects. However, AG heterozygotes were more frequent among patients (73.24% for Greek patients and 54.55% for corresponding non diabetic control subjects; P=0.0262; total cases, 52.99 and 75.00%, respectively; P=0.0039). The rs5404 T allele was only observed in CT heterozygotes (Greek non diabetic control subjects, 39.39% and Greek patients, 22.54%; P=0.0205; total cases, 34.69 and 21.28%, respectively; P=0.0258). Notably, only one genotype, heterozygous AG/CC, was T2D-associated (Greek non-diabetic control subjects, 29.29% and Greek patients, 56.33%; P=0.004; total cases, 32.84 and 56.58%, respectively; P=0.0008). Furthermore, AG/CC was strongly associated with very high (>=8.5%) glycosylated plasma hemoglobin levels among patients (P=0.0002 for all cases). These results reveal the complex heterozygotic SNP association with T2D, and indicate possible synergies of these epigenetic, splicing-regulatory, synonymous SNPs, which modify the splicing potential of two alternative glucose transport-associated genes. PMID- 28357067 TI - Mid-term efficacy and safety of cervical disc arthroplasty versus fusion in cervical spondylosis: A systematic review and meta-analysis. AB - Anterior cervical discectomy and fusion (ACDF) and cervical disc arthroplasty (CDA) are the most commonly used procedures in cervical spondylosis. However, only a few published studies exist in the literature comparing these two operation types, particularly its mid-term efficacy and safety. Furthermore, in those studies, even large sample trials, when compared, have elicited controversial results, making it inconvenient for clinicians to refer to them. The aim of the present study was to clarify the advantages and shortcomings of the two procedures. Articles indexed in the PubMed, Web of Science, Cochrane Library, EMBASE, China Biological Medicine and China National Knowledge Infrastructure (CNKI) databases, as of March 2016, that met our criteria were searched. A total of 18 trials involving 3,040 patients were included in our final analysis. The most important results drawn from the present analysis were as follows: Insignificant differences were identified in the blood loss [weighted mean difference (WMD)=6.23; 95% confidence intervals (CI), -0.85 to 13.32; P=0.08], surgical time [standardized mean difference (SMD)=0.40; 95% CI, -0.01 to 0.82; P=0.06], the time of hospital stay (SMD=0.05; 95% CI, -0.28 to 0.37; P=0.77) and the total complications rate [odds ratio (OR)=0.86; 95% CI, 0.66 to 1.131; P=0.28] on a comparison of the two operation methods. By contrast, comparing CDA with ACDF, the CDA had higher Short Form survey (SF-36) scores (WMD=1.65; 95% CI, 0.61 to 2.69; P=0.002), a larger range of motion in the operation level (SMD=6.53; 95% CI, 3.89 to 9.17; P<0.0001), a higher rate of neurological improvement following the operation (OR=1.80; 95% CI, 1.29 to 2.52; P=0.0006), a lower Visual Analog Scale (VAS) score of neck pain (WMD= 0.16; 95% CI, -0.28 to 0.05; P=0.006) and arm pain (WMD= 0.12; 95% CI, -0.24 to -0.01; P=0.04). In addition, in the mid-term following the surgery, CDA had a lower Neck Disability Index (NDI; SMD=0.18; 95% CI, -0.28 to -0.07; P=0.001) and a lower reoperation rate of adjacent levels (OR=0.54; 95% CI, 0.35 to 0.85; P=0.007) compared with ACDF. Taken together, these results suggested that CDA and ACDF are efficient and safe methods for dealing with cervical spondylosis. However, with respect to certain specific indicators, such as the reoperation rate of adjacent levels following surgery, the former has several advantages. PMID- 28357068 TI - Differential proteomics analysis of liver failure in peripheral blood mononuclear cells using isobaric tags for relative and absolute quantitation. AB - The aim of the present study was to examine differentially expressed proteome profiles for candidate biomarkers in peripheral blood mononuclear cells (PBMCs) of liver failure (LF) patients. Ten patients were diagnosed as LF and 10 age- and gender-matched subjects were recruited as healthy controls. Isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomic technology is efficiently applicable for identification and relative quantitation of the proteomes of PBMCs. Eight-plex iTRAQ coupled with strong cation exchange chromatography, and liquid chromatography coupled with tandem mass spectrometry were used to analyze total proteins in LF patients and healthy control subjects. Molecular variations were detected using the iTRAQ method, and western blotting was used to verify the results. LF is a complex type of medical emergency that evolves following a catastrophic insult to the liver, and its outcome remains the most ominous of all gastroenterologic diseases. Serious complications tend to occur during the course of the disease and further exacerbate the problems. Using the iTRAQ method, differentially expressed proteome profiles of LF patients were determined. In the present study, 627 proteins with different expression levels were identified in LF patients compared with the control subjects; with 409 proteins upregulated and 218 proteins downregulated. Among them, four proteins were significantly differentially expressed; acylaminoacyl-peptide hydrolase and WW domain binding protein 2 were upregulated, and resistin and tubulin beta 2A class IIa were downregulated. These proteins demonstrated differences in their expression levels compared with other proteins with normal expression levels and the significant positive correlation with LF. The western blot results were consistent with the results from iTRAQ. Thus, investigation of the molecular mechanism of the proteins involved in LF may facilitate an improved understanding of the pathogenesis of LF and elucidation of novel biomarker candidates. PMID- 28357069 TI - Efficacy of a potassium-competitive acid blocker for improving symptoms in patients with reflux esophagitis, non-erosive reflux disease, and functional dyspepsia. AB - The aim of the present study was to investigate the efficacy of a potassium competitive acid blocker (PCAB) named vonoprazan (VPZ) for improving symptoms in patients with reflux esophagitis (RE), non-erosive reflux disease (NERD), and functional dyspepsia (FD). A hospital-based, retrospective study of outpatients in our department (Department of Gastroenterology, University of Juntendo, Tokyo, Japan) between March 2015 and August 2016 was performed. The patients who were experiencing heartburn, acid regurgitation, gastric pain, and/or a heavy feeling in the stomach of at least moderate severity at baseline were treated with 20 mg VPZ once daily for 4 weeks. The patients completed the global overall symptom (GOS) scale to determine their symptom severity at baseline and after the 4 week treatment period. The proportions of patients with RE, NERD, and FD achieving improvement of their symptoms, defined as a GOS scale score of 1 ('no problem') or 2 ('minimal problem'), were evaluated. During 4 weeks of VPZ therapy, changes in the gastroesophageal reflux disease (GERD) score, which was defined as the total points for heartburn and acid regurgitation on the GOS scale in patients with RE and NERD, and in the FD score, which was defined as the total points for gastric pain and a heavy feeling in the stomach on the GOS scale in patients with FD, were also evaluated. A total of 88 eligible cases were included in the present study, comprising 20 patients with RE, 25 patients with NERD, and 43 patients with FD. The rates of symptomatic improvement in patients with RE, NERD, and FD were 75.0, 60.0, and 48.8%, respectively. For the patients who were first administered VPZ, the rates of symptomatic improvement were 90.9, 66.7, and 58.8% in patients with RE, NERD, and FD, respectively. For those patients who were resistant to 8 weeks of proton pump inhibitor therapy, the rates of symptomatic improvement were 55.6, 53.8, and 42.3% in patients with RE, NERD, and FD, respectively. The GERD score in patients with RE and NERD, and the FD score in FD patients, were decreased after 4 weeks of VPZ therapy (P<0.01). In patients with RE, NERD and FD, the possibility that PCAB may be used as a novel therapeutic drug was suggested. However, the number of study subjects was small; therefore, further, larger and prospective studies are required. PMID- 28357070 TI - Bioinformatic prediction of the epitopes of Echinococcus granulosus antigen 5. AB - The aim of the present study was to predict and analyze the secondary structure, and B and T cell epitopes of Echinococcus granulosus antigen 5 (Ag5) using online software in order to investigate its immunogenicity and preliminarily evaluate its potential as an effective antigen peptide vaccine for cystic echinococcosis. The PortParam program was used to analyze molecular weight, the theoretical isoelectric point, instability index and other physicochemical properties. The secondary structure of the Ag5 protein was predicted using Self-Optimized Prediction method With Alignment and the tertiary structure of the Ag5 protein was predicted using 3DLigandSite together with Center for Biological Sequence Analysis Prediction Servers. Furthermore, the Immune Epitope Database software was used to predict B cell epitopes, and T cell epitopes were predicted with the BioInformatics and Molecular Analysis Section and SYFPEITHI programs. The results demonstrated that alpha-helixes, beta-turns, random coils and extended strands account for 23.35, 10.95, 41.32, and 24.38% of the secondary structure of the Ag5 protein, respectively. Ten potential B cell epitopes of Ag5 were identified as the amino acids sequences 27-39, 70-80, 117-130, 146-168, 250-262, 284-293, 339 349, 359-371, 403-412 and 454-462, and seven potential T cell epitopes were identified as the amino acid sequences 52-60, 57-65, 182-190, 231-239, 273-281, 318-326 and 467-475. Thus, ten B cell epitopes and seven T cell epitopes were identified on Ag5, suggesting the strong immunogenicity of this protein, which could be applied to design antigen peptide vaccines for echinococcosis. PMID- 28357071 TI - Prostaglandin E2 reduces swine myocardial ischemia reperfusion injury via increased endothelial nitric oxide synthase and vascular endothelial growth factor expression levels. AB - Prostaglandin E2 (PGE2) has been demonstrated to attenuate cardiac ischemia reperfusion (I/R) injury. However, the underlying mechanism of PGE2 in cardiac I/R injury remains unknown. Upregulated expression levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) were reported in acute myocardial infarction (AMI), and were demonstrated to diminish I/R injury. In the current study the involvement of VEGF and eNOS in the myocardial protective effect of PGE2 were investigated in a catheter-based porcine model of AMI. Twenty-two Chinese miniature pigs were randomized into sham-surgery (n=6), control (n=8) and PGE2 (n=8) groups. PGE2 (1 ug/kg) was injected from 10 min prior to left anterior descending occlusion up to 1 h after reperfusion in the PGE2 group. Subsequently, the hemodynamic parameters were evaluated. Thioflavin-S and Evans Blue double staining were performed to evaluate the extent of the myocardial reperfusion area (RA) and no-reflow area (NRA). Immunohistochemical and western blot analysis were used to evaluate protein expression levels of VEGF and eNOS. Left ventricular (LV) systolic pressure significantly improved and LV end-diastolic pressure significantly decreased in the PGE2 group when compared with the control group 2 h after occlusion and 3 h after reperfusion (P<0.05, respectively). The RA and NRA were smaller in the PGE2 group than in the control group (P<0.05, respectively). Furthermore, PGE2 treatment increased the myocardial content of VEGF and eNOS when compared with the control group (P<0.05, respectively). Thus, the results of the present study demonstrate the cardio protective mechanisms of PGE2, which may protect the heart from I/R injury via enhancement of VEGF and eNOS expression levels. PMID- 28357073 TI - Effect of bosentan is correlated with MMP-9/TIMP-1 ratio in bleomycin-induced pulmonary fibrosis. AB - Pulmonary fibrosis (PF) is a life-threatening non-tumorous disease characterized by progressive fibrosis and worsening lung function. Various drugs, such as bleomycin, can contribute to lung injury and PF, with lung injury potentially occurring in 10% of bleomycin users. Bleomycin is the most commonly used drug in the establishment of an animal model of PF in rats. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) serve an important role in controlling tissue organization and fibrosis following injury. The present study examined the effect of bosentan on fibrotic lung tissue in rats administrated with bleomycin. In total, 48 Wistar rats were administrated with bleomycin, with or without bosentan, while the control rats received saline. The lung tissues were microscopically examined by staining with hematoxylin and eosin and Masson's trichome. ELISA was also used to detect the MMP-9 and TIMP-1 concentrations in the plasma. The results indicated that the bosentan-treated groups on the next day and the 15th day showed significant reversal of pathological findings. In addition, the concentrations of MMP-9 and TIMP-1 appeared to be altered following bosentan treatment, improving the bleomycin induced PF. Masson's trichome staining showed high collagen deposition in the lung tissue sections, which may be a direct result of the activity of MMP-9 and TIMP-1. Furthermore, the deposition of collagen was significantly inhibited in bosentan-treated groups. In conclusion, these results demonstrated that bosentan inhibited lung fibrosis induced by bleomycin and it may be used as an inhibitor of PF. PMID- 28357072 TI - Analysis of plasma free amino acid profiles in canine brain tumors. AB - Canine brain tumors are best diagnosed using magnetic resonance imaging (MRI). However, opportunities of MRI examination are restricted due to its limited availability in veterinary facilities; thus, numerous canine brain tumors are diagnosed at an advanced stage. Therefore, development of a noninvasive diagnostic biomarker is required for the early detection of brain tumors. In the present study, plasma free amino acid (PFAA) profiles between dogs with and without brain tumors were compared. A total of 12 dogs with brain tumors, diagnosed based on clinical signs, and on the results of intracranial MRI and/or pathological examination were evaluated. In addition, eight dogs diagnosed with idiopathic epilepsy and 16 healthy dogs were also included. A liquid chromatography system with automated pre-column derivatization functionality was used to measure the levels of 20 amino acids. As a result, the levels of three amino acids (alanine, proline and isoleucine) were increased significantly (1.6-, 1.5- and 1.6-fold, respectively) in the plasma of dogs with brain tumors as compared with the levels in control dogs (all P<0.05). Thus, the PFAA levels of dogs with brain tumors differed from those of healthy dogs. The present study demonstrated that analysis of PFAA levels of dogs with brain tumors may serve as a useful biomarker for the early detection of canine brain tumors. PMID- 28357074 TI - TRAF6 regulates the effects of polarized maturation of tolerability: Marrow derived dendritic cells on collagen-induced arthritis in mice. AB - The study aimed to investigate the relationship between tumor necrosis factor receptor-associated factor 6 (TRAF6) and a differentially mature dendritic cell (mDC) in collagen-induced arthritis (CIA) mice and to determine whether or not TRAF6 regulates the activation of an immature dendritic cell (iDC) and inhibits iDC maturation to induce immune tolerance. The mouse bone marrow stem cells were induced with recombinant granulocyte-macrophage colony-stimulating factor (rmGM CSF) and recombinant interleukin-4 (rmIL-4) to differentiate immature dendritic cells (DCs), which were divided into four groups with different maturation states: rmGM-CSF, rmIL-4; TNF-alpha; LPS; and FK506 group. The levels of the cell surfaces of CD80, CD86, and MHI-II were analyzed by flow cytometry to prove DCs at different levels of maturity. The expression of IL-12 in DCs at different maturation states was detected by enzyme-linked immunosorbent assay (ELISA). The expression of TRAF6 mRNA and protein in each group of DCs was detected by a reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis. The results revealed that the differentiation of bone marrow cells into iDCs was significantly induced by cytokines (rmGM-CSF, IL-4). CD80, CD86, MHC-II were expressed in the four groups, and the difference between them was statistically significant (P<0.05). A higher degree of DC differentiation led to a gradual increase of IL-12 secretion in the four groups. The difference was statistically significant (P<0.05) for this secretion (group D, 10,620.73+/ 276.73 pg/ml). The expression levels of TRAF6 mRNA were significantly higher in group D than those in the other three groups (P<0.01). Although there was no significant difference in the expression levels of TRAF6 mRNA between groups B and C, the expression levels of TRAF6 mRNA between groups B and C were higher than those of the control group. The TRAF6 protein expression was higher in group D than that in the other three groups (P<0.01), and the difference was statistically significant. There was a statistically significant difference in the TRAF6 protein expression between group A and groups B and C, but the expression in group C was higher than that in group B (P<0.01). In conclusion, the expression of co-stimulatory molecules gradually increased in the DCs of different maturation states, and the expression of IL-12, TRAF6 mRNA, and TRAF6 protein positively correlated with the degree of DC maturation. TRAF6 is important in iDC polarity and maturation. PMID- 28357075 TI - De novo, systemic, deleterious amino acid substitutions are common in large cytoskeleton-related protein coding regions. AB - Human mutagenesis is largely random, thus large coding regions, simply on the basis of probability, represent relatively large mutagenesis targets. Thus, we considered the possibility that large cytoskeletal-protein related coding regions (CPCRs), including extra-cellular matrix (ECM) coding regions, would have systemic nucleotide variants that are not present in common SNP databases. Presumably, such variants arose recently in development or in recent, preceding generations. Using matched breast cancer and blood-derived normal datasets from the cancer genome atlas, CPCR single nucleotide variants (SNVs) not present in the All SNPs(142) or 1000 Genomes databases were identified. Using the Protein Variation Effect Analyzer internet-based tool, it was discovered that apparent, systemic mutations (not shared among others in the analysis group) in the CPCRs, represented numerous deleterious amino acid substitutions. However, no such deleterious variants were identified among the (cancer blood-matched) variants shared by other members of the analysis group. These data indicate that private SNVs, which potentially have a medical consequence, occur de novo with significant frequency in the larger, human coding regions that collectively impact the cytoskeleton and ECM. PMID- 28357077 TI - Circulating osteocyte-derived exosomes contain miRNAs which are enriched in exosomes from MLO-Y4 cells. AB - Signaling molecules produced by osteocytes have been proposed to serve as soluble factors that contribute to bone remodeling, as well as to homeostasis of other organs. However, to the best of our knowledge, there are currently no studies investigating the role of osteocyte-secreted exosomes. In the present study, ablation of osteocytes in mice [osteocyte-less (OL)] was used to examine the microRNA (miRNA) levels of plasma-circulating exosomes. In order to investigate the function of osteocyte-secreted exosomes, exosomes derived from MLO-Y4 cells were extracted and their miRNA expression levels were examined using miRNA array analysis and deep sequencing. Comparison of miRNA expression levels between plasma exosomes from OL mouse plasma and MLO-Y4-derived exosomes revealed that decreases in the number of miRNAs from exosomes circulating in the OL mouse plasma may be caused by a decrease in secretion of exosomes from osteocytes. These results suggest that osteocytes secrete exosomes containing characterized miRNAs and then circulate in the blood, and may thus transfer their components, including miRNAs, to recipient cells where they function as signaling molecules in other organs and/or tissues to regulate biological responses. PMID- 28357076 TI - Association of p53 codon 72 polymorphism with susceptibility to hepatocellular carcinoma in a Chinese population from northeast Sichuan. AB - The p53 tumor suppressor gene is key in tumor development and progression, and the single nucleotide polymorphism (SNP) of the p53 gene codon 72 (p53Arg/Pro) changes the structure of the protein. In addition, it affects its activity, which may affect cancer risk. The aim of the present study was to investigate the association between p53 codon 72 polymorphism and susceptibility to hepatocellular carcinoma (HCC) in a Chinese population from northeast Sichuan. A total of 342 HCC patients and 347 non-cancer control subjects were recruited, and the polymorphism of p53 codon 72 was measured by TaqMan(r) minor groove binder fluorescent quantitative polymerase chain reaction assay. The distribution frequency of p53 sites of arginine (Arg)/Arg, Arg/proline (Pro), Pro/Pro were 18.4, 48.8 and 32.8% in the control group, as compared with 18.7, 49.9 and 31.4% in the case group, which indicated that there was no difference between two groups (chi2=0.14; P=0.93). Upon further stratification with smoking, alcohol consumption, gender and hepatitis B virus (HBV) infection, no risk increasing genotype was identified. However, interactions between p53 codon 72 SNP and smoking, alcohol consumption and HBV infection may increase the risk of HCC [smoking odds ratio (OR), 2.00; 95% confidence interval (CI), 1.21-3.29; alcohol consumption OR, 1.87; 95% CI, 1.08-3.26; HBV infection OR, 1.84; 95% CI, 1.10 3.08]. No significant association was identified between p53 codon 72 polymorphism and HCC, and it may not have an independent effect on the susceptibility to HCC in a Chinese population from northeast Sichuan. However, interaction between genetic factors and environment exposure significantly increased the risk of HCC. PMID- 28357078 TI - Efficacy of intra-articular magnesium for postoperative analgesia in total hip arthroplasty. AB - The aim of the present study was to compare the efficacy of intra-articular magnesium sulphate and a saline placebo for postoperative pain control following total hip arthroplasty (THA). Sixty patients underwent THA and were randomly allocated into two groups to receive intra-articular injections of either 10 ml magnesium sulphate (100 mg/ml; magnesium group, n=30) or 10 ml normal saline solution (control group, n=30). Postoperative analgesia was maintained by intravenous morphine injection. The outcome measurements were visual analogue score (VAS), morphine consumption and Harris hip score (HHS). The two groups were well matched. The outcome of VAS at rest was significantly lower at postoperative hours 6 and 12 in the magnesium group as compared with the control group, although the difference was insignificant preoperatively and at postoperative hours 2, 4, 24 and 48, and days 3, 7 and 14. This indicator during activity was also lower in the magnesium group at postoperative hour 24 than that of the control group, although the difference was insignificant preoperatively and at hour 48, and days 7 and 14. The consumption of morphine (the total quantity) at 0 6, 6-12 and 0-48 h in the magnesium group was significantly lower than in the control group, although no significant differences were observed at 12-24 and 24 48 h between the groups. The improvements of HHS from preoperative to postoperative scores were statistically significant, however, no significant differences were identified between groups. Thus, the findings indicate that intra-articular magnesium sulphate injections provided improved pain control and reduced the need for morphine when compared with a saline placebo following THA. PMID- 28357079 TI - Cyclin D1 G870A polymorphism: Association with uterine leiomyoma risk and in silico analysis. AB - Uterine leiomyoma (UL) is the most common benign tumor causing considerable morbidity during the reproductive years in women. Cyclin D1 (CCND1) is a cell cycle regulatory protein that is required for the G1 phase, and increased expression levels of this protein may affect tumorigenesis. The present study aimed to assess the possible effect of the CCND1 G870A polymorphism on UL susceptibility. A total of 154 women with UL and 197 healthy women who were age-, body mass index (BMI)- and ethnicity-matched were genotyped for the CCND1 G870A (rs9344) polymorphism using the polymerase chain reaction-restriction fragment length polymorphism method. The effects of G870A transition on the structure of mRNA and proteins of CCND1 was evaluated using bioinformatics tools. The frequency of the CCND1 870AA genotype was significantly higher in women with UL compared with the control subjects, and the risk of UL was 1.4-fold higher in women with the AA genotype when compared with the GG genotype before and after adjusting for age, BMI, and ethnicity [odds ratio (OR), 1.4; 95% confidence interval (CI), 1.1-2 (P=0.02)]. The frequency of CCND1 870GA genotype was not significantly different between the two groups. The frequency of the CCND1 870A allele was significantly higher in the women with UL when compared with the control subjects (57 vs. 48%; P=0.02). The in silico analysis revealed that the G870A transition may fundamentally alter the structure of the CCND1-mRNA. Thus, the CCND1 870AA genotype was associated with UL susceptibility in a sample of women from the southeast of Iran. PMID- 28357080 TI - Association of renal function with clinical parameters and conditions in a longitudinal population-based epidemiological study. AB - The aim of the present study was to examine the association of renal function with clinical parameters and conditions in the general population. Study subjects comprised 6,027 community-dwelling individuals who were recruited to the Inabe Health and Longevity Study: A longitudinal genetic epidemiological study of atherosclerotic, cardiovascular and metabolic diseases. The cutoff value, which was used to divide the subjects into those with normal and those with low estimated glomerular filtration rate (eGFR), was 60 ml/min/1.73 m2. Bonferroni's correction was applied to establish the statistical significance of the association. Longitudinal analysis using the generalized linear mixed-effect model, following adjustments for age and gender, revealed that the eGFR was significantly associated (P<0.0017) with serum levels of triglycerides, low density lipoprotein cholesterol, uric acid, blood glycosylated hemoglobin content, fasting plasma glucose and body mass index. These parameters decreased curvilinearly with increases in eGFR. Furthermore, eGFR correlated positively with serum levels of high-density lipoprotein (HDL) cholesterol. Longitudinal analysis using the generalized estimating equation following adjustment for age and gender indicated a significant association (P<0.0024) between eGFR and prevalence of hypertension, type 2 diabetes mellitus, hypo-HDL cholesterolemia, hyperuricemia and obesity. Thus, low eGFR results in detrimental effects on various clinical parameters and conditions, resulting in increased risk of hypertension, dyslipidemia, type 2 diabetes mellitus, hyperuricemia and obesity. PMID- 28357081 TI - Lectin, galactoside-binding, soluble, 3 rs4652 A/C gene variation and the risk for rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a complex genetic disease. The lectin, galactoside binding, soluble, 3 (LGALS3) gene, encodes a member of the galectin family of carbohydrate binding proteins, and is one of the best examples of a non-human leukocyte antigen gene associated with a risk for RA in various populations. In the current study, the association between LGALS3 rs4652 gene polymorphism and RA was examined. This case-control study was performed on the 120 patients with RA and 120 healthy subjects. Genomic DNA was extracted from whole blood, and gene polymorphism was tested using a tetra-primer amplification refractory mutation system-polymerase chain reaction. The results demonstrated that LGALS3 rs4652 AC genotype increased the risk of RA (OR=11.622, 95% CI=4.473-28.656; P=0.001) when compared with the AA genotype. However, the CC genotype and the C allele were not associated with RA. These findings indicated an association between LGALS3 rs4652 variation and the risk of RA in a sample of Iranian individuals. Further studies with larger sample sizes and populations of different ethnicities are required to validate our findings. PMID- 28357083 TI - Primary laryngeal localization of multiple myeloma: A case report. AB - Multiple myeloma is a lymphoproliferative disease that may involve the bone marrow as well as extramedullary soft tissues. However, laryngeal localization of multiple myeloma is extremely rare. We herein present the case of a 68-year-old male patient with a history of dyspnea, dysphonia and dysphagia. Laryngoscopic examination revealed a lesion involving the right glottis and right vestibular (false) vocal fold, with absence of ipsilateral laryngeal motility and constriction of the airway. Computed tomography and magnetic resonance imaging revealed a gross swelling infiltrating the right glottis and right false vocal fold, sized 33*19*33 mm, with sub-centimeter laterocervical lymph nodes bilaterally. Careful integration of the clinical manifestations with the radiological and pathological data led to the diagnosis of multiple myeloma. Given the rarity of this localization, the purpose of this study was to increase knowledge of this disease among ear, nose and throat specialists, in order to enable a more timely diagnosis. PMID- 28357084 TI - Sclerosing adenosis: Ultrasonographic and mammographic findings and correlation with histopathology. AB - The present study was conducted to evaluate the radiological findings, particularly the ultrasonographic (US) characteristics of sclerosing adenosis (SA), and their correlation with histopathological results. A retrospective review identified 191 patients with a total of 200 lesions histopathologically confirmed as SA following breast surgery between July 2009 and December 2012. Of the 191 patients, 145 (151 lesions) with SA as the major component were included for US and mammographic (MG) analysis. All 145 patients analyzed were female, with a mean age +/- standard deviation of 46.8+/-7.8 years (range, 25-71 years). All 145 patients underwent US examination and the imaging findings included heterogeneously echogenic areas in 9.3% (14/151), masses in 51.7% (78/151), masses with calcifications in 13.9% (21/151), focal acoustic shadowing in 4.0% (6/151) and were negative in 21.2% (32/151) patients. Among the 119 lesions with visible abnormalities, 87.4% (104/119) were hypoechoic, 58.0% (69/119) were irregular in shape, 52.1% (62/119) had an ill-defined margin, calcifications were found in 17.6% (21/119) and 7.6% (9/119) were hypervascular, while none of the characteristics mentioned above were significantly correlated with histopathology. A total of 136 patients underwent MG at the Fudan University Shanghai Cancer Center, and the imaging findings included microcalcifications in 31.6% (43/136), masses in 23.5% (32/136), asymmetric focal density in 14.7% (20/136), focal architectural distortion in 22.8% (31/136), and were negative in 7.4% (10/136). The mass lesions were fewer on MG compared with US (23.5 vs. 65.6%, respectively). The area under the curve of US distinguishing between benign and malignant lesions was significantly larger compared with that of MG (0.547 vs. 0.497, respectively; P=0.036). In the 60 lesions that were overestimated by Breast Imaging Reporting and Data System US category, one or more characteristics of malignancy were found on US imaging. The most common finding of SA was masses with or without calcifications on US and microcalcifications on MG. The accuracy of US was limited, but higher compared with that of MG; however, SA mimicking the characteristics of malignancy may contribute to misdiagnosis with US. PMID- 28357085 TI - Long-term survival and prognosis associated with conversion surgery in patients with metastatic gastric cancer. AB - In gastric cancer, primary systemic chemotherapy is the standard approach for the management of patients with initially unresectable metastasis, and it occasionally leads to a reduction in the size of the lesion, which facilitates surgical resection. The aim of this study was to examine the prognosis of patients who were able to undergo complete resection following chemotherapy. A total of 10 patients who underwent radical surgery for stage IV primary gastric cancer after chemotherapy between 2009 and 2015 at the Department of Surgery of Hokkaido Social Work Association Obihiro Hospital (Obihiro, Japan) were retrospectively investigated. Three regimens were used (S-1, n=1; S-1 + cisplatin, n=8; and S-1 + docetaxel, n=1). The mean time from chemotherapy to surgery was 210 days. One total gastrectomy + splenectomy + colectomy, one total gastrectomy + splenectomy, four total gastrectomies and three distal gastrectomies were performed. There were two cases of pancreatic fistula formation postoperatively. All the patients survived for >1 year. Of the 10 patients, 5 survived without recurrence. The median survival time was 871.1 days after diagnosis. Therefore, curative resection after chemotherapy is associated with a better prognosis in stage IV gastric cancer patients. PMID- 28357082 TI - The role of peroxiredoxins in cancer. AB - Peroxiredoxins (PRDXs) are a ubiquitously expressed family of small (22-27 kDa) non-seleno peroxidases that catalyze the peroxide reduction of H2O2, organic hydroperoxides and peroxynitrite. They are highly involved in the control of various physiological functions, including cell growth, differentiation, apoptosis, embryonic development, lipid metabolism, the immune response, as well as cellular homeostasis. Although the protective role of PRDXs in cardiovascular and neurological diseases is well established, their role in cancer remains controversial. Increasing evidence suggests the involvement of PRDXs in carcinogenesis and in the development of drug resistance. Numerous types of cancer cells, in fact, are characterized by an increase in reactive oxygen species (ROS) production, and often exhibit an altered redox environment compared with normal cells. The present review focuses on the complex association between oxidant balance and cancer, and it provides a brief account of the involvement of PRDXs in tumorigenesis and in the development of chemoresistance. PMID- 28357086 TI - A large psammomatoid ossifying fibroma with proptosis: A case report. AB - The psammomatoid ossifying fibroma (POF) is a rare and benign fibro-osseous lesion predominantly affecting the paranasal sinuses and orbits of children and young adults. The diagnosis and management of the lesion remains challenging. The present study reported a rare case of a large POF in a 39-year-old male patient. The patient had a 30 year history of a slowly growing tumor and this had resulted in right craniofacial deformity, as well as right lateral displacement of the eye ball. Due to the large tumor size, surgical removal of the lesion was the predominant treatment. At 5 months after complete surgical resection, the patient was free from any symptoms. The radiological and histological findings, as well as the surgical management, were presented and the relevant literature was reviewed. PMID- 28357087 TI - Comparison of laparoscopic vs. open surgery for rectal cancer. AB - This study was conducted to evaluate the safety of laparoscopic radical resection for rectal cancer. A total of 64 cases of rectal cancer patients undergoing radical surgery between January, 1998 and March, 2010 were collected. The patients were divided into the laparoscopic rectal surgery group (LS group, n=31) and the open surgery group (OS group, n=33). Operation time, postoperative recovery, complications and tumor-free survival rate were compared between the two groups. The inclusion criteria were as follows: Standard Karnofsky score >70 prior to surgery, definitive pathological diagnosis and complete clinical data. The exclusion criteria were concomitant tumors affecting survival. With the Dixon operation, the LS group had a longer operation time compared with the OS group (271.2+/-56.2 vs. 216.0+/-62.7 min, respectively; P=0.036), and an earlier time of oral intake (3.0+/-0.9 vs. 4.7+/-1.0 days, respectively; P=0.000). There were no significant differences between the LS and OS groups in terms of intraoperative blood loss, number of lymph nodes retrieved, duration of postoperative hyperthermia and hospitalization time (P>0.05). With the Miles operation, there were no obvious differences between the LS and OS groups regarding operation time, intraoperative blood loss, number of lymph nodes retrieved, time of oral intake, duration of postoperative hyperthermia and hospitalization time (P>0.05). Furthermore, there were no significant differences between the LS and OS groups with the Dixon or Miles operation in terms of 3-year tumor-free survival rate (P>0.05). Thus, laparoscopic surgery appears to be a safe and feasible option for the treatment of rectal cancer. PMID- 28357089 TI - Chromothripsis and progression-free survival in metastatic colorectal cancer. AB - Metastatic dissemination of the primary tumor is the major cause of death in colorectal cancer (CRC) patients. Multiple chromosomal breaks and chromothripsis, a phenomenon involving multiple chromosomal fragmentations occurring in a single catastrophic event, are associated with cancer genesis, progression and developing of metastases. The aim of this study was to evaluate the effect of chromothripsis and total breakpoint count (breakpoint instability index) on progression-free survival (PFS). A total of 19 patients with metastatic CRC (mCRC) receiving FOLFOX first-line palliative chemotherapy between August, 2011 and October, 2012 were selected for this study. The results indicated that the highest breakpoint count was observed in chromosomes 1, 2 and 6. Chromothripsis was detected in 52.6% of the study patients. Furthermore, chromothripsis was associated with an increased median PFS (mPFS; 14 vs. 8 months, respectively; P=0.03), but an association with overall survival was not identified. The present study demonstrated that chromothripsis affected CRC patient survival, suggesting a role for this event as a prognostic and predictive marker in mCRC treatment. PMID- 28357090 TI - Raynaud's of the tongue following chemoradiation for squamous cell carcinoma of the oropharynx. AB - Raynaud's of the tongue following radiation alone or chemoradiotherapy (CRT) is a rare occurrence. The present study reports a case where typical symptoms and signs of Raynaud's phenomenon involving the tongue occurred ~18 months following CRT treatment in a 53-year-old female, who was a smoker prior to CRT with stage T2N2cM0 local-regional advanced stage IV oropharyngeal cancer. The patient was treated using cisplatin chemotherapy and intensity-modulated radiation with a dose of 70 Gray (Gy). The intermittent episodes of painful discoloration of the tongue were exacerbated due to the cold and emotional stress. No definite clinical or laboratory evidence of connective tissue disorder was identified. To the best of our knowledge, this is the first reported case of Raynaud's of the tongue following CRT without primary Raynaud's of the digits. The possible pathogenesis involving vascular and neural mechanism is discussed in the case report. PMID- 28357088 TI - Fever of unknown origin revealed to be primary splenic lymphoma: A rare case report with review of the literature. AB - Fever is a common clinical presentation of a number of diseases. A sustained unexplained fever >38.3 degrees C lasting for >3 weeks without an established diagnosis despite intensive diagnostic evaluation is referred to as fever of unknown origin (FUO). FUO remains a clinical challenge for physicians, as it may be attributed to a wide range of disorders, mainly infections, malignancies, non infectious inflammatory diseases and miscellaneous diseases. We herein report the case of a 59-year-old male patient who presented with prolonged unexplained fever and was found to have a diffusely enlarged hypermetabolic spleen, as shown on 18F fluorodeoxyglucose positron emission tomography/computed tomography examination. Following splenectomy, histopathological examination revealed primary splenic lymphoma (PSL) of B-cell origin. The patient received 6 courses of systemic chemotherapy with rituximab, etoposide, cyclophosphamide, doxorubicin, vincristine and prednisone (R-ECHOP regimen) and responded well to treatment. Thus, in patients with FUO and splenomegaly, the possibility of PSL should be taken into consideration. PMID- 28357091 TI - Colon cancer metastasis to the mandibular gingiva with partial occult squamous differentiation: A case report and literature review. AB - Metastasis is the primary cause of death among patients with colon cancer. However, the number of available studies regarding oral cavity metastases from colon cancer is currently limited. We herein report an unusual case of a 60-year old male patient who developed an oral cavity metastasis from colon cancer. A total of 12 clinical case studies reporting colon cancer metastases to the mandibular gingival region were also reviewed, with the aim to elucidate the clinical and pathological characteristics of this disease entity in order to improve clinical diagnosis and treatment. It was demonstrated that patients with oral cavity metastases from colon cancer were predominantly in the sixth or seventh decades of life. The mandible was the main site of metastatic tumors to the oral cavity, while the occurrence of gingival metastases was comparatively rare. Moreover, the diagnoses of an oral metastatic tumor and primary colon cancer were often synchronous and were frequently accompanied with metastases to other organs. Several key aspects were suggested that should be accounted for when diagnosing colon cancer patients, including focusing attention to oral symptoms when examining cancer patients, utilizing a multidisciplinary approach for differential diagnosis and utilizing postoperative pathological examination to accurately diagnose the type of tumor and optimize the efficacy of treatment. PMID- 28357092 TI - Extravascular type of intravascular papillary endothelial hyperplasia mimicking parotid gland neoplasia and the possible role of ferritin in the pathogenesis: A case report. AB - Intravascular papillary endothelial hyperplasia (IPEH) is defined as a vascular lesion characterized by extensive proliferation of vascular endothelial cells. This lesion was first described by Pierre Masson in 1923 as intravascular hemangioendothelioma. The most frequent sites of involvement are the skin and subcutis. IPEH comprises ~2% of the vascular tumors of the skin and subcutaneous tissue and it has a predilection for the head, neck, trunk and the extremities. The diagnosis is based on histopathology. We herein present the second case of Masson's tumor of the parotid gland described in literature. The patient was a 70 year-old female. Magnetic resonance imaging revealed an irregular lesion with smooth margins, initially considered to be compatible with pleomorphic adenoma. Immunohistochemical analysis revealed positivity of the tumor cells for ferritin heavy and light chains, vimentin and CD31. The aim of the present study was to emphasize the immunohistochemical characteristics and briefly discuss the potential role of ferritin in the pathogenesis of IPEH. PMID- 28357094 TI - High-grade serous ovarian cancer 3 years after bilateral salpingectomy: A case report. AB - Although epithelial ovarian cancer commonly originates from the ovarian surface epithelium and/or ovarian inclusion cysts, it was recently proposed that high grade serous ovarian cancer (HGSC) develops from the Fallopian tubes. In our department, we encountered a case of HGSC that contradicts the hypothesis of a tubal origin for HGSC. A 51-year-old postmenopausal woman had undergone hysterectomy, left oophorectomy and bilateral salpingectomy for uterine myoma. Three years later, the patient was diagnosed with stage IV ovarian cancer and underwent primary debulking surgery. The pathological examination revealed HGSC, although there was no evidence of serous tubal intraepithelial carcinoma or any other type of cancer in the previously resected left ovary and bilateral Fallopian tubes. Moreover, p53 overexpression was not detected in the right ovarian cancer specimen, while paired box gene 8, a marker of Fallopian tube epithelium, was highly expressed. Therefore, HGSC may develop from an inclusion cyst with metaplasia of from the ovarian surface epithelium. PMID- 28357093 TI - Triple-phase 99mTc-3P-RGD2 imaging of peripheral primitive neuroectodermal tumor in the hip muscle group with bone metastasis. AB - Peripheral primitive neuroectodermal tumors (pPNETs) are a group of aggressive neoplasms that are most commonly encountered in pediatric patients and may be located in the abdomen, pelvis, thoracopulmonary region and, rarely, in the head and neck region. pPNETs in adults are extremely rare. The present study reports a case of pPNET located in the hip muscles with bone metastasis. The patient was a 44-year-old woman who complained of progressive pain and swelling with a mass near the left hip. Computed tomography (CT) and enhanced CT revealed a soft tissue mass lesion in the hip muscle group measuring 4.3*4.3*4.4 cm. The lesion was ill-defined, heterogeneous, exhibiting mild post-contrast enhancement. There was a large number of bent neovessels and several branches from the left internal iliac artery and deep femoral artery on enhanced CT scan. Triple-phase dynamic imaging with integrin alphavbeta3-targeted 99mTc-3P-RGD2 as the radiotracer revealed increased blood perfusion and radiotracer aggregation in the large, ill defined, heterogeneous, hypodense mass and adjacent bone. The patient was suspected of having pPNET with bone metastasis, which was confirmed by histological examination of a sample obtained by needle aspiration. Due to the high blood perfusion of primary pPNETs and high RGD uptake by the primary and metastatic lesions, chemoembolization and anti-angiogenic therapy were considered to be the optimal therapeutic choice. This also suggested that 177Lu-labeled RGD has great potential for the targeted treatment of pPNETs with multiple metastases. PMID- 28357096 TI - Spontaneous splenic rupture in an acute leukemia patient with splenic tuberculosis: A case report. AB - Spontaneous splenic rupture, also referred to as atraumatic splenic rupture, is a rare but life-threatening emergency condition. Without timely diagnosis and treatment, the mortality rate of splenic rupture approaches 100%. The etiology of atraumatic splenic rupture varies; it is reportedly associated with neoplasms or splenic infection, but is rarely encountered in patients with both conditions. We herein report the case of a 58-year-old male patient with acute myeloid leukemia (AML) complicated by splenic tuberculosis (TB), who presented with spontaneous rupture of the spleen. Pathological examination of the resected spleen revealed multifocal granulomatosis with caseous necrosis. However, with timely diagnosis and surgical intervention, the patient recovered successfully and is currently on consolidation therapy. To the best of our knowledge, this is the first case of spontaneous splenic rupture in AML with splenic TB. The relevant literature on spontaneous splenic rupture was also reviewed and the potential etiology and treatment were discussed. PMID- 28357095 TI - Hepatectomy combined with microwave ablation of the spleen for treatment of hepatocellular carcinoma complicated with splenomegaly: A retrospective study. AB - The present retrospective study aimed to investigate the mid-term safety and efficacy of hepatectomy combined with microwave ablation of the partial spleen for treatment of liver cancer complicated with hypersplenism. A retrospective analysis was performed on 23 patients who underwent hepatectomy combined with microwave ablation of the partial spleen for liver cancer, complicated with hypersplenism that was secondary to cirrhosis. The splenic and ablated volumes were calculated according to a contrast-enhanced computed tomography scan prior to and 2 weeks after the operation. Complete blood count and liver function tests were examined prior to and following the surgery, and complications and changes in the blood tests were monitored for 6 months. Over this period of investigation, the splenic volume was reduced by a mean value of 34.0%. The levels of serum alanine aminotransferase and aspartate aminotransferase were increased on the first day after the operation (P<0.05), although they recovered to the normal level within 1 week (P<0.05). The total level of bilirubin increased slightly, along with moderately decreased levels of albumin and cholinesterase on the first day, although these changes were not significant compared with the baseline (P>0.05). The white blood cell count was persistently significantly higher compared with the baseline over the course of the 6 months (P>0.05). The platelet count did not increase significantly for the first week after the operation (P>0.05); however, it was revealed to be significantly increased 1 month after the surgery (P<0.05). No significant complications were occurred during the follow-up period. In conclusion, hepatectomy combined with microwave ablation of the spleen was demonstrated to be a safe and effective procedure for patients with liver cancer and hypersplenism in the mid-term. PMID- 28357097 TI - Surgical management and follow-up of lateral skull base tumors: An 8-year review. AB - The purpose of the present article was to describe the diagnostic evaluation of, and surgical approaches to, lateral skull base tumors (LSBTs). The study is a retrospective review of 21 patients diagnosed with tumors that involve lateral skull base (8 with malignant diseases and 13 with benign lesions) who were surgically treated during a 8-year period. The transparotid-transmandibular (38%) was the most commonly performed surgical procedure, followed by the transmandibular (24%), the transmaxillary (24%), the transcervical approach (10%) and the combined approach (4%). The surgical procedures were uneventful and there were no postoperative mortalities. Complications were encountered in 12 cases, and morbidity was not remarkable during the perioperative stages. After an average follow-up of 46 months, only 1 of 14 patients with benign diseases had a recurrence following the resection of a pleomorphic adenoma. Of 7 patients with malignant tumors, 5 are alive with no evidence of disease. The majority of the benign lateral skull base tumors can be removed surgically with a low rate of complications and recurrence. However, malignant neoplasms carry a poor prognosis and a low rate of disease-free survival. PMID- 28357098 TI - Pulmonary sclerosing hemangioma with a rare symptom: A case report and review of the literature. AB - Pulmonary sclerosing hemangioma (PSH) is a relatively rare benign tumor. However, as it occurs only rarely, the natural course of the tumor is not well understood. In the present study, a case is presented of a 35-year-old woman who underwent intermittent fevers for more than one year. This case highlighted fever as a rare symptom of PSH. Fever is possibly one of the symptoms of PSH, although it is less likely to occur. Another symptom of the patient was that the tumor grew quickly in two months. The lesion was diagnosed as multiple sclerosing hemangioma of the lung (i.e., PSH), in which papillary, solid and sclerotic patterns appeared. Immunohistochemical evaluation of the lesion revealed positive staining for thyroid transcription factor 1 (TTF1), epithelial membrane antigen (EMA), pancytokeratin (PCK) and cytoskeleton 7 (CK7). In the present case study, the biological activity of PSH was identified to be aggressive. A review of the literature was performed in order to comment further on the clinical and pathological features of this rare disease. PMID- 28357099 TI - Spontaneous regression of hepatocellular carcinoma in a Caucasian male patient: A case report and review of the literature. AB - Hepatocellular carcinoma (HCC) is the most common primary hepatic cancer. As it often presents at an advanced stage, it generally has a poor prognosis. Spontaneous regression is a rare finding in HCC, and is often associated with tumour ischemia or a systemic inflammatory response. We herein present the case of a Caucasian patient with spontaneous regression of advanced HCC, not associated with either mechanism. Our patient was a 74-year old Caucasian male who presented with advanced biopsy-proven HCC, with alpha-fetoprotein levels of >16,600 kU/l. On computed tomography examination, multiple metastases were identified. Due to the poor performance status and as the patient declined treatment, he was referred to a general practitioner for supportive palliative care. Six months later, the patient was alive and feeling well. He had suffered a cerebrovascular accident with ensuing partial hemiparesis, and had been initiated on enalapril, furosemide and curcumin. On re-evaluation, the lung lesions had disappeared, whereas both the liver and peritoneal lesions had decreased in size. Following a review of the literature, the conclusion was that this case of spontaneous regression of advanced HCC was not caused by ischemia, inflammation, or any other previously reported mechanism. Further research is required to elucidate the mechanisms underlying spontaneous regression of HCC. PMID- 28357100 TI - Interstitial lung disease associated with trastuzumab monotherapy: A report of 3 cases. AB - We herein report 3 cases of female patients with breast cancer who developed interstitial lung disease (ILD) during trastuzumab monotherapy in an adjuvant setting. Prior chemotherapy included 4 cycles of epirubicin and cyclophosphamide in patients 1 and 2, and 4 cycles of docetaxel, cyclophosphamide and trastuzumab in patient 3. Patient 1 presented with a cough and fever after the fourth cycle of trastuzumab. Patient 2 experienced rapid deterioration of oxygen saturation without subjective symptoms within 3 h of the first administration of trastuzumab. Patient 3 was unexpectedly diagnosed with organizing pneumonia in a scheduled computed tomography (CT) scan after the first course of trastuzumab. Based on clinical data, such as decreased PaO2 level, increased serum levels of KL-6 and/or lactate dehydrogenase, and findings on chest CT, these patients were diagnosed with drug-induced ILD. Considering the clinical course, trastuzumab was incriminated as the cause of ILD, particularly in patients 1 and 2. All 3 patients improved due to the timely diagnosis, discontinuation of trastuzumab and immediate administration of corticosteroid therapy. Although ILD is a rare adverse event associated with trastuzumab, it may cause rapid deterioration without preceding symptoms. Close observation and early diagnosis are required to avoid an unfavorable outcome. PMID- 28357101 TI - Laparoscopic hepatectomy in a morbidly obese patient with liver cirrhosis: A case report. AB - Cirrhotic patients constitute a high-risk population, and present a major challenge for the performance of minimally invasive laparoscopic resections due to difficulties in parenchymal transection. The present study describes the case of a 71-year-old morbidly obese male patient who was referred to our department with a hepatic mass identified on routine abdominal ultrasound. Abdominal computer tomography and magnetic resonance imaging confirmed a mass in segments V VI of the liver, highly suspicious for HCC. The patient's past medical history additionally included non-alcoholic steatohepatitis, diabetes mellitus and arterial hypertension and myocardial infarction. The patient's body mass index was 45 kg/m2, and the American Society of Anesthesiologists' classification of preoperative risk was 3. The patient underwent laparoscopic resection of segments V-VI and cholecystectomy. Two years postoperatively, the patient remains disease free and in excellent condition. To the best of our knowledge, this is the first report on laparoscopic liver resection for such a morbidly obese patient in the context of advanced liver cirrhosis. PMID- 28357102 TI - Prognostic value of circulating tumor cells in advanced gastric cancer patients receiving chemotherapy. AB - The identification of circulating tumor cells (CTCs) may provide important prognostic information in several types of solid tumors, including gastric cancer. The aim of this study was to investigate whether CTC count may be used to predict survival in patients with advanced gastric cancer treated with chemotherapy. The CELLectionTM Epithelial Enrich kit was used to isolate and purify CTCs from samples of peripheral blood. Immunofluorescent staining was used for CTC counting. High CTC counts were associated with poor tumor differentiation and high serum CEA levels (P=0.021 and 0.005, respectively). After 3 months, 16 patients with decreasing CTC counts after the first cycle of chemotherapy obtained complete response, partial response or stable disease, while 13 patients with increasing CTC counts developed progressive disease. The patients with decreasing CTC counts also exhibited longer progression-free survival (PFS) (P<=0.001) and overall survival (OS) (P=0.002) compared with those with increasing CTC counts. Among all 59 patients, those with a CTC count of <=2 cells/5 ml blood exhibited longer PFS (P<=0.001) and OS (P<=0.001) compared with those with a CTC count of >2 cells/5 ml blood. The multivariate analysis suggested that an increase of the CTC count after the first cycle of chemotherapy was only an independent prognostic marker of poor PFS (P=0.019). However, a baseline CTC count of >2 cells/5 ml blood was an independent poor prognostic marker for PFS (P=0.008) and OS (P=0.001) in all 59 patients. Our study suggested that patients with a low baseline CTC count or decrease of the CTC count after the first cycle of chemotherapy may benefit significantly from palliative chemotherapy. In conclusion, CTC count may be a good chemotherapy monitoring marker and an ideal prognostic marker for patients receiving palliative chemotherapy. PMID- 28357103 TI - VEGF, Flt-1, and microvessel density in primary tumors as predictive factors of colorectal cancer prognosis. AB - Angiogenesis in the primary tumor is known to be necessary for tumor progression in adenocarcinomas of the colon. However, whether angiogenesis in the primary tumors of patients with colorectal cancer affects their prognosis has yet to be fully elucidated. The aim of the present study was to assess the association between selected pathoclinical parameters and overall survival of resectable colorectal cancer patients with the expression of angiogenesis-promoting factors, including vascular endothelial growth factor (VEGF) and Fms-like tyrosine kinase receptor (Flt-1), and microvessel density (MVD) in the primary tumor. VEGF and Flt-1 expression were assessed, as well as MVD (with anti-CD34) by immunohistochemistry in 139 archived primary colorectal cancer tissue samples. These results were compared with the overall survival of the patients and potential prognostic pathoclinical parameters. A higher MVD in the tumors expressing Flt-1 (P=0.04) was identified. However, there was no correlation between the pathoclinical parameters of colon cancer and Flt-1 expression, VEGF expression, or MVD in the tumor. Furthermore, the intensity of VEGF expression, Flt-1 expression and tumor MVD did not correlate with the overall survival of the patients. Therefore, although increased expression of VEGF and Flt-1 was correlated with an increased expression of MVD in the primary tumors of resectable colorectal cancer patients, these factors were not correlated with prognostic pathoclinical factors and overall survival. PMID- 28357104 TI - Clinical significance of the prostate-specific antigen doubling time prior to and following radical prostatectomy to predict the outcome of prostate cancer. AB - With the advent of serum prostate-specific antigen (PSA), a larger number of prostate cancers in the early phase have been successfully detected. Although decisions to perform prostate biopsies are routinely based on PSA levels, the PSA level is easily influenced by benign prostatic hyperplasia, with poor specificity. Therefore, the aim of the present study was to assess the clinical significance of prostate-specific antigen doubling time (PSADT) prior to and following radical prostatectomy. In total, 488 patients with T1c-3N0M0 prostate cancer who underwent radical prostatectomy were included. Preoperative and postoperative PSADT were retrospectively correlated with pathological and clinical outcomes. Preoperative PSADT was measured in 204 of the 488 patients. In total, 16 out of 20 patients with a preoperative PSADT of >24 months had a cancer confined to the prostate compared with 105 of 184 patients with a PSADT of <24 months. The PSA non-recurrence rate at 5 years for patients with a preoperative PSADT of >24 months was significantly better compared with those with a preoperative PSADT of <24 months (P=0.011). Patients with a PSADT of >24 months and stable PSADT were associated with PSA recurrence following surgery, based on multivariate analysis. Postoperative PSADT was measured in 51 of 111 patients with PSA failure following surgery. Pathologically, 7 of 8 patients with a post PSADT of >24 months had a cancer confined to the prostate compared with 14 of 43 patients with a post-PSADT of <24 months. These results suggest that patients with longer preoperative PSADTs appeared to have a favorable pathological result and a higher PSA non-recurrence rate compared with those with shorter preoperative PSADTs. A longer postoperative PSADT may facilitate the observation of patients with PSA recurrence without immediate secondary treatments. PMID- 28357106 TI - Persistent arthralgia, vomiting and hypercalcemia as the initial manifestations of hyperthyroidism: A case report. AB - A 53-year-old woman presented with persistent edema and pain of the metacarpophalangeal and proximal interphalangeal joints and the wrist, knee and ankle joints, with more recent intermittent nausea and vomiting. Treatment for rheumatoid arthritis and osteoarthritis was ineffective. No clinical manifestations typical of hyperthyroidism were observed. The results of the thyroid function tests were as follows: Thyroid-stimulating hormone, 0.003 uIU/ml; triiodothyronine (T3), 4.44 ng/ml;, thyroxine (T4) >30 ug/dl; free T3, 14.03 pg/ml; and free T4, 8.84 ng/dl. The laboratory tests revealed an elevated serum calcium level (2.96 mmol/l); moderate hypophosphatemia (0.84 mmol/l); significantly reduced serum intact parathyroid hormone (4.8 pg/ml); normal 25 hydroxy vitamin D (52.13 nmol/l) and bone-specific alkaline phosphatase (22.1 ng/ml); and elevated osteocalcin (128.8 ng/ml). X-ray and quantitative ultrasound examinations revealed extensive osteoporosis of the hands, skull, knees and pelvis, with a bone mineral density of 0.254 g/cm2 (T-score, -3.2). Anti-thyroid therapy (methimazole, 30 mg/day; salmon calcitonin, 50 IU/day; and alendronate, 70 mg/week) was initiated. After 2 weeks, the serum calcium and phosphate levels were normalized (2.44 and 1.19 mmol/l, respectively) and calcitonin was discontinued. After 3 months, the patient had no nausea, vomiting or joint pain, and her appetite was normal, with a weight gain of ~10 kg. Euthyroidism was achieved and the serum calcium and phosphate levels were normalized (2.31 and 1.12 mmol/l, respectively) and maintained for 6 months, by which time the osteocalcin level had diminished (80.40 ng/ml). This rare case of arthralgia, hypercalcemia and extensive osteoporosis as the first manifestations of hyperthyroidism suggests that, even without typical symptoms, hyperthyroidism should be considered in the differential diagnosis of patients with persistent arthralgia. PMID- 28357105 TI - Osteonecrosis of the jaw associated with everolimus: A case report. AB - Everolimus, a mammalian target of rapamycin inhibitor, has recently been approved for the treatment of metastatic estrogen receptor-positive breast cancer, at a daily dose of 10 mg in combination with exemestane. Osteonecrosis of the jaw (ONJ) is a rare but severe condition, characterized by exposed necrotic bone, and is associated with various drugs that are often used to treat advanced malignancies. We herein report the case of a patient with breast cancer who developed ONJ during treatment with everolimus, which improved after discontinuation of the drug. To the best of our knowledge, this is the first reported case of everolimus-associated ONJ in a patient receiving everolimus for metastatic breast cancer. In 2014, an 80-year-old woman was started on treatment with everolimus and exemestane for stage IIB estrogen receptor-positive breast cancer. Within 2 months, the left side of her face became edematous, with localized heat and tenderness of the left mandibular region and a 3-mm round area of exposed bone. There was purulent discharge and the surrounding gingiva was edematous and erythematous. The left mandible exhibited a low signal intensity area on T1-weighted magnetic resonance imaging. Treatment was discontinued and ONJ showed improvement after 2 months. Therefore, when prescribing everolimus for metastatic breast cancer, oncologists should be aware of the possibility of ONJ as a complication. PMID- 28357107 TI - Paclitaxel and platinum-based chemotherapy results in transient dyslipidemia in cancer patients. AB - Paclitaxel and cisplatin (TP) are common chemotherapeutic agents extensively used for treating lung and esophageal cancers. The present study reported three patients with transient hypertriglyceridemia (HTG) following TP chemotherapy. Serum triglyceride (TG) levels returned to baseline at chemotherapy intermission. No patient had any history of HTG or any evidence of pancreatitis or other complications of HTG. No regular elevation of any other serum lipids, including cholesterol, high-density lipoprotein and low-density lipoprotein, was observed. However, treatment of mice with TP decreased TG and slightly increased cholesterol. The findings of the present study suggested that TP chemotherapy results in transient dyslipidemia, and physicians must monitor TG levels during chemotherapy to avoid TG-associated complications. PMID- 28357108 TI - An increased neutrophil-to-lymphocyte ratio predicts poorer survival following recurrence for patients with breast cancer. AB - The aim of the present study was to evaluate the association between changes in the neutrophil-to-lymphocyte ratio and the survival rate, as well as tumor subtype, in recurrent breast cancer. Patients with recurrent breast cancer following surgery were included in this study. NLR was calculated and compared between two time points: Pre-treatment and recurrence. The associations between the longitudinal NLR change, the NLR at the time of recurrence and overall survival following recurrence (OSrec) were evaluated. A total of 89 patients were evaluated. NLR increased by 0.59 at recurrence, as compared with the initial treatment (P<0.05). The triple negative (TN) type demonstrated 4.59 in NLR, which was the highest among the four subtypes at the time of recurrence (P<0.05). The highest change (an increase of 2.0) was observed in TN type cancer (P<0.05). Patients with high NLR upon recurrence demonstrated significantly shorter OSrec rates (P<0.05). On the other hand, patients with an NLR increased by more than a third quartile demonstrated a shorter OSrec rate (P=0.06). When adjusted by covariates, the NLR and tumor subtype were determined to be associated with OSrec (P<0.05). Therefore, an increased NLR predicts survival, even in patients with recurrent breast cancer, and the NLR is potentially useful as an inflammation marker for TN breast cancer. PMID- 28357109 TI - Atypical breast adenosquamous carcinoma following acute myeloid leukemia in a middle-aged woman: A case report. AB - Adenosquamous carcinoma of the breast is a rare cancer that develops as glands and tubules admixed with solid nests of squamous cells in a spindle cell background. Furthermore, its occurrence following AML is also rare. To the best of our knowledge, based on a review of the relevant literature, thus far there have not been any welldocumented cases. In the present case report, we report on a middle-aged woman with a 2year history of acute myeloid leukemia (AML) who was admitted to hospital due to a mass in the right breast, with concurrent cutaneous lesions on the breast. The clinical and pathological investigations resulted in the diagnosis of adenosquamous carcinoma of the breast. The patient underwent a modified radical mastectomy (MRM). Subsequently, the patient received chemotherapy, involved-field radiation therapy and target therapy. At 9 months after the final cycle of chemotherapy, and while she was on targeted therapy with trastuzumab (6 mg administered every 3 weeks), the patient presented with extensive dermatomal skin lesions. A biopsy report revealed metastatic lesions of invasive ductal carcinoma in the abdomen, so chemotherapy resumed with a course lasting for 6 cycles, with the identical treatments, but lacking trastuzumab. PMID- 28357110 TI - Identical twins with mature cystic teratomas treated with laparoscopic surgery: Two case reports. AB - Mature cystic teratomas are the most common among all ovarian neoplasms, representing 30-40% of the cases. However, to the best of our knowledge, there have been only two reports of mature cystic teratomas occurring in identical twins to date. We herein report a case of identical twins with mature cystic teratomas who were treated with laparoscopic surgery. A 32-year-old woman was referred to our hospital due to a tumor in the right ovary. The patient underwent laparoscopic resection of the ovarian tumor and the pathological diagnosis was benign mature cystic teratoma. Two years later, the identical twin of the abovementioned patient was referred to our hospital also due to a right ovarian tumor. The patient underwent laparoscopic resection of the ovarian tumor and the pathological diagnosis was benign mature cystic teratoma. Therefore, for early diagnosis, it may be important to consider the possibility of mature cystic teratoma in the identical twin of a patient, even in the absence of symptoms. PMID- 28357112 TI - Immunoglobulin G4-related disease: a rare steroid-responsive disease. AB - A 70-year-old man presented with progressive dyspnoea and weight loss. Physical examination revealed only mild pale conjunctiva. The workup showed mild anaemia, mild impaired renal function, and high globulin level. Multiple myeloma was excluded by normal serum protein electrophoresis. The chest radiography and computed tomography (CT) revealed bilateral multifocal patchy infiltration with mediastinal adenopathy. Bronchoscopy was performed. Bronchoalveolar lavage (BAL) fluid examination was negative for infection and malignancy. Tissue pathology revealed diffuse lymphoplasmacytic cell infiltration. Immunohistochemistry revealed positive highlight for CD38, immunoglobulin G (IgG), and IgG4. Serum IgG subclass was requested and showed an IgG4 level of 7230 mg/dL. Examination of bone marrow and submental lymph node pathology were also positive for IgG4. IgG4 related disease with pulmonary involvement was diagnosed. Treatment with prednisolone (30 mg/day) resulted in improvement in his dyspnoea and almost complete resolution of the pulmonary infiltration on repeated CT at 6 month. This case highlighted a rare occurrence of IgG4-related disease which was successfully treated with steroid. PMID- 28357111 TI - Typing of killer-cell immunoglobulin-like receptors and their cognate human leukocyte antigen class I ligands predicts survival of Chinese Han patients with metastatic non-small-cell lung cancer. AB - Non-small-cell lung cancer (NSCLC) may establish an immunosuppressive tumor microenvironment that is conducive to tumor growth. Natural killer (NK) cells play a pivotal role in immunological surveillance. Activation of NK cells partially depends on the interactions between killer-cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands. We herein investigated the association of KIRs and HLA ligands with survival in metastatic NSCLC (mNSCLC) patients treated with chemotherapy in a Chinese Han population. Polymerase chain reaction with sequence-specific primers was used to type 15 KIRs at the DNA and mRNA level and 6 HLA ligands in 70 mNSCLC patients. Survival curves were estimated using the Kaplan-Meier method and compared with the log rank test. Cox proportional hazard regression model was applied for multivariate survival analysis, with the stepwise selection, to determine independent predictors of survival. It was observed that patients with KIR2DS4del gene expression at the mRNA level or HLA-Bw4T80 exhibited poor overall survival (OS). The multivariate analysis revealed that HLA-Bw4T80 and KIR2DS4del expression were independent predictors of OS. This observation indicated that the KIR/HLA ligand is a promising predictor of survival in mNSCLC and may also provide a strategy for treatment stratification and patient management. PMID- 28357113 TI - Identification of animal movement patterns using tri-axial magnetometry. AB - BACKGROUND: Accelerometers are powerful sensors in many bio-logging devices, and are increasingly allowing researchers to investigate the performance, behaviour, energy expenditure and even state, of free-living animals. Another sensor commonly used in animal-attached loggers is the magnetometer, which has been primarily used in dead-reckoning or inertial measurement tags, but little outside that. We examine the potential of magnetometers for helping elucidate the behaviour of animals in a manner analogous to, but very different from, accelerometers. The particular responses of magnetometers to movement means that there are instances when they can resolve behaviours that are not easily perceived using accelerometers. METHODS: We calibrated the tri-axial magnetometer to rotations in each axis of movement and constructed 3-dimensional plots to inspect these stylised movements. Using the tri-axial data of Daily Diary tags, attached to individuals of number of animal species as they perform different behaviours, we used these 3-d plots to develop a framework with which tri-axial magnetometry data can be examined and introduce metrics that should help quantify movement and behaviour. . RESULTS: Tri-axial magnetometry data reveal patterns in movement at various scales of rotation that are not always evident in acceleration data. Some of these patterns may be obscure until visualised in 3D space as tri-axial spherical plots (m-spheres). A tag-fitted animal that rotates in heading while adopting a constant body attitude produces a ring of data around the pole of the m-sphere that we define as its Normal Operational Plane (NOP). Data that do not lie on this ring are created by postural rotations of the animal as it pitches and/or rolls. Consequently, stereotyped behaviours appear as specific trajectories on the sphere (m-prints), reflecting conserved sequences of postural changes (and/or angular velocities), which result from the precise relationship between body attitude and heading. This novel approach shows promise for helping researchers to identify and quantify behaviours in terms of animal body posture, including heading. CONCLUSION: Magnetometer-based techniques and metrics can enhance our capacity to identify and examine animal behaviour, either as a technique used alone, or one that is complementary to tri-axial accelerometry. PMID- 28357118 TI - A phase 1 study comparing the proposed biosimilar BS-503a with bevacizumab in healthy male volunteers. AB - This is a randomized, double-blind, single-dose, parallel group phase 1 study to assess pharmacokinetic similarity, safety, and tolerability of BS-503a, a proposed bevacizumab biosimilar. A total of 114 male healthy subjects were randomized (1:1) to receive a single 3 mg/kg intravenous dose of either BS-503a or bevacizumab (Avastin(r)). Pharmacokinetic (PK) blood samples were collected up to Day 78, and serum drug concentrations were measured using a validated enzyme linked immunosorbent assay. Pharmacokinetic similarity was evaluated using area under the serum concentration-time curve from zero to infinity (AUC inf) as a primary PK parameter, and maximum serum concentration (Cmax) and area under the serum concentration-time curve from zero to the last measurable time (AUC last) as secondary PK parameters. The 90% confidence intervals (CIs) of geometric mean ratio of AUC inf ranged 0.980-1.105, which met the predefined criteria of 0.80 1.25. The 90% CIs of geometric mean ratios for Cmax and AUC last were 1.009-1.125 and 0.982-1.096, respectively, falling into the same criteria. At least one drug related treatment emergent adverse event occurred in 18 and 21 subjects treated with BS-503a and bevacizumab, respectively. The most common adverse events were headache, epistaxis, and rhinorrhea. Most adverse events were mild or moderate; however, one drug-related serious adverse event of duodenal ulcer perforation was reported by a subject 47 days after treatment of BS-503a. In conclusion, BS-503a was demonstrated to have highly similar PK to bevacizumab and adverse events observed were consistent with those observed for bevacizumab. PMID- 28357114 TI - Protein Corona-Induced Modification of Silver Nanoparticle Aggregation in Simulated Gastric Fluid. AB - Due to their widespread incorporation into a range of biomedical and consumer products, the ingestion of silver nanoparticles (AgNPs) is of considerable concern to human health. However, the extent to which AgNPs will be modified within the gastric compartment of the gastrointestinal tract is still poorly understood. Studies have yet to fully evaluate the extent of physicochemical changes to AgNPs in the presence of biological macromolecules, such as pepsin, the most abundant protein in the stomach, or the influence of AgNPs on protein structure and activity. Herein, AgNPs of two different sizes and surface coatings (20 and 110 nm, citrate or polyvinylpyrrolidone) were added to simulated gastric fluid (SGF) with or without porcine pepsin at three pHs (2.0, 3.5, and 5.0), representing a range of values between preprandial (fasted) and postprandial (fed) conditions. Rapid increases in diameter were observed for all AgNPs, with a greater increase in diameter in the presence of pepsin, indicating that pepsin facilitated AgNPs aggregation. AgNPs interaction with pepsin only minimally reduced the protein's proteolytic functioning capability, with the greatest inhibitory effect caused by smaller (20 nm) particles of both coatings. No changes in pepsin secondary structural elements were observed for the different AgNPs, even at high particle concentrations. This research highlights the size dependent kinetics of nanoparticle aggregation or dissolution from interaction with biological elements such as proteins in the gastrointestinal tract. Further, these results demonstrate that, in addition to mass, knowing the chemical form and aggregation state of nanoparticles is critical when evaluating toxicological effects from nanoparticle exposure in the body. PMID- 28357119 TI - Influence of age on intestinal bile acid transport in C57BL/6 mice. AB - Intestinal and hepatic bile acid transporters are important for enterohepatic bile acid circulation and pharmacokinetics. Based on previous literature, we hypothesized that the expression of bile acid transporters and intestinal bile acid absorption are lower in older individuals. Here, we measured active taurocholate absorption across the ileum of male C57BL/6 mice in two different age cohorts - young (age range of 89-224 days) and old (age range of 613-953 days). Also examined in these mice were mRNA expression of the major bile acid transporters - Asbt and Ostalpha/beta in the ileum, and Ntcp, Oatp1b2 and Bsep in the liver. Mean intestinal taurocholate absorption was significantly lower (~50%) in mice in the older cohort compared to those in the younger cohort. In the ileum, the expression of Asbt was significantly lower in the older cohort, but expression of Ostalpha/beta was not affected by age. The lower capacity for intestinal bile acid absorption in the older animals is consistent with their lower expression level of Asbt. Of the hepatic bile acid transporters examined, expression of Ntcp and Oatp1b2 were significantly lower in the older mice. This is the first study to directly measure intestinal bile acid absorption as a function of age. The data suggest a lower capacity for intestinal bile acid absorption in older animals. Also, lower expression of Asbt, Ntcp, and Oatp1b2 in older individuals could influence pharmacokinetics of drug substrates. PMID- 28357120 TI - GABAB receptor allosteric modulators exhibit pathway-dependent and species selective activity. AB - Positive modulation of the GABAB receptor (GABABR) represents a potentially useful therapeutic approach for the treatment of nicotine addiction. The positive allosteric modulators (PAMs) of GABABR GS39783 and BHF177 enhance GABA-stimulated [35S]GTP gammaS-binding, and have shown efficacy in a rodent nicotine self administration procedure reflecting aspects of nicotine dependence. Interestingly, the structural related analog, NVP998, had no effect on nicotine self-administration in rats despite demonstrating similar pharmacokinetic properties. Extensive in vitro characterization of GS39783, BHF177, and NVP998 activity on GABABR-regulated signaling events, including modulation of cAMP, intracellular calcium levels, and ERK activation, revealed that these structurally related molecules display distinct pathway-specific signaling activities that correlate with the dissimilarities observed in rodent models and may be predictive of in vivo efficacy. Furthermore, these GABABR allosteric modulators exhibit species-dependent activity. Collectively, these data will be useful in guiding the development of GABABR allosteric modulators that display optimal in vivo efficacy in a preclinical model of nicotine dependence, and will identify those that have the potential to lead to novel antismoking therapies. PMID- 28357121 TI - Uricosuric targets of tranilast. AB - Uric acid, generated from the metabolism of purines, has both proven and emerging roles in human disease. Serum uric acid in humans is determined by production and by the net balance of reabsorption and secretion in kidney and intestine. In the human kidney, epithelial reabsorption dominates over secretion, such that in normal subjects there is at least 90% net reabsorption of filtered urate resulting in a fractional excretion of <10%. Tranilast, an anti-inflammatory drug with pleiotropic effects, has a marked hypouricemic, uricosuric effect in humans. We report here that tranilast is a potent inhibitor of [14C]-urate transport mediated by the major reabsorptive urate transporters (URAT1, GLUT9, OAT4, and OAT10) in Xenopus oocytes; this provides an unequivocal molecular mechanism for the drug's uricosuric effect. Tranilast was found to inhibit urate transport mediated by URAT1 and GLUT9 in a fully reversible and noncompetitive (mixed) manner. In addition, tranilast inhibits the secretory urate transporters NPT1, OAT1, and OAT3 without affecting the secretory efflux pump ABCG2. Notably, while benzbromarone and probenecid inhibited urate as well as nicotinate transport, tranilast inhibited the urate transport function of URAT1, GLUT9, OAT4, OAT10, and NPT1, without significantly affecting nicotinate transport mediated by SMCT1 (IC 50 ~1.1 mmol/L), SMCT2 (IC 50 ~1.0 mmol/L), and URAT1 (IC 50 ~178 MUmol/L). In summary, tranilast causes uricosuria by inhibiting all the major reabsorptive urate transporters, selectively affecting urate over nicotinate transport. These data have implications for the treatment of hyperuricemia and gout, the pharmacology of tranilast, and the structure-function analysis of urate transport. PMID- 28357122 TI - Therapeutically targeting guanylate cyclase-C: computational modeling of plecanatide, a uroguanylin analog. AB - Plecanatide is a recently developed guanylate cyclase-C (GC-C) agonist and the first uroguanylin analog designed to treat chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). GC-C receptors are found across the length of the intestines and are thought to play a key role in fluid regulation and electrolyte balance. Ligands of the GC-C receptor include endogenous agonists, uroguanylin and guanylin, as well as diarrheagenic, Escherichia coli heat-stable enterotoxins (ST). Plecanatide mimics uroguanylin in its 2 disulfide-bond structure and in its ability to activate GC-Cs in a pH dependent manner, a feature associated with the presence of acid-sensing residues (Asp2 and Glu3). Linaclotide, a synthetic analog of STh (a 19 amino acid member of ST family), contains the enterotoxin's key structural elements, including the presence of three disulfide bonds. Linaclotide, like STh, activates GC-Cs in a pH independent manner due to the absence of pH-sensing residues. In this study, molecular dynamics simulations compared the stability of plecanatide and linaclotide to STh. Three-dimensional structures of plecanatide at various protonation states (pH 2.0, 5.0, and 7.0) were simulated with GROMACS software. Deviations from ideal binding conformations were quantified using root mean square deviation values. Simulations of linaclotide revealed a rigid conformer most similar to STh. Plecanatide simulations retained the flexible, pH-dependent structure of uroguanylin. The most active conformers of plecanatide were found at pH 5.0, which is the pH found in the proximal small intestine. GC-C receptor activation in this region would stimulate intraluminal fluid secretion, potentially relieving symptoms associated with CIC and IBS-C. PMID- 28357124 TI - Antibiotic-associated suspected adverse drug reactions among hospitalized patients in Uganda: a prospective cohort study. AB - We sought to determine the prevalence at admission and incidence during hospitalization of antibiotic-associated suspected adverse drug reactions (aa ADRs) among Ugandan inpatients; and to characterize these aa-ADRs. We conducted a prospective cohort study of 762 consented adults admitted on medical and gynecological wards of the 1790-bed Mulago National Referral Hospital. Thirty percent were known HIV-seropositive (232/762). Nineteen percent (148/762; 95% CI: 17-22%) of inpatients experienced at least one aa-ADR. At hospital admission, 6% (45/762; 95% CI: 4-8%) of patients had at least one aa-ADR; and 15% (45/300; 11 20%) of those who had received antibiotics in the 4-weeks preadmission. Twenty four (53%) of these 45 patients had serious aa-ADRs. The incidence of aa-ADRs was 19% (117/629; 95% CI: 16-22%) of patients who received antibiotics [community acquired: 9% (27/300; 95% CI: 6-13%); hospital-acquired: 16% (94/603; 95% CI: 13 19%)]: 39 (33%) of 117 patients had serious aa-ADRs. Of 269 aa-ADRs, 115 (43%) were community-acquired, 66 (25%) probable/definite, 171 (64%) preventable, 86 (32%) serious, and 24 (9%) rare. Ceftriaxone was the most frequently implicated for serious hospital-acquired aa-ADRs. Cotrimoxazole, isoniazid, rifampicin, ethambutol, and pyrazinamide were the most frequently linked to serious community acquired aa-ADRs. Fatal jaundice (isoniazid), life-threatening difficulty in breathing with shortness of breath (rifampicin) and disabling itchy skin rash with numbness of lower swollen legs (ethambutol, isoniazid) were observed. Pharmaceutical quality testing of implicated antibiotics could be worthwhile. Periodic on-ward collection and analysis of antibiotic-safety-data standardized by consumption is an efficient method of tracking antibiotics with 1%-risk for serious aa-ADRs. PMID- 28357123 TI - Adverse reactions to fluoroquinolones in the Nigerian population: an audit of reports submitted to the National Pharmacovigilance Centre from 2004 to 2016. AB - Adverse drug reactions (ADRs) recorded in national pharmacovigilance databases in developed countries have been analyzed. However, adverse reactions to fluoroquinolones were observed globally despite their wide use and safety concerns. We provided information on the pattern of adverse reactions to fluoroquinolones reported spontaneously to the National Pharmacovigilance Centre (NPC), Nigeria. ADRs to fluoroquinolones reported to the NPC, over a period of 12 years, were analyzed. Evaluation was done for annual reports, age and gender of patients, type of reporter, suspected fluoroquinolones and adverse reactions, onset and outcome of ADRs, and causality. A total of 18527 ADR reports were received by the NPC. Antibiotics accounted for 1371(7.4%) of the total reports and fluoroquinolones accounted for 256 (18.7%) cases. A total of 540 ADRs due to fluoroquinolones was experienced by the patients. Multiple ADRs were experienced by 165 (65%) patients. Norfloxacin (2; 0.8%), moxifloxacin (3; 1.2%), ofloxacin (10; 3.9%), ciprofloxacin (112; 43.8%), and levofloxacin (129; 50.4%) were responsible for the ADRs. Neurological disorders (121; 22.4%), gastrointestinal disorders (118; 21.9%), and skin-appendage disorders (116; 21.5%) were the most reported ADRs, while pruritus (41; 7.6%), abdominal pain (34; 6.3%), vomiting (34; 6.3%), and skin rash (27; 5.0%) were the most frequently reported specific ADRs. Thirty-four (6.4%) patients experienced serious ADRs. Fluoroquinolones accounted for a small but significant proportion of ADRs spontaneously reported to the NPC in Nigeria. Ciprofloxacin and levofloxacin were the two most culpable fluoroquinolones due to their inappropriate use or increased use in multi-drug resistant tuberculosis (MDR-TB) treatment. PMID- 28357125 TI - In vitro analysis of factors influencing CYP1A2 expression as potential determinants of interindividual variation. AB - Individual differences in drug metabolism contribute to interindividual variation that characterizes responses to drugs and risk in exposure to foreign chemicals. Large individual differences are found in expression levels of CYP1A2, a major drug-metabolizing enzyme. Underlying causes for this variation are not well understood. Several factors, including tobacco smoking, consumption of cruciferous vegetables, and sex, have been associated with modulating CYP1A2 expression. To understand factors regulating expression of CYP1A2 in establishing a causal relationship, this study examined effects of cigarette smoke condensate (CSC), indole-3-carbinol (I3C), and 17beta-estradiol (estradiol) on CYP1A2 expression in in vitro systems using human liver and lung cells. Treatment with CSC (2-25 MUg/mL) significantly increased levels of CYP1A2 in six cell lines examined, in a concentration- and time-dependent manner. Fold changes in expression levels relative to controls varied among cell lines. CYP1A2 enzymatic activity also increased with CSC exposure. Treatment of H1299 and HepB3 cells with dietary agent I3C (50 and 100 MUmol/L) increased CYP1A2 expression. In human cell lines H1299 and H1395, treatment with estradiol (10 and 100 nmol/L) significantly reduced expression of CYP1A2. Using ChIP assays, effects of CSC on histone modifications were analyzed. Increases in H3K4me3 and H4K16ac were observed at several segments in the CYP1A2 gene, whereas H3K27me3 decreased, following CSC treatment. These results suggest that CYP1A2 expression is affected epigenetically by CSC. Additional studies will be needed to further establish regulatory mechanisms underlying effects of various environmental, dietary, and endogenous factors on CYP1A2 expression in better predicting individual variation. PMID- 28357126 TI - The anti-inflammatory compound palmitoylethanolamide inhibits prostaglandin and hydroxyeicosatetraenoic acid production by a macrophage cell line. AB - The anti-inflammatory agent palmitoylethanolamide (PEA) reduces cyclooxygenase (COX) activity in vivo in a model of inflammatory pain. It is not known whether the compound reduces prostaglandin production in RAW264.7 cells, whether such an action is affected by compounds preventing the breakdown of endogenous PEA, whether other oxylipins are affected, or whether PEA produces direct effects upon the COX-2 enzyme. RAW264.7 cells were treated with lipopolysaccharide and interferon-gamma to induce COX-2. At the level of mRNA, COX-2 was induced >1000 fold following 24 h of the treatment. Coincubation with PEA (10 MUmol/L) did not affect the levels of COX-2, but reduced the levels of prostaglandins D2 and E2 as well as 11- and 15-hydroxyeicosatetraenoic acid, which can also be synthesised by a COX-2 pathway in macrophages. These effects were retained when hydrolysis of PEA to palmitic acid was blocked. Linoleic acid-derived oxylipin levels were not affected by PEA. No direct effects of PEA upon the oxygenation of either arachidonic acid or 2-arachidonoylglycerol by COX-2 were found. It is concluded that in lipopolysaccharide and interferon-gamma-stimulated RAW264.7 cells, PEA reduces the production of COX-2-derived oxylipins in a manner that is retained when its metabolism to palmitic acid is inhibited. PMID- 28357127 TI - Metabolic effects of a mitochondrial-targeted coenzyme Q analog in high fat fed obese mice. AB - We recently reported that mitoquinone (mitoQ, 500 MUmol/L) added to drinking water of C57BL/6J mice attenuated weight gain, decreased food intake, increased hypothalamic orexigenic gene expression, and mitigated oxidative stress when administered from the onset of high-fat (HF) feeding. Here, we examined the effects of mitoQ on pre-existing obesity in C57BL/6J mice first made obese by 107 days of HF feeding. In contrast to our preventative study, we found that already obese mice did not tolerate mitoQ at 500 MUmol/L. Within 4 days of administration, obese mice markedly decreased food and water intake and lost substantial weight necessitating a dose reduction to 250 MUmol/L. Food and water intake then improved. Over the next 4 weeks, body mass of the mitoQ-treated mice increased faster than vehicle-treated controls but did not catch up. Over the subsequent 10 weeks, weights of the mitoQ-treated group remained significantly less than vehicle control, but percent fat and food intake did not differ. Although the mitoQ-treated groups continued to drink less, there was no difference in percent body fluid and no laboratory evidence of dehydration at study end. At the time of killing, hypothalamic NPY gene expression was reduced in the mitoQ-treated mice . Liver fat was markedly increased by HF feeding but did not differ between mitoQ and vehicle groups and, in contrast to our previous preventative study, there was no improvement in plasma alanine amino transferase or liver hydroperoxides. In summary, administration of mitoQ to already obese mice attenuated weight gain, but showed limited overall benefit. PMID- 28357128 TI - Impact of comorbidity on adverse drug reaction profile in a cohort of patients treated with Artemisinin combination therapies for uncomplicated malaria in Nigeria. AB - Artemisinin-based combination antimalarial therapy (ACTs), is still highly effective in uncomplicated falciparum malaria, however, there remain some concerns in relation to its safety and tolerability. Comorbid disease conditions may influence susceptibility to adverse drug reactions (ADRs) as the presence of multiple disease conditions may predisposes patients to ADRs due to the use of many medicines. There is therefore need to assess the impact of comorbidities on the ADR profile of malaria patients treated with ACTs. The study was carried out in health care facilities spread across Nigeria. From the database of over 10,000 patients recruited into an initial cohort, data for 1000 patients with comorbidities was extracted and matched with a control group of 1000 randomly selected patients with no comorbidity. There were 1105 adverse drug reactions in all, of which 66.2% were recorded in patients with comorbidity, and 34% are patients without comorbidity. The mean age of patients with comorbidities was 38.3 +/- 17.5 years and 23.8 +/- 17.2 for those without comorbidity. Out of the 979 patients with comorbidity, 36% were hypertensive, 2.2% hypertensive-diabetes, 16.4% peptic ulcer disease, 10.4% HIV/AIDS, 4.4% diabetes and 4.3% were asthmatic. Patients with comorbidity were three times more likely to have adverse drug reaction than those without comorbidity (Odds ration = 2.96; 95% CI = 2.23 3.93). HIV/AIDS and osteoarthritis were significantly associated with development of adverse drug reactions. Probability was <0.0001. Age, weight, and height of patients were also found to be risk factor for development of adverse drug reactions. PMID- 28357129 TI - Ultraviolet irradiation increases green fluorescence of dihydrorhodamine (DHR) 123: false-positive results for reactive oxygen species generation. AB - Dihydrorhodamine (DHR) 123 is a fluorophore commonly used for measuring reactive oxygen species (ROS), often after exposing cells to ultraviolet (UV) irradiation or oxidative burst inducers such as Phorbol 12-myristate 13-acetate (PMA). However, the negative effects of UV irradiation on oxidation of DHR123 itself to green fluorescence rhodamine (R) 123 under different experimental conditions (e.g., different buffers, media, cells, ROS detection techniques) have not been fully appreciated. We determined the effect of UV on DHR123 fluorescence, using a cell-free system, and A549 epithelial cells, NIH/3T3 fibroblast cells, Jurkat T cells, primary human T cells, HL-60 neutrophils and primary human neutrophils. We found that UV irradiation rapidly increases green fluorescence of DHR123 in cell free solutions. The intensity of green fluorescence increases with increasing amounts of DHR123 and UV exposure. The fluorescence increase was greater in Roswell Park Memorial Institute medium (RPMI) than DMEM media. The presence of DMSO (0-1.25%, v/v) in RPMI further increases the fluorescence signal. Phosphate buffered solution (PBS) and Hanks' Balanced Salt Solution (HBSS) generate considerable background signal with DHR123, and increasing DMSO concentration greatly increases the fluorescence signal in these buffers. However, after UV irradiation the amount of DHR123 that remains unoxidized generates sufficient fluorescence signal to measure the ROS produced by H2O2 and peroxidase in vitro or Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated ROS production within HL-60 neutrophils or primary human neutrophils. We conclude that UV irradiation oxidizes DHR123 to generate Rhodamine 123 (R123) green fluorescence signal, and that the R123 present in the culture supernatant could give erroneous results in plate reader assays. However, flow cytometry and fluorescence microscopy reliably detect ROS in cells such as neutrophils. Overall, avoiding false-positive results when detecting ROS using DHR123 requires selection of, agonists, the correct buffers, media, cell types, and measurement techniques. PMID- 28357130 TI - Off-label drug use in hospitalized children: a prospective observational study at Gondar University Referral Hospital, Northwestern Ethiopia. AB - Most of the medications which are currently used for the treatment of childhood diseases are either not licensed or being prescribed outside the terms of the product license (off-label prescribing). This study aimed at determining the extent of unlicensed and off-label drug uses and associated factors in children hospitalized in Gondar University Referral Hospital, Northwest Ethiopia. An institution-based prospective cross-sectional study was employed from April 15 to July 15, 2016. A total of 243 pediatric patients admitted to Gondar university referral hospital were included in the study using simple random sampling method. Data were collected using structured questionnaire, and the data collected were entered and analyzed using Statistical Packages for Social Sciences (SPSS) version 20. From the total of 800 drugs prescribed, 607 (75.8%) were off-label. Off-label medicine use was frequently observed in antimicrobials (60.6%) followed by central nervous system drugs (14.3%). The extent off-label prescribing was highest in age group of 6-13 years (30%). Inappropriate dosing and frequency (42.3%) were the most common reason for off-label medicine use. Having other variables controlled, age group and undergoing surgical procedure remained to be significant predictors of off-label prescribing in the multivariate regression analysis. Implementing evidence-based approach in prescribing by generating more quality literatures on the safety profile and effectiveness of off-label would improve the injudicious use of drugs in pediatric population. PMID- 28357133 TI - The association between self-reported and clinically determined hypomanic symptoms and the onset of major mood disorders. AB - BACKGROUND: Hypomanic symptoms may be a useful predictor of mood disorder among young people at high risk for bipolar disorder. AIMS: To determine whether hypomanic symptoms differentiate offspring of parents with bipolar disorder (high risk) and offspring of well parents (control) and predict the development of mood episodes. METHOD: High-risk and control offspring were prospectively assessed using semi-structured clinical interviews annually and completed the Hypomania Checklist-32 Revised (HCL-32). Clinically significant sub-threshold hypomanic symptoms (CSHS) were coded. RESULTS: HCL-32 total and active or elated scores were higher in control compared with high-risk offspring, whereas 14% of high risk and 0% of control offspring had CSHS. High-risk offspring with CSHS had a fivefold increased risk of developing recurrent major depression (P=0.0002). The median onset of CSHS in high-risk offspring was 16.4 (6-31) years and was before the onset of major mood episodes. CONCLUSIONS: CSHS are precursors to major mood episodes in high-risk offspring and could identify individuals at ultra-high risk for developing bipolar disorder. DECLARATION OF INTEREST: None. COPYRIGHT AND USAGE: (c) The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license. PMID- 28357132 TI - Subclinical psychotic experiences and subsequent contact with mental health services. AB - BACKGROUND: Although psychotic experiences in people without diagnosed mental health problems are associated with mental health service use, few studies have assessed this prospectively or measured service use by real-world clinical data. AIMS: To describe and investigate the association between psychotic experiences and later mental health service use, and to assess the role of symptoms of common mental health disorders in this association. METHOD: We linked a representative survey of south-east London (SELCoH-1, n=1698) with health records from the local mental healthcare provider. Cox regression estimated the association of PEs with rate of mental health service use. RESULTS: After adjustments, psychotic experiences were associated with a 1.75-fold increase in the rate of subsequent mental health service use (hazard ratio (HR) 1.75, 95% CI 1.03-2.97) compared with those without PEs. Participants with PEs experienced longer care episodes compared with those without. CONCLUSIONS: Psychotic experiences in the general population are important predictors of public mental health need, aside from their relevance for psychoses. We found psychotic experiences to be associated with later mental health service use, after accounting for sociodemographic confounders and concurrent psychopathology. DECLARATION OF INTEREST: None. COPYRIGHT AND USAGE: (c) The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY) license. PMID- 28357134 TI - Mental health among young adults in prison: the importance of childhood-onset conduct disorder. AB - BACKGROUND: The psychiatric health burden of prisoners is substantial. However, there is a lack of high-quality studies of psychiatric disorders among young adults with a high risk of reoffending. AIMS: To investigate the lifetime prevalence of psychiatric disorders and use of mental health services among young male violent offenders and the impact of childhood-onset conduct disorder (COCD). METHOD: A nationally representative cohort (n = 270, age 18-25) of male offenders was followed back in medical records and clinically assessed by gold standard methods. Lifetime prevalences are presented together with odds ratios (ORs) as risk estimates in relation to COCD. RESULTS: Previous use of psychiatric services among the participants was high but their lifetime psychiatric morbidity was even higher, with 93% meeting criteria for at least one Axis I disorder. The COCD group was overrepresented in most clinical categories and carried five times higher odds (OR = 5.1, 95% CI 2.0-12.8) of a psychotic disorder, three times higher odds (OR = 3.2, 95% CI 1.2-8.5) of a substance use disorder and two times higher odds of a mood disorder (OR = 2.3, 95% CI 1.3-4.0) or anxiety disorder (OR = 2.0, 95% CI 1.1-3.5). CONCLUSIONS: The mental health burden is substantial among young violent offenders, and COCD is an important indicator of future mental health problems which must be a priority for public health efforts. DECLARATION OF INTEREST: None. COPYRIGHT AND USAGE: (c) The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license. PMID- 28357131 TI - Aquatic therapy for boys with Duchenne muscular dystrophy (DMD): an external pilot randomised controlled trial. AB - BACKGROUND: Standard treatment of Duchenne muscular dystrophy (DMD) includes regular physiotherapy. There are no data to show whether adding aquatic therapy (AT) to land-based exercises helps maintain motor function. We assessed the feasibility of recruiting and collecting data from boys with DMD in a parallel group pilot randomised trial (primary objective), also assessing how intervention and trial procedures work. METHODS: Ambulant boys with DMD aged 7-16 years established on steroids, with North Star Ambulatory Assessment (NSAA) score >=8, who were able to complete a 10-m walk test without aids or assistance, were randomly allocated (1:1) to 6 months of either optimised land-based exercises 4 to 6 days/week, defined by local community physiotherapists, or the same 4 days/week plus AT 2 days/week. Those unable to commit to a programme, with >20% variation between NSAA scores 4 weeks apart, or contraindications to AT were excluded. The main outcome measures included feasibility of recruiting 40 participants in 6 months from six UK centres, clinical outcomes including NSAA, independent assessment of treatment optimisation, participant/therapist views on acceptability of intervention and research protocols, value of information (VoI) analysis and cost-impact analysis. RESULTS: Over 6 months, 348 boys were screened: most lived too far from centres or were enrolled in other trials; 12 (30% of the targets) were randomised to AT (n = 8) or control (n = 4). The mean change in NSAA at 6 months was -5.5 (SD 7.8) in the control arm and -2.8 (SD 4.1) in the AT arm. Harms included fatigue in two boys, pain in one. Physiotherapists and parents valued AT but believed it should be delivered in community settings. Randomisation was unattractive to families, who had already decided that AT was useful and who often preferred to enrol in drug studies. The AT prescription was considered to be optimised for three boys, with other boys given programmes that were too extensive and insufficiently focused. Recruitment was insufficient for VoI analysis. CONCLUSIONS: Neither a UK-based RCT of AT nor a twice weekly AT therapy delivered at tertiary centres is feasible. Our study will help in the optimisation of AT service provision and the design of future research. TRIAL REGISTRATION: ISRCTN41002956. PMID- 28357135 TI - Circumferential silicone sponge scleral buckling induced axial length changes: case series and comparison to literature. AB - BACKGROUND: This study compared axial length changes induced by circumferential scleral buckling using a silicone sponge with literature reports for solid silicone rubber. METHODS: Records of patients treated with scleral buckling in 2009-2013 using a silicone sponge, with preoperative axial length biometry measurements were reviewed. Additional information included age, type of surgery, additional surgeries, phakic status and anatomical success of reattachment. Patients underwent repeat biometry. The medical literature was reviewed for articles describing axial length changes induced by circumferential buckling using solid silicone rubber. RESULTS: Twenty-eight patients (mean age 49.7 years, range 16-72) met the inclusion criteria. Mean axial length was 25.38 mm preoperatively and 26.12 mm at least 6 months postoperatively (SD 0.50 +/- 0.09, p < 0.001); a mean increase of 0.74 mm. Half the patients subsequently underwent cataract surgery. Post-operative changes were not significant compared to pre surgical refraction and corneal astigmatism. Axial length change was not significant between sexes (9 women and 19 men). CONCLUSIONS: Axial length changes induced by circumferential scleral buckling using silicone sponge exclusively are similar to those reported in the literature for solid silicone rubber buckles. Scleral buckling using a silicone sponge, which may offer several surgical advantages, induces an acceptable axial length change similar to that seen with widely-used solid silicone rubber buckles. PMID- 28357136 TI - Repeatability and Agreement of Central Corneal Thickness and Keratometry Measurements between Four Different Devices. AB - Background. To estimate repeatability and comparability of central corneal thickness (CCT) and keratometry measurements obtained by four different devices in healthy eyes. Methods. Fifty-five healthy eyes from 55 volunteers were enrolled in this study. CCT (IOLMaster 700, Pentacam HR, and Cirrus HD-OCT) and keratometry readings (IOLMaster 700, Pentacam HR, and iDesign) were measured. For statistical analysis, the corneal spherocylinder was converted into power vectors (J0, J45). Repeatability was assessed by intraclass correlation coefficient (ICC). Agreement of measurements between the devices was evaluated by the Bland Altman method. Results. The analysis of repeatability of CCT data of IOLMaster 700, Pentacam HR, and Cirrus HD-OCT showed high ICCs (range 0.995 to 0.999). The comparison of CCT measurements revealed statistically significant differences between Pentacam HR versus IOLMaster 700 (p < 0.0001) and Pentacam HR versus Cirrus HD-OCT (p < 0.0001), respectively. There was no difference in CCT measurements between IOLMaster 700 and Cirrus HD-OCT (p = 0.519). The repeatability of keratometry readings (J0 and J45) of IOLMaster 700, Pentacam HR, and iDesign was also high with ICCs ranging from 0.974 to 0.999. The Pentacam HR revealed significantly higher J0 in comparison to IOLMaster 700 (p = 0.009) and iDesign (p = 0.041); however, no significant difference was between IOLMaster 700 and iDesign (p = 0.426). Comparison of J45 showed no significant difference between IOLMaster 700, Pentacam HR, and iDesign. These results were in accordance with Bland-Altman plots. Conclusion. In clinical practice, the devices analyzed should not be used interchangeably due to low agreement regarding CCT as well as keratometry readings. PMID- 28357138 TI - Growth of Infants with Intestinal Failure or Feeding Intolerance Does Not Follow Standard Growth Curves. AB - Objective. Infants with intestinal failure or feeding intolerance are nutritionally compromised and are at risk for extrauterine growth restriction. The aim of the study was to evaluate growth velocities of infants with intestinal failure and feeding intolerance for the first three months of age and to determine growth percentiles at birth and at 40-week postmenstrual age (PMA). Methods. A chart review of infants followed by the Texas Children's Hospital Intestinal Rehabilitation Team was conducted from April 2012 to October 2014. Weekly weight, length, and head circumference growth velocities were calculated. Growth data were compared to Olsen growth curves to determine exact percentiles. Results. Data from infants (n = 164) revealed that average growth velocities of 3 month-old infants (weight gain, 19.97 g/d; length, 0.81 cm/week; head circumference, 0.52 cm/week) fluctuated and all were below expected norms. At discharge or death, average growth velocities had further decreased (length, 0.69 cm/week; head circumference, 0.45 cm/week) except for weight, which showed a slight increase (weight, 20.56 g/d). Weight, length, and head circumference percentiles significantly decreased from birth to 40-week PMA (P < 0.001). Conclusions. Growth of infants with intestinal failure or feeding intolerance did not follow standard growth curves. PMID- 28357137 TI - Diet-Induced Obesity Is Associated with an Impaired NK Cell Function and an Increased Colon Cancer Incidence. AB - Obesity is associated with an increased colon cancer incidence, but underlying mechanisms remained unclear. Previous studies showed altered Natural killer (NK) cell functions in obese individuals. Therefore, we studied the impact of an impaired NK cell functionality on the increased colon cancer risk in obesity. In vitro investigations demonstrated a decreased IFN-gamma secretion and cytotoxicity of human NK cells against colon tumor cells after NK cell preincubation with the adipokine leptin. In addition, leptin incubation decreased the expression of activating NK cell receptors. In animal studies, colon cancer growth was induced by injection of azoxymethane (AOM) in normal weight and diet induced obese rats. Body weight and visceral fat mass were increased in obese animals compared to normal weight rats. AOM-treated obese rats showed an increased quantity, size, and weight of colon tumors compared to the normal weight tumor group. Immunohistochemical analyses demonstrated a decreased number of NK cells in spleen and liver in obesity. Additionally, the expression levels of activating NK cell receptors were lower in spleen and liver of obese rats. The results show for the first time that the decreased number and impaired NK cell function may be one cause for the higher colon cancer risk in obesity. PMID- 28357139 TI - Effect of Focused Bedside Ultrasonography in Hypotensive Patients on the Clinical Decision of Emergency Physicians. AB - We assessed the effect of focused point of care ultrasound (POCUS) used for critical nontraumatic hypotensive patients presenting to the emergency department of our hospital on the clinical decisions of the physicians and whether it led to the modification of the treatment modality. This prospective clinical study was conducted at the Emergency Department of Antalya Training and Research Hospital. Nontraumatic patients aged 18 and older who presented to our emergency department and whose systolic blood pressure was <100 mmHg or shock index (heart rate/systolic blood pressure) was >1 were included in the study. While the most probable preliminary diagnosis established by the physician before POCUS was consistent with the definitive diagnosis in 60.6% (n = 109) of 180 patients included in the study, it was consistent with the definitive diagnosis in 85.0% (n = 153) of the patients after POCUS (p < 0.001). POCUS performed for critical hypotensive patients presenting to the emergency department is an appropriate diagnostic tool that can be used to enable the physicians to make the accurate preliminary diagnosis and start the appropriate treatment in a short time. PMID- 28357140 TI - The Noncell Autonomous Requirement of Proboscipedia for Growth and Differentiation of the Distal Maxillary Palp during Metamorphosis of Drosophila melanogaster. AB - The Drosophila maxillary palpus that develops during metamorphosis is composed of two elements: the proximal maxillary socket and distal maxillary palp. The HOX protein, Proboscipedia (PB), was required for development of the proximal maxillary socket and distal maxillary palp. For growth and differentiation of the distal maxillary palp, PB was required in the cells of, or close to, the maxillary socket, as well as the cells of the distal maxillary palp. Therefore, PB is required in cells outside the distal maxillary palp for the expression, by some mechanism, of a growth factor or factors that promote the growth of the distal maxillary palp. Both wingless (wg) and hedgehog (hh) genes were expressed in cells outside the distal maxillary palp in the lancinia and maxillary socket, respectively. Both wg and hh were required for distal maxillary palp growth, and hh was required noncell autonomously for distal maxillary palp growth. However, expression of wg-GAL4 and hh-GAL4 during maxillary palp differentiation did not require PB, ruling out a direct role for PB in the regulation of transcription of these growth factors. PMID- 28357142 TI - Aerobic Exercise Effects on Ocular Dominance Plasticity with a Phase Combination Task in Human Adults. AB - Several studies have shown that short-term monocular patching can induce ocular dominance plasticity in normal adults, in which the patched eye becomes stronger in binocular viewing. There is a recent study showing that exercise enhances this plasticity effect when assessed with binocular rivalry. We address one question, is this enhancement from exercise a general effect such that it is seen for measures of binocular processing other than that revealed using binocular rivalry? Using a binocular phase combination task in which we directly measure each eye's contribution to the binocularly fused percept, we show no additional effect of exercise after short-term monocular occlusion and argue that the enhancement of ocular dominance plasticity from exercise could not be demonstrated with our approach. PMID- 28357141 TI - Intrahemispheric Perfusion in Chronic Stroke-Induced Aphasia. AB - Stroke-induced alterations in cerebral blood flow (perfusion) may contribute to functional language impairments and recovery in chronic aphasia. Using MRI, we examined perfusion in the right and left hemispheres of 35 aphasic and 16 healthy control participants. Across 76 regions (38 per hemisphere), no significant between-subjects differences were found in the left, whereas blood flow in the right was increased in the aphasic compared to the control participants. Region of-interest (ROI) analyses showed a varied pattern of hypo- and hyperperfused regions across hemispheres in the aphasic participants; however, there were no significant correlations between perfusion values and language abilities in these regions. These patterns may reflect autoregulatory changes in blood flow following stroke and/or increases in general cognitive effort, rather than maladaptive language processing. We also examined blood flow in perilesional tissue, finding the greatest hypoperfusion close to the lesion (within 0-6 mm), with greater hypoperfusion in this region compared to more distal regions. In addition, hypoperfusion in this region was significantly correlated with language impairment. These findings underscore the need to consider cerebral perfusion as a factor contributing to language deficits in chronic aphasia as well as recovery of language function. PMID- 28357144 TI - "Black Esophagus" or Gurvits Syndrome: A Rare Complication of Diabetic Ketoacidosis. AB - Acute esophageal necrosis (AEN) also known as "black esophagus" or necrotizing esophagitis is a rare syndrome characterized by a striking diffuse patchy or circumferential black appearance of the esophageal mucosa that preferentially affects the distal esophagus and terminates at the gastroesophageal junction. Only 88 patients over a span of 40 years have received this diagnosis, and the prevalence of this disease ranges from 0.001 to 0.2% of cases in literature. It more commonly affects men (4 : 1 ratio) in the sixth decade of life. It is associated with a high mortality rate, approaching 32%. We report a case of AEN presenting in the setting of diabetic ketoacidosis (DKA), affecting both the proximal and distal esophagus. PMID- 28357143 TI - A Rapid Biochemical and Radiological Response to the Concomitant Therapy with Temozolomide and Radiotherapy in an Aggressive ACTH Pituitary Adenoma. AB - Background and Importance. In the last eight years temozolomide (TMZ) has been used as the last-line treatment modality for aggressive pituitary tumors to be applied after the failure of surgery, medical therapy, and radiotherapy. The objective was to achieve a rapid control of tumor growth and hormone normalization with concurrent chemoradiotherapy in a patient with very aggressive ACTH pituitary adenoma. Clinical Presentation. We describe a patient with an aggressive ACTH-producing adenoma treated with concurrent temozolomide and radiotherapy. The patient suffered from an aggressive ACTH adenoma resistant to surgical and medical treatment. After two months of concurrent temozolomide and radiotherapy, cortisol normalization and significant tumor shrinkage were observed. After 22 months of follow-up, there is still no evidence of tumor recurrence. Conclusion. Concurrent treatment with temozolomide and irradiation appears to be highly effective in the achievement of the tumor volume control as well as in the control of ACTH secretion in aggressive ACTH adenoma. PMID- 28357145 TI - Pneumoperitoneum Secondary to Spontaneously Perforated Pyometra. AB - Pyometra, by definition, is a collection of purulent fluid within the uterine cavity. Incidence has been estimated to range from 0.1% to 0.5%. Typically, this is linked to postmenopausal women; however, it has been linked to premenopausal women with concordant use of intrauterine devices. Based on our knowledge, there have been less than 50 recorded cases reported in the English literature regarding perforation of pyometra resulting in acute abdomen and fewer than 25 resulting in pneumoperitoneum. We report a patient who was evaluated for diffuse peritonitis caused by perforated pyometra who was successfully treated with surgical intervention. PMID- 28357146 TI - Dysplastic L5-S1 Spondyloptosis in a 3-Year-Old Child: A Case Report and Review of the Literature. AB - A three-year-old girl presented with primary complaint of severe low back pain with radiation to both lower limbs below the knees since 2 months following history of fall and marked restriction of her daily routine activities. After clinicoradiological evaluation she was diagnosed of having dysplastic L5-S1 spondyloptosis. A staged procedure was planned after thorough discussion with her parents. During initial stage she underwent posterior decompression along L5-S1 segment including exposure of bilateral L5 and S1 nerve roots followed by instrumented reduction (L3-S2 5.5 mm pedicle screws) utilizing a rotational translational technique. No interbody fusion was done at L5-S1 level and inner nuts of bilateral L3, L4, and S2 screws were intentionally kept loose. Subsequently after about symptom-free three-year follow up, she presented with recurrence of symptoms and underwent revision surgery as per initial plan discussed with her parents. Removals of posterior implants were done followed by stabilization with larger diameter pedicle screws (6.5 mm) at L5 and S1 level. During the same stage through anterior transperitoneal approach L5-S1 interbody fusion was done. At one-year follow-up after second-stage definitive surgery, patient remains symptom-free and fully active without any radiological evidence of reduction loss or implant failure. PMID- 28357147 TI - Dual Fixation of Calcaneal Tuberosity Avulsion with Concomitant Achilles Tendon Rupture: A Novel Hybrid Technique. AB - Fracture of the calcaneal tuberosity with a concomitant Achilles tendon rupture presents a difficult challenge for the treating surgeon. The ultimate goal of treatment is to restore function of both the gastrocnemius-soleus complex and the Achilles tendon. This particular subset of fractures occurs often in diabetics and elderly patients with osteoporosis making fixation of the displaced fragment rather complex. If the Achilles tendon disruption is only discovered later once the fracture is healed, subsequent management is difficult with surgical treatment being more morbid. While this is a rare injury, the consequences of a missed chronic Achilles tendon disruption are severe with significant dysfunction. It is therefore important to have a high index of suspicion for concomitant injury and to be prepared for dual fixation. We present a novel hybrid surgical fixation technique, which may be used in this instance. PMID- 28357148 TI - Anti-K1 (Kell) Antibody Expressed in Maternal Breastmilk: A Case Report of a Neonate with Multiple Intrauterine Transfusions and Postnatal Exposure to Kell Antibody in Maternal Breastmilk. AB - Hemolytic disease of the fetus and newborn is a common consideration in newborn medicine, especially among the jaundiced. Maternal breastmilk provides numerous benefits to the infant, including nutrition and immunologic factors. Here, we present an infant who received three intrauterine transfusions for anemia secondary to anti-K1 (Kell), anti-C, and anti-e antibodies and whose maternal breastmilk tested positive for anti-Kell antibodies. The infant required another transfusion at 4 weeks of life for anemia. We review the pathophysiology of anti Kell antibodies, the immunology of breast milk, and the intersection of these two topics. PMID- 28357149 TI - Festination Correlates with SNCA Polymorphism in Chinese Patients with Parkinson's Disease. AB - The genetic basis of festination, a common motor symptom in Parkinson's disease (PD), remains unclear. Since polymorphism in the alpha-synuclein (SNCA) gene is associated with PD phenotype, we examined whether such polymorphism is also associated with festination. SNCA polymorphisms rs11931074 and rs894278 were genotyped in a consecutive series of 258 patients with PD, of whom 122 (47.3%) suffered festination. Univariate analysis revealed significant differences in genotype and minor allele frequencies at rs11931074 or rs894278 between patients with festination and those without it (all p < 0.05). Based on logistic regression, a GG or GT genotype at rs11931074 was associated with higher risk of festination among patients with PD (OR 2.077, 95% CI 1.111-3.883, p = 0.022), as was the TT genotype at rs894278 (OR 2.271, 95% CI 1.246-4.139, p = 0.007). Therefore, we conclude that festination is associated with polymorphism at rs11931074 or rs894278 among patients with PD. PMID- 28357151 TI - Caprine Endometrial Mesenchymal Stromal Stem Cell: Multilineage Potential, Characterization, and Growth Kinetics in Breeding and Anestrous Stages. AB - The endometrial layer of the uterus contains a population of cells with similar characteristics of mesenchymal stem cells (MSCs). In the present study, caprine endometrial mesenchymal stromal stem cells (En-MSCs) characters and differentiation potential to chondrogenic, osteogenic, and adipogenic cell lines as well as their growth kinetics in breeding and anestrous stages were evaluated. En-MSCs were enzymatically isolated from endometrial layer of the uterus of adult goats and were cultured and subcultured until passage 4. The growth kinetics and population doubling time (PDT) of caprine En-MSCs in breeding and anestrous stages were determined. En-MSCs in passage 4 were used for the karyotyping and differentiation into chondrocytes, osteocytes, and adipocytes. The PDT in anestrus phase was 40.6 h and in cyclic goats was 53 h. En-MSCs were fibroblast like in all passages. The number of chromosomes was normal (2n = 60) with no chromosomal instability. Chondrogenic, osteogenic, and adipogenic differentiation of En-MSCs was confirmed by staining with Alcian blue, Alizarin red, and Oil Red O, respectively. Caprine En-MSCs demonstrated to be an alternative source of MSCs for cell therapy purposes in regenerative medicine. PMID- 28357150 TI - Systematic Review and Critical Analysis of Cost Studies Associated with Parkinson's Disease. AB - Parkinson's disease (PD) is the second most prevalent neurodegenerative disease worldwide, affecting more than four million people. Typically, it affects individuals above 45, when they are still productive, compromising both aging and quality of life. Therefore, the cost of the disease must be identified, so that the use of resources can be rational and efficient. Additionally, in Brazil, there is a lack of research on the costs of neurodegenerative diseases, such as PD, a gap addressed in this study. This systematic review critically addresses the various methodologies used in original research around the world in the last decade on the subject, showing that costs are hardly comparable. Nonetheless, the economic and social impacts are implicit, and important information for public health agents is provided. PMID- 28357152 TI - A Highly Sensitive Multicommuted Flow Analysis Procedure for Photometric Determination of Molybdenum in Plant Materials without a Solvent Extraction Step. AB - A highly sensitive analytical procedure for photometric determination of molybdenum in plant materials was developed and validated. This procedure is based on the reaction of Mo(V) with thiocyanate ions (SCN-) in acidic medium to form a compound that can be monitored at 474 nm and was implemented employing a multicommuted flow analysis setup. Photometric detection was performed using an LED-based photometer coupled to a flow cell with a long optical path length (200 mm) to achieve high sensitivity, allowing Mo(V) determination at a level of MUg L 1 without the use of an organic solvent extraction step. After optimization of operational conditions, samples of digested plant materials were analyzed employing the proposed procedure. The accuracy was assessed by comparing the obtained results with those of a reference method, with an agreement observed at 95% confidence level. In addition, a detection limit of 9.1 MUg L-1, a linear response (r = 0.9969) over the concentration range of 50-500 MUg L-1, generation of only 3.75 mL of waste per determination, and a sampling rate of 51 determinations per hour were achieved. PMID- 28357153 TI - The Demand for Disaster Microinsurance for Small Businesses in Urban Slums: The Results of Surveys in Three Indian Cities. AB - BACKGROUND: Small informal businesses make up the core markets for many poor urban communities, providing essential goods, services, and livelihoods. Many of these communities and businesses exist in hazardous locations. In most cases, these business owners do not have access to proper coping mechanisms including risk transfer and lack resilience to shocks. Access to risk-transfer in the form of insurance for these small businesses is extremely limited. This demand survey is the first phase of an intervention to test disaster microinsurance for these businesses. Previous research has examined the demand for and value of microinsurance to protect poor households but not micro- and medium-sized informal urban businesses. OBJECTIVE: This study investigates knowledge about and demand for microinsurance among small informal business owners in three different cities of India. METHODS: Survey of all informal business owners (n=4919) identified through purposive sampling of the most vulnerable in three proposed study sites: Guwahati in Assam (n=1622), Puri in Odisha (n=1551) and Cuddalore in Tamil Nadu (n=1746). RESULTS: Our findings reflect that while small business owners largely did not know about disaster microinsurance, after describing it, a vast majority wanted to subscribe to such a program. Without it, they often rely on personal savings, forgo basic necessities, or take out costly loans that trap them in debt to cope with disasters. DISCUSSION: This research supports the need for more experiments on actual adoption patterns, feasibility studies, and innovative trial programs by governments, non-governmental organizations, and insurance providers. PMID- 28357154 TI - Vaccine Hesitancy: In Search of the Risk Communication Comfort Zone. AB - INTRODUCTION: This paper reports the findings of a national online survey to parents of children aged 5 and younger. The objectives of the study were to assess parental understanding of childhood immunizations, identify sources of information that they trust for vaccine-related content, assess where parents with young children stand on the key issues in the public debate about vaccination, and identify which risk communication messages are most effective for influencing the behaviours of vaccine hesitant parents. METHODS: A total of 1,000 surveys (closed and open-ended questions) were administered in November 2015 using the Angus Reid Forum Panel, a key consumer panel consisting of approximately 150,000 Canadian adults aged 18 and older, spread across all geographic regions of Canada. RESULTS: Approximately 92% of the Canadian parents surveyed consider vaccines safe and effective, and trust doctors and public health officials to provide timely and credible vaccine-related information. However, a concerning number of them either believe or are uncertain whether there is a link between vaccines and autism (28%), worry that vaccines might seriously harm their children (27%), or believe the pharmaceutical industry is behind the push for mandatory immunization (33%). Moreover, despite the common assumption that social media are becoming the go-to source of health news and information, most parents still rely on traditional media and official government websites for timely and credible information about vaccines and vaccine preventable diseases, particularly during community-based disease outbreaks. Finally, parents reported high levels of support for pro-vaccine messaging that has been demonstrated in previous research to have little to no positive impact on behaviour change, and may even be counterproductive. DISCUSSION: The study's results are highly relevant in a context where public health officials are expending significant resources to increase rates of childhood immunization and combat vaccine hesitancy. The data offer insight into where parents stand on the political and public debate about mandatory vaccination, what aspects of vaccine science remain uncertain to them, which media and institutional sources they use and trust to navigate the health information environment, how they look for information and whom they trust during periods of health emergency or crisis, and which communication strategies are considered most effective in persuading vaccine hesitant parents to immunize their children. PMID- 28357156 TI - Does Zika Virus Cause Microcephaly - Applying the Bradford Hill Viewpoints. AB - INTRODUCTION: Zika virus has been documented since 1952, but been associated with mild, self-limiting disease. Zika virus is classified as an arbovirus from a family of Flaviviridae and primarily spread by Aedes Aegypti mosquitos. However, in a large outbreak in Brazil in 2015, Zika virus has been associated with microcephaly. METHODS: In this review we applied the Bradford-Hill viewpoints to investigate the association between Zika virus and microcephaly. We examined historical studies, available data and also compared historical rates of microcephaly prior to the Zika virus outbreak. The available evidence was reviewed against the Bradford Hill viewpoints. RESULTS: All the nine criteria were met to varying degrees: strength of association, consistency of the association, specificity, temporality, plausibility, coherence, experimental evidence, biological gradient and analogy. Conclusion: Using the Bradford Hill Viewpoints as an evaluation framework for causation is highly suggestive that the association between Zika virus and microcephaly is causal. Further studies using animal models on the viewpoints which were not as strongly fulfilled would be helpful. PMID- 28357155 TI - Analytical and Clinical Validity Study of FirstStepDx PLUS: A Chromosomal Microarray Optimized for Patients with Neurodevelopmental Conditions. AB - INTRODUCTION: Chromosomal microarray analysis (CMA) is recognized as the first tier test in the genetic evaluation of children with developmental delays, intellectual disabilities, congenital anomalies and autism spectrum disorders of unknown etiology. ARRAY DESIGN: To optimize detection of clinically relevant copy number variants associated with these conditions, we designed a whole-genome microarray, FirstStepDx PLUS (FSDX). A set of 88,435 custom probes was added to the Affymetrix CytoScanHD platform targeting genomic regions strongly associated with these conditions. This combination of 2,784,985 total probes results in the highest probe coverage and clinical yield for these disorders. RESULTS AND DISCUSSION: Clinical testing of this patient population is validated on DNA from either non-invasive buccal swabs or traditional blood samples. In this report we provide data demonstrating the analytic and clinical validity of FSDX and provide an overview of results from the first 7,570 consecutive patients tested clinically. We further demonstrate that buccal sampling is an effective method of obtaining DNA samples, which may provide improved results compared to traditional blood sampling for patients with neurodevelopmental disorders who exhibit somatic mosaicism. PMID- 28357157 TI - A New Paradigm for Uterine Fibroid Treatment: Transcervical, Intrauterine Sonography-Guided Radiofrequency Ablation of Uterine Fibroids with the Sonata System. AB - PURPOSE OF REVIEW: This article provides the current evidence related to transcervical radiofrequency ablation of uterine fibroids under integrated intrauterine sonography guidance (the Sonata System). RECENT FINDINGS: Published data on the treatment of fibroids with the Sonata System has demonstrated significant median reductions in total (73.3%) and perfused (73.3%) uterine fibroid volume, menstrual bleeding (72.3%), symptom severity (62.5%), and improvements in health-related quality of life (127%) at 12 months post-ablation. A clinical trial under an FDA Investigational Device Exemption is in progress. SUMMARY: The Sonata System is a promising treatment modality for uterine fibroids. As an incisionless, minimally invasive treatment that does not require general anesthesia or hospitalization, it has the potential for redefining the current paradigm for management of symptomatic fibroids. PMID- 28357158 TI - Binary Classifier Calibration Using an Ensemble of Linear Trend Estimation. AB - Learning accurate probabilistic models from data is crucial in many practical tasks in data mining. In this paper we present a new non-parametric calibration method called ensemble of linear trend estimation (ELiTE). ELiTE utilizes the recently proposed l1 trend ltering signal approximation method [22] to find the mapping from uncalibrated classification scores to the calibrated probability estimates. ELiTE is designed to address the key limitations of the histogram binning-based calibration methods which are (1) the use of a piecewise constant form of the calibration mapping using bins, and (2) the assumption of independence of predicted probabilities for the instances that are located in different bins. The method post-processes the output of a binary classifier to obtain calibrated probabilities. Thus, it can be applied with many existing classification models. We demonstrate the performance of ELiTE on real datasets for commonly used binary classification models. Experimental results show that the method outperforms several common binary-classifier calibration methods. In particular, ELiTE commonly performs statistically significantly better than the other methods, and never worse. Moreover, it is able to improve the calibration power of classifiers, while retaining their discrimination power. The method is also computationally tractable for large scale datasets, as it is practically O(N log N) time, where N is the number of samples. PMID- 28357159 TI - Correction: No population bias to left-hemisphere language in 4-year-olds with language impairment. AB - [This corrects the article DOI: 10.7717/peerj.507.]. PMID- 28357160 TI - Mapping the Internal Anatomy of the Lateral Brainstem: Anatomical Study with Application to Far Lateral Approaches to Intrinsic Brainstem Tumors. AB - INTRODUCTION: Intramedullary brainstem tumors present a special challenge to the neurosurgeon. Unfortunately, there is no ideal part of the brainstem to incise for approaches to such pathology. Therefore, the present study was performed to identify what incisions on the lateral brainstem would result in the least amount of damage to eloquent tracts and nuclei. Case illustrations are also discussed. MATERIALS AND METHODS: Eight human brainstems were evaluated. Based on dissections and the use of standard atlases of brainstem anatomy, the most important deeper brainstem structures were mapped to the surface of the lateral brainstem. RESULTS: With these data, we defined superior acute and inferior obtuse corridors for surgical entrance into the lateral brainstem that would minimize injury to deeper tracts and nuclei, the damage to which would result in significant morbidity. CONCLUSIONS: To our knowledge, a superficial map of the lateral brainstem for identifying deeper lying and clinically significant nuclei and tracts has not previously been available. Such data might decrease patient morbidity following biopsy or tumor removal or aspiration of brainstem hemorrhage. Additionally, this information can be coupled with the previous literature on approaches into the fourth ventricular floor for more complex, multidimensional lesions. PMID- 28357161 TI - Defining Health Across the Cancer Continuum. AB - Health is not defined by the absence of disease or suffering, but by response to a series of life events that can markedly alter the quality and quantity of life. Patients with cancer experience significant but dynamic physical, psychosocial, and financial challenges. With the increasing number of patients with early stage cancers transitioning to survivorship, there is a critical need to address health promotion and overall well-being. For those with advanced cancer, discussion about prognosis and early integration of palliative care can have a profound impact on the quality of life. Effective communication between healthcare providers and patients is important in aligning treatment recommendations with patient goals and preferences throughout cancer therapy. This review provides a dynamic definition of health and proposes actionable guidelines for health promotion at any point along the cancer continuum: survivorship after early cancer or when goals of care transition to improve quality at the end of life. PMID- 28357163 TI - Radiographic Pearls in the Evaluation of an Extradural Thoracic Meningioma: A Case Report. AB - Spinal meningiomas are the most common of adult spinal tumors. Spinal meningiomas account for up to 45% of all intradural spinal tumors in adults and up to 25% of all spinal tumors. While spinal meningiomas are traditionally classified as intradural lesions, up to 14% may have an extradural component. Preoperative evaluation and directed use of imaging techniques are key in these rare but observed cases, to accurately diagnose and direct therapy. In this report, the authors present a case of a 61-year-old female with an incidentally found, exclusively extradural thoracic meningioma treated with surgical resection, highlighting key radiographic pearls in the evaluation of these uncommon lesions. PMID- 28357165 TI - Persistent Afebrile Abdominal Pain: An Unusual Case of Segmental Colitis in an Immunocompromised Host. AB - : In this report we describe a case of a 66-year-old woman who presented with right upper quadrant abdominal pain and bloody diarrhea. A workup revealed immunodeficiency, an immunologic profile with low complement levels resembling systemic lupus erythematosus, and a circumferential colonic wall lesion located in the ascending colon. After endoscopy and biopsy, the mass lesion was attributed to "double hit" diffuse large B-cell lymphoma, categorized as high grade large B-cell non-Hodgkin lymphoma according to the most recent revised 2016 World Health Organisation classification and considered to be a rare and highly aggressive tumor. The diagnosis of colonic lymphoma can be challenging due to a diversity of clinical presentation and requires a high index of suspicion. As the literature of such documented reports is limited, this case suggests further investigations. ABBREVIATIONS: GI: gastrointestinal tract, DLBCL: diffuse large B cell lymphoma, DH: double hit lymphoma, SLE: systemic lupus erythematosus, ANA: antinuclear antibodies, anti-ssDNA: anti-single-stranded DNA, BCL: B-cell lymphoma protein, MUM-1/IRF4: multiple myeloma oncogene 1/interferon regulatory factor 4, HGBL: high grade B-cell lymphoma, anti-dsDNA: anti-double-stranded DNA. PMID- 28357164 TI - Subdural Thoracolumbar Spine Hematoma after Spinal Anesthesia: A Rare Occurrence and Literature Review of Spinal Hematomas after Spinal Anesthesia. AB - Spinal hematomas are a rare but serious complication of spinal epidural anesthesia and are typically seen in the epidural space; however, they have been documented in the subdural space. Spinal subdural hematomas likely exist within a traumatically induced space within the dural border cell layer, rather than an anatomical subdural space. Spinal subdural hematomas present a dangerous clinical situation as they have the potential to cause significant compression of neural elements and can be easily mistaken for spinal epidural hematomas. Ultrasound can be an effective modality to diagnose subdural hematoma when no epidural blood is visualized. We have reviewed the literature and present a full literature review and a case presentation of an 82-year-old male who developed a thoracolumbar spinal subdural hematoma after spinal epidural anesthesia. Anticoagulant therapy is an important predisposing risk factor for spinal epidural hematomas and likely also predispose to spinal subdural hematomas. It is important to consider spinal subdural hematomas in addition to spinal epidural hematomas in patients who develop weakness after spinal epidural anesthesia, especially in patients who have received anticoagulation. PMID- 28357162 TI - Health, Health Care, and Systems Science: Emerging Paradigm. AB - Health is a continuum of an optimized state of a biologic system, an outcome of positive relationships with the self and others. A healthy system follows the principles of systems science derived from observations of nature, highlighting the character of relationships as the key determinant. Relationships evolve from our decisions, which are consequential to the function of our own biologic system on all levels, including the genome, where epigenetics impact our morphology. In healthy systems, decisions emanate from the reciprocal collaboration of hippocampal memory and the executive prefrontal cortex. We can decide to change relationships through choices. What is selected, however, only represents the cognitive interpretation of our limited sensory perception; it strongly reflects inherent biases toward either optimizing state, making a biologic system healthy, or not. Health or its absence is then the outcome; there is no inconsequential choice. Public health effort should not focus on punitive steps (e.g. taxation of unhealthy products or behaviors) in order to achieve a higher level of public's health. It should teach people the process of making healthy decisions; otherwise, people will just migrate/shift from one unhealthy product/behavior to another, and well-intended punitive steps will not make much difference. Physical activity, accompanied by nutrition and stress management, have the greatest impact on fashioning health and simultaneously are the most cost-effective measures. Moderate-to-vigorous exercise not only improves aerobic fitness but also positively influences cognition, including memory and senses. Collective, rational societal decisions can then be anticipated. Health care is a business system principally governed by self-maximizing decisions of its components; uneven and contradictory outcomes are the consequences within such a non optimized system. Health is not health care. We are biologic systems subject to the laws of biology in spite of our incongruous decisions that are detrimental to health. A biologic system/a human body originates from structural, deterministic genes as well as shared epigenetic memory of our ancestors affecting our bodily function and structure. The political governing systems' vertical hierarchy has control over money and laws, neither of which materially affect individual lifestyle/behavioral choices toward health. Improved health comes from focusing on enhancing the biologic age and not the chronologic one, which simply represents a linear time from a birth certificate to a death certificate and is applicable only in its extremes. "Age-related diseases" are simply reflections of a given culture. Biologic age, reflecting the actual state of health, could be used in all health-related assessments including health-life insurance premiums, licensing of job categories, etc., all with a broader and healthy societal impact. PMID- 28357167 TI - A Case Series of Bee Sting Keratopathy With Different Outcomes in Malaysia. AB - We report three patients with corneal bee sting at our tertiary care center in a three-year period starting from 2014 to 2016. All patients sustained a bee sting injury to the cornea. All patients received early preoperative topical antibiotics, topical cycloplegic and intensive topical steroids. However, the timing of the initial presentation, the duration, and the location of the retained stinger differed in each case leading to different postsurgical outcomes. PMID- 28357166 TI - Spontaneous Intracranial Hypotension Presenting as a "Pseudo-Chiari 1. AB - Spontaneous intracranial hypotension (SIH) is classified as a decrease in cerebrospinal fluid (CSF) pressure secondary to a CSF leakage and consequent descent of the brain into the foramen magnum. Diagnosing SIH can be difficult due to its overlapping findings with Arnold-Chiari type 1 Malformation (CM1) where the cerebellar tonsils herniate into the foramen magnum. The similarity of both conditions calls for a more reliable imaging technique to localize the CSF leak which could narrow the differential diagnosis and aid in choosing the correct treatment. Here, we present a case of a 28-year-old female, ten weeks post-partum with symptoms similar to SIH. MRI of the brain was remarkable for tonsillar herniation below the foramen magnum. Literature was reviewed for additional neuroradiology techniques that would aid in narrowing our differential diagnosis. Interestingly, computed tomography-, digital subtraction-, and magnetic resonance myelography with intrathecal gadolinium are the preferred techniques for diagnosis of high flow and low flow CSF leaks, respectively. These modalities further aid in choosing the correct treatment while avoiding complications. Literature suggests that treatment for CM1 involves posterior fossa decompression, whereas the mainstay of treatment for SIH involves an epidural blood patch (EBP). Thus, our patient was treated with an EBP and recovered without complication. PMID- 28357168 TI - Giant Osteolipoma Fixed to the Greater Trochanter of the Femur in a Seventy-Year Old Elderly Woman. AB - A lipoma containing mature osseous elements is called osteolipoma. This article describes a giant osteolipoma fixed to the periosteum of the greater trochanter of the femur. A seventy-year-old woman presented with a large subcutaneous mass in the right buttock which had been present for six years. On local examination, a giant mass that was ovoid, firm, non-tender, well demarcated, subcutaneous, and relatively fixed to the greater trochanter was palpated in the right buttock. A medical imaging and fluoro-deoxy-glucose (FDG) bone scan revealed a large lipomatous and metabolically active lesion arising from the periosteum of the greater trochanter of femur. The excisional mass of 17 * 8 * 7 cm3 was well encapsulated and had an osseous basal portion. Cut sections of the mass revealed mainly yellow fatty tissue surrounded by a thin fibrous capsule with numerous interlacing thin lamellar bony structures. The definitive pathological diagnosis was osteolipoma without evidence of malignancy. No recurrence was observed at eight months follow-up. Osteolipoma with an osseous basal portion is rare. Surgical excision is the treatment of choice and the prognosis is good. To the best of our knowledge, this is the first report of an unusual giant osteolipoma fixed to the periosteum of the greater trochanter of the femur. PMID- 28357169 TI - Low-profile Visualized Intraluminal Support Junior Device for the Treatment of Intracranial Aneurysms. AB - OBJECTIVE: Early case series suggest that the recently introduced Low-profile Visualized Intraluminal Support Junior (LVIS Jr.) device (MicroVention-Terumo, Inc., Tustin, CA) may be used to treat wide-necked aneurysms that would otherwise require treatment with intrasaccular devices or open surgery. We report our single-center experience utilizing LVIS Jr. to treat intracranial aneurysms involving 1.8-2.5 mm parent arteries. METHODS: We retrospectively reviewed records of patients treated with the LVIS Jr. device for intracranial aneurysms at a single center. A total of 21 aneurysms were treated in 18 patients. Aneurysms were 2-25 mm in diameter; one was ruptured, while three had recurred after previous rupture and treatment. Lesions were distributed across the anterior (n=12) and posterior (n=9) circulations. Three were fusiform morphology. RESULTS: Stent deployment was successful in 100% of cases with no immediate complications. Seventeen aneurysms were treated with stent-assisted coil embolization resulting in immediate complete occlusion in 94% of cases. Two fusiform aneurysms arising from the posterior circulation were further treated with elective clip ligation after delayed expansion and recurrence; no lesions required further endovascular treatment. Four aneurysms were treated by flow diversion with stand-alone LVIS Jr. stent, and complete occlusion was achieved in three cases. Small foci of delayed ischemic injury were noted in two patients in the setting of antiplatelet medication noncompliance. No in-stent stenosis, migration, hemorrhage, or permanent deficits were observed. Good functional outcome based on the modified Rankin Scale score (mRS <= 2) was achieved in 100% of cases. CONCLUSION: Our midterm results suggest that the LVIS Jr. stent may be used for a variety of intracranial aneurysms involving small parent arteries (1.8 2.5 mm) with complete angiographic occlusion, parent vessel preservation, and functional clinical outcomes. This off-label expansion would increase the number of aneurysms amenable to endovascular treatment. Future studies may build upon our experiences with flow diversion and treatment of complex or multiple lesions. PMID- 28357170 TI - Does Vitamin D Deficiency Lead to Hypertension? AB - Hypertension (HTN) or high blood pressure is one of the most chronic and deadliest disorders in the world. There are many risk factors responsible for HTN which include age, race, using tobacco, high salt intake, etc. One of the risk factors we would like to highlight is low vitamin D levels. While there is strong evidence that Vitamin D plays an important role in maintaining bone and muscle health, there has been recent debate regarding its role in hypertension. However, there are many studies that have shown an indirect relation between 25 hydroxyvitamin D serum level and blood pressure. However, we suggest that more studies, especially randomised trials, should be conducted. PMID- 28357171 TI - Value-Based Care in the Worldwide Battle Against Cancer. AB - Globally, an increasing and aging population is contributing to the prevalence of cancer. To be effective, cancer care needs to involve the coordination of multidisciplinary specialties, and also needs to be affordable, accessible, and capable of producing optimal patient outcomes. Porter and Teisberg (2006) have postulated that shifting current healthcare strategies from volume-based to patient-centric care redirects economic competition to providing treatments which promote the best patient outcomes while driving down costs. Therefore, the value in value-based healthcare (VBH) is defined as patient outcome per currency spent on providing care. Based on the experiences of healthcare organizations currently transitioning to the value-based system, this review details actionable guidelines to transition current cancer care practices to the value-based system in four main steps: by defining universal clinical and patient-reported measures, creating cancer-specific units that provide the full care cycle, establishing a data capture model to routinely determine the value of the care delivered, and continually improving treatment strategies through research. As healthcare providers in more developed countries move to value-based care, those located in less developed countries should also be assisted in their transition to relieve the cancer burden globally. PMID- 28357173 TI - Status Epilepticus and Blindness in a Patient with Carfilzomib-Associated Posterior Reversible Encephalopathy Syndrome. AB - Posterior reversible encephalopathy syndrome (PRES) is a neurological condition characterized by headaches, visual disturbances, and seizures. A magnetic resonance imaging (MRI) scan of an affected brain typically shows symmetrical white matter edema in the posterior cerebral hemispheres. The onset of PRES can constitute a medical emergency, especially when accompanied by status epilepticus. If promptly recognized and treated, the clinical syndrome and associated radiological findings are usually resolved in a matter of weeks or months. Carfilzomib is a proteasome inhibitor that is newly approved for relapsing myeloma in a patient who has received one or more lines of therapy. In this paper, we report on a 52-year-old female on carfilzomib for multiple myeloma who developed PRES following her second dose of treatment. She was admitted for chronic obstructive pulmonary disease (COPD) exacerbation, and while she was in the hospital, she developed a severe headache, blindness, and status epilepticus. A brain MRI showed signs consistent with PRES. After carfilzomib was discontinued, her symptoms resolved within three days. Unfortunately, the patient passed away shortly after being discharged, so there was no opportunity to perform a repeat MRI. PMID- 28357172 TI - The Use of WhatsApp Smartphone Messaging Improves Communication Efficiency within an Orthopaedic Surgery Team. AB - INTRODUCTION: Effective and timely communication is important for any surgical specialty to function. The use of smartphones is prevalent amongst doctors. Numerous smartphone applications offer the potential for fast and cost-effective communication. WhatsApp is a commonly used application that is free, easy to use, and capable of text and multimedia messaging. We report on the use of WhatsApp over a six month period in our unit. MATERIALS AND METHODS: WhatsApp communication between non-consultant members of an orthopaedic team over a six month period was analysed. Both the phones and the WhatsApp application were password-protected, and patient details were anonymised. A series of 20 communications using the hospital pager system and the telephone system were also analysed. RESULTS: A total of 5,492 messages were sent during the six-month period and were part of 1,916 separate communication events. The vast majority of messages, 5,090, were related to patient care. A total of 195 multimedia messages were sent and these included images of radiographs and wounds. When using the hospital telephones, the length of time spent on a communication averaged 5.78 minutes and using the hospital pager system averaged 7.45 minutes. Using the WhatsApp messaging system has potentially saved up to 7,664 minutes over the study period. All participants found WhatsApp easy to use and found it to be more efficient than the traditional pager system Conclusion: Compared to the traditional pager systems, the use of WhatsApp is easy, inexpensive, and reliable and can help improve the efficiency of communication within a surgical team. PMID- 28357174 TI - Production mechanisms of leptons, photons, and hadrons and their possible feedback close to lightning leaders. AB - It has been discussed that lightning flashes emit high-energy electrons, positrons, photons, and neutrons with single energies of several tens of MeV. In the first part of this paper we study the absorption of neutron beams in the atmosphere. We initiate neutron beams of initial energies of 350 keV, 10 MeV, and 20 MeV at source altitudes of 4 km and 16 km upward and downward and see that in all these cases neutrons reach ground altitudes and that the cross-section areas extend to several km2. We estimate that for terrestrial gamma-ray flashes approximately between 10 and 2000 neutrons per ms and m2 are possibly detectable at ground, at 6 km, or at 500 km altitude. In the second part of the paper we discuss a feedback model involving the generation and motion of electrons, positrons, neutrons, protons, and photons close to the vicinity of lightning leaders. In contrast to other feedback models, we do not consider large-scale thundercloud fields but enhanced fields of lightning leaders. We launch different photon and electron beams upward at 4 km altitude. We present the spatial and energy distribution of leptons, hadrons, and photons after different times and see that leptons, hadrons, and photons with energies of at least 40 MeV are produced. Because of their high rest mass hadrons are measurable on a longer time scale than leptons and photons. The feedback mechanism together with the field enhancement by lightning leaders yields particle energies even above 40 MeV measurable at satellite altitudes. PMID- 28357175 TI - Innovative measures to combat rare diseases in China: The national rare diseases registry system, larger-scale clinical cohort studies, and studies in combination with precision medicine research. AB - China is facing the great challenge of treating the world's largest rare disease population, an estimated 16 million patients with rare diseases. One effort offering promise has been a pilot national project that was launched in 2013 and that focused on 20 representative rare diseases. Another government-supported special research program on rare diseases - the "Rare Diseases Clinical Cohort Study" - was launched in December 2016. According to the plan for this research project, the unified National Rare Diseases Registry System of China will be established as of 2020, and a large-scale cohort study will be conducted from 2016 to 2020. The project plans to develop 109 technical standards, to establish and improve 2 national databases of rare diseases - a multi-center clinical database and a biological sample library, and to conduct studies on more than 50,000 registered cases of 50 different rare diseases. More importantly, this study will be combined with the concept of precision medicine. Chinese population specific basic information on rare diseases, clinical information, and genomic information will be integrated to create a comprehensive predictive model with a follow-up database system and a model to evaluate prognosis. This will provide the evidence for accurate classification, diagnosis, treatment, and estimation of prognosis for rare diseases in China. Numerous challenges including data standardization, protecting patient privacy, big data processing, and interpretation of genetic information still need to be overcome, but research prospects offer great promise. PMID- 28357178 TI - From promising molecules to orphan drugs: Early clinical drug development. AB - Phase-1 (also known as "First-in-Man") clinical trials initiate the early clinical development of possible new medicines. Patient participation in this early phase of clinical trials is rather limited. After successful phase 1 trials, further phase 2 and phase 3 clinical trials in patients may lead to a marketing authorization. In the first 15 years of the European Union Orphan Drug Directive, 4.5% of the orphan drug applications were authorized. However, for many of these orphan drugs, no phase 1 studies were required, as these products were already well known pharmaceutical substances, with a clearly defined pharmacological profile. Furthermore, for 19 orphan drugs, already authorized by the European Medicines Agency (EMA), the original rare indication was extended to another rare disease and no phase 1 trials were needed. Phase 1 studies need to be performed in a sufficient number of volunteers even for medicinal products intended for a very limited number of patients. PMID- 28357177 TI - Pancreatic neuroendocrine tumors. AB - Pancreatic neuroendocrine neoplasms (pNENs) are a heterogeneous group of tumors including well differentiated pancreatic neuroendocrine tumors (pNETs) and neuroendocrine carcinomas (pNECs). The incidence of pNENs has increased over the past few decades. Although, the understanding and interest for this tumor have also increased significantly, the debate about classification and diagnosis continues. Although the primary treatment for pNENs is surgical resection, there is still a lack of effective therapeutic options for patients with advanced unresectable pNENs. Although many therapeutic methods have proven effective, the choice of treatment and specific programs are still unclear. Our article presents an overview of pNENs, with a focus on their diagnostic work-up, clinical presentation and treatment options. PMID- 28357176 TI - Novel and emerging therapies in the treatment of recessive dystrophic epidermolysis bullosa. AB - Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of inherited blistering diseases that affects ~ 500,000 people worldwide. Clinically, individuals with EB have fragile skin and are susceptible to blistering following minimal trauma, with mucous membrane and other organ involvement in some subtypes. Within the spectrum of EB, ~ 5% of affected individuals have the clinically more severe recessive dystrophic (RDEB) variant with a prevalence of 8 per one million of the population. RDEB is caused by loss of-function mutations in the type VII collagen gene, COL7A1, which leads to reduced or absent type VII collagen (C7) and a paucity of structurally effective anchoring fibrils at the dermal-epidermal junction (DEJ). Currently, there is no cure for RDEB, although considerable progress has been made in testing novel treatments including gene therapy (lentiviral and gamma retroviral vectors for COL7A1 supplementation in keratinocytes and fibroblasts), as well as cell therapy (use of allogeneic fibroblasts, mesenchymal stromal cells (MSCs), and bone marrow transplantation (BMT)). Here, we review current treatment modalities available as well as novel and emerging therapies in the treatment of RDEB. Clinical trials of new translational therapies in RDEB offer hope for improved clinical management of patients as well as generating broader lessons for regenerative medicine that could be applicable to other inherited or acquired abnormalities of wound healing or scarring. PMID- 28357179 TI - Interferon-stimulated gene 20-kDa protein (ISG20) in infection and disease: Review and outlook. AB - Interferon-stimulated exonuclease gene 20 (ISG20) is an RNA exonuclease in the yeast RNA exonuclease 4 homolog (REX4) subfamily and the DEDDh exonuclease family, and this gene codes for a 20-kDa protein. Those exonucleases are involved in cleaving single-stranded RNA and DNA. ISG20 is also referred to as HEM45 (HeLa estrogen-modulated, band 45). Expression of ISG20 can be induced or regulated by both type I and II interferons (IFNs) in various cell lines. ISG20 plays a role in mediating interferon's antiviral activities. In addition, ISG20 may be a potential susceptibility biomarker or pharmacological target in some inflammatory conditions. Exonucleases are useful components of many physiological processes. Despite recent advances in our understanding of the functions of ISG20, much work remains to be done with regard to uncovering the mechanism of action of ISG20 in specific diseases and adapting ISG20 for use as a biomarker of disease. This review describes current information on ISG20 and its potential use in marking disease. This review describes several research achievements thus far and it seeks to provide some new ideas for future related research. PMID- 28357180 TI - Diagnosis and treatment of Dent disease in 10 Chinese boys. AB - Dent disease is a rare X-linked recessive proximal tubular disorder that affects mostly male patients in childhood or early adult life. Dent disease is clinically characterized by the presence of low molecular weight proteinuria (LMWP), hypercalciuria, medullary nephrocalcinosis, nephrolithiasis, and progressive renal failure. The clinical features, diagnosis, and treatment of Dent disease were examined in 10 Chinese boys. All 10 childhood cases of Dent disease in China presented with tubular proteinuria in the nephrotic range and hypercalciuria. The ratio of alpha1-microglobulinuria to microalbuminuria, if close to or above 1, can be used as a diagnostic criterion for tubuloproteinuria. Lotensin was ineffective at treating proteinuria while dihydrochlorothiazide reduced urine calcium excretion. PMID- 28357181 TI - Prevalence of vestibular symptoms in individuals with auditory neuropathy spectrum disorder - A retrospective study. AB - The objective of the study was to retrospectively determine the prevalence of vestibular symptoms in individuals with auditory neuropathy spectrum disorder (ANSD). It was also attempted to determine the prevalence of vestibular symptoms and factors (gender and age of reported hearing loss) that could affect the prevalence in individuals with ANSD. The vestibular symptoms reported in the case history were analyzed in individuals diagnosed with ANSD. The symptoms reported by a total of 316 individuals (185 females and 131 males) with ANSD were analyzed. The result of the study showed that one in five individuals with ANSD reported at least one of the vestibular symptom. The vestibular symptoms were in more females and in individuals with earlier onset of hearing loss. The result of the study supports that there is a vestibular damage in individuals with ANSD. However, it is essential to carry out prospective studies validating these vestibular symptoms with objective vestibular tests before generalizing the results. PMID- 28357182 TI - Expression of GPR17, a regulator of oligodendrocyte differentiation and maturation, in Nasu-Hakola disease brains. AB - The G protein-coupled receptor 17 (GPR17), a Gi-coupled GPCR, acts as an intrinsic timer of oligodendrocyte differentiation and myelination. The expression of GPR17 is upregulated during differentiation of oligodendrocyte precursor cells (OPCs) into premyelinating oligodendrocytes (preoligodendrocytes), whereas it is markedly downregulated during terminal maturation of myelinating oligodendrocytes. Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder caused by a loss-of-function mutation of either TYROBP (DAP12) or TREM2. Pathologically, the brains of NHD patients exhibit extensive demyelination designated leukoencephalopathy, astrogliosis, accumulation of axonal spheroids, and activation of microglia predominantly in the white matter of frontal and temporal lobes. Although GPR17 is a key regulator of oligodendrogenesis, a pathological role of GPR17 in NHD brains with relevance to development of leukoencephalopathy remains unknown. We studied the expression of GPR17 in five NHD brains and eight control brains by immunohistochemistry. We identified GPR17-immunoreactive preoligodendrocytes with a multipolar ramified morphology distributed in the white matter and the grey matter of all cases examined. However, we did not find statistically significant differences in the number of GPR17-expressing cells between NHD and control brains both in the white matter and the grey matter due to great variability from case to case. These observations do not support the view that GPR17-positive preoligodendrocytes play a central role in the development of leukoencephalopathy in NHD brains. PMID- 28357183 TI - Tuberculosis and Guillain-Barre syndrome: A chance association? AB - An 18-year-old boy presented with acute-onset quadriparesis that had developed 4 weeks prior. He had an intermittent fever and significant weight loss during this period. After extensive investigations, the patient was diagnosed with an acute motor and sensory axonal neuropathy (AMSAN) variant of Guillain-Barre syndrome (GBS) and disseminated tuberculosis with mediastinal lymphadenopathy, pericarditis, and pleural effusion. Plasmapheresis was performed and first-line anti-tubercular therapy was administered. At the follow-up at 6 months, the patient was asymptomatic, he had no residual weakness and could walk without support, and tuberculosis had completely resolved on X-rays. Many infectious agents have been known to trigger GBS, but only a few cases of GBS and tuberculosis have been reported. This association needs to be evaluated further. PMID- 28357184 TI - Gomez-Lopez-Hernandez syndrome: First reported case from the Indian subcontinent. AB - Gomez-Lopez-Hernandez syndrome (GLHS) is a rare neurocutaneous syndrome characterized by a triad of findings: partial alopecia of the scalp, trigeminal anaesthesia, and rhombencephalosynapsis. GLHS is also known as cerebello trigeminal-dermal dysplasia. Besides this triad, a number of varying traits have been described in 35 previously reported cases. Reported here is a case of a four year-old boy, born out of consanguineous marriage, presenting with the classic triad of findings, i.e. partial alopecia of the scalp, trigeminal anaesthesia, and rhombencephalosynapsis. To the extent known, this is the first case of GLHS reported from India. If a child presents with alopecia and rhom bencephalosynapsis, GLHS should be considered in the differential diagnosis. A host of studies can be used to determine the exact pathogenesis, and confirming the diagnosis of GLHS is an important step in prenatal testing for at-risk pregnancies. PMID- 28357185 TI - Microdeletion of chromosome 1q21.3 in fraternal twins is associated with mental retardation, microcephaly, and epilepsy. AB - Reported here are twins, both of whom have a 1q21.3 microdeletion and who exhibit key features common to previously reported cases such as microcephaly and developmental delay. However, some clinical findings and deleted genes differed from those in previously reported cases. The karyotype was normal 46, XX for both of the twins. Array comparative genomic hybridization (CGH) identified a 2.6 Mb deletion on chromosome 1q21.3 (chr1: 153,514,121-156,171,335 bp) in case 1 and a 1.6 Mb deletion on chromosome 1q21.3 (chr1: 154,748,365-156,358,923 bp) in case 2. The deleted region includes DPM3, MUC1, GBA, PKLR, RIT1, and LAMTOR2 in both siblings. To the extent known, this is the second report of a 1q21.3 microdeletion in a family with mental retardation, developmental delay, seizures, and some dysmorphic features, thus expanding the phenotypic spectrum. PMID- 28357187 TI - Thrombocytosis in a patient with upper gastrointestinal bleeding. AB - Reported here is a case of upper gastrointestinal bleeding secondary to a peptic ulcer involving an extremely high platelet count of 989 * 109/L. Myeloproliferative neoplasms were ruled out on the basis of gene mutation testing and a bone marrow biopsy. After the cessation of index bleeding, the platelet count decreased markedly. Thus, reactive thrombocytosis was considered as a possibility. PMID- 28357186 TI - Lesch-Nyhan syndrome: The saga of metabolic abnormalities and self-injurious behavior. AB - Lesch-Nyhan syndrome (LNS) is an X-linked recessive disorder of purine metabolism caused by a mutation in Xq26.2-q26.3 (OMIM 308000.0004). The presence of the diagnostic triad, i.e. signs of self-injurious behavior (SIB) and results of pedigree analysis and novel molecular biology & genetic testing, confirms the diagnosis of LNS. With a level of hypoxanthine guanine phosphoribosyl-transferase 1 (HPRT1) enzyme activity < 2%, patients develop neurological, neurocognitive, and neuromotor symptoms along with SIB. Described here is a case of 4-year-old boy who was diagnosed with LNS. The boy displayed SIB, i.e. biting of the lips and fingers, and he had cerebral venous sinus thrombosis caused by LNS. PMID- 28357188 TI - Audiological findings from an adult with thin cochlear nerves. AB - Reported here are audiological findings from an adult with thin cochlear nerves. Magnetic resonance imaging (MRI) revealed that he had a thinner cochlear nerve in the left ear than in the right ear. He had a higher degree of hearing loss in the left ear and poor speech recognition scores for both ears. He had normal middle ear and cochlear functioning. The auditory brainstem response and acoustic reflexes were absent, indicating a retrocochlear pathology. Long latency responses (LLR) revealed normal cortical functioning. Hence, implantation of an auditory brainstem implant might be an option, but the patient would need to be aware of its limitations. This case highlights the importance of MRI in evaluating congenital malformations of the cochlear nerve when audiological findings indicate a retrocochlear pathology. PMID- 28357189 TI - Griscelli syndrome subtype 2 with hemophagocytic lympho-histiocytosis: A case report and review of literature. AB - Griscelli syndrome (GS) is a rare autosomal recessive disorder resulting in pigmentary dilution of the skin and hair with variable phenotypes depending upon subtypes. Mutations in 3 distinct genes MYO5A, RAB27A, MLPH are responsible for 3 subtypes (GS1, GS2, and GS3) of GS respectively. GS subtype 2 commonly develops hemophagocytic lymphohistiocytosis (HLH) and recurrent infections due to immunodeficiency. We hereby report a 20 month old male child presenting with silvery gray hair, hypomelanosis and features of hemophagocytosis. The diagnosis of a type 2 GS was made in response to a set of clinical features: hypopigmentation of skin and the silvered reflection of the hair, absence of psychomotor retardation, the occurrence of an accelerated phase (hemophagocytosis) and, above all, a pathognomonic appearance by microscopic examination of a hair. The absence of giant granules in the nucleated cells made it possible to eliminate Chediak-Higashi syndrome, which shares a close clinical spectrum with GS. This case promotes awareness about this rare case of GS as a high indicator of suspicion about this potentially fatal condition and aids in prompt diagnosis and foresees complications. Early bone marrow transplant is the only curative treatment for GS-2. PMID- 28357190 TI - Investigating country-specific music preferences and music recommendation algorithms with the LFM-1b dataset. AB - Recently, the LFM-1b dataset has been proposed to foster research and evaluation in music retrieval and music recommender systems, Schedl (Proceedings of the ACM International Conference on Multimedia Retrieval (ICMR). New York, 2016). It contains more than one billion music listening events created by more than 120,000 users of Last.fm. Each listening event is characterized by artist, album, and track name, and further includes a timestamp. Basic demographic information and a selection of more elaborate listener-specific descriptors are included as well, for anonymized users. In this article, we reveal information about LFM-1b's acquisition and content and we compare it to existing datasets. We furthermore provide an extensive statistical analysis of the dataset, including basic properties of the item sets, demographic coverage, distribution of listening events (e.g., over artists and users), and aspects related to music preference and consumption behavior (e.g., temporal features and mainstreaminess of listeners). Exploiting country information of users and genre tags of artists, we also create taste profiles for populations and determine similar and dissimilar countries in terms of their populations' music preferences. Finally, we illustrate the dataset's usage in a simple artist recommendation task, whose results are intended to serve as baseline against which more elaborate techniques can be assessed. PMID- 28357191 TI - Psychiatric Co-Morbidities in Pregnant Women with Opioid Use Disorders: Prevalence, Impact, and Implications for Treatment. AB - PURPOSE OF REVIEW: This review seeks to investigate three questions: What is the prevalence of comorbid psychiatric diagnoses among pregnant women with opioid use disorder (OUD)? How do comorbid psychiatric illnesses impact pregnant women with OUD? And how do comorbid psychiatric illnesses affect the ability of pregnant women with OUD to adhere to and complete OUD treatment? RECENT FINDINGS: Based on this literature review, 25-33% of pregnant women with OUD have a psychiatric comorbidity, with depression and anxiety being especially common. However, of the 17 studies reviewed only 5 have prevalence rates of dual diagnosis in pregnant women with OUD as their primary outcome measures, their N's were typically small, methods for determining psychiatric diagnosis were variable, and many of the studies were undertaken with women presenting for treatment which carries with its implicit selection bias. Of the women enrolled in treatment programs for SUD, those with psychiatric comorbidity were more likely to have impaired psychological and family/social functioning than those without psychiatric comorbidity. Greater severity of comorbid psychiatric illness appears to predict poorer adherence to treatment, but more research is needed to clarify this relationship with the psychiatric illness is less severe. SUMMARY: While cooccurrence of psychiatric disorders in pregnant women with opioid use disorder appears to be common, large population-based studies with validated diagnostic tools and longitudinal assessments are needed to obtain definitive rates and characteristics of cooccurring illnesses. Integrated prenatal, addiction, and psychiatric treatment in a setting that provides social support to pregnant patients with OUD is most effective in maintaining women in treatment. More research is still needed to identify optimal treatment settings, therapy modalities, and medication management for dually diagnosed pregnant women with OUD. PMID- 28357194 TI - Alcohol health warnings can influence the speed of consumption. AB - AIM: Recent research has shown that adopting strong (i.e. high fear) visual health-warning messages can increase the perceived health risks and intentions to reduce alcohol consumption. Separately, it is known that the speed at which alcohol is consumed has dramatic effects on the level of intoxication. In the present study we aimed to combine these two separate areas to understand whether the speed of alcohol consumption is influenced by the type of alcohol health warning contained on the beverage. SUBJECT AND METHODS: In the present study, female participants (N = 45) consumed an alcoholic beverage in a relaxed environment in one of three conditions: no health-warning label, a text-only health-warning label or a pictorial health-warning label with text. RESULTS: We found that compared with the control condition, the beverage was consumed at a slower rate in the two health-warning conditions, which surprisingly did not differ from each other. Despite these effects, product acceptability did not differ between the text-only and control conditions. CONCLUSION: These are the first set of results to demonstrate how the use of strong health warnings on alcoholic beverages can influence actual drinking rate and further suggest that the beneficial effects of slowed consumption are possible in the absence of any reduction in consumer acceptability. PMID- 28357195 TI - Causes of variability in prevalence rates of communicable diseases among secondary school Students in Kisumu County, Kenya. AB - PURPOSE: To determine causes of variability in communicable disease prevalence rates among students in secondary schools to inform policy formulation in the public health sector. METHODS: A representative cluster sample size for students was estimated using Fisher et al.'s formula while schools, sub-counties and education zones were clustered and sample size was calculated based on coefficient of variation by school type. Data were collected by questionnaire, medical examination using standard procedures, and focus group discussion, and descriptive analysis was performed on the completed questions. Comparisons between risk factors were made by chi-square and ANOVA analysis using SPSS for Windows (version 15.2; Chicago, IL) software. A p value of < 0.05 was considered statistically significant. RESULTS: There was significant variation between communicable disease prevalence rates and age (X24, 0.05 = 2.458), school size (X212, 0.05 = 18.636), gender (X24, 0.05 = 5.723) and class of students (X212, 0.05 = 15.202), and bed and desk spacing (p < 0.05 at 95% CI). However, there was no significant association in prevalence rates between both locality and type of school. There was strong evidence that student age has an effect on prevalence rates. The prevalence rate of malaria was higher in male (14.02%) than female students (6.68%) compared to prevalence of diarrhea, which was higher in female (7.96%) than male students. CONCLUSION: This study has revealed that the prevalences of diarrhea, tuberculosis, pneumonia and other respiratory tract infections are lower among female secondary school students than males and that the prevalence of malaria is higher in males than females. Age of secondary school students is a significant vulnerability factor for malaria, diarrhea, tuberculosis and pneumonia, which were the important communicable diseases most prevalent among secondary school students in Kisumu County, Kenya. PMID- 28357193 TI - What Is Trained During Food Go/No-Go Training? A Review Focusing on Mechanisms and a Research Agenda. AB - PURPOSE OF REVIEW: During food go/no-go training, people consistently withhold responses toward no-go food items. We discuss how food go/no-go training may change people's behavior toward no-go food items by comparing three accounts: (a) the training strengthens 'top-down' inhibitory control over food-related responses, (b) the training creates automatic 'bottom-up' associations between no go food items and stopping responses, and (c) the training leads to devaluation of no-go food items. RECENT FINDINGS: Go/no-go training can reduce intake of food and choices for food and facilitate short-term weight loss. It appears unlikely that food go/no-go training strengthens top-down inhibitory control. There is some evidence suggesting the training could create automatic stop associations. There is strong evidence suggesting go/no-go training reduces evaluations of no go food items. SUMMARY: Food go/no-go training can change behavior toward food and evaluation of food items. To advance knowledge, more research is needed on the underlying mechanisms of the training, the role of attention during go/no-go training, and on when effects generalize to untrained food items. PMID- 28357196 TI - Health literacy of patients admitted for elective surgery. AB - AIM: Patients with limited health literacy have poorer surgical outcomes. However, current studies assessing the prevalence of limited health literacy in patients expecting surgery are small scale. We aimed to provide insight into the health literacy level of patients undergoing planned surgery. SUBJECT AND METHODS: Patients aged >=18 years visiting the preoperative screening department were approached in the waiting area and invited to participate in a brief interview including the Functional Communicative Critical Health Literacy (FCCHL). RESULTS: In total, 225 patients (84.9% response) were studied. Based on the FCCHL, 37.3% of the patients were classified as having limited health literacy. The mean score in the critical domain (2.7 +/- 0.9) was lower than scores in the functional (3.3 +/- 0.6) and communicative (3.3 +/- 0.6) domains. CONCLUSION: More than one third of the patients admitted to the hospital for surgery had limited health literacy. Healthcare professionals should be aware of the different health literacy levels and tailor their information provision strategies accordingly. PMID- 28357192 TI - Psychopharmacology of Tobacco and Alcohol Comorbidity: a Review of Current Evidence. AB - PURPOSE OF THE REVIEW: Comorbidity of alcohol and tobacco use is highly prevalent and may exacerbate the health effects of either substance alone. However, the mechanisms underlying this comorbidity are not well understood. This review will examine the evidence for shared neurobiological mechanisms of alcohol and nicotine comorbidity and experimental studies of the behavioural consequences of these interactions. RECENT FINDINGS: Studies examining the shared neurobiology of alcohol and nicotine have identified two main mechanisms of comorbidity: (1) cross-reinforcement via the mesolimbic dopamine pathway and (2) cross-tolerance via shared genetic and nAChR interaction. Animal and human psychopharmacological studies demonstrate support for these two mechanisms of comorbidity. SUMMARY: Human behavioural studies indicate that (1) alcohol and tobacco potentiate each other's rewarding effects and (2) nicotine reduces the sedative and intoxication effects of alcohol. Together, these findings provide a strong evidence base to support the role of the cross-reinforcement and cross-tolerance as mechanisms underlying the comorbidity of alcohol and tobacco use. Methodological concerns in the literature and recommendations for future studies are discussed alongside implications for treatment of comorbid alcohol and tobacco use. PMID- 28357198 TI - Cyclic AMP-Induced p53 Destabilization is Independent of CREB in Pre-B Acute Lymphoblastic Leukemia Cells. AB - Elevated cAMP levels in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells attenuate the doxorubicin-induced p53 accumulation and protect cells against apoptosis. cAMP responsive element binding protein (CREB) is a cAMP stimulated transcription factor that regulates genes whose deregulated expression cooperate in oncogenesis. In the present study, we investigated the role of CREB on inhibitory effect of cAMP on apoptosis and p53 accumulation in BCP-ALL NALM-6 cells. To determine whether targeting CREB can modulate the effect of cAMP on doxorubicin-induced apoptosis, we knocked down CREB in NALM-6 cells using lentiviral CREB shRNA. Knocked down cells were treated with doxorubicin in the presence or absence of cAMP-elevating agents. p53 protein level and apoptosis were assessed by western blot analysis and flow cytometry, respectively. p53 protein expression was reduced in cells treated with combination of cAMP elevating agents and doxorubicin in contrast to cells treated with doxorubicin alone even in CREB-knocked down cells. Apoptosis assay showed that the cAMP elevating agents decreased doxorubicin-induced apoptosis in CREB-knocked down and control cells. Although, CREB plays a particularly important role in cAMP signaling pathway our data suggest that CREB does not mediate the inhibitory effect of cAMP on doxorubicin-induced apoptosis and p53 accumulation in BCP-ALL NALM-6 cells. PMID- 28357199 TI - A Comparison Between the Effect of Cuminum Cyminum and Vitamin E on the Level of Leptin, Paraoxonase 1, HbA1c and Oxidized LDL in Diabetic Patients. AB - Diabetes is one of the most common metabolic diseases in the world. Vitamin E reduces protein glycation and improves insulin sensitivity, while cumin is effective in remission of diabetes. Therefore this study was designed to evaluate the effects of vitamin E and cumin essential oil, on the blood level of leptin,glycosylated hemoglobin (HbA1C) and also on lipid profile in diabetic patients.In this double blind clinical trial, 95 diabetic patients were selected and randomly dividedinto three groups.The first group received cumin essential oil in capsule form. The second group received Vitamin E, and the third group was used ascontrol receiving oral gelatin capsules as placebo for three months period.Blood glucose, lipid profile, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), leptin, HbA1c, oxidized LDL (oxLDL), and paraoxonase1 activity were measured. The results showed reduction in oxLDL and significant increase in paraoxonase 1 in Vitamin E group by the end of the third month period (P<0.05). Cumin group showed decrease in blood glucose, HbA1C, triglyceride, leptin and ox LDL. ApoA1 and paraoxonase1 were also increased by cumin treatment (P<0.05).Diabetic complications may have been reduced by intake of Vitamin E and cumin essential oil. Cumin in comparison with vitamin E has broader impact and it is more beneficial in terms of ability to reduce the diabetic index. PMID- 28357197 TI - Bioinformatics Analysis Reveals Genes Involved in the Pathogenesis of Ameloblastoma and Keratocystic Odontogenic Tumor. AB - Pathogenesis of odontogenic tumors is not well known. It is important to identify genetic deregulations and molecular alterations. This study aimed to investigate, through bioinformatic analysis, the possible genes involved in the pathogenesis of ameloblastoma (AM) and keratocystic odontogenic tumor (KCOT). Genes involved in the pathogenesis of AM and KCOT were identified in GeneCards. Gene list was expanded, and the gene interactions network was mapped using the STRING software. "Weighted number of links" (WNL) was calculated to identify "leader genes" (highest WNL). Genes were ranked by K-means method and Kruskal-Wallis test was used (P<0.001). Total interactions score (TIS) was also calculated using all interaction data generated by the STRING database, in order to achieve global connectivity for each gene. The topological and ontological analyses were performed using Cytoscape software and BinGO plugin. Literature review data was used to corroborate the bioinformatics data. CDK1 was identified as leader gene for AM. In KCOT group, results show PCNA and TP53. Both tumors exhibit a power law behavior. Our topological analysis suggested leader genes possibly important in the pathogenesis of AM and KCOT, by clustering coefficient calculated for both odontogenic tumors (0.028 for AM, zero for KCOT). The results obtained in the scatter diagram suggest an important relationship of these genes with the molecular processes involved in AM and KCOT. Ontological analysis for both AM and KCOT demonstrated different mechanisms. Bioinformatics analyzes were confirmed through literature review. These results may suggest the involvement of promising genes for a better understanding of the pathogenesis of AM and KCOT. PMID- 28357201 TI - Should We Perform Semen Analysis, DNA Fragmentation, and Hypo-osmotic Swelling Tests together? AB - Semen analysis, sperm DNA fragmentation (SDF) and hypo-osmotic swelling test (HOST) are usually performed for the evaluation of sperm fertilizing ability. There are some debates over the necessity of SDF and HOST incorporation in male infertility work-up.Semen of 77 men was evaluated by SDF and HOST through three semen analyses. Sperm parameters were arranged into different categories: <5%, 5 15%, >15% for normal morphology; <50%, 50-70%, >70 % for motility; and <10, 10 20, 21-34, 35-50, >50 million/ml for concentration. SDF analysis was performed and values under 30% were assumed to be normal. Normal range of HOST was considered to be >60%.Only normal sperm morphology had significant relationship with DF rate (P<0.001). Normal morphology, motility, and concentration of sperms had significant relationship with HOST (P<0.001, 0.05, and <0.003,respectively). There was a significant negative correlation between sperm morphology and DF rate. The correlations between sperm parameters and percentage of HOST were significantly positive (r: 0.44, 0.19, and 0.32 for morphology, motility, and concentration, respectively). Receiver operating characteristic curve (ROC) showed that sperm morphology is a strong predictor of the rate of DF and HOST (accuracy: 0.74' and 0.81, respectively). The best sperm morphology cut off point for DF and HOST rate prediction was 4.5% and 5.5%, respectively.Sperm morphology had significant correlation with DF rate and HOST and is supposed to be a predictor for these tests. Performing these three tests collectively for evaluation of semen samples would not be necessarily required in all cases. PMID- 28357202 TI - A Novel Nonsense Mutation in PANK2 Gene in Two Patients with Pantothenate Kinase Associated Neurodegeneration. AB - Pantothenate kinase- associated neurodegeneration (PKAN) syndrome is a rare autosomal recessive disorder characterized by progressive extrapyramidal dysfunction and iron accumulation in the brain and axonal spheroids in the central nervous system. It has been shown that the disorder is caused by mutations in PANK2 gene which codes for a mitochondrial enzyme participating in coenzyme A biosynthesis. Here we report two cases of classic PKAN syndrome with early onset of neurodegenerative disorder. Mutational analysis has revealed that both are homozygous for a novel nonsense mutation in PANK2 gene (c.T936A (p.C312X)). The high prevalence of consanguineous marriages in Iran raises the likelihood of occurrence of autosomal recessive disorders such as PKAN and necessitates proper premarital genetic counseling. Further research is needed to provide the data on the prevalence of PKAN and identification of common PANK2 mutations in Iranian population. PMID- 28357200 TI - Analysis of Copy Number Variations in Patients with Autism Using Cytogenetic and MLPA Techniques: Report of 16p13.1p13.3 and 10q26.3 Duplications. AB - Autism is a common neuropsychiatric disorder affecting 1 in 68 children. Copy number variations (CNVs) are known to be major contributors of autism spectrum disorder (ASD). There are different whole genome or targeted techniques to identify CNVs in the patients including karyotyping, multiplex ligation-dependent probe amplification (MLPA) and array CGH. In this study, we used karyotyping and MLPA to detect CNVs in 50 Iranian patients with autism. GTG banding and 4 different MLPA kits (2 subtelomeric and 2 autism kits) were utilized. To elevate our detection rate, we selected the sporadic patients who had additional clinical features including intellectual disability, seizure, attention deficit hyperactivity disorder, and abnormal head circumference. Two out of 50 patients (4%) showed microscopic chromosome abnormalities and 5 out of 50 (10%) demonstrated copy number gains or losses using MLPA kits. Including one overlapping result between karyotype and MLPA techniques, our overall detection rate was 6 out of 50 (12%). Three out of 6 CNVs were de novo and three others were paternally inherited. Two of CNVs detected by karyotyping and MLPA tests were 16p13.1q13.3 and 10q26.3 duplications, respectively. For these two CNVs genotype and phenotype of the patients were compared with other studies. Although the pathogenicity of cytogenetic results was certain, most of MLPA results needed to be better refined using other more accurate techniques such as array CGH. Our findings suggest that it might be possible to obtain some useful information using MLPA technique but it cannot be used as a single diagnostic tool for the autism. PMID- 28357203 TI - A Novel Splicesite Mutation in the EDAR Gene Causes Severe Autosomal Recessive Hypohydrotic (Anhidrotic) Ectodermal Dysplasia in an Iranian Family. AB - Hypohidrotic ectodermal dysplasia (HED) is a rare congenital disorder arising from deficient development of ectoderm-derived structures including skin, nails, glands and teeth. The phenotype of HED is associated with mutation in EDA, EDAR, EDARADD and NEMO genes, all of them disruptingNF-kappaB signaling cascade necessary for initiation, formation and differentiation in the embryo and adult. Here we describe a novel acceptor splice site mutation c.730-2 A>G(IVS 8-2 A>G) in EDAR gene in homozygous form in all affected members of a family,and in heterozygous form in carriers. Bioinformatics analysis showed that this mutation can create a new broken splicing site and lead to aberrant splicing. PMID- 28357204 TI - Eosinophilic cystitis with recurrent urinary retention: case report. AB - Eosinophilic cystitis is a rare inflammatory disease of the bladder whose origin, pathogenesis, and treatment are unknown. Frequency, dysuria, and hematuria are frequent symptoms. Here, we report a rare occurrence of recurrent urinary retention and repetitive catheterization. A 67-year-old male presented with acute urinary retention and intermittent gross hematuria of 2 weeks duration. Urethral catheterization followed by a trial without catheter, was successful. Complete blood count showed presence of eosinophils (eosinophilia) and computed tomography of kidneys, ureter and bladder with contrast showed thickened bladder wall and small prostate. Cystoscopy revealed an erythematous lesion over the anterior wall. The rest of the mucosa was normal. Transurethral biopsies of the lesion were performed and histologic examination showed features of eosinophilic cystitis. Despite multiple medication regimens containing corticosteroids and antihistamines, he presented with recurrent urinary retention, approximately once every month. After 6 months, he was started on bethanechol, which led to no catheterization for up to 2 years. To the best of our knowledge, this is the first report on the successful use of bethanechol as a treatment for eosinophilic cystitis with recurrent urinary retention. PMID- 28357205 TI - One cell, one love: a journal for microbial research. PMID- 28357206 TI - Tracking autophagy during proliferation and differentiation of Trypanosoma brucei. AB - Autophagy is a lysosome-dependent degradation mechanism that sequesters target cargo into autophagosomal vesicles. The Trypanosoma brucei genome contains apparent orthologues of several autophagy-related proteins including an ATG8 family. These ubiquitin-like proteins are required for autophagosome membrane formation, but our studies show that ATG8.3 is atypical. To investigate the function of other ATG proteins, RNAi compatible T. brucei were modified to function as autophagy reporter lines by expressing only either YFP-ATG8.1 or YFP ATG8.2. In the insect procyclic lifecycle stage, independent RNAi down-regulation of ATG3 or ATG7 generated autophagy-defective mutants and confirmed a pro survival role for autophagy in the procyclic form nutrient starvation response. Similarly, RNAi depletion of ATG5 or ATG7 in the bloodstream form disrupted autophagy, but did not impede proliferation. Further characterisation showed bloodstream form autophagy mutants retain the capacity to undergo the complex cellular remodelling that occurs during differentiation to the procyclic form and are equally susceptible to dihydroxyacetone-induced cell death as wild type parasites, not supporting a role for autophagy in this cell death mechanism. The RNAi reporter system developed, which also identified TOR1 as a negative regulator controlling YFP-ATG8.2 but not YFP-ATG8.1 autophagosome formation, will enable further targeted analysis of the mechanisms and function of autophagy in the medically relevant bloodstream form of T. brucei. PMID- 28357208 TI - Early manifestations of replicative aging in the yeast Saccharomyces cerevisiae. AB - The yeast Saccharomyces cerevisiae is successfully used as a model organism to find genes responsible for lifespan control of higher organisms. As functional decline of higher eukaryotes can start as early as one quarter of the average lifespan, we asked whether S. cerevisiae can be used to model this manifestation of aging. While the average replicative lifespan of S. cerevisiae mother cells ranges between 15 and 30 division cycles, we found that resistances to certain stresses start to decrease much earlier. Looking into the mechanism, we found that knockouts of genes responsible for mitochondria-to-nucleus (retrograde) signaling, RTG1 or RTG3, significantly decrease the resistance of cells that generated more than four daughters, but not of the younger ones. We also found that even young mother cells frequently contain mitochondria with heterogeneous transmembrane potential and that the percentage of such cells correlates with replicative age. Together, these facts suggest that retrograde signaling starts to malfunction in relatively young cells, leading to accumulation of heterogeneous mitochondria within one cell. The latter may further contribute to a decline in stress resistances. PMID- 28357209 TI - A novel mechanism involved in the coupling of mitochondrial biogenesis to oxidative phosphorylation. AB - Mitochondria are essential organelles that are central to a multitude of cellular processes, including oxidative phosphorylation (OXPHOS), which produces most of the ATP in animal cells. Thus it is important to understand not only the mechanisms and biogenesis of this energy production machinery but also how it is regulated in both physiological and pathological contexts. A recent study by Ostojic et al. [Cell Metabolism (2013) 18, 567-577] has uncovered a regulatory loop by which the biogenesis of a major enzyme of the OXPHOS pathway, the respiratory complex III, is coupled to the energy producing activity of the mitochondria. PMID- 28357210 TI - Stalling autophagy: a new function for Listeria phospholipases. AB - Listeria monocytogenes is a Gram-positive bacterial pathogen that induces its own uptake in non-phagocytic cells. Following invasion, Listeria escapes from the entry vacuole through the secretion of a pore-forming toxin, listeriolysin O (LLO) that acts to damage and disrupt the vacuole membrane. Listeria then replicates in the cytosol and is able to spread from cell-to-cell using actin based motility. In addition to LLO, Listeria produces two phospholipase toxins, a phosphatidylinositol-specific phospholipase C (PI-PLC, encoded by plcB) and a broad-range phospholipase C (PC-PLC, encoded by plcA), which contribute to bacterial virulence. It has long been recognized that secretion of PI- and PC-PLC enables the disruption of the double membrane vacuole during cell-to-cell spread, and those phospholipases have also been shown to augment LLO-dependent escape from the entry endosome. However, a specific role for Listeria phospholipases during the cytosolic stage of infection has not been previously reported. In a recent study, we demonstrated that Listeria PI-PLC and PC-PLC contribute to the bacterial escape from autophagy through a mechanism that involves direct inhibition of the autophagic flux in the infected cells [Tattoli et al. EMBO J (2013), 32, 3066-3078]. PMID- 28357207 TI - Reduced TORC1 signaling abolishes mitochondrial dysfunctions and shortened chronological lifespan of Isc1p-deficient cells. AB - The target of rapamycin (TOR) is an important signaling pathway on a hierarchical network of interacting pathways regulating central biological processes, such as cell growth, stress response and aging. Several lines of evidence suggest a functional link between TOR signaling and sphingolipid metabolism. Here, we report that the TORC1-Sch9p pathway is activated in cells lacking Isc1p, the yeast orthologue of mammalian neutral sphingomyelinase 2. The deletion of TOR1 or SCH9 abolishes the premature aging, oxidative stress sensitivity and mitochondrial dysfunctions displayed by isc1Delta cells and this is correlated with the suppression of the autophagic flux defect exhibited by the mutant strain. The protective effect of TOR1 deletion, as opposed to that of SCH9 deletion, is not associated with the attenuation of Hog1p hyperphosphorylation, which was previously implicated in isc1Delta phenotypes. Our data support a model in which Isc1p regulates mitochondrial function and chronological lifespan in yeast through the TORC1-Sch9p pathway although Isc1p and TORC1 also seem to act through independent pathways, as isc1Deltator1Delta phenotypes are intermediate to those displayed by isc1Delta and tor1Delta cells. We also provide evidence that TORC1 downstream effectors, the type 2A protein phosphatase Sit4p and the AGC protein kinase Sch9p, integrate nutrient and stress signals from TORC1 with ceramide signaling derived from Isc1p to regulate mitochondrial function and lifespan in yeast. Overall, our results show that TORC1-Sch9p axis is deregulated in Isc1p-deficient cells, contributing to mitochondrial dysfunction, enhanced oxidative stress sensitivity and premature aging of isc1Delta cells. PMID- 28357212 TI - On the link between cell cycle and infection of the Alphaproteobacterium Brucella abortus. AB - Bacteria of the Brucella genus are responsible for brucellosis, a worldwide zoonosis. These bacteria are known to have a peculiar intracellular trafficking, with a first long and non-proliferative endosomal stage and a second proliferation stage, often associated with its localization of the bacteria in the endoplasmic reticulum (ER). However, the status of the bacterial cell cycle during the non-proliferative phase was still unknown. In a recent study [Nat. Communic. 5:4366], we followed the cell cycle of B. abortus in culture and inside the host cells. In culture, B. abortus initiates the replication of its large chromosome before the small chromosome. The origin and terminator regions of these two chromosomes display distinct localization and dynamics within B. abortus. In HeLa cells and RAW264.7 macrophages, the bacteria in G1 (i.e. before the initiation of chromosomes replication) are preferentially found during the endosomal stage of the infection. During this period, growth is also arrested. The cell cycle arrest and resume during the B. abortus trafficking in host cell suggest that like the model Alphaproteobacterium Caulobacter crescentus, these bacteria are able to block their cell cycle at the G1 phase when starvation is sensed. PMID- 28357211 TI - The dual role of cyclin C connects stress regulated gene expression to mitochondrial dynamics. AB - Following exposure to cytotoxic agents, cellular damage is first recognized by a variety of sensor mechanisms. Thenceforth, the damage signal is transduced to the nucleus to install the correct gene expression program including the induction of genes whose products either detoxify destructive compounds or repair the damage they cause. Next, the stress signal is disseminated throughout the cell to effect the appropriate changes at organelles including the mitochondria. The mitochondria represent an important signaling platform for the stress response. An initial stress response of the mitochondria is extensive fragmentation. If the damage is prodigious, the mitochondria fragment (fission) and lose their outer membrane integrity leading to the release of pro-apoptotic factors necessary for programmed cell death (PCD) execution. As this complex biological process contains many moving parts, it must be exquisitely coordinated as the ultimate decision is life or death. The conserved C-type cyclin plays an important role in executing this molecular Rubicon by coupling changes in gene expression to mitochondrial fission and PCD. Cyclin C, along with its cyclin dependent kinase partner Cdk8, associates with the RNA polymerase holoenzyme to regulate transcription. In particular, cyclin C-Cdk8 repress many stress responsive genes. To relieve this repression, cyclin C is destroyed in cells exposed to pro oxidants and other stressors. However, prior to its destruction, cyclin C, but not Cdk8, is released from its nuclear anchor (Med13), translocates from the nucleus to the cytoplasm where it interacts with the fission machinery and is both necessary and sufficient to induce extensive mitochondria fragmentation. Furthermore, cytoplasmic cyclin C promotes PCD indicating that it mediates both mitochondrial fission and cell death pathways. This review will summarize the role cyclin C plays in regulating stress-responsive transcription. In addition, we will detail this new function mediating mitochondrial fission and PCD. Although both these roles of cyclin C are conserved, this review will concentrate on cyclin C's dual role in the budding yeast Saccharomyces cerevisiae. PMID- 28357213 TI - Divide and conquer: processive transport enables multidrug transporters to tackle challenging drugs. AB - Multidrug transporters are membrane proteins that catalyze efflux of antibiotics and other toxic compounds from cells, thereby conferring drug resistance on various organisms. Unlike most solute transporters that transport a single type of compound or similar analogues, multidrug transporters are extremely promiscuous. They transport a broad spectrum of dissimilar drugs and represent a serious obstacle to antimicrobial or anticancer chemotherapy. Many challenging aspects of multidrug transporters, which are unique, have been studied in detail, including their ability to interact with chemically unrelated drugs, and how they utilize energy to drive efflux of compounds that are not only structurally but electrically different. A new and surprising dimension of the promiscuous nature of multidrug transporters has been described recently: they can move long molecules through the membrane in a processive manner. PMID- 28357215 TI - Functional analysis of lipid metabolism genes in wine yeasts during alcoholic fermentation at low temperature. AB - Wine produced by low-temperature fermentation is mostly considered to have improved sensory qualities. However few commercial wine strains available on the market are well-adapted to ferment at low temperature (10 - 15 degrees C). The lipid metabolism of Saccharomyces cerevisiae plays a central role in low temperature adaptation. One strategy to modify lipid composition is to alter transcriptional activity by deleting or overexpressing the key genes of lipid metabolism. In a previous study, we identified the genes of the phospholipid, sterol and sphingolipid pathways, which impacted on growth capacity at low temperature. In the present study, we aimed to determine the influence of these genes on fermentation performance and growth during low-temperature wine fermentations. We analyzed the phenotype during fermentation at the low and optimal temperature of the lipid mutant and overexpressing strains in the background of a derivative commercial wine strain. The increase in the gene dosage of some of these lipid genes, e.g., PSD1, LCB3, DPL1 and OLE1, improved fermentation activity during low-temperature fermentations, thus confirming their positive role during wine yeast adaptation to cold. Genes whose overexpression improved fermentation activity at 12 degrees C were overexpressed by chromosomal integration into commercial wine yeast QA23. Fermentations in synthetic and natural grape must were carried out by this new set of overexpressing strains. The strains overexpressing OLE1 and DPL1 were able to finish fermentation before commercial wine yeast QA23. Only the OLE1 gene overexpression produced a specific aroma profile in the wines produced with natural grape must. PMID- 28357214 TI - Angiotensin II type 1 receptor blockers increase tolerance of cells to copper and cisplatin. AB - The human pathology Wilson disease (WD) is characterized by toxic copper (Cu) accumulation in brain and liver, resulting in, among other indications, mitochondrial dysfunction and apoptosis of hepatocytes. In an effort to identify novel compounds that can alleviate Cu-induced toxicity, we screened the Pharmakon 1600 repositioning library using a Cu-toxicity yeast screen. We identified 2 members of the drug class of Angiotensin II Type 1 receptor blockers (ARBs) that could increase yeast tolerance to Cu, namely Candesartan and Losartan. Subsequently, we show that specific ARBs can increase yeast tolerance to Cu and/or the chemotherapeutic agent cisplatin (Cp). The latter also induces mitochondrial dysfunction and apoptosis in mammalian cells. We further demonstrate that specific ARBs can prevent the prevalence of Cu-induced apoptotic markers in yeast, with Candesartan Cilexetil being the ARB which demonstrated most pronounced reduction of apoptosis-related markers. Next, we tested the sensitivity of a selection of yeast knockout mutants affected in detoxification of reactive oxygen species (ROS) and Cu for Candesartan Cilexetil rescue in presence of Cu. These data indicate that Candesartan Cilexetil increases yeast tolerance to Cu irrespectively of major ROS-detoxifying proteins. Finally, we show that specific ARBs can increase mammalian cell tolerance to Cu, as well as decrease the prevalence of Cu-induced apoptotic markers. All the above point to the potential of ARBs in preventing Cu-induced toxicity in yeast and mammalian cells. PMID- 28357217 TI - Plasmodium spp. membrane glutathione S-transferases: detoxification units and drug targets. AB - Membrane glutathione S-transferases from the class of membrane-associated proteins in eicosanoid and glutathione metabolism (MAPEG) form a superfamily of detoxification enzymes that catalyze the conjugation of reduced glutathione (GSH) to a broad spectrum of xenobiotics and hydrophobic electrophiles. Evolutionarily unrelated to the cytosolic glutathione S-transferases, they are found across bacterial and eukaryotic domains, for example in mammals, plants, fungi and bacteria in which significant levels of glutathione are maintained. Species of genus Plasmodium, the unicellular protozoa that are commonly known as malaria parasites, do actively support glutathione homeostasis and maintain its metabolism throughout their complex parasitic life cycle. In humans and in other mammals, the asexual intraerythrocytic stage of malaria, when the parasite feeds on hemoglobin, grows and eventually asexually replicates inside infected red blood cells (RBCs), is directly associated with host disease symptoms and during this critical stage GSH protects the host RBC and the parasite against oxidative stress from parasite-induced hemoglobin catabolism. In line with these observations, several GSH-dependent Plasmodium enzymes have been characterized including glutathione reductases, thioredoxins, glyoxalases, glutaredoxins and glutathione S-transferases (GSTs); furthermore, GSH itself have been found to associate spontaneously and to degrade free heme and its hydroxide, hematin, which are the main cytotoxic byproducts of hemoglobin catabolism. However, despite the apparent importance of glutathione metabolism for the parasite, no membrane associated glutathione S-transferases of genus Plasmodium have been previously described. We recently reported the first examples of MAPEG members among Plasmodium spp. PMID- 28357216 TI - Overexpression of the transcription factor Yap1 modifies intracellular redox conditions and enhances recombinant protein secretion. AB - Oxidative folding of secretory proteins in the endoplasmic reticulum (ER) is a redox active process, which also impacts the redox conditions in the cytosol. As the transcription factor Yap1 is involved in the transcriptional response to oxidative stress, we investigate its role upon the production of secretory proteins, using the yeast Pichia pastoris as model, and report a novel important role of Yap1 during oxidative protein folding. Yap1 is needed for the detoxification of reactive oxygen species (ROS) caused by increased oxidative protein folding. Constitutive co-overexpression of PpYAP1 leads to increased levels of secreted recombinant protein, while a lowered Yap1 function leads to accumulation of ROS and strong flocculation. Transcriptional analysis revealed that more than 150 genes were affected by overexpression of YAP1, in particular genes coding for antioxidant enzymes or involved in oxidation-reduction processes. By monitoring intracellular redox conditions within the cytosol and the ER using redox-sensitive roGFP1 variants, we could show that overexpression of YAP1 restores cellular redox conditions of protein-secreting P. pastoris by reoxidizing the cytosolic redox state to the levels of the wild type. These alterations are also reflected by increased levels of oxidized intracellular glutathione (GSSG) in the YAP1 co-overexpressing strain. Taken together, these data indicate a strong impact of intracellular redox balance on the secretion of (recombinant) proteins without affecting protein folding per se. Re-establishing suitable redox conditions by tuning the antioxidant capacity of the cell reduces metabolic load and cell stress caused by high oxidative protein folding load, thereby increasing the secretion capacity. PMID- 28357218 TI - Proline cis-trans isomerization is influenced by local lysine acetylation deacetylation. AB - Acetylation of lysine residues has several characterised functions in chromatin. These include neutralization of the lysine's positive charge to directly influence histone tail-DNA/internucleosomal interactions or indirect effects via bromodomain-containing effector proteins. Recently, we described a novel function of lysine acetylation to influence proline isomerization and thus local protein conformation. We found that acetylation of lysine 14 in the histone H3 N-terminal tail (H3K14ac), an intrinsically disordered domain, increased the proportion of neighbouring proline 16 (H3P16) in the trans conformation. This conformation of the tail was associated with reduced tri-methylation on histone H3 lysine 4 (H3K4me3) due to both decreased methylation by the Set1 methyltransferase (with the me3-specific subunit Spp1) and increased demethylation by the demethylase Jhd2. Interestingly, H3K4me3 on individual genes was differentially affected by substitution of H3K14 or H3P16, with ribosomal protein genes losing the least H3K4me3 and environmental stress-induced genes losing the most. PMID- 28357220 TI - Measurement of apoptosis by SCAN(c), a system for counting and analysis of fluorescently labelled nuclei. AB - Apoptosis-like programmed cell death (A-PCD) is a universal process common to all types of eukaryotic organisms. Because A-PCD-associated processes are conserved, it is possible to define A-PCD by a standard set of markers. Many of the popular methods to measure A-PCD make use of fluorescent ligands that change in intensity or cellular localization during A-PCD. In single cell organisms, it is possible to quantify levels of A-PCD by scoring the number of apoptotic cells using flow cytometry instruments. In a multicellular organism, quantification of A-PCD is more problematic due to the complex nature of the tissue. The situation is further complicated in filamentous fungi, in which nuclei are divided between compartments, each containing a number of nuclei, which can also migrate between the compartments. We developed SCAN(c), a System for Counting and Analysis of Nuclei, and used it to measure A-PCD according to two markers - chromatin condensation and DNA strand breaks. The package includes three modules designed for counting the number of nuclei in multi-nucleated domains, scoring the relative number of nuclei with condensed chromatin, and calculating the relative number of nuclei with DNA strand breaks. The method provides equal or better results compared with manual counting, the analysis is fast and can be applied on large data sets. While we demonstrated the utility of the software for measurement of A-PCD in fungi, the method is readily adopted for measurement of A PCD in other types of multicellular specimens. PMID- 28357219 TI - Rewiring yeast acetate metabolism through MPC1 loss of function leads to mitochondrial damage and decreases chronological lifespan. AB - During growth on fermentable substrates, such as glucose, pyruvate, which is the end-product of glycolysis, can be used to generate acetyl-CoA in the cytosol via acetaldehyde and acetate, or in mitochondria by direct oxidative decarboxylation. In the latter case, the mitochondrial pyruvate carrier (MPC) is responsible for pyruvate transport into mitochondrial matrix space. During chronological aging, yeast cells which lack the major structural subunit Mpc1 display a reduced lifespan accompanied by an age-dependent loss of autophagy. Here, we show that the impairment of pyruvate import into mitochondria linked to Mpc1 loss is compensated by a flux redirection of TCA cycle intermediates through the malic enzyme-dependent alternative route. In such a way, the TCA cycle operates in a "branched" fashion to generate pyruvate and is depleted of intermediates. Mutant cells cope with this depletion by increasing the activity of glyoxylate cycle and of the pathway which provides the nucleocytosolic acetyl-CoA. Moreover, cellular respiration decreases and ROS accumulate in the mitochondria which, in turn, undergo severe damage. These acquired traits in concert with the reduced autophagy restrict cell survival of the mpc1? mutant during chronological aging. Conversely, the activation of the carnitine shuttle by supplying acetyl-CoA to the mitochondria is sufficient to abrogate the short-lived phenotype of the mutant. PMID- 28357221 TI - Loss of wobble uridine modification in tRNA anticodons interferes with TOR pathway signaling. AB - Previous work in yeast has suggested that modification of tRNAs, in particular uridine bases in the anticodon wobble position (U34), is linked to TOR (target of rapamycin) signaling. Hence, U34 modification mutants were found to be hypersensitive to TOR inhibition by rapamycin. To study whether this involves inappropriate TOR signaling, we examined interaction between mutations in TOR pathway genes (tip41?, sap190?, ppm1?, rrd1?) and U34 modification defects (elp3?, kti12?, urm1?, ncs2?) and found the rapamycin hypersensitivity in the latter is epistatic to drug resistance of the former. Epistasis, however, is abolished in tandem with a gln3? deletion, which inactivates transcription factor Gln3 required for TOR-sensitive activation of NCR (nitrogen catabolite repression) genes. In line with nuclear import of Gln3 being under control of TOR and dephosphorylation by the Sit4 phosphatase, we identify novel TOR-sensitive sit4 mutations that confer rapamycin resistance and importantly, mislocalise Gln3 when TOR is inhibited. This is similar to gln3? cells, which abolish the rapamycin hypersensitivity of U34 modification mutants, and suggests TOR deregulation due to tRNA undermodification operates through Gln3. In line with this, loss of U34 modifications (elp3?, urm1?) enhances nuclear import of and NCR gene activation (MEP2, GAP1) by Gln3 when TOR activity is low. Strikingly, this stimulatory effect onto Gln3 is suppressed by overexpression of tRNAs that usually carry the U34 modifications. Collectively, our data suggest that proper TOR signaling requires intact tRNA modifications and that loss of U34 modifications impinges on the TOR-sensitive NCR branch via Gln3 misregulation. PMID- 28357222 TI - Mitochondrial protein import under kinase surveillance. AB - Despite the simplicity of the yeast Saccharomyces cerevisiae, its basic cellular machinery tremendously mirrors that of higher eukaryotic counterparts. Thus, this unicellular organism turned out to be an invaluable model system to study the countless mechanisms that govern life of the cell. Recently, it has also enabled the deciphering of signalling pathways that control flux of mitochondrial proteins to the organelle according to metabolic requirements. For decades mitochondria were considered autonomous organelles that are only partially incorporated into cellular signalling networks. Consequently, only little has been known about the role of reversible phosphorylation as a meaningful mechanism that orchestrates mitochondrial biology accordingly to cellular needs. Therefore, research in this direction has been vastly neglected. However, findings over the past few years have changed this view and new exciting fields in mitochondrial biology have emerged. Here, we summarize recent discoveries in the yeast model system that point towards a vital role of reversible phosphorylation in regulation of mitochondrial protein import. PMID- 28357223 TI - Deletion of AIF1 but not of YCA1/MCA1 protects Saccharomyces cerevisiae and Candida albicans cells from caspofungin-induced programmed cell death. AB - Caspofungin was the first member of a new class of antifungals called echinocandins to be approved by a drug regulatory authority. Like the other echinocandins, caspofungin blocks the synthesis of beta(1,3)-D-glucan of the fungal cell wall by inhibiting the enzyme, beta(1,3)-D-glucan synthase. Loss of beta(1,3)-D-glucan leads to osmotic instability and cell death. However, the precise mechanism of cell death associated with the cytotoxicity of caspofungin was unclear. We now provide evidence that Saccharomyces cerevisiae cells cultured in media containing caspofungin manifest the classical hallmarks of programmed cell death (PCD) in yeast, including the generation of reactive oxygen species (ROS), the fragmentation of mitochondria, and the production of DNA strand breaks. Our data also suggests that deleting AIF1 but not YCA1/MCA1 protects S. cerevisiae and Candida albicans from caspofungin-induced cell death. This is not only the first time that AIF1 has been specifically tied to cell death in Candida but also the first time that caspofungin resistance has been linked to the cell death machinery in yeast. PMID- 28357224 TI - Intersubunit communications within KaiC hexamers contribute the robust rhythmicity of the cyanobacterial circadian clock. AB - Circadian rhythms, endogenous oscillations with periods of ~24 h, are found in many organisms, and they enhance fitness in alternating day/night environments. In cyanobacteria, three clock proteins, KaiA, KaiB, and KaiC, control the timekeeping mechanism. KaiC, the central component of the system, is a hexameric ATPase that also has autokinase and autophosphatase activities. It has been assumed that KaiC's hexameric structure was critical for regulation of the circadian clock; however, the underlying molecular mechanism of such regulation has remained unclear. Recently, we elucidated the regulation of KaiC's activities by its phosphorylation state, in the context of its hexameric structure. We found that local interactions at subunit interfaces regulate KaiC's activities by coupling the nucleotide-binding states. We also discovered the mechanism of regulation by intersubunit communication in KaiC hexamers. Our observations suggest that intersubunit communication precisely synchronizes KaiC subunits to avoid dephasing, and contributes to the robustness of circadian rhythms in cyanobacteria [Kitayama, Y. et al. Nat. Commun. 4:2897 doi: 10.1038/ncomms3897 (2013)]. PMID- 28357226 TI - Protein oxidation in the intermembrane space of mitochondria is substrate specific rather than general. AB - In most cellular compartments cysteine residues are predominantly reduced. However, in the bacterial periplasm, the ER and the mitochondrial intermembrane space (IMS), sulfhydryl oxidases catalyze the formation of disulfide bonds. Nevertheless, many IMS proteins contain reduced cysteines that participate in binding metal- or heme-cofactors. In this study, we addressed the substrate specificity of the mitochondrial protein oxidation machinery. Dre2 is a cysteine rich protein that is located in the cytosol. A large fraction of Dre2 bound to the cytosolic side of the outer membrane of mitochondria. Even when Dre2 is artificially targeted to the IMS, its cysteine residues remain in the reduced state. This indicates that protein oxidation in the IMS of mitochondria is not a consequence of the apparent oxidizing environment in this compartment but rather is substrate-specific and determined by the presence of Mia40-binding sites. PMID- 28357227 TI - Salt stress causes cell wall damage in yeast cells lacking mitochondrial DNA. AB - The yeast cell wall plays an important role in maintaining cell morphology, cell integrity and response to environmental stresses. Here, we report that salt stress causes cell wall damage in yeast cells lacking mitochondrial DNA (rho0). Upon salt treatment, the cell wall is thickened, broken and becomes more sensitive to the cell wall-perturbing agent sodium dodecyl sulfate (SDS). Also, SCW11 mRNA levels are elevated in rho0 cells. Deletion of SCW11 significantly decreases the sensitivity of rho0 cells to SDS after salt treatment, while overexpression of SCW11 results in higher sensitivity. In addition, salt stress in rho0 cells induces high levels of reactive oxygen species (ROS), which further damages the cell wall, causing cells to become more sensitive towards the cell wall-perturbing agent. PMID- 28357228 TI - Mnemons: encoding memory by protein super-assembly. AB - Memory is mainly understood as the recollection of past events. The human brain and its simplest unit, the synapse, belong to the places in which such memories are physically stored. From an experimental point of view, memory can be tested in humans by recall. However, in other organisms, memory is reflected in its use by individuals to learn about and adapt their behavior to their environment. Under this criterion, even unicellular organisms are able to learn from their environments and show the ability to adapt their responses to repeating stimuli. This indicates that they are able to keep track of their histories and use these traces to elaborate adapted responses, making these traces akin to memory encodings. Understanding these phenomena may even help us to dissect part of the rather complex molecular orchestration happening in our synapses. When exposed unsuccessfully to mating pheromone, i.e. when mating does not happen, budding yeast cells become refractory to the mating signal. This refractory state is restricted to the mother cell and not inherited by the daughter cells, even though it is stable for most if not the entire life span of the mother cell. Interestingly, both stability and asymmetric segregation of the acquired state are explained by the molecular mechanism underlying its establishment, which shows important analogies and distinctions to prions. Here we discuss these similarities and differences. PMID- 28357225 TI - Genome-wide studies of telomere biology in budding yeast. AB - Telomeres are specialized DNA-protein structures at the ends of eukaryotic chromosomes. Telomeres are essential for chromosomal stability and integrity, as they prevent chromosome ends from being recognized as double strand breaks. In rapidly proliferating cells, telomeric DNA is synthesized by the enzyme telomerase, which copies a short template sequence within its own RNA moiety, thus helping to solve the "end-replication problem", in which information is lost at the ends of chromosomes with each DNA replication cycle. The basic mechanisms of telomere length, structure and function maintenance are conserved among eukaryotes. Studies in the yeast Saccharomyces cerevisiae have been instrumental in deciphering the basic aspects of telomere biology. In the last decade, technical advances, such as the availability of mutant collections, have allowed carrying out systematic genome-wide screens for mutants affecting various aspects of telomere biology. In this review we summarize these efforts, and the insights that this Systems Biology approach has produced so far. PMID- 28357229 TI - Fatal attraction in glycolysis: how Saccharomyces cerevisiae manages sudden transitions to high glucose. AB - In the model eukaryote Saccharomyces cerevisiae, it has long been known that a functional trehalose pathway is indispensable for transitions to high glucose conditions. Upon addition of glucose, cells with a defect in trehalose 6 phosphate synthase (Tps1), the first committed step in the trehalose pathway, display what we have termed an imbalanced glycolytic state; in this state the flux through the upper part of glycolysis outpaces that through the lower part of glycolysis. As a consequence, the intermediate fructose 1,6-bisphosphate (FBP) accumulates at low concentrations of ATP and inorganic phosphate (Pi). Despite significant research efforts, a satisfactory understanding of the regulatory role that trehalose metabolism plays during such transitions has remained infamously unresolved. In a recent study, we demonstrate that the startup of glycolysis exhibits two dynamic fates: a proper, functional, steady state or the imbalanced state described above. Both states are stable, attracting states, and the probability distribution of initial states determines the fate of a yeast cell exposed to glucose. Trehalose metabolism steers the dynamics of glycolysis towards the proper functional state through its ATP hydrolysis activity; a mechanism that ensures that the demand and supply of ATP is balanced with Pi availability under dynamic conditions. [van Heerden et al. Science (2014), DOI: 10.1126/science.1245114.]. PMID- 28357230 TI - Massive gene swamping among cheese-making Penicillium fungi. AB - Horizontal gene transfers (HGT), i.e., the transmission of genetic material between species not directly attributable to meiotic gene exchange, have long been acknowledged as a major driver of prokaryotic evolution and is increasingly recognized as an important source of adaptation in eukaryotes. In fungi in particular, many convincing examples of HGT have been reported to confer selective advantages on the recipient fungal host, either promoting fungal pathogenicity on plants or increasing their toxicity by the acquisition of secondary metabolic clusters, resulting in adaptation to new niches and in some cases eventually even in speciation. These horizontal gene transfers involve single genes, complete metabolic pathways or even entire chromosomes. A recent study has uncovered multiple recent horizontal transfers of a 575 kb genomic island in cheese Penicillium fungi, representing ca. 2% of the Penicillium roqueforti's genome, that may confer selective advantage in the competing cheese environment where bacteria and fungi occur. Novel phylogenomic methods are being developed, revealing massive HGT among fungi. Altogether, these recent studies indicate that HGT is a crucial mechanism of rapid adaptation, even among eukaryotes. PMID- 28357231 TI - Metabolites in aging and autophagy. PMID- 28357233 TI - De novo peroxisome biogenesis revisited. AB - We describe an alternative peroxisome formation pathway in yeast pex3 and pex19 cells, which relies on the existence of small peroxisomal remnants that are present in these cells. This groundbreaking result challenges current models prescribing that peroxisomes derive de novo from the ER. Our data also has major implications for the sorting pathway of specific peroxisomal membrane proteins (PMPs). We propose a novel sorting pathway for the PMPs Pex13 and Pex14 that is independent of the known Pex3/Pex19 machinery. PMID- 28357234 TI - Transcriptional and genomic mayhem due to aging-induced nucleosome loss in budding yeast. AB - All eukaryotic genomes are assembled into a nucleoprotein structure termed chromatin, which is comprised of regular arrays of nucleosomes. Each nucleosome consists of eight core histone protein molecules around which the DNA is wrapped 1.75 times. The ultimate consequence of packaging the genome into chromatin is that the DNA sequences are relatively inaccessible. This allows the cell to use a comprehensive toolbox of chromatin-altering machineries to reveal access to the DNA sequence at the right time and right place in order to allow genomic processes, such as DNA repair, transcription and replication, to occur in a tightly-regulated manner. In other words, chromatin provides the framework that allows the regulation of all genomic processes, because the machineries that mediate transcription, repair and DNA replication themselves are relatively non sequence specific and if the genome were naked, they would presumably perform their tasks in a random and unregulated manner. We recently provided support for this prediction in Zheng et al., [Genes and Development (2014) 28: 396-408] by investigating a physiologically relevant scenario in which we had found that cells lose half of the core histone proteins, that is, during the mitotic aging (also called replicative aging) of budding yeast. Using new spike-in normalization techniques, we found that the occupancy of nucleosomes at most DNA sequences is reduced by 50%, leading to transcriptional induction of every single gene. This loss of histones during aging was also accompanied by a significantly increased frequency of genomic instability including DNA breaks, chromosomal translocations, retrotransposition, and transfer of mitochondrial DNA into the nuclear genome (Figure 1). PMID- 28357232 TI - Longevity pathways and maintenance of the proteome: the role of autophagy and mitophagy during yeast ageing. AB - Ageing is a complex and multi-factorial process that results in the progressive accumulation of molecular alterations that disrupt different cellular functions. The budding yeast Saccharomyces cerevisiae is an important model organism that has significantly contributed to the identification of conserved molecular and cellular determinants of ageing. The nutrient-sensing pathways are well recognized modulators of longevity from yeast to mammals, but their downstream effectors and outcomes on different features of ageing process are still poorly understood. A hypothesis that is attracting increased interest is that one of the major functions of these "longevity pathways" is to contribute to the maintenance of the proteome during ageing. In support of this hypothesis, evidence shows that TOR/Sch9 and Ras/PKA pathways are important regulators of autophagy that in turn are essential for healthy cellular ageing. It is also well known that mitochondria homeostasis and function regulate lifespan, but how mitochondrial dynamics, mitophagy and biogenesis are regulated during ageing remains to be elucidated. This review describes recent findings that shed light on how longevity pathways and metabolic status impact maintenance of the proteome in both yeast ageing paradigms. These findings demonstrate that yeast remain a powerful model system for elucidating these relationships and their influence on ageing regulation. PMID- 28357235 TI - Live longer on MARS: a yeast paradigm of mitochondrial adaptive ROS signaling in aging. AB - Adaptive responses to stress, including hormesis, have been implicated in longevity, but their mechanisms and outcomes are not fully understood. Here, I briefly summarize a longevity mechanism elucidated in the budding yeast chronological lifespan model by which Mitochondrial Adaptive ROS Signaling (MARS) promotes beneficial epigenetic and metabolic remodeling. The potential relevance of MARS to the human disease Ataxia-Telangiectasia and as a potential anti-aging target is discussed. PMID- 28357236 TI - Hormesis: a fundamental concept in biology. AB - This paper assesses the hormesis dose response concept, including its historical foundations, frequency, generality, quantitative features, mechanistic basis and biomedical, pharmaceutical and environmental health implications. The hormetic dose response is highly generalizable, being independent of biology model (i.e. common from plants to humans), level of biological organization (i.e. cell, organ and organism), endpoint, inducing agent and mechanism, providing the first general and quantitative description of plasticity. The hormetic dose response describes the limits to which integrative endpoints (e.g. cell proliferation, cell migration, growth patterns, tissue repair, aging processes, complex behaviors such as anxiety, learning, memory, and stress, preconditioning responses, and numerous adaptive responses) can be modulated (i.e., enhanced or diminished) by pharmaceutical, chemical and physical means. Thus, the hormesis concept is a fundamental concept in biology with a wide range of biological implications and biomedical applications. PMID- 28357237 TI - When less is more: hormesis against stress and disease. AB - All living organisms need to adapt to ever changing adverse conditions in order to survive. The phenomenon termed hormesis describes an evolutionarily conserved process by which a cell or an entire organism can be preconditioned, meaning that previous exposure to low doses of an insult protects against a higher, normally harmful or lethal dose of the same stressor. Growing evidence suggests that hormesis is directly linked to an organism's (or cell's) capability to cope with pathological conditions such as aging and age-related diseases. Here, we condense the conceptual and potentially therapeutic importance of hormesis by providing a short overview of current evidence in favor of the cytoprotective impact of hormesis, as well as of its underlying molecular mechanisms. PMID- 28357239 TI - Prokaryotic Argonautes - variations on the RNA interference theme. AB - The discovery of RNA interference (RNAi) has been a major scientific breakthrough. This RNA-guided RNA interference system plays a crucial role in a wide range of regulatory and defense mechanisms in eukaryotes. The key enzyme of the RNAi system is Argonaute (Ago), an endo-ribonuclease that uses a small RNA guide molecule to specifically target a complementary RNA transcript. Two functional classes of eukaryotic Ago have been described: catalytically active Ago that cleaves RNA targets complementary to its guide, and inactive Ago that uses its guide to bind target RNA to down-regulate translation efficiency. A recent comparative genomics study has revealed that Argonaute-like proteins are also encoded by prokaryotic genomes. Interestingly, there is a lot of variation among these prokaryotic Argonaute (pAgo) proteins with respect to domain architecture: some resemble the eukaryotic Ago (long pAgo) containing a complete or disrupted catalytic site, while others are truncated versions (short pAgo) that generally contain an incomplete catalytic site. Prokaryotic Agos with an incomplete catalytic site often co-occur with (predicted) nucleases. Based on this diversity, and on the fact that homologs of other RNAi-related protein components (such as Dicer nucleases) have never been identified in prokaryotes, it has been predicted that variations on the eukaryotic RNAi theme may occur in prokaryotes. PMID- 28357238 TI - Morphed and moving: TNFalpha-driven motility promotes cell dissemination through MAP4K4-induced cytoskeleton remodeling. AB - Cell dissemination from an initial site of growth is a highly coordinated and controlled process that depends on cell motility. The mechanistic principles that orchestrate cell motility, namely cell shape control, traction and force generation, are highly conserved between cells of different origins. Correspondingly, the molecular mechanisms that regulate these critical aspects of migrating cells are likely functionally conserved too. Thus, cell motility deregulation of unrelated pathogenesis could be caused and maintained by similar mechanistic principles. One such motility deregulation disorder is the leukoproliferative cattle disease Tropical Theileriosis, which is caused by the intracellular, protozoan parasite Theileria annulata. T. annulata transforms its host cell and promotes the dissemination of parasite-infected cells throughout the body of the host. An analogous condition with a fundamentally different pathogenesis is metastatic cancer, where oncogenically transformed cells disseminate from the primary tumor to form distant metastases. Common to both diseases is the dissemination of motile cells from the original site. However, unlike metastatic cancer, host cell transformation by Theileria parasites can be reverted by drug treatment and cell signaling be analyzed under transformed and non-transformed conditions. We have used this reversible transformation model and investigated parasite control of host cell motile properties in the context of inflammatory signaling in Ma M. et al. [PLoS Pathog (2014) 10: e1004003]. We found that parasite infection promotes the production of the inflammatory cytokine TNFalpha in the host macrophage. We demonstrated that increased TNFalpha triggers motile and invasive properties by enhancing actin cytoskeleton remodeling and cell motility through the ser/thr kinase MAP4K4. We concluded that inflammatory conditions resulting in increased TNFalpha could facilitate cell dissemination by activating the actin cytoskeleton regulatory kinase MAP4K4. We discuss here the relevance of TNFalpha-MAP4K4 signaling for pathogen-driven cell dissemination and its potential impact on the induction of metastasis in human cancer. PMID- 28357240 TI - Autophagy extends lifespan via vacuolar acidification. AB - Methionine restriction (MetR) is one of the rare regimes that prolongs lifespan across species barriers. Using a yeast model, we recently demonstrated that this lifespan extension is promoted by autophagy, which in turn requires vacuolar acidification. Our study is the first to place autophagy as one of the major players required for MetR-mediated longevity. In addition, our work identifies vacuolar acidification as a key downstream element of autophagy induction under MetR, and possibly after rapamycin treatment. Unlike other amino acids, methionine plays pleiotropic roles in many metabolism-relevant pathways. For instance, methionine (i) is the N-terminal amino acid of every newly translated protein; (ii) acts as the central donor of methyl groups through S-adenosyl methionine (SAM) during methylation reactions of proteins, DNA or RNA; and (iii) provides the sulfhydryl groups for FeS-cluster formation and redox detoxification via transsulfuration to cysteine. Intriguingly, MetR causes lifespan extension, both in yeast and in rodents. We could show that in Saccharomyces cerevisiae, chronological lifespan (CLS) is increased in two specific methionine-auxotrophic strains (namely Deltamet2 and Deltamet15). PMID- 28357242 TI - Heat shock protein 90 and calcineurin pathway inhibitors enhance the efficacy of triazoles against Scedosporium prolificans via induction of apoptosis. AB - Scedosporium prolificans is a pathogenic mold resistant to current antifungals, and infection results in high mortality. Simultaneous targeting of both ergosterol biosynthesis and heat shock protein 90 (Hsp90) or the calcineurin pathway in S. prolificans may be an important strategy for enhancing the potency of antifungal agents. We hypothesized that the inactive triazoles posaconazole (PCZ) and itraconazole (ICZ) acquire fungicidal activity when combined with the calcineurin inhibitor tacrolimus (TCR) or Hsp90 inhibitor 17-demethoxy-17-(2 propenylamino) geldanamycin (17AAG). PCZ, ICZ, TCR and 17AAG alone were inactive in vitro against S. prolificans spores (MICs > 128 MUg/ml). In contrast, MICs for PCZ or ICZ in combination with TCR or 17AAG (0.125-0.50 MUg/ml) were much lower compared with drug alone. In addition PCZ and ICZ in combination with TCR or 17AAG became fungicidal. Because apoptosis is regulated by the calcineurin pathway in fungi and is under the control of Hsp90, we hypothesized that this synergistic fungicidal effect is mediated via apoptosis. This observed fungicidal activity was mediated by increased apoptosis of S. prolificans germlings, as evidenced by reactive oxygen species accumulation, decreased mitochondrial membrane potential, phosphatidylserine externalization, and DNA fragmentation. Furthermore, induction of caspase-like activity was correlated with TCR or 17AAG + PCZ/ICZ-induced cell death. In conclusion, we report for the first time that PCZ or ICZ in combination with TCR or 17AAG renders S. prolificans exquisitely sensitive to PCZ or ICZ via apoptosis. This finding may stimulate the development of new therapeutic strategies for patients infected with this recalcitrant fungus. PMID- 28357243 TI - At neutral pH the chronological lifespan of Hansenula polymorpha increases upon enhancing the carbon source concentrations. AB - Dietary restriction is generally assumed to increase the lifespan in most eukaryotes, including the simple model organism Saccharomyces cerevisiae. However, recent data questioned whether this phenomenon is indeed true for yeast. We studied the effect of reduction of the carbon source concentration on the chronological lifespan of the yeast Hansenula polymorpha using four different carbon sources. Our data indicate that reduction of the carbon source concentration has a negative (glucose, ethanol, methanol) or positive (glycerol) effect on the chronological lifespan. We show that the actual effect of carbon source concentrations largely depends on extracellular factor(s). We provide evidence that H. polymorpha acidifies the medium and that a low pH of the medium alone is sufficient to significantly decrease the chronological lifespan. However, glucose-grown cells are less sensitive to low pH compared to glycerol grown cells, explaining why only the reduction of the glycerol-concentration (which leads to less medium acidification) has a positive effect on the chronological lifespan. Instead, the positive effect of enhancing the glucose concentrations is much larger than the negative effect of the medium acidification at these conditions, explaining the increased lifespan with increasing glucose concentrations. Importantly, at neutral pH, the chronological lifespan also decreases with a reduction in glycerol concentrations. We show that for glycerol cultures this effect is related to acidification independent changes in the composition of the spent medium. Altogether, our data indicate that in H. polymorpha at neutral pH the chronological lifespan invariably extends upon increasing the carbon source concentration. PMID- 28357244 TI - Decoding the biosynthesis and function of diphthamide, an enigmatic modification of translation elongation factor 2 (EF2) AB - Diphthamide is a highly conserved modification of archaeal and eukaryal translation elongation factor 2 (EF2) and yet why cells need EF2 to contain diphthamide is unclear. In yeast, the first steps of diphthamide synthesis and the genes (DPH1-DPH5) required to form the intermediate diphthine are well documented. However, the last step, amidation of diphthine to diphthamide, had largely been ill-defined. Remarkably, through mining genome-wide synthetic gene array (SGA) and chemical genomics databases, recent studies by Uthman et al. [PLoS Genetics (2013) 9, e1003334] and Su et al. [Proc. Natl. Acad. Sci. USA (2012) 109, 19983-19987] have identified two more diphthamide players, DPH6 and DPH7. Consistent with roles in the amidation step, dph6 and dph7 deletion strains fail to complete diphthamide synthesis and accumulate diphthine-modified EF2. In contrast to Dph6, the catalytically relevant amidase, Dph7 appears to be regulatory. As shown by Uthman et al., it promotes dissociation of diphthine synthase (Dph5) from EF2, allowing diphthine amidation by Dph6 to occur and thereby coupling diphthine synthesis to the terminal step in the pathway. Remarkably, the study by Uthman et al. suggests that Dph5 has a novel role as an EF2 inhibitor that affects cell growth when diphthamide synthesis is blocked or incomplete and, importantly, shows that diphthamide promotes the accuracy of EF2 performance during translation. PMID- 28357241 TI - Cell-autonomous mechanisms of chronological aging in the yeast Saccharomyces cerevisiae. AB - A body of evidence supports the view that the signaling pathways governing cellular aging - as well as mechanisms of their modulation by longevity-extending genetic, dietary and pharmacological interventions - are conserved across species. The scope of this review is to critically analyze recent advances in our understanding of cell-autonomous mechanisms of chronological aging in the budding yeast Saccharomyces cerevisiae. Based on our analysis, we propose a concept of a biomolecular network underlying the chronology of cellular aging in yeast. The concept posits that such network progresses through a series of lifespan checkpoints. At each of these checkpoints, the intracellular concentrations of some key intermediates and products of certain metabolic pathways - as well as the rates of coordinated flow of such metabolites within an intricate network of intercompartmental communications - are monitored by some checkpoint-specific "master regulator" proteins. The concept envisions that a synergistic action of these master regulator proteins at certain early-life and late-life checkpoints modulates the rates and efficiencies of progression of such processes as cell metabolism, growth, proliferation, stress resistance, macromolecular homeostasis, survival and death. The concept predicts that, by modulating these vital cellular processes throughout lifespan (i.e., prior to an arrest of cell growth and division, and following such arrest), the checkpoint-specific master regulator proteins orchestrate the development and maintenance of a pro- or anti-aging cellular pattern and, thus, define longevity of chronologically aging yeast. PMID- 28357245 TI - Genome evolution in yeast reveals connections between rare mutations in human cancers. AB - Cancer cells are riddled with mutations. Less than one percent of these are thought to be mutations that drive cancer phenotypes. However, a recent study conducted on the yeast knockout collections by Teng et al. [Mol. Cell (2013) 52: 485-494] provides hard evidence that single gene deletions/mutations in most non essential genes can drive the selection for cancer-like mutations. PMID- 28357247 TI - Effect of paraquat-induced oxidative stress on gene expression and aging of the filamentous ascomycete Podospora anserina AB - Aging of biological systems is influenced by various factors, conditions and processes. Among others, processes allowing organisms to deal with various types of stress are of key importance. In particular, oxidative stress as the result of the generation of reactive oxygen species (ROS) at the mitochondrial respiratory chain and the accumulation of ROS-induced molecular damage has been strongly linked to aging. Here we view the impact of ROS from a different angle: their role in the control of gene expression. We report a genome-wide transcriptome analysis of the fungal aging model Podospora anserina grown on medium containing paraquat (PQ). This treatment leads to an increased cellular generation and release of H2O2, a reduced growth rate, and a decrease in lifespan. The combined challenge by PQ and copper has a synergistic negative effect on growth and lifespan. The data from the transcriptome analysis of the wild type cultivated under PQ-stress and their comparison to those of a longitudinal aging study as well as of a copper-uptake longevity mutant of P. anserina revealed that PQ stress leads to the up-regulation of transcripts coding for components involved in mitochondrial remodeling. PQ also affects the expression of copper-regulated genes suggesting an increase of cytoplasmic copper levels as it has been demonstrated earlier to occur during aging of P. anserina and during senescence of human fibroblasts. This effect may result from the induction of the mitochondrial permeability transition pore via PQ-induced ROS, leading to programmed cell death as part of an evolutionary conserved mechanism involved in biological aging and lifespan control. PMID- 28357249 TI - Mutagenesis by host antimicrobial peptides: insights into microbial evolution during chronic infections. AB - Antimicrobial peptides (AMPs) are produced by the mammalian immune system to fight invading pathogens. The best understood function of AMPs is to integrate into the membranes of microbes, thereby disrupting and killing cells. However, a recent study [PLoS Pathogens (2014) 10, e1004083] provides evidence that at subinhibitory levels, AMPs promote mutations in bacterial DNA, which enhance bacterial survival. In particular, in the bacterium Pseudomonas aeruginosa, one AMP called LL-37 can promote mutations, which enable the bacteria to overproduce a protective sugar coating, a process called mucoid conversion. P. aeruginosa mucoid conversion is a major risk factor for those suffering from cystic fibrosis (CF), one of the most common lethal, heritable diseases in the US. LL-37 was found to produce mutations by penetrating the bacterial cell and binding to bacterial DNA. It was proposed that LL-37 binding DNA disrupts normal DNA replication and potentiates mutations. Importantly, LL-37 induced mutagenesis was also found to promote resistance to rifampicin in both P. aeruginosa and E. coli. This suggests that AMP-induced mutagenesis may be important for a broad range of chronic diseases and pathogens. PMID- 28357248 TI - Exogenous addition of histidine reduces copper availability in the yeast Saccharomyces cerevisiae. AB - The basic amino acid histidine inhibited yeast cell growth more severely than lysine and arginine. Overexpression of CTR1, which encodes a high-affinity copper transporter on the plasma membrane, or addition of copper to the medium alleviated this cytotoxicity. However, the intracellular level of copper ions was not decreased in the presence of excess histidine. These results indicate that histidine cytotoxicity is associated with low copper availability inside cells, not with impaired copper uptake. Furthermore, histidine did not affect cell growth under limited respiration conditions, suggesting that histidine cytotoxicity is involved in deficiency of mitochondrial copper. PMID- 28357250 TI - Where antibiotic resistance mutations meet quorum-sensing. AB - We do not need to rehearse the grim story of the global rise of antibiotic resistant microbes. But what if it were possible to control the rate with which antibiotic resistance evolves by de novo mutation? It seems that some bacteria may already do exactly that: they modify the rate at which they mutate to antibiotic resistance dependent on their biological environment. In our recent study [Krasovec, et al. Nat. Commun. (2014), 5, 3742] we find that this modification depends on the density of the bacterial population and cell-cell interactions (rather than, for instance, the level of stress). Specifically, the wild-type strains of Escherichia coli we used will, in minimal glucose media, modify their rate of mutation to rifampicin resistance according to the density of wild-type cells. Intriguingly, the higher the density, the lower the mutation rate (Figure 1). Why this novel density-dependent 'mutation rate plasticity' (DD MRP) occurs is a question at several levels. Answers are currently fragmentary, but involve the quorum-sensing gene luxS and its role in the activated methyl cycle. PMID- 28357251 TI - A non-proteolytic function of ubiquitin in transcription repression. AB - Regulation of transcription is vitally important for maintaining normal cellular homeostasis and is also the basis for cellular differentiation, morphogenesis and the adaptability of any organism. Transcription activators, which orchestrate time and locus-specific assembly of complex transcription machinery, act as key players in these processes. One way in which these activators are controlled is by the covalent attachment of the conserved protein, ubiquitin (Ub), which can serve as either a proteolytic or non-proteolytic signal. For a subset of the activators, polyubiquitination-dependent degradation of the activator controls its abundance. In these cases transcription activation can require protein synthesis as well as internal or external stimulus. In contrast, other activators have been reported to undergo mono- or oligoubiquitination that does not lead to protein degradation. The mechanisms by which monoubiquitination of transcription activators affect their activities have been poorly understood. In a recent study, we demonstrated that monoubiquitination of some transcription activators can inhibit transcription by recruiting the AAA+ ATPase Cdc48 (also known in metazoan organisms as p97 or valosin-contain protein, VCP), which then extracts the ubiquitinated activator from DNA. PMID- 28357252 TI - Multiple metabolic requirements for size homeostasis and initiation of division in Saccharomyces cerevisiae. AB - Most cells must grow before they can divide, but it is not known how cells determine when they have grown enough so they can commit to a new round of cell division. Several parameters affect the timing of initiation of division: cell size at birth, the size cells have to reach when they commit to division, and how fast they reach that size. We report that Saccharomyces cerevisiae mutants in metabolic and biosynthetic pathways differ in these variables, controlling the timing of initiation of cell division in various ways. Some mutants affect the size at birth, size at initiation of division, the rate of increase in size, or any combination of the above. Furthermore, we show that adenylate kinase, encoded by ADK1, is a significant determinant of the efficiency of size control mechanisms. Finally, our data argue strongly that the cell size at division is not necessarily a function of the rate cells increase in size in the G1 phase of the cell cycle. Taken together, these findings reveal an unexpected diversity in the G1 cell cycle phenotypes of metabolic and biosynthetic mutants, suggesting that growth requirements for cell division are multiple, distinct and imposed throughout the G1 phase of the cell cycle. PMID- 28357253 TI - The replication timing program in the hands of two HDACs. AB - In eukaryotes, duplication of genomic information depends on the sequential activation of multiple replication origins distributed along the chromosomes. Replication origins differ in initiation time, chromatin structure and three dimensional position in the nucleus. Recently, we have performed a systematic analysis of the role of histone deacetylases (HDACs) in the regulation of origin activity in budding yeast. We have found that the epigenetic regulation of repetitive sequences is a key determinant of the DNA replication program. Indeed, our study revealed that two histone deacetylases, Rpd3 and Sir2, have opposite effects on the replication timing program. Rpd3 delays initiation at late origins, whereas Sir2 promotes efficient activation of early origins. Remarkably, we also found that Rpd3 and Sir2 regulate initiation at ~200 replication origins located within the ribosomal DNA (rDNA) array. We propose that this epigenetic regulation of repetitive origins controls the replication timing program by modulating the availability of limiting initiation factors. PMID- 28357246 TI - Sphingolipids and mitochondrial function, lessons learned from yeast. AB - Mitochondrial dysfunction is a hallmark of several neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, but also of cancer, diabetes and rare diseases such as Wilson's disease (WD) and Niemann Pick type C1 (NPC). Mitochondrial dysfunction underlying human pathologies has often been associated with an aberrant cellular sphingolipid metabolism. Sphingolipids (SLs) are important membrane constituents that also act as signaling molecules. The yeast Saccharomyces cerevisiae has been pivotal in unraveling mammalian SL metabolism, mainly due to the high degree of conservation of SL metabolic pathways. In this review we will first provide a brief overview of the major differences in SL metabolism between yeast and mammalian cells and the use of SL biosynthetic inhibitors to elucidate the contribution of specific parts of the SL metabolic pathway in response to for instance stress. Next, we will discuss recent findings in yeast SL research concerning a crucial signaling role for SLs in orchestrating mitochondrial function, and translate these findings to relevant disease settings such as WD and NPC. In summary, recent research shows that S. cerevisiae is an invaluable model to investigate SLs as signaling molecules in modulating mitochondrial function, but can also be used as a tool to further enhance our current knowledge on SLs and mitochondria in mammalian cells. PMID- 28357254 TI - Time resolved DNA occupancy dynamics during the respiratory oscillation uncover a global reset point in the yeast growth program. AB - The structural dynamics of chromatin have been implicated in the regulation of fundamental eukaryotic processes, such as DNA transcription, replication and repair. Although previous studies have revealed that the chromatin landscape, nucleosome remodeling and histone modification events are intimately tied into cellular energetics and redox state, few studies undertake defined time-resolved measurements of these state variables. Here, we use metabolically synchronous, continuously-grown yeast cultures to measure DNA occupancy and track global patterns with respect to the metabolic state of the culture. Combined with transcriptome analyses and ChIP-qPCR experiments, these paint an intriguing picture where genome-wide nucleosome focusing occurs during the recovery of energy charge, followed by clearance of the promoter regions and global transcriptional slow-down, thus indicating a nucleosome-mediated "reset point" for the cycle. The reset begins at the end of the catabolic and stress-response transcriptional programs and ends prior to the start of the anabolic and cell growth transcriptional program, and the histones on genes from both the catabolic and anabolic superclusters are deacetylated. PMID- 28357255 TI - Extracellular calcium triggers unique transcriptional programs and modulates staurosporine-induced cell death in Neurospora crassa. AB - Alterations in the intracellular levels of calcium are a common response to cell death stimuli in animals and fungi and, particularly, in the Neurospora crassa response to staurosporine. We highlight the importance of the extracellular availability of Ca2+ for this response. Limitation of the ion in the culture medium further sensitizes cells to the drug and results in increased accumulation of reactive oxygen species (ROS). Conversely, an approximately 30-fold excess of external Ca2+ leads to increased drug tolerance and lower ROS generation. In line with this, distinct staurosporine-induced cytosolic Ca2+ signaling profiles were observed in the absence or presence of excessive external Ca2+. High-throughput RNA sequencing revealed that different concentrations of extracellular Ca2+ define distinct transcriptional programs. Our transcriptional profiling also pointed to two putative novel Ca2+-binding proteins, encoded by the NCU08524 and NCU06607 genes, and provides a reference dataset for future investigations on the role of Ca2+ in fungal biology. PMID- 28357257 TI - Combinatorial stress responses: direct coupling of two major stress responses in Escherichia coli. AB - Nitrogen is an essential element for all life, and this is no different for the bacterial cell. Numerous cellular macromolecules contain nitrogen, including proteins, nucleic acids and cell wall components. In Escherichia coli and related bacteria, the nitrogen stress (Ntr) response allows cells to rapidly sense and adapt to nitrogen limitation by scavenging for alternative nitrogen sources through the transcriptional activation of transport systems and catabolic and biosynthetic operons by the global transcriptional regulator NtrC. Nitrogen starved bacterial cells also synthesize the (p)ppGpp effector molecules of a second global bacterial stress response - the stringent response. Recently, we showed that the transcription of relA, the gene which encodes the major (p)ppGpp synthetase in E. coli, is activated by NtrC during nitrogen starvation. Our results revealed that in E. coli and related bacteria, NtrC functions in combinatorial stress and serves to couple two major stress responses, the Ntr response and stringent response. PMID- 28357256 TI - Cell wall dynamics modulate acetic acid-induced apoptotic cell death of Saccharomyces cerevisiae. AB - Acetic acid triggers apoptotic cell death in Saccharomyces cerevisiae, similar to mammalian apoptosis. To uncover novel regulators of this process, we analyzed whether impairing MAPK signaling affected acetic acid-induced apoptosis and found the mating-pheromone response and, especially, the cell wall integrity pathways were the major mediators, especially the latter, which we characterized further. Screening downstream effectors of this pathway, namely targets of the transcription factor Rlm1p, highlighted decreased cell wall remodeling as particularly important for acetic acid resistance. Modulation of cell surface dynamics therefore emerges as a powerful strategy to increase acetic acid resistance, with potential application in industrial fermentations using yeast, and in biomedicine to exploit the higher sensitivity of colorectal carcinoma cells to apoptosis induced by acetate produced by intestinal propionibacteria. PMID- 28357258 TI - Prokaryotic ancestry and gene fusion of a dual localized peroxiredoxin in malaria parasites. AB - Horizontal gene transfer has emerged as a crucial driving force for the evolution of eukaryotes. This also includes Plasmodium falciparum and related economically and clinically relevant apicomplexan parasites, whose rather small genomes have been shaped not only by natural selection in different host populations but also by horizontal gene transfer following endosymbiosis. However, there is rather little reliable data on horizontal gene transfer between animal hosts or bacteria and apicomplexan parasites. Here we show that apicomplexan homologues of peroxiredoxin 5 (Prx5) have a prokaryotic ancestry and therefore represent a special subclass of Prx5 isoforms in eukaryotes. Using two different immunobiochemical approaches, we found that the P. falciparum Prx5 homologue is dually localized to the parasite plastid and cytosol. This dual localization is reflected by a modular Plasmodium-specific gene architecture consisting of two exons. Despite the plastid localization, our phylogenetic analyses contradict an acquisition by secondary endosymbiosis and support a gene fusion event following a horizontal prokaryote-to-eukaryote gene transfer in early apicomplexans. The results provide unexpected insights into the evolution of apicomplexan parasites as well as the molecular evolution of peroxiredoxins, an important family of ubiquitous, usually highly concentrated thiol-dependent hydroperoxidases that exert functions as detoxifying enzymes, redox sensors and chaperones. PMID- 28357260 TI - Targeting of chromatin readers: a novel strategy used by the Shigella flexneri virulence effector OspF to reprogram transcription. AB - Shigella flexneri, a gram-negative bacterium responsible of bacillary dysentery, uses multiple strategies to overcome host immune defense. We have decrypted how this bacterium manipulates host-cell chromatin binders to take control of immune gene expression. We found that OspF, an injected virulence factor previously identified as a repressor of immune gene expression, targets the chromatin reader HP1gamma. Heterochromatin Protein 1 family members specifically recognize and bind histone H3 methylated at Lys 9. Although initially identified as chromatin associated transcriptional silencers in heterochromatin, their location in euchromatin indicates an active role in gene expression. Notably, HP1gamma phosphorylation at Serine 83 defines a subpopulation exclusively located to euchromatin, targeted to the site of transcriptional elongation. We showed that OspF directly interacts with HP1gamma, and causes HP1 dephosphorylation, suggesting a model in which this virulence effector "uses" HP1 proteins as beacons to target and repress immune gene expression (Harouz, et al. EMBO J (2014)). OspF alters HP1gamma phosphorylation mainly by inactivating the Erk activated kinase MSK1, spotlighting it as a new HP1 kinase. In vivo, infectious stresses trigger HP1gamma phosphorylation in the colon, principally in the lamina propria and the intestinal crypts. Several lines of evidence suggest that HP1 proteins are modified as extensively as histones, and decrypting the impact of these HP1 post-translational modifications on their transcriptional activities in vivo will be the next challenges to be taken up. PMID- 28357261 TI - A pseudokinase couples signaling pathways to enable asymmetric cell division in a bacterium. AB - Bacteria face complex decisions when initiating developmental events such as sporulation, nodulation, virulence, and asymmetric cell division. These developmental decisions require global changes in genomic readout, and bacteria typically employ intricate (yet poorly understood) signaling networks that enable changes in cell function. The bacterium Caulobacter crescentus divides asymmetrically to yield two functionally distinct cells: a motile, chemotactic swarmer cell, and a sessile stalked cell with replication and division capabilities. Work from several Caulobacter labs has revealed that differentiation requires concerted regulation by several two-component system (TCS) signaling pathways that are differentially positioned at the poles of the predivisional cell (Figure 1). The strict unidirectional flow from histidine kinase (HK) to the response regulator (RR), observed in most studied TCS, is difficult to reconcile with the notion that information can be transmitted between two or more TCS signaling pathways. In this study, we uncovered a mechanism by which daughter cell fate, which is specified by the DivJ-DivK-PleC system and effectively encoded in the phosphorylation state of the single-domain RR DivK, is communicated to the CckA-ChpT-CtrA signaling pathway that regulates more than 100 genes for polar differentiation, replication initiation and cell division. Using structural biology and biochemical findings we proposed a mechanistic basis for TCS pathway coupling in which the DivL pseudokinase is repurposed as a sensor rather than participant in phosphotransduction. PMID- 28357259 TI - Two distinct and competitive pathways confer the cellcidal actions of artemisinins. AB - The biological actions of artemisinin (ART), an antimalarial drug derived from Artemisia annua, remain poorly understood and controversial. Besides potent antimalarial activity, some of artemisinin derivatives (together with artemisinin, hereafter referred to as ARTs), in particular dihydroartemisinin (DHA), are also associated with anticancer and other antiparasitic activities. In this study, we used baker's yeast Saccharomyces cerevisiae as cellular and genetic model to investigate the molecular and cellular properties of ARTs. Two clearly separable pathways exist. While all ARTs exhibit potent anti mitochondrial actions as shown before, DHA exerts an additional strong heme dependent, likely mitochondria-independent inhibitory action. More importantly, heme antagonizes the mitochondria-dependent cellcidal action. Indeed, when heme synthesis was inhibited, the mitochondria-dependent cellcidal action of ARTs could be dramatically strengthened, and significant yeast growth inhibition at as low as 100 nM ART, an increase of about 25 folds in sensitivity, was observed. We conclude that ARTs are endowed with two major and distinct types of properties: a potent and specific mitochondria-dependent reaction and a more general and less specific heme-mediated reaction. The competitive nature of these two actions could be explained by their shared source of the consumable ARTs, so that inhibition of the heme-mediated degradation pathway would enable more ARTs to be available for the mitochondrial action. These properties of ARTs can be used to interpret the divergent antimalarial and anticancer actions of ARTs. PMID- 28357262 TI - Starting with a degron: N-terminal formyl-methionine of nascent bacterial proteins contributes to their proteolytic control. PMID- 28357263 TI - Elongation factor-P at the crossroads of the host-endosymbiont interface. AB - Elongation factor P (EF-P) is an ancient bacterial translational factor that aids the ribosome in polymerizing oligo-prolines. EF-P structurally resembles tRNA and binds in-between the exit and peptidyl sites of the ribosome to accelerate the intrinsically slow reaction of peptidyl-prolyl bond formation. Recent studies have identified in separate organisms, two evolutionarily convergent EF-P post translational modification systems (EPMS), split predominantly between gammaproteobacteria, and betaproteobacteria. In both cases EF-P receives a post translational modification, critical for its function, on a highly conserved residue that protrudes into the peptidyl-transfer center of the ribosome. EPMSs are comprised of a gene(s) that synthesizes the precursor molecule used in modifying EF-P, and a gene(s) encoding an enzyme that reacts with the precursor molecule to catalyze covalent attachment to EF-P. However, not all organisms genetically encode a complete EPMS. For instance, some symbiotic bacteria harbor efp and the corresponding gene that enzymatically attaches the modification, but lack the ability to synthesize the substrate used in the modification reaction. Here we highlight the recent discoveries made regarding EPMSs, with a focus on how these incomplete modification pathways shape or have been shaped by the endosymbiont-host relationship. PMID- 28357264 TI - Per aspera ad astra: When harmful chromosomal translocations become a plus value in genetic evolution. Lessons from Saccharomyces cerevisiae. AB - In this review we will focus on chromosomal translocations (either spontaneous or induced) in budding yeast. Indeed, very few organisms tolerate so well aneuploidy like Saccharomyces, allowing in depth studies on chromosomal numerical aberrations. Many wild type strains naturally develop chromosomal rearrangements while adapting to different environmental conditions. Translocations, in particular, are valuable not only because they naturally drive species evolution, but because they might allow the artificial generation of new strains that can be optimized for industrial purposes. In this area, several methodologies to artificially trigger chromosomal translocations have been conceived in the past years, such as the chromosomal fragmentation vector (CFV) technique, the Cre-loxP procedure, the FLP/FRT recombination method and, recently, the bridge - induced translocation (BIT) system. An overview of the methodologies to generate chromosomal translocations in yeast will be presented and discussed considering advantages and drawbacks of each technology, focusing in particular on the recent BIT system. Translocants are important for clinical studies because translocated yeast cells resemble cancer cells from morphological and physiological points of view and because the translocation event ensues in a transcriptional de regulation with a subsequent multi-factorial genetic adaptation to new, selective environmental conditions. The phenomenon of post-translocational adaptation (PTA) is discussed, providing some new unpublished data and proposing the hypothesis that translocations may drive evolution through adaptive genetic selection. PMID- 28357266 TI - A bacterial volatile signal for biofilm formation. AB - Bacteria constantly monitor the environment they reside in and respond to potential changes in the environment through a variety of signal sensing and transduction mechanisms in a timely fashion. Those signaling mechanisms often involve application of small, diffusible chemical molecules. Volatiles are a group of small air-transmittable chemicals that are produced universally by all kingdoms of organisms. Past studies have shown that volatiles can function as cell-cell communication signals not only within species, but also cross-species. However, little is known about how the volatile-mediated signaling mechanism works. In our recent study (Chen, et al. mBio (2015), 6: e00392-15), we demonstrated that the soil bacterium Bacillus subtilis uses acetic acid as a volatile signal to coordinate the timing of biofilm formation within physically separated cells in the community. We also showed that the bacterium possesses an intertwined gene network to produce, secrete, sense, and respond to acetic acid, in stimulating biofilm formation. Interestingly, many of those genes are highly conserved in other bacterial species, raising the possibility that acetic acid may act as a volatile signal for cross-species communication. PMID- 28357265 TI - DNA damage checkpoint adaptation genes are required for division of cells harbouring eroded telomeres. AB - In budding yeast, telomerase and the Cdc13p protein are two key players acting to ensure telomere stability. In the absence of telomerase, cells eventually enter a growth arrest which only few can overcome via a conserved process; such cells are called survivors. Survivors rely on homologous recombination-dependent mechanisms for telomeric repeat addition. Previously, we showed that such survivor cells also manage to bypass the loss of the essential Cdc13p protein to give rise to Cdc13-independent (or cap-independent) strains. Here we show that Cdc13 independent cells grow with persistently recognized DNA damage, which does not however result in a checkpoint activation; thus no defect in cell cycle progression is detectable. The absence of checkpoint signalling rather is due to the accumulation of mutations in checkpoint genes such as RAD24 or MEC1. Importantly, our results also show that cells that have lost the ability to adapt to persistent DNA damage, also are very much impaired in generating cap independent cells. Altogether, these results show that while the capping process can be flexible, it takes a very specific genetic setup to allow a change from canonical capping to alternative capping. We hypothesize that in the alternative capping mode, genome integrity mechanisms are abrogated, which could cause increased mutation frequencies. These results from yeast have clear parallels in transformed human cancer cells and offer deeper insights into processes operating in pre-cancerous human cells that harbour eroded telomeres. PMID- 28357270 TI - Groupthink: chromosomal clustering during transcriptional memory. PMID- 28357269 TI - Micafungin induced apoptosis in Candida parapsilosis independent of its susceptibility to micafungin. AB - We hypothesized that the cell wall inhibitor micafungin (MICA) induces apoptosis in both MICA-susceptible (MICA-S) and MICA-non-susceptible (MICA-NS) Candida parapsilosis. Antifungal activity and apoptosis were analyzed in MICA-S and MICA NS C. parapsilosis strains following exposure to micafungin for 3 h at 37 degrees C in RPMI 1640 medium. Apoptosis was characterized by detecting phosphatidylserine externalization (PS), plasma membrane integrity, reactive oxygen species (ROS) generation, mitochondrial membrane potential changes, adenosine triphosphate (ATP) release, and caspase-like activity. Apoptosis was detected in MICA exposed (0.25 to 1 mg/L) susceptible C. parapsilosis strains and was associated with apoptosis of 20-52% of analyzed cells versus only 5-30% of apoptosis in MICA-NS cells exposed to micafungin (0.5 to 2 mg/L; P = 0.001). The MICA antifungal activity was correlated with apoptotic cells showing increased dihydrorhodamine-123 staining (indicating ROS production), Rh-123 staining (decreased mitochondrial membrane potential), elevated ATP, and increased metacaspase activity. In conclusion, MICA is pro-apoptotic in MICA-S cells, but still exerts apoptotic effects in MICA -NS C. parapsilosis. PMID- 28357267 TI - Electron microscopy for ultrastructural analysis and protein localization in Saccharomyces cerevisiae. AB - The yeast Saccharomyces cerevisiae is a key model system for studying of a multitude of cellular processes because of its amenability to genetics, molecular biology and biochemical procedures. Ultrastructural examinations of this organism, though, are traditionally difficult because of the presence of a thick cell wall and the high density of cytoplasmic proteins. A series of recent methodological and technical developments, however, has revived interest in morphological analyses of yeast (e.g. 123). Here we present a review of established and new methods, from sample preparation to imaging, for the ultrastructural analysis of S. cerevisiae. We include information for the use of different fixation methods, embedding procedures, approaches for contrast enhancement, and sample visualization techniques, with references to successful examples. The goal of this review is to guide researchers that want to investigate a particular process at the ultrastructural level in yeast by aiding in the selection of the most appropriate approach to visualize a specific structure or subcellular compartment. PMID- 28357268 TI - Oxygen availability strongly affects chronological lifespan and thermotolerance in batch cultures of Saccharomyces cerevisiae. AB - Stationary-phase (SP) batch cultures of Saccharomyces cerevisiae, in which growth has been arrested by carbon-source depletion, are widely applied to study chronological lifespan, quiescence and SP-associated robustness. Based on this type of experiments, typically performed under aerobic conditions, several roles of oxygen in aging have been proposed. However, SP in anaerobic yeast cultures has not been investigated in detail. Here, we use the unique capability of S. cerevisiae to grow in the complete absence of oxygen to directly compare SP in aerobic and anaerobic bioreactor cultures. This comparison revealed strong positive effects of oxygen availability on adenylate energy charge, longevity and thermotolerance during SP. A low thermotolerance of anaerobic batch cultures was already evident during the exponential growth phase and, in contrast to the situation in aerobic cultures, was not substantially increased during transition into SP. A combination of physiological and transcriptome analysis showed that the slow post-diauxic growth phase on ethanol, which precedes SP in aerobic, but not in anaerobic cultures, endowed cells with the time and resources needed for inducing longevity and thermotolerance. When combined with literature data on acquisition of longevity and thermotolerance in retentostat cultures, the present study indicates that the fast transition from glucose excess to SP in anaerobic cultures precludes acquisition of longevity and thermotolerance. Moreover, this study demonstrates the importance of a preceding, calorie-restricted conditioning phase in the acquisition of longevity and stress tolerance in SP yeast cultures, irrespective of oxygen availability. PMID- 28357271 TI - Yeast proteinopathy models: a robust tool for deciphering the basis of neurodegeneration. AB - Protein quality control or proteostasis is an essential determinant of basic cell health and aging. Eukaryotic cells have evolved a number of proteostatic mechanisms to ensure that proteins retain functional conformation, or are rapidly degraded when proteins misfold or self-aggregate. Disruption of proteostasis is now widely recognized as a key feature of aging related illness, specifically neurodegenerative disease. For example, Alzheimer's disease, Huntington's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis (ALS) each target and afflict distinct neuronal cell subtypes, yet this diverse array of human pathologies share the defining feature of aberrant protein aggregation within the affected cell population. Here, we review the use of budding yeast as a robust proxy to study the intersection between proteostasis and neurodegenerative disease. The humanized yeast model has proven to be an amenable platform to identify both, conserved proteostatic mechanisms across eukaryotic phyla and novel disease specific molecular dysfunction. Moreover, we discuss the intriguing concept that yeast specific proteins may be utilized as bona fide therapeutic agents, to correct proteostasis errors across various forms of neurodegeneration. PMID- 28357273 TI - Histone deacetylases: revealing the molecular base of dimorphism in pathogenic fungi. AB - Fungi, as every living organism, interact with the external world and have to adapt to its fluctuations. For pathogenic fungi, such interaction involves adapting to the hostile environment of their host. Survival depends on the capacity of fungi to detect and respond to external stimuli, which is achieved through a tight and efficient genetic control. Chromatin modifications represent a well-known layer of regulation that controls gene expression in response to environmental signals. However, less is known about the chromatin modifications that are involved in fungal virulence and the specific cues and signalling pathways that target chromatin modifications to specific genes. In a recently published study, our research group identified one such regulatory pathway. We demonstrated that the histone deacetylase (HDAC) Hos2 is involved in yeast-to hyphal transition (dimorphism) and it is associated with the virulence of the maize pathogen Ustilago maydis, the causative agent of smut disease in corn. Hos2 activates mating-type genes by directly binding to their gene bodies. Furthermore, Hos2 acts downstream of the nutrient-sensing cyclic AMP-Protein Kinase A pathway. We also found that another HDAC, Clr3, contributes to this regulation, possibly in cooperation with Hos2. As a whole, our data suggest that there is a direct link between changes in the environment and acetylation of nucleosomes within certain genes. We propose that histone acetylation is critical to the proper timing and induction of transcription of the genes encoding factors that coordinate changes in morphology with pathogenesis. PMID- 28357272 TI - A central role for TOR signalling in a yeast model for juvenile CLN3 disease. AB - Yeasts provide an excellent genetically tractable eukaryotic system for investigating the function of genes in their biological context, and are especially relevant for those conserved genes that cause disease. We study the role of btn1, the orthologue of a human gene that underlies an early onset neurodegenerative disease (juvenile CLN3 disease, neuronal ceroid lipofuscinosis (NCLs) or Batten disease) in the fission yeast Schizosaccharomyces pombe. A global screen for genetic interactions with btn1 highlighted a conserved key signalling hub in which multiple components functionally relate to this conserved disease gene. This signalling hub includes two major mitogen-activated protein kinase (MAPK) cascades, and centers on the Tor kinase complexes TORC1 and TORC2. We confirmed that yeast cells modelling CLN3 disease exhibit features consistent with dysfunction in the TORC pathways, and showed that modulating TORC function leads to a comprehensive rescue of defects in this yeast disease model. The same pathways may be novel targets in the development of therapies for the NCLs and related diseases. PMID- 28357274 TI - Quorum protection, growth and survival. AB - For the growth of a cell culture, one inoculates not with one cell but with a quorum of cells. This most often a requirement, not just a convenience, and most of us take this for granted without question. Here this observation is re examined to understand why a quorum may be required to grow cells. The importance of quorums may be widespread in the aspects of microbiology they affect. It is very likely that quorums are connected with and have a large impact on the determination of Minimal Inhibitory Concentrations. It is also possible that low cell density may adversely affect cell survival, however, this is an area where even less is known. The need for a quorum might affect other aspects of microbial cell culture, cell isolation and cell preservation. Effects also extend to mammalian cell culture. Here I seek to review studies that have been documented and speculate on how the information might be utilized in the future. PMID- 28357276 TI - Microbial hara-kiri: Exploiting lysosomal cell death in malaria parasites. AB - The antimalarial drug chloroquine (CQ) has been sidelined in the fight against falciparum malaria due to wide-spread CQ resistance. Replacement drugs like sulfadoxine, pyrimethamine and mefloquine have also since been surpassed with the evolution of multi-drug resistant parasites. Even the currently recommended artemisinin-based combination therapies show signs of compromise due to the recent spread of artemisinin delayed-clearance parasites. Though there have been promising breakthroughs in the pursuit of new effective antimalarials, the development and strategic deployment of such novel chemical entities takes time. We therefore argue that there is a crucial need to re-examine the usefulness of 'outdated' drugs like chloroquine, and explore if they might be effective alternative therapies in the interim. We suggest that a novel parasite cell death (pCD) pathway may be exploited through the reformulation of CQ to address this need. PMID- 28357275 TI - Arabidopsis Bax Inhibitor-1 inhibits cell death induced by pokeweed antiviral protein in Saccharomyces cerevisiae. AB - Apoptosis is an active form of programmed cell death (PCD) that plays critical roles in the development, differentiation and resistance to pathogens in multicellular organisms. Ribosome inactivating proteins (RIPs) are able to induce apoptotic cell death in mammalian cells. In this study, using yeast as a model system, we showed that yeast cells expressing pokeweed antiviral protein (PAP), a single-chain ribosome-inactivating protein, exhibit apoptotic-like features, such as nuclear fragmentation and ROS production. We studied the interaction between PAP and AtBI-1 (Arabidopsis thaliana Bax Inhibitor-1), a plant anti-apoptotic protein, which inhibits Bax induced cell death. Cells expressing PAP and AtBI-1 were able to survive on galactose media compared to PAP alone, indicating a reduction in the cytotoxicity of PAP in yeast. However, PAP was able to depurinate the ribosomes and to inhibit total translation in the presence of AtBI 1. A C-terminally deleted AtBI-1 was able to reduce the cytotoxicity of PAP. Since anti-apoptotic proteins form heterodimers to inhibit the biological activity of their partners, we used a co-immunoprecipitation assay to examine the binding of AtBI-1 to PAP. Both full length and C-terminal deleted AtBI-1 were capable of binding to PAP. These findings indicate that PAP induces cell death in yeast and AtBI-1 inhibits cell death induced by PAP without affecting ribosome depurination and translation inhibition. PMID- 28357277 TI - EzrA: a spectrin-like scaffold in the bacterial cell division machinery. AB - Much progress has been made in identifying the components of the divisome, the assembly of proteins that undertakes the vital process of cell division in bacteria. However, how the highly interdependent processes on either side of the membrane are coordinated during division is a major unresolved question. How is the degradation and synthesis of the cell wall on the outside of the cell coordinated with cytokinesis and membrane fission, which are driven from the inside of the cell by the tubulin homologue FtsZ? A possible key mediator of such coordination is the membrane protein EzrA, as it interacts both with FtsZ and the penicillin binding proteins (PBPs) that synthesize peptidoglycan. Cleverley et al. [Nature Communications (2014) 5, 5421] have recently solved the crystal structure of the cytoplasmic domain of B. subtilis EzrA, which points to an important scaffolding role for EzrA in the divisome. The structure resembles the eukaryotic, cytoskeletal spectrin proteins, which link actin filaments in the cytoskeleton and also connect the actin cytoskeleton to membrane-bound integrin proteins. PMID- 28357278 TI - Live fast, die soon: cell cycle progression and lifespan in yeast cells. AB - Our understanding of lifespan has benefited enormously from the study of a simple model, the yeast Saccharomyces cerevisiae. Although a unicellular organism, yeasts undergo many of the processes directly related with aging that to some extent are conserved in mammalian cells. Nutrient-limiting conditions have been involved in lifespan extension, especially in the case of caloric restriction, which also has a direct impact on cell cycle progression. In fact, other environmental stresses (osmotic, oxidative) that interfere with normal cell cycle progression also influence the lifespan of cells, indicating a relationship between lifespan and cell cycle control. In the present review we compile and discuss new findings related to how cell cycle progression is regulated by other nutrients. We centred this review on the analysis of phosphate, also give some attention to nitrogen, and the impact of these nutrients on lifespan. PMID- 28357279 TI - Mitochondrial type II NAD(P)H dehydrogenases in fungal cell death. AB - During aerobic respiration, cells produce energy through oxidative phosphorylation, which includes a specialized group of multi-subunit complexes in the inner mitochondrial membrane known as the electron transport chain. However, this canonical pathway is branched into single polypeptide alternative routes in some fungi, plants, protists and bacteria. They confer metabolic plasticity, allowing cells to adapt to different environmental conditions and stresses. Type II NAD(P)H dehydrogenases (also called alternative NAD(P)H dehydrogenases) are non-proton pumping enzymes that bypass complex I. Recent evidence points to the involvement of fungal alternative NAD(P)H dehydrogenases in the process of programmed cell death, in addition to their action as overflow systems upon oxidative stress. Consistent with this, alternative NAD(P)H dehydrogenases are phylogenetically related to cell death - promoting proteins of the apoptosis inducing factor (AIF)-family. PMID- 28357281 TI - Characterization of the Maf family of polymorphic toxins in pathogenic Neisseria species. AB - In addition to harmless commensal species, Neisseria genus encompasses two pathogenic species, N. meningitidis (the meningococcus) and N. gonorrhoeae (the gonococcus), which are responsible for meningitis and genital tract infections, respectively. Since the publication of the first Neisseria genome in 2000, the presence of several genomic islands (GI) comprising maf genes has been intriguing. These GIs account for approximately 2% of the genome of the pathogenic Neisseria species and the function of the proteins encoded by maf genes remained unknown. We showed that maf genes encode a functional toxin immunity system where MafB is a toxin neutralized by an immunity protein named MafI. A strain can harbor several MafB/MafI modules with distinct toxic activities. MafB toxins are polymorphic toxins with a conserved N-terminal region and a variable C-terminal region. MafB N-terminal regions consist of a signal peptide and a domain named DUF1020 that is only found in the genus Neisseria. MafB C-terminal regions are highly polymorphic and encode toxic activities. We evidenced the presence of MafB in the culture supernatant of meningococcal cells and we observed a competitive advantage for a strain overexpressing a MafB toxin. Therefore, we characterized a highly variable family of toxin-immunity modules found in multiple loci in pathogenic Neisseria species. PMID- 28357282 TI - New roles for autophagy and spermidine in T cells. AB - The conserved lysosomal degradation pathway autophagy is now recognised as an essential cog in immune function. While functionally widespread in the innate immune system, knowledge of its roles in adaptive immunity is more limited. Although autophagy has been implicated in naive T cell homeostasis, its requirement in antigen-specific T cells during infection was unknown. Using a murine model where the essential autophagy gene Atg7 is deleted in the T cell lineage, we have shown that autophagy is dispensable for effector CD8+ T cell responses, but crucial for the formation of memory CD8+ T cells. Here, we suggest reasons why autophagy might be important for the formation of long-lasting immunity. Like in the absence of autophagy, T cell memory formation during ageing is also defective. We observed diminished autophagy levels in T cells from aged mice, linking autophagy to immunosenescence. Importantly, T cell responses to influenza vaccination could be significantly improved using the autophagy inducing compound spermidine. These results suggest the autophagy pathway as a desirable target to improve aged immunity and modulate T cell function. PMID- 28357280 TI - Yeast as a tool for studying proteins of the Bcl-2 family. AB - Permeabilization of the outer mitochondrial membrane that leads to the release of cytochrome c and several other apoptogenic proteins from mitochondria into cytosol represents a commitment point of apoptotic pathway in mammalian cells. This crucial event is governed by proteins of the Bcl-2 family. Molecular mechanisms, by which Bcl-2 family proteins permeabilize mitochondrial membrane, remain under dispute. Although yeast does not have apparent homologues of these proteins, when mammalian members of Bcl-2 family are expressed in yeast, they retain their activity, making yeast an attractive model system, in which to study their action. This review focuses on using yeast expressing mammalian proteins of the Bcl-2 family as a tool to investigate mechanisms, by which these proteins permeabilize mitochondrial membranes, mechanisms, by which pro- and antiapoptotic members of this family interact, and involvement of other cellular components in the regulation of programmed cell death by Bcl-2 family proteins. PMID- 28357283 TI - Translate to divide: sontrol of the cell cycle by protein synthesis. AB - Protein synthesis underpins much of cell growth and, consequently, cell multiplication. Understanding how proliferating cells commit and progress into the cell cycle requires knowing not only which proteins need to be synthesized, but also what determines their rate of synthesis during cell division. PMID- 28357284 TI - Modeling human Coenzyme A synthase mutation in yeast reveals altered mitochondrial function, lipid content and iron metabolism. AB - Mutations in nuclear genes associated with defective coenzyme A biosynthesis have been identified as responsible for some forms of neurodegeneration with brain iron accumulation (NBIA), namely PKAN and CoPAN. PKAN are defined by mutations in PANK2, encoding the pantothenate kinase 2 enzyme, that account for about 50% of cases of NBIA, whereas mutations in CoA synthase COASY have been recently reported as the second inborn error of CoA synthesis leading to CoPAN. As reported previously, yeast cells expressing the pathogenic mutation exhibited a temperature-sensitive growth defect in the absence of pantothenate and a reduced CoA content. Additional characterization revealed decreased oxygen consumption, reduced activities of mitochondrial respiratory complexes, higher iron content, increased sensitivity to oxidative stress and reduced amount of lipid droplets, thus partially recapitulating the phenotypes found in patients and establishing yeast as a potential model to clarify the pathogenesis underlying PKAN and CoPAN diseases. PMID- 28357285 TI - Modeling non-hereditary mechanisms of Alzheimer disease during apoptosis in yeast. AB - Impaired protein degradation and mitochondrial dysfunction are believed to contribute to neurodegenerative disorders, including Alzheimer disease (AD). In patients suffering from non-hereditary AD, UBB+1, the frameshift variant of ubiquitin B, accumulated in neurons affected by neurofibrillary tangles, which is a pathological hallmark. We established a yeast model expressing high levels of UBB+1, and could demonstrate that UBB+1 interfered with both the ubiquitin proteasome system (UPS) and mitochondrial function. More precisely, UBB+1 promoted the mitochondrion-localized production of the basic amino acids arginine, ornithine, and lysine, which we identified as the decisive toxic event culminating in apoptosis. Inducing the UPS activity at mitochondria prevented the lethal basic amino acid accumulation and avoided UBB+1-triggered cell loss. The arginine/ornithine metabolism is altered in brains of AD patients, and VMS1, the mitochondrion-specific UPS component, co-existed with UBB+1 in neurofibrillary tangles. Therefore, our data suggest that aberrant basic amino acid synthesis is a crucial link between UPS dysfunction and mitochondrial damage during AD progression. PMID- 28357288 TI - Exogenous folates stimulate growth and budding of Candida glabrata. AB - Folate, vitamin B9, is well recognized as being essential for cell growth. The utilization of folate is common to all cells, but the source of it may be quite different. For example, mammalian cells depend on exogenous uptake of folates, while plants and microbes can synthesize them. There has been little consideration of uptake of folate in microbial cells, and studies on the effects of folates in mammalian cells, where conditions are restricted. This study shows that exogenous folates (folic acid or folinic acid), causes Candida glabrata cells suspended in water alone to undergo two cycles of cell division and to form multiple buds. The effect was limited to cells in the stationary phase and more profound in quiescent cells. These data indicate a novel response of yeast to folates that may increase the utility of yeast as a model to study folate transport and signaling. PMID- 28357289 TI - Cytokinins beyond plants: synthesis by Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis (M. tuberculosis) resides mainly inside macrophages, which produce nitric oxide (NO) to combat microbial infections. Earlier studies revealed that proteasome-associated genes are required for M. tuberculosis to resist NO via a previously uncharacterized mechanism. Twelve years later, we elucidated the link between proteasome function and NO resistance in M. tuberculosis in Molecular Cell, 57 (2015), pp. 984-994. In a proteasome degradation-defective mutant, Rv1205, a homologue of the plant enzyme LONELY GUY (LOG) that is involved in the synthesis of phytohormones called cytokinins, accumulates and as a consequence results in the overproduction of cytokinins. Cytokinins break down into aldehydes that kill mycobacteria in the presence of NO. Importantly, this new discovery reveals for the first time that a mammalian bacterial pathogen produces cytokinins and leaves us with the question: why is M. tuberculosis, an exclusively human pathogen, producing cytokinins? PMID- 28357287 TI - Toxoplasma gondii inhibits cytochrome c-induced caspase activation in its host cell by interference with holo-apoptosome assembly. AB - Inhibition of programmed cell death pathways of mammalian cells often facilitates the sustained survival of intracellular microorganisms. The apicomplexan parasite Toxoplasma gondii is a master regulator of host cell apoptotic pathways. Here, we have characterized a novel anti-apoptotic activity of T. gondii. Using a cell free cytosolic extract model, we show that T. gondii interferes with the activities of caspase 9 and caspase 3/7 which have been induced by exogenous cytochrome c and dATP. Proteolytic cleavage of caspases 9 and 3 is also diminished suggesting inhibition of holo-apoptosome function. Parasite infection of Jurkat T cells and subsequent triggering of apoptosome formation by exogenous cytochrome cin vitro and in vivo indicated that T. gondii also interferes with caspase activation in infected cells. Importantly, parasite inhibition of cytochrome c-induced caspase activation considerably contributes to the overall anti-apoptotic activity of T. gondii as observed in staurosporine-treated cells. Co-immunoprecipitation showed that T. gondii abolishes binding of caspase 9 to Apaf-1 whereas the interaction of cytochrome c with Apaf-1 remains unchanged. Finally, T. gondii lysate mimics the effect of viable parasites and prevents holo apoptosome functionality in a reconstituted in vitro system comprising recombinant Apaf-1 and caspase 9. Beside inhibition of cytochrome c release from host cell mitochondria, T. gondii thus also targets the holo-apoptosome assembly as a second mean to efficiently inhibit the caspase-dependent intrinsic cell death pathway. PMID- 28357290 TI - Understanding grapevine-microbiome interactions: implications for viticulture industry. AB - Until recently, the analysis of complex communities such as that of the grapevine microbe holobiont has been limited by the fact that most microbes are not culturable under laboratory conditions (less than 1%). However, metagenomics, the study of the genetic material recovered directly from environmental samples without the need for enrichment or of culturing, has led to open an unprecedented era in the field of microbiology. Importantly, this technological advance has now become so pervasive that it is being regularly applied to explore soils and plants of agricultural interest. Interestingly, many large companies are taking notice, with significant financial investment being used to exploring ways to manipulate the productivity, disease resistance and stress tolerance for crops by influencing the microbiome. To understand which microbes one needs to manipulate to influence this valuable characteristics, we need to sequence the microbiome and capture the genetic and hence functional metabolic information contained therein. For viticulture and other agricultural fields where the crop is also associated to particular flavor properties that may also be manipulated, understanding how the bacteria, fungi and viruses influence the development and hence chemical makeup of the crop is essential. PMID- 28357286 TI - Yeast as a model system to study metabolic impact of selenium compounds. AB - Inorganic Se forms such as selenate or selenite (the two more abundant forms in nature) can be toxic in Saccharomyces cerevisiae cells, which constitute an adequate model to study such toxicity at the molecular level and the functions participating in protection against Se compounds. Those Se forms enter the yeast cell through other oxyanion transporters. Once inside the cell, inorganic Se forms may be converted into selenide through a reductive pathway that in physiological conditions involves reduced glutathione with its consequent oxidation into diglutathione and alteration of the cellular redox buffering capacity. Selenide can subsequently be converted by molecular oxygen into elemental Se, with production of superoxide anions and other reactive oxygen species. Overall, these events result in DNA damage and dose-dependent reversible or irreversible protein oxidation, although additional oxidation of other cellular macromolecules cannot be discarded. Stress-adaptation pathways are essential for efficient Se detoxification, while activation of DNA damage checkpoint and repair pathways protects against Se-mediated genotoxicity. We propose that yeast may be used to improve our knowledge on the impact of Se on metal homeostasis, the identification of Se-targets at the DNA and protein levels, and to gain more insights into the mechanism of Se-mediated apoptosis. PMID- 28357291 TI - A safety catch for ornithine decarboxylase degradation. PMID- 28357295 TI - Handcuffs for bacteria - NDP52 orchestrates xenophagy of intracellular Salmonella. PMID- 28357292 TI - Coordinate responses to alkaline pH stress in budding yeast. AB - Alkalinization of the medium represents a stress condition for the budding yeast Saccharomyces cerevisiae to which this organism responds with profound remodeling of gene expression. This is the result of the modulation of a substantial number of signaling pathways whose participation in the alkaline response has been elucidated within the last ten years. These regulatory inputs involve not only the conserved Rim101/PacC pathway, but also the calcium-activated phosphatase calcineurin, the Wsc1-Pkc1-Slt2 MAP kinase, the Snf1 and PKA kinases and oxidative stress-response pathways. The uptake of many nutrients is perturbed by alkalinization of the environment and, consequently, an impact on phosphate, iron/copper and glucose homeostatic mechanisms can also be observed. The analysis of available data highlights cases in which diverse signaling pathways are integrated in the gene promoter to shape the appropriate response pattern. Thus, the expression of different genes sharing the same signaling network can be coordinated, allowing functional coupling of their gene products. PMID- 28357294 TI - Struggling for breath in Sherbrooke - 1st Symposium on "One mitochondrion, many diseases" in Sherbrooke, Quebec, Canada, March 11th, 2015. PMID- 28357293 TI - Polyamines directly promote antizyme-mediated degradation of ornithine decarboxylase by the proteasome. AB - Ornithine decarboxylase (ODC), a ubiquitin-independent substrate of the proteasome, is a homodimeric protein with a rate-limiting function in polyamine biosynthesis. Polyamines regulate ODC levels by a feedback mechanism mediated by ODC antizyme (OAZ). Higher cellular polyamine levels trigger the synthesis of OAZ and also inhibit its ubiquitin-dependent proteasomal degradation. OAZ binds ODC monomers and targets them to the proteasome. Here, we report that polyamines, aside from their role in the control of OAZ synthesis and stability, directly enhance OAZ-mediated ODC degradation by the proteasome. Using a stable mutant of OAZ, we show that polyamines promote ODC degradation in Saccharomyces cerevisiae cells even when OAZ levels are not changed. Furthermore, polyamines stimulated the in vitro degradation of ODC by the proteasome in a reconstituted system using purified components. In these assays, spermine shows a greater effect than spermidine. By contrast, polyamines do not have any stimulatory effect on the degradation of ubiquitin-dependent substrates. PMID- 28357296 TI - Entamoeba histolytica - tumor necrosis factor: a fatal attraction. PMID- 28357297 TI - Wanted Plasmodium falciparum, dead or alive. AB - Mechanisms of cell death in unicellular parasites have been subjects of debate for the last decade, with studies demonstrating evidence of apoptosis or non apoptosis like mechanisms, including necrosis, and autophagy. Recent clarifications on the definition of regulated or accidental cell death by The Nomenclature Committee on Cell Death provides an opportunity to reanalyze some data, re-evaluate conclusions in the light of parasite diversity, and to propose alternative arguments in the context of malaria drug resistance, considering lack of really new drugs in the pipeline. Deciphering the mechanisms of death may help in detection of new drug targets and the design of innovative drugs. However, classifications have been evolving rapidly since initial description of "programmed cell death", leading to some uncertainty as to whether Plasmodium cell death is accidental or regulated. PMID- 28357299 TI - In Entamoeba histolytica, a BspA family protein is required for chemotaxis toward tumour necrosis factor. AB - BACKGROUND: Entamoeba histolytica cell migration is essential for the development of human amoebiasis (an infectious disease characterized by tissue invasion and destruction). The tissue inflammation associated with tumour necrosis factor (TNF) secretion by host cells is a well-documented feature of amoebiasis. Tumour necrosis factor is a chemoattractant for E. histolytica, and the parasite may have a TNF receptor at its cell surface. METHODS: confocal microscopy, RNA Sequencing, bioinformatics, RNA antisense techniques and histological analysis of human colon explants were used to characterize the interplay between TNF and E. histolytica. RESULTS: an antibody against human TNF receptor 1 (TNFR1) stained the E. histolytica trophozoite surface and (on immunoblots) binds to a 150-kDa protein. Proteome screening with the TNFR1 sequence revealed a BspA family protein in E. histolytica that carries a TNFR signature domain and six leucine rich repeats (named here as "cell surface protein", CSP, in view of its cellular location). Cell surface protein shares structural homologies with Toll-Like receptors, colocalizes with TNF and is internalized in TNF-containing vesicles. Reduction of cellular CSP levels abolished chemotaxis toward TNF and blocked parasite invasion of human colon. CONCLUSIONS: there is a clear link between TNF chemotaxis, CSP and pathogenesis. PMID- 28357298 TI - Yeast as a tool to explore cathepsin D function. AB - Cathepsin D has garnered increased attention in recent years, mainly since it has been associated with several human pathologies. In particular, cathepsin D is often overexpressed and hypersecreted in cancer cells, implying it may constitute a therapeutic target. However, cathepsin D can have both anti- and pro-survival functions depending on its proteolytic activity, cellular context and stress stimulus. Therefore, a more detailed understanding of cathepsin D regulation and how to modulate its apoptotic functions is clearly needed. In this review, we provide an overview of the role of cathepsin D in physiological and pathological scenarios. We then focus on the opposing functions of cathepsin D in apoptosis, particularly relevant in cancer research. Emphasis is given to the role of the yeast protease Pep4p, the vacuolar counterpart of cathepsin D, in life and death. Finally, we discuss how insights from yeast cathepsin D and its role in regulated cell death can unveil novel functions of mammalian cathepsin D in apoptosis and cancer. PMID- 28357301 TI - Evolutionary rewiring of bacterial regulatory networks. AB - Bacteria have evolved complex regulatory networks that enable integration of multiple intracellular and extracellular signals to coordinate responses to environmental changes. However, our knowledge of how regulatory systems function and evolve is still relatively limited. There is often extensive homology between components of different networks, due to past cycles of gene duplication, divergence, and horizontal gene transfer, raising the possibility of cross-talk or redundancy. Consequently, evolutionary resilience is built into gene networks homology between regulators can potentially allow rapid rescue of lost regulatory function across distant regions of the genome. In our recent study [Taylor, et al. Science (2015), 347(6225)] we find that mutations that facilitate cross-talk between pathways can contribute to gene network evolution, but that such mutations come with severe pleiotropic costs. Arising from this work are a number of questions surrounding how this phenomenon occurs. PMID- 28357300 TI - Human Thyroid Cancer-1 (TC-1) is a vertebrate specific oncogenic protein that protects against copper and pro-apoptotic genes in yeast. AB - The human Thyroid Cancer-1 (hTC-1) protein, also known as C8orf4 was initially identified as a gene that was up-regulated in human thyroid cancer. Here we show that hTC-1 is a peptide that prevents the effects of over-expressing Bax in yeast. Analysis of the 106 residues of hTC-1 in available protein databases revealed direct orthologues in jawed-vertebrates, including mammals, frogs, fish and sharks. No TC-1 orthologue was detected in lower organisms, including yeast. Here we show that TC-1 is a general pro-survival peptide since it prevents the growth- and cell death-inducing effects of copper in yeast. Human TC-1 also prevented the deleterious effects that occur due to the over-expression of a number of key pro-apoptotic peptides, including YCA1, YBH3, NUC1, and AIF1. Even though the protective effects were more pronounced with the over-expression of YBH3 and YCA1, hTC-1 could still protect yeast mutants lacking YBH3 and YCA1 from the effects of copper sulfate. This suggests that the protective effects of TC-1 are not limited to specific pathways or processes. Taken together, our results indicate that hTC-1 is a pro-survival protein that retains its function when heterologously expressed in yeast. Thus yeast is a useful model to characterize the potential roles in cell death and survival of cancer related genes. PMID- 28357303 TI - Why are essential genes essential? - The essentiality of Saccharomyces genes. AB - Essential genes are defined as required for the survival of an organism or a cell. They are of particular interests, not only for their essential biological functions, but also in practical applications, such as identifying effective drug targets to pathogenic bacteria and fungi. The budding yeast Saccharomyces cerevisiae has approximately 6,000 open reading frames, 15 to 20% of which are deemed as essential. Some of the essential genes, however, appear to perform non essential functions, such as aging and cell death, while many of the non essential genes play critical roles in cell survival. In this paper, we reviewed and analyzed the levels of essentiality of the Saccharomyces cerevisiae genes and have grouped the genes into four categories: (1) Conditional essential: essential only under certain circumstances or growth conditions; (2) Essential: required for survival under optimal growth conditions; (3) Redundant essential: synthetic lethal due to redundant pathways or gene duplication; and (4) Absolute essential: the minimal genes required for maintaining a cellular life under a stress-free environment. The essential and non-essential functions of the essential genes were further analyzed. PMID- 28357305 TI - Membrane depolarization-triggered responsive diversification leads to antibiotic tolerance. AB - Bacterial populations are known to harbor a small fraction of so-called persister cells that have the remarkable ability to survive treatment with very high doses of antibiotics. Recent studies underscore the importance of persistence in chronic infections, yet the nature of persisters remains poorly understood. We recently showed that the universally conserved GTPase Obg modulates persistence via a (p)ppGpp-dependent mechanism that proceeds through expression of hokB. HokB is a membrane-bound toxin that causes the membrane potential to collapse. The resulting drop in cellular energy levels triggers a switch to the persistent state, yielding protection from antibiotic attack. Obg-mediated persistence is conserved in the human pathogen Pseudomonas aeruginosa, making Obg a promising target for therapies directed against bacterial persistence. PMID- 28357304 TI - The lysosomotropic drug LeuLeu-OMe induces lysosome disruption and autophagy independent cell death in Trypanosoma brucei. AB - BACKGROUND: Trypanosoma brucei is a blood-borne, protozoan parasite that causes African sleeping sickness in humans and nagana in animals. The current chemotherapy relies on only a handful of drugs that display undesirable toxicity, poor efficacy and drug-resistance. In this study, we explored the use of lysosomotropic drugs to induce bloodstream form T. brucei cell death via lysosome destabilization. METHODS: We measured drug concentrations that inhibit cell proliferation by 50% (IC50) for several compounds, chosen based on their lysosomotropic effects previously reported in Plasmodium falciparum. The lysosomal effects and cell death induced by L-leucyl-L-leucyl methyl ester (LeuLeu-OMe) were further analyzed by flow cytometry and immunofluorescence analyses of different lysosomal markers. The effect of autophagy in LeuLeu-OMe induced lysosome destabilization and cytotoxicity was also investigated in control and autophagy-deficient cells. RESULTS: LeuLeu-OMe was selected for detailed analyses due to its strong inhibitory profile against T. brucei with minimal toxicity to human cell lines in vitro. Time-dependent immunofluorescence studies confirmed an effect of LeuLeu-OMe on the lysosome. LeuLeu-OMe-induced cytotoxicity was also found to be dependent on the acidic pH of the lysosome. Although an increase in autophagosomes was observed upon LeuLeu-OMe treatment, autophagy was not required for the cell death induced by LeuLeu-OMe. Necrosis appeared to be the main cause of cell death upon LeuLeu-OMe treatment. CONCLUSIONS: LeuLeu-OMe is a lysosomotropic agent capable of destabilizing lysosomes and causing necrotic cell death in bloodstream form of T. brucei. PMID- 28357306 TI - The role of transcriptional 'futile cycles' in autophagy and microbial pathogenesis. AB - Eukaryotic cells utilize macroautophagy (hereafter autophagy) to recycle cellular materials during nutrient stress. Target of rapamycin (Tor) is a central regulator of this process, acting by post-translational mechanisms, phosphorylating preformed autophagy-related (Atg) proteins to repress autophagy during log-phase growth. We recently reported an additional role for post transcriptional regulation of autophagy, whereby the mRNA decapping protein, Dcp2, undergoes Tor-dependent phosphorylation, resulting in increased ATG mRNA decapping and degradation under nutrient-rich, repressing conditions. Dephosphorylation of Dcp2 during starvation is associated with dissociation of the decapping-ATG mRNA complex, with resultant stabilization of, and accumulation of, ATG transcripts, leading to induction of autophagy. Regulation of mRNA degradation occurs in concert with known mRNA synthetic inductive mechanisms to potentiate overall transcriptional regulation. This mRNA degradative pathway thus constitutes a type of transcriptional 'futile cycle' where under nutrient-rich conditions transcript is constantly being generated and degraded. As nutrient levels decline, steady state mRNA levels are increased by both inhibition of degradation as well as increased de novo synthesis. A role for this regulatory process in fungal virulence was further demonstrated by showing that overexpression of the Dcp2-associated mRNA-binding protein Vad1 in the AIDS associated pathogen Cryptococcus neoformans results in constitutive repression of autophagy even under starvation conditions as well as attenuated virulence in a mouse model. In summary, Tor-dependent post-transcriptional regulation of autophagy plays a key role in the facilitation of microbial pathogenesis. PMID- 28357302 TI - From the baker to the bedside: yeast models of Parkinson's disease. AB - The baker's yeast Saccharomyces cerevisiae has been extensively explored for our understanding of fundamental cell biology processes highly conserved in the eukaryotic kingdom. In this context, they have proven invaluable in the study of complex mechanisms such as those involved in a variety of human disorders. Here, we first provide a brief historical perspective on the emergence of yeast as an experimental model and on how the field evolved to exploit the potential of the model for tackling the intricacies of various human diseases. In particular, we focus on existing yeast models of the molecular underpinnings of Parkinson's disease (PD), focusing primarily on the central role of protein quality control systems. Finally, we compile and discuss the major discoveries derived from these studies, highlighting their far-reaching impact on the elucidation of PD associated mechanisms as well as in the identification of candidate therapeutic targets and compounds with therapeutic potential. PMID- 28357307 TI - Feelin' it: Differential oxidative stress sensing mediated by Cyclin C. PMID- 28357309 TI - Peering into the 'black box' of pathogen recognition by cellular autophagy systems. AB - Autophagy is an intracellular process that plays an important role in protecting eukaryotic cells and maintaining intracellular homeostasis. Pathogens, including bacteria and viruses, that enter cells can signal induction of selective autophagy resulting in degradation of the pathogen in the autolysosome. Under such circumstances, the specific recognition and targeting of the invading pathogen becomes a crucial step for the subsequent initiation of selective autophagosome formation. However, the nature of the signal(s) on the pathogen surface and the identity of host molecule(s) that presumably bind the signal molecules remain relatively poorly characterized. In this review we summarise the available evidence regarding the specific recognition of invading pathogens by which they are targeted into host autophagy pathways. PMID- 28357311 TI - Intracellular phase for an extracellular bacterial pathogen: MgtC shows the way. AB - Pseudomonas aeruginosa is an extracellular pathogen known to impair host phagocytic functions. However, our recent results identify MgtC as a novel actor in P. aeruginosa virulence, which plays a role in an intramacrophage phase of this pathogen. In agreement with its intracellular function, P. aeruginosamgtC gene expression is strongly induced when the bacteria reside within macrophages. MgtC was previously known as a horizontally-acquired virulence factor important for multiplication inside macrophages in several intracellular bacterial pathogens. MgtC thus provides a singular example of a virulence determinant that subverts macrophages both in intracellular and extracellular pathogens. Moreover, we demonstrate that P. aeruginosa MgtC is required for optimal growth in Mg2+ deprived medium, a property shared by MgtC factors from intracellular pathogens and, under Mg2+ limitation, P. aeruginosa MgtC prevents biofilm formation. We propose that MgtC has a similar function in intracellular and extracellular pathogens, which contributes to macrophage resistance and fine-tune adaptation to the host in relation to the different bacterial lifestyles. MgtC thus appears as an attractive target for antivirulence strategies and our work provides a natural peptide as MgtC antagonist, which paves the way for the development of MgtC inhibitors. PMID- 28357310 TI - A single mutation in the 15S rRNA gene confers non sense suppressor activity and interacts with mRF1 the release factor in yeast mitochondria. AB - We have determined the nucleotide sequence of the mim3-1 mitochondrial ribosomal suppressor, acting on ochre mitochondrial mutations and one frameshift mutation in Saccharomyces cerevisiae. The 15s rRNA suppressor gene contains a G633 to C transversion. Yeast mitochondrial G633 corresponds to G517 of the E.coli 15S rRNA, which is occupied by an invariant G in all known small rRNA sequences. Interestingly, this mutation has occurred at the same position as the known MSU1 mitochondrial suppressor which changes G633 to A. The suppressor mutation lies in a highly conserved region of the rRNA, known in E.coli as the 530-loop, interacting with the S4, S5 and S12 ribosomal proteins. We also show an interesting interaction between the mitochondrial mim3-1 and the nuclear nam3-1 suppressors, both of which have the same action spectrum on mitochondrial mutations: nam3-1 abolishes the suppressor effect when present with mim3-1 in the same haploid cell. We discuss these results in the light of the nature of Nam3, identified by 1 as the yeast mitochondrial translation release factor. A hypothetical mechanism of suppression by "ribosome shifting" is also discussed in view of the nature of mutations suppressed and not suppressed. PMID- 28357308 TI - The many facets of homologous recombination at telomeres. AB - The ends of linear chromosomes are capped by nucleoprotein structures called telomeres. A dysfunctional telomere may resemble a DNA double-strand break (DSB), which is a severe form of DNA damage. The presence of one DSB is sufficient to drive cell cycle arrest and cell death. Therefore cells have evolved mechanisms to repair DSBs such as homologous recombination (HR). HR-mediated repair of telomeres can lead to genome instability, a hallmark of cancer cells, which is why such repair is normally inhibited. However, some HR-mediated processes are required for proper telomere function. The need for some recombination activities at telomeres but not others necessitates careful and complex regulation, defects in which can lead to catastrophic consequences. Furthermore, some cell types can maintain telomeres via telomerase-independent, recombination-mediated mechanisms. In humans, these mechanisms are called alternative lengthening of telomeres (ALT) and are used in a subset of human cancer cells. In this review, we summarize the different recombination activities occurring at telomeres and discuss how they are regulated. Much of the current knowledge is derived from work using yeast models, which is the focus of this review, but relevant studies in mammals are also included. PMID- 28357314 TI - Spermidine cures yeast of prions. AB - Prions are self-perpetuating amyloid protein aggregates which underlie various neurodegenerative diseases in mammals. The molecular basis underlying their conversion from a normally soluble protein into the prion form remains largely unknown. Studies aimed at uncovering these mechanism(s) are therefore essential if we are to develop effective therapeutic strategies to counteract these disease causing entities. Autophagy is a cellular degradation system which has predominantly been considered as a non-selective bulk degradation process which recycles macromolecules in response to starvation conditions. We now know that autophagy also serves as a protein quality control mechanism which selectively degrades protein aggregates and damaged organelles. These are commonly accumulated in various neurodegenerative disorders including prion diseases. In our recent study [Speldewinde et al. Mol. Biol. Cell. (2015)] we used the well established yeast [PSI+]/Sup35 and [PIN!+ ]/Rnq1 prion models to show that autophagy prevents sporadic prion formation. Importantly, we found that spermidine, a polyamine that has been used to increase autophagic flux, acts as a protective agent which prevents spontaneous prion formation. PMID- 28357315 TI - Biofilm assembly becomes crystal clear - filamentous bacteriophage organize the Pseudomonas aeruginosa biofilm matrix into a liquid crystal. AB - Pseudomonas aeruginosa is an opportunistic bacterial pathogen associated with many types of chronic infection. At sites of chronic infection, such as the airways of people with cystic fibrosis (CF), P. aeruginosa forms biofilm-like aggregates. These are clusters of bacterial cells encased in a polymer-rich matrix that shields bacteria from environmental stresses and antibiotic treatment. When P. aeruginosa forms a biofilm, large amounts of filamentous Pf bacteriophage (phage) are produced. Unlike most phage that typically lyse and kill their bacterial hosts, filamentous phage of the genus Inovirus, which includes Pf phage, often do not, and instead are continuously extruded from the bacteria. Here, we discuss the implications of the accumulation of filamentous Pf phage in the biofilm matrix, where they interact with matrix polymers to organize the biofilm into a highly ordered liquid crystal. This structural configuration promotes bacterial adhesion, desiccation survival, and antibiotic tolerance - all features typically associated with biofilms. We propose that Pf phage make structural contributions to P. aeruginosa biofilms and that this constitutes a novel form of symbiosis between bacteria and bacteriophage. PMID- 28357313 TI - Ergosterone-coupled Triazol molecules trigger mitochondrial dysfunction, oxidative stress, and acidocalcisomal Ca2+ release in Leishmania mexicana promastigotes. AB - The protozoan parasite Leishmania causes a variety of sicknesses with different clinical manifestations known as leishmaniasis. The chemotherapy currently in use is not adequate because of their side effects, resistance occurrence, and recurrences. Investigations looking for new targets or new active molecules focus mainly on the disruption of parasite specific pathways. In this sense, ergosterol biosynthesis is one of the most attractive because it does not occur in mammals. Here, we report the synthesis of ergosterone coupled molecules and the characterization of their biological activity on Leishmania mexicana promastigotes. Molecule synthesis involved three steps: ergosterone formation using Jones oxidation, synthesis of Girard reagents, and coupling reaction. All compounds were obtained in good yield and high purity. Results show that ergosterone-triazol molecules (Erg-GTr and Erg-GTr2) exhibit an antiproliferative effect in low micromolar range with a selectivity index ~10 when compared to human dermic fibroblasts. Addition of Erg-GTr or Erg-GTr2 to parasites led to a rapid [Ca2+]cyt increase and acidocalcisomes alkalinization, indicating that Ca2+ was released from this organelle. Evaluation of cell death markers revealed some apoptosis-like indicators, as phosphatidylserine exposure, DNA damage, and cytosolic vacuolization and autophagy exacerbation. Furthermore, mitochondrion hyperpolarization and superoxide production increase were detected already 6 hours after drug addition, denoting that oxidative stress is implicated in triggering the observed phenotype. Taken together our results indicate that ergosterone-triazol coupled molecules induce a regulated cell death process in the parasite and may represent starting point molecules in the search of new chemotherapeutic agents to combat leishmaniasis. PMID- 28357312 TI - Histone modifications as regulators of life and death in Saccharomyces cerevisiae. AB - Apoptosis or programmed cell death is an integrated, genetically controlled suicide program that not only regulates tissue homeostasis of multicellular organisms, but also the fate of damaged and aged cells of lower eukaryotes, such as the yeast Saccharomyces cerevisiae. Recent years have revealed key apoptosis regulatory proteins in yeast that play similar roles in mammalian cells. Apoptosis is a process largely defined by characteristic structural rearrangements in the dying cell that include chromatin condensation and DNA fragmentation. The mechanism by which chromosomes restructure during apoptosis is still poorly understood, but it is becoming increasingly clear that altered epigenetic histone modifications are fundamental parameters that influence the chromatin state and the nuclear rearrangements within apoptotic cells. The present review will highlight recent work on the epigenetic regulation of programmed cell death in budding yeast. PMID- 28357316 TI - The curious case of vanishing mitochondria. AB - Due to their involvement in the energy metabolism, mitochondria are essential for most eukaryotic cells. Microbial eukaryotes living in low oxygen environments possess reduced forms of mitochondria, namely mitochondrion-related organelles (MROs). These do not produce ATP by oxidative phosphorylation on their membranes and some do not produce ATP at all. Still, they are indispensable because of other essential functions such as iron-sulphur (Fe-S) cluster assembly. Recently, the first microbial eukaryote with neither mitochondrion nor MRO was characterized - Monocercomonoides sp. Genome and transcriptome sequencing of Monocercomonoides revealed that it lacks all hallmark mitochondrial proteins. Crucially, the essential mitochondrial pathway for the Fe-S cluster assembly (ISC) was replaced by a bacterial sulphur mobilization (SUF) system. The discovery of such bona fide amitochondriate eukaryote broadens our knowledge about the diversity and plasticity of eukaryotic cells and provides a substantial contribution to our understanding of eukaryotic cell evolution. PMID- 28357317 TI - Accumulation of metabolic side products might favor the production of ethanol in Pho13 knockout strains. PMID- 28357318 TI - VDAC regulates AAC-mediated apoptosis and cytochrome c release in yeast. AB - Mitochondrial outer membrane permeabilization is a key event in apoptosis processes leading to the release of lethal factors. We have previously shown that absence of the ADP/ATP carrier (AAC) proteins (yeast orthologues of mammalian ANT proteins) increased the resistance of yeast cells to acetic acid, preventing MOMP and the release of cytochrome c from mitochondria during acetic acid - induced apoptosis. On the other hand, deletion of POR1 (yeast voltage-dependent anion channel - VDAC) increased the sensitivity of yeast cells to acetic acid. In the present work, we aimed to further characterize the role of yeast VDAC in acetic acid - induced apoptosis and assess if it functionally interacts with AAC proteins. We found that the sensitivity to acetic acid resulting from POR1 deletion is completely abrogated by the absence of AAC proteins, and propose that Por1p acts as a negative regulator of acetic acid - induced cell death by a mechanism dependent of AAC proteins, by acting on AAC - dependent cytochrome c release. Moreover, we show that Por1p has a role in mitochondrial fusion that, contrary to its role in apoptosis, is not affected by the absence of AAC, and demonstrate that mitochondrial network fragmentation is not sufficient to induce release of cytochrome c or sensitivity to acetic acid - induced apoptosis. This work enhances our understanding on cytochrome c release during cell death, which may be relevant in pathological scenarios where MOMP is compromised. PMID- 28357319 TI - Phylogenetic profiles of all membrane transport proteins of the malaria parasite highlight new drug targets AB - In order to combat the on-going malaria epidemic, discovery of new drug targets remains vital. Proteins that are essential to survival and specific to malaria parasites are key candidates. To survive within host cells, the parasites need to acquire nutrients and dispose of waste products across multiple membranes. Additionally, like all eukaryotes, they must redistribute ions and organic molecules between their various internal membrane bound compartments. Membrane transport proteins mediate all of these processes and are considered important mediators of drug resistance as well as drug targets in their own right. Recently, using advanced experimental genetic approaches and streamlined life cycle profiling, we generated a large collection of Plasmodium berghei gene deletion mutants and assigned essential gene functions, highlighting potential targets for prophylactic, therapeutic, and transmission-blocking anti-malarial drugs. Here, we present a comprehensive orthology assignment of all Plasmodium falciparum putative membrane transport proteins and provide a detailed overview of the associated essential gene functions obtained through experimental genetics studies in human and murine model parasites. Furthermore, we discuss the phylogeny of selected potential drug targets identified in our functional screen. We extensively discuss the results in the context of the functional assignments obtained using gene targeting available to date. PMID- 28357320 TI - Putative mitochondrial alpha-ketoglutarate-dependent dioxygenase Fmp12 controls utilization of proline as an energy source in Saccharomyces cerevisiae. AB - The amino acid proline functions as a nitrogen source and as a stress protectant in the yeast Saccharomyces cerevisiae. However, utilization of proline as a carbon source in S. cerevisiae cells has not been studied yet. In the process of study on the physiological roles of the found-in-mitochondrial-proteome (FMP) genes in proline metabolism, we found that Deltafmp12 cells could grow better than wild-type cells on agar plate medium containing proline as the sole nitrogen and carbon sources. In contrast, overexpression of FMP12 negatively affected cell growth under the same condition. The Fmp12 protein was localized in the mitochondria and was constitutively expressed. Deletion of the genes that encode mitochondrial enzymes, such as proline dehydrogenase (PUT1), Delta1-pyrroline-5 carboxylate dehydrogenase (PUT2), alanine transaminase (ALT1), and alpha ketoglutarate dehydrogenase subunit (KGD1), abolished the enhanced cell growth in Deltafmp12. These results provided the first evidence that proline can be utilized as a carbon source via the mitochondrial proline metabolic pathway and the subsequent tricarboxylic acid (TCA) cycle in S. cerevisiae. The function of Fmp12, which has a similarity with alpha-ketoglutarate-dependent dioxygenases of the yeast Candida species and human, might inhibit cell growth by skipping the ATP production step of the TCA cycle. PMID- 28357321 TI - B cell-helping functions of gut microbial metabolites. AB - Commensal microflora profoundly affects the host immune system. It has long been observed that commensal bacteria enhance antibody production in the host by producing antigens for B cell receptors (BCR) and ligands for Toll-like receptors (TLR). We recently reported that the microbial metabolites short-chain fatty acids (SCFAs) regulate the metabolism and gene expression in B cells to promote antibody production (Kim et al. Gut Microbial Metabolites Fuel Host Antibody Responses. Cell Host & Microbe. 2016; 20(2):202-14). The B-cell helping function of SCFAs and its implication in the host immune system are discussed in this article. PMID- 28357323 TI - The ubiquitin-conjugating enzyme, Ubc1, indirectly regulates SNF1 kinase activity via Forkhead-dependent transcription. AB - The SNF1 kinase in Saccharomyces cerevisiae is an excellent model to study the regulation and function of the AMP-dependent protein kinase (AMPK) family of serine-threonine protein kinases. Yeast discoveries regarding the regulation of this non-hormonal sensor of metabolic/environmental stress are conserved in higher eukaryotes, including poly-ubiquitination of the alpha-subunit of yeast (Snf1) and human (AMPKalpha) that ultimately effects subunit stability and enzyme activity. The ubiquitin-cascade enzymes responsible for targeting Snf1 remain unknown, leading us to screen for those that impact SNF1 kinase function. We identified the E2, Ubc1, as a regulator of SNF1 kinase function. The decreased Snf1 abundance found upon deletion of Ubc1 is not due to increased degradation, but instead is partly due to impaired SNF1 gene expression, arising from diminished abundance of the Forkhead 1/2 proteins, previously shown to contribute to SNF1 transcription. Ultimately, we report that the Fkh1/2 cognate transcription factor, Hcm1, fails to enter the nucleus in the absence of Ubc1. This implies that Ubc1 acts indirectly through transcriptional effects to modulate SNF1 kinase activity. PMID- 28357322 TI - How do yeast sense mitochondrial dysfunction? AB - Apart from energy transformation, mitochondria play important signaling roles. In yeast, mitochondrial signaling relies on several molecular cascades. However, it is not clear how a cell detects a particular mitochondrial malfunction. The problem is that there are many possible manifestations of mitochondrial dysfunction. For example, exposure to the specific antibiotics can either decrease (inhibitors of respiratory chain) or increase (inhibitors of ATP synthase) mitochondrial transmembrane potential. Moreover, even in the absence of the dysfunctions, a cell needs feedback from mitochondria to coordinate mitochondrial biogenesis and/or removal by mitophagy during the division cycle. To cope with the complexity, only a limited set of compounds is monitored by yeast cells to estimate mitochondrial functionality. The known examples of such compounds are ATP, reactive oxygen species, intermediates of amino acids synthesis, short peptides, Fe-S clusters and heme, and also the precursor proteins which fail to be imported by mitochondria. On one hand, the levels of these molecules depend not only on mitochondria. On the other hand, these substances are recognized by the cytosolic sensors which transmit the signals to the nucleus leading to general, as opposed to mitochondria-specific, transcriptional response. Therefore, we argue that both ways of mitochondria-to nucleus communication in yeast are mostly (if not completely) unspecific, are mediated by the cytosolic signaling machinery and strongly depend on cellular metabolic state. PMID- 28357324 TI - Sulfur transfer and activation by ubiquitin-like modifier system Uba4*Urm1 link protein urmylation and tRNA thiolation in yeast. AB - Urm1 is a unique dual-function member of the ubiquitin protein family and conserved from yeast to man. It acts both as a protein modifier in ubiquitin-like urmylation and as a sulfur donor for tRNA thiolation, which in concert with the Elongator pathway forms 5-methoxy-carbonyl-methyl-2-thio (mcm5s2) modified wobble uridines (U34) in anticodons. Using Saccharomyces cerevisiae as a model to study a relationship between these two functions, we examined whether cultivation temperature and sulfur supply previously implicated in the tRNA thiolation branch of the URM1 pathway also contribute to proper urmylation. Monitoring Urm1 conjugation, we found urmylation of the peroxiredoxin Ahp1 is suppressed either at elevated cultivation temperatures or under sulfur starvation. In line with this, mutants with sulfur transfer defects that are linked to enzymes (Tum1, Uba4) required for Urm1 activation by thiocarboxylation (Urm1-COSH) were found to maintain drastically reduced levels of Ahp1 urmylation and mcm5s2U34 modification. Moreover, as revealed by site specific mutagenesis, the S-transfer rhodanese domain (RHD) in the E1-like activator (Uba4) crucial for Urm1-COSH formation is critical but not essential for protein urmylation and tRNA thiolation. In sum, sulfur supply, transfer and activation chemically link protein urmylation and tRNA thiolation. These are features that distinguish the ubiquitin-like modifier system Uba4*Urm1 from canonical ubiquitin family members and will help elucidate whether, in addition to their mechanistic links, the protein and tRNA modification branches of the URM1 pathway may also relate in function to one another. PMID- 28357325 TI - Threading Granules in Freiburg. 2nd International Symposium on "One Mitochondrion, Many Diseases - Biological and Molecular Perspectives", a FRIAS Junior Researcher Conference, Freiburg im Breisgau, Germany, March 9th/10th, 2016. AB - Altered mitochondrial activities play an important role in many different human disorders, including cancer and neurodegeneration. At the Freiburg Institute of Advanced Studies (FRIAS) Junior Researcher Conference "One Mitochondrion, Many Diseases - Biological and Molecular Perspectives" (University of Freiburg, Freiburg, Germany), junior and experienced researches discussed common and distinct mechanisms of mitochondrial contributions to various human disorders. PMID- 28357326 TI - The interaction between herpes simplex virus 1 genome and promyelocytic leukemia nuclear bodies (PML-NBs) as a hallmark of the entry in latency. AB - Herpes simplex virus 1 (HSV-1) is a human pathogen that establishes latency in the nucleus of infected neurons in the PNS and the CNS. At the transcriptional level latency is characterized by a quasi-complete silencing of the extrachromosomal viral genome that otherwise expresses more than 80 genes during the lytic cycle. In neurons, latency is anticipated to be the default transcriptional program; however, limited information exists on the molecular mechanisms that force the virus to enter the latent state. Our recent study demonstrates that the interaction of the viral genomes with the nuclear architecture and specifically the promyelocytic leukemia nuclear bodies (PML-NBs) is a major determinant for the entry of HSV-1 into latency (Maroui MA, Calle A et al. (2016). Latency entry of herpes simplex virus 1 is determined by the interaction of its genome with the nuclear environment. PLoS Pathogens 12(9): e1005834.). PMID- 28357327 TI - NprR, a moonlighting quorum sensor shifting from a phosphatase activity to a transcriptional activator. AB - Regulation of biological functions requires factors (proteins, peptides or chemicals) able to sense and translate environmental conditions or any circumstances in order to modulate the transcription of a gene, the stability of a transcript or the activity of a protein. Quorum sensing is a regulation mechanism connecting cell density to the physiological state of a single cell. In bacteria, quorum sensing coordinates virulence, cell fate and commitment to sporulation and other adaptation properties. The critical role of such regulatory systems was demonstrated in pathogenicity and adaptation of bacteria from the Bacillus cereus group (i.e. B. cereus and Bacillus thuringiensis). Furthermore, using insects as a model of infection, it was shown that sequential activation of several quorum sensing systems allowed bacteria to switch from a virulence state to a necrotrophic lifestyle, allowing their survival in the host cadaver, and ultimately to the commitment into sporulation. The chronological development of these physiological states is directed by quorum sensors forming the RNPP family. Among them, NprR combines two distinct functions connecting sporulation to necrotrophism in B. thuringiensis. In the absence of its cognate signaling peptide (NprX), NprR negatively controls sporulation by acting as a phosphatase. In the presence of NprX, it acts as a transcription factor regulating a set of genes involved in the survival of the bacteria in the insect cadaver. PMID- 28357328 TI - Francisella IglG protein and the DUF4280 proteins: PAAR-like proteins in non canonical Type VI secretion systems? AB - Type VI secretion systems (T6SS) are bacterial molecular machines translocating effector proteins into target cells. T6SS are widely present in Gram-negative bacteria where they predominantly act to kill neighboring bacteria. This secretion system is reminiscent of the tail of contractile bacteriophages and consists of a contractile sheath anchored in the bacterial envelope and an inner tube made of stacks of the Hcp protein. The Hcp tube is capped with a VgrG trimer and a spike protein termed PAAR, which acts as the membrane-puncturing device. Francisella tularensis, the agent of tularemia, is an intracellular bacterium replicating within the host cytosol. Upon entry into the host cell, F. tularensis rapidly lyses the host vacuolar membrane to reach the host cytosol. This escape is dependent on the Francisella Pathogenicity Island (FPI), which is encoding an atypical T6SS. Among the 17 proteins encoded by the FPI, most of them required for virulence, eight have some homology to canonical T6SS proteins. We recently identified the function of one protein of unknown function encoded within the FPI, IglG. By three-dimensional modelling and following validation by different techniques, we found that IglG adopts a fold resembling the one of PAAR proteins. Importantly, IglG features a domain of unknown function DUF4280, present in numerous bacterial species. We thus propose to rename this domain of unknown function, PAAR-like domain, and discuss here the characteristics of this domain and its distribution in both Gram-negative and Gram-positive bacteria. PMID- 28357329 TI - Autophagy: one more Nobel Prize for yeast. AB - The recent announcement of the 2016 Nobel Prize in Physiology or Medicine, awarded to Yoshinori Ohsumi for the discoveries of mechanisms governing autophagy, underscores the importance of intracellular degradation and recycling. At the same time, it further cements yeast, in which this field decisively developed, as a prolific model organism. Here we provide a quick historical overview that mirrors both the importance of autophagy as a conserved and essential process for cellular life and death as well as the crucial role of yeast in its mechanistic characterization. PMID- 28357330 TI - Physiology, phylogeny, and LUCA. AB - Genomes record their own history. But if we want to look all the way back to life's beginnings some 4 billion years ago, the record of microbial evolution that is preserved in prokaryotic genomes is not easy to read. Microbiology has a lot in common with geology in that regard. Geologists know that plate tectonics and erosion have erased much of the geological record, with ancient rocks being truly rare. The same is true of microbes. Lateral gene transfer (LGT) and sequence divergence have erased much of the evolutionary record that was once written in genomes, and it is not obvious which genes among sequenced genomes are genuinely ancient. Which genes trace to the last universal ancestor, LUCA? The classical approach has been to look for genes that are universally distributed. Another approach is to make all trees for all genes, and sift out the trees where signals have been overwritten by LGT. What is left ought to be ancient. If we do that, what do we find? PMID- 28357331 TI - Autophagy: machinery and regulation. AB - Macroautophagy/autophagy is an evolutionarily conserved cellular degradation process that targets cytoplasmic materials including cytosol, macromolecules and unwanted organelles. The discovery and analysis of autophagy-related (Atg) proteins have unveiled much of the machinery of autophagosome formation. Although initially autophagy was regarded as a survival response to stress, recent studies have revealed its significance in cellular and organismal homeostasis, development and immunity. Autophagic dysfunction and dysregulation are implicated in various diseases. In this review, we briefly summarize the physiological roles, molecular mechanism, regulatory network, and pathophysiological roles of autophagy. PMID- 28357332 TI - Bax mitochondrial relocation is linked to its phosphorylation and its interaction with Bcl-xL. AB - The heterologous expression of Bax, and other Bcl-2 family members, in the yeast Saccharomyces cerevisiae, has proved to be a valuable reporter system to investigate the molecular mechanisms underlying their interaction with mitochondria. By combining the co-expression of Bax and Bcl-xL mutants with analyzes of their localization and interaction in mitochondria and post mitochondrial supernatants, we showed that the ability of Bax and Bcl-xL to interact is dependent both on Bax phosphorylation - mimicked by a substitution S184D - and by Bax and Bcl-xL localization. This, and previous data, provide the molecular basis for a model of dynamic equilibrium for Bax localization and activation, regulated both by phosphorylation and Bcl-xL. PMID- 28357333 TI - Impact of histone H4K16 acetylation on the meiotic recombination checkpoint in Saccharomyces cerevisiae. AB - In meiotic cells, the pachytene checkpoint or meiotic recombination checkpoint is a surveillance mechanism that monitors critical processes, such as recombination and chromosome synapsis, which are essential for proper distribution of chromosomes to the meiotic progeny. Failures in these processes lead to the formation of aneuploid gametes. Meiotic recombination occurs in the context of chromatin; in fact, the histone methyltransferase Dot1 and the histone deacetylase Sir2 are known regulators of the pachytene checkpoint in Saccharomyces cerevisiae. We report here that Sas2-mediated acetylation of histone H4 at lysine 16 (H4K16ac), one of the Sir2 targets, modulates meiotic checkpoint activity in response to synaptonemal complex defects. We show that, like sir2, the H4-K16Q mutation, mimicking constitutive acetylation of H4K16, eliminates the delay in meiotic cell cycle progression imposed by the checkpoint in the synapsis-defective zip1 mutant. We also demonstrate that, like in dot1, zip1-induced phosphorylation of the Hop1 checkpoint adaptor at threonine 318 and the ensuing Mek1 activation are impaired in H4-K16 mutants. However, in contrast to sir2 and dot1, the H4-K16R and H4-K16Q mutations have only a minor effect in checkpoint activation and localization of the nucleolar Pch2 checkpoint factor in ndt80-prophase-arrested cells. We also provide evidence for a cross-talk between Dot1-dependent H3K79 methylation and H4K16ac and show that Sir2 excludes H4K16ac from the rDNA region on meiotic chromosomes. Our results reveal that proper levels of H4K16ac orchestrate this meiotic quality control mechanism and that Sir2 impinges on additional targets to fully activate the checkpoint. PMID- 28357334 TI - The transcription factors ADR1 or CAT8 are required for RTG pathway activation and evasion from yeast acetic acid-induced programmed cell death in raffinose. AB - Yeast Saccharomyces cerevisiae grown on glucose undergoes programmed cell death (PCD) induced by acetic acid (AA-PCD), but evades PCD when grown in raffinose. This is due to concomitant relief of carbon catabolite repression (CCR) and activation of mitochondrial retrograde signaling, a mitochondria-to-nucleus communication pathway causing up-regulation of various nuclear target genes, such as CIT2, encoding peroxisomal citrate synthase, dependent on the positive regulator RTG2 in response to mitochondrial dysfunction. CCR down-regulates genes mainly involved in mitochondrial respiratory metabolism. In this work, we investigated the relationships between the RTG and CCR pathways in the modulation of AA-PCD sensitivity under glucose repression or de-repression conditions. Yeast single and double mutants lacking RTG2 and/or certain factors regulating carbon source utilization, including MIG1, HXK2, ADR1, CAT8, and HAP4, have been analyzed for their survival and CIT2 expression after acetic acid treatment. ADR1 and CAT8 were identified as positive regulators of RTG-dependent gene transcription. ADR1 and CAT8 interact with RTG2 and with each other in inducing cell resistance to AA-PCD in raffinose and controlling the nature of cell death. In the absence of ADR1 and CAT8, AA-PCD evasion is acquired through activation of an alternative factor/pathway repressed by RTG2, suggesting that RTG2 may play a function in promoting necrotic cell death in repressing conditions when RTG pathway is inactive. Moreover, our data show that simultaneous mitochondrial retrograde pathway activation and SNF1-dependent relief of CCR have a key role in central carbon metabolism reprogramming which modulates the yeast acetic acid stress response. PMID- 28357335 TI - Inhibition of Abeta42 oligomerization in yeast by a PICALM ortholog and certain FDA approved drugs. AB - The formation of small Abeta42 oligomers has been implicated as a toxic species in Alzheimer disease (AD). In strong support of this hypothesis we found that overexpression of Yap1802, the yeast ortholog of the human AD risk factor, phosphatidylinositol binding clathrin assembly protein (PICALM), reduced oligomerization of Abeta42 fused to a reporter in yeast. Thus we used the Abeta42 reporter system to identify drugs that could be developed into therapies that prevent or arrest AD. From a screen of 1,200 FDA approved drugs and drug-like small compounds we identified 7 drugs that reduce Abeta42 oligomerization in yeast: 3 antipsychotics (bromperidol, haloperidol and azaperone), 2 anesthetics (pramoxine HCl and dyclonine HCl), tamoxifen citrate, and minocycline HCl. Also, all 7 drugs caused Abeta42 to be less toxic to PC12 cells and to relieve toxicity of another yeast AD model in which Abeta42 aggregates targeted to the secretory pathway are toxic. Our results identify drugs that inhibit Abeta42 oligomers from forming in yeast. It remains to be determined if these drugs inhibit Abeta42 oligomerization in mammals and could be developed as a therapeutic treatment for AD. PMID- 28357336 TI - Mitochondrial proteomics of the acetic acid - induced programmed cell death response in a highly tolerant Zygosaccharomyces bailii - derived hybrid strain. AB - Very high concentrations of acetic acid at low pH induce programmed cell death (PCD) in both the experimental model Saccharomyces cerevisiae and in Zygosaccharomyces bailii, the latter being considered the most problematic acidic food spoilage yeast due to its remarkable intrinsic resistance to this food preservative. However, while the mechanisms underlying S. cerevisiae PCD induced by acetic acid have been previously examined, the corresponding molecular players remain largely unknown in Z. bailii. Also, the reason why acetic acid concentrations known to be necrotic for S. cerevisiae induce PCD with an apoptotic phenotype in Z. bailii remains to be elucidated. In this study, a 2-DE based expression mitochondrial proteomic analysis was explored to obtain new insights into the mechanisms involved in PCD in the Z. bailii derived hybrid strain ISA1307. This allowed the quantitative assessment of expression of protein species derived from each of the parental strains, with special emphasis on the processes taking place in the mitochondria known to play a key role in acetic acid - induced PCD. A marked decrease in the content of proteins involved in mitochondrial metabolism, in particular, in respiratory metabolism (Cor1, Rip1, Lpd1, Lat1 and Pdb1), with a concomitant increase in the abundance of proteins involved in fermentation (Pdc1, Ald4, Dld3) was registered. Other differentially expressed identified proteins also suggest the involvement of the oxidative stress response, protein translation, amino acid and nucleotide metabolism, among other processes, in the PCD response. Overall, the results strengthen the emerging concept of the importance of metabolic regulation of yeast PCD. PMID- 28357337 TI - The transcriptional repressor Sum1p counteracts Sir2p in regulation of the actin cytoskeleton, mitochondrial quality control and replicative lifespan in Saccharomyces cerevisiae. AB - Increasing the stability or dynamics of the actin cytoskeleton can extend lifespan in C. elegans and S. cerevisiae. Actin cables of budding yeast, bundles of actin filaments that mediate cargo transport, affect lifespan control through effects on mitochondrial quality control. Sir2p, the founding member of the Sirtuin family of lifespan regulators, also affects actin cable dynamics, assembly, and function in mitochondrial quality control. Here, we obtained evidence for novel interactions between Sir2p and Sum1p, a transcriptional repressor that was originally identified through mutations that genetically suppress sir2? phenotypes unrelated to lifespan. We find that deletion of SUM1 in wild-type cells results in increased mitochondrial function and actin cable abundance. Furthermore, deletion of SUM1 suppresses defects in actin cables and mitochondria of sir2? yeast, and extends the replicative lifespan and cellular health span of sir2? cells. Thus, Sum1p suppresses Sir2p function in control of specific aging determinants and lifespan in budding yeast. PMID- 28357338 TI - Location, location, location. Salmonella senses ethanolamine to gauge distinct host environments and coordinate gene expression. AB - Chemical and nutrient signaling mediate all cellular processes, ensuring survival in response to changing environmental conditions. Ethanolamine is a component of phosphatidylethanolamine, a major phospholipid of mammalian and bacterial cell membranes. Ethanolamine is abundant in the gastrointestinal (GI) tract from dietary sources as well as from the normal turnover of intestinal epithelial and bacterial cells in the gut. Additionally, mammalian cells maintain intracellular ethanolamine concentrations through low and high-affinity uptake systems and the internal recycling of phosphatidylethanolamine; therefore, ethanolamine is ubiquitous throughout the mammalian host. Although ethanolamine has profound signaling activity within mammalian cells by modulating inflammatory responses and intestinal physiology, ethanolamine is best appreciated as a nutrient for bacteria that supports growth. In our recent work (Anderson, et al. PLoS Pathog (2015), 11: e1005278), we demonstrated that Salmonella enterica serovar Typhimurium (Salmonella) exploits ethanolamine signaling to adapt to distinct host environments to precisely coordinate expression of genes encoding metabolism and virulence, which ultimately enhances disease progression. PMID- 28357339 TI - Learning epigenetic regulation from mycobacteria. AB - In a eukaryotic cell, the transcriptional fate of a gene is determined by the profile of the epigenetic modifications it is associated with and the conformation it adopts within the chromatin. Therefore, the function that a cell performs is dictated by the sum total of the chromatin organization and the associated epigenetic modifications of each individual gene in the genome (epigenome). As the function of a cell during development and differentiation is determined by its microenvironment, any factor that can alter this microenvironment should be able to alter the epigenome of a cell. In the study published in Nature Communications (Yaseen 2015 Nature Communications 6:8922 doi: 10.1038/ncomms9922), we show that pathogenic Mycobacterium tuberculosis has evolved strategies to exploit this pliability of the host epigenome for its own survival. We describe the identification of a methyltransferase from M. tuberculosis that functions to modulate the host epigenome by methylating a novel, non-canonical arginine, H3R42 in histone H3. In another study, we showed that the mycobacterial protein Rv2966c methylates cytosines present in non-CpG context within host genomic DNA upon infection. Proteins with ability to directly methylate host histones H3 at a novel lysine residue (H3K14) has also been identified from Legionella pnemophilia (RomA). All these studies indicate the use of non-canonical epigenetic mechanisms by pathogenic bacteria to hijack the host transcriptional machinery. PMID- 28357341 TI - Differentiated cytoplasmic granule formation in quiescent and non-quiescent cells upon chronological aging. AB - Stationary phase cultures represent a complicated cell population comprising at least two different cell types, quiescent (Q) and non-quiescent (NQ) cells. Q and NQ cells have different lifespans and cell physiologies. However, less is known about the organization of cytosolic protein structures in these two cell types. In this study, we examined Q and NQ cells for the formation of several stationary phase-prevalent granule structures including actin bodies, proteasome storage granules, stress granules, P-bodies, the compartment for unconventional protein secretion (CUPS), and Hsp42-associated stationary phase granules (Hsp42-SPGs). Most of these structures preferentially form in NQ cells, except for Hsp42-SPGs, which are enriched in Q cells. When nutrients are provided, NQ cells enter mitosis less efficiently than Q cells, likely due to the time requirement for reorganizing some granule structures. We observed that heat shock-induced misfolded proteins often colocalize to Hsp42-SPGs, and Q cells clear these protein aggregates more efficiently, suggesting that Hsp42-SPGs may play an important role in the stress resistance of Q cells. Finally, we show that the cell fate of NQ cells is largely irreversible even if they are allowed to reenter mitosis. Our results reveal that the formation of different granule structures may represent the early stage of cell type differentiation in yeast stationary phase cultures. PMID- 28357340 TI - Mitochondrial regulation of cell death: a phylogenetically conserved control. AB - Mitochondria are fundamental for eukaryotic cells as they participate in critical catabolic and anabolic pathways. Moreover, mitochondria play a key role in the signal transduction cascades that precipitate many (but not all) regulated variants of cellular demise. In this short review, we discuss the differential implication of mitochondria in the major forms of regulated cell death. PMID- 28357343 TI - Shaping meiotic chromosomes with SUMO: a feedback loop controls the assembly of the synaptonemal complex in budding yeast. AB - The synaptonemal complex (SC) is a meiosis-specific chromosomal structure in which homologous chromosomes are intimately linked through arrays of specialized proteins called transverse filaments (TF). Widely conserved in eukaryote meiosis, the SC forms during prophase I and is essential for accurate segregation of homologous chromosomes at meiosis I. However, the basic mechanism overlooking formation and regulation of the SC has been poorly understood. By using the budding yeast Saccharomyces cerevisiae, we recently showed that SC formation is controlled through the attachment of multiple molecules of small ubiquitin-like modifier (SUMO) to a regulator of TF assembly. Intriguingly, this SUMOylation is activated by TF, implicating the involvement of a positive feedback loop in the control of SC assembly. We discuss the implication of this finding and possible involvement of a similar mechanism in regulating other processes. PMID- 28357342 TI - Towards understanding the gliotoxin detoxification mechanism: in vivo thiomethylation protects yeast from gliotoxin cytotoxicity. AB - Gliotoxin (GT) is a mycotoxin produced by some species of ascomycete fungi including the opportunistic human pathogen Aspergillus fumigatus. In order to produce GT the host organism needs to have evolved a self-protection mechanism. GT contains a redox-cycling disulfide bridge that is important in mediating toxicity. Recently is has been demonstrated that A. fumigatus possesses a novel thiomethyltransferase protein called GtmA that has the ability to thiomethylate GT in vivo, which aids the organism in regulating GT biosynthesis. It has been suggested that thiomethylation of GT and similar sulfur-containing toxins may play a role in providing self-protection in host organisms. In this work we have engineered Saccharomyces cerevisiae, a GT-naive organism, to express A. fumigatus GtmA. We demonstrate that GtmA can readily thiomethylate GT in yeast, which results in protection of the organism from exogenous GT. Our work has implications for understanding the evolution of GT self-protection mechanisms in organisms that are GT producers and non-producers. PMID- 28357344 TI - Mek1/Mre4 is a master regulator of meiotic recombination in budding yeast. AB - Sexually reproducing organisms create gametes with half the somatic cell chromosome number so that fusion of gametes at fertilization does not change the ploidy of the cell. This reduction in chromosome number occurs by the specialized cell division of meiosis in which two rounds of chromosome segregation follow a single round of chromosome duplication. Meiotic crossovers formed between the non sister chromatids of homologous chromosomes, combined with sister chromatid cohesion, physically connect homologs, thereby allowing proper segregation at the first meiotic division. Meiotic recombination is initiated by programmed double strand breaks (DSBs) whose repair is highly regulated such that (1) there is a bias for recombination with homologs rather than sister chromatids, (2) crossovers are distributed throughout the genome by a process called interference, (3) crossover homeostasis regulates the balance between crossover and non-crossover repair to maintain a critical number of crossovers and (4) each pair of homologs receives at least one crossover. It was previously known that the imposition of interhomolog bias in budding yeast requires meiosis-specific modifications to the DNA damage response and the local activation of the meiosis specific Mek1/Mre4 (hereafter Mek1) kinase at DSBs. However, because inactivation of Mek1 results in intersister, rather than interhomolog DSB repair, whether Mek1 had a role in interhomolog pathway choice was unknown. A recent study by Chen et al. (2015) reveals that Mek1 indirectly regulates the crossover/non-crossover decision between homologs as well as genetic interference. It does this by enabling phosphorylation of Zip1, the meiosis-specific transverse filament protein of the synaptonemal complex (SC), by the conserved cell cycle kinase, Cdc7-Dbf4 (DDK). These results suggest that Mek1 is a "master regulator" of meiotic recombination in budding yeast. PMID- 28357345 TI - What's old is new again: yeast mutant screens in the era of pooled segregant analysis by genome sequencing. AB - While once de-rigueur for identification of genes involved in biological processes, screening of chemically induced mutant populations is an approach that has largely been superseded for model organisms such as Saccharomyces cerevisiae. Availability of single gene deletion/overexpression libraries and combinatorial synthetic genetic arrays provide yeast researchers more structured ways to probe genetic networks. Furthermore, in the age of inexpensive DNA sequencing, methodologies such as mapping of quantitative trait loci (QTL) by pooled segregant analysis and genome-wide association enable the identification of multiple naturally occurring allelic variants that contribute to polygenic phenotypes of interest. This is, however, contingent on the capacity to screen large numbers of individuals and existence of sufficient natural phenotypic variation within the available population. The latter cannot be guaranteed and non-selectable, industrially relevant phenotypes, such as production of volatile aroma compounds, pose severe limitations on the use of modern genetic techniques due to expensive and time-consuming downstream analyses. An interesting approach to overcome these issues can be found in Den Abt et al. 1 (this issue of Microbial Cell), where a combination of repeated rounds of chemical mutagenesis and pooled segregant analysis by whole genome sequencing was applied to identify genes involved in ethyl acetate formation, demonstrating a new path for industrial yeast strain development and bringing classical mutant screens into the 21st century. PMID- 28357347 TI - Insights into dynamin-associated disorders through analysis of equivalent mutations in the yeast dynamin Vps1. AB - The dynamins represent a superfamily of proteins that have been shown to function in a wide range of membrane fusion and fission events. An increasing number of mutations in the human classical dynamins, Dyn-1 and Dyn-2 has been reported, with diseases caused by these changes ranging from Charcot-Marie-Tooth disorder to epileptic encephalopathies. The budding yeast, Saccharomyces cerevisiae expresses a single dynamin-related protein that functions in membrane trafficking, and is considered to play a similar role to Dyn-1 and Dyn-2 during scission of endocytic vesicles at the plasma membrane. Large parts of the dynamin protein are highly conserved across species and this has enabled us in this study to select a number of disease causing mutations and to generate equivalent mutations in Vps1. We have then studied these mutants using both cellular and biochemical assays to ascertain functions of the protein that have been affected by the changes. Specifically, we demonstrate that the Vps1-G397R mutation (Dyn-2 G358R) disrupts protein oligomerization, Vps1-A447T (Dyn-1 A408T) affects the scission stage of endocytosis, while Vps1-R298L (Dyn-1 R256L) affects lipid binding specificity and possibly an early stage in endocytosis. Overall, we consider that the yeast model will potentially provide an avenue for rapid analysis of new dynamin mutations in order to understand the underlying mechanisms that they disrupt. PMID- 28357346 TI - Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells. AB - In the past decade, yeast have been frequently employed to study the molecular mechanisms of human neurodegenerative diseases, generally by means of heterologous expression of genes encoding the relevant hallmark proteins. However, it has become evident that substantial posttranslational modifications of many of these proteins are required for the development and progression of potentially disease relevant changes. This is exemplified by the neuronal tau proteins, which are critically involved in a class of neuro-degenerative diseases collectively called tauopathies and which includes Alz-heimer's disease (AD) as its most common representative. In the course of the disease, tau changes its phosphorylation state and becomes hyperphosphory-lated, gets truncated by proteolytic cleavage, is subject to O-glycosylation, sumoylation, ubiquitinylation, acetylation and some other modifications. This poses the important question, which of these posttranslational modifications are naturally occurring in the yeast model or can be reconstituted by heterol-ogous gene expression. Here, we present an overview on common modifica-tions as they occur in tau during AD, summarize their potential relevance with respect to disease mechanisms and refer to the native yeast enzyme orthologs capable to perform these modifications. We will also discuss potential approaches to humanize yeast in order to create modification patterns resembling the situation in mammalian cells, which could enhance the value of Saccharomyces cerevisiae and Kluyveromyces lactis as disease models. PMID- 28357349 TI - Control of the gut microbiome by fecal microRNA. AB - Since their discovery in the early 90s, microRNAs (miRNAs), small non-coding RNAs, have mainly been associated with posttranscriptional regulation of gene expression on a cell-autonomous level. Recent evidence has extended this role by adding inter-species communication to the manifold functional range. In our latest study [Liu S, et al., 2016, Cell Host & Microbe], we identified miRNAs in gut lumen and feces of both mice and humans. We found that intestinal epithelial cells (IEC) and Hopx+ cells were the two main sources of fecal miRNA. Deficiency of IEC-miRNA resulted in gut dysbiosis and WT fecal miRNA transplantation restored the gut microbiota. We investigated potential mechanisms for this effect and found that miRNAs were able to regulate the gut microbiome. By culturing bacteria with miRNAs, we found that host miRNAs were able to enter bacteria, specifically regulate bacterial gene transcripts and affect bacterial growth. Oral administration of synthetic miRNA mimics affected specific bacteria in the gut. Our findings describe a previously unknown pathway by which the gut microbiome is regulated by the host and raises the possibility that miRNAs may be used therapeutically to manipulate the microbiome for the treatment of disease. PMID- 28357348 TI - Genomic saturation mutagenesis and polygenic analysis identify novel yeast genes affecting ethyl acetate production, a non-selectable polygenic trait. AB - Isolation of mutants in populations of microorganisms has been a valuable tool in experimental genetics for decades. The main disadvantage, however, is the inability of isolating mutants in non-selectable polygenic traits. Most traits of organisms, however, are non-selectable and polygenic, including industrially important properties of microorganisms. The advent of powerful technologies for polygenic analysis of complex traits has allowed simultaneous identification of multiple causative mutations among many thousands of irrelevant mutations. We now show that this also applies to haploid strains of which the genome has been loaded with induced mutations so as to affect as many non-selectable, polygenic traits as possible. We have introduced about 900 mutations into single haploid yeast strains using multiple rounds of EMS mutagenesis, while maintaining the mating capacity required for genetic mapping. We screened the strains for defects in flavor production, an important non-selectable, polygenic trait in yeast alcoholic beverage production. A haploid strain with multiple induced mutations showing reduced ethyl acetate production in semi-anaerobic fermentation, was selected and the underlying quantitative trait loci (QTLs) were mapped using pooled-segregant whole-genome sequence analysis after crossing with an unrelated haploid strain. Reciprocal hemizygosity analysis and allele exchange identified PMA1 and CEM1 as causative mutant alleles and TPS1 as a causative genetic background allele. The case of CEM1 revealed that relevant mutations without observable effect in the haploid strain with multiple induced mutations (in this case due to defective mitochondria) can be identified by polygenic analysis as long as the mutations have an effect in part of the segregants (in this case those that regained fully functional mitochondria). Our results show that genomic saturation mutagenesis combined with complex trait polygenic analysis could be used successfully to identify causative alleles underlying many non-selectable, polygenic traits in small collections of haploid strains with multiple induced mutations. PMID- 28357350 TI - Bactericidal antibiotics induce programmed metabolic toxicity. AB - The misuse of antibiotics has led to the development and spread of antibiotic resistance in clinically important pathogens. These resistant infections are having a significant impact on treatment outcomes and contribute to approximately 25,000 deaths in the U.S. annually. If additional therapeutic options are not identified, the number of annual deaths is predicted to rise to 317,000 in North America and 10,000,000 worldwide by 2050. Identifying therapeutic methodologies that utilize our antibiotic arsenal more effectively is one potential way to extend the useful lifespan of our current antibiotics. Recent studies have indicated that modulating metabolic activity is one possible strategy that can impact the efficacy of antibiotic therapy. In this review, we will address recent advances in our knowledge about the impacts of bacterial metabolism on antibiotic effectiveness and the impacts of antibiotics on bacterial metabolism. We will particularly focus on two studies, Lobritz, et al. (PNAS, 112(27): 8173-8180) and Belenky et al. (Cell Reports, 13(5): 968-980) that together demonstrate that bactericidal antibiotics induce metabolic perturbations that are linked to and required for bactericidal antibiotic toxicity. PMID- 28357351 TI - When and where? Pathogenic Escherichia coli differentially sense host D-serine using a universal transporter system to monitor their environment. AB - Sensing environmental stimuli is critically important for bacteria when faced with the multitude of adversities presented within the host. Responding appropriately to these signals and in turn integrating these responses into the regulatory network of the cell allows bacteria to control precisely when and where they should establish colonization. D-serine is an abundant metabolite of the human urinary tract but is a toxic metabolite for Escherichia coli that lack a D-serine tolerance locus. Enterohaemorrhagic E. coli (EHEC) cannot catabolize D serine for this reason and colonize the large intestine specifically, an environment low in D-serine. EHEC can however use D-serine sensing to repress colonization thus signaling the presence of an unfavorable environment. In our recent work (Connolly, et al. PLoS Pathogens (2016) 12(1): e1005359), we describe the discovery of a functional and previously uncharacterized D-serine uptake system in E. coli. The genes identified are highly conserved in all E. coli lineages but are regulated differentially in unique pathogenic backgrounds. The study identified that EHEC, counter-intuitively, increase D-serine uptake in its presence but that this is a tolerated process and is used to increase the transcriptional response to this signal. It was also found that the system has been integrated into the transcriptional network of EHEC-specific virulence genes, demonstrating an important pathotype-specific adaptation of core genome components. PMID- 28357352 TI - Chromatin binding and silencing: Two roles of the same protein Lem2. AB - Transcriptionally repressed chromatin localizes to specific areas within the eukaryotic nucleus and is often found at the nuclear periphery, which is thought to provide a specialized compartment for gene silencing. However, the molecular mechanisms that establish this spatial chromatin organization are still poorly understood. In our recent work (Barrales et al. 2016), we identified the nuclear envelope protein Lem2, a homolog of metazoan lamin-associated proteins (LAPs), as a relevant factor for heterochromatin silencing and perinuclear localization in the fission yeast Schizosaccharomyces pombe. Several other LAPs have previously been reported to associate with heterochromatin, and it has been proposed that this interaction might directly contribute to gene repression, perhaps through tethering via chromatin-binding domains like the LEM domain. We demonstrated that the LEM domain of Lem2 is indeed essential for centromere binding and perinuclear tethering. However, we made the surprising finding that tethering via the LEM domain is functionally independent of Lem2's role in silencing, which instead is mediated by a different part of the protein, the MSC domain. Our study demonstrates that tethering and silencing, although mediated by the same molecule, Lem2, can be mechanistically separated. This further unveils a complex function of this protein at the interface between the nuclear periphery and silent chromatin, which might be preserved among the other members of this conserved family of LEM proteins. PMID- 28357353 TI - Phosphatidylthreonine: An exclusive phospholipid regulating calcium homeostasis and virulence in a parasitic protest. PMID- 28357354 TI - The complexities of bacterial-fungal interactions in the mammalian gastrointestinal tract. PMID- 28357355 TI - The molecular and cellular action properties of artemisinins: what has yeast told us? AB - Artemisinin (ART) or Qinghaosu is a natural compound possessing superior anti malarial activity. Although intensive studies have been done in the medicinal chemistry field to understand the structure-effect relationship, the biological actions of artemisinin are poorly understood and controversial. Due to the current lack of a genetic amiable model to address this question, and an accidental finding made more than a decade ago during our initial exploratory efforts that yeast Saccharomyces cerevisiae can be inhibited by artemisinin, we have since been using the baker's yeast as a model to probe the molecular and cellular properties of artemisinin and its derivatives (ARTs) in living cells. ARTs were found to possess potent and specific anti-mitochondrial properties and, to a lesser extent, the ability to generate a relatively general oxidative damage. The anti-mitochondrial effects of artemisinin were later confirmed with purified mitochondria from malaria parasites. Inside some cells heme appears to be a primary reducing agent and reduction of ARTs by heme can induce a relatively nonspecific cellular damage. The molecular basis of the anti-mitochondrial properties of ARTs remains not well elucidated yet. We propose that the anti mitochondrial and heme-mediated ROS-generating properties constitute two cellcidal actions of ARTs. This review summarizes what we have learned from yeast about the basic biological properties of ARTs, as well as some key unanswered questions. We believe yeast could serve as a window through which to peek at some of the biological action secrets of ARTs that might be difficult for us to learn otherwise. PMID- 28357357 TI - Optogenetic monitoring identifies phosphatidylthreonine-regulated calcium homeostasis in Toxoplasma gondii. AB - Toxoplasma gondii is an obligate intracellular parasite, which inflicts acute as well as chronic infections in a wide range of warm-blooded vertebrates. Our recent work has demonstrated the natural occurrence and autonomous synthesis of an exclusive lipid phosphatidylthreonine in T. gondii. Targeted gene disruption of phosphatidylthreonine synthase impairs the parasite virulence due to unforeseen attenuation of the consecutive events of motility, egress and invasion. However, the underlying basis of such an intriguing phenotype in the parasite mutant remains unknown. Using an optogenetic sensor (gene-encoded calcium indicator, GCaMP6s), we show that loss of phosphatidylthreonine depletes calcium stores in intracellular tachyzoites, which leads to dysregulation of calcium release into the cytosol during the egress phase of the mutant. Consistently, the parasite motility and egress phenotypes in the mutant can be entirely restored by ionophore-induced mobilization of calcium. Collectively, our results suggest a novel regulatory function of phosphatidylthreonine in calcium signaling of a prevalent parasitic protist. Moreover, our application of an optogenetic sensor to monitor subcellular calcium in a model intracellular pathogen exemplifies its wider utility to other entwined systems. PMID- 28357358 TI - Translational Repression in Malaria Sporozoites. AB - Malaria is a mosquito-borne infectious disease of humans and other animals. It is caused by the parasitic protozoan, Plasmodium. Sporozoites, the infectious form of malaria parasites, are quiescent when they remain in the salivary glands of the Anopheles mosquito until transmission into a mammalian host. Metamorphosis of the dormant sporozoite to its active form in the liver stage requires transcriptional and translational regulations. Here, we summarize recent advances in the translational repression of gene expression in the malaria sporozoite. In sporozoites, many mRNAs that are required for liver stage development are translationally repressed. Phosphorylation of eukaryotic Initiation Factor 2alpha (eIF2alpha) leads to a global translational repression in sporozoites. The eIF2alpha kinase, known as Upregulated in Infectious Sporozoite 1 (UIS1), is dominant in the sporozoite. The eIF2alpha phosphatase, UIS2, is translationally repressed by the Pumilio protein Puf2. This translational repression is alleviated when sporozoites are delivered into the mammalian host. PMID- 28357356 TI - Formaldehyde fixation is detrimental to actin cables in glucose-depleted S. cerevisiae cells. AB - Actin filaments form cortical patches and emanating cables in fermenting cells of Saccharomyces cerevisiae. This pattern has been shown to be depolarized in glucose-depleted cells after formaldehyde fixation and staining with rhodamine tagged phalloidin. Loss of actin cables in mother cells was remarkable. Here we extend our knowledge on actin in live glucose-depleted cells co-expressing the marker of actin patches (Abp1-RFP) with the marker of actin cables (Abp140-GFP). Glucose depletion resulted in appearance of actin patches also in mother cells. However, even after 80 min of glucose deprivation these cells showed a clear network of actin cables labeled with Abp140-GFP in contrast to previously published data. In live cells with a mitochondrial dysfunction (rho0 cells), glucose depletion resulted in almost immediate appearance of Abp140-GFP foci partially overlapping with Abp1-RFP patches in mother cells. Residual actin cables were clustered in patch-associated bundles. A similar overlapping "patchy" pattern of both actin markers was observed upon treatment of glucose-deprived rho+ cells with FCCP (the inhibitor of oxidative phosphorylation) and upon treatment with formaldehyde. While the formaldehyde-targeted process stays unknown, our results indicate that published data on yeast actin cytoskeleton obtained from glucose-depleted cells after fixation should be considered with caution. PMID- 28357359 TI - Chemical proteomics approach reveals the direct targets and the heme-dependent activation mechanism of artemisinin in Plasmodium falciparum using an artemisinin based activity probe. AB - Artemisinin and its analogues are currently the most effective anti-malarial drugs. The activation of artemisinin requires the cleavage of the endoperoxide bridge in the presence of iron sources. Once activated, artemisinins attack macromolecules through alkylation and propagate a series of damages, leading to parasite death. Even though several parasite proteins have been reported as artemisinin targets, the exact mechanism of action (MOA) of artemisinin is still controversial and its high potency and specificity against the malaria parasite could not be fully accounted for. Recently, we have developed an unbiased chemical proteomics approach to directly probe the MOA of artemisinin in P. falciparum. We synthesized an artemisinin analogue with an alkyne tag, which can be coupled with biotin through click chemistry. This enabled selective purification and identification of 124 protein targets of artemisinin. Many of these targets are critical for the parasite survival. In vitro assays confirmed the specific artemisinin binding and inhibition of selected targets. We thus postulated that artemisinin kills the parasite through disrupting its biochemical landscape. In addition, we showed that artemisinin activation requires heme, rather than free ferrous iron, by monitoring the extent of protein binding using a fluorescent dye coupled with the alkyne-tagged artemisinin. The extremely high level of heme released from the hemoglobin digestion by the parasite makes artemisinin exceptionally potent against late-stage parasites (trophozoite and schizont stages) compared to parasites at early ring stage, which have low level of heme, mainly derived from endogenous synthesis. Such a unique activation mechanism also confers artemisinin with extremely high specificity against the parasites, while the healthy red blood cells are unaffected. Our results provide a sound explanation of the MOA of artemisinin and its specificity against malaria parasites, which may benefit the optimization of treatment strategies and the battle against the emerging drug resistance. PMID- 28357360 TI - Construction and evaluation of yeast expression networks by database-guided predictions. AB - DNA-Microarrays are powerful tools to obtain expression data on the genome-wide scale. We performed microarray experiments to elucidate the transcriptional networks, which are up- or down-regulated in response to the expression of toxic polyglutamine proteins in yeast. Such experiments initially generate hit lists containing differentially expressed genes. To look into transcriptional responses, we constructed networks from these genes. We therefore developed an algorithm, which is capable of dealing with very small numbers of microarrays by clustering the hits based on co-regulatory relationships obtained from the SPELL database. Here, we evaluate this algorithm according to several criteria and further develop its statistical capabilities. Initially, we define how the number of SPELL-derived co-regulated genes and the number of input hits influences the quality of the networks. We then show the ability of our networks to accurately predict further differentially expressed genes. Including these predicted genes into the networks improves the network quality and allows quantifying the predictive strength of the networks based on a newly implemented scoring method. We find that this approach is useful for our own experimental data sets and also for many other data sets which we tested from the SPELL microarray database. Furthermore, the clusters obtained by the described algorithm greatly improve the assignment to biological processes and transcription factors for the individual clusters. Thus, the described clustering approach, which will be available through the ClusterEx web interface, and the evaluation parameters derived from it represent valuable tools for the fast and informative analysis of yeast microarray data. PMID- 28357361 TI - The bacterial cell cycle checkpoint protein Obg and its role in programmed cell death. AB - The phenomenon of programmed cell death (PCD), in which cells initiate their own demise, is not restricted to multicellular organisms. Unicellular organisms, both eukaryotes and prokaryotes, also possess pathways that mediate PCD. We recently identified a PCD mechanism in Escherichia coli that is triggered by a mutant isoform of the essential GTPase ObgE (Obg of E. coli). Importantly, the PCD pathway mediated by mutant Obg (Obg*) differs fundamentally from other previously described bacterial PCD pathways and thus constitutes a new mode of PCD. ObgE was previously proposed to act as a cell cycle checkpoint protein able to halt cell division. The implication of ObgE in the regulation of PCD further increases the similarity between this protein and eukaryotic cell cycle regulators that are capable of doing both. Moreover, since Obg is conserved in eukaryotes, the elucidation of this cell death mechanism might contribute to the understanding of PCD in higher organisms. Additionally, if Obg*-mediated PCD is conserved among different bacterial species, it will be a prime target for the development of innovative antibacterials that artificially induce this pathway. PMID- 28357362 TI - Bacterial outer membrane vesicle biogenesis: a new mechanism and its implications. AB - Outer membrane vesicle (OMV) release by Gram-negative bacteria has been observed and studied for decades. First considered as a by-product of cell lysis, it soon became evident that OMVs are actively secreted from the outer membrane (OM) of Gram-negative bacteria. Accordingly, these small particles (~ 10-300 nm in diameter) consist mainly of OM components like phospholipids (PLs), OM proteins, and lipopolysaccharides or lipooligosaccharides. However, OMVs may also comprise periplasmic, inner membrane, or cytoplasmic components. Since the shedding of substantial amounts of OM material represents a significant energy cost to the bacterial cell, OMV production must have some vital biological functions for Gram negative bacteria. Indeed, intense research on that topic revealed that OMVs play important roles in bacterial physiology and pathogenesis, ranging from secretion and delivery of biomolecules (for example, toxins, DNA, or quorum sensing molecules) over stress response and biofilm formation to immunomodulation and adherence to host cells. Only recently researchers have begun to elucidate the mechanistic aspects of OMV formation, but a general mechanism for the biogenesis of these vesicles is still lacking. Here we review the findings and implications of our recent study published in Nature Communications (Roier S, et al. (2016) Nat. Commun. 7:10515), where we propose a novel and highly conserved bacterial OMV biogenesis mechanism based on PL accumulation in the outer leaflet of the OM. This mechanism might not only have important pathophysiological roles in vivo, but also represents the first general mechanism of OMV formation applicable to all Gram-negative bacteria. PMID- 28357363 TI - Metabolic network structure and function in bacteria goes beyond conserved enzyme components. AB - For decades, experimental work has laid the foundation for our understanding of the linear and branched pathways that are integrated to form the metabolic networks on which life is built. Genetic and biochemical approaches applied in model organisms generate empirical data that correlate genes, gene products and their biological activities. In the post-genomic era, these results have served as the basis for the genome annotation that is routinely used to infer the metabolic capabilities of an organism and mathematically model the presumed metabolic network structure. At large, genome annotation and metabolic network reconstructions have demystified genomic content of non-culturable microorganisms and allowed researchers to explore the breadth of metabolisms in silico. Mis annotation aside, it is unclear whether in silico reconstructions of metabolic structure from component parts accurately captures the higher levels of network organization and flux distribution. For this approach to provide accurate predictions, one must assume that the conservation of metabolic components leads to conservation of metabolic network architecture and function. This assumption has not been rigorously tested. Here we describe the implications of a recent study (MBio 5;7(1): e01840-15), which demonstrated that conservation of metabolic components was not sufficient to predict network structure and function. PMID- 28357364 TI - Evidence for the hallmarks of human aging in replicatively aging yeast. AB - Recently, efforts have been made to characterize the hallmarks that accompany and contribute to the phenomenon of aging, as most relevant for humans 1. Remarkably, studying the finite lifespan of the single cell eukaryote budding yeast (recently reviewed in 2 and 3) has been paramount for our understanding of aging. Here, we compile observations from literature over the past decades of research on replicatively aging yeast to highlight how the hallmarks of aging in humans are present in yeast. We find strong evidence for the majority of these, and summarize how yeast aging is especially characterized by the hallmarks of genomic instability, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, and mitochondrial dysfunction. PMID- 28357366 TI - Inhibition of Zika virus by Wolbachia in Aedes aegypti. AB - Through association with cases of microcephaly in 2015, Zika virus (ZIKV) has transitioned from a relatively unknown mosquito-transmitted pathogen to a global health emergency, emphasizing the need to improve existing mosquito control programs to prevent future disease outbreaks. The response to Zika must involve a paradigm shift from traditional to novel methods of mosquito control, and according to the World Health Organization should incorporate the release of mosquitoes infected with the bacterial endosymbiont Wolbachiapipientis. In our recent paper [Dutra, HLC et al., Cell Host & Microbe 2016] we investigated the potential of Wolbachia infections in Aedes aegypti to restrict infection and transmission of Zika virus recently isolated in Brazil. Wolbachia is now well known for its ability to block or reduce infection with a variety of pathogens in different mosquito species including the dengue (DENV), yellow fever, and chikungunya viruses, and malaria-causing Plasmodium, and consequently has great potential to control mosquito-transmitted diseases across the globe. Our results demonstrated that the wMel Wolbachia strain in Brazilian Ae. aegypti is a strong inhibitor of ZIKV infection, and furthermore appears to prevent transmission of infectious viral particles in mosquito saliva, which highlights the bacterium's suitability for more widespread use in Zika control. PMID- 28357365 TI - Cox1 mutation abrogates need for Cox23 in cytochrome c oxidase biogenesis. AB - Cox23 is a known conserved assembly factor for cytochrome c oxidase, although its role in cytochrome c oxidase (CcO) biogenesis remains unresolved. To gain additional insights into its role, we isolated spontaneous suppressors of the respiratory growth defect in cox23? yeast cells. We recovered independent colonies that propagated on glycerol/lactate medium for cox23? cells at 37 degrees C. We mapped these mutations to the mitochondrial genome and specifically to COX1 yielding an I101F substitution. The I101F Cox1 allele is a gain-of function mutation enabling yeast to respire in the absence of Cox23. CcO subunit steady-state levels were restored with the I101F Cox1 suppressor mutation and oxygen consumption and CcO activity were likewise restored. Cells harboring the mitochondrial genome encoding I101F Cox1 were used to delete genes for other CcO assembly factors to test the specificity of the Cox1 mutation as a suppressor of cox23? cells. The Cox1 mutant allele fails to support respiratory growth in yeast lacking Cox17, Cox19, Coa1, Coa2, Cox14 or Shy1, demonstrating its specific suppressor activity for cox23? cells. PMID- 28357367 TI - Antibiotic use in childhood alters the gut microbiota and predisposes to overweight. AB - A correlation between the use of antibiotics in early life and the excessive weight gain in later childhood has been shown in several large cohort studies all over the world. One hypothesis explaining this association is the pervasive impact that antibiotics may have on the intestinal microbiota, and this has been supported by recent mouse studies. Studies have shown dramatic changes in the intestinal microbiota of adults in response to oral antibiotic treatments. However, little is known about the impact of antibiotics on the intestinal microbiota of children, although antibiotics account for the majority of the medication prescribed to children in Western countries. PMID- 28357368 TI - House of cellulose - a new hideout for drug tolerant Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis (Mtb) causes tuberculosis (TB). The treatment of TB requires administration of multiple drugs for long durations because of the unusual drug tolerance of Mtb. The phenotypic drug tolerance of genetically drug susceptible Mtb in humans can be explained by its ability to form biofilms. Recent studies from different laboratories suggest that Mtb forms biofilms that harbour drug-tolerant bacteria. These findings have created a new area of research in the field of mycobacterial physiology. Recently, my laboratory has reported that Mtb cells organise themselves into biofilms in response to intracellular thiol reductive stress (Trivedi et al. Nature communications. 2016). Bacteria residing in these biofilms are tolerant towards antimycobacterial drugs. Cellulose is a key component of the extracellular polymeric substances that hold mycobacterial cells together in these biofilms. Here, I discuss the implications of these findings and new hypotheses arising from this study on the biology of Mtb biofilms. PMID- 28357371 TI - A novel component of the mitochondrial genome segregation machinery in trypanosomes. AB - We recently described a new component (TAC102) of the mitochondrial genome segregation machinery (mtGSM) in the protozoan parasite Trypanosoma brucei. T. brucei belongs to a group of organisms that contain a single mitochondrial organelle with a single mitochondrial genome (mt-genome) per cell. The mt-genome consists of 5000 minicircles (1 kb) and 25 maxicircles (23 kb) that are catenated into a large network. After replication of the network its segregation is driven by the separating basal bodies, which are homologous structures to the centrioles organizing the spindle apparatus in many eukaryotes. The structure connecting the basal body to the mt-genome was named the Tripartite Attachment Complex (TAC) owing its name to the distribution across three areas in the cell including the two mitochondrial membranes. PMID- 28357369 TI - Functions and regulation of the MRX complex at DNA double-strand breaks. AB - DNA double-strand breaks (DSBs) pose a serious threat to genome stability and cell survival. Cells possess mechanisms that recognize DSBs and promote their repair through either homologous recombination (HR) or non-homologous end joining (NHEJ). The evolutionarily conserved Mre11-Rad50-Xrs2 (MRX) complex plays a central role in the cellular response to DSBs, as it is implicated in controlling end resection and in maintaining the DSB ends tethered to each other. Furthermore, it is responsible for DSB signaling by activating the checkpoint kinase Tel1 that, in turn, supports MRX function in a positive feedback loop. The present review focuses mainly on recent works in the budding yeast Saccharomyces cerevisiae to highlight structure and regulation of MRX as well as its interplays with Tel1. PMID- 28357370 TI - Attenuation of polyglutamine-induced toxicity by enhancement of mitochondrial OXPHOS in yeast and fly models of aging. AB - Defects in mitochondrial biogenesis and function are common in many neurodegenerative disorders, including Huntington's disease (HD). We have previously shown that in yeast models of HD, enhancement of mitochondrial biogenesis through overexpression of Hap4, the catalytic subunit of the transcriptional complex that regulates mitochondrial gene expression, alleviates the growth arrest induced by expanded polyglutamine (polyQ) tract peptides in rapidly dividing cells. However, the mechanism through which HAP4 overexpression exerts this protection remains unclear. Furthermore, it remains unexplored whether HAP4 overexpression and increased respiratory function during growth can also protect against polyQ-induced toxicity during yeast chronological lifespan. Here, we show that in yeast, mitochondrial respiration and oxidative phosphorylation (OXPHOS) are essential for protection against the polyQ-induced growth defect by HAP4 overexpression. In addition, we show that not only increased HAP4 levels, but also alternative interventions, including calorie restriction, that result in enhanced mitochondrial biogenesis confer protection against polyQ toxicity during stationary phase. The data obtained in yeast models guided experiments in a fly model of HD, where we show that enhancement of mitochondrial biogenesis can also protect against neurodegeneration and behavioral deficits. Our results suggest that therapeutic interventions aiming at the enhancement of mitochondrial respiration and OXPHOS could reduce polyQ toxicity and delay disease onset. PMID- 28357372 TI - Bacterial genotoxin functions as immune-modulator and promotes host survival. AB - Bacterial genotoxins are effectors that cause DNA damage in target cells. Many aspects of the biology of these toxins have been characterised in vitro, such as structure, cellular internalisation pathways and effects on the target cells. However, little is known about their function in vivo. Salmonella enterica serovar Typhi (S. Typhi) is a Gram-negative, intracellular bacterium that causes typhoid fever, a debilitating disease infecting more than 20 million people every year. S. Typhiproduce a genotoxin named typhoid toxin (TT), but its role in the contest of host infection is poorly characterized. The major obstacle in addressing this issue is that S. Typhi is exclusively a human pathogen. To overcome this limitation, we have used as model bacterium S. Typhimurium, and engineered it to produce endogenous levels of an active and inactive typhoid toxin, hereby named as TT (or genotoxic) and cdtB (or control), respectively. To our surprise, infection with the genotoxin strain strongly suppressed intestinal inflammation, leading to a better survival of the host during the acute phase of infection, suggesting typhoid toxin may exert a protective role. The presence of a functional genotoxin was also associated with an increased frequency of asymptomatic carriers. PMID- 28357373 TI - Cryptococcus flips its lid - membrane phospholipid asymmetry modulates antifungal drug resistance and virulence. AB - Human fungal infections are increasing in prevalence and acquisition of antifungal drug resistance, while our antifungal drug armamentarium remains very limited, constituting a significant public health problem. Despite the fact that prominent antifungal drugs target the fungal cell membrane, very little is known about how fungal membrane biology regulates drug-target interactions. Asymmetrical phospholipid distribution is an essential property of biological membranes, which is maintained by a group of transporters that dynamically translocate specific phospholipid groups across the membrane bilayer. Lipid flippase is the enzyme responsible for translocation of certain phospholipids, including phosphatidylserine (PS), across the plasma membrane from the exocytoplasmic to the cytoplasmic leaflet. Loss of lipid flippase leads to abnormal phospholipid distribution and impaired intracellular vesicular trafficking. The recent research article by Huang et al. reported that in pathogenic fungus Cryptococcus neoformans loss of lipid flippase activity sensitized cryptococcal cells to multiple classes of antifungal drugs, including the cell wall active echinocandins, and abolished fungal virulence in murine models. This finding demonstrates that lipid flippase may promote fungal drug resistance and virulence and indicates that this enzyme may represent a novel antifungal drug target. PMID- 28357374 TI - Sexually transmitted infections: old foes on the rise. AB - Sexually transmitted infections (STIs) are commonly spread via sexual contact. It is estimated that one million STIs are acquired every day worldwide. Besides their impact on sexual, reproductive and neonatal health, they can cause disastrous and life-threatening complications if left untreated. In addition to this personal burden, STIs also represent a socioeconomic problem, deriving in treatment costs of tremendous proportions. Despite a substantial progress in diagnosis, treatment and prevention, the incidence of many common STIs is increasing, and STIs continue to represent a global public health problem and a major cause for morbidity and mortality. With this Special Issue, Microbial Cell provides an in-depth overview of the eight major STIs, covering all relevant features of each infection. PMID- 28357375 TI - Syphilis: Re-emergence of an old foe. AB - Syphilis is caused by infection with Treponema pallidum subsp. pallidum, a not yet-cultivable spiral-shaped bacterium that is usually transmitted by sexual contact with an infected partner or by an infected pregnant woman to her fetus. There is no vaccine to prevent syphilis. Diagnosis and treatment of infected individuals and their contacts is key to syphilis control programs that also include sex education and promotion of condom use to prevent infection. Untreated syphilis can progress through four stages: primary (chancre, regional lymphadenopathy), secondary (disseminated skin eruptions, generalized lymphadenopathy), latent (decreased re-occurrence of secondary stage manifestations, absence of symptoms), and tertiary (gummas, cardiovascular syphilis and late neurological symptoms). The primary and secondary stages are the most infectious. WHO estimates that each year 11 million new cases of syphilis occur globally among adults aged 15-49 years. Syphilis has re-emerged in several regions including North America, Western Europe, China and Australia. Host-associated factors that drive the re-emergence and spread of syphilis include high-risk sexual activity, migration and travel, and economic and social changes that limit access to health care. Early, uncomplicated syphilis is curable with a single intramuscular injection of benzathine penicillin G (BPG), the first line drug for all stages of syphilis. Emergence of macrolide-resistant T. pallidum has essentially precluded the empirical use of azithromycin as a second-line drug for treatment of syphilis. Virulence attributes of T. pallidum are poorly understood. Genomic and proteomic studies have provided some new information concerning how this spirochete may evade host defense mechanisms to persist for long periods in the host. PMID- 28357376 TI - Gonorrhea - an evolving disease of the new millennium. AB - Etiology, transmission and protection: Neisseria gonorrhoeae (the gonococcus) is the etiological agent for the strictly human sexually transmitted disease gonorrhea. Infections lead to limited immunity, therefore individuals can become repeatedly infected. Pathology/symptomatology: Gonorrhea is generally a non complicated mucosal infection with a pustular discharge. More severe sequellae include salpingitis and pelvic inflammatory disease which may lead to sterility and/or ectopic pregnancy. Occasionally, the organism can disseminate as a bloodstream infection. Epidemiology, incidence and prevalence: Gonorrhea is a global disease infecting approximately 60 million people annually. In the United States there are approximately 300, 000 cases each year, with an incidence of approximately 100 cases per 100,000 population. Treatment and curability: Gonorrhea is susceptible to an array of antibiotics. Antibiotic resistance is becoming a major problem and there are fears that the gonococcus will become the next "superbug" as the antibiotic arsenal diminishes. Currently, third generation extended-spectrum cephalosporins are being prescribed. Molecular mechanisms of infection: Gonococci elaborate numerous strategies to thwart the immune system. The organism engages in extensive phase (on/off switching) and antigenic variation of several surface antigens. The organism expresses IgA protease which cleaves mucosal antibody. The organism can become serum resistant due to its ability to sialylate lipooligosaccharide in conjunction with its ability to subvert complement activation. The gonococcus can survive within neutrophils as well as in several other lymphocytic cells. The organism manipulates the immune response such that no immune memory is generated which leads to a lack of protective immunity. PMID- 28357377 TI - Chlamydia trachomatis Genital Infections. AB - Etiology, transmission and protection: Chlamydia trachomatis is the leading cause of bacterial sexually transmitted infection (STI) globally. However, C. trachomatis also causes trachoma in endemic areas, mostly Africa and the Middle East, and is a leading cause of preventable blindness worldwide. Epidemiology, incidence and prevalence: The World Health Organization estimates 131 million new cases of C. trachomatis genital infection occur annually. Globally, infection is most prevalent in young women and men (14-25 years), likely driven by asymptomatic infection, inadequate partner treatment and delayed development of protective immunity. Pathology/Symptomatology: C. trachomatis infects susceptible squamocolumnar or transitional epithelial cells, leading to cervicitis in women and urethritis in men. Symptoms are often mild or absent but ascending infection in some women may lead to Pelvic Inflammatory Disease (PID), resulting in reproductive sequelae such as ectopic pregnancy, infertility and chronic pelvic pain. Complications of infection in men include epididymitis and reactive arthritis. Molecular mechanisms of infection: Chlamydiae manipulate an array of host processes to support their obligate intracellular developmental cycle. This leads to activation of signaling pathways resulting in disproportionate influx of innate cells and the release of tissue damaging proteins and pro-inflammatory cytokines. Treatment and curability: Uncomplicated urogenital infection is treated with azithromycin (1 g, single dose) or doxycycline (100 mg twice daily x 7 days). However, antimicrobial treatment does not ameliorate established disease. Drug resistance is rare but treatment failures have been described. Development of an effective vaccine that protects against upper tract disease or that limits transmission remains an important goal. PMID- 28357378 TI - Trichomoniasis - are we giving the deserved attention to the most common non viral sexually transmitted disease worldwide? AB - ETIOLOGY: Trichomonas vaginalis is the etiologic agent of trichomoniasis, the most common non-viral sexually transmitted disease (STD) in the world. Transmission: Trichomoniasis is transmitted by sexual intercourse and transmission via fomites is rare. Epidemiology, incidence and prevalence: The WHO estimates an incidence of 276 million new cases each year and prevalence of 187 million of infected individuals. However, the infection is not notifiable. Pathology/Symptomatology: The T. vaginalis infection results in a variety of clinical manifestations - in most cases the patients are asymptomatic, but some may develop signs typically associated to the disease. Importantly, the main issue concerning trichomoniasis is its relationship with serious health consequences such as cancer, adverse pregnancy outcomes, infertility, and HIV acquisition. Molecular mechanisms of infection: To achieve success in parasitism trichomonads develop a complex process against the host cells that includes dependent- and independent-contact mechanisms. This multifactorial pathogenesis includes molecules such as soluble factors, secreted proteinases, adhesins, lipophosphoglycan that culminate in cytoadherence and cytotoxicity against the host cells. Treatment and curability: The treatment with metronidazole or tinidazole is recommended; however, cure failures remain problematic due to noncompliance, reinfection and/or lack of treatment of sexual partners, inaccurate diagnosis, or drug resistance. Therefore, new therapeutic alternatives are urgently needed. Protection: Strategies for protection including sexual behavior, condom usage, and therapy have not contributed to the decrease on disease prevalence, pointing to the need for innovative approaches. Vaccine development has been hampered by the lack of long-lasting humoral immunity associated to the absence of good animal models. PMID- 28357379 TI - Hepatitis B virus and its sexually transmitted infection - an update. AB - EPIDEMIOLOGY: incidence and prevalence: About 5% of the world's population has chronic hepatitis B virus (HBV) infection, and nearly 25% of carriers develop chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The prevalence of chronic HBV infection in human immunodeficiency virus (HIV)-infected individuals is 5%-15%; HIV/HBV coinfected individuals have a higher level of HBV replication, with higher rates of chronicity, reactivation, occult infection, and HCC than individuals with HBV only. The prevalence of HBV genotype A is significantly higher among men who have sex with men (MSM), compared with the rest of the population. Molecular mechanisms of infection, pathology, and symptomatology: HBV replication begins with entry into the hepatocyte. Sodium taurocholate cotransporting polypeptide was identified in 2012 as the entry receptor of HBV. Although chronic hepatitis B develops slowly, HIV/HBV coinfected individuals show more rapid progression to cirrhosis and HCC. Transmission and protection: The most common sources of HBV infection are body fluids. Hepatitis B (HB) vaccination is recommended for all children and adolescents, and all unvaccinated adults at risk for HBV infection (sexually active individuals such as MSM, individuals with occupational risk, and immunosuppressed individuals). Although HB vaccination can prevent clinical infections (hepatitis), it cannot prevent 100% of subclinical infections. Treatment and curability: The goal of treatment is reducing the risk of complications (cirrhosis and HCC). Pegylated interferon alfa and nucleos(t)ide analogues (NAs) are the current treatments for chronic HBV infection. NAs have improved the outcomes of patients with cirrhosis and HCC, and decreased the incidence of acute liver failure. PMID- 28357380 TI - Genital Herpes: Insights into Sexually Transmitted Infectious Disease. AB - Etiology, transmission and protection: Herpes simplex virus-2 (HSV-2) is a leading cause of sexually transmitted infections with recurring manifestations throughout the lifetime of infected hosts. Currently no effective vaccines or prophylactics exist that provide complete protection or immunity from the virus, which is endemic throughout the world. Pathology/Symptomatology: Primary and recurrent infections result in lesions and inflammation around the genital area and the latter accounts for majority of genital herpes instances. Immunocompromised patients including neonates are susceptible to additional systemic infections including debilitating consequences of nervous system inflammation. Epidemiology, incidence and prevalence: More than 500 million people are infected worldwide and most reported cases involve the age groups between 16-40 years, which coincides with an increase in sexual activity among this age group. While these numbers are an estimate, the actual numbers may be underestimated as many people are asymptomatic or do not report the symptoms. Treatment and curability: Currently prescribed medications, mostly nucleoside analogs, only reduce the symptoms caused by an active infection, but do not eliminate the virus or reduce latency. Therefore, no cure exists against genital herpes and infected patients suffer from periodic recurrences of disease symptoms for their entire lives. Molecular mechanisms of infection: The last few decades have generated many new advances in our understanding of the mechanisms that drive HSV infection. The viral entry receptors such as nectin-1 and HVEM have been identified, cytoskeletal signaling and membrane structures such as filopodia have been directly implicated in viral entry, host motor proteins and their viral ligands have been shown to facilitate capsid transport and many host and HSV proteins have been identified that help with viral replication and pathogenesis. New understanding has emerged on the role of autophagy and other innate immune mechanisms that are subverted to enhance HSV pathogenesis. This review summarizes our current understanding of HSV-2 and associated diseases and available or upcoming new treatments. PMID- 28357383 TI - Using microbes as a key tool to unravel the mechanism of autophagy and the functions of the ATG proteins. AB - The study of microbe infections has always been a very effective approach to unveil and dissect cellular pathways. Autophagy is not an exception. Although some of the breakthrough discoveries in the field were obtained using yeast, pathogens have been and still are a great tool to discover and characterize new molecular and functional aspects of autophagy. Research on pathogens has helped to acquire knowledge about selective types of autophagy and the assembly of the autophagy machinery, i.e the autophagy-related (ATG) proteins, but also about alternative cellular roles of this pathway, such as secretion. Finally, microbes have also served to discover and characterize unconventional functions of the ATG proteins, which are uncoupled from their role in autophagy. In our recent study, we have taken advantage of viruses as a screening tool to determine the extent of the unconventional functions of the ATG proteome and characterize one of them. PMID- 28357385 TI - Toxin-mediated gene regulatory mechanism in Staphylococcus aureus. AB - The dangerous human pathogen Staphylococcus aureus relies heavily on toxins to cause disease, but toxin production can put a strong burden on the bacteria's energy balance. Thus, controlling the synthesis of proteins solely needed in times of toxin production represents a way for the bacteria to avoid wasting energy. One hypothetical manner to accomplish this sort of regulation is by gene regulatory functions of the toxins themselves. There have been several reports about gene regulation by toxins in S. aureus, but these were never verified on the molecular level. In our study published in MBio [Joo et al., 7(5). pii: e01579-16], we show that phenol-soluble modulins (PSMs), important peptide toxins of S. aureus, release a repressor from the promoter of the operon encoding the toxin export system, thereby enabling toxin secretion. This study describes the first molecular regulatory mechanism exerted by an S. aureus toxin, setting a paradigmatic example of how S. aureus toxins may influence cell functions to adjust them to times of toxin production. PMID- 28357384 TI - Improvement of biochemical methods of polyP quantification. AB - Polyphosphate (polyP) is an abundant and physiologically important biomolecule for virtually any living cell. Therefore, determination of changes in cellular content of polyP is crucial for its functional characterization. Determination of cellular polyP has been performed by many different methods, and the lack of a standardized procedure is possibly responsible for the large dispersion of results found in the relevant literature. For a relatively simple organism, such as the yeast Saccharomyces cerevisiae, this variation can be up to 12-fold. polyP extraction and determination of free phosphate released by enzymatic degradation of the polymer is a method quite common and relatively straightforward for polyP determination. By using the yeast S. cerevisiae as model, we have experimentally evaluated the different steps in this procedure in order to identify critical issues that might explain the disparate reported results. As the main output of this evaluation we propose a straightforward and robust procedure that can be used as gold standard protocol for cellular polyP purification and determination from unicellular organisms, thus providing consistency to measurements and facilitating inter-laboratory comparisons and biological interpretation of the results. PMID- 28357386 TI - A new role for Holliday junction resolvase Yen1 in processing DNA replication intermediates exposes Dna2 as an accessory replicative helicase. AB - DNA replication is mediated by a multi-protein complex known as the replisome. With the hexameric MCM (minichromosome maintenance) replicative helicase at its core, the replisome splits the parental DNA strands, forming replication forks (RFs), where it catalyses coupled leading and lagging strand DNA synthesis. While replication is a highly effective process, intrinsic and oncogene-induced replication stress impedes the progression of replisomes along chromosomes. As a consequence, RFs stall, arrest, and collapse, jeopardizing genome stability. In these instances, accessory fork progression and repair factors, orchestrated by the replication checkpoint, promote RF recovery, ensuring the chromosomes are fully replicated and can be safely segregated at cell division. Homologous recombination (HR) proteins play key roles in negotiating replication stress, binding at stalled RFs and shielding them from inappropriate processing. In addition, HR-mediated strand exchange reactions restart stalled or collapsed RFs and mediate error-free post-replicative repair. DNA transactions at stalled RFs further involve various DNA editing factors, notably helicases and nucleases. A study by Olmezer et al. (2016) has recently identified a role for the structure specific nuclease Yen1 (GEN1 in human) in the resolution of dead-end DNA replication intermediates after RF arrest. This new function of Yen1 is distinct from its previously known role as a Holliday junction resolvase, mediating the removal of branched HR intermediates, and it becomes essential for viable chromosome segregation in cells with a defective Dna2 helicase. These findings have revealed greater complexity in the tasks mediated by Yen1 and expose a replicative role for the elusive helicase activity of the conserved Dna2 nuclease helicase. PMID- 28357387 TI - S. pombe placed on the prion map. AB - Schizosaccharomyces pombe has been used extensively as a model organism, however it is only recently that the first prion in this organism, a copper transporter protein encoded by ctr4, has been conclusively demonstrated. Prions are found in a wide range of organisms and have been implicated in a number of human neurodegenerative diseases. Research into the biology of prions has been carried out mainly in the budding yeast Saccharomyces cerevisiae, however there are many questions still to be addressed. Now, with the identification of the Ctr4 prion in S. pombe, further work in the two yeasts and comparisons of prion biology in these organisms should lead to a greater understanding of prions and their role in disease. PMID- 28357382 TI - HPV disease transmission protection and control. AB - Human papillomaviruses (HPVs) represent a large collection of viral types associated with significant clinical disease of cutaneous and mucosal epithelium. HPV-associated cancers are found in anogenital and oral mucosa, and at various cutaneous sites. Papillomaviruses are highly species and tissue restricted, and these viruses display both mucosotropic, cutaneotropic or dual tropism for epithelial tissues. A subset of HPV types, predominantly mucosal, are also oncogenic and cancers with these HPV types account for more than 200,000 deaths world-wide. Host control of HPV infections requires both innate and adaptive immunity, but the viruses have developed strategies to escape immune detection. Viral proteins can disrupt both innate pathogen-sensing pathways and T-cell based recognition and subsequent destruction of infected tissues. Current treatments to manage HPV infections include mostly ablative strategies in which recurrences are common and only active disease is treated. Although much is known about the papillomavirus life cycle, viral protein functions, and immune responsiveness, we still lack knowledge in a number of key areas of PV biology including tissue tropism, site-specific cancer progression, codon usage profiles, and what are the best strategies to mount an effective immune response to the carcinogenic stages of PV disease. In this review, disease transmission, protection and control are discussed together with questions related to areas in PV biology that will continue to provide productive opportunities of discovery and to further our understanding of this diverse set of human viral pathogens. PMID- 28357381 TI - Recent Insights into the HIV/AIDS Pandemic. AB - Etiology, transmission and protection: Transmission of HIV, the causative agent of AIDS, occurs predominantly through bodily fluids. Factors that significantly alter the risk of HIV transmission include male circumcision, condom use, high viral load, and the presence of other sexually transmitted diseases. Pathology/Symptomatology: HIV infects preferentially CD4+ T lymphocytes, and Monocytes. Because of their central role in regulating the immune response, depletion of CD4+ T cells renders the infected individual incapable of adequately responding to microorganisms otherwise inconsequential. Epidemiology, incidence and prevalence: New HIV infections affect predominantly young heterosexual women and homosexual men. While the mortality rates of AIDS related causes have decreased globally in recent years due to the use of highly active antiretroviral therapy (HAART) treatment, a vaccine remains an elusive goal. Treatment and curability: For those afflicted HIV infection remains a serious illness. Nonetheless, the use of advanced therapeutics have transformed a dire scenario into a chronic condition with near average life spans. When to apply those remedies appears to be as important as the remedies themselves. The high rate of HIV replication and the ability to generate variants are central to the viral survival strategy and major barriers to be overcome. Molecular mechanisms of infection: In this review, we assemble new details on the molecular events from the attachment of the virus, to the assembly and release of the viral progeny. Yet, much remains to be learned as understanding of the molecular mechanisms used in viral replication and the measures engaged in the evasion of immune surveillance will be important to develop effective interventions to address the global HIV pandemic. PMID- 28357389 TI - Mutational analysis of fructose-1,6-bis-phosphatase FBP1 indicates partially independent functions in gluconeogenesis and sensitivity to genotoxic stress. AB - Fructose-1,6-bisphosphatase (FBP1) is a key enzyme in the evolutionary conserved pathway of gluconeogenesis. We had shown in an earlier study that FBP1 is involved in the response and sensitivity to methyl-methanesulfonate (MMS)-induced DNA damage in yeast. In the work presented here we performed an alanine screen mutational analysis of several evolutionary conserved amino acid residues of FBP1, which were selected based on conserved residues and structural studies of mammalian and yeast homologues of FBP1. Mutants were examined for enzymatic activity, and yeast cells expressing these mutants were tested for growth on non fermentable and MMS-containing media. The results obtained support predicted vital roles of several residues for enzymatic activity and led to the identification of residues indispensable for the MMS-sensitizing effect. Despite an overlap between these two properties, careful analysis revealed two mutations, Asn75 and His324, which decouple the enzymatic activity and the MMS-sensitizing effect, indicating two distinctive biological activities linked in this key gluconeogenesis enzyme. PMID- 28357388 TI - Balanced CoQ6 biosynthesis is required for lifespan and mitophagy in yeast. AB - Coenzyme Q is an essential lipid with redox capacity that is present in all organisms. In yeast its biosynthesis depends on a multiprotein complex in which Coq7 protein has both catalytic and regulatory functions. Coq7 modulates CoQ6 levels through a phosphorylation cycle, where dephosphorylation of three amino acids (Ser/Thr) by the mitochondrial phosphatase Ptc7 increases the levels of CoQ6. Here we analyzed the role of Ptc7 and the phosphorylation state of Coq7 in yeast mitochondrial function. The conversion of the three Ser/Thr to alanine led to a permanently active form of Coq7 that caused a 2.5-fold increase of CoQ6 levels, albeit decreased mitochondrial respiratory chain activity and oxidative stress resistance capacity. This resulted in an increase in endogenous ROS production and shortened the chronological life span (CLS) compared to wild type. The null PTC7 mutant (ptc7?) strain showed a lower biosynthesis rate of CoQ6 and a significant shortening of the CLS. The reduced CLS observed in ptc7Delta was restored by the overexpression of PTC7 but not by the addition of exogenous CoQ6. Overexpression of PTC7 increased mitophagy in a wild type strain. This finding suggests an additional Ptc7 function beyond the regulation of CoQ biosynthesis. Genetic disruption of PTC7 prevented mitophagy activation in conditions of nitrogen deprivation. In brief, we show that, in yeast, Ptc7 modulates the adaptation to respiratory metabolism by dephosphorylating Coq7 to supply newly synthesized CoQ6, and by activating mitophagy to remove defective mitochondria at stationary phase, guaranteeing a proper CLS in yeast. PMID- 28357390 TI - Breaking the bilayer: OMV formation during environmental transitions. AB - Gram-negative bacteria maintain the barrier properties of the outer membrane (OM) in a wide array of physiological conditions despite their inability to degrade lipopolysaccharide (LPS) and protein material present in the outer leaflet of the OM. Through characterization of the native dynamics of outer membrane LPS change we recently described a mechanism in which these diderm organisms overcome this design flaw. In response to different environmental stimuli Salmonellaenterica modulates the export of specific structural variants of lipid A via outer membrane vesicles (OMVs). We proposed that the polymorphic model for regulation of membrane lipid content could largely account for the structural differences between secreted and retained lipid A species. However, differences in OMV production levels and size observed between environmental conditions remain unexplained. Further exploration into the relationship between OMV production level and content specificity may shed light onto the enigmatic mechanisms of OMV formation. PMID- 28357391 TI - The tug-of-war over MTOR in Legionella infections. AB - A ruptured bacteria-containing organelle within the cytosol of an infected eukaryotic cell frequently initiates host defense responses that restrict pathogen replication. Therefore, source for lipids must be found to accommodate the organelle membrane expansion required to support bacterial replication. How host cells are manipulated to provide lipids for the expansion of pathogen occupied organelles is not well understood. By investigating the interaction between macrophages and the human pulmonary pathogen Legionella pneumophila we uncovered that the host metabolic checkpoint kinase Mechanistic target of rapamycin (MTOR) is a central regulator of the pathogen niche expansion program. PMID- 28357392 TI - Transceptors as a functional link of transporters and receptors. AB - Cells need to communicate with their environment in order to obtain nutrients, grow, divide and respond to signals related to adaptation in changing physiological conditions or stress. A very basic question in biology is how cells, especially of those organisms living in rapidly changing habitats, sense their environment. Apparently, this question is of particular importance to all free-living microorganisms. The critical role of receptors, transporters and channels, transmembrane proteins located in the plasma membrane of all types of cells, in signaling environmental changes is well established. A relative newcomer in environment sensing are the so called transceptors, membrane proteins that possess both solute transport and receptor-like signaling activities. Now, the transceptor concept is further enlarged to include micronutrient sensing via the iron and zinc high-affinity transporters of Saccharomyces cerevisiae. Interestingly, what seems to underline the transport and/or sensing function of receptors, transporters and transceptors is ligand-induced conformational alterations recognized by downstream intracellular effectors. PMID- 28357395 TI - New insights into the function of a versatile class of membrane molecular motors from studies of Myxococcus xanthus surface (gliding) motility. AB - Cell motility is a central function of living cells, as it empowers colonization of new environmental niches, cooperation, and development of multicellular organisms. This process is achieved by complex yet precise energy-consuming machineries in both eukaryotes and bacteria. Bacteria move on surfaces using extracellular appendages such as flagella and pili but also by a less-understood process called gliding motility. During this process, rod-shaped bacteria move smoothly along their long axis without any visible morphological changes besides occasional bending. For this reason, the molecular mechanism of gliding motility and its origin have long remained a complete mystery. An important breakthrough in the understanding of gliding motility came from single cell and genetic studies in the delta-proteobacterium Myxococcus xanthus. These early studies revealed, for the first time, the existence of bacterial Focal Adhesion complexes (FA). FAs are formed at the bacterial pole and rapidly move towards the opposite cell pole. Their attachment to the underlying surface is linked to cell propulsion, in a process similar to the rearward translocation of actomyosin complexes in Apicomplexans. The protein machinery that forms at FAs was shown to contain up to seventeen proteins predicted to localize in all layers of the bacterial cell envelope, the cytosolic face, the inner membrane (IM), the periplasmic space and the outer membrane (OM). Among these proteins, a proton gated channel at the inner membrane was identified as the molecular motor. Thus, thrust generation requires the transduction of traction forces generated at the inner membrane through the cell envelope beyond the rigid barrier of the bacterial peptidoglycan. PMID- 28357394 TI - A multigene family encoding surface glycoproteins in Trypanosoma congolense. AB - Trypanosoma congolense, the causative agent of the most important livestock disease in Africa, expresses specific surface proteins involved in its parasitic lifestyle. Unfortunately, the complete repertoire of such molecules is far from being deciphered. As these membrane components are exposed to the host environment, they could be used as therapeutic or diagnostic targets. By mining the T. congolense genome database, we identified a novel family of lectin-like glycoproteins (TcoClecs). These molecules are predicted to have a transmembrane domain, a tandem repeat amino acid motif, a signal peptide and a C-type lectin like domain (CTLD). This paper depicts several experimental arguments in favor of a surface localization in bloodstream forms of T. congolense. A TcoClec gene was heterologously expressed in U-2 OS cells and the product could be partially found at the plasma membrane. TcoClecs were also localized at the surface of T. congolense bloodstream forms. The signal was suppressed when the cells were treated with a detergent to remove the plasma membrane or with trypsin to " shave " the parasites and remove their external proteins. This suggests that TcoClecs could be potential diagnostic or therapeutic antigens of African animal trypanosomiasis. The potential role of these proteins in T. congolense as well as in other trypanosomatids is discussed. PMID- 28357393 TI - Identification of Ftr1 and Zrt1 as iron and zinc micronutrient transceptors for activation of the PKA pathway in Saccharomyces cerevisiae. AB - Multiple types of nutrient transceptors, membrane proteins that combine a transporter and receptor function, have now been established in a variety of organisms. However, so far all established transceptors utilize one of the macronutrients, glucose, amino acids, ammonium, nitrate, phosphate or sulfate, as substrate. This is also true for the Saccharomyces cerevisiae transceptors mediating activation of the PKA pathway upon re-addition of a macronutrient to glucose-repressed cells starved for that nutrient, re-establishing a fermentable growth medium. We now show that the yeast high-affinity iron transporter Ftr1 and high-affinity zinc transporter Zrt1 function as transceptors for the micronutrients iron and zinc. We show that replenishment of iron to iron-starved cells or zinc to zinc-starved cells triggers within 1-2 minutes a rapid surge in trehalase activity, a well-established PKA target. The activation with iron is dependent on Ftr1 and with zinc on Zrt1, and we show that it is independent of intracellular iron and zinc levels. Similar to the transceptors for macronutrients, Ftr1 and Zrt1 are strongly induced upon iron and zinc starvation, respectively, and they are rapidly downregulated by substrate-induced endocytosis. Our results suggest that transceptor-mediated signaling to the PKA pathway may occur in all cases where glucose-repressed yeast cells have been starved first for an essential nutrient, causing arrest of growth and low activity of the PKA pathway, and subsequently replenished with the lacking nutrient to re-establish a fermentable growth medium. The broadness of the phenomenon also makes it likely that nutrient transceptors use a common mechanism for signaling to the PKA pathway. PMID- 28357397 TI - Advancing host-directed therapy for tuberculosis. AB - Tuberculosis (TB) drug-development strategies, a wide range of candidate host directed therapies (HDT)s-including new and repurposed drugs, biologics, and cellular therapies-have been proposed to accelerate eradication of infection and overcome the problems associated with current treatment regimens. By investigating the interaction between macrophages and the intracellular parasite Toxoplasma gondii (T. gondii), we uncovered that infection-induced signaling pathways suggest possibilities for the development of novel therapeutic modalities for TB that target the intracellular signaling pathways permitting the replication of Mycobacterium tuberculosis (MTB). PMID- 28357396 TI - Chlamydia trachomatis' struggle to keep its host alive. AB - Bacteria of the phylum Chlamydiae infect a diverse range of eukaryotic host species, including vertebrate animals, invertebrates, and even protozoa. Characteristics shared by all Chlamydiae include their obligate intracellular lifestyle and a biphasic developmental cycle. The infectious form, the elementary body (EB), invades a host cell and differentiates into the replicative form, the reticulate body (RB), which proliferates within a membrane-bound compartment, the inclusion. After several rounds of division, RBs retro-differentiate into EBs that are then released to infect neighboring cells. The consequence of this obligatory transition between replicative and infectious forms inside cells is that Chlamydiae absolutely depend on the viability and functionality of their host cell throughout the entire infection cycle. We recently conducted a forward genetic screen in Chlamydia trachomatis, a common sexually transmitted human pathogen, and identified a mutant that caused premature death in the majority of infected host cells. We employed emerging genetic tools in Chlamydia to link this cytotoxicity to the loss of the protein CpoS (Chlamydia promoter of survival) that normally localizes to the membrane of the pathogen-containing vacuole. CpoS deficient bacteria also induced an exaggerated type-1 interferon response in infected cells, produced reduced numbers of infectious EBs in cell culture, and were cleared faster from the mouse genital tract in a transcervical infection model in vivo. The analysis of this CpoS-deficient mutant yielded unique insights into the nature of cell-autonomous defense responses against Chlamydia and highlighted the importance of Chlamydia-mediated control of host cell fate for the success of the pathogen. PMID- 28357398 TI - Machine Learning in Multimodal Medical Imaging. PMID- 28357400 TI - Intra-Abdominal Hypertension Causes Bacterial Growth in Lungs: An Animal Study. AB - To study the effect of intra-abdominal hypertension (IAH) on the frequency of pneumonia with an experimental study, thirteen Sprague-Dawley rats were included. Eight out of thirteen animals were randomly assigned to receive 10 ml of benzalkonium chloride 0.2% (megacolon group) and five animals received 10 ml NaCl 0.9% (controls). Animals were anaesthetized by intramuscular delivery of ketamine. The incidence of positivity for bacteria lung tissue cultures and mesenteric lymph node cultures was assessed at the 21st day after animals' sacrification, or before in case of death. All megacolon group animals presented progressive increase of the abdomen and increased IAP (>=10 mmHg) whereas the frequency of their evacuations was almost eliminated. Controls presented normal evacuations, no sign of abdominal distention, and normal IAP. In megacolon group animals, there was evidence of significant amount of bacteria in lung cultures. In contrast, no bacteria were found in control animals. PMID- 28357399 TI - Loss of PI3K p110alpha in the Adipose Tissue Results in Infertility and Delayed Puberty Onset in Male Mice. AB - Deletion of PI3K catalytic subunit p110alpha in adipose tissue (aP2 Cre/p110alphaflx/flx, alpha-/- hereafter) results in increased adiposity, glucose intolerance, and liver steatosis. Because this endocrine organ releases hormones like leptin, which are important in reproductive physiology, we investigated the reproductive phenotype of alpha-/- males. Compared to controls, alpha-/- males displayed delayed onset of puberty accompanied by a reduction in plasma LH levels and testicular weight. At postnatal day 30, alpha-/- mice exhibited normal body weight but elevated fasted plasma leptin levels. Testicular leptin gene expression was increased, whereas expression of the cholesterol transporter StAR and of P450 cholesterol side chain cleavage enzyme was decreased. Adult alpha-/- males were infertile and exhibited hyperandrogenemia with normal basal LH, FSH, and estradiol levels. However, neither sperm counts nor sperm motility was different between genotypes. The mRNA levels of leptin and of 17-beta dehydrogenase 3, and enzyme important for testosterone production, were significantly higher in the testis of adult alpha-/- males. The mRNA levels of ERalpha, an important regulator of intratesticular steroidogenesis, were lower in the testis of adult and peripubertal alpha-/- males. We propose that chronic hyperleptinemia contributes to the negative impact that disrupting PI3K signaling in adipocytes has on puberty onset, steroidogenesis, and fertility in males. PMID- 28357401 TI - Computational Analysis of Specific MicroRNA Biomarkers for Noninvasive Early Cancer Detection. AB - Cancer is a complex disease residing in various tissues of human body, accompanied with many abnormalities and mutations in genomes, transcriptome, and epigenome. Early detection plays a crucial role in extending survival time of all major cancer types. Recent advances in microarray and sequencing techniques have given more support to identifying effective biomarkers for early detection of cancer. MicroRNAs (miRNAs) are more and more frequently used as candidates for biomarkers in cancer related studies due to their regulation of target gene expression. In this paper, the comparative analysis is used to discover miRNA expression patterns in cancer versus normal samples on early stage of eight prevalent cancer types. Our work focuses on the specific miRNAs biomarkers identification and function analysis. Several identified miRNA biomarkers in this paper are matched well with those reported in existing researches, and most of them could serve as potential candidate indicators for clinical early diagnosis applications. PMID- 28357402 TI - COPAR: A ChIP-Seq Optimal Peak Analyzer. AB - Sequencing data quality and peak alignment efficiency of ChIP-sequencing profiles are directly related to the reliability and reproducibility of NGS experiments. Till now, there is no tool specifically designed for optimal peak alignment estimation and quality-related genomic feature extraction for ChIP-sequencing profiles. We developed open-sourced COPAR, a user-friendly package, to statistically investigate, quantify, and visualize the optimal peak alignment and inherent genomic features using ChIP-seq data from NGS experiments. It provides a versatile perspective for biologists to perform quality-check for high-throughput experiments and optimize their experiment design. The package COPAR can process mapped ChIP-seq read file in BED format and output statistically sound results for multiple high-throughput experiments. Together with three public ChIP-seq data sets verified with the developed package, we have deposited COPAR on GitHub under a GNU GPL license. PMID- 28357404 TI - PainVision(r) Apparatus for Assessment of Efficacy of Pulsed Radiofrequency Combined with Pharmacological Therapy in the Treatment of Postherpetic Neuralgia and Correlations with Measurements. AB - Objective. PainVision device was a developed application for the evaluation of pain intensity. The objective was to assess the efficacy and safety of pulsed radiofrequency (PRF) combined with pharmacological therapy in the treatment of postherpetic neuralgia (PHN). We also discussed the correlation of the measurements. Method. Forty patients with PHN were randomized for treatment with PRF combined with pharmacological therapy (PRF group, n = 20) or pharmacological therapy (control group, n = 20) at postoperative 48 hours. The efficacy measure was pain degree (PD) that was assessed by PainVision and visual analog scale (VAS), short form Mcgill pain questionnaire (SF-Mcgill), and numeric rate scale sleep interference score (NRSSIS). Correlations between PD, VAS, SF-Mcgill, and NRSSIS were determined. Results. The PD for persistent pain (PP) and breakthrough pain (BTP) at postoperative 48 hours assessed by PainVision were significantly lower in PRF group than in control group (PD-PP, P < 0.01; PD-BTP, P < 0.01). PD and VAS were highly correlated for both persistent pain (r = 0.453, rho = 0.008) and breakthrough pain (r = 0.64, rho = 0.001). Conclusion. PRF was well tolerated and superior to isolated pharmacological therapy in the treatment of PHN. PainVision device showed great value in the evaluation of pain intensity and PD had an excellent correlation with VAS and SF-Mcgill. PMID- 28357403 TI - Effect of Prior Atorvastatin Treatment on the Frequency of Hospital Acquired Pneumonia and Evolution of Biomarkers in Patients with Acute Ischemic Stroke: A Multicenter Prospective Study. AB - Objective. To investigate whether prior treatment of atorvastatin reduces the frequency of hospital acquired pneumonia (HAP). Methods. Totally, 492 patients with acute ischemic stroke and Glasgow Coma Scale <= 8 were enrolled in this study. Subjects were assigned to prior atorvastatin treatment group (n = 268, PG) and no prior treatment group (n = 224, NG). All the patients were given 20 mg atorvastatin every night during their hospital stay. HAP frequency and 28-day mortality were measured. Levels of inflammatory biomarkers [white blood cell (WBC), procalcitonin (PCT), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6)] were tested. Results. There was no significant difference in the incidence of HAP between PG and NG (25.74% versus. 24.55%, p > 0.05) and 28-day mortality (50.72% versus 58.18%, p > 0.05). However, prior statin treatment did modify the mortality of ventilator associated pneumonia (VAP) (36.54% versus 58.14%, p = 0.041) and proved to be a protective factor (HR, 0.564; 95% CI, 0.310~0.825, p = 0.038). Concentrations of TNF-alpha and IL-6 in PG VAP cases were lower than those in NG VAP cases (p < 0.01). Conclusions. Prior atorvastatin treatment in patients with ischemic stroke was associated with a lower concentration of IL-6 and TNF-alpha and improved the outcome of VAP. This clinical study has been registered with ChiCTR-ROC-17010633 in Chinese Clinical Trial Registry. PMID- 28357405 TI - Outdoor Growth Characterization of an Unknown Microalga Screened from Contaminated Chlorella Culture. AB - Outdoor microalgae cultivation process is threatened by many issues, such as pest pollution and complex, changeable weather. Therefore, it is difficult to have identical growth rate for the microalgae cells and to keep their continuous growth. Outdoor cultivation requires the algae strains not only to have a strong ability to accumulate oil, but also to adapt to the complicated external environment. Using 18S rRNA technology, one wild strain Scenedesmus sp. FS was isolated and identified from the culture of Chlorella zofingiensis. Upon contamination by Scenedesmus sp., the species could quickly replace Chlorella zofingiensis G1 and occupy ecological niche in the outdoor column photobioreactors. The results indicated that Scenedesmus sp. FS showed high alkali resistance. It also showed that even under the condition of a low inoculum rate (OD680, 0.08), Scenedesmus sp. FS could still grow in the outdoor raceway pond under a high alkaline environment. Even under unoptimized conditions, the oil content of Scenedesmus sp. FS could reach more than 22% and C16-C18 content could reach up to 79.68%, showing that this species has the potential for the biodiesel production in the near future. PMID- 28357406 TI - Comparison of Ramosetron with Palonosetron for Prevention of Postoperative Nausea and Vomiting in Patients Receiving Opioid-Based Intravenous Patient-Controlled Analgesia after Gynecological Laparoscopy. AB - We aimed to compare the effects of ramosetron and palonosetron in the prevention of postoperative nausea and vomiting (PONV) in patients that received opioid based intravenous patient-controlled analgesia (IV-PCA) after gynecological laparoscopy. We reviewed the electronic medical records of 755 adults. Patients were classified into two groups, ramosetron (group R, n = 589) versus palonosetron (group P, n = 166). Based on their confounding factors, 152 subjects in each group were selected after the implementation of propensity score matching. The overall incidence of PONV at postoperative day (POD) 0 was lower in group R compared to group P (26.9% versus 36.8%; P = 0.043). The severity of nausea was lower in group R than in group P on postoperative day (POD) 0 (P = 0.012). Also, the complete responder proportion of patients was significantly higher in group R compared to that in group P on POD 0 (P = 0.043). In conclusion, ramosetron showed a greater efficacy in the prevention of postoperative nausea at POD 0 compared to palonosetron in patients after gynecological laparoscopy. PMID- 28357409 TI - Reduced pupillary reward sensitivity in Parkinson's disease. AB - Abnormalities in reward processing may be a critical part of understanding nonmotor manifestations of Parkinson's disease (PD). Dysfunction in dopaminergic pathways, which signal upcoming rewards, might result in altered motivation by incentives. To examine this proposal, we studied 16 patients with PD, both ON and OFF their normal dopaminergic medication, comparing them with healthy controls. Participants performed a speeded saccade task to obtain monetary rewards. Crucially, we manipulated the reward available from trial to trial, by presenting an auditory incentive precue before each saccade. The effects of incentives on pupil dilatation (an index of autonomic response) were measured. Individuals with PD showed diminished autonomic reward effects, compared with age-matched controls. When tested ON medication, pupil responses to reward increased, demonstrating that dopaminergic drugs can restore reward sensitivity. These findings reveal blunted autonomic responses to incentives in PD, which can be modulated by dopaminergic drugs. PMID- 28357408 TI - Patient-Reported Outcomes After Multiligament Knee Injury: MCL Repair Versus Reconstruction. AB - BACKGROUND: Management of the medial collateral ligament (MCL) in the setting of a multiligamentous knee injury (MLKI) represents an area of great controversy. PURPOSE: Our study was designed to compare long-term patient-reported outcomes (PROs) after MCL repair versus reconstruction in the setting of a multiligamentous injury of the knee. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: At a single institution, 68 patients were identified over a 10-year period as having MCL intervention in the setting of MLKI. Of these patients, 34 (50%) were successfully contacted via telephone to collect Lysholm and International Knee Documentation Committee (IKDC) scores. A retrospective chart review of these subjects was also conducted to identify patient and surgical factors affecting PROs. RESULTS: At a mean 6-year follow-up (range, 2-11 years), the mean Lysholm score was 77.4 +/- 23.1 and mean IKDC score was 72.6 +/- 23.6. Univariate analyses identified time to surgery (P = .005) and MCL reconstruction (P = .001) as risk factors for Lysholm score <=75. Univariate analyses identified patient age (P = .049), time to surgery (P = .018), and MCL reconstruction (P = .004) as risk factors for IKDC score <=75. On subsequent multivariate analysis, MCL reconstruction was found to be a predictor of Lysholm or IKDC score of <=75. CONCLUSION: Patients undergoing MCL repair in the setting of MLKI generally had higher PROs than those undergoing reconstructions at a mean 6 years of follow-up. Further work is needed to elucidate patient and surgical factors that may influence subjective outcomes after multiligament knee injuries. PMID- 28357407 TI - Role of MicroRNA-103a Targeting ADAM10 in Abdominal Aortic Aneurysm. AB - MicroRNAs (miRNAs) are deregulated in various vascular ailments including abdominal aortic aneurysm (AAA). MiR-103 is involved in vascular, metabolic, and malignant diseases, but whether it participates in the pathogenesis of AAA remains elusive. ADAM10 plays a vital role in the formation of aneurysm, but whether miRs modulate its activity during AAA formation is totally unknown. In this study, we detected the significantly increased protein expression of ADAM10 in angiotensin II induced murine AAA specimens, while the mRNA expression of ADAM10 was similar between AAA and control, suggesting the posttranscriptional regulation. The ADAM10 specific inhibitor GI254023X dramatically reduced the macrophage infiltration of murine abdominal aorta. Bioinformatic predictions suggest that ADAM10 is the target of miR-103a/107 but the binding site is exclusive. At the cellular level, miR-103a-1 suppressed the protein expression of ADAM10, while antisense miR-103a-1 increased its expression. Particularly, with the progression of murine AAA, the mRNA expression of miR-103a/107 substantially decreased and the protein expression of ADAM10 greatly increased. Together, our data afford the new insight that miR-103a inhibited AAA growth via targeting ADAM10, which might be a promising therapeutic strategy to alleviate AAA. PMID- 28357410 TI - Phenotypes, genotypes, and prevalence of congenital myopathies older than 5 years in Denmark. AB - OBJECTIVE: Congenital myopathy as a nosologic entity has long been recognized, but knowledge of overall and subtype prevalence and phenotype-genotype relationship is scarce, especially in the adult population. METHODS: A national cohort of 107 patients >=5 years diagnosed with congenital myopathy were prospectively assessed clinically, histologically, and genetically. RESULTS: Twenty-five patients were excluded because of atypical features or alternative etiologies. The remaining 82 were on average 28 years old. Histologic examination revealed 14 (17%) with core disease, 15 (18%) centronuclear myopathy, 12 (15%) nemaline rods, 27 (33%) congenital fiber-type disproportion or type I predominance, and 14 (17%) nonspecific myopathic changes. Genetic etiology was identified in 46 patients (56.1%); 22.0% were heterozygous or compound heterozygous for mutations in RYR1, 7.3% had DNM2 mutations, and 7.3% NEB mutations. Less than 5% had mutations in ACTA1, TPM2/3, MTM1, TTN, SEPN1, or SC4NA. A genetic cause was established in 83% with specific histology (cores/rods/centronuclear myopathy) vs 29% with unspecific histology. The detailed clinical examination found gene-dependent discrepancies in the pattern of muscle affection and walking ability. Although walking ability was delayed in patients with ACTA1, TPM2/3, and RYR1 mutations, it was within normal limits in patients with NEB and DNM2 mutations. CONCLUSIONS: We found that overall, genetic and histologic prevalence of congenital myopathy in Denmark differs from previous retrospective reports. Less RYR1 and more DNM2 and NEB mutations and less core histology were present in our cohort. These differences may be explained by our prospective design, the older cohort of patients, and by differences in genetic background. PMID- 28357412 TI - Establishing prevalence in rare neuromuscular diseases: A lesson from congenital myopathies. PMID- 28357411 TI - GNAO1 encephalopathy: Broadening the phenotype and evaluating treatment and outcome. AB - OBJECTIVE: To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1-related disease. METHODS: We reviewed clinical information, video recordings, and neuroimaging of a newly identified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected by next generation sequencing techniques. RESULTS: Patients first presented in early childhood (median age of presentation 10 months, range 0-48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, although tetrabenazine was effective in partially controlling dyskinesia for 2/7 patients. Emergency deep brain stimulation (DBS) was life saving in 1 patient, resulting in immediate clinical benefit with complete cessation of violent hyperkinetic movements. Five patients had well-controlled epilepsy and 1 had drug-resistant seizures. Structural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident in 5 patients. One patient had a diffuse astrocytoma (WHO grade II), surgically removed at age 16. CONCLUSIONS: Our findings support the causative role of GNAO1 mutations in an expanded spectrum of early-onset epilepsy and movement disorders, frequently exacerbated by specific triggers and at times associated with self injurious behavior. Tetrabenazine and DBS were the most useful treatments for dyskinesia. PMID- 28357413 TI - Next-Generation Sequencing Combined with Specific PCR Assays To Determine the Bacterial 16S rRNA Gene Profiles of Middle Ear Fluid Collected from Children with Acute Otitis Media. AB - The aim of the study was to analyze the bacteriome of acute otitis media with a novel modification of next-generation sequencing techniques. Outpatient children with acute otitis media were enrolled in the study, and middle ear fluids were collected during 90 episodes from 79 subjects aged 5 to 42 months (median age, 19 months). The bacteriome profiles of middle ear fluid samples were determined by a nested-PCR amplification of the 16S rRNA gene (V4 region), followed by mass sequencing. The profiling results were compared to the results of specific PCR assays targeting selected prevalent pathogens. Bacteriome profiling using nested amplification of low-volume samples was aided by a bioinformatic subtraction of signal contaminants from the recombinant polymerase, achieving a sensitivity slightly lower than that of specific PCR detection. Streptococcus pneumoniae was detected in 28 (31%) samples, Haemophilus influenzae in 24 (27%), Moraxella catarrhalis in 18 (20%), Staphylococcus spp. in 21 (23%), Turicella otitidis in 5 (5.6%), Alloiococcus otitidis in 3 (3.3%), and other bacteria in 14 (16%) using bacteriome profiling. S. pneumoniae was the dominant pathogen in 14 (16%) samples, H. influenzae in 15 (17%), M. catarrhalis in 5 (5.6%), T. otitidis in 2, and Staphylococcus auricularis in 2. Weaker signals of Prevotella melaninogenica, Veillonella dispar, and Veillonella montpellierensis were noted in several samples. Fourteen samples (16%) were not explainable by bacterial pathogens; novel causative agents were not detected. In conclusion, unbiased bacteriome profiling helped in depicting the true mutual quantitative ratios of ear bacteria, but at present, its complicated protocol impedes its routine clinical use. IMPORTANCE Although S. pneumoniae, H. influenzae, and M. catarrhalis have been long established as the most important pathogens in acute otitis media using culture and specific PCR assays, the knowledge of their mutual quantitative relations and possible roles of other bacteria is incomplete. The advent of unbiased bacteriome 16S rRNA gene profiling has allowed the detection of nearly all bacteria present in the sample, and it helps in depicting their mutual quantitative ratios. Due to the difficulties in performing mass sequencing in low volume samples, only a few bacteriome-profiling studies of otitis media have been published, all limited to cases of chronic otitis media. Here, we present a study on samples obtained from young children with acute otitis media, successfully using a strategy of nested PCR coupled with mass sequencing, and demonstrate that the method can confer quantitative information hardly obtainable by other methods. PMID- 28357414 TI - A Novel Staphylococcus Podophage Encodes a Unique Lysin with Unusual Modular Design. AB - Drug-resistant staphylococci, particularly Staphylococcus aureus and Staphylococcus epidermidis, are leading causes of hospital-acquired infections. Bacteriophages and their peptidoglycan hydrolytic enzymes (lysins) are currently being explored as alternatives to conventional antibiotics; however, only a limited diversity of staphylococcal phages and their lysins has yet been characterized. Here, we describe a novel staphylococcal phage and its lysins. Bacteriophage Andhra is the first reported S. epidermidis phage belonging to the family Podoviridae. Andhra possesses an 18,546-nucleotide genome with 20 open reading frames. BLASTp searches revealed that gene product 10 (gp10) and gp14 harbor putative catalytic domains with predicted peptidase and amidase activities, characteristic functions of phage lysins. We purified these proteins and show that both Andhra_gp10 and Andhra_gp14 inhibit growth and degrade cell walls of diverse staphylococci, with Andhra_gp10 exhibiting more robust activity against the panel of cell wall substrates tested. Site-directed mutagenesis of its predicted catalytic residues abrogated the activity of Andhra_gp10, consistent with the presence of a catalytic CHAP domain on its C terminus. The active site location combined with the absence of an SH3b cell wall binding domain distinguishes Andhra_gp10 from the majority of staphylococcal lysins characterized to date. Importantly, close homologs of Andhra_gp10 are present in related staphylococcal podophages, and we propose that these constitute a new class of phage-encoded lysins. Altogether, our results reveal insights into the biology of a rare family of staphylococcal phages while adding to the arsenal of antimicrobials with potential for therapeutic use. IMPORTANCE The spread of antibiotic resistance among bacterial pathogens is inciting a global public health crisis. Drug-resistant Staphylococcus species, especially S. aureus and S. epidermidis, have emerged in both hospital and community settings, underscoring the urgent need for new strategies to combat staphylococcal infections. Bacterial viruses (phages) and the enzymes that they use to degrade bacterial cell walls (lysins) show promise as alternative antimicrobials; however, only a limited variety of staphylococcal phages and their lysins have yet been identified. Here, we report the discovery and characterization of a novel staphylococcal phage, Andhra. We show that Andhra encodes two lysins (Andhra_gp10 and Andhra_gp14) that inhibit growth and degrade the cell walls of diverse staphylococci, including S. aureus and S. epidermidis strains. Andhra and its unique lysins add to the arsenal of antimicrobials with potential for therapeutic use. PMID- 28357415 TI - Mindfulness-based Intervention for Perinatal Grief Education and Reduction among Poor Women in Chhattisgarh, India: a Pilot Study. AB - INTRODUCTION: Stillbirth is a significant public health problem in low-to-middle income countries and results in perinatal grief, often with negative psychosocial impact. In low-resource settings, such as Chhattisgarh, India, where needs are high, it is imperative to utilize low-cost, effective interventions. Mindfulness based stress reduction (MBSR) is an empirically sound intervention that has been utilized for a broad range of physical and mental health problems, and is adaptable to specific populations. The main objective of this pilot study was to explore the feasibility and effectiveness of a shortened, culturally adapted mindfulness-based intervention to address complex grief after stillbirth. METHODS: We used an observational, pre-post-6-week post study design. The study instrument was made up of descriptive demographic questions and validated scales and was administered as a structured interview due to low literacy rates. We used a community participatory approach to culturally adapt the five-week mindfulness based intervention and delivered it through two trained local nurses. Quantitative and qualitative data analyses explored study outcomes as well as acceptability and feasibility of the intervention. RESULTS: 29 women with a history of stillbirth enrolled, completed the pretest and began the intervention; 26 completed the five-week intervention and post-test (89.7%), and 23 completed the six-week follow-up assessment (88.5%). Pretest results included elevated psychological symptoms and high levels of perinatal grief, including the active grief, difficulty coping, and despair subscales. General linear modeling repeated measures was used to explore posttest and six-week follow up changes from baseline, controlling for significantly correlated demographic variables. These longitudinal results included significant reduction in psychological symptoms; four of the five facets of mindfulness changed in the desired direction, two significantly; as well as significant reduction in overall perinatal grief and on each of the three subscales. DISCUSSION: The shortened, culturally adapted, mindfulness-based intervention pilot study was well received and had very low attrition. We also found significant reductions of perinatal grief and mental health symptoms over time, as well as a high degree of practice of mindfulness skills by participants. This study not only sheds light on the tremendous mental health needs among rural women of various castes who have experienced stillbirth in Chhattisgarh, it also points to a promising effective intervention with potential to be taken to scale for wider delivery. PMID- 28357416 TI - A System for Enzymatic Lysine Methylation in a Desired Sequence Context. AB - A number of lysine-specific methyltransferases (KMTs) are responsible for the post-translational modification of cellular proteins on lysine residues. Most KMTs typically recognize specific motifs in unstructured, short peptide sequences. However, we have recently discovered a novel KMT that appeared to have a more relaxed sequence specificity, namely, valosin-containing protein (VCP) KMT, which trimethylates Lys-315 in the molecular chaperone VCP. On the basis of this, here, we explored the possibility of using the VCP-KMT/VCP system to obtain specific lysine methylation of desired sequences grafted onto a VCP-derived scaffold. We generated VCP-derived proteins in which three amino acid residues on each side of Lys-315 had been replaced by various sequences representing lysine methylation sites in histone H3. We found that all of these chimeric proteins were subject to efficient VCP-KMT-mediated methylation in vitro, and methylation was also observed in mammalian cells. Thus, we here describe a versatile system for introducing lysine methylation into a desired peptide sequence, and the approach should be readily expandable for generating combinatorial libraries of methylated sequences. PMID- 28357418 TI - Distribution of dopant ions around poly(3,4-ethylenedioxythiophene) chains: a theoretical study. AB - The effect of counterions and multiple polymer chains on the properties and structure of poly(3,4-ethylenedioxythiophene) (PEDOT) doped with ClO4- has been examined using density functional theory (DFT) calculations with periodic boundary conditions (PBCs). Calculations on a one-dimensional periodic model with four explicit polymer repeat units and two ClO4- molecules indicate that the latter are separated as much as possible, with the salt structure and band gap obtained from such ClO4- distribution being in excellent agreement with those determined experimentally. On the other hand, DFT calculations on periodic models that include two chains indicate that neighboring PEDOT chains are shifted along the molecular axis by a half of the repeat unit length, with dopant ions intercalated between the polymer molecules acting as cement. In order to support these structural features, classical molecular dynamics (MD) simulations have been performed on a multiphasic system consisting of 69 explicit PEDOT chains anchored onto a steel surface, explicit ClO4- anions embedded in the polymer matrix, and an acetonitrile phase layer onto the polymer matrix. Analyses of the radial distribution functions indicate that the all-anti conformation, the relative disposition of adjacent PEDOT chains and the distribution of ClO4- dopant ions are fully consistent with periodic DFT predictions. The agreement between two such different methodologies allows reinforcing the microscopic understanding of the PEDOT film structure. PMID- 28357419 TI - Crystallization of supercooled fenofibrate studied at ambient and elevated pressures. AB - In this work, we have performed a detailed investigation on the crystallization tendency of the modeled glass-forming pharmaceutical compound, fenofibrate. To do this, we have employed four different experimental techniques allowing following of the crystallization process. This has included dielectric spectroscopy, optical microscopy, X-ray diffraction and differential scanning calorimetry. From the crystallization kinetic studies carried out at atmospheric pressure, we have determined the temperature dependence of the crystal growth rate and the overall crystallization rate. It was found that the time scale of the molecular motions responsible for alpha-relaxation correlates much better with the crystal growth rate than with the overall crystallization rate. Experiments carried out under varying thermodynamic conditions while remaining on the same timescale of alpha relaxation have demonstrated that the crystallization tendency of the supercooled fenofibrate significantly slows down with increasing pressure. Lastly, we have also shown that the thermodynamic history of reaching crystallization conditions has a substantial impact on its overall progress. PMID- 28357420 TI - SMI-Ribosome inactivating protein conjugates selectively inhibit tumor cell growth. AB - Cell-targeting conjugates of Saporin 6, a ribosome inactivating protein (RIP), were prepared using the Saporin Ala 157 Cys mutant, a small molecule inhibitor (SMI) of integrins alphavbeta3/alphavbeta5, and a potent cytotoxin, auristatin F (AF). The conjugates selectively and potently inhibited proliferation of tumor cells expressing the target integrins. We anticipate that the small molecule-RIP bioconjugate approach can be broadly applied using other small molecule drugs. PMID- 28357417 TI - Coordinated Action of Biological Processes during Embryogenesis Can Cause Genome Wide Linkage Disequilibrium in the Human Genome and Influence Age-Related Phenotypes. AB - A role of non-Mendelian inheritance in genetics of complex, age-related traits is becoming increasingly recognized. Recently, we reported on two inheritable clusters of SNPs in extensive genome-wide linkage disequilibrium (LD) in the Framingham Heart Study (FHS), which were associated with the phenotype of premature death. Here we address biologically-related properties of these two clusters. These clusters have been unlikely selected randomly because they are functionally and structurally different from matched sets of randomly selected SNPs. For example, SNPs in LD from each cluster are highly significantly enriched in genes (p=7.1*10-22 and p=5.8*10-18), in general, and in short genes (p=1.4*10 47 and p=4.6*10-7), in particular. Mapping of SNPs in LD to genes resulted in two, partly overlapping, networks of 1764 and 4806 genes. Both these networks were gene enriched in developmental processes and in biological processes tightly linked with development including biological adhesion, cellular component organization, locomotion, localization, signaling, (p<10-4, q<10-4 for each category). Thorough analysis suggests connections of these genetic networks with different stages of embryogenesis and highlights biological interlink of specific processes enriched for genes from these networks. The results suggest that coordinated action of biological processes during embryogenesis may generate genome-wide networks of genetic variants, which may influence complex age-related phenotypes characterizing health span and lifespan. PMID- 28357421 TI - Toward steric control of guest binding modality: a cationic Co(ii) complex exhibiting cation binding and zero-field relaxation. AB - We present the syntheses and characterization of several salts of a trigonal prismatic cobalt(ii) complex with a 1,3,5-triaminocyclohexane (tach)-derived ditopic ligand. The air- and moisture-stable tetraphenylborate salt (2) shows slow magnetic relaxation under both zero and applied dc fields. This complex also exhibits an unexpected ability to interact with a cationic sodium guest ion, highlighting the ambifunctional binding nature of amide groups within an iminopyridine scaffold. PMID- 28357422 TI - Interlocked benzenes in triangular pi-architectures: anchoring groups dictate ion binding and transmission. AB - Macrocyclic compounds like crown ethers, calixarenes, etc. are well explored in the literature as receptors for alkali metal ions. In most of these studies, the size of the macrocyclic cavity has evolved as the prominent determining criterion for the selective binding of various ions. However, approaches to systematically tailor the ion transport properties via the interplay of topological as well as electronic properties of the hosts are rarely addressed. Herein, we investigate the performance of [2.2.2]PCPs ([2.2.2]paracyclophane and [2.2.2]paracyclophene) and cyclohexaphenylene (CHP) as receptors for the alkali ions, Li+, Na+ and K+. The three macrocycles differ in terms of the groups (ethylene, vinylene and phenylene) anchoring the three benzene rings into triangular three-dimensional architectures, thereby providing opportunities for controlling the topological and the electronic features of the cavities. Based on electronic structure calculations, we predict that PCPs and CHP could be used in conjunction with dehydrobenzoannulenes that possess similar triangular pi-architectures in two dimensions to achieve selective ion transmission. Furthermore, an extended network of CHP, graphenylene, is shown for the first time to be potentially useful in energy storage applications in lithium ion batteries akin to graphyne and graphdiyne. The ion binding properties of graphenylenes would be rather interesting to investigate experimentally for energy applications, particularly in the context of the recent successful synthesis of one of the members of the graphenylene family. Overall, we have attempted to provide a unified description of the cationic interactions with 2D and 3D triangular pi-architectures, describing the utility of materials like graphyne, graphdiyne and graphenylene for ion sensing and separation and energy storage applications. PMID- 28357423 TI - Polyfluoroarylation of oxazolones: access to non-natural fluorinated amino acids. AB - Herein, conditions are provided for the formation and use of the oxazolone enolate for the nucleophilic substitution of highly fluorinated (hetero)arenes, which after unmasking yield highly fluorinated non-natural amino acids and derivatives. In addition, the properties and chemical behavior of this new class of amino acids are explored. The utility is demonstrated in the one pot synthesis of medicinally relevant 2-aminohydantoins. PMID- 28357424 TI - Recognition-mediated particle detection under microfluidic flow with waveguide coupled 2D photonic crystals: towards integrated photonic virus detectors. AB - Label-free biodetection schemes compatible with standard CMOS fabrication methods constitute an important goal, as these are enabling tools for the mass production of high-sensitivity biosensors. Two-dimensional slab photonic crystal (2D slab PhC) sensors have been posited as ultrahigh-sensitivity detection components, but to date recognition-mediated detection of viruses or simulants under flow has not been demonstrated. We report the design and optimization of a new W1 waveguide coupled 2D slab-PhC sensor, with a geometry well suited to virus detection. Proof of concept experiments with fluorescent latex particles verified that the sensor could respond to infiltration of a single particle, both in air and under an aqueous cover layer. Subsequent experiments with antibody-functionalized sensors and virus simulants confirmed the ability of the device to detect virus-sized particles under flow via a recognition-mediated process. This work sets the stage for incorporation of 2D slab-PhC sensors into fully integrated photonic sensor systems. PMID- 28357425 TI - Time-dependent vibrational spectral analysis of first principles trajectory of methylamine with wavelet transform. AB - The fluctuation dynamics of amine stretching frequencies, hydrogen bonds, dangling N-D bonds, and the orientation profile of the amine group of methylamine (MA) were investigated under ambient conditions by means of dispersion-corrected density functional theory-based first principles molecular dynamics (FPMD) simulations. Along with the dynamical properties, various equilibrium properties such as radial distribution function, spatial distribution function, combined radial and angular distribution functions and hydrogen bonding were also calculated. The instantaneous stretching frequencies of amine groups were obtained by wavelet transform of the trajectory obtained from FPMD simulations. The frequency-structure correlation reveals that the amine stretching frequency is weakly correlated with the nearest nitrogen-deuterium distance. The frequency frequency correlation function has a short time scale of around 110 fs and a longer time scale of about 1.15 ps. It was found that the short time scale originates from the underdamped motion of intact hydrogen bonds of MA pairs. However, the long time scale of the vibrational spectral diffusion of N-D modes is determined by the overall dynamics of hydrogen bonds as well as the dangling ND groups and the inertial rotation of the amine group of the molecule. PMID- 28357426 TI - Specific and relative detection of urinary microRNA signatures in bladder cancer for point-of-care diagnostics. AB - We present a dual-isothermal cascade strategy assisted by a lateral flow peptide nucleic acid biosensor for point-of-care detection of urinary microRNAs without a temperature protocol and complex instruments. The proposed assay is expected to be of great promise for bladder cancer diagnosis and point-of-care diagnostics. PMID- 28357427 TI - Asymmetric hydrogenation of maleic anhydrides catalyzed by Rh/bisphosphine thiourea: efficient construction of chiral succinic anhydrides. AB - Asymmetric hydrogenation of various 3-substituted maleic anhydrides catalyzed by Rh/bisphosphine-thiourea (ZhaoPhos) under mild conditions was successfully developed. A wide range of 3-alkyl and 3-aryl maleic anhydrides were hydrogenated well to provide the desired products 3-substituted succinic anhydrides in one hour with excellent results (full conversions, up to 99% yield, 99% ee, 3000 TON). Importantly, we developed a creative and efficient synthetic route to construct the key intermediate of the hypoglycemic drug mitiglinide through our catalytic system. PMID- 28357432 TI - A bidirectional synthesis of spiroacetals via Rh(ii)-catalysed C-H insertion. AB - Acyclic methylene acetals bearing two diazoester subunits have been converted to [5,5]-spiroacetals via bidirectional C-H insertion under Rh(ii) catalysis. Using a chiral Rh(ii) catalyst, the major diastereomer can be produced in high enantiomeric excess (89%). PMID- 28357433 TI - Bioinspired assembly of small molecules in cell milieu. AB - Self-assembly, the autonomous organization of components to form patterns or structures, is a prevalent process in nature at all scales. Particularly, biological systems offer remarkable examples of diverse structures (as well as building blocks) and processes resulting from self-assembly. The exploration of bioinspired assemblies not only allows for mimicking the structures of living systems, but it also leads to functions for applications in different fields that benefit humans. In the last several decades, efforts on understanding and controlling self-assembly of small molecules have produced a large library of candidates for developing the biomedical applications of assemblies of small molecules. Moreover, recent findings in biology have provided new insights on the assemblies of small molecules to modulate essential cellular processes (such as apoptosis). These observations indicate that the self-assembly of small molecules, as multifaceted entities and processes to interact with multiple proteins, can have profound biological impacts on cells. In this review, we illustrate that the generation of assemblies of small molecules in cell milieu with their interactions with multiple cellular proteins for regulating cellular processes can result in primary phenotypes, thus providing a fundamentally new molecular approach for controlling cell behavior. By discussing the correlation between molecular assemblies in nature and the assemblies of small molecules in cell milieu, illustrating the functions of the assemblies of small molecules, and summarizing some guiding principles, we hope this review will stimulate more molecular scientists to explore the bioinspired self-assembly of small molecules in cell milieu. PMID- 28357435 TI - Crinoids: ancient organisms, modern chemistry. AB - Covering: 1877 to 2017The ancestors of present-day crinoids are thought to be some of the earliest echinoderms, with fossil records dating back to the early Paleozoic Era (Ordovician Period, 505-440 million years ago). Their bright colours have been noted for over 100 years, and are attributed to a series of polyketide-derived pigments. Some crinoid metabolites display a range of biological activities, including cytotoxicity and fish anti-feedant activity. This review is divided into two parts. Part 1 is encyclopedic in scope, collating information on the >50 known metabolites isolated from crinoids, including their taxonomic source, collection location, chemical structure and biological activities. During the compilation of this data, two distinct themes emerged. Firstly, there is little variation in the class of metabolites produced by crinoids, irrespective of their species or geographic origin. Secondly, the complete and unambiguous assignment of crinoid metabolite structures has been, in many cases, a difficult task. This has been due to a lack of spectroscopic technology available in the past, the presence of proton-poor chemical structures, or both. Thus, Part 2 provides a critical discussion of crinoid chemistry, including the biosynthetic origin of crinoid pigments, as well as the pitfalls and solutions experienced by ourselves and other chemists when elucidating the chemical structures of crinoid metabolites. PMID- 28357436 TI - Effect of particle concentration on the microstructural and macromechanical properties of biocompatible magnetic hydrogels. AB - We analyze the effect of nanoparticle concentration on the physical properties of magnetic hydrogels consisting of polymer networks of the human fibrin biopolymer with embedded magnetic particles, swollen by a water-based solution. We prepared these magnetic hydrogels by polymerization of mixtures consisting mainly of human plasma and magnetic nanoparticles with OH- functionalization. Microscopic observations revealed that magnetic hydrogels presented some cluster-like knots that were connected by several fibrin threads. By contrast, nonmagnetic hydrogels presented a homogeneous net-like structure with only individual connections between pairs of fibers. The rheological analysis demonstrated that the rigidity modulus, as well as the viscoelastic moduli, increased quadratically with nanoparticle content following a square-like function. Furthermore, we found that time for gel point was shorter in the presence of magnetic nanoparticles. Thus, we can conclude that nanoparticles favor the cross-linking process, serving as nucleation sites for the attachment of the fibrin polymer. Attraction between the positive groups of the fibrinogen, from which the fibrin is polymerized, and the negative OH- groups of the magnetic particle surface qualitatively justifies the positive role of the nanoparticles in the enhancement of the mechanical properties of the magnetic hydrogels. Indeed, we developed a theoretical model that semiquantitatively explains the experimental results by assuming the indirect attraction of the fibrinogen through the attached nanoparticles. Due to this attraction the monomers condense into nuclei of the dense phase and by the end of the polymerization process the nuclei (knots) of the dense phase cross link the fibrin threads, which enhances their mechanical properties. PMID- 28357437 TI - DFT study on the interfacial properties of vertical and in-plane BiOI/BiOIO3 hetero-structures. AB - Composite photocatalysts with hetero-structures usually favor the effective separation of photo-generated carriers. In this study, BiOIO3 was chosen to form a hetero-structure with BiOI, due to its internal polar field and good lattice matching with BiOI. The interfacial properties and band offsets were focused on and analyzed in detail by DFT calculations. The results show that the charge depletion and accumulation mainly occur in the region near the interface. This effect leads to an interfacial electric field and thus, the photo-generated electron-hole pairs can be easily separated and transferred along opposite directions at the interface, which is significant for the enhancement of the photocatalytic activity. Moreover, according to the analysis of band offsets, the vertical BiOI/BiOIO3 belongs to the type-II hetero-structure, while the in-plane BiOI/BiOIO3 belongs to the type-I hetero-structure. The former type of hetero structure has more favorable effects to enhance the photocatalytic activity of BiOI than that of the latter type of hetero-structure. In the case of the vertical BiOI/BiOIO3 hetero-structure, photo-generated electrons can move from the conduction band of BiOI to that of BiOIO3, while holes can move from the valence band of BiOIO3 to that of BiOI under solar radiation. In addition, the introduced internal electric field functions as a selector that can promote the separation of photo-generated carriers, resulting in the higher photocatalytic quantum efficiency. These findings illustrate the underlying mechanism for the reported experiments, and can be used as a basis for the design of novel highly efficient composite photocatalysts with hetero-structures. PMID- 28357434 TI - Quantitative proteomic characterization of redox-dependent post-translational modifications on protein cysteines. AB - Protein thiols play a crucial role in redox signaling, in the regulation of enzymatic activity and protein function, and in maintaining redox homeostasis in living systems. The unique chemical reactivity of the thiol group makes protein cysteines susceptible to reactions with reactive oxygen and nitrogen species that form various reversible and irreversible post-translational modifications (PTMs). The reversible PTMs in particular are major components of redox signaling and are involved in the regulation of various cellular processes under physiological and pathological conditions. The biological significance of these redox PTMs in both healthy and disease states has been increasingly recognized. Herein, we review recent advances in quantitative proteomic approaches for investigating redox PTMs in complex biological systems, including general considerations of sample processing, chemical or affinity enrichment strategies, and quantitative approaches. We also highlight a number of redox proteomic approaches that enable effective profiling of redox PTMs for specific biological applications. Although technical limitations remain, redox proteomics is paving the way to a better understanding of redox signaling and regulation in both healthy and disease states. PMID- 28357438 TI - Towards a correlative approach for characterising single virus particles by transmission electron microscopy and nanoscale Raman spectroscopy. AB - The morphology and structure of biological nanoparticles, such as viruses, can be efficiently analysed by transmission electron microscopy (TEM). To chemically characterise such nanoparticles in heterogeneous samples at the single particle level, we suggest tip-enhanced Raman spectroscopy (TERS) as a correlative method. Here we describe a TERS-compatible staining procedure for TEM which involves sample pre-scanning by TEM imaging, nanoparticle relocalisation by atomic force microscopy (AFM) followed by spectroscopic characterization of the virus nanoparticles using TERS. First successful correlative measurements are demonstrated on tobacco mosaic virus particles deposited on silicon-based TEM sample supports. In addition, the advantages and problems of this methodology are discussed. PMID- 28357439 TI - Hydrogen generation from glucose catalyzed by organoruthenium catalysts under mild conditions. AB - Concerns about the depletion of fossil fuel reserves and environmental pollution make hydrogen an attractive alternative energy source. Here, we first describe a catalytic reaction system that produces H2 from glucose using a homogeneous catalyst [(p-cymene)Ru(NH3)]Cl2 with the maximum TOF = 719 h-1 at 98 degrees C and an initial pH = 0.5. PMID- 28357440 TI - Buckling of elastomer sheets under non-uniform electro-actuation. AB - Dielectric elastomer sheets undergo in-plane expansion when stimulated by a transverse electric field. We study experimentally how dielectric plates subjected to a non-uniform voltage distribution undergo buckling instabilities. Two different configurations involving circular plates are investigated: plates freely floating on a bath of water, and plates clamped on a frame. We describe theoretically the out-of-plane deformation of the plates within the framework of weakly non-linear plate equations. This study constitutes a first step of a route to control the 3D activation of dielectric elastomers. PMID- 28357441 TI - Dynamic pattern of wrinkles in a dielectric elastomer. AB - A membrane of a dielectric elastomer may undergo electromechanical phase transition from the flat to wrinkled state, when the applied voltage reaches a critical value. The wrinkled region is observed to expand at the expense of the flat region during the phase transition. In this paper, we report on a dynamic pattern of wrinkles in a circular membrane of a dielectric elastomer. During phase transition, both the flat and wrinkled regions move interchangeably in the membrane. The radial prestretch is found to significantly affect electromechanical phase transition. For example, a membrane with a small prestretch can exhibit a dynamic pattern of wrinkles, which is essentially related to snap-through instability. However, a membrane with a large prestretch undergoes continuous phase transition, without exhibiting a dynamic pattern. An analytical model is developed to interpret these experimental phenomena. Finite element simulations are performed to predict the wrinkle morphology, especially the coexistence of flat and wrinkled regions. Both the theoretical calculations and finite element simulations are qualitatively consistent with the experiments. Additionally, we observe another type of electromechanical behavior involving a dynamic pattern of wrinkles with different wavelengths. The membrane first undergoes continuous transition from the flat to wrinkled state, followed by discontinuous transition from one wrinkled state to another. These results may inspire new applications for dielectric elastomers such as on-demand patterning of wrinkles for microfluidics and stretchable electronics. PMID- 28357442 TI - Mean platelet volume is associated with lower risk of overall and non-vascular mortality in a general population. Results from the Moli-sani study. AB - Larger mean platelet volume (MPV) has been associated with adverse health outcomes in high-risk populations or patients with cardiovascular disease (CVD). We tested the association of MPV with mortality in a prospective cohort study including 17,402 subjects randomly recruited from an adult general population within the Moli-sani study (2005-2010). Two distinct subgroups (with or without CVD at baseline) were subsequently analysed. Hazard ratios (HR) were calculated using multivariable Cox-proportional hazard models. Over a median follow up of eight years (137,547 person-years), 925 all-cause deaths occurred (330 vascular, 351 cancer and 244 other deaths). In a multivariable model, the highest MPV quintile (mean MPV=10.0 fL), as compared to the lowest one, was associated with reduced risk of overall mortality (HR=0.79; 95 % confidence interval 0.64-0.98), cancer death (HR=0.70; 0.49-1.00) and death from other non- vascular/non cancer causes (HR=0.55; 0.36-0.84) but not with vascular mortality. The inverse association with overall death appeared even stronger in the subgroup without CVD at baseline (HR=0.64; 0.50-0.81). In contrast, within 920 subjects reporting a previous CVD event, larger MPV was associated with higher risk of total mortality (HR=1.69; 1.05-2.72; p for interaction=0.048) and with a trend of risk for other cause-specific deaths. In conclusion, larger MPV is associated with lower risk of overall and non-vascular death in subjects apparently free from CVD, but appears to be a predictive marker of death in patients with CVD history. The latter is a likely effect modifier of the association between MPV and death. PMID- 28357443 TI - High on treatment platelet reactivity as a risk factor for adverse left ventricular remodelling after STEMI. PMID- 28357444 TI - Tailoring treatment of haemophilia B: accounting for the distribution and clearance of standard and extended half-life FIX concentrates. AB - The prophylactic administration of factor IX (FIX) is considered the most effective treatment for haemophilia B. The inter-individual variability and complexity of the pharmacokinetics (PK) of FIX, and the rarity of the disease have hampered identification of an optimal treatment regimens. The recent introduction of extended half-life recombinant FIX molecules (EHL-rFIX), has prompted a thorough reassessment of the clinical efficacy, PK and pharmacodynamics of plasma-derived and recombinant FIX. First, using longer sampling times and multi-compartmental PK models has led to more precise (and favourable) PK for FIX than was appreciated in the past. Second, investigating the distribution of FIX in the body beyond the vascular space (which is implied by its complex kinetics) has opened a new research field on the role for extravascular FIX. Third, measuring plasma levels of EHL-rFIX has shown that different aPTT reagents have different accuracy in measuring different FIX molecules. How will this new knowledge reflect on clinical practice? Clinical decision making in haemophilia B requires some caution and expertise. First, comparisons between different FIX molecules must be assessed taking into consideration the comparability of the populations studied and the PK models used. Second, individual PK estimates must rely on multi-compartmental models, and would benefit from adopting a population PK approach. Optimal sampling times need to be adapted to the prolonged half-life of the new EHL FIX products. Finally, costs considerations may apply, which is beyond the scope of this manuscript but might be deeply connected with the PK considerations discussed in this communication. PMID- 28357446 TI - Impact of light rail transit on traffic-related pollution and stroke mortality. AB - OBJECTIVES: This paper evaluates the changes in vehicle exhaust and stroke mortality for the general public residing in the surrounding area of the light rail transit (LRT) in Houston, Texas, after its opening. METHODS: The number of daily deaths due to stroke for 2002-2005 from the surrounding area of the original LRT line (exposure group) and the control groups was analyzed using an interrupted time-series analysis. Ambient concentrations of acetylene before and after the opening of LRT were also compared. RESULTS: A statistically significant reduction in the average concentration of acetylene was observed for the exposure sites whereas the reduction was negligible at the control site. Poisson regression models applied to the stroke mortality data indicated a significant reduction in daily stroke mortality after the opening of LRT for the exposure group, while there was either an increase or a considerably smaller reduction for the control groups. CONCLUSIONS: The findings support the idea that LRT systems provide health benefits for the general public and that the reduction in motor vehicle-related air pollution may have contributed to these health benefits. PMID- 28357445 TI - The decade of Roma Inclusion: did it make a difference to health and use of health care services? AB - OBJECTIVES: We investigated whether the severely disadvantaged health of Hungarian Roma adults living in segregated settlements changed by the Decade of Roma Inclusion program. METHODS: We compared the results of two paired health interview surveys that we carried out using the same methodology before and after the Decade, on the general Hungarian and Roma populations. RESULTS: Self perceived health status of younger Roma worsened, while it improved among older Roma. Reported experience of discrimination reduced considerably and health care utilization improved in general. Positive changes in smoking and nutrition, and negative changes in alcohol consumption and overweight were observed. Many of observed changes can plausibly be linked to various government policies, including a quadrupling of public works expenditure, banning smoking in public places, restricting marketing of tobacco products, increasing cigarette prices, and a new tax on unhealthy foods. Liberalization of rules on alcohol distillation coincided with worsening alcohol consumption. CONCLUSIONS: We have shown that Roma remain severely disadvantaged and present an innovative sampling method which can be used to monitor changes in groups where identification is a challenge. PMID- 28357447 TI - Organic and Inorganic Pollutant Concentrations Suggest Anthropogenic Contamination of Soils Along the Manali-Leh Highway, Northwestern Himalaya, India. AB - Most studies on roadside soil pollution have been performed in areas where petrol is the main fuel. Very little work has been conducted in regions where diesel predominates. We collected soil samples from four sites that span a precipitation gradient along the Manali-Leh Highway in northwestern Himalaya, India. This road traverses rough terrain and most of the vehicles that travel along it are diesel driven. At each site, we collected samples at incremental distances from the highway (0, 2, 5, 10, 20, and 150 m), and at each distance we collected samples from three depths (3, 9, and 15 cm). We assessed the concentrations of 10 heavy metals (Al, Fe, Cr, Cu, Pb, Ni, Co, Zn, V, and Ba), total sulphur, and total organic carbon (TOC) at each distance, and we measured the concentration of 16 polycyclic aromatic hydrocarbons (PAHs) at 2 m from the highway. Overall, we found that metal concentrations are low and there is no relationship between concentrations and distance from the highway, or depth within the soil profile. Sulphur concentrations, on the other hand, are high in roadside soils and there is a negative relationship between concentration and distance from the highway. PAH concentrations are low, but the proportion of different ringed species suggests that their source is anthropogenic. Correlations between TOC and the various pollutants further suggest that diesel vehicles and potentially biomass combustion are starting to affect the roadside environment in remote northwestern India. We suggest that pollutant concentrations be regularly monitored. PMID- 28357449 TI - Myricetin protects cardiomyocytes from LPS - induced injury. AB - BACKGROUND: Sepsis-induced cardiomyopathy is a well-known cause of mortality. Recent evidence has highlighted the important role of myricetin in anti inflammation and anti-oxidative stress. However, little is known about its effect on endotoxin-induced cardiomyopathy. We examined the effect of myricetin on lipopolysaccharide (LPS)-induced cardiomyocyte injury and the underlying mechanisms in vitro. METHODS: mRNA expression of interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha was examined via reverse transcription quantitative polymerase chain reaction (RT-qPCR). Protein expression levels of NF kappaB/p65, IkappaB, IL-1beta, IL-6, and TNF-alpha were assesses via Western blotting. Immunofluorescence (IF) was used to determine the nuclear translocation of p65. Commercial kits were employed to detect the level of oxidative markers and to quantify NF-kappaB/p65 both in the cytoplasm and the nucleus. Finally, terminal deoxy-nucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) was performed to evaluate the apoptosis of H9c2 cardiomyocytes. RESULTS: The results showed that myricetin blunted the overexpression of IL-1beta, IL-6, and TNF-alpha markedly by inhibiting the NF-kappaB/P65 signaling pathway. Furthermore, myricetin treatment led to the downregulation of reactive oxygen species (ROS) accompanied by increased expression of superoxide dismutase and glutathione peroxidase. TUNEL-positive nuclei were rarely detected following myricetin treatment. CONCLUSION: Our findings suggest that myricetin is a valuable protective agent against endotoxin-induced early inflammatory responses in H9c2 cardiomyocytes, which involves regulation of ROS and the IkappaB/NF kappab signaling pathway. PMID- 28357448 TI - [Electrical isolation of the left atrial appendage : Benefits and risks]. AB - The left atrial appendage (LAA) is an extension originating from the body of the left atrium. The LAA is derived from the primary atrium and shows anatomical and physiological deviations from the left atrium. Different LAA morphologies exist. The LAA is not only the most frequent origin of intracardiac thrombi, it also frequently shows triggers responsible for the initiation or maintenance of atrial tachyarrhythmia and atrial fibrillation (AF). Isolation of the LAA using radiofrequency energy in addition to isolation of the pulmonary vein has recently gained importance due to the potential for increasing the clinical success rates, particularly in patients with persistent and long-standing persistent AF; however, after LAA isolation the incidence of LAA thrombi and systemic thromboembolisms might be increased even under treatment with oral anticoagulants, depending on the ablation strategy used. Thus, mechanical occlusion of the LAA should be discussed with patients after electrical isolation of the LAA. PMID- 28357450 TI - An Alternative Strategy for Bridge-to-Transplant/Recovery in Small Children with Dilated Cardiomyopathy. AB - Dilated cardiomyopathy in children still has a poor prognosis with high rates of mortality and cardiac transplantation (resp. around 20 and 25%). Awaiting transplantation or possible recovery, these pediatric patients are mechanically supported with extracorporeal membrane oxygenation or a paracorporeal ventricular assist device, both resulting in higher survival rates but also entailing considerable risks of infection, thrombosis, or bleeding. A new indication for an old technique, i.e., pulmonary artery banding, presents itself as an interesting alternative to mechanical circulatory support in selected infants and small children with dilated LV cardiomyopathy and preserved RV function. Here we present a brief review of literature and report on two patients in whom PAB has been successfully implemented as either bridge-to-recovery or bridge-to transplant. PMID- 28357451 TI - Comparison of supine and prone positions for percutaneous nephrolithotomy in treatment of staghorn stones. AB - INTRODUCTION: Percutaneous nephrolithotomy (PNL) is the primary treatment modality for management of staghorn stones. PNL in supine position has important advantages over prone positon. However, studies comparing prone and supine positions for PNL in staghorn stone patients have conflicting results, and the aim of the current study was to compare prone and supine positions for PNL in staghorn stone cases. PATIENTS AND METHODS: Data of patients underwent PNL for staghorn stones in supine or prone position by a single urologist were collected prospectively. The supine and prone position groups were compared for stone free rate (SFR) and complication rates. All patients were evaluated with NCCT for evaluation of SFR. Chi-square test was used to compare categorical variables and Student t test was applied for continuous variables of the treatment groups. RESULTS: The groups were similar for demographic and stone-related characteristics. Multi-caliceal and intercostal access was more common in prone position. Operation duration was significantly shorter and hemoglobin drop was significantly less in supine group. SFR was 64.1 and 60.4% in the supine and prone groups, respectively (p = 0.72). Complication rates were similar in the two groups but Clavien III complications were observed in two patients in the prone group. CONCLUSIONS: PNL in supine position is an effective treatment for management of staghorn stones. The need for multi-caliceal and intercostal puncture is less when combined with retrograde intrarenal surgery. PNL in supine position should be considered as primary treatment option in staghorn stone cases. PMID- 28357453 TI - ? PMID- 28357452 TI - Determinants of health-related quality of life for patients after urinary lithotripsy: ureteroscopic vs. shock wave lithotripsy. AB - PURPOSE: To compare the longitudinal health-related quality of life (HRQoL) after surgical intervention with ureteroscopic lithotripsy (URSL) and shock wave lithotripsy (SWL) and to evaluate the factors affecting HRQoL in urolithiasis patients. METHODS: A total of 262 patients who underwent lithotripsy (SWL, n = 61; URSL, n = 201) for upper urinary tract calculi treatment between June 2012 and January 2015 were evaluated. All patients were administered the Short-Form 36 item survey (SF-36) to assess HRQoL at four timepoints: before surgery, on the day of discharge, and 1 and 6 months after lithotripsy. Stone-free rates, complications, and analgesic requirements were evaluated to compare the effects of the two procedures on HRQoL. RESULTS: At the day of discharge, patients in the URSL group had significantly lower mean scores on five different subscales of the SF-36 questionnaire, namely, physical functioning, role-physical, social functioning, role-emotional, and mental health. The stone-free rate at 3 months after lithotripsy was significantly lower in the SWL group (72.1% vs. URSL, 93.0%; p < 0.001). The hospital stay was shorter in the SWL group (2.1 +/- 0.07 vs. URSL, 4.1 +/- 0.13 days; p < 0.001), and the analgesia requirements were also lower in the SWL group (0.3 +/- 0.08 vs. URSL, 0.9 +/- 0.20; p < 0.001). CONCLUSIONS: The post-lithotripsy HRQoL was superior for SWL compared to URSL on the discharge date despite the lower stone-free rate of the former. The longer hospital stay and higher postoperative pain appeared to be the determinants of the lower HRQoL in the URSL group. PMID- 28357454 TI - [Surgery versus conservative treatment for persisting abdominal pain after diverticulitis]. PMID- 28357455 TI - [Importance of the lymph node status in patients with hilar cholangiocarcinoma]. PMID- 28357456 TI - [Are antibiotics neccessary in a first episode of uncomplicated diverticulitis?] PMID- 28357457 TI - [Unusual cause of recurrent gluteal abscess formation]. PMID- 28357458 TI - [Necrosis with mummification of the foot in a 33-year-old man with anxiety disorder]. PMID- 28357459 TI - Predictive validity of the qSOFA criteria for sepsis in non-ICU inpatients. PMID- 28357460 TI - Naltrexone moderates the relationship between cue-induced craving and subjective response to methamphetamine in individuals with methamphetamine use disorder. AB - RATIONALE: Reductions in cue-induced craving and subjective response to drugs of abuse are commonly used as initial outcome measures when testing novel medications for the treatment of addiction. Yet neither the relationship between these two measures at the individual level nor the moderating effects of pharmacotherapies on this relationship has been examined. OBJECTIVE: This secondary data analysis sought to examine (1) the predictive relationship between cue-induced craving and subsequent acute subjective response to methamphetamine (MA) and (2) whether the opioid-receptor antagonist naltrexone moderated this association in a sample of non-treatment-seeking individuals who met DSM-IV criteria for MA use disorder (abuse or dependence). METHODS: Participants (n = 30) completed two 4-day medication regimens (oral naltrexone 50 mg or placebo, in a randomized, counterbalanced, and double-blind fashion). On day 4 of each medication regimen, participants completed a cue-reactivity paradigm followed by intravenous MA administration. Methamphetamine craving was assessed after the cue reactivity paradigm, and subjective response to MA was assessed during MA infusion. RESULTS: Cue-induced craving for MA was positively associated with post infusion subjective MA effects, including positive (i.e., stimulation, good effects, feel drug, high), negative (i.e., anxious and depressed), and craving related (i.e., want more, would like access to drug, crave) responses. Naltrexone, vs. placebo, significantly reduced the association between cue induced craving and positive subjective response to MA. CONCLUSIONS: The findings indicate that naltrexone moderates the predictive relationship between cue induced craving and positive subjective effects of MA, thereby suggesting a behavioral mechanism by which naltrexone may be efficacious in treating MA use disorder. PMID- 28357461 TI - Association between proximal internal carotid artery steno-occlusive disease and diffuse wall thickening in its petrous segment: a magnetic resonance vessel wall imaging study. AB - PURPOSE: Significant stenosis or occlusion in carotid arteries may lead to diffuse wall thickening (DWT) in the arterial wall of downstream. This study aimed to investigate the correlation between proximal internal carotid artery (ICA) steno-occlusive disease and DWT in ipsilateral petrous ICA. METHODS: Symptomatic patients with atherosclerotic stenosis (>0%) in proximal ICA were recruited and underwent carotid MR vessel wall imaging. The 3D motion sensitized driven equilibrium prepared rapid gradient-echo (3D-MERGE) was acquired for characterizing the wall thickness and longitudinal extent of the lesions in petrous ICA and the distance from proximal lesion to the petrous ICA. The stenosis degree in proximal ICA was measured on the time-of-flight (TOF) images. RESULTS: In total, 166 carotid arteries from 125 patients (mean age 61.0 +/- 10.5 years, 99 males) were eligible for final analysis and 64 showed DWT in petrous ICAs. The prevalence of severe DWT in petrous ICA was 1.4%, 5.3%, 5.9%, and 80.4% in ipsilateral proximal ICAs with stenosis category of 1%-49%, 50%-69%, 70%-99%, and total occlusion, respectively. Proximal ICA stenosis was significantly correlated with the wall thickness in petrous ICA (r = 0.767, P < 0.001). Logistic regression analysis showed that proximal ICA stenosis was independently associated with DWT in ipsilateral petrous ICA (odds ratio (OR) = 2.459, 95% confidence interval (CI) 1.896-3.189, P < 0.001]. CONCLUSION: Proximal ICA steno occlusive disease is independently associated with DWT in ipsilateral petrous ICA. PMID- 28357462 TI - Effect of Cadmium Stress on Non-enzymatic Antioxidant and Nitric Oxide Levels in Two Varieties of Maize (Zea mays). AB - Cadmium (Cd) is one of the most toxic heavy metals that inhibit physiological processes of plants. Hence, the present study sought to investigate the effect of cadmium-contaminated seeds from two varieties of maize (Zea mays) on non enzymatic antioxidant and nitric oxide levels. Seeds of yellow and white maize were exposed to different concentrations of Cd (0, 1, 3 and 5 ppm) for two weeks. The results from this study revealed that both varieties of maize bio-accumulate Cd in leaves in a dose-dependent manner. In addition, Cd exposure caused a significant (p < 0.05) decrease in total phenolic, GSH and nitric oxide (NO) levels at the highest concentration tested when compared with control. Therefore, the observed decrease in NO and endogenous antioxidant status by Cd treatment in maize plants could suggest some possible mechanism of action for Cd-induced oxidative stress and counteracting effect of the plants against Cd toxicity. PMID- 28357465 TI - [Herpes zoster vaccination efficacy in adults 70 years of age or older : ZOE-70 study]. PMID- 28357463 TI - Age-specific neural strategies to maintain motor performance after an acute social stress bout. AB - Stress due to cognitive demands and fatigue have shown to impair motor performance in older adults; however, the effect of social stress and its influence on prefrontal cortex (PFC) functioning in older adults during upper extremity motor performance tasks is not known. The present study explored the after-effects of an acute social stress bout on neural strategies, measured using PFC and hand/arm muscle activation, and adopted by younger and older adults to maintain handgrip force control. Nine older [74.1 (6.5) years; three men, six women] and ten younger [24.2 (5.0) years, four men, six women] adults performed handgrip force control trials at 30% maximum voluntary contractions before and after the Trier Social Stress Test (TSST). PFC activity was measured using functional near infrared spectroscopy and muscle activity from the flexor and extensor carpi radialis (FCR/ECR) was measured using electromyography. In general, aging was associated with decreased force steadiness and force complexity with a concomitant increase in bilateral PFC activity. While motor performance remained comparable before and after the TSST stress session in both age groups, the associated neural strategies differed between groups. While the stress condition was associated with lower FCR and ECR activity in younger adults despite no change in the PFC activation, stress was associated with increases in FCR activity in older adults. This stress-related compensatory neural strategy of increasing hand/arm muscle activation, potentially via the additional recruitment of the stress-motor neural circuitry, may have played a role in maintaining motor performance in older adults. PMID- 28357467 TI - [Ulcers in obesity-associated chronic venous insufficiency]. AB - BACKGROUND: Chronic venous insufficiency is a frequently occurring disease consisting of a characteristic symptom complex and ulcerations. Normally, varicose veins with reflux or obstruction can be found. However, these symptoms have also been described in obese people and are considered functional chronic venous insufficiency. The aim of this work was to present patients with ulceration in obesity-associated chronic venous insufficiency and to describe typical features of ulceration in obese people. MATERIALS AND METHODS: Seven patients with ulcerations of the lower limbs in obesity-associated chronic venous insufficiency were examined. Duplex sonography was performed; reflux or stenosis as well as a peripheral arterial occlusive disease could be excluded. RESULTS: In all, 7 patients presented with grade I-III obesity. The duplex sonographic examination showed no evidence of reflux or obstruction. However, multiple ulcers were found located on the proximal or ventrolateral lower limb. Most of them occurred posttraumatically or after insect bites with typical signs of chronic venous disease including hyperpigmentation and erythema. CONCLUSION: The cause of obesity-associated chronic venous insufficiency has been associated with an increased intraabdominal pressure due to abdominal fat masses. It leads to venous hypertension. Therapy consists of consequent compression therapy combined with suitable wound care, weight reduction, and regular exercise. PMID- 28357466 TI - [Fundamentals of the microbiome]. AB - Until the middle of the 20th century, clinical microbiology was limited to bacterial cultures enabling the detection of pathogenic microorganisms. Knowledge about the mutual relationship between humans and microorganisms has increased slowly. With the introduction of culture-independent analysis methods, comprehensive cataloging of the human microbiome was possible for the first time. Since then, compositional changes in relation to diseases have been studied. The goals of the Human Microbiome Project and MetaHIT include comparative studies of healthy and diseased individuals. Numerous libraries on time- and location dependent changes of the microbiota composition in human diseases have been created. However, a mathematical correlation does not equal biological or medical relevance. Future research needs to validate the hypotheses generated in these studies in functional experiments and evaluate their true impact on clinical practice. PMID- 28357464 TI - Monosodium glutamate-associated alterations in open field, anxiety-related and conditioned place preference behaviours in mice. AB - The present study investigated changes in behaviour associated with oral monosodium glutamate (a flavouring agent), using the open field, elevated plus maze and conditioned place preference (CPP) paradigms, respectively. Mice were assigned to two groups for CPP [monosodium glutamate (MSG)-naive (n = 40) and MSG pretreated (n = 40)] and two groups for open field (OF) and elevated plus maze (EPM) tests [n = 40 each], respectively. Animals in respective groups were then divided into four subgroups (n = 10) (vehicle or MSG (80, 160 and 320 mg/kg)). MSG-naive mice were observed in the CPP box in three phases (pre-conditioning, conditioning and post-conditioning). Mice were conditioned to MSG or an equivalent volume of saline. The MSG pretreatment group received vehicle or respective doses of MSG daily for 21 days, prior to conditioning. Mice in the OF or EPM groups received vehicle or doses of MSG (orally) for 21 days, at 10 ml/kg. Open field or EPM behaviours were assessed on days 1 and 21. At the end of the experiments, mice in the OF groups were sacrificed and brain homogenates used to assay glutamate and glutamine. Results showed that administration of MSG was associated with a decrease in rearing, dose-related mixed horizontal locomotor, grooming and anxiety-related response and an increase in brain glutamate/glutamine levels. Following exposure to the CPP paradigm, MSG-naive and MSG-pretreated mice both showed 'drug-paired' chamber preference. The study concluded that MSG (at the administered doses) was associated with changes in open field activities, anxiety-related behaviours and brain glutamate/glutamine levels; its ingestion also probably leads to a stimulation of the brain reward system. PMID- 28357468 TI - Salvage radiotherapy with or without concurrent chemotherapy for pelvic recurrence after hysterectomy alone for early-stage uterine cervical cancer. AB - PURPOSE: Treatment outcomes of patients with pelvic recurrence after hysterectomy alone for uterine cervical cancer who received salvage radiotherapy (RT) with or without concurrent chemotherapy were investigated. METHODS: Salvage RT for recurrent cervical cancer confined to the pelvic cavity after hysterectomy alone was received by 33 patients. The median interval between initial hysterectomy and recurrence was 26 months. Whole-pelvic irradiation was delivered to median dose of 45 Gy, followed by a boost with a median dose of 16 Gy to the gross tumor volume. Cisplatin-based concurrent chemotherapy was administered to 29 patients. RESULTS: The median follow-up period was 53 months for surviving patients. Most patients (97.0%) completed salvage RT of >=45 Gy. Complete response (CR) was achieved in 23 patients (69.7%). Pelvic sidewall involvement and evaluation with positron-emission tomography-computed tomography were significantly associated with CR. The 5-year progression-free survival (PFS), local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS) rates were 62.7, 79.5, 72.5, and 60.1%, respectively. Initial International Federation of Gynecology and Obstetrics stage, pelvic sidewall involvement, and CR status were significant factors for PFS and OS rates in multivariate analysis. The incidence of severe acute and late toxicities (>=grade 3) was 12.1 and 3.0%, respectively. CONCLUSION: Aggressive salvage RT with or without concurrent chemotherapy for recurrent cervical cancer confined to the pelvic cavity was feasible, with promising treatment outcomes and acceptable toxicities. However, even more intensive novel treatment strategies should be investigated for patients with unfavorable prognostic factors. PMID- 28357471 TI - Mechanical load exerted by PET-G aligners during mesial and distal derotation of a mandibular canine : An in vitro study. AB - INTRODUCTION: The six force-moment (F/M) components exerted by aligners of different thickness during simulated mesiorotation and distorotation of a mandibular canine were studied. MATERIALS AND METHODS: An acrylic mandibular model with a separated right canine mounted on a hexapod via a 3D F/M sensor was used. Duran+(r) aligners (Scheu Dental, Germany) of thickness 0.5, 0.625, and 0.75 mm were fabricated on plaster models with the measurement tooth in its neutral position. The F/M values were recorded during progressive mesiorotation or distorotation of tooth 43 in 1 degrees steps up to +/-15 degrees , corresponding to 0.5 mm displacements of the tooth's interdental contacts. Each rotation step included renewed seating of the aligner on the acrylic model. Three aligners were tested three times each for each thickness and direction of rotation. RESULTS: The median rotational moments for the 0.5 mm aligner and 15 degrees distorotation of tooth 43 was 27.49 Nmm (interquartile range, IQR 1.45 Nmm). The corresponding values for the 0.625 and 0.75 mm aligners were 41.04 Nmm (IQR 5.62 Nmm) and 42.48 Nmm (IQR 2.17 Nmm), respectively. The average rotational moments for distorotation were 15% higher than for mesiorotation (p = 0.01). Relatively high collateral F/M components, specifically an intrusive force and labiolingual and mesiodistal tipping moments, were observed. CONCLUSION: To avoid overloading of periodontal structures, derotation of lower canines should be limited to 10 degrees per setup step, leading to rotational moments of about 15 Nmm. The mechanical behavior of the 0.625 and 0.75 mm aligners were similar; thus, it may be omitted from the aligner sequence. Further studies are required to investigate specific aligner modifications or attachments for minimizing collateral F/M components or unwanted movements, respectively, during canine derotation. PMID- 28357470 TI - Differential molecular regulation of processing and membrane expression of Type-I BMP receptors: implications for signaling. AB - The Type-I bone morphogenetic protein receptors (BMPRs), BMPR1A and BMPR1B, present the highest sequence homology among BMPRs, suggestive of functional similitude. However, sequence elements within their extracellular domain, such as signal sequence or N-glycosylation motifs, may result in differential regulation of biosynthetic processing and trafficking and in alterations to receptor function. We show that (i) BMPR1A and the ubiquitous isoform of BMPR1B differed in mode of translocation into the endoplasmic reticulum; and (ii) BMPR1A was N glycosylated while BMPR1B was not, resulting in greater efficiency of processing and plasma membrane expression of BMPR1A. We further demonstrated the importance of BMPR1A expression and glycosylation in ES-2 ovarian cancer cells, where (i) CRISPR/Cas9-mediated knockout of BMPR1A abrogated BMP2-induced Smad1/5/8 phosphorylation and reduced proliferation of ES-2 cells and (ii) inhibition of N glycosylation by site-directed mutagenesis, or by tunicamycin or 2-deoxy-D glucose treatments, reduced biosynthetic processing and plasma membrane expression of BMPR1A and BMP2-induced Smad1/5/8 phosphorylation. PMID- 28357472 TI - L-Threonine and its analogue added to autoclaved solid medium suppress trichothecene production by Fusarium graminearum. AB - Fusarium graminearum produces trichothecene mycotoxins under certain nutritional conditions. When L-Thr and its analogue L-allo-threonine were added to brown rice flour solid medium before inoculation, trichothecene production after 4 days of incubation was suppressed. A time-course analysis of gene expression demonstrated that L-Thr suppressed transcription of Tri6, a trichothecene master regulator gene, and a terpene cyclase Tri5 gene. Regulation of trichothecene biosynthesis by altering major primary metabolic processes may open up the possibility to develop safe chemicals for the reduction of mycotoxin contamination might be developed. PMID- 28357469 TI - Mechanisms controlling diversification of olfactory sensory neuron classes. AB - Animals survive in harsh and fluctuating environments using sensory neurons to detect and respond to changes in their surroundings. Olfactory sensory neurons are essential for detecting food, identifying danger, and sensing pheromones. The ability to sense a large repertoire of different types of odors is crucial to distinguish between different situations, and is achieved through neuronal diversity within the olfactory system. Here, we review the developmental mechanisms used to establish diversity of olfactory sensory neurons in various model organisms, including Caenorhabditis elegans, Drosophila, and vertebrate models. Understanding and comparing how different olfactory neurons develop within the nervous system of different animals can provide insight into how the olfactory system is shaped in humans. PMID- 28357473 TI - Effect of Anaerobiasis or Hypoxia on Pseudomonas aeruginosa Inhibition of Aspergillus fumigatus Biofilm. AB - Pseudomonas aeruginosa (Pa) and Aspergillus fumigatus (Af) are the major bacterial and fungal pathogens in the airways of cystic fibrosis (CF) patients. This is likely related to their ability to form biofilms. Both microbes have been associated with CF disease progression. The interplay between these two pathogens has been studied under aerobic conditions, though accumulating data indicates that much of the CF airway is hypoxic or anaerobic. We studied the microbial interaction in these latter environments. Pa is an aggressor against Af forming biofilm or as established Af biofilm, whether Pa is cultivated in aerobic, hypoxic, or anaerobic conditions, or tested in aerobic or hypoxic conditions. Pa cells are generally more effective than planktonic or biofilm culture filtrates. Pa growth is less in anaerobic conditions, and filtrates less effective after anaerobic or hypoxic growth, or against hypoxic Af. These, and other comparisons shown, indicate that Pa would be less effective in such environments, as would be the case in a CF mucus plug. These observations would explain why Pa becomes established in CF airways before Af, and why Af may persist during disease progression. PMID- 28357474 TI - New advances in exopolysaccharides production of Streptococcus thermophilus. AB - Streptococcus thermophilus is the most important thermophilic dairy starter, and is widely used in the dairy industry. Streptococcus thermophilus exopolysaccharides received wide attention over recent decades, because they can improve the properties of the dairy product and confer beneficial health effects. The understanding of the regulatory and biosynthetic mechanisms of EPS will improve the EPS biosynthesis, increase the productivity of EPSs, and develop EPSs with desirable properties. The structure of EPSs is the focus of this study. Revealing the structure-function relationship can lead to increase the knowledge base and from there to increased research of EPS. The EPS yield is a key limiting factor in the research and utilization of EPS. In the present review, biosynthetic pathways and genetics of S. thermophilus EPSs were described and reviewed. At the same time, functional properties and applications of EPS, and strategies for enhancement of EPS production are discussed. PMID- 28357475 TI - ISCR2 is associated with the dissemination of multiple resistance genes among Vibrio spp. and Pseudoalteromonas spp. isolated from farmed fish. AB - 58 multiresistant strains representing diverse genera were isolated from farmed fish in an aquaculture facility. Resistant rates of strains harboring ISCR2, an insertion sequence type element, were higher than those in which this element was absent. Full genome sequencing of a Vibrio isolate containing ISCR2 confirmed that it is associated with multiple resistance genes, many of which are of clinical relevance. We describe the structural variation within ISCR2, and its distribution throughout multiple diverse aquatic genera, including Vibrio, Shewenalla, Pseudoalteromonas and Psychrobacter, suggesting the potential role of ISCR2 in disseminating antibiotic resistance. We also observe, and experimentally verify, a novel macrolide resistance gene that is also associated with ISCR2. PMID- 28357478 TI - Application of environmental DNA analysis to inform invasive fish eradication operations. AB - Environmental DNA (eDNA) detection of non-native species has considerable potential to inform management decisions, including identifying the need for population control and/or eradication. An invasive species of European concern is the Asian cyprinid fish, topmouth gudgeon (Pseudorasbora parva). Here, eDNA analyses were applied at a commercial angling venue in southern England to inform operations aiming to eradicate P. parva, which had only ever been observed in one of the venue's seven unconnected angling ponds. Eradication of P. parva was initially attempted by repeated depletion of the population using fish traps (crayfish traps fitted with 5 mm mesh netting) and the introduction of native predators over a 4-year period. The very low number of P. parva captured following these eradication efforts suggested a possible population crash. Conventional PCR analysis of water samples using species-specific primers was applied to all seven ponds to confirm that P. parva was present in only one pond, that the eradication attempt had indeed failed and that the species' distribution in the pond appeared to be restricted to three bankside locations. The continued presence of P. parva at these locations was confirmed by subsequent trapping. Water samples from an adjacent, unconnected stream were also analysed using the eDNA methodology, but no DNA of P. parva was detected. The results suggest that further management action to eradicate P. parva be focused on the pond shown to contain the isolated P. parva population and thereby eliminate the risk of further dispersal. This study is the first to apply eDNA analysis to assess the efficacy of an eradication attempt and to provide evidence that the species was unlikely to be present in the other ponds, thus reducing the resources needed to control the species. PMID- 28357477 TI - Wnt5a is elevated in heart failure and affects cardiac fibroblast function. AB - : Wnt signaling is dysregulated in heart failure (HF) and may promote cardiac hypertrophy, fibrosis, and inflammation. Blocking the Wnt ligand Wnt5a prevents HF in animal models. However, the role of Wnt5a in human HF and its functions in cardiac cells remain unclear. Here, we investigated Wnt5a regulation in HF patients and its effects on primary mouse and human cardiac fibroblasts. Serum Wnt5a was elevated in HF patients and associated with hemodynamic, neurohormonal, and clinical measures of disease severity. In failing human hearts, Wnt5a protein correlated with interleukin (IL)-6 and tissue inhibitor of metalloproteinase (TIMP)-1. Wnt5a messenger RNA (mRNA) levels were markedly upregulated in failing myocardium and both mRNA and protein levels declined following left ventricular assist device therapy. In primary mouse and human cardiac fibroblasts, recombinant Wnt5a dose-dependently upregulated mRNA and protein release of IL-6 and TIMP-1. Wnt5a did not affect beta-catenin levels, but activated extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. Importantly, inhibition of ERK1/2 activation attenuated Wnt5a-induced release of IL-6 and TIMP-1. In conclusion, our results show that Wnt5a is elevated in the serum and myocardium of HF patients and is associated with measures of progressive HF. Wnt5a induces IL-6 and TIMP-1 in cardiac fibroblasts, which might promote myocardial inflammation and fibrosis, and thereby contribute to HF progression. KEY MESSAGES: * Wnt5a is elevated in serum and myocardium of HF patients and is associated with measures of progressive HF. * In cardiac fibroblasts, Wnt5a upregulates interleukin (IL)-6 and tissue inhibitor of metalloproteinase (TIMP)-1 through the ERK pathway. * Wnt5a-mediated effects might promote myocardial inflammation and fibrosis, and thereby contribute to HF progression. PMID- 28357479 TI - [Differences in the outcome of seriously injured children depending on treatment level]. AB - INTRODUCTION: Many publications, mainly from other countries, suggest that the treatment of seriously injured children might be better in specialised paediatric trauma centres than in general trauma centres. Data from Germany are not available yet, but those from abroad were used for the recommendations made by the German Association for Trauma Surgery (DGU) on the topic of paediatric trauma in the "White Paper on Trauma Care". The goal of this study was to analyse whether the outcome of severely injured children is dependent on treatment level and on the availability of a paediatric surgeon based on the given data. MATERIALS AND METHODS: Data from the "TraumaRegister DGU" between 2002 and 2012 were used. Children aged 1-15 years treated during the period 2002-2012 were included. Severity had to reach a minimum Injury Severity Score (ISS) of 9 and the treatment had to involve a stay at an Intensive Care Unit. Patients with an ISS >=9 who died were also included to take into consideration children with particularly severe injuries. RESULTS: Hospitals without a paediatric surgeon transferred the patients significantly more frequently (p < 0.001). Mean hospital stay was shorter in centres with a paediatric surgeon, with slightly longer median stays at an Intensive Care Unit. Hospitals without a paediatric surgeon performed slightly more frequent surgical interventions on injured children (barely significant at p = 0.045). The death rate and the calculated Revised Injury Severity Classification (RISC) II prognosis were the same with or without the presence of a paediatric surgeon. No difference was found in the Glasgow Outcome Score (GOS) between the group with and the group without involvement of a paediatric surgeon. DISCUSSION: Overall, the medical care of seriously injured and polytraumatised children in Germany is good at all levels of treatment whether a paediatric surgeon is involved or not. PMID- 28357476 TI - Type I interferon as a biomarker in autoimmunity and viral infection: a leukocyte subset-specific analysis unveils hidden diagnostic options. AB - : Interferon alpha and its surrogates, including IP-10 and SIGLEC1, paralleled changes of disease activity in systemic lupus erythematosus (SLE). However, the whole blood interferon signature (WBIFNS)-the current standard for type I IFN assessment in SLE-does not correlate with SLE disease activity in individual patients over time. The underlying causes for this apparent contradiction have not been convincingly demonstrated. Using a multicenter dataset of gene expression data from leukocyte subsets in SLE, we identify distinctive subset specific contributions to the WBIFNS. In a subsequent analysis, the effects of type I interferon on cellular blood composition in patients with SLE and hepatitis B were also studied over time. We found that type I interferon mediates significant alterations in whole blood composition, including a neutropenia and relative lymphocytosis. Given different effects of type 1 interferon on different leukocyte subsets, these shifts confound measurement of a type 1 interferon signature in whole blood. To minimize and overcome these limitations of the WBIFNS, we suggest to measure IFN-induced transcripts or proteins in a specific leukocyte subset to improve clinical impact of interferon biomarkers. KEY MESSAGES: Myeloid cells contribute more to the WBIFNS in SLE than their lymphocytic counterpart. Very similar leukocyte subsets reveal distinctive IFN signatures. IFN alpha mixes up composition of blood and leads to a preferential neutropenia, yielding relative lymphocytosis. PMID- 28357481 TI - Disulfide-modified antigen for detection of celiac disease-associated anti-tissue transglutaminase autoantibodies. AB - A simple and rapid immunosensor for the determination of the celiac disease related antibody, anti-tissue transglutaminase, was investigated. The antigenic protein tissue transglutaminase was chemically modified, introducing disulfide groups through different moieties of the molecule (amine, carboxylic, and hydroxyl groups), self-assembled on gold surfaces, and used for the detection of IgA and IgG autoantibodies. The modified proteins were evaluated using enzyme linked immunosorbent assay and surface plasmon resonance, which showed that only introduction of the disulfide groups through amine moieties in the tissue transglutaminase preserved its antigenic properties. The disulfide-modified antigen was co-immobilized via chemisorption with a poly(ethylene glycol) alkanethiol on gold electrodes. The modified electrodes were then exposed to IgA anti-tissue transglutaminase antibodies and subsequently to horseradish peroxidase-labeled anti-idiotypic antibodies, achieving a detection limit of 260 ng ml-1. Immunosensor performance in the presence of complex matrixes, including clinically relevant serum reference solutions and real patient samples, was evaluated. The introduction of disulfides in the antigenic protein enabled a simple and convenient one-step surface immobilization procedure involving only spontaneous gold-thiol covalent binding. Complete amperometric assay time was 30 min. PMID- 28357482 TI - Immunoassay quantification of human insulin added to ternary parenteral nutrition containers: comparison of two methods. AB - Adding insulin directly into infusion bags seems to be a useful method for controlling hyperglycemia in patients under ternary parenteral nutrition (TPN). Its efficacy is assessed by glycemic monitoring but few data are available on insulin stability in this situation. Among the various methods for quantifying insulin levels in human serum, the immunoassay ones seemed potentially appropriate for a TPN admixture containing high lipid concentrations. We sought to identify and validate which of two immunoassay methods was the better to quantify human insulin and consequently be adapted to studying its stability in a TPN admixture. Two immunoassay methods to quantify recombinant human insulin were assessed in industrial TPN: an immunoradiometric assay (IRMA) and an immunoelectrochemiluminometric assay (IECMA). Validation trials for both methods were based on the accuracy profile method. Interference with immunometric assays due to the high lipidic content of TPN was eliminated through an improved preparation protocol using a bovine serum albumin (BSA) diluted in phosphate buffer saline (PBS). The relative total error of IECMA varied from 1.74 to 4.52% while it varied from -0.32 to 8.37% with IRMA. Only IECMA provided an accuracy profile with a 95% confidence interval of calculated-tolerance limits falling between the chosen acceptance limits (i.e., total error <=+/-10%). IECMA combined with a BSA dilution is a simple and semi-automatic method that provides an accurate quantification of human insulin in a TPN admixture without any interference from lipids. PMID- 28357483 TI - Tracing the fate and transport of secondary plant metabolites in a laboratory mesocosm experiment by employing mass spectrometric imaging. AB - Mass spectrometric imaging (MSI) has received considerable attention in recent years, since it allows the molecular mapping of various compound classes, such as proteins, peptides, glycans, secondary metabolites, lipids, and drugs in animal, human, or plant tissue sections. In the present study, the application of laser based MSI analysis of secondary plant metabolites to monitor their transport from the grass leaves of Dactylis glomerata, over the crop of the grasshopper Chorthippus dorsatus to its excrements, and finally in the soil solution is described. This plant-herbivore-soil pathway was investigated under controlled conditions by using laboratory mesocosms. From six targeted secondary plant metabolites (dehydroquinic acid, quinic acid, apigenin, luteolin, tricin, and rosmarinic acid), only quinic acid, and dehydroquinic acid, an in-source-decay (ISD) product of quinic acid, could be traced in nearly all compartments. The tentative identification of secondary plant metabolites was performed by MS/MS analysis of methanol extracts prepared from the investigated compartments, in both the positive and negative ion mode, and subsequently compared with the results generated from the reference standards. Except for tricin, all secondary metabolites could be tentatively identified by this approach. Additional liquid chromatography mass spectrometry (LC-MS) experiments were carried out to verify the MSI results and revealed the presence of quinic acid only in grass and chewed grass, whereas apigenin-hexoside-pentoside and luteolin-hexoisde-pentoside could be traced in the grasshopper body and excrement extracts. In summary, the MSI technique shows a trade-off between sensitivity and spatial resolution. Graphical abstract Monitoring quinic acid in a mesocosm experiment by mass spectrometric imaging (MSI). PMID- 28357484 TI - New approach for cystic fibrosis diagnosis based on chloride/potassium ratio analyzed in non-invasively obtained skin-wipe sweat samples by capillary electrophoresis with contactless conductometric detection. AB - A new approach for sweat analysis used in cystic fibrosis (CF) diagnosis is proposed. It consists of a noninvasive skin-wipe sampling followed by analysis of target ions using capillary electrophoresis with contactless conductometric detection (C4D). The skin-wipe sampling consists of wiping a defined skin area with precleaned cotton swab moistened with 100 MUL deionized water. The skin-wipe sample is then extracted for 3 min into 400 MUL deionized water, and the extract is analyzed directly. The developed sampling method is cheap, simple, fast, and painless, and can replace the conventional pilocarpine-induced sweat chloride test commonly applied in CF diagnosis. The aqueous extract of the skin-wipe sample content is analyzed simultaneously by capillary electrophoresis with contactless conductometric detection using a double opposite end injection. A 20 mmol/L L-histidine/2-(N-morpholino)ethanesulfonic acid and 2 mmol/L 18-crown-6 at pH 6 electrolyte can separate all the major ions in less than 7 min. Skin-wipe sample extracts from 30 study participants-ten adult patients with CF (25-50 years old), ten pediatric patients with CF (1-15 years old), and ten healthy control individuals (1-18 years old)-were obtained and analyzed. From the analyzed ions in all samples, a significant difference between chloride and potassium concentrations was found in the CF patients and healthy controls. We propose the use of the Cl-/K+ ratio rather than the absolute Cl- concentration and a cutoff value of 4 in skin-wipe sample extracts as an alternative to the conventional sweat chloride analysis. The proposed Cl-/K+ ion ratio proved to be a more reliable indicator, is independent of the patient's age, and allows better differentiation between non-CF individuals and CF patients having intermediate values on the Cl- sweat test. Figure New approach for cystic fibrosis diagnosis based on skin-wipe sampling of forearm and analysis of ionic content (Cl-/K+ ratio) in skin-wipe extracts by capillary electrophoresis with contactless conductometric detection. PMID- 28357486 TI - The human microbiome, from Achilles armour to Nessus' shirt. PMID- 28357487 TI - Lesson of 15-year exposure to Bisphenol A: a critical discussion of biomonitoring studies. PMID- 28357485 TI - Non-protein thiol imaging and quantification in live cells with a novel benzofurazan sulfide triphenylphosphonium fluorogenic compound. AB - Thiols (-SH) play various roles in biological systems. They are divided into protein thiols (PSH) and non-protein thiols (NPSH). Due to the significant roles thiols play in various physiological/pathological functions, numerous analytical methods have been developed for thiol assays. Most of these methods are developed for glutathione, the major form of NPSH. Majority of these methods require tissue/cell homogenization before analysis. Due to a lack of effective thiol specific fluorescent/fluorogenic reagents, methods for imaging and quantifying thiols in live cells are limited. Determination of an analyte in live cells can reveal information that cannot be revealed by analysis of cell homogenates. Previously, we reported a thiol-specific thiol-sulfide exchange reaction. Based on this reaction, a benzofurazan sulfide thiol-specific fluorogenic reagent was developed. The reagent was able to effectively image and quantify total thiols (PSH+NPSH) in live cells through fluorescence microscopy. The reagent was later named as GUALY's reagent. Here we would like to report an extension of the work by synthesizing a novel benzofurazan sulfide triphenylphosphonium derivative [(((7,7'-thiobis(benzo[c][1,2,5]oxadiazole-4,4' sulfonyl))bis(methylazanediyl))bis(butane-4,1-diyl))bis(triphenylphosphonium) (TBOP)]. Like GUALY's reagent, TBOP is a thiol-specific fluorogenic agent that is non-fluorescent but forms fluorescent thiol adducts in a thiol-specific fashion. Different than GUALY's reagent, TBOP reacts only with NPSH but not with PSH. TBOP was effectively used to image and quantify NPSH in live cells using fluorescence microscopy. TBOP is a complementary reagent to GUALY's reagent in determining the roles of PSH, NPSH, and total thiols in thiol-related physiological/pathological functions in live cells through fluorescence microscopy. Graphical Abstract Live cell imaging and quantification of non-protein thiols by TBOP. PMID- 28357488 TI - Study on inter-ethnic human differences in bioactivation and detoxification of estragole using physiologically based kinetic modeling. AB - Considering the rapid developments in food safety in the past decade in China, it is of importance to obtain insight into what extent safety and risk assessments of chemicals performed for the Caucasian population apply to the Chinese population. The aim of the present study was to determine physiologically based kinetic (PBK) modeling-based predictions for differences between Chinese and Caucasians in terms of metabolic bioactivation and detoxification of the food borne genotoxic carcinogen estragole. The PBK models were defined based on kinetic constants for hepatic metabolism derived from in vitro incubations using liver fractions of the two ethnic groups, and used to evaluate the inter-ethnic differences in metabolic activation and detoxification of estragole. The models predicted that at realistic dietary intake levels, only 0.02% of the dose was converted to the ultimate carcinogenic metabolite 1'-sulfooxyestragole in Chinese subjects, whereas this amounted to 0.09% of the dose in Caucasian subjects. Detoxification of 1'-hydroxyestragole, mainly via conversion to 1'-oxoestragole, was similar within the two ethnic groups. The 4.5-fold variation in formation of the ultimate carcinogenic metabolite of estragole accompanied by similar rates of detoxification may indicate a lower risk of estragole for the Chinese population at similar levels of exposure. The study provides a proof of principle for how PBK modeling can identify differences in ethnic sensitivity and provide a more refined risk assessment for a specific ethnic group for a compound of concern. PMID- 28357490 TI - Annexin A10 optimally differentiates between intrahepatic cholangiocarcinoma and hepatic metastases of pancreatic ductal adenocarcinoma: a comparative study of immunohistochemical markers and panels. AB - Discriminating intrahepatic cholangiocarcinoma (ICC) from hepatic metastases of pancreatic ductal adenocarcinoma (mPDAC) can be challenging. While pathologists might depend on clinical information regarding a primary tumor, their diagnosis will lead the patient either to potentially curative surgery (for ICC) or to palliation (for mPDAC). Beyond the validation of recently published potential biomarkers for PDAC (primary or metastatic) in a large cohort, we assessed diagnostic performance of the most promising candidates in the challenging task of discriminating metastatic PDAC (mPDAC) from ICC. In a training set of 87 ICC and 88 pPDAC, our previously identified biomarkers Annexin A1 (ANXA1), ANXA10, and ANXA13 were tested and compared with 11 published biomarkers or panels (MUCIN 1, Agrin, S100P, MUC5 AC, Laminin, VHL, CK 17, N-Cadherin, ELAC2, PODXL and HSPG2). Biomarkers with best results were further tested in an independent series of biopsies of 27 ICC and 36 mPDAC. Highest AUC values (between 0.72 and 0.84) for the discrimination between ICC and pPDAC were found in the training set for Annexin A1, Annexin A10, MUC5 AC, CK17, and N-Cadherin. These markers were further tested on an independent series of liver biopsies containing ICC or mPDAC. Diagnostic characteristics were evaluated for individual markers as well as for 3* panels. ANXA 10 showed the highest diagnostic potential of all single markers, correctly classifying 75% of mPDAC and 85% of ICC. Our results suggest that ANXA10 may be useful to differentiate between ICC and mPDAC, when only a tissue specimen is available. PMID- 28357489 TI - Molecular genetic and immunotherapeutic targets in metastatic melanoma. AB - In recent years, melanoma treatment has radically changed with the emergence of targeted therapies and immunotherapies. Both have led to improved survival for patients with advanced or unresectable melanoma. Targeted therapies with BRAF inhibitors in the lead use the presence of activating driver mutations to inhibit tumour growth. Forty to 60% of melanomas harbour BRAF mutations, which makes them susceptible to treatment with BRAF and/or MEK inhibitors. In parallel, the development of immunotherapeutic agents has also expanded. These agents stimulate the endogenous immune system of the patient to eradicate cancer cells. Immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA 4) and programmed death 1 (PD-1) resulted in durable responses in a subset of patients. An important issue with immunotherapy lies in the identification of patients who will benefit from treatment. In this review, we will discuss these recent developments in melanoma therapy and highlight the role of the pathologist in both types of treatment. PMID- 28357491 TI - Acid sphingomyelinase/ceramide regulates carotid intima-media thickness in simulated weightless rats. AB - Structural adaptation of arteries to weightlessness might lower the working ability or even threaten the physical health of astronauts, but the underlying mechanism is unclear. Acid sphingomyelinase (ASM) catalyzes ceramide (Cer) generation controlling arterial remodeling through multiple signaling pathways. In the present study, we aimed to investigate the contribution of ASM/Cer to the changes of common carotid artery intima-media thickness (CIMT) induced by simulated weightlessness. Hindlimb-unloaded tail-suspended (HU) rats were used to simulate the effect of weightlessness. Morphology of the carotid artery (CA) was examined by hematoxylin-eosin staining. Protein content of ASM or proliferating cell nuclear antigen (PCNA) was detected by Western blot. Cer level was measured by immunohistochemistry analysis. Apoptosis events were observed by transferase mediated dUTP nick end labeling (TUNEL) staining. During 4 weeks of tail suspension, CIMT was increased gradually in HU but not in their synchronous control rats (P < 0.05). Correspondingly, the CA of HU rats had a lower apoptosis and higher proliferation of vascular smooth muscle cells (VSMCs). As compared to the control, both ASM protein expression and Cer content were reduced significantly in CA of HU rats (P < 0.05), incubation of which with permeable Cer reversed the changes in apoptosis and proliferation substantially. Furthermore, when the ASM protein content as well as Cer level in CA of control rats was diminished by using an ASM inhibitor, an increase of CIMT along with reduced apoptosis and enhanced proliferation of VSMCs was found. Our results suggest that by controlling the balance between apoptosis and proliferation, ASM/Cer plays an important role in the regulation of CIMT during simulated weightlessness. PMID- 28357492 TI - Patient-based outcomes after medial patellofemoral ligament reconstruction. AB - PURPOSE: The purpose of this study was to evaluate subjective outcomes after medial patellofemoral ligament (MPFL) reconstructions. METHODS: Fifty-four knees of 46 patients who received MPFL reconstruction for recurrent patellar dislocations were examined with a minimum follow-up of two years. To assess patient-based outcomes, the Knee Injury and Osteoarthritis Outcome Score (KOOS) and the Kujala score were assessed. RESULTS: The mean Kujala score was significantly improved from 64.6 +/- 22.1 pre-operatively to 84.7 +/- 11.8 post operatively (P < 0.001). The mean KOOS was also significantly improved post operatively in all five subscales. Further, the mean scores of 41 out of the 42 questions for the KOOS were significantly improved after surgery, except those of the question about "grinding and clicking". When the KOOS was assessed individually, the scores on one or more subscales out of the five were worsened post-operatively in eight patients, and seven of the eight patients had decreased post-operative pain subscale scores. Furthermore, those eight patients (worse group) were compared with patients without any worsened scores on any of the subscales (better group). The mean pre-operative pain and sports/recreation function subscale scores were significantly higher in the worse group whereas the mean post-operative pain and symptoms subscale scores were significantly lower in the worse group than in the better group. CONCLUSIONS: Overall, satisfactory patient-based outcomes were obtained after MPFL reconstruction in most of the patients. However, patients who only have mild pain pre-operatively tend to have worse subjective outcomes, and a caution may be needed when performing MPFL reconstruction on these patients. PMID- 28357493 TI - Intra-operative multi-dimensional fluoroscopy of guidepin placement prior to iliosacral screw fixation for posterior pelvic ring injuries and sacroiliac dislocation: an early case series. AB - PURPOSE: Traditional fluoroscopic techniques during percutaneous fixation of the posterior pelvic ring at times cannot adequately visualize errant or malpositioned iliosacral screws. Intra-operative fluoroscopic techniques have been advanced using multi-dimensional fluoroscopy to generate computed tomography like images. This provides the surgeon not only the ability to assess iliosacral screw placement, but also the opportunity to assess reduction. We present a case series of four patients in which the Ziehm RFD multi-dimensional fluoroscopy was used to assess reduction and guidepin placement prior to definitive iliosacral screw fixation. METHODS: Four patients at our university level 1 trauma center with posterior pelvic ring disruptions were treated with percutaneous iliosacral screw fixation. Traditional fluoroscopic techniques were used during guidepin placement. Multi-dimensional fluoroscopy was performed using the Ziehm RFD 3D to assess guidepin placement and reduction prior to definitive iliosacral screw fixation. RESULTS: Our case series highlights two patients in which multi dimensional fluoroscopy was utilized to ensure safe placement of iliosacral screws. In one of these two patients, a change was made after reviewing the imaging as a guidepin was found to be intruded into bilateral S2 neural tunnels. We also present two patient examples in which multidimensional fluoroscopy was used to assess reduction achieved by less invasive methods, precluding the need for direct visualization using more extensive open approaches. CONCLUSIONS: This retrospective case series demonstrates the direct impact that the Ziehm RFD 3D technology provides in surgical management of patients with complex posterior pelvic ring injuries. PMID- 28357494 TI - Recurrent chordoma with orbital and eyelid invasion. PMID- 28357495 TI - Signal intensity change on unenhanced T1-weighted images in dentate nucleus and globus pallidus after multiple administrations of gadoxetate disodium: an intraindividual comparative study. AB - PURPOSE: To investigate whether there is an increased signal intensity (SI) of dentate nucleus (DN) and globus pallidus (GP) on unenhanced T1-weighted magnetic resonance imaging (MRI), in patients who had undergone multiple administrations of gadoxetate disodium. MATERIALS AND METHODS: We retrospectevely included stage III melanoma patients, who had been previously enrolled in a trial of adjuvant therapy and who had undergone whole-body contrast-enhanced MRIs with gadoxetate disodium every three months for their follow-up. The SI ratios of DN-to-pons and GP-to-thalamus on unenhanced T1-weighted images were calculated. The difference in SI ratios between the first and the last MRI examinations was assessed and a linear mixed model was performed to detect how SI ratios varied with the number of administrations. RESULTS: Eighteen patients were included in our study. The number of gadoxetate disodium administrations ranged from 2 to 18. Paired t-test did not show any significant difference in DN-to-pons (p=0.21) and GP-to-thalamus (p=0.09) SI ratios by the end of the study. DN-to-pons SI ratio and GP-to thalamus SI ratio did not significantly increase with increasing the number of administrations (p=0.14 and p=0.06, respectively). CONCLUSION: Multiple administrations of gadoxetate disodium are not associated with increased SI in DN and GP in the brain. KEY POINTS: * Gadolinium may deposit in the human brain after multiple GBCA administrations. * Gadolinium deposition is associated with increased T1W signal intensity * Increase in signal intensity is most apparent within the DN and GP * Multiple administrations of gadoxetate disodium do not increase T1W signal. PMID- 28357496 TI - Diagnostic performance of a CT-based scoring system for diagnosis of anastomotic leakage after esophagectomy: comparison with subjective CT assessment. AB - OBJECTIVE: To develop a CT-based prediction score for anastomotic leakage after esophagectomy and compare it to subjective CT interpretation. METHODS: Consecutive patients who underwent a CT scan for a clinical suspicion of anastomotic leakage after esophagectomy with cervical anastomosis between 2003 and 2014 were analyzed. The CT scans were systematically re-evaluated by two radiologists for the presence of specific CT findings and presence of an anastomotic leak. Also, the original CT interpretations were acquired. These results were compared to patients with and without a clinical confirmed leak. RESULTS: Out of 122 patients that underwent CT for a clinical suspicion of anastomotic leakage; 54 had a confirmed leak. In multivariable analysis, anastomotic leakage was associated with mediastinal fluid (OR = 3.4), esophagogastric wall discontinuity (OR = 4.9), mediastinal air (OR = 6.6), and a fistula (OR = 7.2). Based on these criteria, a prediction score was developed resulting in an area-under-the-curve (AUC) of 0.86, sensitivity of 80%, and specificity of 84%. The original interpretation and the systematic subjective CT assessment by two radiologists resulted in AUCs of 0.68 and 0.75 with sensitivities of 52% and 69%, and specificities of 84% and 82%, respectively. CONCLUSION: This CT-based score may provide improved diagnostic performance for diagnosis of anastomotic leakage after esophagectomy. KEY POINTS: * A CT-based score provides improved diagnostic performance for diagnosis of anastomotic leakage. * Leakage associations include mediastinal fluid, mediastinal air, wall discontinuity, and fistula. * A scoring system yields superior diagnostic accuracy compared to subjective CT assessment. * Radiologists may suggest presence of anastomotic leakage based on a prediction score. PMID- 28357497 TI - Reducing Operating Room Turnover Time for Robotic Surgery Using a Motor Racing Pit Stop Model. AB - BACKGROUND: Operating room (OR) turnover time, time taken between one patient leaving the OR and the next entering, is an important determinant of OR utilization, a key value metric for hospital administrators. Surgical robots have increased the complexity and number of tasks required during an OR turnover, resulting in highly variable OR turnover times. We sought to streamline the turnover process and decrease robotic OR turnover times and increase efficiency. METHODS: Direct observation of 45 pre-intervention robotic OR turnovers was performed. Following a previously successful model for handoffs, we employed concepts from motor racing pit stops, including briefings, leadership, role definition, task allocation and task sequencing. Turnover task cards for staff were developed, and card assignments were distributed for each turnover. Forty one cases were observed post-intervention. RESULTS: Average total OR turnover time was 99.2 min (95% CI 88.0-110.3) pre-intervention and 53.2 min (95% CI 48.0 58.5) at 3 months post-intervention. Average room ready time from when the patient exited the OR until the surgical technician was ready to receive the next patient was 42.2 min (95% CI 36.7-47.7) before the intervention, which reduced to 27.2 min at 3 months (95% CI 24.7-29.7) post-intervention (p < 0.0001). CONCLUSIONS: Role definition, task allocation and sequencing, combined with a visual cue for ease-of-use, create efficient, and sustainable approaches to decreasing robotic OR turnover times. Broader system changes are needed to capitalize on that result. Pit stop and other high-risk industry models may inform approaches to the management of tasks and teams. PMID- 28357498 TI - Computer-aided analysis for optimal screw insertion in lateral mass of C1: An anatomical study. AB - INTRODUCTION: Motion preserving techniques in C1 ring fractures are increasingly used especially in young patients. Therefore, lateral mass screws are inserted in the first vertebra and connected by a rod. The purpose of this study was to determine safe zones regarding the vertebral arteries and the medulla oblongata for optimal lateral mass screw positioning when fusing the C1-ring. MATERIALS AND METHODS: Images of the cervical spine of 50 patients (64-line CT scanner) were evaluated and virtual screws were positioned in both lateral masses of the first vertebra using 3D-reconstructions of CT scans. The length of the screws, the insertion angles in two planes, the distance to the vertebral artery, and the spinal canal was investigated. Descriptive statistics was used and gender dependent differences were calculated using student t-test. A diameter of 4 mm was chosen for the screws. RESULTS: The mean screw length was 30.0 +/- 2.3 mm on the right and 30.1 +/- 2.1 mm on the left side. The arithmetic mean for the transverse angle was 16.4 +/- 5.6 degrees on the right and 15.6 +/- 6.3 degrees on the left, the sagittal angle averaged 8.3 +/- 3.8 degrees on the right, and 11.0 +/- 4.9 degrees on the left side. The mean distance between screw and spinal canal has been determined on the right with 2.4 +/- 0.7 mm and 2.2 +/- 0.6 mm on the left side. The distance from the C1 lateral mass screw to the vertebral artery was on average 7.1 +/- 1.5 mm on the right side (significant correlation with gender, p value: 0.03) and 7.4 +/- 1.4 mm on the left side. CONCLUSIONS: Screws should be positioned with a slightly converging angle of 16 degrees and a slightly ascending angle of 10 degrees . Due to the required high precision technique intraoperatively multiplanar 2 D or 3 D imaging is recommended to avoid harm to the vertebral artery or the spinal canal. PMID- 28357499 TI - Mrc1/Claspin: a new role for regulation of origin firing. AB - Mrc1 and its vertebrate homologue Claspin serve as a mediator for replication stress checkpoint signaling, receiving the signal from Mec1/Rad3/ATR sensor kinase and transmitting it to the effector Rad53/Cds1/Chk1 kinase. They are likely to be a part of the replisome and facilitate the S-phase progression by promoting replication fork progression. Recent reports on Mrc1/Claspin indicate their new role in regulating the replication initiation through interaction with Cdc7, a key conserved serine-threonine kinase that triggers firing at each replication origin. Mrc1/Claspin has a specific domain that specifically interacts with Cdc7, and this domain is involved also in intramolecular interaction with its N-terminal segment. Mechanisms for novel regulation of origin firing and its timing through recruitment of Cdc7 to Mrc1/Claspin will be discussed. PMID- 28357500 TI - Diversion colitis 25 years later: the phenomenon of the disease. AB - BACKGROUND: Diversion colitis (DC) seems to be common in stoma patients, and the restoration of the continuity of the digestive tract is crucial for relief from the inflammatory process. No prospective studies of the late effects of DC on the lower gastrointestinal (GI) tract mucosa and the clinical condition of patients have been reported. METHODS: Data from 23 patients who underwent stoma creation were analysed during the reversal period (A) and at an average of 3 months (B1) and 5.6 years (B2) after restoration of GI tract continuity. Every monitoring visit included endoscopy, histology and assessment of the clinical condition of patients. RESULTS: Shortly after GI tract restoration (B1), a significant decrease in inflammation was observed. The Ki67 positivity percentage increased, but this was not significant. At an average of 5.6 years after restoration (group B2), the clinical symptoms were mild. More patients presented with endoscopically detected inflammation of the mucosa, but its severity was not significantly higher than that at 3 months after reversal. Histological inflammation was more common, and its severity was significantly higher than that shortly after reversal but similar to that before reversal. The Ki67 positivity percentage decreased at the last examination (B2). CONCLUSIONS: The results of this study show a complex recurrence of histological inflammation several years after GI tract restoration but without clinical and endoscopic inflammation and with good clinical condition. DC can potentially have a late influence on the rectal mucosa, even after stoma closure. PMID- 28357501 TI - Robot-assisted intersphincteric resection facilitates an efficient sphincter saving in patients with low rectal cancer. AB - PURPOSE: Few investigations of robot-assisted intersphincteric resection (ISR) are presently available to support this procedure as a safe and efficient procedure. We aimed to evaluate the utility of robot-assisted ISR by comparison between ISR and abdominoperineal resection (APR) using both robot-assisted and open approaches. METHODS: The 558 patients with lower rectal cancer (LRC) who underwent curative operation was enrolled between July 2010 and June 2015 to perform either by robot-assisted (ISR vs. APR = 310 vs. 34) or open approaches (144 vs. 70). Perioperative and functional outcomes including urogenital and anorectal dysfunctions were measured. Recurrence and survival were examined in 216 patients in which >3 years had elapsed after the operation. RESULTS: The robot-assisted approach was the most significant parameter to determine ISR achievement among potent parameters (OR = 3.467, 95% CI = 2.095-5.738, p < 0.001). Early surgical complications occurred more frequently in the open ISR group (16 vs. 7.7%, p = 0.01). The voiding and male sexual dysfunctions were significantly more frequent in the open ISR (p < 0.05). The fecal incontinence and lifestyle alteration score was greater in the open ISR than in the robot assisted ISR at 12 and 24 months, respectively (p < 0.05). However, the 3-year cumulative rates of local recurrence and survival did not differ between the two groups. CONCLUSIONS: The current procedure of robot-assisted ISR replaced a significant portion of APR to achieve successful SSO via mostly transabdominal approach and double-stapled anastomosis. The robot-assisted ISR with minimal invasiveness might be a help to reduce anorectal and urogenital dysfunctions. PMID- 28357502 TI - Evidence for two distinct phenotypes of chronic kidney disease in individuals with type 1 diabetes mellitus. AB - AIMS/HYPOTHESIS: In a retrospective, observational, cross-sectional, single centre study, we assessed the prevalence and correlates of different CKD phenotypes (with and without albuminuria) in a large cohort of patients of white ethnicity with type 1 diabetes. METHODS: From 2001 to 2009, 408 men and 369 women with type 1 diabetes (age 40.2 +/- 11.7 years, diabetes duration 19.4 +/- 12.2 years, HbA1c 7.83 +/- 1.17% [62.0 +/- 12.9 mmol/mol]) were recruited consecutively. Albumin-to-creatinine ratio (ACR) and eGFR (Modification of Diet in Renal Disease) were obtained for all individuals, together with CKD stage. Diabetic retinopathy and peripheral polyneuropathy were detected in 41.5% and 8.1%, respectively, and cardiovascular disease (CVD) occurred in 8.5%. Adjudications of CKD phenotype were made by blinded investigators. RESULTS: Normo (ACR <3.4), micro- (ACR 3.4-34) or macroalbuminuria (ACR >=34 mg/mmol) were present in 91.6%, 6.4% and 1.9% of individuals, respectively. eGFR categories 1 (>=90 ml min-1 [1.73 m]-2), 2 (60-89 ml min-1 [1.73 m]-2) and 3 (<60 ml min-1 [1.73 m]-2) were present in 57.3%, 39.0% and 3.7%, respectively. The majority of participants had no CKD (89.4%), while stages 1-2 and >=3 CKD were detected in 6.8% and 3.7%, respectively. The albuminuric (Alb+) and non-albuminuric (Alb-) phenotypes were present in 12 (41.4%) and 17 (58.6%) individuals with stage >=3 CKD, respectively. Individuals with an ACR <3.4 mg/mmol were subdivided into those with normal albuminuria (<1.1 mg/mmol; 77.2%) and mildly increased albuminuria (1.1-3.4 mg/mmol; 14.4%), and individuals with stage 2 CKD were subdivided into those with eGFR 75-89 ml min-1 [1.73 m]-2 and 60-74 ml min-1 [1.73 m]-2. ACR <3.4 mg/mmol (88.7%) and even <1.1 mg/mmol (70.4%) were common in individuals with eGFR 60-74 ml min-1 [1.73 m]-2. The prevalence of ACR <1.1 mg/mmol was lower but still significant (34.5%) in those with stage >=3 CKD. In logistic regression analysis, stages 1-2 and >=3 CKD were independently associated with age, HbA1c, gamma-glutamyltransferase, fibrinogen, hypertension, but not with sex, BMI, smoking, HDL-cholesterol or triacylglycerol. Inclusion of advanced retinopathy removed HbA1c from the model. The CKD Alb+ phenotype correlated with diabetes duration, HbA1c, HDL-cholesterol, fibrinogen and hypertension, while the CKD Alb- phenotype was associated with age and hypertension, but not with diabetes duration, HbA1c and fibrinogen. CONCLUSIONS/INTERPRETATION: The Alb- CKD phenotype is present in a significant proportion of individuals with type 1 diabetes supporting the hypothesis of two distinct pathways (Alb+ and Alb-) of progression towards advanced kidney disease in type 1 diabetes. These are probably distinct pathways as suggested by different sets of covariates associated with the two CKD phenotypes. PMID- 28357503 TI - Small-fibre neuropathy in men with type 1 diabetes and erectile dysfunction: a cross-sectional study. AB - AIMS/HYPOTHESIS: The aim of this study was to identify the contribution of small- and large-fibre neuropathy to erectile dysfunction in men with type 1 diabetes mellitus. METHODS: A total of 70 participants (29 without and 41 with erectile dysfunction) with type 1 diabetes and 34 age-matched control participants underwent a comprehensive assessment of large- and small-fibre neuropathy. RESULTS: The prevalence of erectile dysfunction in participants with type 1 diabetes was 58.6%. After adjusting for age, participants with type 1 diabetes and erectile dysfunction had a significantly higher score on the Neuropathy Symptom Profile (mean +/- SEM 5.3 +/- 0.9 vs 1.8 +/- 1.2, p = 0.03), a higher vibration perception threshold (18.3 +/- 1.9 vs 10.7 +/- 2.4 V, p = 0.02), and a lower sural nerve amplitude (5.0 +/- 1.1 vs 11.7 +/- 1.5 mV, p = 0.002), peroneal nerve amplitude (2.1 +/- 0.4 vs 4.7 +/- 0.5 mV, p < 0.001) and peroneal nerve conduction velocity (34.8 +/- 1.5 vs 41.9 +/- 2.0 m/s, p = 0.01) compared with those without erectile dysfunction. There was also evidence of a marked small fibre neuropathy with an impaired cold threshold (19.7 +/- 1.4 degrees C vs 27.3 +/- 1.8 degrees C, p = 0.003), warm threshold (42.9 +/- 0.8 degrees C vs 39.0 +/- 0.9 degrees C, p = 0.005) and heart rate variability (21.5 +/- 3.1 vs 30.0 +/- 3.7 beats/min, p = 0.001) and reduced intraepidermal nerve fibre density (2.8 +/- 0.7 vs 5.9 +/- 0.7/mm, p = 0.008), corneal nerve fibre density (12.6 +/- 1.5 vs 23.9 +/- 2.0/mm2, p < 0.001), corneal nerve branch density (12.7 +/- 2.5 vs 31.6 +/- 3.3/mm2, p < 0.001) and corneal nerve fibre length (8.3 +/- 0.7 vs 14.5 +/- 1.0 mm/mm2, p < 0.001) in participants with type 1 diabetes and erectile dysfunction. Erectile dysfunction correlated significantly with measures of both large- and small-fibre neuropathy. CONCLUSIONS/INTERPRETATION: Small-fibre neuropathy is prominent in patients with type 1 diabetes, and is associated with erectile dysfunction and can be objectively quantified using corneal confocal microscopy. This may allow the identification of patients who are less likely to respond to conventional therapies such as phosphodiesterase type 5 inhibitors. PMID- 28357504 TI - Effect of simultaneous vaccination with H1N1 and GAD-alum on GAD65-induced immune response. AB - AIMS/HYPOTHESIS: A European Phase III trial of GAD formulated with aluminium hydroxide (GAD-alum) failed to reach its primary endpoint (preservation of stimulated C-peptide secretion from baseline to 15 months in type 1 diabetes patients), but subgroup analysis showed a clinical effect when participants from Nordic countries were excluded, raising concern as to whether the mass vaccination of the Swedish and Finnish populations with the Pandemrix influenza vaccine could have influenced the study outcomes. In the current study, we aimed to assess whether Pandemrix vaccination affects the specific immune responses induced by GAD-alum and the C-peptide response. METHODS: In this secondary analysis, we analysed data acquired from the Swedish participants in the Phase III GAD-alum trial who received subcutaneous GAD-alum vaccination (two doses, n = 43; four doses, n = 46) or placebo (n = 48). GAD autoantibodies (GADA) and H1N1 autoantibodies, GAD65-induced cytokine secretion and change in fasting and stimulated C-peptide levels from baseline to 15 months were analysed with respect to the relative time between H1N1 vaccination and the first injection of GAD alum. RESULTS: GADA levels at 15 months were associated with the relative time between GAD-alum and Pandemrix administration in participants who received two doses of the GAD-alum vaccine (p = 0.015, r = 0.4). Both in participants treated with two doses and four doses of GAD-alum, GADA levels were higher when the relative time between vaccines was >=210 days (p < 0.05). In the group that received two doses of GAD-alum, levels of several GAD65-induced cytokines were higher in participants who received the H1N1 vaccination and the first GAD-alum injection at least 150 days apart, and the change in fasting and stimulated C peptide at 15 months was associated with the relative time between vaccines. Neither of these effects were observed in individuals who received four doses of GAD-alum. CONCLUSIONS/INTERPRETATION: In individuals who received two doses of GAD-alum, receiving the Pandemrix vaccine closer to the first GAD-alum injection, i.e. <150 days, seemed to affect both GAD65-induced immune response and C-peptide preservation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00723411. PMID- 28357505 TI - Identification of Left Ventricle Failure on Pulmonary Artery CTA: Diagnostic Significance of Decreased Aortic & Left Ventricle Enhancement. AB - PURPOSE: This study aimed to identify findings on non-ECG-gated CT pulmonary angiography (CTPA) indicating decreased left ventricle (LV) systolic function, later confirmed by echocardiogram. METHODS: After obtaining institutional review board approval, review was performed of emergency department (ED) patients who had CTPA and follow-up echocardiogram within 48 h, over 18 months. Patients with pulmonary embolus, suboptimal CTPA, arrhythmias or pericardial tamponade were excluded. One hundred thirty-seven patients were identified and divided into cases (LVEF <40%, n = 52) and controls (LVEF >50%, n = 85). Two reviewers performed these analyses: measurement of enhancement in main pulmonary artery (MPA), LV, and aorta; subjective enhancement of LV and aorta (Ao) relative to MPA using a four-point Likert scale; contrast transit time (TD) to trigger CTPA and LV short & long axis dimensions. When available, the most recent N-terminal pro-B type natriuretic peptide (NT-proBNP) level was recorded. RESULTS: Decreased aortic and LV subjective enhancement were the best predictors of LV systolic dysfunction. For Ao/MPA ratio, an optimal cutoff value of 0.20 resulted in a sensitivity of 0.54 and specificity of 0.93 (AUC = 0.83, 0.78-0.88 95% CI). A threshold of 86.7 HU for Ao enhancement resulted in a sensitivity of 0.68 and specificity of 0.90 (AUC = 0.82, 0.77-0.88 95% CI). A LV short axis diameter of more than 54.3 mm had a sensitivity of 0.62 and specificity of 0.98 (AUC = 0.88, 0.83-0.92 95% CI). For the LV long axis diameter, a cutoff of 87.5 mm resulted in a sensitivity of 0.66 and specificity of 0.84 (AUC = 0.78, 0.72-0.84 95% CI). With bolus timing, cases had a longer TD (13.4 vs. 10.4 s, p < 0.0001). CONCLUSION: Unsuspected LV systolic dysfunction can be recognized on a CTPA by identification of decreased aortic enhancement, LV enlargement and increased TD. This has important diagnostic implications for the patient presenting with shortness of breath, chest pain, or dyspnea. PMID- 28357507 TI - Examination of climatological wind patterns and simulated pollen dispersion in a complex island environment. AB - Complex terrain creates small-scale circulations which affect pollen dispersion but may be missed by meteorological observing networks and coarse-grid meteorological models. On volcanic islands, these circulations result from differing rates of surface heating between land and sea as well as rugged terrain. We simulated the transport of bentgrass, ryegrass, and maize pollen from 30 sources within the agricultural regions of the Hawaiian island Kaua'i during climatological conditions spanning season conditions and the La Nina, El Nino, and neutral phases of the El Nino-Southern Oscillation. Both pollen size and source location had major effects on predicted dispersion over and near the island. Three patterns of pollen dispersion were identified in response to prevailing wind conditions: southwest winds transported pollen inland, funneling pollen grains through valleys; east winds transported pollen over the ocean, with dispersive tails for the smallest pollen grains following the mean wind and extending as far as the island of Ni'ihau 35 km away; and northeast winds moved pollen inland counter to the prevailing flow due to a sea breeze circulation that formed over the source region. These results are the first to predict the interactions between complex island terrain and local climatology on grass pollen dispersion. They demonstrate how numerical modeling can provide guidance for field trials by illustrating the common flow regimes present in complex terrain, allowing field trials to focus on areas where successful sampling is more likely to occur. PMID- 28357508 TI - Influence of geomagnetic activity and atmospheric pressure in hypertensive adults. AB - We performed a study of the systolic and diastolic arterial blood pressure behavior under natural variables such as the atmospheric pressure and the horizontal geomagnetic field component. We worked with a group of eight adult hypertensive volunteers, four men and four women, with ages between 18 and 27 years in Mexico City during a geomagnetic storm in 2014. The data was divided by gender, age, and day/night cycle. We studied the time series using three methods: correlations, bivariate analysis, and superposed epoch (within a window of 2 days around the day of occurrence of a geomagnetic storm) analysis, between the systolic and diastolic blood pressure and the natural variables. The correlation analysis indicated a correlation between the systolic and diastolic blood pressure and the atmospheric pressure and the horizontal geomagnetic field component, being the largest during the night. Furthermore, the correlation and bivariate analyses showed that the largest correlations are between the systolic and diastolic blood pressure and the horizontal geomagnetic field component. Finally, the superposed epoch analysis showed that the largest number of significant changes in the blood pressure under the influence of geomagnetic field occurred in the systolic blood pressure for men. PMID- 28357506 TI - The long-term outcomes of hepatitis C virus core antigen-positive Japanese renal allograft recipients. AB - BACKGROUND: The impact of hepatitis C virus (HCV) infections on patient long-term survival after renal transplants is unclear. METHOD: To clarify the long-term outcomes of Japanese renal allograft recipients with HCV infections, we studied the cases of 187 patients (118 males and 69 females; 155 living donor cases, and 32 deceased donor cases; median follow-up period: 250 months) who underwent an initial renal transplant at Kanazawa Medical University from 1974 onwards. RESULT: In this cohort, 35 patients (18.7%) were HCV core antigen (Ag)-positive, and 13 of them (37.1%) died (due to liver cirrhosis (4 cases), hepatocellular carcinoma (1 case), fibrosing cholestatic hepatitis due to HCV (1 case), and infections complicated with chronic hepatitis (6 cases)). However, only 14 of the 145 (9.7%) recipients died in the HCV-Ag/HCV antibody (Ab)-negative group. The Kaplan-Meier life table method indicated that the HCV-infected group exhibited significantly lower patient and death-censored allograft survival rates (log-rank test; patient survival: Chi-square: 11.2, p = 0.004; graft survival: Chi-square: 25.7, p < 0.001). The survival rate of the HCV-Ag-positive recipients decreased rapidly at 240 months after the renal transplant procedure. In addition, a Cox proportional hazards model indicated that positivity for the HCV-Ag was the most important independent risk factor for post-renal transplant survival and allograft function [survival: hazard ratio (HR) 3.93 (1.54-10.03), p = 0.004; graft function: HR 2.09 (1.14-3.81), p = 0.016]. CONCLUSION: HCV infection is a harmful risk factor for patient survival (especially at >=20 years post-renal transplant) and renal allograft function in allograft recipients. PMID- 28357510 TI - Tracking unnecessary negative urinalyses to reduce healthcare costs: a transversal study. AB - About 7 million urinalyses are reimbursed yearly by the French public healthcare system, but the results of most of these tests are normal. The aim of this study was to estimate the prevalence of negative urinalyses in ambulatory care, identify the associated factors and assess the relevance of prescriptions by general practitioners (GPs) according to French guidelines. A cross-sectional study was conducted in patients over 18 coming for urinalyses in two French ambulatory laboratories. Patients received a questionnaire on their symptoms, the reason for performing urinalysis and the use of urinary dipsticks. GP who prescribed urinalyses received a questionnaire assessing their practice. A total of 510 patients were included, and 71% of urinalyses were negative. Urinalyses were prescribed to 283 patients by GPs. Compared to those of specialists, GP prescriptions were associated with fewer negative urinalyses (59 vs 86%; p < 0.01). Among the negative urinalyses prescribed by GPs, the reasons of prescription were as follows: suspected urinary tract infection (UTI) (42.7%), control of bacteriological cure after UTI (24%), fever or abdominal pain (13%) and routine test (7%). About 35% of urinalyses were not indicated according to guidelines. Only 12% of patients used dipsticks before performing urinalysis although 87% of GPs were favourable to their use if they were provided by healthcare services. The annual cost of non-indicated urinalyses is estimated at 13 million euro. A systematic use of dipsticks provided by healthcare services could help to reduce health costs and the unnecessary use of antibiotics. PMID- 28357509 TI - Downregulation of lizard immuno-genes in the regenerating tail and myogenes in the scarring limb suggests that tail regeneration occurs in an immuno-privileged organ. AB - Amputated tails of lizards regenerate while limbs form scars which histological structure is very different from the original organs. Lizards provide useful information for regenerative medicine and some hypotheses on the loss of regeneration in terrestrial vertebrates. Analysis of tail and limb transcriptomes shows strong downregulation in the tail blastema for immunoglobulins and surface B and T receptors, cell function, and metabolism. In contrast, in the limb blastema genes for myogenesis, muscle and cell function, and extracellular matrix deposition but not immunity are variably downregulated. The upregulated genes show that the regenerating tail is an embryonic organ driven by the Wnt pathway and non-coding RNAs. The strong inflammation following amputation, the non activation of the Wnt pathway, and the upregulation of inflammatory genes with no downregulation of immune genes indicate that the amputated limb does not activate an embryonic program. Intense inflammation in limbs influences in particular the activity of genes coding for muscle proteins, cell functions, and stimulates the deposition of dense extracellular matrix proteins resulting in scarring limb outgrowths devoid of muscles. The present study complements that on upregulated genes, and indicates that the regenerating tail requires immune suppression to maintain this embryonic organ connected to the rest of the tail without be rejected or turned into a scar. It is hypothesized that the evolution of the adaptive immune system determined scarring instead of organ regeneration in terrestrial vertebrates and that lizards evolved the process of tail regeneration through a mechanism of immuno-evasion. PMID- 28357511 TI - Structural basis of Zika virus methyltransferase inhibition by sinefungin. AB - Zika virus is considered a major global threat to human kind. Here, we present a crystal structure of one of its essential enzymes, the methyltransferase, with the inhibitor sinefungin. This structure, together with previously solved structures with bound substrates, will provide the information needed for rational inhibitor design. Based on the structural data we suggest the modification of the adenine moiety of sinefungin to increase selectivity and to covalently link it to a GTP analogue, to increase the affinity of the synthesized compounds. PMID- 28357512 TI - Characterization and genome comparisons of three Achromobacter phages of the family Siphoviridae. AB - In this study, we present the characterization and genomic data of three Achromobacter phages belonging to the family Siphoviridae. Phages 83-24, JWX and JWF were isolated from sewage samples in Paris and Braunschweig, respectively, and infect Achromobacter xylosoxidans, an emerging nosocomial pathogen in cystic fibrosis patients. Analysis of morphology and growth parameters revealed that phages 83-24 and JWX have similar properties, both have nearly the same head and tail measurements, and both have a burst size between 85 and 100 pfu/cell. In regard to morphological properties, JWF had a much longer and more flexible tail compared to other phages. The linear double-stranded DNAs of all three phages are terminally redundant and not circularly permutated. The complete nucleotide sequences consist of 81,541 bp for JWF, 49,714 bp for JWX and 48,216 bp for 83 24. Analysis of the genome sequences showed again that phages JWX and 83-24 are quite similar. Comparison to the GenBank database via BLASTN revealed partial similarities to Roseobacter phage RDJL phi1 and Burkholderia phage BcepGomr. In contrast, BLASTN analysis of the genome sequence of phage JWF revealed only few similarities to non-annotated prophage regions in different strains of Burkholderia and Mesorhizobium. PMID- 28357513 TI - Not later, but longer: sleep, chronotype and light exposure in adolescents with remitted depression compared to healthy controls. AB - The relationship between sleep and adolescent depression is much discussed, but still not fully understood. One important sleep variable is self-selected sleep timing, which is also referred to as chronotype. Chronotype is mostly regulated by the circadian clock that synchronises the internal time of the body with the external light dark cycle. A late chronotype as well as a misalignment between internal time and external time such as social jetlag has been shown to be associated with depressive symptoms in adults. In this study, we investigated whether adolescents with remitted depression differ from healthy controls in terms of chronotype, social jetlag and other sleep-related variables. For this purpose, we assessed chronotype and social jetlag with the Munich ChronoType Questionnaire (MCTQ), subjective sleep quality with the Pittsburgh Sleep Quality Index (PSQI) and used continuous wrist-actimetry over 31 consecutive days to determine objective sleep timing. Given the potentially mediating effect of light on chronotype and depressive symptoms, we measured light exposure with a light sensor on the actimeter. In our sample, adolescents with remitted depression showed similar chronotypes and similar amounts of social jetlag compared to controls. However, patients with remitted depression slept significantly longer on work-free days and reported a worse subjective sleep quality than controls. Additionally, light exposure in remitted patients was significantly higher, but this finding was mediated by living in a rural environment. These findings indicate that chronotype might be modified during remission, which should be further investigated in longitudinal studies. PMID- 28357514 TI - Angiographic study of the clinical liaison of drug-eluting stent and paclitaxel eluting balloon in unifocal side branch ostium stenosis (ASCLEPIUS). AB - A reliable stenting strategy for treating isolated side branch (SB) ostium stenosis is not well established. The purpose of this study was to examine the 6 month angiographic outcome of a novel technique, called the shoulder technique, on this lesion subtype. Symptomatic patients with isolated SB ostium stenosis, defined as >=75% diameter stenosis at SB ostium and <50% diameter stenosis in main vessel (MV), were treated with paclitaxel-eluting balloon in MV and drug eluting stent in SB using the shoulder technique. Angiographic restudy was performed at 5-9 months and clinical follow-up was scheduled regularly every 3 months. There were 46 patients of age 66 +/- 12 years with male predominance (76%) recruited. Diagonal ostium (67%) was the most frequent target lesion site. The size and length of paclitaxel-eluting balloon and drug-eluting stent used in MV and SB were 3.01 +/- 0.25 and 20 +/- 4 mm, and 2.39 +/- 0.25 and 17 +/- 6 mm, respectively. Angiographic restudy was performed on 43 (93.5%) patients at 6.5 +/ 1.6 months. The late loss in MV and SB were 0.04 +/- 0.19 and 0.19 +/- 0.32 mm, respectively. Angiographic restensosis was seen in 2 (4.7%) patients at SB, whereas no stenosis was induced in MV. Improvement of symptom was reported in 36 (78%) patients. At 1-year follow-up, no death, myocardial infarction, and stent thrombosis was observed; target vessel revascularization was performed on 3 (6.5%) patients. Treatment of isolated SB ostium stenosis using the shoulder technique is associated with a favorable short-term angiographic outcome. PMID- 28357516 TI - [Transcutaneous osseointegration (part 1)]. PMID- 28357517 TI - ? PMID- 28357515 TI - Clinical features and predictors of patients with critical limb ischemia who responded to autologous mononuclear cell transplantation for therapeutic angiogenesis. AB - The clinical features of patients with critical limb ischemia (CLI) who responded to angiogenesis using autologous peripheral blood mononuclear cell transplantation (PB-MNC) have not yet been fully characterized, and there are no useful predictors to judge the curative effect in the early period after PB-MNC. This study sought to clarify the clinical features and predictors in patients with CLI who were successfully treated using PB-MNC. 30 consecutive patients [arteriosclerosis obliterans: 24 patients, thromboangiitis obliterans: 6 patients] who were diagnosed with major amputation despite maximal medical therapy were enrolled in this study. The study endpoint was major amputation within 3 months after PB-MNC. The collected data were evaluated for correlation between patients with and without major amputation within 3 months after PB-MNC. Six patients underwent major amputation and 1 patient underwent minor amputation. In the patients with major amputation, transcutaneous oxygen tension before PB MNC and transplanted CD34-positive cells were lower than those of patients without major amputation. In the patients with amputation, interleukin-6 (IL-6) continued to increase after the first PB-MNC, and basic fibroblast growth factor (bFGF) decreased within 3 days after the first PB-MNC. PB-MNC was useful for the patients who were managed for inflammation and who had revascularization of the upper-popliteal arteries and two of the infra-popliteal arteries by endovascular and/or surgical revascularization. Variation in IL-6 and bFGF in the early period after PB-MNC could be useful predictors for the requirement of amputation within 3 months after PB-MNC. PMID- 28357518 TI - Longitudinal relaxation optimized amide 1H-CEST experiments for studying slow chemical exchange processes in fully protonated proteins. AB - Chemical Exchange Saturation Transfer (CEST) experiments are increasingly used to study slow timescale exchange processes in biomolecules. Although 15N- and 13C CEST have been the approaches of choice, the development of spin state selective 1H-CEST pulse sequences that separate the effects of chemical and dipolar exchange [T. Yuwen, A. Sekhar and L. E. Kay, Angew Chem Int Ed Engl 2016 doi: 10.1002/anie.201610759 (Yuwen et al. 2017)] significantly increases the utility of 1H-based experiments. Pulse schemes have been described previously for studies of highly deuterated proteins. We present here longitudinal-relaxation optimized amide 1H-CEST experiments for probing chemical exchange in protonated proteins. Applications involving a pair of proteins are presented establishing that accurate 1H chemical shifts of sparsely populated conformers can be obtained from simple analyses of 1H-CEST profiles. A discussion of the inherent differences between 15N-/13C- and 1H-CEST experiments is presented, leading to an optimal strategy for recording 1H-CEST experiments. PMID- 28357520 TI - Herbal medicinal products and phytotherapy-a thematic issue. PMID- 28357521 TI - Contact dermatitis: a historical perspective. AB - Contact dermatitis is a common skin condition that can have a considerable impact on patient quality of life and function. Historically, contact dermatitis has played a significant role in the evolution of dermatology as the understanding of a relationship between environmental exposure and specific skin disease became more widely accepted. Reports about this relationship can be found throughout the history of humanity, thousands of years ago. The Egyptians were perhaps the first to document this relationship in ancient history, and documentation has also been found in several other cultures and nations such as the Chinese, Indians, Europeans, and American colonizers. The patch test emerged over a century ago and has remained a powerful tool for diagnosing and directing patients. This paper provides historical and curious facts about contact dermatitis. PMID- 28357519 TI - Low Working Memory rather than ADHD Symptoms Predicts Poor Academic Achievement in School-Aged Children. AB - This study examined whether working memory (WM), inattentive symptoms, and/or hyperactive/impulsive symptoms significantly contributed to academic, behavioral, and global functioning in 8-year-old children. One-hundred-sixty 8-year-old children (75.6% male), who were originally recruited as preschoolers, completed subtests from the Wechsler Intelligence Scale for Children-Fourth Edition, Integrated and Wechsler Individual Achievement Test-Second Edition to assess WM and academic achievement, respectively. Teachers rated children's academic and behavioral functioning using the Vanderbilt Rating Scale. Global functioning, as rated by clinicians, was assessed by the Children's Global Assessment Scale. Multiple linear regressions were completed to determine the extent to which WM (auditory-verbal and visual-spatial) and/or inattentive and hyperactive/impulsive symptom severity significantly contributed to academic, behavioral, and/or global functioning. Both auditory-verbal and visual-spatial WM but not ADHD symptom severity, significantly and independently contributed to measures of academic achievement (all p < 0.01). In contrast, both WM and inattention symptoms (p < 0.01), but not hyperactivity-impulsivity (p > 0.05) significantly contributed to teacher-ratings of academic functioning. Further, inattention and hyperactivity/impulsivity (p < 0.04), but not WM (p > 0.10) were significantly associated with teacher-ratings of behavioral functioning and clinician-ratings of global functioning. Taken together, it appears that WM in children may be uniquely related to academic skills, but not necessarily to overall behavioral functioning. PMID- 28357522 TI - More frequent requests for day-case cataract surgery : An impressive mind switch in the Austrian population within 7 years. AB - BACKGROUND: Cataract surgery is the most commonly performed elective surgical procedure worldwide. While the operation has been mainly conducted as day-case (outpatient) surgery throughout the world since the beginning of this millennium, this development has been much slower in Austria. The number of patients requesting day-case surgery has markedly increased in the last few years. METHODS: Prior to the introduction of a day clinic at our department in 2007, we evaluated the patients' acceptance of day-case surgery using a questionnaire. At the time, less than half of the patients wished to undergo day-case surgery. Another survey was performed 7 years later to determine if there were any changes. RESULTS: The desire for day-case surgery increased significantly from 38.8 to 87.1%. The mean age of the patients and their visual impairment had decreased. Home care improved, but not to the same extent. The number of patients who had to travel more than an hour to reach the hospital had significantly increased. CONCLUSIONS: Improvements in perioperative limitations and most of all patients becoming accustomed to the idea have led to an impressive mind switch, culminating in a clear desire for day-case cataract surgery. PMID- 28357524 TI - Molecular connections of obesity and aging: a focus on adipose protein 53 and retinoblastoma protein. AB - Obesity is an induced health problem that human beings have been facing with non optimal treatment so far. Humans are on average getting fatter with age, and obesity and aging interact each other to shorten lifetime and decrease life quality. Obesity also causes several aging related-disorders such as cancer, strokes, cardiovascular disease, high blood pressure and type 2 diabetes. So, the molecular connections between aging and obesity are promising targets for bio medical researches and innovative therapies of many health problems. In this review, we discuss the findings of adipose p53 and Rb-two central molecular linkages between aging and obesity-on lipid metabolism and obesity. PMID- 28357523 TI - Early nutrition and ageing: can we intervene? AB - Ageing, a complex process that results in progressive decline in intrinsic physiological function leading to an increase in mortality rate, has been shown to be affected by early life nutrition. Accumulating data from animal and epidemiological studies indicate that exposure to a suboptimal nutritional environment during fetal life can have long-term effects on adult health. In this paper, we discuss the impact of early life nutrition on the development of age associated diseases and life span. Special emphasis is given to studies that have investigated the molecular mechanisms underlying these effects. These include permanent structural and cellular changes including epigenetics modifications, oxidative stress, DNA damage and telomere shortening. Potential strategies targeting these mechanisms, in order to prevent or alleviate the detrimental effects of suboptimal early nutrition on lifespan and age-related diseases, are also discussed. Although recent reports have already identified effective therapeutic interventions, such as antioxidant supplementation, further understanding of the extent and nature of how early nutrition influences the ageing process will enable the development of novel and more effective approaches to improve health and extend human lifespan in the future. PMID- 28357525 TI - Sexual Trajectories of Lesbian, Gay, and Bisexual Adults in the Netherlands. AB - Studies on sexual trajectories of lesbian, gay, and bisexual (LGB) people generally focus on the first same-sex attraction and sexual experience, and their relation to self-identification and coming out as LGB. Relational and opposite sex experiences are generally not taken into account. The aim of this study was to provide a more comprehensive overview of LGBs' sexual trajectories and to distinguish subsamples with different trajectories. A sample of same-sex attracted members of an online research panel (N = 3054) completed a sexual health questionnaire, including items about the timing of sexual and relational milestones. Results showed that the majority of gay men and lesbian women had same-sex sexual and relational experiences, whereas most bisexual men and women had had experiences with the opposite sex. Among gay men and lesbian women, two trajectories emerged, differing mainly on whether people had been sexually or romantically involved with opposite-sex partners, and on age of first same-sex attraction. Among those who were not exclusively attracted to the same sex, six patterns emerged, which differed especially with regard to the nature and comprehensiveness of their same-sex experiences. Within the exclusively same-sex attracted group, the trajectory with no heterosexual experiences related to higher levels of psychological adjustment. For non-exclusive sexually attracted people, trajectories including experience of same-sex relationships seem to be most beneficial. In conclusion, both relational and opposite-sex experiences proved to be important elements of LGB men and women's sexual trajectories. PMID- 28357526 TI - Religion and Sexual Identity Fluidity in a National Three-Wave Panel of U.S. Adults. AB - Research has shown that cross-sectional estimates of sexual identities overlook fluidity in those identities. Research has also shown that social factors, such as competing identities, can influence sexual identity fluidity. We contributed to this literature in two ways. First, we utilized a representative panel of US adults (N = 1034) surveyed in 2010, 2012, and 2014 by the General Social Survey. The addition of a third observation allowed us to examine more complexity in sexual identity fluidity. We found that 2.40% of US adults reported at least one change in sexual identity across the 4 years, with 1.59% reporting one change and 0.81% reporting two changes. Our second contribution came from examining the role of religion, as past research has suggested that religion can destabilize and prolong sexual identity development. We found that lesbian or gay individuals (N = 17), bisexuals (N = 15), and females (N = 585) showed more sexual identity fluidity compared to heterosexuals (N = 1003) and males (N = 450), respectively. Marital status, age, race, and education did not have significant associations with sexual identity fluidity. Regarding the role of religion, we found that participants identifying as more religious in Wave 1 showed more fluidity in sexual identity across later observations. Further analysis showed that higher levels of religiosity make it more likely that lesbian or gay individuals will be fluid in sexual identity, but this is not the case for heterosexual individuals. This finding reinforces past qualitative research that has suggested that religion can extend or complicate sexual minorities' identity development. PMID- 28357527 TI - The impact of pre- and post-natal psycho-educational intervention on the construction of parenthood. AB - A pilot study was conducted to assess the merits and feasibility of a standardized postnatal psycho-educational interview on mothers' mental wellbeing, self-efficacy, and mother-child and couple relationships. A comparison of prenatal psycho-educational interview (n = 23) vs. pre- and post-natal psycho educational interviews (n = 26) was carried out. Parental self-efficacy and the mother-child relationship were significantly improved for the group who received a post-natal interview at 2 and 3 months postpartum in addition to a prenatal interview. Pre- and post-natal interviews improve the construction of parenthood. PMID- 28357528 TI - A prospective study of mitochondrial DNA copy number and the risk of prostate cancer. AB - PURPOSE: Evidence suggests that mitochondrial DNA (mtDNA) copy number increases in response to DNA damage. Increased mtDNA copy number has been observed in prostate cancer (PCa) cells, suggesting a role in PCa development, but this association has not yet been investigated prospectively. METHODS: We conducted a nested case-control study (793 cases and 790 controls) of men randomized to the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) to evaluate the association between pre-diagnosis mtDNA copy number, measured in peripheral blood leukocytes, and the risk of PCa. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) and polytomous logistic regression to analyze differences in associations by non aggressive (Stage I/II AND Gleason grade < 8) or aggressive (Stage III/IV OR Gleason grade >= 8) PCa. RESULTS: Although mtDNA copy number was not significantly associated with PCa risk overall (OR 1.23, 95% CI 0.97-1.55, p = 0.089), increasing mtDNA copy number was associated with an increased risk of non aggressive PCa (OR 1.29, 95% CI 1.01-1.65, p = 0.044) compared to controls. No association was observed with aggressive PCa (OR 1.02, 95% CI 0.64-1.63, p = 0.933). Higher mtDNA copy number was also associated with increased PSA levels among controls (p = 0.014). CONCLUSIONS: These results suggest that alterations in mtDNA copy number may reflect disruption of the normal prostate glandular architecture seen in early-stage disease, as opposed to reflecting the large number of tumor cells seen with advanced PCa. PMID- 28357530 TI - Magnetic resonance imaging of first trimester pregnancy: expected intrauterine contents in relation to gestational age. AB - PURPOSE: To determine if and when fetal structures are identifiable during first trimester pregnancy on magnetic resonance imaging (MRI) in women with acute abdominopelvic pain. METHODS: Sixty-four first trimester MRI examinations performed for evaluation of abdominopelvic pain were reviewed retrospectively. T2 weighted images were assessed independently by three radiologists for the presence of gestational sac, yolk sac, fetal pole, and limb buds. Mean sac diameter and sac volume were determined, and logistic regression analyses were performed. Criterion values for fetal structures and gestational sac size were calculated using receiver operating characteristic analysis. RESULTS: A gestational sac is present in all but two cases. The yolk sac is never identified. A fetal pole is identified at a gestational age (GA), mean sac diameter (MSD), and gestational sac volume (GSV) of greater than 6.4 weeks, 1.7 cm, and 8.9 mL, respectively. Limb buds are identified at a GA, MSD, and GSV of greater than 8.1 weeks, 3.4 cm, and 27.1 mL, respectively. There is a significant correlation between GA and gestational sac size, including the MSD (r 2 = 0.85, P < 0.01) and GSV (r 2 = 0.86, P < 0.01). CONCLUSIONS: The gestational sac is readily demonstrated on T2-weighted images, but the yolk sac is not identified on routine MRI. The fetal pole and limb buds are seen on MRI at a similar GA and MSD as with published values using transvaginal sonography. PMID- 28357529 TI - Differentiating pheochromocytoma from lipid-poor adrenocortical adenoma by CT texture analysis: feasibility study. AB - OBJECTIVES: To investigate the feasibility of using CT texture analysis (CTTA) to differentiate pheochromocytoma from lipid-poor adrenocortical adenoma (lp-ACA). METHODS: Ninety-eight pheochromocytomas and 66 lp-ACAs were included in this retrospective study. CTTA was performed on unenhanced and enhanced images. Receiver operating characteristic (ROC) analysis was performed, and the area under the ROC curve (AUC) was calculated for texture parameters that were significantly different for the objective. Diagnostic accuracies were evaluated using the cutoff values of texture parameters with the highest AUCs. RESULTS: Compared to lp-ACAs, pheochromocytomas had significantly higher mean gray-level intensity (Mean), entropy, and mean of positive pixels (MPP), but lower skewness and kurtosis on unenhanced images (P < 0.001). On enhanced images, these texture quantifiers followed a similar trend where Mean, entropy, and MPP were higher, but skewness and kurtosis were lower in pheochromocytomas. Standard deviation (SD) was also significantly higher in pheochromocytomas on enhanced images. Mean and MPP quantified from no filtration on unenhanced CT images yielded the highest AUC of 0.86 +/- 0.03 (95% CI 0.81-0.91) at a cutoff value of 34.0 for Mean and MPP, respectively (sensitivity = 79.6%, specificity = 83.3%, accuracy = 81.1%). CONCLUSIONS: It was feasible to use CTTA to differentiate pheochromocytoma from lp-ACA. PMID- 28357531 TI - Extensive lymph node dissection during pancreaticoduodenectomy: a risk factor for hepatic steatosis? AB - PURPOSE: The first reports of hepatic steatosis following pancreaticoduodenectomy (PD) were published several years ago; however, clear risk factors remain to be identified. Therefore, the aim of this study was to identify the risk factors for hepatic steatosis post-PD. METHODS: We studied 90 patients who had undergone PD between September 2005 and January 2015. The inclusion criteria were as follows: available unenhanced CT within one month before PD and at least one unenhanced CT acquisition between PD and chemotherapy initiation. Using scanners, we studied the liver and spleen density as well as the surface areas of visceral (VF) and subcutaneous fat (SCF). These variables were previously identified by univariate and multivariate analyses. RESULTS: Hepatic steatosis occurred in 25.6% of patients at 45.2 days, on average, post-PD. Among the patients with hepatic steatosis, the average liver density was 52 HU before PD and 15.1 HU post-PD (p < 0.001). The Patients with hepatic steatosis lost more VF (mean, 28 vs. 11 cm2) and SCF (28.8 vs. 13.7 cm2) (p < 0.01 and p = 0.01, respectively). Portal vein resection and extensive lymph node dissection were independent risk factors in the multivariate analysis (odds ratio [OR] 5.29, p = 0.009; OR 3.38, p = 0.04, respectively). CONCLUSION: Portal vein resection and extensive lymph node dissection are independent risk factors for post-PD hepatic steatosis. PMID- 28357532 TI - CT detection of fat retention in the bladder after partial nephrectomy. AB - PURPOSE: This study aimed to investigate the frequency of fat retention in the bladder using postoperative computed tomography (CT) and the associated imaging or clinical findings in patients who underwent renal tumor surgery. METHODS: We retrospectively reviewed postoperative CT images from 123 patients who underwent surgery for renal tumors (92 patients after partial nephrectomy and 31 after total nephrectomy). Furthermore, we evaluated preoperative tumor characteristics per an established standardized nephrometry scoring system (the R.E.N.A.L Nephrometry Score) for patients with partial nephrectomy. We also investigated whether collecting system repair occurred during surgery. RESULTS: Fat retention in the bladder was found in 5 patients (5.4%) after partial nephrectomy, but was not observed in any patients after total nephrectomy. No fat retention was seen immediately after partial nephrectomy (4-8 days), but occurred 2-15 months after the surgery. Subsequently, intravesical fat retention disappeared in 3 patients (8, 24, and 16 months later), and it persisted from 19-22 months after surgery in the remaining 2 patients. Collecting system repair occurred in 25 patients (27%) with partial nephrectomy. There was no statistically significant association between fat retention in the bladder and intraoperative collecting system repair (p = 0.12). The association with intravesical fat retention was not significant for either tumor size, distance to the collecting system, or the R.E.N.A.L. Nephrometry Score. CONCLUSION: Fat retention in the bladder after partial nephrectomy can be observed using CT, although it is relatively rare. It is clinically asymptomatic and disappears spontaneously in most cases. PMID- 28357533 TI - Increased ceramide production sensitizes breast cancer cell response to chemotherapy. AB - BACKGROUND: Advanced breast cancer remains clinically challenging due to its resistance to chemotherapy. To understand the underlying mechanisms of resistance and identify drugable target, the involvement of ceramide metabolism is investigated. METHODS: Ceramide levels in breast cancer tissues derived from 30 patients with stage IV breast cancer before and after chemotherapy were analyzed using liquid chromatography mass spectrometry. mRNA and protein levels of ceramide enzymes were examined using western blot and QRT-PCR. The effects of ceramide analog were investigated using cellular assays and xenograft tumor model. RESULTS: The results demonstrated that pro-apoptotic ceramide was significantly lower in all patients after chemotherapy, suggesting that downregulation of ceramide is a common feature of breast cancer patients in response to chemotherapy. Molecular characteristics analysis of ceramide indicated C16:0 as the predominant sphingolipid regulated by chemotherapy in breast cancer patients. Mechanistically, ceramide levels were suppressed by chemotherapy via increasing mRNA and protein levels of UDP-glucose ceramide glucosyltransferase (UGCG). Importantly, inhibition of UGCG using siRNA or upregulation of cellular ceramide levels using C2 ceramide alone inhibited proliferation and induced apoptosis of breast cancer cells, and enhanced the inhibitory effects of chemotherapeutic drugs in vitro and in vivo. CONCLUSIONS: This study clearly demonstrated that the decreased ceramide production via up regulating UGCG was involved in the resistance of breast cancer cells to chemotherapy. Stimulating ceramide or decreasing UGCG can potentially be useful for breast cancer treatment. PMID- 28357534 TI - The relationship between microstructural alterations of the brain and clinical measurements in children and adolescents with hair pulling disorder. AB - Several studies have evaluated gray matter abnormalities and white matter integrity in adults with hair pulling disorder (HPD). However, no prior studies have defined the relationship between neuroimaging parameters and clinical measurements in children and adolescents with HPD. The purposes of this study were to determine the correlation between magnetic resonance imaging (MRI) indices and clinical measurements in children and adolescents with HPD, and to compare HPD patients with age- and sex- matched healthy controls (HC). Pediatric HPD patients (n = 9) and HC subjects (n = 10), aged 9-17 years, were recruited. Three-dimensional T1-weighted structural MRI (3D T1W) and diffusion-tensor imaging (DTI) scans were obtained for each subject. Gray matter and white matter volumes were calculated from 3D T1W. Fractional anisotropy (FA) and average diffusion coefficients (Dav) were mapped from DTI. Voxel-based and region-of interest correlations between MRI indices and clinical measurements were analyzed. In addition, two-sample t-tests were used to compare voxel-based tissue volumes, FA, and Dav maps between the two groups. Alterations in both brain tissue volume and white matter integrity were associated with symptom severity, especially in the precuneus, anterior cingulate, temporal cortex, and frontal cortex regions. FA values in HPD patients were significantly higher than those observed in HC subjects, particularly in the cerebellum and cuneus regions. Alterations of brain tissue volumes and microstructural changes are associated with severity of clinical symptoms in children and adolescents with HPD. Fractional anisotropy is the most sensitive method to distinguish pediatric HPD patients from healthy children. The results of this study can facilitate use of MRI indices to follow the transition from pediatric HPD to adult HPD. PMID- 28357535 TI - Emotional intelligence moderates the relationship between regional gray matter volume in the bilateral temporal pole and critical thinking disposition. AB - Critical thinking enables people to form sound beliefs and provides a basis for emotional life. Research has indicated that individuals with better critical thinking disposition can better recognize and regulate their emotions, though the neuroanatomical mechanisms involved in this process remain to be elucidated. Further, the influence of emotional intelligence on the relationship between brain structure and critical thinking disposition has not been examined. The present study utilized voxel-based morphometry (VBM) to investigate the neural structures underlying critical thinking disposition in a large sample of college students (N = 296). Regional gray matter volume (rGMV) in the bilateral temporal pole, which reflects an individual's ability to process social and emotional information, was negatively correlated with critical thinking disposition. In addition, rGMV in bilateral para hippocampal regions -regions involved in contextual association/emotional regulation-exhibited negative correlation with critical thinking disposition. Further analysis revealed that emotional intelligence moderated the relationship between rGMV of the temporal pole and critical thinking disposition. Specifically, critical thinking disposition was associated with decreased GMV of the temporal pole for individuals who have relatively higher emotional intelligence rather than lower emotional intelligence. The results of the present study indicate that people who have higher emotional intelligence exhibit more effective and automatic processing of emotional information and tend to be strong critical thinkers. PMID- 28357536 TI - Pediatric high-grade glioma: current molecular landscape and therapeutic approaches. AB - High-grade pediatric central nervous system glial tumors are comprised primarily of anaplastic astrocytomas (AA, WHO grade III) and glioblastomas (GBM, WHO grade IV). High-grade gliomas are most commonly diagnosed in the primary setting in children, but as in adults, they can also arise as a result of transformation of a low-grade malignancy, though with limited frequency in the pediatric population. The molecular genetics of high-grade gliomas in the pediatric population are distinct from their adult counterparts. In contrast to the adult population, high-grade gliomas in children are relatively infrequent, representing less than 20% of cases. PMID- 28357537 TI - Influence of Cooking Conditions on Carotenoid Content and Stability in Porridges Prepared from High-Carotenoid Maize. AB - Maize is a staple food crop in many developing countries, hence becoming an attractive target for biofortification programs toward populations at risk of micronutrient deficiencies. A South African white endosperm maize inbred line was engineered with a carotenogenic mini-pathway to generate high-carotenoid maize, which accumulates beta-carotene, lutein and zeaxanthin. As maize porridge is a traditional meal for poor populations in sub-Saharan African countries, high carotenoid maize was used as raw material to prepare different maize meals. The objective of this work was to assess the impact of popular home-cooking techniques and different cooking parameters (temperature, time and pH) on the final carotenoid content in the cooked product, using a spectrophotometric technique based on the mean absorption of carotenoids at 450 nm. Carotenoid levels were not only preserved, but also enhanced in high-carotenoid maize porridges. The carotenoid content was increased when temperatures <=95 degrees C were combined with short cooking times (10-60 min). The most optimum thermal treatment was 75 degrees C/10 min. When treated under those conditions at pH 5, high-carotenoid maize porridges doubled the initial carotenoid content up to 88 MUg/g dry weight. Regarding to cooking techniques, the highest carotenoid content was found when unfermented thin porridges were prepared (51 MUg/g dry weight of high-carotenoid maize porridge). We conclude that high-carotenoid maize may contribute to enhance the dietary status of rural populations who depend on maize as a staple food. PMID- 28357538 TI - Anatomical variants of sphenoid sinuses pneumatisation: a CT scan study on a Northern Italian population. AB - Sphenoid bone may be affected by different variants of pneumatisation, which have a relevant importance from a clinical and surgical point of view. The description of such variants in different populations may give useful information. However, few articles describe the variability of sphenoid pneumatised structures and none of them focuses on Northern Italian population. Variants of pneumatisation of sphenoid bone were described in a sample of 300 Northern Italian patients who underwent a CT scan. More than fifty-seven percent of patients showed a form of anatomical variant: the most common form was the pneumatised pterygoid processes (39.6%), followed by dorsum sellae (32.9%) and clinoid processes (20.3%), without statistically significant differences between males and females (p > 0.01). In 26.3% of patients, a combined pneumatisation of these three structures was observed, being the combination pterygoid processes-dorsum sellae the most frequent (11.3%). In 9.3%, all the three sphenoid structures were affected. This article is the first description of the prevalence of different variants of pneumatisation in a Northern Italian population: the occurrence of such forms has to be acknowledged for their possible clinical and surgical consequences. PMID- 28357541 TI - Obituary: Hans-Jurgen Rehm 1927-2017. PMID- 28357540 TI - Vanillin biosynthetic pathways in plants. AB - MAIN CONCLUSION: The present review compiles the up-to-date knowledge on vanillin biosynthesis in plant systems to focus principally on the enzymatic reactions of in planta vanillin biosynthetic pathway and to find out its impact and prospect in future research in this field. Vanillin, a very popular flavouring compound, is widely used throughout the world. The principal natural resource of vanillin is the cured vanilla pods. Due to the high demand of vanillin as a flavouring agent, it is necessary to explore its biosynthetic enzymes and genes, so that improvement in its commercial production can be achieved through metabolic engineering. In spite of significant advancement in elucidating vanillin biosynthetic pathway in the last two decades, no conclusive demonstration had been reported yet for plant system. Several biosynthetic enzymes have been worked upon but divergences in published reports, particularly in characterizing the crucial biochemical steps of vanillin biosynthesis, such as side-chain shortening, methylation, and glucoside formation and have created a space for discussion. Recently, published reviews on vanillin biosynthesis have focused mainly on the biotechnological approaches and bioconversion in microbial systems. This review, however, aims to compile in brief the overall vanillin biosynthetic route and present a comparative as well as comprehensive description of enzymes involved in the pathway in Vanilla planifolia and other plants. Special emphasis has been given on the key enzymatic biochemical reactions that have been investigated extensively. Finally, the present standpoint and future prospects have been highlighted. PMID- 28357539 TI - Screening of rice mutants with improved saccharification efficiency results in the identification of CONSTITUTIVE PHOTOMORPHOGENIC 1 and GOLD HULL AND INTERNODE 1. AB - MAIN CONCLUSION: The screening of rice mutants with improved cellulose to glucose saccharification efficiency (SE) identifies reduced xylan and/or ferulic acid, and a qualitative change of lignin to impact SE. To ensure the availability of sustainable energy, considerable effort is underway to utilize lignocellulosic plant biomass as feedstock for the production of biofuels. However, the high cost of degrading plant cell wall components to fermentable sugars (saccharification) has been problematic. One way to overcome this barrier is to develop plants possessing cell walls that are amenable to saccharification. In this study, we aimed to identify new molecular factors that influence saccharification efficiency (SE) in rice. By screening 22 rice mutants, we identified two lines, 122 and 108, with improved SE. Reduced xylan and ferulic acid within the cell wall of line 122 were probable reasons of improved SE. Line 108 showed reduced levels of thioglycolic-released lignin; however, the amount of Klason lignin was comparable to the wild-type, indicating that structural changes had occurred in the 108 lignin polymer which resulted in improved SE. Positional cloning revealed that the genes responsible for improved SE in 122 and 108 were rice CONSTITUTIVE PHOTOMORPHOGENIC 1 (OsCOP1) and GOLD HULL AND INTERNODE 1 (GH1), respectively, which have not been previously reported to influence SE. The screening of mutants for improved SE is an efficient approach to identify novel genes that affect SE, which is relevant in the development of crops as biofuel sources. PMID- 28357542 TI - Novel thermostable amine transferases from hot spring metagenomes. AB - Hot spring metagenomes, prepared from samples collected at temperatures ranging from 55 to 95 degrees C, were submitted to an in silico screening aimed at the identification of novel amine transaminases (ATAs), valuable biocatalysts for the preparation of optically pure amines. Three novel (S)-selective ATAs, namely Is3 TA, It6-TA, and B3-TA, were discovered in the metagenome of samples collected from hot springs in Iceland and in Italy, cloned from the corresponding metagenomic DNAs and overexpressed in recombinant form in E. coli. Functional characterization of the novel ATAs demonstrated that they all possess a thermophilic character and are capable of performing amine transfer reactions using a broad range of donor and acceptor substrates, thus suggesting a good potential for practical synthetic applications. In particular, the enzyme B3-TA revealed to be exceptionally thermostable, retaining 85% of activity after 5 days of incubation at 80 degrees C and more than 40% after 2 weeks under the same condition. These results, which were in agreement with the estimation of an apparent melting temperature around 88 degrees C, make B3-TA, to the best of our knowledge, the most thermostable natural ATA described to date. This biocatalyst showed also a good tolerance toward different water-miscible and water-immiscible organic solvents. A detailed inspection of the homology-based structural model of B3-TA showed that the overall active site architecture of mesophilic (S) selective ATAs was mainly conserved in this hyperthermophilic homolog. Additionally, a subfamily of B3-TA-like transaminases, mostly uncharacterized and all from thermophilic microorganisms, was identified and analyzed in terms of phylogenetic relationships and sequence conservation. PMID- 28357544 TI - A new source of resistance to 2-furaldehyde from Scheffersomyces (Pichia) stipitis for sustainable lignocellulose-to-biofuel conversion. AB - Aldehyde inhibitory compounds derived from lignocellulosic biomass pretreatment have been identified as a major class of toxic chemicals that interfere with microbial growth and subsequent fermentation for advanced biofuel production. Development of robust next-generation biocatalyst is a key for a low-cost biofuel production industry. Scheffersomyces (Pichia) stipitis is a naturally occurring C 5 sugar utilization yeast; however, little is known about the genetic background underlying its potential tolerance to biomass conversion inhibitors. We investigated and identified five uncharacterized putative aryl-alcohol dehydrogenase genes (SsAADs) from this yeast as a new source of resistance against biomass fermentation inhibitor 2-furaldehyde (furfural) by gene expression, gene cloning, and direct enzyme assay analysis using partially purified proteins. All five proteins from S. stipitis showed furfural reduction using cofactor NADH. An optimum active temperature was observed at 40 degrees C for SsAad1p; 30 degrees C for SsAad3p, SsAad4p, and SsAad5p; and 20 degrees C for SsAad2p. SsAad2p, SsAad3p, and SsAad4p showed tolerance to a wide range of pH from 4.5 to 8, but SsAad1p and SsAad5p were sensitive to pH changes beyond 7. Genes SsAAD2, SsAAD3, and SsAAD4 displayed significantly enhanced higher levels of expression in response to the challenge of furfural. Their encoding proteins also showed higher levels of specific activity toward furfural and were suggested as core functional enzymes contributing aldehyde resistance in S. stipitis. PMID- 28357543 TI - Comparison of internal process control viruses for detection of food and waterborne viruses. AB - Enteric viruses are pathogens associated with food- and waterborne outbreaks. The recovery of viruses from food or water samples is affected by the procedures applied to detect and concentrate them. The incorporation of an internal process control virus to the analyses allows monitoring the performance of the methodology. The aim of this study was to produce a recombinant adenovirus (rAdV) and apply it together with bacteriophage PP7 as process controls. The rAdV carries a DNA construction in its genome to differentiate it from wild-type adenovirus by qPCR. The stability of both control viruses was evaluated at different pH conditions. The rAdV was stable at pH 3, 7, and 10 for 18 h. PP7 infectious particles were stable at pH 7 and showed a 2.14 log reduction at pH 10 and total decay at pH 3 after 18 h. Three virus concentration methods were evaluated: hollow-fiber tap water ultrafiltration, wastewater ultracentrifugation, and elution-PEG precipitation from lettuce. Total and infectious viruses were quantified and their recoveries were calculated. Virus recovery for rAdV and PP7 by ultrafiltration showed a wide range (2.10-84.42 and 13.54-84.62%, respectively), whereas that by ultracentrifugation was 5.05-13.71 and 6.98-13.27%, respectively. The performance of ultracentrifugation to concentrate norovirus and enteroviruses present in sewage was not significantly different to the recovery of control viruses. For detection of viruses from lettuce, genomic copies of PP7 were significantly more highly recovered than adenovirus (14.74-18.82 and 0.00-3.44%, respectively). The recovery of infectious virus particles was significantly affected during sewage ultracentrifugation and concentration from lettuce. The simultaneous use of virus controls with dissimilar characteristics and behaviors might resemble different enteric viruses. PMID- 28357545 TI - Growth kinetics and scale-up of Agrobacterium tumefaciens. AB - Production of recombinant proteins in plants through Agrobacterium-mediated transient expression is a promising method of producing human therapeutic proteins, vaccines, and commercial enzymes. This process has been shown to be viable at a large scale and involves growing large quantities of wild-type plants and infiltrating the leaf tissue with a suspension of Agrobacterium tumefaciens bearing the genes of interest. This study examined one of the steps in this process that had not yet been optimized: the scale-up of Agrobacterium production to sufficient volumes for large-scale plant infiltration. Production of Agrobacterium strain C58C1 pTFS40 was scaled up from shake flasks (50-100 mL) to benchtop (5 L) scale with three types of media: Lysogeny broth (LB), yeast extract peptone (YEP) media, and a sucrose-based defined media. The maximum specific growth rate (MU max) of the strain in the three types of media was 0.46 +/- 0.04 h-1 in LB media, 0.43 +/- 0.03 h-1 in YEP media, and 0.27 +/- 0.01 h-1 in defined media. The maximum biomass concentration reached at this scale was 2.0 +/- 0.1, 2.8 +/- 0.1, and 2.6 +/- 0.1 g dry cell weight (DCW)/L for the three media types. Production was successfully scaled up to a 100-L working volume reactor with YEP media, using k L a as the scale-up parameter. PMID- 28357547 TI - XLV Neuroradiology Congress : Valencia, Spain (October 27-29, 2016). PMID- 28357546 TI - A metabolic engineering strategy for producing conjugated linoleic acids using the oleaginous yeast Yarrowia lipolytica. AB - Conjugated linoleic acids (CLAs) have been found to have beneficial effects on human health when used as dietary supplements. However, their availability is limited because pure, chemistry-based production is expensive, and biology-based fermentation methods can only create small quantities. In an effort to enhance microbial production of CLAs, four genetically modified strains of the oleaginous yeast Yarrowia lipolytica were generated. These mutants presented various genetic modifications, including the elimination of beta-oxidation (pox1-6?), the inability to store lipids as triglycerides (dga1? dga2? are1? lro1?), and the overexpression of the Y. lipolytica ?12-desaturase gene (YlFAD2) under the control of the constitutive pTEF promoter. All strains received two copies of the pTEF-oPAI or pPOX-oPAI expression cassettes; PAI encodes linoleic acid isomerase in Propionibacterium acnes. The strains were cultured in neosynthesis or bioconversion medium in flasks or a bioreactor. The strain combining the three modifications mentioned above showed the best results: when it was grown in neosynthesis medium in a flask, CLAs represented 6.5% of total fatty acids and in bioconversion medium in a bioreactor, and CLA content reached 302 mg/L. In a previous study, a CLA degradation rate of 117 mg/L/h was observed in bioconversion medium. Here, by eliminating beta-oxidation, we achieved a much lower rate of 1.8 mg/L/h. PMID- 28357549 TI - FDG uptake in cervical lymph nodes in children without head and neck cancer. AB - BACKGROUND: Reactive cervical lymphadenopathy is common in children and may demonstrate increased 18F-fluoro-deoxyglucose (18F-FDG) uptake on positron emission tomography/computed tomography (PET/CT). OBJECTIVE: We sought to evaluate the frequency and significance of 18F-FDG uptake by neck lymph nodes in children with no history of head and neck cancer. MATERIALS AND METHODS: The charts of 244 patients (114 female, mean age: 10.4 years) with a variety of tumors such as lymphoma and post-transplant lymphoproliferative diseases (PTLD), but no head and neck cancers, who had undergone 18F-FDG PET/CT were reviewed retrospectively. Using the maximum standardized uptake value (SUVmax), increased 18F-FDG uptake by neck lymph nodes was recorded and compared with the final diagnosis based on follow-up studies or biopsy results. RESULTS: Neck lymph node uptake was identified in 70/244 (28.6%) of the patients. In 38 patients, the lymph nodes were benign. In eight patients, the lymph nodes were malignant (seven PTLD and one lymphoma). In 24 patients, we were not able to confirm the final diagnosis. Seven out of the eight malignant lymph nodes were positive for PTLD. The mean SUVmax was significantly higher in malignant lesions (4.2) compared with benign lesions (2.1) (P = 0.00049). CONCLUSION: 18F-FDG uptake in neck lymph nodes is common in children and is frequently due to reactive lymph nodes, especially when the SUVmax is <3.2. The frequency of malignant cervical lymph nodes is higher in PTLD patients compared with other groups. PMID- 28357550 TI - Attendance Trajectory Classes Among Divorced and Separated Mothers and Fathers in the New Beginnings Program. AB - We examined attendance trajectories among mothers and fathers in the effectiveness trial of the New Beginnings Program, a parenting-focused prevention program for divorced and separated parents. We also investigated attendance trajectory class differences on two sets of pretest covariates: one set previously linked to participation in programs not specifically targeting divorced parents (i.e., sociodemographics, perceived parenting skills, child problem behaviors, parent psychological distress) and another that might be particularly salient to participation in the context of divorce (i.e., interparental conflict, level of parent-child contact, previous marital status to the ex-spouse). For mothers and fathers, results supported four attendance trajectory classes: (1) non-attenders (NA), (2) early dropouts (ED), (3) declining attenders (DA), and (4) sustained attenders (SA). In the final model testing multiple covariates simultaneously, mothers who were EDs and DAs were more likely to be Latina than SAs, and EDs reported more interparental conflict than SAs. Mother trajectory groups did not differ on parenting skills, child problem behavior, or mother-child contact in the final or preliminary models. In the final model for fathers, EDs rated their children higher on externalizing than DAs, had less contact with their children than DAs and NAs, and reported less distress than SAs. Father trajectory groups did not differ on fathers' age, ethnicity, income, perceived parenting skills, or interparental conflict in the final or preliminary models. Results highlight qualitatively distinct latent classes of mothers and fathers who disengage from a parenting intervention at various points. We discuss implications for intervention engagement strategies and translational science. PMID- 28357551 TI - Changes in the microbial community during repeated anaerobic microbial dechlorination of pentachlorophenol. AB - Pentachlorophenol (PCP) has been widely used as a pesticide in paddy fields and has imposed negative ecological effect on agricultural soil systems, which are in typically anaerobic conditions. In this study, we investigated the effect of repeated additions of PCP to paddy soil on the microbial communities under anoxic conditions. Acetate was added as the carbon source to induce and accelerate cycles of the PCP degradation. A maximum degradation rate occurred at the 11th cycle, which completely transformed 32.3 MUM (8.6 mg L-1) PCP in 5 days. Illumina high throughput sequencing of 16S rRNA gene was used to profile the diversity and abundance of microbial communities at each interval and the results showed that the phyla of Bacteroidates, Firmicutes, Proteobacteria, and Euryarchaeota had a dominant presence in the PCP-dechlorinating cultures. Methanosarcina, Syntrophobotulus, Anaeromusa, Zoogloea, Treponema, W22 (family of Cloacamonaceae), and unclassified Cloacamonales were found to be the dominant genera during PCP dechlorination with acetate. The microbial community structure became relatively stable as cycles increased. Treponema, W22, and unclassified Cloacamonales were firstly observed to be associated with PCP dechlorination in the present study. Methanosarcina that have been isolated or identified in PCP dechlorination cultures previously was apparently enriched in the PCP dechlorination cultures. Additionally, the iron-cycling bacteria Syntrophobotulus, Anaeromusa, and Zoogloea were enriched in the PCP dechlorination cultures indicated they were likely to play an important role in PCP dechlorination. These findings increase our understanding for the microbial and geochemical interactions inherent in the transformation of organic contaminants from iron rich soil, and further extend our knowledge of the PCP transforming microbial communities in anaerobic soil conditions. PMID- 28357552 TI - XII Brazilian Congress of Pediatric Neurosurgery : April 19-22th, 2017 - Florianopolis, Brazil. PMID- 28357553 TI - Misdiagnosed syrinx in a patient with neuroschisis and Klippel-Feil syndrome: case report. AB - INTRODUCTION: Patients with Klippel-Feil syndrome can present with a myriad of symptoms and imaging findings. Herein, we present a case of Klippel-Feil syndrome that was initially misdiagnosed with syringomyelia. We review this case and discuss the imaging findings. CONCLUSIONS: Neuoroschisis should be suspected in patients with Klippel-Feil syndrome and differentiated from syringomyelia. PMID- 28357554 TI - Outcome of treatment after failed endoscopic third ventriculostomy (ETV) in infants with aqueductal stenosis: results from the International Infant Hydrocephalus Study (IIHS). AB - INTRODUCTION: After an endoscopic third ventriculostomy (ETV) fails, it is unclear how well subsequent treatment fares, especially in comparison to shunts inserted as primary treatment. In this study, we present a further analysis of the infants enrolled a prospective multicentre study who failed ETV and describe the outcome of their subsequent treatment, comparing this to those who received shunt as their primary treatment. METHODS: This was a post hoc analysis of data from the International Infant Hydrocephalus Study (IIHS)-a prospective, multicentre study of infants with hydrocephalus from aqueductal stenosis who received either an ETV or shunt. In the current analysis, we compared the results of the 38 infants who failed ETV and the 43 infants who received primary shunt. Patients were followed prospectively for time to treatment failure, defined as the need for repeat CSF diversion procedure (shunt or ETV) or death due to hydrocephalus. RESULTS: There were a total of 81 patients: 43 primary shunts, 34 shunt post-ETV, and 4 repeat ETV. The median time between the primary ETV and the second intervention was 29 days (IQR 14-69), with no significant difference between repeat ETV and shunt post-ETV. Median length of available follow-up was 800 days (IQR 266-1651), during which time, failure was noted in 3 (75.0%) repeat ETV patients, 10 (29.4%) shunt post-ETV patients, and 9 (20.9%) primary shunt patients. In an adjusted Cox regression model, the risk of failure was higher for repeat ETV compared to primary shunt, but there was no significant difference between primary shunt and shunt post-ETV. No other variable showed statistical significance. CONCLUSIONS: In our prospective study of infants with aqueductal stenosis, there was no significant difference in failure outcome of shunts inserted after a failed ETV and primary shunts. Therefore, our data do not support the notion that previous ETV confers either a protective or negative effect on subsequently-placed shunts. Larger studies, in a wider ranging population, are required to establish how widely these data apply. TRIAL REGISTRATION: NCT00652470. PMID- 28357555 TI - Morphological study and relations of the fascia vasto-adductoria. AB - The precise description of the fascia vasto-adductoria (FVA) has become an issue of great surgical and clinical importance. Neurovascular entrapment within the adductor canal (AC) may simulate many clinical conditions for cases presented with medial knee or leg pain and ischemic manifestations of the leg. The aim of the present work is to describe the morphological features of the FVA and to elucidate its neurovascular relations. Forty thigh specimens, pertaining to 15 embalmed and five fresh adult human cadavers, were dissected in pursuit of this aim. The FVA was a continuous subsartorial fascia, roofing the whole length of AC and extended between two points lying at a mean distance of 25.6 and 7 cm proximal to the base of patella. It was subdivided into two parts; proximal thin quadrangular (proximal part of FVA) and distal thick pentagonal (vastoadductor membrane; VAM) and the subsartorial space was observed superficial to it. The mean length of its proximal and distal parts was 7.8 and 7.9 cm, respectively. The proximal part of FVA, while stretched across the vastus medialis (VM) and the adductor longus (AL) muscles, became attached to the wall of the femoral artery and overlaid the femoral vessels, the saphenous nerve (SN), and an arterial pedicle for VM muscle. It was constantly pierced by two arterial pedicles arising from the femoral artery to the sartorius muscle and occasionally (50%) by a communicating nerve branch arising from the SN to join the medial femoral cutaneous nerve. The VAM stretched across the VM muscle and both the AL and adductor magnus (AM) muscles and overlaid the SN, its subsartorial and lower medial femoral cutaneous branches, femoral vessels, 1-3 arterial pedicles for the sartorius and descending genicular vessels. The VAM originated from the tendinous fibres of the AM tendon and constantly spread anterolaterally. It was constantly pierced by 1-3 arterial pedicles to sartorius muscle and both the lower medial femoral cutaneous branch and the subsartorial branches of the SN. An arterial pedicle to the VM muscle and perforating veins between the superficial veins and the femoral vein proved to pierce it in 8/40 specimens. Entrapment of the SN at the distal narrow aperture of the AC, or one of its cutaneous branches at the piercing sites of the FVA, should be remembered when diagnosing cases presented with medial knee or leg pain. The attachment of the proximal part of the FVA to the wall of the femoral artery could add to the mechanism of its potential compression. True AC block should be done deep to the FVA to ensure effective SN analgesia. Its site is recommended to be at the distal one cm of the proximal part of the AC which is at a distance of 16-17 cm proximal to the base of patella. The VAM, being an anatomical connection between the VM and AM muscles, is theorized to increase the mechanical efficiency of the VM oblique muscle to maintain the knee extensor mechanism. PMID- 28357556 TI - Ossification center of the humeral shaft in the human fetus: a CT, digital, and statistical study. AB - PURPOSE: The knowledge of the development of the humeral shaft ossification center may be useful both in determining the fetal stage and maturity and for detecting congenital disorders, as well. This study was performed to quantitatively examine the humeral shaft ossification center with respect to its linear, planar, and volumetric parameters. MATERIALS AND METHOD: Using methods of CT, digital image analysis, and statistics, the size of the humeral shaft ossification center in 48 spontaneously aborted human fetuses aged 17-30 weeks was studied. RESULTS: With no sex differences, the best-fit growth dynamics for the humeral shaft ossification center was modeled by the following functions: y = -78.568 + 34.114 * ln (age) +/- 2.160 for its length, y = -12.733 + 5.654 * ln(age) +/- 0.515 for its proximal transverse diameter, y = -4.750 + 2.609 * ln (age) +/- 0.294 for its middle transverse diameter, y = -10.037 + 4.648 * ln (age) +/- 0.560 for its distal transverse diameter, y = -146.601 + 11.237 * age +/- 19.907 for its projection surface area, and y = 121.159 + 0.001 * (age)4 +/- 102.944 for its volume. CONCLUSIONS: With no sex differences, the ossification center of the humeral shaft grows logarithmically with respect to its length and transverse diameters, linearly with respect to its projection surface area, and fourth-degree polynomially with respect to its volume. The obtained morphometric data of the humeral shaft ossification center are considered normative for respective prenatal weeks and may be of relevance in both the estimation of fetal ages and the ultrasonic diagnostics of congenital defects. PMID- 28357557 TI - Single bolus low-dose of ketamine does not prevent postpartum depression: a randomized, double-blind, placebo-controlled, prospective clinical trial. AB - PURPOSE: Postpartum depression is a common complication of childbirth. In the last decade, it has been suggested that subdissociative-dose ketamine is a fast acting antidepressant. We aimed to investigate the efficacy of low-dose ketamine administered during caesarean section in preventing postpartum depression. METHODS: Using a randomized, double-blind, placebo-controlled design, 330 parturients who were scheduled to undergo caesarean section were enrolled in this trial. The parturients were randomly assigned to receive intravenous ketamine (0.25 mg/kg diluted to 10 mL with 0.9% saline) or placebo (10 mL of 0.9% saline) within 5 min following clamping of the neonatal umbilical cord. The primary outcome was the degree of depression, which was evaluated using the Edinburgh Postnatal Depression Scale (EPDS) (a threshold of 9/10 was used) at 3 days and 6 weeks after delivery. The secondary outcome was the numeric rating scale score of pain at 3 day and 6 week postpartum. RESULTS: No significant differences were found in the prevalence of postpartum depression between the two groups at 3 days and 6 weeks after delivery. The pain scores measured at 3 days postoperatively were not significantly different between the groups, whereas the scores measured at 6 week postpartum were significantly reduced in the treatment group compared with the saline group (P = 0.014). CONCLUSIONS: Intra-operative low-dose ketamine (0.25 mg/kg) does not have a preventive effect on postpartum depression. PMID- 28357558 TI - Effects and safety of GnRH-a as a luteal support in women undertaking assisted reproductive technology procedures: follow-up results for pregnancy, delivery, and neonates. AB - PURPOSE: To investigate the effects and safety of gonadotropin releasing hormone analogue (GnRH-a) as an addition to progesterone luteal support in women who underwent in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) and achieved a clinical pregnancy. METHODS: A retrospective analysis was conducted on 214 patients who underwent IVF/ICSI-ET procedures with standard long mid-luteal protocol, of which 123 received GnRH-a-free protocol and 91 received GnRH-a-added protocol. The patients' pregnancy and delivery course, and their neonates' status at birth and growth/development after birth were statistically compared. RESULTS: There was no significant difference between both study groups regarding embryo risks and maternal complications during early pregnancy. as well as fetal risks during the middle and late stages and neonate risks during birth, except that the twin pregnancies of the GnRH-a-added group had a considerably greater male/female ratio, and a significantly higher rate of premature delivery and low birth weight than those of the GnRH-a-free group. In addition, there was no significant difference in neonate risks within 2 years after birth between both cohorts. CONCLUSION: With precautions taken to control the number of implanted embryos and reduce the incidence of twinning pregnancy, the addition of GnRH-a to luteal support is relatively safe and effective. PMID- 28357559 TI - The role of transvaginal ultrasonography for detecting ovarian cancer in an asymptomatic screening population: a systematic review. AB - INTRODUCTION: The purpose of this study was to systematically analyze the effect of transvaginal ultrasonography in an asymptomatic female population as an annual screening procedure with regard to mortality data. Studies were evaluated descriptively on their strengths and weaknesses considering the methods and results. METHODS: We evaluated 632 international studies by selecting only randomized controlled trials (RCTs). Three RCTs concerning transvaginal ultrasonography were found, performed in Japan, the USA, and Great Britain. DISCUSSION: Currently, no clear recommendation for the screening for ovarian cancer in an asymptomatic population can be given based on these three studies. The authors could not show a change in mortality using transvaginal ultrasonography for annual screening. CONCLUSION: An annual palpation does not offer a beneficial effect. The development of new ultrasound machines with higher image resolution in combination with a well-standardized algorithm for ovarian cancer in upcoming years might provide an improvement regarding mortality. The current studies do not show a benefit in screening an asymptomatic population annually with transvaginal ultrasonography, but the most recent publication showed a trend toward lower mortality in patients who underwent screening after 7 14 years of follow-up. Nevertheless, all three heterogeneous RCTs had weaknesses in their methods and therefore they neither contradict the general recommendation for screening in an asymptomatic population nor do they support it. PMID- 28357560 TI - Maternal and neonatal outcomes after induction of labor: a population-based study. AB - PURPOSE: To evaluate maternal and neonatal outcomes at and beyond term associated with induction of labor compared to spontaneous onset of labor stratified by week of gestational age. METHODS: In this retrospective cohort study, data form 402,960 singleton pregnancies from the Austria Perinatal Registry were used to estimate odds ratios of secondary cesarean delivery, operative vaginal delivery, epidural analgesia, fetal scalp blood testing, episiotomy, 3rd/4th-degree lacerations, retained placenta, 5-min APGAR <7, umbilical artery pH <7.1, and admission to neonatal intensive care unit. Multivariate logistic regression models based on deliveries with gestational age >=37 + 0 were applied for adjustment for possible confounders. RESULTS: Induction of labor was associated with increased odds for cesarean delivery (adjusted OR; 99% confidence interval: 1.53; 1.45-1.60), operative vaginal delivery (1.21; 1.15-1.27), epidural analgesia (2.12; 2.03-2.22), fetal scalp blood testing (1.40; 1.28-1.52), retained placenta (1.32; 1.22-1.41), 5-min APGAR <7 (1.55; 1.27-1.89), umbilical artery pH <7.1 (1.26; 1.15-1.38), and admission to neonatal intensive care unit (1.41; 1.31-1.51). In a subgroup of induction of labor with the indication, "post term pregnancy" induction was similarly associated with adverse outcomes. CONCLUSIONS: In Austria, induction of labor is associated with increased odds of adverse maternal and neonatal outcomes. However, due to residual confounding, currently, no recommendations for treatment can be derived. PMID- 28357561 TI - Laparoendoscopic single-site surgery versus conventional laparoscopy for hysterectomy: a systematic review and meta-analysis. AB - PURPOSE: To assess the safety and effectiveness of LESS compared to conventional hysterectomy. METHODS: The systematic review and meta-analysis was performed according to the MOOSE guideline, and quality of evidence was assessed using GRADE. Different databases were searched up to 4th of August 2016. Randomized controlled trials and cohort studies comparing LESS to the conventional laparoscopic hysterectomy were considered for inclusion. RESULTS: Of the 668 unique articles, 23 were found relevant. We investigated safety by analyzing the complication rate and found no significant differences between both groups [OR 0.94 (0.61, 1.44), I 2 = 19%]. We assessed effectiveness by analyzing conversion risk, postoperative pain, and patient satisfaction. For conversion rates to laparotomy, no differences were identified [OR 1.60 (0.40, 6.38), I 2 = 45%]. In 3.5% of the cases in the LESS group, an additional port was needed during LESS. For postoperative pain scores and patient satisfaction, some of the included studies reported favorable results for LESS, but the clinical relevance was non significant. Concerning secondary outcomes, only a difference in operative time was found in favor of the conventional group [MD 11.3 min (5.45-17.17), I 2 = 89%]. The quality of evidence for our primary outcomes was low or very low due to the study designs and lack of power for the specified outcomes. Therefore, caution is urged when interpreting the results. CONCLUSION: The single-port technique for benign hysterectomy is feasible, safe, and equally effective compared to the conventional technique. No clinically relevant advantages were identified, and as no data on cost effectiveness are available, there are currently not enough valid arguments to broadly implement LESS for hysterectomy. PMID- 28357563 TI - The association of psychopathology with concurrent level of functioning and subjective well-being in persons with schizophrenia spectrum disorders. AB - The objective is to investigate the relationship between psychopathology measured by the positive and negative syndrome scale (PANSS) and concurrent global assessment of functioning (GAF) and subjective well-being under neuroleptics (SWN) in patients with schizophrenia spectrum disorder (SSD) regarding severity of illness and disease phase. We analyzed a sample of 202 SSD patients consisting of first episode psychosis (FEP) and multiple episode psychosis (MEP) patients followed up to 12 months using linear mixed models. All PANSS syndromes except excitement were associated with GAF scores (positive syndrome: p < 0.001, d = 1.21; negative syndrome: p = 0.029, d = 0.015; disorganized syndrome: p < 0.001, d = 0.37; anxiety/depression syndrome: p < 0.001, d = 0.49), and positive symptoms had an increasing impact on global functioning with higher severity of illness (mildly ill: p = 0.039, d = 0.22; moderately ill: p < 0.001, d = 0.28; severely ill: p < 0.001, d = 0.69). SWN was associated with positive (p = 0.002, d = 0.22) and anxiety/depression (p < 0.001, d = 0.38) syndromes. Subgroup analyses showed differing patterns depending on illness severity and phase. Over all our results show different patterns of associations of psychopathology and concurrent functioning and subjective well-being. These findings contribute knowledge on the possible role of specific psychopathological syndromes for the functioning and well-being of our patients and may enable tailored treatments depending on severity and phase of illness. PMID- 28357562 TI - In vivo imaging of oxidative stress and fronto-limbic white matter integrity in young adults with mood disorders. AB - Fronto-limbic connectivity is compromised in mood disorders, as reflected by impairments in white matter (WM) integrity revealed by diffusion tensor imaging. Although the underlying mechanisms remain unclear, disruption to normal myelination due to oxidative stress is thought to play a key role. We aimed to determine whether fronto-limbic WM integrity is compromised, and associated with in vivo antioxidant levels (indexed by glutathione; GSH), in young adults with unipolar depression (DEP) and bipolar (BD) disorders. Ninety-four patients with DEP, 76 with BD and 59 healthy controls (18-30 years) underwent diffusion tensor and proton magnetic resonance spectroscopy imaging. Fractional anisotropy (FA) was calculated from the cingulum bundle (cingulate, hippocampus), fornix, stria terminalis (ST) and uncinate fasciculus tracts. GSH concentration was measured in anterior cingulate cortex (ACC) and hippocampus (HIPP). Compared to controls, DEP showed significantly reduced FA in ST, whereas BD did not significantly differ in FA across the five tracts. There were significant positive correlations between ST-FA and HIPP-GSH across groups. Regression analysis revealed that having DEP or BD and reduced HIPP-GSH were significantly associated with reduced ST-FA. Similarly, decreased ST-FA was associated with poorer neuropsychological performance in conjunction with having DEP. Our findings suggest a structural disconnectivity specific to the limbic region of young adults with DEP. Decreased WM integrity was associated with depleted levels of hippocampal GSH suggesting that this particular disruption may be linked to oxidative stress at early stages of illness. Young adults with BD do not have the same degree of impairment. PMID- 28357565 TI - Anti-glomerular basement membrane glomerulonephritis with thrombotic microangiopathy: a case report. PMID- 28357564 TI - The use of nonhuman primate models to understand processes in Parkinson's disease. AB - Research with animal models has led to critical health advances that have saved or improved the lives of millions of human beings. Specifically, nonhuman primate's genetic and anatomo-physiological similarities to humans are especially important for understanding processes like Parkinson's disease, which only occur in humans. Unambiguously, the unique contribution made by nonhuman primate research to our understanding of Parkinson's disease is widely recognized. For example, monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) parkinsonisms are responsive to dopamine replacement therapies, mimicking what is seen in PD patients. Moreover, groundbreaking neuroanatomical and electrophysiological studies using this monkey model in the 1980s and 1990s enabled researchers to identify the neuronal circuits responsible for the cardinal motor features of PD. This led to the development of subthalamic surgical ablation and deep brain stimulation, the current therapeutic gold standard for neurosurgical treatment. More recently, the mechanisms of alpha synuclein spreading testing the prion hypothesis for PD have yielded exciting results. In this review, we discuss and highlight how the findings from nonhuman primate research contribute to our understanding of idiopathic Parkinson's disease. PMID- 28357567 TI - Emetine induces estrogen receptor alpha degradation and prevents 17beta-estradiol induced breast cancer cell proliferation. PMID- 28357566 TI - Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis. AB - Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43Q331K mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43Q331K gene from motor neurons is shown to delay onset of motor symptoms and appearance of TDP-43-mediated aberrant nuclear morphology, and abrogate subsequent death of motor neurons. However, reduction of mutant TDP-43 selectively in motor neurons did not prevent age-dependent degeneration of axons and neuromuscular junction loss, nor did it attenuate astrogliosis or microgliosis. Thus, disease mechanism is non-cell autonomous with mutant TDP-43 expressed in motor neurons determining disease onset but progression defined by mutant acting within other cell types. PMID- 28357568 TI - High-resolution metal artifact reduction MR imaging of the lumbosacral plexus in patients with metallic implants. AB - OBJECTIVE: To assess the quality and accuracy of metal artifact reduction sequence (MARS) magnetic resonance imaging (MRI) for the diagnosis of lumbosacral neuropathies in patients with metallic implants in the pelvis. MATERIALS AND METHODS: Twenty-two subjects with lumbosacral neuropathy following pelvic instrumentation underwent 1.5-T MARS MRI including optimized axial intermediate weighted and STIR turbo spin echo sequences extending from L5 to the ischial tuberosity. Two readers graded the visibility of the lumbosacral trunk, sciatic, femoral, lateral femoral cutaneous, and obturator nerves and the nerve signal intensity of nerve, architecture, caliber, course, continuity, and skeletal muscle denervation. Clinical examination and electrodiagnostic studies were used as the standard of reference. Descriptive, agreement, and diagnostic performance statistics were applied. RESULTS: Lumbosacral plexus visibility on MARS MRI was good (4) or very good (3) in 92% of cases with 81% exact agreement and a Kendall's W coefficient of 0.811. The obturator nerve at the obturator foramen and the sciatic nerve posterior to the acetabulum had the lowest visibility, with good or very good ratings in only 61% and 77% of cases respectively. The reader agreement for nerve abnormalities on MARS MRI was excellent, ranging from 95.5 to 100%. MARS MRI achieved a sensitivity of 86%, specificity of 67%, positive predictive value of 95%, and negative predictive value of 40%, and accuracy of 83% for the detection of neuropathy. CONCLUSION: MARS MRI yields high image quality and diagnostic accuracy for the assessment of lumbosacral neuropathies in patients with metallic implants of the pelvis and hips. PMID- 28357570 TI - Sodium Tetradecyl Sulfate-Induced Acute Allergic Interstitial Nephritis. PMID- 28357569 TI - Leukemic stem cells: identification and clinical application. AB - Leukemic stem cells (LSCs) in acute myeloid leukemia (AML) represent a low frequency subpopulation of leukemia cells that possess stem cell properties distinct from the bulk leukemia cells, including self-renewal capacity and drug resistance. Due to these properties, LSCs are supposed to facilitate the development of relapse. The existence of LSCs is demonstrated by the ability to engraft and initiate human AML in immune-compromised mouse models. Although several lines of evidence suggest the complex heterogeneity of phenotypes displayed by LSC, many studies consider the CD34+/CD38- compartment as the most relevant. To increase the understanding of the true LSC, techniques such as multicolor flow cytometry, side-population assay and ALDH assay are utilized in many laboratories and could aid in this. A better understanding of different LSC phenotypes is necessary to enhance risk group classification, guide clinical decision-making and to identify new therapeutic targets. These efforts to eliminate LSC should ultimately improve the dismal AML outcome by preventing relapse development. PMID- 28357571 TI - Predicting Treatment Response of Colorectal Cancer Liver Metastases to Conventional Lipiodol-Based Transarterial Chemoembolization Using Diffusion Weighted MR Imaging: Value of Pretreatment Apparent Diffusion Coefficients (ADC) and ADC Changes Under Therapy. AB - PURPOSE: To use absolute pretreatment apparent diffusion coefficients (ADC) derived from diffusion-weighted MR imaging (DWI) to predict response to repetitive cTACE for unresectable liver metastases of colorectal carcinoma (CRLM) at 1 and 3 months after start of treatment. MATERIALS AND METHODS: Fifty-five metastases in 34 patients were examined with DWI prior to treatment and 1 month after initial cTACE. Treatment was performed in 4-week intervals. Response was evaluated at 1 and 3 months after start of therapy. Metastases showing a decrease of >=30% in axial diameter were classified as responding lesions. RESULTS: One month after initial cTACE, seven lesions showed early response. There was no significant difference in absolute pretreatment ADC values between responding and non-responding lesions (p = 0.94). Three months after initial cTACE, 17 metastases showed response. There was a significant difference (p = 0.021) between absolute pretreatment ADC values of lesions showing response (median 1.08 * 10-3 mm2/s) and no response (median 1.30 * 10-3 mm2/s). Pretreatment ADC showed fair diagnostic value to predict response (AUC 0.7). Lesions showing response at 3 months also revealed a significant increase in ADC between measurements before treatment and at one month after initial cTACE (p < 0.001). Applying an increase in ADC of 12.17%, response at 3 months after initial cTACE could be predicted with a sensitivity and specificity of 77 and 74%, respectively (AUC 0.817). Furthermore, there was a strong and significant correlation (r = 0.651, p < 0.001) between percentage change in size after third cTACE and percentage change in ADC. CONCLUSION: In patients with CRLM, ADC measurements are potential biomarkers for assessing response to cTACE. PMID- 28357572 TI - Safety and Efficacy of Y-90 Radioembolization After Prior Major Hepatic Resection. AB - PURPOSE: To evaluate the safety and efficacy of yttrium-90 radioembolization (RE) following left or right hepatic lobectomy. MATERIALS AND METHODS: Between 2011 and 2016, 15 patients underwent RE with Y90-resin microspheres following right (8/15) or left (7/15) hepatic lobectomy. In eight patients, the whole liver remnant was treated during a single session, whereas the remaining seven patients received up to 3 selective RE at 1- to 2-month intervals. The administered patient activity was calculated based on the body surface area (BSA) method in all cases. In addition, CT-based volumetry of the liver remnant was performed and used to calculate the absorbed liver dose. Patient follow-up data were retrospectively analyzed regarding signs of radioembolization-induced liver disease (REILD), defined as occurrence of bilirubin >3.0 mg/dl and ascites within 1-2 months after treatment without tumor progression or bile duct occlusion. RESULTS: The mean volume of the liver remnant was 1.471 +/- 341 ml, the mean administered amount of activity amounted to 1.31 +/- 0.74 GBq, and the calculated mean absorbed dose was 42.8 +/- 20.6 Gy. The early response to treatment was generally positive, with only one patient showing signs of progressive disease of the treated area on follow-up examinations within the first 2 months post-RE. None of the 15 patients developed a REILD. CONCLUSION: Y-90 radioembolization following extended hepatic lobectomy appears to be safe and effective. Although the standard BSA-based dosing seems to suffice to avoid REILD, it results in quite variable liver doses due to variable hypertrophy of the liver remnant post hepatectomy. LEVEL OF EVIDENCE: Level IV, Case series. PMID- 28357574 TI - Percutaneous Imaging-Guided Screw Fixation of Osteoporotic Transverse Fractures of the Lower Sacrum with Cement Augmentation: Report of 2 Cases. AB - Osteoporotic fractures of the sacrum usually involve the sacral ala and can be managed with percutaneous cementoplasty if conservative therapy failed to achieve bone consolidation. On the other hand, isolated transverse fractures of the lowest sacrum are more rare, with little literature focusing on their management in the osteoporotic population. If pseudoarthrosis occurs in this location, sacroplasty is not an optimal therapeutic option because of the poor biomechanical resistance of cement to multi-directional stresses. Hence, we report two cases of chronic unhealed transverse fractures of the lowest sacrum successfully managed with percutaneous image-guided screw fixation augmented with cement injection. At last follow-up available, both patients experienced complete pain relief, without evidences of failure of the osteosynthesis on CT-scan controls. PMID- 28357573 TI - Retrospective Evaluation of Safety, Efficacy and Risk Factors for Pneumothorax in Simultaneous Localizations of Multiple Pulmonary Nodules Using Hook Wire System. AB - PURPOSE: To evaluate the safety and efficacy of the hook wire system in the simultaneous localizations for multiple pulmonary nodules (PNs) before video assisted thoracoscopic surgery (VATS), and to clarify the risk factors for pneumothorax associated with the localization procedure. METHODS: Between January 2010 and February 2016, 67 patients (147 nodules, Group A) underwent simultaneous localizations for multiple PNs using a hook wire system. The demographic, localization procedure-related information and the occurrence rate of pneumothorax were assessed and compared with a control group (349 patients, 349 nodules, Group B). Multivariate logistic regression analyses were used to determine the risk factors for pneumothorax during the localization procedure. RESULTS: All the 147 nodules were successfully localized. Four (2.7%) hook wires dislodged before VATS procedure, but all these four lesions were successfully resected according to the insertion route of hook wire. Pathological diagnoses were acquired for all 147 nodules. Compared with Group B, Group A demonstrated significantly longer procedure time (p < 0.001) and higher occurrence rate of pneumothorax (p = 0.019). Multivariate logistic regression analysis indicated that position change during localization procedure (OR 2.675, p = 0.021) and the nodules located in the ipsilateral lung (OR 9.404, p < 0.001) were independent risk factors for pneumothorax. CONCLUSION: Simultaneous localizations for multiple PNs using a hook wire system before VATS procedure were safe and effective. Compared with localization for single PN, simultaneous localizations for multiple PNs were prone to the occurrence of pneumothorax. Position change during localization procedure and the nodules located in the ipsilateral lung were independent risk factors for pneumothorax. PMID- 28357575 TI - Ultrasound-Guided Biopsies of Bone Lesions Without Cortical Disruption Using Fusion Imaging and Needle Tracking: Proof of Concept. AB - OBJECTIVE: To assess the technical feasibility and safety of combined fusion imaging and needle tracking under ultrasound guidance to target bone lesions without cortical disruption. MATERIALS AND METHODS: Between January 2016 and March 2016, seven patients underwent US-guided biopsy of bone lesions without cortical disruption. Targeted bone lesions were measuring more than 1.5 cm with a thin cortex, a trans-osseous pathway not exceeding 2 cm and without any adjacent vulnerable structures. First three procedures were performed in the CT suite to aid the needle tracking where necessary (group 1), the remaining four procedures were performed in the US suite (group 2). In group 1, deviation from the real position of the bone trocar (estimated on CT) was compared to the virtual position (estimated on the fusion CT-US images). In both group, procedure data and histopathological results were collected, and compared to the suspected diagnosis and follow-up. RESULTS: Mean procedure duration was 44 min. Total number of synchronisation points for combined fusion imaging were 3.3 on average. In group 1, mean deviation between the virtual and real CT coordinates was 5.3 mm on average. All biopsies yielded adequate quality analysable bone sample. Histopathological analysis revealed malignancy in three cases, non-specific inflammation in two cases, and normal bone in two cases. The four benign results were confirmed as true negative results. There were no immediate or post procedural complications. CONCLUSION: The use of combined fusion imaging and needle tracking ultrasound guidance to target bone lesions without cortical disruption seems technically feasible, provided the patient and lesion selection is appropriate. PMID- 28357576 TI - A Novel External Carotid Arterial Sheath System for Intra-arterial Infusion Chemotherapy of Head and Neck Cancer. AB - PURPOSE: The purpose of this study was to describe a novel system for treating advanced head and neck cancer consisting of an external carotid arterial sheath (ECAS) and a microcatheter to inject drugs retrogradely into multiple feeding arteries through the superficial temporal artery (STA). MATERIALS AND METHODS: Four consecutive patients with head and neck cancer that had more than one feeding artery were enrolled in this study. The ECAS was made of polyurethane and surface-coated with heparin resin to prevent thrombus formation, allowing it to remain in place for a prolonged period of time. The ECAS was inserted through the STA, and its tip was placed between the maxillary artery and facial artery. The tumor-feeding arteries were selected using a hooked-shaped microcatheter through the ECAS. RESULTS: A total of 13 target arteries were selected in the four patients. The microcatheter inserted via the ECAS was used to catheterize ten arteries (five lingual arteries and five facial arteries). The remaining three lingual arteries were directly selected by the catheter without ECAS. All of the target arteries were able to be catheterized superselectively. The technical success rate was 100%. Vascular occlusion, which might have been caused by the ECAS, was observed in one patient. No neurologic toxicities occurred. CONCLUSION: This ECAS system is a new approach for retrograde superselective intra-arterial chemotherapy that covers the entire tumor with anticancer drugs. It has the potential to increase the effectiveness of therapy for advanced head and neck cancer. LEVEL OF EVIDENCE: Level 4, Case Series. PMID- 28357577 TI - A comparison of two methods for quantifying parasitic nematode fecundity. AB - Accurate measures of nematode fecundity can provide important information for investigating parasite life history evolution, transmission potential, and effects on host health. Understanding differences among fecundity assessment protocols and standardizing methods, where possible, will enable comparisons across different studies and host and parasite species and systems. Using the trichostrongyle nematode Cooperia fuelleborni isolated from wild African buffalo (Syncerus caffer), we compared egg recovery and enumeration between two methods for measuring the fecundity of female worms. The first method, in utero egg count, involves visual enumeration of the eggs via microscopic inspection of the uterine system. The second method, ex utero egg count, involves dissolving the same specimens from above in a sodium chloride solution to release the eggs from the female's uterus, then enumeration under an inverted microscope. On average, the ex utero method resulted in 34% more eggs than the in utero method. However, results indicate that the two methods used to quantify parasitic nematode fecundity are highly correlated. Thus, while both methods are viable options for estimating relative nematode fecundity, we recommend caution in undertaking comparative studies that utilize egg count data collected using different methods. PMID- 28357578 TI - Effect of fatty acid interaction on myoglobin oxygen affinity and triglyceride metabolism. AB - Recent studies have suggested myoglobin (Mb) may have other cellular functions in addition to storing and transporting O2. Indeed, NMR experiments have shown that the saturated fatty acid (FA) palmitate (PA) can interact with myoglobin (Mb) in its ligated state (MbCO and MbCN) but does not interact with Mb in its deoxygenated state. The observation has led to the hypothesis that Mb can also serve as a fatty acid transporter. The present study further investigates fatty acid interaction with the physiological states of Mb using the more soluble but unsaturated fatty acid, oleic acid (OA). OA binds to MbCO but does not bind to deoxy Mb. OA binding to Mb, however, does not alter its O2 affinity. Without any Mb, muscle has a significantly lower level of triglyceride (TG). In Mb knock-out (MbKO) mice, both heart and skeletal muscles have lower level of TG relative to the control mice. Training further decreases the relative TG in the MbKO skeletal muscle. Nevertheless, the absence of Mb and lower TG level in muscle does not impair the MbKO mouse performance as evidenced by voluntary wheel running measurements. The results support the hypothesis of a complex physiological role for Mb, especially with respect to fatty acid metabolism. PMID- 28357579 TI - Epithelial cell types and their proposed roles in maintaining the mucosal barrier in human chagasic-megacolonic mucosa. AB - Patients suffering from chagasic megacolon must have an intact mucosal barrier as they survive this chronic disease for decades. A key structure of the mucosal barrier are epithelial cells. Vasoactive-intestinal-peptide (VIP)-positive nerve fibres are involved in influencing, e.g., epithelial cell proliferation, mucus secretion (e.g., mucin 2 and trefoil factor 3 of goblet cells) and inflammation or autoimmunity, all putative and/or known factors altered in chagasic megacolon. We analyzed qualitatively and quantitatively goblet cells, their specific markers, such as mucin 2 (MUC2) and trefoil factor 3 (TFF3) and enterocytes, the relation of VIP-immunoreactive nerve fibres to the epithelia, the distribution of gelsolin, a protein involved in chronic inflammation processes in the epithelia, and the proliferation rate of epithelial cells by combined 4',6-diamidino-2 phenylindole (DAPI) and phosphohistone-H3 (PHH3) staining. Goblet cells were the dominating epithelial cell type. They accounted for 38.4% of all epithelial cells in controls and changed to 58.9% in the megacolonic parts. In contrast to the overall expression in goblet cells of control epithelia, TFF3 was confined to goblet cells at the base of the crypts whereas MUC2 was found only in luminal goblet cells. Gelsolin-positive goblet cells were predominantly recognized within the controls. Finally, the mean value of mitosis increased from 1.5% within the controls up to 2.6% in the anal parts of the chagasic sepcimens. Taken together, increased cell proliferation, preponderance of goblet cells, differential MUC 2, and TFF 3 expression might all be factors maintaining an intact mucosal barrier within chagasic megacolon. PMID- 28357580 TI - The relationship between oxygen uptake kinetics and neuromuscular fatigue in high intensity cycling exercise. AB - PURPOSE: In theory, a slow oxygen uptake ([Formula: see text]) kinetics leads to a greater accumulation of anaerobic by-products, which can, in turn, induce more neuromuscular fatigue. However, the existence of this relationship has never been tested. METHODS: After two sessions to measure peak [Formula: see text], peak power output (POpeak), and [Formula: see text] kinetics responses in the unfatigued state (tau [Formula: see text] MOD), 10 healthy young adults performed a 6-min cycling bout at 80% POpeak (INT6-min). [Formula: see text] kinetics responses were also measured during INT6-min. Neuromuscular fatigue was measured isometrically pre- and post-INT6-min (immediately post- and 15-s post-INT6-min) with an innovative cycle ergometer. RESULTS: Maximal voluntary contraction (MVC) force, high-frequency doublet amplitude, and the ratio of low- to high-frequency doublet amplitudes decreased by 34 +/- 7, 43 +/- 11, and 31 +/- 13%, respectively (all P < 0.01). A significant Spearman's rank correlation was observed between the change in low-frequency doublet force (DeltaDb10) immediately after INT6-min and both tau [Formula: see text] MOD and tau [Formula: see text] INT6-min (rho = 0.68 and rho = -0.67, both P < 0.05). When considering the largest responses from the two neuromuscular evaluations post-INT6-min, significant correlations were also found between tau [Formula: see text] MOD and DeltaDb10 (rho = -0.74; P < 0.05) and between tau[Formula: see text] INT6-min and both DeltaDb10 and low frequency fatigue (rho = -0.70 and rho = -0.66; both P < 0.05). CONCLUSION: The present results suggest that subjects with slow [Formula: see text] kinetics experience more peripheral fatigue, in particular more excitation-contraction coupling failure, likely due to a greater accumulation of protons and/or inorganic phosphates. PMID- 28357581 TI - Malaria: An Update. AB - India is endemic for malaria with unstable transmission inhibiting the development of immunity and predisposing all age groups to the disease. Children under five are the greatest sufferers with maximum mortality. P. falciparum and P. vivax cause majority of cases. Fever is the cardinal symptom, though no set of signs and symptoms reliably distinguishes malaria from other causes of fever. In all suspected cases parasitological diagnosis should be confirmed before starting the treatment. Microscopy of blood smears is the gold standard for diagnosis. Rapid diagnostic tests are to be used where microscopy results are not available within 24 h. In complicated malaria and high risk patients like HIV, treatment can be commenced before confirmation, though all efforts to establish the diagnosis should be made. Chloroquine is used for uncomplicated vivax malaria while artemisinin based combination therapy (ACTs) is used for uncomplicated falciparum malaria. For complicated malaria, IV artesunate is the drug of choice irrespective of the Plasmodium species. It is important to follow recommendations diligently to decrease morbidity and mortality due to malaria and to avoid the problem of drug resistance. The gains of the past decade should be scaled up to make malaria elimination and eradication a reality. PMID- 28357582 TI - Management of Hodgkins Lymphoma: ICMR Consensus Document. AB - Pediatric Hodgkins lymphoma is a highly curable disease even in the developing world. Current treatment paradigms follow a risk and response based approach. The goal is to minimise treatment related short and long-term toxicity while maintaining excellent survival. A confirmed histopathological diagnosis and full staging work-up are essential prior to embarking on treatment and guidelines for these are provided in the text. All patients require combination chemotherapy while radiotherapy is usually reserved for a select subgroup depending on the protocol used. It is important to follow these patients for relapse in the first five years and life-long for late effects as most of them will be cured. PMID- 28357583 TI - Motor exam of patients with spinal cord injury: a terminological imbroglio. AB - The description of the motor deficit of patients with spinal cord injury (SCI) varies significantly, leading to confusion within the neurological terminology. This paper proposes a concise and easy to use terminology to describe the motor deficit of patients with SCI. A broad review of the origin of the nomenclature used to describe the motor deficit of patients with SCI was performed and discussed. The prefix: "hemi" should be used to describe paralysis of one half of the body; "mono" for one limb; "para" for lower limbs, di" for two symmetrical segments and/or parts in both sides of the body; "tri" for three limbs, or two limbs and one side of the face; and "tetra" for four limbs. The suffix: "plegia" should be used for total paralysis of a limb or part of the body, and "paresis" for partial paralysis. The term "brachial" refers to the upper limbs; and "podal" to the lower limbs. According to the spinal cord origin of the main key muscles for the limbs, patients with complete injury affecting spinal cord segments C1-5 usually presents with "tetraplegia"; C6-T1 presents with "paraplegia and brachial diparesis"; T2-L2 with "paraplegia"; and L3-S1 with "paraparesis". PMID- 28357585 TI - Uneven cerebral hemodynamic change as a cause of neurological deterioration in the acute stage after direct revascularization for moyamoya disease: cerebral hyperperfusion and remote ischemia caused by the 'watershed shift'. AB - Superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis is the standard surgical treatment for moyamoya disease (MMD). The main potential complications of this treatment are cerebral hyperperfusion (CHP) syndrome and ischemia, and their managements are contradictory to each other. We retrospectively investigated the incidence of the simultaneous manifestation of CHP and infarction after surgery for MMD. Of the 162 consecutive direct revascularization surgeries performed for MMD, we encountered two adult cases (1.2%) manifesting the simultaneous occurrence of symptomatic CHP and remote infarction in the acute stage. A 47-year-old man initially presenting with infarction developed CHP syndrome (aphasia) 2 days after left STA-MCA anastomosis, as assessed by quantitative single-photon emission computed tomography (SPECT). Although lowering blood pressure ameliorated his symptoms, he developed cerebral infarction at a remote area in the acute stage. Another 63 year-old man, who initially had progressing stroke, presented with aphasia due to focal CHP in the left temporal lobe associated with acute infarction at the tip of the left frontal lobe 1 day after left STA-MCA anastomosis, when SPECT showed a paradoxical decrease in cerebral blood flow (CBF) in the left frontal lobe despite a marked increase in CBF at the site of anastomosis. Symptoms were ameliorated in both patients with the normalization of CBF, and there were no further cerebrovascular events during the follow-up period. CHP and cerebral infarction may occur simultaneously not only due to blood pressure lowering against CHP, but also to the 'watershed shift' phenomenon, which needs to be elucidated in future studies. PMID- 28357586 TI - Behavioral inhibition system sensitivity enhances motor cortex suppression when watching fearful body expressions. AB - Influential theories suggest that a defensive behavioral inhibition system (BIS) supports the inhibition of action tendencies when facing potential threats. However, little is known about threat-related inhibitory mechanisms in humans and their relations to inter-individual differences in BIS sensitivity. To address this issue, we used paired-pulse TMS to investigate early human motor cortex (M1) responses to social signals of potential threats, like another's fearful body posture. In two experiments, participants observed pictures of fearful and happy postures, and neutral postures that were either dynamic (in Exp1) or static (in Exp2). To test suppression of M1 excitatory activity, we assessed intracortical facilitation (ICF) in an early phase of threat monitoring by administering TMS pulses at 100-125 ms from picture onset. We investigated the motor representation of hand and arm muscles that are differentially involved in flexion, extension, and abduction. As a control, we also assessed corticospinal excitability and short intracortical inhibition. In both experiments, and independently of the muscle, watching fearful bodies suppressed ICF relative to watching happy and non emotional (dynamic or static) body expressions. Remarkably, greater fear-related ICF suppression was found in participants who scored higher on a self-report questionnaire assessing BIS sensitivity. These findings suggest that observing fearful body language activates a defensive suppression of M1 excitatory activity that is influenced by the personality disposition to experience fear and anxiety when facing potential threats. This BIS-related motor suppression may have the functional role of transiently suppressing action tendencies to promote threat monitoring and, ultimately, survival. PMID- 28357584 TI - Association of cytochrome P4502E1 and NAD(P)H:quinone oxidoreductase 1 genetic polymorphisms with susceptibility to large artery atherosclerotic ischemic stroke: a case-control study in the Turkish population. AB - Stroke, a major cause of death and disability, is described as interruption or severe reduction of blood flow in cerebral arteries. Oxidative stress plays an important role in the pathogenesis of atherosclerosis and carotid atherosclerosis is a risk factor for stroke. Combination of multiple environmental and genetic risk factors is thought to increase stroke. Therefore, investigation of the polymorphisms of enzymes is of crucial importance to determine the molecular etiology of the disease. To test this hypothesis, we performed a case-control study in which we compared the distribution of CYP2E1 and NQO1 genotypes between 245 large artery atherosclerotic ischemic stroke patients and 145 controls, using PCR-RFLP. A significant difference was observed between stroke patients and controls with respect to the CYP2E1*5B genotype (odds ratio; OR 8.069, P = 0.011) and allele (OR 7.876, P = 0.011) distribution. However, this polymorphism was not a significant predictor of disease status in logistic regression analysis. NQO1*2 polymorphism genotype distribution was significantly different between patients and controls (P = 0.027) and heterozygote *1*2 genotype was found to be a protective factor against large artery atherosclerotic ischemic stroke in logistic regression analysis (OR 0.562, P = 0.018). This is the first study conducted regarding the association of CYP2E1 and NQO1 genetic polymorphisms and large artery atherosclerotic ischemic stroke risk in Turkish population. PMID- 28357587 TI - Three cases of L4-5 Baastrup's disease due to L5-S1 spondylolytic spondylolisthesis. AB - PURPOSE: Baastrup's disease is characterized by degeneration of spinous processes and interspinous soft tissue, which may cause spinal stenosis. Purpose of this article is to report the possible new cause of Baastrup's disease and result of surgical treatments. METHODS: Authors treated three cases of Baastrup's disease on L4-L5 with L5-S1 spondylolytic listhesis. Conservative treatment did not relieve the pain; therefore, surgical treatments were planned according to each specific disease condition. RESULTS: In one case, anterior lumbar interbody fusion of L5-S1 was performed, and after surgery, the size of epidural cyst on L4 L5 was decreased. L4-L5 bilateral laminectomy was performed to directly decompress posterior epidural cyst in a case with stable L5-S1 spondylolytic listhesis. In last case, facet joints and spinous process were removed by L5-S1 posterior lumbar interbody fusion (PLIF) surgery. After the surgery, patients' back and leg pain was improved and postoperative MRI revealed successful decompression of the spinal canal. Improvement in back and leg symptoms was noted at 12-month follow-up. CONCLUSIONS: Baastrup's disease at the L4-L5 level may have developed from the instability caused by L5-S1 spondylolytic spondylolisthesis. Viable treatment options include the fusion of L5-S1 or a laminectomy at the L4-L5 level. PMID- 28357589 TI - Use of a Web-Based Calculator and a Structured Report Generator to Improve Efficiency, Accuracy, and Consistency of Radiology Reporting. AB - While medical calculators are common, they are infrequently used in the day-to day radiology practice. We hypothesized that a calculator coupled with a structured report generator would decrease the time required to interpret and dictate a study in addition to decreasing the number of errors in interpretation. A web-based application was created to help radiologists calculate leg-length discrepancies. A time motion study was performed to evaluate if the calculator helped to decrease the time for interpretation and dictation of leg-length radiographs. Two radiologists each evaluated two sets of ten radiographs, one set using the traditional pen and paper method and the other set using the calculator. The time to interpret each study and the time to dictate each study were recorded. In addition, each calculation was checked for errors. When comparing the two methods of calculating the leg lengths, the manual method was significantly slower than the calculator for all time points measured: the mean time to calculate the leg-length discrepancy (131.8 vs. 59.7 s; p < 0.001), the mean time to dictate the report (31.8 vs. 11 s; p < 0.001), and the mean total time (163.7 vs. 70.7 s; p < 0.001). Reports created by the calculator were more accurate than reports created via the manual method (100 vs. 90%), although this result was not significant (p = 0.16). A calculator with a structured report generator significantly improved the time required to calculate and dictate leg length discrepancy studies. PMID- 28357590 TI - Non-machinery dialysis that achieves blood purification therapy without using full-scale dialysis machines. AB - An electrical or water supply and a blood purification machine are required for renal replacement therapy. There is a possibility that acute kidney injury can occur in large numbers and on a wide scale in the case of a massive earthquake, and there is the potential risk that the current supply will be unable to cope with acute kidney injury cases. However, non-machinery dialysis requires exclusive circuits and has the characteristic of not requiring the full-scale dialysis machines. We performed perfusion experiments that used non-machinery dialysis and recent blood purification machines in 30-min intervals, and the effectiveness of non-machinery dialysis was evaluated by the assessing the removal efficiency of potassium, which causes lethal arrhythmia during acute kidney injury. The non-machinery dialysis potassium removal rate was at the same level as continuous blood purification machines with a dialysate flow rate of 5 L/h after 15 min and continuous blood purification machines with a dialysate flow rate of 3 L/h after 30 min. Non-machinery dialysis required an exclusive dialysate circuit, the frequent need to replace bags, and new dialysate exchanged once every 30 min. However, it can be seen as an effective renal replacement therapy for crush-related acute kidney injury patients, even in locations or facilities not having the full-scale dialysis machines. PMID- 28357591 TI - Development and Pretesting of a Questionnaire to Assess Patient Experiences and Satisfaction with Medications (PESaM Questionnaire). AB - BACKGROUND: The aim of this study was to develop, together with the Lung Foundation Netherlands and Dutch Kidney Patients Association, patients and clinicians, a measure to evaluate patient experiences with the orphan drugs pirfenidone (for idiopathic pulmonary fibrosis [IPF]) and eculizumab (for atypical haemolytic uraemic syndrome [aHUS]), as well as a generic measure of patient experiences and satisfaction with medications. METHODS: Development of the Patient Experiences and Satisfaction with Medications (PESaM) questionnaire consisted of four phases: literature review (phase I); focus groups and individual patient interviews (phase II); item generation (phase III); and face and content validity testing (phase IV). Literature review aimed to identify existing disease-specific and generic patient experience measures to provide guidance on the domains of medication use relevant to patients, the number of items and type of response categories, and to generate an initial pool of items. Subsequent focus groups and patient interviews were conducted to gain insight into the perceived effectiveness of the therapies, the burden of side effects, and how the medication impacted on a patient's daily life. Focus groups and interviews were recorded and transcribed verbatim. Coding was carried out by highlighting passages in the text and assigning each passage a code representing the following predefined categories: (1) perceived effectiveness; (2) side effects; (3) ease of use; and (4) impact of medication. Using data from phase I and II, a panel of experts selected items relevant for inclusion in the questionnaire. Individual patient interviews with IPF and aHUS patients (n = 18), using a retrospective verbal probing technique, were conducted to assess face validity, time needed to fill out the questionnaire, and content validity. RESULTS: The PESaM questionnaire that was developed consisted of two disease specific modules that assessed patient experiences with pirfenidone for the treatment of IPF, and eculizumab for the treatment of aHUS, a generic module, applicable to any medication, and a module to assess patient expectations. Review of the literature identified multiple disease- or medication-specific questionnaires and two generic patient satisfaction questionnaires. Common domains across most questionnaires were effectiveness, side effects, ease of use and overall satisfaction. Patient interviews revealed the social impact (e.g. unable to go outside) of side effects such as photosensitivity associated with pirfenidone and the risk of infection associated with eculizumab. Each PESaM module focuses on patients' perceived effectiveness of the medication, side effects, and ease of use, and the impact these aspects have on physical and emotional health and daily life. The generic module additionally includes items related to satisfaction with the medication. Individual interviews with patients in phase IV confirmed, in general, that questions and response options of the modules were clear and content validity was good. The mean time to complete the modules ranged from 6 min for the disease-specific (aHUS) module to 9 min for the generic module. CONCLUSIONS: We developed the PESaM questionnaire to quantitatively assess patient experiences and satisfaction with medications. A validation study is currently underway to examine the psychometric properties of the PESaM questionnaire. PMID- 28357592 TI - Awareness and knowledge of cardiovascular disease risk factors among medical students. AB - BACKGROUND: The aim of this study was to assess the knowledge and attitude of medical students in relation to cardiovascular disease (CVD) risk factors as well as to assess the impact of medical education on their knowledge and recognition of the importance of implementation of preventive measures. METHODS: This cross sectional study included 514 students in the second year of studying at the Faculty of Medicine in Belgrade, Serbia (younger students response rate 79.57%) and 511 students in the last year of education (older students response rate 90.21%). For data collection, an anonymous self-administered questionnaire was used, which included two types of questions about CVD risk factors and questions about the student's attitude. RESULTS: Older students knew significantly more about CVD risk factors than students who were at the beginning of their medical studies; however, more than half of the older students did not know the correct answers about CVD risk factors. The only exceptions were questions about "bad" and "good" cholesterol, metabolic syndrome (MSy) and lipid lowering therapy in high risk subjects. Physical inactivity, obesity, type 2 diabetes, smoking and hypertension were not ranked highly enough as important CVD risk factors. Compared groups of students did not significantly differ in attitude scores. The majority of them recognized CVD as the leading cause of death, had normal weight and knew their own blood pressure. CONCLUSION: Knowledge of medical students from Belgrade about CVD risk factors should be improved. PMID- 28357593 TI - The relationship between subclinical thyroid dysfunction and the risk of fracture or low bone mineral density: a systematic review and meta-analysis of cohort studies. AB - Our aim was to assess the risk of fractures or low bone mineral density (BMD) associated with subclinical thyroid dysfunction among cohorts. We systematically searched Medline (via PubMed), EMBASE, Cochrane Library, Web of Science, CENTRAL and SinoMed up to 31 July 2016 to identify cohort studies which have analyzed associations between subclinical thyroid dysfunction and fracture or BMD. A total of 19 population-based cohorts including 79,368 participants with relationships between subclinical thyroid dysfunction and fractures or BMD were identified as eligible for this meta-analysis. Subclinical hypothyroidism was associated with relative risks (RRs) of 1.34 (95% confidence interval [CI] 1.14, 1.58; I 2 = 32%) for hip fracture, 1.27 (95% CI 1.02, 1.58; I 2 = 51.9%) for any location of fracture, and 1.25 (95% CI 1.04, 1.50) for forearm fracture. Subclinical hyperthyroidism was associated with RRs of 1.71 (95% CI 1.06, 2.76; I 2 = 0.0%) for spine fracture, 1.20 (95% CI 1.03, 1.39; I 2 = 0.0%) for non-spine fracture, 1.44 (95% CI 1.21, 1.71; I 2 = 0.0%) for hip fracture, and 1.38 (95% CI 1.21, 1.58; I 2 = 0.0%) for any location of fracture. Subgroup analysis was conducted according to whether thyroid/anti-thyroid drug users were excluded or not and the results were similar. The change in BMD at the hip (weighted mean difference [WMD] = -0.060, 95% CI -0.116, -0.004; I 2 = 0.0%) and femoral neck (WMD = 0.046, 95% CI -0.077, -0.015; I 2 = 0.0%) was significantly decreased in the subclinical hyperthyroidism group compared with the euthyroidism groups in females. We failed to find any associations between the change in BMD and subclinical hypothyroidism. The overall quality of evidence was low in all outcomes. Subclinical hyperthyroidism and subclinical hypothyroidism were associated with an increased risk of fractures. Although subclinical hyperthyroidism was related to reduced BMD, no evidence could prove a definite association between subclinical hypothyroidism and the risk of low BMD. PMID- 28357594 TI - Knockdown of Ggps1 in chondrocyte expedites fracture healing by accelerating the progression of endochondral ossification in mice. AB - Bone fracture healing is achieved through the proliferation and differentiation of stem cells, while bone marrow stem cells (BMSCs) contribute to endochondral ossification. During fracture healing, mesenchymal progenitor cells first form a cartilaginous blastema that becomes vascularized to recruit precursor cells of osteoblasts through the bone morphogenetic protein 2 (Bmp2)/Smad-dependent Runx2 pathway. Statins deplete geranylgeranyl diphosphate (GGPP), which participates in the regulation of BMSCs differentiation, through the inhibition of 3-hydroxy-3 methylglutaryl (HMG)-CoA reductase, leading to impaired protein geranylgeranylation, which strongly impacts the bone synthesis induced by Bmp2. Accordingly, we would like to investigate the role of geranylgeranyl diphosphate synthase 1 (Ggps1) in bone fracture via endochondral ossification in mice. We used a Cre-loxP system, namely the tamoxifen-inducible Collagen 2-CreERT2 Ggps1 fl/fl, to eliminate specifically the Ggps1 activity in chondrocytes of 8-10-week old mice. We found that the endochondral bone formation, calcification and vasculogenesis of the bony callus were accelerated in fractures in Ggps1-/-mice. Together, the results of this study confirm that the specific deletion of Ggps1, using the Collagen 2-CreERT2 mice, will accelerate the fracture healing process by activating the Bmp2/Smad-dependent Runx2 pathway. In addition, we managed to improve the fracture healing process by inhibiting the Ggps1 activity and its related products with statin drugs. PMID- 28357595 TI - Increasing the yield of middle silk gland expression system through transgenic knock-down of endogenous sericin-1. AB - Various genetically modified bioreactor systems have been developed to meet the increasing demands of recombinant proteins. Silk gland of Bombyx mori holds great potential to be a cost-effective bioreactor for commercial-scale production of recombinant proteins. However, the actual yields of proteins obtained from the current silk gland expression systems are too low for the proteins to be dissolved and purified in a large scale. Here, we proposed a strategy that reducing endogenous sericin proteins would increase the expression yield of foreign proteins. Using transgenic RNA interference, we successfully reduced the expression of BmSer1 to 50%. A total 26 transgenic lines expressing Discosoma sp. red fluorescent protein (DsRed) in the middle silk gland (MSG) under the control of BmSer1 promoter were established to analyze the expression of recombinant. qRT PCR and western blotting showed that in BmSer1 knock-down lines, the expression of DsRed had significantly increased both at mRNA and protein levels. We did an additional analysis of DsRed/BmSer1 distribution in cocoon and effect of DsRed protein accumulation on the silk fiber formation process. This study describes not only a novel method to enhance recombinant protein expression in MSG bioreactor, but also a strategy to optimize other bioreactor systems. PMID- 28357597 TI - Erratum to: Effects of Mental Stress Induction on Heart Rate Variability in Patients with Panic Disorder. PMID- 28357596 TI - Combined sense-antisense Alu elements activate the EGFP reporter gene when stable transfection. AB - Alu elements in the human genome are present in more than one million copies, accounting for 10% of the genome. However, the biological functions of most Alu repeats are unknown. In this present study, we detected the effects of Alu elements on EGFP gene expression using a plasmid system to find the roles of Alu elements in human genome. We inserted 5'-4TMI-Alus-CMV promoter-4TMI-Alus (or antisense Alus)-3' sequences into the pEGFP-C1 vector to construct expression vectors. We altered the copy number of Alus, the orientation of the Alus, and the presence of an enhancer (4TMI) in the inserted 5'-4TMI-Alus-CMV promoter-4TMI Alus (or antisense Alus)-3' sequences. These expression vectors were stably transfected into HeLa cells, and EGFP reporter gene expression was determined. Our results showed that combined sense-antisense Alu elements activated the EGFP reporter gene in the presence of enhancers and stable transfection. The combined sense-antisense Alu vectors carrying four copies of Alus downstream of inserted CMV induced much stronger EGFP gene expression than two copies. Alus downstream of inserted CMV were replaced to AluJBs (having 76% homology with Alu) to construct expression vectors. We found that combined sense-antisense Alu (or antisense AluJB) vectors induced strong EGFP gene expression after stable transfection and heat shock. To further explore combined sense-antisense Alus activating EGFP gene expression, we constructed Tet-on system vectors, mini-C1 Alu-sense-sense and mini-C1-Alu-sense-antisense (EGFP gene was driven by mini CMV). We found that combined sense-antisense Alus activated EGFP gene in the presence of reverse tetracycline repressor (rTetR) and doxycycline (Dox). Clone experiments showed that Mini-C1-Alu-sense-antisense vector had more positive cells than that of Mini-C1-Alu-sense-sense vector. The results in this paper proved that Alu repetitive sequences inhibited gene expression and combined sense antisense Alus activated EGFP reporter gene when Alu transcribes, which suggests that Alus play roles in maintaining gene expression (silencing genes or activating genes) in human genome. PMID- 28357598 TI - The effect of Er:YAG laser irradiation on the bond stability of self-etch adhesives at different dentin depths. AB - The aim of this study was to evaluate the effect of Er:YAG laser irradiation on the micro-shear bond strength of self-etch adhesives to the superficial dentin and the deep dentin before and after thermocycling. Superficial dentin and deep dentin surfaces were prepared by flattening of the occlusal surfaces of extracted human third molars. The deep or superficial dentin specimens were randomized into three groups according to the following surface treatments: group I (control group), group II (Er:YAG laser; 1.2 W), and group III (Er:YAG laser; 0.5 W). Clearfil SE Bond or Clearfil S3 Bond was applied to each group's dentin surfaces. After construction of the composite blocks on the dentin surface, the micro-shear bond testing of each adhesive was performed at 24 h or after 15,000 thermal cycles. The data were analyzed using a univariate analysis of variance and Tukey's test (p < 0.05). Laser irradiation in superficial dentin did not significantly affect bond strength after thermocycling (p > 0.05). However, deep dentin specimens irradiated with laser showed significantly higher bond strengths than did control specimens after thermocycling (p < 0.05). Thermocycling led to significant deterioration in the bond strengths of all deep-dentin groups. The stable bond strength after thermocycling was measured for all of the superficial dentin groups. No significant difference was found between the 0.5 and 1.2 W output power settings. In conclusion, the effect of laser irradiation on the bond strength of self-etch adhesives may be altered by the dentin depth. Regardless of the applied surface treatment, deep dentin showed significant bond degradation. PMID- 28357599 TI - Medical Expulsive Therapy: Is It Time to SUSPEND Judgement? AB - Medical expulsive therapy (MET) has been a matter of debate for many years. A number of randomised controlled trials (RCTs) and meta-analyses have been conducted, but outcomes have been varied. This makes it challenging to determine the benefit of using MET as an adjunct in patients with expectantly managed ureteric stones. This article aimed to summarize both the historic and the more contemporary literature in this area by focusing on published meta-analyses and recent RCTs. Studies of interest were those comparing either an alpha-blocker or a calcium channel blocker with a control. Outcome measures of interest were expulsion rates, expulsion times, and medication-related side effects. All systematic reviews included are in favour of MET versus controls. However, many of the component RCTs had limitations such as a high risk of bias, incomplete blinding and heterogeneous inclusion criteria. A recent well-powered RCT found no benefit of MET for the purpose of conservatively managed ureteric stones. This study had some limitations that stimulated further research in the area, adding to the uncertainty. The most recent RCT and meta-analysis indicates MET is more beneficial in both larger (>5 mm) and distal stones. Uncertainty remains in this arena, and there is a need for a robust multi-institution study to assess MET in a cohort of patients who are expectantly managed with ureteric stones. This should serve to counter the marked heterogeneity and limitations of existing trials and meta-analyses. PMID- 28357600 TI - Erratum to: The Natural Course of Atopic Dermatitis and the Association with Asthma. PMID- 28357601 TI - A Review of Microinvasive Combined Phaco-Vitrectomy: Recent Technical Advances. AB - Combined cataract and vitreoretinal surgery results in better compliance in patients with posterior segment pathology and should be the preferred approach to reduce the high rate of cataract development after vitreoretinal surgery and to improve earlier visual acuity. Technological advances in both anterior and posterior segment surgery are leading to the development of instruments with a smaller diameter and more efficient tools, resulting in a minimizing of the tissue trauma related to the surgery, acceleration of functional recovery and increasing patient comfort. In this review we report on recent advances that allow this miniaturization process while maintaining the efficacy and safety of microinvasive combined surgical procedures, with a focus on pumps, illumination, phaco tip and the vitrectomy probe. PMID- 28357602 TI - The clinical importance of the thyroid nodules during anti-tumor necrosis factor therapy in patients with axial spondyloarthritis. AB - The clinical importance of the thyroid nodules in patients with axial spondyloarthritis (ax-SpA) rests with the need to exclude thyroid malignancy. The aim of this study is to assess the risk of thyroid malignancy in ax-SpA patients receiving anti-TNF therapy. From September 2015 until December 2015, 70 patients diagnosed with ax-SpA were included in the research. Forty of the patients had received anti-TNF therapy, and 30 of the patients were anti-TNF naive. All cases were screened for the presence of nodules in the thyroid gland with ultrasound. Of the patients that received anti-TNF therapy, 15 (37.5%); and of the anti-TNF naive patients, 11 (36.7%) had thyroid nodule(s). Four patients from the anti-TNF group underwent fine needle aspiration biopsy of the nodules, and two of them were diagnosed with papillary thyroid carcinoma. None of the nodules in anti-TNF naive patients required biopsy. When compared to the normal population, the standardized incidence ratio (SIR) was found to be increased in both male (SIR 2.03, 95% CI 1.9 to 18) and female (SIR 2.7, 95% CI 2.6 to 24) cases. It is not yet established whether the development of cancer during the treatment process is the effect of the treatment or if it is a part of the natural course of the disease or if it is coincidental. We saw a mild increase in thyroid malignancies in ax-SpA patients who received anti-TNF therapy. Therefore, we believe that the thyroid gland should also be taken into consideration while screening for malignancy before anti-TNF therapy. PMID- 28357603 TI - Volatile-Mediated Interactions between Cabbage Plants in the Field and the Impact of Ozone Pollution. AB - Plants constitutively release volatile organic compounds (VOCs), but qualitatively and quantitatively alter their emission of VOCs in response to biotic and abiotic stresses. The blend of VOCs emitted reflects the physiological status of the plant. Plants may be exposed to the VOC blend emitted by their near neighbors and gain information that allows them to adjust their own defenses. These plant-plant interactions may potentially be exploited to protect crops from pests, but they can be disturbed by abiotic factors making the process sensitive to environmental perturbation. Despite numerous studies describing plant-plant interactions, relatively few have been conducted with agriculturally significant cultivated plant varieties under field conditions. Here we studied plant-plant interactions in a conspecific association of Brassica oleracea var. capitata (cabbage) and show that undamaged plants exposed to neighbors damaged by the herbivore Pieris brassicae are primed for stronger volatile emissions upon subsequent herbivore attack. We conducted a field study in an ozone free-air concentration enrichment (FACE) facility with ambient and elevated ozone levels and found that elevated tropospheric ozone significantly alters the priming of VOCs in receiver plants. We conclude that plant-plant interactions may prime defensive attributes of receiver plants under field conditions, but are impaired by ozone pollution. Therefore, when planning the manipulation of plant-plant interactions for agricultural purposes, the potential effects of atmospheric pollutants should be considered. PMID- 28357604 TI - Affine kinematics in planar fibrous connective tissues: an experimental investigation. AB - The affine transformation hypothesis is usually adopted in order to link the tissue scale with the fibers scale in structural constitutive models of fibrous tissues. Thanks to the recent advances in imaging techniques, such as multiphoton microscopy, the microstructural behavior and kinematics of fibrous tissues can now be monitored at different stretching within the same sample. Therefore, the validity of the affine hypothesis can be investigated. In this paper, the fiber reorientation predicted by the affine assumption is compared to experimental data obtained during mechanical tests on skin and liver capsule coupled with microstructural imaging using multiphoton microscopy. The values of local strains and the collagen fibers orientation measured at increasing loading levels are used to compute a theoretical estimation of the affine reorientation of collagen fibers. The experimentally measured reorientation of collagen fibers during loading could not be successfully reproduced with this simple affine model. It suggests that other phenomena occur in the stretching process of planar fibrous connective tissues, which should be included in structural constitutive modeling approaches. PMID- 28357605 TI - Erratum to: Coevolution of foraging behavior with intrinsic growth rate: risk taking in naturally and artificially selected growth genotypes of Menidia menidia. PMID- 28357606 TI - Genetic variations in the alanine-glyoxylate aminotransferase 2 (AGXT2) gene and dimethylarginines levels in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is associated with high rates of cardiovascular events mainly due to coronary and cerebrovascular atherosclerotic disease. Asymmetric (ADMA) and symmetric (SDMA) dimethylarginines are endogenous inhibitors of nitric oxide synthase and have been repeatedly linked with adverse cardiovascular outcomes in the general population and various disease settings. Alanine glyoxylate aminotransferase 2 (AGTX2) is considered an alternative metabolic pathway contributing to the clearance of dimethylarginines in humans. The aim of the current study was to investigate the effect of specific AGXT-2 gene polymorphisms on circulating levels of ADMA or SDMA in patients with RA. Serum ADMA and SDMA levels were measured in 201 individuals with RA [median age: 67 years (IQR: 59-73), 155 females]. Two single nucleotide polymorphisms (SNPs) in the AGXT-2 gene-rs37369 and rs28305-were genotyped. Distributions of SDMA and ADMA were skewed, hence comparisons across the gene polymorphisms were performed using Kruskal-Wallis tests, and summarized using medians and interquartile ranges. Univariable analysis did not demonstrate a significant difference in the levels of SDMA or ADMA amongst the different genotypic groups of either rs37369AGXT2 (p = 0.800, 0.977) or rs28305AGXT2 (p = 0.463, 0.634). In multivariable analyses, ADMA levels were found to be significantly associated with erythrocyte sedimentation rate and estimated glomerular filtration rate, whilst SDMA levels were significantly associated with estimated glomerular filtration rate and quantitative insulin sensitivity check index. After adjustments for these factors, the relationship between the AGXT2 gene variants and both ADMA and SDMA remained non-significant. Our study in a well characterized RA population did not show an association between serum concentrations of dimethylarginines and genetic variants of the AGXT2 gene. PMID- 28357608 TI - About HER2 monitoring using liquid biopsies in patients with gastric cancer. PMID- 28357607 TI - Social support and its interrelationships with demand-control model factors on presenteeism and absenteeism in Japanese civil servants. AB - OBJECTIVES: To elucidate the impact of social support and its interrelations with other demand-control-support (DCS) model factors on presenteeism and absenteeism, and to determine which DCS factors were most influential. METHODS: Questionnaires from 2535 local government employees were analyzed. The Brief Job Stress Questionnaire (BJSQ) was used to assess DCS factors including job demand, job control, and social support from supervisors and coworkers. The Stanford Presenteeism Scale 13-item version (SPS-13) was used to evaluate both absenteeism (absent days) and presenteeism. For the latter, the Work Impairment Score (WIS) and the Work Output Score (WOS) were also used. Possible confounder-adjusted logistic and negative binomial regression analyses were performed to obtain odds ratios (ORs) for WIS and WOS and relative risks (RRs) for absenteeism according to DCS factors. RESULTS: Higher job control had a significantly protective effect on higher WIS in both males and females and a lower WOS in males. Based on a point estimate of an OR per 1 standard deviation change of each DCS factor, job control had the strongest effect on higher WIS in both males and females and a lower WOS in males. Higher job demand resulted in significantly higher ORs for both male and female WIS, and a lower WOS in females. Support from supervisors had a significantly protective effect on higher WIS in females and a lower WOS in males. Support from coworkers had a significantly protective effect on higher WIS in males. Higher support from coworkers had a significantly protective effect on absenteeism among both males and females, and higher job control had a significantly protective effect in females. The combination of high job strain and low support from supervisors had a significantly worsening effect, except for absenteeism in females. High job strain and low support from coworkers had a significantly worsening effect except for WOS in males. CONCLUSIONS: The results suggest job control was the DCS factor most related to presenteeism. Higher support from supervisors and coworkers had a protective effect on presenteeism, and higher job demand had a worsening effect. Higher support from coworkers had a protective effect on absenteeism among both males and females. Interventions should focus on improving job control as a possible countermeasure to presenteeism, and encouraging support from coworkers as a possible countermeasure to absenteeism. PMID- 28357609 TI - The Inhibitory Effect of C-phycocyanin Containing Protein Extract (C-PC Extract) on Human Matrix Metalloproteinases (MMP-2 and MMP-9) in Hepatocellular Cancer Cell Line (HepG2). AB - Spirulina platensis :have been studied for several biological activities. In the current study C-phycocyanin containing protein extract (C-PC extract) of Spirulina platensis have been studied for its effect on human matrix metalloproteinases (MMP-1, MMP-2 and MMP-9) and tissue inhibitors of MMPs (TIMP-1 and TIMP-2). In the present study, breast cancer cell line (MDA-MB 231) and hepatocellular cancer cell line (HepG2) were examined for inhibition of MMPs at different levels of expression after C-PC extract treatment. Herein, we have demonstrated that C-PC extract significantly reduced activity of MMP-2 by 55.13% and MMP-9 by 57.9% in HepG2 cells at 15 MUg concentration. Additionally, the treatment has reduced mRNA expression of MMP-2 and MMP-9 at 20 MUg concentration by 1.65-folds and 1.66-folds respectively. The C-PC extract treatment have also downregulated a mRNA expression of TIMP-2 by 1.12 folds at 20 MUg concentration in HepG2 cells. Together, these results indicate that C-PC, extract successfully inhibited MMP-2 and -9 at different levels of expression and TIMP-2 at a mRNA expression level; however, extract did not have any effect on MMP-1 expressed in MDA-MB231 and TIMP-1 expressed in HepG2 cells as well as the exact mechanism of inhibition of MMP-2, MMP-9 and TIMP-2 remained unclear. PMID- 28357610 TI - Unusual Cause of Dysphagia in a Post-Stroke Patient. AB - Vallecular cysts are formed when the duct of a mucous gland or lingual tonsillar crypt is dilated owing to obstruction from inflammation, irritation, or trauma. Small cysts are usually asymptomatic; however, cyst growth results in dysphagia, odynophagia, and acute airway complications. As complete transoral laser excision of a vallecular cyst often results in cyst resolution and improved symptoms, proper diagnosis and management of vallecular lesions are important. We describe the evaluation and treatment of a 53-year-old man with a history of intracerebral hemorrhage in the left basal ganglia who presented with dysphagia caused by a vallecular cyst. PMID- 28357611 TI - Development of visual field defect after first-detected optic disc hemorrhage in preperimetric open-angle glaucoma. AB - PURPOSE: To evaluate functional progression in preperimetric glaucoma (PPG) with disc hemorrhage (DH) and to determine the time interval between the first detected DH and development of glaucomatous visual field (VF) defect. METHODS: A total of 87 patients who had been first diagnosed with PPG were enrolled. The medical records of PPG patients without DH (Group 1) and with DH (Group 2) were reviewed. When glaucomatous VF defect appeared, the time interval from the diagnosis of PPG to the development of VF defect was calculated and compared between the two groups. In group 2, the time intervals from the first-detected DH to VF defect of the single- and recurrent-DH were compared. RESULTS: Of the enrolled patients, 45 had DH in the preperimetric stage. The median time interval from the diagnosis of PPG to the development of VF defect was 73.3 months in Group 1, versus 45.4 months in Group 2 (P = 0.042). The cumulative probability of development of VF defect after diagnosis of PPG was significantly greater in Group 2 than in Group 1. The median time interval from first-detected DH to the development of VF defect was 37.8 months. The median time interval from DH to VF defect and cumulative probability of VF defect after DH did not show a statistical difference between single and recurrent-DH patients. CONCLUSIONS: The median time interval between the diagnosis of PPG and the development of VF defect was significantly shorter in PPG with DH. The VF defect appeared 37.8 months after the first-detected DH in PPG. PMID- 28357613 TI - Analysis of a broad range of perfluoroalkyl acids in accipiter feathers: method optimization and their occurrence in Nam Co Basin, Tibetan Plateau. AB - Perfluoroalkyl acids (PFAAs) are ubiquitous in the environment. They are prone to accumulate in organisms and have raised public attention in recent decades. Feather samples have been successfully applied as nondestructive indicators for several contaminants. However, a sophisticated analytical method for determining PFAAs in feathers is still lacking. In the present study, a series of conditions, such as the use of the solid-phase extraction cartridge type and extraction/digestion methods, were optimized for the analysis of 13 PFAAs in feathers. According to the spiked recoveries, a weak-anion exchange cartridge was chosen and the methanol was selected as the extraction solvent. In the present study, an optimized pretreatment procedure combined with high-performance liquid chromatography-electrospray ionization-tandem mass spectrometric (HPLC-ESI-MS/MS) method was established for the determination of PFAAs in feathers. The recoveries and method detection limits of the PFAAs ranged from 71 to 120% and 0.16 to 0.54 ng/g, respectively. Finally, 13 PFAAs in four accipiter feather samples from Nam Co Basin, Tibetan Plateau, were analyzed, indicating that PFOS was the predominant PFAA in accipiter feathers, with an average of 4.67 ng/g, followed by the short-chain PFAAs, PFBS and PFBA, with averages of 1.91 and 1.39 ng/g, respectively. These results partly indicated the current situation of PFAA pollution in the Nam Co Basin, especially the existence of short-chain PFAAs in this region. PMID- 28357614 TI - A Mathematical Study to Control Visceral Leishmaniasis: An Application to South Sudan. AB - In this manuscript, we propose and analyze a compartmental model of visceral leishmaniasis (VL). We model the human population with six compartments including asymptomatic, symptomatic and PKDL-infected, animal population as second host and sandfly population as the vector. Furthermore, the non-adult stage of the sandfly population is introduced in the system, which was not considered before in the literature. We show that the increase in the number of host of sandfly population generates a backward bifurcation. Thus, multiple hosts will cause disease persistence even if the basic reproduction number ([Formula: see text]) is below unity. We perform a sensitivity analysis of important model parameters with respect to some epidemiologically significant responses. We validate our model by calibrating it to weekly VL incidence data from South Sudan for the year 2013. We perform cost-effectiveness analysis on different interventions: treatment, non adult control, adult control and their different layered combinations based on their implementation cost (in USD) and case reduction. We also use a global sensitivity analysis technique to understand the effect of important parameters of our model on the implementation cost of different controls. This cost effectiveness study and cost-sensitivity analysis are relatively new in existing literature of this disease. PMID- 28357612 TI - The tailored sperm cell. AB - Sperm are ubiquitous and yet unique. Genes involved in sexual reproduction are more divergent than most genes expressed in non-reproductive tissues. It has been argued that sperm have been altered during evolution more than any somatic cell. Profound variations are found at the level of morphology, motility, search strategy for the egg, and the underlying signalling mechanisms. Sperm evolutionary adaptation may have arisen from sperm competition (sperm from rival males compete within the female's body to fertilize eggs), cryptic female choice (the female's ability to choose among different stored sperm), social cues tuning sperm quality or from the site of fertilization (internal vs. external fertilization), to name a few. Unquestionably, sperm represent an invaluable source for the exploration of biological diversity at the level of signalling, motility, and evolution. Despite the richness in sperm variations, only a few model systems for signalling and motility have been studied in detail. Using fast kinetic techniques, electrophysiological recordings, and optogenetics, the molecular players and the sequence of signalling events of sperm from a few marine invertebrates, mammals, and fish are being elucidated. Furthermore, recent technological advances allow studying sperm motility with unprecedented precision; these studies provide new insights into flagellar motility and navigation in three dimensions (3D). The scope of this review is to highlight variations in motile sperm across species, and discuss the great promise that 3D imaging techniques offer into unravelling sperm mysteries. PMID- 28357615 TI - Dimorphism by Singularity Theory in a Model for River Ecology. AB - Geritz, Gyllenberg, Jacobs, and Parvinen show that two similar species can coexist only if their strategies are in a sector of parameter space near a nondegenerate evolutionarily singular strategy. We show that the dimorphism region can be more general by using the unfolding theory of Wang and Golubitsky near a degenerate evolutionarily singular strategy. Specifically, we use a PDE model of river species as an example of this approach. Our finding shows that the dimorphism region can exhibit various different forms that are strikingly different from previously known results in adaptive dynamics. PMID- 28357616 TI - Prenatal screening for chromosomal abnormalities in IVF patients that opted for preimplantation genetic screening/diagnosis (PGS/D): a need for revised algorithms in the era of personalized medicine. AB - Obstetricians offer prenatal screening for most common chromosomal abnormalities to all pregnant women including those that had in vitro fertilization (IVF) and preimplantation genetic screening/diagnosis (PGS/D). We propose that free fetal DNA in maternal circulation together with the second trimester maternal serum alfa feto protein (MSAFP) and ultrasound imaging is the best prenatal screening test for chromosomal abnormalities and congenital anomalies in IVF-PGD/S patients because risk estimations from all other prenatal screening algorithms for chromosomal abnormalities depend heavily on maternal age which is irrelevant in PGS/D patients. PMID- 28357617 TI - Interaction of various types of photosystem I complexes with exogenous electron acceptors. AB - Interaction of photosystem I (PS I) complexes from cyanobacteria Synechocystis sp. PCC 6803 containing various quinones in the A1-site (phylloquinone PhQ in the wild-type strain (WT), and plastoquinone PQ or 2,3-dichloronaphthoquinone Cl 2 NQ in the menB deletion strain) and different numbers of Fe4S4 clusters (intact WT and FX-core complexes depleted of FA/FB centers) with external acceptors has been studied. The efficiency of interaction was estimated by measuring the light induced absorption changes at 820 nm due to the reduction of the special pair of chlorophylls (P700+) by an external acceptor(s). It was shown that externally added Cl 2 NQ is able to effectively accept electrons from the terminal iron sulfur clusters of PS I. Moreover, the efficiency of Cl 2 NQ as external acceptor was higher than the efficiency of the commonly used artificial electron acceptor, methylviologen (MV) for both the intact WT PS I and for the FX-core complexes. The comparison of the efficiency of MV interaction with different types of PS I complexes revealed gradual decrease in the following order: intact WT > menB > FX core. The effect of MV on the recombination kinetics in menB complexes of PS I with Cl 2 NQ in the A1-site differed significantly from all other PS I samples. The obtained effects are considered in terms of kinetic efficiency of electron acceptors in relation to thermodynamic and structural characteristics of PS I complexes. PMID- 28357618 TI - Long-Term Results of Laparoscopic Sleeve Gastrectomy for Morbid Obesity: 5 to 8 Year Results. PMID- 28357619 TI - Milk Fermented by Lactic Acid Bacteria Enhances the Absorption of Dietary Sphingomyelin in Rats. AB - Supplementation with sphingomyelin has been reported to prevent disease and maintain good health. However, intact sphingomyelin and ceramides are poorly absorbed compared with glycerolipids. Therefore, if the bioavailability of dietary sphingomyelin can be increased, supplementation would be more effective at lower doses. The aim of this study in rats was to evaluate the effect of fermented milk on the bioavailability of dietary sphingomyelin in rats. After the rats had fasted for 15 h, test solutions were administrated orally. Blood samples were collected from the tail vein before and 90, 180, 270, and 360 min after administration. Compared with sphingomyelin/milk phospholipids concentrate (MPL) alone, co-ingestion of sphingomyelin/MPL with fermented milk caused an approximate twofold significant increase in serum ceramides containing d16:1 sphingosine with 16:0, 22:0, 23:0 and 24:0 fatty acids, which was derived from the ingested sphingomyelin. While nonfat milk also increased the serum levels of these ceramides, fermented milk was more effective. Co-ingestion of the upper layer of fermented milk or exopolysaccharide concentrate prepared from fermented milk significantly increased serum ceramide levels. X-ray diffraction analysis also showed addition of fermented milk or EPS concentrate to sphingomyelin eliminated the characteristic peak of sphingomyelin. This study demonstrated for the first time that co-ingestion of dietary sphingomyelin and fermented milk, compared with ingestion of dietary sphingomyelin alone, caused a significant increase in the absorption of sphingomyelin. Our results indicate exopolysaccharides in fermented milk may contribute to inhibition of sphingomyelin crystallization, resulting in enhanced absorption of dietary sphingomyelin in rats. PMID- 28357620 TI - Toxicity of three aphicides to the generalist predators Chrysoperla carnea (Neuroptera: Chrysopidae) and Orius insidiosus (Hemiptera: Anthocoridae). AB - Recent widespread infestations of the invasive sugarcane aphid, Melanaphis sacchari (Zehntner) (Hemiptera: Aphididae), in sorghum fields in the southern USA have created demand for insecticides that will provide effective control of sugarcane aphid, while conserving those beneficial species that contribute to biological control of the pest. We tested the susceptibility of both adult and immature stages of two aphid predators, the green lacewing, Chrysoperla carnea (Stephens) (Neuroptera: Chrysopidae), and the insidious flower bug, Orius insidiosus (Say) (Hemiptera: Anthocoridae), to three aphicides, flonicamid, sulfoxaflor and flupyradifurone. Flonicamid was innocuous to both species regardless of life stage or route of exposure. Lacewing adults were more susceptible to sulfoxaflor and flupyradifurone than were larvae, and had higher mortality when fed contaminated honey solution than when contacting residues on an inert surface. When laid in sunflower stems treated with these two materials, eggs of O. insidiosus hatched successfully, but nymphs experienced significant mortality when exposed to treated stems, likely due to phytophagous behavior that resulted in some insecticide ingestion. Despite these impacts, we conclude that both sulfoxaflor and flupyradifurone are likely to be relatively innocuous in comparison to more broad-spectrum insecticides and are thus potentially compatible with biological control and overall management of M. sacchari in grain sorghum. PMID- 28357621 TI - Improved campesterol production in engineered Yarrowia lipolytica strains. AB - OBJECTIVES: To engineer Yarrowia lipolytica for improving the heterologous production of campesterol (a key precursor to manufacture pharmaceutical steroids). RESULTS: By screening 7-dehydrocholesterol reductase (DHCR7) from diverse species, DHCR7 from Danio rerio was the best candidate for campesterol synthesis. Overexpression of ACL (ATP: citrate lyase) or POX2 (peroxisome acyl CoA oxidase 2) were key to improving campesterol production. The highest yield of campesterol was 942 mg/l was with the strain overexpressing POX2 in a 5 l bioreactor via high cell density fermentation process with a restricted supply of carbon sourc, sunflower seed oil. CONCLUSIONS: A promising platform to synthesize downstream steroid drugs was established. Efficient approaches were provided to improve the production of desired molecules in Y. lipolytica with high oil utilization efficiency. PMID- 28357622 TI - The attribution of intentionality: the role of skill and morality. AB - The present study contributes to the discussion on the different components which constitute the intentionality concept about an undesired side effect, focusing on the morality and the skill. Two hundred and forty participants were asked to read a brief story about a car accident, in which it was explained the motivation of the high speed and objective and subjective skill of the agent to drive the car, and to fill in six questions about intentionality, objective risk, mental representation of risk, risk acceptance and blameworthiness for the outcome. The principal results showed that when the motivation is morally negative, people judge the side effect more intentional, also because they make more severe judgments about risk and blameworthiness. Moreover, when people are objectively proficient to perform the action (objective skill) the side effect is considered less risky and intentional and, in the case of a negative outcome, they are judged less severely than if they have a poor ability. Finally, a self-assessment of low skill to make the action (subjective skill) leads people to assess higher risks and, consequently, more intentionality for the side effect. The results are discussed on the basis of the literature about some specific components that make up the intentionality concept. PMID- 28357623 TI - Impact of pharmaceutical care on pain and agitation in a medical intensive care unit in Thailand. AB - Background Currently, a lack of pharmaceutical care exists concerning pain and agitation in medical intensive care units (MICU) in Thailand. Pharmaceutical care focusing on analgesics/sedatives would improve clinical outcomes. Objective To investigate the impact of pharmaceutical care of pain and agitation on ICU length of stay (LOS), hospital LOS, ventilator days and mortality. Setting The MICU of a university hospital. Method A before/after study was conducted on mechanically ventilated patients receiving analgesics/sedatives. Medical chart reviews and data collection were conducted in the retrospective group (no pharmacists involved). In the prospective group, pharmacists involved with the critical care team helped select analgesics/sedatives for individual patients. Main outcome measure ICU LOS Results In total, 90 and 66 patients were enrolled in retrospective and prospective groups, respectively. The median duration of ICU LOS was reduced from 10.00 (2.00-72.00) in the retrospective group to 6.50 days (2.00-30.00) in the prospective group (p = 0.002). The median hospital stay was reduced from 30.50 days (2.00-119.00) in the retrospective group to 17.50 days (2.00-110.00) in the prospective group (p < 0.001). Also, the median ventilator days was reduced from 14.00 days (2.00-90.00) to 8.50 days (1.00-45.00), p = 0.008. Mortality was 53.03% in the prospective group and 46.67% in the retrospective group (p = 0.432). Conclusion Pharmacist participation in a critical care team resulted in a significant reduction in the duration of ICU LOS, hospital LOS and ventilator days, but not mortality. PMID- 28357624 TI - A simple method to reconstruct the molar mass signal of respiratory gas to assess small airways with a double-tracer gas single-breath washout. AB - For the assessment of small airway diseases, a noninvasive double-tracer gas single-breath washout (DTG-SBW) with sulfur hexafluoride (SF6) and helium (He) as tracer components has been proposed. It is assumed that small airway diseases may produce typical ventilation inhomogeneities which can be detected within one single tidal breath, when using two tracer components. Characteristic parameters calculated from a relative molar mass (MM) signal of the airflow during the washout expiration phase are analyzed. The DTG-SBW signal is acquired by subtracting a reconstructed MM signal without tracer gas from the signal measured with an ultrasonic sensor during in- and exhalation of the double-tracer gas for one tidal breath. In this paper, a simple method to determine the reconstructed MM signal is presented. Measurements on subjects with and without obstructive lung diseases including the small airways have shown high reliability and reproducibility of this method. PMID- 28357625 TI - A case of double stent implantation for left main coronary artery occlusion in transcatheter aortic valve implantation using SAPIEN XT device. AB - Transcatheter aortic valve implantation is an established alternative and less invasive procedure to replace heart valves in symptomatic aortic stenosis patients; however, severe, life-threatening complications still exist. Coronary artery occlusion is a primary complication. We report a case of left main coronary artery occlusion after transcatheter aortic valve replacement, which was ameliorated using a double stent implantation technique. PMID- 28357626 TI - Reasoning strategies with rational numbers revealed by eye tracking. AB - Recent research has begun to investigate the impact of different formats for rational numbers on the processes by which people make relational judgments about quantitative relations. DeWolf, Bassok, and Holyoak (Journal of Experimental Psychology: General, 144(1), 127-150, 2015) found that accuracy on a relation identification task was highest when fractions were presented with countable sets, whereas accuracy was relatively low for all conditions where decimals were presented. However, it is unclear what processing strategies underlie these disparities in accuracy. We report an experiment that used eye-tracking methods to externalize the strategies that are evoked by different types of rational numbers for different types of quantities (discrete vs. continuous). Results showed that eye-movement behavior during the task was jointly determined by image and number format. Discrete images elicited a counting strategy for both fractions and decimals, but this strategy led to higher accuracy only for fractions. Continuous images encouraged magnitude estimation and comparison, but to a greater degree for decimals than fractions. This strategy led to decreased accuracy for both number formats. By analyzing participants' eye movements when they viewed a relational context and made decisions, we were able to obtain an externalized representation of the strategic choices evoked by different ontological types of entities and different types of rational numbers. Our findings using eye-tracking measures enable us to go beyond previous studies based on accuracy data alone, demonstrating that quantitative properties of images and the different formats for rational numbers jointly influence strategies that generate eye-movement behavior. PMID- 28357627 TI - Anser EMT: the first open-source electromagnetic tracking platform for image guided interventions. AB - PURPOSE: Electromagnetic tracking is the gold standard for instrument tracking and navigation in the clinical setting without line of sight. Whilst clinical platforms exist for interventional bronchoscopy and neurosurgical navigation, the limited flexibility and high costs of electromagnetic tracking (EMT) systems for research investigations mitigate against a better understanding of the technology's characterisation and limitations. The Anser project provides an open source implementation for EMT with particular application to image-guided interventions. METHODS: This work provides implementation schematics for our previously reported EMT system which relies on low-cost acquisition and demodulation techniques using both National Instruments and Arduino hardware alongside MATLAB support code. The system performance is objectively compared to other commercial tracking platforms using the Hummel assessment protocol. RESULTS: Positional accuracy of 1.14 mm and angular rotation accuracy of [Formula: see text] are reported. Like other EMT platforms, Anser is susceptible to tracking errors due to eddy current and ferromagnetic distortion. The system is compatible with commercially available EMT sensors as well as the Open Network Interface for image-guided therapy (OpenIGTLink) for easy communication with visualisation and medical imaging toolkits such as MITK and 3D Slicer. CONCLUSIONS: By providing an open-source platform for research investigations, we believe that novel and collaborative approaches can overcome the limitations of current EMT technology. PMID- 28357628 TI - Addressing multi-label imbalance problem of surgical tool detection using CNN. AB - PURPOSE: A fully automated surgical tool detection framework is proposed for endoscopic video streams. State-of-the-art surgical tool detection methods rely on supervised one-vs-all or multi-class classification techniques, completely ignoring the co-occurrence relationship of the tools and the associated class imbalance. METHODS: In this paper, we formulate tool detection as a multi-label classification task where tool co-occurrences are treated as separate classes. In addition, imbalance on tool co-occurrences is analyzed and stratification techniques are employed to address the imbalance during convolutional neural network (CNN) training. Moreover, temporal smoothing is introduced as an online post-processing step to enhance runtime prediction. RESULTS: Quantitative analysis is performed on the M2CAI16 tool detection dataset to highlight the importance of stratification, temporal smoothing and the overall framework for tool detection. CONCLUSION: The analysis on tool imbalance, backed by the empirical results, indicates the need and superiority of the proposed framework over state-of-the-art techniques. PMID- 28357629 TI - Testing the validity of conflict drift-diffusion models for use in estimating cognitive processes: A parameter-recovery study. AB - Researchers and clinicians are interested in estimating individual differences in the ability to process conflicting information. Conflict processing is typically assessed by comparing behavioral measures like RTs or error rates from conflict tasks. However, these measures are hard to interpret because they can be influenced by additional processes like response caution or bias. This limitation can be circumvented by employing cognitive models to decompose behavioral data into components of underlying decision processes, providing better specificity for investigating individual differences. A new class of drift-diffusion models has been developed for conflict tasks, presenting a potential tool to improve analysis of individual differences in conflict processing. However, measures from these models have not been validated for use in experiments with limited data collection. The present study assessed the validity of these models with a parameter-recovery study to determine whether and under what circumstances the models provide valid measures of cognitive processing. Three models were tested: the dual-stage two-phase model (Hubner, Steinhauser, & Lehle, Psychological Review, 117(3), 759-784, 2010), the shrinking spotlight model (White, Ratcliff, & Starns, Cognitive Psychology, 63(4), 210-238, 2011), and the diffusion model for conflict tasks (Ulrich, Schroter, Leuthold, & Birngruber, Cogntive Psychology, 78, 148-174, 2015). The validity of the model parameters was assessed using different methods of fitting the data and different numbers of trials. The results show that each model has limitations in recovering valid parameters, but they can be mitigated by adding constraints to the model. Practical recommendations are provided for when and how each model can be used to analyze data and provide measures of processing in conflict tasks. PMID- 28357630 TI - Age-structured population model of cell survival. AB - Age-structured cell population model was introduced to describe cell survival. The impact of the environment on the cell population is represented by drug plasma concentration. A key model variable is the hazard of cell removal that is a subject to the environment effect. The model is capable of describing cohort and random labeling cell survival data. In addition, it accounts for cell loss due to labeling of cell sample, but it lacks ability to describe the effect of label elution on the survival data. The model was applied to red blood cell (RBC) survival data in two groups of Wistar rats obtained by two techniques: cohort labeling using 14C-glycine (N = 4) and random labeling using biotin (N = 8). The Weibull probability density function was selected for the RBC lifespan distribution. The data were simultaneously fitted by the mixed effects model implemented in Monolix 4.3.3. The estimated typical values of RBC lifespan and age were 53.7 and 27.8 days, respectively. A noticeable effect of biotinylation on RBC survival was observed that resulted in a significant difference between the means of individual RBC lifespan for two groups. The model provides a mechanistic framework flexible enough to account for various experimental designs to generate the cell survival data. Despite model qualification using animal data, the model has the same potential to be applied to cell survival data analysis in humans. PMID- 28357631 TI - Role of TIM-3 in ovarian cancer. AB - Evidences have suggested that immunotherapy for ovarian cancer is effective. Immune checkpoints have emerged in the field of cancer immunotherapy. Multiple studies have shown negative regulation of TIM-3 expression on CD4+ and CD8+ T cells and other immunocytes. Overexpression of TIM-3 in innate immune cells has been found in certain types of tumor. The blockade of TIM-3 leads to sustained anti-tumor reactions. TIM-3 plays an inhibitive role for immunity in ovarian cancer. TIM-3 is involved in the development of various subtypes of ovarian cancer and thus has the potential to be a therapeutic target for treatment of ovarian cancer. PMID- 28357632 TI - Radiotherapy for adrenal gland metastases from hepatocellular carcinoma. AB - BACKGROUND: Several studies have found benefits of radiotherapy for adrenal metastasis from hepatocellular carcinoma (HCC). However, the efficacy, safety and outcome issues have not yet been fully addressed. Therefore, we performed this study to further elucidate the feasibility and outcome of radiotherapy in treating adrenal metastasis from HCC. METHODS: We retrospectively analyzed 81 patients with adrenal metastasis from HCC between 2001 and 2015. Eighteen patients received helical tomotherapy and 63 patients received conventional radiotherapy, including two-dimensional (2-D) or three-dimensional conformal radiotherapy (3-D CRT). The median radiation dose was 50 Gy (range 26-64 Gy) with median fraction size of 2.0 Gy (range 2.0-5.0 Gy). Tumor responses, adverse effects, patient outcomes and prognostic factors were analyzed. RESULTS: An objective response (complete and partial response) was achieved in 55.6% patients. The helical tomotherapy group showed higher objective response rate than the conventional radiotherapy group (P = 0.031). The major adverse effects were anorexia (51.8%), nausea (41.9%), and fatigue (35.8%). Similar toxicity profile occurred in the 2-D, 3-D CRT and helical tomotherapy groups. The overall survival (OS) rate at 1, 2 and 5 years was 59.9, 35.0, and 12.9%, respectively, with a median survival of 15 months. Patients who received helical tomotherapy achieved a better OS compared to the conventional radiotherapy group (P = 0.047). However, multivariate analysis indicated that radiotherapy technique was not an independent prognostic factor for patient outcome. CONCLUSION: These results suggest that radiotherapy offers a noninvasive approach in controlling adrenal metastasis from HCC with promising local control and acceptable tolerability. PMID- 28357633 TI - The TNM 8 M1b and M1c classification for non-small cell lung cancer in a cohort of patients with brain metastases. AB - BACKGROUND AND PURPOSE: According to the recent TNM 8 classification, patients with metastatic non-small cell lung cancer (NSCLC) and single extrathoracic metastasis should be classified as stage M1b, while those with 2 or more metastases comprise stage M1c. The purpose of this study was to analyze the impact of this classification in patients with brain metastases. MATERIALS AND METHODS: This retrospective study included 172 patients treated with individualized approaches. Actuarial survival was calculated. Uni- and multivariate analyses were performed. RESULTS: Thirty patients (17%) were staged as M1b. Those with squamous cell cancer were more likely to harbor M1b disease (29%, adenocarcinoma 14%, other histology 17%, p = 0.16). Median survival was 5.4 months (8.0 months in case of M1b disease and 4.5 months in case of M1c disease, p = 0.001). Multivariate analysis confirmed the role of M1b stage. M1b patients managed with upfront surgery or radiosurgery had significantly longer median survival than those who received whole-brain irradiation (21.0 vs. 3.5 months, p = 0.0001) and the potential to survive beyond 5 years. CONCLUSIONS: We found the M1b classification to provide clinically relevant information. The multivariate analysis suggested that patients with M1b disease, better performance status and younger age have better survival. PMID- 28357634 TI - Bioactive flavonoids from Flos Sophorae. AB - Three new flavonoid glycosides-soyaflavonosides A (1), B (2), and C (3)-together with 23 known ones were obtained from the 70% EtOH extract of Flos Sophorae (Sophora japonica, Leguminosae). Their structures were elucidated by chemical and spectroscopic methods. Among the known isolates, 14, 18, 20, 22, and 26 were isolated from the Sophora genus for the first time; 12, 19, 24, and 25 were obtained from the species firstly. Moreover, NMR data for compounds 18 and 26 are reported for the first time here. Meanwhile, compounds 4, 8-13, 15, 16, 19, 21, and 22 presented obvious inhibitory effects on TG accumulation in HepG2 cells. Analysis of the structure-activity relationship indicated that all of the quercetin glycosides examined in this study possess significant activity that is not significantly influenced by the amount of glycosyl present, whereas increasing the amount of glycosyl reduced the activities of isorhamnetin glycosides and orobol. In addition, a high dose (30 MUmol/l) of kaempferol was found to inhibit HepG2 cell growth, while a low dose (10 MUmol/l) was observed to decrease TG accumulation. PMID- 28357635 TI - Two new polyhydroxyl polyacetylenes from fruits of Herpetospermum caudigerum. AB - Two new polyhydroxy polyacetylenes, herpecaudenes A and B (1 and 2), were isolated from the ethanol extract of fruits of Herpetospermum caudigerum, an important Tibetan medicine. The structures of them were elucidated on the basis of extensive spectroscopic methods including UV, IR, HRESIMS, 1H and 13C NMR, HMBC, HSQC, and 1H-1H COSY. Compound 2 showed significant inhibitory effects on NO production in LPS-activated RAW 264.7 macrophages with IC50 values of 7.05 +/- 1.59 uM. PMID- 28357636 TI - Probable Catastrophic Antiphospholipid Syndrome with Intracerebral Hemorrhage Secondary to Epstein-Barr Viral Infection. AB - BACKGROUND: Catastrophic antiphospholipid syndrome (CAPS) is a rare, severe variant of antiphospholipid syndrome with a high mortality rate. We report a unique case of CAPS secondary to Epstein-Barr viral (EBV) infection complicated by pulmonary and intracerebral hemorrhage. A review of the CAPS literature relevant to intensive care practice is used to outline a rational approach to diagnosis and management. METHODS: All data are from a single patient admitted to the Neurosciences Critical Care Unit in Addenbrooke's Hospital, Cambridge, in March 2016. Medline, Web of Science, PubMed, and the Cochrane Library were searched through September 2016 without restrictions for cases of CAPS, management of CAPS in the intensive care unit, and hemorrhage complicating CAPS. The patient gave express written consent to access and publish these data. RESULTS: This is only the second reported case of probable CAPS secondary to EBV infection. Furthermore, pulmonary and intracerebral hemorrhage is rare manifestations of this multisystem prothrombotic state which provided unique challenges to the management. CONCLUSIONS: While rare, CAPS should be considered in any patient presenting with rapidly progressive multiorgan failure, evidence of thrombotic microangiopathy, and antiphospholipid antibodies. A high index of suspicion is required as early, aggressive, multimodal treatment with anticoagulation, and immunosuppression improves outcomes. PMID- 28357637 TI - Acute Resective Surgery for the Treatment of Refractory Status Epilepticus. AB - BACKGROUND: To identify the role of acute surgical intervention in the treatment of refractory status epilepticus (RSE). METHODS: Retrospective review of consecutive patients who underwent epilepsy surgery from 2006 to 2015 was done to identify cases where acute surgical intervention was employed for the treatment of RSE. In addition, the adult and pediatric RSE literature was reviewed for reports of surgical treatment of RSE. RESULTS: Nine patients, aged 20-68 years, with various etiologies were identified to have undergone acute surgical resection for the treatment of RSE, aided by electrocorticography. Patients required aggressive medical therapy with antiepileptic drugs and intravenous anesthetic drugs for 10-54 days and underwent extensive neurodiagnostic testing prior to resective surgery. Eight out of nine patients survived and five patients were seizure-free at the last follow-up. The literature revealed 13 adult and 48 pediatric cases where adequate historical detail was available for review and comparison. CONCLUSIONS: We present the largest cohort of consecutive adult patients who underwent resective surgery in the setting of RSE. We also reveal that surgery can be efficacious in aborting status and in some can lead to long term seizure freedom. Acute surgical intervention is a viable option in prolonged RSE and proper evaluation for such intervention should be conducted, although the timing and type of surgical intervention remain poorly defined. PMID- 28357640 TI - Azospirillum spp. from native forage grasses in Brazilian Pantanal floodplain: biodiversity and plant growth promotion potential. AB - A sustainable alternative to improve yield and the nutritive value of forage is the use of plant growth-promoting bacteria (PGPB) that release nutrients, synthesize plant hormones and protect against phytopathogens (among other mechanisms). Azospirillum genus is considered an important PGPB, due to the beneficial effects observed when inoculated in several plants. The aim of this study was to evaluate the diversity of new Azospirillum isolates and select bacteria according to the plant growth promotion ability in three forage species from the Brazilian Pantanal floodplain: Axonopus purpusii, Hymenachne amplexicaulis and Mesosetum chaseae. The identification of bacterial isolates was performed using specific primers for Azospirillum in PCR reactions and partial sequencing of the 16S rRNA and nifH genes. The isolates were evaluated in vitro considering biological nitrogen fixation (BNF) and indole-3-acetic acid (IAA) production. Based on the results of BNF and IAA, selected isolates and two reference strains were tested by inoculation. At 31 days after planting the plant height, shoot dry matter, shoot protein content and root volume were evaluated. All isolates were able to fix nitrogen and produce IAA, with values ranging from 25.86 to 51.26 mg N mL-1 and 107-1038 umol L-1, respectively. The inoculation of H. amplexicaulis and A. purpusii increased root volume and shoot dry matter. There were positive effects of Azospirillum inoculation on Mesosetum chaseae regarding plant height, shoot dry matter and root volume. Isolates MAY1, MAY3 and MAY12 were considered promising for subsequent inoculation studies in field conditions. PMID- 28357639 TI - Ghrelin ameliorates nerve growth factor Dysmetabolism and inflammation in STZ induced diabetic rats. AB - Diabetic encephalopathy is characterized by cognitive impairment and neuroinflammation, deficient neurotrophic support, and neuronal and synaptic loss. Ghrelin, a 28 amino acid peptide, is associated with neuromodulation and cognitive improvement, which has been considered as a potential protective agent for several neurodegenerative diseases. Here we sought to investigate the role of ghrelin in preventing diabetic-related neuropathology. We found that ghrelin attenuated astrocytic activation and reduced levels of interleukin-6 and tumor necrosis factor-alpha in streptozotocin-induced diabetic rats. In addition, ghrelin inhibited p38 mitogen-associated protein kinase activation. The upregulation of nerve growth factor (NGF) precursor and matrix metalloproteinase (MMP)-9 and downregulation of mature NGF and MMP-7 in the diabetic brain were reversed by ghrelin. Treatment with ghrelin elevated synaptophysin expression and synaptic density in diabetic rats. Taken together, our results demonstrate that ghrelin ameliorates diabetes-related neurodegeneration by preventing NGF dysmetabolism and synaptic degeneration through regulating MMP levels as well as inhibiting neuroinflammation. PMID- 28357641 TI - [Distribution of species and kdr gene frequency among Anopheles gambiae s.s. and Anopheles coluzzii populations in five agricultural sites in Cote d'Ivoire]. AB - The resistance of Anopheles gambiae s.l. to insecticides constitutes a concern for the programs of malaria control because it can be an obstacle to effective control of the vectors. The follow-up of this resistance is a priority to work out strategies of management and to preserve the means of that major malaria vector control activities. The general objective of this study is to identify the species within An. gambiae s.l., and to determine the frequency of the Kdr gene in An. gambiae s.s. and An. coluzzii in five agricultural sites in Ivory Coast: an urban site, two semirural sites (coffee-trees/cacao-trees, orchard) and two rural sites (rice site and a traditional village without agricultural insecticide). During this study, 2285 specimens of An. gambiae s.l. were analyzed for this purpose. An. gambiae s.s. (in the past called molecular form S) and An. coluzzii (in the past called molecular form M) were the only species of the complex An. gambiae identified in all the sites. The frequency of the Kdr mutation varied from 0.37 in the site without agricultural insecticide to 0.95 in the urban site where there is an intense use of insecticides. Three areas of these species distribution were observed: an area where the species An. gambiae s.s. is dominant (sites located in savanna), an area with predominance of An. coluzzii (in the southern forested area) and an intermediate area where the two species were in a same proportion (pre-forested site).The Kdr mutation was identified in the two species in all the sites in savanna and forest, except in the site without agricultural insecticide where only An. gambiae was resistant. It shows the increase of the receptive potential of An. gambiae s.l. with respect to the Kdr gene and the extension of the resistance to insecticide of this species in Ivory Coast. PMID- 28357642 TI - Genome-wide gene expression profiling of tongue squamous cell carcinoma by RNA seq. AB - OBJECTIVE: Tongue squamous cell carcinoma (TSCC) is significantly more malignant than other type of oral squamous cell carcinoma (OSCC). In this study, we aimed to identify specific global gene expression signatures of TSCC to investigate the more invasive behavior of the deeply infiltrating cancer. METHODS: Using RNA-seq technology, we detected gene expression of 20 TSCCs, 20 matched paratumor tissues, and 10 healthy normal mucosa tissues. Enrichment analysis of gene ontology (GO) and pathway was conducted using online tools DAVID for the dysregulated genes. Additionally, we performed the quantitative real-time RT-PCR (qRT-PCR) to validate the findings of RNA-Seq in 10 samples of TSCC, matched paratumor, and normal mucosa, respectively. RESULTS: We detected 252 differentially expressed genes (DEGs) between TSCC and matched paratumor tissue, including 117 up-regulated and 135 down-regulated genes. For comparison between TSCC and normal mucosa, 234 DEGS were identified, consisting of 67 up-regulated and 167 down-regulated genes. For both two comparisons, GO categories of muscle contraction (GO: 0006936), epidermis development (GO: 0008544), epithelial cell differentiation (GO: 0030855), and keratinization (GO: 0031424) were commonly enriched. Altered gene expression affected some cancer-related pathways, such as tight junction. The qRT-PCR validation showed that gene expression patterns of FOLR1, NKX3-1, TFF3, PIGR, NEFL, MMP13, and HMGA2 were fully in concordance with RNA-Seq results. CONCLUSION: Findings in this study demonstrated the genetic and molecular alterations associated with TSCC, providing new clues for understanding the molecular mechanisms of TSCC pathogenesis. PMID- 28357644 TI - Effects of feeding practices on milk yield and composition in peri-urban and rural smallholder dairy cow and pastoral camel herds in Kenya. AB - Associations between feeding practices, milk yield, and composition were assessed in smallholder rural and peri-urban dairy cow (n = 97) and pastoral camel (n = 15) herds. A cross-sectional survey supplemented by follow-up collection of feed and milk samples for laboratory analyses was conducted. Data was analyzed using descriptive, correlation, and analysis of variance statistics. Feeding practices in rural smallholder dairy cows' herds were pastured based (87.7%) with napier grass (89.4%) and concentrates (93.9%) as forage and concentrate supplements. In smallholder peri-urban dairy cows' herds, it was napier grass based (68.4%) with concentrates (100%), oat forages (42.9%), and crop residues (28.6%). Pastoral camel herds were shrub browsing (53%), rangeland pasture grazing (20%), or Euphorbia tirucalli feeding (27%). Smallholder rural farmers offered more feeds (16.1 vs 15.3 kg/day) than peri-urban farmers, hence net energy for lactation (1.4 vs 1.3 Mcal/kg), crude protein (CP) (10 vs 12%), and milk yields (12 vs 9 kg/herd/day) was higher. Milk fat was higher in smallholder peri-urban (4.3%) than that of rural (3.9%). In pastoral camels, E. tirucalli feeding had higher daily milk yield/herd, fat, and CP (63 kg, 4.5 and 3.6%) than shrub browsing (35 kg, 4.2 and 3.0%) and grazing (23 kg yield, 2.6 and 2.7%). Five feeding practices out of 14 in smallholder dairy cattle herds resulted in more than 10 kg milk/cow/day because of low forage-to-concentrate ratio (2.5), inclusion of legume crop residue, or processing forages. They present opportunities for improved production in smallholder herds. In pastoral camel, E. tirucalli feeding showed the highest potential. PMID- 28357643 TI - Raloxifene but not alendronate can compensate the impaired osseointegration in osteoporotic rats. AB - OBJECTIVES: Alendronate and raloxifene, a bisphosphonate and a selective estrogen modulator, respectively, are established osteoporosis therapies. Current evidence suggests that simultaneous application of osteoporosis therapies modulates osseointegration. However, alendronate shows inconsistent findings and raloxifene has not been studied comprehensively. This study aimed to evaluate the bone dynamics and molecular and microstructural features at the peri-implant bone interface in osteoporotic rats. MATERIALS AND METHODS: Thirty female rats underwent ovariectomy and were fed a diet low in calcium and phosphate and treated with alendronate or raloxifene for 30 days or underwent fictional ovariectomy surgery (SHAM) prior to implant insertion in the tibia; osteoporosis therapies continued thereafter. After 42 days, peri-implant bone was evaluated by histometric and micro-CT analysis. Fluorochrome incorporation and gene expression was determined to evaluate bone turnover. RESULTS: We report here that alendronate had no impact on bone-to-implant contacts and the mineral apposition rate. The RANKL/OPG ratio and local bone volume, however, were increased compared to the untreated osteoporotic rats. Even though signaling to bone resorption activity through RANKL production was observed in the alendronate group, the blockade of bone resorption activity that occurs in decorrence to alendronate activity took place and resulted in an increase in bone volume. Raloxifene significantly increased osseointegration in osteoporotic rats, as indicated by bone-to-implant contacts, mineral apposition, and local bone volume. Raloxifene, however, had no considerable impact on the RANKL/OPG ratio compared to untreated osteoporotic rats. As expected, the SH group showed higher bone-to-implant contacts and mineral apposition rates than the untreated osteoporotic rats. CONCLUSIONS: These findings suggest that raloxifene but not alendronate can compensate for the impaired osseointegration in osteoporotic rats. CLINICAL RELEVANCE: Regarding the superiority of raloxifene observed in the improvement of bone dynamics response, this statement suggests that raloxifene could be a good option for osteoporosis patients in oral rehabilitation procedures. PMID- 28357645 TI - Seroprevalence and risk factors for leptospirosis in cattle, sheep, and goats at consorted rearing from the State of Piaui, northeastern Brazil. AB - Leptospirosis is an endemic disease in Latin America, caused by pathogenic bacteria of the genus Leptospira. It is considered one of the main causes responsible for the negative economic impact on global livestock by causing reproductive problems. The research aimed to determine the prevalence of leptospirosis in cattle, sheep, and goats at consorted rearing in the micro region of Teresina, Piaui state, northeastern Brazil, as well as to identify prevalent serovars and risk factors associated with seroprevalence. Serum samples were analyzed in 336 sheep, 292 goats, and 253 cattle using microscopic agglutination test (MAT). Overall, 378 samples were positive to MAT, with seroprevalence of 42.9%. The prevalences in cattle, sheep, and goats were 50.5, 40.5, and 34.6%, respectively. All herds presented at least one seropositive animal; the Hardjo/Wolffi serovar association was the most common in cattle and Icterohaemorrhagiae in goats and sheep. Beef production (OR = 4.9), cattle herd over 35 animals (OR = 4.0), feeding on pasture (OR = 6.4), weir and/or stream as water source (OR = 2.1), and no veterinary services (OR = 2.9) were risk factors for cattle infection. For sheep, intensive management system (OR = 5.3), suspended slatted facilities (OR = 2.2), more than 20 sheep in reproductive age (OR = 1.9), and absence of deworming (OR = 3.5) were the risk factors, while for goats, the identified risk factors were sheep herd over 52 animals (OR = 1.9) and no veterinary services (OR = 1.8). We conclude that the infection was spreading in consorted herds in this region. Thus, it would be interesting and important to conduct educative activities to farmers on the economic impacts of this disease and the need of preventive and control strategies mainly focused on sanitary measures and animal handling. PMID- 28357646 TI - The Usefulness of Non-Toxic Plant Metabolites in the Control of Bacterial Proliferation. AB - The effect of generally recognised as safe (GRAS) plant metabolites in regulating the growth of human pathogenic and probiotic bacteria and in the formation of biofilm was investigated. Thymol, carvacrol and eugenol showed the strongest antibacterial action against both pathogenic and probiotic microorganisms, at a subinhibitory concentration (SIC) of <=50 MUg ml-1. Genistein, hydroquinone, p hydroxybenzoic acid and resveratrol also showed antibacterial effects but at a wide concentration range (SIC = 50-1000 MUg ml-1). Catechin, gallic acid, protocatechuic acid and cranberry extracts were the most biologically compatible molecules (SIC >= 1000 MUg ml-1). Regarding the effect on biofilm, it was observed that thymol, carvacrol and eugenol showed antibiofilm activity against all potential pathogenic bacteria tested whilst specifically enhancing probiotic aggregation. Catechin, genistein and cranberry extracts did not inhibit the pathogenic aggregation but they stimulated probiotic biofilm formation, whilst gallic acid, protocateuchic acid, hydroquinone, p-hydroxybenzoic acid and resveratrol did not show opposite effect on biofilm formation between pathogenic and probiotic microorganisms. These results indicate that an appropriate combination of GRAS plant metabolites, which have traditionally been used as dietary constituents due to their health-promoting characteristics, can also be extremely useful in the regulation of bacterial proliferation in the intestinal microbiota. Hence, it is suggested to apply these natural GRAS molecules as dietary supplements in the food industry in order to promote probiotic viability and to prevent or reduce colonisation or proliferation of intestinal pathogens. PMID- 28357647 TI - [Impact of natural lithium ressources on suicide mortality in Chile 2000-2009: a geographical analysis]. AB - BACKGROUND: There is increasing evidence for the hypothesis that lithium salts at naturally occurring levels in drinking water may have a moderating effect on suicide rates of the exposed population. The aim of this study was to examine whether the lithium rich Atacama region in Chile is associated with lower suicide mortality in comparison to other regions. METHODS: Suicide data was acquired from the Chilean Ministry of Health. Socio-economic variables (rate of unemployment, urbanity, median household income, percentage of indeginous population) were obtained for all regions of Chile from the national statistical institute. We calculated annual suicide rates per 100,000 for each group for the years 2000 2009 and tested the hypothesis that suicide rates are lower in lithium rich regions in comparison to other regions of Chile. RESULTS: The lithium rich Atacama Desert shows a significantly lower suicide rate (9.99 per 100,000) in comparison to other parts of Chile (12.50 per 100,000) (t = 4.75, df = 18, p < 0.001). CONCLUSIONS: Chilean regions rich in naturally occurring lithium salts show lower suicide mortality rates in comparison to other regions. Although causality cannot be proven by this design, these findings add to previous findings and warrant further research on the effects of naturally occurring low dose lithium on health. PMID- 28357648 TI - Ameliorated Effects of (-)-Epigallocatechin Gallate Against Toxicity Induced by Vanadium in the Kidneys of Wistar Rats. AB - The aim of the study was to assess the protective effect of (-)-epigallocatechin gallate (EGCG), a flavonoid abundant in green tea, against ammonium metavanadate (AMV)-induced oxidative stress in male Wistar rats. Four groups of animals have been used, a control group and three test groups. In the first test group, AMV was intra-peritoneally (i.p) injected daily (5 mg/kg body weight for five consecutive days). The second test group of animals was also injected daily with EGCG (5 mg/kg body weight) during the same period. However, the third test group was i.p. injected with both AMV and EGCG (5 mg/kg body weight for five consecutive days). When given alone, AMV induced an oxidative stress evidenced by an increase of lipid peroxidation levels (expressed as TBARS concentration) in kidney. In these animals, activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) were significantly decreased, suggesting significant reduction of the antioxidant defense system at the cell level. Kidney histological sections, showed glomerular hypertrophy and tubular dilatation. In AMV-treated animals receiving EGCG, the oxidative stress was much less pronounced and activities of antioxidant enzymes were kept close to control values. Histopathological changes were less prominent. Our results confirm that green tea and other sources of flavonoids might confer a strong protection against ammonium metavanadate-induced oxidative stress. PMID- 28357649 TI - Content of Minerals and Fatty Acids and Their Correlation with Phytochemical Compounds and Antioxidant Activity of Leguminous Seeds. AB - The aim of the study was to determine the mineral composition and fatty acid profile in the seeds of selected Fabaceae species and cultivars and to assess their correlations with phytochemicals and antioxidant activity. The Andean lupine was characterised by a particularly high level of Mg and K as well as Cu, Zn, and Fe (P < 0.05). There were various correlations (P < 0.05) between the total phenols and tannins and these elements. The highest contribution of alpha linolenic acid (ALA, 18:3, n-3) in total fatty acids was noted in the lentil (13.8 in 100 g-1 fat), common bean (11.9 in 100 g-1 fat), and pea seeds (10.4 in 100 g-1 fat) (P = 0.028). In turn, the white lupine contained the highest content of ALA-0.67 g 100 g-1 seeds; its lowest level was determined in the broad bean 0.03 g 100 g-1 seeds. The seeds exhibited a high proportion of hypocholesterolemic fatty acids (on average 86%). The 2,2-diphenyl-1 picrylhydrazyl antiradical activity was positively correlated with UFA and PUFA (P < 0.05). This indicates great protective potential of legume seeds for prevention and treatment of diet-dependent diseases. PMID- 28357650 TI - Screening for symptom burden and supportive needs of patients with glioblastoma and brain metastases and their caregivers in relation to their use of specialized palliative care. AB - PURPOSE: Patients with brain tumors have a high symptom burden and multiple supportive needs. Needs of caregivers are often unattended. This study aims to determine screening-based symptom burden and supportive needs of patients and caregivers with regard to the use of specialized palliative care (SPC). METHODS: Seventy-nine patients with glioblastoma and brain metastases and 46 caregivers were screened with standardized questionnaires following diagnosis and 2 months later. The screening assessed symptom burden, quality of life (QoL), distress, and supportive needs. RESULTS: The most relevant symptoms were drowsiness, tiredness, and low well-being (53-58%). The most prevalent patient supportive needs were the need for information about available resources, the illness, and possible lifestyle changes (50-56%). The most prevalent caregiver needs were information about the illness, lifestyle changes, and about available resources (56-74%). Patients who received SCP and their caregivers had higher symptom burden and supportive needs than those without SPC. They reported moderate improvement in pain, distress, and QoL, while patients without SPC also improved their QoL, but had small to moderate deteriorations in pain, drowsiness, nauseas, well-being, and other problems. Distress of caregivers with SPC improved with moderate to large effect sizes but still was on a high level and remained stable for those without SPC. CONCLUSIONS: Symptom burden and supportive needs were high, but even more caregivers than patients expressed high distress and supportive needs. SPC appears to reach the target group, both patients and caregivers with elevated symptom burden. Targeted interventions are needed to improve tiredness and drowsiness. PMID- 28357652 TI - Optimized acoustic biochip integrated with microfluidics for biomarkers detection in molecular diagnostics. AB - The development of integrated platforms incorporating an acoustic device as the detection element requires addressing simultaneously several challenges of technological and scientific nature. The present work was focused on the design of a microfluidic module, which, combined with a dual or array type Love wave acoustic chip could be applied to biomedical applications and molecular diagnostics. Based on a systematic study we optimized the mechanics of the flow cell attachment and the sealing material so that fluidic interfacing/encapsulation would impose minimal losses to the acoustic wave. We have also investigated combinations of operating frequencies with waveguide materials and thicknesses for maximum sensitivity during the detection of protein and DNA biomarkers. Within our investigations neutravidin was used as a model protein biomarker and unpurified PCR amplified Salmonella DNA as the model genetic target. Our results clearly indicate the need for experimental verification of the optimum engineering and analytical parameters, in order to develop commercially viable systems for integrated analysis. The good reproducibility of the signal together with the ability of the array biochip to detect multiple samples hold promise for the future use of the integrated system in a Lab-on-a-Chip platform for application to molecular diagnostics. PMID- 28357651 TI - Cancer patients' control preferences in decision making and associations with patient-reported outcomes: a prospective study in an outpatient cancer center. AB - PURPOSE: "Shared decision making" has been proposed as a prerequisite of patient centered care. However, little is known on factors, which may influence cancer patients' decision control preferences (DCP) in routine care. This study investigated possible determinants of the patients' DCP with respect to patient characteristics and patient-reported outcomes (PROs). METHODS: Consecutive patients presenting at a comprehensive cancer center between May 2014 and October 2014 were offered a self-administered electronic questionnaire including standardized PRO measures and patients' DCP. Results were linked with patient characteristics from the hospital information system and analyzed using cross sectional methods. RESULTS: Out of 126 patients participating, 102 (81%; 65% male; mean age 62 years) completed the DCP-item. Overall, 49% (n = 50) preferred shared treatment decision responsibility, 29% (n = 30) preferred to leave the control to his/her physician, whereas 22% (n = 22) preferred to be in control of his/her treatment decision. Higher age (p = 0.035) and elevated distress levels (p = 0.038) were significantly associated with an increased willingness to leave the decision control to the physician. Further sociodemographic and PRO measures were not associated with patients' DCP. CONCLUSION: Our findings demonstrate that DCP assessment in routine cancer care is possible and provides important information to the treating oncologist. Information on DCP combined with PRO may contribute to more individualized decision making in cancer care. PMID- 28357653 TI - Identifying drug resistant cancer cells using microbubble well arrays. AB - Drug resistance is a characteristic of tumor initiating cells that can give rise to metastatic disease. In this work we demonstrate the use of microbubble well arrays as a cell culture platform to enumerate and characterize drug resistant cells in a human derived tumorigenic squamous cell carcinoma cell line. The spherical architecture and compliant hydrophobic composition of the microbubble well favors single cell survival, clonal proliferation and formation of spheres that do not grow on standard tissue culture plastic and are resistant to cisplatin. Spheres form in isolation and in microbubble wells containing proliferating cells and to some degree they stain positive for common stem cell markers CD44 and CD133. Spheres are also observed in cellularized primary human tumors cultured in microbubble arrays. This proof-of-concept study illustrates the potential for microbubble array technology to enumerate cancer cells resistant to standard care drugs with the ability to test alternative drug combinations. This capability can be developed for designing patient specific treatment strategies. Recovery of drug-resistant cells will allow a more full characterization of their gene expression profile thereby expanding our fundamental knowledge and ability to develop new targets to fight metastatic disease. PMID- 28357654 TI - Human adipocyte differentiation and characterization in a perfusion-based cell culture device. AB - Adipocytes have gained significant attention recently, because they are not only functioning as energy storage but also as endocrine cells. Adipocytes secret various signaling molecules, including adiponectin, MCP-1, and IL-6, termed collectively as "adipokines". Adipokines regulate glucose metabolism, thereby play an important role in obesity, diabetes type 2, and other metabolic disorders. Conventionally, to study the secretory function, adipocytes are cultured in vitro in static conditions. However, static culturing condition falls short of mimicking the interstitial fluid flows in living systems. Here, we developed a perfusion device which allows dynamic culture of adipocytes under constant and mild flow using a double-layered fluidic structure. Adipocytes were cultured in the bottom layer while the culture media were constantly flown in the upper layer and perfused through a porous membrane that separate the two chambers. The porous membrane between the two chambers physically separates the cells from the flow stream while maintain a fluidic connection by diffusion. This setting not only provides continuous nutrient supply to adipocytes but also maintains a steady and mild shear stress on the cell membrane. It was found the perfusion-based culture conditions promoted faster growth of primary preadipocytes and stimulated greater adipogenesis compared to static culture condition. Adipocytes cultured under perfusion systems produced more MCP-1 and IL 6, but less adiponectin. When stimulated with TNF-alpha, adipocytes expressed higher level of MCP-1 and IL-6, but lower level of adiponectin. No significant glucose uptake regulation was observed after treating the adipocytes with insulin in both static and perfusion-based culture. Our results demonstrate that perfusion-base culture has played a role in the adipocyte function particularly the secretion of adipokines. More future studies are required to unveil the mechanisms behind perfusion's impact on adipocytes. PMID- 28357655 TI - Is breast compression associated with breast cancer detection and other early performance measures in a population-based breast cancer screening program? AB - PURPOSE: We aimed to investigate early performance measures in a population-based breast cancer screening program stratified by compression force and pressure at the time of mammographic screening examination. Early performance measures included recall rate, rates of screen-detected and interval breast cancers, positive predictive value of recall (PPV), sensitivity, specificity, and histopathologic characteristics of screen-detected and interval breast cancers. METHODS: Information on 261,641 mammographic examinations from 93,444 subsequently screened women was used for analyses. The study period was 2007 2015. Compression force and pressure were categorized using tertiles as low, medium, or high. chi 2 test, t tests, and test for trend were used to examine differences between early performance measures across categories of compression force and pressure. We applied generalized estimating equations to identify the odds ratios (OR) of screen-detected or interval breast cancer associated with compression force and pressure, adjusting for fibroglandular and/or breast volume and age. RESULTS: The recall rate decreased, while PPV and specificity increased with increasing compression force (p for trend <0.05 for all). The recall rate increased, while rate of screen-detected cancer, PPV, sensitivity, and specificity decreased with increasing compression pressure (p for trend <0.05 for all). High compression pressure was associated with higher odds of interval breast cancer compared with low compression pressure (1.89; 95% CI 1.43-2.48). CONCLUSIONS: High compression force and low compression pressure were associated with more favorable early performance measures in the screening program. PMID- 28357656 TI - Physiologically Based Pharmacokinetic and Absorption Modeling for Osmotic Pump Products. AB - Physiologically based pharmacokinetic (PBPK) and absorption modeling approaches were employed for oral extended-release (ER) drug products based on an osmotic drug delivery system (osmotic pumps). The purpose was to systemically evaluate the in vivo relevance of in vitro dissolution for this type of formulation. As expected, in vitro dissolution appeared to be generally predictive of in vivo PK profiles, because of the unique feature of this delivery system that the in vitro and in vivo release of osmotic pump drug products is less susceptible to surrounding environment in the gastrointestinal (GI) tract such as pH, hydrodynamic, and food effects. The present study considered BCS (Biopharmaceutics Classification System) class 1, 2, and 3 drug products with half-lives ranging from 2 to greater than 24 h. In some cases, the colonic absorption models needed to be adjusted to account for absorption in the colon. C max (maximum plasma concentration) and AUCt (area under the concentration curve) of the studied drug products were sensitive to changes in colon permeability and segmental GI transit times in a drug product-dependent manner. While improvement of the methodology is still warranted for more precise prediction (e.g., colonic absorption and dynamic movement in the GI tract), the results from the present study further emphasized the advantage of using PBPK modeling in addressing product-specific questions arising from regulatory review and drug development. PMID- 28357657 TI - Development and Validation of a Health and Work Survey Based on the Rasch Model among Portuguese Workers. AB - The purpose of this study was to develop the Health and Work Survey (INSAT) and examine the validity of the discomfort rating scale. Data were collected from 706 Portuguese workers from six economic sectors with the support of the Health and Work Survey (INSAT - Inquerito Saude e Trabalho). The INSAT is a self administered questionnaire to assessing working conditions, health and wellbeing, and to provide information to the occupational health systems in the organisations. For the survey instrument validation, the Rasch Partial Credit Model (PCM) was used to analyse item fit statistics. From the application of PCM, Person Separation Reliability was obtained (0.8761) and the value can be considered very good (>0.8). From the statistical analysis, the Overall Model fit information, given by Outfit Mean square/Infit Mean square, is between 0.5 and 1.5, meaning "Productive for measurement" and "acceptable fit overall". The INSAT items can generate predictable response patterns. We recommend that the INSAT discomfort rating scale and some other items should be reviewed in future works. In any event, this tool proves to be useful in assessing the relationship between work and health and in evaluating key main risk factors, helping to prevent problems and improving occupational health systems. PMID- 28357658 TI - Serological and Molecular Methods to Study Epidemiological Aspects of Human T Cell Lymphotropic Virus Type 1 Infection. AB - We estimated that at least 5-10 million individuals are infected with HTLV-1. Importantly, this number is based on the study of nearly 1.5 billion people living in known human T-cell lymphotropic virus type 1 (HTLV-1) endemic areas, for which reliable epidemiological data are available. However, for some highly populated regions including India, the Maghreb, East Africa, and some regions of China, no consistent data are yet available which prevents a more accurate estimation. Thus, the number of HTLV-1 infected people in the world is probably much higher. The prevalence of HTLV-1 prevalence varies depending on age, sex, and economic level in most HTLV-1 endemic areas. HTLV-1 seroprevalence gradually increases with age, especially in women. HTLV-1 has a simian origin and was originally acquired by humans through interspecies transmission from STLV-1 infected monkeys in the Old World. Three main modes of HTLV-1 transmission have been described; (1) from mother-to-child after prolonged breast-feeding lasting more than six months, (2) through sexual intercourse, which mainly, but not exclusively, occurs from male to female and lastly, (3) from contaminated blood products, which contain HTLV-1 infected lymphocytes. In specific areas, such as Central Africa, zoonotic transmission from STLV-1 infected monkeys to humans is still ongoing.The diagnostic methods used to study the epidemiological aspects of HTLV-1 infection mainly consist of serological assays for the detection of antibodies specifically directed against different HTLV-1 antigens. Screening tests are usually based on enzyme-linked immunoabsorbent assay (ELISA), chemiluminescence enzyme-linked immunoassay (CLEIA) or particle agglutination (PA). Confirmatory tests include mostly Western blots (WB)s or innogenetics line immunoassay (INNO-LIATM) and to a lesser extent immunofluorescence assay (IFA). The search for integrated provirus in the DNA from peripheral blood cells can be performed by qualitative and/or quantitative polymerase chain reaction (qPCR). qPCR is widely used in most diagnostic laboratories and quantification of proviral DNA is useful for the diagnosis and follow-up of HTLV-1 associated diseases such as adult T-cell leukemia (ATL) and tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM). PCR also provides amplicons for further sequence analysis to determine the HTLV-1 genotype present in the infected person. The use of new generation sequencing methodologies to molecularly characterize full and/or partial HTLV-1 genomic regions is increasing. HTLV-1 genotyping generates valuable molecular epidemiological data to better understand the evolutionary history of this virus. PMID- 28357659 TI - Molecular Epidemiology Database for Sequence Management and Data Mining. AB - A central database to aggregate sequence information from a range of epidemiological aspects including HTLV-1 pathogenesis, origin, and evolutionary dynamic would be useful to scientists and physicians worldwide. This Chapter describes two online tools for studies related to HTLV-1, the HTLV-1 Molecular Epidemiology Database and the HTLV-1 Subtyping Tool. The HTLV-1 Molecular Epidemiology Database is a tool for sequence management and data mining which allows researchers to download sequences with clinical and demographic information. The HTLV-1 Subtyping Tool is an online software used for HTLV-1 genotyping, the algorithm consists in the alignment of a query sequence with a carefully selected set of predefined reference strains, followed by phylogenetic analysis. PMID- 28357660 TI - Reporter Systems to Study HTLV-1 Transmission. AB - The retrovirus Human T-lymphotropic virus type 1 (HTLV-1) preferentially infects CD4+ T-cells via cell-to-cell transmission, while cell-free infection of T-cells is inefficient. Substantial insights into the different routes of transmission have largely been obtained by imaging techniques or by flow cytometry. Recently, strategies to quantify infection events with HTLV-1 improved. In this chapter, we present two different methods to quantitate virus transmission. Both methods are based on measuring gene activity of luciferase with a cost-saving in-house luciferase assay. First, we established a reporter Jurkat T-cell line carrying a luciferase gene under the control of the HTLV-1 core promoter U3R. Upon co culture with chronically HTLV-1-infected T-cell lines, reporter cells are infected, and upon expression of the viral transactivator Tax, the viral promoter is activated resulting in enhanced luciferase activity. However, this assay as presented here does not exclude cell fusion as the mechanism allowing intracellular Tax-dependent activation of luciferase gene expression. Therefore, we describe a second method, the single-cycle replication-dependent reporter system developed by Mazurov et al. (PLoS Pathog 6:e1000788, 2010) that allows quantitation of HTLV-1 infection in co-cultured cells. Taken together, both methods facilitate quantitation of HTLV-1 transmission and will help to unravel pathways required for cell-to-cell transmission on a quantitative basis. PMID- 28357661 TI - Quantitative Analysis of Human T-Lymphotropic Virus Type 1 (HTLV-1) Infection Using Co-Culture with Jurkat LTR-Luciferase or Jurkat LTR-GFP Reporter Cells. AB - Unlike HIV-1, HTLV-1 viral transmission requires cell-to-cell contacts, while cell-free virions are poorly infectious and almost absent from body fluids. Though the virus uses three nonexclusive mechanisms to infect new target cells: (1) MTOC polarization followed by formation of a virological synapse and viral transfer into a synaptic cleft, (2) genesis of a viral biofilm and its transfer of embedded viruses, or (3) HTLV-1 transmission using conduits. The Tax transactivator and the p8 viral proteins are involved in virological synapse and nanotube formation respectively.HTLV-1 transcription from the viral promoter (i.e., LTR) requires the Tax protein that is absent from the viral particle and is expressed after productive infection. The present chapter focuses on a series of protocols used to quantify HTLV-1 de novo infection of target cells. These techniques do not discriminate between the different modes of transmission, but allow an accurate measure of productive infection. We used cell lines that are stably transfected with LTR-GFP or LTR-luciferase plasmids and quantified Green Fluorescent Protein expression or luciferase activity, since both of them reflect Tax expression. PMID- 28357662 TI - Isolation of Exosomes from HTLV-Infected Cells. AB - Exosomes are small vesicles, approximately 30-100 nm in diameter, that transport various cargos, such as proteins and nucleic acids, between cells. It has been previously shown that exosomes can also transport viral proteins, such as the HTLV protein Tax, and viral RNAs, potentially contributing to disease pathogenesis. Therefore, it is important to understand their impact on recipient cells. Here, we describe methods of isolating and purifying exosomes from cell culture or tissue through ultracentrifugation, characterizing exosomes by surface biomarkers, and assays that evaluate the effect of exosomes on cells. PMID- 28357663 TI - A Luciferase Functional Quantitative Assay for Measuring NF-KB Promoter Transactivation Mediated by HTLV-1 and HTLV-2 Tax Proteins. AB - HTLV-1 and HTLV-2 viruses express Tax transactivator proteins required for viral genome transcription and capable of transforming cells in vivo and in vitro. Although Tax oncogenic potential needs to be further elucidated, it is well established that Tax proteins activate, among others, transcription factors of the NF-KB family, which are involved in immune and inflammatory responses, cell growth, apoptosis, stress responses and oncogenesis. Here, we describe a reporter gene assay applied for quantitative analysis of Tax-dependent NF-KB activation. The procedure is based on co-transfection of two individual vectors containing the cDNA for firefly and Renilla luciferase enzymes and vectors expressing Tax proteins. The luciferase expression is driven by cis-NF-KB promoter regulatory elements responsive to Tax transactivating factor. This assay is particularly useful to investigate Tax influence on NF-KB activation mediated by viral or host factors. PMID- 28357664 TI - Generation of a Tet-On Expression System to Study Transactivation Ability of Tax 2. AB - HTLV Tax proteins (Tax-1 and Tax-2) are known to be able to transactivate several host cellular genes involved in complex molecular pathways. Here, we describe a stable and regulated high-level expression model based on Tet-On system, to study the capacity of Tax-2 to transactivate host genes. In particular, the Jurkat Tet On cell line suitable for evaluating the ability of Tax-2 to stimulate transactivation of a specific host gene, CCL3L1 (C-C motif chemokine ligand 3 like 1 gene), was selected. Then, a plasmid expressing tax-2 gene under control of a tetracycline-response element was constructed. To avoid the production of a fusion protein between the report gene and the inserted gene, a bidirectional plasmid was designed. Maximum expression and fast response time were achieved by using nucleofection technology as transfection method. After developing an optimized protocol for efficiently transferring tax-2 gene in Jurkat Tet-On cellular model and exposing transfected cells to Dox (doxycycline, a tetracycline derivate), a kinetics of tax-2 expression through TaqMan Real-time PCR assay was determined. PMID- 28357665 TI - EGF Uptake and Degradation Assay to Determine the Effect of HTLV Regulatory Proteins on the ESCRT-Dependent MVB Pathway. AB - The endosomal sorting complex required for transport (ESCRT) pathway plays key roles in multivesicular bodies (MVBs) formation and lysosomal degradation of membrane receptors, viral budding, and midbody abscission during cytokinesis. The epidermal growth factor receptor (EGFR) is regarded as a prototypical cargo of the MVB/ESCRT pathway and following stimulation by epidermal growth factor (EGF) EGFR/EGF complexes are internalized, sorted into MVBs, and degraded by lysosomes or recycled back to the cell membrane. Here, we describe an assay to analyze the effect of human T-cell leukemia (HTLV) regulatory proteins on the functionality of ESCRT-dependent MVB/lysosomal trafficking of EGFR/EGF complexes. This is performed by direct visualization and quantification of the rate of EGF Alexa595/EGFR internalization and degradation in HeLa cells expressing HTLV regulatory proteins by immunofluorescence and western blot. PMID- 28357666 TI - Methods for Identifying and Examining HTLV-1 HBZ Post-translational Modifications. AB - Post-translational modifications (PTMs) are chemical alterations to individual amino acids that alter a protein's conformation, stability, and/or function. Several pathogenic viruses have been shown to encode proteins with PTMs, including human T-cell leukemia virus type 1 (HTLV-1) Tax and Rex regulatory proteins. HTLV-1 basic leucine zipper protein (HBZ) was hypothesized to feature PTMs due to its functional activities and interactions with cellular transcription factors and acetyltransferases. Here, we describe the approach used to identify, via mass spectrometry, the PTMs of HBZ. In addition, we describe methods to determine the functional relevance of the identified PTMs. PMID- 28357667 TI - High-Throughput Mapping and Clonal Quantification of Retroviral Integration Sites. AB - We describe here a method to identify the position of retroviral insertion sites and simultaneously to quantify the absolute abundance of each clone, i.e., the number of cells having the provirus inserted at a given place in the host genome. The method is based on random shearing of the host cell DNA, followed by a linker mediated PCR to amplify the genomic regions flanking the proviruses, and high throughput sequencing of the amplicons. The quantification of the abundance of each infected clone allowed us to develop two new metrics: i. the oligoclonality index, which quantifies the nonuniformity of the distribution of clone abundance, and ii. an estimator of the total number of clones in the body of the host. These new tools are valuable for the study of retroviral infections and can also be adapted for the tracking of gene-edited cells. PMID- 28357668 TI - STR Profiling of HTLV-1-Infected Cell Lines. AB - Many investigations of the replication and pathogenesis of human T-cell leukemia virus type 1 (HTLV-1) employ chronically infected cell lines, cell lines stabilized from primary adult T-cell leukemia cells, and noninfected T-cell lines. The validity of data obtained from such studies depends on the unambiguous identification of each cell line, which can be performed by short-tandem-repeat (STR) profiling (DNA fingerprinting). While kit-based profiling represents the standard method for cell line authentication, not all labs have ready access to the required capillary electrophoresis equipment, and the costs of such tests can become substantial, especially if the cell lines are to be tested frequently. We analyzed DNA from a panel of HTLV-1-infected cell lines and noninfected T-cell lines using a commercial STR kit and then analyzed the same DNA for individual STR markers followed by nondenaturing polyacrylamide gel electrophoresis. This simplified method should facilitate routine confirmation of cell line identity in diverse laboratory settings. PMID- 28357669 TI - Expression of HTLV-1 Genes in T-Cells Using RNA Electroporation. AB - Human T-cell leukemia virus type 1 (HTLV-1) infects about 20 million people world wide. Around 5% of the infected individuals develop adult T-cell leukemia (ATL) or a neurological disease termed tropical spastic paraparesis (TSP) after a clinical latency of years to decades. Through the use of two promoters and alternative splicing HTLV-1 expresses at least 12 different proteins. HTLV-1 establishes a life-long persistent infection by inducing the clonal expansion of infected cells, a property largely ascribed to the viral genes Tax and HBZ. However, the fact that ATL arises in a minority of infected individuals after a long clinical latency suggests the existence of factors counterbalancing the oncogenic potential of HTLV-1 in the context of natural infection.To study the role of the different HTLV-1 gene products in the HTLV-1 life cycle, we optimized a transfection protocol for primary T-cells using an approach based on the electroporation of in vitro-transcribed RNA. Results showed that the RNA transfection technique combines a high transfection efficiency with low toxicity, not only in Jurkat T-cells but also in primary T-cells. These findings suggest that RNA electroporation is preferable for experiments aimed at investigating the role of HTLV-1 gene products in the context of primary T-cells, which represent the main target of HTLV-1 in vivo. PMID- 28357670 TI - Quantification of Cell Turnover in the Bovine Leukemia Virus Model. AB - In a perspective of a comparative virology approach, characterization of the bovine leukemia virus (BLV) model may be helpful to better understand infection by the related human T-lymphotropic virus type 1 (HTLV-1). In this paper, we first provide detailed protocols to inoculate cloned BLV proviruses into sheep or cattle. We also describe methods to quantify apoptosis ex vivo and cell turnover in vivo. PMID- 28357671 TI - Analysis of NK Cell Function and Receptor Expression During HTLV-1 and HTLV-2 Infection. AB - Cytofluorimetric analysis is a typical method in immunology to evaluate phenotype and function of Natural Killer (NK) cells derived from HTLV-1/2 infected patients and healthy donors. Here, we described protocols to NK cells phenotypical and cytotoxicity assay, performed by flow cytometry on fresh and immune-magnetically or flow cytometry sorted NK cells. A new developed protocol able to evaluate IFNgamma production has been included. PMID- 28357672 TI - Overview of Targeted Therapies for Adult T-Cell Leukemia/Lymphoma. AB - Adult T-Cell Leukemia/lymphoma (ATL) is the first human malignancy associated with a chronic infection by a retrovirus, the human T-cell lymphotropic virus type I (HTLV-I). ATL occurs, after a long latency period, only in about 5% of 10 20 millions infected individuals. ATL has a dismal prognosis with a median survival of less than 1 year, mainly due to its resistance to chemotherapy and to a profound immunosuppression. The viral oncoprotein, Tax, plays a major role in ATL oncogenic transformation by interfering with cell proliferation, cell cycle, apoptosis, and DNA repair. The diversity in ATL clinical features and prognosis led to Shimoyama classification of ATL into four clinical subtypes (acute, lymphoma, chronic, and smoldering) requiring different therapeutic strategies. Clinical trials, mainly conducted in Japan, demonstrated that combination of chemotherapy could induce acceptable response rate in the lymphoma subtype but not in acute ATL. However, long-term prognosis remains poor for both subtypes, due to a high relapse rate. Similarly, whether managed by a watchful waiting or treated with chemotherapy, the indolent forms (smoldering and chronic) have a poor long-term outcome. An international meta-analysis showed improved survival in the leukemic subtypes of ATL (chronic, smoldering as well as a subset of the acute subtype) with the use of two antiviral agents, zidovudine and interferon alpha, and accordingly, this combination should be considered the standard first line treatment in this context. ATL patients with lymphoma subtype benefit from induction chemotherapy, given simultaneously or sequentially with an antiviral combination of zidovudine and interferon-alpha. Allogeneic hematopoietic stem cells transplantation remains a promising and potentially curative approach but is limited to a small number of patients. Novel drugs such as arsenic trioxide in combination with interferon-alpha or monoclonal antibodies such as anti-CXCR4 have shown promising results and warrant further investigation. PMID- 28357673 TI - The Granulocyte-to-Lymphocyte Ratio as a Marker of Surgical Stress and a Predictor of Postoperative Infectious Complications After Gastric Cancer Surgery: An Analysis of Patients Enrolled in a Prospective Randomized Trial. AB - BACKGROUND: The granulocyte-to-lymphocyte ratio (GLR) in the blood may be a useful marker of surgical stress (SS) following surgery for cancer. The aim of the present study was to compare the SS by measuring the GLR, and further study the value of the GLR in predicting postoperative infectious complications (ICs). METHODS: Data from 201 gastric cancer patients at Fujian Medical University Union Hospital who were enrolled in our prospective randomized controlled trial were extracted for this study. Blood samples to perioperatively measure the GLR were routinely taken. Additional external validation was performed using the dataset (n = 135) from Nanfang Hospital who were enrolled in the same trial. RESULTS: Patients undergoing either laparoscopic or open resection showed a similar preoperative GLR, as well as similar GLRs, on postoperative days (PODs) 1 and 3. The GLR on POD 5 was lower in the laparoscopic group compared with the open group (p = 0.014), and the optimal predictive GLR thresholds of postoperative ICs in both the laparoscopic and open groups were the same on POD 5, i.e. 6.5 and 7.4, respectively. The GLR on POD 5 was identified as an independent factor for postoperative ICs in both the laparoscopic and open groups. Similar results were found in the validation dataset. CONCLUSION: The GLR status not only correlates with SS but may also be a reliable predictor of ICs for gastric cancer patients after gastrectomy. The ideal GLR thresholds on POD 5 for ICs following laparoscopic and open gastrectomy are 6.5 and 7.4, respectively. PMID- 28357674 TI - Surgical Outcomes After Open, Laparoscopic, and Robotic Gastrectomy for Gastric Cancer. AB - BACKGROUND: In contrast to the significant advantages of laparoscopic versus open gastrectomy, robotic gastrectomy has shown little benefit over laparoscopic gastrectomy. This study aimed to compare multi-dimensional aspects of surgical outcomes after open, laparoscopic, and robotic gastrectomy. METHODS: Data from 915 gastric cancer patients who underwent gastrectomy by one surgeon between March 2009 and May 2015 were retrospectively reviewed. Perioperative parameters were analyzed for short-term outcomes. Surgical success was defined as the absence of conversion to open surgery, major complications, readmission, positive resection margin, or fewer than 16 retrieved lymph nodes. RESULTS: This study investigated 241 patients undergoing open gastrectomy, 511 patients undergoing laparoscopic gastrectomy, and 173 patients undergoing robotic gastrectomy. For each approach, the respective incidences were as follows: conversion to open surgery (not applicable, 0.4%, and 0%; p = 0.444), in-hospital major complications (5.8, 2.7, and 1.2%; p = 0.020), delayed complications requiring readmission (2.9, 2.0, and 1.2%; p = 0.453), positive resection margin (1.7, 0, and 0%; p = 0.003), and inadequate number of retrieved lymph nodes (0.4, 4.1, and 1.7%; p = 0.010). Compared with open and laparoscopic surgery, robotic gastrectomy had the highest surgical success rate (90, 90.8, and 96.0%). Learning curve analysis of success using cumulative sum plots showed success with the robotic approach from the start. Multivariate analyses identified age, sex, and gastrectomy extent as significant independent parameters affecting surgical success. Surgical approach was not a contributing factor. CONCLUSIONS: Open, laparoscopic, and robotic gastrectomy exhibited different incidences and causes of surgical failure. Robotic gastrectomy produced the best surgical outcomes, although the approach method itself was not an independent factor for success. PMID- 28357675 TI - What is the role of nephrologists and nurses of the dialysis department in providing fertility care to CKD patients? A questionnaire study among care providers. AB - PURPOSE: This study evaluated current fertility care for CKD patients by assessing the perspectives of nephrologists and nurses in the dialysis department. METHODS: Two different surveys were distributed for this cross sectional study among Dutch nephrologists (N = 312) and dialysis nurses (N = 1211). RESULTS: Response rates were 50.9% (nephrologists) and 45.4% (nurses). Guidelines on fertility care were present in the departments of 9.0% of the nephrologists and 15.6% of the nurses. 61.7% of the nephrologists and 23.6% of the nurses informed >=50% of their patients on potential changes in fertility due to a decline in renal function. Fertility subjects discussed by nephrologists included "wish to have children" (91.2%), "risk of pregnancy for patients' health" (85.8%), and "inheritance of the disease" (81.4%). Barriers withholding nurses from discussing FD were based on "the age of the patient" (62.6%), "insufficient training" (55.2%), and "language and ethnicity" (51.6%). 29.2% of the nurses felt competent in discussing fertility, 8.3% had sufficient knowledge about fertility, and 75.7% needed to expand their knowledge. More knowledge and competence were associated with providing fertility health care (p < 0.01). CONCLUSIONS: In most nephrology departments, the guidelines to appoint which care provider should provide fertility care to CKD patients are absent. Fertility counseling is routinely provided by most nephrologists, nurses often skip this part of care mainly due to insufficiencies in self-imposed competence and knowledge and barriers based on cultural diversity. The outcomes identified a need for fertility guidelines in the nephrology department and training and education for nurses on providing fertility care. PMID- 28357677 TI - Identification of a Novel Somatic Mutation Leading to Allele Dropout for EGFR L858R Genotyping in Non-Small Cell Lung Cancer. AB - OBJECTIVE: While PCR-based genotyping methods abound in molecular testing for lung cancer therapy, these approaches may not provide the robust sensitivity to detect accurate genotypes in a variable cancer genomic background. METHODS: Here, we describe a study of a clinical tumor specimen containing a novel somatic single nucleotide variant that caused allele drop-out in EGFR L858R genotyping, resulting in a false-negative interpretation and impacting patient clinical management. RESULTS: We demonstrate that a subsequent unbiased next-generation sequencing approach correctly identified the driver mutation, and therefore may be more reliable for somatic variant detection. CONCLUSIONS: These findings magnify the potential pitfalls of PCR amplification-based approaches and stress the importance of unbiased and sensitive molecular testing strategies for therapeutic marker detection as molecular testing becomes the standard for determining clinical management of cancer patients. PMID- 28357678 TI - Reconsidering Parenting in Chinese Culture: Subtypes, Stability, and Change of Maternal Parenting Style During Early Adolescence. AB - Parenting in Chinese culture has been a central topic and there have been debate on whether western-derived parenting style is applicable to Chinese cultures in terms of both behavioral profiles and their relationships with child and adolescent adjustment. This study identified the subtypes of Chinese maternal parenting style and examined their stability and changes over the transition to early adolescence. In an urban Chinese sample (N = 2173, 48% girls), four waves of longitudinal data were collected when the adolescents were in the fifth (M = 11.27 years), sixth, seventh, and eighth grades. Latent profile analysis identified four subtypes of parenting style: authoritative, authoritarian, average-level undifferentiated, and strict-affectionate. Adolescents of authoritative mothers exhibited the best overall adjustment, while adolescents of authoritarian mothers showed the worst adjustment. Adolescents of strict affectionate mothers generally adjusted as well as those of authoritative mothers, except they showed lower academic achievement. The strict-affectionate parenting represented a culture-specific subtype of parenting style in Chinese culture. Latent transition analysis revealed high stability of parenting styles during early adolescence, but transitions between subtypes were also evident. These findings highlight the importance of revisiting Chinese parenting and examining the developmental course of parenting style. PMID- 28357676 TI - Porcine epidemic diarrhea virus virus-like particles produced in insect cells induce specific immune responses in mice. AB - Porcine epidemic diarrhea virus (PEDV), which causes 80-100% mortality in neonatal piglets, is one of the most devastating viral diseases affecting swine worldwide. To date, the lack of effective vaccines and drugs is the main problem preventing control of the global spread of PEDV. In this study, we produced PEDV virus-like particles (VLPs) composed of S, M, and E proteins with a baculovirus expression system and tested them via indirect immunofluorescence assay (IFA)and Western blot analysis. Electron microscopy showed that the morphological structure of the PEDV VLPs was similar to that of the protovirus. Microneutralization assays and ELISpot analysis demonstrated that PEDV VLPs induced highly specific antibody responses and Th2-mediated humoral immunity. As a result, the PEDV VLPs displayed excellent immunogenicity in mice. Therefore, a VLP-based vaccine has the potential to prevent PEDV infection. PMID- 28357679 TI - Changes in quality of life after elective surgery: an observational study comparing two measures. AB - PURPOSE: Our main objective was to compare the change in a validated quality of life measure to a global assessment measure. The secondary objectives were to estimate the minimum clinically important difference (MCID) and to describe the change in quality of life by surgical specialty. METHODS: This prospective cohort study included 7902 adult patients undergoing elective surgery. Changes in the Veterans RAND 12-Item Health Survey (VR-12), composed of a physical component summary (PCS) and a mental component summary (MCS), were calculated using preoperative and postoperative questionnaires. The latter also contained a global assessment question for quality of life. We compared PCS and MCS to the global assessment using descriptive statistics and weighted kappa. MCID was calculated using an anchor-based approach. Analyses were pre-specified and registered (NCT02771964). RESULTS: By the change in VR-12 scores, an equal proportion of patients experienced improvement and deterioration in quality of life (28% for PCS, 25% for MCS). In contrast, by the global assessment measure, 61% reported improvement, while only 10% reported deterioration. Agreement with the global assessment was slight for both PCS (kappa = 0.20, 57% matched) and MCS (kappa = 0.10, 54% matched). The MCID for the overall VR-12 score was approximately 2.5 points. Patients undergoing orthopedic surgery showed the most improvement in quality of life measures, while patients undergoing gastrointestinal/hepatobiliary or urologic surgery showed the most deterioration. CONCLUSIONS: Subjective global quality of life report does not agree well with a validated quality of life instrument, perhaps due to patient over-optimism. PMID- 28357680 TI - Visual function quality of life measure changes upon conversion to neovascular age-related macular degeneration in second eyes. AB - PURPOSE: To determine changes in quality of life measures when choroidal neovascularization (CNV) developed in the second eye of patients with initially unilateral neovascular age-related macular degeneration (AMD). METHODS: We analyzed responses to the 39-item National Eye Institute Visual Function Questionnaire (NEI-VFQ), 36-item Short Form Health Survey (SF-36), and Hospital Anxiety and Depression Scale (HADS) at baseline, and prior to and following second eye CNV diagnosis in 92 participants enrolled in two Submacular Surgery Trials. Paired t-tests for sample sizes over 30 and Wilcoxon signed-rank tests for sample sizes <30 were performed to compare scores. RESULTS: CNV development resulted in statistically and clinically significant changes in responses to 20 of 39 NEI-VFQ items, indicating visual function decline during a mean interval of 25 months. Little difference was noted between baseline scores and prior to CNV diagnosis, which averaged 8.9 months duration. Subscales demonstrated a statistically significant decline in general vision, near activities, distance activities, social functioning, role difficulties, dependency, and driving. There were minimal changes in the HADS and SF-36 scales. CONCLUSION: CNV development in the second eye had a dramatic effect on visual functioning based on patient responses to the NEI-VFQ questionnaire. Our investigation is believed to be the first study using data collected prospectively to demonstrate vision-related quality of life changes that resulted from development of CNV in AMD patients. PMID- 28357681 TI - What contributes to long-term quality of life in breast cancer patients who are undergoing surgery? Results of a multidimensional study. AB - PURPOSE: This study aims to examine the key determinants of long-term quality of life in breast cancer patients who are undergoing surgery using a multidimensional approach and taking into account preoperative and post-operative psychological characteristics such as anxiety, depression, posttraumatic growth, body image, and physical activity as well as medical parameters. METHODS: The study involved 63 breast cancer patients from the Department of Surgery at the University of Szeged. Assessments occurred 1 day before surgery as well as 3 days and 18 months after surgery using the Spielberger State and Trait Anxiety Inventory (STAI), Beck's Depression Inventory (BDI), Functional Assessment of Cancer Therapy-Breast Cancer Scale (FACT-B), Posttraumatic Growth Inventory (PTGI) and Breast Impact of Treatment Scale (BITS). Data relating to physical activity, medical parameters and sociodemographic characteristics were also collected. RESULTS: The level of depression did not change over time. State anxiety decreased 18 months after the surgery compared to before the surgery; however, there was a greater decrease immediately after the surgery and then anxiety increased again 18 months later. Trait anxiety was associated with quality of life, posttraumatic growth and body image. Posttraumatic growth and the level of depression were found to be possible contributing factors to the increase in long-term quality of life. CONCLUSIONS: The results show that the timely detection and proper management of psychological distress and the enhancement of posttraumatic growth are of great value, as they might be important contributing factors to long-term quality of life in breast cancer patients. PMID- 28357683 TI - Targeting Frailty in Heart Failure. AB - OPINION STATEMENT: Frailty is a systemic syndrome characterized by impaired physiologic reserve, slowness, weakness, and wasting. It is associated with, but distinct from, aging, disability, and multimorbidity. Frailty is extremely common in patients with heart failure and portends a worse prognosis. The two syndromes worsen one another via complex molecular and cellular mechanisms which are not fully understood but include increased levels of stress hormones and cytokines. In this article, we discuss the mechanisms of frailty and review common frailty metrics. We review and summarize the literature on the impact of frailty in heart failure and discuss treatment and management options. PMID- 28357684 TI - Setting Ideal Lubricant Mixing Time for Manufacturing Tablets by Evaluating Powder Flowability. AB - We investigated the effectiveness of using Carr's flowability index (FI) and practical angle of internal friction (Phi) as indexes for setting the target Mg St mixing time needed for preparing tablets with the target physical properties. We used FI as a measure of flowability under non-loaded conditions, and Phi as a measure of flowability under loaded conditions for pharmaceutical powders undergoing direct compression with varying concentrations of Mg-St and mixing times. We evaluated the relationship between Mg-St mixing conditions and pharmaceutical powder flowability, analyzed the correlation between the physical properties of the tablets (i.e., tablet weight variation, drug content uniformity, hardness, friability, and disintegration time of tablets prepared using the pharmaceutical powder), and studied the effect of Mg-St mixing conditions and pharmaceutical powder flowability on tablet properties. Mg-St mixing time highly correlated with pharmaceutical powder FI (R 2 = 0.883) while Mg-St concentration has low correlation with FI, and FI highly correlated with the physical properties of the tablet (R 2 values: weight variation 0.509, drug content variation 0.314, hardness 0.525, friability 0.477, and disintegration time 0.346). Therefore, using pharmaceutical powder FI as an index could enable prediction of the physical properties of a tablet without the need for tableting, and setting the Mg-St mixing time by using pharmaceutical powder FI could enable preparation of tablets with the target physical properties. Thus, the FI of the intermediate product (i.e., pharmaceutical powder) is an effective index for controlling the physical properties of the finished tablet. PMID- 28357682 TI - Quality of life independently predicts long-term mortality but not vascular events: the Northern Manhattan Study. AB - PURPOSE: Cardiovascular disease is a major contributor to morbidity and mortality, and prevention relies on accurate identification of those at risk. Studies of the association between quality of life (QOL) and mortality and vascular events incompletely accounted for depression, cognitive status, social support, and functional status, all of which have an impact on vascular outcomes. We hypothesized that baseline QOL is independently associated with long-term mortality in a large, multi-ethnic urban cohort. METHODS: In the prospective, population-based Northern Manhattan Study, Spitzer QOL index (SQI, range 0-10, with ten signifying the highest QOL) was assessed at baseline. Participants were followed over a median 11 years for stroke, myocardial infarction (MI), and vascular and non-vascular death. Multivariable Cox proportional hazards regression estimated hazard ratio and 95% confidence interval (HR, 95% CI) for each outcome, with SQI as the main predictor, dichotomized at 10, adjusting for baseline demographics, vascular risk factors, history of cancer, social support, cognitive status, depression, and functional status. RESULTS: Among 3298 participants, mean age was 69.7 + 10.3 years; 1795 (54.5%) had SQI of 10. In fully adjusted models, SQI of 10 (compared to SQI <10) was associated with reduced risk of all-cause mortality (HR 0.80, 95% CI 0.72-0.90), vascular death (0.81, 0.69-0.97), non-vascular death (0.78, 0.67-0.91), and stroke or MI or death (0.82, 0.74-0.91). In fully adjusted competing risk models, there was no association with stroke (0.93, 0.74-1.17), MI (0.98, 0.75-1.28), and stroke or MI (1.03, 0.86-1.24). Results were consistent when SQI was analyzed continuously. CONCLUSION: In this large population-based cohort, highest QOL was inversely associated with long-term mortality, vascular and non-vascular, independently of baseline primary vascular risk factors, social support, cognition, depression, and functional status. QOL was not associated with non-fatal vascular events. PMID- 28357685 TI - Familial Acute Myeloid Leukemia and Myelodysplasia in Hungary. AB - Although genetic predisposition to haematological malignancies has long been known, genetic testing is not yet the part of the routine diagnostics. In the last ten years, next generation sequencing based studies identified novel germline mutations in the background of familial aggregation of certain haematologic disorders including myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). This is supported by the fact that the myeloid neoplasms with genetic predisposition represent a new category in the revised 2016 World Health Organization classification. According to the new classification, these disorders are subdivided based on the clinical and genetic features, including myeloid neoplasms with germline predisposition alone, or with pre-existing platelet disorder, cytopaenias or other organ failures. The predisposing genetic factors include mutations in the RUNX1, CEBPA, GATA2, ANKRD26, ETV6, DDX41, TERC or TERT and SRP72 genes. The genes affected in these syndromes are important regulators of haemopoiesis and are frequently implicated in leukaemogenesis, providing deeper insight into the understanding of normal and malignant haemopoiesis. Despite the growing knowledge of germline predisposing events in the background of familial myeloid malignancies, the germline genetic component is still unknown in a subset of these pedigrees. Here, we present the first study of inherited myeloid malignancies in Hungary. We identified three families with apparent clustering of myeloid malignancies with nine affected individuals across these pedigrees. All tested individuals were negative for CEBPA, GATA2, RUNX1, ANKRD26, ETV6, DDX41, TERC or TERT and SRP72 mutations, suggesting the presence of so far unidentified predisposing mutations. PMID- 28357686 TI - Evaluation of cell interaction with polymeric biomaterials based on hyaluronic acid and chitosan. AB - Tissue engineering involves the development of new materials or devices capable of specific interactions with biological tissues, searching the use of biocompatible materials as scaffolds for in vitro cell growth, and functional tissue development, that is subsequently implanted into patient. The aim of the current study was to evaluate the initial aspects of cell interaction with the polymeric biomaterials blends based on hyaluronic acid with chitosan. The hypothesis approach involves synthesis and analysis of swelling and thermal degradation (thermal gravimetric analysis) of the polymer blend; and Vero cell interaction with the biomaterial, through analysis of cytotoxicity, adhesion and cell morphology. The blend resulted in a biomaterial with a high swelling ratio that can allow nutrient distribution and absorption. The thermal gravimetric analysis results showed that the blend had two stages of degradation at temperatures very close to those observed for pure polymers, confirming that the physical mixing of hydrogels occurred, resulting in the presence of both hyaluronic acid and chitosan in the blend. The evaluation of indirect cytotoxicity showed that the blend was non cytotoxic for Vero cells, and the quantitative analysis performed with the MTT could verify a cell viability of 98%. The cells cultured on the blend showed adhesion, spreading and proliferation on this biomaterial, distinguished from the pattern of the control cells. These results showed that the blends produced from hyaluronic acid and chitosan hydrogels are promising for applications in tissue engineering, aiming at future cartilaginous tissue. PMID- 28357687 TI - Efficacy and safety of non-suture dural closure using a novel dural substitute consisting of polyglycolic acid felt and fibrin glue to prevent cerebrospinal fluid leakage-A non-controlled, open-label, multicenter clinical trial. AB - The objective of this study is to evaluate the efficacy and safety of non-suture dural closure using a novel dural substitute (GM111) consisting of polyglycolic acid felt with a fibrin-glue-coated area commensurate in size with the dural defect. This was a non-controlled, open-label, multicenter clinical trial. The efficacy evaluation endpoints were (1) GM111's intra-operative capability to close dural defects and (2) prevention of cerebrospinal fluid (CSF) leakage and subcutaneous CSF retention throughout the postoperative period (evaluated by diagnostic imaging). Patients meeting the following three preoperative and two intra-operative selection criteria were enrolled: (1) between 12 and <75 years of age; (2) the dura is surmised to be defective and in need of reconstruction; (3) informed written consent was obtained from the patient; (4) the surgical wound is class 1; and (5) the size of duraplasty is >=0.2 cm2 to <100 cm2. Sixty patients were enrolled. The craniotomy site was supratentorial in 77.2%, infratentorial in 12.3% and sellar in 10.5%. The GM111 prosthesis size ranged from 0.24 to 42 cm2. To evaluate the efficacy, intra-operative closure was confirmed by Valsalva's maneuver, water infusion, etc., in all patients. CSF leakage and subcutaneous CSF retention throughout the postoperative period were found in four patients. Adverse events for which a causal relationship with GM111 could not be ruled out occurred in 8.8% of the patients. There were no instances of postoperative infection due to GM111. GM111 showed good closure capability and safety when used for non-suture dural closure. PMID- 28357688 TI - Uterus transplantation and beyond. AB - Uterus transplantation is today the only available treatment for absolute uterine factor infertility which is caused by either congenital/surgical uterine absence or that a present uterus is non-functioning. Structured animal-based research, from rodents to nonhuman primates, was the scientific basis for a successful introduction of uterus transplantation as a clinical procedure. The patient groups for uterus transplantation, the preclinical research and data from the published human cases will be covered herein. During recent years the concept of bioengineering of organs and tissues has emerged. Creation of a bioengineered uterus is in the initial research state, with experiments performed in rodents. The research that has been performed to create a bioengineered uterus will be summarized. In conclusion, uterus transplantation is now a clinical experimental procedure for treatment of uterine factor infertility. In parallel to the establishment of this combined assisted reproduction technique and transplantation procedure as a routine clinical procedure, we predict that uterus bioengineering will develop further towards introduction within the human setting, but that this process will take several years. PMID- 28357690 TI - Reaction mechanisms of DNT with hydroxyl radicals for advanced oxidation processes-a DFT study. AB - In advanced oxidation processes (AOPs), the detailed degradation mechanisms of a typical explosive of 2,4-dinitrotoluene (DNT) can be investigated by the density function theory (DFT) method at the SMD/M062X/6-311+G(d) level. Several possible degradation routes for DNT were explored in the current study. The results show that, for oxidation of the methyl group, the dominant degradation mechanism of DNT by hydroxyl radicals (*OH) is a series of sequential H-abstraction reactions, and the intermediates obtained are in good agreement with experimental findings. The highest activation energy barrier is less than 20 kcal mol-1. Other routes are dominated by an addition-elimination mechanism, which is also found in 2,4,6 trinitrotoluene, although the experiment did not find the corresponding products. In addition, we also eliminate several impossible mechanisms, such as dehydration, HNO3 elimination, the simultaneous addition of two *OH radials, and so on. The information gained about these degradation pathways is helpful in elucidating the detailed reaction mechanism between nitroaromatic explosives and hydroxyl radicals for AOPs. Graphical Abstract The degradation mechanism of an important explosive, 2,6-dinitrotoluene (DNT), by the hydroxyl radical for advanced oxidation progresses. PMID- 28357691 TI - Selective detection of cyanogen halides by BN nanocluster: a DFT study. AB - The electronic sensitivity and adsorption behavior toward cyanogen halides (X-CN; X = F, Cl, and Br) of a B12N12 nanocluster were investigated by means of density functional theory calculations. The X-head of these molecules was predicted to interact weakly with the BN cluster because of the positive sigma-hole on the electronic potential surface of halogens. The X-CN molecules interact somewhat strongly with the boron atoms of the cluster via the N-head, which is accompanied by a large charge transfer from the X-CN to the cluster. The change in enthalpy upon the adsorption process (at room temperature and 1 atm) is about -19.2, 23.4, and -30.5 kJ mol-1 for X = F, Cl, and Br, respectively. The LUMO level of the BN cluster is largely stabilized after the adsorption process, and the HOMO LUMO gap is significantly decreased. Thus, the electrical conductivity of the cluster is increased, and an electrical signal is generated that can help to detect these molecules. By increasing the atomic number of X, the signal will increase, which makes the sensor selective for cyanogen halides. Also, it was indicated that the B12N12 nanocluster benefits from a short recovery time as a sensor. PMID- 28357689 TI - Porotic paradox: distribution of cortical bone pore sizes at nano- and micro levels in healthy vs. fragile human bone. AB - Bone is a remarkable biological nanocomposite material showing peculiar hierarchical organization from smaller (nano, micro) to larger (macro) length scales. Increased material porosity is considered as the main feature of fragile bone at larger length-scales. However, there is a shortage of quantitative information on bone porosity at smaller length-scales, as well as on the distribution of pore sizes in healthy vs. fragile bone. Therefore, here we investigated how healthy and fragile bones differ in pore volume and pore size distribution patterns, considering a wide range of mostly neglected pore sizes from nano to micron-length scales (7.5 to 15000 nm). Cortical bone specimens from four young healthy women (age: 35 +/- 6 years) and five women with bone fracture (age: 82 +/- 5 years) were analyzed by mercury porosimetry. Our findings showed that, surprisingly, fragile bone demonstrated lower pore volume at the measured scales. Furtnermore, pore size distribution showed differential patterns between healthy and fragile bones, where healthy bone showed especially high proportion of pores between 200 and 15000 nm. Therefore, although fragile bones are known for increased porosity at macroscopic level and level of tens or hundreds of microns as firmly established in the literature, our study with a unique assessment range of nano-to micron-sized pores reveal that osteoporosis does not imply increased porosity at all length scales. Our thorough assessment of bone porosity reveals a specific distribution of porosities at smaller length-scales and contributes to proper understanding of bone structure which is important for designing new biomimetic bone substitute materials. PMID- 28357692 TI - Performance of a recent light fluorescence device for detection of occlusal carious lesions in children and adolescents. AB - AIM: To assess the validity and reliability of a recent light fluorescence device, Soprolife(r) (Sopro-Acteon group) in detecting occlusal caries in children and adolescents and to compare its diagnostic performance with DIAGNOPen(r) (Kavo). METHODS: A multi-centre study was carried out to validate Soprolife(r) in 103 children, aged from 5-15 years, on 310 primary and 433 permanent posterior teeth. The sensitivity (SE), specificity (SP) and the area under the Receiver Operating Characteristic (ROC) curve (AUC) were evaluated using visual International Caries Detection and Assessment System (ICDAS) and radiographic examinations as the gold standards. The performance of the Soprolife(r) was compared with that of the DIAGNOPen(r) on the same teeth. The reproducibility was assessed using weighted Kappa coefficient. RESULTS: When all carious lesions using ICDAS 1-6 were considered, SE, SP and AUC for the Soprolife(r) were 88.50, 70.73 and 0.84 respectively. The validity was significantly higher for primary teeth (AUC = 0.90) than for permanent teeth (0.80); the validity of the Soprolife(r) (0.84) was significantly higher than that of DIAGNOPen(r) (0.80). The inter- and intra-examiner kappa coefficients were 0.87 and 0.85 respectively. CONCLUSION: The Soprolife(r) was a valid instrument providing reproducible results, particularly for primary teeth. PMID- 28357693 TI - Arachis hypogaea L. produces mimic and inhibitory quorum sensing like molecules. AB - A wide variety of plant-associated soil bacteria (rhizobacteria) communicate with each other by quorum sensing (QS). Plants are able to detect and produce mimics and inhibitor molecules of the QS bacterial communicative process. Arachis hypogaea L. (peanut) establishes a nitrogen-fixing symbiosis with rhizobia belonging to the genus Bradyrhizobium. These bacteria use a QS mechanism dependent on the synthesis of N-acyl homoserine lactones (AHLs). Given the relevance that plant-rhizobacteria interactions have at the ecological level, this work addresses the involvement of peanut in taking part in the QS mechanism. By using biosensor bacterial strains capable of detecting AHLs, a series of standard and original bioassays were performed in order to determine both (i) the production of QS-like molecules in vegetal materials and (ii) the expression of the QS mechanism throughout plant-bacteria interaction. Mimic QS-like molecules (mQS) linked to AHLs with long acyl chains (lac-AHL), and inhibitor QS-like molecules (iQS) linked to AHLs with short acyl chains (sac-AHL) were detected in seed and root exudates. The results revealed that synthesis of specific signaling molecules by the plant (such as mQS and iQS) probably modulates the function and composition of the bacterial community established in its rhizosphere. Novel bioassays of QS detection during peanut-Bradyrhizobium interaction showed an intense production of QS signals in the contact zone between root and bacteria. It is demonstrated that root exudates stimulate the root colonization and synthesis of lac-AHL by Bradyrhizobium strains in the plant rhizosphere, which leads to the early stages of the development of beneficial plant-bacteria interactions. PMID- 28357694 TI - Erratum to: Who Should Be Considered for Islet Transplantation Alone? PMID- 28357696 TI - Increased Prevalence of NAFLD in IBD Patients. PMID- 28357695 TI - Impaired Interoception in a Preclinical Model of Functional Dyspepsia. AB - INTRODUCTION: The etiologies of functional dyspepsia symptoms, including postprandial distress syndrome, remain unknown. We tested the hypothesis that neonatal colon inflammation induces postprandial distress syndrome-like symptoms in adult life that associate with increased activation of vagal afferent pathways and forebrain limbic regions. RESULTS: These rats showed a significant decrease in nutrient meal consumption to satiety after an overnight fast, decrease in gastric emptying, decrease in total distance traveled, and decrease in percent distance traveled in midfield versus control rats in open field test, indicating postprandial anxiety- and depression-like behaviors. Adult naive rats treated with oral iodoacetamide to induce H. pylori-like mild gastritis demonstrated similar postprandial effects as the above rats. CONCLUSIONS: We concluded that neonatal colon inflammation is a risk factor for the development of postprandial distress syndrome-like symptoms. While mild gastritis can induce symptoms similar to those of neonatal colon inflammation, gastritis in these rats does not worsen the symptoms. PMID- 28357697 TI - Predictors of Clinical Response and Remission at 1 Year Among a Multicenter Cohort of Patients with Inflammatory Bowel Disease Treated with Vedolizumab. AB - BACKGROUND: Vedolizumab (VDZ) has demonstrated long-term efficacy in Crohn's disease (CD) and ulcerative colitis (UC) in phase III trials. AIMS: Our aim was to evaluate the efficacy of VDZ at week 54 in inflammatory bowel disease (IBD) in a multicenter cohort of patients. METHODS: Adult patients completing induction therapy with VDZ were eligible for this study. Clinical response and remission was assessed using the Harvey-Bradshaw Index (HBI) for CD, the Simple Clinical Colitis Activity Index for UC and physician assessment. RESULTS: Among 136 total patients (96 CD and 40 UC), 76 (56%) demonstrated clinical response or remission at week 54. In univariate analysis, for patients with CD concomitant initiation of immunomodulator therapy (2.71, 95% CI 1.11-6.57), the addition of an immunomodulator (OR 11.49, 3.16-41.75) and CRP < 3 (4.92, 95% CI 1.99-12.15) was associated with increased odds of clinical response or remission at week 54. For UC patients, hospitalization after VDZ induction was associated with decreased odds of response or remission at week 54 (OR 0.22, 95% CI 0.05-0.88). On multivariate analysis in CD, addition of an immunomodulator (OR 8.33, 95% CI 2.15 32.26) remained significant predictors of clinical response or remission at week 54. CONCLUSIONS: Among a multicenter cohort of patients with IBD demonstrating primary response to VDZ, the addition of combination therapy with an immunomodulator is a significant predictor of clinical response or remission at week 54 in patients with CD. PMID- 28357702 TI - Lower inhibitory control interacts with greater pain catastrophizing to predict greater pain intensity in women with migraine and overweight/obesity. AB - BACKGROUND: Pain catastrophizing (PC) is associated with more severe and disabling migraine attacks. However, factors that moderate this relationship are unknown. Failure of inhibitory control (IC), or the ability to suppress automatic or inappropriate responses, may be one such factor given previous research showing a relationship between higher PC and lower IC in non-migraine samples, and research showing reduced IC in migraine. Therefore, we examined whether lower IC interacts with increased PC to predict greater migraine severity as measured by pain intensity, attack frequency, and duration. METHODS: Women (n = 105) aged 18-50 years old (M = 38.0 +/- 1.2) with overweight/obesity and migraine who were seeking behavioral treatment for weight loss and migraine reduction completed a 28-day smartphone-based headache diary assessing migraine headache severity. Participants then completed a modified computerized Stroop task as a measure of IC and self-report measures of PC (Pain Catastrophizing Scale [PCS]), anxiety, and depression. Linear regression was used to examine independent and joint associations of PC and IC with indices of migraine severity after controlling for age, body mass index (BMI) depression, and anxiety. RESULTS: Participants on average had BMI of 35.1 +/- 6.5 kg/m2and reported 5.3 +/- 2.6 migraine attacks (8.3 +/- 4.4 migraine days) over 28 days that produced moderate pain intensity (5.9 +/- 1.4 out of 10) with duration of 20.0 +/- 14.2 h. After adjusting for covariates, higher PCS total (beta = .241, SE = .14, p = .03) and magnification subscale (beta = .311, SE = .51, p < .01) scores were significant independent correlates of longer attack duration. IC interacted with total PCS (beta = 1.106, SE = .001, p = .03) rumination (beta = 1.098, SE = .001, p = .04), and helplessness (beta = 1.026, SE = .001, p = .04) subscale scores to predict headache pain intensity, such that the association between PC and pain intensity became more positive at lower levels of IC. CONCLUSIONS: Results showed that lower IC interacted with higher PC, both overall and specific subcomponents, to predict higher pain intensity during migraine attacks. Future studies are needed to determine whether interventions to improve IC could lead to less painful migraine attacks via improvements in PC. PMID- 28357703 TI - Refractory burning mouth syndrome: clinical and paraclinical evaluation, comorbiities, treatment and outcome. AB - BACKGROUND: Burning Mouth Syndrome (BMS) is a chronic pain condition characterized by persistent intraoral burning without related objective findings and unknown etiology that affects elderly females mostly. There is no satisfactory treatment for BMS. We aimed to observe the long-term efficacy of high velanfaxine doses combined with systemic and topical administered clonazepam in a particular subgroup of BMS patients who do not respond to current clinical management. RESULTS: Eight (66.1 +/- 6.2 years old females) out of 14 BMS patients fulfilled the inclusion criteria and were treated with venlafaxine (300 mg/d) and clonazepam (5 mg/d) for 35.4 +/- 12.1 (mean +/- SD) months. The average duration of the symptoms at baseline was 4.3 +/- 1.4 years and the overall mean daily pain intensity score was 8.6 +/- 1.3 (VAS); pain was in tongue and within the oral mucosa, accompanying by oral and facial dysesthesia. In five patients tasting was abnormal. All patients had positive history of concomitant primary headache. The average score of Hamilton Rating scale for Anxiety and Depression was 21 +/- 4.2, and 26.1 +/- 2.9, respectively. Previous ineffective treatments include anticonvulsants and anti-depressants. All patients responded (more than 50% decrease in VAS) after three months treatment (mean VAS 3.2 +/- 2.2) with no remarkable adverse events. CONCLUSION: BMS deserves bottomless psychiatric evaluation and management when current available treatments fail. Treatment with venlafaxine combined with topical and systemic clonazepam may be effective in refractory BMS cases but further investigation in a large-scale controlled study is needed to confirm these results. PMID- 28357704 TI - Hazardous Drug Diversion of Valproate from a General Practitioner to his Patient's Dog. AB - General practitioners are key stakeholders in good prescribing practices. More than half of patients have at least one unintended medication discrepancy upon hospital admission, some of which have the potential to cause severe discomfort or clinical deterioration. We report a case of a drug mistakenly administered to a 66-year-old man with cirrhosis and chronic alcoholism. Based on his regular prescription, he received 1 g/day of valproate during a hospitalization for cardiac valve surgery. This anticonvulsant was initially prescribed by his general practitioner for his epileptic dog and has been added to his own prescription to be covered by the French national health insurance. The aim of this article is to emphasize that general practitioners, physicians, and pharmacists have a major role to play in preventing the diversion of prescription drugs and limiting the risk of adverse drug events. PMID- 28357705 TI - Minocycline for the Treatment of Multidrug and Extensively Drug-Resistant A. baumannii: A Review. AB - Acinetobacter baumannii can cause life-threatening nosocomial infections associated with high rates of morbidity and mortality. In recent years, the increasing number of infections due to extensively drug-resistant Acinetobacter with limited treatment options has resulted in a need for additional therapeutic agents, and a renaissance of older, neglected antimicrobials. This has led to an increased interest in the use of minocycline to treat these infections. Minocycline has been shown to overcome many resistance mechanisms affecting other tetracyclines in A. baumannii, including tigecycline. Additionally, it has favorable pharmacokinetic and pharmacodynamic properties, as well as excellent in vitro activity against drug-resistant A. baumannii. Available data support therapeutic success with minocycline, while ease of dosing with no need for renal or hepatic dose adjustments and improved safety have made it an appealing therapy. This review will focus on the mechanisms of action and resistance to tetracyclines in A. baumannii, the in vitro activity, pharmacokinetic and pharmacodynamic properties of minocycline against A. baumannii, and finally the clinical experience with minocycline for the treatment of invasive infections due to this pathogen. PMID- 28357707 TI - Comment on Nuno Solinis R, et al. "Value of Treating All Stages of Chronic Hepatitis C: A Comprehensive Review of Clinical and Economic Evidence". PMID- 28357706 TI - The Burden and Long-term Respiratory Morbidity Associated with Respiratory Syncytial Virus Infection in Early Childhood. AB - INTRODUCTION: The REGAL (RSV Evidence-a Geographical Archive of the Literature) series provide a comprehensive review of the published evidence in the field of respiratory syncytial virus (RSV) in Western countries over the last 20 years. The objective of this fifth publication was to determine the long-term respiratory morbidity associated with RSV lower respiratory tract infection (RSV LRTI) in early life. METHODS: A systematic review was undertaken for articles published between January 1, 1995 and December 31, 2015. This was supplemented by inclusion of papers published whilst drafting the manuscript. Studies reporting data on the incidence and long-term wheezing and asthma following RSV LRTI in early life were included. Study quality and strength of evidence (SOE) were graded using recognized criteria. RESULTS: A total of 2337 studies were identified of which 74 were included. Prospective, epidemiologic studies consistently demonstrated that RSV LRTI is a significant risk factor for on-going respiratory morbidity characterized by transient early wheezing and recurrent wheezing and asthma within the first decade of life and possibly into adolescence and adulthood (high SOE). RSV LRTI was also associated with impaired lung function in these children (high SOE). Respiratory morbidity has been shown to result in reduced quality of life and increased healthcare resource use (moderate SOE). The mechanisms through which RSV contributes to wheezing/asthma development are not fully understood, but appear to relate to the viral injury, preexisting abnormal lung function and/or other factors that predispose to wheezing/asthma, including genetic susceptibility, altered immunology, eosinophilia, and associated risk factors such as exposure to environmental tobacco smoke (high SOE). CONCLUSION: There is growing evidence that RSV LRTI in early childhood is associated with long-term wheezing and asthma and impaired lung function. Future research should aim to fully elucidate the pathophysiological mechanisms through which RSV causes recurrent wheezing/asthma. PMID- 28357709 TI - Erratum to: The Use of Lectin Histochemistry for Detecting Apoptotic Cells in the Seminiferous Epithelium. PMID- 28357708 TI - A Review of Diagnostic Methods for Invasive Fungal Diseases: Challenges and Perspectives. AB - Invasive fungal diseases are associated with a high morbidity and mortality, particularly in the context of immunosuppression. Diagnosis of invasive fungal diseases is usually complicated by factors such as poor clinical suspicion and unspecific clinical findings. Access to modern diagnostic tools is frequently limited in developing countries. Here, we describe five real-life clinical cases from a Brazilian tertiary hospital, in order to illustrate how to best select diagnostic tests in patients with different fungal infections. PMID- 28357711 TI - Polymer-Nucleic Acid Interactions. AB - Gene therapy is an important therapeutic strategy in the treatment of a wide range of genetic disorders. Polymers forming stable complexes with nucleic acids (NAs) are non-viral gene carriers. The self-assembly of polymers and nucleic acids is typically a complex process that involves many types of interaction at different scales. Electrostatic interaction, hydrophobic interaction, and hydrogen bonds are three important and prevalent interactions in the polymer/nucleic acid system. Electrostatic interactions and hydrogen bonds are the main driving forces for the condensation of nucleic acids, while hydrophobic interactions play a significant role in the cellular uptake and endosomal escape of polymer-nucleic acid complexes. To design high-efficiency polymer candidates for the DNA and siRNA delivery, it is necessary to have a detailed understanding of the interactions between them in solution. In this chapter, we survey the roles of the three important interactions between polymers and nucleic acids during the formation of polyplexes and summarize recent understandings of the linear polyelectrolyte-NA interactions and dendrimer-NA interactions. We also review recent progress optimizing the gene delivery system by tuning these interactions. PMID- 28357710 TI - EGFR signaling pathways are wired differently in normal 184A1L5 human mammary epithelial and MDA-MB-231 breast cancer cells. AB - Because of differences in the downstream signaling patterns of its pathways, the role of the human epidermal growth factor family of receptors (HER) in promoting cell growth and survival is cell line and context dependent. Using two model cell lines, we have studied how the regulatory interaction network among the key proteins of HER signaling pathways may be rewired upon normal to cancerous transformation. We in particular investigated how the transcription factor STAT3 and several key kinases' involvement in cancer-related signaling processes differ between normal 184A1L5 human mammary epithelial (HME) and MDA-MB-231 breast cancer epithelial cells. Comparison of the responses in these cells showed that normal-to-cancerous cellular transformation causes a major re-wiring of the growth factor initiated signaling. In particular, we found that: i) regulatory interactions between Erk, p38, JNK and STAT3 are triangulated and tightly coupled in 184A1L5 HME cells, and ii) STAT3 is only weakly associated with the Erk-p38 JNK pathway in MDA-MB-231 cells. Utilizing the concept of pathway substitution, we predicted how the observed differences in the regulatory interactions may affect the proliferation/survival and motility responses of the 184A1L5 and MDA MB-231 cells when exposed to various inhibitors. We then validated our predictions experimentally to complete the experiment-computation-experiment iteration loop. Validated differences in the regulatory interactions of the 184A1L5 and MDA-MB-231 cells indicated that instead of inhibiting STAT3, which has severe toxic side effects, simultaneous inhibition of JNK together with Erk or p38 could be a more effective strategy to impose cell death selectively to MDA MB-231 cancer cells while considerably lowering the side effects to normal epithelial cells. Presented analysis establishes a framework with examples that would enable cell signaling researchers to identify the signaling network structures which can be used to predict the phenotypic responses in particular cell lines of interest. PMID- 28357712 TI - Determination of Relative Counterion Binding Constant to Cationic Micelles. AB - The efficiency of counterion affinity towards ionic micelles is often described in terms of the degree of counterion binding (beta X ) to ionic micelles or the conventional ion-exchange constant ([Formula: see text]) or relative binding constant ([Formula: see text]) of X - and Br- counterions. This review describes the use of ionized phenyl salicylate ions, PSa-, as a new probe to determine [Formula: see text] values using a semiempirical spectrophotometric method. The value of [Formula: see text] is found to be comparable to reported values obtained using different probes by the semiempirical kinetic method as well as different physical methods. Application of semiempirical methods for calculation of [Formula: see text] or [Formula: see text] values involves an inherent assumption that these values are independent of the physicochemical characteristics of the probe molecule. PMID- 28357713 TI - Relationship of the lungs to the left atrium of particular relevance for ablation of atrial fibrillation. AB - BACKGROUND: Symptoms of possible lung and pleural injury such as chest pain and hemoptysis occur during and after radiofrequency ablation (RFA) and cryoablation (CA) of the left atrium (LA) for treatment of atrial fibrillation (AF). We determined the anatomical relationship of the lungs to the LA with particular reference to areas commonly targeted during AF ablation. METHODS: Distances from the LA endocardium to the lungs were measured from pre-procedure CT angiograms of 100 consecutive patients (71 males, age 60 +/- 8 years) who underwent AF ablation. RESULTS: In 97% of the patients, the posterior right pulmonary vein antrum was <5 mm from the lower lobe of the right lung (RLL) over a supero inferior distance of 3.6 +/- 1.5 cm (minimum distance 1.2 +/- 0.7 mm). The right inferior pulmonary vein (RIPV) ostium was <5 mm from the RLL in 94% (mean 2.7 +/- 1.9 mm). The right superior pulmonary vein ostium was <5 mm from the RLL in 29% (mean 7.1 +/- 3.8 mm). The medial segment of the right middle lobe was <5 mm from the carina between right pulmonary veins in 83% (mean 3.6 +/- 1.9 mm). The mitral isthmus was <5 mm from the lingula in 5% (mean 9.4 +/- 3.6 mm). The inferior lobe of the left lung was <5 mm from the posterior aspect of the ostia of the left inferior and superior pulmonary veins in 9 and 0%, respectively. The bronchi were <5 mm from the LA in 5%. CONCLUSIONS: The lungs are intimately related to sites of the LA commonly targeted during AF RFA. Whether this anatomical proximity translates into clinically significant potential for collateral lung damage during RFA merits further study. PMID- 28357714 TI - The Role for Cardiovascular Remodeling in Cardiovascular Outcomes. AB - PURPOSE OF REVIEW: Ischemic and non-ischemic injury to the heart causes deleterious changes in ventricular size, shape, and function. This adverse remodeling is mediated by neurohormonal and hemodynamic alterations and is reflected in non-invasive measures of left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and left ventricular end-diastolic volume (LVEDV). These measures are closely linked to cardiovascular outcomes and have become key surrogate endpoints for evaluating the therapeutic efficacy of contemporary treatments for heart failure with reduced ejection fraction (HFrEF). In this review, we critically evaluate recent published data (2015-2016) from randomized clinical trials (RCTs) and observational studies of HFrEF therapies to assess the role of ventricular remodeling on outcomes. RECENT FINDINGS: These data highlight the benefits of certain guideline-directed medical therapies (GDMT) such as cardiac resynchronization therapy, surgical revascularization, and mechanical circulatory support on remodeling, while revealing the limitations of other therapies-routine mitral valve repair for patients with moderate ischemic mitral regurgitation and adjuncts to percutaneous coronary intervention in patients with ST elevation myocardial infarction (cyclosporine A and bioabsorbable cardiac matrix). The new angiotensin receptor blocker/neprilysn inhibitor, sacubitril/valsartan, demonstrates convincing improvements in clinical outcomes with a study of remodeling parameters to follow; the new cardiac myosin activator, omecamtiv mecarbil, demonstrates improvement in remodeling parameters without a clear early clinical benefit. The concepts and contemporary trials reviewed in this paper reinforce the value of non-invasive measures of ventricular remodeling (LVEF, LVESV, and LVEDV) as important metrics across a range of cardiovascular therapies. Global non-invasive measures of cardiovascular remodeling have roughly paralleled or preceded hard clinical outcomes. Additionally, the capacity for reverse remodeling in HFrEF with GDMT motivates continued research in the fields of implementation science, diagnostic imaging, and gene-based therapeutics. PMID- 28357716 TI - In vitro cytotoxicity assessment of a West Virginia chemical spill mixture involving 4-methylcyclohexanemethanol and propylene glycol phenyl ether. AB - Thousands of gallons of industrial chemicals, crude 4-methylcyclohexanemethanol (MCHM) and propylene glycol phenyl ether (PPh), leaked from industrial tanks into the Elk River in Charleston, West Virginia, USA, on January 9, 2014. A considerable number of people were reported to exhibit symptoms of chemical exposure and an estimated 300,000 residents were advised not to use or drink tap water. At the time of the spill, the existing toxicological data of the chemicals were limited for a full evaluation of the health risks, resulting in concern among those in the impacted regions. In this preliminary study, we assessed cell viability and plasma membrane degradation following a 24-h exposure to varying concentrations (0-1000 MUM) of the two compounds, alone and in combination. Evaluation of different cell lines, HEK-293 (kidney), HepG2 (liver), H9c2 (heart), and GT1-7 (brain), provided insight regarding altered cellular responses in varying organ systems. Single exposure to MCHM or PPh did not affect cell viability, except at doses much higher than the estimated exposure levels. Certain co-exposures significantly reduced metabolic activity and increased plasma membrane degradation in GT1-7, HepG2, and H9c2 cells. These findings highlight the importance of examining co-exposures to fully understand the potential toxic effects. PMID- 28357715 TI - No Dose Adjustment is Recommended for Digoxin, Warfarin, Atorvastatin or a Combination Oral Contraceptive When Coadministered with Dulaglutide. AB - BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the treatment of type 2 diabetes mellitus are known to delay gastric emptying (GE). The potential effect of the GLP-1 RA dulaglutide on the pharmacokinetics (PK) of four orally administered drugs and on the pharmacodynamic (PD) effect of warfarin was investigated. METHODS: In four separate clinical pharmacology studies, digoxin, warfarin, atorvastatin and Ortho-Cyclen(r) were orally administered to healthy subjects with and without a subcutaneous dose of dulaglutide 1.5 mg. The effect of dulaglutide coadministration was assessed based on the PK parameters of key analytes. For warfarin PD, the effect of dulaglutide on the international normalized ratio (INR) was evaluated. RESULTS: Areas under the concentration-time curves (AUCs) with and without dulaglutide were similar for all analytes except atorvastatin, where it was reduced by 21%. Maximum concentrations (C max) were generally lower following coadministration with dulaglutide, with statistically significant reductions (90% confidence intervals of geometric least squares means ratios outside 0.80-1.25) for all analytes except R-warfarin. For all analytes, there was a general trend for the time to C max (t max) to increase following coadministration with dulaglutide. For warfarin, dulaglutide coadministration had no statistically significant effect on the maximum INR (INRmax); however, a 2% increase in area under the INR curve (AUCINR) was observed. CONCLUSIONS: Dulaglutide did not affect the absorption of the tested medications to a clinically relevant degree. Based on the PK and PD evaluations, no dose adjustments for digoxin, warfarin, atorvastatin and Ortho-Cyclen(r) are recommended when coadministered with dulaglutide. CLINICAL TRIAL REGISTRATION NUMBERS: NCT01458210, NCT01436201, NCT01432938, and NCT01250834. PMID- 28357718 TI - Land use impacts on river health of Uma Oya, Sri Lanka: implications of spatial scales. AB - Human actions on landscapes are a principal threat to the ecological integrity of river ecosystems worldwide. Tropical landscapes have been poorly investigated in terms of the impact of catchment land cover alteration on water quality and biotic indices in comparison to temperate landscapes. Effects of land cover in the catchment at two spatial scales (catchment and site) on stream physical habitat quality, water quality, macroinvertebrate indices and community composition were evaluated for Uma Oya catchment in the upper Mahaweli watershed, Sri Lanka. The relationship between spatial arrangement of land cover in the catchment and water quality, macroinvertebrate indices and community composition was examined using univariate and multivariate approaches. Results indicate that chemical water quality variables such as conductivity and total dissolved solids are mostly governed by the land cover at broader spatial scales such as catchment scale. Shannon diversity index was also affected by catchment scale forest cover. In stream habitat features, nutrients such as N-NO3-, macroinvertebrate family richness, %shredders and macroinvertebrate community assemblages were predominantly influenced by the extent of land cover at 200 m site scale suggesting that local riparian forest cover is important in structuring macroinvertebrate communities. Thus, this study emphasizes the importance of services provided by forest cover at catchment and site scale in enhancing resilience of stream ecosystems to natural forces and human actions. Findings suggest that land cover disturbance effects on stream ecosystem health could be predicted when appropriate spatial arrangement of land cover is considered and has widespread application in the management of tropical river catchments. PMID- 28357717 TI - Assessment of urban sustainability efficiency based on general data envelopment analysis: a case study of two cities in western and eastern China. AB - Sustainable urban development focuses on enhancing urban well-being, while also balancing the demands of urban social and economic development, natural resource consumption, and environmental pollution. This work used general data envelopment analysis to assess the urban sustainability efficiency (USE) and sustainability potential (SP) in Lanzhou and Xiamen, two cities that are characteristic of urban areas in western and eastern China. The assessment indicator system included important natural and urban welfare factors as input and output indices, respectively. The results showed that overall urban sustainability efficiency increased in Lanzhou and Xiamen from 1985 to 2010, but that the sustainability of natural resources clearly decreased. The urban sustainability efficiency of Xiamen was higher than that of Lanzhou, and the sustainability potential of Xiamen was lower than that of Lanzhou; this indicates that Xiamen performed better in terms of urban sustainable development. The urban sustainability efficiency in Xiamen has increased with increasing urban population, and the rate and scale of economic development have been higher than in Lanzhou. The assessment and analysis performed in this study show that cities with different natural resources and development characteristics have different forms, patterns, and trajectories of sustainable development. PMID- 28357719 TI - Bubble size distribution in a laboratory-scale electroflotation study. AB - The performance of electroflotation (EF) is strongly influenced by the size of O2 and H2 bubbles. Therefore, in this study, the bubble sizes are measured in a lab scale EF cell using a high-speed camera. The mean bubble size is found to vary in the range of 32.7-68.6 MUm under different operating conditions. This study shows that the electrode material, current density, water pH, ionic strength, and frother (Tennafroth 250) concentration are important factors in controlling the bubble size. Furthermore, four mathematical distributions (normal, log-normal, Weibull, and gamma distributions) are fitted to the experimental data, among which the log-normal distribution is found to be the best fit based on the lower Anderson-Darling (AD) value. PMID- 28357720 TI - Assessment of tap water quality and corrosion scales from the selected distribution systems in northern Pakistan. AB - Corrosion deposits formed within drinking water distribution systems deteriorate drinking water quality and resultantly cause public health consequences. In the present study, an attempt was made to investigate the concurrent conditions of corrosion scales and the drinking water quality in selected water supply schemes (WSS) in districts Chitral, Peshawar, and Abbottabad, northern Pakistan. Characterization analyses of the corrosion by-products revealed the presence of alpha-FeOOH, gamma-FeOOH, Fe3O4, and SiO2 as major constituents with different proportions. The constituents of all the representative XRD peaks of Peshawar WSS were found insignificant as compared to other WSS, and the reason could be the variation of source water quality. Well-crystallized particles in SEM images indicated the formation of dense oxide layer on corrosion by-products. A wider asymmetric vibration peak of SiO2 appeared only in Chitral and Abbottabad WSS, which demonstrated higher siltation in the water source. One-way ANOVA analysis showed significant variations in pH, turbidity, TDS, K, Mg, PO4, Cl, and SO4 values, which revealed that these parameters differently contributed to the source water quality. Findings from this study suggested the implementation of proper corrosion prevention measures and the establishment of international collaboration for best corrosion practices, expertise, and developing standards. PMID- 28357721 TI - Heavy metal accumulation and ecosystem engineering by two common mine site nesting ant species: implications for pollution-level assessment and bioremediation of coal mine soil. AB - The present study focuses on the abundance, heavy metal content, and the impact of ecosystem engineering activities of two coal mine site-inhabiting ant species, Cataglyphis longipedem and Camponotus compressus. The abundance of Ct. longipedem increased while that of C. compressus decreased, with increasing soil pollution. Correspondence analysis reveals a close association between soil heavy metal concentrations and Ct. longipedem abundance, but this association is lacking in the case of C. compressus. Cataglyphis ants which occupy stress-characterized niches appear to be pre-adapted to tolerate heavy metal pollution. Higher concentrations of Zn and Mn in Ct. longipedem may contribute to the strengthening of the cuticular structures, necessary for nest excavation in the hard, arid soil and for single load carrying. C. compressus ants appear to be pollution sensitive. Their higher Fe content may be related to metal uptake via plant derived liquids and species-specific regulatory mechanisms. The metal pollution index and biota-to-soil accumulation factors, calculated by using the ant body metal content of the two species, indicate an overall decrease of soil heavy metal concentrations with increase of the site age, which reflects the degree of pollution related to the mine site age. The concentrations of total and available heavy metals (Fe, Zn, Mn, Pb, and Cu) were significantly lower in the ant nest debris soil as compared to the reference soil. The results of the present study highlight the role of ants as bioindicators and in bioremediation of contaminated soil. PMID- 28357722 TI - Health among disaster survivors and health professionals after the Haiyan Typhoon: a self-selected Internet-based web survey. AB - BACKGROUND: Natural disasters affected millions of people worldwide every year. Evaluation of disaster health and health response interventions is faced with several methodological challenges. This study aimed (1) to describe survivors' and health professionals' health, 30 months after a natural disaster using a web based self-selected Internet sample survey designed and (2) to evaluate the health effects of disaster response interventions, in the present study with a focus on disaster radio. METHODS: A web-based survey was used to conduct a cross sectional study approximately 30 months after typhoon Haiyan. The GHQ-12, EQ-5D 3L, and EQ-VAS instruments were used in addition to study-specific questions. A self-selected Internet sample was recruited via Facebook. RESULTS: In total, 443 survivors, from what 73 were health professionals, participated in the study. The Haiyan typhoon caused both physical and mental health problems as well as social consequences for the survivors. Mental health problems were more frequently reported than physical injuries. Health professionals reported worse overall health and a higher frequency of mental health problems compared to other survivors. CONCLUSIONS: There were short-term and long-term physical, psychological, and social consequences for the survivors as a result of the Haiyan typhoon. Mental health problems were more frequently reported and lasted longer than physical problems. Health professionals deployed during the disaster reported worse health, especially concerning mental health problems. The survey used was found useful to describe health after disasters. PMID- 28357723 TI - Role of curative treatment in patients with intermediate-stage hepatocellular carcinoma. AB - PURPOSE: To retrospectively evaluate the role of curative treatment in patients with intermediate-stage hepatocellular carcinomas (HCCs), and to identify the subgroup having benefit from curative treatment. METHODS: From April 2000 to December 2014, 100 patients with intermediate-stage HCCs underwent either curative treatment (hepatectomy: n = 23, radiofrequency ablation (RFA); n = 29, both: n = 4) or transarterial chemoembolization (TACE): n = 44) as initial treatments for HCCs. Overall survival, influence of treatment allocation on prognosis, and factors affecting treatment allocation were evaluated. RESULTS: The 5-year survival rate was 59.2% [95% confidence interval (CI) 51.6-66.8%] in the curative group, and 25.1% (95% CI 11.5-38.7%) in the TACE group. Treatment allocation was the only significant prognostic factor (p = 0.014, hazard ratio: 0.382, 95% CI 0.177-0.821). The curative group consisted of more patients with Child-Pugh A (p = 0.0016) than the TACE group, a tumor number of 3 or fewer (p < 0.0001), a unilobar tumor location (p = 0.02), within 4 of 7 cm criterion (p = 0.001), and within up-to-7 criterion (p = 0.04). Child-Pugh A, within the 4 of 7 cm criterion, and a unilobar tumor location were significantly linked with treatment allocation in multivariate analysis. CONCLUSIONS: Curative treatment can prolong survival in selected patients with intermediate-stage HCCs. PMID- 28357724 TI - Correlation between right ventricular T1 mapping and right ventricular dysfunction in non-ischemic cardiomyopathy. AB - Right ventricular (RV) fibrosis is increasingly recognized as the underlying pathological substrate in a variety of clinical conditions. We sought to employ cardiac magnetic resonance (CMR) techniques of strain imaging and longitudinal relaxation time (T1) mapping to better examine the relationship between RV function and structure. Our aim was to initially evaluate the feasibility of these techniques to evaluate the right ventricle. We then sought to explore the relationship between RV function and underlying fibrosis, along with examining the evolution of RV remodeling according to the amount of baseline fibrosis. Echocardiography was performed in 102 subjects with non-ischemic cardiomyopathy. Right ventricular parameters were assessed including: fractional area change (FAC) and longitudinal strain. The same cohort underwent CMR. Post-contrast T1 mapping was performed as a marker of fibrosis with a Look-Locker technique using inversion recovery imaging. Mid-ventricular post-contrast T1 values of the RV free wall, RV septum and lateral LV were calculated using prototype analysis software. Biventricular volumetric data including ejection fraction was measured by CMR using a cine short axis stack. CMR strain analysis was also performed to assess 2D RV longitudinal and radial strain. Simultaneous biochemical and anthropometric data were recorded. Subjects were followed over a median time of 29 months (IQR 20-37 months) with echocardiography to evaluate temporal change in RV FAC according to baseline post-contrast T1 values. Longitudinal data analysis was performed to adjust for patient loss during follow-up. Subjects (62% men, 51 +/- 15 years) had mild to moderately impaired global RV systolic function (RVEF = 39 +/- 15%; RVEDV = 187 +/- 69 ml; RVESV = 119 +/- 68 ml) and moderate left ventricular dysfunction at baseline (LVEF 30 +/- 17%). Good correlation was observed between mean LV and RV post-contrast T1 values (r = 0.652, p < 0.001), with similar post-contrast T1 values maintained in both the RV free wall and septum (r = 0.761, p < 0.001). CMR RVEF demonstrated a proportional correlation with echocardiographic measures of RV longitudinal function and CMR RV strain (longitudinal r = -0.449, p = 0.001; radial r = -0.549, p < 0.001). RVEF was related to RV post-contrast T1 values, particularly in those with RV dysfunction (free wall T1 r = 0.259 p = 0.027; septal T1 r = 0.421 p < 0.001). RV strain was also related to RV post-contrast T1 values (r = -0.417, p = 0.002). Linear regression analysis demonstrated strain and post-contrast T1 values to be independently associated with RVEF. Subjects with severe RV dysfunction (CMR RVEF <25%) demonstrated lower RV CMR strain (longitudinal p = 0.018; radial p < 0.001), RV T1 values (free wall p = 0.013; septum <0.001) and RV longitudinal echocardiography parameters despite no difference in afterload. During follow-up, those with RV free wall post-contrast T1 values >= 350 ms demonstrated ongoing improvement in FAC (Delta6%), whilst values <350 ms were associated with deterioration in RV function (DeltaFAC = -5%) (p = 0.026). CMR provides a comprehensive method by which to evaluate right ventricular function. Post contrast T1 mapping and CMR strain imaging are technically feasible and provide incremental information regarding global RV function and structure. The proportional relationship between RV function and post-contrast T1 values supports that myocardial fibrosis is a causative factor of RV dysfunction in NICM, irrespective of RV afterload. This same structural milieu also appears integral to the propensity for both positive and negative RV remodeling long term, suggestive that this is also determined by the degree of underlying RV fibrosis. PMID- 28357726 TI - Validation of the "smart" minimum FFR Algorithm in an unselected all comer population of patients with intermediate coronary stenoses. AB - Using data from a commercial pressure wire system (St. Jude Medical) we previously developed an automated "smart" algorithm to determine a reproducible value for minimum FFR (smFFR) and confirmed that it correlated very closely with measurements made off-line by experienced coronary physiology core laboratories. In this study we used the same "smart" minimum algorithm to analyze data derived from a different, commercial pressure wire system (Philips Volcano) and compared the values obtained to both operator-defined steady state FFR and the online automated minimum FFR reported by the pressure wire analyser. For this analysis, we used the data collected during the VERIFY 2 study (Hennigan et al. in Circ Cardiovasc Interv, doi: 10.1161/CIRCINTERVENTIONS.116.004016 ) in which we measured FFR in 257 intermediate coronary stenoses (mean DS 48%) in 197 patients. Maximal hyperaemia was induced using intravenous adenosine (140 mcg/kg/min). We recorded both the online minimum FFR generated by the analyser and the operator reported steady state FFR. Subsequently, the raw pressure tracings were coded, anonymised and 256/257 were subjected to further off-line analysis using the smart minimum FFR (smFFR) algorithm. The operator-defined steady state FFR correlated well with smFFR: r = 0.988 (p < 0.001), average bias 0.008 (SD 0.014), 95% limits of agreement -0.020 to 0.036. The online automated minimum FFR also correlated well with the smFFR: r = 0.998 (p < 0.001), average bias 0.004 (SD 0.006), 95% limits of agreement -0.016 to 0.008. Finally, the online automated minimum FFR correlated well the operator-reported steady state FFR: r = 0.988 (p < 0.001), average bias 0.012 (SD 0.014), 95% limits of agreement -0.039 to 0.015. In 95% of lesions studied (244/256), the operator reported steady-state FFR, smFFR, and online automated minimum FFR agreed with each other to within 0.04, which is within the previously reported test/retest limits of agreement of FFR reported by an experienced core lab. Disagreements >0.05 among methods were rare but in these cases the two automated algorithms almost always agreed with each other rather than with the operator-reported value. Within the VERIFY 2 dataset, experienced operators reported a similar FFR value to both an online automated minimum (Philips Volcano) and off-line "smart" minimum computer algorithm. Thus, treatment decisions and clinical studies using either method will produce nearly identical results. PMID- 28357728 TI - ? PMID- 28357725 TI - Ventricular pacing site separation by cardiac computed tomography: validation for the prediction of clinical response to cardiac resynchronization therapy. AB - Cardiac Resynchronization Therapy (CRT) fails to provide benefit in up to one third of patients. Maximizing the geographic separation of right and left ventricular pacing lead sites has been suggested as one way to improve response. Cardiac CT provides an opportunity to explore 3-dimensional inter-lead distance (ILD) measures for the prediction of CRT response. The objective of this study was to investigate associations between standardized measures of ILD by cardiac CT and echocardiographic response to CRT. Forty-two consecutive patients undergoing CRT had serial clinical and echocardiographic evaluations performed in addition to a post-procedural cardiac-gated CT with blinded measurement of direct and circumferential (via the myocardium) ILD measures. Clinical response to CRT, the primary clinical outcome, was defined as a >=15% reduction in LVESV using echocardiography at 6-months. The mean age and ejection fraction was 63.6 +/- 8.9 years and 25.2 +/- 7.8%, respectively. The primary outcome occurred in 35 of 42 patients (83%). Both direct and circumferential CT-based ILD measures were associated with the primary outcome by univariate analysis. Receiver Operator Characteristic analysis identified Circumferential ILD to have the strongest predictive accuracy (AUC 0.78). Inter- and intra-observer reproducibility of CT derived ILD measures was excellent. Circumferential ILD measures on cardiac CT are predictive of clinical response to CRT. Incorporation of these measures into the selection of optimal pacing targets, particularly from pre-procedural CT coronary vein imaging may be of therapeutic benefit and warrants further investigation. PMID- 28357727 TI - A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies. AB - BACKGROUND: The combination of everolimus and the imidazoquinoline derivative, BEZ235 (dactolisib), a dual PI3K/mTOR inhibitor, demonstrated synergy in a preclinical model. OBJECTIVE: To establish clinical feasibility, a phase Ib dose escalation trial investigating safety and pharmacokinetics of this combination in patients with advanced tumors was performed. PATIENTS AND METHODS: BEZ235 was orally administered daily in escalating doses of 200, 400, and 800 mg along with everolimus at 2.5 mg daily in 28-day cycles. Nineteen patients were enrolled. Adverse events and tumor responses were evaluated using CTCAE v4.0 and RECIST 1.1, respectively. Pharmacokinetic analyses were performed. RESULTS: Common toxicities observed included fatigue, diarrhea, nausea, mucositis, and elevated liver enzymes. No confirmed responses were observed. BEZ235 pharmacokinetics exhibited dose-proportional increases in Cmax and AUC0-24 over the three doses, with high inter-individual variability. Non-compartmental and population pharmacokinetic-based simulations indicated significant increases in everolimus Cmax and AUC0-24 on day 28 and decreased clearance to 13.41 L/hr. CONCLUSIONS: The combination of BEZ235 and everolimus demonstrated limited efficacy and tolerance. BEZ235 systemic exposure increased in a dose-proportional manner while oral bioavailability was quite low, which may be related to gastrointestinal specific toxicity. The changes in steady-state pharmacokinetics of everolimus with BEZ235 highlight potential drug-drug interactions when these two drugs are administered together. Clinicaltrials.gov: NCT01508104. PMID- 28357729 TI - ? PMID- 28357730 TI - ? PMID- 28357731 TI - [Mechanisms of chronification in tumor pain?] PMID- 28357732 TI - ? PMID- 28357733 TI - ? PMID- 28357734 TI - ? PMID- 28357735 TI - ? PMID- 28357736 TI - ? PMID- 28357737 TI - ? PMID- 28357738 TI - ? PMID- 28357739 TI - ? PMID- 28357740 TI - ? PMID- 28357741 TI - ? PMID- 28357742 TI - ? PMID- 28357743 TI - ? PMID- 28357745 TI - ? PMID- 28357744 TI - ? PMID- 28357746 TI - ? PMID- 28357747 TI - ? PMID- 28357749 TI - ? PMID- 28357750 TI - ? PMID- 28357748 TI - ? PMID- 28357751 TI - ? PMID- 28357752 TI - ? PMID- 28357753 TI - ? PMID- 28357754 TI - ? PMID- 28357755 TI - ? PMID- 28357756 TI - ? PMID- 28357757 TI - ? PMID- 28357758 TI - ? PMID- 28357759 TI - ? PMID- 28357762 TI - ? PMID- 28357760 TI - ? PMID- 28357763 TI - ? PMID- 28357764 TI - ? PMID- 28357765 TI - ? PMID- 28357766 TI - [Early detection of actinic keratoses]. PMID- 28357767 TI - [Early detection and early treatment of depressive disorder]. PMID- 28357768 TI - [Diagnosis and treatment of Parkinson's disease]. PMID- 28357769 TI - [Hip pain]. PMID- 28357770 TI - [Less is more - cough and acute upper respiratory tract infections]. PMID- 28357771 TI - [Medical care for refugees in Germany]. PMID- 28357772 TI - Switch to Combined GLP1 Receptor Agonist Lixisenatide with Basal Insulin Glargine in Poorly Controlled T2DM Patients with Premixed Insulin Therapy: A Clinical Observation and Pilot Study in Nine Patients. AB - INTRODUCTION: To prove the feasibility and safety of a conversion to once-daily injected GLP1 agonist (lixisenatide) and long-acting basal insulin analogue (glargine) in patients with T2DM and poorly controlled glycemia previously treated with multiple injections of premixed insulins (iPremix) in an outpatient setting. METHODS: Nine patients with T2DM currently receiving iPremix formulations and poor glycemic control were switched to once-daily injected lixisenatide (Lixi) and basal insulin analogue glargine (iGlar) for a 12-week period. Efficacy was defined as A1c reduction of at least 0.4% and weight loss of 0.5 kg or higher. RESULTS: Five of nine patients achieved A1c reductions of 0.4% (4 mmol/mol) or higher and six of nine patients a weight loss of 0.5 kg or higher. A mean A1C reduction of 0.5% +/- 0.5% (6 mmol/mol) and mean weight loss of -1.4 +/- 3.6 kg were observed in all patients. Total daily insulin dose after 12 weeks declined from 56 +/- 26 IU with iPremix formulations to 47 +/- 17 IU in patients taking combined iGlar and Lixi. Corrections with fast acting insulin glulisine (iGlu) were necessary in two patients on a regular basis and in four patients on an irregular basis (2.3 IU mean total daily dose). Two patients did not need additional iGlu. Postprandial glucose profiles were lower in the combined group compared with iPremix throughout the day, which resolved in the afternoon. No metabolic derangements occurred. Mild hypoglycemia and gastrointestinal symptoms were the most often reported adverse events affecting three patients. CONCLUSION: The conversion to once-daily injected GLP1 agonist Lixi and basal iGlar could safely be performed in an outpatient setting and was associated with better postprandial glycemic control throughout the day, except dinner, compared to iPremix. CLINICAL TRIAL REGISTRATION: EU clinical trials register EudraCT number 2013-005334-37 and ClinicalTrials.gov NCT02168491. FUNDING: Sponsored by the Medical University of Vienna and in part supported by Sanofi-Aventis. PMID- 28357773 TI - Centralized Pan-Middle East Survey on the Under-Treatment of Hypercholesterolemia: Results from the CEPHEUS II Study in Egypt. AB - INTRODUCTION: As part of the CEPHEUS study, CEPHEUS I was conducted in 2010 and 2011 in Cairo and then the CEPHEUS II study was carried out in Alexandria and Delta Regions in Egypt between April 2014 and August 2015 to determine the proportion of dyslipidemic patients on lipid-lowering treatment reaching LDL-C treatment goals. METHODS: We conducted an open-label, observational, multicenter, cross-sectional survey where 90 investigators enrolled 1127 patients receiving lipid-lowering drugs for at least 3 months. After signing informed consent forms, the study questionnaires were completed by patients and investigators. Blood samples were taken for laboratory investigations. Patients with missing LDL-C data were excluded from the analysis and results from 896 patients were analyzed according to European Atherosclerosis Society and EAS/ESC 2011 guidelines. RESULTS: Out of 896 patients enrolled based on the risk stratification of EAS/ESC 2011 guidelines, 12.4% were classified as low risk, 20.0% as moderate risk, 2.5% as high risk, and 65.2% as very high risk. Achievement goals were 84.7, 44.7, 18.2, and 22.3% for low-risk, moderate-risk, high-risk, and very high risk patients, respectively, with an overall achievement goal of 34.4%. The study population included 50.2% diabetes, 64.4% hypertension, 54.9% metabolic syndrome, 32.2% family history of cardiovascular disease, 23.1% smokers, and 33.8% secondary prevention. Lipid-lowering agents were prescribed as a monotherapy to 90.1% and in combination in 9.9% with goal achievements of 34 and 38%, respectively (p > 0.05). Statins were prescribed to 86.9% of patients. The most frequent prescribed statins were rosuvastatin (47.1%) and atorvastatin (36.0%), followed by simvastatin (9.2%). Treatment goal was achieved in 34.2, 36.0, and 31.7% for rosuvastatin, atorvastatin, and simvastatin, respectively, with no significant difference in achievement goals (p > 0.05). CONCLUSIONS: Hypercholesterolemia is still not being effectively managed in many at-risk patients in Egypt. The majority of patients enrolled in the study were being actively treated with lipid-lowering medications yet the percentage goal achievement was less when compared to CEPHEUS results. PMID- 28357774 TI - Inappropriate inferences from registry data: Pitfalls of inaccurate data handling? PMID- 28357775 TI - Alpha Wavelet Power as a Biomarker of Antidepressant Treatment Response in Bipolar Depression. AB - There is mounting evidence of a link between the properties of electroencephalograms (EEGs) of depressive patients and the outcome of pharmacotherapy. The goal of this study was to develop an EEG biomarker of antidepressant treatment response which would require only a single EEG measurement. We recorded resting 21-channel EEG in 17 in-patients suffering from bipolar depression in eyes-closed and eyes-open conditions. The EEG measurement was performed at the end of a short washout period which followed previous unsuccessful pharmacotherapy. We calculated the normalized wavelet power of alpha rhythm using two referential montages and an average reference montage. The difference in the normalized alpha wavelet power between 10 responders and 7 non responders was most strongly pronounced in link mastoid montage in the eyes closed condition. In particular, in the occipital (O1, O2, Oz) channels the wavelet power of responders was up to 84 % higher than that of non-responders. Using a novel classification algorithm we were able to correctly predict the outcome of treatment with 90 % sensitivity and 100 % specificity. The proposed biomarker requires only a single EEG measurement and consequently is intrinsically different from biomarkers which exploit the changes in prefrontal EEG induced by pharmacotherapy over a given time. PMID- 28357776 TI - Awareness of resuscitation guidelines in pregnant women. PMID- 28357777 TI - Public's Views toward Return of Secondary Results in Genomic Sequencing: It's (Almost) All about the Choice. AB - The therapeutic use of genomic sequencing creates novel and unresolved questions about cost, clinical efficacy, access, and the disclosure of sequencing results. The disclosure of the secondary results of sequencing poses a particularly challenging ethical problem. Experts disagree about which results should be shared and public input - especially important for the creation of disclosure policies - is complicated by the complex nature of genetics. Recognizing the value of deliberative democratic methods for soliciting informed public opinion on matters like these, we recruited participants from a clinical research site for an all-day deliberative democracy (DD) session. Participants were introduced to the clinical and ethical issues associated with genomic sequencing, after which they discussed the tradeoffs and offered their opinions about policies for the return of secondary results. Participants (n = 66; mean age = 57 (SD = 15); 70% female; 76% white) were divided into 10 small groups (5 to 8 participants each) allowing interactive deliberation on policy options for the return of three categories of secondary results: 1) medically actionable results; 2) risks for adult-onset disorders identified in children; and 3) carrier status for autosomal recessive disorders. In our qualitative analysis of the session transcripts, we found that while participants favored choice and had a preference for making information available, they also acknowledged the risks (and benefits) of learning such information. Our research reveals the nuanced reasoning used by members of the public when weighing the pros and cons of receiving genomic information, enriching our understanding of the findings of surveys of attitudes regarding access to secondary results. PMID- 28357778 TI - Impact of Panel Gene Testing for Hereditary Breast and Ovarian Cancer on Patients. AB - Recent advances in next generation sequencing have enabled panel gene testing, or simultaneous testing for mutations in multiple genes for a clinical condition. With more extensive and widespread genetic testing, there will be increased detection of genes with moderate penetrance without established clinical guidelines and of variants of uncertain significance (VUS), or genetic variants unknown to either be disease-causing or benign. This study surveyed 232 patients who underwent genetic counseling for hereditary breast and ovarian cancer to examine the impact of panel gene testing on psychological outcomes, patient understanding, and utilization of genetic information. The survey used standardized instruments including the Impact of Event Scale (IES), Multidimensional Impact of Cancer Risk Assessment (MICRA), Satisfaction with Decision Instrument (SWD), Ambiguity Tolerance Scale (AT-20), genetics knowledge, and utilization of genetic test results. Study results suggested that unaffected individuals with a family history of breast or ovarian cancer who received positive results were most significantly impacted by intrusive thoughts, avoidance, and distress. However, scores were also modestly elevated among unaffected patients with a family history of breast and ovarian cancer who received VUS, highlighting the impact of ambiguous results that are frequent among patients undergoing genetic testing with large panels of genes. Potential risk factors for increased genetic testing-specific distress in this study included younger age, black or African American race, Hispanic origin, lower education level, and lower genetic knowledge and highlight the need for developing strategies to provide effective counseling and education to these communities, particularly when genetic testing utilizes gene panels that more commonly return VUS. More detailed pre-test education and counseling may help patients appreciate the probability of various types of test results and how results would be used clinically, and allow them to make more informed decisions about the type of genetic testing to select. PMID- 28357779 TI - A Comprehensive Review of Pediatric Tumors and Associated Cancer Predisposition Syndromes. AB - An understanding of the role of inherited cancer predisposition syndromes in pediatric tumor diagnoses continues to develop as more information is learned through the application of genomic technology. Identifying patients and their relatives at an increased risk for developing cancer is an important step in the care of this patient population. The purpose of this review is to highlight various tumor types that arise in the pediatric population and the cancer predisposition syndromes associated with those tumors. The review serves as a guide for recognizing genes and conditions to consider when a pediatric cancer referral presents to the genetics clinic. PMID- 28357781 TI - Utility of baseline serum phosphorus levels for predicting remission in acromegaly patients. AB - PURPOSE: High GH and IGF I levels increase tubular phosphate reabsorption in patients with acromegaly. We aimed to investigate the utility of serum phosphorus levels as an indicator for predicting chance of remission in acromegaly patients. DESIGN: Fifty-one patients (n: 51; F: 24, M: 27) with diagnosis of acromegaly were included in the study. Plasma IGF-1, Phosphorus (P) and nadir GH levels on oral glucose tolerance test (OGTT) at the time of diagnosis were analysed retrospectively. Patients were classified into two groups according to their plasma P levels; P <= 4.5 mg/dl (Group-1, n: 23, 45.1%), P > 4.5 mg/dl (Group-2, n: 28, 54.9%). Two groups were compared according to remission status; remission (n: 27) and non-remission (n: 24). Remission was defined with absence of clinical symptoms, normal plasma IGF-1 (adjusted for age and gender) and GH levels (<1 mcg/dl) at least 3 months after initial treatment. RESULTS: Serum P levels decreased significantly after treatment in both groups (p < 0.001). There was a significant correlation between baseline phosphorus levels and remission rates, nadir GH in OGTT, pituitary adenoma size and Ki-67 scores (p = 0.001, r: -0.51; p = 0.01, r: 0.44; p = 0.001, r: 0.52; p = 0.02, r: 0.71, respectively). Mean baseline P levels were significantly higher in patients with non-remission (4.8 vs 4.2, P < 0.001). Logistic regression analysis did not reveal an independent effect on remission with any of these risk factors. CONCLUSION: High serum P levels may be an indicator for a low likelihood of onset of remission in acromegaly patients. Further studies with wider spectrum are needed to make specific suggestions. PMID- 28357780 TI - Targeting TDO in cancer immunotherapy. AB - Tryptophan-2,3-dioxygenase (TDO) is a homotetrameric heme-containing protein catalyzing the initial step in the kynurenine pathway, which oxidates the 2,3 double bond of the indole ring in L-tryptophan and catalyzes it into kynurenine (KYN). The upregulation of TDO results in a decrease in tryptophan and the accumulation of KYN and its metabolites. These metabolites can affect the proliferation of T cells. Increasing evidence demonstrates that TDO is a promising therapeutic target in the anti-tumor process. Despite its growing popularity, there are only a few reviews focusing on TDO in tumors. Hence, we herein review the biological features and regulatory mechanisms of TDO. Additionally, we focus on the role of TDO in the anti-tumor immune response in different tumors. Finally, we also provide our viewpoint regarding the future developmental directions of TDO in cancer research, especially in relation to the development and application of TDO inhibitors as novel cancer treatments. PMID- 28357782 TI - Psychological characteristics of Italian gender dysphoric adolescents: a case control study. AB - PURPOSE: Gender dysphoria (GD) is associated with clinically significant distress and impairment in social, scholastic, and other important areas of functioning, especially when early onset is reported. The aim of the present study is to assess the psychopathological features associated with GD in adolescence, comparing a group of gender dysphoric adolescents (GDs) with a group of non referred adolescents (NRs), in terms of body uneasiness, suicide risk, psychological functioning, and intensity of GD. METHODS: A sample of 46 adolescents with GD and 46 age-matched NRs was evaluated (mean +/- SD age = 16.00 +/- 1.49 and 16.59 +/- 1.11 respectively, p > 0.05). Subjects were asked to complete the Body Uneasiness Test (BUT) to explore body uneasiness, the Youth Self Report (YSR) to measure psychological functioning, the Multi-Attitude Suicide Tendency Scale (MAST) for suicide risk, and the Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults (GIDYQ-AA) for GD assessment. RESULTS: Adolescents with GD reported significantly higher levels of body uneasiness (BUT-GSI, F = 380.13, p < 0.0001), as well as a worse psychological functioning (YSR, F = 13.06 and p < 0.0001 for "total problem scale" and F = 12.53, p = 0.001 for "internalizing" scale) as compared to NRs. When YSR subscales were considered, GDs showed significantly higher scores in the "withdrawal/depression", "anxiety/depression", and "social problems" (all p < 0.0001). In addition, GDs showed significantly higher levels in the "attraction to death" and "repulsion by life" scales and lower scores in the "attraction to life" scale (all p < 0.0001). Finally, GIDYQ-AA score was significantly lower (meaning a higher level of gender dysphoria symptoms) in GDs vs. NRs (p < 0.0001). CONCLUSIONS: GD adolescents reported significantly higher body dissatisfaction and suicidal risk compared to NRs. In addition, results confirmed a significant impairment in social psychological functioning in adolescents with GD. PMID- 28357783 TI - Diabetic retinopathy: new therapeutic perspectives based on pathogenic mechanisms. AB - Diabetic retinopathy (DR) is the leading cause of visual impairment and preventable blindness and represents a significant socioeconomic cost for healthcare systems worldwide. In early stages of DR the only therapeutic strategy that physicians can offer is a tight control of the risk factors for DR (mainly blood glucose and blood pressure). The currently available treatments for DR are applicable only at advanced stages of the disease and are associated with significant adverse effects. Therefore, new treatments for the early stages of DR are needed. However, in early stages of DR invasive treatments such as intravitreal injections are too aggressive, and topical treatment seems to be an emerging route. In the present review, therapeutic strategies based on the main pathogenic mechanisms involved in the development of DR are reviewed. The main gap in the clinical setting is the treatment of early stages of DR and, therefore, this review emphasizes in this issue by giving an overview of potential druggable targets. By understanding of disease-specific pathogenic mechanisms, biological heterogeneity and progression patterns in early and advanced DR a more personalised approach to patient treatment will be implemented. PMID- 28357784 TI - Expression of a new laccase from Moniliophthora roreri at high levels in Pichia pastoris and its potential application in micropollutant degradation. AB - Laccases have gained significant attention due to their emerging applications including bioremediation, biomass degradation and biofuel cells. One of the prerequisites for the industrial application of laccases is their sufficient availability. However, expression levels of recombinantly expressed laccases are often low. In this study Mrl2, a new laccase from the basidiomycete Moniliophthora roreri, was cloned in Pichia pastoris and produced in an optimized fed-batch process at an exceptionally high yield of 1.05 g l-1. With a redox potential of 0.58 V, Mrl2 belongs to mid-redox potential laccases. However, Mrl2 demonstrated high kcat values of 316, 20, 74, and 36 s-1 towards 2,2'-azino-bis(3 ethylbenzthiazoline-6-sulfonic acid) (ABTS), syringaldazine (SGZ), 2,6 dimethoxyphenol (2,6-DMP) and guaiacol, respectively. Mrl2 remained stable above pH 6 and in the presence of many metal ions, which is important for application in bioremediation. Mrl2 was investigated for the ability to degrade endocrine disrupting chemicals (EDCs) and non-steroidal anti-inflammatory drugs (NSDAIs) at neutral pH value. The enzyme accepted and converted estrone, 17beta-estradiol, estriol, the synthetic contraceptive 17alpha-ethinyl estradiol and bisphenol A at pH 7 faster than high-potential laccases from Trametes versicolor. For example, within 30 min Mrl2 removed more than 90% bisphenol A, 17beta-estradiol, 17alpha ethinyl estradiol and estriol, respectively. The concentration of the recalcitrant drug diclofenac dropped by 56% after 20 h incubation with Mrl2. PMID- 28357785 TI - Patterns of unmet needs in adolescent and young adult (AYA) cancer survivors: in their own words. AB - PURPOSE: Categorization of the needs of AYA cancer survivors is primarily based on quantitative analyses of epidemiological and observational research. The present study classified the phenomenological experiences of AYA survivors based on their own language. METHODS: A systematic approach for selecting qualitative studies of unmet needs in AYA cancer survivors was used. Following selection based on quality, survivor statements were entered verbatim and thematic analysis was conducted using NVivo qualitative research software. RESULTS: A total of 1993 AYA cancer survivors (post-treatment) were included in 58 studies (78% individual interviews). Mean age was 27.6 with an average of 8.6 years post-primary treatment. The organizational framework reported in this study was based on a heterogeneous group of cancer types. Thirteen themes including symptoms, function, reproductive health, emotional well-being, health management, health care system, social interaction, romantic relationships, cancer disclosure, normalcy, career development and employment, and school and fiscal concerns were identified. Forty-eight subthemes were also identified covering such areas as fertility, integrative health services, advice for cancer disclosure, family interaction, and insurance challenges. CONCLUSION: Direct analysis of text identified many common unmet needs similarly reported in the quantitative literature. The phenomenological data also provided a breakdown of unmet needs into subthemes or elements of unmet needs. IMPLICATIONS FOR CANCER SURVIVORS: This information can help form the basis for a personalized, valid, and reliable evaluation tool of the range of unmet needs in AYA survivors. PMID- 28357787 TI - Visual evaluation and differentiation of renal oncocytomas from renal cell carcinomas by means of 99mTc-sestamibi SPECT/CT. AB - BACKGROUND: Despite the progress in the quality of multiphasic CT and MRI scans, it is still difficult to fully characterize a solid kidney lesion. Approximately 10% of all solid renal tumours turn out to be oncocytomas. In actual clinical practice, this is verified only following unnecessary surgery or a renal biopsy/ablation. The objective of our pilot study examines whether 99mTc sestamibi SPECT/CT can play a crucial role in the characterization of solid renal neoplasms and the differentiation of oncocytomas from renal cell carcinomas. The study included 27 patients identified with 31 solid renal lesions. All patients were discussed in a multidisciplinary conference, and a decision for surgery or biopsy was taken. Prior to invasive procedures, patients underwent a SPECT/CT with 99mTc-sestamibi. Visual evaluation was performed, and any focal 99mTc sestamibi uptake detected on SPECT in the localisation of tumour was considered as positive. RESULTS: Eleven out of 12 oncocytomas (91.6%) displayed positive uptake of 99mTc-sestamibi. Three hybrid tumours (mixed-type oncocytoma and chromophobe renal cancer) were positive on SPECT/CT. One papillary renal cell carcinoma had a slight uptake of 99mTc-sestamibi. The remaining 11 renal cell carcinomas were sestamibi negative. CONCLUSIONS: Differentiation of benign renal oncocytomas from renal cell carcinomas seems very promising on 99mTc-sestamibi SPECT/CT examination. Additional supplement to visual evaluation, i.e. quantitative tools, should be sought for an accurate estimate of biological behaviour and hence a secure diagnosis. PMID- 28357786 TI - The Real Role of beta-Blockers in Daily Cardiovascular Therapy. AB - The role of beta-adrenoceptor antagonists (beta-blockers) in cardiovascular therapy has been subject to diverse trends and changes over the decades. With the advent of a wide variety of excellent drugs for the treatment of antihypertension, beta-blockers have been relegated from the first-line treatment of essential hypertension. However, they remain the drugs of first choice in recommendations from the respective medical societies for heart failure, coronary artery disease, and atrial fibrillation as well as in hypertension complicated with heart failure, angina pectoris, or prior myocardial infarction. When indicated, cardioselective beta-blockers should be prescribed in patients with diabetes mellitus or chronic obstructive pulmonary disease. We review the available evidence for the use of beta-blockers in clinical conditions in which recommendations can be made for everyday practice. PMID- 28357788 TI - Distribution, sources, and potential risk of polycyclic aromatic hydrocarbons in soils from an industrial district in Shanxi, China. AB - Concentration, composition profile, orientation distribution, sources, and potential risks of 16 polycyclic aromatic hydrocarbons (PAHs) were analyzed in 76 surface (0-25 cm) soil samples collected from the Changzhi industrial district in July 2014 using a gas chromatography mass spectrometer (GC-MS QP2010 Ultra) system. The composition patterns of the PAHs were dominated by the presence of four-ring PAHs (average 42.9%), followed by three-ring (average 25.9%), five-ring PAHs (average 25.6%), two-ring PAHs (average 5.03%), and lastly, six-ring PAHs (average 0.641%). Source apportionment of the soil PAHs was also performed by the diagnostic ratios, principal component analysis (PCA), and coefficient of divergence (CD) analysis indicated signatures of PAHs sources (including incineration, coal/wood combustion, and vehicular exhaust emission). The total concentration of 16 PAHs (?16PAHs) found in the roadsides soils (RS) ranged from 2197 to 25,041 MUg kg-1, with an arithmetic mean value of 12,245 MUg kg-1; followed by the village soils (VS), which ranged from 2059 to 21,240 MUg kg-1, with a mean of 8976 MUg kg-1; and lastly, the agricultural soils (AS), which ranged from 794 to 16,858 MUg kg-1, with a mean of 3456 MUg kg-1. According to the numerical effect-based soils quality guidelines of Maliszewska-Kordybach, the levels of PAHs in the sampled industrial areas range from high to heavy contamination. The values of total benzo[a]pyrene toxicity equivalent values (?Bapeq16PAHs) in the sample areas ranged from 0.087 to 3611 MUg kg-1 with an average of 969 MUg kg-1. According to the soil quality guidelines of Canada, values found in the highest range (100 MUg kg-1), which are equal to those of ?Bapeq16PAHs found in the industrial area samples, will exert adverse biological effects. The results of this research could potentially be useful for local governments to control toxicity exposure, promote actions to alleviate PAHs contamination, and to manage human health at both work and industrial areas. PMID- 28357789 TI - Cadmium and copper induced changes in growth, oxidative metabolism and terpenoids of Tanacetum parthenium. AB - Morphological and biochemical responses of feverfew plants exposed to low (5 MUM) and high (35 and 70 MUM) levels of Cd or Cu were investigated. Increasing metal supply notably reduced the plant biomass. Elevated Cd and Cu levels also resulted in an increase in the leaf proline content. Besides, decrease in ascorbic acid (AsA) and glutathione (GSH) contents was similar in the leaves of Cd- and Cu treated plants, indicating altered biosynthesis of AsA and GSH under metal excess. High metal doses stimulated increase in antioxidative enzyme activities that could be related to elevated hydrogen peroxide (H2O2) content and subsequent lipid peroxidation. Cd was typically more accumulated in shoots and roots than Cu, leading to higher translocation factor at high Cd doses. In terms of essential oil content, it seems that Cd had an inhibitory effect during the experiment, whereas Cu was found to stimulate it only at 5 MUM. Furthermore, high Cd supply enhanced the relative proportion of monoterpene hydrocarbons, while Cu increased the proportion of sesquiterpenes, especially at 5 MUM. This result provides the first evidence of the response of feverfew plants to Cd or Cu by associating stress-related responses with changes in terpenoids. PMID- 28357790 TI - Association between dietary lead intake and 10-year mortality among Chinese adults. AB - Blood lead level is associated with increased risk of mortality, but dietary lead exposure and mortality, particularly with cancer, has not been studied in the general population. The objective of the study was to assess the association between lead intake and 10-year mortality among 2832 Chinese adults. Food intake was measured by 3-day weighed food record in 2002. We documented 184 deaths (63 cancer deaths and 70 cardiovascular disease (CVD) deaths) during 27,742 person years of follow-up. Dietary lead intake was positively associated with cancer and all-cause mortality. Across quartiles of lead intake, hazard ratios (HRs) for cancer mortality were 1.00, 0.80 (0.33-1.92), 1.52 (0.65-3.56), and 3.00 (1.06 8.44) (p for trend 0.028). HRs for all-cause mortality were 1.00, 1.28 (0.83 1.98), 1.24 (0.78-1.97), and 2.24 (1.28-3.94) (p for trend 0.011). Each 30 MUg/day increase of lead intake was associated with 25% (95% CI 3-52%) increase of all-cause mortality. There was an interaction between lead intake and hypertension in relation to CVD mortality (p for interaction 0.003): HRs conferred by every 30 MUg/day of lead intake were 1.57 (0.98-2.52) and 1.06 (0.81 1.39) among those with or without hypertension. Dietary lead intake was positively related to cancer and all-cause mortality. PMID- 28357791 TI - Role of brassinosteroids in alleviating toxin-induced stress of Verticillium dahliae on cotton callus growth. AB - Brassinosteroids are well known to mitigate biotic stresses; however, their role to induce tolerance against Verticillium dahliae is unknown. The current study employed V. dahliae (Vd) toxin as pathogen-free model system to induce stress on cotton callus growth, and its amelioration was investigated using 24 epibrassinolide (EBR). Results revealed that EBR has ameliorative effects against Vd toxin with greater seen effect when callus was treated with EBR prior to its exposure to Vd toxin (pre-EBR treatment) than EBR applied along with Vd toxin simultaneously (co-EBR treatment). Pre-EBR-treated calli remained green, while 65 and 90% callus browning was observed in co-EBR- and Vd toxin-alone-treated callus, respectively. Likewise, the fresh weight of the pre-EBR-treated callus was 52% higher than Vd toxin-alone treatment, whereas this increase was only 23% in co-EBR-treated callus. Meanwhile, EBR treatment of the cotton callus has also increased the contents of chlorophylls a and b, carotenoids, total phenols, flavonoids, soluble sugars, and proteins and increased the activity of enzymes involved in secondary metabolism like polyphenol oxidase (PPO), phenylalanine ammonialyase (PAL), cinnamyl alchol dehydrogenase (CAD), and shikimate dehydrogenase (SKDH) over Vd toxin-alone treatment with higher increments being observed in pre-EBR-treated callus. Furthermore, EBR treatment mimicked the DNA damage and improved the structure of mitochondria, granum, stroma thylakoids, and the attachment of ribosomes with the endoplasmic reticulum. This EBR-mediated mitigation was primarily associated with substantially increased contents of photosynthetic pigments and regulation of secondary metabolism. PMID- 28357793 TI - Ecological risk assessment of toxic organic pollutant and heavy metals in water and sediment from a landscape lake in Tianjin City, China. AB - To estimate the ecological risk of toxic organic pollutant (formaldehyde) and heavy metals (mercury (Hg), arsenic (As), cadmium (Cd), and chromium (Cr)) in water and sediment from a landscape Lake in Tianjin City, an ecological risk assessment was performed. The risk quotient (RQ) method and the AQUATOX model were used to assess the ecological risk of formaldehyde in landscape water. Meanwhile, the RQ method and the potential ecological risk index method were used to assess the ecological risk of four heavy metals in water and sediment from the studied landscape lake, respectively. The results revealed that the maximum concentration of formaldehyde in landscape water was lower than the environmental quality standards of surface water in China. The maximum simulated concentrations of formaldehyde in phytoplankton and invertebrates were 3.15 and 22.91 MUg/L, respectively, which were far less than its toxicity data values (1000 and 510 MUg/L, respectively), suggesting that formaldehyde in landscape water was at a safe level for aquatic organisms. The RQ model indicated that the risks of phytoplankton and invertebrates were higher than that of fish posed by Hg and Cd in landscape water, and the risks from As and Cr were acceptable for all test organisms. Cd is the most important pollution factor among all heavy metals in sediment from studied landscape lake, and the pollution factor sequence of heavy metals was Hg > As > Cr > Cd. The values of risk index (RI) for four heavy metals in samples a and b were 43.48 and 72.66, which were much lower than the threshold value (150), suggesting that the ecological risk posed by heavy metals in sediment was negligible. PMID- 28357792 TI - Preliminary recovery study of a commercial molecularly imprinted polymer for the extraction of glyphosate and AMPA in different environmental waters using MS. AB - A commercial molecularly imprinted polymer (MIP) dedicated to glyphosate (GLY) and its main metabolite, aminomethylphosphonic acid (AMPA), was lately assessed as "POCIS-like" sampler on mineral water. The obtained results were encouraging with 111 and 122 mL day-1 as sampling rates for GLY and AMPA, respectively. Therefore, before applying this passive sampler to environmental waters, the commercial phase was tested on different water matrices as a solid-phase extraction (SPE) device. The SPE protocol was carried on 250 mg of MIP with the following three steps: conditioning by Milli-Q water, loading of the sample (15 mL), and elution of the analytes by 4 mL 0.1 M HCl that were evaporated to dryness and recovered in 15 mL of the suitable solvent for analysis. This protocol was first applied to mineral water spiked by GLY and AMPA at environmental concentration levels (25-750 ng L-1). Analyses were carried out by ultra-performance liquid chromatography hyphenated to tandem mass after derivatization of GLY and AMPA by 9-fluorenylmethylchloroformate. The linear correlation between concentrations measured with and without SPE on MIP was proved.Furthermore, other extractions showed that high concentrations of metal ion interferents (lead(II), cadmium(II), and zinc(II)) in groundwaters did not reduce SPE performance of the MIP.Then, concentration assays were undertaken and brought noteworthy results, such as the recovery of 80% GLY and AMPA from groundwater spiked at 10 ng L-1 and concentrated 100 times. For this purpose, ion exclusion chromatography hyphenated to mass was applied without previous derivatization of the analytes. The same concentration factor and analytical method were applied to 100 ng L-1 spiked sea water with recoveries of 96% for GLY and 121% for AMPA. PMID- 28357794 TI - Chemical investigation and quality of urban dew collections with dust precipitates. AB - The quality and chemical composition of urban dew collections with dust precipitates without pre-cleaning of the collecting surface WSF (white standard foil) were investigated for 16 out of 20 collected samples with collected volumes ranging from 22 to 230 ml. The collection period was from March to July 2015 at an urban area, Jubaiha, which is located in the northern part of the capital city Amman, Jordan. The obtained results indicated the predominance of Ca2+ and SO42- ions (ratio 2.2:1) that originated from Saharan soil dust; where the collected samples were alkaline (mean pH = 7.35) with high mineralization (429.22 mg/L) exceeding the previously reported dew values in Amman-Jordan. A relocation of NaCl and to a less extent Mg2+ from sea to land by Saharan wind is indicated by the percent sea-salt fraction calculations (over 100 and 52, respectively). The collected samples exhibited high total organic carbon (TOC) values ranging from 11.86 to 74.60 mg/L, presence of particulate settled material with turbidity ranging from 20.10 to 520.00 NTU, and presence of undesired elements like boron (mean = 1.48 mg/L) that made it different in properties from other dew water collections at clean surfaces, and exceeding the standard limits for drinking water for these parameters set by Jordanian Drinking Water standards (JS286/2015)/WHO standard. The quality of this water is more close to that for raw or agricultural water but if it is meant to be used as potable source of water, at least sand and activated charcoal filters are needed to purify it. PMID- 28357795 TI - The effectiveness of dietary sunflower meal and exogenous enzyme on growth, digestive enzymes, carcass traits, and blood chemistry of broilers. AB - High costs of conventional protein feed sources including soybean meal (SBM) generated the need for finding other alternatives. Thus, the present study was designed to evaluate the impact of graded replacements of SBM by sunflower seed meal (SFM) with or without enzyme supplementation on growth performance, digestive enzymes, carcass traits, and blood profile of broiler chickens. A total of 240 unsexed 1-week-old broiler chicks (Hubbard) were randomly divided into eight treatment groups of 30 chicks each in five replicates each of six chicks in a factorial design (4 * 2) arrangement, including four levels of SFM (0, 25, 50, and 75% replacing SBM) and two levels of enzyme (0- or 0.1-g/kg diet) supplementation. Performance traits including feed conversion ratio, body weight, and weight gain were significantly (P < 0.01) improved with increasing SFM up to 50% substitution for SBM or with enzyme supplementation in broiler diet during the experiment. However, feed intake of broiler chicks was decreased with enzyme supplementation (P < 0.05). The activities of digestive enzymes (protease and amylase) were significantly (P < 0.05) influenced and enhanced by SFM and enzyme inclusion in diets, respectively. The activities of protease and amylase were improved with SFM diet supplemented with 0.1 g/kg enzyme in comparison with those with the un-supplemented diet. The evaluated carcass traits were not statistically (P > 0.05) influenced by feeding SFM meal or enzyme addition. Biochemical blood parameters were significantly (P < 0.01) affected by SFM, enzyme, or their interaction in broiler diets, except for globulin that was not affected by dietary enzyme. It is concluded that increasing SFM level in the diet up to 50% replacing SBM with the supplementation of enzyme improved the growth performance and enhanced positively carcass traits as well as the activity of digestive enzymes in broiler chickens. PMID- 28357796 TI - Effect of microscale ZVI/magnetite on methane production and bioavailability of heavy metals during anaerobic digestion of diluted pig manure. AB - Low methane production and high levels of heavy metal in pig slurries limit the feasibility of anaerobic digestion of pig manure. In this study, changes in the methane production and bioavailability of heavy metals in the anaerobic digestion of diluted pig manure were evaluated using single and combined action of microscale zero-valence iron (ZVI) and magnetite. After 30 days of anaerobic digestion, the methane yield ranged from 246.9 to 334.5 mL/g VS added, which increased by 20-26% in the group added with microscale ZVI and/or magnetite relative to that in the control group. Results of the first-order kinetic model revealed that addition of microscale ZVI and/or magnetite increased the biogas production potential, rather than the biogas production rate constant. These treatments also changed the distribution of chemical fractions for heavy metal. The addition of ZVI decreased the bioavailability of Cu and Zn in the solid digested residues. Moreover, a better performance was observed in the combined action of microscale ZVI and magnetite, and the ZVI anaerobic corrosion end product, magnetite, might help enhance methane production through direct interspecies electron transfer in ZVI-anaerobic digestion process. PMID- 28357797 TI - Modeling technical change in climate analysis: evidence from agricultural crop damages. AB - This study accounts for the Hicks neutral technical change in a calibrated model of climate analysis, to identify the optimum level of technical change for addressing climate changes. It demonstrates the reduction to crop damages, the costs to technical change, and the net gains for the adoption of technical change for a climate-sensitive Pakistan economy. The calibrated model assesses the net gains of technical change for the overall economy and at the agriculture-specific level. The study finds that the gains of technical change are overwhelmingly higher than the costs across the agriculture subsectors. The gains and costs following technical change differ substantially for different crops. More importantly, the study finds a cost-effective optimal level of technical change that potentially reduces crop damages to a minimum possible level. The study therefore contends that the climate policy for Pakistan should consider the role of technical change in addressing climate impacts on the agriculture sector. PMID- 28357798 TI - The longevity of para-aminopropiophenone (PAPP) wild dog baits and the implications for effective and safe baiting campaigns. AB - Considerable effort goes into mitigating the impacts caused by invasive animals and prohibiting their establishment or expansion. In Australia, management of wild dogs (Canis lupus dingo and their hybrids) and their devastating impacts is reliant upon poison baiting. The recent release of baits containing the humane toxin para-aminopropiophenone (PAPP) offers potential improvements for control of wild dogs, but little is known about the environmental persistence of PAPP in manufactured baits that could be used to inform best practice guidelines. We investigated the degradation rate of PAPP wild dog baits (DOGABAITTM) under typical field usage and storage conditions in north-eastern Australia and calculated optimal deployment and withholding periods. The PAPP content of buried baits declines faster than surface-laid baits, but both presentations retained lethal doses to wild and domestic dogs for considerable periods (6-16 weeks). Domestic or working dogs should be suitably restrained or excluded from baited areas for extended periods, particularly under dry conditions, to minimise poisoning risk. The period of persistence of PAPP baits may provide opportunities to improve the duration or longer term efficacy of baiting campaigns, but care is needed to protect domestic and working dogs to ensure responsible and safe use. PMID- 28357799 TI - What about the detoxification mechanisms underlying ozone sensitivity in Liriodendron tulipifera? AB - Liriodendron tulipifera (known as the tulip tree) is a woody species that has been previously classified as sensitive to ozone (O3) in terms of visible leaf injuries and photosynthetic primary reactions. The objective of this work is to give a thorough description of the detoxification mechanisms that are at the basis of O3 sensitivity. Biochemical and molecular markers were used to characterize the response of 1-year-old saplings exposed to O3 (120 ppb, 5 h day 1, for 45 consecutive days) under controlled conditions. O3 effects resulted in a less efficient metabolism of Halliwell-Asada cycle as confirmed by the diminished capacity to convert the oxidized forms of ascorbate and glutathione in the reduced ones (AsA and GSH, respectively). The reduced activity of AsA and GSH regenerating enzymes indicates that de novo AsA biosynthesis occurred. This compound could be a cofactor of several plant-specific enzymes that are involved in the early part of the phenylpropanoid and flavonoid biosynthesis pathway, as confirmed by the significant rise of PAL activity (+75%). The induction of the defence-related secondary metabolites (in particular, rutin and caffeic acid were about threefold higher) and the concomitant increase in transcript levels of PAL and CHS genes (+120 and 30%, respectively) suggest that L. tulipifera utilized this route in order to partially counteract the O3-induced oxidative damage. PMID- 28357800 TI - Comparison of normal and dusty day impacts on fractional exhaled nitric oxide and lung function in healthy children in Ahvaz, Iran. AB - Children are the vulnerable group at risk of adverse health effects related to air pollution due to dust storm in Ahvaz. The purpose of this study was to compare the values of fractional exhaled nitric oxide (FENO) and lung functions as parameters of adverse health effects of particulate matter (PM) in dusty and normal (non-dusty) days in elementary schoolchildren. The study was conducted among elementary school students in Ahvaz. The healthy elementary schoolchildren (N = 105) were selected from different districts for FENO and lung function sampling during the dusty and normal days. The values of PM10 and PM2.5 during dusty days were higher than during normal days. Mean values of FENO during the normal and dusty days were 14.23 and 20.3 ppb, respectively, and the difference between these values was statistically significant (p < 0.05). Lung function results showed a statistically significant difference between the mean values of forced vital capacity during the dusty and normal days (p < 0.05). The results revealed a significant difference both in the values of inflammatory biomarker and in the lung function tests in dusty and normal days. Based on our results, fractional exhaled nitric oxide could be a useful short-term biomarker of particulate pollution effect coupled with spirometry. PMID- 28357801 TI - Nitrogen contamination in groundwater in an agricultural region along the New Silk Road, northwest China: distribution and factors controlling its fate. AB - Nitrogen contamination is a global concern and has been a serious problem in agricultural areas. The present study was carried out in an intensively irrigated region of northwest China along the New Silk Road, Yinchuan Plain, where the residents depend on the groundwater as the primary source for drinking. To understand the nitrogen contamination in the aquifer system, the distribution of nitrate and ammonium and its controlling factors were studied based on hydrochemical, hydrogeological, and isotopic analyses. 11.37 and 40% of phreatic water samples are categorized as NO3-N and NH4-N pollution in accordance with the WHO standards. A total of 59.52% of confined water samples has high NH4-N values, exceeding the permissible limit for drinking purpose. The results indicate NO3-N predominates in the shallow water and NH4-N predominates in the deep water for the single phreatic aquifer. For the multilayer structure area, NO3-N predominates in the phreatic aquifer of the western and the southern parts of the plain; NH4-N predominates in the phreatic aquifer of the middle and the northern parts of the plain, and in the confined aquifers where groundwater pumping had been performed. The mixture of synthetic fertilizer and manure/sewage is primarily responsible for the phreatic water based on isotopic analysis. In the confined aquifers, higher NH4-N concentrations are mainly attributed to intensive pumping under higher pumping rates. The results of this study can be used as a scientific basis for the future research on nitrogen in the plain. They can also be used by scholars and decision makers who are interested in groundwater protection and sustainable development. PMID- 28357802 TI - Studies on the protective effect of the artichoke (Cynara scolymus) leaf extract against cadmium toxicity-induced oxidative stress, hepatorenal damage, and immunosuppressive and hematological disorders in rats. AB - Our objective was to explore the protective effect of artichoke leaf extract (ALE) against cadmium (Cd) toxicity-induced oxidative organ damage in rats. Male albino Wistar rats were divided into four equal groups of eight animals each. The first group was assigned as a control. Groups 2-4 were orally administered with ALE (300 mg/kg bw), Cd (CdCl2, 100 mg/L drinking water), and ALE plus Cd, respectively, daily for 4 weeks. After treatment with Cd, the liver and kidney malondialdehyde (MDA) increased significantly compared with the control rats. The sera interleukin (IL)-1beta, tumor necrosis factor (TNF-alpha), and IL-10, liver transaminase, urea, creatinine, and peripheral neutrophil count were significantly increased in Cd-exposed rats compared to the control group. The reduced glutathione (GSH), glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase (CAT) decreased in the liver and kidney in Cd-exposed group. In combination treatment, Cd and ALE significantly improved immune response, an antioxidant system, and hepatorenal function with a significant decline in MDA. In conclusion, ALE ameliorates the immunosuppressive and hepatorenal oxidative injury stimulated by Cd in rats. These results suggest that artichoke has shown promising effects against adverse effects of Cd toxicity. PMID- 28357803 TI - Rainwater harvesting in American Samoa: current practices and indicative health risks. AB - Roof-harvested rainwater (RHRW) is an important alternative source of water that many island communities can use for drinking and other domestic purposes when groundwater and/or surface water sources are contaminated, limited, or simply not available. The aim of this pilot-scale study was to investigate current RHRW practices in American Samoa (AS) and to evaluate and compare the quality of water from common potable water sources including RHRW stored in tanks, untreated stream water, untreated municipal well water, and treated municipal tap water samples. Samples were analyzed using culture-based methods, quantitative polymerase chain reaction (qPCR), and 16S amplicon sequencing-based methods. Based on indicator bacteria (total coliform and Escherichia coli) concentrations, the quality of RHRW was slightly lower than well and chlorinated tap water but exceeded that of untreated stream water. Although no Giardia or Leptospira spp. were detected in any of the RHRW samples, 86% of the samples were positive for Cryptosporidium spp. All stream water samples tested positive for Cryptosporidium spp. Opportunistic pathogens (Pseudomonas aeruginosa and Mycobacterium intracellulare) were also detected in the RHRW samples (71 and 21% positive samples, respectively). Several potentially pathogenic genera of bacteria were also detected in RHRW by amplicon sequencing. Each RHRW system was characterized by distinct microbial communities, 77% of operational taxonomic units (OTUs) were detected only in a single tank, and no OTU was shared by all the tanks. Risk of water-borne illness increased in the following order: chlorinated tap water/well water < RHRW < stream water. Frequent detection of opportunistic pathogens indicates that RHRW should be treated before use. Stakeholder education on RHRW system design options as well as on importance of regular cleaning and proper management techniques could improve the quality of the RHRW in AS. PMID- 28357804 TI - Airborne trace elements near a petrochemical industrial complex in Thailand assessed by the lichen Parmotrema tinctorum (Despr. ex Nyl.) Hale. AB - Several trace elements discharged by the petrochemical industry are toxic to humans and the ecosystem. In this study, we assessed airborne trace elements in the vicinity of the Map Ta Phut petrochemical industrial complex in Thailand by transplanting the lichen Parmotrema tinctorum to eight industrial, two rural, and one clean air sites between October 2013 and June 2014. After 242 days, the concentrations of As, Cd, Co, Cr, Cu, Hg, Mo, Ni, Pb, Sb, Ti, V, and Zn in lichens at most industrial sites were higher than those at the rural and the control sites; in particular, As, Cu, Mo, Sb, V, and Zn were significantly higher than at the control site (p < 0.05). Contamination factors (CFs) indicated that Cd, Cu, Mo, and Sb, which have severe health impacts, heavily contaminated at most industrial sites. Principal component analysis (PCA) showed that most elements were associated with industry, with lesser contributions from traffic and agriculture. Based on the pollution load indexes (PLIs), two industrial sites were highly polluted, five were moderately polluted, and one had a low pollution level, whereas the pollution load at the rural sites was comparable to background levels. This study reinforces the utility of lichens as cost-effective biomonitors of airborne elements, suitable for use in developing countries, where adequate numbers of air monitoring instruments are unavailable due to financial, technical, and policy constraints. PMID- 28357805 TI - Peroxynitrite Activates the NLRP3 Inflammasome Cascade in SOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis. AB - Neuroinflammation, characterized by the appearance of reactive microglial and astroglial cells, is one of the several pathogenic mechanisms of amyotrophic lateral sclerosis (ALS), a fast-progressing and fatal neurodegenerative disease. Cerebrospinal fluid and spinal cord of ALS patients and SOD1 mutant mice show high concentrations of IL-1beta. This interleukin, expressed as an inactive precursor, undergoes a proteolytic maturation by caspase1, whose activation, in turn, depends on inflammasomes. Whether and how inflammasome is activated in ALS models is still to be clarified. The mechanism of inflammasome activation was studied in murine microglial cells overexpressing hSOD1(G93A) and verified in the spinal cord of hSOD1(G93A) mice. Murine microglial hSOD1(G93A) cells express all the inflammasome components and LPS activates caspase1 leading to an increase in the secretion of IL-1beta. By activating NF-kappaB, LPS increases ROS and NO levels that spontaneously react to form peroxynitrite, thus leading to protein nitration. Reduction in peroxynitrite levels results in a decrease in caspase1 activity. Protein nitration and caspase1 activity are concomitantly increased in the spinal cord of pre-symptomatic SOD1(G93A) mice. Oxidative/nitrosative stress induces peroxynitrite formation that may be a key trigger of caspase1/inflammasome activation. Peroxynitrite formation may play a critical role in inflammasome activation and might be exploited as potential therapeutic target for ALS. PMID- 28357806 TI - Apoptosis Induced by the UV Filter Benzophenone-3 in Mouse Neuronal Cells Is Mediated via Attenuation of Eralpha/Ppargamma and Stimulation of Erbeta/Gpr30 Signaling. AB - Although benzophenone-3 (BP-3) has frequently been reported to play a role in endocrine disruption, there is insufficient data regarding the impact of BP-3 on the nervous system, including its possible adverse effects on the developing brain. Our study demonstrated that BP-3 caused neurotoxicity and activated apoptosis via an intrinsic pathway involving the loss of mitochondrial membrane potential and the activation of caspases-9 and -3 and kinases p38/MAPK and Gsk3beta. These biochemical alterations were accompanied by ROS production, increased apoptotic body formation and impaired cell survival, and by an upregulation of the genes involved in apoptosis. The BP-3-induced effects were tissue-specific and age-dependent with the most pronounced effects observed in neocortical cells at 7 days in vitro. BP-3 changed the messenger RNA (mRNA) expression levels of Eralpha, Erbeta, Gpr30, and Ppargamma in a time-dependent manner. At 3 h of exposure, BP-3 downregulated estrogen receptor mRNAs but upregulated Ppargamma mRNA. After prolonged exposures, BP-3 downregulated the receptor mRNAs except for Erbeta mRNA that was upregulated. The BP-3-induced patterns of mRNA expression measured at 6 and 24 h of exposure reflected alterations in the protein levels of the receptors and paralleled their immunofluorescent labeling. Eralpha and Ppargamma agonists diminished, but Erbeta and Gpr30 agonists stimulated the BP-3-induced apoptotic and neurotoxic effects. Receptor antagonists caused the opposite effects, except for ICI 182,780. This is in line with a substantial reduction in the effects of BP-3 in cells with siRNA silenced Erbeta/Gpr30 and the maintenance of BP-3 effects in Eralpha- and Ppargamma siRNA-transfected cells. We showed for the first time that BP-3 affected mRNA and protein expression levels of Eralpha, Erbeta, Gpr30, and Ppargamma, paralleled BP-3-induced apoptosis and neurotoxicity. Therefore, we suggest that BP-3-evoked apoptosis of neuronal cells is mediated via attenuation of Eralpha/Ppargamma and stimulation of Erbeta/Gpr30 signaling. PMID- 28357807 TI - Dual MicroRNA to Cellular Prion Protein Inhibits Propagation of Pathogenic Prion Protein in Cultured Cells. AB - Prion diseases are fatal transmissible neurodegenerative disorders affecting humans and various mammals. In spite of intensive efforts, there is no effective cure or treatment for prion diseases. Cellular forms of prion protein (PrPC) is essential for propagation of abnormal isoforms of prion protein (PrPSc) and pathogenesis. The effect of an artificial dual microRNA (DmiR) on PrPC suppression and resultant inhibition of prion replication was determined using prion-infectible cell cultures: differentiated C2C12 culture and primary mixed neuronal and glial cells culture (MNGC). Processing of DmiR by prion-susceptible myotubes, but not by reserve cells, in differentiated C2C12 culture slowed prion replication, implying an importance of cell type-specific PrPC targeting. In MNGC, reduction of PrPC with DmiR was effective for suppressing prion replication. MNGC lentivirally transduced with non-targeting control miRNAs (scrambled) reduced prion replication at a level similar to that with a synthetic analogue of viral RNA, poly I:C. The results suggest that a synergistic combination of the immunostimulatory RNA duplexes (miRNA) and PrPC silencing with DmiR might augment a therapeutic potential of RNA interference. PMID- 28357808 TI - PKMzeta Is Not Required for Development of Postsurgical Pain. AB - Previous studies have shown that protein kinase M zeta (PKMzeta), a brain specific isoform of protein kinase C, is involved in the central processing of nociception in several pain models by using a synthetic zeta inhibitory peptide. In the present study, we investigated whether PKMzeta contributes to the pathogenesis of postsurgical pain using both conditional and conventional PKMzeta knockout mice. Our results showed that the expression of PKMzeta in anterior cingulate cortex, but not spinal cord, of the conditional PKMzeta knockout mice was inhibited following tamoxifen injection. And the conditional PKMzeta knockout mice displayed similar plantar incision-produced postsurgical pain responses as those in wild-type mice. Moreover, the expression of PKMzeta was inhibited in both anterior cingulate cortex and spinal cord of the conventional PKMzeta knockout mice. And there were no significant differences in the development of postsurgical pain among wild-type, heterozygous, and homozygous conventional PKMzeta knockout mice. These data suggest that PKMzeta is not required for the development of postsurgical pain after plantar incision. PMID- 28357810 TI - Erratum to: Scintigraphic outlook of patients and regions with myocardial necrosis at myocardial perfusion scintigraphy. PMID- 28357811 TI - Use of fluorine-18 sodium fluoride for the diagnosis of transthyretin cardiac amyloidosis: The birth of a new technique. PMID- 28357809 TI - Neuroprotective Effects of Temsirolimus in Animal Models of Parkinson's Disease. AB - Parkinson's disease (PD) is a disorder caused by degeneration of dopaminergic neurons. At the moment, there is no cure. Recent studies have shown that autophagy may have a protective function against the advance of a number of neurodegenerative diseases. Temsirolimus is an analogue of rapamycin that induces autophagy by inhibiting mammalian target of rapamycin complex 1. For this purpose, in the present study we investigated the neuroprotective effects of temsirolimus (5 mg/kg intraperitoneal) on 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced (MPTP) neurotoxicity in in vivo model of PD. At the end of the experiment, brain tissues were processed for histological, immunohistochemical, Western blot, and immunofluorescent analysis. Treatment with temsirolimus significantly ameliorated behavioral deficits, increased the expression of specific markers of PD such as tyrosine hydroxylase, dopamine transporter, as well as decreased the upregulation of alpha-synuclein in the substantia nigra after MPTP induction. Furthermore, Western blot and immunohistochemistry analysis showed that temsirolimus administration significantly increased autophagy process. In fact, treatment with temsirolimus maintained high Beclin-1, p62, and microtubule-associated protein 1A/1B-light chain 3 expression and inhibited the p70S6K expression. In addition, we showed that temsirolimus has also anti-inflammatory properties as assessed by the significant inhibition of the expression of mitogen-activated protein kinases such as p-JNK, p-p38, and p-ERK, and the restored levels of neurotrophic factor expression such as BDNF and NT-3. On the basis of this evidence, we clearly demonstrate that temsirolimus is able to modulate both the autophagic process and the neuroinflammatory pathway involved in PD, actions which may underlie its neuroprotective effect. PMID- 28357812 TI - Clinical performance of Rb-82 myocardial perfusion PET and Tc-99m-based SPECT in patients with extreme obesity. AB - BACKGROUND: We evaluated the performance of stress imaging with technetium-99m labeled tetrofosmin single-photon emission computed tomography (SPECT) and rubidium-82 positron emission tomography (PET) in patients with extreme obesity, defined as body mass index >=40 kg/m2. METHODS: We identified patients with extreme obesity who underwent angiography in our center and either stress SPECT or PET within the previous six months. Cohorts of patients with extreme obesity and a <5% pretest likelihood of CAD who underwent SPECT (N = 25) or PET (N = 25) were also included. RESULTS: In total, 108 patients who underwent SPECT (N = 57) or PET (N = 51) were identified. Scan interpretation was classified as definitely normal or abnormal in 83.3% of PET and 60.5% of SPECT scans, respectively (P < .01). PET demonstrated higher diagnostic accuracy and normalcy rate. PET was found to have higher specificity for the pooled cohort. Similar findings were observed using stenosis cut-offs of >=50% and >=70%. CONCLUSIONS: In patients with extreme obesity, PET enabled more definitive scan interpretation with less artifact compared to SPECT. PET provided higher diagnostic accuracy and specificity in the detection of obstructive coronary artery disease. PMID- 28357814 TI - Before hierarchy: the rise and fall of Stephen Jay Gould's first macroevolutionary synthesis. AB - Few of Stephen Jay Gould's accomplishments in evolutionary biology have received more attention than his hierarchical theory of evolution, which postulates a causal discontinuity between micro- and macroevolutionary events. But Gould's hierarchical theory was his second attempt to supply a theoretical framework for macroevolutionary studies-and one he did not inaugurate until the mid-1970s. In this paper, I examine Gould's first attempt: a proposed fusion of theoretical morphology, multivariate biometry and the experimental study of adaptation in fossils. This early "macroevolutionary synthesis" was predicated on the notion that parallelism and convergence dominate the history of higher taxa, and moreover, that they can be explained in terms of adaptation leading to mechanical improvement. In this paper, I explore the origins and contents of Gould's first macroevolutionary synthesis, as well as the reasons for its downfall. In addition, I consider how various developments during the mid-1970s led Gould to identify hierarchy and constraint as the leading themes of macroevolutionary studies-and adaptation as a macroevolutionary red herring. PMID- 28357813 TI - Rate of Adverse Effects of Medium- to High-Dose Glucocorticoid Therapy in Systemic Lupus Erythematosus: A Systematic Review of Randomized Control Trials. AB - BACKGROUND AND OBJECTIVES: The efficacy of glucocorticoids (GCs) in treating systemic lupus erythematosus (SLE) is beyond doubt. However, GCs-related adverse effects (AEs) are multiple and serious. Despite the current available evidence suggesting to reduce daily doses of prednisone <7.5 mg/day, or even to withdraw it, in the real-life practice, it is not uncommon to see patients receiving medium doses (up to 30 mg/day prednisone or equivalent) or high doses (>=30 mg/day). METHODS: We systematically reviewed the literature with a priori strategy, to assess the rate of AEs related to medium or high doses of GCs in patients with SLE, analyzing randomized control trials with at least one of the treatment groups including GCs alone at medium or high doses. RESULTS: We found a rate of 9/100 patients/year for hyperglycemias/diabetes, 25/100 patients/year for infections, and 12/100 patients/year for avascular necrosis of the hip. Interestingly, when adjusting for GC dose and treatment duration, we observed no difference in terms of AEs comparing patients receiving medium versus high doses. CONCLUSIONS: In the era when treat-to-target strategies have been proposed in order to control SLE disease activity, improved health-related quality of life, and reduced morbidity and mortality, using GCs in a more restrictive way should be a goal to prevent major complications in patients with SLE. PMID- 28357815 TI - Agenesis of the left hepatic lobe undergoing laparoscopic hepatectomy for hepatocellular carcinoma: a case report. AB - BACKGROUND: Agenesis of the left hepatic lobe is a rare anomaly. It is defined as the absence of liver tissue to the left of the gallbladder fossa. Additionally, agenesis of the left hepatic lobe accompanied by hepatocellular carcinoma is quite rare. We experienced the case of a patient with agenesis of the left hepatic lobe, undergoing laparoscopic hepatectomy for HCC. CASE PRESENTATION: A 79-year-old man was referred to our department with epigastralgia. Abdominal computed tomography revealed agenesis of the left hepatic lobe, accompanied by hepatocellular carcinoma in segments 7 and 8. He underwent laparoscopic partial hepatectomy of segments 7 and 8. The operative findings revealed complete agenesis of the liver to the left of the falciform ligament. The patient had a favorable clinical course without liver dysfunction or any complications. CONCLUSIONS: We experienced a case with agenesis of the left hepatic lobe undergoing laparoscopic hepatectomy for HCC. Awareness of such anomaly is important for surgeons to avoid postoperative complications. PMID- 28357816 TI - Metastatic mixed acinar-endocrine carcinoma of the pancreas treated with a multidisciplinary approach: a case report. AB - BACKGROUND: Pancreatic neoplasms are usually characterized by ductal, acinar, or endocrine differentiation. Mixed exocrine and endocrine pancreatic tumours are extremely rare. Here, we report a case of pancreatic mixed acinar-endocrine carcinoma (MAEC) with multiple synchronous liver metastases that were treated with surgery and transcatheter arterial chemoembolization (TACE) that later recurred in the stomach. CASE PRESENTATION: A 45-year-old female with severe anaemia was referred to our hospital. Computed tomography (CT) demonstrated a hypervascular tumour, 17 cm in diameter, that was in the tail of the pancreas. In addition, there were multiple hypervascular tumours in the liver. She underwent a distal pancreatectomy with splenectomy after the liver metastases were treated with TACE. Pathology confirmed that the pancreatic tumour was MAEC. After 4.5 years, a follow-up CT showed a hypervascular tumour at the upper part of the stomach. Gastric endoscopy showed a big tumefactive lesion with surface irregularities, gastric erosion, and multiple dilated vessels in the fornix and greater curvature of the stomach. She underwent a proximal gastrectomy and survived 7 years and 2 months after the start of the treatment. CONCLUSIONS: This is the first report of a metastatic stomach tumour from pancreatic MAEC, which was successfully treated with a multidisciplinary approach. Additionally, we review the literature and discuss the treatment of MAEC. PMID- 28357817 TI - A Database of Transition-Metal-Coordinated Peptide Cross-Sections: Selective Interaction with Specific Amino Acid Residues. AB - Ion mobility mass spectrometry (IMS-MS) techniques were used to generate a database of 2288 collision cross sections of transition-metal-coordinated tryptic peptide ions. This database consists of cross sections for 1253 [Pep + X]2+ and 1035 [Pep + X + H]3+, where X2+ corresponds to Mn2+, Co2+, Ni2+, Cu2+, or Zn2+. This number of measurements enables the extraction of structural trends for transition-metal-coordinated peptide ions. The range of structures and changes in collision cross sections for X2+-coordinated species (compared with protonated species of the same charge state) is similar to Mg2+-coordinated species. This suggests that the structures are largely determined by similarities in cation size with differences among the cross section distributions presumably caused by X2+ interactions with specific functional groups offered by the residue R-groups or the peptide backbone. Cross section contributions for individual residues upon X2+ solvation are assessed with the derivation of intrinsic size parameters (ISPs). The comparison of the [Pep + X]2+ ISPs with those previously reported for [Pep + Mg]2+ ions displays a lower contribution to the cross section for His, carboxyamidomethylated Cys, and Met, and is consistent with specific metal residue interactions identified within protein X-ray crystallography databases. Graphical Abstract ?. PMID- 28357818 TI - Otitis externa in military divers: more frequent and less harmful than reported. AB - INTRODUCTION: Although otitis externa (OE) is a common disease, data related to (military) divers are limited. This study aimed to determine the incidence of OE in military divers during their initial training. We also wished to consider seasonal influences on incidence and whether early detection increases completion of the diving course. METHODS: From January 2011 to October 2016 the Royal Netherlands Navy Diving School trained 189 divers. Up to December 2015 we used the training records for the analyses. From January 2016 onward all divers were prospectively screened. Pearson's chi-squared 2 and Fisher's exact tests were used to analyse the data. RESULTS: In the 162 included divers, 30 cases of OE were identified. The incidence in 2016 was significantly higher than in 2011-2015 (17/35 (49%) versus 13/127 (10%), P < 0.001). Almost all cases developed after three weeks of diving. No influence of season was found (P = 0.354). Early diagnosis and treatment of OE does not seem to affect completion of diving courses (P = 0.28). Only in three cases did a diver have to discontinue the course due to OE. DISCUSSION: This study suggests that OE is more frequent among military divers than earlier reported, most likely caused by prolonged water exposure. Diving activities can often be continued with standard topical treatment. PMID- 28357819 TI - A comparative evaluation of two decompression procedures for technical diving using inflammatory responses: compartmental versus ratio deco. AB - INTRODUCTION: The aim of this study was to compare two decompression procedures commonly adopted by technical divers: the ZH-L16 algorithm modified by 30/85 gradient factors (compartmental decompression model, CDM) versus the 'ratio decompression strategy' (RDS). The comparison was based on an analysis of changes in diver circulating inflammatory profiles caused by decompression from a single dive. METHODS: Fifty-one technical divers performed a single trimix dive to 50 metres' sea water (msw) for 25 minutes followed by enriched air (EAN50) and oxygen decompression. Twenty-three divers decompressed according to a CDM schedule and 28 divers decompressed according to a RDS schedule. Peripheral blood for detection of inflammatory markers was collected before and 90 min after diving. Venous gas emboli were measured 30 min after diving using 2D echocardiography. Matched groups of 23 recreational divers (dive to 30 msw; 25 min) and 25 swimmers were also enrolled as control groups to assess the effects of decompression from a standard air dive or of exercise alone on the inflammatory profile. RESULTS: Echocardiography at the single 30 min observation post dive showed no significant differences between the two decompression procedures. Divers adopting the RDS showed a worsening of post-dive inflammatory profile compared to the CDM group, with significant increases in circulating chemokines CCL2 (P = 0.001) and CCL5 (P = 0.006) levels. There was no increase in chemokines following the CDM decompression. The air scuba group also showed a statistically significant increase in CCL2 (P < 0.001) and CCL5 (P = 0.003) levels post dive. No cases of decompression sickness occurred. CONCLUSION: The ratio deco strategy did not confer any benefit in terms of bubbles but showed the disadvantage of increased decompression-associated secretion of inflammatory chemokines involved in the development of vascular damage. PMID- 28357820 TI - Preventive effect of rosiglitazone on liver injury in a mouse model of decompression sickness. AB - BACKGROUND AND AIMS: Severe decompression sickness (DCS) is a multi-organ injury. This study investigated the preventive effects of rosiglitazone on liver injury following rapid decompression in mice and examined the underlying mechanisms. METHODS: Mice were randomly divided into four groups: a control group, vehicle group, and rosiglitazone (5 and 10 mg.kg-1) groups, the latter three being exposed to a pressure of 911 kPa. Haematoxylin and eosin staining, plasma levels of alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase and blood cell counts were used to evaluate liver injury at 30 min after rapid decompression. The expression of endothelial and inducible nitric oxide synthase (iNOS) and its phosphorylation were measured to uncover the underlying molecular mechanisms. RESULTS: A significant increase in plasma ALT, red blood cells and platelets, and a decrease in neutrophils were observed in the vehicle group. Furthermore, the expression of iNOS, E-selectin and the total level of NO in hepatic tissue, and soluble E-selectin in the plasma were significantly elevated in the vehicle group. Rosiglitazone pre-treatment prevented the increases in ALT (and AST), soluble E-selectin concentration, red blood cells and platelet counts. Moreover, rosiglitazone reduced over-expression of iNOS and the NO level, prevented the fall in neutrophil count and promoted the phosphorylation of iNOS in the liver. CONCLUSIONS: Pre-treatment with rosiglitazone ameliorated liver injury from severe DCS. This preventive effect may be partly mediated by stimulating endothelial NO production, improving endothelial function and limiting inflammatory processes. PMID- 28357821 TI - Tenth European Consensus Conference on Hyperbaric Medicine: recommendations for accepted and non-accepted clinical indications and practice of hyperbaric oxygen treatment. AB - The tenth European Consensus Conference on Hyperbaric Medicine took place in April 2016, attended by a large delegation of experts from Europe and elsewhere. The focus of the meeting was the revision of the European Committee on Hyperbaric Medicine (ECHM) list of accepted indications for hyperbaric oxygen treatment (HBOT), based on a thorough review of the best available research and evidence based medicine (EBM). For this scope, the modified GRADE system for evidence analysis, together with the DELPHI system for consensus evaluation, were adopted. The indications for HBOT, including those promulgated by the ECHM previously, were analysed by selected experts, based on an extensive review of the literature and of the available EBM studies. The indications were divided as follows: Type 1, where HBOT is strongly indicated as a primary treatment method, as it is supported by sufficiently strong evidence; Type 2, where HBOT is suggested as it is supported by acceptable levels of evidence; Type 3, where HBOT can be considered as a possible/optional measure, but it is not yet supported by sufficiently strong evidence. For each type, three levels of evidence were considered: A, when the number of randomised controlled trials (RCTs) is considered sufficient; B, when there are some RCTs in favour of the indication and there is ample expert consensus; C, when the conditions do not allow for proper RCTs but there is ample and international expert consensus. For the first time, the conference also issued 'negative' recommendations for those conditions where there is Type 1 evidence that HBOT is not indicated. The conference also gave consensus-agreed recommendations for the standard of practice of HBOT. PMID- 28357822 TI - An assessment of the performance of the Baxter elastomeric (LV10) InfusorTM pump under hyperbaric conditions. AB - INTRODUCTION: There are limited data on the use of elastomeric infusion pumps during hyperbaric oxygen treatment. AIM: This study evaluated the flow rate of the Baxter elastomeric LV10 InfusorTM pump under normobaric (101.3 kPa) and three hyperbaric conditions of 203 kPa, 243 kPa and 284 kPa. METHODS: Elastomeric pumps were secured to participants in the same manner as for a typical patient, except that a container collected the delivered antibiotic solution. Pumps and tubing were weighed before and after the test period to determine volume delivered and to calculate flow rates at sea level and the three commonly used hyperbaric treatment pressures at two different time periods, 0-2 hours (h) and 19-21 h into the infusion. RESULTS: The mean flow rates in ml.h-1 (SD) were: 9.5 (0.4), 10.3 (0.6), 10.4 (0.6), 10.4 (0.5) at 0-2 h and 10.5 (1.0), 12.2 (0.6), 9.4 (0.5), 10.3 (0.9) at 19-21 h for the normobaric, 203 kPa, 243 kPa and 284 kPa conditions respectively. There was no significant association between flow rate and time period (P = 0.166) but the 203 kPa flow rates were significantly faster than the other flow rates (P = 0.008). In retrospect, the 203 kPa experiments had all been conducted with the same antibiotic solution (ceftazidime 6 g). Repeating that experimental arm using flucloxacillin 8 g produced flow rates of 10.4 (0.8) ml.h 1, with no significant associations between flow rate and time period (P = 0.652) or pressure (P = 0.705). CONCLUSION: In this study, the flow rate of the Baxter LV10 InfusorTM device was not significantly affected by increases in ambient pressure across the pressure range of 101.3 kPa to 284 kPa, and flow rates were generally within a clinically acceptable range of 9-12 ml.h-1. However, there was evidence that the specific antibiotic solution might affect flow rates and this requires further study. PMID- 28357824 TI - Identifying and acting on inappropriate metadata: a critique of the Grattan Institute Report on questionable care in Australian hospitals. AB - INTRODUCTION: In an era of ever-increasing medical costs, the identification and prohibition of ineffective medical therapies is of considerable economic interest to healthcare funding bodies. Likewise, the avoidance of interventions with an unduly elevated clinical risk/benefit ratio would be similarly advantageous for patients. Regrettably, the identification of such therapies has proven problematic. A recent paper from the Grattan Institute in Australia (identifying five hospital procedures as having the potential for disinvestment on these grounds) serves as a timely illustration of the difficulties inherent in non clinicians attempting to accurately recognize such interventions using non clinical, indirect or poorly validated datasets. AIM: To evaluate the Grattan Institute report and associated publications, and determine the validity of their assertions regarding hyperbaric oxygen treatment (HBOT) utilisation in Australia. METHODS: Critical analysis of the HBOT metadata included in the Grattan Institute study was undertaken and compared against other publicly available Australian Government and independent data sources. The consistency, accuracy and reproducibility of data definitions and terminology across the various publications were appraised and the authors' methodology was reviewed. Reference sources were examined for relevance and temporal eligibility. RESULTS: Review of the Grattan publications demonstrated multiple problems, including (but not limited to): confusing patient-treatments with total patient numbers; incorrect identification of 'appropriate' vs. 'inappropriate' indications for HBOT; reliance upon a compromised primary dataset; lack of appropriate clinical input, muddled methodology and use of inapplicable references. These errors resulted in a more than seventy-fold over-estimation of the number of patients potentially treated inappropriately with HBOT in Australia that year. CONCLUSION: Numerous methodological flaws and factual errors have been identified in this Grattan Institute study. Its conclusions are not valid and a formal retraction is required. PMID- 28357823 TI - Performance of the BBraun perfusor space syringe driver under hyperbaric conditions. AB - BACKGROUND: The BBraun Perfusor SpaceTM syringe driver is already in use by ambulance services and retrieval teams but has not previously been assessed for hyperbaric chamber use. METHODS: Pump flow accuracy was tested at rates between 1 and 40 ml. h-1 using three different brands of 50 ml syringe. Function of the occlusion alarms was assessed using the same syringes. The hyperbaric profile involved pressurisation to 284 kPa at 30 kPa. min-1, 30 min at 284 kPa and decompression at 30 kPa. min-1. Output was recorded from differences in weight of collection containers. A single device was tested. RESULTS: Performance was highly dependent on the syringe type used, with two of the three 50 ml syringes used demonstrating 'stiction' at both low and high occlusion pressure alarm settings, most marked during pressurisation. On decompression from 284 kPa all syringes alarmed at significantly lower pressures. Because of the stiction problems only the flow measurements for the BBrown Omni! x 50 ml syringes are reported. At a pressure of 284 kPa, the difference between programmed and delivered rates was within the manufacturer's specification of 10%: at 40 ml. h-1 (median variation 1.25%, IQR 0.5-1.7%), 10 ml. h-1 (8.6%, IQR 8-9.2%), 5 ml. h-1 (-8.8%, IQR - 1.6-8.8%) and 1 ml. h-1 (-4%, IQR 4-12%). Pressurisation was associated with significantly lower flow rates whilst decompression was associated with significantly increased rates. Limited testing at 405 kPa was also within the manufacturer's specifications. CONCLUSION: A BBraun Infusor Space syringe driver performed within acceptable performance criteria but is highly dependent on syringe type and flow rates. The potential for the device to under deliver on pressurisation and over deliver on depressurisation, however, suggests vigilance and appropriate rate adjustments may be necessary during these phases. PMID- 28357826 TI - Anton's syndrome as a presentation of decompression illness. AB - We present a case of a patient with Anton's syndrome due to decompression illness (DCI) after recreational scuba diving. Visual anosognosia, or denial of loss of vision, which is associated with lack of awareness regarding visual loss in the setting of cortical blindness, is known as Anton's syndrome (also termed Anton Babinski syndrome). Our patient presented with progressive neurological DCI treated with repeated recompression. The anosogosia resolved after 48 h. Subsequent echocardiography revealed a persistent (patent) foramen ovale. PMID- 28357825 TI - The prevalence of electrocardiogram abnormalities in professional divers. AB - BACKGROUND: The underwater environment presents physiological challenges for the cardiovascular, renal and pulmonary systems. Increases in external hydrostatic pressure reduce the capacity of the venous compartment and cause blood to move toward the lung. The aim of this study was to evaluate retrospectively electrocardiographic (ECG) changes in a cohort of professional divers. METHODS: Between January 2009 and January 2012, 225 randomly selected professional divers, 204 male (91%) and 21 female (9%) attended our clinic for their biannual diving medical assessment. Their ECG records were evaluated retrospectively. RESULTS: The most common ECG abnormality observed was incomplete right bundle branch block (IRBBB) in 30 divers (13.3%). Eleven divers (4.9%) showed right QRS axis deviation (seven with IRBBB). Six divers had a sinus tachycardia; in four divers there was early repolarization; three divers had ventricular extrasystoles; one diver had ST elevation in lead V3; there was one with sinus arrhythmia and another with T-wave inversion in leads V2, V3 and aVF. These ECG changes were evaluated retrospectively by a cardiologist who made various recommendations for further review including bubble contrast echocardiography for IRBBB. CONCLUSIONS: No serious ECG abnormalities were identified, but IRBBB should be further investigated because of its association with persistent (patent) foramen ovale. Rapid cardiological review of ECGs could be achieved using modern communications technology, such as telecardiography, and further clinical investigations directed by specialist recommendation arranged promptly if indicated. PMID- 28357827 TI - USN Treatment Table 9. AB - The United States Navy (USN) introduced Treatment Table 9 (USN TT9) in 1999. Its purpose is to provide a dosing protocol for cases of incomplete resolution of decompression sickness (DCS) and arterial gas embolism following initial provision of USN Treatment Table 6 (USN TT6). It also can be used for several non diving-related acute toxicities. Prior to USN TT9, it was and remains common to use USN Treatment Table 5 (USN TT5) for 'follow-up' therapy. An exception might be cases of severe residual neurologic injury, where some prefer to repeat USN TT6. The primary role of USN TT5, however, is for treatment of 'pain only' (Type 1) DCS that has fully resolved within 10 minutes of the first oxygen breathing period at 60 feet of seawater (fsw) (284 kPa). It is thought helpful here to point out that USN TT9 offers certain safety and operational advantages over USN TT5. As USN TT9 employs a maximum pressure of 243 kPa, a marked risk reduction exists for the injured diver in terms of CNS oxygen toxicity. Seizures are reported during treatment of divers using US Navy protocols, some as early as the second and in one case during the first oxygen breathing period at 284 kPa (Mitchell SJ, personal communication, 2016). The inside attendant likewise enjoys an iatrogenic DCS risk reduction. While air breathing exposure time at 60 fsw on USN TT5 appears modest at first blush, the table can be extended at 30 fsw (203 kPa) for two additional oxygen/air cycles. Such extensions result in a not inconsiderable total exposure time of three hours. DCS risk is also increased if the treatment represents a repetitive dive for the attendant, a not uncommon event. Given the ongoing occurrence of inside attendant DCS, in some cases career ending and twice with fatal outcome, its mitigation should be aggressively pursued (author's personal files). From an operational perspective, both treatment pressure and sequencing of oxygen/air breathing cycles during delivery of USN TT9 are essentially identical to that commonly employed during multiplace chamber delivery of hyperbaric oxygen treatment. Accordingly, it is straightforward enough to incorporate follow-up decompression illness cases into daily clinical practice. Not having this dosing 'match', i.e., using USN TT5, might otherwise disrupt regularly scheduled cases. In my capacity as a medical claims adjudicator and clinical resource, I am involved, to varying degrees, in more than 300 cases of decompression illness each year. In those involving more than a single treatment, it is very much the exception, even after 17 years since its introduction, that USN TT9 is employed. The primary purpose of this correspondence, then, is to make mention of the advantages of USN TT9 and remind providers that it is indeed a standard of care in cases of incomplete relief for those who choose to base decompression injury management decisions on USN treatment procedures. PMID- 28357828 TI - Cerebral arterial gas embolism, ingestion of hydrogen peroxide and flight. AB - We read with interest the recent report by Smedley et al. on an interesting case of cerebral arterial gas embolism (CAGE) after pre-flight ingestion of hydrogen peroxide (H2O2). The authors discuss the safety of aero-medical transfer following H2O2 ingestion. We agree with the possible problems but the concern on the other side of the coin needs to be mentioned; can transfer be delayed is the big question? Indeed, as reported by others, ingestion of even a small amount of concentrated H2O2 can result in CAGE. Hence, whether aero-medical transfer proceeds or not, severe, life-threatening embolism can occur. Since it was reported that "complete neurologic recovery occurred quickly with hyperbaric therapy", this supports the contention that the fastest transfer of the patient for hyperbaric treatment should be the primary focus. PMID- 28357829 TI - Factors affecting health-promoting lifestyle profile in Iranian male seafarers working on tankers. AB - BACKGROUND: Seafaring is a risky occupation that is associated with a high incidence of lifestyle-related diseases. The present study was carried out to examine health promotion behaviour and its associated factors in seafarers of the National Iranian Tanker Company. MATERIALS AND METHODS: A cross-sectional study was performed on 200 Iranian male seafarers in 2015. A self-administered socio demographic and Health Promotion Lifestyle Profile II (HPLP-II) questionnaire was completed. One-way analysis of variance was used to identify significant differences among the various departments. The t-test was utilised to compare the HPLP-II scores according to the demographic variables. Multiple linear regression analysis was performed to assess the association between demographic variables and the overall HPLP-II score, in addition to the six health-promoting lifestyle subscale scores. RESULTS: The mean age of the participants was 35.93 +/- 9.51 years. Most of the seafarers were categorised as having a moderate (32%) or good lifestyle (61.5%). The mean lifestyle score was 136.14 +/- 19.90, with the subscale spiritual growth showing the highest score (26.16 +/- 5.03) and the subscale exercise behaviour showing the lowest score (19.95 +/- 4.23). The lowest score for nutrition was found among the seafarers working in the engine department (engine: 20.41 +/- 4.50, deck: 23.52 +/- 4.97, and galley: 24.83 +/- 4.64) (p < 0.05). Working in the engine department was found to have a significant negative effect on the nutrition score (B = -3.57, p < 0.05). Moreover, educational level was found to have a significant positive effect on spiritual growth (B = 2.97, p < 0.05). CONCLUSIONS: The findings suggest that health-related issues in this occupation, especially workers in the engine room, are a matter of concern. PMID- 28357830 TI - Preparation and medical follow-up for a single-handed transatlantic rowing race. AB - BACKGROUND: A single-handed transatlantic rowing race was organised between Senegal and French Guyana (2600 nautical miles). During the race, rowers adjust their lifestyle to maintain an optimal level of performance. Nutrition, circadian rhythm disturbance, psychological state, pain and other medical problems impact on physical abilities and increase the occurrence of accidents. We surveyed the prevalence of medical complications during this race and the preparation that we could suggest for this kind of activity. MATERIALS AND METHODS: This is a descriptive, retrospective case series study. Follow-up consisted of sending out a questionnaire and performing individual interviews. RESULTS: A total of 23 participants including 1 woman and 22 men; mean age of 46.5 years (range: 35-59) entered the race. The race lasted for 39 to 52 days with participants rowing between 10 and 12 h/day. Nine participants dropped out. Energy intake was 4500 to 6000 kcal/day and fluid intake was 4 to 5.5 L/day. Mean weight loss was 13.3 kg. The resting period was 6 +/- 1 h/24 h divided into 1.5 to 2 h periods essentially during darkness. A total of 92% of the racers required medical care for dermatological problems; other conditions requiring medical care were: tendinitis in 10 cases, diarrhoea in 4, moderate to severe seasickness in 4, hallucinations in 3, panic attacks in 2, burns in 2, and disembarkation syndrome ("land sickness") lasting from 45 min to 6 h in 13. CONCLUSIONS: Physiological and psychological impact of this type of event is still unclear. The most common medical problems are dermatological, rheumatological complications and minor trauma. Medical and psychological preparation should be offered to candidates for these competitions. PMID- 28357831 TI - Mermaid health - identifying health issues related to mermaiding. AB - BACKGROUND: Mermaiding - swimming with a leg-covering monofin mimicking the tail of a mermaid - is an emerging aquatic activity, which has gained a marked popularity over the last few years. However, no study so far has documented the potential health issues or risks of injuries related to this practice. MATERIALS AND METHODS: This study surveyed professional mermaids cumulating an estimated total of 19,147 h of in-water mermaiding, regarding their health issues and injuries. While mermaiding bears some risks, the occurrence of problematic conditions appears limited. Interestingly, the profile of health issues experienced by professional mermaids is unique and specific, and clearly different from both professional swimmers and surfers. RESULTS: Self-reported health issues related to mermaiding could be divided into issues specifically related to mermaiding activities (ear issues, reported by 87.5% of the respondents; sea life encounters, 50%; cold-related issues, 37.5%; compromised access to air, 25%), issues related to the tail and fins (back pain, 50%; lower limbs issues, 37.5%), and issues related to water quality (eye issues, 25%; waterborne diseases, 12.5%). Clear differences appear between professional and recreational mermaiding activities. CONCLUSIONS: The results presented here will help to build safer conditions for mermaiding activities and to develop adapted responses from health specialists to help this unique yet growing population of aquatic performers and athletes. PMID- 28357832 TI - Prevalence of consumption of addictive substances amongst Moroccan fishermen. AB - BACKGROUND: The prevalence of toxic habits is constantly increasing in developing countries and all professional sectors are concerned. Seafarers are a particular target because of the dangerousness and complexity of their work. However, few studies have investigated toxic habits in this population. The aim of the study was to determine the prevalence of the use and misuse of addictive substances in seafarers and to appreciate poly-consumptions according to socio-demographic and occupational characteristics. MATERIALS AND METHODS: This cross-sectional study was conducted amongst 1,219 fishermen. Subjects filled a questionnaire during their medical examination. The questionnaire covered socio-demographic and occupational characteristics, toxic habits (tobacco, alcohol, cannabis and others psychotropic substances). The misuse was assessed by specific tests: dependence on smoking tobacco (Fagerstrom), Cannabis Abuse Screening Test (CAST) and Alcohol Use Disorders Identification Test (AUDIT). RESULTS: The prevalence of consumption was 58.5% for smoking tobacco, 36.2% for cannabis, and 36.5% for alcohol. Amongst consumers, the prevalence of dependence or misuse was 49% for smoking tobacco, 61.2% for cannabis and 86% for alcohol. Only 115 (9.4%) people had no toxic habit. 56.4% had one toxic habit, 20.4% had two toxic habits, 11.9% had three toxic habits and 1.9% had four toxic habits. The most frequent associations were tobacco-cannabis (10.5%) and tobacco-alcohol (6.1%). CONCLUSIONS: In this sector, occupational health physicians have to play a key role in raising awareness and fighting against toxic habits. PMID- 28357834 TI - Analysis of occupational injuries in the sea fishing industry according to the type of fishery and the fishing activity. AB - BACKGROUND: Sea fishing is one of the most dangerous occupations. Numerous studies have already sought to evaluate the risk level of this occupation through the analysis of the frequency and seriousness of occupational injuries. The purpose of the present study is to analyse these accidents in terms of two main characteristics of the vessels involved: the fishery type (high seas, offshore, coastal, or inshore fishery) and the fishing activity (use of passive or active gears). MATERIALS AND METHODS: Injury rates were calculated for the Brittany region and for the year 2012. A second analysis was carried out on 8,286 reported injuries that occurred in France from 2002 to 2012, while vessels were in the process of fishing. RESULTS: This first analysis shows that the incidence rate is very high (103 per 1,000 full-time equivalent fishermen) and that it depends more on the fishery type than on the fishing activity; the highest rates concern the offshore and the coastal fleets. Results of the second analysis show that the nature of accidents depends more on the fishing activity than on the type of fishery. CONCLUSIONS: These findings lead to a discussion of the causes of the highest incidence rate values and the causes of the observed variations. The discussion also involves the methodological difficulties related to the incidence rate calculations. PMID- 28357833 TI - The assessment of seafarers' knowledge, attitudes and practices related to STI/HIV/AIDS in northern Morocco. AB - BACKGROUND: The purpose of this study was to assess the knowledge, attitudes and practices of seafarers in relation to sexually transmitted infections (STI) and human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS). MATERIALS AND METHODS: This transversal, descriptive and behavioural study was conducted in 2014 on a representative sample of 1447 seafarers. RESULTS: The rate of participation was 95%. The mean age was 36.1 +/- 8.2 years. Knowledge about transmission and prevention mode was satisfactory on HIV/AIDS; however, some misconceptions still persist. The level of stigmatisation and discrimination towards people living with the virus was considered high. The prevalence of sexual high-risk behaviour was significant: 32% had at least two sexual partners and 26.3% have had sex with sex workers, 60% of them were not protected; 42.8% have never used the condom and only 15.1% used it systematically. The sailors who had sexual intercourse under the influence of alcohol or drugs are less protected. As too HIV testing, only 10.2% did it. CONCLUSIONS: This study showed a gap in knowledge about transmission and prevention of HIV infection/AIDS and sexual risk behaviour. Increasing awareness and information among seafarers is of prime importance. PMID- 28357835 TI - Identification of World Health Organisation ship's medicine chest contents by Anatomical Therapeutic Chemical (ATC) classification codes. AB - BACKGROUND: Ships should carry mandatory given amounts of medicinal products and basic first aid items, collectively known as the ship's medicine chest. Type and quantities of these products/items are suggested by the World Health Organisation (WHO) and regulated by individual flag states. In countries that lack national legislation, it is assumed that ships should follow WHO indications. An objective difficulty mainly involving vessels of international long-haul routes could be to recognise medicinal compounds obtained in other countries for replacing products used or expired. Language barrier may complicate, if not make it impossible to interpret the name of the medicinal product and/or of the active principle as indicated in a box printed in a completely different language. Handling of the ship's pharmacy may be difficult in case of purchasing of drugs abroad due to language barriers. Medicinal products are identified by the international non proprietary name of the active principle and/or by their chemical or invented (branded) names. This may make the identification of a medicinal product difficult, primarily if it is purchased abroad and the box and instructions are written in the language of the country where it is marketed. Therefore, there is a simpler classification system of the medicinal compounds the ATC (ATC: Anatomy, Therapeutic properties, Chemical, pharmacological properties). This paper has reviewed the list of medicinal products recommended by WHO and assigned to each one the ATC code as a solution to the problem of medicinal compounds organisation. MATERIALS AND METHODS: Two researchers independently examined the list of medicinal compounds indicated in the third edition of the International Medical Guide for Ships and attributed to each compound the ATC code according to the 2013 Guidelines for ATC classification and Defined Daily Dose (DDD) assignment. RESULTS: The ATC code was attributed to the medicinal compounds indicated in the third edition of the International Medical Guide for Ships. CONCLUSIONS: The availability of an objective system to identify medicinal products is required for ships, which will contribute in making the identification of items purchased simpler, making it easier to understand which drug seafarers need to be administer, and consequently reduce possible therapeutic mistakes. PMID- 28357836 TI - Safety of hyperbaric oxygen therapy in mechanically ventilated patients. AB - BACKGROUND: To evaluate the epidemiology of patients who require mechanical ventilation during hyperbaric oxygen therapy. MATERIALS AND METHODS: One-hundred fifty patients who required mechanical ventilation during hyperbaric oxygen therapy were prospectively studied during a 6-year period in a French university hyperbaric centre. We analysed the indication of hyperbaric oxygen therapy, agent used for sedation, presence of a chest tube, need for vasopressor agents and tolerance and appearance of side effects. Finally, we compared the outcomes of patients according to the presence or absence of acute respiratory distress syndrome (ARDS). RESULTS: Eleven children and 139 adult patients were included (n = 150) in the study. In both populations, carbon monoxide poisoning (51%) and iatrogenic gas embolism (33%) were the two main causes of intubation and mechanical ventilation. The combination of midazolam and sufentanil was used in 85 (67%) patients. All of the patients were given a bolus of a neuromuscular blocker during the hyperbaric session, despite the presence of ARDS in 35 patients. Patient-ventilator asynchrony was the most frequent side effect in 6 (5%) patients and was often the consequence of suboptimal sedation. Mortality was higher in the group with ARDS (23%). CONCLUSIONS: Carbon monoxide poisoning and iatrogenic gas embolism are the two main diseases of the patients who required mechanical ventilation during hyperbaric oxygen therapy in this study. Mechanical ventilation is a safe method for patients during hyperbaric oxygen therapy. Sedation needs to be perfected to avoid patient-ventilator asynchrony. PMID- 28357838 TI - Female professional divers. Similarities and differences between male and female professional divers. AB - BACKGROUND: The aim of the present study was to explore the potential differences between female and male professional divers with regards to demographics, diving certificates, areas of diving, diving activity and health effects. MATERIALS AND METHODS: The Norwegian Labour Inspection Authority's Diving certificate register contains data on all professional inshore divers who have held a certificate at any time since 1980. Forty nine per cent of these divers responded to the "Norwegian diver 2011" questionnaire. RESULTS: Of these divers 64 female and 1327 male divers completed the questionnaire about their professional diving career, certificate, year of onset and the year they stopped diving professionally if they were not still active in the diving industry. The level of general education was higher among female divers. More males than females were fully certified in diving. The mean age was lower among female than male fully certified divers. Fully certified female divers reported a lower total number of dives, shallower dives and diving for a shorter period of time than the male divers. They also had a lower percentage of work within the quay/construction sector and more often worked as teachers/instructors. A lower percentage of fully certified females than males had experienced decompression sickness (16.7% vs. 26.9%). Life threatening events and psychologically challenging events were less common among females, as were adverse health effects. No such gender differences were seen for divers with a restricted certificate. CONCLUSIONS: The fully certified, female professional divers in our study had a very short diving career, reported fewer and shallower dives, and chose less physically demanding jobs than their male counterparts. They also had a higher level of education, reported less health problems and a better quality of life. The health effects seem to be related to the type of work rather than to gender. PMID- 28357837 TI - Diving under the influence: issues in researching personality and inert gas narcosis. AB - BACKGROUND: This paper considers the relationship between measures of personality and mood states, and susceptibility to inert gas narcosis. It briefly reviews the topics of inert gas narcosis affecting personality, and personality affecting the susceptibility to inert gas narcosis. There appears to be is a theoretical argument for a possible relationship between measures of personality, mood states, and susceptibility to narcosis. Practically, such a relationship may speak to issues in selection, training and preparation, risk assessments, and even accident investigation in the diving and/or hyperbaric environment. MATERIALS AND METHODS: Twenty one divers completed measures of personality and mood states, and were then compressed to 709 kPa (equivalent to 60 msw) in a dry compression chamber, where they completed a task measuring speed of information processing, and a scale measuring subjective narcosis. RESULTS AND CONCLUSIONS: The main finding was the absence of any significant correlations between measures of personality traits and mood, and susceptibility to inert gas narcosis. Although the study found no evidence of any major relationship, it is presented as a case study to highlight some of the issues and pitfalls involved in such research. The lessons learned - including the careful defining and describing of concepts, and choosing of samples and measurements - are used to discuss some of the methodological and conceptual issues and future directions for researchers to consider. PMID- 28357839 TI - Should we be worried about sexual transmission of Zika and other arboviruses? PMID- 28357840 TI - Possible outbreak of skin infections due to Panton-Valentine leukocidin-positive methicillin-resistant Staphylococcus aureus on a commercial ship in 2012-2014. PMID- 28357841 TI - The Maritime Labour Convention, 2006, as an ally for International Maritime Health Association. PMID- 28357842 TI - Acute Kidney Injury in Critically Ill Children and Young Adults. PMID- 28357843 TI - Shortened Antimicrobial Treatment for Acute Otitis Media. PMID- 28357844 TI - Shortened Antimicrobial Treatment for Acute Otitis Media. PMID- 28357845 TI - Shortened Antimicrobial Treatment for Acute Otitis Media. PMID- 28357846 TI - Myasthenia Gravis. PMID- 28357847 TI - Myasthenia Gravis. PMID- 28357848 TI - Myasthenia Gravis. PMID- 28357849 TI - Rhodium-Catalyzed Cycloadditions between 3-Diazoindolin-2-imines and 1,3-Dienes. AB - Azepino[2,3-b]indoles were regioselectively prepared through rhodium-catalyzed formal aza-[4 + 3] cycloaddition between 3-diazoindolin-2-imines and 1,3-dienes in moderate to good yields. Using 2-[(trimethylsilyl)oxy]-1,3-butadiene as the diene component, azepino[2,3-b]indol-4(1H)-ones were constructed. Furthermore, the reactions of cyclic dienes, such as 1,3-cyclohexadiene and 1,3 cyclopentadiene, furnished the corresponding [3 + 2] cycloaddition products. PMID- 28357851 TI - Synthesis and Characterization of Functionalized [12]Cycloparaphenylenes Containing Four Alternating Biphenyl and Naphthyl Units. AB - Functionalized [12]cycloparaphenylenes ([12]CPPs) containing four alternating biphenyl and naphthyl units were synthesized. A macrocyclic furan-containing CPP precursor was used for the Diels-Alder reaction with the parent benzyne or 3,6 dimethoxybenzyne to form the corresponding macrocyclic carbon frameworks. The subsequent reductive deoxygenation of the Diels-Alder adducts with Fe2(CO)9 followed by oxidative aromatization with 2,3-dichloro-5,6-dicyano-1,4 benzoquinone produced the functionalized [12]CPPs. The effect of macrocyclic ring size on the reaction rate of oxidative aromatization was investigated. PMID- 28357850 TI - The Influence of Intrinsic Framework Flexibility on Adsorption in Nanoporous Materials. AB - For applications of metal-organic frameworks (MOFs) such as gas storage and separation, flexibility is often seen as a parameter that can tune material performance. In this work we aim to determine the optimal flexibility for the shape selective separation of similarly sized molecules (e.g., Xe/Kr mixtures). To obtain systematic insight into how the flexibility impacts this type of separation, we develop a simple analytical model that predicts a material's Henry regime adsorption and selectivity as a function of flexibility. We elucidate the complex dependence of selectivity on a framework's intrinsic flexibility whereby performance is either improved or reduced with increasing flexibility, depending on the material's pore size characteristics. However, the selectivity of a material with the pore size and chemistry that already maximizes selectivity in the rigid approximation is continuously diminished with increasing flexibility, demonstrating that the globally optimal separation exists within an entirely rigid pore. Molecular simulations show that our simple model predicts performance trends that are observed when screening the adsorption behavior of flexible MOFs. These flexible simulations provide better agreement with experimental adsorption data in a high-performance material that is not captured when modeling this framework as rigid, an approximation typically made in high-throughput screening studies. We conclude that, for shape selective adsorption applications, the globally optimal material will have the optimal pore size/chemistry and minimal intrinsic flexibility even though other nonoptimal materials' selectivity can actually be improved by flexibility. Equally important, we find that flexible simulations can be critical for correctly modeling adsorption in these types of systems. PMID- 28357852 TI - Enhancement of Surface Wettability by Incorporating Polar Initiator Fragments at Chain Ends of Low-Molecular-Weight Polymers. AB - Simple methods for enhancing hydrophilicity of hydrocarbon polymers are of broad scientific and technological interest. Polystyrene was synthesized via free radical polymerization with initiator fragments incorporated at chain ends. Compared with high molecular weight polystyrene or chains with nonpolar ends, the dynamic receding water contact angle is reduced by as much as ~30 degrees in ~4 kg/mol polystyrene with -COOH and nitrile chain ends. This remarkable enhancement results in surface hydrophilicity that is higher than that of poly(methyl methacrylate). This effective methodology incorporating polar moieties at chain ends of nonpolar polymers can be adapted to existing formulations for enhanced surface properties. PMID- 28357853 TI - Total Synthesis and Structural Determination of the Dimeric Tetrahydroxanthone Ascherxanthone A. AB - The first total synthesis of the dimeric tetrahydroxanthone ascherxanthone A has been accomplished. This synthetic strategy features (1) enantioselective intramolecular allylic C-H oxidation to construct a core chiral chromane, (2) intramolecular aldol reaction/dehydration to form the enone group, and (3) intermolecular Suzuki-Miyaura coupling to connect two monomeric tetrahydroxanthones. This synthetic work allowed us to determine the axial chirality of the 2,2'-biaryl C-C bond and the absolute configuration of the ascherxanthone A. This approach should facilitate the preparation of derivatives and structurally related natural products for medicinal studies. PMID- 28357854 TI - DBU-Mediated Diastereoselective Aldol-Type Cyanomethylation of Isatins. AB - An efficient, metal-free approach to 3-substituted 3-hydroxyoxindole by DBU mediated highly diastereoselective addition of aryl acetonitrile to N-protected isatin under mild conditions has been developed. The reaction proceeds smoothly to produce respective cyanomethylated adducts in good yield and excellent diastereoselectivity. Further transformation of the cyanide group allowed the synthesis of an advance intermediate of corresponding (+/-) CPC analogue. The mechanistic insight toward the aldol-type cyanomethylation of N-tritylisatin with benzyl cyanide was obtained by DFT calculations. PMID- 28357855 TI - Single-Mode Lasing from "Giant" CdSe/CdS Core-Shell Quantum Dots in Distributed Feedback Structures. AB - "Giant" semiconductor quantum dots (GQDs) have tremendous potential for applications in laser devices. Here, CdSe/CdS core-shell GQDs (11 monolayers) have been synthesized as lasing gain material. The photoluminescence decay of the GQD ensemble is single-exponential, and the two-photon absorption cross-section is above 105 GM. This article presents a versatile method for fabrication of CdSe/CdS GQD distributed feedback (DFB) lasers by laser interference ablation. A high-quality surface-relief grating structure can be readily created on the GQD thin films, and the relationship between laser beam intensity and surface modulation depth is studied. With appropriate periods, single-mode lasing emission has been detected from these devices under excitation wavelengths of 400 and 800 nm. The laser thresholds are as low as 0.028 and 1.03 mJ cm-2, with the lasing Q-factors of 709 and 586, respectively. Lasing operation is realized from the direct laser interference-ablated QD DFB structures for the first time. PMID- 28357856 TI - Synthesis of Nickel Phosphide Electrocatalysts from Hybrid Metal Phosphonates. AB - Transition-metal phosphides (TMPs) have recently emerged as efficient and inexpensive electrocatalysts for electrochemical water splitting. The synthesis of nanostructured phosphides often involves highly reactive and hazardous phosphorous-containing compounds. Herein, we report the synthesis of nickel phosphides through thermal treatment under H2(5%)/Ar of layered nickel phenylphosphonate (NiPh) or methylphosphonate (NiMe) that act as single-source precursors. Ni12P5, Ni12P5-Ni2P, and Ni2P nanoparticles (NPs) with sizes of ca. 15-45 nm coated with a thin shell of carbonaceous material were produced. Thermogravimetric analysis coupled with mass spectrometry (TG-MS) showed that H2, H2O, P2, and -C6H5 are the main compounds formed during the transformation of the precursor under argon and no hazard phosphorous-containing compounds are created, making this a simple and relatively safe route for fabricating nanostructured TMPs. The H2 most likely reacts with the -PO3 groups of the precursor to form H2O and P2, and the latter subsequently reacts with the metal to produce the phosphide. The Ni12P5-Ni2P and Ni2P NPs efficiently catalyze the hydrogen evolution reaction (HER), with Ni2P showing the best performance and generating a current density of 10 mA cm-2 at an overpotential of 87 mV and exhibiting long term stability. Co2P and CoP NPs were also synthesized following this method. This approach may be utilized to explore the rich metal phosphonate chemistry for fabricating phosphide-based materials for electrochemical energy conversion and storage applications. PMID- 28357857 TI - Coupling Radical Homoallylic Expansions with C-C Fragmentations for the Synthesis of Heteroaromatics: Quinolines from Reactions of o-Alkenylarylisonitriles with Aryl, Alkyl, and Perfluoroalkyl Radicals. AB - Selective addition of radicals to isonitriles can be harnessed for initiating reaction cascades designed to overcome the stereoelectronic restrictions on homoallylic ring expansion in alkyne reactions and to develop a new general route for the preparation of N-heteroaromatics. This method utilizes alkenes as synthetic equivalents of alkynes by coupling homoallylic ring expansion to yield the formal "6-endo" products with aromatization via stereoelectronically assisted C-C bond scission. Computational analysis of the homoallyic expansion potential energy surface reveals that the indirect 5-exo/3-exo/retro-3-exo path is faster than the direct 6-endo-trig closure, revealing the general exo-preference for the cyclization processes. PMID- 28357859 TI - Electrostatic Repulsion between Unique Arginine Residues Is Essential for the Efficient in Vitro Assembly of the Transmembrane Domain of a Trimeric Autotransporter. AB - Haemophilus influenzae adhesin (Hia) belongs to the trimeric autotransporter family and mediates the adherence of these bacteria to the epithelial cells of host organisms. Hia contains a passenger and a transmembrane domain. The transmembrane domain forms a 12-stranded beta-barrel in which four strands are provided by each subunit. The beta-barrel has a pore that is traversed by three alpha-helices. This domain has a unique arginine cluster, in which the side chains of the three arginine residues located at position 1077 (Arg1077) protrude into the pore of the beta-barrel. This arrangement seems to be unfavorable for assembly, because of repulsion between the positive charges. In this study, we investigated the in vitro assembly of the Hia transmembrane minimum domain (mHiaTD) and found that the dissociated mHiaTD reassembled in detergent solution. To investigate the role of Arg1077 in trimer assembly, we generated mutant proteins in which Arg1077 was replaced with methionine or lysine. The reassembly kinetics of the mutants was compared with that of the wild-type protein. The methionine mutant showed misassembly, whereas the lysine mutant showed reversible assembly, similar to that observed for the wild-type protein. These results show that electrostatic repulsion between the positive charges of Arg1077 is important for preventing the formation of misassembled oligomers by the mHiaTD in vitro. PMID- 28357858 TI - Phosphoproteomic Analysis of Paper Mulberry Reveals Phosphorylation Functions in Chilling Tolerance. AB - Paper mulberry is a valuable woody species with a good chilling tolerance. In this study, phosphoproteomic analysis, physiological measurement, and mRNA quantification were employed to explore the molecular mechanism of chilling (4 degrees C) tolerance in paper mulberry. After chilling for 6 h, 427 significantly changed phosphoproteins were detected in paper mulberry seedlings without obvious physiological injury. When obvious physiological injury occurred after chilling for 48 h, a total of 611 phosphoproteins were found to be significantly changed at the phosphorylation level. Several protein kinases, especially CKII, were possibly responsible for these changes according to conserved sequence analysis. The results of Gene Ontology analysis showed that phosphoproteins were mainly responsible for signal transduction, protein modification, and translation during chilling. Additionally, transport and cellular component organization were enriched after chilling for 6 and 48 h, respectively. On the basis of the protein protein interaction network analysis, a protein kinase and phosphatases hub protein (P1959) were found to be involved in cross-talk between Ca2+, BR, ABA, and ethylene-mediated signaling pathways. We also highlighted the phosphorylation of BpSIZ1 and BpICE1 possibly impacted on the CBF/DREB-responsive pathway. From these results, we developed a schematic for the chilling tolerance mechanism at phosphorylation level. PMID- 28357860 TI - A G-Quadruplex Hydrogel via Multicomponent Self-Assembly: Formation and Zero Order Controlled Release. AB - Stimuli-sensitive hydrogels are ideal candidates for biomedical and bioengineering purposes, although applications of hydrogels may be limited, due in part to the limited choice of suitable materials for constructing hydrogels, the complexity in the synthesis of the source materials, and the undesired fast then-slow drug-release behaviors of usual hydrogels. Herein, we describe the fabrication of a new supramolecular guanosine (G)-quadruplex hydrogel by multicomponent self-assembly of endogenous guanosine (G), 2-formylboronic acid (2 FPBA), and tris(2-aminoethyl)amine (TAEA) in the presence of KCl in an easy and convenient way. The features of the G-quadruplex hydrogel include (1) versatility and commercial availability of building blocks with different functions, (2) dynamic iminoboronate bonds with pH and glucose responsiveness, and (3) zero order drug-release behavior because of the superficial peel-off of the hydrogel in response to stimuli. The structure, morphology, and properties of the G quadruplex hydrogel were well-characterized, and satisfactory zero-order drug release was successfully achieved. This kind of supramolecular G-quadruplex hydrogels may find applications in biological fields. PMID- 28357861 TI - Influence of the Hole Transporting Layer on the Thermal Stability of Inverted Organic Photovoltaics Using Accelerated-Heat Lifetime Protocols. AB - High power conversion efficiency (PCE) inverted organic photovoltaics (OPVs) usually use thermally evaporated MoO3 as a hole transporting layer (HTL). Despite the high PCE values reported, stability investigations are still limited and the exact degradation mechanisms of inverted OPVs using thermally evaporated MoO3 HTL remain unclear under different environmental stress factors. In this study, we monitor the accelerated lifetime performance under the ISOS-D-2 protocol (heat conditions 65 degrees C) of nonencapsulated inverted OPVs based on the thiophene based active layer materials poly(3-hexylthiophene) (P3HT), poly[[4,8-bis[(2 ethylhexyl)oxy]benzo[1,2-b:4,5-b']dithiophene-2,6-diyl][3-fluoro-2-[(2 ethylhexyl)carbonyl]thieno[3,4-b]thiophenediyl]] (PTB7), and thieno[3,2 b]thiophene-diketopyrrolopyrrole (DPPTTT) blended with [6,6]-phenyl C71-butyric acid methyl ester (PC[70]BM). The presented investigation of degradation mechanisms focus on optimized P3HT:PC[70]BM-based inverted OPVs. Specifically, we present a systematic study on the thermal stability of inverted P3HT:PC[70]BM OPVs using solution-processed poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) and evaporated MoO3 HTL. Using a series of measurements and reverse engineering methods, we report that the P3HT:PC[70]BM/MoO3 interface is the main origin of failure of the P3HT:PC[70]BM-based inverted OPVs under intense heat conditions, a trend that is also observed for the other two thiophene-based polymers used in this study. PMID- 28357862 TI - Bio-inspired Herringbone Foldamers: Strategy for Changing the Structure of Helices. AB - Cyclic oligomers of azole peptides were isolated from a multitude of marine organisms and were used for a large number of molecular machines. As shown previously, oligomers derived from achiral imidazole amino acids fold into canonical helices. Here we show that a minor change, the introduction of a methyl group in the delta position, results in a significant change in the secondary structure of the corresponding oligomers. Instead of a canonical helix, a noncanonical herringbone helix is formed. In the latter, the slope along the helix changes its sign at least twice per turn. This strategy allows a remarkable change of the secondary structure via a small modification. By means of enantiomerically pure amino acids, we were able to control, for the first time, both the helicity of the helix and the form of the herringbone. The investigation of the underlying herringbone basic element and its folding to a noncanonical helix were conducted by NMR and CD spectroscopy, as well as by X-ray crystallography and quantum chemical calculations. PMID- 28357863 TI - Functional Cryogel Microstructures Prepared by Light-Induced Cross-Linking of a Photoreactive Copolymer. AB - A novel, highly efficient method for the preparation of functional, microstructured and surface-attached cryogels is described. Photoinduced C,H insertion reactions are used to generate cryogels in a single, rapid photo-cross linking process. To this end, solutions containing both a photoreactive copolymer and the (bio)molecules to be immobilized are placed on a polymeric substrate followed by freezing and a short UV exposure. This strategy combines photolithography and cryogel formation allowing for a simultaneous generation and (bio)functionalization of cryogels in a single reaction step. To demonstrate the potential of the generated materials for bioanalytical applications, we successfully prepared DNA and protein cryogel microarrays. PMID- 28357864 TI - Synthesis of Isothiocyanates and Unsymmetrical Thioureas with the Bench-Stable Solid Reagent (Me4N)SCF3. AB - A highly efficient, selective, and rapid transformation of primary amines and diamines to isothiocyanates and cyclic thioureas is disclosed. As opposed to established approaches that employ toxic or volatile electrophilic liquids and require reaction control (i.e., slow addition, cooling), this protocol utilizes the bench-stable, solid reagent (Me4N)SCF3 at room temperature. The method is characterized by operational simplicity, high speed, efficiency, high functional group tolerance, and late-stage applicability. The byproducts are solids, allowing isolation of the target compounds by filtration. PMID- 28357865 TI - Phosphorus-Containing Bis-allenes: Synthesis and Heterocyclization Reactions Mediated by Iodine or Copper Dibromide. AB - Bisphosphorylallenes were easily obtained in multigram scale from the Wittig-type rearrangement of bispropargyl alcohols. Unlike other conjugated bis-allenes, these reagents underwent a double cyclization mediated by iodine or copper dibromide leading to the formation of bis-1,2-oxaphospholenes. PMID- 28357866 TI - Enantioselective Construction of the ABCDE Pentacyclic Core of the Strychnos Alkaloids. AB - An efficient enantioselective 12-step synthesis of the ABCDE pentacyclic core of the Strychnos alkaloids is described. A key feature of this approach is an organocatalyzed enantioselective desymmetrization to generate the morphan core in high ee and dr. After palladium-catalyzed installation of the indole moiety, a subsequent 5-exo-trig dearomatizing atom transfer radical cyclization was developed to construct the C-ring. Following a series of functional group interconversions, the pentacyclic amine core was obtained with all the relevant architecture including five stereocenters pertaining to the Strychnos alkaloids. PMID- 28357867 TI - Differentially Substituted Phosphines via Decarbonylation of Acylphosphines. AB - A new route to phosphines was developed by a method that features a "pre-join and transform" process that proceeds via acylphosphine intermediates that may be readily prepared from carboxylic acids and disubstituted phosphines. The efficient decarbonylations of these acylphosphines using a nickel catalyst delivered the corresponding phosphines. This method shows that the carboxyl group can play a role similar to halides or triflates for introducing a substituted phosphorus atom on an aromatic ring. PMID- 28357868 TI - Design and Applications of N-tert-Butyl Sulfinyl Squaramide Catalysts. AB - A new chiral HBD system, N-tert-butyl sulfinyl squaramide, was designed and synthesized. The core N-tert-butyl sulfinyl squaramide with an 1-aminoindan-2-ol skeleton was found to be an efficient catalyst in the enantioselective Friedel Crafts alkylation of indoles and acyl phosphonates. PMID- 28357869 TI - Role of Nanostructuring and Microstructuring in Silver Antimony Telluride Compounds for Thermoelectric Applications. AB - Thermoelectric (TE) materials are of utmost significance for conversion of heat flux into electrical power in the low-power regime. Their conversion efficiency depends strongly on the microstructure. AgSbTe2-based compounds are high efficiency TE materials suitable for the mid-temperature range. Herein, we explore an Ag16.7Sb30Te53.3 alloy (at %) subjected to heat treatments at 380 degrees C for different durations aimed at nucleation and coarsening of Sb2Te3 precipitates. To characterize the Sb2Te3-precipitation, we use a set of methods combining thermal and electrical measurements in concert with transmission electron microscopy and atom probe tomography. We find correlations between the measured TE transport coefficients and the applied heat treatments. Specifically, the lowest electrical and thermal conductivity values are obtained for the as quenched state, whereas the highest values are observed for alloys aged for 8 h. In turn, long-term heat treatments result in intermediate values of transport coefficients. We explain these findings in terms of interplay between precipitate formation and variations in the matrix composition, highlighting the importance of thermal stability of the material under service conditions. PMID- 28357871 TI - A Novel PPh3 Mediated One-Pot Method for Synthesis of 3-Aryl or Alkyl 1,2 Benzisoxazoles. AB - A novel, efficient, and facile protocol has been developed for transforming 2 hydroxybenzonitriles and bromides into a range of 3-aryl or alkyl substituted 1,2 benzisoxazoles in good to excellent yields mediated by PPh3. The electronic and steric effects of bromides on the reaction are discussed. This is the first example to construct a C-C bond and heterocycle in a Barbier-Grignard-type reaction featuring easier recovery of PPh3 than a metallic catalyst in one step. PMID- 28357872 TI - Enantioselective Total Synthesis of (+)-Lysergol: A Formal anti Carbopalladation/Heck Cascade as the Key Step. AB - The enantioselective synthesis of (+)-lysergol was completed in 12 steps and an overall yield of 13% starting from a known literature precursor. The key step relies on a domino reaction containing a formal anti-carbopalladation, which is terminated by a beta-silyl-directed Heck reaction. During this transformation, the two six-membered rings of the ergot scaffold are formed in a completely stereospecific manner. PMID- 28357870 TI - Multicomponent Condensation Reactions via ortho-Quinone Methides. AB - Iron(III) salts promote the condensation of aldehydes or acetals with electron rich phenols to generate ortho-quinone methides that undergo Diels-Alder condensations with alkenes. The reaction sequence occurs in a single vessel to afford benzopyrans in up to 95% yield. The reaction was discovered while investigating a two-component strategy using 2-(hydroxy(phenyl)methyl)phenols to access the desired ortho-quinone methide in a Diels-Alder condensation. The two component condensation also afforded the corresponding benzopyran products in yields up to 97%. Taken together, the two- and three-component strategies using ortho-quinone methide intermediates provide efficient access to benzopyrans in good yields and selectivities. PMID- 28357873 TI - Optimal Hotspots of Dynamic Surfaced-Enhanced Raman Spectroscopy for Drugs Quantitative Detection. AB - Surface-enhanced Raman spectroscopy (SERS) as a powerful qualitative analysis method has been widely applied in many fields. However, SERS for quantitative analysis still suffers from several challenges partially because of the absence of stable and credible analytical strategy. Here, we demonstrate that the optimal hotspots created from dynamic surfaced-enhanced Raman spectroscopy (D-SERS) can be used for quantitative SERS measurements. In situ small-angle X-ray scattering was carried out to in situ real-time monitor the formation of the optimal hotspots, where the optimal hotspots with the most efficient hotspots were generated during the monodisperse Au-sol evaporating process. Importantly, the natural evaporation of Au-sol avoids the nanoparticles instability of salt induced, and formation of ordered three-dimensional hotspots allows SERS detection with excellent reproducibility. Considering SERS signal variability in the D-SERS process, 4-mercaptopyridine (4-mpy) acted as internal standard to validly correct and improve stability as well as reduce fluctuation of signals. The strongest SERS spectra at the optimal hotspots of D-SERS have been extracted to statistics analysis. By using the SERS signal of 4-mpy as a stable internal calibration standard, the relative SERS intensity of target molecules demonstrated a linear response versus the negative logarithm of concentrations at the point of strongest SERS signals, which illustrates the great potential for quantitative analysis. The public drugs 3,4-methylenedioxymethamphetamine and alpha-methyltryptamine hydrochloride obtained precise analysis with internal standard D-SERS strategy. As a consequence, one has reason to believe our approach is promising to challenge quantitative problems in conventional SERS analysis. PMID- 28357875 TI - A Study of the Effect of Surfactants on the Aggregation Behavior of Crude Oil Aqueous Dispersions through Steady-State Fluorescence Spectrometry. AB - Unconventional crude oil as heavy, extra heavy, bitumen, tight, and shale oils will meet 10% of worldwide needs for 2035, perhaps earlier. Petroleum companies will face problems concerning crude oil extraction, production, transport, and refining, and some of these are addressed by the use of surfactants and other chemicals. For example, water-in-crude oil emulsions are frequently found during the production of mature wells where enhanced recovery techniques have been deployed. Nevertheless, the selection of adequate surfactant, dosage, type of water (sea, tap or oilfield), kind of crude oil (light, heavy, extra heavy, tight, shale, bitumen) affect the effectivity of treatment and usual bottle tests give limited information. We developed a fluorescence technique to study the effect of surfactants on medium, heavy, and extra heavy crude oil employing the natural fluorophore molecules from petroleum. We first carried out the characterization of commercial and synthetic surfactants, then dispersions of petroleum in water were studied by steady-state fluorometry and the size of petroleum aggregates were measured. The aggregation of petroleum incremented from medium to extra heavy crude oil and we discussed the effect of different surfactants on such aggregation. PMID- 28357874 TI - Gender's Effects to the Early Symptoms of Alzheimer's Disease in 5 Asian Countries. AB - BACKGROUND: Asia has the greatest population and more patients with dementia in the world. Early recognition of clinical symptoms of Alzheimer's disease (AD) is crucial for dementia care. In order to foster collaboration in AD care, a uniformed manner to report the early clinical symptoms of AD is necessary. METHODS: We have recruited clinically diagnosed patients with AD at their very mild stage with Clinical Dementia Rating (CDR) 0.5 in Taiwan, Japan, China, Philippines, and Singapore. Demographic characteristics and psychometrics including Ascertain of Dementia-8 (AD8) questionnaire were administrated to collect and report the clinical presentation in these countries. RESULTS: In total, 713 clinically diagnosed patients with AD at very mild stage, CDR 0.5, have been recruited from these 5 countries. "Repeats questions, stories, or statements" were consistently the frequently reported symptom across these countries. Taiwan, China, and Singapore have the higher AD8 total score compared to that in Japan and Philippines. Japan and Philippines have the gender-related differences in clinical presentation of early AD. CONCLUSION: Difficulties in using small trouble appliance and in handling complicated financial affairs were frequently reported in Japan female, compared to male, patients with AD. Identifying the clinical symptom of AD and the gender-related issues would be crucial in the dementia care in Asia. PMID- 28357877 TI - Stimulated Raman Scattering Interferometer for Molecular-Selective Tomographic Imaging. AB - Development of a stimulated Raman scattering (SRS) interferometer is presented. In the apparatus, a SRS signal generated in a sample is collinearly overlapped with a reference beam, and the interference pattern between the signal and reference beams is obtained. From the interference pattern, the phase of the SRS signal can be measured. From the phase of the signal, the spatial distribution of the target molecule can be obtained with high positioning precision. In the present article, the SRS interferometer was developed and the first SRS interference signal was obtained from a polyethylene film. The phase change of the SRS interference pattern caused by scanning the sample position along the direction of the incident light propagation was measured. From the result, the sample position difference for a sub-micron was detected with uncertainties of 15%. The tomographic images of a triple-layered polymer film were successfully obtained. The SRS interferometer would become a core optical technique of a novel molecular-selective tomographic imaging method. PMID- 28357878 TI - Variation in the Inpatient Management of Pediatric Anaphylaxis. PMID- 28357876 TI - Noninvasive prenatal screening for fetal common sex chromosome aneuploidies from maternal blood. AB - Objective To explore the feasibility of high-throughput massively parallel genomic DNA sequencing technology for the noninvasive prenatal detection of fetal sex chromosome aneuploidies (SCAs). Methods The study enrolled pregnant women who were prepared to undergo noninvasive prenatal testing (NIPT) in the second trimester. Cell-free fetal DNA (cffDNA) was extracted from the mother's peripheral venous blood and a high-throughput sequencing procedure was undertaken. Patients identified as having pregnancies associated with SCAs were offered prenatal fetal chromosomal karyotyping. Results The study enrolled 10 275 pregnant women who were prepared to undergo NIPT. Of these, 57 pregnant women (0.55%) showed fetal SCA, including 27 with Turner syndrome (45,X), eight with Triple X syndrome (47,XXX), 12 with Klinefelter syndrome (47,XXY) and three with 47,XYY. Thirty-three pregnant women agreed to undergo fetal karyotyping and 18 had results consistent with NIPT, while 15 patients received a normal karyotype result. The overall positive predictive value of NIPT for detecting SCAs was 54.54% (18/33) and for detecting Turner syndrome (45,X) was 29.41% (5/17). Conclusion NIPT can be used to identify fetal SCAs by analysing cffDNA using massively parallel genomic sequencing, although the accuracy needs to be improved particularly for Turner syndrome (45,X). PMID- 28357879 TI - A Comparative Investigation of the Combined Effects of Pre-Processing, Wavelength Selection, and Regression Methods on Near-Infrared Calibration Model Performance. AB - Near-infrared (NIR) spectroscopy is being widely used in various fields ranging from pharmaceutics to the food industry for analyzing chemical and physical properties of the substances concerned. Its advantages over other analytical techniques include available physical interpretation of spectral data, nondestructive nature and high speed of measurements, and little or no need for sample preparation. The successful application of NIR spectroscopy relies on three main aspects: pre-processing of spectral data to eliminate nonlinear variations due to temperature, light scattering effects and many others, selection of those wavelengths that contribute useful information, and identification of suitable calibration models using linear/nonlinear regression . Several methods have been developed for each of these three aspects and many comparative studies of different methods exist for an individual aspect or some combinations. However, there is still a lack of comparative studies for the interactions among these three aspects, which can shed light on what role each aspect plays in the calibration and how to combine various methods of each aspect together to obtain the best calibration model. This paper aims to provide such a comparative study based on four benchmark data sets using three typical pre processing methods, namely, orthogonal signal correction (OSC), extended multiplicative signal correction (EMSC) and optical path-length estimation and correction (OPLEC); two existing wavelength selection methods, namely, stepwise forward selection (SFS) and genetic algorithm optimization combined with partial least squares regression for spectral data (GAPLSSP); four popular regression methods, namely, partial least squares (PLS), least absolute shrinkage and selection operator (LASSO), least squares support vector machine (LS-SVM), and Gaussian process regression (GPR). The comparative study indicates that, in general, pre-processing of spectral data can play a significant role in the calibration while wavelength selection plays a marginal role and the combination of certain pre-processing, wavelength selection, and nonlinear regression methods can achieve superior performance over traditional linear regression-based calibration. PMID- 28357880 TI - Diffuse Reflectance Spectroscopy of Hidden Objects, Part I: Interpretation of the Reflection-Absorption-Scattering Fractions in Near-Infrared (NIR) Spectra of Polyethylene Films. AB - Investigation of a sample covered by an interfering layer is required in many fields, e.g., for process control, biochemical analysis, and many other applications. This study is based on the analysis of spectra collected by near infrared (NIR) diffuse reflectance spectroscopy. Each spectrum is a composition of a useful, target spectrum and a spectrum of an interfering layer. To recover the target spectrum, we suggest using a new phenomenological approach, which employs the multivariate curve resolution (MCR) method. In general terms, the problem is very complex. We start with a specific problem of analyzing a system, which consists of several layers of polyethylene (PE) film and underlayer samples with known spectral properties. To separate information originating from PE layers and the target, we modify the system versus both the number of the PE layers as well as the reflectance properties of the target sample. We consider that the interfering spectrum of the layer can be modeled using three components, which can be tentatively called transmission, absorption, and scattering contributions. The novelty of our approach is that we do not remove the reflectance and scattering effects from the spectra, but study them in detail aiming to use this information to recover the target spectrum. PMID- 28357881 TI - A new anthraquinone and a new naphthoquinone from the whole plant of Spermacoce latifolia. AB - A phytochemical study on the whole plant of Spermacoce latifolia led to the isolation of a new anthraquinone, 1,2,6-trihydroxy-5-methoxy-9,10-anthraquinone (1), and a new naphthoquinone, (2R)-6-hydroxy-7-methoxy-dehydroiso-alpha lapachone (2), together with three known anthraquinones (3-5). Their structures were established on the basis of detailed spectroscopic analysis, including one- and two-dimensional NMR, ESI-MS, and HR-ESI-MS techniques. All the compounds were isolated from S. latifolia for the first time. Compounds 1, 2, 4, and 5 showed significant antibacterial activity toward Bacillus subtilis with MIC values ranging from 0.9 to 31.2 MUg/ml, and compound 4 aslo exhibited antibacterial activity against Bacillus cereus with a MIC value 62.5 MUg/ml. Compound 1 was further revealed to show significant in vitro alpha-glucosidase inhibitory activity with IC50 value of 0.653 mM. PMID- 28357883 TI - Positive mood on negative self-statements: paradoxical intervention in geriatric patients with major depressive disorder. AB - OBJECTIVES: Mood regulation is said to be age-specific. Negative self-statements (NST) are used to induce negative mood. However, little is known about NST in older persons and geriatric patients with major depressive disorder. METHOD: We investigated healthy young (YC) and older (OC) control subjects and older patients with major depressive disorder (OP). Subjects were exposed to NST subsequent to baseline assessment comprising psychological and psychometric tests. Preferences for emotionally salient stimuli were measured with an eye tracking task. RESULTS: Mood in YC shifted towards depressive mood or remained stable on NST. In OC and more so in OP some subjects responded paradoxically subsequent to NST with mood being more positive than at baseline. Extent and direction of mood change correlated with prevailing mood at baseline and total score in the Hamilton Depression Anxiety Scale. At baseline, YC had a preference for 'happy' stimuli. Subsequent to NST view preference shifted towards 'sad.' In contrast, OC had no preference at baseline but shifted towards 'happy' on NST. CONCLUSIONS: Mood change on NST is age-specific. In geriatric patients with depressive disorder, however, NST may induce a shift towards more positive mood and thus may be used in future as a therapeutic intervention. PMID- 28357882 TI - Pulse pressure in acute coronary syndromes: Comparative prognostic significance with systolic blood pressure. AB - BACKGROUND: Pulse pressure is a readily available vital sign that has been shown to independently predict outcomes in several cardiovascular disease states. We investigated the prognostic significance of pulse pressure (PP) and systolic blood pressure (SBP) among patients with acute coronary syndromes (ACS). METHODS: A total of 14,514 patients with ACS in the prospective, multicentre Global Registry of Acute Coronary Events (GRACE), expanded GRACE (GRACE-2) and Canadian Registry of Acute Coronary Events (CANRACE) were stratified by initial PP on presentation. Patient characteristics and in-hospital outcomes were compared by PP quartiles and the independent prognostic significance of PP for in-hospital mortality was quantified. We compared the discriminative ability (c-statistic) of models incorporating either PP or SBP. RESULTS: Patients with higher PPs were older, more frequently female and had higher prevalence rates of conventional cardiovascular risk factors (all p < 0.01). Lower PP was associated with ST segment elevation myocardial infarction presentation, higher GRACE risk scores and higher rates of adverse in-hospital outcomes ( p < 0.001). PP was strongly correlated with SBP (Pearson's correlation coefficient = 0.79, p < 0.001). After adjustment for other GRACE risk model predictors, lower PP was independently associated with in-hospital mortality (first vs. fourth quartile [reference]: adjusted odds ratio 2.57, 95% confidence interval 1.80-3.67). The c-statistic was slightly higher for the multivariable model incorporating SBP as compared to the model with PP (0.868 vs. 0.864, respectively, p = 0.028) for in-hospital mortality. CONCLUSION: Higher presenting PP is associated with increased age and more prevalent cardiovascular risk factors, whereas patients with lower PP present with worse clinical characteristics and in-hospital outcomes. Lower PP is an independent adverse prognosticator in ACS. However, PP did not improve the discriminatory performance of the GRACE risk score compared with SBP. PMID- 28357884 TI - An intriguing case of acute myocardial ischaemia in a patient with severe respiratory failure with veno-venous extracorporeal support. AB - We describe a case of a young woman requiring veno-venous extracorporeal support for severe secondary respiratory failure who developed a myocardial ischaemia due to an intermittent obstruction of the right coronary sinus by a fluttering thrombus. She was medically treated with full anticoagulation regimen, needed for the veno-venous extracorporeal membrane oxygenation support, without any other ischaemic or embolic event. PMID- 28357885 TI - Community-based misoprostol for the prevention of post-partum haemorrhage: A narrative review of the evidence base, challenges and scale-up. AB - Achieving Sustainable Development Goal targets for 2030 will require persistent investment and creativity in improving access to quality health services, including skilled attendance at birth and access to emergency obstetric care. Community-based misoprostol has been extensively studied and recently endorsed by the WHO for the prevention of post-partum haemorrhage. There remains little consolidated information about experience with implementation and scale-up to date. This narrative review of the literature aimed to identify the political processes leading to WHO endorsement of misoprostol for the prevention of post partum haemorrhage and describe ongoing challenges to the uptake and scale-up at both policy and community levels. We review the peer-reviewed and grey literature on expansion and scale-up and present the issues central to moving forward. PMID- 28357886 TI - CLINICAL APPRAISAL AND RETINAL IMAGING IN POSTERIOR MICROPHTHALMOS. AB - PURPOSE: To report a critical case series of five patients with posterior microphthalmos and the review of their clinical findings with the analyses of retinal imaging. METHOD: Case series. Complete ophthalmological examinations including optical coherence tomography (OCT) were evaluated. RESULTS: All patients had decreased visual acuity with high hyperopic refraction. Dilated fundus examination demonstrated that elevated papillomacular retinal folds with anterior segment were unremarkable. Total axial lengths measurements showed reduced axial lengths and B-scan ultrasonography revealed sclerochoroidal thickening. Moreover, papillomacular folds were confirmed by OCT. CONCLUSION: Dilated fundus examination, fundus fluorescein angiography, orbital ultrasonography, and proper OCT evaluation will be helpful to reach a diagnosis. PMID- 28357887 TI - Infant disorganized attachment: Clarifying levels of analysis. AB - Lack of clarity regarding the infant disorganized attachment classification has caused confusion in the clinical, forensic, and research contexts in which it is used. This article offers distinctions to clarify the concept with the goal of increasing understanding and identifying potential misapplications. In particular, attention is drawn to the fact that there are many indices used to code "disorganized attachment," and that so far they have been validated as a set rather than individually; and it is noted that the construct validation of disorganization in naturalistic settings is partially finished. Clinicians and social workers should be cautious in their interpretations of such behavior. PMID- 28357888 TI - Evaluation of initial cell adhesion on poly (2-methoxyethyl acrylate) (PMEA) analogous polymers. AB - Cell adhesion is a major concern in biomaterial development. Generally, cells adhere to polymeric substrates via the interaction between integrins and proteins adsorbed on the substrates. Previously, it was reported that poly (2-methoxyethyl acrylate) (PMEA) and its analogous polymers can alter the integrin dependency for cell adhesion. In particular, integrin-independent adhesion was observed on PMEA. However, initial adhesion mechanisms, including integrin-independent adhesion mechanisms, on PMEA are not well characterized. In this study, initial cell adhesion within 10 min was characterized on PMEA analogous polymers. Protein adsorption was suppressed on PMEA compared with tissue culture polystyrene, but the cell adhesion site in adsorbed fibronectin was exposed to the cells similarly. HT-1080 cells adhered on PMEA in a serum medium even in the presence of EDTA, suggesting that the cells adhered via both integrin-dependent and integrin-independent mechanisms. Finally, the cell adhesion force was measured by single-cell force spectroscopy. The cell adhesion force was not changed on PMEA in serum and serum-free media, suggesting that the cells adhered on PMEA directly. In conclusion, the control of protein adsorption is useful for regulating integrin dependency for cell adhesion and following the expression of cell functions regulated by integrins. PMID- 28357889 TI - Applications of Lawesson's reagent in the synthesis of naturally occurring steroids and terpenoids. AB - Steroids and terpenoids are among the most biologically significant classes of natural products possessing a variety of biological activities. The replacement of one or more oxygen atoms in a steroid or terpenoid molecule by a heteroatom affects the chemical properties of that particular steroid or terpenoid, and that replacement often results in alterations of its biological properties, which is sometimes valuable. One possible modification is the thionation that could have some influence on such activity. Among the various thionating reagents, Lawesson's reagent was found to be most suitable and showed versatile properties, including chemoselectivity and functional group tolerance. In this review, we present the role of Lawesson's reagent in the synthesis of thioanalogues of natural steroids and terpenoids. PMID- 28357890 TI - Pneumonia and inflammation in acute decompensated heart failure: a registry-based analysis of 1939 patients. AB - BACKGROUND: The prognostic impact of pneumonia and signs of systemic inflammation in patients with acute decompensated heart failure (ADHF) has not been fully elucidated yet. The aim of the present study was thus to investigate the association of pneumonia and the inflammation surrogate C-reactive protein with all-cause mortality in patients admitted for ADHF. METHODS: We analysed data of 1939 patients admitted for ADHF. Patients were dichotomised according to the presence or absence of pneumonia. The primary endpoint of all-cause mortality was determined by death registry linkage. RESULTS: In total, 412 (21.2%) patients had concomitant pneumonia. Median C-reactive protein levels were higher in patients with compared to patients without pneumonia (24.9 versus 9.8 mg/l, respectively; P<0.001). All-cause mortality was significantly higher in patients with pneumonia ( P<0.001). In adjusted Cox regression models, pneumonia as well as C-reactive protein were independently associated with in-hospital mortality. Only C-reactive protein remained as independent predictor for long-term mortality. CONCLUSION: Pneumonia is relatively common in ADHF and a predictor for in-hospital mortality. However, inflammation in general seems to be more important than pneumonia itself for long-term prognosis. Compared to community-acquired pneumonia studies, C reactive protein levels were rather low and therefore pneumonia might be over diagnosed in ADHF patients. PMID- 28357891 TI - Earliest memories in Israeli kibbutz upbringing: it is parental engagement that makes a difference. AB - Culture and parenting shape the ability to recall early childhood experiences. This research focused on the unique context of upbringing in the Israeli kibbutz and examined how cultural orientation and experiences of parental engagement in Kibbutz and non-Kibbutz settings shaped adults' earliest memories. Participants were 108 women (study 1) and 75 women and men (study 2) who were raised in traditional kibbutz upbringing or in a non-kibbutz family setting. In addition to reporting their earliest memory and age at earliest memory, participants estimated retrospectively the amount of daily time spent in interaction with parents, caregivers, and other children during the time of earliest memory. Overall, upbringing-related variations in cultural orientation were evident in the content of memories. A prediction of later age at earliest memory due to limited opportunities for parent-child interaction characteristic of traditional kibbutz upbringing was not supported. Rather, in both studies, age at earliest memory was linked to retrospective estimation of parental engagement, after controlling for childhood ecology. Study 2 revealed also a link of age at earliest memory to retrospective estimation of involvement with non-parental caregivers. These findings are congruent with the social-interaction model's claims about the importance of interaction with caregiving adults to autobiographical memory's development. PMID- 28357892 TI - Suspected Synthetic Cannabinomimetic Intoxication: Case Series and Review. AB - PURPOSE: The purpose of this work was to retrospectively review patient cases presenting to the University of Kentucky Chandler Medical Center (UKCMC) emergency department (ED) with symptoms of suspected synthetic cannabinomimetic (SC) intoxication. These drugs, currently undetected by standard urine drug screen tests, comprise a structurally diverse group of compounds designed to mimic the psychoactive effects of Delta9-tetrahydrocannabinol (Delta9-THC), the primary psychoactive cannabinoid in marijuana. SUMMARY: Fourteen cases of suspected SC intoxication were identified between July 1, 2015, through September 30, 2015. The median patient age was 25.5 years (range: 13-45 years), and most (64%) patients were males. The most common psychoactive symptom was agitation (n = 6, 42.9%), while the most common physical symptoms were altered level of consciousness (n = 9, 64.3%) and mydriasis (n = 3, 21.4%). Most cases resolved without complication in 24 hours; 2 patients required hospitalization. CONCLUSION: Recent legislation has failed to curb the public health concerns emanating from SC misuse. Education about the risks of SC use along with additional regulation may be required to remove the false sense of safety that some individuals, especially adolescents and young adults, may associate with these compounds, which are often misconstrued as "herbal marijuana." Clinicians need to be prepared to identify and treat symptoms of SC intoxication as incidents of toxicity continue to rise. PMID- 28357895 TI - Two routes toward optimism: how agentic and communal themes in autobiographical memories guide optimism for the future. AB - Autobiographical memories are particularly adaptive because they function not only to preserve the past, but also to direct our future thoughts and behaviours. Two studies were conducted to examine how communal and agentic themes of positive autobiographical memories differentially predicted the route from autobiographical memories to optimism for the future. Across two studies, results revealed that the degree to which participants focused on communal themes in their autobiographical memories predicted their experience of nostalgia. In turn, the experience of nostalgia increased participants' levels of self-esteem and in turn, optimism for the future. By contrast, the degree to which participants focused on agentic themes in their memories predicted self-esteem and optimism, operating outside the experience of nostalgia. These effects remained even after controlling for self-focused attention. Together, these studies provide greater understanding of the interrelations among autobiographical memory, self-concept, and time, and demonstrate how agency and communion operate to influence perceptions of one's future when thinking about the past. PMID- 28357894 TI - Poly(malic acid) bearing Doxorubicin and N-Acetyl Galactosamine as a site specific prodrug for targeting hepatocellular carcinoma. AB - In the past, several systems of drug delivery carriers have been designed with a high capacity to target specific cells and/or tissues and a reduced non-specific toxicity. In this context, we synthesized and characterized novel poly(malic acid) derivatives bearing Doxorubicin (Dox), Poly(ethylene glycol) (PEG) and/or N Acetyl Galactosamine (NAcGal) for drug delivery. These poly(malic acid) derivatives were obtained by chemical modification of the carboxylic acid lateral groups of poly(malic acid) (PMLA). The resulting nanoplatforms were evaluated for their in vitro cytotoxicity using the human HepaRG hepatoma cell line. Results reveal that the PMLA nanoplatform modified with PEG and Dox has an IC50 of 936 nM corresponding to a Dox concentration of 47 nM, while the grafting of NAcGal onto the nanoplatform reduced the IC50 to 527 nM corresponding to a Dox concentration of 26 nM. The presence of the targeting moiety, NAcGal, thus improves the cellular toxicity of the Dox. PMID- 28357896 TI - A novel thermally stable heteropolysaccharide-based bioflocculant from hydrocarbonoclastic strain Kocuria rosea BU22S and its application in dye removal. AB - A new bioflocculant named pKr produced by hydrocarbonoclastic strain Kocuria rosea BU22S (KC152976) was investigated. Gas chromatography-flame ionization detector (GC-FID) analysis confirmed the high potential of the strain BU22S in the degradation of n-alkanes. Plackett-Burman experimental design and response surface methodology were carried out to optimize pKr production. Glucose, peptone and incubation time were found to be the most significant factors affecting bioflocculant production. Maximum pKr production was about 4.72 +/- 0.02 g/L achieved with 15.61 g/L glucose, 6.45 g/L peptone and 3 days incubation time. Chemical analysis of pKr indicated that it contained 71.62% polysaccharides, 16.36% uronic acid and 2.83% proteins. Thin layer chromatography analysis showed that polysaccharides fraction consisted of galactose and xylose. Fourier transform infrared analysis revealed the presence of many functional groups, hydroxyl, carboxyl, methoxyl, acetyl and amide that likely contribute to flocculation. K. rosea pKr showed high flocculant potential using kaolin clay at different pH (2-11), temperature (0-100 degrees C) and cation concentrations. The bioflocculant was particularly effective in flocculating soluble anionic dyes, Reactive Blue 4 and Acid Yellow, with a decolorization efficiency of 76.4% and 72.6%, respectively. The outstanding flocculating performances suggest that pKr could be useful for bioremediation applications. PMID- 28357897 TI - Mindfulness training attenuates the increase in salivary cortisol concentration associated with competition in highly trained wheelchair-basketball players. AB - This study determined the effect of 8 wk of mindfulness training (MT) on salivary cortisol (sCort) and rate of salivary Immunoglobulin-A (sIgA) secretion in wheelchair-basketball players during a competition period. The mindful group completed 8 weeks of MT in addition to training and competition. sCort and rate of sIgA secretion were measured at baseline, at 2-week intervals, the end and 2 weeks following the intervention. A significant time and group interaction was observed for sCort (F = 3.297, P = 0.040, ES = 0.191); sCort increased in the control group from MT-BL to MT-2wk (P = 0.001) and remained significantly elevated at MT-4wk (P = 0.013) and MT-6wk (P = 0.002). sCort decreased from MT 6wk to MT-8wk (P < 0.001) and concentrations were not different at MT-8wk and Post-2wk to MT-BL (P > 0.05). Mindful group sCort increased from MT-BL to MT-2wk (P = 0.042) but decreased to concentrations no different to MT-BL for the rest of the intervention period (P > 0.05). There were no group differences in rate of sIgA secretion during the intervention (P = 0.810). It was concluded that 8 weeks of MT attenuated the increase in sCort associated with the competition period. PMID- 28357898 TI - The Patient Enrolled in a Managed Care Insurance Plan or the Physician Being Part of a Network: What Drives the Efficiency Gain? PMID- 28357899 TI - ? PMID- 28357900 TI - Optimizing Comparisons of PHC Systems: An Example Comparing Switzerland and France with a Standard Monitoring Tool. PMID- 28357901 TI - Routine Data in Health Services Research: an Underused Resource. PMID- 28357902 TI - ? PMID- 28357903 TI - ? PMID- 28357904 TI - ? PMID- 28357905 TI - ? PMID- 28357906 TI - Medical Overuse in Switzerland: How Frequent is Preoperative Chest Radiography? PMID- 28357907 TI - ? PMID- 28357908 TI - Gaps in Hepatitis C Care of People Who Use Drugs. PMID- 28357909 TI - Nitrite enhances liver graft protection against cold ischemia reperfusion injury through a NOS independent pathway. AB - INTRODUCTION: Nitrite has been found to protect liver graft from cold preservation injury. However, the cell signaling pathway involved in this protection remains unclear. Here, we attempt to clarify if the NOS pathway by using the NOS inhibitor, L-NAME (L-NG-Nitroarginine methyl ester). ANIMALS AND METHODS: Rat livers were conserved for 24 h at 4 degrees C in (IGL-1) solution enriched or not with nitrite at 50 nM. In a third group, rats were pretreated with 50 mg/kg of L-NAME before their liver procurement and preservation in IGL-1 supplemented with nitrite (50 nM) and L-NAME (1 mM). After 24 h of cold storage, rat livers were ex-vivo perfused at 37 degrees C during 2 h. Control livers were perfused without cold storage. RESULTS: Nitrite effectively protected the rat liver grafts from the onset of cold I/R injury. L-NAME treatment did not abolish the beneficial effects of nitrite. Liver damage, protein oxidation and lipid peroxidation remained at low levels in both nitrite-treated groups when compared to IGL-1 group. Antioxidant enzyme activities and functional parameters were unchanged after NOS inhibition. CONCLUSION: Despite NOS inhibition by L-NAME, nitrite can still provide hepatic protection during cold I/R preservation. This suggests that nitrite acts through a NOS-independent pathway. PMID- 28357910 TI - Reverse Intensity Correction for Raman Spectral Library Search. AB - A reverse intensity correction method was developed for spectral library searches to correct for instrument response without the side effect of magnifying the noise in the low responsivity region of test spectra. Instead of applying relative intensity correction to the sample test spectra to match the standardized library spectra, a reverse intensity correction is applied to the standardized library spectra to match the uncorrected sample spectrum. This simple procedural change improves library search performance, especially for dispersive charge-coupled device Raman analyzers using near-infrared excitations, where the instrument response often varies greatly across the spectral range, and signal-to-noise ratio in the low responsivity regions is typically poor. PMID- 28357911 TI - Advances in urothelial bladder cancer immunotherapy, dawn of a new age of treatment. AB - Urothelial bladder cancer displays a high number of somatic mutations that render these tumors more responsive to immunotherapy. Several immunotherapeutic agents were examined in patients with advanced stage urothelial bladder cancer and recently atezolizumab - an (PDL-1) immune checkpoint inhibitor antibody - was approved for the treatment of patients with metastatic disease progressing after platinum combination therapy. Despite the great success, there are still some unanswered questions and ongoing trials that are in progress to define the role of combination therapy and sequencing strategies. The objective of our manuscript is to summarize the most recent data on immunotherapy in advanced urothelial cancer. Current challenges and future perspectives of immunotherapy as a monotherapy or in combination strategies will also be analyzed. PMID- 28357912 TI - Bioinformatic prediction and experimental validation of a PE38-based recombinant immunotoxin targeting the Fn14 receptor in cancer cells. AB - AIM: AFn14R can serve as an ideal target for cancer immunotherapy. Here, a combined bioinformatic and experimental approach was applied to characterize an immunotoxin consisting of single-chain variable fragment antibody that targets Fn14 and a toxin fragment (PE38). METHODS & RESULTS: Flow cytometry results showed that the rate of PE38-P4A8 binding to Fn14 was approximately 60 and 40% in HT-29 and A549 cells, respectively. Moreover, 1 ng/ul of immunotoxin was able to lyse approximately 53 and 41% of HT-29 and A549, respectively. PE38-P4A8 showed stability in mouse serum (~90%) after 3-h incubation. Most importantly, using bioinformatics for determining the structure and function of fusion proteins can be very helpful in designing of experiments. CONCLUSION: Coupled with bioinformatics, experimental approaches revealed that PE38-P4A8 could be used as a promising therapeutic agent for cancer cells expressing Fn14. PMID- 28357913 TI - Current update of adoptive immunotherapy using cytokine-induced killer cells to eliminate malignant gliomas. AB - The therapeutic outcome for those with malignant glioma is poor, even though diverse therapeutic modalities have been developed. Immunotherapy has emerged as a therapeutic approach for malignant gliomas, making it possible to selectively treat tumors while sparing normal tissue. Here, we review clinical trials of adoptive immunotherapy approaches for malignant gliomas. We also describe a clinical trial that examined the efficacy and safety of autologous cytokine induced killer (CIK) cells along with concomitant chemoradiotherapy for newly diagnosed glioblastoma. These CIK cells identify and kill autologous tumor cells. This review focuses on the use of adoptive immunotherapy for malignant gliomas and reviews the current literature on the concept of antitumor activity mediated by CIK cells. PMID- 28357914 TI - Short review of potential synergies of immune checkpoint inhibition and radiotherapy with a focus on Hodgkin lymphoma: radio-immunotherapy opens new doors. AB - Radiotherapy is an established local treatment in patients with various malignancies. Systemic responses following local irradiation have been described as abscopal effects. Modern cancer immunotherapy with immune checkpoint inhibitors has shown impressive response rates and prolongation of survival even in heavily pretreated patients with advanced solid malignancies and lymphomas. Radiotherapy has been shown to modulate immune response, and its application in the context of immune checkpoint inhibition has recently evolved into an active field of research. Prospective studies investigating combination treatment are currently ongoing and will answer questions as to the optimal schedule and radiation dosing. This short review focuses on the immunomodulatory role of radiotherapy and the use of immune checkpoint inhibition with a special focus on Hodgkin lymphoma. PMID- 28357915 TI - Early relapse in a case of primary bone marrow diffuse large B-cell lymphoma treated with rituximab-CHOP. AB - As an uncommon disease, primary bone marrow diffuse large B-cell lymphoma (PBM DLBCL) is rarely reported in recent years. In this paper, we discuss a case of a 58-year-old man who presented with fever and fatigue, and was diagnosed with PBM DLBCL. Although the initial diagnosis reflected a positive expression of CD20 by lymphoma cells, the course of disease appeared as a rapid remission but a quick recurrence, after eight cycles of rituximab-based immunochemotherapy (R-CHOP). With the positive expression of CD20 in recurrent lesions, he received another four cycles of rituximab-based immunochemotherapy (R-GDP). However, an earlier relapse still occurred, and he died of CNS involvement. PBM DLBCL has been classified as an aggressive type of DLBCL, which should be heavily treated since the initial diagnosis. MYC-BCL2 gene rearrangement and P53 gene mutation cannot be ignored. Of note, rituximab resistance has become a severe and urgent problem in the rituximab era. PMID- 28357917 TI - The ongoing evolution of antibody-based treatments for Ebola virus infection. AB - The 2014-2016 Ebola virus outbreak in West Africa was the deadliest in history, prompting the evaluation of various drug candidates, including antibody-based therapeutics for the treatment of Ebola hemorrhagic fever (EHF). Prior to 2014, only convalescent blood products from EHF survivors had been administered to newly infected individuals as a form of treatment. However, during the recent outbreak, monoclonal antibody cocktails such as ZMapp, ZMAb and MB-003 were either tested in a human clinical safety and efficacy trial or provided to some based on compassionate grounds. This review aims to discuss the evolution of antibody-based treatments for EHF, their clinical trial efficacy and the development of new antibody-based therapies currently advancing in preclinical testing. PMID- 28357916 TI - Chimeric antigen receptor engineered stem cells: a novel HIV therapy. AB - Despite the success of combination antiretroviral therapy (cART) for suppressing HIV and improving patients' quality of life, HIV persists in cART-treated patients and remains an incurable disease. Financial burdens and health consequences of lifelong cART treatment call for novel HIV therapies that result in a permanent cure. Cellular immunity is central in controlling HIV replication. However, HIV adopts numerous strategies to evade immune surveillance. Engineered immunity via genetic manipulation could offer a functional cure by generating cells that have enhanced antiviral activity and are resistant to HIV infection. Recently, encouraging reports from several human clinical trials using an anti CD19 chimeric antigen receptor (CAR) modified T-cell therapy for treating B-cell malignancies have provided valuable insights and generated remarkable enthusiasm in engineered T-cell therapy. In this review, we discuss the development of HIV specific chimeric antigen receptors and the use of stem cell based therapies to generate lifelong anti-HIV immunity. PMID- 28357918 TI - Systemic therapy for previously untreated advanced BRAF-mutated melanoma: navigating a shifting landscape. PMID- 28357919 TI - Simple Silica Column-Based Method to Quantify Inorganic Polyphosphates in Cartilage and Other Tissues. AB - OBJECTIVE: Inorganic polyphosphates (polyP) play a multitude of roles in mammalian biology. PolyP research is hindered by the lack of a simple and sensitive quantification method. The aim of this study was to develop a robust method for quantifying the low levels of polyP in mammalian tissue such as cartilage, which is rich in macromolecules that interfere with its determination. DESIGN: Native and in vitro formed tissues were digested with proteinase K to release sequestrated polyP. The tissue digest was loaded on to silica spin columns, followed by elution of bound polyP and various treatments were assessed to minimize non-polyP fluorescence. The eluent was then quantified for polyP content using fluorometry based on DAPI (4',6-diamidino-2-phenylindole) fluorescence shift occurring with polyP. RESULTS: Proteinase K pretreatment reduced the inhibitory effect of proteins on polyP recovery. The eluent was contaminated with nucleic acids and glycosaminoglycans, which cause extraneous fluorescence signals. These were then effectively eliminated by nucleases treatment and addition of concentrated Tris buffer. PolyP levels were quantified and recovery ratio determined using samples spiked with a known amount of polyP. This silica spin column method was able to recover at least 80% of initially loaded polyP, and detect as little as 10-10 mol. CONCLUSIONS: This sensitive, reproducible, easy to do method of quantifying polyP will be a useful tool for investigation of polyP biology in mammalian cells and tissues. Although the protocol was developed for mammalian tissues, this method should be able to quantify polyP in most biological sources, including fluid samples such as blood and serum. PMID- 28357920 TI - Investigation of the Sensitivity of Transmission Raman Spectroscopy for Polymorph Detection in Pharmaceutical Tablets. AB - Polymorph detection is critical for ensuring pharmaceutical product quality in drug substances exhibiting polymorphism. Conventional analytical techniques such as X-ray powder diffraction and solid-state nuclear magnetic resonance are utilized primarily for characterizing the presence and identity of specific polymorphs in a sample. These techniques have encountered challenges in analyzing the constitution of polymorphs in the presence of other components commonly found in pharmaceutical dosage forms. Laborious sample preparation procedures are usually required to achieve satisfactory data interpretability. There is a need for alternative techniques capable of probing pharmaceutical dosage forms rapidly and nondestructively, which is dictated by the practical requirements of applications such as quality monitoring on production lines or when quantifying product shelf lifetime. The sensitivity of transmission Raman spectroscopy for detecting polymorphs in final tablet cores was investigated in this work. Carbamazepine was chosen as a model drug, polymorph form III is the commercial form, whereas form I is an undesired polymorph that requires effective detection. The concentration of form I in a direct compression tablet formulation containing 20% w/w of carbamazepine, 74.00% w/w of fillers (mannitol and microcrystalline cellulose), and 6% w/w of croscarmellose sodium, silicon dioxide, and magnesium stearate was estimated using transmission Raman spectroscopy. Quantitative models were generated and optimized using multivariate regression and data preprocessing. Prediction uncertainty was estimated for each validation sample by accounting for all the main variables contributing to the prediction. Multivariate detection limits were calculated based on statistical hypothesis testing. The transmission Raman spectroscopic model had an absolute prediction error of 0.241% w/w for the independent validation set. The method detection limit was estimated at 1.31% w/w. The results demonstrated that transmission Raman spectroscopy is a sensitive tool for polymorphs detection in pharmaceutical tablets. PMID- 28357921 TI - Potential Adverse Consequences of Early Discharge for Newborns Who Meet American Academy of Pediatrics Criteria. PMID- 28357922 TI - Reliability assessment and correlation analysis of 3 protocols to measure trunk muscle strength and endurance. AB - Different methods have been developed to quantify trunk muscle strength and endurance. However, some important protocol characteristics are still unclear, hindering the selection of the most suitable tests in each specific situation. The aim of this study was to examine the reliability and the relationship between 3 representative tests of the most common type of protocols used to assess trunk muscle strength and endurance. Twenty-seven healthy men performed each test twice spaced 1 month apart.Trunk strength and endurance were evaluated with an isokinetic dynamometer and 2 field tests including Biering-Sorensen test and Flexion-rotation trunk test. All tests showed a good relative consistency (intraclass correlation coefficient [ICC]> 0.75), except for the isokinetic endurance variables which had low-moderate reliability (0.37 < ICC > 0.65). Absolute reliability seemed slightly better in the isokinetic protocol than in the field tests, which showed about 12% of test-retest score increase. No significant correlations were found between test scores. After a familiarisation period for the field tests, the 3 protocols can be used to obtain reliable measures of trunk muscle strength and endurance. Based on the correlation analysis, these measures are not related, which highlights the importance of selecting the most suitable trunk test for each situation. PMID- 28357923 TI - Performance of CarbaNP and CIM tests in OXA-48 carbapenemase-producing Enterobacteriaceae. AB - This study applied two phenotypic tests, namely "Carbapenemase Nordmann-Poirel" (CarbaNP) test and "Carbapenem Inactivation Method" (CIM), against the isolates carrying the carbapenem resistance genes. The study included 83 carbapenem resistant Enterobacteriaceae isolates producing oxacillinase-48 (OXA-48) and 30 carbapenem-sensitive Enterobacteriaceae isolates. Out of the total isolates studied, 77 isolates (92.77%) were identified as Klebsiella pneumoniae and six isolates (7.23%) were identified as Escherichia coli by Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry. Polymerase chain reaction (PCR) method used to detect resistance genes found that 74 isolates (89.16%) produced OXA-48 carbapenemase, whereas nine isolates (10.84%) produced both OXA 48 and New Delhi metallo-beta-lactamase-1 (NDM-1). The isolates producing both OXA-48 and NDM-1 were found to be positive by both phenotypic tests. Among isolates carrying only blaOXA-48 gene alone, nine isolates (13.04%) for CarbaNP test and two isolates for CIM test (2.90%) displayed false negative results, respectively. The sensitivity of CarbaNP and CIM tests was found to be 89.16% and 97.59%, respectively, whereas the specificity was determined to be 100% for both tests. These findings suggest that CarbaNP and CIM tests are useful tools to identify the carbapenemase producers. Molecular methods like PCR are recommended to verify false negative tests predicted to have OXA-48 activity. PMID- 28357925 TI - Evaluation of e-beam irradiation effects on the toxicity of slaughterhouse wastewaters. AB - Slaughterhouse industry produces large volumes of polluted wastewater, which cause negative impacts on the environment. The objective of this study was to assess the effect of electron-beam irradiation on the ecotoxicity of slaughterhouse effluents with absorbed doses up to 35 kGy. Two acute toxicity assays were applied to evaluate the efficiency of irradiation onto toxicity of wastewater. The exposed living-organisms were a luminescent bacteria Vibrio fischeri, and a freshwater microcrustacean Daphnia similis. Also, the total organic carbon was analysed in order to determine any possible organic carbon removal after irradiation. The ecotoxicological results evidenced that both living-organisms were suitable for the measurements. Therefore, the results demonstrated the toxicity of the effluent and its similarity for both organisms as well as the potential of radiation to reduce these effects. The 35 kGy dose was very effective for reducing toxic effects of slaughterhouse wastewater for daphnids suggesting that ionizing radiation could be used as a tool for removing toxic charge of such effluents. The type of contamination presented by the effluent justify the needs for alternatives of treatment. PMID- 28357924 TI - Association study of the FTO gene polymorphisms with the risk of pulmonary tuberculosis in a sample of Iranian population. AB - AIM: The aim of the present study was to find out the impact of fat mass and obesity-associated (FTO) gene on risk of pulmonary tuberculosis (PTB) in a sample of Iranian population. METHODS: This case-control study was carried out on a total of 354 subjects including 185 PTB patients and 169 healthy subjects. Genotyping of FTO rs9939609 and rs8050136 variants was done using polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: FTO rs9939609 variant showed no statistically significant difference in allele and genotype frequencies between PTB patients and controls. The rs8050136 polymorphism marginally increased the risk of PTB in dominant (OR = 1.53, 95% CI = 1.00-2.33, p = 0.055, CA+AA vs. CC) inheritance model tested, where rs8050136 A allele significantly increased the risk of PTB (OR = 1.42, 95% CI = 1.02-1.97, p = 0.045) compared with C allele. CONCLUSION: The finding of the present study showed an association between FTO rs9939609 variant and risk of PTB. Further studies with larger sample sizes and different ethnicities are necessary to confirm the findings. PMID- 28357926 TI - Primary and secondary progressive MS have a similar age at onset of progression - YES. PMID- 28357927 TI - Primary and secondary progressive MS have a similar age at onset of progression - NO. PMID- 28357928 TI - Primary and secondary progressive MS have a similar age at onset of progression - Commentary. PMID- 28357929 TI - Effects of touchscreen gesture's type and direction on finger-touch input performance and subjective ratings. AB - This study examined how finger-touch input performance (i.e. task completion time, failure status, and error rate) and subjective ratings (i.e. performance and physical demand) are influenced by touchscreen gestures' type and direction. Twenty participants performed one-touch (i.e. drag and swipe) and two-touch (i.e. pinch and spread) gesture tasks on a tablet, using several major directions (i.e. eight directions for one-touch and four directions for two-touch gestures). The results showed that swipe was approximately 4.5 times faster than drag, but pinch and spread showed no significant difference in task completion time. Dragging and pinching showed more failures or higher error rates compared to swiping and spreading, respectively. One-touch gestures in the horizontal directions were rated to have higher performance and lower physical demand than those in the vertical and diagonal directions. Two-touch gestures in the horizontal directions took the shortest time but caused more failures and higher error rates. Practitioner Summary: This study provides evidence for the effects of touchscreen gestures' type and direction on human performance and subjective ratings, which varied depending on the number of fingers used. Designers should arrange related touchscreen components accordingly, to improve touch-finger input performance and reduce user workload. PMID- 28357930 TI - Quality reporting of carotid intima-media thickness methodology; Current state of the science in the field of spinal cord injury. AB - OBJECTIVES: Carotid intima-media thickness (cIMT) may be used increasingly as a cardiovascular disease (CVD) screening tool in individuals with spinal cord injury (SCI) as other routine invasive diagnostic tests are often unfeasible. However, variation in cIMT acquisition and analysis methods is an issue in the current published literature. The growth of the field is dependent on cIMT quality acquisition and analysis to ensure accurate reporting of CVD risk. The purpose of this study is to evaluate the quality of the reported methodology used to collect cIMT values in SCI. METHODS: Data from 12 studies, which measured cIMT in individuals with SCI, were identified from the Medline, Embase and CINAHL databases. The quality of the reported methodologies was scored based on adherence to cIMT methodological guidelines abstracted from two consensus papers. RESULTS: Five studies were scored as 'moderate quality' in methodological reporting, having specified 9 to 11 of 15 quality reporting criterion. The remaining seven studies were scored as 'low quality', having reported less than 9 of 15 quality reporting criterion. No study had methodological reporting that was scored as 'high quality'. The overall reporting of quality methodology was poor in the published SCI literature. CONCLUSIONS: A greater adherence to current methodological guidelines is needed to advance the field of cIMT in SCI. Further research is necessary to refine cIMT acquisition and analysis guidelines to aid authors designing research and journals in screening manuscripts for publication. PMID- 28357931 TI - Monitoring, exposure and risk assessment of sulfur dioxide residues in fresh or dried fruits and vegetables in China. AB - Sulfur dioxide residues in 20 kinds of products collected from 23 provinces of China (Jilin, Beijing, Shanxi, Shandong, Henan, Hebei, Jiangsu, Anhui, Shanghai, Zhejiang, Fujian, Guangdong, Guangxi, Yunnan, Guizhou, Hunan, Hubei, Chongqing, Sichuan, Gansu, Neimenggu, Xinjiang and Hainan) were analysed, and a health risk assessment was performed. The detection rates of sulfur dioxide residues in fresh vegetables, fresh fruits, dried vegetables and dried fruits were 11.1-95.9%, 12.6 92.3%, 70.3-80.0% and 26.0-100.0%, respectively; the mean concentrations of residues were 2.7-120.8, 3.8-35.7, 26.9-99.1 and 12.0-1120.4 mg kg-1, respectively. The results indicated that fresh vegetables and dried products are critical products; the daily intakes (EDIs) for children were higher than others; the hazard indexes (HI) for four groups were 0.019-0.033, 0.001-0.005, 0.007 0.016 and 0.002-0.005 at P50, respectively. But the HI was more than 1 at P99 by intake dried fruits and vegetables. Although the risk for consumers was acceptable on the whole, children were the most vulnerable group. Uncertainty and sensitivity analyses indicated that the level of sulfur dioxide residues was the most influential variable in this model. Thus, continuous monitoring and stricter regulation of sulfites using are recommended in China. PMID- 28357932 TI - The physical education predisposition scale: Preliminary tests of reliability and validity in Australian students. AB - The main aim of this study was to psychometrically test the Physical Education Predisposition Scale (PEPS) with a cohort of Australian students, to assess secondary school students' perceived PE ability and PE worth. Secondary aims were to explore how the two variables were related and to investigate age and gender differences. Altogether, 266 Year 7, 8, 9 and 10 students (aged 12-16 years), from four schools within the South Eastern region of Melbourne, completed the PEPS at both time points. Principal components analysis revealed the presence of a simple two-factor structure explaining 66.9% of the variance. Factor 1 (labelled perceived PE worth) reflected enjoyment and attitude (alpha = .91), and factor 2 (labelled perceived PE ability) represented perceptions of competence and self-efficacy (alpha = .92). Significant positive correlations were observed between the two factors (r = .50-.82, P < .001). Boys scored significantly higher than girls on perceived PE ability (P = .01), and year 7 students scored significantly higher compared to Year 9 students (P = .002). Our results support the potential of the PEPS as a concise measurement tool for use in the PE setting, for both teachers and researchers. PMID- 28357935 TI - Live Wait Times. AB - People in North Wales who need treatment for injuries can now obtain up-to-the minute information on waiting times at the region's minor injuries units and emergency departments. PMID- 28357933 TI - Tensions within management roles in healthcare organisations. AB - Aim This article reports the results of a study that gives an insight into ward leaders' perspectives of their leadership role and explores how they deliver leadership at ward level within organisational constraints and processes. Previous studies have been evaluations of clinical leadership in general, or literature reviews of the ward leader role. The aim of this study was to examine the leadership role of ward sisters and to understand how they lead improvements in quality of care on their wards. Methods A qualitative methodology was used, incorporating 19 in-depth interviews with ward leaders and modern matrons. Results Three main themes were identified: empty conformity, authority and autonomy, and visibility and leading by example. Participants aimed to be role models in leading and maintaining standards of care for patients, but this was sometimes constrained by organisational processes, lack of authority and autonomy, and lack of support and preparation. Conclusion Perceived differences between nursing and health service management mean that ward leaders' efforts to lead improvements in quality care are often undermined. Ward leaders must strike a balance between leading high-quality nursing care, in the context of organisational and political performance requirements, and the demands of administrative work, while often lacking autonomy and authority. PMID- 28357936 TI - Does leadership style of modern matrons contribute to safer and more effective clinical services? AB - At the time of writing, the author was a modern matron in a surgical division of an NHS teaching hospital in London. This article considers the differences between leadership and management, and discusses the skills required by modern matrons to lead safe and successful clinical services. It also examines three leadership styles - transactional, transformational and situational - and their relevance to the role of modern matron. PMID- 28357937 TI - Organisational development. AB - The aim of the NHS Improvement national leadership and improvement strategy is to encourage leaders at all levels to develop leadership skills in their staff and themselves. It focuses on fostering compassionate, collaborative and inclusive leadership. PMID- 28357938 TI - Local health plans. AB - Health services and local councils in England have joined together to develop proposals to improve health and care. The proposals, known as sustainability and transformation plans, cater to the needs of local populations. PMID- 28357939 TI - Blogshot webinar. AB - Blogshots are a way of giving information in a concise form through an image shared on social media. PMID- 28357940 TI - Approved apprenticeship pathways offer new routes into nursing. AB - The government has given the go-ahead to a new set of learning standards for healthcare apprentices. PMID- 28357941 TI - Opening the door to your nursing potential. AB - It was only when I started teaching an undergraduate community health course that I became aware of the general lack in knowledge about nursing career options. PMID- 28357942 TI - Half of nurses say they want to quit the profession. AB - More than half of nurses are considering quitting the NHS as work pressures continue to ratchet up, an exclusive survey by RCNi's Nursing Standard and the Sunday Mirror has revealed. PMID- 28357943 TI - Chancellor allocates extra funds for STPs. AB - Additional funds for sustainability and transformation plans (STPs) were announced in the spring budget. PMID- 28357945 TI - 'Always put patients first'. AB - What is your job? I am an integrated pathway manager in the combined community and acute care group at Sheffield Teaching Hospitals NHS Foundation Trust. My role involves managing one of the city's four community nursing teams, which will soon have therapy services integrated with them. I also manage our community nursing flexible workforce department and the community assistive technology team. PMID- 28357944 TI - New way to recognise advanced skills. AB - The RCN is introducing a credential that will recognise the level of expertise and skill of advanced-level nurses. PMID- 28357948 TI - Steps towards an advanced clinical practice standard. AB - Advanced clinical practice is increasingly heralded as one of the solutions to the workforce and financial challenges in healthcare systems. Expectations are high and policy directives explicitly or implicitly call for healthcare professionals to apply advanced-level knowledge and skills to the delivery of timely, individualised, safe and effective care for patients with complex needs. PMID- 28357949 TI - Jeremy Hunt outlines his four priorities. AB - Senior nurses can help make improvements in four priority areas, the health secretary told the chief nursing officer for England's summit last month. PMID- 28357951 TI - Ten-point plan for practice nursing. AB - A new plan for practice nursing is to be published by NHS England, Jane Cummings revealed at her chief nursing officer summit. PMID- 28357950 TI - NHS England chief calls for more nurses. AB - Nursing associates should not replace registered nurses, the chief executive of NHS England said. PMID- 28357952 TI - How to talk about cancer. AB - While 50% of people born after 1960 in the UK will develop cancer at some point, many find talking about it difficult. Cancer Research UK has therefore developed a free, online cancer awareness course, Talking About Cancer, as part of its Talk Cancer programme. PMID- 28357953 TI - Mary Seacole awards. AB - This year's Mary Seacole awards have been launched by NHS Employers. PMID- 28357954 TI - EU nurses need our support, says CNO. AB - Nurses from the European Union (EU) face an 'uncertain future' and need our support, Jane Cummings said, as she opened her fifth chief nursing officer (CNO) for England's summit in Birmingham. PMID- 28357956 TI - Conflicts of interest guidance. AB - NHS England has published guidelines on how to manage conflicts of interest to ensure transparent and accountable healthcare. PMID- 28357955 TI - Social media toolkit. AB - Skills for Health has launched a free, online social media toolkit to offer healthcare organisations information and advice about using social media. PMID- 28357957 TI - NM welcomes Barry Quinn as consultant editor. AB - Assistant director of nursing at Chelsea and Westminster NHS Foundation Trust, London, Barry Quinn has been appointed consultant editor of Nursing Management journal. PMID- 28357959 TI - Let's work together to spread good practice. AB - Hundreds of the country's most senior nurses and midwives met in Birmingham last month at the annual summit of England's chief nursing officer (CNO). It proved to be a great opportunity to hear some of the most influential thinkers and speakers in healthcare, including the chief nurse herself, Jane Cummings. PMID- 28357960 TI - Deep nursing: a thoughtful, co-created nursing process. AB - This article examines some of the challenges in nursing practice experienced by patients and nurses in the UK and Ireland, and considers some of the associated stressors in the system. Nurses must respond to these challenges by crafting their own practice, and the article offers a blueprint for developing personal nursing practice through acceptance, paying detailed attention to patients, taking time with patients and personal reflection. It draws on innovations in learning disability practice to suggest that care should be jointly thought through and co-created by patients and nurses, and that this process of thoughtful engagement constitutes 'deep nursing'. PMID- 28357961 TI - Implications of Brexit for nurses. AB - This time last year, the UK was engaged in the EU referendum campaign. There were arguments and assertions on both sides about the risks and benefits, including to the NHS, of staying or leaving. PMID- 28357963 TI - Nursing expertise is guaranteed. AB - Many of us entering the later years of our nursing careers will consider ourselves to be leaders in our clinical fields. PMID- 28357964 TI - Physical restraint in healthcare settings. AB - Essential facts In January, new guidance was drawn up for police and healthcare professionals, outlining for the first time how and when police officers should be involved in physically restraining people in healthcare settings in England and Wales. PMID- 28357965 TI - Racial differences in seroprevalence of HAV and HEV in blood donors in the Western Cape, South Africa: a clue to the predominant HEV genotype? AB - Hepatitis E virus (HEV) infection is a major cause of acute hepatitis worldwide. This infection causes major water-borne outbreaks in low- and middle-income countries, whilst in industrialised countries this infection is zoonotic. These differences in epidemiology are related to different HEV genotypes. HEV genotype 3 is a zoonotic infection, whilst genotype 2 causes large outbreaks. This study determined the seroprevalence of HEV in blood donors from the Western Cape. Anti hepatitis A virus (anti-HAV) antibody was detected in 184/300 (61%) donors. Antibody to HEV (anti-HEV) was detected in 78 of 300 donors (26%). It was highest in mixed race donors (62/100), followed by white donors (23/100) and lowest in black donors (19/100) P = 0.019. Since it is thought that genotypes 1 and 2 predominate both viruses would be acquired by the oro-faecal route, it is surprising that HEV seroprevalence does not mirror that of HAV. We postulate that this may reflect differences in socio-economic status and consumption of dietary meat. So the marked divergence between HEV and HAV seroprevalence may be the result of different routes of transmission. Further data are needed to explore the risk factors associated with HEV infection. PMID- 28357967 TI - In-patient suicide in psychiatry - an Indian experience. PMID- 28357966 TI - A randomised controlled study of mindfulness meditation versus relaxation therapy in the management of tinnitus. AB - OBJECTIVE: Psychotherapeutic interventions have been adopted effectively in the management of tinnitus for a long time. This study compared mindfulness meditation and relaxation therapy for management of tinnitus. METHODS: In this randomised controlled trial, patients were recruited for five sessions of mindfulness meditation or five sessions of relaxation therapy. Patients' responses were evaluated using the Tinnitus Reaction Questionnaire as a primary outcome measure, and the Hospital Anxiety and Depression Scale, visual analogue scale and a health status indicator as secondary outcome measures. RESULTS: A total of 86 patients were recruited. Thirty-four patients completed mindfulness meditation and 27 patients completed relaxation therapy. Statistically significant improvement was seen in all outcome measures except the health status indicator in both treatment groups. The change in treatment scores was greater in the mindfulness meditation group than in the relaxation therapy group. CONCLUSION: This study suggests that although both mindfulness meditation and relaxation therapy are effective in the management of tinnitus, mindfulness meditation is superior to relaxation therapy. PMID- 28357968 TI - Echocardiographic right ventricular function correlations with cardiac catheterisation data in biventricular congenital heart patients. AB - BACKGROUND: Newer echocardiographic techniques may allow for more accurate assessment of right ventricular function. Adult studies have correlated these echocardiographic measurements with invasive data, but minimal data exist in the paediatric congenital heart population. The purpose of this study was to evaluate echocardiographic measurements that correlate best with right ventricular systolic and diastolic catheterisation parameters. METHODS: Patients with two ventricle physiology who underwent simultaneous echocardiogram and cardiac catheterisation were included in this study. Right ventricular systolic echocardiographic data included fractional area change, displacement, tissue Doppler imaging s' wave, global longitudinal strain, and strain rate s' wave. Diastolic echocardiographic data included tricuspid E and A waves, tissue Doppler imaging e' and a' waves, and strain rate e' and a' waves. E/tissue Doppler imaging e', tissue Doppler imaging e'/tissue Doppler imaging a', E/strain rate e', and strain rate e'/strain rate a' ratios were also calculated. Catheterisation dP/dt was used as a marker for systolic function and right ventricular end-diastolic pressure for diastolic function. RESULTS: A total of 32 patients were included in this study. The median age at catheterisation was 3.1 years (0.3-17.6 years). The DP/dt was 493+/-327 mmHg/second, and the right ventricular end-diastolic pressure was 7.7+/-2.4 mmHg. There were no significant correlations between catheterisation dP/dt and systolic echocardiographic parameters. Right ventricular end-diastolic pressure correlated significantly with strain rate e' (r=-0.4, p=0.02), strain rate a' (r=-0.5, p=0.03), and E/tissue Doppler imaging e' (r=0.4, p=0.04). CONCLUSION: Catheterisation dP/dt did not correlate with echocardiographic measurements of right ventricular systolic function. Strain rate and tissue Doppler imaging analysis significantly correlated with right ventricular end-diastolic pressure. These values should be further studied to determine whether they may be used as an alternative method to estimate right ventricular end-diastolic pressure in this patient population. PMID- 28357969 TI - Lurasidone for major depressive disorder with mixed features and anxiety: a post hoc analysis of a randomized, placebo-controlled study. AB - OBJECTIVE: The aim of this post-hoc analysis was to evaluate the efficacy of lurasidone in treating patients with major depressive disorder (MDD) with mixed features who present with mild and moderate-to-severe levels of anxiety. METHODS: The data in this analysis were derived from a study of patients meeting the DSM IV-TR criteria for unipolar MDD, with a Montgomery-Asberg Depression Rating Scale (MADRS) total score >=26, presenting with two or three protocol-defined manic symptoms, who were randomized to 6 weeks of double-blind treatment with either lurasidone 20-60 mg/day (n=109) or placebo (n=100). Anxiety severity was evaluated using the Hamilton Anxiety Rating Scale (HAM-A). To evaluate the effect of baseline anxiety on response to lurasidone, the following two anxiety groups were defined: mild anxiety (HAM-A<=14) and moderate-to-severe anxiety (HAM A>=15). Change from baseline in MADRS total score was analyzed for each group using a mixed model for repeated measures. RESULTS: Treatment with lurasidone was associated with a significant week 6 change versus placebo in MADRS total score for patients with both mild anxiety (-18.4 vs. -12.8, p<0.01, effect size [ES]=0.59) and moderate-to-severe anxiety (-22.0 vs. -13.0, p<0.001, ES=0.95). Treatment with lurasidone was associated with a significant week 6 change versus placebo in HAM-A total score for patients with both mild anxiety (-7.6 vs. -4.0, p<0.01, ES=0.62), and moderate-to-severe anxiety (-11.4 vs. -6.1, p<0.0001, ES=0.91). CONCLUSIONS: In this post-hoc analysis of an MDD with mixed features and anxiety population, treatment with lurasidone was associated with significant improvement in both depressive and anxiety symptoms in subgroups with mild and moderate-to-severe levels of anxiety at baseline. PMID- 28357970 TI - Situational and Dispositional Factors that Predict Motivation: a Multilevel Study. AB - This study aimed to test a multilevel mediation model which examined the relationship between the perceived motivational climate created by coaches at team level and motivational regulations towards sport at individual level, as mediated by individual goal orientations. 211 university athletes from 20 teams training in different types of sport completed a battery of instruments that measured the variables included in the model. The statistics significance level was .05. Results of the multilevel mediation model revealed that the task involving climate at team level positively predicted individual task orientation (gamma01 = .77, p .05). The results are in line with previous research that have focused in the study of motivational climate at individual level, but the present study make a novel contribution by providing the perspective of a multilevel mediation model and thereby clarifying the phenomenon at team level. PMID- 28357971 TI - Palliative and end-of-life care in the masters of social work curriculum. AB - : ABSTRACTObjective:There is a shortage of social workers who have palliative care expertise. The aging U.S. population and advances in extending life for seriously ill persons require social workers in a wide range of health care and other settings with specialized palliative care expertise, as well as those with basic competence in palliative care. The objective of the present study was to document course content on palliative care in MSW programs in the United States and Canada. METHOD: A cross-sectional design with an online questionnaire was used. All 248 accredited MSW programs in the United States and 32 programs in Canada were invited to participate. The measures included the characteristics of the courses on palliative care. RESULTS: Of the 105 participating programs, only 10 had courses dedicated to palliative care, 9 of which were part of a specialization/certificate program. Few programs had plans to develop a dedicated course. There were 106 courses in 63 MSW programs with some content on palliative care. The majority of these had <25%, and few had at least 50%, of palliative care content. SIGNIFICANCE OF RESULTS: Curricula are needed for preparing MSW graduates for specialty hospice and palliative care practice and non-specialty practice. While there are practice competencies for specialty practitioners, consensus on a core curriculum for all MSW students would be beneficial. Consensus on basic palliative care knowledge and skills for non-specialty social workers in health care and other settings and subsequent curriculum development are also needed. Innovative ways in which to introduce basic and more specialized content on palliative care into the already-crowded MSW curricula will be needed. PMID- 28357972 TI - Dyadic psychological intervention for patients with cancer and caregivers in home based specialized palliative care: The Domus model. AB - : ABSTRACTObjective:Patients with incurable cancer and their informal caregivers have numerous psychological and psychosocial needs. Many of these patients wish to receive their care and die at home. Few home-based specialized palliative care (SPC) interventions systematically integrate psychological support. We present a psychological intervention for patient-caregiver dyads developed for an ongoing randomized controlled trial (RCT) of home-based SPC, known as Domus, as well as the results of an assessment of its acceptability and feasibility. METHOD: The Domus model of SPC for patients with incurable cancer and their caregivers offered systematic psychological assessment and dyadic intervention as part of interdisciplinary care. Through accelerated transition to SPC, the aim of the model was to enhance patients' chances of receiving care and dying at home. Integration of psychological support sought to facilitate this goal by alleviating distress in patients and caregivers. Psychologists provided needs based sessions based on existential-phenomenological therapy. Feasibility and acceptability were investigated by examining enrollment, nonparticipation, and completion of psychological sessions. RESULTS: Enrollment in the RCT and uptake of the psychological intervention indicated that it was feasible and acceptable to patients and caregivers. The strengths of the intervention included its focus on dyads, psychological distress, and existential concerns, as well as interdisciplinary collaboration and psychological interventions offered according to need. Its main limitation was a lack of an intervention for other family members. SIGNIFICANCE OF RESULTS: Our results show that psychological intervention can be systematically integrated into SPC and that it appears feasible to provide dyadic needs-based sessions with an existential therapeutic approach. The Domus RCT will provide evidence of the efficacy of a novel model of multidisciplinary SPC. PMID- 28357973 TI - Perceptions of the care received from Australian palliative care services: A caregiver perspective. AB - : ABSTRACTBackground:Caregiver satisfaction and experience surveys help health professionals to understand, measure, and improve the quality of care provided for patients and their families. OBJECTIVE: Our aim was to explore caregiver perceptions of the care received from Australian specialist palliative care services. METHOD: Caregivers of patients receiving palliative care in services registered with Australia's Palliative Care Outcomes Collaboration were invited to participate in a caregiver survey. The survey included the FAMCARE-2 and four items from the Ongoing Needs Identification: Caregiver Profile questionnaire. RESULTS: Surveys were completed by 1,592 caregivers from 49 services. Most respondents reported high satisfaction and positive experiences. Caregivers receiving care from community-based palliative care teams were less satisfied with the management of physical symptoms and comfort (odds ratio [OR] = 0.29; 95% confidence interval [CI95%] = 0.14, 0.59), with patient psychological care (OR = 0.56; CI95% = 0.32, 0.98), and with family support (OR = 0.52; CI95% = 0.35, 0.77) than caregivers of patients in an inpatient setting. If aged over 60 years, caregivers were less likely to have their information needs met regarding available support services (OR = 0.98; CI95% = 0.97, 0.98) and carer payments (OR = 0.99; CI95% = 0.98, 1.00). Also, caregivers were less likely to receive adequate information about carer payments if located in an outer regional area (OR = 0.41; CI95% = 0.25, 0.64). With practical training, caregivers receiving care from community services reported inadequate information provision to support them in caring for patients (OR = 0.60; CI95% = 0.45, 0.81). SIGNIFICANCE OF RESULTS: While our study identified caregivers as having positive and satisfactory experiences across all domains of care, there is room for improvement in the delivery of palliative care across symptom management, as well as patient and caregiver support, especially in community settings. Caregiver surveys can facilitate the identification and evaluation of both patients' and caregivers' experiences, satisfaction, distress, and unmet needs. PMID- 28357974 TI - Immunisation status and determinants of left-behind children aged 12-72 months in central China. AB - Many parents move from rural China to urban areas in search of job opportunities, and leave their children behind to be raised by relatives. We aimed to assess the immunisation coverage, including the 1:3:3:3:1 vaccine series (one dose of Bacilli Chalmette-Guerin vaccine; three doses of live attenuated oral poliomyelitis vaccine; three doses of diphtheria, tetanus and pertussis combined; three doses of hepatitis B vaccine; and one dose of measles-containing vaccine), in children aged 12-72 months and identify the determinants of immunisation uptake among left-behind children in Hubei Province, Central China, in 2014. In this cross-sectional study using the World Health Organization's cluster sampling technique, we surveyed 1368 children from 44 villages in 11 districts of Hubei Province. The socio-demographic and vaccination status data were collected by interviewing primary caregivers using a semi-structured questionnaire and reviewing the immunisation cards of the children. Univariate and multivariate analyses were used to identify the determinants of complete vaccination and age appropriate vaccination. For each dose of the five vaccines, the vaccination coverage in the left-behind and non-left-behind children was >90%; however, the age-appropriate vaccination coverage for each vaccine was lower in left-behind than in non-left-behind children. For the five vaccines, the fully vaccinated rate of left-behind children were lower than those of non-left-behind children (89.1%, 92.7%; P = 0.013) and age-appropriate immunisation rate of left-behind children were lower than those of non-left-behind children (65.7%, 79.9%; P < 0.001). After controlling for potential confounders, we found that the parenting pattern, annual household income and attitude of the primary caregiver towards vaccination significantly influenced the vaccination status of children. Moreover, we noted a relatively high prevalence of delayed vaccination among left behind children. Hence, we believe that the age-appropriate immunisation coverage rate among left-behind children in rural areas should be further improved by delivering and sustaining primary care services. PMID- 28357976 TI - Household dietary diversity, vitamin A consumption and food security in rural Tigray, Ethiopia. AB - OBJECTIVE: To describe: household dietary diversity across four zones in Ethiopia; the relationship between household dietary diversity and consumption of vitamin A-rich foods; and the relationship between household dietary diversity and food security status. DESIGN: This was a cross-sectional survey. Data were collected using structured questionnaires in the local language. Household dietary diversity scores measured types of foods households consumed, and households were classified by food security status using a modified version of the Household Food Insecurity Access Scale. An ordinal logistics regression model was created to assess the relationship between three tiers of dietary diversity (low, medium and high) and food security while controlling for agricultural zone, educational variables and household characteristics. SETTING: Rural households in Tigray, Ethiopia. SUBJECTS: Three hundred households in Tigray, Ethiopia, were interviewed. RESULTS: Of the households, 23, 47 and 30 % had low, medium and high dietary diversity, respectively. Among households with high dietary diversity, eggs and fruit were the most common foods added to the diet. In the fully adjusted model, participants who reported being food secure had 1.8 increased odds of greater dietary diversity (95 % CI 1.0, 3.2) compared with participants who were food insecure. CONCLUSIONS: Food security was positively associated with dietary diversity. In order to enhance health, interventions that improve dietary diversity and vitamin A consumption should remain important areas of focus for health leaders in the region. PMID- 28357975 TI - Feasibility and Efficacy of Brief Computerized Training to Improve Emotion Recognition in Premanifest and Early-Symptomatic Huntington's Disease. AB - OBJECTIVES: Deficits in the recognition of negative emotions emerge before clinical diagnosis in Huntington's disease (HD). To address emotion recognition deficits, which have been shown in schizophrenia to be improved by computerized training, we conducted a study of the feasibility and efficacy of computerized training of emotion recognition in HD. METHODS: We randomly assigned 22 individuals with premanifest or early symptomatic HD to the training or control group. The training group used a self-guided online training program, MicroExpression Training Tool (METT), twice weekly for 4 weeks. All participants completed measures of emotion recognition at baseline and post-training time points. Participants in the training group also completed training adherence measures. RESULTS: Participants in the training group completed seven of the eight sessions on average. Results showed a significant group by time interaction, indicating that METT training was associated with improved accuracy in emotion recognition. CONCLUSIONS: Although sample size was small, our study demonstrates that emotion recognition remediation using the METT is feasible in terms of training adherence. The evidence also suggests METT may be effective in premanifest or early-symptomatic HD, opening up a potential new avenue for intervention. Further study with a larger sample size is needed to replicate these findings, and to characterize the durability and generalizability of these improvements, and their impact on functional outcomes in HD. (JINS, 2017, 23, 314 321). PMID- 28357977 TI - Food-based dietary guidelines: a comparative analysis between the Dietary Guidelines for the Brazilian Population 2006 and 2014. AB - OBJECTIVE: In 2014, the Brazilian Ministry of Health launched the second edition of the Dietary Guidelines for the Brazilian Population (DGBP), which deploys the new food classification NOVA. It esteems that the second DGBP overcomes the limitations in the previous food guide, reformulating the diet concepts, food pattern, culture and system. The present paper analyses the advances and limits established in the second edition, contrasting with its first edition. DESIGN: The study employs a discourse analysis. The corpus was established through four stages: (i) floating reading of the empirical materials; (ii) deepening readings; (iii) selected discursive sequences; and (iv) organization of the discursive sequences into a matrix for analysis. The data analysis used three steps: (i) identification of similar texts in external materials; (ii) elucidation of linguistic effect through deepening readings of the external materials; and (iii) systematic analysis to identify sequences that expressed equivalence or disparities. SETTING: Brazil. SUBJECTS: DGBP 2006 and 2014. RESULTS: Adoption of the NOVA food classification, based on food processing level, enabled the development of dietary guidelines that consider the limitations of the nutritional discourse and may incorporate the sociocultural and social environmental discourses, evoking pleasure in food, diversity of feeding habits and stimulating culinary practices as promoters of healthy eating practices. CONCLUSIONS: The second DGBP enables a new way of thinking about meals and foods, on the strengthening of socio-cultural dimensions of feeding, and on addressing food and nutritional guidelines on culinary practices, eating and edibility. PMID- 28357978 TI - Monochloramine Loss Mechanisms in Tap Water. AB - Chloramination has been widely applied for drinking water disinfection, with monochloramine (NH2Cl) the dominant chloramine species. However, under neutral pH, NH2Cl can autodecompose and react with chemical components in drinking water, thus decreasing disinfection efficiency. In tap water, the NH2Cl loss rate can be influenced by temperature, pH, Cl/N molar ratio, the initial NH2Cl concentration, and the natural organic matter (NOM) concentration. A good prediction of NH2Cl loss can assist in the operation of drinking water treatment plants. In this research, a kinetic rate constant )and a reactive site fraction (S = 0.43 +/- 0.06) for the reaction between free chlorine released from NH2Cl autodecoposition and tap water NOM were derived from a kinetic model to predict the NH2Cl loss under various conditions. A temperature dependent model was also developed. The model predictions match well with the experimental results, which demonstrates the validity of the model and provides a convenient and accurate method for NH2Cl loss calculations. PMID- 28357979 TI - Adsorption of As(V), Cd(II) and Pb(II), in Multicomponent Aqueous Systems using Activated Carbons. AB - This paper studies the use of two activated carbon samples made of cocoa pod husk (CPH-AC) and one commercial activated carbon sample in the adsorption of As(V), Cd(II) and Pb(II) from multicomponent synthetic solutions and from the Puyango-Tumbes River water, a river located in northwest Peru. The characterization of the activated carbon samples was conducted. The CPH-AC samples exhibited a specific surface area (SBET) between 709 and 1117 m2/g and a pH point of zero charge (pHPZC) between 4.4 +/- 0.2 and 5 +/- 0.2, while the commercial material gave an SBET value of 775 m2/g and a pHPZC value of 7.6 +/- 0.1. All the evaluated samples displayed the capacity to adsorb As(V), Cd(II) and Pb(II) from both aqueous systems. The adsorption efficiency for Pb was outstanding reaching the value of 89%. A pseudo-second order kinetic model was satisfactorily applied for most of the activated carbon samples. PMID- 28357980 TI - Manual curation and reannotation of the genomes of Clostridium difficile 630Deltaerm and C. difficile 630. AB - PURPOSE: We resequenced the genome of Clostridium difficile 630Deltaerm (DSM 28645), a model strain commonly used for the generation of insertion mutants. METHODOLOGY: The genome sequence was obtained by a combination of single-molecule real-timeand Illumina sequencing technology. RESULTS: Detailed manual curation and comparison to the previously published genomic sequence revealed sequence differences including inverted regions and the presence of plasmid pCD630. Manual curation of our previously deposited genome sequence of the parental strain 630 (DSM 27543) led to an improved genome sequence. In addition, the sequence of the transposon Tn5397 was completely identified. We manually revised the current manual annotation of the initial sequence of strain 630 and modified either gene names, gene product names or assigned EC numbers of 57 % of genes. The number of hypothetical and conserved hypothetical proteins was reduced by 152. This annotation was used as a template to annotate the most recent genome sequences of the strains 630Deltaerm and 630. CONCLUSION: Based on the genomic analysis, several new metabolic features of C. difficile are proposed and could be supported by literature and subsequent experiments. PMID- 28357981 TI - Surveillance for nervous necrosis virus-specific antibodies in barramundi Lates calcarifer in Australian hatcheries. AB - We conducted single point-in-time and repeated cross-sectional studies of the prevalence of antibodies against nervous necrosis virus (NNV) in populations of adult barramundi Lates calcarifer in Australia. Serum samples collected between 2002 and 2012 were analyzed with indirect ELISA (n = 468). Most of the samples were sourced from broodstock with unknown exposure history, and these were compared with reference populations with confirmed history of exposure to NNV. Non-lethally collected gonad fluid samples from economically valuable barramundi broodstock (n = 164) were tested for the presence of NNV using RT-quantitative PCR at the time of blood sampling to compare infectivity with serostatus, but no virus was detected. NNV-specific immunoreactivity in broodstock was significantly lower than that for immunized and persistently infected populations. Seroprevalence increased over time in broodstock sampled longitudinally, probably reflecting repeated exposure to NNV in a region where the virus was endemic. The seroprevalence for the broodstock was 23.8% over the entire sample period while a cross-sectional survey conducted in 2012 found a seroprevalence of 34.5% with no significant difference between populations based on the geographic region or the history of occurrence of viral nervous necrosis (VNN) disease in the progeny in the respective hatcheries. Although serological surveillance was useful for studying the history of exposure of barramundi to NNV, the lack of association between serostatus in broodstock and the subsequent occurrence of VNN disease in their progeny indicates that ELISA tests for anti-NNV antibodies are not suitable for the purpose of preventing vertical transmission of NNV in barramundi. PMID- 28357982 TI - Co-infection of Acipenserid herpesvirus 2 (AciHV-2) and Streptococcus iniae in cultured white sturgeon Acipenser transmontanus. AB - A mortality event in cultured white sturgeon Acipenser transmontanus (Richardson, 1836) sub-adults was investigated. After transfer between farms, high mortality was observed in fish, associated with back arching, abnormal swimming, and ulcerative skin lesions. Necropsy of moribund individuals revealed hemorrhagic ascites and petechial hemorrhages in the coelomic peritoneum and serosa of internal organs. Acipenserid herpesvirus 2 (AciHV-2) was isolated from external tissue samples, then identified and genotyped by sequencing of the terminase and polymerase genes. In addition, Streptococcus iniae was recovered from internal organs of affected fish. Histologic changes were limited to interstitial hematopoietic areas of the kidney and consisted of small foci of necrosis accompanied by fibrin deposition, minimal inflammatory response, and small numbers of bacterial cocci compatible with streptococci. Identity was confirmed by partial sequencing of the 16S rRNA, rpoB, and gyrB genes. Genetic fingerprinting demonstrated a genetic profile distinct from S. iniae isolates recovered from previous outbreaks in wild and cultured fish in North America, South America, and the Caribbean. Although the isolates were resistant to white sturgeon complement in serum killing assays, in vivo challenges failed to fulfill Koch's postulates. However, the clinical presentation, coupled with consistent recovery of S. iniae and AciHV-2 from moribund fish, suggests viral and bacterial co-infection were the proximate cause of death. To our knowledge, this represents the first report of AciHV-2 and S. iniae co-infection in cultured white sturgeon. PMID- 28357983 TI - Experimental challenges with Renibacterium salmoninarum in Arctic charr Salvelinus alpinus. AB - Arctic charr Salvelinus alpinus L. is an important species in Icelandic aquaculture and the most common wild salmonid in Iceland. A study on the course of infection with the bacterium Renibacterium salmoninarum was conducted using 3 different challenge methods in brackish and fresh water. Bacterial isolation, ELISA and PCR tests were used for detection of the bacterium in multiple organ samples. In an experiment, run for 34 wk in brackish water, infection was established by intraperitoneal injection with 5 * 106 colony forming units (CFU) fish-1. There were external and internal symptoms of bacterial kidney disease (BKD) and mortalities between 6 and 13 wk after injection. A cohabitation trial was run simultaneously and infection was well established after 4 wk, as demonstrated by the detection methods applied. Symptoms of BKD were not seen and all but 1 cohabitant survived. In a separate experiment, infection was established by pumping a fixed amount of water from a tank with fingerlings infected by intraperitoneal injection into tanks with naive fish, in fresh or brackish water, for 6 wk. Fish in the inflow tanks were reared for an additional 3 wk. There were neither macroscopic symptoms nor mortalities. ELISA and PCR tests showed that infection started to take hold after 3 wk. The challenge trials demonstrated that Arctic charr is susceptible to R. salmoninarum. Cohabitation and inflow of water from tanks with infected fish provide useful models for further studies on R. salmoninarum infection acquired in a natural way in Arctic charr. PMID- 28357984 TI - Development of a multiplex PCR method for the simultaneous detection of four myxosporeans infecting gibel carp Carassius auratus gibelio. AB - Gibel carp Carassius auratus gibelio (Bloch), a commercially important freshwater cultured fish in China, is threatened by myxosporeans, particularly Thelohanellus wuhanensis, Myxobolus honghuensis, M. wulii and M. turpisrotundus. Here, we developed a multiplex PCR assay for simultaneous detection of these 4 myxosporeans. The specific primers for each species were designed based on the 28S rDNA gene of T. wuhanensis, the ITS-5.8S rDNA of M. honghuensis and M. wulii, and the 18S rDNA gene of M. turpisrotundus. Specificity testing confirmed that the 4 primer sets have no cross-reactivity with other related myxosporean species tested. Detection limits of the multiplex PCR assay were 0.2, 0.3, 3.1 and 3.8 spores for T. wuhanensis, M. honghuensis, M. wulii and M. turpisrotundus, respectively. Following screening of 104 field samples, the analytical sensitivity of the present multiplex PCR assay was found to be similar to the sensitivity obtained by the singleplex PCR assays and was higher than that of microscopic examination. Moreover, Kappa analysis showed a strong agreement between the results of the singleplex and multiplex PCR assays, indicating that the developed multiplex PCR assay was an efficient approach for the diagnosis of the 4 myxosporeans infecting gibel carp. PMID- 28357985 TI - Fine-scale transition to lower bacterial diversity and altered community composition precedes shell disease in laboratory-reared juvenile American lobster. AB - The American lobster Homarus americanus supports a valuable commercial fishery in the Northeastern USA and Maritime Canada; however, stocks in the southern portion of the lobster's range have shown declines, in part due to the emergence of shell disease. Epizootic shell disease is a bacterially induced cuticular erosion that renders even mildly affected lobsters unmarketable because of their appearance, and in more severe cases can cause mortality. Despite the importance of this disease, the associated bacterial communities have not yet been fully characterized. We sampled 2 yr old, laboratory-reared lobsters that displayed signs of shell disease at the site of disease as well as at 0.5, 1, and 1.5 cm away from the site of disease to determine how the bacterial community changed over this fine spatial scale. Illumina sequencing of the 16S rRNA gene revealed a distinct bacterial community at the site of disease, with significant reductions in bacterial diversity and richness compared to more distant sampling locations. The bacterial community composition 0.5 cm from the site of disease was also altered, and there was an observable decrease in bacterial diversity and richness, even though there were no signs of disease at that location. Given the distinctiveness of the bacterial community at the site of disease and 0.5 cm from the site of disease, we refer to these communities as affected and transitionary, and suggest that these bacteria, including the previously proposed causative agent, Aquimarina 'homaria', are important for the initiation and progression of this laboratory model of shell disease. PMID- 28357986 TI - Seasonal variation in chaetognath and parasite species assemblages along the northeastern coast of the Yucatan Peninsula. AB - Chaetognaths are abundant carnivores with broad distributions that are intermediate hosts of trophically transmitted parasites. Monthly variations in chaetognath and parasite species distributions, abundance, prevalence, and intensity related to seasonal environmental changes were recorded in 2004 and 2005 in Laguna Nichupte, a coral reef, and the adjoining continental shelf of Quintana Roo, Mexico. Of 12 chaetognath species plus Sagitta spp., only 5 (Ferosagitta hispida, Flaccisagitta enflata, Sagitta spp., Serratosagitta serratodentata, and Pterosagitta draco) were parasitized. These species were parasitized with 33 types of flatworms and unidentified cysts (likely protozoan ciliates), having an overall mean prevalence of 6%. Digenean metacercaria larvae numerically dominated the parasite assemblages. Cluster analysis defined 2 chaetognath species assemblages. One included 7 species inside Laguna Nichupte, where F. hispida was numerically dominant (98.9%); the other contained 13 chaetognath species in the continental shelf-coral reef region, where F. enflata was abundant (53%). Canonical correspondence analysis showed that Laguna Nichupte had highly variable and hostile conditions (relatively low salinity and high temperature) for chaetognath species except for F. hispida. The higher density of F. hispida promoted greater parasite diversity (23 types), dominated by Brachyphallus sp. metacercariae. F. enflata prevailed in the continental shelf coral reef area, which had stable high salinity and relatively low temperature. Monilicaecum and unidentified digenean 'type g' infected 5 chaetognath species on the continental shelf. Distinct primary hosts (mollusks and copepods) and contrasting environmental conditions (salinity, dissolved oxygen concentration, and temperature) between Laguna Nichupte and the continental shelf promoted distinct chaetognath species assemblages, resulting in distinct parasite diversity and prevalence patterns. PMID- 28357987 TI - Health status of corals surrounding Kish Island, Persian Gulf. AB - Corals in the Persian Gulf exist in a harsh environment with extreme temperature and salinity fluctuations. Understanding the health of these hardy corals may prove useful for predicting the survival of other marine organisms facing the impacts of global climate change. In this study, the health state of corals was surveyed along belt transects at 4 sites on the east side of Kish Island, Iran. Corals had a patchy distribution, low colony densities and species diversity, and were dominated by Acropora, Porites, and Dipsastrea. We found chronic sedimentation on corals, a high prevalence of old partial mortality, abundant bioeroders, and overgrowth of corals by sponges and bryozoans. These are all signs indicating suboptimal environmental conditions for coral reefs. Four types of tissue loss lesions consistent with disease were found: Porites multi-focal chronic tissue loss, Porites peeling tissue loss, Porites focal chronic tissue loss, and Dipsastrea focal sub-acute tissue loss. Overall disease prevalence was 3.6% and there were significant differences in prevalence among the 3 most abundant coral genera. Acropora was numerically dominant within transects yet showed no signs of disease, whereas Porites had a 14% disease prevalence, indicating differential susceptibility to disease among genera. Other coral lesions included pigmentation response in Porites associated with algae invasion or boring organisms, sponge overgrowth, and mucus sheathing in Dipsastrea. The Persian Gulf region is understudied, and this represents one of the first quantitative surveys of coral health and disease on these reefs. PMID- 28357989 TI - Impact of new data for neutron-rich heavy nuclei on theoretical models for r process nucleosynthesis. AB - Current models for the r process are summarized with an emphasis on the key constraints from both nuclear physics measurements and astronomical observations. In particular, we analyze the importance of nuclear physics input such as beta decay rates; nuclear masses; neutron-capture cross sections; beta-delayed neutron emission; probability of spontaneous fission, beta- and neutron-induced fission, fission fragment mass distributions; neutrino-induced reaction cross sections, etc. We highlight the effects on models for r-process nucleosynthesis of newly measured beta-decay half-lives, masses, and spectroscopy of neutron-rich nuclei near the r-process path. We overview r-process nucleosynthesis in the neutrino driven wind above the proto-neutron star in core collapse supernovae along with the possibility of magneto-hydrodynamic jets from rotating supernova explosion models. We also consider the possibility of neutron star mergers as an r-process environment. A key outcome of newly measured nuclear properties far from stability is the degree of shell quenching for neutron rich isotopes near the closed neutron shells. This leads to important constraints on the sites for r process nucleosynthesis in which freezeout occurs on a rapid timescale. PMID- 28357988 TI - Isolation of Lacinutrix venerupis strains associated with disease outbreaks in sea bream Sparus aurata and European sea bass Dicentrarchus labrax. AB - Four Gram-negative bacterial isolates were recovered from 2 disease outbreaks that occurred in 2013 affecting European sea bass Dicentrarchus labrax fry and sea bream Sparus aurata adults. Main symptoms were erratic swimming, eroded fins and, in the sea bream outbreak, haemorrhages on the body surface; bacteria were always recovered from internal organs, almost in pure culture. On the basis of phenotypic characterization and 16S rRNA gene sequence analysis, the isolates were identified as Lacinutrix venerupis, a bacterium not previously reported as a fish pathogen. The highest 16S rDNA sequence similarities were recorded with the type strain of this species (99.9-100% similarity), while other species showed similarities below 97%, the closest relative being L. mariniflava (96.3% similarity). Phenotypic characterization showed some discrepancies with the L. venerupis type strain (mainly in BIOLOG GN profile); however, DNA-DNA hybridization assays with L. venerupis and L. mariniflava type strains confirmed that these isolates belong to the former species (levels of DNA relatedness were 98-100% and 38-50%, respectively). Finally, a virulence evaluation of the isolates using Senegalese sole Solea senegalensis fry was also performed; significant mortalities (80-100% mortality within 4 d) were recorded after intraperitoneal injection, but only with high doses of bacteria (107colony forming units fish-1). Further studies will be necessary to determine the importance of this species as a fish pathogen. PMID- 28357990 TI - Determination of intrinsic mobility of a bilayer oxide thin-film transistor by pulsed I-V method. AB - Amorphous oxide semiconductor thin-film transistors (TFT) have been considered as outstanding switch devices owing to their high mobility. However, because of their amorphous channel material with a certain level of density of states, a fast transient charging effect in an oxide TFT occurs, leading to an underestimation of the mobility value. In this paper, the effects of the fast charging of high-performance bilayer oxide semiconductor TFTs on mobility are examined in order to determine an accurate mobility extraction method. In addition, an approach based on a pulse I D -V G measurement method is proposed to determine the intrinsic mobility value. Even with the short pulse I D -V G measurement, a certain level of fast transient charge trapping cannot be avoided as long as the charge-trap start time is shorter than the pulse rising time. Using a pulse-amplitude-dependent threshold voltage characterization method, we estimated a correction factor for the apparent mobility, thus allowing us to determine the intrinsic mobility. PMID- 28357992 TI - Adsorption and diffusion of mono, di, and trivalent ions on two-dimensional TiS2. AB - A comparative study of the monovalent (Li, Na, and K) and multivalent (Be, Mg, Ca, and Al) metal ion adsorption and diffusion on an electronically semi-metallic two-dimensional nanosheet of 1T structured TiS2 is presented here to contribute to the search for abundant, cheap, and nontoxic ingredients for efficient rechargeable metal ion batteries. The total formation energy of the metal ion adsorption and the Bader charge analysis show that the divalent Mg and Ca ions can have a charge storage density double that of the monovalent Li, Na, and K ions, while the Be and Al ions form metallic clusters even at a low adsorption density because of their high bulk energies. The adsorption of Mg ions shows the lowest averaged open circuit voltage (0.13 V). The activation energy barriers for the diffusion of metal ions on the surface of the monolayer successively decrease from Li to K and Be to Ca. Mg and Ca, being divalent, are capable of storing a higher power density than Li while K and Na have a higher rate capability than the Li ions. Therefore, rechargeable Li ion batteries can be totally or partially replaceable by Mg ion batteries, where high power density and high cell voltage are required, while the abundant, cheap, and fast Na ions can be used for green grid applications. PMID- 28357991 TI - A new multivariate empirical mode decomposition method for improving the performance of SSVEP-based brain-computer interface. AB - OBJECTIVE: Accurate and efficient detection of steady-state visual evoked potentials (SSVEP) in electroencephalogram (EEG) is essential for the related brain-computer interface (BCI) applications. APPROACH: Although the canonical correlation analysis (CCA) has been applied extensively and successfully to SSVEP recognition, the spontaneous EEG activities and artifacts that often occur during data recording can deteriorate the recognition performance. Therefore, it is meaningful to extract a few frequency sub-bands of interest to avoid or reduce the influence of unrelated brain activity and artifacts. This paper presents an improved method to detect the frequency component associated with SSVEP using multivariate empirical mode decomposition (MEMD) and CCA (MEMD-CCA). EEG signals from nine healthy volunteers were recorded to evaluate the performance of the proposed method for SSVEP recognition. MAIN RESULTS: We compared our method with CCA and temporally local multivariate synchronization index (TMSI). The results suggest that the MEMD-CCA achieved significantly higher accuracy in contrast to standard CCA and TMSI. It gave the improvements of 1.34%, 3.11%, 3.33%, 10.45%, 15.78%, 18.45%, 15.00% and 14.22% on average over CCA at time windows from 0.5 s to 5 s and 0.55%, 1.56%, 7.78%, 14.67%, 13.67%, 7.33% and 7.78% over TMSI from 0.75 s to 5 s. The method outperformed the filter-based decomposition (FB), empirical mode decomposition (EMD) and wavelet decomposition (WT) based CCA for SSVEP recognition. SIGNIFICANCE: The results demonstrate the ability of our proposed MEMD-CCA to improve the performance of SSVEP-based BCI. PMID- 28357993 TI - Fabrication of fluorescent composite hydrogel using in situ synthesis of upconversion nanoparticles. AB - Fluorescent composite hydrogels have found widespread applications, especially in spatial and temporal monitoring of in vivo hydrogel behaviors via the emitting optical signal. However, most existing fluorescent composite hydrogels suffer from limited capability of deep tissue imaging and complicated fabrication routes. We herein report a facile method for fabricating fluorescent composite hydrogels based on the in situ synthesis of NaYF4:Yb, Er upconversion nanoparticles (UCNPs). This approach employs polyacrylamide (PAAm) hydrogels as a template, where the interconnected pores within the hydrogel act as nanoreactors to confine the growth of nanocrystals. We then obtained a fluorescent composite hydrogel exhibiting upconversion fluorescence and enhanced mechanical properties. The fluorescence spectra show that the fluorescence intensity decreases with decreasing size of the UCNPs. We investigated the relationship between the optical properties of the fluorescent composite hydrogel and the incorporated UCNPs based on the morphology, size, and distribution of the UCNPs by using scanning electron microscopy and transmission electron microscopy. In addition, we demonstrated the applicability of the synthesized hydrogel for deep tissue imaging through an in vitro tissue penetration experiment. Compressive and dynamic rheological testing reveal enhanced mechanical properties with increasing UCNP concentration. The fabricated upconversion fluorescent composite hydrogel may pave the way for monitoring the in vivo behavior of biomimetic materials via deep tissue imaging. PMID- 28357994 TI - Rapid quantification of live/dead lactic acid bacteria in probiotic products using high-sensitivity flow cytometry. AB - A laboratory-built high-sensitivity flow cytometer (HSFCM) was employed for the rapid and accurate detection of lactic acid bacteria (LAB) and their viability in probiotic products. LAB were stained with both the cell membrane-permeable SYTO 9 green-fluorescent nucleic acid stain and the red-fluorescent nucleic acid stain, propidium iodide, which penetrates only bacteria with compromised membranes. The side scatter and dual-color fluorescence signals of single bacteria were detected simultaneously by the HSFCM. Ultra-high temperature processing milk and skim milk spiked with Lactobacillus casei were used as the model systems for the optimization of sample pretreatment and staining. The viable LAB counts measured by the HSFCM were in good agreement with those of the plate count method, and the measured ratios between the live and dead LAB matched well with the theoretical ratios. The established method was successfully applied to the rapid quantification of live/dead LAB in yogurts and fermented milk beverages of different brands. Moreover, the concentration and viability status of LAB in ambient yogurt, a relatively new yet popular milk product in China, are also reported. PMID- 28357995 TI - Recent advances in the spin Hall effect of light. AB - The spin Hall effect (SHE) of light, as an analogue of the SHE in electronic systems, is a promising candidate for investigating the SHE in semiconductor spintronics/valleytronics, high-energy physics and condensed matter physics, owing to their similar topological nature in the spin-orbit interaction. The SHE of light exhibits unique potential for exploring the physical properties of nanostructures, such as determining the optical thickness, and the material properties of metallic and magnetic thin films and even atomically thin two dimensional materials. More importantly, it opens a possible pathway for controlling the spin states of photons and developing next-generation photonic spin Hall devices as a fundamental constituent of the emerging spinoptics. In this review, based on the viewpoint of the geometric phase gradient, we give a detailed presentation of the recent advances in the SHE of light and its applications in precision metrology and future spin-based photonics. PMID- 28357996 TI - Doxycycline-loaded coaxial nanofiber coating of titanium implants enhances osseointegration and inhibits Staphylococcus aureus infection. AB - Few studies have been reported that focus on developing implant surface nanofiber (NF) coating to prevent infection and enhance osseointegration by local drug release. In this study, coaxial doxycycline (Doxy)-doped polycaprolactone/polyvinyl alcohol (PCL/PVA) NFs were directly deposited on a titanium (Ti) implant surface during electrospinning. The interaction of loaded Doxy with both PVA and PCL NFs was characterized by Raman spectroscopy. The bonding strength of Doxy-doped NF coating on Ti implants was confirmed by a stand single-pass scratch test. The improved implant osseointegration by PCL/PVA NF coatings in vivo was confirmed by scanning electron microscopy, histomorphometry and micro computed tomography (MUCT) at 2, 4 and 8 weeks after implantation. The bone contact surface (%) changes of the NF coating group (80%) is significantly higher than that of the no NF group (<5%, p < 0.05). Finally, we demonstrated that a Doxy-doped NF coating effectively inhibited bacterial infection and enhanced osseointegration in an infected (Staphylococcus aureus) tibia implantation rat model. Doxy released from NF coating inhibited bacterial growth up to 8 weeks in vivo. The maximal push-in force of the Doxy-NF coating (38 N) is much higher than that of the NF coating group (6.5 N) 8 weeks after implantation (p < 0.05), which was further confirmed by quantitative histological analysis and MUCT. These findings indicate that coaxial PCL/PVA NF coating doped with Doxy and/or other drugs have great potential in enhancing implant osseointegration and preventing infection. PMID- 28357997 TI - Effects of Acupuncture on mRNA Levels of Apoptotic Factors in Perihematomal Brain Tissue During the Acute Phase of Cerebral Hemorrhage. AB - BACKGROUND To explore the time-dependent effects of acupuncture on mRNA levels of the apoptotic factors BCL-2 and BAX in a rat cerebral hemorrhage model, slow injection of autologous blood to the caudate nucleus was used to generate the cerebral hemorrhage model. MATERIAL AND METHODS A sham surgery control group, groups with acupuncture applied 3, 9, 24, and 48 hours after model induction, and time-matched model-only control groups were used. In situ hybridization was used to detect BCL-2 and BAX mRNA expression, and semi-quantitative RT-PCR was used to measure the expression. RESULTS The number of BCL-2 and BAX mRNA-positive cells significantly increased during the acute phase of cerebral hemorrhage. BCL-2 mRNA was significantly upregulated in acupuncture groups compared to other groups, whereas BAX mRNA levels in the acupuncture groups were lower in the other groups, except for the sham surgery group. Additionally, earlier acupuncture intervention was associated with a lower ratio of expression between the two genes. Changes in BCL-2 and BAX mRNA expression were consistent with changes in the number of cells positive for BCL-2 and BAX mRNA; however, the change in the expression ratio was consistent with the change in the number of cells positive for BCL-2 mRNA, but opposite to the change in the number of cells positive for BAX mRNA. CONCLUSIONS Acupuncture ameliorated changes in expression of apoptotic factors in the brain induced by acute cerebral hemorrhage and may thus protect the brain, with greater efficacy when the delay before acupuncture was minimized. PMID- 28357998 TI - Incidence of atrial fibrillation and its risk prediction model based on a prospective urban Han Chinese cohort. AB - Prediction models of atrial fibrillation (AF) have been developed; however, there was no AF prediction model validated in Chinese population. Therefore, we aimed to investigate the incidence of AF in urban Han Chinese health check-up population, as well as to develop AF prediction models using behavioral, anthropometric, biochemical, electrocardiogram (ECG) markers, as well as visit-to visit variability (VVV) in blood pressures available in the routine health check up. A total of 33 186 participants aged 45-85 years and free of AF at baseline were included in this cohort, to follow up for incident AF with an annually routine health check-up. Cox regression models were used to develop AF prediction model and 10-fold cross-validation was used to test the discriminatory accuracy of prediction model. We developed three prediction models, with age, sex, history of coronary heart disease (CHD), hypertension as predictors for simple model, with left high-amplitude waves, premature beats added for ECG model, and with age, sex, history of CHD and VVV in systolic and diabolic blood pressures as predictors for VVV model, to estimate risk of incident AF. The calibration of our models ranged from 1.001 to 1.004 (P for Hosmer Lemeshow test >0.05). The area under receiver operator characteristics curve were 78%, 80% and 82%, respectively, for predicting risk of AF. In conclusion, we have identified predictors of incident AF and developed prediction models for AF with variables readily available in routine health check-up. PMID- 28357999 TI - Epithelial tension in the second heart field promotes mouse heart tube elongation. AB - Extension of the vertebrate heart tube is driven by progressive addition of second heart field (SHF) progenitor cells to the poles of the heart. Defects in this process cause a spectrum of congenital anomalies. SHF cells form an epithelial layer in splanchnic mesoderm in the dorsal wall of the pericardial cavity. Here we report oriented cell elongation, polarized actomyosin distribution and nuclear YAP/TAZ in a proliferative centre in the posterior dorsal pericardial wall during heart tube extension. These parameters are indicative of mechanical stress, further supported by analysis of cell shape changes in wound assays. Time course and mutant analysis identifies SHF deployment as a source of epithelial tension. Moreover, cell division and oriented growth in the dorsal pericardial wall align with the axis of cell elongation, suggesting that epithelial tension in turn contributes to heart tube extension. Our results implicate tissue-level forces in the regulation of heart tube extension. PMID- 28358000 TI - The Par3 polarity protein is an exocyst receptor essential for mammary cell survival. AB - The exocyst is an essential component of the secretory pathway required for delivery of basolateral proteins to the plasma membranes of epithelial cells. Delivery occurs adjacent to tight junctions (TJ), suggesting that it recognizes a receptor at this location. However, no such receptor has been identified. The Par3 polarity protein associates with TJs but has no known function in membrane traffic. We now show that, unexpectedly, Par3 is essential for mammary cell survival. Par3 silencing causes apoptosis, triggered by phosphoinositide trisphosphate depletion and decreased Akt phosphorylation, resulting from failure of the exocyst to deliver basolateral proteins to the cortex. A small region of PAR3 binds directly to Exo70 and is sufficient for exocyst docking, membrane protein delivery and cell survival. PAR3 lacking this domain can associate with the cortex but cannot support exocyst function. We conclude that Par3 is the long sought exocyst receptor required for targeted membrane-protein delivery. PMID- 28358003 TI - Loss of anti-contractile effect of perivascular adipose tissue in offspring of obese rats. AB - This corrects the article DOI: 10.1038/ijo.2016.62. PMID- 28358001 TI - SGK1 affects RAN/RANBP1/RANGAP1 via SP1 to play a critical role in pre-miRNA nuclear export: a new route of epigenomic regulation. AB - The serum- and glucocorticoid-regulated kinase (SGK1) controls cell transformation and tumor progression. SGK1 affects mitotic stability by regulating the expression of RANBP1/RAN. Here, we demonstrate that SGK1 fluctuations indirectly modify the maturation of pre-miRNAs, by modulating the equilibrium of the RAN/RANBP1/RANGAP1 axis, the main regulator of nucleo cytoplasmic transport. The levels of pre-miRNAs and mature miRNAs were assessed by qRT-PCR, in total extracts and after differential nuclear/cytoplasmic extraction. RANBP1 expression is the limiting step in the regulation of SGK1-SP1 dependent nuclear export. These results were validated in unrelated tumor models and primary human fibroblasts and corroborated in tumor-engrafted nude mice. The levels of pri-miRNAs, DROSHA, DICER and the compartmental distribution of XPO5 were documented. Experiments using RANGTP conformational antibodies confirmed that SGK1, through RANBP1, decreases the level of the GTP-bound state of RAN. This novel mechanism may play a role in the epigenomic regulation of cell physiology and fate. PMID- 28358002 TI - Pressure modulates the self-cleavage step of the hairpin ribozyme. AB - The ability of certain RNAs, denoted as ribozymes, to not only store genetic information but also catalyse chemical reactions gave support to the RNA world hypothesis as a putative step in the development of early life on Earth. This, however, might have evolved under extreme environmental conditions, including the deep sea with pressures in the kbar regime. Here we study pressure-induced effects on the self-cleavage of hairpin ribozyme by following structural changes in real-time. Our results suggest that compression of the ribozyme leads to an accelerated transesterification reaction, being the self-cleavage step, although the overall process is retarded in the high-pressure regime. The results reveal that favourable interactions between the reaction site and neighbouring nucleobases are strengthened under pressure, resulting therefore in an accelerated self-cleavage step upon compression. These results suggest that properly engineered ribozymes may also act as piezophilic biocatalysts in addition to their hitherto known properties. PMID- 28358004 TI - Epidemic trend of periodontal disease in elderly Chinese population, 1987-2015: a systematic review and meta-analysis. AB - Periodontal disease is a common oral health problem in the elderly population. The prevalence varied substantially due to absence of a universal diagnostic criteria. We conducted a systematic review to identify the epidemiological characteristics of periodontal diseases among Chinese elderly people. A total of 19 articles were included. The pooled detection rates for three indicators, including bleeding on probing (BOP), pocket depth (PD) and clinical attachment loss (CAL), were 53.9% (95% CI: 43.8-63.9%), 57.0% (50.8-63.2%), and 70.1% (65.4 74.8%), respectively. No significant differences in these indicators between urban and rural population. When stratified by gender, BOP (+) detection rates did not show any differences, but the detection rates of PD >= 4 mm and CAL >= 4 mm were significantly higher in males than in females (59.3% [53.4-65.2%] versus 50.8% [43.5-58.0%], RRPD = 1.13 [1.01-1.26]; 73.8% [70.0-77.7%] versus 65.2% [60.2-70.2%], RRCAL = 1.21 [1.11-1.32]). No statistically significant differences were observed between CAL >= 4 mm and PD >= 4 mm (RR = 1.12, [0.83-1.50]). A geographical map based on available data during 1987-2015 showed wide variations of periodontal disease across the mainland China. Some factors such as heterogeneity of case definitions, no specific diagnosis of periodontitis, and variable quality of the included studies could affect the final results. Hence, further high-quality epidemiological studies with standardized diagnostic criteria are needed. PMID- 28358005 TI - Structural intermediates and directionality of the swiveling motion of Pyruvate Phosphate Dikinase. AB - Pyruvate phosphate dikinase (PPDK) is a vital enzyme in cellular energy metabolism catalyzing the ATP- and Pi-dependent formation of phosphoenolpyruvate from pyruvate in C4 -plants, but the reverse reaction forming ATP in bacteria and protozoa. The multi-domain enzyme is considered an efficient molecular machine that performs one of the largest single domain movements in proteins. However, a comprehensive understanding of the proposed swiveling domain motion has been limited by not knowing structural intermediates or molecular dynamics of the catalytic process. Here, we present crystal structures of PPDKs from Flaveria, a model genus for studying the evolution of C4 -enzymes from phylogenetic ancestors. These structures resolve yet unknown conformational intermediates and provide the first detailed view on the large conformational transitions of the protein in the catalytic cycle. Independently performed unrestrained MD simulations and configurational free energy calculations also identified these intermediates. In all, our experimental and computational data reveal strict coupling of the CD swiveling motion to the conformational state of the NBD. Moreover, structural asymmetries and nucleotide binding states in the PPDK dimer support an alternate binding change mechanism for this intriguing bioenergetic enzyme. PMID- 28358006 TI - Specialist nectar-yeasts decline with urbanization in Berlin. AB - Nectar yeasts are common inhabitants of insect-pollinated flowers but factors determining their distribution are not well understood. We studied the influence of host identity, environmental factors related to pollution/urbanization, and the distance to a target beehive on local distribution of nectar yeasts within Robinia pseudoacacia L. and Tilia tomentosa Moench in Berlin, Germany. Nectar samples of six individuals per species were collected at seven sites in a 2 km radius from each target beehive and plated on YM-Agar to visualise the different morphotypes, which were then identified by sequencing a section of the 26S rDNA gene. Multivariate linear models were used to analyze the effects of all investigated factors on yeast occurrence per tree. Yeast distribution was mainly driven by host identity. The influence of the environmental factors (NO2, height of construction, soil sealing) strongly depended on the radius around the tree, similar to the distance of the sampled beehive. Incidence of specialist nectar borne yeast species decreased with increasing pollution/urbanization index. Given that specialist yeast species gave way to generalist yeasts that have a reduced dependency on pollinators for between-flower dispersal, our results indicate that increased urbanization may restrict the movement of nectar-specialized yeasts, via limitations of pollinator foraging behavior. PMID- 28358007 TI - Cholesterol-mediated allosteric regulation of the mitochondrial translocator protein structure. AB - Cholesterol is an important regulator of membrane protein function. However, the exact mechanisms involved in this process are still not fully understood. Here we study how the tertiary and quaternary structure of the mitochondrial translocator protein TSPO, which binds cholesterol with nanomolar affinity, is affected by this sterol. Residue-specific analysis of TSPO by solid-state NMR spectroscopy reveals a dynamic monomer-dimer equilibrium of TSPO in the membrane. Binding of cholesterol to TSPO's cholesterol-recognition motif leads to structural changes across the protein that shifts the dynamic equilibrium towards the translocator monomer. Consistent with an allosteric mechanism, a mutation within the oligomerization interface perturbs transmembrane regions located up to 35 A away from the interface, reaching TSPO's cholesterol-binding motif. The lower structural stability of the intervening transmembrane regions provides a mechanistic basis for signal transmission. Our study thus reveals an allosteric signal pathway that connects membrane protein tertiary and quaternary structure with cholesterol binding. PMID- 28358010 TI - High Speed Computational Ghost Imaging via Spatial Sweeping. AB - Computational ghost imaging (CGI) achieves single-pixel imaging by using a Spatial Light Modulator (SLM) to generate structured illuminations for spatially resolved information encoding. The imaging speed of CGI is limited by the modulation frequency of available SLMs, and sets back its practical applications. This paper proposes to bypass this limitation by trading off SLM's redundant spatial resolution for multiplication of the modulation frequency. Specifically, a pair of galvanic mirrors sweeping across the high resolution SLM multiply the modulation frequency within the spatial resolution gap between SLM and the final reconstruction. A proof-of-principle setup with two middle end galvanic mirrors achieves ghost imaging as fast as 42 Hz at 80 * 80-pixel resolution, 5 times faster than state-of-the-arts, and holds potential for one magnitude further multiplication by hardware upgrading. Our approach brings a significant improvement in the imaging speed of ghost imaging and pushes ghost imaging towards practical applications. PMID- 28358009 TI - An Improved Racetrack Structure for Transporting a Skyrmion. AB - Magnetic skyrmions are promising building blocks for next generation data storage due to their stability, small size and extremely low currents to drive them, which can be used instead of traditional magnetic domain walls to store information as data bits in metalic racetrack memories. However, skyrmions can drift from the direction of electron flow due to the Magnus force and thus may annihilate at the racetrack edges, resulting in the loss of information. Here we propose a new skyrmion-based racetrack structure by adding high-K materials (materials with high magnetic crystalline anisotropy) at the edges, which confines the skyrmions in the center region of the metalic racetrack efficiently. This design can overcome both the clogging and annihilation of skyrmions according to our micromagnetic simulation, which occur normally for skyrmions moving on a racetrack under small and large driving currents, respectively. Phase diagrams for skyrmion motion on the proposed racetrack with various values of current density and racetrack edge width have been calculated and given, showing that skyrmions can be driven at a high speed (about 300 m/s) in the racetrack under relatively smaller driving currents. This design offers the possiblity of building an ultrafast and energy-efficient skyrmion transport device. PMID- 28358008 TI - Modified SJH alleviates FFAs-induced hepatic steatosis through leptin signaling pathways. AB - Samjunghwan (SJH) is an herbal formula used in traditional Korean medicine. This prescription has long been used in treatment of aging and lifestyle diseases. The current study showed the effect and mechanisms of anti-hepatic steatosis action of modified SJH (mSJH) in vitro and in vivo. Treatment with mSJH resulted in significantly decreased intracellular lipid accumulation in steatosis-induced cells. Furthermore, mSJH triggered the phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase as well as increased the expression of leptin at both protein and gene levels. In addition, C57BL6 mice fed high-fat diet (HFD) showed significant improvements in body, liver weights and fat weights; and serum, hepatic and fecal lipid parameters in response to the treatment with mSJH. Furthermore, mSJH showed favorable effects on the hepatic expression of several genes related to lipid metabolism. Betaine, one of constituents of mSJH exerted fundamental beneficial impact on FFAs-induced cells. However, the beneficial effects of mSJH were diminished upon blocking of leptin signaling by dexamethasone, suggesting the leptin signaling as a key component in mSJH mediated modulation of lipid homeostasis. Our results suggest that mSJH exerts an anti-hepatic steatosis effect via activation of leptin and associated signaling cascades related to lipid metabolism. PMID- 28358011 TI - STITCHER 2.0: primer design for overlapping PCR applications. AB - Overlapping polymerase chain reaction (PCR) is a common technique used by researchers in very diverse fields that enables the user to 'stitch' individual pieces of DNA together. Previously, we have reported a web based tool called STITCHER that provides a platform for researchers to automate the design of primers for overlapping PCR applications. Here we present STITCHER 2.0, which represents a substantial update to STITCHER. STITCHER 2.0 is a newly designed web tool that automates the design of primers for overlapping PCR. Unlike STITCHER, STITCHER 2.0 considers diverse algorithmic parameters, and returns multiple result files that include a facility for the user to draw their own primers as well as comprehensive visual guides to the user's input, output, and designed primers. These result files provide greater control and insight during experimental design and troubleshooting. STITCHER 2.0 is freely available to all users without signup or login requirements and can be accessed at the following webpage: www.ohalloranlab.net/STITCHER2.html. PMID- 28358012 TI - Suppression of FOXM1 Transcriptional Activities via a Single-Stranded DNA Aptamer Generated by SELEX. AB - The transcription factor FOXM1 binds to its consensus sequence at promoters through its DNA binding domain (DBD) and activates proliferation-associated genes. The aberrant overexpression of FOXM1 correlates with tumorigenesis and progression of many cancers. Inhibiting FOXM1 transcriptional activities is proposed as a potential therapeutic strategy for cancer treatment. In this study, we obtained a FOXM1-specific single stranded DNA aptamer (FOXM1 Apt) by SELEX with a recombinant FOXM1 DBD protein as the target of selection. The binding of FOXM1 Apt to FOXM1 proteins were confirmed with electrophoretic mobility shift assays (EMSAs) and fluorescence polarization (FP) assays. Phosphorthioate modified FOXM1 Apt (M-FOXM1 Apt) bound to FOXM1 as wild type FOXM1 Apt, and co localized with FOXM1 in nucleus. M-FOXM1-Apt abolished the binding of FOXM1 on its consensus binding sites and suppressed FOXM1 transcriptional activities. Compared with the RNA interference of FOXM1 in cancer cells, M-FOXM1 Apt repressed cell proliferation and the expression of FOXM1 target genes without changing FOXM1 levels. Our results suggest that the obtained FOXM1 Apt could be used as a probe for FOXM1 detection and an inhibitor of FOXM1 transcriptional functions in cancer cells at the same time, providing a potential reagent for cancer diagnosis and treatment in the future. PMID- 28358013 TI - Characterization of three-dimensional field distribution of bowtie aperture using quasi-spherical waves and surface plasmon polaritons. AB - We present an analytical formula to predict the three-dimensional field distribution of a nanoscale bowtie aperture using quasi-spherical waves (QSWs) and surface plasmon polaritons, which are excited by the fundamental waveguide mode and local plasmons of the aperture, respectively. Assuming two separate bowtie apertures in a metal film, we analysed the decay characteristics of QSWs using a finite difference time-domain method. To verify the formula, we recorded the spot patterns of the bowtie aperture on a photoresist film using various exposure times, and fit the patterns to the analytical formula in terms of the width and depth of the patterns. In addition, it was found that the formula successfully represented the dipole characteristics of the spot patterns, which were in agreement with the surface geometry, with a root-mean-square error of 9.4%. We expect that our theoretical formula will extend the potential applications of nanoscale bowtie apertures to plasmonic device fabrication, three dimensional plasmonic lithography, and other technologies. PMID- 28358015 TI - Prevalence, Awareness, Treatment, and Control of Hypertension among Kazakhs with high Salt Intake in Xinjiang, China: A Community-based Cross-sectional Study. AB - Hypertension is a leading cause of death worldwide; data on hypertension among ethnic minorities in China are sparse. This study aimed to estimate hypertension prevalence, awareness, treatment, and control in a Kazakh population, and to assess the association between salt intake and the above measures. A cross sectional survey was conducted among Kazakh adults (>=30 years old) in the town of Hongdun, Altay, Xinjiang. Survey procedures included a questionnaire, physical measurement, and laboratory tests. Of 1805 eligible individuals, 1668 (92.4%) were included in the analysis. After adjustment for gender, age, and occupation, prevalence of hypertension was 45.5%. The proportions with awareness, treatment, control, or medication-control were 61.0%, 28.8%, 2.9% and 10.1%, respectively. Higher prevalence was seen among nomads and farmers (50.7% and 44.6%, respectively). However, the proportions with treatment or control were lower than seen among urban citizens. Hypertension prevalence was higher in those with higher salt intake (p = 0.0008). In contrast, the proportions with awareness (p = 0.0389), treatment (p = 0.0010), control (p = 0.0503), and medication-control (p = 0.2012) reduced as salt intake increased. In conclusion, hypertension prevalence is high in this population, but the proportions with awareness, treatment, or control are sub-optimal. Public health interventions that improve hypertension prevention and control, particularly among nomads, is needed. PMID- 28358014 TI - Untargeted metabolomics analysis reveals key pathways responsible for the synergistic killing of colistin and doripenem combination against Acinetobacter baumannii. AB - Combination therapy is deployed for the treatment of multidrug-resistant Acinetobacter baumannii, as it can rapidly develop resistance to current antibiotics. This is the first study to investigate the synergistic effect of colistin/doripenem combination on the metabolome of A. baumannii. The metabolite levels were measured using LC-MS following treatment with colistin (2 mg/L) or doripenem (25 mg/L) alone, and their combination at 15 min, 1 hr and 4 hr (n = 4). Colistin caused early (15 min and 1 hr) disruption of the bacterial outer membrane and cell wall, as demonstrated by perturbation of glycerophospholipids and fatty acids. Concentrations of peptidoglycan biosynthesis metabolites decreased at 4 hr by doripenem alone, reflecting its mechanism of action. The combination induced significant changes to more key metabolic pathways relative to either monotherapy. Down-regulation of cell wall biosynthesis (via D sedoheptulose 7-phosphate) and nucleotide metabolism (via D-ribose 5-phosphate) was associated with perturbations in the pentose phosphate pathway induced initially by colistin (15 min and 1 hr) and later by doripenem (4 hr). We discovered that the combination synergistically killed A. baumannii via time dependent inhibition of different key metabolic pathways. Our study highlights the significant potential of systems pharmacology in elucidating the mechanism of synergy and optimizing antibiotic pharmacokinetics/pharmacodynamics. PMID- 28358016 TI - Plasma Apolipoprotein A-V Predicts Long-term Survival in Chronic Hepatitis B Patients with Acute-on-Chronic Liver Failure. AB - Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a life threatening condition, and the lipid metabolism disorder is common in the development of this disease. This prospective observational study aimed to define the characteristics of plasma apolipoprotein A-V (apoA-V) in long-term outcome prediction of HBV-ACLF, and a total of 330 HBV-ACLF patients were included and followed for more than 12 months. In this cohort, the 4-week, 12-week, 24-week and 48-week cumulative mortality of HBV-ACLF was 18.2%(60/330), 50.9%(168/330), 59.7%(197/330) and 63.3%(209/330), respectively. As compared to survivors, the non-survivors had significantly lower concentrations of plasma apoA-V on admission. Plasma apoA-V concentrations were positively correlated with prothrombin time activity (PTA), and negatively correlated with interleukin-10, tumor necrosis factor-alpha, and iMELD scores. Though plasma apoA-V, PTA, total bilirubin(TBil) and blood urea nitrogen(BUN) were all independent factors to predict one-year outcomes of HBV-ACLF, plasma apoA-V had the highest prediction accuracy. And its optimal cutoff value for one-year survival prediction was 480.00 ng/mL, which had a positive predictive value of 84.68% and a negative predictive value of 92.23%. In summary, plasma apoA-V decreases significantly in non-survivors of HBV-ACLF, and it may be regarded as a new predictive marker for the prognosis of patients with HBV-ACLF. PMID- 28358018 TI - Irreversibility transition of colloidal polycrystals under cyclic deformation. AB - Cyclically loaded disordered particle systems, such as granular packings and amorphous media, display a non-equilibrium phase transition towards irreversibility. Here, we investigate numerically the cyclic deformation of a colloidal polycrystal with impurities and reveal a transition to irreversible behavior driven by the displacement of dislocations. At the phase transition we observe enhanced particle diffusion, system size effects and broadly distributed strain bursts. In addition to provide an analogy between the deformation of amorphous and polycrystalline materials, our results allow to reinterpret Zener pinning of grain boundaries as a way to prevent the onset of irreversible crystal ordering. PMID- 28358017 TI - Electron tomographic analysis reveals ultrastructural features of mitochondrial cristae architecture which reflect energetic state and aging. AB - Within mitochondria, the ability to produce energy relies upon the architectural hallmarks of double membranes and cristae invaginations. Herein, we describe novel features of mitochondrial cristae structure, which correspond to the energetic state of the organelle. In concordance with high-energy demand, mitochondria of Drosophila indirect flight muscle exhibited extensive intra mitochondrial membrane switches between densely packed lamellar cristae that resulted in a spiral-like cristae network and allowed for bidirectional matrix confluency. This highly interconnected architecture is expected to allow rapid equilibration of membrane potential and biomolecules across integrated regions. In addition, mutant flies with mtDNA replication defect and an accelerated aging phenotype accumulated mitochondria that contained subsections of swirling membrane alongside normal cristae. The swirling membrane had impaired energy production capacity as measured by protein composition and function. Furthermore, mitochondrial fusion and fission dynamics were affected in the prematurely aged flies. Interestingly, the normal cristae that remained in the mitochondria with swirling membranes maintained acceptable function that camouflaged them from quality control elimination. Overall, structural features of mitochondrial cristae were described in three-dimension from serial section electron tomographic analysis which reflect energetic state and mtDNA-mediated aging. PMID- 28358019 TI - Scaling trends and performance evaluation of 2-dimensional polarity-controllable FETs. AB - Two-dimensional semiconducting materials of the transition-metal-dichalcogenide family, such as MoS2 and WSe2, have been intensively investigated in the past few years, and are considered as viable candidates for next-generation electronic devices. In this paper, for the first time, we study scaling trends and evaluate the performances of polarity-controllable devices realized with undoped mono- and bi-layer 2D materials. Using ballistic self-consistent quantum simulations, it is shown that, with the suitable channel material, such polarity-controllable technology can scale down to 5 nm gate lengths, while showing performances comparable to the ones of unipolar, physically-doped 2D electronic devices. PMID- 28358020 TI - NMR-based metabolomics Reveals Alterations of Electro-acupuncture Stimulations on Chronic Atrophic Gastritis Rats. AB - Chronic atrophic gastritis (CAG) is a common gastrointestinal disease which has been considered as precancerous lesions of gastric carcinoma. Previously, electro acupuncture stimulation has been shown to be effective in ameliorating symptoms of CAG. However the underlying mechanism of this beneficial treatment is yet to be established. In the present study, an integrated histopathological examination along with molecular biological assay, as well as 1H NMR analysis of multiple biological samples (urine, serum, stomach, cortex and medulla) were employed to systematically assess the pathology of CAG and therapeutic effect of electro acupuncture stimulation at Sibai (ST 2), Liangmen (ST 21), and Zusanli (ST 36) acupoints located in the stomach meridian using a rat model of CAG. The current results showed that CAG caused comprehensive metabolic alterations including the TCA cycle, glycolysis, membrane metabolism and catabolism, gut microbiota-related metabolism. On the other hand, electro-acupuncture treatment was found able to normalize a number of CAG-induced metabolomics changes by alleviating membrane catabolism, restoring function of neurotransmitter in brain and partially reverse the CAG-induced perturbation in gut microbiota metabolism. These findings provided new insights into the biochemistry of CAG and mechanism of the therapeutic effect of electro-acupuncture stimulations. PMID- 28358021 TI - Degradation of topological surface state by nonmagnetic S doping in SrxBi2Se3. AB - Research on possible topological superconductivity has grown rapidly over the past several years, from fundamental studies to the development of next generation technologies. Recently, it has been reported that the SrxBi2Se3 exhibits superconductivity with topological surface state, making this compound a promising candidate for investigating possible topological superconductivity. However, whether or not the topological surface state is robust against impurities is not clear in this system. Here we report a detailed investigation on the lattice structure, electronic and magnetic properties, as well as the topological superconducting properties of SrxBi2Se3-ySy samples. It is found that the superconducting transition temperature keeps nearly unchanged in all samples, despite of a gradual decrease of the superconducting shielding volume fraction with increasing S doping content. Meanwhile, the Shubnikov-de Hass oscillation results of the SrxBi2Se3-ySy samples reveal that the topological surface states are destroyed in S doped samples, suggesting the topological character is degraded by nonmagnetic dopants. PMID- 28358022 TI - Hot-Volumes as Uniform and Reproducible SERS-Detection Enhancers in Weakly Coupled Metallic Nanohelices. AB - Reproducible and enhanced optical detection of molecules in low concentrations demands simultaneously intense and homogeneous electric fields acting as robust signal amplifiers. To generate such sophisticated optical near-fields, different plasmonic nanostructures were investigated in recent years. These, however, exhibit either high enhancement factor (EF) or spatial homogeneity but not both. Small interparticle gaps or sharp nanostructures show enormous EFs but no near field homogeneity. Meanwhile, approaches using rounded and separated monomers create uniform near-fields with moderate EFs. Here, guided by numerical simulations, we show how arrays of weakly-coupled Ag nanohelices achieve both homogeneous and strong near-field enhancements, reaching even the limit forreproducible detection of individual molecules. The unique near-field distribution of a single nanohelix consists of broad hot-spots, merging with those from neighbouring nanohelices in specific array configurations and generating a wide and uniform detection zone ("hot-volume"). We experimentally assessed these nanostructures via surface-enhanced Raman spectroscopy, obtaining a corresponding EF of ~107 and a relative standard deviation <10%. These values demonstrate arrays of nanohelices as state-of-the-art substrates for reproducible optical detection as well as compelling nanostructures for related fields such as near-field imaging. PMID- 28358023 TI - Relevance of secretor status genotype and microbiota composition in susceptibility to rotavirus and norovirus infections in humans. AB - Host genetic factors, such as histo-blood group antigens (HBGAs), are associated with susceptibility to norovirus (NoV) and rotavirus (RV) infections. Recent advances point to the gut microbiome as a key player necessary for a viral pathogen to cause infection. In vitro NoV attachment to host cells and resulting infections have been linked to interactions with certain bacterial types in the gut microbiota. We investigated the relationship between host genotype, gut microbiota, and viral infections. Saliva and fecal samples from 35 adult volunteers were analysed for secretor status genotype, the gut microbiota composition by 16S rRNA gene sequencing, and salivary IgA titers to NoV and RV. Higher levels of IgA against NoV and RV were related to secretor-positive status. No significant differences were found between the FUT2 genotype groups, although the multivariate analysis showed a significant impact of host genotype on specific viral susceptibilities in the microbiome composition. A specific link was found between the abundance of certain bacterial groups, such as Faecalibacterium and Ruminococcus spp., and lower IgA titers against NoV and RV. As a conclusion, we can state that there is a link between host genetics, gut microbiota, and susceptibility to viral infections in humans. PMID- 28358024 TI - Downregulation of LIMK1-ADF/cofilin by DADS inhibits the migration and invasion of colon cancer. AB - This study aimed to explore whether the downregulation of LIM kinase 1 (LIMK1) actin depolymerization factor (ADF, also known as destrin)/cofilin by diallyl disulfide (DADS) inhibited the migration and invasion of colon cancer. Previous studies have shown that silencing LIMK1 could significantly enhance the inhibitory effect of DADS on colon cancer cell migration and invasion, suggesting that LIMK1 was a target molecule of DADS, which needed further confirmation. This study reported that LIMK1 and destrin were highly expressed in colon cancer and associated with poor prognosis of patients with colon cancer. Also, the expression of LIMK1 was positively correlated with the expression of destrin. The overexpression of LIMK1 significantly promoted colon cancer cell migration and invasion. DADS obviously inhibited migration and invasion by suppressing the phosphorylation of ADF/cofilin via downregulation of LIMK1 in colon cancer cells. Furthermore, DADS-induced suppression of cell proliferation was enhanced and antagonized by the knockdown and overexpression of LIMK1 in vitro and in vivo, respectively. Similar results were observed for DADS-induced changes in the expression of vimentin, CD34, Ki-67, and E-cadherin in xenografted tumors. These results indicated that LIMK1 was a potential target molecule for the inhibitory effect of DADS on colon cancer cell migration and invasion. PMID- 28358025 TI - Qubit-flip-induced cavity mode squeezing in the strong dispersive regime of the quantum Rabi model. AB - Squeezed states of light are a set of nonclassical states in which the quantum fluctuations of one quadrature component are reduced below the standard quantum limit. With less noise than the best stabilised laser sources, squeezed light is a key resource in the field of quantum technologies and has already improved sensing capabilities in areas ranging from gravitational wave detection to biomedical applications. In this work we propose a novel technique for generating squeezed states of a confined light field strongly coupled to a two-level system, or qubit, in the dispersive regime. Utilising the dispersive energy shift caused by the interaction, control of the qubit state produces a time-dependent change in the frequency of the light field. An appropriately timed sequence of sudden frequency changes reduces the quantum noise fluctuations in one quadrature of the field well below the standard quantum limit. The degree of squeezing and the time of generation are directly controlled by the number of frequency shifts applied. Even in the presence of realistic noise and imperfections, our protocol promises to be capable of generating a useful degree of squeezing with present experimental capabilities. PMID- 28358027 TI - Temperature-tunable Fano resonance induced by strong coupling between Weyl fermions and phonons in TaAs. AB - Strong coupling between discrete phonon and continuous electron-hole pair excitations can induce a pronounced asymmetry in the phonon line shape, known as the Fano resonance. This effect has been observed in various systems. Here we reveal explicit evidence for strong coupling between an infrared-active phonon and electronic transitions near the Weyl points through the observation of a Fano resonance in the Weyl semimetal TaAs. The resulting asymmetry in the phonon line shape, conspicuous at low temperatures, diminishes continuously with increasing temperature. This behaviour originates from the suppression of electronic transitions near the Weyl points due to the decreasing occupation of electronic states below the Fermi level (EF) with increasing temperature, as well as Pauli blocking caused by thermally excited electrons above EF. Our findings not only elucidate the mechanism governing the tunable Fano resonance but also open a route for exploring exotic physical phenomena through phonon properties in Weyl semimetals. PMID- 28358026 TI - Molecular characterization reveals the complexity of previously overlooked coral exosymbiont interactions and the implications for coral-guild ecology. AB - Several obligate associate crabs and shrimps species may co-occur and interact within a single coral host, leading to patterns of associations that can provide essential ecological services. However, knowledge of the dynamics of interactions in this system is limited, partly because identifying species involved in the network remains challenging. In this study, we assessed the diversity of the decapods involved in exosymbiotic assemblages for juvenile and adult Pocillopora damicornis types alpha and beta on reefs of New Caledonia and Reunion Island. This approach revealed complex patterns of association at regional and local scales with a prevalence of assemblages involving crab-shrimp partnerships. Furthermore, the distinction of two lineages in the snapping shrimp Alpheus lottini complex, rarely recognized in ecological studies, reveals a key role for cryptic diversity in structuring communities of mutualists. The existence of partnerships between species that occurred more commonly than expected by chance suggests an increased advantage for the host or a better adaptation of associated species to local environmental conditions. The consideration of cryptic diversity helps to accurately describe the complexity of interaction webs for diverse systems such as coral reefs, as well as the functional roles of dominant associated species for the persistence of coral populations. PMID- 28358028 TI - Sequence-selective encapsulation and protection of long peptides by a self assembled FeII8L6 cubic cage. AB - Self-assembly offers a general strategy for the preparation of large, hollow high symmetry structures. Although biological capsules, such as virus capsids, are capable of selectively recognizing complex cargoes, synthetic encapsulants have lacked the capability to specifically bind large and complex biomolecules. Here we describe a cubic host obtained from the self-assembly of FeII and a zinc porphyrin-containing ligand. This cubic cage is flexible and compatible with aqueous media. Its selectivity of encapsulation is driven by the coordination of guest functional groups to the zinc porphyrins. This new host thus specifically encapsulates guests incorporating imidazole and thiazole moieties, including drugs and peptides. Once encapsulated, the reactivity of a peptide is dramatically altered: encapsulated peptides are protected from trypsin hydrolysis, whereas physicochemically similar peptides that do not bind are cleaved. PMID- 28358029 TI - Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy. AB - The structure of the cornea is vital to its transparency, and dystrophies that disrupt corneal organization are highly heritable. To understand the genetic aetiology of Fuchs endothelial corneal dystrophy (FECD), the most prevalent corneal disorder requiring transplantation, we conducted a genome-wide association study (GWAS) on 1,404 FECD cases and 2,564 controls of European ancestry, followed by replication and meta-analysis, for a total of 2,075 cases and 3,342 controls. We identify three novel loci meeting genome-wide significance (P<5 * 10-8): KANK4 rs79742895, LAMC1 rs3768617 and LINC00970/ATP1B1 rs1200114. We also observe an overwhelming effect of the established TCF4 locus. Interestingly, we detect differential sex-specific association at LAMC1, with greater risk in women, and TCF4, with greater risk in men. Combining GWAS results with biological evidence we expand the knowledge of common FECD loci from one to four, and provide a deeper understanding of the underlying pathogenic basis of FECD. PMID- 28358030 TI - Allosteric cross-talk in chromatin can mediate drug-drug synergy. AB - Exploitation of drug-drug synergism and allostery could yield superior therapies by capitalizing on the immensely diverse, but highly specific, potential associated with the biological macromolecular landscape. Here we describe a drug drug synergy mediated by allosteric cross-talk in chromatin, whereby the binding of one drug alters the activity of the second. We found two unrelated drugs, RAPTA-T and auranofin, that yield a synergistic activity in killing cancer cells, which coincides with a substantially greater number of chromatin adducts formed by one of the compounds when adducts from the other agent are also present. We show that this occurs through an allosteric mechanism within the nucleosome, whereby defined histone adducts of one drug promote reaction of the other drug at a distant, specific histone site. This opens up possibilities for epigenetic targeting and suggests that allosteric modulation in nucleosomes may have biological relevance and potential for therapeutic interventions. PMID- 28358031 TI - Serine protease SP105 activates prophenoloxidase in Asian corn borer melanization, and is regulated by serpin-3. AB - Melanization reaction, resulting from the activation of prophenoloxidase, is a vital immune response in insects for encapsulating and killing the invasive organisms. Prophenoloxidase needs to be proteolytically activated by its upstream prophenoloxidase-activating protease (PAP) in melanization. Identification and characterization of PAPs facilitates the understanding of the molecular mechanisms involved in insect immunity. We here cloned a full-length cDNA for a serine protease, named as SP105, from Asian corn borer, Ostrinia furnacalis (Guenee). The open reading frame of SP105 encodes 424-amino acid residue protein with a 19-residue signal peptide. Sequence comparison indicates that SP105 is most similar to Manduca sexta PAP3, a defined prophenoloxidase-activating protease. qRT-PCR analysis showed that SP105 mRNA levels increased significantly after a bacterial injection. Recombinant SP105 directly cleaved and activated Asian corn borer prophenoloxidase and therefore acted as the prophenoloxidase activating protease. Additionally, SP105 formed SDS-stable complexes with a serine protease inhibitor, serpin-3, and its activity in activating prophenoloxidase was efficiently inhibited by serpin-3. Our work thus illustrated a prophenoloxidase-activating protease and revealed its regulation by serpin-3. The results would allow further advances in the understanding of the melanization in Asian corn borer and other insects. PMID- 28358032 TI - A Hierarchical Feature and Sample Selection Framework and Its Application for Alzheimer's Disease Diagnosis. AB - Classification is one of the most important tasks in machine learning. Due to feature redundancy or outliers in samples, using all available data for training a classifier may be suboptimal. For example, the Alzheimer's disease (AD) is correlated with certain brain regions or single nucleotide polymorphisms (SNPs), and identification of relevant features is critical for computer-aided diagnosis. Many existing methods first select features from structural magnetic resonance imaging (MRI) or SNPs and then use those features to build the classifier. However, with the presence of many redundant features, the most discriminative features are difficult to be identified in a single step. Thus, we formulate a hierarchical feature and sample selection framework to gradually select informative features and discard ambiguous samples in multiple steps for improved classifier learning. To positively guide the data manifold preservation process, we utilize both labeled and unlabeled data during training, making our method semi-supervised. For validation, we conduct experiments on AD diagnosis by selecting mutually informative features from both MRI and SNP, and using the most discriminative samples for training. The superior classification results demonstrate the effectiveness of our approach, as compared with the rivals. PMID- 28358033 TI - Disparities in correlating microstructural to nanostructural preservation of dinosaur femoral bones. AB - Osteohistological researches on dinosaurs are well documented, but descriptions of direct correlations between the bone microstructure and corresponding nanostructure are currently lacking. By applying correlative microscopy, we aimed to verify that well-preserved osteohistological features correlate with pristine fossil bone nanostructures from the femoral bones of Koreanosaurus boseongensis. The quality of nanostructural preservation was evaluated based on the preferred orientation level of apatite crystals obtained from selected area electron diffraction (SAED) patterns and by measuring the "arcs" from the {100} and {002} diffraction rings. Unlike our expectations, our results revealed that well preserved microstructures do not guarantee pristine nanostructures and vice versa. Structural preservation of bone from macro- to nanoscale primarily depends on original bioapatite density, and subsequent taphonomical factors such as effects from burial, pressure, influx of external elements and the rate of diagenetic alteration of apatite crystals. Our findings suggest that the efficient application of SAED analysis opens the opportunity for comprehensive nanostructural investigations of bone. PMID- 28358035 TI - Oral health status in Sichuan Province: findings from the oral health survey of Sichuan, 2015-2016. AB - To investigate oral health status in the residents of Sichuan Province, southwest China, a cross-sectional study was performed using the latest Oral Health Survey Basic Methods recommended by the World Health Organization. A multistage stratified random cluster-sampling method was used to enroll participants from the following three groups: children aged 3-5 years, adolescents aged 12 years, and people aged 65-74 years. In these three groups, the mean numbers of teeth that were affected by caries were 3.28, 0.86 and 5.13, respectively, resulting in a prevalence of 63.47%, 37.20% and 83.20%, respectively. Relative to the high rate of decayed teeth, the prevalence of fillings was very low in all age groups (0.97%, 7.24% and 5.43%, respectively). In the 12-year-old adolescent group, only 3.61% had good pit and fissure sealing. In addition, the rate of dental fluorosis was 24.80%, and the Community Fluorosis Index value was 0.39. In the elder group, the community periodontal index was 2.92. The prevalence in the elderly of having lost at least one tooth was 75.54%. Additionally, 4.44% of these participants were edentulous. The incidence of dental prosthesis was 51.75%, the proportion with a removable partial denture, a fixed denture, full dentures, dental implants and an informal fixed bridge was 21.59%, 11.45%, 4.64%, 0 and 16.67%, respectively. In this study, 8.2% of the elderly participants were affected by different types of oral mucosal lesions. Among such lesions, recurrent aphthous ulcers were most prevalent (2.69%) and oral lichen planuses were second (1.6%). The conclusion presented in this survey is that oral diseases, especially dental caries and periodontal disease, are frequent and common in Sichuan province, China. Moreover, the treatment rate is very low, and primary prevention and treatment options are therefore urgently needed in this population. PMID- 28358034 TI - In silico identification of potential inhibitors targeting Streptococcus mutans sortase A. AB - Dental caries is one of the most common chronic diseases and is caused by acid fermentation of bacteria adhered to the teeth. Streptococcus mutans (S. mutans) utilizes sortase A (SrtA) to anchor surface proteins to the cell wall and forms a biofilm to facilitate its adhesion to the tooth surface. Some plant natural products, especially several flavonoids, are effective inhibitors of SrtA. However, given the limited number of inhibitors and the development of drug resistance, the discovery of new inhibitors is urgent. Here, the high-throughput virtual screening approach was performed to identify new potential inhibitors of S. mutans SrtA. Two libraries were used for screening, and nine compounds that had the lowest scores were chosen for further molecular dynamics simulation, binding free energy analysis and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties analysis. The results revealed that several similar compounds composed of benzofuran, thiadiazole and pyrrole, which exhibited good affinities and appropriate pharmacokinetic parameters, were potential inhibitors to impede the catalysis of SrtA. In addition, the carbonyl of these compounds can have a key role in the inhibition mechanism. These findings can provide a new strategy for microbial infection disease therapy. PMID- 28358036 TI - Interleukin-1 and estrogen protect against disseminating dentoalveolar infections. AB - Dentoalveolar bacterial infections cause localized tissue and bone destruction, but usually remain well-localized within teeth in immunocompetent hosts. However, in certain cases these infections may invade head and neck tissues, resulting in orofacial abscesses, cellulitis and sepsis, with resultant high morbidity and even mortality. In the present studies, we developed a novel model of spreading dentoalveolar infections in mice by treatment with neutralizing antibodies against both interleukin-1alpha (IL-1alpha) and IL-1beta. Surprisingly male but not female mice given anti-IL-1 antibodies developed orofacial abscesses, weight loss, splenomegaly and sepsis. Female mice developed abscesses and sepsis comparable to males following ovariectomy (OVX), which was reversed by estrogen supplementation. Anti-IL-1 blockade inhibited IL-12, interferon gamma (IFNgamma) and IL-6 but not IL-10 expression in infrabony lesions, suggestive of a local anti-inflammatory response. There was greater infiltration of neutrophils and other inflammatory cells into lesions in anti-IL-1-treated animals; however, blood leukocytes had reduced bacterial phagocytic and killing activity ex vivo. Estrogen directly stimulated IL-1 production by macrophages, suggesting that the resistance of females to disseminating dentoalveolar infections may be due to their heightened pro-inflammatory responses following bacterial challenge, leading to enhanced localization of these infections. PMID- 28358037 TI - Type 1 diabetes mellitus. AB - Type 1 diabetes mellitus (T1DM), also known as autoimmune diabetes, is a chronic disease characterized by insulin deficiency due to pancreatic beta-cell loss and leads to hyperglycaemia. Although the age of symptomatic onset is usually during childhood or adolescence, symptoms can sometimes develop much later. Although the aetiology of T1DM is not completely understood, the pathogenesis of the disease is thought to involve T cell-mediated destruction of beta-cells. Islet-targeting autoantibodies that target insulin, 65 kDa glutamic acid decarboxylase, insulinoma-associated protein 2 and zinc transporter 8 - all of which are proteins associated with secretory granules in beta-cells - are biomarkers of T1DM-associated autoimmunity that are found months to years before symptom onset, and can be used to identify and study individuals who are at risk of developing T1DM. The type of autoantibody that appears first depends on the environmental trigger and on genetic factors. The pathogenesis of T1DM can be divided into three stages depending on the absence or presence of hyperglycaemia and hyperglycaemia-associated symptoms (such as polyuria and thirst). A cure is not available, and patients depend on lifelong insulin injections; novel approaches to insulin treatment, such as insulin pumps, continuous glucose monitoring and hybrid closed-loop systems, are in development. Although intensive glycaemic control has reduced the incidence of microvascular and macrovascular complications, the majority of patients with T1DM are still developing these complications. Major research efforts are needed to achieve early diagnosis, prevent beta-cell loss and develop better treatment options to improve the quality of life and prognosis of those affected. PMID- 28358038 TI - Candidate Genes for Inherited Autism Susceptibility in the Lebanese Population. AB - Autism spectrum disorder (ASD) is characterized by ritualistic-repetitive behaviors and impaired verbal/non-verbal communication. Many ASD susceptibility genes implicated in neuronal pathways/brain development have been identified. The Lebanese population is ideal for uncovering recessive genes because of shared ancestry and a high rate of consanguineous marriages. Aims here are to analyze for published ASD genes and uncover novel inherited ASD susceptibility genes specific to the Lebanese. We recruited 36 ASD families (ASD: 37, unaffected parents: 36, unaffected siblings: 33) and 100 unaffected Lebanese controls. Cytogenetics 2.7 M Microarrays/CytoScanTM HD arrays allowed mapping of homozygous regions of the genome. The CNTNAP2 gene was screened by Sanger sequencing. Homozygosity mapping uncovered DPP4, TRHR, and MLF1 as novel candidate susceptibility genes for ASD in the Lebanese. Sequencing of hot spot exons in CNTNAP2 led to discovery of a 5 bp insertion in 23/37 ASD patients. This mutation was present in unaffected family members and unaffected Lebanese controls. Although a slight increase in number was observed in ASD patients and family members compared to controls, there were no significant differences in allele frequencies between affecteds and controls (C/TTCTG: gamma2 value = 0.014; p = 0.904). The CNTNAP2 polymorphism identified in this population, hence, is not linked to the ASD phenotype. PMID- 28358039 TI - Structure and vacancy distribution in copper telluride nanoparticles influence plasmonic activity in the near-infrared. AB - Copper chalcogenides find applications in different domains including photonics, photothermal therapy and photovoltaics. CuTe nanocrystals have been proposed as an alternative to noble metal particles for plasmonics. Although it is known that deviations from stoichiometry are a prerequisite for plasmonic activity in the near-infrared, an accurate description of the material and its (optical) properties is hindered by an insufficient understanding of the atomic structure and the influence of defects, especially for materials in their nanocrystalline form. We demonstrate that the structure of Cu1.5+/-xTe nanocrystals can be determined using electron diffraction tomography. Real-space high-resolution electron tomography directly reveals the three-dimensional distribution of vacancies in the structure. Through first-principles density functional theory, we furthermore demonstrate that the influence of these vacancies on the optical properties of the nanocrystals is determined. Since our methodology is applicable to a variety of crystalline nanostructured materials, it is expected to provide unique insights concerning structure-property correlations. PMID- 28358041 TI - High-performance nanotube-enhanced perovskite photodetectors. AB - Organic-inorganic perovskites have already shown a tremendous potential for low cost light-harvesting devices. Yet, the relatively low carrier mobilities in bulk perovskites still prevent large-area devices with performances competing with state-of-the-art technologies. Here, we tackle this fundamental challenge by incorporating single-wall carbon nanotubes within a perovskite matrix by means of a simple two-step method in ambient air. Using this nano-engineered hybrid film, we demonstrate large-area photodetectors with responsivities up-to 13.8 A.W-1 and a broad spectral response from 300 to 800 nm, indicating that photocurrent generation arises from the charge transfer from the perovskite matrix to the embedded nanotube network. As the nanotubes facilitate the carrier extraction, these photodetectors also show a fast response time of 10 ms. This is significantly faster than most of previous reports on perovskite-based photodetectors, including devices with much smaller photosensitive areas. This approach is also well-suited for large-scale production of other perovskite-based light-harvesting devices. PMID- 28358040 TI - ATHB17 enhances stress tolerance by coordinating photosynthesis associated nuclear gene and ATSIG5 expression in response to abiotic stress. AB - Photosynthesis is sensitive to environmental stress and must be efficiently modulated in response to abiotic stress. However, the underlying mechanisms are not well understood. Here we report that ARABIDOPSIS THALIANA HOMEOBOX 17 (ATHB17), an Arabidopsis HD-Zip transcription factor, regulated the expression of a number of photosynthesis associated nuclear genes (PhANGs) involved in the light reaction and ATSIG5 in response to abiotic stress. ATHB17 was responsive to ABA and multiple stress treatments. ATHB17-overexpressing plants displayed enhanced stress tolerance, whereas its knockout mutant was more sensitive compared to the wild type. Through RNA-seq and quantitative real-time reverse transcription PCR (qRT-PCR) analysis, we found that ATHB17 did not affect the expression of many known stress-responsive marker genes. Interestingly, we found that ATHB17 down-regulated many PhANGs and could directly modulate the expression of several PhANGs by binding to their promoters. Moreover, we identified ATSIG5, encoding a plastid sigma factor, as one of the target genes of ATHB17. Loss of ATSIG5 reduced salt tolerance while overexpression of ATSIG5 enhanced salt tolerance, similar to that of ATHB17. ATHB17 can positively modulate the expression of many plastid encoded genes (PEGs) through regulation of ATSIG5. Taken together, our results suggest that ATHB17 may play an important role in protecting plants by adjusting expression of PhANGs and PEGs in response to abiotic stresses. PMID- 28358042 TI - Spatial and molecular resolution of diffuse malignant mesothelioma heterogeneity by integrating label-free FTIR imaging, laser capture microdissection and proteomics. AB - Diffuse malignant mesothelioma (DMM) is a heterogeneous malignant neoplasia manifesting with three subtypes: epithelioid, sarcomatoid and biphasic. DMM exhibit a high degree of spatial heterogeneity that complicates a thorough understanding of the underlying different molecular processes in each subtype. We present a novel approach to spatially resolve the heterogeneity of a tumour in a label-free manner by integrating FTIR imaging and laser capture microdissection (LCM). Subsequent proteome analysis of the dissected homogenous samples provides in addition molecular resolution. FTIR imaging resolves tumour subtypes within tissue thin-sections in an automated and label-free manner with accuracy of about 85% for DMM subtypes. Even in highly heterogeneous tissue structures, our label free approach can identify small regions of interest, which can be dissected as homogeneous samples using LCM. Subsequent proteome analysis provides a location specific molecular characterization. Applied to DMM subtypes, we identify 142 differentially expressed proteins, including five protein biomarkers commonly used in DMM immunohistochemistry panels. Thus, FTIR imaging resolves not only morphological alteration within tissue but it resolves even alterations at the level of single proteins in tumour subtypes. Our fully automated workflow FTIR guided LCM opens new avenues collecting homogeneous samples for precise and predictive biomarkers from omics studies. PMID- 28358044 TI - Evaluation and use of disaccharides as energy source in protein-free mammalian cell cultures. AB - Mammalian cells are generally considered to be unable to utilize polysaccharides for cell growth because the phospholipid bilayer in the cell membrane has very low permeability to sugars. With the recent discovery of the only known animal disaccharide transporter, a sucrose transporter, we considered the potential use of polysaccharides as energy source, because that can impact biopharmaceutical manufacturing by potentially increasing carbohydrate loading in the culture medium and decreasing lactate accumulation. In this study, we found that mammalian cells can utilize maltose for growth in the absence of glucose and successfully adapted CHO-K1, CHO-DG44 and HEK293 cells to grow in glucose-free, maltose-containing serum-free protein-free media. We then cultivated a non adapted CHO-K1 producer cell line in media containing both glucose and maltose to show that the cells can utilize maltose in a biphasic manner, that maltose enters the cells, and that maltose utilization only took place in the presence of the cells. This is the first report of a protein-free mammalian cell culture using a disaccharide as energy source. PMID- 28358045 TI - Glass-ceramic optical fiber containing Ba2TiSi2O8 nanocrystals for frequency conversion of lasers. AB - A glass-ceramic optical fiber containing Ba2TiSi2O8 nanocrystals fabricated using a novel combination of the melt-in-tube method and successive heat treatment is reported for the first time. For the melt-in-tube method, fibers act as a precursor at the drawing temperature for which the cladding glass is softened while the core glass is melted. It is demonstrated experimentally that following heat treatment, Ba2TiSi2O8 nanocrystals with diameters below 10 nm are evenly distributed throughout the fiber core. Comparing to the conventional rod-in-tube method, the melt-in-tube method is superior in terms of controllability of crystallization to allow for the fabrication of low loss glass-ceramic fibers. When irradiated using a 1030 nm femtosecond laser, an enhanced green emission at a wavelength of 515 nm is observed in the glass-ceramic fiber, which demonstrates second harmonic generation of a laser action in the fabricated glass-ceramic fibers. Therefore, this new glass-ceramic fiber not only provides a highly promising development for frequency conversion of lasers in all optical fiber based networks, but the melt-in-tube fabrication method also offers excellent opportunities for fabricating a wide range of novel glass-ceramic optical fibers for multiple future applications including fiber telecommunications and lasers. PMID- 28358043 TI - Phylogenomic evolutionary surveys of subtilase superfamily genes in fungi. AB - Subtilases belong to a superfamily of serine proteases which are ubiquitous in fungi and are suspected to have developed distinct functional properties to help fungi adapt to different ecological niches. In this study, we conducted a large scale phylogenomic survey of subtilase protease genes in 83 whole genome sequenced fungal species in order to identify the evolutionary patterns and subsequent functional divergences of different subtilase families among the main lineages of the fungal kingdom. Our comparative genomic analyses of the subtilase superfamily indicated that extensive gene duplications, losses and functional diversifications have occurred in fungi, and that the four families of subtilase enzymes in fungi, including proteinase K-like, Pyrolisin, kexin and S53, have distinct evolutionary histories which may have facilitated the adaptation of fungi to a broad array of life strategies. Our study provides new insights into the evolution of the subtilase superfamily in fungi and expands our understanding of the evolution of fungi with different lifestyles. PMID- 28358046 TI - Phosphatidylinositol (4,5)-bisphosphate dynamically regulates the K2P background K+ channel TASK-2. AB - Two-pore domain K2P K+ channels responsible for the background K+ conductance and the resting membrane potential, are also finely regulated by a variety of chemical, physical and physiological stimuli. Hormones and transmitters acting through Gq protein-coupled receptors (GqPCRs) modulate the activity of various K2P channels but the signalling involved has remained elusive, in particular whether dynamic regulation by membrane PI(4,5)P2, common among other classes of K+ channels, affects K2P channels is controversial. Here we show that K2P K+ channel TASK-2 requires PI(4,5)P2 for activity, a dependence that accounts for its run down in the absence of intracellular ATP and its full recovery by addition of exogenous PI(4,5)P2, its inhibition by low concentrations of polycation PI scavengers, and inhibition by PI(4,5)P2 depletion from the membrane. Comprehensive mutagenesis suggests that PI(4,5)P2 interaction with TASK 2 takes place at C-terminus where three basic aminoacids are identified as being part of a putative binding site. PMID- 28358047 TI - NMDA receptor antagonism with novel indolyl, 2-(1,1-Dimethyl-1,3-dihydro benzo[e]indol-2-ylidene)-malonaldehyde, reduces seizures duration in a rat model of epilepsy. AB - N-methyl-D-aspartate receptors (NMDAR) play a central role in epileptogensis and NMDAR antagonists have been shown to have antiepileptic effects in animals and humans. Despite significant progress in the development of antiepileptic therapies over the previous 3 decades, a need still exists for novel therapies. We screened an in-house library of small molecules targeting the NMDA receptor. A novel indolyl compound, 2-(1,1-Dimethyl-1,3-dihydro-benzo[e]indol-2-ylidene) malonaldehyde, (DDBM) showed the best binding with the NMDA receptor and computational docking data showed that DDBM antagonised the binding sites of the NMDA receptor at lower docking energies compared to other molecules. Using a rat electroconvulsive shock (ECS) model of epilepsy we showed that DDBM decreased seizure duration and improved the histological outcomes. Our data show for the first time that indolyls like DDBM have robust anticonvulsive activity and have the potential to be developed as novel anticonvulsants. PMID- 28358049 TI - CXCR3+ monocytes/macrophages are required for establishment of pulmonary metastases. AB - We present a new foundational role for CXCR3+ monocytes/macrophages in the process of tumor engraftment in the lung. CXCR3 is associated with monocytic and lymphocytic infiltration of inflamed or tumor-bearing lung. Although the requirement for tumor-expressed CXCR3 in metastatic engraftment has been demonstrated, the role of monocyte-expressed CXCR3 had not been appreciated. In a murine model of metastatic-like melanoma, engraftment was coordinate with CXCR3+ monocyte/macrophage accumulation in the lungs and was sensitive to pharmacologic inhibition of CXCR3 signaling. Tumor engraftment to lung was impaired in CXCR3-/- mice, and transient reconstitution with circulating CXCR3-replete monocytes was sufficient to restore engraftment. These data illustrate the paradoxical pro tumor role for CXCR3 in lung immunobiology wherein the CXCR3 axis drives both the anti-tumor effector cell chemoattraction and pro-tumor infiltration of the lungs and suggests a potential therapeutic target for lung-tropic metastasizing cancers. PMID- 28358048 TI - Microbial reduction of Fe(III)-bearing clay minerals in the presence of humic acids. AB - Both Fe(III)-bearing clay minerals and humic acids (HAs) are abundant in the soils and sediments. Previous studies have shown that bioreduction of structural Fe(III) in clay minerals could be accelerated by adding anthraquinone compound as a redox-active surrogate of HAs. However, a quinoid analogue could not reflect the adsorption and complexation properties of HA, and little is known about the effects of real HAs at environmental concentration on bioreduction of clay minerals. Here, it was shown that 10-200 mg l-1 of natural or artificially synthesized HAs could effectively stimulate the bioreduction rate and extent of Fe(III) in both iron-rich nontronite NAu-2 and iron-deficient montmorillonite SWy 2. After adsorption to NAu-2, electron-transfer activities of different HA fractions were compared. Additionally, Fe(II) complexation by HAs also contributed to improvement of clay-Fe(III) bioreduction. Spectrosopic and morphological analyses suggested that HA addition accelerated the transformation of NAu-2 to illite, silica and siderite after reductive dissolution. PMID- 28358050 TI - Antibody-dependent-cellular-cytotoxicity-inducing antibodies significantly affect the post-exposure treatment of Ebola virus infection. AB - Passive immunotherapy with monoclonal antibodies (mAbs) is an efficacious treatment for Ebola virus (EBOV) infections in animal models and humans. Understanding what constitutes a protective response is critical for the development of novel therapeutic strategies. We generated an EBOV-glycoprotein pseudotyped Human immunodeficiency virus to develop sensitive neutralizing and antibody-dependent cellular cytotoxicity (ADCC) assays as well as a bioluminescent-imaging-based mouse infection model that does not require biosafety level 4 containment. The in vivo treatment efficiencies of three novel anti-EBOV mAbs at 12 h post-infection correlated with their in vitro anti-EBOV ADCC activities, without neutralizing activity. When they were treated with these mAbs, natural killer cell (NK)-deficient mice had lower viral clearance than WT mice, indicating that the anti-EBOV mechanism of the ADCC activity of these mAbs is predominantly mediated by NK cells. One potent anti-EBOV mAb (M318) displayed unprecedented neutralizing and ADCC activities (neutralization IC50, 0.018 MUg/ml; ADCC EC50, 0.095 MUg/ml). These results have important implications for the efficacy of antiviral drugs and vaccines as well as for pathogenicity studies of EBOV. PMID- 28358051 TI - Single crystalline superstructured stable single domain magnetite nanoparticles. AB - Magnetite nanoparticles exhibit magnetic properties that are size and organization dependent and, for applications that rely on their magnetic state, they usually have to be monodisperse. Forming such particles, however, has remained a challenge. Here, we synthesize 40 nm particles of magnetite in the presence of polyarginine and show that they are composed of 10 nm building blocks, yet diffract like single crystals. We use both bulk magnetic measurements and magnetic induction maps recorded from individual particles using off-axis electron holography to show that each 40 nm particle typically contains a single magnetic domain. The magnetic state is therefore determined primarily by the size of the superstructure and not by the sizes of the constituent sub-units. Our results fundamentally demonstrate the structure - property relationship in a magnetic mesoparticle. PMID- 28358052 TI - HIVed, a knowledgebase for differentially expressed human genes and proteins during HIV infection, replication and latency. AB - Measuring the altered gene expression level and identifying differentially expressed genes/proteins during HIV infection, replication and latency is fundamental for broadening our understanding of the mechanisms of HIV infection and T-cell dysfunction. Such studies are crucial for developing effective strategies for virus eradication from the body. Inspired by the availability and enrichment of gene expression data during HIV infection, replication and latency, in this study, we proposed a novel compendium termed HIVed (HIV expression database; http://hivlatency.erc.monash.edu/) that harbours comprehensive functional annotations of proteins, whose genes have been shown to be dysregulated during HIV infection, replication and latency using different experimental designs and measurements. We manually curated a variety of third party databases for structural and functional annotations of the protein entries in HIVed. With the goal of benefiting HIV related research, we collected a number of biological annotations for all the entries in HIVed besides their expression profile, including basic protein information, Gene Ontology terms, secondary structure, HIV-1 interaction and pathway information. We hope this comprehensive protein-centric knowledgebase can bridge the gap between the understanding of differentially expressed genes and the functions of their protein products, facilitating the generation of novel hypotheses and treatment strategies to fight against the HIV pandemic. PMID- 28358053 TI - A Raf-like protein kinase BHP mediates blue light-dependent stomatal opening. AB - Stomata in the plant epidermis open in response to blue light and affect photosynthesis and plant growth by regulating CO2 uptake and transpiration. In stomatal guard cells under blue light, plasma membrane H+-ATPase is phosphorylated and activated via blue light-receptor phototropins and a signaling mediator BLUS1, and H+-ATPase activation drives stomatal opening. However, details of the signaling between phototropins and H+-ATPase remain largely unknown. In this study, through a screening of specific inhibitors for the blue light-dependent H+-ATPase phosphorylation in guard cells, we identified a Raf like protein kinase, BLUE LIGHT-DEPENDENT H+-ATPASE PHOSPHORYLATION (BHP). Guard cells in the bhp mutant showed impairments of stomatal opening and H+-ATPase phosphorylation in response to blue light. BHP is abundantly expressed in the cytosol of guard cells and interacts with BLUS1 both in vitro and in vivo. Based on these results, BHP is a novel signaling mediator in blue light-dependent stomatal opening, likely downstream of BLUS1. PMID- 28358054 TI - Argininosuccinate Synthase 1-Deficiency Enhances the Cell Sensitivity to Arginine through Decreased DEPTOR Expression in Endometrial Cancer. AB - Argininosuccinate synthetase 1 (ASS1) is a rate-limiting enzyme in arginine biosynthesis. Although ASS1 expression levels are often reduced in several tumors and low ASS1 expression can be a poor prognostic factor, the underlying mechanism has not been elucidated. In this study, we reveal a novel association between ASS1 and migration/invasion of endometrial tumors via regulation of mechanistic target of rapamycin complex (mTORC) 1 signaling. ASS1-knockout cells showed enhanced migration and invasion in response to arginine following arginine starvation. In ASS1-knockout cells, DEPTOR, an inhibitor of mTORC1 signal, was downregulated and mTORC1 signaling was more activated in response to arginine. ASS1 epigenetically enhanced DEPTOR expression by altering the histone methylation. Consistent with these findings, tumor cells at the invasive front of endometrioid carcinoma cases showed lower ASS1 and DEPTOR expression. Our findings suggest that ASS1 levels in each tumor cell are associated with invasion capability in response to arginine within the tumor microenvironment through mTORC1 signal regulation. PMID- 28358056 TI - Rheotaxis in the Ediacaran epibenthic organism Parvancorina from South Australia. AB - Diverse interpretations of Ediacaran organisms arise not only from their enigmatic body plans, but also from confusion surrounding the sedimentary environments they inhabited and the processes responsible for their preservation. Excavation of Ediacaran bedding surfaces of the Rawnsley Quartzite in South Australia has provided the opportunity to study the community structure of the Ediacara biota, as well as the autecology of individual organisms. Analysis of two bedding surfaces preserving large numbers of Parvancorina illustrates that individuals display a preferred, unidirectional orientation aligned with current, as indicated by the identified current proxies: tool marks, overfolded edges of Dickinsonia, felled fronds and drag structures generated by uprooted frond holdfasts. Taphonomic and morphological evidence suggests that the preferred orientations of Parvancorina individuals are not the result of passive current alignment, but represent a rheotactic response at some stage during their life cycle. These results illustrate a previously unrecognized life mode for an Ediacaran organism and arguably the oldest known example of rheotaxis in the fossil record. The morphology and previously suggested phylogenetic affinities of Parvancorina are also re-evaluated. Apart from possessing a bilaterally symmetrical body, there are no unequivocal morphological characters to support placement of Parvancorina within the Euarthropoda or even the Bilateria. PMID- 28358057 TI - Synthesis and biological evaluation of novel ursolic acid analogues as potential alpha-glucosidase inhibitors. AB - Ursolic acid (UA) is a major pentacyclic triterpenoid in plants, vegetables and fruits, which has been reported to have a potential anti-diabetic activity. Despite various semi-synthetic ursolic acid derivatives already described, new derivatives still need to be designed and synthesized to further improve the anti diabetic activity. In the present study, two series of novel UA derivatives, were synthesized and their structures were confirmed. The enzyme inhibition activities of semi-synthesized analogues against alpha-glucosidase were screened in vitro. The results indicated that most of UA derivatives showed a significant inhibitory activity, especially analogues UA-O-i with the IC50 values of 0.71 +/- 0.27 MUM, which was more potential than other analogues and the positive control. Furthermore, molecular docking studies were also investigated to verify the in vitro study. Structure modification at the C-3 and C-2 positions of UA was an effective approach to obtain the desired ligand from UA, whose structure was in accordance with the active pocket. Besides, suitable hydrophobic group at the position of C-2 might play an important role for the docking selectivity and binding affinity between the ligand and the homology modelling protein. These results could be helpful for designing more potential alpha-glucosidase inhibitors from UA in the future. PMID- 28358055 TI - FUS affects circular RNA expression in murine embryonic stem cell-derived motor neurons. AB - The RNA-binding protein FUS participates in several RNA biosynthetic processes and has been linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Here we report that FUS controls back-splicing reactions leading to circular RNA (circRNA) production. We identified circRNAs expressed in in vitro-derived mouse motor neurons (MNs) and determined that the production of a considerable number of these circRNAs is regulated by FUS. Using RNAi and overexpression of wild-type and ALS-associated FUS mutants, we directly correlate the modulation of circRNA biogenesis with alteration of FUS nuclear levels and with putative toxic gain of function activities. We also demonstrate that FUS regulates circRNA biogenesis by binding the introns flanking the back splicing junctions and that this control can be reproduced with artificial constructs. Most circRNAs are conserved in humans and specific ones are deregulated in human-induced pluripotent stem cell-derived MNs carrying the FUSP525L mutation associated with ALS. PMID- 28358059 TI - Science communication: Take rural road trips to promote science. PMID- 28358061 TI - Kenneth J. Arrow (1921-2017). PMID- 28358058 TI - MiR-126 and miR-126* regulate shear-resistant firm leukocyte adhesion to human brain endothelium. AB - Leukocyte adhesion to brain endothelial cells, the blood-brain barrier main component, is a critical step in the pathogenesis of neuroinflammatory diseases such as multiple sclerosis (MS). Leukocyte adhesion is mediated mainly by selectins, cell adhesion molecules and chemokines induced by pro-inflammatory cytokines such as TNFalpha and IFNgamma, but the regulation of this process is not fully clear. This study investigated the regulation of firm leukocyte adhesion to human brain endothelium by two different brain endothelial microRNAs (miRs), miR-126 and miR-126*, that are downregulated by TNFalpha and IFNgamma in a human brain endothelial cell line, hCMEC/D3. Using a leukocyte adhesion in vitro assay under shear forces mimicking blood flow, we observed that reduction of endothelial miR-126 and miR-126* enhanced firm monocyte and T cell adhesion to hCMEC/D3 cells, whereas their increased expression partially prevented THP1, Jurkat and primary MS patient-derived PBMC firm adhesion. Furthermore, we observed that miR-126* and miR-126 downregulation increased E-selectin and VCAM1, respectively, while miR-126 overexpression reduced VCAM1 and CCL2 expression by hCMEC/D3 cells, suggesting that these miRs regulate leukocyte adhesion by modulating the expression of adhesion-associated endothelial mRNA targets. Hence, human brain endothelial miR-126 and miR-126* could be used as a therapeutic tool to reduce leukocyte adhesion and thus reduce neuroinflammation. PMID- 28358064 TI - A low-spin Fe(iii) complex with 100-ps ligand-to-metal charge transfer photoluminescence. AB - Transition-metal complexes are used as photosensitizers, in light-emitting diodes, for biosensing and in photocatalysis. A key feature in these applications is excitation from the ground state to a charge-transfer state; the long charge transfer-state lifetimes typical for complexes of ruthenium and other precious metals are often essential to ensure high performance. There is much interest in replacing these scarce elements with Earth-abundant metals, with iron and copper being particularly attractive owing to their low cost and non-toxicity. But despite the exploration of innovative molecular designs, it remains a formidable scientific challenge to access Earth-abundant transition-metal complexes with long-lived charge-transfer excited states. No known iron complexes are considered photoluminescent at room temperature, and their rapid excited-state deactivation precludes their use as photosensitizers. Here we present the iron complex [Fe(btz)3]3+ (where btz is 3,3'-dimethyl-1,1'-bis(p-tolyl)-4,4'-bis(1,2,3-triazol 5-ylidene)), and show that the superior sigma-donor and pi-acceptor electron properties of the ligand stabilize the excited state sufficiently to realize a long charge-transfer lifetime of 100 picoseconds (ps) and room-temperature photoluminescence. This species is a low-spin Fe(iii) d5 complex, and emission occurs from a long-lived doublet ligand-to-metal charge-transfer (2LMCT) state that is rarely seen for transition-metal complexes. The absence of intersystem crossing, which often gives rise to large excited-state energy losses in transition-metal complexes, enables the observation of spin-allowed emission directly to the ground state and could be exploited as an increased driving force in photochemical reactions on surfaces. These findings suggest that appropriate design strategies can deliver new iron-based materials for use as light emitters and photosensitizers. PMID- 28358066 TI - Neuroscience: Auditory landscape on the cognitive map. PMID- 28358065 TI - Using coherence to enhance function in chemical and biophysical systems. AB - Coherence phenomena arise from interference, or the addition, of wave-like amplitudes with fixed phase differences. Although coherence has been shown to yield transformative ways for improving function, advances have been confined to pristine matter and coherence was considered fragile. However, recent evidence of coherence in chemical and biological systems suggests that the phenomena are robust and can survive in the face of disorder and noise. Here we survey the state of recent discoveries, present viewpoints that suggest that coherence can be used in complex chemical systems, and discuss the role of coherence as a design element in realizing function. PMID- 28358068 TI - Evolution: Diet drives primate brain size. PMID- 28358067 TI - Animal welfare: Make animal models more meaningful. PMID- 28358069 TI - Seismology: Quake shows rare complexity. PMID- 28358070 TI - Cancer therapy: The leukaemia epigenome targeted. PMID- 28358071 TI - Environmental science: Eating ourselves dry. PMID- 28358072 TI - Inorganic chemistry: Making iron glow. PMID- 28358074 TI - Groundwater depletion embedded in international food trade. AB - Recent hydrological modelling and Earth observations have located and quantified alarming rates of groundwater depletion worldwide. This depletion is primarily due to water withdrawals for irrigation, but its connection with the main driver of irrigation, global food consumption, has not yet been explored. Here we show that approximately eleven per cent of non-renewable groundwater use for irrigation is embedded in international food trade, of which two-thirds are exported by Pakistan, the USA and India alone. Our quantification of groundwater depletion embedded in the world's food trade is based on a combination of global, crop-specific estimates of non-renewable groundwater abstraction and international food trade data. A vast majority of the world's population lives in countries sourcing nearly all their staple crop imports from partners who deplete groundwater to produce these crops, highlighting risks for global food and water security. Some countries, such as the USA, Mexico, Iran and China, are particularly exposed to these risks because they both produce and import food irrigated from rapidly depleting aquifers. Our results could help to improve the sustainability of global food production and groundwater resource management by identifying priority regions and agricultural products at risk as well as the end consumers of these products. PMID- 28358075 TI - Cancer: Imaging with antibodies. PMID- 28358078 TI - Astronomy: Landslides cause comet eruptions. PMID- 28358079 TI - Ageing: Senescent cells cleared out. PMID- 28358077 TI - Mapping of a non-spatial dimension by the hippocampal-entorhinal circuit. AB - During spatial navigation, neural activity in the hippocampus and the medial entorhinal cortex (MEC) is correlated to navigational variables such as location, head direction, speed, and proximity to boundaries. These activity patterns are thought to provide a map-like representation of physical space. However, the hippocampal-entorhinal circuit is involved not only in spatial navigation, but also in a variety of memory-guided behaviours. The relationship between this general function and the specialized spatial activity patterns is unclear. A conceptual framework reconciling these views is that spatial representation is just one example of a more general mechanism for encoding continuous, task relevant variables. Here we tested this idea by recording from hippocampal and entorhinal neurons during a task that required rats to use a joystick to manipulate sound along a continuous frequency axis. We found neural representation of the entire behavioural task, including activity that formed discrete firing fields at particular sound frequencies. Neurons involved in this representation overlapped with the known spatial cell types in the circuit, such as place cells and grid cells. These results suggest that common circuit mechanisms in the hippocampal-entorhinal system are used to represent diverse behavioural tasks, possibly supporting cognitive processes beyond spatial navigation. PMID- 28358081 TI - Molecular biology: Drug stalls protein translation. PMID- 28358080 TI - Diversity: Boost diversity in biomedical research. PMID- 28358082 TI - Planetary science: Titan's electrified dunes. PMID- 28358083 TI - A retrograde co-orbital asteroid of Jupiter. AB - Recent theoretical work in celestial mechanics has revealed that an asteroid may orbit stably in the same region as a planet, despite revolving around the Sun in the sense opposite to that of the planet itself. Asteroid 2015 BZ509 was discovered in 2015, but with too much uncertainty in its measured orbit to establish whether it was such a retrograde co-orbital body. Here we report observations and analysis that demonstrates that asteroid 2015 BZ509 is indeed a retrograde co-orbital asteroid of the planet Jupiter. We find that 2015 BZ509 has long-term stability, having been in its current, resonant state for around a million years. This is long enough to preclude precise calculation of the time or mechanism of its injection to its present state, but it may be a Halley-family comet that entered the resonance through an interaction with Saturn. Retrograde co-orbital asteroids of Jupiter and other planets may be more common than previously expected. PMID- 28358084 TI - Cancer: Tumour stem-cell surprises. PMID- 28358085 TI - Virology: What makes bird flu jump species? PMID- 28358087 TI - Animal behaviour: Playful call makes parrots merry. PMID- 28358086 TI - Biosafety: National biosafety standards differ. PMID- 28358088 TI - Planetary science: Reckless orbiting in the Solar System. PMID- 28358090 TI - Cancer: How fat boosts breast cancer. PMID- 28358091 TI - Humanities: Blind spot in the March for Science. PMID- 28358089 TI - Exploiting non-covalent pi interactions for catalyst design. AB - Molecular recognition, binding and catalysis are often mediated by non-covalent interactions involving aromatic functional groups. Although the relative complexity of these so-called pi interactions has made them challenging to study, theory and modelling have now reached the stage at which we can explain their physical origins and obtain reliable insight into their effects on molecular binding and chemical transformations. This offers opportunities for the rational manipulation of these complex non-covalent interactions and their direct incorporation into the design of small-molecule catalysts and enzymes. PMID- 28358092 TI - In Retrospect: Forty years of cellular clues from worms. PMID- 28358093 TI - A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer. AB - Cancer stem cells (CSCs) have been hypothesized to represent the driving force behind tumour progression and metastasis, making them attractive cancer targets. However, conclusive experimental evidence for their functional relevance is still lacking for most malignancies. Here we show that the leucine-rich repeat containing G-protein-coupled receptor 5 (Lgr5) identifies intestinal CSCs in mouse tumours engineered to recapitulate the clinical progression of human colorectal cancer. We demonstrate that selective Lgr5+ cell ablation restricts primary tumour growth, but does not result in tumour regression. Instead, tumours are maintained by proliferative Lgr5- cells that continuously attempt to replenish the Lgr5+ CSC pool, leading to rapid re-initiation of tumour growth upon treatment cessation. Notably, CSCs are critical for the formation and maintenance of liver metastasis derived from colorectal cancers. Together, our data highlight distinct CSC dependencies for primary versus metastasic tumour growth, and suggest that targeting CSCs may represent a therapeutic opportunity for managing metastatic disease. PMID- 28358095 TI - Brexit triggered, preprint push and a stem-cell first. PMID- 28358094 TI - Transboundary health impacts of transported global air pollution and international trade. AB - Millions of people die every year from diseases caused by exposure to outdoor air pollution. Some studies have estimated premature mortality related to local sources of air pollution, but local air quality can also be affected by atmospheric transport of pollution from distant sources. International trade is contributing to the globalization of emission and pollution as a result of the production of goods (and their associated emissions) in one region for consumption in another region. The effects of international trade on air pollutant emissions, air quality and health have been investigated regionally, but a combined, global assessment of the health impacts related to international trade and the transport of atmospheric air pollution is lacking. Here we combine four global models to estimate premature mortality caused by fine particulate matter (PM2.5) pollution as a result of atmospheric transport and the production and consumption of goods and services in different world regions. We find that, of the 3.45 million premature deaths related to PM2.5 pollution in 2007 worldwide, about 12 per cent (411,100 deaths) were related to air pollutants emitted in a region of the world other than that in which the death occurred, and about 22 per cent (762,400 deaths) were associated with goods and services produced in one region for consumption in another. For example, PM2.5 pollution produced in China in 2007 is linked to more than 64,800 premature deaths in regions other than China, including more than 3,100 premature deaths in western Europe and the USA; on the other hand, consumption in western Europe and the USA is linked to more than 108,600 premature deaths in China. Our results reveal that the transboundary health impacts of PM2.5 pollution associated with international trade are greater than those associated with long-distance atmospheric pollutant transport. PMID- 28358096 TI - Trump's pipeline permit is bad for both the US economy and the environment. PMID- 28358097 TI - How Brexit is changing the lives of eight researchers. PMID- 28358098 TI - Five ways consortia can catalyse open science. PMID- 28358099 TI - Biological underpinnings of chronic fatigue syndrome begin to emerge. PMID- 28358100 TI - An early start on tackling childhood cancers. PMID- 28358101 TI - Battle between quantum and thermodynamic laws heats up. PMID- 28358102 TI - Cruel fusion: What a young man's death means for childhood cancer. PMID- 28358103 TI - Remember why we work on cancer. PMID- 28358104 TI - Election chaos over Russian science president. PMID- 28358105 TI - How giant marine reptiles terrorized the ancient seas. PMID- 28358106 TI - Canada budget falls flat with scientists. PMID- 28358107 TI - Brexit must preserve advisory networks. PMID- 28358108 TI - Forensics: Germany considers wider use of DNA evidence in criminal cases. PMID- 28358109 TI - Gates Foundation announces open-access publishing venture. PMID- 28358110 TI - Integrating Sequence-based GWAS and RNA-Seq Provides Novel Insights into the Genetic Basis of Mastitis and Milk Production in Dairy Cattle. AB - Connecting genome-wide association study (GWAS) to biological mechanisms underlying complex traits is a major challenge. Mastitis resistance and milk production are complex traits of economic importance in the dairy sector and are associated with intra-mammary infection (IMI). Here, we integrated IMI-relevant RNA-Seq data from Holstein cattle and sequence-based GWAS data from three dairy cattle breeds (i.e., Holstein, Nordic red cattle, and Jersey) to explore the genetic basis of mastitis resistance and milk production using post-GWAS analyses and a genomic feature linear mixed model. At 24 h post-IMI, genes responsive to IMI in the mammary gland were preferentially enriched for genetic variants associated with mastitis resistance rather than milk production. Response genes in the liver were mainly enriched for variants associated with mastitis resistance at an early time point (3 h) post-IMI, whereas responsive genes at later stages were enriched for associated variants with milk production. The up- and down-regulated genes were enriched for associated variants with mastitis resistance and milk production, respectively. The patterns were consistent across breeds, indicating that different breeds shared similarities in the genetic basis of these traits. Our approaches provide a framework for integrating multiple layers of data to understand the genetic architecture underlying complex traits. PMID- 28358111 TI - Fluorescent nanodiamonds enable quantitative tracking of human mesenchymal stem cells in miniature pigs. AB - Cell therapy is a promising strategy for the treatment of human diseases. While the first use of cells for therapeutic purposes can be traced to the 19th century, there has been a lack of general and reliable methods to study the biodistribution and associated pharmacokinetics of transplanted cells in various animal models for preclinical evaluation. Here, we present a new platform using albumin-conjugated fluorescent nanodiamonds (FNDs) as biocompatible and photostable labels for quantitative tracking of human placenta choriodecidual membrane-derived mesenchymal stem cells (pcMSCs) in miniature pigs by magnetic modulation. With this background-free detection technique and time-gated fluorescence imaging, we have been able to precisely determine the numbers as well as positions of the transplanted FND-labeled pcMSCs in organs and tissues of the miniature pigs after intravenous administration. The method is applicable to single-cell imaging and quantitative tracking of human stem/progenitor cells in rodents and other animal models as well. PMID- 28358112 TI - Low phonon energies and wideband optical windows of La2O3-Ga2O3 glasses prepared using an aerodynamic levitation technique. AB - xLa2O3-(100 - x)Ga2O3 binary glasses were synthesized by an aerodynamic levitation technique. The glass-forming region was found to be 20 <= x <= 57. The refractive indices were greater than 1.92 and increased linearly with increasing x. The polarizabilities of oxide ions were estimated to be 2.16-2.41 A3, indicating that the glasses were highly ionic. The glasses were transparent over a very wide range from the ultraviolet to the mid-infrared region. The widest transparent window among the oxide glasses was from 270 nm to 10 MUm at x = 55. From the Raman scattering spectra, a decrease in bridging oxide ions and an increase in non-bridging oxide ions were confirmed to occur with increasing La2O3 content. The maximum phonon energy was found to be approximately 650 cm-1, being one of the lowest among oxide glasses. These results show that La2O3-Ga2O3 binary glasses should be promising host materials for optical applications such as lenses, windows, and filters over a very wide wavelength range. PMID- 28358113 TI - A novel pathway for amyloids self-assembly in aggregates at nanomolar concentration mediated by the interaction with surfaces. AB - A limitation of the amyloid hypothesis in explaining the development of neurodegenerative diseases is that the level of amyloidogenic polypeptide in vivo is below the critical concentration required to form the aggregates observed in post-mortem brains. We discovered a novel, on-surface aggregation pathway of amyloidogenic polypeptide that eliminates this long-standing controversy. We applied atomic force microscope (AFM) to demonstrate directly that on-surface aggregation takes place at a concentration at which no aggregation in solution is observed. The experiments were performed with the full-size Abeta protein (Abeta42), a decapeptide Abeta(14-23) and alpha-synuclein; all three systems demonstrate a dramatic preference of the on-surface aggregation pathway compared to the aggregation in the bulk solution. Time-lapse AFM imaging, in solution, show that over time, oligomers increase in size and number and release in solution, suggesting that assembled aggregates can serve as nuclei for aggregation in bulk solution. Computational modeling performed with the all-atom MD simulations for Abeta(14-23) peptide shows that surface interactions induce conformational transitions of the monomer, which facilitate interactions with another monomer that undergoes conformational changes stabilizing the dimer assembly. Our findings suggest that interactions of amyloidogenic polypeptides with cellular surfaces play a major role in determining disease onset. PMID- 28358114 TI - Decorating unoxidized-carbon nanotubes with homogeneous Ni-Co spinel nanocrystals show superior performance for oxygen evolution/reduction reactions. AB - We present a new concept for homogeneous spinel nanocrystal-coating on high crystalline pristine-carbon nanotubes (CNTs) for efficient and durable oxygen evolution reaction (OER) and oxygen reduction reaction (ORR). Oxidized CNTs have widely been used to functionalize with metal or metal oxides since the defect sites act as anchoring for metal oxide binding. However, such defects on the tubes cause the decrease in electrical conductivity and stability, leading to lower catalyst performance. In the present study, at first, pristine multi-walled carbon nanotubes (MWNTs) were wrapped by pyridine-based polybenzimidazole (PyPBI) to which uniform NixCo3-xO4 nanocrystals were homogeneously deposited by the solvothermal method without damaging the MWNTs, in which PyPBI acted as efficient anchoring sites for the deposition of spinel oxide nanocrystals with ~5 nm size. The obtained catalyst (MWNT-PyPBI-NixCo3-xO4) outperformed most state-of-the-art non-precious metal-based bifunctional catalysts; namely, for OER, the potential at 10 mA cm-2 and Tafel slope in 1 M KOH solution were 1.54 V vs. RHE and 42 mV dec-1, respectively. For ORR, the onset and half-wave potentials are 0.918 V and 0.811 V vs. RHE, respectively. Moreover, the MWNT-PyPBI-NixCo3-xO4 demonstrates an excellent durability for both ORR and OER. PMID- 28358115 TI - Azole-resistant Aspergillus fumigatus harboring TR34/L98H, TR46/Y121F/T289A and TR53 mutations related to flower fields in Colombia. AB - Resistance to triazoles in Aspergillus fumigatus has been reported in azole-naive patients in Europe, Asia, Australia and North America. This resistance has been linked to fungicide-driven mutations in the cyp51A gene and its promoter region. We investigated the presence of environmental azole-resistant A. fumigatus strains related to the use of azole fungicides in Colombia. Soil samples were collected from flower beds, flower fields and public gardens from the outskirts, suburbs and city centre of Bogota. Out of the 86 soil samples taken, 17 (19.8%) grew A. fumigatus of whom eight (9.3%) contained 40 strains able to grow on azole containing itraconazole and/or voriconazole supplemented media. All but one triazole-resistant strains were isolated from soil samples collected from flower fields and flower beds (39/40). Importantly, the majority had the TR46/Y121F/T289A, TR34/L98H, and TR53 molecular resistance mechanisms and one azole resistant strain had a wild-type cyp51A gene. Soil samples from flower fields and beds contained 4 azole fungicides (penconazole, difenoconazole, tetraconazole and tebuconazole) above the limit of detection. Our findings underline the need for extensive investigations to determine azole-resistant A. fumigatus prevalence in both clinical and environmental samples in other regions of Latin America. PMID- 28358116 TI - Work Function Tuning in Two-Dimensional MoS2 Field-Effect-Transistors with Graphene and Titanium Source-Drain Contacts. AB - Based on the first principles calculation, we investigate the electronic band structures of graphene-MoS2 and Ti-MoS2 heterojunctions under gate-voltages. By simultaneous control of external electric fields and carrier charging concentrations, we show that the graphene's Dirac point position inside the MoS2 bandgap is easily modulated with respect to the co-varying Fermi level, while keeping the graphene's linear band structure around the Dirac point. The easy modulation of graphene bands is not confined to the special cases where the conduction-band-minimum point of MoS2 and the Dirac point of graphene are matched up in reciprocal space, but is generalized to their dislocated cases. This flexibility caused by the strong decoupling between graphene and MoS2 bands enhances the gate-controlled switching performance in MoS2-graphene hybrid stacking-device. PMID- 28358117 TI - Altered (neo-) lacto series glycolipid biosynthesis impairs alpha2-6 sialylation on N-glycoproteins in ovarian cancer cells. AB - The (neo-) lacto series glycosphingolipids (nsGSLs) comprise of glycan epitopes that are present as blood group antigens, act as primary receptors for human pathogens and are also increasingly associated with malignant diseases. Beta-1, 3 N-acetyl-glucosaminyl-transferase 5 (B3GNT5) is suggested as the key glycosyltransferase for the biosynthesis of nsGSLs. In this study, we investigated the impact of CRISPR-Cas9 -mediated gene disruption of B3GNT5 (?B3GNT5) on the expression of glycosphingolipids and N-glycoproteins by utilizing immunostaining and glycomics-based PGC-UHPLC-ESI-QTOF-MS/MS profiling. ?B3GNT5 cells lost nsGSL expression coinciding with reduction of alpha2-6 sialylation on N-glycoproteins. In contrast, disruption of B4GALNT1, a glycosyltransferase for ganglio series GSLs did not affect alpha2-6 sialylation on N-glycoproteins. We further profiled all known alpha2-6 sialyltransferase encoding genes and showed that the loss of alpha2-6 sialylation is due to silencing of ST6GAL1 expression in ?B3GNT5 cells. These results demonstrate that nsGSLs are part of a complex network affecting N-glycosylation in ovarian cancer cells. PMID- 28358120 TI - Excitonic structure and pumping power dependent emission blue-shift of type-II quantum dots. AB - In this work we study theoretically and experimentally the multi-particle structure of the so-called type-II quantum dots with spatially separated electrons and holes. Our calculations based on customarily developed full configuration interaction ap- proach reveal that exciton complexes containing holes interacting with two or more electrons exhibit fairly large antibinding energies. This effect is found to be the hallmark of the type-II confinement. In addition, an approximate self-consistent solution of the multi-exciton problem allows us to explain two pronounced phenomena: the blue-shift of the emission with pumping and the large inhomogeneous spectral broadening, both of those eluding explanation so far. The results are confirmed by detailed intensity and polarization resolved photoluminescence measurements on a number of type-II samples. PMID- 28358118 TI - CombiROC: an interactive web tool for selecting accurate marker combinations of omics data. AB - Diagnostic accuracy can be improved considerably by combining multiple markers, whose performance in identifying diseased subjects is usually assessed via receiver operating characteristic (ROC) curves. The selection of multimarker signatures is a complicated process that requires integration of data signatures with sophisticated statistical methods. We developed a user-friendly tool, called CombiROC, to help researchers accurately determine optimal markers combinations from diverse omics methods. With CombiROC data from different domains, such as proteomics and transcriptomics, can be analyzed using sensitivity/specificity filters: the number of candidate marker panels rising from combinatorial analysis is easily optimized bypassing limitations imposed by the nature of different experimental approaches. Leaving to the user full control on initial selection stringency, CombiROC computes sensitivity and specificity for all markers combinations, performances of best combinations and ROC curves for automatic comparisons, all visualized in a graphic interface. CombiROC was designed without hard-coded thresholds, allowing a custom fit to each specific data: this dramatically reduces the computational burden and lowers the false negative rates given by fixed thresholds. The application was validated with published data, confirming the marker combination already originally described or even finding new ones. CombiROC is a novel tool for the scientific community freely available at http://CombiROC.eu. PMID- 28358119 TI - Three dimensional characterization of GaN-based light emitting diode grown on patterned sapphire substrate by confocal Raman and photoluminescence spectromicroscopy. AB - We performed depth-resolved PL and Raman spectral mappings of a GaN-based LED structure grown on a patterned sapphire substrate (PSS). Our results showed that the Raman mapping in the PSS-GaN heterointerface and the PL mapping in the InxGa1 xN/GaN MQWs active layer are spatially correlated. Based on the 3D construction of E2(high) Raman peak intensity and frequency shift, V-shaped pits in the MQWs can be traced down to the dislocations originated in the cone tip area of PSS. Detail analysis of the PL peak distribution further revealed that the indium composition in the MQWs is related to the residual strain propagating from the PSS-GaN heterointerface toward the LED surface. Numerical simulation based on the indium composition distribution also led to a radiative recombination rate distribution that shows agreement with the experimental PL intensity distribution in the InxGa1-xN/GaN MQWs active layer. PMID- 28358121 TI - Chemical interaction mechanism of 10-MDP with zirconia. AB - Currently, the functional monomer 10-methacryloyloxy-decyl-dihydrogen-phosphate (10-MDP) was documented to chemically bond to zirconia ceramics. However, little research has been conducted to unravel the underlying mechanisms. This study aimed to assess the chemical interaction and to demonstrate the mechanisms of coordination between 10-MDP and zirconium oxide using 1H and 31P magic angle spinning (MAS) nuclear magnetic resonance (NMR) and two dimensional (2D) 1H -> 31P heteronuclear correlation (HETCOR) NMR. In addition, shear bond-strength (SBS) tests were conducted to determine the effect of 10-MDP concentration on the bonding effectiveness to zirconia. These SBS tests revealed a 10-MDP concentration-dependent SBS with a minimum of 1-ppb 10-MDP needed. 31P-NMR revealed that one P-OH non-deprotonated of the PO3H2 group from 10-MDP chemically bonded strongly to zirconia. 1H-31P HETCOR NMR indicated that the 10-MDP monomer can be adsorbed onto the zirconia particles by hydrogen bonding between the P=O and Zr-OH groups or via ionic interactions between partially positive Zr and deprotonated 10-MDP (P-O-). The combination of 1H NMR and 2D 1H-31P HETCOR NMR enabled to describe the different chemical states of the 10-MDP bonds with zirconia; they not only revealed ionic but also hydrogen bonding between 10-MDP and zirconia. PMID- 28358122 TI - Differentiation of Pancreatic Cyst Types by Analysis of Rheological Behavior of Pancreatic Cyst Fluid. AB - Differentiation between mucinous and non-mucinous pancreatic cysts is exceedingly important and challenging, particularly as the former bears malignant transformation potential. Pancreatic cyst fluid (PCF)-based diagnostics, including analyses of biochemical markers, as well as cytology, has shown inadequate accuracy. Herein, a preliminary single-center study of 22 PCF samples, collected by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA), assessed the rheological behavior of PCF and its correlation with lesion type. The dependence of PCF shear viscosity on shear rate was found to follow a power law and could be fitted using Ostwald-de Waele model. Three types of flow curves were identified, where two types correlated with non-mucinous cysts, differing by their power law exponent, and the third type corresponding to mucinous cysts. Viscosity measured at a high shear rate was shown to serve as an accurate and independent marker distinguishing between mucinous and non-mucinous cysts, with an optimal cutoff value of etac = 1.3 cP The accuracy of this novel technique proved superior to string-sign, cytology, carcinoembryonic antigen, and amylase assessments. Moreover, the combined predictive value of etac and patient age provided for sensitivity and specificity of 100% and 95.5%, respectively. This simple and rapid diagnostic tool can be immediately implemented after EUS-FNA sampling. PMID- 28358123 TI - Molecular Therapy for Degenerative Disc Disease: Clues from Secretome Analysis of the Notochordal Cell-Rich Nucleus Pulposus. AB - Degenerative disc disease (DDD) is associated with spinal pain often leading to long-term disability. However, the non-chondrodystrophic canine intervertebral disc is protected from the development of DDD, ostensibly due to its retention of notochordal cells (NC) in the nucleus pulposus (NP). In this study, we hypothesized that secretome analysis of the NC-rich NP will lead to the identification of key proteins that delay the onset of DDD. Using mass spectrometry, we identified 303 proteins including components of TGFbeta- and Wnt signaling, anti-angiogeneic factors and proteins that inhibit axonal ingrowth in the bioactive fractions of serum free, notochordal cell derived conditioned medium (NCCM). Ingenuity Pathway Analysis revealed TGFbeta1 and CTGF as major hubs in protein interaction networks. In vitro treatment with TGFbeta1 and CTGF promoted the synthesis of healthy extra-cellular matrix proteins, increased cell proliferation and reduced cell death in human degenerative disc NP cells. A single intra-discal injection of recombinant TGFbeta1 and CTGF proteins in a pre clinical rat-tail disc injury model restored the NC and stem cell rich NP. In conclusion, we demonstrate the potential of TGFbeta1 and CTGF to mitigate the progression of disc degeneration and the potential use of these molecules in a molecular therapy to treat the degenerative disc. PMID- 28358124 TI - Domain-specific interactions between MLN8237 and human serum albumin estimated by STD and WaterLOGSY NMR, ITC, spectroscopic, and docking techniques. AB - Alisertib (MLN8237) is an orally administered inhibitor of Aurora A kinase. This small-molecule inhibitor is under clinical or pre-clinical phase for the treatment of advanced malignancies. The present study provides a detailed characterization of the interaction of MLN8237 with a drug transport protein called human serum albumin (HSA). STD and WaterLOGSY nuclear magnetic resonance (NMR)-binding studies were conducted first to confirm the binding of MLN8237 to HSA. In the ligand orientation assay, the binding sites of MLN8237 were validated through two site-specific spy molecules (warfarin sodium and ibuprofen, which are two known site-selective probes) by using STD and WaterLOGSY NMR competition techniques. These competition experiments demonstrate that both spy molecules do not compete with MLN8237 for the specific binding site. The AutoDock-based blind docking study recognizes the hydrophobic subdomain IB of the protein as the probable binding site for MLN8237. Thermodynamic investigations by isothermal titration calorimetry (ITC) reveal that the non-covalent interaction between MLN8237 and HSA (binding constant was approximately 105 M-1) is driven mainly by favorable entropy and unfavorable enthalpy. In addition, synchronous fluorescence, circular dichroism (CD), and 3D fluorescence spectroscopy suggest that MLN8237 may induce conformational changes in HSA. PMID- 28358125 TI - A golden goat genome. AB - The newly described de novo goat genome sequence is the most contiguous diploid vertebrate assembly generated thus far using whole-genome assembly and scaffolding methods. The contiguity of this assembly is approaching that of the finished human and mouse genomes and suggests an affordable roadmap to high quality references for thousands of species. PMID- 28358126 TI - Corrigendum: Uncovering Listeria monocytogenes hypervirulence by harnessing its biodiversity. PMID- 28358127 TI - Erratum: Distinct Salmonella Enteritidis lineages associated with enterocolitis in high-income settings and invasive disease in low-income settings. PMID- 28358129 TI - 25 more years. AB - This month, to celebrate a quarter century of excellence in genetics, we are highlighting selections from the past work we have published. We will then publish a number of forward-looking Perspectives in the coming months to examine and chart the future directions of our field. In parallel, we will also consult researchers for their answers to current questions of interest to the genetics and genomics community for discussion throughout the year. PMID- 28358130 TI - Genetic interactions improve models of quantitative traits. AB - A study of genetic variation in yeast has identified key quantitative trait loci (QTLs) that suppress the effects of variation at multiple other loci. These loci prove essential to accurately modeling yeast growth in response to different environments. PMID- 28358131 TI - Erratum: Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. PMID- 28358128 TI - Corrigendum: Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer. PMID- 28358132 TI - Ultrasensitive detection of TCR hypervariable-region sequences in solid-tissue RNA-seq data. PMID- 28358133 TI - Resequencing at scale in neurodevelopmental disorders. AB - An international collaboration has assembled DNA samples and detailed phenotypic information from >13,000 individuals with a clinical diagnosis of either autism spectrum disorder (ASD) or intellectual disability/developmental delay (ID/DD). The application of molecular inversion probe technologies to sequence 208 candidate genes at scale in this impressive resource has identified a large set of plausibly causative mutations for these disorders. PMID- 28358134 TI - Celebrating parasites. PMID- 28358135 TI - Monolithic integration of a lithium niobate microresonator with a free-standing waveguide using femtosecond laser assisted ion beam writing. AB - We demonstrated integrating a high quality factor lithium niobate microdisk resonator with a free-standing membrane waveguide. Our technique is based on femtosecond laser direct writing which produces the pre-structure, followed by focused ion beam milling which reduces the surface roughness of sidewall of the fabricated structure to nanometer scale. Efficient light coupling between the integrated waveguide and microdisk was achieved, and the quality factor of the microresonator was measured as high as 1.67 * 105. PMID- 28358136 TI - Tubular Cardiac Tissues Derived from Human Induced Pluripotent Stem Cells Generate Pulse Pressure In Vivo. AB - Human induced pluripotent stem (iPS) cell-derived cardiac cells provide the possibility to fabricate cardiac tissues for transplantation. However, it remains unclear human bioengineered cardiac tissues function as a functional pump in vivo. Human iPS cells induced to cardiomyocytes in suspension were cultured on temperature-responsive dishes to fabricate cardiac cell sheets. Two pairs of triple-layered sheets were transplanted to wrap around the inferior vena cava (IVC) of nude rats. At 4 weeks after transplantation, inner pressure changes in the IVC were synchronized with electrical activations of the graft. Under 80 pulses per minute electrical stimulation, the inner pressure changes at 8 weeks increased to 9.1 +/- 3.2 mmHg, which were accompanied by increases in the baseline inner pressure of the IVC. Immunohistochemical analysis revealed that 0.5-mm-thick cardiac troponin T-positive cardiac tissues, which contained abundant human mitochondria, were clearly engrafted lamellar around the IVC and surrounded by von Willebrand factor-positive capillary vessels. The mRNA expression of several contractile proteins in cardiac tissues at 8 weeks in vivo was significantly upregulated compared with those at 4 weeks. We succeeded in generating pulse pressure by tubular human cardiac tissues in vivo. This technology might lead to the development of a bioengineered heart assist pump. PMID- 28358138 TI - Photostability of plasma polymerized gamma-terpinene thin films for encapsulation of OPV. AB - Optically transparent, smooth, defect-free, chemically inert and with good adhesion to a variety of substrates, plasma polymers from plant-derived secondary metabolites have been identified as promising encapsulating materials for organic electronics and photovoltaics. Here, we demonstrate that an encapsulating layer of plasma polymerized gamma-terpinene reduces degradation-related loss in conversion efficiency in PCPDTBT:PC70BM solar cells under ambient operating conditions. The stability of gamma-terpinene films was then investigated under extreme UV irradiation conditions as a function of deposition power. When exposed to ambient air, prolonged exposure to UV-A and UV-B light led to notable ageing of the polymer. Photooxidation was identified as the main mechanism of degradation, confirmed by significantly slower ageing when oxygen was restricted through the use of a quartz cover. Under unnatural high-energy UV-C irradiation, significant photochemical degradation and oxidation occurred even in an oxygen poor environment. PMID- 28358139 TI - HLA-B*15:21 and carbamazepine-induced Stevens-Johnson syndrome: pooled-data and in silico analysis. AB - HLA-B*15:02 screening before carbamazepine (CBZ) prescription in Asian populations is the recommended practice to prevent CBZ-induced Stevens-Johnson syndrome (CBZ-SJS). However, a number of patients have developed CBZ-SJS even having no HLA-B*15:02. Herein, we present the case of a Thai patient who had a negative HLA-B*15:02 screening result but later developed CBZ-SJS. Further HLA typing revealed HLA-B*15:21/B*13:01. HLA-B*15:21 is a member of the HLA-B75 serotype and is commonly found in Southeast Asian populations. Based on this case, we hypothesised that if all HLA-B*15:02 carriers were prevented from CBZ prescription, another common HLA-B75 serotype marker would show its association with CBZ-SJS. To test this hypothesis, we pooled data from previous association studies in Asian populations, excluded all cases with HLA-B*15:02, and analysed the association significance of HLA-B75 serotype markers. A significant association was found between CBZ-SJS and HLA-B*15:21 and HLA-B*15:11. We also applied an in silico analysis and found that all HLA-B75 serotype molecules shared similar capability in binding the CBZ molecule. In summary, this report provides the first evidence of a positive association between HLA-B*15:21 and CBZ SJS and the first in silico analysis of CBZ binding sites and details of the molecular behaviour of HLA-B75 molecule to explain its molecular action. PMID- 28358137 TI - Identification and evolution of a plant cell wall specific glycoprotein glycosyl transferase, ExAD. AB - Extensins are plant cell wall glycoproteins that act as scaffolds for the deposition of the main wall carbohydrate polymers, which are interlocked into the supramolecular wall structure through intra- and inter-molecular iso-di-tyrosine crosslinks within the extensin backbone. In the conserved canonical extensin repeat, Ser-Hyp4, serine and the consecutive C4-hydroxyprolines (Hyps) are substituted with an alpha-galactose and 1-5 beta- or alpha-linked arabinofuranoses (Arafs), respectively. These modifications are required for correct extended structure and function of the extensin network. Here, we identified a single Arabidopsis thaliana gene, At3g57630, in clade E of the inverting Glycosyltransferase family GT47 as a candidate for the transfer of Araf to Hyp-arabinofuranotriose (Hyp-beta1,4Araf-beta1,2Araf-beta1,2Araf) side chains in an alpha-linkage, to yield Hyp-Araf4 which is exclusively found in extensins. T-DNA knock-out mutants of At3g57630 showed a truncated root hair phenotype, as seen for mutants of all hitherto characterized extensin glycosylation enzymes; both root hair and glycan phenotypes were restored upon reintroduction of At3g57630. At3g57630 was named Extensin Arabinose Deficient transferase, ExAD, accordingly. The occurrence of ExAD orthologs within the Viridiplantae along with its' product, Hyp-Araf4, point to ExAD being an evolutionary hallmark of terrestrial plants and charophyte green algae. PMID- 28358141 TI - Spin filtering effect generated by the inter-subband spin-orbit coupling in the bilayer nanowire with the quantum point contact. AB - The spin filtering effect in the bilayer nanowire with quantum point contact is investigated theoretically. We demonstrate the new mechanism of the spin filtering based on the lateral inter-subband spin-orbit coupling, which for the bilayer nanowires has been reported to be strong. The proposed spin filtering effect is explained as the joint effect of the Landau-Zener intersubband transitions caused by the hybridization of states with opposite spin (due to the lateral Rashba SO interaction) and the confinement of carriers in the quantum point contact region. PMID- 28358142 TI - Thermochromic Luminescent Materials and Multi-Emission Bands in d10 Clusters. AB - Thermochromic luminescent compounds with d10 metal ions are interesting materials for applications such as sensors or display devices. However, these properties are difficult to predict prior to their synthesis. In this communication, we investigated materials with structural assemblies known to be responsible of distinct luminescence mechanisms and show that they can be interesting potential thermometers. Thus, we compared the synthesis of a zinc halide and a copper halide based compounds which only differ in their ability to create clusters with metallophilic interactions. The compounds synthesized by hydrothermal method have been structurally characterized by Single-crystal X-ray diffraction, Solid-State NMR, FTIR, UV-Visible spectroscopy, thermal analysis and EPR. The photoluminescence properties of the two materials have been characterized at different temperatures. The copper bromide compound shows luminescence thermochromism in a wide spectrum of colors owing to the formation of clusters generating multi-emission bands while the zinc bromide exhibits a single emission band and no thermochromism. PMID- 28358140 TI - A pilot study on transient ischemic stroke induced with endothelin-1 in the rhesus monkeys. AB - Endothelin-1 (ET-1), a vasoconstrictor, has recently been used to induce focal ischemia in rodents and marmoset monkeys. The rhesus monkey, however, has numerous advantages to the rodent and marmoset that make it a superior and irreplaceable animal model for studying stroke in the brain. In the present study, after mapping the preferred hand representation in two healthy male monkeys with intracortical micro-stimulation, ET-1 was microinjected into the contralateral motor cortex (M1) to its preferred hand. The monkeys had been trained in three manual dexterity tasks before the microinjection and were tested for these tasks following the ET-1 injection. Brain Magnetic Resonance Imaging scans were performed 1, 7, 14 and 28 days post ischemia. It was found that ET-1 impaired the manual dexterity of the monkeys in the vertical slot and rotating Brinkman board tasks 3-8 days after the injection. Brain imaging found that severe edema was present 7 days after the focal ischemia. This data suggest that ET-1 can induce transient ischemic stroke in rhesus monkey and that ET-1 induced focal ischemia in non-human primates is a potential model to study the mechanism of stroke and brain repair after stroke. PMID- 28358143 TI - Facile Fabrication of Platinum-Cobalt Alloy Nanoparticles with Enhanced Electrocatalytic Activity for a Methanol Oxidation Reaction. AB - Decreasing the cost associated with platinum-based catalysts along with improving their catalytic properties is a major challenge for commercial direct methanol fuel cells. In this work, a simple and facile strategy was developed for the more efficient preparation of multi-walled carbon nanotube (MWCNT) -supported Pt/CoPt composite nanoparticles (NPs) via solution plasma sputtering with subsequent thermal annealing. Quite different from general wet synthesis methods, Pt/CoPt composite NPs were directly derived from metal wire electrodes without any additions. The obtained Pt/CoPt/MWCNTs composite catalysts exhibited tremendous improvement in the electro-oxidation of methanol in acidic media with mass activities of 1719 mA mg-1Pt. This value is much higher than that of previous reports of Pt-Co alloy and commercial Pt/C (3.16 times) because of the many active sites and clean surface of the catalysts. The catalysts showed good stability due to the special synergistic effects of the CoPt alloy. Pt/CoPt/MWCNTs can be used as a promising catalyst for direct methanol fuel cells. In addition, this solution plasma sputtering-assisted synthesis method introduces a general and feasible route for the synthesis of binary alloys. PMID- 28358145 TI - Retraction of: application of food-specific IgG antibody detection in allergy dermatosis. AB - [This retracts the article DOI: 10.1515/med-2015-0067.]. PMID- 28358146 TI - Structural modelling and phylogenetic analyses of PgeIF4A2 (Eukaryotic translation initiation factor) from Pennisetum glaucum reveal signature motifs with a role in stress tolerance and development. AB - Eukaryotic translation initiation factor 4A (eIF4A) is an indispensable component of the translation machinery and also play a role in developmental processes and stress alleviation in plants and animals. Different eIF4A isoforms are present in the cytosol of the cell, namely, eIF4A1, eIF4A2, and eIF4A3 and their expression is tightly regulated in cap-dependent translation. We revealed the structural model of PgeIF4A2 protein using the crystal structure of Homo sapiens eIF4A3 (PDB ID: 2J0S) as template by Modeller 9.12. The resultant PgeIF4A2 model structure was refined by PROCHECK, ProSA, Verify3D and RMSD that showed the model structure is reliable with 77 % amino acid sequence identity with template. Investigation revealed two conserved signatures for ATP-dependent RNA Helicase DEAD-box conserved site (VLDEADEML) and RNA helicase DEAD-box type, Q-motif in sheet-turn helix and alpha-helical region respectively. All these conserved motifs are responsible for response during developmental stages and stress tolerance in plants. PMID- 28358144 TI - Novel conjugates of aminoadamantanes with carbazole derivatives as potential multitarget agents for AD treatment. AB - A new group of compounds, promising for the design of original multitarget therapeutic agents for treating neurodegenerative diseases, based on conjugates of aminoadamantane and carbazole derivatives was synthesized and investigated. Compounds of these series were found to interact with a group of targets that play an important role in the development of this type of diseases. First of all, these compounds selectively inhibit butyrylcholinesterase, block NMDA receptors containing NR2B subunits while maintaining the properties of MK-801 binding site blockers, exert microtubules stabilizing properties, and possess the ability to protect nerve cells from death at the calcium overload conditions. The leading compound C-2h has been shown the most promising effects on all analyzed parameters. Thus, these compounds can be regarded as promising candidates for the design of multi-target disease-modifying drugs for treatment of AD and/or similar neuropathologies. PMID- 28358147 TI - A plant Bcl-2-associated athanogene is proteolytically activated to confer fungal resistance. AB - The Bcl-2-associated athanogene (BAG) family is a multifunctional group of proteins involved in numerous cellular functions ranging from apoptosis to tumorigenesis. These proteins are evolutionarily conserved and encode a characteristic region known as the BAG domain. BAGs function as adapter proteins forming complexes with signaling molecules and molecular chaperones. In humans, a role for BAG proteins has been suggested in tumor growth, HIV infection, and neurodegenerative diseases; as a result, the BAGs are attractive targets for therapeutic interventions, and their expression in cells may serve as a predictive tool for disease development. The Arabidopsis genome contains seven homologs of BAG family proteins (Figure 1), including four with a domain organization similar to animal BAGs (BAG1-4). The remaining three members (BAG5 7) contain a predicted calmodulin-binding motif near the BAG domain, a feature unique to plant BAG proteins that possibly reflects divergent mechanisms associated with plant-specific functions. As reported for animal BAGs, plant BAGs also regulate several stress and developmental processes (Figure 2). The recent article by Li et al. focuses on the role of BAG6 in plant innate immunity. This study shows that BAG6 plays a key role in basal plant defense against fungal pathogens. Importantly, this work further shows that BAG6 is proteolytically activated to induce autophagic cell death and resistance in plants. This finding underscores the importance of proteases in the execution of plant cell death, yet little is known about proteases and their substrates in plants. PMID- 28358148 TI - Enantioselective Diels-Alder-lactamization organocascades employing a furan-based diene. AB - alpha,beta-Unsaturated acylammonium salts are useful dienophiles enabling highly enantioselective and stereodivergent Diels-Alder-initiated organocascades with furan-based dienes. Complex polycyclic systems can thus be obtained from readily prepared dienes, commodity acid chlorides, and a chiral isothiourea organocatalyst under mild conditions. We describe the use of furan-based dienes bearing pendant sulfonamides leading to the generation of oxa-bridged, trans fused tricyclic gamma-lactams. This process constitutes the first highly enantio- and diastereoselective, organocatalytic Diels-Alder cycloadditions with these typically problematic dienes due to their reversibility. Computational studies suggest that the high diastereoselectivity with these furan dienes may be due to a reversible Diels-Alder cycloaddition for the endo adducts. In addition, the utility of this methodology is demonstrated through a concise approach to a core structure with similarity to the natural product isatisine A and a nonpeptidyl ghrelin-receptor inverse agonist. PMID- 28358149 TI - Syntheses and kinetic studies of cyclisation-based self-immolative spacers. AB - Kinetic analysis of the disassembly of self-immolative spacers based on cyclisation processes was performed. Five compounds were synthesized belonging to two different series, and their kinetic constants were determined. Electron donating substituents gave a slight acceleration but the main effect was steric, and the Thorpe-Ingold effect was indeed particularly effective. Comparison with the self-immolative spacers based on elimination processes showed that cyclisations gave comparable or lower rate, but the corresponding spacers are more difficult to modulate. PMID- 28358151 TI - Swelling-induced structural changes and microparticle uptake of gelatin gels probed by NMR and CLSM. AB - Gelatin gels are increasingly involved in many industrial applications due to several advantages including cost efficiency and biocompatibility. Generally, their production requires the use of aqueous solvents, which cause significant swelling, due to the ability of solvent molecules to penetrate through the gel microstructure and increase its volume. Since swelling mechanisms and their effect on the gel structure are not fully understood, further investigations are required. In this work, we combine macroscopic measurements of the swelling ratio (SR) with Nuclear Magnetic Resonance (NMR) and Confocal Laser Scanning Microscopy (CLSM) to investigate changes in the gelatin structure as a function of both polymer concentration and swelling time. SR values increase as a function of time until a maximum is reached and then show a slight drop for all the gelatin concentrations after 24 h swelling time, probably due to a network relaxation process. NMR allows determination of mass transport and molecular dynamics of water inside the gelatin pores, while CLSM is used to visualize the penetration of tracers (polystyrene microbeads) with a diameter much larger than the gel pores. Structural parameters, such as average pore size and tortuosity, are estimated. In particular, the pore size decreases for higher polymer concentration and increases during swelling, until reaching a maximum, and then dropping at longer times. The penetration of tracers provides evidence of the heterogeneity of the gel structure and shows that single microcarriers can be loaded in gelatin gels upon swelling. PMID- 28358152 TI - Inhibition of the MurA enzyme in Fusobacterium nucleatum by potential inhibitors identified through computational and in vitro approaches. AB - Fusobacterium nucleatum plays a key role in several diseases such as periodontitis, gingivitis, appendicitis, and inflammatory bowel disease (IBD). The development of antibiotic resistance by this bacterium demands novel therapeutic intervention. Our recent study has reported UDP-N-acetylglucosamine 1 carboxyvinyltransferase (MurA) as one of the potential target proteins in F. nucleatum. In this study, we proposed two novel MurA inhibitors through in silico screening and evaluated their mode of inhibition by in vitro experiments. It was found that MurA structural arrangement (inside-out alpha/beta barrel) was stabilized by L/FXXXG(A) motif-based interactions. The protein was maintained in an open or substrate-free conformation due to repulsive forces between two parallelly arranged positively charged residues of domain I and II. In this conformation, we identified six best compounds that held key interactions with the substrate-binding pocket via a structure-based virtual screening of natural and chemical compound libraries. However, among these, only orientin and quercetin-3-O-d-glucuronide (Q3G) showed better interaction capability through consistent H-bond occupancy and lowest binding free energy during molecular dynamic simulations. In vitro inhibition studies evidenced the mixed and uncompetitive mode of inhibition by orientin and Q3G, respectively, with purified MurA protein. This explains the binding of orientin in both open and closed (substrate-bound) conformations of MurA, and Q3G binding in only closed conformation. Therefore, the Q3G binding mode was predicted on a MurA-substrate complex, which highlighted its constant H-bond with Cys118, a phosphoenolpyruvate (PEP) interacting residue. This suggests that Q3G may interrupt the PEP binding, thereby inhibiting the MurA activity. Thus, the current study discusses the structure of MurA and demonstrates the inhibitory action of two novel compounds. PMID- 28358153 TI - Domino reaction of cyclic sulfamidate imines with Morita-Baylis-Hillman acetates promoted by DABCO: a metal-free approach to functionalized nicotinic acid derivatives. AB - A facile, green, metal-free new one-pot synthetic strategy has been developed for easy access to a wide array of medicinally promising functionalized pyridines having an ester, a nitrile or an acetyl group at the C-3 position in good to excellent yields via a domino SN2/elimination/6pi-aza electrocyclization/aromatization reaction of several 4-aryl/hetero-aryl substituted 5-membered cyclic sulfamidate imines with a broad range of MBH acetates of acrylate/acrylonitrile/MVK in 2-MeTHF promoted by DABCO as an organobase under an O2 atmosphere. Moreover, a biologically interesting triazolopyridine derivative was achieved through a unique procedure. PMID- 28358155 TI - A tunable copper-catalyzed multicomponent reaction towards alkaloid-inspired indole/lactam polycycles. AB - A versatile copper(i)-catalyzed cascade multicomponent reaction strategy between readily available (Z)-3-iodoacrylic acids, terminal alkynes, and primary amines is reported, leading to a great diversity of complex heterocyclic backbones based on biorelevant indole/lactam scaffolds. PMID- 28358156 TI - Selective synthesis of mono- and bis-butenolide alpha-aminomethyl adducts. AB - The selective installation of alpha-methylamine residues at the butenolide core is described using alpha-bromomethylene-gamma-butenolide and primary as well as secondary amines in methanol at 0 degrees C. The preparation of mono- and bis butenolide alpha-adducts is described. Bis-gamma-butenolide adducts as well as mono alpha-aminomethyl-gamma-butenolides can be selectively obtained depending on the nature of the reacting primary amine. In contrast, the use of secondary amines allows two different pathways leading either to the expected amino derivatives or to the formation of a C-O bond. PMID- 28358157 TI - Optical diagnosis - highlighting the clinical applications of vibrational spectroscopy. PMID- 28358158 TI - Direct monitoring of pulmonary disease treatment biomarkers using plasmonic gold nanorods with diffusion-sensitive OCT. AB - The solid concentration of pulmonary mucus (wt%) is critical to respiratory health. In patients with respiratory disease, such as Cystic Fibrosis (CF) and Chronic Obstructive Pulmonary Disorder (COPD), mucus hydration is impaired, resulting in high wt%. Mucus with high wt% is a hallmark of pulmonary disease that leads to obstructed airways, inflammation, and infection. Methods to measure mucus hydration in situ and in real-time are needed for drug development and personalized therapy. We employed plasmonic gold nanorod (GNR) biosensors that intermittently collide with macromolecules comprising the mucus mesh as they self diffuse, such that GNR translational diffusion (DT) is sensitive to wt%. GNRs are attractive candidates for bioprobes due to their anisotropic optical scattering that makes them easily distinguishable from native tissue using polarization sensitive OCT. Using principles of heterodyne dynamic light scattering, we developed diffusion-sensitive optical coherence tomography (DS-OCT) to spatially resolve changing DT in real-time. DS-OCT enables, for the first time, direct monitoring of changes in nanoparticle diffusion rates that are sensitive to nanoporosity with spatial and temporal resolutions of 4.7 MUm and 0.2 s. DS-OCT therefore enables us to measure spatially-resolved changes in mucus wt% over time. In this study, we demonstrate the applicability of DS-OCT on well differentiated primary human bronchial epithelial cells during a clinical mucus hydrating therapy, hypertonic saline treatment (HST), to reveal, for the first time, mucus mixing, cellular secretions, and mucus hydration on the micrometer scale that translate to long-term therapeutic effects. PMID- 28358160 TI - Highly stiff yet elastic microcapsules incorporating cellulose nanofibrils. AB - Microcapsules with high mechanical stability and elasticity are desirable in a variety of contexts. We report a single-step method to fabricate such microcapsules by microfluidic interfacial complexation between high stiffness cellulose nanofibrils (CNF) and an oil-soluble cationic random copolymer. Single capsule compression measurements reveal an elastic modulus of 53 MPa for the CNF based capsule shell with complete recovery of deformation from strains as large as 19%. We demonstrate the ability to manipulate the shell modulus by the use of polyacrylic acid (PAA) as a binder material, and observe a direct relationship between the shell modulus and the PAA concentration, with moduli as large as 0.5 GPa attained. These results demonstrate that CNF incorporation provides a facile route for producing strong yet flexible microcapsule shells. PMID- 28358161 TI - Post-translational modifications involved in the biosynthesis of thiopeptide antibiotics. AB - Thiopeptide antibiotics are a class of typical ribosomally synthesized and post translationally modified peptides (RiPPs) with complex chemical structures that are difficult to construct via chemical synthesis. To date, more than 100 thiopeptides have been discovered, and most of these compounds exhibit remarkable biological activities, such as antibacterial, antitumor and immunosuppressive activities. Therefore, studies of the biosynthesis of thiopeptides can contribute to the development of new drug leads and facilitate the understanding of the complex post-translational modifications (PTMs) of peptides and/or proteins. Since the biosynthetic gene clusters of thiopeptides were first discovered in 2009, several research studies regarding the biochemistry and enzymology of thiopeptide biosyntheses have been reported, indicating that their characteristic framework is constructed via a cascade of common PTMs and that additional specific PTMs diversify the molecules. In this review, we primarily summarize recent advances in understanding the biosynthesis of thiopeptide antibiotics and propose some potential applications based on our insights into the biosynthetic logic and machinery. PMID- 28358162 TI - Ligands and complexes based on piperidine and their exploitation of the ring opening polymerisation of rac-lactide. AB - A range of ligands based upon 2-(aminomethyl)piperidine have been successfully complexed to Mg(ii), Zn(ii) and group IV metal centres. These complexes have been characterised both in solution and solid state with different coordination geometries realised dependant on the nature of the ligand. For the Mg(ii) and Zn(ii) complexes, M(1-2)2, were isolated and analysed by DOSY NMR spectroscopy. These ligands also furnished diastereomeric group IV complexes, M(1-2)2(OiPr)2. Group IV salalen and salan complexes, M(4-5)(OR)2 were also found to be diastereomeric in nature, with either beta-cis or alpha-cis geometriesrespectively. The tridentate ligand, 6H2, yielded five coordinate complexes with both Ti(iv) and Zr(iv). All complexes were screened for the ring opening polymerisation of rac-lactide under both solvent and melt conditions. For the Mg(ii) and Zn(ii) complexes, good activity was observed with Zn(1-2)2 demonstrating immortal polymerisation characteristics. PMID- 28358164 TI - Thiolysis of NBD-based dyes for colorimetric and fluorescence detection of H2S and biothiols: design and biological applications. AB - Hydrogen sulfide (H2S) is an important endogenous signaling molecule with multiple biological functions. The development of colorimetric and fluorescent probes for the visualization of H2S is useful for studying H2S biology. This review details up-to-date research on H2S probes based on thiolysis reactions of NBD (7-nitro-1,2,3-benzoxadiazole) amines or ethers (thioethers). The reactivity and selectivity of NBD-based dyes are discussed. The design principles of NBD based probes are highlighted. The advantages and disadvantages of NBD-based probes are compared, and their biological applications are discussed. PMID- 28358165 TI - Palladium-catalyzed tandem addition/cyclization in aqueous medium: synthesis of 2 arylindoles. AB - An efficient protocol to construct 2-arylindoles was developed through palladium catalyzed tandem addition/cyclization of potassium aryltrifluoroborates with aliphatic nitriles in aqueous medium. The use of water as the reaction medium makes the synthesis process environmentally benign. A plausible mechanism for the formation of 2-arylindoles involving sequential nucleophilic addition followed by an intramolecular cyclization is proposed. Moreover, the utility of this catalytic tandem transformation was also demonstrated in an efficient gram-scale synthesis. This method provides an alternative synthetic tool for accessing a more diverse array of 2-arylindoles. PMID- 28358166 TI - Repeated peptide receptor radiotherapy in multiple recurrences of a metastasized neuroendocrine tumor. PMID- 28358167 TI - Digital Dermoscopy Monitoring: Is it Time to Define a Quality Standard? PMID- 28358168 TI - Efficacy of Botulinum Toxin B Injection for Raynaud's Phenomenon and Digital Ulcers in Patients with Systemic Sclerosis. AB - The efficacy and safety of botulinum toxin B (BTX-B) for treatment of Raynaud's phenomenon and digital ulcers in patients with systemic sclerosis was assessed. A total of 45 patients with systemic sclerosis who had Raynaud's phenomenon were blinded and divided randomly into 4 groups: a no-treatment control group, and 3 treatment groups, using 250, 1,000 or 2,000 international units (U) of BTX-B injections in the hand with more severe symptoms. Four weeks after injection, pain/numbness visual analogue scale scores and Raynaud's score in the groups treated with 1,000 and 2,000 U BTX-B were significantly lower than in the control group and the group treated with 250 U BTX-B. These beneficial effects were sustained until 16 weeks after the single injection. At 4 weeks after injection skin temperature recovery in the group treated with 2,000 U BTX-B was significantly improved. The numbers of digital ulcers in the groups treated with 1,000 and 2,000 U BTX-B were significantly lower than in the control group. In conclusion, 1,000 and 2,000 U BTX-B injections significantly suppressed the activity of Raynaud's phenomenon and digital ulcers in patients with SSc without serious adverse events. PMID- 28358169 TI - Is This Melanoma? A Quiz. PMID- 28358170 TI - Shift in Occupational Risk for Basal Cell Carcinoma from Outdoor to Indoor Workers: A Large Population-based Case-control Register Study from Sweden. AB - Basal cell carcinoma (BCC) is the most common form of cancer worldwide. Exposure of the skin to ultraviolet (UV) radiation, from sunlight and other sources, is the most important risk factor. The aim of this large-scale case-control study was to determine which occupations are associated with increased risk of BCC in Sweden. The case cohort comprised 74,247 patients with BCC and the control cohort comprised 574,055 subjects linked to population-based registers. Compared with the occupational category of farmers, foresters and gardeners we observed elevated risks of BCC for almost all occupational categories studied. Legal workers with odds ratio (OR) 2.69 (95% confidence interval (CI) 2.36-3.06), dentists OR 2.69 (95% CI 2.35-3.08) and physicians OR 2.47 (95% CI 2.24-2.74) had the highest risk for both sexes taken together. In conclusion, there appears to have been a change in the risk of BCC from outdoor to indoor occupations in Sweden, possibly related to exposure to UV radiation during leisure activities exceeding occupational sun exposure as the main cause of BCC in Sweden. PMID- 28358171 TI - Secondary Comedones in a Case of Acne Conglobata Correlate with Double-ended Pseudocomedones in Hidradenitis Suppurativa. PMID- 28358172 TI - Expression of Filaggrin and its Degradation Products in Human Skin Following Erythemal Doses of Ultraviolet B Irradiation. AB - Epidermal filaggrin level is affected by ultraviolet B irradiation in animal and experimental models. This study examined the effect of ultraviolet B irradiation on epidermal filaggrin and natural moisturizing factors in vivo in healthy adults (n = 22). Participants were irradiated with 2 minimal erythema doses of ultraviolet B on the skin. Biopsies and tape strips were collected from skin irradiated 24 and 72 h earlier and from non-irradiated skin (control). Real-time quantitative PCR on skin biopsies showed significantly reduced profilaggrin mRNA expression 24 h after irradiation (mean relative mRNA expression +/- standard deviation: control, 3.86 +/- 2.06 vs. 24 h, 1.52 +/- 0.640; p = 0.02; n = 8). Immunohistochemistry showed aberrant spatial distribution of filaggrin protein 72 h after irradiation (n = 3). High-pressure liquid chromatography of tape extracts showed no change in mean total natural moisturizing factor levels after irradiation, but mean trans-urocanic acid was significantly reduced, as expected (n = 8). In conclusion, erythemal doses of ultraviolet B exert acute effects on profilaggrin mRNA and filaggrin protein in human skin in vivo. PMID- 28358173 TI - Return-to-work coordination programmes for improving return to work in workers on sick leave. AB - BACKGROUND: To limit long-term sick leave and associated consequences, insurers, healthcare providers and employers provide programmes to facilitate disabled people's return to work. These programmes include a variety of coordinated and individualised interventions. Despite the increasing popularity of such programmes, their benefits remain uncertain. We conducted a systematic review to determine the long-term effectiveness of return-to-work coordination programmes compared to usual practice in workers at risk for long-term disability. OBJECTIVES: To assess the effects of return-to-work coordination programmes versus usual practice for workers on sick leave or disability. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 11), MEDLINE, Embase, CINAHL and PsycINFO up to 1 November 2016. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that enrolled workers absent from work for at least four weeks and randomly assigned them to return-to work coordination programmes or usual practice. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles, abstracts and full-text articles for study eligibility; extracted data; and assessed risk of bias from eligible trials. We contacted authors for additional data where required. We conducted random-effects meta-analyses and used the GRADE approach to rate the quality of the evidence. MAIN RESULTS: We identified 14 studies from nine countries that enrolled 12,568 workers. Eleven studies focused on musculoskeletal problems, two on mental health and one on both. Most studies (11 of 14) followed workers 12 months or longer. Risk of bias was low in 10 and high in 4 studies, but findings were not sensitive to their exclusion.We found no benefits for return-to-work coordination programmes on return-to-work outcomes.For short-term follow-up of six months, we found no effect on time to return to work (hazard ratio (HR) 1.32, 95% confidence interval (CI) 0.93 to 1.88, low-quality evidence), cumulative sickness absence (mean difference (MD) -16.18 work days per year, 95% CI -32.42 to 0.06, moderate-quality evidence), the proportion of participants at work at end of the follow-up (risk ratio (RR) 1.06, 95% CI 0.86 to 1.30, low-quality evidence) or on the proportion of participants who had ever returned to work, that is, regardless of whether they had remained at work until last follow-up (RR 0.87, 95% CI 0.63 to 1.19, very low-quality evidence).For long-term follow-up of 12 months, we found no effect on time to return to work (HR 1.25, 95% CI 0.95 to 1.66, low-quality evidence), cumulative sickness absence (MD -14.84 work days per year, 95% CI -38.56 to 8.88, low-quality evidence), the proportion of participants at work at end of the follow-up (RR 1.06, 95% CI 0.99 to 1.15, low quality evidence) or on the proportion of participants who had ever returned to work (RR 1.03, 95% CI 0.97 to 1.09, moderate-quality evidence).For very long-term follow-up of longer than 12 months, we found no effect on time to return to work (HR 0.93, 95% CI 0.74 to 1.17, low-quality evidence), cumulative sickness absence (MD 7.00 work days per year, 95% CI -15.17 to 29.17, moderate-quality evidence), the proportion of participants at work at end of the follow-up (RR 0.94, 95% CI 0.82 to 1.07, low-quality evidence) or on the proportion of participants who had ever returned to work (RR 0.95, 95% CI 0.88 to 1.02, low-quality evidence).We found only small benefits for return-to-work coordination programmes on patient reported outcomes. All differences were below the minimal clinically important difference (MID). AUTHORS' CONCLUSIONS: Offering return-to-work coordination programmes for workers on sick leave for at least four weeks results in no benefits when compared to usual practice. We found no significant differences for the outcomes time to return to work, cumulative sickness absence, the proportion of participants at work at end of the follow-up or the proportion of participants who had ever returned to work at short-term, long-term or very long-term follow up. For patient-reported outcomes, we found only marginal effects below the MID. The quality of the evidence ranged from very low to moderate across all outcomes. PMID- 28358175 TI - The safety and efficacy of the use of the flexible laryngeal mask airway with positive pressure ventilation in elective ENT surgery: a 15-year retrospective single-center study. AB - BACKGROUND: The use of flexible laryngeal mask airway (FLMA) in elective ear, nose and throat (ENT) surgery offers significant advantages, but is frequently considered inferior to tracheal intubation (TI) for ventilation and airway protection. We investigated the safety and success rate of intraoperative FLMA use with positive pressure ventilation (PPV), and the factors responsible for FLMA failure. METHODS: A 15-year single center retrospective study. FLMA failure was defined as the need for FLMA removal and TI, either during induction (primary failure), or after turning the patient over to the surgeon (secondary failure). Strict failure criteria included the inability to achieve and/or maintain all 3 essential FLMA functions, such as ventilation (tidal volume >=6 mL/kg), airway protection from above the cuff (airway sealing pressure [ASP] >12 cm H2O), and separation of the respiratory and gastrointestinal tracts (absent gastric insufflation during PPV). RESULTS: In 685 patients, FLMA was successfully inserted in 94%. Secondary failure rate was 1.5%, with half of failures observed intraoperatively. The inability to seat FLMA during induction or FLMA dislodgment were the most common reasons for failures. The number of FLMA insertion attempts and low ASP were associated with FLMA primary failure and the need for TI. There were no complications. CONCLUSIONS: The results suggest an acceptably low failure rate of use of FLMA with PPV in selected ENT surgical procedures. True intraoperative FLMA failure is uncommon. We advocate observing strict criteria for adequacy of FLMA placement, and close monitoring of FLMA function intraoperatively at all times. PMID- 28358174 TI - The role of minimally invasive surgery in neuroendocrine pancreatic tumors. AB - Minimally invasive surgery has an established role in the treatment of patients with pancreatic neuroendocrine tumors (pNETs). Enucleation is an established treatment option for insulinomas. The necessity of organ sparing surgery is well established in the case of multiple pNETs. A number of studies have demonstrated the efficacy and safety of laparoscopic surgery for the treatment of pNETs. However, pNETs are rare, and large studies focusing on pNET patients are difficult to be designed unless multicenter experience is collected. Authors investigating the role of minimally invasive pancreatic surgery should be encouraged to report separately the results that involve patients presenting with pNETs. A European registry of patients with pNETs treated with minimally invasive surgery would allow further investigation of the optimal treatment of these patients. Especially in the case of syndromic pNETs, that are rare entities, co operation and exchange of information is needed among different centers for sharing experience and transferring knowledge. Existing data come from small cohort studies, case series and case reports. Given that, pancreatic surgery is especially demanding advanced surgery with training that is not yet standardized, further research is needed for defining its role in the treatment of pancreatic neuroendocrine tumors. Regarding the role of robot-assisted surgery in the treatment of pNETS, data are quite scarce. PMID- 28358176 TI - Early versus late tracheostomy in pediatric intensive care unit: does it matter? A 6-year experience. AB - BACKGROUND: The aim of this study is to examine the clinical data of children who underwent tracheostomy during their stay in Pediatric Intensive Care Unit (PICU), in order to describe the relationship between the timing of tracheostomy, the length of PICU stay and the occurrence of ventilator-associated pneumonia (VAP). METHODS: This is a retrospective cohort study that collects all patients undergoing tracheostomy during their PICU stay over a six-year period. Data collection included PICU length of stay, days of intubation, days of mechanical ventilation, primary indication for tracheostomy, information about VAP and decannulations. The early tracheostomy group was defined as patients who had ten or fewer days of continuous ventilation, whereas the late tracheostomy group had more than ten days of continuous ventilation. RESULTS: A significant decrease in the rate of VAP incidence was noticed in the early tracheostomy group vs. late group (P=0.004, OR=0.39, 95% CI: 0.18-0.85). No differences were observed about decannulation, need of long-term ventilation and death rate. Significant decreases of days of mechanical ventilation and PICU stay were found in subgroup of patients who underwent early tracheostomy and were decannulated within 18 months. CONCLUSIONS: No standard timing for tracheostomy placement has been established in the pediatric population. Early tracheostomy can shorten the days of ventilation and hospitalization in PICU and reduce the incidence of VAP, but further studies are needed to identify patient categories in which it can be of benefit. PMID- 28358177 TI - Survey on monitoring analgesia and sedation in the Italian Pediatric Intensive Care Units. AB - BACKGROUND: Admission in Pediatric Intensive Care Unit requires management and monitoring of analgesia and sedation, in order to reduce their adverse effects, and to prevent withdrawal syndrome and delirium. The aim of this study was to evaluate the management of analgesia and sedation in critically ill children admitted in the Italian Pediatric Intensive Care Units. METHODS: For this survey we have submitted a telematics questionnaire to 24 nursing coordinators of the Pediatric Intensive Care Units or Neonatal Intensive Care Units admitting critically ill children. RESULTS: Twenty Intensive Care Units (ICUs) replied to the questionnaire. The association of benzodiazepines and opioids was the first choice in 92.8% of analgesic and sedative strategies. Seventy percent of ICUs adopted a protocol for analgesic and sedative drugs used before performing invasive and/or painful procedures in critically ill children. Ninety percent of them followed a protocol for the assessment of pain, 75% adopting the Face, Legs, Activity, Cry, Consolability Scale. Sixty percent of ICUs followed a protocol for sedation, 58% used the Comfort Scale to monitor the level of it. Forty percent adopted a protocol for the withdrawal syndrome, 75% of them monitored the patients with the WAT-1 Scale. Ten percent of Pediatric Intensive Care Units followed a protocol for management of delirium; seventy-five percent did not monitor it. CONCLUSIONS: Despite an increasing sensitivity in pain and sedation management over the last five years, knowledge and monitoring of abstinence syndrome and delirium need to be improved. PMID- 28358178 TI - Time-to-intubation in obese patients. A randomized study comparing direct laryngoscopy and videolaryngoscopy in experienced anesthetists. AB - BACKGROUND: Airway management may be difficult in obese patients. Moreover, during prolonged intubation, oxygen desaturation develops rapidly. Videolaryngoscopy improves the view of the larynx, and the Storz(r) C-MACTM has been shown to be superior to other videolaryngoscopes in terms of intubation time in obese patients. However, no effort has been made to compare the Storz(r) C MACTM with direct laryngoscopy. The aim of the study was to evaluate if the use of Storz(r) C-MACTM may reduce intubation time when compared to direct laryngoscopy (classic Macintosh(r) blade). METHODS: Eighty patients with Body Mass Index >35 kg/m2 were randomized to orotracheal intubation using either Macintosh(r) laryngoscope, or the Storz(r) C-MACTM with the standard Macintosh blade. Patients had no previous history of a difficult airway. Time-to-intubation (TTI) was defined as the time from the moment anesthetist took the laryngoscope until end-tidal carbon dioxide was detected. RESULTS: No significant difference in TTI could be demonstrated between the two devices tested (mean difference -1.7 s (95% CI:-6.9 to 3.5 s). All patients in the videolaryngoscopy group were successfully intubated with the allocated device, whereas five patients in the direct laryngoscopy group required an alternative device for successful intubation. No significant difference regarding the subjective difficulty of intubation and postoperative sore throat between groups was demonstrated. CONCLUSIONS: In obese patients the airway may be secured equally fast using direct laryngoscopy (Macintosh(r)) and with videolaryngoscopy using the Stortz(r) C-MACTM. The risk for failed intubation, however, appears to be greater with direct laryngoscopy, especially in male obese patients. PMID- 28358179 TI - Perioperative cardiac arrest in the operating room environment: a review of the literature. AB - INTRODUCTION: Cardiac arrest in the operating room (OR) environment is a rare but potentially catastrophic event with mortality rates of more than 50%. Contributing factors are known, and the event is generally rapidly recognized, as patients are usually under full monitoring. The nature of the cardiac arrest in the OR is different to other environments as it is not only related to the patient's conditions but likewise to the anaesthetic and the surgical procedure. The aim of this article is to review recent literature on cardiac arrest in the immediate perioperative environment with a focus on incidence, causes and treatment. EVIDENCE ACQUISITION: Retrospective analysis of literature published in PubMed. EVIDENCE SYNTHESIS: Several recent retrospective registry studies have investigated the incidence of perioperative cardiac arrest; in non-cardiac surgery patients, the incidence is reported to range from 0.2 to 1.1 per 10,000 adults and from 1.4 to 4.6 per 10,000 children. CONCLUSIONS: Successful management of cardiac arrest during surgery and beyond requires not only individual technical skills and a well-organized team response, but also an institutional safety culture embedded in everyday practice through continuous education, training and multidisciplinary cooperation. Evidence based guidelines and standardized treatment algorithms addressing the particularities of peri operative cardiac arrest would be helpful to facilitate training. Existing guidelines are not comprehensive enough to cover specific aspects in depth; for the future, more detailed and more explicit guidelines are required. PMID- 28358180 TI - An unusual cause of pseudo-desaturation. PMID- 28358181 TI - Hypoglossal paralysis after septum correction: surgery or anesthesia consequence? PMID- 28358182 TI - Intensive care in the very old: how gently should we go into that good night? PMID- 28358183 TI - Point-of-care coagulation tests and medication-induced hypertriglyceridemia in extracorporeal membrane oxygenation patients. PMID- 28358184 TI - The role of drug-coated balloons in in-stent restenosis. AB - Despite a constantly expanding spectrum of therapeutic options for lower limb artery disease, there is not yet a well-defined consensus on the specific type of endovascular treatment that is best suited. Clinical data on patients with femoropopliteal disease treated with drug-coated balloons have not been elaborated sufficiently, especially in the case of in-stent restenosis. For this review a systematic research of the medical databases (Pubmed) has been conducted. Keywords such as "drug-coated balloons" (DCB), "drug-eluting balloons," "in-stent restenosis", "de novo stenosis", "angioplasty", "superficial femoral artery," "popliteal artery," "above the knee," "below the knee," "peripheral artery disease" (PAD) have been used. Furthermore, data from reviews, original contributions regarding randomized controlled studies, observational studies, registries and single center experiences have been included. Many trials have shown superiority for DCB- over percutaneous transluminal angioplasty treatment alone in TASC IIA and TASC IIB femoropopliteal lesions. However, the currently available DCB systems are different in terms of efficacy and long-term outcomes depending on their mechanical and pharmacological features. Moreover, angiographic characteristics of femoropopliteal lesions classified by Tosaka seem to influence subsequent outcomes of DCB treatment. Lastly, there is still lack of reliable prospective long-term data regarding DCB technology. PMID- 28358186 TI - Evaluation of 2 diuretic 18Fluorine-Fluorodeoxyglucose positron emission tomography/computed tomography imaging protocols for intra-pelvic cancer. AB - BACKGROUND: 18F-Fluorodeoxyglucose (FDG) PET/CT plays an important part in the oncological evaluation of the abdomen and pelvis, but the interpretation and quantification is often hampered by intense physiological urinary activity. We evaluate 2 different diuretic imaging protocols by comparing intensity of urinary activity and we look at the impact of multiple variables on the final urinary activity. METHODS: Comparative analysis of 102 patients (median age: 64) having intra-pelvic carcinoma. After full body acquisition, 58 patients were administered 20 mg of furosemide 90 min post injection of FDG (P90). For 44 patients, 20 mg of furosemide was administered 30 min post injection of FDG (P30). Comparisons between groups were performed using the Mann- Whitney test and Chi-square. The BMI, creatinine, clearance, age, injected activity, diuretic protocol, gender and glycaemia were evaluated with multivariate analysis for their impact on the final urinary activity. RESULTS: Concerning the comparison of the urinary activity we observe a significant difference (p 0.0029) between P90 and P30 for the SUVmax (median 4.3 (range 1.6: 17.7) vs. 6.0 (range 2.9: 15.1)), and for the SUVmean (p<0.001) (median 2.4 (range 1.1; 9.9) vs. 3.8 (range 2.0; 10.1)). For 2 patients of P30, the acquisition was interrupted because the patient needed to void. Multivariate analysis shows that creatinine and creatinine clearance do not have a significant independent impact on the final bladder activity. CONCLUSIONS: By comparing the 2 diuretic imaging protocols, we found a significant lower urinary activity for the P90 protocol and the regression decision tree shows that the P90 protocol is mostly superior. The P30 protocol, which seems to be less well tolerated, is adequate in the group of patients with an injected activity of less than 240 MBq and older than 65 years, if P90 is not feasible. For most patients with injected activity >= 240 MBq or BMI of >=25 and a glycaemia > 120 mg/dl, a significant amount of residual urinary activity remains for both protocols. PMID- 28358185 TI - Lasers in the treatment of acne. AB - Acne is a chronic disease of the pilosebaceous units, presenting as inflammatory or noninflammatory lesions, affecting primarily the face but also the back and chest. The mainstay of treatment remains topical retinoids, benzoyl peroxide, azelaic acid, antibiotics, and isotretinoin, many of which result in poor compliance, lack of durable remission, and incur adverse effects. The use of lasers to treat acne is continuously increasing because of their minimal complications, limited number of office-based treatments required, potential benefits of simultaneously treating acne scarring, and the rapid onset of results. The 1450 nm diode laser, 585- and 595-nm pulsed dye lasers (PDLs), near infrared diode lasers, 1320 nm Nd:YAG laser, 532 nm potassium titanyl phosphate laser, 1064 nm long-pulsed Nd:YAG laser, 1540 nm Erbium (Er):Glass Laser, and the 1550 nm Er:Glass fractional laser are among the most common lasers used to treat acne and acne scarring. These lasers target the underlying causes of acne including the colonization of Priopionibacterium acnes, high levels of sebum production, altered keratinization, inflammation, and bacterial colonization of hair follicles on the face, neck, and back. We review the efficacy and side effect profiles of various lasers used to treat acne. PMID- 28358187 TI - Discovery of Novel Succinate Dehydrogenase Inhibitors by the Integration of in Silico Library Design and Pharmacophore Mapping. AB - Succinate dehydrogenase (SDH) has been demonstrated as a promising target for fungicide discovery. Crystal structure data have indicated that the carboxyl "core" of current SDH inhibitors contributed largely to their binding affinity. Thus, identifying novel carboxyl "core" SDH inhibitors would remarkably improve the biological potency of current SDHI fungicides. Herein, we report the discovery and optimization of novel carboxyl scaffold SDH inhibitor via the integration of in silico library design and a highly specific amide feature-based pharmacophore model. To our delight, a promising SDH inhibitor, A16c (IC50 = 1.07 MUM), with a novel pyrazol-benzoic scaffold was identified, which displayed excellent activity against Rhizoctonia solani (EC50 = 11.0 MUM) and improved potency against Sclerotinia sclerotiorum (EC50 = 5.5 MUM) and Phyricularia grisea (EC50 = 12.0 MUM) in comparison with the positive control thifluzamide, with EC50 values of 0.09, 33.2, and 33.4 MUM, respectively. The results showed that our virtual screening strategy could serve as a powerful tool to accelerate the discovery of novel SDH inhibitors. PMID- 28358188 TI - Effective Integration of Targeted Tumor Imaging and Therapy Using Functionalized InP QDs with VEGFR2 Monoclonal Antibody and miR-92a Inhibitor. AB - Rapid diagnosis and targeted drug treatment require agents that possess multiple functions. Nanomaterials that facilitate optical imaging and direct drug delivery have shown great promise for effective cancer treatment. In this study, we first modified near-infrared fluorescent indium phosphide quantum dots (InP QDs) with a vascular endothelial growth factor receptor 2 (VEGFR2) monoclonal antibody to afford targeted drug delivery function. Then, a miR-92a inhibitor, an antisense microRNA that enhances the expression of tumor suppressor p63, was attached to the VEGFR2-InP QDs via electrostatic interactions. The functionalized InP nanocomposite (IMAN) selectively targets tumor sites and allows for infrared imaging in vivo. We further explored the mechanism of this active targeting. The IMAN was endocytosed and delivered in the form of microvesicles via VEGFR2-CD63 signaling. Moreover, the IMAN induced apoptosis of human myelogenous leukemia cells through the p63 pathway in vitro and in vivo. These results indicate that the IMAN may provide a new and promising chemotherapy strategy against cancer cells, particularly by its active targeting function and utility in noninvasive three-dimensional tumor imaging. PMID- 28358189 TI - Effect of Annealing on Exciton Diffusion in a High Performance Small Molecule Organic Photovoltaic Material. AB - Singlet exciton diffusion was studied in the efficient organic photovoltaic electron donor material DTS(FBTTh2)2. Three complementary time-resolved fluorescence measurements were performed: quenching in planar heterojunctions with an electron acceptor, exciton-exciton annihilation, and fluorescence depolarization. The average exciton diffusivity increases upon annealing from 1.6 * 10-3 to 3.6 * 10-3 cm2 s-1, resulting in an enhancement of the mean two dimensional exciton diffusion length (LD = (4Dtau)1/2) from 15 to 27 nm. About 30% of the excitons get trapped very quickly in as-cast films. The high exciton diffusion coefficient of the material leads to it being able to harvest excitons efficiently from large donor domains in bulk heterojunctions. PMID- 28358190 TI - A Novel "Prebinding" Strategy Dramatically Enhances Sortase-Mediated Coupling of Proteins to Liposomes. AB - We have examined quantitatively the efficiency and the kinetics of sortase A mediated coupling of model substrate proteins (derived from green fluorescent protein and the SNAP variant of O-alkylguanine-DNA alkyltransferase) to large unilamellar liposomes incorporating low levels of oligopeptide-modified acceptor lipids. Under normal reaction conditions, even using high concentrations of S. aureus or S. pyogenes sortase A and optimal protein coupling substrates and acceptor lipids, protein-liposome coupling is slow, gives at best modest coupling yields, and is markedly limited by the hydrolytic activity of sortase. We demonstrate, however, that these limitations can be overcome under "prebinding" conditions that promote initial reversible association of sortase and the substrate protein with the liposome surface. Using oligohistidine-tagged sortase and substrate proteins and liposomes incorporating an acceptor lipid together with a Ni(II)-chelating lipid derivative, high coupling rates and yields can be obtained at low sortase concentrations, while virtually eliminating adverse effects of sortase hydrolytic activity on protein coupling. The prebinding approach described here can readily be adapted, and if necessary rendered virtually "traceless", to accommodate diverse protein coupling substrates and end uses of the protein-modified liposomes. PMID- 28358191 TI - Ligand Mediated Transformation of Cesium Lead Bromide Perovskite Nanocrystals to Lead Depleted Cs4PbBr6 Nanocrystals. AB - Lead halide perovskite nanocrystals (NCs) have emerged as attractive nanomaterials owing to their excellent optical and optoelectronic properties. Their intrinsic instability and soft nature enable a post-synthetic controlled chemical transformation. We studied a ligand mediated transformation of presynthesized CsPbBr3 NCs to a new type of lead-halide depleted perovskite derivative nanocrystal, namely Cs4PbBr6. The transformation is initiated by amine addition, and the use of alkyl-thiol ligands greatly improves the size uniformity and chemical stability of the derived NCs. The thermodynamically driven transformation is governed by a two-step dissolution-recrystallization mechanism, which is monitored optically. Our results not only shed light on a decomposition pathway of CsPbBr3 NCs but also present a method to synthesize uniform colloidal Cs4PbBr6 NCs, which may actually be a common product of perovskite NCs degradation. PMID- 28358192 TI - Iron Binding Properties of Recombinant Class A Protein Disulfide Isomerase from Arabidopsis thaliana. AB - The protein disulfide isomerase (PDI) family comprises a wide set of enzymes mainly involved in thiol-disulfide exchange reactions in the endoplasmic reticulum. Class A PDIs (PDI-A) constitute the smallest members of the family, consisting of a single thioredoxin (TRX) module without any additional domains. To date, their catalytic activity and cellular function are still poorly understood. To gain insight into the role of higher-plant class A PDIs, the biochemical properties of rAtPDI-A, the recombinant form of Arabidopsis thaliana PDI-A, have been investigated. As expressed, rAtPDI-A has only little oxidoreductase activity, but it appears to be capable of binding an iron-sulfur (Fe-S) cluster, most likely a [2Fe-2S] center, at the interface between two protein monomers. A mutational survey of all cysteine residues of rAtPDI-A indicates that only the second and third cysteines of the CXXXCKHC stretch, containing the putative catalytic site CKHC, are primarily involved in cluster coordination. A key role is also played by the lysine residue. Its substitution with glycine, which restores the canonical PDI active site CGHC, does not influence the oxidoreductase activity of the protein, which remains marginal, but strongly affects the binding of the cluster. It is therefore proposed that the unexpected ability of rAtPDI-A to accommodate an Fe-S cluster is due to its very unique CKHC motif, which is conserved in all higher-plant class A PDIs, differentiating them from all other members of the PDI family. PMID- 28358193 TI - Single Enzyme Direct Biomineralization of CdSe and CdSe-CdS Core-Shell Quantum Dots. AB - Biomineralization is the process by which biological systems synthesize inorganic materials. Herein, we demonstrate an engineered cystathionine gamma-lyase enzyme, smCSE that is active for the direct aqueous phase biomineralization of CdSe and CdSe-CdS core-shell nanocrystals. The nanocrystals are formed in an otherwise unreactive buffered solution of Cd acetate and selenocystine through enzymatic turnover of the selenocystine to form a reactive precursor, likely H2Se. The particle size of the CdSe core nanocrystals can be tuned by varying the incubation time to generated particle sizes between 2.74 +/- 0.63 nm and 4.78 +/- 1.16 nm formed after 20 min and 24 h of incubation, respectively. Subsequent purification and introduction of l-cysteine as a sulfur source facilitates the biomineralization of a CdS shell onto the CdSe cores. The quantum yield of the resulting CdSe-CdS core-shell particles is up to 12% in the aqueous phase; comparable to that reported for more traditional chemical synthesis routes for core-shell particles of similar size with similar shell coverage. This single enzyme route to functional nanocrystals synthesis reveals the powerful potential of biomineralization processes. PMID- 28358195 TI - Correction to "Monte Carlo Simulation on Complex Formation of Proteins and Polysaccharides". PMID- 28358194 TI - New Scalable Approach toward Shape Memory Polymer Composites via "Spring-Buckle" Microstructure Design. AB - Shape memory polymers (SMPs) have attracted tremendous research interest since their discovery. However, most advances in research of SMPs are based on molecular designs, i.e., "bottom-up" strategies. Due to the viscoelasticity of polymers, slow and incomplete shape variations are inevitable for most existing SMPs. Here, we propose a simple and scalable approach to design and fabricate SMP composites (SMPCs) based on a "spring-buckle" microstructure design. Specifically, a highly elastic "spring" is employed as a basic skeleton for the SMPCs, onto which self-adhesive and stimuli-responsive "buckles" are installed as reversible switch units. The resultant SMPCs with such "spring-buckle" microstructure enable quick programming at ambient temperature and ultrafast (2-3 s) and nearly complete (~100%) shape recovery triggered by organic solvents, benefiting from a unique capillary effect. This structural approach provides a novel design philosophy for shape memory materials and opens up new opportunities for their applications in sensor, actuator, aerospace, and other applications. PMID- 28358197 TI - Surface Propensity of Atmospherically Relevant Amino Acids Studied by XPS. AB - Amino acids constitute an important fraction of the water-soluble organic nitrogen (WSON) compounds in aerosols and are involved in many processes in the atmosphere. In this work, we applied X-ray photoelectron spectroscopy (XPS) to study aqueous solutions of four amino acids, glycine, alanine, valine, and methionine, in their zwitterionic forms. We found that amino acids with hydrophilic side chains and smaller size, GLY and ALA, tend to stay in the bulk of the liquid, while the hydrophobic and bigger amino acids, VAL and MET, are found to concentrate more on the surface. We found experimental evidence that the amino acids have preferential orientation relative to the surface, with the hydrophobic side chain being closer to the surface than the hydrophilic carboxylate group. The observed amino acid surface propensity has implications in atmospheric science as the surface interactions play a central role in cloud droplet formation, and they should be considered in climate models. PMID- 28358196 TI - Clerodane Diterpenoid Glucosides from the Stems of Tinospora sinensis. AB - Ten new clerodane diterpenoid glucosides (1-10) and three known analogues (11-13) were isolated from an EtOAc extract of the stems of Tinospora sinensis. Spectroscopic analyses and chemical methods were used to elucidate the structures of these isolates. The absolute configurations of tinosinenosides A-C (1-3) were established by using experimental and calculated ECD data. Their cytotoxicity against the human epithelioid cervical carcinoma (HeLa) cell line and the nitric oxide production inhibitory activity of lipopolysaccharide-activated N9 microglial cells were tested. 1-Deacetyltinosposide A (12) exhibited mild cytotoxicity against HeLa cells, with an IC50 value of 8.35 +/- 0.60 MUM. PMID- 28358198 TI - A Domino Palladium-Catalyzed Cyclization: One-Pot Synthesis of 4b-Alkyl-10-phenyl 4b,5-dihydroindeno[2,1-a]indenes via Carbopalladation Followed by C-H Activation. AB - An effective domino one-pot [Pd]-catalysis for the construction of novel tetracyclic compounds was described. This process involved in the construction of three C-C bonds from simple and readily available 1-bromo-2-isopropenylbenzenes and internal alkynes. A variety of fused tetracyclic dihydroindeno-indenes were accomplished. PMID- 28358199 TI - Controlled Modification of Superconductivity in Epitaxial Atomic Layer-Organic Molecule Heterostructures. AB - Self-assembled organic molecules can potentially be an excellent source of charge and spin for two-dimensional (2D) atomic-layer superconductors. Here we investigate 2D heterostructures based on In atomic layers epitaxially grown on Si and highly ordered metal-phthalocyanine (MPc, M = Mn, Cu) through a variety of techniques: scanning tunneling microscopy, electron transport measurements, angle resolved photoemission spectroscopy, X-ray magnetic circular dichroism, and ab initio calculations. We demonstrate that the superconducting transition temperature (Tc) of the heterostructures can be modified in a controllable manner. Particularly, the substitution of the coordinated metal atoms from Mn to Cu is found to reverse the Tc shift from negative to positive directions. This distinctive behavior is attributed to a competition of charge and spin effects, the latter of which is governed by the directionality of the relevant d-orbitals. The present study shows the effectiveness of molecule-induced surface doping and the significance of microscopic understanding of the molecular states in these 2D heterostructures. PMID- 28358200 TI - Functional Silver-Coated Colloidosomes as Targeted Carriers for Small Molecules. AB - Colloidosomes have attracted great interest in recent years because of their capability for storage and delivery of small molecules for medical and pharmaceutical applications. However, traditional polymer shell colloidosomes leak low molecular weight drugs due to their intrinsic shell permeability. Here, we report aqueous core colloidosomes with a silver shell, which seals the core and makes the shell impermeable. The silver-coated colloidosomes were prepared by reacting l-ascorbic acid in the microcapsule core with silver nitrate in the wash solution. The silver shell colloidosomes were then modified by using 4,4' dithiodibutyric acid and cross-linked with rabbit Immunoglobulin G (IgG). Label free surface plasmon resonance was used to test the specific targeting of the functional silver shell with rabbit antigen. To break the shells, ultrasound treatment was used. The results demonstrate that a new type of functional silver coated colloidosome with immunoassay targeting, nonpermeability, and ultrasound sensitivity could be applied to many medical applications. PMID- 28358201 TI - Access to Fully Alkylated Germanes by B(C6F5)3-Catalyzed Transfer Hydrogermylation of Alkenes. AB - Various cyclohexa-2,5-dien-1-yl-substituted germanes are shown to serve as easy to-handle surrogates of hydrogermanes, including gaseous MeGeH3 and Me2GeH2. The Ge-H functional group is liberated by treatment with catalytic amounts of B(C6F5)3 and participates in situ in the B(C6F5)3-catalyzed hydrogermylation of alkenes. The range of suitable alkenes is broad, and the overall procedure provides a convenient access to tetraalkyl-substituted germanes at room temperature. Transfer hydrogermylation of internal alkynes works equally well and selectively forms the trans or cis diastereomer depending on the electronic bias of the C=C bond. PMID- 28358202 TI - Cobalt(III)- and Rhodium(III)-Catalyzed C-H Amidation and Synthesis of 4 Quinolones: C-H Activation Assisted by Weakly Coordinating and Functionalizable Enaminone. AB - Cobalt(III) and rhodium(III) catalysts exhibited complementary scope in C-H amidation of aryl enaminones. The amidation reactions proceeded with broad scope under the assistance of a weakly coordinating and bifunctional enaminone directing group. The electrophilicity of the enaminone group can be further utilized in subsequent hydrolysis-cyclization reactions to afford NH 4-quinolones in telescoping reactions. PMID- 28358203 TI - Ru(II)-Catalyzed C-H Functionalization on Maleimides with Electrophiles: A Demonstration of Umpolung Strategy. AB - The unconventional nucleophilic reactivity of maleimides, innate electrophiles, has been realized under Ru(II)-catalysis such that exposure to electrophiles delivered products of C-H chalcogenation and amidation in good yields (up to 94%). This protocol features mild conditions and operational simplicity with broad substrate scope, uses an inexpensive and air-stable catalyst, and also represents the first example of Ru(II) catalyzed C-H selenylation of alkenes. PMID- 28358205 TI - Annulative pi-Extension (APEX) of Heteroarenes with Dibenzosiloles and Dibenzogermoles by Palladium/o-Chloranil Catalysis. AB - Annulative pi-extension (APEX) reactions of heteroarenes are described herein. A catalytic system comprising a cationic palladium species and o-chloranil using dimethyldibenzosiloles as pi-extending agents enabled the extension of the pi system of benzo[b]thiophenes. pi-Extended dibenzofurans and carbazoles could also be obtained from benzofuran and N-tosylindole, respectively, with dimethyldibenzogermole as a germanium-based pi-extending agent. Mechanistic investigations indicated two possible reaction pathways involving carbopalladation-based double C-H arylation of benzothiophene or formal cycloaddition/oxidation cascades. PMID- 28358204 TI - Scope of the Reactions of Indolyl- and Pyrrolyl-Tethered N-Sulfonyl-1,2,3 triazoles: Rhodium(II)-Catalyzed Synthesis of Indole- and Pyrrole-Fused Polycyclic Compounds. AB - An efficient synthesis of tetrahydrocarboline-type products and polycyclic spiroindolines has been achieved. The transformation proceeds via rhodium(II) catalyzed intramolecular annulations of indolyl- and pyrrolyl-tethered N-sulfonyl 1,2,3-triazoles. The reaction could be tuned toward either the formal [3 + 2] cycloaddition or the C-H functionalization reaction depending on the electronic and structural features of the substrates, leading to the production of a variety of structurally related heterocyclic compounds. PMID- 28358206 TI - Metal-Free [2 + 1 + 2]-Cycloaddition of Tosylhydrazones with Hexahydro-1,3,5 triazines To Form Imidazolidines. AB - A novel protocol toward imidazolidines has been accomplished using tosylhydrazones and hexahydro-1,3,5-triazines as the substrates under metal-free reaction conditions. Importantly, the role of LiOtBu has been confirmed not only to release the diazo but also to promote the cycloaddition. Further mechanistic investigations reveal that the reaction proceeds through a stepwise [2 + 1 + 2] process. PMID- 28358207 TI - Control over the Emission Properties of [5]Helicenes Based on the Symmetry and Energy Levels of Their Molecular Orbitals. AB - The effect of different substituents on the fluorescence properties of [5]helicene derivatives was investigated in terms of molecular orbital symmetry. Unsubstituted [5]helicene is nonemissive due to the symmetry-forbidden S1 -> S0 transition. However, the fluorescence emission rate constant (kf) of [5]helicenes is efficiently increased by removing the orbital degeneracy involved in the S1 -> S0 transition. As a result, we achieved a [5]helicene derivative exhibiting a high fluorescence quantum yield (Phif = 0.23) and short emission lifetime (?tauf? = 1.5 ns), which is in marked contrast to unsubstituted [5]helicene (Phif = 0.04 and ?tauf? = 26 ns). PMID- 28358208 TI - Imidazole-Appended Macrocyclic Complexes of Fe(II), Co(II), and Ni(II) as ParaCEST Agents. AB - The solution chemistry and solid state structures of the Co(II), Fe(II), and Ni(II) complexes of N,N'-bis(imidazole-2-ylmethyl)-4,10-diaza-15-crown-5 (HINO) are reported. The Co(II) and Ni(II) complexes of HINO are the first examples of paraCEST agents (paramagnetic chemical exchange saturation transfer) that feature exchangeable imidazole NH protons. The crystal structures of [Co(HINO)]CoCl4.H2O and [Fe(HINO)](CF3SO3)2 have the metal ions coordinated to four nitrogen and three oxygen donor atoms of the macrocyclic ligand in a distorted pentagonal bipyramidal geometry. In [Ni(HINO)](CF3SO3)2, the nickel ion is bound to only two of the three ether oxygens and three nitrogens to produce a complex with a distorted octahedral geometry. The 1H NMR spectra of the three paramagnetic complexes show resonances characteristic of effective C2 symmetry in solution. CEST peaks attributed to the imidazole NH proton of the pendent group are observed at 32 and 55 ppm away from bulk water for [Co(HINO)]2+ and [Ni(HINO)]2+, respectively, on a 11.7 or 9.4 T NMR spectrometer. For both complexes, an optimal CEST effect was observed at pH 7.2, and the rate constant for proton exchange under these conditions was 1.0 * 103 s-1. [Fe(HINO)]2+ did not produce a CEST peak due to oxidation of the complex in water at neutral pH. The CEST peak of [Co(HINO)]2+ or [Ni(HINO)]2+ is observed in the presence of human serum albumin (HSA). These complexes show enhanced kinetic inertness toward dissociation in acid or in the presence of HSA in comparison to analogous complexes with amide pendent groups. PMID- 28358209 TI - Quantifying the Electrostatics of Polycation-Lipid Bilayer Interactions. AB - Mechanistic insight into how polycations disrupt and cross cell membranes is needed for understanding and controlling polycation-membrane interactions, yet such information is surprisingly difficult to obtain at the molecular level. We use second harmonic and vibrational sum frequency generation spectroscopies along with quartz crystal microbalance with dissipation monitoring and computer simulations to quantify the interaction of poly(allylamine) hydrochloride (PAH) and its monomeric precursor allylamine hydrochloride (AH) with lipid bilayers. We find PAH adsorption to be reversible and nondisruptive to the bilayer under the conditions of our experiments. With an observed free adsorption energy of -52.7 +/- 0.6 kJ/mol, PAH adsorption was found to be surprisingly less favorable relative to AH (-14.6 +/- 0.4 kJ/mol) when considering a simple additive model. By experimentally quantifying the number of adsorbates and the average amount of charge carried by each adsorbate, we find that the PAH is associated with only 70% of the positive charges it could hold while the AH remains mostly charged while attached to the membrane. Simulations indicate that PAH pulls in condensed counterions from solution to avoid charge-repulsion along its backbone and with other PAH molecules to attach to, and completely cover, the bilayer surface. In addition, computations indicate that the amine groups shift their pKa values due to the confined environment upon adsorption to the surface. Our results provide experimental constraints for theoretical calculations, which yield atomistic views of the structures that are formed when polycations interact with lipid membranes that will be important for predicting polycation-membrane interactions. PMID- 28358210 TI - Structural and Sequence Similarity Makes a Significant Impact on Machine-Learning Based Scoring Functions for Protein-Ligand Interactions. AB - The prediction of protein-ligand binding affinity has recently been improved remarkably by machine-learning-based scoring functions. For example, using a set of simple descriptors representing the atomic distance counts, the RF-Score improves the Pearson correlation coefficient to about 0.8 on the core set of the PDBbind 2007 database, which is significantly higher than the performance of any conventional scoring function on the same benchmark. A few studies have been made to discuss the performance of machine-learning-based methods, but the reason for this improvement remains unclear. In this study, by systemically controlling the structural and sequence similarity between the training and test proteins of the PDBbind benchmark, we demonstrate that protein structural and sequence similarity makes a significant impact on machine-learning-based methods. After removal of training proteins that are highly similar to the test proteins identified by structure alignment and sequence alignment, machine-learning-based methods trained on the new training sets do not outperform the conventional scoring functions any more. On the contrary, the performance of conventional functions like X-Score is relatively stable no matter what training data are used to fit the weights of its energy terms. PMID- 28358211 TI - P(O)R2-Directed Enantioselective C-H Olefination toward Chiral Atropoisomeric Phosphine-Olefin Compounds. AB - An effective synthesis of chiral atropoisomeric biaryl phosphine-olefin compounds via palladium-catalyzed enantioselective C-H olefination has been developed for the first time. The reactions are operationally simple, tolerate wide functional groups, and have a good ee value. Notably, P(O)R2 not only acts as the directing group to direct C-H activation in order to make a useful ligand but also serves to facilitate composition of the product in a useful manner in this transformation. PMID- 28358213 TI - Effect of Nanoparticle Surfactants on the Breakup of Free-Falling Water Jets during Continuous Processing of Reconfigurable Structured Liquid Droplets. AB - Structured liquids, whose 3-D morphology can adapt and respond to external stimuli, represent a revolutionary materials platform for next-generation energy technologies, such as batteries, photovoltaics, and thermoelectrics. Structured liquids can be crafted by the jamming of interfacial assemblies of nanoparticle (NP) surfactants. Due to the interactions between functional groups on nanoparticles dispersed in one liquid and polymers having complementary end functionality dissolved in a second immiscible fluid, the anchoring of a well defined number of polymer chains onto the NPs leads to the formation of NP surfactants that assemble at the interface and reduce the interfacial energy. Microfluidic techniques provide a simple and versatile route to produce one liquid phase in a second where the shape of the dispersed liquid phase can range from droplets to tubules depending on the flow conditions and the interfacial energies. In this study, the effect of NP surfactants on Plateau-Rayleigh (PR) instabilities of a free-falling jet of an aqueous dispersion of carboxylic acid functionalized silica NPs into a toluene phase containing amine-terminated polydimethylsiloxane (PDMS-NH2) is investigated. NP surfactants were found to significantly affect the breakup of laminar liquid jets, resulting in longer jet breakup lengths and dripping to jetting flow transitions. PMID- 28358212 TI - Bi- and Tetracyclic Spirotetronates from the Coal Mine Fire Isolate Streptomyces sp. LC-6-2. AB - The structures of 12 new "enantiomeric"-like abyssomicin metabolites (abyssomicins M-X) from Streptomyces sp. LC-6-2 are reported. Of this set, the abyssomicin W (11) contains an unprecedented 8/6/6/6 tetracyclic core, while the bicyclic abyssomicin X (12) represents the first reported naturally occurring linear spirotetronate. Metabolite structures were determined based on spectroscopic data and X-ray crystallography, and Streptomyces sp. LC-6-2 genome sequencing also revealed the corresponding putative biosynthetic gene cluster. PMID- 28358214 TI - Making Graphene Nanoribbons Photoluminescent. AB - We demonstrate the alignment-preserving transfer of parallel graphene nanoribbons (GNRs) onto insulating substrates. The photophysics of such samples is characterized by polarized Raman and photoluminescence (PL) spectroscopies. The Raman scattered light and the PL are polarized along the GNR axis. The Raman cross section as a function of excitation energy has distinct excitonic peaks associated with transitions between the one-dimensional parabolic subbands. We find that the PL of GNRs is intrinsically low but can be strongly enhanced by blue laser irradiation in ambient conditions or hydrogenation in ultrahigh vacuum. These functionalization routes cause the formation of sp3 defects in GNRs. We demonstrate the laser writing of luminescent patterns in GNR films for maskless lithography by the controlled generation of defects. Our findings set the stage for further exploration of the optical properties of GNRs on insulating substrates and in device geometries. PMID- 28358215 TI - Estimation of pi-pi Electronic Couplings from Current Measurements. AB - The pi-pi interactions between organic molecules are among the most important parameters for optimizing the transport and optical properties of organic transistors, light-emitting diodes, and (bio-) molecular devices. Despite substantial theoretical progress, direct experimental measurement of the pi-pi electronic coupling energy parameter t has remained an old challenge due to molecular structural variability and the large number of parameters that affect the charge transport. Here, we propose a study of pi-pi interactions from electrochemical and current measurements on a large array of ferrocene-thiolated gold nanocrystals. We confirm the theoretical prediction that t can be assessed from a statistical analysis of current histograms. The extracted value of t ~35 meV is in the expected range based on our density functional theory analysis. Furthermore, the t distribution is not necessarily Gaussian and could be used as an ultrasensitive technique to assess intermolecular distance fluctuation at the subangstrom level. The present work establishes a direct bridge between quantum chemistry, electrochemistry, organic electronics, and mesoscopic physics, all of which were used to discuss results and perspectives in a quantitative manner. PMID- 28358216 TI - Evaluation of the Safety and Tolerability of Conjunctival Ring for Posterior Segment of the Eye. AB - PURPOSE: To evaluate the safety and tolerability of conjunctival rings (CRs), a novel device for drug delivery to the posterior segment of the eye. METHODS: In animal studies, CRs containing 5% dexamethasone sodium phosphate (DSP) or vehicle solution were placed on the right and left eyes of C57BL/6J mice, respectively. Contact lenses (CLs) containing vehicle solution were used as a control. Twenty four hours after placement of the CRs, corneal fluorescein staining was graded based on the McDonald-Shadduck scoring system, ranging from 0 to 4. In humans, CRs containing vehicle solution were placed on the right eye of healthy volunteers for 9 hours. The corneal curvature, corneal thickness, intraocular pressure, visual acuity, tear production (Schirmer I test), tear film break-up time and fluorescein staining scores of the cornea (scores ranging from 0 to 3) and conjunctiva (scores ranging from 0 to 6) were assessed before and after wearing the CRs. The release characteristics of DSP from CRs were also evaluated. RESULTS: In animal experiments, corneal fluorescein staining scores were 1 or less in all the groups, and there was no significant difference between the CR group and the CL group. In the preclinical safety evaluation of CR for humans, ophthalmic examination revealed that CR caused no significant changes in all the parameters investigated including corneal curvature (p = 0.77), corneal thickness (p = 0.96), intraocular pressure (p = 0.59), visual acuity (p = 0.14), Schirmer I test results (p = 0.76), tear film break-up time (p = 0.68), corneal fluorescein staining scores (p = 0.64), and conjunctival fluorescein staining scores (p = 0.52). The DSP release from CRs occurs within a few hours, which is similar to the drug-release property of medicated CL, as reported previously. CONCLUSIONS: The current data showed the safety and tolerability of CR as a drug delivery device for the treatment of posterior segment diseases. PMID- 28358217 TI - Influence of route of administration/drug formulation and other factors on adherence to treatment in rheumatoid arthritis (pain related) and dyslipidemia (non-pain related). AB - OBJECTIVES: A comprehensive review was performed to investigate the effect of route of administration on medication adherence and persistence in rheumatoid arthritis (RA) and to compare adherence/persistence with oral medications between RA and a non-painful disease (dyslipidemia). RESEARCH DESIGN AND METHODS: Comprehensive database searches were performed to identify studies investigating medication adherence and/or persistence in adults with RA receiving conventional synthetic or biologic agents. Similar searches were performed for studies of patients with dyslipidemia receiving statins. Studies had to be published after 1998 in English and involve >=6 months' follow up. MAIN OUTCOME MEASURES: Adherence and persistence were compared between the different routes of drug administration in RA, and between the two diseases for oral medications. RESULTS: A total of 35 and 28 papers underwent data extraction for RA and dyslipidemia, respectively. Within the constraints of the analysis, adherence and persistence rates appeared broadly similar for the different routes of drug administration in RA. Adherence to oral medications was also broadly similar across the two diseases, but persistence was lower in dyslipidemia. Poor adherence has clinical consequences in both diseases: greater disease activity and risk of flare in RA, and increased serum cholesterol levels and risk of heart and cerebrovascular disease in dyslipidemia. Over 1-3 years, poor adherence to biologic RA medications led to increased resource use and medical costs but lower total direct costs due to reduced biologic drug costs. Conversely, poor adherence to dyslipidemia medications resulted in increased total direct costs. In both diseases, adherence improved with patient education/support. CONCLUSIONS: The route of drug administration and the symptomatic (pain) nature of the disease do not appear to be dominant factors for drug adherence or persistence in RA. LIMITATION: The wide range of adherence and persistence values and definitions across studies made comparisons between drug formulations and diseases difficult. PMID- 28358218 TI - Do Associations Between Pleasure Ratings and Condom Use During Penile-Vaginal Intercourse Vary by Relationship Type?: A Study of Canadian University Students. AB - Research suggests the relationship between pleasure and condom use during penile vaginal intercourse (PVI) is associated with relationship status. This online study examined pleasure ratings and condom use at last PVI, stratifying by partner type, among a national sample of Canadian university students. Participants were 715 undergraduates (60.7% women, 39.3% men) who reported on their most recent sexual experience. Condom use decreased with level of relationship commitment, whereas ratings of pleasure increased. Overall, participants were more likely to rate their most recent PVI as Very pleasurable when condoms were not used compared to when condoms were used. However, when stratified by partner type, these differences largely disappeared. For women, with one exception, there were no differences in pleasure between PVI with and without condoms across most partner-type categories. Women in committed dating relationships were more likely to report their last PVI as very pleasurable if condoms were not used than women in these same relationships who had used condoms. Across relationship categories, men who did and did not use condoms did not differ in terms of their pleasure ratings. The results of this study suggest relationship context should be taken into account when assessing condom use experiences. PMID- 28358219 TI - Supporting Evidence-Informed Teaching in Biomedical and Health Professions Education Through Knowledge Translation: An Interdisciplinary Literature Review. AB - : Phenomenon: The purpose of "systematic" reviews/reviewers of medical and health professions educational research is to identify best practices. This qualitative article explores the question of whether systematic reviews can support "evidence informed" teaching and contrasts traditional systematic reviewing with a knowledge translation (KT) approach to this objective. APPROACH: Degrees of freedom analysis (DOFA) is used to examine the alignment of systematic review methods with educational research and the pedagogical strategies and approaches that might be considered with a decision-making framework developed to support valid assessment. This method is also used to explore how KT can be used to inform teaching and learning. FINDINGS: The nature of educational research is not compatible with most (11/14) methods for systematic review. The inconsistency of systematic reviewing with the nature of educational research impedes both the identification and implementation of "best-evidence" pedagogy and teaching. This is primarily because research questions that do support the purposes of review do not support educational decision making. By contrast to systematic reviews of the literature, both a DOFA and KT are fully compatible with informing teaching using evidence. A DOFA supports the translation of theory to a specific teaching or learning case, so could be considered a type of KT. The DOFA results in a test of alignment of decision options with relevant educational theory, and KT leads to interventions in teaching or learning that can be evaluated. Examples of how to structure evaluable interventions are derived from a KT approach that are simply not available from a systematic review. Insights: Systematic reviewing of current empirical educational research is not suitable for deriving or supporting best practices in education. However, both "evidence-informed" and scholarly approaches to teaching can be supported as KT projects, which are inherently evaluable and can generate actionable evidence about whether the decision or intervention worked for students, instructors, and the institution. A DOFA can also support evidence- and theory-informed teaching to develop an understanding of what works, why, and for whom. Thus KT, but not systematic reviewing, can support decision making around pedagogy (and pedagogical innovation) that can also inform new teaching and learning initiatives; it can also point to new avenues of empirical research in education that are informed by, and can inform, theory. PMID- 28358220 TI - Vitreous Hyper-Reflective Dots in Optical Coherence Tomography and Retinal Tear in Patients with Acute Posterior Vitreous Detachment. AB - PURPOSE: To report the presence of hyper-reflective dots in the vitreous cavity using spectral-domain optical coherence tomography (SD-OCT) in patients with acute symptomatic posterior vitreous detachment (PVD) and investigate their association with the presence of retinal tear. METHODS: The medical records of 77 patients with acute symptomatic PVD, who were examined between March 2013 and February 2015, were reviewed. The severity of vitreous hyper-reflective dots (VHDs) was graded using SD-OCT images, and the presence of retinal tear was assessed. RESULTS: Forty-one (53.2%) eyes had mild VHDs, 13 (16.9%) eyes had moderate VHDs, and 14 (18.2%) eyes had severe VHDs. Retinal tear was found in 21 (27.3%) eyes. The presence of severe VHDs was associated with an increased likelihood of retinal tear (positive likelihood ratio, 9.78; 95% confidence interval, 3.02-31.63). In 14 (66.7%) eyes with retinal tear, the mean number of VHDs significantly decreased from 23.2 +/- 20.27 to 2.3 +/- 2.66 at a mean follow up interval of 2.8 +/- 1.48 weeks (P = 0.002). CONCLUSIONS: The presence of severe VHDs is suggestive of retinal tear in patients with acute symptomatic PVD. However, this SD-OCT finding should be limited to the acute phase of PVD. PMID- 28358221 TI - Descriptive Epidemiology of Non-Time-Loss Injuries in Collegiate and High School Student-Athletes. AB - CONTEXT: Research on non-time-loss (NTL) injuries, which result in less than 24 hours of restriction from participation, is limited. OBJECTIVE: To describe the epidemiology of NTL injuries among collegiate and high school student-athletes. DESIGN: Descriptive epidemiology study. SETTING: Aggregate injury and exposure data collected from a convenience sample of National College Athletic Association varsity teams and 147 high schools in 26 states. PATIENTS OR OTHER PARTICIPANTS: Collegiate and high school student-athletes participating in men's and boys' baseball, basketball, football, lacrosse, soccer, and wrestling and women's and girls' basketball, field hockey, lacrosse, soccer, softball, and volleyball during the 2009-2010 through 2013-2014 and the 2011-2012 through 2013 2014 academic years, respectively, participated. Collegiate student-athletes participating in men's and women's ice hockey were also included. MAIN OUTCOME MEASURE(S): Injury data from the National Collegiate Athletic Association Injury Surveillance Program and the National Athletic Treatment, Injury and Outcomes Network were analyzed. Injury counts, rates per 1000 athlete-exposures (AEs), and rate ratios were reported with 95% confidence intervals (CIs). RESULTS: A total of 11 899 and 30 122 NTL injuries were reported in collegiate and high school student-athletes, respectively. The proportion of NTL injuries in high school student-athletes (80.3%) was 1.61 times greater than that of collegiate student-athletes (49.9%; 95% CI = 1.59, 1.63). The NTL injury rate in high school student-athletes (8.75/1000 athlete-exposures [AEs]) was 2.18 times greater than that of collegiate student-athletes (4.02/1000 AEs; 95% CI = 2.13, 2.22). Men's ice hockey (5.27/1000 AEs) and boys' football (11.94/1000 AEs) had the highest NTL injury rates among collegiate and high school athletes, respectively. Commonly injured body parts in collegiate and high school student athletes were the hip/thigh/upper leg (17.5%) and hand/wrist (18.2%), respectively. At both levels, contusions, sprains, and strains were the most frequent diagnoses. Contact with another player was the most cited injury mechanism (college = 38.0%, high school = 46.3%). CONCLUSIONS: Non-time-loss injuries compose large proportions of collegiate and high school sports injuries. However, the NTL injury rate was higher in high school than in collegiate student athletes. Tracking NTL injuries will help to better describe the breadth of injuries sustained by athletes and managed by athletic trainers. PMID- 28358222 TI - Valacyclovir as Initial Treatment for Acute Retinal Necrosis: A Pharmacokinetic Modeling and Simulation Study. AB - PURPOSE: Acute retinal necrosis (ARN) is a feared complication of infectious retinitis most commonly caused by varicella zoster virus (VZV). We performed a pharmacokinetic modeling and simulation study by integrating the existing understanding of physiology with previously published data to evaluate the vitreal penetration of oral valacyclovir for the treatment of ARN, under various dosing scenarios. METHOD: We compared different oral valacyclovir dosing regimens with intravenous acyclovir. The vitreous compartment was modeled as a peripheral compartment, and paired serum and vitreal acyclovir concentrations were obtained from previously published data of adult patients with ARN undergoing vitrectomy. The efficacy threshold for vitreal acyclovir concentrations was based on the previously reported IC50 values for VZV. RESULTS: Based on the minimum vitreal acyclovir concentrations (Cmin) relative to the mean IC50 for VZV, valacyclovir 1.5 g every 8 hours performed similarly to intravenous acyclovir 700 mg every 8 hours, with the minimum concentration (Cmin) exceeding the mean IC50 after the second dose. In contrast, the standard dosing regimen for herpes zoster, valacyclovir 1 g every 8 hours, performed inferiorly to the intravenous acyclovir regimen throughout the dosing interval. CONCLUSIONS: Modeling and simulation data support oral valacyclovir for the treatment of ARN, although the required dosing exceeds the recommended FDA dose size for herpes zoster. PMID- 28358224 TI - Erratum. PMID- 28358223 TI - Ameliorative effects of pyrazinoic acid against oxidative and metabolic stress manifested in rats with dimethylhydrazine induced colonic carcinoma. AB - Pyrazinoic acid (PA) is structurally similar to nicotinic acid which acts on G protein-coupled receptor (GPR109A). GPR109A expresses in colonic and intestinal epithelial sites, and involves in DNA methylation and cellular apoptosis. Therefore, it may be assumed that PA has similar action like nicotinic acid and may be effective against colorectal carcinoma (CRC). CRC was produced via subcutaneous injection of dimethylhydrazine (DMH) at 40 mg/kg body weight once in a week for 4 weeks. After that, PA was administered orally at 2 doses of 10 and 25 mg/kg daily for 15 d to observe the antiproliferative effect. Various physiologic, oxidative stress, molecular parameters, histopathology, RT-PCR and NMR based metabolomics were performed to evaluate the antiproliferative potential of PA. Our results collectively suggested that PA reduced body weight, tumor volume and incidence no. to normal. It restored various oxidative stress parameters and normalized IL-2, IL-6, and COX-2 as compared with carcinogen control. In molecular level, overexpressed IL-6 and COX-2 genes became normal after PA administration. Again, normal tissue architecture was prominent after PA administration. Score plots of PLS-DA models exhibited that PA treated groups were significantly different from CRC group. We found that CRC rat sera have increased levels of acetate, glutamine, o-acetyl-glycoprotein, succinate, citrulline, choline, o-acetyl choline, tryptophan, glycerol, creatinine, lactate, citrate and decreased levels of 3-hydroxy butyrate, dimethyl amine, glucose, maltose, myoinositol. Further the PA therapy has ameliorated the CRC-induced metabolic alterations, signifying its antiproliferative properties. In conclusion, our study provided the evidence that PA demonstrated good antiproliferative effect on DMH induced CRC and thus demonstrated the potential of PA as a useful drug for future anticancer therapy. PMID- 28358225 TI - Improved solubility and oral bioavailability of apigenin via Soluplus/Pluronic F127 binary mixed micelles system. AB - The aim of this study was to develop a novel mix micelles system composing of two biocompatible copolymers of Soluplus(r) and Pluronic F127 to improve the solubility, oral bioavailability of insoluble drug apigenin (AP) as model drug. The AP-loaded mixed micelles (AP-M) were prepared by ethanol thin-film hydration method. The formed optimal formulation of AP-M were provided with small size (178.5 nm) and spherical shape at ratio of 4:1 (Soluplus(r):Pluronic F127), as well as increasing solubility of to 5.61 mg/mL in water which was about 3442-fold compared to that of free AP. The entrapment efficiency and drug loading of AP-M were 95.72 and 5.32%, respectively, and a sustained release of AP-M was obtained as in vitro release study indicated. Transcellular transport study showed that the cell uptake of AP was increased in Caco-2 cell transport models. The oral bioavailability of AP-M was 4.03-fold of free AP in SD rats, indicating the mixed micelles of Soluplus(r) and Pluronic F127 is an industrially feasible drug delivery system to promote insoluble drug oral absorption in the gastrointestinal tract. PMID- 28358226 TI - Excess maternal and postnatal thyroxine alters chondrocyte numbers and the composition of the extracellular matrix of growth cartilage in rats. AB - : Purpose/Aim: The aim of this study was to evaluate the effects of excess maternal and postnatal thyroxine on chondrocytes and the extracellular matrix (ECM) of growth cartilage. MATERIALS AND METHODS: We used 16 adult female Wistar rats divided into two groups: thyroxine treatment and control. From weaning to 40 days of age, offspring of the treated group (n = 8) received L-thyroxine. Plasma free T4 was measured. Histomorphometric analysis was performed on thyroids and femurs of all offspring. Alcian blue histochemical staining and real-time reverse transcription polymerase chain reaction measurements of gene expression levels of Sox9, Runx2, Aggrecan, Col I, Col II, Alkaline phosphatase, Mmp2, Mmp9, and Bmp2 were performed. Data were analyzed for statistical significance by student's t test. RESULTS: Excess maternal and postnatal thyroxine reduced the intensity of Alcian blue staining, altered the number of chondrocytes in proliferative and hypertrophic zones in growth cartilage, and reduced the gene expression of Sox9, Mmp2, Mmp9, Col II, and Bmp2 in the growth cartilage of all offspring. Additionally, excess thyroxine altered the gene expression of Runx2, Aggrecan and Col I, and this effect was dependent on age. CONCLUSIONS: Excess thyroxine in neonates suppresses chondrocyte proliferation, stimulates chondrocyte hypertrophy and changes the ECM composition by reducing the amount of proteoglycans and glycosaminoglycans (GAGs). Prolonged exposure to excess thyroxine suppresses chondrocyte activity in general, with a severe reduction in the proteoglycan content of cartilage and the expression of gene transcripts essential for endochondral growth and characteristics of the chondrocyte phenotype. PMID- 28358228 TI - Current and emerging pharmacologic options for the management of patients with chronic and acute decompensated heart failure. AB - INTRODUCTION: For many years heart failure (HF) was known as a fatal disease with an ominous prognosis. In the last decades better understanding of the pathophysiological mechanisms underlying HF has resulted in major breakthrough in the management and improvement in the natural history of this clinical syndrome. Areas covered: The review is focused on current and upcoming pharmacological therapies in patients with chronic and acute HF, starting with brief overview of drugs which improve the outcomes in patients with chronic HF with reduced ejection fraction (EF) including neurohormonal antagonists, angiotensin receptor neprilysin inhibitor and If- channel inhibitor, then presenting the summary of symptomatic treatment, the pharmacotherapy in chronic HF with preserved and mid range EF and in acute HF. Finally, we report the emerging pharmacologic options and ongoing clinical trials and future directions in pharmacotherapy. Expert commentary: The guidelines-recommended therapies in HF with reduced EF need to be widely implemented into the everyday clinical practice. Better clinical characterization of HF with preserved, mid-range EF and acute HF, with better understanding of the underlying pathophysiological mechanisms may ultimately result in a development of effective strategies improving ominous outcomes in these patients. PMID- 28358227 TI - The Effect of Surgical Stress on Postoperative Talphabeta and Tgammadelta Cell Distribution. AB - BACKGROUND: It was previously shown that appropriate distribution of immune cells between different tissues and organs of the body is required for proper function of the immune system. Our previous experiments demonstrated that surgical trauma in mice induces Tgammadelta lymphocyte migration from peripheral blood to peritoneal lymphoid organs. Tgammadelta cells have regulatory activity as they suppress the cell-mediated immune response in vitro via TGF-beta. In the current study, we aim to evaluate the influence of surgery on both Tabeta and Tgammadelta lymphocyte distribution in patients that underwent operation. MATERIALS AND METHODS: We investigated the percentage of Talphabeta and Tgammadelta cells in peripheral blood of patients undergoing standard surgical procedures (gastric resection, colorectal resection, cholecystectomy, and strumectomy) before and 3 days after operation. The percentage of Talphabeta and Tgammadelta cells was evaluated by FACS Canto II cytofluorimeter. RESULTS: We showed that only major surgery located in the peritoneal cavity (gastric and colorectal surgery) decreases the percentage of Tgammadelta cells in peripheral blood as opposed to less traumatic surgery (strumectomy and cholecystectomy) which does not have such effect. However, significant reduction of Tgammadelta cells after operation was only observed in a group of patients that underwent gastrectomy. Additionally, we found that gastrectomy results in significant reduction of cumulative Tgammadelta CD4 and Tgammadelta CD25 lymphocyte counts. CONCLUSION: Surgery results in decreased percentage of Tgammadelta lymphocytes in peripheral human blood, and this correlates with the severity and location of the surgical trauma. This observation may help to predict postoperative recovery after gastroabdominal surgery. PMID- 28358229 TI - Intractable Acute Pain Related to Fluoroquinolone-Induced Peripheral Neuropathy. AB - Fluoroquinolones are widely prescribed antibiotics, used for various infectious etiologies. These antibiotics carry the possibility of the serious adverse effect of peripheral neuropathy, with a true incidence not known owing to its rare existence. Recently, the Food and Drug Administration (FDA) has required alterations to drug labels to highlight this adverse effect of fluoroquinolones. This is a case report of a single patient at an inpatient neurology service at an urban academic medical center in the United States. The patient is a 20-year-old male, with well-controlled type 1 diabetes mellitus, presenting with a short duration of bilateral lower extremity pain following a 10-day course of levofloxacin for suspected epididymitis. The patient was initially diagnosed with complex regional pain syndrome and treated with a variety of pain medications, including lidocaine infusions, hydromorphone, methadone, and ketamine infusions. After review of the patient's history and limited response to medical management, the patient's condition was reclassified as an adverse effect from fluoroquinolone treatment. Pain of unknown etiology can be perplexing, both for the physician and the patient. Reporting of similar incidents attributed to medication adverse effects will increase the awareness of this type of neuropathy, avoid future cases of misdiagnosis, and enable early detection and treatment. PMID- 28358230 TI - Exploring HIV Risk and Ex-Offender Status Among African American Church Populations: Considerations for Faith-Based Settings. AB - Studies with the general population indicate that involvement in the correctional system is strongly associated with the risk of contracting HIV and other sexually transmitted infections. However, limited studies have examined ex-offender status and HIV risk among African Americans-a population disproportionately impacted by incarceration and HIV-and even fewer have examined these risks among African American church-affiliated populations. This study examined ex-offender status, HIV risks, and perceptions of church involvement in HIV prevention strategies among 484 participants affiliated with African American churches. Findings indicate ex-offender participants were more likely to have been tested for HIV and believed the church should be involved in HIV prevention strategies. Future research, practice, and recommendations on the design of culturally and religiously tailored interventions for ex-offender HIV prevention, screening, and linkage to care in African American church settings are discussed. PMID- 28358231 TI - Primary Care Program in Prison: A Review of the Literature. AB - Nurses take on the role of primary caregiver in the prison setting, as they are usually the first to approach the prisoner, and they govern access to all aspects of the health care system. The aim of this review was to assess the effects of the use of the primary care model in a correctional setting. Major literature databases relevant to the specified areas were searched for studies published from 2004 to 2013. Three studies reported some implications for prisoners, nursing practice, and the correctional facility, as generated by using the primary care model in the prison setting. The primary care model can improve relevant outcomes for health management in the prison setting. PMID- 28358232 TI - Medical Parole and Aging Prisoners: A Qualitative Study. AB - The population of geriatric prisoners in the United States will reach unprecedented levels in the coming decades. Geriatric prisoners are at increased risk for deteriorating health and experience the onset of disease earlier than the aging population at large. Medical parole is an underutilized program that allows aging prisoners to transition to community-based health care. This article presents original key informant interview data and analysis of the perceptions of medical parole. Three dominant themes emerged: (1) drugs and nonviolent crimes; (2) politics, costs, and consequences; and (3) quality of health care and sense of security in prison. Participants rejected the possibility that medical care provided is below the clinical standard or is the cause of geriatric prisoners' deteriorating health and consistently implied that medical care at this prison is better than most Americans receive. Participants perceived their careers more as contributions to public health than criminal justice. PMID- 28358233 TI - Measurement of Health-Related Quality of Life in Primary Antibody-Deficient Patients. AB - BACKGROUND: Primary immunodeficiency diseases are a group of disorders that result from a variety of defects of the immune system. Primary antibody deficiencies (PADs) are the most common forms of these disorders. Occurrence of recurrent infections, autoimmune diseases, cancers, and lymphoproliferative disorders is higher in PAD patients. Chronicity of these diseases, delayed diagnosis, inadequate treatment, and treatment side effects may affect the quality of life (QoL) of PAD patients. Evaluating QoL is important for patient care, understanding the burden of these diseases, and finding the patients' major health problems. We investigated the QoL in a group of PAD patients undergoing regular follow-up and treatment at the Children's Medical Center Hospital in Tehran, Iran. METHODS: Seventy patients with a diagnosis of PAD in two age groups (younger and older than 18 years) were included. QoL was measured using PedsQL and SF-36 questionnaires. Correlation of demographic, clinical, and immunological parameters with QoL scores was assessed and patients' scores were compared with the normal population, using nonparametric tests of SPSS software. RESULTS: Patients expressed significantly reduced scores in some mental and physical components. Patients with longer follow-up periods had higher scores in mental components but physical component scores were still low. There was no significant correlation between sex, age, and disease types with scores. CONCLUSIONS: PAD patients had significantly lower scores in mental and physical components compared to normal population. By early diagnosis and long-term follow-up periods, we may be able to prevent complications and help patients to have a better QoL. PMID- 28358234 TI - Iodine Storage and Metabolism of Mild to Moderate Iodine-Deficient Pregnant Rats. AB - BACKGROUND: Severe iodine deficiency during pregnancy results in neurodevelopmental disorders in children, while the consequences of mild to moderate iodine deficiency (MMID) are uncertain. The concentration of iodine in the thyroid is the most accurate indicator of iodine nutrition. This study aimed to evaluate whether the iodine stores in the thyroid cover the needs of the mother and the fetus in iodine-sufficient and MMID conditions by inductively coupled plasma-mass spectrometry. METHODS: One hundred four-week-old female Wistar rats were randomly divided into MMID (low iodine intake [L]) and normal (normal iodine intake [N]) groups. The rats were fed for the next three months, and after pregnancy they were further divided into two subgroups, respectively: low iodine pregnancy (LP) and low iodine pregnancy with iodine supplement (LP+), and normal iodine intake pregnancy (NP) and normal iodine intake pregnancy with iodine supplement (NP+). The iodine intake of pregnant rats in the NP+ and LP+ groups was twice as much as in the NP and LP groups. The rats were sacrificed on gestational day 15 and postnatal day 7. The iodine concentration in the thyroid of the maternal and newborn rats, maternal serum, placenta, and amniotic fluid were determined by inductively coupled plasma-mass spectrometry. RESULTS: The concentration of iodine in the thyroid of the N group was significantly higher than that in the L group before pregnancy. The concentration of iodine in the maternal thyroids of the LP group decreased during pregnancy, whereas that of the NP group did not change significantly. There was no significant difference in the iodine concentration in the thyroid of mothers and offspring between the NP and NP+ groups, but it was significant between LP and LP+ groups. The concentration of iodine in amniotic fluid was significantly different between the four groups. CONCLUSION: There is sufficient iodine storage in the thyroid of maternal rats with normal iodine intake during pregnancy, and there is no need for iodine supplementation. However, iodine stores are insufficient in rats with MMID. Iodine supplementation can increase the iodine concentration in the thyroid of maternal rats with MMID and their offspring, as well as in the amniotic fluid during pregnancy. PMID- 28358235 TI - The Aging Semantic Differential in Mandarin Chinese: Measuring Attitudes toward Older Adults in China. AB - The Aging Semantic Differential (ASD) is the most widely used instrument to measure young people's attitudes towards older adults. This study translated the ASD to Mandarin and examined its psychometric properties. The Mandarin-ASD contains three latent factors (Personality and Mental Health, Societal Participation, and Physical) that have high internal reliability and reasonable discriminate validity. Social work researchers, practitioners and allied professionals may utilize the ASD-Mandarin instrument to measure young people's attitudes towards older adults in China. We issue a call for a universal-ASD that can be applied across different cultural contexts. PMID- 28358236 TI - Experiential avoidance, distress tolerance, and substance use cravings among adults in residential treatment for substance use disorders. AB - Substance use cravings are a known predictor of relapse to substance use following treatment for a substance use disorder. Thus, research on factors that may be correlated with cravings, and could then be targeted in substance use treatment, is needed. Both distress tolerance and experiential avoidance, similar but distinct constructs, are independently associated with substance use cravings. However, no known research has examined these constructs as simultaneous predictors of substance use cravings, which may have important implications for treatment. The current study examined this in a sample of men and women in residential substance use treatment (n = 117). The authors used pre existing data from a larger study where men and women were recruited for participation from a residential substance use treatment facility. The majority of the sample was male (n = 87; 74.3%) and Caucasian (92.2%). The mean age was 41.27 (standard deviation = 10.68). Better distress tolerance and lower experiential avoidance were negatively and significantly associated with alcohol and drug cravings, but only experiential avoidance remained significantly and negatively associated with cravings when both predictors were examined simultaneously. The current findings provide preliminary support for the importance of decreasing experiential avoidance in substance use treatment, which may result in reduced substance use cravings. PMID- 28358237 TI - Combined Treatment with Demecolcine and 6-Dimethylaminopurine during Postactivation Improves Developmental Competence of Somatic Cell Nuclear Transfer Embryos in Pigs. AB - This study determined the effects of postactivation treatment with demecolcine and/or 6-dimethylaminopurine (6-DMAP) on in vivo and in vitro developmental competence of somatic cell nuclear transfer (SCNT) embryos in pigs. SCNT embryos were treated for 4 hours with 0.4 ug/mL demecolcine, 2 mM 6-DMAP, or both after electric activation, then transferred to surrogate pigs or cultured for 7 days. The formation rate of SCNT embryos with a single pronucleus was higher in combined treatment with demecolcine and 6-DMAP (95.2%) than treatment with demecolcine alone (87.1%). Blastocyst formation of SCNT embryos was significantly increased in combined treatment with demecolcine and 6-DMAP (48.7%) compared with demecolcine (22.2%) or 6-DMAP alone (37.3%). Fluctuation of maturation promoting factor activity showed different patterns among various postactivation treatments. Pregnancy was established in 1 of 5 surrogates after transfer of SCNT embryos that were treated with demecolcine and 6-DMAP. The pregnant surrogate delivered one healthy live piglet. The results of our study demonstrated that postactivation treatment with demecolcine and 6-DMAP together improved preimplantation development and supported normal in vivo development of SCNT pig embryos, probably influencing MPF activity and nuclear remodeling, including induction of single pronucleus formation after electric activation. PMID- 28358238 TI - Expression Profiling and Identification of Novel SNPs in CatSper2 Gene and Their Influence on Sperm Motility Parameters in Bovines. AB - 122 randomly selected Vrindavani cattle were studied to detect polymorphism in four fragments of the CatSper2 gene that were comprised of exon 2, 4, 5, and 6 with flanking regions. Using PCR-SSCP and sequencing analysis, three SNPs (T157C, C273A, and A274C) in the first fragment, one SNP (C30G) in the second fragment, and two SNPs (T86G and T292C) in the fourth fragment were identified. The third fragment did not reveal any polymorphism. The SNPs were used for construction of haplotypes and three haplotypes were found. The least square analysis of variance revealed a significant (P < 0.01) effect of haplotype on all three motility parameters. The haplotype II and III were nonsignificantly different from each other while being significantly (P < 0.01) different from haplotype I. The nonsignificant difference of haplotype II with III can lead to a hypothesis that T>G or C>T SNPs may not play a role in sperm motility. However, when the comparison was made between haplotype I and II, it can be inferred that C>T SNP may have a role in sperm motility, as haplotype II has better motility parameters. Expression profiling of Catper2 gene revealed nonsignificant down regulation of CatSper2 gene in poor motility sperm compared to good motility sperm. PMID- 28358239 TI - Training on the DSM-5 Cultural Formulation Interview improves cultural competence in general psychiatry residents: A pilot study. AB - The objective of this study was to assess whether a 1-hour didactic session on the DSM-5 Cultural Formulation Interview (CFI) improves the cultural competence of general psychiatry residents. The main hypothesis was that teaching adult psychiatry residents a 1-hour session on the CFI would improve cultural competence. The exploratory hypothesis was that trainees with more experience in cultural diversity would have a greater increase in cultural competency scores. Psychiatry residents at a metropolitan, county hospital completed demographics and preintervention questionnaires, were exposed to a 1-hour session on the CFI, and were given a postintervention questionnaire. The questionnaire was an adapted version of the validated Cultural Competence Assessment Tool . Paired samples t tests compared pre- to posttest change. Hierarchical linear regression assessed whether pretraining characteristics predicted posttest scores. The mean change of total pre- and posttest scores was significant ( p = .002), as was the mean change in subscales Nonverbal Communications ( p < .001) and Cultural Knowledge ( p = .002). Demographic characteristics did not predict higher posttest scores (when covarying for pretest scores). Psychiatry residents' cultural competence scores improved irrespective of previous experience in cultural diversity. More research is needed to further explore the implications of the improved scores in clinical practice. PMID- 28358240 TI - Molecular MR Imaging of Myeloperoxidase Distinguishes Steatosis from Steatohepatitis in Nonalcoholic Fatty Liver Disease. AB - Purpose To test whether MPO-Gd, an activatable molecular magnetic resonance (MR) imaging agent specific for myeloperoxidase (MPO) activity, could detect MPO activity in nonalcoholic steatohepatitis (NASH) mouse models and human liver biopsy samples. Materials and Methods In this study, 20 leptin receptor-deficient and three MPO knockout mice were injected with endotoxin (lipopolysaccharide) or fed a methionine and choline-deficient (MCD) diet to induce experimental NASH and underwent MR imaging with MPO-Gd. Saline-injected and control diet-fed leptin receptor-deficient mice were used as respective controls. MPO protein and activity measurements and histologic analyses were performed. Eleven human liver biopsy samples underwent MPO-Gd-enhanced MR imaging ex vivo and subsequent histologic evaluation. Results were compared with Student t test or Mann-Whitney U test. Results With endotoxin, a significantly increased contrast-to-noise ratio (CNR) was found compared with sham (mean CNR, 1.81 [95% confidence interval {CI}: 1.53, 2.10] vs 1.02 [95% CI: 0.89, 1.14]; P = .03) at MPO-Gd MR imaging. In the diet-induced NASH model, an increased CNR was also found compared with sham mice (mean CNR, 1.33 [95% CI: 1.27, 1.40] vs 0.98 [95% CI: 0.83, 1.12]; P = .008). Conversely, CNR remained at baseline in NASH mice imaged with gadopentetate dimeglumine and in MPO knockout NASH mice with MPO-Gd, which proves specificity of MPO-Gd. Ex vivo molecular MR imaging of liver biopsy samples from NASH and control patients confirmed results from animal studies (mean CNR for NASH vs control patients, 2.61 [95% CI: 1.48, 3.74] vs 1.29 [95% CI: 1.06, 1.52]; P = .004). Conclusion MPO-Gd showed elevated MPO activity in NAFLD mouse models and human liver biopsy samples. (c) RSNA, 2017 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on April 6, 2017. PMID- 28358242 TI - A 12-year retrospective review of bullous systemic lupus erythematosus in cutaneous and systemic lupus erythematosus patients. AB - Objective The aim of this study was to investigate the clinical features, laboratory findings, systemic manifestations, treatment and outcome of patients with bullous systemic lupus erythematosus in a tertiary care center in Thailand. Methods We performed a retrospective review from 2002 to 2014 of all patients who fulfilled the diagnostic criteria for bullous systemic lupus erythematosus to evaluate for the clinical characteristics, extracutaneous involvement, histopathologic features, immunofluorescence pattern, serological abnormalities, internal organ involvement, treatments and outcome. Results Among 5149 patients with cutaneous lupus erythematosus and/or systemic lupus erythematosus, 15 developed vesiculobullous lesions. Ten patients had validation of the diagnosis of bullous systemic lupus erythematosus, accounting for 0.19%. Bullous systemic lupus erythematosus occurred after the diagnosis of systemic lupus erythematosus in six patients with a median onset of 2.5 months (0-89). Four out of 10 patients developed bullous systemic lupus erythematosus simultaneously with systemic lupus erythematosus. Hematologic abnormalities and renal involvement were found in 100% and 90%, respectively. Polyarthritis (40%) and serositis (40%) were less frequently seen. Systemic corticosteroids, immunosuppressants, antimalarials and dapsone offered resolution of cutaneous lesions. Conclusion Bullous systemic lupus erythematosus is an uncommon presentation of systemic lupus erythematosus. Blistering can occur following or simultaneously with established systemic lupus erythematosus. We propose that clinicians should carefully search for systemic involvement, especially hematologic and renal impairment, in patients presenting with bullous systemic lupus erythematosus. PMID- 28358241 TI - Communication between oncologists and lymphoma survivors during follow-up consultations: A qualitative analysis. AB - Cancer survivors often experience both short- and long-term challenges as a result of their cancer treatment. Many patients report feeling "lost in transition" following cancer treatment. The oncologist plays a key role in helping the patient to transition to survivorship. The purpose of this paper is to provide a descriptive understanding of the clinical care delivered during follow-up visits for lymphoma patients transitioning from active therapy into survivorship. We used thematic text analysis to identify themes in transcripts of audio recordings of 21 physicians and their patients in follow-up visits within 3 years of completing lymphoma treatment. Conversations between oncologists and patients during follow-up visits addressed a variety of themes, including specific health concerns, follow-up care, health promotion, prior treatment and test results, overall health status, emotional communication and affective tone, post-treatment rehabilitation, discussions occurring in the patient's physical examination, and social issues. However, the frequency with which these themes were discussed varied. In addition, there did not appear to be a consistent framework for these visits. The varied nature of the follow-up visits analyzed in this study suggests the need for increased structure in survivorship-care consultations. PMID- 28358243 TI - Professional Quality of Life and Changes in Spirituality Among VHA Chaplains: A Mixed Methods Investigation. AB - A mixed method design was implemented to examine the spirituality and emotional well-being of Veterans Health Administration (VHA) chaplains and how potential changes in spirituality and emotional well-being may affect their professional quality of life. Four distinct categories of changes emerged from the narrative statements of a nationally representative sample of 267 VHA chaplains: (1) positive changes (e.g., increased empathy), (2) negative changes (e.g., dysthymic mood, questioning religious beliefs), (3) combination of positive and negative changes, and (4) no change (e.g., sustenance through spirituality or self-care). Most chaplains reported positive (37%) or no change (30%) in their spirituality and/or emotional well-being. However, quantitative analyses revealed that chaplains who reported negative changes endorsed greater burnout and secondary traumatic stress. Overall, these findings suggest VHA chaplains are predominantly spiritually resilient, but negative changes in the spiritual domain can occur, potentially increasing the risk of adverse changes in professional quality of life. PMID- 28358245 TI - Changes in the demographics of intravenous drug users with mycotic common femoral artery pseudoaneurysm as a consequence of self-injection does not influence outcome following emergency ligation. AB - Objectives The reported annual incidence of mycotic pseudoaneurysm of the common femoral artery in intravenous drug users has been estimated at 0.03%. Over the past 5 years in Scotland, the proportion of people receiving specialist attention for heroin use over the age of 40 years has increased from 15 to 22%. Although routinely managed with arterial ligation (without reconstruction), some series have reported rates of major limb amputation of up to 10%. We sought to define whether this management strategy was still acceptable in an older population. Methods Retrospective review of patients presenting to a tertiary vascular service with mycotic pseudoaneurysm of the common femoral artery due to arterial injection by intravenous drug users between October 2010 and March 2016. Variables of interest included patient demographics and requirement for major amputation. Results There were 55 patients identified. The annual incidence of mycotic pseudoaneurysm of the common femoral artery in intravenous drug users was 2.1%. It was more common in men (3:1) and the mean age at presentation was 41 years (standard deviation +/- 8 years). Three patients underwent major limb amputation during the index admission for severe limb ischaemia (two transfemoral amputations; one hip-disarticulation). Following discharge two patients were readmitted (134 and 200 days, respectively, following primary ligation) for major limb amputation due to of critical limb ischaemia. Conclusions Despite the increasing age of intravenous drug users presenting with mycotic pseudoaneurysm of the common femoral artery primary ligation of pseudoaneurysm would seem to remain an appropriate therapeutic intervention. PMID- 28358244 TI - Clonal outbreaks of [ Pasteurella] pneumotropica biovar Heyl in two mouse colonies. AB - The aim of this study was to document the pathogenic role of biovar Heyl of [ Pasteurella] pneumotropica in mouse colonies. Fifty-three isolates associated with mastitis and orbital, cutaneous and vaginal abscesses as well as isolates from the nose and vagina of healthy mice were investigated. According to phenotypic characteristics and rpoB sequencing, the isolates were identified as [ P.] pneumotropica biovar Heyl. Pulsed-field gel electrophoresis (PFGE) revealed five closely related profiles separated by only one to four fragments. The outbreak strains diverged from epidemiologically unrelated strains with the same rpoB sequence type, as shown by the PFGE profiles. The investigation documented that members of biovar Heyl of [ P.] pneumotropica caused disease outbreaks in mouse colonies since the clonality indicated a primary role of [ P.] pneumotropica biovar Heyl in the infections observed. PMID- 28358247 TI - Negative Effects of Acid Violet-17 and MBB Dual In Vitro on Different Ocular Cell Lines. AB - PURPOSE: Vital dyes have become a clinical standard during vitrectomy to visualize anatomical structures. It was the aim of this study to test the effect of two vital dyes (AV 17-M with 5% mannitol and MBB Dual) on different intraocular cells, to see whether in vitro test can be used as reliable preclinical testing tool. METHODS: Cell morphology was assessed via phase contrast pictures, cell viability via MTS assay and total cell amount via crystal violet staining. ARPE19 and 661W cells were chosen for toxicology testing at different exposure times (60 seconds, 15 minutes and 30 minutes). Vital dyes were completely removed after the staining period. RESULTS: Treatment with AV 17-M changed the morphology and the cell number at every time point investigated on ARPE19 and 661 W cells. ARPE19 cells treated with AV 17-M or MBB Dual displayed only a slight or no decrease in cell viability after the three different exposure times. AV-17 without medium to simulate a possible intraoperative use after fluid air exchange showed a decrease in viability of 6%, 24% and 14%. A difference in cell density of 21%, 46% and 34% was noted after CV staining for AV 17-M, MBB Dual led to a decrease of 2%, 16% and 3% after 30 minutes compared to BSS. AV 17 M directly applied on 661W decreased viability significantly by 18% after 60 seconds, 33% after 15 minutes and 40% after 30 minutes. Cell density of 661W cells exposed relevant negative effects; after incubation of 60 seconds with AV 17-M, the cell amount was significantly lowered by 41% and MBB Dual by 12%. After 15 minutes, a loss of 48% cell amount was detected with AV 17-M and after 30 min 51%. MBB Dual led to 37% loss after 15 minutes and to 28% loss after 30 minutes. CONCLUSION: AV 17-M with 5% mannitol has a negative effect on different ocular cells. PMID- 28358246 TI - Effects of direct renin inhibition versus angiotensin II receptor blockade on angiotensin profiles in non-diabetic chronic kidney disease. AB - BACKGROUND: Direct renin inhibition (DRI) is clinically inferior to other blockers of the renin-angiotensin system (RAS). Thus far, the underlying molecular causes of this finding remain unknown. METHODS: Twenty four patients with non-diabetic chronic kidney disease (CKD) stages III-IV and albuminuria were randomized to DRI or angiotensin receptor blocker (ARB). Employing a novel mass spectrometry method, the concentrations of renin, aldosterone and plasma angiotensin peptides [Ang I, Ang II, Ang-(1-7), Ang-(1-5), Ang-(2-8), Ang-(3-8)] were quantified before and after an 8-week treatment. RESULTS: While blood pressure, renal function and albuminuria decreased comparably in both groups, profound RAS component differences were observed: DRI led to a massive renin increase, while suppressing both vasoconstrictive (Ang I and Ang II) and vasodilatory RAS metabolites (Ang-(1-7) and Ang-(1-5)). In contrast, ARB led to a four-fold increase of Ang I and Ang II, while Ang-(1-7) and Ang-(1-5) increased moderately but significantly. With ARB treatment, a decreased aldosterone-to-Ang II ratio suggested efficacy in blocking AT1 receptor. CONCLUSIONS: DRI therapy abolishes all RAS effector peptides. ARB increases both vasoconstrictive and vasodilative angiotensins, while this is accompanied by efficient blockade of vasoconstrictive effects. These differential molecular regulations should be considered when selecting optimal antihypertensive and disease-modifying therapy in CKD patients. Key messages Direct renin inhibition leads to a complete and lasting abolition of both classical and alternative RAS components. Angiotensin receptor blockade leads to effective receptor blockade and up-regulation of alternative RAS components. Differential molecular regulations of the RAS should be considered when selecting optimal antihypertensive and disease-modifying therapy in CKD patients. PMID- 28358249 TI - Development of an internet version of the Lidcombe Program of early stuttering intervention: A trial of Part 1. PMID- 28358248 TI - Atypical choroid plexus papilloma: clinicopathological and neuroradiological features. AB - Background Atypical choroid plexus papilloma (APP) is a rare, newly introduced entity with intermediate characteristics. To date, few reports have revealed the magnetic resonance (MR) findings. Purpose To analyze the clinicopathological and MR features of APP. Material and Methods The clinicopathological data and preoperative MR images of six patients with pathologically proven APP were retrospectively reviewed. The MR features including tumor location, contour, signal intensity, degree of enhancement, intratumoral cysts, and necrosis; and flow voids, borders, peritumoral edema, and associated hydrocephalus were analyzed. Results The APP were located in the ventricle (n = 4) and cerebellopontine angle (CPA, n = 2). Tumor dissemination along the spinal subarachnoid space was found in one patient. The tumors appeared as milt lobulated (n = 5) or round mass (n = 1), with slightly heterogeneous signals (n = 5) or mixed signals (n = 1) on T1-weighted and T2-weighted images. Heterogeneous and strong enhancement were found in five cases on contrast-enhanced images. Three of four intraventricular tumors had a partly blurred border with ventricle wall. Four tumors had mild to moderate extent of surrounding edema signals. A slight hydrocephalus was seen in four patients. Incomplete capsule was seen in four tumors at surgery. Histopathologically, mild nuclear atypia was seen in all tumors with a mitotic rate of 2-5 per 10 high-power fields. Conclusion APP should be included in the differential diagnosis when an intraventricular or CPA tumor appearing as a multi-lobulated solid mass with slight heterogeneity, heterogeneous strong enhancement, partly blurred borders, mild to moderate peritumoral edema, or slight hydrocephalus are present. PMID- 28358250 TI - Ten Questions With .... PMID- 28358251 TI - Boundary-Pushing Healthcare Tech. PMID- 28358253 TI - Comparison of Accelerated Corneal Collagen Cross-linking Types for Treating Keratoconus. AB - PURPOSE: To compare the results of different protocols for accelerated corneal collagen cross-linking (CXL) in patients with progressive keratoconus. MATERIALS AND METHOD: This prospective comparative study involved 40 patients treated with intended UV-A radiance of 5.4 J/cm2 in 74 eyes (Group 1) and 42 patients treated with radiance of 7.2 J/cm2 in 72 eyes (Group 2). Visual acuity, subjective manifest refraction and corneal topography were analyzed before and 12 months after surgery in both groups. Postoperative complications were also noted. The results of the two protocols were statistically compared. RESULTS: There were no statistically significant differences between the groups in uncorrected distance visual acuity, corrected distance visual acuity or corneal topography pre- or postoperatively. The differences in keratometric readings (K apex, SimK1 and SimK2) and refractive results were not significant. CONCLUSION: The application of total intended UV-A radiance of 5.4 J/cm2 or 7.2 J/cm2 for accelerated CXL in patients with progressive keratoconus resulted in similar refractive and topographic outcomes. PMID- 28358254 TI - Risk Factors Related with Retroperitoneal Laparoscopic Converted to Open Nephrectomy for Nonfunctioning Renal Tuberculosis. AB - PURPOSE: The present study was designed to investigate the risk factors affecting the conversion to open surgery in retroperitoneal laparoscopic nephrectomy of nonfunctioning renal tuberculosis (TB). PATIENTS AND METHODS: The records of 144 patients who underwent a retroperitoneal laparoscopic nephrectomy procedure by a single surgeon were retrospectively reviewed. The following factors, including age, sex, body mass index (BMI), diabetes status, hypertension status, side of kidney, size of kidney, degree of calcification, mild perirenal extravasation, contralateral hydronephrosis, the time of anti-TB, and surgeon experience were analyzed. Univariate and multivariate logistic regression analyses were used for statistical assessment. RESULTS: Twenty-three patients were converted to open surgery and the conversion rate was 15.97%. In univariate analysis, BMI >=35 kg/m2 (p = 0.023), hypertension (p = 0.011), diabetes (p = 0.003), and kidney size (p = 0.032) were the main factors of conversion to open surgery. Sex, age, side, anti-TB time, calcification, mild extravasation, and surgeon experience were not significantly related. In multivariate regression analysis, BMI >=35 kg/m2, hypertension, diabetes, and enlargement of kidney were the most important factors for conversion to open surgery. CONCLUSIONS: Depending on the results achieved by a single surgeon, BMI >=30 kg/m2, diabetes, hypertension, and enlargement of kidney significantly increased the conversion risk in retroperitoneal laparoscopic nephrectomy for nonfunctioning renal TB. PMID- 28358255 TI - The IFN-1 > BID > ROS pathway: Linking DNA damage with HSPC malfunction. PMID- 28358257 TI - Effectiveness of Corticosteroid Monotherapy for Dyspnea Relief in Patients with Terminal Cancer. AB - Dyspnea is a common symptom in patients with cancer, particularly those with late stage terminal disease. It markedly affects terminal cancer patients, reducing their quality of life. Reduced quality of life also affects survival; therefore, dyspnea is a prognostic factor. However, the role of corticosteroids, which often are used to alleviate dyspnea, has not been sufficiently validated. In this study, we retrospectively investigated whether corticosteroid monotherapy was effective for dyspnea palliation. The effectiveness rate of corticosteroid therapy was 45% in nine male and two female study subjects (mean age: 74.5 years; range: 64-86 years). No significant differences were found between responders and nonresponders in the first-day corticosteroid doses (25.5 +/- 10.86 vs. 36.1 +/- 16.39 mg, P = .29) or doses administered on 2 days (47.7 +/- 25.99 vs. 72.2 +/- 32.78 mg, P = .25). The mean +/- standard error assessment score changed significantly from 2.7 +/- 0.14 at the beginning of corticosteroid administration to 1.5 +/- 0.37 at the time of maximum effect (P = .028); however, the decrease to 2.1 +/- 0.25 at the final administration was not significant (P = .068). This indicates that corticosteroid therapy relieved dyspnea and could provide an early stage treatment option. PMID- 28358256 TI - Fluorescent multi-responsive cross-linked P(N-isopropylacrylamide)-based nanocomposites for cisplatin delivery. AB - Magnetic, pH and temperature-sensitive, poly(N-isopropylacrylamide) (PNIPAM) based nanocomposites with fluorescent properties were synthesized by free radical copolymerization-cross linking of NIPAM, N,N-dimethylaminoethyl methacrylate (DMAEMA) and 4-acrylamidofluorescein (AFA). The model anti-cancer drug, cisplatin (CDDP), was loaded into the resulted nanogel. For the production of CDDP-loaded nanocomposite, Fe3O4 magnetic nanoparticles (MNPs) and CDDP were loaded into the nanogel. Field-emission scanning electron microscopy (FE-SEM) indicated that the size of nanogel and CDDP-loaded nanocomposite were about 90 and 160 nm, respectively. The encapsulation efficiency of CCDP was found up to 65%. The loaded CCDP showed sustained thermal and pH-responsive drug release. A high level of drug release was observed under the conditions of low pH and high temperature. The lower critical solution temperature (LCST) of synthesized nanogel was about 40 degrees C. CDDP-loaded nanocomposite showed a volume phase transition from 282 to 128 nm at its LCST. Accordingly, in this study, the synthesized nanocomposite can be employed as a stimuli-responsive anti-cancer drug delivery system and the pH and temperature of solution have the potential to monitor the drug release. PMID- 28358258 TI - Prevalence and Antimicrobial Resistance of Salmonella in Market Raw Oysters in Taiwan. AB - We tested 137 samples of domestic shucked oysters and 114 samples of imported oysters collected from traditional retail markets and supermarkets during 2010 and 2011 in Taiwan for the presence of Salmonella . We obtained a total of 91 Salmonella isolates, representing nine serotypes, from 80 of the domestic samples. We did not find any Salmonella in the imported oysters. The presence of Salmonella contamination tended to be specific to the area from which the oysters were harvested: the Dongshih area had a significantly higher contamination rate (68.8%) than the Budai (20.0%) and Wanggong (9.1%) areas. In addition, the rate of Salmonella contamination was higher in oysters that were packed or sold with water (P < 0.05). The most commonly identified Salmonella serotypes were Saintpaul (26.4%), Newport (22.0%), and Infantis (13.2%). We screened the isolates for susceptibility to nine antimicrobials and compared them genetically by using PCR for the class 1 integron (int1), tetA, tetB, and blaPSE-1 genes. Eighteen isolates (19.8%) were resistant to at least one antimicrobial agent, and the most frequent resistances were those to tetracycline and oxytetracycline (n = 12, 14.3%).We detected the antimicrobial resistance genes int1, tetA, tetB, and blaPSE-1 in 16.5, 26.4, 6.6, and 22.0% of the isolates, respectively. Eleven of the 18 antimicrobial-resistant isolates contained one or two int1 cassettes, suggesting that the presence of int1 is highly correlated with antimicrobial resistance in Salmonella isolates from oysters. The consumption of oysters is increasing in Taiwan, and information related to Salmonella contamination in oysters is rather limited. Our results indicate that raw oyster consumption from retail markets in Taiwan is associated with a human health hazard owing to Salmonella , including multidrug-resistant Salmonella strains. PMID- 28358259 TI - Transfer of Campylobacter and Salmonella from Poultry Meat onto Poultry Preparation Surfaces. AB - Thermophilic Campylobacter and Salmonella enterica are major causes of gastrointestinal foodborne infection. Survival of these pathogens on food associated surfaces is a risk contributing to their spread through the food system. This study examined the transfer of two strains each of C. jejuni , C. coli , Salmonella Enteritidis, and Salmonella Typhimurium from chicken meat to a knife or scissors used on either a plastic or wooden cutting board. Each strain of Campylobacter and Salmonella at ~108 CFU mL-1 was inoculated (5 mL) onto 25 g of chicken meat with skin and allowed to attach (for 10 min). The meat was then cut (20 times per implement) into 1-cm2 pieces with either a knife or scissors on either a plastic or wooden cutting board. The numbers of pathogens transferred from meat onto cutting implements and cutting board surfaces were enumerated. The surfaces were subsequently either rinsed with water or rinsed with water and wiped with a kitchen towel to mimic commonly used superficial cleaning practices for these implements, and the numbers of pathogens were enumerated again. The bacterial numbers for both pathogens were determined on thin-layer agar. The attachment of the Salmonella strains to chicken meat (~7.0 to 7.8 log CFU cm-2) was higher than the attachment of the Campylobacter strains (~4.6 to 6.6 log CFU cm-2). All four Salmonella strains transferred in higher numbers (~1.9 to 6.3 log CFU cm-2) to all surfaces than did the Campylobacter strains (~1.1 to 3.9 log CFU cm-2). The transfer rates of both pathogens from the chicken meat to all the surfaces examined varied substantially between ~0 and 21.1%. The highest rate of transfer (~21.1%) observed was for C. coli 2875 when transferred from the chicken meat to the scissors. Most cleaning treatments reduced the numbers of both pathogens (~0.3 to 4.1 log CFU cm-2) transferred to all the surfaces. Our study gives insights into the risks associated with the transfer of Campylobacter and Salmonella from poultry to the surfaces used in poultry preparation. PMID- 28358260 TI - Study of Biofilm Formation Ability of Foodborne Arcobacter butzleri under Different Conditions. AB - The transmission of Arcobacter butzleri , an emerging food- and waterborne pathogen, is possibly favored by its ability to adhere to abiotic surfaces. In this study, we assessed the biofilm formation ability of 42 A. butzleri isolates recovered from different food products. Overall, nine isolates (21.4%) were able to adhere to polystyrene. Among them, a chicken-derived isolate was classified as strongly adherent. Based on the chi-square test, no relation was found between the adhesive abilities of the isolates and their source (P > 0.05). An aerobic atmosphere enhanced the adhesion ability of the majority of the adherent isolates (66.7%), because when tested in microaerobic conditions, a t test indicated that only three isolates increased their biofilm formation ability significantly (P < 0.05). In addition, seven (77.8%) of these nine isolates were able to adhere to glass surfaces, and viable cells were recovered from all the stainless steel coupons tested. Therefore, our results confirm the biofilm formation ability of A. butzleri , which may be influenced by the incubation atmosphere and the abiotic surface. PMID- 28358261 TI - A Meta-Analysis of the Global Prevalence Rates of Staphylococcus aureus and Methicillin-Resistant S. aureus Contamination of Different Raw Meat Products. AB - Previous research has indicated that raw meats are frequently contaminated with Staphylococcus aureus , but data regarding the pooled prevalence rates of S. aureus and methicillin-resistant S. aureus (MRSA) contamination in different types of raw meat products (beef, chicken, and pork) and across different periods, regions, and purchase locations remain inconsistent. We systematically searched the PubMed, EMBASE, Ovid, Web of Science, and HighWire databases to identify studies published up to June 2016. The STROBE guidelines were used to assess the quality of the 39 studies included in this meta-analysis. We observed no significant differences in the pooled prevalence rates of S. aureus and MRSA contamination identified in various raw meat products, with overall pooled prevalence rates of 29.2% (95% confidence interval [CI], 22.8 to 35.9%) and 3.2% (95% CI, 1.8 to 4.9%) identified for the two contaminants, respectively. In the subgroup analyses, the prevalence of S. aureus contamination in chicken products was highest in Asian studies and significantly decreased over time worldwide. In European studies, the prevalence rates of S. aureus contamination in chicken and pork products were lower than those reported on other continents. The pooled prevalence rates of S. aureus contamination in chicken and pork products and MRSA contamination in beef and pork products were significantly higher in samples collected from retail sources than in samples collected from slaughterhouses and processing plants. These results highlight the need for good hygiene during transportation to and manipulation at retail outlets to reduce the risk of transmission of S. aureus and MRSA from meat products to humans. PMID- 28358262 TI - Microbiological and Sensory Quality of Fresh Ready-to-Eat Artichoke Hearts Packaged under Modified Atmosphere. AB - In recent years the sales of minimally processed vegetables have grown exponentially as a result of changes in consumer habits. The availability of artichoke buds as a ready-to-eat product would be, therefore, highly advantageous. However, minimally processed artichoke hearts are difficult to preserve because of their rapid browning and the proliferation of naturally occurring microorganisms. We developed artichoke hearts prepared as ready-to-eat products that maintain the characteristics of the fresh product. The microbiological stability, sensory qualities, and shelf life of the processed artichoke hearts were determined. During the shelf life, Salmonella, Listeria monocytogenes , and Escherichia coli counts were below the limits legally established by European regulations for minimally processed vegetables. The pH played an important role in microbial growth. Artichoke hearts had lower microbial counts in experiments conducted at pH 4.1 than in experiments conducted at pH 4.4, although the recommended threshold value for total plate count (7 log CFU/g) was not exceeded in either case. Sensory parameters were affected by the microorganisms, and artichoke products at lower pH had better sensory qualities. Vacuum impregnation techniques, modified atmosphere packaging, and low storage temperature were very effective for increasing the shelf life of minimally processed artichokes. The average shelf life was approximately 12 to 15 days. PMID- 28358263 TI - LncRNA CCAT1 modulates the sensitivity of paclitaxel in nasopharynx cancers cells via miR-181a/CPEB2 axis. AB - Recent studies reported that long non-coding RNA (lncRNA) might play critical roles in regulating chemo-resistant of multiple types of cancer. This study aimed to investigate whether long non-coding RNA CCAT1 was involved in Paclitaxel resistance in nasopharyngeal carcinoma (NPC). qRT-PCR was used for testing the expression of CCAT1, miR-181a and CPEB2 in tumor tissues and NPC cancers. NPC cells were transfected with siRNAs to suppress the mRNA level of CCAT1 in NPC cells. MTT assays and flow cytometry analysis were used to assess the sensitivity of paclitaxel in NPC cells. Luciferase reporter assays were used to examine the interaction of CCAT1 or CPEB2 to miR-181a. Our findings revealed that the upregulated CCAT1 results in significantly enhancing paclitaxel resistance in nasopharyngeal cancer cells. Bioinformatics analysis and luciferase reporter assay indicated that the upregulated CCAT1 sponges miR-181a in NPC cells. Furthermore, RNA immuno-precipitation assays showed that miR-181a could directly bind to CCAT1 mRNA in NPC cells. We restored miR-181a in NPC cells, and found restoration of miR-181a re-sensitized the NPC cells to paclitaxel in vitro. In addition, our results also showed that miR-181a was a modulator of paclitaxel sensitivity due to its regulative effect on cell apoptosis via targeting CPEB2 in NPC cells. Taken together, lncRNA CCAT1 regulates the sensitivity of paclitaxel in NPC cells via miR-181a/CPEB2 axis. PMID- 28358264 TI - The absence of the CD163 receptor has distinct temporal influences on intracerebral hemorrhage outcomes. AB - Hemoglobin (Hb) toxicity precipitates secondary brain damage following intracerebral hemorrhage (ICH). CD163 is an anti-inflammatory Hb scavenger receptor and CD163-positive macrophages/microglia locally accumulate post-bleed, yet no studies have investigated the role of CD163 after ICH. ICH was induced in wildtype and CD163-/- mice and various anatomical and functional outcomes were assessed. At 3 d, CD163-/- mice have 43.4 +/- 5.0% (p = 0.0002) and 34.8 +/- 3.4% (p = 0.0003) less hematoma volume and tissue injury, respectively. Whereas, at 10 d, CD163-/- mice have 49.2 +/- 15.0% larger lesions (p = 0.0385). An inflection point was identified, where CD163-/- mice perform better on neurobehavioral testing and have less mortality before 4 d, but increased mortality and worse function after 4 d (p = 0.0389). At 3 d, CD163-/- mice have less Hb, iron, and blood-brain barrier dysfunction, increased astrogliosis and neovascularization, and no change in heme oxygenase 1 (HO1) expression. At 10 d, CD163-/- mice have increased iron and VEGF immunoreactivity, but no significant change in HO1 or astrogliosis. These novel findings reveal that CD163 deficiency has distinct temporal influences following ICH, with early beneficial properties but delayed injurious effects. While it is unclear why CD163 deficiency is initially beneficial, the late injurious effects are consistent with the key anti inflammatory role of CD163 in the recovery phase of tissue damage. PMID- 28358265 TI - What survivors want: Understanding the needs of sexual assault survivors. AB - OBJECTIVE: Sexual assault is a pervasive crime on our college campuses and many survivors do not seek post-assault resources. This study will explore components of alternative interventions to consider in the development of campus-based interventions for sexual assault survivors. PARTICIPANTS: Three stakeholder groups including survivors (n = 8), healthcare providers (n = 6), and advocates (n = 19) were recruited from May 2014 to December 2014 from two university campus communities using flyers and purposive sampling. METHODS: A qualitative study design utilized semi-structured interviews and semi-structured focus groups with survivors, healthcare providers, and advocates. RESULTS: Five themes emerged to consider for future campus-based sexual assault interventions: (a) culture of caring, (b) one-stop shop, (c) validation, (d) survivor control and agency, and (e) confidentiality. CONCLUSIONS: Although accessible and effective options for post-assault care do currently exist, participants described alternative future interventions that were either (a) print materials or (b) technology-based. PMID- 28358267 TI - Dementia discourse - A rethink? PMID- 28358266 TI - Natural history of patients with tuberous sclerosis complex related renal angiomyolipoma. AB - OBJECTIVE: To examine temporal relationships between tuberous sclerosis complex (TSC) and renal angiomyolipoma diagnosis and outcomes, treatment, and healthcare utilization. METHODS: Administrative data from the MarketScan Commercial Database was used to select TSC-related renal angiomyolipoma patients during 1 January 2000-31 March 2013. Patients were followed until the earliest of inpatient death or end of enrollment or study. Occurrence of kidney-related outcomes, kidney related procedures, and all-cause healthcare utilization and time to occurrence were reported. Kaplan-Meier curves were used to display the unadjusted distribution of time to outcome. RESULTS: A total of 605 patients were selected (<18 years N = 225; >=18 years N = 380). Mean time from TSC to renal angiomyolipoma diagnosis was 25.7 months in younger and 16.9 months in older patients. Patients >=18 years had higher rates of chronic kidney disease (CKD), hematuria, kidney failure, embolization (EMB), and partial and complete nephrectomy compared to patients <18 years (all p < .05). Mean time from TSC related renal angiomyolipoma diagnosis to CKD, hematuria, kidney failure, EMB, first emergency room and inpatient visits was shorter in older compared to younger patients (all p < .05). Probability of developing CKD was approximately 0.8 and 0.95 within 3 years in younger and older patients, respectively. CONCLUSIONS: Patients with TSC-related renal angiomyolipoma had high rates of kidney-related outcomes and procedures. These events sometimes preceded the angiomyolipoma diagnosis. A key study limitation was that due to the small sample size, results may have been biased by outliers. Research is needed to determine whether earlier angiomyolipoma diagnosis can impact occurrence of events and reduce healthcare utilization. PMID- 28358268 TI - Exploring the potential for secondary uses of Dementia Care Mapping (DCM) data for improving the quality of dementia care. AB - The reuse of existing datasets to identify mechanisms for improving healthcare quality has been widely encouraged. There has been limited application within dementia care. Dementia Care Mapping is an observational tool in widespread use, predominantly to assess and improve quality of care in single organisations. Dementia Care Mapping data have the potential to be used for secondary purposes to improve quality of care. However, its suitability for such use requires careful evaluation. This study conducted in-depth interviews with 29 Dementia Care Mapping users to identify issues, concerns and challenges regarding the secondary use of Dementia Care Mapping data. Data were analysed using modified Grounded Theory. Major themes identified included the need to collect complimentary contextual data in addition to Dementia Care Mapping data, to reassure users regarding ethical issues associated with storage and reuse of care related data and the need to assess and specify data quality for any data that might be available for secondary analysis. PMID- 28358269 TI - Gaps in understanding the experiences of homecare workers providing care for people with dementia up to the end of life: A systematic review. AB - This systematic review of the literature explores the perspectives and experiences of homecare workers providing care for people with dementia living at home up to the end of life. A search of major English language databases in 2016 identified 378 studies on the topic, of which 12 met the inclusion criteria. No empirical research was identified that specifically addressed the research question. However, synthesis of the findings from the broader literature revealed three overarching themes: value of job role, emotional labour and poor information and communication. The role of homecare workers supporting a person with dementia up to the end of life remains under-researched, with unmet needs for informational, technical and emotional support reported. The effective components of training and support are yet to be identified. PMID- 28358270 TI - Quality of life on the views of older family carers of people with dementia. AB - Older family carers of people with dementia represent an increasing but overlooked population of family carers. This research aimed to explore how these individuals make sense of their own quality of life and to identify the factors that enhance or compromise this. Four focus groups were conducted in 2014 with 19 older family carers in community-based support groups in Nottinghamshire, United Kingdom. Data were transcribed verbatim and analysed using Interpretative Phenomenological Analysis. Thirty-three subthemes emerged and were collated into three superordinate themes: 1) aspects of care and caregiving, 2) feelings and concerns, and 3) satisfaction with life and caregiving. This study identified a broad range of aspects that are of particular importance to the quality of life of older family carers of people with dementia. These findings are expected to inform future research as well as health and social care providers with the aim of improving life quality for this population. PMID- 28358271 TI - To dialyse or not to dialyse - Is that the question? A psychosocial perspective on dilemmas concerning dialysis for people with dementia. AB - There is increasing recognition that the organisation of health care into specialist areas of practice can be counterproductive for older people with multiple morbidities and that dementia can raise particular challenges in health care. In the context of treatment for chronic kidney disease, these challenges concern complex decisions about the suitability and efficacy of dialysis and other treatments. This article draws on a literature review to present a psychosocial perspective on these decisions. It considers the value of the concept of 'dementia friendliness' for nephrology practice and suggests how this could provide a valuable frame of reference for the multidisciplinary nephrology team to ensure they are best equipped to work with people living with dementia and their carers and to ensure that the individual patient is truly at the centre of their treatment regime. PMID- 28358272 TI - Evaluation of rapid post-mortem test kits for bovine spongiform encephalopathy (BSE) screening in Japan: Their analytical sensitivity to atypical BSE prions. AB - A classical type of bovine spongiform encephalopathy (C-BSE), recognized in 1987, had a large impact on public health due to its zoonotic link to variant Creutzfeldt-Jakob disease by the human consumption of dietary products contaminated with the C-BSE prion. Thus, a number of countries implemented BSE surveillance using rapid post-mortem test kits that were approved for detection of the C-BSE prion in the cattle brain. However, as atypical BSE (L- and H-BSE) cases emerged in subsequent years, the efficacy of the kits for the detection of atypical BSE prions became a matter of concern. In response to this, laboratories in the European Union and Canada evaluated the kits used in their countries. Here, we carried out an evaluation study of NippiBL(r), a kit currently used for BSE screening in Japan. By applying the kit to cattle brains of field cases of C BSE and L-BSE, and an experimental case of H-BSE, we showed its comparable sensitivities to C, L-, and H-BSE prions, and satisfactory performance required by the European Food Safety Authority. In addition to NippiBL(r), two kits (TeSeE(r) and FRELISA(r)) formerly used in Japan were effective for detection of the L-BSE prion, although the two kits were unable to be tested for the H-BSE prion due to the discontinuation of domestic sales during this study. These results indicate that BSE screening in Japan is as effective as those in other countries, and it is unlikely that cases of atypical BSE have been overlooked. PMID- 28358274 TI - Comparison of two approaches to prevention of mental health problems in college students: Enhancing coping and executive function skills. AB - OBJECTIVE: College students face a significant number of stressors, increasing risk for internalizing and externalizing psychopathology. The current study examines two promising avenues of intervention aimed to reduce stress and prevent psychopathology in this population: a coping skills group and a cognitive training program. PARTICIPANTS: 62 undergraduate students from two universities were recruited from 2013 to 2015. METHODS: Students were randomized to a 6-week coping skills group or cognitive training program and completed measures of stress, coping, executive function, and symptoms of anxiety, depression and Attention-Deficit Hyperactivity Disorder (ADHD) at pre- and post-intervention. RESULTS: Participants in both conditions reported significant decreases in social stress, executive function difficulties, and anxiety symptoms post-intervention. Students in the cognitive program improved significantly more on measures of behavior regulation and ADHD symptoms compared to the coping group at post intervention. CONCLUSIONS: Brief stress management interventions targeting coping and executive function may benefit college students at risk for psychopathology. PMID- 28358276 TI - Corrigendum. PMID- 28358275 TI - Demographic and clinical profiles of type 2 diabetes mellitus patients initiating sitagliptin in the real-world setting. AB - OBJECTIVE: Dipeptidyl peptidase-4 (DPP-4) inhibitors have been used for the management of type 2 diabetes (T2D) for over a decade; however, there is a limited understanding of the evolution of their use in the real-world setting over this time period. This study evaluated the demographics and clinical characteristics of patients initiating sitagliptin over a 10 year period in the United States. RESEARCH DESIGN AND METHODS: Quintiles electronic medical records database was used to identify adults with a new prescription of sitagliptin over two 5 year time periods: 2006-2010 (n = 57,604), and 2011-2015 (n = 147,326). In addition, we also evaluated how the most recent (year 2015) profile of sitagliptin initiators (n = 29,295) compares to the treated T2D patients (N = 474,877) in 2015. MAIN OUTCOME MEASURES: No outcomes were assessed. Descriptive statistics were used to summarize baseline patient characteristics. RESULTS: The overall demographics and clinical characteristics of patients initiating sitagliptin were generally similar over the two time periods; however, baseline HbA1c (median) was higher in the later time period: 7.6% vs. 7.9% respectively. Sitagliptin was initiated in patients across a broad range of age (18-79) years, body mass index (BMI) (10-70) kg/m2 and HbA1c (3-20) %. The most prevalent comorbidities observed in these patients were hypertension (93%), hyperlipidemia (81%), obesity (55%), chronic kidney disease (22%) and cardiovascular disease (21%). Additionally, when we assessed the treated T2D patients and patients initiating sitagliptin in 2015, several characteristics were comparable such as age (median) (64 vs. 63) years and BMI (33 vs. 33) kg/m2, and the most prevalent comorbidities were hypertension (97 vs. 95) %, and hyperlipidemia (86 vs. 81) % respectively. CONCLUSION: The overall demographic and comorbidity profile of patients initiating sitagliptin did not substantially change over the last decade and is similar to the treated T2D population. PMID- 28358277 TI - Evaluation of Head and Brain Injury Risk Functions Using Sub-Injurious Human Volunteer Data. AB - Risk assessment models are developed to estimate the probability of brain injury during head impact using mechanical response variables such as head kinematics and brain tissue deformation. Existing injury risk functions have been developed using different datasets based on human volunteer and scaled animal injury responses to impact. However, many of these functions have not been independently evaluated with respect to laboratory-controlled human response data. In this study, the specificity of 14 existing brain injury risk functions was assessed by evaluating their ability to correctly predict non-injurious response using previously conducted sled tests with well-instrumented human research volunteers. Six degrees-of-freedom head kinematics data were obtained for 335 sled tests involving subjects in frontal, lateral, and oblique sled conditions up to 16 Gs peak sled acceleration. A review of the medical reports associated with each individual test indicated no clinical diagnosis of mild or moderate brain injury in any of the cases evaluated. Kinematic-based head and brain injury risk probabilities were calculated directly from the kinematic data, while strain based risks were determined through finite element model simulation of the 335 tests. Several injury risk functions substantially over predict the likelihood of concussion and diffuse axonal injury; proposed maximum principal strain-based injury risk functions predicted nearly 80 concussions and 14 cases of severe diffuse axonal injury out of the 335 non-injurious cases. This work is an important first step in assessing the efficacy of existing brain risk functions and highlights the need for more predictive injury assessment models. PMID- 28358278 TI - Sleep Disorders and Therapeutic Management: A Survey in a French Population of Prisoners. AB - In a French prison, most inmates reported not being satisfied with their sleep. Life habits between good and bad sleepers were not significantly different except for television and smoking. The most frequently reported symptom of insomnia was several awakenings at night, and the most frequently cited etiologies were rumination of thoughts and noise. Most patients reported that their sleeping problems began or worsened after incarceration. A quarter of the inmates were following a hypnotic treatment, and most of these treatments began in prison. Only 42% of patients were satisfied with its effectiveness. These observations enabled us to make recommendations for healthy sleep patterns such as respecting normal night-and-day cycles, encouraging to stop smoking, and promoting appropriate use of hypnotic treatments. PMID- 28358279 TI - Incidence of late onset neutropenia associated with rituximab use in B cell lymphoma patients undergoing autologous stem cell transplantation. AB - Reversible late onset neutropenia associated with rituximab has been reported with incidence rates varying from 15 to 70% in B cell lymphoma patients receiving autologous stem cell transplantation. We conducted a retrospective descriptive study at one tertiary care center in adult B cell lymphoma patients treated with rituximab and autologous stem cell transplantation between 1 January 2004 and 30 June 2014. Late onset neutropenia was defined as an absolute neutrophil count <1.0 * 109 cells/L after neutrophil engraftment and less than six months post autologous stem cell transplantation. The primary objective was to determine the incidence of late onset neutropenia. The secondary objectives were to examine whether the use of rituximab with re-induction therapy, mobilization or high dose chemotherapy regimens increased the risk for late onset neutropenia, and to evaluate infectious complications. Of 315 subjects, 92 (29.2%) developed late onset neutropenia. Mobilization regimens containing rituximab (OR 2.90 95% CI: 1.31-6.40), high dose chemotherapy containing rituximab (OR 1.87 95% CI: 1.14 3.05), and exposure to rituximab in either or both regimens (OR 3.05 95% CI: 1.36 6.88) significantly increased the risk of late onset neutropenia. While neutropenic, 17.4% experienced an infection, 7.6% experienced febrile neutropenia, and 5.4% were hospitalized. In conclusion, rituximab with mobilization or high dose chemotherapy may increase the risk of late onset neutropenia post autologous stem cell transplantation. PMID- 28358280 TI - * Comparison of Autologous, Allogeneic, and Cell-Free Scaffold Approaches for Engineered Tendon Repair in a Rabbit Model-A Pilot Study. AB - Tendons are subjected to high strength dynamic mechanical forces in vivo. Mechanical strength is an essential requirement for tendon scaffold materials. A composite scaffold was used in this study to provide mechanical strength, which was composed of an inter part of nonwoven polyglycolic acid (PGA) fibers and an outer part of the net knitted with PGA and polylactic acid (PLA) fibers in a ratio of 4:2. This study compared three different approaches for in vivo tendon engineering, that is, cell-free scaffold and allogeneic and autologous cell seeded scaffolds, using a rabbit Achilles tendon repair model. Dermal fibroblasts were, respectively, isolated from the dermis of regular rabbits or green fluorescence protein transgenic rabbits as the autologous and the allogeneic cell sources, respectively. The cell scaffolds and cell-free scaffolds were implanted to bridge a partial segmental defect of rabbit Achilles tendon. The engineered tendons were harvested at 7 and 13 months postsurgery for various examinations. The results showed that all three groups could achieve in vivo tendon regeneration similarly with slightly better tissue formation in autologous group than in other two groups, including better scaffold degradation and relatively thicker collagen fibrils. There were no statistically significant differences in mechanical parameters among three groups. This work demonstrated that allogeneic fibroblasts and scaffold alone are likely to be used for tendon tissue engineering. PMID- 28358283 TI - Characterization of a thermo-alkali-stable laccase from Bacillus subtilis cjp3 and its application in dyes decolorization. AB - In this work, a novel bacterial strain exhibiting laccase activity was isolated from black liquor and identified as Bacillus subtilis cjp3. The CotA-laccase gene was cloned from strain cjp3 and expressed in Escherichia coli. The purified recombinant laccase has a maximum activity of 7320 U/L, maintaining high stabilities under a wide pH range and high temperature conditions. Nearly no loss of laccase activity was observed even at pH 9.0 after 10 h of incubation. Reactive blue 19, reactive black 5 and indigo carmine could be efficiently decolorized by the purified laccase in the presence of a mediator ABTS. More than 86% of tested dyes were removed in 4 h at pH = 9.0. The recombinant laccase can work well in a broad range of temperatures of 20-80 degrees C(>80% relative activity). These special properties indicated the potential use of the CotA laccase in treating wastewater containing synthetic dyes. PMID- 28358282 TI - Efficacy of a film-forming medical device containing sunscreen (50+) and piroxicam 0.8% in actinic keratosis and field cancerization: a multicenter, assessor-blinded, 3 month trial. AB - INTRODUCTION: Sunscreen protection in subjects with actinic keratosis (AK) is highly recommended to prevent clinical evolution of this in situ skin cancer condition. Use of topical anti-cyclooxygenase drugs such as diclofenac and piroxicam reduces the number of lesions and improves the cancerization field. A film-forming medical device in a cream formulation containing organic and inorganic sun-filters (50+ SPF) and piroxicam 0.8% (ACTX) has shown in a pilot, single-center, open trial to reduce AK lesions improving the cancerization field. AIM: We evaluated in a multicenter, assessor-blinded, 3 month trial the efficacy of ACTX in AK. METHODS: A total of 70 subjects with at least three AK lesions on the scalp or face were enrolled after written informed consent. Primary outcomes of the study were the clinical evolution of number of AK lesions on a target zone area and the evolution of dermoscopy features of the target lesion, assessing erythema, scaling, pigmentation, and follicular plug, using a 5 point score (from 0 to 4; maximum score: 16). Lesion count and dermoscopy score were evaluated in a blind fashion assessing digital color high definition coded images. A secondary outcome was the Investigator Global Score (IGS) of clinical evolution of the target area using a 7 point scale from -2 (significantly worse) to +4 (completely cured). IGS was evaluated in an open fashion. Subjects were instructed to apply the cream twice daily on the target area, using one finger-tip unit for the treatment of a 35 cm2 area. RESULTS: All but one subject (40 men and 30 women, mean age 73 years) concluded the study period. At baseline the mean (+/-SD) number of AK lesions in the target area were 7.0 (5.9) with a median value of 5 and the dermoscopy score of the target lesion was 7.0 (2.3) with a median value of 7.0. ACTX treatment reduced AK lesions to 3.2 (2.9), (p = .0001; Wilcoxon Test), representing a 55% relative reduction. Dermoscopy score was reduced to 3.3 (2.6) (p = .0001) (a reduction of 53%). The IGS after ACTX treatment was +1.9 (1.1), with a median of 2.0. A total of 86% of subjects showed a clinical improvement of IGS (>=1) with a very significant/complete clearance (score +3 or +4) in 42% subjects. No change or a worsening of AK lesions was observed in 14% of the subjects. The product was well tolerated. No serious adverse events were reported during the duration of the trial. CONCLUSION: In this multicenter, assessor-blinded trial, the use of a film-forming medical device with sun protection and anti-inflammatory actions was effective in reducing AK lesions and improving the dermoscopy aspect of the target lesion in 86% of treated subjects. A head-to-head trial evaluating the efficacy of this medical device in comparison with diclofenac is warranted to establish whether this therapeutic approach could offer additional advantages in term of AK lesion reduction compared to an established topical treatment. (Trial ID: ISRCTN72020277). PMID- 28358284 TI - Molecular Cloning of Porcine SUN5 Gene and Association between a SNP with Litter Size Trait. AB - SUN domain-containing protein 5 (SUN5) is an important reproduction related gene. In this study, we cloned the full-length coding sequence of porcine SUN5 gene through RT-PCR. Sequence analysis of this gene revealed that the pig SUN5 gene encodes a protein of 383 amino acids that has high homology with the SUN5 protein of eight species: wild Bactrian camel (95%), alpaca (95%), Yangtze River dolphin (94%), sperm whale (94%), sheep (93%), black flying fox (93%), goat (92%), and horse (91%). This gene is structured into 13 exons and 12 introns as revealed by computer-assisted analysis. The prediction of transmembrane helices showed that pig SUN5 protein might be a transmembrane protein. PCR-Taq I-RFLP was established to detect the GU475008:c.138 G>A substitution of porcine SUN5 gene coding sequence and eight pig breeds displayed obvious genotype and allele frequency differences at this mutation locus. Association of this SNP with litter size traits was assessed in Large White (n = 200) and Landrace (n = 200) pig populations, and the results demonstrated that this polymorphic locus was significantly associated with the litter size of all parities in Large White and Landrace sows (P < 0.05). Therefore, the SUN5 gene could be a useful candidate gene for increasing the litter size in pigs. PMID- 28358285 TI - External apical root resorption concurrent with orthodontic forces: the genetic influence. AB - Root resorption is a pathological process of multifactorial origin related to the permanent loss of dental root structure in response to a mechanical, inflammatory, autoimmune or infectious stimulus. External apical root resorption (EARR) is a frequent clinical complication secondary to orthodontic tooth movement; apart from variables related to treatment, environmental factors and/or interindividual genetic variations can confer susceptibility or resistance to its occurrence. In this context, genetic predisposition has been described as an etiological factor, together with mechanical factors derived from orthodontic treatment. In recent years, international research groups have determined the degree of influence of some genetic biomarkers in defining increased/reduced susceptibility to postorthodontic EARR. The influences of the IL1 gene cluster (IL1B, IL1A, IL1RN, IL6), P2RX7, CASP1, OPG (TNFRSF11B), RANK (TNFRSF11A), Osteopontin (OPN), TNFalpha, the vitamin D receptor (TaqI), TNSALP and IRAK1 have been analyzed. The objective of the present review study was to compile and analyze the latest information about the genetic background predisposing to EARR during orthodontic treatment. Genetics-based studies along with other basic science research in the field might help to clarify the exact nature of EARR, the influence of genetic inheritance and possibly lead to the prevention or even eradication of this phenomenon during orthodontic treatment. PMID- 28358273 TI - New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets. AB - Colorectal cancer (CRC), despite numerous therapeutic and screening attempts, still remains a major life-threatening malignancy. CRC etiology entails both genetic and environmental factors. Macroautophagy/autophagy and the unfolded protein response (UPR) are fundamental mechanisms involved in the regulation of cellular responses to environmental and genetic stresses. Both pathways are interconnected and regulate cellular responses to apoptotic stimuli. In this review, we address the epidemiology and risk factors of CRC, including genetic mutations leading to the occurrence of the disease. Next, we discuss mutations of genes related to autophagy and the UPR in CRC. Then, we discuss how autophagy and the UPR are involved in the regulation of CRC and how they associate with obesity and inflammatory responses in CRC. Finally, we provide perspectives for the modulation of autophagy and the UPR as new therapeutic options for CRC treatment. PMID- 28358281 TI - DNA methylation aberrancies as a guide for surveillance and treatment of human cancers. AB - DNA methylation aberrancies are hallmarks of human cancers and are characterized by global DNA hypomethylation of repetitive elements and non-CpG rich regions concomitant with locus-specific DNA hypermethylation. DNA methylation changes may result in altered gene expression profiles, most notably the silencing of tumor suppressors, microRNAs, endogenous retorviruses and tumor antigens due to promoter DNA hypermethylation, as well as oncogene upregulation due to gene-body DNA hypermethylation. Here, we review DNA methylation aberrancies in human cancers, their use in cancer surveillance and the interplay between DNA methylation and histone modifications in gene regulation. We also summarize DNA methylation inhibitors and their therapeutic effects in cancer treatment. In this context, we describe the integration of DNA methylation inhibitors with conventional chemotherapies, DNA repair inhibitors and immune-based therapies, to bring the epigenome closer to its normal state and increase sensitivity to other therapeutic agents to improve patient outcome and survival. PMID- 28358286 TI - Association of cytokines polymorphisms with chronic peridontitis and rheumatoid arthritis in a Mexican population. AB - OBJECTIVE: Historically, it has been shown that rheumatoid arthritis (RA) and periodontitis (PE) share pathophysiological similarities and possibly a genetic background. In order to elucidate the genetic background between both diseases, we evaluated the distributions of five SNPs genotypes and all the possible haplotypes composed in subjects with isolated RA, PE, combined diseases and healthy controls. MATERIALS AND METHODS: The study population consisted of 280 Mexican subjects. Genomic DNA was isolated from buccal epithelial cells collected by cheek scrapings and analyzed for the determination of the following SNPs: IL 1alpha + 4845 (rs17561), IL-1alpha -889 (rs1800587), IL-1beta + 3954 (rs1143634), IL-1beta -511(rs16944) and TNF-alpha -308 (rs1800629). RESULTS: After adjustment for age, sex and smoking status, multiple logistic regression analysis revealed a no significant association in the genotype frequencies of TNF-alpha -308 and IL 1alpha + 4845 SNPs. Otherwise a significant association was observed in IL-1beta + 3954 and IL-1beta -511 (p < 0.05) while IL-1alpha -889 was of borderline statistical significance (p = 0.054). Also, we found three negative associated haplotypes with PE: IL-1alpha + 4845 G/IL-1beta -511 A, IL-1beta + 3954 C/IL 1beta -511 A and interestingly IL-1alpha -889 C/IL-1beta -511 A also with a positive association with RA. CONCLUSIONS: Some genotypes and haplotypes are associated with the diseases. But it seems that the genetic background of the association between RA and PE needs to be explored deeper. PMID- 28358287 TI - Follow-up of children's oral health-related quality of life after dental general anaesthesia treatment. AB - OBJECTIVE: Our aim was to analyze longitudinally the impact of young children's dental general anaesthesia (DGA) treatment on their OHRQoL and to determine their post-operative oral health status at the six-month follow-up together with parental ratings of their children's oral health. MATERIAL AND METHODS: We conducted a prospective follow-up study of OHRQoL among Lithuanian child patients treated under general anaesthesia (n = 144). The study consisted of clinical dental examinations performed by two examiners at the time of DGA and at the six month recall, along with OHRQoL surveys and data collected from the patients' files. The dmft index and Silness-Loe plaque index served as clinical measures. The survey tool for assessing the children's OHRQoL was the previously tested Lithuanian version of the ECOHIS. The Wilcoxon signed-rank test served for the statistical analysis (p < 0.05). RESULTS: The ECOHIS scores clearly decreased post-operatively, indicating a significant (p < 0.001) improvement in the children's OHRQoL after the DGA treatment. The ECOHIS scores were lower immediately after the DGA treatment and remained low at the six-month recall. Parents rated their child's oral health as higher after the DGA treatment (p < 0.001). The majority (75%) of the patients had poor or satisfactory oral hygiene at follow-up. CONCLUSIONS: This longitudinal study showed a sustained improvement in the children's OHRQoL six months after their DGA treatment. Post-operative parental ratings of their child's oral health were higher after the DGA treatment, but the children exhibited insufficient oral hygiene and new caries lesions. An appropriate follow-up system for children receiving DGA treatment with special focus on preventive care is needed. PMID- 28358289 TI - Effect of local hIL-10 gene therapy on experimental periodontitis in ovariectomized rats. AB - OBJECTIVE: To investigate the effect of local hIL-10 gene therapy on experimental periodontitis in rats and to elucidate the mechanism underlying this effect. MATERIAL AND METHODS: Experimental periodontitis was induced in ovariectomized (OVX) rats using a silk ligature. We then injected 5 MUg of hIL-10 plasmid with 5 MUl of liposomes or 5 MUg of vector plasmid with 5 MUl of liposomes into the palatal side of the gingival mucosa of the upper left second molar once every two days. The rats were killed 48 hours after the seventh injection. The body weight; bone mineral density of the whole body, pelvis and spine; resorption of the alveolar bone; and number of cytokine-positive cells were measured to determine the effects of hIL-10 on the periodontal tissue. RESULTS: hIL-10 was expressed in periodontal tissues after local gene delivery. The expressed hIL-10 protein inhibited alveolar bone resorption and downregulated IL-1beta, IL-6, TNF-alpha, RANKL and MMP-8 in the periodontal ligament in the root furcation region. CONCLUSIONS: Local hIL-10 gene transfer suppressed alveolar bone resorption in OVX rats, and this effect was probably associated with the decline in the expression of pro-inflammatory cytokines in the periodontal tissues. PMID- 28358288 TI - Profile of orofacial dysfunction in Brazilian children using the Nordic Orofacial Test-Screening. AB - OBJECTIVE: The parameters of orofacial dysfunction (OFD) in children can guide clinicians and researchers in the monitoring of deviations from normality. The aim for this study was to evaluate manifestation patterns and the prevalence of OFD in children. MATERIALS AND METHODS: A population-based cross-sectional study was conducted involving 531 schoolchildren (8-10 years old) in a small city in southern Brazil. OFD was evaluated using the Nordic Orofacial Test-Screening (NOT S). Poisson multiple regression analysis with robust variance was used to estimate adjusted NOT-S rate ratios (ratio of arithmetic means) among the different categories of covariables and their respective 95% confidence interval (RR: 95%CI). RESULTS: The mean NOT-S score was 2.1 (SD 1.4, median: 2.0; range: 0 8). The majority of children (87.6%) had at least one domain of the scale affected. The most affected were Chewing and Swallowing (50.5%), Habits (41.4%) and Breathing (26.4%). NOT-S scores were lower among children from higher income families (RR = 0.73; 95% CI: 0.61-0.87) and higher among those with difficulty regarding access to dental services (RR = 1.14; 95% CI: 1.01-1.28), those with sleep bruxism (RR = 1.18; 95% CI: 1.04-1.32) and those with open bite (RR = 1.65; 95% CI: 1.42-1.93). CONCLUSIONS: The prevalence of OFD was high and both socioeconomic and clinical factors exerted an influence on NOT-S scores. PMID- 28358290 TI - Adsorption of selected emerging contaminants onto PAC and GAC: Equilibrium isotherms, kinetics, and effect of the water matrix. AB - The removal of three emerging contaminants (ECs) (amitriptyline hydrochloride (AH), methyl salicylate (MS) and 2-phenoxyethanol (PE)) dissolved in several water matrices by means of their adsorption onto powdered activated carbon (PAC) and granular activated carbon (GAC) has been investigated. When dissolved in ultrapure water, adsorption of the ECs followed the trend of AH > MS > PE, with a positive effect of the adsorbent dose. According to the analysis of the adsorption isotherms and adsorption kinetics, PAC showed strongly higher adsorption efficiency in both capacity and velocity of the adsorption, in agreement with its higher mesoporosity. Equilibrium isotherm data were fitted by Langmuir and Freundlich models. Pseudo-second order kinetics modeled very successfully the adsorption process. Finally, the effect of the presence of dissolved organic matter (DOM) in the water matrices (ultrapure water, surface water and two effluents from wastewater treatment plants) on the adsorption of the selected ECs onto PAC was established, as well as its performance on the removal of water quality parameters. Results show a negative effect of the DOM content on the adsorption efficiency. Over 50% of organic matter was removed with high PAC doses, revealing that adsorption onto PAC is an effective technology to remove both micro-pollutants and DOM from water matrices. PMID- 28358291 TI - Feasibility and utility of an integrated medical imaging and informatics smartphone system for management of acute stroke. AB - Background Rapid dissemination and coordination of clinical and imaging data among multidisciplinary team members are essential for optimal acute stroke care. Aim To characterize the feasibility and utility of the Synapse Emergency Room mobile (Synapse ERm) informatics system. Methods We implemented the Synapse ERm system for integration of clinical data, computerized tomography, magnetic resonance, and catheter angiographic imaging, and real-time stroke team communications, in consecutive acute neurovascular patients at a Comprehensive Stroke Center. Results From May 2014 to October 2014, the Synapse ERm application was used by 33 stroke team members in 84 Code Stroke alerts. Patient age was 69.6 (+/-17.1), with 41.5% female. Final diagnosis was: ischemic stroke 64.6%, transient ischemic attack 7.3%, intracerebral hemorrhage 6.1%, and cerebrovascular-mimic 22.0%. Each patient Synapse ERm record was viewed by a median of 10 (interquartile range 6-18) times by a median of 3 (interquartile range 2-4) team members. The most used feature was computerized tomography, magnetic resonance, and catheter angiography image display. In-app tweet team, communications were sent by median 1 (interquartile range 0-1, range 0-13) users per case and viewed by median 1 (interquartile range 0-3, range 0-44) team members. Use of the system was associated with rapid treatment times, faster than national guidelines, including median door-to-needle 51.0 min (interquartile range 40.5-69.5) and median door-to-groin 94.5 min (interquartile range 85.5 121.3). In user surveys, the mobile information platform was judged easy to employ in 91% (95% confidence interval 65%-99%) of uses and of added help in stroke management in 50% (95% confidence interval 22%-78%). Conclusion The Synapse ERm mobile platform for stroke team distribution and integration of clinical and imaging data was feasible to implement, showed high ease of use, and moderate perceived added utility in therapeutic management. PMID- 28358292 TI - Pulmonary exposure to metallic nanomaterials during pregnancy irreversibly impairs lung development of the offspring. AB - Due to the growing commercial applications of manufactured nanoparticles (NPs), toxicological studies on NPs, especially during the critical window of development, are of major importance. The aim of the study was to assess the impact of respiratory exposure to metallic and metal oxide NPs during pregnancy on lung development of the offspring and to determine the key parameters involved in lung alterations. Pregnant mice were exposed to weekly doses of 100 MUg (total dose 300 MUg) of titanium dioxide (TiO2), cerium oxide (CeO2), silver (Ag) NPs or saline solution by nonsurgical intratracheal instillation. The offspring lungs were analyzed at different stages of lung development: fetal stage (gestational day 17.5), pulmonary alveolarization (post-delivery day 14.5) and lung maturity (post-delivery day 49.5). Regardless of the type of NP, maternal exposure during gestation induced long-lasting impairment of lung development of the offspring. This effect was accompanied by: i) decreased placental efficiency together with the presence of NPs in placenta, ii) no increase of inflammatory mediators present in amniotic fluid, placenta or offspring lungs and iii) decreased pulmonary expression of vascular endothelial growth factor-alpha (VEGF-alpha) and matrix metalloproteinase 9 (MMP-9) at the fetal stage, and fibroblast growth factor-18 (FGF-18) at the alveolarization stage. Respiratory exposure to metallic NPs during pregnancy induces stereotyped impairment of lung development with a lasting effect in adult mice, independently of the chemical nature of the NP. PMID- 28358293 TI - OLDER AND YOUNGER ADULTS' STRATEGIC CONTROL OF METACOGNITIVE MONITORING: THE ROLE OF CONSEQUENCES, TASK EXPERIENCE, AND PRIOR KNOWLEDGE. AB - : Background/Study Context: Although explicit memory abilities decline during older adulthood, there is evidence that suggests that metacognitive capabilities are relatively well preserved. However, it is unclear what effect aging, consequences of forgetting, prior knowledge, and task experience have on the strategic control and use of one's metacognitive capabilities. METHODS: In the current study, older and younger adults were presented with six unique lists of words (Experiment 1), related and unrelated word pairs (Experiment 2), or items within specific scenarios (e.g., items to bring on a picnic; Experiment 3). For each item, participants assigned it a point value (from 0 to 10) that was akin to "betting" on the likelihood the item would be remembered. If the item was recalled (free recall in Experiments 1 and 3, cued recall in Experiment 2), participants received the points they had assigned to it, but if the item was forgotten they lost those points. Participants were told to maximize their point score and were told their score at the end of each list. RESULTS: Although younger adults remembered more words in Experiment 1, older and younger adults were equally able to remember items assigned higher values, and accuracy of predictions and point scores increased with task experience. In Experiments 2 and 3, when participants were able to rely on semantic knowledge, age-related differences in memory performance were eliminated. CONCLUSION: The results suggest that both younger and older adults achieve accurate metacognitive insight and are able to use this knowledge strategically in order to maximize goal related memory outcomes and performance. PMID- 28358294 TI - Online Modulation of Selective Attention is not Impaired in Healthy Aging. AB - : Background/Study Context: Reduced processing speed pervades a great many aspects of human aging and cognition. However, little is known about one aspect of cognitive aging in which speed is of the essence, namely, the speed with which older adults can deploy attention in response to a cue. METHODS: The authors compared rapid temporal modulation of cued visual attention in younger (Mage = 22.3 years) and older (Mage = 68.9 years) adults. On each trial of a short-term memory task, a cue identified which of two briefly presented stimuli was task relevant and which one should be ignored. After a short delay, subjects demonstrated recall by reproducing from memory the task-relevant stimulus. This produced estimates of (i) accuracy with which the task-relevant stimulus was recalled, (ii) the influence of stimuli encountered on previous trials (a prototype effect), and (iii) the influence of the trial's task-irrelevant stimulus. RESULTS: For both groups, errors in recall were considerably smaller when selective attention was cued before rather than after presentation of the stimuli. Both groups showed serial position effects to the same degree, and both seemed equally adept at exploiting the stimuli encountered on previous trials as a means of supplementing recall accuracy on the current trial. CONCLUSION: Younger and older subjects may not differ reliably in capacity for cue-directed temporal modulation of selective attention, or in ability to draw on previously seen stimuli as memory support. PMID- 28358295 TI - Body Adiposity Index, but not Visceral Adiposity Index, Correlates with Inflammatory Markers in Sarcopenic Obese Elderly Women. AB - : Background/Study Context: The association of body adiposity index (BAI) and visceral adiposity index (VAI) with inflammatory markers has yet to be understood. The aim of this work was to investigate the association of BAI and VAI with inflammatory markers in elderly women with sarcopenic obesity (SO). METHODS: A total of 130 women (age: 66.7 +/- 5.2 years) underwent body composition analysis by dual-energy x-ray absorptiometry (DEXA). Volunteers were classified according to SO definition. BAI, VAI, and waist-to-hip ratio (WHR) were calculated. Blood samples were collected for C-reactive protein (CRP), tumor necrosis factor, and interleukin-6 (IL-6) measurements. RESULTS: SO prevalence was 20.8%. BAI correlated with the DEXA-derived body fat content (rS = .90), CRP (rS = .55), and IL-6 (rS = .53), whereas WHR correlated with CRP (rS = .60) only (all p < .01). VAI did not correlate with any of the inflammatory variables. CONCLUSION: Simple and cheap anthropometric indices such as BAI and WHR may be better predictors of low-grade inflammation than VAI in elderly women with SO. PMID- 28358296 TI - Identifying Frailty and its Outcomes in Older People in Rural Tanzania. AB - : Background/Study Context: Interest in frailty is growing in low- and middle income countries, due to demographic aging and resource limitations. However, there is a paucity of data on the nature of frailty in Africa. METHODS: The study collected frailty data from people aged 70 years and over living in six villages in the rural Hai District of northern Tanzania. At baseline, a limited data set was collected for 1198 people and a more comprehensive data set for a stratified sample of 296 people. A 40-item frailty index was constructed. Data regarding mortality and dependency were collected at 3-year follow-up. RESULTS: A higher frailty index score was significantly correlated with greater age, never having attended school, falls, mortality, and dependency in activities of daily living. Logistic regression modeling revealed functional disability and cognitive function to be significant independent predictors of the outcome "mortality or dependency." CONCLUSIONS: In resource-poor settings, brief frailty screening assessments may be a useful way of identifying those most in need of support. PMID- 28358297 TI - SPATIAL UPDATING OF HAPTIC ARRAYS ACROSS THE LIFE SPAN. AB - : Background/Study Context: Aging research addressing spatial learning, representation, and action is almost exclusively based on vision as the input source. Much less is known about how spatial abilities from nonvisual inputs, particularly from haptic information, may change during life-span spatial development. This research studied whether learning and updating of haptic target configurations differs as a function of age. METHODS: Three groups of participants, ranging from 20 to 80 years old, felt four-target table-top circular arrays and then performed several tasks to assess life-span haptic spatial cognition. Measures evaluated included egocentric pointing, allocentric pointing, and array reconstruction after physical or imagined spatial updating. RESULTS: All measures revealed reliable differences between the oldest and youngest participant groups. The age effect for egocentric pointing contrasts with previous findings showing preserved egocentric spatial abilities. Error performance on allocentric pointing and map reconstruction tasks showing a clear age effect, with the oldest participants exhibiting the greatest error, is in line with other studies in the visual domain. Postupdating performance sharply declined with age but did not reliably differ between physical and imagined updating. CONCLUSION: Results suggest that there is a general trend for age related degradation of spatial abilities after haptic learning, with the greatest declines manifesting in all measures in people over 60 years of age. Results are interpreted in terms of a spatial aging effect on mental transformations of three dimensional representations of space in working memory. PMID- 28358298 TI - Confidence Moderates the Role of Control Beliefs in the Context of Age-Related Changes in Misinformation Susceptibility. AB - : Background/Study Context: The present experiment investigated the role of confidence and control beliefs in susceptibility to the misinformation effect in young and older adults. Control beliefs are perceptions about one's abilities or competence and the extent to which one can influence performance outcomes. It was predicted that level of control beliefs would influence misinformation susceptibility and overall memory confidence. METHODS: Fifty university students (ages 18-26) and 37 community-dwelling older adults (ages 62-86) were tested. Participants viewed a video, answered questions containing misinformation, and then completed a source-recognition test to determine whether the information presented was seen in the video, the questionnaire only, both, or neither. For each response, participants indicated their level of confidence. RESULTS: The relationship between control beliefs and memory performance was moderated by confidence. That is, individuals with lower control beliefs made more errors as confidence decreased. Additionally, the relationship between confidence and memory performance differed by age, with greater confidence related to more errors for young adults. CONCLUSION: Confidence is an important factor in how control beliefs and age are related to memory errors in the misinformation effect. This may have implications for the legal system, particularly with eyewitness testimony. The confidence of an individual should be considered if the eyewitness is a younger adult. PMID- 28358299 TI - Feeding schemes and C/N ratio of a laboratory-scale step-fed sequencing batch reactor for liquid swine manure treatment. AB - This study was undertaken to investigate the effect of two split feeding schemes (600 mL/200 mL and 400 mL/400 mL, designated as FS1 and FS2, respectively) on the performance of a step-fed sequencing batch reactor (SBR) in treating liquid swine manure for nutrient removal. The SBR was run on an 8-h cycle with a repeated pattern of anaerobic/anoxic/aerobic phases in each cycle and the two feedings always occurred at the beginning of each anaerobic phase. A low-level aeration was used (1.0 L/m3.sec) for the anoxic/aerobic phase to facilitate nitrification and phosphorus uptake while reducing the energy consumption. The results showed that FS1 reduced NH4+-N by 98.7% and FS2 by 98.3%. FS1 had 12.3 mg/L NO3-N left in the effluent, while FS2 had 4.51 mg/L. For soluble phosphorus removal, FS1 achieved 95.2%, while FS2 reached only 68.5%. Both feeding schemes achieved >= 95% removal of COD. A good power regression was observed between total nitrogen (sum of all three nitrogen species) and the carbon to nitrogen (C/N) ratio, with the correlation coefficients of 0.9729 and 0.9542 for FS1 and FS2, respectively, based on which it was concluded that higher C/N ratios were required to achieve higher nitrogen removal efficiencies. PMID- 28358300 TI - Localizing order to boost signaling. AB - B-cell receptors form ordered clusters to recruit kinases and exclude phosphatases. PMID- 28358302 TI - Dual-channel extraordinary ultraviolet transmission through an aluminum nanohole array. AB - Ultraviolet (UV) surface plasmon (SP) has distinct applications in UV filters, high-density optical storage, spectral enhancement, optical detectors, and nanolithography, which are closely related to plasmon-induced extraordinary optical transmission (EOT). However, such EOT in the UV region has not been the subject of detailed research. We report UV transmission based on theoretical research using the finite-difference time-domain method, by modulating the Al thickness, hole size, array periodicity, and SiO2 overlayer thickness. It is notable that we can obtain dual-channel UV transmission peaks with excellent qualities such as high transmissivity, zero cross-talk, narrow bandwidth, and perfect symmetry, by optimizing the parameters. The UV transmission peaks have been discovered to non-monotonously shift with increasing hole size. Although array periodicity has great influence on the transmission peak position, the peak energy in the UV region is much less than the value predicted by the well-known periodicity-related surface plasmon polariton (SPP) wavelength equation; the energy discrepancy in the UV region can reach above 20%, which is much larger than the value (typically 4%) in the visible-infrared region. Furthermore, the SiO2 overlayer may significantly modify the transmission properties. The Al nanohole arrays have also been found to exhibit distinct multi-band UV electric field enhancement properties with special interface effect and size effect. Such extraordinary dual-channel UV transmission with zero cross-talk, based on a very simple Al nanohole array, has promising application in dual-channel UV filters, high-density optical storage, and plasmon-enhanced fluorescence/Raman spectroscopy, which generally involves two wavebands (writing/reading storage or exciting/emission wavelengths). This study is expected to broaden our fundamental understanding of the UV EOT phenomenon, and provide references for experimental research and application of deep-UV and near-UV-related dual-band plasmonic devices. PMID- 28358301 TI - The impact of pseudophakia on vision-related quality of life in the general population - The Gutenberg Health Study. AB - Cataract surgery is the most frequently performed surgical procedure worldwide. We aim to determine the prevalence of having implanted an artificial lens (pseudophakia) and of no lens (aphakia) and to compare visual function.As part of the Gutenberg Health study, a population-based cross-sectional study was conducted in Germany. An ophthalmological examination including slit-lamp examination was conducted. Prevalence including 95% confidential intervals were calculated and analyses were conducted for systemic and ocular associated factors with pseudophakia using multivariable logistic regression models. Vision-related quality of life was assessed using a standardized questionnaire and Rasch transformation.14,696 people were included. Of these, 1.55% [1.36%-1.77%] had unilateral pseudophakia and 3.08% [2.81%-3.37%] had bilateral pseudophakia. Unilateral aphakia was present in 21 people and bilateral aphakia in 2 people. Pseudophakia was independently associated with age, higher body weight and lower body height, diabetes and smoking. Vision-related quality of life values were similar for those with bilateral phakia and pseudophakia but were lower for those with unilateral pseudophakia.The pseudophakia status is related to several cardiovascular risk factors, indicating a relationship to an aging effect that causes premature lens opacification. Bilateral pseudophakia can almost imitate the physiological condition of phakia except for the need to use glasses. PMID- 28358305 TI - Electrochemical Field-Effect Transistor Utilization to Study the Coupling Success Rate of Photosynthetic Protein Complexes to Cytochrome c. AB - Due to the high internal quantum efficiency, reaction center (RC) proteins from photosynthetic organisms have been studied in various bio-photoelectrochemical devices for solar energy harvesting. In vivo, RC and cytochrome c (cyt c; a component of the biological electron transport chain) can form a cocomplex via interprotein docking. This mechanism can be used in vitro for efficient electron transfer from an electrode to the RC in a bio-photoelectrochemical device. Hence, the success rate in coupling RCs to cyt c is of great importance for practical applications in the future. In this work, we use an electrochemical transistor to study the binding of the RC to cytochrome. The shift in the transistor threshold voltage was measured in the dark and under illumination to estimate the density of cytochrome and coupled RCs on the gate of the transistor. The results show that ~33% of the cyt cs on the transistor gate were able to effectively couple with RCs. Due to the high sensitivity of the transistor, the approach can be used to make photosensors for detecting low light intensities. PMID- 28358303 TI - A Novel Bio-Psychosocial-Behavioral Treatment Model in Schizophrenia. AB - Despite the substantial burden of illness in schizophrenia, there has been a discrepancy between the beneficial effects of an increased use of antipsychotic medications and achieving limited recovery or remission. Because the focus of the most common antipsychotic medications is on dopamine, which is associated with positive symptoms, there is an unmet need for patients with negative symptoms. Since cognitive and negative symptoms rather than positive symptoms are more closely associated with psychosocial impairments in patients with schizophrenia, the non-dopaminergic systems including glutamate and gamma-aminobutyric acid (GABA) of the prefrontal cortex should be of concern as well. The balance of excitation and inhibition has been associated with epigenetic modifications and thus can be analyzed in terms of a neurodevelopmental and neural circuitry perspective. Hence, a novel bio-psychosocial-behavioral model for the treatment of schizophrenia is needed to account for the non-dopaminergic systems involved in schizophrenia, rather than dopaminergic mechanisms. This model can be understood from the viewpoint of neurodevelopment and neural circuitry and should include the staging care, personalized care, preventive care, reducing the cognitive deficits, and reducing stigma. Thomas R. Insel proposed this as a goal for schizophrenia treatment to be achieved by 2030. PMID- 28358304 TI - Characteristic Variations and Similarities in Biochemical, Molecular, and Functional Properties of Glyoxalases across Prokaryotes and Eukaryotes. AB - The glyoxalase system is the ubiquitous pathway for the detoxification of methylglyoxal (MG) in the biological systems. It comprises two enzymes, glyoxalase I (GLYI) and glyoxalase II (GLYII), which act sequentially to convert MG into d-lactate, thereby helping living systems get rid of this otherwise cytotoxic byproduct of metabolism. In addition, a glutathione-independent GLYIII enzyme activity also exists in the biological systems that can directly convert MG to d-lactate. Humans and Escherichia coli possess a single copy of GLYI (encoding either the Ni- or Zn-dependent form) and GLYII genes, which through MG detoxification provide protection against various pathological and disease conditions. By contrast, the plant genome possesses multiple GLYI and GLYII genes with a role in abiotic stress tolerance. Plants possess both Ni2+- and Zn2+ dependent forms of GLYI, and studies on plant glyoxalases reveal the various unique features of these enzymes distinguishing them from prokaryotic and other eukaryotic glyoxalases. Through this review, we provide an overview of the plant glyoxalase family along with a comparative analysis of glyoxalases across various species, highlighting similarities as well as differences in the biochemical, molecular, and physiological properties of these enzymes. We believe that the evolution of multiple glyoxalases isoforms in plants is an important component of their robust defense strategies. PMID- 28358306 TI - Effect of the Biofilm Age and Starvation on Acid Tolerance of Biofilm Formed by Streptococcus mutans Isolated from Caries-Active and Caries-Free Adults. AB - Streptococcus mutans (S. mutans) is considered a leading cause of dental caries. The capability of S. mutans to tolerate low pH is essential for its cariogenicity. Aciduricity of S. mutans is linked to its adaptation to environmental stress in oral cavity. This study aimed to investigate the effect of biofilm age and starvation condition on acid tolerance of biofilm formed by S. mutans clinical isolates. S. mutans clinical strains isolated from caries-active (SM593) and caries-free (SM18) adults and a reference strain (ATCC25175) were used for biofilm formation. (1) Both young and mature biofilms were formed and then exposed to pH 3.0 for 30 min with (acid-adapted group) or without (non adapted group) pre-exposure to pH 5.5 for three hours. (2) The mature biofilms were cultured with phosphate-buffered saline (PBS) (starved group) or TPY (polypeptone-yeast extract) medium (non-starved group) at pH 7.0 for 24 h and then immersed in medium of pH 3.0 for 30 min. Biofilms were analyzed through viability staining and confocal laser scanning microscopy. In all three strains, mature, acid-adapted and starved biofilms showed significantly less destructive structure and more viable bacteria after acid shock than young, non-adapted and non-starved biofilms, respectively (all p < 0.05). Furthermore, in each condition, SM593 biofilm was denser, with a significantly larger number of viable bacteria than that of SM18 and ATCC25175 (all p < 0.05). Findings demonstrated that mature, acid-adapted and starvation might protect biofilms of all three S. mutans strains against acid shock. Additionally, SM593 exhibited greater aciduricity compared to SM18 and ATCC25175, which indicated that the colonization of high cariogenicity of clinical strains may lead to high caries risk in individuals. PMID- 28358308 TI - The Role of Molecular Modeling in TiO2 Photocatalysis. AB - Molecular Modeling methods play a very important role in TiO2 photocatalysis. Recent advances in TiO2 photocatalysis have produced a number of interesting surface phenomena, reaction products, and various novel visible light active photocatalysts with improved properties. Quantum mechanical calculations appear promising as a means of describing the mechanisms and the product distributions of the photocatalytic degradation reactions of organic pollutants in both gas and aqueous phases. Since quantum mechanical methods utilize the principles of particle physics, their use may be extended to the design of new photocatalysts. This review introduces molecular modeling methods briefly and emphasizes the use of these methods in TiO2 photocatalysis. The methods used for obtaining information about the degradabilities of the pollutant molecules, predicting reaction mechanisms, and evaluating the roles of the dopants and surface modifiers are explained. PMID- 28358307 TI - Marine Collagen Peptides from the Skin of Nile Tilapia (Oreochromis niloticus): Characterization and Wound Healing Evaluation. AB - Burns can cause tremendous economic problems associated with irreparable harm to patients and their families. To characterize marine collagen peptides (MCPs) from the skin of Nile tilapia (Oreochromis niloticus), molecular weight distribution and amino acid composition of MCPs were determined, and Fourier transform infrared spectroscopy (FTIR) was used to analyze the chemical structure. Meanwhile, to evaluate the wound healing activity, in vitro and in vivo experiments were carried out. The results showed that MCPs prepared from the skin of Nile tilapia by composite enzymatic hydrolysis were composed of polypeptides with different molecular weights and the contents of polypeptides with molecular weights of less than 5 kDa accounted for 99.14%. From the amino acid composition, the majority of residues, accounting for over 58% of the total residues in MCPs, were hydrophilic. FTIR indicated that the main molecular conformations inside MCPs were random coil. In vitro scratch assay showed that there were significant effects on the scratch closure by the treatment of MCPs with the concentration of 50.0 MUg/mL. In the experiments of deep partial-thickness scald wound in rabbits, MCPs could enhance the process of wound healing. Therefore, MCPs from the skin of Nile tilapia (O. niloticus) have promising applications in wound care. PMID- 28358310 TI - Intestinal Transport Characteristics and Metabolism of C-Glucosyl Dihydrochalcone, Aspalathin. AB - Insight into the mechanisms of intestinal transport and metabolism of aspalathin will provide important information for dose optimisation, in particular for studies using mouse models. Aspalathin transportation across the intestinal barrier (Caco-2 monolayer) tested at 1-150 uM had an apparent rate of permeability (Papp) typical of poorly absorbed compounds (1.73 * 10-6 cm/s). Major glucose transporters, sodium glucose linked transporter 1 (SGLT1) and glucose transporter 2 (GLUT2), and efflux protein (P-glycoprotein, PgP) (1.84 * 10-6 cm/s; efflux ratio: 1.1) were excluded as primary transporters, since the Papp of aspalathin was not affected by the presence of specific inhibitors. The Papp of aspalathin was also not affected by constituents of aspalathin-enriched rooibos extracts, but was affected by high glucose concentration (20.5 mM), which decreased the Papp value to 2.9 * 10-7 cm/s. Aspalathin metabolites (sulphated, glucuronidated and methylated) were found in mouse urine, but not in blood, following an oral dose of 50 mg/kg body weight of the pure compound. Sulphates were the predominant metabolites. These findings suggest that aspalathin is absorbed and metabolised in mice to mostly sulphate conjugates detected in urine. Mechanistically, we showed that aspalathin is not actively transported by the glucose transporters, but presumably passes the monolayer paracellularly. PMID- 28358309 TI - Zerumbone Alleviates Neuropathic Pain through the Involvement of l-Arginine Nitric Oxide-cGMP-K+ ATP Channel Pathways in Chronic Constriction Injury in Mice Model. AB - The present study investigates the involvement of the l-arginine-Nitric Oxide cGMP-K+ ATP pathways responsible for the action of anti-allodynic and antihyperalgesic activities of zerumbone in chronic constriction injury (CCI) induced neuropathic pain in mice. The role of l-arginine-NO-cGMP-K+ was assessed by the von Frey and the Randall-Selitto tests. Both allodynia and hyperalgesia assessments were carried out on the 14th day post CCI, 30 min after treatments were given for each respective pathway. Anti-allodynic and antihyperalgesic effects of zerumbone (10 mg/kg, i.p) were significantly reversed by the pre treatment of l-arginine (10 mg/kg), 1H [1,2,4]Oxadiazole[4,3a]quinoxalin-1-one (ODQ), a soluble guanosyl cyclase blocker (2 mg/kg i.p.) and glibenclamide (ATP sensitive potassium channel blocker) (10 mg/kg i.p.) (p < 0.05). Taken together, these results indicate that systemic administration of zerumbone produces significant anti-allodynic and antihyperalgesic activities in neuropathic pain in mice possibly due to involvement of the l-arginine-NO-cGMP-PKG-K+ ATP channel pathways in CCI model. PMID- 28358312 TI - Chemical Synthesis and Characterization of an Equinatoxin II(1-85) Analogue. AB - The chemical synthesis of an 85 residue analogue of the pore-forming protein, Equinatoxin II (EqtII), was achieved. Peptide precursors with over 40 residues were assembled by solid phase synthesis. The EqtII(1-46) fragment was modified to the reactive C-terminal thioester and native chemical ligation was performed with the A47C mutated EqtII(47-85) peptide to form the EqtII(1-85) analogue. Circular dichroism spectroscopy indicated that the N-terminal domain of EqtII(1-46) and EqtII(1-85) maintains predominantly an alpha-helical structure in solution and also in the presence of lipid micelles. This demonstrates the feasibility of assembling the full 179 residue protein EqtII via chemical means. Site-specific isotopic labels could be incorporated for structural studies in membranes by solid-state NMR spectroscopy. PMID- 28358311 TI - Targeting TNF and TNF Receptor Pathway in HIV-1 Infection: from Immune Activation to Viral Reservoirs. AB - Several cellular functions such as apoptosis, cellular proliferation, inflammation, and immune regulation involve the tumor necrosis factor-alpha (TNF)/TNF receptor (TNFR) pathway. Human immunodeficiency virus 1 (HIV-1) interacts with the TNF/TNFR pathway. The activation of the TNF/TNFR pathway impacts HIV-1 replication, and the TNF/TNFR pathway is the target of HIV-1 proteins. A hallmark of HIV-1 infection is immune activation and inflammation with increased levels of TNF in the plasma and the tissues. Therefore, the control of the TNF/TNFR pathway by new therapeutic approaches could participate in the control of immune activation and impact both viral replication and viral persistence. In this review, we will describe the intricate interplay between HIV 1 proteins and TNF/TNFR signaling and how TNF/TNFR activation modulates HIV-1 replication and discuss new therapeutic approaches, especially anti-TNF therapy, that could control this pathway and ultimately favor the clearance of infected cells to cure HIV-infected patients. PMID- 28358313 TI - Identification of Novel A2/C2 Inter-Genotype Recombinants of Hepatitis B Virus from a Korean Chronic Patient Co-Infected with Both Genotype A2 and C2. AB - Nearly all cases of Hepatitis B virus (HBV) infections in South Korea have the C2 genotype. Here, we have identified a chronically infected patient who was co infected with HBV of both the A2 and C2 genotypes by screening 135 Korean chronically infected patients using direct sequencing protocols targeting the 1032-bp polymerase reverse transcriptase (RT) region. Further polymerase chain reaction (PCR)-cloning analysis (22 clones) of the RT showed that this patient had genotype C2 (12 clones), genotype A2 (six clones) and A2/C2 inter-genotype HBV recombinants (four clones). BootScan analysis showed that three of the four recombinants have different types of recombination breakpoints in both the RT and overlapping hepatitis B surface antigen (HBsAg) region. Given the significance of HBsAg as a diagnostic or vaccination target against HBV infection, clinical implications of these identified recombinants should be studied in the future. To our knowledge, this is the first report on A2/C2 inter-genotype HBV recombinants. PMID- 28358314 TI - Oxidative Stress-Induced Afterdepolarizations and Protein Kinase C Signaling. AB - BACKGROUND: Hydrogen peroxide (H2O2)-induced oxidative stress has been demonstrated to induce afterdepolarizations and triggered activities in isolated myocytes, but the underlying mechanisms remain not fully understood. We aimed to explore whether protein kinase C (PKC) activation plays an important role in oxidative stress-induced afterdepolarizations. METHODS: Action potentials and ion currents of isolated rabbit cardiomyocytes were recorded using the patch clamp technique. H2O2 (1 mM) was perfused to induce oxidative stress and the specific classical PKC inhibitor, Go 6983 (1 MUM), was applied to test the involvement of PKC. RESULTS: H2O2 perfusion prolonged the action potential duration and induced afterdepolarizations. Pretreatment with Go 6983 prevented the emergence of H2O2 induced afterdepolarizations. Additional application of Go 6983 with H2O2 effectively suppressed H2O2-induced afterdepolarizations. H2O2 increased the late sodium current (INa,L) (n = 7, p < 0.01) and the L-type calcium current (ICa,L) (n = 5, p < 0.01), which were significantly reversed by Go 6983 (p < 0.01). H2O2 also increased the transient outward potassium current (Ito) (n = 6, p < 0.05). However, Go 6983 showed little effect on H2O2-induced enhancement of Ito. CONCLUSIONS: H2O2 induced afterdepolarizations via the activation of PKC and the enhancement of ICa,L and INa,L. These results provide evidence of a link between oxidative stress, PKC activation and afterdepolarizations. PMID- 28358315 TI - Sample Preparation Strategies for the Effective Quantitation of Hydrophilic Metabolites in Serum by Multi-Targeted HILIC-MS/MS. AB - The effect of endogenous interferences of serum in multi-targeted metabolite profiling HILIC-MS/MS analysis was investigated by studying different sample preparation procedures. A modified QuEChERS dispersive SPE protocol, a HybridSPE protocol, and a combination of liquid extraction with protein precipitation were compared to a simple protein precipitation. Evaluation of extraction efficiency and sample clean-up was performed for all methods. SPE sorbent materials tested were found to retain hydrophilic analytes together with endogenous interferences, thus additional elution steps were needed. Liquid extraction was not shown to minimise matrix effects. In general, it was observed that a balance should be reached in terms of recovery, efficient clean-up, and sample treatment time when a wide range of metabolites are analysed. A quick step for removing phospholipids prior to the determination of hydrophilic endogenous metabolites is required, however, based on the results from the applied methods, further studies are needed to achieve high recoveries for all metabolites. PMID- 28358319 TI - Effective Subcritical Butane Extraction of Bifenthrin Residue in Black Tea. AB - As a natural and healthy beverage, tea is widely enjoyed; however, the pesticide residues in tea leaves affect the quality and food safety. To develop a highly selective and efficient method for the facile removal of pesticide residues, the subcritical butane extraction (SBE) technique was employed, and three variables involving temperature, time and extraction cycles were studied. The optimum SBE conditions were found to be as follows: extraction temperature 45 degrees C, extraction time 30 min, number of extraction cycles 1, and in such a condition that the extraction efficiency reached as high as 92%. Further, the catechins, theanine, caffeine and aroma components, which determine the quality of the tea, fluctuated after SBE treatment. Compared with the uncrushed leaves, pesticide residues can more easily be removed from crushed leaves, and the practical extraction efficiency was 97%. These results indicate that SBE is a useful method to efficiently remove the bifenthrin, and as appearance is not relevant in the production process, tea leaves should first be crushed and then extracted in order that residual pesticides are thoroughly removed. PMID- 28358318 TI - Simultaneous Detection of Both RNA and DNA Viruses Infecting Dry Bean and Occurrence of Mixed Infections by BGYMV, BCMV and BCMNV in the Central-West Region of Mexico. AB - A multiplex reverse transcription polymerase chain reaction (RT-PCR) assay was developed to simultaneously detect bean common mosaic virus (BCMV), bean common mosaic necrotic virus (BCMNV), and bean golden yellow mosaic virus (BGYMV) from common bean leaves dried with silica gel using a single total nucleic acid extraction cetyl trimethyl ammonium bromide (CTAB) method. A mixture of five specific primers was used to amplify three distinct fragments corresponding to 272 bp from the AC1 gene of BGYMV as well as 469 bp and 746 bp from the CP gene of BCMV and BCMNV, respectively. The three viruses were detected in a single plant or in a bulk of five plants. The multiplex RT-PCR was successfully applied to detect these three viruses from 187 field samples collected from 23 municipalities from the states of Guanajuato, Nayarit and Jalisco, Mexico. Rates of single infections were 14/187 (7.5%), 41/187 (21.9%), and 35/187 (18.7%), for BGYMV, BCMV, and BCMNV, respectively; 29/187 (15.5%) samples were co-infected with two of these viruses and 10/187 (5.3%) with the three viruses. This multiplex RT-PCR assay is a simple, rapid, sensitive, and cost-effective method for detecting these viruses in the common bean and can be used for routine molecular diagnosis and epidemiological studies. PMID- 28358320 TI - From Marine Venoms to Drugs: Efficiently Supported by a Combination of Transcriptomics and Proteomics. AB - The potential of marine natural products to become new drugs is vast; however, research is still in its infancy. The chemical and biological diversity of marine toxins is immeasurable and as such an extraordinary resource for the discovery of new drugs. With the rapid development of next-generation sequencing (NGS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), it has been much easier and faster to identify more toxins and predict their functions with bioinformatics pipelines, which pave the way for novel drug developments. Here we provide an overview of related bioinformatics pipelines that have been supported by a combination of transcriptomics and proteomics for identification and function prediction of novel marine toxins. PMID- 28358317 TI - The MYCN Protein in Health and Disease. AB - MYCN is a member of the MYC family of proto-oncogenes. It encodes a transcription factor, MYCN, involved in the control of fundamental processes during embryonal development. The MYCN protein is situated downstream of several signaling pathways promoting cell growth, proliferation and metabolism of progenitor cells in different developing organs and tissues. Conversely, deregulated MYCN signaling supports the development of several different tumors, mainly with a childhood onset, including neuroblastoma, medulloblastoma, rhabdomyosarcoma and Wilms' tumor, but it is also associated with some cancers occurring during adulthood such as prostate and lung cancer. In neuroblastoma, MYCN-amplification is the most consistent genetic aberration associated with poor prognosis and treatment failure. Targeting MYCN has been proposed as a therapeutic strategy for the treatment of these tumors and great efforts have allowed the development of direct and indirect MYCN inhibitors with potential clinical use. PMID- 28358321 TI - The Influence of Tetrodotoxin (TTX) on the Distribution and Chemical Coding of Caudal Mesenteric Ganglion (CaMG) Neurons Supplying the Porcine Urinary Bladder. AB - The treatment of micturition disorders creates a serious problem for urologists. Recently, new therapeutic agents, such as neurotoxins, are being considered for the therapy of urological patients. The present study investigated the chemical coding of caudal mesenteric ganglion (CaMG) neurons supplying the porcine urinary bladder after intravesical instillation of tetrodotoxin (TTX). The CaMG neurons were visualized with retrograde tracer Fast blue (FB) and their chemical profile was disclosed with double-labeling immunohistochemistry using antibodies against tyrosine hydroxylase (TH), neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), somatostatin (SOM), calbindin (CB), galanin (GAL) and neuronal nitric oxide synthase (nNOS). It was found that in both the control (n = 6) and TTX-treated pigs (n = 6), the vast majority (92.6% +/- 3.4% and 88.8% +/- 2%, respectively) of FB-positive (FB+) nerve cells were TH+. TTX instillation caused a decrease in the number of FB+/TH+ neurons immunopositive to NPY (88.9% +/- 5.3% in the control animals vs. 10.6% +/- 5.3% in TTX-treated pigs) or VIP (1.7% +/- 0.6% vs. 0%), and an increase in the number of FB+/TH+ neurons immunoreactive to SOM (8.8% +/- 1.6% vs. 39% +/- 12.8%), CB (1.8% +/- 0.7% vs. 12.6% +/- 2.7%), GAL (1.7% +/- 0.8% vs. 10.9% +/- 2.6%) or nNOS (0% vs. 1.1% +/- 0.3%). The present study is the first to suggest that TTX modifies the chemical coding of CaMG neurons supplying the porcine urinary bladder. PMID- 28358322 TI - Development of TRPM8 Antagonists to Treat Chronic Pain and Migraine. AB - A review. Development of pharmaceutical antagonists of transient receptor potential melastatin 8 (TRPM8) have been pursued for the treatment of chronic pain and migraine. This review focuses on the current state of this progress. PMID- 28358323 TI - Identification of a Ribose-Phosphate Pyrophosphokinase that Can Interact In Vivo with the Anaphase Promoting Complex/Cyclosome. AB - 5-Phospho-d-ribosyl-1-diphosphate (PRPP) synthase (PRS) catalyzes the biosynthesis of PRPP, which is an important compound of metabolism in most organisms. However, no PRS genes have been cloned, let alone studied for their biological function in rubber tree. In this study, we identify a novel protein (PRS4) that interacts in vivo with rubber tree anaphase promoting complex/cyclosome (APC/C) subunit 10 (HbAPC10) by yeast two-hybrid assays. PRS4 has been cloned from rubber tree and named as HbPRS4. Blastp search in the genome of Arabidopsis thaliana showed that HbPRS4 shared the highest similarity with AtPRS4, with 80.71% identity. qRT-PCR was used to determine the expression of HbPRS4 in different tissues and under various treatments. HbPRS4 was preferentially expressed in the bark. Moreover, the expression level of HbPRS4 was significantly induced by the proteasome inhibitor MG132 treatment, suggesting it might be regulated by the ubiquitin/26S proteasome pathway. The amount of HbPRS4 transcript was obviously decreased after mechanical wounding and abscisic acid (ABA) treatments, while a slight increase was observed at 24 h after ABA treatment. HbPRS4 transcript in the latex was significantly upregulated by ethephon (ET) and methyl jasmonate (MeJA) treatments. These results suggested that HbPRS4 may be a specific substrate of HbAPC10 indirectly regulating natural rubber biosynthesis in rubber tree. PMID- 28358316 TI - Theranostic Biomarkers for Schizophrenia. AB - Schizophrenia is a highly heritable, chronic, severe, disabling neurodevelopmental brain disorder with a heterogeneous genetic and neurobiological background, which is still poorly understood. To allow better diagnostic procedures and therapeutic strategies in schizophrenia patients, use of easy accessible biomarkers is suggested. The most frequently used biomarkers in schizophrenia are those associated with the neuroimmune and neuroendocrine system, metabolism, different neurotransmitter systems and neurotrophic factors. However, there are still no validated and reliable biomarkers in clinical use for schizophrenia. This review will address potential biomarkers in schizophrenia. It will discuss biomarkers in schizophrenia and propose the use of specific blood based panels that will include a set of markers associated with immune processes, metabolic disorders, and neuroendocrine/neurotrophin/neurotransmitter alterations. The combination of different markers, or complex multi-marker panels, might help in the discrimination of patients with different underlying pathologies and in the better classification of the more homogenous groups. Therefore, the development of the diagnostic, prognostic and theranostic biomarkers is an urgent and an unmet need in psychiatry, with the aim of improving diagnosis, therapy monitoring, prediction of treatment outcome and focus on the personal medicine approach in order to improve the quality of life in patients with schizophrenia and decrease health costs worldwide. PMID- 28358324 TI - Anti-Inflammatory Effect of Titrated Extract of Centella asiatica in Phthalic Anhydride-Induced Allergic Dermatitis Animal Model. AB - Centella asiatica has potent antioxidant and anti-inflammatory properties. However, its anti-dermatitic effect has not yet been reported. In this study, we investigated the anti-dermatitic effects of titrated extract of Centella asiatica (TECA) in a phthalic anhydride (PA)-induced atopic dermatitis (AD) animal model as well as in vitro model. An AD-like lesion was induced by the topical application of five percent PA to the dorsal skin or ear of Hos:HR-1 mouse. After AD induction, 100 MUL of 0.2% and 0.4% of TECA (40 MUg or 80 MUg/cm2) was spread on the dorsum of the ear or back skin three times a week for four weeks. We evaluated dermatitis severity, histopathological changes and changes in protein expression by Western blotting for inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and NF-kappaB activity, which were determined by electromobility shift assay (EMSA). We also measured TNF-alpha, IL-1beta, IL-6, and IgE concentration in the blood of AD mice by enzyme-linked immunosorbent assay (ELISA). TECA treatment attenuated the development of PA-induced atopic dermatitis. Histological analysis showed that TECA inhibited hyperkeratosis, mast cells and infiltration of inflammatory cells. TECA treatment inhibited expression of iNOS and COX-2, and NF-kappaB activity as well as the release of TNF-alpha, IL 1beta, IL-6, and IgE. In addition, TECA (1, 2, 5 MUg/mL) potently inhibited Lipopolysaccharide (LPS) (1 MUg/mL)-induced NO production, expression of iNOS and COX-2, and NF-kappaB DNA binding activities in RAW264.7 macrophage cells. Our data demonstrated that TECA could be a promising agent for AD by inhibition of NF kappaB signaling. PMID- 28358326 TI - An Exact Model-Based Method for Near-Field Sources Localization with Bistatic MIMO System. AB - In this paper, we propose an exact model-based method for near-field sources localization with a bistatic multiple input, multiple output (MIMO) radar system, and compare it with an approximated model-based method. The aim of this paper is to propose an efficient way to use the exact model of the received signals of near-field sources in order to eliminate the systematic error introduced by the use of approximated model in most existing near-field sources localization techniques. The proposed method uses parallel factor (PARAFAC) decomposition to deal with the exact model. Thanks to the exact model, the proposed method has better precision and resolution than the compared approximated model-based method. The simulation results show the performance of the proposed method. PMID- 28358325 TI - Sensing Attribute Weights: A Novel Basic Belief Assignment Method. AB - Dempster-Shafer evidence theory is widely used in many soft sensors data fusion systems on account of its good performance for handling the uncertainty information of soft sensors. However, how to determine basic belief assignment (BBA) is still an open issue. The existing methods to determine BBA do not consider the reliability of each attribute; at the same time, they cannot effectively determine BBA in the open world. In this paper, based on attribute weights, a novel method to determine BBA is proposed not only in the closed world, but also in the open world. The Gaussian model of each attribute is built using the training samples firstly. Second, the similarity between the test sample and the attribute model is measured based on the Gaussian membership functions. Then, the attribute weights are generated using the overlap degree among the classes. Finally, BBA is determined according to the sensed attribute weights. Several examples with small datasets show the validity of the proposed method. PMID- 28358328 TI - Gelidium elegans Regulates the AMPK-PRDM16-UCP-1 Pathway and Has a Synergistic Effect with Orlistat on Obesity-Associated Features in Mice Fed a High-Fat Diet. AB - The incidence of obesity is rising at an alarming rate throughout the world and is becoming a major public health concern with incalculable social and economic costs. Gelidium elegans (GENS), also previously known as Gelidium amansii, has been shown to exhibit anti-obesity effects. Nevertheless, the mechanism by which GENS is able to do this remains unclear. In the present study, our results showed that GENS prevents high-fat diet (HFD)-induced weight gain through modulation of the adenosine monophosphate-activated protein kinase (AMPK)-PR domain containing16 (PRDM16)-uncoupling protein-1 (UCP-1) pathway in a mice model. We also found that GENS decreased hyperglycemia in mice that had been fed a HFD compared to corresponding controls. We also assessed the beneficial effect of the combined treatment with GENS and orlistat (a Food and Drug Administration approved obesity drug) on obesity characteristics in HFD-fed mice. We found that in HFD-fed mice, the combination of GENS and orlistat is associated with more significant weight loss than orlistat treatment alone. Moreover, our results demonstrated a positive synergistic effect of GENS and orlistat on hyperglycemia and plasma triglyceride level in these animals. Thus, we suggest that a combination therapy of GENS and orlistat may positively influence obesity-related health outcomes in a diet-induced obese population. PMID- 28358327 TI - Coenzyme-A-Independent Transacylation System; Possible Involvement of Phospholipase A2 in Transacylation. AB - The coenzyme A (CoA)-independent transacylation system catalyzes fatty acid transfer from phospholipids to lysophospholipids in the absence of cofactors such as CoA. It prefers to use C20 and C22 polyunsaturated fatty acids such as arachidonic acid, which are esterified in the glycerophospholipid at the sn-2 position. This system can also acylate alkyl ether-linked lysophospholipids, is involved in the enrichment of arachidonic acid in alkyl ether-linked glycerophospholipids, and is critical for the metabolism of eicosanoids and platelet-activating factor. Despite their importance, the enzymes responsible for these reactions have yet to be identified. In this review, we describe the features of the Ca2+-independent, membrane-bound CoA-independent transacylation system and its selectivity for arachidonic acid. We also speculate on the involvement of phospholipase A2 in the CoA-independent transacylation reaction. PMID- 28358330 TI - Analysis of DNA Methylation Status in Bodily Fluids for Early Detection of Cancer. AB - Epigenetic alterations by promoter DNA hypermethylation and gene silencing in cancer have been reported over the past few decades. DNA hypermethylation has great potential to serve as a screening marker, a prognostic marker, and a therapeutic surveillance marker in cancer clinics. Some bodily fluids, such as stool or urine, were obtainable without any invasion to the body. Thus, such bodily fluids were suitable samples for high throughput cancer surveillance. Analyzing the methylation status of bodily fluids around the cancer tissue may, additionally, lead to the early detection of cancer, because several genes in cancer tissues are reported to be cancer-specifically hypermethylated. Recently, several studies that analyzed the methylation status of DNA in bodily fluids were conducted, and some of the results have potential for future development and further clinical use. In fact, a stool DNA test was approved by the U.S. Food and Drug Administration (FDA) for the screening of colorectal cancer. Another promising methylation marker has been identified in various bodily fluids for several cancers. We reviewed studies that analyzed DNA methylation in bodily fluids as a less-invasive cancer screening. PMID- 28358329 TI - The Changing Landscape of Pulmonary Arterial Hypertension in the Adult with Congenital Heart Disease. AB - Pulmonary arterial hypertension associated with congenital heart disease (PAH CHD) is a common type of pulmonary arterial hypertension (PAH) and a frequent complication of congenital heart disease (CHD). PAH-CHD represents a heterogeneous patient population and it is important to distinguish between the underlying cardiac defects considering the prognostic and therapeutic implications. Improved interventional techniques have enabled repair or palliation of most cardiac defects, though a substantial number of patients remain at high risk for PAH after closure. Traditionally, the treatment and management of PAH-CHD patients has been limited to palliative and supportive care, and based on expert opinion rather than clinical trials. Recently, however, the availability of advanced PAH-specific treatment has opened up a new field for the clinical management of this condition. Nevertheless, there is limited evidence on the optimal therapeutic approach for PAH-CHD. Herein, we discuss the current and novel therapeutic options for PAH-CHD as well as highlight several challenges in the clinical management at present. PMID- 28358331 TI - Absorption, Metabolic Stability, and Pharmacokinetics of Ginger Phytochemicals. AB - We have previously demonstrated promising anticancer efficacy of orally-fed whole ginger extract (GE) in preclinical prostate models emphasizing the importance of preservation of the natural "milieu". Essentially, GE primarily includes active ginger phenolics viz., 6-gingerol (6G), 8-gingerol (8G), 10-gingerol (10G), and 6 shogaol (6S). However, the druglikeness properties of active GE phenolics like solubility, stability, and metabolic characteristics are poorly understood. Herein, we determined the physicochemical and biochemical properties of GE phenolics by conducting in vitro assays and mouse pharmacokinetic studies with and without co-administration of ketoconazole (KTZ). GE phenolics showed low to moderate solubility in various pH buffers but were stable in simulated gastric and intestinal fluids, indicating their suitability for oral administration. All GE phenolics were metabolically unstable and showed high intrinsic clearance in mouse, rat, dog, and human liver microsomes. Upon oral administration of 250 mg/kg GE, sub-therapeutic concentrations of GE phenolics were observed. Treatment of plasma samples with beta-glucuronidase (betagd) increased the exposure of all GE phenolics by 10 to 700-fold. Co-administration of KTZ with GE increased the exposure of free GE phenolics by 3 to 60-fold. Interestingly, when the same samples were treated with betagd, the exposure of GE phenolics increased by 11 to 60-fold, suggesting inhibition of phase I metabolism by KTZ but little effect on glucuronide conjugation. Correlating the in vitro and in vivo results, it is reasonable to conclude that phase II metabolism seems to be the predominant clearance pathway for GE phenolics. We present evidence that the first-pass metabolism, particularly glucuronide conjugation of GE phenolics, underlies low systemic exposure. PMID- 28358333 TI - RAGE Plays a Role in LPS-Induced NF-kappaB Activation and Endothelial Hyperpermeability. AB - Endothelial functional dysregulation and barrier disruption contribute to the initiation and development of sepsis. The receptor for advanced glycation end products (RAGE) has been demonstrated to be involved in the pathogenesis of sepsis. The present study aimed to investigate the role of RAGE in lipopolysaccharide (LPS)-induced nuclear factor-kappaB (NF-kappaB) activation in endothelial cells and the consequent endothelial hyperpermeability. LPS-induced upregulation of RAGE protein expression in human umbilical vein endothelial cells (HUVECs) was detected by western blotting. Activation of NF-kappaB was revealed using western blotting and immunofluorescent staining. LPS-elicited endothelial hyperpermeability was explored by transendothelial electrical resistance (TER) assay and endothelial monolayer permeability assay. The blocking antibody specific to RAGE was used to confirm the role of RAGE in LPS-mediated NF-kappaB activation and endothelial barrier disruption. We found that LPS upregulated the protein expression of RAGE in a dose- and time-dependent manner in HUVECs. Moreover, LPS triggered a significant phosphorylation and degradation of IkappaBalpha, as well as NF-kappaB p65 nuclear translocation. Moreover, we observed a significant increase in endothelial permeability after LPS treatment. However, the RAGE blocking antibody attenuated LPS-evoked NF-kappaB activation and endothelial hyperpermeability. Our results suggest that RAGE plays an important role in LPS-induced NF-kappaB activation and endothelial barrier dysfunction. PMID- 28358332 TI - Selenium and Sulfur to Produce Allium Functional Crops. AB - Selenium is an element that must be considered in the nutrition of certain crops since its use allows the obtaining of biofortified crops with a positive impact on human health. The objective of this review is to present the information on the use of Se and S in the cultivation of plants of the genus Allium. The main proposal is to use Allium as specialist plants for biofortification with Se and S, considering the natural ability to accumulate both elements in different phytochemicals, which promotes the functional value of Allium. In spite of this, in the agricultural production of these species, the addition of sulfur is not realized to obtain functional foods and plants more resistant; it is only sought to cover the necessary requirements for growth. On the other hand, selenium does not appear in the agronomic management plans of most of the producers. Including S and Se fertilization as part of agronomic management can substantially improve Allium crop production. Allium species may be suitable to carry out biofortification with Se; this practice can be combined with the intensive use of S to obtain crops with higher production and sensory, nutritional, and functional quality. PMID- 28358335 TI - Copper to Zinc Ratio as Disease Biomarker in Neonates with Early-Onset Congenital Infections. AB - Copper (Cu) and zinc (Zn) are essential trace elements for regular development. Acute infections alter their metabolism, while deficiencies increase infection risks. A prospective observational case-control study was conducted with infected (n = 21) and control (n = 23) term and preterm newborns. We analyzed trace element concentrations by X-ray fluorescence, and ceruloplasmin (CP) by Western blot. Median concentration of Cu at birth (day 1) was 522.8 [387.1-679.7] MUg/L, and Zn was 1642.4 +/- 438.1 MUg/L. Cu and Zn correlated positively with gestational age in control newborns. Cu increased in infected newborns from day 1 to day 3. CP correlated positively to Cu levels at birth in both groups and on day 3 in the group of infected neonates. The Cu/Zn ratio was relatively high in infected newborns. Interleukin (IL)-6 concentrations on day 1 were unrelated to Cu, Zn, or the Cu/Zn ratio, whereas C-reactive protein (CRP) levels on day 3 correlated positively to the Cu/Zn -ratio at both day 1 and day 3. We conclude that infections affect the trace element homeostasis in newborns: serum Zn is reduced, while Cu and CP are increased. The Cu/Zn ratio combines both alterations, independent of gestational age. It may, thus, constitute a meaningful diagnostic biomarker for early-onset infections. PMID- 28358334 TI - Glucose Plus Fructose Ingestion for Post-Exercise Recovery-Greater than the Sum of Its Parts? AB - Carbohydrate availability in the form of muscle and liver glycogen is an important determinant of performance during prolonged bouts of moderate- to high intensity exercise. Therefore, when effective endurance performance is an objective on multiple occasions within a 24-h period, the restoration of endogenous glycogen stores is the principal factor determining recovery. This review considers the role of glucose-fructose co-ingestion on liver and muscle glycogen repletion following prolonged exercise. Glucose and fructose are primarily absorbed by different intestinal transport proteins; by combining the ingestion of glucose with fructose, both transport pathways are utilised, which increases the total capacity for carbohydrate absorption. Moreover, the addition of glucose to fructose ingestion facilitates intestinal fructose absorption via a currently unidentified mechanism. The co-ingestion of glucose and fructose therefore provides faster rates of carbohydrate absorption than the sum of glucose and fructose absorption rates alone. Similar metabolic effects can be achieved via the ingestion of sucrose (a disaccharide of glucose and fructose) because intestinal absorption is unlikely to be limited by sucrose hydrolysis. Carbohydrate ingestion at a rate of >=1.2 g carbohydrate per kg body mass per hour appears to maximise post-exercise muscle glycogen repletion rates. Providing these carbohydrates in the form of glucose-fructose (sucrose) mixtures does not further enhance muscle glycogen repletion rates over glucose (polymer) ingestion alone. In contrast, liver glycogen repletion rates are approximately doubled with ingestion of glucose-fructose (sucrose) mixtures over isocaloric ingestion of glucose (polymers) alone. Furthermore, glucose plus fructose (sucrose) ingestion alleviates gastrointestinal distress when the ingestion rate approaches or exceeds the capacity for intestinal glucose absorption (~1.2 g/min). Accordingly, when rapid recovery of endogenous glycogen stores is a priority, ingesting glucose-fructose mixtures (or sucrose) at a rate of >=1.2 g.kg body mass-1.h-1 can enhance glycogen repletion rates whilst also minimising gastrointestinal distress. PMID- 28358336 TI - Patterns of Gene Expression in Western Corn Rootworm (Diabrotica virgifera virgifera) Neonates, Challenged with Cry34Ab1, Cry35Ab1 and Cry34/35Ab1, Based on Next-Generation Sequencing. AB - With Next Generation Sequencing technologies, high-throughput RNA sequencing (RNAseq) was conducted to examine gene expression in neonates of Diabrotica virgifera virgifera (LeConte) (Western Corn Rootworm, WCR) challenged with individual proteins of the binary Bacillus thuringiensis insecticidal proteins, Cry34Ab1 and Cry35Ab1, and the combination of Cry34/Cry35Ab1, which together are active against rootworm larvae. Integrated results of three different statistical comparisons identified 114 and 1300 differentially expressed transcripts (DETs) in the Cry34Ab1 and Cry34/35Ab1 treatment, respectively, as compared to the control. No DETs were identified in the Cry35Ab1 treatment. Putative Bt binding receptors previously identified in other insect species were not identified in DETs in this study. The majority of DETs (75% with Cry34Ab1 and 68.3% with Cry34/35Ab1 treatments) had no significant hits in the NCBI nr database. In addition, 92 DETs were shared between Cry34Ab1 and Cry34/35Ab1 treatments. Further analysis revealed that the most abundant DETs in both Cry34Ab1 and Cry34/35Ab1 treatments were associated with binding and catalytic activity. Results from this study confirmed the nature of these binary toxins against WCR larvae and provide a fundamental profile of expression pattern of genes in response to challenge of the Cry34/35Ab1 toxin, which may provide insight into potential resistance mechanisms. PMID- 28358337 TI - Neoantimycins A and B, Two Unusual Benzamido Nine-Membered Dilactones from Marine Derived Streptomyces antibioticus H12-15. AB - An actinomycete strain (H12-15) isolated from a sea sediment in a mangrove district was identified as Streptomycesantibioticus on the basis of 16S rDNA gene sequence analysis as well as the investigation of its morphological, physiological, and biochemical characteristics. Two novel benzamido nonacyclic dilactones, namely neoantimycins A (1) and B (2), together with the known antimycins A1ab (3a,b), A2a (4), and A9 (5), were isolated from the culture broth of this strain. Compounds 1 and 2 are the first natural modified ATNs with an unusual benzamide unit. The structures of these new compounds, including their absolute configuration, were established on the basis of HRMS, NMR spectroscopic data, and quantum chemical ECD calculations. Their cytotoxicities against human breast adenocarcinoma cell line MCF-7, the human glioblastoma cell line SF-268, and the human lung cancer cell line NCI-H460 were also tested. All compounds exhibited mild cytotoxic activity. However, Compounds 1 and 2 showed no activity against C. albicans at the test concentration of 1 mg/mL via paper disc diffusion, while the known antimycins showed obvious antifungal activity. PMID- 28358338 TI - Heat Wave Vulnerability Mapping for India. AB - Assessing geographic variability in heat wave vulnerability forms the basis for planning appropriate targeted adaptation strategies. Given several recent deadly heatwaves in India, heat is increasingly being recognized as a public health problem. However, to date there has not been a country-wide assessment of heat vulnerability in India. We evaluated demographic, socioeconomic, and environmental vulnerability factors and combined district level data from several sources including the most recent census, health reports, and satellite remote sensing data. We then applied principal component analysis (PCA) on 17 normalized variables for each of the 640 districts to create a composite Heat Vulnerability Index (HVI) for India. Of the total 640 districts, our analysis identified 10 and 97 districts in the very high and high risk categories (> 2SD and 2-1SD HVI) respectively. Mapping showed that the districts with higher heat vulnerability are located in the central parts of the country. On examination, these are less urbanized and have low rates of literacy, access to water and sanitation, and presence of household amenities. Therefore, we concluded that creating and mapping a heat vulnerability index is a useful first step in protecting the public from the health burden of heat. Future work should incorporate heat exposure and health outcome data to validate the index, as well as examine sub district levels of vulnerability. PMID- 28358339 TI - Novel Palladium(II) Complexes that Influence Prominin-1/CD133 Expression and Stem Cell Factor Release in Tumor Cells. AB - New Pd(II) complexes of 1,7-bis(2-methoxyphenyl)hepta-1,6-diene-3,5-dione were synthesized and structurally characterized. The complexes were tested in vitro on human colon and hepatic carcinoma cell lines, normal hepatic cells and hematopoietic progenitor cells. Biological tests proved that Pd(II) complexes 1 and 2 (containing a curcumin derivative) exhibit a strong in vitro antitumor effect against the cells derived from human colorectal carcinoma and the hepatic metastasis of a colorectal carcinoma. Complex 1 has an outstanding inhibitory effect against BRAF-mutant colon carcinoma and hepatocarcinoma cell growth; 1 and 2 are both more active than the free ligand and have the capacity to trigger early apoptotic processes. By flow cytometric measurements, an important decrease of prominin-1 (CD133) molecule expression on tumor cells membrane was identified in cell populations subjected to 1 and 2. Quantitative immune enzymatic assay proved restrictions in stem cell factor (SCF) release by treated tumor cells. Although less cytotoxic, the free ligand inhibits the surface marker CD133 expression in hepatocarcinoma cells, and in HT-29 colon carcinoma. The new synthesized Pd(II) complexes 1 and 2 exhibit an important potential through their selective cytotoxic activity and by targeting the stem-like tumor cell populations, which leads to the tumor growth arrest and prevention of metastasis. PMID- 28358341 TI - Preserving Source Location Privacy for Energy Harvesting WSNs. AB - Fog (From cOre to edGe) computing employs a huge number of wireless embedded devices to enable end users with anywhere-anytime-to-anything connectivity. Due to their operating nature, wireless sensor nodes often work unattended, and hence are exposed to a variety of attacks. Preserving source-location privacy plays a key role in some wireless sensor network (WSN) applications. In this paper, a redundancy branch convergence-based preserved source location privacy scheme (RBCPSLP) is proposed for energy harvesting sensor networks, with the following advantages: numerous routing branches are created in non-hotspot areas with abundant energy, and those routing branches can merge into a few routing paths before they reach the hotspot areas. The generation time, the duration of routing, and the number of routing branches are then decided independently based on the amount of energy obtained, so as to maximize network energy utilization, greatly enhance privacy protection, and provide long network lifetimes. Theoretical analysis and experimental results show that the RBCPSLP scheme allows a several-fold improvement of the network energy utilization as well as the source location privacy preservation, while maximizing network lifetimes. PMID- 28358342 TI - A Two-Phase Time Synchronization-Free Localization Algorithm for Underwater Sensor Networks. AB - Underwater Sensor Networks (UWSNs) can enable a broad range of applications such as resource monitoring, disaster prevention, and navigation-assistance. Sensor nodes location in UWSNs is an especially relevant topic. Global Positioning System (GPS) information is not suitable for use in UWSNs because of the underwater propagation problems. Hence, some localization algorithms based on the precise time synchronization between sensor nodes that have been proposed for UWSNs are not feasible. In this paper, we propose a localization algorithm called Two-Phase Time Synchronization-Free Localization Algorithm (TP-TSFLA). TP-TSFLA contains two phases, namely, range-based estimation phase and range-free evaluation phase. In the first phase, we address a time synchronization-free localization scheme based on the Particle Swarm Optimization (PSO) algorithm to obtain the coordinates of the unknown sensor nodes. In the second phase, we propose a Circle-based Range-Free Localization Algorithm (CRFLA) to locate the unlocalized sensor nodes which cannot obtain the location information through the first phase. In the second phase, sensor nodes which are localized in the first phase act as the new anchor nodes to help realize localization. Hence, in this algorithm, we use a small number of mobile beacons to help obtain the location information without any other anchor nodes. Besides, to improve the precision of the range-free method, an extension of CRFLA achieved by designing a coordinate adjustment scheme is updated. The simulation results show that TP-TSFLA can achieve a relative high localization ratio without time synchronization. PMID- 28358340 TI - Research Progress on 18F-Labeled Agents for Imaging of Myocardial Perfusion with Positron Emission Tomography. AB - Coronary artery disease (CAD) is the leading cause of death in the world. Myocardial perfusion imaging (MPI) plays a significant role in non-invasive diagnosis and prognosis of CAD. However, neither single-photon emission computed tomography nor positron emission tomography clinical MPI agents can absolutely satisfy the demands of clinical practice. In the past decades, tremendous developments happened in the field of 18F-labeled MPI tracers. This review summarizes the current state of 18F-labeled MPI tracers, basic research data of those tracers, and the future direction of MPI tracer research. PMID- 28358343 TI - Acoustic NLOS Identification Using Acoustic Channel Characteristics for Smartphone Indoor Localization. AB - As the demand for indoor localization is increasing to support our daily life in large and complex indoor environments, sound-based localization technologies have attracted researchers' attention because they have the advantages of being fully compatible with commercial off-the-shelf (COTS) smartphones, they have high positioning accuracy and low-cost infrastructure. However, the non-line-of-sight (NLOS) phenomenon poses a great challenge and has become the technology bottleneck for practical applications of acoustic smartphone indoor localization. Through identifying and discarding the NLOS measurements, the positioning performance can be improved by incorporating only the LOS measurements. In this paper, we focus on identifying NLOS components by characterizing the acoustic channels. Firstly, by analyzing indoor acoustic propagations, the changes of acoustic channel from the line-of-sight (LOS) condition to the NLOS condition are characterized as the difference of channel gain and channel delay between the two propagation scenarios. Then, an efficient approach to estimate relative channel gain and delay based on the cross-correlation method is proposed, which considers the mitigation of the Doppler Effect and reduction of the computational complexity. Nine novel features have been extracted, and a support vector machine (SVM) classifier with a radial-based function (RBF) kernel is used to realize NLOS identification. The experimental result with an overall 98.9% classification accuracy based on a data set with more than 10 thousand measurements shows that the proposed identification approach and features are effective in acoustic NLOS identification for acoustic indoor localization via a smartphone. In order to further evaluate the performance of the proposed SVM classifier, the performance of an SVM classifier is compared with that of traditional classifiers based on logistic regression (LR) and linear discriminant analysis (LDA). The results also show that a SVM with the RBF kernel function method outperforms others in acoustic NLOS identification. PMID- 28358344 TI - The Electrochemical Behavior of Carbon Fiber Microelectrodes Modified with Carbon Nanotubes Using a Two-Step Electroless Plating/Chemical Vapor Deposition Process. AB - Carbon fiber microelectrode (CFME) has been extensively applied in the biosensor and chemical sensor domains. In order to improve the electrochemical activity and sensitivity of the CFME, a new CFME modified with carbon nanotubes (CNTs), denoted as CNTs/CFME, was fabricated and investigated. First, carbon fiber (CF) monofilaments grafted with CNTs (simplified as CNTs/CFs) were fabricated in two key steps: (i) nickel electroless plating, followed by (ii) chemical vapor deposition (CVD). Second, a single CNTs/CF monofilament was selected and encapsulated into a CNTs/CFME with a simple packaging method. The morphologies of as-prepared CNTs/CFs were characterized by scanning electron microscopy. The electrochemical properties of CNTs/CFMEs were measured in potassium ferrocyanide solution (K4Fe(CN)6), by using a cyclic voltammetry (CV) and a chronoamperometry method. Compared with a bare CFME, a CNTs/CFME showed better CV curves with a higher distinguishable redox peak and response current; the higher the CNT content was, the better the CV curves were. Because the as-grown CNTs significantly enhanced the effective electrode area of CNTs/CFME, the contact area between the electrode and reactant was enlarged, further increasing the electrocatalytic active site density. Furthermore, the modified microelectrode displayed almost the same electrochemical behavior after 104 days, exhibiting remarkable stability and outstanding reproducibility. PMID- 28358346 TI - A Data-Driven Diagnostic Framework for Wind Turbine Structures: A Holistic Approach. AB - The complex dynamics of operational wind turbine (WT) structures challenges the applicability of existing structural health monitoring (SHM) strategies for condition assessment. At the center of Europe's renewable energy strategic planning, WT systems call for implementation of strategies that may describe the WT behavior in its complete operational spectrum. The framework proposed in this paper relies on the symbiotic treatment of acting environmental/operational variables and the monitored vibration response of the structure. The approach aims at accurate simulation of the temporal variability characterizing the WT dynamics, and subsequently at the tracking of the evolution of this variability in a longer-term horizon. The bi-component analysis tool is applied on long-term data, collected as part of continuous monitoring campaigns on two actual operating WT structures located in different sites in Germany. The obtained data driven structural models verify the potential of the proposed strategy for development of an automated SHM diagnostic tool. PMID- 28358345 TI - Multiphysics and Thermal Response Models to Improve Accuracy of Local Temperature Estimation in Rat Cortex under Microwave Exposure. AB - The rapid development of wireless technology has led to widespread concerns regarding adverse human health effects caused by exposure to electromagnetic fields. Temperature elevation in biological bodies is an important factor that can adversely affect health. A thermophysiological model is desired to quantify microwave (MW) induced temperature elevations. In this study, parameters related to thermophysiological responses for MW exposures were estimated using an electromagnetic-thermodynamics simulation technique. To the authors' knowledge, this is the first study in which parameters related to regional cerebral blood flow in a rat model were extracted at a high degree of accuracy through experimental measurements for localized MW exposure at frequencies exceeding 6 GHz. The findings indicate that the improved modeling parameters yield computed results that match well with the measured quantities during and after exposure in rats. It is expected that the computational model will be helpful in estimating the temperature elevation in the rat brain at multiple observation points (that are difficult to measure simultaneously) and in explaining the physiological changes in the local cortex region. PMID- 28358349 TI - Fluorescence based real time monitoring of fouling in process chromatography. AB - A real time monitoring of fouling in liquid chromatography has been presented. The versatility of the approach has been proven by successful implementation in three case studies with an error <1%. The first application demonstrates the monitoring of protein A ligand density and foulant concentration for assessing performance of protein A chromatography resin during purification of monoclonal antibodies. The observations have been supported from LC-MS/MS studies that were independently performed. The second application involves monitoring of foulant deposition during multimode cation exchange chromatography based purification of human serum albumin. Finally, in the third application, monitoring of foulants during multimodal hydrophobic interaction chromatography of recombinant human granulocyte colony stimulating factor is demonstrated. In all three cases, it is observed that the fluorescence intensity consistently increases with resin reuse as more foulants are deposited over time. The proposed approach can be readily used for real time monitoring of fouling and process control. PMID- 28358347 TI - The Enzymology of 2-Hydroxyglutarate, 2-Hydroxyglutaramate and 2 Hydroxysuccinamate and Their Relationship to Oncometabolites. AB - Many enzymes make "mistakes". Consequently, repair enzymes have evolved to correct these mistakes. For example, lactate dehydrogenase (LDH) and mitochondrial malate dehydrogenase (mMDH) slowly catalyze the reduction of 2 oxoglutarate (2-OG) to the oncometabolite l-2-hydroxyglutarate (l-2-HG). l-2-HG dehydrogenase corrects this error by converting l-2-HG to 2-OG. LDH also catalyzes the reduction of the oxo group of 2-oxoglutaramate (2-OGM; transamination product of l-glutamine). We show here that human glutamine synthetase (GS) catalyzes the amidation of the terminal carboxyl of both the l- and d- isomers of 2-HG. The reaction of 2-OGM with LDH and the reaction of l-2-HG with GS generate l-2-hydroxyglutaramate (l-2-HGM). We also show that l-2-HGM is a substrate of human omega-amidase. The product (l-2-HG) can then be converted to 2 OG by l-2-HG dehydrogenase. Previous work showed that 2-oxosuccinamate (2-OSM; transamination product of l-asparagine) is an excellent substrate of LDH. Finally, we also show that human omega-amidase converts the product of this reaction (i.e., l-2-hydroxysuccinamate; l-2-HSM) to l-malate. Thus, omega-amidase may act together with hydroxyglutarate dehydrogenases to repair certain "mistakes" of GS and LDH. The present findings suggest that non-productive pathways for nitrogen metabolism occur in mammalian tissues in vivo. Perturbations of these pathways may contribute to symptoms associated with hydroxyglutaric acidurias and to tumor progression. Finally, methods for the synthesis of l-2-HGM and l-2-HSM are described that should be useful in determining the roles of omega-amidase/4- and 5-C compounds in photorespiration in plants. PMID- 28358350 TI - Corrigendum: Defective Acetylcholine Receptor Subunit Switch Precedes Atrophy of Slow-Twitch Skeletal Muscle Fibers Lacking ERK1/2 Kinases in Soleus Muscle. PMID- 28358348 TI - The Associations between Types of Ambient PM2.5 and Under-Five and Maternal Mortality in Africa. AB - Exploring the effects of different types of PM2.5 is necessary to reduce associated deaths, especially in low- and middle-income countries (LMICs). Hence we determined types of ambient PM2.5 before exploring their effects on under-five and maternal mortality in Africa. The spectral derivate of aerosol optical depth (AOD) from Moderate Resolution Imaging Spectroradiometer (MODIS) products from 2000 to 2015 were employed to determine the aerosol types before using Generalized Linear and Additive Mixed-Effect models with Poisson link function to explore the associations and penalized spline for dose-response relationships. Four types of PM2.5 were identified in terms of mineral dust, anthropogenic pollutant, biomass burning and mixture aerosols. The results demonstrate that biomass PM2.5 increased the rate of under-five mortality in Western and Central Africa, each by 2%, and maternal mortality in Central Africa by 19%. Anthropogenic PM2.5 increased under-five and maternal deaths in Northern Africa by 5% and 10%, respectively, and maternal deaths by 4% in Eastern Africa. Dust PM2.5 increased under-five deaths in Northern, Western, and Central Africa by 3%, 1%, and 10%, respectively. Mixture PM2.5 only increased under-five deaths and maternal deaths in Western (incidence rate ratio = 1.01, p < 0.10) and Eastern Africa (incidence rate ratio = 1.06, p < 0.01), respectively. The findings indicate the types of ambient PM2.5 are significantly associated with under-five and maternal mortality in Africa where the exposure level usually exceeds the World Health Organization's (WHO) standards. Appropriate policy actions on protective and control measures are therefore suggested and should be developed and implemented accordingly. PMID- 28358351 TI - Corrigendum: Effects of Nitrogen and Shading on Root Morphologies, Nutrient Accumulation, and Photosynthetic Parameters in Different Rice Genotypes. PMID- 28358352 TI - Corrigendum: Host-ant specificity of endangered large blue butterflies (Phengaris spp., Lepidoptera: Lycaenidae) in Japan. PMID- 28358353 TI - A new tyrannosaur with evidence for anagenesis and crocodile-like facial sensory system. AB - A new species of tyrannosaurid from the upper Two Medicine Formation of Montana supports the presence of a Laramidian anagenetic (ancestor-descendant) lineage of Late Cretaceous tyrannosaurids. In concert with other anagenetic lineages of dinosaurs from the same time and place, this suggests that anagenesis could have been a widespread mechanism generating species diversity amongst dinosaurs, and perhaps beyond. We studied the excellent fossil record of the tyrannosaurid to test that hypothesis. Phylogenetic analysis places this new taxon as the sister species to Daspletosaurus torosus. However, given their close phylogenetic relationship, geographic proximity, and temporal succession, where D. torosus (~76.7-75.2 Ma) precedes the younger new species (~75.1-74.4 Ma), we argue that the two forms most likely represent a single anagenetic lineage. Daspletosaurus was an important apex predator in the late Campanian dinosaur faunas of Laramidia; its absence from later units indicates it was extinct before Tyrannosaurus rex dispersed into Laramidia from Asia. In addition to its evolutionary implications, the texture of the facial bones of the new taxon, and other derived tyrannosauroids, indicates a scaly integument with high tactile sensitivity. Most significantly, the lower jaw shows evidence for neurovasculature that is also seen in birds. PMID- 28358355 TI - Identifying large-scale patterns of unpredictability and response to insolation in atmospheric data. AB - Understanding the complex dynamics of the atmosphere is of paramount interest due to its impact in the entire climate system and in human society. Here we focus on identifying, from data, the geographical regions which have similar atmospheric properties. We study surface air temperature (SAT) time series with monthly resolution, recorded at a regular grid covering the Earth surface. We consider two datasets: NCEP CDAS1 and ERA Interim reanalysis. We show that two surprisingly simple measures are able to extract meaningful information: i) the distance between the lagged SAT and the incoming solar radiation and ii) the Shannon entropy of SAT and SAT anomalies. The distance uncovers well-defined spatial patterns formed by regions with similar SAT response to solar forcing while the entropy uncovers regions with similar degree of SAT unpredictability. The entropy analysis also allows identifying regions in which SAT has extreme values. Importantly, we uncover differences between the two datasets which are due to the presence of extreme values in one dataset but not in the other. Our results indicate that the distance and entropy measures can be valuable tools for the study of other climatological variables, for anomaly detection and for performing model inter-comparisons. PMID- 28358354 TI - Cultivar-specific gene modulation in Vitis vinifera: analysis of the promoters regulating the expression of WOX transcription factors. AB - The family of Wuschel-related Homeobox (WOX) genes is a class of transcription factors involved in the early stages of embryogenesis and organ development in plants. Some of these genes have shown different transcription levels in embryogenic tissues and mature organs in two different cultivars of Vitis vinifera: 'Chardonnay' (CH) and 'Cabernet Sauvignon' (CS). Therefore, we investigated the genetic basis responsible for these differences by cloning and sequencing in both the cultivars the promoter regions (~2000 bp) proximal to the transcription start site of five VvWOX genes. We then introduced these promoters into Arabidopsis thaliana for expression pattern characterisation using the GUS reporter gene. In the transgenic Arabidopsis, two promoters isolated from CS (pVvWOX13C_CS and pVvWOX6_CS) induced increased expression compared to the sequence isolated in CH, confirming the data obtained in grapevine tissues. These results were corroborated by transient expression assays using the agroinfiltration approach in grapevine somatic embryos. Truncated versions of pVvWOX13C demonstrated that few nucleotide differences between the sequences isolated from CH and CS are pivotal for the transcriptional regulation of VvWOX13C. Analysis of promoters using heterologous and homologous systems appear to be effective for exploring gene modulation linked with intervarietal sequence variation in grapevine. PMID- 28358356 TI - Method for detection of hydrogen peroxide in HT22 cells. AB - We have proposed a new method which can be applied in assessing the intracellular production of hydrogen peroxide. Using this assay we have examined the hydrogen peroxide generation during the L-glutamate induced oxidative stress in the HT22 hippocampal cells. The detection of hydrogen peroxide is based on two crucial reagents cis-[Cr(C2O4)(pm)(OH2)2]+ (pm denotes pyridoxamine) and 2-ketobutyrate. The results obtained indicate that the presented method can be a promising tool to detect hydrogen peroxide in biological samples, particularly in cellular experimental models. PMID- 28358357 TI - Hybrid three-dimensional dual- and broadband optically tunable terahertz metamaterials. AB - The optically tunable properties of the hybrid three-dimensional (3D) metamaterials with dual- and broadband response frequencies are theoretically investigated in the terahertz spectrum. The planar double-split-ring resonators (DSRRs) and the standup double-split-ring resonators are fabricated on a sapphire substrate, forming a 3D array structures. The bi-anisotropy of the hybrid 3D metamaterials is considered because the stand-up DSRRs are not symmetrical with respect to the electric field vector. Due to the electric and magnetic response realized by the planar and the standup double-split-ring resonators respectively, the dual-band resonance response and the negative refractive index can be achieved. The potential of the phase modulation under photoexcitation is also demonstrated. Further analysis indicates that, photoexcitation of free carriers in the silicon within the capacitive region of the standup DSRRs results in a broad resonance response bandwidth (about 0.47 THz), and also functions as a broadband negative refractive index that roughly lies between 0.80 and 2.01 THz. This tunable metamaterials is proposed for the potential application of electromagnetic wave propagation in terahertz area. PMID- 28358359 TI - Corrigendum: Direct coupling: a possible strategy to control fruit production in alternate bearing. PMID- 28358360 TI - Erratum: Insights into functional and evolutionary analysis of carbaryl metabolic pathway from Pseudomonas sp. strain C5pp. PMID- 28358358 TI - The cerebellum in dual-task performance in Parkinson's disease. AB - Parkinson's disease (PD) patients have difficulty in performing a dual-task. It has been suggested that the cerebellum is important in dual-tasking. We used functional MRI to investigate the role of the cerebellum in performing a dual motor and cognitive task in PD patients. We have examined whether there are any areas additionally activated for dual-task performance, and compared the neural activity and functional connectivity pattern in the cerebellum between PD patients and healthy controls. We found that the right cerebellar vermis and left lobule V of cerebellar anterior lobe were additionally activated for dual-task performance in healthy controls and for motor task in PD patients. We didn't find any cerebellar regions additionally activated while performing dual-task in PD patients. In addition, the right cerebellar vermis had enhanced connectivity with motor and cognitive associated networks in PD patients. PD patients have limited cerebellar resources that are already utilized for single tasks and, for dual tasks, cannot augment as necessary in order to integrate motor and cognitive networks. PMID- 28358361 TI - Tumor-treating fields elicit a conditional vulnerability to ionizing radiation via the downregulation of BRCA1 signaling and reduced DNA double-strand break repair capacity in non-small cell lung cancer cell lines. AB - The use of tumor-treating fields (TTFields) has revolutionized the treatment of recurrent and newly diagnosed glioblastoma (GBM). TTFields are low-intensity, intermediate frequency, alternating electric fields that are applied to tumor regions and cells using non-invasive arrays. The predominant mechanism by which TTFields are thought to kill tumor cells is the disruption of mitosis. Using five non-small cell lung cancer (NSCLC) cell lines we found that there is a variable response in cell proliferation and cell killing between these NSCLC cell lines that was independent of p53 status. TTFields treatment increased the G2/M population, with a concomitant reduction in S-phase cells followed by the appearance of a sub-G1 population indicative of apoptosis. Temporal changes in gene expression during TTFields exposure was evaluated to identify molecular signaling changes underlying the differential TTFields response. The most differentially expressed genes were associated with the cell cycle and cell proliferation pathways. However, the expression of genes found within the BRCA1 DNA-damage response were significantly downregulated (P<0.05) during TTFields treatment. DNA double-strand break (DSB) repair foci increased when cells were exposed to TTFields as did the appearance of chromatid-type aberrations, suggesting an interphase mechanism responsible for cell death involving DNA repair. Exposing cells to TTFields immediately following ionizing radiation resulted in increased chromatid aberrations and a reduced capacity to repair DNA DSBs, which were likely responsible for at least a portion of the enhanced cell killing seen with the combination. These findings suggest that TTFields induce a state of 'BRCAness' leading to a conditional susceptibility resulting in enhanced sensitivity to ionizing radiation and provides a strong rationale for the use of TTFields as a combined modality therapy with radiation or other DNA-damaging agents. PMID- 28358362 TI - Deletion of Stk40 impairs definitive erythropoiesis in the mouse fetal liver. AB - The serine threonine kinase Stk40 has been shown to involve in mouse embryonic stem cell differentiation, pulmonary maturation and adipocyte differentiation. Here we report that targeted deletion of Stk40 leads to fetal liver hypoplasia and anemia in the mouse embryo. The reduction of erythrocytes in the fetal liver is accompanied by increased apoptosis and compromised erythroid maturation. Stk40 /- fetal liver cells have significantly reduced colony-forming units (CFUs) capable of erythroid differentiation, including burst forming unit-erythroid, CFU erythroid (CFU-E), and CFU-granulocyte, erythrocyte, megakaryocyte and macrophage, but not CFU-granulocyte/macrophages. Purified Stk40-/- megakaryocyte erythrocyte progenitors produce substantially fewer CFU-E colonies compared to control cells. Moreover, Stk40-/- fetal liver erythroblasts fail to form normal erythroblastic islands in association with wild type or Stk40-/- macrophages, indicating an intrinsic defect of Stk40-/- erythroblasts. Furthermore, the hematopoietic stem and progenitor cell pool is reduced in Stk40-/- fetal livers but still retains the multi-lineage reconstitution capacity. Finally, comparison of microarray data between wild type and Stk40-/- E14.5 fetal liver cells reveals a potential role of aberrantly activated TNF-alpha signaling in Stk40 depletion induced dyserythropoiesis with a concomitant increase in cleaved caspase-3 and decrease in Gata1 proteins. Altogether, the identification of Stk40 as a regulator for fetal erythroid maturation and survival provides new clues to the molecular regulation of erythropoiesis and related diseases. PMID- 28358363 TI - miR-127 enhances myogenic cell differentiation by targeting S1PR3. AB - MicroRNAs (miRNAs) have recently been implicated in muscle stem cell function. miR-127 is known to be predominantly expressed in skeletal muscle, but its roles in myogenic differentiation and muscle regeneration are unknown. Here, we show that miR-127 is upregulated during C2C12 and satellite cell (SC) differentiation and, by establishing C2C12 cells stably expressing miR-127, demonstrate that overexpression of miR-127 in C2C12 cells enhances myogenic cell differentiation. To investigate the function of miR-127 during muscle development and regeneration in vivo, we generated miR-127 transgenic mice. These mice exhibited remarkably accelerated muscle regeneration compared with wild-type mice by promoting SC differentiation. Mechanistically, we demonstrated that the gene encoding sphingosine-1-phosphate receptor 3 (S1PR3), a G-protein-coupled receptor for sphingosine-1-phosphate, is a target of miR-127 required for its function in promoting myogenic cell differentiation. Importantly, overexpression of miR-127 in muscular dystrophy model mdx mice considerably ameliorated the disease phenotype. Thus, our findings suggest that miR-127 may serve as a potential therapeutic target for the treatment of skeletal muscle disease in humans. PMID- 28358364 TI - Functional inhibition of acid sphingomyelinase by Fluphenazine triggers hypoxia specific tumor cell death. AB - Owing to lagging or insufficient neo-angiogenesis, hypoxia is a feature of most solid tumors. Hypoxic tumor regions contribute to resistance against antiproliferative chemotherapeutics, radiotherapy and immunotherapy. Targeting cells in hypoxic tumor areas is therefore an important strategy for cancer treatment. Most approaches for targeting hypoxic cells focus on the inhibition of hypoxia adaption pathways but only a limited number of compounds with the potential to specifically target hypoxic tumor regions have been identified. By using tumor spheroids in hypoxic conditions as screening system, we identified a set of compounds, including the phenothiazine antipsychotic Fluphenazine, as hits with novel mode of action. Fluphenazine functionally inhibits acid sphingomyelinase and causes cellular sphingomyelin accumulation, which induces cancer cell death specifically in hypoxic tumor spheroids. Moreover, we found that functional inhibition of acid sphingomyelinase leads to overactivation of hypoxia stress-response pathways and that hypoxia-specific cell death is mediated by the stress-responsive transcription factor ATF4. Taken together, the here presented data suggest a novel, yet unexplored mechanism in which induction of sphingolipid stress leads to the overactivation of hypoxia stress-response pathways and thereby promotes their pro-apoptotic tumor-suppressor functions to specifically kill cells in hypoxic tumor areas. PMID- 28358365 TI - Madecassic acid, the contributor to the anti-colitis effect of madecassoside, enhances the shift of Th17 toward Treg cells via the PPARgamma/AMPK/ACC1 pathway. AB - The imbalance between Th17 and Treg cells substantially contributes to the intestinal immune disturbance and subsequent tissue injury in ulcerative colitis. The triterpenoid-rich fraction of Centella asiatica was able to ameliorate dextran sulfate sodium-induced colitis in mice. Here we explored its active ingredient and underlying mechanism with a focus on restoring the Th17/Treg balance. The four main triterpenoids occurring in C. asiatica were shown to attenuate colitis in mice by oral administration. The most effective ingredient madecassoside lost anti-colitis effect when applied topically in the colon, and madecassic acid was recognized to be the active form of madecassoside. Oral administration of madecassic acid decreased the percentage of Th17 cells and downregulated the expression of RORgammat, IL-17A, IL-17F, IL-21 and IL-22 and increased the percentage of Treg cells and the expression of Foxp3 and IL-10 in the colons of mice with colitis, but it did not affect Th1 and Th2 cells. Under Th17-polarizing conditions, madecassic acid downregulated ACC1 expression and enhanced the shift of Th17 cells toward Treg cells, but it did not affect the differentiation of Treg cells under Treg-polarizing conditions. Both compound C and AMPK siRNA inhibited the madecassic acid-mediated downregulation of ACC1 expression and shift of Th17 cells to Treg cells under Th17-polarizing conditions. GW9662, T0070907 and PPARgamma siRNA blocked the effect of madecassic acid on AMPK activation, ACC1 expression and shift of Th17 cells to Treg cells. Furthermore, madecassic acid was identified as a PPARgamma agonist, as it promoted PPARgamma transactivation. The correlation between activation of PPARgamma and AMPK, downregulation of ACC1 expression, restoration of Th17/Treg balance and attenuation of colitis by madecassic acid was validated in mice with DSS-induced colitis. In conclusion, madecassic acid was the active form of madecassoside in ameliorating colitis by restoring the Th17/Treg balance via regulating the PPARgamma/AMPK/ACC1 pathway. PMID- 28358366 TI - Forkhead box A3 attenuated the progression of fibrosis in a rat model of biliary atresia. AB - Biliary atresia is a rare, devastating disease of infants where a fibroinflammatory process destroys the bile ducts, leading to fibrosis and biliary cirrhosis, and death if untreated. The cause and pathogenesis remain largely unknown. We tried to investigate factors involved in biliary atresia, especially forkhead box A3 (Foxa3), which might exert a role in the treatment of liver disease. We used RNA sequencing to sequence the whole transcriptomes of livers from six biliary atresia and six choledochal cysts patients. Then, we employed a rat disease model by bile duct ligation (BDL) and adenovirus transduction to address the function of Foxa3 in biliary atresia. We found that tight junction, adherence junction, cell cycle, apoptosis, chemokine singling, VEGF and MAPK signaling pathways were enriched in biliary atresia livers. We showed that Foxa3 expression was notably decreased in liver samples from biliary atresia patients. More importantly, we found that its lower expression predicted a poorer overall survival of biliary atresia patients. Rats that received BDL surgery and Foxa3 expression adenovirus resulted in a significant decrease in the deposition of collagen, and expression of profibrotic cytokines (transforming growth factor-beta and connective tissue growth factor) and fibrosis markers (alpha-smooth muscle actin, collagen I and collagen III), as compared with rats that received BDL surgery and control adenovirus. Our data suggested a protection role for Foxa3 during the progression of liver fibrosis in biliary atresia, and thereby supported increasing Foxa3 as a targeted treatment strategy. PMID- 28358367 TI - Overexpression of EphB2 in hippocampus rescues impaired NMDA receptors trafficking and cognitive dysfunction in Alzheimer model. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease, which affects more and more people. But there is still no effective treatment for preventing or reversing the progression of the disease. Soluble amyloid-beta (Abeta) oligomers, also known as Abeta-derived diffusible ligands (ADDLs) play an important role in AD. Synaptic activity and cognition critically depend on the function of glutamate receptors. Targeting N-methyl-D-aspartic acid (NMDA) receptors trafficking and its regulation is a new strategy for AD early treatment. EphB2 is a key regulator of synaptic localization of NMDA receptors. Abeta oligomers could bind to the fibronectin repeats domain of EphB2 and trigger EphB2 degradation in the proteasome. Here we identified that overexpression of EphB2 with lentiviral vectors in dorsal hippocampus improved impaired memory deficits and anxiety or depression-like behaviors in APPswe/PS1-dE9 (APP/PS1) transgenic mice. Phosphorylation and surface expression of GluN2B-containing NMDA receptors were also improved. Overexpression of EphB2 also rescued the ADDLs induced depletion of the expression of EphB2 and GluN2B-containing NMDA receptors trafficking in cultured hippocampal neurons. These results suggest that improving the decreased expression of EphB2 and subsequent GluN2B-containing NMDA receptors trafficking in hippocampus may be a promising strategy for AD treatment. PMID- 28358368 TI - A novel and promising therapeutic approach for NSCLC: recombinant human arginase alone or combined with autophagy inhibitor. AB - Recombinant human arginase (rhArg), an enzyme capable of depleting arginine, has been shown to be an effective therapeutic approach for various cancers. Non-small cell lung cancer (NSCLC), a histological subtype of pulmonary carcinoma, has a high rate of morbidity and mortality in the world. Thus, the need for novel and more effective treatment is urgent. In this study, it is the first time to report that rhArg could induce significant cytotoxicity and caspase-dependent apoptosis in NSCLC cells. Subsequently, our research revealed that rhArg dramatically stimulated autophagic response in NSCLC cells, which was proved by the formation and accumulation of autophagosomes and the conversion of microtubule-associated protein light chain 3 (LC3) from LC3-I to LC3-II. Furthermore, blocking autophagy by chloroquine or LY294002 remarkably enhanced rhArg-induced cytotoxicity and caspase-dependent apoptosis, suggesting that autophagy acted a cytoprotective role in rhArg-treated NSCLC cells. Further experiments showed that two signaling pathways including the Akt/mTOR and extracellular signal-regulated kinase pathway, and mitochondrial-derived reactive oxygen species (ROS) production were involved in rhArg-induced autophagy and apoptosis. Meanwhile, N-acetyl-L cysteine, a common antioxidant, was employed to scavenge ROS, and we detected that it could significantly block rhArg-induced autophagy and cytotoxicity, indicating that ROS played a vital role in arginine degradation therapy. Besides, xenograft experiment showed that combination with autophagy inhibitor potentiated the anti-tumor efficacy of rhArg in vivo. Therefore, these results provided a novel prospect and viewpoint that autophagy acted a cytoprotective role in rhArg treated NSCLC cells, and treatment with rhArg alone or combined with autophagy inhibitor could be a novel and promising therapeutic approach for NSCLC in vivo and in vitro. PMID- 28358369 TI - MiRNA199a-3p suppresses tumor growth, migration, invasion and angiogenesis in hepatocellular carcinoma by targeting VEGFA, VEGFR1, VEGFR2, HGF and MMP2. AB - Increasing significance of tumor-stromal interaction in development and progression of cancer implies that signaling molecules in the tumor microenvironment (TME) might be the effective therapeutic targets for hepatocellular carcinoma (HCC). Here, the role of microRNA miR-199a-3p in the regulation of TME and development of HCC has been investigated by several in vitro and in vivo assays. Expression of miR-199a-3p was observed significantly low in HCC tissues and its overexpression remarkably inhibited in vivo tumor growth and metastasis to lung in NOD-SCID mice. In vitro restoration of miR-199a 3p expression either in endothelial cells (ECs) or in cancer cells (CACs) significantly diminished migration of ECs in co-culture assay. Again incubation of miR-199a-3p transfected ECs with either conditioned media (CM) of CACs or recombinant VEGF has reduced tube formation, in ECs and it was also dropped upon growth in CM of either anti-VEGF antibody-treated or miR-199a-3p-transfected CACs. In addition, bioinformatics and luciferase-reporter assays revealed that miR-199a-3p inhibited VEGF secretion from CACs and VEGFR1 and VEGFR2 expression on ECs and thus restricted cross talk between CACs and ECs. Again, restoration of miR-199a-3p in hepatic stellate cells (HSCs) reduced migration and invasion of CACs in co-culture assay, while it was enhanced by the overexpression of HGF suggesting miR-199a-3p has hindered HSC-CACs cross talk probably by inhibiting HGF and regulating matrix metalloproteinase MMP2, which were found as targets of miR-199a-3p subsequently by luciferase-reporter assay and gelatin zymography, respectively. Thus, these findings collectively highlight that miR-199a-3p restricts metastasis, invasion and angiogenesis in HCC and hence it may be considered as one of the powerful effective therapeutics for management of HCC patients. PMID- 28358370 TI - The role of autophagy in asparaginase-induced immune suppression of macrophages. AB - Erwinia asparaginase, a bacteria-derived enzyme drug, has been used in the treatment of various cancers, especially acute lymphoblastic leukemia (ALL). One of the most significant side effects associated with asparaginase administration is immune suppression, which limits its application in clinic. Macrophages are phagocytic immune cells and have a central role in inflammation and host defense. We reported here that asparaginase disturbed the function of macrophages including phagocytosis, proliferation, ROS and nitric oxide secretion, interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) secretion, and major histocompatibility complex II (MHC-II) molecule expression, thus induced immune suppression in interferon-gamma and lipopolysaccharide-stimulated macrophages. We also observed that asparaginase inhibited autophagy in macrophages via activating Akt/mTOR and suppressing Erk1/2 signaling pathway as evidenced by less formation of autophagosomes, downregulation of autophagy related protein LC3-II, and decreased number of autophagy-like vacuoles. Further study discovered that treatment with autophagy inhibitor 3-MA in place of asparaginase on activated macrophages could also downregulate phagocytosis, cytokine secretion, and MHC-II expression. Moreover, incubation with autophagy inducer trehalose restored the capacity of phagocytosis, IL-6 and TNF-alpha secretion, and MHC-II expression in macrophages. These results prove the important role of autophagy in the function of macrophages, and activation of autophagy can overcome asparaginase-induced immune suppression in macrophages. PMID- 28358371 TI - Cell-based therapy using miR-302-367 expressing cells represses glioblastoma growth. AB - Glioblastomas are incurable primary brain tumors that affect patients of all ages. The aggressiveness of this cancer has been attributed in part to the persistence of treatment-resistant glioblastoma stem-like cells. We have previously discovered the tumor-suppressor properties of the microRNA cluster miR 302-367, representing a potential treatment for glioblastoma. Here, we attempted to develop a cell-based therapy by taking advantage of the capability of glioma cells to secrete exosomes that enclose small RNA molecules. We engineered primary glioma cells to stably express the miR-302-367. Remarkably, these cells altered, in a paracrine-dependent manner, the expression of stemness markers, the proliferation and the tumorigenicity of neighboring glioblastoma cells. Further characterization of the secretome derived from miR-302-367 expressing cells showed that a large amount of miR-302-367 was enclosed in exosomes, which were internalized by the neighboring glioblastoma cells. This miR-302-367 cell-to-cell transfer resulted in the inhibition of its targets such as CXCR4/SDF1, SHH, cyclin D, cyclin A and E2F1. Orthotopic xenograft of miR-302-367-expressing cells together with glioblastoma stem-like cells efficiently altered the tumor development in mice brain. PMID- 28358372 TI - TNF-alpha-induced LRG1 promotes angiogenesis and mesenchymal stem cell migration in the subchondral bone during osteoarthritis. AB - The incomplete understanding of aberrant neovascularization, which contributes to osteoarthritis suggests that additional modulators have yet to be identified. Our objective was to identify the role of Leucine-rich-alpha-2-glycoprotein1 (LRG1), a new regulator of pathogenic angiogenesis, in osteoarthritis progression and to develop effective treatment strategies. In this study, immunohistochemistry showed that LRG1 was increased in the subchondral bone and articular cartilage in anterior cruciate ligament transection (ACLT) mice. Further studies were focused on the role of LRG1 in osteoarthritis. Results showed that LRG1 promoted angiogenesis and mesenchymal stem cells (MSC) migration, which contribute to aberrant bone formation in the subchondral bone. Moreover, tumor necrosis factor alpha (TNF-alpha), not interleukin-1beta (IL-1beta), IL-6 or IL-17, induced the LRG1 expression in human umbilical vein endothelial cells and this effect was inhibited by p38 mitogen-activated protein kinase or NF-kappaB inhibitor. Notably, inhibition of TNF-alpha and LRG1 activity by Lenalidomide, an inhibitor of TNF-alpha production, in ACLT mice attenuated degeneration of osteoarthritis articular cartilage. This study shows that TNF-alpha is the predominant proinflammatory cytokine that induces the secretion of LRG1. LRG1 contributes to angiogenesis-coupled de novo bone formation by increasing angiogenesis and recruiting MSCs in the subchondral bone of osteoarthritis joints. Inhibition of TNF-alpha and LRG1 by Lenalidomide could be a potential therapeutic approach. PMID- 28358373 TI - Myogenic differentiation triggers PML nuclear body loss and DAXX relocalization to chromocentres. AB - The promyelocytic leukemia protein (PML) is expressed in most normal human tissues and forms nuclear bodies (NBs) that have roles in gene regulation and cellular processes such as DNA repair, cell cycle control, and cell fate decisions. Using murine C2C12 myoblasts, we demonstrate that activation of skeletal muscle differentiation results in loss of PML and PML NBs prior to myotube fusion. Myotube formation was associated with marked chromatin reorganization and the relocalization of DAXX from PML NBs to chromocentres. MyoD expression was sufficient to cause PML NB loss, and silencing of PML induced DAXX relocalization. Fusion of C2C12 cells using the reptilian reovirus p14 fusogenic protein failed to disrupt PML NBs yet still promoted DAXX redistribution and loss; whereas ectopic expression of PML in differentiated cells only partially restored PML NB formation and DAXX localization at NBs. Finally, we determined that the C-terminal SUMO-interacting motif of DAXX is required for its colocalization with ATRX in heterochromatin domains during myotube formation. These data support a model in which activation of myogenic differentiation results in PML NB loss, chromatin reorganization and DAXX relocalization, and provides a paradigm for understanding the consequence of PML loss in other cellular contexts, such as during cancer development and progression. PMID- 28358374 TI - miR-491-5p, mediated by Foxi1, functions as a tumor suppressor by targeting Wnt3a/beta-catenin signaling in the development of gastric cancer. AB - Accumulated evidence has suggested that microRNAs (miRNAs) have an important role in tumor development and progression by regulating diverse signaling pathways. However, the precise role of miRNAs in gastric cancer (GC) has not been elucidated. In this study, we describe the function and regulation network of miR 491-5p in GC. miR-491-5p is frequently downregulated in GC tissues compared with adjacent non-cancerous tissues. Forced expression of miR-491-5p significantly inhibits proliferation and colony formation, and promotes apoptosis in GC cells. Through bioinformatic analysis and luciferase assays, we confirm that miR-491-5p targets Wnt3a. Silencing Wnt3a inhibits cell proliferation and induces apoptosis. Similarly, restoration of Wnt3a counteracts the effects of miR-491-5p expression. Moreover, bioinformatic and luciferase assays indicate that the expression of miR 491-5p is regulated by Foxi1, which binds to its promoter and activates miR-491 5p expression. In conclusion, to the best of our knowledge, our findings are the first to demonstrate that Foxi1 is a key player in the transcriptional control of miR-491-5p and that miR-491-5p acts as an anti-oncogene by targeting Wnt3a/beta catenin signaling in GC. Our study reveals that Foxi1/miR-491-5p/Wnt3a/beta catenin signaling is critical in the progression of GC. Targeting the pathway described in this study may open up new prospects to restrict the progression of GC. PMID- 28358375 TI - Novel prosurvival function of Yip1A in human cervical cancer cells: constitutive activation of the IRE1 and PERK pathways of the unfolded protein response. AB - Cancer cells are under chronic endoplasmic reticulum (ER) stress due to hypoxia, low levels of nutrients, and a high metabolic demand for proliferation. To survive, they constitutively activate the unfolded protein response (UPR). The inositol-requiring protein 1 (IRE1) and protein kinase RNA-like ER kinase (PERK) signaling branches of the UPR have been shown to have cytoprotective roles in cancer cells. UPR-induced autophagy is another prosurvival strategy of cancer cells, possibly to remove misfolded proteins and supply nutrients. However, the mechanisms by which cancer cells exploit the UPR and autophagy machinery to promote survival and the molecules that are essential for these processes remain to be elucidated. Recently, a multipass membrane protein, Yip1A, was shown to function in the activation of IRE1 and in UPR-induced autophagy. In the present study, we explored the possible role of Yip1A in activation of the UPR by cancer cells for their survival, and found that depletion of Yip1A by RNA interference (RNAi) induced apoptotic cell death in HeLa and CaSki cervical cancer cells. Intriguingly, Yip1A was found to activate the IRE1 and PERK pathways of the UPR constitutively in HeLa and CaSki cells. Yip1A mediated the phosphorylation of IRE1 and also engaged in the transcription of PERK. The activation of these signaling pathways upregulated the expression of anti-apoptotic proteins and autophagy-related proteins. These events might enhance resistance to apoptosis and promote cytoprotective autophagy in HeLa and CaSki cells. The present study is the first to uncover a key prosurvival modulator, Yip1A, which coordinates IRE1 signaling with PERK signaling to support the survival of HeLa and CaSki cervical cancer cells. PMID- 28358376 TI - RelA/p65 inhibition prevents tendon adhesion by modulating inflammation, cell proliferation, and apoptosis. AB - Peritendinous tissue fibrosis which leads to poor tendon function is a worldwide clinical problem; however, its mechanism remains unclear. Transcription factor RelA/p65, an important subunit in the NF-kappaB complex, is known to have a critical role in many fibrotic diseases. Here, we show that RelA/p65 functions as a core fibrogenic regulator in tendon adhesion and that its inhibition exerts an anti-fibrogenic effect on peritendinous adhesion. We detected the upregulation of the NF-kappaB pathway in human tendon adhesion using a gene chip microarray assay and revealed the overexpression of p65 and extracellular matrix (ECM) proteins Collagen I, Collagen III, and alpha-smooth muscle actin (alpha-SMA) in human fibrotic tissues by immunohistochemistry and western blotting. We also found that in a rat model of tendon injury, p65 expression correlated with tendon adhesion, whereas its inhibition by small interfering (si)RNA prevented fibrous tissue formation and inflammatory reaction as evidenced by macroscopic, biomechanical, histological, immunohistochemical, and western blotting analyses. Furthermore, in cultured fibroblasts, p65-siRNA, p65-specific inhibitor, Helenalin and JSH23 suppressed cell proliferation and promoted apoptosis, whereas inhibiting the mRNA and protein expression of ECM components and cyclo-oxygenase-2, an inflammatory factor involved in tendon adhesion. Our findings indicate that p65 has a critical role in peritendinous tissue fibrosis and suggest that p65 knockdown may be a promising therapeutic approach to prevent tendon adhesion. PMID- 28358378 TI - The lure of the lipids: how defensins exploit membrane phospholipids to induce cytolysis in target cells. PMID- 28358379 TI - Children's outcomes at 2-year follow-up after 4 years of structured multi professional medical-ethical decision-making in a neonatal intensive care unit. AB - OBJECTIVE: We reviewed our decisions about continuation/withdrawal of life sustaining treatments in a group of critically ill newborns who were discussed in structured medical ethical decision-making meetings, and provide the surviving children's outcomes at 2-year follow-up. STUDY DESIGN: In an explorative observational study, 61 cases were evaluated. The children involved had been discussed in such a structured way from 2009 to 2012 in a level III-D neonatal intensive care unit. RESULTS: Decisions made were: full treatment (n=6), earlier restriction cancelled (n=3), treatment restriction (n=30) and palliative care (n=22). Parents of six children disagreed with the decision proposed. Thirteen (54%) of the 24 children who survived (39%) had moderate to severe neurological problems; 8 (33%) had additional sequelae; only one 2-year-old child was healthy. CONCLUSIONS: Decisions made varied to a large extent. The poor outcomes should be disseminated among decision makers. Future studies must explore new ways to improve outcome prediction, extend follow-up periods and consider what living with severe handicaps really means for both child and family. PMID- 28358380 TI - Permission form synopses to improve parents' understanding of research: a randomized trial. AB - OBJECTIVE: We hypothesized that, among parents of potential neonatal research subjects, an accompanying cover sheet added to the permission form (intervention) would increase understanding of the research, when compared to a standard form (control). STUDY DESIGN: This pilot study enrolled parents approached for one of two index studies: one randomized trial and one observational study. A one-page cover sheet described critical study information. Families were randomized 1:1 to receive the cover sheet or not. Objective and subjective understanding and satisfaction were measured. RESULTS: Thirty-two parents completed all measures (17 control, 15 intervention). There were no differences in comprehension score (16.8+/-5.7 vs 16.3+/-3.5), subjective understanding (median 6 vs 6.5), or overall satisfaction with consent (median 7 vs 6.5) between control and intervention groups (all P>0.50). CONCLUSION: A simplified permission form cover sheet had no effect on parents' understanding of studies for which their newborns were being recruited. PMID- 28358381 TI - Success of labor induction for pre-eclampsia at preterm and term gestational ages. AB - OBJECTIVE: Determine the impact of gestational age (GA) on vaginal delivery following induction of labor (IOL) for pre-eclampsia, and evaluate factors that influence successful induction. STUDY DESIGN: Population-based retrospective cohort of 1 034 552 live births in Ohio (2006-2012). The rate of vaginal delivery in women with pre-eclampsia who underwent induction was calculated with 95% confidence intervals, stratified by week of GA at birth. Factors associated with the decision to undergo IOL, and success of IOL were evaluated, and multivariable logistic regression estimated the strength of association. RESULTS: 18 296 (71.3%) of the patients who underwent IOL had a vaginal delivery. The majority achieved vaginal delivery at both preterm (66% at 23-36 weeks) and term GAs (72%). Factors most strongly associated with vaginal delivery following IOL for pre-eclampsia included prior vaginal delivery and young maternal age. CONCLUSION: The majority of women with pre-eclampsia who undergo IOL achieve vaginal birth, even at early GAs. PMID- 28358377 TI - Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells. AB - Inhibition of complex I (CI) of the mitochondrial respiratory chain by BAY 87 2243 ('BAY') triggers death of BRAFV600E melanoma cell lines and inhibits in vivo tumor growth. Here we studied the mechanism by which this inhibition induces melanoma cell death. BAY treatment depolarized the mitochondrial membrane potential (Deltapsi), increased cellular ROS levels, stimulated lipid peroxidation and reduced glutathione levels. These effects were paralleled by increased opening of the mitochondrial permeability transition pore (mPTP) and stimulation of autophagosome formation and mitophagy. BAY-induced cell death was not due to glucose shortage and inhibited by the antioxidant alpha-tocopherol and the mPTP inhibitor cyclosporin A. Tumor necrosis factor receptor-associated protein 1 (TRAP1) overexpression in BAY-treated cells lowered ROS levels and inhibited mPTP opening and cell death, whereas the latter was potentiated by TRAP1 knockdown. Knockdown of autophagy-related 5 (ATG5) inhibited the BAY stimulated autophagosome formation, cellular ROS increase and cell death. Knockdown of phosphatase and tensin homolog-induced putative kinase 1 (PINK1) inhibited the BAY-induced Deltapsi depolarization, mitophagy stimulation, ROS increase and cell death. Dynamin-related protein 1 (Drp1) knockdown induced mitochondrial filamentation and inhibited BAY-induced cell death. The latter was insensitive to the pancaspase inhibitor z-VAD-FMK, but reduced by necroptosis inhibitors (necrostatin-1, necrostatin-1s)) and knockdown of key necroptosis proteins (receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and mixed lineage kinase domain-like (MLKL)). BAY-induced cell death was also reduced by the ferroptosis inhibitor ferrostatin-1 and overexpression of the ferroptosis inhibiting protein glutathione peroxidase 4 (GPX4). This overexpression also inhibited the BAY-induced ROS increase and lipid peroxidation. Conversely, GPX4 knockdown potentiated BAY-induced cell death. We propose a chain of events in which: (i) CI inhibition induces mPTP opening and Deltapsi depolarization, that (ii) stimulate autophagosome formation, mitophagy and an associated ROS increase, leading to (iii) activation of combined necroptotic/ferroptotic cell death. PMID- 28358382 TI - Standardized feeding regimen for reducing necrotizing enterocolitis in preterm infants: an updated systematic review. AB - OBJECTIVE: A systematic review (2005) of observational studies has reported 87% reduction in the incidence of necrotizing enterocolitis (NEC) after introducing standardized feeding regimen (SFR) in preterm infants. Considering the many new studies in this field since 2005 and the continued health burden of NEC, we aimed to systematically review the incidence of NEC in preterm infants 'before' vs 'after' implementing a SFR. STUDY DESIGN: PubMed, EMBASE, CINAHL and E-abstracts from the Pediatric Academic Society meetings and other pediatric and neonatal conference proceedings were searched in May 2016. Observational studies reporting incidence of NEC before and after implementing a SFR were included. Relevant data were extracted independently by two reviewers. Meta-analysis was conducted using random effects model (REM) and results rechecked with fixed effects model. RESULTS: Pooled results from 15 observational studies (N=18 160) using REM showed that SFR significantly reduced the incidence of NEC (risk ratio 0.22; 95% confidence interval 0.13 to 0.36; P<0.00001; I2=74%). The results remained significant after comparing studies in two epochs (1978 to 2003 vs 2004 to 2016). CONCLUSION: SFR continues to be an important tool in prevention of NEC in preterm infants. PMID- 28358383 TI - The effect of maternal age on fetal and neonatal mortality. AB - OBJECTIVE: Determine the gestational age at which the risk of fetal or neonatal death associated with delaying delivery by 1 week exceeds the risk of neonatal death associated with immediate delivery, stratified by maternal age intervals. STUDY DESIGN: We conducted a retrospective cohort study of live births, stillbirths and neonatal deaths that occurred in the United States between 2010 and 2013 using birth data. Women were classified into six age categories. Singleton, non-anomalous pregnancies without hypertensive disease or diabetes were included. Relative risks were obtained using a generalized linear model comparing the rate of death associated with immediate delivery to those of expectant management. RESULTS: For all age groups with the exception of women 44 years and older, immediate delivery was associated with lower relative risk of death by 39 weeks. For <25, 25 to 29, 30 to 34, 35 to 39, 40 to 44, odds ratios (OR) and confidence intervals (CI) were 1.0 (0.32 to 3.10), 0.67 (0.19 to 2.37), 0.80 (0.21 to 2.98), 0.67 (0.19 to 2.36) and 0.45 (0.16 to 1.31), respectively. In women 44 years and older, immediate delivery was associated with a lower relative risk of death by 38 weeks (OR: 0.35, CI: 0.14 to 0.90). CONCLUSION: Women greater than 44 years old may benefit from delivery by 38 weeks gestational age to reduce the risk of stillbirth. PMID- 28358384 TI - Field testing of decision coaching with a decision aid for parents facing extreme prematurity. AB - OBJECTIVE: The objective of this study is to assess and modify an existing decision aid and field-test decision coaching with the modified aid during consultations with parents facing potential delivery at 23 to 24 weeks gestation. STUDY DESIGN: International Patient Decision Aid Standards instrument (IPDASi) scoring deficits, multi-stakeholder group feedback and alpha-testing guided modifications. Feasibility/acceptability were assessed. The Decisional Conflict Scale was used to measure participants' decisional conflict before (T1) and immediately after (T2) the consultation. RESULTS: IPDASi assessment of the existing aid (score 11/35) indicated it required updated data, more information and a palliative care description. Following modification, IPDASi score increased to 26/35. Twenty subjects (12 pregnancies) participated in field-testing; 15 completed all questionnaires. Most participants (89%) would definitely recommend this form of consultation. Decisional conflict scores decreased (P<0.001) between T1 (52+/-25) and T2 (10+/-16). CONCLUSION: Field testing demonstrated that consultations using the aid with decision coaching were feasible, reduced decisional conflict and may facilitate shared decision-making. PMID- 28358385 TI - Group versus traditional prenatal care in low-risk women delivering at term: a retrospective cohort study. AB - OBJECTIVE: Group prenatal care (GC) models are receiving increasing attention as a means of preventing preterm birth; yet, there are limited data on whether group care improves perinatal outcomes in women who deliver at term. The purpose of this study was to evaluate our institutional experience with GC over the past decade and test the hypothesis that GC, compared with traditional individual care (TC), improves perinatal outcomes in women who deliver at term. STUDY DESIGN: We performed a retrospective cohort study of women delivering at term who participated in GC compared with TC. A group of 207 GC patients who delivered at term from 2004 to 2014 were matched in a 1:2 ratio to 414 patients with term singleton pregnancies who delivered at our institution during the same period by delivery year, maternal age, race and insurance status. The primary outcome was low birth weight (<2500 g). Secondary outcomes included early term birth (37.0 to 38 6/7 weeks), 5 min APGAR score <7, special care nursery admission, neonatal intensive care unit (NICU) admission, neonatal demise, cesarean section and number of prenatal visits. Outcomes were compared between the two groups using univariable statistics. RESULTS: Baseline characteristics were similar between the two matched groups. GC was associated with a significant reduction in low birth weight infants compared with TC (11.1% vs 19.6%; relative risk (RR) 0.57; 95% confidence interval (CI) 0.37 to 0.87). Patients in GC were significantly less likely than controls to require cesarean delivery, have low 5 min APGAR scores and need higher-level neonatal care (NICU: 1.5% vs 6.5%; RR 0.22; 95% CI 0.07 to 0.72). There were no significant differences in rates of early term birth and neonatal demise. CONCLUSIONS: Low-risk women participating in GC and delivering at term had a lower risk of low birth weight and other adverse perinatal outcomes compared with women in TC. This suggests GC is a promising alternative to individual prenatal care to improve perinatal outcomes in addition to preterm birth. PMID- 28358386 TI - Lack of pregnancy warnings on over-the-counter dermatologic products containing potentially harmful hydroquinone. AB - OBJECTIVE: To determine the presence of pregnancy warnings on over-the-counter (OTC) dermatologic products with hydroquinone, a potentially harmful ingredient. STUDY DESIGN: Data were obtained from the Food and Drug Administration National Drug Code Directory and Label Repository to identify OTC dermatologic products containing hydroquinone. Products were stratified based on pregnancy or general warning presence (WP) or absence (WA). Product characteristics were compared between groups: hydroquinone concentration, presence of external packaging, indication and warning statements. RESULTS: Of the 112 products studied, 21 had a pregnancy warning and 3 included a general warning against use: WP (n=24) and WA (n=88) group. External packaging was more prevalent in the WP group compared to WA (62.5% vs 29.5%, P=0.004). CONCLUSIONS: Majority of OTC dermatologic products containing hydroquinone did not have a pregnancy warning. This highlights the need for improved labeling and informs providers caring for pregnant women of OTC labeling limitations. PMID- 28358387 TI - Bacterial kinesin light chain (Bklc) links the Btub cytoskeleton to membranes. AB - Bacterial kinesin light chain is a TPR domain-containing protein encoded by the bklc gene, which co-localizes with the bacterial tubulin (btub) genes in a conserved operon in Prosthecobacter. Btub heterodimers show high structural homology with eukaryotic tubulin and assemble into head-to-tail protofilaments. Intriguingly, Bklc is homologous to the light chain of the microtubule motor kinesin and could thus represent an additional eukaryotic-like cytoskeletal element in bacteria. Using biochemical characterization as well as cryo-electron tomography we show here that Bklc interacts specifically with Btub protofilaments, as well as lipid vesicles and could thus play a role in anchoring the Btub filaments to the membrane protrusions in Prosthecobacter where they specifically localize in vivo. This work sheds new light into possible ways in which the microtubule cytoskeleton may have evolved linking precursors of microtubules to the membrane via the kinesin moiety that in today's eukaryotic cytoskeleton links vesicle-packaged cargo to microtubules. PMID- 28358388 TI - Reactive Hyperemia Index in Patients on Maintenance Hemodialysis: Cross-sectional Data from a Cohort Study. AB - Previous studies suggested that the reactive hyperemia index (RHI) is a promising cardiovascular risk predictor. We aimed to evaluate clinical determinants of RHI and its association with circulating endothelial injury and cardiac markers in hemodialysis patients. Among 368 patients recruited, RHI was evaluated by peripheral arterial tonometry (PAT) on a midweek nondialysis day. Clinical determinants of RHI were explored by multiple stepwise regression analysis and associations between RHI and circulating markers were evaluated by general linear models. The major cause of a failed PAT test was poor signal (82.1%). Intraclass correlation coefficient for reproducibility evaluation was 0.74. Multiple regression analysis showed traditional clinical factors only explained 7% of the variance of natural logarithm RHI (LnRHI) in the patients. In association analyses, LnRHI showed significant positive associations with Von Willebrand factor (vWF) (p = 0.04) and tissue factor (p = 0.047). It also associated positively with troponins (p <= 0.02 for both). In conclusion, performance of the PAT test was acceptable in dialysis patients and traditional clinical variables had very limited influence on RHI in these subjects. Among a panel of conventional endothelial injury markers, RHI showed very modest associations with only vWF and tissue factor. RHI associated positively with troponins in the patients. PMID- 28358389 TI - Quantitative analysis of molecular partition towards lipid membranes using surface plasmon resonance. AB - Understanding the interplay between molecules and lipid membranes is fundamental when studying cellular and biotechnological phenomena. Partition between aqueous media and lipid membranes is key to the mechanism of action of many biomolecules and drugs. Quantifying membrane partition, through adequate and robust parameters, is thus essential. Surface Plasmon Resonance (SPR) is a powerful technique for studying 1:1 stoichiometric interactions but has limited application to lipid membrane partition data. We have developed and applied a novel mathematical model for SPR data treatment that enables determination of kinetic and equilibrium partition constants. The method uses two complementary fitting models for association and dissociation sensorgram data. The SPR partition data obtained for the antibody fragment F63, the HIV fusion inhibitor enfuvirtide, and the endogenous drug kyotorphin towards POPC membranes were compared against data from independent techniques. The comprehensive kinetic and partition models were applied to the membrane interaction data of HRC4, a measles virus entry inhibitor peptide, revealing its increased affinity for, and retention in, cholesterol-rich membranes. Overall, our work extends the application of SPR beyond the realm of 1:1 stoichiometric ligand-receptor binding into a new and immense field of applications: the interaction of solutes such as biomolecules and drugs with lipids. PMID- 28358390 TI - MicroRNA exocytosis by large dense-core vesicle fusion. AB - Neurotransmitters and peptide hormones are secreted into outside the cell by a vesicle fusion process. Although non-coding RNA (ncRNA) that include microRNA (miRNA) regulates gene expression inside the cell where they are transcribed, extracellular miRNA has been recently discovered outside the cells, proposing that miRNA might be released to participate in cell-to-cell communication. Despite its importance of extracellular miRNA, the molecular mechanisms by which miRNA can be stored in vesicles and released by vesicle fusion remain enigmatic. Using next-generation sequencing, vesicle purification techniques, and synthetic neurotransmission, we observe that large dense-core vesicles (LDCVs) contain a variety of miRNAs including miR-375. Furthermore, miRNA exocytosis is mediated by the SNARE complex and accelerated by Ca2+. Our results suggest that miRNA can be a novel neuromodulator that can be stored in vesicles and released by vesicle fusion together with classical neurotransmitters. PMID- 28358391 TI - Visual deprivation selectively reshapes the intrinsic functional architecture of the anterior insula subregions. AB - The anterior insula (AI) is the core hub of salience network that serves to identify the most relevant stimuli among vast sensory inputs and forward them to higher cognitive regions to guide behaviour. As blind subjects were usually reported with changed perceptive abilities for salient non-visual stimuli, we hypothesized that the resting-state functional network of the AI is selectively reorganized after visual deprivation. The resting-state functional connectivity (FC) of the bilateral dorsal and ventral AI was calculated for twenty congenitally blind (CB), 27 early blind (EB), 44 late blind (LB) individuals and 50 sighted controls (SCs). The FCs of the dorsal AI were strengthened with the dorsal visual stream, while weakened with the ventral visual stream in the blind than the SCs; in contrast, the FCs of the ventral AI of the blind was strengthened with the ventral visual stream. Furthermore, these strengthened FCs of both the dorsal and ventral AI were partially negatively associated with the onset age of blindness. Our result indicates two parallel pathways that selectively transfer non-visual salient information between the deprived "visual" cortex and salience network in blind subjects. PMID- 28358393 TI - On-chip human microvasculature assay for visualization and quantification of tumor cell extravasation dynamics. AB - Distant metastasis, which results in >90% of cancer-related deaths, is enabled by hematogenous dissemination of tumor cells via the circulation. This requires the completion of a sequence of complex steps including transit, initial arrest, extravasation, survival and proliferation. Increased understanding of the cellular and molecular players enabling each of these steps is key to uncovering new opportunities for therapeutic intervention during early metastatic dissemination. As a protocol extension, this article describes an adaptation to our existing protocol describing a microfluidic platform that offers additional applications. This protocol describes an in vitro model of the human microcirculation with the potential to recapitulate discrete steps of early metastatic seeding, including arrest, transendothelial migration and early micrometastases formation. The microdevice features self-organized human microvascular networks formed over 4-5 d, after which the tumor can be perfused and extravasation events are easily tracked over 72 h via standard confocal microscopy. Contrary to most in vivo and in vitro extravasation assays, robust and rapid scoring of extravascular cells, combined with high-resolution imaging, can be easily achieved because of the confinement of the vascular network to one plane close to the surface of the device. This renders extravascular cells clearly distinct and allows tumor cells of interest to be identified quickly as compared with those in thick tissues. The ability to generate large numbers of devices (~36) per experiment further allows for highly parametric studies, which are required when testing multiple genetic or pharmacological perturbations. This is coupled with the capability for live tracking of single-cell extravasation events, allowing both tumor and endothelial morphological dynamics to be observed in high detail with a moderate number of data points. PMID- 28358392 TI - Analyzing trapped protein complexes by Virotrap and SFINX. AB - The analysis of protein interaction networks is one of the key challenges in the study of biology. It connects genotypes to phenotypes, and disruption of such networks is associated with many pathologies. Virtually all the approaches to the study of protein complexes require cell lysis, a dramatic step that obliterates cellular integrity and profoundly affects protein interactions. This protocol starts with Virotrap, a novel approach that avoids the need for cell homogenization by fusing the protein of interest to the HIV-1 Gag protein, trapping protein complexes in virus-like particles. By using the straightforward filtering index (SFINX), which is a powerful and intuitive online tool (http://sfinx.ugent.be) that enables contaminant removal from candidate lists resulting from mass-spectrometry-based analysis, we provide a complete workflow for researchers interested in mammalian protein complexes. Given direct access to mass spectrometers, researchers can process up to 24 samples in 7 d. PMID- 28358394 TI - Long-read ChIA-PET for base-pair-resolution mapping of haplotype-specific chromatin interactions. AB - Chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) is a robust method for capturing genome-wide chromatin interactions. Unlike other 3C based methods, it includes a chromatin immunoprecipitation (ChIP) step that enriches for interactions mediated by specific target proteins. This unique feature allows ChIA-PET to provide the functional specificity and higher resolution needed to detect chromatin interactions, which chromosome conformation capture (3C)/Hi-C approaches have not achieved. The original ChIA-PET protocol generates short paired-end tags (2 * 20 base pairs (bp)) to detect two genomic loci that are far apart on linear chromosomes but are in spatial proximity in the folded genome. We have improved the original approach by developing long-read ChIA-PET, in which the length of the paired-end tags is increased (up to 2 * 250 bp). The longer PET reads not only improve the tag-mapping efficiency but also increase the probability of covering phased single-nucleotide polymorphisms (SNPs), which allows haplotype-specific chromatin interactions to be identified. Here, we provide the detailed protocol for long-read ChIA-PET that includes cell fixation and lysis, chromatin fragmentation by sonication, ChIP, proximity ligation with a bridge linker, Tn5 tagmentation, PCR amplification and high throughput sequencing. For a well-trained molecular biologist, it typically takes 6 d from cell harvesting to the completion of library construction, up to a further 36 h for DNA sequencing and <20 h for processing of raw sequencing reads. PMID- 28358395 TI - Carbon nanotube filled with magnetic iron oxide and modified with polyamidoamine dendrimers for immobilizing lipase toward application in biodiesel production. AB - Superparamagnetic multi-walled carbon nanotubes (mMWCNTs) were prepared by filling multi-walled carbon nanotubes (MWCNTs) with iron oxide, and further modified by linking polyamidoamine (PAMAM) dendrimers (mMWCNTs-PAMAM) on the surface. Then, mMWCNTs-PAMAM was employed as the carrier and successfully immobilized Burkholderia cepacia lipase (BCL) via a covalent method (BCL-mMWCNTs G3). The maximum activity recovery of the immobilized lipase was 1,716% and the specific activity increased to 77,460 U/g-protein, 17-fold higher than that of the free enzyme. The immobilized lipase displayed significantly enhanced thermostability and pH-resistance, and could efficiently catalyze transesterification to produce biodiesel at a conversion rate of 92.8%. Moreover, it possessed better recycling performance. After 20 cycles of repeated used, it still retained ca. 90% of its original activity, since the carbon nanotube-enzyme conjugates could be easily separated from the reaction mixture by using a magnet. This study provides a new perspective for biotechnological applications by adding a magnetic property to the unique intrinsic properties of nanotubes. PMID- 28358396 TI - Combined effects of temperature and the herbicide diuron on Photosystem II activity of the tropical seagrass Halophila ovalis. AB - Tropical seagrasses are at their highest risk of exposure to photosystem II (PSII) herbicides when elevated rainfall and runoff from farms transports these toxicants into coastal habitats during summer, coinciding with periods of elevated temperature. PSII herbicides, such as diuron, can increase the sensitivity of corals to thermal stress, but little is known of the potential for herbicides to impact the thermal optima of tropical seagrass. Here we employed a well-plate approach to experimentally assess the effects of diuron on the photosynthetic performance of Halophila ovalis leaves across a 25 degrees C temperature range (36 combinations of these stressors across 15-40 degrees C). The thermal optimum for photosynthetic efficiency (?) in H. ovalis was 31 degrees C while lower and higher temperatures reduced ? as did all elevated concentrations of diuron. There were significant interactions between the effects of temperature and diuron, with a majority of the combined stresses causing sub additive (antagonistic) effects. However, both stressors caused negative responses and the sum of the responses was greater than that caused by temperature or diuron alone. These results indicate that improving water quality (reducing herbicide in runoff) is likely to maximise seagrass health during extreme temperature events that will become more common as the climate changes. PMID- 28358397 TI - Cilia distribution and polarity in the epithelial lining of the mouse middle ear cavity. AB - The middle ear conducts sound to the cochlea for hearing. Otitis media (OM) is the most common illness in childhood. Moreover, chronic OM with effusion (COME) is the leading cause of conductive hearing loss. Clinically, COME is highly associated with Primary Ciliary Dyskinesia, implicating significant contributions of cilia dysfunction to COME. The understanding of middle ear cilia properties that are critical to OM susceptibility, however, is limited. Here, we confirmed the presence of a ciliated region near the Eustachian tube orifice at the ventral region of the middle ear cavity, consisting mostly of a lumen layer of multi ciliated and a layer of Keratin-5-positive basal cells. We also found that the motile cilia are polarized coordinately and display a planar cell polarity. Surprisingly, we also found a region of multi-ciliated cells that line the posterior dorsal pole of the middle ear cavity which was previously thought to contain only non-ciliated cells. Our study provided a more complete understanding of cilia distribution and revealed for the first time coordinated polarity of cilia in the epithelium of the mammalian middle ear, thus illustrating novel structural features that are likely critical for middle ear functions and related to OM susceptibility. PMID- 28358398 TI - Changes in initial COPD treatment choice over time and factors influencing prescribing decisions in UK primary care: in UK primary care: a real-world, retrospective, observational. AB - Prescribing patterns in chronic obstructive pulmonary disease (COPD) are often inconsistent with published guidelines. This retrospective, observational study utilised data from the Optimum Patient Care Research Database to examine the changes in COPD prescribing patterns over time and to identify predictors of physician treatment choice for patients newly diagnosed with COPD. Initial therapy was defined as the treatment(s) prescribed at or within 1 year before COPD diagnosis. Changes over time were assessed in three cohorts based on the date of diagnosis: (1) 1997-2001; (2) 2002-2006; and (3) 2007-2010. Factors affecting the odds of being prescribed any initial therapy or any initial maintenance therapy were identified by univariable and multivariable logistic regression. The analysis included 20,154 patients, 45% of whom were prescribed an initial regimen containing an inhaled corticosteroid (ICS), whereas 28% received no initial pharmacological treatment. Prescribing of ICS monotherapy decreased over time, as did the proportion of patients receiving no therapy at or within 1 year before diagnosis. Comorbid asthma, a high exacerbation rate, increased symptoms and poor lung function each increased the likelihood of being prescribed any initial therapy or initial maintenance therapy; comorbid asthma and an annual rate of ?3 exacerbations were the strongest predictors. In conclusion, our analyses revealed major differences between actual prescribing behaviour and guideline recommendations for patients with newly diagnosed COPD, with many patients receiving no treatment and large numbers of patients receiving ICS containing regimens. Predictors of initial therapy were identified. PMID- 28358400 TI - Ionothermal synthesis of novel Pb-OH-Cu-X (X = Cl, Br and I) quaternary heterometallic frameworks with tunable optical properties. AB - Reported herein is the new application of ionothermal synthesis for inorganic optical materials. Under ionothermal conditions with different imidazolium ionic liquids, novel quaternary heterometallic frameworks based on [Pb4(OH)4] cubane and [CuCl4] or [CuBr4] chains and [Cu2I6] binuclear clusters have been successfully produced. Simple chlorine, bromine and iodine replacement leads to not only the space group change (tetragonal I41/acd for 1 and 2, and orthorhombic Fddd for 3) but also the topological net transformation (8,12-net for 1 and 2, and 6,6-net for 3). Notably, compounds 1, 2 and 3 all show tunable solid-state semiconducting and luminescence properties. PMID- 28358399 TI - Influence of human population movements on urban climate of Beijing during the Chinese New Year holiday. AB - The population movements for the Chinese New Year (CNY) celebrations, known as the world's largest yearly migration of human beings, have grown rapidly in the past several decades. The massive population outflows from urban areas largely reduce anthropogenic heat release and modify some other processes, and may thus have noticeable impacts on urban climate of large cities in China. Here, we use Beijing as an example to present observational evidence for such impacts over the period of 1990-2014. Our results show a significant cooling trend of up to 0.55 degrees C per decade, particularly at the nighttime during the CNY holiday relative to the background period. The average nighttime cooling effect during 2005-2014 reaches 0.94 degrees C relative to the 1990s, significant at the 99% confidence level. The further analysis supports that the cooling during the CNY holiday is attributable primarily to the population outflow of Beijing. These findings illustrate the importance of population movements in influencing urban climate despite certain limitations. As the world is becoming more mobile and increasingly urban, more efforts are called for to understand the role of human mobility at various spatial and temporal scales. PMID- 28358401 TI - Nanomaterial-based bone regeneration. AB - Bone diseases/injuries have been driving an urgent quest for bone substitutes for bone regeneration. Nanoscaled materials with bone-mimicking characteristics may create suitable microenvironments to guide effective bone regeneration. In this review, the natural hierarchical architecture of bone and its regeneration mechanisms are elucidated. Recent progress in the development of nanomaterials which can promote bone regeneration through bone-healing mimicry (e.g., compositional, nanocrystal formation, structural, and growth factor-related mimicking) is summarized. The nanoeffects of nanomaterials on the regulation of bone-related biological functions are highlighted. How to prepare nanomaterials with combinative bone-biomimicry features according to the bone healing process is prospected in order to achieve rapid bone regeneration in situ. PMID- 28358404 TI - Assumption-free morphological quantification of single anisotropic nanoparticles and aggregates. AB - Characterizing the morphometric parameters of noble metal nanoparticles for sensing and catalysis is a persistent challenge due to their small size and complex shape. Herein, we present an approach to determine the volume, surface area, and curvature of non-symmetric anisotropic nanoparticles using electron tomography and design-based stereology without the use of segmentation tools or modeling of the particles. Finally, we apply these tools to aggregates to estimate their fractal dimension. PMID- 28358407 TI - Structural, electronic and mechanical properties of sp3-hybridized BN phases. AB - Motivated by the discovery of new phases of carbon under cold high-pressure compression, we performed a global structure search of high-pressure phases of boron nitride (BN). Ten new bulk phases were identified, each energetically more stable than the graphite-like hexagonal BN (h-BN) under high pressures. All ten high-pressure phases could be viewed as involving a stacking of buckled h-BN layers. Some of these solid structures can be fabricated through the cold high pressure compression of h-BN films. According to the buckling of the h-BN layers, the new BN phases could be classified into three groups. The atomic structures, relative stabilities, electronic structures, and mechanical properties were studied in detail. A strong dependence of the relative stability, band structure, and mechanical properties on the buckling of h-BN was observed. The computed electronic band structures suggested that most of the high-pressure BN phases were insulators with wide and indirect band gaps. The calculated elastic constants and hardness suggested that several of the BN structures were superhard materials with potential applications in materials science and engineering. The computed transition paths indicated that the direct transition from h-BN to four of the new sp3-hybridized BN structures, or specifically to w-BN or bct-BN, were likely to occur through cold compression. For the other five of the new BN structures, although deeper local minima existed in the transition path, their formation through cold compression of h-BN was still plausible due to the low transition barrier from the deeper local minima to the targeted structure. PMID- 28358402 TI - Mesoporous iron-carboxylate metal-organic frameworks synthesized by the double template method as a nanocarrier platform for intratumoral drug delivery. AB - Metal-organic frameworks as a powerful platform for drug delivery have attracted significant attention in recent years. In this study, mesoporous iron-metal organic framework nanoparticles (mesoMOFs) were synthesized via the double template method. Cetyltrimethylammonium bromide (CTAB) and citric acid (CA) were chosen as the double-template agent. The mesoMOFs were characterized by EDX, elemental analysis, TG, BET, SEM, TEM, and DLS. The anticancer drug doxorubicin hydrochloride (DOX) was encapsulated in the mesoMOFs, and the DOX loading content was up to 55 wt%. The mesoMOFs are non-toxic to both 4T1 breast cancer cells and 3T3 fibroblasts. The DOX-loaded mesoMOFs exhibit a better anti-tumor effect than free doxorubicin in vitro. The in vivo anticancer activities of the DOX-loaded mesoMOFs were investigated in 4T1 breast cancer-bearing mice. The intratumoral injection of DOX-loaded mesoMOFs revealed that the mesoMOFs could significantly reduce the systemic toxicity of DOX, sustainably release DOX, and maintain an effective DOX concentration for chemotherapy. The DOX-loaded mesoMOFs exhibit excellent therapeutic efficacy and low side effects in local chemotherapy. PMID- 28358410 TI - Operando chemistry of catalyst surfaces during catalysis. AB - Chemistry of a catalyst surface during catalysis is crucial for a fundamental understanding of mechanism of a catalytic reaction performed on the catalyst in the gas or liquid phase. Due to the pressure- or molecular density-dependent entropy contribution of gas or liquid phase of the reactants and the potential formation of a catalyst surface during catalysis different from that observed in an ex situ condition, the characterization of the surface of a catalyst under reaction conditions and during catalysis can be significant and even necessary for understanding the catalytic mechanism at a molecular level. Electron-based analytical techniques are challenging for studying catalyst nanoparticles in the gas or liquid phase although they are necessary techniques to employ. Instrumentation and further development of these electron-based techniques have now made in situ/operando studies of catalysts possible. New insights into the chemistry and structure of catalyst nanoparticles have been uncovered over the last decades. Herein, the origin of the differences between ex situ and in situ/operando studies of catalysts, and the technical challenges faced as well as the corresponding instrumentation and innovations utilized for characterizing catalysts under reaction conditions and during catalysis, are discussed. The restructuring of catalyst surfaces driven by the pressure of reactant(s) around a catalyst, restructuring in reactant(s) driven by reaction temperature and restructuring during catalysis are also reviewed herein. The remaining challenges and possible solutions are briefly discussed. PMID- 28358411 TI - Advanced Glycation End Products are Increased in the Skin and Blood of Patients with Severe Psoriasis. AB - Psoriasis is frequently associated with metabolic comorbidities. Advanced glycation end products (AGEs) are highly oxidant, biologically active compounds that accumulate in tissues in association with hyperglycaemia, hyperlipidaemia and oxidative stress. This is a cross-sectional case-control study involving 80 patients with mild/severe psoriasis and 80 controls matched for age, sex and body mass index (40 with severe eczema, 40 healthy individuals). Patients and healthy individuals with a smoking habit, diabetes, dyslipidaemia, hypercholesterolaemia, hypertension or who were under systemic treatment were excluded from the study. Skin AGEs were measured in normal-appearing skin by a standard fluorescence technique, and blood AGEs (total AGEs, pentosidine and AGEs receptor) by enzyme linked immunosorbent assay. Levels of cutaneous AGEs (p < 0.04), serum AGEs (p < 0.03) and pentosidine (p <0.05) were higher in patients with severe psoriasis. Cutaneous AGEs correlated well with serum AGEs (r = 0.93, p < 0.0001) and with Psoriasis Area and Severity Index score (r = 0.91, p < 0.0001). Receptor levels were lower (p < 0.001) in severe psoriasis, and inversely correlated with disease severity (r = -0.71, p < 0.0002). Patients with severe psoriasis have accumulation of skin and serum AGEs, independent of associated metabolic disorders. PMID- 28358412 TI - Anticarcinogenic effects of water extract of sporoderm-broken spores of Ganoderma lucidum on colorectal cancer in vitro and in vivo. AB - Ganoderma lucidum (G. lucidum) polysaccharides (GLPs) have been used as traditional Chinese medicine for cancer prevention for many years. However, the mechanism by which GLP exerts its chemopreventive activities remains elusive. In addition, it is unclear whether sporoderm-broken spores of G. lucidum water extract (BSGLWE), which contains mainly GLPs, has anticancer effects on colorectal cancer. The present study investigated the anticancer effects and potential mechanisms of BSGLWE on colorectal cancer in vivo and in vitro. Our results showed that BSGLWE significantly inhibited colorectal cancer HCT116 cell viability in a time- and dose-dependent manner. Flow cytometry analysis indicated that BSGLWE disrupted cell cycle progression at G2/M phase via downregulation of cyclin B1 and cyclin A2, and upregulation of P21 at mRNA levels. Moreover, BSGLWE induced apoptosis by decreasing Bcl-2 and survivin at mRNA levels, and reduced Bcl-2, PARP, pro-caspase-3 and pro-caspase-9 at protein levels. Furthermore, BSGLWE suppressed tumor growth in vivo by regulating the expression of genes and proteins associated with cell cycle and apoptosis, which was further confirmed by a reduction of Ki67, PCNA, and Bcl-2 expression as determined by immunohistochemistry staining. NSAID activated gene-1 (NAG-1), a pro-apoptotic gene, was significantly upregulated in vivo and in vitro upon BSGLWE treatment at both mRNA and protein levels. In addition, the relative amounts of secreted NAG-1 in cell culture medium or serum of nude mice were all upregulated upon BSGLWE treatments, suggesting a role of NAG-1 in BSGLWE-induced anticolorectal cancer activity. This is the first study to show that BSGLWE inhibits colorectal cancer carcinogenesis through regulating genes responsible for cell proliferation, cell cycle and apoptosis cascades. These findings indicate that BSGLWE possesses chemopreventive potential in colorectal cancer which may serve as a promising anticancer agent for clinical applications. PMID- 28358413 TI - Nationwide survey of Baller-Gerold syndrome in Japanese population. AB - Baller-Gerold syndrome (BGS) is a rare autosomal genetic disorder characterized by radial aplasia/hypoplasia and craniosynostosis. The causative gene for BGS encodes RECQL4, which belongs to the RecQ helicase family. To understand BGS patients in Japan, a nationwide survey was conducted, which identified 2 families and 3 patients affected by the syndrome. All the three patients showed radial defects and craniosynostosis. In one patient who showed a dislocated joint of the hip and flexion contracture of both the elbow joints and wrists at birth, a homozygous large deletion in the RECQL4 gene was identified. This is the first reported case of BGS in Japan caused by RECQL4 gene mutation. PMID- 28358414 TI - Salinomycin exhibits anti-angiogenic activity against human glioma in vitro and in vivo by suppressing the VEGF-VEGFR2-AKT/FAK signaling axis. AB - Tumor angiogenesis plays a crucial role in tumor growth, progression and metastasis, and suppression of tumor angiogenesis has been considered as a promising anticancer strategy. Salinomycin (SAL), an antibiotic, displays novel anticancer potential against several human cancer cells in vitro and in vivo. However, little information concerning its anti-angiogenic properties is available. Therefore, the anti-angiogenic effect of SAL and the underlying mechanism in human glioma were evaluated in the present study. The results indicated that SAL treatment significantly inhibited human umbilical vein endothelial cell (HUVEC) proliferation, migration, invasion and capillary-like tube formation. Further investigation on intracellular mechanisms showed that SAL markedly suppressed FAK and AKT phosphorylation, and downregulated vascular endothelial growth factor (VEGF) expression in HUVECs. Pretreatment of cells with a PI3K inhibitor (LY294002) and FAK inhibitor (PF562271) markedly enhanced SAL induced inhibition of HUVEC proliferation and migration, respectively. Moreover, U251 human glioma xenograft growth was also effectively blocked by SAL treatment in vivo via inhibition of angiogenesis involving FAK and AKT depho-sphorylation. Taken together, our findings validated that SAL inhibits angiogenesis and human glioma growth through suppression of the VEGF-VEGFR2-AKT/FAK signaling axis, indicating the potential application of SAL for the treatment of human glioma. PMID- 28358415 TI - Expression levels of transcription factors c-Fos and c-Jun and transmembrane protein HAb18G/CD147 in urothelial carcinoma of the bladder. AB - The aim of the present study was to investigate the prognostic significance of the expression of transcription factors, c-Fos, c-Jun and transmembrane protein CD147, in urothelial carcinoma of the bladder (UCB). The current study investigated the clinical significance of these factors in the development, progression and survival analysis of UCB. Immunohistochemistry was employed to analyze c-Fos, c-Jun and CD147 expression in 41 UCB cases and 34 non-cancerous human bladder tissues. These results were scored in a semi-quantitative manner based on the intensity and percentage of tumor cells that presented immunoreactivity. Protein levels of CD147, c-Fos and c-Jun expression were upregulated in 22 (53.7%), 10 (24.4%) and 9 (22.0%) UCB cases, respectively. High levels of c-Jun correlated with the AJCC cancer staging manual (7th edition; P=0.038). Univariate analysis revealed that upregulated CD147 (P=0.038) or c-Jun (P=0.008) was associated with poor overall survival (OS), respectively. Further analysis revealed that either CD147-c-Fos-c-Jun co-expression (P=0.004), or CD147 c-Jun co-expression (P=0.037) and c-Fos-c-Jun co-expression (P<0.001) were associated with poor OS. Multivariate analysis suggested that either upregulation of CD147, c-Jun or c-Fos were independent risk indicators for death in UCB patients. Increased expression of c-Jun or CD147, as well as co-expression of CD147-c-Jun, c-Jun-c-Fos or CD147-c-Jun-c-Fos has prognostic significance for UCB patients. Therefore, high CD147 and c-Jun expression may serve roles in tumor progression and may be diagnostic and therapeutic targets in UCB whether alone or in combination. PMID- 28358417 TI - [Editorial] Environmental and occupational risk factors associated with different pathological conditions. AB - A wide body of evidence indicates that environmental and occupational risk factors are associated with the development of pathological disorders. The pathogenic role of many environmental pollutants or occupational contaminants is already known and has been extensively investigated. However, the molecular mechanisms of action and the pathogenic effects of many substances remain unknown. Therefore, there is a need to better investigate the role of new environmental and occupational risk factors that may cause the development of several diseases. PMID- 28358418 TI - With no interaction, knockdown of Apollon and MDR1 reverse the multidrug resistance of human chronic myelogenous leukemia K562/ADM cells. AB - Chemotherapy is the main treatment method for patients with chronic myeloid leukemia (CML) and has achieved marked results. However, the acquisition of multidrug resistance (MDR) has seriously affected the quality of life and survival rate of patients. The overexpression of the inhibitors of apoptosis proteins (IAPs) and the adenosine triphosphate (ATP)-dependent binding cassette (ABC) transporters are the two main causes of MDR. Apollon and MDR1 are the most important and representative members, respectively, among the IAPs and ABC transporters. In the present study, we investigated the role of Apollon and MDR1 in chemotherapy resistance and their mechanism of interaction. We respectively knocked down the expression of Apollon and MDR1 using short hairpin RNA (shRNA) in adriamycin (ADM) resistant human CML K562 cells and examined the drug sensitivity, the consequences with regard to ADM accumulation and the alterations in the expression of Apollon and MDR1. The expression levels of Apollon and MDR1 mRNA were higher in the K562/ADM cells compared with the parental K562 cells as determined by reverse transcription-polymerase chain reaction (RT-PCR). The plasmids of Apollon and MDR1 shRNA were respectively stably transfected into K562/ADM cells using Lipofectamine 2000. The transfection efficiency was detected by fluorescence microscopy. Cell Counting Kit-8 (CCK-8) assay revealed that Apollon or MDR1 knockdown significantly increased the chemosensitivity of the K562/ADM cells to ADM. Flow cytometric assay revealed that K562/ADM/shMDR1 cells exhibited a significantly increased intracellular accumulation of ADM, and that changes were not found in the K562/ADM/shApollon cells. Compared with the parental K562/ADM cells, a significantly decreased expression of Apollon mRNA and protein was determined in the K562/ADM/shApollon cells without affecting the expression of MDR1 as determined by RT-PCR and western blotting. Likewise, the expression levels of MDR1 mRNA and protein also markedly downregulated in the K562/ADM/shMDR1 cells had no effect on Apollon expression. Collectively, our findings demonstrated, for the first time, that downregulation of Apollon or MDR1 through stable transfection with the Apollon- or MDR1-targeting shRNA induced MDR reversal through respective inhibition of Apollon or MDR1 expression and function. However, the reversal mechanism of Apollon and MDR1 revealed no direct interaction with each other. PMID- 28358416 TI - Cibotium barometz polysaccharides stimulate chondrocyte proliferation in vitro by promoting G1/S cell cycle transition. AB - Cibotium barometz polysaccharides (CBPS) are one of the most important bioactive components extracted from the Cibotium barometz plant, which belongs to the Dicksoniaceae family. It has been widely used for the treatment of orthopedic diseases in traditional Chinese medicine. However, the molecular mechanisms behind the therapeutic effects of CBPS remain to be clarified. In the present study, the concentration of CBPS was detected by phenol-vitriol colorimetry. Furthermore, the effects stimulated by CBPS on the viability and G1/S cell cycle transition in primary chondrocytes from Sprague-Dawley rats were investigated. A cell viability assay demonstrated that chondrocyte proliferation may be enhanced by CBPS in a dose- and time-dependent manner. The mechanism underlying the promotion of chondrocyte cell cycle was suggested to involve the stimulation of G1 to S phase transition. To further confirm the results, reverse transcription quantitative polymerase chain reaction and western blot analyses were used to detect the expression of mRNA and protein levels of cyclin D1, cyclin-dependent kinase 4 and retinoblastoma protein. The results suggested that CBPS may stimulate chondrocyte proliferation via promoting G1/S cell cycle transition. Since osteoarthritis is characterized by deficient proliferation in chondrocytes, the present study indicates that CBPS may potentially serve as a novel method for the treatment of osteoarthritis. PMID- 28358419 TI - Oncostatin M in William's E medium is suitable for initiation of hepatocyte differentiation in human induced pluripotent stem cells. AB - William's E (WE) is a suitable medium for the differentiation of human induced pluripotent stem (iPS) cells to the hepatocyte lineage. The aim of the present study was to investigate various growth factors in their ability to promote hepatocyte differentiation of iPS cells in WE medium. Human iPS 201B7 cells were cultured in WE medium supplemented with growth factors, and mRNA expression levels and promoter activities of alpha-fetoprotein (AFP) and albumin were examined by reverse transcription-quantitative polymerase chain reaction and luciferase assay, respectively. In addition, time course analysis of AFP mRNA expression was performed in 201B7 cells cultured in WE medium supplemented with oncostatin M. The results demonstrated that mRNA expression levels of AFP were significantly elevated by most growth factors tested as supplements in WE medium, except all-trans retinoic acid, compared with cells cultured in ReproFF (a medium that maintains pluripotency). The highest increase in AFP mRNA expression levels was observed by oncostatin M stimulation. Albumin mRNA expression levels were increased by all-trans retinoic acid and insulin-transferrin-selenium supplementation in WE medium compared with cells cultured in ReproFF. Oncostatin M supplementation significantly stimulated the promoter activity of the AFP gene, but no growth factor tested significantly stimulated the promoter activity of the albumin gene. By time course analysis, significant increase of AFP mRNA expression was observed on the sixth day post-stimulation, compared with cells cultured in WE medium alone. In conclusion, the present study demonstrated that oncostatin M supplementation in WE medium was sufficient to initiate hepatocyte differentiation in iPS cells. PMID- 28358420 TI - Attenuation of UV-B exposure-induced inflammation by abalone hypobranchial gland and gill extracts. AB - Exposure to solar ultraviolet B (UV-B) is a known causative factor for many skin complications such as wrinkles, black spots, shedding and inflammation. Within the wavelengths 280-320 nm, UV-B can penetrate to the epidermal level. This investigation aimed to test whether extracts from the tropical abalone [Haliotis asinina (H. asinina)] mucus-secreting tissues, the hypobranchial gland (HBG) and gills, were able to attenuate the inflammatory process, using the human keratinocyte HaCaT cell line. Cytotoxicity of abalone tissue extracts was determined using an AlamarBlue viability assay. Results showed that HaCaT cells could survive when incubated in crude HBG and gill extracts at concentrations between <11.8 and <16.9 ug/ml, respectively. Subsequently, cell viability was compared between cultured HaCaT cells exposed to serial doses of UV-B from 1 to 11 (x10) mJ/cm2 and containing 4 different concentrations of abalone extract from both the HBG and gill (0, 0.1, 2.5, 5 ug/ml). A significant increase in cell viability was observed (P<0.001) following treatment with 2.5 and 5 ug/ml extract. Without extract, cell viability was significantly reduced upon exposure to UV-B at 4 mJ/cm2. Three morphological changes were observed in HaCaT cells following UV-B exposure, including i) condensation of cytoplasm; ii) shrunken cells and plasma membrane bubbling; and iii) condensation of chromatin material. A calcein AM-propidium iodide live-dead assay showed that cells could survive cytoplasmic condensation, yet cell death occurred when damage also included membrane bubbling and chromatin changes. Western blot analysis of HaCaT cell COX 2, p38, phospho-p38, SPK/JNK and phospho-SPK/JNK following exposure to >2.5 ug/ml extract showed a significant decrease in intensity for COX-2, phospho-p38 and phospho-SPK/JNK. The present study demonstrated that abalone extracts from the HGB and gill can attenuate inflammatory proteins triggered by UV-B. Hence, the contents of abalone extract, including cellmetabolites and peptides, may provide new agents for skin anti-inflammation, preventing damage due to UV-B. PMID- 28358421 TI - Extravasated platelet aggregation in the livers of rats with drug-induced hepatic sinusoidal obstruction syndrome. AB - Oxaliplatin-based chemotherapy plays an important role in the treatment of colorectal liver metastases. Oxaliplatin, however, causes sinusoidal obstruction syndrome (SOS), which is characterized by portal hypertension, splenomegaly, thrombocytopenia, and liver dysfunction. SOS is diagnosed histopathologically by disruption of the sinusoidal endothelium, collagen deposition, fibrosis especially around zone 3, dilatation of the sinusoidal space and congestion. This study assessed the characteristics of a rat model of SOS. SOS was induced in rats by administration of monocrotaline (MCT). Blood chemistries and macroscopic and microscopic findings were compared in rats administered MCT and vehicle (control group). Levels of expression in the liver of CD41, P-selectin, rat endothelial cell antigen-1, CD34, and cleaved caspase-3 were analyzed immunohistochemically. Moreover, livers of these rats were analyzed by electron microscopy. Macroscopically, MCT-treated rats showed accumulation of bloody ascites and blue liver and were diagnosed with SOS histologically. Serum concentrations of aspartate aminotransferase (P=0.003), alanine aminotransferase (P=0.008), total bilirubin (P=0.012), direct-bilirubin (P=0.007), indirect-bilirubin (P=0.003), lactate dehydrogenase (P<0.001) and hyaluronic acid (P=0.016) were significantly higher, and platelet counts significantly lower (P=0.004), in MCT-treated than in control rats. The livers of MCT-treated rats were immunohistochemically positive for CD41 and P-selectin, suggesting platelet aggregates; for rat endothelial cell antigen-1 and CD34, suggesting sinusoidal endothelial disorder; and for cleaved caspase-3, suggesting hepatocyte apoptosis. Electron microscopic findings revealed platelet aggregation in the space of Disse in the MCT group. Extravasated platelet aggregation in Disse's space may be involved in the development of SOS. PMID- 28358422 TI - Lentivirus-mediated overexpression of CD97/ADGRE5 reverses dysregulated high glucose-induced endothelial cell migration. AB - Elevated blood glucose levels contribute to a series of complications in patients with diabetes mellitus, including chronic ulcers and accelerated atherosclerosis. Dysregulated endothelial migration induced by high glucose is important in vascular-associated complications. In the present study, cluster of differentiation (CD)97/adhesion G protein-coupled receptor 5 (ADGRE5), a member of the G protein-coupled receptor protein family, stimulated angiogenesis was investigated to determine its role in cell models of diabetes mellitus using lentivirus-mediated overexpression and siRNA transfection. The results revealed reduced expression in high glucose-treated human umbilical vein endothelial cells and in the endothelium of diabetic mice. Among the three CD97 isoforms, the majority of the expression of CD97 (EGF1,2,5) in the endothelial cells was regulated by high levels of glucose. Using stable lentivirus-mediated transfection and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology, the present study constructed CD97-overexpression and CD97-knockout endothelial cell lines. Migration assays showed that the lentivirus-mediated overexpression of CD97/ADGRE5 improved the inhibition of high glucose-induced endothelial cell migration. In addition, using cytoskeleton staining, it was found that CD97 promoted membrane ruffling and lamellipodia formation. Cell division cycle 42, a small GTP-binding protein, and its downstream factor, actin-related protein 2, were involved in CD97-induced actin reorganization in endothelial cells. Additionally, the use of transcription factor filter plate assays revealed that the nuclear translocation of signal transducer and activator of transcription 1 stimulated by high glucose contributed to the inhibited transcription of CD97. In conclusion, the present study established that the overexpression of CD97 improved high glucose-induced dysfunction of endothelial cell migration. These findings provide insight to assist in identifying therapeutic targets with potential to ameliorate certain vascular complications of diabetes. PMID- 28358424 TI - Exome sequencing reveals novel IRXI mutation in congenital heart disease. AB - Genetic variation in specific transcription factors during heart formation may lead to congenital heart disease (CHD) or even miscarriage. The aim of the present study was to identify CHD-associated genes using next generation sequencing (NGS). The whole exome DNA sequence was obtained from a stillborn fetus diagnosed with tricuspid atresia and complete transposition of the great arteries using high-throughput sequencing methods. Subsequently, genetic variants of CHD-associated genes were selected and verified in 215 non-syndromic CHD patients and 249 healthy control subjects using polymerase chain reaction combined with Sanger sequencing. Genetic variants of previously reported CHD inducing genes, such as cysteine rich with EGF like domains 1 and cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 2, were discovered through the NGS analysis. In addition, a novel non-synonymous mutation of the iroquois homeobox 1 (IRX1) gene (p.Gln240Glu) was identified. A total of three non-synonymous mutations (p.Gln240Glu, p.Ser298Asn and p.Ala381Glu) of the IRX1 gene were verified in 215 non-syndromic CHD patients, but not in 249 healthy volunteers. The results demonstrated that NGS is a powerful tool to study the etiology of CHD. In addition, the results suggest that genetic variants of the IRX1 gene may contribute to the pathogenesis of CHD. PMID- 28358423 TI - Circulating microRNA-194 regulates human melanoma cells via PI3K/AKT/FoxO3a and p53/p21 signaling pathway. AB - In the present study, we analyzed the role of microRNA-194 circulating regulated human melanoma cell growth. We found that microRNA-194 expression was markedly suppressed in human melanoma patients, compared with negative control group. Next, disease-free survival (DFS) and overall survival (OS) of high expression in human melanoma patients was higher than those of low expression in human melanoma patients. MicroRNA-194 overexpression inhibited cell proliferation, induced apoptosis, increased caspase-3/-9 activities and promoted Bax/Bcl-2 of human melanoma cells. Furthermore, microRNA-194 overexpression also suppressed PI3K/AKT/FoxO3a signaling pathway and induced p53/p21 signaling pathway. PI3K inhibitor, suppressed PI3K, phosphorylation-AKT, FoxO3a protein expression and increased the effects of microRNA-194 overexpression on cell growth, apoptosis, caspase-3/-9 activities and Bax/Bcl-2 protein expression of human melanoma cells through the induction of p53/p21 signaling pathway. Taken together, these data indicate that circulating microRNA-194 regulated human melanoma cells via PI3K/AKT/FoxO3a and p53/p21 signaling pathway. PMID- 28358426 TI - 2-Deoxy-D-glucose initiates hepatocyte differentiation in human induced pluripotent stem cells. AB - To initiate hepatocyte differentiation in human induced pluripotent stem (iPS) cells, cells are cultured in a medium lacking glucose but supplemented with galactose (hepatocyte selection medium, HSM) or in medium supplemented with oncostatin M and small molecules (hepatocyte differentiation inducer, HDI). In the present study, 2-Deoxy-D-glucose (2DG), an analogue of glucose, was utilized instead of glucose deprivation and the effect of 2DG supplementation on iPS differentiation was examined. First, 201B7 cells, an iPS cell line, were cultured in HSM or HDI media for 2 days and then subjected to reverse transcription quantitative polymerase chain reaction (RT-qPCR) in order to analyze expression levels of established hepatocyte markers, including cytosolic aspartate aminotransferase (AST), mitochondrial AST, alanine aminotransferase (ALT), and glycerol kinase. mRNA expression levels of mitochondrial AST, ALT, and glycogen synthase significantly increased following culture in HSM and HDI compared with ReproFF media. Cytosolic AST mRNA expression levels significantly increased following culture in HDI compared with ReproFF media, but not in HSM. To test the effect of 2DG on iPS differentiation, 201B7 cells were cultured in ReproFF, a feeder-free medium that retains pluripotency, supplemented with 2DG. Following 7 days of culture, the cells were subjected to RT-qPCR to analyze expression levels of alpha-fetoprotein (AFP), a marker of immature hepatocytes. AFP mRNA expression levels significantly increased with the addition of 0.1 uM 2DG in the media, and galactose addition acted synergistically with 2DG to further upregulate AFP expression. In conclusion, the present study demonstrated that hepatocyte differentiation was initiated in iPS cells cultured in HSM and HDI media and that 2DG could be used as a supplement instead of glucose deprivation to initiate hepatocyte differentiation in iPS cells. PMID- 28358425 TI - ORMDL3 is associated with airway remodeling in asthma via the ERK/MMP-9 pathway. AB - ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) has been previously implicated in asthma pathogenesis, its effect on airway remodeling remains to be elucidated. The present study examined the expression levels of ORMDL3 in a mouse model of asthma. Mice were divided into three groups: Asthmatic model (n=10), budesonide-treated (n=10) and a control group (n=8). Asthma was induced by sensitization with ovalbumin (OVA) and aluminum hydroxide on day 1, 7 and 14. Subsequently mice were exposed to OVA three times per week from day 28. In order to investigate the mechanism of airway remodeling 100 ug/kg aerosol budesonide was administered to 6 animals prior to exposure to OVA. The condition of lung tissues was assessed through histology, and the expression levels of ORMDL3, phosphorylated-extracellular-signal regulated kinase (p-ERK) and matrix metallopeptidase-9 (MMP-9) were quantified using immunohistochemistry, reverse transcription-quantitative polymerase chain reaction and western blotting. A severe inflammatory response and airway remodeling were pretreatment with budesonide. Expression levels of ORMDL3, phosphorylated (p)-ERK and MMP-9 were significantly greater in the asthma-model group; however, in the group pretreated with budesonide their expression was reduced. Expression levels of ORMDL3, p-ERK and MMP-9 were significantly positively correlated with bronchial wall thickness. ORMDL3 expression was significantly positively correlated with p-ERK and MMP-9. Therefore, increased ORMDL3 expression may induce the p-ERK/MMP-9 pathway to promote pathological airway remodeling in patients with asthma. PMID- 28358427 TI - H19 promotes the migration and invasion of colon cancer by sponging miR-138 to upregulate the expression of HMGA1. AB - Colon cancer is the most common digestive system malignancy, along with high mortality rate, familial transmissibility and hepatic metastasis. Our study investigated the role of long non-coding RNA H19 in colon cancer. We found that H19 was overexpressed in colon cancer tissues and cell lines, the interference of H19 by short hairpin RNA (shRNA) effectively decreased the migration and invasion of colon cancer cells (HT-29 and RKO). Besides, miR-138 was predicted a target of H19, and low expression of miR-138 was found in colon cancer tissues and cells. The silence of H19 strongly increased the expression of miR-138. The decreased level of miR-138 was elevated adding miR-138 mimic in RKO cells transfected with lncRNA-H19. Similarly, the upregulated level of miR-138 was downregulated adding miR-138 inhibitor in RKO cells transfected with H19 shRNA. The luciferase reporter confirmed the targeting reaction between H19 and miR-138. Moreover, the high-mobility group A (HMGA1) protein was predicted as a target of miR-138. HMGA1 was suppressed by H19 shRNA and could be up-regulated by miR-138 inhibitor. The migration and invasion ability of colon cancer was restrained by H19 shRNA and promoted by miR-138 inhibitor. Finally, the in vivo experiment revealed that H19 shRNA strongly reduced the tumor growth and tumor volume. H19 shRNA also inhibited metastasis via suppressing hepatic metastases and the expression of metastasis-related proteins. Taken together, our research indicated an H19-miR138 HMGA1 pathway in regulating the migration and invasion of colon cancer, providing new insight for treatment of colon cancer. PMID- 28358428 TI - Novel therapeutic effects of sesamin on diabetes-induced cardiac dysfunction. AB - Diabetes is a risk factor that increases the occurrence and severity of cardiovascular events. Cardiovascular complications are the leading cause of mortality of 75% of patients with diabetes >40 years old. Sesamin, the bioactive compound extracted from Sesamum indicum, is a natural compound that has diverse beneficial effects on hypoglycemia and reducing cholesterol. The aim of this study is to investigate sesamin effects to diabetes-inducing cardiac hypertrophy. In the present study bioinformatics analysis demonstrated cardiac hypertrophy signaling may be the most important pathway for upregulating genes in sesamin treated groups. To verify the bioinformatics prediction, sesamin was used as the main bioactive compound to attenuate the impact of diabetes induced by streptozotocin (STZ) on cardiac function in a rat model. The results revealed that oral administration of sesamin for 4 weeks (100 and 200 mg/kg body weight) marginally improved blood glucose levels, body weight and significantly ameliorated the effects on heart rate and blood pressure in rats with type 1 diabetes relative to control rats. The QT interval of sesamin was also reduced relative to the control group. The findings indicated that sesamin has potential cardioprotective effects in the STZ-induced diabetes model. This suggested that this can be used as a novel treatment for patients with diabetes with cardiac dysfunction complication. PMID- 28358429 TI - Heat shock exerts anticancer effects on liver cancer via autophagic degradation of aquaporin 5. AB - Previous studies described that the expression of aquaporin 5 (AQP5) was altered in tumors of various organs. AQP5 is attracting attention as a new cancer therapeutic target. In the present study, heat shock-induced changes in AQP5 expression were evaluated by immunofluorescent staining (IF) and western blotting (WB) of liver cancer cells. AQP5 knockdown experiments or a heat shock treatment were conducted, and their effects on cell volume, proliferation, cell cycle, the activity of apoptosis and migration/invasion were compared. Cycloheximide (CHX) chase experiments and double IF of AQP5 and light chain 3B (LC3B) were performed to investigate the mechanisms underlying changes in AQP5 expression. The results showed that IF and WB revealed decrease in AQP5 expression on cellular membranes and in the cytoplasm of heated cells. AQP5 knockdown and heat shock similarly decreased cell volume, suppressed migration/invasion and proliferation, and induced early apoptosis and partial G0/G1 arrest. CHX chase experiments revealed that heat shock accelerated the degradation of AQP5, which was rescued under CHX and the autophagy inhibitor, bafilomycin A1 (BafA1). Double IF showed the co localization of AQP5 and LC3B on BafA1-treated heated cells. In conclusion, we demonstrated that heat shock decreased AQP5 on cellular membranes and in the cytoplasm by activating autophagic degradation, and heat shock and AQP5 knockdown exerted similar anticancer effects, suggesting that heat shock exerts anticancer effects via the autophagic degradation of AQP5. PMID- 28358431 TI - Erythromycin attenuates metalloprotease/anti-metalloprotease imbalance in cigarette smoke-induced emphysema in rats via the mitogen-activated protein kinase/nuclear factor-kappaB activation pathway. AB - The present study investigated whether erythromycin (ERY) reduces cigarette smoke (CS)-induced emphysema in rats and aimed to determine the anti-inflammatory effect of ERY, which may identify potential treatments for chronic obstructive pulmonary disease. Furthermore, the current study focused on the potential effects on the imbalance between matrix metalloprotease (MMP) and anti-MMP activity, the phosphorylation of mitogen-activated protein kinases (MAPKs) and the nuclear factor-kappaB (NF-kappaB) signaling pathway. Wistar rats were divided into the following three groups (n=12 each): control (ERY vehicle only, without any CS exposure), CS (animals were exposed to CS for 12 weeks) and CS + ERY (animals were exposed to CS for 12 weeks and received 100 mg/kg/day ERY). The recruitment of inflammatory cells into the bronchoalveolar lavage fluid (BALF) and the histopathology of lung tissue from all groups was evaluated to grade the severity of the emphysema. The expression of MMP-2, MMP-9 and tissue inhibitor of metalloproteinase-1 was evaluated by immunohistochemistry and western blotting. The activation of MAPKs, NF-kappaB and inhibitor of NF-kappaB (IkappaBalpha), in lung tissues was examined by western blotting. Treatment with ERY resulted in fewer inflammatory cells and cytokines in the BALF, and fewer emphysema associated changes in the lungs compared with control. The stimulus of CS promoted the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p38, but not c-Jun NH2-terminal kinase, thereby inducing the activation of the ERK/MAPK signaling pathway in rats. Furthermore, CS exposure increased the expression of NF-kappaB and decreased the expression of IkappaBalpha. The levels of phosphorylated ERK1/2 and p38 were significantly reduced in rats with CS induced emphysema when treated with ERY compared with the CS group. The results of the present study therefore indicate that oral administration of ERY may suppress CS-induced emphysema by regulating inflammatory cytokines and the MMP/anti-MMP imbalance via the MAPK/NF-kappaB pathway. PMID- 28358432 TI - iRGD as a tumor-penetrating peptide for cancer therapy (Review). AB - As a tumor-targeting and -penetrating peptide, iRGD binds to alphav integrins and neuropilin-1 receptors, which are expressed at high levels on tumor cells and the surfaces of vasculature. Subsequently, iRGD penetrates deep into the tumor parenchyma with antitumor drugs, imaging agents, immune modulators and biological products. These substances are either chemically linked to the peptide or co injected with the peptide. The iRGD peptide can be readily synthesized, exhibits significantly improved penetration, compared with traditional peptides, and can effectively inhibit tumor metastasis. Therefore, the peptide is now used widely for the diagnosis and treatment of cancer. However, whether the peptide is able to promote the entry of drugs into non-targeted cells remains to be fully elucidated. In this review, an overview of iRGD is presented, focusing on its identification, mechanism of action and previous studies on its roles in various types of cancer. Studies in previous years have demonstrated the potential of the iRGD protein for tumors diagnosis and targeted treatment, which warrants further investigation. PMID- 28358430 TI - Comparison of the PI3KCA pathway in circulating tumor cells and corresponding tumor tissue of patients with metastatic breast cancer. AB - The aim of the present study was to compare the phosphatidylinositol 3-kinase (PI3KCA)-AKT serine/threonine kinase (AKT) pathway in circulating tumor cells (CTCs) and corresponding cancerous tissues. Stemness-like circulating tumor cells (slCTCs) and CTCs in epithelial-mesenchymal transition (EMT) have been implicated as the active source of metastatic spread in breast cancer (BC). In this regard, the PI3KCA-AKT signaling pathway was demonstrated to be implicated in and to be frequently mutated in BC. The present study compared this pathway in slCTCs/CTCs in EMT and the corresponding tumor tissues of 90 metastatic BC patients (pts). slCTCs and CTCs in EMT were isolated using the AdnaTest EMT-1/StemCell for the detection of aldehyde dehydrogenase 1 family member A1 (ALDH1) (singleplex PCR) and PI3KCA, AKT2 and twist family bHLH transcription factor 1 (multiplex PCR). Tumor tissue was investigated for PI3KCA hotspot mutations using Sanger sequencing of genomic DNA from micro-dissected formalin-fixed paraffin-embedded tissue, and for the expression of ALDH1 and phosphorylated AKT (pAKT), and phosphatase and tensin homolog (PTEN) loss, by immunohistochemistry. slCTCs were identified in 23% of pts (21/90 pts) and CTCs in EMT in 56% (50/90 pts) of pts. pAKT and ALDH1 positivity in tumor tissue was identified in 47 and 9% of cases, respectively, and a PTEN loss was observed in 18% of pts. A significant association was detected between pAKT expression in cancerous tissue and AKT2 expression in CTCs (P=0.037). PI3KCA mutations were detected in 32% of pts, most frequently on exons 21 (55%) and 10 (45%). Pts with PI3KCA mutations in tumor tissue had a significantly longer overall survival than pts with wild-type PI3KCA expression (P=0.007). Similar results were obtained for pts with aberrant PI3KCA signaling in CTCs and/or aberrant signaling in cancerous tissue (P=0.009). Therapy-resistant CTCs, potentially derived from the primary tumor or metastatic tissue, may be eliminated with specific PI3K pathway inhibitors, alone or in combination, to improve the prognosis of metastatic BC pts. PMID- 28358433 TI - TGFBI gene mutations analysis in Chinese families with corneal dystrophies. AB - The aim of the present study was to examine the clinical features of three Chinese families with autosomal dominant corneal dystrophy (CD) and examine transforming growth factor-beta-induced (TGFBI) gene mutations in these families. The TGFBI gene mutations were detected using direct sequencing of the whole coding regions and exon-intron boundaries of the TGFBI gene in the affected members from the three families with CD. The phenotypes of all affected individuals in the three families were observed via slit lamp examination. Sections of the cornea were used for biopsy following keratoplasty. Three types of TGFBI gene mutations, R124C, H626R and R124H, were detected in the patients from these three families. One family, with the R124C mutation, was diagnosed with lattice corneal dystrophy type 1, and the family with the H626R mutation was diagnosed with lattice corneal dystrophy type IIIB. The family with the R124H mutation was diagnosed with granular corneal dystrophy type 2. The TGFBI gene mutations were considered underlying factors in the molecular mechanism underlying the pathogenesis of cornea dystrophy. Therefore, the detection of TGFBI gene mutations may be useful in the differential diagnosis of CD. PMID- 28358434 TI - Effects of GSK2606414 on cell proliferation and endoplasmic reticulum stress associated gene expression in retinal pigment epithelial cells. AB - GSK2606414 is a novel, highly selective inhibitor of protein kinase R-like endoplasmic reticulum kinase (PERK). GSK2606414 and its analogues have recently been demonstrated to delay tumor growth and prevent neurodegeneration. The present study investigated the effects of GSK2606414 on proliferation, apoptosis, and the expression of activating transcription factor 4 (ATF4), CCAAT/enhancer binding protein homologous protein (CHOP) and vascular endothelial growth factor (VEGF) in human retinal pigment epithelial (RPE) cells under endoplasmic reticulum (ER) stress. ARPE-19 human RPE cells were treated with 0.01-50 uM GSK2606414, and ER stress was induced by thapsigargin (TG) treatment. Cell proliferation was assessed using the Cell Counting kit-8 cell viability assay. Apoptosis was detected by Annexin-V/propidium iodide double staining using flow cytometry. Western blot analysis was used to measure eukaryotic initiation factor 2alpha (eIF2alpha) phosphorylation levels. ATF4, CHOP and VEGF mRNA expression levels were assessed using reverse transcription-quantitative polymerase chain reaction. GSK2606414 treatment inhibited RPE cell proliferation in a dose dependent manner, however it did not induce apoptosis. In addition, GSK2606414 treatment inhibited eIF2alpha phosphorylation and reduced CHOP and VEGF mRNA expression levels in RPE cells under TG-induced ER stress. To the best of our knowledge, the present study is the first to demonstrate that GSK2606414 has a potential antiproliferative effect in RPE cells in vitro. This effect appeared to be achieved via inhibition of the PERK/ATF4/CHOP signaling pathway and suppression of VEGF expression levels. PMID- 28358436 TI - Rare Case of Giant Pulmonary Hydatid Cyst in a Female Patient Living in Taiz Governorate. AB - Pulmonary hydatid cyst is a common disorder in many areas of the world. In Yemen, echinococcosis is an endemic disease, however, hydatid disease of the lung is uncommon and usually caused by Echinococcus granulosus. We present a case of a 23 year old female who complained of shortness of breath, dry cough and left-sided dull aching pain for the past few weeks. Chest X-ray revealed a large, well demarcated mass involving the left mid and lower lung zones with mediastinal shift to the right. Computed tomographic scan revealed a giant, low attenuation fluid density mass with enhancing wall. The diagnosis of giant hydatid cyst was confirmed by surgery and histopathological examination. Pulmonary hydatid cyst can assume a very large size without causing any symptoms and can be discovered incidentally while performing chest X-ray for another reason. PMID- 28358437 TI - Super-resolution for Medical Image via Sparse Representation and Adaptive M estimator. AB - Objective: The goal of super-resolution is to generate high-resolution images from low-resolution input images. Methods: In this paper, a combined method based on sparse signal representation and adaptive M-estimator is proposed for single image super-resolution. With the sparse signal representation, the correlation between the sparse representation of high-resolution patches and that of low resolution patches for the identical image is learned as a set of joint dictionaries and a set of high-resolution patches is obtained for high- and low resolution patches. Then the dictionaries and high-resolution patches are used to produce the high-resolution image for a low-resolution single image. Results: At the post-processing phase, the adaptive M-estimator, combining the advantages of traditional L1 and L2 norms, is used to give further processing for the resultant high-resolution image, to reduce the artefact by learning and reconstitution, and improve the performance. Conclusion: Three experimental results show the performance improvement of the proposed algorithm over other methods. PMID- 28358435 TI - Clinical significance of T cell clonality and expression levels of immune-related genes in endometrial cancer. AB - Immune microenvironment characterized by T cell clonality as well as expression signatures of immune-related genes in endometrial cancer tissues may play significant roles in clinical outcome of patients. We aimed to investigate the clinical significance of immune-related gene expression and TCR repertoire in endometrial cancer. Using total RNAs extracted from 32 endometrioid endometrial cancer cases, we performed quantitative real-time PCR to measure mRNA expression levels of immune-related genes including TRB, CD8, GZMA, HLA-A, CD11c and PD-L1. Higher mRNA expression levels of CD8 (P=0.039) and CD11c (P=0.046) in the 32 tissue samples were significantly associated with longer progression-free survival (PFS). Expression levels of CD8 (P<0.001) and CD11c (P=0.048) were also significantly associated with longer PFS in 540 cases in TCGA database. We also performed T cell receptor beta (TCRbeta) sequencing of tumor-infiltrating lymphocytes (TILs) on an Illumina MiSeq platform. To evaluate clonal expansion of TCRbeta clonotypes, we adjusted the number of abundant TCRbeta clonotypes by TRB mRNA expression levels and examined TCR clonality with the expression levels of immune-related genes and clinicopathological factors. The cases with high clonal T cell expansion along with high PD-L1 expression in cancer tissues was related to higher mRNA expression levels of CD8 (P<0.001), GZMA (P<0.001) and HLA-A (P=0.027), showed a significantly longer PFS (P=0.015), indicating a possibility that these parameters may serve as faborable prognostic factors. Considering clinical stage, mRNA expression of CD8 (P=0.037), GZMA (P=0.027) and HLA-A (P=0.022) was significantly higher in tumors at an early stage. Thus, we identified clinical and prognostic significance of immune microenvironment including the T cell clonality of TILs as well as PD-L1 and CD11c mRNA expression levels in endometrial cancer tissues. PMID- 28358438 TI - Penetrating Ocular Trauma with Retained Intraocular Foreign Body: Management, Follow-up and Medico-legal Evaluation. AB - Ocular trauma is the leading cause of acquired monocular blindness, accounting for 1.97-6% of such cases. Particularly, penetrating ocular injuries are among the most common eye injuries with this kind of outcome. Early diagnosis and prompt management are crucial to avoid complications, and the especially dreaded enucleation. In this article, the authors describe the clinical management, and evaluate the visual and anatomical results obtained in a case of ocular injury with retained intraocular foreign body (IOFB) in a 20-year old female patient. The course of treatment involved a combination of penetrating keratoplasty with a temporary keratoprosthesis, phacoemulsification with intraocular lens implantation and pars plana vitrectomy. At three years from the initial injury, the patient was able to count fingers at 30 centimetres and anatomical restitutio ad integrum of the globe had been achieved. PMID- 28358439 TI - Cleidotrapezius: An Unusual Variant Slip from the Sternocleidomastoid. PMID- 28358440 TI - Montelukast for Postinfectious Cough: A Systematic Review of Randomized Controlled Trials. AB - Objectives: To systematically assess the efficacy and safety of montelukast for postinfectious cough (PIC) and to propose a recommendation via a systematic review of all available randomized controlled trials (RCTs). Methods: Electronic databases and relevant journals were searched for RCTs from inception to July 2014. In addition, some unpublished literature was also searched. All studies included in the systematic review met the same inclusion criteria. Methodological quality and evidence quality were examined according to Cochrane handbook. The data were extracted and trial quality was assessed independently by two reviewers. Results: Fourteen RCTs involving 1372 patients were included in our review. The methodological quality of the included trials was poor because one or more biases were observed in these studies. The quality of evidence was low to moderate levels. All trials reported better effect favouring montelukast treatment. Findings suggested that compared with other Western medication and Chinese medicine, montelukast showed significant effects in shortening cough relief time, increasing the clinic obvious effective rate, decreasing coughing frequency and severity, and improving quality of life. Adverse events were mentioned in six studies, but no serious adverse effects were reported in any of them. Conclusions: Montelukast demonstrated potential positive efficacy and safety for PIC; however, we could not come to a firm conclusion on the efficacy and safety of montelukast for PIC. More high quality randomized controlled trials are required to confirm the efficacy and safety of montelukast for PIC. PMID- 28358441 TI - Pharmacology and Anti-infective Role of Raxibacumab: A Novel Monoclonal Antibody for the Treatment of Anthrax. AB - Anthrax, caused by Bacillus anthracis (B anthracis), poses a potential threat as a bioterror agent because after inhalation, the spores rapidly cause bacteraemia and toxaemia. It produces a toxin consisting of three proteins ie protective antigen (PA), oedema factor (EF) and lethal factor (LF). Protective antigen plays a central role in the pathophysiology of anthrax and offers an excellent therapeutic target for treatment of anthrax. Raxibacumab is a recombinant, fully human, IgG1lambda monoclonal antibody directed against PA of B anthracis. It inhibits PA binding to the anthrax toxin receptor and inhibits toxin-mediated cell death. It has been approved under animal rule or animal efficacy rule by the United States Food and Drug Administration which comes into play when it is not feasible or ethical to perform controlled clinical trials in humans. It has shown promising results in various animal studies which includes significantly improved survival rates in the raxibacumab group than non-raxibacumab group. PMID- 28358442 TI - Variations of Vascular Endothelial Growth Factor and Pigment Epithelial-derived Factor Are Related to Retinopathy of Prematurity in Human Babies. AB - Background: To examine the role of variations in vascular endothelial growth factor (VEGF) and pigment epithelial-derived factor (PEDF) levels and VEGF/PEDF ratio in predicting the occurrence of retinopathy of prematurity (ROP) in extremely premature human babies. Methods: This is a retrospective hospital based case-control study of 54 preterm neonates born at or before 32 weeks of gestation between 2006 and 2007 at the Neonatal Intensive Care Unit of the First People's Hospital affiliated to Fudan University. Birthweight was less than 1250 g. Eleven diagnosed with ROP were identified as cases. A control group of 43 infants, closely matched for birthweight and gestational age, was selected. The levels of VEGF and PEDF were measured at different time points of postnatal ages. Two-way repeated measure analysis of variance (ANOVA) was performed to examine the time trend. Results: Vascular endothelial growth factor level in ROP cases showed an increasing trend during the postnatal 35 day age (p < 0.01), while it was persistently decreasing in the control group (p = 0.025). In contrast, PEDF level in the control group was steadily increasing with postnatal day ages, while it remained approximately at the same level in the study group. On the other hand, the PEDF/ VEGF ratio in cases was found to be extremely high at the beginning, then continuously declined during the entire study period, while it remained steady in the control group during the same period. Conclusion: Increased expression of VEGF levels was found to be associated with older postnatal day age in our study. Monitoring of variations in VEGF level and PEDF/VEGF ratio might be helpful in predicting the occurrence of ROP in premature human babies. PMID- 28358443 TI - Metastatic Melanoma of the Parotid Glands Bilaterally. AB - Melanoma is the most serious form of skin cancers and life-time risk of melanoma is increasing rapidly both in men and women. Melanoma in the parotid gland is seen rarely and it is more likely to be metastatic disease. We present here a rare case of metastatic malignant melanoma from the forehead skin to the parotid glands bilaterally. PMID- 28358444 TI - Micronutrients and Their Role in Oral Cancer: A Review. AB - Cancer is one of the leading causes of death across the world. Oral cancer is the sixth most common type of cancer in the world. The incidence of oral cancer increases with the increase in the consumption of carcinogens such as tobacco and alcohol as seen in south and southeast Asia. Oral cancer is seen to arise from pre-existing leukoplakia and oral submucous fibrosis. Antioxidants have been hypothesized to be chemopreventive agents for several cancers. Micronutrients such as zinc, copper and selenium, along with antioxidants are required for the production of various enzymes that help prevent DNA damage caused by free radicals. PMID- 28358445 TI - Paediatric Medulloblastoma: An Updated Review. AB - Medulloblastoma is one of the most common malignant tumours of the central nervous system in children. It affects two persons per million per year worldwide and is increasing. More than 70% of patients diagnosed with medulloblastoma are predominantly below age 10 years. Histological variants of medulloblastoma are recognized as classic, nodular-desmoplastic, large cell/anaplastic and medulloblastoma with extensive nodularity. Symptoms include headache, general malaise, failure to feed, vomiting, clumsiness and other presentations that mimic common and benign childhood pathologies seen in primary care. Study data suggested an inverse correlation between high-stage disease and duration of symptoms. Currently, medulloblastoma is classified clinically into high risk and standard (average) risk depending upon factors solely clinical - age, metastases and resection. The treatment strategies for medulloblastoma are maximal safe resection (plus/minus cerebrospinal fluid diversion), neuraxis radiotherapy and chemotherapy. Medulloblastoma is the first brain tumour to show efficacy of chemotherapy in large prospective trials. Effective chemotherapy regimens remain elusive for almost all patients with high-grade cortical or brainstem gliomas and for most young patients with residual or metastatic disease of any histology. Conventional chemotherapeutic agents continue to be developed to reduce toxicity and/or improve efficacy. Recent advances in tumour biology have changed the emphasis to novel agents that target molecular changes crucial for tumour proliferation or survival. The toxicity and efficacy of several of these novel agents are currently being assessed in children with brain tumours. PMID- 28358447 TI - Cytomegalovirus Identification in Blood and Urine of Newborns by Nested Polymerase Chain Reaction. AB - Aim: To study the frequency of congenital cytomegalovirus (CMV) infection in newborns admitted to the Division of Neonatology, using nested polymerase chain reaction (PCR) and DNA to detect differences in blood and urine specimens. Methods: The study was carried out for eight months. Newborns (n = 520) hospitalized in five hospitals in Campo Grande, Mato Grosso do Sul, Brazil, were checked for CMV by analysing blood and urine samples. Results: Cytomegalovirus was PCR positive in 13 urine and 10 blood samples. Of the 13 positive urine patients, three (23%) had no clinical signs suggestive of CMV, and another three (23%) patients admitted to the neonatal intensive care unit (NICU) had no definite findings of bacterial infection, with negative blood culture and some clinical signs consistent with CMV as cholestasis, hepatomegaly and eosinophilia. Three patients were on mechanical ventilation and showed improvement after prescription of ganciclovir. One CMV positive child progressed to death. Conclusion: Cytomegalovirus detection in urine was slightly more efficient than in blood, and showed better sensitivity than in serological analysis (p < 0.01) therefore, boiled urine may be a better and easier specimen tool for CMV diagnosis in neonatal infection. The findings of the present research suggest that patients admitted to the NICU, especially premature infants, whose laboratory results are not compatible with bacterial infection, and exhibiting signs suggestive of CMV infection should have PCR done on urine for confirmation. PMID- 28358446 TI - Evaluation of Health-related Quality of Life in Paediatric Patients with Acute Lymphoblastic Leukaemia. AB - Objective: Health-related quality of life (HRQOL) measurement is used for assessing the impact of diseases and medical treatments on physical, psychological and social aspects of an individual's health and life. The Paediatric Quality of Life InventoryTM (PedsQLTM) is a widely used instrument to measure paediatric HRQOL in children. The aim of this study is to investigate the HRQOL in paediatric patients with acute lymphoblastic leukaemia and determine the precautions for improving the quality of their life. Methods: Paediatric Quality of Life InventoryTM 4.0 was administered to 75 paediatric patients with acute lymphoblastic leukaemia, and 50 healthy age- and gender-matched children. Results: Health-related quality of life scores were significantly lower in patients with acute lymphoblastic leukaemia than in healthy controls in this study. Conclusions: It is thought that determination of the psychosocial, as well as the physical impacts of the disease on the child, will positively influence the treatment given by improving the quality of life of both the child and the family. PMID- 28358448 TI - The Place of Atopy in the Aetiology of Acute Appendicitis in Children. AB - Objective: Appendicitis, the most common cause of abdominal pain requiring surgery in children, refers to inflammation of the vermiform appendix. The aetiology of appendicitis is multifactorial, although it is affected by several precursor factors. The purpose of this study was to investigate whether allergic diseases cause a predisposition to appendicitis. Subjects and Methods: One hundred and sixteen patients who underwent surgery for acute appendicitis and who had a diagnosis of acute appendicitis confirmed pathologically, and a control group of 124 individuals of similar ages and genders, were enrolled. The level of inflammation of appendiceal material in cases diagnosed with acute appendicitis was classified pathologically. The skin prick test (SPT) was used to determine allergic sensitization. Results: A significant difference was determined between the patient and control groups in terms of skin prick positivity (p < 0.05). Conclusions: While there are several known factors implicated in the causation of acute appendicitis, the cause cannot be identified in some cases. We think that atopy may also be a risk factor in the development of acute appendicitis. PMID- 28358449 TI - Clinical and Therapeutic Implications of Histone Acetylation in Breast Cancer. AB - The contribution of epigenetic changes in triggering breast cancer initiation, promotion, progression and metastasis is an established fact. Altered expression profiling of several genes on DNA is also influenced by histone modifications. In this review, the role of those enzymes regulating histone modifications is discussed. These enzymes are termed as histone acetyltransferases (HATs) and his tone deacetylases (HDACs). Understanding of the mode of action of these enzymes will be helpful in exploring their antagonistic role on histone DNA complex. In addition to this, the significance of potential histone deacetylases inhibitors (HDIs) as potential cancer therapeutic marker is also discussed. PMID- 28358450 TI - Prevalence of Oral Lesions in the Elderly. AB - Objective: Geriatric dentistry refers to dealing with oral diseases including prevention and treatment in old individuals. The aim of this investigation was to examine the types and frequency of oral lesions in the elderly. Subjects and Methods: The study involved 75 elderly persons. The clinical diagnosis was established by correlating the aetiological factor associated with the lesion and by systematic examination of the oral mucosa and classifying those alterations according to the epidemiological guidelines for the diagnosis of oral mucosal diseases. During the clinical examination, the following elements were analysed: features of the lesion, anatomical location, extension, aetiological factors or related factors, dental status, alcohol, tobacco, trauma, use of prosthesis and if such were well adapted. Results: Sixty lesions were diagnosed in 75 patients. These were classified according to clinical, histopathological and microbiological diagnosis and were distributed into 15 different clinical entities. The more prevalent pathologies were inflammatory, reactive and associated with long-term use of prostheses or ill-adapted prostheses, since 67% of the patients with lesions were using prostheses. Of the lesions related to prosthesis use, denture stomatitis was the most common one, representing 20 cases (33.3%). The second most frequent lesion was erythematous candidiasis (10%). The other most frequent lesions in this study were lingua plicata, xerostomia and pseudomembranous candidiasis. Conclusion: Oral and perioral tissues undergo different functional and structural changes with ageing. The role of the dentist and stomatologist includes the management of systemic, nutritional and pharmacological oral manifestations in order to establish an early diagnosis and subsequent accurate treatment. PMID- 28358451 TI - Thyroid Hormone Levels in Chronic Schizophrenic Patients: Association with Psychopathology. AB - Objectives: Thyroid disorders are highly prevalent in patients with schizophrenia. Changes in the levels of thyroid hormones cause the occurrence of psychiatric disorders and affect the response to treatment. The aim of this study was to investigate the changes in thyroid hormone levels in patients with chronic schizophrenia, and to demonstrate any association between psychiatric symptoms and hormones. Methods: Sixty-three patients with schizophrenia and 53 controls were included in this study. The serum levels of free triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) in patients and controls were tested by using the chemiluminescence immunoassay. Symptoms were assessed via the Positive and Negative Syndrome Scale (PANSS). Results: The level of FT4 in the schizophrenia group was statistically significantly lower than the control group (p = 0.045). There was no significant difference between the clinical subtypes of schizophrenia and thyroid hormone levels. There was a mild negative correlation between PANSS negative subscale scores and levels of TSH (p = 0.023). Conclusion: These findings suggest that the subclinical hypothyroidism observed in the chronic schizophrenic patients may be associated with the treatment of neuroleptics. The possible alterations of thyroid hormones should be considered in chronic schizophrenic patients for treatment with neuroleptics. PMID- 28358452 TI - Effects of Different Local Anaesthetics on Oto-acoustic Emission Tests after Spinal Anaesthesia. AB - Purpose: To evaluate whether there is any effect of different local anaesthetic agents on hearing loss after spinal anaesthesia. Methods: Thirty American Society of Anesthesiologists (ASA) I patients without a hearing problem were included in the study. Transient evoked oto-acoustic emissions (TEOAE) were examined. Patients were randomly separated into two groups: Group L, 15 mg isobaric levobupivacaine application and Group B, 15 mg isobaric bupivacaine application, for spinal anaesthesia. Oto-acoustic emission measurements were repeated on patients at the 24th hour after spinal anaesthesia application. Results: No significant difference was found in the output values of the right and left ears according to the input values in group L at no kHz (p > 0.05). No significant difference was found in the output values of the right and left ears according to the input values in any kHz of Group B (p > 0.05). Conclusion: Fifteen milligrammes of isobaric bupivacaine and levobupivacaine had no significant difference on the effect of hearing loss after spinal anaesthesia. Hearing loss after spinal anaesthesia has many unknown issues, and deserves to be explored by performing many studies. PMID- 28358453 TI - Giant Cell Arteritis - Who to Refer to? AB - Giant cell arteritis is a systemic immune-mediated vasculitis affecting the medium and large arteries. Typical symptoms include new headache, jaw claudication, tender temporal artery, polymyalgia rheumatica, fever and anorexia. Visual loss resulting from giant cell arteritis is an ophthalmic emergency and requires immediate assessment and referral to the ophthalmologist for prompt treatment with steroids. This article provides a systematic approach to the diagnosis and management of giant cell arteritis. PMID- 28358454 TI - Treatment of One Case with Cryoglobulinaemia Secondary to Connective Tissue Disease with Small Doses of Rituximab. AB - Objective: This study aims to observe the clinical efficacy of low-dose rituximab in patients with cryoglobulinaemia secondary to connective tissue diseases. Methods: Rituximab (100 mg) was infused in patients once a week for four weeks, combined with prednisone (20 mg) once a day, and reduced regularly. Treatment effect was observed regularly. Results: Joint pain, fever, rash and fatigue symptoms in patients eased. The serology (globulin, erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase and others) parameters returned to normal. Conclusion: Low-dose rituximab therapy for cryoglobulinaemia secondary to connective tissue diseases was safe and effective, and can be used as a treatment option in this condition. PMID- 28358455 TI - Cushing Syndrome Caused by a Pancreatic Neuroendocrine Tumour and Its Pelvic Metastases. AB - Cushing's syndrome caused by an ectopic tumour secreting adrenocorticotropic hormone (ACTH) is not common. Furthermore, an ACTH-secreting panreatic neoplasm is extremely rare. We present a 27-year old female patient suffering from a pancreatic neuroendocrine tumour (p-NET) with extensive pelvic metastases, which could secrete ACTH and cause Cushing's syndrome. The postoperative pathologic examinations of this patient prompted pancreatic poorly differentiated neuroendocrine tumour with extensive metastases of bilateral ovarian, uterus and pelvic peritoneum. The immunohistochemical staining of her tumour tissues was positive for Chromogranin A, Synaptophysin and ACTH. The main aim of this article is to share the experience of her diagnosis and treatment and to review the relevant literature, with an emphasis on discussing the possible transfer modes. Moreover, we strongly suggest that a careful examination of pelvic cavity during the follow-up of patients diagnosed as ACTH-secreting p-NET should also be carried out. PMID- 28358456 TI - Cutaneous Chylous Bubbles and Lymphatic Pilar Reflux in a Patient with Juxta articular Dercum's Disease: A Very Rare Case. PMID- 28358457 TI - Polypharmacy and the Risk of Malnutrition among Independently-living Elderly Persons in Trinidad. AB - Objective: In this study, we evaluated the association of polypharmacy and nutritional status among independently-living elderly persons attending the outpatient clinics at the Eric Williams Medical Sciences Complex (EWMSC). Method: Participants were recruited at the outpatient pharmacy at EWMSC. Face-to-face interviews were conducted using a questionnaire consisting of sociodemographic, health and nutritional status items. Anthropometry was taken using standard procedures. Participants gave oral and written consent prior to enrolment in the study. Participation was voluntary. The study wasapproved by the Ethics Committee, EWMSC. Results: One hundred and three persons - polypharmacy (>= 6 medications) = 57; non-polypharmacy (< 6 medications) = 46 persons) - participated in the study. There was no significant difference in the age, gender, weight, height, body mass index (BMI), mid-arm circumference, calf circumference, highest educational level achieved and marital status between the groups. The number of medications prescribed was significantly positively associated with the number of ailments (r = 0.56; p < 0.001) and the risk of malnutrition (r = 0.30; p = 0.006). Persons with polypharmacy were significantly more likely than their non-polypharmacy counterparts to be at increased risk for malnutrition (OR = 3.94, 95% CI: 1.52, 10.13; p = 0.004). This finding remained highly significant after simultaneous adjustment for age, gender, ethnicity, highest educational level achieved, marital status and number of diseases (p = 0.03). Conclusion: Among participants, polypharmacy and number of ailments were positively associated with an increased risk of malnutrition. Nonetheless, the mechanisms underlying these associations remain unclear. PMID- 28358475 TI - Intelligent Textiles with Comfort Regulation and Inhibition of Bacterial Adhesion Realized by Cross-Linking Poly(n-isopropylacrylamide-co-ethylene glycol methacrylate) to Cotton Fabrics. AB - Comfort regulation and inhibition of bacterial adhesion to textiles is realized by cross-linking thermoresponsive random copolymer to the cotton fabrics. By introduction of ethylene glycol methacrylate (EGMA) monomers into n isopropylacrylamide (NIPAM) with a molar ratio of 2:18, the obtained random copolymer poly(n-isopropylacrylamide-co-ethylene glycol methacrylate), abbreviated as P(NIPAM-co-EGMA), presents a transition temperature (TT) of 40 degrees C in an aqueous solution with a concentration of 1 mg/mL. Because of the additional EGMA in the copolymer, the obtained P(NIPAM-co-EGMA) shows a glass transition temperature (Tg) of 0 degrees C, which is much lower than that of pure PNIPAM (Tg = 140 degrees C). Therefore, the introduction of P(NIPAM-co EGMA) into the cotton fabrics will have little influence on the softness of the fabrics. Due to the cross-linked P(NIPAM-co-EGMA) layer on the cotton fabrics, the porosity of the polymer layer can be adjusted by varying the external temperature below or above TT, showing that regulation of the air and moisture permeability as well as the body comfort are feasible in the cotton fabrics cross linked with P(NIPAM-co-EGMA). In addition, the cross-linked P(NIPAM-co-EGMA) layer is capable of absorbing moisture in the ambient atmosphere to form a hydrated layer on top, which can inhibit bacterial adhesion to the textiles. PMID- 28358476 TI - Ultrafine TiO2 Confined in Porous-Nitrogen-Doped Carbon from Metal-Organic Frameworks for High-Performance Lithium Sulfur Batteries. AB - Ultrafine TiO2 confined in porous-nitrogen-doped carbon is synthesized from a single metal-organic framework precursor. As a novel interlayer for lithium sulfur batteries, the TiO2@NC composite can act as both a high efficiency lithium polysulfide barrier to suppress the side reactions and an additional current collector to enhance the polysulfide redox reactions. The lithium-sulfur battery with a TiO2@NC interlayer delivers a high reversible capacity of 1460 mAh g-1 at 0.2 C and capacity retention of 71% even after 500 cycles with high rate capability. PMID- 28358477 TI - Structural Study on the Reaction Mechanism of a Free Serine Kinase Involved in Cysteine Biosynthesis. AB - A free serine kinase (SerK) is involved in l-cysteine biosynthesis in the hyperthermophilic archaeon Thermococcus kodakarensis. The enzyme converts ADP and l-serine (Ser) into AMP and O-phospho-l-serine (Sep), which is a precursor of l cysteine. SerK is the first identified enzyme that phosphorylates free serine, while serine/threonine protein kinases have been well studied. SerK displays low sequence similarities to known kinases, suggesting that its reaction mechanism is different from those of known kinases. Here, we determined the crystal structures of SerK from T. kodakarensis (Tk-SerK). The overall structure is divided into two domains. A large cleft is found between the two domains in the AMP complex and in the ADP complex. The cleft is closed in the ternary product complex (Sep, AMP, and Tk-SerK) and may also be in the ternary substrate complex (Ser, ADP, and Tk SerK). The closure may reorient the carboxyl group of E30 near to the Ogamma atom of Ser. The Ogamma atom is considered to be deprotonated by E30 and to attack the beta-phosphate of ADP to form Sep. The substantial decrease in the activity of the E30A mutant is consistent with this mechanism. Our structures also revealed the residues that contribute to the ligand binding. The conservation of these residues in uncharacterized proteins from bacteria may raise the possibility of the presence of free Ser kinases not only in archaea but also in bacteria. PMID- 28358478 TI - Free-Standing Atomically Thin ZnO Layers via Oxidation of Zinc Chalcogenide Nanosheets. AB - Monolayer ZnO represents a class of new two-dimensional (2D) materials that are expected to exhibit unique optoelectronic properties and applications. Here we report a novel strategy to synthesize free-standing atomically thin ZnO layers via the oxidation of hydrothermally grown ultrathin zinc chalcogenide nanosheets. With micrometer-scaled lateral size, the obtained ultrathin ZnO layer has a thickness of ~2 nm, and the layered structure still maintained well after high temperature oxidation. The thermal treatment strongly improves the crystal quality as well without inducing cracks or pinholes in the ultrathin layers. The atomically thin ZnO layers are highly luminescent with dominant green emission. High quality white light is obtained from the mixed phosphors containing the ZnO layers, exhibiting their potential as compelling ultraviolet-excited phosphors. PMID- 28358479 TI - Cyclometalated Platinum(II) Cyanometallates: Luminescent Blocks for Coordination Self-Assembly. AB - A family of cyanide-bridged heterometallic aggregates has been constructed of the chromophoric cycloplatinated metalloligands and coordinatively unsaturated d10 fragments {M(PPh3)n}. The tetranuclear complexes of general composition [Pt(C^N)(CN)2M(PPh3)2]2 [C^N = ppy, M = Cu (1), Ag (2); C^N = tolpy (Htolpy = 2 (4-tolyl)-pyridine), M = Cu (4), Ag (5); C^N = F2ppy (HF2ppy = 2-(4, 6 difluorophenyl)-pyridine), M = Cu (7), Ag (8)] demonstrate a squarelike arrangement of the molecular frameworks, which is achieved due to favorable coordination geometries of the bridging ligands and the metal ions. Variation of the amount of the ancillary phosphine (for M = Ag) afforded compounds [Pt(C^N)(CN)2Ag(PPh3)]2 (C^N = ppy, 3; C^N = tolpy, 6); for the latter one an alternative cluster topology, stabilized by the Pt-Ag metallophilic and eta1 Cipso(C^N)-Ag bonding, was observed. The solid-state structures of all of the title species 1-8 were determined crystallographically. The complexes exhibit moderately strong room-temperature phosphorescence as crystalline powders (Phiem = 16-34%, lambdaem = 470-511 nm). The luminescence studies and time-dependent density functional theory computational analysis indicate that the photophysical behavior is dominated by the 3pi-pi* electronic transitions localized on the cyclometalated fragment and mixed with MPtLCT contribution, while the d10 phosphine motifs have a negligible contribution into the frontier orbitals and therefore show a little influence on the emission performance of the described compounds. PMID- 28358480 TI - Hydroxylamine Promoted Goethite Surface Fenton Degradation of Organic Pollutants. AB - In this study, we construct a surface Fenton system with hydroxylamine (NH2OH), goethite (alpha-FeOOH), and H2O2 (alpha-FeOOH-HA/H2O2) to degrade various organic pollutants including dyes (methyl orange, methylene blue, and rhodamine B), pesticides (pentachlorophenol, alachlor, and atrazine), and antibiotics (tetracycline, chloramphenicol, and lincomycin) at pH 5.0. In this surface Fenton system, the presence of NH2OH could greatly promote the H2O2 decomposition on the alpha-FeOOH surface to produce .OH without releasing any detectable iron ions during the alachlor degradation, which was different from some previously reported heterogeneous Fenton counterparts. Moreover, the .OH generation rate constant of this surface Fenton system was 102-104 times those of previous heterogeneous Fenton processes. The interaction between alpha-FeOOH and NH2OH was investigated with using attenuated total reflectance Fourier transform infrared spectroscopy and density functional theory calculations. The effective degradation of organic pollutants in this surface Fenton system was ascribed to the efficient Fe(III)/Fe(II) cycle on the alpha-FeOOH surface promoted by NH2OH, which was confirmed by X-ray photoelectron spectroscopy analysis. The degradation intermediates and mineralization of alachlor in this surface Fenton system were then systematically investigated using total organic carbon and ion chromatography, liquid chromatography-mass spectrometry, and gas chromatography mass spectrometry. This study offers a new strategy to degrade organic pollutants and also sheds light on the environmental effects of goethite. PMID- 28358481 TI - Fluorescence and SERS Imaging for the Simultaneous Absolute Quantification of Multiple miRNAs in Living Cells. AB - The simultaneous imaging and quantification of multiple intracellular microRNAs (miRNAs) are particularly desirable for the early diagnosis of cancers. However, simultaneous direct imaging with absolute quantification of multiple intracellular RNAs remains a great challenge, particularly for miRNAs, which have significantly different expression levels in living cells. We designed dual signal switchable (DSS) nanoprobes using the fluorescence-Raman signal switch. The intracellular uptake and dynamic behaviors of the probe are monitored by its fluorescence signal. Meanwhile, real-time quantitative detection of multiple miRNAs is made possible by measurements of the surface-enhanced Raman spectroscopy (SERS) ratios. Moreover, the signal 1:n ratio amplification mode only responds to low-abundance miRNA (asymmetric signal amplification mode) for simultaneous visualization and quantitative detection of significantly different levels of miRNAs in living cells. miR-21 and miR-203 were successfully detected in living MCF-7 cells, in agreement with in vitro results from the same batch of cell lysates. The reported dual-spectrum imaging method promises to offer a new strategy for the intracellular imaging and detection of various types of biomolecules. PMID- 28358482 TI - Surface-Enhanced Infrared Spectroscopy Using Resonant Nanoantennas. AB - Infrared spectroscopy is a powerful tool widely used in research and industry for a label-free and unambiguous identification of molecular species. Inconveniently, its application to spectroscopic analysis of minute amounts of materials, for example, in sensing applications, is hampered by the low infrared absorption cross-sections. Surface-enhanced infrared spectroscopy using resonant metal nanoantennas, or short "resonant SEIRA", overcomes this limitation. Resonantly excited, such metal nanostructures feature collective oscillations of electrons (plasmons), providing huge electromagnetic fields on the nanometer scale. Infrared vibrations of molecules located in these fields are enhanced by orders of magnitude enabling a spectroscopic characterization with unprecedented sensitivity. In this Review, we introduce the concept of resonant SEIRA and discuss the underlying physics, particularly, the resonant coupling between molecular and antenna excitations as well as the spatial extent of the enhancement and its scaling with frequency. On the basis of these fundamentals, different routes to maximize the SEIRA enhancement are reviewed including the choice of nanostructures geometries, arrangements, and materials. Furthermore, first applications such as the detection of proteins, the monitoring of dynamic processes, and hyperspectral infrared chemical imaging are discussed, demonstrating the sensitivity and broad applicability of resonant SEIRA. PMID- 28358483 TI - Mechanistic Aspects of the Formation of Adsorbable Organic Bromine during Chlorination of Bromide-containing Synthetic Waters. AB - During chlorination of bromide-containing waters, a significant formation of brominated disinfection byproducts is expected. This is of concern because Br DBPs are generally more toxic than their chlorinated analogues. In this study, synthetic water samples containing dissolved organic matter (DOM) extracts and bromide were treated under various disinfection scenarios to elucidate the mechanisms of Br-DBP formation. The total concentration of Br-DBPs was measured as adsorbable organic bromine (AOBr). A portion of the bromine (HOBr) was found to react with DOM via electrophilic substitution (<=40%), forming AOBr, and the remaining HOBr reacted with DOM via electron transfer with a reduction of HOBr to bromide (>=60%). During chlorination, the released bromide is reoxidized (recycled) by chlorine to HOBr, leading to further electrophilic substitution of unaltered DOM sites and chlorinated DOM moieties. This leads to an almost complete bromine incorporation to DOM (>=87%). The type of DOM (3.06 <= SUVA254 <= 4.85) is not affecting this process, as long as the bromine-reactive DOM sites are in excess and a sufficient chlorine exposure is achieved. When most reactive sites were consumed by chlorine, Cl-substituted functional groups (Cl-DOM) are reacting with HOBr by direct bromination leading to Br-Cl-DOM and by bromine substitution of chlorine leading to Br-DOM. The latter finding was supported by hexachlorobenzene as a model compound from which bromoform was formed during HOBr treatment. To better understand the experimental findings, a conceptual kinetic model allowing to assess the contribution of each AOBr pathway was developed. A simulation of distribution system conditions with a disinfectant residual of 1 mgC2 L-1 showed complete conversion of Br- to AOBr, with about 10% of the AOBr formed through chlorine substitution by bromine. PMID- 28358484 TI - Structure Determination and Mechanism of Formation of a seco-Moreliane Derivative Supported by Computational Analysis. AB - Basic hydrolysis of a dichloromethane extract of Stevia lucida yielded (4R,5S,7R,9R,10R,11R)-7,9-dihydroxylongipin-2-en-1-one (1), which was oxidized and subjected to acidic conditions to generate the new seco-moreliane derivative 3. The structure of 3 was established based on NMR data interpretation and confirmed computationally. A plausible mechanism for the carbocationic rearrangement of the trione 2 to the seco-moreliane 3 was supported by DFT computations. PMID- 28358485 TI - The Primary Photochemistry of Vision Occurs at the Molecular Speed Limit. AB - Ultrafast photochemical reactions are initiated by vibronic transitions from the reactant ground state to the excited potential energy surface, directly populating excited-state vibrational modes. The primary photochemical reaction of vision, the isomerization of retinal in the protein rhodopsin, is known to be a vibrationally coherent reaction, but the Franck-Condon factors responsible for initiating the process have been difficult to resolve with conventional time resolved spectroscopies. Here we employ experimental and theoretical 2D photon echo spectroscopy to directly resolve for the first time the Franck-Condon factors that initiate isomerization on the excited potential energy surface and track the reaction dynamics. The spectral dynamics reveal vibrationally coherent isomerization occurring on the fastest possible time scale, that of a single period of the local torsional reaction coordinate. We successfully model this process as coherent wavepacket motion through a conical intersection on a ~30 fs time scale, confirming the reaction coordinate as a local torsional coordinate with a frequency of ~570 cm-1. As a result of spectral features being spread out along two frequency coordinates, we unambiguously assign reactant and product states following passage through the conical intersection, which reveal the key vibronic transitions that initiate the vibrationally coherent photochemistry of vision. PMID- 28358486 TI - Separation of Semiconducting Carbon Nanotubes for Flexible and Stretchable Electronics Using Polymer Removable Method. AB - Electronics that are soft, conformal, and stretchable are highly desirable for wearable electronics, prosthetics, and robotics. Among the various available electronic materials, single walled carbon nanotubes (SWNTs) and their network have exhibited high mechanical flexibility and stretchability, along with comparable electrical performance to traditional rigid materials, e.g. polysilicon and metal oxides. Unfortunately, SWNTs produced en masse contain a mixture of semiconducting (s-) and metallic (m-) SWNTs, rendering them unsuitable for electronic applications. Moreover, the poor solubility of SWNTs requires the introduction of insulating surfactants to properly disperse them into individual tubes for device fabrication. Compared to other SWNT dispersion and separation methods, e.g., DNA wrapping, density gradient ultracentrifugation, and gel chromatography, polymer wrapping can selectively disperse s-SWNTs with high selectivity (>99.7%), high concentration (>0.1 mg/mL), and high yield (>20%). In addition, this method only requires simple sonication and centrifuge equipment with short processing time down to 1 h. Despite these advantages, the polymer wrapping method still faces two major issues: (i) The purified s-SWNTs usually retain a substantial amount of polymers on their surface even after thorough rinsing. The low conductivity of the residual polymers impedes the charge transport in SWNT networks. (ii) Conjugated polymers used for SWNT wrapping are expensive. Their prices ($100-1000/g) are comparable or even higher than those of SWNTs ($10-300/g). These utilized conjugated polymers represent a large portion of the overall separation cost. In this Account, we summarize recent progresses in polymer design for selective dispersion and separation of SWNTs. We focus particularly on removable and/or recyclable polymers that enable low-cost and scalable separation methods. First, different separation methods are compared to show the advantages of the polymer wrapping methods. In specific, we compare different characterization methods used for purity evaluation. For s-SWNTs with high purity, i.e., >99%, short-channel (smaller than SWNT length) electrical measurement is more reliable than optical methods. Second, possible sorting mechanism and molecular design strategies are discussed. Polymer parameters such as backbone design and side chain engineering affect the polymer-SWNT interactions, leading to different dispersion concentration and selectivity. To address the above-mentioned limiting factors in both polymer contamination and cost issues, we describe two important polymer removal and cycling approaches: (i) changing polymer wrapping conformation to release SWNTs; (ii) depolymerization of conjugated polymer into small molecular units that have less affinity toward SWNTs. These methods allow the removal and recycling of the wrapping polymers, thus providing low-cost and clean s-SWNTs. Third, we discuss various applications of polymer-sorted s-SWNTs, including flexible/stretchable thin-film transistors, thermoelectric devices, and solar cells. In these applications, polymer-sorted s-SWNTs and their networks have exhibited good processability, attractive mechanical properties, and high electrical performance. An increasing number of studies have shown that the removable polymer approaches can completely remove polymer residues in SWNT networks and lead to enhanced charge carrier mobility, higher conductivity, and better heterojunction interface. PMID- 28358487 TI - Large-Scale Silicon Nanophotonic Metasurfaces with Polarization Independent Near Perfect Absorption. AB - Optically thin perfect light absorbers could find many uses in science and technology. However, most physical realizations of perfect absorption for the optical range rely on plasmonic excitations in nanostructured metallic metasurfaces, for which the absorbed light energy is quickly lost as heat due to rapid plasmon decay. Here we show that a silicon metasurface excited in a total internal reflection configuration can absorb at least 97% of incident near infrared light due to interferences between coherent electric and magnetic dipole scattering from the silicon nanopillars that build up the metasurface and the reflected wave from the supporting glass substrate. This "near-perfect" absorption phenomenon loads more than 50 times more light energy into the semiconductor than what would be the case for a uniform silicon sheet of equal surface density, irrespective of incident polarization. We envisage that the concept could be used for the development of novel light harvesting and optical sensor devices. PMID- 28358488 TI - Extension to the Silyl-Tethered Radical Cyclization: Cyclohex-2-en-1-oxy Vinyl Silanes in Stereoselective Radical Addition/Cyclization Cascades. AB - A novel radical cascade reaction of xanthates with 1 [(vinyldimethylsilyl)oxy]cyclohex-2-enes is developed. Due to the steric and electronic differentiation of the two olefinic functions, exclusive regioselectivity and high stereoselectivity of the addition-cyclization are observed. Several methods for modification of both the silicon tether and the xanthate function are reported. PMID- 28358489 TI - Facet-Specific Adsorption of Tripeptides at Aqueous Au Interfaces: Open Questions in Reconciling Experiment and Simulation. AB - The adsorption of three homo-tripeptides, HHH, YYY, and SSS, at the aqueous Au interface is investigated, using molecular dynamics simulations. We find that consideration of surface facet effects, relevant to experimental conditions, opens up new questions regarding interpretations of current experimental findings. Our well-tempered metadynamics simulations predict the rank ordering of the tripeptide binding affinities at aqueous Au(111) to be YYY > HHH > SSS. This ranking differs with that obtained from existing experimental data which used surface-immobilized Au nanoparticles as the target substrate. The influence of Au facet on these experimental findings is then considered, via our binding strength predictions of the relevant amino acids at aqueous Au(111) and Au(100)(1 * 1). The Au(111) interface supports an amino acid ranking of Tyr > HisA ? HisH > Ser, matching that of the tripeptides on Au(111), while the ranking on Au(100) is HisA > Ser ? Tyr ? HisH, with only HisA showing non-negligible binding. The substantial reduction in Tyr amino acid affinity for Au(100) vs Au(111) offers one possible explanation for the experimentally observed weaker adsorption of YYY on the nanoparticle-immobilized substrate compared with HHH. In a separate set of simulations, we predict the structures of the adsorbed tripeptides at the two aqueous Au facets, revealing facet-dependent differences in the adsorbed conformations. Our findings suggest that Au facet effects, where relevant, may influence the adsorption structures and energetics of biomolecules, highlighting the possible influence of the structural model used to interpret experimental binding data. PMID- 28358491 TI - Race Differentiation Based on Raman Spectroscopy of Semen Traces for Forensic Purposes. AB - Several novel methods to determine externally visible characteristics of body fluid donors have been developed in recent years. These tests can help forensic investigators make predictions about the appearance of a suspect or victim, such as their sex, race, hair color, or age. While their potential benefit is undeniable, these methods destroy the physical evidence in the process. Raman spectroscopy has recently been used as a nondestructive technique to test for many of these characteristics. Here, we present the results from a study to determine the race of semen donors. Using Raman spectroscopy and multivariate data analysis, we were able to build a statistical model that accurately identified the race of all 18 semen donors in the calibration data set, as well as seven additional external validation donors. These results demonstrate Raman spectroscopy's potential to differentiate Caucasian and Black semen donors using chemometrics. PMID- 28358490 TI - GoldHelix: Gold Nanoparticles Forming 3D Helical Superstructures with Controlled Morphology and Strong Chiroptical Property. AB - Plasmonic nanoparticles, particularly gold nanoparticles (GNPs) hold a great potential as structural and functional building blocks for three-dimensional (3D) nanoarchitectures with specific optical applications. However, a rational control of their assembly into nanoscale superstructures with defined positioning and overall arrangement still remains challenging. Herein, we propose a solution to this challenge by using as building blocks: (1) nanometric silica helices with tunable handedness and sizes as a matrix and (2) GNPs with diameter varying from 4 to 10 nm to prepare a collection of helical GNPs superstructures (called Goldhelices hereafter). These nanomaterials exhibit well-defined arrangement of GNPs following the helicity of the silica template. Strong chiroptical activity is evidenced by circular dichroism (CD) spectroscopy at the wavelength of the surface plasmon resonance (SPR) of the GNPs with a anisotropy factor (g-factor) of the order of 1 * 10-4, i.e., 10-fold larger than what is typically reported in the literature. Such CD signals were simulated using a coupled dipole method which fit very well the experimental data. The measured signals are 1-2 orders of magnitude lower than the simulated signals, which is explained by the disordered GNPs grafting, the polydispersity of the GNPs, and the dimension of the nanohelices. These Goldhelices based on inorganic templates are much more robust than previously reported organic-based chiroptical nanostructures, making them good candidates for complex hierarchical organization, providing a promising approach for light management and benefits in applications such as circular polarizers, chiral metamaterials, or chiral sensing in the visible range. PMID- 28358492 TI - beta-FeOOH Nanorods/Carbon Foam-Based Hierarchically Porous Monolith for Highly Effective Arsenic Removal. AB - Arsenic pollution in waters has become a worldwide issue, constituting a severe hazard to whole ecosystems and public health worldwide. Accordingly, it is highly desirable to design high-performance adsorbents for arsenic decontamination. Herein, a feasible strategy is developed for in situ growth of beta-FeOOH nanorods (NRs) on a three-dimensional (3D) carbon foam (CF) skeleton via a simple calcination process and subsequent hydrothermal treatment. The as-fabricated 3D beta-FeOOH NRs/CF monolith can be innovatively utilized for arsenic remediation from contaminated aqueous systems, accompanied by remarkably high uptake capacity of 103.4 mg/g for arsenite and 172.9 mg/g for arsenate. The superior arsenic uptake performance can be ascribed to abundant active sites and hydroxyl functional groups available as well as efficient mass transfer associated with interconnected hierarchical porous networks. In addition, the as-obtained material exhibits exceptional sorption selectivity toward arsenic over other coexisting anions at high levels, which can be ascribed to strong affinity between active sites and arsenic. More importantly, the free-standing 3D porous monolith not only makes it easy for separation and collection after treatment but also efficiently prevents the undesirable potential release of nanoparticles into aquatic environments while maintaining the outstanding properties of nanometer scale building blocks. Furthermore, the monolith absorbent is able to be effectively regenerated and reused for five cycles with negligible decrease in arsenic removal. In view of extremely high adsorption capacities, preferable sorption selectivity, satisfactory recyclability, as well as facile separation nature, the obtained 3D beta-FeOOH NRs/CF monolith holds a great potential for arsenic decontamination in practical applications. PMID- 28358493 TI - Rapid and Efficient Method for the Detection of Microplastic in the Gastrointestinal Tract of Fishes. AB - The rising evidence of microplastic pollution impacts on aquatic organisms in both marine and freshwater ecosystems highlights a pressing need for adequate and comparable detection methods. Available tissue digestion protocols are time consuming (>10 h) and/or require several procedural steps, during which materials can be lost and contaminants introduced. This novel approach comprises an accelerated digestion step using sodium hydroxide and nitric acid in combination to digest all organic material within 1 h plus an additional separation step using sodium iodide which can be used to reduce mineral residues in samples where necessary. This method yielded a microplastic recovery rate of >=95%, and all tested polymer types were recovered with only minor changes in weight, size, and color with the exception of polyamide. The method was also shown to be effective on field samples from two benthic freshwater fish species, revealing a microplastic burden comparable to that indicated in the literature. As a consequence, the present method saves time, minimizes the loss of material and the risk of contamination, and facilitates the identification of plastic particles and fibers, thus providing an efficient method to detect and quantify microplastics in the gastrointestinal tract of fishes. PMID- 28358495 TI - Tripodal S-Ligand Complexes of Copper(I) as Catalysts for Alkene Aziridination, Sulfide Sulfimidation, and C-H Amination. AB - Copper(I) complexes of tris(thioimidazolyl)borates (R'TmR), including [Cu(TmPh)(PR"3)] (R" = Ph, Cu1; Cy, Cu2) and [Cu(R'TmPh)(PR"3)]+ (R' = N methylimidazole; R" = Ph, Cy) were prepared and characterized by spectroscopic methods. The X-ray crystal structures of Cu1 and Cu2 feature a tripodal TmPh ligand coordinated in kappa3-S,S,S mode. Using Cu2 as a catalyst (loading: 1 mol %), the aziridination of styrenes and sulfimidation of thioanisoles with PhI?NTs at RT for 3 and 0.5 h, respectively, both resulted in product yields of up to 99%. Cu2 also catalyzed intramolecular amination of the aryl C-H bond of vinyl azides with up to 98% yield. DFT calculations were performed to gain insight into the mechanism of the Cu2-catalyzed aziridination reaction. PMID- 28358494 TI - Phosphonate MOFs Composite as Off-On Fluorescent Sensor for Detecting Purine Metabolite Uric Acid and Diagnosing Hyperuricuria. AB - The recent discovery of lanthanide organic frameworks (Ln-MOFs) offers the potential for biomarkers or metabolites sensing. This is another field that is closely connected with life science and medicine. In this work, a stable and luminescent phosphonate Ln-MOFs MIL-91(Al:Eu) and its derivatives composite Cu2+@MIL-91(Al:Eu) were synthesized. The rebound of luminescence of Cu2+@MIL 91(Al:Eu) that origin of Eu3+ is observed in the presence of uric acid. This On Off-On pattern is utilized for detecting uric acid, which is the final metabolite of purine. The composite reveals excellent selectivity and sensitivity for sensing uric acid. The detection of uric acid in real urine is also investigated. The effective detection of uric acid and tentative diagnosis of hyperuricuria on the basis of test paper is demonstrated. PMID- 28358496 TI - Ultraviolet Patterned Calixarene-Derived Supramolecular Gels and Films with Spatially Resolved Mechanical and Fluorescent Properties. AB - Supramolecular assemblies have in the past been considered mechanically weak and in most cases unable to withstand their own weight. Calixarene-derived networks can, however, provide robust supramolecular gels. Incorporating a photoreactive stilbene moiety, we show that the aggregation state of the material can be tuned by heating and UV exposure in order to control the mechanical as well as the fluorescent properties. Regulating the extent of heating to control the proportion of H-aggregates and J-aggregates and further cross-linking of H aggregates by control over UV exposure allows for adjustable photopatterning of the fluorescence as well as the material stiffness in the range from ~100 to 450 kPa. We expect this straightforward supramolecular system will be suitable for advanced prototyping in applications where modulus and shape are important design criteria. PMID- 28358497 TI - beta-Selective Reductive Coupling of Alkenylpyridines with Aldehydes and Imines via Synergistic Lewis Acid/Photoredox Catalysis. AB - Umpolung (polarity reversal) strategies of aldehydes and imines have dramatically expanded the scope of carbonyl and iminyl chemistry by facilitating reactions with non-nucleophilic reagents. Herein, we report the first visible light photoredox-catalyzed beta-selective reductive coupling of alkenylpyridines with carbonyl or iminyl derivatives with the aid of a Lewis acid co-catalyst. Our process tolerates complex molecular scaffolds (e.g., sugar, natural product, and peptide derivatives) and is applicable to the preparation of compounds containing a broad range of heterocyclic moieties. Mechanistic investigations indicate that the key step involves single-electron-transfer reduction of aldehydes or imines followed by the addition of resulting ketyl or alpha-aminoalkyl radicals to Lewis acid-activated alkenylpyridines. PMID- 28358498 TI - Can Coinage Metal Atoms Be Capable of Serving as an Excess Electron Source of Alkalides with Considerable Nonlinear Optical Responses? AB - Alkalides, as a representative kind of excess electron compounds, have been demonstrated to be potential nonlinear optical (NLO) materials with large static first hyperpolarizabilities (beta0). The possibility of utilizing coinage metal atoms as a novel excess electron source to design a series of alkalides, i.e., (M@36adz)M' (M = Cu, Ag, and Au; M' = Li, Na, and K), was examined by density functional theory calculations. The alkalide characteristics of these compounds are guaranteed by their HOMOs and VIE values as well as NBO analysis. In particular, all proposed alkalides exhibit considerable first hyperpolarizabilities (beta0) up to 61 590 au, indicating that they can be considered as novel NLO molecules of high performance. Moreover, a larger cage complexant has been considered, and the resulting (Ag+@TriPip222)K- alkalide possesses a remarkably large beta0 value of 180 068 au. We hope that this work will provide a new recipe for designing excess electron compounds and, on the other hand, attract more research interest and efforts in exploring new, unconventional alkalides. PMID- 28358499 TI - Investigation of a Quantum Monte Carlo Protocol To Achieve High Accuracy and High Throughput Materials Formation Energies. AB - High-throughput calculations based on density functional theory (DFT) methods have been widely implemented in the scientific community. However, depending on both the properties of interest as well as particular chemical/structural phase space, accuracy even for correct trends remains a key challenge for DFT. In this work, we evaluate the use of quantum Monte Carlo (QMC) to calculate material formation energies in a high-throughput environment. We test the performance of automated QMC calculations on 21 compounds with high quality reference data from the Committee on Data for Science and Technology (CODATA) thermodynamic database. We compare our approach to different DFT methods as well as different pseudopotentials, showing that errors in QMC calculations can be progressively improved especially when correct pseudopotentials are used. We determine a set of accurate pseudopotentials in QMC via a systematic investigation of multiple available pseudopotential libraries. We show that using this simple automated recipe, QMC calculations can outperform DFT calculations over a wide set of materials. Out of 21 compounds tested, chemical accuracy has been obtained in formation energies of 11 structures using our QMC recipe, compared to none using DFT calculations. PMID- 28358500 TI - Molecular Mechanism of Dioxin Formation from Chlorophenol based on Electron Paramagnetic Resonance Spectroscopy. AB - Few studies have investigated the free radical intermediates involved in the formation of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) from chlorophenol. This study clarified the reaction pathways during thermochemical formation of PCDDs from 2,3,6-trichlorophenol (TCP) over a Cu(II)O/silica matrix, which was used to simulate fly ash, at 298-523 K. The reaction was studied using electron paramagnetic resonance (EPR) spectroscopy and theoretical calculations. In situ EPR indicated the TCP radical (TCPR) formed by hydrogen abstraction of TCP. Five elementary processes including dimerization of TCPR, ortho-chloride abstraction, Smiles rearrangement, ring closure, and intra-annular elimination of Cl were proposed to occur during formation of PCDDs. The proposed mechanism was further confirmed by the detection of PCDD products from thermochemical experiments in a tube furnace. Several dominant congeners, including 1,2,6,9 tetrachlorodibenzo-p-dioxin (TeCDD), 1,2,6,7-TeCDD, 1,2,8,9-TeCDD, and 1,4,6,9 TeCDD were detected by gas chromatography/quadrupole time-of-flight mass spectrometry, and further confirmed by gas chromatography/high resolution mass spectrometry. The detected PCDD products agree with the proposed PCDD formation mechanism. Relatively high temperatures were found to lead to dechlorination of TCPR to form phenoxy radicals in addition to PCDD/Fs. These radicals will be attached to particles, which will increase their lifetimes. These reactions were further verified by molecular orbital theory calculations. The discovery of persistent phenoxy radicals is of environmental significance because of their potential toxicity. The details of this mechanism could be used for controlling PCDD/F formation during industrial thermal processes. PMID- 28358501 TI - Markers, Reactions, and Interactions during the Aging of Pinus Resin Assessed by Raman Spectroscopy. AB - The resin extracted from the species of the Pinus genus (Pinaceae family) is a widely used material. Primarily, resins are made up of two types of diterpenoids: abietanes and pimaranes. Their composition changes with aging, affecting their chemical and physical properties; however, the chemical changes that occur during aging are not yet fully known. Understanding the evolution of pimaranes and abietanes and the chemical composition of the aged resins is essential to make the most of this substance and of its derivatives. A systematic study of the aging of Pinus resin with Raman complemented with infrared (IR) spectroscopy was carried out. This study provided new information about the interactions among the constituting molecules in resins aged over many years. In particular the formation of intermolecular hydrogen bonds in aged samples was detected for the first time, and the formation of acid anhydrides from the reaction between pimaranes was demonstrated. Furthermore, Raman and IR spectra band assignments are proposed, and the specific markers of the main compounds of the resin are tagged. This will facilitate the qualitative analysis of resin compounds. PMID- 28358502 TI - Bioactive Triterpenoids from the Twigs of Chaenomeles sinensis. AB - Chaenomeles sinensis has been consumed traditionally for the treatment of throat diseases, diarrhea, inflammatory diseases, and dry beriberi. Repeated chromatography of the CHCl3-soluble fraction from the 80% MeOH extract of C. sinensis twigs led to the isolation of three new triterpenoids, sinenic acid A (1), 3beta-O-cis-feruloyl-2alpha,19alpha-dihydroxyurs-12-en-28-oic acid (2), and 3beta-O-cis-caffeoylbetulin (3), together with 20 analogues. The chemical structures of 1-3 were determined using diverse NMR techniques and HRMS data analysis, chemical methods, and computational approaches supported by advanced statistics (CP3). All the purified compounds were evaluated not only for their cytotoxicity against four human tumor cell lines (A549, SK-OV-3, SK-MEL-2, and HCT-15) but for their potential neuroprotective effects through induction of nerve growth factor in C6 glioma cells. Their anti-inflammatory effects were also assessed by measuring nitric oxide levels in lipopolysaccharide-insulted murine microglia BV2 cells. PMID- 28358504 TI - Oxidation-State-Dependent Vibrational Dynamics Probed with 2D-IR. AB - In an effort to examine the role of electronic structure and oxidation states in potentially modifying intramolecular vibrational dynamics and intermolecular solvation, we have used 2D-IR to study two distinct oxidation states of an organometallic complex. The complex, [1,1' bis(diphenylphosphino)ferrocene]tetracarbonyl chromium (DPPFCr), consists of a catalytic diphenylphosphino ferrocene redox-active component as well as a Cr that can be switched from a Cr(0) to a Cr(I) oxidation state using a chemical oxidant in dichloromethane (DCM) solution. The DPPFCr(I) radical cation is sufficiently stable to investigate with 2D-IR spectroscopy, which provides dynamical information such as vibrational relaxation, intramolecular vibrational redistribution, as well as solvation dynamics manifested as spectral diffusion. Our measurements show that the primarily intramolecular dynamical processes vibrational relaxation and redistribution-differ significantly between the two oxidation states, with faster relaxation in the oxidized DPPFCr(I) radical cation. The primarily intermolecular spectral diffusion dynamics, however, exhibit insignificant oxidation state dependence. We speculate that the low nucleophilicity (i.e., donicity) of the DCM solvent, which is chosen to facilitate the chemical oxidation, masks any potential changes in solvation dynamics accompanying the substantial decrease in the 2.5 D molecular dipole moment of DPPFCr(I) relative to DPPFCr(0) (7.5 D). PMID- 28358503 TI - Coupled Effect of Ferrous Ion and Oxygen on the Electron Selectivity of Zerovalent Iron for Selenate Sequestration. AB - Although the electron selectivity (ES) of zerovalent iron (ZVI) for target contaminant and its utilization ratio (UR) decide the removal capacity of ZVI, little effort has been made to improve them. Taking selenate [Se(VI)] as a target contaminant, this study investigated the coupled influence of aeration gas and Fe(II) on the ES and UR of ZVI. Oxygen was necessary for effective removal of Se(VI) by ZVI without Fe(II) addition. Due to the application of 1.0 mM Fe(II), the ES of ZVI was increased from 3.2-3.6% to 6.2-6.8% and the UR of ZVI was improved by 5.0-19.4% under aerobic conditions, which resulted in a 100-180% increase in the Se(VI) removal capacity by ZVI. Se(VI) reduction by Fe0 was a heterogeneous redox reaction, and the enrichment of Se(VI) on ZVI surface was the first step of electron transfer from Fe0 core to Se(VI). Oxygen promoted the generation of iron (hydr)oxides, which facilitated the enrichment of Se(VI) on the ZVI particle surface. Therefore, the high oxygen fraction (25-50%) in the purging gas resulted in only a slight decrease in the ES of ZVI. Fe(II) addition resulted in a pH drop and promoted the generation of lepidocrocite and magnetite, which benefited Se(VI) adsorption and the following electron transfer from underlying Fe0 to surface-located Se(VI). PMID- 28358505 TI - Temperature-Responsive Ionic Liquids: Fundamental Behaviors and Catalytic Applications. AB - Temperature-responsive ionic liquids (ILs), their fundanmental behaviors, and catalytic applications were introduced, especially the concepts of upper critical solution temperature (UCST) and lower critical solution temperature (LCST). It is described that, during a catalytic reaction, they form a homogeneous mixture with the reactants and products at reaction temperature but separate from them afterward at ambient conditions. It is shown that this behavior offers an effective alternative approach to overcome gas/liquid-solid interface mass transfer limitations in many catalytic transformations. It should be noted that IL-based thermomorphic systems are rarely elaborated until now, especially in the field of catalytic applications. The aim of this article is to provide a comprehensive review about thermomorphic mixtures of an IL with H2O and/or organic compounds. Special focus is laid on their temperature dependence concerning UCST and LCST behavior, including systems with conventional ILs, metal containing ILs, polymerized ILs, as well as the thermomorphic behavior induced via host-guest complexation. A wide range of applications using thermoregulated IL systems in chemical catalytic reactions as well as enzymatic catalysis were also demonstrated in detail. The conclusion is drawn that, due to their highly attractive behavior, thermoregulated ILs have already and will find more applications, not only in catalysis but also in other areas. PMID- 28358506 TI - Disaggregation is a Mechanism for Emission Turn-On of ortho Aminomethylphenylboronic Acid-Based Saccharide Sensors. AB - ortho-Aminomethylphenylboronic acid-based receptors with appended fluorophores are commonly used as molecular sensors for saccharides in aqueous media. The mechanism for fluorescence modulation in these sensors has been attributed to some form of photoinduced electron transfer (PET) quenching, which is diminished in the presence of saccharides. Using a well-known boronic acid-based saccharide sensor (3), this work reveals a new mechanism for fluorescence turn-on in these types of sensors. Compound 3 exhibits an excimer, and the associated ground-state aggregation is responsible for fluorescence modulation under certain conditions. When fructose was titrated into a solution of 3 in 2:1 water/methanol with NaCl, the fluorescence intensity increased. Yet, when the same titration was repeated in pure methanol, a solvent in which the sensor does not aggregate, no fluorescence response to fructose was observed. This reveals that the fluorescence increase is not fully associated with fructose binding, but instead disaggregation of the sensor in the presence of fructose. Further, an analogue of the sensor that does not contain a boronic acid (4) responded nearly identically to 3 in the presence of fructose, despite having no functional group with which to bind the saccharide. This further supports the claim that fluorescence modulation is not primarily a result of binding, but of disaggregation. Using an indicator displacement assay and isothermal titration calorimetry, it was confirmed that fructose does indeed bind to the sensor. Thus, our evidence reveals that while binding occurs with fructose in the aqueous solvent system used, it is not related to the majority of the fluorescence modulation. Instead, disaggregation dominates the signal turn-on, and is thus a mechanism that should be investigated in other ortho-aminomethylphenylboronic acid-based sensors. PMID- 28358507 TI - Protein Degradation via CRL4CRBN Ubiquitin Ligase: Discovery and Structure Activity Relationships of Novel Glutarimide Analogs That Promote Degradation of Aiolos and/or GSPT1. AB - We previously disclosed the identification of cereblon modulator 3 (CC-885), with potent antitumor activity mediated through the degradation of GSPT1. We describe herein the structure-activity relationships for analogs of 3 with exploration of the structurally related dioxoisoindoline class. The observed activity of protein degradation could in part be rationalized through docking into the previously disclosed 3-CRBN-GSPT1 cocrystal ternary complex. For SAR that could not be rationalized through the cocrystal complex, we sought to predict SAR through a QSAR model developed in house. Through these analyses, selective protein degradation could be achieved between the two proteins of interest, GSPT1 and Aiolos. PMID- 28358508 TI - Cr0.5Nb24.5O62 Nanowires with High Electronic Conductivity for High-Rate and Long Life Lithium-Ion Storage. AB - Intercalation-type TiNbxO2+2.5x (x = 2, 5, and 24) anode materials have recently become more interesting for lithium-ion batteries (LIBs) due to their large theoretical capacities of 388-402 mAh g-1. However, the Ti4+/Nb5+ ions in TiNbxO2+2.5x with empty 3d/4d orbitals usually lead to extremely low electronic conductivity of <10-9 S cm-1, greatly restricting their practical capacity and rate capability. Herein, we report a class of highly conductive Cr0.5Nb24.5O62 nanowires as an intercalation-type anode material for high-performance LIBs. The as-made Cr0.5Nb24.5O62 nanowires show an open shear ReO3 crystal structure (C2 space group) with 4% tetrahedra and a conducting characteristic with ultrahigh electronic conductivity of 3.6 * 10-2 S cm-1 and a large Li+-ion diffusion coefficient of 2.19 * 10-13 cm2 s-1. These important characteristics make them deliver outstanding electrochemical properties in term of the largest reversible capacity (344 mAh g-1 at 0.1 C) in all the known niobium- and titanium-based anode materials, safe working potential (~1.65 V vs Li/Li+), high first-cycle Coulombic efficiency (90.8%), superior rate capability (209 mAh g-1 at 30 C), and excellent cycling stability, making them among the best for LIBs in niobium- and titanium-based anode materials. PMID- 28358509 TI - How Solvent Dynamics Controls the Schlenk Equilibrium of Grignard Reagents: A Computational Study of CH3MgCl in Tetrahydrofuran. AB - The Schlenk equilibrium is a complex reaction governing the presence of multiple chemical species in solution of Grignard reagents. The full characterization at the molecular level of the transformation of CH3MgCl into MgCl2 and Mg(CH3)2 in tetrahydrofuran (THF) by means of ab initio molecular dynamics simulations with enhanced-sampling metadynamics is presented. The reaction occurs via formation of dinuclear species bridged by chlorine atoms. At room temperature, the different chemical species involved in the reaction accept multiple solvation structures, with two to four THF molecules that can coordinate the Mg atoms. The energy difference between all dinuclear solvated structures is lower than 5 kcal mol-1. The solvent is shown to be a direct key player driving the Schlenk mechanism. In particular, this study illustrates how the most stable symmetrically solvated dinuclear species, (THF)CH3Mg(MU-Cl)2MgCH3(THF) and (THF)CH3Mg(MU-Cl)(MU CH3)MgCl(THF), need to evolve to less stable asymmetrically solvated species, (THF)CH3Mg(MU-Cl)2MgCH3(THF)2 and (THF)CH3Mg(MU-Cl)(MU-CH3)MgCl(THF)2, in order to yield ligand exchange or product dissociation. In addition, the transferred ligands are always departing from an axial position of a pentacoordinated Mg atom. Thus, solvent dynamics is key to successive Mg-Cl and Mg-CH3 bond cleavages because bond breaking occurs at the most solvated Mg atom and the formation of bonds takes place at the least solvated one. The dynamics of the solvent also contributes to keep relatively flat the free energy profile of the Schlenk equilibrium. These results shed light on one of the most used organometallic reagents whose structure in solvent remains experimentally unresolved. These results may also help to develop a more efficient catalyst for reactions involving these species. PMID- 28358510 TI - Reentrant Variation of Single-Chain Elasticity of Polyelectrolyte Induced by Monovalent Salt. AB - The interactions between monovalent counterions and polyelectrolyte are important in chemical and biological systems. The condensation and screening effect of counterions complicate the polyelectrolyte solutions. By means of single-molecule AFM, the single-chain mechanics of a strong polyelectrolyte, poly(sodium styrenesulfonate) (PSSNa), in KCl aqueous solutions over almost whole concentration range have been studied. The M-FJC model has been used to describe the single-chain elasticity of PSSNa in KCl solutions with a parameter of single chain modulus (K0). Along with the increase of the concentration of KCl from zero to almost the saturation concentration, a reentrant variation of K0 of single PSSNa chain can be observed. When [K+] is between 0.01 to 3 M, the charges on the PSSNa backbone are almost completely screened, i.e., the PSSNa chain is virtually neutral in this case. Because K0 has a positive correlation with the net charge of the polymer chain, the increased K0 at very high KCl concentrations (>=3.5 M) indicates that the chain is charged again. Due to the negative charges on the backbone of PSSNa, only the positively charged counterions (K+) can be adsorbed on the chain. Thus, the PSSNa chain should be positively charged when KCl concentrations >=3.5 M. That is, the charge inversion occurs in this case, which is induced by a monovalent salt. This finding may lay the foundation for the future applications of drug delivery and gene therapy. PMID- 28358511 TI - Energetic Effect of the Carboxylic Acid Functional Group in Indole Derivatives. AB - The standard molar enthalpy of formation, in the gaseous phase, at T = 298.15 K, was calculated by combining, for each compound, the standard molar enthalpy of formation, in the crystalline phase, and the standard molar enthalpy of sublimation, yielding -(222.2 +/- 3.5) kJ.mol-1 and -(234.1 +/- 2.1) kJ.mol-1 for indole-3-carboxylic acid and 1-methylindole-3-carboxylic acid, respectively. Computational studies, at the G3(MP2) composite level, were conducted for indole 3-carboxylic acid and 1-methylindole-3-carboxylic acid as a complement of the experimental work, and they were also extended to the remaining isomers, indole-2 carboxylic acid, 1-methylindole-2-carboxylic acid, 3-methylindole-2-carboxylic acid, and 2-methylindole-3-carboxylic acid, to provide reliable estimates of the corresponding thermochemical parameters. The agreement of the estimates of the standard gas-phase enthalpy of formation so obtained, indole-2-carboxylic acid (223.6 +/- 0.8) kJ.mol-1, 1-methylindole-2-carboxylic acid -(223.7 +/- 0.8) kJ.mol-1, 3-methylindole-2-carboxylic acid -(251.6 +/- 1.0) kJ.mol-1, indole-3 carboxylic acid -(227.1 +/- 1.1) kJ.mol-1, 1-methylindole-3-carboxylic acid (238.0 +/- 1.0) kJ.mol-1, and 2-methylindole-3-carboxylic acid -(267.2 +/- 1.0) kJ.mol-1, with the available experimental data gives us additional confidence for the situations not studied experimentally. The enthalpic effect resulting from the entrance of the carboxyl group into the indole ring was discussed, and an enthalpic stabilization was found for indole and pyrrole derivatives when compared with other similar systems. PMID- 28358512 TI - Lead-Based Metal-Organic Framework with Stable Lithium Anodic Performance. AB - A microporous Pb-based metal-organic framework (MOF) [Pb(4,4'-ocppy)2].7H2O (Pb MOF) has been constructed from 4-(4-carboxyphenyl)pyridine N-oxide and Pb(NO3)2. Structural analysis reveals that the Pb-MOF possesses three-dimensional framework with a one-dimensional rhombic channel. When tested as a lithium-ion battery anode, a reversible lithium storage capacity of 489 mAh g-1 was maintained after 500 cycles at 100 mA g-1 as well as excellent cycling stability. The superior electrochemical performance may be derived from the sustenance of the Pb-MOF framework and compositional features of the organic moiety. PMID- 28358513 TI - Discovery of Novel 1,4-Diacylpiperazines as Selective and Cell-Active eIF4A3 Inhibitors. AB - Eukaryotic initiation factor 4A3 (eIF4A3), a member of the DEAD-box RNA helicase family, is one of the core components of the exon junction complex (EJC). The EJC is known to be involved in a variety of RNA metabolic processes typified by nonsense-mediated RNA decay (NMD). In order to identify molecular probes to investigate the functions and therapeutic relevance of eIF4A3, a search for selective eIF4A3 inhibitors was conducted. Through the chemical optimization of 1,4-diacylpiperazine derivatives identified via high-throughput screening (HTS), we discovered the first reported selective eIF4A3 inhibitor 53a exhibiting cellular NMD inhibitory activity. A surface plasmon resonance (SPR) biosensing assay ascertained the direct binding of 53a and its analog 52a to eIF4A3 and revealed that the binding occurs at a non-ATP binding site. Compounds 52a and 53a represent novel molecular probes for further study of eIF4A3, the EJC, and NMD. PMID- 28358515 TI - Targeting to the Bone: Alendronate-Directed Combretastatin A-4 Bearing Antiangiogenic Polymer-Drug Conjugates. AB - Selective targeting of tumor site with chemotherapeutic agents appears to be one of the most effective methods to address many of the problems encountered with conventional chemotherapy. In this work, poly(oligoethylene glycol)methacrylate (POEGMA) based bone-targeting polymers bearing an antiangiogenic drug combretastatin A4 (CA4) were synthesized using free radical polymerization. Targeted and nontargeting copolymers were evaluated for their bone targeting efficiency, cytotoxicities against endothelial cells, namely, HUVECs and U2-OS and Saos-2 cancerous cell lines, as well as their antiangiogenic activity against endothelial cell tube formation by HUVECs. It is observed that the drug conjugated polymers conjugated with the bisphosphonate groups containing drug alendronate (ALN) have remarkably high affinity for bone mineral when compared to the polymer-drug conjugates devoid of the bisphosphonate groups. Both targeted and nontargeted polymer-drug conjugates show a sustained drug release in rat plasma with an overall release of 80-93% over 5 days. In vitro studies revealed high levels of cytotoxicity of the polymer-drug conjugates against HUVECs and U2 OS, and moderate cytotoxicity toward Saos-2. Importantly, the CA4 conjugated copolymers displayed excellent level of antiangiogenic activity as deduced from in vitro endothelial cell tube formation assay using HUVECs. Overall, a novel bone-targeting antiangiogenic polymer-drug conjugate that can be further elaborated to carry additional anticancer drugs is disclosed. PMID- 28358516 TI - Highly Efficient Green-Emitting Phosphors Ba2Y5B5O17 with Low Thermal Quenching Due to Fast Energy Transfer from Ce3+ to Tb3. AB - This paper demonstrates a highly thermally stable and efficient green-emitting Ba2Y5B5O17:Ce3+, Tb3+ phosphor prepared by high-temperature solid-state reaction. The phosphor exhibits a blue emission band of Ce3+ and green emission lines of Tb3+ upon Ce3+ excitation in the near-UV spectral region. The effect of Ce3+ to Tb3+ energy transfer on blue to green emission color tuning and on luminescence thermal stability is studied in the samples codoped with 1% Ce3+ and various concentrations (0-40%) of Tb3+. The green emission of Tb3+ upon Ce3+ excitation at 150 degrees C can keep, on average, 92% of its intensity at room temperature, with the best one showing no intensity decreasing up to 210 degrees C for 30% Tb3+. Meanwhile, Ce3+ emission intensity only keeps 42% on average at 150 degrees C. The high thermal stability of the green emission is attributed to suppression of Ce3+ thermal de-excitation through fast energy transfer to Tb3+, which in the green-emitting excited states is highly thermally stable such that no lifetime shortening is observed with raising temperature to 210 degrees C. The predominant green emission is observed for Tb3+ concentration of at least 10% due to efficient energy transfer with the transfer efficiency approaching 100% for 40% Tb3+. The internal and external quantum yield of the sample with Tb3+ concentration of 20% can be as high as 76% and 55%, respectively. The green phosphor, thus, shows attractive performance for near-UV-based white-light emitting diodes applications. PMID- 28358514 TI - Interdependence of Inhibitor Recognition in HIV-1 Protease. AB - Molecular recognition is a highly interdependent process. Subsite couplings within the active site of proteases are most often revealed through conditional amino acid preferences in substrate recognition. However, the potential effect of these couplings on inhibition and thus inhibitor design is largely unexplored. The present study examines the interdependency of subsites in HIV-1 protease using a focused library of protease inhibitors, to aid in future inhibitor design. Previously a series of darunavir (DRV) analogs was designed to systematically probe the S1' and S2' subsites. Co-crystal structures of these analogs with HIV-1 protease provide the ideal opportunity to probe subsite interdependency. All-atom molecular dynamics simulations starting from these structures were performed and systematically analyzed in terms of atomic fluctuations, intermolecular interactions, and water structure. These analyses reveal that the S1' subsite highly influences other subsites: the extension of the hydrophobic P1' moiety results in 1) reduced van der Waals contacts in the P2' subsite, 2) more variability in the hydrogen bond frequencies with catalytic residues and the flap water, and 3) changes in the occupancy of conserved water sites both proximal and distal to the active site. In addition, one of the monomers in this homodimeric enzyme has atomic fluctuations more highly correlated with DRV than the other monomer. These relationships intricately link the HIV-1 protease subsites and are critical to understanding molecular recognition and inhibitor binding. More broadly, the interdependency of subsite recognition within an active site requires consideration in the selection of chemical moieties in drug design; this strategy is in contrast to what is traditionally done with independent optimization of chemical moieties of an inhibitor. PMID- 28358517 TI - Total Synthesis of Scholarisine K and Alstolactine A. AB - The first asymmetric total syntheses of scholarisine K and alstolactine A have been accomplished. Our syntheses feature (1) ring closure metathesis and an intramolecular Heck reaction to construct the 1,3-bridged [3,3,1] bicycle (C-D ring), (2) intramolecular alkylation followed by Fischer indolization to form the basic skeleton of akuammilines, and (3) bioinspired, acid-promoted epoxide opening/lactonization to generate the second lactone ring of alstolactine A. These results provide evidence of a biogenetic relationship between scholarisine K and alstolactine A, which should facilitate the preparation of other akuammiline-type natural products and their derivatives for functional studies. PMID- 28358519 TI - Diagnoses of traumatic brain injury not clearly associated with deployment, active component, U.S. Armed Forces, 2001-2016. AB - From 2001 through 2016, a total of 276,858 active component service members received first-time diagnoses of traumatic brain injury (TBI). Person-time and incident cases of TBI were assigned to one of three groups. Group 1 included only service members' person-time before their first-ever deployments. Group 2 included service members' person-time during their overseas deployments and the 30 days after their return from deployment. Group 3 included only service members' person-time more than 30 days after return from deployment. The crude overall incidence rate of TBI among deployed service members (1,690.5 cases per 100,000 person-years [p-yrs]) was 1.5 times that of service members in group 1 (1,141.3 cases per 100,000 p-yrs), and 1.2 times that of service members in group 3 (1,451.2 cases per 100,000 p-yrs). The portion of the surveillance period during which the annual incidence rates of TBI in groups 3 and 2 exceeded the rates in group 1 likely represents, at least in part, the increased risk of service in an active combat zone. For group 2, this period extended from 2007 through 2013. For group 3, this period lasted from 2007 through 2016. Examination of the TBI case-defining encounters with recorded injury causes yielded leading causes similar to those of TBIs in same-aged civilians (land transport and slips, trips, and falls). Factors that may explain why the TBI incidence rates among the previously deployed were higher than those of the never-deployed group are discussed. PMID- 28358518 TI - Polarization-Dependent Optical Response in Anisotropic Nanoparticle-DNA Superlattices. AB - DNA-programmable assembly has been used to prepare superlattices composed of octahedral and spherical nanoparticles, respectively. These superlattices have the same body-centered cubic lattice symmetry and macroscopic rhombic dodecahedron crystal habit but tunable lattice parameters by virtue of the DNA length, allowing one to study and determine the effect of nanoscale structure and lattice parameter on the light-matter interactions in the superlattices. Backscattering measurements and finite-difference time-domain simulations have been used to characterize these two classes of superlattices. Superlattices composed of octahedral nanoparticles exhibit polarization-dependent backscattering but via a trend that is opposite to that observed in the polarization dependence for analogous superlattices composed of spherical nanoparticles. Electrodynamics simulations show that this polarization dependence is mainly due to the anisotropy of the nanoparticles and is observed only if the octahedral nanoparticles are well-aligned within the superlattices. Both plasmonic and photonic modes are identified in such structures, both of which can be tuned by controlling the size and shape of the nanoparticle building blocks, the lattice parameters, and the overall size of the three-dimensional superlattices (without changing habit). PMID- 28358520 TI - Update: Heat illness, active component, U.S. Armed Forces, 2016. AB - In 2016, there were 2,536 incident diagnoses of heat illness among active component service members (incidence rate: 1.96 cases per 1,000 person-years [p yrs]). The overall crude incidence rates of heat stroke and "other heat illness" were 0.31 and 1.65 per 1,000 p-yrs, respectively. In 2016, subgroup-specific incidence rates of heat stroke were highest among males and service members aged 19 years or younger, Asian/Pacific Islanders, Marine Corps and Army members, recruit trainees, and those in combat-specific and "other" occupations. Subgroup specific incidence rates of "other heat illnesses" in 2016 were highest among females, service members aged 19 years or younger, Marine Corps and Army members, recruit trainees, and service members in combat-specific occupations. During 2012 2016, a total of 572 diagnoses of heat injuries were documented among service members serving in Iraq/Afghanistan; 7.9% (n=45) of those diagnoses were for heat stroke. Commanders, small unit leaders, training cadre, and supporting medical personnel must ensure that military members whom they supervise and support are informed regarding risks, preventive countermeasures, early signs and symptoms, and first-responder actions related to heat illnesses. PMID- 28358521 TI - Update: Exertional rhabdomyolysis, active component, U.S. Armed Forces, 2012 2016. AB - Among active component service members in 2016, there were 525 incident diagnoses of rhabdomyolysis likely due to physical exertion and/or heat stress ("exertional rhabdomyolysis"). The crude incidence rate in 2016 was 40.7 cases per 100,000 person-years. Annual rates of incident diagnoses of exertional rhabdomyolysis increased 46.2% between 2013 and 2016, with the greatest percentage change occurring between 2014 and 2015. In 2016, relative to their respective counterparts, the highest incidence rates of exertional rhabdomyolysis affected service members who were male; younger than 20 years of age; and black, non Hispanic. During the surveillance period, annual incidence rates were highest among service members of the Marine Corps, intermediate among those in the Army, and lowest among those in the Air Force and Navy. Most cases of exertional rhabdomyolysis were diagnosed at installations that support basic combat/recruit training or major ground combat units of the Army or the Marine Corps. Medical care providers should consider exertional rhabdomyolysis in the differential diagnosis when service members (particularly recruits) present with muscular pain or swelling, limited range of motion, or the excretion of dark urine (possibly due to myoglobinuria) after strenuous physical activity, particularly in hot, humid weather. PMID- 28358522 TI - Update: Exertional hyponatremia, active component, U.S. Armed Forces, 2001-2016. AB - From 2001 through 2016, there were 1,519 incident diagnoses of exertional hyponatremia among active component service members (incidence rate: 6.9 cases per 100,000 person-years [p-yrs]). The incidence rate in 2016 (6.6 cases per 100,000 p-yrs) represented a decrease of 23.3% from 2015. Compared to their respective counterparts, overall incidence rates of exertional hyponatremia were higher among females, those aged 19 years or younger, and recruit trainees. The overall incidence rate during the surveillance period was highest in the Marine Corps, intermediate in the Army and Air Force, and lowest in the Navy. Overall incidence rates were lowest among black, non-Hispanic service members and highest among white, non-Hispanic and Asian/Pacific Islander service members. Service members (particularly recruit trainees) and their supervisors must be vigilant for early signs of heat-related illnesses and must be knowledgeable of the dangers of excessive water consumption and the prescribed limits for water intake during prolonged physical activity (e.g., field training exercises, personal fitness training, recreational activities) in hot, humid weather. PMID- 28358523 TI - Two is more valid than one: Examining the factor structure of the Self-Compassion Scale (SCS). AB - The Self-Compassion Scale (SCS; Neff, 2003a) is the most widely used measure of self-compassion. Self-compassion, as measured by the SCS, is robustly linked to psychological health (Macbeth & Gumley, 2012; Zessin, Dickhauser, & Garbade, 2015). The SCS is currently understood as exhibiting a higher-order structure comprised of 6 first-order factors and 1 second-order general self-compassion factor. Recently, some researchers have questioned the internal validity of this 1-factor conceptualization, and posit that the SCS may instead be comprised of 2 general factors-self-compassion and self-coldness. The current paper provides an in-depth examination of the internal structure of the SCS using oblique, higher order, and bifactor structural models in a sample of 1,115 college students. The bifactor model comprised of 2 general factors-self-compassion and self-coldness and 6 specific factors demonstrated the best fit to the data. Results also indicated the Self-Coldness factor accounted for unique variance in depression, anxiety, and stress, whereas the Self-Compassion factor only accounted for unique variance in its association with depression, providing further evidence for the presence of 2 distinct factors. Results did not provide support for the 1-factor composition of self-compassion currently used in research. Implications for using, scoring, and interpreting the SCS are discussed. (PsycINFO Database Record PMID- 28358525 TI - Veterans individual placement and support towards advancing recovery: Methods and baseline clinical characteristics of a multisite study. AB - OBJECTIVE: This article describes the methodology and the baseline characteristics of veterans with posttraumatic stress disorder (PTSD) enrolled in a multisite trial comparing supported employment individual placement and support (IPS) to a stepwise vocational transitional work program (TWP). METHOD: The Veterans Affairs Cooperative Studies Program randomized 541 veterans with PTSD across 12 Veterans Affairs Medical Centers to either IPS or TWP. Demographic and clinical characteristics were evaluated at baseline. RESULTS: Participants averaged 42 (SD +/- 11) years of age and had PTSD for 13 (SD +/- 11) years. The group was comprised of 18% female, 42% African Americans, and 16% Latino participants. Approximately 60% of participants served in the military since 2001, 89% were receiving or applying for service-connected disability, 60% had PTSD from nonsexual combat-related trauma, and 17% had PTSD from military sexual trauma. One third had not held a competitive job in the past 3 years; the average length of unemployment was 2.8 (SD +/- 4) years. Unique study features included the focus on veterans with PTSD, a comparison of a promising practice with a usual-care practice, and the outcome criterion of achieving steady competitive employment. Conclusions and Implication for Practice: This study is the first large-scale randomized trial of IPS in a PTSD population. These baseline findings illustrate the characteristics of the study sample, which are representative of a veteran population in need of vocational rehabilitation services and can be used to help guide the implementation of tailored veteran-centered programs. (PsycINFO Database Record PMID- 28358524 TI - Loneliness predicts self-reported cold symptoms after a viral challenge. AB - OBJECTIVE: Loneliness is a well-established risk factor for poor physical health. Much less is known about how loneliness affects patient-reported outcomes (PROs), such as somatic symptoms, which are increasingly important for guiding symptom management and assessing quality of patient care. The current study investigates whether (a) loneliness and social isolation predict cold symptoms independent of each other, and (b) whether loneliness is a more robust risk factor than objective social isolation for experiencing cold symptoms. METHOD: As part of a larger parent study, 213 healthy participants completed the Short Loneliness Scale (LON) and the Social Network Index (SNI) at baseline. They were given nasal drops containing rhinovirus 39 (RV39; i.e., a common cold virus), then quarantined for 5 days during which they reported on subjective cold symptoms in addition to being monitored for objective indicators of infection. Data from 160 of the participants (who were infected with the virus) were used in the present analyses. RESULTS: A hierarchical multiple regression revealed that baseline loneliness predicted self-reported cold symptoms over time (assessed via area under the curve), over and above demographic variables, season of participation, and depressive affect. Interestingly, social network size and diversity did not predict cold symptoms. CONCLUSIONS: These findings suggest that the perception of loneliness is more closely linked to self-reported illness symptoms than objectively measured social isolation. Assessing psychosocial factors such as loneliness when treating and evaluating the common cold could contribute to health care practitioners' understanding of their patients' experiences with acute illness. (PsycINFO Database Record PMID- 28358527 TI - "Going out" of the box: Close intercultural friendships and romantic relationships spark creativity, workplace innovation, and entrepreneurship. AB - The present research investigates whether close intercultural relationships promote creativity, workplace innovation, and entrepreneurship-outcomes vital to individual and organizational success. We triangulate on these questions with multiple methods (longitudinal, experimental, and field studies), diverse population samples (MBA students, employees, and professional repatriates), and both laboratory and real-world measures. Using a longitudinal design over a 10 month MBA program, Study 1 found that intercultural dating predicted improved creative performance on both divergent and convergent thinking tasks. Using an experimental design, Study 2 established the causal connection between intercultural dating and creativity: Among participants who had previously had both intercultural and intracultural dating experiences, those who reflected on an intercultural dating experience displayed higher creativity compared to those who reflected on an intracultural dating experience. Importantly, cultural learning mediated this effect. Extending the first 2 studies, Study 3 revealed that the duration of past intercultural romantic relationships positively predicted the ability of current employees to generate creative names for marketing products, but the number of past intercultural romantic partners did not. In Study 4, we analyzed an original dataset of 2,226 professional repatriates from 96 countries who had previously worked in the U.S. under J-1 visas: Participants' frequency of contact with American friends since returning to their home countries positively predicted their workplace innovation and likelihood of becoming entrepreneurs. Going out with a close friend or romantic partner from a foreign culture can help people "go out" of the box and into a creative frame of mind. (PsycINFO Database Record PMID- 28358528 TI - "Using recruitment source timing and diagnosticity to enhance applicants' occupation-specific human capital": Correction to Campion, Ployhart, and Campion (2017). AB - Reports an error in "Using Recruitment Source Timing and Diagnosticity to Enhance Applicants' Occupation-Specific Human Capital" by Michael C. Campion, Robert E. Ployhart and Michael A. Campion (Journal of Applied Psychology, Advanced Online Publication, Feb 02, 2017, np). In the article, the following headings were inadvertently set at the wrong level: Method, Participants and Procedure, Measures, Occupation specific human capital, Symbolic jobs, Relevant majors, Occupation-specific capital hotspots, Source timing, Source diagnosticity, Results, and Discussion. All versions of this article have been corrected. (The following abstract of the original article appeared in record 2017-04566-001.) This study proposes that reaching applicants through more diagnostic recruitment sources earlier in their educational development (e.g., in high school) can lead them to invest more in their occupation-specific human capital (OSHC), thereby making them higher quality candidates. Using a sample of 78,157 applicants applying for jobs within a desirable professional occupation in the public sector, results indicate that applicants who report hearing about the occupation earlier, and applicants who report hearing about the occupation through more diagnostic sources, have higher levels of OSHC upon application. Additionally, source timing and diagnosticity affect the likelihood of candidates applying for jobs symbolic of the occupation, selecting relevant majors, and attending educational institutions with top programs related to the occupation. These findings suggest a firm's recruiting efforts may influence applicants' OSHC investment strategies. (PsycINFO Database Record PMID- 28358529 TI - Can super smart leaders suffer from too much of a good thing? The curvilinear effect of intelligence on perceived leadership behavior. AB - Although researchers predominately test for linear relationships between variables, at times there may be theoretical and even empirical reasons for expecting nonlinear functions. We examined if the relation between intelligence (IQ) and perceived leadership might be more accurately described by a curvilinear single-peaked function. Following Simonton's (1985) theory, we tested a specific model, indicating that the optimal IQ for perceived leadership will appear at about 1.2 standard deviations above the mean IQ of the group membership. The sample consisted of midlevel leaders from multinational private-sector companies. We used the leaders' scores on the Wonderlic Personnel Test (WPT)-a measure of IQ to predict how they would be perceived on prototypically effective leadership (i.e., transformational and instrumental leadership). Accounting for the effects of leader personality, gender, age, as well as company, country, and time fixed effects, analyses indicated that perceptions of leadership followed a curvilinear inverted-U function of intelligence. The peak of this function was at an IQ score of about 120, which did not depart significantly from the value predicted by the theory. As the first direct empirical test of a precise curvilinear model of the intelligence-leadership relation, the results have important implications for future research on how leaders are perceived in the workplace. (PsycINFO Database Record PMID- 28358526 TI - Default mode functional connectivity is associated with social functioning in schizophrenia. AB - Individuals with schizophrenia display notable deficits in social functioning. Research indicates that neural connectivity within the default mode network (DMN) is related to social cognition and social functioning in healthy and clinical populations. However, the association between DMN connectivity, social cognition, and social functioning has not been studied in schizophrenia. For the present study, the authors used resting-state neuroimaging data to evaluate connectivity between the main DMN hubs (i.e., the medial prefrontal cortex [mPFC] and the posterior cingulate cortex-anterior precuneus [PPC]) in individuals with schizophrenia (n = 28) and controls (n = 32). The authors also examined whether DMN connectivity was associated with social functioning via social attainment (measured by the Specific Levels of Functioning Scale) and social competence (measured by the Social Skills Performance Assessment), and if social cognition mediates the association between DMN connectivity and these measures of social functioning. Results revealed that DMN connectivity did not differ between individuals with schizophrenia and controls. However, connectivity between the mPFC and PCC hubs was significantly associated with social competence and social attainment in individuals with schizophrenia but not in controls as reflected by a significant group-by-connectivity interaction. Social cognition did not mediate the association between DMN connectivity and social functioning in individuals with schizophrenia. The findings suggest that fronto-parietal DMN connectivity in particular may be differentially associated with social functioning in schizophrenia and controls. As a result, DMN connectivity may be used as a neuroimaging marker to monitor treatment response or as a potential target for interventions that aim to enhance social functioning in schizophrenia. (PsycINFO Database Record PMID- 28358530 TI - Hispanic and Asian performance on selection procedures: A narrative and meta analytic review of 12 common predictors. AB - Hispanics are both the largest and fastest growing minority group in the U.S. workforce. Asians also make up a substantial and increasing portion of the workforce. Unfortunately, empirical research on how these groups perform selection procedures appears to be lacking. To address this critical gap, we identified and reviewed research from a variety of literatures relevant to Hispanic and/or Asian performance on 12 commonly used staffing procedures. We also contacted authors of studies that included members of these subgroups and requested the relevant data. On the basis of our review, we provide updated estimates of Hispanic-White and Asian-White differences for the predictors, which often differ from existing estimates of these differences. Further, we provide the first known meta-analytic estimates for Hispanics and Asians on many predictors, such as vocational interests and physical ability. We discuss the implications of the findings for staffing research and practice. We also identify critical next steps for future research regarding these 2 important, yet largely neglected, groups. (PsycINFO Database Record PMID- 28358531 TI - What happens during annual appraisal interviews? How leader-follower interactions unfold and impact interview outcomes. AB - Despite a wealth of research on antecedents and outcomes of annual appraisal interviews, the ingredients that make for a successful communication process within the interview itself remain unclear. This study takes a communication approach to highlight leader-follower dynamics in annual appraisal interviews. We integrate relational leadership theory and recent findings on leader-follower interactions to argue (a) how supervisors' task- and relation-oriented statements can elicit employee involvement during the interview process and (b) how these communication patterns affect both supervisors' and employees' perceptions of the interview. Moreover, we explore (c) how supervisor behavior is contingent upon employee contributions to the appraisal interview. We audiotaped 48 actual annual appraisal interviews between supervisors and their employees. Adopting a multimethod approach, we used quantitative interaction coding (N = 32,791 behavioral events) as well as qualitative open-axial coding to explore communication patterns among supervisors and their employees. Lag sequential analysis revealed that supervisors' relation-oriented statements triggered active employee contributions and vice versa. These relation-activation patterns were linked to higher interview success ratings by both supervisors and employees. Moreover, our qualitative findings highlight employee disagreement as a crucial form of active employee contributions during appraisal interviews. We distinguish what employees disagreed about, how the disagreement was enacted, and how supervisors responded to it. Overall employee disagreement was negatively related to ratings of supervisor support. We discuss theoretical implications for performance appraisal and leadership theory and derive practical recommendations for promoting employee involvement during appraisal interviews. (PsycINFO Database Record PMID- 28358532 TI - The content of the message matters: The differential effects of promotive and prohibitive team voice on team productivity and safety performance gains. AB - We propose that it is important to take the content of team voice into account when examining its impact on team processes and outcomes. Drawing on regulatory focus theory (Higgins, 1997), we argue that promotive team voice and prohibitive team voice help teams achieve distinct collective outcomes-that is, team productivity performance gains and team safety performance gains, respectively. Further, we identify mechanisms through which promotive and prohibitive team voices uniquely influence team outcomes as well as boundary conditions for such influences. In data collected from 88 production teams, we found that promotive team voice had a positive association with team productivity performance gains. By contrast, prohibitive team voice had a positive association with team safety performance gains. The relationship between promotive team voice and team productivity performance gains was mediated by team innovation, and the relationship between prohibitive team voice and team safety performance gains was mediated by team monitoring. In addition, the indirect effect of prohibitive team voice on team safety performance gains via team monitoring was stronger when prior team safety performance was lower. We discuss the theoretical and practical implications of these findings. (PsycINFO Database Record PMID- 28358533 TI - What I don't know won't hurt you: The relation between professed ignorance and later knowledge claims. AB - Testimony is a valuable source of information for young learners, in particular if children maintain vigilance against errors while still being open to learning from imperfectly knowledgeable sources. We find support for this idea by examining how children evaluate individual speakers who present very different epistemic risks by being previously ignorant or inaccurate. Results across 2 experiments show that children attribute knowledge to (Experiment 1) and endorse new claims made by speakers (Experiment 2) who previously professed ignorance about familiar object labels, but not to speakers whose labels were previously inaccurate. Study 2 further clarifies that children are not simply relying on links between informational access and knowledge; children rejected testimony from a previously inaccurate speaker even when she had perceptual access to support her claim. These results show that children actively monitor the reliability of a speaker's knowledge claims, distinguish unreliable speakers from those who sometimes admit ignorance, raising new questions about how such admissions factor in to children's appraisal of the scope and limits of a person's knowledge. (PsycINFO Database Record PMID- 28358534 TI - Adolescent support seeking as a path to adult functional independence. AB - The potential importance of depending on others during adolescence to establish independence in young adulthood was examined across adolescence to emerging adulthood. Participants included 184 teens (46% male; 42% non-White), their mothers, best friends, and romantic partners, assessed at ages 13-14, 18, 21-22, and 25. Path analyses showed that associations were both partner and age specific: markers of independence were predicted by participants' efforts to seek support from mothers at age 13, best friends at 18, and romantic partners at 21. More important, analyses controlled for support seeking from these partners at other ages, as well as for other potentially confounding variables including attachment security, scholastic/job competence, and physical attractiveness over time. Moreover, analyses suggested the transfer of support seeking behavior from mothers to best friends to romantic partners over time based on support given by the previous partner at an earlier age. (PsycINFO Database Record PMID- 28358535 TI - A longitudinal twin study of general cognitive ability over four decades. AB - In this longitudinal study we examined the stability of general cognitive ability (GCA), as well as heterogeneity and genetic and environmental influences underlying individual differences in change. We investigated GCA from young adulthood through late midlife in 1,288 Vietnam Era Twin Study of Aging participants at ages ~20, ~56, and ~62 years. The correlations among the 3 occasions ranged from .73 to .85, reflecting substantial stability. The heritability was significant on each of the 3 occasions and ranged from .59 to .66. The influence of the shared environment was not significant at any of the ages. The genetic correlations across the 3 occasions ranged from .95 to .99 and did not differ significantly from 1.0. The nonshared environmental correlations ranged from .21 to .47. Latent growth curve analysis was applied to characterize trajectories over the 42-year period. Slope was significantly different from 0 and indicated that there was modest change over time. There was a significant genetic influence on initial level of GCA (h2 = .67), but not change (h2 = .23). Genetic factors primarily contribute to stability, while change reflects the influence of nonshared environmental influences. There was a significant negative correlation between initial level of GCA and change (r = -.31). Latent class growth analysis identified 4 trajectories. In general, the 4 groups followed parallel trajectories and were differentiated mainly by differences in AFQT performance level at the time of military induction. (PsycINFO Database Record PMID- 28358536 TI - Negative emotionality and discipline as long-term predictors of behavioral outcomes in African American and European American children. AB - The present study examined the early parenting and temperament determinants of children's antisocial and positive behaviors in a low-income, diverse ethno racial sample. Participants were from the Early Head Start Research and Evaluation Project, which included 960 European American (initial M age = 15.00 months; 51.2% female) and 880 African American mothers and their children (initial M age = 15.10 months; 49.2% female) followed from 15 months of age to 5th grade. For European American children, findings showed direct and indirect effects (via self-regulation) of early negative emotionality on later behaviors. For African American children, discipline practices in infancy had direct long term implications for behaviors in 5th grade. Discussion highlights the interplay of parenting, temperament, and culture from infancy to late childhood. (PsycINFO Database Record PMID- 28358537 TI - Eliminating age differences in children's and adults' suggestibility and memory conformity effects. AB - We examined whether typical developmental trends in suggestion-induced false memories (i.e., age-related decrease) could be changed. Using theoretical principles from the spontaneous false memory field, we adapted 2 often-used false memory procedures: misinformation (Experiment 1) and memory conformity (Experiment 2). In Experiment 1, 7- to 9-year-old children (n = 33) and adults (n = 39) received stories containing associatively related details. They then listened to misinformation in the form of short narratives preserving the meaning of the story. Children and adults were equally susceptible to the misinformation effect. In Experiment 2, younger (7- to 8-year-olds, n = 30) and older (11- to 12 year-olds, n = 30) children and adults (n = 30) viewed pictures containing associatively related details. They viewed these pictures in pairs. Although the pictures differed, participants believed they had viewed the same pictures. Participants had to report what they could recollect during collaborative and individual recall tests. Children and adults were equally susceptible to memory conformity effects. When correcting for response bias, adults' false memory scores were even higher than children's. Our results show that age trends in suggestion-induced false memories are not developmentally invariant. (PsycINFO Database Record PMID- 28358538 TI - Political efficacy in adolescence: Development, gender differences, and outcome relations. AB - The present study focuses on political efficacy in terms of students' competence self-perceptions related to the domain of politics. The investigation addresses the mean level development and longitudinal relations to outcome variables including gender differences. Drawing on a sample of N = 2,504 German students, political efficacy, along with meaningful outcome variables (i.e., political information behavior, political knowledge, and interest in politics), was measured at 2 measurement points, once in Grade 7 and once in Grade 10. Students' mean levels of political efficacy increased from the first to the second measurement point, and boys consistently displayed higher levels. Political efficacy demonstrated reciprocal relations to political information behavior and political knowledge, and showed a unidirectional relation to interest in politics across time. The pattern of outcome relations was invariant across gender. This study contributes to research and theory on political socialization in adolescence as it outlines temporal relations among, and gender differences in, facets of political socialization. Therefore, this study also offers new practical insights into effectively facilitating political education in adolescent students. (PsycINFO Database Record PMID- 28358539 TI - Analogical processes in children's understanding of spatial representations. AB - We propose that map reading can be construed as a form of analogical mapping. We tested 2 predictions that follow from this claim: First, young children's patterns of performance in map reading tasks should parallel those found in analogical mapping tasks; and, second, children will benefit from guided alignment instructions that help them see the relational correspondences between the map and the space. In 4 experiments, 3-year-olds completed a map reading task in which they were asked to find hidden objects in a miniature room, using a corresponding map. We manipulated the availability of guided alignment (showing children the analogical mapping between maps and spaces; Experiments 1, 2, and 3a), the format of guided alignment (gesture or relational language; Experiment 2), and the iconicity of maps (Experiments 3a and 3b). We found that (a) young children's difficulties in map reading follow from known patterns of analogical development-for example, focusing on object similarity over relational similarity; and (b) guided alignment based on analogical reasoning led to substantially better performance. Results also indicated that children's map reading performance was affected by the format of guided alignment, the iconicity of the maps, and the order of tasks. The results bear on the developmental mechanisms underlying young children's learning of spatial representations and also suggest ways to support this learning. (PsycINFO Database Record PMID- 28358541 TI - Cultural context shapes essentialist beliefs about religion. AB - The present study investigates the processes by which essentialist beliefs about religious categories develop. Children (ages 5 and 10) and adults (n = 350) from 2 religious groups (Jewish and Christian), with a range of levels of religiosity, completed switched-at-birth tasks in which they were told that a baby had been born to parents of 1 religion but raised by parents of another religion. Results indicated that younger children saw religion-based categories as possible essential kinds, regardless of the child's own religious background, but that culture-specific patterns emerged across development. This work shows that cultural context plays a powerful role in guiding the development of essentialist beliefs about religious categories. (PsycINFO Database Record PMID- 28358540 TI - Executive control goes to school: Implications of preschool executive performance for observed elementary classroom learning engagement. AB - The transition to elementary school is accompanied by increasing demands for children to regulate their attention and behavior within the classroom setting. Executive control (EC) may be critical for meeting these demands; however, few studies have rigorously examined the association between EC and observed classroom behavior. This study examined EC in preschool (age 5 years 3 months) as a predictor of classroom learning engagement behaviors in first grade, using a battery of performance-based EC tasks and live classroom observations in a longitudinal sample of 313 children. Multilevel modeling results indicated that stronger EC predicted more focused engagement and fewer task management and competing responses, controlling for socioeconomic status, child sex, and age at observations. Results suggest that early EC may support subsequent classroom engagement behaviors that are critical for successful transition to elementary school and long-term learning trajectories. (PsycINFO Database Record PMID- 28358543 TI - Dispositional pathways to trust: Self-esteem and agreeableness interact to predict trust and negative emotional disclosure. AB - Expressing our innermost thoughts and feelings is critical to the development of intimacy (Reis & Shaver, 1988), but also risks negative evaluation and rejection. Past research suggests that people with high self-esteem are more expressive and self-disclosing because they trust that others care for them and will not reject them (Gaucher et al., 2012). However, feeling good about oneself may not always be enough; disclosure may also depend on how we feel about other people. Drawing on the principles of risk regulation theory (Murray et al., 2006), we propose that agreeableness-a trait that refers to the positivity of interpersonal motivations and behaviors-is a key determinant of trust in a partner's caring and responsiveness, and may work in conjunction with self-esteem to predict disclosure. We examined this possibility by exploring how both self-esteem and agreeableness predict a particularly risky and intimate form of self-disclosure, the disclosure of emotional distress. In 6 studies using correlational, partner report, and experimental methods, we demonstrate that self-esteem and agreeableness interact to predict disclosure: People who are high in both self esteem and agreeableness show higher emotional disclosure. We also found evidence that trust mediates this effect. People high in self-esteem and agreeableness are most self-revealing, it seems, because they are especially trusting of their partners' caring. Self-esteem and agreeableness were particularly important for the disclosure of vulnerable emotions (i.e., sadness; Study 5) and disclosures that were especially risky (Study 6). These findings illustrate how dispositional variables can work together to explain behavior in close relationships. (PsycINFO Database Record PMID- 28358542 TI - Multilevel modeling of single-case data: A comparison of maximum likelihood and Bayesian estimation. AB - The focus of this article is to describe Bayesian estimation, including construction of prior distributions, and to compare parameter recovery under the Bayesian framework (using weakly informative priors) and the maximum likelihood (ML) framework in the context of multilevel modeling of single-case experimental data. Bayesian estimation results were found similar to ML estimation results in terms of the treatment effect estimates, regardless of the functional form and degree of information included in the prior specification in the Bayesian framework. In terms of the variance component estimates, both the ML and Bayesian estimation procedures result in biased and less precise variance estimates when the number of participants is small (i.e., 3). By increasing the number of participants to 5 or 7, the relative bias is close to 5% and more precise estimates are obtained for all approaches, except for the inverse-Wishart prior using the identity matrix. When a more informative prior was added, more precise estimates for the fixed effects and random effects were obtained, even when only 3 participants were included. (PsycINFO Database Record PMID- 28358544 TI - Developmental pathways linking childhood temperament with antisocial behavior and substance use in adolescence: Explanatory mechanisms in the peer environment. AB - This study investigated 3 developmental pathways involving the peer environment that may explain how certain temperamental dispositions in childhood may become manifested in later antisocial behavior and substance use. A total of 411 (52% boys) Canadian children were followed annually from ages 6 to 15 years. The study tested whether the temperamental traits approach, negative reactivity and attention (assessed at ages 6-7 years), were associated with overt antisocial behavior, covert antisocial behavior and illicit substance use (assessed at ages 14-15 years), via poor social preference among peers, inflated social self perception and antisocial behavior of peer-group affiliates (assessed throughout ages 8-13 years). Results indicated that negative reactivity was indirectly associated with overt antisocial behavior and substance use via poor social preference. Specifically, negative reactivity in earlier childhood predicted poor social preference in later childhood and early adolescence. This poor social standing among peers, in turn, predicted more engagement in overt antisocial behavior but less substance use in later adolescence. Over and above the influence of social preference, negative reactivity predicted engagement in all 3 outcomes via children's antisocial behavior in childhood and early adolescence. Inflated social self-perception and antisocial behavior of peer-group affiliates did not mediate the link between temperament and the outcomes under scrutiny. No sex differences in developmental pathways from temperament to the outcomes were found. To further our understanding of the developmental link between childhood temperament and later antisocial behavior and substance use, we need to recognize the role of peer environmental factors, specifically poor preference among peers. (PsycINFO Database Record PMID- 28358545 TI - Multidimensional assessment of self-regulated learning with middle school math students. AB - This study examined the convergent and predictive validity of self-regulated learning (SRL) measures situated in mathematics. The sample included 100 eighth graders from a diverse, urban school district. Four measurement formats were examined including, 2 broad-based (i.e., self-report questionnaire and teacher ratings) and 2 task-specific measures (i.e., SRL microanalysis and behavioral traces). Convergent validity was examined across task-difficulty, and the predictive validity was examined across 3 mathematics outcomes: 2 measures of mathematical problem solving skill (i.e., practice session math problems, posttest math problems) and a global measure of mathematical skill (i.e., standardized math test). Correlation analyses were used to examine convergent validity and revealed medium correlations between measures within the same category (i.e., broad-based or task-specific). Relations between measurement classes were not statistically significant. Separate regressions examined the predictive validity of the SRL measures. While controlling all other predictors, a SRL microanalysis metacognitive-monitoring measure emerged as a significant predictor of all 3 outcomes and teacher ratings accounted for unique variance on 2 of the outcomes (i.e., posttest math problems and standardized math test). Results suggest that a multidimensional assessment approach should be considered by school psychologists interested in measuring SRL. (PsycINFO Database Record PMID- 28358546 TI - Assessing children's perceptions of academic interventions: The Kids Intervention Profile. AB - The psychometric properties of the Kids Intervention Profile (KIP), a rating scale designed to measure academic intervention acceptability from the perspective of students, were examined as well as the influence of background factors on students' acceptability ratings. Data were extracted from 4 randomized controlled trials investigating the effects of a performance feedback intervention on third-grade students' writing fluency (n = 228). Results indicated that the KIP contains 2 factors (General Intervention Acceptability, Skill Improvement) and has adequate internal consistency and stability across a 3 week period. There were gender differences in students' acceptability ratings, with female students rating the intervention as significantly more acceptable than males. In addition, results suggested a modest, positive relationship between students' intervention acceptability ratings and their intervention outcomes. Considerations regarding the use of the KIP, as well as limitations of the study, are discussed. (PsycINFO Database Record PMID- 28358547 TI - Schedule of human-controlled periods structures bottlenose dolphin (Tursiops truncatus) behavior in their free-time. AB - Behavioral patterns are established in response to predictable environmental cues. Animals under human care frequently experience predictable, human controlled events each day, but very few studies have questioned exactly how behavioral patterns are affected by such activities. Bottlenose dolphins (Tursiops truncatus) maintained for public display are good models to study such patterns since they experience multiple daily human-controlled periods (e.g., shows, training for shows, medical training). Thus, we investigated the effect of training session schedule on their "free-time" behavior, studying 29 individuals within 4 groups from 3 European facilities. Our initial time budget analyses revealed that among the behaviors studied, dolphins spent the most time engaged in synchronous swimming, and within this category swam most at slow speeds and in close proximity to each other. "Slow-close" synchronous swimming peaked shortly after training sessions and was low shortly before the next session. Play behavior had significantly higher frequencies in juveniles than in adults, but the effect was only seen during the in-between session period (interval neither shortly before nor after sessions). Anticipatory behavior toward sessions was significantly higher shortly before sessions and lower afterward. We conclude that dolphin behaviors unconnected to the human-controlled periods were modulated by them: slow-close synchronous swimming and age-dependent play, which have important social dimensions and links to welfare. We discuss potential parallels to human-controlled periods in other species, including humans themselves. Our findings could be taken into account when designing welfare assessments, and aid in the provision of enrichment and maintaining effective schedules beneficial to animals themselves. (PsycINFO Database Record PMID- 28358548 TI - Does retrieval practice enhance learning and transfer relative to restudy for term-definition facts? AB - In many pedagogical contexts, term-definition facts that link a concept term (e.g., "vision") with its corresponding definition (e.g., "the ability to see") are learned. Does retrieval practice involving retrieval of the term (given the definition) or the definition (given the term) enhance subsequent recall, relative to restudy of the entire fact? Moreover, does any benefit of retrieval practice for the term transfer to later recall of the definition, or vice versa? We addressed those questions in 4 experiments. In each, subjects first studied term-definition facts and then trained on two thirds of the facts using multiple choice tests with feedback. Half of the test questions involved recalling terms; the other half involved recalling definitions. The remaining facts were either not trained (Experiment 1) or restudied (Experiments 2-4). A 48-hr delayed multiple-choice (Experiments 1-2) or short answer (Experiments 3a-4) final test assessed recall of all terms or all definitions. Replicating and extending prior research, retrieval practice yielded improved recall and positive transfer relative to no training. Relative to restudy, however, retrieval practice consistently enhanced subsequent term retrieval, enhanced subsequent definition retrieval only after repeated practice, and consistently yielded at best minimal positive transfer in either direction. Theoretical and practical implications are discussed. (PsycINFO Database Record PMID- 28358549 TI - Bayesian models of cognition revisited: Setting optimality aside and letting data drive psychological theory. AB - Recent debates in the psychological literature have raised questions about the assumptions that underpin Bayesian models of cognition and what inferences they license about human cognition. In this paper we revisit this topic, arguing that there are 2 qualitatively different ways in which a Bayesian model could be constructed. The most common approach uses a Bayesian model as a normative standard upon which to license a claim about optimality. In the alternative approach, a descriptive Bayesian model need not correspond to any claim that the underlying cognition is optimal or rational, and is used solely as a tool for instantiating a substantive psychological theory. We present 3 case studies in which these 2 perspectives lead to different computational models and license different conclusions about human cognition. We demonstrate how the descriptive Bayesian approach can be used to answer different sorts of questions than the optimal approach, especially when combined with principled tools for model evaluation and model selection. More generally we argue for the importance of making a clear distinction between the 2 perspectives. Considerable confusion results when descriptive models and optimal models are conflated, and if Bayesians are to avoid contributing to this confusion it is important to avoid making normative claims when none are intended. (PsycINFO Database Record PMID- 28358550 TI - The correlation between exposure to neighborhood violence and perpetration of moderate physical violence among Arab-Palestinian youth: Can it be moderated by parent-child support and gender? AB - In the current study, we examined the role of parent-child support as a protective factor that moderates the correlation between exposure to neighborhood violence and perpetration of moderate physical violence among 3,187 Arab Palestinian adolescents who live in Israel (aged 12 to 18), from 21 different schools who were selected randomly. The probability sampling method was a nonproportional multistage stratified cluster sample. We also examined gender differences across this protective process. Participants completed a structured, anonymous self-report questionnaire. The findings of the study reveal that 47.3% of the adolescents had perpetrated moderate physical violence against others at least once during the month preceding the study. Moreover, exposure of adolescents to violence in their neighborhood correlated significantly and positively with perpetration of moderate physical violence. A moderation analysis was tested and found that this correlation was stronger among adolescents who had poor parent-child support than among those who had strong parent-child support. Furthermore, the findings reveal that the correlation of exposure to neighborhood violence with perpetration of moderate physical violence was not moderated by gender. However, parent-child support correlated strongly with lower levels of perpetration of moderate physical violence among males than females. The findings of the study highlight the critical role of parental factors in decreasing violent behaviors among adolescents (especially boys) as well as among adolescents who are at risk for exposure to violence in their neighborhoods. In light of the findings, we recommend that practitioners working with these adolescents include parents in intervention programs. (PsycINFO Database Record PMID- 28358551 TI - Normal-range verbal-declarative memory in schizophrenia. AB - OBJECTIVE: Cognitive impairment is prevalent and related to functional outcome in schizophrenia, but a significant minority of the patient population overlaps with healthy controls on many performance measures, including declarative-verbal memory tasks. In this study, we assessed the validity, clinical, and functional implications of normal-range (NR), verbal-declarative memory in schizophrenia. METHOD: Performance normality was defined using normative data for 8 basic California Verbal Learning Test (CVLT-II; Delis, Kramer, Kaplan, & Ober, 2000) recall and recognition trials. Schizophrenia patients (n = 155) and healthy control participants (n = 74) were assessed for performance normality, defined as scores within 1 SD of the normative mean on all 8 trials, and assigned to normal- and below-NR memory groups. RESULTS: NR schizophrenia patients (n = 26) and control participants (n = 51) did not differ in general verbal ability, on a reading-based estimate of premorbid ability, across all 8 CVLT-II-score comparisons or in terms of intrusion and false-positive errors and auditory working memory. NR memory patients did not differ from memory-impaired patients (n = 129) in symptom severity, and both patient groups were significantly and similarly disabled in terms of functional status in the community. CONCLUSION: These results confirm a subpopulation of schizophrenia patients with normal, verbal-declarative-memory performance and no evidence of decline from higher premorbid ability levels. However, NR patients did not experience less severe psychopathology, nor did they show advantage in community adjustment relative to impaired patients. (PsycINFO Database Record PMID- 28358552 TI - Determinants of risk-taking in HIV-associated neurocognitive disorders. AB - OBJECTIVE: Decision-making involves fronto-striatal brain areas that are particularly vulnerable to the effects of HIV infection. Some studies report impaired decision-making in people with HIV/AIDS with past or present addictions and/or accompanying HIV-associated neurocognitive disorders (HAND). The authors investigated risk-based decision-making in HIV/AIDS, separating individuals with or without accompanying HAND. METHOD: A total of 288 HIV-infected persons underwent standardized neuropsychological testing. Participants were profiled based on neuropsychological and clinical assessments into 2 groups, neurocognitively normal (NN, n = 205) and HAND (n = 83). Risk-based decision making was assessed via the Game of Dice Task (GDT). Sample characteristics were summarized by principal component analysis (PCA) prior to regression analyses predicting GDT performance. RESULTS: The NN group performed within the normative range of the GDT, but the HAND group was impaired in all GDT measures. Across all participants, GDT performance was predicted by a combination of psychiatric comorbidities, alcohol abuse, education/premorbid IQ, and neuropsychological performance. Further analyses revealed marijuana use as an important additional predictor of impaired GDT performance. Within the GDT-impaired HAND group only, past or present immunosuppression emerged as the most robust predictor of GDT performance. Metabolic disorders and antiretroviral toxicity were also predictors of GDT performance in the HAND group. CONCLUSION: The majority of HIV-infected individuals were unimpaired in the GDT. Some influence of psychiatric and substance use comorbidities on GDT performance emerged in the entire cohort. However, GDT deficits were restricted to individuals with HAND, related to immunosuppression, metabolic disorders and antiretroviral toxicity in this group only. (PsycINFO Database Record PMID- 28358553 TI - Shifts of spatial attention underlie numerical comparison and mental arithmetic: Evidence from a patient with right unilateral neglect. AB - OBJECTIVES: Recent findings suggest that mental arithmetic involves shifting attention on a mental continuum in which numbers would be ordered from left to right, from small to large numbers, with addition and subtraction causing rightward or leftward shifts, respectively. Neuropsychological data showing that brain-damaged patients with left neglect experience difficulties in solving subtraction but not addition problems support this hypothesis. However, the reverse dissociation is needed to establish the causal role of spatial attention in mental arithmetic. METHOD: R.H., a 65-year-old left-brain-damaged patient exhibiting right unilateral visuospatial and representational neglect, was tested with various numerical tasks including numerical comparison, arithmetic problem solving, and numerical interval bisection. RESULTS: In numerical comparison, R.H. showed a selective response latency increase when judging numbers larger than the references whereas his performance was normal for numbers smaller than the references. In the arithmetic task, R.H. was impaired in solving addition but not subtraction problems. In contrast, performance in number bisection shows a deviation toward larger numbers. CONCLUSION: These results establish a double dissociation between subtraction and addition solving in patients with left versus right neglect and demonstrate clear evidence that attentional mechanisms are crucial for mental arithmetic. We suggest that attention shifts are involved whenever a number is represented relative to another on a mental continuum, be it during numerical comparison or arithmetic problem-solving. R.H.'s performance in numerical interval bisection indicates that this task involves processes that are distinct from those involved in number comparison and mental arithmetic. (PsycINFO Database Record PMID- 28358554 TI - Attenuated hemispheric asymmetry in metaphor processing among adults with ADHD. AB - OBJECTIVE: To characterize the hemispheric processing of metaphors in adults with ADHD compared to controls. METHOD: We investigated the hemispheric processing of metaphors in 24 adult participants diagnosed with ADHD and 24 control participants. The hemispheric processing was examined using a divided visual field paradigm, in which different kinds of metaphors as well as literal word pairs and unrelated word pairs were presented either to the right visual field/left hemisphere (RVF/LH) or to the left visual field/right hemisphere (LVF/RH). RESULTS: Control participants processed metaphors more efficiently when presented in the LVF/RH than when presented in the RVF/LH, whereas participants with ADHD demonstrated attenuated asymmetry of hemispheric processing. Furthermore, asymmetry of hemispheric processing, together with sustained attention, contributed significantly to the prediction of self-report of ADHD symptoms. CONCLUSION: Our results suggest that the hemispheric processing of adults with ADHD is less lateralized than the hemispheric processing of control participants. Moreover, the diminished lateralization of metaphor processing along with deficient sustained attention may reflect distinct cognitive mechanisms underlying ADHD and as such our results support multiple pathway models of ADHD. (PsycINFO Database Record PMID- 28358555 TI - Dynamically tracking anxious individuals' affective response to valenced information. AB - Past research has shown that an individual's feelings at any given moment reflect currently experienced stimuli as well as internal representations of similar past experiences. However, anxious individuals' affective reactions to streams of interrelated valenced information (vs. reactions to static stimuli that are arguably less ecologically valid) are rarely tracked. The present study provided a first examination of the newly developed Tracking Affect Ratings Over Time (TAROT) task to continuously assess anxious individuals' affective reactions to streams of information that systematically change valence. Undergraduate participants (N = 141) completed the TAROT task in which they listened to narratives containing positive, negative, and neutral physically- or socially relevant events, and indicated how positive or negative they felt about the information they heard as each narrative unfolded. The present study provided preliminary evidence for the validity and reliability of the task. Within scenarios, participants higher (vs. lower) in anxiety showed many expected negative biases, reporting more negative mean ratings and overall summary ratings, changing their pattern of responding more quickly to negative events, and responding more negatively to neutral events. Furthermore, individuals higher (vs. lower) in anxiety tended to report more negative minimums during and after positive events, and less positive maximums after negative events. Together, findings indicate that positive events were less impactful for anxious individuals, whereas negative experiences had a particularly lasting impact on future affective responses. The TAROT task is able to efficiently capture a number of different cognitive biases, and may help clarify the mechanisms that underlie anxious individuals' biased negative processing. (PsycINFO Database Record PMID- 28358556 TI - Measuring emotional and cognitive empathy using dynamic, naturalistic, and spontaneous emotion displays. AB - Most measures of nonverbal receiving ability use posed expressions as stimuli. As empathy measures, such stimuli lack ecological validity, as the participant is not actually experiencing emotion. An alternative approach uses natural and dynamic displays of spontaneous expressions. The Communication of Affect Receiving Ability Test (CARAT) uses as stimuli spontaneous facial expressions and gestures filmed by an unobtrusive camera of solitary participants responding to emotional images. This article reports the development and initial validation of the CARAT-Spontaneous, Posed, Regulated (CARAT-SPR), which measures both abilities to detect emotion from spontaneous displays (emotion communication accuracy) and to differentiate spontaneous, posed, and regulated displays (expression categorization ability). Although spontaneous displays are natural responses to emotional images, posed displays involve asking the sender to display "as if" responding to a particular sort of image when no image is in fact present (simulation), while Regulated displays involve asking the sender to display "as if" responding to a particular sort of image when an image of opposite valence is in fact present (masking). Expression categorization ability involves judging deception-simulation and masking-and conceptually involves a kind of perspective-taking or cognitive empathy. Emotion communication using spontaneous clips achieved a high level of accuracy and was strongly correlated with ratings of sender expressivity. Expression categorization ability was not significantly correlated with expressivity ratings and was modestly negatively correlated with emotion communication accuracy. In a brief version of the CARAT SPR, women showed evidence of greater emotion signal detection, whereas men reported greater confidence in expression categorization. (PsycINFO Database Record PMID- 28358558 TI - Infant differential behavioral responding to discrete emotions. AB - Emotional communication regulates the behaviors of social partners. Research on individuals' responding to others' emotions typically compares responses to a single negative emotion compared with responses to a neutral or positive emotion. Furthermore, coding of such responses routinely measure surface level features of the behavior (e.g., approach vs. avoidance) rather than its underlying function (e.g., the goal of the approach or avoidant behavior). This investigation examined infants' responding to others' emotional displays across 5 discrete emotions: joy, sadness, fear, anger, and disgust. Specifically, 16-, 19-, and 24 month-old infants observed an adult communicate a discrete emotion toward a stimulus during a naturalistic interaction. Infants' responses were coded to capture the function of their behaviors (e.g., exploration, prosocial behavior, and security seeking). The results revealed a number of instances indicating that infants use different functional behaviors in response to discrete emotions. Differences in behaviors across emotions were clearest in the 24-month-old infants, though younger infants also demonstrated some differential use of behaviors in response to discrete emotions. This is the first comprehensive study to identify differences in how infants respond with goal-directed behaviors to discrete emotions. Additionally, the inclusion of a function-based coding scheme and interpersonal paradigms may be informative for future emotion research with children and adults. Possible developmental accounts for the observed behaviors and the benefits of coding techniques emphasizing the function of social behavior over their form are discussed. (PsycINFO Database Record PMID- 28358557 TI - Social anxiety is characterized by biased learning about performance and the self. AB - People learn about their self from social information, and recent work suggests that healthy adults show a positive bias for learning self-related information. In contrast, social anxiety disorder (SAD) is characterized by a negative view of the self, yet what causes and maintains this negative self-view is not well understood. Here the authors use a novel experimental paradigm and computational model to test the hypothesis that biased social learning regarding self evaluation and self-feelings represents a core feature that distinguishes adults with SAD from healthy controls. Twenty-one adults with SAD and 35 healthy controls (HCs) performed a speech in front of 3 judges. They subsequently evaluated themselves and received performance feedback from the judges and then rated how they felt about themselves and the judges. Affective updating (i.e., change in feelings about the self over time, in response to feedback from the judges) was modeled using an adapted Rescorla-Wagner learning model. HCs demonstrated a positivity bias in affective updating, which was absent in SAD. Further, self-performance ratings revealed group differences in learning from positive feedback-a difference that endured at an average of 1 year follow up. These findings demonstrate the presence and long-term endurance of positively biased social learning about the self among healthy adults, a bias that is absent or reversed among socially anxious adults. (PsycINFO Database Record PMID- 28358559 TI - Understanding reappraisal as a multicomponent process: The psychological health benefits of attempting to use reappraisal depend on reappraisal success. AB - When is reappraisal-reframing a situation's meaning to alter its emotional impact associated with psychological health? To answer this question, we should consider that reappraisal is a multicomponent process that includes, first, deciding to attempt to use reappraisal and, second, implementing reappraisal with varying degrees of success. Although theories of emotion regulation suggest that both attempting reappraisal more frequently and implementing reappraisal more successfully are necessary to achieve greater psychological health, no research has directly tested this assumption. We propose that daily diaries are particularly well suited to assess these 2 components because diaries can capture repeated attempts and success in daily life and with relative precision. In a sample of community adults (N = 219), we found that among participants experiencing elevated life stress (but not among those experiencing lower life stress), attempting reappraisal more frequently was associated with fewer depressive symptoms for those who used reappraisal more successfully, but was associated with somewhat more depressive symptoms for those who used reappraisal less successfully. These findings suggest that attempting reappraisal is associated with benefits only when individuals can implement it successfully. Thus, to fully understand the health implications of emotion regulation, we must consider it as a multicomponent process. (PsycINFO Database Record PMID- 28358560 TI - Clustering by well-being in workplace social networks: Homophily and social contagion. AB - Social interaction among employees is crucial at both an organizational and individual level. Demonstrating the value of recent methodological advances, 2 studies conducted in 2 workplaces and 2 countries sought to answer the following questions: (a) Do coworkers interact more with coworkers who have similar well being? and, if yes, (b) what are the processes by which such affiliation occurs? Affiliation was assessed via 2 methodologies: a commonly used self-report measure (i.e., mutual nominations by coworkers) complemented by a behavioral measure (i.e., sociometric badges that track physical proximity and social interaction). We found that individuals who share similar levels of well-being (e.g., positive affect, life satisfaction, need satisfaction, and job satisfaction) were more likely to socialize with one another. Furthermore, time-lagged analyses suggested that clustering in need satisfaction arises from mutual attraction (homophily), whereas clustering in job satisfaction and organizational prosocial behavior results from emotional contagion. These results suggest ways in which organizations can physically and socially improve their workplace. (PsycINFO Database Record PMID- 28358563 TI - Emotion perception and empathy: An individual differences test of relations. AB - Numerous theories posit a positive relation between perceiving emotion expressed in the face of a stranger (emotion perception) and feeling or cognitively understanding the emotion of that person (affective and cognitive empathy, respectively). However, when relating individual differences in emotion perception with individual differences in affective or cognitive empathy, effect sizes are contradictory, but often not significantly different from zero. Based on 4 studies (study ns range from 97 to 486 persons; ntotal = 958) that differ from one another on many design and sample characteristics, applying advanced modeling techniques to control for measurement error, we estimate relations between affective empathy, cognitive empathy, and emotion perception. Relations are tested separately for each of the 6 basic emotions (an emotion-specific model) as well as across all emotions (an emotion-general model). Reflecting the literature, effect sizes and statistical significance with an emotion-general model vary across the individual studies (rs range from -.001 to .24 for emotion perception with affective empathy and -.01 to .39 for emotion perception with cognitive empathy), with a meta-analysis of these results indicating emotion perception is weakly related with affective (r = .13, p = .003) and cognitive empathy (r = .13, p = .05). Relations are not strengthened in an emotion-specific model. We argue that the weak effect sizes and inconsistency across studies reflects a neglected distinction of measurement approach-specifically, empathy is assessed as typical behavior and emotion perception is assessed as maximal effort and conclude with considerations regarding the measurement of each construct. (PsycINFO Database Record PMID- 28358561 TI - Influences of oxytocin and respiratory sinus arrhythmia on emotions and social behavior in daily life. AB - The literature concerning biological influences on positive social behavior shows that, in nonthreatening contexts, tonic oxytocin (OT) and respiratory sinus arrhythmia (RSA) each predict positive, affiliative behaviors toward certain others and are associated with positive health outcomes. The purpose of this investigation was to determine the degree to which the positive affiliative correlates of OT and RSA can be distinguished when observed at the level of everyday life events. A sample of midlife adults (N = 73) provided tonic indices of these biological characteristics, as well as perceptions of a variety of common life events alongside reports of their emotions during those events. OT and RSA each independently moderated the link between perceived event sociality and positive emotions, whereas only RSA predicted the probability of being with other people during an event. These findings suggest that OT and RSA may each be linked to positive social experiences in complementary yet distinct ways. (PsycINFO Database Record PMID- 28358562 TI - Partner-expected affect: How you feel now is predicted by how your partner thought you felt before. AB - Romantic partners can modulate each other's emotions in many ways, resulting in interwoven emotional lives. Here, building on findings from basic psychological research, we propose a novel way of such interconnectedness, termed partner expected affect, in which perceptions of a partner's feelings may positively predict how this partner will actually feel at a later moment in time. We evaluated this hypothesis by means of an experience sampling study in which 100 romantic partners (50 couples) reported on the level of valence and arousal of their own feelings and of the perceived feelings of their partners 10 times a day throughout a week. In line with expectations, we found that how individuals were feeling at a particular moment was positively predicted by how their partner thought they felt at the previous moment (on top of how they felt at the previous moment and how their partner felt at the previous moment), at least when they had interacted with each other in between. This finding identifies a novel potential way in which people may shape each other's feelings and paves the way to further examine the nature and boundary conditions of such partner-expected affect. (PsycINFO Database Record PMID- 28358564 TI - LATEST: A model of saccadic decisions in space and time. AB - Many of our actions require visual information, and for this it is important to direct the eyes to the right place at the right time. Two or three times every second, we must decide both when and where to direct our gaze. Understanding these decisions can reveal the moment-to-moment information priorities of the visual system and the strategies for information sampling employed by the brain to serve ongoing behavior. Most theoretical frameworks and models of gaze control assume that the spatial and temporal aspects of fixation point selection depend on different mechanisms. We present a single model that can simultaneously account for both when and where we look. Underpinning this model is the theoretical assertion that each decision to move the eyes is an evaluation of the relative benefit expected from moving the eyes to a new location compared with that expected by continuing to fixate the current target. The eyes move when the evidence that favors moving to a new location outweighs that favoring staying at the present location. Our model provides not only an account of when the eyes move, but also what will be fixated. That is, an analysis of saccade timing alone enables us to predict where people look in a scene. Indeed our model accounts for fixation selection as well as (and often better than) current computational models of fixation selection in scene viewing. (PsycINFO Database Record PMID- 28358566 TI - Use of tools and misuse of embodied cognition: Reply to Buxbaum (2017). AB - Osiurak and Badets (2016) examined the validity of the manipulation-based versus the reasoning-based approaches to tool use in light of studies in experimental psychology and neuropsychology. They concluded that the reasoning-based approach seems to be more promising than the manipulation-based approach for understanding the current literature. Buxbaum (2017) questioned this conclusion and raised certain theoretical limitations with regard to the reasoning-based approach. She also suggested that this approach is not well-equipped to integrate the existing psychological and neuroanatomical data in the tool use domain. In this context, she presented a neurocognitive model-the "Two Action Systems Plus" (2AS+) framework-deeply anchored in the embodied cognition approach. In this reply, we address the key points raised by Buxbaum, leading us to draw 2 new conclusions. The first is that the reasoning-based approach integrates the existing psychological and neuroanatomical data not only in the tool use domain, but also in the motor control domain. As a matter of fact, it is even better equipped than the 2AS+ to account for recent neuroscience data. The second is that the 2AS+ suffers from epistemological and theoretical limitations, generating confusion as to what manipulation knowledge-a core concept in this model-precisely is. To sum up, 2AS+ illustrates potential misuse of embodied cognition, viewing tool use mainly as a matter of manipulation and not of understanding mechanical actions between tools and objects. (PsycINFO Database Record PMID- 28358567 TI - The cost of work-related stress to society: A systematic review. AB - A systematic review of the available evidence examining the cost of work-related stress (WRS) would yield important insights into the magnitude of this social phenomenon. The objective of this review was to collate, extract, and synthesize economic evaluations of the cost of WRS to society. A research protocol was developed. Included cost-of-illness (COI) studies estimated the cost of WRS at a societal level, and were published in English, French or German. Searches were carried out in ingentaconnect, EBSCO, JSTOR, Science Direct, Web of Knowledge, Google, and Google scholar. Included studies were assessed against 10 COI quality assessment criteria. Fifteen studies met the inclusion criteria and were reviewed. These originated from Australia, Canada, Denmark, France, Sweden, Switzerland, the United Kingdom, and the EU-15. The total estimated cost of WRS was observed to be considerable and ranged substantially from US$221.13 million to $187 billion. Productivity related losses were observed to proportionally contribute the majority of the total cost of WRS (between 70 to 90%), with health care and medical costs constituting the remaining 10 to 30%. The evidence reviewed here suggests a sizable financial burden imposed by WRS on society. The observed range of cost estimates was understood to be attributable to variations in definitions of WRS; the number and type of costs estimated; and, in how production loss was estimated. It is postulated that the cost estimates identified by this review are likely conservative because of narrow definitions of WRS and the exclusion of diverse range of cost components. (PsycINFO Database Record PMID- 28358565 TI - Learning, remembering, and predicting how to use tools: Distributed neurocognitive mechanisms: Comment on Osiurak and Badets (2016). AB - The reasoning-based approach championed by Francois Osiurak and Arnaud Badets (Osiurak & Badets, 2016) denies the existence of sensory-motor memories of tool use except in limited circumstances, and suggests instead that most tool use is subserved solely by online technical reasoning about tool properties. In this commentary, I highlight the strengths and limitations of the reasoning-based approach and review a number of lines of evidence that manipulation knowledge is in fact used in tool action tasks. In addition, I present a "two route" neurocognitive model of tool use called the "Two Action Systems Plus (2AS+)" framework that posits a complementary role for online and stored information and specifies the neurocognitive substrates of task-relevant action selection. This framework, unlike the reasoning based approach, has the potential to integrate the existing psychological and functional neuroanatomic data in the tool use domain. (PsycINFO Database Record PMID- 28358569 TI - Daily job demands and employee work engagement: The role of daily transformational leadership behavior. AB - Using job demands-resources (JD-R) theory, the present study integrates the challenge stressor-hindrance stressor framework and leadership theory to investigate the relationship between daily transformational leadership behavior and employee work engagement. We hypothesized that daily transformational leadership behavior (a) sustains employee work engagement on days characterized by high challenge job demands, and (b) protects work engagement on days characterized by high hindrance job demands. Teachers filled out a short online questionnaire at the end of each workday during a 2-week period (N = 271 * 5.68 days = 1539). Results of latent moderated structural equation modeling showed that teachers' daily challenge demands (workload and cognitive demands) had a positive relationship with work engagement on the days transformational leadership was high (vs. low). In addition, teachers' daily hindrance demands (role-conflict, but not family to work conflict) had a negative relationship with work engagement on the days transformational leadership was low (vs. high). These findings show that the function of transformational leadership behavior changes from day to day, and depends on the type of job demand. We discuss the practical and theoretical implications of these findings. (PsycINFO Database Record PMID- 28358568 TI - Cognitive functioning, aging, and work: A review and recommendations for research and practice. AB - There is a larger proportion and number of older adults in the labor force than ever before. Furthermore, older adults in the workforce are working until later ages. Although a great deal of research has examined physical health and well being of working older adults, less research has focused on cognitive functioning. The purpose of this article is to provide a broad contemporary and multidisciplinary review of the intersection between cognitive functioning, aging, and work as a follow-up to a paper previously written by Fisher et al. (2014). We begin by providing definitions and background about cognitive functioning and how it changes over the life span. Next we discuss theories relevant to the intersection of cognitive functioning and work, including the use it-or-lose-it hypothesis, the cognitive reserve hypothesis, hypotheses regarding environmental influences on intellectual functioning, and the job-demands resources model. Then we summarize recent research about the effects of work on cognitive functioning, as well as ways that cognitive functioning may influence work motivation, learning, development, training, and safety. We conclude by emphasizing the importance of person-environment fit, suggesting avenues for future research, and discussing practical implications for the field of occupational health psychology. (PsycINFO Database Record PMID- 28358570 TI - Enhancing daily well-being at work through lunchtime park walks and relaxation exercises: Recovery experiences as mediators. AB - Only few studies so far have examined recovery from work during workday breaks. In this intervention study, based on the effort-recovery model and the conservation of resources theory, we examined how to enhance recovery during lunch breaks. More specifically, we examined the within-person effects of lunchtime park walks and relaxation exercises on employees' levels of concentration, strain, and fatigue experienced at the end of a working day. We moreover tested whether detachment from work and enjoyment experienced during lunch breaks transmitted the effects of these activities to well-being outcomes. Participants in the park walk (n = 51) and relaxation (n = 46) groups were asked to complete a 15-min exercise during their lunch break on 10 consecutive working days. Afternoon well-being, lunchtime detachment, and lunchtime enjoyment were assessed twice a week before, during, and after the intervention, altogether for 5 weeks. Multilevel analysis results showed that park walks at lunchtime were related to better concentration and less fatigue in the afternoon through enjoyment. Relaxation exercises were related to better concentration in the afternoon via detachment. In addition, relaxation exercises were directly linked to lower levels of strain and fatigue in the afternoon. Our study suggests that on days on which employees engage in recovering activities during lunch breaks, they experience higher levels of well-being at the end of a working day. These results add to the theory-based knowledge on recovery during workday breaks and highlight the importance of breaks for organizational practices. (PsycINFO Database Record PMID- 28358571 TI - Psychosocial working conditions among high-skilled workers: A latent transition analysis. AB - Theories of psychosocial working conditions assume an interaction of different work environment characteristics. Most studies detail various aspects of such interactions, while fewer investigate the comprehensive patterns of interrelated variables. This exploratory study distinguishes patterns of psychosocial working conditions, describes their characteristics, and investigates their change over 6 years. The working conditions of 1,744 high-skilled workers in Sweden, of a representative sample of the working population, were empirically classified into 4 distinct patterns: (a) the Supporting pattern with a very low workload, very low time pressure, medium learning opportunities, high creativity requirements, and very high autonomy; (b) the Constraining pattern with a very low workload, very low time pressure, low learning opportunities, medium creativity requirements, and very low autonomy; (c) the Demanding pattern with a high workload, high time pressure, medium learning opportunities, high creativity requirements, and very low autonomy; and (d) the Challenging pattern with a high workload, high time pressure, very high learning opportunities, very high creativity requirements, and very high autonomy. Importantly, these patterns were associated with significant differences in worker well-being. From an individual perspective, working conditions most often changed from patterns with a high workload and time pressure to patterns with lower levels of these demands. Over time, the prevalence of the Constraining pattern increased while that of the Challenging pattern decreased. To conclude, a person-centered approach broadens the understanding of the complex interplay between psychosocial working conditions and their longitudinal change, which can improve the tailoring of occupational health interventions. (PsycINFO Database Record PMID- 28358572 TI - Advances in recovery research: What have we learned? What should be done next? AB - Job-stress recovery during nonwork time is an important factor for employee well being. This article reviews the recovery literature, starting with a brief historical overview. It provides a definition of recovery that differentiates between recovery as a process and recovery as an outcome. Empirical studies have shown that recovery activities (e.g., physical exercise) and recovery experiences (e.g., psychological detachment from work) are negatively associated with strain symptoms (e.g., exhaustion) and positively associated with positive well-being indicators (e.g., vigor). Recovery activities and recovery experiences suffer when employees face a high level of job stressors. Psychological mechanisms underlying recovery seem to be similar across different temporal recovery settings (e.g., work breaks, free evenings, vacations) and seem to be enhanced in natural environments. Intervention studies have pointed to a diverse set of strategies for how everyday job-stress recovery can be supported. This article discusses 5 avenues for future research, with a particular focus on individual and contextual factors that may influence recovery as well as highlighting more complex temporal patterns than those uncovered in previous research. (PsycINFO Database Record PMID- 28358573 TI - Investigating the longitudinal effects of surface acting on managers' functioning through psychological needs. AB - This study is based on the premise that managers are expected to regulate their emotions in the form of surface acting. More specifically, drawing on self determination theory, we explored the role of psychological needs for autonomy, competence, and relatedness in explaining the influence of surface acting on supervisors' job satisfaction and work engagement over time. Data were collected at 2 time points, over a 3-month period, from a sample of 435 French managers working in the health care industry. Results revealed that surface acting negatively predicted managers' job satisfaction and work engagement over time, through the satisfaction of their psychological needs. However, managers' need thwarting did not explain these positive outcomes. Overall, these findings provide insight into the longitudinal adverse effects of managers' surface acting on their functioning and corroborate the distinct role of psychological need satisfaction and thwarting. Theoretical contributions and perspectives, as well as implications for practice are discussed. (PsycINFO Database Record PMID- 28358574 TI - The decade-long effect of work insecurity on husbands' and wives' midlife health mediated by anxiety: A dyadic analysis. AB - Although the detrimental physical health effects of work insecurity have been noted in previous research, less is known about the mediating processes, such as anxiety symptoms, that link work insecurity to physical health. Even less research has explored these effects at specific life stages and how these effects may impact significant others, even though the impact of this stress may vary across the life course and the mutual influences between married partners may cause dyadic effects stemming from partners' work insecurity. To fill these gaps, the current study incorporates theories that emphasize the stress-work connection, such as stress appraisal theory (Lazarus, 1999) and resource conservation theory (Hobfoll, 1989), into a neurobiological stress-health perspective. This study uses a sample of 330 consistently married, dual-earner husbands and wives who provided data at multiple time points over a 10-year period from 1991 to 2001. Results from a model including growth curves of work insecurity and anxiety symptoms when respondents were in their early middle years and reports of physical illness in their later middle years generally supported the hypothesized model. Both the level and rate of change in work insecurity were related to the change in anxiety symptoms over time. Similarly, the level and rate of change in anxiety symptoms from 1991 to 1994 were linked to subsequent illness years later in 2001. There was only partial support for the existence of partner effects. Findings are discussed as they relate to previous research as well as policy and clinical implications. (PsycINFO Database Record PMID- 28358575 TI - PDTRT Special Section: Methodological issues in personality disorder research. AB - Introduces Personality Disorders: Theory, Research, and Treatment ongoing Special Section concerned with methodological issues in personality disorder research. This second edition includes two papers, one which discusses the value and advantages of sampling the views, opinions, and perceptions of clinicians in personality disorder research, and the other which takes a critical look at the ways in which structural equation modeling techniques have been used in the study of personality disorders, symptoms, and traits. (PsycINFO Database Record PMID- 28358576 TI - Assessing the assessors: The feasibility and validity of clinicians as a source for personality disorder research. AB - The use of knowledgeable informants is a particularly valuable tool for the diagnosis and assessment of personality disorder (PD). This review details the use of one particular type of informant-practicing clinicians-in PD research. We detail a wide variety of studies that have employed clinicians as an assessment source, including those focused on interrater agreement, comparative validity with other methods, cognitive factors of diagnosis, and opinion surveys. We demonstrate limitations, such as potential biases and limited convergent validity, which caution against the assumption that clinicians' ratings should be considered a gold-standard. Nonetheless, we also highlight the potential value of research that focuses on clinicians due to its external validity to real-world practice settings. Finally, we outline several issues to consider when sampling clinicians, such as participation rate and sample size, and call for future research that collects ratings from clinicians using systematic, well-validated measures. (PsycINFO Database Record PMID- 28358577 TI - Structural equation modeling of personality disorders and pathological personality traits. AB - Structural equation modeling (SEM) is a family of related statistical techniques that lend themselves to understanding the complex relationships among variables that differ among individuals in the population. SEM techniques have become increasingly popular in the study of personality disorders (PDs) and maladaptive personality traits. The current article takes a critical look at the ways in which SEM techniques have been used in the study of PDs, PD symptoms, and pathological personality traits. By far the most common use of SEM in the study of PDs has been to examine the latent structure of these constructs, with an overwhelming bulk of the evidence in favor of a dimensional, as opposed to categorical, conceptualization. Other common uses of SEM in this area are factor models that examine the joint multivariate space of PDs, maladaptive personality traits, and psychopathology. Relatively underused, however, are observed or latent variable path models. We review the strengths and weaknesses of the work done to date, focusing on ways that these SEM studies have been either theoretically and/or statistically sound. Finally, we offer suggestions for future research examining PDs with SEM techniques. (PsycINFO Database Record PMID- 28358578 TI - Breastfeeding Initiation in Mothers with Repeat Cesarean Section: The Impact of Marital Status. AB - BACKGROUND: Approximately 90% of mothers with a primary C-section have a subsequent C-section. To date, research has demonstrated that primary C-sections are associated with breastfeeding noninitiation. However, it is unknown if this association persists after the primary C-section. Furthermore, literature has shown a differing relationship between breastfeeding initiations by marital status. Due to the high proportion of women who give birth while unmarried, investigating differences by marital status will add a significant contribution to breastfeeding literature. This study investigates the association between repeat C-section and breastfeeding initiation within marital status groups using a nationally representative cross-sectional survey. MATERIALS AND METHODS: Data from the 2004 to 2011 Pregnancy Risk Assessment Monitoring System were analyzed. The sample was restricted to women with a previous singleton live birth who had C section and whose infant was alive at the time of interview (N = 34,854). Multiple logistic regression analyses were conducted to obtain crude and adjusted odds ratio (AOR) and 95% confidence intervals (CIs). RESULTS: After adjusting for potential confounders, married women who had a repeat C-section were 2.2 times (AOR = 2.16, 95% CI = 1.69-2.77) more likely to never breastfeed compared to women with vaginal birth after caesarean section (VBAC). Similarly, the odds of breastfeeding noninitiation were 76% (AOR = 1.76, 95% CI = 1.47-2.12) higher among women with a repeat C-section compared to women with VBAC. No significant associations were exhibited among nonmarried women. CONCLUSIONS: Enhanced educational programs and counseling support may be needed to help families cope with delivery challenges and resulting stressors that may reduce their desire to initiate breastfeeding in the postpartum period. PMID- 28358579 TI - Correction to: Breastfeed Med 2016;11:413-415. PMID- 28358580 TI - Peroxiredoxin 5 Decreases Beta-Amyloid-Mediated Cyclin-Dependent Kinase 5 Activation Through Regulation of Ca2+-Mediated Calpain Activation. AB - AIMS: Aberrant Cdk5 (cyclin-dependent kinase 5) and oxidative stress are crucial components of diverse neurodegenerative disorders, including Alzheimer's disease (AD). We previously reported that a change in peroxiredoxin (Prx) expression is associated with protection from neuronal death. The aim of the current study was to analyze the role of Prx in regulating Cdk5 activation in AD. RESULTS: We found that of the six Prx subtypes, Prx5 was increased the most in cellular (N2a-APPswe cells) model of AD. Prx5 in the brain of APP (amyloid precursor protein) transgenic mouse (Tg2576) was more increased than a nontransgenic mouse. We evaluated Prx5 function by using overexpression (Prx5-WT), a mutation in the catalytic residue (Prx5-C48S), and knockdown. Increased neuronal death and Cdk5 activation by amyloid beta oligomer (AbetaO) were rescued by Prx5-WT expression, but not by Prx5-C48S or Prx5 knockdown. Prx5 plays a role in Cdk5 regulation by inhibiting the conversion of p35 to p25, which is increased by AbetaO accumulation. Prx5 is also upregulated in both the cytosol and mitochondria and it protects cells from AbetaO-mediated oxidative stress by eliminating intracellular and mitochondrial reactive oxygen species. Moreover, Prx5 regulates Ca2+ and Ca2+-mediated calpain activation, which are key regulators of p35 cleavage to p25. Innovation and Conclusion: Our study represents the first demonstration that Prx5 induction is a key factor in the suppression of Cdk5 related neuronal death in AD and we show that it functions via regulation of Ca2+ mediated calpain activation. Antioxid. Redox Signal. 27, 715-726. PMID- 28358582 TI - Acupuncture Meridian Energies in Patients Who Are Mentally Disturbed. AB - BACKGROUND AND OBJECTIVE: Acupuncture medicine states that different pathologies exhibit different patterns of excitation in the 24 main acupuncture meridians. Previous exploratory work has shown that groups of patients with the same pathology exhibit such characteristic patterns when limited numbers of acupuncture points are measured with the AcuGraph meridian energy measuring device. This study reports patterns of meridian energies observed in an exploratory assessment of different classes of patient with mental disturbance. METHODS: This study was a three-group cross-sectional design. Participants were patients who had been diagnosed by their GP with anxiety (n = 21) and depression (n = 26) and who were entering a treatment program, along with age- and sex matched controls (n = 44). Patients diagnosed with mild mental disturbance who were aged 20-50 years were eligible to take part. Patients with any cut, wart, or mole on their fingertips or with excess sweating, which would interfere with conductance measurements, were excluded. The assessment comprised conductance values at Jing-Well acupuncture points by AcuGraph4 on entry into the treatment program. RESULTS: Patients with anxiety had higher meridian energy levels (81.84 +/- 38.63) and significant Upper-Lower imbalances (p < 0.05) favoring the upper meridians. Patients with depression had lower energy levels and lower standard deviations (53.36 +/- 33.48) as a group. Controls exhibited intermediate energy levels but recorded the lowest scoring variances (62.61 +/- 27.05) of the three groups. Kidney meridians had the lowest energy for both of the pathology groups. For the group suffering with anxiety, bladder meridians were also low. CONCLUSION: Higher variances in AcuGraph4 measurements were observed in patients with either anxiety or depression compared with controls whose variances were the lowest. These results are in accordance with previous observations of greater variance in conductance values in pathology groups. With regard to meridian energies, the lowest were in those with depression, while those with anxiety were the highest. Controls exhibited intermediate energy levels. PMID- 28358581 TI - Mechanism of the Antitumor and Radiosensitizing Effects of a Manganese Porphyrin, MnHex-2-PyP. AB - AIMS: Cationic manganese (Mn)-substituted N-pyridylporphyrin-based potent mimics of the family of superoxide dismutases (SODs) protect normal tissues from injury related to ionizing radiation (IR) by reducing levels of reactive oxygen and nitrogen species (ROS/RNS). Furthermore, Mn-porphyrins have demonstrated antitumor and radiosensitizing effects on cancer cells by promoting IR-induced tumor vasculature damage and apoptotic processes. In this study, we explored the underlying mechanisms of Mn-porphyrin-mediated tumor radiosensitization using murine mammary carcinoma 4T1 and melanoma B16 cells in vitro and in vivo. RESULTS: Combination treatment with MnTnHex-2-PyP and IR substantially reduced cell viability, clonogenic cell survival, and DNA damage repair and synergistically increased IR-induced apoptosis of 4T1 and B16 cells. MnTnHex-2 PyP in combination with IR caused a significant delay in growth of 4T1 and B16 xenograft tumors. MnTnHex-2-PyP dose-dependently enhanced IR-mediated production of H2O2-derived species, but not superoxide. Catalase overexpression reversed MnTnHex-2-PyP-enhanced ROS production and apoptosis. Demonstrated suppression of phosphorylation of several mitogen-activated protein (MAP) kinases and activation of NF-kappaB by MnTnHex-2-PyP/IR, which presumably inhibited activation of the antiapoptotic pathway, are in agreement with our other data on the apoptosis of cancer cells. Innovation and Conclusions: MnTnHex-2-PyP exerted a radiosensitizing effect on 4T1 and B16 tumor models in vitro and in vivo via pro oxidative actions and therefore bears a large therapeutic potential. When combined with IR, it attenuated DNA damage repair and triggered a shift from prosurvival pathways to apoptotic cell death, likely due to increased ROS production and disturbed cellular redox balance, acting at the level of nuclear factor kappaB (NF-kappaB). Antioxid. Redox Signal. 27, 1067-1082. PMID- 28358583 TI - Genetic Relatedness Among Shiga Toxin-Producing Escherichia coli Isolated Along the Animal Food Supply Chain and in Gastroenteritis Cases in Qatar Using Multilocus Sequence Typing. AB - INTRODUCTION: Pathogenic Escherichia coli has been listed among the most important bacteria associated with foodborne illnesses around the world. We investigated the genetic relatedness among Shiga toxin-producing E. coli (STEC) isolated along the animal food supply chain and from humans diagnosed with gastroenteritis in Qatar. METHODS: Samples were collected from different sources along the food supply chain and from patients admitted to the hospital with complaints of gastroenteritis. All samples were screened for the presence of E. coli O157:H7 and non-O157 STEC using a combination of bacterial enrichment and molecular detection techniques. A proportional sampling approach was used to select positive samples from each source for further multilocus sequence typing (MLST) analysis. Seven housekeeping genes described for STEC were amplified by polymerase chain reaction, sequenced, and analyzed by MLST. Isolates were characterized by allele composition, sequence type (ST) and assessed for epidemiologic relationship within and among different sources. Nei's genetic distance was calculated at the allele level between sample pools in each site downstream. RESULTS: E. coli O157:H7 occurred at a higher rate in slaughterhouse and retail samples than at the farm or in humans in our sampling. The ST171, an ST common to enterotoxigenic E. coli and atypical enteropathogenic E. coli, was the most common ST (15%) in the food supply chain. None of the genetic distances among the different sources was statistically significant. CONCLUSION: Enterohemorrhagic E. coli pathogenic strains are present along the supply chain at different levels and with varying relatedness. Clinical isolates were the most diverse, as expected, considering the polyclonal diversity in the human microbiota. The high occurrence of these food adulterants among the farm products suggests that implementation of sanitary measures at that level might reduce the risk of human exposure. PMID- 28358585 TI - Etiology of bacterial vaginosis and polymicrobial biofilm formation. AB - Microorganisms in nature rarely exist in a planktonic form, but in the form of biofilms. Biofilms have been identified as the cause of many chronic and persistent infections and have been implicated in the etiology of bacterial vaginosis (BV). Bacterial vaginosis is the most common form of vaginal infection in women of reproductive age. Similar to other biofilm infections, BV biofilms protect the BV-related bacteria against antibiotics and cause recurrent BV. In this review, an overview of BV-related bacteria, conceptual models and the stages involved in the polymicrobial BV biofilm formation will be discussed. PMID- 28358584 TI - Assessing the Usefulness and Validity of Frailty Markers in Critically Ill Adults. AB - RATIONALE: Identifying frailty by the presence of a critical number of frailty markers has been difficult to operationalize in the intensive care unit (ICU), where patients often cannot complete performance measures or answer complex questions. OBJECTIVES: To assess the construct and predictive validity of a questionnaire-based approach to identifying frailty in adult ICU patients. METHODS: We conducted an observational cohort study of adults admitted to a medical or surgical ICU at one of two hospitals in New York. We asked patients or surrogates about demographic information, frailty markers, and prehospital disability status. ICU physicians completed the Clinical Frailty Scale (CFS), a judgment-based frailty assessment tool. We examined the relationship between individual frailty markers, CFS, and demographic correlates of frailty such as age, prehospital living arrangement, and prehospital disability. We assessed the predictive validity of possible frailty phenotypes, using hospital and 6-month outcomes. RESULTS: Among 95 study participants (mean age [SD], 57.1 [17.5] yr), 80% reported one or more of seven frailty markers (median [interquartile range], 3 [1-4]). The most common frailty markers were impaired mobility (60%), impaired physical activity (60%), and decreased strength (44.2%). Patients with more frailty markers were older (mean age [SD] of those with at least three frailty markers: 62.3 [17.7] vs. 51.6 [15.8] yr; P < 0.001) compared with those with fewer than three markers, and were more likely to be judged frail by CFS (57.0 vs. 19.6%; P = 0.001), although of the 49 patients with three or more frailty markers, CFS identified 36.7% as not frail. Malnutrition and fatigue or low energy were not significantly associated with other frailty correlates. Survivors with more frailty markers were more likely to die or report increased disability at follow-up. In multivariate models, a frailty phenotype defined as at least three of the seven frailty markers performed similarly to CFS in predicting death or increased disability at 6 months (adjusted odds ratio [95% confidence interval], 3.3 [1.2-9.0] vs. 3.8 [1.2-11.7]) for CFS. CONCLUSIONS: Asking patients or surrogates about frailty markers may be a valid approach to identifying critically ill adults with a frailty phenotype associated with increased risk of adverse outcomes. Larger studies measuring frailty markers may provide insight into factors that impact short- and long-term outcomes after ICU admission. PMID- 28358587 TI - A Novel Curative Treatment Strategy for Patients with Lower Grade Rectal Gastrointestinal Stromal Tumor: Chemoreduction Combined with Transanal Endoscopic Microsurgery. AB - BACKGROUND: A multimodal treatment has been applied for patients with rectal gastrointestinal stromal tumor (GIST) that represents 5% of the total localization. Meanwhile, transanal endoscopic microsurgery (TEM) offers a minimally invasive method for full-thickness tumor excision with negative margins and low morbidity. We report the single most extensive analysis of data from China to evaluate the feasibility and safety of the procedure combined with neoadjuvant imatinib therapy to treat patients with rectal GISTs. MATERIALS AND METHODS: All the clinical data were obtained for patients who underwent the procedure in our hospital from February 2008 to May 2015, and the data were retrospectively analyzed. RESULTS: Full-thickness excision by TEM was performed on 25 patients with rectal GIST by using primary surgical excision, 8 of whom had received perioperative chemotherapy after histopathological confirmation under the care of medical oncologists. No obvious postoperative complications were observed. The average tumor downsizing ratio was 14.5%, which apparently enabled oversized tumors to be resected by TEM. The comparative risk did not increase during or after the procedure. We did not observe recurrence or metastasis in any of the 25 patients during the median 3-year follow-up period after the procedures. CONCLUSIONS: The perioperative imatinib treatment effectively allowed oversized rectal GIST tumors to be resected by TEM, and the procedures did not exhibit an increased risk. Exclusively, the TEM procedure with alternative neoadjuvant imatinib therapy is a feasible and safe modality for treating patients with rectal GISTs. PMID- 28358589 TI - Evaluation of Genetic Diversity, Population Structure, and Relationship Between Legendary Vechur Cattle and Crossbred Cattle of Kerala State, India. AB - The legendary Vechur cattle of Kerala, described as a very short breed, and the crossbred (CB) Sunandini cattle population exhibited great phenotypic variation; hence, the present study attempted to analyze the genetic diversity existing between them. A set of 14 polymorphic microsatellites were chosen from FAO-ISAG panel and amplified from genomic DNA isolated from blood samples of 30 Vechur and 64 unrelated crossbred cattle, using fluorescent labeled primers. Both populations revealed high genetic diversity as evidenced from high observed number of alleles, Polymorphic Information Content and expected heterozygosity. Observed heterozygosity was lesser (0.699) than expected (0.752) in Vechur population which was further supported by positive FIS value of 0.1149, indicating slight level of inbreeding in Vechur population. Overall, FST value was 0.065, which means genetic differentiation between crossbred and Vechur population was 6.5%, indicating that the crossbred cattle must have differentiated into a definite population that is different from the indigenous Vechur cows. Structure analysis indicated that the two populations showed distinct differences, with two underlying clusters. The present study supports the separation between Taurine and Zebu cattle and throws light onto the genetic diversity and relationship between native Vechur and crossbred cattle populations in Kerala state. PMID- 28358588 TI - The Burnia: Laparoscopic Sutureless Inguinal Hernia Repair in Girls. AB - INTRODUCTION: Laparoscopic inguinal hernia repair in children is in evolution. Multiple methods of passing the suture around the peritoneum at the level of the internal inguinal ring exist. Cauterization of the peritoneum at the internal ring is thought to increase scarring and decrease recurrence. We have employed a sutureless, cautery only, laparoscopic single port repair of inguinal hernias and patent processus vaginalis (PPV) in girls. METHODS: After institutional ethical review was obtained, a retrospective review of sutureless laparoscopic inguinal hernia repairs in girls by 4 surgeons at separate institutions was performed. Patient demographics, intraoperative findings, and postoperative outcomes were recorded and analyzed. The technique involves an umbilical 30 degrees camera and either a separate 3 mm stab incision in the midclavicular line or a 3 mm Maryland grasper placed next to the camera, and the distal most portion of the hernia sac is grasped and pulled into the abdomen and cauterized obliterating the sac. RESULTS: Eighty inguinal hernias were repaired using this technique in 67 girls between July 2009 and September 2015. The ages and weights ranged from 1 month to 16 years and from 2 to 69 kg, respectively. There was one conversion to open approach because an incarcerated ovary was too close to the ring. A single umbilical incision was utilized in 85%. Fifty-seven percent patients had hernias on the right whereas 42% had hernias on the left. Of the patients with presumed unilateral hernias, 22 patients were found to have PPV and were treated through the same incisions, 17/22 were found during a contralateral hernia surgery and 5/22 were found incidentally during appendectomy. Average operative time for unilateral and bilateral hernias was 22 minutes (5-38 minutes) and 31 minutes (11 65 minutes), respectively. No patient required a hospital stay because of the hernia repair. At an average of 25 months follow-up (1.6-75 months), there were no recurrences. The only complication was a single lateral port site hernia on a 2 kg, former 24 week postmenstrual age girl before adapting the technique to single-site surgery for all. CONCLUSIONS: Laparoscopic sutureless inguinal hernia repair is safe and effective in girls of all ages. The single-site modification allows for superior cosmetic result and lower complication profile. The Burnia allows for adequate treatment of unilateral and bilateral inguinal hernias with a single incision in the umbilicus. PMID- 28358590 TI - Cellulitis Secondary to Liquid Nitrogen Cryotherapy: Case Report and Literature Review. AB - BACKGROUND: Liquid nitrogen cryotherapy is a commonly used technique to treat a wide variety of dermatologic conditions including actinic keratoses, non-melanoma skin cancers, verrucae, and seborrheic keratoses. The risks associated with liquid nitrogen cryotherapy are important to know and discuss with patients prior to treatment. OBJECTIVE: We report a case of cellulitis secondary to liquid nitrogen cryotherapy for actinic keratosis. We sought to review the literature for an estimate of secondary infection rates following cryotherapy treatment. METHODS: We searched Pubmed using the terms cryotherapy and infection or cellulitis. We then looked at articles classified as clinical trials where cryotherapy was used to treat skin conditions. We then selected clinical trials that listed cellulitis or infection as an adverse event. RESULTS AND CONCLUSION: There were no case reports, case series, or review articles detailing the risk of infection from liquid nitrogen cryotherapy. We found 8 articles classified as clinical trials on Pubmed that did list infection as an adverse event. The risk of infection from these studies varied from approximately 2% to 30%. There was a great degree of heterogeneity in treatment sites, length of treatment, and treatment targets. While it is difficult to determine the true incidence of infection from liquid nitrogen cryotherapy, clinicians should endeavor to inform patients of this potential risk. PMID- 28358591 TI - Central Sleep Apnea and Stiff Person Syndrome: A Case Report. PMID- 28358586 TI - Utility of microfluidic devices to study the platelet-endothelium interface. AB - The integration of biomaterials and understanding of vascular biology has led to the development of perfusable endothelialized flow models, which have been used as valuable tools to study the platelet-endothelium interface under shear. In these models, the parameters of geometry, compliance, biorheology, and cellular complexity are varied to recapitulate the physical biology of platelet recruitment and activation under physiologically relevant conditions of blood flow. In this review, we summarize the mechanistic insights learned from perfusable microvessel models and discuss the potential utility as well as challenges of endothelialized microfluidic devices to study platelet function in the bloodstream in vitro. PMID- 28358592 TI - Increased circulating oxidised low-density lipoprotein and antibodies to oxidised low-density lipoprotein in preeclampsia. AB - Enhanced oxidative stress is involved in the pathogenesis of endothelial dysfunction in preeclampsia (PE). Circulating oxidised LDL (oxLDL) and antibodies to oxLDL (Ab-oxLDL) have been found to be associated with atherosclerosis. The objectives of this study were to investigate the association of oxLDL and Ab oxLDL with PE and to assess the association between oxLDL and Ab-oxLDL. The levels of oxLDL and Ab-oxLDL were measured by enzyme-linked immunoassay in 78 women with preeclampsia (PE group) and 78 women with normal pregnancy (control group). The PE group had higher oxLDL and Ab-oxLDL levels than the control group (485.1vs.145.9 ng/ml, p < .001) and (578.7 vs 216.2 mU/ml, p < .001), respectively. However, Ab-oxLDL levels were not associated with the levels of oxLDL, age, BMI, gestational age, systolic blood pressure (SBP) and diastolic blood pressure (DBP) in both the groups. In conclusion, our study showed that PE was associated with increased oxLDL and Ab-oxLDL, which may reflect the enhanced oxidative stress in PE. Impact Statement Preeclampsia (PE) is a potentially life threatening condition and both maternal and foetal complications can develop if it is not monitored appropriately. The pathogenesis of endothelial dysfunction in PE is related to the enhanced oxidative stress and oxidation of LDL. However, more studies were required as previous studies had not shown a consistent association of oxLDL and Ab-oxLDL with PE. Our study showed significant association of oxLDL and Ab-oxLDL with PE, indicating that their levels may be reliable indicators of oxidation stress and of the risk of PE. Levels of oxidative stress markers may have implications for clinical practice, such as their association with intrauterine growth restriction (IUGR), HELLP syndrome or eclampsia, foetal birth weight and premature delivery. Further research is still needed, ideally as a prospective cohort study to investigate the association of oxLDL and Ab-oxLDL with such outcome parameters. PMID- 28358593 TI - A Case of Amoxicillin-Induced Acute Generalized Exanthematous Pustulosis Presenting as Septic Shock. AB - This case report demonstrates the challenges of diagnosing and managing acute generalized exanthematous pustulosis (AGEP) presenting as septic shock. The disseminated, erythematous, pustular rash is a common feature. However, extensive organ involvement and life-threatening hypotension are unusual. The constellation of signs has not previously been documented following amoxicillin therapy. Toxic epidermal necrolysis (TEN) and toxic shock syndrome (TSS) were considered in addition to AGEP because of the systemic presentation. AGEP was diagnosed following histopathology (TEN was ruled out based on limited necrotic keratinocytes and lack of epidermal necrosis) and a negative antistreptolysin O titer (eliminated TSS). Antibiotic therapy for septic shock was provided before the diagnosis was confirmed as AGEP. Upon confirmation of the AGEP diagnosis, antibiotics were discontinued and a 5-day course of oral prednisone (40 mg/d) was initiated in addition to topical half-strength (0.05%) betamethasone valerate. The patient rapidly improved and was discharged. Outpatient patch testing confirmed amoxicillin as the culprit drug. In conclusion, it is critical to realize that AGEP cannot be ruled out with a septic shock presentation. Recent drug history is critical in recognizing an adverse drug reaction, and patch testing is useful for determining the culpable drug when the diagnosis is AGEP. PMID- 28358594 TI - Psychiatric Symptoms in Survivors of Acute Respiratory Distress Syndrome. Effects of Age, Sex, and Immune Modulation. AB - RATIONALE: Psychiatric morbidity after acute respiratory distress syndrome (ARDS) is common, and our current ability to predict psychiatric symptoms based on patient- and illness-specific factors is limited. OBJECTIVES: We assessed symptoms of anxiety, depression, and posttraumatic stress disorder (PTSD) in long term survivors of ARDS, as well as the associated changes in cortisol levels. METHODS: The participants were enrolled in a randomized, double-blind, placebo controlled trial of granulocyte macrophage-colony stimulating factor (GM-CSF) or placebo conducted at three academic medical centers. There were 132 patients enrolled, and 44 patients completed 6-month follow-up questionnaires (45% of survivors). RESULTS: Six months after enrollment, survivors completed the Post Traumatic Stress Syndrome 10 Questions Inventory, Impact of Event Scale, and Hospital Anxiety and Depression Scale to assess psychiatric symptoms. Plasma cortisol levels during treatment were measured by immunoassay. Thirty-six percent of patients reported significant psychiatric symptoms on at least one scale. GM CSF-treated patients reported more severe posttraumatic stress and depression symptoms than patients in the placebo group. In multiple regression analyses, younger age, female sex, higher severity of illness, fewer steroid treatment days, and GM-CSF treatment were all independently associated with more severe psychiatric symptoms on at least one scale. CONCLUSIONS: 6 months after ARDS, age, sex, illness severity, steroids, and GM-CSF treatment were associated with psychiatric symptom scores. These associations should be confirmed in a larger population. Clinical Trial registered with clinicaltrials.gov (NCT00201409). PMID- 28358595 TI - Treatment of Enterocutaneous Fistulas, Then and Now. AB - BACKGROUND: An enterocutaneous fistula (ECF) is an aberrant connection between the gastrointestinal tract and the skin or atmosphere (enteroatmospheric fistula [EAF]). Multimodal treatment includes surgical procedures, nutrition support, and wound care. We evaluated our practice and compared our outcomes with previous results published from our institution. MATERIALS AND METHODS: We performed a retrospective analysis of hospitalized ECF/EAF patients admitted between January 2011 and November 2015. Patients with internal fistulas; active inflammatory bowel disease; malignancy; radiation treatment; end-stage renal, hepatic, or cardiac disease; and active alcoholism were excluded. Data collected included demographics, fistula characteristics, nutrition therapy, treatment, operative success, and hospital mortality. Parametric and nonparametric tests for independent and paired groups were performed. RESULTS: Thirty-one patients were included in the analysis. The median (interquartile range) age was 60 (53-76) years, and 81% were female. Parenteral nutrition was initially prescribed in 80% of patients, but 61% received enteral nutrition (EN) at some point during their hospitalization. Two patients were fed by fistuloclysis. Eighty percent of the patients underwent surgical repair a median of 12 months after diagnosis with 92% operative success. Surgical repair had a modest correlation with home discharge (rho = 0.517, P = .003). A large proportion of patients (77%) were discharged home. The in-hospital mortality at our institution decreased from 44% in 1960 to 21% in 1970 to 3% in the current study. CONCLUSIONS: Modern treatment of ECF/EAF, including EN and advanced local wound care, is associated with improvements in clinical outcomes such as hospital mortality. PMID- 28358596 TI - Endophytic actinobacteria: Diversity, secondary metabolism and mechanisms to unsilence biosynthetic gene clusters. AB - Endophytic actinobacteria, which reside in the inner tissues of host plants, are gaining serious attention due to their capacity to produce a plethora of secondary metabolites (e.g. antibiotics) possessing a wide variety of biological activity with diverse functions. This review encompasses the recent reports on endophytic actinobacterial species diversity, in planta habitats and mechanisms underlying their mode of entry into plants. Besides, their metabolic potential, novel bioactive compounds they produce and mechanisms to unravel their hidden metabolic repertoire by activation of cryptic or silent biosynthetic gene clusters (BGCs) for eliciting novel secondary metabolite production are discussed. The study also reviews the classical conservative techniques (chemical/biological/physical elicitation, co-culturing) as well as modern microbiology tools (e.g. next generation sequencing) that are being gainfully employed to uncover the vast hidden scaffolds for novel secondary metabolites produced by these endophytes, which would subsequently herald a revolution in drug engineering. The potential role of these endophytes in the agro-environment as promising biological candidates for inhibition of phytopathogens and the way forward to thoroughly exploit this unique microbial community by inducing expression of cryptic BGCs for encoding unseen products with novel therapeutic properties are also discussed. PMID- 28358598 TI - Abstract of Papers Presented at the Seventy-Fifth Annual Meeting of the IAMFES. AB - Abstracts of most papers submitted for presentation at the 75th Annual Meeting of the IAMFES appear on this and the following pages. The complete text of some of the papers will appear in future issues of the Journal of Food Protection or Dairy and Food Sanitation. PMID- 28358597 TI - Common genetic polymorphisms of adenosine A2A receptor do not influence response to regadenoson. AB - AIM: Hemodynamic response to regadenoson varies greatly, and underlying mechanisms for variability are poorly understood. We hypothesized that five common variants of adenosine A2A receptor (ADORA2A) are associated with altered response to regadenoson. METHODS: Consecutive subjects (n = 357) undergoing resting regadenoson nuclear stress imaging were enrolled. Genotyping was performed using Taqman-based assays for rs5751862, rs2298383, rs3761422, rs2267076 and rs5751876. RESULTS: There was no significant difference in heart rate or blood pressure between different genotypes following regadenoson administration. There was also no significant difference in myocardial ischemia detected by nuclear perfusion imaging as defined by summed difference score, or in self-reported side effects among the genotypes tested. CONCLUSION: The common A2A variants studied are not associated with variability in hemodynamic response to regadenoson or variability in detection of ischemia with nuclear perfusion stress imaging. PMID- 28358599 TI - A Double-Blind Randomized Placebo-Controlled Pilot Study of Azithromycin in Youth with Acute-Onset Obsessive-Compulsive Disorder. AB - OBJECTIVES: Sudden and severe onset of obsessive-compulsive disorder (OCD) may present secondary to infectious and/or immune-mediated triggers. We assessed the preliminary efficacy, tolerability, and safety of azithromycin compared with placebo in the treatment of OCD and associated symptoms in children with pediatric acute-onset neuropsychiatric syndrome (PANS). METHODS: Thirty-one youth aged 4-14 years (M = 8.26 +/- 2.78 years, 62.5% male) were randomized to receive either placebo or azithromycin for 4 weeks (10 mg/kg up to 500 mg per day). Both groups were administered twice daily probiotics. The primary outcome, obsessive compulsive symptom severity, was assessed using the OCD Clinical Global Impressions Severity (CGI-S OCD) and Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). RESULTS: Participants in the azithromycin group (n = 17) showed significantly greater reductions in OCD severity on the CGI-S OCD than the placebo group (n = 14) posttreatment (p = 0.003), although there were no significant differences on the CY-BOCS. Significantly more participants in the azithromycin condition met treatment responder criteria on the CGI-I OCD at the end of week 4 (41.2%, n = 7) in comparison to the placebo group (7.1%, n = 1; p = 0.045). Tic severity moderated treatment response, with greater tic severity being associated with enhanced treatment response on the CGI-S OCD. Azithromycin was well tolerated with minimal adverse effects and no study dropouts due to side effects. However, the azithromycin group showed a trend toward significantly greater electrocardiography QTc (p = 0.060) at the end of week 4, and significantly more reports of loose or abnormal stools (p = 0.009). CONCLUSION: This double blind pilot study suggests that azithromycin may be helpful in treating youth meeting the PANS diagnosis, especially those with elevated levels of both OCD and tic symptoms. Azithromycin was well tolerated, but the potential for cardiac risks suggests that additional monitoring may be needed to ensure safety. PMID- 28358600 TI - Pallidal Stimulation in an 11-Year-Old Boy with Treatment-Resistant Tourette Syndrome. PMID- 28358601 TI - Pharmacogenetics in the treatment of pre-eclampsia: current findings, challenges and perspectives. AB - Pre-eclampsia (PE) is defined as pregnancy-induced hypertension and proteinuria, and is a major cause of maternal and perinatal morbidity and mortality. A large subgroup of pregnant women with PE is nonresponsive to antihypertensive drugs, including methyldopa, nifedipine and hydralazine. Pharmacogenomics may help to guide the individualized therapy for this nonresponsive subgroup. However, just a few pharmacogenetic studies examined the effects of genetic polymorphisms on response to antihypertensive drugs in PE, and the criteria of responsiveness used to define responsive or nonresponsive subgroups to antihypertensive therapy should be replicated by others. We review these gene-drugs interactions, novel approaches to pharmacogenomics research and potential novel drugs for PE therapy. Finally, we discuss the challenges and perspectives of pharmacogenetics in the treatment of PE. PMID- 28358602 TI - In Vitro Incorporation of Radioiodinated Eugenol on Adenocarcinoma Cell Lines (Caco2, MCF7, and PC3). AB - Recently, the synthesis of radiolabeled plant origin compounds has been increased due to their high uptake on some cancer cell lines. Eugenol (EUG), a phenolic natural compound in the essential oils of different spices such as Syzygium aromaticum (clove), Pimenta racemosa (bay leaves), and Cinnamomum verum (cinnamon leaf), has been exploited for various medicinal applications. EUG has antiviral, antioxidant, and anti-inflammatory functions and several anticancer properties. The objective of this article is to synthesize radioiodinated (131I) EUG and investigate its effect on Caco2, MCF7, and PC3 adenocarcinoma cell lines. It is observed that radioiodinated EUG would have potential on therapy and imaging due to its notable uptakes in studied cells. PMID- 28358603 TI - Metastatic Thymoma in a Scarlet Macaw ( Ara macao ). AB - A 49-year-old female scarlet macaw ( Ara macao ) was presented with a mass in the cervical region. The bird showed no evidence of pain or discomfort, it swallowed food normally, and its breathing pattern was unremarkable. Results of contrast radiographic imaging revealed a well-demarcated mass in the right cervical region not related to the crop. After surgical resection and histopathologic evaluation, a malignant nodular stage of an epithelioid cortical-type thymoma was diagnosed. One year later, metastasis of the thymoma to the lung was diagnosed and confirmed at postmortem examination. The final diagnosis was corrected to malignant nodular stage of an epithelioid cortical-type thymoma with metastasis to the lung. This is the first report in an avian species of a malignant thymoma with metastasis to the lung after complete resection of the initial cervical thymoma and a survival time of 1 year. PMID- 28358604 TI - Infundibular Pulmonic Stenosis in a Moluccan Cockatoo (Cacatua moluccensis). AB - A 31-year-old female Moluccan cockatoo (Cacatua moluccensis) was examined for intermittent foot clenching of 4 months' duration. Physical examination revealed feather-destructive behavior and clinical findings compatible with hypovitaminosis A. Neurologic examination was unremarkable. Results of radiographs, hematologic testing, plasma biochemical analyses, and measurement of lead and trace element blood concentrations were unremarkable, except for degenerative joint disease of several thoracic intervertebral joints and a low blood copper concentration. Increased dietary copper was recommended. After a 6 month period without clinical signs, the bird presented again for episodes of foot weakness. Radiographic review was suggestive of mild pulmonary trunk enlargement. Echocardiography revealed mild mitral and aortic regurgitation, dilation of the ascending aorta, and a dilated right ventricle with turbulent right ventricular outflow. An electrocardiogram revealed a sinus rhythm and normal-appearing complexes. Nonselective fluoroscopic angiography was performed 3 weeks later because of persistent episodes of foot clenching and weakness. Infundibular pulmonic stenosis, poststenotic dilation of the pulmonic trunk, and proximal main pulmonary arteries were identified, as well as a mild narrowing of the descending aorta compatible with aortic stenosis. The bird was discharged without medication but with dietary recommendations and experienced 2 clenching episodes in the days after the last visit. No recurrence of clinical signs has been reported over the 18-month follow-up period. To our knowledge, this is the first report of infundibular pulmonic stenosis in a bird. This case illustrates the application of basic and advanced diagnostic imaging modalities in evaluating cardiac disease in birds. PMID- 28358605 TI - Therapeutic Use of Regional Limb Perfusion in a Chicken. AB - A 2-year-old, 3.8-kg male Rhode Island red rooster was examined for lameness and progressive swelling of the right foot of several month's duration. Radiographs of the right foot demonstrated soft tissue swelling and a smoothly marginated periosteal reaction evident of inflammation affecting the bones. Results of a complete blood count showed a moderate leukocytosis and an elevated total protein concentration. Systemic antibiotic and anti-inflammatory therapy was started, but the bird had not improved at recheck examination. After intravenous catheterization of the medial metatarsal vein and placing a tourniquet at the femoral-tibiotarsal joint of the right leg, regional limb perfusion with amikacin and flunixin meglumine was performed. Dimensions of both feet were measured with digital calipers, and surface temperatures of the feet were measured with an infrared thermometer. The rooster had improved activity level with decrease in lameness and measurable decrease in swelling of the right foot. Regional limb perfusion with intravenous antibiotics and nonsteroidal anti-inflammatory drugs is a viable treatment modality in avian species for suspected distal limb infection and cellulitis. This technique has potential valuable implications for a variety of avian species. Fluid support should be provided if using nephrotoxic drugs. PMID- 28358606 TI - Stifle Disarticulation as a Pelvic Limb Amputation Technique in a Cockatiel ( Nymphicus hollandicus ) and a Northern Cardinal ( Cardinalis cardinalis ). AB - This clinical report describes the use of stifle disarticulation in 2 avian patients as an alternative to transfemoral limb amputation. A northern cardinal ( Cardinalis cardinalis ) was presented for soft tissue swelling and a traumatic fracture of the third digit of the left limb, with secondary bacterial infection and necrosis. A 25-year-old cockatiel ( Nymphicus hollandicus ) was diagnosed with distal extremity necrosis after a nonunion of a closed tibiotarsal fracture. In both cases amputation was recommended due to the poor prognosis for healing and because both birds were poor surgical candidates for traditional methods of amputation due to patient size or age. Therefore, stifle disarticulation surgery for amputation of the pelvic limb was performed successfully in both cases and recovery was unremarkable. The outcomes of these 2 cases suggest that stifle disarticulation may be used as an alternative to transfemoral amputation in birds where prolonged surgery, anesthesia, or patient size precludes traditional amputation techniques. PMID- 28358607 TI - Radiation Therapy of Periorbital Lymphoma in a Blue-and-Gold Macaw (Ara ararauna). AB - An adult male blue and gold macaw (Ara ararauna) was presented for evaluation of a right periorbital mass. Results of diagnostic tests, including periorbital ultrasound, fine-needle aspirate, and cytologic examination, confirmed a diagnosis of periocular lymphoma. Radiographs were suggestive of disseminated disease but because of concerns about the patient's quality of life, localized radiation therapy to address the periorbital disease was pursued. Coarse fractionated radiation therapy was initiated, and the mass regressed rapidly during the 3-week course of treatment. The macaw tolerated the treatments well, maintained vision in the affected eye, and activity level and appetite improved. Three months after treatment was completed, the bird died. Necropsy revealed T cell-rich B-cell-infiltrative lymphoma of the spleen, liver, and kidneys, with some residual neoplastic cells found in the right periorbital region. This case demonstrates a radiation therapy protocol that reduced a tumor mass in a localized treatment of periorbital lymphoma in a macaw. PMID- 28358609 TI - What Is Your Diagnosis? PMID- 28358610 TI - Scientific Data: How Do You Manage It Without Losing It? PMID- 28358611 TI - The Effect of Manual Restraint on Physiological Parameters in Barred Owls ( Strix varia ). AB - Manual restraint is commonly necessary when working with avian species in medical, laboratory, and field settings. Despite their prevalence, little is known about the stress response in raptorial bird species. To further understand the effect of restraint on the stress response in birds of prey, 12 barred owls ( Strix varia ) were manually restrained for 15 minutes. Physiological parameters (cloacal temperature, respiratory rate, heart rate) were followed over time and recorded at defined points during the restraint period. Heart rate decreased significantly over the restraint period by a mean +/- SD of -73 +/- 46 beats/min. Respiratory rate also decreased significantly (median: -11 breaths/min, interquartile range: -8 to -18). Cloacal temperature increased significantly over time in manually restrained owls (median: +1.5 degrees C [+2.7 degrees F], interquartile range: 1.3 degrees C-2.1 degrees C [2.3 degrees F-3.8 degrees F]). This study is the first to document stress hyperthermia in an owl species. Similar to another raptorial bird, the red-tailed hawk ( Buteo jamaicensis ), both heart rate and respiratory rate decreased and cloacal temperature increased over time in restrained barred owls. Barred owls appear to cope differently to restraint stress when compared to psittacine species. PMID- 28358612 TI - Management and Case Outcome of Gastric Impaction in Four Raptors: A Case Series. AB - Four captive raptors, an American kestrel ( Falco sparverius ), peregrine falcon ( Falco peregrinus ), golden eagle ( Aquila chrysaetos ), and barn owl ( Tyto alba ), were diagnosed with ventricular and/or proventricular foreign material impactions consisting of artificial turf substrate, paper and plastic substrate, grass, and newspaper. Partial or total anorexia was reported in all birds and decreased casting in 2 birds. Survey radiographs confirmed presence of gastric enlargement in all 4 birds. The kestrel and eagle were treated unsuccessfully with gastroscopy and gastric lavage, respectively, followed by surgical intervention to remove the ventricular impactions. Both birds died of undetermined causes after surgery. The peregrine falcon died before medical or surgical intervention was started, and the owl was managed successfully with oral mineral oil and liquid diet to facilitate egestion of the foreign material as a pellet. Lead poisoning was suspected as the predisposing cause for foreign body ingestion in the eagle, but underlying causes for pica in the other birds were not determined. Radiographs can provide useful diagnostic information in sick raptors that exhibit vomiting or changes in appetite or casting frequency, and may help guide treatment decisions of impacted birds. Careful consideration of substrate, enrichment items, and access to potential foreign material that could be ingested may be the best pre-emptive management strategy in captive raptors. PMID- 28358613 TI - Determination of Tear Production and Intraocular Pressure With Rebound Tonometry in Wild Humboldt Penguins ( Spheniscus humboldti ). AB - Tear production and intraocular pressures (IOPs) were determined in 38 and 102 wild Humboldt penguins (Spheniscus humboldti), respectively, from the Punta San Juan Marine Protected Area in Ica, Peru. Tear production was measured by Schirmer tear test, and IOP was measured with a TonoVet rebound tonometer. Adult (n = 90) and chick (n = 12) penguins were sampled from 2 different beaches (north and south facing) during 2 sampling years (2010 and 2011). Results showed a mean +/- SD (range) of 9 +/- 4 (2-20) mm/min for tear production and 28 +/- 9 (3-49) mm Hg for IOP. Tear production in penguins differed between beach and sex, whereas IOP differed between age, year, and beach. The IOPs were negatively correlated with packed cell volume. Tear production and IOP values had greater variation in this population than it has in other avian species. Previous investigations of IOP and tear production in Spheniscus species were conducted with birds housed under professional care in artificial marine and freshwater environments. This is the first study, to our knowledge, investigating tear production and IOP in wild penguins and establishes valuable reference intervals for this species. PMID- 28358614 TI - Plasma Concentrations of Fentanyl Achieved With Transdermal Application in Chickens. AB - Providing appropriate analgesia is an important concern in any species. Fentanyl, a MU-receptor specific opioid, use is common in mammalian species but has been incompletely evaluated for this purpose in avian species. Transdermal fentanyl patches were applied to domestic chickens (n = 10) of varying breeds for 72 hours. Repeated blood samples were collected from the birds to assess time concentration of fentanyl and norfentanyl in plasma, as assayed by liquid chromatography-mass spectrometry, throughout patch application and for 48 hours after patch removal. Compartmental modeling was used to characterize the elimination profiles. Evaluation as a large bolus, followed by slower elimination rates over the remaining time, best fit the data as a one-compartment open model. Although maximum plasma fentanyl concentrations varied substantially by individual birds, chickens trended into 2 general groups of maximum plasma concentration, clearance, and volume of distribution, which was attributed to absorption variability. For all birds, harmonic mean of elimination half-life was 7.2 +/- 3.7 hours and showed less individual variation than the other pharmacokinetic parameters. Because the application of transdermal fentanyl patches in the chickens achieved plasma fentanyl concentrations considered therapeutic in people, this approach could provide an additional analgesic option for avian patients. PMID- 28358615 TI - Semen Collection and Spermatozoa Characteristics in the Kea Parrot (Nestor notabilis). AB - We describe the seminal characteristics of the kea parrot (Nestor notabilis), an endangered species endemic to the South Island of New Zealand. Semen was collected in the full breeding season from 6 birds in the collection of an amateur aviculturist. The manual massage technique was used. A total of 25 ejaculates was collected and evaluated for volume, degree of contamination, and spermatozoa concentration; motility and kinetic parameters were assessed on diluted samples (modified Tyrode's Albumin Lactate Pyruvate, pH 8.2, temperature 37.5 degrees C) with a computer-aided sperm analyzer. Four ejaculates were not analyzed because of an excessively high degree of contamination. Semen color ranged from transparent or turbid yellow to whitish. The geometric mean of spermatozoa number/ejaculate was 765.9 +/- 2084.7 * 106. Total and progressive motility were 71.7% +/- 20.0% and 59.8% +/- 22.0%, respectively. Great variability was observed both among birds and among different ejaculates of the same subject. The seminal characteristics of kea are worth further investigation, with the aim of relating semen quality to fertility and defining a minimum inseminating dose for breeding purposes. A deeper knowledge of male reproductive biology also can increase the success of breeding programs and enable the use of the kea as a model species for other more threatened species, such as the kaka ( Nestor meridionalis ) and the kakapo (Strigops habroptila). PMID- 28358616 TI - Nucleotide Sequence Variations in Autolysis Genes of ST59 Methicillin-Resistant Staphylococcus aureus Isolates. AB - Biofilm formation is a virulence factor of bacteria. The goal of this study was to understand the mechanisms of biofilm formation by methicillin-resistant Staphylococcus aureus (MRSA). Whole-genome sequencing of eight MRSA strains was performed to identify sequence variations in genes related to biofilm formation. Thirty-one genes involved in MRSA biofilm formation were analyzed and 11 amino acid sequence variations in four genes related to autolysis were found. These variations include E121D and H387 N in ArlS; Q117K, T424S, K428T, A509S, V752E, A754V, and T771A in Atl; T184K in CidC; and D251N in CidR. Among the 26 clinical MRSA isolates studied, 13 isolates were nonbiofilm producers and were found to harbor these mutations. Furthermore, all of these 13 isolates belonged to ST59. Ten of these 13 ST59 isolates became able to produce biofilms when they were incubated with extracellular DNA from MRSA N315. Results of this study suggest that sequence variations in arlS, atl, cidC, and cidR genes may render MRSA unable to produce biofilms. Further investigations are needed to correlate these sequence variations with the biofilm-forming ability of MRSA isolates. PMID- 28358617 TI - Bioactivity of Variant Molecular Weight Chitosan Against Drug-Resistant Bacteria Isolated from Human Wounds. AB - Chitosan available from crab shells is usually of high molecular weight which may result in reduced efficiency for its antibacterial activity. One of the techniques for improving chitosan antibacterial efficiency is reducing its molecular weight. The irradiation of chitosan by gamma radiations is considered to be one of the most effective and widely used methods for improving its antibacterial activity. Chitosan obtained from crab shells was irradiated with gamma radiations at different doses, and effects on chitosan were analyzed by molecular weight determination and Fourier Transform Infrared spectroscopy. Unirradiated and irradiated chitosans were studied for their antibacterial properties against bacterial pathogens, that is, Pseudomonas aeruginosa (SS29), Escherichia coli (SS2, SS9), Proteus mirabilis (SS77), and Staphylococcus aureus (LM15). Studies have shown that irradiation has significantly developed and improved the antibacterial activity of crab shell chitosan. A correlation was found between bacterial metabolites and antibacterial activity by the analysis for 4-hydroxy-2-alkylquinolines and related metabolites of P. aeruginosa (SS29) in the absence and presence of chitosan by liquid chromatography mass spectrometer, exhibiting the suppression of these virulence factors due to chitosan. Antibacterial efficiency of chitosan was found to be molecular weight dependent and applied concentration of the chitosan. The findings suggest on the use of low-molecular weight chitosan as antibacterial agent in pharmaceutical preparations. PMID- 28358618 TI - Lullaby of a Palliative Care Doctor. PMID- 28358619 TI - Estimating Demand for and Supply of Pediatric Preventive Dental Care for Children and Identifying Dental Care Shortage Areas, Georgia, 2015. AB - OBJECTIVES: Demand for dental care is expected to outpace supply through 2025. The objectives of this study were to determine the extent of pediatric dental care shortages in Georgia and to develop a general method for estimation that can be applied to other states. METHODS: We estimated supply and demand for pediatric preventive dental care for the 159 counties in Georgia in 2015. We compared pediatric preventive dental care shortage areas (where demand exceeded twice the supply) designated by our methods with dental health professional shortage areas designated by the Health Resources & Services Administration. We estimated caries risk from a multivariate analysis of National Health and Nutrition Examination Survey data and national census data. We estimated county-level demand based on the time needed to perform preventive dental care services and the proportion of time that dentists spend on pediatric preventive dental care services from the Medical Expenditure Panel Survey. RESULTS: Pediatric preventive dental care supply exceeded demand in Georgia in 75 counties: the average annual county-level pediatric preventive dental care demand was 16 866 hours, and the supply was 32 969 hours. We identified 41 counties as pediatric dental care shortage areas, 14 of which had not been designated by the Health Resources & Services Administration. CONCLUSIONS: Age- and service-specific information on dental care shortage areas could result in more efficient provider staffing and geographic targeting. PMID- 28358620 TI - Daily Coffee Intake Inhibits Pancreatic Beta Cell Damage and Nonalcoholic Steatohepatitis in a Mouse Model of Spontaneous Metabolic Syndrome, Tsumura Suzuki Obese Diabetic Mice. AB - BACKGROUND: Metabolic syndrome is one of the most important health issues worldwide. Obesity causes insulin resistance, hyperlipidemia, diabetes, and various diseases throughout the body. The liver phenotype, which is called nonalcoholic steatohepatitis (NASH), frequently progresses to hepatocellular carcinoma. We recently established a new animal model, Tsumura-Suzuki obese diabetic (TSOD) mice, which spontaneously exhibit obesity, diabetes, hyperlipidemia, and NASH with liver nodules. METHODS: We examined the effects of coffee intake on various conditions of the metabolic syndrome using TSOD mice. The daily volume of coffee administered was limited so that it reflected the appropriate quantities consumed in humans. To clarify the effects of the specific components, animals were divided into two coffee-intake groups that included with and without caffeine. RESULTS: Coffee intake did not significantly affect obesity and hyperlipidemia in TSOD mice. In contrast, coffee intake caused various degrees of improvement in the pancreatic beta cell damage and steatohepatitis with liver carcinogenesis. Most of the effects were believed to be caused by a synergistic effect of caffeine with other components such as polyphenols. However, the antifibrotic effects of coffee appeared to be due to the polyphenols rather than the caffeine. CONCLUSIONS: A daily habit of drinking coffee could possibly play a role in the prevention of metabolic syndrome. PMID- 28358621 TI - Time-Dependent Differences in the Influence of Perivascular Adipose Tissue on Vasomotor Functions in Metabolic Syndrome. AB - BACKGROUND: Metabolic syndrome (MetS) facilitates the development of cardiovascular disease due to atherosclerosis, which is accelerated by defects of the vascular endothelium. Vascular dysfunction in response to nitric oxide (NO) occurs in the mesenteric arteries of an animal model of MetS, SHRSP.Z Leprfa/IzmDmcr (SHRSP.ZF) rats. Vascular responses to vasodilators are affected by perivascular adipose tissue (PVAT) that surrounds the outsides of arteries. In this study, we assessed the role of PVAT in vascular dysfunction observed in SHRSP.ZF. METHODS: To determine the effects of PVAT on vasodilators in SHRSP.ZF and control Wistar-Kyoto (WKY) rats, we used organ bath bioassay techniques to assay acetylcholine and nitroprusside-induced relaxations of isolated mesenteric arterial ring preparations with PVAT intact or removed. RESULTS: A PVAT-mediated enhancement of relaxations induced by acetylcholine and nitroprusside occurred in SHRSP.ZF at 20 weeks of age, but not at 10 and 30 weeks, and did not occur in WKY. Furthermore, the enhancing effects of PVAT from SHRSP.ZF at 20 weeks could not be substituted by replacement with PVAT from either WKY or 30-week-old SHRSP.ZF, was inhibited by NO synthase inhibitor, and abolished by removal of the arteries' endothelium. Cyclic guanosine monophosphate (cGMP) accumulation elicited by nitroprusside was higher in SHRSP.ZF arteries with PVAT than arteries without PVAT at 20 weeks, but the enhancement of cGMP accumulation did not occur at 30 weeks. CONCLUSIONS: PVAT may regulate arterial tone by releasing diffusible vasorelaxing factor(s), which, through endothelium-derived NO production, compensates for impaired vasodilations at early stages of MetS. PMID- 28358622 TI - Cytological and Molecular Characterization of ZmWAK-Mediated Head-Smut Resistance in Maize. AB - Head smut, caused by the fungal pathogen Sporisorium reilianum, poses a threat to maize production worldwide. ZmWAK, a cell wall-associated receptor kinase, confers quantitative resistance to head smut disease. Here, two near-isogenic lines (NILs), susceptible line Huangzao4 and its ZmWAK-converted resistant line Huangzao4R, were used to decipher the role of ZmWAK in head smut resistance. Cytological and molecular characterization in response to S. reilianum infection was compared between two NILs. Upon S. reilianum infection, the growth of pathogen hyphae was severely arrested in the ZmWAK-converted resistant line Huangzao4R, relative to its susceptible parental line Huangzao4. Infected cells exhibited apoptosis-like features in Huangzao4R and hyphae were sequestered within dead cells, whereas pathogen invasion caused autophagy in Huangzao4, which failed to prevent hyphal spreading. Integrated transcriptomic and metabolomic analysis indicated that ZmWAK functions as a hub in the trade-off between growth and defense, whereby ZmWAK promotes cell growth in the absence of the pathogen and switches to a defense response upon S. reilianum attack. These findings shed light on an elegant regulatory mechanism governed by ZmWAK in the trade-off between growth and head smut defense. PMID- 28358623 TI - One Target, Two Mechanisms: The Impact of 'Candidatus Liberibacter asiaticus' and Its Vector, Diaphorina citri, on Citrus Leaf Pigments. AB - Huanglongbing (HLB) is currently the largest threat to global citrus production. We examined the effect of HLB pathogen 'Candidatus Liberibacter asiaticus' infection or infestation by its vector, Diaphorina citri, on 'Valencia' sweet orange leaf pigments using high-performance liquid chromatography, followed by gene expression analysis for 46 involved genes in carotenoid and chlorophyll biosynthesis pathways. Both 'Ca. L. asiaticus' and D. citri alter the total citrus leaf pigment balance with a greater impact by 'Ca. L. asiaticus'. Although zeaxanthin was accumulated in 'Ca. L. asiaticus'-infected leaves, chlorophyllide a was increased in D. citri-infested plants. Our findings support the idea that both 'Ca. L. asiaticus' and D. citri affect the citrus pigments and promote symptom development but using two different mechanisms. 'Ca. L. asiaticus' promotes chlorophyll degradation but accelerates the biosynthesis of carotenoid pigments, resulting in accumulation of abscisic acid and its precursor, zeaxanthin. Zeaxanthin also has a photoprotective role. By contrast, D. citri induced the degradation of most carotenoids and accelerated chlorophyll biosynthesis, leading to chlorophyllide a accumulation. Chlorophyllide a might have an antiherbivory role. Accordingly, we suggest that citrus plants try to defend themselves against 'Ca. L. asiaticus' or D. citri using multifaceted defense systems, based on the stressor type. These findings will help in better understanding the tritrophic interactions among plant, pathogen, and vector. PMID- 28358624 TI - Understanding Antiretroviral Treatment Adherence Among HIV-Positive Women at Four Postpartum Time Intervals: Qualitative Results from the Kabeho Study in Rwanda. AB - As lifelong antiretroviral therapy (ART) for pregnant women is implemented, it is important to understand the attitudes and norms affecting women's postpartum ART adherence. This is a qualitative cross-sectional study of HIV-positive postpartum women (n = 112) enrolled in a 2-year observational prospective cohort in Rwanda. Informed by the Theory of Reasoned Action (TRA), we conducted in-depth interviews with women whose children were 0-6, 7-12, 13-18, or 21-24 months of age to describe factors contributing to adherence and changes over time. Positive ART attitudes reported by women included mothers' health promotion, prevention of infant HIV infection, higher CD4 count, and improved physical appearance. Negative attitudes were few, but included side effects and the lifelong nature of treatment. Learning from people living with HIV (PLHIV) was identified as a norm facilitating adherence; ART adherence was inhibited by fear of disclosure or stigmatization in communities and clinics. Poor adherence behaviors were common immediately after HIV diagnosis, not necessarily during prevention of mother-to child transmission (PMTCT). Women with older children, most of whom stopped breastfeeding by 13-18 months, reported more barriers and missed doses than women with younger children. The TRA was useful in identifying the collective influence of attitudes, norms, and intentions on behavior. Findings suggest that HIV positive women are vulnerable to poor adherence following HIV diagnosis and around the time of breastfeeding cessation. Lifelong treatment adherence can be supported through PLHIV exemplifying long-term ART use, fewer and less stigmatizing clinic visits, and counseling messages highlighting the benefits of drugs on appearance and illness prevention and incorporating biological feedback. PMID- 28358626 TI - Correction: What Is Your Diagnosis? PMID- 28358628 TI - Pathology in Practice. PMID- 28358625 TI - Sexual Orientation Differences in Satisfaction with Healthcare: Findings from the Behavioral Risk Factor Surveillance System, 2014. AB - PURPOSE: In the United States, the Affordable Care Act and marriage equality may have eased sexual orientation-based differences in access to healthcare coverage, but limited research has investigated sexual orientation-based differences in healthcare satisfaction. The purpose of this study was to examine whether satisfaction with healthcare varied by sexual orientation in a large population based sample of adults. METHODS: Data are from the 2014 Behavioral Risk Factor Surveillance System, including items about sexual orientation and healthcare (n = 113,317). Healthcare coverage included employer-based insurance; individually purchased insurance; Medicare; Medicaid; or TRICARE, VA, or military care. Respondents indicated whether they were "very satisfied, somewhat satisfied, or not at all satisfied" with healthcare. RESULTS: After adjusting for several sociodemographic covariates, lesbian, gay, and bisexual status was associated with lower satisfaction with healthcare with individually purchased insurance (adjusted odds ratio = 1.49, 95% confidence interval = 1.24-1.80). CONCLUSION: Efforts are needed to examine and reduce sexual orientation differences in satisfaction with healthcare. PMID- 28358629 TI - Reconstruction of a mandibular segmental defect with a customized 3-dimensional printed titanium prosthesis in a cat with a mandibular osteosarcoma. AB - CASE DESCRIPTION A 12-year-old neutered male domestic shorthair cat had been treated for a mass arising from the lingual aspect of the caudal right mandibular body. Cytoreductive surgery of the mass had been performed twice over a 2-year period, but the mass recurred following both surgeries. The mass was diagnosed as an osteosarcoma, and the cat was referred for further evaluation and treatment. CLINICAL FINDINGS Clinical findings were unremarkable, except for a 2-cm-diameter mass arising from the lingual aspect of the right mandible and mild anemia and lymphopenia. Pre- and postcontrast CT scans of the head, neck, and thorax were performed, revealing that the osteosarcoma was confined to the caudal right mandibular body, with no evidence of lymph node or pulmonary metastasis. TREATMENT AND OUTCOME The stereolithographic files of the CT scan of the head were sent for computer-aided design and manufacture of a customized 3-D-printed titanium prosthesis. Segmental mandibulectomy was performed, and the mandibular defect was reconstructed in a single stage with the 3-D-printed titanium prosthesis. The cat had 1 minor postoperative complication but had no signs of eating difficulties at any point after surgery. The cat was alive and disease free 14 months postoperatively. CLINICAL RELEVANCE Reconstruction of the mandible of a cat following mandibulectomy was possible with computer-aided design and manufacture of a customized 3-D-printed titanium prosthesis. Cats have a high rate of complications following mandibulectomy, and these initial findings suggested that mandibular reconstruction may reduce the risk of these complications and result in a better functional outcome. PMID- 28358631 TI - Survival analysis of hypotensive cats admitted to an intensive care unit with or without hyperlactatemia: 39 cases (2005-2011). AB - OBJECTIVE To examine the association between blood lactate concentration and survival to hospital discharge in critically ill hypotensive cats. DESIGN Retrospective case series. ANIMALS 39 cats admitted to an intensive care unit of a university veterinary hospital between January 2005 and December 2011 for which blood lactate concentration was recorded <= 1 hour before or after a Doppler derived arterial blood pressure measurement <= 90 mm Hg (ie, hypotension) was obtained. PROCEDURES Medical records of each cat were reviewed to assess survival to hospital discharge, illness severity, duration of hospitalization, age, body weight, and PCV. Results were compared between hypotensive cats with and without hyperlactatemia (blood lactate concentration >= 2.5 mmol/L). RESULTS 6 of 39 (15%) hypotensive cats survived to hospital discharge. Twelve (31%) cats were normolactatemic (blood lactate concentration < 2.5 mmol/L), and 27 (69%) were hyperlactatemic. Hypotensive cats with normolactatemia had a higher blood pressure and higher survival rate than hypotensive cats with hyperlactatemia. Five-day Kaplan-Meier survival rates were 57% for normolactatemic cats and 17% for hyperlactatemic cats. Age, body weight, duration of hospitalization, PCV, and illness severity did not differ significantly between hypotensive cats with and without hyperlactatemia. CONCLUSIONS AND CLINICAL RELEVANCE Hypotensive, normolactatemic cats in an intensive care unit had a significantly greater chance of survival to hospital discharge than their hyperlactatemic counterparts. Blood lactate concentration may be a useful prognostic indicator for this patient population when used in conjunction with other clinical and laboratory findings. PMID- 28358632 TI - Pathology in Practice. PMID- 28358633 TI - Diagnostic Imaging in Veterinary Dental Practice. PMID- 28358634 TI - Effects of alfaxalone administered intravenously to healthy yearling loggerhead sea turtles (Caretta caretta) at three different doses. AB - OBJECTIVE To compare physiologic and anesthetic effects of alfaxalone administered IV to yearling loggerhead sea turtles (Caretta caretta) at 3 different doses. DESIGN Randomized crossover study. ANIMALS 9 healthy yearling loggerhead sea turtles. PROCEDURES Animals received each of 3 doses of alfaxalone (3 mg/kg [1.4 mg/lb], 5 mg/kg [2.3 mg/lb], or 10 mg/kg [4.5 mg/lb]) administered IV in randomly assigned order, with a minimum 7-day washout period between doses. Endotracheal intubation was attempted following anesthetic induction, and heart rate, sedation depth, cloacal temperature, and respirations were monitored. Times to first effect, induction, first voluntary muscle movement, first respiration, and recovery were recorded. Venous blood gas analysis was performed at 0 and 30 minutes. Assisted ventilation was performed if apnea persisted 30 minutes following induction. RESULTS Median anesthetic induction time for all 3 doses was 2 minutes. Endotracheal intubation was accomplished in all turtles following induction. Heart rate significantly increased after the 3- and 5-mg/kg doses were administered. Median intervals from alfaxalone administration to first spontaneous respiration were 16, 22, and 54 minutes for the 3-, 5-, and 10-mg/kg doses, respectively, and median intervals to recovery were 28, 46, and 90 minutes, respectively. Assisted ventilation was required for 1 turtle after receiving the 5-mg/kg dose and for 5 turtles after receiving the 10-mg/kg dose. The 10-mg/kg dose resulted in respiratory acidosis and marked hypoxemia at 30 minutes. CONCLUSIONS AND CLINICAL RELEVANCE IV alfaxalone administration to loggerhead sea turtles resulted in a rapid anesthetic induction and dose dependent duration of sedation. Assisted ventilation is recommended if the 10 mg/kg dose is administered. PMID- 28358635 TI - Prevalence of Alaria infection in companion animals in north central Oklahoma from 2006 through 2015 and detection in wildlife. AB - OBJECTIVE To determine the prevalence of Alaria infection in cats and dogs in north central Oklahoma over various periods and investigate whether wild animal species in this region were also infected. DESIGN Combined cross-sectional study and case series. SAMPLE Results of parasitological testing of fecal samples from 5,417 client-owned dogs and 1,246 client-owned cats (2006 through 2014); fecal samples from 837 shelter or rescue dogs and 331 shelter or rescue cats (2013 and 2014) and 268 feral cats (2015); tongue or jowl samples from cadavers of 43 wild pigs, 3 opossums, and 1 raccoon; and intestinal tract segments from cadavers of 48 cats and 5 coyotes. PROCEDURES Various parasite recovery techniques were performed to detect various Alaria stages in samples. Recovered adult trematodes and mesocercariae were used for PCR assay and sequencing of the 28S rRNA gene. RESULTS Prevalence of Alaria infection was significantly higher in feral cats (9.0%) than in shelter or rescue cats (0.6%) and client-owned cats (1.4%) and in shelter or rescue dogs (1.8%) than in client-owned dogs (0.2%). Mesocercariae were recovered from tissue samples from 11 (26%) wild pigs and 1 opossum. Amplicon sequences from adult trematodes and mesocercariae were 100% identical to each other and 99% homologous to GenBank sequences of Alaria alata and Alaria mustelae. CONCLUSIONS AND CLINICAL RELEVANCE Prevalence of Alaria infection in the study area has increased in dogs and cats since 1990, when infections were rare. Prevalence in wild pigs was similar to that in Eurasia, where A alata is considered an emerging zoonotic parasite. PMID- 28358636 TI - Seroprevalence of heartworm infection, risk factors for seropositivity, and frequency of prescribing heartworm preventives for cats in the United States and Canada. AB - OBJECTIVE To determine the seroprevalence of heartworm infection, risk factors for seropositivity, and frequency of prescribing heartworm preventives for cats. DESIGN Prospective cross-sectional study. ANIMALS 34,975 cats from 1,353 veterinary clinics (n = 26,707) and 125 animal shelters (8,268) in the United States and Canada. PROCEDURES Blood samples were collected from all cats and tested with a point-of-care ELISA for Dirofilaria immitis antigen, FeLV antigen, and FIV antibody. Results were compared among geographic regions and various cat groupings. RESULTS Seropositivity for heartworm antigen in cats was identified in 35 states but not in Canada; overall seroprevalence in the United States was 0.4%. Seroprevalence of heartworm infection was highest in the southern United States. A 3-fold increase in the proportion of seropositive cats was identified for those with (vs without) outdoor access, and a 2.5-fold increase was identified for cats that were unhealthy (vs healthy) when tested. Seroprevalence was 0.3% in healthy cats, 0.7% in cats with oral disease, 0.9% in cats with abscesses or bite wounds, and 1.0% in cats with respiratory disease. Coinfection with a retrovirus increased the risk of heartworm infection. Heartworm preventives were prescribed for only 12.6% of cats at testing, and prescribing was more common in regions with a higher seroprevalence. CONCLUSIONS AND CLINICAL RELEVANCE At an estimated prevalence of 0.4%, hundreds of thousands of cats in the United States are likely infected with heartworms. Given the difficulty in diagnosing infection at all clinically relevant parasite stages and lack of curative treatment options, efforts should be increased to ensure all cats receive heartworm preventives. PMID- 28358638 TI - Letters to the Editor. PMID- 28358637 TI - ECG of the Month. PMID- 28358640 TI - What Is Your Diagnosis? PMID- 28358639 TI - Review of hazards to female reproductive health in veterinary practice. AB - OBJECTIVE To review publications that address female reproductive health hazards in veterinary practice, summarize best practices to mitigate reproductive risks, and identify current knowledge gaps. DESIGN Systematized review. SAMPLE English language articles describing chemical, biological, and physical hazards present in the veterinary workplace and associations with adverse reproductive outcomes or recommendations for minimizing risks to female reproductive health. PROCEDURES Searches of the CAB abstracts database were performed in July 2012 and in May 2015 with the following search terms: veterinarians AND occupational hazards and vets.id AND occupational hazards.sh. Searches of the PubMed database were conducted in November 2012 and in May 2015 with the following medical subject heading terms: occupational exposure AND veterinarians; anesthetics, inhalation/adverse effects AND veterinarians; risk factors AND pregnancy AND veterinarians; pregnancy outcome AND veterinarians; and animal technicians AND occupational exposure. Two additional PubMed searches were completed in January 2016 with the terms disinfectants/toxicity AND female AND fertility/drug effects and veterinarians/psychology AND stress, psychological. No date limits were applied to searches. RESULTS 4 sources supporting demographic trends in veterinary medicine and 118 resources reporting potential hazards to female reproductive health were identified. Reported hazards included exposure to anesthetic gases, radiation, antineoplastic drugs, and reproductive hormones; physically demanding work; prolonged standing; and zoonoses. CONCLUSIONS AND CLINICAL RELEVANCE Demographic information suggested that an increasing number of women of reproductive age will be exposed to chemical, biological, and physical hazards in veterinary practice. Information on reproductive health hazards and minimizing risk, with emphasis on developing a safety-focused work culture for all personnel, should be discussed starting in veterinary and veterinary technical schools and integrated into employee training. PMID- 28358641 TI - Intrapericardial cystic hematoma in a dog treated by thoracoscopic subtotal pericardectomy. AB - CASE DESCRIPTION A 2-year-old castrated male mixed-breed dog was evaluated because of a 1-week history of respiratory distress and abdominal distension. Thoracic radiography and echocardiography at that time revealed an enlarged cardiac silhouette and pericardial effusion; abdominal radiography and ultrasonography revealed ascites. CLINICAL FINDINGS At the initial referral examination 5 weeks later, the dog weighed 37.5 kg (82.5 lb) and appeared clinically normal. The only abnormality detected was a grade I/VI systolic murmur on the left side of the thorax. Echocardiography revealed a large fat- and fluid filled cystic structure located next to the right ventricle with scant pericardial effusion. Computed tomography revealed a bilobed peripherally contrast-enhancing structure within the right ventral aspect of the pericardium; the right ventricle appeared compressed by the cyst. TREATMENT AND OUTCOME Initial treatment consisted of pericardiocentesis and abdominocentesis to alleviate clinical signs. Thoracoscopic subtotal pericardectomy was performed 6 weeks after the initial treatment. The cyst was completely excised, and multiple adhesions between the visceral and parietal pericardium were transected, without surgical or anesthetic complications. Histologic examination of the cyst revealed chronic inflammation with histiocytic infiltration, suggesting possible foreign body reaction or chronic inflammation and hemorrhage. These findings supported a diagnosis of cystic hematoma of the pericardium. The dog remained clinically normal for at least 16 months after surgery. CLINICAL RELEVANCE This report represents a rare case of intrapericardial cystic hematoma in a dog. Minimally invasive surgery was performed without complications, suggesting that thoracoscopic subtotal pericardectomy is a feasible treatment option for affected dogs. PMID- 28358642 TI - Combined modality therapy improves overall survival for angiosarcoma. PMID- 28358643 TI - Polymorphisms, differentiation, and phylogeny of 10 Tibetan goat populations inferred from mitochondrial D-loop sequences. AB - China has abundant population of Tibetan goats, but available information regarding genetic structure and phylogenetic status remains limited. Here, 130 mitochondrial D-loop sequences of individuals from 10 Tibetan goat populations located in distinct plateau areas were analyzed. Eighty-six haplotypes were defined, among which 97.7% were group-specific haplotypes. Haplotype and nucleotide diversity indices were 0.990 +/- 0.003 and 0.0145 +/- 0.0013, respectively. The pairwise Wright's F-statistics ranged from -0.028 to 0.385, and over half of them were greater than 0.05, indicating apparent genetic differentiation among the populations. AMOVA analysis (FST = 0.0858) manifested that the genetic structure has become weak. Phylogenetic trees revealed four haplogroups (A, B, C, and D), suggesting that Tibetan goats had four origins. Mismatch distribution analyses and neutrality tests indicated that at least one population expansion event occurred during the demographic history of Tibetan goat. These results will provide a more complete understanding of Tibetan goat genetic resources. PMID- 28358644 TI - Exercise addiction risk and health in male and female amateur endurance cyclists. AB - Background and aims To determine the relationship between the risk of exercise addiction (REA) and health status in amateur endurance cyclists. Methods In 859 (751 men and 108 women) cyclists and 718 inactive subjects (307 men and 411 women), we examined the REA (Exercise Addiction Inventory), training status (volume, frequency, experience, and performance), socioeconomic status, quality of life (QoL) (SF-12), quality of sleep (Pittsburgh Sleep Quality Index), anxiety and depression (Hospital Anxiety and Depression Scale), and cardiometabolic risk: body mass index, physical activity (International Physical Activity Questionnaire), physical condition (International Fitness Scale), adherence to the Mediterranean diet (Mediterranean Diet Adherence Screener), alcohol and tobacco consumption. Results In total, 17% of the cyclists showed evidence of REA and 83% showed low REA. REA occurred independent of age, sex, training, and socioeconomic status (all ps > .05). Regardless of REA, the cyclists displayed a better physical QoL and a lower cardiometabolic risk than the inactive subjects (all ps < .05). The cyclists with REA displayed worse values of mental QoL, quality of sleep, and anxiety than cyclists with low REA (all ps < .05). The REA group had better values of mental QoL and anxiety and similar values of quality of sleep than the inactive subjects. The differences in mental QoL between the REA and low REA groups were significantly greater in women (p = .013). There was no Addiction * Sex interaction in the other analyzed variables. Conclusion Our results suggest that an increased prevalence of REA limits the benefits that amateur endurance cycling has on mental health and quality of sleep. PMID- 28358646 TI - Short-hairpin Mediated Myostatin Knockdown Resulted in Altered Expression of Myogenic Regulatory Factors with Enhanced Myoblast Proliferation in Fetal Myoblast Cells of Goats. AB - Myostatin (MSTN) is a well-known negative regulator of skeletal muscle development. Reduced expression due to natural mutations in the coding region and knockout as well as knockdown of MSTN results in an increase in the muscle mass. In the present study, we demonstrated as high as 60 and 52% downregulation (p < 0.01) of MSTN mRNA and protein in the primary fetal myoblast cells of goats using synthetic shRNAs (n = 3), without any interferon response. We, for the first time, evaluated the effect of MSTN knockdown on the expression of MRFs (namely, MyoD, Myf5), follistatin (FST), and IGFs (IGF-1 & IGF-2) in goat myoblast cells. MSTN knockdown caused an upregulation (p < 0.05) of MyoD and downregulation (p < 0.01) of MYf5 and FST expression. Moreover, we report up to ~four fold (p < 0.001) enhanced proliferation in myoblasts after four days of culture. The anti MSTN shRNA demonstrated in the present study could be used for the production of transgenic goats to increase the muscle mass. PMID- 28358647 TI - Co-Optimization Free Lunches: Tractability of Optimal Black-Box Algorithms for Maximizing Expected Utility. AB - Co-optimization problems often involve settings in which the quality ( utility) of a potential solution is dependent on the scenario within which it is evaluated, and many such scenarios exist. Maximizing expected utility is simply the goal of finding the potential solution whose expected utility value over all possible scenarios is best. Such problems are often approached using coevolutionary algorithms. We are interested in the design of generally well performing black-box algorithms for this problem, that is, algorithms which have access to the utility function only via input-output queries. We research this matter by focusing on three main questions: 1) are some algorithms strictly better than others when judged in aggregation over all possible instances of the problem? that is, is there "free lunch"? 2) do optimal algorithms exist? and 3) if so, do they have a tractable implementation? For a specific expected-utility maximization context, involving several assumptions and performance choices, we answer all three questions affirmatively and concretely: we provide examples of free lunch; we describe the general operation of optimal algorithms; we characterize situations when this operation has a very simple and efficient implementation, situations when the computational cost can be significantly reduced, and situations when tractability of optimal algorithms might be out of reach. PMID- 28358645 TI - The relationship between second-to-fourth digit (2D:4D) ratios and problematic and pathological Internet use among Turkish university students. AB - Background and aims The ratio of the second and fourth fingers (2D:4D ratio) is a sexually dimorphic trait, with men tending to have lower values than women. This ratio has been related to prenatal testosterone concentrations and addictive behaviors including problematic video-gaming. We aimed to investigate the possible association between 2D:4D ratios and Internet addiction and whether such a relationship would be independent of impulsivity. Methods A total of 652 university students (369 women, 283 men), aged 17-27 years, were enrolled in the study. Problematic and pathological Internet use (PPIU) was assessed using the Internet Addiction Test (IAT). The participants also completed the Barratt Impulsiveness Scale (version 11; BIS-11) and had their 2D:4D ratios measured. Results 2D:4D ratios were not significantly different in women with PPIU and in those with adaptive Internet use (AIU). Men with PPIU exhibited lower 2D:4D ratios on both hands when compared with those with AIU. Correlation analysis revealed that 2D:4D ratios on both hands were negatively correlated with IAT scores among men, but not among women. The multiple linear regression analysis revealed that age, duration of weekly Internet use, impulsiveness, and 2D:4D ratios on the right hand were independently associated with IAT scores among men, and impulsivity did not mediate the relationship between 2D:4D ratios and PPIU. Conclusions For men, 2D:4D ratios on the right hand were inversely correlated with Internet addiction severity even after controlling for individual differences in impulsivity. These findings suggest that high prenatal testosterone levels may contribute to the occurrence of PPIU among men. PMID- 28358648 TI - The Psychology of Yoga Practitioners: A Cluster Analysis. AB - Yoga practitioners (N = 261) completed the revised Expression of Spirituality Inventory (ESI) and the Multidimensional Body-Self Relations Questionnaire. Cluster analysis revealed three clusters: Cluster A scored high on all four spiritual constructs. They had high positive evaluations of their appearance, but a lower orientation towards their appearance. They tended to have a high evaluation of their fitness and health, and higher body satisfaction. Cluster B showed lower scores on the spiritual constructs. Like Cluster A, members of Cluster B tended to show high positive evaluations of appearance and fitness. They also had higher body satisfaction. Members of Cluster B had a higher fitness orientation and a higher appearance orientation than members of Cluster A. Members of Cluster C had low scores for all spiritual constructs. They had a low evaluation of, and unhappiness with, their appearance. They were unhappy with the size and appearance of their bodies. They tended to see themselves as overweight. There was a significant difference in years of practice between the three groups (Kruskall-Wallis, p = .0041). Members of Cluster A have the most years of yoga experience and members of Cluster B have more yoga experience than members of Cluster C. These results suggest the possible existence of a developmental trajectory for yoga practitioners. Such a developmental sequence may have important implications for yoga practice and instruction. PMID- 28358652 TI - Decipher Postprostatectomy: Is It Ready for Clinical Use? PMID- 28358653 TI - Untapped Potential of Observational Research to Inform Clinical Decision Making: American Society of Clinical Oncology Research Statement. AB - ASCO believes that high-quality observational studies can advance evidence-based practice for cancer care and are complementary to randomized controlled trials (RCTs). Observational studies can generate hypotheses by evaluating novel exposures or biomarkers and by revealing patterns of care and relationships that might not otherwise be discovered. Researchers can then test these hypotheses in RCTs. Observational studies can also answer or inform questions that either have not been or cannot be answered by RCTs. In addition, observational studies can be used for postmarketing surveillance of new cancer treatments, particularly in vulnerable populations. The incorporation of observational research as part of clinical decision making is consistent with the position of many leading institutions. ASCO identified five overarching recommendations to enhance the role of observational research in clinical decision making: (1) improve the quality of electronic health data available for research, (2) improve interoperability and the exchange of electronic health information, (3) ensure the use of rigorous observational research methodologies, (4) promote transparent reporting of observational research studies, and (5) protect patient privacy. PMID- 28358649 TI - Organizational Context and Female Faculty's Perception of the Climate for Women in Academic Medicine. AB - PURPOSE: Gender inequalities in the careers of faculty in academic medicine could partially be attributed to an organizational climate that can exclude or be nonsupportive of women faculty. This study explores the climate for women faculty from a systems perspective at the organizational and individual levels based on the perceptions of women faculty. Race differences were also investigated. MATERIALS AND METHODS: Cross-sectional survey data from women faculty (N = 3127) at 13 purposively sampled medical schools and an institutional assessment of organizational characteristics were used. Organizational factors related to the climate for women were identified using bivariate statistics. The association between perceived climate for women and organizational characteristics, individual perceptions of the work environment and individual career, and personal characteristics with control variables were investigated using hierarchical linear regression models. Organizational effects by race/ethnicity were estimated using interaction terms. RESULTS: The climate for women faculty varied across institutions and by classification as minority-serving institutions (MSIs). Respondent's report of existence of an office for women's affairs, trust in leadership, and satisfaction with mentoring were positively associated with the climate for women. Perceived workplace discrimination and work-family conflict were inversely associated with a positive climate. No race/ethnicity differences were observed in the multivariable analysis. CONCLUSIONS: The climate for women faculty in academic medicine should not be regarded constant across organizations, specifically between MSIs and non-MSIs. Efforts to advance a positive climate for women could focus on improving trust in leadership, increasing support for structures/offices for women, and mitigating perceived discrimination and work-family conflict. PMID- 28358654 TI - Cigarette Smoking and Pancreatic Cancer Survival. AB - Purpose Cigarette smoking is associated with increased incidence of pancreatic cancer. However, few studies have prospectively evaluated the association of smoking with patient survival. Patients and Methods We analyzed survival by smoking status among 1,037 patients from two large US prospective cohort studies diagnosed from 1986 to 2013. Among 485 patients from four prospective US cohorts, we also evaluated survival by prediagnostic circulating levels of cotinine, a metabolite of nicotine that is proportional to tobacco smoke exposure. On the basis of prediagnosis cotinine levels, we classified patients as nonsmokers (< 3.1 ng/mL), light smokers (3.1-20.9 ng/mL), or heavy smokers (>= 21.0 ng/mL). We estimated hazard ratios (HRs) for death by using Cox proportional hazards models, with adjustment for age, sex, race/ethnicity, body mass index, diabetes status, diagnosis year, and cancer stage. Results The multivariable-adjusted HR for death was 1.37 (95% CI, 1.11 to 1.69) comparing current smokers with never smokers ( P = .003). A statistically significant negative trend in survival was observed for increasing pack-years of smoking ( Ptrend = .008), with HR for death of 1.49 (95% CI, 1.05 to 2.10) for > 60 pack-years of smoking versus never smoking. Survival among former smokers was similar to that for never smokers, regardless of time since quitting. Heavy smokers defined by prediagnostic circulating cotinine levels had a multivariable-adjusted HR for death of 1.76 (95% CI, 1.23 to 2.51) compared with nonsmokers. Among patients with circulating cotinine levels measured within 5 years before diagnosis, heavy smokers had a multivariable adjusted HR for death of 2.47 (95% CI, 1.24 to 4.92) compared with nonsmokers. Conclusion Cigarette smoking was associated with a reduction in survival among patients with pancreatic cancer. PMID- 28358655 TI - Individual Patient-Level Meta-Analysis of the Performance of the Decipher Genomic Classifier in High-Risk Men After Prostatectomy to Predict Development of Metastatic Disease. AB - Purpose To perform the first meta-analysis of the performance of the genomic classifier test, Decipher, in men with prostate cancer postprostatectomy. Methods MEDLINE, EMBASE, and the Decipher genomic resource information database were searched for published reports between 2011 and 2016 of men treated by prostatectomy that assessed the benefit of the Decipher test. Multivariable Cox proportional hazards models fit to individual patient data were performed; meta analyses were conducted by pooling the study-specific hazard ratios (HRs) using random-effects modeling. Extent of heterogeneity between studies was determined with the I2 test. Results Five studies (975 total patients, and 855 patients with individual patient-level data) were eligible for analysis, with a median follow up of 8 years. Of the total cohort, 60.9%, 22.6%, and 16.5% of patients were classified by Decipher as low, intermediate, and high risk, respectively. The 10 year cumulative incidence metastases rates were 5.5%, 15.0%, and 26.7% ( P < .001), respectively, for the three risk classifications. Pooling the study specific Decipher HRs across the five studies resulted in an HR of 1.52 (95% CI, 1.39 to 1.67; I2 = 0%) per 0.1 unit. In multivariable analysis of individual patient data, adjusting for clinicopathologic variables, Decipher remained a statistically significant predictor of metastasis (HR, 1.30; 95% CI, 1.14 to 1.47; P < .001) per 0.1 unit. The C-index for 10-year distant metastasis of the clinical model alone was 0.76; this increased to 0.81 with inclusion of Decipher. Conclusion The genomic classifier test, Decipher, can independently improve prognostication of patients postprostatectomy, as well as within nearly all clinicopathologic, demographic, and treatment subgroups. Future study of how to best incorporate genomic testing in clinical decision-making and subsequent treatment recommendations is warranted. PMID- 28358657 TI - The Cost of Structure Learning. AB - Human learning is highly efficient and flexible. A key contributor to this learning flexibility is our ability to generalize new information across contexts that we know require the same behavior and to transfer rules to new contexts we encounter. To do this, we structure the information we learn and represent it hierarchically as abstract, context-dependent rules that constrain lower-level stimulus-action-outcome contingencies. Previous research showed that humans create such structure even when it is not needed, presumably because it usually affords long-term generalization benefits. However, computational models predict that creating structure is costly, with slower learning and slower RTs. We tested this prediction in a new behavioral experiment. Participants learned to select correct actions for four visual patterns, in a setting that either afforded (but did not promote) structure learning or enforced nonhierarchical learning, while controlling for the difficulty of the learning problem. Results replicated our previous finding that healthy young adults create structure even when unneeded and that this structure affords later generalization. Furthermore, they supported our prediction that structure learning incurred a major learning cost and that this cost was specifically tied to the effort in selecting abstract rules, leading to more errors when applying those rules. These findings confirm our theory that humans pay a high short-term cost in learning structure to enable longer-term benefits in learning flexibility. PMID- 28358656 TI - Dynamics of White Matter Plasticity Underlying Working Memory Training: Multimodal Evidence from Diffusion MRI and Relaxometry. AB - Adaptive working memory (WM) training may lead to cognitive benefits that are associated with white matter plasticity in parietofrontal networks, but the underlying mechanisms remain poorly understood. We investigated white matter microstructural changes after adaptive WM training relative to a nonadaptive comparison group. Microstructural changes were studied in the superior longitudinal fasciculus, the main parietofrontal connection, and the cingulum bundle as a comparison pathway. MRI-based metrics were the myelin water fraction and longitudinal relaxation rate R1 from multicomponent relaxometry (captured with the mcDESPOT approach) as proxy metrics of myelin, the restricted volume fraction from the composite hindered and restricted model of diffusion as an estimate of axon morphology, and fractional anisotropy and radial diffusivity from diffusion tensor imaging. PCA was used for dimensionality reduction. Adaptive training was associated with benefits in a "WM capacity" component and increases in a microstructural component (increases in R1, restricted volume fraction, fractional anisotropy, and reduced radial diffusivity) that predominantly loaded on changes in the right dorsolateral superior longitudinal fasciculus and the left parahippocampal cingulum. In contrast, nonadaptive comparison activities were associated with the opposite pattern of reductions in WM capacity and microstructure. No group differences were observed for the myelin water fraction metric suggesting that R1 was a more sensitive "myelin" index. These results demonstrate task complexity and location-specific white matter microstructural changes that are consistent with tissue alterations underlying myelination in response to training. PMID- 28358658 TI - Supramodal Theta, Gamma, and Sustained Fields Predict Modality-specific Modulations of Alpha and Beta Oscillations during Visual and Tactile Working Memory. AB - Flexible control over currently relevant sensory representations is an essential feature of primate cognition. We investigated the neurophysiological bases of such flexible control in humans during an intermodal working memory task in which participants retained visual or tactile sequences. Using magnetoencephalography, we first show that working memory retention engages early visual and somatosensory areas, as reflected in the sustained load-dependent suppression of alpha and beta oscillations. Next, we identify three components that are also load dependent but modality independent: medial prefrontal theta synchronization, frontoparietal gamma synchronization, and sustained parietal event-related fields. Critically, these domain-general components predict (across trials and within load conditions) the modality-specific suppression of alpha and beta oscillations, with largely unique contributions per component. Thus, working memory engages multiple complementary frontoparietal components that have discernible neuronal dynamics and that flexibly modulate retention-related activity in sensory areas in a manner that tracks the current contents of working memory. PMID- 28358659 TI - When to Take a Gesture Seriously: On How We Use and Prioritize Communicative Cues. AB - When people talk, their speech is often accompanied by gestures. Although it is known that co-speech gestures can influence face-to-face communication, it is currently unclear to what extent they are actively used and under which premises they are prioritized to facilitate communication. We investigated these open questions in two experiments that varied how pointing gestures disambiguate the utterances of an interlocutor. Participants, whose event-related brain responses were measured, watched a video, where an actress was interviewed about, for instance, classical literature (e.g., Goethe and Shakespeare). While responding, the actress pointed systematically to the left side to refer to, for example, Goethe, or to the right to refer to Shakespeare. Her final statement was ambiguous and combined with a pointing gesture. The P600 pattern found in Experiment 1 revealed that, when pointing was unreliable, gestures were only monitored for their cue validity and not used for reference tracking related to the ambiguity. However, when pointing was a valid cue (Experiment 2), it was used for reference tracking, as indicated by a reduced N400 for pointing. In summary, these findings suggest that a general prioritization mechanism is in use that constantly monitors and evaluates the use of communicative cues against communicative priors on the basis of accumulated error information. PMID- 28358660 TI - Individual Differences in Face Identity Processing with Fast Periodic Visual Stimulation. AB - A growing body of literature suggests that human individuals differ in their ability to process face identity. These findings mainly stem from explicit behavioral tasks, such as the Cambridge Face Memory Test (CFMT). However, it remains an open question whether such individual differences can be found in the absence of an explicit face identity task and when faces have to be individualized at a single glance. In the current study, we tested 49 participants with a recently developed fast periodic visual stimulation (FPVS) paradigm [Liu-Shuang, J., Norcia, A. M., & Rossion, B. An objective index of individual face discrimination in the right occipitotemporal cortex by means of fast periodic oddball stimulation. Neuropsychologia, 52, 57-72, 2014] in EEG to rapidly, objectively, and implicitly quantify face identity processing. In the FPVS paradigm, one face identity (A) was presented at the frequency of 6 Hz, allowing only one gaze fixation, with different face identities (B, C, D) presented every fifth face (1.2 Hz; i.e., AAAABAAAACAAAAD...). Results showed a face individuation response at 1.2 Hz and its harmonics, peaking over occipitotemporal locations. The magnitude of this response showed high reliability across different recording sequences and was significant in all but two participants, with the magnitude and lateralization differing widely across participants. There was a modest but significant correlation between the individuation response amplitude and the performance of the behavioral CFMT task, despite the fact that CFMT and FPVS measured different aspects of face identity processing. Taken together, the current study highlights the FPVS approach as a promising means for studying individual differences in face identity processing. PMID- 28358661 TI - Evaluation of the Effects of Photobiomodulation on Bone Healing in Healthy and Streptozotocin-Induced Diabetes in Rats. AB - OBJECTIVE: This study aimed to assess the effects of Photobiomodulation (PBM) with pulsed wave laser on Hounsfield unit (HU) and bone strength at a catabolic response (bone resorption) of a callus bone defect in healthy and streptozotocin (STZ)- induced type I diabetes mellitus (TI DM) in rats. BACKGROUND DATA: Conflicting results exist regarding the effect of PBM on bone healing in healthy and diabetic animals. MATERIALS AND METHODS: We randomly divided 20 adult female rats into the following groups: (1) control, no TI DM, and no PBM; (2) no TI DM and PBM; (3) TI DM and no PBM; and (4) TI DM and PBM. TI DM was induced by STZ. All rats underwent partial transversal standardized osteotomies in their right tibias. The rats received PBM (890 nm, 80 Hz, 1.5 J/cm2) thrice per week during 30 days. At 4 weeks after the surgery, the rats were sacrificed and their tibias submitted to computed tomography scanning to measure HU. The samples underwent a three-point bending test to evaluate bone strength. RESULTS: Analysis of variance (ANOVA) (p = 0.013) results showed that treatment by PBM significantly increased the biomechanical property (stress high load) of the callus defect from the partial tibia osteotomy in healthy rats compared to the control groups. However, we observed no significant increase in the biomechanical properties of the laser treated diabetic bone defect compared to the control diabetic group. The ANOVA for the HU of callus density produced a p value of 0.000. A significant increase existed in the mean callus density in the healthy groups compared to the diabetic groups. CONCLUSIONS: The 80-Hz laser did not significantly enhance bone repair from an osteotomy of the tibia in an experimental model of TI DM rats. PMID- 28358662 TI - Effect of Laser Photobiomodulation with Gradual or Constant Doses in the Regeneration of Rats' Mental Nerve After Lesion by Compression. AB - OBJECTIVE: Assess morphologically the efficacy of constant dose (CD) or gradual dose (GD) in photobiomodulation therapy (PBMT) during the regeneration process of rats' mental nerve after compression lesion. MATERIALS AND METHODS: Forty-eight male Wistar rats were used and divided into four groups (n = 12): negative control (NC): lesion by compression; positive control (PC): no lesion; GD: lesion by compression and PBMT with GD; and CD: lesion by compression and PBMT with CD. One day after the surgery, the groups GD and CD underwent PBMT daily in three equidistant points around the incision area. The parameters were wavelength of 808 nm, 100 mW, CD received treatment with 120 J/cm2, while GD underwent the protocol of application: 1st and 4th sessions: 80 J/cm2; 5th to 8th sessions: 90 J/cm2; 9th to 12th sessions: 100 J/cm2; 13th to 16th sessions: 110 J/cm2; and 17th to 20th sessions: 120 J/cm2. Euthanasias were performed at 3, 7, 14, and 21 days. Qualitative and quantitative analysis of the mental nerves were performed with ANOVA (analysis of variance) and Tukey tests (p <= 0.05). RESULTS: It was observed that PBMT was able to accelerate the process of nerve regeneration presenting an increase in the number of myelinated fibers starting at 14 days of treatment for groups CD and GD, and at 21 days they were similar to PC. It was observed a better lamellar organization of myelin sheath at 7 days for GD and at 14 days for CD, similar to PC. Both GD and CD presented significant differences compared to NC and PC for thickness of the myelin sheath, outer perimeter, internal area, and number of myelin fibers. CONCLUSIONS: PBMT presented positive effect on the regeneration of nerve starting at 14 days, and after 21 days there was no difference between GD and CD. PMID- 28358663 TI - A Retrospective Evaluation of Partial Glossectomy for Early Tongue Cancer Using a Carbon Dioxide Laser. AB - OBJECTIVE: The purpose of this study was to retrospectively evaluate the postoperative results of partial glossectomy for early tongue cancer using a carbon dioxide laser (CO2 laser). BACKGROUND DATA: CO2 lasers are frequently used for the excision or treatment of soft tissue in a range of diseases, including oral cancer, leukoplakia, mucocele, anomalies of the labial and lingual frenum, and peri-implantitis. MATERIALS AND METHODS: We retrospectively reviewed 31 primary cases of early superficial tongue cancer that were treated using CO2 lasers. In this study, early superficial cancer of the tongue is defined as a T1 or T2 tumor (TNM classification, NOMO; type, superficial spread, or exophytic; depth, <5 mm). The lesions were stained with 10% Lugol's solution and excised with a 5- or 10-mm safety margin from the nonstained area or induration using a CO2 laser. The raw surface was covered with a polyglycolic acid sheet using fibrin glue spray (n = 23), sutures (n = 6), or both (n = 2). Five of the patients showed a bleeding tendency: 1 was taking warfarin 100 mg per day, 1 was taking 350 mg per day, 2 were taking aspirin 100 mg per day, and 1 was taking aspirin 200 mg per day. RESULTS: There were no cases of postoperative bleeding. Regarding postoperative pain, all patients could stop taking analgesic drugs by 1 month after undergoing the operation. In regards to postoperative difficulty to swallow, all could start swallowing rice gruel 2 days after the operation. The surgical margin was unclear in two cases due to the thermal denaturation of the excisional margin. The 2-year local control rate was 100% and subsequent cervical lymph node metastasis rate was 6.5%. CONCLUSIONS: In terms of recurrence, metastasis, postoperative bleeding, postoperative pain, and swallowing, partial glossectomy for early tongue cancer using a CO2 laser might therefore help improve the postoperative course. PMID- 28358664 TI - HIF-1 in cancer therapy: two decade long story of a transcription factor. AB - BACKGROUND: Oxygen (O2) homeostasis is an indispensable requirement of eukaryotes. O2 concentration in cellular milieu is defined as normoxia (~21% O2), physoxia (~1-13% O2) or hypoxia (~0.1-1% O2). Hypoxia, a striking micro environmental feature in tumorigenesis, is countered by tumor cells via induction of O2 governed transcription factor, hypoxia inducible factor-1 (HIF-1). Post discovery, HIF-1 has emerged as a promising anticancer therapeutic target during the last two decades. Recent reports have highlighted that enhanced levels of HIF 1 correlate with tumor metastasis leading to poor patient prognosis. MATERIAL AND METHODS: A systematic search in PubMed and SciFinder for the literature on HIF-1 biology and therapeutic importance in cancer was carried out. RESULTS: This review highlights the initial description as well as the recent insights into HIF 1 biology and regulation. We have focused on emerging data regarding varied classes of HIF-1 target genes affecting various levels of crosstalk among tumorigenic pathways. We have emphasized on the fact that HIF-1 acts as a networking hub coordinating activities of multiple signaling molecules influencing tumorigenesis. Emerging evidences indicate role of many HIF-induced proteomic and genomic alterations in malignant progression by mediating a myriad of genes stimulating angiogenesis, anaerobic metabolism and survival of cancer cells in O2-deficient microenvironment. CONCLUSIONS: Better understanding of the crucial role of HIF-1 in carcinogenesis could offer promising new avenues to researchers and aid in elucidating various open issues regarding the use of HIF-1 as an anticancer therapeutic target. In spite of large efforts in this field, many questions still remain unanswered. Hence, future investigations are necessary to devise, assess and refine methods for translating previous research efforts into novel clinical practices in cancer treatment. PMID- 28358666 TI - A study of the beam-specific interplay effect in proton pencil beam scanning delivery in lung cancer. AB - BACKGROUND: For lung tumors with large motion amplitudes, the use of proton pencil beam scanning (PBS) can produce large dose errors. In this study, we assess under what circumstances PBS can be used to treat lung cancer patients who exhibit large tumor motion, based on the quantification of tumor motion and the dose interplay. MATERIAL AND METHODS: PBS plans were optimized on average 4DCT datasets using a beam-specific PTV method for 10 consecutive patients with locally advanced non-small-cell-lung-cancer (NSCLC) treated with proton therapy to 6660/180 cGy. End inhalation (CT0) and end exhalation (CT50) were selected as the two extreme scenarios to acquire the relative stopping power ratio difference (Deltarsp) for a respiration cycle. The water equivalent difference (DeltaWET) per radiological path was calculated from the surface of patient to the iCTV by integrating the Deltarsp of each voxel. The magnitude of motion of voxels within the target follows a quasi-Gaussian distribution. A motion index (MI (>5mm WET)), defined as the percentage of target voxels with an absolute integral DeltaWET larger than 5 mm, was adopted as a metric to characterize interplay. To simulate the treatment process, 4D dose was calculated by accumulating the spot dose on the corresponding respiration phase to the reference phase CT50 by deformable image registration based on spot timing and patient breathing phase. RESULTS: The study indicated that the magnitude of target underdose in a single fraction plan is proportional to the MI (p < .001), with larger motion equating to greater dose degradation and standard deviations. The target homogeneity, minimum, maximum and mean dose in the 4D dose accumulations of 37 fractions varied as a function of MI. CONCLUSIONS: This study demonstrated that MI can predict the level of dose degradation, which potentially serves as a clinical decision tool to assess whether lung cancer patients are potentially suitable to receive PBS treatment. PMID- 28358665 TI - Is there a different dose-effect relation between the primary tumor and involved lymph nodes in locally advanced non-small-cell lung cancer? A hypothesis generating study. AB - PURPOSE: It is unknown whether the dose-response relation of the primary tumor in NSCLC is different from that of the involved lymph nodes (LN). As the recurrence rate is much lower in LN, we hypothesized that LN need a lower radiation dose. MATERIAL AND METHODS: A retrospective analysis of prospective data was performed on patients with locally advanced NSCLC treated with (chemo)radiotherapy. The impact of EQD2,T prescription dose on relapse was analyzed using Cox regression modeling correcting for baseline diameter. RESULTS: From 2006 to 2010, 75 consecutive patients were included, resulting in 142 lymph nodes in the analysis. Any relapse (locoregional/distant) occurred in 58 patients (77%), while involved nodal relapse (INR) was observed in 13% of patients. No dose-response relationship was observed for INR (p = .22). Primary tumor progression was seen in 40% of patients together with a significant dose-response relationship (p = .033). Baseline nodal diameter was not associated with INR (p = .76), while primary tumor diameter was a highly significant predictor for relapse (p = .0031). CONCLUSIONS: These results suggest that LN control may be achieved at lower radiation doses than needed for the primary tumor. Prospective dose de escalation studies on LN are warranted to decrease the incidence of severe esophagitis without compromising local tumor control. PMID- 28358667 TI - Optimizing SABR delivery for synchronous multiple lung tumors using volumetric modulated arc therapy. AB - BACKGROUND: Volumetric-modulated arc therapy (VMAT) delivery for stereotactic ablative radiotherapy (SABR) of multiple lung tumors allows for faster treatments. We report on clinical outcomes and describe a general approach for treatment planning. MATERIAL AND METHODS: Patients undergoing multi iso-center VMAT-based SABR for >=2 lung lesions between 2009 and 2014 were identified from the VU University Medical Center and London Health Sciences Centre. Patients were eligible if the start date of the SABR treatment for the different lesions was within a time range of 30 days. SABR was delivered using separate iso-centers for lesions at a substantial distance from each other. Tumors were either treated with a single fraction of 34 Gy, or using three risk-adapted dose-fractionation schemes, namely three fractions of 18 Gy, five fractions of 11 Gy, or eight fractions of 7.5 Gy, depending on the tumor size and the location. Multivariable analysis was performed to assess factors predictive of clinical outcomes. RESULTS: Of 84 patients (188 lesions) identified, 46% were treated for multiple metastases and 54% for multiple primary NSCLC. About 97% were treated for two or three lesions, and 56% had bilateral disease. After a median follow-up of 28 months, median overall survival (OS) for primary tumors was 27.6 months, and not reached for metastatic lesions (p = .028). Grade >=3 toxicity was observed in 2% of patients. Multivariable analysis showed that grade 2 or higher radiation pneumonitis (n = 9) was best predicted by a total lung V35Gy of >=6.5% (in 2Gy/fraction equivalent) (p = .007). CONCLUSION: Severe toxicity was uncommon following SABR using VMAT for up to three lung tumors. Further investigations of planning parameters are needed in patients presenting with more lesions. PMID- 28358668 TI - Evolution of [18F]fluorodeoxyglucose and [18F]fluoroazomycin arabinoside PET uptake distributions in lung tumours during radiation therapy. AB - BACKGROUND: Dose painting (DP) aims to improve radiation therapy (RT) outcome by targeting radioresistant tumour regions identified through functional imaging, e.g., positron emission tomography (PET). Importantly, the expected benefit of DP relies on the ability of PET imaging to identify tumour areas which could be consistently targeted throughout the treatment. In this study, we analysed the spatial stability of two potential DP targets in lung cancer patients undergoing RT: the tumour burden surrogate [18F]fluorodeoxyglucose (FDG) and the hypoxia surrogate [18F]fluoroazomycin arabinoside (FAZA). MATERIALS AND METHODS: Thirteen patients with unresectable lung tumours underwent FDG and FAZA 4D-PET/CT before (pre), and during the second (w2) and third (w3) weeks of RT. All PET/CT were reconstructed in their time-averaged midposition (MidP) for further analysis. The metabolic tumour volume (MTV: FDG standardised uptake value (SUV) > 50% SUVmax) and the hypoxic volume (HV: FAZA SUV >1.4) were delineated within the gross tumour volume (GTVCT). The stability of FDG and FAZA PET uptake distributions during RT was subsequently assessed through volume-overlap analysis and voxel based correlation analysis. RESULTS: The volume-overlap analysis yielded median overlapping fraction (OF) of 0.86 between MTVpre and MTVw2 and 0.82 between MTVpre and MTVw3. In patients with a detectable HV, median OF was 0.82 between HVpre and HVw2 and 0.90 between HVpre and HVw3. The voxel-based correlation analysis yielded median Spearman's correlation coefficient (rS) of 0.87 between FDGpre and FDGw2 and 0.83 between FDGpre and FDGw3. Median rS was 0.78 between FAZApre and FAZAw2 and 0.79 between FAZApre and FAZAw3. CONCLUSIONS: FDG and FAZA PET uptake distributions were spatially stable during the 3 first weeks of RT in patients with unresectable lung cancer, both based on volume- and voxel-based indicators. This might allow for a consistent targeting of high FDG or FAZA PET uptake regions as part of a DP strategy. PMID- 28358670 TI - Correction: Constitutive scaffolding of multiple Wnt enhanceosome components by Legless/BCL9. PMID- 28358669 TI - Factors in Placement and Enrollment of Primary Care Patients in YMCA's Diabetes Prevention Program, Bronx, New York, 2010-2015. AB - INTRODUCTION: The reach of the New York State YMCA's Diabetes Prevention Program (DPP) to at-risk populations may be increased through integration with primary care settings. Although considerable effort has been made in the referral and retention of patients, little is known about the factors associated with the placement of potential participants into YMCA's DPP. METHODS: Among Montefiore Health System (MHS) patients referred to YMCA's DPP (n = 1,249) from July 10, 2010, through November 11, 2015, we identified demographic factors (eg, age, preferred language) and primary care practice-level factors (eg, time between referral and start of session, session season) associated with placement into a session and subsequent drop-out. We also evaluated factors associated with weight loss. RESULTS: Patients were predominantly female (71%) and aged 45 years or older (71%). Patients preferring sessions in Spanish were less often placed in sessions. Patients aged 18 to 44 years were less often placed (P = .01) and enrolled (P = .001) than patients aged 60 years or older. Sessions conducted in the summer and spring had higher enrollment than fall and winter months. Patients who started the YMCA's DPP within 2 months of their referral date were more often enrolled (54.4%) than patients who waited 4 or more months (21.6%) to start their sessions. Patients aged 45 to 59 years lost marginally less weight than those aged 60 years or older (-3.1% vs -3.8%; P = .07). CONCLUSION: Although this evaluation gives some insight into the barriers to placement and enrollment in YMCA's DPP, challenges remain. Efforts are under way to increase referral of patients to community-based DPPs. PMID- 28358671 TI - Gland Instance Segmentation Using Deep Multichannel Neural Networks. AB - OBJECTIVE: A new image instance segmentation method is proposed to segment individual glands (instances) in colon histology images. This process is challenging since the glands not only need to be segmented from a complex background, they must also be individually identified. METHODS: We leverage the idea of image-to-image prediction in recent deep learning by designing an algorithm that automatically exploits and fuses complex multichannel information regional, location, and boundary cues-in gland histology images. Our proposed algorithm, a deep multichannel framework, alleviates heavy feature design due to the use of convolutional neural networks and is able to meet multifarious requirements by altering channels. RESULTS: Compared with methods reported in the 2015 MICCAI Gland Segmentation Challenge and other currently prevalent instance segmentation methods, we observe state-of-the-art results based on the evaluation metrics. CONCLUSION: The proposed deep multichannel algorithm is an effective method for gland instance segmentation. SIGNIFICANCE: The generalization ability of our model not only enable the algorithm to solve gland instance segmentation problems, but the channel is also alternative that can be replaced for a specific task. PMID- 28358673 TI - Intrinsic Manifold SLIC: A Simple and Efficient Method for Computing Content Sensitive Superpixels. AB - Superpixels are perceptually meaningful atomic regions that can effectively capture image features. Among various methods for computing uniform superpixels, simple linear iterative clustering (SLIC) is popular due to its simplicity and high performance. In this paper, we extend SLIC to compute content-sensitive superpixels, i.e., small superpixels in content-dense regions with high intensity or colour variation and large superpixels in content-sparse regions. Rather than using the conventional SLIC method that clusters pixels in , we map the input image to a 2-dimensional manifold , whose area elements are a good measure of the content density in . We propose a simple method, called intrinsic manifold SLIC (IMSLIC), for computing a geodesic centroidal Voronoi tessellation (GCVT)-a uniform tessellation-on , which induces the content-sensitive superpixels in . In contrast to the existing algorithms, IMSLIC characterizes the content sensitivity by measuring areas of Voronoi cells on . Using a simple and fast approximation to a closed-form solution, the method can compute the GCVT at a very low cost and guarantees that all Voronoi cells are simply connected. We thoroughly evaluate IMSLIC and compare it with eleven representative methods on the BSDS500 dataset and seven representative methods on the NYUV2 dataset. Computational results show that IMSLIC outperforms existing methods in terms of commonly used quality measures pertaining to superpixels such as compactness, adherence to boundaries, and achievable segmentation accuracy. We also evaluate IMSLIC and seven representative methods in an image contour closure application, and the results on two datasets, WHD and WSD, show that IMSLIC achieves the best foreground segmentation performance. PMID- 28358672 TI - Generalisability of a Virtual Trials Method for Glycaemic Control in Intensive Care. AB - BACKGROUND: Elevated blood glucose (BG) concentrations (Hyperglycaemia) are a common complication in critically ill patients. Insulin therapy is commonly used to treat hyperglycaemia, but metabolic variability often results in poor BG control and low BG (hypoglycaemia). OBJECTIVE: This paper presents a model-based virtual trial method for glycaemic control protocol design, and evaluates its generalisability across different populations. METHODS: Model-based insulin sensitivity (SI) was used to create virtual patients from clinical data from three different ICUs in New Zealand, Hungary, and Belgium. Glycaemic results from simulation of virtual patients under their original protocol (self-simulation) and protocols from other units (cross simulation) were compared. RESULTS: Differences were found between the three cohorts in median SI and inter-patient variability in SI. However, hour-to-hour intra-patient variability in SI was found to be consistent between cohorts. Self and cross-simulation results were found to have overall similarity and consistency, though results may differ in the first 24-48 h due to different cohort starting BG and underlying SI. CONCLUSIONS AND SIGNIFICANCE: Virtual patients and the virtual trial method were found to be generalisable across different ICUs. This virtual trial method is useful for in silico protocol design and testing, given an understanding of the underlying assumptions and limitations of this method. PMID- 28358674 TI - Embedding Based on Function Approximation for Large Scale Image Search. AB - The objective of this paper is to design an embedding method that maps local features describing an image (e.g., SIFT) to a higher dimensional representation useful for the image retrieval problem. First, motivated by the relationship between the linear approximation of a nonlinear function in high dimensional space and the state-of-the-art feature representation used in image retrieval, i.e., VLAD, we propose a new approach for the approximation. The embedded vectors resulted by the function approximation process are then aggregated to form a single representation for image retrieval. Second, in order to make the proposed embedding method applicable to large scale problem, we further derive its fast version in which the embedded vectors can be efficiently computed, i.e., in the closed-form. We compare the proposed embedding methods with the state of the art in the context of image search under various settings: when the images are represented by medium length vectors, short vectors, or binary vectors. The experimental results show that the proposed embedding methods outperform existing the state of the art on the standard public image retrieval benchmarks. PMID- 28358675 TI - Binary Quadratic Programing for Online Tracking of Hundreds of People in Extremely Crowded Scenes. AB - Multi-object tracking has been studied for decades. However, when it comes to tracking pedestrians in extremely crowded scenes, we are limited to only few works. This is an important problem which gives rise to several challenges. Pre trained object detectors fail to localize targets in crowded sequences. This consequently limits the use of data-association based multi-target tracking methods which rely on the outcome of an object detector. Additionally, the small apparent target size makes it challenging to extract features to discriminate targets from their surroundings. Finally, the large number of targets greatly increases computational complexity which in turn makes it hard to extend existing multi-target tracking approaches to high-density crowd scenarios. In this paper, we propose a tracker that addresses the aforementioned problems and is capable of tracking hundreds of people efficiently. We formulate online crowd tracking as Binary Quadratic Programing. Our formulation employs target's individual information in the form of appearance and motion as well as contextual cues in the form of neighborhood motion, spatial proximity and grouping, and solves detection and data association simultaneously. In order to solve the proposed quadratic optimization efficiently, where state-of art commercial quadratic programing solvers fail to find the solution in a reasonable amount of time, we propose to use the most recent version of the Modified Frank Wolfe algorithm, which takes advantage of SWAP-steps to speed up the optimization. We show that the proposed formulation can track hundreds of targets efficiently and improves state-of-art results by significant margins on eleven challenging high density crowd sequences. PMID- 28358676 TI - Multi-Grained Random Fields for Mitosis Identification in Time-Lapse Phase Contrast Microscopy Image Sequences. AB - This paper proposes a multi-grained random fields (MGRFs) model for mitosis identification. To deal with the difficulty in hidden state discovery and sequential structure modeling in mitosis sequences only containing gradual visual pattern changes, we design the graphical structure to transform individual sequence into a set of coarse-to-fine grained sequencesconveying diverse temporal dynamics. Furthermore, we propose the corresponding probabilistic model for joint temporal learning and feature learning. To deal with the non-convex formulation of MGRF, we decomposemodel training into two sub-tasks, layer-wise sequential learning of both temporal dynamics and visual feature and new layer generation by graph-based sequential grouping, and optimize the model by alternating between them iteratively. The proposed method is validated on very challenging mitosis data set of C3H10T1/2 and C2C12 stem cells. Extensive comparison experiments demonstrate its superiority to the state of the arts. PMID- 28358677 TI - Ultrafast Synthetic Transmit Aperture Imaging Using Hadamard-Encoded Virtual Sources With Overlapping Sub-Apertures. AB - The development of ultrafast ultrasound imaging offers great opportunities to improve imaging technologies, such as shear wave elastography and ultrafast Doppler imaging. In ultrafast imaging, there are tradeoffs among image signal-to noise ratio (SNR), resolution, and post-compounded frame rate. Various approaches have been proposed to solve this tradeoff, such as multiplane wave imaging or the attempts of implementing synthetic transmit aperture imaging. In this paper, we propose an ultrafast synthetic transmit aperture (USTA) imaging technique using Hadamard-encoded virtual sources with overlapping sub-apertures to enhance both image SNR and resolution without sacrificing frame rate. This method includes three steps: 1) create virtual sources using sub-apertures; 2) encode virtual sources using Hadamard matrix; and 3) add short time intervals (a few microseconds) between transmissions of different virtual sources to allow overlapping sub-apertures. The USTA was tested experimentally with a point target, a B-mode phantom, and in vivo human kidney micro-vessel imaging. Compared with standard coherent diverging wave compounding with the same frame rate, improvements on image SNR, lateral resolution (+33%, with B-mode phantom imaging), and contrast ratio (+3.8 dB, with in vivo human kidney micro-vessel imaging) have been achieved. The f-number of virtual sources, the number of virtual sources used, and the number of elements used in each sub-aperture can be flexibly adjusted to enhance resolution and SNR. This allows very flexible optimization of USTA for different applications. PMID- 28358678 TI - Low Dimensional Representation of Fisher Vectors for Microscopy Image Classification. AB - Microscopy image classification is important in various biomedical applications, such as cancer subtype identification, and protein localization for high content screening. To achieve automated and effective microscopy image classification, the representative and discriminative capability of image feature descriptors is essential. To this end, in this paper, we propose a new feature representation algorithm to facilitate automated microscopy image classification. In particular, we incorporate Fisher vector (FV) encoding with multiple types of local features that are handcrafted or learned, and we design a separation-guided dimension reduction method to reduce the descriptor dimension while increasing its discriminative capability. Our method is evaluated on four publicly available microscopy image data sets of different imaging types and applications, including the UCSB breast cancer data set, MICCAI 2015 CBTC challenge data set, and IICBU malignant lymphoma, and RNAi data sets. Our experimental results demonstrate the advantage of the proposed low-dimensional FV representation, showing consistent performance improvement over the existing state of the art and the commonly used dimension reduction techniques. PMID- 28358679 TI - Ultrasound Pixel-Based Beamforming With Phase Alignments of Focused Beams. AB - We previously developed unified pixel-based (PB) beamforming to generate high resolution sonograms, based on field pattern analysis. In this framework, we found that the transmit waveshape away from the focus could be characterized by two spherical pulses. These correspond to the maximal and minimal distances from the imaging point to the active aperture. The beamformer uses this model to select the highest energy signals from backscattered data. A spatiotemporal interpolation formula is used to provide a smooth transition in regions near the focal depth where there is no dominant reflected pulse. In this paper, we show that the unified PB approach is less robust at lower center frequencies. The interpolated data is suboptimal for a longer transmit waveshape. As a result, the spatial resolution at the focal depth is lower than that in other regions. By further exploring the field pattern, we propose a beamformer that is more robust to variations in beamwidth. The new method, named coherent PB beamforming, aligns and compounds the pulse data directly in the transition regions. In simulation and phantom studies, the coherent PB approach is shown to outperform the unified PB approach in spatial resolution. It helps regain optimal resolution at the focal depth while still maintaining good image quality in other regions. We also demonstrate the new method on in vivo data where its improvements over the unified PB method are demonstrated on scanned objects with a more complicated structure. PMID- 28358680 TI - Fast Orthogonal Row-Column Electronic Scanning With Top-Orthogonal-to-Bottom Electrode Arrays. AB - Recently, top-orthogonal-to-bottom electrode 2-D arrays were introduced as a practical design for 3-D ultrasound imaging without requiring the wiring of a 2-D grid of elements. However, previously proposed imaging schemes suffered from speed or image-quality limitations. Here, we propose a new imaging scheme which we call Fast Orthogonal Row-Column Electronic Scanning (FORCES). This new approach takes advantage of bias sensitivity to enable high-quality and fast B scan imaging. We compare this imaging scheme with an equivalent linear array, a previously proposed row-column imaging scheme, as well as with the Explososcan imaging scheme for 2-D arrays through simulations. In a point phantom simulation, the lateral (azimuthal) resolution of a 64 *64 element 6.67-MHz lambda /2-pitch array using the FORCES imaging scheme with an f-number of 1.7 was 0.52 mm with similar in-plane image quality to an equivalent linear array but with improved and electronically steerable elevational resolution. When compared with other 3-D imaging schemes in point phantom simulations, the FORCES imaging scheme showed an azimuthal resolution improvement of 54% compared with Explososcan. Compared with a previously introduced row-column method, the FORCES imaging scheme had similar resolution but a 25-dB decrease in sidelobe amplitude, significantly impacting contrast to noise in scattering phantoms. PMID- 28358681 TI - Fast Nonlinear Ultrasound Propagation Simulation Using a Slowly Varying Envelope Approximation. AB - Medical systems usually consider linear propagation of ultrasound, an approximation of reality. However, numerous studies have attempted to accurately simulate the nonlinear pressure wave distortion and to evaluate the contribution of harmonic frequencies. In such simulations, the computation time is very large, except for the method based on the angular spectrum scheme where the derivative order is reduced using the Fourier transform. However, the harmonic computation is usually limited to the second harmonic because of quasi-linear approximation. In this paper, a slowly varying envelope approximation (SVEA) is used in the Fourier domain to compute the entire nonlinear distortion induced, including high harmonics and nonlinear mixing frequencies. The simulation by SVEA is evaluated by comparison with other simulation tools. The obtained deviation and difference remain low enough to fully validate such an approximation. Moreover, the simulator is implemented on a GPU to obtain a very fast tool, where the full nonlinear distorted [Formula: see text] field is computed in less than 10 s. PMID- 28358682 TI - Curvilinear 3-D Imaging Using Row-Column-Addressed 2-D Arrays With a Diverging Lens: Feasibility Study. AB - Constructing a double-curved row-column-addressed (RCA) 2-D array or applying a diverging lens over the flat RCA 2-D array can extend the imaging field-of-view (FOV) to a curvilinear volume without increasing the aperture size, which is necessary for applications, such as abdominal and cardiac imaging. Extended FOV and low channel count of double-curved RCA 2-D arrays make 3-D imaging possible with equipment in the price range of conventional 2-D imaging. This paper proposes a delay-and-sum beamformation scheme specific to double-curved RCA 2-D arrays and validates its focusing ability based on simulations. A synthetic aperture imaging sequence with single element transmissions is designed for imaging down to 14 cm at a volume rate of 88 Hz. Using a diverging lens with an f number of -1 circumscribing the underlying RCA array, the imaging quality of a double-curved lambda/2 -pitch 3-MHz 62 + 62 RCA 2-D array is investigated as a function of depth within a curvilinear FOV of 60 degrees *60 degrees . The simulated double-curved 2-D array exhibits the same full-width-at-half-maximum values for a point scatterer within its curvilinear FOV at a fixed radial distance compared with a flat 2-D array within its rectilinear FOV. The results of this paper demonstrate that the proposed beamforming approach is accurate for achieving correct time-of-flight calculations, and hence avoids geometrical distortions. PMID- 28358683 TI - Robust Object Tracking With Discrete Graph-Based Multiple Experts. AB - Variations of target appearances due to illumination changes, heavy occlusions, and target deformations are the major factors for tracking drift. In this paper, we show that the tracking drift can be effectively corrected by exploiting the relationship between the current tracker and its historical tracker snapshots. Here, a multi-expert framework is established by the current tracker and its historical trained tracker snapshots. The proposed scheme is formulated into a unified discrete graph optimization framework, whose nodes are modeled by the hypotheses of the multiple experts. Furthermore, an exact solution of the discrete graph exists giving the object state estimation at each time step. With the unary and binary compatibility graph scores defined properly, the proposed framework corrects the tracker drift via selecting the best expert hypothesis, which implicitly analyzes the recent performance of the multi-expert by only evaluating graph scores at the current frame. Three base trackers are integrated into the proposed framework to validate its effectiveness. We first integrate the online SVM on a budget algorithm into the framework with significant improvement. Then, the regression correlation filters with hand-crafted features and deep convolutional neural network features are introduced, respectively, to further boost the tracking performance. The proposed three trackers are extensively evaluated on three data sets: TB-50, TB-100, and VOT2015. The experimental results demonstrate the excellent performance of the proposed approaches against the state-of-the-art methods. PMID- 28358684 TI - GRASS: A Gradient-Based Random Sampling Scheme for Milano Retinex. AB - Retinex is an early and famous theory attempting to estimate the human color sensation derived from an observed scene. When applied to a digital image, the original implementation of retinex estimates the color sensation by modifying the pixels channel intensities with respect to a local reference white, selected from a set of random paths. The spatial search of the local reference white influences the final estimation. The recent algorithm energy-driven termite retinex (ETR), as well as its predecessor termite retinex, has introduced a new path-based image aware sampling scheme, where the paths depend on local visual properties of the input image. Precisely, the ETR paths transit over pixels with high gradient magnitude that have been proved to be important for the formation of color sensation. Such a sampling method enables the visit of image portions effectively relevant to the estimation of the color sensation, while it reduces the analysis of pixels with less essential and/or redundant data, i.e., the flat image regions. While the ETR sampling scheme is very efficacious in detecting image pixels salient for the color sensation, its computational complexity can be a limit. In this paper, we present a novel Gradient-based RAndom Sampling Scheme that inherits from ETR the image aware sampling principles, but has a lower computational complexity, while similar performance. Moreover, the new sampling scheme can be interpreted both as a path-based scanning and a 2D sampling. PMID- 28358685 TI - Robust, Efficient Depth Reconstruction With Hierarchical Confidence-Based Matching. AB - In recent years, taking photos and capturing videos with mobile devices have become increasingly popular. Emerging applications based on the depth reconstruction technique have been developed, such as Google lens blur. However, depth reconstruction is difficult due to occlusions, non-diffuse surfaces, repetitive patterns, and textureless surfaces, and it has become more difficult due to the unstable image quality and uncontrolled scene condition in the mobile setting. In this paper, we present a novel hierarchical framework with multi-view confidence-based matching for robust, efficient depth reconstruction in uncontrolled scenes. Particularly, the proposed framework combines local cost aggregation with global cost optimization in a complementary manner that increases efficiency and accuracy. A depth map is efficiently obtained in a coarse-to-fine manner by using an image pyramid. Moreover, confidence maps are computed to robustly fuse multi-view matching cues, and to constrain the stereo matching on a finer scale. The proposed framework has been evaluated with challenging indoor and outdoor scenes, and has achieved robust and efficient depth reconstruction. PMID- 28358686 TI - Scale Invariant and Noise Robust Interest Points With Shearlets. AB - Shearlets are a relatively new directional multi-scale framework for signal analysis, which have been shown effective to enhance signal discontinuities, such as edges and corners at multiple scales even in the presence of a large quantity of noise. In this paper, we consider blob-like features in the shearlets framework. We derive a measure, which is very effective for blob detection, and, based on this measure, we propose a blob detector and a keypoint description, whose combination outperforms the state-of-the-art algorithms with noisy and compressed images. We also demonstrate that the measure satisfies the perfect scale invariance property in the continuous case. We evaluate the robustness of our algorithm to different types of noise, including blur, compression artifacts, and Gaussian noise. Furthermore, we carry on a comparative analysis on benchmark data, referring, in particular, to tolerance to noise and image compression. PMID- 28358687 TI - Color Fringe Correction by the Color Difference Prediction Using the Logistic Function. AB - This paper proposes a new color fringe correction method that preserves the object color well by the color difference prediction using the logistic function. We observe two characteristics between normal edge (NE) and degraded edge (DE) due to color fringe: 1) the DE has relatively smaller R-G and B-G correlations than the NE and 2) the color difference in the NE can be fitted by the logistic function. The proposed method adjusts the color difference of the DE to the logistic function by maximizing the R-G and B-G correlations in the corrected color fringe image. The generalized logistic function with four parameters requires a high computational load to select the optimal parameters. In experiments, a one-parameter optimization can correct color fringe gracefully with a reduced computational load. Experimental results show that the proposed method restores well the original object color in the DE, whereas existing methods give monochromatic or distorted color. PMID- 28358688 TI - Feature Selection Based on High Dimensional Model Representation for Hyperspectral Images. AB - In hyperspectral image analysis, the classification task has generally been addressed jointly with dimensionality reduction due to both the high correlation between the spectral features and the noise present in spectral bands, which might significantly degrade classification performance. In supervised classification, limited training instances in proportion with the number of spectral features have negative impacts on the classification accuracy, which is known as Hughes effects or curse of dimensionality in the literature. In this paper, we focus on dimensionality reduction problem, and propose a novel feature selection algorithm, which is based on the method called high dimensional model representation. The proposed algorithm is tested on some toy examples and hyperspectral datasets in comparison with conventional feature-selection algorithms in terms of classification accuracy, stability of the selected features and computational time. The results show that the proposed approach provides both high classification accuracy and robust features with a satisfactory computational time. PMID- 28358689 TI - Prospective Fall-Risk Prediction Models for Older Adults Based on Wearable Sensors. AB - Wearable sensors can provide quantitative, gait-based assessments that can translate to point-of-care environments. This investigation generated elderly fall-risk predictive models based on wearable-sensor-derived gait data and prospective fall occurrence, and identified the optimal sensor type, location, and combination for single and dual-task walking. 75 individuals who reported six month prospective fall occurrence (75.2 +/- 6.6 years; 47 non-fallers and 28 fallers) walked 7.62 m under single-task and dual-task conditions while wearing pressure-sensinginsoles and tri-axial accelerometers at the head, pelvis, and left and right shanks. Fall-risk classificationmodels were assessed for all sensor combinations and three model types: neural network, naive Bayesian, and support vector machine. The best performing model used a neural network, dual task gait data, and input parameters from head, pelvis, and left shank accelerometers (accuracy = 57%, sensitivity = 43%, and specificity = 65%). The best single-sensor model used a neural network, dual-task gait data, and pelvis accelerometer parameters (accuracy = 54%, sensitivity = 35%, and specificity = 67%). Single-task and dual-task gait assessments provided similar fall-risk model performance. Fall-risk predictive models developed for point-of-care environments should use multi-sensor dual-task gait assessment with the pelvis location considered if assessment is limited to a single sensor. PMID- 28358690 TI - A Framework of Temporal-Spatial Descriptors-Based Feature Extraction for Improved Myoelectric Pattern Recognition. AB - The extraction of the accurate and efficient descriptors of muscular activity plays an important role in tackling the challenging problem of myoelectric control of powered prostheses. In this paper, we present a new feature extraction framework that aims to give an enhanced representation of muscular activities through increasing the amount of information that can be extracted from individual and combined electromyogram (EMG) channels. We propose to use time domain descriptors (TDDs) in estimating the EMG signal power spectrum characteristics; a step that preserves the computational power required for the construction of spectral features. Subsequently, TDD is used in a process that involves: 1) representing the temporal evolution of the EMG signals by progressively tracking the correlation between the TDD extracted from each analysis time window and a nonlinearly mapped version of it across the same EMG channel and 2) representing the spatial coherence between the different EMG channels, which is achieved by calculating the correlation between the TDD extracted from the differences of all possible combinations of pairs of channels and their nonlinearly mapped versions. The proposed temporal-spatial descriptors (TSDs) are validated on multiple sparse and high-density (HD) EMG data sets collected from a number of intact-limbed and amputees performing a large number of hand and finger movements. Classification results showed significant reductions in the achieved error rates in comparison to other methods, with the improvement of at least 8% on average across all subjects. Additionally, the proposed TSDs achieved significantly well in problems with HD-EMG with average classification errors of <5% across all subjects using windows lengths of 50 ms only. PMID- 28358691 TI - Identification and Functional Inference for Tumor-associated Long Non-coding RNA. AB - Gastric cancer is one of the top leading causes of cancer mortality worldwide especially in China. In recent years, some lncRNAs are discovered to be dysregulated in many cancers. The study on long non-coding RNAs (lncRNAs) relationship with cancers has attracted increasing attention. The molecular mechanism of gastric cancer remains largely unclear factors, especially for lncRNAs. Experiments are feasible to obtain related information, however, experimental identification of cancer-related lncRNAs usually possesses high time complexity and high cost. In this paper, a computational method is proposed to determine the relationship between lncRNA and gastric cancer by reusing the exon based array of gastric cancer. One specific lncRNAs LINC00365 and its target differentially expressed genes whose products are predicted as blood, urine or salvia-excretory are identified to be candidates for a combined biomarker for gastric cancer. Further biological function and molecular mechanism of the gastric cancer related lncRNAs and coding gene biomarkers are inferred in terms of multi-source biological knowledge. PMID- 28358692 TI - Hyperbolic Gradient Operator and Hyperbolic Back-Propagation Learning Algorithms. AB - In this paper, we first extend the Wirtinger derivative which is defined for complex functions to hyperbolic functions, and derive the hyperbolic gradient operator yielding the steepest descent direction by using it. Next, we derive the hyperbolic backpropagation learning algorithms for some multilayered hyperbolic neural networks (NNs) using the hyperbolic gradient operator. It is shown that the use of the Wirtinger derivative reduces the effort necessary for the derivation of the learning algorithms by half, simplifies the representation of the learning algorithms, and makes their computer programs easier to code. In addition, we discuss the differences between the derived Hyperbolic-BP rules and the complex-valued backpropagation learning rule (Complex-BP). Finally, we make some experiments with the derived learning algorithms. As a result, we find that the convergence rates of the Hyperbolic-BP learning algorithms are high even if the fully activation functions are used, and discover that the Hyperbolic-BP learning algorithm for the hyperbolic NN with the split-type hyperbolic activation function has an ability to learn hyperbolic rotation as its inherent property. PMID- 28358693 TI - A Scalable and Pragmatic Method for the Safe Sharing of High-Quality Health Data. AB - The sharing of sensitive personal health data is an important aspect of biomedical research. Methods of data de-identification are often used in this process to trade the granularity of data off against privacy risks. However, traditional approaches, such as HIPAA safe harbor or -anonymization, often fail to provide data with sufficient quality. Alternatively, data can be de-identified only to a degree which still allows us to use it as required, e.g., to carry out specific analyses. Controlled environments, which restrict the ways recipients can interact with the data, can then be used to cope with residual risks. The contributions of this article are twofold. First, we present a method for implementing controlled data sharing environments and analyze its privacy properties. Second, we present a de-identification method which is specifically suited for sanitizing health data which is to be shared in such environments. Traditional de-identification methods control the uniqueness of records in a dataset. The basic idea of our approach is to reduce the probability that a record in a dataset has characteristics which are unique within the underlying population. As the characteristics of the population are typically not known, we have implemented a pragmatic solution in which properties of the population are modeled with statistical methods. We have further developed an accompanying process for evaluating and validating the degree of protection provided. The results of an extensive experimental evaluation show that our approach enables the safe sharing of high-quality data and that it is highly scalable. PMID- 28358694 TI - Active Learning of Regular Expressions for Entity Extraction. AB - We consider the automatic synthesis of an entity extractor, in the form of a regular expression, from examples of the desired extractions in an unstructured text stream. This is a long-standing problem for which many different approaches have been proposed, which all require the preliminary construction of a large dataset fully annotated by the user. In this paper, we propose an active learning approach aimed at minimizing the user annotation effort: the user annotates only one desired extraction and then merely answers extraction queries generated by the system. During the learning process, the system digs into the input text for selecting the most appropriate extraction query to be submitted to the user in order to improve the current extractor. We construct candidate solutions with genetic programming (GP) and select queries with a form of querying-by-committee, i.e., based on a measure of disagreement within the best candidate solutions. All the components of our system are carefully tailored to the peculiarities of active learning with GP and of entity extraction from unstructured text. We evaluate our proposal in depth, on a number of challenging datasets and based on a realistic estimate of the user effort involved in answering each single query. The results demonstrate high accuracy with significant savings in terms of computational effort, annotated characters, and execution time over a state-of the-art baseline. PMID- 28358696 TI - A Modified Method for Purifying Gallbladder Epithelial Cells Using Fluorescence activated Cell Sorting. AB - BACKGROUND: We have previously reported a procedure for isolating and culturing biliary epithelial cells (BECs). The aim of this study was to reconsider the method for obtaining pure BECs using the mouse gallbladder. MATERIALS AND METHODS: Cells that were obtained from the gallbladder alone were sorted by fluorescence-activated cell sorting (FACS) for purifying based on the expression of the epithelial cell adhesion molecule (EpCAM). The viability rate was measured based on the negative expression of 7-aminoactinomycin D (7-AAD). RESULTS: More than 75% of cells from the gallbladder were determined to be pure BECs. An analysis of the EpCAM revealed that 73.3% of the cells were 7-AAD-negative. Finally, the 0.82*106 pure BECs that survived were obtained and seeded on a collagen gel plate. However, these pure BECs showed almost no proliferation. CONCLUSION: Pure BECs could be accumulated using FACS. However, the number of BECs was insufficient for the culturing process. PMID- 28358697 TI - Assessment of Radiobiological alpha/beta Ratio in Lung Cancer and Fibroblast Cell Lines Using Viability Assays. AB - BACKGROUND/AIM: Altered fractionation is an area of intense clinical research in radiation oncology. Estimation of the alpha/beta ratio of individual carcinomas after establishment of primary cell cultures from tumor biopsies may prove of importance in the individualization of radiotherapy schemes. MATERIALS AND METHODS: Here we proposed a simple method to estimate the alpha/beta ratio in cultured cell lines (two lung carcinomas: A549 and H1299; one lung fibroblast cell line: MRC5), using viability assays. RESULTS: For the A549 cell line, the alpha/beta ratio ranged from 14-25 Gy, for H1299 from 11-43 Gy and for the MRC5 fibroblast cell line this was far lower, ranging from 0.69 to 6 Gy. The alpha/beta ratio decreased when extracted from comparisons of lower dose per fraction schemes. CONCLUSION: The alpha/beta ratio of a cell line can be easily defined after simple viability/dose fractionation experiments. PMID- 28358695 TI - Induction of TGF-beta by Irradiation or Chemotherapy in Fanconi Anemia (FA) Mouse Bone Marrow Is Modulated by Small Molecule Radiation Mitigators JP4-039 and MMS350. AB - BACKGROUND/AIM: Total-body irradiation and/or administration of chemotherapy drugs in bone marrow transplantation induce cytokines that can suppress engraftment. Fanconi Anemia (FA) patients have a hyperactive responsiveness to the inhibitory cytokine, transforming growth factor-beta (TGF-beta). Small molecule radiation mitigator drugs, JP4-039 and MMS350, were evaluated for suppression of irradiation or drug-induced TGF-beta. MATERIALS AND METHODS: In vivo induction of TGF-beta by total-body ionizing irradiation (TBI), L phenylalanine mustard (L-PAM), busulfan or fludarabine, was quantified. In parallel, mitigator drug amelioration of TGF-beta induction in FA D2-/- (FANCD2-/ ) mouse bone marrow, was studied in vitro. Tissue culture medium, cell lysates, and mouse plasma were analyzed for TGF-beta levels. RESULTS: Induction of TGF beta levels in FANCD2-/- and FANCD2+/+ mice and in mouse bone marrow were modulated by both JP4-039 and MMS350. CONCLUSION: Bone marrow transplantation in FA recipients may benefit from administration of small molecule agents that suppress TGF-beta induction. PMID- 28358698 TI - Increased Numbers of CD4+CD25+ and CD8+CD25+ T-Cells in Peripheral Blood of Patients with Rheumatoid Arthritis with Parvovirus B19 Infection. AB - AIM: To investigate T-cell subpopulations in peripheral blood of human parvovirus B19 DNA-positive (B19+) and -negative (B19-) patients with rheumatoid arthritis (RA) and healthy persons. PATIENTS AND METHODS: Blood samples were collected from 115 patients with RA and 47 healthy volunteers; 27 patients with RA and nine controls were B19+ Cluster of differentiation (CD) 4, 8, 25 and 45RA were analyzed on blood cells. CD25 expression on CD4+CD45RA+, CD4+CD45RA-, CD8+CD45RA+, CD8+CD45RA- subsets were analyzed by flow cytometry. RESULTS: The percentage of CD25low and CD25hi cells was increased on CD4+CD45RA+, CD4+CD45RA- T-cells and the percentage of CD25+ cells was increased on CD8+CD45RA+, CD8+CD45RA- T-cells of B19+ patients with RA in comparison with B19- patients and controls. CONCLUSION: Raised levels of CD4 and CD8 regulatory T-cells in B19+ RA patients could cause down-regulation of antiviral clearance mechanisms and lead to activation of persistent human parvovirus B19 infection in patients with RA. PMID- 28358699 TI - Chemopreventive Action by Ethanol-extracted Brazilian Green Propolis on Post initiation Phase of Inflammation-associated Rat Colon Tumorigenesis. AB - BACKGROUND/AIM: Propolis has since long been utilized in numerous folk medicines with a variety of medicinal properties. In this study, the effects of ethanol extracted (EEP) and water-extracted (WEP) Brazilian green propolis on the post initiation phase of inflammation-associated rat colon tumorigenesis were directly compared. MATERIALS AND METHODS: Male F344 rats at 6 weeks of age were subcutaneously injected with 1,2-dimethylhydrazine (DMH) at 40 mg/kg body weight twice during the first week, followed by 1% dextran sodium sulfate (DSS) in drinking water for one week. After a 1-week no-treatment period, animals were administered either basal Oriental MF powdered diet, or 1% EEP or 1% WEP in the basal diet until week 32. RESULTS: Post-initiation treatment with EEP significantly reduced the multiplicity of colorectal carcinomas compared to the control (0.40+/-0.13/rat vs. 2.29+/-0.84/rat, respectively, p<0.05), and EEP also reduced the tumor volume. Immunohistochemically, expression of inflammation associated proteins inducible nitric oxide synthase, tumor necrotic factor alpha, nuclear factor kappa B and glutathione peroxidase-2 were significantly diminished in colorectal tumors from EEP-treated rats. CONCLUSION: Suppression of inflammation and oxidative stress, which had been triggered by DMH and promoted by DSS, was a primary mechanism by which EEP suppressed carcinogenesis. PMID- 28358700 TI - Bevacizumab Modulation of the Interaction Between the MCF-7 Cell Line and the Chick Embryo Chorioallantoic Membrane. AB - AIM: To evaluate the interaction between MCF-7 breast cancer cells and the chick embryo chorioallantoic membrane (CAM) and the ability of bevacizumab to modulate this process. MATERIALS AND METHODS: We implanted MCF-7 cells onto CAM and repeatedly added bevacizumab to a subset of eggs. We then evaluated the morphological and immunohistochemical profiles of CAM and MCF-7. RESULTS: MCF-7 cells entered the mesoderm and stimulated the mesenchymal cells to acquire vasculogenic and myofibroblastoid features. MCF-7 cells developed an estrogen receptor-, progesterone receptor-, p53- and Ki67-negative status and entered the epithelial-mesenchymal transition. Bevacizumab down-regulated the expression of B cell lymphoma 2 protein (BCL-2), vascular endothelial growth factor (VEGF) and E cadherin in MCF-7 and inhibited vasculogenesis. CONCLUSION: MCF-7 cells turn the mesoderm of CAM into a surrogate tumor stroma. CAM induces a triple-negative, non proliferative but still anti-apoptotic status in MCF-7 cells. Although antivasculogenic, bevacizumab stimulates MCF-7 cells to acquire a more aggressive status. PMID- 28358701 TI - Effects of Caspase 9 Gene Polymorphism in Patients with Prostate Cancer. AB - BACKGROUND: Prostate cancer is one of the most common solid tumors and the second leading cause of the death due to malignancy in men. Caspase 9 (CASP9) is a member of the intrinsic pathway and plays a central role in the apoptosis. PATIENTS AND METHODS: Genotyping of the CASP9 (rs1052576) polymorphism were performed using real-time polymerase chain reaction for blood samples of prostate cancer patients (n=69) and controls (n=76). RESULTS: There were no significant differences between the groups in the frequency of CASP9 genotypes (chi2=1.363; p=0.506). Patients with CASP9 (rs1052576) CT genotype were 12.8 fold higher in pathological stage of pT2a compared to any other stages of cancer (OR=0.078, 95% CI= 0.009-0.062; p=0.004). Also TT genotype carriers were 11.3 times lower in pathological stage of pT2a (OR=11.33, 95% CI=2.39-53.748; p=0.000). C allele carriers were 11.36 fold higher in pathological stage of pT2a compared to any other stages of cancer (OR=0.088, 95% CI=0.019-0.418; p=0.002). CONCLUSION: CASP9 (rs1052576) C allele was decreasing the risk for pathological stage of patients with prostate cancer and also CT genotype had positive impact on pathological stage of patients with prostate cancer. CASP9 (rs1052576) TT genotype was seemed to be associated with higher risk of pathological stage. Those results implicated that CASP9 variations could be associated with severity of prostate cancer. PMID- 28358702 TI - The Effect of Geraniol on Liver Regeneration After Hepatectomy in Rats. AB - Geraniol is a monoterpenoid alcohol that has a hepatoprotective effect. We investigated the regenerative effects of geraniol in rats after a 70% partial hepatectomy (PH). Using Wistar albino rats, nine groups were created: Group I was the control group, while the remaining groups received a single intraperitoneal dose of saline, Silymarin, or geraniol after PH. A 70% PH was performed on all groups except for groups II and III. Blood serum samples were obtained for alanine amino transferase (ALT) analysis. Then liver tissues were harvested for histological and real-time polymerase chain reaction (PCR) analyses. Tumor necrosis factor-alpha (TNFalpha) and interleukin 6 (IL6) gene expression were examined 24 and 48 h after PH. ALT levels were found to be statistically significantly increased in all PH-treated groups. TNFalpha and IL6 gene expression levels were elevated in geraniol-treated groups. Histological evaluation revealed a hepatoprotective effect for geraniol-treated groups. Our results suggest that geraniol plays a significant role during liver regeneration, which involves the elevated expression of TNFalpha and IL6 48 h after PH. PMID- 28358703 TI - Centrosome Aberration Frequency and Disease Association in B-Acute Lymphoblastic Leukemia. AB - Recent developments in genome-wide genetic analysis in B-acute lymphoblastic leukemia (B-ALL) have provided insight into disease pathogenesis and prognosis. B ALL cases usually carry a primary genetic event, often a chromosome translocation, and a constellation of secondary genetic alterations that are acquired and selected dynamically in a nonlinear fashion. As far as we are aware of, for the first time, we studied centrosome aberration in patients with B-ALL to understand the progression of the disease. A cytogenetic study was carried out by GTG-banded karyotyping and fluorescence in situ hybridization. DNA index study was carried out with flow cytometry. Indirect immunostaining of centrosomes was performed on mononuclear cells using primary and corresponding secondary antibodies for centrosome-specific protein gamma-tubulin. Three primary and corresponding secondary antibodies to three different centrosome-specific proteins, namely alpha-tubulin, gamma-tubulin and pericentrin, were used for indirect immunostaining. The study was carried out on 50 patients with B-ALL. Centrosomal abnormalities were detected in 36 (72%) patients and the remainder (28%) had normal centrosome structure and numbers. Out of these 36 patients with abnormal centrosome, structural abnormalities were detected in 12 (33.3%) and numerical abnormalities in six (16.6%). Both structural and numerical aberrations were detected in 18 (50%) patients. When correlated with the cytogenetic and DNA index findings, 26/27 (96.2%) patients had centrosome defects concomitant with both abnormal karyotype and aneuploidy. Out of 50 patients with B-ALL, 17 (34%) had normal karyotype detected by both karyotype and DNA index, among these, seven (41.17%) patients had centrosome aberration. The morphological and structural abnormalities of the centrosome present in B-ALL cells have a role in disease development and can be considered as prognostic markers. PMID- 28358704 TI - Prevalence of Neurotropic Viruses in Malignant Glioma and Their Onco-Modulatory Potential. AB - BACKGROUND: the association between infectious agents and tumour aetiology is relevant in about 20% of cases. PATIENTS AND METHODS: We tested high-grade glioma tissues from 45 patients for the presence of viral nucleic acids of six herpes viruses, human adenoviruses (A-G), and two neurotropic human viruses (enteroviruses, tick-borne encephalitis virus). Real-time polymerase chain reaction was used with immunolabelling. RESULTS: Three species of herpes viruses were detected: HSV-2, Epstein-Barr virus (EBV), HHV-6, and one human enterovirus. Plasma of these patients was not infected with viruses. In sera of patients, low HSV-1 and HSV-2 immunoreactivity were found in five cases, although these were not detected in their tumour tissue. CONCLUSION: Certain common viruses (HSV-1, HSV-2, EBV, human cytomegalovirus) are chronically present in the sera of patients with glioblastoma, but not necessarily in their tissues. Possibly both are associated with glioma progression, as we only found viruses in glioblastoma multiforme, but not in lower stages of glioma. Low titres of viruses in the blood indicate chronic viral virulence. PMID- 28358705 TI - Mild Versus Conventional Ovarian Stimulation for Poor Responders Undergoing IVF/ICSI. AB - BACKGROUND/AIM: Mild stimulation protocols have been implemented to be offered to subfertile patients who respond poorly to ovarian stimulation. We aimed to compare the efficacy of mild versus conventional gonadotropin-releasing hormone (GnRH)-agonist and antagonist protocols in poor responders undergoing in vitro fertilization/intra-cytoplasmic sperm injection (IVF/ICSI) cycles. PATIENTS AND METHODS: A total of 58 poorly-responding patients were divided into two groups: mild group (n=33), receiving clomiphene citrate 100 mg and 0.25 mg of cetrorelix with 150 IU of gonadotrophins daily; conventional group (n=25), undergoing the long GnRH-agonist or -antagonist protocols. The primary outcome was the number of cumulus oocyte complexes (COCs) retrieved. RESULTS: A lower number of COCs [median (range)=1 (0-4) vs. 3 (0-8.4), p<0.001] was retrieved in the mild stimulation compared to the conventional group. Secondary outcomes favored the conventional group, whereas live birth (9.1% vs. 12%), clinical pregnancy (12.1% vs. 20%) and miscarriage rate (40% vs. 40%) were similar in the two groups. CONCLUSION: Mild ovarian stimulation is inferior to conventional regimes when applied to poor responders undergoing IVF/ICSI, in terms of the numbers of retrieved COCs. PMID- 28358706 TI - Chemoradiation Including Paclitaxel for Locally Recurrent Muscle-invasive Bladder Cancer in Elderly Patients. AB - BACKGROUND/AIM: To evaluate outcomes and toxicities of chemoradiation with a less intensive paclitaxel regimen for locally recurrent bladder cancer. PATIENTS AND METHODS: Three elderly patients received simultaneous chemoradiation for recurrent muscle-invasive bladder cancer. Chemotherapy included two courses (three times 25 mg/m2 over 1.5 weeks) of paclitaxel. Radiotherapy doses were 59.4 Gy to the bladder and 50.4 Gy to regional lymph nodes. Survival, local control and toxicities were retrospectively evaluated. RESULTS: One patient died after 71 months, two were alive after 69 and 98 months, respectively. No local recurrence was not observed. Five-year survival and local control rates were 100%. Two patients experienced grade 1 acute dysuria, one patient grade 1 diarrhea. Late toxicities were also mild; two patients had grade 1 dysuria. CONCLUSION: Chemoradiation with a less intensive paclitaxel regimen resulted in excellent 5 year results and was very well tolerated. It may be a reasonable option for elderly patients who cannot tolerate more intensive approaches. PMID- 28358707 TI - Polymorphisms of Platelet Glycoprotein Receptors and Cell Adhesion Molecules in Fetuses with Fetal Growth Restriction and Their Mothers As Detected with Pyrosequencing. AB - BACKGROUND: Vascular thrombotic tendency may lead to fetal growth restriction (FGR). Altered platelet function and genetic heterogeneity may play a role in this procedure. We investigated whether maternal or fetal genotypic frequencies of genes polymorphisms for certain platelet receptor and cell adhesion molecules are altered in FGR. MATERIALS AND METHODS: We compared the maternal and fetal genotypic frequencies of single nucleotide polymorphisms (SNPs) in four genes coding for platelet receptors and cell adhesion molecules [integrin alpha subunit 2 (ITGA2)C807T, integrin subunit beta 3(ITGB3) T1565C, platelet cell adhesion protein 1 (PECAM1) CTG-GTG and selectin P(SELP)A/C]. A total of 32 fetuses with fetal growth restriction and their mothers were matched with 18 normal controls. Using maternal venous blood and umbilical cord blood samples, nucleotide sequences were determined from pyrograms. Genotypic frequencies were calculated and analyzed using appropriate tests and logistic regression. RESULTS: There was no statistical difference in the proportion of heterozygotes or homozygotes for any of the genotypic frequencies between FGR and control groups in mothers or fetuses. CONCLUSION: Our study demonstrated no association of maternal or fetal ITGA2 C807T SNP, ITGB3 T1565C SNP, PECAM1 CTG - GTG and SELP A/C polymorphisms with FGR. PMID- 28358709 TI - Lack of Definite Association of Vitamin D Deficiency with Diabetic Neuropathy. Investigation in Greek and in Bangladeshi Patients. AB - AIM: Determination of the 25(OH) vitamin D levels in Greek-born and in Bangladeshi immigrant patients in Greece with diabetes with and without polyneuropathy. MATERIALS AND METHODS: The method for the detection and staging of polyneuropathy proposed by Dyck, 1988 was used. RESULTS: A total of 111 Bangladeshi immigrants and 101 Greek diabetic patients took part in the study. Vitamin D levels were significantly lower in Bangladeshi than in Greek diabetic patients, and were significantly lower in Greek patients with small-fiber neuropathy. In Bangladeshi patients, there was no statistically significant difference in the subgroup of patients with polyneuropathy in comparison to those without polyneuropathy. CONCLUSION: The association of vitamin D deficiency only with a small number of Greek patients with exclusively small-fiber neuropathy does not allow us to draw a definite conclusion on the role of vitamin D in the pathogenesis of diabetic neuropathy. PMID- 28358708 TI - Improvement of Perioperative Outcomes in Major Gynecological and Gynecologic Oncological Surgery with Hemostatic Gelatin-Thrombin Matrix. AB - AIM: To assess the impact of the use of intraoperative hemostatic gelatin thrombin matrix (HM) (Floseal(r), Baxter Healthcare) on transfusion rates and short-term perioperative outcomes in gynecological surgery. PATIENTS AND METHODS: In this retrospective, single-center study, we evaluated data of 215 patients (83 cases and 132 controls) undergoing extensive gynecological surgery (e.g. oncological procedures) with and without intraoperative HM application. RESULTS: Cases and controls did not differ according to age, preoperative hemoglobin (Hb) concentration, and Hb or C-reactive protein (CRP) levels at discharge. Patients receiving HM had significantly reduced operative (168 vs. 199 min, p=0.02) and hospitalization (9 vs. 14 days, p<0.001) times. The mean postoperative Hb drop (3.33 vs. 4.51 g/dl, p<0.001), and the mean postoperative increase in CRP (94.9 vs. 149.1 mg/l, p<0.001) were significantly less pronounced within the HM group. Despite more prevalent coagulopathy (48 vs. 31%, p=0.02), e.g. due to anticoagulant use (15.7 vs. 3%, p<0.001), patients treated using HM needed less frequent transfusions of packed red blood cells [odds ratio (OR)= 0.13, 95% confidence interval (CI)=0.07-0.24) and fresh frozen plasma (OR=0.51, 95% CI=0.24 1.05). In comparison to controls, the need for surgical revisions (OR 0.1, CI 95% 0.02-0.42) and intensive-care unit admissions (OR 0.15, 95% CI=0.08-0.30) was lower in patients treated with HM. CONCLUSION: To our knowledge, our study is the largest case-control study focusing on Floseal(r) use in gynecology. The use of HM was associated with significantly better short-term perioperative outcomes. Due to its local action, HM seems to be particularly useful in patients in which anticoagulant medication cannot be paused. PMID- 28358710 TI - Sclerotherapy for Orbital Lymphangioma - Case Series and Literature Review. AB - Orbital lymphangioma is a lymphatic system lesion that commonly presents in childhood. Management of these lesions is complex. Sclerotherapy is a therapy used to treat and shrink lesions prior to or as an alternative to surgery. We present three cases of orbital lymphangioma that were treated with sclerotherapy. Case 1: A 6-month-old boy was presented in 2010 with right ptosis and proptosis. Magnetic resonance imaging (MRI) identified a lesion involving the right orbit and face. Case 2: A 3-year-old girl was presented in 2011 with intermittent right periorbital swelling and medial canthal bleeding. MRI identified a soft-tissue lesion in the right orbit, extending into the face. Case 3: A 3-year-old girl was presented in 2012 with vomiting, and painful right proptosis. MRI identified an intra-conal lesion in the right orbit with fluid filled levels. All three patients were treated with sclerotherapy (sodium tetradecylsulfate). Sclerotherapy is a promising treatment for orbital lymphangioma. Its use may prevent the need for, or minimise the amount of surgical management. Several sclerosants are now commonly used to treat these lesions. PMID- 28358711 TI - The influence of implant body and thread design of mini dental implants on the loading of surrounding bone: a finite element analysis. AB - Mini dental implants (MDI) were once thought of as transitional implants for treatment in selected clinical situations. Their reduced diameter makes them a very attractive option for patients with poor tolerance to maxillary and mandibular prostheses. Using the method of finite element analysis, a series of different designed MDI prototypes have been investigated. The prototypes differed in the geometry of implant body and/or design of implant head. The load transfer of the implant prototypes to the idealised alveolar bone has been regarded and the prototypes have been compared to each other and to a number of standard commercial implants. The prototype models have been virtually placed in the idealised bone with a cortical thickness of 1.5 mm and loaded laterally 30 degrees from the implant's long axis. The condition of immediate loading was assumed for the numerical analyses through defining a contact interface between the implant and bone bed. The numerical analysis in this study showed that the design of the investigated prototype MDI of group 3 (mini-ball head) is the most advantageous design. PMID- 28358712 TI - Anti-inflammatory activity of Elaeagnus angustifolia fruit extract on rat paw edema. AB - BACKGROUND: The Elaeagnus angustifolia fruit has been traditionally used in Iranian herbal medicine to treat diarrhea and rheumatoid arthritis. In the present study, the effects of E. angustifolia fruit extract on the acute and chronic phases of formalin-induced rat paw edema were examined. METHODS: The acute and chronic anti-inflammatory effects of E. angustifolia fruit extract were investigated through the subcutaneous injection of 100 MUL of formalin (2.5%) into a rat's hind paw. Thirty minutes before the procedure, the experimental groups were treated intraperitoneally with hydroalcoholic fruit extracts of E. angustifolia (concentrations of 100, 300, 700, and 1000 mg/kg); sodium salicylate (SS, 400 mg/kg) and distilled water were used as positive and negative control groups, respectively. Treatment with SS and the fruit extracts were performed daily for 8 days, and the degree of edema was measured by using mercury plethysmometer and digital caliper. RESULTS: In the acute anti-inflammatory study, the extract showed a significant anti-inflammatory effect in a dose dependent manner. The results of 1000 mg/kg of the extract was significantly different compared with the negative control group (p<0.05) and was comparable to sodium salicylate (p<0.05). Results from the chronic study suggested that E. angustifolia extract significantly reduced paw edema and inflammation in a dose dependent manner. The results also showed that the measurement by digital caliper and mercury plethysmometer were both reliable and might be applied interchangeably (p<0.01). Phytochemical tests indicated that the hydroalcoholic fruit extract of E. angustifolia was positive for cardiac glycosides, flavonoids, terpenoids, and saponins. CONCLUSIONS: Based on our findings, the E. angustifolia fruit extract probably has acute and chronic anti-inflammatory activities to support its applications in folk medicine. PMID- 28358714 TI - Effects of L-thyroxine treatment on heart functions in infants with congenital hypothyroidism. AB - BACKGROUND: Impaired heart functions in newborns with hypothyroidism should be reversed by levothyroxine substitution therapy. The aim of the study was to investigate heart functions with congenital hypothroidism (CH) in newborns and changes after levothyroxine substitution therapy, measured with tissue Doppler echocardiography and conventional echocardiography. METHODS: The study included 30 neonates with CH and 34 healthy controls. Echocardiography were performed at baseline, 2nd week and 6th month of therapy. RESULTS: Heart systolic function was normal. Mitral E velocities and mitral E/A ratios were significantly lower in patients at baseline. Tei indices were significantly higher in patients and a significant negative correlation was detected between free thyroxine levels and Tei indices.When early and late post-treatment echocardiography findings are compared, a non-significant difference was detected. CONCLUSIONS: Neonates with CH may exhibit systolic and diastolic heart dysfunction, which can be reversed by early L-T4 substitution treatment. The Tei index index should be measured in addition to conventional echocardiography. PMID- 28358713 TI - The effect of extracellular ATP on rat uterine contraction from different gestational stages and its possible mechanisms of action. AB - BACKGROUND: The mechanisms underlying the onset of labor are not fully understood. Extracellular adenosine 5'-triphosphate (ATP) is known to cause uterine contractions in different species but the exact underlying mechanisms are poorly investigated to date. The aims of this study were to investigate the effect of extracellular ATP on spontaneous uterine contractions from different gestational stages and to elucidate its possible underlying mechanisms. METHODS: Longitudinal uterine strips were obtained from rats in different gestational stages (nonpregnant, late-pregnant, and term-pregnant). The effects of 1 mM ATP were examined on uterine contractions generated spontaneously, depolarized by high-KCl (60 mM), induced by oxytocin (5 nM), in the presence of high external Ca2+, or in the absence of external Ca2+. RESULTS: Application of 1 mM extracellular ATP significantly increased the force of spontaneous contraction in uterine strips obtained from all gestational stages with prominent increase in term-pregnant rats compared to other gestations. ATP significantly increased the force induced by depolarization (122%, p=0.010, n=6), oxytocin (129%, p=0.001, n=7), high-Ca2+ (145%, p=0.005, n=6) and it was able to cause transient contraction in the absence of external Ca2+ (33%, p<0.01). CONCLUSIONS: Extracellular ATP is able to increase the force and frequency of uterine contractions and its effect increases with the progression of pregnancy and it involves Ca2+ influx and release. These findings open a new window for clinicians to consider ATP as a therapeutic target to control the uterine activity during difficult labors. PMID- 28358715 TI - Pediatric endocrinology is pediatrics is public health. PMID- 28358716 TI - Teaching community health assessment through a global health elective in rural Haiti. PMID- 28358717 TI - Structural and vibrational properties of corundum-type In2O3 nanocrystals under compression. AB - This work reports the structural and vibrational properties of nanocrystals of corundum-type In2O3 (rh-In2O3) at high pressures by using angle-dispersive x-ray diffraction and Raman scattering measurements up to 30 GPa. The equation of state and the pressure dependence of the Raman-active modes of the corundum phase in nanocrystals are in good agreement with previous studies on bulk material and theoretical simulations on bulk rh-In2O3. Nanocrystalline rh-In2O3 showed stability under compression at least up to 20 GPa, unlike bulk rh-In2O3 which gradually transforms to the orthorhombic Pbca (Rh2O3-III-type) structure above 12 14 GPa. The different stability range found in nanocrystalline and bulk corundum type In2O3 is discussed. PMID- 28358719 TI - Properties of quasiperiodic functions. AB - Today, quasiperiodic tilings are well known and have been studied in great detail since they are very useful to describe the properties of metallic and soft matter quasicrystals. A closely related topic are quasiperiodic functions which have also gained large interest recently. Different types of such functions and there interrelation will be presented here. The main topic will be quasiperiodic potentials generated by laser beams and their variability. The distribution of extremal points and local isomorphisms of quasiperiodic functions will also be addressed. PMID- 28358718 TI - Imaging three-dimensional innervation zone distribution in muscles from M-wave recordings. AB - OBJECTIVE: To localize neuromuscular junctions in skeletal muscles in vivo which is of great importance in understanding, diagnosing and managing of neuromuscular disorders. APPROACH: A three-dimensional global innervation zone imaging technique was developed to characterize the global distribution of innervation zones, as an indication of the location and features of neuromuscular junctions, using electrically evoked high-density surface electromyogram recordings. MAIN RESULTS: The performance of the technique was evaluated in the biceps brachii of six intact human subjects. The geometric centers of the distributions of the reconstructed innervation zones were determined with a mean distance of 9.4 +/- 1.4 cm from the reference plane, situated at the medial epicondyle of the humerus. A mean depth was calculated as 1.5 +/- 0.3 cm from the geometric centers to the closed points over the skin. The results are consistent with those reported in previous histology studies. It was also found that the volumes and distributions of the reconstructed innervation zones changed as the stimulation intensities increased until the supramaximal muscle response was achieved. SIGNIFICANCE: Results have demonstrated the high performance of the proposed imaging technique in noninvasively imaging global distributions of the innervation zones in the three-dimensional muscle space in vivo, and the feasibility of its clinical applications, such as guiding botulinum toxin injections in spasticity management, or in early diagnosis of neurodegenerative progression of amyotrophic lateral sclerosis. PMID- 28358720 TI - Synthesis, characterization, and photoluminescence of Er2O3-Er2SO2 nanoparticles on reduced graphene oxide. AB - Thermal reduction of erbium nitrate and S-doped reduced graphene oxide (rGO) mixture resulted in the formation of small (~3-18 nm sized) Er2O3-Er2SO2 nanoparticles with a high degree of surface coverage on the reduced GO support. The morphology, structure, and the chemical composition of the synthesized nanoparticles have been studied by scanning and transmission electron microscopy, x-ray photoelectron spectroscopy, x-ray diffraction, and by optical spectroscopies. The rGO-supported Er2O3-Er2SO2 nanoparticles (Er2O3-Er2SO2/rGO) demonstrate sufficiently strong light emission (luminescence and upconversion) in the visible and near-infrared range via intra-4f Er3+ optical transitions. The reported synthetic approach demonstrates a novel method for synthesizing Er containing nanoparticles for sensor applications. PMID- 28358721 TI - Cavity theory applications for kilovoltage cellular dosimetry. AB - Relationships between macroscopic (bulk tissue) and microscopic (cellular) dose descriptors are investigated using cavity theory and Monte Carlo (MC) simulations. Small, large, and multiple intermediate cavity theory (SCT, LCT, and ICT, respectively) approaches are considered for 20 to 370 keV incident photons; ICT is a sum of SCT and LCT contributions weighted by parameter d. Considering MUm-sized cavities of water in bulk tissue phantoms, different cavity theory approaches are evaluated via comparison of [Formula: see text] (where D w,m is dose-to-water-in-medium and D m,m is dose-to-medium-in-medium) with MC results. The best overall agreement is achieved with an ICT approach in which [Formula: see text], where L is the mean chord length of the cavity and beta is given by [Formula: see text] (R CSDA is the continuous slowing down approximation range of an electron of energy equal to that of incident photons). Cell nucleus doses, D nuc, computed with this ICT approach are compared with those from MC simulations involving multicellular soft tissue models considering a representative range of cell/nucleus sizes and elemental compositions. In [Formula: see text] of cases, ICT and MC predictions agree within [Formula: see text]; disagreement is at most 8.8%. These results suggest that cavity theory may be useful for linking doses from model-based dose calculation algorithms (MBDCAs) with energy deposition in cellular targets. Finally, based on the suggestion that clusters of water molecules associated with DNA are important radiobiological targets, two approaches for estimating dose-to-water by application of SCT to MC results for D m,m or D nuc are compared. Results for these two estimates differ by up to [Formula: see text], demonstrating the sensitivity of energy deposition within a small volume of water in nucleus to the geometry and composition of its surroundings. In terms of the debate over the dose specification medium for MBDCAs, these results do not support conversion of D m,m to D w,m using SCT. PMID- 28358723 TI - Synthesis of MoS2/graphene hybrid supported Au and Ag nanoparticles with multi functional catalytic properties. AB - The detection and removal of nitroaromatic compounds is an important issue for environmental protection. In this study, a hybrid of molybdenum disulfide (MoS2) and graphene (GR) was first synthesized using a facile hydrothermal method. Au and Ag nanoparticles were then deposited onto the surface of the MoS2/GR hybrid with sodium citrate as the stabilizer and reductant. Compared to using pure MoS2 as the support, the obtained Au (Ag)-MoS2/GR composites showed improved activity for electrochemical detection and chemical reduction of 4-nitrophenol. The activity enhancement appears to be due to the addition of GR, which could improve the conductivity as well as provide more active sites. The successful synthesis of Au (Ag)-MoS2/GR composites could provide new multi-function catalysts for environmental protection. PMID- 28358722 TI - BGO as a hybrid scintillator / Cherenkov radiator for cost-effective time-of flight PET. AB - Due to detector developments in the last decade, the time-of-flight (TOF) method is now commonly used to improve the quality of positron emission tomography (PET) images. Clinical TOF-PET systems based on L(Y)SO:Ce crystals and silicon photomultipliers (SiPMs) with coincidence resolving times (CRT) between 325 ps and 400 ps FWHM have recently been developed. Before the introduction of L(Y)SO:Ce, BGO was used in many PET systems. In addition to a lower price, BGO offers a superior attenuation coefficient and a higher photoelectric fraction than L(Y)SO:Ce. However, BGO is generally considered an inferior TOF-PET scintillator. In recent years, TOF-PET detectors based on the Cherenkov effect have been proposed. However, the low Cherenkov photon yield in the order of ~10 photons per event complicates energy discrimination-a severe disadvantage in clinical PET. The optical characteristics of BGO, in particular its high transparency down to 310 nm and its high refractive index of ~2.15, are expected to make it a good Cherenkov radiator. Here, we study the feasibility of combining event timing based on Cherenkov emission with energy discrimination based on scintillation in BGO, as a potential approach towards a cost-effective TOF-PET detector. Rise time measurements were performed using a time-correlated single photon counting (TCSPC) setup implemented on a digital photon counter (DPC) array, revealing a prompt luminescent component likely to be due to Cherenkov emission. Coincidence timing measurements were performed using BGO crystals with a cross-section of 3 mm * 3 mm and five different lengths between 3 mm and 20 mm, coupled to DPC arrays. Non-Gaussian coincidence spectra with a FWHM of 200 ps were obtained with the 27 mm3 BGO cubes, while FWHM values as good as 330 ps were achieved with the 20 mm long crystals. The FWHM value was found to improve with decreasing temperature, while the FWTM value showed the opposite trend. PMID- 28358724 TI - Nanoselective area growth of defect-free thick indium-rich InGaN nanostructures on sacrificial ZnO templates. AB - Nanoselective area growth (NSAG) by metal organic vapor phase epitaxy of high quality InGaN nanopyramids on GaN-coated ZnO/c-sapphire is reported. Nanopyramids grown on epitaxial low-temperature GaN-on-ZnO are uniform and appear to be single crystalline, as well as free of dislocations and V-pits. They are also indium rich (with homogeneous 22% indium incorporation) and relatively thick (100 nm). These properties make them comparable to nanostructures grown on GaN and AlN/Si templates, in terms of crystallinity, quality, morphology, chemical composition and thickness. Moreover, the ability to selectively etch away the ZnO allows for the potential lift-off and transfer of the InGaN/GaN nanopyramids onto alternative substrates, e.g. cheaper and/or flexible. This technology offers an attractive alternative to NSAG on AlN/Si as a platform for the fabrication of high quality, thick and indium-rich InGaN monocrystals suitable for cheap, flexible and tunable light-emitting diodes. PMID- 28358725 TI - Electron beam induced etching of carbon nanotubes enhanced by secondary electrons in oxygen. AB - Multi-walled carbon nanotubes (CNTs) are subjected to electron-beam-induced etching (EBIE) in oxygen. The EBIE process is observed in situ by environmental transmission electron microscopy. The partial pressure of oxygen (10 and 100 Pa), energy of the primary electrons (80 and 200 keV), and environment of the CNTs (suspended or supported on a silicon nitride membrane) are investigated as factors affecting the etching rate. The EBIE rate of CNTs was markedly promoted by the effects of secondary electrons that were emitted from a silicon nitride membrane under irradiation by primary electrons. Membrane supported CNTs can be cut by EBIE with a spatial accuracy better than 3 nm, and a nanogap of 2 nm can be successfully achieved between the ends of two suspended CNTs. PMID- 28358726 TI - Local delivery of thyroid hormone enhances oligodendrogenesis and myelination after spinal cord injury. AB - OBJECTIVE: Traumatic spinal cord injury (SCI) causes apoptosis of myelin-forming oligodendrocytes (OLs) and demyelination of surviving axons, resulting in conduction failure. Remyelination of surviving denuded axons provides a promising therapeutic target for spinal cord repair. While cell transplantation has demonstrated efficacy in promoting remyelination and functional recovery, the lack of ideal cell sources presents a major obstacle to clinical application. The adult spinal cord contains oligodendrocyte precursor cells and multipotent neural stem/progenitor cells that have the capacity to differentiate into mature, myelinating OLs. However, endogenous oligodendrogenesis and remyelination processes are limited by the upregulation of remyelination-inhibitory molecules in the post-injury microenvironment. Multiple growth factors/molecules have been shown to promote OL differentiation and myelination. APPROACH: In this study we screened these therapeutics and found that 3, 3', 5-triiodothyronine (T3) is the most effective in promoting oligodendrogenesis and OL maturation in vitro. However, systemic administration of T3 to achieve therapeutic doses in the injured spinal cord is likely to induce hyperthyroidism, resulting in serious side effects. MAIN RESULTS: In this study we developed a novel hydrogel-based drug delivery system for local delivery of T3 to the injury site without eliciting systemic toxicity. SIGNIFICANCE: Using a clinically relevant cervical contusion injury model, we demonstrate that local delivery of T3 at doses comparable to safe human doses promoted new mature OL formation and myelination after SCI. PMID- 28358727 TI - Salvage Islet Auto Transplantation After Relaparatomy. AB - BACKGROUND: To assess feasibility, safety, and metabolic outcome of islet auto transplantation (IAT) in patients undergoing completion pancreatectomy because of sepsis or bleeding after pancreatic surgery. METHODS: From November 2008 to October 2016, approximately 22 patients were candidates to salvage IAT during emergency relaparotomy because of postpancreatectomy sepsis (n = 11) or bleeding (n = 11). Feasibility, efficacy, and safety of salvage IAT were compared with those documented in a cohort of 36 patients who were candidate to simultaneous IAT during nonemergency preemptive completion pancreatectomy through the pancreaticoduodenectomy. RESULTS: The percentage of candidates that received the infusion of islets was significantly lower in salvage IAT than simultaneous IAT (59.1% vs 88.9%, P = 0.008), mainly because of a higher rate of inadequate islet preparations. Even if microbial contamination of islet preparation was significantly higher in candidates to salvage IAT than in those to simultaneous IAT (78.9% vs 20%, P < 0.001), there was no evidence of a higher rate of complications related to the procedure. Median follow-up was 5.45 +/- 0.52 years. Four (36%) of 11 patients reached insulin independence, 6 patients (56%) had partial graft function, and 1 patient (9%) had primary graft nonfunction. At the last follow-up visit, median fasting C-peptide was 0.43 (0.19-0.93) ng/mL; median insulin requirement was 0.38 (0.04-0.5) U/kg per day, and median HbA1c was 6.6% (5.9%-8.1%). Overall mortality, in-hospital mortality, metabolic outcome, graft survival, and insulin-free survival after salvage IAT were not different from those documented after simultaneous IAT. CONCLUSIONS: Our data demonstrate the feasibility, efficacy, and safety of salvage IAT after relaparotomy. PMID- 28358730 TI - Individualized antiretroviral therapeutic approaches: less can be more. PMID- 28358729 TI - Detection of HIV RNA in dried blood spots and oral fluids. AB - : We evaluated detection of HIV-1 RNA from dried blood spots (DBS) and oral fluid specimens. Between February 2010 and August 2014, HIV-1 was newly diagnosed in eight (2.6%) study participants who had median blood HIV-1 RNA of 61 500 copies/ml (interquartile range 7500-146 000). RNA was detected in seven (87.5%) DBS and three (37.5%) oral fluid swabs but was not detected in either specimen from one participant. DBS may be a reasonable specimen collection method to detect acute infection. PMID- 28358731 TI - Major health impact of accelerated aging in young HIV-infected individuals on antiretroviral therapy. AB - BACKGROUND: Aging among HIV-infected individuals on antiretroviral therapy (ART) is a significant clinical challenge; however, studies assessing multidimensional aspects of aging are lacking. We characterized 10 geriatric conditions encompassing multiple functional domains, its health impact and associated risk factors in HIV-infected and age-matched uninfected controls. METHODS: HIV infected individuals were recruited from the outpatient clinic in University Malaya Medical Centre, Malaysia and controls from the community. All participants were aged at least 25 years of age with no acute illness, and HIV-infected individuals were on stable ART. Geriatric conditions were assessed and the burden scored as a composite of geriatric conditions present in an individual (total score = 10). Multivariate regression analysis was performed to determine the risk factors and health impact associated with the burden of geriatric conditions. RESULTS: We analyzed data from 336 HIV-infected individuals (total HIV+), of whom 172 were matched for age, sex, and ethnicity with 172 HIV-uninfected controls (matched subset). In the total HIV-positive cohort, median (interquartile range) age was 44 (38-51) years and CD4 T-cell count was 562 (398-737) cells/MUl. The burden of geriatric conditions was significantly higher in the HIV-infected group compared with controls (P < 0.001). With an increasing geriatric condition burden, quality-of-life scores were 2.2-times poorer, healthcare use five times greater, and mortality risk scores four times higher in the HIV-infected group compared with matched controls. Both sociobehavioural and HIV-related clinical factors were independently associated with an increasing burden of geriatric condition in HIV. CONCLUSIONS: A high burden of geriatric conditions with significant impact on health outcomes, including mortality risk scores are observed among HIV-infected individuals on ART in a resource-limited setting. PMID- 28358733 TI - Plasma dickkopf-related protein 1, an antagonist of the Wnt pathway, is associated with HIV-associated neurocognitive impairment. AB - OBJECTIVE: Dickkopf-related protein 1 (DKK1) is a soluble antagonist of the Wningless (Wnt) pathway. It binds to and sequesters low-density lipoprotein receptor-related proteins 5/6 away from Wnts. Because the Wnt pathway regulates synaptic transmission and plasticity, we hypothesized that increased DKK1 would increase the risk for neurocognitive impairment (NCI) in HIV-positive (HIV) individuals. We evaluated, here, the relationship between plasma DKK1 and global NCI. METHODS: Plasma samples and data from 41 HIV to 42 HIV adults were obtained from the University of California, San Diego, California, USA. Concentrations of DKK1 and a comparator protein, monocyte chemoattractant protein-1 (MCP-1), were quantified in plasma by immunoassay. All study participants completed a standardized comprehensive neuropsychological test battery and their performance was summarized using the global deficit score method. RESULTS: A higher DKK1 level was associated with NCI among HIV participants (d = 0.63, P = 0.05), particularly among the 26 participants whose plasma HIV RNA level was suppressed (d = 0.74, P = 0.08). DKK1 level was not associated with NCI among HIV participants (P = 0.98). was not associated with NCI in either group. In HIV adults with suppressed plasma HIV RNA, a receiver operator characteristic curve identified that a DKK1 level of at least 735 pg/ml had a positive predictive value of 83.3% for a diagnosis of NCI. This association did not weaken after accounting for the effect of AIDS, nadir CD4 T-cell count, addictive drug use, or demographic characteristics. CONCLUSION: DKK1 is a specific biomarker for NCI in HIV adults, implicating the Wnt pathway in HIV neuropathogenesis. PMID- 28358736 TI - HIV type 2 epidemic in Spain: challenges and missing opportunities. AB - : HIV type 2 (HIV-2) is a neglected virus despite estimates of 1-2 million people infected worldwide. HIV-2 is less efficiently transmitted than HIV-1 by sex and from mother to child. Although AIDS may develop in HIV-2 carriers, it takes longer than in HIV-1-infected patients. In contrast with HIV-1 infection, there is no global pandemic caused by HIV-2, as the virus is largely confined to West Africa. In a less extent and due to socioeconomic ties and wars, HIV-2 is prevalent in Portugal and its former colonies in Brazil, India, Mozambique and Angola. Globally, HIV-2 infections are steadily declining over time. A total of 338 cases of HIV-2 infection had been reported at the Spanish HIV-2 registry until December 2016, of whom 63% were men. Overall 72% were sub-Saharan Africans, whereas 16% were native Spaniards. Dual HIV-1 and HIV-2 coinfection was found in 9% of patients. Heterosexual contact was the most likely route of HIV-2 acquisition in more than 90% of cases. Roughly one-third presented with CD4 cell counts less than 200 cells/MUl and/or AIDS clinical events. Plasma HIV-2 RNA was undetectable at baseline in 40% of patients. To date, one-third of HIV-2 carriers have received antiretroviral therapy, using integrase inhibitors 32 individuals. New diagnoses of HIV-2 in Spain have remained stable since 2010 with an average of 15 cases yearly. Illegal immigration from Northwestern African borders accounts for over 75% of new HIV-2 diagnoses. Given the relatively large community of West Africans already living in Spain and the continuous flux of immigration from endemic regions, HIV-2 infection either alone or as coinfection with HIV-1 should be excluded once in all HIV-seroreactive persons, especially when showing atypical HIV serological profiles, immunovirological disconnect (CD4 cell count loss despite undetectable HIV-1 viremia) and/or high epidemiological risks (birth in or sex partners from endemic regions). PMID- 28358734 TI - Intracellular HIV-1 RNA and CD4+ T-cell activation in patients starting antiretrovirals. AB - OBJECTIVE: To assess if the reduction in HIV-1 RNA in CD4 T cells is correlated with the persistence of immune activation following early antiretroviral therapy (ART). DESIGN: Clinical trial (NCT01285050). METHODS: Next-generation sequencing was used to study total RNA from activated CD4 T cells (CD38 and human leukocyte antigen - antigen D related (HLA-DR) expressing) collected from 19 treatment naive HIV-1/hepatitis C virus-infected patients before and early after ART initiation (>=12 weeks after plasma HIV-1 RNA <50 copies/ml). To validate comparisons, pre and post-ART measures were adjusted for input RNA and overall read number. RESULTS: As expected, ART use was associated with a median [interquartile range (IQR)] 4.3% (2.2-8.3) reduction in the proportion of activated CD4 T cells (P = 0.0008). Whereas in those activated CD4 T cells no consistent differences in overall gene expression were detected, interferon stimulated gene expression declined (P < 2 * 10). Pre-ART, sorted activated CD4 T cells contained a median (IQR) of 959 (252-1614) HIV-1 reads/10 reads compared with 72 (55-152) HIV-1 reads/10 reads after at least 12 weeks of suppressive ART (P = 8 * 10). The decrease in HIV-1 reads in activated CD4 T cells was associated with the change in plasma HIV-1 RNA levels (r = 0.77, P = 2 * 10) and the change in the proportion of activated CD4 T cells (r = 0.70, P = 0.0016). CONCLUSION: Months of ART led to a marked decrease in cell-associated HIV-1 RNA and interferon-stimulated genes expression in activated CD4 T cells that were strongly associated with the reduction in the proportion of activated CD4 T cells. PMID- 28358738 TI - alpha7-Nicotinic acetylcholine receptor inhibition by indinavir: implications for cognitive dysfunction in treated HIV disease. AB - OBJECTIVE: The study set out to determine if the HIV protease inhibitor, indinavir, alters responsiveness of alpha7-nicotinic acetylcholine receptors to acetylcholine. DESIGN: Treatment with HAART has dramatically reduced development of HIV-associated dementia and more severe forms of cognitive impairment. However, many individuals continue to experience cognitive decline of uncertain cause. Previous studies have failed to demonstrate significant alterations of functional brain connectivity, structural brain changes, or changes in cerebral blood flow sufficient to explain cognitive decline in virally suppressed individuals. This suggests that the mechanisms underlying development and progression of cognitive problems likely occurs at a micro rather than macro level, such as disruptions in neurotransmitter system signaling. MATERIALS AND METHODS: Indinavir's effects on alpha7-nicotinic acetylcholine receptor activity was tested using a ScreenPatch IonWorks Barracuda-based assay in a mammalian cell model. RESULTS: At low concentrations (0.0003-10 MUmol/l) indinavir acts as a positive allosteric modulator (EC50 = 0.021 MUmol/l), whereas at concentrations greater than 10 MUmol/l (30-100 MUmol/l) indinavir acts as an inhibitor of the alpha7-nicotinic acetylcholine receptor. CONCLUSION: At concentrations greater than 10 MUmol/l indinavir reduces synaptic transmission in the acetylcholine neurotransmitter system, which could possibly contribute to cognitive dysfunction. These results suggest that further experiments should be considered to assess whether patients might benefit from treatment with cholinesterase inhibitors that counteract the effects of indinavir. PMID- 28358737 TI - Delay in sexual maturation in perinatally HIV-infected youths is mediated by poor growth. AB - OBJECTIVE: To evaluate the association between HIV infection and sexual maturation, and mediation of this association by HIV effects on growth. DESIGN: Pooled data were analyzed from two longitudinal cohort studies, the International Maternal Pediatric Adolescent AIDS Clinical Trials P219/219C Study (1993-2007) and the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol (2007-2015), including perinatally HIV-infected (PHIV) and HIV-exposed uninfected (PHEU) youths. METHODS: We evaluated age at sexual maturity among 2539 PHIV and PHEU adolescents based on annual physician-assessed pubertal staging measures. Interval-censored regression models were used to evaluate associations of HIV infection with age at maturity. Mediation analyses accounting for height and BMI Z-scores at specific ages were used to estimate direct and indirect effects of HIV infection on age at sexual maturity. RESULTS: Mean ages at sexual maturity for PHIV girls (n = 1032) were 15.5 years for both female breast and pubic hair and 15.9 and 15.8 years for PHIV boys (n = 1054) for genitalia and pubic hair, respectively. PHIV youths matured approximately 6 months later on average than PHEU (n = 221 girls and 232 boys), and this difference persisted after adjustment for race/ethnicity and birth cohort. BMI and height Z-scores mediated the association between HIV infection and later maturation in girls, accounting for up to 74% of the total HIV effect. Only height Z-scores mediated the effect of HIV on male age at maturity, accounting for up to 98% of the HIV effect. CONCLUSION: PHIV youths attain sexual maturity later on average than PHEU youths. Much of this difference may be attributable to deficient growth, suggesting directions for future interventions. PMID- 28358741 TI - Novel genetic associations and gene-gene interactions of chemokine receptor and chemokine genetic polymorphisms in HIV/AIDS. AB - OBJECTIVE: To investigate the influence of candidate polymorphisms on chemokine receptor/ligand genes on HIV infection and AIDS progression (HIV/AIDS). DESIGN: Fifteen polymorphisms of the CCR3, CCR4, CCR5, CCR6, CCR8, CXCR3, CXCR6, CCL20, CCL22 and CXCL10 genes were analysed in 206 HIV-positive patients classified as rapid progressors (n = 40), or nonrapid progressors (n = 166), and in 294 HIV seronegative patients. METHODS: The polymorphisms were genotyped using minisequencing. Genetic models were tested using binomial logistic regression; nonparametric multifactor dimensionality reduction (MDR) was used to detect gene gene interactions. RESULTS: The CCR3 rs3091250 [TT, adjusted odds ratio (AOR): 2.147, 95% confidence interval (CI) 1.076-4.287, P = 0.030], CCR8 rs2853699 (GC/CC, AOR: 1.577, 95% CI 1.049-2.371, P = 0.029), CXCL10 rs56061981 (CT/TT, AOR: 1.819, 95% CI 1.074-3.081, P = 0.026) and CCL22 rs4359426 (CA/AA, AOR: 1.887, 95% CI 1.021-3.487, P = 0.043) polymorphisms were associated with susceptibility to HIV infection. The CCL20 rs13034664 (CC, OR: 0.214, 95% CI 0.063-0.730, P = 0.014) and CCL22 rs4359426 (CA/AA, OR: 2.685, 95% CI 1.128 6.392, P = 0.026) variants were associated with rapid progression to AIDS. In MDR analyses revealed that the CXCL10 rs56061981 and CCL22 rs4359426 combination was the best model, with 57% accuracy (P = 0.008) for predicting susceptibility to HIV infection. CONCLUSION: Our results provide new insights into the influence of candidate chemokine receptor/ligand polymorphisms and significant evidence for gene-gene interactions on HIV/AIDS susceptibility. PMID- 28358744 TI - SHORT-TERM OUTCOMES OF HYBRID 23-, 25-, AND 27-GAUGE VITRECTOMY FOR COMPLEX DIABETIC TRACTIONAL RETINAL DETACHMENT REPAIR. AB - PURPOSE: To describe the short-term outcomes of complex diabetic retinal detachment repair using hybrid 23-gauge or 25-gauge vitrectomy instruments with a 27-gauge vitrectomy system. METHODS: Retrospective, interventional, consecutive case series. Ten eyes of 10 patients undergoing hybrid pars plana vitrectomy for diabetic tractional retinal detachment were reviewed. RESULTS: Combined use of 25 gauge and 27-gauge instrumentation was used in 8 of 10 eyes and combined use of 23-gauge and 27-gauge instrumentation in 2 of 10 eyes. In all cases, a 27-gauge vitreous cutter was used for membrane dissection and delamination. All eyes had successful anatomical reattachment at a mean follow-up of 207 +/- 55 days. Snellen visual acuity improved from a mean of 20/822 preoperatively to 20/566 at the final follow-up (P = 0.55). Mean intraocular pressure remained stable at 13 +/- 3.4 mmHg preoperatively to 13.6 +/- 5.4 mmHg at the final follow-up (P = 0.76). No intraoperative or postoperative complications were encountered. CONCLUSION: Concurrent use of the 27-gauge vitreous cutter with 23-gauge or 25 gauge instrumentation was effective during diabetic tractional retinal detachment repair. This hybrid technique was not associated with any significant intraoperative or short-term postoperative complications. PMID- 28358742 TI - Similar effectiveness of direct-acting antiviral against hepatitis C virus in patients with and without HIV infection. AB - OBJECTIVE: We compared the baseline characteristics, effectiveness, and tolerance of direct-acting antiviral drug (DAA)-based regimens taken by hepatitis C virus (HCV)-monoinfected and HCV/HIV-coinfected individuals in clinical practice. DESIGN: We performed a prospective observational study in two tertiary centres in Madrid, Spain, which included all HCV-monoinfected and HCV/HIV-coinfected patients undergoing HCV treatment with all-oral DAA regimens in a routine clinical setting, from April 2015 to November 2015. We evaluated sustained virological response 12 weeks after the end of therapy (SVR12), adverse events, and baseline and treatment characteristics. RESULTS: The study population comprised 1634 patients: 1152 HCV-monoinfected patients (70%) and 482 HCV/HIV coinfected patients (30%). Fifty percent had cirrhosis, and 47% were peginterferon/ribavirin-experienced. HCV/HIV-coinfected patients were younger [median age (interquartile range) 51 (48-54) years vs. 59 (50-68) years; P < 0.001), more frequently male (76 vs. 54%; P < 0.001), and infected with genotypes 1a (37 vs. 17%; P < 0.001), 3 (15 vs. 7%; P < 0.001), and 4 (23 vs. 4%; P < 0.001). One of every three patients took ribavirin. SVR12 was 94% (95% confidence interval 91.7-96%) and 97% (95% confidence interval 95.7-99.4%) in coinfected and monoinfected patients, respectively, with no significant differences between the groups after adjustment for cirrhosis, genotype, and DAA combination. DAA-based regimens were well tolerated, and only 1% of patients had severe adverse events, with no differences between the populations. CONCLUSIONS: HCV/HIV-infected patients treated with all-oral DAA combinations achieved high rates of SVR12 that were similar to those of HCV-monoinfected patients under real-life conditions. Safety and tolerance were excellent, even in patients with end-stage liver disease. PMID- 28358743 TI - MASSIVE SUBRETINAL GAS AFTER VITRECTOMY SURGERY: MECHANISM AND MANAGEMENT. AB - PURPOSE: To describe the complication of subretinal gas after pars plana vitrectomy for rhegmatogenous retinal detachment, as well as its management. METHODS: The presence of subretinal gas was noted on postoperative Day 1 after pars plana vitrectomy for a chronic rhegmatogenous retinal detachment. Resolution of subretinal gas was facilitated by an infusion line and external sclerotomy to expand the vitreous cavity. Residual subretinal gas was removed through a posterior retinotomy after fluid-air exchange. RESULTS: This technique resulted in the successful evacuation of subretinal gas, allowing for chorioretinal adhesion and reattachment of the retina. CONCLUSION: Subretinal gas can rarely occur after pars plana vitrectomy for rhegmatogenous retinal detachment. This complication can be successfully managed by way of external drainage, followed by evacuation of residual gas through fluid-air exchange and posterior retinotomy. PMID- 28358745 TI - STENOTROPHOMONAS MALTOPHILIA ENDOPHTHALMITIS 1 MONTH AFTER INTRAVITREAL AFLIBERCEPT. AB - PURPOSE: Endophthalmitis caused by Stenotrophomonas maltophilia is rare and has been described after cataract surgery and open globe injuries. We report a patient with endophthalmitis caused by this organism after uncomplicated intravitreal aflibercept injection. METHODS: A 70-year-old man with a history of anti-vascular endothelial growth factor therapy for diabetic macular edema presented 23 days after aflibercept injection with clinical diagnosis of endophthalmitis. The patient initially had mild pain, conjunctival congestion, and anterior chamber cell; 2 days later, the patient returned with hand motion visual acuity, hypopyon, and dense vitritis. RESULTS: A tap and inject procedure was performed. The aqueous sample confirmed the presence of S. maltophilia. Antimicrobial testing showed susceptibility to ceftazidime which was used during the initial treatment. After resolution of the vitritis and hypopyon, the visual acuity returned to 20/70 at his 3-month follow-up examination. CONCLUSION: Stenotrophomonas maltophilia is a rare infectious agent associated with intravitreal injection and may present 1 month after treatment. PMID- 28358746 TI - SOLITARY RETINAL CAPILLARY HEMANGIOMA IN A PATIENT WITH BILATERAL CHORIORETINAL COLOBOMA. AB - PURPOSE: To report a case showing a very rare association of chorioretinal coloboma and retinal capillary hemangioma in a previously healthy patient. METHODS: Observational case report. RESULTS: A 21-year-old woman presented at our clinic for vision screening. She had a history of bilateral chorioretinal coloboma with amblyopia in her left eye. Her best-corrected visual acuity was 20/25 in her right eye and 20/200 in her left eye. On slit-lamp examination, iris coloboma was observed in the left eye. Fundus evaluation showed inferior chorioretinal coloboma in both eyes, and an elevated, round, and orange-red retinal lesion with feeder vessels localized in the midperipheral region of the right eye. The patient was diagnosed as having solitary retinal capillary hemangioma and underwent argon laser therapy for treating the tumoral lesion. Diagnostic studies were negative for von Hippel-Lindau disease. This is the first reported case of solitary retinal capillary hemangioma associated with bilateral chorioretinal coloboma. CONCLUSION: Chorioretinal coloboma is a congenital defect of the eye caused by improper closure of the embryonic fissure. Retinal capillary hemangioma is a vascular retinal tumor that may occur sporadically or as part of the von Hippel-Lindau syndrome. We report a rare association of chorioretinal coloboma and retinal capillary hemangioma in a previously healthy patient.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially. PMID- 28358747 TI - Binaural Interaction Effects of 30-50 Hz Auditory Steady State Responses. AB - OBJECTIVES: Auditory stimuli modulated by modulation frequencies within the 30 to 50 Hz region evoke auditory steady state responses (ASSRs) with high signal to noise ratios in adults, and can be used to determine the frequency-specific hearing thresholds of adults who are unable to give behavioral feedback reliably. To measure ASSRs as efficiently as possible a multiple stimulus paradigm can be used, stimulating both ears simultaneously. The response strength of 30 to 50Hz ASSRs is, however, affected when both ears are stimulated simultaneously. The aim of the present study is to gain insight in the measurement efficiency of 30 to 50 Hz ASSRs evoked with a 2-ear stimulation paradigm, by systematically investigating the binaural interaction effects of 30 to 50 Hz ASSRs in normal hearing adults. DESIGN: ASSRs were obtained with a 64-channel EEG system in 23 normal-hearing adults. All participants participated in one diotic, multiple dichotic, and multiple monaural conditions. Stimuli consisted of a modulated one octave noise band, centered at 1 kHz, and presented at 70 dB SPL. The diotic condition contained 40 Hz modulated stimuli presented to both ears. In the dichotic conditions, the modulation frequency of the left ear stimulus was kept constant at 40 Hz, while the stimulus at the right ear was either the unmodulated or modulated carrier. In case of the modulated carrier, the modulation frequency varied between 30 and 50 Hz in steps of 2 Hz across conditions. The monaural conditions consisted of all stimuli included in the diotic and dichotic conditions. RESULTS: Modulation frequencies >=36 Hz resulted in prominent ASSRs in all participants for the monaural conditions. A significant enhancement effect was observed (average: ~3 dB) in the diotic condition, whereas a significant reduction effect was observed in the dichotic conditions. There was no distinct effect of the temporal characteristics of the stimuli on the amount of reduction. The attenuation was in 33% of the cases >3 dB for ASSRs evoked with modulation frequencies >=40 Hz and 50% for ASSRs evoked with modulation frequencies <=36 Hz. CONCLUSIONS: Binaural interaction effects as observed in the diotic condition are similar to the binaural interaction effects of middle latency responses as reported in the literature, suggesting that these responses share a same underlying mechanism. Our data also indicated that 30 to 50 Hz ASSRs are attenuated when presented dichotically and that this attenuation is independent of the stimulus characteristics as used in the present study. These findings are important as they give insight in how binaural interaction affects the measurement efficiency. The 2-ear stimulation paradigm of the present study was, for the most optimal modulation frequencies (i.e., >=40 Hz), more efficient than a 1-ear sequential stimulation paradigm in 66% of the cases. PMID- 28358748 TI - Effect of Thoracic Epidural Anesthesia on Ventricular Excitability in a Porcine Model. AB - BACKGROUND: Imbalances in the autonomic nervous system, namely, excessive sympathoexcitation, contribute to ventricular tachyarrhythmias. While thoracic epidural anesthesia clinically suppresses ventricular tachyarrhythmias, its effects on global and regional ventricular electrophysiology and electrical wave stability have not been fully characterized. The authors hypothesized that thoracic epidural anesthesia attenuates myocardial excitability and the proarrhythmic effects of sympathetic hyperactivity. METHODS: Yorkshire pigs (n = 15) had an epidural catheter inserted (T1 to T4) and a 56-electrode sock placed on the heart. Myocardial excitability was measured by activation recovery interval, dispersion of repolarization, and action potential duration restitution at baseline and during programed ventricular extrastimulation or left stellate ganglion stimulation, before and 30 min after thoracic epidural anesthesia (0.25% bupivacaine). RESULTS: After thoracic epidural anesthesia infusion, there was no change in baseline activation recovery interval or dispersion of repolarization. During programmed ventricular extrastimulation, thoracic epidural anesthesia decreased the maximum slope of ventricular electrical restitution (0.70 +/- 0.24 vs. 0.89 +/- 0.24; P = 0.021) reflecting improved electrical wave stability. Thoracic epidural anesthesia also reduced myocardial excitability during left stellate ganglion stimulation-induced sympathoexcitation through attenuated shortening of activation recovery interval (-7 +/- 4% vs. -4 +/- 3%; P = 0.001), suppression of the increase in dispersion of repolarization (313 +/- 293% vs. 185 +/- 234%; P = 0.029), and reduction in sympathovagal imbalance as measured by heart rate variability. CONCLUSIONS: Our study describes the electrophysiologic mechanisms underlying antiarrhythmic effects of thoracic epidural anesthesia during sympathetic hyperactivity. Thoracic epidural anesthesia attenuates ventricular myocardial excitability and induces electrical wave stability through its effects on activation recovery interval, dispersion of repolarization, and the action potential duration restitution slope. PMID- 28358749 TI - Lost in Translation: The 2016 John W. Severinghaus Lecture on Translational Research. PMID- 28358750 TI - BIRD ATTACK OCULAR INJURIES. AB - BACKGROUND/PURPOSE: To report 30 patients with bird attack-related eye injuries. METHODS: This study was performed among patients coming to Farabi Eye Hospital, Tehran, Iran, from 2010 to 2015 with a history of bird attack causing eye injury. The inclusion criteria were a history of bird attack by pecking causing eye injury and having treatment and follow-up record for at least 6 months after treatment. The primary eye examinations included a full ophthalmic examination including evaluation of uncorrected visual acuity and best-corrected visual acuity (BCVA), anterior segment slit lamp biomicroscopy, and photography. For all patients with penetrating injury, primary repair was undertaken. RESULTS: Thirty patients (10 females and 20 males) with a mean age of 23.3 +/- 18.5 years entered the study. The most common zone of injury was zone 1 (P < 0.001), and lensectomy was not needed in majority of patients (P < 0.001). The most common bird causing the injury was mynah (P < 0.001). Those patients with baseline BCVA of less than 20/200 or those with endophthalmitis had statistically worse final BCVA after treatment. Patients attacked by mynah bird had significantly better pretreatment uncorrected visual acuity and BCVA. CONCLUSION: The most common bird causing the eye injury among the sample of patients from Iran was mynah, which differs with previous studies indicating the rooster attack as the most common cause of eye injury. The authors also found that the most common zone of injury was zone 1, and the presence of endophthalmitis and lower baseline BCVA were significant risk factors for worse visual outcomes. PMID- 28358751 TI - 27-GAUGE VITRECTOMY WOUND INTEGRITY: A Randomized Pilot Study Comparing Angled Versus Straight Entry in Fluid-Filled Vitrectomized Eyes. AB - PURPOSE: To compare clinical outcomes using angled versus straight trocar insertion during 27-gauge pars plana vitrectomy for epiretinal membrane. METHODS: Pilot randomized controlled trial. Thirty eyes of 30 patients undergoing 27-gauge pars plana vitrectomy with membrane peeling for epiretinal membrane were randomized 1:1 to receive angled or straight trocar insertion. Intraocular pressure (IOP) and postoperative wound-related complications were compared. RESULTS: Fifteen eyes were randomized to each the angled and straight incision groups. No significant difference in phakic status (P = 0.71) or preoperative IOP (15.1 +/- 3.4 vs. 14.6 +/- 3.0 mmHg, P = 0.67) existed between groups. On postoperative Day 1, eyes in the straight group had lower IOP compared with the angled group (11.8 +/- 3.9 vs. 15.3 +/- 5.2 mmHg, P = 0.04) and a relative decrease in IOP compared with preoperative values (11.8 +/- 3.9 vs. 15.1 +/- 3.4 mmHg, P < 0.01). No IOP difference between groups was present at Day 7 (P = 0.43) or Day 30 (P = 0.42). Postoperative complications included transient hypotony (1 eye, straight group) and serous choroidal detachment (1 eye, angled group). CONCLUSION: Eyes with straight incisions had transiently lower IOP on postoperative Day 1, possibly suggestive of subclinical wound leak in the very early postoperative period. Overall, rates of hypotony and sclerotomy-related complications were similarly low between wound construction strategies. PMID- 28358753 TI - Reply. PMID- 28358752 TI - Correspondence. PMID- 28358756 TI - Goddess of Imagination. PMID- 28358755 TI - Patients' Knowledge and Attitudes Towards Regular Alcohol Urine Screening: A Survey Study. AB - BACKGROUND: Despite its wide implementation, there is a paucity of data supporting the effectiveness of regular alcohol urine screening (RAUS) in maintaining abstinence. This study aims at investigating if RAUS serves other purposes, what attitudes patients display towards it, and patients' technical knowledge about basic screening notions. METHOD: We conducted a cross-sectional survey among adults with alcohol dependence, attending outpatient alcohol dependence treatment. It aimed at investigating patients' attitudes and beliefs towards RAUS, and technical notions of alcohol urine screening. For attitude assessment, we adapted the Drug Attitude Inventory (DAI-10) to the field of alcohol urine screening. Internal consistency, test-retest reliability, and concurrent validity were evaluated for the adapted questionnaire. RESULTS: In all, 128 patients completed the questionnaire. Patients rated RAUS as high. The DAI-10 mean score was 7.2 (SD = 3.6). Internal consistency analysis revealed a Cronbach alpha of 0.718. Test-retest reliability evaluation yielded an intraclass correlation coefficient of 0.932. The score of a single Likert-type question about overall perceived value was 8.5 (SD = 2). Their correlation with mean DAI 10 score was of r = 0.254, with P = 0.009. Apart from relapse prevention, patients frequently reported other functions such as showing professionals and family members that they do not drink, or having a closer contact with professionals. A majority of patients believed alcohol use goes undetected after 48 hours from last ingestion. CONCLUSION: Regular alcohol screening is highly valued by alcohol outpatients. It seems that apart from relapse prevention, other functions related to therapeutic alliance building, social desirability, and impression management also play a key role. PMID- 28358754 TI - Open-label Study of Injectable Extended-release Naltrexone (XR-NTX) in Healthcare Professionals With Opioid Dependence. AB - OBJECTIVES: Healthcare professionals (HCPs) with opioid dependence are at risk for relapse and death, particularly in the first year of recovery; however, maintenance treatment with opioid agonists is controversial in this safety sensitive group. We evaluated long-term safety, tolerability, and treatment outcomes of injectable, intramuscular, extended-release naltrexone (XR-NTX) in opioid-dependent HCPs. METHODS: This single-arm, multisite, open-label study was conducted in opioid-dependent HCPs who had been detoxified from opioids for at least 2 weeks. Subjects received monthly XR-NTX injections for up to 24 months, combined with counseling via intensive outpatient substance abuse treatment programs. Assessments included monthly urine opioid drug tests and routine safety assessments, along with a trimonthly short form (36) Health Survey, opioid craving questionnaire, and Treatment Satisfaction Questionnaire for Medication. RESULTS: Of 49 opioid-dependent HCPs screened, 38 enrolled and received at least 1 XR-NTX injection. Most were female (n = 31) and nurses or nursing assistants (n = 30). More than half (n = 21; 55.3%) received at least 12 injections. Seven discontinued due to adverse events (3 anxiety, 2 headache, 1 injection-site mass, 1 derealization). None experienced relapses to opioid dependence necessitating detoxification, overdose, or death during treatment. At 24 months, mean opioid craving fell by 45.2%, and short form (36) mental component scores improved by 31.1% from baseline and approached normal levels. Of 22 unemployed subjects at baseline, 45.5% improved employment status at 24 months. CONCLUSIONS: Long-term (2 years) XR-NTX was associated with no new safety concerns, and, compared with shorter-term studies in the general population, similar or better rates of retention, opioid-negative urines, opioid craving reduction, mental health functional quality of life improvement, and re-employment. PMID- 28358758 TI - Idiopathic Sialolithiasis: Scalpel Versus Current Trends in Management. AB - Idiopathic sialolithiasis is one of the most common affliction of the salivary glands with the submandibular gland most frequently involved. The article discusses the occurrence and incidence of this condition with a review of different diagnostic and treatment modalities. In light of several advances to diagnose and treat sialolithiasis, a simple sialolithotomy for idiopathic submandibular gland sialolithiasis may prove to be a preferred treatment for selected patients as it remains a cost-effective and simple out-patient department procedure with minimal/no complications and a highly satisfactory outcome. For stones slightly proximal in the Wharton duct, a "dual" approach of milking the gland to bring the stone more distally followed by a sialolithotomy with a scalpel proves to be a quick and effective procedure. PMID- 28358759 TI - Salvage of a Necrotic Flap. AB - OBJECTIVE: To report the case of a 68-year-old woman with a skin basal cell carcinoma on the nasal dorsum. After excision, the soft tissue defect was reconstructed using a rectangular advancement flap. However, 2 days later skin necrosis was observed. This report was issued to advise how to avoid and manage skin necrosis after regional flap placement. METHODS: This is a retrospective study. RESULTS: Superficial skin necrosis recovered completely after proper medical management. CONCLUSIONS: When planning an advancement flap, care should be taken to design the flap properly and not to injure flap blood supply to avoid skin necrosis. In addition, surgeons should be aware of the difference between superficial and total flap necrosis. PMID- 28358760 TI - The Degree of Surgical Frontal Volume Correction in Metopic Synostosis Determines Long-Term Outcomes. AB - Metopic synostosis results in a keel-shaped forehead, reduced frontal intracranial volume (ICV), and lower frontal to total volume ratio. The ratio improves with cranioplasty, but at 3 years of age, the ratio is still not normalized when compared to that in normal children. The aim of the present study was to investigate whether a low frontal to total ICV ratio at 3 years of age was due to relapse or insufficient correction.All children surgically treated for metopic synostosis in combination with a spring at Sahlgrenska University Hospital with subsequent spring extraction between 2002 and 2008 (n = 20) were included. A MATLAB program was used to measure frontal and total ICV.Preoperatively, the frontal to total ICV ratio was 9.8 +/- 1.3% (mean +/- standard deviation). At spring removal, 6 months after cranioplasty, the ratio had increased to 11.8 +/- 2.4%. At 3 years of age, the ratio was 11.6 +/- 1.9%. In age-matched normal children, the ratio was 14.4 +/- 1.9% preoperatively, 15.3 +/- 2.2% at time of spring extraction, and 13.4 +/- 1.4% at 3 years of age.Cranioplasty thus improved the frontal to total ICV ratio, but did not normalize it. The ratio did not change from 6 months after the cranioplasty to 3 years of age. These results indicate that a more pronounced frontal volume correction during cranioplasty is necessary to achieve a normalized distribution of ICV in metopic synostosis. PMID- 28358762 TI - Craniosynostosis and Guanine Nucleotide-binding Protein Alpha Stimulating Mutation: Risk of Bleeding Diathesis and Circulatory Collapse in Patients Undergoing Cranial Vault Reconstruction. AB - Reconstruction of the craniosynostosis deformity is a relatively safe operation with low overall complication risks. Despite expected risk of significant blood loss, life-threatening bleeding is relatively rare, and there is a low incidence of reported deaths in the literature. Several modalities have been described for perioperative mitigation of blood loss and transfusion requirements. Due to the low overall risk of life-threatening bleeding and circulatory collapse, it is judicious that any potential causes of such unusual but potentially significant fatal bleeding complication be evaluated and reported to increase awareness for craniofacial surgeons treating these conditions. In this report and literature review, the authors present a highly unusual patient with significant bone bleeding and circulatory collapse in a metopic craniosynostosis patient with guanine nucleotide-binding protein alpha stimulating (GNAS) mutation; perform a literature review regarding bleeding diathesis in craniosynostosis patients with GNAS mutations; and suggest guidelines to potentially prevent mortality in such patients. PMID- 28358761 TI - Histomorphometric Comparison of Bone Regeneration in Critical-Sized Bone Defects Using Demineralized Bone Matrix, Platelet-Rich Fibrin, and Hyaluronic Acid as Bone Substitutes. AB - AIM: To compare bone regeneration in the critical-sized bone defects grafted with demineralized bone matrix, platelet-rich fibrin, and hyaluronic acid in rats. MATERIALS AND METHODS: Forty Wistar Albino rats allocated into 4 experimental groups: platelet-rich fibrin (PRF) group, noncross-linked hyaluronic acid gel (HA) group, demineralized bone matrix in putty form (DBM) group, and control group. A critical-sized defect of 8 mm was formed involving the sagittal suture for each rat under anesthetic induction. All animals were sacrificed at 21st day after surgery and histomorphometric parameters of total horizontal length (THL) and total vertical length (TVL) of newly produced bone and longest bone trabecula (LBT) were measured in the histologic slides. The difference between experimental groups for these parameters was analyzed. RESULTS: There was statistically significant difference in THL and LBT but not in TVL. Total horizontal length was significantly increased in DBM group compared with control and HA groups (P < 0.05). There was also statistically significant increase in THL in PRF group compared with control group (P < 0.05). Longest bone trabecula significantly increased in DBM group compared with HA group (P < 0.05). There was also statistically significant increase in HA group compared with control group (P < 0.05) and LBT significantly increased in PRF group compared with HA group (P < 0.05). CONCLUSION: The sole usage of HA does not effectively increase bone regeneration when compared with DBM and PRF. The DBM and PRF do not have superiority to each other in the bone regeneration while they are superior to HA. PMID- 28358763 TI - Whole Blood in Pediatric Craniofacial Reconstruction Surgery. AB - BACKGROUND: Pediatric complex cranial vault reconstruction (CCVR) surgery is often associated with significant blood loss and transfusion. The authors recently changed our transfusion practice during CCVR to using whole blood (WB) instead of reconstituted blood (RB). The aim of this study was to assess the impact of this practice change. Our hypothesis was that replacement with WB would be as effective as RB for the outcomes of total perioperative blood donor exposures (BDEs) and the incidence of laboratory evidence of postoperative coagulopathy. METHODS: The authors queried the Pediatric Craniofacial Surgery Perioperative Registry for children ages <=48 months from our institution who underwent CCVR and received either RB or WB. The primary outcomes of total perioperative BDEs and the incidence of laboratory evidence of postoperative coagulopathy were compared between the 2 cohorts. RESULTS: The query returned 59 subjects in the RB cohort and 52 subjects in the WB cohort. There were no significant differences in demographic variables between the 2 groups. Patients in the WB cohort were more likely to have <=1 BDEs when compared to the RB cohort (62% versus 39%, respectively, P = 0.02). There was no significant difference in the incidence of postoperative coagulation laboratory test abnormalities between the WB and RB cohorts (0% versus 3.4%, respectively, P = 0.50). CONCLUSION: There was no postoperative coagulopathy in the WB cohort. Whole blood was also associated with significantly fewer perioperative BDEs. Whole blood appears to be as effective as RB for replacement of blood loss in craniofacial surgery. PMID- 28358764 TI - A Thirty-Year Experience With Head and Neck Flap Reconstruction. AB - BACKGROUND: Head and neck (HN) defects after tumor extirpation can be challenging to repair. Historically, pedicled flaps were the mainstay for reconstruction, but recently, free tissue transfer has been preferred. This study compares patient characteristics and flap outcomes for HN defects over a 30-year period at the authors' institution. METHODS: Head and neck cancer patients receiving flap reconstruction from 1983 to 2013 were included. Records were reviewed for demographic and perioperative data. Flap complications were compared and statistical tests were 2-tailed with a significance level of 0.05. RESULTS: Eight hundred sixty-one patients fulfilled inclusion and exclusion criteria. Pedicled reconstruction predominated during early time-points (96.3% pedicled), compared with later years (69.5% free-tissue). Free flaps were associated with significantly longer operative times (643.5 versus 429.7 minutes, P<0.0001) and postoperative stays (16.89 versus 14.01 nights, P = 0.0005) and had higher rates of emergent reoperation, total flap loss, hematoma, and donor site morbidity. Previous irradiation did not affect major complication rate for either flap type. CONCLUSIONS: A shift from pedicled to free flaps for HN reconstruction occurred over the last 30 years. Free flaps had a higher complication profile in this cohort, which was largely accounted for by a higher return rate to the operating room compared with pedicled flaps (17.31% versus 5.46%, P<0.0001). Additionally, this complication profile may reflect the increasingly common use of free tissue flaps for more complex reconstructions. Several of these differences in complication rates between flap types were no longer significant in the last 5 years of this study. PMID- 28358765 TI - Introduction of the American Academy of Facial Plastic and Reconstructive Surgery FACE TO FACE Database. AB - The American Academy of Facial Plastic and Reconstructive Surgery FACE TO FACE database was created to gather and organize patient data primarily from international humanitarian surgical mission trips, as well as local humanitarian initiatives. Similar to cloud-based Electronic Medical Records, this web-based user-generated database allows for more accurate tracking of provider and patient information and outcomes, regardless of site, and is useful when coordinating follow-up care for patients. The database is particularly useful on international mission trips as there are often different surgeons who may provide care to patients on subsequent missions, and patients who may visit more than 1 mission site. Ultimately, by pooling data across multiples sites and over time, the database has the potential to be a useful resource for population-based studies and outcome data analysis. The objective of this paper is to delineate the process involved in creating the AAFPRS FACE TO FACE database, to assess its functional utility, to draw comparisons to electronic medical records systems that are now widely implemented, and to explain the specific benefits and disadvantages of the use of the database as it was implemented on recent international surgical mission trips. PMID- 28358766 TI - Early Complications and Associated Perioperative Factors in Nonsyndromic Craniosynostosis. AB - This is the first Eastern center-based retrospective report on early complications and associated perioperative factors of nonsyndromic craniosynostosis (NSC). The authors' purpose is to tailor preoperative counseling, convey objective perioperative data, and determinants for early complications in NSC so as to enhance exchanges with international center. Inclusion criteria required a diagnosis of NSC confirmed by 3-dimentional computed tomography scans and complete medical record. Genetic evidence of syndromic craniosynostosis was excluded. Study population was divided into 4 groups based on the suture involvement, which were compared with respect to demographics, perioperative factors, and the occurrence of complications. Demographic data were analyzed using descriptive statistics. Categorical variables were analyzed using the Fisher exact test. Continuous variables were analyzed using the Kruskal-Wallis test. To better study key determinants for early complications, regression analysis was performed. It revealed a predominance of sagittal (n = 36) throughout the time period studied. Eastern China (n = 33) and Southwest China (n = 13) were the top 2 districts where patients came. The authors also reported an overall rate of early complication of 80% (n = 52). The most common were pyrexia (n = 50). Blood loss was a risk (P = 0.041; OR, 1.102); meanwhile, transfusion of concentrated red blood cells was a higher risk (P = 0.035; OR, 2.033). This study represents the authors' initial 4 years practice in NSC. The authors are endeavoring to enhance exchanges with Western centers. PMID- 28358767 TI - Academic Productivity of Faculty Associated With Craniofacial Surgery Fellowship Programs. AB - BACKGROUND: The H-index is increasingly being used as a measure of academic productivity and has been applied to various surgical disciplines. Here the authors calculate the H-index of craniofacial surgery fellowship faculty in North America in order to determine its utility for academic productivity among craniofacial surgeons. METHODS: A list of fellowship programs was obtained from the website of the American Society of Craniofacial Surgery. Faculty demographics and institution characteristics were obtained from official program websites and the H-index was calculated using Scopus (Elsevier, USA). Data were assessed using bivariate analysis tools (Kruskal-Wallis and Mann-Whitney tests) to determine the relationship between independent variables and career publications, H-index and 5 year H-index (H5-index) of faculty. Dunn test for multiple comparisons was also calculated. RESULTS: A total of 102 faculty members from 29 craniofacial surgery fellowship programs were identified and included. Faculty demographics reflected a median age of 48 (interquartile range [IQR] 13), a predominantly male sample (88/102, 89.7%), and the rank of assistant professor being the most common among faculty members (41/102, 40.2%). Median of career publications per faculty was 37 (IQR 52.5) and medians of H-index and H5-index were 10.0 (IQR 13.75) and 3.5 (IQR 3.25), respectively. Greater age, male gender, Fellow of the American College of Surgeons membership, higher academic rank, and program affiliation with ranked research medical schools were significantly associated with higher H-indices. CONCLUSIONS: Variables associated with seniority were positively associated with the H-index. These results suggest that the H-index may be used as an adjunct in determining academic productivity for promotions among craniofacial surgeons. PMID- 28358769 TI - Reflecting on the Past and Looking Forward. PMID- 28358770 TI - Editorial. PMID- 28358768 TI - Impact of Ophthalmic Surgeon Experience on Early Postoperative Central Corneal Thickness After Cataract Surgery. AB - PURPOSE: To assess the impact of surgeon experience on early postoperative central corneal thickness (CCT) in eyes that have undergone phacoemulsification based cataract surgery. METHODS: One hundred sixty eyes underwent phacoemulsification-based cataract surgery performed by an experienced surgeon (n = 110; senior group) or a surgically less experienced ophthalmic assistant (n = 50; junior group), using the divide-and-conquer or tilt-and-tumble technique for cataractous lens extraction. The primary endpoint was postoperative corneal edema 2 hours after surgery, determined by pachymetry-based CCT. RESULTS: Mean age of patients was 71.5 +/- 9.1 years. Mean CCT at postoperative hour 2 was 622.8 +/- 69.3 MUm: an increase of 14.3% +/- 10.8 from 545.3 +/- 33.7 MUm preoperatively (P = 0.0028). Mean CCT at postoperative hour 2 and postoperative corneal edema were significantly higher for the junior group than the senior group, with mean respective increases of 105.8 +/- 81.4 MUm (19.3% +/- 14.2%) and 66.4 +/- 3.7 MUm (12.3% +/- 8.3%), P = 0.0001. After adjustment for confounding factors, surgical experience was the only factor significantly associated with corneal edema: beta = 39.58; SD = 11.05; P = 0.0005. Other intergroup differences observed included significantly longer mean operating and mean ultrasound times in the junior group than in the senior group. A final corneal suture was used more frequently in the senior than in the junior group, at rates of 32.7% and 2.0%, respectively, P < 0.0001. CONCLUSIONS: Greater surgical experience was found to be associated with reduced early postoperative corneal edema, shorter operative time, and shorter ultrasound time. This suggests that beyond mastering the initial learning curve of phacoemulsification, surgical experience enables faster and safer surgery. PMID- 28358772 TI - Orthopaedic Snafus: When Adverse Events Happen in Orthopaedics. PMID- 28358771 TI - Orthopaedic Snafus: When Adverse Events Happen in Orthopaedics. AB - The potential for adverse events exists when treating and managing orthopaedic patients in the intraoperative or postoperative environments, especially when it comes to falls, surgical site infections, venous thromboembolism, and injuries to nerves and blood vessels. Orthopaedic nurses play a vital role in the promotion and use of evidence-based interventions to decrease the incidence of these adverse events, improve quality of care, and minimize the financial burden related to these adverse events. PMID- 28358774 TI - The Effect of a Rapid Rehabilitation Program on Patients Undergoing Unilateral Total Knee Arthroplasty. PMID- 28358773 TI - The Effect of a Rapid Rehabilitation Program on Patients Undergoing Unilateral Total Knee Arthroplasty. AB - BACKGROUND: Few studies have looked at longer term functional outcomes of rapid rehabilitation (physical therapy in the postanesthesia care unit on the day of surgery) for patients undergoing total knee arthroplasty. PURPOSE: The purpose of this interdisciplinary study (physical therapy and nursing) was to assess the effect of a rapid rehabilitation program on inpatient length of stay (LOS) and functional recovery. METHODS: Functional outcomes were measured by the Knee Injury Osteoarthritis Outcome Score presurgically and at 4 and 12 weeks postoperatively and by progression along a physical therapy rehabilitation pathway. RESULTS: Experimental group LOS was significantly shorter than the control group (p = .0261). Multilevel regression modeling showed that KOOS and physical therapy clinical pathway score trajectories did not differ significantly between groups. Patients receiving rapid rehabilitation were 2.5 (95% CI [0.958, 6.53]) times more likely to have a positive physical therapy rehabilitation trajectory than patients in the control group. CONCLUSION: Findings validated earlier study results in terms of LOS; however, further research is needed to assess the effect of rapid rehabilitation on longer term functional outcomes. PMID- 28358775 TI - Nursing Care of the Patient Undergoing an Anterior Approach to Total Hip Arthroplasty. AB - The anterior, anterolateral, direct lateral, transtrochanteric, and posterior techniques have historically been the surgical approach to a total hip arthroplasty; however, a forthcoming technique called the direct anterior approach has been demonstrated to produce many patient and physician quality outcomes. These favorable outcomes can include shorter hospital stay, earlier mobility and functionality, decreased medical costs, and increased patient satisfaction scores. Appropriate nursing care during the preoperative, intraoperative, and postoperative phases is essential. The purpose of this article is to describe the nursing care for a patient undergoing a direct anterior approach to hip arthroplasty. PMID- 28358776 TI - Nursing Care of the Patient Undergoing an Anterior Approach to Total Hip Arthroplasty. PMID- 28358777 TI - Improving Patient Education at a Large Midwest Urban Orthopaedic Center. AB - A large Midwest urban orthopaedic center sought to improve dissemination and documentation of its education information given to its patients. A new electronic, partially automated patient education delivery system was implemented that disseminates and documents targeted patient education modules. The program triggers automatic dissemination of general education based on patient demographics. Surgical education modules are disseminated manually. The semiautomated electronic education program successfully placed the center in compliance with Stage 2 Meaningful Use and showed improved dissemination of educational materials. The orthopaedic center and patients would benefit from further review and intervention to increase patient compliance with education materials. PMID- 28358779 TI - Early Identification and Treatment of Osteoporosis in a Rural Internal Medicine Clinic: A Quasi-Experimental Approach toQuality Improvement. AB - Osteoporosis affects more than 44 million individuals in the United States annually while disease management continues to fall short of the recommended guidelines. This study institutes a practice change for osteoporosis/osteopenia screening and treatment founded on current evidence-based guidelines. A retrospective chart review was evaluated for current trends in the identification and treatment of osteoporosis/osteopenia in female patients older than 65 years. Data were then compared with identical data collected after implementing an evidence-based osteoporosis guideline tool. Quantitative analysis indicated poor adherence of established osteoporosis guidelines by providers. In comparison, after implementation of the osteoporosis treatment guideline tool, there was an improvement of more than 40% in the identification and treatment of osteoporosis/osteopenia. Utilization of the evidence-based osteoporosis guideline tool resulted in quality improvement in identifying and treating those with or at risk for osteoporosis/osteopenia. PMID- 28358778 TI - Presurgical Concerns of Primary Family Caregivers of Children With Cerebral Palsy. AB - BACKGROUND: Primary family caregivers (PFCs) of children with cerebral palsy have many worries and concerns when their children face orthopedic surgery. Levels of PFC stress about the upcoming surgery is related to the child's level of gross motor function as well as the support they receive from medical professionals. PURPOSE: The purposes of the present study were to (1) explore the levels of concern about orthopedic surgery; and (2) explore the predictive factors associated with concerns about orthopedic surgery among PFCs of children with cerebral palsy during the preoperative period. METHODS: A cross-sectional, correlational study was conducted. Primary family caregivers were assessed preoperatively using the Single-event Multilevel Surgery Scale, Social Support Scale, Gross Motor Function Classification System-Expanded and Revised, and background information form. Primary family caregivers were recruited from the outpatient department of orthopedic surgery and pediatric rehabilitation of a medical center in northern Taiwan. Data were analyzed by descriptive analysis, Pearson product-moment correlation, and multiple regression analysis. RESULTS: A total of 63 eligible subjects were enrolled in this study. Primary family caregivers had moderate levels of concern and mild-to-moderate levels of social support. The higher severity of motor function impairment in children with cerebral palsy, prior caregiving by PFCs for another family member, and PFCs' lower level of social support from healthcare providers were associated with higher levels of PFC concern. CONCLUSIONS: Concerns about orthopedic surgery is an overlooked issue that needs more attention from healthcare providers. This study determined that PFCs who perceived a lack of social support from their healthcare providers and those with children who had limited gross motor function were more concerned and anxious about their children's upcoming orthopedic surgery. Health professionals should provide adequate health education and counseling to help PFCs of children with cerebral palsy in the decision-making process prior to orthopedic surgery. PMID- 28358780 TI - The Cure That Lies Within: The Mind-Body Connection in Orthopaedics. AB - The mind and the body are clearly intertwined in ways that are only now being discovered. In the orthopaedic world, injuries and diseases are often classified and described in a very organized, discrete fashion-The radius is fractured, the ACL or meniscus or rotator cuff is torn, the ankle is sprained, and/or the lumbar spine has a disc herniation. Although it is, in many ways, almost comforting to think about injuries or orthopaedic issues in this manner, what about the many patients who fail to fall into this classification? What about the thousands of patients with severe unexplained chronic pain or patients who just are not improving with the typical treatment algorithm. What about patients who present with multiple overlapping symptoms that do not fall into any of the classic diagnosis patterns? The mismatch between the actual health needs of typical patients and the standard acute medical response produces an immense waste of medical resources and incredible frustration for both the patient and the provider and creates a real risk that acute conditions will go untreated and become chronic. After more than a decade of traditional orthopaedic and musculoskeletal practice, its tremendous benefits as well as its limitations have become apparent. These limitations have sparked a search for integration of mind body considerations to fill some of these gaps. Although this can prove to be quite challenging in today's healthcare world of maximizing volume and decreasing costs, it has proven to be an invaluable resource for both personal growth and patient and family satisfaction. The goals of this 2-part article are to dissect the relatively new concept of the mind-body connection in orthopaedics. The article aims to provide a framework that illustrates how the mind will predictably create objective observable phenomena in the body. The central focus of this framework is the role of the sympathetic nervous system and its effect on the chemistry, biomechanics, and appearance of various tissues in the body. Further identified are factors contributing to the aberrant emotional response as a means to empower practitioners and patients in recognizing the link between negative perception and observable symptoms. Our hope is to ultimately introduce a model of empowerment that when presented to a patient/family can produce a proactive response and, in turn, enhance current orthopaedic and pain management practices. PMID- 28358781 TI - The Cure That Lies Within: The Mind-Body Connection in Orthopaedics. PMID- 28358782 TI - Topical Nonsteroidal Anti-Inflammatory Drugs for Chronic Musculoskeletal Pain in Adults. PMID- 28358785 TI - Avulsion Fracture of the Medial Collateral Ligament. PMID- 28358783 TI - Avulsion Fracture of the Medial Collateral Ligament. PMID- 28358786 TI - ONCB Orthopaedic Nurses Certification Board, New Certificants. PMID- 28358787 TI - ONCB Orthopaedic Nurses Certification Board, Recertificants. PMID- 28358788 TI - An Application of Business Process Management to Health Care Facilities. AB - The purpose of this article is to help health care facility managers and personnel identify significant elements of their facilities to address, and steps and actions to follow, when applying business process management to them. The ABPMP (Association of Business Process Management Professionals) life-cycle model of business process management is adopted, and steps from Lean, business process reengineering, and Six Sigma, and actions from operations management are presented to implement it. Managers of health care facilities can find in business process management a more comprehensive approach to improving their facilities than Lean, Six Sigma, business process reengineering, and ad hoc approaches that does not conflict with them because many of their elements can be included under its umbrella. Furthermore, the suggested application of business process management can guide and relieve them from selecting among these approaches, as well as provide them with specific steps and actions that they can follow. This article fills a gap in the literature by presenting a much needed comprehensive application of business process management to health care facilities that has specific steps and actions for implementation. PMID- 28358791 TI - Methadone Prescribing and Overdose and the Association with Medicaid Preferred Drug List Policies - United States, 2007-2014. AB - Drug overdose is a leading cause of injury death in the United States; 47,055 fatal drug overdoses were reported in 2014, a 6.5% increase from the previous year (1), driven by opioid use disorder (2,3). Methadone is an opioid prescribed for pain management and is also provided through opioid treatment programs to treat opioid use disorders. Because methadone might remain in a person's system long after the pain-relieving benefits have been exhausted, it can cause slow or shallow breathing and dangerous changes in heartbeat that might not be perceived by the patient (4,5). In December 2006, the Food and Drug Administration issued a Public Health Advisory that alerted health care professionals to reports of death and life-threatening adverse events, such as respiratory depression and cardiac arrhythmias, in patients receiving methadone (4); in January 2008, a voluntary manufacturer restriction limited distribution of the 40 mg formulation of methadone.* CDC analyzed state mortality and health care data and preferred drug list (PDL) policies to 1) compare the percentage of deaths involving methadone with the rate of prescribing methadone for pain, 2) characterize variation in methadone prescribing among payers and states, and 3) assess whether an association existed between state Medicaid reimbursement PDL policies and methadone overdose rates. The analyses found that, from 2007 to 2014, large declines in methadone-related overdose deaths occurred. Prescriptions for methadone accounted for 0.85% of all opioid prescriptions for pain in the commercially insured population and 1.1% in the Medicaid population. In addition, an association was observed between Medicaid PDLs requiring prior authorization for methadone and lower rates of methadone overdose among Medicaid enrollees. PDL policies requiring prior authorization might help to reduce the number of methadone overdoses. PMID- 28358790 TI - Prognostic Value of High-Sensitivity C-Reactive Protein, Procalcitonin and Pancreatic Stone Protein in Pediatric Sepsis. AB - BACKGROUND To investigate the prognostic value of procalcitonin (PCT), high sensitivity C-reactive protein (hs-CRP), and pancreatic stone protein (PSP) in children with sepsis. MATERIAL AND METHODS A total of 214 patients with sepsis during hospitalization were enrolled. Serum levels of PCT, hs-CRP, and PSP were measured on day 1 of hospitalization and the survival rates of children were recorded after a follow-up of 28 days. Pearson's correlation analysis was conducted to test the association of PCT, hs-CRP, and PSP with pediatric critical illness score (PCIS). Logistic regression models were used to analyze the risk factors contributing to patients' death. The AUC was used to determine the value of PCT, hs-CRP, and PSP in the prognosis of patients with sepsis. RESULTS The expression of PCT, hs-CRP, and PSP in the dying patients was higher than in the surviving patients (p<0.001). Pearson's correlation analysis showed that serum PCT, hs-CRP, and PSP levels were negatively correlated with PCIS (p<0.001). Multivariate logistic regression revealed that PCT, hs-CRP, and PSP were independent risk factors for the prognosis of patients with sepsis (p<0.001). ROC analysis showed the AUC values of PCT, hs-CRP, and PSP were 0.83 (95% CI, 0.77 0.88), 0.76 (95% CI, 0.70-0.82), and 0.73 (95% CI, 0.67-0.79), respectively. The combined AUC value of PCT, hs-CRP, and PSP, was 0.92 (95% CI, 0.87-0.95), which was significantly increased compared with PCT, hs-CRP, or PSP (p<0.001). CONCLUSIONS The combination of serum PCT, hs-CRP, and PSP represents a promising biomarker of risk, and is a useful clinical tool for risk stratification of children with sepsis. PMID- 28358793 TI - Announcement: National Public Health Week - April 3-9, 2017. AB - CDC joins the American Public Health Association (APHA) in celebration of National Public Health Week, April 3-9, 2017. Since 1995, APHA has led the observance of National Public Health Week during the first full week of April. The week recognizes the impact of public health on the health of the nation. The 2017 observance focuses on making the United States the Healthiest Nation in One Generation by 2030 by spotlighting the importance of prevention, employing successful strategies for collaboration, and promoting the critical role of a strong public health system. PMID- 28358792 TI - Notes from the Field: Adverse Events Following a Mass Yellow Fever Immunization Campaign - Kongo Central Province, Democratic Republic of the Congo, September 2016. PMID- 28358794 TI - QuickStats: Percentage of U.S. Women Aged 21-65 Years Who Never Had a Papanicolaou Test (Pap Test),* by Place of Birth and Length of Residence in the United States? - National Health Interview Survey, 2013 and 2015S. AB - In 2013 and 2015 combined, 6.8% of U.S. women aged 21-65 years had never received a Pap test in their lifetime. Foreign-born women were more than twice as likely as U.S. born women to have never received a Pap test (13.4% versus 5.2%). Foreign born women who lived in the United States for <25% of their lifetime were almost twice as likely as those who resided in the United States for >=25% of their lifetime (21.5% versus 10.9%) to have never received a Pap test. PMID- 28358795 TI - Zika Virus Transmission - Region of the Americas, May 15, 2015-December 15, 2016. AB - Zika virus, a mosquito-borne flavivirus that can cause rash with fever, emerged in the Region of the Americas on Easter Island, Chile, in 2014 and in northeast Brazil in 2015 (1). In response, in May 2015, the Pan American Health Organization (PAHO), which serves as the Regional Office of the Americas for the World Health Organization (WHO), issued recommendations to enhance surveillance for Zika virus. Subsequently, Brazilian investigators reported Guillain-Barre syndrome (GBS), which had been previously recognized among some patients with Zika virus disease, and identified an association between Zika virus infection during pregnancy and congenital microcephaly (2). On February 1, 2016, WHO declared Zika virus-related microcephaly clusters and other neurologic disorders a Public Health Emergency of International Concern.* In March 2016, PAHO developed case definitions and surveillance guidance for Zika virus disease and associated complications (3). Analysis of reports submitted to PAHO by countries in the region or published in national epidemiologic bulletins revealed that Zika virus transmission had extended to 48 countries and territories in the Region of the Americas by late 2016. Reported Zika virus disease cases peaked at different times in different areas during 2016. Because of ongoing transmission and the risk for recurrence of large outbreaks, response efforts, including surveillance for Zika virus disease and its complications, and vector control and other prevention activities, need to be maintained. PMID- 28358796 TI - Yellow Fever Outbreak - Kongo Central Province, Democratic Republic of the Congo, August 2016. AB - On April 23, 2016, the Democratic Republic of the Congo's (DRC's) Ministry of Health declared a yellow fever outbreak. As of May 24, 2016, approximately 90% of suspected yellow fever cases (n = 459) and deaths (45) were reported in a single province, Kongo Central Province, that borders Angola, where a large yellow fever outbreak had begun in December 2015. Two yellow fever mass vaccination campaigns were conducted in Kongo Central Province during May 25-June 7, 2016 and August 17 28, 2016. In June 2016, the DRC Ministry of Health requested assistance from CDC to control the outbreak. As of August 18, 2016, a total of 410 suspected yellow fever cases and 42 deaths were reported in Kongo Central Province. Thirty seven of the 393 specimens tested in the laboratory were confirmed as positive for yellow fever virus (local outbreak threshold is one laboratory-confirmed case of yellow fever). Although not well-documented for this outbreak, malaria, viral hepatitis, and typhoid fever are common differential diagnoses among suspected yellow fever cases in this region. Other possible diagnoses include Zika, West Nile, or dengue viruses; however, no laboratory-confirmed cases of these viruses were reported. Thirty five of the 37 cases of yellow fever were imported from Angola. Two-thirds of confirmed cases occurred in persons who crossed the DRC Angola border at one market city on the DRC side, where <=40,000 travelers cross the border each week on market day. Strategies to improve coordination between health surveillance and cross-border trade activities at land borders and to enhance laboratory and case-based surveillance and health border screening capacity are needed to prevent and control future yellow fever outbreaks. PMID- 28358798 TI - Screening for Excessive Alcohol Use and Brief Counseling of Adults - 17 States and the District of Columbia, 2014. AB - Excessive and/or risky alcohol use* resulted in $249 billion in economic costs in 2010 (1) and >88,000 deaths in the United States every year from 2006 to 2010 (2). It is associated with birth defects and disabilities (e.g., fetal alcohol spectrum disorders [FASDs]), increases in chronic diseases (e.g., heart disease and breast cancer), and injuries and violence (e.g., motor vehicle crashes, suicide, and homicide).? Since 2004, the U.S. Preventive Services Task Force (USPSTF) has recommended alcohol misuse screening and brief counseling (also known as alcohol screening and brief intervention or ASBI) for adults aged >=18 years (3).S Among adults, ASBI reduces episodes of binge-level consumption, reduces weekly alcohol consumption, and increases compliance with recommended drinking limits in those who have an intervention in comparison to those who do not (3). A recent study suggested that health care providers rarely talk with patients about alcohol use (4). To estimate the prevalence of U.S. adults who reported receiving elements of ASBI, CDC analyzed 2014 Behavioral Risk Factor Surveillance System (BRFSS) data from 17 states and the District of Columbia (DC). Weighted crude and age-standardized overall and state-level prevalence estimates were calculated by selected drinking patterns and demographic characteristics. Overall, 77.7% of adults (age-standardized estimate) reported being asked about alcohol use by a health professional in person or on a form during a checkup, but only 32.9% reported being asked about binge-level alcohol consumption (3). Among binge drinkers, only 37.2% reported being asked about alcohol use and advised about the harms of drinking too much, and only 18.1% reported being asked about alcohol use and advised to reduce or quit drinking. Widespread implementation of ASBI and other evidence-based interventions could help reduce excessive alcohol use in adults and related harms. PMID- 28358797 TI - Evaluation of Automated Molecular Testing Rollout for Tuberculosis Diagnosis Using Routinely Collected Surveillance Data - Uganda, 2012-2015. AB - In 2012, Uganda introduced the use of GeneXpert MTB/RIF (Cepheid, Sunnyvale CA), a sensitive, automated, real-time polymerase chain reaction-based platform for tuberculosis (TB) diagnosis, for programmatic use among children, adults with presumptive human immunodeficiency virus (HIV)-associated TB, and symptomatic persons at risk for rifampicin (RIF)-resistant TB. The effect of using the platform's Xpert MTB/RIF assay on TB care and control was assessed using routinely collected programmatic data; in addition, a retrospective review of district quarterly summaries using abstracted TB register data from purposively selected facilities in the capital city of Kampala was conducted. Case notification rates were calculated and nonparametric statistical methods were used for analysis. No statistically significant differences were observed in case notification rates before and after the Xpert MTB/RIF assay became available, although four of 10 districts demonstrated a statistically significant difference in bacteriologically confirmed TB. Once the GeneXpert MTB/RIF platform is established and refined, a more comprehensive evaluation should be conducted. PMID- 28358800 TI - Mitochondria-A billion years of cohabitation. PMID- 28358799 TI - Sodium Intake Among Persons Aged >=2 Years - United States, 2013-2014. AB - High sodium consumption can increase hypertension, a major risk factor for cardiovascular diseases (1). Reducing sodium intake can lower blood pressure, and sodium reduction in the U.S. population of 40% over 10 years might save at least 280,000 lives (2). Average sodium intake in the United States remains in excess of Healthy People 2020 objectives,* and monitoring sources of sodium in the U.S. population can help focus sodium reduction measures (3,4). Data from 2013-2014 What We Eat in America (WWEIA), the dietary intake portion of the National Health and Nutrition Examination Survey (NHANES),? were analyzed to determine the ranked percentage sodium contribution of selected food categories and sources of sodium intake from all reported foods and beverages, both overall and by demographic subgroups. These latest data include updated food codes and separate estimates for intake among non-Hispanic Asians.S In 2013-2014, 70% of dietary sodium consumed by persons in the United States came from 25 food categories; breads were the top contributor, accounting for 6% of sodium consumed. A majority of sodium consumed was from food obtained at stores; however, sodium density (mg/1,000 kcal) was highest in food obtained at restaurants. A variety of commonly consumed foods contributes to U.S. sodium intake, emphasizing the importance of sodium reduction across the food supply (4). PMID- 28358802 TI - Knowledge, practices and perceptions of geo-helminthes infection among parents of pre-school age children of coastal region, Kenya. AB - BACKGROUND: Soil-transmitted helminthes (STHs) are common human parasitic diseases in most of the developing world particularly in Kenya. The ongoing National School-Based Deworming Programme (NSBDP) was launched in 2012 and is currently targeting 28 of the 47 endemic Counties. In an effort to improve treatment intervention strategies among Pre-School Age Children (PSAC) attending Early Childhood Development Centres (ECDC), we sought to assess parents' knowledge, perceptions and practices on worm infection. METHODOLOGY: We conducted a qualitative cross-sectional study in four endemic sub-counties of two counties of coastal region of Kenya. A total of 20 focus group discussions (FGDs) categorized by gender were conducted among parents of pre-school age children. Participants were purposively selected based on homogenous characteristics with the saturation model determining the number of focus group discussions conducted. The data collected was analyzed manually by study themes. FINDINGS: The majority of the parents had knowledge on worms and modes of transmission of the parasitic infections among the pre-school children. Also, most of the participants knew the causes of worm infection and the pre- disposing factors mentioned included poor hygiene and sanitation practices. Due to poor knowledge of signs and symptoms, misconceptions about the drugs administered during the NSBDP were common with a large majority of the parents indicating that the drugs were ineffective in worm control. The findings also indicated that most of the participants sought medical care on the onset of the signs and symptoms of worm infestation and preferred services provided at public health facilities as opposed to private health facilities or buying drugs from the local market citing mistrust of such services. Cultural beliefs, high cost of building and availability of vast pieces of land for human waste disposal were factors that contributed to low or lack of latrine ownership and usage by a large majority of the respondents. CONCLUSIONS: Our results show that to a large extent the parents of the pre-school age children have information on worm infections. However, some cultural beliefs and practices on the pathology and mode of transmission mentioned could be a hindrance to prevention and control efforts. There is need to implement health promotion campaigns to strengthen the impact of control strategies and reduce infection. PMID- 28358801 TI - ECG-derived spatial QRS-T angle is associated with ICD implantation, mortality and heart failure admissions in patients with LV systolic dysfunction. AB - BACKGROUND: Increased spatial QRS-T angle has been shown to predict appropriate implantable cardioverter defibrilIator (ICD) therapy in patients with left ventricular systolic dysfunction (LVSD). We performed a retrospective cohort study in patients with left ventricular ejection fraction (LVEF) 31-40% to assess the relationship between the spatial QRS-T angle and other advanced ECG (A-ECG) as well as echocardiographic metadata, with all-cause mortality or ICD implantation for secondary prevention. METHODS: 534 patients <=75 years of age with LVEF 31-40% were identified through an echocardiography reporting database. Digital 12-lead ECGs were retrospectively matched to 295 of these patients, for whom echocardiographic and A-ECG metadata were then generated. Data mining was applied to discover novel ECG and echocardiographic markers of risk. Machine learning was used to develop a model to predict possible outcomes. RESULTS: 49 patients (17%) had events, defined as either mortality (n = 16) or ICD implantation for secondary prevention (n = 33). 72 parameters (58 A-ECG, 14 echocardiographic) were univariately different (p<0.05) in those with vs. without events. After adjustment for multiplicity, 24 A-ECG parameters and 3 echocardiographic parameters remained different (p<2x10-3). These included the posterior-to-leftward QRS loop ratio from the derived vectorcardiographic horizontal plane (previously associated with pulmonary artery pressure, p = 2x10 6); spatial mean QRS-T angle (134 vs. 112 degrees , p = 1.6x10-4); various repolarisation vectors; and a previously described 5-parameter A-ECG score for LVSD (p = 4x10-6) that also correlated with echocardiographic global longitudinal strain (R2 = - 0.51, P < 0.0001). A spatial QRS-T angle >110 degrees had an adjusted HR of 3.4 (95% CI 1.6 to 7.4) for secondary ICD implantation or all cause death and adjusted HR of 4.1 (95% CI 1.2 to 13.9) for future heart failure admission. There was a loss of complexity between A-ECG and echocardiographic variables with an increasing degree of disease. CONCLUSION: Spatial QRS-T angle >110 degrees was strongly associated with arrhythmic events and all-cause death. Deep analysis of global ECG and echocardiographic metadata revealed underlying relationships, which otherwise would not have been appreciated. Delivered at scale such techniques may prove useful in clinical decision making in the future. PMID- 28358803 TI - Efficacy of polymyxin B-immobilized fiber hemoperfusion for patients with septic shock caused by Gram-negative bacillus infection. AB - : Septic shock-associated mortality in intensive care units (ICUs) remains high, with reported rates ranging 30-50%. In particular, Gram-negative bacilli (GNB), which induce significant inflammation and consequent multiple organ failure, are the etiological bacterial agent in 40% of severe sepsis cases. Hemoperfusion using polymyxin B-immobilized fiber (PMX), which adsorbs endotoxin, is expected to reduce the inflammatory sepsis cascade due to GNB. However, the clinical efficacy of this treatment has not yet been demonstrated. Here, we aimed to verify the efficacy of endotoxin adsorption therapy using PMX through a retrospective analysis of 413 patients who received broad spectrum antimicrobial treatment for GNB-related septic shock between January 2009 and December 2012 in 11 ICUs of Japanese tertiary hospitals. After aligning the patients' treatment time phases, we classified patients in two groups depending on whether PMX hemoperfusion (PMXHP) therapy was administered or not within 24 hours after ICU admission (PMXHP group: n = 134, conventional group: n = 279). The primary study endpoint was the mortality rate at 28 days after ICU admission. The mean age was 72.4 (standard deviation: 12.6) years, and the mean Sequential Organ Failure Assessment score at ICU admission was 9.9 (3.4). The infection sites included intra-abdominal (38.0%), pulmonary (18.9%), and urinary tract (32.2%), and two thirds of all patients had GNB-related bacteremia. Notably, the mortality at 28 days after ICU admission did not differ between the groups (PMXHP: 29.1% vs. conventional: 29.0%, P = 0.98), and PMXHP therapy was not found to improve this outcome in a Cox regression analysis (hazard ratio = 1.16; 95% confidence interval, 0.81-1.64, P = 0.407). We conclude that PMX-based endotoxin adsorption within 24 hours from ICU admission was not associated with mortality among patients with septic shock due to GNB. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR ID: UMIN000012748). PMID- 28358804 TI - A critical analysis of computational protein design with sparse residue interaction graphs. AB - Protein design algorithms enumerate a combinatorial number of candidate structures to compute the Global Minimum Energy Conformation (GMEC). To efficiently find the GMEC, protein design algorithms must methodically reduce the conformational search space. By applying distance and energy cutoffs, the protein system to be designed can thus be represented using a sparse residue interaction graph, where the number of interacting residue pairs is less than all pairs of mutable residues, and the corresponding GMEC is called the sparse GMEC. However, ignoring some pairwise residue interactions can lead to a change in the energy, conformation, or sequence of the sparse GMEC vs. the original or the full GMEC. Despite the widespread use of sparse residue interaction graphs in protein design, the above mentioned effects of their use have not been previously analyzed. To analyze the costs and benefits of designing with sparse residue interaction graphs, we computed the GMECs for 136 different protein design problems both with and without distance and energy cutoffs, and compared their energies, conformations, and sequences. Our analysis shows that the differences between the GMECs depend critically on whether or not the design includes core, boundary, or surface residues. Moreover, neglecting long-range interactions can alter local interactions and introduce large sequence differences, both of which can result in significant structural and functional changes. Designs on proteins with experimentally measured thermostability show it is beneficial to compute both the full and the sparse GMEC accurately and efficiently. To this end, we show that a provable, ensemble-based algorithm can efficiently compute both GMECs by enumerating a small number of conformations, usually fewer than 1000. This provides a novel way to combine sparse residue interaction graphs with provable, ensemble-based algorithms to reap the benefits of sparse residue interaction graphs while avoiding their potential inaccuracies. PMID- 28358805 TI - Fasting regulates EGR1 and protects from glucose- and dexamethasone-dependent sensitization to chemotherapy. AB - Fasting reduces glucose levels and protects mice against chemotoxicity, yet drugs that promote hyperglycemia are widely used in cancer treatment. Here, we show that dexamethasone (Dexa) and rapamycin (Rapa), commonly administered to cancer patients, elevate glucose and sensitize cardiomyocytes and mice to the cancer drug doxorubicin (DXR). Such toxicity can be reversed by reducing circulating glucose levels by fasting or insulin. Furthermore, glucose injections alone reversed the fasting-dependent protection against DXR in mice, indicating that elevated glucose mediates, at least in part, the sensitizing effects of rapamycin and dexamethasone. In yeast, glucose activates protein kinase A (PKA) to accelerate aging by inhibiting transcription factors Msn2/4. Here, we show that fasting or glucose restriction (GR) regulate PKA and AMP-activated protein kinase (AMPK) to protect against DXR in part by activating the mammalian Msn2/4 ortholog early growth response protein 1 (EGR1). Increased expression of the EGR1 regulated cardioprotective peptides atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in heart tissue may also contribute to DXR resistance. Our findings suggest the existence of a glucose-PKA pathway that inactivates conserved zinc finger stress-resistance transcription factors to sensitize cells to toxins conserved from yeast to mammals. Our findings also describe a toxic role for drugs widely used in cancer treatment that promote hyperglycemia and identify dietary interventions that reverse these effects. PMID- 28358806 TI - Antioxidant, antimicrobial, antiparasitic, and cytotoxic properties of various Brazilian propolis extracts. AB - Propolis is known for its biological properties and its preparations have been continuously investigated in an attempt to solve the problem of their standardization, an issue that limits the use of propolis in food and pharmaceutical industries. The aim of this study was to evaluate in vitro antioxidant, antimicrobial, antiparasitic, and cytotoxic effects of extracts of red, green, and brown propolis from different regions of Brazil, obtained by ethanolic and supercritical extraction methods. We found that propolis extracts obtained by both these methods showed concentration-dependent antioxidant activity. The extracts obtained by ethanolic extraction showed higher antioxidant activity than that shown by the extracts obtained by supercritical extraction. Ethanolic extracts of red propolis exhibited up to 98% of the maximum antioxidant activity at the highest extract concentration. Red propolis extracts obtained by ethanolic and supercritical methods showed the highest levels of antimicrobial activity against several bacteria. Most extracts demonstrated antimicrobial activity against Staphylococcus aureus. None of the extracts analyzed showed activity against Escherichia coli or Candida albicans. An inhibitory effect of all tested ethanolic extracts on the growth of Trypanosoma cruzi Y strain epimastigotes was observed in the first 24 h. However, after 96 h, a persistent inhibitory effect was detected only for red propolis samples. Only ethanolic extracts of red propolis samples R01Et.B2 and R02Et.B2 showed a cytotoxic effect against all four cancer cell lines tested (HL-60, HCT-116, OVCAR-8, and SF-295), indicating that red propolis extracts have great cytotoxic potential. The biological effects of ethanolic extracts of red propolis revealed in the present study suggest that red propolis can be a potential alternative therapeutic treatment against Chagas disease and some types of cancer, although high activity of red propolis in vitro needs to be confirmed by future in vivo investigations. PMID- 28358807 TI - Color adaptation induced from linguistic description of color. AB - Recent theories propose that language comprehension can influence perception at the low level of perceptual system. Here, we used an adaptation paradigm to test whether processing language caused color adaptation in the visual system. After prolonged exposure to a color linguistic context, which depicted red, green, or non-specific color scenes, participants immediately performed a color detection task, indicating whether they saw a green color square in the middle of a white screen or not. We found that participants were more likely to perceive the green color square after listening to discourses denoting red compared to discourses denoting green or conveying non-specific color information, revealing that language comprehension caused an adaptation aftereffect at the perceptual level. Therefore, semantic representation of color may have a common neural substrate with color perception. These results are in line with the simulation view of embodied language comprehension theory, which predicts that processing language reactivates the sensorimotor systems that are engaged during real experience. PMID- 28358808 TI - Interventions to treat mental disorders during pregnancy: A systematic review and multiple treatment meta-analysis. AB - BACKGROUND: For women suffering from an antepartum mental disorder (AMD), there is lack of evidence-based treatment algorithms due to the complicated risk benefit analysis for both mother and unborn child. We aimed to provide a comprehensive overview of pharmacological and non-pharmacological interventions to treat AMD and performed a meta-analysis of the estimated treatment effect on the psychiatric symptoms during pregnancy. METHODS: MedLine, PsycINFO and Embase databases were searched by two independent reviewers for clinical trials with a control condition on treatment of women with AMD, i.e. major depressive (MDD), anxiety, psychotic, eating, somatoform and personality disorders. We inventoried the effect of the treatment, i.e. decrease of psychiatric symptoms at the end of the treatment or postpartum. We adhered to the PRISMA-protocol. FINDINGS: Twenty nine trials were found involving 2779 patients. Trials studied patients with depressive disorders (k = 28), and anxiety disorders (k = 1). No pharmacological trials were detected. A form of psychotherapy, like Cognitive Behavioural Therapy (g = -0.61; 95%CI:-0.73 to -0.49, I2 = 0%; k = 7) or Interpersonal Psychotherapy (g = -0.67; 95%CI:-1.27 to -0.07; I2 = 79%; k = 4), holds robust benefit for pregnant women with MDD. Body-oriented interventions (g = -0.43; 95%CI:-0.61 to 0.25; I2 = 17%; k = 7) and acupuncture (g = -0.43; 95%CI:-0.80 to -0.06; I2 = 0%; k = 2) showed medium sized reduction of depressive symptoms. Bright light therapy (g = -0.59; 95%CI:-1.25 to 0.06; I2 = 0%; k = 2), and food supplements (g = 0.51; 95%CI:-1.02 to 0.01; I2 = 20%; k = 3) did not show significant treatment effects. One study was found on Integrative Collaborative Care. CONCLUSIONS: This meta-analysis found a robust moderate treatment effect of CBT for MDD during pregnancy, and to a lesser extent for IPT. As an alternative, positive results were found for body-oriented interventions and acupuncture. No evidence was found for bright light therapy and food supplements. Only non-pharmacological trials on women with MDD were found. Research on a wider range of AMD is needed. PMID- 28358809 TI - Oxidative modification and electrochemical inactivation of Escherichia coli upon cold atmospheric pressure plasma exposure. AB - Cold atmospheric pressure plasmas (CAPPs) are known to have bactericidal effects but the mechanism of their interaction with microorganisms remains poorly understood. In this study the bacteria Escherichia coli were used as a model and were exposed to CAPPs. Different gas compositions, helium with or without adjunctions of nitrogen or oxygen, were used. Our results indicated that CAPP induced bacterial death at decontamination levels depend on the duration, post treatment storage and the gas mixture composition used for the treatment. The plasma containing O2 in the feeding gas was the most aggressive and showed faster bactericidal effects. Structural modifications of treated bacteria were observed, especially significant was membrane leakage and morphological changes. Oxidative stress caused by plasma treatment led to significant damage of E. coli. Biochemical analyses of bacterial macromolecules indicated massive intracellular protein oxidation. However, reactive oxygen and nitrogen species (RONS) are not the only actors involved in E. coli's death, electrical field and charged particles could play a significant role especially for He-O2 CAPP. PMID- 28358810 TI - Prognostic significance of nestin expression in patients with resected non-small cell lung cancer treated with platinum-based adjuvant chemotherapy; relationship between nestin expression and epithelial to mesenchymal transition related markers. AB - INTRODUCTION: Although adjuvant platinum-based chemotherapy (AC) has been shown to improve survival of patients with completely resected stage II and stage IIIA non-small cell lung cancer (NSCLC), its effect is limited. Nestin is a class VI intermediate filament protein expressed in neural stem cells and several cancer cells including NSCLC. In the present study, we aimed to determine its prognostic significance concerning survival in NSCLC patients receiving AC. METHODS: Nestin expression in cancer cells was immunohistochemically studied in 90 patients with completely resected stage II and stage IIIA NSCLC treated with AC and its association with clinicopathologic parameters, including ABCG2, E-cadherin, and vimentin expression, was evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of nestin expression on survival. RESULTS: Nestin expression was observed in 28 of the 90 (31.1%) NSCLCs. Clinicopathologically, nestin expression was associated with loss of E cadherin expression (P = 0.006) and vimentin positive expression (P < 0.001). In survival analysis, nestin expression was significantly associated with a poorer prognosis (P = 0.028). Multivariable analysis confirmed that nestin expression is an independent prognostic indicator in NSCLC patients receiving AC (HR = 2.56; 95% CI, 1.23-5.30, P = 0.01). CONCLUSION: The present study reveals that nestin expression is a prognostic indicator of a poorer survival probability in NSCLC patients receiving AC, although its prognostic significance still requires confirmation with larger patient populations. PMID- 28358811 TI - Alterations in airway microbiota in patients with PaO2/FiO2 ratio <= 300 after burn and inhalation injury. AB - BACKGROUND: Injury to the airways after smoke inhalation is a major mortality risk factor in victims of burn injuries, resulting in a 15-45% increase in patient deaths. Damage to the airways by smoke may induce acute respiratory distress syndrome (ARDS), which is partly characterized by hypoxemia in the airways. While ARDS has been associated with bacterial infection, the impact of hypoxemia on airway microbiota is unknown. Our objective was to identify differences in microbiota within the airways of burn patients who develop hypoxemia early after inhalation injury and those that do not using next generation sequencing of bacterial 16S rRNA genes. RESULTS: DNA was extracted from therapeutic bronchial washings of 48 patients performed within 72 hours of hospitalization for burn and inhalation injury at the North Carolina Jaycee Burn Center. DNA was prepared for sequencing using a novel molecule tagging method and sequenced on the Illumina MiSeq platform. Bacterial species were identified using the MTToolbox pipeline. Patients with hypoxemia, as indicated by a PaO2/FiO2 ratio <= 300, had a 30% increase in abundance of Streptococcaceae and Enterobacteriaceae and 84% increase in Staphylococcaceae as compared to patients with a PaO2/FiO2 ratio > 300. Wilcoxon rank-sum test identified significant enrichment in abundance of OTUs identified as Prevotella melaninogenica (p = 0.042), Corynebacterium (p = 0.037) and Mogibacterium (p = 0.048). Linear discriminant effect size analysis (LefSe) confirmed significant enrichment of Prevotella melaninognica among patients with a PaO2/FiO2 ratio <= 300 (p<0.05). These results could not be explained by differences in antibiotic treatment. CONCLUSIONS: The airway microbiota following burn and inhalation injury is altered in patients with a PaO2/FiO2 ratio <= 300 early after injury. Enrichment of specific taxa in patients with a PaO2/FiO2 ratio <= 300 may indicate airway environment and patient changes that favor these microbes. Longitudinal studies are necessary to identify stably colonizing taxa that play roles in hypoxemia and ARDS pathogenesis. PMID- 28358812 TI - Periodontitis increases rheumatic factor serum levels and citrullinated proteins in gingival tissues and alter cytokine balance in arthritic rats. AB - This study investigated some immunological features by experimental periodontitis (EP) and rheumatoid arthritis (RA) disease interact in destructive processes in arthritic rats. Rats were assigned to the following groups: EP +RA; RA; EP; and Negative Control. RA was induced by immunizations with type-II collagen and a local immunization with Complete Freund's adjuvant in the paw. Periodontitis was induced by ligating the right first molars. The serum level of rheumatoid factor (RF) and anti-citrullinated protein antibody (ACCPA) were measured before the induction of EP (T1) and at 28 days after (T2) by ELISA assay. ACCPA levels were also measured in the gingival tissue at T2. The specimens were processed for morphometric analysis of bone loss, and the gingival tissue surrounding the first molar was collected for the quantification of interleukin IL-1beta, IL-4, IL-6, IL-17 and TNF-alpha using a Luminex/MAGpix assay. Paw edema was analyzed using a plethysmometer. Periodontitis increased the RF and ACCPA levels in the serum and in the gingival tissue, respectively. Besides, the level of paw swelling was increased by EP and remained in progress until the end of the experiment, when EP was associated with RA. Greater values of IL-17 were observed only when RA was present, in spite of PE. It can be concluded that periodontitis increases rheumatic factor serum levels and citrullinated proteins level in gingival tissues and alter cytokine balance in arthritic rats; at the same time, arthritis increases periodontal destruction, confirming the bidirectional interaction between diseases. PMID- 28358813 TI - Prevalence and associated factors of pterygium among adults living in Gondar city, Northwest Ethiopia. AB - PURPOSE: The aim of this study was to assess the prevalence and associated factors of pterygium among adults living in Gondar city, Northwest Ethiopia. METHODS: A cross sectional design study was carried out in 390 participants in Gondar city from April 15 to May 7, 2016. Basic ophthalmic examination was performed using portable slit lamb, 3.5x magnifying loop with torch light and a pretested and structured questionnaire was completed. The raw data has been entered into EPI INFO 3.5.1 and analyzed by SPPSS version 20. Descriptive statistics was summarized descriptive data. Logistic regression was used to summarize the predictors of pterygium. The variables with p-value less than 0.05 were considered as significant risks of pterygium. RESULT: The prevalence of pterygium among study participants was 151(38.7% (95%CI; 33.8-43.8)). Among those who have pterygium, 149(98.7%) were developed pterygium on the nasal side and 15(9.9%) on temporal side of the either eye and 13(8.6%) have both. Age between 41-60(AOR = 2.20(95%CI: 1.22, 3.39)), age between 61-86(AOR = 7.97(95%CI: 2.74, 23.17)), male sex (AOR = 2.20(95%CI: 1.28, 3.82)), outdoor working area(AOR = 3.75(95%CI: 2.18, 6.46)), the use of traditional eye medication (AOR = 2.55 (95%CI: 1.04, 5.90)) and family history of pterygium (AOR = 6.68(95% CI: 2.53, 17.60)) were positively associated with pterygium whereas use of sunglass/hat (AOR = 0.40(95%CI:0.20, 0.78)) was negatively associated. CONCLUSION: There is a high prevalence of pterygium in Gondar city northwest Ethiopia. Old age, male sex, outdoor working area, utilization of traditional eye medication and family history of pterygium were statistically significant predictors of pterygium. The use of sunglass/hat was protective against pterygium. PMID- 28358814 TI - Dysfunctions of the basal ganglia-cerebellar-thalamo-cortical system produce motor tics in Tourette syndrome. AB - Motor tics are a cardinal feature of Tourette syndrome and are traditionally associated with an excess of striatal dopamine in the basal ganglia. Recent evidence increasingly supports a more articulated view where cerebellum and cortex, working closely in concert with basal ganglia, are also involved in tic production. Building on such evidence, this article proposes a computational model of the basal ganglia-cerebellar-thalamo-cortical system to study how motor tics are generated in Tourette syndrome. In particular, the model: (i) reproduces the main results of recent experiments about the involvement of the basal ganglia cerebellar-thalamo-cortical system in tic generation; (ii) suggests an explanation of the system-level mechanisms underlying motor tic production: in this respect, the model predicts that the interplay between dopaminergic signal and cortical activity contributes to triggering the tic event and that the recently discovered basal ganglia-cerebellar anatomical pathway may support the involvement of the cerebellum in tic production; (iii) furnishes predictions on the amount of tics generated when striatal dopamine increases and when the cortex is externally stimulated. These predictions could be important in identifying new brain target areas for future therapies. Finally, the model represents the first computational attempt to study the role of the recently discovered basal ganglia cerebellar anatomical links. Studying this non-cortex-mediated basal ganglia cerebellar interaction could radically change our perspective about how these areas interact with each other and with the cortex. Overall, the model also shows the utility of casting Tourette syndrome within a system-level perspective rather than viewing it as related to the dysfunction of a single brain area. PMID- 28358815 TI - AZALEP a randomized controlled trial of azathioprine to treat leprosy nerve damage and Type 1 reactions in India: Main findings. AB - BACKGROUND: Leprosy Type 1 reactions are difficult to treat and only 70% of patients respond to steroid treatment. Azathioprine has been used as an immune suppressant and we tested its efficacy in treating leprosy T1R. METHODOLOGY: Randomised controlled trial adding azathioprine to steroid treatment for leprosy reactions. This trial was conducted in four leprosy hospitals in India. Patients with a new leprosy Type 1 reaction affecting either skin or nerve were recruited. They were given a 20 week course of oral prednisolone either with placebo or azathioprine 50mg for 24, 36 or 48 weeks. Outcomes were measured using a verified combined clinical reaction severity score (CCS) and the score difference between baseline and end of study calculated. An intention to treat analysis was done on the 279 patients who had an outcome. PRINCIPAL FINDINGS: 345 patients were recruited, 145 were lost due to adverse events, loss to follow up or death. 36% needed extra steroids due to a recurrence of their skin and/or nerve reaction. 76% of patients had improvements in their CCS the end of the study, 22% had no change and 1.1% deteriorated. Adding azathioprine to steroid treatment did not improve CCS. So the improvements were attributable to treatment with steroids. We analysed the skin, sensory and motor scores separately and found that skin improvement contributed most with 78.9% of patients having skin improvement, azathioprine treatment for 48 weeks improved sensory scores it also improved motor scores but so did treatment with prednisolone alone. We identified significant adverse effects attributable to steroid treatment. When azathioprine and Dapsone were given together significant numbers of patients developed significant anaemia. CONCLUSIONS: Azathioprine is not recommended for the treatment of leprosy reactions and does not improve steroid treatment. Recurrent reactions are a major challenge. We have also identified that 65% of patients with sensory and 50% with motor nerve damage do not improve. Future studies should test giving azathioprine in the treatment of nerve damage and giving a higher dose for 48 weeks to patients. These findings highlight the difficulty in switching off leprosy inflammation and the need for better treatments for reactions and nerve damage. There is also a research need to identify patients who have recurrences and optimize treatments for them. Patients with recurrences may benefit from combined treatment with steroids and azathioprine. We have also shown that significant numbers of patients treated with steroids develop adverse effects and this needs to be highlighted in leprosy programmes. Research is needed to identify patients who do not respond to steroid treatment and develop alternative treatments for them. TRIAL REGISTRATION: ClinicalTrials.gov This trial was registered with the Indian Council of Medical research clinical Trial register as a clinical trial Number-REFCTRI/2016/12/007558. PMID- 28358816 TI - Comparison of O-polysaccharide and hemolysin co-regulated protein as target antigens for serodiagnosis of melioidosis. AB - BACKGROUND: Melioidosis is a severe disease caused by Burkholderia pseudomallei. Clinical manifestations are diverse and acute infections require immediate treatment with effective antibiotics. While culture is the current diagnostic standard, it is time-consuming and has low sensitivity. In endemic areas, inaccessibility to biosafety level 3 facilities and a lack of good serodiagnostic tools can impede diagnosis and disease surveillance. Recent studies have suggested that O-polysaccharide (OPS) and hemolysin co-regulated protein 1 (Hcp1) are promising target antigens for serodiagnosis of melioidosis. METHODOLOGY/PRINCIPLE FINDINGS: We evaluated rapid ELISAs using crude antigens, purified OPS and Hcp1 to measure antibody levels in three sets of sera: (i) 419 serum samples from melioidosis patients, Thai and U.S. healthy donors, (ii) 120 serum samples from patients with other bacterial infections, and (iii) 423 serum samples from 200 melioidosis patients obtained upon admission and at 12 and 52 weeks post-recovery. We observed significantly higher antibody levels using the crude antigen prepared from wild type B. pseudomallei K96243 compared to that of an OPS-mutant. The areas under receiver operator characteristics (AUROCCs) for diagnosis were compared for individual Hcp1-ELISA or OPS-ELISA or combined Hcp1/OPS-ELISA. For Thai donors, AUROCCs were highest and comparable between the Hcp1-ELISA and the combined Hcp1/OPS-ELISA (0.95 versus 0.94). For U.S. donors, the AUROCC was highest for the combined Hcp1/OPS-ELISA (0.96). Significantly higher seropositivity was observed in diabetic patients compared to those without diabetes for both the Hcp1-ELISA (87.3% versus 69.7%) and OPS-ELISA (88.1% versus 60.6%). Although antibody levels for Hcp1 were highest upon admission, the titers declined by week 52 post-recovery. CONCLUSIONS/SIGNIFICANCE: Hcp1 and OPS are promising candidates for serodiagnosis of melioidosis in different groups of patients. The Hcp1-ELISA performed better than the OPS-ELISA in endemic areas, thus, Hcp1 represents a promising target antigen for the development of POC tests for acute melioidosis. PMID- 28358817 TI - Downregulation of UBC9 promotes apoptosis of activated human LX-2 hepatic stellate cells by suppressing the canonical NF-kappaB signaling pathway. AB - UBC9, the only known E2-conjugating enzyme involved in SUMOylation, is a key regulator in fibrosis. However, the roles of UBC9 in liver fibrosis remain unclear. Therefore, in this study, we investigated the roles of UBC9 in HSC apoptosis and liver fibrogenesis. Our results showed that the UBC9 levels in activated LX-2 cells, HepG2 and SMMC-7721 were increased compared with LO2, and the expression of UBC9 in activated LX-2 cells, HepG2 and SMMC-7721 were no significant differences. The expression of UBC9 was effectively down-regulated by the UBC9-shRNA plasmid, and this effect was accompanied by the attenuated expression of the myofibroblast markers smooth muscle actin (alpha-SMA) and Collagen I. Downregulation of UBC9 also promotes activated HSCs apoptosis by up regulating cell apoptosis-related proteins. Further, knockdown of UBC9 in activated HSCs inhibited cell viability and caused cell cycle arrest in the G2 phase. Moreover, knockdown of UBC9 suppressed the activation of NF-kappaB signaling pathways. In conclusion, these results demonstrated that down regulation of UBC9 expression induced activated LX-2 cell apoptosis and promoted cells to return to a quiescent state by inhibiting the NF-kappaB signaling pathway. These results provide novel mechanistic insights for the anti-fibrotic effect of UBC9. PMID- 28358820 TI - Epidemiological evaluation of cat health at a first-response animal shelter in Fukushima, following the Great East Japan Earthquakes of 2011. AB - The Great East Japan Earthquakes of March 11, 2011 caused immense harm to the community and subsequent nuclear accident in Fukushima Prefecture extended the damage. Local residents were forced to evacuated without pets and the left behind animals were rescued from the restricted zone one month later. Unplanned animal rescue and unregulated sheltering caused secondary damage to animals such as disease epidemics at impounded animal shelter. The purpose of this study was to retrospectively evaluate the incidence of upper respiratory infection (URI) and diarrhea in cats at the first response animal shelter in Fukushima, and investigate factors affecting the duration of disease and determinants of treatments performed. Eighty percent and 59% of impounded cats developed URI, 71% and 54% of cats developed diarrhea, and 91% and 83% of cats had at least one disease in 2011 and 2012, respectively. Uses of multiple drug administration (more than five drugs) was associated with prolonged URI and diarrhea. Multiple antibiotics, antihistamines, interferon, and steroids were associated with relapse of and prolonged URI. Developing a standardized treatment protocol for commonly observed diseases at Japanese animal shelters to prevent and control diseases, to promote animal welfare, and protect public health in the face of future disasters is overdue. PMID- 28358818 TI - The antimicrobial volatile power of the rhizospheric isolate Pseudomonas donghuensis P482. AB - Soil and rhizosphere bacteria produce an array of secondary metabolites including a wide range of volatile organic compounds (VOCs). These compounds play an important role in the long-distance interactions and communication between (micro)organisms. Furthermore, bacterial VOCs are involved in plant pathogens inhibition and induction of soil fungistasis and suppressivenes. In the present study, we analysed the volatile blend emitted by the rhizospheric isolate Pseudomonas donghuensis P482 and evaluated the volatile effect on the plant pathogenic fungi and bacteria as well as one oomycete. Moreover, we investigated the role of the GacS/GacA system on VOCs production in P. donghuensis P482. The results obtained demonstrated that VOCs emitted by P. donghuensis P482 have strong antifungal and antioomycete, but not antibacterial activity. The production of certain volatiles such as dimethyl sulfide, S-methyl thioacetate, methyl thiocyanate, dimethyl trisulfide, 1-undecan and HCN is depended on the GacS/GacA two-component regulatory system. Apparently, these compounds play an important role in the pathogens suppression as the gacA mutant entirely lost the ability to inhibit via volatiles the growth of tested plant pathogens. PMID- 28358819 TI - Quantifying the foodscape: A systematic review and meta-analysis of the validity of commercially available business data. AB - This paper reviews studies of the validity of commercially available business (CAB) data on food establishments ("the foodscape"), offering a meta-analysis of characteristics associated with CAB quality and a case study evaluating the performance of commonly-used validity indicators describing the foodscape. Existing validation studies report a broad range in CAB data quality, although most studies conclude that CAB quality is "moderate" to "substantial". We conclude that current studies may underestimate the quality of CAB data. We recommend that future validation studies use density-adjusted and exposure measures to offer a more meaningful characterization of the relationship of data error with spatial exposure. PMID- 28358821 TI - The role of intervention mapping in designing disease prevention interventions: A systematic review of the literature. AB - OBJECTIVE: To assess the role of Intervention Mapping (IM) in designing disease prevention interventions worldwide. METHODS: Systematic search and review of the relevant literature-peer-reviewed and grey-was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. FINDINGS: Only five of the twenty two included studies reviewed were RCTs that compared intervention using IM protocol with placebo intervention, and provided the outcomes in terms of percentage increase in the uptake of disease-prevention programmes, and only one of the five studies provided an effect measure in the form of relative risk (RR = 1.59, 95% CI = 1.08-2.34, p = 0.02). Of the five RCTs, three were rated as strong evidences, one as a medium evidence and one as a weak evidence, and they all reported statistically significant difference between the two study groups, with disease prevention interventions that have used the intervention mapping approach generally reported significant increases in the uptake of disease-prevention interventions, ranging from 9% to 28.5% (0.0001 <= p <= 0.02), On the other hand, all the 22 studies have successfully identified the determinants of the uptake of disease prevention interventions that is essential to the success of disease prevention programmes. CONCLUSION: Intervention Mapping has been successfully used to plan, implement and evaluate interventions that showed significant increase in uptake of disease prevention programmes. This study has provided a good understanding of the role of intervention mapping in designing disease prevention interventions, and a good foundation upon which subsequent reviews can be guided. PMID- 28358822 TI - Dry season limnological conditions and basin geology exhibit complex relationships with delta13C and delta15N of carbon sources in four Neotropical floodplains. AB - Studies in freshwater ecosystems are seeking to improve understanding of carbon flow in food webs and stable isotopes have been influential in this work. However, variation in isotopic values of basal production sources could either be an asset or a hindrance depending on study objectives. We assessed the potential for basin geology and local limnological conditions to predict stable carbon and nitrogen isotope values of six carbon sources at multiple locations in four Neotropical floodplain ecosystems (Parana, Pantanal, Araguaia, and Amazon). Limnological conditions exhibited greater variation within than among systems. delta15N differed among basins for most carbon sources, but delta13C did not (though high within-basin variability for periphyton, phytoplankton and particulate organic carbon was observed). Although delta13C and delta15N values exhibited significant correlations with some limnological factors within and among basins, those relationships differed among carbon sources. Regression trees for both carbon and nitrogen isotopes for all sources depicted complex and in some cases nested relationships, and only very limited similarity was observed among trees for different carbon sources. Although limnological conditions predicted variation in isotope values of carbon sources, we suggest the resulting models were too complex to enable mathematical corrections of source isotope values among sites based on these parameters. The importance of local conditions in determining variation in source isotope values suggest that isotopes may be useful for examining habitat use, dispersal and patch dynamics within heterogeneous floodplain ecosystems, but spatial variability in isotope values needs to be explicitly considered when testing ecosystem models of carbon flow in these systems. PMID- 28358824 TI - Levy noise improves the electrical activity in a neuron under electromagnetic radiation. AB - As the fluctuations of the internal bioelectricity of nervous system is various and complex, the external electromagnetic radiation induced by magnet flux on membrane can be described by the non-Gaussian type distribution of Levy noise. Thus, the electrical activities in an improved Hindmarsh-Rose model excited by the external electromagnetic radiation of Levy noise are investigated and some interesting modes of the electrical activities are exhibited. The external electromagnetic radiation of Levy noise leads to the mode transition of the electrical activities and spatial phase, such as from the rest state to the firing state, from the spiking state to the spiking state with more spikes, and from the spiking state to the bursting state. Then the time points of the firing state versus Levy noise intensity are depicted. The increasing of Levy noise intensity heightens the neuron firing. Also the stationary probability distribution functions of the membrane potential of the neuron induced by the external electromagnetic radiation of Levy noise with different intensity, stability index and skewness papremeters are analyzed. Moreover, through the positive largest Lyapunov exponent, the parameter regions of chaotic electrical mode of the neuron induced by the external electromagnetic radiation of Levy noise distribution are detected. PMID- 28358823 TI - Genome-wide association screens for Achilles tendon and ACL tears and tendinopathy. AB - Achilles tendinopathy or rupture and anterior cruciate ligament (ACL) rupture are substantial injuries affecting athletes, associated with delayed recovery or inability to return to competition. To identify genetic markers that might be used to predict risk for these injuries, we performed genome-wide association screens for these injuries using data from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort consisting of 102,979 individuals. We did not find any single nucleotide polymorphisms (SNPs) associated with either of these injuries with a p-value that was genome-wide significant (p<5x10-8). We found, however, four and three polymorphisms with p-values that were borderline significant (p<10-6) for Achilles tendon injury and ACL rupture, respectively. We then tested SNPs previously reported to be associated with either Achilles tendon injury or ACL rupture. None showed an association in our cohort with a false discovery rate of less than 5%. We obtained, however, moderate to weak evidence for replication in one case; specifically, rs4919510 in MIR608 had a p-value of 5.1x10-3 for association with Achilles tendon injury, corresponding to a 7% chance of false replication. Finally, we tested 2855 SNPs in 90 candidate genes for musculoskeletal injury, but did not find any that showed a significant association below a false discovery rate of 5%. We provide data containing summary statistics for the entire genome, which will be useful for future genetic studies on these injuries. PMID- 28358825 TI - Nature's patchwork: How water sources and soil salinity determine the distribution and structure of halophytic plant communities in arid environments of the Eastern Pamir. AB - The eastern part of the Pamir Mountains, located in Central Asia, is characterized by great climatic continentality and aridity. Wetlands developed in this hostile region are restricted to spring areas, terraces of shallow lakes or floodplains along rivers, and provide diversified ecosystem services e.g. as water reservoirs, refugia for rare species and pastures for domestic cattle. These ecosystems are particularly susceptible to climate changes, that in the Pamir Mountains result in increased temperatures, intense permafrost/glacial melt and alterations of precipitation patterns. Climatic changes affect pasture management in the mountains, causing overutilization of sites located at lower elevations. Thus, both climate and man-induced disturbances may violate the existing ecological equilibrium in high-mountain wetlands of the Eastern Pamir, posing a serious risk to their biodiversity and to food security of the local population. In this context, we sought to assess how environmental drivers (with special focus on soil features and potential water sources) shape the distribution and diversity of halophytic plant communities developed in valleys in the Eastern Pamir. This task was completed by means of a vegetation survey and comprehensive analyses of habitat conditions. The lake terraces and floodplains studied were covered by a repetitive mosaic of plant communities determined by differences in soil moisture and salinity. On lower, wetter sites, this patchwork was formed by Blysmus rufus dominated salt marshes, saline small sedge meadows and saline meadows with Kobresia royleana and Primula pamirica; and on drier, elevated sites, by endemic grasslands with Hordeum brevisubulatum and Puccinellia species and patches of xerohalophytic vegetation. Continuous instability of water sources and summer droughts occurring in the Pamir Mountains may lead to significant structural and functional transformations of described wetland ecosystems. Species more tolerant to decreased soil moisture and/or increased soil salinity will expand, leading to alterations of ecosystem services provided by the Pamirs' wetlands. The described research will help to assess the current state of the wetlands and to predict directions of their future changes. PMID- 28358827 TI - Vitamin D and hypertension: Prospective study and meta-analysis. AB - OBJECTIVES: The study sought to determine the link between vitamin D concentrations and incident hypertension in prospective study and meta-analysis. METHODS: The study was embedded in the Kailuan Study, a population-based cohort of adults that contains underground miners. In 2012, we studied 2,456 men and women free of prevalent hypertension, age 21 to 67 at baseline. Serum 25 hydroxyvitamin D was measured from previously frozen baseline samples using ELISA (Enzyme-Linked ImmunoadSorbent Assay). We use the logistic regression analysis to estimate the odd radio (ORs) 95% confidence intervals (CIs) for 25-hydroxyvitamin D [25(OH)D] concentrations with incident hypertension. To help place our new data in context, we conducted a systemic review and meta-analysis of previous prospective reports of vitamin D and hypertension. RESULTS: During a median follow-up of 2 years, 42.6% of the cohort (n = 1047) developed hypertension. Compared with the 25-hydroxyvitamin D >30ng/ml, 25-hydroxyvitamin D <20 ng/ml was associated with a greater hypertension risk (OR: 1.225 [95% CI: 1.010 to 1.485] p = 0.04), although the association was attenuated and not statistically significant after adjusting for potential confounders (OR: 1.092 [95% CI: 0.866 to 1.377] p = 0.456). This meta-analysis included seven prospective studies for 53,375 participants using adjusted HR founded a significant association between vitamin D deficiencies and incident hypertension (HRs = 1.235 (95% CI: 1.083 to 1.409, p = 0.002)). CONCLUSION: Lower serum 25-hydroxyvitamin D concentrations were not associated with a greater risk of incident hypertension. More research is needed to further determine the role of 25-hydroxyvitamin D in hypertension prevention and therapy. PMID- 28358826 TI - A growing animal model for neonatal repair of large diaphragmatic defects to evaluate patch function and outcome. AB - OBJECTIVES: We aimed to develop a more representative model for neonatal congenital diaphragmatic hernia repair in a large animal model, by creating a large defect in a fast-growing pup, using functional pulmonary and diaphragmatic read outs. BACKGROUND: Grafts are increasingly used to repair congenital diaphragmatic hernia with the risk of local complications. Growing animal models have been used to test novel materials. METHODS: 6-week-old rabbits underwent fiberoptic intubation, left subcostal laparotomy and hemi-diaphragmatic excision (either nearly complete (n = 13) or 3*3cm (n = 9)) and primary closure (Gore-Tex patch). Survival was further increased by moving to laryngeal mask airway ventilation (n = 15). Sham operated animals were used as controls (n = 6). Survivors (90 days) underwent chest X-Ray (scoliosis), measurements of maximum transdiaphragmatic pressure and breathing pattern (tidal volume, Pdi). Rates of herniation, lung histology and right hemi-diaphragmatic fiber cross-sectional area was measured. RESULTS: Rabbits surviving 90 days doubled their weight. Only one (8%) with a complete defect survived to 90 days. In the 3*3cm defect group all survived to 48 hours, however seven (78%) died later (16-49 days) from respiratory failure secondary to tracheal stricture formation. Use of a laryngeal mask airway doubled 90-day survival, one pup displaying herniation (17%). Cobb angel measurements, breathing pattern, and lung histology were comparable to sham. Under exertion, sham animals increased their maximum transdiaphragmatic pressure 134% compared to a 71% increase in patched animals (p<0.05). Patched animals had a compensatory increase in their right hemi-diaphragmatic fiber cross sectional area (p<0.0001). CONCLUSIONS: A primarily patched 3*3cm defect in growing rabbits, under laryngeal mask airway ventilation, enables adequate survival with normal lung function and reduced maximum transdiaphragmatic pressure compared to controls. PMID- 28358828 TI - Significant association between perceived HIV related stigma and late presentation for HIV/AIDS care in low and middle-income countries: A systematic review and meta-analysis. AB - BACKGROUND: Late presentation for human immunodeficiency virus (HIV) care is a major impediment for the success of antiretroviral therapy (ART) outcomes. The role that stigma plays as a potential barrier to timely diagnosis and treatment of HIV among people living with HIV/AIDS (acquired immunodeficiency syndrome) is ambivalent. This review aimed to assess the best available evidence regarding the association between perceived HIV related stigma and time to present for HIV/AIDS care. METHODS: Quantitative studies conducted in English language between 2002 and 2016 that evaluated the association between HIV related stigma and late presentation for HIV care were sought across four major databases. This review considered studies that included the following outcome: 'late HIV testing', 'late HIV diagnosis' and 'late presentation for HIV care after testing'. Data were extracted using a standardized Joanna Briggs Institute (JBI) data extraction tool. Meta- analysis was undertaken using Revman-5 software. I2 and chi-square test were used to assess heterogeneity. Summary statistics were expressed as pooled odds ratio with 95% confidence intervals and corresponding p-value. RESULTS: Ten studies from low- and middle- income countries met the search criteria, including six (6) and four (4) case control studies and cross-sectional studies respectively. The total sample size in the included studies was 3,788 participants. Half (5) of the studies reported a significant association between stigma and late presentation for HIV care. The meta-analytical association showed that people who perceived high HIV related stigma had two times more probability of late presentation for HIV care than who perceived low stigma (pooled odds ratio = 2.4; 95%CI: 1.6-3.6, I2 = 79%). CONCLUSIONS: High perceptions of HIV related stigma influenced timely presentation for HIV care. In order to avoid late HIV care presentation due the fear of stigma among patients, health professionals should play a key role in informing and counselling patients on the benefits of early HIV testing or early entry to HIV care. Additionally, linking the systems and positive case tracing after HIV testing should be strengthened. PMID- 28358829 TI - Lower levels of uric acid and striatal dopamine in non-tremor dominant Parkinson's disease subtype. AB - Parkinson's disease (PD) patients who present with tremor and maintain a predominance of tremor have a better prognosis. Similarly, PD patients with high levels of uric acid (UA), a natural neuroprotectant, have also a better disease course. Our aim was to investigate whether PD motor subtypes differ in their levels of UA, and if these differences correlate with the degree of dopamine transporter (DAT) availability. We included 75 PD patients from whom we collected information about their motor symptoms, DAT imaging and UA concentration levels. Based on the predominance of their motor symptoms, patients were classified into postural instability and gait disorder (PIGD, n = 36), intermediate (I, n = 22), and tremor-dominant (TD, n = 17) subtypes. The levels of UA and striatal DAT were compared across subtypes and the correlation between these two measures was also explored. We found that PIGD patients had lower levels of UA (3.7 vs 4.5 vs 5.3 mg/dL; P<0.001) and striatal DAT than patients with an intermediate or TD phenotype. Furthermore, UA levels significantly correlated with the levels of striatal DAT. We also observed that some PIGD (25%) and I (45%) patients had a predominance of tremor at disease onset. We speculate that UA might be involved in the maintenance of the less damaging TD phenotype and thus also in the conversion from TD to PIGD. Low levels of this natural antioxidant could lead to a major neuronal damage and therefore influence the conversion to a more severe motor phenotype. PMID- 28358830 TI - Migration of small ligands in globins: Xe diffusion in truncated hemoglobin N. AB - In heme proteins, the efficient transport of ligands such as NO or O2 to the binding site is achieved via ligand migration networks. A quantitative assessment of ligand diffusion in these networks is thus essential for a better understanding of the function of these proteins. For this, Xe migration in truncated hemoglobin N (trHbN) of Mycobacterium Tuberculosis was studied using molecular dynamics simulations. Transitions between pockets of the migration network and intra-pocket relaxation occur on similar time scales (10 ps and 20 ps), consistent with low free energy barriers (1-2 kcal/mol). Depending on the pocket from where Xe enters a particular transition, the conformation of the side chains lining the transition region differs which highlights the coupling between ligand and protein degrees of freedom. Furthermore, comparison of transition probabilities shows that Xe migration in trHbN is a non-Markovian process. Memory effects arise due to protein rearrangements and coupled dynamics as Xe moves through it. PMID- 28358831 TI - Ten simple rules for responsible big data research. PMID- 28358832 TI - Ten simple rules for short and swift presentations. PMID- 28358833 TI - Differentiation of malignant and benign breast lesions: Added value of the qualitative analysis of breast lesions on diffusion-weighted imaging (DWI) using readout-segmented echo-planar imaging at 3.0 T. AB - OBJECTIVE: To determine the added value of qualitative analysis as an adjunct to quantitative analysis for the discrimination of benign and malignant lesions in patients with breast cancer using diffusion-weighted imaging (DWI) with readout segmented echo-planar imaging (rs-EPI). METHODS: A total of 99 patients with 144 lesions were reviewed from our prospectively collected database. DWI data were obtained using rs-EPI acquired at 3.0 T. The diagnostic performances of DWI in the qualitative, quantitative, and combination analyses were compared with that of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Additionally, the effect of lesion size on the diagnostic performance of the DWI combination analysis was evaluated. RESULTS: The strongest indicators of malignancy on DWI were a heterogeneous pattern (P = 0.005) and an apparent diffusion coefficient (ADC) value <1.0 * 10-3 mm2/sec (P = 0.002). The area under the curve (AUC) values for the qualitative analysis, quantitative analysis, and combination analysis on DWI were 0.732 (95% CI, 0.651-0.803), 0.780 (95% CI, 0.703-0.846), and 0.826 (95% CI, 0.754-0.885), respectively (P<0.0001). The AUC for the combination analysis on DWI was superior to that for DCE-MRI alone (0.651, P = 0.003) but inferior to that for DCE-MRI plus the ADC value (0.883, P = 0.03). For the DWI combination analysis, the sensitivity was significantly lower in the size <=1 cm group than in the size >1 cm group (80% vs. 95.6%, P = 0.034). CONCLUSIONS: Qualitative analysis of tumor morphology was diagnostically applicable on DWI using rs-EPI. This qualitative analysis adds value to quantitative analyses for lesion characterization in patients with breast cancer. PMID- 28358834 TI - A pair-conformation-dependent scoring function for evaluating 3D RNA-protein complex structures. AB - Computational prediction of RNA-protein complex 3D structures includes two basic steps: one is sampling possible structures and another is scoring the sampled structures to pick out the correct one. At present, constructing accurate scoring functions is still not well solved and the performances of the scoring functions usually depend on used benchmarks. Here we propose a pair-conformation-dependent scoring function, 3dRPC-Score, for 3D RNA-protein complex structure prediction by considering the nucleotide-residue pairs having the same energy if their conformations are similar, instead of the distance-only dependence of the most existing scoring functions. Benchmarking shows that 3dRPC-Score has a consistent performance in three test sets. PMID- 28358836 TI - Selection of key sequence-based features for prediction of essential genes in 31 diverse bacterial species. AB - Genes that are indispensable for survival are essential genes. Many features have been proposed for computational prediction of essential genes. In this paper, the least absolute shrinkage and selection operator method was used to screen key sequence-based features related to gene essentiality. To assess the effects, the selected features were used to predict the essential genes from 31 bacterial species based on a support vector machine classifier. For all 31 bacterial objects (21 Gram-negative objects and ten Gram-positive objects), the features in the three datasets were reduced from 57, 59, and 58, to 40, 37, and 38, respectively, without loss of prediction accuracy. Results showed that some features were redundant for gene essentiality, so could be eliminated from future analyses. The selected features contained more complex (or key) biological information for gene essentiality, and could be of use in related research projects, such as gene prediction, synthetic biology, and drug design. PMID- 28358835 TI - Fast growth conditions uncouple the final stages of chromosome segregation and cell division in Escherichia coli. AB - Homologous recombination between the circular chromosomes of bacteria can generate chromosome dimers. They are resolved by a recombination event at a specific site in the replication terminus of chromosomes, dif, by dedicated tyrosine recombinases. The reaction is under the control of a cell division protein, FtsK, which assembles into active DNA pumps at mid-cell during septum formation. Previous studies suggested that activation of Xer recombination at dif was restricted to chromosome dimers in Escherichia coli but not in Vibrio cholerae, suggesting that FtsK mainly acted on chromosome dimers in E. coli but frequently processed monomeric chromosomes in V. cholerae. However, recent microscopic studies suggested that E. coli FtsK served to release the MatP mediated cohesion and/or cell division apparatus-interaction of sister copies of the dif region independently of chromosome dimer formation. Here, we show that these apparently paradoxical observations are not linked to any difference in the dimer resolution machineries of E. coli and V. cholerae but to differences in the timing of segregation of their chromosomes. V. cholerae harbours two circular chromosomes, chr1 and chr2. We found that whatever the growth conditions, sister copies of the V. cholerae chr1 dif region remain together at mid-cell until the onset of constriction, which permits their processing by FtsK and the activation of dif-recombination. Likewise, sister copies of the dif region of the E. coli chromosome only separate after the onset of constriction in slow growth conditions. However, under fast growth conditions the dif sites separate before constriction, which restricts XerCD-dif activity to resolving chromosome dimers. PMID- 28358837 TI - Dietary changes needed to reach nutritional adequacy without increasing diet cost according to income: An analysis among French adults. AB - OBJECTIVE: To explore the dietary changes needed to achieve nutritional adequacy across income levels at constant energy and diet cost. MATERIALS AND METHODS: Individual diet modelling was used to design iso-caloric, nutritionally adequate optimised diets for each observed diet in a sample of adult normo-reporters aged >=20 years (n = 1,719) from the Individual and National Dietary Survey (INCA2), 2006-2007. Diet cost was estimated from mean national food prices (2006-2007). A first set of free-cost models explored the impact of optimisation on the variation of diet cost. A second set of iso-cost models explored the dietary changes induced by the optimisation with cost set equal to the observed one. Analyses of dietary changes were conducted by income quintiles, adjusting for energy intake, sociodemographic and socioeconomic variables, and smoking status. RESULTS: The cost of observed diets increased with increasing income quintiles. In free-cost models, the optimisation increased diet cost on average (+0.22 +/- 1.03 euros/d) and within each income quintile, with no significant difference between quintiles, but with systematic increases for observed costs lower than 3.85 euros/d. In iso-cost models, it was possible to design nutritionally adequate diets whatever the initial observed cost. On average, the optimisation at iso-cost increased fruits and vegetables (+171 g/day), starchy foods (+121 g/d), water and beverages (+91 g/d), and dairy products (+20 g/d), and decreased the other food groups (e.g. mixed dishes and salted snacks), leading to increased total diet weight (+300 g/d). Those changes were mostly similar across income quintiles, but lower-income individuals needed to introduce significantly more fruit and vegetables than higher-income ones. CONCLUSIONS: In France, the dietary changes needed to reach nutritional adequacy without increasing cost are similar regardless of income, but may be more difficult to implement when the budget for food is lower than 3.85 euros/d. PMID- 28358839 TI - Frequency and clinical significance of short cervix in patients with preterm premature rupture of membranes. AB - OBJECTIVE: Cervical length measurement has been uggested as a useful tool for predicting intra-amniotic infection/inflammation in preterm labor, but little information is available in the setting of preterm premature rupture of membranes (pPROM). We aimed to determine whether a short cervical length is independently associated with an increased risk of intra-amniotic infection or inflammation and impending preterm delivery in women with pPROM. METHODS: This was a retrospective cohort study involving 171 consecutive singleton pregnant women with pPROM (21+0 33+6 weeks' gestation), who underwent amniocentesis. Amniotic fluid (AF) was cultured, and assayed for interleukin (IL)-6 and IL-8. Cervical length was measured at the time of amniocentesis by transvaginal ultrasonography with an aseptic technique. Short cervical length was defined as a cervical length of <=15 mm. Intra-amniotic infection was defined as a positive AF culture for microorganisms and intra-amniotic inflammation was defined as elevated AF concentrations of IL-6 or IL-8 (IL-6 >=1.5 ng/mL and/or IL-8 >=1.3 ng/mL). RESULTS: Fifty (29.2%) women had a sonographic cervical length of <=15mm. On univariate analysis, short cervical length was associated with an increased risk for intra-amniotic infection and/or inflammation; no other parameters studied showed a significant association. Multivariable analyses indicated that short cervical length was significantly associated with a higher risk of impending preterm delivery (within 2 days of measurement, within 7 days of measurement, and before 34 weeks), and remained significant after adjustment for potential confounders. CONCLUSION: In women with pPROM, short cervical length is associated with an increased risk for intra-amniotic infection/inflammation and associated with impending preterm delivery, independent of the presence of intra-amniotic infection/inflammation. PMID- 28358838 TI - Metal-dependent SpoIIE oligomerization stabilizes FtsZ during asymmetric division in Bacillus subtilis. AB - SpoIIE is a bifunctional protein involved in asymmetric septum formation and in activation of the forespore compartment-specific transcription factor sigmaF through dephosphorylation of SpoIIAA-P. The phosphatase activity of SpoIIE requires Mn2+ as a metal cofactor. Here, we show that the presence of a metal cofactor also influences SpoIIE oligomerization and asymmetric septum formation. Absence of Mn2+ from sporulation medium results in a delay of the formation of polar FtsZ-rings, similar to a spoIIE null mutant. We purified the entire cytoplasmic part of the SpoIIE protein, and show that the protein copurifies with bound metals. Metal binding both stimulates SpoIIE oligomerization, and results in the formation of larger oligomeric structures. The presence of SpoIIE oligomers reduces FtsZ GTP hydrolysis activity and stabilizes FtsZ polymers in a light scattering assay. Combined, these results indicate that metal binding is not just required for SpoIIE phosphatase activity but also is important for SpoIIE's role in asymmetric septum formation. PMID- 28358840 TI - A tetrameric peptide derived from bovine lactoferricin as a potential therapeutic tool for oral squamous cell carcinoma: A preclinical model. AB - Oral squamous cell carcinoma is the fifth most common epithelial cancer in the world, and its current clinical treatment has both low efficiency and poor selectivity. Cationic amphipathic peptides have been proposed as new drugs for the treatment of different types of cancer. The main goal of the present work was to determine the potential of LfcinB(20-25)4, a tetrameric peptide based on the core sequence RRWQWR of bovine lactoferricin LfcinB(20-25), for the treatment of OSCC. In brief, OSCC was induced in the buccal pouch of hamsters by applying 7,12 Dimethylbenz(a)anthracene, and tumors were treated with one of the following peptides: LfcinB(20-25)4, LfcinB(20-25), or vehicle (control). Lesions were macroscopically evaluated every two days and both histological and serum IgG assessments were conducted after 5 weeks. The size of the tumors treated with LfcinB(20-25)4 and LfcinB(20-25) was smaller than that of the control group (46.16+/-4.41 and 33.92+/-2.74 mm3 versus 88.77+/-10.61 mm3, respectively). Also, LfcinB(20-25)4 caused acellularity in the parenchymal tumor compared with LfcinB(20-25) and vehicle treatments. Furthermore, our results demonstrated that both LfcinB(20-25)4 and LfcinB(20-25) induced higher degree of apoptosis relative to the untreated tumors (75-86% vs 8%, respectively). Moreover, although the lowest inflammatory response was achieved when LfcinB(20-25)4 was used, this peptide appeared to induce higher levels of IgG antibodies relative to the vehicle and LfcinB(20-25). In addition the cellular damage and selectivity of the LfcinB(20-25)4 peptide was evaluated in vitro. These assays showed that LfcinB(20 25)4 triggers a selective necrotic effect in the carcinoma cell line. Cumulatively, these data indicate that LfcinB(20-25)4 could be considered as a new therapeutic agent for the treatment of OSCC. PMID- 28358841 TI - Is task-shifting a solution to the health workers' shortage in Northern Ghana? AB - OBJECTIVE: To explore the experiences and perceptions of health workers and implementers of task-shifting in rural health facilities in Upper East Region, Ghana. METHODS: Data was collected through field interviews. A total of sixty eight (68) in-depth interviews were conducted with health workers' in primary health care facilities (health centres); Four in-depth interviews with key persons involved in staff management was conducted to understand how task shifting is organised including its strengths and challenges. The health workers interview guide was designed with the aim of getting data on official tasks of health workers, additional tasks assigned to them, how they perceive these tasks, and the challenges associated with the practice of task-shifting. FINDINGS: Task shifting is a practice being used across the health facilities in the study area to help reduce the impact of insufficient health workers. Generally, health workers had a comprehensive training that supported the organisation of task shifting. However, staff members' are sometimes engaged in tasks above their level of training and beyond their actual job descriptions. Adequate training is usually not provided before additional tasks are assigned to staff members. Whilst some health workers perceived the additional tasks they performed as an opportunity to learn new skills, others described these as stressful and overburdening. CONCLUSION: Task-shifting has the potential to contribute to addressing the insufficient health workforce, and thereby improving health delivery system where the procedures are well defined and staff members work in a coordinated and organised manner. The provision of adequate training and supervision for health workers is important in order to improve their expertise before additional tasks are assigned to them so that the quality of care would not be compromised. PMID- 28358843 TI - Phase diagrams and dynamics of a computationally efficient map-based neuron model. AB - We introduce a new map-based neuron model derived from the dynamical perceptron family that has the best compromise between computational efficiency, analytical tractability, reduced parameter space and many dynamical behaviors. We calculate bifurcation and phase diagrams analytically and computationally that underpins a rich repertoire of autonomous and excitable dynamical behaviors. We report the existence of a new regime of cardiac spikes corresponding to nonchaotic aperiodic behavior. We compare the features of our model to standard neuron models currently available in the literature. PMID- 28358842 TI - The risk of clopidogrel resistance is associated with ABCB1 polymorphisms but not promoter methylation in a Chinese Han population. AB - The goal of our study was to investigate the contribution of ABCB1 expression to the risk of clopidogrel resistance (CR). Platelets functions were measured using the Verify-Now P2Y12 assay. Applying Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP), the single-nucleotide polymorphisms (SNPs) was tested. Using bisulphite pyrosequencing assay, we investigated the association of the ABCB1 DNA methylation levels and CR. It was shown that female, hypertension, and lower albumin levels increased the risk of CR (P<0.05). If patients did not have hypoproteinaemia or had hypertension, the SNP in rs1045642 was associated with CR (CC vs. TT: albumin >=35, P = 0.042; hypertension, P = 0.045; C vs. T: albumin >=35, P = 0.033; hypertension, P = 0.040). Additionally, the platelet inhibition of the CT+TT genotype in rs1128503 was larger than that of the CC genotype (P = 0.021). Multivariate logistic regression analysis showed that male, higher albumin and hsCRP decreased the risk of CR, and the stent size maybe positively correlated with CR. The SNP in rs1045642 was related to all cause mortality (P = 0.024). We did not find any relationship between the methylation levels of the ABCB1 promoter and CR. In conclusions, our study indicated that ABCB1 polymorphisms might be useful in further evaluating the pathogenesis of CR. PMID- 28358844 TI - Olfactory effects of a hypervariable multicomponent pheromone in the red-legged salamander, Plethodon shermani. AB - Chemical communication via chemosensory signaling is an essential process for promoting and modifying reproductive behavior in many species. During courtship in plethodontid salamanders, males deliver a mixture of non-volatile proteinaceous pheromones that activate chemosensory neurons in the vomeronasal epithelium (VNE) and increase female receptivity. One component of this mixture, Plethodontid Modulating Factor (PMF), is a hypervariable pheromone expressed as more than 30 unique isoforms that differ between individual males-likely driven by co-evolution with female receptors to promote gene duplication and positive selection of the PMF gene complex. Courtship trials with females receiving different PMF isoform mixtures had variable effects on female mating receptivity, with only the most complex mixtures increasing receptivity, such that we believe that sufficient isoform diversity allows males to improve their reproductive success with any female in the mating population. The aim of this study was to test the effects of isoform variability on VNE neuron activation using the agmatine uptake assay. All isoform mixtures activated a similar number of neurons (>200% over background) except for a single purified PMF isoform (+17%). These data further support the hypothesis that PMF isoforms act synergistically in order to regulate female receptivity, and different putative mechanisms are discussed. PMID- 28358846 TI - Risk factors associated with Tuberculosis (TB) among people living with HIV/AIDS: A pair-matched case-control study in Guangxi, China. AB - BACKGROUND: As one of the poorest provinces in China, Guangxi has a high HIV and TB prevalence, with the annual number of TB/HIV cases reported by health department among the highest in the country. However, studies on the burden of TB HIV co-infection and risk factors for active TB among HIV-infected persons in Guangxi have rarely been reported. OBJECTIVE: To investigate the risk factors for active TB among people living with HIV/AIDS in Guangxi Zhuang autonomous region, China. METHODS: A surveillance survey was conducted of 1 019 HIV-infected patients receiving care at three AIDS prevention and control departments between 2013 and 2015. We investigated the cumulative prevalence of TB during 2 years. To analyze risk factors associated with active TB, we conducted a 1:1 pair-matched case-control study of newly reported active TB/HIV co-infected patients. Controls were patients with HIV without active TB, latent TB infection or other lung disease, who were matched with the case group based on sex and age (+/- 3 years). RESULTS: A total of 1 019 subjects were evaluated. 160 subjects (15.70%) were diagnosed with active TB, including 85 clinically diagnosed cases and 75 confirmed cases. We performed a 1:1 matched case-control study, with 82 TB/HIV patients and 82 people living with HIV/AIDS based on surveillance site, sex and age (+/-3) years. According to multivariate analysis, smoking (OR = 2.996, 0.992 9.053), lower CD 4+ T-cell count (OR = 3.288, 1.161-9.311), long duration of HIV infection (OR = 5.946, 2.221-15.915) and non-use of ART (OR = 7.775, 2.618 23.094) were independent risk factors for TB in people living with HIV/AIDS. CONCLUSION: The prevalence of active TB among people living with HIV/AIDS in Guangxi was 173 times higher than general population in Guangxi. It is necessary for government to integrate control planning and resources for the two diseases. Medical and public health workers should strengthen health education for TB/HIV prevention and treatment and promote smoking cessation. Active TB case finding and early initiation of ART is necessary to minimize the burden of disease among patients with HIV, as is IPT and infection control in healthcare facilities. PMID- 28358845 TI - The association between sleep duration and physical performance in Chinese community-dwelling elderly. AB - BACKGROUND: Physical performance is an important healthy factor in elder people. Good living habits, which include sleep, can maintain physical strength and physical performance. The aim of the present study was to conduct a cross sectional study to determine the association between total sleep duration and physical performance. METHODS: Our study population comprised residents of the township central hospital in the suburban of Tianjin, China. We measured muscle strength, walk speed and balance function by grip, 4-m walk test and timed up and go test (TUGT). We divided sleep duration into four groups <7h, 7-8h, >8-9h, >9h. RESULTS: A total 898 participants had completed data (392 men and 506 women, mean age 67.71 years). In man, adjusted sleep duration was associated with lower grip in > 9 h group, the mean value (95% CI) was 0.429 (0.409, 0.448), and longer TUGT time was also associated with long sleep duration, 10.46s (9.97 s, 10.95 s). In women, adjusted slower 4-m walk speed present an inverse U-shaped relation with sleep duration, by 0.93 m/s (0.86 m/s, 0.98 m/s), 0.97 m/s (0.96 m/s, 1.00 m/s), 0.97 m/s (0.95 m/s, 0.99 m/s) and 0.92 m/s (0.89 m/s, 0.96 m/s); longer TUGT time were associated with long sleep duration (> 9 h), by 11.23 s (10.70 s, 11.77 s). CONCLUSION: In Chinese community-dwelling elderly, lower muscle strength and lower balance function were associated with long sleep duration in men. Slower walk speed and lower balance function were associated with long sleep duration in women. PMID- 28358847 TI - Alpha-1-antitrypsin suppresses oxidative stress in preeclampsia by inhibiting the p38MAPK signaling pathway: An in vivo and in vitro study. AB - This present study was designed to investigate the effects of alpha-1-antitrypsin (AAT) on oxidative stress in preeclampsia (PE) by regulating p38 mitogen activated protein kinase (p38MAPK) signaling pathway. HTR8/SVneo cells were randomly assigned into normal, hypoxia/reoxygenation (H/R), HR + AAT and HR + siRNA-AAT groups. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect the mRNA and protein expressions of p p38MAPK, AAT, signal transducer and activator of transcription 1 (STAT1) and activating transcription factor2 (ATF2). Flow cytometry, scratch test, cell counting kit-8 (CCK-8) assay and the 3-(4,5)-dimethylthiazol (-z-y1)-3,5-di- phenyltetrazolium bromide (MTT) assay were conducted to detect reactive oxygen species (ROS) and cell apoptosis, cell migration, proliferation and cytotoxicity, respectively. Mouse models in PE were established, which were divided into normal pregnancy (NP), PE and PE + AAT groups with blood pressure and urine protein measured. Chromatin immunoprecipitation (ChIP) and enzyme-linked immunosorbent assay (ELISA) were conducted to detect the activity of oxidative stress-related kinases and expressions of inflammatory cytokines and coagulation-related factors in cells and mice placenta. Immunohistochemistry, Western blotting and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were performed to detect AAT and p38MAPK expressions, apoptosis-related protein expressions, and apoptosis rate in mice placenta. Compared with the normal group, the H/R group had decreased expression of AAT, activity of superoxide dismutase (SOD) and GSH-Px, cell proliferation and migration, but increased p38MAPK, STAT1, ATF2, MDA, H2O2, inflammatory cytokines, coagulation-related factors, cell cytotoxicity, ROS, apoptotic factors and apoptosis rate. Compared with the H/R group, the HR + ATT group had increased expressions of AAT, activity of SOD and GSH-Px, cell proliferation and migration but decreased p38MAPK, STAT1, ATF2, malonyldialdehyde (MDA), H2O2, inflammatory cytokines and coagulation-related factors, cell cytotoxicity, ROS, apoptotic factors and apoptosis rate, while opposite results were observed in the HR + siRNA-ATT group. Compared with the NP group, the PE group had decreased activity of SOD and GSH-Px but increased MDA, H2O2, AAT, p38MAPK, inflammatory cytokines, coagulation-related factors and apoptosis rate. The indexes in the PE + AAT group were between the NP and PE groups. Thus, we concluded that AAT suppressed oxidative stress in PE by inhibiting p38MAPK signaling pathway. PMID- 28358850 TI - Adaptive feature selection using v-shaped binary particle swarm optimization. AB - Feature selection is an important preprocessing method in machine learning and data mining. This process can be used not only to reduce the amount of data to be analyzed but also to build models with stronger interpretability based on fewer features. Traditional feature selection methods evaluate the dependency and redundancy of features separately, which leads to a lack of measurement of their combined effect. Moreover, a greedy search considers only the optimization of the current round and thus cannot be a global search. To evaluate the combined effect of different subsets in the entire feature space, an adaptive feature selection method based on V-shaped binary particle swarm optimization is proposed. In this method, the fitness function is constructed using the correlation information entropy. Feature subsets are regarded as individuals in a population, and the feature space is searched using V-shaped binary particle swarm optimization. The above procedure overcomes the hard constraint on the number of features, enables the combined evaluation of each subset as a whole, and improves the search ability of conventional binary particle swarm optimization. The proposed algorithm is an adaptive method with respect to the number of feature subsets. The experimental results show the advantages of optimizing the feature subsets using the V-shaped transfer function and confirm the effectiveness and efficiency of the feature subsets obtained under different classifiers. PMID- 28358848 TI - Comprehensive species set revealing the phylogeny and biogeography of Feliformia (Mammalia, Carnivora) based on mitochondrial DNA. AB - Extant Feliformia species are one of the most diverse radiations of Carnivora (~123 species). Despite substantial recent interest in their conservation, diversification, and systematic study, no previous phylogeny contains a comprehensive species set, and no biogeography of this group is available. Here, we present a phylogenetic estimate for Feliformia with a comprehensive species set and establish a historical biogeography based on mitochondrial DNA. Both the Bayesian and maximum likelihood phylogeny for Feliformia are elucidated in our analyses and are strongly consistent with many groups recognized in previous studies. The mitochondrial phylogenetic relationships of Felidae were for the first time successfully reconstructed in our analyses with strong supported. When divergence times and dispersal/vicariance histories were compared with historical sea level changes, four dispersal and six vicariance events were identified. These vicariance events were closely related with global sea level changes. The transgression of sea into the lowland plains between Eurasia and Africa may have caused the vicariance in these regions. A fall in the sea level during late Miocene to Pliocene produced the Bering strait land bridge, which assisted the migration of American Feliformia ancestors from Asia to North America. In contrast with the 'sweepstakes hypothesis', our results suggest that the climate cooling during 30-27 Ma assisted Feliformia migration from the African mainland to Madagascar by creating a short-lived ice bridge across the Mozambique Channel. Lineages-through-time plots revealed a large increase in lineages since the Mid Miocene. During the Mid-Miocene Climatic Optimum, the ecosystems and population of Feliformia rapidly expanded. Subsequent climate cooling catalyzed immigration, speciation, and the extinction of Feliformia. PMID- 28358849 TI - Extracorporeal life support prior to left ventricular assist device implantation leads to improvement of the patients INTERMACS levels and outcome. AB - BACKGROUND: The objective of this study was to evaluate the outcome of left ventricular assist device (LVAD) implantation after initial extracorporeal life support (ECLS) in patients with cardiogenic shock and the incidence of post implantation right ventricular failure. METHODS & RESULTS: All patients on ECLS therapy for cardiogenic shock prior to LVAD implantation (n = 15) between October 2011 and January 2014 were analyzed. Baseline patient characteristics, as well as detailed pre-operative treatment and postoperative outcome data were collected retrospectively. At time of admission to our unit all patients were classified INTERMACS II or higher (12 [80%] INTERMACS I). Improvement to INTERMACS III temporary cardiac support (TCS) at time of LVAD implantation was successful in 14 patients (93.3%). End-organ function recovered during ECLS support. No patient needed ongoing ECLS or additional right ventricular support after LVAD implantation. Both in-hospital and 30-day mortality was 6.7% (n = 1). The median duration of LVAD support was 687.9 +/- 374.5 days. At the end of the study (follow-up 810.7 +/- 338.9 days), 13 (86.7%) patients were alive. The majority of patients (10 [66.7%]) remained on LVAD support. Transplantation could be performed in 1 (6.7%) patient, 2 (13.3%) patients could be successfully weaned. CONCLUSION: LVAD implantation in ECLS patients leads to improvement of INTERMACS level to INTERMACS III TCS status. Excellent mid-term survival comparable to true INTERMACS III-IV patients could be shown. ECLS prior to LVAD as a bridge-to bridge therapy may help to lower mortality in primarily unstable patients. PMID- 28358851 TI - 5-aminolevulinic acid-mediated photodynamic therapy and its strain-dependent combined effect with antibiotics on Staphylococcus aureus biofilm. AB - Staphylococcus aureus (S. aureus) is hard to be eradicated, not only due to the emergence of antibiotic resistant strains but also because of its ability to form biofilm. Antibiotics are the major approach to treating biofilm infections, but their effects are unsatisfactory. One of the potential alternative treatments for controlling biofilm infections is photodynamic therapy (PDT), which requires the administration of photosensitizer, followed by light activation. 5-aminolevulinic acid (ALA), a natural photosensitizer prodrug, presents favorable characteristics, such as easy penetration and rapid clearance. These advantages enable ALA-based PDT (ALA-PDT) to be well-tolerated by patients and it can be repeatedly applied without cumulative toxicity or serious side effects. ALA-PDT has been proven to be an effective treatment for multidrug resistant pathogens; however, the study of its effect on S. aureus biofilm is limited. Here, we established our PDT system based on the utilization of ALA and a light-emitting diode, and we tested the effect of ALA-PDT on S. aureus biofilm as well as the combined effect of ALA-PDT and antibiotics on S. aureus biofilm. Our results showed that ALA-PDT has a strong antibacterial effect on S. aureus biofilm, which was confirmed by the confocal laser scanning microscope. We also found that lethal photosensitization occurred predominantly in the upper layer of the biofilm, while the residual live bacteria were located in the lower layer of the biofilm. In addition, the improved bactericidal effect was observed in the combined treatment group but in a strain-dependent manner. Our results suggest that ALA-PDT is a potential alternative approach for future clinical use to treat S. aureus biofilm-associated infections, and some patients may benefit from the combined treatment of ALA-PDT and antibiotics, but drug sensitivity testing should be performed in advance. PMID- 28358852 TI - Music training is associated with cortical synchronization reflected in EEG coherence during verbal memory encoding. AB - Music training can improve cognitive functions. Previous studies have shown that children and adults with music training demonstrate better verbal learning and memory performance than those without such training. Although prior studies have shown an association between music training and changes in the structural and functional organization of the brain, there is no concrete evidence of the underlying neural correlates of the verbal memory encoding phase involved in such enhanced memory performance. Therefore, we carried out an electroencephalography (EEG) study to investigate how music training was associated with brain activity during the verbal memory encoding phase. Sixty participants were recruited, 30 of whom had received music training for at least one year (the MT group) and 30 of whom had never received music training (the NMT group). The participants in the two groups were matched for age, education, gender distribution, and cognitive capability. Their verbal and visual memory functions were assessed using standardized neuropsychological tests and EEG was used to record their brain activity during the verbal memory encoding phase. Consistent with previous studies, the MT group demonstrated better verbal memory than the NMT group during both the learning and the delayed recall trials in the paper-and-pencil tests. The MT group also exhibited greater learning capacity during the learning trials. Compared with the NMT group, the MT group showed an increase in long-range left and right intrahemispheric EEG coherence in the theta frequency band during the verbal memory encoding phase. In addition, their event-related left intrahemispheric theta coherence was positively associated with subsequent verbal memory performance as measured by discrimination scores. These results suggest that music training may modulate the cortical synchronization of the neural networks involved in verbal memory formation. PMID- 28358853 TI - A peptide-based approach to evaluate the adaptability of influenza A virus to humans based on its hemagglutinin proteolytic cleavage site. AB - Cleavage activation of the hemagglutinin (HA) protein by host proteases is a crucial step in the infection process of influenza A viruses (IAV). However, IAV exists in eighteen different HA subtypes in nature and their cleavage sites vary considerably. There is uncertainty regarding which specific proteases activate a given HA in the human respiratory tract. Understanding the relationship between different HA subtypes and human-specific proteases will be valuable in assessing the pandemic potential of circulating viruses. Here we utilized fluorogenic peptides mimicking the HA cleavage motif of representative IAV strains causing disease in humans or of zoonotic/pandemic potential and tested them with a range of proteases known to be present in the human respiratory tract. Our results show that peptides from the H1, H2 and H3 subtypes are cleaved efficiently by a wide range of proteases including trypsin, matriptase, human airway tryptase (HAT), kallikrein-related peptidases 5 (KLK5) and 12 (KLK12) and plasmin. Regarding IAVs currently of concern for human adaptation, cleavage site peptides from H10 viruses showed very limited cleavage by respiratory tract proteases. Peptide mimics from H6 viruses showed broader cleavage by respiratory tract proteases, while H5, H7 and H9 subtypes showed variable cleavage; particularly matriptase appeared to be a key protease capable of activating IAVs. We also tested HA substrate specificity of Factor Xa, a protease required for HA cleavage in chicken embryos and relevant for influenza virus production in eggs. Overall our data provide novel tool allowing the assessment of human adaptation of IAV HA subtypes. PMID- 28358855 TI - Correction: Spectrum of Cerebrovascular Disease in Patients with Multiple Myeloma Undergoing Chemotherapy-Results of a Case Control Study. AB - [This corrects the article DOI: 10.1371/journal.pone.0166627.]. PMID- 28358854 TI - Validation of a hairy roots system to study soybean-soybean aphid interactions. AB - The soybean aphid (Aphis glycines) is one of the main insect pests of soybean (Glycine max) worldwide. Genomics approaches have provided important data on transcriptome changes, both in the insect and in the plant, in response to the plant-aphid interaction. However, the difficulties to transform soybean and to rear soybean aphid on artificial media have hindered our ability to systematically test the function of genes identified by those analyses as mediators of plant resistance to the insect. An efficient approach to produce transgenic soybean material is the production of transformed hairy roots using Agrobacterium rhizogenes; however, soybean aphids colonize leaves or stems and thus this approach has not been utilized. Here, we developed a hairy root system that allowed effective aphid feeding. We show that this system supports aphid performance similar to that observed in leaves. The use of hairy roots to study plant resistance is validated by experiments showing that roots generated from cotyledons of resistant lines carrying the Rag1 or Rag2 resistance genes are also resistant to aphid feeding, while related susceptible lines are not. Our results demonstrate that hairy roots are a good system to study soybean aphid-soybean interactions, providing a quick and effective method that could be used for functional analysis of the resistance response to this insect. PMID- 28358856 TI - Dexmedetomidine ameliorates muscle wasting and attenuates the alteration of hypothalamic neuropeptides and inflammation in endotoxemic rats. AB - Dexmedetomidine is generally used for sedaton in critically ill, it could shorten duration of mechanical ventilation, ICU stay and lower basic metabolism. However, the exact mechanism of these positive effects remains unkown. Here we investigated the hypothesis that dexmedetomidine could ameliorate muscle wasting in endotoxemic rats and whether it was related to hypothalamic neuropeptides alteration and inflammation. Fourty-eight adult male Sprague-Dawley rats were intraperitoneally injected with lipopolysaccharide (LPS) (5 mg/kg) or saline, followed by 50 MUg/kg dexmedetomidine or saline administration via the femoral vein catheter (infusion at 5 MUg.kg-1.hr-1). Twenty-four hours after injection, hypothalamus tissues and skeletal muscle were obtained. Muscle wasting was measured by the mRNA expression of two E3 ubiquitin ligases, muscle atrophy F-box (MAFbx) and muscle ring finger 1 (MuRF-1) as well as 3-methylhistidine (3-MH) and tyrosine release. Hypothalamic inflammatory markers and neuropeptides expression were also detected in all four groups. Results showed that LPS administration led to significant increase in hypothalamic inflammation together with muscle wasting. Increased hypothalamic neuropeptides, proopiomelanocortin (POMC), cocaine and amphetamine-related transcript (CART) and neuropeptides Y (NPY) and decreased agouti-related protein (AgRP) were also observed. Meanwhile dexmedetomidine administration ameliorated muscle wasting, hypothalamic inflammation and modulated the alteration of neuropeptides, POMC, CART and AgRP, in endotoxemic rats. In conclusion, dexmedetomidine could alleviate muscle wasting in endotoxemic rats, and it could also attenuate the alteration of hypothalamic neuropeptides and reduce hypothalamic inflammation. PMID- 28358857 TI - Differential autophagic effects of vital dyes in retinal pigment epithelial ARPE 19 and photoreceptor 661W cells. AB - Indocyanine green (ICG) and brilliant blue G (BBG) are commonly used vital dyes to remove internal limiting membrane (ILM) in vitreoretinal surgery. The vital dyes have shown cytotoxic effects in ocular cells. Autophagy is a stress responsive pathway for either protecting cells or promoting cell death. However, the role of autophagy in ocular cells in response to the vital dyes remains unknown. In this study, we found that ICG and BBG reduced cell viability in both human retinal pigment epithelial ARPE-19 and mouse photoreceptor 661W cells. ICG and BBG induced lipidated GFP-LC3-II and LC3-II in ARPE-19 and 661W cells. Combination treatment with the autophagy inhibitor chloroquine indicated that ICG and BBG reduced autophagic flux in ARPE-19 cells, whereas the vital dyes induced autophagic flux in 661W cells. Moreover, genetic and pharmacological ablation of autophagy enhanced vital dyes-induced cytotoxicity in ocular cells. Dietary supplements, including resveratrol, lutein, and CoQ10, induced autophagy and diminished the cytotoxic effects of ICG and BBG in ocular cells. These results suggest that autophagy may protect ARPE-19 and 661W cells from vital dyes-induced damage. PMID- 28358858 TI - A preclinical evaluation of alternative site for islet allotransplantation. AB - The bone marrow cavity (BMC) has recently been identified as an alternative site to the liver for islet transplantation. This study aimed to compare the BMC with the liver as an islet allotransplantation site in diabetic monkeys. Diabetes was induced in Rhesus monkeys using streptozocin, and the monkeys were then divided into the following three groups: Group1 (islets transplanted in the liver with immunosuppressant), Group 2 (islets transplanted in the tibial BMC), and Group 3 (islets transplanted in the tibial BMC with immunosuppressant). The C-peptide and blood glucose levels were preoperatively measured. An intravenous glucose tolerance test (IVGTT) was conducted to assess graft function, and complete blood cell counts were performed to assess cell population changes. Cytokine expression was measured using an enzyme-linked immune sorbent assay (ELISA) and MILLIPLEX. Five monkeys in Group 3 exhibited a significantly increased insulin-independent time compared with the other groups (Group 1: 78.2 +/- 19.0 days; Group 2: 58.8 +/- 17.0 days; Group 3: 189.6 +/- 26.2 days) and demonstrated increases in plasma C-peptide 4 months after transplantation. The infusion procedure was not associated with adverse effects. Functional islets in the BMC were observed 225 days after transplantation using the dithizone (DTZ) and insulin/glucagon stains. Our results showed that allogeneic islets transplanted in the BMC of diabetic Rhesus monkeys remained alive and functional for a longer time than those transplanted in the liver. This study was the first successful demonstration of allogeneic islet engraftment in the BMC of non-human primates (NHPs). PMID- 28358859 TI - Vocalizations of female frogs contain nonlinear characteristics and individual signatures. AB - Anuran vocalization is sexually dimorphic, with males doing the bulk of vocalizing. Female vocalization is rare and has been observed in a handful of species, including the concave-eared torrent frog (Odorrana tormota). Females O. tormota have been reported to emit moderate-level calls to attract males. In contrast to males, female's vocal signals show no evidence of nonlinear phenomena (NLP). However, with females emitting calls so infrequently that this conclusion must be considered tentative in light of the limited supporting data. The present study was undertaken to test the hypotheses that their vocalizations: 1. may not be purely linear, 2. may contain individual signatures, similar to their male counterparts. We recorded 671 calls from six captive gravid females and found that their vocalizations are as complex as male calls, with numerous calls exhibiting complex upward/downward frequency modulations, and 39% of female calls containing at least one component of the NLP, i.e., subharmonics, deterministic chaos, frequency jump, or biphonation. Furthermore, females in captivity tend to call in bouts throughout the day and night, and the call rate varies hourly with a maximum of >10 calls per minute matching the maximum call rate in males. Similar to males, female vocalizations carry individual signatures, and all sound parameters analyzed differ significantly between individuals. This represents the first report ever showing that vocalizations of female anurans: 1. contain NLP, 2. carry individual signatures. Presence of signatures in both the male and female vocalizations opens up the possibility for males (and females) to distinguish individual frogs in both sexes acoustically, and thus their sound communication ability may be more advanced than previously thought. PMID- 28358860 TI - Discover cervical disc arthroplasty versus anterior cervical discectomy and fusion in symptomatic cervical disc diseases: A meta-analysis. AB - OBJECTIVE: Symptomatic cervical disc disease (SCDD) is a common degenerative disease, and Discover artificial cervical disc, a new-generation nonconstrained artificial disk, has been developed and performed gradually to treat it. We performed this meta-analysis to compare the efficacy and safety between Discover cervical disc arthroplasty (DCDA) and anterior cervical discectomy and fusion (ACDF) for SCDD. METHODS: An exhaustive literature search of PubMed, EMBASE, and the Cochrane Library was conducted to identify randomized controlled trials that compared DCDA with ACDF for patients suffering SCDD. A random-effect model was used. Results were reported as standardized mean difference or risk ratio with 95% confidence interval. RESULTS: Of 33 articles identified, six studies were included. Compared with ACDF, DCDA demonstrated shorter operation time (P < 0.0001), and better range of motion (ROM) at the operative level (P < 0.00001). But no significant differences were observed in blood loss, neck disability index (NDI) scores, neck and arm pain scores, Japanese orthopaedic association (JOA) scores, secondary surgery procedures and adverse events (P > 0.05). Subgroup analyses did not demonstrated significant differences. CONCLUSION: In conclusion, DCDA presented shorter operation time, and better ROM at the operative level. However, no significant differences were observed in blood loss, NDI scores, neck and arm pain scores, JOA scores, secondary surgery procedures and adverse events between the two groups. Additionally, more studies of high quality with mid- to long-term follow-up are required in future. PMID- 28358862 TI - Comprehensive framework for visualizing and analyzing spatio-temporal dynamics of racial diversity in the entire United States. AB - The United States is increasingly becoming a multi-racial society. To understand multiple consequences of this overall trend to our neighborhoods we need a methodology capable of spatio-temporal analysis of racial diversity at the local level but also across the entire U.S. Furthermore, such methodology should be accessible to stakeholders ranging from analysts to decision makers. In this paper we present a comprehensive framework for visualizing and analyzing diversity data that fulfills such requirements. The first component of our framework is a U.S.-wide, multi-year database of race sub-population grids which is freely available for download. These 30 m resolution grids have being developed using dasymetric modeling and are available for 1990-2000-2010. We summarize numerous advantages of gridded population data over commonly used Census tract-aggregated data. Using these grids frees analysts from constructing their own and allows them to focus on diversity analysis. The second component of our framework is a set of U.S.-wide, multi-year diversity maps at 30 m resolution. A diversity map is our product that classifies the gridded population into 39 communities based on their degrees of diversity, dominant race, and population density. It provides spatial information on diversity in a single, easy-to-understand map that can be utilized by analysts and end users alike. Maps based on subsequent Censuses provide information about spatio-temporal dynamics of diversity. Diversity maps are accessible through the GeoWeb application SocScape (http://sil.uc.edu/webapps/socscape_usa/) for an immediate online exploration. The third component of our framework is a proposal to quantitatively analyze diversity maps using a set of landscape metrics. Because of its form, a grid-based diversity map could be thought of as a diversity "landscape" and analyzed quantitatively using landscape metrics. We give a brief summary of most pertinent metrics and demonstrate how they can be applied to diversity maps. PMID- 28358861 TI - PCR diagnosis of tick-borne pathogens in Maharashtra state, India indicates fitness cost associated with carrier infections is greater for crossbreed than native cattle breeds. AB - Tick-borne pathogens (TBP) are responsible for significant economic losses to cattle production, globally. This is particularly true in countries like India where TBP constrain rearing of high yielding Bos taurus, as they show susceptibility to acute tick borne disease (TBD), most notably tropical theileriosis caused by Theileria annulata. This has led to a programme of cross breeding Bos taurus (Holstein-Friesian or Jersey) with native Bos indicus (numerous) breeds to generate cattle that are more resistant to disease. However, the cost to fitness of subclinical carrier infection in crossbreeds relative to native breeds is unknown, but could represent a significant hidden economic cost. In this study, a total of 1052 bovine blood samples, together with associated data on host type, sex and body score, were collected from apparently healthy animals in four different agro-climatic zones of Maharashtra state. Samples were screened by PCR for detection of five major TBPs: T. annulata, T. orientalis, B. bigemina, B. bovis and Anaplasma spp.. The results demonstrated that single and co-infection with TBP are common, and although differences in pathogen spp. prevalence across the climatic zones were detected, simplistic regression models predicted that host type, sex and location are all likely to impact on prevalence of TBP. In order to remove issues with autocorrelation between variables, a subset of the dataset was modelled to assess any impact of TBP infection on body score of crossbreed versus native breed cattle (breed type). The model showed significant association between infection with TBP (particularly apicomplexan parasites) and poorer body condition for crossbreed animals. These findings indicate potential cost of TBP carrier infection on crossbreed productivity. Thus, there is a case for development of strategies for targeted breeding to combine productivity traits with disease resistance, or to prevent transmission of TBP in India for economic benefit. PMID- 28358863 TI - Opening the treasure chest: A DNA-barcoding primer set for most higher taxa of Central European birds and mammals from museum collections. AB - DNA-barcoding is a rapidly developing method for efficiently identifying samples to species level by means of short standard DNA sequences. However, reliable species assignment requires the availability of a comprehensive DNA barcode reference library, and hence numerous initiatives aim at generating such barcode databases for particular taxa or geographic regions. Historical museum collections represent a potentially invaluable source for the DNA-barcoding of many taxa. This is particularly true for birds and mammals, for which collecting fresh (voucher) material is often very difficult to (nearly) impossible due to the special animal welfare and conservation regulations that apply to vertebrates in general, and birds and mammals in particular. Moreover, even great efforts might not guarantee sufficiently complete sampling of fresh material in a short period of time. DNA extracted from historical samples is usually degraded, such that only short fragments can be amplified, rendering the recovery of the barcoding region as a single fragment impossible. Here, we present a new set of primers that allows the efficient amplification and sequencing of the entire barcoding region in most higher taxa of Central European birds and mammals in six overlapping fragments, thus greatly increasing the value of historical museum collections for generating DNA barcode reference libraries. Applying our new primer set in recently established NGS protocols promises to further increase the efficiency of barcoding old bird and mammal specimens. PMID- 28358865 TI - Ultrastructure and morphology of antennal sensilla of the adult diving beetle Cybister japonicus Sharp. AB - The morphology and distribution of the antennal sensilla of adult diving beetle Cybister japonicus Sharp (Dytiscidae, Coleoptera), have been examined. Five types of sensilla on the antennae were identified by scanning electron microscope (SEM) and transmission electron microscope (TEM). Sensilla placodea and elongated s. placodea are the most abundant types of sensilla, distributing only on the flagellum. Both these types of sensilla carry multiple pore systems with a typical function as chemoreceptors. Three types of s. coeloconica (Type I-III) were also identified, with the characterization of the pit-in-pit style, and carrying pegs externally different from each other. Our data indicated that both type I and type II of s. coleconica contain two bipolar neurons, while the type III of s. coleconica contains three dendrites in the peg. Two sensory dendrites in the former two sensilla are tightly embedded inside the dendrite sheath, with no space left for sensilla lymph. There are no specific morphological differences in the antennal sensilla observed between males and females, except that the males have longer antennae and more sensilla than the females. PMID- 28358864 TI - Use of the 9-item Shared Decision Making Questionnaire (SDM-Q-9 and SDM-Q-Doc) in intervention studies-A systematic review. AB - BACKGROUND: The Shared Decision Making Questionnaire (SDM-Q-9 and SDM-Q-Doc) is a 9-item measure of the decisional process in medical encounters from both patients' and physicians' perspectives. It has good acceptance, feasibility, and reliability. This systematic review aimed to 1) evaluate the use of the SDM-Q-9 and SDM-Q-Doc in intervention studies on shared decision making (SDM) in clinical settings, 2) describe how the SDM-Q-9 and SDM-Q-Doc performed regarding sensitivity to change, and 3) assess the methodological quality of studies and study protocols that use the measure. METHODS: We conducted a systematic review of studies published between 2010 and October 2015 that evaluated interventions to facilitate SDM. The search strategy comprised three databases (EMBASE, PsycINFO, and Medline), reference tracking, citation tracking, and personal knowledge. Two independent reviewers screened titles and abstracts as well as full texts of potentially relevant records. We extracted the data using a pilot tested sheet, and we assessed the methodological quality of included studies using the Quality Assessment Tools from the U.S. National Institute of Health (NIH). RESULTS: Five completed studies and six study protocols fulfilled the inclusion criteria. The measure was used in a variety of health care settings, mainly in Europe, to evaluate several types of interventions. The reported mean sum scores ranged from 42 to 75 on a scale from 0 to 100. In four studies no significant change was detected in the mean-differences between main groups. In the fifth study the difference was small. Quality assessment revealed a high risk of bias in four of the five completed studies, while the study protocols received moderate quality ratings. CONCLUSIONS: We found a wide range of areas in which the SDM-Q-9 and SDM-Q-Doc were applied. In the future this review may help researchers decide whether the measure fits their purposes. Furthermore, the review revealed risk of bias in previous trials that used the measure, and may help future trials decrease this risk. More research on the measure's sensitivity to change is strongly suggested. PMID- 28358867 TI - Location, location, location: Use of CRISPR-Cas9 for genome editing in human pathogenic fungi. PMID- 28358866 TI - Phenotypically silent Cre recombination within the postnatal ventricular conduction system. AB - The cardiac conduction system (CCS) is composed of specialized cardiomyocytes that initiate and maintain cardiac rhythm. Any perturbation to the normal sequence of electrical events within the heart can result in cardiac arrhythmias. To understand how cardiac rhythm is established at the molecular level, several genetically modified mouse lines expressing Cre recombinase within specific CCS compartments have been created. In general, Cre driver lines have been generated either by homologous recombination of Cre into an endogenous locus or Cre expression driven by a randomly inserted transgene. However, haploinsufficiency of the endogenous gene compromises the former approach, while position effects negatively impact the latter. To address these limitations, we generated a Cre driver line for the ventricular conduction system (VCS) that preserves endogenous gene expression by targeting the Contactin2 (Cntn2) 3' untranslated region (3'UTR). Here we show that Cntn23'UTR-IRES-Cre-EGFP/+ mice recombine floxed alleles within the VCS and that Cre expression faithfully recapitulates the spatial distribution of Cntn2 within the heart. We further demonstrate that Cre expression initiates after birth with preservation of native Cntn2 protein. Finally, we show that Cntn23'UTR-IRES-Cre-EGFP/+ mice maintain normal cardiac mechanical and electrical function. Taken together, our results establish a novel VCS-specific Cre driver line without the adverse consequences of haploinsufficiency or position effects. We expect that our new mouse line will add to the accumulating toolkit of CCS-specific mouse reagents and aid characterization of the cell-autonomous molecular circuitry that drives VCS maintenance and function. PMID- 28358868 TI - Precocious obesity predisposes the development of more severe cisplatin-induced acute kidney injury in young adult mice. AB - Obesity and its consequences can damage the kidney over time. However, less is known about the impact of developing overweight/obesity during childhood on the kidney in adulthood and the renal impact of a superimposed acute kidney injury (AKI). This study evaluated the effect of obesity induced by a high-fat diet initiated soon after weaning on the adult life of mice and their response to superimposed nephrotoxic effects of cisplatin. C57BL/6 post-weaning mice (3 weeks old) were divided into a control group (CT, n = 12) and a high-fat diet group (HF, n = 12). After 9 weeks, animals were further divided into the following groups: CT, CT treated with a single dose of cisplatin (CTCis, 20 mg/kg, i.p.), HF and HF treated with cisplatin (HFCis). The HF group exhibited higher body weight gain compatible with a moderate obesity. Obese mice presented increased visceral adiposity, hyperkalemia, sodium retention, glomerular hyperfiltration and proteinuria, without any significant changes in blood pressure and glycemia. AKI induced by cisplatin was exacerbated in obese animals with a 92% reduction in the GFR versus a 31% decrease in the CTCis group; this sharp decline resulted in severely elevated serum creatinine and urea levels. Acute tubular necrosis induced by cisplatin was worsened in obese mice. The HFCis group exhibited robust systemic and intrarenal inflammation that was significantly higher than that in the CTCis group; the HFCis group also showed a higher degree of renal oxidative stress. In conclusion, the moderate degree of obesity induced shortly after weaning resulted in mild early renal alterations, however, obese young animals were prone to develop a much more severe AKI induced by cisplatin. PMID- 28358869 TI - Learning about and from others' prudence, impatience or laziness: The computational bases of attitude alignment. AB - Peoples' subjective attitude towards costs such as, e.g., risk, delay or effort are key determinants of inter-individual differences in goal-directed behaviour. Thus, the ability to learn about others' prudent, impatient or lazy attitudes is likely to be critical for social interactions. Conversely, how adaptive such attitudes are in a given environment is highly uncertain. Thus, the brain may be tuned to garner information about how such costs ought to be arbitrated. In particular, observing others' attitude may change one's uncertain belief about how to best behave in related difficult decision contexts. In turn, learning from others' attitudes is determined by one's ability to learn about others' attitudes. We first derive, from basic optimality principles, the computational properties of such a learning mechanism. In particular, we predict two apparent cognitive biases that would arise when individuals are learning about others' attitudes: (i) people should overestimate the degree to which they resemble others (false-consensus bias), and (ii) they should align their own attitudes with others' (social influence bias). We show how these two biases non-trivially interact with each other. We then validate these predictions experimentally by profiling people's attitudes both before and after guessing a series of cost benefit arbitrages performed by calibrated artificial agents (which are impersonating human individuals). PMID- 28358870 TI - Guideline appraisal with AGREE II: Systematic review of the current evidence on how users handle the 2 overall assessments. AB - INTRODUCTION: The Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument is the most commonly used guideline appraisal tool. It includes 23 appraisal criteria (items) organized within 6 domains and 2 overall assessments (1. overall guideline quality; 2. recommendation for use). The aim of this systematic review was twofold. Firstly, to investigate how often AGREE II users conduct the 2 overall assessments. Secondly, to investigate the influence of the 6 domain scores on each of the 2 overall assessments. MATERIALS AND METHODS: A systematic bibliographic search was conducted for publications reporting guideline appraisals with AGREE II. The impact of the 6 domain scores on the overall assessment of guideline quality was examined using a multiple linear regression model. Their impact on the recommendation for use (possible answers: "yes", "yes, with modifications", "no") was examined using a multinomial regression model. RESULTS: 118 relevant publications including 1453 guidelines were identified. 77.1% of the publications reported results for at least one overall assessment, but only 32.2% reported results for both overall assessments. The results of the regression analyses showed a statistically significant influence of all domains on overall guideline quality, with Domain 3 (rigour of development) having the strongest influence. For the recommendation for use, the results showed a significant influence of Domains 3 to 5 ("yes" vs. "no") and Domains 3 and 5 ("yes, with modifications" vs. "no"). CONCLUSIONS: The 2 overall assessments of AGREE II are underreported by guideline assessors. Domains 3 and 5 have the strongest influence on the results of the 2 overall assessments, while the other domains have a varying influence. Within a normative approach, our findings could be used as guidance for weighting individual domains in AGREE II to make the overall assessments more objective. Alternatively, a stronger content analysis of the individual domains could clarify their importance in terms of guideline quality. Moreover, AGREE II should require users to transparently present how they conducted the assessments. PMID- 28358871 TI - Post-licensure safety evaluation of dihydroartemisinin piperaquine in the three major ecological zones across Ghana. AB - BACKGROUND: Uncommon and rare adverse events (AEs), with delayed onset may not be detected before new drugs are licensed and deployed. The present study examined the post licensure safety of dihydroartemisinin-piperaquine (DHP) as an additional treatment for malaria in Ghana. The relationship between the incidence of AEs, treatment completion rate, participant characteristics and concomitant medications are reported. METHODS: A study conducted from September 2013 to June 2014 in Navrongo, Kintampo and Dodowa health research centres in Ghana is presented. Participants had confirmed malaria and no known allergy to study drug. Patients provided informed consent and had their symptoms and results of their clinical examinations documented. Treatment with Eurartesim(r) (20/160mg dihydroartemisinin and 40/320mg piperaquine by Sigma-Tau Incorporated) was given, according to the body weight of patients. First treatment doses were under observation but the second and third doses were taken at home except in a sub study involving a nested cohort. Patients were contacted at Day 5 (+/- 2 days) either on telephone or by a home visit to document any AEs experienced. Patients were asked to report to the study team any other AEs that occurred within 28 days post-treatment. All patients in the nested cohort had electrocardiogram (ECG). FINDINGS: A total of 4563 patients, 52.1% females and 48.2% <6 years completed the study. A total of 444 patients were enrolled into the nested cohort. About 33% had temperature >= 37.5 degrees C at enrolment. Approximately 3.4% reported taking prior antimalarials, 19.4% other medications and 86% took at least one concomitant medication. Incidence of AEs was 7.6% including infections (4.6%), gastrointestinal disorders (1.0%) and local reactions at the site of venesection (0.5%). Others were respiratory disorders (0.4%) and nervous system disorders (0.3%). There were nine adverse events of special interest (AESI); itching/pruritus (7), dizziness (1), and skin lesions (1). Patients who took medications prior to enrolment had higher incidence of AEs compared with those without (9.3% vs. 6.1%; P<0.001). Statistically significant associations were found between the reported AEs and age of patients (P<0.001), their body mass index (BMI) (P< 0.001) and parasite densities (P< 0.001). CONCLUSION: Dihydroartemisinin-Piperaquine was well tolerated with no serious safety concerns identified. Obesity and prior enrolment medication were among significant factors associated with increased AEs reporting. PMID- 28358872 TI - Potential sources of bacteria colonizing the cryoconite of an Alpine glacier. AB - We investigated the potential contribution of ice-marginal environments to the microbial communities of cryoconite holes, small depressions filled with meltwater that form on the surface of Forni Glacier (Italian Alps). Cryoconite holes are considered the most biologically active environments on glaciers. Bacteria can colonize these environments by short-range transport from ice marginal environments or by long-range transport from distant areas. We used high throughput DNA sequencing to identify Operational Taxonomic Units (OTUs) present in cryoconite holes and three ice-marginal environments, the moraines, the glacier forefield, and a large (> 3 m high) ice-cored dirt cone occurring on the glacier surface. Bacterial communities of cryoconite holes were different from those of ice-marginal environments and hosted fewer OTUs. However, a network analysis revealed that the cryoconite holes shared more OTUs with the moraines and the dirt cone than with the glacier forefield. Ice-marginal environments may therefore act as sources of bacteria for cryoconite holes, but differences in environmental conditions limit the number of bacterial strains that may survive in them. At the same time, cryoconite holes host a few OTUs that were not found in any ice-marginal environment we sampled, thus suggesting that some bacterial populations are positively selected by the specific environmental conditions of the cryoconite holes. PMID- 28358873 TI - Whole-genome analysis of papillary kidney cancer finds significant noncoding alterations. AB - To date, studies on papillary renal-cell carcinoma (pRCC) have largely focused on coding alterations in traditional drivers, particularly the tyrosine-kinase, Met. However, for a significant fraction of tumors, researchers have been unable to determine a clear molecular etiology. To address this, we perform the first whole genome analysis of pRCC. Elaborating on previous results on MET, we find a germline SNP (rs11762213) in this gene predicting prognosis. Surprisingly, we detect no enrichment for small structural variants disrupting MET. Next, we scrutinize noncoding mutations, discovering potentially impactful ones associated with MET. Many of these are in an intron connected to a known, oncogenic alternative-splicing event; moreover, we find methylation dysregulation nearby, leading to a cryptic promoter activation. We also notice an elevation of mutations in the long noncoding RNA NEAT1, and these mutations are associated with increased expression and unfavorable outcome. Finally, to address the origin of pRCC heterogeneity, we carry out whole-genome analyses of mutational processes. First, we investigate genome-wide mutational patterns, finding they are governed mostly by methylation-associated C-to-T transitions. We also observe significantly more mutations in open chromatin and early-replicating regions in tumors with chromatin-modifier alterations. Finally, we reconstruct cancer evolutionary trees, which have markedly different topologies and suggested evolutionary trajectories for the different subtypes of pRCC. PMID- 28358874 TI - Prognostic implication of histological features associated with EHD2 expression in papillary thyroid carcinoma. AB - Papillary thyroid carcinoma (PTC) is a heterogeneous tumor with various histological and molecular subtypes. EHD2 is involved in endocytosis and endosomal recycling. This study aimed to investigate the prognostic significance of EHD2 expression in PTC and develop a new model for predicting persistent/recurrent disease after thyroidectomy. Pathologic slides of 512 consecutive patients with PTC >= 1 cm were retrospectively reviewed. BRAF mutation analysis and immunohistochemistry for EHD2 were performed. Clinical significance of EHD2 mRNA expression was analyzed in 388 PTC patients using The Cancer Genome Atlas dataset. The presence of dyscohesive cells and psammoma bodies were found have significant association with persistent/recurrent disease (p = 0.049 and p = 0.038, respectively). The best discrimination of disease-free survival was found by dividing patients into three prognostic groups based on the following two risk factors according to the size category: psammoma bodies >= 4 and dyscohesive cells (>= 1% and >= 20% in PTCs of < 2.0 cm and >= 2.0 cm, respectively). In PTCs of >= 2.0 cm, patients with the two risk factors had a hazard ratio of 13.303 (p = 0.005) compared to those without risk factors. High expression level of EHD2 was associated with BRAF V600E (p < 0.001), presence of dyscohesive cells (p = 0.010), and absence of psammoma bodies (p = 0.001). Increased EHD2 mRNA expression level was associated with extrathyroidal extension (p < 0.001), pT3-4 (p < 0.001), lymph node metastasis (p < 0.001), higher risk of recurrence (p < 0.001), and BRAF V600E (p < 0.001). Our prognostic model is useful for predicting persistent/recurrent disease after surgery of PTC. EHD2 mRNA expression could be a novel prognostic marker for PTC patients. PMID- 28358875 TI - Protein aggregation with poly(vinyl) alcohol surfactant reduces double emulsion encapsulated mammalian cell-free expression. AB - Development of artificial cell models requires encapsulation of biomolecules within membrane-bound compartments. There have been limited studies of using mammalian cell-free expression (CFE) system as the 'cytosol' of artificial cells. We exploit glass capillary droplet microfluidics for the encapsulation of mammalian CFE within double emulsion templated vesicles. The complexity of the physicochemical properties of HeLa cell-free lysate poses a challenge compared with encapsulating simple buffer solutions. In particular, we discovered the formation of aggregates in double emulsion templated vesicles encapsulating mammalian HeLa CFE, but not with bacterial CFE. The aggregates did not arise from insolubility of the proteins made from CFE nor due to the interaction of mammalian CFE with the organic solvents in the middle phase of the double emulsions. We found that aggregation is dependent on the concentration of poly(vinyl) alcohol (PVA) surfactant, a critical double emulsion-stabilizing surfactant, and the lysate concentration in mammalian CFE. Despite vesicle instability and reduced protein expression, we demonstrate protein expression by encapsulating mammalian CFE system. Using mass spectrometry and Western blot, we identified and verified that actin is one of the proteins inside the mammalian CFE that aggregated with PVA surfactant. Our work establishes a baseline description of mammalian CFE system encapsulated in double emulsion templated vesicles as a platform for building artificial cells. PMID- 28358876 TI - Human African Trypanosomiasis in a Spanish traveler returning from Tanzania. PMID- 28358878 TI - Correction: Alternatively Activated (M2) Macrophage Phenotype Is Inducible by Endothelin-1 in Cultured Human Macrophages. AB - [This corrects the article DOI: 10.1371/journal.pone.0166433.]. PMID- 28358877 TI - Tuberculosis knowledge, attitudes, and practices among northern Ethiopian prisoners: Implications for TB control efforts. AB - INTRODUCTION: Although awareness is an important component in tuberculosis (TB) control, we do not know how much Ethiopian prisoners know about TB. This study assessed the level of knowledge, attitudes, and practices (KAP) of prisoners about TB in eight northern Ethiopian prisons. METHODS: Data were collected cross sectionally from 615 prisoners using a standardized questionnaire between March and May 2016. The outcome variables were defined considering the basic elements about TB. RESULTS: Out of 615 prisoners, only 37.7% mentioned bacteria as a cause of TB while 21.7% related TB to exposure to cold wind. Eighty-eight per cent correctly mentioned the aerial route of TB transmission and 27.3% had perceived stigma towards TB. The majority (63.7%) was not aware of the possibility of getting multi-drug-resistant strains when they would not adhere to treatment. Overall, only 24% knew the basic elements about TB, 41% had favorable attitudes, and 55% had a good practice. Prisoners who were urban residents were generally more knowledgeable than rural residents (adjusted OR = 2.16; 95% CI = 1.15-4.06). Illiterates were found to be less knowledgeable (adjusted OR = 0.17; 95% CI = 0.06-0.46), less likely to have a favorable attitude (adjusted OR = 0.31; 95% CI = 0.15-0.64), and less good practice (adjusted OR = 0.35; 95% CI = 0.18-0.69). Significant differences were also observed between the different study prisons. CONCLUSIONS: Knowledge of prisoners regarding the cause of TB and consequences of non-adherence to TB treatment was low. Knowledge on the transmission, symptoms, and prevention was fairly high. Health education interventions, focused on the cause and the translation of the knowledge to appropriate practices, are needed in all the study prisons. Special attention should be given to less educated prisoners, and to prisons with a high number of prisoners and those in remote areas. PMID- 28358879 TI - Genetic variation for resistance to high temperature stress of mature sperm - a study in Drosophila. AB - Genetic variation for resistance to heat stress has been found for a number of life-history components in Drosophila species. For male and female fertility (or sterility), stress resistance of the parents is confounded with stress resistance of the haploid gametes. Many genes are known to influence male fertility in Drosophila melanogaster. Some may carry temperature sensitive alleles that reduce fertility through effects on mature sperm when exposed to heat stress. In this study, sperm from each of 320 males were either not heat shocked (control) or exposed to a heat shock (36.9 degrees C for 2 hours) either in the male testes or in the female reproductive tract. We did not detect any temperature sensitive sterility alleles. These results are relevant in relation to haploid gene expression and the findings of considerable amounts of mRNA in mature sperm, potentially important for sperm function and fertilization. PMID- 28358880 TI - Defining Brugia malayi and Wolbachia symbiosis by stage-specific dual RNA-seq. AB - BACKGROUND: Filarial nematodes currently infect up to 54 million people worldwide, with millions more at risk for infection, representing the leading cause of disability in the developing world. Brugia malayi is one of the causative agents of lymphatic filariasis and remains the only human filarial parasite that can be maintained in small laboratory animals. Many filarial nematode species, including B. malayi, carry an obligate endosymbiont, the alpha proteobacteria Wolbachia, which can be eliminated through antibiotic treatment. Elimination of the endosymbiont interferes with development, reproduction, and survival of the worms within the mamalian host, a clear indicator that the Wolbachia are crucial for survival of the parasite. Little is understood about the mechanism underlying this symbiosis. METHODOLOGY/ PRINCIPLE FINDINGS: To better understand the molecular interplay between these two organisms we profiled the transcriptomes of B. malayi and Wolbachia by dual RNA-seq across the life cycle of the parasite. This helped identify functional pathways involved in this essential symbiotic relationship provided by the co-expression of nematode and bacterial genes. We have identified significant stage-specific and gender specific differential expression in Wolbachia during the nematode's development. For example, during female worm development we find that Wolbachia upregulate genes involved in ATP production and purine biosynthesis, as well as genes involved in the oxidative stress response. CONCLUSIONS/ SIGNIFICANCE: This global transcriptional analysis has highlighted specific pathways to which both Wolbachia and B. malayi contribute concurrently over the life cycle of the parasite, paving the way for the development of novel intervention strategies. PMID- 28358881 TI - Dual kinetic curves in reversible electrochemical systems. AB - We introduce dual kinetic chronoamperometry, in which reciprocal relations are established between the kinetic curves of electrochemical reactions that start from symmetrical initial conditions. We have performed numerical and experimental studies in which the kinetic curves of the electron-transfer processes are analyzed for a reversible first order reaction. Experimental tests were done with the ferrocyanide/ferricyanide system in which the concentrations of each component could be measured separately using the platinum disk/gold ring electrode. It is shown that the proper ratio of the transient kinetic curves obtained from cathodic and anodic mass transfer limited regions give thermodynamic time invariances related to the reaction quotient of the bulk concentrations. Therefore, thermodynamic time invariances can be observed at any time using the dual kinetic curves for reversible reactions. The technique provides a unique possibility to extract the non-steady state trajectory starting from one initial condition based only on the equilibrium constant and the trajectory which starts from the symmetrical initial condition. The results could impact battery technology by predicting the concentrations and currents of the underlying non-steady state processes in a wide domain from thermodynamic principles and limited kinetic information. PMID- 28358883 TI - "ReaNet", the Internet utilization among surrogates of critically ill patients with sepsis. AB - CONTEXT: Health-related Internet utilization is common but its use by proxies of critically ill patients is unknown. Our objective was to describe the prevalence and the Internet utilization characteristics among surrogates of critically ill septic patients. We conducted a prospective observational study in French ICUs. Three survey instruments were used to describe ICU organization regarding information delivery, patients and surrogates characteristics. RESULTS: 169 surrogates of 146 septic patients hospitalized in 19 ICUs were included. One sixth of ICUs (n = 3, 16%) had their own website. Majority of patients were males (n = 100, 68%), aged 64+/-1 years old, with a SAPS2 score at 53+/-17 and required vasopressors (n = 117, 83%), mechanical ventilation (n = 116, 82%). More than one quarter required renal replacement therapy (n = 36, 26%). Majority of surrogates were female, in their fifties. Only one in five knew the word sepsis (n = 27, 16%). Majority of proxies internet users (n = 77; 55%) search on the internet about sepsis. The main motivation was curiosity. Majority of surrogates found the information online reliable, suitable for request and concordant. Prior use of health-related Internet (OR = 20.7 [4.30-100.1]), the presence of a nursing staff during family-physician meetings (OR = 3.33 [1.17-9.53]), a younger patient age (OR = 1.32 [1.01-1.72]) and renal replacement therapy requirement (OR = 2.58 [1.06-6.26]) were associated with health-related Internet use. Neither satisfaction with medical care or information provision, neither presence of anxiety-depression symptoms, were associated with health-related Internet use. Majority of surrogates (N = 76 (52%)) would have like receiving a list of selected websites on sepsis. CONCLUSIONS: Majority of proxies of critically ill patients with sepsis use Internet to learn more about sepsis. Internet utilization is independent of satisfaction with global ICU care, perceived quality of information delivery by doctors or the existence of anxiety-depression symptoms during ICU stay. The delivery of a list of recommended web sites on sepsis would have been appreciated. PMID- 28358884 TI - Nitrogen balance along a northern boreal forest fire chronosequence. AB - Fire is a major natural disturbance factor in boreal forests, and the frequency of forest fires is predicted to increase due to climate change. Nitrogen (N) is a key determinant of carbon sequestration in boreal forests because the shortage of N limits tree growth. We studied changes in N pools and fluxes, and the overall N balance across a 155-year non stand-replacing fire chronosequence in sub-arctic Pinus sylvestris forests in Finland. Two years after the fire, total ecosystem N pool was 622 kg ha-1 of which 16% was in the vegetation, 8% in the dead biomass and 76% in the soil. 155 years after the fire, total N pool was 960 kg ha-1, with 27% in the vegetation, 3% in the dead biomass and 69% in the soil. This implies an annual accumulation rate of 2.28 kg ha-1 which was distributed equally between soil and biomass. The observed changes in N pools were consistent with the computed N balance +2.11 kg ha-1 yr-1 over the 155-year post-fire period. Nitrogen deposition was an important component of the N balance. The biological N fixation increased with succession and constituted 9% of the total N input during the 155 post-fire years. N2O fluxes were negligible (<= 0.01 kg ha-1 yr-1) and did not differ among post-fire age classes. The number and intensity of microbial genes involved in N cycling were lower at the site 60 years after fire compared to the youngest and the oldest sites indicating potential differences in soil N cycling processes. The results suggest that in sub-arctic pine forests, the non stand-replacing, intermediate-severity fires decrease considerably N pools in biomass but changes in soil and total ecosystem N pools are slight. Current fire return interval does not seem to pose a great threat to ecosystem productivity and N status in these sub-arctic forests. PMID- 28358882 TI - Proteomic analysis of organic sulfur compound utilisation in Advenella mimigardefordensis strain DPN7T. AB - 2-Mercaptosuccinate (MS) and 3,3'-ditiodipropionate (DTDP) were discussed as precursor substance for production of polythioesters (PTE). Therefore, degradation of MS and DTDP was investigated in Advenella mimigardefordensis strain DPN7T, applying differential proteomic analysis, gene deletion and enzyme assays. Protein extracts of cells cultivated with MS, DTDP or 3-sulfinopropionic acid (SP) were compared with those cultivated with propionate (P) and/or succinate (S). The chaperone DnaK (ratio DTDP/P 9.2, 3SP/P 4.0, MS/S 6.1, DTDP/S 6.2) and a Do-like serine protease (DegP) were increased during utilization of all organic sulfur compounds. Furthermore, a putative bacterioferritin (locus tag MIM_c12960) showed high abundance (ratio DTDP/P 5.3, 3SP/P 3.2, MS/S 4.8, DTDP/S 3.9) and is probably involved in a thiol-specific stress response. The deletion of two genes encoding transcriptional regulators (LysR (MIM_c31370) and Xre (MIM_c31360)) in the close proximity of the relevant genes of DTDP catabolism (acdA, mdo and the genes encoding the enzymes of the methylcitric acid cycle; prpC,acnD, prpF and prpB) showed that these two regulators are essential for growth of A. mimigardefordensis strain DPN7T with DTDP and that they most probably regulate transcription of genes mandatory for this catabolic pathway. Furthermore, proteome analysis revealed a high abundance (ratio MS/S 10.9) of a hypothetical cupin-2-domain containing protein (MIM_c37420). This protein shows an amino acid sequence similarity of 60% to a newly identified MS dioxygenase from Variovorax paradoxus strain B4. Deletion of the gene and the adjacently located transcriptional regulator LysR, as well as heterologous expression of MIM_c37420, the putative mercaptosuccinate dioxygenase (Msdo) from A. mimigardefordensis, showed that this protein is the key enzyme of MS degradation in A. mimigardefordensis strain DPN7T (KM 0.2 mM, specific activity 17.1 MUmol mg 1 min-1) and is controlled by LysR (MIM_c37410). PMID- 28358885 TI - Exogenous lactobacilli mitigate microbial changes associated with grain fermentation (corn, oats, and wheat) by equine fecal microflora ex vivo. AB - Cereal grains are often included in equine diets. When starch intake exceeds foregut digestion starch will reach the hindgut, impacting microbial ecology. Probiotics (e.g., lactobacilli) are reported to mitigate GI dysbioses in other species. This study was conducted to determine the effect of exogenous lactobacilli on pH and the growth of amylolytic and lactate-utilizing bacteria. Feces were collected from 3 mature geldings fed grass hay with access to pasture. Fecal microbes were harvested by differential centrifugation, washed, and re suspended in anaerobic media containing ground corn, wheat, or oats at 1.6% (w/v) starch and one of five treatments: Control (substrate only), L. acidophilus, L. buchneri, L. reuteri, or an equal mixture of all three (107 cells/mL, final concentration). After 24 h of incubation (37 degrees C, 160 rpm), samples were collected for pH and enumerations of total amylolytics, Group D Gram-positive cocci (GPC; Enterococci, Streptococci), lactobacilli, and lactate-utilizing bacteria. Enumeration data were log transformed prior to ANOVA (SAS, v. 9.3). Lactobacilli inhibited pH decline in corn and wheat fermentations (P < 0.0001). Specifically, addition of either L. reuteri or L. acidophilus was most effective at mitigating pH decline with both corn and wheat fermentation, in which the greatest acidification occurred (P < 0.05). Exogenous lactobacilli decreased amylolytics, while increasing lactate-utilizers in corn and wheat fermentations (P < 0.0001). In oat fermentations, L. acidophilus and L. reuteri inhibited pH decline and increased lactate-utilizers while decreasing amylolytics (P < 0.0001). For all substrates, L. reuteri additions (regardless of viability) had the lowest number of GPC and the highest number of lactobacilli and lactate utilizers (P < 0.05). There were no additive effects when lactobacilli were mixed. Exogenous lactobacilli decreased the initial (first 8 h) rate of starch catalysis when wheat was the substrate, but did not decrease total (24 h) starch utilization in any case. These results indicate that exogenous lactobacilli can impact the microbial community and pH of cereal grain fermentations by equine fecal microflora ex vivo. Additionally, dead (autoclaved) exogenous lactobacilli had similar effects as live lactobacilli on fermentation. This latter result indicates that the mechanism by which lactobacilli impact other amylolytic bacteria is not simple resource competition. PMID- 28358886 TI - "We can't get along without each other": Qualitative interviews with physicians about device industry representatives, conflict of interest and patient safety. AB - OBJECTIVES: Physician relationships with device industry representatives have not been previously assessed. This study explored interactions with device industry representatives among physicians who use implantable cardiovascular and orthopedic devices to identify whether conflict of interest (COI) is a concern and how it is managed. DESIGN: A descriptive qualitative approach was used. Physicians who implant orthopedic and cardiovascular devices were identified in publicly available directories and web sites, and interviewed about their relationships with device industry representatives. Sampling was concurrent with data collection and analysis. Data were analyzed and discussed using constant comparative technique by all members of the research team. RESULTS: Twenty-two physicians (10 cardiovascular, 12 orthopedic) were interviewed. Ten distinct representative roles were identified: purchasing, training, trouble-shooting, supplying devices, assisting with device assembly and insertion, supporting operating room staff, mitigating liability, conveying information about recalls, and providing direct and indirect financial support. Participants recognized the potential for COI but representatives were present for the majority of implantations. Participants revealed a tension between physicians and representatives that was characterized as "symbiotic", but required physicians to be vigilant about COI and patient safety, particularly because representatives varied regarding disclosure of device defects. They described a concurrent tension between hospitals, whose policies and business practices were focused on cost-control, and physicians who were required to comply with those policies and use particular devices despite concerns about their safety and effectiveness. CONCLUSIONS: Given the potential for COI and threats to patient safety, further research is needed to establish the clinical implications of the role of, and relationship with device industry representatives; and whether and how hospitals do and should govern interaction with representatives, or support their staff in this regard. PMID- 28358888 TI - Effectiveness of betahistine (48 mg/day) in patients with vestibular vertigo during routine practice: The VIRTUOSO study. AB - BACKGROUND: Vestibular vertigo is associated with substantially reduced quality of life. Betahistine is effective in improving vertigo-associated symptoms, with longer treatment periods leading to greater improvements; however, it is not known whether these effects persist after treatment cessation. METHODS: VIRTUOSO was a prospective, multinational, non-comparative, post-marketing observational programme investigating the effectiveness of betahistine (48 mg/day) and the course of vertigo after the discontinuation of treatment. Patients with vestibular vertigo who were prescribed 48 mg/day betahistine were enrolled in Russia and Ukraine. Treatment duration was up to 2 months, and patients were followed up for 2 months after discontinuation of betahistine. Efficacy endpoints included clinical response (assessed by change in vertigo severity), monthly attack frequency, and physician and patient grading of overall clinical response and improvement of vertigo-associated symptoms. RESULTS: Overall, 309 patients were enrolled and 305 completed the study. Clinical response was rated as good, very good or excellent in 74.1% of patients at end of treatment, with vertigo severity significantly decreased from baseline (p < 0.001). Monthly vertigo attack frequency decreased significantly during the 2 months of treatment (p < 0.001 from baseline) and further decreased during the 2-month follow-up (p < 0.001 from end of treatment). Overall, clinical response was graded as good or excellent by 94.4% of physicians and 95.4% of patients. Clinical improvement was considered either good or excellent by 82.6-90.5% of physicians and patients for nausea, vomiting and faintness. Only one adverse event was reported, with no serious adverse events. CONCLUSION: Our findings suggest that betahistine (48 mg/day) therapy is effective in treating vertigo in routine clinical settings. The observed effects persisted for 2 months after treatment cessation, suggesting that betahistine may facilitate lasting vestibular compensation. PMID- 28358887 TI - Dynasore blocks evoked release while augmenting spontaneous synaptic transmission from primary visceral afferents. AB - The recycling of vesicle membrane fused during exocytosis is essential to maintaining neurotransmission. The GTPase dynamin is involved in pinching off membrane to complete endocytosis and can be inhibited by dynasore resulting in activity-dependent depletion of release-competent synaptic vesicles. In rat brainstem slices, we examined the effects of dynasore on three different modes of glutamate release-spontaneous, evoked, and asynchronous release-at solitary tract (ST) inputs to neurons in the nucleus of the solitary tract (NTS). Intermittent bursts of stimuli to the ST interspersed with pauses in stimulation allowed examination of these three modes in each neuron continuously. Application of 100 MUM dynasore rapidly increased the spontaneous EPSC (sEPSC) frequency which was followed by inhibition of both ST-evoked EPSCs (ST-EPSC) as well as asynchronous EPSCs. The onset of ST-EPSC failures was not accompanied by amplitude reduction-a pattern more consistent with conduction block than reduced probability of vesicle release. Neither result suggested that dynasore interrupted endocytosis. The dynasore response profile resembled intense presynaptic TRPV1 activation. The TRPV1 antagonist capsazepine failed to prevent dynasore increases in sEPSC frequency but did prevent the block of the ST-EPSC. In contrast, the TRPV1 antagonist JNJ 17203212 prevented both actions of dynasore in neurons with TRPV1 expressing ST inputs. In a neuron lacking TRPV1-expressing ST inputs, however, dynasore promptly increased sEPSC rate followed by block of ST-evoked EPSCs. Together our results suggest that dynasore actions on ST-NTS transmission are TRPV1-independent and changes in glutamatergic transmission are not consistent with changes in vesicle recycling and endocytosis. PMID- 28358890 TI - A multifunctional bioactive material that stimulates osteogenesis and promotes the vascularization bone marrow stem cells and their resistance to bacterial infection. AB - The main limitation of tissue engineering lies in the inability to stimulate osteogenesis, angiogenesis of stem cells and broad-spectrum antimicrobial activity. However, the development of multifunctional bioactive materials with these capabilities remains a great challenge. In this study, we prepared mesoporous silica nanoparticles encapsulated with silver nanocrystals (AG-MSN) with uniform sphere size and mesopores. Platelet-derived growth factor BB (PDGF BB) was effectively loaded in the AG-MSN mesopores (P-AG-MSN). The silicon ions (Si) released by P-AG-MSN stimulate osteogenic differentiation of bone marrow stromal cells (BMSC) by activating the alkaline phosphatase (ALP) activity of bone-related genes and increasing protein (OCN, RUNX2 and OPN) expression. Ag+ ions could be slowly released from the interior of the shell, highlighting their durable antibacterial activity. The sustained release of PDGF-BB from P-AG-MSN stimulated the angiogenic differentiation of BMSC, as indicated by the enhanced secretion of vascular endothelial growth factor (VEGF), HIF-1alpha, HGF and ANG-1 and protein expression. Our results show that P-AG-MSN can clearly promote BMSC osteostimulation and vascularization. This research serves as a preliminary study of the utilization of this multifunctional mixture to fabricate a new active biological scaffold that integrates BMSC osteostimulation, vascularization and bactericidal effects by 3D printing technology. PMID- 28358889 TI - Transient microbiota exposures activate dormant Escherichia coli infection in the bladder and drive severe outcomes of recurrent disease. AB - Pathogens often inhabit the body asymptomatically, emerging to cause disease in response to unknown triggers. In the bladder, latent intracellular Escherichia coli reservoirs are regarded as likely origins of recurrent urinary tract infection (rUTI), a problem affecting millions of women worldwide. However, clinically plausible triggers that activate these reservoirs are unknown. Clinical studies suggest that the composition of a woman's vaginal microbiota influences her susceptibility to rUTI, but the mechanisms behind these associations are unclear. Several lines of evidence suggest that the urinary tract is routinely exposed to vaginal bacteria, including Gardnerella vaginalis, a dominant member of the vaginal microbiota in some women. Using a mouse model, we show that bladder exposure to G. vaginalis triggers E. coli egress from latent bladder reservoirs and enhances the potential for life-threatening outcomes of the resulting E. coli rUTI. Transient G. vaginalis exposures were sufficient to cause bladder epithelial apoptosis and exfoliation and interleukin-1-receptor mediated kidney injury, which persisted after G. vaginalis clearance from the urinary tract. These results support a broader view of UTI pathogenesis in which disease can be driven by short-lived but powerful urinary tract exposures to vaginal bacteria that are themselves not "uropathogenic" in the classic sense. This "covert pathogenesis" paradigm may apply to other latent infections, (e.g., tuberculosis), or for diseases currently defined as noninfectious because routine culture fails to detect microbes of recognized significance. PMID- 28358892 TI - Effects of pre-conditioning on behavior and physiology of horses during a standardised learning task. AB - Rein tension is used to apply pressure to control both ridden and unridden horses. The pressure is delivered by equipment such as the bit, which may restrict voluntary movement and cause changes in behavior and physiology. Managing the effects of such pressure on arousal level and behavioral indicators will optimise horse learning outcomes. This study examined the effect of training horses to turn away from bit pressure on cardiac outcomes and behavior (including responsiveness) over the course of eight trials in a standardised learning task. The experimental procedure consisted of a resting phase, treatment/control phase, standardised learning trials requiring the horses (n = 68) to step backwards in response to bit pressure and a recovery phase. As expected, heart rate increased (P = 0.028) when the handler applied rein tension during the treatment phase. The amount of rein tension required to elicit a response during treatment was higher on the left than the right rein (P = 0.009). Total rein tension required for trials reduced (P < 0.001) as they progressed, as did time taken (P < 0.001) and steps taken (P < 0.001). The incidence of head tossing decreased (P = 0.015) with the progression of the trials and was higher (P = 0.018) for the control horses than the treated horses. These results suggest that preparing the horses for the lesson and slightly raising their arousal levels, improved learning outcomes. PMID- 28358893 TI - Halvade-RNA: Parallel variant calling from transcriptomic data using MapReduce. AB - Given the current cost-effectiveness of next-generation sequencing, the amount of DNA-seq and RNA-seq data generated is ever increasing. One of the primary objectives of NGS experiments is calling genetic variants. While highly accurate, most variant calling pipelines are not optimized to run efficiently on large data sets. However, as variant calling in genomic data has become common practice, several methods have been proposed to reduce runtime for DNA-seq analysis through the use of parallel computing. Determining the effectively expressed variants from transcriptomics (RNA-seq) data has only recently become possible, and as such does not yet benefit from efficiently parallelized workflows. We introduce Halvade-RNA, a parallel, multi-node RNA-seq variant calling pipeline based on the GATK Best Practices recommendations. Halvade-RNA makes use of the MapReduce programming model to create and manage parallel data streams on which multiple instances of existing tools such as STAR and GATK operate concurrently. Whereas the single-threaded processing of a typical RNA-seq sample requires ~28h, Halvade RNA reduces this runtime to ~2h using a small cluster with two 20-core machines. Even on a single, multi-core workstation, Halvade-RNA can significantly reduce runtime compared to using multi-threading, thus providing for a more cost effective processing of RNA-seq data. Halvade-RNA is written in Java and uses the Hadoop MapReduce 2.0 API. It supports a wide range of distributions of Hadoop, including Cloudera and Amazon EMR. PMID- 28358891 TI - Plantar fascia enthesopathy is highly prevalent in diabetic patients without peripheral neuropathy and correlates with retinopathy and impaired kidney function. AB - BACKGROUND: Aim of this study was to evaluate the prevalence of plantar fascia (PF) enthesopathy in Type 2 diabetes mellitus (T2DM) patients without distal peripheral neuropathy (DPN). METHODS: We recruited 50 T2DM patients without DPN and 50 healthy controls. DPN was excluded using the Michigan Neuropathy Screening Instrument (MNSI). All patients underwent a bilateral sonographicevaluation of the enthesealportion of the PF. RESULTS: PF thickness was significantly higher in T2DM patients (p<0.0001). T2DM patients presented a higher prevalence of entheseal thickening (p = 0.002), enthesophyte (p = 0.02) and cortical irregularity (p = 0.02). The overall sum of abnormalities was higher in T2DM patients (p<0.0001), as was the percentage of bilateral involvement (p = 0.005). In a logistic regression analysis, retinopathy predicted entheseal thickening (OR 3.5, p = 0.05) and enthesophytes (OR 5.13, p = 0.001); reduced eGFR predicted enthesophytes (OR 2.93, p = 0.04); body mass index (BMI) predicted cortical irregularity (OR 0.87, p = 0.05); mean glucose predicted enthesophyte (OR 1.01, p = 0.03); LDL cholesterol predicted cortical irregularity (OR 0.98, p = 0.02). CONCLUSIONS: Our data suggest that T2DM is associated with PF enthesopathyindependently of DPN. PMID- 28358894 TI - Phylogenetic conservation of substrate use specialization in leaf litter bacteria. AB - Environmental change will influence the ecosystem processes regulated by microbial communities, including leaf litter decomposition. To assess how microbial communities and their functioning might respond to increases in temperature, we quantified the distribution of traits related to carbon substrate utilization and temperature sensitivity in leaf litter bacteria isolated from a natural grassland ecosystem in Southern California. The isolates varied substantially in their carbon substrate use, as well as their response to temperature change. To better predict the functioning and responses in natural communities, we also examined if the functional and response traits were phylogenetically patterned or correlated with one another. We found that the distribution of functional traits displayed a phylogenetic pattern, but the sensitivity of the traits to changes in temperature did not. We also did not detect any correlations between carbon substrate use and sensitivity to changes in temperature. Together, these results suggest that information about microbial composition may provide insights to predicting ecosystem function under one temperature, but that these relationships may not hold under new temperature conditions. PMID- 28358896 TI - Detecting disease-associated genomic outcomes using constrained mixture of Bayesian hierarchical models for paired data. AB - Detecting disease-associated genomic outcomes is one of the key steps in precision medicine research. Cutting-edge high-throughput technologies enable researchers to unbiasedly test if genomic outcomes are associated with disease of interest. However, these technologies also include the challenges associated with the analysis of genome-wide data. Two big challenges are (1) how to reduce the effects of technical noise; and (2) how to handle the curse of dimensionality (i.e., number of variables are way larger than the number of samples). To tackle these challenges, we propose a constrained mixture of Bayesian hierarchical models (MBHM) for detecting disease-associated genomic outcomes for data obtained from paired/matched designs. Paired/matched designs can effectively reduce effects of confounding factors. MBHM does not involve multiple testing, hence does not have the problem of the curse of dimensionality. It also could borrow information across genes so that it can be used for whole genome data with small sample sizes. PMID- 28358895 TI - Filter based phase distortions in extracellular spikes. AB - Extracellular recordings are the primary tool for extracting neuronal spike trains in-vivo. One of the crucial pre-processing stages of this signal is the high-pass filtration used to isolate neuronal spiking activity. Filters are characterized by changes in the magnitude and phase of different frequencies. While filters are typically chosen for their effect on magnitudes, little attention has been paid to the impact of these filters on the phase of each frequency. In this study we show that in the case of nonlinear phase shifts generated by most online and offline filters, the signal is severely distorted, resulting in an alteration of the spike waveform. This distortion leads to a shape that deviates from the original waveform as a function of its constituent frequencies, and a dramatic reduction in the SNR of the waveform that disrupts spike detectability. Currently, the vast majority of articles utilizing extracellular data are subject to these distortions since most commercial and academic hardware and software utilize nonlinear phase filters. We show that this severe problem can be avoided by recording wide-band signals followed by zero phase filtering, or alternatively corrected by reversed filtering of a narrow band filtered, and in some cases even segmented signals. Implementation of either zero phase filtering or phase correction of the nonlinear phase filtering reproduces the original spike waveforms and increases the spike detection rates while reducing the number of false negative and positive errors. This process, in turn, helps eliminate subsequent errors in downstream analyses and misinterpretations of the results. PMID- 28358897 TI - Don't make cache too complex: A simple probability-based cache management scheme for SSDs. AB - Solid-state drives (SSDs) have recently become a common storage component in computer systems, and they are fueled by continued bit cost reductions achieved with smaller feature sizes and multiple-level cell technologies. However, as the flash memory stores more bits per cell, the performance and reliability of the flash memory degrade substantially. To solve this problem, a fast non-volatile memory (NVM-)based cache has been employed within SSDs to reduce the long latency required to write data. Absorbing small writes in a fast NVM cache can also reduce the number of flash memory erase operations. To maximize the benefits of an NVM cache, it is important to increase the NVM cache utilization. In this paper, we propose and study ProCache, a simple NVM cache management scheme, that makes cache-entrance decisions based on random probability testing. Our scheme is motivated by the observation that frequently written hot data will eventually enter the cache with a high probability, and that infrequently accessed cold data will not enter the cache easily. Owing to its simplicity, ProCache is easy to implement at a substantially smaller cost than similar previously studied techniques. We evaluate ProCache and conclude that it achieves comparable performance compared to a more complex reference counter-based cache-management scheme. PMID- 28358898 TI - Correction: Different Effects of Metarhizium anisopliae Strains IMI330189 and IBC200614 on Enzymes Activities and Hemocytes of Locusta migratoria L. AB - [This corrects the article DOI: 10.1371/journal.pone.0155257.]. PMID- 28358899 TI - A systematic review of rodent pest research in Afro-Malagasy small-holder farming systems: Are we asking the right questions? AB - Rodent pests are especially problematic in terms of agriculture and public health since they can inflict considerable economic damage associated with their abundance, diversity, generalist feeding habits and high reproductive rates. To quantify rodent pest impacts and identify trends in rodent pest research impacting on small-holder agriculture in the Afro-Malagasy region we did a systematic review of research outputs from 1910 to 2015, by developing an a priori defined set of criteria to allow for replication of the review process. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We reviewed 162 publications, and while rodent pest research was spatially distributed across Africa (32 countries, including Madagascar), there was a disparity in number of studies per country with research biased towards four countries (Tanzania [25%], Nigeria [9%], Ethiopia [9%], Kenya [8%]) accounting for 51% of all rodent pest research in the Afro-Malagasy region. There was a disparity in the research themes addressed by Tanzanian publications compared to publications from the rest of the Afro-Malagasy region where research in Tanzania had a much more applied focus (50%) compared to a more basic research approach (92%) in the rest of the Afro-Malagasy region. We found that pest rodents have a significant negative effect on the Afro-Malagasy small-holder farming communities. Crop losses varied between cropping stages, storage and crops and the highest losses occurred during early cropping stages (46% median loss during seedling stage) and the mature stage (15% median loss). There was a scarcity of studies investigating the effectiveness of various management actions on rodent pest damage and population abundance. Our analysis highlights that there are inadequate empirical studies focused on developing sustainable control methods for rodent pests and rodent pests in the Africa-Malagasy context is generally ignored as a research topic. PMID- 28358900 TI - Detection of Pneumocystis jirovecii in oral wash from immunosuppressed patients as a diagnostic tool. AB - BACKGROUND: Diagnosis of Pneumocystis jirovecii (PJ) pneumonia ordinarily requires invasive procedures that could be avoided by PCR methodologies, if these could be designed with adequate cut-off values for confounding background carriage. METHODS: We designed a novel quantitative real-time PCR assay to detect the mitochondrial large subunit rRNA gene of PJ in oral washes. To benchmark levels of PJ carriage versus infection, we tested asymptomatic immunosuppressed patients including Danish (n = 88) and West African HIV-infected (n = 142) patients, renal transplant recipients (n = 51), rheumatologic patients (n = 102), patients with inflammatory bowel diseases (n = 98), and healthy blood donors (controls, n = 50). The fungal burden in patients with PJ pneumonia (PCP, n = 7) was also investigated. RESULTS: Danish HIV-infected patients (with viremia/low CD4) and recent transplant recipients were at most risk of being carriers (prevalence of 23% and 16.7% respectively), whereas PJ was rarely detected among rheumatologic patients, patients with inflammatory bowel diseases, and untreated West African HIV patients. PJ was not detected among healthy controls. The fungal burden in patients with PCP fell rapidly on treatment. CONCLUSIONS: The quantitative PCR method described could conceivably discriminate between carriage and disease, given suitable threshold values for the former, and predict treatment efficacy by measures of the fungal burden in daily oral washes. PMID- 28358901 TI - Custom RT-qPCR-array for glaucoma filtering surgery prognosis. AB - Excessive subconjunctival scarring is the main reason of failure of glaucoma filtration surgery. We analyzed conjunctival and systemic gene expression patterns after non penetrating deep sclerectomy (NPDS). To find expression patterns related to surgical failure and their correlation with the clinical outcomes. This study consisted of two consecutive stages. The first was a prospective analysis of wound-healing gene expression profile of six patients after NPDS. Conjunctival samples and peripheral blood samples were collected before and 15, 90,180, and 360 days after surgery. In the second stage, we conducted a retrospective analysis correlating the late conjunctival gene expression and the outcome of the NPDS for 11 patients. We developed a RT-qPCR Array for 88 key genes associated to wound healing. RT-qPCR Array analysis of conjunctiva samples showed statistically significant differences in 29/88 genes in the early stages after surgery, 20/88 genes between 90 and 180 days after surgery, and only 2/88 genes one year after surgery. In the blood samples, the most important changes occurred in 12/88 genes in the first 15 days after surgery. Correspondence analyses (COA) revealed significant differences between the expression of 20/88 genes in patients with surgical success and failure one year after surgery. Different expression patterns of mediators of the bleb wound healing were identified. Examination of such patterns might be used in surgery prognosis. RT-qPCR Array provides a powerful tool for investigation of differential gene expression wound healing after glaucoma surgery. PMID- 28358902 TI - Screening for AMPA receptor auxiliary subunit specific modulators. AB - AMPA receptors (AMPAR) are ligand gated ion channels critical for synaptic transmission and plasticity. Their dysfunction is implicated in a variety of psychiatric and neurological diseases ranging from major depressive disorder to amyotrophic lateral sclerosis. Attempting to potentiate or depress AMPAR activity is an inherently difficult balancing act between effective treatments and debilitating side effects. A newly explored strategy to target subsets of AMPARs in the central nervous system is to identify compounds that affect specific AMPAR auxiliary subunit complexes. This exploits diverse spatio-temporal expression patterns of known AMPAR auxiliary subunits, providing means for designing brain region-selective compounds. Here we report a high-throughput screening-based pipeline that can identify compounds that are selective for GluA2-CNIH3 and GluA2 stargazin complexes. These compounds will help us build upon the growing library of AMPAR-auxiliary subunit specific inhibitors, which have thus far all been targeted to TARP gamma-8. We used a cell-based assay combined with a voltage sensitive dye (VSD) to identify changes in glutamate-gated cation flow across the membranes of HEK cells co-expressing GluA2 and an auxiliary subunit. We then used a calcium flux assay to further validate hits picked from the VSD assay. VU0612951 and VU0627849 are candidate compounds from the initial screen that were identified as negative and positive allosteric modulators (NAM and PAM), respectively. They both have lower IC50/EC50s on complexes containing stargazin and CNIH3 than GSG1L or the AMPAR alone. We have also identified a candidate compound, VU0539491, that has NAM activity in GluA2(R)-CNIH3 and GluA2(Q) complexes and PAM activity in GluA2(Q)-GSG1L complexes. PMID- 28358904 TI - Neurotrophic effects of progranulin in vivo in reversing motor neuron defects caused by over or under expression of TDP-43 or FUS. AB - Progranulin (PGRN) is a glycoprotein with multiple roles in normal and disease states. Mutations within the GRN gene cause frontotemporal lobar degeneration (FTLD). The affected neurons display distinctive TAR DNA binding protein 43 (TDP 43) inclusions. How partial loss of PGRN causes TDP-43 neuropathology is poorly understood. TDP-43 inclusions are also found in affected neurons of patients with other neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. In ALS, TDP-43 inclusions are typically also immunoreactive for fused in sarcoma (FUS). Mutations within TDP-43 or FUS are themselves neuropathogenic in ALS and some cases of FTLD. We used the outgrowth of caudal primary motor neurons (MNs) in zebrafish embryos to investigate the interaction of PGRN with TDP-43 and FUS in vivo. As reported previously, depletion of zebrafish PGRN-A (zfPGRN-A) is associated with truncated primary MNs and impaired motor function. Here we found that depletion of zfPGRN-A results in primary MNs outgrowth stalling at the horizontal myoseptum, a line of demarcation separating the myotome into dorsal and ventral compartments that is where the final destination of primary motor is assigned. Successful axonal outgrowth beyond the horizontal myoseptum depends in part upon formation of acetylcholine receptor clusters and this was found to be disorganized upon depletion of zfPGRN A. PGRN reversed the effects of zfPGRN-A knockdown, but a related gene, zfPGRN-1, was without effect. Both knockdown of TDP-43 or FUS, as well as expression of humanTDP-43 and FUS mutants results in MN abnormalities that are reversed by co expression of hPGRN mRNA. Neither TDP-43 nor FUS reversed MN phenotypes caused by the depletion of PGRN. Thus TDP-43 and FUS lie upstream of PGRN in a gene complementation pathway. The ability of PGRN to override TDP-43 and FUS neurotoxicity due to partial loss of function or mutation in the corresponding genes may have therapeutic relevance. PMID- 28358905 TI - Violent relationships at the social-ecological level: A multi-mediation model to predict adolescent victimization by peers, bullying and depression in early and late adolescence. AB - BACKGROUND: From the social-ecological perspective, exposure to violence at the different developmental levels is fundamental to explain the dynamics of violence and victimization in educational centers. The following study aims at analyzing how these relationships are produced in the Peruvian context, where structural violence situations exist. METHODS: A multi-mediation structural model with 21,416 Peruvian adolescents (M = 13.69; SD = 0.71) was conducted to determine the influence of violence in the school environment on violence perceived within school and violence exercised by teachers. In addition, it was also intended to determine whether these violent relationships predict depression through loneliness, and bullying through peer victimization. The existence of differences between early and late adolescence was also verified. RESULTS: Results confirm that violence in the school setting has high influence on violence exercised by adolescents and teachers within the school. Teacher violence is the most important predictor of depression through loneliness, and encourages peer victimization and the emergence of aggressive behavior. Exposure to violence exercised by support sources-teachers and classmates-explains more than 90% of the total variance explained in bullying behavior. Differences were found between early and late adolescence models. CONCLUSION: The high prevalence of structural violence in school settings facilitates the bullying/victimization dynamics within school. From a social-ecological perspective, this result suggests the importance of network cooperation at a mesosystem level, with teachers from educational centers playing a crucial role in the prevention of bullying/victimization. PMID- 28358903 TI - Clusters of amniotic fluid cells and their associated early neuroepithelial markers in experimental myelomeningocele: Correlation with astrogliosis. AB - Myelomeningocele (MMC) is the most common and severe disabling type of spina bifida resulting in the exposure of vulnerable spinal cord to the hostile intrauterine environment. In this study, we sought to examine the cellular content of fetal amniotic fluid (AF) in MMC and explore a correlation between these cells and pathological development of MMC. MMC was induced in fetal rats by exposing pregnant mothers to all-trans retinoic acid and AF samples were collected before term. Cells were isolated from AF samples and morphologically and phenotypically characterized in short-term cultures. In addition, the spinal cord injury in MMC fetuses was assessed by immunohistochemical examination of astrogliosis. We identified a population of cells from the AF of MMC fetuses (MMC AF) that formed adherent clusters of tightly packed cells, which were absent from the AF of normal control fetuses (norm-AF). MMC-AF clusters contained cells co expressing adherens junction associated proteins (ZO-1), N-cadherin and F-actin at sites of cell-cell contacts. In addition, they expressed markers of early neuroepithelial cells such as SOX-1 and Pax-6 along with other stem/progenitor cell markers such as SOX-2 and nestin. Subpopulations of cells in MMC-AF clusters also expressed more advanced differentiation markers such as doublecortin and GFAP. We found that the appearance of cluster forming cells in cultures from MMC AF correlated with activation of astrogliosis associated with the spinal cord injury in MMC fetuses. In summary, we identified a neuroepithelial cell population in the AF of MMC fetuses that formed adherent clusters in culture and we characterized cellular markers of these cells. Our data suggests that the phase of the disease is a crucial factor in the emergence of these cells into the AF and that these cells may provide a new and important platform for studying the progression of MMC and development of improved strategies for the repair and diagnosis of MMC prenatally. PMID- 28358906 TI - Methodological concerns with laser speckle contrast imaging in clinical evaluation of microcirculation. AB - BACKGROUND: Laser Speckle Contrast Imaging (LSCI) is a non-invasive and fast technique for measuring microvascular blood flow that recently has found clinical use for burn assessment and evaluation of flaps. Tissue motion caused by for example breathing or patient movements may however affect the measurements in these clinical applications, as may distance between the camera and the skin and tissue curvature. Therefore, the aims of this study were to investigate the effect of frame rate, number of frames/image, movement of the tissue, measuring distance and tissue curvature on the measured perfusion. METHODS: Methyl nicotinate-induced vasodilation in the forearm skin was measured using LSCI during controlled motion at different speeds, using different combinations of frame rate and number of frames/image, and at varying camera angles and distances. Experiments were made on healthy volunteers and on a cloth soaked in a colloidal suspension of polystyrene microspheres. RESULTS: Measured perfusion increased with tissue motion speed. The relation was independent of the absolute perfusion in the skin and of frame rate and number of frames/image. The measured perfusion decreased with increasing angles (16% at 60 degrees , p = 0.01). Measured perfusion did not vary significantly between measurement distances from 15 to 40 cm (p = 0.77, %CV 0.9%). CONCLUSION: Tissue motion increases and measurement angles beyond 45 degrees decrease the measured perfusion in LSCI. These findings have to be taken into account when LSCI is used to assess moving or curved tissue surfaces, which is common in clinical applications. PMID- 28358907 TI - The gut microbiota of insecticide-resistant insects houses insecticide-degrading bacteria: A potential source for biotechnological exploitation. AB - The exploration of new niches for microorganisms capable of degrading recalcitrant molecules is still required. We hypothesized the gut microbiota associated with insect-resistant lines carry pesticide degrading bacteria, and predicted they carry bacteria selected to degrade pesticides they were resistant to. We isolated and accessed the pesticide-degrading capacity of gut bacteria from the gut of fifth instars of Spodoptera frugiperda strains resistant to lambda-cyhalothrin, deltamethrin, chlorpyrifos ethyl, spinosad and lufenuron, using insecticide-selective media. Sixteen isolates belonging to 10 phylotypes were obtained, from which four were also associated with the susceptible strain. However, growth of gut bacteria associated with larvae from the susceptible strain was not obtained in any of the insecticide-based selective media tested. Growth of isolates was affected by the concentration of insecticides in the media, and all grew well up to 40 MUg/ml. The insecticide-degrading capacity of selected isolates was assessed by GC or LC-MS/MS analyses. In conclusion, resistant strains of S. frugiperda are an excellent reservoir of insecticide degrading bacteria with bioremediation potential. Moreover, gut-associated bacteria are subjected to the selection pressure imposed by insecticides on their hosts and may influence the metabolization of pesticides in insects. PMID- 28358908 TI - Pharmacogenomics study on cadherin 2 network with regard to HIV infection and methadone treatment outcome. AB - Heroin dependent patients have a high incidence of HIV infection. In contrast to the gene expression method, we developed a systemic correlation analysis method built upon the results of pharmacogenomics study in a methadone maintenance treatment (MMT) cohort consisting of 344 Taiwanese heroin dependent patients. We identified genetic variants and their encoding proteins that may be involved with HIV infection and MMT treatment outcome. Cadherin 2 (CDH2) genetic determinants were identified through the genome-wide pharmacogenomic study. We found significant correlations among HIV infection status, plasma levels of CDH2, cytokine IL-7, ADAM10, and the treatment responses to methadone. Two single nucleotide polymorphisms located within CDH2 gene showed associations with blood pressure and plasma CDH2 concentration. Plasma concentration of CDH2 showed correlations with the level of cytokine IL-7, status of HIV infection, and urine morphine test result. Plasma level of IL-7 was correlated with corrected QT interval (QTc) and gooseflesh skin withdrawal symptom score, while level of ADAM10 was correlated with plasma concentrations of vitamin D metabolite, nicotine metabolite, and R-methadone. The results suggest a novel network involving HIV infection and methadone treatment outcome. PMID- 28358910 TI - Size, age, and habitat determine effectiveness of Palau's Marine Protected Areas. AB - Palau has a rich heritage of conservation that has evolved from the traditional moratoria on fishing, or "bul", to more western Marine Protected Areas (MPAs), while still retaining elements of customary management and tenure. In 2003, the Palau Protected Areas Network (PAN) was created to conserve Palau's unique biodiversity and culture, and is the country's mechanism for achieving the goals of the Micronesia Challenge (MC), an initiative to conserve >=30% of near-shore marine resources within the region by 2020. The PAN comprises a network of numerous MPAs within Palau that vary in age, size, level of management, and habitat, which provide an excellent opportunity to test hypotheses concerning MPA design and function using multiple discreet sampling units. Our sampling design provided a robust space for time comparison to evaluate the relative influence of potential drivers of MPA efficacy. Our results showed that no-take MPAs had, on average, nearly twice the biomass of resource fishes (i.e. those important commercially, culturally, or for subsistence) compared to nearby unprotected areas. Biomass of non-resource fishes showed no differences between no-take areas and areas open to fishing. The most striking difference between no-take MPAs and unprotected areas was the more than 5-fold greater biomass of piscivorous fishes in the MPAs compared to fished areas. The most important determinates of no-take MPA success in conserving resource fish biomass were MPA size and years of protection. Habitat and distance from shore had little effect on resource fish biomass. The extensive network of MPAs in Palau likely provides important conservation and tourism benefits to the Republic, and may also provide fisheries benefits by protecting spawning aggregation sites, and potentially through adult spillover. PMID- 28358909 TI - Amelioration of cognitive impairments in APPswe/PS1dE9 mice is associated with metabolites alteration induced by total salvianolic acid. AB - PURPOSE: Total salvianolic acid (TSA) is extracted from salvia miltiorrhiza; however, to date, there has been limited characterization of its effects on metabolites in Alzheimer's disease model-APPswe/PS1dE9 mice. The main objective of this study was to investigate the metabolic changes in 7-month-old APPswe/PS1dE9 mice treated with TSA, which protects against learning and memory impairment. METHODS: APPswe/PS1dE9 mice were treated with TSA (30 mg/kg.d and 60 mg/kg.d, i.p.) and saline (i.p.) daily from 3.5 months old for 14 weeks; saline treated (i.p.) WT mice were included as the controls. The effects of TSA on learning and memory were assessed by a series of behavioral tests, including the NOR, MWM and step-through tasks. The FBG and plasma lipid levels were subsequently assessed using the GOPOD and enzymatic color methods, respectively. Finally, the concentrations of Abeta42, Abeta40 and metabolites in the hippocampus of the mice were detected via ELISA and GC-TOF-MS, respectively. RESULTS: At 7 months of age, the APPswe/PS1dE9 mice treated with TSA exhibited an improvement in the preference index (PI) one hour after the acquisition phase in the NOR and the preservation of spatial learning and memory in the MWM. Treatment with TSA substantially decreased the LDL-C level, and 60 mg/kg TSA decreased the CHOL level compared with the plasma level of the APPswe/PS1dE9 group. The Abeta42 and Abeta40 levels in the hippocampus were decreased in the TSA-treated group compared with the saline-treated APPswe/PS1dE9 group. The regulation of metabolic pathways relevant to TSA predominantly included carbohydrate metabolism, such as sorbitol, glucose-6-phosphate, sucrose-6-phosphate and galactose, vitamin metabolism involved in cholecalciferol and ascorbate in the hippocampus. CONCLUSIONS: TSA induced a remarkable amelioration of learning and memory impairments in APPswe/PS1dE9 mice through the regulation of Abeta42, Abeta40, carbohydrate and vitamin metabolites in the hippocampus and LDL-C and CHOL in the plasma. PMID- 28358911 TI - Assessment of the retinal posterior pole in dominant optic atrophy by spectral domain optical coherence tomography and microperimetry. AB - BACKGROUND: To assess posterior pole (PP) retinal structure in patients with genetically confirmed autosomal dominant optic atrophy (ADOA) using new spectral domain optical coherence tomography (SD-OCT) segmentation technology. To analyze retinal PP thickness in relation to retinal sensitivity data from microperimetry (MP) in ADOA patients. METHODS AND FINDINGS: This prospective cross-sectional study included 11 patients with ADOA and 11 age-matched healthy subjects. All participants underwent both a "Posterior Pole" and "peripapillary RNFL (pRNFL)" scanning protocol using SD-OCT. Functional mapping of the PP was also performed using MP. A customized program was implemented in order to achieve accurate superimposition of MP sensitivity map onto SD-OCT map. The thickness of the PP different retinal layers and pRNFL was obtained and measured for each eye. Mean retinal sensitivity values and fixation stability were obtained and compared between ADOA patients and healthy subjects. Correlation analysis was performed on a point-to-point basis to evaluate the association between mean thickness and retinal sensitivity of each retinal layer. Total retinal thickness (TRT), Retinal Nerve Fiber Layer (RNFL), Ganglion Cell Layer (GCL), Inner Plexiform Layer (IPL), Inner Nuclear Layer (INL) and Inner Retinal Layers (IRL) at the posterior pole as well as pRNFL were significantly thinner in ADOA patients (P < 0.0001). On the contrary, the Outer Plexiform Layer (OPL) and the Outer Nuclear Layer (ONL) were significantly thicker in the ADOA group (P < 0.001). No significant differences were found in Retinal Pigment Epithelium (RPE) and Outer Retinal Layers (ORL) thickness between ADOA and controls. The average PP retinal sensitivity was significantly reduced in ADOA patients compared with controls (P < 0.001), as measured by microperimeter Nidek MP-1 (MP1). Fixation stability was significantly worse in the ADOA group (P = 0.01). The most severe sensitivity defects in ADOA patients were found at the level of the papillo-macular bundle (PMB). CONCLUSIONS: Inner retinal layers showed pathological changes in ADOA patients. In addition, the whole retinal PP (not only the PMB) was significantly altered in ADOA, both in terms of retinal thickness and sensitivity. PMID- 28358912 TI - Phthalate release in leachate from municipal landfills of central Poland. AB - Phthalate diesters (PAEs) are used as plasticizer additives to polymer chains to make the material more flexible and malleable. PAEs are bonded physically, not chemically, to the polymeric matrix and can migrate to and leach from the product surface, posing a serious danger to the environment and human health. There have been a number of studies on PAE concentrations in landfill leachate conducted in the EU and around the world, though few in Poland. In the present study, the leachate of five municipal landfills was analyzed for the presence of PAEs. Raw leachate was sampled four times over the period of one year in 2015/16. It was the first large study on this subject in Poland. PAEs were detected in the leachate samples on all of the landfills, thereby indicating that PAEs are ubiquitous environmental contaminants. The following PAEs were detected in at least one sample: Di(2-ethylhexyl) phthalate (DEHP), Diethyl phthalate (DEP), Dimethyl phthalate (DMP), Di-n-butyl phthalate (DBP), Di-isobutylphthalate (DIBP). Out of all ten PAEs, DEHP was the most predominant, with concentrations up to 73.9 MUg/L. DEHP was present in 65% of analyzed samples (in 100% of samples in spring, 80% in winter, and 40% in summer and autumn). In only 25% of all samples DEHP was below the acceptable UE limit for surface water (1.3 MUg/L), while 75% was from 1.7 to 56 times higher than that value. On the two largest landfills DEHP concentrations were observed during samples from all four seasons, including on a landfill which has been remediated and closed for the last 5 years. PMID- 28358913 TI - Looking for ugly ducklings: The role of the stability of BrdU-antibody complex and the improved method of the detection of DNA replication. AB - 5-Bromo-2'-deoxyuridine (BrdU) labelling and immunostaining is commonly used for the detection of DNA replication using specific antibodies. Previously, we found that these antibodies significantly differ in their affinity to BrdU. Our present data showed that one of the reasons for the differences in the replication signal is the speed of antibody dissociation. Whereas highly efficient antibodies created stable complexes with BrdU, the low efficiency antibodies were unstable. A substantial loss of the signal occurred within several minutes. The increase of the complex stability can be achieved by i) formaldehyde fixation or ii) a quick reaction with a secondary antibody. These steps allowed the same or even higher signal/background ratio to be reached as in the highly efficient antibodies. Based on our findings, we optimised an approach for the fully enzymatic detection of BrdU enabling the fast detection of replicational activity without a significant effect on the tested proteins or the fluorescence of the fluorescent proteins. The method was successfully applied for image and flow cytometry. The speed of the method is comparable to the approach based on 5-ethynyl-2' deoxyuridine. Moreover, in the case of short labelling pulses, the optimised method is even more sensitive. The approach is also applicable for the detection of 5-trifluoromethyl-2'-deoxyuridine. PMID- 28358914 TI - Analysis of single nucleotide variants of HFE gene and association to survival in The Cancer Genome Atlas GBM data. AB - Human hemochromatosis protein (HFE) is involved in iron metabolism. Two major HFE polymorphisms, H63D and C282Y, have been associated with an increased risk of cancers. Previously, we reported decreased gender effects in overall survival based on H63D or C282Y HFE polymorphisms patients with glioblastoma multiforme (GBM). However, the effect of other single nucleotide variation (SNV) in the HFE gene on the cancer development and progression has not been systematically studied. To expand our finding in a larger sample, and to identify other HFE SNV, we analyzed the frequency of somatic SNV in HFE gene and its relationship to survival in GBM patients using The Cancer Genome Atlas (TCGA) GBM (Caucasian only) database. We found 9 SNVs with increased frequency in blood normal of TCGA GBM patients compared to the 1000Genome. Among 9 SNVs, 7 SNVs were located in the intron and 2 SNVs (i.e., H63D, C282Y) in the exon of HFE gene. The statistical analysis demonstrated that blood normal samples of TCGA GBM have more H63D (p = 0.0002, 95% Confidence interval (CI): 0.2119-0.3223) or C282Y (p = 0.0129, 95% CI: 0.0474-0.1159) HFE polymorphisms than 1000Genome. The Kaplan-Meier survival curve for the 264 GBM samples revealed no difference between wild type (WT) HFE and H63D, and WT HFE and C282Y GBM patients. In addition, there was no difference in the survival of male/female GBM patients based on HFE genotype. There was no correlation between HFE expression and survival. In conclusion, the current results suggest that somatic HFE polymorphisms do not impact GBM patients' survival in the TCGA data set of GBM. PMID- 28358915 TI - Enhancement of Arabidopsis growth characteristics using genome interrogation with artificial transcription factors. AB - The rapidly growing world population has a greatly increasing demand for plant biomass, thus creating a great interest in the development of methods to enhance the growth and biomass accumulation of crop species. In this study, we used zinc finger artificial transcription factor (ZF-ATF)-mediated genome interrogation to manipulate the growth characteristics and biomass of Arabidopsis plants. We describe the construction of two collections of Arabidopsis lines expressing fusions of three zinc fingers (3F) to the transcriptional repressor motif EAR (3F EAR) or the transcriptional activator VP16 (3F-VP16), and the characterization of their growth characteristics. In total, six different 3F-ATF lines with a consistent increase in rosette surface area (RSA) of up to 55% were isolated. For two lines we demonstrated that 3F-ATF constructs function as dominant in trans acting causative agents for an increase in RSA and biomass, and for five larger plant lines we have investigated 3F-ATF induced transcriptomic changes. Our results indicate that genome interrogation can be used as a powerful tool for the manipulation of plant growth and biomass and that it might supply novel cues for the discovery of genes and pathways involved in these properties. PMID- 28358916 TI - Classifying three imaginary states of the same upper extremity using time-domain features. AB - Brain-computer interface (BCI) allows collaboration between humans and machines. It translates the electrical activity of the brain to understandable commands to operate a machine or a device. In this study, we propose a method to improve the accuracy of a 3-class BCI using electroencephalographic (EEG) signals. This BCI discriminates rest against imaginary grasps and elbow movements of the same limb. This classification task is challenging because imaginary movements within the same limb have close spatial representations on the motor cortex area. The proposed method extracts time-domain features and classifies them using a support vector machine (SVM) with a radial basis kernel function (RBF). An average accuracy of 74.2% was obtained when using the proposed method on a dataset collected, prior to this study, from 12 healthy individuals. This accuracy was higher than that obtained when other widely used methods, such as common spatial patterns (CSP), filter bank CSP (FBCSP), and band power methods, were used on the same dataset. These results are encouraging and the proposed method could potentially be used in future applications including BCI-driven robotic devices, such as a portable exoskeleton for the arm, to assist individuals with impaired upper extremity functions in performing daily tasks. PMID- 28358918 TI - Spatial disparity dynamics of ecosystem service values and GDP in Shaanxi Province, China in the last 30 years. AB - The regional policy in China is shifting from solely gross domestic product (GDP) orientation to development that is more balanced between economic growth and ecological protection, as well as achieving equality among regions. Using land use maps and the adjusted value coefficients to assess ecosystem service values (ESV) for the 1980s, 1995, 2000, and 2010, we estimated the ESV in Shaanxi Province for different years, and characterized the spatial and temporal distribution of ESV and GDP. The results demonstrated that the total value of ecosystem services in Shaanxi Province increased from 208.95 billion Yuan in the 1980s to 309.76 billion Yuan in 2010. Variation Coefficient (Cv) and Theil index (T) were used to reflect the disparities of GDP or ESV within the study area. The values of Cv in descending order are GDP, ESV per capita, ESV, and GDP per capita. The Theil indexes of GDP were much greater than the ones of ESV. Variations of Cv and T showed that disparity in GDP kept increasing from the 1980s to 2000, then decreased; while no significant change in regional disparity of ESV were detected in parallel. The cities with higher GDP usually contributed little to ESV, and vice versa. The variation in GDP and ESV, in terms of the prefectural totals and per capita values, increased from the 1980s to 2010. This study provides an accessible way for local decision makers to evaluate the regional balance between economic growth and ecosystem services. PMID- 28358917 TI - Proteomic characterization of epicardial-myocardial signaling reveals novel regulatory networks including a role for NF-kappaB in epicardial EMT. AB - Signaling between the epicardium and underlying myocardium is crucial for proper heart development. The complex molecular interactions and regulatory networks involved in this communication are not well understood. In this study, we integrated mass spectrometry with bioinformatics to systematically characterize the secretome of embryonic chicken EPDC-heart explant (EHE) co-cultures. The 150 protein secretome dataset established greatly expands the knowledge base of the molecular players involved in epicardial-myocardial signaling. We identified proteins and pathways that are implicated in epicardial-myocardial signaling for the first time, as well as new components of pathways that are known to regulate the crosstalk between epicardium and myocardium. The large size of the dataset enabled bioinformatics analysis to deduce networks for the regulation of specific biological processes and predicted signal transduction nodes within the networks. We performed functional analysis on one of the predicted nodes, NF-kappaB, and demonstrate that NF-kappaB activation is an essential step in TGFbeta2/PDGFBB induced cardiac epithelial-to-mesenchymal transition. In summary, we have generated a global perspective of epicardial-myocardial signaling for the first time, and our findings open exciting new avenues for investigating the molecular basis of heart development and regeneration. PMID- 28358919 TI - Beware batch culture: Seasonality and niche construction predicted to favor bacterial adaptive diversification. AB - Metabolic cross-feeding interactions between microbial strains are common in nature, and emerge during evolution experiments in the laboratory, even in homogeneous environments providing a single carbon source. In sympatry, when the environment is well-mixed, the reasons why emerging cross-feeding interactions may sometimes become stable and lead to monophyletic genotypic clusters occupying specific niches, named ecotypes, remain unclear. As an alternative to evolution experiments in the laboratory, we developed Evo2Sim, a multi-scale model of in silico experimental evolution, equipped with the whole tool case of experimental setups, competition assays, phylogenetic analysis, and, most importantly, allowing for evolvable ecological interactions. Digital organisms with an evolvable genome structure encoding an evolvable metabolic network evolved for tens of thousands of generations in environments mimicking the dynamics of real controlled environments, including chemostat or batch culture providing a single limiting resource. We show here that the evolution of stable cross-feeding interactions requires seasonal batch conditions. In this case, adaptive diversification events result in two stably co-existing ecotypes, with one feeding on the primary resource and the other on by-products. We show that the regularity of serial transfers is essential for the maintenance of the polymorphism, as it allows for at least two stable seasons and thus two temporal niches. A first season is externally generated by the transfer into fresh medium, while a second one is internally generated by niche construction as the provided nutrient is replaced by secreted by-products derived from bacterial growth. In chemostat conditions, even if cross-feeding interactions emerge, they are not stable on the long-term because fitter mutants eventually invade the whole population. We also show that the long-term evolution of the two stable ecotypes leads to character displacement, at the level of the metabolic network but also of the genome structure. This difference of genome structure between both ecotypes impacts the stability of the cross-feeding interaction, when the population is propagated in chemostat conditions. This study shows the crucial role played by seasonality in temporal niche partitioning and in promoting cross feeding subgroups into stable ecotypes, a premise to sympatric speciation. PMID- 28358920 TI - In conditions of over-expression, WblI, a WhiB-like transcriptional regulator, has a positive impact on the weak antibiotic production of Streptomyces lividans TK24. AB - Regulators of the WhiB-like (wbl) family are playing important role in the complex regulation of metabolic and morphological differentiation in Streptomyces. In this study, we investigated the role of wblI, a member of this family, in the regulation of secondary metabolite production in Streptomyces lividans. The over-expression of wblI was correlated with an enhanced biosynthesis of undecylprodigiosin and actinorhodin and with a reduction of the biosynthesis of yCPK and of the grey spore pigment encoded by the whiE locus. Five regulatory targets of WblI were identified using in vitro formaldehyde crosslinking and confirmed by EMSA and qRT-PCR. These included the promoter regions of wblI itself, two genes of the ACT cluster (actVA3 and the intergenic region between the divergently orientated genes actII-1 and actII-2) and that of wblA, another member of the Wbl family. Quantitative RT-PCR analysis indicated that the expression of actVA3 encoding a protein of unknown function as well as that of actII-1, a TetR regulator repressing the expression of actII-2, encoding the ACT transporter, were down regulated in the WblI over-expressing strain. Consistently the expression of the transporter actII-2 was up-regulated. The expression of WblA, that is known to have a negative impact on ACT biosynthesis, was strongly down regulated in the WblI over-expressing strain. These data are consistent with the positive impact that WblI over-expression has on ACT biosynthesis. The latter might result from direct activation of ACT biosynthesis and export and from repression of the expression of WblA, a likely indirect, repressor of ACT biosynthesis. PMID- 28358921 TI - Vector-free intracellular delivery by reversible permeabilization. AB - Despite advances in intracellular delivery technologies, efficient methods are still required that are vector-free, can address a wide range of cargo types and can be applied to cells that are difficult to transfect whilst maintaining cell viability. We have developed a novel vector-free method that uses reversible permeabilization to achieve rapid intracellular delivery of cargos with varying composition, properties and size. A permeabilizing delivery solution was developed that contains a low level of ethanol as the permeabilizing agent. Reversal of cell permeabilization is achieved by temporally and volumetrically controlling the contact of the target cells with this solution. Cells are seeded in conventional multi-well plates. Following removal of the supernatant, the cargo is mixed with the delivery solution and applied directly to the cells using an atomizer. After a short incubation period, permeabilization is halted by incubating the cells in a phosphate buffer saline solution that dilutes the ethanol and is non-toxic to the permeabilized cells. Normal culture medium is then added. The procedure lasts less than 5 min. With this method, proteins, mRNA, plasmid DNA and other molecules have been delivered to a variety of cell types, including primary cells, with low toxicity and cargo functionality has been confirmed in proof-of-principle studies. Co-delivery of different cargo types has also been demonstrated. Importantly, delivery occurs by diffusion directly into the cytoplasm in an endocytic-independent manner. Unlike some other vector-free methods, adherent cells are addressed in situ without the need for detachment from their substratum. The method has also been adapted to address suspension cells. This delivery method is gentle yet highly reproducible, compatible with high throughput and automated cell-based assays and has the potential to enable a broad range of research, drug discovery and clinical applications. PMID- 28358922 TI - The microRNA repertoire of Tibetan naked carp Gymnocypris przewalskii: A case study in Schizothoracinae fish on the Tibetan Plateau. AB - Tibetan naked carp Gymnocypris przewalskii is an ideal model system to study highland adaptation of fish, because it evolved specific genetic and phenotypic characteristics to adapt to chronic cold and alkaline environments in Lake Qinghai. MicroRNAs (miRNAs) are small noncoding RNAs that regulating gene expression post-transcriptionally in a wide range of biological processes. In this study, we focus on the role of miRNAs in adaptation of G. przewalskii to extreme conditions in Lake Qinghai. We generate the first miRNAome of G. przewalskii in Schizothoracinae fish. Using several genomic resources, we inferred 341 conserved miRNAs belonged to 152 miRNA families and 43 novel miRNAs in G. przewalskii, and also identified 15 teleost-specific miRNAs. Using a large scale of conserved miRNAs, we constructed a high-confidence phylogenetic tree between teleost and mammals than mitochondria and nuclear genes. In addition, we found that several miRNA family (e.g. miR-10 and let-7) members highly expressed in G. przewalskii, which may function in multiple biological processes. Finally, we predicted a total of 34,258 miRNA targets genes. Conserved miRNAs target genes participating in signal transduction, cell differentiation and biosynthetic process, and showed signature of functional constraint. While novel miRNAs in a species displayed species-specific targets and involved in ion binding, transport and oxidoreductase activity, may affect the expression patterns of targets with signature of gene family expansion or positive selection under extreme environment. Taken together, this study demonstrated that miRNAs may involve into roles of adaptation of G. przewalskii to highland aquatic environment, and also provide insights into miRNA regulatory network in Schizothoracinae fish as a case study. PMID- 28358923 TI - Impact of systemic inflammation on gastric cancer outcomes. AB - BACKGROUND: The prognostic value of neutrophil-lymphocyte ratio (NLR) and Glasgow Prognostic Score (GPS) has been extensively validated in various cancers. We aimed to examine the usefulness of a combination of NLR and GPS (named CNG) for predicting survival outcomes in patients after curative resection for gastric cancer (GC). METHODS: We retrospectively analyzed the records of 1056 patients who underwent curative resection as initial treatment for GC from October 2000 to September 2012. The preoperative CNG was calculated as follows: patients with hypoalbuminemia (< 35 g/L), elevated C-reactive protein (> 10 mg/L), and elevated NLR (>= 2) were allocated a score of 3; patients with two, one, or no abnormal values were allocated a score of 2, 1, or 0, respectively. RESULTS: The NLR and GPS were the only inflammatory variables independently associated with overall survival (OS) in multivariate analysis. When they were replaced by CNG in multivariate analysis, CNG was independently associated with OS (hazard ratio [HR] for CNG 1 [1.367, 95% CI: 1.065-1.755; P = 0.014], CNG 2 [1.887, 95% CI: 1.182-3.011; P = 0.008], and CNG 3 [2.224, 95% CI: 1.238-3.997; P = 0.008]; P = 0.020). In stage-matched analysis, the prognostic significance was still maintained in stage I-III (P = 0.002, P = 0.042, and P < 0.001, respectively). In addition, 5-year survival rates ranged from 92% (stage I) to 35% (stage III) and from 65%(CNG 0) to 18%(CNG 3) with tumor-nodes-metastasis (TNM) stage or CNG alone. However, the combination of TNM and CNG stratified 5-year survival rates from 98% (TNM I, CNG 0) to 12% (TNM III, CNG 3). CONCLUSION: The preoperative CNG is a novel predictor of postoperative survival, and the combination of CNG and TNM effectively stratifies outcomes in patients after curative resection for GC. PMID- 28358924 TI - Processing and targeting of proteins derived from polyprotein with 2A and LP4/2A as peptide linkers in a maize expression system. AB - In the transformation of multiple genes, gene fusion is an attractive alternative to other methods, including sexual crossing, re-transformation, and co transformation, among others. The 2A peptide from the foot-and-mouth disease virus (FMDV) causes the co-translational "cleavage" of polyprotein and operates in a wide variety of eukaryotic cells. LP4, a linker peptide that originates from a natural polyprotein occurring in the seed of Impatiens balsamina, can be split between the first and second amino acids in post-translational processing. LP4/2A is a hybrid linker peptide that contains the first nine amino acids of LP4 and 20 amino acids of 2A. The three linkers have been used as a suitable technique to link the expression of genes in some transgenic plants, but to date the cleavage efficiency of three linkers have not been comprehensively demonstrated in the same transformation system, especially in the staple crop. To verify the functions of 2A, LP4, and LP4/2A linker peptides in transgenic maize, six fusion protein vectors that each encoded a single open reading frame (ORF) incorporating two report genes, Green Fluorescent Protein (GFP) and beta-glucuronidase (GUS), separated by 2A (or modified 2A), LP4 or LP4/2A were assembled to compare the cleavage efficiency of the three linkers in a maize transient expression system. The results demonstrated the more protein production and higher cleavage splicing efficiency with the polyprotein construct linked by the LP4/2A peptide than those of the polyprotein constructs linked by 2A or LP4 alone. Seven other fusion proteins that each encoded a single ORF incorporating two different genes GFP and Red Fluorecent Protein (RFP) with different signal peptides were assembled to study the subcellular localization of genes linked by LP4/2A. The subcellular localization experiments suggested that both types of signal peptide, co translational and post-translational, could lead their proteins to the target localization in maize protoplast transformed by LP4/2A polyprotein construct and it implied the LP4/2A linker peptide could alleviate the inhibition of 2A processing by the carboxy-terminal region of upstream protein of 2A when translocated into the ER. PMID- 28358925 TI - Serum S100B: A proxy marker for grey and white matter status in the absence and presence of (increased risk of) psychotic disorder? AB - S100B is a protein with dose-dependent neurotrophic and neurotoxic effects. Whether S100B in psychotic disorder mirrors pathophysiological mechanisms (which elicit exacerbation of disease) or compensatory action is unclear, as is its validity as a proxy marker for brain status. Insight may be gained by examining associations between serum S100B and indices of grey (cortical thickness (CT)) and white matter (fractional anisotropy (FA)), in relation to the absence or presence of (increased risk of) psychotic disorder. Blood samples and cerebral magnetic resonance imaging (MRI) scans were acquired in 32 patients with psychotic disorder, 44 non-psychotic siblings of patients with psychotic disorder and 26 controls. Interactions between S100B and group were examined in separate models of CT and FA measures with multilevel regression analyses weighted for number of vertices and voxels (i.e. units of volume) respectively. All analyses were adjusted for sex, age, body mass index (BMI), scan sequence, handedness and highest level of education. Neither CT nor FA was associated with S100B. There were no significant S100B * group interactions (CT: chi2 = 0.044, p = 0.978; FA: chi2 = 3.672, p = 0.159). No evidence was present for S100B as a proxy marker of grey or white matter status. The association between S100B and brain measures was not moderated by psychosis risk. PMID- 28358926 TI - Genetically engineered rat gliomas: PDGF-driven tumor initiation and progression in tv-a transgenic rats recreate key features of human brain cancer. AB - Previously rodent preclinical research in gliomas frequently involved implantation of cell lines such as C6 and 9L into the rat brain. More recently, mouse models have taken over, the genetic manipulability of the mouse allowing the creation of genetically accurate models outweighed the disadvantage of its smaller brain size that limited time allowed for tumor progression. Here we illustrate a method that allows glioma formation in the rat using the replication competent avian-like sarcoma (RCAS) virus / tumor virus receptor-A (tv-a) transgenic system of post-natal cell type-specific gene transfer. The RCAS/tv-a model has emerged as a particularly versatile and accurate modeling technology by enabling spatial, temporal, and cell type-specific control of individual gene transformations and providing de novo formed glial tumors with distinct molecular subtypes mirroring human GBM. Nestin promoter-driven tv-a (Ntv-a) transgenic Sprague-Dawley rat founder lines were created and RCAS PDGFA and p53 shRNA constructs were used to initiate intracranial brain tumor formation. Tumor formation and progression were confirmed and visualized by magnetic resonance imaging (MRI) and spectroscopy. The tumors were analyzed using histopathological and immunofluorescent techniques. All experimental animals developed large, heterogeneous brain tumors that closely resembled human GBM. Median survival was 92 days from tumor initiation and 62 days from the first point of tumor visualization on MRI. Each tumor-bearing animal showed time dependent evidence of malignant progression to high-grade glioma by MRI and neurological examination. Post-mortem tumor analysis demonstrated the presence of several key characteristics of human GBM, including high levels of tumor cell proliferation, pseudopalisading necrosis, microvascular proliferation, invasion of tumor cells into surrounding tissues, peri-tumoral reactive astrogliosis, lymphocyte infiltration, presence of numerous tumor-associated microglia- and bone marrow derived macrophages, and the formation of stem-like cell niches within the tumor. This transgenic rat model may enable detailed interspecies comparisons of fundamental cancer pathways and clinically relevant experimental imaging procedures and interventions that are limited by the smaller size of the mouse brain. PMID- 28358927 TI - Aquaglyceroporin-null trypanosomes display glycerol transport defects and respiratory-inhibitor sensitivity. AB - Aquaglyceroporins (AQPs) transport water and glycerol and play important roles in drug-uptake in pathogenic trypanosomatids. For example, AQP2 in the human infectious African trypanosome, Trypanosoma brucei gambiense, is responsible for melarsoprol and pentamidine-uptake, and melarsoprol treatment-failure has been found to be due to AQP2-defects in these parasites. To further probe the roles of these transporters, we assembled a T. b. brucei strain lacking all three AQP genes. Triple-null aqp1-2-3 T. b. brucei displayed only a very moderate growth defect in vitro, established infections in mice and recovered effectively from hypotonic-shock. The aqp1-2-3 trypanosomes did, however, display glycerol uptake and efflux defects. They failed to accumulate glycerol or to utilise glycerol as a carbon-source and displayed increased sensitivity to salicylhydroxamic acid (SHAM), octyl gallate or propyl gallate; these inhibitors of trypanosome alternative oxidase (TAO) can increase intracellular glycerol to toxic levels. Notably, disruption of AQP2 alone generated cells with glycerol transport defects. Consistent with these findings, AQP2-defective, melarsoprol-resistant clinical isolates were sensitive to the TAO inhibitors, SHAM, propyl gallate and ascofuranone, relative to melarsoprol-sensitive reference strains. We conclude that African trypanosome AQPs are dispensable for viability and osmoregulation but they make important contributions to drug-uptake, glycerol-transport and respiratory-inhibitor sensitivity. We also discuss how the AQP-dependent inverse sensitivity to melarsoprol and respiratory inhibitors described here might be exploited. PMID- 28358929 TI - Update in Critical Care Medicine: Evidence Published in 2016. PMID- 28358931 TI - Cancer-Related Anxiety. PMID- 28358932 TI - Update in Hematology and Oncology: Evidence Published in 2016. PMID- 28358928 TI - Regulation of white and brown adipocyte differentiation by RhoGAP DLC1. AB - Adipose tissues constitute an important component of metabolism, the dysfunction of which can cause obesity and type II diabetes. Here we show that differentiation of white and brown adipocytes requires Deleted in Liver Cancer 1 (DLC1), a Rho GTPase Activating Protein (RhoGAP) previously studied for its function in liver cancer. We identified Dlc1 as a super-enhancer associated gene in both white and brown adipocytes through analyzing the genome-wide binding profiles of PPARgamma, the master regulator of adipogenesis. We further observed that Dlc1 expression increases during differentiation, and knockdown of Dlc1 by siRNA in white adipocytes reduces the formation of lipid droplets and the expression of fat marker genes. Moreover, knockdown of Dlc1 in brown adipocytes reduces expression of brown fat-specific genes and diminishes mitochondrial respiration. Dlc1-/- knockout mouse embryonic fibroblasts show a complete inability to differentiate into adipocytes, but this phenotype can be rescued by inhibitors of Rho-associated kinase (ROCK) and filamentous actin (F-actin), suggesting the involvement of Rho pathway in DLC1-regulated adipocyte differentiation. Furthermore, PPARgamma binds to the promoter of Dlc1 gene to regulate its expression during both white and brown adipocyte differentiation. These results identify DLC1 as an activator of white and brown adipocyte differentiation, and provide a molecular link between PPARgamma and Rho pathways. PMID- 28358933 TI - Update in General Internal Medicine: Evidence Published in 2016. PMID- 28358930 TI - Association of Transoral Robotic Surgery With Short-term and Long-term Outcomes and Costs of Care in Oropharyngeal Cancer Surgery. AB - Importance: The treatment of oropharyngeal cancer has undergone a paradigm shift in the past 2 decades, with an increase in the use of nonoperative treatment owing to poor functional outcomes associated with traditional surgical approaches. Transoral robotic surgery (TORS) allows surgical resection of oropharyngeal cancer (OPC) with less morbidity through a minimally invasive approach. Objective: To investigate the relationship among TORS and short- and long-term outcomes and costs in surgically treated patients with OPC. Design, Setting, and Participants: Retrospective cross-sectional analysis of 3573 patients who underwent an ablative procedure for OPC in 2010 to 2012 using the MarketScan Commercial Claim and Encounters database. Main Outcomes and Measures: The association between TORS and short- and long-term outcomes, length of hospitalization, and treatment-related costs was analyzed using descriptive statistics and multivariate regression modeling. Results: Transoral robotic surgery was performed in 304 surgical cases (8.5%); 94.7% of patients were 40 to 64 years old, and 70.7% were male. The use of TORS increased from 4.1% of surgical cases in 2010 to 13.2% of surgical cases in 2012. Patients who underwent TORS had a lower rate of tracheotomy during treatment (3.9% vs 11.4%), and posttreatment gastrostomy tube use (21.9% vs 34.2%), compared with patients undergoing non-TORS procedures. On multivariate analysis, TORS was not associated with significant differences in postoperative complications or length of hospitalization. There was no significant difference in the odds of receiving postoperative radiation therapy between patients who underwent TORS and those who did not; however, among patients receiving radiation therapy, chemoradiation was significantly less likely following TORS (odds ratio [OR], 0.52; 95% CI, 0.29 0.90). TORS was associated with significantly decreased odds of posttreatment gastrostomy (OR, 0.54; 95% CI. 0.30-0.95) and tracheostomy during treatment (OR, 0.17; 95% CI, 0.06-0.55) at 1 year, and was associated with significantly decreased overall treatment-related costs of care (mean incremental cost, -$22 724). Conclusions and Relevance: The use of TORS for surgical resection of OPC is increasing in the United States and is associated with significantly lower use of adjuvant chemoradiation, late gastrostomy and tracheostomy dependence, and lower overall treatment-related costs of care. These data have implications for discussions of value in OPC care at a time of health care reform. PMID- 28358934 TI - Update in Rheumatology: Evidence Published in 2016. PMID- 28358935 TI - Comparison of Neurovascular Characteristics of Facial Skin in Patients After Primary and Revision Rhytidectomies. AB - Importance: Wound healing influences both the cosmetic and functional outcomes of facial surgery. Study of cutaneous innervation may afford insight into patients' preoperative wound healing potential and aid in their selection of appropriate surgical procedures. Objective: To present the quantitative and qualitative differences of epidermal nerve fibers (ENFs), neurotransmitters, vasculature, and mast cells in facial skin among patients after primary and revision rhytidectomies. Design, Setting, and Participants: This pilot study collected cutaneous specimens from 8 female patients aged 42 to 66 years who underwent primary rhytidectomy (n = 5) and revision rhytidectomy (n = 3) at Centennial Lakes Surgery Center, Edina, Minnesota, from July 2010 to March 2014. Tissue was processed for confocal/epifluorescence microscopy and indirect immunofluorescent localization of several neural and tissue antigens as well as basement membrane and mast cell markers. Intervention: Primary rhytidectomy vs revision rhytidectomy with selection of a small area of redundant, otherwise disposed of tissue anterior to the tragus for ENF study. Main Outcomes and Measures: Demographic characteristics included smoking status; 10-point rating scales for facial sensation, pain, and paresthesias; and confocal/epifluorescence microscopy to quantify ENFs, neurotransmitters, vasculature, and mast cells. Results: Patients in the primary rhytidectomy group had a mean (SD) of 54.4 (31.6) ENFs/mm (range, 14.2-99.2 ENFs/mm), and those in the revision rhytidectomy group had a mean (SD) of 18.6 (5.8) ENFs/mm (range, 13.8-25.0 ENFs/mm). A patient in the primary rhytidectomy group was a 25-pack-year smoker and had 14.2 ENFs/mm, the lowest in both groups. In addition to these structural neural changes, functional neural changes in revision rhytidectomy samples included qualitative changes in normal neural antigen prevalence (substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide). Capillary loops appeared less robust and were less common in dermal papilla among samples from both the primary and revision groups, and mast cells were more degranulated. No differences were found in subjective, self-reported postoperative facial sensation. Conclusions and Relevance: Previous skin elevation was associated with decreased epidermal nerve fiber density and qualitative changes in dermal nerves, capillaries, and mast cells in a clinical sample of patients undergoing rhytidectomy. Future research is needed to determine whether histological findings predict wound healing and to better understand the effects of surgery on regenerative capacity of epidermal nerve fibers. Level of Evidence: NA. PMID- 28358936 TI - Association of Radiotherapy Boost for Ductal Carcinoma In Situ With Local Control After Whole-Breast Radiotherapy. AB - Importance: The use of a radiotherapy (RT) boost to the tumor bed after whole breast RT (WBRT) for ductal carcinoma in situ (DCIS) is largely extrapolated from invasive cancer data, but robust evidence specific to DCIS is lacking. Objective: To compare ipsilateral breast tumor recurrence (IBTR) in women with DCIS treated with vs without the RT boost after breast-conserving surgery and WBRT. Design, Setting, and Participants: This retrospective analysis pooled deidentified patient-level data from 10 academic institutions in the United States, Canada, and France from January 1, 1980, through December 31, 2010. All patients had newly diagnosed pure DCIS (no microinvasion), underwent breast-conserving surgery, and received WBRT with or without the boost with a minimum of 5 years of follow-up required for inclusion in the analysis. Given the limited events after WBRT, an a priori power analysis was conducted to estimate the DCIS sample size needed to detect the anticipated benefit of the boost. Data were uniformly recoded at the host institution and underwent primary and secondary reviews before analysis. Sample size calculations (ratio of patients who received the boost dose to those who did not, 2:1; alpha = .05; power = 80%) estimated that 2982 cases were needed to detect a difference of at least 3%. The final analysis included 4131 patients (2661 in the boost group and 1470 in the no-boost group) with a median follow-up of 9 years and media boost dose of 14 Gy. Data were collected from July 2011 through February 2014 and analyzed from March 2014 through August 2015. Interventions: Radiotherapy boost vs no boost. Main Outcomes and Measures: Ipsilateral breast tumor recurrence. Results: The analysis included 4131 patients (median [SD] age, 56.1 [10.9] years; range, 24-88 years). Patients with positive margins, unknown estrogen receptor status, and comedo necrosis were more likely to have received an RT boost. For the entire cohort, the boost was significantly associated with lower IBTR (hazard ratio [HR], 0.73; 95% CI, 0.57 0.94; P = .01) and with IBTR-free survival (boost vs no-boost groups) of 97.1% (95% CI, 0.96-0.98) vs 96.3% (95% CI, 0.95-0.97) at 5 years, 94.1% (95% CI, 0.93 0.95) vs 92.5% (95% CI, 0.91-0.94) at 10 years, and 91.6% (95% CI, 0.90-0.93) vs 88.0% (95% CI, 0.85-0.91) at 15 years. On multivariable analysis accounting for confounding factors, the boost remained significantly associated with reduced IBTR (HR compared with no boost, 0.68; 95% CI, 0.50-0.91; P = .01) independent of age and tamoxifen citrate use. Conclusions and Relevance: This patient-level analysis suggests that the RT boost confers a statistically significant benefit in decreasing IBTR across all DCIS age groups, similar to that seen in patients with invasive breast cancer. These findings suggest that a DCIS RT boost to the tumor bed could be considered to provide an added incremental benefit in decreasing IBTR after a shared discussion between the patient and her radiation oncologist. PMID- 28358938 TI - Update in Cardiology: Evidence Published in 2016. PMID- 28358940 TI - Slowly Enlarging Neck Mass. PMID- 28358937 TI - Abiraterone Acetate for Metastatic Prostate Cancer in Patients With Suboptimal Biochemical Response to Hormone Induction. AB - Importance: Men with metastatic prostate cancer who have a poor response to initial androgen-deprivation therapy (ADT), as reflected by a prostate-specific antigen (PSA) level higher than 4.0 ng/mL after 7 months of ADT, have a poor prognosis, based on historical controls. Objective: To determine the efficacy of abiraterone acetate with prednisone in these high-risk patients with a suboptimal response to hormonal induction. Design, Setting, and Participants: A phase 2 single-arm study was conducted through the National Clinical Trials Network Southwest Oncology Group. Eligible patients had metastatic prostate cancer and a PSA level higher than 4.0 ng/mL between 6 and 12 months after starting ADT. The PSA level could be rising or falling at the time of enrollment, but had to be higher than 4.0 ng/mL. No previous chemotherapy or secondary hormonal therapies were allowed, except in patients receiving a standard, first-generation antiandrogen agent with a falling PSA level at the time of enrollment; this therapy was continued in this cohort. Abiraterone acetate, 1000 mg, once daily with prednisone, 5 mg, twice daily was administered to all participants. A total of 41 men were enrolled between the trial's activation on August 9, 2011, and closure on August 1, 2013. Data analysis was conducted from March 21 to November 29, 2016. Interventions: Abiraterone acetate, 1000 mg, once daily by mouth with prednisone, 5 mg, by mouth twice daily. Main Outcomes and Measures: The primary end point was a PSA level of 0.2 ng/mL or lower within 12 months of starting abiraterone acetate plus prednisone. A partial response (PR) was a secondary end point, defined as a PSA level reduction to lower than 4.0 ng/mL but higher than 0.2 ng/mL. Results: Of the 41 men enrolled, 1 did not receive any protocol treatment and was excluded from analysis. The median (range) age of the 40 participants was 66 (39-85) years. Five (13%) patients achieved a PSA level of 0.2 ng/mL or lower (95% CI, 4%-27%). Thirteen (33%) additional patients achieved a partial response, with a reduction in the PSA level to lower than 4.0 ng/mL but higher than 0.2 ng/mL. Sixteen (40%) patients had no PSA response and 6 (15%) were not assessable and assumed to be nonresponders. The median progression-free survival was 17.5 months (95% CI, 8.6-25.0 months) and the median overall survival was 25.8 months (95% CI, 15.7-25.8 months). There was 1 incident each of grade 4 adverse events of alanine aminotransferase level elevation and rectal hemorrhage. Eleven patients reported grade 3 adverse events. Conclusions and Relevance: This study did not reach its prescribed level of 6 PSA responses of 0.2 ng/mL or lower, although 5 responses were observed. The overall survival and progression-free survival rates observed in this trial are encouraging compared with historical controls. The therapy was generally well tolerated, without any clear signal of any unexpected adverse effects. PMID- 28358939 TI - Peripapillary Retinal Nerve Fiber Layer Vascular Microcirculation in Eyes With Glaucoma and Single-Hemifield Visual Field Loss. AB - Importance: Understanding the differences in vascular microcirculation of the peripapillary retinal nerve fiber layer (RNFL) between the hemispheres in eyes with glaucoma with single-hemifield visual field (VF) defects may provide insight into the pathophysiology of glaucoma. Objective: To investigate the changes in the microcirculation of the peripapillary RNFL of eyes with glaucoma by using optical microangiography. Design, Setting, and Participants: Eyes with glaucoma and single-hemifield VF defect and normal eyes underwent scanning using an optical microangiography system covering a 6.7 * 6.7-mm2 area centered at the optic nerve head. The RNFL microcirculation was measured within an annulus region centered at the optic nerve head divided into superior and inferior hemispheres. Blood flux index (the mean flow signal intensity in the vessels) and vessel area density (the percentage of the detected vessels in the annulus) were measured. Main Outcomes and Measures: Differences in microcirculation between the hemispheres in eyes with glaucoma and normal eyes and correlations among blood flow metrics, VF thresholds, and clinical optical coherence tomography structural measurements were assessed. Results: Twenty-one eyes from 21 patients with glaucoma (7 men and 14 women; mean [SD] age, 63.7 [9.9] years) and 20 eyes from 20 healthy control individuals (9 men and 11 women; mean [SD] age, 68.3 [10.7] years) were studied. In eyes with glaucoma, the abnormal hemisphere showed a thinner RNFL (mean [SE] difference, 23.5 [4.5] MUm; 95% CI, 15.1-32.0 um; P < .001), lower RNFL blood flux index (mean [SE] difference, 0.04 [0.01]; 95% CI, 0.02-0.05; P < .001), and less vessel area density (mean [SE] difference, 0.08% [0.02%]; 95% CI, 0.05%-0.10%; P < .001) than did the normal hemisphere. Compared with normal eyes, reduced RNFL microcirculation was found in the normal hemisphere of eyes with glaucoma, measured by mean [SE] differences in blood flux index (0.06 [0.01]; 95% CI, 0.04-0.09; P < .001) and vessel area density (0.04% [0.02%]; 95% CI, 0.02%-0.08%; P = .003) but not in RNFL thickness (3.4 [4.7] MUm; 95% CI, -6.2 to 12.9 um; P = .48). Strong correlations were found between the blood flux index and VF mean deviation (Spearman rho = 0.44; P = .045) and RNFL thickness (Spearman rho = 0.65; P = .001) in the normal hemisphere of the eye with glaucoma. Conclusions and Relevance: Reduced RNFL microcirculation was detected in the normal hemisphere of eyes with glaucoma, with strong correspondence with VF loss and RNFL thinning. Although the results suggest that vascular dysfunction precedes structural changes seen in glaucoma, longitudinal studies would be needed to confirm this finding. PMID- 28358941 TI - Automatic Gleason grading of prostate cancer using quantitative phase imaging and machine learning. AB - We present an approach for automatic diagnosis of tissue biopsies. Our methodology consists of a quantitative phase imaging tissue scanner and machine learning algorithms to process these data. We illustrate the performance by automatic Gleason grading of prostate specimens. The imaging system operates on the principle of interferometry and, as a result, reports on the nanoscale architecture of the unlabeled specimen. We use these data to train a random forest classifier to learn textural behaviors of prostate samples and classify each pixel in the image into different classes. Automatic diagnosis results were computed from the segmented regions. By combining morphological features with quantitative information from the glands and stroma, logistic regression was used to discriminate regions with Gleason grade 3 versus grade 4 cancer in prostatectomy tissue. The overall accuracy of this classification derived from a receiver operating curve was 82%, which is in the range of human error when interobserver variability is considered. We anticipate that our approach will provide a clinically objective and quantitative metric for Gleason grading, allowing us to corroborate results across instruments and laboratories and feed the computer algorithms for improved accuracy. PMID- 28358942 TI - Negative dielectrophoresis spectroscopy for rare analyte quantification in biological samples. AB - We propose the use of negative dielectrophoresis (DEP) spectroscopy as a technique to improve the detection limit of rare analytes in biological samples. We observe a significant dependence of the negative DEP force on functionalized polystyrene beads at the edges of interdigitated electrodes with respect to the frequency of the electric field. We measured this velocity of repulsion for 0% and 0.8% conjugation of avidin with biotin functionalized polystyrene beads with our automated software through real-time image processing that monitors the Rayleigh scattering from the beads. A significant difference in the velocity of the beads was observed in the presence of as little as 80 molecules of avidin per biotin functionalized bead. This technology can be applied in the detection and quantification of rare analytes that can be useful in the diagnosis and the treatment of diseases, such as cancer and myocardial infarction, with the use of polystyrene beads functionalized with antibodies for the target biomarkers. PMID- 28358943 TI - Comparative study of shear wave-based elastography techniques in optical coherence tomography. AB - We compare five optical coherence elastography techniques able to estimate the shear speed of waves generated by one and two sources of excitation. The first two techniques make use of one piezoelectric actuator in order to produce a continuous shear wave propagation or a tone-burst propagation (TBP) of 400 Hz over a gelatin tissue-mimicking phantom. The remaining techniques utilize a second actuator located on the opposite side of the region of interest in order to create three types of interference patterns: crawling waves, swept crawling waves, and standing waves, depending on the selection of the frequency difference between the two actuators. We evaluated accuracy, contrast to noise ratio, resolution, and acquisition time for each technique during experiments. Numerical simulations were also performed in order to support the experimental findings. Results suggest that in the presence of strong internal reflections, single source methods are more accurate and less variable when compared to the two actuator methods. In particular, TBP reports the best performance with an accuracy error < 4.1 % . Finally, the TBP was tested in a fresh chicken tibialis anterior muscle with a localized thermally ablated lesion in order to evaluate its performance in biological tissue. PMID- 28358944 TI - Update in Pulmonary Medicine: Evidence Published in 2016. PMID- 28358945 TI - Update in Women's Health: Evidence Published in 2016. PMID- 28358946 TI - Policing and Public Health-Strategies for Collaboration. PMID- 28358947 TI - MEKanisms of a Serous Complication. PMID- 28358948 TI - Economic Evaluation of a Home-Based Age-Related Macular Degeneration Monitoring System. AB - Background: Medicare recently approved coverage of home telemonitoring for early detection of incident choroidal neovascularization (CNV) among patients with age related macular degeneration (AMD), but no economic evaluation has yet assessed its cost-effectiveness and budgetary impact. Objectives: To evaluate a home-based daily visual-field monitoring system using simulation methods and to apply the findings of the Home Monitoring of the Eye study to the US population at high risk for wet-form AMD. Design, Setting, and Participants: In this economic analysis, an evaluation of the potential cost, cost-effectiveness, and government budgetary impact of adoption of a home-based daily visual-field monitoring system among eligible Medicare patients was performed. Effectiveness and visual outcomes data from the Age-Related Eye Disease Study 2 Home Monitoring of the Eye study, treatment data from the Wills Eye Hospital Treat & Extend study, and AMD progression data from the Age-Related Eye Disease Study 1 were used to simulate the long-term effects of telemonitoring patients with CNV in one eye or large drusen and/or pigment abnormalities in both eyes. Univariate and probabilistic sensitivity analysis and an alternative scenario using the Treat & Extend study control group outcomes were used to examine uncertainty in these data and assumptions. Interventions: Home telemonitoring of patients with AMD for early detection of CNV vs usual care. Main Outcomes and Measures: Incremental cost effectiveness ratio, net present value of lifetime societal costs, and 10-year nominal government expenditures. Result: Telemonitoring of patients with existing unilateral CNV or multiple bilateral risk factors for CNV (large drusen and retinal pigment abnormalities) incurs $907 (95% CI, -$6302 to $2809) in net lifetime societal costs, costs $1312 (95% CI, $222-$2848) per patient during 10 years from the federal government's perspective, and results in an incremental cost-effectiveness ratio of $35 663 (95% CI, cost savings to $235 613) per quality-adjusted life-year gained. Conclusions and Relevance: Home telemonitoring of patients with AMD who are at risk for CNV was cost-effective compared with scheduled examinations alone. Monitoring patients with existing CNV in one eye is cost saving, but monitoring is generally not cost-effective among patients with low risk of CNV, including those with no or few risk factors. With Medicare coverage, monitoring incurs budgetary expenditures for the government but is cost saving for patients at high risk of AMD. Monitoring could be cost saving to society if monitoring reduced the frequency of scheduled examinations or led to a reduction of one or more injections of ranibizumab. PMID- 28358949 TI - Myopia and Late-Onset Progressive Cone Dystrophy Associate to LVAVA/MVAVA Exon 3 Interchange Haplotypes of Opsin Genes on Chromosome X. AB - Purpose: Rare interchange haplotypes in exon 3 of the OPN1LW and OPN1MW opsin genes cause X-linked myopia, color vision defect, and cone dysfunction. The severity of the disease varies on a broad scale from nonsyndromic high myopia to blue cone monochromatism. Here, we describe a new genotype-phenotype correlation attributed to rare exon 3 interchange haplotypes simultaneously present in the long- and middle-wavelength sensitive opsin genes (L- and M-opsin genes). Methods: A multigenerational family with X-linked high myopia and cone dystrophy was investigated. Results: Affected male patients had infantile onset myopia with normal visual acuity and color vision until their forties. Visual acuity decreased thereafter, along with the development of severe protan and deutan color vision defects. A mild decrease in electroretinography response of cone photoreceptors was detected in childhood, which further deteriorated in middle aged patients. Rods were also affected, however, to a lesser extent than cones. Clinical exome sequencing identified the LVAVA and MVAVA toxic haplotypes in the OPN1LW and OPN1MW opsin genes, respectively. Conclusion: Here, we show that LVAVA haplotype of the OPN1LW gene and MVAVA haplotype of the OPN1MW gene cause apparently nonsyndromic high myopia in young patients but lead to progressive cone-rod dystrophy with deuteranopia and protanopia in middle-aged patients corresponding to a previously unknown disease course. To the best of our knowledge, this is the first report on the joint effect of these toxic haplotypes in the two opsin genes on chromosome X. PMID- 28358951 TI - Functional and Anatomic Outcomes in Patients With Serous Retinal Detachment in Diabetic Macular Edema Treated With Ranibizumab. PMID- 28358950 TI - Quantifying Fundus Autofluorescence in Patients With Retinitis Pigmentosa. AB - Purpose: Using quantitative fundus autofluorescence (qAF), we analyzed short wavelength autofluorescent (SW-AF) rings in RP. Methods: Short-wavelength autofluorescent images (486 nm excitation) of 40 patients with RP (69 eyes) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference. Mean qAF was measured in eight preset segments (qAF8) and in region of interest (ROI)-qAF (200-700 MUm) within and external to the borders of the rings at superior, temporal, and inferior sites relative to the ring. For both groups, qAF in patients with RP was compared to age-similar and race/ethnicity-matched healthy eyes at equivalent retinal locations. Results: In 71% of eyes of RP patients, qAF8 acquired internal to the inner border of the ring, was within the 95% confidence interval (CI) for healthy eyes, while in the remaining RP eyes qAF8 was either higher or lower than the CI. Measured external to the ring, qAF8 values were within the CI in 47% of RP eyes with the other eyes being higher or lower. In 28% of sites measured by ROI-qAF within the SW-AF ring, values were above the 95% CI of healthy controls. Region of interest-qAF measured just external to the ring was within the CI of healthy eyes in 74% of locations. The average local elevation in qAF within the ring was approximately 15%. In SD OCT scans, photoreceptor-attributable reflectivity bands were thinned within and external to the ring. Conclusions: Increased fluorophore production may be a factor in the formation of the SW-AF rings in RP. PMID- 28358952 TI - Author Response: Functional and Anatomic Outcomes in Patients With Serous Retinal Detachment in Diabetic Macular Edema Treated With Ranibizumab. PMID- 28358953 TI - A New Method of Magnification Correction for Accurately Measuring Retinal Vessel Calibers From Fundus Photographs. AB - Purpose: To report a semiautomated retinal vessel caliber measurement system that measures central retinal artery (vein) equivalent (CRAE [CRVE]) with individual correction for magnification errors under conditions assuming optimal focus. Methods: The focusing condition of the subject eye fundus camera optical system was individually determined by constructing an optical model of each eye applying its refractive error, corneal curvature, and axial length (AL) to Gullstrand's schematic eye, and by adjusting the position of the camera's focusing lenses using each eye's refractive error. Once the focusing condition of the entire optical system was fulfilled, magnification of the fundus images was calculated using paraxial ray tracing. Measurements of CRAE (CRVE) were performed in an annular area centered on the optic disc with magnification-corrected diameter from 1.8 to 2.7 mm. Reproducibility of the measurements of the results using the new method and comparison with those using interactive vessel analysis (IVAN) were performed in normal Japanese eyes. Results: Intra- and interexaminer intraclass correlation coefficient (ICC) for CRAE (CRVE) measurements was greater than 0.978. CRAE (CRVE) using the new method averaged 148.9 +/- 10.9 MUm (225.0 +/- 13.9 MUm; mean +/- SD, N = 99). Differences between the new method and IVAN were greater with increasing AL (P < 0.001). The new method yielded CRAE (CRVE) in good agreement with IVAN in eyes with AL of approximately 24 mm. However, the new method yielded smaller values in eyes with shorter AL and vice versa. Conclusions: A new accurate and reproducible method to measure CRAE (CRVE) from fundus photographs was reported. PMID- 28358954 TI - Modulation of Circadian Rhythms Affects Corneal Epithelium Renewal and Repair in Mice. AB - Purpose: In mammalian corneal epithelium, mitosis shows a distinct circadian pattern. However, how this circadian pattern is maintained, and how it or its disruption influence renewal and regeneration remain unclear. Methods: C57BL/6 mice were maintained under 12-hour light/12-hour dark (LD), 12-hour light/12-hour light (LL), 12-hour dark/12-hour dark (DD), or reversed LD (DL, 12-hour dark/12 hour light; jet-lag defined as a shift of 12 hours) conditions. Mitotic cells in corneal epithelium were enumerated and analyzed via immunofluorescence at different zeitgeber times (ZTs). Expression of core clock genes (Clock, Bmal1, Period2, Cry1, and Rev-erbalpha) was qualified via quantitative RT-PCR. The rate and quality of healing at different ZT times and after administration of two small-molecule modifiers of the circadian clock, KL001 and SR8278, was evaluated. Results: In this study, photic cues were found to influence the 24-hour rhythm of corneal clock gene expression and epithelial cell mitosis in mice. Disruption of the circadian clock by exposure to constant light, constant dark, or jet-lag conditions modified the normal 24-hour patterns of corneal epithelial mitosis and corneal clock gene expression. The time of day of wound occurrence affected the rate and quality of corneal healing, with both of these parameters peaking during the more mitotically active hours of the morning. The two small-molecule modifiers of the circadian clock, KL001 and SR8278, had negative and positive effects on corneal wound healing, respectively. Conclusions: Circadian rhythms significantly influence corneal epithelium renewal and repair in mice. Our findings reveal possible opportunities for biological rhythm-based interventional strategies to control corneal healing and restore corneal homeostasis. PMID- 28358955 TI - Bilateral Ocular Pain and Hyperemia in a Patient With Paget Disease of the Bone. PMID- 28358957 TI - Update in Hospital Medicine: Evidence Published in 2016. PMID- 28358956 TI - Ethnic Differences in the Association Between Age-Related Macular Degeneration and Vision-Specific Functioning. AB - Importance: Understanding the link between ethnicity and health is critical to making appropriate public policy decisions. Few population-level data are available about this connection, however, including the influence of ethnicity on the association between age-related macular degeneration (AMD) and vision specific functioning (VSF). Objective: To identify the influence of ethnicity on VSF among Chinese, Malay, and Indian patients with AMD. Design, Setting, and Participants: This cross-sectional, population-based study relied on patients and their data from 3 population-based studies in 3 ethnic groups: Chinese, Malay and Indian. Of 10 033 Chinese, Malay, and Indian adults who participated in the study, 9962 (99.3%) who had gradable fundus images and Visual Function Index (VF 11) data available were included in the analyses for the present study. Uniocular presenting distance visual acuity was measured using the logMAR chart. Separate multiple linear regression models examined the association between AMD and VSF in the 3 ethnic groups, adjusting for age, sex, presenting visual acuity in the better-seeing eye, educational level, income, smoking status, hypertension, diabetes, cardiovascular disease, total cholesterol level, and other eye conditions. Data were collected between January 20, 2004, and December 19, 2011; data analysis was conducted between November 12, 2015, and December 28, 2016. Exposures: Age-related macular degeneration according to fundus photographs graded using a modified Wisconsin Age-Related Maculopathy Grading System. Main Outcomes and Measures: Rasch analysis was used to convert VF-11 questionnaire scores to estimated interval measures of VSF. Results: Of the 9962 participants, the mean (SD) age was 58.8 (10.4) years; 4909 (49.3%) were male; 590 (5.9%) had early AMD (241 Chinese, 161 Malays, and 188 Indians) and 60 (0.6%) had late AMD (25 Chinese, 21 Malays, and 14 Indians). In the adjusted models, compared with no AMD, early AMD was associated with a small reduction in VSF (2.9%; beta = -0.12; 95% CI, -0.23 to -0.00; P = .046) in the Chinese group but not in the Indian and Malay groups. Moreover, Chinese participants with late AMD had a clinically significant 19.1% loss of VSF (beta = -0.78; 95% CI, -1.13 to -0.43, P < .001). In the Malay group, those with late AMD had a 13.5% drop in VSF (beta = -0.49; 95% CI, -1.01 to 0.04; P = .07) compared with their counterparts without AMD. Similarly, late AMD was not associated with VSF in the Indian group. Conclusions and Relevance: Early and late AMD negatively affected VSF in Chinese but not in Indian and Malay participants. This finding suggests that there is an independent ethnic influence in the association of the disease with VSF in multiethnic Asian populations, thus warranting ethnicity-based strategies to delay the onset or progression of AMD. PMID- 28358958 TI - Association of Parathyroid Gland Biopsy Excision Technique With Ex Vivo Radiation Counts During Radioguided Parathyroid Surgery. AB - Importance: Parathyroid biopsy represents a means for normal and hyperfunctional glands to be distinguished intraoperatively. However, no data exist to guide surgeons regarding how much of a parathyroid gland must be biopsied to satisfy the 20% rule. Objective: To quantify the relative proportion of a hyperfunctional parathyroid gland that must be evaluated with the gamma probe to satisfy the 20% rule. Design, Setting, and Participants: A retrospective review of surgical data for 24 consecutive patients (16 women, 18 men; mean [SD] age, 66.6 [10] years; range, 51-83 years) who underwent surgery for primary hyperparathyroidism between May and October, 2015, in a tertieary academic medical center. Main Outcomes and Measures: Extirpated parathyroid glands were sectioned into parallel or pie shaped biopsies and evaluated ex vivo with a gamma probe to determine what percentage of a hyperfunctional gland must be sampled to meet the Norman 20% rule. The hypothesis was formulated during data collection. Results: In total, 253 ex vivo biopsy specimens were obtained from 33 surgically removed parathyroid glands. Parathyroid biopsies satisfied the 20% rule with an accuracy that depended on the relative proportion of the parent gland represented: half or more (96.6%; 95% CI, 91.7%-100.0%), a quarter to one-half (87.0%; 95% CI, 79.3% 94.7%), less than a quarter (63.6%; 95% CI, 54.5%-72.8%). When less than a quarter of the gland was removed, pie-shaped biopsies were more likely to satisfy the 20% rule compared with parallel biopsies of the same weight (78.4% vs 56.2%; absolute difference, 22.2%; 95% CI, 4.7%-39.7%). Conclusions and Relevance: Unless half of a parathyroid gland is biopsied during radioguided parathyroidectomy, the 20% rule cannot reliably rule out the presence of a hyperfunctional parathyroid lesion. Pie-shaped biopsies originating from the center of the gland are associated with a lower rate of false-negative results compared with peripheral biopsies of similar size. Pie-shaped biopsies and biopsy of half or more of each nonexcised parathyroid gland for ex vivo counts may increase the risk of remnant devascularization and resultant hypoparathyroidism. PMID- 28358960 TI - Searching for Objects in Everyday Scenes: Measuring Performance in People With Dry Age-Related Macular Degeneration. AB - Purpose: Treatment success in clinical trials for AMD would ideally be aligned to measurable performance in visual tasks rather than imperceptible changes on clinical charts. We test the hypothesis that patients with dry AMD perform worse than visually healthy peers on computer-based surrogates of "real-world" visual search tasks. Methods: A prospective case-control study was conducted in which patients with dry AMD performed a computer-based "real-world" visual search task. Participants searched for targets within images of everyday scenes while eye movements were recorded. Average search times across the images were recorded as a primary outcome measure. Comparisons were made against a 90% normative limit established in peers with healthy vision (controls). Eye movement parameters were examined as a secondary outcome measure. Results: Thirty-one patients and 33 controls with median (interquartile range) age of 75 (70-79) and 71 (66-75) years and logMAR binocular visual acuity 0.2 (0.18-0.31) and -0.06 (-0.12 to 0), respectively, were examined. Four, 18, and 9 patients were categorized as having early, intermediate, and late AMD, respectively. Nineteen (61%) patients exceeded the 90% normative limits for average search time; this was statistically significant (Fisher's exact test, P < 0.0001). On average, patients made smaller saccades than controls (P < 0.001). Conclusions: People with dry AMD, certainly those with advanced disease, are likely to have measurable difficulties beyond those observed in visually healthy peers on "real-world" search tasks. Further work might establish this type of task as a useful outcome measure for clinical trials. PMID- 28358959 TI - A Bioengineering Approach to Myopia Control Tested in a Guinea Pig Model. AB - Purpose: To investigate the biocompatibility of an injectable hydrogel and its ability to control myopia progression in guinea pigs. Methods: The study used a hydrogel synthesized from acrylated hyaluronic acid with a conjugated cell binding peptide and enzymatically degradable crosslinker. Seven-day-old guinea pigs were first form deprived (FD) with diffusers for 1 week. One group was kept as an FD-only control; two groups received a sub-Tenon's capsule injection of either hydrogel or buffer (sham surgery) at the posterior pole of the eye. Form deprivation treatments were then continued for 3 additional weeks. Treatment effects were evaluated in terms of ocular axial length and refractive error. Safety was evaluated via intraocular pressure (IOP), visual acuity, flash electroretinograms (ERG), and histology. Results: Both hydrogel and sham surgery groups showed significantly reduced axial elongation and myopia progression compared to the FD-only group. For axial lengths, net changes in interocular difference (treated minus control) were 0.04 +/- 0.06, 0.02 +/- 0.09, and 0.24 +/ 0.08 mm for hydrogel, sham, and FD-only groups, respectively (P = 0.0006). Intraocular pressures, visual acuities, and ERGs of treated eyes were not significantly different from contralateral controls. Extensive cell migration into the implants was evident. Both surgery groups showed noticeable Tenon's capsule thickening. Conclusions: Sub-Tenon's capsule injections of both hydrogel and buffer inhibited myopia progression, with no adverse effects on ocular health. The latter unexpected effect warrants further investigation as a potential novel myopia control therapy. That the hydrogel implant supported significant cell infiltration offers further proof of its biocompatibility, with potential application as a tool for drug and cell delivery. PMID- 28358961 TI - Intravitreal Anti-VEGF Injections Reduce Aqueous Outflow Facility in Patients With Neovascular Age-Related Macular Degeneration. AB - Purpose: We assess the effect of intravitreal anti-VEGF injections on tonographic outflow facility. Methods: Patients with age-related macular degeneration who had received unilateral intravitreal anti-VEGF injections were recruited into two groups, those with <=10 and those with >=20 total anti-VEGF injections. Intraocular pressure and tonographic outflow facility of injected and uninjected fellow eyes were measured and compared between groups. Risk factors for development of reduced outflow facility also were assessed. Results: Outflow facility was 12% lower in the injected eyes of patients who received >=20 anti VEGF injections, compared to contralateral uninjected eyes (P = 0.02). In contrast, there was no facility reduction for patients with <=10 anti-VEGF injections (P = 0.4). In patients with ocular hypertension in the uninjected eye (IOP > 21 mm Hg, n = 5), the outflow facility of injected eyes was on average 46% lower (P = 0.01) than in the uninjected fellow eyes. This was significantly greater than the difference observed in patients with IOP <= 21 mm Hg in the uninjected eye (P = 2 * 10-4). In patients with ocular hypertension in the injected eye (n = 6) the differences in facility and IOP between contralateral eyes were significantly greater than in patients with IOP <= 21 mm Hg in the injected eye (P = 2 * 10-4 and P = 7 * 10-4, respectively). Conclusions: Chronic anti-VEGF injections significantly reduce outflow facility in patients with AMD. The greatest facility reduction is observed in patients with baseline ocular hypertension. Ophthalmologists who administer anti-VEGF injections should be aware of these findings and monitor patients closely for changes in IOP or evidence of glaucoma, especially in those with pre-existing ocular hypertension. PMID- 28358963 TI - Determining the Value of Home Monitoring of Patients With Age-Related Macular Degeneration. PMID- 28358964 TI - Treatment of Previously Refractory Ocular Surface Squamous Neoplasia With Topical Cidofovir. PMID- 28358965 TI - Ethnic Differences in Self-reported Visual Function Among Patients With Age Related Macular Degeneration: Implications for Care. PMID- 28358966 TI - FLT3 Mutation Testing in Acute Myeloid Leukemia. PMID- 28358962 TI - VEGF as a Paracrine Regulator of Conventional Outflow Facility. AB - Purpose: Vascular endothelial growth factor (VEGF) regulates microvascular endothelial permeability, and the permeability of Schlemm's canal (SC) endothelium influences conventional aqueous humor outflow. We hypothesize that VEGF signaling regulates outflow facility. Methods: We measured outflow facility (C) in enucleated mouse eyes perfused with VEGF-A164a, VEGF-A165b, VEGF-D, or inhibitors to VEGF receptor 2 (VEGFR-2). We monitored VEGF-A secretion from human trabecular meshwork (TM) cells by ELISA after 24 hours of static culture or cyclic stretch. We used immunofluorescence microscopy to localize VEGF-A protein within the TM of mice. Results: VEGF-A164a increased C in enucleated mouse eyes. Cyclic stretch increased VEGF-A secretion by human TM cells, which corresponded to VEGF-A localization in the TM of mice. Blockade of VEGFR-2 decreased C, using either of the inhibitors SU5416 or Ki8751 or the inactive splice variant VEGF A165b. VEGF-D increased C, which could be blocked by Ki8751. Conclusions: VEGF is a paracrine regulator of conventional outflow facility that is secreted by TM cells in response to mechanical stress. VEGF affects facility via VEGFR-2 likely at the level of SC endothelium. Disruption of VEGF signaling in the TM may explain why anti-VEGF therapy is associated with decreased outflow facility and sustained ocular hypertension. PMID- 28358968 TI - Person-Centered Technology for Older Adults. PMID- 28358967 TI - Acute Bilateral Photoreceptor Degeneration in an Infant After Vaccination Against Measles and Rubella. AB - Importance: Ocular inflammation is occasionally observed after vaccinations, and most of them resolve without permanent visual disturbances. However, there are some rare cases of severe ocular complications following vaccinations. Objective: To report the findings in an infant boy who developed an acute loss of vision bilaterally after Haemophilus influenzae type b, Pneumococcal conjugate vaccination, and measles and rubella vaccination. His vision did not recover. Design, Setting, and Participant: A retrospective review of the medical records of a 13-month-old Japanese boy. Main Outcomes and Measures: Fundus and fluorescein angiographic findings, ultrasonographic and optical coherence tomographic images, and electroretinographic findings. Results: A healthy 13 month-old boy had an acute loss of vision in both eyes 31 days after Haemophilus influenzae type b and Pneumococcal conjugate vaccinations and 24 days after a measles and rubella vaccination. He also developed a common cold 10 days before the vision loss. Ultrasonography showed an exudative retinal detachment 1 day after the onset of the visual reduction; however, his fundi appeared normal 4 days later. His eyes did not pursue objects, and pupillary light reflexes were not present. No signs of anterior uveitis were noted. He was treated with corticosteroids, but his vision did not improve. The retinal vessels gradually attenuated, and diffuse small white punctate lesions appeared in the deep retina. Optical coherence tomography showed a thinner outer nuclear layer and an absent ellipsoid zone. The electroretinograms were nonrecordable. These findings suggested a severe impairment of the photoreceptors, especially their outer segments. Western blot analysis of the patient's sera detected an antibody against recoverin, a calcium-binding protein of photoreceptors. Conclusions and Relevance: We hypothesize that an infection induced severe chorioretinitis with an exudative retinal detachment, which then produced an autoantibody against recoverin. The autoantibody then altered the function of the photoreceptors very rapidly. The initial infection may have been caused by the measles and rubella vaccination. However, because to our knowledge this has not been reported previously, the visual loss after the vaccinations may have been an extremely rare event that was coincidental or may have been related to the vaccination. PMID- 28358971 TI - Nursing Home Medication Reconciliation: A Quality Improvement Initiative. AB - The current quality improvement initiative evaluated the medication reconciliation process within select nursing homes in Washington, DC. The identification of common types of medication discrepancies through monthly retrospective chart reviews of newly admitted patients in two different nursing homes were described. The use of high-risk medications, namely antidiabetic, anticoagulant, and opioid agents, was also recorded. A standardized spreadsheet tool based on multiple medication reconciliation implementation tool kits was created to record the information. The five most common medication discrepancies were incorrect indication (21%), no monitoring parameters (17%), medication name omitted (11%), incorrect dose (10%), and incorrect frequency (8%). Antidiabetic agents in both sites were the most used high-risk medication. This initiative highlights that medication discrepancies on admission are common in nursing homes and may be clinically impactful. More attention needs to be given to work flow processes to improve medication reconciliation considering the increased risk for adverse drug events and hospitalizations. [Journal of Gerontological Nursing and Mental Health Services, 43(4), 9-14.]. PMID- 28358972 TI - Nurse, Patient, and Care Partner Perceptions of a Personalized Safety Plan Screensaver. AB - A patient safety plan dashboard was developed that captures disparate data from the electronic health record that is then displayed as a personalized bedside screensaver. The dashboard aligns all care team members, including patients and families, in the safety plan. The screensaver content includes icons that pertain to common geriatric syndromes. In two phases, interviews were conducted with nurses, nursing assistants, patients, and informal caregivers in a large, tertiary care center. End user perceptions of the content and interface of the personalized safety plan screensavers were identified and strategies to overcome the barriers to use for future iterations were defined. Many themes were identified, ranging from appreciation of the clinical decision support provided by the screensavers to the value of the safety-centric content. Differences emerged stemming from each group of end users' role on the care team. All feedback will inform requirements for improvements to the personalized safety plan screensaver. [Journal of Gerontological Nursing, 43(4), 15-22.]. PMID- 28358974 TI - The Impact of Lumbar Spine Disease and Deformity on Total Hip Arthroplasty Outcomes. AB - Concomitant spine and hip disease in patients undergoing total hip arthroplasty (THA) presents a management challenge. Degenerative lumbar spine conditions are known to decrease lumbar lordosis and limit lumbar flexion and extension, leading to altered pelvic mechanics and increased demand for hip motion. In this study, the effect of lumbar spine disease on complications after primary THA was assessed. The Medicare database was searched from 2005 to 2012 using International Classification of Diseases, Ninth Revision, procedure codes for primary THA and diagnosis codes for preoperative diagnoses of lumbosacral spondylosis, lumbar disk herniation, acquired spondylolisthesis, and degenerative disk disease. The control group consisted of all patients without a lumbar spine diagnosis who underwent THA. The risk ratios for prosthetic hip dislocation, revision THA, periprosthetic fracture, and infection were significantly higher for all 4 lumbar diseases at all time points relative to controls. The average complication risk ratios at 90 days were 1.59 for lumbosacral spondylosis, 1.62 for disk herniation, 1.65 for spondylolisthesis, and 1.53 for degenerative disk disease. The average complication risk ratios at 2 years were 1.66 for lumbosacral spondylosis, 1.73 for disk herniation, 1.65 for spondylolisthesis, and 1.59 for degenerative disk disease. Prosthetic hip dislocation was the most common complication at 2 years in all 4 spinal disease cohorts, with risk ratios ranging from 1.76 to 2.00. This study shows a significant increase in the risk of complications following THA in patients with lumbar spine disease. [Orthopedics. 2017; 40(3):e520-e525.]. PMID- 28358975 TI - Age-Related Outcome of Mobile-Bearing Total Ankle Replacement. AB - The aim of this study was to investigate clinical and radiographic outcomes in patients 50 years and younger vs patients older than 50 years undergoing total ankle replacement. Seventy consecutive patients who underwent primary total ankle replacement were included in this retrospective study. Patients were assessed clinically and radiographically. There was a statistically significant difference between the 2 groups for the American Orthopaedic Foot & Ankle Society score at final follow-up. The younger group had significantly greater improvement compared with the older group. Total ankle arthroplasty is an effective treatment for young, active patients with symptomatic end-stage ankle arthritis. [Orthopedics. 2017; 40(3):e567-e573.]. PMID- 28358976 TI - Analysis of Bony and Internal Organ Injuries Associated With 26,357 Adult Femoral Shaft Fractures and Their Impact on Mortality. AB - The spectrum of injuries associated with femoral shaft fractures and those injuries' association with mortality have not been well delineated previously. Patients in the National Trauma Data Bank who presented with femoral shaft fractures from 2011 to 2012 were analyzed in 3 age groups (18-39, 40-64, and 65+ years). For each group, modified Charlson Comorbidity Index (CCI), mechanism of injury (MOI), injury severity score (ISS), and associated injuries were reported. Multivariate logistic regression was used to identify predictors of mortality. Among the 26,357 patients with femoral shaft fractures, modified CCIs gradually increased with increasing age category and ISS decreased. Motor vehicle accidents were the most common MOI in the younger 2 age groups, whereas falls were the most common MOI in the 65 years and older age group. The top 3 associated bony injuries for the study cohort as a whole were tibia/fibula (20.5%), ribs/sternum (19.1%), and non-shaft femur (18.9%, of which 5.8% of the total cohort were femoral neck) fractures. The top 3 associated internal organ injuries were lung (18.9%), intracranial (13.5%), and liver (6.2%), injuries. A multivariate mortality analysis showed that increasing age, increasing comorbidity burden, and associated injuries all had independent associations with mortality. The injuries most associated with mortality were thoracic organ injuries (adjusted odds ratio [AOR]=3.53), head injuries (AOR=2.93), abdominal organ injuries (AOR=2.78), and pelvic fractures (AOR=1.80). This study used a large, nationwide sample of trauma patients to profile injuries associated with femoral shaft fractures. Associations between injuries and mortality underscore the importance of these findings. [Orthopedics. 2017; 40(3):e506-e512.]. PMID- 28358977 TI - Plantar Plating for the Treatment of Proximal Fifth Metatarsal Fractures in Elite Athletes. AB - Proximal fifth metatarsal fractures, zones II and III, are commonly treated surgically, especially in elite athletes. Intramedullary screw fixation remains the most used construct despite nonunion and refracture. High tensile forces on the plantar-lateral aspect of the fifth metatarsal are difficult to control, and intramedullary screw fixation depends on ideal screw position, length, and width. The authors present a plantar plating technique with cancellous bone autograft for zones II and III proximal fifth metatarsal fractures. Rotational instability and plantar-lateral gapping are resisted by applying a compression plate to the tension side of the fracture, eliminating causes for failure. [Orthopedics. 2017; 40(3):e563-e566.]. PMID- 28358978 TI - Responsiveness and Internal Validity of Common Patient-Reported Outcome Measures Following Total Shoulder Arthroplasty. AB - The Constant-Murley (Constant) score, Western Ontario Osteoarthritis of the Shoulder (WOOS) index, American Shoulder and Elbow Surgeons (ASES) score, and Single Assessment Numeric Evaluation (SANE) score are commonly used to assess patient-reported function following shoulder surgery. However, psychometric properties for these tools are mostly unknown for patients with primary glenohumeral arthritis who have undergone anatomic total shoulder arthroplasty (TSA). The purposes of this study were to (1) compare the responsiveness and internal validity between the 4 patient-reported outcomes (PROs) and (2) identify PRO score values associated with patient satisfaction after TSA. A total of 234 primary TSAs were performed for primary glenohumeral osteoarthritis with a 2-year or greater follow-up. The Constant score, WOOS index, ASES score, SANE score, and patient satisfaction were assessed preoperatively and 2 to 5 years postoperatively. Effect sizes, standardized response means, and relative efficiency were calculated to determine responsiveness, and internal validity was determined via the presence of floor and/or ceiling effects. Receiver operator characteristic (ROC) curves were constructed to identify the minimum outcome score that could correctly identify a satisfied patient. At final follow-up, 88% of patients were satisfied. The PROs had large effect sizes and standardized response means (>=0.83). The minimum score that most correctly identified a patient as satisfied was 78 for ASES score, 18 for WOOS index, 73 for Constant score, and 58 for SANE score. However, the ASES score, WOOS index, and SANE score had marked postoperative ceiling effects, whereas the Constant score was the most responsive and internally valid tool. These results suggest that the Constant score should serve as the primary PRO for patients with primary glenohumeral arthritis, whereas the WOOS index, ASES score, and SANE score could be supplementary assessments. [Orthopedics. 2017; 40(3):e513-e519.]. PMID- 28358979 TI - Pelvimetry for fetal cephalic presentations at or near term for deciding on mode of delivery. AB - BACKGROUND: Pelvimetry assesses the size of a woman's pelvis aiming to predict whether she will be able to give birth vaginally or not. This can be done by clinical examination, or by conventional X-rays, computerised tomography (CT) scanning, or magnetic resonance imaging (MRI). OBJECTIVES: To assess the effects of pelvimetry (performed antenatally or intrapartum) on the method of birth, on perinatal mortality and morbidity, and on maternal morbidity. This review concentrates exclusively on women whose fetuses have a cephalic presentation. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2017) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (including quasi-randomised) assessing the use of pelvimetry versus no pelvimetry or assessing different types of pelvimetry in women with a cephalic presentation at or near term were included. Cluster trials were eligible for inclusion, but none were identified. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: Five trials with a total of 1159 women were included. All used X-ray pelvimetry to assess the pelvis. X-ray pelvimetry versus no pelvimetry or clinical pelvimetry is the only comparison included in this review due to the lack of trials identified that examined other types of radiological pelvimetry or that compared clinical pelvimetry versus no pelvimetry.The included trials were generally at high risk of bias. There is an overall high risk of performance bias due to lack of blinding of women and staff. Two studies were also at high risk of selection bias. We used GRADEpro software to grade evidence for our selected outcomes; for caesarean section we rated the evidence low quality and all the other outcomes (perinatal mortality, wound sepsis, blood transfusion, scar dehiscence and admission to special care baby unit) as very low quality. Downgrading was due to risk of bias relating to lack of allocation concealment and blinding, and imprecision of effect estimates.Women undergoing X-ray pelvimetry were more likely to have a caesarean section (risk ratio (RR) 1.34, 95% confidence interval (CI) 1.19 to 1.52; 1159 women; 5 studies; low-quality evidence). There were no clear differences between groups for perinatal outcomes: perinatal mortality (RR 0.53, 95% CI 0.19 to 1.45; 1159 infants; 5 studies; very low-quality evidence), perinatal asphyxia (RR 0.66, 95% CI 0.39 to 1.10; 305 infants; 1 study), and admission to special care baby unit (RR 0.20, 95% CI 0.01 to 4.13; 288 infants; 1 study; very low-quality evidence). Other outcomes assessed were wound sepsis (RR 0.83, 95% CI 0.26 to 2.67; 288 women; 1 study; very low-quality evidence), blood transfusion (RR 1.00, 95% CI 0.39 to 2.59; 288 women; 1 study; very low-quality evidence), and scar dehiscence (RR 0.59, 95% CI 0.14 to 2.46; 390 women; 2 studies; very low-quality evidence). Again, no clear differences were found for these outcomes between the women who received X-ray pelvimetry and those who did not. Apgar score less than seven at five minutes was not reported in any study. AUTHORS' CONCLUSIONS: X-ray pelvimetry versus no pelvimetry or clinical pelvimetry is the only comparison included in this review due to the lack of trials identified that used other types or pelvimetry (other radiological examination or clinical pelvimetry versus no pelvimetry). There is not enough evidence to support the use of X-ray pelvimetry for deciding on mode of delivery in women whose fetuses have a cephalic presentation. Women who undergo an X-ray pelvimetry may be more likely to have a caesarean section.Further research should be directed towards defining whether there are specific clinical situations in which pelvimetry can be shown to be of value. Newer methods of pelvimetry (CT, MRI) should be subjected to randomised trials to assess their value. Further trials of X-ray pelvimetry in cephalic presentations would be of value if large enough to assess the effect on perinatal mortality. PMID- 28358980 TI - Pharmacological interventions for non-alcohol related fatty liver disease (NAFLD): an attempted network meta-analysis. AB - BACKGROUND: Non-alcohol related fatty liver disease (commonly called non alcoholic fatty liver disease (NAFLD)) is liver steatosis in the absence of significant alcohol consumption, use of hepatotoxic medication, or other disorders affecting the liver such as hepatitis C virus infection, Wilson's disease, and starvation. NAFLD embraces the full spectrum of disease from pure steatosis (i.e. uncomplicated fatty liver) to non-alcoholic steatohepatitis (NASH), via NASH-cirrhosis to cirrhosis. The optimal pharmacological treatment for people with NAFLD remains uncertain. OBJECTIVES: To assess the comparative benefits and harms of different pharmacological interventions in the treatment of NAFLD through a network meta-analysis and to generate rankings of the available pharmacological treatments according to their safety and efficacy. However, it was not possible to assess whether the potential effect modifiers were similar across different comparisons. Therefore, we did not perform the network meta analysis, and instead, assessed the comparative benefits and harms of different interventions using standard Cochrane methodology. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.com to August 2016. SELECTION CRITERIA: We included only randomised clinical trials (irrespective of language, blinding, or publication status) in participants with NAFLD. We excluded trials which included participants who had previously undergone liver transplantation. We considered any of the various pharmacological interventions compared with each other or with placebo or no intervention. DATA COLLECTION AND ANALYSIS: We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on an available participant analysis with Review Manager. We assessed risk of bias according to the Cochrane risk of bias tool, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE. MAIN RESULTS: We identified 77 trials including 6287 participants that met the inclusion criteria of this review. Forty-one trials (3829 participants) provided information for one or more outcomes. Only one trial was at low risk of bias in all domains. All other trials were at high risk of bias in one or more domains. Overall, all the evidence was very low quality. Thirty-five trials included only participants with non-alcohol related steatohepatitis (NASH) (based on biopsy confirmation). Five trials included only participants with diabetes mellitus; 14 trials included only participants without diabetes mellitus. The follow-up in the trials ranged from one month to 24 months.We present here only the comparisons of active intervention versus no intervention in which two or more trials reported at least one of the following outcomes: mortality at maximal follow-up, serious adverse events, and health-related quality of life, the outcomes that determine whether a treatment should be used. Antioxidants versus no interventionThere was no mortality in either group (87 participants; 1 trial; very low quality evidence). None of the participants developed serious adverse events in the trial which reported the proportion of people with serious adverse events (87 participants; 1 trial; very low quality evidence). There was no evidence of difference in the number of serious adverse events between antioxidants and no intervention (rate ratio 0.89, 95% CI 0.36 to 2.19; 254 participants; 2 trials; very low quality evidence). None of the trials reported health-related quality of life. Bile acids versus no interventionThere was no evidence of difference in mortality at maximal follow-up (OR 5.11, 95% CI 0.24 to 107.34; 659 participants; 4 trials; very low quality evidence), proportion of people with serious adverse events (OR 1.56, 95% CI 0.84 to 2.88; 404 participants; 3 trials; very low quality evidence), or the number of serious adverse events (rate ratio 1.01, 95% CI 0.66 to 1.54; 404 participants; 3 trials; very low quality evidence) between bile acids and no intervention. None of the trials reported health-related quality of life. Thiazolidinediones versus no interventionThere was no mortality in either group (74 participants; 1 trial; very low quality evidence). None of the participants developed serious adverse events in the two trials which reported the proportion of people with serious adverse events (194 participants; 2 trials; very low quality evidence). There was no evidence of difference in the number of serious adverse events between thiazolidinediones and no intervention (rate ratio 0.25, 95% CI 0.06 to 1.05; 357 participants; 3 trials; very low quality evidence). None of the trials reported health-related quality of life. Source of fundingTwenty-six trials were partially or fully-funded by pharmaceutical companies that would benefit, based on the results of the trial. Twelve trials did not receive any additional funding or were funded by parties with no vested interest in the results. The source of funding was not provided in 39 trials. AUTHORS' CONCLUSIONS: Due to the very low quality evidence, we are very uncertain about the effectiveness of pharmacological treatments for people with NAFLD including those with steatohepatitis. Further well-designed randomised clinical trials with sufficiently large sample sizes are necessary. PMID- 28358981 TI - A Case of Recurrent Antenatal-Onset Obsessive-Compulsive Disorder With Complete Postpartum Remission. PMID- 28358982 TI - Nitrate Stimulates Anaerobic Microbial Arsenite Oxidation in Paddy Soils. AB - Arsenic (As) bioavailability to rice plants is elevated in flooded paddy soils due to reductive mobilization of arsenite [As(III)]. However, some microorganisms are able to mediate anaerobic As(III) oxidation by coupling to nitrate reduction, thus attenuating As mobility. In this study, we investigated the impact of nitrate additions on As species dynamics in the porewater of four As-contaminated paddy soils. The effects of nitrate on microbial community structure and the abundance and diversity of the As(III) oxidase (aioA) genes were quantified using 16S rRNA sequencing, quantitative PCR, and aioA gene clone libraries. Nitrate additions greatly stimulated anaerobic oxidation of As(III) to As(V) and decreased total soluble As in the porewater in flooded paddy soils. Nitrate additions significantly enhanced the abundance of aioA genes and changed the microbial community structure by increasing the relative abundance of the operational taxonomic units (OTUs) from the genera Acidovorax and Azoarcus. The aioA gene sequences from the Acidovorax related OTU were also stimulated by nitrate. A bacterial strain (ST3) belonging to Acidovorax was isolated from nitrate-amended paddy soil. The strain was able to oxidize As(III) and Fe(II) under anoxic conditions using nitrate as the electron acceptor. Abiotic experiments showed that Fe(II), but not As(III), could be oxidized by nitrite. These results show that nitrate additions can stimulate As(III) oxidation in flooded paddy soils by enhancing the population of anaerobic As(III) oxidizers, offering a potential strategy to decrease As mobility in As-contaminated paddy soils. PMID- 28358984 TI - Room-Temperature Current-Induced Generation and Motion of sub-100 nm Skyrmions. AB - Magnetic skyrmions are nanoscale windings of the spin configuration that hold great promise for technology due to their topology-related properties and extremely reduced sizes. After the recent observation at room temperature of sub 100 nm skyrmions stabilized by interfacial chiral interaction in magnetic multilayers, several pending questions remain to be solved, notably about the means to nucleate individual compact skyrmions or the exact nature of their motion. In this study, a method leading to the formation of magnetic skyrmions in a micrometer-sized track using homogeneous current injection is evidenced. Spin transfer-induced motion of these small electrical-current-generated skyrmions is then demonstrated and the role of the out-of-plane magnetic field in the stabilization of the moving skyrmions is also analyzed. The results of these experimental observations of spin torque induced motion are compared to micromagnetic simulations reproducing a granular type, nonuniform magnetic multilayer in order to address the particularly important role of the magnetic inhomogeneities on the current-induced motion of sub-100 nm skyrmions for which the material grains size is comparable to the skyrmion diameter. PMID- 28358983 TI - Differences in Viscosity of Superior and Inferior Spikelets of Japonica Rice with Various Percentages of Apparent Amylose Content. AB - Viscosity, a crucial characteristic for rice palatability, is affected by endosperm characters. We compared correlations between differences in viscosity of japonica rice with various palatability and endosperm characters. Changes in apparent amylose and protein contents (AAC% and PC%, respectively) and amylopectin side-chain distribution and the relationship of these traits with palatability were investigated in superior and inferior spikelets of good cultivars with low amylose content from Hokkaido and common cultivars from northeastern Japan, using rapid visco analyzer characteristics and rice-grain microstructures. Significant differences occurred in PC%, AAC%, breakdown, setback, peak time, and pasting temperature of different cultivars and grain positions. Amylopectin components showed remarkable differences in grain surfaces, surface layers, and section structure between the grain varieties. Hokkaido cultivars showed better viscosity than northeastern cultivars, particularly initial stage grains. Correlation analysis indicated viscosity was mainly AAC%-dependent, whereas differences in endosperm characteristics between spikelet positions were mainly due to grain-filling temperature. PMID- 28358985 TI - Substitution of a Fluorine Atom in Perfluorobenzonitrile by a Lithiated Nitronyl Nitroxide. AB - A 4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazole-3-oxide-1-oxyl (1) lithium derivative was found to react with perfluorobenzonitrile (2) substituting its para-fluorine atom to form 2-(4-cyanotetrafluorophenyl)-4,4,5,5-tetramethyl-4,5 dihydro-1H-imidazol-3-oxide-1-oxyl (3), a new nitronyl nitroxide containing a multifunctional framework of strong electron-withdrawing nature. This result shows the possibility of obtaining multifunctional nitronyl nitroxides via the interaction of paramagnetic lithium derivatives as C-nucleophiles with polyfluoroarenes activated for nucleophilic substitution. The reaction regioselectivity is supported by the data of quantum-chemical calculations, which also show that the reaction follows a concerted pathway without formation of an intermediate. Reduction of nitronyl nitroxide 3 in system NaNO2-AcOH yielded corresponding iminonitroxide 4. Characterization of persistent radicals 3 and 4 obtained by the SNF synthetic strategy includes X-ray crystal structures, electron spin resonance data, and static magnetic-susceptibility measurements. X ray diffraction analysis of both nitronyl nitroxide and iminonitroxide revealed a complete match of the parameters of their crystal lattices. PMID- 28358986 TI - Quantitative Effects of Biochar Oxidation and Pyrolysis Temperature on the Transport of Pathogenic and Nonpathogenic Escherichia coli in Biochar-Amended Sand Columns. AB - The present study quantifies the transport of Escherichia coli pathogenic O157:H7 and nonpathogenic K12 strains in water-saturated Quincy sand (QS) columns amended with oxidized (OX) or unoxidized (UO) pine wood (PW) or pine bark (PB) biochar produced at either 350 or 600 degrees C. Our results showed that (1) the addition of oxidized biochar into QS columns enhanced the transport of E. coli O157:H7 by 3.1 fold compared to the unoxidized counterparts, likely because of an increase in the repulsive forces due to their higher negative charge densities. (2) The retention of E. coli O157:H7 was 3.3 fold higher than that of E. coli K12 in all biochar-amended sand columns. (3) Increased application rates of unoxidized PW600 biochar from 0 to 20 wt % led to a reduction in the transport of E. coli O157:H7 and K12 from 98 to 10% and from 95 to 70%, respectively. Our data showed that mixing sand with PW350-UO at a 20 wt % application rate almost completely retained the pathogenic E. coli in the subsurface, suggesting that utilizing sand mixed with biochar can act as a promising biofilter capable of protecting natural aquafers from pathogens. PMID- 28358987 TI - Highly Selective Targeting of Hepatic Stellate Cells for Liver Fibrosis Treatment Using a d-Enantiomeric Peptide Ligand of Fn14 Identified by Mirror-Image mRNA Display. AB - Although liver fibrosis is a major public health issue, there is still no effective drug therapy in the clinic. Fibroblast growth factor-inducible 14 (Fn14), a membrane receptor highly specifically expressed in activated hepatic stellate cells (HSCs), is the key driver of liver fibrosis, and thus, it has a great potential as a novel target for the development of effective treatment. Here, we identified a d-enantiomeric peptide ligand of Fn14 through mirror-image mRNA display. This included the chemical synthesis of a d-enantiomer of the target protein (extracellular domain of Fn14), identification of an l-peptide ligand of d-Fn14 using a constructed mRNA peptide library, and identification of a d-enantiomer of the l-peptide, which is a ligand of the natural Fn14 for reasons of symmetry. The obtained d-peptide ligand showed strong binding to Fn14 while maintaining high proteolytic resistance. As a targeting moiety, this d peptide successfully mediated high selectivity of activated HSCs for liposomal vehicles compared to that of other major cell types in the liver and significantly enhanced the accumulation of liposomes in the liver fibrosis region of a carbon tetrachloride-induced mouse model. Moreover, in combination with curcumin as an encapsulated load, a liposomal formulation conjugated with this d peptide showed powerful inhibition of the proliferation of activated HSCs and reduced the liver fibrosis to a significant extent in vivo. This Fn14-targeting strategy may represent a promising approach to targeted drug delivery for liver fibrosis treatment. Meanwhile, the mirror-image mRNA display can provide a new arsenal for the development of d-peptide-based therapeutics against a variety of human diseases. PMID- 28358989 TI - Safety and Histological Effect of Liquid Nitrogen Metered Spray Cryotherapy in the Lung. PMID- 28358988 TI - Trends in the incidence of chronic fatigue syndrome and fibromyalgia in the UK, 2001-2013: a Clinical Practice Research Datalink study. AB - Objective Trends in recorded diagnoses of chronic fatigue syndrome (CFS, also known as 'myalgic encephalomyelitis' (ME)) and fibromyalgia (FM) in the UK were last reported more than ten years ago, for the period 1990-2001. Our aim was to analyse trends in incident diagnoses of CFS/ME and FM for the period 2001-2013, and to investigate whether incidence might vary by index of multiple deprivation (IMD) score. Design Electronic health records cohort study. Setting NHS primary care practices in the UK. Participants Participants: Patients registered with general practices linked to the Clinical Practice Research Datalink (CPRD) primary care database from January 2001 to December 2013. Main outcome measure Incidence of CFS/ME, FM, post-viral fatigue syndrome (PVFS), and asthenia/debility. Results The overall annual incidence of recorded cases of CFS/ME was 14.8 (95% CI 14.5, 15.1) per 100,000 people. Overall annual incidence per 100,000 people for FM was 33.3 (32.8-33.8), for PVFS 12.2 (11.9, 12.5), and for asthenia/debility 7.0 (6.8, 7.2). Annual incidence rates for CFS/ME diagnoses decreased from 17.5 (16.1, 18.9) in 2001 to 12.6 (11.5, 13.8) in 2013 (annual percent change -2.8% (-3.6%, -2.0%)). Annual incidence rates for FM diagnoses decreased from 32.3 (30.4, 34.3) to 27.1 (25.5, 28.6) in 2007, then increased to 38.2 (36.3, 40.1) per 100,000 people in 2013. Overall annual incidence of recorded fatigue symptoms was 2246 (2242, 2250) per 100,000 people. Compared with the least deprived IMD quintile, incidence of CFS/ME in the most deprived quintile was 39% lower (incidence rate ratio (IRR) 0.61 (0.50, 0.75)), whereas rates of FM were 40% higher (IRR 1.40 (0.95, 2.06)). Conclusion These analyses suggest a gradual decline in recorded diagnoses of CFS/ME since 2001, and an increase in diagnoses of fibromyalgia, with opposing socioeconomic patterns of lower rates of CFS/ME diagnoses in the poorest areas compared with higher rates of FM diagnoses. PMID- 28358990 TI - A Feasibility Study on Using an Internet-Panel Survey to Measure Perceptions of E cigarettes in 3 Metropolitan Areas, 2015. AB - OBJECTIVES: Internet-panel surveys are emerging as a means to quickly and cost effectively collect health data, and because of their large memberships, they could be used for community-level surveys. To determine the feasibility of using an internet-panel survey to quickly provide community-level data, we conducted a pilot test of a health survey in 3 US metropolitan areas. METHODS: We conducted internet-panel surveys in Cleveland, Ohio; New York, New York; and Seattle, Washington, in 2015. Slightly more than 500 people responded to the survey in each city. We compared weighted unadjusted prevalence estimates from the internet panel data with estimates from the 2014 Health Information National Trends Survey (HINTS) for the following question in each survey: "Compared to smoking cigarettes, would you say that electronic cigarettes are...much less harmful, less harmful, just as harmful, more harmful, much more harmful, or I've never heard of electronic cigarettes." We used multivariable logistic regression to compare associations of respondents' demographic and health characteristics with perceived harm from e-cigarettes. RESULTS: The prevalence of the perception that e-cigarettes are less harmful than smoking cigarettes ranged from 35.9% to 39.9% in the internet-panel sites and was 43.0% in HINTS. Most patterns of beliefs and respondent characteristics in the internet-panel data were consistent with patterns in HINTS. We found inconsistent patterns between internet-panel sites and HINTS by race/ethnicity and education. CONCLUSIONS: This feasibility study found that internet-panel surveys could quickly produce community-level data for targeted public health interventions and evaluation, but they may be limited in producing estimates among subgroups. PMID- 28358991 TI - Ground Turmeric as a Source of Lead Exposure in the United States. PMID- 28358993 TI - Multimodal Management of Canine Osteoarthritis, Second Edition. PMID- 28358994 TI - Questioning the Effectiveness of Baricitinib for Pulmonary Manifestations of Rheumatoid Arthritis. PMID- 28358995 TI - Use of microfluidics to assess the platelet-based control of coagulation. AB - This paper provides an overview of the various types of microfluidic devices that are employed to study the complex processes of platelet activation and blood coagulation in whole blood under flow conditions. We elaborate on how these devices are used to detect impaired platelet-dependent fibrin formation in blood from mice or patients with specific bleeding disorders. We provide a practical guide on how to assess formation of a platelet-fibrin thrombus under flow, using equipment that is present in most laboratories. In addition, we describe current insights on how blood flow and shear rate alter the location of platelet populations, von Willebrand factor, coagulation factors, and fibrin in a growing thrombus. Finally, we discuss possibilities and limitations for the clinical use of microfluidic devices to evaluate a hemostatic or prothrombotic tendency in patient blood samples. PMID- 28358992 TI - Autophagy Primes Neutrophils for Neutrophil Extracellular Trap Formation during Sepsis. AB - RATIONALE: Neutrophils are key effectors in the host's immune response to sepsis. Excessive stimulation or dysregulated neutrophil functions are believed to be responsible for sepsis pathogenesis. However, the mechanisms regulating functional plasticity of neutrophils during sepsis have not been fully determined. OBJECTIVES: We investigated the role of autophagy in neutrophil functions during sepsis in patients with community-acquired pneumonia. METHODS: Neutrophils were isolated from patients with sepsis and stimulated with phorbol 12-myristate 13-acetate (PMA). The levels of reactive oxygen species generation, neutrophil extracellular trap (NET) formation, and granule release, and the autophagic status were evaluated. The effect of neutrophil autophagy augmentation was further evaluated in a mouse model of sepsis. MEASUREMENTS AND MAIN RESULTS: Neutrophils isolated from patients who survived sepsis showed an increase in autophagy induction, and were primed for NET formation in response to subsequent PMA stimulation. In contrast, neutrophils isolated from patients who did not survive sepsis showed dysregulated autophagy and a decreased response to PMA stimulation. The induction of autophagy primed healthy neutrophils for NET formation and vice versa. In a mouse model of sepsis, the augmentation of autophagy improved survival via a NET-dependent mechanism. CONCLUSIONS: These results indicate that neutrophil autophagy primes neutrophils for increased NET formation, which is important for proper neutrophil effector functions during sepsis. Our study provides important insights into the role of autophagy in neutrophils during sepsis. PMID- 28358996 TI - Multiple viral plaques with sebaceous differentiation associated with an unclassified papillomavirus type in a cat. AB - CASE HISTORY AND CLINICAL FINDINGS A 15-year-old neutered male domestic short haired cat was presented due to multiple 0.5-2 cm-diameter crusting plaques in the left preauricular region, over the bridge of nose, and in the right periocular region. The plaques did not appear to cause discomfort. HISTOPATHOLOGICAL FINDINGS Biopsy samples of four plaques were examined histologically. Three plaques consisted of well-demarcated foci of mild epidermal hyperplasia overlying markedly hyperplastic sebaceous glands. Approximately 60% of the hyperplastic cells contained a large cytoplasmic vacuole that ranged from being clear to containing prominent grey-blue fibrillar material. The fourth plaque was composed solely of epidermal hyperplasia, consistent with previous descriptions of feline viral plaques. MOLECULAR BIOLOGY Papillomavirus DNA was amplified from all four plaques using PCR. A single DNA sequence was amplified from the plaques with sebaceous differentiation. This sequence was identical to the FdPV-MY sequence previously suggested to be from a putative unclassified papillomavirus type. Felis catus papillomavirus type 2 sequences were amplified from the plaque typical of feline viral plaques. Immunohistochemistry to detect p16CDKN2A protein (p16) showed marked immunostaining throughout the hyperplastic epidermis and adnexal structures within the plaques with sebaceous differentiation. DIAGNOSIS Multiple feline viral plaques with variable sebaceous differentiation. CLINICAL RELEVANCE Feline viral plaques with sebaceous differentiation have not been previously reported in cats. The presence of unique cell changes within these lesions, the detection of an unclassified papillomavirus type, and the p16 immunostaining within these plaques suggest that they may have been caused by the papillomavirus that contains the FdPV-MY sequence. PMID- 28358997 TI - Association Between Parental Barriers to Accessing a Usual Source of Care and Children's Receipt of Preventive Services. AB - OBJECTIVES: Preventive health services are important for child development, and parents play a key role in facilitating access to services. This study examined how parents' reasons for not having a usual source of care were associated with their children's receipt of preventive services. METHODS: We used pooled data from the 2011-2014 National Health Interview Survey (n = 34 843 participants). Parents' reasons for not having a usual source of care were framed within the Penchansky and Thomas model of access and measured through 3 dichotomous indicators: financial barriers (affordability), attitudes and beliefs about health care (acceptability), and all other nonfinancial barriers (accessibility, accommodation, and availability). We used multivariable logistic regression models to test associations between parental barriers and children's receipt of past-year well-child care visits and influenza vaccinations, controlling for other child, family, and contextual factors. RESULTS: In 2014, 14.3% (weighted percentage) of children had at least 1 parent without a usual source of care. Children of parents without a usual source of care because they "don't need a doctor and/or haven't had any problems" or they "don't like, trust, or believe in doctors" had 35% lower odds of receiving well-child care (adjusted odds ratio = 0.65; 95% CI, 0.56-0.74) and 23% lower odds of receiving influenza vaccination (adjusted odds ratio = 0.77; 95% CI, 0.69-0.86) than children of parents without those attitudes and beliefs about health care. Financial and other nonfinancial parental barriers were not associated with children's receipt of preventive services. Results were independent of several factors relevant to children's access to preventive health care, including whether the child had a usual source of care. CONCLUSIONS: Parents' attitudes and beliefs about having a usual source of care were strongly associated with their children's receipt of recommended preventive health services. Rates of receipt of child preventive services may be improved by addressing parents' attitudes and beliefs about having a usual source of care. Future studies should assess causes of these associations. PMID- 28359000 TI - Financing patient-centred health care homes through value capture. PMID- 28358998 TI - Vaccine myopia: adult vaccination also needs attention. PMID- 28359001 TI - Using aggregated general practice data to evaluate primary care interventions. PMID- 28359002 TI - Deconfounding confounding part 1: traditional explanations. PMID- 28359004 TI - Instructions for a sick day. PMID- 28359003 TI - Clozapine-induced maculopathy. PMID- 28359005 TI - Post-traumatic stress disorder is a systemic illness, not a mental disorder: is Cartesian dualism dead? PMID- 28359006 TI - Are we using the correct first aid for jellyfish? PMID- 28359007 TI - Physical comorbidities of post-traumatic stress disorder in Australian Vietnam War veterans. AB - OBJECTIVE: To determine whether the prevalence of physical comorbidities in Australian Vietnam War veterans with post-traumatic stress disorder (PTSD) is higher than in trauma-exposed veterans without PTSD. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional analysis of the health status (based on self reported and objective clinical assessments) of 298 Australian Vietnam War veterans enrolled by the Gallipoli Medical Research Institute (Brisbane) during February 2014 - July 2015, of whom 108 were confirmed as having had PTSD and 106 served as trauma-exposed control participants.Main outcomes and measures: Diagnostic psychiatric interview and psychological assessments determined PTSD status, trauma exposure, and comorbid psychological symptoms. Demographic data, and medical and sleep history were collected; comprehensive clinical examination, electrocardiography, spirometry, liver transient elastography, and selected pathology assessments and diagnostic imaging were performed. Outcomes associated with PTSD were identified; regression analysis excluded the effects of potentially confounding demographic and risk factors and comorbid symptoms of depression and anxiety. RESULTS: The mean total number of comorbidities was higher among those with PTSD (17.7; SD, 6.1) than in trauma-exposed controls (14.1; SD, 5.2; P < 0.001). For 24 of 171 assessed clinical outcomes, morbidity was greater in the PTSD group, including for conditions of the gastrointestinal, hepatic, cardiovascular, and respiratory systems, sleep disorders, and laboratory pathology measures. In regression analyses including demographic factors, PTSD remained positively associated with 17 adverse outcomes; after adjusting for the severity of depressive symptoms, it remained significantly associated with ten. CONCLUSION: PTSD in Australian Vietnam veterans is associated with comorbidities in several organ systems, independent of trauma exposure. A comprehensive approach to the health care of veterans with PTSD is needed. PMID- 28359008 TI - Hot water immersion v icepacks for treating the pain of Chironex fleckeri stings: a randomised controlled trial. AB - OBJECTIVE: To investigate the effectiveness of hot water immersion for relieving the pain of major box jellyfish (Chironex fleckeri) stings.Design, interventions: Open label, randomised controlled trial comparing the effects of hot water immersion (45 degrees C) and icepacks.Setting, participants: 42 patients with suspected C. fleckeri stings treated in the emergency department of the Royal Darwin Hospital during September 2005 - October 2008. MAIN OUTCOME MEASURES: The primary outcome was pain severity, assessed with a visual analogue scale (VAS). Secondary outcomes included crossover to the alternative treatment, use of opioid analgesia, emergency department length of stay (LOS), and delayed urticaria. RESULTS: Of 42 patients (26 males; median age, 19 years; IQR, 13-27 years), 25 were allocated to icepack treatment and 17 to hot water immersion. The demographic and baseline VAS data for the two groups were similar. After 30 minutes of treatment, 11 patients (65%) treated with hot water and 14 (56%) treated with icepacks had clinically improved pain scores (absolute difference, 9%; 95% CI, -22% to 39%; P = 0.75). One patient treated with icepacks crossed over to heat immersion. Two patients in each arm received intravenous opioid analgesia. Median emergency department LOS was 1.6 h (IQR, 1.0-1.8 h) for icepack patients and 2.1 h (IQR, 1.6-2.8 h) for heat immersion patients (P = 0.07). Five of seven patients who were followed up developed delayed urticaria. CONCLUSION: Hot water immersion was no more effective than icepacks for reducing the acute pain of box jellyfish stings, but increased emergency department LOS by about 30 minutes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12605000007639. PMID- 28359009 TI - HPV vaccine coverage is increasing in Australia. PMID- 28359010 TI - A systematic review and meta-analysis of treatments for acrophobia. AB - OBJECTIVE: To review the literature on the comparative efficacy of psychological, behavioural and medical therapies for acrophobia (fear of heights). DATA SOURCES: Multiple databases were searched through the Cochrane Common Mental Disorders review group on 1 December 2015. DATA SYNTHESIS: The data were extracted independently and were pooled using RevMan version 5.3.5. The main outcome measures were changes from baseline on questionnaires for measurement of fear of heights, such as the Acrophobia Questionnaire (AQ), Attitude Towards Height Questionnaire (ATHQ), and behavioural avoidance tests. Individual and pooled analyses were conducted. Sixteen studies were included. Analysis of pooled outcomes showed that desensitisation (DS) measured by the post-test AQ anxiety score (standardised mean difference [SMD], -1.24; 95% CI, -1.88 to -0.60) and in vivo exposure (IVE) were effective in the short term compared with control (SMD, 0.74; 95% CI, -1.22 to -0.25). IVE was not effective in the long term (SMD, 0.34; 95%CI -0.76 to 0.08) and there were no follow-up data for DS. Virtual reality exposure (VRE) therapy was effective when assessed with the ATHQ but not the AQ. Augmentation of VRE with medication was promising. The number needed to treat (NNT) ranged from 1.4 (95% CI, 1.0 to 2.2) for IVE therapy with oppositional actions (a psychological process) versus waitlist control to an NNT of 6.0 (95% CI, 2.8 to 35.5) for the rapid phobia cure (a neurolinguistic programming technique) versus a mindfulness exercise as the control activity. It was often unclear if there were biases in the included studies. CONCLUSIONS AND RELEVANCE: A range of therapies are effective for acrophobia in the short term but not in the long term. Many of the comparative studies showed equivalence between therapies, but this finding may be due to a type II statistical error. The quality of reporting was poor in most studies. PMID- 28359011 TI - Diagnostic triage for low back pain: a practical approach for primary care. AB - Diagnostic triage is an essential guideline recommendation for low back pain (LBP), which is the most frequent musculoskeletal condition that general practitioners encounter in Australia. Clinical diagnosis of LBP - informed by a focused history and clinical examination - is the key initial step for GPs, and determines subsequent diagnostic workup and allied health and medical specialist referral. The goal of diagnostic triage of LBP is to exclude non-spinal causes and to allocate patients to one of three broad categories: specific spinal pathology (< 1% of cases), radicular syndrome (~ 5-10% of cases) or non-specific LBP (NSLBP), which represents 90-95% of cases and is diagnosed by exclusion of the first two categories. For specific spinal pathologies (eg, vertebral fracture, malignancy, infection, axial spondyloarthritis or cauda equina syndrome), a clinical assessment may reveal the key alerting features. For radicular syndrome, clinical features distinguish three subsets of nerve root involvement: radicular pain, radiculopathy and spinal stenosis. Differential diagnosis of back-related leg pain is complex and clinical manifestations are highly variable. However, distinctive clusters of characteristic history cues and positive clinical examination signs, particularly from neurological examination, guide differential diagnosis within this triage category. A diagnosis of NSLBP presumes exclusion of specific pathologies and nerve root involvement. A biopsychosocial model of care underpins NSLBP; this includes managing pain intensity and considering risk for disability, which directs matched pathways of care. Back pain is a symptom and not a diagnosis. Careful diagnostic differentiation is required and, in primary care, diagnostic triage of LBP is the anchor for a diagnosis. PMID- 28359012 TI - The renewal of the National Cervical Screening Program. PMID- 28359013 TI - The renewal of the National Cervical Screening Program. PMID- 28359014 TI - Sperm motility activation in the critically endangered booroolong frog: the effect of medium osmolality and phosphodiesterase inhibitors. AB - Effective activation of sperm motility is fundamental to successful artificial fertilisation; however, studies investigating optimal procedures in amphibians are lacking. This study found the optimal osmolality of activation media for sperm motility activation and evaluated the effect of phosphodiesterase (PDE) inhibitors on sperm activation and longevity in the critically endangered booroolong frog, Litoria booroolongensis. To assess the effect of medium osmolality (10, 25, 50, 75, 100 and 200mOsmolkg-1) and PDE inhibitors (control, 2.5mM caffeine, 5mM caffeine, 2.5mM pentoxifylline, 5mM pentoxifylline, 2.5mM theophylline and 5mM theophylline) on initial activation, percentage sperm motility and sperm velocity were quantified using computer-assisted sperm analysis. To assess the effect of PDE inhibitors (control, 2.5mM caffeine and 2.5mM theophylline) on sperm longevity, percentage motility and velocity were assessed hourly until 10h after activation. High (>60%) percentage motility was achieved in a broad range of activation-medium osmolalities (10-75mOsmolkg-1). PDE inhibitors did not have an effect on initial sperm motility or velocity, but caffeine and theophylline improved sperm longevity, significantly increasing motility and velocity at 8, 9 and 10h after activation. Data also show that sperm longevity in L. booroolongensis is extreme, with spermatozoa remaining motile more than twice as long as those of any other anuran amphibian. PMID- 28359015 TI - Brain-focused care in the neonatal intensive care unit: the time has come. PMID- 28359016 TI - Reconstruction of Mandible: A Fully Digital Workflow From Visualized Iliac Bone Grafting to Implant Restoration. AB - PURPOSE: Although digital aids can help surgeons compensate for the shortcomings of traditional mandibular reconstruction techniques to perform surgery more precisely and effectively, the use of these digital techniques has often been fragmented, divided, and incomplete. This article describes the workflow of a fully digital mandibular reconstruction to explore the proper indications and discusses innovations based on the accuracy and effectiveness of digital techniques. MATERIALS AND METHODS: A restoration-oriented mandibular reconstruction was performed by applying different digital techniques. Preoperative virtual surgery and rapid prototyping were used to aid the vascularized iliac bone graft surgery, which offered a solid basis for the ensuing treatment. Subsequently, implant rehabilitation was accomplished with the assistance of computer-assisted design and manufacture, laser treatment, and selective laser melting techniques. RESULT: The workflow of the fully digital mandibular reconstruction successfully achieved a restoration-oriented treatment. These predictable, accurate, and effective digital techniques improved the consistency of pretreatment design and follow-up treatment. The treatment sequence achieved high predictability and reproducibility owing to the use of digital techniques. CONCLUSION: This study shows that a digital workflow can be predictable, accurate, and effective, which suggests that it could be a valid digital protocol for developing a treatment sequence for patients with jaw defects caused by trauma, congenital anomalies, or mandibular tumor resection. PMID- 28359019 TI - Editorial Comment. PMID- 28359018 TI - Scalable fabrication of size-controlled chitosan nanoparticles for oral delivery of insulin. AB - Controlled delivery of protein would find diverse therapeutic applications. Formulation of protein nanoparticles by polyelectrolyte complexation between the protein and a natural polymer such as chitosan (CS) is a popular approach. However, the current method of batch-mode mixing faces significant challenges in scaling up while maintaining size control, high uniformity, and high encapsulation efficiency. Here we report a new method, termed flash nanocomplexation (FNC), to fabricate insulin nanoparticles by infusing aqueous solutions of CS, tripolyphosphate (TPP), and insulin under rapid mixing condition (Re > 1600) in a multi-inlet vortex mixer. In comparison with the bulk-mixing method, the optimized FNC process produces CS/TPP/insulin nanoparticles with a smaller size (down to 45 nm) and narrower size distribution, higher encapsulation efficiency (up to 90%), and pH-dependent nanoparticle dissolution and insulin release. The CS/TPP/insulin nanoparticles can be lyophilized and reconstituted without loss of activity, and produced at a throughput of 5.1 g h-1 when a flow rate of 50 mL min-1 is used. Evaluated in a Type I diabetes rat model, the smaller nanoparticles (45 nm and 115 nm) control the blood glucose level through oral administration more effectively than the larger particles (240 nm). This efficient, reproducible and continuous FNC technique is amenable to scale-up in order to address the critical barrier of manufacturing for the translation of protein nanoparticles. PMID- 28359020 TI - Editorial Comment. PMID- 28359022 TI - Reply by Authors. PMID- 28359021 TI - Editorial Comment. PMID- 28359017 TI - An investigation of doubt in obsessive-compulsive disorder. AB - BACKGROUND: Clinicians have long considered doubt to be a fundamental characteristic of obsessive-compulsive disorder (OCD). However, the clinical relevance of doubt in OCD has not been addressed. METHODS: Participants included 1182 adults with OCD who had participated in family and genetic studies of OCD. We used a clinical measure of the severity of doubt, categorized as none, mild, moderate, severe, or extreme. We evaluated the relationship between doubt and OCD clinical features, Axis I disorders, personality and personality disorder dimensions, impairment, and treatment response. RESULTS: The severity of doubt was inversely related to the age at onset of OCD symptoms. Doubt was strongly related to the number of checking symptoms and, to a lesser extent, to the numbers of contamination/cleaning and hoarding symptoms. Doubt also was related to the lifetime prevalence of recurrent major depression and generalized anxiety disorder; to the numbers of avoidant, dependent, and obsessive-compulsive personality disorder traits; and to neuroticism and introversion. Moreover, doubt was strongly associated with global impairment and poor response to cognitive behavioral treatment (CBT), even adjusting for OCD severity and other correlates of doubt. CONCLUSIONS: Doubt is associated with important clinical features of OCD, including impairment and cognitive-behavioral treatment response. PMID- 28359023 TI - Editorial Comment. PMID- 28359024 TI - Editorial Comment. PMID- 28359025 TI - Reply by Authors. PMID- 28359026 TI - Editorial Comment. PMID- 28359027 TI - Predictors of postoperative bleeding in children undergoing cardiopulmonary bypass: A preliminary Italian study. AB - BACKGROUND: Several characteristics such as demographics, pre-existing conditions, surgical procedure, perioperative coagulopathy may predispose children undergoing cardiopulmonary bypass (CPB) to bleeding complications. As yet, studies on risk factors for postoperative bleeding have brought mixed results. The purpose of our study was therefore to retrospectively evaluate the parameters able to predict postoperative bleeding in a group of consecutive children undergoing cardiac surgery involving CPB. METHODS: We collected demographic and perioperative laboratory data, as well as intraoperative transfusion requirements and blood loss during the first 24h after surgery in a group of consecutive children (aged >=1month) scheduled for cardiac surgery with CPB at Padua University Hospital between June 2014 and April 2015. Cases were patients who experienced a 24-h postoperative blood loss >=80th percentile. Univariate and multivariate logistic regression analyses were performed to determine the independent parameters associated with a high 24-h postoperative chest tube drainage volume. RESULTS: Eighty-three children (M:F 38:45; age range 1-168months) were enrolled. Age<7.7months (p 0.015), postoperative platelets <109*109/L (p 0.003) and postoperative D-dimer >=2350MUg/L (p 0.007) were the variables most significantly and independently associated with excessive 24-h postoperative blood loss. CONCLUSIONS: Although preliminary, our study identified younger age, lower postoperative platelet count and higher D-dimer plasma levels as possible risk factors for postoperative bleeding. As for coagulation parameters, our results suggested consumptive coagulopathy might cause a strong predisposition to postoperative bleeding in children. Large-scale prospective studies would provide insight into the early diagnosis and treatment of CPB related coagulopathies. PMID- 28359028 TI - Poetry as an engagement strategy: A novice teacher experience of its use within lectures. AB - It has been acknowledged the traditional lecture format is a familiar teaching methodology and that there is still much to be learnt from using this in class room based lectures. Whilst the first author was a postgraduate student undertaking a programme in Nurse Education at a University in the Republic of Ireland, poetry was used to challenge undergraduate nursing students' attitudes towards older persons in a large group format. The students were in Year 3 of a Bachelor of Nursing Science General and Intellectual Disability Programmes. Feedback was obtained from the students that comprised of three main themes; Aids Recall of Information; Enriched Learning Experiences, Challenges Attitudes to Person Centred Care. Thus, the paper aims to evaluate using poetry as an engaging teaching strategy within a lecture format for the first time as a novice teacher when drawing out nursing students' attitudes towards older persons with a focus on supporting them in embracing key care skills in the clinical setting. This paper should provide other student educationalists the opportunity to see the value of poetry as a teaching strategy and provide practical tips on its use within the classroom. PMID- 28359029 TI - Is there immune surveillance against chronic myeloid leukaemia? Possibly, but not much. PMID- 28359030 TI - Increase of DNA damage and alteration of the DNA damage response in myelodysplastic syndromes and acute myeloid leukemias. AB - Increased DNA damage and alteration of the DNA damage response (DDR) are critical features of genetic instability presumably implicated in pathogenesis of myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). We used immunofluorescence staining of gammaH2AX and 53BP1 for analyzing DNA double strand breaks (DSB) in MDS and AML cell lines, in CD34+ selected cells of normal and MDS bone marrow (including three cases of chronic myelomonocytic leukemias) and in blasts of AML bone marrow. In addition, we screened for activation of the DDR by immunoblotting of p-ATM, p-ATR, p-CHK1, p-CHK2 and p-TP53. As compared to gammaH2AX foci levels in normal bone marrow samples (0.2 focus per CD34+ cell+/ 0.0; mean+/-standard error of mean), increased levels of gammaH2AX foci were detected in 16/16 MDS bone marrow samples (2.8 foci per CD34+ cell+/-0.5), 18/18 AML bone marrow samples (5.5 foci per blast+/-0.5), 1/1 MDS cell line (6.4 foci per cell) and 6/6 AML cell lines (12.0 foci per cell+/-0.6). gammaH2AX and 53BP1 co-localized in all tested samples forming diffuse, clustered and marginal patterns. Further, DDR proteins were expressed heterogeneously suggesting impairment of the DDR. In summary, our results provide evidence for a continuous increase of DSB across the spectrum from MDS to AML in conjunction with an impaired DDR. Co-localization of gammaH2AX and 53BP1 indicates promotion of (in)effective nonhomologous end-joining repair mechanisms at sites of DSB. Moreover, gammaH2AX/53BP1 foci distribution presumably reveals a non-random spatial organization of the genome in MDS and AML. PMID- 28359031 TI - Emergence of depression following job loss prospectively predicts lower rates of reemployment. AB - Job loss has been associated with the emergence of depression and subsequent long term diminished labor market participation. In a sample of 500 adults who lost their jobs, trajectories of depression severity from four years before to four years after job loss were identified using Latent Growth Mixture Modeling. Rates of unemployment by trajectory were compared at two and four years following job loss. Four trajectories demonstrated optimal model fit including resilience (72%), chronic pre-to-post job loss depression (9%), emergent depression (10%), and remitting depression (9%). Logistic regression comparing reemployment status by class while controlling for age, gender, and education at two-years post job loss revealed no significant differences by class. An identical logistic regression on four-year reemployment revealed significant differences by class with post-hoc analyses revealing emergent depression resulting in a 33.3% reemployment rate compared to resilient individuals (60.4%) together indicating that depression affects reemployment rather than lack of reemployment causing the emergence of depression. The emergence of depression following job loss significantly increases the risk of continued unemployment. However, observed high rates of resilience with resulting downstream benefits in reemployment mitigates significant concern about the effects of wide spread unemployment on ongoing global economic recovery following the Great Recession. PMID- 28359033 TI - Regulation of memory B and plasma cell differentiation. AB - Memory B cell generation and antibody production result from a differentiation process that begins when the surface BCR on naive B cells binds an antigen. How the choice between these fates is tempo-spatially regulated is still obscure, but recent advances have reinforced the concept that the combination of B cell intrinsic heterogeneity and -extrinsic heterogeneity provided by cells such as T cells is a key determinant. As molecular regulators, the transcription factors IRF4 and Bach2, which participate in these fate choices, have been emerging. PMID- 28359032 TI - Psychometrics of the screen for adult anxiety related disorders (SCAARED)- A new scale for the assessment of DSM-5 anxiety disorders. AB - OBJECTIVE: To examine the psychometrics of the Screen for Adult Anxiety Related Disorders (SCAARED). METHODS: The SCAARED was adapted from the Screen for Child Anxiety Related Emotional Disorders. Participants (N=336) ages 18-27 years old were evaluated using the Structured Clinical Interview for DSM-IV Disorders (SCID). The SCAARED was completed at or within two-weeks before the SCID. The psychometrics of the SCAARED were analyzed using standard statistical analyses including principal components, and Receiver Operant Curve analyses. A replication was performed in an age/sex matched independent sample (N=158). RESULTS: The SCAARED showed four factors: somatic/panic/agoraphobia, generalized anxiety, separation anxiety, and social anxiety. The total and each factor scores demonstrated good internal consistency (alpha=0.86-0.97) and good discriminant validity between anxiety and other disorders and within anxiety disorders for generalized and social anxiety. Area Under the Curve for the total and each of the factor scores ranged between 0.72 and 0.84 (p<0.0001). These results were replicated in the independent sample. CONCLUSIONS: The SCAARED showed excellent psychometric properties supporting its use to screen adults for anxiety disorders, longitudinal studies following youth into adulthood and studies comparing child and adult populations. Further replication studies in larger community and clinical samples are indicated. PMID- 28359034 TI - Effect of androgen supplementation on 24-hour activity-rest patterns of aged male rhesus macaques. AB - Like elderly men, old male rhesus macaques show attenuated circulating levels of testosterone and dehydroepiandrosterone sulfate, and many of them also show reduced levels of daytime activity. It is unclear, however, if this age associated behavioral change is causally related to the underlying decrease in circulating androgen levels. To test this possibility, old male rhesus macaques were given daily supplements of testosterone and DHEA for 6 months, designed to mimic the mean 24-hour circulating hormone patterns of young adults. Compared with the young adults, the old controls showed attenuated daytime activity levels. However, there was no difference between the androgen-supplemented old animals and the aged-matched controls, even after 6 months of treatment. The data suggest that age-associated decreases in circulating androgen levels are unlikely to be a primary reason for altered activity-rest patterns in elderly men, and that androgen supplementation paradigms might not provide any obvious therapeutic benefit. PMID- 28359035 TI - Design of MnO2/CeO2-MnO2 hierarchical binary oxides for elemental mercury removal from coal-fired flue gas. AB - MnO2/CeO2-MnO2 hierarchical binary oxide was synthesized for elemental mercury (Hg0) removal from coal-fired flue gas. CeO2 in-situ grow on the surface of carbon spheres, and that CeO2@CSs acted as precursor for porous MnO2/CeO2-MnO2. XRD, Raman, XPS, FT-IR, and H2-TPR were selected for the physical structural and chemical surface analysis. The results indicated that the composite has sufficient surface oxygen and hierarchical porous structure. The Hg0 removal experiments results indicated that MnO2/CeO2-MnO2 exhibited excellent Hg0 removal performance, with an 89% removal efficiency of total 300min at 150 degrees C under 4% O2. MnO2 was the primary active site for Hg0 catalytic oxidation. The porous structure was beneficial for gaseous mercury physically adsorption. In addition, CeO2 enhanced the oxygen capture performance of the composite and the oxidation performance for MnO2. Moreover, the effects of O2, SO2 and H2O were also tested in this study. O2 promoted the Hg0 removal reaction. While SO2 and H2O can poison the MnO2 active site, resulted in a low Hg0 removal efficiency. PMID- 28359036 TI - Treatment technologies used for the removal of As, Cr, Cu, PCP and/or PCDD/F from contaminated soil: A review. AB - The contamination of soils by metals such as arsenic, chromium, copper and organic compounds such as pentachlorophenol (PCP) and dioxins and furans (PCDD/F) is a major problem in industrialized countries. Excavation followed by disposal in an appropriate landfilling is usually used site to manage these contaminated soils. Many researches have been conducted to develop physical, biological, thermal and chemical methods to allow the rehabilitation of contaminated sites. Thermal treatments including thermal desorption seemed to be the most appropriate methods, allowing the removal of more than 99.99% of organic contaminants but, they are ineffective for inorganic compounds. Biological treatments have been developed to remove inorganic and hydrophobic organic contaminants but their applications are limited to soils contaminated by easily biodegradable organic compounds. Among the physical technologies available, attrition is the most commonly used technique for the rehabilitation of soils contaminated by both organic and inorganic contaminants. Chemical processes using acids, bases, redox agents and surfactants seemed to be an interesting option to simultaneously extract organic and inorganic contaminants from soils. This paper will provide an overview of the recent developments in the field of decontamination technologies applicable for the removal of As, Cr, Cu, PCP and/or PCDD/F from contaminated soils. PMID- 28359037 TI - Effects of CO2/N2 dilution on laminar burning velocity of stoichiometric DME-air mixture at elevated temperatures. AB - The laminar burning velocity of CO2/N2 diluted stoichiometric dimethyl ether (DME) air mixtures is determined experimentally at atmospheric pressure and elevated mixture temperatures using a mesoscale high aspect-ratio diverging channel with inlet dimensions of 25mm*2mm. In this method, planar flames at different initial temperatures (Tu) were stabilized inside the channel using an external electric heater. The magnitude of burning velocities was acquired by measuring the flame position and initial temperature. The mass conservation of the mixture entering the inlet and the stationary planar flame front is applied to obtain the laminar burning velocity. Laminar burning velocity at different initial mixture temperatures is plotted with temperature ratio (Tu/Tu,o), where a reference temperature (Tu,o) of 300K is used. Enhancement in the laminar burning velocity is observed with mixture temperature for DME-air mixtures with CO2 and N2 dilutions. A significant decrease in the burning velocity and slight increase in temperature exponent of the stoichiometric DME-air mixture was observed with dilution at same temperatures. The addition of CO2 has profound influence when compared to N2 addition on both burning velocity and temperature exponent. PMID- 28359038 TI - Dual-porosity Mn2O3 cubes for highly efficient dye adsorption. AB - Dual-porosity materials containing both macropores and mesopores are highly desired in many fields. In this work, we prepared dual-porosity Mn2O3 cube materials with large-pore mesopores, in which, macropores are made by using carbon spheres as the hard templates, while the mesopores are produced via a template-free route. The attained dual-porosity Mn2O3 materials have 24nm of large-pore mesopores and 700nm of macropores. Besides, the achieved materials own cubic morphologies with particle sizes as large as 6.0MUm, making them separable in the solution by a facile natural sedimentation. Dye adsorption measurements reveal that the dual-porosity materials possess a very high maximum adsorption capacity of 125.6mg/g, much larger than many reported materials. Particularly, the adsorbents can be recycled and the dye removal efficiency can be well maintained at 98% after four cycles. Adsorption isotherm and kinetics show that the Langmuir model and the pseudo-second-order kinetics model can well describe the adsorption process of Congo Red on the dual-porosity Mn2O3 cube materials. In brief, the reported dual-porosity Mn2O3 demonstrates a good example for controlled preparation of dual-porosity materials with large-pore mesopores, and the macropore-mesopore dual-porosity distribution is good for mass transfer in dye adsorption application. PMID- 28359039 TI - Spatiotemporal patterns of paralytic shellfish toxins and their relationships with environmental variables in British Columbia, Canada from 2002 to 2012. AB - BACKGROUND: Harmful algal blooms produce paralytic shellfish toxins that accumulate in the tissues of filter feeding shellfish. Ingestion of these toxic shellfish can cause a serious and potentially fatal condition known as paralytic shellfish poisoning (PSP). The coast of British Columbia is routinely monitored for shellfish toxicity, and this study uses data from the monitoring program to identify spatiotemporal patterns in shellfish toxicity events and their relationships with environmental variables. METHODS: The dinoflagellate genus Alexandrium produces the most potent paralytic shellfish toxin, saxitoxin (STX). Data on all STX measurements were obtained from 49 different shellfish monitoring sites along the coast of British Columbia for 2002-2012, and monthly toxicity events were identified. We performed hierarchical cluster analysis to group sites that had events in similar areas with similar timing. Machine learning techniques were used to model the complex relationships between toxicity events and environmental variables in each group. RESULTS: The Strait of Georgia and the west coast of Vancouver Island had unique toxicity regimes. Out of the seven environmental variables used, toxicity in each cluster could be described by multivariable models including monthly sea surface temperature, air temperature, sea surface salinity, freshwater discharge, upwelling, and photosynthetically active radiation. The sea surface salinity and freshwater discharge variables produced the strongest univariate models for both geographic areas. CONCLUSIONS: Applying these methods in coastal regions could allow for the prediction of shellfish toxicity events by environmental conditions. This has the potential to optimize biotoxin monitoring, improve public health surveillance, and engage the shellfish industry in helping to reduce the risk of PSP. PMID- 28359040 TI - Comparison of spatiotemporal prediction models of daily exposure of individuals to ambient nitrogen dioxide and ozone in Montreal, Canada. AB - BACKGROUND: In previous studies investigating the short-term health effects of ambient air pollution the exposure metric that is often used is the daily average across monitors, thus assuming that all individuals have the same daily exposure. Studies that incorporate space-time exposures of individuals are essential to further our understanding of the short-term health effects of ambient air pollution. OBJECTIVES: As part of a longitudinal cohort study of the acute effects of air pollution that incorporated subject-specific information and medical histories of subjects throughout the follow-up, the purpose of this study was to develop and compare different prediction models using data from fixed-site monitors and other monitoring campaigns to estimate daily, spatially-resolved concentrations of ozone (O3) and nitrogen dioxide (NO2) of participants' residences in Montreal, 1991-2002. METHODS: We used the following methods to predict spatially-resolved daily concentrations of O3 and NO2 for each geographic region in Montreal (defined by three-character postal code areas): (1) assigning concentrations from the nearest monitor; (2) spatial interpolation using inverse distance weighting; (3) back-extrapolation from a land-use regression model from a dense monitoring survey, and; (4) a combination of a land-use and Bayesian maximum entropy model. We used a variety of indices of agreement to compare estimates of exposure assigned from the different methods, notably scatterplots of pairwise predictions, distribution of differences and computation of the absolute agreement intraclass correlation (ICC). For each pairwise prediction, we also produced maps of the ICCs by these regions indicating the spatial variability in the degree of agreement. RESULTS: We found some substantial differences in agreement across pairs of methods in daily mean predicted concentrations of O3 and NO2. On a given day and postal code area the difference in the concentration assigned could be as high as 131ppb for O3 and 108ppb for NO2. For both pollutants, better agreement was found between predictions from the nearest monitor and the inverse-distance weighting interpolation methods, with ICCs of 0.89 (95% confidence interval (CI): 0.89, 0.89) for O3 and 0.81 (95%CI: 0.80, 0.81) for NO2, respectively. For this pair of methods the maximum difference on a given day and postal code area was 36ppb for O3 and 74ppb for NO2. The back-extrapolation method showed a higher degree of disagreement with the nearest monitor approach, inverse-distance weighting interpolation, and the Bayesian maximum entropy model, which were strongly constrained by the sparse monitoring network. The maps showed that the patterns of agreement differed across the postal code areas and the variability depended on the pair of methods compared and the pollutants. For O3, but not NO2, postal areas showing greater disagreement were mostly located near the city centre and along highways, especially in maps involving the back-extrapolation method. CONCLUSIONS: In view of the substantial differences in daily concentrations of O3 and NO2 predicted by the different methods, we suggest that analyses of the health effects from air pollution should make use of multiple exposure assessment methods. Although we cannot make any recommendations as to which is the most valid method, models that make use of higher spatially resolved data, such as from dense exposure surveys or from high spatial resolution satellite data, likely provide the most valid estimates. PMID- 28359041 TI - Ambient temperature and cardiovascular biomarkers in a repeated-measure study in healthy adults: A novel biomarker index approach. AB - BACKGROUND: Associations of ambient temperature with cardiovascular morbidity and mortality have been well documented in numerous epidemiological studies, but the underlying pathways remain unclear. We investigated whether systemic inflammation, coagulation, systemic oxidative stress, antioxidant activity and endothelial function may be the mechanistic pathways associated with ambient temperature. METHODS: Forty study participants underwent repeated blood collections for 12 times in Beijing, China in 2010-2011. Ambient temperature and air pollution data were measured in central monitors close to student residences. We created five indices as the sum of weighted biomarker percentiles to represent the overall levels of 15 cardiovascular biomarkers in five pathways (systemic inflammation: hs-CRP, TNF-alpha and fibrinogen; coagulation: fibrinogen, PAI-1, tPA, vWF and sP-selectin; systemic oxidative stress: Ox-LDL and sCD36: antioxidant activity: EC-SOD and GPX1; and endothelial function: ET-1, E selectin, ICAM-1 and VCAM-1). We used generalized mixed-effects models to estimate temperature effects controlling for air pollution and other covariates. RESULTS: There were significant decreasing trends in the adjusted means of biomarker indices over the lowest to the highest quartiles of daily temperatures before blood collection. A 10 degrees C decrease at 2-d average daily temperature were associated with increases of 2.5% [95% confidence interval (CI): 0.7, 4.2], 1.6% (95% CI: 0.1, 3.1), 2.7% (95% CI: 0.5, 4.8), 5.5% (95% CI: 3.8, 7.3) and 2.0% (95% CI: 0.3, 3.8) in the indices for systemic inflammation, coagulation, systemic oxidative stress, antioxidant activity and endothelial function, respectively. In contrast, the associations between ambient temperature and individual biomarkers had substantial variation in magnitude and strength. CONCLUSIONS: The altered cardiovascular biomarker profiles in healthy adults associated with ambient temperature changes may help explain the temperature related cardiovascular morbidity and mortality. The biomarker index approach may serve as a novel tool to capture ambient temperature effects. PMID- 28359042 TI - Mass extinction efficiency and extinction hygroscopicity of ambient PM2.5 in urban China. AB - The ambient PM2.5 pollution problem in China has drawn substantial international attentions. The mass extinction efficiency (MEE) and hygroscopicity factor (f(RH)) of PM2.5 can be readily applied to study the impacts on atmospheric visibility and climate. The few previous investigations in China only reported results from pilot studies and are lack of spatial representativeness. In this study, hourly average ambient PM2.5 mass concentration, relative humidity, and atmospheric visibility data from China national air quality and meteorological monitoring networks were retrieved and analyzed. It includes 24 major Chinese cities from nine city-clusters with the period of October 2013 to September 2014. Annual average extinction coefficient in urban China was 759.3+/-258.3Mm-1, mainly caused by dry PM2.5 (305.8.2+/-131.0Mm-1) and its hygroscopicity (414.6+/ 188.1Mm-1). High extinction coefficient values were resulted from both high ambient PM2.5 concentration (68.5+/-21.7ug/m3) and high relative humidity (69.7+/ 8.6%). The PM2.5 mass extinction efficiency varied from 2.87 to 6.64m2/g with an average of 4.40+/-0.84m2/g. The average extinction hygroscopic factor f(RH=80%) was 2.63+/-0.45. The levels of PM2.5 mass extinction efficiency and hygroscopic factor in China were in comparable range with those found in developed countries in spite of the significant diversities among all 24 cities. Our findings help to establish quantitative relationship between ambient extinction coefficient (visual range) and PM2.5 & relative humidity. It will reduce the uncertainty of extinction coefficient estimation of ambient PM2.5 in urban China which is essential for the research of haze pollution and climate radiative forcing. PMID- 28359043 TI - How representative are dissolved organic matter (DOM) extracts? A comprehensive study of sorbent selectivity for DOM isolation. AB - Solid phase extraction (SPE) has become a widespread method for isolating dissolved organic matter (DOM) of diverse origin such as fresh and marine waters. This study investigated the DOM extraction selectivity of 24 commercially available SPE sorbents under identical conditions (pH = 2, methanol elution) on the example of Suwannee River (SR) water and North Sea (NS) water by using DOC analysis and Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). Proton nuclear magnetic resonance (1H NMR) spectroscopy was employed to assess leaching behavior, and HLB sorbent was found to leach substantially, among others. Variable DOC recoveries observed for SR DOM and NS DOM were primarily caused by the respective molecular composition, with subordinated and heterogeneous contributions of relative salinity. Scatter of average H/C and O/C elemental ratios and gross alignment in mass-edited H/C ratios according to five established coarse SPE characteristics was near identical for SR DOM and NS DOM. FTMS-based principal component analysis (PCA) provided essentially analogous alignment of SR DOM and NS DOM molecular compositions according to the five established groups of SPE classification, and corroborated the sorption-mechanism based selectivity of DOM extraction in both cases. Evaluation of structural blanks and leaching of SPE cartridges requires NMR spectroscopy because FT-ICR mass spectrometry alone will not reveal inconspicuous displacements of continual bulk signatures caused by leaching of SPE resin constituents. PMID- 28359044 TI - Bicarbonate-activated persulfate oxidation of acetaminophen. AB - Persulfate (PS) is widely used as an oxidant for in situ chemical remediation of contaminated groundwater. In this study we demonstrated for the first time that PS could be activated by bicarbonate. Acetaminophen was used as the probe compound to examine the reactivity of PS/bicarbonate system. It was found that acetaminophen could be effectively transformed and the reaction rate appeared pseudo-first-order to the concentrations of both acetaminophen and PS. Radical scavenger tests indicated that neither free radicals (SO4- and HO) nor superoxide (O2-) was responsible for acetaminophen transformation. Generation of singlet oxygen (1O2) was verified using furfuryl alcohol (FFA) as a probe. Formation of 1O2 was further quantified in D2O fortified solution based on kinetic solvent isotopic effect (KSIE) but it was found that 1O2 contributed only 51.4% of the total FFA transformation. The other 48.6% was presumed to be ascribed to the reaction with peroxymonocarbonate (HCO4-). However, the transformation of acetaminophen was mostly due to the reaction with HCO4- but not 1O2. Instead of degradation, HCO4- oxidized acetaminophen via a one-electron abstraction mechanism resulting in the generation of acetaminophen radicals which coupled to each other to form dimers and trimers. HCO4- also hydrolyzed rapidly to form hydrogen peroxide (H2O2) which led to the formation of 1O2, during which O2- was a key intermediates. Because bicarbonate is ubiquitously presented in groundwater, the findings of this research provide important insights into the fundamental processes involved in PS oxidation in subsurface. PMID- 28359046 TI - Evaluating 130 microhaplotypes across a global set of 83 populations. AB - Today the primary DNA markers used in forensics are short tandem repeat (STR) polymorphisms (STRPs), initially selected because they are highly polymorphic. However, the increasingly common need to deal with samples with a mixture of DNA from two or more individuals sometimes is complicated by the inherent stutter involved with PCR amplification, especially in strongly unbalanced mixtures when the minor component coincides with the stutter range of the major component. Also, the STRPs in use provide little evidence of ancestry of a single source sample beyond broad "continental" resolution. Methodologies for analyzing DNA have become much more powerful in recent years. Massively parallel sequencing (MPS) is a new method being considered for routine use in forensics. Primarily to aid in mixture deconvolution and avoid the issue of stutter, we have begun to investigate a new type of forensic marker, microhaplotype loci, that will provide useful information on mixtures of DNA and on ancestry when typed using massively parallel sequencing (MPS). We have identified 130 loci and estimated their haplotype (allele) frequencies in 83 different population samples. Many of these loci are shown to be highly informative for individual identification and for mixture identification and deconvolution. PMID- 28359045 TI - Design, synthesis and biological evaluation of novel nitric oxide-donating protoberberine derivatives as antitumor agents. AB - A novel class of NO-donating protoberberine derivatives were synthesized and initially evaluated for their anti-hepatocellular carcinoma activities. Most of the compounds exhibited more potent activity against HepG2 cells than parent compounds berberine and palmatine. In particular, compound 15a exerted the strongest activity with an IC50 value of 1.36 MUM. Moreover, most compounds released moderate levels of NO in vitro, and the antitumor activity of 15a in HepG2 cells was remarkably diminished by an NO scavenger. Interestingly, compound 15a displayed a broad-spectrum antitumor efficacy and possessed good selectivity between tumor cells (HepG2, SMMC-7721, HCT-116, HL-60) and normal liver LO-2 cells. The mechanism studies revealed that 15a blocked the G2 phase of the cell cycle and induced apoptosis of HepG2 cells by mitochondrial depolarization. Furthermore, 15a inhibited tumor growth in H22 liver cancer xenograft mouse model by 62.5% (w/w), which was significantly superior to parent compound palmatine (41.6%, w/w). Overall, the current study may provide a new approach for the discovery of novel antitumor agents. PMID- 28359047 TI - Medical Infrared Thermography assistance in the surgical treatment of axillary Hidradenitis Suppurativa: A case report. AB - BACKGROUND: The purpose of this case report is to highlight for the first time the way Medical Infrared Thermography can be a helpful tool to assist the surgeon in the surgical treatment of Hidradenitis Suppurativa inflammatory disease. METHODS: A 36-year-old man with a 7-year history of Hidradenitis Suppurativa presented inflammatory nodules in the left axilla area corresponding to Hurley stage II. Choice is made to surgically treat this patient using a wide excision protocol combined with a postoperative second intention healing. For the study purpose, an IR FLIR SC620 camera (FLIR Systems, Wilsonville, OR), having a high resolution pixel detector of 640*480 pixels for greater accuracy and higher resolution, has been used. RESULTS: For the first time in the literature, this case report on HS disease supports the idea that real-time medical infrared thermography may be helpful in establishing the true extent of disease preoperatively in the surgical room and in a similar manner, that this technique allows the surgeon to ensure all diseased lesions are removed during surgery. CONCLUSIONS: At least, medical infrared thermography seems to be a powerful tool to control the final wide surgical wound, in order to minimize recurrence risk of such a disease. PMID- 28359049 TI - Improved Neural Regeneration with Olfactory Ensheathing Cell Inoculated PLGA Scaffolds in Spinal Cord Injury Adult Rats. AB - BACKGROUND/AIMS: Every year, around the world, between 250000 and 500000 people suffer from spinal cord injury (SCI). This study investigated the potential for poly (lactic-co-glycolic acid) (PLGA) complex inoculated with olfactory ensheathing cells (OECs) to treat spinal cord injury in a rat model. METHODS: OECs were identified by immunofluorescence based on the nerve growth factor receptor (NGFR) p75. The Basso, Beattie, and Bresnahan (BBB) score, together with an inclined plane (IP) test were used to detect functional recovery. Nissl staining along with the luxol fast blue (LFB) staining were independently employed to illustrate morphological alterations. More so, immunofluorescence labeling of the glial fibrillary acidic protein (GFAP) and the microtubule associated protein-2 (MAP-2), representing astrocytes and neurons respectively, were investigated at time points of weeks 2 and 8 post-operation. RESULTS: The findings showed enhanced locomotor recovery, axon myelination and better protected neurons post SCI when compared with either PLGA or untreated groups (P < 0.05). CONCLUSION: PLGA complexes inoculated with OECs improve locomotor functional recovery in transected spinal cord injured rat models, which is most likely due to the fact it is conducive to a relatively benevolent microenvironment, has nerve protective effects, as well as the ability to enhance remyelination, via a promotion of cell differentiation and inhibition of astrocyte formation. PMID- 28359048 TI - Inhibition of herpes simplex-1 virus replication by 25-hydroxycholesterol and 27 hydroxycholesterol. AB - Oxysterols are known pleiotropic molecules whose antiviral action has been recently discovered. Here reported is the activity of a panel of oxysterols against HSV-1 with the identification of a new mechanism of action. A marked antiviral activity not only of 25HC but also of 27HC against HSV-1 was observed either if the oxysterols were added before or after infection, suggesting an activity unrelated to the viral entry inhibition as proposed by previous literature. Therefore, the relation between the pro-inflammatory activity of oxysterols and the activation of NF-kB and IL-6 induced by HSV-1 in the host cell was investigated. Indeed, cell pre-incubation with oxysterols further potentiated IL-6 production as induced by HSV-1 infection with a consequent boost of the interleukin's total cell secretion. Further, a direct antiviral effect of IL-6 administration to HSV-1 infected cells was demonstrated, disclosing an additional mechanism of antiviral action by both 25HC and 27HC. PMID- 28359050 TI - TAK-242 Protects Against Apoptosis in Coronary Microembolization-Induced Myocardial Injury in Rats by Suppressing TLR4/NF-kappaB Signaling Pathway. AB - BACKGROUND/AIMS: Myocardial apoptosis is heavily implicated in the myocardial injury caused by coronary microembolization (CME), and toll-like receptor 4 (TLR4) is considered to be involved in this apoptotic cascade. Therefore, the present study was designed to investigate the role of TLR4/NF-kappaB signaling pathway regulated by TAK-242, a selective TLR4 signal transduction inhibitor, in the myocardial apoptosis after CME in rats. METHODS: Forty-five rats were randomized (random number) into three groups: sham, CME and CME + TAK-242 (n = 15 per group).CME was induced by injecting polyethylene microspheres (42um) into the left ventricular except the sham group. CME + TAK-242 group was treated with TAK 242 (2mg/kg) via the tail vein 30 minutes before CME modeling. Cardiac function was evaluated 6 hours after operation. Tissue biopsy was stained with HBFP to measure the size of micro-infarction area. TUNEL staining was used to detect myocardial apoptosis. Western blot and qPCR were used to evaluate the expression of TLR4, MyD88, NF-kappaB p65, p-IkappaBalpha and Cleaved caspase-3. RESULTS: Cardiac function in the CME group and CME + TAK-242 group were significantly decreased compared with the sham group (P < 0.05) and the micro-infarction area, the apoptotic index, the expression of TLR4, NF-kappaB p65, p-IkappaBalpha and Cleaved caspase-3 were increased significantly (P < 0.05). Cardiac function in the CME + TAK-242 group was significantly improved compared with the CME group (P < 0.05) and the micro-infarction area, the apoptotic index, the expression of TLR4, MyD88, NF-kappaB p65, p-IkappaBalpha and Cleaved caspase-3 were decreased significantly (P < 0.05). CONCLUSIONS: TAK-242 can effectively improve CME induced cardiac dysfunction by regulating TLR4/NF-kappaB signaling pathway and then reducing the myocardial apoptosis. PMID- 28359052 TI - Association of Interleukin-10 Polymorphisms (rs1800872, rs1800871, and rs1800896) with Predisposition to IgA Nephropathy in a Chinese Han Population: A Case Control Study. AB - BACKGROUND/AIMS: IgA nephropathy (IgAN) is a common form of primary glomerulonephritis worldwide. Previous studies indicated that IL-10 single nucleotide polymorphisms (SNP) play an important role in IgAN pathogenesis, but the results were controversy. This study aimed to investigate the association between IL-10 SNPs (rs1800872, rs1800871, and rs1800896) with IgAN in a Chinese Han population. METHODS: We conducted a case-control study that included 351 patients with IgAN and 310 age-, gender- and ethnicity-matched healthy controls. Three promoter SNPs (rs1800872, rs1800871, and rs1800896) of IL-10 were genotyped by Sequenom MassARRAY. Odds ratios (ORs) with 95% confidence intervals (CI) were used to assess the relationship with IgAN. RESULTS: We found that the rs1800896 did not correlate with IgAN risk, whereas rs1800872 and rs1800871 were significantly associated with increased IgAN risk in all genetic models. The haplotype analysis indicated that the CCA haplotype was associated with increased IgAN risk (OR = 1.36; 95% CI = 1.05-1.75). Moreover, there were no associations between these SNPs and blood pressure or gender, whereas the rs1800896 variant was correlated with higher 24-hour urine protein in patients with IgAN. CONCLUSION: Taken together, these results suggest that IL-10 is a susceptibility gene in patients with IgAN. PMID- 28359051 TI - Postradiation Matrix Metalloproteinase-20 Expression and Its Impact on Dental Micromorphology and Radiation-Related Caries. AB - Recent evidence suggests that head-and-neck radiotherapy (HNRT) increases active forms of matrix metalloproteinase-20 (MMP-20) in human tooth crowns, degrading the dentin-enamel junction (DEJ) and leading to enamel delamination, which is a pivotal step in the formation of radiation-related caries (RRC). Additional participation of enzymatic degradation of organic matrix components in caries progression was attributed to MMP-20 in dentin. Therefore, the current study tested the hypothesis that MMP-20 is overexpressed in the DEJ, dentin-pulp complex components, and carious dentin of post-HNRT patients, leading to detectable micromorphological changes to the enamel and dentin. Thirty-six teeth were studied, including 19 post-HNRT specimens and 17 nonirradiated controls. Optical light microscopy was used to investigate the micromorphological components of the DEJ, dentin-pulp complex components, and carious dentin. The samples were divided into 2 subgroups: nondemineralized ground sections (n = 20) and demineralized histological sections (n = 16). In addition, immunohistochemical analysis using the immunoperoxidase technique was conducted to semiquantitatively assess MMP-20 expression in the DEJ, dentin-pulp complex components, and carious dentin. No apparent damage to the DEJ microstructure or other dentin-pulp complex components was observed and no statistically significant differences were detected in MMP-20 expression (p > 0.05) between the irradiated and control groups. This study rejected the hypothesis that MMP-20 is overexpressed in the DEJ, dentin-pulp complex components, and carious dentin of post-HNRT patients, leading to detectable micromorphological changes. Hence, direct effects of radiation may not be regarded as an independent factor to explain aggressive clinical patterns of RRC. PMID- 28359053 TI - Platelets as a Novel Source of Pro-Inflammatory Chemokine CXCL14. AB - OBJECTIVE: Platelets are a major source of chemokines. Here, we demonstrate for the first time that platelets express significant amounts of CXCL14 and disclose powerful effects of platelet-derived CXCL14 on monocyte and endothelial migration. METHODS: The expression of CXCL14 in platelets and in the supernatant of activated platelets was analysed by immunoblotting, ELISA, and flow cytometry. The effect of platelet-derived CXCL14 on monocyte migration was evaluated using a modified Boyden chamber. The effect of CXCL14 on monocyte phagocytosis was tested by using fluorochrome-labelled E.coli particles. The effect of platelet-derived CXCL14 on endothelial migration was explored by the use of an endothelial scratch assay. RESULTS: Hitherto unrecognized expression of CXCL14 in human and murine platelets was uncovered by immunoblotting. Activation with platelet agonists such as adenosine-di-phosphate (ADP), collagen-related peptide (CRP), or thrombin receptor activating peptide (TRAP), increased CXCL14 surface expression (flow cytometry) and release into the supernatant (immunoblotting, ELISA). Since CXCL14 is known to be chemotactic for CD14+ monocytes, we investigated the chemotactic potential of platelet-derived CXCL14 on human monocytes. Activated platelet supernatant induced monocyte migration, which was counteracted upon neutralization of platelet-derived CXCL14 as compared to IgG control. Blocking of the chemokine receptor CXCR4, but not CXCR7, reduced the number of migratory monocytes towards recombinant CXCL14, suggesting the involvement of CXCR4 in the CXCL14-directed monocyte chemotaxis. Recombinant CXCL14 enhanced the phagocytic uptake of E.coli particles by monocytes. In scratch assays with cultured endothelial cells (HUVECs), platelet-derived CXCL14 counteracted the pro angiogenic effects of VEGF, supporting its previously recognized angiostatic potential. CONCLUSIONS: Platelets are a relevant source of CXCL14. Platelet derived CXCL14 at the site of vascular lesions might play an important role in vascular repair/regeneration. PMID- 28359054 TI - Cepharanthine Induces Autophagy, Apoptosis and Cell Cycle Arrest in Breast Cancer Cells. AB - BACKGROUND: Cepharanthine (CEP) is a biscoclaurine alkaloid extracted from Stephania cepharantha and has been shown to have an anti-tumour effect on different types of cancers. However, the anti-cancer effect of CEP on human breast cancer cells is still unclear. METHODS: We used MTT, clone formation, in vitro scratch, invasion and migration assays to confirm the inhibitory role of CEP on the proliferation of breast cancer cells. Flow cytometry, plasmid construction and western blot analysis were used to study the detailed mechanisms. RESULTS: Our study showed that CEP could inhibit cell proliferation by inducing autophagy, apoptosis, and G0/G1 cell cycle arrest of breast cancer cells. Furthermore, we found that CEP induced autophagy and apoptosis by inhibiting the AKT/mTOR signalling pathway. CONCLUSION: We found that CEP could inhibit growth and motility of MCF-7 and MDA-MB-231 breast cancer cell. Our study revealed an anti-tumour effect of CEP on breast cancer cells and suggests that CEP could be a potential new clinical therapy for breast cancer. PMID- 28359055 TI - Lack of Prenylated Proteins, Autophagy Impairment and Apoptosis in SH-SY5Y Neuronal Cell Model of Mevalonate Kinase Deficiency. AB - BACKGROUND/AIMS: Mevalonate Kinase Deficiency (MKD), is a hereditary disease due to mutations in mevalonate kinase gene (MVK). MKD has heterogeneous clinical phenotypes: the correlation between MVK mutations and MKD clinical phenotype is still to be fully elucidated. Deficiency of prenylated proteins has been hypothesized as possible MKD pathogenic mechanism. Based on this hypothesis and considering that neurologic impairment characterizes Mevalonic Aciduria (MA), the most severe form of MKD, we studied the effects of I268T and N301T MVK mutations on protein prenylation, autophagy and programmed cell death in SH-SY5Y neuroblastoma cell lines. METHODS: SH-SY5Y cells were transiently transfected, with the pCMV-6 plasmid containing MVK wild type and the two mutated sequences. Protein prenylation levels were evaluated using GFP-RhoA-F to assess farnesylation, and GFP-RhoA to evaluate geranylgeranylation; autophagy was measured by evaluating LC3 and p62 protein levels, while Annexin V-FITC and Propidium Iodide staining allowed apoptosis detection. RESULTS: MVK mutants' over expression causes decreased levels of farnesylation and geranylgeranylation, and also increased LC3 lipidation in SH-SY5Y, with concomitant p62 accumulation. Treatment with bafilomycin A1 (an inhibitor of vacuolar H+-ATPase, a late autophagy inhibitor) further increase LC3-II and p62 levels, suggesting that degradation of autophagolysosome could be impaired. SH-SY5Y, with both MVK mutants, showed apoptosis increase; the presence of N301T associated with augmented cell death. CONCLUSIONS: We hypothesize that mevalonate pathway impairment causes alteration of farnesylation and geranylgeranylation proteins and alteration of the autophagic flux; these changes can induce apoptosis, possibly more relevant in the presence of N301T mutation. PMID- 28359057 TI - The Versatile Role of microRNA-30a in Human Cancer. AB - MicroRNAs (miRNAs) are a group of noncoding RNA molecules of 20-23 nucleotides length that negatively regulate gene expressions in numerous cellular processes. Through complementary paring with target mRNAs, miRNAs have frequently emerged as dual regulators of cancer development by acting on multiple signaling pathways, thereby act as novel biomarkers for cancer diagnosis, prognosis, and prediction of response to treatment. As one of them, miR-30a has been found to act as an onco-suppressor of tumorigenesis pathways through inhibition of cellular proliferation, migration and invasion. Simultaneously, miR-30a plays a progressing role in several types of cancer, determined by relevant target genes as well. In the present review, we summarize recent research regarding miR-30a, including its biological function, expression and regulation, especially focusing on its role in cancer development and progression. Clinically, miR-30a may serve as a potential target in the diagnosis and therapy of human cancer. PMID- 28359056 TI - The Construction and Identification of Induced Pluripotent Stem Cells Derived from Acute Myelogenous Leukemia Cells. AB - OBJECTIVE: The present study aimed to establish an induced pluripotent stem cell (iPSC) line from acute myelogenous leukemia (AML) cells in vitro and identify their biological characteristics. METHODS: Cells from the AML-infiltrated skin from an M6 patient were infected with a lentivirus carrying OCT4, SOX2, KLF4 and C-MYC to induce iPSCs. The characteristics of the iPSCs were confirmed by alkaline phosphatase (ALP) staining. The proliferation ability of iPSCs was detected with a CCK-8 assay. The expression of pluripotency markers was measured by immunostaining, and the expression of stem cell-related genes was detected by qRT-PCR; distortion during the induction process was detected by karyotype analysis; the differentiation potential of iPSCs was determined by embryoid body formation and teratoma-formation assays. ALP staining confirmed that these cells exhibited positive staining and had the characteristics of iPSCs. RESULTS: The CCK-8 assay showed that the iPSCs had the ability to proliferate. Immunostaining demonstrated that iPSC clones showed positive expression of NANOG, SSEA-3, SSEA 4, TRA-1-60 and TRA-1-81. qRT-PCR results revealed that the mRNA expression of Nanog, Lin28, Cripto, FOX3, DNMT3b, DPPA2, and DPPA4 significantly increased in iPSCs. Karyotype analysis found no chromosome aberration in the iPSCs. The results of the embryoid body-formation and teratoma-formation assays indicated that the iPSCs had the potential to differentiate into all three germ layers. CONCLUSION: Our study provided evidence that an iPSC line derived from AML cells was successfully established. PMID- 28359058 TI - Sleep Disorder as a Triggering Factor for Relapse in Multiple Sclerosis. AB - BACKGROUND/AIMS: To determine the effect of sleep disturbances on predisposing multiple sclerosis (MS) patients for acute relapse. METHODS: This case-control study was conducted on 80 MS patients including 40 patients in the remission phase and 40 in the relapse phase. Patients were asked to fill in the Pittsburgh Sleep Quality Index to determine their sleep quality during the previous month. Individuals with scores of 5 or less were considered having normal sleep quality. RESULTS: Mean +/- SD ages were 32.5 +/- 7.7 and 30.2 +/- 7.2 years among patients with and without acute relapses, respectively (p > 0.05). The mean disease duration and disease severity (according to Expanded Disability Status Scale [EDSS]) were comparable across the groups (p > 0.05). Among those with and without acute exacerbations, 87.5 and 50% had poor sleep quality, respectively (p = 0.0001), with OR of 1.75 (95% CI 1.25-2.43). The age, gender, EDSS, and disease duration did not associate with sleep quality in either groups (p > 0.05). CONCLUSIONS: This study showed that sleep disturbance might be a trigger for an acute MS exacerbation. Increasing the awareness of specialists and routine screening of sleep disorders in MS patients are warranted, as treatment of these disorders might decrease the likelihood of acute relapses. PMID- 28359059 TI - Toll-Like Receptor-2 and -4 Expression by Maternal Neutrophils in Preterm Labor. AB - BACKGROUND AND AIMS: The inflammatory response in preterm parturition is regulated by the innate immune system. Toll-like receptors (TLR)-2 and TLR-4 are innate immune receptors that recognize the microorganisms most frequently involved in amniotic cavity infections, which are associated with activating the inflammatory response at the maternal-fetal interface during preterm labor. This study aimed to evaluate the expression of TLR-2 and TLR-4 in maternal neutrophils in preterm labor. METHODS: A cross-sectional study was conducted in the Obstetrics Care Unit of Botucatu Medical School, UNESP, Brazil. The preterm group was composed of 20 pregnant women who presented preterm labor and preterm delivery. The control group was composed of 20 nonlaboring pregnant women matched to the preterm group by gestational age. Neutrophils were isolated from peripheral blood and TLR expressions were performed by real-time polymerase chain reaction and flow cytometry. RESULTS: Gene expressions of TLR-2 and TLR-4 in neutrophils from the preterm group were statistically higher than expressions in neutrophils from the matched control group. The percentage of TLR-4+ neutrophils was higher in the preterm group than the matched control group, while the percentage of TLR-2+ neutrophils did not differ between groups. CONCLUSION: TLR-4 expression in maternal neutrophils is associated with spontaneous preterm labor. PMID- 28359060 TI - Growth of Children with Food Allergy?. AB - BACKGROUND: The prevalence of food allergy in children is increasing worldwide. Strict avoidance of identified allergens from the diet is still the cornerstone of the management of food allergies. There are widespread concerns that food allergy and elimination diet may predispose children to nutrient deficiencies and growth failure. AIM: The aim of this paper was to review the current evidence on growth of children suffering from food allergy. Summarised is literature on the effects of the number and type of offending allergens, the child's age and affected organ system, as well as the importance of supervision by a dietician/nutritionist. CONCLUSION: Children suffering from food allergy are stunted at the time of diagnosis and during the elimination diets, irrespective whether or not their nutritional requirements were fulfilled, and/or were under the control of a dietician. This underscores the need for further studies to obtain more precise insight into and better understanding of the mechanisms contributing to growth failure in children suffering from food allergy.?. PMID- 28359061 TI - Intrafamilial Phenotypic Variability and Consequences of Non-Compliance with Treatment in Congenital Adrenal Hyperplasia and Congenital Hypothyroidism within a Single Family?. AB - BACKGROUND: Coexistence of congenital adrenal hyperplasia (CAH) and congenital hypothyroidism (CH) due to TG mutation in the same non-consanguineous family is rare. CASE SERIES: We report 4 siblings born to unrelated parents, the father being an asymptomatic carrier of homozygous p.V281L and heterozygous p.I172N CYP21A2 mutations. Sibling 1 had salt-wasting CAH (CYP21A2 genotype Intron 2 splice/p.I172N and p.V281L). She also had CH (TG genotype p.R296/ p.T1416Rfs*30) and learning difficulties. Poor compliance and morbid obesity resulted in short stature, precocious puberty, hirsutism, amenorrhoea, insulin insensitivity and a possible adrenal adenoma. Sibling 3 (CYP21A2 and TG genotype similar to sibling 1) is a boy presenting with salt-wasting CAH, CH, and developmental delay. He was overweight and underwent precocious puberty. Although siblings 2 and 4 (both females) share the same CYP21A2 genotype (Intron 2 splice/p.V281L), the former only had biochemical evidence of CAH, while the latter presented at 9.8 years of age with a history of pubarche at 7 years and advanced bone age. CONCLUSIONS: We report the unusual occurrence of 2 rare autosomal recessive diseases, CAH and CH. Our cases highlight the phenotypic variability of CAH and CH due to TG mutations, even within a single family, and illustrate the importance of optimal disease control.?. PMID- 28359063 TI - Reimbursed Price of Orphan Drugs: Current Strategies and Potential Improvements. AB - The pricing and reimbursement policies for pharmaceuticals are relevant to balance timely and equitable access for all patients, financial sustainability, and reward for valuable innovation. The proliferation of high-cost specialty medicines is particularly true in rare diseases (RDs) where the pricing mechanism is characterised by a lack of transparency. This work provides an overall picture of current strategies for the definition of the reimbursed prices of orphan drugs (ODs) and highlights some potential improvements. Current strategies and suggestions are presented along 4 dimensions: (1) comprehensive value assessment, (2) early dialogs among relevant stakeholders, (3) innovative reimbursement approaches, and (4) societal participation in producing ODs. Comprehensive value assessment could be achieved by clarifying the approach of distributive justice to adopt, ensuring a representative participation of stakeholders, and with a broad consideration of value-bearing factors. With respect to early dialogs, cross-border cooperation can be determinant to companies and agencies. The cost benefit ratio of early dialogs needs to be demonstrated and the "regulatory capture" effect should be monitored. Innovative reimbursement approaches were developed to balance the need for evidence-based decisions with the timely access to innovative drugs. The societal participation in producing ODs needs to be recognised in a collaborating framework where adaptive agreements can be developed with mutual satisfaction. Such agreements could also impact on coverage and reimbursement decisions as additional elements for the determination of a comprehensive societal value of ODs. Further research is needed to investigate the highlighted open challenges so that RDs will not remain, in practical terms, orphan diseases. PMID- 28359062 TI - A Regional Evaluation of Survival of Infants with End-Stage Renal Disease. AB - BACKGROUND: Information regarding morbidity and mortality of infants born with end-stage renal disease (ESRD) requiring dialysis early in life is critical to optimize patient care and better counsel families. OBJECTIVE: We evaluated outcomes of infants born regionally with ESRD, and those within our broader catchment area referred for dialysis. STUDY DESIGN: We screened deaths at 5 regional referral hospitals, identifying infants with ESRD who did not survive to transfer for dialysis. We also screened all infants <8 weeks old seen at our institution over a 7-year period with ESRD referred for dialysis. We evaluated factors associated with survival to dialysis and transplant. RESULTS: We identified 14 infants from regional hospitals who died prior to transfer and 12 infants at our institution who were dialyzed. Because of the large burden of lethal comorbidities in our regional referral centers, overall survival was low, with 73% dying at birth hospitals. Amongst dialyzed infants, 42% survived to transplant. CONCLUSION: This study is unusual in reporting survival of infants with ESRD including those not referred for dialysis, which yields an expectedly lower survival rate than reported by dialysis registries. PMID- 28359064 TI - Interleukin 17A and Toll-like Receptor 4 in Patients with Arterial Hypertension. AB - BACKGROUND/AIMS: Immune responses are involved in arterial hypertension. An observational cross-sectional case control study was conducted to estimate the association between Toll-like receptor 4 (TLR4) expression and interleukin (IL) 17A serum levels in patients with controlled and non-controlled hypertension. METHODS: We have enrolled 105 non-complicated otherwise healthy hypertensive patients: 53 with well-controlled blood pressure and 52 non-controlled. TLR4 peripheral monocytes expression and serum IL-17A levels were determined by flow cytometry and ELISA, respectively. RESULTS: Non-controlled patients exhibited higher TLR4 expression than well-controlled (25.60 vs. 21.99, P=0.011). TLR4 expression was lower in well-controlled patients who were prescribed beta blockers (18.9 vs. 22.6, P=0.005) and IL-17A concentration was higher in patients using diuretics in either group (1.41 vs. 2.01 pg/ml, P<0.001; well-controlled 1.3 vs. 1.8 pg/ml, P= 0.023; non-controlled 1.6 vs. 2.3 pg/ml, P=0.001). Correlation between IL-17A concentration and hypertension duration was observed in non-controlled patients (Spearman correlation coefficient . rho=0.566, P<0.001) whereas in well-controlled patients a correlation was found between hypertension duration and TLR4 expression (rho=0.322, P=0.020). CONCLUSIONS: Arterial hypertension stimulates the immune response regardless of blood pressure regulation status. Prolonged hypertension influences peripheral monocyte TLR4 expression and IL-17A serum levels. Anti-hypertensive drugs have different immunomodulatory effects: diuretics are associated with higher IL-17A concentration and beta-blockers with lower TLR4 expression. PMID- 28359066 TI - Chromosomal Mapping of Repetitive DNAs in Myiopsitta monachus and Amazona aestiva (Psittaciformes, Psittacidae) with Emphasis on the Sex Chromosomes. AB - Here, for the first time, we describe the karyotype of Myiopsitta monachus (Psittacidae, Arini). We found 2n = 48, corresponding to the lowest diploid number observed in Neotropical Psittaciformes so far, with an uncommonly large W chromosome homomorphic to the Z. In order to better understand the evolution of the sex chromosomes in this species, we applied several molecular cytogenetic approaches, including C-banding, FISH mapping of repetitive DNAs (several microsatellite repeats), and whole-chromosome painting on metaphases of M. monachus. For comparison, another species belonging to the same tribe but with a smaller W chromosome (A. aestiva) was also analyzed. The results show that the constitutive heterochromatin has a very diverse distribution pattern in these species revealing heterochromatic blocks in the centromeric region of all chromosomes and in most of the length of the W chromosome in A. aestiva, while in M. monachus they were found in interstitial and telomeric regions. Concerning the microsatellites, only the sequence (CG)n produced signals on the W chromosome of A. aestiva, in the distal region of both arms. However, in M. monachus, (CAA)n, (CAG)n, and (CG)n probes were accumulated on the W chromosome, and, in addition, the sequence (CAG)n also hybridized to heterochromatic regions in macrochromosomes, as well as in microchromosomes. Based on these results, we suggest that the increase in length of the W chromosome in M. monachus is due to the amplification of repetitive elements, which highlights their significant role in the evolutionary process of sex chromosome differentiation. PMID- 28359065 TI - Evaluating Weight Status and Sex as Moderators of the Association of Serum Leptin with Bone Mineral Density in Children and Adolescents?. AB - BACKGROUND/AIMS: Animal studies suggest that leptin may adversely affect bone mineral density (BMD). Clinical studies have yielded conflicting results. We therefore investigated associations between leptin and bone parameters in children. METHODS: 830 healthy children (age = 11.4 +/- 3.1 years; 75% female; BMI standard deviation score [BMIz] = 1.5 +/- 1.1) had fasting serum leptin measured with ELISA and body composition by dual-energy X-ray absorptiometry. The main effects for leptin and BMIz plus leptin's interactions with sex and BMIz were examined using hierarchical linear regressions for appendicular, pelvis, and lumbar spine BMD as well as bone mineral content (BMC), and bone area (BA). RESULTS: Accounting for demographic, pubertal development, and anthropometric variables, leptin was negatively and independently associated with lumbar spine BMC and BA, pelvis BA, and leg BA (p < 0.05 for all). Sex, but not BMIz, moderated the associations of leptin with bone parameters. In boys, leptin was negatively correlated with leg and arm BMD, BMC at all bone sites, and BA at the subtotal and lumbar spine (p < 0.01 for all). In girls, leptin was positively correlated with leg and arm BMD (p < 0.05 for both). CONCLUSION: Independent of body size, leptin is negatively associated with bone measures; however, these associations are moderated by sex: boys, but not girls, have a negative independent association between leptin and BMD.?. PMID- 28359067 TI - Triggering of Suicidal Erythrocyte Death by Gefitinib. AB - BACKGROUND/AIMS: The epidermal growth factor receptor-tyrosine kinase inhibitor gefitinib is effective against several malignancies and is mainly utilized in the treatment of epidermal growth factor receptor mutation positive non-small cell lung cancer. The anti-cancer effect of the drug involves stimulation of apoptosis. Side effects of gefitinib include anemia. At least in theory, the development of anemia during gefitinib treatment could result from triggering of eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and by cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling potentially stimulating eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i) and generation of oxidative stress. The present study explored, whether gefitinib stimulates eryptosis and, if so, whether its effect involves Ca2+ entry and/or oxidative stress. METHODS: Flow cytometry was employed to quantify cell volume from forward scatter, phosphatidylserine exposure at the cell surface from annexin-V-binding, [Ca2+]i from Fluo3 fluorescence, and reactive oxygen species (ROS) abundance from 2',7' dichlorodihydrofluorescein diacetate (DCFDA) dependent fluorescence. RESULTS: A 48 hours exposure of human erythrocytes to gefitinib (>= 2 ug/ml) significantly decreased forward scatter and significantly increased the percentage of annexin-V binding cells. Gefitinib did not significantly increase Fluo3-fluorescence but the effect of gefitinib on annexin-V-binding was significantly blunted by removal of extracellular Ca2+. Gefitinib further significantly increased DCFDA fluorescence. CONCLUSIONS: Gefitinib triggers erythrocyte shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part dependent on extracellular Ca2+ and paralleled by oxidative stress. PMID- 28359068 TI - The Effect of Combined Treatment with the (Pro)Renin Receptor Blocker HRP and Quinapril in Type 1 Diabetic Rats. AB - BACKGROUND/AIMS: Diabetic nephropathy remains a major clinical problem. The effects of prorenin might be adverse, but the literature data are controversial. We compared the renal effects of the (pro)renin receptor ((P)RR) blockade and angiotensin converting enzyme (ACE) inhibition on the progression of diabetic nephropathy in rats. METHODS: Diabetes (DM) was induced by ip. streptozotocin administration in adult male Sprague-Dawley rats, followed by eight weeks of treatment with the (P)RR blocker "handle region" decoy peptide (HRP, 0,1 mg/kg/day) or with the ACE inhibitor Quinapril (Q, 50 mg/kg/day) and grouped as follows: 1. Control (n=10); 2. DM (n=8); 3. DM+HRP (n=6); 4. DM+Q (n=10); 5. DM+Q+HRP (n=10). Renal functional parameters, histology and gene expressions were evaluated. RESULTS: HRP reduced glomerulosclerosis and podocyte desmin expression, but did not affect proteinuria and tubular ERK(1/2) phosphorylation. Both Q and Q+HRP treatment reduced proteinuria, glomerular and tubular damage, tubular TGF-beta1 expression and ERK(1/2) phosphorylation to the same extent. CONCLUSION: The effects of HRP were partially beneficial on diabetic kidney lesions as HRP reduced damage but did not improve tubular damage and failed to reduce ERK(1/2) phosphorylation in rats. The combination of HRP with Quinapril had no additive effects over Quinapril monotherapy on the progression of diabetic nephropathy. PMID- 28359070 TI - Treatment of Osteochondral Lesions of the Talus: A Critical Analysis Review. PMID- 28359071 TI - Tribocorrosion in Total Hip Arthroplasty. PMID- 28359069 TI - High Risk of Seizures and Epilepsy after Decompressive Hemicraniectomy for Malignant Middle Cerebral Artery Stroke?. AB - BACKGROUND: Decompressive hemicraniectomy (DHC) is a life-saving procedure for treatment of large malignant middle cerebral artery (MCA) strokes. Post-stroke epilepsy is an additional burden for these patients, but its incidence and the risk factors for its development have been poorly investigated. OBJECTIVE: To report the prevalence and risk factors for post-stroke seizures and post-stroke epilepsy after DHC for treatment of large malignant MCA strokes in a cohort of 36 patients. METHODS: In a retrospective cohort study of 36 patients we report the timing and incidence of post-stroke epilepsy. We analyzed if age, sex, vascular risk factors, side of ischemia, reperfusion therapy, stroke etiology, extension of stroke, hemorrhagic transformation, ECASS scores, National Institutes of Health Stroke Scale (NIHSS) scores, or modified Rankin scores were risk factors for seizure or epilepsy after DHC for treatment of large MCA strokes. RESULTS: The mean patient follow-up time was 1,086 days (SD = 1,172). Out of 36 patients, 9 (25.0%) died before being discharged. After 1 year, a total of 11 patients (30.6%) had died, but 22 (61.1%) of them had a modified Rankin score <=4. Thirteen patients (36.1%) developed seizures within the first week after stroke. Seizures occurred in 22 (61.1%) of 36 patients (95% CI = 45.17-77.03%). Out of 34 patients who survived the acute period, 19 (55.9%) developed epilepsy after MCA infarcts and DHC (95% CI = 39.21-72.59%). In this study, no significant differences were observed between the patients who developed seizures or epilepsy and those who remained free of seizures or epilepsy regarding age, sex, side of stroke, presence of the clinical risk factors studied, hemorrhagic transformation, time of craniectomy, and Rankin score after 1 year of stroke. CONCLUSION: The incidence of seizures and epilepsy after malignant MCA infarcts submitted to DHC might be very high. Seizure might occur precociously in patients who are not submitted to anticonvulsant prophylaxis. The large stroke volume and the large cortical ischemic area seem to be the main risk factors for seizure or epilepsy development in this subtype of stroke.?. PMID- 28359072 TI - Tears of the Subscapularis Tendon: A Critical Analysis Review. PMID- 28359073 TI - Fragility Fractures of the Pelvis. PMID- 28359074 TI - Navigation and Robotics in Total Hip Arthroplasty. PMID- 28359075 TI - A Holistic Approach to Antiaging as an Adjunct to Antiaging Procedures: A Review of the Literature. AB - BACKGROUND: Aging is a multifactorial process and depends on both intrinsic and extrinsic factors. Procedural options for diminishing signs of intrinsic aging and cosmetic rejuvenation have expanded dramatically. However, less attention is paid to counseling patients on options for mitigating extrinsic factors related to aging. OBJECTIVE: The objective of this study was to review changes that occur with intrinsic and extrinsic aging, and provide evidence-based holistic counseling recommendations that can be used synergistically with aesthetic procedures to maximize antiaging interventions. MATERIALS AND METHODS: A PubMed search was conducted for articles on intrinsic and extrinsic aging as it relates to skin, fat, muscle, and bone. Key clinical trials and studies on the effect of diet, hormones, exercise, sleep, stress, dental hygiene, smoking, pollution, and oxidative stress on the aging process are reviewed, and treatment recommendations are summarized based on available evidence. RESULTS: Conventional cosmetic procedures and cosmeceuticals work together with nutritious diet, exercise, dental hygiene, hormonal balance, stress reduction, smoking and pollution avoidance, and healthy sleep patterns for a better effect on antiaging. CONCLUSION: A combination approach of multiple nonsurgical modalities along with healthy lifestyle recommendations to minimize intrinsic and extrinsic aging factors allows cosmetic practitioners to target multiple facets of aging concurrently and maximize the aesthetic interventions cosmetic dermatologists/practitioners provide. PMID- 28359076 TI - General Guidelines for Quality Assurance of Immunohistochemistry in a Mohs Lab. AB - BACKGROUND: The adoption of recently created protocols introduces Mohs laboratories to the principles of immunohistochemistry (IHC) performance validation and clinical laboratory regulations that are unique to these evolving technologies. OBJECTIVE: To review Food and Drug Administration (FDA) IHC reagent classifications, IHC validation protocols, and quality assurance (QA) procedures and documentation needed in conjunction with IHC test guidelines. METHODS: A focused review of IHC reagent classifications and guidelines in clinical testing laboratories was conducted using PubMed and FDA source documents. RESULTS: The IHC regulation requirements are determined by the 3 FDA classifications of reagents: in vitro diagnostic reagents, analyte-specific reagents, and research use only reagents. To account for performance variability, IHC reagents benefit from routine validation and QA programs. We present our IHC adoption procedures for QA and documentation of IHC tests in a Mohs laboratory. CONCLUSION: Incorporating a well-organized IHC validation and QA program into Mohs laboratories can increase regulatory compliance and reagent performance. PMID- 28359077 TI - Sleep and survival among women with breast cancer: 30 years of follow-up within the Nurses' Health Study. AB - BACKGROUND: Breast cancer is a leading cause of cancer death in women. Sleep has been linked with mortality among cancer-free population; however, its association with survival among women with breast cancer is understudied. METHODS: Breast cancer patients (N=3682) reported their average sleep duration post diagnosis. Subsamples also provided their pre-diagnosis sleep duration (n=1949) and post diagnosis sleep difficulties (n=1353). Multivariate Cox models estimated hazard ratios (HR) and confidence intervals (CI) of all-cause, breast cancer, and non breast cancer mortality. RESULTS: At diagnosis, the mean age was 64.9 years and 91.7% were stage I or II. Women sleeping ?9 h per night post diagnosis had a strong higher risk of all-cause (multivariate HRs: MV-HR=1.37, CI=1.10-1.71), breast cancer (MV-HR=1.46, CI=1.02-2.07), and non-breast cancer mortality (MV HR=1.34, CI=1.01-1.79), compared to women sleeping 8 h per night. Increased sleep duration post diagnosis (vs unchanged) and regular sleep difficulties (vs rare/none) were associated with a strong elevated risk of all-cause mortality (MV HRincreased duration=1.35, CI=1.04-1.74; MV-HRregular difficulties=1.49, CI=1.02 2.19) and a moderate greater risk of breast cancer and non-breast cancer mortality. CONCLUSIONS: Various facets of sleep were associated with higher all cause mortality risk. If replicated, these findings support evaluation of breast cancer patients' sleep duration and difficulties to identify those at risk for poorer outcomes. PMID- 28359079 TI - Evaluating wait times from screening to breast cancer diagnosis among women undergoing organised assessment vs usual care. AB - BACKGROUND: Timely coordinated diagnostic assessment following an abnormal screening mammogram reduces patient anxiety and may optimise breast cancer prognosis. Since 1998, the Ontario Breast Screening Program (OBSP) has offered organised assessment through Breast Assessment Centres (BACs). For OBSP women seen at a BAC, an abnormal mammogram is followed by coordinated referrals through the use of navigators for further imaging, biopsy, and surgical consultation as indicated. For OBSP women seen through usual care (UC), further diagnostic imaging is arranged directly from the screening centre and/or through their physician; results must be communicated to the physician who is then responsible for arranging any necessary biopsy and/or surgical consultation. This study aims to evaluate factors associated with diagnostic wait times for women undergoing assessment through BAC and UC. METHODS: Of the 2 147 257 women aged 50-69 years screened in the OBSP between 1 January 2002 and 31 December 2009, 155 866 (7.3%) had an abnormal mammogram. A retrospective design identified two concurrent cohorts of women diagnosed with screen-detected breast cancer at a BAC (n=4217; 47%) and UC (n=4827; 53%). Multivariable logistic regression analyses examined associations between wait times and assessment and prognostic characteristics by pathway. A two-sided 5% significance level was used. RESULTS: Screened women with breast cancer were two times more likely to be diagnosed within 7 weeks when assessed through a BAC vs UC (OR=1.91, 95% CI=1.73-2.10). In addition, compared with UC, women assessed through a BAC were significantly more likely to have their first assessment procedure within 3 weeks of their abnormal mammogram (OR=1.25, 95% CI=1.12-1.39), ?3 assessment procedures (OR=1.54, 95% CI=1.41 1.69), ?2 assessment visits (OR=1.86, 95% CI=1.70-2.05), and ?2 procedures per visit (OR=1.41, 95% CI=1.28-1.55). Women diagnosed through a BAC were also more likely than those in UC to have imaging (OR=1.99, 95% CI=1.44-2.75) or a biopsy (OR=3.69, 95% CI=2.64-5.15) vs consultation only at their first assessment visit, and two times more likely to have a core or FNA biopsy than a surgical biopsy (OR=2.08, 95% CI=1.81-2.40). Having ?2 assessment visits was more likely to reduce time to diagnosis for women assessed through a BAC compared with UC (BAC OR=10.58, 95% CI=8.96-12.50; UC OR=4.47, 95% CI=3.94-5.07), as was having ?3 assessment procedures (BAC OR=4.97, 95% CI=4.26-5.79; UC OR=2.95, 95% CI=2.61 3.33). Income quintile affected wait times only in women diagnosed in UC, with those in the two highest quintiles more likely to receive a diagnosis in 7 weeks. CONCLUSIONS: Women with screen-detected breast cancer in OBSP were more likely to have shorter wait times if they were diagnosed through organised assessment. This might be as a result of women diagnosed through a BAC having more procedures per visit, procedures scheduled in shorter intervals, and imaging or biopsy on their first visit. Given the significant improvement in timeliness to diagnosis, women with abnormal mammograms should be managed through organised assessment. PMID- 28359081 TI - Temperament and Early Stuttering Development: Cross-Sectional Findings From a Community Cohort. AB - Purpose: The purpose of this study was to ascertain if there is an association between stuttering severity and behaviors and the expression of temperament characteristics, including precursors of anxiety. Method: We studied temperament characteristics of a prospectively recruited community cohort of children who stutter (N = 173) at ages 3, 4, and 6 years using the Short Temperament Scale STS (Prior, Sanson, Smart & Oberklaid, 2000). Results: Six of 131 statistical tests of association between stuttering severity and behaviors and temperament traits were statistically significant at the 5% level, which was no more than expected by chance alone. Conclusions: On the basis of parent responses to the STS, preschoolers who exhibited different levels of stuttering severity and behaviors did not generally express temperament traits differently from one another. Stuttering severity and stuttering behaviors were not associated with the precursors of anxiety. Overall, taking multiple tests into consideration, results show little evidence of association between stuttering severity and temperament up to 4 years of age or between stuttering behaviors and temperament up to 6 years of age. PMID- 28359078 TI - Safety and utility of image-guided research biopsies in relapsed high-grade serous ovarian carcinoma-experience of the BriTROC consortium. AB - BACKGROUND: Investigating tumour evolution and acquired chemotherapy resistance requires analysis of sequential tumour material. We describe the feasibility of obtaining research biopsies in women with relapsed ovarian high-grade serous carcinoma (HGSC). METHODS: Women with relapsed ovarian HGSC underwent either image-guided biopsy or intra-operative biopsy during secondary debulking, and samples were fixed in methanol-based fixative. Tagged-amplicon sequencing was performed on biopsy DNA. RESULTS: We screened 519 patients in order to enrol 220. Two hundred and two patients underwent successful biopsy, 118 of which were image guided. There were 22 study-related adverse events (AE) in the image-guided biopsies, all grades 1 and 2; pain was the commonest AE. There were pre-specified significant AE in 3/118 biopsies (2.5%). 87% biopsies were fit-for-purpose for genomic analyses. Median DNA yield was 2.87 MUg, and was higher in biopsies utilising 14 G or 16 G needles compared to 18 G. TP53 mutations were identified in 94.4% patients. CONCLUSIONS: Obtaining tumour biopsies for research in relapsed HGSC is safe and feasible. Adverse events are rare. The large majority of biopsies yield sufficient DNA for genomic analyses-we recommend use of larger gauge needles and methanol fixation for such biopsies, as DNA yields are higher but with no increase in AEs. PMID- 28359080 TI - Lithium enhances the antitumour effect of temozolomide against TP53 wild-type glioblastoma cells via NFAT1/FasL signalling. AB - BACKGROUND: We previously showed that activation of the nuclear factor of activated T cells (NFAT)1/Fas ligand (FasL) pathway induces glioma cell death. Lithium (Li) is an inhibitor of glycogen synthase kinase (GSK)-3 that activates NFAT1/FasL signalling. Temozolomide (TMZ) inhibits GSK-3 and activates Fas in tumour protein (TP)53 wild-type (TP53wt) glioma cells. The present study investigated the combinational effects of TMZ and low-dose Li on TP53wt glioma cells. METHODS: The combined effect of TMZ and Li was examined in TP53wt U87 and primary glioma cells and a mouse xenograft model. RESULTS: Combination with 1.2 mM Li potentiated TMZ-induced cell death in TP53wt glioma cells, as determined by neurosphere formation and apoptosis assays. Temozolomide combined with Li treatment inhibited GSK-3 activation, promoted NFAT1 nuclear translocation and upregulated Fas/FasL expression. Targeted knockdown of NFAT1 expression blocked the induction of cell death by TMZ and Li via FasL inhibition. In vivo, combined treatment with TMZ and Li suppressed tumour growth and prolonged the survival of tumour-bearing mice. However, the combination of TMZ and Li did not produce a statistically significant effect in TP53mut glioma cells. CONCLUSIONS: Temozolomide combined with low-dose Li induces TP53wt glioma cell death via NFAT1/FasL signalling. This represents a potential therapeutic strategy for TP53wt glioma treatment. PMID- 28359083 TI - Patient Perception of Speech Outcomes: The Relationship Between Clinical Measures and Self-Perception of Speech Function Following Surgical Treatment for Oral Cancer. AB - Purpose: Treatment for oral cancer can result in speech impairments that can have varying impacts on patient quality of life. This study explored the relationship between clinical measures of speech impairment and the perception that patients had of this change in the early stage of recovery. Method: This was a quasi experimental 1-group pre-post study design carried out on 10 patients with surgical intervention for oral cancer. Two clinical measures (word intelligibility and consonant phoneme error) and 2 patient-perception measures (Speech Handicap Index total score and Speech Handicap Index patient criteria score) were collected at preoperative and 1-month postoperative appointments. Results: Qualitative analysis revealed discordance between clinical and patient perceived measures in 4 of 10 patients. Change in consonant phoneme error and change in word intelligibility were significantly correlated (r = .827). Furthermore, on average, statistically significant relationships were not found between clinical and patient-perceived measures or between the 2 patient perception measures. Conclusions: Discordance between clinical and patient perceived measures was observed in almost half of the sample, indicating that clinical tests did not fully explain the extent of impairment perceived by patients. Speech outcomes should focus on both types of measures, and patient perception outcomes should be carefully considered when recommending speech therapy. PMID- 28359082 TI - Gesture Production in Language Impairment: It's Quality, Not Quantity, That Matters. AB - Purpose: The aim of this study was to determine whether children with language impairment (LI) use gesture to compensate for their language difficulties. Method: The present study investigated gesture accuracy and frequency in children with LI (n = 21) across gesture imitation, gesture elicitation, spontaneous narrative, and interactive problem-solving tasks, relative to typically developing (TD) peers (n = 18) and peers with low language and educational concerns (n = 21). Results: Children with LI showed weaknesses in gesture accuracy (imitation and gesture elicitation) in comparison to TD peers, but no differences in gesture rate. Children with low language only showed weaknesses in gesture imitation and used significantly more gestures than TD peers during parent-child interaction. Across the whole sample, motor abilities were significantly related to gesture accuracy but not gesture rate. In addition, children with LI produced proportionately more extending gestures, suggesting that they may use gesture to replace words that they are unable to articulate verbally. Conclusion: The results support the notion that gesture and language form a tightly linked communication system in which gesture deficits are seen alongside difficulties with spoken communication. Furthermore, it is the quality, not quantity of gestures that distinguish children with LI from typical peers. PMID- 28359084 TI - Genetic Evidence for Multifactorial Control of the Reproductive Axis in Zebrafish. AB - It is generally believed that kisspeptin and gonadotropin-releasing hormone (GnRH) are required for reproduction in vertebrates. In this study, we generated gnrh3-null zebrafish and found that gnrh3 mutation did not impair gonad development and reproductive capacity. Moreover, zebrafish triple knockout mutant lacking gnrh3 and the 2 kiss1s genes undergo normal puberty and gonad maturation. The expression of follicle-stimulating hormone beta (fshbeta) and luteinizing hormone beta (lhbeta) was not significantly altered whereas the expression of neuropeptide Y (npy), tachykinin 3 (tac3), and secretogranin-II (sgII) was significantly increased in the triple knockout mutant, suggesting that compensation mechanisms exist to stimulate the reproductive axis in the absence of kiss and gnrh. Our results challenge the prevailing view that GnRH is indispensable for reproduction across species. These data provide genetic evidence that different mechanisms have evolved for the neuroendocrine control of reproduction between mammals and fish: pulsatile release of GnRH to the portal system is the final gateway to stimulate the reproductive axis in mammals, whereas multiple factors act in parallel with GnRH to stimulate the reproductive axis in certain fish species. PMID- 28359085 TI - Osteonecrosis of the Femoral Head: Lipotoxicity Exacerbation in MSC and Modifications of the Bone Marrow Fluid. AB - Osteonecrosis of the femoral head (ON) is a multifactorial bone disease that can evolve to a progressive destruction of the hip joint. Different pathogenic processes have been proposed, among them, an increase of bone marrow (BM) fat resulting from adipocyte accumulation. Marrow adipocytes are active BM residents that influence the microenvironment by releasing cytokines, adipokines, and free fatty acids (FA). We explored the impact of palmitate (Palm) and oleate on function and survival of BM-derived mesenchymal stromal cells (MSC) of osteonecrotic patients (ONMSC) and healthy volunteers. Moreover, we analyzed the FA profile of the serum and the BM supernatant fluid (BMSF). We demonstrated that exposure to the saturated FA Palm favored MSC differentiation through the adipogenic lineage at the expense of the osteoblastic phenotype. Moreover, adipogenesis was intensified in ONMSC. The susceptibility to Palm toxicity was aggravated in ONMSC concomitantly with a greater activation of the proapoptotic extracellular signal-regulated kinase pathway. Moreover, cellular mechanisms implicated in the protection against lipotoxicity, such as stearoyl-coenzyme A desaturase 1 and carnitine palmitoyl transferase 1 expression, were dysregulated in ONMSC. Palm-induced interleukin (IL)-6 and IL-8 secretion was also exacerbated in ONMSC. Our results established that, in the serum, the FA profiles were comparable in ON and healthy subjects. However, both the concentrations and the FA composition were modified in the BMSF of ON patients, highlighting a drastic change of the BM microenvironment in ON patients. Altogether, our work suggests that marrow adipocyte enlargement could affect the process of bone remodeling and, therefore, play a role in the pathogenesis of ON. PMID- 28359086 TI - The Arcuate Estrogen-Regulated Transcriptome: Estrogen Response Element-Dependent and -Independent Signaling of ERalpha in Female Mice. AB - To influence energy homeostasis and reproduction, 17beta-estradiol (E2) controls the arcuate nucleus (ARC) through multiple receptor-mediated mechanisms, but primarily via estrogen receptor (ER) alpha, which signals through both estrogen response element (ERE)-dependent and -independent mechanisms. To determine ERalpha-mediated, ERE-dependent, and ERE-independent E2 signaling in the ARC, we examined the differential regulation of the mouse arcuate transcriptome by E2 using three mice genotypes: (1) wild-type, (2) ERalpha knock-in/knockout (ERE independent mechanisms), and (3) total ERalpha knockout (ERalpha-independent mechanisms). Females were ovariectomized and injected with oil or E2, and RNA sequencing on the ARC was used to identify E2-regulated genes in each genotype. Our results show that E2 regulates numerous genes involved in cell signaling, cytoskeleton structure, inflammation, neurotransmission, neuropeptide production, and transcription. Furthermore, ERE-independent signaling regulates ARC genes expressed in kisspeptin neurons and transcription factors that control the hypothalamic/pituitary/gonadal axis. Interestingly, a few genes involved in mitochondrial oxidative respiration were regulated by E2 through ERalpha independent signaling. A comparison within oil- and E2-treated females across the three genotypes suggests that genes involved in cell growth and proliferation, extracellular matrices, neuropeptides, receptors, and transcription are differentially expressed across the genotypes. Comparing with previously published chromatin immunoprecipitation sequencing analysis, we found that ERE independent regulation in the ARC is mainly mediated by tethering of ERalpha, which is consistent with previous findings. We conclude that the mouse arcuate estrogen-regulated transcriptome is regulated by multiple receptor-mediated mechanisms to modulate the central control of energy homeostasis and reproduction, including novel E2-responsive pathways. PMID- 28359088 TI - Sex Hormone-Binding Globulin Reduction in Metabolic Disorders May Play a Role in NAFLD Development. AB - Low plasma sex hormone-binding globulin (SHBG) levels are a hallmark in chronic metabolic diseases, including nonalcoholic fatty liver disease (NAFLD), which represents a spectrum of disease ranging from hepatocellular steatosis through steatohepatitis to fibrosis and irreversible cirrhosis. The functional link between altered SHBG production and NAFLD development and progression remains unclear. We investigated the effects of overexpressing human SHBG in 2 mouse models of NAFLD: a genetically induced double transgenic mouse and a diet-induced model. Remarkably, SHBG overexpression in both NAFLD models significantly reduced liver fat accumulation by reducing key lipogenic enzymes. These findings were corroborated by modulating SHBG expression and by adding exogenous SHBG in HepG2 cells, suggesting the cell autonomous nature of the mechanism. Mechanistically, exogenous SHBG treatment downregulated key lipogenic enzymes by reducing PPARgamma messenger RNA and protein levels through activation of extracellular signal-regulated kinase-1/2 mitogen-activated protein kinase pathway. Taking together, we found that SHBG modulates hepatic lipogenesis. This is of importance because reduction of SHBG plasma levels in obese and type 2 diabetic subjects could be directly associated with NAFLD development through an increase in hepatic lipogenesis. Our results point to SHBG as a therapeutic target for preventing or arresting NAFLD development. PMID- 28359087 TI - Glucocorticoids Induce Bone and Muscle Atrophy by Tissue-Specific Mechanisms Upstream of E3 Ubiquitin Ligases. AB - Glucocorticoid excess, either endogenous with diseases of the adrenal gland, stress, or aging or when administered for immunosuppression, induces bone and muscle loss, leading to osteopenia and sarcopenia. Muscle weakness increases the propensity for falling, which, combined with the lower bone mass, increases the fracture risk. The mechanisms underlying glucocorticoid-induced bone and muscle atrophy are not completely understood. We have demonstrated that the loss of bone and muscle mass, decreased bone formation, and reduced muscle strength, hallmarks of glucocorticoid excess, are accompanied by upregulation in both tissues in vivo of the atrophy-related genes atrogin1, MuRF1, and MUSA1. These are E3 ubiquitin ligases traditionally considered muscle-specific. Glucocorticoids also upregulated atrophy genes in cultured osteoblastic/osteocytic cells, in ex vivo bone organ cultures, and in muscle organ cultures and C2C12 myoblasts/myotubes. Furthermore, glucocorticoids markedly increased the expression of components of the Notch signaling pathway in muscle in vivo, ex vivo, and in vitro. In contrast, glucocorticoids did not increase Notch signaling in bone or bone cells. Moreover, the increased expression of atrophy-related genes in muscle, but not in bone, and the decreased myotube diameter induced by glucocorticoids were prevented by inhibiting Notch signaling. Thus, glucocorticoids activate different mechanisms in bone and muscle that upregulate atrophy-related genes. However, the role of these genes in the effects of glucocorticoids in bone is unknown. Nevertheless, these findings advance our knowledge of the mechanism of action of glucocorticoids in the musculoskeletal system and provide the basis for novel therapies to prevent glucocorticoid-induced atrophy of bone and muscle. PMID- 28359089 TI - Dual Role of Insulin in Spexin Regulation: Functional Link Between Food Intake and Spexin Expression in a Fish Model. AB - Spexin (SPX), a neuropeptide discovered by the bioinformatics approach, has been recently identified as a satiety factor in a fish model. However, the functional link between feeding and SPX expression as well as the signal transduction for SPX regulation are totally unknown. In this study, we used goldfish as a model to examine the functional role of insulin as a postprandial signal for SPX regulation in bony fish. In goldfish, feeding could elevate plasma levels of glucose, insulin, and SPX with concurrent rises in insulin and SPX messenger RNA (mRNA) expression in the liver. Similar elevation in SPX mRNA level was also observed in the liver and brain areas involved in appetite control in goldfish after intraperitoneal injection of glucose and insulin, respectively. In parallel experiments with goldfish hepatocytes and brain cell culture, insulin signal induced by glucose was shown to exert a dual role in SPX regulation, namely (1) acting as an autocrine/paracrine signal to trigger SPX mRNA expression in the liver and (2) serving as an endocrine signal to induce SPX gene expression in the brain. Apparently, the peripheral (in the liver) and central actions of insulin (in the brain) on SPX gene expression were mediated by insulin receptor (to a lesser extent by insulin-like growth factor I receptor) coupled to mitogen activated protein kinase kinase 3/6/p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin but not mitogen activated protein kinase kinase 1/2/extracellular signal-regulated kinase 1/2 cascades. Our findings indicate that an insulin component inducible by glucose is present in the liver of the fish model and may serve as the postprandial signal linking food intake with SPX expression both in the central as well as at the hepatic level. PMID- 28359090 TI - Corrigendum. PMID- 28359091 TI - BMP15 Mutations Associated With Primary Ovarian Insufficiency Reduce Expression, Activity, or Synergy With GDF9. AB - Context: Bone morphogenetic protein (BMP)15 is an oocyte-specific growth factor, which, together with growth differentiation factor (GDF) 9, regulates folliculogenesis and ovulation rate. Multiple mutations in BMP15 have been identified in women with primary ovarian insufficiency (POI), supporting a pathogenic role; however, the underlying biological mechanism of many of these mutants remains unresolved. Objectives: To determine how mutations associated with ovarian dysfunction alter the biological activity of human BMP15. Design: The effects of 10 mutations in BMP15 on protein production, activation of granulosa cells, and synergy with GDF9 were assessed. Results: Sequencing of 35 patients with POI identified both an unrecognized BMP15 variant (c.986G>A, R329H) and a variant (c.581T>C, F194S) previously associated with the condition. Assessing expression and activity of these and 8 other BMP15 mutants identified: (1) multiple variants, including L148P, F194S, and Y235C, with reduced mature protein production; (2) three variants (R138H, A180T, and R329H) with ~fourfold lower activity than wild-type BMP15; and (3) 3 variants (R68W, F194S, and N196K) with a significantly reduced ability to synergize with GDF9. Conclusions: Mutations in BMP15 associated with POI reduce mature protein production, activity, or synergy with GDF9. The latter effect is perhaps most interesting given that interactions with GDF9 most likely underlie the physiology of BMP15 in the human ovary. PMID- 28359092 TI - The Association of Weight Loss and Cardiometabolic Outcomes in Obese Children: Systematic Review and Meta-regression. AB - Background: Excess body weight in children is associated with multiple immediate and long-term medical comorbidities. We aimed to identify the degree of reduction in excess body weight associated with cardiometabolic changes (lipid panel, liver function tests, systolic blood pressure (SBP), diastolic blood pressure, glycosylated hemoglobin, and fasting blood glucose) in overweight and obese children. Methods: We conducted a comprehensive search of MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Scopus through February 12, 2015. We included randomized controlled trials and cohort studies that evaluated interventions to treat pediatric obesity (medication, surgery, lifestyle, and community-based interventions) with >= a 6-month follow-up. We used a random effects meta-regression approach to assess the association between body mass index (BMI)/weight and cardiometabolic changes. Results: We included 42 studies (37 randomized controlled trials and five cohorts) enrolling 3807 children (mean age, 12.2 years; weight, 74.7 kg; and BMI, 31.7 kg/m2). Studies had overall moderate to low risk of bias. A 1-mm Hg decrease in SBP was significantly associated with a decrease of 0.16 kg/m2 (P = .04) in BMI. A 1-mg/dL increase in HDL was significantly associated with a 0.74-kg decrease in weight (P = .02). A 1 mg/dL decrease in triglycerides was significantly associated with a 0.1-kg decrease in weight (P = .03). The remaining associations were not statistically significant. Conclusions: Weight reduction in children is associated with significant changes in several cardiometabolic outcomes, particularly HDL, SBP, and triglycerides. The magnitude of improvement may help in setting expectations and may inform shared decision-making and counseling. PMID- 28359094 TI - Birth Weight in Different Etiologies of Disorders of Sex Development. AB - Context: It is well established that boys are heavier than girls at birth. Although the cause of birth weight (BW) difference is unknown, it has been proposed that it could be generated from prenatal androgen action. Objective: The aim of the current study was to determine the BW of children with disorders of sex development (DSD) of different etiologies and to evaluate the effects of androgen action on BW. Methods: Data regarding diagnosis, BW, gestational age, karyotype, and concomitant conditions were collected from the International Disorders of Sex Development (I-DSD) Registry (www.i-dsd). BW standard deviation score was calculated according to gestational age. Cases were evaluated according to disorder classification in I-DSD (i.e., disorders of gonadal development, androgen excess, androgen synthesis, androgen action, nonspecific disorder of undermasculinization groups, and Leydig cell defect). Results: A total of 533 cases were available; 400 (75%) cases were 46,XY, and 133 (25%) cases were 46,XX. Eighty cases (15%) were born small for gestational age (SGA). Frequency of SGA was higher in the 46,XY group (17.8%) than in the 46,XX (6.7%) group (P = 0.001). Mean BW standard deviation scores of cases with androgen excess and androgen deficiency [in disorders of gonadal development, androgen synthesis, and Leydig cell defect groups and androgen receptor gene (AR) mutation-positive cases in disorders of androgen action groups] were similar to normal children with the same karyotype. SGA birth frequency was higher in the AR mutation-negative cases in disorders of androgen action group and in the nonspecific disorders of the undermasculinization group. Conclusions: BW dimorphism is unlikely to be explained by fetal androgen action per se. 46,XY DSDs due to nonspecific disorders of undermasculinization are more frequently associated with fetal growth restriction, SGA, and concomitant conditions. PMID- 28359093 TI - Diabetes-Specific Regulation of Adipocyte Metabolism by the Adipose Tissue Extracellular Matrix. AB - Context: The role of the extracellular matrix (ECM) in regulating adipocyte metabolism in the context of metabolic disease is poorly defined. Objective: The objective of this study was to define the metabolic phenotype of adipocytes associated with human diabetes (DM) and the role of the ECM in regulating adipocyte metabolism. Design: Adipose tissues from obese patients were studied in standard 2-dimensional (2D) cell culture and an in vitro model of decellularized adipose tissue ECM repopulated with human adipocytes, and results were correlated with DM status. Setting: This study was conducted at the Academic University Medical Center and Veteran's Administration Hospital. Patients: Seventy patients with morbid obesity undergoing bariatric surgery were included in the study. Interventions: Visceral and subcutaneous adipose tissues were collected at the time of bariatric surgery. Outcome measures: This study used metabolic assays for glucose uptake, lipolysis, and lipogenesis in adipocytes in 2D cell culture and 3 dimensional ECM culture. Results: Adipocytes from subjects with DM manifest decreased glucose uptake and decreased lipolysis in 2D culture. ECM supports differentiation of mature adipocytes and recapitulates DM-specific differences in adipocyte metabolism observed in 2D culture. ECM from subjects without DM partially rescues glucose uptake and lipolytic defects in adipocytes from subjects with DM, whereas ECM from subjects with DM impairs glucose uptake in adipocytes from subjects without DM. Conclusions: DM is associated with adipocyte metabolic dysfunction. The ECM regulates adipocyte metabolism. Nondiabetic ECM rescues metabolic dysfunction in DM adipocytes, whereas DM ECM imparts features of metabolic dysfunction to nondiabetic adipocytes. These findings suggest the ECM as a target for manipulating adipose tissue metabolism. PMID- 28359095 TI - Radiotherapy, Especially at Young Age, Increases the Risk for De Novo Brain Tumors in Patients Treated for Pituitary/Sellar Lesions. AB - Context: De novo brain tumors developing after treatment of pituitary/sellar lesions have been reported, but it is unknown whether this is linked to any of the treatment modalities. Objective: To study the occurrence of malignant brain tumors and meningiomas in a large cohort of patients treated for pituitary/sellar lesions, with special emphasis on the role of radiotherapy (RT). Patients and Methods: Patients (n = 8917) who were hypopituitary due to pituitary adenomas, craniopharyngiomas, and other sellar tumors followed in KIMS (Pfizer International Metabolic Database) from 1994 to 2012 were included. Treatment consisted of surgery and/or medical therapy in 4927 patients, RT alone, or with surgery in 3236 patients; data were missing in 754. Incidence rate ratios (RRs) were analyzed through Poisson regression methods with internal comparisons. Results: During 53,786 patient-years, 17 cases of malignant brain tumors (13 exposed to RT) and 27 meningiomas (22 exposed to RT) were reported. RR for RT vs no RT was 3.34 [95% confidence interval (CI), 1.06 to 10.6] for malignant brain tumors, and 4.06 (95% CI, 1.51 to 10.9) for meningiomas. The risk of developing a malignant brain tumor increased by 2.4-fold (P = 0.005) and meningioma by 1.6 fold with every 10 years of younger age at RT (P = 0.05). Incidence rates were similar in patients treated with conventional RT compared with stereotactic RT. Conclusion: RT of pituitary tumors is associated with increased risk of developing malignant brain tumors and meningiomas, especially when given at younger ages. In balancing risks and benefits of RT, our findings emphasize that special consideration should be given to the age of the patient. PMID- 28359096 TI - Early Maternal Thyroid Function During Gestation Is Associated With Fetal Growth, Particularly in Male Newborns. AB - Background: Intrauterine growth patterns are influenced by maternal thyroid function during gestation and by fetal sex. It is unknown, however, whether the relationships between maternal thyrotropin (TSH) and free thyroxine (fT4) levels in early pregnancy and fetal growth outcomes are modified by fetal sex. Design: Data were obtained from a community-based cohort study of pregnant women living in Amsterdam (Amsterdam Born Children and Their Development study). TSH and fT4 levels were determined during the first prenatal screening at median 13 weeks (interquartile range, 12 to 14). Women with live-born singletons and no overt thyroid dysfunction were included (N = 3988). Associations between these maternal hormones and birth weight, small for gestational age (SGA), and large for gestational age (LGA) were analyzed separately for each sex. Results: After adjustments, 1 pmol/L increase in maternal fT4 levels was associated with a reduction in birth weight of 33.7 g (P < 0.001) in male newborns and 16.1 g (P < 0.05) in female newborns. Increased maternal fT4 was not associated with increased odds for SGA, but was associated with a decreased odds for LGA in boys [per 1 pmol/L; odds ratio (OR), 0.79; 95% confidence interval (CI), 0.69 to 0.90]. Maternal subclinical hypothyroidism in early pregnancy (TSH > 2.5 mU/L, 7.3%) was associated with increased odds for LGA in male newborns (OR, 1.95; 95% CI, 1.22 to 3.11). Conclusion: Maternal fT4 in early pregnancy was observed to be inversely associated with birth weight, with a stronger relationship in males. Male infants also had increased odds for LGA in mothers with subclinical hypothyroidism. Sexual dimorphism appears to be present in the relationship between maternal thyroid metabolism and fetal intrauterine growth, with stronger associations in male infants. PMID- 28359098 TI - Attenuation of Resting but Not Load-Mediated Protein Synthesis in Prostate Cancer Patients on Androgen Deprivation. AB - Context: Androgen deprivation therapy (ADT) is a common prostate cancer (PCa) treatment but results in muscular atrophy. Periodic increases in muscle protein synthesis (MPS) that occur after resistance exercise or protein intake may ameliorate this muscle loss, but the impact of these anabolic stimuli during ADT is unclear. Objective: To determine the acute MPS response to whey protein supplementation with and without resistance exercise during ADT. Design: Acute response in PCa patients vs age-matched controls (CON). Setting: Academic laboratory setting. Participants: PCa patients on ADT (N = 8) and CON (N = 10). Intervention: A standardized diet was consumed for 2 days prior to performing unilateral knee extension resistance exercise followed by ingestion of 40 g of whey protein. Main Outcome Measures: Bilateral biopsies and stable isotope infusions were used to determine MPS rates at rest after protein ingestion with and without resistance exercise. Results: Baseline MPS during ADT was suppressed relative to CON (P = 0.01). Protein consumption stimulated MPS in both groups (approximate twofold increase, both P < 0.001), but to a greater extent in CON (P = 0.003). Protein plus resistance exercise increased MPS (~3.4-fold increase, both P < 0.001) to a greater extent than did protein alone (P < 0.001), but with no difference between groups (P = 0.380). Conclusions: ADT reduces basal and protein feeding-induced rises in MPS; however, combined protein ingestion with resistance exercise stimulated MPS to a similar degree as CON. Testosterone appears to play a role in maintaining muscle mass but is not necessary to initiate a robust response in MPS following resistance exercise when combined with protein ingestion. PMID- 28359097 TI - A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management. AB - Context: Middle-aged and older men (>=50 years), especially those who are obese and suffer from comorbidities, not uncommonly present with clinical features consistent with androgen deficiency and modestly reduced testosterone levels. Commonly, such men do not demonstrate anatomical hypothalamic-pituitary testicular axis pathology but have functional hypogonadism that is potentially reversible. Evidence Acquisition: Literature review from 1970 to October 2016. Evidence Synthesis: Although definitive randomized controlled trials are lacking, evidence suggests that in such men, lifestyle measures to achieve weight loss and optimization of comorbidities, including discontinuation of offending medications, lead to clinical improvement and a modest increase in testosterone. Also, androgen deficiency-like symptoms and end-organ deficits respond to targeted treatments (such as phosphodiesterase-5 inhibitors for erectile dysfunction) without evidence that hypogonadal men are refractory. Unfortunately, lifestyle interventions remain difficult and may be insufficient even if successful. Testosterone therapy should be considered primarily for men who have significant clinical features of androgen deficiency and unequivocally low testosterone levels. Testosterone should be initiated either concomitantly with a trial of lifestyle measures, or after such a trial fails, after a tailored diagnostic work-up, exclusion of contraindications, and appropriate counseling. Conclusions: There is modest evidence that functional hypogonadism responds to lifestyle measures and optimization of comorbidities. If achievable, these interventions may have demonstrable health benefits beyond the potential for increasing testosterone levels. Therefore, treatment of underlying causes of functional hypogonadism and of symptoms should be used either as an initial or adjunctive approach to testosterone therapy. PMID- 28359099 TI - Pediatric Obesity-Assessment, Treatment, and Prevention: An Endocrine Society Clinical Practice Guideline. AB - Cosponsoring Associations: The European Society of Endocrinology and the Pediatric Endocrine Society. This guideline was funded by the Endocrine Society. Objective: To formulate clinical practice guidelines for the assessment, treatment, and prevention of pediatric obesity. Participants: The participants include an Endocrine Society-appointed Task Force of 6 experts, a methodologist, and a medical writer. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The Task Force commissioned 2 systematic reviews and used the best available evidence from other published systematic reviews and individual studies. Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Endocrine Society committees and members and co-sponsoring organizations reviewed and commented on preliminary drafts of this guideline. Conclusion: Pediatric obesity remains an ongoing serious international health concern affecting ~17% of US children and adolescents, threatening their adult health and longevity. Pediatric obesity has its basis in genetic susceptibilities influenced by a permissive environment starting in utero and extending through childhood and adolescence. Endocrine etiologies for obesity are rare and usually are accompanied by attenuated growth patterns. Pediatric comorbidities are common and long-term health complications often result; screening for comorbidities of obesity should be applied in a hierarchal, logical manner for early identification before more serious complications result. Genetic screening for rare syndromes is indicated only in the presence of specific historical or physical features. The psychological toll of pediatric obesity on the individual and family necessitates screening for mental health issues and counseling as indicated. The prevention of pediatric obesity by promoting healthful diet, activity, and environment should be a primary goal, as achieving effective, long lasting results with lifestyle modification once obesity occurs is difficult. Although some behavioral and pharmacotherapy studies report modest success, additional research into accessible and effective methods for preventing and treating pediatric obesity is needed. The use of weight loss medications during childhood and adolescence should be restricted to clinical trials. Increasing evidence demonstrates the effectiveness of bariatric surgery in the most seriously affected mature teenagers who have failed lifestyle modification, but the use of surgery requires experienced teams with resources for long-term follow up. Adolescents undergoing lifestyle therapy, medication regimens, or bariatric surgery for obesity will need cohesive planning to help them effectively transition to adult care, with continued necessary monitoring, support, and intervention. Transition programs for obesity are an uncharted area requiring further research for efficacy. Despite a significant increase in research on pediatric obesity since the initial publication of these guidelines 8 years ago, further study is needed of the genetic and biological factors that increase the risk of weight gain and influence the response to therapeutic interventions. Also needed are more studies to better understand the genetic and biological factors that cause an obese individual to manifest one comorbidity vs another or to be free of comorbidities. Furthermore, continued investigation into the most effective methods of preventing and treating obesity and into methods for changing environmental and economic factors that will lead to worldwide cultural changes in diet and activity should be priorities. Particular attention to determining ways to effect systemic changes in food environments and total daily mobility, as well as methods for sustaining healthy body mass index changes, is of importance. PMID- 28359100 TI - Response to PD Miller, Underdiagnosis and Undertreatment of Osteoporosis: The Battle To Be Won. PMID- 28359101 TI - Treatment of Pediatric Obesity: An Umbrella Systematic Review. AB - Objective: Multiple interventions are available to reduce excess body weight in children. We appraised the quality of evidence supporting each intervention and assessed the effectiveness on different obesity-related outcomes. Methods: We conducted a systematic search for systematic reviews of randomized controlled trials evaluating pediatric obesity interventions applied for >=6 months. We assessed the quality of evidence for each intervention using GRADE (Grading of Recommendation, Assessment, Development, and Evaluation) approach. Results: From 16 systematic reviews, we identified 133 eligible randomized controlled trials. Physical activity interventions reduced systolic blood pressure and fasting glucose (low to moderate quality of evidence). Dietary interventions with low carbohydrate diets had a similar effect to low-fat diets in terms of body mass index (BMI) reduction (moderate quality of evidence). Educational interventions reduced waist circumference, BMI, and diastolic blood pressure (low quality of evidence). Pharmacological interventions reduced BMI (metformin, sibutramine, orlistat) and waist circumference (sibutramine, orlistat) and increased high density lipoprotein cholesterol (sibutramine) but also raised systolic and diastolic blood pressure (sibutramine). Surgical interventions (laparoscopic adjustable gastric banding, Roux-en-Y gastric bypass, sleeve gastrectomy) resulted in the largest BMI reduction (moderate quality of evidence). Combined interventions consisting of dietary modification, physical activity, behavioral therapy, and education significantly reduced systolic and diastolic blood pressure, BMI, and triglycerides. Combined parent-child interventions and parent only interventions had similar effects on BMI (low quality of evidence). Conclusions: Several childhood obesity interventions are effective in improving metabolic and anthropometric measures. A comprehensive multicomponent intervention, however, appears to have the best overall outcomes. PMID- 28359102 TI - Surgery for Neck Recurrence of Differentiated Thyroid Cancer: Outcomes and Risk Factors. AB - Background: Persistent/recurrent disease in the neck is frequent in patients with differentiated thyroid cancer (DTC). Objective: Assess efficacy, safety, and prognostic factors of first neck reoperation in DTC. Methods: Retrospective study of consecutive patients undergoing neck reoperation for recurrent/persistent DTC in a referral cancer center. Response after reoperation was defined according to the 2015 American Thyroid Association guidelines. Findings: One hundred sixty-one DTC patients were enrolled (64% females, median age 35 years, 96% papillary DTC). Initial stage was pT3 in 43% and pT4 in 10%, pN1 in 74%. Aggressive histology was present in 25% of the patients, in both primary and persistent/recurrent tumor. Four patients had no malignancy in the reoperative specimen, and 1 patient died due to postoperative hematoma and was excluded from further analysis. Following reoperation, 15 patients (10%) had persistent structural disease, 16 (10%) had biochemical incomplete response, 26 (17%) had indeterminate response, and 99 (63%) had complete response (CR), among whom 24 relapsed later. After a median follow-up of 5 years, only 83 patients (53%) had CR without the need for further treatments. The rate of permanent complications was: hypoparathyroidism 2%, laryngeal nerve palsy 0.6%, other 6%. Age >=45 years, aggressive histology, and lymph node ratio >=0.6 at initial surgery were independent risk factors for incomplete response after reoperation. Male sex, aggressive histology, and >=10 metastases at reoperation were independent risk factors of secondary relapse following CR achieved with reoperation. Conclusion: A careful risk-benefit analysis should guide surgical decision, particularly in patients with risk factors for incomplete response. PMID- 28359103 TI - Letter to the Editor: Metabolically Healthy (and Fit?) Obesity. PMID- 28359104 TI - Letter to the Editor: Severe Rebound-Associated Vertebral Fractures After Denosumab Discontinuation: Nine Clinical Cases Report. PMID- 28359106 TI - Erratum. PMID- 28359105 TI - Response to the Letter by Trovas. PMID- 28359107 TI - Corrigendem. PMID- 28359109 TI - Biomarkers of Pelvic Endometriosis. PMID- 28359108 TI - Worldwide Dissatisfaction With the Diagnostic Process and Initial Treatment of PCOS. PMID- 28359110 TI - Influence of Body Image in Women Undergoing Treatment for Breast Cancer. AB - Objective The objective of this study was to investigate the self-esteem of women with and without breast cancer regarding their body image. Methods A quantitative, case-control study in which 90 women with breast cancer were evaluated in the case group, and 77 women without breast cancer in the control group. For data collection, the body satisfaction scale (BSS), a scale adapted and validated in Brazil, and the Rosenberg self-esteem questionnaire were used. For the statistical analysis of the data, the Statistical Package for the Social Sciences software (IBM-SPSS, Chicago, Il, US), version 16.0 was used. Results Compared with the women without breast cancer, those with breast cancer were more dissatisfied with body image related to appearance. Women undergoing neoadjuvant chemotherapy were more dissatisfied with their appearance compared with those with cancer who were not undergoing this treatment. Mastectomy also accounted for more dissatisfaction concerning appearance among women who underwent the procedure compared with the women who were submitted to breast-conserving therapy. Conclusion Women with breast cancer were more dissatisfied with their body image compared with those without breast cancer, particularly following mastectomy or during chemotherapy. The self-esteem was found to be negatively affected in patients who were dissatisfied with their body image. PMID- 28359111 TI - [Medical Rehabilitation as an Attractive Field of Work for Medical Doctors? - A Qualitative Survey]. AB - In the German Health system there is an increasing competition in the recruitment of specialised staff, especially for rehabilitation centres, which are deemed less attractive. Therefore, this study examines the attractiveness of the field of medical rehabilitation from the point of view of medical professionals. We conducted 16 semi-structured interviews with doctors from 7 rehabilitation centres with different medical specialisations. The interviews were digitized and transcribed. A structured content analysis was carried out using the software MAXQDA 11. 745 codes were identified and assigned to the categories "attractiveness", "unfavourable aspects" and "special features" of rehabilitation. Regarding medical rehabilitation, the interviewees appreciated especially the predictable, flexible working environment with little time pressure. Other than working with rehabilitative patients working as part of an interdisciplinary team was of high importance for the interviewees. Among the special features of rehabilitation in comparison with acute care were the higher relevance of the bio-psycho-social model of health and illness as well as the higher proportion of communication and organisation. Medical rehabilitation in Germany is an attractive field of work for medical doctors. This fact should be considered more with regards to rehabilitation's public image. PMID- 28359112 TI - [Rehabilitation Processes in Out- and Inpatient Rehabilitation after Radical Prostatectomy]. AB - We evaluated processes in in- and outpatient rehabilitation after radical prostatectomy. Overall, we analyzed motivation and expectations of 119 in- and 719 outpatients (aged<=64) at the beginning of rehabilitation as well as satisfaction and the amount of interventions at the end. Compared to inpatients outpatients had a higher socio-economic status and better physical condition. Both groups reported similar outcomes regarding motivation, expectation and satisfaction. Furthermore in- and outpatients got a comparable amount of interventions, but both groups differed to some extent in regard to the kind of interventions. In- and outpatients are comparable in regard to their received amount of interventions. Discrepancies concerning the kind of interventions are due to differences between in- and outpatients. The results indicate specific patients' characteristics in both settings, but more research is needed to verify these findings. PMID- 28359113 TI - [Development and Current Status of the Health Education Curriculum of the German Pension Insurance]. AB - The health education curriculum of the German pension insurance comprises 27 patient education programs that are mostly indication-based. The curriculum aims to support the implementation of patient-oriented patient education in German rehabilitation centers. The effectiveness of several of the educational programs was evaluated in controlled trials with heterogeneous results. Overall, the dissemination of the evaluated programs in rehabilitation practice can be recommended. They constitute an essential part of the overall treatment concept, but are often modified in clinical practice. In particular, the physician led modules are frequently conducted in larger group settings. It is currently considered how these routine working conditions might be reflected in the quality assurance system of the German pension insurance and a cross-organizational conceptual framework. PMID- 28359114 TI - ? PMID- 28359115 TI - ? PMID- 28359117 TI - ? PMID- 28359116 TI - ? PMID- 28359118 TI - ? PMID- 28359119 TI - ? PMID- 28359120 TI - ? PMID- 28359121 TI - ? PMID- 28359122 TI - ? PMID- 28359123 TI - ? PMID- 28359124 TI - ? PMID- 28359126 TI - ? PMID- 28359125 TI - ? PMID- 28359127 TI - ? PMID- 28359128 TI - ? PMID- 28359129 TI - ? PMID- 28359130 TI - ? PMID- 28359131 TI - [Sports Injuries and Illnesses of the German National Team during the 2016 Olympic Summer Games in Rio de Janeiro]. AB - : Background This article aims to survey and describe the injuries and illnesses of the German Team during the 2016 Olympic Games in Rio de Janeiro. Methods Through an electronic documentation system, injuries and illnesses requiring treatment were recorded and evaluated. An injury or illness was defined as any physical symptom that required medical attention and impaired participation in training and/or competition. The classification distinguished between type of injury (acute or overload), region and type of illness (infections, skin, allergy, etc.). Results A total of 808 treatments were performed on the German team during Rio 2016. Out of 283 musculoskeletal-related treatments, 160 were performed on the lower limb. 70 treatments addressed back problems. 164 treatments were performed due to upper respiratory tract infections. When extrapolated to 1000 athletes, 617 treatments were required due to illness while 672 treatments addressed musculoskeletal problems. The number of treatments for injuries and illness is almost identical. In addition to less severe problems, the following serious injuries occurred: lethal traumatic brain injury, acute thigh compartment syndrome, ACL tear with a medial meniscal lesion and antero lateral instability, isolated ACL tear, stress fracture of the base of the third metatarsal bone, acute lateral ankle instability, AC joint dislocation, and infected bursa prepatellaris. CONCLUSIONS: The documentation system is reliable for "injury and illness surveillance" at multi-sport events. Treatment numbers are consistent with the 2012 Summer Games in London, so a reliable strategy can be assumed. In addition to illnesses predominantly affecting the upper respiratory tract, the system also recorded serious musculoskeletal injuries, which implicates the need for an interdisciplinary setup of the medical team. The methods used for data collection currently do not allow for the identification of risk factors for injuries and illness and should therefore be extended in the future. PMID- 28359132 TI - Point-of-Care Testing in Liver Disease and Liver Surgery. AB - The alterations in coagulation and hemostasis that accompany liver disease are complex, and while patients with this disease have traditionally been perceived as having a bleeding diathesis, it is now understood that in stable patients hemostasis is "re-balanced." Hepatic surgery, and particularly liver transplantation, can be associated with large fluid shifts, massive bleeding, and coagulopathy, as well as postoperative thrombosis. Point-of-care tests (POCTs) of coagulation facilitate goal-directed treatments and hemostatic monitoring in dynamic environments where the coagulation status can alter rapidly and often unpredictably. POCTs reflect more accurately the re-balanced hemostatic system than do conventional coagulation tests (CCTs). Viscoelastic POCT-guided transfusion algorithms permit a reduction in blood product administration and are a key component of patient blood management programs. Moreover, viscoelastic POCTs are better able to identify patients with hypercoagulability than CCTs. With thrombosis increasingly recognized to be a problem in patients with liver disease, POCTs hold promise for both individualized bleeding and thrombosis management. PMID- 28359133 TI - Point-of-Care Coagulation Testing in Cardiac Surgery. AB - Bleeding complications after cardiac surgery are common and are associated with increased morbidity and mortality. Their etiology is multifactorial, and treatment decisions are time sensitive. Point-of-care (POC) testing has an advantage over standard laboratory tests for faster turn-around times, and timely decision on coagulation intervention(s). The most common POC coagulation testing is the activated clotting time (ACT), used to monitor heparin therapy while on cardiopulmonary bypass. Viscoelastic coagulation tests including thromboelastometry (ROTEM) and thromboelastography (TEG) have been recommended for the treatment of postoperative bleeding after cardiac surgery because the ROTEM/TEG-guided treatment algorithms reduced the use of blood products. Other POC tests are commercially available, but there is sparse evidence for their routine use in cardiac surgery. These devices include heparin management systems, POC prothrombin time and activated partial thromboplastin time, POC fibrinogen assay, and whole blood platelet function tests. There are multiple confounding elements and conditions associated with cardiac surgery, which can significantly alter test results. Anemia and thrombocytopenia are regularly associated with deviations in many POC devices. In summary, POC coagulation testing allows for rapid clinical decisions in hematological interventions, and, when used in conjunction with a proper transfusion algorithm, may reduce blood product usage, and potentially complications associated with blood transfusion. PMID- 28359134 TI - Circulating Extracellular DNA: Cause or Consequence of Thrombosis? AB - Thrombosis leads to ischemic organ damage in cardiovascular and thromboembolic diseases. Neutrophils promote thrombosis in vitro and in vivo by releasing neutrophil extracellular traps (NETs). NETs are composed of DNA filaments coated with histones and neutrophil enzymes such as myeloperoxidase (MPO). Circulating extracellular DNA (ceDNA) is widely used as a surrogate marker to monitor NET formation in thrombosis. This narrative review summarizes the association of ceDNA with human thrombosis. Levels of ceDNA indicate the extent and outcome of several cardiovascular and thromboembolic diseases, including myocardial infarction, stroke, and venous thromboembolism. ceDNA correlates with markers of coagulation and platelet consumption, thus supporting the hypothesis that ceDNA may be a surrogate marker of thrombus formation. In addition, ceDNA levels correlate with markers of cell injury and size of ischemic lesions, suggesting that ceDNA does not derive from NETs but is probably released from damaged organs. Few studies identified NET-specific biomarkers such as DNA-MPO complexes in the blood of patients with thrombosis. In conclusion, it remains to be established whether ceDNA in patients derives from NETs and is a cause or consequence of thrombosis. PMID- 28359135 TI - Scoring Systems for Estimating the Risk of Anticoagulant-Associated Bleeding. AB - Anticoagulant medications are frequently used to prevent and treat thromboembolic disease. However, the benefits of anticoagulants must be balanced with a careful assessment of the risk of bleeding complications that can ensue from their use. Several bleeding risk scores are available, including the Outpatient Bleeding Risk Index, HAS-BLED, ATRIA, and HEMORR2HAGES risk assessment tools, and can be used to help estimate patients' risk for bleeding on anticoagulants. These tools vary by their individual risk components and in how they define and weigh clinical factors. However, it is not yet clear how best to integrate bleeding risk tools into clinical practice. Current bleeding risk scores generally have modest predictive ability and limited ability to predict the most devastating complication of anticoagulation, intracranial hemorrhage. In clinical practice, bleeding risk tools should be paired with a formal determination of thrombosis risk, as their results may be most influential for patients at the lower end of thrombosis risk, as well as for highlighting potentially modifiable risk factors for bleeding. Use of bleeding risk scores may assist clinicians and patients in making informed and individualized anticoagulation decisions. PMID- 28359136 TI - Point-of-Care Testing in Burn Patients. AB - Severe burn injury has an impact on the coagulation system, but a unique definition regarding these changes is still missing. The results of conventional coagulation assays (CCAs) measured in daily clinical practice are often interpreted as coagulopathic, which implies a bleeding tendency. However, viscoelastic coagulation assays (VCA) like Rotational Thromboelastometry (ROTEM) and Thromboelastography (TEG) depict a hypercoagulable state. Therefore, hemostatic interventions should not be indicated according to deranged CCA results, but only in case of clinically relevant bleeding plus indicative VCA results. Massive blood loss mainly results from surgical excision of burn wounds. VCAs seem to be capable of guiding target-oriented coagulation management in this context. Owing to the increased thromboembolic risk, it appears rational to individualize pharmacologic venous thromboembolism prophylaxis by using sensitive laboratory tests and drug monitoring. Studies evaluating the use of new VCA test modifications are highly warranted and may substantially improve outcome in this difficult-to-treat patient population. PMID- 28359137 TI - An Ultrasensitive Gold Nanoparticle-based Lateral Flow Test for the Detection of Active Botulinum Neurotoxin Type A. AB - Botulism is a severe and potentially lethal paralytic disease caused by several botulinum neurotoxin-producing Clostridia spp. In China, the majority of the cases caused by botulism were from less-developed rural areas. Here, we designed specific substrate peptides and reconfigured gold nanoparticle-based lateral flow test strip (LFTS) to develop an endopeptidase-based lateral flow assay for the diagnosis of botulism. We performed this lateral flow assay on botulinum neurotoxin-spiked human serum samples. The as-prepared LFTS had excellent performance in the detection of botulinum neurotoxin using only 1 MUL of simulated serum, and its sensitivity and specificity were comparable to that of mouse lethality assay. Moreover, the assay takes only half a day and does not require highly trained laboratory staff, specialized facility, or equipment. Finally, our LFTS can be potentially extended to other serotypes of BoNTs by designing specific substrate peptides against the different types of BoNTs. Overall, we demonstrate a strategy by which LFTS and endopeptidase activity assays can be integrated to achieve facile and economic diagnosis of botulism in resource-limited settings. PMID- 28359138 TI - Mechanical Deformation Mechanisms and Properties of Prion Fibrils Probed by Atomistic Simulations. AB - Prion fibrils, which are a hallmark for neurodegenerative diseases, have recently been found to exhibit the structural diversity that governs disease pathology. Despite our recent finding concerning the role of the disease-specific structure of prion fibrils in determining their elastic properties, the mechanical deformation mechanisms and fracture properties of prion fibrils depending on their structures have not been fully characterized. In this work, we have studied the tensile deformation mechanisms of prion and non-prion amyloid fibrils by using steered molecular dynamics simulations. Our simulation results show that the elastic modulus of prion fibril, which is formed based on left-handed beta helical structure, is larger than that of non-prion fibril constructed based on right-handed beta-helix. However, the mechanical toughness of prion fibril is found to be less than that of non-prion fibril, which indicates that infectious prion fibril is more fragile than non-infectious (non-prion) fibril. Our study sheds light on the role of the helical structure of amyloid fibrils, which is related to prion infectivity, in determining their mechanical deformation mechanisms and properties. PMID- 28359139 TI - Photoluminescence Study of the Interface Fluctuation Effect for InGaAs/InAlAs/InP Single Quantum Well with Different Thickness. AB - Photoluminescence (PL) is investigated as a function of the excitation intensity and temperature for lattice-matched InGaAs/InAlAs quantum well (QW) structures with well thicknesses of 7 and 15 nm, respectively. At low temperature, interface fluctuations result in the 7-nm QW PL exhibiting a blueshift of 15 meV, a narrowing of the linewidth (full width at half maximum, FWHM) from 20.3 to 10 meV, and a clear transition of the spectral profile with the laser excitation intensity increasing four orders in magnitude. The 7-nm QW PL also has a larger blueshift and FWHM variation than the 15-nm QW as the temperature increases from 10 to ~50 K. Finally, simulations of this system which correlate with the experimental observations indicate that a thin QW must be more affected by interface fluctuations and their resulting potential fluctuations than a thick QW. This work provides useful information on guiding the growth to achieve optimized InGaAs/InAlAs QWs for applications with different QW thicknesses. PMID- 28359140 TI - Gold Nanoparticles as a Direct and Rapid Sensor for Sensitive Analytical Detection of Biogenic Amines. AB - A new optical sensor was developed for rapid screening with high sensitivity for the existence of biogenic amines (BAs) in poultry meat samples. Gold nanoparticles (GNPs) with particle size 11-19 nm function as a fast and sensitive biosensor for detection of histamine resulting from bacterial decarboxylation of histidine as a spoilage marker for stored poultry meat. Upon reaction with histamine, the red color of the GNPs converted into deep blue. The appearance of blue color favorably coincides with the concentration of BAs that can induce symptoms of poisoning. This biosensor enables a semi-quantitative detection of analyte in real samples by eye-vision. Quality evaluation is carried out by measuring histamine and histidine using different analytical techniques such as UV-vis, FTIR, and fluorescence spectroscopy as well as TEM. A rapid quantitative readout of samples by UV-vis and fluorescence methods with standard instrumentation were proposed in a short time unlike chromatographic and electrophoretic methods. Sensitivity and limit of detection (LOD) of 6.59 * 10-4 and 0.6 MUM, respectively, are determined for histamine as a spoilage marker with a correlation coefficient (R 2) of 0.993. PMID- 28359141 TI - The Study of Electrical Properties for Multilayer La2O3/Al2O3 Dielectric Stacks and LaAlO3 Dielectric Film Deposited by ALD. AB - The capacitance and leakage current properties of multilayer La2O3/Al2O3 dielectric stacks and LaAlO3 dielectric film are investigated in this paper. A clear promotion of capacitance properties is observed for multilayer La2O3/Al2O3 stacks after post-deposition annealing (PDA) at 800 degrees C compared with PDA at 600 degrees C, which indicated the recombination of defects and dangling bonds performs better at the high-k/Si substrate interface for a higher annealing temperature. For LaAlO3 dielectric film, compared with multilayer La2O3/Al2O3 dielectric stacks, a clear promotion of trapped charges density (N ot) and a degradation of interface trap density (D it) can be obtained simultaneously. In addition, a significant improvement about leakage current property is observed for LaAlO3 dielectric film compared with multilayer La2O3/Al2O3 stacks at the same annealing condition. We also noticed that a better breakdown behavior for multilayer La2O3/Al2O3 stack is achieved after annealing at a higher temperature for its less defects. PMID- 28359142 TI - Structural Properties Characterized by the Film Thickness and Annealing Temperature for La2O3 Films Grown by Atomic Layer Deposition. AB - La2O3 films were grown on Si substrates by atomic layer deposition technique with different thickness. Crystallization characteristics of the La2O3 films were analyzed by grazing incidence X-ray diffraction after post-deposition rapid thermal annealing treatments at several annealing temperatures. It was found that the crystallization behaviors of the La2O3 films are affected by the film thickness and annealing temperatures as a relationship with the diffusion of Si substrate. Compared with the amorphous La2O3 films, the crystallized films were observed to be more unstable due to the hygroscopicity of La2O3. Besides, the impacts of crystallization characteristics on the bandgap and refractive index of the La2O3 films were also investigated by X-ray photoelectron spectroscopy and spectroscopic ellipsometry, respectively. PMID- 28359143 TI - Electronic Properties of a New All-Inorganic Perovskite TlPbI3 Simulated by the First Principles. AB - All-inorganic perovskites have been recognized as promising photovoltaic materials. We simulated the perovskite material of TlPbI3 using ab initio electronic structure calculations. The band gap of 1.33 eV is extremely close to the theoretical optimum value. Compared TlPbI3 with CsPbI3, the total energy ( 3980 eV) of the former is much lower than the latter. The partial density of states (PDOS) of TlPbI3 shows that a strong bond exists between Tl and I, resulting in the lower total energy and more stable existence than CsPbI3. PMID- 28359144 TI - Mind Bomb-Binding Partner RanBP9 Plays a Contributory Role in Retinal Development. AB - Ran-binding protein family member, RanBP9 has been reported in various basic cellular mechanisms and neuropathological conditions including schizophrenia. Previous studies have reported that RanBP9 is highly expressed in the mammalian brain and retina; however, the role of RanBP9 in retinal development is largely unknown. Here, we present the novel and regulatory roles of RanBP9 in retinal development of a vertebrate animal model, zebrafish. Zebrafish embryos exhibited abundant expression of ranbp9 in developing brain tissues as well as in the developing retina. Yeast two-hybrid screening demonstrated the interaction of RanBP9 with Mind bomb, a component of Notch signaling involved in both neurogenesis and neural disease autism. The interaction is further substantiated by co-localization studies in cultured cells. Knockdown of ranbp9 resulted in retinal dysplasia with defective proliferation of retinal cells, downregulation of neuronal differentiation marker huC, elevation of neural proliferation marker her4, and alteration of cell cycle marker p57kip2. Expression of the Muller glial cell marker glutamine synthase was also affected in knockdown morphants. Our results suggest that Mind bomb-binding partner RanBP9 plays a role during retinal cell development of zebrafish embryogenesis. PMID- 28359146 TI - Transforming Growth Factor beta1/Smad4 Signaling Affects Osteoclast Differentiation via Regulation of miR-155 Expression. AB - Transforming growth factor beta1 (TGFbeta1)/Smad4 signaling plays a pivotal role in maintenance of the dynamic balance between bone formation and resorption. The microRNA miR-155 has been reported to exert a significant role in the differentiation of macrophage and dendritic cells. The goal of this study was to determine whether miR-155 regulates osteoclast differentiation through TGFbeta1/Smad4 signaling. Here, we present that TGFbeta1 elevated miR-155 levels during osteoclast differentiation through the stimulation of M-CSF and RANKL. Additionally, we found that silencing Smad4 attenuated the upregulation of miR 155 induced by TGFbeta1. The results of luciferase reporter experiments and ChIP assays demonstrated that TGFbeta1 promoted the binding of Smad4 to the miR-155 promoter at a site located in 454 bp from the transcription start site in vivo, further verifying that miR-155 is a transcriptional target of the TGFbeta1/Smad4 pathway. Subsequently, TRAP staining and qRT-PCR analysis revealed that silencing Smad4 impaired the TGFbeta1-mediated inhibition on osteoclast differentiation. Finally, we found that miR-155 may target SOCS1 and MITF to suppress osteoclast differentiation. Taken together, we provide the first evidence that TGFbeta1/Smad4 signaling affects osteoclast differentiation by regulation of miR 155 expression and the use of miR-155 as a potential therapeutic target for osteoclast-related diseases shows great promise. PMID- 28359145 TI - Neuroprotective Effects of Protein Tyrosine Phosphatase 1B Inhibition against ER Stress-Induced Toxicity. AB - Several lines of evidence suggest that endoplasmic reticulum (ER) stress plays a critical role in the pathogenesis of many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Protein tyrosine phosphatase 1B (PTP1B) is known to regulate the ER stress signaling pathway, but its role in neuronal systems in terms of ER stress remains largely unknown. Here, we showed that rotenone-induced toxicity in human neuroblastoma cell lines and mouse primary cortical neurons was ameliorated by PTP1B inhibition. Moreover, the increase in the level of ER stress markers (eIF2alpha phosphorylation and PERK phosphorylation) induced by rotenone treatment was obviously suppressed by concomitant PTP1B inhibition. However, the rotenone-induced production of reactive oxygen species (ROS) was not affected by PTP1B inhibition, suggesting that the neuroprotective effect of the PTP1B inhibitor is not associated with ROS production. Moreover, we found that MG132 induced toxicity involving proteasome inhibition was also ameliorated by PTP1B inhibition in a human neuroblastoma cell line and mouse primary cortical neurons. Consistently, downregulation of the PTP1B homologue gene in Drosophila mitigated rotenone- and MG132-induced toxicity. Taken together, these findings indicate that PTP1B inhibition may represent a novel therapeutic approach for ER stress mediated neurodegenerative diseases. PMID- 28359148 TI - Dirac Nodal Lines and Tilted Semi-Dirac Cones Coexisting in a Striped Boron Sheet. AB - The enchanting Dirac fermions in graphene stimulated us to seek other 2D Dirac materials, and boron monolayers may be a good candidate. So far, a number of monolayer boron sheets have been theoretically predicted, and three have been experimentally prepared. However, none of intrinsic sheets possess Dirac electrons near the Fermi level. Herein, by means of density functional theory computations, we identified a new boron monolayer, namely, hr-sB, with two types of Dirac fermions coexisting in the sheet: One type is related to Dirac nodal lines traversing Brillouin zone (BZ) with velocities approaching 106 m/s, and the other is related to tilted semi-Dirac cones with strong anisotropy. This newly predicted boron monolayer consists of hexagon and rhombus stripes. With an exceptional stability comparable to the experimentally achieved boron sheets, it is rather optimistic to grow hr-sB on some suitable substrates such as the Ag (111) surface. PMID- 28359149 TI - Hydroheteroarylation of Unactivated Alkenes Using N-Methoxyheteroarenium Salts. AB - We report the first reductive coupling of unactivated alkenes with N-methoxy pyridazinium, imidazolium, quinolinium, and isoquinolinium salts under hydrogen atom transfer (HAT) conditions, and an expanded scope for the coupling of alkenes with N-methoxy pyridinium salts. N-Methoxy pyridazinium, imidazolium, quinolinium, and isoquinolinium salts are accessible in 1-2 steps from the commercial arenes or arene N-oxides (25-99%). N-Methoxy imidazolium salts are accessible in three steps from commercial amines (50-85%). In total 36 discrete methoxyheteroarenium salts bearing electron-donating, electron-withdrawing, alkyl, aryl, halogen, and haloalkyl substituents were prepared (several in multigram quantities) and coupled with 38 different alkenes. The transformations proceed under neutral conditions at ambient temperature, provide monoalkylation products exclusively, and form a single alkene addition regioisomer. Preparatively useful and complementary site selectivities in the addition of secondary and tertiary radicals to pyidinium salts are documented: harder secondary radicals favor C-2 addition (2->10:1), while softer tertiary radicals favor bond formation to C-4 (4.7->29:1). A diene possessing a 1,2-disubstituted and 2,2-disubstituted alkene undergoes hydropyridylation at the latter exclusively (61%) suggesting useful site selectivities can be obtained in polyene substrates. The methoxypyridinium salts can also be employed in dehydrogenative arylation, borono-Minisci, and tandem arylation processes. Mechanistic studies support the involvement of a radical process. PMID- 28359147 TI - Functional Enhancers As Master Regulators of Tissue-Specific Gene Regulation and Cancer Development. AB - Tissue-specific transcription is critical for normal development, and abnormalities causing undesirable gene expression may lead to diseases such as cancer. Such highly organized transcription is controlled by enhancers with specific DNA sequences recognized by transcription factors. Enhancers are associated with chromatin modifications that are distinct epigenetic features in a tissue-specific manner. Recently, super-enhancers comprising enhancer clusters co-occupied by lineage-specific factors have been identified in diverse cell types such as adipocytes, hair follicle stem cells, and mammary epithelial cells. In addition, noncoding RNAs, named eRNAs, are synthesized at super-enhancer regions before their target genes are transcribed. Many functional studies revealed that super-enhancers and eRNAs are essential for the regulation of tissue-specific gene expression. In this review, we summarize recent findings concerning enhancer function in tissue-specific gene regulation and cancer development. PMID- 28359151 TI - Glutamic Acids Bearing Calix[4]arene Micelles: pH-Controllable Aggregation Number Corresponding to Regular Polyhedra. AB - We have prepared a new calix[4]arene-based lipid containing glutamic acid as the hydrophilic group. The alpha-amine and the gamma-carboxylic acid groups of the glutamic acid moiety allowed a continuous change in the state of the headgroup from cationic to zwitterionic and then to anionic with increasing pH. Accompanying this headgroup change, micelles of the lipid underwent a morphological transformation from spherical to cylindrical and again to spherical. The morphological transition was ascribed to the change in the lipid conformation corresponding to the pH conditions. Interestingly, at acidic and basic pH, the spherical micelles demonstrated monodispersity in terms of the aggregation number, which agreed with the vertex numbers of Platonic solids, indicating the formation of Platonic micelles. At acidic and basic pH, the lipid conformations were almost identical, but there was a slight difference in the hydrophilic volume, which might affect the packing behavior of the lipid in micelles and account for the difference in the aggregation number. This study clearly demonstrates the precise pH-controllable aggregation number of micelles, which belong to the Platonic micelle systems. PMID- 28359150 TI - Role of Surface Stress on the Reactivity of Anatase TiO2(001). AB - In contrast with theoretical predictions in which anatase TiO2(001) and its (1 * 4) reconstructed surfaces are highly reactive, recent experimental results show this surface to be inert except for the defect sites. In this report, based on a systematic study of anatase TiO2(001)-(1 * 4) surface using first-principles calculations, the tensile stress is shown to play a crucial role on the surface reactivity. The predicted high reactivity based on add-molecule model is due to the large surface tensile stress, which can be easily suppressed by a stress release mechanism. We show that various surface defects can induce stress release concomitantly with surface passivation. Thus the synthesis of anatase(001) surface with few defects is essential to improve the reactivity, which can be achieved, for example, via H2O adsorption. Our study provides a uniform interpretation of controversial experimental observations and theoretical predictions on anatase TiO2(001) surface and further proposes new insights into the origin of surface reactivity. PMID- 28359152 TI - Enhancement of the Hydrogen-Bonding Network of Water Confined in a Polyelectrolyte Brush. AB - Water existing in the vicinity of polyelectrolytes exhibits unique structural properties, which demonstrate key roles in chemistry, biology, and geoscience. In this study, X-ray absorption and emission spectroscopy was employed to observe the local hydrogen-bonding structure of water confined in a charged polyelectrolyte brush. Even at room temperature, a majority of the water molecules confined in the polyelectrolyte brush exhibited one type of hydrogen bonding configuration: a slightly distorted, albeit ordered, configuration. The findings from this study provide new insight in terms of the correlation between the function and local structure of water at the interface of biological materials under physiological conditions. PMID- 28359154 TI - Eucheuma cottonii Sulfated Oligosaccharides Decrease Food Allergic Responses in Animal Models by Up-regulating Regulatory T (Treg) Cells. AB - In the present study, the anti-food allergy activity of Eucheuma cottonii sulfated oligosaccharide (ESO) was investigated. ESO was obtained by enzymatic degradation and purified by column chromatography. RBL-2H3 cells and BALB/c mouse model were used to test the anti-food allergy activity of ESO. The effects of ESO on the regulatory T (Treg) cells and bone marrow-derived mast cells (BMMCs) were investigated by flow cytometry. The results of in vivo assay showed that ESO decreased the levels of mast cell protease-1 and histamine and inhibited the levels of specific IgE by 77.7%. In addition, the production of interleukin (IL) 4 and IL-13 was diminished in the ESO groups compared to the non-ESO-treated group. Furthermore, ESO could up-regulate Treg cells by 22.2-97.1%. In conclusion, ESO decreased the allergy response in mice by reducing basophil degranulation, up-regulating Treg cells via Forkhead box protein 3 (Foxp3), and releasing IL-10. ESO may have preventive and therapeutic potential in allergic disease. PMID- 28359155 TI - Visualization and Inhibition of Mitochondria-Nuclear Translocation of Apoptosis Inducing Factor by a Graphene Oxide-DNA Nanosensor. AB - High concentrations of oxidized low density lipoprotein (oxLDL) induce aberrant apoptosis of vascular smooth muscle cells (VSMCs) in atherosclerotic plaques. This apoptosis cannot be blocked completely by the inhibition of caspase, and it eventually potentiates plaque disruption and risk for cardiovascular disease. Given the important role of apoptosis inducing factor (AIF) in caspase independent apoptosis, here we develop an AIF-targeting nanosensor by the assembly of graphene oxide (GO) nanosheets and dye-labeled DNA hybrid structures. This nanosensor selectively localizes in the cytosol of VSMCs, where it exhibits a "turn-off" fluorescence signal. Under oxLDL stimuli, the release of AIF from mitochondria into cytosol liberates the DNA hybrid structures from the surface of GO and results in a "turn-on" fluorescence signal. This nanosensor is shown to possess rapid response, high sensitivity, and selectivity for AIF that enables real-time imaging of AIF translocation in VSMCs. Using this novel nanosensor, a better assessment of the apoptotic level of VSMCs and a more accurate evaluation of the extent of atherosclerotic lesions can be obtained. More importantly, the abundant binding between DNA hybrid structures and AIF inhibits the translocation of AIF into the nucleus and subsequent apoptosis in VSMCs. This inhibition may help stabilize plaque and reduce the risk of heart attack and stroke. PMID- 28359153 TI - Harnessing Alkyl Amines as Electrophiles for Nickel-Catalyzed Cross Couplings via C-N Bond Activation. AB - We developed a strategy to harness alkyl amines as alkylating agents via C-N bond activation. This Suzuki-Miyaura cross coupling of alkylpyridinium salts, readily formed from primary amines, is the first example of a metal-catalyzed cross coupling via C-N bond activation of an amine with an unactivated alkyl group. This reaction enjoys broad scope and functional group tolerance. Primary and secondary alkyl groups can be installed. Preliminary studies suggest a NiI/NiIII catalytic cycle. PMID- 28359156 TI - Solvent- and Pressure-Induced Phase Changes in Two 3D Copper Glutarate-Based Metal-Organic Frameworks via Glutarate (+gauche ? -gauche) Conformational Isomerism. AB - Two isoreticular three-dimensional copper(II) glutarate-based pillared-layered metal-organic frameworks (MOFs) with flexible pillars, [Cu2(glu)2(bpa)] and [Cu2(glu)2(bpp)] (bpa = 1,2-bis(4-pyridyl)ethane; bpp = 1,3-bis(4 pyridyl)propane), undergo spontaneous phase changes upon solvent loss at room temperature. Using single-crystal X-ray diffraction analysis (SCXRD), we show that the phase changes result in new narrow-channel forms that experience a large reduction in solvent-accessible volume. Moreover, the [Cu2(glu)2(bpa)] MOF displays a stepped sorption isotherm for the uptake of CO2 at room temperature. This is indicative of reversion of the framework to the wide-channel form under CO2 pressure. Supercritical CO2 was used to isolate the gas-included structures, and by means of SCXRD we were able to determine the positions of the CO2 molecules in the channels of the frameworks. Finally, we report the use of molecular modeling simulations to elucidate the phase-change mechanism, including the energetic changes involved. Structural limitations in both MOFs allow for only direct gauche-gauche enantiomeric interconversion of the glutarate moieties. PMID- 28359157 TI - Inflammation Effects on Stent Restenosis. PMID- 28359158 TI - Relevant Insertion Site Anatomy of the Conventus Distal Radius System. AB - BACKGROUND: The Conventus Distal Radius System (DRS) is an intramedullary fixation scaffold inserted into the lateral aspect of the distal radius. The purpose of this study was to identify insertion site anatomy to illustrate risks associated with the minimally invasive nature of radial-sided implant application. METHODS: Ten cadavers were utilized. Using fluoroscopy, the 1.1-mm Kirschner wire and template was introduced per manufacturer's guidelines, access guide assembled, and dissection carried out to the superficial radial nerve (SRN) with preservation of the native location. The access guide marked the insertion location for the side-cut drill. This point was measured in relationship to structures nearby, including the SRN, brachioradialis (BR), lateral antebrachial cutaneous nerve (LABCN), and radial styloid (RS). RESULTS: The large guide contacted the SRN in 4 of 10 cadavers and was volar to it in 6 of 10. When volar, the mean distance was 1.7 mm. The tip of the RS to the large access guide averaged 44.5 mm. The small guide contacted the SRN in 2 of 10, was volar to it in 4 of 10, and between the bifurcation in 4 of 10. When volar, the distance averaged 3.25 mm. When bifurcated, the distance from the small guide to both the dorsal and volar branches was 3.5 mm. The distance from the RS to the small guide averaged 37.8 mm. The LABCN was found in the field of dissection in 4 of 10 cadavers. CONCLUSIONS: Several structures are at risk during insertion of the Conventus DRS; thus, knowledge of the relevant anatomy of this minimally invasive approach is crucial to optimize outcomes and patient satisfaction, and to avoid nerve injury. PMID- 28359160 TI - The association between insomnia symptoms and risk of cardio-cerebral vascular events: A meta-analysis of prospective cohort studies. AB - Background Insomnia symptoms have been suggested to be associated with the risk of cardio-cerebral events. However, the results of previous studies have been inconsistent. Therefore, we conducted a meta-analysis to examine whether there were associations between cardio-cerebral vascular events and insomnia symptoms, including difficulty initiating sleep, difficulty maintaining sleep, early morning awakening or non-restorative sleep. Design A meta-analysis of prospective cohort studies. Methods PubMed, Web of science and the Cochrane Library were searched without language restriction. Prospective cohort studies of adults with at least a 2-year follow-up duration were included. Random effect models were used in order to pool the results for each insomnia symptom. Subgroup and sensitivity analyses were conducted in order to assess potential heterogeneity, and funnel plots and Egger's tests were used in order to assess publication bias. Results Fifteen studies (23 cohorts) were included. Positive associations were observed between difficulty initiating sleep, difficulty maintaining sleep and non-restorative sleep with risk of cardio-cerebral vascular events. The pooled relative risks and 95% confidence intervals were 1.27 (1.15-1.40), 1.11 (1.04 1.19) and 1.18 (1.05-1.33), respectively. However, less evidence existed to support the conclusions about the association between early-morning awakening and cardio-cerebral vascular events. Conclusion Our meta-analysis demonstrated that insomnia symptoms of difficulty initiating sleep, difficulty maintaining sleep and non-restorative sleep were associated with an increased risk of future cardio cerebral vascular events. PMID- 28359162 TI - Shifting Landscapes: The Impact of Centralized and Decentralized Nursing Station Models on the Efficiency of Care. AB - OBJECTIVE: The focus of this research was to analyze the impact of decentralized and centralized hospital design layouts on the delivery of efficient care and the resultant level of caregiver satisfaction. BACKGROUND: An interdisciplinary team conducted a multiphased pre- and postoccupancy evaluation of a cardiovascular service line in an academic hospital that moved from a centralized to decentralized model. This study examined the impact of walkability, room usage, allocation of time, and visibility to better understand efficiency in the care environment. METHOD: A mixed-methods data collection approach was utilized, which included pedometer measurements of staff walking distances, room usage data, time studies in patient rooms and nurses' stations, visibility counts, and staff questionnaires yielding qualitative and quantitative results. RESULTS: Overall, the data comparing the centralized and decentralized models yielded mixed results. This study's centralized design was rated significantly higher in its ability to support teamwork and efficient patient care with decreased staff walking distances. The decentralized unit design was found to positively influence proximity to patients in a larger design footprint and contribute to increased visits to and time spent in patient rooms. CONCLUSION: Among the factors contributing to caregiver efficiency and satisfaction are nursing station design, an integrated team approach, and the overall physical layout of the space on walkability, allocation of caregiver time, and visibility. However, unit design alone does not solely impact efficiency, suggesting that designers must consider the broader implications of a culture of care and processes. PMID- 28359161 TI - Effective Medicinal Plant in Cancer Treatment, Part 2: Review Study. AB - Cancer is the second cause of death after cardiovascular diseases. With due attention to rapid progress in the phytochemical study of plants, they are becoming popular because of their anticancer effects. The aim of this study was to investigate the effective medicinal plants in the treatment of cancer and study their mechanism of action. In order to gather information the keywords "traditional medicine," "plant compounds," "medicinal plant," "medicinal herb," "toxicity," "anticancer effect," "cell line," and "treatment" were searched in international databases such as ScienceDirect, PubMed, and Scopus and national databases such as Magiran, Sid, and Iranmedex, and a total of 228 articles were collected. In this phase, 49 nonrelevant articles were excluded. Enhancement P53 protein expression, reducing the expression of proteins P27, P21, NFkappaB expression and induction of apoptosis, inhibition of the PI3K/Akt pathway, and reduction of the level of acid phosphatase and lipid peroxidation are the most effective mechanisms of herbal plants that can inhibit cell cycle and proliferation. Common treatments such as radiotherapy and chemotherapy can cause some complications. According to results of this study, herbal extracts have antioxidant compounds that can induce apoptosis and inhibit cell proliferation by the investigated mechanisms. PMID- 28359163 TI - Pityriasis rosea-like eruption induced by isotretinoin. AB - Pityriasis rosea is a common, self-limited and inflammatory skin disease. The etiology is not clearly known. Viral agents, autoimmunity, psychogenic factors and drugs have all been suggested as risk factors. Isotretinoin is usually used in the treatment of resistant, nodulocytic acne. We present a case of pityriasis rosea-like eruption induced by isotretinoin. To our knowledge, this is the second clinical case of pityriasis rosea-like eruption induced by isotretinoin. PMID- 28359164 TI - [Validation of the French Version of Parental Multidimensional Neglectful Behavior Scale]. PMID- 28359165 TI - Testing a Resilience Training Program in Police Recruits: A Pilot Study. AB - BACKGROUND: Stress from multiple sources is inherent in law enforcement. However, it is possible to modify responses to stress with resilience training that includes teaching techniques to modify emotional and physical responses to stress, interface with mental health professionals, and practice sessions to improve self-regulation of responses to stress including coherence, a measure of heart rate variability. A gap exists in the research, however, regarding evaluation of the duration of effects after the initial resilience training. METHOD: Subjects included ( N = 34) recruits enrolled in summer 2015 at the Milwaukee Police Academy. An experimental design was used to compare recruits who received resilience training to recruits in the control group. RESULTS: No statistically significant differences between the groups were found for self reported measures of stress and resilience. For the treatment group ( n = 17), change in coherence was significant ( p < .001) and improvement in the Personal Organizational Quality Assessment Emotional Buoyancy subscale correlated significantly with the number of practice sessions ( r = .63, p = .01) and marginally with change in coherence ( r = .47, p = .07). CONCLUSION: Results confirm several significant effects of resilience training with recruits. PMID- 28359166 TI - Leisure-Time Physical Activity and Characteristics of Social Network Support for Exercise Among Latinas. AB - PURPOSE: To examine the association between characteristics of social support for exercise and moderate-to-vigorous leisure-time physical activity (LTPA) among Latinas. DESIGN: This cross-sectional study used baseline data from a cluster randomized controlled trial. SETTING: The study was conducted in 16 churches located in San Diego County. PARTICIPANTS: Participants (N = 436) were Latinas between 18 and 65 years old who did not self-report >150 minutes or did not exceed 250 minutes of moderate-to-vigorous PA per week measured by accelerometer. MEASURES: Latinas listed up to 6 individuals who had provided support for exercise within the past 6 months, including their gender, relationship with the respondent, types of support provided, and respondent's satisfaction with support. Self-reported LTPA was dichotomized (none vs any). ANALYSES: We generated dyads between Latinas who named >=1 supporter (n = 323) and each supporter they named (n = 569 dyads). Logistic regression analyses were conducted using generalized estimating equations to adjust for multiple observations per participant. RESULTS: Having an exercise partner (odds ratio [OR]: 2.16; 95% confidence interval [CI]: 1.01-4.62), help with household duties (OR: 2.70; 95% CI: 1.35-3.38), being "very much" satisfied with support (OR: 2.33; 95% CI: 1.26 4.30), and naming >2 supporters (OR: 2.57; 95% CI: 1.06-6.25) was positively associated with LTPA. CONCLUSIONS: Findings suggest specific aspects of support for exercise that should be targeted in future interventions to promote LTPA. PMID- 28359167 TI - Biological aspects of human migration and mobility. AB - This paper reviews how migration, both geographical and social, impacts on variation in some human biological traits. Migration and mobility are considered in relation to anthropometric traits and indices, psychometric traits, health, disease and nutrition, temperature regulation and metabolism, mental health and gene flow. It is well known that migration is important in disease transmission but, as this paper demonstrates, migration can have both positive and negative impacts on both donor and recipient populations for a wide range of human traits. PMID- 28359168 TI - Building the evidence for lipid resuscitation therapy. PMID- 28359169 TI - The management of patients with chronic heart failure: the growing role of e Health. AB - INTRODUCTION: The increasing pandemic of heart failure is becoming a serious challenge for the health care system. The medical world is searching for solutions which could decrease its scale and improve patients' quality of life and prognosis. Telemanagement of heart failure patients is a new promising option. Technical and technological platforms to perform e-Health management in heart failure patients' homes have become available. This paper's aims are to present different forms of e-Health including telecare, home monitoring of cardiovascular implantable electronic devices, remote monitoring of hemodynamic implantable devices and telerehabilitation in providing optimal long term management for heart failure patients. Areas covered: E-education and self monitoring, structured telephone support and telemonitoring, remote monitoring of cardiovascular implantable electronics devices and hemodynamic implantable electronic devices and telerehabilitation. Expert commentary: The data analyzed in the paper suggests that remote monitoring is capable of identifying life threatening deterioration and helps heart failure patients avoid seeking medical assistance in hospitals and that home-based telerehabilitation is well accepted, safe, effective and has high adherence among HF patients. PMID- 28359170 TI - Immunotherapy for the treatment of Hodgkin lymphoma. AB - INTRODUCTION: Most patients with Hodgkin lymphoma (HL) enjoy durable remissions following front-line treatment but 30% of patients are refractory or relapse after first line therapy. Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) can cure an additional 50-55% of relapsing patients but new treatments are needed for patients with HL who are refractory or relapse after ASCT. Immunotherapy has emerged as a promising treatment for the management of these patients. The availability of the anti-CD30 antibody brentuximab vedotin and new targeted drugs such as immune checkpoint inhibitors, show promising clinical activity in patients with HL and are important milestones for the management of patients with HL particularly for those who have progressed after standard initial therapy and ASCT. Areas covered: Overview of the results from the most relevant clinical trials including monoclonal antibody-based therapy in HL. Phase 2 and phase 3 trials including brentuximab vedotin and immune checkpoints inhibitors in patients with Hodgkin lymphoma have been reviewed. In addition, the potential impact of these new therapies in the management of patients with newly diagnosed HL has also been addressed. Expert commentary: Anti CD30 antibody brentuximab vedotin and immune checkpoint inhibitors have shown promising results in patients with relapsed and refractory HL. Administration of these therapies earlier in the course of the disease might reduce the proportion of relapsed or refractory patients and, subsequently, minimize the number of patients undergoing high-dose therapy and autologous stem cell transplantation. We have little doubt that this will have substantial effects on the outcome for future generations of HL patients. PMID- 28359171 TI - A novel pen-based Bluetooth-enabled insulin delivery system with insulin dose tracking and advice. AB - INTRODUCTION: Diabetes is growing in prevalence internationally. As more individuals require insulin as part of their treatment, technology evolves to optimize delivery, improve adherence, and reduce dosing errors. Insulin pens outperform vial and syringe in simplicity, dosing accuracy, and user preference. Bolus advisors improve dosing confidence and treatment adherence. The InPen System offers a novel approach to treatment via a wireless pen that syncs to a mobile application featuring a bolus advisor, enabling convenient insulin dose tracking and more accurate bolus advice among other features. Areas covered: Existing technology for insulin delivery and bolus advice are reviewed. The mechanics and functionality of the InPen device are delineated. Findings from formative testing and usability studies of the InPen system are reported. Future directions for the InPen system in the treatment of diabetes are discussed. Expert opinion: Diabetes management is complex and largely data-driven. The InPen System offers a promising new opportunity to avail insulin pen-users of features known to improve treatment efficacy, which have otherwise primarily been available to those using pumps. Given that the majority of insulin users do not use insulin pumps, the InPen System is poised to improve glucose control in a significant portion of the diabetes population. PMID- 28359173 TI - Recommendation or refusal but why not quality of surgery? PMID- 28359172 TI - Efficacy of a new device to optimize positive pressure ventilation via face mask in edentulous patients: a randomized trial. AB - BACKGROUND: Mask ventilation is routinely performed during anesthesia. Under some circumstances, it might be difficult to perform, such as in edentulous patients, due to inadequate mask seal. We developed a new device called NIPARA and studied its use For ventilation optimization in edentulous patients. METHODS: This randomized controlled trial included edentulous adults who had no other predictors of difficult airway, scheduled to undergo general anesthesia. Patients were assigned either to the NIPARA device group or to the control group (oral airway only). The primary outcomes were peak inspiratory pressure and tidal volume values of the first 14 breaths. The secondary outcome was the incidence of complications. RESULTS: Data from 37 patients were collected during a one-year period (twenty in the NIPARA device group and 17 in the control group). The difference in mean PIP was not statistically significant. The tidal volume was 1.5 times greater in the NIPARA group than in the control group. One patient from the intervention group had minimal oral trauma. CONCLUSION: In the administration of face mask ventilation, NIPARA is an effective device that significantly improves the tidal volume administered in edentulous patients. PMID- 28359174 TI - Chemotherapy preparation processes: Methodological issues on reliability and validity. PMID- 28359175 TI - Precipitation, Climate Change, and Parasitism of Prairie Dogs by Fleas that Transmit Plague. AB - Fleas (Insecta: Siphonaptera) are hematophagous ectoparasites that can reduce the fitness of vertebrate hosts. Laboratory populations of fleas decline under dry conditions, implying that populations of fleas will also decline when precipitation is scarce under natural conditions. If precipitation and hence vegetative production are reduced, however, then herbivorous hosts might suffer declines in body condition and have weakened defenses against fleas, so that fleas will increase in abundance. We tested these competing hypotheses using information from 23 yr of research on 3 species of colonial prairie dogs in the western United States: Gunnison's prairie dog (Cynomys gunnisoni, 1989-1994), Utah prairie dog (Cynomys parvidens, 1996-2005), and white-tailed prairie dog (Cynomys leucurus, 2006-2012). For all 3 species, flea-counts per individual varied inversely with the number of days in the prior growing season with >10 mm of precipitation, an index of the number of precipitation events that might have caused a substantial, prolonged increase in soil moisture and vegetative production. Flea-counts per Utah prairie dog also varied inversely with cumulative precipitation of the prior growing season. Furthermore, flea-counts per Gunnison's and white-tailed prairie dog varied inversely with cumulative precipitation of the just-completed January and February. These results complement research on black-tailed prairie dog (Cynomys ludovicianus) and might have important ramifications for plague, a bacterial disease transmitted by fleas that devastates populations of prairie dogs. In particular, our results might help to explain why, at some colonies, epizootics of plague, which can kill >95% of prairie dogs, are more likely to occur during or shortly after periods of reduced precipitation. Climate change is projected to increase the frequency of droughts in the grasslands of western North America. If so, then climate change might affect the occurrence of plague epizootics among prairie dogs and other mammalian species that associate with them. PMID- 28359176 TI - Old World cutaneous leishmaniasis challenges in Morocco, Algeria, Tunisia and Iran (MATI): a collaborative attempt to combat the disease. AB - Cutaneous leishmaniasis (CL) is a main public health problem in Morocco, Algeria, Tunisia and Iran, known as the MATI region. During the biennial meeting of Pasteur Institutes of the MATI region in November 2016 in Tehran, a Leishmania panel formed of scientists with different expertise in CL research from the MATI and Institut Pasteur in Paris, proposed a new consortium to develop an integrative research approach to better understand this disease. The proposed consortium synergizes three complementary thematics on Leishmania genetics, host immune response, and vector transmission. Moreover, assessing the social impact of CL with the aim to raise awareness at both the national and international levels will be a major focus of this consortium. PMID- 28359177 TI - Response to the letter regarding the article: Association Between Perinatal Hypoxic-Ischemic Conditions and Attention-Deficit Hyperactivity Disorder (ADHD): A Meta-analysis. PMID- 28359178 TI - The impact of multiple sclerosis on the identity of mothers in Italy. AB - PURPOSE: This paper reports on one of the themes that emerged from the analysis of the study, regarding the perceived influence of multiple sclerosis (MS) on the identity of mothers in the socio-cultural context of Italy. METHOD: In-depth interviews were conducted with 16 women at various stages of MS, with follow up interviews with seven of the women. Phenomenology guided the methodology and the analysis was conducted using interpretative phenomenological analysis. RESULTS: Through the research the value of motherhood to the women who participated emerged. The findings illustrated how many strove to maintain control of their MS, which led to some making comparisons of themselves and other mothers and feeling different. Some women described how they adjusted their roles and found strength in being mothers but others spoke of their feelings of loss. Most women described living in the moment, appreciating the present and living each day as it came. Another significant experience was fear of stigma, both realized in the form of "pity" from others, and the perceived and actual associated stigma for their families. This contributed to why some women were reluctant to disclose their condition. The mothers who took part in this study differed in how they perceived their disabled identity. CONCLUSION: Although this study was conducted in the socio-cultural setting of Italy, the findings have implications for professionals working with disabled mothers and women with MS in Italy and beyond; including recognizing the value associated with fully identifying oneself as a mother, rather than solely focusing on doing mothering tasks. Implications for Rehabilitation Professionals need to be mindful of the value of motherhood for women with multiple sclerosis. Professionals should support women who feel like they are battling with maintaining control of their multiple sclerosis, who may be adjusting their identity as mothers; recognizing that they may be influenced by the stage of their multiple sclerosis and whether they were diagnosed before or after having their children. Women can have feelings of loss related to their ability to fully participate in their children's lives and professionals should work with women to help them identify the value of their mothering role not only in physically participating in activities but also in being emotionally and physically present as a mother. PMID- 28359179 TI - Tackling non-muscle invasive bladder cancer in the clinic. AB - INTRODUCTION: Non-muscle invasive bladder cancer (NMIBC) is a common disease process with a high propensity for recurrence and risk of progression to muscle invasive or systemic disease. Optimal management of NMIBC depends on appropriate resection and staging, risk-based use of intravesical therapy and tailored surveillance. Current challenges include compliance with guideline recommendations and cancers which are refractory to standard therapies. Areas covered: This review summarizes the conventional management of NMIBC - which relies on strict cystoscopic surveillance and intravesical therapies with chemotherapy and/or immunotherapy in the form of bacillus Calmette-Guerin (BCG). As many patients will be resistant to conventional treatment, investigational therapies and novel prognostic models will also be discussed. Expert commentary: For decades, the management of NMIBC has been predicated on intravesical therapies, most often through the instillation of BCG which has proven clinical efficacy over transurethral resection alone. Despite this, many patients will recur or progress after BCG therapy. While radical cystectomy remains the standard for such patients, suitable alternatives are being actively investigated. An increased interest in immunotherapy for malignancy has reinvigorated this field and on-going advances in disease prognostication are likely to improve upon the existing treatment paradigms for NMIBC. PMID- 28359180 TI - Influence of grapefruit juice on pharmacokinetics of triptolide in rats grapefruit juice on the effects of triptolide. AB - 1. Triptolide, a major pharmacological component isolated from Tripterygium wilfordii Hook F (TWHF), is a substrate of both CYP3A4 and P-glycoprotein (P-gp). 2. This study investigates the effects of GFJ on the pharmacokinetics of triptolide in rats. 3. The pharmacokinetics of orally administered triptolide with or without GFJ pretreatment were investigated. A mechanistic study was also undertaken using the Caco-2 cell transwell model and rat liver microsomes incubation systems to support the in vivo pharmacokinetic data. 4. The results indicated that coadministration of GFJ could increase the systemic exposure of triptolide significantly, including area under the curve (828.58 +/- 79.72 versus 541.53 +/- 45.23 ng.h/mL) and maximum plasma concentration (273.58 +/- 27.98 versus 193.67 +/- 10.08 ng/mL). The apparent permeability of triptolide across the Caco-2 cell transwell model increased significantly with the pretreatment of GFJ (from 1.62 +/- 0.25 * 10-6 to 2.51 +/- 0.41 * 10-6 cm/s), and the metabolic stability of triptolide was also increased from 32.6 +/- 5.1 to 52.5 +/- 7.8 min with the pretreatment of GFJ, and the difference was significant (p < 0.05). 5. In conclusion, GFJ could increase the systemic exposure of triptolide in rats, when GFJ and triptolide was coadministered, and it might work mainly through increasing the absorption of triptolide by inhibiting P-gp, or through slowing down the metabolism of triptolide in rat liver by inhibiting the activity of CYP3A4. PMID- 28359181 TI - Serious games for upper limb rehabilitation: a systematic review. AB - The aim of this research is to carry out a systematic review of the use of technological gaming platforms with serious games in the upper limb rehabilitation of patients with neuromotor disorders. Through a systematic review, the first two authors defined the inclusion criteria and extracted the data, resulting in 38 studies collected from B-On, PubMed and Medline. Ninety-two per cent of the selected articles were published since 2010. This review documents 35 different gaming platforms types. Twenty-one of the 38 articles included in this review conducted a clinical trial and of those only eight report improvements in the target population following the use of the games and platforms. This review concludes that a new paradigm is emerging in the rehabilitation field, characterized by the systematic use of technological gaming platforms with serious games in/for rehabilitation. The use of this approach seems to be beneficial. However, to facilitate the full integration of these platforms, it is necessary to conduct more research in this area, explore new approaches and carry out in-depth clinical studies into the benefits of these platforms. Implications for rehabilitation This review states that the use serious games and gaming platforms for upper limb rehabilitation are starting a new paradigm in the rehabilitation. For a full integration of this technologies in the rehabilitation field more studies are needed. PMID- 28359182 TI - Sex after amputation: the relationships between sexual functioning, body image, mood and anxiety in persons with a lower limb amputation. AB - AIM: The study examined the relationships between psychological variables and sexual functioning in persons with lower limb amputations. METHOD: Sixty-five participants (n = 49 males, n = 16 females) with lower limb amputations completed a battery of self-report questionnaires regarding their current psychological well-being and their current sexual activity. Measures included the anxiety items on the Hospital Anxiety and Depression Scale, the Beck Depression Inventory - Second Edition, Body Image Quality of Life Inventory, Body Exposure Self Consciousness during Intimate Situations and the Golombok-Rust Inventory of Sexual Satisfaction. RESULTS: Half of all participants with lower limb amputations were not currently sexually active. Approximately 60% of those who were sexually active scored within the clinical range for overall sexual dysfunction. Overall levels of sexual dysfunction were associated with significantly higher levels of anxiety (r = 0.40, p < 0.005), depression (r = 0.41, p < 0.015) and body exposure self-consciousness during sexual activities (r = 0.56, p < 0.005). Body image self-consciousness during sexual activities was the strongest predictor of sexual dysfunction. CONCLUSIONS: Psychological challenges following limb loss are strongly associated with levels of sexual dysfunction. The study highlights the need for psychological and psychosexual assessment and intervention following limb loss to enhance sexual functioning and overall quality of life. Implications for Rehabilitation Only half of the participants with a lower limb amputation were sexually active. Over 60% of those who were sexually active reported clinical levels of sexual dysfunction. One third of the entire sample scored within the clinical range for depression and for anxiety. Depression, anxiety and body image issues were significantly associated with sexual dysfunction in the current sample of individuals with lower limb amputation. There is a need for psychosexual assessment following limb loss to ensure that appropriate and timely interventions are made available. Interventions that target the psychological factors related to sexual dysfunction are likely to improve overall quality of life for these individuals. PMID- 28359183 TI - Changes in drug transport and metabolism and their clinical implications in non alcoholic fatty liver disease. AB - INTRODUCTION: The incidence of non-alcoholic fatty liver disease (NAFLD) is rising, especially in Western countries. Drug treatment in patients with NAFLD is common since it is linked to other conditions like diabetes, obesity, and cardiovascular disease. Consequently, changes in drug metabolism may have serious clinical implications. Areas covered: A literature search for studies in animal models or patients with obesity, fatty liver, non-alcoholic steatohepatitis (NASH) or NASH cirrhosis published before November 2016 was performed. After discussing epidemiology and animal models for NAFLD, we summarized both basic as well as clinical studies investigating changes in drug transport and metabolism in NAFLD. Important drug groups were assessed separately with emphasis on clinical implications for drug treatment in patients with NAFLD. Expert opinion: Given the frequency of NAFLD even today, a high degree of drug treatment in NAFLD patients appears safe and well-tolerated despite considerable changes in hepatic uptake, distribution, metabolism and transport of drugs in these patients. NASH causes changes in biliary excretion, systemic concentrations, and renal handling of drugs leading to alterations in drug efficacy or toxicity under specific circumstances. Future clinical drug studies should focus on this special patient population in order to avoid serious adverse events in NAFLD patients. PMID- 28359184 TI - Combined behavioural markers of cognitive biases are associated with anhedonia. AB - Biases towards negative information, as well as away from positive information, are associated with psychopathology. Examining biases in multiple processes has been theorised to be more predictive than examining bias in any process alone. Anhedonia is a core symptom of psychopathology and predictive of future psychopathological symptoms. Finding that combined biases are associated with anhedonia would advance knowledge of the nature of emotional processing biases and the value of objective performance-based measures for identifying early risk markers. Participants (N = 139) completed tasks that assess latency bias (dot probe) and biased recognition (two-alternative forced-choice) of emotional information, as well as an anhedonia measure. An index was computed for each task's performance reflecting biased processing of positive and negative words. Only combined biases on both tasks were associated with anhedonia. Attentional bias was positively associated with anhedonia, but only when recognition bias for emotional words was high. Thus, assessing biases in multiple domains increased sensitivity to uncover relationships between emotional processing biases and anhedonic symptoms. PMID- 28359185 TI - Rat's Polycystic Ovary Due to Intraventromedial Hypothalamus Morphine Injection. AB - BACKGROUND AND OBJECTIVE: The most important alkaloid of opium family, morphine, may show unfavorable effect on the reproductive organs. This research investigated the effect of microinjection of morphine into the rat's ventromedial hypothalamus (VMH) on cystic genesis in the ovary and the health of neurons of VMH. MATERIALS AND METHODS: Female rats (Wistar, weighing 200-250 g) kept under standard conditions were cannulated under anesthesia by Stoelting stereotaxic instrument at the coordinates anterior-posterior: -1.92, ventral: 9, lateral: 0.5. After being recovered, they were microinjected single morphine (0.1-0.4 ug/rat, once intra-VMH) and/or naloxone hydrochloride (0.1-0.4 ug/rat, once intra VMH) using a 5-uL Hamilton syringe with the polyethylene tubing. The control group solely given physiological saline (1 uL/rat, intra-VMH). Three days after the experiment, both ovary and brain samples were collected from the control and the experimental groups, and they were studied histopathologically. The brain samples were checked out with the aid of the cresyl violet, and the ovaries were stained by the hematoxylin and eosin. The samples were also biometrically examined to compare the ovaries' cystic formations. Also, the number of healthy or injured neurons in the nuclei was compared. RESULTS: The ovaries of morphine treated rats showed polycystic characteristics in comparison with the control samples. In addition, the brain slices of the morphine-treated rats illustrated a significant decrease in intact neurons. Both mal effects were resolved in the presence of naloxone. CONCLUSION: These results may show that the morphine induces anovulatory infertility probably by hypothalamus-pituitary-ovary axis dysfunction. PMID- 28359186 TI - Impact of Lactational Exposure to Polychlorinated Biphenyl Causes Epigenetic Modification and Impairs Sertoli Cells Functional Regulators in F1 Progeny. AB - Polychlorinated biphenyl (PCB) is an endocrine-disrupting chemical. Sertoli cells (SCs) provide physical and nutritional support for developing germ cells. Dysfunction in SCs has adverse effects on spermatogenesis. Previously, we found that the lactational exposure of PCBs (1, 2, and 5 mg/kg birth weight/day, orally from postnatal days 1 to 20) decreased the follicle-stimulating hormone receptor (FSHR) and androgen receptor (AR) expression in SCs of F1 progeny. Transcription factors initiate and regulate the transcription of genes. DNA methylation plays an important role in epigenetic gene regulation. Hence, this study was aimed to identify the level of transcription factors regulating FSHR, AR gene expression, and DNA methylation in the promoter of these genes in SCs of both F1 prepuberal and puberal offspring. DNA methylation in the promoter of FSHR and AR genes was examined by sodium bisulfite conversion technique. The protein levels of transcription factors (steroidogenic factor 1 [SF1], upstream stimulatory factors 1 and 2, c-fos, c-jun, and CREB-binding protein) and enzymes DNA methyltransferases (Dnmt1, Dnmt3ab, Dnmt3l, and histone deacetylase 1 [HDAC1]) were analyzed by Western blotting. The transcription factors that regulate the FSHR and AR gene in SCs were decreased in both the PCB-exposed F1 progeny. Methylation was observed in the promoter of FSHR, AR, and SF1. The protein levels of Dnmt1, Dnmt3ab, Dnmt3l, and HDAC1 were increased in the PCBs-treated groups. Subsequently, it leads to transcriptional repression of the genes in SCs. Our finding suggests that PCBs caused epigenetic change in SCs, thereby it impaired SCs function in F1 progeny. PMID- 28359187 TI - Prediction of Future Epilepsy in Neonates With Hypoxic-Ischemic Encephalopathy Who Received Selective Head Cooling. AB - Epilepsy outcomes after therapeutic hypothermia for neonates with hypoxic ischemic encephalopathy are understudied. The authors used multivariable logistic regression to predict epilepsy in neonates after selective head cooling. Sensitivity analyses used magnetic resonance imaging (MRI) and electroencephalogram (EEG) interpretations by different clinicians. Fifty neonates had 2-year follow-up. Nine developed epilepsy. Predictors included pH <=6.8 on day of birth (adjusted odds ratio [OR] 19 [95% confidence interval (CI) 1-371]), burst suppression on EEG on day 4 (8.2 [1.3-59]), and MRI deep gray matter injury (OR 33 [2.4-460]). These factors stratify neonates into low (0-1 factors; 3% [0%-14%] risk), medium (2 factors; 56% [21%-86%] risk), and high-risk groups (3 factors; 100% [29%-100%] risk) for epilepsy. The stratification was robust to varying clinical interpretations of the MRI and EEG. Neonates with hypoxic-ischemic encephalopathy who undergo selective head cooling appear at risk of epilepsy if they have 2 to 3 identified factors. If validated, this rule may help counsel families and identify children for close clinical follow-up. PMID- 28359188 TI - The Effectiveness of Simulation on Recognizing and Managing Clinical Deterioration: Meta-Analyses. AB - The purpose of these meta-analyses was to quantitatively synthesize the effectiveness of simulation on student nurses' and registered nurses' ability to recognize and manage clinical deterioration in the acute care setting. A search of the literature resulted in 22 reports and 19 studies meeting inclusion criteria. Four random-effects analyses were conducted to examine two-group posttest and single-group pre-posttest intervention effect sizes for knowledge and performance. A total of 41 effect sizes were calculated from the data extracted. The standardized mean difference ( d) for two-group posttest knowledge was d = 0.964 ( p = .001) and for performance was d = 1.382 ( p <= .001). The standardized mean difference for single-group pre-posttest knowledge was d = 1.231 ( p <= .001) and performance was d = 1.610 ( p <= .001). Findings indicate that simulation-based interventions have a positive effect on knowledge and performance. As simulation is increasingly used as a teaching modality in nursing, further research should aim to test standardized simulation-based education programs. PMID- 28359189 TI - Outlook in the application of Chlamydomonas reinhardtii chloroplast as a platform for recombinant protein production. AB - Microalgae, also called microphytes, are a vast group of microscopic photosynthetic organisms living in aquatic ecosystems. Microalgae have attracted the attention of biotechnology industry as a platform for extracting natural products with high commercial value. During last decades, microalgae have been also used as cost-effective and easily scalable platform for the production of recombinant proteins with medical and industrial applications. Most progress in this field has been made with Chlamydomonas reinhardtii as a model organism mainly because of its simple life cycle, well-established genetics and ease of cultivation. However, due to the scarcity of existing infrastructure for commercial production and processing together with relatively low product yields, no recombinant products from C. reinhardtii have gained approval for commercial production and most of them are still in research and development. In this review, we focus on the chloroplast of C. reinhardtii as an algal recombinant expression platform and compare its advantages and disadvantages to other currently used expression systems. We then discuss the strategies for engineering the chloroplast of C. reinhardtii to produce recombinant cells and present a comprehensive overview of works that have used this platform for the expression of high-value products. PMID- 28359190 TI - Availability and need of home adaptations for personal mobility among individuals with spinal cord injury. AB - OBJECTIVE: To identify the availability and unmet need of home adaptations (HAs) among the Swiss population with spinal cord injury (SCI). DESIGN: Cross-sectional study. SETTING: Swiss Spinal Cord Injury Community Survey 2012. PARTICIPANTS: Individuals aged 16 or older with chronic SCI living in Switzerland. INTERVENTIONS: Not applicable. OUTCOME MEASURES: The availability of ten HAs (self-report) was analyzed by sex, age, living situation, indoor mobility, SCI severity, SCI etiology and time since SCI. The unmet need (self-report of not having a HA but needing it) of HAs was analyzed by financial hardship. RESULTS: Among the 482 study participants (mean age 55.2 years, standard deviation 15.0 years, 71.6% males), 85.1% had at least one HA. The most frequent HA was a wheelchair accessible shower (62.7%). Availability of HAs markedly varied with indoor mobility (e.g. 38.4% of participants using a wheelchair had a stair lift compared to 17.4% of those walking) and with SCI severity (e.g. 54.8% of those with complete paraplegia had a wheelchair accessible kitchen worktop compared to 26.0% of those with incomplete paraplegia). Unmet need was highest for adjustable kitchen worktops (78.7% of those with a need) and adjustable kitchen cabinets (75.7%) and lowest for wheelchair accessible showers (9.4%) and grab bars next to the toilet (8.5%). No significant differences in unmet need were found when stratifying for financial hardship. CONCLUSION: Availability of HAs is dependent on indoor mobility and SCI severity. There is a considerable degree of unmet need for selected HAs, which couldn't be explained by financial hardship. PMID- 28359191 TI - The (in)stability of 21st century orthopedic patient contact information and its implications on clinical research: A cross-sectional study. AB - BACKGROUND: In clinical research, minimizing patients lost to follow-up is essential for data validity. Researchers can employ better methodology to prevent patient loss. We examined how orthopedic surgery patients' contact information changes over time to optimize data collection for long-term outcomes research. METHODS: Patients presenting to orthopedic outpatient clinics completed questionnaires regarding methods of contact: home phone, cell phone, mailing address, and e-mail address. They reported currently available methods of contact, if they changed in the past 5 and 10 years, and when they changed. Differences in the rates of change among methods were assessed via Fisher's exact tests. Whether participants changed any of their contact information in the past 5 and 10 years was determined via multivariate modeling, controlling for demographic variables. RESULTS: Among 152 patients, 51% changed at least one form of contact information within 5 years, and 66% changed at least one form within 10 years. The rate of change for each contact method was similar over 5 (15%-28%) and 10 years (26%-41%). One patient changed all four methods of contact within the past 5 years and seven within the past 10 years. Females and younger patients were more likely to change some type of contact information. CONCLUSION: The type of contact information least likely to change over 5-10 years is influenced by demographic factors such as sex and age, with females and younger participants more likely to change some aspect of their contact information. Collecting all contact methods appears necessary to minimize patients lost to follow-up, especially as technological norms evolve. PMID- 28359193 TI - Corrigendum. PMID- 28359192 TI - Impact of individual clinical outcomes on trial participants' perspectives on enrollment in emergency research without consent. AB - BACKGROUND: Evidence suggests that patients are generally accepting of their enrollment in trials for emergency care conducted under exception from informed consent. It is unknown whether individuals with more severe initial injuries or worse clinical outcomes have different perspectives. Determining whether these differences exist may help to structure post-enrollment interactions. METHODS: Primary clinical data from the Progesterone for the Treatment of Traumatic Brain Injury trial were matched to interview data from the Patients' Experiences in Emergency Research-Progesterone for the Treatment of Traumatic Brain Injury study. Answers to three key questions from Patients' Experiences in Emergency Research-Progesterone for the Treatment of Traumatic Brain Injury study were analyzed in the context of enrolled patients' initial injury severity (initial Glasgow Coma Scale and Injury Severity Score) and principal clinical outcomes (Extended Glasgow Outcome Scale and Extended Glasgow Outcome Scale relative to initial injury severity). The three key questions from Patients' Experiences in Emergency Research-Progesterone for the Treatment of Traumatic Brain Injury study addressed participants' general attitude toward inclusion in the Progesterone for the Treatment of Traumatic Brain Injury trial (general trial inclusion), their specific attitude toward being included in Progesterone for the Treatment of Traumatic Brain Injury trial under the exception from informed consent (personal exception from informed consent enrollment), and their attitude toward the use of exception from informed consent in the Progesterone for the Treatment of Traumatic Brain Injury trial in general (general exception from informed consent enrollment). Qualitative analysis of interview transcripts was performed to provide contextualization and to determine the extent to which respondents framed their attitudes in terms of clinical experience. RESULTS: Clinical data from Progesterone for the Treatment of Traumatic Brain Injury trial were available for all 74 patients represented in the Patients' Experiences in Emergency Research Progesterone for the Treatment of Traumatic Brain Injury study (including 46 patients for whom the surrogate was interviewed due to the patient's cognitive status or death). No significant difference was observed regarding acceptance of general trial inclusion or acceptance of general exception from informed consent enrollment between participants with favorable neurological outcomes and those with unfavorable outcomes relative to initial injury. Agreement with personal enrollment in Progesterone for the Treatment of Traumatic Brain Injury trial under exception from informed consent, however, was significantly higher among participants with favorable outcomes compared to those with unfavorable outcomes (89% vs 59%, p = 0.003). There was also a statistically significant relationship between more severe initial injury and increased acceptance of personal exception from informed consent enrollment ( p = 0.040) or general exception from informed consent use ( p = 0.034) in Progesterone for the Treatment of Traumatic Brain Injury trial. Many individuals referenced personal experience as a basis for their attitudes, but these references were not used to support negative views. CONCLUSION: Patients and surrogates of patients with unfavorable clinical outcomes were somewhat less accepting of their own inclusion in the Progesterone for the Treatment of Traumatic Brain Injury trial under exception from informed consent than were patients or surrogates of patients with favorable clinical outcomes. These findings suggest a need to identify optimal strategies for communicating with patients and their surrogates regarding exception from informed consent enrollment when clinical outcomes are poor. PMID- 28359195 TI - Chinese Herbal Medicine for the Optimal Management of Polycystic Ovary Syndrome. AB - Polycystic ovary syndrome (PCOS) is a complex heterogeneous disorder characterized by androgen excess and ovulatory dysfunction; it is now known to be closely linked to metabolic syndrome. Recent research suggests that insulin resistance plays an important role in the pathogenesis of PCOS which may lead to the excessive production of androgens by ovarian theca cells. Currently there is no single drug that can treat both the reproductive and metabolic complications of the disorder. Existing pharmaceutical agents such as hormonal therapies have been associated with side effects and are not appropriate for PCOS women with infertility. Additionally, insulin sensitizing agents useful for treating the metabolic abnormalities in PCOS have limited efficacy for treating reproductive aspects of the disorder. Chinese herbal medicines have a long history of treating gynaecological problems and infertility and therefore may be a novel approach to the treatment of PCOS. Current research demonstrates that the compounds isolated from herbs have shown beneficial effects for PCOS and when combined in an herbal formula can target both reproductive and metabolic defects simultaneously. Therefore, further investigation into Chinese herbal medicine in the treatment of PCOS is warranted. PMID- 28359194 TI - Data monitoring committees: Promoting best practices to address emerging challenges. AB - BACKGROUND AND PURPOSE: Data monitoring committees are responsible for safeguarding the interests of study participants and assuring the integrity and credibility of clinical trials. The independence of data monitoring committees from sponsors and investigators is essential in achieving this mission. Creative approaches are needed to address ongoing and emerging challenges that potentially threaten data monitoring committees' independence and effectiveness. METHODS: An expert panel of representatives from academia, industry and government sponsors, and regulatory agencies discussed these challenges and proposed best practices and operating principles for effective functioning of contemporary data monitoring committees. RESULTS AND CONCLUSIONS: Prospective data monitoring committee members need better training. Options could include didactic instruction as well as apprenticeships to provide real-world experience. Data monitoring committee members should be protected against legal liability arising from their service. While avoiding breaches in confidentiality of interim data remains a high priority, data monitoring committees should have access to unblinded efficacy and safety data throughout the trial to enable informed judgments about risks and benefits. Because overly rigid procedures can compromise their independence, data monitoring committees should have the flexibility necessary to best fulfill their responsibilities. Data monitoring committee charters should articulate principles that guide the data monitoring committee process rather than list a rigid set of requirements. Data monitoring committees should develop their recommendations by consensus rather than through voting processes. The format for the meetings of the data monitoring committee should maintain the committee's independence and clearly establish the leadership of the data monitoring committee chair. The independent statistical group at the Statistical Data Analysis Center should have sufficient depth of knowledge about the study at hand and experience with trials in general to ensure that the data monitoring committee has access to timely, reliable, and readily interpretable insights about emerging evidence in the clinical trial. Contracts engaging data monitoring committee members for industry-sponsored trials should have language customized to the unique responsibilities of data monitoring committee members rather than use language appropriate to consultants for product development. Regulatory scientists would benefit from experiencing data monitoring committee service that does not conflict with their regulatory responsibilities. PMID- 28359196 TI - Prunella vulgaris Attenuates Diabetic Renal Injury by Suppressing Glomerular Fibrosis and Inflammation. AB - Diabetic nephropathy is both the most common complication and the leading cause of mortality associated with diabetes. Prunella vulgaris, a well-known traditional medicinal plant, is used for the cure of abscess, scrofula, hypertension and urinary diseases. This study confirmed whether an aqueous extract of Prunella vulgaris (APV) suppresses renal inflammation and fibrosis. In human mesangial cell (HMC), pretreatment of APV attenuated 25[Formula: see text]mM HG-induced suppressed TGF-[Formula: see text] and Smad-2/4 expression; it increased the expression level of Smad-7. Connective tissue growth factor (CTGF) and collagen IV, fibrosis biomarkers, were significantly decreased by APV. APV suppressed inflammatory factors such as intracellular cell adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1). APV inhibited activation and translocation of nuclear factor kappa-B (NF-[Formula: see text]B) in HG stimulated HMCs. Moreover, APV significantly improved HG-induced ROS in a dose dependent manner. In diabetic rat models, APV significantly decreased blood glucose, blood urea nitrogen (BUN) and ameliorated plasma creatinine (PCr). APV reduced the PAS positivity staining intensity and basement membrane thickening in glomeruli of diabetic rats. Fibrosis related proteins such as collagen IV and TGF [Formula: see text]1 were also inhibited by APV. These results suggest that APV has a significant protective effect against diabetic renal dysfunction including inflammation and fibrosis through disruption of the TGF-[Formula: see text]/Smad signaling. Therefore, APV may be useful in potential therapies that target glomerulonephritis and glomerulosclerosis, which lead to diabetic nephropathy. PMID- 28359197 TI - Mechanisms of Traditional Chinese Medicine in the Treatment of Mammary Gland Hyperplasia. AB - Mammary gland hyperplasia (MGH) occurs with high frequency among middle-aged women and is closely related to breast cancer. The treatment of this disease has become a research hotspot. Many patients with MGH are worried about the potential side effects of the synthetic drugs they are on. Thus, they seek alternative therapy, such as traditional Chinese medicine (TCM). In recent years, along with the Chinese herbs and its active ingredients, TCM compounds have been widely accepted and implemented in the treatment of MGH, whose mechanism hitherto is not completely clear. In this paper, we elaborate the mechanism of TCM in the treatment of MGH from the perspectives of sexual hormone levels, the expression of ER and PR, hemorheology, free radical activity and lipid peroxidation, VEGF and BFGF, cell proliferation activities, anti-apoptosis gene BcL-2, promoting apoptosis gene Bax, ERK, and tumor suppressor gene. In conclusion, TCM appears to be promising for MGH treatment. This paper will provide an overview of the mechanism of TCM in the treatment of MGH. In the near term, a better understanding of TCM will be achieved through comprehensive studies of its molecular mechanism. PMID- 28359198 TI - Anticancer Properties and Pharmaceutical Applications of Plumbagin: A Review. AB - It has been shown that plumbagin, a bioactive naphthoquinone isolated from three major plant families viz. Plumbaginaceae, Ebenceae and Droseraceae, definitively exhibits anticancer potential in diverse cancer cells both in vitro and in vivo. Plumbagin shows antineoplastic effects via multi-channel molecular mechanisms, including the induction of apoptosis and autophagy, the disruption of the cell cycle, the inhibition of invasion and metastasis, and anti-angiogenesis. Plumbagin inhibits the growth of cancer cells mainly through the modulation of the signals of PI3K/Akt/mTOR, AMPK, Ras, and so on. The pharmaceutical applications of plumbagin combined with nanocarriers to achieve better therapeutic efficiency are discussed in this review Among them, liposomes, nanoparticles, microspheres, micelles, and nisosomes are used in cancer treatment. The anticancer study of plumbagin in vivo is also summarized in this review. On the whole, we aim to review the research progress of plumbagin both in pharmacological and pharmaceutical filed, which may provide some reference for further research of plumbagin. PMID- 28359199 TI - Protective Effect of Cymbopogon citratus Essential Oil in Experimental Model of Acetaminophen-Induced Liver Injury. AB - To investigate the hepatoprotective effect of Cymbopogon citratus or lemongrass essential oil (LGO), it was used in an animal model of acute liver injury induced by acetaminophen (APAP). Swiss mice were pretreated with LGO (125, 250 and 500[Formula: see text]mg/kg) and SLM (standard drug, 200[Formula: see text]mg/kg) for a duration of seven days, followed by the induction of hepatotoxicity of APAP (single dose, 250[Formula: see text]mg/kg). The liver function markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transferase were determined to evaluate the hepatoprotective effects of the LGO. The livers were used to determine myeloperoxidase (MPO) activity, nitric oxide (NO) production and histological analysis. The effect of LGO on leukocyte migration was evaluated in vitro. Anti oxidant activity was performed by assessing the free radical 2,2-diphenyl-1 picrylhydrazyl (DPPH) in vitro. LGO pretreatment decreased significantly the levels of ALT, AST and ALP compared with APAP group. MPO activity and NO production were decreased. The histopathological analysis showed an improved of hepatic lesions in mice after LGO pretreatment. LGO inhibited neutrophil migration and exhibited anti-oxidant activity. Our results suggest that LGO has protective activity against liver toxicity induced by paracetamol. PMID- 28359200 TI - Selective Loss of Smaller Spines in Schizophrenia. AB - OBJECTIVE: Decreased density of dendritic spines in adult schizophrenia subjects has been hypothesized to result from increased pruning of excess synapses in adolescence. In vivo imaging studies have confirmed that synaptic pruning is largely driven by the loss of large or mature synapses. Thus, increased pruning throughout adolescence would likely result in a deficit of large spines in adulthood. Here, the authors examined the density and volume of dendritic spines in deep layer 3 of the auditory cortex of 20 schizophrenia and 20 matched comparison subjects as well as aberrant voltage-gated calcium channel subunit protein expression linked to spine loss. METHOD: Primary auditory cortex deep layer 3 spine density and volume was assessed in 20 pairs of schizophrenia and matched comparison subjects in an initial and replication cohort (12 and eight pairs) by immunohistochemistry-confocal microscopy. Targeted mass spectrometry was used to quantify postsynaptic density and voltage-gated calcium channel protein expression. The effect of increased voltage-gated calcium channel subunit protein expression on spine density and volume was assessed in primary rat neuronal culture. RESULTS: Only the smallest spines are lost in deep layer 3 of the primary auditory cortex in subjects with schizophrenia, while larger spines are retained. Levels of the tryptic peptide ALFDFLK, found in the schizophrenia risk gene CACNB4, are inversely correlated with the density of smaller, but not larger, spines in schizophrenia subjects. Consistent with this observation, CACNB4 overexpression resulted in a lower density of smaller spines in primary neuronal cultures. CONCLUSIONS: These findings require a rethinking of the overpruning hypothesis, demonstrate a link between small spine loss and a schizophrenia risk gene, and should spur more in-depth investigations of the mechanisms that govern new or small spine generation and stabilization under normal conditions as well as how this process is impaired in schizophrenia. PMID- 28359202 TI - Response to: 'Birth control in epilepsy: we need to know more'. PMID- 28359201 TI - A 5-Year Observational Study of Patients With Treatment-Resistant Depression Treated With Vagus Nerve Stimulation or Treatment as Usual: Comparison of Response, Remission, and Suicidality. AB - OBJECTIVE: The Treatment-Resistant Depression Registry investigated whether adjunctive vagus nerve stimulation (VNS) with treatment as usual in depression has superior long-term outcomes compared with treatment as usual only. METHOD: This 5-year, prospective, open-label, nonrandomized, observational registry study was conducted at 61 U.S. sites and included 795 patients who were experiencing a major depressive episode (unipolar or bipolar depression) of at least 2 years' duration or had three or more depressive episodes (including the current episode), and who had failed four or more depression treatments (including ECT). Patients with a history of psychosis or rapid-cycling bipolar disorder were excluded. The primary efficacy measure was response rate, defined as a decrease of >=50% in baseline Montgomery-Asberg Depression Rating Scale (MADRS) score at any postbaseline visit during the 5-year study. Secondary efficacy measures included remission. RESULTS: Patients had chronic moderate to severe depression at baseline (the mean MADRS score was 29.3 [SD=6.9] for the treatment-as-usual group and 33.1 [SD=7.0] for the adjunctive VNS group). The registry results indicate that the adjunctive VNS group had better clinical outcomes than the treatment-as-usual group, including a significantly higher 5-year cumulative response rate (67.6% compared with 40.9%) and a significantly higher remission rate (cumulative first-time remitters, 43.3% compared with 25.7%). A subanalysis demonstrated that among patients with a history of response to ECT, those in the adjunctive VNS group had a significantly higher 5-year cumulative response rate than those in the treatment-as-usual group (71.3% compared with 56.9%). A similar significant response differential was observed among ECT nonresponders (59.6% compared with 34.1%). CONCLUSIONS: This registry represents the longest and largest naturalistic study of efficacy outcomes in treatment-resistant depression, and it provides additional evidence that adjunctive VNS has enhanced antidepressant effects compared with treatment as usual in this severely ill patient population. PMID- 28359203 TI - Distinct fatty acid composition of some edible by-products from bovines fed high or low silage diets. AB - In the present study, it was hypothesized that the incorporation of fatty acids is distinct among ruminant tissues and that it could be modulated by diet composition. To test this hypothesis, fatty acid composition, including conjugated linoleic acid isomers, of the most relevant beef by-products (brain, heart, kidney, liver, pancreas and tongue) from young bulls those fed distinct silage levels was assessed. Data indicated a large variation in fatty acid profile and conjugated linoleic acid composition among edible by-products. The most abundant fatty acids were C16:0 (kidney), C18:0 (heart and liver) and C18:1 c9 (brain, pancreas and tongue) followed by C20:4 n-6, except in brain (C22:6 n-3 predominates). Brain, as shown by principal component analysis, presents a distinct fatty acid composition compared to the other beef by-products analysed. In addition, high silage diet relative to low silage diet promoted an increase of n-3 polyunsaturated fatty acid, t11, t13 and t11, c13 conjugated linoleic acid in heart, kidney, liver and pancreas. Overall, the data suggested that beef by products had, in general, high contents of cholesterol, saturated fatty acid and trans fatty acid, as well as high levels of conjugated linoleic acid. Therefore, from a nutritional point of view they are recommended only in small amounts as part of a balanced diet. PMID- 28359205 TI - Quality stability and sensory attributes of apple juice processed by thermosonication, pulsed electric field and thermal processing. AB - Worldwide, apple juice is the second most popular juice, after orange juice. It is susceptible to enzymatic browning spoilage by polyphenoloxidase, an endogenous enzyme. In this study, Royal Gala apple juice was treated by thermosonication (TS: 1.3 W/mL, 58 C, 10 min), pulsed electric field (PEF: 24.8 kV/cm, 60 pulses, 169 us treatment time, 53.8 C) and heat (75 C, 20 min) and stored at 3.0 C and 20.0 C for 30 days. A sensory analysis was carried out after processing. The polyphenoloxidase activity, antioxidant activity and total color difference of the apple juice were determined before and after processing and during storage. The sensory analysis revealed that thermosonication and pulsed electric field juices tasted differently from the thermally treated juice. Apart from the pulsed electric field apple juice stored at room temperature, the processed juice was stable during storage, since the pH and soluble solids remained constant and fermentation was not observed. Polyphenoloxidase did not reactivate during storage. Along storage, the juices' antioxidant activity decreased and total color difference increased (up to 6.8). While the antioxidant activity increased from 86 to 103% with thermosonication and was retained after pulsed electric field, thermal processing reduced it to 67%. The processing increased the total color difference slightly. No differences in the total color difference of the juices processed by the three methods were registered after storage. Thermosonication and pulsed electric field could possibly be a better alternative to thermal preservation of apple juice, but refrigerated storage is recommended for pulsed electric field apple juice. PMID- 28359206 TI - Influence of vegetable coagulant and ripening time on the lipolytic and sensory profile of cheeses made with raw goat milk from Canary breeds. AB - Free fatty acids and sensory profiles were obtained for cheeses made with raw goat milk and vegetable coagulant, derived from the cardoon flower ( Cynara cardunculus), at different ripening times (7 and 20 days). A solid-liquid phase extraction method followed by solid-phase extraction and gas chromatography was used. Profiles were also obtained with cheeses made with commercial coagulant, traditional kid rennet paste, and mixture coagulant (vegetable coagulant-kid rennet). The use of vegetable coagulant and vegetable coagulant-kid rennet is common in traditional Protected Designation of Origin cheeses such as " Queso Flor de Guia" and " Queso Media Flor de Guia" (Spain). Contents of short-chain free fatty acids (7.5-22.5 mmol.kg-1), medium-chain free fatty acids (0.4-3.7 mmol.kg-1), and long-chain free fatty acids (0.2-2.1 mmol.kg-1) varied depending on the coagulant type and the ripening time. Vegetable coagulant cheeses present odour intensity and flavour intensity much higher than commercial coagulant cheeses in the sensory analysis for cheeses obtained with seven days of ripening, but the values decrease when increasing the ripening time. Multivariate analysis allowed us to differentiate cheese samples according to the ripening time when using lipolytic profile and according to the coagulant type using the sensory profile. PMID- 28359207 TI - Asthma prevalence disparities and differences in sociodemographic associations with asthma, between Native Hawaiian/Other Pacific Islander, Asian, and White adults in Hawaii - Behavioral Risk Factor Surveillance System (BRFSS), 2001-2010. AB - OBJECTIVES: Despite high asthma prevalence, relatively little is known about the epidemiology of asthma in Hawaii or among Native Hawaiian/Other Pacific Islanders (NHOPI). We sought to better characterize racial/ethnic differences in asthma prevalence and in sociodemographic factors associated with asthma among Hawaii adults. DESIGN: We conducted multivariable logistic regression using 2001-2010 Behavioral Risk Factor Surveillance System data from Hawaii, and computed adjusted prevalence and ratios. RESULTS: Asthma prevalence markedly varied between self-identified census categories of race in Hawaii, with NHOPI having the highest estimates of both lifetime (20.9%, 95% confidence interval [CI]: 19.5%-22.4%) and current (12.2%, CI: 11.2%-13.3%) asthma. Highest asthma prevalence among NHOPI persisted after controlling for potential confounders and within most sociodemographic categories. Among females Asians reported the lowest asthma prevalence, whereas among males point estimates of asthma prevalence were often lowest for Whites. Females often had greater asthma prevalence than males of the same race, but the degree to which gender modified asthma prevalence differed by both race and sociodemographic strata. Gender disparities in asthma prevalence were greatest and most frequent among Whites, and for current asthma among all races. Sociodemographic factors potentially predictive of adult asthma prevalence in Hawaii varied by race and gender. CONCLUSION: Asthma disproportionately affects or is recognized more often among women and NHOPI adults in Hawaii, and occurs less or is under-reported among Asian women. The sociodemographic characteristics included in this study's model did not explain asthma disparities between races and/or gender. This investigation provides a baseline with which to plan additionally needed prevention programs, epidemiological investigations, and surveillance for asthma in Hawaii. PMID- 28359208 TI - Omega-3-Fortified Lipid-Based Nutrient Supplement: Development, Characterization, and Consumer Acceptability. AB - BACKGROUND: Incorporation of omega-3 polyunsaturated fatty acid (PUFA) sources to lipid-based nutrition supplement (LNS) formulations for undernourished populations presents a challenge due to reduced shelf life and poor consumer acceptability. OBJECTIVE: To systematically develop an omega-3-fortified LNS formulation, using flaxseed oil (FO), by optimizing its processing stability and evaluating its sensory acceptance. METHODS: LNS formulations were formulated to yield approximately 452 kcal, 13.2 g of protein, 30 g of fat, and 53 g of carbohydrates per 100 g. Response surface methodology (RSM) with 4-factor-3 level: omega-3 fatty acid source (FO; 0%-10%), antioxidant (ascorbyl palmitate: 0.0%-0.03%), emulsifier (soy lecithin: 0.5%-1.5%), and storage time (0-6 months at 40 degrees C) was used to optimize LNS's functionality and storage stability. Factor effects were evaluated for peroxide value, oil separation, water activity, moisture content, hardness, and vitamin C content of the samples. Consumer acceptability was assessed using a 9-point hedonic scale. RESULTS: After 6 months of accelerated storage, the addition of FO to LNS formula resulted in increased peroxide values (7.75 mEq/kg fat) and lipid separation and a reduction in vitamin C and water activity. Optimal levels to maximize storage time and FO and minimize oxidation were 0.02% antioxidant, 1.5% emulsifier, and 4.9% FO. Indian women and students accepted LNS formulations with or without FO similar to other commercial supplements. CONCLUSION: An LNS containing FO with improved omega-6/omega-3 PUFA ratio was successfully formulated with staple Indian ingredients and optimized for storage stability using RSM. PMID- 28359209 TI - Trained Cohorts of University Students are a Useful Resource for Conducting Dietary Surveys in Mongolia. AB - BACKGROUND: Population-based dietary assessment is important for informing national nutrition policy. The developing country setting presents challenges for robust implementation of dietary surveys, yet effective nutrition interventions are often urgently required. OBJECTIVE: To develop and evaluate a low-cost approach to epidemiologic dietary assessment in Mongolia, involving the use of large cohorts of local public health and medical students as research assistants for collecting diet records. METHODS: From 2011 to 2016, over 200 Mongolian medical and public health university students were trained to collect paired summer and winter 3-day weighed diet records from urban and rural study populations across the geographic expanse of Mongolia. Students were supervised during data collection, and their performance and experience during training and data collection were qualitatively evaluated from their own perspectives as well as those of the investigators. RESULTS: Students collected detailed and thorough diet records and generally reported positive feedback regarding training and data collection. Frequent supervision of students during data collection proved to be extremely worthwhile. While rural participants were amenable to having students follow them, students faced several challenges in assessing the diets of urban participants. These challenges may best be addressed by separately training these participants beforehand. CONCLUSIONS: With adequate training and supervision, university students may be a useful and cost-effective resource for large-scale dietary surveys in regions where their use would be practical and culturally appropriate. Further research is warranted to study how well this approach may be adapted outside Mongolia and to other dietary assessment methods and technologies. PMID- 28359210 TI - Trends in Iron, Zinc, and Vitamin A Status Biomarkers Among Colombian Children: Results From 2 Nationally Representative Surveys. AB - BACKGROUND: Micronutrient deficiencies are still highly prevalent in countries undergoing the nutrition transition, but nationally representative data documenting their burden in children are exceedingly rare. OBJECTIVE: To examine the distribution and recent trends in micronutrient status biomarkers of Colombian children. METHODS: We compared the distributions of plasma ferritin, serum zinc, and vitamin A in Colombian children between 2005 and 2010 using 2 cross-sectional, nationally representative surveys overall and by categories of sociodemographic variables. Analysis for ferritin included boys and nonpregnant girls aged 1 to 17 years. Analyses for zinc and vitamin A included children aged 1 to 4 years. RESULTS: The mean 2010 to 2005 differences in ferritin, zinc, and vitamin A were 2.5 ug/L (95% confidence interval [CI]: 1.3 to 3.7), -34.9 ug/dL (95% CI: -39.6 to -30.2), and -11.5 ug/dL (95% CI: -12.3 to -10.7), respectively, after adjusting for sociodemographic characteristics. These differences varied significantly by region of residence. In 2010, region of residence was a significant correlate for all 3 micronutrients. Other important correlates included age and maternal education for ferritin and body mass index-for-age Z score, maternal education, wealth index, food insecurity, and urbanicity for vitamin A. CONCLUSIONS: Plasma ferritin was slightly higher in 2010 than in 2005, whereas serum zinc and vitamin A were substantially lower in 2010. In the absence of obvious causal explanations, it is uncertain whether this decline represents a worsening of micronutrient status in Colombian children or an artifact due to systematic laboratory or data management errors incurred in the surveys. PMID- 28359211 TI - Emergency Food Assistance in Northern Syria: An Evaluation of Transfer Programs in Idleb Governorate. AB - BACKGROUND: The war in Syria has left millions struggling to survive amidst violent conflict, pervasive unemployment, and food insecurity. Although international assistance funding is also at an all-time high, it is insufficient to meet the needs of conflict-affected populations, and there is increasing pressure on humanitarian stakeholders to find more efficient, effective ways to provide assistance. OBJECTIVE: To evaluate 3 different assistance programs (in kind food commodities, food vouchers, and unrestricted vouchers) in Idleb Governorate of Syria from December 2014 and March 2015. METHODS: The evaluation used repeated survey data from beneficiary households to determine whether assistance was successful in maintaining food security at the household level. Shopkeeper surveys and program monitoring data were used to assess the impact on markets at the district/governorate levels and compare the cost-efficiency and cost-effectiveness of transfer modalities. RESULTS: Both in-kind food assistance and voucher programs showed positive effects on household food security and economic measures in Idleb; however, no intervention was successful in improving all outcomes measured. Food transfers were more likely to improve food access and food security than vouchers and unrestricted vouchers. Voucher programs were found to be more cost-efficient than in-kind food assistance, and more cost effective for increasing household food consumption. CONCLUSION: Continuation of multiple types of transfer programs, including both in-kind assistance and vouchers, will allow humanitarian actors to remain responsive to evolving access and security considerations, local needs, and market dynamics. PMID- 28359213 TI - Caring for perinatally HIV-infected children: call for mental care for the children and the caregivers. AB - Antiretroviral therapy has dramatically improved the survival rate of perinatally HIV-infected children. For them to thrive, it is necessary to understand better their mental health issues. Caregivers play an important role in children's daily care and caregiver mental health may relate to children's mental health. However, this association has rarely been studied. Accordingly, the present study examined the associations between depression of caregivers and that of perinatally HIV infected children in Kigali, Rwanda. We conducted a cross-sectional study of 475 perinatally HIV-infected children aged 7-14 years and their caregivers. We collected children's depression score data via face-to-face interviews with children using the Beck Depression Inventory for Youth. We also collected sociodemographic data using a semi-structured questionnaire with caregivers. In addition, we measured children's weight, height, and collected their clinical records. Data were analyzed via linear and logistic regression analyses. Of all children, 22% had symptoms of depression. Among those who had depressive symptoms (n= 105), 49% had never received psychological support. In both the linear and logistic regression analysis, caregiver's high depression scores were positively associated with children's higher depression scores (AOR: 3.064, 95% CI: 1.723, 4.855, and AOR: 1.759, 95% CI: 1.129, 2.740, respectively). Taking Efavirenz and low height-for-age were also positively associated with higher depression scores among HIV-infected children. Mental health needs to be addressed to improve quality of life of perinatally HIV-infected children. Caregiver's depression was positively associated with children's depressive symptoms. Caring for both children and the caregivers' mental health may prevent the mutual fostering of depression. PMID- 28359212 TI - A randomized clinical trial of adolescents with HIV/AIDS: pediatric advance care planning. AB - The objective of this study is to determine if pediatric advance care planning (pACP) increases adolescent/family congruence in end-of-life (EOL) treatment preferences longitudinally. Adolescents aged 14-21 years with HIV/AIDS and their families were randomized (N = 105 dyads) to three-60-minute sessions scheduled one week apart: either the pACP intervention (survey administered independently, facilitated conversation with adolescent and family present, completion of legal advance directive document with adolescent and family present) or an active control (developmental history, safety tips, nutrition and exercise education). This longitudinal, single-blinded, multi-site, randomized controlled trial was conducted in six pediatric hospital-based HIV-clinics, located in high HIV mortality cities. The Statement of Treatment Preferences measured adolescent/family congruence in EOL treatment preferences at immediately following the facilitated pACP conversation (Session 2), and at 3-month post intervention. The mean age of adolescent participants was 18 years (range 14-21 years); 54% were male; and 93% were African-American. One-third had an AIDS diagnosis. Immediately post-intervention the Prevalence Adjusted Bias Adjusted Kappa showed substantial treatment preference agreement for pACP dyads compared to controls (High burden/low chance of survival, PABAK = 0.688 vs. 0.335; Functional impairment, PABAK = 0.687 vs. PABAK= 0.34; Mental impairment, PABKA = 0.717 vs. 0.341). Agreement to limit treatments was greater among intervention dyads than controls (High burden: 14.6% vs. 0%; Functional impairment = 22.9% vs. 4.4%; and Mental impairment: 12.5% vs. 4.4%). Overall treatment preference agreement among pACP dyads was high immediately post-intervention, but decreased over time. In contrast, treatment agreement among control dyads was low and remained low over time. As goals of care change over time with real experiences, additional pACP conversations are needed. PMID- 28359214 TI - Highly bioavailable nanocalcium from oyster shell for preventing osteoporosis in rats. AB - Oyster shell is one of the foremost natural sources of calcium and is used as an alternative treatment for osteoporosis. In this study, we demonstrated that zinc activated nanopowdered oyster shell (Zn-NPOS) effectively reduced bone loss compared with powdered oyster shell (POS) in an ovariectomized rat (OVX) model. As a result of nanosizing, the solubility and bioavailability of the oyster shell were greatly improved, and its effectiveness was further enhanced by zinc activation. Bone analysis indicated greater recovery from ovariectomy-induced bone loss following Zn-NPOS treatment. Moreover, Zn-NPOS treatment resulted in higher bone strength and superior trabecular architecture compared with NPOS and POS treatments. Furthermore, Zn-NPOS showed greater efficiency in increasing bone formation and reducing bone resorption markers. Therefore, nanosizing with zinc activation could be a viable strategy for improving the efficiency of oyster shells used for osteoporosis prevention. PMID- 28359215 TI - Comorbidities Might Condition the Recovery of Quality of Life in Survivors of Sepsis. AB - PURPOSE: To assess how preexisting disabling comorbidities (DC) affect the recovery rate of quality of life (QOL) over time in sepsis survivors. METHODS: A prospective study was conducted on sepsis survivors who answered the 36-Item Short Form Health Survey (SF-36) 7 days after discharge from the intensive care unit. Subsequent interviews were held at 3, 6, and 12 months. The results of the physical component score (PCS) and mental component score (MCS) of the SF-36 were evaluated. Patients were divided into 2 groups to compare patients with DC (DC group) and without DC (no-DC group). Quantile regression was used to model changes in PCS and MCS between different time points. RESULTS: Seventy-nine sepsis survivors were enrolled. After controlling for baseline age and QOL, the QOL scores were lower among patients with DC than in no-DC patients. The QOL of DC group got worse when compared to no-DC group. Recovery rate of PCS and MCS was higher in the DC group than in the no-DC group (PCS: 20.51 vs 16.96, P < .01; MCS: 19.24 vs 9.66, P < .01). Their baseline QOL was recovered only by 6 months after the sepsis episode. CONCLUSION: Quality-of-life impairment and its recovery rhythm in patients with sepsis appear to be conditioned by coexisting DC. PMID- 28359216 TI - Revisiting Ultrasound-Guided Subclavian/Axillary Vein Cannulations: Importance of Pleural Avoidance With Rib Trajectory. AB - The Centers for Disease Control and Prevention guidelines for the prevention of catheter-related bloodstream infections suggest using "a subclavian site, rather than an internal jugular or a femoral site, in adult patients." This recommendation is based on evidence of lower rates of thrombosis and catheter related bloodstream infections in patients with subclavian central venous catheters (CVCs) compared to femoral or internal jugular sites. However, preference toward a subclavian approach to CVC insertion is hindered by increased risk of mechanical complications, especially pneumothorax, when compared to other sites. This is largely related to the proximity of the subclavian vein to the pleural space and the traditional "blind" or anatomic landmark approach used in subclavian vein cannulation. We revisit a method that may provide increased safety and avoidance of pneumothorax during ultrasound-guided subclavian/axillary vein cannulation. This is achieved by directing the needle toward the subclavian vein at a point where it traverses over the second rib, providing a protective rib shield between the vessel and pleura as a safety net for operators. The technique also allows for increased compressibility of the subclavian/axillary vein in the event of bleeding complication. PMID- 28359217 TI - Efferocytosis-induced prostaglandin E2 production impairs alveolar macrophage effector functions during Streptococcus pneumoniae infection. AB - Alveolar macrophages (AMs) are multitasking cells that maintain lung homeostasis by clearing apoptotic cells (efferocytosis) and performing antimicrobial effector functions. Different PRRs have been described to be involved in the binding and capture of non-opsonized Streptococcus pneumoniae, such as TLR-2, mannose receptor (MR) and scavenger receptors (SRs). However, the mechanism by which the ingestion of apoptotic cells negatively influences the clearance of non-opsonized S. pneumoniae remains to be determined. In this study, we evaluated whether the prostaglandin E2 (PGE2) produced during efferocytosis by AMs inhibits the ingestion and killing of non-opsonized S. pneumoniae. Resident AMs were pre treated with an E prostanoid (EP) receptor antagonist, inhibitors of cyclooxygenase and protein kinase A (PKA), incubated with apoptotic Jurkat T cells, and then challenged with S. pneumoniae. Efferocytosis slightly decreased the phagocytosis of S. pneumoniae but greatly inhibited bacterial killing by AMs in a manner dependent on PGE2 production, activation of the EP2-EP4/cAMP/PKA pathway and inhibition of H2O2 production. Our data suggest that the PGE2 produced by AMs during efferocytosis inhibits H2O2 production and impairs the efficient clearance non-opsonized S. pneumoniae by EP2-EP4/cAMP/PKA pathway. PMID- 28359218 TI - The critical role of myeloperoxidase in Streptococcus pneumoniae clearance and tissue damage during mouse acute otitis media. AB - We have recently reported that neutrophils play a pivotal role in innate defense against Streptococcus pneumoniae ( Spn) during mouse acute otitis media (AOM). However, the underlying mechanism remains unclear. By constructing models of pneumococcal AOM in C57BL/6 mice and using a specific inhibitor in vivo, we investigated the role of myeloperoxidase (MPO), one of the most important protein components of neutrophils. Experiment results showed a significant increase in MPO production of the recruited neutrophils in Spn-infected mice. Neutrophils killed Spn in a MPO-dependent manner. MPO facilitated the generation of reactive oxygen species (ROS), and consequently promoted Spn clearance at an early stage and exacerbated tissue damage. Moreover, MPO induced neutrophil apoptosis and necrosis, which, in turn, worsened tissue damage. In summary, our study demonstrates that neutrophil MPO plays a paradoxical role in bacterial clearance and tissue damage in pneumococcal AOM. PMID- 28359221 TI - Structured Pyramidal Neural Networks. AB - The Pyramidal Neural Networks (PNN) are an example of a successful recently proposed model inspired by the human visual system and deep learning theory. PNNs are applied to computer vision and based on the concept of receptive fields. This paper proposes a variation of PNN, named here as Structured Pyramidal Neural Network (SPNN). SPNN has self-adaptive variable receptive fields, while the original PNNs rely on the same size for the fields of all neurons, which limits the model since it is not possible to put more computing resources in a particular region of the image. Another limitation of the original approach is the need to define values for a reasonable number of parameters, which can turn difficult the application of PNNs in contexts in which the user does not have experience. On the other hand, SPNN has a fewer number of parameters. Its structure is determined using a novel method with Delaunay Triangulation and k means clustering. SPNN achieved better results than PNNs and similar performance when compared to Convolutional Neural Network (CNN) and Support Vector Machine (SVM), but using lower memory capacity and processing time. PMID- 28359220 TI - The effect of initial treatment on hearing prognosis in idiopathic sudden sensorineural hearing loss: a nationwide survey in Japan. AB - OBJECTIVE: To investigate the hearing prognosis of idiopathic sudden sensorineural hearing loss (SSNHL) treated with different initial therapies. METHODS: Subjects consisted of patients diagnosed with idiopathic SSNHL within 7 days from onset and showing severe hearing loss (>=60 dB), who were registered in a Japanese multicenter database between April 2014 and March 2016. Subjects were divided into four groups according to initial therapy: (1) steroids, (2) steroids + Prostaglandins (PGs), (3) intratympanic steroids (ITS), and (4) no steroids. Hearing outcomes were compared among the groups. RESULTS: In total, 1305 patients were enrolled. The final hearing level and hearing gain of patients treated with steroids + PGs were significantly higher than those of patients treated with steroids alone or no steroids. The ratio of good prognosis (complete recovery or marked improvement) in patients treated with steroids + PGs was higher than that in patients treated with steroids alone or no steroids. There was no difference in the prognosis of patients treated with steroids alone or no steroids. CONCLUSION: A large number of patients with idiopathic SSNHL were registered in a multicenter database. PG use in combination with steroid administration was associated with a good hearing prognosis in patients with severe hearing loss. PMID- 28359219 TI - Modification of sample processing for the Limulus amebocyte lysate assay enhances detection of inflammogenic endotoxin in intact bacteria and organic dust. AB - The pro-inflammatory potency and causal relationship with asthma of inhaled endotoxins have underscored the importance of accurately assessing the endotoxin content of organic dusts. The Limulus amebocyte lysate (LAL) assay has emerged as the preferred assay, but its ability to measure endotoxin in intact bacteria and organic dusts with similar sensitivity as purified endotoxin is unknown. We used metabolically radiolabeled Neisseria meningitidis and both rough and smooth Escherichia coli to compare dose-dependent activation in the LAL with purified endotoxin from these bacteria and shed outer membrane (OM) blebs. Labeled [14C]-3 OH-fatty acids were used to quantify the endotoxin content of the samples. Purified meningococcal and E. coli endotoxins and OM blebs displayed similar specific activity in the LAL assay to the purified LPS standard. In contrast, intact bacteria exhibited fivefold lower specific activity in the LAL assay but showed similar MD-2-dependent potency as purified endotoxin in inducing acute airway inflammation in mice. Pre-treatment of intact bacteria and organic dusts with 0.1 M Tris-HCl/10 mM EDTA increased by fivefold the release of endotoxin. These findings demonstrate that house dust and other organic dusts should be extracted with Tris/EDTA to more accurately assess the endotoxin content and pro inflammatory potential of these environmental samples. PMID- 28359222 TI - Online Automated Seizure Detection in Temporal Lobe Epilepsy Patients Using Single-lead ECG. AB - Automated seizure detection in a home environment has been of increased interest the last couple of decades. The electrocardiogram is one of the signals that is suited for this application. In this paper, a new method is described that classifies different heart rate characteristics in order to detect seizures from temporal lobe epilepsy patients. The used support vector machine classifier is trained on data from other patients, so that the algorithm can be used directly from the start of each new recording. The algorithm was tested on a dataset of more than 918[Formula: see text]h of data coming from 17 patients containing 127 complex partial and generalized partial seizures. The algorithm was able to detect 81.89% of the seizures, with on average 1.97 false alarms per hour. These results show a strong drop in the number of false alarms of more than 50% compared to other heart rate-based patient-independent algorithms from the literature, at the expense of a slightly higher detection delay of 17.8s on average. PMID- 28359223 TI - Epileptic Discharge Related Functional Connectivity Within and Between Networks in Benign Epilepsy with Centrotemporal Spikes. AB - Benign epilepsy with centrotemporal spikes (BECTS) is a common childhood epilepsy syndrome associated with abnormalities in neurocognitive domains, particularly during interictal epileptiform discharges (IEDs). Here, we investigated the effects of IEDs on brain's intrinsic connectivity networks in 43 BECTS patients and 28 matched healthy controls (HCs). Patients were further divided into IED and non-IED subgroups based on simultaneous EEG-fMRI recordings. Functional connectivity within and between five networks, corresponding to seizure origination and cognitive processes, were analyzed to measure IED effects. We found that patients exhibited increased connectivity within the auditory network (AN) and the somato-motor network (SMN), and decreased connectivity within the basal ganglia network and the dorsal attention network, suggesting that both transient and chronic seizure activity may disturb normal network organization. The IED group showed decreased functional connectivity within the default mode network (DMN) compared with the non-IED group and HCs, implying that the DMN was selectively impaired during epileptiform discharges associated with altered self referential cognitive functions. Moreover, the IED group exhibited increased positive correlations between the AN and the SMN, which suggests a possible excessive influence of centrotemporal spiking on information processing in the auditory system. The association between epileptic activity and network dysfunctions highlights their importance in investigating the pathological mechanism underlying BECTS. PMID- 28359224 TI - Evaluation of porphyrin loaded dry alginate foams containing poloxamer 407 and beta-cyclodextrin-derivatives intended for wound treatment. AB - Dry alginate foams intended for antibacterial photodynamic therapy (aPDT) of infected wounds were prepared. aPDT is a treatment modality involving light of appropriate wavelength, oxygen and a photosensitizer (PS) to produce radicals that attack biological targets (e.g. bacteria). The hydrophobic 5,10,15,20 tetrakis(4-hydroxyphenyl)porphyrin (THPP) was chosen as a model PS and loaded into the foams. The foams contained a poloxamer (Pluronic F127) and/or beta cyclodextrin (betaCD)-derivatives, i.e. methylbetaCD (MbetaCD), heptakis(2,6-di-O methyl)-betaCD (HkbetaCD) or hydroxypropylbetaCD (HPbetaCD).The physical characteristics of the various foams prepared and the THPP load, release and photostability were evaluated. All the foams were thin and flexible and could easily be handled and cut to fit a potential wound. Fast disintegration were observed for dry foams in water or phosphate buffered saline, while in Hanks' balanced salt solution the foams absorbed liquid without losing their integrity. All the foams had a similar THPP load of 0.12-0.13% w/w. The presence of betaCD derivatives improved THPP release, however, no differences were observed between the different types of betaCD-derivatives evaluated. THPP loaded into the foams was photolabile, which induced a color change combined with fading. Alginate foams formulated with PF127, betaCD-derivatives and THPP demonstrated applicability as delivery vehicles for PSs in aPDT of wounds. PMID- 28359229 TI - The Good Enough Doctor. PMID- 28359226 TI - Prevention of fetal infection in heifers challenged with bovine viral diarrhoea virus type 1a by vaccination with a type 1c or type 1a vaccine. AB - AIMS: To evaluate a vaccine containing type 1c bovine viral diarrhoea (BVD) virus for prevention of fetal infection in pregnant heifers when challenged with New Zealand BVD virus type 1a 6 months after vaccination, compared to unvaccinated heifers and heifers vaccinated with a vaccine containing type 1a BVD virus. METHODS: Fifty five crossbred Friesian heifers, free from BVD virus and antibody, were randomly allocated to three groups. Twenty five heifers were vaccinated twice with a vaccine containing type 1c BVD virus (T1c group), and 10 heifers with a vaccine containing type 1a BVD virus (T1a group), and 20 heifers were unvaccinated (NC group). After oestrus synchronisation the heifers were bred by artificial insemination followed by natural bull mating. Six months after booster vaccination 15 heifers from the T1c group, eight from the T1a group, and 15 from the NC group, were exposed to four calves that were persistently infected with type 1a BVD virus, for 4 weeks. At the beginning of the challenge phase 36/38 heifers were 72-74 days pregnant and 2/38 heifers were approximately 53 days pregnant. Approximately 52 days after the start of the challenge the heifers were subjected to euthanasia and fetal tissues were collected for the detection of BVD virus by ELISA in fetal heart blood and PCR in fetal tissues. RESULTS: Based on PCR results, BVD virus was detected in 15/15 fetuses in the NC group, compared to 4/14 fetuses in the T1c group and 3/8 fetuses in the T1a group. The proportion of BVD virus-positive fetuses was lower in both vaccinated groups compared to the NC group (p<0.002), but there was no difference in proportions between the vaccinated groups (p=1.00). Fetal protection, expressed as the prevented fraction, was 71.4 (95% CI=41.9-91.6)% and 62.5 (95% CI=24.5-91.5)% for the T1c and T1a groups, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: The vaccines containing killed type 1c and type 1a BVD viruses significantly reduced fetal infection following challenge with a New Zealand type 1a BVD virus. Prevention of fetal infection by vaccination may not be 100%, and the risk of persistently infected calves being born to some vaccinated cattle should be acknowledged and managed as part of a BVD control programme. PMID- 28359230 TI - Hydroxypyridinone Derivatives: A Fascinating Class of Chelators with Therapeutic Applications - An Update. AB - Hydroxypyridinones (HPs) are a family of N-heterocyclic metal chelators, which have been an attractive target in the development of a variety of new pharmaceutical drugs, due to their high metal chelating efficacy/specificity and easy derivatization to tune the desired biological properties. In fact, along the last decades, hydroxypyridinone derivatives, but mostly 3-hydroxy-4-pyridinone (3,4-HP), have been intensively used in drug design, following either a multitarget approach, in which one chelating unity is extrafunctionalized (hybridized) to enable the interaction with other important specific biological sites, or a polydenticity approach, in which more than one chelating moiety is conveniently attached to one scaffold, to increase the metal chelating efficacy. This review represents an update of the most recent publications (2014-2016) in mono-HP hybrids, namely as potential anti-Alzheimer's drugs, inhibitors of metalloenzymes and anti-microbials, and also polychelating compounds (poly- HP), in view of potential application, such as anti-microbial/biostatic agents, luminescent biosensors or diagnostic agents. PMID- 28359231 TI - Gold - Old Drug with New Potentials. AB - BACKGROUND: Research into gold-based drugs for a range of human diseases has seen a revival in recent years. This article reviews the most important applications of gold products in different fields of human pathology. Au(I) and Au(III) compounds have been re-introduced in clinical practice for targeting the cellular components involved in the onset and progression of viral and parasitic diseases, rheumatoid arthritis and cancer. RESULTS: After some brief historical notes, this article takes into account the applications of gold compounds against Mycobacterium tuberculosis, and also in tuberculosis and in rheumatoid arthritis treatment. The use of gold containing drugs in the cure of cancer are then considered, with special emphasis to the use of nanoparticles and to the photo thermal cancer therapy. The use of colloidal gold in diagnostics, introduced in the last decade is widely discussed. As a last point a survey on the adverse effects and on the toxicity of the various gold derivatives in use in medicine is presented. CONCLUSION: In this review, we described the surprisingly broad spectrum of possible uses of gold in diagnostics and in therapeutic approaches to multiple human diseases, ranging from degenerative to infectious diseases, and to cancer. In particular, gold nanoparticles appear as attractive elements in modern clinical medicine, combining high therapeutic properties, high selectivity in targeting cancer cells and low toxicity. PMID- 28359232 TI - Identification and Characterization of a Chemical Compound that Inhibits Methionyl-tRNA Synthetase from Pseudomonas aeruginosa. AB - BACKGROUND: Pseudomonas aeruginosa is an opportunistic pathogen problematic in causing nosocomial infections and is highly susceptible to development of resistance to multiple antibiotics. The gene encoding methionyl-tRNA synthetase (MetRS) from P. aeruginosa was cloned and the resulting protein characterized. METHODS: MetRS was kinetically evaluated and the KM for its three substrates, methionine, ATP and tRNAMet were determined to be 35, 515, and 29 MUM, respectively. P. aeruginosaMetRS was used to screen two chemical compound libraries containing 1690 individual compounds. RESULTS: A natural product compound (BM01C11) was identified that inhibited the aminoacylation function. The compound inhibited P. aeruginosa MetRS with an IC50 of 70 MUM. The minimum inhibitory concentration (MIC) of BM01C11 was determined against nine clinically relevant bacterial strains, including efflux pump mutants and hypersensitive strains of P. aeruginosa and E. coli. The MIC against the hypersensitive strain of P. aeruginosa was 16 MUg/ml. However, the compound was not effective against the wild-type and efflux pump mutant strains, indicating that efflux may not be responsible for the lack of activity against the wild-type strains. When tested in human cell cultures, the cytotoxicity concentration (CC50) was observed to be 30 MUg/ml. The compound did not compete with methionine or ATP for binding MetRS, indicating that the mechanism of action of the compound likely occurs outside the active site of aminoacylation. CONCLUSION: An inhibitor of P. aeruginosa MetRS, BM01C11, was identified as a flavonoid compound named isopomiferin. Isopomiferin inhibited the enzymatic activity of MetRS and displayed broad spectrum antibacterial activity. These studies indicate that isopomiferin may be amenable to development as a therapeutic for bacterial infections. PMID- 28359233 TI - In Vivo Hypoglycemic Studies of Polyherbal Phytoceuticals, Their Pharmacokinetic Studies and Dose Extrapolation by Allometric Scaling. AB - BACKGROUND: This work reports the safety profiling, in vivo hypoglycemic and pharmacokinetic studies of three phytoceuticals viz. conventional and sustained release tablets and microspheres each containing a polyherbal product phytocomposite (PHC) as the active ingredient. PHC is prepared from the leaf extracts of Ficus benghalensis: Syzigium cumini: Ocimum sanctum mixed in the weight ratio of 1:1:2. Further no observed adverse effect level (NOAEL), maximum recommended starting dose (MRSD) in human and prediction of human pharmacokinetic parameters have been accomplished by allometric equations. METHODS: Acute and sub chronic studies of the phytoceuticals were done as per OECD and in vivo hypoglycemic studies in STZ induced diabetic rats. Plasma concentrations of the active constituent rutin (pharmacologically active compound of PHC) were determined by HPLC and other pharmacokinetic parameters using PK Solver. Repeated dose toxicity was carried out to determine the NOAEL value, MRSD estimated using allometric formulas of body surface area and clearance (CL) and volume of distribution (Vd) predicted by allometric equations of single species scaling. RESULTS: Phytoceuticals showed a wide range of safety profile with a significant lowering of blood gluco-lipid level. The values of the pharmacokinetic parameters for different doses of phytoceuticals showed that the active concentration was maintained in plasma level and each formulation complied with their relevant quality criteria. NOAEL value was 5000 mg/kg/body weight and MRSD was 4864.86 mg. CONCLUSION: Phytoceuticals prepared are safe and effectively controlled blood gluco lipid level. Animal to human dose extrapolation and prediction of human pharmacokinetic parameters by allometry was convenient. PMID- 28359234 TI - Identification of Novel 5,6-Dimethoxyindan-1-one Derivatives as Antiviral Agents. AB - BACKGROUND: Discovery of novel antiviral agents is essential because viral infection continues to threaten human life globally. Various heterocyclic small molecules have been developed as antiviral agents. The 5,6-dimethoxyindan-1-on nucleus is of considerable interest as this ring is the key constituent in a range of bioactive compounds, both naturally occurring and synthetic, and often of considerable complexity. OBJECTIVE: The main purpose of this research was to discover and develop small molecule heterocycles as broad-spectrum of antiviral agents. METHOD: A focused small set of 5,6-dimethoxyindan-1-one analogs (6-8) along with a thiopene derivative (9) was screened for selected viruses (Vaccinia virus - VACA, Human papillomavirus - HPV, Zika virus - ZIKV, Dengue virus - DENV, Measles virus - MV, Poliovirus 3 - PV, Rift Valley fever virus - RVFV, Tacaribe virus - TCRV, Venezuelan equine encephalitis virus - VEEV, Herpes simplex virus 1 -HSV-1 and Human cytomegalovirus - HCMV) using the National Institute of Allergy and Infectious Diseases (NIAID)'s Division of Microbiology and Infectious Diseases (DMID) antiviral screening program. RESULTS: These molecules demonstrated moderate to excellent antiviral activity towards variety of viruses. The 5,6-dimethoxyindan-1-one analog (7) demonstrated high efficacy towards vaccinia virus (EC50: <0.05 uM) and was nearly 232 times more potent than the standard drug Cidofovir (EC50: 11.59 uM) in primary assay whereas it demonstrated moderate activity (EC50: >30.00 uM) in secondary plaque reduction assay. The thiophene analog (9) has shown very good viral inhibition towards several viruses such as Human papillomavirus, Measles virus, Rift Valley fever virus, Tacaribe virus and Herpes simplex virus 1. CONCLUSION: Our research identified a novel 5,6 dimethoxyindan-1-one analog (compound 7), as a potent antiviral agent for vaccinia virus, and heterocyclic chalcone analog (compound 9) as a broad spectrum antiviral agent. PMID- 28359235 TI - Halving Your Cake and Eating it, Too: A Case-based Discussion and Review of Metabolic Rehabilitation for Obese Adults with Diabetes. AB - BACKGROUND: The global epidemic of obesity will see normal weight adults constituting a mere one-third of the global population by 2025. Although appetite and weight are regulated by a complex integration of neurological, endocrine and gastrointestinal feedback mechanisms, there is a constant interaction between psychological state, physical impairment, presence of comorbid chronic disease and medications. METHODS: We discuss two cases and reveal a practical approach to investigating and managing patients with obesity and diabetes in the 'real world'. Within this scope, the aetiology, associated disease burden, and pharmacological therapies for the treatment of the obese patient with type 2 diabetes are reviewed. An insight into non-surgical metabolic rehabilitation is also provided. SUMMARY: Lifestyle, including diet, exercise, medications, as well as genetic predisposition, and rarely, endocrinopathies should be considered in the assessment of the obese patient. Investigations are not complex and include cardiometabolic and nutritional screens and an assessment for institution of graded, safe levels of exercise. In more complicated patients, referral to a multidisciplinary outpatient program may be necessary and it is not uncommon for patients to lose between 10-20% of their initial weight. Despite this, metabolic surgery may be necessary as further weight loss with long-term weight maintenance may be medically indicated. The type of surgery is tailored to the patient's medical risk and co-morbidities as well as likelihood of compliance with the required follow-up. CONCLUSION: It is the opinion of the authors that metabolic rehabilitation should be intensive, multidisciplinary, and have a supervised exercise program, as the gold standard of care. These suggestions are based on the clinical pearls gained over two decades of clinical experience working in one of Australia's most innovative multidisciplinary metabolic rehabilitation programs caring for patients with severe obesity. PMID- 28359236 TI - Effects of PHA-665752 and Cetuximab Combination Treatment on In Vitro and Murine Xenograft Growth of Human Colorectal Cancer Cells with KRAS or BRAF Mutations. AB - BACKGROUND: It remains unknown whether blockade of c-Met signaling and epidermal growth factor receptor signaling is effective in suppressing the growth of human colorectal cancer (CRC) cells. In this study, we investigated the effects of the c-Met inhibitor PHA-665752 alone and in combination with cetuximab on the growth of human CRC cells in vitro and in mouse xenografts. METHODS: Human CRC cell lines (Caco2, HCT-116, and HT-29) and mice bearing HCT-116 xenografts were treated with cetuximab in the absence or presence of PHA-665752. Cell viability and apoptosis were examined using the MTT and TUNEL assays, respectively. Vimentin was measured by immunohistochemistry as a marker for epithelial-to mesenchymal transition. Western blotting was used to determine signaling protein expression levels. RESULTS: The MTT assay showed that the growth of Caco2, HCT 116, and HT-29 cells was inhibited by PHA-665752 in a dose-dependent manner, but only Caco2 cell growth was suppressed by cetuximab. Combination treatment with PHA-665752 and cetuximab inhibited the proliferation of Caco2 cells and RAS mutant CRC cell lines. However, relative to the PHA-665752-alone treatment group, HT-29 cells with a BRAF mutation showed no noticeable effect. The mean tumor volume in mice treated with cetuximab in combination with PHA-665752 was significantly smaller than that in the mice treated with only cetuximab (P = 0.033) or PHA-665752 (P < 0.01). Similarly, the expression of vimentin in the mice treated with PHA-665752 in combination with cetuximab was significantly lower than that in the mice treated with cetuximab or PHA-665752 alone (P < 0.05 in each case). TUNEL assays revealed that treatment with PHA-665752 in combination with cetuximab markedly increased CRC cell apoptosis. Western blotting analysis of signaling protein expression showed that PHA- 665752 inhibited Met phosphorylation (P < 0.05). In addition, treatment with cetuximab alone or in combination with PHA-665752 effectively inhibited EGFR phosphorylation (P < 0.05). CONCLUSION: Combination treatment with PHA-665752 and cetuximab suppressed in vitro and in vivo CRC cell growth more than treatment with either agent alone did. PMID- 28359237 TI - Influence of Aldo-keto Reductase 1C3 in Prostate Cancer - A Mini Review. AB - BACKGROUND: Aldo-keto reductase 1C3 (AKR1C3) is an important oxidoreductase with multiple substrates, that are involved in producing extra-testicular androgens. Its activity is influenced by environmental exposures, as well as by genetic variants. These genetic variants could therefore produce variable testosterone levels and subsequent androgen receptor (AR) activation. This could lead to differential downstream production of the prostate-specific antigen (PSA). As PSA level is used for clinical evaluation of the prostate, these variations could impact prostate cancer (PC) diagnosis, as well as PC management outcomes. This review brings together information with regards to key functions of this enzyme, its relevance in PC, its transcriptional regulation, clinical aspects associated with genetics, differential regulation in cancer and cancer progression, and the types of AKR1C3 inhibitors with future therapeutic value. CONCLUSION: Based on these discussions, hypotheses are forwarded for future applicability of this enzyme and its genetic variants in transformational medical practices in PC. Options for the use of personalised AKR1C3 inhibitor drugs for late stage PC are also discussed. PMID- 28359239 TI - Oncolytic Virotherapy and Gene Therapy Strategies for Hepatobiliary Cancers. AB - Advanced liver cancers and biliary cancers represent diseases with dismal prognosis because of frequent local invasion and metastasis. Effective therapeutic agents for these cancers have not been established. Oncolytic viruses (OVs) constitute a novel class of promising, selective anticancer agents and recent studies have elucidated their unique features. Moreover, clinical trials are demonstrating promising results. Numerous OVs are being tested in preclinical models of hepatocellular carcinoma (HCC). The lead agent Pexa-Vec (pexastimogene devacirepvec, JX-594), a recombinant Wyeth strain vaccinia virus, has demonstrated preliminary evidence of safety and efficacy for HCC in clinical trials. Few other OVs have entered clinical testing. Relatively few preclinical studies and clinical trials exist for biliary cancers. In this review, we introduce various approaches using OVs to treat the intractable hepatobiliary cancers. PMID- 28359240 TI - Elaborating the Role of Natural Products on the Regulation of Autophagy and their Potentials in Breast Cancer Therapy. AB - Autophagy is an intracellular lysosomal/vacuolar degradation system, in which the inner cytoplasmic cell membrane is degraded by the lysosomal hydrolases, followed by the resulting products released back into the cytosol. It is involved in many physiological processes which are crucial for cell growth and survival. However, disturbance in the autophagic process is often associated with a variety of human diseases, such as cancer. Breast cancer is one of the most malignant tumors characterized by the imbalanced cell proliferation, apoptosis as well as disordered autophagy regulation. The alterations of autophagy related genes or protein levels in breast cancer cells also suggested a potential implication of autophagy in breast cancer development and progression. Many natural products had been reported as potential anti-cancer agents or being considered as direct or indirect sources of new chemotherapy adjuvants to enhance the efficacy or to ameliorate the side effects through the modulation of autophagy. Investigation of the underlying mechanism of these compounds could be crucial for the development of new therapeutic or chemopreventive options for breast cancer treatment. In this review, a summary of those natural products that can regulate autophagy in breast cancer is presented and the potential value of such autophagy modulators on the development of anti-cancer drugs is also discussed. PMID- 28359241 TI - Obesity and Cancer: Biological Links and Treatment Implications. AB - Obesity is an epidemic disease and correlates with cardiovascular diseases increasing the overall mortality. However, it has been recently demonstrated that cancer is an unexpected consequence of obesity. In most of the studies, it is evaluated with body mass index (BMI): high BMI increases cancer risk and reduces survival of many solid tumors. The main biologic and clinic topics regarding obese cancer patients are here presented and discussed. Hyperinsulinemia and Insulin-like Growth Factors (IGFs) are among the most important links between cancer and obesity. However, adipose tissue (AT) also produces sex hormones, pro inflammatory cytokines and hypoxia which in turn promote initiation and progression of tumors. One of the major clinic concern about obese cancer patients is the risk of chemotherapy-related toxicity. Previous studies showed that obese patients do not experience significant increased toxicity compared to non-obese patients. Thus, the increasing incidence and scientific knowledge of obesity should prompt the researchers to study for personalization of therapy in obese patients with cancer rather than for the simple chemotherapy "depotentiation". It has been demonstrated that weight loss reduces cancer risk and can ameliorate compliance to therapy. Thus, social politics as well as therapies against obesity may impact on cancer risk, treatment and survival. PMID- 28359238 TI - HR+, HER2- Advanced Breast Cancer and CDK4/6 Inhibitors: Mode of Action, Clinical Activity, and Safety Profiles. AB - BACKGROUND: Cyclin-dependent kinase (CDK) 4/6 inhibitor-based therapies have shown great promise in improving clinical outcomes for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2 ) advanced breast cancer. OBJECTIVES: 1. Discuss the mode of action of the three CDK4/6 inhibitors in late clinical development: palbociclib (PD-0332991; Pfizer), ribociclib (LEE011; Novartis), and abemaciclib (LY2835219; Lilly). 2. Describe the efficacy and safety data relating to their use in HR+, HER2- advanced breast cancer. 3. Discuss the key side effects associated with CDK4/6 inhibitors along with considerations for adverse event management and patient monitoring. METHOD: Relevant information and data were assimilated from manuscripts, congress publications, and online sources. RESULTS: CDK4/6 inhibitors have demonstrated improved progression-free survival in combination with endocrine therapy compared with endocrine therapy alone. The side-effect profile of each agent is described, along with implications for patient monitoring, and considerations for patient care providers and pharmacists. CONCLUSION: Addition of a CDK4/6 inhibitor to endocrine therapy increases efficacy and delays disease progression. Insight into the unique side-effect profiles of this class of agents and effective patient monitoring will facilitate the successful use of CDK4/6 inhibitor-based therapies in the clinic. PMID- 28359243 TI - Redox Biotransformation and Delivery of Anthracycline Anticancer Antibiotics: How Interpretable Structure-activity Relationships of Lethality Using Electrophilicity and the London Formula for Dispersion Interaction Work. AB - BACKGROUND: Quantum chemical methods and molecular mechanics approaches face a lot of challenges in drug metabolism study because of either insufficient accuracy, huge computational cost, or lack of clear molecular level pictures for building computational models. Low-cost QSAR methods can often be carried out, even though molecular level pictures are not well defined; however, they show difficulty in identifying the mechanisms of drug metabolism and delineating the effects of chemical structures on drug toxicity because a certain amount of molecular descriptors are difficult to be interpreted. OBJECTIVE: In order to make a breakthrough of QSAR, mechanistically interpretable molecular descriptors were used to correlate with biological activity to establish structure-activity plots. The biological activity is the lethality of anthracycline anticancer antibiotics denoted as log LD50. The mechanistically interpretable molecular descriptors include electrophilicity and the mathematical function in the London formula for dispersion interaction. METHOD: The descriptors were calculated using quantum chemical methods. RESULTS: The plots for electrophilicity, which is interpreted as redox reactivity of anthracyclines, can describe oxidative degradation for detoxification and reductive bioactivation for toxicity induction. The plots for the dispersion interaction function, which represents the attraction between anthracyclines and biomolecules, can describe efflux from and influx into the target cells of toxicity. The plots can also identify three structural scaffolds of anthracyclines that have different metabolic pathways, resulting in their different toxicity behavior. CONCLUSION: This structure dependent toxicity behavior revealed in the plots can provide perspectives on drug design and drug metabolism study. PMID- 28359242 TI - Small-molecule Inhibitors of Epigenetic Mutations as Compelling Drugtargets for Myelodysplastic Syndromes. AB - BACKGROUND: Involvement of mutations in epigenetic mechanism in the development of heterogeneous MDS and its evolution to AML has been understood with at least one mutation and median of 2-3 mutations of the landscapes of driver mutations in ~40 genes described in >90% MDS patients. Exclusivity and cooperating effects of mutations have directed therapeutic implementation with hypomethylating agents and identified a number of first-in-class small molecules as inhibitors of mutational expression. Preclinical and clinical trials have already been initiated for some synthetic and natural products and established proof-of concept for mitigation of mutagenic effects. OBJECTIVE: The present review article entails the mutational signatures in DNA-methylation and hydroxymethylation, histone acetylation and Deacetylation, polycomb repressor complex (PRC2), and small molecule inhibitors of these mutational expressions. METHOD: Information has been collected from the recently published literature available mainly through Google search in Medline and PubMed database. Special emphasis was paid on the literature available during 2009-2016. RESULT: The up-to date information accumulated on signature-mutations and their inhibitors has to integrate the function of clonal hematopoiesis of indeterminate potential (CHIP) and mutational complexities for re-defining MDS-genesis. Nevertheless, molecular understanding of MDS heterogeneity and its transformation to AML is expanding at fast pace with expanding knowledge on abundant non-coding RNAs (ncRNAs), which forms the basis of targeted drug-tailoring, and will further develop personalized medicines based on individual genetic blue-prints. CONCLUSION: Mutation-specific targeted epigenetic drugs, which have already sensitized drug-makers and regulators, may promise attestation of 'del5q and lenalidomide'-like specific drugs for every mutational signature independently or in combination with standard therapeutic elements used for MDS-management, and that will add to understand their antagonistic/synergistic effects. PMID- 28359244 TI - Potential Therapeutic Targets in Energy Metabolism Pathways of Breast Cancer. AB - BACKGROUND: Mutations in proto-oncogenes and tumor suppressor genes make cancer cells proliferate indefinitely. As they possess almost all mechanisms for cell proliferation and survival like healthy cells, it is difficult to specifically target cancer cells in the body. Current treatments in most of the cases are harmful to healthy cells as well. Thus, it would be of great prudence to target specific characters of cancer cells. Since cancer cells avidly use glucose and glutamine to survive and proliferate by upregulating the relevant enzymes and their specific isoforms having important regulatory roles, it has been of great interest recently to target the energy-related metabolic pathways as part of the therapeutic interventions. OBJECTIVE: This paper summarizes the isozymes overexpressed in breast cancer, their roles of energy metabolism and cross-talks with other important signaling pathways in regulating proliferation, invasion and metastasis in breast cancer. METHOD: Information has been collected from recently published literature available on Google Scholar and PubMed. Where available, in vivo results were given more importance over in vitro works. RESULT: Like many other cancers, breast cancer shows increased dependence on glycolysis rather than mitochondrial respiration, the main energy source in healthy cells. Cancer cells alter the cellular energy system in a way that helps minimize level of reactive oxygen species and simultaneously produce enough macromolecules- proteins, lipids and nucleotides for cellular proliferation. The altered system enables the cells to grow, proliferate, metastasize and to develop drug resistance. Certain isozymes of metabolic enzymes are overexpressed in breast cancer and the degree of expression of these enzymes vary among subtypes. CONCLUSION: A clear understanding of the variations of energy metabolism in different molecular subtypes of breast cancer would help in treating each type with a very customized, safer and efficient treatment regimen. Anti-cancer drugs or RNAi or combination of both targeting cancer cell specific isozymes of metabolic enzymes mentioned in this article could offer a great treatment modality for breast cancer. PMID- 28359245 TI - The beta 2-Adrenergic Agonist Salbutamol Inhibits Migration, Invasion and Metastasis of the Human Breast Cancer MDA-MB- 231 Cell Line. AB - BACKGROUND: Breast cancer is the most diagnosed and the major cause of cancer death in women worldwide. Metastasis is the main cause of these deaths. The metastatic cascade involves multiple steps and it has been described that adrenergic receptors can modulate this process at multiple levels. However, beta adrenergic action in breast cancer is controversial. We have previously shown that beta-adrenergic agonists inhibit cell proliferation and tumor growth of numerous breast cancer models. OBJECTIVE: The purpose of the present investigation was to evaluate adrenergic effect in parameters related to tumor progression (migration, invasion and metastases) in two human breast cancer cell lines. METHODS: Migration was assessed in IBH-6 and MDA-MB-231 cells by time lapse videomicroscopy and modified Boyden chambers. Invasion was evaluated by Transwells coated with Matrigel and expression of pro-metastatic genes was determined by RT-qPCR. Experimental metastases studies were performed by injection of the cells in the tail vein of NSG immuno-deficient mice. RESULTS: In both cell lines, salbutamol (beta2-agonist) and propranolol (beta-blocker) significantly diminished cell migration while epinephrine exerted opposite effects. Moreover, salbutamol inhibited invasion of both breast cancer cell lines and enhanced adhesion to extracellular matrix. Salbutamol treatment was also able to decrease the expression of pro-metastatic genes in MDA-MB-231 cells. Finally, this compound decreased the number and size of MDA-MB-231 lung experimental metastases in NSG immuno- deficient mice. No effect on the establishment of IBH-6 metastases was observed. CONCLUSION: Our results suggest that salbutamol could be an effective adjuvant drug for the treatment of metastatic breast cancer. PMID- 28359246 TI - In-silico & In-vitro Identification of Structure-Activity Relationship Pattern of Serpentine & Gallic Acid Targeting PI3Kgamma as Potential Anticancer Target. AB - BACKGROUND: Natural products showed anticancer activity and often induce apoptosis or autophagy in cancer cells through the PI3K/Akt/mTOR signaling pathways. The potential of natural products as PI3Ks inhibitors has been reported, which suggest PI3Ks a promising anticancer target. Phosphoinositide 3 kinase is a family of related intracellular signal transducer enzymes or lipid kinases that regulate different cellular processes involved in cancer. OBJECTIVE: To identify the molecular reason behind the similar target based activity of selected shikimate pathway metabolites on PI3Kgamma, a detail structure-activity relationship study was performed. METHOD: In the studied work, anticancer potential of plant molecules gallic acid and serpentine was evaluated against PI3Kgamma isoform and compared with wortmannin, a steroid metabolite of the fungi and a non-specific covalent known inhibitor of PI3Ks by using in-silico QSAR, docking, ADMET, chemical isolation from plant, NMR and in-vitro activity. RESULTS: A predictive QSAR model was developed by applying multiple linear regression which revealed identification of key structural properties regulating the inhibitory activity of serpentine and gallic acid on PI3Kgamma. The model exhibited acceptable statistical parameters such as r2 0.76, r2CV 0.72, and q2 0.55. Structural elucidation was done through NMR studies. Predicted activities were further evaluated through in-vitro testing of gallic acid and serpentine targeting PI3Kgamma. CONCLUSION: The identified chemical features modulating the activity were amide, amine, and secondary amine groups counts, highest occupied molecule orbital (HOMO) energy and valence connectivity index (order 2). In silico ADME and toxicity risk assessment was done for pharmacokinetic and bioavailability compliance evaluation. PMID- 28359247 TI - Method to Assess Interactivity of Drugs with Nonparallel Concentration Effect Relationships. AB - BACKGROUND: Commonly used methods for analyzing interactivity between drugs (e.g. synergy, antagonism) such as isobologram, combination index, and curve shift are based on the Loewe Additivity principle of dose equivalence and the inherent assumption of similar concentration- effect (C-E) including parallel curves and equal maximum effects (Emax), and therefore are not suitable for drugs with dissimilar C-E. This study describes a new method that is without this limitation and has the additional advantage of enabling statistical analysis. METHODS AND RESULTS: The method comprises two steps. First, based on the dose equivalence principle, the experimentally obtained C-E of one drug was used to calculate the equally effective C-E of the other drug at no interactivity; the resulting two zero-interactivity C-E formed the upper and lower boundaries of Additivity Envelope. Next, 95% confidence intervals calculated from experimental data were added to Additivity Envelope to obtain Uncertainty Envelope (UE). Experimentally observed effects of drug combinations (C-Ecomb,observed) located within UE indicate additivity whereas C-Ecomb,observed located above or below UE indicate statistically significant (p<0.05) synergy or antagonism, respectively. Additional in silico studies demonstrated the shape and size of Additivity Envelope, which determines the ability to detect drug interactivity, depended on the Drug A-to-B concentration ratios and the ratios of their C-E curve shape parameter. Analyses of experimental results of combinations of drugs with nonparallel C-E and/or unequal Emax indicated UE as more versatile and provided more information, compared to earlier methods. CONCLUSION: UE is a broadly applicable method for analysis, including statistical significance assessment, of drug interactivity. PMID- 28359248 TI - Immunomodulatory Activity of MicroRNAs: Potential Implications for Multiple Myeloma Treatment. AB - Multiple myeloma (MM) is an incurable plasma cell neoplasm accounting for about 10% of all hematologic malignancies. Recently, emerging evidence is disclosing the complexity of bone marrow interactions between MM cells and infiltrating immune cells, which have been reported to promote proliferation, survival and drug resistance of tumor cells. MicroRNAs (miRNAs) are small non-coding RNA molecules with regulatory functions in the cell, whose expression has predictive and prognostic value in different malignancies. MiRNAs are gaining increasing interest due to their capability to polarize the immune-response through different mechanisms, which include the molecular reprogramming of immune cells. This characteristic, together with the antitumor activity of miRNA mimics or inhibitors, make the miRNA network an attractive area of investigation for novel anti-MM therapeutic approaches. In this review, we will discuss the recent advances in the understanding of the interplay between MM cells and bone marrow resident immune cells, with special focus on the molecular and functional changes induced by miRNA network modulation. We will finally indicate potential targets for therapeutic intervention. PMID- 28359249 TI - Autophagy Inhibition in Childhood Nephroblastoma and the Therapeutic Significance. AB - BACKGROUND: Autophagy is a physiological pathway characterized by lysosomedependent self-digestion to recycle damaged or superfluous cellular content. Deregulation of autophagy hampers the maintenance of cellular homeostasis and contributes to tumorigenesis. However, during anticancer therapy, autophagy activation contributes to development of resistance. Thus autophagy has been recognized as an important pathway and a therapeutic target in cancer. Nephroblastoma (Wilm's tumor) is a common childhood malignancy. The role of autophagy in nephroblastoma is largely uninvestigated. OBJECTIVE: This study is to investigate the change of autophagy level in nephroblastoma, and whether autophagy could be a therapeutic target in anaplastic nephroblastoma. METHOD: In clinical samples of childhood nephroblastoma, autophagy activity was evaluated by the expressions of selected autophagy markers as well as the presence of autophagosome ultrastructure. Use of autophagy inhibitors alone and in combination with conventional chemotherapeutics, was studied both in vivo and in vitro. RESULTS: In nephroblastoma, there was decrease in the Beclin 1 level and the number of autophagosomes, suggesting autophagy inhibition. Furthermore, in two anaplastic nephroblastoma cell lines, G401 and SK-NEP1, autophagy inhibitors further enhanced the efficacy of conventional chemotherapeutics including vincristine and cisplatin. In G401 tumor model established in nude mice, combinational use of chloroquine, an inhibitor of autophagy degradation, further decreased the tumor mass compared with single use of the chemotherapeutics vindesine, although no statistical significance was achieved. CONCLUSION: Our results suggest that autophagy deregulation is involved in nephroblastoma, and targeting autophagy can serve as a potential adjuvant strategy for the highly malignant cases. PMID- 28359250 TI - Insight into Discovery of Next Generation Reversible TMLR Inhibitors Targeting EGFR Activating and Drug Resistant T790M Mutants. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) is a well-recognised drug target exploited for treating non-small cell lung cancer (NSCLC). Gefitinib and erlotinib are first generation clinically employed inhibitors used against EGFR activating mutants. However, during course of treatment these inhibitors become ineffective due to the emergence of an acquired secondary mutation. Subsequently, in order to overcome non-responsiveness second and third generation inhibitors were designed having covalent bond and irreversible mode of action. However, these inhibitors were shown to be toxic. This led to the discovery of lead candidates with completely different mode of action and therapeutic efficacy. OBJECTIVE: We have reviewed the recent efforts undertaken by researchers in discovering newer noncovalent reversible next generation inhibitors for treating NSCLC. METHODS: We first studied the optimization steps and pharmacokinetic variables of the synthesised molecules. We also analysed bonds and interactions using PDB X-ray crystal structures as well as scaffold and selectivity analysis was undertaken. RESULTS: We identified that ligand lipophilic efficiency driven potency is a preferable optimisation parameter for maintaining drug likeliness of the molecule. Also, few h-bonds were recognised as major players in affecting the binding of compound. The scaffold analysis revealed that ligand molecules with pyrimidine core exhibit higher inhibitory activity against TMLR, as well as higher selectivity with respect to other kinases. CONCLUSION: Next generation reversible inhibitors exhibited unique binding mode and were found to occupy three major pockets (ribose pocket, back pocket and hinge region), which is critical for increasing the selectivity of the compound against TMLR mutants. PMID- 28359251 TI - Applying Knowledge of Enzyme Biochemistry to the Prediction of Functional Sites for Aiding Drug Discovery. AB - Enzymes are biological catalysts that play an important role in determining the patterns of chemical transformations pertaining to life. Many milestones have been achieved in unraveling the mechanisms in which the enzymes orchestrate various cellular processes using experimental and computational approaches. Experimental studies generating nearly all possible mutations of target enzymes have been aided by rapid computational approaches aiming at enzyme functional classification, understanding domain organization, functional site identification. The functional architecture, essentially, is involved in binding or interaction with ligands including substrates, products, cofactors, inhibitors, providing for their function, such as in catalysis, ligand mediated cell signaling, allosteric regulation and post-translational modifications. With the increasing availability of enzyme information and advances in algorithm development, computational approaches have now become more capable of providing precise inputs for enzyme engineering, and in the process also making it more efficient. This has led to interesting findings, especially in aberrant enzyme interactions, such as hostpathogen interactions in infection, neurodegenerative diseases, cancer and diabetes. This review aims to summarize in retrospection - the mined knowledge, vivid perspectives and challenging strides in using available experimentally validated enzyme information for characterization. An analytical outlook is presented on the scope of exploring future directions. PMID- 28359252 TI - Early urinary biomarkers of diabetic nephropathy in type 1 diabetes mellitus show involvement of kallikrein-kinin system. AB - BACKGROUND: Additional urinary biomarkers for diabetic nephropathy (DN) are needed, providing early and reliable diagnosis and new insights into its mechanisms. Rigorous selection criteria and homogeneous study population may improve reproducibility of the proteomic approach. METHODS: Long-term type 1 diabetes patients without metabolic comorbidities were included, 11 with sustained microalbuminuria (MA) and 14 without MA (nMA). Morning urine proteins were precipitated and resolved by 2D electrophoresis. Principal component analysis (PCA) and Projection to latent structures discriminatory analysis (PLS DA) were adopted to assess general data validity, to pick protein fractions for identification with mass spectrometry (MS), and to test predictive value of the resulting model. RESULTS: Proteins (n = 113) detected in more than 90% patients were considered representative. Unsupervised PCA showed excellent natural data clustering without outliers. Protein spots reaching Variable Importance in Projection score above 1 in PLS (n = 42) were subjected to MS, yielding 33 positive identifications. The PLS model rebuilt with these proteins achieved accurate classification of all patients (R2X = 0.553, R2Y = 0.953, Q2 = 0.947). Thus, multiple earlier recognized biomarkers of DN were confirmed and several putative new biomarkers suggested. Among them, the highest significance was met in kininogen-1. Its activation products detected in nMA patients exceeded by an order of magnitude the amount found in MA patients. CONCLUSIONS: Reducing metabolic complexity of the diseased and control groups by meticulous patients' selection allows to focus the biomarker search in DN. Suggested new biomarkers, particularly kininogen fragments, exhibit the highest degree of correlation with MA and substantiate validation in larger and more varied cohorts. PMID- 28359253 TI - Association of IL1 beta gene polymorphism and allograft functions in renal transplant recipients :a case control study from Kashmir Valley. AB - BACKGROUND: Cytokines have been found to be the important mediators during renal graft outcome. Therefore, we designed this study to investigate the role of recipients' IL-1 beta promoter (-511) and IL-1 beta exon-5 (+3954) polymorphisms with the risk of graft outcome. METHODOLOGY: We enrolled one hundred recipients of living-related renal transplants together with the age and sex matched controls from the healthy population not having any renal abnormality for this study. Genotype frequencies of the IL-1 beta promoter (-511) and IL-1 beta exon-5 (+3954) were analyzed using PCR-RFLP technique. RESULTS: Our results revealed significant differences in the healthy control group and patient group in IL 1beta +3954 (p < 0.001). The frequency of variant type TT genotype was higher in RE group as compared to SGF and showed 4 fold risk of rejection (OR = 4.54, p < 0.069) although p value was not significant. The frequency of wild type CC genotype and CT was not significant (p value 0.89 and 0.74 respectively). CONCLUSION: Our findings suggest that there is a prevalence of mutated allele of IL-1 gene cluster in our population, which may be responsible for renal dysfunction. PMID- 28359255 TI - A neural joint model for entity and relation extraction from biomedical text. AB - BACKGROUND: Extracting biomedical entities and their relations from text has important applications on biomedical research. Previous work primarily utilized feature-based pipeline models to process this task. Many efforts need to be made on feature engineering when feature-based models are employed. Moreover, pipeline models may suffer error propagation and are not able to utilize the interactions between subtasks. Therefore, we propose a neural joint model to extract biomedical entities as well as their relations simultaneously, and it can alleviate the problems above. RESULTS: Our model was evaluated on two tasks, i.e., the task of extracting adverse drug events between drug and disease entities, and the task of extracting resident relations between bacteria and location entities. Compared with the state-of-the-art systems in these tasks, our model improved the F1 scores of the first task by 5.1% in entity recognition and 8.0% in relation extraction, and that of the second task by 9.2% in relation extraction. CONCLUSIONS: The proposed model achieves competitive performances with less work on feature engineering. We demonstrate that the model based on neural networks is effective for biomedical entity and relation extraction. In addition, parameter sharing is an alternative method for neural models to jointly process this task. Our work can facilitate the research on biomedical text mining. PMID- 28359254 TI - Development of a genus-specific next generation sequencing approach for sensitive and quantitative determination of the Legionella microbiome in freshwater systems. AB - BACKGROUND: Next Generation Sequencing (NGS) has revolutionized the analysis of natural and man-made microbial communities by using universal primers for bacteria in a PCR based approach targeting the 16S rRNA gene. In our study we narrowed primer specificity to a single, monophyletic genus because for many questions in microbiology only a specific part of the whole microbiome is of interest. We have chosen the genus Legionella, comprising more than 20 pathogenic species, due to its high relevance for water-based respiratory infections. METHODS: A new NGS-based approach was designed by sequencing 16S rRNA gene amplicons specific for the genus Legionella using the Illumina MiSeq technology. This approach was validated and applied to a set of representative freshwater samples. RESULTS: Our results revealed that the generated libraries presented a low average raw error rate per base (<0.5%); and substantiated the use of high fidelity enzymes, such as KAPA HiFi, for increased sequence accuracy and quality. The approach also showed high in situ specificity (>95%) and very good repeatability. Only in samples in which the gammabacterial clade SAR86 was present more than 1% non-Legionella sequences were observed. Next-generation sequencing read counts did not reveal considerable amplification/sequencing biases and showed a sensitive as well as precise quantification of L. pneumophila along a dilution range using a spiked-in, certified genome standard. The genome standard and a mock community consisting of six different Legionella species demonstrated that the developed NGS approach was quantitative and specific at the level of individual species, including L. pneumophila. The sensitivity of our genus-specific approach was at least one order of magnitude higher compared to the universal NGS approach. Comparison of quantification by real-time PCR showed consistency with the NGS data. Overall, our NGS approach can determine the quantitative abundances of Legionella species, i. e. the complete Legionella microbiome, without the need for species-specific primers. CONCLUSIONS: The developed NGS approach provides a new molecular surveillance tool to monitor all Legionella species in qualitative and quantitative terms if a spiked-in genome standard is used to calibrate the method. Overall, the genus-specific NGS approach opens up a new avenue to massive parallel diagnostics in a quantitative, specific and sensitive way. PMID- 28359256 TI - Morintides: cargo-free chitin-binding peptides from Moringa oleifera. AB - BACKGROUND: Hevein-like peptides are a family of cysteine-rich and chitin-binding peptides consisting of 29-45 amino acids. Their chitin-binding property is essential for plant defense against fungi. Based on the number of cysteine residues in their sequences, they are divided into three sub-families: 6C-, 8C- and 10C-hevein-like peptides. All three subfamilies contain a three-domain precursor comprising a signal peptide, a mature hevein-like peptide and a C terminal domain comprising a hinge region with protein cargo in 8C- and 10C hevein-like peptides. RESULTS: Here we report the isolation and characterization of two novel 8C-hevein-like peptides, designated morintides (mO1 and mO2), from the drumstick tree Moringa oleifera, a drought-resistant tree belonging to the Moringaceae family. Proteomic analysis revealed that morintides comprise 44 amino acid residues and are rich in cysteine, glycine and hydrophilic amino acid residues such as asparagine and glutamine. Morintides are resistant to thermal and enzymatic degradation, able to bind to chitin and inhibit the growth of phyto pathogenic fungi. Transcriptomic analysis showed that they contain a three-domain precursor comprising an endoplasmic reticulum (ER) signal sequence, a mature peptide domain and a C-terminal domain. A striking feature distinguishing morintides from other 8C-hevein-like peptides is a short and protein-cargo-free C terminal domain. Previously, a similar protein-cargo-free C-terminal domain has been observed only in ginkgotides, the 8C-hevein-like peptides from a gymnosperm Ginkgo biloba. Thus, morintides, with a cargo-free C-terminal domain, are a stand alone class of 8C-hevein-like peptides from angiosperms. CONCLUSIONS: Our results expand the existing library of hevein-like peptides and shed light on molecular diversity within the hevein-like peptide family. Our work also sheds light on the anti-fungal activity and stability of 8C-hevein-like peptides. PMID- 28359257 TI - Plasma Urotensin II levels in children and adolescents with chronic kidney disease: a single-centre study. AB - BACKGROUND: Increased plasma Urotensin II (UII) levels have been found in adults with renal diseases. Studies in children are scarce. The objective of the study is to estimate plasma UII levels in subjects with chronic kidney disease (CKD) stages 3 to 5 and renal transplant recipients (RTR). In addition, the correlation of UII with anthropometric features and biochemical parameters was assessed. METHODS: Fifty-four subjects, aged 3 to 20 years old, 23 with CKD, 13 with end stage kidney disease (ESKD) undergoing hemodialysis (HD) and 18 RTR were enrolled. A detailed clinical evaluation was performed. Biochemical parameters of renal and liver function were measured. Plasma UII levels were measured in all patients and in 117 healthy controls, using a high sensitive enzyme immunoassay (EIA) kit. All data were analyzed using STATATM (Version 10.1). RESULTS: Median UII and mean log-transformed UII levels were significantly higher in CKD and RTR patients compared to healthy subjects (p < 0.001). HD patients had higher but not statistically significant UII and log-UII levels than controls. UII levels increased significantly at the end of the HD session and were higher than controls and in line to those of other patients. The geometric scores of UII in HD (before dialysis), CKD and RTR patients increased respectively by 42, 136 and 164% in comparison with controls. Metabolic acidosis was associated with statistical significant change in log-UII levels (p = 0.001). Patients with metabolic acidosis had an increase in UII concentration by 76% compared to those without acidosis. CONCLUSIONS: Children and adolescents with CKD, particularly those who are not on HD and RTR, have significantly higher levels of UII than healthy subjects. UII levels increase significantly at the end of the HD session. The presence of metabolic acidosis affects significantly plasma UII levels. PMID- 28359258 TI - What influences birth place preferences, choices and decision-making amongst healthy women with straightforward pregnancies in the UK? A qualitative evidence synthesis using a 'best fit' framework approach. AB - BACKGROUND: English maternity care policy has supported offering women choice of birth setting for over twenty years, but only 13% of women in England currently give birth in settings other than obstetric units (OUs). It is unclear why uptake of non-OU settings for birth remains relatively low. This paper presents a synthesis of qualitative evidence which explores influences on women's experiences of birth place choice, preference and decision-making from the perspectives of women using maternity services. METHODS: Qualitative evidence synthesis of UK research published January 1992-March 2015, using a 'best-fit' framework approach. Searches were run in seven electronic data bases applying a comprehensive search strategy. Thematic framework analysis was used to synthesise extracted data from included studies. RESULTS: Twenty-four papers drawing on twenty studies met the inclusion criteria. The synthesis identified support for the key framework themes. Women's experiences of choosing or deciding where to give birth were influenced by whether they received information about available options and about the right to choose, women's preferences for different services and their attributes, previous birth experiences, views of family, friends and health care professionals and women's beliefs about risk and safety. The synthesis additionally identified that women's access to choice of place of birth during the antenatal period varied. Planning to give birth in OU was straightforward, but although women considering birth in a setting other than hospital OU were sometimes well-supported, they also encountered obstacles and described needing to 'counter the negativity' surrounding home birth or birth in midwife-led settings. CONCLUSIONS: Over the period covered by the review, it was straightforward for low risk women to opt for hospital birth in the UK. Accessing home birth was more complex and contested. The evidence on freestanding midwifery units (FMUs) is more limited, but suggests that women wanting to opt for an FMU birth experienced similar barriers. The extent to which women experienced similar problems accessing alongside midwifery units (AMUs) is unclear. Women's preferences for different birth options, particularly for 'hospital' vs non hospital settings, are shaped by their pre-existing values, beliefs and experience, and not all women are open to all birth settings. PMID- 28359259 TI - Propofol and sufentanil may affect the patients' sleep quality independently of the surgical stress response: a prospective nonrandomized controlled trial in 1033 patients' undergone diagnostic upper gastrointestinal endoscopy. AB - BACKGROUND: It is unknown whether sedative per se contributes to the postoperative sleep disturbance. Diagnostic upper gastrointestinal endoscopy (UGE) is a minimally invasive procedure which is not likely to cause tissue trauma and pain. The purpose of this study was to evaluate the sleep quality of patients undergoing routine (without sedative) diagnostic UGE or UGE with sedative, before, 1 week, and 1 month after the procedure. METHODS: One thousand and thirty-three patients undergoing UGE were enrolled. Patients chose sedative or without sedative. Propofol and sufentanil were administered to the sedative group, not allowed for the routine group. The Pittsburgh Sleep Quality Index (PSQI) was measured before, 1 week and 1 month after the procedure. RESULTS: Five hundred and ten patients were enrolled in the sedative group and 523 in the routine group. One week after the procedure, patients in the sedative group showed significantly higher PSQI scores (worse sleep quality) than the baseline PSQI scores (p < 0.001), but there was no significant change for the routine group in the same period (p = 0.096). One month after the procedure, there was no significant difference in PSQI scores between the two groups compared with the baseline values (p = 0.358 for sedative group, p = 0.161 for routine group). There were also no significant difference in the PSQI scores between the two groups in the entire 1 month follow-up period (p = 0.885). CONCLUSIONS: The sedative group showed impaired sleep quality 1 week after diagnostic UGE. Propofol and sufentanil may independently affect the sleep quality of patients after sedative of diagnostic UGE for only one week. TRIAL REGISTRATION: This study is registered on Chinese Clinical Trial Registry ( IDChiCTR-OCH-13003128 ). Registered 2 April 2013. PMID- 28359260 TI - Developmental features of cotton fibre middle lamellae in relation to cell adhesion and cell detachment in cultivars with distinct fibre qualities. AB - BACKGROUND: Cotton fibre quality traits such as fibre length, strength, and degree of maturation are determined by genotype and environment during the sequential phases of cotton fibre development (cell elongation, transition to secondary cell wall construction and cellulose deposition). The cotton fibre middle lamella (CFML) is crucial for both cell adhesion and detachment processes occurring during fibre development. To explore the relationship between fibre quality and the pace at which cotton fibres develop, a structural and compositional analysis of the CFML was carried out in several cultivars with different fibre properties belonging to four commercial species: Gossypium hirsutum, G. barbadense, G. herbaceum and G. arboreum. RESULTS: Cotton fibre cell adhesion, through the cotton fibre middle lamella (CFML), is a developmentally regulated process determined by genotype. The CFML is composed of de-esterified homogalacturonan, xyloglucan and arabinan in all four fibre-producing cotton species: G. hirsutum, G. barbadense, G. herbaceum and G. arboreum. Conspicuous paired cell wall bulges are a feature of the CFML of two G. hirsutum cultivars from the onset of fibre cell wall detachment to the start of secondary cell wall deposition. Xyloglucan is abundant in the cell wall bulges and in later stages pectic arabinan is absent from these regions. CONCLUSIONS: The CFML of cotton fibres is re-structured during the transition phase. Paired cell wall bulges, rich in xyloglucan, are significantly more evident in the G. hirsutum cultivars than in other cotton species. PMID- 28359261 TI - Single-step SNP-BLUP with on-the-fly imputed genotypes and residual polygenic effects. AB - BACKGROUND: Single-step genomic best linear unbiased prediction (BLUP) evaluation combines relationship information from pedigree and genomic marker data. The inclusion of the genomic information into mixed model equations requires the inverse of the combined relationship matrix [Formula: see text], which has a dense matrix block for genotyped animals. METHODS: To avoid inversion of dense matrices, single-step genomic BLUP can be transformed to single-step single nucleotide polymorphism BLUP (SNP-BLUP) which have observed and imputed marker coefficients. Simple block LDL type decompositions of the single-step relationship matrix [Formula: see text] were derived to obtain different types of linearly equivalent single-step genomic mixed model equations with different sets of reparametrized random effects. For non-genotyped animals, the imputed marker coefficient terms in the single-step SNP-BLUP were calculated on-the-fly during the iterative solution using sparse matrix decompositions without storing the imputed genotypes. Residual polygenic effects were added to genotyped animals and transmitted to non-genotyped animals using relationship coefficients that are similar to imputed genotypes. The relationships were further orthogonalized to improve convergence of iterative methods. RESULTS: All presented single-step SNP BLUP models can be solved efficiently using iterative methods that rely on iteration on data and sparse matrix approaches. The efficiency, accuracy and iteration convergence of the derived mixed model equations were tested with a small dataset that included 73,579 animals of which 2885 were genotyped with 37,526 SNPs. CONCLUSIONS: Inversion of the large and dense genomic relationship matrix was avoided in single-step evaluation by using fully orthogonalized single step SNP-BLUP formulations. The number of iterations until convergence was smaller in single-step SNP-BLUP formulations than in the original single-step GBLUP when heritability was low, but increased above that of the original single step when heritability was high. PMID- 28359262 TI - Increased breast cancer mortality only in the lower education group: age-period cohort effect in breast cancer mortality by educational level in South Korea, 1983-2012. AB - BACKGROUND: A steadily increasing pattern of breast cancer mortality has been reported in South Korea since the late 1980s. This paper explored the trends of educational inequalities of female breast cancer mortality between 1983 and 2012 in Korea, and conducted age-period-cohort (APC) analysis by educational level. METHODS: Age-standardized mortality rates of breast cancer per 100,000 person years were calculated. Relative index of inequality (RII) for breast cancer mortality was used as an inequality measure. APC analyses were conducted using the Web tool for APC analysis provided by the Division of Cancer Epidemiology and Genetics at the U.S. National Cancer Institute. RESULTS: An increasing trend in breast cancer mortality among Korean women between 1983 and 2012 was due to the increased mortality of the lower education groups (i.e., no formal education or primary education and secondary education groups), not the highest education group. The breast cancer mortality was higher in women with a tertiary education than in women with no education or a primary education during 1983-1992, and the reverse was true in 1993-2012. Consequently, RII was changed from positive to negative associations in the early 2000s. The lower education groups had the increased breast cancer mortality and significant cohort and period effects between 1983 and 2012, whereas the highest group did not. CONCLUSIONS: APC analysis by socioeconomic position used in this study could provide an important clue for the causes on breast cancer mortality. The long-term monitoring of socioeconomic patterning in breast cancer risk factors is urgently needed. PMID- 28359263 TI - Parental exposures to occupational asthmagens and risk of autism spectrum disorder in a Danish population-based case-control study. AB - BACKGROUND: Environmental exposures and immune conditions during pregnancy could influence development of autism spectrum disorder (ASD) in offspring. However, few studies have examined immune-triggering exposures in relation to ASD. We evaluated the association between parental workplace exposures to risk factors for asthma ("asthmagens") and ASD. METHODS: We conducted a population-based case control study in the Danish population using register linkage. Our study population consisted of 11,869 ASD cases and 48,046 controls born from 1993 through 2007. Cases were identified by ICD-10 codes in the Danish Psychiatric Central Register. ASD cases and controls were linked to parental Danish International Standard Classification of Occupations (DISCO-88) job codes. Parental occupational asthmagen exposure was estimated by linking DISCO-88 codes to an asthma-specific job-exposure matrix. RESULTS: Our maternal analyses included 6706 case mothers and 29,359 control mothers employed during the pregnancy period. We found a weak inverse association between ASD and any maternal occupational asthmagen exposure, adjusting for sociodemographic covariates (adjusted OR: 0.92, 95% CI: 0.86-0.99). In adjusted analyses, including 7647 cases and 31,947 controls with employed fathers, paternal occupational asthmagen exposure was not associated with ASD (adjusted OR: 0.98, 95% CI: 0.92-1.05). CONCLUSIONS: We found a weak inverse association between maternal occupational asthmagen exposure and ASD, and a null association between paternal occupational exposure and ASD. We suggest that unmeasured confounding negatively biased the estimate, but that this unmeasured confounding is likely not strong enough to bring the effect above the null. Overall, our results were consistent with no positive association between parental asthmagen exposure and ASD in the children. PMID- 28359264 TI - Congenic rats with higher arylamine N-acetyltransferase 2 activity exhibit greater carcinogen-induced mammary tumor susceptibility independent of carcinogen metabolism. AB - BACKGROUND: Recent investigations suggest role(s) of human arylamine N acetyltransferase 1 (NAT1) in breast cancer. Rat NAT2 is orthologous to human NAT1 and the gene products are functional homologs. We conducted in vivo studies using F344.WKY-Nat2 rapid/slow rats, congenic at rat Nat2 for high (rapid) and low (slow) arylamine N-acetyltransferase activity, to assess a possible role for rat NAT2 in mammary tumor susceptibility. METHODS: Mammary carcinogens, methylnitrosourea (MNU) and 7,12-dimethylbenzanthracene (DMBA) neither of which is metabolized by N-acetyltransferase, were administered to assess mammary tumors. MNU was administered at 3 or 8 weeks of age. DMBA was administered at 8 weeks of age. NAT2 enzymatic activity and endogenous acetyl-coenzyme A (AcCoA) levels were measured in tissue samples and embryonic fibroblasts isolated from the congenic rats. RESULTS: Tumor latency was shorter in rapid NAT2 rats compared to slow NAT2 rats, with statistical significance for MNU administered at 3 and 8 weeks of age (p = 0.009 and 0.050, respectively). Tumor multiplicity and incidence were higher in rapid NAT2 rats compared to slow NAT2 rats administered MNU or DMBA at 8 weeks of age (MNU, p = 0.050 and 0.035; DMBA, p = 0.004 and 0.027, respectively). Recombinant rat rapid-NAT2, as well as tissue samples and embryonic fibroblasts derived from rapid NAT2 rats, catalyzed p-aminobenzoic acid N-acetyl transfer and folate-dependent acetyl-coenzyme A (AcCoA) hydrolysis at higher rates than those derived from rat slow-NAT2. Embryonic fibroblasts isolated from rapid NAT2 rats displayed lower levels of cellular AcCoA than slow NAT2 rats (p < 0.01). CONCLUSIONS: A novel role for rat NAT2 in mammary cancer was discovered unrelated to carcinogen metabolism, suggesting a role for human NAT1 in breast cancer. PMID- 28359265 TI - Tonggyu-tang, a traditional Korean medicine, suppresses pro-inflammatory cytokine production through inhibition of MAPK and NF-kappaB activation in human mast cells and keratinocytes. AB - BACKGROUND: Allergic diseases including allergic rhinitis, asthma, and atopic dermatitis are increasing worldwide. Common medications used to treat these inflammatory disorders are anti-histamines and corticosteroids, but they have their own limitations such as short duration and severe side effects. Thus, interest in complementary and alternative medicine is continually growing. Here, we investigate the anti-inflammatory mechanisms of Tonggyu-tang (TGT), a traditional Korean medicine that has been used to treat patients with allergic nasal disorders. METHODS: We measured mRNA expressions and production of pro inflammatory cytokines such as interleukin (IL)-4, IL-6, IL-8 and tumor necrosis factor alpha (TNF-alpha) by RT-PCR and ELISA assays in HMC-1 (human mast cell line-1) and HaCaT cells, immortalized human keratinocytes. Moreover, we evaluated the effect of TGT on two major inflammation-related pathways, mitogen activated protein kinase (MAPK) and NF-kappaB signaling pathway in these two cells. RESULTS: Our results revealed that that TGT significantly reduced the expression and production of inflammatory cytokines such as IL-4, IL-6, IL-8, and TNF-alpha in the agonist-treated HMC-1 and HaCaT cells. We also found that TGT suppressed MAPK signaling pathway including extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38), and c-Jun N-terminal kinase (JNK) as well as NF-kappaB pathway, which are known to regulate inflammatory cytokine expression. CONCLUSION: Taken together, our results demonstrate that TGT inhibits expression of pro-inflammatory cytokines by suppressing MAPK and NF-kB pathway in both mast cells and keratinocytes, suggesting the potential use of TGT in treating allergic inflammatory diseases. PMID- 28359266 TI - Identification of Novel Class of Triazolo-Thiadiazoles as Potent Inhibitors of Human Heparanase and their Anticancer Activity. AB - BACKGROUND: Expression and activity of heparanase, an endoglycosidase that cleaves heparan sulfate (HS) side chains of proteoglycans, is associated with progression and poor prognosis of many cancers which makes it an attractive drug target in cancer therapeutics. METHODS: In the present work, we report the in vitro screening of a library of 150 small molecules with the scaffold bearing quinolones, oxazines, benzoxazines, isoxazoli(di)nes, pyrimidinones, quinolines, benzoxazines, and 4-thiazolidinones, thiadiazolo[3,2-a]pyrimidin-5-one, 1,2,4 triazolo-1,3,4-thiadiazoles, and azaspiranes against the enzymatic activity of human heparanase. The identified lead compounds were evaluated for their heparanase-inhibiting activity using sulfate [35S] labeled extracellular matrix (ECM) deposited by cultured endothelial cells. Further, anti-invasive efficacy of lead compound was evaluated against hepatocellular carcinoma (HepG2) and Lewis lung carcinoma (LLC) cells. RESULTS: Among the 150 compounds screened, we identified 1,2,4-triazolo-1,3,4-thiadiazoles bearing compounds to possess human heparanase inhibitory activity. Further analysis revealed 2,4-Diiodo-6-(3-phenyl [1, 2, 4]triazolo[3,4-b][1, 3, 4]thiadiazol-6yl)phenol (DTP) as the most potent inhibitor of heparanase enzymatic activity among the tested compounds. The inhibitory efficacy was demonstrated by a colorimetric assay and further validated by measuring the release of radioactive heparan sulfate degradation fragments from [35S] labeled extracellular matrix. Additionally, lead compound significantly suppressed migration and invasion of LLC and HepG2 cells with IC50 value of ~5 MUM. Furthermore, molecular docking analysis revealed a favourable interaction of triazolo-thiadiazole backbone with Asn-224 and Asp-62 of the enzyme. CONCLUSIONS: Overall, we identified biologically active heparanase inhibitor which could serve as a lead structure in developing compounds that target heparanase in cancer. PMID- 28359267 TI - Aberrant expression of ALK and EZH2 in Merkel cell carcinoma. AB - BACKGROUND: Distinct characteristic features categorize Merkel cell carcinoma (MCC) into two subgroups according to the Merkel cell polyomavirus infection. Many mutational studies on MCC have been carried out in recent years without identifying a prominent driver mutation. However, there is paucity reporting the expression of cancer genes at the RNA level in MCC tumors. In this study, we studied the RNA expression profiles of 26 MCC tumors, with a goal to identify prospective molecular targets that could improve the treatment strategies of MCC. METHODS: RNA expression of 50 cancer-related genes in 26 MCC tumors was analyzed by targeted amplicon based next-generation sequencing using the Ion Torrent technology and the expression compared with that of normal, non-cancerous skin samples. Sequencing data were processed using Torrent SuiteTM Software. Expression profiles of MCV-negative and MCV-positive tumors were compared. Fluorescence in situ hybridization was performed to study ALK rearrangements and immunohistochemistry to study ALK expression in tumor tissue. RESULTS: ALK, CDKN2A, EZH2 and ERBB4 were overexpressed, and EGFR, ERBB2, PDGFRA and FGFR1 were underexpressed in MCC tumors compared to normal skin. In the MCV-negative tumors, MET, NOTCH1, FGFR3, and SMO were overexpressed and JAK3 and NPM1 were under expressed compared to the MCV-positive tumors. CONCLUSIONS: High expression of ALK, CDKN2A and EZH2 was recorded in MCC tumors. No ALK fusion was seen by FISH analysis. Overexpression of EZH2 suggests its potential as a drug target in MCC. PMID- 28359268 TI - Antibiotic consumption in laboratory confirmed vs. non-confirmed bloodstream infections among very low birth weight neonates in Poland. AB - BACKGROUND: Newborns are a population in which antibiotic consumption is extremely high. Targeted antibiotic therapy should help to reduce antibiotics consumption. The aim of this study was an assessment of antibiotic usage in bloodstream infections treatment in the Polish Neonatology Surveillance Network (PNSN) and determining the possibility of applying this kind of data in infection control, especially for the evaluation of standard methods of microbiological diagnostics. METHODS: Data were collected between 01.01.2009 and 31.12.2013 in five teaching NICUs from the PNSN. The duration of treatment in days (DOT) and the defined daily doses (DDD) were used for the assessment of antibiotics consumption. RESULTS: The median DOT for a single case of BSI amounted to 8.0 days; whereas the median consumption expressed in DDD was 0.130. In the case of laboratory confirmed BSI, median DOT was 8 days, and consumption-0.120 DDD. Median length of therapy was shorter for unconfirmed cases: 7 days, while the consumption of antibiotics was higher-0.140 DDD (p < 0.0001). High consumption of glycopeptides expressed in DOTs was observed in studied population, taking into account etiology of infection. CONCLUSIONS: Even application of classical methods of microbiological diagnostics significantly reduces the consumption of antibiotics expressed by DDD. However, the high consumption of glycopeptides indicates the necessity of applying rapid diagnostic assays. Nevertheless, the assessment of antibiotic consumption in neonatal units represents a methodological challenge and requires the use of different measurement tools. PMID- 28359269 TI - The role of the built environment in explaining educational inequalities in walking and cycling among adults in the Netherlands. AB - BACKGROUND: This study examined whether characteristics of the residential built environment (i.e. population density, level of mixed land use, connectivity, accessibility of facilities, accessibility of green) contributed to educational inequalities in walking and cycling among adults. METHODS: Data from participants (32-82 years) of the 2011 survey of the Dutch population-based GLOBE study were used (N = 2375). Highest attained educational level (independent variable) and walking for transport, cycling for transport, walking in leisure time and cycling in leisure time (dependent variables) were self-reported in the survey. GIS systems were used to obtain spatial data on residential built environment characteristics. A four-step mediation-based analysis with log-linear regression models was used to examine to contribution of the residential built environment to educational inequalities in walking and cycling. RESULTS: As compared to the lowest educational group, the highest educational group was more likely to cycle for transport (RR 1.13, 95% CI 1.04-1.23), walk in leisure time (RR 1.12, 95% CI 1.04-1.21), and cycle in leisure time (RR 1.12, 95% CI 1.03-1.22). Objective built environment characteristics were related to these outcomes, but contributed minimally to educational inequalities in walking and cycling. On the other hand, compared to the lowest educational group, the highest educational group was less likely to walk for transport (RR 0.91, 95% CI 0.82-1.01), which could partly be attributed to differences in the built environment. CONCLUSION: This study found that objective built environment characteristics contributed minimally to educational inequalities in walking and cycling in the Netherlands. PMID- 28359270 TI - Preliminary experience with laparoscopic common bile duct exploration. AB - BACKGROUND: Herein we present our experience with laparoscopic common bile duct exploration (LCBDE) in managing common bile duct stones. METHODS: Data of 129 consecutive patients who underwent laparoscopic cholecystectomy (LC) and LCBDE done at our institutes from April 2011 through June 2016 were prospectively recorded and retrospectively reviewed. RESULTS: Since 2011, 3012 laparoscopic cholecystectomy were performed at our institutes, intraoperative cholangiogram (IOC) was done in 295 (9.8%) patients which detected choledocholithiasis in 129 (4.3%) of them. LCBDE was successful to clear the common bile duct (CBD) in 123/129 (95.4%). Six patients underwent postoperative endoscopic retrograde cholangiopancreatography (ERCP) because of incomplete CBD clearance (4 cases), symptomatic stenosed papilla (2 cases). LCBDE was performed in 103 patients via trans-cystic approach and choledochotomy one in 26 patients. In the choledochotomy group, seven patients had primary closure of the CBD, CBD was closed over T-tube in nine patients whereas the remaining 10 patients the CBD was closed over antegrade inserted stent. The median time of hospital stay was 4 (range; 1-15) days. No patients showed retained CBD stones with mean follow up was 9 +/- 3.4 months. CONCLUSION: LCBDE is a safe and cost effective option for CBD stones in short-term outcome and can be performed provided proper laparoscopic expertise and facilities are available. PMID- 28359271 TI - The 2016 classification criteria for primary Sjogren's syndrome: what's new? AB - New 2016 ACR/EULAR classification criteria for primary Sjogren's syndrome (SS) have been developed and endorsed by the ACR. The newly proposed criteria include simple-to-perform items.Two important points of the new criteria should be considered. Firstly, they indicate that either salivary gland biopsy or anti-Ro must be positive in order to corroborate the inflammatory and autoimmune nature of the disease. Secondly, the criteria recognize the systemic nature of SS, namely that patients without salivary or ocular glandular symptoms, but with extraglandular manifestations and B cell activation markers were also included in the SS classification. Additionally, the new criteria modified some technical points. The ocular staining score threshold was increased to 5 due to the higher specificity. The immunological profile includes only anti-Ro antibodies, while positivity for antinuclear antibodies and rheumatoid factor or isolated anti-La was excluded due to a lack of specificity.The 2016 ACR/EULAR criteria are suitable for early identification of SS, providing patients with the opportunity of enrollment in clinical trials for new specific treatment. Although validation has been successful, the real life application of these criteria will test their performance. PMID- 28359272 TI - Effects of chalazia on corneal astigmatism : Large-sized chalazia in middle upper eyelids compress the cornea and induce the corneal astigmatism. AB - BACKGROUND: A chalazion is a common eyelid disease that causes eye morbidity due to inflammation and cosmetic disfigurement. Corneal topographic changes are important factors in corneal refractive surgery, intraocular lens power calculations for cataract surgery, and visual acuity assessments. However, the effects of chalazia on corneal astigmatism have not been thoroughly investigated. The changes in corneal astigmatism according to chalazion size and location is necessary for better outcome of ocular surgery. The aim of this study is to evaluate changes in corneal astigmatism according to chalazion size and location. METHODS: In this cross-sectional study, a total of 44 eyes from 33 patients were included in the chalazion group and 70 eyes from 46 patients comprised the control group. Chalazia were classified according to location and size. An autokeratorefractometer (KR8100, Topcon; Japan) and a GalileiTM dual-Scheimpflug analyzer (Ziemer Group; Port, Switzerland) were utilized to evaluate corneal changes. RESULT: Oblique astigmatism was greater in the chalazion group compared with the control group (p < 0.05). Astigmatism by simulated keratometry (simK), steep K by simK, total root mean square, second order aberration, oblique astigmatism, and vertical astigmatism were significantly greater in the upper eyelid group (p < 0.05). Astigmatism by simK, second order aberration, oblique astigmatism, and vertical astigmatism were significantly greater in the large sized chalazion group (p < 0.05). Corneal wavefront aberration was the greatest in the upper eyelid chalazion group, whole area group, and large-sized chalazion group (p < 0.05). CONCLUSIONS: Large-sized chalazia in the whole upper eyelid should be treated in the early phase because they induced the greatest change in corneal topography. Chalazion should be treated before corneal topography is performed preoperatively and before the diagnosis of corneal diseases. PMID- 28359273 TI - A comparison of generic drug prices in seven European countries: a methodological analysis. AB - BACKGROUND: Policymakers and researchers frequently compare the prices of medicines between countries. Such comparisons often serve as barometers of how pricing and reimbursement policies are performing. The aim of this study was to examine methodological challenges to comparing generic drug prices. METHODS: We calculated all commonly used price indices based on 2013 IMS Health data on sales of 3156 generic drugs in seven European countries. RESULTS: There were large differences in generic drug prices between countries. However, the results varied depending on the choice of index, base country, unit of volume, method of currency conversion, and therapeutic category. The results also differed depending on whether one looked at the prices charged by manufacturers or those charged by pharmacists. CONCLUSIONS: Price indices are a useful statistical approach for comparing drug prices across countries, but researchers and policymakers should interpret price indices with caution given their limitations. Price-index results are highly sensitive to the choice of method and sample. More research is needed to determine the drivers of price differences between countries. The data suggest that some governments should aim to reduce distribution costs for generic drugs. PMID- 28359274 TI - Allergic diseases in children with attention deficit hyperactivity disorder: a systematic review and meta-analysis. AB - BACKGROUND: Reports of frequent manifestation of allergic diseases in children with attention deficit hyperactivity disorder (ADHD) have been the subject of mounting clinical interest. However, evidence supporting the association between ADHD and allergies is inconsistent and has yet to be systematically reviewed. The objective of this study was to compile and assess available studies on the association between ADHD and allergic diseases in children. METHODS: A comprehensive search using MEDLINE, EMBASE, the Cochrane library, and CINAHL databases was completed in 23 November 2015. The inclusion criteria for studies were that the research assessed allergic diseases in children, 18 years of age and younger, with a diagnosis of ADHD and that a distinct comparison group was incorporated. Any comparative studies, encompassing both randomized controlled trials and observational studies, were considered for inclusion. Two review authors independently assessed the quality of the selected studies by the use of validated assessment tools, performed data extraction and conducted meta-analysis according to Cochrane Collaboration guidelines. RESULTS: Five eligible studies were included in this systematic review. Of these studies, three were case control and two were cross sectional studies. A majority of information from the five studies was classified as having low or unclear risk of bias. The meta analysis showed an association between children with ADHD and asthma compared with the control groups (OR: 1.80, 95% CI: 1.57 - 2.07; five studies, low quality of evidence), but did not indicate an association between food allergy and ADHD (OR: 1.13, 95% CI: 0.88 - 1.47; three studies very low quality of evidence). The odds of experiencing allergic rhinitis, atopic dermatitis, and allergic conjunctivitis were slightly higher in children with ADHD compared with control groups, though a substantial statistical heterogeneity was notable in the overall effect estimates. CONCLUSIONS: The findings from this review and meta-analysis show that children with ADHD are more likely to have asthma, allergic rhinitis, atopic dermatitis, and allergic conjunctivitis than their counterparts. Interventions including strategies for managing allergies in children with ADHD would be beneficial. PMID- 28359276 TI - Perceived stress among 20-21 year-olds and their future labour market participation - an eight-year follow-up study. AB - BACKGROUND: Labour market participation among young adults is essential for their future socioeconomic status and health. The aim of this study was to investigate the association between perceived stress among 20-21 year-olds and their labour market participation 8 years later as well as investigate any potential gender differences. METHODS: A cohort of 1640 young adults born in 1983 completed a questionnaire in 2004 in which perceived stress was measured. The cohort was followed in a register of social benefits for 12 months in 2011-2012 and was categorized into active and passive labour market participation. Logistic regression was used to analyse the association between perceived stress and future labour market participation, taking into account effects of potential confounders. The analyses were stratified by gender. RESULTS: The effects of perceived stress on future labour market participation differed significantly among young women and young men (p = 0.029). For young men, higher levels of perceived stress reduced the risk of future passive labour market participation, when adjusting for socioeconomic factors, self-rated health and copings strategies (p = 0.045). For young women, higher levels of perceived stress increased the risk of future passive labour market participation, when adjusting for the same potential confounding factors, although unlike the men, this association was not statistically significant (p = 0.335). CONCLUSION: The observed gender difference has important implications from a public health point of view. Healthcare professionals might need to differentiate between the genders in terms of health communication, research and when developing preventive strategies. PMID- 28359275 TI - Leg pain location and neurological signs relate to outcomes in primary care patients with low back pain. AB - BACKGROUND: Low back pain (LBP) patients with related leg pain and signs of nerve root involvement are considered to have a worse prognosis than patients with LBP alone. However, it is unclear whether leg pain location above or below the knee and the presence of neurological signs are important in primary care patients. The objectives of this study were to explore whether the four Quebec Task Force categories (QTFC) based on the location of pain and on neurological signs have different characteristics at the time of care seeking, whether these QTFC are associated with outcome, and if so whether there is an obvious ranking of the four QTFC on the severity of outcomes. METHOD: Adult patients seeking care for LBP in chiropractic or general practice were classified into the four QTFC based on self-reported information and clinical findings. Analyses were performed to test the associations between the QTFC and baseline characteristics as well as the outcomes global perceived effect and activity limitation after 2 weeks, 3 months, and 1 year and also 1-year trajectories of LBP intensity. RESULTS: The study comprised 1271 patients; 947 from chiropractic practice and 324 from general practice. The QTFC at presentation were statistically significantly associated with most of the baseline characteristics, with activity limitation at all follow-up time points, with global perceived effect at 2 weeks but not 3 months and 1 year, and with trajectories of LBP. Severity of outcomes in the QTFC increased from LBP alone, across LBP with leg pain above the knee and below the knee to LBP with nerve root involvement. However, the variation within the categories was considerable. CONCLUSION: The QTFC identify different LBP subgroups at baseline and there is a consistent ranking of the four categories with respect to outcomes. The differences between outcomes appear to be large enough for the QTFC to be useful for clinicians in the communication with patients. However, due to variation of outcomes within each category individuals' outcome cannot be precisely predicted from the QTFC alone. It warrants further investigation to find out if the QTFC can improve existing prediction tools and guide treatment decisions. PMID- 28359277 TI - Do healthier lifestyles lead to less utilization of healthcare resources? AB - BACKGROUND: Governments are urged to determine methods to control the use of medical resources and curb the rise of healthcare costs. The question is, do health behaviors have an impact on the use of medical resources? This study aims to identify and understand the difference in the number of outpatient visits and health examinations based on various health behaviors and to determine whether patients seek medical care for illness from the same physicians. METHODS: This study used the dataset derived from the Department of Budget, Accounting and Statistics of Kaohsiung, Taiwan in 2005. Persons older than 15 years were surveyed using an on-site questionnaire. A total of 2911 persons were enrolled in this study. Independent t-tests, chi-square tests, one-way ANOVA, multiple linear regression and binominal logistic regression were used in the data analysis. RESULTS: The regression model for the frequency of doctor visits, health examinations, and whether the same physician is sought for medical care has demonstrated significant correlations with gender, age and education-level variables. Four health behaviors (i.e., exercise habits, dietary habits, regular blood pressure measurement, drinking habits) exhibited a significant correlation with healthcare utilization (P <0.05). CONCLUSIONS: Healthy lifestyles lead to an increase in the utilization of preventive health services. However, there is not much significantly reducing the number of outpatient visits in people with health behaviors. Specifically, people with regular exercise habits and who take their blood pressure measurement regularly have an increased number of outpatient visits. It is suggested that more available and accessible health consultation services be provided to inculcate in the general public the importance of maintaining a healthy lifestyle. PMID- 28359278 TI - Review of 11 national policies for rare diseases in the context of key patient needs. AB - Rare diseases collectively exert a global public health burden in the severity of their manifestations and the total number of people they afflict. For many patients, considerable barriers exist in terms of access to appropriate care, delayed diagnosis and limited or non-existing treatment options. Motivated by these challenges, the rare disease patient community has played a critical role, elevating the patient voice and mobilizing legislation to support the development of programs that address the needs of patients with rare diseases.The US Orphan Drug Act of 1983 served as a key milestone in this journey, providing a roadmap for other countries to introduce and implement similar orphan drug legislation; more recently, the European Union (EU) has gone further to encourage the widespread adoption and implementation of rare disease plans or strategies designed to more adequately address the comprehensive needs of patients with rare diseases. Despite these legislative efforts and the growing contributions of patient advocacy groups in moving forward implementation and adoption of rare disease programs, gaps still exist across the policy landscape for several countries. To gain deeper insights into the challenges and opportunities to address key needs of rare disease patients, it is critical to define the current status of rare disease legislation and policy across a geographically and economically diverse selection of countries. We analyzed the rare disease policy landscape across 11 countries: Germany, France, the United Kingdom, Canada, Bulgaria, Turkey, Argentina, Mexico, Brazil, China, and Taiwan. The status and implementation of policy was evaluated for each country in the context of key patient needs across 5 dimensions: improving coordination of care, diagnostic resources, access to treatments, patient awareness and support, and promoting innovative research. Our findings highlight the continuing role of the patient community in driving the establishment and adoption of legislation and programs to improve rare disease care. Further, we found that while national rare disease plans provide important guidance for improving care, implementation of plans is uneven across countries. More research is needed to demonstrate the effect of specific elements of rare disease plans on patient outcomes. PMID- 28359279 TI - Low-volume versus high-volume initiated trans-anal irrigation therapy in adults with chronic constipation: study protocol for a randomised controlled trial. AB - BACKGROUND: Constipation is common in adults and up to 20% of the population report this symptom. Chronic constipation (CC), usually defined as more than 6 months of symptoms, is less common but results in 0.5 million UK GP consultations per annum. The effect of symptoms on measured quality of life (QOL) is significant, and CC consumes significant health care resources. In the UK, it is estimated that 10% of district nursing time is spent on constipation. Trans-anal irrigation therapy has become a widely used treatment despite a lack of robust efficacy data to support its use. The long-term outcome of treatment is also unclear. A randomised comparison of two different methods of irrigation (high- and low-volume) will provide valuable evidence of superiority of one system over the other, as well as providing efficacy data for the treatment as a whole. METHODS: Participants will be recruited based on predetermined eligibility criteria. Following informed consent, they will be randomised to either high volume (HV) or low-volume (LV) irrigation and undergo standardised radiological and physiological investigations. Following training, they will commence home irrigation with the allocated device. Data will be collected at 1, 3, 6 and 12 months according to a standardised outcomes framework. The primary outcome is PAC QOL, measured at 3 months. The study is powered to detect a 10% difference in outcome between systems at 3 months; this means that 300 patients will need to be recruited. DISCUSSION: This study will be the first randomised comparison of two different methods of trans-anal irrigation. It will also be the largest prospective study of CC patients treated with irrigation. It will provide evidence for the effectiveness of irrigation in the treatment of CC, as well as the comparative effectiveness of the two methods. This will enable more cost effective and evidence-based use of irrigation. Also, the results will be combined with the other studies in the CapaCiTY programme to generate an evidence based treatment algorithm for CC in adults. TRIAL REGISTRATION: ISRCTN, identifier: ISRCTN11093872 . Registered on 11 November 2015. Trial not retrospectively registered. Protocol version 3 (22 January 2016). PMID- 28359281 TI - 17beta-estradiol regulates the expression of apolipoprotein M through estrogen receptor alpha-specific binding motif in its promoter. AB - BACKGROUND: We have previously demonstrated that estrogen could significantly enhance expression of apolipoprotein M (apoM), whereas the molecular basis of its mechanism is not fully elucidated yet. To further investigate the mechanism behind the estrogen induced up-regulation of apoM expression. RESULTS: Our results demonstrated either free 17beta-estradiol (E2) or membrane-impermeable bovine serum albumin-conjugated E2 (E2-BSA) could modulate human apoM gene expression via the estrogen receptor alpha (ER-alpha) pathway in the HepG2 cells. Moreover, experiments with the luciferase activity analysis of truncated apoM promoters could demonstrate that a regulatory region (from-1580 to -1575 bp ( GGTCA-)) upstream of the transcriptional start site of apoM gene was essential for the basal transcriptional activity that regulated by the ER-alpha. With the applications of an electrophoresis mobility shift assay and a chromatin immunoprecipitation assay, we could successfully identify a specific ER-alpha binding element in the apoM promoter region. CONCULSION: In summary, the present study indicates that 17beta-estradiol induced up-regulation of apoM in HepG2 cells is through an ER-alpha-dependent pathway involving ER-alpha binding element in the promoter of the apoM gene. PMID- 28359280 TI - Alcohol-free essential oils containing mouthrinse efficacy on three-day supragingival plaque regrowth: a randomized crossover clinical trial. AB - BACKGROUND: To evaluate the antiplaque effects of an alcohol-free mouthrinse containing essential oils-Listerine Zero (LZ)-and an alcohol-based essential oils mouthrinse (EO+) compared with a positive control of 0.20% chlorhexidine mouthrinse (CHX) and a negative control of a placebo solution (saline), using an in vivo plaque regrowth model of three days. METHODS: The study was designed as a double-masked, randomized, crossover clinical trial, involving 21 volunteers to compare four different mouthrinses, using a three-day plaque regrowth model. After receiving thorough professional prophylaxis at baseline, over the next three days each volunteer refrained from all oral hygiene measures and performed two daily rinses with 15 mL of the test mouthrinses. EO+ was compared with LZ. CHX rinse served as a positive control and a placebo solution as a negative control. At the end of each experimental period, the Plaque Index (PI) was assessed and a panelist completed through a visual analogue scale (VAS) questionnaire evaluating the organoleptic properties of each product. Each participant underwent a 14-day washout period and then there was another allocation. RESULTS: LZ showed the same inhibitory activity on plaque regrowth compared with EO+ in the whole mouth (PI = 1.72 versus 1.65, respectively), but there was less of an effect compared to the CHX (overall PI of 1.07) and a more efficient activity than the saline solution negative control (PI = 2.31). The difference of 0.07 between LZ and EO+ was not statistically significant. CONCLUSIONS: LZ seems to have the same inhibiting effect on plaque regrowth as EO+ and a less inhibiting effect than the CHX control. Both LZ and EO+, as well as the CHX control, show a better inhibiting effect on plaque regrowth than the placebo solution. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02894593 . Registered on 4 September 2016. PMID- 28359282 TI - A modification to geographically weighted regression. AB - BACKGROUND: Geographically weighted regression (GWR) is a modelling technique designed to deal with spatial non-stationarity, e.g., the mean values vary by locations. It has been widely used as a visualization tool to explore the patterns of spatial data. However, the GWR tends to produce unsmooth surfaces when the mean parameters have considerable variations, partly due to that all parameter estimates are derived from a fixed- range (bandwidth) of observations. In order to deal with the varying bandwidth problem, this paper proposes an alternative approach, namely Conditional geographically weighted regression (CGWR). METHODS: The estimation of CGWR is based on an iterative procedure, analogy to the numerical optimization problem. Computer simulation, under realistic settings, is used to compare the performance between the traditional GWR, CGWR, and a local linear modification of GWR. Furthermore, this study also applies the CGWR to two empirical datasets for evaluating the model performance. The first dataset consists of disability status of Taiwan's elderly, along with some social-economic variables and the other is Ohio's crime dataset. RESULTS: Under the positively correlated scenario, we found that the CGWR produces a better fit for the response surface. Both the computer simulation and empirical analysis support the proposed approach since it significantly reduces the bias and variance of data fitting. In addition, the response surface from the CGWR reviews local spatial characteristics according to the corresponded variables. CONCLUSIONS: As an explanatory tool for spatial data, producing accurate surface is essential in order to provide a first look at the data. Any distorted outcomes would likely mislead the following analysis. Since the CGWR can generate more accurate surface, it is more appropriate to use it exploring data that contain suspicious variables with varying characteristics. PMID- 28359283 TI - Differentiated resistance training of the paravertebral muscles in patients with unstable spinal bone metastasis under concomitant radiotherapy: study protocol for a randomized pilot trial. AB - BACKGROUND: Metastatic bone disease is a common and severe complication in patients with advanced cancer. Radiotherapy (RT) has long been established as an effective local treatment for metastatic bone disorder. This study assesses the effects of RT combined with muscle-training exercises in patients with unstable bone metastases of the spinal column from solid tumors. The primary goal of this study is to evaluate the feasibility of muscle-training exercises concomitant to RT. Secondly, quality of life, fatigue, overall and bone survival, and local control will be assessed. METHODS/DESIGN: This study is a single-center, prospective, randomized, controlled, explorative intervention study with a parallel-group design to determine multidimensional effects of a course of exercises concomitant to RT on patients who have unstable metastases of the vertebral column, first under therapeutic instruction and subsequently performed by the patients themselves independently for strengthening the paravertebral muscles. On the days of radiation treatment the patients will be given four different types of exercises to ensure even isometric muscle training of all the spinal muscles. In the control group progressive muscle relaxation will be carried out parallel to RT. The patients will be randomized into two groups: differentiated muscle training or progressive muscle relaxation with 30 patients in each group. DISCUSSION: Despite the clinical experience that RT is an effective treatment for bone metastases, there is insufficient evidence for a positive effect of the combination with muscle-training exercises in patients with unstable bone metastases. Our previous DISPO-1 trial showed that adding muscle-training exercises to RT is feasible, whereas this was not proven in patients with an unstable spinal column. Although associated with several methodological and practical challenges, this randomized controlled trial is needed. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02847754 . Registered on 27 July 2016. PMID- 28359284 TI - Development of nanoparticle-based optical sensors for pathogenic bacterial detection. AB - BACKGROUND: Pathogenic bacteria contribute to various globally important diseases, killing millions of people each year. Various fields of medicine currently benefit from or may potentially benefit from the use of nanotechnology applications, in which there is growing interest. Disease-related biomarkers can be rapidly and directly detected by nanostructures, such as nanowires, nanotubes, nanoparticles, cantilevers, microarrays, and nanoarrays, as part of an accurate process characterized by lower sample consumption and considerably higher sensitivity. There is a need for accurate techniques for pathogenic bacteria identification and detection to allow the prevention and management of pathogenic diseases and to assure food safety. CONCLUSION: The focus of this review is on the current nanoparticle-based techniques for pathogenic bacterial identification and detection using these applications. PMID- 28359285 TI - Atypical periodic alternating nystagmus responding to high-dose intravenous immunoglobulins: a case report. AB - BACKGROUND: Acquired periodic alternating nystagmus (PAN) is a rare but well defined syndrome that consists of a horizontal nystagmus that cyclically reverses its direction. PAN can be caused by degenerative, neoplastic, or toxic diseases of the cerebellum and, in a few cases, by subacute cerebellar ataxia of immune origin. CASE PRESENTATION: A 44-year-old man came to our attention because of rapidly progressive gait instability and blurred vision. Clinical examination showed PAN and a mild pancerebellar syndrome. Eye movement recordings disclosed a short cycle PAN with significant slow-phase velocity only in darkness. Under the effect of a gamma-aminobutyric acid type B (GABAB) agonist, PAN was not modified. Right after treatment with intravenous immunoglobulin (IVIg) was started, PAN was essentially eliminated. Three months after last dose of IVIg, this nystagmus reappeared. CONCLUSIONS: IVIg resolved PAN in this patient. This finding may point to an autoimmune mechanism underlying this patient's nystagmus. This case suggests that the usefulness of IVIg at treating PAN might be worth a consideration in similar clinical settings. PMID- 28359288 TI - Termination of prehospital resuscitative efforts: a study of documentation on ethical considerations at the scene. AB - BACKGROUND: Discussions on ethical aspects of life-and-death decisions within the hospital are often made in plenary. The prehospital physician, however, may be faced with ethical dilemmas in life-and-death decisions when time-critical decisions to initiate or refrain from resuscitative efforts need to be taken without the possibility to discuss matters with colleagues. Little is known whether these considerations regarding ethical issues in crucial life-and-death decisions are documented prehospitally. This is a review of the ethical considerations documented in the prehospital medical records of patients in a Danish prehospital setting for whom the decision to resuscitate or not was made at the scene. METHODS: The study is based on discharge summaries of all patients subjected to crucial life-and-death decisions by the Mobile Emergency Care Unit in Odense in the years 2010 to 2014. The medical records with possible documentation of ethical issues were independently reviewed by two philosophers in order to identify explicit ethical or philosophical considerations pertaining to the decision to resuscitate or not. RESULTS: In total, 1275 patients were either declared dead at the scene without exhibiting layman's reliable signs of death or admitted to hospital following resuscitation. In a total of 62 patients, 85 specific ethical issues related to resuscitation were documented. The expressions of the ethical considerations were generally vague or unclear and almost exclusively concerned the interests of the patient and not the relatives. In the vast majority of cases where an ethical content was identified, the ethical considerations led to a decision to terminate treatment. CONCLUSIONS: A strengthened practice of documenting ethical considerations in prehospital life and-death decision-making in the patient's medical records is required. We suggest that a template be implemented in the prehospital medical records describing the basis for any ethical decisions. This template should contain information regarding the persons involved in the deliberations and notes on ethical considerations. The documentation should include considerations concerning the patient's end-of-life wishes, the estimations of the quality of life before and after the incident, and a summary of other ethical concerns taken into account, such as the integrity of the patient and frame of mind of relatives. PMID- 28359287 TI - Activity of the novel BCR kinase inhibitor IQS019 in preclinical models of B-cell non-Hodgkin lymphoma. AB - BACKGROUND: Pharmacological inhibition of B cell receptor (BCR) signaling has recently emerged as an effective approach in a wide range of B lymphoid neoplasms. However, despite promising clinical activity of the first Bruton's kinase (Btk) and spleen tyrosine kinase (Syk) inhibitors, a small fraction of patients tend to develop progressive disease after initial response to these agents. METHODS: We evaluated the antitumor activity of IQS019, a new BCR kinase inhibitor with increased affinity for Btk, Syk, and Lck/Yes novel tyrosine kinase (Lyn), in a set of 34 B lymphoid cell lines and primary cultures, including samples with acquired resistance to the first-in-class Btk inhibitor ibrutinib. Safety and efficacy of the compound were then evaluated in two xenograft mouse models of B cell lymphoma. RESULTS: IQS019 simultaneously engaged a rapid and dose-dependent de-phosphorylation of both constitutive and IgM-activated Syk, Lyn, and Btk, leading to impaired cell proliferation, reduced CXCL12-dependent cell migration, and induction of caspase-dependent apoptosis. Accordingly, B cell lymphoma-bearing mice receiving IQS019 presented a reduced tumor outgrowth characterized by a decreased mitotic index and a lower infiltration of malignant cells in the spleen, in tight correlation with downregulation of phospho-Syk, phospho-Lyn, and phospho-Btk. More interestingly, IQS019 showed improved efficacy in vitro and in vivo when compared to the first-in-class Btk inhibitor ibrutinib, and was active in cells with acquired resistance to this latest. CONCLUSIONS: These results define IQS019 as a potential drug candidate for a variety of B lymphoid neoplasms, including cases with acquired resistance to current BCR targeting therapies. PMID- 28359286 TI - The double-edged sword of (re)expression of genes by hypomethylating agents: from viral mimicry to exploitation as priming agents for targeted immune checkpoint modulation. AB - Hypomethylating agents (HMAs) have been widely used over the last decade, approved for use in myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML). The proposed central mechanism of action of HMAs, is the reversal of aberrant methylation in tumor cells, thus reactivating CpG-island promoters and leading to (re)expression of tumor suppressor genes. Recent investigations into the mode of action of azacitidine (AZA) and decitabine (DAC) have revealed new molecular mechanisms that impinge on tumor immunity via induction of an interferon response, through activation of endogenous retroviral elements (ERVs) that are normally epigenetically silenced. Although the global demethylation of DNA by HMAs can induce anti-tumor effects, it can also upregulate the expression of inhibitory immune checkpoint receptors and their ligands, resulting in secondary resistance to HMAs. Recent studies have, however, suggested that this could be exploited to prime or (re)sensitize tumors to immune checkpoint inhibitor therapies. In recent years, immune checkpoints have been targeted by novel therapies, with the aim of (re)activating the host immune system to specifically eliminate malignant cells. Antibodies blocking checkpoint receptors have been FDA-approved for some solid tumors and a plethora of clinical trials testing these and other checkpoint inhibitors are under way. This review will discuss AZA and DAC novel mechanisms of action resulting from the re-expression of pathologically hypermethylated promoters of gene sets that are related to interferon signaling, antigen presentation and inflammation. We also review new insights into the molecular mechanisms of action of transient, low-dose HMAs on various tumor types and discuss the potential of new treatment options and combinations. PMID- 28359290 TI - Suppression of MyD88-dependent signaling alleviates neuropathic pain induced by peripheral nerve injury in the rat. AB - BACKGROUND: MyD88 is the adaptor protein of MyD88-dependent signaling pathway of TLRs and IL-1 receptor and regulates innate immune response. However, it was not clear whether and how MyD88 and related signaling pathways in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH) are involved in neuropathic pain. METHODS: Chronic constriction injury (CCI) was used to induce neuropathic pain in the rat. The expression of MyD88, TRIF, IBA1, and GFAP was detected with immunofluorescent staining and Western blot. The expression of interleukin-1 beta (IL-1beta), high mobility group box 1 (HMGB1), NF-kappaB-p65, phosphorylated NF kappaB-p65, ERK, phosphorylated ERK, and tumor necrosis factor-alpha (TNF-alpha) was detected with Western blot. Pain-related behavioral effects of MyD88 homodimerization inhibitory peptide (MIP) were accessed up to 3 weeks after intrathecal administration. RESULTS: Peripheral nerve injury significantly increased the protein level of MyD88 in the DRG and SDH, but had no effect on TRIF. MyD88 was found partly distributed in the nociceptive neurons in the DRGs and the astrocytes and microglia in the SDH. HMGB1 and IL-1beta were also found upregulated in nociceptive pathways of CCI rats. Intrathecal application of MIP significantly alleviated mechanical and thermal hyperalgesia in the CCI rats and also reversed CCI-induced upregulation of MyD88 in both DRG and SDH. Further investigation revealed that suppression of MyD88 protein reduced the release of TNF-alpha and glial activation in the SDH in the CCI rats. CONCLUSIONS: MyD88 dependent TIR pathway in the DRG and SDH may play a role in CCI-induced neuropathic pain. MyD88 might serve as a potential therapeutic target for neuropathic pain. PMID- 28359289 TI - Insecticide resistance in malaria vectors along the Thailand-Myanmar border. AB - BACKGROUND: There is a paucity of data about the susceptibility status of malaria vectors to Public Health insecticides along the Thailand-Myanmar border. This lack of data is a limitation to guide malaria vector-control in this region. The aim of this study was to assess the susceptibility status of malaria vectors to deltamethrin, permethrin and DDT and to validate a simple molecular assay for the detection of knock-down resistance (kdr) mutations in the study area. METHODS: Anopheles mosquitoes were collected in four sentinel villages during August and November 2014 and July 2015 using human landing catch and cow bait collection methods. WHO susceptibility tests were carried out to measure the mortality and knock-down rates of female mosquitoes to deltamethrin (0.05%), permethrin (0.75%) and DDT (4%). DNA sequencing of a fragment of the voltage-gated sodium channel gene was carried out to identify knock-down resistance (kdr) mutations at position 1014 in mosquitoes surviving exposure to insecticides. RESULTS: A total of 6295 Anopheles belonging to ten different species were bioassayed. Resistance or suspected resistance to pyrethroids was detected in An. barbirostris (s.l.) (72 and 84% mortality to deltamethrin (n = 504) and permethrin (n = 493) respectively), An. hyrcanus (s.l.) (33 and 48% mortality to deltamethrin (n = 172) and permethrin (n = 154), respectively), An. jamesii (87% mortality to deltamethrin, n = 111), An. maculatus (s.l.) (85 and 97% mortality to deltamethrin (n = 280) and permethrin (n = 264), respectively), An. minimus (s.l.) (92% mortality, n = 370) and An. vagus (75 and 95% mortality to deltamethrin (n =148) and permethrin (n = 178), respectively). Resistance or suspected resistance to DDT was detected in An. barbirostris (s.l.) (74% mortality, n = 435), An. hyrcanus (s.l.) (57% mortality, n = 91) and An. vagus (97% mortality, n = 133). The L1014S kdr mutation at both heterozygous and homozygous state was detected only in An. peditaeniatus (Hyrcanus Group). CONCLUSION: Resistance to pyrethroids is present along the Thailand-Myanmar border, and it represents a threat for malaria vector control. Further investigations are needed to better understand the molecular basis of insecticide resistance in malaria vectors in this area. PMID- 28359291 TI - Curcumin suppresses gastric tumor cell growth via ROS-mediated DNA polymerase gamma depletion disrupting cellular bioenergetics. AB - BACKGROUND: Curcumin, as a pro-apoptotic agent, is extensively studied to inhibit tumor cell growth of various tumor types. Previous work has demonstrated that curcumin inhibits cancer cell growth by targeting multiple signaling transduction and cellular processes. However, the role of curcumin in regulating cellular bioenergetic processes remains largely unknown. METHODS: Western blotting and qRT PCR were performed to analyze the protein and mRNA level of indicated molecules, respectively. RTCA, CCK-8 assay, nude mice xenograft assay, and in vivo bioluminescence imaging were used to visualize the effects of curcmin on gastric cancer cell growth in vitro and in vivo. Seahorse bioenergetics analyzer was used to investigate the alteration of oxygen consumption and aerobic glycolysis rate. RESULTS: Curcumin significantly inhibited gastric tumor cell growth, proliferation and colony formation. We further investigated the role of curcumin in regulating cellular redox homeostasis and demonstrated that curcumin initiated severe cellular apoptosis via disrupting mitochondrial homeostasis, thereby enhancing cellular oxidative stress in gastric cancer cells. Furthermore, curcumin dramatically decreased mtDNA content and DNA polymerase gamma (POLG) which contributed to reduced mitochondrial oxygen consumption and aerobic glycolysis. We found that curcumin induced POLG depletion via ROS generation, and POLG knockdown also reduced oxidative phosphorylation (OXPHOS) activity and cellular glycolytic rate which was partially rescued by ROS scavenger NAC, indiating POLG plays an important role in the treatment of gastric cancer. Data in the nude mice model verified that curcumin treatment significantly attenuated tumor growth in vivo. Finally, POLG was up-regulated in human gastric cancer tissues and primary gastric cancer cell growth was notably suppressed due to POLG deficiency. CONCLUSIONS: Together, our data suggest a novel mechanism by which curcumin inhibited gastric tumor growth through excessive ROS generation, resulting in depletion of POLG and mtDNA, and the subsequent disruption of cellular bioenergetics. PMID- 28359292 TI - Cardiac 4D phase-contrast CMR at 9.4 T using self-gated ultra-short echo time (UTE) imaging. AB - BACKGROUND: Time resolved 4D phase contrast (PC) cardiovascular magnetic resonance (CMR) in mice is challenging due to long scan times, small animal ECG gating and the rapid blood flow and cardiac motion of small rodents. To overcome several of these technical challenges we implemented a retrospectively self-gated 4D PC radial ultra-short echo-time (UTE) acquisition scheme and assessed its performance in healthy mice by comparing the results with those obtained with an ECG-triggered 4D PC fast low angle shot (FLASH) sequence. METHODS: Cardiac 4D PC CMR images were acquired at 9.4 T in healthy mice using the proposed self-gated radial center-out UTE acquisition scheme (TE/TR of 0.5 ms/3.1 ms) and a standard Cartesian 4D PC imaging sequence (TE/TR of 2.1 ms/5.0 ms) with a four-point Hadamard flow encoding scheme. To validate the proposed UTE flow imaging technique, experiments on a flow phantom with variable pump rates were performed. RESULTS: The anatomical images and flow velocity maps of the proposed 4D PC UTE technique showed reduced artifacts and an improved SNR (left ventricular cavity (LV): 8.9 +/- 2.5, myocardium (MC): 15.7 +/- 1.9) compared to those obtained using a typical Cartesian FLASH sequence (LV: 5.6 +/- 1.2, MC: 10.1 +/- 1.4) that was used as a reference. With both sequences comparable flow velocities were obtained in the flow phantom as well as in the ascending aorta (UTE: 132.8 +/- 18.3 cm/s, FLASH: 134.7 +/- 13.4 cm/s) and pulmonary artery (UTE: 78.5 +/- 15.4 cm/s, FLASH: 86.6 +/- 6.2 cm/s) of the animals. Self-gated navigator signals derived from information of the oversampled k-space center were successfully extracted for all animals with a higher gating efficiency of time spent on acquiring gated data versus total measurement time (UTE: 61.8 +/- 11.5%, FLASH: 48.5 +/- 4.9%). CONCLUSIONS: The proposed self-gated 4D PC UTE sequence enables robust and accurate flow velocity mapping of the mouse heart in vivo at high magnetic fields. At the same time SNR, gating efficiency, flow artifacts and image quality all improved compared to the images obtained using the well established, ECG-triggered, 4D PC FLASH sequence. PMID- 28359295 TI - Rad51 inhibition sensitizes breast cancer stem cells to PARP inhibitor in triple negative breast cancer. PMID- 28359294 TI - Temporal dynamics of the tick Ixodes ricinus in northern Europe: epidemiological implications. AB - BACKGROUND: Tick-borne pathogens pose an increasing threat to human and veterinary health across the northern hemisphere. While the seasonal activity of ticks is largely determined by climatic conditions, host-population dynamics are also likely to affect tick abundance. Consequently, abundance fluctuations of rodents in northern Europe are expected to be translated into tick dynamics, and can hence potentially affect the circulation of tick-borne pathogens. We quantified and explained the temporal dynamics of the tick Ixodes ricinus in the northernmost part of its European geographical range, by estimating (i) abundance in vegetation and (ii) infestation load in the most common rodent species in the study area, the bank vole Myodes glareolus. RESULTS: Ixodes ricinus nymphs and adult females, the life stages responsible for the most of tick bites in humans, peaked in May-June and August-September. Larvae and nymphs were simultaneously active in June and abundance of questing larvae and nymphs in the vegetation showed a positive association with bank vole abundance. Moreover, infesting larvae and nymphs were aggregated on bank voles, and the infestation of bank voles with I. ricinus larvae and nymphs was positively associated with bank vole abundance. CONCLUSION: Our results indicate early summer and early autumn as periods of increased risk for humans to encounter I. ricinus ticks in boreal urban forests and suggest a 2 years life-cycle for I. ricinus with two cohorts of ticks during the same year. Moreover, we identified a simultaneous activity of larvae and nymphs which allows co-feeding on the rodent host, which in turn supports the transmission of several important zoonotic tick-borne pathogens. Finally, we showed that a high density of the rodent host may enhance the risk that ticks and, potentially, tick-borne pathogens pose to human health. PMID- 28359296 TI - Motorbike-handlebar hernia - a rare traumatic abdominal wall hernia: a case report and review of the literature. AB - BACKGROUND: Handlebar hernias are very rare and arise following a sudden force from a handle-like object impacting a focal area of the abdomen, which results in a disruption of the underlying abdominal muscle and fascia without necessarily disrupting the overlying skin. Other than a reducible swelling on the abdominal wall, the physical examination of such patients is usually unremarkable and the diagnosis could easily be missed. CASE PRESENTATION: An 8-year-old Cameroonian boy with no significant past history presented to our emergency service with a tender left flank swelling following a road traffic accident. He was knocked down by a motorbike with resulting impact of the handlebar on his abdomen. A handlebar hernia was diagnosed on the basis of a reducible abdominal swelling with a positive cough impulse. A herniorrhaphy was done the following day after resuscitation and his postoperative period was uneventful. CONCLUSIONS: Handlebar hernias, although rare, should be suspected when patients present with an abdominal swelling following blunt abdominal trauma involving a handlebar-like object. A good history and physical examination are usually enough to pose an early diagnosis of handlebar hernia. Management typically involves surgical intervention to prevent complications. The timing and surgical approach should be decided on a case-by-case basis. PMID- 28359293 TI - Memory performance-related dynamic brain connectivity indicates pathological burden and genetic risk for Alzheimer's disease. AB - BACKGROUND: The incidence of Alzheimer's disease (AD) strongly relates to advanced age and progressive deposition of cerebral amyloid-beta (Abeta), hyperphosphorylated tau, and iron. The purpose of this study was to investigate the relationship between cerebral dynamic functional connectivity and variability of long-term cognitive performance in healthy, elderly subjects, allowing for local pathology and genetic risk. METHODS: Thirty seven participants (mean (SD) age 74 (6.0) years, Mini-Mental State Examination 29.0 (1.2)) were dichotomized based on repeated neuropsychological test performance within 2 years. Cerebral Abeta was measured by 11C Pittsburgh Compound-B positron emission tomography, and iron by quantitative susceptibility mapping magnetic resonance imaging (MRI) at an ultra-high field strength of 7 Tesla (7T). Dynamic functional connectivity patterns were investigated by resting-state functional MRI at 7T and tested for interactive effects with genetic AD risk (apolipoprotein E (ApoE)-epsilon4 carrier status). RESULTS: A relationship between low episodic memory and a lower expression of anterior-posterior connectivity was seen (F(9,27) = 3.23, p < 0.008), moderated by ApoE-epsilon4 (F(9,27) = 2.22, p < 0.005). Inherent node strength was related to local iron (F(5,30) = 13.2; p < 0.022). CONCLUSION: Our data indicate that altered dynamic anterior-posterior brain connectivity is a characteristic of low memory performance in the subclinical range and genetic risk for AD in the elderly. As the observed altered brain network properties are associated with increased local iron, our findings may reflect secondary neuronal changes due to pathologic processes including oxidative stress. PMID- 28359297 TI - Significance evaluation in factor graphs. AB - BACKGROUND: Factor graphs provide a flexible and general framework for specifying probability distributions. They can capture a range of popular and recent models for analysis of both genomics data as well as data from other scientific fields. Owing to the ever larger data sets encountered in genomics and the multiple testing issues accompanying them, accurate significance evaluation is of great importance. We here address the problem of evaluating statistical significance of observations from factor graph models. RESULTS: Two novel numerical approximations for evaluation of statistical significance are presented. First a method using importance sampling. Second a saddlepoint approximation based method. We develop algorithms to efficiently compute the approximations and compare them to naive sampling and the normal approximation. The individual merits of the methods are analysed both from a theoretical viewpoint and with simulations. A guideline for choosing between the normal approximation, saddle point approximation and importance sampling is also provided. Finally, the applicability of the methods is demonstrated with examples from cancer genomics, motif-analysis and phylogenetics. CONCLUSIONS: The applicability of saddlepoint approximation and importance sampling is demonstrated on known models in the factor graph framework. Using the two methods we can substantially improve computational cost without compromising accuracy. This contribution allows analyses of large datasets in the general factor graph framework. PMID- 28359298 TI - Monocyte/lymphocyte ratio predicts the severity of coronary artery disease: a syntax score assessment. AB - BACKGROUND: We aimed to explore whether monocyte to lymphocyte ratio (MLR) provides predictive value of the lesion severity in patients with coronary artery disease (CAD). METHODS: Five hundred forty-three patients undergoing coronary angiography were analyzed in this retrospective study. Patients with coronary stenosis were divided into three groups on the basis of Syntax score. The control group consisted of patients with normal coronary arteries. MLR was calculated by dividing monocytes count by lymphocytes count obtained from routine blood examination. Multivariate logistic analysis was used to assess risk factors of CAD. Ordinal logistic regression analysis was used to assess the relationship between MLR and the lesion severity of coronary arteries. RESULTS: MLR was found to be an independent risk factor of the presence of CAD (OR: 3.94, 95% CI: 1.20 12.95) and a predictor of the lesion severity (OR: 2.05, 95% CI: 1.15-3.66). Besides, MLR was positively correlated with Syntax score(r = 0.437, p < 0.001). In the receiver-operating characteristic (ROC) curve analysis, MLR, with an optimal cut-off value of 0.25, predicted the severe coronary lesion with a sensitivity of 60.26% and specificity of 78.49%. CONCLUSIONS: MLR was an independent risk factor of the presence of CAD, and a predictor of the lesion severity. Compared to neutrophil to lymphocyte ratio (NLR), MLR has better performance to reflect the severity of coronary lesion. PMID- 28359299 TI - Adaptive differentiation coincides with local bioclimatic conditions along an elevational cline in populations of a lichen-forming fungus. AB - BACKGROUND: Many fungal species occur across a variety of habitats. Particularly lichens, fungi forming symbioses with photosynthetic partners, have evolved remarkable tolerances for environmental extremes. Despite their ecological importance and ubiquity, little is known about the genetic basis of adaption in lichen populations. Here we studied patterns of genome-wide differentiation in the lichen-forming fungus Lasallia pustulata along an altitudinal gradient in the Mediterranean region. We resequenced six populations as pools and identified highly differentiated genomic regions. We then detected gene-environment correlations while controlling for shared population history and pooled sequencing bias, and performed ecophysiological experiments to assess fitness differences of individuals from different environments. RESULTS: We detected two strongly differentiated genetic clusters linked to Mediterranean and temperate oceanic climate, and an admixture zone, which coincided with the transition between the two bioclimates. High altitude individuals showed ecophysiological adaptations to wetter and more shaded conditions. Highly differentiated genome regions contained a number of genes associated with stress response, local environmental adaptation, and sexual reproduction. CONCLUSIONS: Taken together our results provide evidence for a complex interplay between demographic history and spatially varying selection acting on a number of key biological processes, suggesting a scenario of ecological speciation. PMID- 28359300 TI - Highly localized divergence within supergenes in Atlantic cod (Gadus morhua) within the Gulf of Maine. AB - BACKGROUND: Atlantic cod (Gadus morhua), is known to vary genetically across the North Atlantic, Greenland, and Newfoundland. This genetic variation occurs both spatially and temporally through decades of heavy fishing, and is concentrated in three linkage disequilibrium blocks, previously defined by pedigreed linkage mapping analysis. Variation within these genomic regions is correlated with both seawater temperature and behavioral ecotype. The full extent and nature of these linkage groups is important information for interpreting cod genetic structure as a tool for future fisheries management. RESULTS: We conducted whole genome sequencing for 31 individual cod from three sub-populations in the Gulf of Maine. Across the genome, we found 3,390,654 intermediate to high frequency Single Nucleotide Polymorphisms (SNPs). We show that pairwise linkage analysis among these SNPs is a powerful tool to detect linkage disequilibrium clusters by recovering the three previously detected linkage groups and identifying the 1031 genes contained therein. Across these genes, we found significant population differentiation among spawning groups in the Gulf of Maine and between Georges Bank and Gulf of Maine. Coordinated divergence among these genes and their differentiation at both short and long spatial scales suggests that they are acting as linked supergenes in local adaptation of cod populations. CONCLUSIONS: Differentiation between SNPs in linkage disequilibrium blocks is the major signal of genetic differentiation between all groups tested within the Gulf of Maine. Our data provide a map of genes contained in these blocks, allowing an enhanced search for neutral genetic structure for demographic inference and fisheries modeling. Patterns of selection and the history of populations may be possible to identify in cod using this description of linkage disequilibrium blocks and future data sets to robustly separate neutral and selected genetic markers. PMID- 28359301 TI - Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer. AB - BACKGROUND: Epigenetic information can be used to identify clinically relevant genomic variants single nucleotide polymorphisms (SNPs) of functional importance in cancer development. Super-enhancers are cell-specific DNA elements, acting to determine tissue or cell identity and driving tumor progression. Although previous approaches have been tried to explain risk associated with SNPs in regulatory DNA elements, so far epigenetic readers such as bromodomain containing protein 4 (BRD4) and super-enhancers have not been used to annotate SNPs. In prostate cancer (PC), androgen receptor (AR) binding sites to chromatin have been used to inform functional annotations of SNPs. RESULTS: Here we establish criteria for enhancer mapping which are applicable to other diseases and traits to achieve the optimal tissue-specific enrichment of PC risk SNPs. We used stratified Q-Q plots and Fisher test to assess the differential enrichment of SNPs mapping to specific categories of enhancers. We find that BRD4 is the key discriminant of tissue-specific enhancers, showing that it is more powerful than AR binding information to capture PC specific risk loci, and can be used with similar effect in breast cancer (BC) and applied to other diseases such as schizophrenia. CONCLUSIONS: This is the first study to evaluate the enrichment of epigenetic readers in genome-wide associations studies for SNPs within enhancers, and provides a powerful tool for enriching and prioritizing PC and BC genetic risk loci. Our study represents a proof of principle applicable to other diseases and traits that can be used to redefine molecular mechanisms of human phenotypic variation. PMID- 28359303 TI - The IGCA staging system is more accurate than AJCC7 system in stratifying survival of patients with gastric cancer in stage III. AB - BACKGROUND: A new staging system recently proposed by the IGCA has demonstrated a better capacity of stratifying different prognoses for gastric cancer than the 7th edition AJCC staging system (AJCC7). The aim of this study was to evaluate the efficacy of the IGCA system in Chinese patients. METHODS: Medical records of patients with gastric cancer who received curative surgery in our center from January 2003 to December 2011 were reviewed retrospectively. All the lesions were staged according to both AJCC7 and IGCA staging systems. Overall survival (OS) of the patients was used as the observation endpoint. RESULTS: One thousand five hundred twenty-six cases were included in this study. By comparing the AJCC7 system with the IGCA systems, 395 cases were stratified into different stages, most of which were in stage III. The IGCA system could better stratify stage IIIB and IIIC patients (5-year OS, 38.1% vs. 29.0%; P = 0.005) than the AJCC7 system (5-year OS, 38.2% vs. 35.9%; P = 0.148). T3N3bM0, T4aN2M0 and T4aN3bM0 made up 97.5% (385/395) of the stage shift. T3N3bM0, which was stratified to stage IIIB in the AJCC7 system, showed a significant poorer prognosis than T4aN2M0 and T4aN3aM0, which were staged to IIIB and IIIC in the same system. The improper staging was revised in the IGCA staging system. CONCLUSIONS: The IGCA staging system can stratify stage III gastric cancer patients more properly than the AJCC7 system. PMID- 28359302 TI - Transcriptome analysis of the two unrelated fungal beta-lactam producers Acremonium chrysogenum and Penicillium chrysogenum: Velvet-regulated genes are major targets during conventional strain improvement programs. AB - BACKGROUND: Cephalosporins and penicillins are the most frequently used beta lactam antibiotics for the treatment of human infections worldwide. The main industrial producers of these antibiotics are Acremonium chrysogenum and Penicillium chrysogenum, two taxonomically unrelated fungi. Both were subjects of long-term strain development programs to reach economically relevant antibiotic titers. It is so far unknown, whether equivalent changes in gene expression lead to elevated antibiotic titers in production strains. RESULTS: Using the sequence of PcbC, a key enzyme of beta-lactam antibiotic biosynthesis, from eighteen different pro- and eukaryotic microorganisms, we have constructed a phylogenetic tree to demonstrate the distant relationship of both fungal producers. To address the question whether both fungi have undergone similar genetic adaptions, we have performed a comparative gene expression analysis of wild-type and production strains. We found that strain improvement is associated with the remodeling of the transcriptional landscape in both fungi. In P. chrysogenum, 748 genes showed differential expression, while 1572 genes from A. chrysogenum are differentially expressed in the industrial strain. Common in both fungi is the upregulation of genes belonging to primary and secondary metabolism, notably those involved in precursor supply for beta-lactam production. Other genes not essential for beta lactam production are downregulated with a preference for those responsible for transport processes or biosynthesis of other secondary metabolites. Transcriptional regulation was shown to be an important parameter during strain improvement in different organisms. We therefore investigated deletion strains of the major transcriptional regulator velvet from both production strains. We identified 567 P. chrysogenum and 412 A. chrysogenum Velvet target genes. In both deletion strains, approximately 50% of all secondary metabolite cluster genes are differentially regulated, including beta-lactam biosynthesis genes. Most importantly, 35-57% of Velvet target genes are among those that showed differential expression in both improved industrial strains. CONCLUSIONS: The major finding of our comparative transcriptome analysis is that strain improvement programs in two unrelated fungal beta-lactam antibiotic producers alter the expression of target genes of Velvet, a global regulator of secondary metabolism. From these results, we conclude that regulatory alterations are crucial contributing factors for improved beta-lactam antibiotic titers during strain improvement in both fungi. PMID- 28359304 TI - Determination of the Cell Permissiveness Spectrum, Mode of RNA Replication, and RNA-Protein Interaction of Zika Virus. AB - BACKGROUND: Two lineages of Zika virus (ZIKV) have been classified according to the phylogenetic analysis: African and Asian lineages. It is unclear whether differences exist between the two strains in host cell permissiveness, this information is important for understanding viral pathogenesis and designing anti viral strategies. METHODS: In the present study, we comparatively studied the permissive spectrum of human cells for both the African (MR766) and Asian strains (PRVABC59) using an RNA in situ hybridization (RISH) to visualize RNA replication, an immunofluorescence technology, and a western blot assay to determine viral protein production, and a real-time RT-PCR to examine viral RNA multiplication level. The experiments were undertaken in the condition of cell culture. RESULTS: We identified several human cell lines, including fibroblast, epithelial cells, brain cells, stem cells, and blood cells that are susceptible for the infection of both Asian and African strains. We did not find any differences between the MR766 and the PRVABC59 in the permissiveness, infection rate, and replication modes. Inconsistent to a previous report (Hamel et al. JVI 89:8880-8896, 2015), using RISH or real-time RT-PCR, we found that human foreskin fibroblast cells were not permissive for ZIKV infection. Instead, human lung fibroblast cells (MRC-5) were fully permissive for ZIKV infection. Surprisingly, a direct interaction of ZIKV RNA with envelop (E) protein (a structure protein) was demonstrated by an RNA chromatin immunoprecipitation (ChIP) assay. Three binding sites were identified in the ZIKV RNA genome for the interaction with the E protein. CONCLUSION: Our results imply that the E protein may be important for viral RNA replication, and provide not only the information of ZIKV permissiveness that guides the usage of human cells for the ZIKV studies, but also the insight into the viral RNA-E protein interaction that may be targeted for intervention by designing small molecule drugs. PMID- 28359305 TI - Antenatal nephromegaly and propionic acidemia: a case report. AB - BACKGROUND: Propionic acidemia (PA) is a rare but severe recessive autosomal disease, presenting with non specific signs in the first years of life. Prenatal diagnosis is invasive (amniocentesis) and limited to suspect cases. No screening test has been described, in particular no correlations between prenatal sonography and PA have been documented so far. CASE PRESENTATION: We report the case of a boy with fetal bilateral nephromegaly and hyperechogenic kidneys, along with neonatal acute kidney injury; no etiology could be found in the first months of life. At 3 months of life, he presented with tachypnea and altered mental status, which lead to the diagnosis of PA. The renal ultrasound at 8 months of life, after a symptomatic treatment of PA had been initiated, showed a regression of the renal abnormalities. CONCLUSION: This case describes PA as a novel cause of large and hyperechogenic kidneys in the antenatal period. It suggests that, when confronted to fetal nephromegaly, hyperechogenic kidneys and risk factors of metabolic disease such as consanguineous parents, PA should be considered, and a prenatal test should be proposed. PMID- 28359306 TI - Clinicians' adherence to clinical practice guidelines for cardiac function monitoring during antipsychotic treatment: a retrospective report on 434 patients with severe mental illness. AB - BACKGROUND: Severe mental illness (SMI) has considerable excess morbidity and mortality, a proportion of which is explained by cardiovascular diseases, caused in part by antipsychotic (AP) induced QT-related arrhythmias and sudden death by Torsade de Point (TdP). The implementation of evidence-based recommendations for cardiac function monitoring might reduce the incidence of these AP-related adverse events. To investigate clinicians' adherence to cardiac function monitoring before and after starting AP, we performed a retrospective assessment of 434 AP-treated SMI patients longitudinally followed-up for 5 years at an academic community mental health center. METHODS: We classified antipsychotics according to their risk of inducing QT-related arrhythmias and TdP (Center for Research on Therapeutics, University of Arizona). We used univariate tests and multinomial or binary logistic regression model for data analysis. RESULTS: Univariate and multinomial regression analysis showed that psychiatrists were more likely to perform pre-treatment electrocardiogram (ECG) and electrolyte testing with AP carrying higher cardiovascular risk, but not on the basis of AP pharmacological class. Univariate and binomial regression analysis showed that cardiac function parameters (ECG and electrolyte balance) were more frequently monitored during treatment with second generation AP than with first generation AP. CONCLUSIONS: Our data show the presence of weaknesses in the cardiac function monitoring of AP-treated SMI patients, and might guide future interventions to tackle them. PMID- 28359307 TI - Clinical impact of postoperative loss in psoas major muscle and nutrition index after radical cystectomy for patients with urothelial carcinoma of the bladder. AB - BACKGROUND: Although the significance of preoperative nutritional status has been investigated, there is no report regarding the relationship of their postoperative changes on outcomes in patients who underwent radical cystectomy for bladder cancer. Here, we report the clinical impact of the change, from baseline, in nutritional status and volume of abdominal skeletal muscle mass and adipose tissue after radical cystetomy. METHODS: A retrospective analysis of 89 patients with bladder cancer, who underwent curative radical cystectomy, was conducted to assess the time course of change, from baseline, in body composition and nutritional status at 1, 3, 6, 12, and 24 months, after surgery. Skeletal muscle mass and abdominal adipose tissue mass were quantified by unenhanced computed tomography images. Two different nutritional indices, the Prognostic Nutritional Index and the Controlling Nutritional Status score were calculated from laboratory blood tests. We evaluated the prognostic value of the rate of change in the body composition and nutritional status after radical cystectomy. RESULTS: The cross-sectional area at the level of the third lumbar vertebra of the psoas major muscle and nutritional indices showed a transient deterioration at 1 and 3 months after radical cystectomy, with a return to baseline values from 6 to 24 months. A <= -10% loss in the area of the psoas muscle was associated with a shorter overall survival, compared to those with a > -10 change [hazard ratio (HR) 2.2, P = 0.02]. Multivariate analyzes identified sarcopenia status at baseline (HR 2.2, P = 0.03) and a <= -10% loss in the psoas muscle (HR 2.4, P = 0.02) were identified as independent prognostic factors for overall survival. A subanalysis of patients without sarcopenia identified a worse survival outcome for patients with a <= -10% loss in the psoas muscle (HR 2.6, P = 0.03) and <= - 5 change in the Prognostic Nutritional Index (HR 3.6, P = 0.01). CONCLUSION: Further research is required to establish appropriate rehabilitation protocols and nutritional interventions after radical cystectomy for maintaining skeletal muscle mass and nutrition status which could counteract physical deterioration and improve outcomes. PMID- 28359308 TI - Revealing cancer subtypes with higher-order correlations applied to imaging and omics data. AB - BACKGROUND: Patient stratification to identify subtypes with different disease manifestations, severity, and expected survival time is a critical task in cancer diagnosis and treatment. While stratification approaches using various biomarkers (including high-throughput gene expression measurements) for patient-to-patient comparisons have been successful in elucidating previously unseen subtypes, there remains an untapped potential of incorporating various genotypic and phenotypic data to discover novel or improved groupings. METHODS: Here, we present HOCUS, a unified analytical framework for patient stratification that uses a community detection technique to extract subtypes out of sparse patient measurements. HOCUS constructs a patient-to-patient network from similarities in the data and iteratively groups and reconstructs the network into higher order clusters. We investigate the merits of using higher-order correlations to cluster samples of cancer patients in terms of their associations with survival outcomes. RESULTS: In an initial test of the method, the approach identifies cancer subtypes in mutation data of glioblastoma, ovarian, breast, prostate, and bladder cancers. In several cases, HOCUS provides an improvement over using the molecular features directly to compare samples. Application of HOCUS to glioblastoma images reveals a size and location classification of tumors that improves over human expert based stratification. CONCLUSIONS: Subtypes based on higher order features can reveal comparable or distinct groupings. The distinct solutions can provide biologically- and treatment-relevant solutions that are just as significant as solutions based on the original data. PMID- 28359309 TI - Electroacupuncture for tapering off long-term benzodiazepine use: study protocol of randomized controlled trial. AB - BACKGROUND: Conventional approaches for benzodiazepine tapering have their limitations. Anecdotal studies have shown that acupuncture is a potential treatment for facilitating successful benzodiazepine tapering. As of today, there was no randomized controlled trial examining its efficacy and safety. The purpose of the study is to evaluate the efficacy of using electroacupuncture as an adjunct treatment to gradual tapering of benzodiazepine doses in complete benzodiazepine cessation in long-term benzodiazepine users. METHODS/DESIGN: The study protocol of a randomized, assessor- and subject-blinded, controlled trial is presented. One hundred and forty-four patients with histories of using benzodiazepines in >=50% of days for more than 3 months will be randomly assigned in a 1:1 ratio to receive either electroacupuncture or placebo electroacupuncture combined with gradual benzodiazepine tapering schedule. Both experimental and placebo treatments will be delivered twice per week for 4 weeks. Major assessments will be conducted at baseline, week 6 and week 16 post-randomization. Primary outcome is the cessation rate of benzodiazepine use. Secondary outcomes include the percentage change in the doses of benzodiazepine usage and the severity of withdrawal symptoms experienced based on the Benzodiazepine Withdrawal Symptom Questionnaire, insomnia as measured by the Insomnia Severity Index, and anxiety and depressive symptoms as evaluated by the Hospital Anxiety and Depression Scale. Adverse events will also be measured at each study visit. DISCUSSION: Results of this study will provide high quality evidence of the efficacy and safety of electroacupuncture as an adjunct treatment for benzodiazepine tapering in long-term users. TRIAL REGISTRATION: ClinicalTrials.gov NCT02475538 . PMID- 28359310 TI - Increased Kruppel-like factor 12 in recurrent implantation failure impairs endometrial decidualization by repressing Nur77 expression. AB - BACKGROUND: Decidualization is a prerequisite for successful implantation and the establishment of pregnancy. A critical role of impaired decidualization in subfertility has been established. In human endometrial stromal cells (hESCs), Kruppel-like factor 12 (KLF12) and Nur77 are novel regulators of decidualization. We investigated whether KLF12 impaired the decidualization of hESCs in recurrent implantation failure (RIF) patients. METHODS: Endometrial tissues and hESCs were collected from RIF patients (n = 34) and fertile controls (n = 30) for in vitro analysis. Primary hESCs isolated from RIF endometrial tissues were used to evaluate the biological functions of KLF12 and Nur77. In addition, their molecular mechanisms were investigated by adenovirus-mediated overexpression. Gene expression regulation was examined by real-time-quantitative PCR (qRT-PCR), immunostaining and luciferase reporter assay. Further, blastocyst-like spheroid (BLS) and blastocyst implantation models were performed to examine the roles of KLF12 and Nur77 during embryo expansion on hESCs. RESULTS: hESCs from the RIF patients showed a poor decidual response, mainly characterized by decreased decidual prolactin (dPRL) secretion, impaired transformation and limited BLS expansion. In addition, KLF12 expression was increased in endometrial tissues from the RIF patients compared with those from the fertile controls, especially in stromal compartments. The opposite results were observed for Nur77 expression in these tissues. KLF12 repressed hESC decidualization by decreasing Nur77 expression. Mechanistically, KLF12 bound to a conserved site in the Nur77 promoter region. Nur77 overexpression significantly reversed the KLF12-mediated repression of dPRL expression, decidual transformation and BLS/blastocyst expansion. CONCLUSIONS: KLF12 impairs endometrial decidualization by transcriptionally repressing Nur77, and Nur77 overexpression reverses the poor decidual response of hESCs in RIF patients. PMID- 28359311 TI - Effect of vulcanization temperature and dental stone colour on colour degradation of maxillofacial silicone elastomers. AB - BACKGROUND: Colour degradation is a major problem in maxillofacial silicone elastomers. Recent studies have focused on colour stability and the mechanical properties of the silicone elastomers. A colour match is also essential for the acceptance of the prosthesis by the patient. The aim of this study is to assess the colour degradation of the silicone elastomer after being moulded in different colours of dental stones at two different vulcanization temperatures. METHODS: Five different colours of dental stones were used to fabricate a total of 120 silicone blocks using a Cosmesil M511 maxillofacial silicone elastomer. Vulcanization was completed at two different temperatures (25 and 100 degrees Celsius). Colour measurements were obtained with a Conica Minolta spectrophotometer. The CIEDE2000 formula was used to calculate the colour differences (?E00). Two-way ANOVA, one-way ANOVA with Bonferroni corrected post hoc p values and independent samples t-test were used for the statistical analyses. RESULTS: High temperature vulcanization causes lightening of the maxillofacial silicone elastomers without regard to the dental stone colour (p = 0.001). Specimens moulded in green stone lightened least at room temperature (p = 0.999). Compared to the control group, at high temperature, all specimens moulded in coloured dental stones darkened significantly (p < 0.001 for white, blue and yellow; p = 0.006 for green; p = 0.045 for reddish-brown). In the high temperature group, the shift to a green chroma was significant in the white, yellow and green dental stones groups (p = 0.001, p = 0.002, p < 0.001, respectively). The mean b* of the high temperature control group was higher than that of the room temperature control group (p < 0.001). The only ?E00 score lower than the perceptibility threshold for dental materials (?E00 = 1.30) was between the room temperature control group and the room temperature green dental stone group (?E00 = 0.96). CONCLUSIONS: Green and blue dental stones cause less colour degradation in silicone elastomers. Reddish-brown dental stones cause the most colour degradation in silicone elastomers. At 100 degrees C, the colour of the silicone elastomer lightens and yellows even if the elastomer is vulcanized in a stainless steel mould. White, yellow and reddish-brown dental stones make the silicone elastomer appear more yellow even if the elastomer is vulcanized at room temperature. PMID- 28359312 TI - Extended-spectrum beta-lactamase-producing Pseudomonas aeruginosa in camel in Egypt: potential human hazard. AB - BACKGROUND: The rapid increase of extended-spectrum beta-lactamase (ESBL) producing bacteria are a potential health hazard. Development of antimicrobial resistance in animal pathogens has serious implications for human health, especially when such strains could be transmitted to human. In this study, the antimicrobial resistance due to ESBL producing Pseudomonas aeruginosa in the camel meat was investigated. METHODS: In this study meat samples from 200 healthy camels at two major abattoirs in Egypt (Cairo and Giza) were collected. Following culture on cetrimide agar, suspected P. aeruginosa colonies were confirmed with a Vitek 2 system (bioMe'rieux). P. aeruginosa isolates were phenotypically identified as ESBL by double disk synergy test. Additionally antimicrobial susceptibility testing of ESBL producing P. aeruginosa isolates were done against 11 antimicrobial drugs and carried out by disk diffusion method. The ESBL genotypes were determined by polymerase chain reaction according to the presence of the bla PER-1, bla CTX-M, bla SHV, and bla TEM. RESULTS: Pseudomonas aeruginosa was isolated from 45 camel meat sample (22.5%). The total percentage of ESBL producing P. aeruginosa was 45% (21/45) from camel meat isolates. Antibiogram results revealed the highest resistance was for c, ceftriaxone and rifampicin followed by cefepime and aztreonam. The prevalence rates of beta lactamase genes were recorded (bla PER-1 28.5%, bla CTX-M 38%, bla SHV 33.3% and bla TEM 23.8%). CONCLUSIONS: This study illustrates the presence of high rates of ESBL-P. aeruginosa in camels that represents an increasing alarming for the risk of transmission to human and opens the door for current and future antibiotics therapy failure. Livestock associated ESBL-P. aeruginosa is a growing disaster, therefore, attention has to be fully given to livestock associated ESBL-bacteria which try to find its way to human beings. PMID- 28359313 TI - An examination of the causes, consequences, and policy responses to the migration of highly trained health personnel from the Philippines: the high cost of living/leaving-a mixed method study. AB - BACKGROUND: Dramatic increases in the migration of human resources for health (HRH) from developing countries like the Philippines can have consequences on the sustainability of health systems. In this paper, we trace the outflows of HRH from the Philippines, map out its key causes and consequences, and identify relevant policy responses. METHODS: This mixed method study employed a decentered, comparative approach that involved three phases: (a) a scoping review on health workers' migration of relevant policy documents and academic literature on health workers' migration from the Philippines; and primary data collection with (b) 37 key stakeholders and (c) household surveys with seven doctors, 329 nurses, 66 midwives, and 18 physical therapists. RESULTS: Filipino health worker migration is best understood within the context of macro-, meso-, and micro-level factors that are situated within the political, economic, and historical/colonial legacy of the country. Underfunding of the health system and un- or underemployment were push factors for migration, as were concerns for security in the Philippines, the ability to practice to full scope or to have opportunities for career advancement. The migration of health workers has both negative and positive consequences for the Philippine health system and its health workers. Stakeholders focused on issues such as on brain drain, gain, and circulation, and on opportunities for knowledge and technology transfer. Concomitantly, migration has resulted in the loss of investment in human capital. The gap in the supply of health workers has affected the quality of care delivered, especially in rural areas. The opening of overseas opportunities has commercialized health education, compromised its quality, and stripped the country of skilled learning facilitators. The social cost of migration has affected emigres and their families. At the household level, migration has engendered increased consumerism and materialism and fostered dependency on overseas remittances. Addressing these gaps requires time and resources. At the same time, migration is, however, seen by some as an opportunity for professional growth and enhancement, and as a window for drafting more effective national and inter-country policy responses to HRH mobility. CONCLUSIONS: Unless socioeconomic conditions are improved and health professionals are provided with better incentives, staying in the Philippines will not be a viable option. The massive expansion in education and training designed specifically for outmigration creates a domestic supply of health workers who cannot be absorbed by a system that is underfunded. This results in a paradox of underservice, especially in rural and remote areas, at the same time as underemployment and outmigration. Policy responses to this paradox have not yet been appropriately aligned to capture the multilayered and complex nature of these intersecting phenomena. PMID- 28359314 TI - Alpinia oxyphylla Miq. fruit extract activates IGFR-PI3K/Akt signaling to induce Schwann cell proliferation and sciatic nerve regeneration. AB - BACKGROUND: It is known that the medicinal herb Alpinia oxyphylla Miq. is widely used as a remedy for diarrhea as well as the symptoms accompanying hypertension and cerebrovascular disorders. Moreover, it has also been reported that Alpinia oxyphylla Miq. has beneficial effects on anti-senescence and neuro-protection. This study focuses on the molecular mechanisms by which the Alpinia oxyphylla Miq. fruits promote neuron regeneration. METHODS: A piece of silicone rubber was guided across a 15 mm gap in the sciatic nerve of a rat. This nerve gap was then filled with various doses of Alpinia oxyphylla Miq. fruits to assess their regenerative effect on damaged nerves. Further, we investigated the role of Alpinia oxyphylla Miq. fruits in RSC96 Schwann cell proliferation. RESULTS: Our current results showed that treatment with the extract of Alpinia oxyphylla Miq. fruits triggers the phosphorylated insulin-like growth factor-1 receptor- phosphatidylinositol 3-kinase/serine-threonine kinase pathway, and up-regulated the proliferating cell nuclear antigen in a dose-dependent manner. Cell cycle analysis on RSC96 Schwann cells showed that, after exposure to Alpinia oxyphylla Miq. fruit extract, the transition from the first gap phase to the synthesis phase occurs in 12-18 h. The expression of the cell cycle regulatory proteins cyclin D1, cyclin E and cyclin A increased in a dose-dependent manner. Transfection with a small interfering RNA blocked the expression of phosphatidylinositol 3-kinase and induced down-regulation both on the mRNA and protein levels, which resulted in a reduction of the expression of the survival factor B-cell lymphoma 2. CONCLUSION: We provide positive results that demonstrate that Alpinia oxyphylla Miq. fruits facilitate the survival and proliferation of RSC96 cells via insulin-like growth factor-1 signaling. PMID- 28359315 TI - Perceptions of malaria control and prevention in an era of climate change: a cross-sectional survey among CDC staff in China. AB - BACKGROUND: Though there was the significant decrease in the incidence of malaria in central and southwest China during the 1980s and 1990s, there has been a re emergence of malaria since 2000. METHODS: A cross-sectional survey was conducted amongst the staff of eleven Centers for Disease Control and Prevention (CDC) in China to gauge their perceptions regarding the impacts of climate change on malaria transmission and its control and prevention. Descriptive analysis was performed to study CDC staff's knowledge, attitudes, perceptions and suggestions for malaria control in the face of climate change. RESULTS: A majority (79.8%) of CDC staff were concerned about climate change and 79.7% believed the weather was becoming warmer. Most participants (90.3%) indicated climate change had a negative effect on population health, 92.6 and 86.8% considered that increasing temperatures and precipitation would influence the transmission of vector-borne diseases including malaria. About half (50.9%) of the surveyed staff indicated malaria had re-emerged in recent years, and some outbreaks were occurring in new geographic areas. The main reasons for such re-emergence were perceived to be: mosquitoes in high-density, numerous imported cases, climate change, poor environmental conditions, internal migrant populations, and lack of health awareness. CONCLUSIONS: This study found most CDC staff endorsed the statement that climate change had a negative impact on infectious disease transmission. Malaria had re-emerged in some areas of China, and most of the staff believed that this can be managed. However, high densities of mosquitoes and the continuous increase in imported cases of malaria in local areas, together with environmental changes are bringing about critical challenges to malaria control in China. This study contributes to an understanding of climate change related perceptions of malaria control and prevention amongst CDC staff. It may help to formulate in-house training guidelines, community health promotion programmes and policies to improve the capacity of malaria control and prevention in the face of climate change in China. PMID- 28359316 TI - Evaluation of pancreatic cancer cell migration with multiple parameters in vitro by using an optical real-time cell mobility assay device. AB - BACKGROUND: Migration of cancer cell correlates with distant metastasis and local invasion, which are good targets for cancer treatment. An optically accessible device "TAXIScan" was developed, which provides considerably more information regarding the cellular dynamics and less quantity of samples than do the existing methods. Here, we report the establishment of a system to analyze the nature of pancreatic cancer cells using TAXIScan and we evaluated lysophosphatidic acid (LPA)-elicited pancreatic cell migration. METHODS: Pancreatic cancer cell lines, BxPC3, PANC-1, AsPC1, and MIAPaCa-2, were analyzed for adhesion as well as migration towards LPA by TAXIScan using parameters such as velocity and directionality or for the number of migrated cells by the Boyden chamber methods. To confirm that the migration was initiated by LPA, the expression of LPA receptors and activation of intracellular signal transductions were examined by quantitative reverse transcriptase polymerase reaction and western blotting. RESULTS: Scaffold coating was necessary for the adhesion of pancreatic cancer cells, and collagen I and Matrigel were found to be good scaffolds. BxPC3 and PANC-1 cells clearly migrated towards the concentration gradient formed by injecting 1 MUL LPA, which was abrogated by pre-treatment with LPA inhibitor, Ki16425 (IC50 for the directionality ~ 1.86 MUM). The LPA dependent migration was further confirmed by mRNA and protein expression of LPA receptors as well as phosphorylation of signaling molecules. LPA1 mRNA was highest among the 6 receptors, and LPA1, LPA2 and LPA3 proteins were detected in BxPC3 and PANC-1 cells. Phosphorylation of Akt (Thr308 and Ser473) and p42/44MAPK in BxPC3 and PANC-1 cells was observed after LPA stimulation, which was clearly inhibited by pre-treatment with a compound Ki16425. CONCLUSIONS: We established a novel pancreatic cancer cell migration assay system using TAXIScan. This assay device provides multiple information on migrating cells simultaneously, such as their morphology, directionality, and velocity, with a small volume of sample and can be a powerful tool for analyzing the nature of cancer cells and for identifying new factors that affect cell functions. PMID- 28359317 TI - A Single Nucleotide Polymorphism in the FADS1 Gene is Associated with Plasma Fatty Acid and Lipid Profiles and Might Explain Gender Difference in Body Fat Distribution. AB - BACKGROUND: Genotyping of the rs174547 polymorphism in the fatty acid desaturase 1 gene (FADS1) shows that it is associated with the FA composition of plasma phospholipids and lipid metabolic indices among several ethnic groups. However, this association requires further confirmation in the Chinese population, and little is known about the effect of polymorphisms in fatty acid-related genes on body fat distribution. METHODS: Anthropometric measurements of 951 Chinese adults aged 18-79 were obtained and body fat distribution was estimated using dual energy X-ray absorptiometry. The FA composition of plasma phospholipids was measured by gas chromatography. Multiple linear regression assessed whether the rs174547 genotype was associated with FA composition, body fat distribution, and metabolic traits in additive, dominant, and recessive models. RESULTS: The rs174547 C minor allele was associated with a higher proportion of linoleic acid, lower arachidonic acid and docosahexaenoic acid, as well as lower delta-6 desaturase and delta-5-desaturase activity. Female C allele carriers had lower android fat percentages and lower levels of low-density lipoprotein-cholesterol, while male C allele carriers had lower gynoid fat percentages and higher triglyceride after adjusting for age, income, BMI, behavioral risk factors, and regional fat percentages. CONCLUSION: An association of FADS1 rs174547 with the FA composition of plasma phospholipids was identified among this Chinese adult population. The association with body fat distribution and lipid metabolic indices differed between men and women, which might explain sexual differences in body fat distribution and lipid metabolism. PMID- 28359318 TI - 24h-gene variation effect of combined bevacizumab/erlotinib in advanced non squamous non-small cell lung cancer using exon array blood profiling. AB - BACKGROUND: The SAKK 19/05 trial investigated the safety and efficacy of the combined targeted therapy bevacizumab and erlotinib (BE) in unselected patients with advanced non-squamous non-small cell lung cancer (NSCLC). Although activating EGFR mutations were the strongest predictors of the response to BE, some patients not harboring driver mutations could benefit from the combined therapy. The identification of predictive biomarkers before or short after initiation of therapy is therefore paramount for proper patient selection, especially among EGFR wild-types. The first aim of this study was to investigate the early change in blood gene expression in unselected patients with advanced non-squamous NSCLC treated by BE. The second aim was to assess the predictive value of blood gene expression levels at baseline and 24h after BE therapy. METHODS: Blood samples from 43 advanced non-squamous NSCLC patients taken at baseline and 24h after initiation of therapy were profiled using Affymetrix' exon arrays. The 24h gene dysregulation was investigated in the light of gene functional annotations using gene set enrichment analysis. The predictive value of blood gene expression levels was assessed and validated using an independent dataset. RESULTS: Significant gene dysregulations associated with the 24h-effect of BE were detected from blood-based whole-genome profiling. BE had a direct effect on "Pathways in cancer", by significantly down-regulating genes involved in cytokine-cytokine receptor interaction, MAPK signaling pathway and mTOR signaling pathway. These pathways contribute to phenomena of evasion of apoptosis, proliferation and sustained angiogenesis. Other signaling pathways specifically reflecting the mechanisms of action of erlotinib and the anti angiogenesis effect of bevacizumab were activated. The magnitude of change of the most dysregulated genes at 24h did not have a predictive value regarding the patients' response to BE. However, predictive markers were identified from the gene expression levels at 24h regarding time to progression under BE. CONCLUSIONS: The 24h-effect of the combined targeted therapy BE could be accurately monitored in advanced non-squamous NSCLC blood samples using whole genome exon arrays. Putative predictive markers at 24h could reflect patients' response to BE after adjusting for their mutational status. Trial registration ClinicalTrials.gov: NCT00354549. PMID- 28359320 TI - Novel intramedullary device for lengthening transfemoral residual limbs. AB - BACKGROUND: Lower limb loss is a highly disabling medical condition that can severely impact a person's quality of life. Recovery becomes especially challenging if an amputee has a short residual limb, which can complicate proper prosthetic fitting, causing discomfort, difficulties in suspension, and reduced mobility. Current limb lengthening techniques such as the Ilizarov apparatus and external fixators are cumbersome, uncomfortable, and have high complication rates. In this study, we investigated the effectiveness of a novel limb lengthening device that uses intramedullary bone lengthening and requires only one percutaneous rod at the end of the limb during the distraction phase. Only the intramedullary nail remains after the distraction phase, and no external components are required during the consolidation phase. We hypothesize that this system would create a much easier experience for the patient. METHODS: The system was first tested in a mock surgical implantation using plastic femur bones. The device was then tested in a series of cadaveric experiments using pelvis-to-knee specimens by a group of surgeons. Surgeons evaluated the surgical insertion technique, soft tissue considerations, hardware fixation strategies, and the effectiveness of the distraction mechanism. Revisions and improvements to the device and surgical procedure were made based on the results from the cadaveric experiments. RESULTS: A questionnaire was given to two visiting surgeons following the final iteration of the device. The surgeons reported that the system effectively lengthened the limb, was sturdy, and could be installed efficiently. However, there remains a risk of infection and soft tissue imbalances, similar to that introduced by an external fixator device. Suggestions on how to improve the design of the device and mitigate infection through postoperative management and surgical standard of care will be considered for future clinical trials. CONCLUSIONS: The described intramedullary residual limb lengthening device has evolved from a prototype to a mature model tested in six cadaveric experiments to date. Further mechanical and functional testing is needed to finalize the device before testing in patients. PMID- 28359319 TI - Endocrine therapy initiation, discontinuation and adherence and breast imaging among 21-gene recurrence score assay-eligible women under age 65. AB - BACKGROUND: Aside from chemotherapy utilization, limited data are available on the relationship between gene expression profiling (GEP) testing and breast cancer care. We assessed the relationship between GEP testing and additional variables and the outcomes of endocrine therapy initiation, discontinuation and adherence, and breast imaging exams in women under age 65 years. METHODS: Data from five state cancer registries were linked with claims data and GEP results. We assessed variables associated with survivorship care outcomes in an incident cohort of 5014 commercially insured women under age 65 years, newly diagnosed with stage I or II hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2) non-positive breast cancer from 2006 to 2010. RESULTS: Among tested women, those with high Oncotype DX(r) Breast Recurrence Score(r) (RS) were significantly less likely to initiate endocrine therapy than women with low RS tumors (OR 0.40 (95% CI 0.20 to 0.81); P = 0.01). Among all test-eligible women, receipt of Oncotype DX testing was associated with a greater likelihood of endocrine therapy initiation (OR 2.48 (95% CI 2.03 to 3.04); P <0.0001). The odds of initiation were also significantly higher for tested vs. untested women among women who did not initiate chemotherapy within six months of diagnosis (OR 3.25 (95% CI 2.53 to 4.16)), with no effect in women who received chemotherapy. Discontinuation and adherence and breast imaging exams were unrelated to tested status or RS. CONCLUSIONS: Lower endocrine therapy initiation rates among women with high RS tumors and among untested women not receiving chemotherapy are concerning, given its established efficacy. Additional research is needed to suggest mechanisms to close this gap. PMID- 28359321 TI - The origin of Rosenthal fibers and their contributions to astrocyte pathology in Alexander disease. AB - Rosenthal fibers (RFs) are cytoplasmic, proteinaceous aggregates. They are the pathognomonic feature of the astrocyte pathology in Alexander Disease (AxD), a neurodegenerative disorder caused by heterozygous mutations in the GFAP gene, encoding glial fibrillary acidic protein (GFAP). Although RFs have been known for many years their origin and significance remain elusive issues. We have used mouse models of AxD based on the overexpression of human GFAP (transgenic, TG) and a point mutation in mouse GFAP (knock-in, KI) to examine the formation of RFs and to find astrocyte changes that correlate with the appearance of RFs. We found RFs of various sizes and shapes. The smallest ones appear as granular depositions on intermediate filaments. These contain GFAP and the small heat shock protein, alphaB-crystallin. Their aggregation appears to give rise to large RFs. The appearance of new RFs and the growth of previously formed RFs occur over time. We determined that DAPI is a reliable marker of RFs and in parallel with Fluoro-Jade B (FJB) staining defined a high variability in the appearance of RFs, even in neighboring astrocytes. Although many astrocytes in AxD with increased levels of GFAP and with or without RFs change their phenotype, only some cells with large numbers of RFs show a profound reconstruction of cellular processes, with a loss of fine distal processes and the appearance of large, lobulated nuclei, likely due to arrested mitosis. We conclude that 1) RFs appear to originate as small, osmiophilic masses containing both GFAP and alphaB-crystallin deposited on bundles of intermediate filaments. 2) RFs continue to form within AxD astrocytes over time. 3) DAPI is a reliable marker for RFs and can be used with immunolabeling. 4) RFs appear to interfere with the successful completion of astrocyte mitosis and cell division. PMID- 28359322 TI - Mutation of Kinesin-6 Kif20b causes defects in cortical neuron polarization and morphogenesis. AB - BACKGROUND: How neurons change their cytoskeleton to adopt their complex polarized morphology is still not understood. Growing evidence suggests that proteins that help build microtubule structures during cell division are also involved in building and remodeling the complex cytoskeletons of neurons. Kif20b (previously called MPP1 or Mphosph1) is the most divergent member of the Kinesin 6 family of "mitotic" kinesins that also includes Kif23/MKLP1 and Kif20a/MKLP2. We previously isolated a loss-of-function mouse mutant of Kif20b and showed that it had a thalamocortical axon guidance defect and microcephaly. METHODS: We demonstrate here, using the mouse mutant, that Kif20b is required for neuron morphogenesis in the embryonic neocortex. In vivo and in vitro cortical neurons were labeled and imaged to analyze various aspects of morphogenesis. RESULTS: Loss of Kif20b disrupts polarization as well as neurite outgrowth, branching and caliber. In vivo, mutant cortical neurons show defects in orientation, and have shorter thinner apical dendrites that branch closer to the cell body. In vitro, without external polarity cues, Kif20b mutant neurons show a strong polarization defect. This may be due in part to loss of the polarity protein Shootin1 from the axonal growth cone. Those mutant neurons that do succeed in polarizing have shorter axons with more branches, and longer minor neurites. These changes in shape are not due to alterations in cell fate or neuron layer type. Surprisingly, both axons and minor neurites of mutant neurons have increased widths and longer growth cone filopodia, which correlate with abnormal microtubule organization. Live analysis of axon extension shows that Kif20b mutant axons display more variable growth with increased retraction. CONCLUSIONS: These results demonstrate that Kif20b is required cell-autonomously for proper morphogenesis of cortical pyramidal neurons. Kif20b regulates neuron polarization, and axon and dendrite branching, outgrowth, and caliber. Kif20b protein may act by bundling microtubules into tight arrays and by localizing effectors such as Shootin1. Thus it may help shape neurites, sustain consistent axon growth, and inhibit branching. This work advances our understanding of how neurons regulate their cytoskeleton to build their elaborate shapes. Finally, it suggests that neuronal connectivity defects may be present in some types of microcephaly. PMID- 28359323 TI - Posterior wedge osteotomy and debridement for Andersson lesion with severe kyphosis in ankylosing spondylitis. AB - BACKGROUND: Andersson lesion is a well-known complication in ankylosing spondylitis. Recently, owing to the worry about the healing of fracture, some scholars advocated additional anterior surgery or other procedures were necessary, which increase the risk of the nerve injury. The purpose of this study is to introduce our experience and to explore the efficacy and feasibility of posterior wedge osteotomy and debridement through Andersson Lesion for surgical treatment of severe kyphosis in ankylosing spondylitis. METHODS: From January 2012 to January 2014, a retrospective study of 14 Andersson lesion patients with severe kyphosis in ankylosing spondylitis treated with surgery was completed with an at least 2-year follow-up. The debridement procedure, before posterior wedge osteotomy in posterior approach, must scrape all sclerosis bone until healthy cancellous bone appears. Radiographic and clinical results and complications were assessed with an average follow-up of 24 months. The CT scan was obtained preoperatively and at the final follow-up to assess the displacement of the fracture preoperatively, the safety of screw insertion, the healing of the fracture at the final follow-up. The Bridwell interbody fusion grading system was used to assess the healing of the fracture. RESULTS: Local kyphosis was substantially corrected from 51.7 +/- 15.6 to 7.1 +/- 19.5, with a mean correction of 44 degrees . The global kyphosis (GK) changed from 60.6 +/- 28.3 to 20.3 +/- 10.3 (P = 0.000). The mean VAS back pain scores decreased from 6.7 +/- 0.8 preoperatively to 0.75 +/- 0.6 after a 2-year follow-up (P = 0.000). The ODI score improved from 60.56 +/- 15.1% preoperatively to 23.46 +/- 8.2% after a 2 year follow-up (P = 0.000). The CT scan showed solid fusion at the level of the AL, and no internal fixation loose. All patients achieved grade 1 fusion. No major complication occurred. CONCLUSIONS: The posterior wedge osteotomy and debridement through AL can be used to correct the severe kyphosis in ankylosing spondylitis, achieving favorable clinical outcomes, good fusion, and satisfactory deformity correction. PMID- 28359324 TI - Cerebrospinal fluid cell-free mitochondrial DNA is associated with HIV replication, iron transport, and mild HIV-associated neurocognitive impairment. AB - BACKGROUND: Mitochondria are abundant organelles critical for energy metabolism and brain function. Mitochondrial DNA (mtDNA), released during cellular injury and as part of the innate immune response to viral pathogens, contains CpG motifs that act as TLR-9 ligands. We investigated relationships between cerebrospinal fluid (CSF) cell-free mtDNA levels and HIV viral load (VL), biomarkers of inflammation and iron transport, and neurocognitive (NC) function in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort. METHODS: We quantified cell-free mtDNA in CSF by droplet digital PCR in 332 CHARTER participants who underwent comprehensive neuropsychiatric evaluation. NC performance was assessed using the global deficit score (GDS) as either a continuous or a binary measure (GDS >= 0.5, impaired vs. GDS < 0.5, unimpaired). CSF, clinical, and biomarker data from the earliest available time point were analyzed. Cell-free mtDNA associations with CSF inflammation and iron-related biomarkers [CXCL10, IL-6, IL 8, TNF-a, transferrin (TF), ceruloplasmin (CP), and vascular endothelial growth factor (VEGF)], VL, and GDS were evaluated by multivariable regression. RESULTS: CSF cell-free mtDNA levels were significantly lower in participants with undetectable (vs. detectable) VL in either plasma (p < 0.001) or CSF (p < 0.001) and in those on antiretroviral therapy (ART; p < 0.001). Participants on ART with undetectable VL in both CSF and plasma had lower mtDNA levels than those with detectable VL in both compartments (p = 0.001). Higher mtDNA levels were observed in participants in the highest vs. lowest tertile (T3 vs. T1) of CSF CXCL10 (T3 vs. T1, p < 0.001) and TNF-a (T3 vs. T1, p < 0.05) in unadjusted analyses. MtDNA levels also correlated with CSF leukocyte count. After adjusting for CSF leukocyte count and VL, mtDNA levels were also associated with other inflammation and iron-related biomarkers in CSF, including TF (T3 vs. T1, p < 0.05) and CP (T3 vs. T1, p < 0.05). With additional correction for ART use, mtDNA was also negatively associated with CSF VEGF (p < 0.05) and IL-6 (p = 0.05). We observed no associations of CSF mtDNA levels with age or GDS-defined NC impairment. CONCLUSIONS: CSF cell-free mtDNA levels were associated with HIV RNA and ART status, as well as with biomarkers of iron transport and VEGF, a growth factor with known effects on mitochondrial integrity and autophagy. CSF mtDNA may be a biomarker of iron dysregulation and/or neuroinflammation during HIV infection. PMID- 28359325 TI - Early versus late BCG vaccination in HIV-1-exposed infants in Uganda: study protocol for a randomized controlled trial. AB - BACKGROUND: Bacillus Calmette-Guerin (BCG) vaccination may have nonspecific effects, i.e., effects on childhood morbidity and mortality that go beyond its effect on the risk of childhood tuberculosis (TB). Though the available scientific literature is mostly from observational studies, and is fraught with controversy, BCG vaccination at birth may protect infants in high-mortality populations against serious infections other than TB. Yet, other studies indicate that giving BCG later in infancy may modify immune responses to non-TB antigens and potentially enhance immunity, potentially also against tuberculosis (TB). It is unclear whether BCG vaccination very early in life offers adequate protection against TB and other infections among HIV-1-exposed children because even those who remain uninfected with HIV-1 show signs of impaired immunocompetence early in infancy. This study will compare BCG vaccination at birth with BCG vaccination at 14 weeks of age in HIV-1-exposed infants. METHODS: This is an individually randomized controlled trial in 2200 HIV-1-exposed infants. The intervention is BCG vaccination within 24 h of birth while the comparator is BCG given at 14 weeks of age. The study co-primary outcomes are severe illness in the first 14 weeks of life, and production of tumor necrosis factor, interleukin (IL)-1beta, IL-6 and interferon-gamma in response to mycobacterial and nonmycobacterial antigens. The study is being conducted in three health centers in Uganda. DISCUSSION: A well-timed BCG vaccination could have important nonspecific effects in HIV-1-exposed infants. This trial could inform the development of appropriate timing of BCG vaccination for HIV-1-exposed infants. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02606526 . Registered on 12 November 2015. PMID- 28359326 TI - Hsp90beta promoted endothelial cell-dependent tumor angiogenesis in hepatocellular carcinoma. AB - BACKGROUND: Vascular endothelial growth factor receptors (VEGFRs) are the major receptors involved in endothelial cell-dependent tumor angiogenesis. There are studies account for the effects of Hsp90 on angiogenesis, but the role and mechanism of Hsp90beta isoforms and NVP-BEP800, a specific inhibitor of Hsp90beta, in tumor angiogenesis is rarely mentioned. METHODS: Immunohistochemistry and statistical analysis was used to evaluate the correlation between Hsp90beta expression, CD31 endothelial cell-dependent vessel density, and VEGFRs expression in tissue samples of 96 HCCs. Kaplan-Meier survival analysis and COX proportional hazards analysis the relation of Hsp90beta and prognosis. HUVEC cells were transfected with Hsp90beta or treated with NVP BEP800, and then cell proliferation, migration, invasion and tube formation were investigated. The VEGFR1 and VEGFR2 expression was determined by Western blot and immunofluorescence. The VEGFR1 and VEGFR2 promoter activities were detected by dual luciferase report system. In vivo, the angiogenesis promotion of Hsp90beta and anti-angiogenesis efficacy of NVP-BEP800 was tested in HCC xenograft models. Histological analysis was performed on tumor samples to evaluate Hsp90beta, VEGFRs expression and MVD. RESULTS: This study investigated the correlation between Hsp90beta expression and CD31+ endothelial cell-dependent vessel density. Hsp90beta promoted VEGFRs expression by increasing their promoter activities. The proliferation, migration, invasion, and tube formation activities of human endothelial cells significantly increased when Hsp90beta was overexpressed. NVP BEP800 down-regulated VEGFRs expression to significantly reduce tubular differentiation, as well as endothelial cell proliferation, migration, and invasion. Furthermore, NVP-BEP800 decreased VEGFR1 and VEGFR2 promoter activities. In vivo, Hsp90beta promoted VEGFRs and CD31 expression in human hepatocellular carcinoma tumor xenografts and was associated with increased tumor microvessel density. After 18 days of treatment with 30 mg/kg/day NVP-BEP800, VEGFRs and CD31 expression significantly decreased. CONCLUSION: Hsp90beta induced endothelial cell-dependent tumor angiogenesis by activating VEGFRs transcription. NVP-BEP800 has potential as a therapeutic strategy for inhibiting tumor angiogenesis by decreasing endothelial cell progression and metastasis. It can help develop a therapeutic strategy for tumor treatment through the inhibition of endothelial cell progression and metastasis. PMID- 28359327 TI - Monoamine oxidase B inhibitor, selegiline, reduces 18F-THK5351 uptake in the human brain. AB - BACKGROUND: 18F-THK5351 is a quinoline-derived tau imaging agent with high affinity to paired helical filaments (PHF). However, high levels of 18F-THK5351 retention in brain regions thought to contain negligible concentrations of PHF raise questions about the interpretation of the positron emission tomography (PET) signals, particularly given previously described interactions between quinolone derivatives and monoamine oxidase B (MAO-B). Here, we tested the effects of MAO-B inhibition on 18F-THK5351 brain uptake using PET and autoradiography. METHODS: Eight participants (five mild cognitive impairment, two Alzheimer's disease, and one progressive supranuclear palsy) had baseline 18F AZD4694 and 18F-THK5351 scans in order to quantify brain amyloid and PHF load, respectively. A second 18F-THK5351 scan was conducted 1 week later, 1 h after a 10-mg oral dose of selegiline. Three out of eight patients also had a third 18F THK5351 scan 9-28 days after the selegiline administration. The primary outcome measure was standardized uptake value (SUV), calculated using tissue radioactivity concentration from 50 to 70 min after 18F-THK5351 injection, normalizing for body weight and injected radioactivity. The SUV ratio (SUVR) was determined using the cerebellar cortex as the reference region. 18F-THK5351 competition autoradiography studies in postmortem tissue were conducted using 150 and 500 nM selegiline. RESULTS: At baseline, 18F-THK5351 SUVs were highest in the basal ganglia (0.64 +/- 0.11) and thalamus (0.62 +/- 0.14). In the post selegiline scans, the regional SUVs were reduced on average by 36.7% to 51.8%, with the greatest reduction noted in the thalamus (51.8%) and basal ganglia (51.4%). MAO-B inhibition also reduced 18F-THK5351 SUVs in the cerebellar cortex (41.6%). The SUVs remained reduced in the three patients imaged at 9-28 days. Tissue autoradiography confirmed the effects of MAO-B inhibition on 18F-THK5351 uptake. CONCLUSIONS: These results indicate that the interpretation of 18F THK5351 PET images, with respect to tau, is confounded by the high MAO-B availability across the entire brain. In addition, the heterogeneous MAO-B availability across the cortex may limit the interpretation of 18F-THK5351 scans using reference region methods. PMID- 28359328 TI - Stem loop-mediated isothermal amplification test: comparative analysis with classical LAMP and PCR in detection of Entamoeba histolytica in Kenya. AB - BACKGROUND: Entamoeba histolytica, the causative agent for amoebiasis is a considerable burden to population in the developing countries where it accounts for over 50 million infections. The tools for detection of amoebiasis are inadequate and diagnosis relies on microscopy which means a significant percent of cases remain undiagnosed. Moreover, tests formats that can be rapidly applied in rural endemic areas are not available. METHODS: In this study, a loop-mediated isothermal test (LAMP) based on 18S small subunit ribosomal RNA gene was designed with extra reaction accelerating primers (stem primers) and compared with the published LAMP and PCR tests in detection of E. histolytica DNA in clinical samples. RESULTS: The stem LAMP test indicated shorter time to results by an average 11 min and analytical sensitivity of 10-7 (~30 pg/ml) compared to the standard LAMP and PCR which showed sensitivities levels of 10-5 (~3 ng/ml) and 10 4 (~30 ng/ml) respectively using tenfold serial dilution of DNA. In the analysis of clinical specimens positive for Entamoeba spp. trophozoites and cysts using microscopy, the stem LAMP test detected E. histolytica DNA in 36/126, standard LAMP test 20/126 and PCR 17/126 cases respectively. There was 100% agreement in detection of the stem LAMP test product using fluorescence of SYTO-9 dye in real time machine, through addition of 1/10 dilution of SYBR(r) Green I and electrophoresis in 2% agarose gel stained with ethidium bromide. CONCLUSION: The stem LAMP test developed in this study indicates potential towards detection of E. histolytica. PMID- 28359329 TI - Comparison of stool versus rectal swab samples and storage conditions on bacterial community profiles. AB - BACKGROUND: Sample collection for gut microbiota analysis from in-patients can be challenging. Collection method and storage conditions are potential sources of variability. In this study, we compared the bacterial microbiota from stool stored under different conditions, as well as stool and swab samples, to assess differences due to sample storage conditions and collection method. METHODS: Using bacterial 16S rRNA gene sequence analysis, we compared the microbiota profiles of stool samples stored and collected under various conditions. Stool samples (2 liquid, 1 formed) from three different patients at two hospitals were each evaluated under the following conditions: immediately frozen at -80 degrees C, stored at 4 degrees C for 12-48 hours before freezing at -80 degrees C and stored at -20 degrees C with 1-2 thaw cycles before storage at -80 degrees C. Additionally, 8 stool and 30 rectal swab samples were collected from 8 in patients at one hospital. Microbiota differences were assessed using the Yue and Clayton dissimilarity index (thetaYC distance) and analysis of molecular variance (AMOVA). RESULTS: Regardless of the storage conditions, the bacterial communities of aliquots from the same stool samples were very similar based on thetaYC distances (median intra-sample thetaYC distance: 0.035, IQR: 0.015-0.061) compared to aliquots from different stool samples (median inter-sample thetaYC distance: 0.93, IQR: 0.85-0.97) (Wilcoxon test p-value: <0.0001). For the stool and rectal swab comparison, samples from different patients, regardless of sample collection method, were significantly different (AMOVA p-values: <0.001-0.029) compared to no significant difference between all stool and swab samples (AMOVA p value: 0.976). The thetaYC dissimilarity index between swab and stool samples was significantly lower within individuals (median 0.17, IQR: 0.10-0.27) than between individuals (median 0.93, IQR: 0.85-0.97) (Wilcoxon test p-value: <0.0001), indicating minimal differences between stool and swab samples collected from the same individual over the sampling period. CONCLUSION: For gastrointestinal microbiota studies based on bacterial 16S rRNA gene sequence analysis, interim stool sample storage at 4 degrees C or -20 degrees C, rather than immediate storage at -80 degrees C, does not significantly alter results. Additionally, stool and rectal swab microbiotas from the same subject were highly similar, indicating that these sampling methods could be used interchangeably to assess the community structure of the distal GI tract. PMID- 28359330 TI - Evolutionarily recent, insertional fission of mitochondrial cox2 into complementary genes in bilaterian Metazoa. AB - BACKGROUND: Mitochondrial genomes (mtDNA) of multicellular animals (Metazoa) with bilateral symmetry (Bilateria) are compact and usually carry 13 protein-coding genes for subunits of three respiratory complexes and ATP synthase. However, occasionally reported exceptions to this typical mtDNA organization prompted speculation that, as in protists and plants, some bilaterian mitogenomes may continue to lose their canonical genes, or may even acquire new genes. To shed more light on this phenomenon, a PCR-based screen was conducted to assess fast evolving mtDNAs of apocritan Hymenoptera (Arthropoda, Insecta) for genomic rearrangements that might be associated with the modification of mitochondrial gene content. RESULTS: Sequencing of segmental inversions, identified in the screen, revealed that the cytochrome oxidase subunit II gene (cox2) of Campsomeris (Dielis) (Scoliidae) was split into two genes coding for COXIIA and COXIIB. The COXII-derived complementary polypeptides apparently form a heterodimer, have reduced hydrophobicity compared with the majority of mitogenome encoded COX subunits, and one of them, COXIIB, features increased content of Cys residues. Analogous cox2 fragmentation is known only in two clades of protists (chlorophycean algae and alveolates), where it has been associated with piecewise relocation of this gene into the nucleus. In Campsomeris mtDNA, cox2a and cox2b loci are separated by a 3-kb large cluster of several antiparallel overlapping ORFs, one of which, qnu, seems to encode a nuclease that may have played a role in cox2 fission. CONCLUSIONS: Although discontinuous mitochondrial protein genes encoding fragmented, complementary polypeptides are known in protists and some plants, split cox2 of Campsomeris is the first case of such a gene arrangement found in animals. The reported data also indicate that bilaterian animal mitogenomes may be carrying lineage-specific genes more often than previously thought, and suggest a homing endonuclease-based mechanism for insertional mitochondrial gene fission. PMID- 28359331 TI - In vitro antioxidant and, alpha-glucosidase inhibitory activities and comprehensive metabolite profiling of methanol extract and its fractions from Clinacanthus nutans. AB - BACKGROUND: This study was aimed to evaluate antioxidant and alpha-glucosidase inhibitory activity, with a subsequent analysis of total phenolic and total flavonoid content of methanol extract and its derived fractions from Clinacanthus nutans accompanied by comprehensive phytochemical profiling. METHODS: Liquid liquid partition chromatography was used to separate methanolic extract to get hexane, ethyl acetate, butanol and residual aqueous fractions. The total antioxidant activity was determined by 2,2-diphenyl-1-picrylhydrazy (DPPH) radical scavenging and ferric reducing antioxidant power assay (FRAP). The antidiabetic activity of methanol extract and its consequent fractions were examined by alpha-glucosidase inhibitory bioassay. The chemical profiling was carried out by gas chromatography coupled with quadrupole time-of-flight mass spectrometry (GC Q-TOF MS). RESULTS: The total yield for methanol extraction was (12.63 +/- 0.98) % (w/w) and highest fractionated value found for residual aqueous (52.25 +/- 1.01) % (w/w) as compared to the other fractions. Significant DPPH free radical scavenging activity was found for methanolic extract (63.07 +/- 0.11) % and (79.98 +/- 0.31) % for ethyl acetate fraction among all the fractions evaluated. Methanol extract was the most prominent in case of FRAP (141.89 +/- 0.87 MUg AAE/g) whereas most effective reducing power observed in ethyl acetate fraction (133.6 +/- 0.2987 MUg AAE/g). The results also indicated a substantial alpha-glucosidase inhibitory activity for butanol fraction (72.16 +/- 1.0) % and ethyl acetate fraction (70.76 +/- 0.49) %. The statistical analysis revealed that total phenolic and total flavonoid content of the samples had the significant (p < 0.05) impact on DPPH free radical scavenging and alpha-glucosidase inhibitory activity. CONCLUSION: Current results proposed the therapeutic potential of Clinacanthus nutans, especially ethyl acetate and butanol fraction as chemotherapeutic agent against oxidative related cellular damages and control the postprandial hyperglycemia. The phytochemical investigation showed the existence of active constituents in Clinacanthus nutans extract and fractions. PMID- 28359332 TI - The quality of health services provided to remote dwelling aboriginal infants in the top end of northern Australia following health system changes: a qualitative analysis. AB - BACKGROUND: In Australia the health outcomes of remote dwelling Aboriginal infants are comparable to infants in developing countries. This research investigates service quality, from the clinicians' perspective and as observed and recorded by the researcher, in two large Aboriginal communities in the Top End of northern Australia following health system changes. METHODS: Data were collected from semi-structured interviews with 25 clinicians providing or managing child health services in the two study sites. Thirty hours of participant observation was undertaken in the 'baby-rooms' at the two remote health centres between June and December 2012. The interview and observational data, as well as field notes were integrated and analysed thematically to explore clinicians' perspectives of service delivery to infants in the remote health centres. RESULTS: A range of factors affecting the quality of care, mostly identified before health system changes were instigated, persisted. These factors included ineffective service delivery, inadequate staffing and culturally unsafe practices. The six themes identified in the data: 'very adhoc', 'swallowed by acute', 'going under', 'a flux', 'a huge barrier' and 'them and us' illustrate how these factors continue, and when combined portray a 'very chaotic system'. CONCLUSION: Service providers perceived service provision and quality to be inadequate, despite health system changes. Further work is urgently needed to improve the quality, cultural responsiveness and effectiveness of services to this population. PMID- 28359333 TI - The immune-regulating effect of Xiao'er Qixingcha in constipated mice induced by high-heat and high-protein diet. AB - BACKGROUND: Xiao'er Qixingcha (EXQ) has been extensively applied to relieve dyspepsia and constipation in children for hundreds of years in China. However, the therapeutic mechanism underlying its efficacy remained to be defined. The present study aimed to clarify the possible laxative and immune-regulating effects of EXQ on two models of experimental constipation in mice, which mimicked the pediatric constipation caused by high-heat and high-protein diet (HHPD). METHODS: The two models of constipated mice were induced by HHPD or HHPD + atropine respectively. To investigate the laxative and immune-regulating activities of EXQ, animals were treated with three doses of EXQ (0.75, 1.5 and 3 g/kg) for 7 consecutive days. The fecal output parameters (number and weight), weight of intestinal content and, the thymus and spleen indexes were measured. The levels of sIgA, IL-10, TNF-alpha and LPS in colon and serum were determined by ELISA. Furthermore, the pathological changes of colon tissue were examined after routine H&E staining. RESULTS: Both HHPD and HHPD + atropine treatments obviously inhibited the fecal output and reduced the colonic sIgA, prominently increased the levels of IL-10 and TNF-alpha in colonic tissue and elevated the contents of LPS in serum and colonic tissues. In contrast, oral administration of EXQ significantly improved the feces characters and dose-dependently decreased the intestinal changes in both models. In HHPD model test, EXQ efficaciously boosted the sIgA level in a dose-dependent manner, significantly elicited decreases in TNF-alpha and IL-10 levels, and evidently decreased the spleen and thymus indexes. In HHPD + atropine model test, EXQ treatment reversed the pathological changes by not only dramatically decreasing the spleen index and the levels of LPS and IL-10, but also markedly elevating the thymus index. Furthermore, microscopic observation revealed that EXQ treatment maintained the integrity of colonic mucosa, and protected the colonic tissues from inflammation in the both models. CONCLUSIONS: EXQ exhibited prominent laxative activity and effectively protected the colonic mucosal barrier in two models of constipated mice, of which the mechanism might be closely associated with its propulsive and immune-regulating properties. The current results not only validated the rationale for the clinical application of EXQ in pediatric constipation related symptoms, but also threw new light on the immune-inflammatory responses accompanied with chronic constipation pathology. PMID- 28359335 TI - Disease severity determines health-seeking behaviour amongst individuals with influenza-like illness in an internet-based cohort. AB - BACKGROUND: Seasonal influenza epidemics place considerable strain on health services. Robust systems of surveillance are therefore required to ensure preparedness. Sentinel surveillance does not accurately capture the community burden of epidemics as it misses cases that do not present to health services. In this study, Flusurvey (an internet-based community surveillance tool) was used to examine how severity of disease influences health-seeking behaviour in the UK. METHODS: Logistic regression with random effects was used to investigate the association between health-seeking and symptom severity, duration of illness and reduction in self-reported health-score over four flu seasons between 2011 and 2015. RESULTS: The majority of individuals did not seek care. In general, there was very strong evidence for an association between all severity indicators and visiting a health service (p < 0.0001). Being female (OR 1.62, 95% CI 1.23-2.14, p = 0.0003) and a self-diagnosis of the flu (OR 3.39, 95% CI 2.38-4.83, p < 0.0001) were also associated with increased likelihood of visiting a health service. During the 2012-13 and 2014-15 flu seasons, there was a significantly larger proportion of individuals with more severe sets of symptoms and a longer duration of illness. Despite this, the proportion of individuals with particular sets of symptoms visiting a health service showed only very slight variation across years. CONCLUSIONS: Traditional surveillance systems capture only the more severe episodes of illness. However, in spite of variation in flu activity, the proportion of individuals visiting a health service remains relatively stable within specific sets of symptoms across years. These data could be used in combination with data on consultation rates to provide better estimates of community burden. PMID- 28359334 TI - Cytokine cascades induced by mechanical trauma injury alter voltage-gated sodium channel activity in intact cortical neurons. AB - BACKGROUND: Traumatic brain injury (TBI) triggers both immediate (primary) and long-term (secondary) tissue damages. Secondary damages can last from hours to days or even a lifetime. Secondary damages implicate several mechanisms, including influence of inflammatory mediators, mainly cytokines, on excitability of ion channels. However, studies should further explore the effects of inflammatory cytokines on voltage-gated sodium channels (VGSCs) and excitability in distal intact neurons. METHODS: Mixed cultures of mouse cortical astrocytes and neurons were subjected to mechanical injury (trauma) to mimic TBI in vitro. Expression of various cytokines in these cultures were measured by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. A trauma conditioned medium with or without brain-derived neurotrophic factor (BDNF) was added to mouse primary cortical neurons for 6 and 24 h to mimic combined effects of multiple inflammatory cytokines on VGSCs. Spike behaviors of distal intact neurons were examined by whole-cell patch-clamp recordings. RESULTS: Mechanical injury in mixed cortical neuron-astrocyte cultures significantly increased expression levels of multiple cytokines, including interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, chemokine (C-C motif) ligand-5, IL-10, and transforming growth factor-beta1, at 6 and 24 h after injury. Incubation in trauma-conditioned medium increased functional VGSCs in neuronal membranes and Na+ currents. Enhanced VGSCs were almost completely abolished by BDNF, and reinforcement of Na+ currents was also reduced in a dose dependent manner. BDNF (30 ng/mL) also significantly reversed reduced neuronal cell viability, which was induced by medium conditioned at 6 h. At 6 and 24 h, trauma-conditioned medium significantly increased spike frequency but not spike threshold. CONCLUSIONS: In TBI, the combined effect of inflammatory cytokines is directly involved in VGSC, Na+ current, and excitability dysfunction in distal intact neurons. BDNF may partly exert neuroprotective effects by maintaining balance of VGSC function in distal intact neurons. PMID- 28359337 TI - Supply kits for antenatal and childbirth care during antenatal care and delivery: a mixed-methods systematic review, the qualitative approach. AB - Antenatal care reduces maternal and perinatal mortality and morbidity through the detection and treatment of some conditions, but its coverage is less than optimal within certain populations. Supply kits for maternal health were designed to overcome barriers present when providing care during pregnancy and childbirth particularly to women from underserved population.We conducted a mixed-methods systematic review on the use of supply kits. This manuscript presents the findings from qualitative studies that reported barriers, facilitators, and user's recommendation in the adoption and implementation of any type of kit designed to be used during pregnancy or childbirth.This review included eight studies, and seven were implemented in developing countries. Most studies assessed the implementation of clean delivery kits to be used during labour and delivery, and contributed to gain insights into factors that may hinder or foster the use of kits.Clean delivery kits were conceived to cope with barriers related mainly to access. The most important barrier identified were those related to the socio-cultural and the lack of knowledge dimension such as who held the decision making authority in the household, as well as popular beliefs behind the idea that birth preparation could bring bad luck, may prevent clients from adhering to their use. In addition, financial constraints and limited understanding of the instructions of use were accessibility barriers found. On the other hand, once used, clean delivery kits for maternal health were accepted by women and health workers. Convenience, hygienic components, and avoidance of delays in receiving care were viewed as satisfactory features.Supply kits are mostly affordable and easily deployable. Increasing awareness among the population about the offered kits and providing information on their benefits emerges as a critical step to foster use in settings where kits are available. Implementation of this strategy requires low complexity resources and could make the use of kits an accepted alternative to increase the use of evidence-based interventions and thus improve quality of care during pregnancy, childbirth and neonatal period mainly at the community level in low income countries and remote areas with low access. PMID- 28359336 TI - Effect of Electroacupuncture on the NTS is modulated primarily by acupuncture point selection and stimulation frequency in normal rats. AB - BACKGROUND: The effect of electroacupuncture (EA) is affected by both the acupuncture point selection and the frequency of stimulation. However, little is known regarding acupuncture point and simulation frequency selection. Neuronal activation of the nucleus of the solitary tract (NTS) is one of the important targets of EA for modulating gastrointestinal function. This study investigated the effects of various combinations of EA frequencies and acupuncture points on NTS neurons. METHODS: Rats were randomly divided into normal, 2 Hz EA, 100 Hz EA and the alternate 2/100 Hz EA groups. Then rats in each group were randomly divided into the following two subgroups according to the acupuncture point: ST 36 group and ST 25 group. All the rats underwent electrode implantation surgery. Rats in all EA groups received one treatment with EA (a constant square wave at, 2 Hz,100 Hz or 2/100 Hz frequencies with intensities ranging from 1 to 2 mA), and NTS neuronal activation was recorded before and after EA treatment. Finally, to confirm the effect of EA on the NTS, minimal acupuncture was administered and its effect on NTS was detected. RESULTS: ST 36 stimulated with 2 Hz EA significantly increased the population of excited NTS neurons and spike frequency. However, ST 36 stimulated with 100 Hz or 2/100 Hz EA produced only a transient effect on the activity of NTS neurons and did not induce any effect on the spike frequency. Furthermore, the excitatory effect of 100 Hz or 2/100 Hz EA on NTS neurons in the ST 36 group was lower than 2 Hz EA at the same point. When applied to ST 25, 2 Hz EA had no significant excitatory effect on NTS neurons or spike frequency. However, 100 Hz EA or 2/100 Hz EA at ST 25 decreased both NTS neuronal excitability and spike frequency. By comparing the effects of different EA combinations, it was shown 2 Hz EA applied to ST 36 had the strongest excitatory effect on NTS neurons, while 100 Hz EA applied to ST 25 had the greatest inhibitory effect. Minimal acupuncture stimulation produced no effect on NTS neurons. CONCLUSION: EA's effects on NTS were mainly affected by the acupuncture point selection, but the frequency of EA also played a role. Different combinations of acupuncture points and frequency selection may lead to different EA effects on NTS neuronal excitability. PMID- 28359338 TI - Development of the Good Health Research Practice course: ensuring quality across all health research in humans. AB - Quality and ethics need to be embedded into all areas of research with human participants. Good Clinical Practice (GCP) guidelines are international ethical and scientific quality standards for designing, conducting, recording and reporting trials involving human participants. Compliance with GCP is expected to provide public assurance that the rights, safety and wellbeing of participants are protected and that the clinical research data are credible. However, whilst GCP guidelines, particularly their principles, are recommended across all research types, it is difficult for non-clinical trial research to fit in with the exacting requirements of GCP. There is therefore a need for guidance that allows health researchers to adhere to the principles of GCP, which will improve the quality and ethical conduct of all research involving human participants. These concerns have led to the development of the Good Health Research Practice (GHRP) course. Its goal is to ensure that research is conducted to the highest possible standards, similar to the conduct of trials to GCP. The GHRP course provides training and guidance to ensure quality and ethical conduct across all health-related research. The GHRP course has been run so far on eight occasions. Feedback from delegates has been overwhelmingly positive, with most delegates stating that the course was useful in developing their research protocols and documents. Whilst most training in research starts with a guideline, GHRP has started with a course and the experience gained over running the courses will be used to write a standardised guideline for the conduct of health-related research outside the realm of clinical trials, so that researchers, funders and ethics committees do not try to fit non-trials into clinical trials standards. PMID- 28359339 TI - High dose statin prophylaxis in cardiopulmonary bypass related surgery: clinical utility. AB - BACKGROUND: Previous studies from our group demonstrated the anti-inflammatory properties of statins on cardiopulmonary bypass (CPB), through inhibition of neutrophil transendothelial migration. We sought to determine the utility of preoperative statin on patients undergoing cardiac surgery, to investigate any moderating effects on the systemic inflammatory response (SIRS) with CPB, and to evaluate any clinical impact on our patients. METHODS: This is a prospective, randomised controlled trial with national regulatory body approval. Eligible patients were already on oral statin therapy. They were then randomly assigned to either investigation arm (n = 15, atorvastatin 80 mg for 2 weeks before surgery) or control arm (n = 15, no change to current statin therapy). Blood and urine samples were collected at 3 timepoints. Postoperative clinical measures were documented. RESULTS: Patients in the investigation arm have significantly lower troponin level (p = 0.016), and lower level of urine neutrophil gelatinase associated lipocalin (NGAL; p = 0.002); thus demonstrating a lesser degree of cardiac and renal injury in these patients. Higher level of Interleukin-8 (IL-8) at baseline (p = 0.036) and 4 h post cross-clamp removal (p = 0.035) in the investiation arm. A similar trend is also observed in Matrix Metalloproteinase-9 (MMP-9; p > 0.05). There were however no differences in clinical outcomes. CONCLUSIONS: Maximizing the dose of statin in patients waiting for cardiac surgery has measurable biological effects. There is evidence of less cardiac and renal damage. The use of preoperative statins and in particular, high dose preoperative statin therapy, may prove a useful new tool for optimal preparation of patients for cardiac surgery. TRIAL REGISTRATION: EudraCT no. 2012-003396-20 . Registered 05 November 2012. PMID- 28359340 TI - World Malaria Report: time to acknowledge Plasmodium knowlesi malaria. AB - BACKGROUND: The 2016 World Health Organization (WHO) World Malaria Report documents substantial progress towards control and elimination of malaria. However, major challenges remain. In some regions of Southeast Asia, the simian parasite Plasmodium knowlesi has emerged as an important cause of human malaria, and the authors believe this species warrants regular inclusion in the World Malaria Report. MAIN TEXT: Plasmodium knowlesi is the most common cause of malaria in Malaysia, and cases have also been reported in nearly all countries of Southeast Asia. Outside of Malaysia, P. knowlesi is frequently misdiagnosed by microscopy as Plasmodium falciparum or Plasmodium vivax. Thus, P. knowlesi may be underdiagnosed in affected regions and its true incidence underestimated. Acknowledgement in the World Malaria Report of the regional importance of P. knowlesi will facilitate efforts to improve surveillance of this emerging parasite. Furthermore, increased recognition will likely lead to improved delivery of effective treatment for this potentially fatal infection, as has occurred in Malaysia where P. knowlesi case-fatality rates have fallen despite rising incidence. In a number of knowlesi-endemic countries, substantial progress has been made towards the elimination of P. vivax and P. falciparum. However, efforts to eliminate these human-only species should not preclude efforts to reduce human malaria from P. knowlesi. The regional importance of knowlesi malaria was recognized by the WHO with its recent Evidence Review Group meeting on knowlesi malaria to address strategies for prevention and mitigation. CONCLUSION: The WHO World Malaria Report has an appropriate focus on falciparum and vivax malaria, the major causes of global mortality and morbidity. However, the authors hope that in future years this important publication will also incorporate data on the progress and challenges in reducing knowlesi malaria in regions where transmission occurs. PMID- 28359341 TI - Monitoring of breathing motion in image-guided PBS proton therapy: comparative analysis of optical and electromagnetic technologies. AB - BACKGROUND: Motion monitoring is essential when treating non-static tumours with pencil beam scanned protons. 4D medical imaging typically relies on the detected body surface displacement, considered as a surrogate of the patient's anatomical changes, a concept similarly applied by most motion mitigation techniques. In this study, we investigate benefits and pitfalls of optical and electromagnetic tracking, key technologies for non-invasive surface motion monitoring, in the specific environment of image-guided, gantry-based proton therapy. METHODS: Polaris SPECTRA optical tracking system and the Aurora V3 electromagnetic tracking system from Northern Digital Inc. (NDI, Waterloo, CA) have been compared both technically, by measuring tracking errors and system latencies under laboratory conditions, and clinically, by assessing their practicalities and sensitivities when used with imaging devices and PBS treatment gantries. Additionally, we investigated the impact of using different surrogate signals, from different systems, on the reconstructed 4D CT images. RESULTS: Even though in controlled laboratory conditions both technologies allow for the localization of static fiducials with sub-millimetre jitter and low latency (31.6 +/- 1 msec worst case), significant dynamic and environmental distortions limit the potential of the electromagnetic approach in a clinical setting. The measurement error in case of close proximity to a CT scanner is up to 10.5 mm and precludes its use for the monitoring of respiratory motion during 4DCT acquisitions. Similarly, the motion of the treatment gantry distorts up to 22 mm the tracking result. CONCLUSIONS: Despite the line of sight requirement, the optical solution offers the best potential, being the most robust against environmental factors and providing the highest spatial accuracy. The significant difference in the temporal location of the reconstructed phase points is used to speculate on the need to apply the same monitoring system for imaging and treatment to ensure the consistency of detected phases. PMID- 28359343 TI - Socioeconomic Status and Non-Fatal Adult Injuries in Selected Atlanta (Georgia USA) Hospitals. AB - BACKGROUND: Injury mortality data for adults in the United States and other countries consistently show higher mortality for those with lower socioeconomic status (SES). Data are sparse regarding the role of SES among adult, non-fatal US injuries. The current study estimated non-fatal injury risk by household income using hospital emergency department (ED) visits. METHODS: A total of 1,308,892 ED visits at 10 Atlanta (Georgia USA) hospitals from 2001-2004 (347,866 injuries) were studied. The SES was based on US census-block group income, with subjects assigned to census blocks based on reported residence. Logistic regression was used to determine risk by SES for injuries versus all other ED visits, adjusting for demographics, hospital, and weather. Supplemental analyses using hospital data from 2010-2013, without data on SES, were conducted to determine whether earlier patterns by race, age, and gender persisted. RESULTS: Risk for many injury categories increased with higher income. Odds ratio by quartiles of increasing income (lowest quartile as referent, 95% confidence interval [CI] given for upper most quartile) were 1.00, 1.23, 1.34, 1.40 (95% CI 1.36-1.45) for motor vehicle accidents; 1.00, 1.03, 1.11, 1.24 (95% CI 1.20-1.29) for being struck by objects; 1.00. 0.99, 1.04, 1.12 (95% CI 1.00-1.25) for suicide; and 1.00, 1.03, 1.05, 1.12 (95% CI 1.09-1.15) for falls. In contrast, decreased injury risk with increased household income was seen for assaults (1.00, 0.83, 0.73, 0.67 [95% CI 0.63-0.72], by increasing quartiles). These trends by income did not differ markedly by race and gender. Whites generally had less risk of injuries, with the exception of assaults and motor vehicle accidents. Males had higher risk of injury than females, with the exception of falls and suicide attempts. Patterns of risk for race, age, and gender were consistent between 2001 2004 and 2010-2013. CONCLUSION: For most non-fatal injuries, those with higher income had more risk of ED visits, although the opposite was true for assault. Hulland E , Chowdhury R , Sarnat S , Chang HH , Steenland K . Socioeconomic status and non-fatal adult injuries in selected Atlanta (Georgia USA) hospitals. Prehosp Disaster Med. 2017;32(4):403-413. PMID- 28359342 TI - Measuring the impact of ambulatory red blood cell transfusion on home functional status: study protocol for a pilot randomized controlled trial. AB - BACKGROUND: Red blood cell (RBC) transfusion is frequently employed in both ambulatory and hospital environments with the aim of improving patient functional status. In the ambulatory setting, this practice is particularly common in patients with malignancy due to anemia associated with their cancer therapy. Increasingly, the efficacy of this US$10.5 billion per year practice has been called into question. While it is often standard of care for patients with chemotherapy-induced anemia to receive ambulatory RBC transfusions, it is unclear to what extent such transfusions affect home functional status. It is also unclear whether or not changes in functional status in this population can be objectively quantified using wearable activity monitors. We propose to directly measure the impact of outpatient RBC transfusions on at-home functional status by recording several physiological parameters and quantifiable physical activity metrics, e.g., daily energy expenditure and daily total step count, using the ActiGraph wGT3X-BT. This device is an accelerometer-based wearable activity monitor similar in size to a small watch and is worn at the waist. Study participants will wear the device during the course of their daily activities giving us quantifiable insight into activity levels in the home environment. METHODS/DESIGN: This will be a randomized crossover pilot clinical trial with a participant study duration of 28 days. The crossover nature allows each patient to serve as their own control. Briefly, patients presenting at a tertiary medical center's Ambulatory Infusion Center (AIC) will be randomized to either: (1) receive an RBC transfusion as scheduled (transfusion) or (2) abstain from the scheduled transfusion (no transfusion). After an appropriate washout period, participants will crossover from the transfusion arm to the no-transfusion arm or vice versa. Activity levels will be recorded continuously throughout the study using an accelerometry monitor. In addition to device data, functional status and health outcomes will be collected via a weekly telephone interview. The primary outcome measure will be daily energy expenditure. Performance metrics, such as step count changes, will also be evaluated. Additional secondary outcome measures will include daily sedentary time and Patient-reported Outcomes Measurement Information System (PROMIS) Global 10 Survey scores. DISCUSSION: This trial will provide important information on the feasibility and utility of using accelerometry monitors to directly assess the impact of RBC transfusion on patients' functional status. The results of the study will inform the merit and methods of a more definitive future trial evaluating the impact of ambulatory RBC transfusions in the target population. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02835937 . Registered on 15 July 2016. PMID- 28359345 TI - The risk of use small matrices to measure specialization in host-parasite interaction networks: a comment to Rivera-Garcia et al. (2016). AB - In the last years, there were a growing number of studies using the metric H 2' to calculate complementary specialization in host-parasite interaction networks. However, only a few studies have explored the sensitivity of H 2' to network dimensions (i.e. species richness and number of interactions), which consequently could generate studies that are not comparable among them or lead to biased conclusions. In this study, we used the recent published study conducted by Rivera-Garcia et al. in 2016 involving host-bat fly networks as an example to call attention to the risk of using H 2' to calculate specialization for small matrices. After conducting analyses based on both empirical and simulated data, we show that H 2' values are strongly affected by randomly allocation of species interactions to another cell in the matrix for small networks and that therefore the results and conclusions presented in Rivera-Garcia et al. in 2016 are only an artefact of the dataset used. Therefore, we fully recommended taking into account the careful use of small networks to measuring specialization in host-parasite interactions. PMID- 28359344 TI - The retina visual cycle is driven by cis retinol oxidation in the outer segments of cones. AB - Vertebrate rod and cone photoreceptors require continuous supply of chromophore for regenerating their visual pigments after photoactivation. Cones, which mediate our daytime vision, demand a particularly rapid supply of 11-cis retinal chromophore in order to maintain their function in bright light. An important contribution to this process is thought to be the chromophore precursor 11-cis retinol, which is supplied to cones from Muller cells in the retina and subsequently oxidized to 11-cis retinal as part of the retina visual cycle. However, the molecular identity of the cis retinol oxidase in cones remains unclear. Here, as a first step in characterizing this enzymatic reaction, we sought to determine the subcellular localization of this activity in salamander red cones. We found that the onset of dark adaptation of isolated salamander red cones was substantially faster when exposing directly their outer vs. their inner segment to 9-cis retinol, an analogue of 11-cis retinol. In contrast, this difference was not observed when treating the outer vs. inner segment with 9-cis retinal, a chromophore analogue which can directly support pigment regeneration. These results suggest, surprisingly, that the cis-retinol oxidation occurs in the outer segments of cone photoreceptors. Confirming this notion, pigment regeneration with exogenously added 9-cis retinol was directly observed in the truncated outer segments of cones, but not in rods. We conclude that the enzymatic machinery required for the oxidation of recycled cis retinol as part of the retina visual cycle is present in the outer segments of cones. PMID- 28359346 TI - Deletion of p75NTR enhances the cholinergic innervation pattern of the visual cortex. AB - The cholinergic system is involved in cortical plasticity, attention, and learning. Within the visual cortex the cholinergic system seems to play a role in visual perception. The cholinergic neurons which project into the visual cortex are located in the basal forebrain. It has been shown that mice deficient for the low-affinity neurotrophin receptor p75NTR display increased numbers of cholinergic neurons in the basal forebrain and a denser cholinergic innervation of the hippocampus. This prompted us to analyze whether the cholinergic system is altered in adult p75NTR deficient mice. By analyzing the densities of cholinergic fibers within layer IV as well as within layer V of the visual cortex, we found that adult p75NTR deficient mice display increased cholinergic fiber densities. However, this increase was not accompanied by an increase in the density of local cholinergic neurons within the visual cortex. This indicates that the enhanced cholinergic innervation of the visual cortex is due to alteration of the cholinergic neurons located in the basal forebrain, projecting to the visual cortex. The increased cholinergic innervation of the visual cortex makes the p75NTR deficient mice an attractive model to study the necessity of the cholinergic system for the visual cortex. PMID- 28359347 TI - Characteristics of Muller glial cells in MNU-induced retinal degeneration. AB - Retinal Muller glial cells have been shown to undergo reactive gliosis in a variety of retinal diseases. Upregulation of glial fibrillary acidic protein (GFAP) is a hallmark of Muller cell activation. Reactive gliosis after retinal detachment or ischemia/reperfusion is characterized by hypertrophy and downregulation of inwardly rectifying K+ (Kir) currents. However, this kind of physiological alteration could not be detected in slowly progressing retinal degenerations. The photoreceptor toxin N-methyl-N-nitrosourea (MNU) leads to the rapid loss of cells in the outer nuclear layer and subsequent Muller cell activation. Here, we investigated whether Muller cells from MNU-treated mice exhibit reactive gliosis. We found that Muller cells showed increased GFAP expression and increased membrane capacitance, indicating hypertrophy. Membrane potential and Kir channel-mediated K+ currents were not significantly altered whereas Kir4.1 mRNA expression and Kir-mediated inward current densities were markedly decreased. This suggests that MNU-induced Muller cell gliosis is characterized by plasma membrane increase without alteration in the membrane content of Kir channels. Taken together, our findings show that Muller cells of MNU-treated mice are reactive and respond with a form of gliosis which is characterized by cellular hypertrophy but no changes in Kir current amplitudes. PMID- 28359348 TI - Eye movement patterns and visual attention during scene viewing in 3- to 12-month olds. AB - Recently, two attentional modes have been associated with specific eye movement patterns during scene processing. Ambient mode, characterized by short fixations and long saccades during early scene inspection, is associated with localization of objects. Focal mode, characterized by longer fixations, is associated with more detailed object feature processing during later inspection phase. The aim of the present study was to investigate the development of these attentional modes. More specifically, we examined whether indications of ambient and focal attention modes are similar in infants and adults. Therefore, we measured eye movements in 3- to 12-months-old infants while exploring visual scenes. Our results show that both adults and 12-month-olds had shorter fixation durations within the first 1.5 s of scene viewing compared with later time phases (>2.5 s); indicating that there was a transition from ambient to focal processing during image inspection. In younger infants, fixation durations between two viewing phases did not differ. Our results suggest that at the end of the first year of life, infants have developed an adult-like scene viewing behavior. The evidence for the existence of distinct attentional processing mechanisms during early infancy furthermore underlines the importance of the concept of the two modes. PMID- 28359349 TI - A tale of two neurotransmitters. AB - Amacrine cells are a diverse set of local circuit neurons of the inner retina, and they all release either GABA or glycine, amino acid neurotransmitters that are generally inhibitory. But some types of amacrine cells have another function besides inhibiting other neurons. One glycinergic amacrine cell, the Aii type, excites a subset of bipolar cells via extensive gap junctions while inhibiting others at chemical synapses. Many types of GABAergic amacrine cells also release monoamines, acetylcholine, or neuropeptides. There is now good evidence that another type of amacrine cell releases glycine at some of its synapses and releases the excitatory amino acid glutamate at others. The glutamatergic synapses are made onto a subset of retinal ganglion cells and amacrine cells and have the asymmetric postsynaptic densities characteristic of central excitatory synapses. The glycinergic synapses are made onto other types of ganglion cells and have the symmetric postsynaptic densities characteristic of central inhibitory synapses. These amacrine cells, which contain vesicular glutamate transporter 3, will be the focus of this brief review. PMID- 28359350 TI - Dissociating early and late visual processing via the Ebbinghaus illusion. AB - Visual perception is not instantaneous; the perceptual representation of our environment builds up over time. This can strongly affect our responses to visual stimuli. Here, we study the temporal dynamics of visual processing by analyzing the time course of priming effects induced by the well-known Ebbinghaus illusion. In slower responses, Ebbinghaus primes produce effects in accordance with their perceptual appearance. However, in fast responses, these effects are reversed. We argue that this dissociation originates from the difference between early feedforward-mediated gist of the scene processing and later feedback-mediated more elaborate processing. Indeed, our findings are well explained by the differences between low-frequency representations mediated by the fast magnocellular pathway and high-frequency representations mediated by the slower parvocellular pathway. Our results demonstrate the potentially dramatic effect of response speed on the perception of visual illusions specifically and on our actions in response to objects in our visual environment generally. PMID- 28359352 TI - Collective and negotiated design for a clinical trial addressing smoking cessation supports for Aboriginal and Torres Strait Islander mothers in NSW, SA and Qld - developing a pilot study. AB - Tobacco smoking leads to one in five deaths of Aboriginal Australians and accounts for 17% of the reversible health gap. One in two Aboriginal women are reported to smoke during pregnancy, with no effective strategies currently available for health practitioners to utilise for supporting Aboriginal women. Aboriginal community participation in primary health research is crucial to implementing ethical research, with a clear benefit to the people and communities involved. However, currently there is little evidence on how Aboriginal programs and interventions are being developed in partnership with Aboriginal people and communities. 'Indigenous Counselling and Nicotine (ICAN) QUIT in Pregnancy' aims to address the prevalence of smoking during pregnancy by enhancing health providers' training in offering evidence-based smoking cessation care to Aboriginal mothers during pregnancy. This paper outlines the participatory research approach adopted for the developmental phase of the 'ICAN QUIT in Pregnancy' project developed in partnership with two Aboriginal Community Controlled Health Services in NSW, and negotiation processes undertaken to implement a pilot intervention across NSW, SA and Qld. PMID- 28359351 TI - Differential gene expression of BMP2 and BMP receptors in chick retina & choroid induced by imposed optical defocus. AB - Recent studies have demonstrated the defocus sign-dependent, bidirectional gene expression regulation of bone morphogenetic proteins, BMP2, 4 and 7 in chick RPE. In this study, we examined the effects of imposed positive (+10 D) and negative ( 10 D) lenses on the gene expression of these BMPs and BMP receptors (BMPR1A, BMPR1B, BMPR2) in chick retina and choroid after monocular lens treatment for 2 or 48 h, as indicators of the roles of retinal and choroidal BMPs and receptors in postnatal eye growth regulation. In retina, although all genes were expressed, neither +10 nor -10 D lenses, worn for either 2 or 48 h, significantly altered gene expression. In contrast, treatment-related differential gene expression was detected in the choroid for both BMPs and their receptors, although interestingly, with the +10 D lens, BMP2 was up-regulated by 156.7 +/- 19.7% after 2 h, while BMPR1A was down-regulated to 82.3 +/- 12.5% only after 48 h. With the -10 D lens, only the gene expression of BMPR1B was significantly altered, being up-regulated by 162.3 +/- 21.2% after 48 h. Untreated birds showed no difference in expression between their two eyes, for any of the genes examined. The finding that retinal gene expression for BMP2, 4, 7 and their receptors are not affected by short-term optical defocus contrasts with previous observations of sign-dependent expression changes for the same genes in the RPE. The latter changes were also larger and more consistent in direction than the choroidal gene expression changes reported here. The interrelationship between these various changes and their biological significance for eye growth regulation are yet to be elucidated. PMID- 28359353 TI - Guitar-String Suture to Facilitate Closure of a Finger-like Flap for Reconstruction of the Nose. AB - INTRODUCTION: The basic principle of a lobed or finger-like transposition flap is that, after covering the defect with the transposed tissue, the donor site is closed primarily. With large defects, a second lobe may be added to the flap if primary closure of the area left by the first lobe is not possible. The flap can often be made to adapt to the defect, but this maneuver, in combination with primary closure of the adjacent tissue, can sometimes produce excessive tension and compromise the blood supply. MATERIAL AND METHODS: We present a series of 4 patients with epithelial tumors of the lateral wall of the nose. The defects left by surgical excision were covered by finger-like transposition flaps. Subcutaneous sutures called guitar-string sutures were used to reduce the size of the defect and facilitate tension-free closure. CONCLUSIONS: We propose use of the guitar-string subcutaneous suture in those cases in which the defect is larger than the area that can be covered by the flap. This will make it easier to adapt the flap to the defect and will reduce the risk of excessive tension causing necrosis of the transposed tissue. PMID- 28359354 TI - Supplementation with concentrated milk protein in patients undergoing hematopoietic stem cell transplantation. AB - OBJECTIVE: The aim of this study was to analyze the influence of dietary supplementation with whey protein concentrate (WPC) in the incidence of oral mucositis (OM) in patients undergoing hematopoietic stem cell transplantation (HSCT). METHODS: Patients were supplemented with a daily intake of WPC delivering 50% of the daily protein requirements (DPR) according to the Dietary Reference Intakes and classified later based on the amount of ingested supplement until OM median onset. RESULTS: We evaluated 73 patients. Forty-three were part of the historical control and 30 were supplemented with WPC. The OM had a mean duration of 5.3 d (SD 4.5), ranging from the day of the infusion of stem cells until the 17th day after infusion and a median of 5 d after infusion. OM duration was influenced by the conditioning protocol (P < 0.01) and WPC (P = 0.01). Patients who consumed the WPC in an amount >=40% of DPR had a 35% reduction in duration of OM, and the incidence of OM grades 3 and 4 was 11 times smaller. Body mass index, serum albumin, and adverse reactions, such as diarrhea, nausea and vomiting, dysphagia, dry mouth and drooling, showed no statistically significant differences. CONCLUSION: WPC intake >=40% of DPR helped to reduce the severity and duration of OM. The use of WPC in patients undergoing HSCT was shown to be safe, encouraging new studies in this population to assess its action mechanism. PMID- 28359356 TI - Nutritional approach to preterm infants on noninvasive ventilation: An update. AB - Nutrition and pulmonary function in very-low-birth-weight infants (VLBWIs) are strictly related. Preterm infants on noninvasive ventilation may have respiratory instability that can interfere with feeding tolerance. Moreover, feeding may impair pulmonary function. These infants have nutritional requirements different from nonventilated infants. The main challenge of the nutritional support in such patients is to guarantee adequate caloric intake while avoiding episodes of feeding intolerance. The aim of this study was to review the issues and strategies of enteral feeding of preterm infants on noninvasive ventilation. PMID- 28359355 TI - Is the presence of a validated malnutrition screening tool associated with better nutritional care in hospitalized patients? AB - OBJECTIVE: The aims of this study were to evaluate the association between the use of clinical guidelines and the use of validated screening tools, evaluate the nutritional screening policy in hospitals, and examine the association between the use of validated screening tools and the prevalence of malnutrition and nutritional interventions in hospitalized patients. METHODS: This was a cross sectional, multicenter study. Data were collected using a standardized questionnaire on three levels: institution (presence of a guideline for malnutrition), department (use of a validated screening tool), and patient (e.g., malnutrition prevalence). RESULTS: In all, 53 hospitals with 5255 patients participated. About 45% of the hospitals indicated that they have guidelines for malnutrition. Of the departments surveyed, 38.6% used validated screening tools as part of a standard procedure. The nutritional status of 74.5% of the patients was screened during admission, mostly on the basis of clinical observation and patient weight. A validated screening tool was used for 21.2% of the patients. Significant differences between wards with and without validated screening tools were found with regard to malnutrition prevalence (P = 0.002) and the following interventions: referral to a dietitian (P < 0.001), provision of energy-enriched snacks (P = 0.038), adjustment of consistency (food/drinks; P = 0.004), monitoring of the nutritional intake (P = 0.001), and adjustment of the meal ambiance (P < 0.001). CONCLUSION: Nutritional screening with validated tools in hospitalized patients remains poor. Generally, the nutritional status of patients is screened with unreliable parameters such as clinical observation and body mass index. The results of the present study suggest that the use of validated malnutrition screening tools is associated with better nutritional care and lower malnutrition prevalence rates in hospitalized patients. PMID- 28359357 TI - HMGB1 as a new biomarker of celiac disease in children: A multicenter study. AB - OBJECTIVE: Despite the availability of specific sierology and point-of-care tests, the phenotypic heterogeneity and the symptoms fluctuation as well as the "open-window" existing among the late and silent forms cause often a delayed celiac disease (CD) diagnosis. Recently, it has been reported that high mobility group box 1 (HMGB1) mediates inflammation and gastrointestinal barrier failure. The aim of this study was to detect serum HMGB1 levels at CD diagnosis and to evaluate the relationship between serum HMGB1 levels and clinical and histologic phenotypes. METHODS: 49 CD children and 44 healthy children were enrolled. Specific antitissue transglutaminase type 2, antideaminated form of gliadin antibodies, serum HMGB1 levels, and typical histopathological changes in duodenal mucosa were performed in all patients. Mucosal lesions were classified according to Marsh classification. In relation to clinical presentation, we classified patients into: typical, atypical and silent forms. RESULTS: Serum HMGB1 levels were significantly higher in those with CD than those in the healthy control group (P < 0.001). Significant differences in serum HMGB1 levels were detected in children with typical CD form compared to both children with atypical CD form (P < 0.001) and children with silent CD form (P < 0.001). By using the Marsh classification, significant differences were found between subjects with grade 3 B-B1 and 3 C-B2 and villous atrophy, respectively (P < 0.05). On the contrary, no significant differences in serum HMGB1 levels in subgroups of children with grade 3 A compared to grade 3 B-B1 were detected. CONCLUSIONS: HMGB1 is upregulated at diagnosis in all CD children, especially in typical form, and reflecting the histologic severity of disease. PMID- 28359358 TI - Rice bran enzymatic extract reduces atherosclerotic plaque development and steatosis in high-fat fed ApoE-/- mice. AB - OBJECTIVE: Rice bran is a by-product of rice milling and is rich in bioactive molecules such as gamma-oryzanol, phytosterols, and tocotrienols. The rice bran enzymatic extract (RBEE) previously showed vessel remodeling prevention and lipid lowering, antioxidant, anti-inflammatory, and antiapoptotic activities. The aim of this study was to identify RBEE hypolipidemic mechanisms and to study the effects of RBEE on the progression of atherosclerosis disease and linked vascular dysfunction and liver steatosis in apolipoprotein E-knockout (ApoE-/-) mice fed low- or high-fat (LFD, HFD, respectively) and cholesterol diets. METHODS: ApoE-/- mice were fed LFD (13% kcal) or HFD (42% kcal) supplemented or not supplemented with 1 or 5% RBEE (w/w) for 23 wk. Then, serum, aorta, liver, and feces were collected and flash frozen for further analysis. RESULTS: RBEE supplementation of HFD improved serum values by augmenting high-density lipoprotein cholesterol and preventing total cholesterol and aspartate aminotransferase increase. 3-hydroxy-3 methylglutaryl-coenzyme A (HMG-CoA) reductase activity was attenuated (1 and 5% RBEE) and cholesterol excretion increased (5% RBEE). Diet supplementation with 5% RBEE reduced plaque development regardless of the diet. In HFD-fed mice, both doses of RBEE reduced lipid deposition and macrophage infiltration in the aortic sinus and downregulated intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression. None of these effects was observed in mice fed LFD. Liver steatosis was reduced by RBEE supplementation of LFD (1% RBEE) and HFD (1 and 5% RBEE) and nuclear peroxisome proliferator-activated receptor-alpha expression upregulated in the HDF 5% RBEE group. CONCLUSION: Regular consumption of RBEE-supplemented HFD reduced plaque development and liver steatosis by decreasing inflammation and hyperlipidemia through an HMG-CoA reductase activity and lipid excretion-related mechanism. PMID- 28359359 TI - Association between polyunsaturated fatty acids and inflammatory markers in patients in secondary prevention of cardiovascular disease. AB - OBJECTIVE: The aim of this study was to assess the association between polyunsaturated fatty acids (PUFAs) and inflammatory biomarkers among patients in secondary prevention of cardiovascular disease (CVD). METHODS: In this cross sectional substudy from BALANCE Program Trial, we have collected data from 364 patients with established CVD. Twenty-four-hour dietary recalls and plasma FA concentrations were analyzed to estimate the FA intake. Inflammatory biomarkers measurement consisted of interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12, C reactive protein, adiponectin, and tumor necrosis factor-alpha. After log transformation of inflammatory biomarkers, multivariate-adjusted general linear model was used to examine the effect of FA intake. The association was adjusted for body mass index, waist circumference, energy, smoking status, age, total cholesterol, low-density lipoprotein cholesterol, physical activity, and calcium channel blockers. RESULTS: PUFAs were inversely associated with C-reactive protein levels (P = 0.006) and with IL-1 beta. The increase of 1 g/1000 kcal in PUFAs, omega-3, and omega-6 reduces, on average, 6%, 48%, and 8% respectively, the mean concentration of IL-1 beta. CONCLUSION: Omega-3 and omega-6 FA intakes are inversely associated with inflammatory biomarkers among CVD patients. Additional studies on omega-3 and omega-6 intake in relation to inflammatory biomarkers in patients in secondary prevention of CVD are needed, particularly regarding dietary patterns that are rich in some sources of PUFA. PMID- 28359360 TI - Postprandial changes in glucose oxidation and insulin sensitivity in metabolic syndrome: Influence of fibroblast growth factor 21 and vitamin D status. AB - OBJECTIVE: Metabolic inflexibility due to insulin resistance has been reported in metabolic syndrome (MetS). Fibroblast growth factor 21 (FGF21) and vitamin D status may improve insulin sensitivity. The aim of this study was to investigate glucose-induced thermogenesis and oxidation in MetS, and to examine whether changes in FGF21 or prevailing vitamin D status modulated defined metabolic parameters. METHODS: Forty-eight overweight and obese older adults (14 men, 34 women; ages 51 +/- 15 y) were studied. Resting metabolic rate (RMR) and respiratory quotient (RQ) were measured before and intermittently for 2 h after an oral glucose tolerance test (OGTT). The total area under the curve (TAUC) was calculated. Insulin sensitivity index (ISI) was determined as 104/(insulin * glucose) for fasting and 2 h venous blood. Fat mass (FM) and fat free mass (FFM) were measured by dual-energy x-ray absorptiometry. Participants were grouped by metabolic syndrome (MetS+ for disease presence; MetS- when no disease was present) and by median 25 hydroxyvitamin D (OHD) concentration as VD_low and VD_high. 25 OHD was also tested as a continuous variable. A parsimonious 2 * 2 analysis of variance included age, FM, FFM and MetS * sex interaction. RESULTS: Adjusted RMR was similar between groups but an interactive effect of MetS and sex was noted. Fasting RQ was significantly different between vitamin groups (VD_low: 0.835 +/- 0.008 versus VD_high: 0.810 +/- 0.008; P = 0.024) and fasting ISI was significantly greater in MetS- compared with MetS+ (P = 0.037). Postglucose increases in thermogenesis, RQ, and FGF21 were significant, but ISI decreased. Adjusted postprandial TAUC_RQ (VD_low: 1.71 +/- 0.01; VD_high: 1.74 +/- 0.001; P = 0.041) and ISI_2 h (VD_low: 35.41 +/- 0.21; VD_high: 101.90 +/- 0.21; P = 0.001) were significantly different. Adjusted FGF21 was similar across all comparisons before and after OGTT. CONCLUSIONS: Higher vitamin D status, but not FGF21, was associated with greater postprandial glucose oxidation and improved insulin sensitivity. PMID- 28359361 TI - Association between serum zinc and later development of metabolic syndrome in middle aged and older men: The Kuopio Ischaemic Heart Disease Risk Factor Study. AB - OBJECTIVE: The aim of this study was to investigate associations of serum zinc with incident metabolic syndrome and its components in middle-aged and older Finnish men. METHODS: An 11-y prospective follow-up study conducted among 683 men from the Kuopio Ischaemic Heart Disease Risk Factor Study who were 42 to 60 y old at baseline in 1984 to 1989. The main outcome was incident metabolic syndrome, defined by the National Cholesterol Education Program (NCEP) criteria. Other outcomes were the individual components of the NCEP metabolic syndrome: Fasting blood glucose, serum triacylglycerols, serum high-density lipoprotein (HDL) cholesterol, hypertension, and waist circumference. RESULTS: During the average follow-up of 11 y, 139 men (20.4%) developed metabolic syndrome. Those in the highest tertile of serum zinc had 84% higher risk (95% confidence interval 12 to 201%, P trend across tertiles = 0.015) to develop metabolic syndrome compared with those in the lowest tertile, after adjustment for several potential confounders. The association between serum zinc and incident metabolic syndrome was attenuated by adjustment for waist circumference, serum HDL cholesterol, or hypertension. Serum zinc was also directly associated with higher waist circumference and hypertension and inversely associated with HDL cholesterol at the 11 y examinations. CONCLUSIONS: We found a direct association between serum zinc and incidence of metabolic syndrome in middle-aged and older eastern Finnish men. Further studies are warranted to explore the mechanisms. PMID- 28359362 TI - Real-time image-guided nasogastric feeding tube placement: A case series using Kangaroo with IRIS Technology in an ICU. AB - OBJECTIVE: Pulmonary misplacement during the blind insertion of enteral feeding tubes is frequent, particularly in ventilated and neurologically impaired patients. This is probably the first clinical study using the Kangaroo Feeding Tube with IRIS technology (IRIS) which incorporates a camera designed to provide anatomic landmark visualization during insertion. The study aim was to evaluate IRIS performance during bedside gastric placement. METHODS: This is the first prospective study to collect data on the use of IRIS. Twenty consecutive unconscious patients requiring enteral nutrition were recruited at a single center. IRIS placement was considered complete when a clear image of the gastric mucosa appeared. Correct placement was confirmed using a contrast-enhanced abdominal X-ray. To evaluate the device performance over time, the camera was activated every other day up to 17 d postplacement. RESULTS: In 7 (35%) patients, the trachea was initially visualized, requiring a second placement attempt with the same tube. The IRIS camera allowed recognition of the gastric mucosa in 18 (90%) patients. The esophagogastric junction was identified in one patient, while in a second patient the quality of visualization was poor. Contrast-enhanced X ray confirmed the gastric placement of IRIS in all patients. IRIS allowed identification of gastric mucosa in 14 (70%) patients 3 d after placement. Performance progressively declined with time (P = 0.006, chi-square for trend). CONCLUSION: IRIS placement could have spared X-ray confirmation in almost all patients and prevented misplacement into the airway in about one third. Visualization quality needs to be improved, particularly after the first week. PMID- 28359363 TI - Impact of nutrition support on clinical outcome and cost-effectiveness analysis in patients at nutritional risk: A prospective cohort study with propensity score matching. AB - OBJECTIVES: There is a lack of evidence regarding the economic effects of nutrition support in patients at nutritional risk. The aim of this study was to perform a cost-effectiveness analysis by comparing an adequate nutrition support cohort with a no-support cohort. METHOD: A prospective observational study was performed in the surgical and medical gastroenterology wards. We identified patients at nutritional risk and the provision of nutrition support by the staff, unaware of the risk status, was recorded. Cost data were obtained from each patient's statement of accounts, and effectiveness was measured by the rate of infectious complication. To control for potential confounding variables, the propensity score method with matching was carried out. The incremental cost effectiveness ratio was calculated based on the matched population. RESULTS: We screened 3791 patients, and 440 were recruited for the analysis. Patients in the nutrition support cohort had a lower incidence of infectious complications than those in the no-support cohort (9.1 versus 18.1%; P = 0.007). This result was similar in the 149 propensity matched pairs (9.4 versus 24.2%; P < 0.001). The median hospital length of stay was significantly reduced among the matched nutrition support patients (13 versus 15 d; P < 0.001). The total costs were similar among the matched pairs (US $6219 versus $6161). The incremental cost effectiveness analysis suggested that nutrition support cost US $392 per patient prevented from having infectious complications. CONCLUSION: Nutrition support was associated with fewer infectious complications and shorter length of stay in patients at nutritional risk. The incremental cost-effectiveness ratio indicated that nutrition support had not increased costs significantly. PMID- 28359364 TI - Age-dependent risk factors for malnutrition in traumatology and orthopedic patients. AB - OBJECTIVE: The aim of this study was to investigate the prevalence of risk of malnutrition (RoM) in an orthopedic and traumatology patient cohort with a broad range of ages. In addition to the classical indicators for risk assessment (low body mass index, weight loss, and comorbidity), this study aimed to analyze the effects of lifestyle factors (eating pattern, smoking, physical activity) on RoM. METHODS: The prospective cohort study included 1053 patients in a level 1 trauma center in Germany. RoM was assessed by Nutritional Risk Screening (NRS) 2002 and for the elderly additionally by Mini Nutritional Assessment (MNA). Age-dependent risk factors identified in univariate statistical analysis were used for multivariate logistic regression models. RESULTS: The prevalence of patients at RoM (NRS >=3) was 22%. In the three age categories (<50 y, 50-69 y, and >=70 y), loss of appetite, weight loss, number of comorbidities, drugs and gastrointestinal symptoms significantly increased RoM in univariate statistical analysis. In patients ages >=70 y, several disease- and lifestyle-related factors (not living at home, less frequent consumption of vegetables and whole meal bread, low physical activity, and smoking) were associated with RoM. Multivariate logistic regression model for the total study population identified weight loss (odds ratio [OR], 6.09; 95% confidence interval [CI], 4.14-8.83), loss of appetite (OR, 3.81; 95% CI, 2.52-5.78), age-specific low BMI (OR, 1.87; 95% CI, 1.18-2.97), number of drugs taken (OR, 1.19; 95% CI, 1.12-1.26), age (OR, 1.03; 95% CI, 1.02-1.04), and days per week with vegetable consumption (OR, 0.938; 95% CI, 0.89-0.99) as risk factors. CONCLUSION: Malnutrition in trauma and orthopedic patients is not only a problem related to age. Lifestyle-related factors also contribute significantly to malnutrition in geriatric patients. PMID- 28359365 TI - Soy isoflavone supplementation improves longitudinal bone growth and bone quality in growing female rats. AB - OBJECTIVES: The aim of this study was to investigate the effects of soy isoflavone on tibia length, bone mineral density (BMD), and structural parameters in growing female rats. METHODS: Three-week-old female Sprague-Dawley rats were randomly assigned to four experimental groups: control (CON: distilled water gavage); low-dose isoflavone (low-IF: 10 mg/kg body weight [BW]/d gavage); high dose isoflavone (high-IF: 50 mg/kg BW/d gavage); and 17 beta-estradiol (E2: subcutaneous injection of 10 MUg). All animals received a soy-free diet and vaginal opening was monitored daily. After an 8-wk treatment period, bone-related parameters (alkaline phosphatase [ALP], osteocalcin [OC], N-terminal telopeptide [NTx], bone length, failure load, stiffness, BMD, and structural parameters) were analyzed. RESULTS: Serum ALP levels of the high-IF group were higher than those of the CON group (P < 0.05); however, serum OC levels of the high-IF group were lower than those of the CON, low-IF, and E2 groups (P < 0.05). The tibias and femurs of the low-IF group were longer than those of the CON and high-IF groups (P < 0.05). Bone volume, trabecular number, and BMD of trabecular bone of the high-IF and E2 groups were higher than those of the CON and low-IF groups (P < 0.05). The trabecular thickness of the high-IF group was higher than that of the CON and low-IF groups (P < 0.05). The failure load of the high-IF group was higher than those of the CON group (P < 0.05). Age and body weight at vaginal opening of the E2 group were significantly lower than those of the CON, low-IF, and high-IF groups (P < 0.05). CONCLUSIONS: This study suggests that 8 wk of low dose supplementation with soy isoflavone stimulates longitudinal bone growth. Additionally, high-dose supplementation with soy isoflavone may improve bone quality (BMD and structural parameters) in growing female rats. PMID- 28359366 TI - University students' on-campus food purchasing behaviors, preferences, and opinions on food availability. AB - OBJECTIVE: Emerging adulthood (18-24 y) where >50% of young adults attend tertiary education, is a transitional period that may provide an opportunity to influence future eating behaviors. The aim of this study was to identify possible strategies for encouraging healthy eating in university food environments. METHOD: Over 4 wk, students from a large university completed an anonymous researcher-designed survey with both closed (n = 41) and open-ended (n = 3) questions assessing food purchasing, food choice behaviors, and opinions of the campus food environment. Results were reported as proportions (%) or mean +/- SD. Chi-square analysis was used to determine differences between sex and campuses. The study took place at an Australian urban university with seven campuses. We recruited 653 currently enrolled students by convenience sampling. RESULTS: Respondents were mostly women (77%), aged <25 y (83%), and enrolled full time (96%). Almost all participants purchased food or beverages on campus (93%), with the most frequently purchased items being hot beverages and sandwiches. The greatest determinants of food choice were taste, value, convenience, and cost. Female students placed more importance on health-related factors and followed more special dietary behaviors than male students. The most common improvements suggested were lowering the cost and increasing the variety of food. CONCLUSION: As most students purchase food on campus, there are opportunities to intervene to improve diet quality. Our results indicate demand for healthy food and that price manipulation is an important lever for change. This information will be used for changing the local university food environment but may be useful for planning interventions at other universities. PMID- 28359367 TI - Nutritional regulation of coupling factor 6, a novel vasoactive and proatherogenic peptide. AB - High sodium, high glucose, and obesity are important risk factors for age-related diseases such as cardiovascular disease (CVDs), stroke, and cancer. Coupling factor 6 (CF6) is released from vascular endothelial cells and functions as a circulating peptide that inhibits prostacyclin and nitric oxide generation by intracellular acidosis. High glucose elevates CF6 by activation of protein kinase C and p38 mitogen-activated protein kinase, whereas CF6 causes type 2 diabetes mellitus, resulting in a high glucose vicious cycle. Low glucose increases inhibitory factor peptide 1, an endogenous inhibitor of CF6. High salt intake increases CF6 through nuclear factor kappaB signaling, whereas CF6 induces salt sensitive hypertension and salt-induced congestive heart failure. Oral administration of vitamin C cancels salt-induced increase in CF6, and estrogen replacement leads to the delayed onset of CF6-induced salt-sensitive hypertension and the rescue from cardiac systolic dysfunction. Because CF6 contributes to the onset of CVDs, nutritional regulation of CF6 will shed light on the understanding of preventive strategy and mechanisms for CVDs and a target for therapy. PMID- 28359368 TI - Egg consumption and heart health: A review. AB - Cardiovascular disease is the leading cause of death in the United States. Until recently, reducing dietary cholesterol has been a part of the American Heart Association (AHA) and American College of Cardiology (ACC) guidelines on lifestyle management, despite inconclusive evidence to support the recommendation. Considering eggs are a rich source of dietary cholesterol (typically containing 141-234 mg per egg), individuals with increased risk for CVD are advised not to consume eggs. Furthermore, based on the 2012 AHA/ACC guidelines, individuals with lower risk for CVD have previously been advised to avoid consuming eggs due to the high content of dietary cholesterol. Rather than strictly limiting cholesterol intake, the AHA and ACC guidelines now recommend dietary patterns that emphasize fruits, vegetables, whole grains, low-fat dairy products, poultry, fish, and nuts as an approach to favorably alter blood lipid levels. Of note, the 2015-2020 Dietary Guidelines for Americans have removed the recommendation of limiting cholesterol intake to no more than 300 mg per day; however, the guidelines advise that individuals should eat as little dietary cholesterol as possible while consuming a healthy eating pattern. The purpose of this review is to summarize the documented health risks of egg consumption in individuals with low and high risk for CVD and determine whether current recommendations are warranted based on the available literature. We also aim to provide guidance for future studies that will help further elucidate the health modulating effect of eggs. PMID- 28359371 TI - Apples, orange, and pears. Transcatheter aortic valve implantation in intermediate risk patients has borne fruit. PMID- 28359370 TI - Ramadan model of intermittent fasting for 28 d had no major effect on body composition, glucose metabolism, or cognitive functions in healthy lean men. AB - OBJECTIVES: There has been a parallel increase in the incidence of obesity and diabetes as well as the number of daily meals. However, evidence is lacking regarding the role of intermittent fasting. The aim of this study was to determine the effects of a Ramadan model of intermittent fasting (RIF; 14 h of daytime abstinence from food and drinking) for 28 d on body composition, glucose metabolism, and cognitive function. METHODS: Ten healthy, lean men were included in a nonrandomized, crossover, intervention study. Testing was performed before a control period of 28 d, as well as before and after 28 d of RIF. Whole-body dual energy x-ray absorptiometry, magnetic resonance imaging of the abdomen, fitness test, oral glucose tolerance test, and cognitive function tests were performed. As secondary outcome, the participants' physical activity and 72-h glycemic responses were monitored 6 d within each of the periods. Dietary intake, appetite, and mood questionnaires also were assessed. RESULTS: Comparing Delta differences from testing days; body mass index changes from the control period (Delta mean: 0.2 kg/m2, 95% confidence interval [CI], -2 to 0.5) and the RIF period (Delta mean: -0.3 kg/m2, 95% CI, -0.6 to -0.1) were significantly different (P < 0.05). Secondary outcomes within the RIF period showed an increased area under curve (AUC) for hunger accompanied by a reduced AUC for satiety (both, P < 0.05), less mean steps per day (P < 0.05), and less positive feelings in the afternoon (P < 0.01) compared with the control period. No changes were observed in any of the other evaluated parameters. CONCLUSIONS: Free-living participants were able to comply with 14 h of daily daytime abstinence from food and drinking for 28 d with only a minor effect on body mass index and without any effects on body composition, glucose metabolism, and cognitive function. PMID- 28359369 TI - Apolipoprotein A2 -265 T>C polymorphism interacts with dietary fatty acids intake to modulate inflammation in type 2 diabetes mellitus patients. AB - OBJECTIVE: Several investigations have been conducted regarding the interaction between Apolipoprotein A2 (APOA2) -265 T>C polymorphism and dietary intake of saturated fatty acids (SFAs) on obesity in healthy individuals or type 2 diabetes mellitus (T2 DM) patients. The aim of the present study is to examine the effect of this interaction on inflammatory markers in T2 DM patients. METHODS: This is a comparative cross-sectional study on 180 T2 DM patients with known APOA2 genotype. Dietary intake was assessed by food-frequency questionnaire and serum levels of inflammatory markers (interleukin [IL]-18, pentraxin 3, and high sensitivity C-reactive protein [hs-CRP]) were measured. The subjects were dichotomized into "high" and "low" categories, based on the median dietary intake of polyunsaturated fatty acids (PUFAs), monounsaturated fatty acids (MUFAs), and SFAs. The data were analyzed by analysis of covariance multivariate interaction model. RESULTS: In CC genotype, higher median intake of omega-3 PUFAs and MUFAs was associated with decreased serum levels of IL-18 and hs-CRP (P = 0.014 and 0.008, respectively). In T-allele carriers, higher median intake of SFAs was associated with increased serum hs-CRP level (P < 0.001). There was a significant relationship between APOA2 polymorphism and omega-3 PUFA intake on serum IL-18 level (P interaction = 0.03). Moreover, the relationship between this polymorphism and SFA and MUFA intake on serum hs-CRP level was statistically significant (P interaction = 0.03 and 0.024, respectively). CONCLUSIONS: In T2 DM patients, the dietary intake of antiinflammatory fatty acids, such as omega-3 PUFAs and MUFAs, could reduce the inflammatory effects associated with the CC genotype. In addition, proinflammatory fatty acids, such as SFAs, could overcome the antiinflammatory effect of the T-allele. Further studies are needed to confirm these findings. PMID- 28359372 TI - Transcatheter aortic valve replacement in intermediate-risk patients. PMID- 28359373 TI - Are there negative consequences of public reporting? The hype and the reality. PMID- 28359374 TI - The American Association for Thoracic Surgery/Society of Thoracic Surgeons position statement on developing clinical practice documents. PMID- 28359375 TI - The regurgitant bicuspid aortic valve: Recalibrating our surgical strategies. PMID- 28359376 TI - Living without lungs? Bilateral pneumonectomy and dual circulatory support: A step forward in the search for a total artificial lung. PMID- 28359377 TI - University vaccine campaign increases meningococcal ACWY vaccine coverage. PMID- 28359378 TI - 'Mendelian randomization': an approach for exploring causal relations in epidemiology. AB - OBJECTIVES: To assess the current status of Mendelian randomization (MR) approach in effectively influencing the observational epidemiology for examining causal relationships. METHODS: Narrative review on studies related to principle, strengths, limitations, and achievements of MR approach. RESULTS: Observational epidemiological studies have repeatedly produced several beneficiary associations which were discarded when tested by standard randomized controlled trials (RCTs). The technique which is more feasible, highly similar to RCTs, and has the potential to establish a causal relationship between modifiable exposures and disease outcomes is known as MR. The technique uses genetic variants related to modifiable traits/exposures as instruments for detecting causal and directional associations with outcomes. CONCLUSIONS: In the last decade, the approach of MR has methodologically developed and progressed to a stage of high acceptance among the epidemiologists and is gradually expanding the landscape of causal relationships in non-communicable chronic diseases. PMID- 28359379 TI - Eating breakfast regularly is related to higher school connectedness and academic performance in Canadian middle- and high-school students. PMID- 28359381 TI - Gender differences in the association of smartphone addiction with food group consumption among Korean adolescents. PMID- 28359380 TI - Validation of an Arabic version of an instrument to measure waterpipe smoking behavior. AB - OBJECTIVES: Reliable and valid measures of waterpipe smoking are essential to study its health effects. The purpose of this study was to examine the reliability and validity of an Arabic translation of Maziak questionnaire that assesses various aspects of waterpipe smoking in epidemiological studies. STUDY DESIGN: A cross-sectional study. METHODS: This questionnaire was translated, back translated, and culturally adapted to the local Arabic dialect. Construct and convergent validity were assessed in a sample of 119 daily waterpipe smokers (WPS) and 30 occasional WPS, defined as smoking at least one waterpipe per week but less than daily from Beirut and Doha (mean age = 52.4 years, males = 61.7%). Construct validity was assessed by comparing the smoking behavior of daily and occasional WPS. Convergent validity was assessed by correlating daily smoking intensity ('number of waterpipe smoked per day') with 'number of waterpipe smoked yesterday' and by correlating lifetime smoking exposure (waterpipe-year) calculated by multiplying number of waterpipe smoked per day * duration of waterpipe smoking with alternate measures obtained graphically (graphical waterpipe-year) or adjusted (adjusted waterpipe-year). Criterion validity was assessed by correlating daily smoking intensity and lifetime smoking exposure with serum cotinine level. Test-retest reliability was analyzed by re administering the questionnaire to 30 daily and 30 occasional WPS after 2 weeks. RESULTS: Smoking intensity, patterns of use, and willingness to quit differed significantly between daily and occasional WPS. Daily smoking intensity correlated strongly with the number of waterpipe smoked yesterday (rs = 0.68, P < 0.001), but not in the occasional WPS (rs = 0.13, P = 0.70). Waterpipe-year correlated very strongly with adjusted waterpipe-year and graphical waterpipe year (rs = 0.98, P < 0.001 and rs = 0.92, P < 0.001, respectively). Waterpipe year, daily smoking intensity, and number of waterpipe smoked yesterday, correlated weakly but significantly with serum cotinine levels (rs = 0.243, P = 0.01; rs = 0.359, P < 0.01 and rs = 0.387, P < 0.01, respectively). The type and pattern of waterpipe use items showed high test-retest reliability with near perfect agreement (k > 0.9), the sharing and intention to quit waterpipe items had substantial agreement (k > 0.6), and the intent to quit item showed moderate agreement (k > 0.4). CONCLUSION: The questionnaire showed strong reliability, face validity, construct and convergent validity, and a weak but statistically significant criterion validity. Maziak questionnaire is valid and reliable for assessing waterpipe smoking patterns, intensity, and willingness to quit. PMID- 28359383 TI - Sex-specific associations with youth obesity in Queensland, Australia. PMID- 28359382 TI - Critical assessment of the research outcomes of European birth cohorts: linking environmental factors with non-communicable diseases. AB - OBJECTIVES: The objective of this review paper was to stimulate collaborative discussions toward the development of a general concept of an open source protocol for a feasible and efficient longitudinal birth cohort study exploring non-communicable diseases (NCDs), their multifactorial etiology and relations between various risk factors. STUDY DESIGN: The present paper systematically reviews the design of existing birth cohorts in Europe containing environmental exposure data, and assesses a quantity and quality of their research outcomes as their potential to be an effective tool for studying non-communicable diseases and their risk factors. METHODS: European birth cohorts with more than 3000 participants have been included in the study. A total number of scientific papers published in the internationally recognized journals and their impact factors and citation records were evaluated for all cohorts as surrogates for their efficiency to contribute to NCDs understanding and thus their prevention. RESULTS: The birth cohorts contributing most significantly to the NCD understanding shared common features: (i) study size between 10,000 and 15,000 mother-child pairs; (ii) repeated assessment of children from prenatal into adulthood; and (iii) availability of biological samples. Smaller cohorts and cohorts with a specific focus generated a lower number of publications; however, these often received considerably a higher number of citations. CONCLUSIONS: General cohort studies with 10,000-15,000 mother-child pairs allow a broader context interpretation, publish a higher number of articles, and often lead to the formation of infrastructures for 'spin-off (nested) studies'. PMID- 28359384 TI - Associations between singing to babies and symptoms of postnatal depression, wellbeing, self-esteem and mother-infant bond. PMID- 28359385 TI - Alcohol misuse-a national pandemic: an investigation to identify whether implementing an alcohol brief intervention service would benefit patients attending an oral and maxillofacial (OMFS) department. PMID- 28359386 TI - Delhi's health system exceptionalism: inadequate progress for a global capital city. AB - OBJECTIVES: India has proclaimed commitment to the goal of Universal Health Coverage and Delhi, the National Capital Territory, has increased investment in public health and other health services over the past decade. The research investigates whether Delhi's increased investment in health over this period is associated with a reduction in premature deaths, after the age of 1 year, which could have been avoided with better access to effective health care interventions (amenable mortality). STUDY DESIGN: A population-based study of changes in amenable mortality (AM) in Delhi over the 2003-2013 period. METHODS: To calculate AM, a list of International Classification of Disease (ICD) codes from the published literature was relied upon. In defining AM in India, an upper age limit of 69 years was adopted, rather than the more common limit of 74 years. Population estimates and vital statistics were downloaded from the Delhi Statistical Handbook. Deaths by cause and age, including medical certification, are from the Vital Statistics site of the Delhi Government. To age-adjust these data, the direct method was employed, using weights derived from the 2010 United Nations world standard population. RESULTS: The research found that, between 2004 and 2013, the age-adjusted rate of AM rose from 0.87 to 1.09. The leading causes of death in both years were septicemia and tuberculosis. Maternal mortality is well above the global level for middle-income countries. CONCLUSION: Recent investments in public health and health care and the capacity to leverage them to improve access to effective care have not been sufficient to overcome the crushing poverty and inequalities within Delhi. Large and growing numbers of residents die prematurely each year due to causes that are amenable to public health and health care interventions. PMID- 28359387 TI - How to improve opportunistic screening by using EMRs and other data. The prevalence of undetected diabetes mellitus in target population in Croatia. AB - OBJECTIVES: Opportunistic screening for type 2 diabetes (T2D) has not been adopted as part of routine practice. The aim of the study was to investigate the yield of opportunistic target screening for T2D in Croatia and to evaluate the process of screening by using data from electronic medical record. STUDY DESIGN: We conducted opportunistic screening in 23 general practitioners (GPs) in a population of 13,344 patients aged 45-70 years. METHODS: First, after excluding patients with T2D, patients with risk factors for T2D were derived from the electronic medical record and GP's assessment during the preconsultation phase. Second, those with data about normoglycemia in past three years were excluded. Remaining patients started the consultation phase during their usual visit, when they were offered capillary fasting plasma glucose testing in the next consultation. RESULTS: Prevalence of T2D was 10.9% (new 1.4%). A total of 5568 (46.1%) patients had risks and 2849 (51.2%) had data about normoglycemia in the last three years. Using those data, number needed to invite to screening (NNI) was reduced to half: from 46.1% to 22.5%. One hundred eighty-four patients were screened positive for T2D in two capillary fasting plasma glucose tests (yield 9.8%). Number needed to screen (NNS) in order to detect one T2D was 10.3 patients. Among risks for T2D, overweight was the best predictive factor for undiagnosed T2D (odds ratio [OR]: 2.11, confidence interval [CI]:1.41-3.15, P < .001). Logistic regression showed that in targeted population, overweight patients with a family history in fold were 2.5 times more likely to have T2D (OR: 2.54, CI 1.78-.61, P < .001). CONCLUSIONS: Total yield in targeted population was 1,4%. By using data about normoglycemia from EMRs, NNI was reduced by half and NNS was 10.3 patients. Our findings suggest the model for improvement in opportunistic screening. PMID- 28359388 TI - The 2015 Nepal earthquake disaster: lessons learned one year on. AB - INTRODUCTION: The 2015 earthquake in Nepal killed over 8000 people, injured more than 21,000 and displaced a further 2 million. One year later, a national workshop was organized with various Nepali stakeholders involved in the response to the earthquake. The workshop provided participants an opportunity to reflect on their experiences and sought to learn lessons from the disaster. METHODS: One hundred and thirty-five participants took part and most had been directly involved in the earthquake response. They included representatives from the Ministry of Health, local and national government, the armed forces, non governmental organizations, health practitioners, academics, and community representatives. Participants were divided into seven focus groups based around the following topics: water, sanitation and hygiene, hospital services, health and nutrition, education, shelter, policy and community. Facilitated group discussions were conducted in Nepalese and the key emerging themes are presented. RESULTS: Participants described a range of issues encountered, some specific to their area of expertize but also more general issues. These included logistics and supply chain challenges, leadership and coordination difficulties, impacts of the media as well as cultural beliefs on population behaviour post-disaster. Lessons identified included the need for community involvement at all stages of disaster response and preparedness, as well as the development of local leadership capabilities and community resilience. A 'disconnect' between disaster management policy and responses was observed, which may result in ineffective, poorly planned disaster response. CONCLUSION: Finding time and opportunity to reflect on and identify lessons from disaster response can be difficult but are fundamental to improving future disaster preparedness. The Nepal Earthquake National Workshop offered participants the space to do this. It garnered an overwhelming sense of wanting to do things better, of the need for a Nepal centric approach and the need to learn the lessons of the past to improve disaster management for the future. PMID- 28359389 TI - Severe obesity among American Indian tribal youth in the Southwest. PMID- 28359390 TI - A disease called stigma: the experience of stigma among African men with TB diagnosis in London. AB - OBJECTIVES: Tuberculosis (TB) is a highly stigmatised disease. This paper sought to explore the experiences and meanings of stigma among African men with a previous TB diagnosis. STUDY DESIGN: Qualitative approach with ten men recruited from a community based organisation offering health support to the men. METHODS: In-depth semi-structured interviews. RESULTS: Men were unable to recognise TB symptoms and subsequently made late clinical presentation when they were also diagnosed with HIV. A few were diagnosed when in immigration detention centres. The experience of late diagnosis informed their understanding of the word stigma. The link between HIV and TB compounded experiences of stigma which led to depression and compromised HIV confidentiality. CONCLUSION: TB late diagnosis among the men has implications for population health. Multidisciplinary teams supporting ongoing TB education programmes should include African men's organisations, due to the close supportive links such organisations have with African men. PMID- 28359391 TI - Study types and reliability of Real World Evidence compared with experimental evidence used in Polish reimbursement decision-making processes. AB - OBJECTIVES: The aim of this study was to identify the relationship and impact between Real World Evidence (RWE) and experimental evidence (EE) in Polish decision-making processes for the drugs from selected Anatomical Therapeutic Chemical (ATC) groups. STUDY DESIGN: Descriptive study. METHODS: A detailed analysis was performed for 58 processes from five ATC code groups in which RWE for effectiveness, or effectiveness and safety were cited in Agency for Health Technology Assessment and Tariff System's (AOTMiT) documents published between January 2012 and September 2015: Verification Analysis of AOTMiT, Statement of the Transparency Council of AOTMiT, and Recommendation of the President of AOTMiT. RESULTS: In 62% of the cases, RWE supported the EE and confirmed its main conclusions. The majority of studies in the EE group showed to be RCTs (97%), and the RWE group included mainly cohort studies (89%). There were more studies without a control group within RWE compared with the EE group (10% vs 1%). Our results showed that EE are more often assessed using Jadad, NICE or NOS scale by AOTMiT compared with RWE (93% vs 48%). When the best evidence within a given decision-making process is analysed, half of RWE and two-thirds of EE are considered high quality evidence. CONCLUSIONS: RWE plays an important role in the decision-making processes on public funding of drugs in Poland, contributing to nearly half (45%) of all the evidence considered. There exist such processes in which the proportion of RWE is dominant, with one process showing RWE as the only evidence presented. PMID- 28359392 TI - Large variation in predictors of mortality by levels of self-rated health: Results from an 18-year follow-up study. AB - OBJECTIVES: To analyze the variation in factors associated with mortality risk at different levels of self-rated health (SRH). STUDY DESIGN: Retrospective cohort study. METHODS: Cox regression analysis was used to examine the association between mortality and demographic, socioeconomic and health-related predictors for respondents with good, average, and poor SRH in a longitudinal data set from Estonia with up to 18 years of follow-up time. RESULTS: In respondents with good SRH, male sex, older age, lower income, manual occupation, ever smoking, and heavy alcohol consumption predicted higher mortality. These covariates, together with marital status, illness-related limitations, and underweight predicted mortality in respondents with average SRH. For poor SRH, only being never married and having illness-related limitations predicted mortality risk in addition to older age and male sex. CONCLUSIONS: The predictors of all-cause mortality are not universal but depend on the level of SRH. The higher mortality of respondents with poor SRH could to a large extent be attributed to health problems, whereas in the case of average or good SRH, factors other than the presence of illness explained outcome mortality. PMID- 28359393 TI - Did the weight loss in the Prevention of Diabetes and Obesity in South Asians (PODOSA) trial differ by sex? An exploratory analysis. PMID- 28359395 TI - INSPiRE: an integrated approach to tackling household air pollution and improving health in rural Cambodia. PMID- 28359394 TI - Preferences for oral fluid rapid HIV self-testing among social media-using young black, Hispanic, and white men-who-have-sex-with-men (YMSM): implications for future interventions. AB - OBJECTIVES: We assessed preferences of social media-using young black, Hispanic and white men-who-have-sex-with-men (YMSM) for oral fluid rapid HIV self-testing, as compared to other currently available HIV testing options. We also identified aspects of the oral fluid rapid HIV self-test that might influence preferences for using this test instead of other HIV testing options and determined if consideration of HIV testing costs and the potential future availability of fingerstick rapid HIV self-testing change HIV testing preferences. STUDY DESIGN: Anonymous online survey. METHODS: HIV-uninfected YMSM across the United States recruited from multiple social media platforms completed an online survey about willingness to use, opinions about and their preferences for using oral fluid rapid HIV self-testing and five other currently available HIV testing options. In a pre/post questionnaire format design, participants first indicated their preferences for using the six HIV testing options (pre) before answering questions that asked their experience with and opinions about HIV testing. Although not revealed to participants and not apparent in the phrasing of the questions or responses, the opinion questions concerned aspects of oral fluid rapid HIV self-testing (e.g. its possible advantages/disadvantages, merits/demerits, and barriers/facilitators). Afterward, participants were queried again about their HIV testing preferences (post). After completing these questions, participants were asked to re-indicate their HIV testing preferences when considering they had to pay for HIV testing and if fingerstick blood sample rapid HIV self-testing were an additional testing option. Aspects about the oral fluid rapid HIV self-test associated with increased preference for using the test (post-assessment vs pre-assessment of opinion topics) were identified through multivariable regression models that adjusted for participant characteristics. RESULTS: Of the 1975 YMSM participants, the median age was 22 years (IQR 20-23); 19% were black, 36% Hispanic, and 45% white; and 18% previously used an oral fluid rapid HIV self-test. Although views about oral fluid rapid HIV self-testing test were favorable, few intended to use the test. Aspects about the oral fluid rapid HIV self-test associated with an increased preference for using the test were its privacy features, that it motivated getting tested more often or as soon as possible, and that it conferred feelings of more control over one's sexual health. Preferences for the oral fluid rapid HIV self-test were lower when costs were considered, yet these YMSM were much more interested in fingerstick blood sampling than oral fluid sampling rapid HIV self-testing. CONCLUSIONS: Despite the perceived advantages of the oral fluid rapid HIV self-test and favorable views about it by this population, prior use as well as future intention in using the test were low. Aspects about oral fluid rapid HIV self-testing identified as influential in this study might assist in interventions aimed to increase its use among this high HIV risk population as a means of encouraging regular HIV testing, identifying HIV-infected persons, and linking them to care. Although not yet commercially available in the United States, fingerstick rapid HIV self testing might help motivate YMSM to be tested more than oral fluid rapid HIV self testing. PMID- 28359396 TI - Patterns and correlates of physical activity in adolescents in Dhaka city, Bangladesh. AB - OBJECTIVES: Despite the widely acknowledged public health importance of physical activity (PA), few studies have examined levels of PA in Bangladesh. The purpose of this study was to investigate the patterns and correlates of PA in adolescents in Bangladesh. STUDY DESIGN: Cross-sectional survey. METHODS: A total of 798 students, aged 13-17 years; 48% girls, from eight purposively selected secondary schools in Dhaka city, Bangladesh completed a self-administered questionnaire including the 3-Day PA Recall. Parents completed a separate questionnaire to provide household/family-level data. Multilevel generalized linear modelling was used to identify the correlates of PA for boys and girls. RESULTS: Two-thirds (66%) of the adolescents met the recommendations of 60 min/day of moderate to vigorous PA (MVPA) daily, with more boys than girls (76% and 55%, respectively). The most common activities reported were walking for travel (42%), cricket (33%) and household chores (30%). Multivariable modelling showed that girls' PA was positively associated with mother's education level, walking to school, involvement in school sports and having home sports equipment. Boys' PA was positively associated with mother's employment, having home sports equipment, having a playground at school and walking to school. CONCLUSIONS: One third of adolescents in Bangladesh were insufficiently active with girls less active than boys. Walking to school and access to sports facilities including playgrounds and home equipment may be important to promote activity among Bangladeshi adolescents, with special attention to the girls. PMID- 28359397 TI - Health impact assessment as an instrument to examine the health implications of education policies. AB - OBJECTIVES: Health impact assessment (HIA) is a systematic process that can be used by public health professionals to examine the potential health effects of a policy, plan, program, or project that originates outside of the health sector. This article presents a case study of how an interdisciplinary team utilized an HIA to analyze the potential health impact of full-day kindergarten (FDK) on communities in Nevada. STUDY DESIGN: Case study. METHODS: With stakeholder and community engagement, we conducted a multistage HIA that included qualitative and quantitative data collection and analysis, a review of existing literature, and projections. The team considered several pathways through which FDK could impact health in Nevada: (1) school performance; (2) physical development (physical activity and nutrition education); and (3) access to school-based meals and health screenings. RESULTS: Findings indicated that access to FDK could enhance opportunities for Nevada's children to harness school-based services, increase physical activity, and promote nutrition education. In addition, based on existing research that suggests relationships between (1) FDK attendance and 3rd and 5th grade math and reading standardized test scores and (2) 3rd and 5th grade test scores and high school graduation, as well as available state and national data, we estimated that access to FDK could increase high school graduation in Nevada by 499-820 students per year. CONCLUSIONS: This HIA demonstrated that access to FDK could impact both student and adult health in Nevada. Our engagement of public health professionals along with stakeholders and the community in the HIA process demonstrated that HIAs can be an important tool for public health professionals to examine the effects on community health of policies, programs, plans or projects that arise outside of the health sector. PMID- 28359398 TI - Causes of deafness in the Punjab region of Pakistan and the role of consanguinity. PMID- 28359400 TI - Let's talk. PMID- 28359399 TI - Falls amongst older people in Southeast Asia: a scoping review. AB - OBJECTIVES: The older population in the Southeast Asian region is accelerating and is expected to surpass the proportion of the ageing population in North America and Europe in the future. This study aims to identify the research literature related to falls among older people in Southeast Asia, to examine current practice and discuss the future direction on falls prevention and interventions in the region. STUDY DESIGN: A scoping review design was used. METHODS: A systematic literature search was conducted using the Medline, CINAHL, AMED, Ageline, PsycINFO, Web of Sciences, Scopus, Thai-Journal Citation Index, MyCite and trial registries databases. RESULTS: Thirty-seven studies and six study protocols were included, from Thailand, Malaysia, Singapore, Vietnam, Indonesia and the Philippines. One-sixth of the studies involved interventions, while the remainder were observational studies. The observational studies mainly determined the falls risk factors. The intervention studies comprised multifactorial interventions and single interventions such as exercises, educational materials and visual correction. Many of the studies replicated international studies and may not have taken into account features unique to Southeast Asia. CONCLUSION: Our review has revealed studies evaluating falls and management of falls in the Southeast Asian context. More research is required from all Southeast Asian countries to prepare for the future challenges of managing falls as the population ages. PMID- 28359402 TI - In this issue.... PMID- 28359401 TI - Japanese guidelines for allergic diseases 2017. PMID- 28359403 TI - Transcutaneous electrical nerve stimulator of 5000 Hz frequency provides better analgesia than that of 100 Hz frequency in mice muscle pain model. AB - Transcutaneous electrical nerve stimulators (TENSs) have been proved to be effective in muscle pain management for several decades. However, there is no consensus for the optimal TENS program. Previous research demonstrated that a 100 Hz TENS (L-TENS) provided better analgesia than a conventional TENS (< 5 Hz). However, no research compared a higher-frequency (> 100 Hz) TENS with a 100 Hz TENS. We used a 5000 Hz (5 kHz) frequency TENS (M-TENS) and an L-TENS to compare analgesic effect on a mice skin/muscle incision retraction model. Three groups of mice were used (sham, L-TENS, and M-TENS) and applied with different TENS programs on Day 4 after the mice skin/muscle incision retraction model; TENS therapy was continued as 20 min/d for 3 days. Mice analgesic effects were measured via Von Frey microfilaments with the up-down method. After therapy, mice spinal cord dorsal horn and dorsal root ganglion (DRG) were harvested for cytokine evaluation (tumor necrosis factor-alpha and interleukin-1beta) with the Western blotting method. Our data demonstrated that the M-TENS produced better analgesia than the L-TENS. Cytokine in the spinal cord or DRG all expressed lower than that of the sham group. However, there is no difference in both cytokine levels between TENSs of different frequencies in the spinal cord and DRG. We concluded that the M-TENS produced faster and better mechanical analgesia than the L-TENS in the mice skin/muscle incision retraction model. Those behavior differences were not in accordance with cytokine changes in the spinal cord or DRG. PMID- 28359404 TI - Relationship of mast cell density with lymphangiogenesis and prognostic parameters in breast carcinoma. AB - In many cancers, mast cell density (MCD) in the tumor microenvironment is associated with tumor progression and, to a greater extent, angiogenesis. Our study was designed to investigate the correlation between MCD, tumor lymphangiogenesis, and several well-established prognostic parameters in breast cancer. One hundred and four cases of invasive breast carcinoma diagnosed in our clinic between 2007 and 2011 were included. Mast cells and lymphatic vessels were stained with toluidine blue and D2-40, respectively, and their densities were calculated in various areas of tumors and lymph nodes. The variables of MCD and lymphatic vessel density (LVD) were compared using prognostic parameters as well as with each other. As tumor size and volume increased, MCD increased comparably in metastatic lymph nodes; intratumoral and peritumoral LVD also increased. Lymphovascular invasion, lymphatic invasion, perineural invasion, and estrogen receptor positivity were positively related to intratumoral MCD. The relationship between peritumoral MCD and nontumoral breast tissue MCD was statistically significant. Stage was correlated with MCD in metastatic lymph nodes. Metastatic lymph node MCD and intratumoral MCD were also significantly related. Stage, lymphatic invasion, perineural invasion, lymphovascular invasion, and metastatic lymph node MCD were all correlated with intratumoral and/or peritumoral LVD. As nuclear grade increased, intratumoral LVD became higher. In breast carcinoma, MCD, depending on its location, was related to several prognostic parameters. Notably, mast cells may have at least some effect on lymphangiogenesis, which appears to be a predictor of tumor progression. PMID- 28359405 TI - Distribution and number of Cajal-like cells in testis tissue with azoospermia. AB - We investigated the number and distribution of Cajal-like cells in patients with azoospermia. A total of 99 patients with non-obstructive azoospermia were divided into subgroups [19 patientsin hypospermatogenesis group (S1), 40 patients in maturation arrest group (S2), 20 patients in a Sertoli cell-only syndrome (S3), and 20 patients in a testicular atrophy and fibrosis group (S4)], and 20 patients with obstructive azoospermia group (S0). Sections stained with a c-kit antibody were studied by light microscopy to determine the number and distribution of Cajal-like cells in peritubular and perivascular areas of testis. The number of Cajal-like cells were higher in all the non-obstructive groups than in the obstructive group (S0: 2.43 cells/mm2, S1: 3.14 cells/mm2, S2: 4.00 cells/mm2, S3: 4.57 cells/mm2, S4: 3.86 cells/mm2) but statistically significantly different (p<0.05) in the S2 and S3 subgroups only. Distribution of Cajal-like cells were similar in all groups. The number and distribution of Cajal-like cells in non obstructive groups suggest that these cells may affect spermatogenesis. This cellular type can be responsible for the regulation of cellular motility or spermatogenesis. Electrophysiological and electron microscopic studies are needed to better define morphology and function of Cajal-like cells in the testis, especially totally the normal testis tissue. PMID- 28359406 TI - The eIF3a Arg803Lys genetic polymorphism is associated with susceptibility to and chemoradiotherapy efficacy in cervical carcinoma. AB - We aimed to explore the correlations between eukaryotic translation initiation factor 3, subunit A (eIF3a) polymorphisms and susceptibility to and chemoradiotherapy efficacy in cervical carcinoma. Between August 2007 and August 2011, 176 patients with cervical carcinoma were enrolled as the case group, and 180 healthy individuals were selected as the control group. eIF3a Arg803Lys C>T genotypes were detected by hemi-nested polymerase chain reaction restriction fragment length polymorphism. All patients received chemoradiotherapy and were evaluated for efficacy. Compared with carriers of the CC genotype, carriers of the T genotype of the eIF3a Arg803Lys C>T polymorphism had a higher risk of cervical carcinoma. The eIF3a Arg803Lys C>T polymorphism was associated with tumor size, differentiation degree, Federation of Gynecology and Obstetrics (FIGO) stage, and lymph node metastasis (LNM). The overall response rate of the case group was 69.32% (122/176). The response rate of CC genotype carriers was higher compared to patients with the CT+TT genotypes. Binary-logistic regression analysis showed that tumor size, FIGO stage, LNM, and the eIF3a Arg803Lys C>T polymorphism were influencing factors for chemoradiotherapy efficacy. Univariate analysis revealed that age, eIF3a Arg803Lys C>T polymorphism, differentiation degree, FIGO stage, and LNM were prognostic factors of cervical carcinoma, and multivariate analysis showed that age >= 60 years, higher FIGO stage, and LNM, as well as the CT and TT genotypes of the eIF3a Arg803Lys C>T polymorphism, were risk factors related to the prognosis of cervical carcinoma. The eIF3a Arg803Lys C>T polymorphism is connected with a higher susceptibility to cervical carcinoma and may affect chemoradiotherapy efficacy in and prognosis of cervical carcinoma. PMID- 28359407 TI - Role of interleukin-6 and pentraxin 3 as an early marker in Peyronie's disease. AB - Inflammation is mechanistically involved in the development of Peyronie's disease (PD). The aim of this study is to assess the relevance of serum pentraxin 3 (PTX3) and interleukin-6 (IL-6) concentrations in PD. The study enrolled 40 patients with PD in the acute phase and 40 healthy controls. Plasma PTX3 and IL-6 concentrations were evaluated in 40 patients in the acute phase of PD and 40 healthy controls by enzyme-linked immunosorbent assay. Serum concentrations of both PTX3 and IL-6 were significantly higher in the PD patients than in the control group (p=0.001 and p=0.001, respectively). There was a significant correlation between concentration of PTX3 and painful erections. IL-6 concentrations were significantly higher in patients with erectile dysfunction. IL-6 and PTX3 levels showed no correlation with age, serum C-reactive protein, degree of curvature, and disease duration. IL-6 trans-signaling and PTX3 amplification at the site of inflammation could have a role in pathophysiological mechanisms of PD. Biological drugs may be used for treatment during the acute phase of the disease based on this mechanism. PMID- 28359408 TI - Robotic versus conventional laparoscopic cholecystectomy: A comparative study of medical resource utilization and clinical outcomes. AB - Conventional laparoscopic cholecystectomy (CLC) is currently the standard of surgical procedure for gallstone disease. Robotic cholecystectomy (RC) has revolutionized the field of minimally invasive surgery; it is safe and ergonomic, but expensive. The aim of this study is to compare the medical resource utilization and clinical outcomes between the two procedures. This study was conducted retrospectively by assessing data of the clinical outcomes and medical resource of 78 patients receiving RC and 367 patients receiving CLC. We reviewed the data of operation times, length of hospital stay, hospital charges, outpatient department visits, outpatient department service charges, and postoperative complications, which were retrieved from the health information system (HIS) database in this hospital. Patients in both groups had similar demographic and clinical features. The RC group had longer length of hospital stay (p=0.056), significantly longer operation time (p=0.035), and much more hospital charges (p=0.001). The RC group, however, experienced less postoperative complication rates (average 3.8% vs. 20.4%, p=0.001). Conversion rate was 1.9% in the CLC group versus 0% in the RC group (p=0.611). Most complications were mild, and following the Clavien-Dindo classification, there were two cases (2.5%) Grade I for the RC group; 50 cases (13.6%) Grade I and 14 cases (3.81%) Grade II for the CLC group (p<0.001 and 0.001, respectively). Procedure-related complications of Grade IIIa status were encountered in nine patients (2.45%) in the CLC group and none in the RC group (p=0.002).The RC group consumed more medical resources in the index hospitalization; however, they experienced significantly less postoperative complications. PMID- 28359409 TI - Surgical management of urinary stones with abnormal kidney anatomy. AB - In spite of the fact that urologic surgical techniques used by urologists are becoming more and more minimally invasive and easier because of developing technologies, surgical approaches for the urinary stones in kidneys with abnormal anatomy are still confusing. The objective of this article is to determine the treatment options in these kidneys. For this purpose, between 2005 and 2015, we retrospectively evaluated patients operated for urolithiasis with various congenital renal anomalies in five referral urology clinics in our country. Of the 178 patients (110 male, 60 female), 96 had horseshoe kidneys, 42 had pelvic ectopic kidneys (PEKs), and 40 had isolated rotation anomalies (IRAs) of the kidney. We evaluated the patients for stone-free rate (SFR), mean operation time, mean hospitalization time, and complication rate. In horseshoe kidney, SFRs for retrograde intrarenal surgery (RIRS) and percutaneous nephrolithotomy (PNL) groups were 72.2% and 90%, respectively. In PEKs, these rates were 83.6% and 100% for RIRS and laparoscopic pyelolithotomy, respectively. SFRs in kidneys with IRA were 75% for RIRS and 83.3% for PNL. The mean operation time for RIRS and PNL groups in horseshoe kidney was 40.5+/-11.2 minutes and 74.5+/-19.3 minutes, respectively. In PEKs, these times were 52.1+/-19.3 minutes and 53.1+/-24.3 minutes for RIRS and laparoscopic pyelolithotomy, respectively. Mean operation time in kidneys with IRA was 48.7+/-14.4 minutes for RIRS and 53.2+/-11.3 minutes for PNL. Mean hospitalization times for RIRS and PNL groups in horseshoe kidneys were 1.4+/-0.7 days and 2.2+/-1.4 days, respectively. In PEKs, these times were 2.7+/-1.8 days and 1.9+/-0.4 days for RIRS and laparoscopic pyelolithotomy, respectively. Mean operation time in kidneys with IRA was 1.5+/-0.9 days for RIRS and 1.8+/-0.6 days for PNL. The results of our study showed that RIRS could be used in all of types of abnormal kidneys with small- and medium-sized renal calculi safely and satisfactorily. PMID- 28359410 TI - An uncommon cause of anterior elbow pain: Diagnosis and injection for bicipitoradial bursitis using ultrasonography. PMID- 28359411 TI - Interaction Between Spironolactone and Natriuretic Peptides in Patients With Heart Failure and Preserved Ejection Fraction: From the TOPCAT Trial. AB - OBJECTIVES: The aims of this study were to explore the relationship of baseline levels of natriuretic peptides (NPs) with outcomes and to test for an interaction between baseline levels of NPs and the effects spironolactone. BACKGROUND: Plasma NPs are considered to be helpful in the diagnosis of heart failure (HF) with preserved ejection fraction (HFpEF), and elevated levels are associated with adverse outcomes. Levels of NPs higher than certain cutoffs are often used as inclusion criteria in clinical trials of HFpEF to increase the likelihood that patients have HF and to select patients at higher risk for events. Whether treatments have a differential effect on outcomes across the spectrum of NP levels is unclear. METHODS: The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) trial randomized patients with HFpEF and either prior hospitalization for HF or elevated natriuretic peptide levels (B-type NP [BNP] >=100 pg/ml or N-terminal proBNP >=360 pg/ml) to spironolactone or placebo. Baseline BNP (n = 430) or N-terminal proBNP (n = 257) levels were available in 687 patients enrolled from the Americas in the elevated NP stratum of TOPCAT. RESULTS: Higher levels of NPs were independently associated with an increased risk for TOPCAT's primary endpoint of cardiovascular mortality, aborted cardiac arrest, or hospitalization for HF when analyzed either continuously or grouped by terciles, adjusting for region of enrollment, age, sex, atrial fibrillation, diabetes, renal function, body mass index, and heart rate. There was a significant interaction between the effect of spironolactone and baseline NP terciles for the primary outcome (p = 0.017), with greater benefit of the drug in the lower compared with higher NP terciles. CONCLUSIONS: Similar to the effects of irbesartan in the I-PRESERVE (Irbesartan in Heart Failure With Preserved Ejection Fraction) trial, a greater benefit of spironolactone was observed in the group with lower levels of NPs and overall risk in TOPCAT. Elevated NPs in HFpEF identify patients at higher risk for events but who may be less responsive to treatment. The mechanism of this apparent interaction between disease severity and response to therapy requires further exploration. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302). PMID- 28359412 TI - Natriuretic Peptide Levels and Interaction With Treatment in HFpEF: Intriguing Findings in a "House of Cards"? PMID- 28359413 TI - Limited Added Value of Circulating Inflammatory Biomarkers in Chronic Heart Failure. AB - OBJECTIVES: This study sought to evaluate whether a panel of biomarkers improved prognostication in patients with heart failure (HF) and reduced ejection fraction of ischemic origin using a systematized approach according to suggested requirements for validation of new biomarkers. BACKGROUND: Modeling combinations of multiple circulating markers could potentially identify patients with HF at particularly high risk and aid in the selection of individualized therapy. METHODS: From a panel of 20 inflammatory and extracellular matrix biomarkers, 2 different biomarker panels were created and added to the Seattle HF score and the prognostic model from the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) study (n = 1,497), which included conventional clinical characteristics and C-reactive protein and N-terminal pro-B-type natriuretic peptide. Interactions with statin treatment were also assessed. RESULTS: The two models-model 1 (endostatin, interleukin 8, soluble ST2, troponin T, galectin 3, and chemokine [C-C motif] ligand 21) and model 2 (troponin T, soluble ST2, galectin 3, pentraxin 3, and soluble tumor necrosis factor receptor 2) significantly improved the CORONA and Seattle HF models but added only modestly to their Harrell's C statistic and net reclassification index. In addition, rosuvastatin had no effect on the levels of a wide range of inflammatory and extracellular matrix markers, but there was a tendency for patients with a lower level of biomarkers in the 2 panels to have a positive effect from statin treatment. CONCLUSIONS: In the specific HF patient population studied, a multimarker approach using the particular panel of biomarkers measured was of limited clinical value for identifying future risk of adverse outcomes. PMID- 28359414 TI - A Multibiomarker Approach to Heart Failure Prognostication: A Work in Progress. PMID- 28359415 TI - Soluble Urokinase-Type Plasminogen Activator Receptor Improves Risk Prediction in Patients With Chronic Heart Failure. AB - OBJECTIVES: This study investigated the predictive value of soluble urokinase type plasminogen activator receptor (suPAR) in patients with chronic heart failure (CHF). BACKGROUND: SuPAR originates from proteolytic cleavage of the membrane-bound receptor from activated immune and endothelial cells and reflects the level of immune activation. As inflammation plays a crucial role in the complex pathophysiology of CHF, we hypothesized that suPAR might be a suitable prognostic biomarker in patients with CHF. METHODS: SuPAR levels were determined in 319 patients with CHF admitted to our outpatient department for heart failure and in a second cohort consisting of 346 patients with CHF, for validation. RESULTS: During a median follow-up time of 3.2 years, 119 patients (37.3%) died. SuPAR was a strong predictor of mortality with a crude hazard ratio (HR) per increase of 1 SD (HR per 1 SD) of 1.96 (95% confidence interval [CI]: 1.63 to 2.35; p < 0.001) in univariate analysis and remained significant after comprehensive multivariate adjustment with an adjusted HR per 1 SD of 1.38 (95% CI: 1.04 to 1.83; p = 0.026). SuPAR added prognostic value beyond the multivariate model indicated by improvements in C-statistics (area under the curve: 0.72 vs 0.74, respectively; p = 0.02), the category-free net reclassification index (24.9%; p = 0.032), and the integrated discrimination improvement (0.011; p = 0.05). Validation in the second cohort yielded consistent results. CONCLUSIONS: SuPAR is a strong and independent predictor of mortality in patients with CHF, potentially suitable to refine risk assessment in this vulnerable group of patients. Our results emphasize the impact of immune activation on survival in patients with CHF. PMID- 28359416 TI - Prognostic Outcomes in Patients With Heart Failure: A New SuPAR Biomarker for Risk Prediction? PMID- 28359418 TI - Partnering With Patients to Develop Better Heart Failure Trials. PMID- 28359417 TI - Early Adoption of Sacubitril/Valsartan for Patients With Heart Failure With Reduced Ejection Fraction: Insights From Get With the Guidelines-Heart Failure (GWTG-HF). AB - OBJECTIVES: The aim of this study was to assess the prevalence and variation in angiotensin receptor/neprilysin inhibitor (ARNI) prescription among a real-world population with heart failure with reduced ejection fraction (HFrEF). BACKGROUND: The U.S. Food and Drug Administration approved sacubitril/valsartan for patients with HFrEF in July 2015. Little is known about the early patterns of use of this novel therapy. METHODS: The study included patients discharged alive from hospitals in Get With the Guidelines-Heart Failure (GWTG-HF), a registry of hospitalized patients with heart failure, between July 2015 and June 2016 who had documentation of whether ARNIs were prescribed at discharge. Patient and hospital characteristics were compared among patients with HFrEF (ejection fraction <=40%) with and without ARNI prescription at discharge, excluding those with documented contraindications to ARNIs. To evaluate hospital variation, hospitals with at least 10 eligible hospitalizations during the study period were assessed. RESULTS: Of 21,078 patients hospitalized with HFrEF during the study period, 495 (2.3%) were prescribed ARNIs at discharge. Patients prescribed ARNIs were younger (median age 65 years vs. 70 years; p < 0.001), had lower ejection fractions (median 23% vs. 25%; p < 0.001), and had higher use of aldosterone antagonists (45% vs. 31%; p < 0.001) at discharge. At the 241 participating hospitals with 10 or more eligible admissions, 125 (52%) reported no discharge prescriptions of ARNIs. CONCLUSIONS: Approximately 2.3% of patients hospitalized for HFrEF in a national registry were prescribed ARNI therapy in the first 12 months following Food and Drug Administration approval. Further study is needed to identify and overcome barriers to implementing new evidence into practice, such as ARNI use among eligible patients with HFrEF. PMID- 28359419 TI - Factors That May Affect Body Change During and After Hospitalization for Acute Heart Failure. PMID- 28359420 TI - Reply: Factors That May Affect Body Change During and After Hospitalization for Acute Heart Failure. PMID- 28359421 TI - Amiodarone and Beta-Blockers in Patients With Heart Failure and Atrial Fibrillation. PMID- 28359422 TI - Data Sharing From the Editors' Perspective: Our Hope With Limitations. PMID- 28359423 TI - Correction. PMID- 28359424 TI - The Opioid Epidemic: Searching for Answers. PMID- 28359425 TI - Contribution of Group Therapeutic Factors to the Outcome of Cognitive-Behavioral Therapy for Patients with Panic Disorder. AB - BACKGROUND: Investigating the contribution of therapeutic factors arising from the collective nature or group therapy to treat mental disorders may help therapists maximize the outcome of therapy. Studies about the role of therapeutic factors in cognitive-behavioral group therapy (CBGT) for panic disorder (PD) patients are still scarce. OBJECTIVES: To identify the therapeutic factors rated as the most useful by patients during CBGT. Also, we aimed to investigate the relationship between patient rating of therapeutic factors and specific stages of CBGT. DESIGN: Non-controlled clinical trial. METHODS: A 12-session CBGT protocol was set up, covering psychoeducation, techniques for anxiety coping, cognitive restructuring, interoceptive and naturalistic exposure, and live exposure to avoidant behavior. PD symptom severity was assessed before and after the CBGT protocol. Yalom's Curative Factors Questionnaire was self-administered at the end of each session to evaluate the 12 therapeutic factors. RESULTS: The sample consisted of 16 patients, who produced 192 assessments of therapeutic factors. Severity of symptoms improved at the end of CBGT, with a large effect size (>1.0). Different ratings were attributed to therapeutic factors at different phases of CBGT. Seven factors were rated as significantly helpful: altruism, interpersonal learning/input, guidance, identification, family reenactment, self understanding, and existential factors. CONCLUSIONS: Therapeutic factors are dynamic and interdependent. Therefore, recognizing the impact of these factors during CBGT may potentially contribute to a better understanding of the therapeutic process. PMID- 28359426 TI - Content Validity of a Psychotherapeutic Intervention Model in Nursing: A Modified e-Delphi Study. AB - AIM: To estimate the content validity of a psychotherapeutic intervention model in nursing. BACKGROUND: Mental health nurses encounter great extrinsic difficulties when it comes to providing psychotherapeutic interventions due to the fact that they are not allowed to perform such practice in some countries. In this light, the pursuit of a psychotherapeutic intervention model in nursing seems germane to guide the professionals' psychotherapeutic practice, contributing hereof to increase mental health nurses' professional autonomy. DESIGN: Modified e-Delphi. METHODS: Data were collected from October 2015 to January 2016 by means of three rounds of online questionnaires. The initial questionnaire was structured into five sections: general structure of the model, patients' exclusion criteria, assessment framework, nursing diagnoses, and nursing psychotherapeutic interventions. From the 42 experts invited, at least twenty (20) participated in each round. RESULTS: The experts achieved consensus with regard to the conclusion that nursing psychotherapeutic interventions should always seek to address a nursing diagnosis. These defined furthermore that a psychotherapeutic intervention model in nursing should be exercised by means of 3 to 12 sessions using Nursing Interventions Classification (NIC) as a resource. Finally, experts deemed that the model should follow the principles of integrative psychotherapy, so that techniques from different schools of psychotherapy could therefore be used in conjunction to promote the resolution of a nursing diagnosis. CONCLUSION: Achieving consensus about the structure of a psychotherapeutic intervention model in nursing is imperative to guide nurses in the provision of nursing psychotherapeutic interventions and to enable an effective evaluation of the health gains associated with its implementation. PMID- 28359427 TI - The Relationship Between Treatment Adherence and Social Support in Psychiatric Patients in the East of Turkey. AB - This study was conducted to determine the relationship between the adherence to treatment and social support in psychiatric patients. The study was completed with a total of 324 psychiatric patients. The data gathering tools used were Demographics Questionnaire, Morisky Medication Adherence Scale and Multi Dimensional Scale of Perceived Social Support. The study sample consisted of psychiatric patients who were selected from the population by using the simple random sampling method. Among the patients, 50.9% adhered to the treatment, and 14.5% did not. Patients living in city and country-town, with high income and living with family were found to have more social support. A positive, significant relationship was found among scales (p<0.05). As the mean scores of social support increased, patients' adherence to treatment increased. PMID- 28359428 TI - Demographics and Health Profiles of Depressive Symptoms in Korean Older Adults. AB - This study examined the demographics and health characteristics of depressive symptoms of Korean older adults. Data were from the 2014 survey of the Korean Longitudinal Study of Aging (KLoSA). Hierarchical logistic regression was conducted to identify risk factors of depressive symptoms. Model 2 including socio-demographics and health characteristics explained 19.2% of depressive symptoms. Significant risk factors of depressive symptoms were men, age of 53-60 years, mid-sized city and rural area residents, less than high-school education, adults without spouse, 1st (lowest) quintile of annual household income, body shape as underweight, ex-smokers, non-drinkers, no regular exercise, perceived health status as poor, limited activities of daily living, and the number of comorbidities. Interventions to reduce depressive symptoms in these populations should include strategies to change some of these modifiable risk factors. PMID- 28359429 TI - Don't Just Survive, Thrive: Understanding How Acute Psychiatric Nurses Develop Resilience. AB - With one in five Canadians estimated to experience mental illness, retention of registered nurses in the acute psychiatric hospital setting becomes a pressing issue. The key for these nurses to survive and potentially even thrive in practice has been identified as resilience. From interviews with four registered nurses, maintaining a "vast" perspective, becoming an "expert" of self, clarifying "belief systems", and being "present" through "staying awake" were identified as key in developing resilience. Although participants expressed that the development of resilience is an individual process, the concept of development was similar. Developing personal resilience may be a matter of self development. PMID- 28359430 TI - Reciprocal Abuse: Elder Neglect and Abuse by Primary Caregivers and Caregiver Burden and Abuse in Turkey. AB - The aim of the study was to determine the relationship between the neglect and abuse that older people were exposed to by their primary caregivers and the experiences of caregivers' burden and abuse by their charges. This descriptive, cross-sectional and correlational study was conducted with 186 individuals over the age of 65 and 136 caregivers. The data were collected using questionnaires to determine neglect and abuse experienced by both older people and caregivers, and the Zarit Burden Scale. Abuse rate of the older people and their caregivers is both high and similar. This study is to make psychiatric nursing professionals aware of the problem of elder abuse and neglect. For researchers, educators, practitioners, and policymakers in the fields of aging, health, and mental health this study provides important data about elder abuse and neglect. PMID- 28359431 TI - The Effectiveness of Psychoeducational Interventions in Reducing the Care Burden of Family Members Caring for the Elderly in Turkey: A Randomized Controlled Study. AB - OBJECTIVE: To examine the effectiveness of psychoeducational intervention that is based on the McGill Model of Nursing in reducing the burden of caregivers and improving self-efficacy and adaptive coping in people who provide care for the older person. METHODS: This study was conducted using a pre- and post-test control group and repeated measures experimental design in a family health center service area located in Istanbul. This study was conducted with 33 caregivers in each group. The data were collected using the questionnaire form, the Zarit Burden Interview, the General Self-Efficacy Scale and the Cognitive Emotion Regulation Questionnaire. RESULTS: According to the findings of the study, the post-test Zarit Burden Interview points of the intervention group trained for according to McGill Model of Nursing will decrease compared with the control group after the intervention hypothesis was accepted; the post-test General Self Efficacy Scale and adaptive subscales of the Cognitive Emotion Regulation Questionnaire scores will increase after the intervention hypothesis was also accepted. CONCLUSION: It was found that the psychoeducational intervention based on the McGill Nursing Model was efficient. PMID- 28359432 TI - Diabetes Knowledge Among Adults with Serious Mental Illness and Comorbid Diabetes Mellitus. AB - This study examined the association between psychiatric symptoms and diabetes knowledge (DK) among 90 adults with serious mental illness (SMI) and type 2 diabetes. The relationship between DK and glucose control (i.e., A1C) was also examined. In a hierarchical linear regression, greater negative symptom severity and lower cognitive functioning both predicted lower DK, though cognitive functioning superseded negative symptom severity when analyzed simultaneously. A Pearson correlation showed no significant relationship between DK and A1C. Although symptom severity and cognitive functioning are both related to DK among this population, cognitive functioning maybe particularly important. PMID- 28359433 TI - Social Support Moderates the Effects of Self-esteem and Depression on Quality of Life Among Chinese Rural Elderly in Nursing Homes. PMID- 28359434 TI - Anxiety Management in Primary Care: Implementing the National Institute of Clinical Excellence Guidelines. AB - More than 40 million Americans suffer from anxiety disorders, ranking them as one of the most common mental health disorders in America. The purpose of this pilot study was to educate providers on the National Institute Clinical Excellence (NICE) anxiety guidelines and monitor providers' perceived competence in managing anxiety. Results showed perceived competence increased significantly pre intervention to immediately post-intervention (p=0.001), and data revealed the scores did not change significantly immediately post-to six-weeks post (p=0.170). Providers who implemented the guidelines into practice had significantly higher scores (p=0.026) than those who did not implement the guidelines. PMID- 28359435 TI - The Trauma of Birth or Parenting a Child: Effect on Parents' Negative Emotion in China. AB - The present study assessed negative emotions associated with the traumas of infertility and child rearing (child's disability or death) and the correlates of duration of trauma. The widely used Chinese Mental Health Scale was used to assess negative emotions in 294 individuals who experienced the aforementioned traumas and 124 who did not (control group). Results showed that individuals with infertility exhibited greater anxiety, depression, and solitude than the control group; bereaved parents and had greater solitude and fear than control group; and parents of children with disabilities had greater solitude than the control group. Parents who experienced the death of a child had more fear and physiological maladjustment than parents of a child with disabilities. In addition, individuals without parenting experience had higher scores on solitude, fear, and physiological disease than those with parenting experience. After controlling for demographic variables, the duration of trauma significantly negatively predicted depression in the infertile group and for bereaved parents. The results suggest that in order to prevent psychological and physiological health problems among infertile couples, parents of a disabled child, and parents who experience the death of child, family and community-based strategies should be developed and implemented. PMID- 28359436 TI - The Mentally Ill in Jail: Contemporary Clinical and Practice Perspectives for Psychiatric-Mental Health Nursing. AB - Individuals with serious mental illnesses (SMI) who are incarcerated pose major treatment challenges for both correctional personnel and healthcare providers, yet deserve the same high standards of care as those in traditional mental health facilities. The literature references these challenges as types of mental health treatment disparities, and calls for improvement measures from clinicians, researchers, policy-makers, and advocates. From the standpoint of psychiatric mental health (PMH) nursing, this paper explores, examines, and offers some contemporary clinical and practice perspectives for providing best-practice psychiatric care for SMI individuals who are in jails. The diverse roles of PMH nursing can contribute meaningfully to tackling quality improvement initiatives on mental health treatment agendas for SMI inmates. PMID- 28359437 TI - Theoretical Approaches to Enhancing Motivation for Adherence to Antidepressant Medications. AB - PROBLEM: Adherence to antidepressants is a major challenge in our health care system, with a high percentage of patients discontinuing their medications within six months. AIMS: The purpose of this position paper is to discuss theoretical frameworks that address the psychological beliefs, benefits and barriers and feelings of autonomy that affect a person's willingness and motivation to take anti-depressant medications within a therapeutic relationship with a nurse practitioner. METHODS: Three theoretical frameworks were selected to highlight particular perspectives relevant to enhancing patient motivation for medication adherence. The Self-Regulation Model, Health Belief Model, and Self-Determination Theory combined with motivational interviewing all offer guidance on strategies for improving adherence to antidepressants. CONCLUSIONS: The Self-Regulation Model underscores the importance of illness representations that prompt considering patient perceptions of depression that affect adherence. The Health Belief Model focuses on cost-benefit considerations that affect patient's adherence, along with perceived control. Finally, Self-Determination Theory combined with motivational interviewing offers strategies that enhance autonomy and optimize collaboration and motivation for adherence. RELEVANCE FOR CLINICAL PRACTICE: These three theoretical models are applied to a vignette for a patient who is having difficulty with adherence to antidepressant medication. PMID- 28359438 TI - Patterns of Bedtime Preparation for In-patients with Schizophrenia: A Pilot Study. PMID- 28359439 TI - Management of the Diseases of Mesenteric Arteries and Veins: Clinical Practice Guidelines of the European Society of Vascular Surgery (ESVS). PMID- 28359440 TI - Editor's Choice - Management of the Diseases of Mesenteric Arteries and Veins: Clinical Practice Guidelines of the European Society of Vascular Surgery (ESVS). PMID- 28359441 TI - Genetics and Evolution of Leishmania parasites. PMID- 28359442 TI - The other C word. PMID- 28359443 TI - Access to medicines: lessons from the HIV response. PMID- 28359444 TI - Preconception ART and preterm birth: real effect or selection bias? PMID- 28359445 TI - Preconception ART and preterm birth: real effect or selection bias? - Authors' reply. PMID- 28359446 TI - Neglected risk factors for HIV and Toxoplasma gondii co-infection. PMID- 28359447 TI - Neglected risk factors for HIV and Toxoplasma gondii co-infection. PMID- 28359448 TI - Neglected risk factors for HIV and Toxoplasma gondii co-infection - Authors' reply. PMID- 28359449 TI - Not just PrEP: other reasons for London's HIV decline. PMID- 28359450 TI - Continuing education: Caveat emptor. PMID- 28359451 TI - Time to talk about the gender gap in dentist earnings. PMID- 28359452 TI - Human dignity. PMID- 28359454 TI - Correction. PMID- 28359453 TI - Author's response. PMID- 28359455 TI - Meeting commentary: Santa Fe Group Salon Expanding Oral Healthcare for America's Seniors, September 28-30, 2016. AB - BACKGROUND AND OVERVIEW: A meeting to explore ways to expand access to oral health care for seniors-possibly by expanding a dental benefit in Medicare-was convened in Arlington, VA, by the Santa Fe Group. Four factors motivated the meeting: PRACTICAL IMPLICATIONS: The model Medicare dental benefit presented generated much discussion. There was agreement that any dental benefit must attract participating dentists. Agreement was also reached on the importance of public demonstration projects to further establish cost savings from dental care for patients with comorbid diseases, the need to collaborate with nondental advocacy and policy groups to establish that overall health benefits for seniors are gained by adding oral health care, and the necessity of oral health literacy campaigns working directly at the community level with the general public and others, including educators and the media, as well as with policy makers and providers from all health fields and at all levels of professional training. PMID- 28359456 TI - Is it time to change how you make changes? PMID- 28359457 TI - The ethics of presenting a fair and honest treatment plan. PMID- 28359458 TI - Erratum to "Genetic identification of Rickettsia sp. strain Atlantic rainforest in an endemic area of a mild spotted fever in Rio Grande do Sul state, Southern Brazil" [Acta Trop. 162 (2016) 142-145]. PMID- 28359459 TI - Tracheal Resection and Reconstruction: How I Teach It. PMID- 28359460 TI - Teamwork and Communication Skills in Cardiothoracic Surgery. AB - Teamwork and communication skills are essential for the safe practice of cardiothoracic surgery. In this article, we will summarize the literature on teamwork and the culture of safety, and discuss how surgeons may directly improve the outcomes of their patients by addressing these factors. PMID- 28359461 TI - Invited Commentary. PMID- 28359462 TI - Invited Commentary. PMID- 28359463 TI - Invited Commentary. PMID- 28359464 TI - Invited Commentary. PMID- 28359465 TI - Invited Commentary. PMID- 28359466 TI - Invited Commentary. PMID- 28359467 TI - Invited Commentary. PMID- 28359468 TI - Invited Commentary. PMID- 28359469 TI - Invited Commentary. PMID- 28359470 TI - Alternatives to Lobectomy for High-Risk Patients With Early-Stage Non-Small Cell Lung Cancer. AB - The standard of care for the surgical management of non-small cell lung cancer remains a lobectomy. For patients with limited pulmonary reserve, lesser resections or nonoperative therapies may be indicated. The purpose of this review is to evaluate the outcomes from more limited resections as well as the evidence for the efficacy of photon-based and proton-based stereotactic body radiotherapy, radiofrequency ablation, and microwave thermal ablation. In doing so, the goal of this review is to provide surgeons with an evidence-based treatment menu for treating patients who are not candidates for lobectomy. PMID- 28359471 TI - Targeting Immune Checkpoints in Esophageal Cancer: A High Mutational Load Tumor. AB - Checkpoint inhibitors (eg, programmed cell death protein 1 [PD-1], programmed cell death ligand 1 [PD-L1], cytotoxic T-lymphocyte associated protein 4 [CTLA-4] antibodies) are changing how we understand cancer and provide a means to develop modern immunotherapies. An emergent notion relates success with checkpoint inhibitors with high mutational load tumors. There are few studies that examine checkpoint protein expression and relate these to clinical outcomes after the conventional treatment of patients with esophageal cancer, which has a high mutational load. The objective of this review is to summarize the literature that examines checkpoint expression and clinical outcomes, as well as propose an accelerated approach to introducing these therapies into the clinic to treat patients with esophageal cancer. PMID- 28359472 TI - The American Association for Thoracic Surgery/Society of Thoracic Surgeons Position Statement on Developing Clinical Practice Documents. PMID- 28359473 TI - Fifty-Third Annual Meeting, The Society of Thoracic Surgeons. PMID- 28359474 TI - Reply. PMID- 28359475 TI - Contemporary Thoracic Aortic and Abdominal Injuries: An Emergency Strategy. PMID- 28359476 TI - Reply. PMID- 28359477 TI - Pain Control With Bupivacaine After Lung Resections. PMID- 28359478 TI - Reply. PMID- 28359479 TI - Prosthesis Size Selection for Patients With Severe Mitral Stenosis. PMID- 28359480 TI - Rebuilding the Physiological Ellipse: Are All Left Ventricles the Same? PMID- 28359481 TI - Corrigendum. PMID- 28359482 TI - Editor's Commentary. PMID- 28359483 TI - Use of the Lotus Transcatheter Valve to Treat Severe Native Aortic Regurgitation. AB - Transcatheter aortic valve implantation (TAVI) has become the standard treatment for aortic stenosis in high-risk patients. TAVI for native valve aortic regurgitation is technically more demanding because of a lack of anchoring calcification, a lower index incidence, heterogeneous causes, and larger anatomy. We present 3 cases in which the Lotus TAV was used to treat severe native aortic regurgitation (AR) successfully. PMID- 28359484 TI - Occult Internal Mammary Artery Neurofibromatosis: A Case for Caution in Coronary Revascularization. AB - Intrathoracic neurofibromas are relatively uncommon in patients with neurofibromatosis. They are usually asymptomatic and may be discovered incidentally. We present the case of a 51-year-old, African American man with neurofibromatosis type 1 who underwent coronary revascularization. Intraoperatively, numerous neurofibromas were discovered, one of which was attached to the left internal mammary artery. The procedure was uncomplicated despite the challenging intraoperative findings. Special considerations in the management of patients with neurofibromatosis undergoing cardiac surgery are discussed, including risks, preoperative imaging and the importance of excision of suspicious tumors. PMID- 28359485 TI - Giant Coronary Artery Aneurysm in a Middle-Aged Woman. AB - Giant coronary artery aneurysm (CAA) is a rare clinicopathologic entity, and there is a dearth of information regarding presentation, diagnosis, and subsequent management. We present a case of a giant aneurysm of the proximal right coronary artery (RCA) that was 1.5 * 1.5 cm with direct communication between the aneurysmal cavity and the aortic sinus. The deficit in the RCA ostium was closed with a patch of bovine pericardium. The distal communication of the aneurysm to the mid-RCA was clearly delineated and tied off. The distal RCA was grafted under bypass with a long saphenous vein. Although our case is not unique, it does represent an uncommon presentation of a rare disease process. PMID- 28359486 TI - Intraoperative Bioprosthetic Valve Dysfunction Causing Severe Mitral Regurgitation. AB - Structural degeneration of bioprosthetic valves usually occurs gradually over time. Failure of a bioprosthetic valve immediately after implantation is extremely rare. Possible causes include obstruction of valve leaflets from preserved subvalvular tissue during chordal-sparing mitral valve replacement (MVR) or strut entrapment by suture loops. We report 2 cases of acute bioprosthetic mitral valve (MV) dysfunction involving newly implanted Perimount Theon (Edwards Lifesciences, Irvine, CA) bioprostheses, causing severe transvalvular mitral regurgitation (MR). Rapid diagnosis was achieved with the use of intraoperative transesophageal echocardiography (TEE). Operative assessment and examination of the explanted valves could not determine a definite cause of failure in either case. PMID- 28359487 TI - New Presentation of Hemolysis After Papillary Muscles Approximation for Mitral Valve Repair. AB - Hemolysis is a well-recognized complication after prosthetic valve replacement, especially with perivalvular leaks. Hemolytic anemia associated with mitral valve (MV) repair is less common. We report the case of a young man with severe hemolytic anemia caused by turbulence of blood flow through a very small quadrangle orifice due to early failure of MV repair. The patient underwent redo MV biologic prosthesis replacement and tricuspid valve annuloplasty. The hemolysis completely disappeared few months later. In this case, we describe a new presentation of mechanical hemolysis due to early failure of MV repair that has not been described in the literature. PMID- 28359488 TI - Left Atrial and Carotid Body Paraganglioma. AB - We report a rare case of left atrial paraganglioma with a synchronous carotid body paraganglioma in a 30-year-old man with succinate dehydrogenase B gene mutation. The patient initially presented with a neck mass and palpitations. Laboratory test results showed elevated catecholamine levels. A cardiac paraganglioma was identified by computed tomography, meta-iodobenzylguanidine scintigraphy, and magnetic resonance imaging. Surgical resection of both paragangliomas were performed on two separate occasions. Serum and urine catecholamine levels returned to normal range. On follow-up, there was no recurrence of the cardiac paraganglioma. Radiotherapy was subsequently initiated for recurrence in the carotid body paraganglioma. PMID- 28359489 TI - Palpitations and a Left Ventricular Mass: An Odd Presentation of Left Dominant Arrhythmogenic Cardiomyopathy. AB - A 20-year-old woman presented with palpitations. Echocardiography demonstrated a left ventricular mass involving the posterolateral apical wall and protruding into the ventricular cavity. Evaluation with magnetic resonance imaging (MRI) suggested fatty consistency with all edges well defined except the medial, which was ill defined, raising concern for an invasive liposarcoma. Open core needle biopsy demonstrated mature adipocytes infiltrating the myocardium with extensive interstitial fibrosis. The diagnosis was left-dominant arrhythmogenic cardiomyopathy. Two-year MRI follow-up demonstrates no change in size. This case illustrates the use and limits of cardiac MRI and the value of open cardiac biopsy in diagnosis. PMID- 28359490 TI - How Could These Mini Saccular Aneurysms of Ascending Aorta Be Classified? AB - The wall of a true aneurysm is composed of all histologic layers of the aorta. A false aneurysm represents a small, contained rupture of aorta followed by bulging of the corresponding area that is usually sustained by a fibrous peel. Aortic dissection is defined as a separation of the lamellae of the aortic wall. Herein, we describe an unusual clinical presentation of aortic dissection in a 37-year old male patient that presented severe aortic regurgitation and unusual bulges with linear intimal fissures in ascending aorta underwent mechanical aortic valve replacement and interposition of tubular vascular graft in ascending aorta. PMID- 28359491 TI - Tricuspid Valve Repair With Artificial Chorda After Previous Ventricular Septal Defect Repair. AB - We evaluated a 49-year-old man with severe tricuspid valve regurgitation and coronary artery disease who had undergone congenital ventricular septal defect repair four decades previously. We found an enlarged, prolapsed commissure between the anterior and septal leaflets and a ruptured septal leaflet chorda. Two mattress sutures closed the commissure, with the leaflets' height matched by inverting the prolapsed site ventricularly. After implanting the annuloplasty band, we undertook chordal replacement using expanded polytetrafluoroethylene sutures. Artificial chorda length was determined using a small tourniquet and the saline test. Two coronary artery bypass grafts were also implanted. Postoperative echocardiography demonstrated no tricuspid regurgitation. PMID- 28359492 TI - The First Cardiac Operation Using Cardiopulmonary Bypass. AB - The first open heart operation ever performed was by Clarence Dennis on April 5, 1951, at the University of Minnesota. For several years he had worked developing a heart-lung machine. The operation was on a young girl considered to have an ostium secundum atrial septal defect, but at the procedure a large ostium primum was identified instead. It could not be repaired, and the child died. The anatomic details of this heart have not been previously presented. For historical purposes, the clinical history, intraoperative course, and pathologic details will be discussed and shown. PMID- 28359493 TI - Twin-to-Twin Heart Transplantation: A Unique Event With a 25-Year Follow-Up. AB - Solid organ transplantation in pediatric patients has been a reality since 1954, when the first kidney transplantation was successfully performed between identical twins. We report the long-term outcomes, with more than 25 years of follow-up, in a patient born with hypoplastic left heart syndrome (HLHS) who received a heart transplant from a dizygotic twin. While we would not wish for this situation to reoccur, we hope that in reporting it, we can add to the discussion surrounding pediatric heart transplantation and the management of HLHS. PMID- 28359494 TI - Migration of an Atrial Septal Occluder Device With Formation of Abdominal Aortic Dissection. AB - Atrial septal defects can be closed surgically or percutaneously. However, percutaneous closure of atrial septal defects carries some risks. Embolization of the atrial septal occluder is the major adverse event. Embolization of the device into the main pulmonary artery, left atrium, right ventricle, aortic arch, descending aorta, abdominal aorta, iliac bifurcation, and iliac arteries can be seen. We report the case of a 19-year-old man with migration of an Amplatzer (St Jude Medical, St Paul, MN) atrial septal occluder into the iliac bifurcation with the development of abdominal aortic dissection 1 month after successful percutaneous closure. PMID- 28359495 TI - Pediatric Heart Transplantation With Lecompte Maneuver Owing to Extremely Oversized Donor Allograft. AB - The techniques and outcomes of heart transplantation in the pediatric population continue to improve over the years, although the supply of organs remains limited. Donor-to-recipient size matching is critical, especially in neonates and small infants. We present a novel strategy for heart transplantation that includes the Lecompte maneuver because of the features of the donor allograft available in a 8-month-old patient with a cardiac fibroma. We discuss the basis principles for extending the indication of this procedure to exceptional transplantation scenarios and describe the results at long-term follow-up. PMID- 28359496 TI - Transposition of the Great Arteries With Total Anomalous Pulmonary Venous Connection. AB - Transposition of the great arteries (TGA) with total anomalous pulmonary venous connection (TAPVC) is a rare association. Very few such cases have been reported. Among them 1 patient underwent anatomic repair. The rest received repair at the atrial level with either a modified Senning technique or a Mustard technique. We report a rare combination of TGA, TAPVC draining to the coronary sinus, and left juxtaposition of the atrial appendages with a diminutive right atrium. The anomalies were successfully repaired by anatomic correction. PMID- 28359497 TI - Repair of Atrioventricular Septal Defect and Transposition in Left Isomerism. AB - We report the successful primary anatomic correction of an atrioventricular septal defect with transposition of the great arteries and pulmonary stenosis in a 4-year-old girl with left isomerism by common atrioventricular valve division, Mustard-type atrial septation, and a Rastelli operation with ventricular septal defect enlargement. To the best of our knowledge, this is the first report of total correction for this combination of cardiac anomalies. PMID- 28359498 TI - Stenting of Complex Malignant Central-Airway Obstruction Guided by a Three Dimensional Printed Model Of The Airways. AB - Conversion of anatomic images into physical objects using three-dimensional printing (3DP) is changing the way surgeons anticipate selected technical challenges. We report herein a case of malignant central airway obstruction in the right main bronchus. Because stenting of the primary right carina is difficult, as it depends on many diameters and distance measurements, we used 3DP to plan and guide the procedure. After virtual resolution of the extrinsic compression, a three-dimensional printed model of the airways helped us choose the model and dimensions of the stent, and allowed us to modify its accuracy before insertion. PMID- 28359499 TI - Surgical Treatment of Squamous Carcinoma in an Antethoracic Skin Tube Used for Esophageal Replacement. AB - Occasionally, enteric conduits are unavailable or impractical for esophageal replacement. Cutaneous tubes are rarely employed alternatives that remain useful in specific circumstances. We present the case of a patient with a long standing skin tube complicated by malignancy that was replaced with a new skin tube. PMID- 28359500 TI - Uniportal Video-Assisted Thoracoscopic Surgery Resection of a Giant Midesophageal Diverticulum. AB - We describe a new video-assisted technique for the management of a giant midesophageal diverticulum using a single 5-cm port. It maintained the same principles of the traditional open technique as diverticulectomy, myotomy, and fundoplication. The better visualization of the main esophageal body, diverticulum, and esophagogastric junction and the better alignment of the stapler cartridge to the longitudinal axis of the esophagus are all technical factors supporting our procedure. Heavily calcified mediastinal lymph nodes and diffuse pleural adhesions are the main contraindications. However, future experiences are needed before this technique can be recommended as acceptable treatment. PMID- 28359501 TI - Completely Thrombosed Tricuspid Pouch Mimicking a Cardiac Tumor. PMID- 28359502 TI - Late Left Coronary Artery Compromise After Corevalve Implantation: Insights From Instant Free Ratio Analysis. PMID- 28359503 TI - Huge Cardiac Myxoma. PMID- 28359504 TI - Late Consequences of a Much Earlier Decision. PMID- 28359505 TI - Management of Retrograde False Lumen Perfusion After Hybrid Arch Repair in Acute Aortic Dissection. AB - Patients with acute aortic dissections involving the arch and descending aorta can effectively be treated using the frozen elephant trunk technique. We describe here the novel technique of temporary banding of the descending aorta onto the stent of the hybrid graft in 3 patients who developed unmanageable bleeding from the distal suture line due to retrograde false lumen perfusion and disintegration of the adventitia. Retrograde false lumen perfusion was stopped and therefore bleeding controlled in all patients. Temporal aortic banding represents a novel, feasible, and effective bailout technique for otherwise unmanageable bleeding with fatal outcome in hybrid arch surgery. PMID- 28359506 TI - Single-Stage Hybrid Repair of Right Aortic Arch With Kommerell's Diverticulum. AB - Kommerell diverticulum is uncommon, and it carries risks of dissection or rupture. Hybrid aortic arch repair is being used increasingly for this pathology. We report the hybrid arch repair of Kommerell diverticulum in a 72-year-old woman known for muscular dystrophy and right aortic arch with aberrant left subclavian artery. Head-vessel debranching was performed through median sternotomy using a handmade, bifurcated, Dacron graft. Stent-grafting was performed from the ascending aorta to the proximal descending aorta. To our knowledge, this report is the first description of debranching using a custom-made graft for hybrid repair of Kommerell diverticulum. PMID- 28359507 TI - A Novel Arterial Cannulation Technique for Selective Regional Cerebral Perfusion. AB - A selective regional cerebral perfusion has been widely adopted for brain protection in neonatal or infant aortic arch surgeries. The anastomosis of the small polytetrafluoroethylene tube graft to the innominate artery has been used for the selective regional cerebral perfusion in many institutions. We have developed a specially designed cannula tip that allows bidirectional blood flow and provides secure positioning of the polytetrafluoroethylene tube graft at the innominate artery. Innominate artery cannulation using this device reduces arterial clamping time and permits us to perform the arterial cannulation in a much easier and secure manner. PMID- 28359508 TI - Functional Chest Wall Reconstruction With a Biomechanical Three-Dimensionally Printed Implant. AB - Chest wall resection and reconstruction for neoplastic diseases has unique oncologic, structural, and functional challenges. In a young and fit patient with a mediastinal mass and extensive anterior chest wall invasion, purely structural solutions were deemed insufficient. We hereby present a novel three-dimensionally printed patient-specific titanium implant of sternum and ribs. This osteointegrable implant was designed with biomechanical capabilities using a unique "Greek wave" folding pattern. Postoperative dynamic computed tomography showed that the implant allowed for controlled flexing during the respiratory cycle. Three-dimensional printing with biocompatible materials could enable a new generation of chest wall implants strongly focused on functional reconstruction. PMID- 28359510 TI - Myocarditis: An Intersection Between Genetic and Acquired Causes of Human Cardiomyopathy. PMID- 28359509 TI - Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis. AB - BACKGROUND: Myocarditis is inflammation of the heart muscle that can follow various viral infections. Why children only rarely develop life-threatening acute viral myocarditis (AVM), given that the causal viral infections are common, is unknown. Genetic lesions might underlie such susceptibilities. Mouse genetic studies demonstrated that interferon (IFN)-alpha/beta immunity defects increased susceptibility to virus-induced myocarditis. Moreover, variations in human TLR3, a potent inducer of IFNs, were proposed to underlie AVM. OBJECTIVES: This study sought to evaluate the hypothesis that human genetic factors may underlie AVM in previously healthy children. METHODS: We tested the role of TLR3-IFN immunity using human induced pluripotent stem cell-derived cardiomyocytes. We then performed whole-exome sequencing of 42 unrelated children with acute myocarditis (AM), some with proven viral causes. RESULTS: We found that TLR3- and STAT1 deficient cardiomyocytes were not more susceptible to Coxsackie virus B3 (CVB3) infection than control cells. Moreover, CVB3 did not induce IFN-alpha/beta and IFN-alpha/beta-stimulated genes in control cardiomyocytes. Finally, exogenous IFN alpha did not substantially protect cardiomyocytes against CVB3. We did not observe a significant enrichment of rare variations in TLR3- or IFN-alpha/beta related genes. Surprisingly, we found that homozygous but not heterozygous rare variants in genes associated with inherited cardiomyopathies were significantly enriched in AM-AVM patients compared with healthy individuals (p = 2.22E-03) or patients with other diseases (p = 1.08E-04). Seven of 42 patients (16.7%) carried rare biallelic (homozygous or compound heterozygous) nonsynonymous or splice-site variations in 6 cardiomyopathy-associated genes (BAG3, DSP, PKP2, RYR2, SCN5A, or TNNI3). CONCLUSIONS: Previously silent recessive defects of the myocardium may predispose to acute heart failure presenting as AM, notably after common viral infections in children. PMID- 28359511 TI - Adding Defibrillation Therapy to Cardiac Resynchronization on the Basis of the Myocardial Substrate. AB - BACKGROUND: Patients with nonischemic dilated cardiomyopathy (DCM) may be at lower risk for ventricular arrhythmias compared with those with ischemic cardiomyopathy (ICM). In addition, DCM has been identified as a predictor of positive response to cardiac resynchronization therapy (CRT). OBJECTIVES: The aim of this study was to investigate the impact of an additional implantable cardioverter-defibrillator over CRT, according to underlying heart disease, in a large study group of primary prevention patients with heart failure. METHODS: This was an observational, multicenter, European cohort study of 5,307 consecutive patients with DCM or ICM, no history of sustained ventricular arrhythmias, who underwent CRT implantation with (n = 4,037) or without (n = 1,270) a defibrillator. Propensity-score and cause-of-death analyses were used to compare outcomes. RESULTS: After a mean follow-up period of 41.4 +/- 29.0 months, patients with ICM had better survival when receiving CRT with a defibrillator compared with those who received CRT without a defibrillator (hazard ratio for mortality adjusted on propensity score and all mortality predictors: 0.76; 95% confidence interval [CI]: 0.62 to 0.92; p = 0.005), whereas in patients with DCM, no such difference was observed (hazard ratio: 0.92; 95% CI: 0.73 to 1.16; p = 0.49). Compared with recipients of defibrillators, the excess mortality in patients who did not receive defibrillators was related to sudden cardiac death in 8.0% among those with ICM but in only 0.4% of those with DCM. CONCLUSIONS: Among patients with heart failure with indications for CRT, those with DCM may not benefit from additional primary prevention implantable cardioverter defibrillator therapy, as opposed to those with ICM. PMID- 28359512 TI - Should Nonischemic CRT Candidates Receive CRT-P or CRT-D? PMID- 28359514 TI - Atrial Fibrillation: A Threat to the Failing Heart? PMID- 28359513 TI - Exercise Training in Patients With Chronic Heart Failure and Atrial Fibrillation. AB - BACKGROUND: The safety and efficacy of aerobic exercise in heart failure (HF) patients with atrial fibrillation (AF) has not been well evaluated. OBJECTIVES: This study examined whether outcomes with exercise training in HF vary according to AF status. METHODS: HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) randomized 2,331 ambulatory HF patients with ejection fraction <=35% to exercise training or usual care. We examined clinical characteristics and outcomes (mortality/hospitalization) by baseline AF status (past history of AF or AF on baseline electrocardiogram vs. no AF) using adjusted Cox models and explored an interaction with exercise training. We assessed post randomization AF events diagnosed via hospitalizations for AF and reports of serious arrhythmia caused by AF. RESULTS: Of 2,292 patients with baseline rhythm data, 382 (17%) had AF, 1,602 (70%) had sinus rhythm, and 308 (13%) had "other" rhythm. Patients with AF were older and had lower peak Vo2. Over a median follow up of 2.6 years, AF was associated with a 24% per year higher rate of mortality/hospitalization (hazard ratio [HR]: 1.53; 95% confidence interval [CI]: 1.34 to 1.74; p < 0.001) in unadjusted analysis; this did not remain significant after adjustment (HR: 1.15; 95% CI: 0.98 to 1.35; p = 0.09). There was no significant difference in AF event rates by randomized treatment assignment in the overall population or by baseline AF status (all p > 0.10). There was no interaction between AF and exercise training on measures of functional status or clinical outcomes (all p > 0.10). CONCLUSIONS: AF in patients with chronic HF was associated with older age, reduced exercise capacity at baseline, and a higher overall rate of clinical events, but not a differential response to exercise training for clinical outcomes or changes in exercise capacity. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437). PMID- 28359515 TI - Electrocardiographic Criteria for the Diagnosis of Left Ventricular Hypertrophy. AB - BACKGROUND: Current electrocardiographic (ECG) criteria for the diagnosis of left ventricular hypertrophy (LVH) have low sensitivity. OBJECTIVES: The goal of this study was to test a new method to improve the diagnostic performance of the electrocardiogram. METHODS: The study was divided into 2 groups, a test and a validation cohort. In the test cohort, 94 patients were analyzed, including 47 with the diagnosis of hypertensive crisis and 47 with normal blood pressure at admission. Echocardiography was used to estimate the left ventricular mass index. Area under the curve (AUC) analysis was used for comparison of single and combined leads. The McNemar test was used to assess agreement among the ECG criteria against the left ventricular mass index. The proposed ECG criteria involved measuring the amplitude of the deepest S wave (SD) in any single lead and adding it to the S wave amplitude of lead V4 (SV4). Currently accepted LVH ECG criteria such as Cornell voltage and Sokolow-Lyon were used for comparison. The validation cohort consisted of 122 consecutive patients referred for an echocardiogram regardless of the admitting diagnosis. RESULTS: The SD was the most accurate single lead measurement for the diagnosis of LVH (AUC: 0.80; p < 0.001). When both cohorts were analyzed, the SD + SV4 criteria outperformed Cornell voltage with a significantly higher sensitivity (62% [95% confidence interval [CI]: 50% to 72%] vs. 35% [95% CI: 24% to 46%]). The specificities of all the criteria were >=90%, with no significant difference among them. CONCLUSIONS: The proposed criteria for the ECG diagnosis of LVH improved the sensitivity and overall accuracy of the test. PMID- 28359516 TI - The Enduring Role of the Electrocardiogram as a Diagnostic Tool in Cardiology. PMID- 28359517 TI - The Benefit of Donor-Recipient Matching for Patients Undergoing Heart Transplantation. AB - BACKGROUND: Heart transplant volumes are not matching growing demand, and donor heart use may be decreasing. OBJECTIVES: This study sought to investigate the benefit of heart transplantation compared with waiting while accounting for the estimated risk of a given donor-recipient match. METHODS: This study identified 28,548 heart transplant candidates in the Organ Procurement and Transplant Network between July 2006 and December 2015. Donor-recipient match quality was estimated from the donor risk index. A time-dependent covariate Cox model was used to determine the effect of donor-recipient match quality on the likelihood of a composite outcome while waiting for a transplant or after transplantation. The composite outcome was death or delisting as too ill. RESULTS: Donor and recipient risk estimates were inversely related to the candidate urgency. Net benefit from heart transplantation was evident across all estimates of donor recipient status 1A and 1B candidates: status 1A (lowest-risk quartile hazard ratio [HR]: 0.37; 95% confidence interval [CI]: 0.31 to 0.43; highest-risk quartile HR: 0.52; 95% CI: 0.44 to 0.61) and status 1B candidates (lowest-risk quartile HR: 0.41; 95% CI: 0.36 to 0.47; highest-risk quartile HR: 0.66; 95% CI: 0.58 to 0.74). Status 2 candidates showed a benefit from heart transplantation; however, survival benefit was delayed. For the highest-risk donor-recipient matches, a net benefit of transplantation occurred immediately for status 1A candidates, after 12 months for status 1B candidates, and after 3 years for status 2 candidates. CONCLUSIONS: This study demonstrated a survival benefit of heart transplantation across all ranges of estimated donor-recipient match risk for status 1A and status 1B candidates. Donor heart acceptance should be the favored strategy for these candidates. The benefit of transplantation for status 2 candidates was less apparent and dependent on estimated donor-recipient match risk, suggesting that a measure of donor-recipient match quality may be useful when considering the immediate benefit of heart transplantation for status 2 candidates in stable condition. PMID- 28359518 TI - Addressing the Growing U.S. Donor Heart Shortage: Waiting for Godot or a Transplant? PMID- 28359519 TI - Pulmonary Hypertension in Heart Failure: Pathophysiology, Pathobiology, and Emerging Clinical Perspectives. AB - Pulmonary hypertension is a common hemodynamic complication of heart failure. Interest in left-sided pulmonary hypertension has increased remarkably in recent years because its development and consequences for the right heart are now seen as mainstay abnormalities that begin in the early stages of the disease and bear unfavorable prognostic insights. However, some knowledge gaps limit our ability to influence this complex condition. Accordingly, attention is now focused on: 1) establishing a definitive consensus for a hemodynamic definition, perhaps incorporating exercise and fluid challenge; 2) implementing the limited data available on the pathobiology of lung capillaries and small arteries; 3) developing standard methods for assessing right ventricular function and, hopefully, its coupling to pulmonary circulation; and 4) searching for effective therapies that may benefit lung vessels and the remodeled right ventricle. The authors review the pathophysiology, pathobiology, and emerging clinical perspectives on pulmonary hypertension across the broad spectrum of heart failure stages. PMID- 28359521 TI - Leadership in Cardiology: Development of Cardiologists as Leaders to Improve Our Health Care System. PMID- 28359520 TI - State Requirements for Automated External Defibrillators in American Schools: Framing the Debate About Legislative Action. AB - Installation of automated external defibrillators (AEDs) in schools has been associated with increased survival after sudden cardiac arrest. An authoritative academic research database was interrogated to identify all current state statutes pertaining to AEDs in schools. As of February 2016, 17 of 50 U.S. states (34%) require AED installation in at least some of their schools; the remaining states have no legislation. However, requirements are far from comprehensive in these 17 states. Only 5 states offer unequivocal funding to schools for purchasing AEDs. A minority of U.S. states have legislation requiring AED placement in schools, and even fewer provide funding. State legislatures that have not yet enacted legislation requiring AEDs in schools may look to neighboring states for examples of child and adult lifesaving law. Placement of an AED in schools should be implemented with an emergency response plan that trains staff in the recognition and response to cardiac arrest. PMID- 28359522 TI - Deficiencies in Global Health Training for Cardiovascular Fellows. PMID- 28359523 TI - Electrophysiologically Guided Thoracoscopic Surgery for Advanced Atrial Fibrillation: 5-Year Follow-up. PMID- 28359524 TI - Midwall Fibrosis and 5-Year Outcome in Moderate and Severe Aortic Stenosis. PMID- 28359525 TI - Comment on the EXPLORE Trial. PMID- 28359526 TI - Percutaneous Intervention for Concurrent Chronic Total Occlusions in Patients With STEMI: We Should EXPLORE More! PMID- 28359527 TI - Reply: Comments on PCI for Concurrent CTOs in Patients With STEMI: We Should EXPLORE More! PMID- 28359528 TI - Reply: HDL-C and Mortality. PMID- 28359529 TI - HDL-C and Mortality. PMID- 28359530 TI - Analysis of the optimal sampling rate for state estimation in sensor networks with delays. AB - When addressing the problem of state estimation in sensor networks, the effects of communications on estimator performance are often neglected. High accuracy requires a high sampling rate, but this leads to higher channel load and longer delays, which in turn worsens estimation performance. This paper studies the problem of determining the optimal sampling rate for state estimation in sensor networks from a theoretical perspective that takes into account traffic generation, a model of network behaviour and the effect of delays. Some theoretical results about Riccati and Lyapunov equations applied to sampled systems are derived, and a solution was obtained for the ideal case of perfect sensor information. This result is also interesting for non-ideal sensors, as in some cases it works as an upper bound of the optimisation solution. PMID- 28359531 TI - An imbalance fault detection method based on data normalization and EMD for marine current turbines. AB - This paper proposes an imbalance fault detection method based on data normalization and Empirical Mode Decomposition (EMD) for variable speed direct drive Marine Current Turbine (MCT) system. The method is based on the MCT stator current under the condition of wave and turbulence. The goal of this method is to extract blade imbalance fault feature, which is concealed by the supply frequency and the environment noise. First, a Generalized Likelihood Ratio Test (GLRT) detector is developed and the monitoring variable is selected by analyzing the relationship between the variables. Then, the selected monitoring variable is converted into a time series through data normalization, which makes the imbalance fault characteristic frequency into a constant. At the end, the monitoring variable is filtered out by EMD method to eliminate the effect of turbulence. The experiments show that the proposed method is robust against turbulence through comparing the different fault severities and the different turbulence intensities. Comparison with other methods, the experimental results indicate the feasibility and efficacy of the proposed method. PMID- 28359532 TI - Editorial Comment. PMID- 28359533 TI - Editorial Comment. PMID- 28359534 TI - Author Reply. PMID- 28359535 TI - Fetal Vascular Origins of Bronchopulmonary Dysplasia. PMID- 28359536 TI - Use of multiple functional traits of protozoa for bioassessment of marine pollution. AB - Ecological parameters based on multiply functional traits have many advantages for monitoring programs by reducing "signal to noise" ratios of observed species data. To identify potential indicators for bioassessment of marine pollution in function space, the functional patterns of protozoan communities and relationships with environmental changes were studied in coastal waters of the Yellow Sea during a 1-year period. The results showed that: (1) the spatial variability in functional trait distributions of the protozoa was significantly associated with changes in environmental variables, especially chemical oxygen demand (COD) and nutrients on spatial scale; (2) the functional traits, especially food resources and feeding type, were significantly correlated with COD and nutrients; and (3) the functional diversity indices were generally related to nutrients or COD. Based on the results, we suggest that the functional traits and diversity indices of protozoan communities may be used as more effective indicators for bioassessment of marine pollution. PMID- 28359537 TI - Macrophage density in early surveillance biopsies predicts future renal transplant function. AB - Inflammation impairs renal allograft survival but is difficult to quantify by eye at low densities. Here we measured leukocyte abundance in early surveillance biopsies by digital image analysis to test for a role of chemokine receptor genotypes and analyze the predictive value of leukocyte subsets to allograft function. In six-week surveillance biopsies, T-cell (CD3), B-cell (CD20), macrophage (CD68), and dendritic cell (CD209) densities were assessed in whole slide scans. Renal cortical CD3, CD20, and CD68 were significantly higher in histologic rejection. The CCR2 V64I genotype was associated with lower CD3 and CD209 densities. Above-median CD68 density was significantly associated with lower combined patient and graft survival with a hazard ratio of 3.5 (95% confidence interval 1.1-11.0). Both CD20 and CD68 densities inversely correlated with estimated glomerular filtration rate (eGFR) four years after transplantation. Additionally, CD68 correlated with eGFR loss. Among histological measurements including a complete Banff classification, only CD68 density was a significant predictor of an eGFR under 30ml/min after four years (odds ratio 7.4, 1.8-31.0) and part of the best eGFR prediction set in a multivariable linear regression analysis of multiple clinical and pathologic parameters. In a second independent cohort, the original CD68 median maintained its discriminative power for survival and eGFR. Thus, digital high-resolution assessment of CD68+ leukocyte infiltration significantly improves prognostic value of early renal transplant biopsies. PMID- 28359538 TI - Radiation-induced rib fractures after stereotactic body radiation therapy: Predict to prevent? PMID- 28359539 TI - It is the function of regenerating liver parenchyma that explains the small for size syndrome. PMID- 28359540 TI - Five-year-olds do not show ambiguity aversion in a risk and ambiguity task with physical objects. AB - Ambiguity aversion arises when a decision maker prefers risky gambles with known probabilities over equivalent ambiguous gambles with unknown probabilities. This phenomenon has been consistently observed in adults across a large body of empirical work. Evaluating ambiguity aversion in young children, however, has posed methodological challenges because probabilistic representations appropriate for adults might not be understood by young children. Here, we established a novel method for representing risk and ambiguity with physical objects that overcomes previous methodological limitations and allows us to measure ambiguity aversion in young children. We found that individual 5-year-olds exhibited consistent choice preferences and, as a group, exhibited no ambiguity aversion in a task that evokes ambiguity aversion in adults. Across individuals, 5-year-olds exhibited greater variance in ambiguity preferences compared with adults tested under similar conditions. This suggests that ambiguity aversion is absent during early childhood and emerges over the course of development. PMID- 28359541 TI - Ischaemic stroke and liver fibrosis. PMID- 28359542 TI - Food avoidance in patients with inflammatory bowel disease: What, when and who? AB - BACKGROUND & AIMS: Patients with inflammatory bowel diseases avoid a variety of foods. However, it remains unclear how this behavior varies across patients. This cross-sectional study investigated how the food avoidance pattern in inflammatory bowel disease varies according to disease's activity, disease's subtype, Crohn's location, and prior history of bowel resection, strictures, and fistulae. METHODS: Outpatients with Crohn's disease (n = 173) and ulcerative colitis (n = 72) reported which food they avoid when they perceive they are in remission or in active disease using a list of 82 food items classified in 10 categories. Medical charts were reviewed for patients' characteristics. Linear regression analyses were used to compare food exclusion rates between patients' subgroups and food categories. RESULTS: During remission, food exclusion rates varied from 1 to 39%. Most avoided foods were those with capsaicin, meat alternatives, and raw vegetables. Overall, food exclusion rates were 38% higher in Crohn's disease than ulcerative colitis (P < 0.001), and 50% higher in stricturing than non stricturing Crohn's disease (P < 0.001). During active disease, food exclusion rates were 69% higher than in remission (P < 0.001). Similar differences between subgroups were again observed during active disease though less noticeable than in remission. No association was found with other disease characteristics. Avoided foods were very similar across patients except for alcoholic beverages and foods rich in dietary fibers/residue, which were avoided more specifically during active disease and in Crohn's disease, respectively. CONCLUSIONS: Food avoidance is common among patients with inflammatory bowel diseases, and most particularly in those with stricturing Crohn's disease. Specificities in avoidance pattern suggest that the clinical response to dietary restrictions may differ according to the disease's characteristics. PMID- 28359543 TI - Monitoring in vivo function of cortical microglia. AB - Microglia, the innate immune cells of the brain, are becoming increasingly recognized as an important player both in the context of physiological brain function and brain pathology. To fulfill their executive functions microglia can modify their morphology, migrate or move their processes in a directed fashion, and modify the intracellular Ca2+ dynamics leading to modifications in gene expression, phagocytosis, release of cytokines and other inflammation markers, etc. Here we describe the recently developed tools enabling in vivo monitoring of morphology and Ca2+ signaling of microglia and show how these techniques may be used for examining microglial function in healthy and diseased brain. PMID- 28359544 TI - Corrigendum to : [British Journal of Oral and Maxillofacial Surgery 54/1 (2016) 83-87]. PMID- 28359545 TI - Automated Identification of Diabetic Retinopathy Using Deep Learning. AB - PURPOSE: Diabetic retinopathy (DR) is one of the leading causes of preventable blindness globally. Performing retinal screening examinations on all diabetic patients is an unmet need, and there are many undiagnosed and untreated cases of DR. The objective of this study was to develop robust diagnostic technology to automate DR screening. Referral of eyes with DR to an ophthalmologist for further evaluation and treatment would aid in reducing the rate of vision loss, enabling timely and accurate diagnoses. DESIGN: We developed and evaluated a data-driven deep learning algorithm as a novel diagnostic tool for automated DR detection. The algorithm processed color fundus images and classified them as healthy (no retinopathy) or having DR, identifying relevant cases for medical referral. METHODS: A total of 75 137 publicly available fundus images from diabetic patients were used to train and test an artificial intelligence model to differentiate healthy fundi from those with DR. A panel of retinal specialists determined the ground truth for our data set before experimentation. We also tested our model using the public MESSIDOR 2 and E-Ophtha databases for external validation. Information learned in our automated method was visualized readily through an automatically generated abnormality heatmap, highlighting subregions within each input fundus image for further clinical review. MAIN OUTCOME MEASURES: We used area under the receiver operating characteristic curve (AUC) as a metric to measure the precision-recall trade-off of our algorithm, reporting associated sensitivity and specificity metrics on the receiver operating characteristic curve. RESULTS: Our model achieved a 0.97 AUC with a 94% and 98% sensitivity and specificity, respectively, on 5-fold cross-validation using our local data set. Testing against the independent MESSIDOR 2 and E-Ophtha databases achieved a 0.94 and 0.95 AUC score, respectively. CONCLUSIONS: A fully data driven artificial intelligence-based grading algorithm can be used to screen fundus photographs obtained from diabetic patients and to identify, with high reliability, which cases should be referred to an ophthalmologist for further evaluation and treatment. The implementation of such an algorithm on a global basis could reduce drastically the rate of vision loss attributed to DR. PMID- 28359546 TI - Attributable mortality of hospital-acquired bloodstream infections in Ireland. AB - AIM: To estimate the attributable mortality of hospital-acquired bloodstream infections (HA-BSI) in Ireland. METHODS: A retrospective case-cohort study was conducted, based on notifications from Irish microbiology laboratories and administrative patient records from six Irish hospitals from January 2007 to December 2013. Probabilistic linkage was used to link 1252 cases of bloodstream infection from a cohort of 343,189 hospitalized patients. Independent predictors of mortality were determined using a multi-variable logistic regression model, and included: patient age, emergency or re-admission to hospital, length of stay in an intensive care unit, number of procedures, number of diagnoses, major diagnostic category and presence of HA-BSI. RESULTS: Attributable mortality was calculated from the crude mortality of case subjects after adjusting for other predictors of mortality, and was found to be 15.3% (95% confidence interval 14.8 15.8%). The study was further stratified according to the causative organism, including: Escherichia coli, Enterococcus faecium, Enterococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus aureus and Streptococcus pneumoniae, and, where available, their antimicrobial resistance patterns. The highest attributable mortality among these organisms was reported for E. faecium at 18.1% and the lowest attributable mortality was reported for E. coli at 13.6%. A significantly higher attributable mortality was found for antimicrobial resistance patterns of some organisms, most notably for meticillin resistant S. aureus at 19.5%, vs meticillin-susceptible S. aureus at 13.3%. CONCLUSIONS: HA-BSI is an important cause of mortality, and attributable mortality differs significantly among causative organisms and antimicrobial resistance patterns. PMID- 28359547 TI - Reply from the authors and part of the investigation team. PMID- 28359548 TI - Serum cytokeratin-18 fragment levels as noninvasive marker of nonalcoholic steatohepatitis in the chilean population. AB - : Nonalcoholic steatohepatitis (NASH) is the most aggressive form of nonalcoholic fatty liver disease (NAFLD) and involves the risk of progression to more advanced stages of liver disease. Non-invasive methods are needed to identify patients with NASH. OBJECTIVE: To evaluate the diagnostic performance of the determination of serum levels of cytokeratin-18 (CK-18) as a non-invasive marker of NASH in the Chilean population. METHODS: Serum CK-18 levels were determined in a group of 41 patients with biopsy-proven NAFLD. NASH diagnosis was based on Brunt's criteria (histological parameters and ballooning), and the NAFLD activity score (NAS) and the presence of fibrosis were determined. The correlation between the NAFLD activity score (NAS) and CK-18 was evaluated with Spearman's rank correlation coefficient. A ROC curve was produced to assess the diagnostic value of CK-18 for NASH. The NAFLD fibrosis score (NFS) (to predict fibrosis and NASH) was compared to CK-18 with simple linear regression. Data were expressed in median [25th-75th percentile] and evaluated with the Wilcoxon rank test. RESULTS: The mean age of the study group (23% male) was 50.4+/-11.1 years. 34.2% were diagnosed with NASH (NAS>=5). CK-18 levels were significantly higher in patients with NASH versus those without NASH (183.6 IU/l [97.4 to 734.4] vs. 117.2 IU/l [83.8 to 954.8], p= 0.016). CK-18 levels were a good predictor of NASH on biopsy with an area under the curve (AUC) of 0.732 (95% CI, 0.572 to 0.897). A CK-18 cut-off of 130.5 IU/l had a sensitivity of 92.9%, specificity of 63%, positive predictive value of 56.5% and negative predictive value of 94.4%, and was able to correctly classify 73.2% of patients with NASH. NFS identified advanced liver fibrosis (AUC 0.739, 95% CI, 0.56-0.91), but was of limited value to identify NASH (AUC 0.413, 95% CI, 0.21-0.61). CONCLUSION: CK-18 is a good non-invasive marker for NASH. Although NFS was found to be an accurate marker of advanced liver fibrosis, it was not of value to identify NASH. In patients with NAFLD, CK-18 and NFS could be useful in predicting NASH and liver fibrosis, respectively. PMID- 28359549 TI - Tailgut cysts: Presentation of four cases. PMID- 28359550 TI - Out-of-pocket expenditure and financial protection in the Chilean health care system-A systematic review. AB - BACKGROUND: Protection against financial risk due to medical spending is an explicit health guarantee within Chile's AUGE health reform. This paper seeks to analyze the degree to which out-of-pocket expenditure still expose Chilean households to financial catastrophe and impoverishment, and to explore inequalities in financial protection. METHODS: A systematic literature review was conducted to identify empirical studies analyzing financial protection in Chile. The search included databases as well as grey literature, i.e. governmental and institutional webpages. The indicators are based on the conceptual framework of financial protection, as portrayed in the World Health Report 2013. RESULTS: We identify n=16 studies that fulfill the inclusion criteria. Empirical studies indicate that 4% of Chilean households faced catastrophic health expenditure defined as out-of-pocket expenditure exceeding 30% of household's capacity to pay, while less than 1% were pushed into poverty in 2012. In contrast to prior studies, recent data report that even publicly insured who should be fully protected from co-payments were affected by catastrophic health expenditure. Also in the private insurance system financial catastrophe is a common risk. CONCLUSION: Despite health reform efforts, financial protection is insufficient and varies to the disadvantage of the poor and vulnerable groups. More research is required to understand why current mechanisms are not as effective as expected and to enable according reforms of the insurance system. PMID- 28359551 TI - Physician payment schemes and physician productivity: Analysis of Turkish healthcare reforms. AB - Following healthcare reforms in Turkey, inpatient and outpatient care provided in public hospitals more than doubled from 2003 to 2006. An important component of the reforms has been a shift from a salary based physician compensation scheme to one where fee-for-service component is dominant. The change did not only incentivize physicians to provide a higher volume of services but also encouraged them to practice full-time, rather than dual-time, in public hospitals. Lacking figures on full-time equivalent figures at hospital level, earlier research used head-counts for physician workforce and found technological change and scale economies to be important determinants. We employ data envelopment analysis and find that, under plausible scenarios regarding the number of dual vs full-time physician numbers, most of the change in hospital services may be explained only by the shift to full-time practice. Our estimations find the change in technology and scale economies to play a relatively minor role. PMID- 28359552 TI - Development of aqueous mobile phase using chaotrope for the chromatographic determination of melamine in infant formula. AB - Direct analysis of melamine using reverse phase chromatography is a challenge because this compound's small size and strong polar nature leads to abnormal peak symmetry as well as poor retention. Here, we introduce a simple and reliable reverse phase liquid chromatographic method using sodium hexafluorophosphate to modify an acidic aqueous eluent, resulting in improved chromatographic behaviors of melamine in complex food matrices. Variables affecting the retention mechanism, including chaotrope type, concentration and stationary phase, were investigated. Under optimum conditions, melamine retention, separation efficiency, peak shape and reproducibility were significantly improved as compared to other methods that use ionic liquids or a micellar mobile phase. No interference affected melamine detection when infant formula was applied as the food matrix. Analytical reliability was demonstrated through estimation of validation parameters such as specificity, linearity, precision, accuracy and recovery. This method is suitable for routine analysis of melamine in infant formula. More noteworthy, this is the first time that an organic solvent-free mobile phase using chaotropic salt, meeting the concept of green chemistry, has been proposed. PMID- 28359553 TI - Planar yeast estrogen screen with resorufin-beta-d-galactopyranoside as substrate. AB - For the planar yeast estrogen screen (pYES), 4-methylumbelliferyl-beta-d galactopyranoside was generally employed as substrate, delivering blue fluorescing 4-methylumbelliferone after enzymatic cleavage by the YES reporter beta-d-galactosidase as the positive signal for the presence of estrogen active compounds (EAC). As environmental samples like waste water also contain blue fluorescent components, it is difficult to differentiate them from pYES signals. Therefore, resorufin-beta-d-galactopyranoside (RGP), providing the orange fluorescing resorufin after enzymatic cleavage, was introduced as pYES substrate to determine EAC. With 17beta-estradiol (E2) and 17alpha-ethinylestradiol (EE2), mean limits of detection and quantitation of 3.5 and 6.5pg/zone, respectively, were determined. Obtained recoveries for both E2 and EE2 from spiked water samples in a concentration range of 2-20ng/L were close to 100%. The application of the RGP-pYES on waste water influent and effluent samples showed the clear detection of EAC without interferences. Estrone (E1), Estriol, E2, and an unknown EAC were found in the influent sample (E2 with a mean of 16.9 ng/L and a precision of 11% RSD; n=4), while another unknown EAC was observed in the effluent sample. In addition, the presence of conjugated EAC in the influent was demonstrated by hydrolysis with beta-glucuronidase, when the signals of E1 and the unknown increased by about 25% and 100%, respectively. PMID- 28359554 TI - Solvent bar microextraction using a reverse micelle containing extraction phase for the determination of warfarin from human plasma by high-performance liquid chromatography. AB - For the first time, solvent bar microextraction using a reverse micelle RMM-SBME as extraction phase was developed for extraction of warfarin in human plasma sample. The reverse micelle of a cationic surfactant (hexadecyltrimethylammonium bromide) in 1-octanol was applied as supported and acceptor phase in SBME. In this process, the analyte was extracted from aqueous samples into a reverse micelle impregnated and also filled in the wall pores and lumen the polypropylene hollow fiber membrane by the electrostatic interactions between the analyte and the surfactant head groups. The influences of fundamental parameters affecting extraction efficiency of warfarin including sample solution pH, surfactant concentration and extraction time were studied using central composite design optimization method. The analysis of extracted analyte was performed by high performance liquid chromatography with ultra violet detector. Under the optimum condition, the sample containing 40ngmL-1 of warfarin was extracted with extraction recovery of 97.8% that pertained to enrichment factor of 260. A good linearity over a concentration range 1-600ngmL-1 with correlation coefficient value of 0.9989 was provided by the current method. Limits of detection and inner and inter-day relative standard deviation were 0.3ngmL-1 and less than 4.4%, respectively. This method was compared to conventional SBME, and illustrated higher extraction efficiency. The method needs minimal sample preparation time since the porous hollow fiber membrane prevents from being extracted potential interfering materials, acts as a filter, and any extra cleanup was not required. The method with bar of 3cm and acceptor phase volume of 8.5MUL is environmentally green/friendly method. The proposed method was successfully applied for the preconcentration and determination of warfarin in plasma sample. PMID- 28359555 TI - Simple four column classification can dictate treatment for intra articular tibial plateau fractures much better than ten segment classification. PMID- 28359556 TI - Valve replacement surgery in severe chronic kidney disease. AB - BACKGROUND: The impact of prosthetic choices in patients with severe chronic kidney disease (CKD) on long-term outcomes has not been well established. METHODS: The study involved 152 adult patients (61.6+/-14.1yrs.; 64 females) undergoing heart valve surgery who had stage 4 (n=87) or 5 CKD (end-stage; n=65) based on Kidney Disease Outcomes Quality Initiative Guidelines. To reduce the impact of selection bias between mechanical (n=92) and bio-prostheses groups (n=60), propensity score analyses were conducted. RESULTS: Patients undergoing bioprosthetic replacement were significantly older and had poorer left ventricular function compared with those undergoing mechanical valve replacements. Early mortality rates were 10.0% in the Bio-prostheses group and 9.8% in the Mechanical group (P>0.99). During a median duration of 22.1months (Quartile 1-3, 4.7-68.1months; 87.5% complete), 56 patients died and 12 patients experienced valve-related complications. The unadjusted outcomes showed no significant differences in survival (P=0.23) and freedom from valve-related events (P=0.17). After adjustment, there was no significant difference in survival (Hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.62-1.71; P=0.91), however the bio-prostheses group showed significant superior outcomes of freedom from valve-related event (HR, 4.49; 95% CI, 1.04-19.45; P=0.045). CONCLUSIONS: Valve replacement in CKD patients showed very high mortality risks and limited life expectancy even in younger individuals. When compared with bioprosthetic replacement, mechanical valve replacement showed similar survival rate but with greater risks of developing major valve-related complications in these patients. Therefore, bioprosthetic replacement may be a more reasonable option over mechanical replacement in these high-risk patients. PMID- 28359557 TI - Chemocauterization of second branchial cleft fistula using trichloroacetic acid: A preliminary report. AB - OBJECTIVE: Although second branchial cleft fistula (BCF) can be well treated with surgical excision, neck scarring is unavoidable. We previously reported chemocauterization with trichloroacetic acid (TCA) to close various fistulas. Here, we report chemocauterization of a second BCF without a consequent incision scar. METHODS: This procedure was applied in four pediatric patients whose parents were reluctant to undergo surgical excision for a second BCF. Under general anesthesia, a thin metal suction tip or cut down tube was inserted through the skin opening. Normal saline with or without dye was injected to identify the pharyngeal opening around the palatine tonsil, and 75% TCA solution mixed with dye was injected. Leaked TCA at the pharynx was sucked out meticulously to avoid extensive and unexpected injury to the mucosa, and the external opening was sealed with a thin adhesive film. RESULTS: There were no immediate complications and recurrence of a second BCF in all patients during the median follow-up of 23 months (range, 18-88 months) with minimal neck scarring. CONCLUSION: TCA chemocauterization of second BCF could be a simple, less invasive, and feasible treatment option in pediatric patients. PMID- 28359558 TI - Sialendoscopic removal of fish bone-induced sialoliths in the duct of the submandibular gland. AB - Obstructive sialadenitis of the submandibular gland is commonly caused by sialoliths, but more rarely by foreign body-induced sialoliths. Here, we report minimally invasive sialendoscopic removal of fish bone-induced sialoliths in the duct of the submandibular gland. A 43-year-old woman presented with recurrent swelling of the right submandibular gland at other hospital. Computed tomography (CT) showed an 8-mm linear calcification in the posterior part of Wharton's duct. The lesion was deemed difficult to remove and she was followed up. However, because the lesion did not resolve spontaneously within 9 months and chronic sialadenitis symptoms persisted, she was referred to our department for endoscopic removal. CT showed a linear calcification (5.6*1.2*0.8mm) connecting 2 spherical calcifications (2.3*2.1*1.9mm; 1.8*1.4*1.1mm) in the anterior part of Wharton's duct. The patient underwent endoscopic removal of the lesion using a 1.6-mm-diameter sialendoscope under local anesthesia. The specimen contained a fish bone connecting 2 sialoliths. The patient was unaware of the fish-bone injury. After removal, there was no recurrence of submandibular gland swelling during 6 months follow-up. PMID- 28359559 TI - Preoperative anemia and outcomes in patients undergoing surgery for inflammatory bowel disease. AB - BACKGROUND: Anemia is the most common extraintestinal manifestation in patients with inflammatory bowel disease (IBD), and has been linked to severity of the disease. The aim of the study was to assess the impact of anemia on postoperative outcomes in patients with IBD. METHODS: We retrospectively reviewed patients with IBD from the NSQIP database over an 8-year period. Patients were grouped based on the presence of anemia. The impact of anemia on postoperative morbidity, mortality and length of stay was assessed. RESULTS: A total of 15,761 patients met our criteria. Half of the patients were anemic upon presentation. Anemic patients were more likely to have a history of steroid use, present with sepsis and require an emergency operation. In multivariate analysis, anemia was a significant predictor of overall morbidity, serious morbidity and increased length of stay. CONCLUSIONS: Anemic patients with IBD present more often with sepsis and require emergency surgery compared to their peers. In addition, anemia serves as an independent predictor of overall complications, serious morbidity and increased length of stay following abdominal operations. PMID- 28359561 TI - [One more contribution to Geriatric intervention in older people hospitalised due to hip fracture]. PMID- 28359560 TI - Distal scar-to-midline distance in pilonidal Limberg flap surgery is a recurrence promoting factor: A multicenter, case-control study. AB - BACKGROUND: The Limberg flap (LF) procedure is widely performed for the treatment of sacrococcygeal pilonidal sinus (SPS); however, recurrences continues to be observed. The aim of this study was to assess the relationship between LF designs and the risk of SPS recurrence. METHODS: Sixty-one cases with recurrent disease (study group) and 194 controls, with a minimum of 5 recurrence-free years following surgery (control group), were included in the study. LF reconstructions performed in each group were classified as off-midline closure (OMC) and non-OMC types. Subsequently, the 2 groups were analyzed. RESULTS: After adjustment for all variables, non-OMC types showed the most prominent correlation with recurrence, followed by interrupted suturing type, family history of SPS, smoking, prolonged healing time, and younger age. The best cut-off value for the critical distance from the midline was found to be 11 mm (with 72% sensitivity and 95% specificity for recurrence). CONCLUSIONS: We recommend OMC modifications, with the flap tailored to create a safe margin of at least 2 cm between the flap borders and the midline. PMID- 28359562 TI - [The importance of body mass index in the strength]. PMID- 28359563 TI - Management of pancreatic trauma: a literature review. AB - The European Union of Medical Specialists, founded in 1958, is the largest and oldest european medical organization. It includes 39 member states (of the European Union and others), and represents a total of 1.600.000 medical specialists. The main objective of the UEMS is to influence european healthcare politics by promoting the interests of the european medical specialists, establishing high standards in practice and training, as well as continuing medical education and professional development, and guaranteeing quality in specialist practice. The UEMS is developing several projects to face current and future challenges related to surgical training, education, acreditation, revalidation and professional development: i.- First, the UEMS is developing homogeneous requisites for European Training (ETRs), ii.- To manage the quality control process of the ETRs and evaluation of the organization, the UEMS has created the Council of european specialized medial evaluations (CESMA), iii.- The UEMS has been greatly involved in the acreditation process of training centres in all of Europe, iv.- in relation to continuing medical education, the European Accreditation Council for Continuing Medical Education (EACCME) is the main project of the UEMS for the accreditation of educational events and v.- the UEMS has established the Network of Accredited Clinical Skills Centres of Europe (UEMS NASCE), that facilitates the accreditation and cooperation of training centres in Europe. In conclusion, with the great support of National Surgical Societies of the UEMS and the Surgery Section a series of solid projects have been established to support the professional development of the collective in Europe. This process constitutes a continuous effort that is very gratifying, with the aim to set the standards for a brilliant future for surgery students and specialized surgeons. PMID- 28359564 TI - Cingulate Overexpression of Mitogen-Activated Protein Kinase Phosphatase-1 as a Key Factor for Depression. AB - BACKGROUND: Depression is frequently associated with chronic pain or chronic stress. Among cortical areas, the anterior cingulate cortex (ACC, areas 24a and 24b) appears to be important for mood disorders and constitutes a neuroanatomical substrate for investigating the underlying molecular mechanisms. The current work aimed at identifying ACC molecular factors subserving depression. METHODS: Anxiodepressive-like behaviors in C57BL/6J male mice were induced by neuropathic pain, unpredictable chronic mild stress, and optogenetic ACC stimulation and were evaluated using novelty suppressed feeding, splash, and forced swim tests. ACC molecular changes in chronic pain-induced depression were uncovered through whole genome expression analysis. Further mechanistic insights were provided by chromatin immunoprecipitation, Western blot, and immunostaining. The causal link between molecular changes and depression was studied using knockout, pharmacological antagonism, and local viral-mediated gene knockdown. RESULTS: Under chronic pain-induced depression, gene expression changes in the ACC highlighted the overexpression of a regulator of the mitogen-activated protein kinase pathway, mitogen-activated protein kinase phosphatase-1 (MKP-1). This upregulation is associated with the presence of transcriptionally active chromatin marks (acetylation) at its proximal promoter region as well as increased cyclic adenosine monophosphate response element-mediated transcriptional activity and phosphorylation of cyclic adenosine monophosphate response element binding protein and activating transcription factor. MKP-1 overexpression is also observed with unpredictable chronic mild stress and repeated ACC optogenetic stimulation and is reversed by fluoxetine. A knockout, an antagonist, or a local silencing of MKP-1 attenuates depressive-like behaviors, pointing to an important role of this phosphatase in depression. CONCLUSIONS: These data point to ACC MKP-1 as a key factor in the pathophysiology of depression and a potential target for treatment development. PMID- 28359565 TI - Deficits in Neurite Density Underlie White Matter Structure Abnormalities in First-Episode Psychosis. AB - BACKGROUND: Structural abnormalities across multiple white matter tracts are recognized in people with early psychosis, consistent with dysconnectivity as a neuropathological account of symptom expression. We applied advanced neuroimaging techniques to characterize microstructural white matter abnormalities for a deeper understanding of the developmental etiology of psychosis. METHODS: Thirty five first-episode psychosis patients, and 19 healthy controls, participated in a quantitative neuroimaging study using neurite orientation dispersion and density imaging, a multishell diffusion-weighted magnetic resonance imaging technique that distinguishes white matter fiber arrangement and geometry from changes in neurite density. Fractional anisotropy (FA) and mean diffusivity images were also derived. Tract-based spatial statistics compared white matter structure between patients and control subjects and tested associations with age, symptom severity, and medication. RESULTS: Patients with first-episode psychosis had lower regional FA in multiple commissural, corticospinal, and association tracts. These abnormalities predominantly colocalized with regions of reduced neurite density, rather than aberrant fiber bundle arrangement (orientation dispersion index). There was no direct relationship with active symptoms. FA decreased and orientation dispersion index increased with age in patients, but not control subjects, suggesting accelerated effects of white matter geometry change. CONCLUSIONS: Deficits in neurite density appear fundamental to abnormalities in white matter integrity in early psychosis. In the first application of neurite orientation dispersion and density imaging in psychosis, we found that processes compromising axonal fiber number, density, and myelination, rather than processes leading to spatial disruption of fiber organization, are implicated in the etiology of psychosis. This accords with a neurodevelopmental origin of aberrant brain-wide structural connectivity predisposing individuals to psychosis. PMID- 28359567 TI - A geospatial analysis of land use and stormwater management on fecal coliform contamination in North Carolina streams. AB - Although non-point source (NPS) pathogen pollution is a leading cause of stream impairment in the United States, the sources of NPS pollution are often difficult to ascertain. While previous studies have employed land use regression methods to develop a greater understanding of the sources and dynamics of microbial NPS pollution, little work has explicitly considered the effects of local, state, and federal stormwater management policies on water quality across multiple watersheds or at larger spatial scales. How do land use and stormwater management efforts collectively influence fecal coliform (FC) levels at a regional or multiple-watershed scale? We construct a unique spatial regression model of stream FC pollution (n=327 monitoring stations) throughout the state of North Carolina (USA), incorporating both land cover and urban development variables. We then use a subset of our data (nbmp=80 monitoring stations) to incorporate local stormwater control measures and stormwater management policies. Results demonstrate that the inclusion of policy and management variables improves the explanatory capacity for FC levels (R2=0.4412 versus R2=0.5323). Locally, this model can be used to better target stream restoration and water quality mitigation actions and investments, as well as help to predict FC levels at unmonitored locations throughout North Carolina's stream network. More generally, the novel structure of this model can also help examine the large-scale effects of stormwater regulations on surface water pathogen levels, helping researchers and planners better predict water quality in the absence of extensive monitoring station data. PMID- 28359566 TI - Increased Plasma Beta-Secretase 1 May Predict Conversion to Alzheimer's Disease Dementia in Individuals With Mild Cognitive Impairment. AB - BACKGROUND: Increased beta-secretase 1 (BACE1) activity has consistently been detected in brain tissue and cerebrospinal fluid of subjects with mild cognitive impairment (MCI) and probable Alzheimer's disease (AD) compared with control subjects. The collection of cerebrospinal fluid by lumbar puncture is invasive. We sought to identify the presence of plasma BACE1 activity and determine potential alterations in subjects with MCI with clinical follow-up examinations for 3 years using patients with diagnosed probable AD dementia compared with healthy control subjects. METHODS: Seventy-five patients with probable AD, 96 individuals with MCI, and 53 age-matched and sex-matched healthy control subjects were recruited from three independent international academic memory clinics and AD research expert centers. Plasma BACE1 activity was measured by a synthetic fluorescence substrate enzyme-linked immunosorbent assay. BACE1 protein expression was assessed by Western blotting using three different antibodies that recognize the epitopes of the N-terminus, C-terminus, and full-length BACE1. RESULTS: Compared with healthy control subjects, plasma BACE1 activity (Vmax) significantly increased by 53.2% in subjects with MCI and by 68.9% in patients with probable AD. Subjects with MCI who converted to probable AD dementia at follow-up examinations exhibited significantly higher BACE1 activity compared with cognitively stable MCI nonconverters and showed higher levels of BACE1 activity than patients with AD. CONCLUSIONS: Plasma BACE1 activity is significantly increased in MCI converters and patients with probable AD. The sensitivities and specificities of BACE1 activity for the patients were 84% and 88%, respectively. Our results indicate that plasma BACE1 activity may be a biomarker for AD risk and could predict progression from prodromal to probable AD dementia. PMID- 28359568 TI - Characterization of urban CO2 column abundance with a portable low resolution spectrometer (PLRS): Comparisons with GOSAT and GEOS-Chem model data. AB - We presented the characterization of urban CO2 column abundance (XCO2) in Hefei, China using a portable low resolution spectrometer (PLRS). An optimized correction spectrum was introduced in the spectral fitting to improve CO2 retrieval. A pronounced seasonal cycle and diurnal variation were observed with a precision of ~0.12%. The CO2 concentrations in winter are about 5-10ppm higher than those in summer. Most diurnal variations exhibited downward trends. The measurement in the early morning is about 2-5ppm higher than the late afternoon observation. The causes of the seasonal and diurnal trends were systematic analyzed. The coincident CO2 time series were compared with the Greenhouse Gases Observing SATellite (GOSAT) data and the GEOS-Chem global 3-D tropospheric chemistry model data. We found the ground based (g-b) PLRS data are systematically higher than the GOSAT and the GEOS-Chem data. Compared to the GOSAT data, the g-b PLRS data are 0.26ppm (0.07%) higher with a standard deviation of 1.70ppm (0.43%). Compared to the smoothed GEOS-Chem model data, the g-b PLRS data shows a 1.31ppm (0.33%) higher with a standard deviation of 5.30ppm (0.87%). The g-b PLRS generally reproduced the seasonal cycle observed by GOSAT and GEOS-Chem model with correlation coefficients (r) of 0.82 and 0.64, respectively. PMID- 28359569 TI - Understanding controls on redox processes in floodplain sediments of the Upper Colorado River Basin. AB - Floodplains, heavily used for water supplies, housing, agriculture, mining, and industry, are important repositories of organic carbon, nutrients, and metal contaminants. The accumulation and release of these species is often mediated by redox processes. Understanding the physicochemical, hydrological, and biogeochemical controls on the distribution and variability of sediment redox conditions is therefore critical to developing conceptual and numerical models of contaminant transport within floodplains. The Upper Colorado River Basin (UCRB) is impacted by former uranium and vanadium ore processing, resulting in contamination by V, Cr, Mn, As, Se, Mo and U. Previous authors have suggested that sediment redox activity occurring within organic carbon-enriched bodies located below the groundwater level may be regionally important to the maintenance and release of contaminant inventories, particularly uranium. To help assess this hypothesis, vertical distributions of Fe and S redox states and sulfide mineralogy were assessed in sediment cores from three floodplain sites spanning a 250km transect of the central UCRB. The results of this study support the hypothesis that organic-enriched reduced sediments are important zones of biogeochemical activity within UCRB floodplains. We found that the presence of organic carbon, together with pore saturation, are the key requirements for maintaining reducing conditions, which were dominated by sulfate-reduction products. Sediment texture was found to be of secondary importance and to moderate the response of the system to external forcing, such as oxidant diffusion. Consequently, fine-grain sediments are relatively resistant to oxidation in comparison to coarser-grained sediments. Exposure to oxidants consumes precipitated sulfides, with a disproportionate loss of mackinawite (FeS) as compared to the more stable pyrite. The accompanying loss of redox buffering capacity creates the potential for release of sequestered radionuclides and metals. Because of their redox reactivity and stores of metals, C, and N, organic enriched sediments are likely to be important to nutrient and contaminant mobility within UCRB floodplain aquifers. PMID- 28359570 TI - Sensitivity of ACL volume and T2* relaxation time to magnetic resonance imaging scan conditions. AB - Anterior cruciate ligament (ACL) volume and T2* relaxation times from magnetic resonance (MR) images have been previously shown to predict the structural properties of healing ligaments. We investigated whether MR imaging scan resolution and condition (in vivo, in situ, or ex vivo) affected ACL volume and T2* relaxation times in intact ligaments. ACLs of 14 pigs were imaged using a 3T scanner and a six-channel flexcoil using at least two of four possible scan conditions: (1) in vivo moderate resolution (n=14); (2) in vivo high resolution (n=7); (3) in situ high resolution acquired within 60 minutes of euthanasia (n=6); and (4) ex vivo high resolution following hind limb disarticulation and one freeze-thaw cycle (n=7). T2* relaxation times were mapped to the ACL voxels. The total ACL volume was then divided into four sub-volumes (Vol1-4) based on predetermined increasing ranges of T2* times. ACL T2* statistics (first quartile, median, and standard deviation (SD)) were computed. Scan resolution had no effect on the total ACL volume, but Vol1 and first quartile T2* times decreased with high resolution and in situ/ex vivo scan conditions. The most dramatic differences in T2* summary statistics were between in vivo moderate and ex vivo high resolution scan conditions that included a freeze-thaw cycle: ACL T2* SD increased by over 50% in 9 animals, and more than 90% in 4 animals. Our results indicated that T2*-based prediction models to quantify in vivo structural properties of healing ligaments should be based on high resolution in vivo MR scan conditions. PMID- 28359571 TI - Achilles tendon stress is more sensitive to subject-specific geometry than subject-specific material properties: A finite element analysis. AB - This study used subject-specific measures of three-dimensional (3D) free Achilles tendon geometry in conjunction with a finite element method to investigate the effect of variation in subject-specific geometry and subject-specific material properties on tendon stress during submaximal isometric loading. Achilles tendons of eight participants (Aged 25-35years) were scanned with freehand 3D ultrasound at rest and during a 70% maximum voluntary isometric contraction. Ultrasound images were segmented, volume rendered and transformed into subject-specific 3D finite element meshes. The mean (+/-SD) lengths, volumes and cross-sectional areas of the tendons at rest were 62+/-13mm, 3617+/-984mm3 and 58+/-11mm2 respectively. The measured tendon strain at 70% MVIC was 5.9+/-1.3%. Subject specific material properties were obtained using an optimisation approach that minimised the difference between measured and modelled longitudinal free tendon strain. Generic geometry was represented by the average mesh and generic material properties were taken from the literature. Local stresses were subsequently computed for combinations of subject-specific and generic geometry and material properties. For a given geometry, changing from generic to subject-specific material properties had little effect on the stress distribution in the tendon. In contrast, changing from generic to subject-specific geometry had a 26-fold greater effect on tendon stress distribution. Overall, these findings indicate that the stress distribution experienced by the living free Achilles tendon of a young and healthy population during voluntary loading are more sensitive to variation in tendon geometry than variation in tendon material properties. PMID- 28359572 TI - Forests and Their Canopies: Achievements and Horizons in Canopy Science. AB - Forest canopies are dynamic interfaces between organisms and atmosphere, providing buffered microclimates and complex microhabitats. Canopies form vertically stratified ecosystems interconnected with other strata. Some forest biodiversity patterns and food webs have been documented and measurements of ecophysiology and biogeochemical cycling have allowed analyses of large-scale transfer of CO2, water, and trace gases between forests and the atmosphere. However, many knowledge gaps remain. With global research networks and databases, and new technologies and infrastructure, we envisage rapid advances in our understanding of the mechanisms that drive the spatial and temporal dynamics of forests and their canopies. Such understanding is vital for the successful management and conservation of global forests and the ecosystem services they provide to the world. PMID- 28359573 TI - Next-Generation Global Biomonitoring: Large-scale, Automated Reconstruction of Ecological Networks. AB - We foresee a new global-scale, ecological approach to biomonitoring emerging within the next decade that can detect ecosystem change accurately, cheaply, and generically. Next-generation sequencing of DNA sampled from the Earth's environments would provide data for the relative abundance of operational taxonomic units or ecological functions. Machine-learning methods would then be used to reconstruct the ecological networks of interactions implicit in the raw NGS data. Ultimately, we envision the development of autonomous samplers that would sample nucleic acids and upload NGS sequence data to the cloud for network reconstruction. Large numbers of these samplers, in a global array, would allow sensitive automated biomonitoring of the Earth's major ecosystems at high spatial and temporal resolution, revolutionising our understanding of ecosystem change. PMID- 28359574 TI - Gene Drives and Rodent Control: Response to Piaggio et al. PMID- 28359575 TI - Inaccuracy and bias in adult skeletal age estimation: Assessing the reliability of eight methods on individuals of varying body sizes. AB - Accurate age estimations are essential for identifying human skeletal remains and narrowing missing persons searches. This study examines how BMI, body mass, and stature influence inaccuracy and bias in adult skeletal age estimations obtained using eight methods. 746 skeletons from the Hamann-Todd and William Bass Collections were used. Underweight BMI, light body mass, and short-stature individuals have the most error associated with their age estimates and are consistently under-aged between 3 to 13years. Obese BMI, heavy body mass, and tall-stature individuals are consistently over-aged between 3 to 8.5years. The most reliable methods for smaller-bodied individuals are Kunos et al. (first rib) and Buckberry-Chamberlain (auricular surface); for individuals in the average range, Iscan et al. (fourth ribs) and Passalacqua (sacrum); and for larger-bodied individuals, Iscan et al., Passalacqua, and Rouge-Maillart et al. (auricular surface and acetabulum). Lovejoy et al. (auricular surface) and Suchey-Brooks (pubic symphysis) produce consistent inaccuracy and bias scores across all body size groups. The least reliable method for smaller-bodied individuals is Iscan et al.; for larger-bodied individuals, Buckberry-Chamberlain; and across all body size groups, DiGangi et al. (first rib). PMID- 28359576 TI - Teaching congenital heart disease: A new era? PMID- 28359577 TI - Resection of pulmonary sarcomatous metastases: Cut to cure? PMID- 28359578 TI - Simulation in congenital cardiac surgical education: We have arrived. PMID- 28359579 TI - Therapeutic interventional endoscopic bail-out in life-threatening surgical complications. PMID- 28359580 TI - Racialized legal status as a social determinant of health. AB - This article advances the concept of racialized legal status (RLS) as an overlooked dimension of social stratification with implications for racial/ethnic health disparities. We define RLS as a social position based on an ostensibly race-neutral legal classification that disproportionately impacts racial/ethnic minorities. To illustrate the implications of RLS for health and health disparities in the United States, we spotlight existing research on two cases: criminal status and immigration status. We offer a conceptual framework that outlines how RLS shapes disparities through (1) primary effects on those who hold a legal status and (2) spillover effects on racial/ethnic in-group members, regardless of these individuals' own legal status. Primary effects of RLS operate by marking an individual for material and symbolic exclusion. Spillover effects result from the vicarious experiences of those with social proximity to marked individuals, as well as the discredited meanings that RLS constructs around racial/ethnic group members. We conclude by suggesting multiple avenues for future research that considers RLS as a mechanism of social inequality with fundamental effects on health. PMID- 28359581 TI - Health inequities in the age of austerity: The need for social protection policies. AB - This commentary assesses the impacts of the global austerity drive on health inequities in the aftermath of the global financial crisis of 2008. In doing so, it first locates the origins of austerity within the 40 year history of neoliberal economic orthodoxy. It then describes the global diffusion of austerity since 2008, and its key policy tenets. It next describes the already visible impacts of austerity-driven welfare reform on trends in health equity, and documents how austerity has exacerbated health inequities in countries with weak social protection policies. We finally identify the components of an alternative policy response to the financial crisis than that of austerity, with specific reference to the need for shifts in national and global taxation policies and public social protection policies and spending. We conclude with a call for a reorientation of public policy towards making human health an overarching global policy goal, and how this aligns with the multilaterally agreed upon Sustainable Development Goals. PMID- 28359582 TI - Variation in Recombination Rate: Adaptive or Not? AB - Rates of meiotic recombination are widely variable both within and among species. However, the functional significance of this variation remains largely unknown. Is the observed within-species variation in recombination rate adaptive? Recent work has revealed new insight into the scale and scope of population-level variation in recombination rate. These data indicate that the magnitude of within population variation in recombination is similar among taxa. The apparent similarity of the variance in recombination rate among individuals between distantly related species suggests that the relative costs and benefits of recombination that establish the upper and lower bounds may be similar across species. Here we review the current data on intraspecific variation in recombination rate and discuss the molecular and evolutionary costs and benefits of recombination frequency. We place this variation in the context of adaptation and highlight the need for more empirical studies focused on the adaptive value of variation in recombination rate. PMID- 28359583 TI - Enhancer-Derived lncRNAs Regulate Genome Architecture: Fact or Fiction? AB - How does the non-coding portion of the genome contribute to the regulation of genome architecture? A recent paper by Tan et al. focuses on the relationship between cis-acting complex-trait-associated lincRNAs and the formation of chromosomal contacts in topologically associating domains (TADs). PMID- 28359586 TI - Muscarinic acetylcholine receptors participate in small intestinal mucosal homeostasis. AB - BACKGROUND: Intestinal mucosal homeostasis is controlled by multiple factors and an intact, functional mucosa is essential for survival. Maintenance of the epithelium begins with crypt base stem cells which eventually give rise to all epithelial cell types. Evidence suggests an important role of the enteric cholinergic nervous system in these processes. We hypothesized that mice with altered muscarinic signaling would exhibit differences in mucosal morphometric and proliferative parameters compared to wild-type mice. METHODS: Mouse lines specifically deficient in one of the five muscarinic acetylcholine receptors (M1KO-M5KO) were used for experiments. Distal ileal segments were obtained and histologic sections created. Villus height and crypt depth were measured using H&E-stained sections, while crypt proliferation index (CPI) was calculated using Ki67-stained sections. RESULTS: The ileal mucosa from mice deficient in mAChRs exhibited differences from wild-type ileal mucosa in nearly all measured parameters. Knockout of mAChR2, mAChR3 and mAChR5 resulted in changes in all measured parameters. Ileal mucosa from M2KO mice showed an unexpected combination decreased VH but paradoxically increased CD and CPI. CONCLUSIONS: Alterations in mAChR signaling causes change in ileal mucosal morphometry and crypt cell proliferation. While all mAChR subtypes may be involved, mAChR2, mAChR3, and mAChR5 appear to be critical for mucosal homeostasis. Further characterization of these pathways is warranted. PMID- 28359584 TI - Specialize and Divide (Twice): Functions of Three Aurora Kinase Homologs in Mammalian Oocyte Meiotic Maturation. AB - The aurora kinases (AURKs) comprise an evolutionarily conserved family of serine/threonine kinases involved in mitosis and meiosis. While most mitotic cells express two AURK isoforms (AURKA and AURKB), mammalian germ cells also express a third, AURKC. Although much is known about the functions of the kinases in mitosis, less is known about how the three isoforms function to coordinate meiosis. This review is aimed at describing what is known about the three isoforms in female meiosis, the similarities and differences between kinase functions, and speculates as to why mammalian germ cells require expression of three AURKs instead of two. PMID- 28359587 TI - Optimizing surgical resection of the bleeding Meckel diverticulum in children. AB - PURPOSE: Meckel diverticula containing gastric heterotopia predispose to local hyperacidity, mucosal ulceration, and gastrointestinal bleeding in children. Eradication of acid-producing oxyntic cells is performed by either of two surgical methods: segmental enterectomy including the diverticulum or diverticulectomy only. METHODS: Retrospective review of all children having surgical resection of a Meckel diverticulum at a tertiary-referral children's hospital from 2002 to 2016 was performed. Demographic data, surgical method, pathological specimens, and outcomes were evaluated. RESULTS: 102 children underwent surgical resection of a Meckel diverticulum during the study period. 27 (26.5%) children presented with bleeding, of which 16 (59%) had diverticulectomy only, and 11 (41%) had segmental ileal resection. All Meckel diverticula in children presenting with bleeding contained gastric heterotopia, and resection margins were free of gastric mucosa. Histologically, 19 specimens showed microscopic features of ulceration, on average 2.95mm (SD 4.49) from the nearest gastric mucosa (range: 0-16mm). Mean length of hospitalization after ileal resection was 4.0days (SD 1.2) compared to 1.6days (SD 0.9) for diverticulectomy only (p<0.001), with no re-bleeding occurrences. CONCLUSION: In the operative management of children having a bleeding Meckel diverticulum, diverticulectomy only completely eradicates gastric heterotopia without increased risk of continued bleeding or complications and significantly shortens hospitalization. LEVEL OF EVIDENCE: Treatment Study: Level III. PMID- 28359585 TI - Imaging Translational and Post-Translational Gene Regulatory Dynamics in Living Cells with Antibody-Based Probes. AB - Antibody derivatives, such as antibody fragments (Fabs) and single-chain variable fragments (scFvs), are now being used to image traditionally hard-to-see protein subpopulations, including nascent polypeptides being translated and post translationally modified proteins. This has allowed researchers to directly image and quantify, for the first time, translation initiation and elongation kinetics with single-transcript resolution and the temporal ordering and kinetics of post translational histone and RNA polymerase II modifications. Here, we review these developments and discuss the strengths and weaknesses of live-cell imaging with antibody-based probes. Further development of these probes will increase their versatility and open new avenues of research for dissecting complex gene regulatory dynamics. PMID- 28359588 TI - Centrifugal pumps and hemolysis in pediatric extracorporeal membrane oxygenation (ECMO) patients: An analysis of Extracorporeal Life Support Organization (ELSO) registry data. AB - PURPOSE: It is currently unclear whether centrifugal pumps cause more hemolysis than roller pumps in extracorporeal membrane oxygenation (ECMO) circuits. The aim of this study was to help answer that question in pediatric patients. METHODS: A limited deidentified data set was extracted from the international multicenter Extracorporeal Life Support Organization (ELSO) registry comprising all reported ECMO runs for patients 18years or younger between 2010 and 2015. Logistic regression was used to evaluate a possible association between hemolysis and pump type, controlling for patient demographics, circuit factors, and complications. RESULTS: 14,776 ECMO runs for 14,026 patients had pump type recorded. Centrifugal pumps were employed in 60.4% of ECMO circuits. Hemolysis was a reported complication for 1272 (14%) centrifugal pump runs and for 291 (5%) roller pump runs. 1755 (20%) centrifugal pump runs reported kidney injury as compared to 797 (14%) roller pump runs. In the full logistic regression, the odds of hemolysis were significantly greater for runs using centrifugal pumps (OR 3.3, 95% CI 2.9 3.8, p<0.001). CONCLUSIONS: In this retrospective analysis of a large international data set, the use of centrifugal pumps was associated with increased rates of hemolysis, hyperbilirubinemia, and kidney injury. TYPE OF STUDY: Retrospective cohort study. LEVEL OF EVIDENCE: Level III. PMID- 28359589 TI - Extracorporeal and intracorporeal approaches of single-incision laparoscopic appendectomy in children: is one superior to another? AB - BACKGROUND: Single-incision laparoscopic surgery has been widely popularized for pediatric appendicitis. Various techniques have been proposed with two main approaches: extracorporeal and intracorporeal. The purpose of this study is to compare the result of different approaches in single-incision laparoscopic appendectomy (SILA) in children. MATERIAL AND METHODS: With IRB approval, patients less than 18years of age who underwent SILA were enrolled from July 2012 to December 2015. The patients were divided into three groups based on surgical approach: extracorporeal (Extra), mixed (Mix), and intracorporeal (Intra) approaches. Parameters were retrospectively reviewed, including age, gender, white blood cell (WBC), operation time, operative findings, time to diet, length of hospital stay (LOS), and complications. Statistical analysis was performed separately for simple and complicated appendicitis. RESULTS: There were 32, 32, and 24 patients with simple appendicitis in Extra, Mix, and Intra respectively. There were 27, 15, and 31 patients with complicated appendicitis in the three groups, respectively. No significant difference was noted in the mean age, gender distribution, or WBCs between the different groups. A higher percentage of patients with complicated appendicitis received intracorporeal approach than those with simple appendicitis (42.5% vs. 27.3%, p=0.044). In simple appendicitis, the LOS was significantly longer in Extra as compared to Mix (p=0.043). Otherwise, the mean LOS, time to diet, and complications were not significantly different. The mean operation time was similar between groups of simple appendicitis (56.5+/-19.5, 63.6+/-23.5, and 70.1+/-23.1 min, p=0.08), whereas it was significantly shorter in Extra of complicated appendicitis (67.6+/ 16.4, 86.6+/-19.0, and 89.9+/-23.4 min, p<0.001). Multivariate analysis showed that intracorporeal approach is an independent factor for prolonged operation time in both simple and complicated appendicitis. CONCLUSIONS: Different approaches of SILA in children have similar outcomes for both simple and complicated appendicitis. Extracorporeal is the most time efficient; however, intracorporeal can be helpful to deal with complex situations. LEVEL OF EVIDENCE: III. PMID- 28359590 TI - Factors associated with early recurrence after congenital diaphragmatic hernia repair. AB - BACKGROUND: The purpose of this study was to identify patient and treatment characteristics associated with early (in hospital) hernia recurrence after congenital diaphragmatic hernia (CDH) repair. METHODS: Data from the Congenital Diaphragmatic Hernia Study Group registry were queried from 2007 to 2015. Recurrence of the diaphragmatic hernia after initial repair and prior to death or discharge was determined at the time of reoperation. Minimally invasive surgery (MIS) approaches included laparoscopy or thoracoscopy, and open approaches consisted of laparotomy or thoracotomy. Multivariate regression analysis was performed. RESULTS: Of 3984 patients, 3332 (84%) underwent CDH repair. 76 (2.3%) patients had an early recurrence. The rate of recurrence was less variable over time for patients undergoing laparotomy vs thoracoscopy (range: 1.1-3.7% vs 1.7 8.9% annually). Timing of repair, whether performed after, during, or before ECMO did not significantly alter recurrence rates (0% vs 4.2% vs 3.0%, p=0.116). Larger defect size (C: OR 4.3, 95% CI 1.2-15.4; D: OR 7.1, 95% CI 1.7-29.1) and an MIS approach (OR 3.2, 95% CI 1.7-6.0) were the only independent predictors of recurrence. CONCLUSION: Larger defect size and an MIS approach were associated with higher rates of early recurrence, while ECMO use and timing of repair with ECMO were not. TYPE OF STUDY: Treatment study. LEVEL OF EVIDENCE: II. PMID- 28359591 TI - Single stage management of Gustilo type III A/B tibia fractures: Fixed with nail & covered with fasciocutaneous flap. AB - PURPOSE: To evaluate the role of immediate and definitive management of Gustilo type III A/B tibia fractures with intramedullary nailing and fasciocutaneous flap. METHODS: From August 2010 to July 2012, 22 patients with Gustilo Grade III A/B tibia fractures were managed with a single stage treatment of ipsilateral fasciocutaneous flap & reamed intramedullary nailing and were included in the study. The severity of the injury was calculated with Ganga Hospital injury severity score. RESULTS: The mean age of patients was 41 years and the follow-up time ranged from six months to one year. Among the 22 patients, 73% were type III B fractures with upper leg involved in 55% of them. The time interval from injury to completion of surgery was 8-14 h. The incidence of bone infection requiring secondary procedure was 9%; the major and minor soft tissue complication rate was 9% and 14% respectively. The limb salvage rate was 100%. CONCLUSION: Multidisciplinary management of severe lower limb trauma is important and provides good outcomes. Intramedullary nailing and immediate flap fixation can achieve early bone union and good soft tissue coverage, leading to good outcomes in patient with Grade III A & B tibia fractures. PMID- 28359592 TI - Clinical efficacy and safety of limited internal fixation combined with external fixation for Pilon fracture: A systematic review and meta-analysis. AB - PURPOSE: To compare the clinical efficacy and complications of limited internal fixation combined with external fixation (LIFEF) and open reduction and internal fixation (ORIF) in the treatment of Pilon fracture. METHODS: We searched databases including Pubmed, Embase, Web of science, Cochrane Library and China Biology Medicine disc for the studies comparing clinical efficacy and complications of LIFEF and ORIF in the treatment of Pilon fracture. The clinical efficacy was evaluated by the rate of nonunion, malunion/delayed union and the excellent/good rate assessed by Mazur ankle score. The complications including infections and arthritis symptoms after surgery were also investigated. RESULTS: Nine trials including 498 pilon fractures of 494 patients were identified. The meta-analysis found no significant differences in nonunion rate (RR = 1.60, 95% CI: 0.66 to 3.86, p = 0.30), and the excellent/good rate (RR = 0.95, 95% CI: 0.86 to 1.04, p = 0.28) between LIFEF group and ORIF group. For assessment of infections, there were significant differences in the rate of deep infection (RR = 2.18, 95% CI: 1.34 to 3.55, p = 0.002), and the rate of arthritis (RR = 1.26, 95% CI: 1.03 to 1.53, p = 0.02) between LIFEF group and ORIF group. CONCLUSION: LIFEF has similar effect as ORIF in the treatment of pilon fractures, however, LIFEF group has significantly higher risk of complications than ORIF group does. So LIFEF is not recommended in the treatment of pilon fracture. PMID- 28359593 TI - Response to "Re. Analysis of the Elective Treatment Process for Critical Limb Ischaemia with Tissue Loss: Diabetic Patients Require Rapid Revascularisation". PMID- 28359595 TI - Shelf life of diluted human interferon-alpha for veterinary clinical use. AB - BACKGROUND: Oral, low-dose, human interferon (IFN)-alpha treatments have shown efficacy in different models of viral and autoimmune diseases. Human IFN-alpha is commonly used at a daily dose between 1 and 10 IU/kg body weight. Registered products matching these doses at convenient concentrations are lacking. AIM: The stability of sterile, diluted, human leukocyte IFN-alpha was investigated under cold-chain and room temperature conditions. RESULTS: Diluted IFN-alpha displayed moderate decay at room temperature (20-23 degrees C), which should restrict the shelf life to 3-4 days after compounding. On the contrary, a substantial stability was demonstrated over 6 months under cold-chain conditions. Such a stability of IFN-alpha was correlated with the maintenance of Class I MHC modulating properties. CONCLUSION: A shelf life of six months can be envisaged for sterile, diluted preparations of human IFN-alpha under cold-chain conditions, and batch size should be adjusted in accordance with this property. PMID- 28359594 TI - Improvement in postoperative mortality in elective gastrectomy for gastric cancer: Analysis of predictive factors in 1066 patients from a single centre. AB - BACKGROUND: Gastrectomy represents the main treatment for gastric adenocarcinoma. This procedure is associated with substantial morbidity and mortality. The aim of this study was to evaluate the postoperative mortality changes across the study period and to identify predictive factors of 30-day mortality after elective gastrectomy for gastric cancer. METHODS: This was a retrospective cohort study of a prospective database from a single centre. Patients treated with an elective gastrectomy from 1996 to 2014 for gastric adenocarcinoma were included. We compared postoperative mortality between four time periods: 1996-2000, 2001-2005, 2006-2010, and 2011-2014. Univariate and multivariate analyses were applied to identify predictors of 30-day postoperative mortality. RESULTS: We included 1066 patients (median age 65 years; 67% male). The 30-day mortality rate was 4.7%. Mortality decreased across the four time periods; from 6.5% to 1.8% (P = 0.022). In the univariate analysis, age, ASA score, albumin <3.5, multivisceral resection, splenectomy, intrathoracic esophagojejunal anastomosis, R status, and T status were significantly associated with postoperative mortality. In the multivariate analysis, ASA class 3 (OR 10.06; CI 1.97-51.3; P = 0.005) and multivisceral resection (OR 1.6; CI 1.09-2.36; P = 0.016) were associated with higher postoperative 30-day mortality; surgery between 2011 and 2014 was associated with lower postoperative 30-day mortality (OR 0.55; CI 0.33-0.15; P = 0.030). CONCLUSION: There was a decrease in postoperative 30-day mortality during this 18-year period at our institution. We have identified ASA score and multivisceral resection as predictors of 30-day mortality for elective gastrectomy for cancer. PMID- 28359596 TI - [Primary care in Ireland]. AB - Spanish doctors are still leaving the country to look for quality work. Ireland is not a country with many Spanish professionals but it is interesting to know its particular Health care system. Ireland is one of the countries with a national health care system, although it has a mixture of private health care insurance schemes. People have a right to health care if they have been living in Ireland at least for a year. Access to the primary care health system depends on age and income: free of charge for Category 1 and co-payments for the rest. This division generates great inequalities among the population. Primary Care doctors are self-employed, and they work independently. However, since 2001 they have tended to work in multidisciplinary teams in order to strengthen the Primary Care practice. Salary is gained from a combination of public and private incomes which are not differentiated. The role of the General Practitioner consists in the treatment of acute and chronic diseases, minor surgery, child care, etc. There is no coordination between Primary and Secondary care. Access to specialised medicine is regulated by the price of consultation. Primary Care doctors are not gatekeepers. To be able to work here, doctors must have three years of training after medical school. After that, Continuing Medical Education is compulsory, and the college of general practitioners monitors it annually. The Irish health care system does not fit into the European model. Lack of a clear separation between public and private health care generates great inequalities. The non-existence of coordination between primary and specialised care leads to inefficiencies, which Ireland cannot allow itself after a decade of economic crisis. PMID- 28359598 TI - IDF Congress 2017 - Shaping the future of diabetes. PMID- 28359599 TI - [Masters in health economics in Spain. Highly valued and useful training]. PMID- 28359600 TI - Characteristics of tree nut challenges in tree nut allergic and tree nut sensitized individuals. AB - BACKGROUND: Characteristics and outcomes of tree nut (TN) oral food challenges (OFCs) in patients with TN allergy or sensitization alone are poorly studied. OBJECTIVE: To determine the relation between TN sensitization levels and OFC outcomes. METHODS: Open TN OFCs performed from 2007 through 2015 at a referral center were analyzed to compare outcome based on skin prick test (SPT) wheal size, food-specific immunoglobulin E (sIgE), peanut co-allergy, and TN sensitization only vs TN allergy with sensitization to other TNs. Delayed OFC was defined as longer than 12 months from the time of an sIgE level lower than 2 kUA/L. RESULTS: Overall passage rate was 86% for 156 TN OFCs in 109 patients (54 almond, 28 cashew, 27 walnut, 18 hazelnut, 14 pecan, 13 pistachio, and 2 Brazil nut). Passage rates were 76% (n = 67) in patients with a history of TN allergy who were challenged to another TN to which they were sensitized and 91% (n = 65) in those with TN sensitization only (mean sIgE 1.53 kUA/L; range 0.35-9.14). Passage rates were 89% (n = 110 of 124) for a TN sIgE level lower than 2 kUA/L and 69% (11 of 16) for a TN sIgE level of at least 2 kUA/L. In 44 challenges in patients with peanut allergy and TN co-sensitization, the TN OFC passage rate was 96%. In 41 TN OFCs with a TN SPT wheal size of at least 3 mm, 61% passed, with a mean wheal size of 4.8 mm (range 3-11) in those passing vs 9 mm (range 3-20) in those failing. CONCLUSION: TN challenges are frequently passed in patients with TN sensitization with or without a history of TN reactivity despite a TN SPT wheal of at least 3 mm or a TN sIgE level of at least 2 kUA/L. Nearly all patients with peanut allergy and TN co-sensitization passed the TN challenge, questioning the clinical relevance of "co-allergy." PMID- 28359602 TI - [Intelligent systems tools in the diagnosis of acute coronary syndromes: A systemic review]. AB - BACKGROUND: Acute myocardial infarction is the leading cause of non-communicable deaths worldwide. Its diagnosis is a highly complex task, for which modelling through automated methods has been attempted. A systematic review of the literature was performed on diagnostic tests that applied intelligent systems tools in the diagnosis of acute coronary syndromes. METHODS: A systematic review of the literature is presented using Medline, Embase, Scopus, IEEE/IET Electronic Library, ISI Web of Science, Latindex and LILACS databases for articles that include the diagnostic evaluation of acute coronary syndromes using intelligent systems. The review process was conducted independently by 2 reviewers, and discrepancies were resolved through the participation of a third person. The operational characteristics of the studied tools were extracted. RESULTS: A total of 35 references met the inclusion criteria. In 22 (62.8%) cases, neural networks were used. In five studies, the performances of several intelligent systems tools were compared. Thirteen studies sought to perform diagnoses of all acute coronary syndromes, and in 22, only infarctions were studied. In 21 cases, clinical and electrocardiographic aspects were used as input data, and in 10, only electrocardiographic data were used. Most intelligent systems use the clinical context as a reference standard. High rates of diagnostic accuracy were found with better performance using neural networks and support vector machines, compared with statistical tools of pattern recognition and decision trees. CONCLUSIONS: Extensive evidence was found that shows that using intelligent systems tools achieves a greater degree of accuracy than some clinical algorithms or scales and, thus, should be considered appropriate tools for supporting diagnostic decisions of acute coronary syndromes. PMID- 28359601 TI - Reply to: "Peculiarities of progressive external ophthalmoplegia due to single mtDNA deletions". PMID- 28359603 TI - Balance of the unsuccessful systematization of measurement uncertainty in medical laboratories. PMID- 28359604 TI - Extra corporeal photochemotherapy in steroid refractory graft versus host disease: A review of guidelines and recommendations. AB - Regardless of remarkable progresses in prevention and treatment approaches, graft versus host disease (GVHD) remains a major impediment for successful allogeneic hematopoietic stem cells transplantation (HSCT) and leads to morbidity and mortality in transplanted patients. Corticosteroids are the standard therapy for GVHD; however, a great number of patients will not respond sufficiently and others will be significantly affected by adverse effects of steroids. Extracorporeal photochemotherapy (ECP), as one of the numerous second line therapies, through modulation of immune cells may improves GVHD affected organ function in steroid-refractory forms. Considering to widespread utilization of ECP as a therapeutic strategy, we performed review on current literature of ECP, regarding the treatment strategies, monitoring protocols and technical aspects in chronic and acute GVHD. PMID- 28359606 TI - Diagnosis and Treatment of Drug-Resistant Tuberculosis. AB - In the last 2 decades, drug-resistant tuberculosis has become a threat and a challenge to worldwide public health. The diagnosis and treatment of these forms of tuberculosis are much more complex and prognosis clearly worsens as the resistance pattern intensifies. Nevertheless, it is important to remember that with the appropriatesystematic clinical management, most of these patients can be cured. These guidelines itemize the basis for the diagnosis and treatment of all tuberculosis patients, from those infected by strains that are sensitive to all drugs, to those who are extensively drug-resistant. Specific recommendations are given forall cases. The current and future role of new molecular methods for detecting resistance, shorter multi-drug-resistant tuberculosis regimens, and new drugs with activity against Mycobacterium tuberculosis are also addressed. PMID- 28359607 TI - Endotracheal Tuberculosis in a Patient with Smear-Negative Sputum. PMID- 28359605 TI - Two cases of permanent indwelling catheter for long-term administration of intrapleural chemotherapy. PMID- 28359608 TI - Changes in Ventilatory Response to Exercise in Trained Athletes: Respiratory Physiological Benefits Beyond Cardiovascular Performance. AB - INTRODUCTION: The beneficial impact of an 8-month competitive season on the ventilatory profile response to exercise in soccer players has never been evaluated. MATERIAL AND METHODS: Ventilatory profile (evaluated by determining individual tidal volume [VT] relative to minute ventilation [VE] inflection points during exercise) and metabolic responses to incremental exercise were evaluated in 2 professional soccer teams before and after an 8-month competitive season. RESULTS: No differences between teams in anthropometric characteristics or in resting cardiopulmonary variables, included oxygen uptake (VO2) and heart rate (HR), before and during the competitive season were found. At iso-speed, there were overall improvements in carbon dioxide output (VCO2), VE/VO2, VE/VCO2, VE and respiratory frequency (fR) during the season. The VT/VE inflection points 1 and 2 occurred with greater exercise time, HR, VO2, VCO2, VE and VT during the competitive season. CONCLUSIONS: Despite very high baseline performance and a negligible improvement in VO2, an 8-month competitive season improved ventilatory profile response to exercise in elite athletes. PMID- 28359609 TI - Pregnant Women: An Overlooked Asset to Plasmodium falciparum Malaria Elimination Campaigns? AB - Community chemotherapy campaigns to reduce malaria transmission often exclude pregnant women due to safety concerns related to the drugs. However, pregnant women might represent an important source of human-to-mosquito infection due to frequent parasite carriage with higher densities of parasites (often detectable by microscopy), attractiveness to mosquitoes, and modified sleeping behaviour. Accumulating evidence of the safety of artemisinin-based combination therapies for the treatment of malaria during gestation suggests that malaria elimination programmes should reconsider this exclusion. Including pregnant women will increase intervention coverage and impact, and may thereby accelerate progress towards the desired endpoint (e.g., elimination) or increase the chances of success. Studies assessing infectiousness of pregnant women and gametocyte dynamics during different trimesters of pregnancy will be valuable to support the planning of community treatment campaigns. PMID- 28359610 TI - Methicillin-resistant Staphylococcus aureus nasal carriage between healthy students of medical and nonmedical universities. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a challenge for public health, and community-acquired (CA) infections seem to be increasing among people in different areas. METHODS: A total of 700 healthy student volunteers residing in dormitories of universities in Urmia, Iran, were enrolled in this study. After identification of the isolates, antibiotic susceptibility, presence of mecA and pvl genes, and staphylococcal cassette chromosome mec (SCCmec) typing were evaluated. RESULTS: Nasal screening identified 137 (19.6%) carriers of S aureus, and 18 (13.14%) were MRSA isolates. The antimicrobial susceptibility patterns of isolates revealed high resistance to penicillin (93.4%). All isolates were sensitive to vancomycin. The SCCmec typing showed that most MRSA strains belonged to SCCmec type IV (n = 14; 77.8%). Only 1 (5.56%) MRSA isolates carried the pvl gene. CONCLUSIONS: Our findings revealed the relatively high frequency of S aureus nasal carriers and the advent of multidrug resistance among these isolates. Most MRSA isolates were SCCmec type IV; the transfer of such MRSA strains from carriers to other individuals in crowded living conditions such as dormitories can act as a risk factor for outbreak of CA MRSA and is a serious threat for the study groups. PMID- 28359611 TI - Risk factors, characteristics, and outcomes of candidemia in an adult intensive care unit in Turkey. AB - Thirty-six patients with candidemia and 37 control patients were included consecutively to determine the characteristics of candidemia episodes. The patients with candidemia had higher mortality with higher Sequential Organ Failure Assessment scores and frequency of use of a central venous catheter, total parenteral nutrition, and broad-spectrum antibiotics; chronic renal failure with replacement therapy; and longer stay in an intensive care unit. Candida albicans was the predominant species followed by Candida glabrata, Candida tropicalis, and Candida parapsilosis. All isolates of C glabrata were itraconazole-resistant. PMID- 28359612 TI - Evaluation of one-way valves used in medical devices for prevention of cross contamination. AB - BACKGROUND: One-way valves used in day use devices (used on multiple patients throughout a day without reprocessing between patients) are intended to reduce the potential for cross-contamination between patients resulting from the backflow of patient fluids. One-way valves are typically designed to withstand high levels of back pressure before failure; however, they may not be explicitly designed as a means of infection control as used in medical device applications. METHODS: Five different medical grade one-way valves were placed in low pressure configurations. After flushing in the intended direction of flow, bacteriophage, bacteria, or dye was placed patient side for 24 hours. The upstream device side of the valve was then evaluated for microbial growth or presence of visible dye. RESULTS: Leakage (ie, backflow) of the microorganisms occurred with a variety of one-way valve designs across a range of fluid properties tested. CONCLUSIONS: This study describes testing of the one-way valves (component-level testing) for the potential of cross-contamination. Although day use medical device systems may use numerous other factors to prevent patient cross-contamination, this work demonstrates that one-way valves themselves may not prevent leakage of contaminated fluid if the fluid is able to reach the upstream side of the one-way valve. PMID- 28359613 TI - Reduction of blood culture contamination rates after implementation of a phlebotomist team. PMID- 28359614 TI - Effectiveness of a balance-focused exercise program for enhancing functional fitness of older adults at risk of falling: A randomised controlled trial. AB - This study examined the effectivenss of a balance-focused training program (i.e., Exercise for Balance Improvement Program, ExBP) in improving functional fitness of older nonfallers at risk of falling. Sixty-one participants were randomly assigned to receive 16 weeks of ExBP or Tai Chi (TC) training, or no treatment (CON) with an 8-week follow-up. The Senior Fitness Test battery was applied to assess functional fitness. After the intervention, results revealed significant improvements in all fitness components in the ExBP group. Compared with the CON group, the ExBP group demonstrated more improvements in lower extremity muscle strength, agility and balance, and aerobic endurance. The ExBP group also displayed more improvements in aerobic endurance than the TC group in posttest and follow-up test. Therefore, the balance-focused exercise can be applied as an effective way in improving overall functional fitness among older nonfallers who are at risk of falling. PMID- 28359615 TI - From Capstone/Dissertation to publication: Let's try this again! PMID- 28359616 TI - Recognising the boundary between heroism and futility in veterinary intensive care. PMID- 28359617 TI - Fluid-Attenuated Inversion Recovery (FLAIR) Signal Intensity Can Identify Stroke Within 6 and 8 Hours. AB - BACKGROUND: Patients with wake-up or unknown time of onset stroke are usually excluded from recanalization. However, a few studies indicate that some magnetic resonance sequences can help predict time from symptom onset (SxO). Our goal was to assess the value of fluid-attenuated inversion recovery (FLAIR) signal intensity ratio (SIR) in identifying patients within 6 and 8 hours of stroke onset. MATERIALS AND METHODS: We studied consecutive acute stroke patients with known time of onset who underwent magnetic resonance imaging (MRI) within 48 hours of SxO. SIR was calculated as the value of the FLAIR signal intensity of the identified area of infarction divided by the signal intensity in the homologous contralateral side of the brain. RESULTS: Out of 160 patients included in this study, 72 and 80 patients had MRI within 6 and 8 hours of SxO, respectively. We found a positive correlation between SIR and time from SxO (Pearson coefficient, .63). Receiver operating characteristic curves indicated that SIR <= 1.18 could accurately identify patients within 6 hours of SxO (86% sensitivity, 79% specificity) and a SIR <= 1.20 can be identified within 8 hours (89% sensitivity, 76% specificity). Among patients with no visible FLAIR hyperintensity, 83% (95% CI, 77%-89%) were within the 6-hour window. CONCLUSION: Quantitative assessment of FLAIR sequence can be used to identify patients within 6 and 8 hours of stroke onset. PMID- 28359618 TI - Adjuvanticity of a CTLA-4 3' UTR complementary oligonucleotide for emulsion formulated recombinant subunit and inactivated vaccines. AB - Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is recognized as a critical inhibitory regulator of T-cell proliferation and activation, opposing the action of CD28 mediated co-stimulation. Interfering or blocking CTLA-4 can result in continuous T-cell activation required for the full immune response to pathogenic microbes and vaccines. To test if nucleic acid-based CTLA-4 inhibitors could be developed into a novel adjuvant, we designed two oligonucleotides, CMD-1 and CMD-2, with the sequences complementary to the conserve regions identical between human and mouse CTLA-4 mRNA 3' untranslated region (3' UTR), and tested their in vitro effects on CTLA-4 production and their adjuvanticity for vaccines in mice. We found that CMD-1 inhibited the antigen-induced CTLA-4 up-regulation on the CD4+ T cells by interfering its mRNA expression, maintained higher levels of CD80 and CD86 on the CD11c+ cells and promoted the recalled proliferation of the CD4+ T cells and CD19+ B cells, and that the CMD-1 enhanced the antibody response against recombinant PCV2b capsid protein or inactivated foot-and-mouth disease virus in both ICR and BALB/c mice. These data suggest that the CMD-1 could be used as a novel vaccine adjuvant capable of inhibiting inhibitory signals rather than inducing stimulatory signals of immune cells. PMID- 28359619 TI - Predictors of influenza vaccination in the U.S. among children 9-13years of age. AB - BACKGROUND AND OBJECTIVES: U.S. estimates of seasonal influenza (flu) vaccine uptake in 2014-2015 were 62% for 5-12year olds, dropping to 47% for 13-17year olds. The Healthy People 2020 goal for these age groups is 80%. It is important to understand factors associated with influenza vaccination, especially for those ages where rates begin to decline. The objective of this study was to identify factors associated with influenza vaccination acceptance in 9-13year old children. METHODS: An online U.S. survey of mothers of children aged 9-13 assessed children's influenza vaccine uptake in the previous season, healthcare utilization, sociodemographics, and vaccine attitudes. Multivariable logistic regression identified independent predictors of influenza vaccine status. RESULTS: There were 2363 respondents (Mean age=38years old). Referent children were 57% female and 66% non-minority race/ethnicity with a mean age of 10.6years. By maternal report, 59% of children had received an influenza vaccine in the previous season. Predictors of influenza vaccine uptake included a recommendation or strong recommendation from a health care provider, seeing a health care provider in the past year, positive attitudes regarding the influenza vaccine, and being a minority race. Child gender, age, insurance coverage, and whether the child had a regular healthcare provider were not associated with influenza vaccine uptake (p=n.s.). CONCLUSIONS: This sample reported overall rates of influenza vaccine uptake similar to national surveillance data, but still lower than national goals. Provider recommendations along with health attitudes and seeing a health care provider were associated with vaccine uptake. Promising interventions may include more directive physician messaging for influenza vaccine uptake in youth, encouraging more regular well-child visits during the adolescent years, and promoting influenza vaccination at alternative sites. PMID- 28359620 TI - Pertussis vaccination in pregnancy: State of the art. AB - Pertussis vaccination in pregnancy has been introduced by several national advisory bodies, mostly in industrialized countries, as a means to protect young infants from disease by high titers of maternal antibodies. Most recommendations derive from epidemiological needs, but many knowledge gaps remained after implementation. This report aims to overview the solved and unsolved aspects of prenatal vaccination with a pertussis containing vaccine. PMID- 28359621 TI - Varicella seroepidemiology in United States air force recruits: A retrospective cohort study comparing immunogenicity of varicella vaccination and natural infection. AB - BACKGROUND/OBJECTIVES: Infection with varicella zoster virus (VZV) produces lifelong immunity, but duration of post-vaccination immunity has not been established. The purpose of this study is to determine if a difference exists in the long-term seropositivity of anti-VZV antibodies in a cohort of young adults who were vaccinated against varicella as compared to a similar cohort with a history of chickenpox disease, and to determine which variables best predict waning seropositivity following varicella vaccination. METHODS: This retrospective cohort study captures immunization and serology data from approximately 10,000 recruits who entered basic military training between January 1, 2008, and December 31, 2015, and who have childhood immunization records in the Air Force Aeromedical Services Information Management System. Varicella vaccine immunogenicity was determined relative to the immunogenicity of chickenpox disease, as measured by multiplex flow immunoassay. Among vaccine recipients, waning seroimmunity was modeled and adjusted for several important covariates. RESULTS: Basic military trainees who received varicella vaccine in childhood were 24% less likely to be seropositive to VZV than trainees who were exempt from vaccine due to a history of chickenpox disease. There was no significant difference in seropositivity between male and female trainees. The odds of a vaccinated trainee being seropositive to VZV decreased by 8% with each year elapsed since vaccination. Seroprevalence declined below estimated herd immunity thresholds in vaccinated trainees born after 1994, and in the cohort as a whole for trainees born after 1995. CONCLUSION: Despite prior vaccination, seroimmunity in a large cohort of young adults unexposed to wild-type VZV failed to meet the estimated threshold for herd immunity. If vaccination in accordance with the current US VZV vaccination schedule is inadequate to maintain herd immunity, young adults not previously exposed to wild-type VZV may be at increased risk for varicella outbreaks. PMID- 28359622 TI - [Corneal ectasia complicating a lime burn]. PMID- 28359623 TI - [Congenital cerulean cataract]. PMID- 28359624 TI - [Bilateral serous retinal detachment as a complication of preeclampsia]. PMID- 28359625 TI - Progression of visual field defect in an unilateral glaucoma patient after an unilateral photorefractive keratectomy. PMID- 28359627 TI - [Uncomplicated massive central retinal artery embolism]. PMID- 28359626 TI - Effects of femtosecond and excimer lasers on implanted KAMRA corneal inlay in animal models. AB - PURPOSE: To evaluate the effect of femtosecond laser and excimer laser on an intracorneal inlay (KAMRA(r)) implanted in animal models. METHODS: Femtosecond laser was used to create corneal intrastromal pockets at 250MUm depth in five porcine eyes. Four intact KAMRA inlays, examined by slit-lamp biomicroscopy and light microscopy, were implanted in the pocket of four eyes. A standard LASIK flap was created above each implanted inlay in the four eyes using a femtosecond laser with flap thicknesses of 150MUm, 130MUm, 110MUm and 90MUm. In the fifth porcine eye, a LASIK flap was created using femtosecond laser at 110MUm depth, and a fifth inlay was then implanted in the 250MUm pocket. Excimer laser ablation was performed under the flap targeting a -3.00 refraction. The inlay was then explanted, examined and reimplanted in the same pocket followed by a second similar excimer laser ablation. RESULTS: Significant burn, shrinkage and distortion of microholes were noted in all the first four inlays following the femtosecond laser flap creation at all the various flap thicknesses. The damage was noted to be more prominent as the distance between the flap and inlay decreased. No apparent effect was noted on the fifth inlay following repeated excimer laser ablations. CONCLUSION: Unlike excimer laser, femtosecond laser appears to be hazardous and damaging to the intracorneal KAMRA inlay when applied above it. PMID- 28359628 TI - [Iris mammillations]. PMID- 28359629 TI - [Multimodal imaging in primary intraocular lymphoma]. AB - INTRODUCTION: Vitreoretinal lymphoma is a serious disease with highly varied clinical presentations. The goal of this work is to identify the various presentations (clinical, imaging) in order to improve screening for this disease. MATERIALS AND METHOD: We collected data of patients followed on our service for vitreoretinal lymphoma. The fundus exam, autofluorescence and angiography data were classified in order to identify signs, which might lead to earlier diagnosis of lymphoma. RESULTS: The diagnosis of vitreoretinal lymphoma was confirmed by vitrectomy or cerebral biopsy for 12 patients (8 women and 4 men). Three clinical presentations were identified: no retinal involvement (2 patients), retinal infiltrate (4 patients) or acute retinal necrosis (3 patients). One patient had no imaging (deceased before it could be obtained), and two patients had uninterpretable imaging. CONCLUSION: Vitreoretinal lymphoma remains a rare and under-diagnosed disease. The prognosis is related to early diagnosis. Multimodal imaging can help to diagnose early vitreoretinal lymphoma in some cases. PMID- 28359630 TI - Neural Cell Adhesion Molecules of the Immunoglobulin Superfamily Regulate Synapse Formation, Maintenance, and Function. AB - Immunoglobulin superfamily adhesion molecules are among the most abundant proteins in vertebrate and invertebrate nervous systems. Prominent family members are the neural cell adhesion molecules NCAM and L1, which were the first to be shown to be essential not only in development but also in synaptic function and as key regulators of synapse formation, synaptic activity, plasticity, and synaptic vesicle recycling at distinct developmental and activity stages. In addition to interacting with each other, adhesion molecules interact with ion channels and cytokine and neurotransmitter receptors. Mutations in their genes are linked to neurological disorders associated with abnormal development and synaptic functioning. This review presents an overview of recent studies on these molecules and their crucial impact on neurological disorders. PMID- 28359632 TI - Oligo-evidence for antiemetic efficacy in the emergency department. PMID- 28359631 TI - Shapeshifting to Survive: Shape Determination and Regulation in Caulobacter crescentus. AB - Bacterial cell shape is a genetically encoded and inherited feature that is optimized for efficient growth, survival, and propagation of bacteria. In addition, bacterial cell morphology is adaptable to changes in environmental conditions. Work in recent years has demonstrated that individual features of cell shape, such as length or curvature, arise through the spatial regulation of cell wall synthesis by cytoskeletal proteins. However, the mechanisms by which these different morphogenetic factors are coordinated and how they may be globally regulated in response to cell cycle and environmental cues are only beginning to emerge. Here, we have summarized recent advances that have been made to understand morphology in the dimorphic Gram-negative bacterium Caulobacter crescentus. PMID- 28359633 TI - The role of perineural invasion in treatment decisions for oral cancer patients: A review of the literature. AB - PURPOSE: The role of perineural invasion (PNI) in the management of patients with oral squamous cell carcinoma (OSSC) is still controversial, and there is no consensus regarding the most appropriate therapeutic approach. The purpose of this study is to review the findings in the literature describing OSCC as a neurotropic malignancy, with the aim of correlating perineural invasion with treatment decisions and disease prognosis. MATERIALS AND METHODS: A literature search was conducted of references based on the MEDLINE and Cochrane Database of Systematic Reviews, with subject keywords including four main categories: perineural invasion, perineural spread, oral squamous cell cancinoma, neurotropic carcinoma. RESULTS: In this systematic review and analysis, more than 350 publications met the eligibility criteria of the authors. CONCLUSION: Perineural invasion (PNI) is a widely recognized indicator of poor prognosis in oral cancer patients, strongly correlating with aggressive tumor behavior, disease recurrence, and increased morbidity and mortality. Elective neck dissection could be an indicator in improving neck control in PNI-positive patients, while the addition of adjuvant postoperative radiotherapy may not significantly improve survival rates. Various molecular markers have been correlated with perineural tumor spread, but further investigations are required before targeting PNI as part of advanced cancer therapies. PMID- 28359634 TI - Synthesis of sub-micronic and nanometric PMMA particles via emulsion polymerization assisted by ultrasound: Process flow sheet and characterization. AB - PMMA particle synthesis was performed from MMA (methyl methacrylate) and water mixtures, exposed to different ultrasonic systems and frequencies. The sonication sequence was 20kHz->580kHz->858kHz->1138kHz, and the solution was sampled after each irradiation step for polymerization. Effects of sonication parameters (time, power), polymerization method (thermo-initiated or photo-initiated), use of small amounts of surfactant (Triton X-100TM or Tween(r) 20) and initial MMA quantity were investigated on particle size and synthesis yields. Particle size and size distribution were measured by DLS (Dynamic Light Scattering), and confirmed via SEM (Scanning Electron Microscopy) images. Synthesis yield was calculated using the dry weight method. Particle composition was estimated using FTIR (Fourier Transform Infra-Red) spectroscopy. PMMA (polymethylmethacrylate) monodispersed particles were successfully synthesized, with a possibility of control in the 78 310nm size range. These sized-controlled particles were synthesized with a 7.5 85% synthesis yield (corresponding to 7.5-40g/L particle solid content), depending on operational parameters. Furthermore, a trade-off between particle size and synthesis yield can be proposed: 20kHz->10min waiting time->580kHz >858kHz leading to 90nm particles diameter with 72% yield in less than 40min for the whole sequence. Thus, the synthesis under ultrasound can be found easy to implement and time efficient, ensuring the success of the scale-up approach and opening up industrial applications for this type of polymeric particles. PMID- 28359635 TI - Protein fold recognition based on sparse representation based classification. AB - Knowledge of protein fold type is critical for determining the protein structure and function. Because of its importance, several computational methods for fold recognition have been proposed. Most of them are based on well-known machine learning techniques, such as Support Vector Machines (SVMs), Artificial Neural Network (ANN), etc. Although these machine learning methods play a role in stimulating the development of this important area, new techniques are still needed to further improve the predictive performance for fold recognition. Sparse Representation based Classification (SRC) has been widely used in image processing, and shows better performance than other related machine learning methods. In this study, we apply the SRC to solve the protein fold recognition problem. Experimental results on a widely used benchmark dataset show that the proposed method is able to improve the performance of some basic classifiers and three state-of-the-art methods to feature selection, including autocross covariance (ACC) fold, D-D, and Bi-gram. Finally, we propose a novel computational predictor called MF-SRC for fold recognition by combining these three features into the framework of SRC to achieve further performance improvement. Compared with other computational methods in this field on DD dataset, EDD dataset and TG dataset, the proposed method achieves stable performance by reducing the influence of the noise in the dataset. It is anticipated that the proposed predictor may become a useful high throughput tool for large-scale fold recognition or at least, play a complementary role to the existing predictors in this regard. PMID- 28359636 TI - Hepatic perivascular epithelioid tumor (PEComa). A case report. AB - A 37-year-old female had liver nodules found in an abdominal ultrasound scan. The radiological features were suggestive of hepatocellular adenomas, although there were some atypical findings. Two years later, one of the nodules showed dimensional progression and intralesional hemorrhage. The patient underwent a left hepatectomy and the postoperative course was uneventful. The histological exam and the immunohistochemistry were consistent with the diagnosis of PEComa. The PEComa is a mesenchymal tumor rarely described in the liver. The preoperative diagnosis of PEComa is very difficult and, with this report, the authors intend to increase the limited knowledge relating to natural history and optimal treatment of this rare condition. PMID- 28359637 TI - Development and evaluation of a social cognitive theory-based instrument to assess correlations for physical activity among people with spinal cord injury. AB - BACKGROUND: People with spinal cord injury (SCI) are more susceptible to sedentary lifestyles because of the displacement of physical functioning and the copious barriers. Benefits of physical activity for people with SCI include physical fitness, functional capacity, social integration and psychological well being. OBJECTIVE: The purpose of this study was to develop and test a social cognitive theory-based instrument aimed to predict physical activity among people with SCI. METHODS: An instrument was developed through the utilization and modification of previous items from the literature, an expert panel review, and cognitive interviewing, and tested among a sample of the SCI population using a cross-sectional design. Statistical analysis included descriptives, correlations, multiple regression, and exploratory factor analysis. RESULTS: The physical activity outcome variable was significantly and positively correlated with self regulatory efficacy (r = 0.575), task self-efficacy (r = 0.491), self-regulation (r = 0.432), social support (r = 0.284), and outcome expectations (r = 0.247). Internal consistency for the constructs ranged from 0.82 to 0.96. Construct reliability values for the self-regulation (0.95), self-regulatory efficacy (0.96), task self-efficacy (0.94), social support (0.84), and outcome expectations (0.92) each exceeded the 0.70 a priori criteria. CONCLUSIONS: The factor analysis was conducted to seek modifications of current instrument to improve validity and reliability. The data provided support for the convergent validity of the five-factor SCT model. This study provides direction for further development of a valid and reliable instrument for predicting physical activity among people with SCI. PMID- 28359638 TI - Indications and Predictors for Reconstructive Surgery After Hand Burns. AB - PURPOSE: The objective of this study was to analyze the prevalence, indications, and type of reconstructive surgery and predictors of the outcomes of reconstructive surgery after hand burns. METHODS: A retrospective cohort study was conducted that included all patients admitted with acute hand burns in the Dutch burn centers from January 1998 through December 2002. The details of reconstruction including frequency, timing, indication, and techniques were collected over a 10-year follow-up period. RESULTS: Hand burns were seen in 42% (n = 562 of 1,334) of all patients admitted with acute burns. Reconstructive surgery during the 10-year follow-up period was required in 15%. Contractures, especially of the first web space and little finger, were the most frequent indications for reconstructive surgery. Web spaces 1 to 3 and the little finger were the location most frequently operated on. The most frequently performed surgical technique was release of the contractures and the use of a random flap. Eighty percent of the reconstructive surgery patients required more than 1 reconstructive procedure, most often within 2 years of the initial injury. Secondary operations at the same location were required in 12%. In 40% of the patients, the first reconstructive surgery was performed within the first postburn year. Significant independent factors related to the need for reconstructive hand surgery were a larger area of full-thickness burns and surgical treatment of the hand during the acute phase. CONCLUSIONS: Reconstructive surgery was required in 15% of patients who sustained hand burns. The majority of the patients requiring reconstructive surgery of the hand needed 2 or more operations to correct the contractures of the hand. Contractures of the little finger and first web space were the locations most frequently operated on. Patients with more extensive burns and who required hand surgery during the acute phase were more likely to need reconstructive surgery. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV. PMID- 28359639 TI - Lateral Para-Olecranon Approach for the Treatment of Distal Humeral Fracture. AB - PURPOSE: To assess the outcomes of the lateral para-olecranon triceps-splitting approach for the treatment of distal humeral fracture. METHODS: Ten patients (3 males, 7 females) with a mean age of 59 years were retrospectively reviewed. There were 2 A2, 3 C1, and 5 C2 fractures according to the AO/ASIF classification. Types B3 and C3 fractures were excluded from this study because the olecranon osteotomy approach was indicated to visualize the anterior fragment. The triceps was split at the midline, and the anconeus muscle was incised from the proximal ulna. The lateral half of the triceps along with anconeus was retracted laterally as a single unit. The distal part of the humerus could be visualized from medial and lateral windows by retracting the medial half of the triceps. The articular fragment was anatomically reduced and fixed temporarily with a Kirschner wire, and the reconstructed distal articular block was then fixed to the humeral shaft with double locking plates. RESULTS: After surgery, average elbow flexion was 127 degrees (range, 110 degrees -145 degrees ), and extension was -10 degrees (range, -20 degrees -0 degrees ) at the average follow-up time of 12.4 months (range, 8-20 months). Seven patients had normal muscle strength against full resistance (manual muscle testing grade 5), and the other 3 patients had slightly reduced muscle strength (grade 4). No articular stepoffs of more than 1 mm were seen on postoperative radiographs. There were no cases of triceps insufficiency and nonunion. The average (+/- SD) Mayo Elbow Score was 93.5 +/- 5.8 points at the final follow-up. CONCLUSIONS: The lateral para-olecranon approach is useful for the management of selected fractures of the distal humerus, preserving extension strength and providing satisfactory clinical outcomes, with no risk of olecranon osteotomy-related complications. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V. PMID- 28359640 TI - Headless Compression Screw Versus Kirschner Wire Fixation for Metacarpal Neck Fractures: A Biomechanical Study. AB - PURPOSE: This study aimed to determine the biomechanical stability of headless compression screws in the fixation of metacarpal neck fractures and to compare them with another common, less invasive form of fixation, K-wires. The hypothesis was that headless compression screws would show higher stiffness and peak load to failure than K-wire fixation. METHODS: Eight matched-paired hands (n = 31), using the ring and little finger metacarpals, had metacarpal fractures simulated at the physeal scar. Each group was stabilized with either a 3.5-mm headless compression screw or 2 0.045-in (1.1-mm) K-wires. Nineteen metacarpals were tested in 3-point bending and 12 in axial loading. Peak load to failure and stiffness were calculated from the load displacement curve. Bone mineral density was recorded for each specimen. RESULTS: Bone mineral density was similar in the 2 groups tested for 3-point bending and axial loading. Stiffness was not significantly different in 3-point bending for headless compression screws and K-wires (means, 141.3 vs 194.5 N/mm) but it was significant in axial loading (means, 178.0 vs 111.6 N/mm). Peak load to failure was significantly higher in headless compression screws in 3-point bending (means, 401.2 vs 205.3 N) and axial loading (means, 467.5 vs 198.3 N). CONCLUSIONS: Compared with K-wires, headless compression screws for metacarpal neck fractures are biomechanically superior in load to failure, 3-point bending, and axial loading. CLINICAL RELEVANCE: Headless compression screws demonstrate excellent biomechanical stability in metacarpal neck fractures. In conjunction with promising clinical studies, these data suggest that headless compression screws may be an option for treating metacarpal neck fractures. PMID- 28359641 TI - Prospective Evaluation of Sleep Improvement Following Carpal Tunnel Release Surgery. AB - PURPOSE: Sleep disturbance due to nighttime awakening is a well-documented symptom of carpal tunnel syndrome. While relief of nighttime waking following carpal tunnel release (CTR) has been demonstrated, the effect of CTR on overall sleep quality has not been fully investigated. We hypothesized that CTR would result in significant improvement in overall sleep quality as well as patients' overall satisfaction with their sleep habits. METHODS: Cases of carpal tunnel syndrome with positive nerve studies, and treated with CTR, were prospectively enrolled. Demographic data, electromyography (EMG) severity, Quick Disabilities of the Arm, Shoulder, and Hand questionnaire, and Insomnia Severity Index (ISI) scale data were collected. RESULTS: A total of 398 patients were enrolled, with 99% available at 2 weeks and 64% available at 3-month final follow-up. At final follow-up, average Quick Disabilities of the Arm, Shoulder, and Hand score improved significantly from the preoperative value. Average ISI score on all 7 sleep categories on the survey improved significantly from before surgery to the first postoperative visit. However, the total ISI score did not further improve significantly between the 2-week and the 3-month postoperative visits. The ISI score improvements did not correlate with EMG severity. CONCLUSIONS: Patients undergoing CTR demonstrated significant improvement in mean scores for 7 aspects of sleep quality. Sleep improvement was unrelated to preoperative EMG severity and was experienced within 2 weeks of surgery. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 28359642 TI - Effect of Hormonal Replacement Therapy on Voice. AB - OBJECTIVE: This study aimed to investigate the effect of hormonal therapy (HRT) on voice in a group of menopausal women, taking into consideration body mass index (BMI) as a confounding factor and its potential role as a substitute for HRT. SUBJECTS AND METHODS: A total of 53 menopausal women, 34 not on HRT and 19 on HRT, were recruited. Demographic variables included age, gender, smoking, and BMI. All subjects were asked about the presence or absence of the following symptoms: hoarseness, deepening of the voice, pitch breaks, throat clearing, dryness in the throat, and vocal fatigue. Acoustic analysis was performed, and Voice Handicap Index-10 was also completed. RESULTS: The mean BMI was 25.90 +/- 5.39 and 25.77 +/- 4.26 in patients on HRT and not on HRT, respectively. There was no statistical difference in the Voice Handicap Index-10 score and the prevalence of any of the phonatory symptoms in menopausal women not on HRT compared with menopausal women on HRT. However, menopausal women not on HRT had significantly lower habitual pitch than those on HRT (P value of 0.022). On the other hand, the jitter was significantly higher in those on HRT (P value of 0.033). CONCLUSION: Hormonal therapy has an impact on the habitual pith in menopausal women with comparable BMI. Those on HRT have a higher habitual pitch than those not on HRT. PMID- 28359644 TI - Thermodynamics of tunnel formation upon substrate binding in a processive glycoside hydrolase. AB - Glycoside hydrolases (GHs) catalyze the hydrolysis of glycosidic bonds and are key enzymes in carbohydrate metabolism. Efficient degradation of recalcitrant polysaccharides such as chitin and cellulose is accomplished due to synergistic enzyme cocktails consisting of accessory enzymes and mixtures of GHs with different modes of action and active site topologies. The substrate binding sites of chitinases and cellulases often have surface exposed aromatic amino acids and a tunnel or cleft topology. The active site of the exo-processive chitinase B (ChiB) from Serratia marcescens is partially closed, creating a tunnel-like catalytic cleft. To gain insight in the fundamental principles of substrate binding in this enzyme, we have studied the contribution of five key residues involved in substrate binding and tunnel formation to the thermodynamics of substrate binding. Mutation of Trp97, Phe190, Trp220 and Glu221, which are all part of the tunnel walls, resulted in significant less favorable conformational entropy change (DeltaS degrees conf) upon binding (-TDeltaDeltaS degrees conf = ~5 kcal/mol). This suggest that these residues are important for the structural rigidity and pre-shaping of the tunnel prior to binding. Mutation of Asp316, which, by forming a hydrogen bond to Trp97 is crucial in the active-site tunnel roof, resulted in a more favorable DeltaS degrees conf relative to the wild type (-TDeltaDeltaS degrees conf = -2.2 kcal/mol). This shows that closing the tunnel roof comes with an entropy cost, as previously suggested based on the crystal structures of GHs with tunnel topologies in complex with their substrates. PMID- 28359643 TI - Insights Into the Role of Collagen in Vocal Fold Health and Disease. AB - As one of the key fibrous proteins in the extracellular matrix, collagen plays a significant role in the structural and biomechanical characteristics of the vocal fold. Anchored fibrils of collagen create secure structural regions within the vocal folds and are strong enough to sustain vibratory impact and stretch during phonation. This contributes tensile strength, density, and organization to the vocal folds and influences health and pathogenesis. This review offers a comprehensive summary for a current understanding of collagen within normal vocal fold tissues throughout the life span as well as vocal pathology and wound repair. Further, collagen's molecular structure and biosynthesis are discussed. Finally, collagen alterations in tissue injury and repair and the incorporation of collagen-based biomaterials as a method of treating voice disorders are reviewed. PMID- 28359645 TI - Morphometry of the Tibial Plateau at the Surface and Resected Levels. AB - BACKGROUND: We aim to make an anthropometric analysis of tibial plateau at the surface level and the resected level and analyze the correlation in lengths between 2 levels. We hypothesized that lengths at the surface level were longer than those at the resected level, which brought soft tissue tolerance for tibial component to overhang. METHODS: Anthropometric data were measured using three dimensional structures reconstructed from tibial plateaus of 100 knees in 100 Chinese subjects (50 men and 50 women). Mediolateral, medial anteroposterior, and lateral anteroposterior lengths at the surface level and the resected level were measured, and the Pearson's correlation coefficients of these data were calculated. RESULTS: Mediolateral and medial anteroposterior lengths at the surface level were longer than those at the resected level by a mean 2.38 +/- 1.29 and 1.99 +/- 1.76 mm, respectively. Lateral anteroposterior length at the surface level was shorter than that at the resected level by a mean 1.54 +/- 2.49 mm. All these differences between 2 levels had no gender difference. CONCLUSION: Our findings suggest that tibial overhang could be better tolerated in the medial compared to the lateral compartment but this hypothesis has to be further investigated in a clinical study. PMID- 28359646 TI - Letter to the Editor on "The Prevalence of Positive Findings on Metal Artifact Reduction Sequence Magnetic Resonance Imaging in Metal-on-Metal Total Hip Arthroplasty": Part 2. PMID- 28359647 TI - Long interval prostaglandin as an alternative to progesterone-eCG based protocols for timed AI in sheep. AB - To compare the reproductive performance after TAI in ewes synchronized with mid (12 or 13) or long (14-16 d) interval prostaglandin (PG) or progesterone plus eCG (P4-eCG) based protocols, 440 multiparous Corriedale ewes were synchronized with two PG injections administered 12-16 d apart (PG12, PG13, PG14, PG15 and PG16 respectively), or P4-eCG (MAP sponges 14 d and eCG). Cervical TAI (Day 0) was performed with fresh semen. It was evaluated the ovulated ewes (OE, %) and the ovulation rate (OR) on Day 8 by trans-rectal ultrasonography, the rate of non return to service between Days 13 and 21 by painted rams, and the pregnancy rate, prolificacy and fecundity on Day 60 by trans-abdominal ultrasonography. No significant differences were found in OE among groups (P>0.05), but P4-eCG achieved higher OR (P<0.05) compared to PG protocols, without differences among them (P>0.05). Similar NRR-21, pregnancy and fecundity were observed among PG15 (64.3, 62.9 and 84.3), PG16 (59.7, 59.7 and 77.8) and P4-eCG (70.3, 66.2 and 95.9), but higher compared to PG12 (42.5, 39.7 and 52.1) and PG13 group (44.0, 40.0 and 48.0, respectively; P<0.05). PG14 achieved intermediate results compared to other groups. No differences were found in prolificacy among groups (P>0.05), except PG13 that was lower compared to P4-eCG (P<0.05). In conclusion, long interval between PG injections (15 or 16 d) determined better reproductive outcome that mid interval (12 or 13 d), equating the P4-eCG based protocol after cervical TAI with fresh semen during the breeding season in sheep. PMID- 28359648 TI - Tachykinin neurokinin 3 receptor antagonists: a new treatment for cardiovascular disease? AB - Great progress has been made in reducing cardiovascular mortality over the past 50 years. Nevertheless, prevalence is rising in some settings and remains higher in men than in women, even with the same level of established risk factors. To gain new insights, researchers are now considering cardiovascular disease in relation to the well known evolutionary biology model of growth and reproduction trading off against longevity, with trials of calorie restriction underway. However, calorie restriction has not been as successful as expected in primates and it is increasingly realised that effects on the reproductive axis might also be important. In this paper, the modulation of the reproductive axis using existing agents that have such properties-tachykinin neurokinin 3 receptor antagonists-is proposed as a way of reducing cardiovascular disease and combating a leading cause of global morbidity and mortality. PMID- 28359649 TI - Department of Error. PMID- 28359650 TI - Corrigendum to "Differential susceptibility to acetaminophen-induced liver injury in sub-strains of C57BL/6 mice: 6N versus 6J" [Food and Chem. Toxicol. 98 (Part B) (2016) 107-118]. PMID- 28359651 TI - [Therapeutic adherence in asthma in France: A general review]. AB - INTRODUCTION: Adherence in asthma is a paramount issue of disease management. A general review of the French publications on this topic has been conducted. METHODS: Research equations used for bibliographic databases (MEDLINE, Science Direct, Banque de donnees en sante publique, Cochrane and Cairn.info) comprised the following keywords: "asthma", "therapeutic adherence" and "France". These publications unrelated to asthma, focused on asthma management without exploring adherence, or those conducted in populations without French patients were excluded. RESULTS: A total of 82 articles have been selected (36 surveys, 4 randomized trials and 42 reviews/syntheses). Whatever the methodology used and publication year, the inadequate therapeutic adherence in asthma was steadily reported, notably for controllers and the quality of use of inhaled devices. CONCLUSION: The present review highlights the sustainability of adherence-related issues in asthma and the need to improve patients' knowledge on asthma and the finality of therapy. It also highlights the need of an improved communication between patients and physicians is also advocated. Further studies with more recent data are desirable to assess changes in disease management of asthma and the impact of potential future corrective interventions. PMID- 28359652 TI - Automated classification of neonatal sleep states using EEG. AB - OBJECTIVE: To develop a method for automated neonatal sleep state classification based on EEG that can be applied over a wide range of age. METHODS: We collected 231 EEG recordings from 67 infants between 24 and 45weeks of postmenstrual age. Ten minute epochs of 8 channel polysomnography (N=323) from active and quiet sleep were used as a training dataset. We extracted a set of 57 EEG features from the time, frequency, and spatial domains. A greedy algorithm was used to define a reduced feature set to be used in a support vector machine classifier. RESULTS: Performance tests showed that our algorithm was able to classify quiet and active sleep epochs with 85% accuracy, 83% sensitivity, and 87% specificity. The performance was not substantially lowered by reducing the epoch length or EEG channel number. The classifier output was used to construct a novel trend, the sleep state probability index, that improves the visualisation of brain state fluctuations. CONCLUSIONS: A robust EEG-based sleep state classifier was developed. It performs consistently well across a large span of postmenstrual ages. SIGNIFICANCE: This method enables the visualisation of sleep state in preterm infants which can assist clinical management in the neonatal intensive care unit. PMID- 28359653 TI - Combining transcranial magnetic stimulation and subdural electrodes for pain modulation. PMID- 28359654 TI - Future Perspectives in Cancer Screening and Early Detection. PMID- 28359655 TI - In vitro and in vivo evaluation of a novel integrated wearable artificial lung. AB - BACKGROUND: Conventional extracorporeal membrane oxygenation (ECMO) is cumbersome and is associated with high morbidity and mortality. We are currently developing the Pittsburgh Ambulatory Assist Lung (PAAL), which is designed to allow for ambulation of lung failure patients during bridge to transplant or recovery. In this study, we investigated the in vitro and acute in vivo performance of the PAAL. METHODS: The PAAL features a 1.75-inch-diameter, cylindrical, hollow-fiber membrane (HFM) bundle of stacked sheets, with a surface area of 0.65 m2 integrated with a centrifugal pump. The PAAL was tested on the bench for hydrodynamic performance, gas exchange and hemolysis. It was then tested in 40- to 60-kg adult sheep (n = 4) for 6 hours. The animals were cannulated with an Avalon Elite 27Fr dual-lumen catheter (DLC) inserted through the right external jugular into the superior vena cava (SVC), right atrium (RA) and inferior vena cava (IVC). RESULTS: The PAAL pumped >250 mm Hg at 3.5 liters/min at a rotation speed of 2,100 rpm. Oxygenation performance met the target of 180 ml/min at 3.5 liters/min of blood flow in vitro, resulting in a gas-exchange efficiency of 278 ml/min/m2. The normalized index of hemolysis (NIH) for the PAAL and cannula was 0.054 g per 100 liters (n = 2) at 3.5 liters/min, as compared with 0.020 g per 100 liters (n = 2) for controls (DLC cannula and a Centrimag pump). Plasma-free hemoglobin (pfHb) was <20 mg/dl for all animals. Blood left the device 100% oxygenated in vivo and oxygenation reached 181 ml/min at 3.8 liters/min. CONCLUSION: The PAAL met in vitro and acute in vivo performance targets. Five-day chronic sheep studies are planned for the near future. PMID- 28359656 TI - In-Center Nocturnal Hemodialysis Versus Conventional Hemodialysis: A Systematic Review of the Evidence. AB - BACKGROUND: Owing to its longer treatment duration-up to 8 hours per dialysis treatment-in-center thrice-weekly nocturnal hemodialysis (HD) is receiving greater attention. To better understand the evidence for in-center nocturnal HD, we sought to systematically review the literature to determine the effects of in center nocturnal HD versus conventional HD on clinically relevant outcomes. STUDY DESIGN: We searched MEDLINE, Embase, Evidence-Based Medicine Reviews (EBMR), Web of Science, and Scopus from the earliest date in the database to November 2016. SETTING & POPULATION: Adults receiving in-center nocturnal HD compared with those receiving conventional HD. SELECTION CRITERIA FOR STUDIES: All quasi-experimental and observational studies were considered; randomized trials were sought but not found. PREDICTOR: Nocturnal vs conventional in-center HD. OUTCOMES: Indexes of blood pressure and left ventricular hypertrophy, markers of anemia, measures of bone mineral metabolism, nutrition, quality of life, sleep quality, episodes of intradialytic hypotension, hospitalization, and mortality. RESULTS: Of 2,086 identified citations, 21 met the inclusion criteria, comprising a total of 1,165 in-center nocturnal HD patients and 15,865 conventional HD patients. Although there was substantial heterogeneity in reporting of outcomes, we pooled data for measures of blood pressure, anemia, and mineral metabolism. Though heterogeneity was generally high, in-center nocturnal HD was associated with improved systolic blood pressure (-3.18 [95% CI, -5.58 to -0.78) mm Hg, increased hemoglobin levels (0.53 [95% CI, 0.11-0.94] g/dL), and lower serum phosphate levels (-0.97 [95% CI, -1.48 to -0.46] mg/dL). LIMITATIONS: No randomized trials have been conducted to address the clinical effects of in-center nocturnal HD. The quality of the observational literature contributing to the results of this review was generally poor to moderate. Confounded outcomes are a significant concern. Publication bias and outcome reporting bias remain possibilities. CONCLUSIONS: Relative to conventional HD, in-center nocturnal HD was associated with improvements in several clinically relevant outcomes. Other benefits may not have been detected due to small sample sizes of included studies; no prespecified outcome was worse with in-center nocturnal HD. PMID- 28359657 TI - Association of Vitamin D Metabolites With Arterial Function in the Hemodialysis Fistula Maturation Study. AB - BACKGROUND: Disturbances in vitamin D metabolism are common in patients with end stage renal disease and may contribute to vascular dysfunction. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: We evaluated 558 of 602 participants at baseline of the Hemodialysis Fistula Maturation (HFM) Study, a 7-center prospective cohort study of a cohort of patients with chronic kidney disease awaiting arteriovenous fistula (AVF) creation surgery. FACTOR: 4 vitamin D metabolites measured with liquid chromatography-tandem mass spectroscopy from samples obtained within 4 weeks prior to AVF surgery. OUTCOMES: Vasodilator functions and measurements of arterial stiffness. MEASUREMENTS: Trained HFM Study personnel measured brachial artery flow-mediated dilation, nitroglycerin-mediated dilation, and carotid-femoral and carotid-radial pulse wave velocities (PWVs) prior to AVF creation. We evaluated associations after basic adjustment for sex, age, and clinical site and more fully adjusted additionally for baseline education, smoking, body mass index, diabetes, dialysis status, and medication use. RESULTS: Mean participant age was 55+/-13 (SD) years and 65% were receiving maintenance dialysis. None of the vitamin D metabolites were significantly associated with flow-mediated dilation, carotid-femoral PWV, or carotid-radial PWV in basic or fully adjusted analyses. Higher serum concentrations of bioavailable vitamin D and 1,25-dihydroxyvitamin D were associated with 0.62% and 0.58% greater nitroglycerin-mediated dilation values, respectively, in basic models; however, these associations were no longer statistically significant with full adjustment. There were no significant associations of vitamin D metabolites with carotid-femoral or carotid-radial PWV in fully adjusted analyses. LIMITATIONS: Cross-sectional ascertainment of vitamin D metabolites and vascular functions late during the course of kidney disease. CONCLUSIONS: Serum concentrations of vitamin D metabolites are not associated with vasodilator functions or vascular stiffness at baseline in a cohort study of patients with chronic kidney disease awaiting AVF creation surgery. Laboratory measurements of vitamin D metabolites are unlikely to provide useful information regarding vascular functions in this setting. PMID- 28359658 TI - Unrecognized Fibrinogen A alpha-Chain Amyloidosis: Results From Targeted Genetic Testing. AB - BACKGROUND: Fibrinogen A alpha-chain (AFib) amyloidosis results from autosomal dominant mutations in the gene encoding AFib (FGA). Patients with this disorder typically present with proteinuria. Isolated cases of AFib amyloidosis, carrying the FGA p.Glu545Val variant, were identified in the district of Braga, in northwest Portugal. This observation led us to hypothesize that this disorder might be an unrecognized cause of kidney disease in that region and prompted us to carry out targeted genetic testing for the p.Glu545Val variant in the local hemodialysis population and family members of identified cases. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 3 groups of participants: (1) kidney biopsy registry, n=4; (2) hemodialysis facility, n=122 of 267 patients; and (3) genetically at-risk individuals; n=69 of 167 family members. OUTCOMES: Kidney disease, kidney disease progression, and survival. RESULTS: The p.Glu545Val variant was identified in all 4 patients of the biopsy registry, 12 of 122 (9.8%) hemodialysis patients tested, and 34 of 69 (49%) relatives tested. These 50 cases belonged to 13 unrelated families with kidney disease or amyloidosis identified in 61% of probands. 35 individuals presented with hypertension at a mean of 51.0+/-10.4 years. Of these, 30 developed kidney disease at a mean of 56.7+/-12.0 years, and 21 initiated dialysis therapy at a mean of 61.4+/-11.3 years. Heart, liver, spleen, colon, and ileum were involved along the progression of the disease. Kidney disease was formerly attributed to hypertension in 25% of patients with AFib amyloidosis undergoing hemodialysis. LIMITATIONS: Retrospective data collection for patients with amyloidosis previously diagnosed. CONCLUSIONS: AFib amyloidosis appears to be an under-recognized disorder in Braga, Portugal, where we found a high frequency of the FGA p.Glu545Val variant. Due to the nonspecific nature of its major clinical features, the diagnosis of AFib amyloidosis should have a high index of suspicion, particularly in populations in which hypertension is prevalent. PMID- 28359660 TI - Clinician-patient communication measures: drilling down into assumptions, approaches, and analyses. AB - OBJECTIVE: To critically examine properties of clinician-patient communication measures and offer suggestions for selecting measures appropriate to the purposes of research or clinical practice assessment. METHODS: We analyzed different types of communication measures by focusing on their ontological properties. We describe their relative advantages and disadvantages with respect to different types of research questions. RESULTS: Communication measures vary along dimensions of reporter (observer vs. participant), focus of measurement (behavior, meaning, or quality), target, and timing. Observer coded measures of communication behavior function well as dependent variables (e.g., evaluating communication skill interventions, examining variability related to gender or race), but are less effective as predictors of perceptions and health outcomes. Measures of participants' judgments (e.g., what the communication means or how well it was done) capture patients' or clinicians' experiences (e.g., satisfaction) and can be useful for predicting outcomes, especially in longitudinal designs. CONCLUSION: In the absence of a theoretically coherent set of measures that could be used across research programs and applied setting, users should take steps to select measures with properties that are optimally matched to specific questions. PRACTICE IMPLICATIONS: Quality assessments of clinician-patient communication should take into account the timing of the assessment and use measures that drill down into specific aspects of patient experience to mitigate ceiling effects. PMID- 28359659 TI - A stakeholder-driven approach to improve the informed consent process for palliative chemotherapy. AB - OBJECTIVE: Patients often anticipate cure from palliative chemotherapy. Better resources are needed to convey its risks and benefits. We describe the stakeholder-driven development and acceptability testing of a prototype video and companion booklet supporting informed consent (IC) for a common palliative chemotherapy regimen. METHODS: Our multidisciplinary team (researchers, advocates, clinicians) employed a multistep process of content development, production, critical evaluation, and iterative revisions. Patient/clinician stakeholders were engaged throughout using stakeholder advisory panels, featuring their voices within the intervention, conducting surveys and qualitative interviews. A national panel of 57 patient advocates, and 25 oncologists from nine US practices critiqued the intervention and rated its clarity, accuracy, balance, tone, and utility. Participants also reported satisfaction with existing chemotherapy IC materials. RESULTS: Few oncologists (5/25, 20%) or advocates (10/22, 45%) were satisfied with existing IC materials. In contrast, most rated our intervention highly, with 89-96% agreeing it would be useful and promote informed decisions. Patient voices were considered a key strength. Every oncologist indicated they would use the intervention regularly. CONCLUSION: Our intervention was acceptable to advocates and oncologists. A randomized trial is evaluating its impact on the chemotherapy IC process. PRACTICE IMPLICATIONS: Stakeholder-driven methods can be valuable for developing patient educational interventions. PMID- 28359661 TI - Performance evaluation of a novel anaerobic digestion operation process for treating high-solids content chicken manure: Effect of reduction of the hydraulic retention time at a constant organic loading rate. AB - A novel feeding strategy was adopted in this study and the effect of reduction in hydraulic retention time (HRT) on the anaerobic digestion of chicken manure (CM) with a constant organic loading rate of 6.0gVS/L/d was investigated. The lab scale CSTR was operated at 38 degrees C and HRTCM was reduced from 52days to 5days. At HRTCM of 20-45days, the reactor was relatively stable in terms of the volumetric biogas production rates and specific biogas production (SBP), which were 2.2-2.4L/L/d and 338.3-418.7mL/gVSadded, respectively. However, process instability and VFA accumulation occurred when the HRTCM was reduced to 10days due to excess microbes washout. The reduction in HRTCM to 5days caused SBP to decrease to 198.7mL/gVSadded and the acetic acid content to exceed 6000mg/L. The biomass balance model showed that the biomass concentration at HRTCM of 20-52days (0.473-0.615gVSS/L) was notably higher than that at HRTCM of 5-10days (0.173gVSS/L). PMID- 28359662 TI - Assessing the transmission dynamics of measles in Japan, 2016. AB - OBJECTIVES: Despite the verification of measles elimination, Japan experienced multiple generations of measles transmission following importation events in 2016. The purpose of the present study was to analyze the transmission dynamics of measles in Japan, 2016, estimating the transmission potential in the partially vaccinated population. METHODS: All diagnosed measles cases were notified to the government, and the present study analyzed two pieces of datasets independently, i.e., the transmission tree of the largest outbreak in Osaka (n=49) and the final size distribution of all importation events (n=23 events). Branching process model was employed to estimate the effective reproduction number Rv, and the analysis of transmission tree in Osaka enabled us to account for the timing of introducing contact tracing and case isolation. RESULTS: Employing a negative binomial distribution for the offspring distribution, the model with time dependent decline in Rv due to interventions appeared to best fit to the transmission tree data with Rv of 9.20 (95% CI (confidence interval): 2.08, 150.68) and the dispersion parameter 0.32 (95% CI: 0.07, 1.17) before interventions were introduced. The relative transmissibility in the presence of interventions from week 34 was estimated at 0.005. Analyzing the final size distribution, models for subcritical and supercritical processes fitted equally well to the observed data, and the estimated reproduction number from both models did not exclude the possibility that Rv>1. CONCLUSIONS: Our results likely reflect the highly contagious nature of measles, indicating that Japan is at risk of observing multiple generations of measles transmission given imported cases. Considering that importation events may continue in the future, supplementary vaccination of adults needs to be considered. PMID- 28359663 TI - Higher Maximal Occlusal Bite Force in Endodontically Treated Teeth Versus Vital Contralateral Counterparts. AB - INTRODUCTION: Decreased sensitivity to occlusal load could lead to a greater risk of damage to endodontically treated teeth. Therefore, this study aims to test whether root canal treatment reduces the sensitivity of the treated teeth to occlusal load. METHODS: This is a comparative cross-sectional study of 124 patients who received root canal treatment. Treated teeth were compared with vital teeth on the contralateral side. After interviews with participants, their maximal bite forces (MBFs) of their root canal-treated and contralateral untreated teeth were measured using a digital bite fork force transducer. Data were analyzed by comparing the mean MBF of root canal-treated and control teeth. RESULTS: The mean MBF (+/- standard deviation) was 226.6 N (+/-168.7) for root canal-treated teeth and 207.93 N (+/-158.08) for control teeth. Root canal treated teeth had a significantly higher difference in the mean MBF than the control group (P < .0001) using the paired sample t test. A univariate analysis test showed that differences in the MBF were affected by molar relationship, overbite, and the quality of root filling. CONCLUSIONS: The difference in the MBF was significantly higher in root canal-treated teeth, which is consistent with the function of dental pulp as a highly sensitive sensor. Therefore, the reduction in the sensitivity of teeth to an applied load after pulp removal may increase the risk of overloading. This may, in turn, increase the frequency of tooth damage after root canal treatment. PMID- 28359665 TI - Incidental Findings in Small Field of View Cone-beam Computed Tomography Scans. AB - INTRODUCTION: The use of cone-beam computed tomography (CBCT) in endodontics has increased in recent years. In clinical application of small field of view (FOV) CBCTs, these scans are not reviewed routinely by a radiologist. Studies of large FOV CBCT scans show the prevalence of incidental findings to be greater than 90%. The purpose of this study was to evaluate the prevalence of missed findings by endodontic residents as compared with a radiologist on small FOV CBCT scans. METHODS: Two hundred three small FOV CBCTs obtained for endodontic purposes were analyzed by an endodontic resident and a medical radiologist. The reported findings of each practitioner were compared to evaluate for missed incidental findings by the endodontic resident. RESULTS: The radiologist reported abnormalities in 176 of the 203 subjects (87%), with a total of 310 abnormalities reported. The endodontic resident reported abnormalities in 102 of the 203 subjects (50%), with a total of 126 abnormalities reported. The percentage of scans with any abnormality reported by the radiologist was significantly greater than the endodontic resident (P < .001). There was no significant difference between jaw locations in percentage of missed findings for the 3 most common types of finding-rarefying osteitis, sinusitis/mucosal lining thickening, and excess restorative material in the periapical area. Rarefying osteitis was missed significantly less than the other 2 types of findings (P < .001). CONCLUSIONS: A radiologist is significantly more likely to identify incidental findings in small FOV CBCT scans than an endodontic resident. Scan location had no significant association with the rate of missed findings. PMID- 28359664 TI - Omega 3 Fatty Acids Reduce Bone Resorption While Promoting Bone Generation in Rat Apical Periodontitis. AB - INTRODUCTION: This study evaluated the effects of the dietary supplement omega 3 polyunsaturated fatty acids (omega-3 PUFAs) on pulp exposure-induced apical periodontitis (AP) in rats. METHODS: Twenty-eight male rats were divided into groups: control untreated rats (C), control rats treated with omega-3 PUFAs alone (C-O), rats with pulp exposure-induced AP, and rats with pulp exposure-induced AP treated with omega-3 PUFAs (AP-O). The omega-3 PUFAs were administered orally, once a day, for 15 days before pulp exposure and, subsequently, 30 days after pulp exposure. Rats were killed 30 days after pulp exposure, and jaws were subjected to histologic and immunohistochemical analyses. Immunohistochemical analyses were performed to detect tartrate-resistant acid phosphatase-positive osteoclasts and osteocalcin-positive osteoblasts on the bone surface of periapical area. Results were statistically evaluated by using analysis of variance and Tukey honestly significant difference, and P < .05 was considered statistically significant. RESULTS: The bone resorption lesion was significantly larger in the AP group compared with AP-O, C, and C-O groups (P < .05). The level of inflammatory cell infiltration was significantly elevated, and the number of tartrate-resistant acid phosphatase-positive osteoclasts was significantly higher in the periapical lesions of the AP group compared with AP-O, C, and C-O groups (P < .05). The number of osteocalcin-positive osteoblasts was significantly increased in the AP-O group compared with the AP group (P > .05). CONCLUSIONS: Supplementation with omega-3 PUFAs not only suppresses bone resorption but also promotes new bone formation in the periapical area of rats with AP in conjunction with downregulation of inflammatory cell infiltration into the lesion. PMID- 28359667 TI - Mitochondrial membrane protein-associated neurodegeneration. PMID- 28359666 TI - Sequence of the R1 plasmid and comparison to F and R100. AB - The R1 antibiotic resistance plasmid, originally discovered in a clinical Salmonella isolate in London, 1963, has served for decades as a key model for understanding conjugative plasmids. Despite its scientific importance, a complete sequence of this plasmid has never been reported. We present the complete genome sequence of R1 along with a brief review of the current knowledge concerning its various genetic systems and a comparison to the F and R100 plasmids. R1 is 97,566 nucleotides long and contains 120 genes. The plasmid consists of a backbone largely similar to that of F and R100, a Tn21-like transposon that is nearly identical to that of R100, and a unique 9-kb sequence that bears some resemblance to sequences found in certain Klebsiella oxytoca strains. These three regions of R1 are separated by copies of the insertion sequence IS1. Overall, the structure of R1 and comparison to F and R100 suggest a fairly stable shared conjugative plasmid backbone into which a variety of mobile elements have inserted to form an "accessory" genome, containing multiple antibiotic resistance genes, transposons, remnants of phage genes, and genes whose functions remain unknown. PMID- 28359668 TI - The Anterolateral Ligament Has Similar Biomechanical and Histologic Properties to the Inferior Glenohumeral Ligament. AB - PURPOSE: To characterize the tensile and histologic properties of the anterolateral ligament (ALL), inferior glenohumeral ligament (IGHL), and knee capsule. METHODS: Standardized samples of the ALL (n = 19), anterolateral knee capsule (n = 15), and IGHL (n = 13) were isolated from fresh-frozen human cadavers for uniaxial tensile testing to failure. An additional 6 samples of the ALL, capsule, and IGHL were procured for histologic analysis and determination of elastin content. RESULTS: All investigated mechanical properties were significantly greater for both the ALL and IGHL when compared with capsular tissue. In contrast, no significant differences between the ALL and IGHL were found for any property. The elastic modulus of ALL and IGHL samples was 174 +/- 92 MPa and 139 +/- 60 MPa, respectively, compared with 62 +/- 30 MPa for the capsule (P = .001). Ultimate stress was significantly lower (P < .001) for the capsule, at 13.4 +/- 7.7 MPa, relative to the ALL and IGHL, at 46.4 +/- 20.1 MPa and 38.7 +/- 16.3 MPa, respectively. The ultimate strain at failure was 37.8% +/- 7.9% for the ALL and 39.5% +/- 9.4% for the IGHL; this was significantly greater (P = .041 and P = .02, respectively) for both relative to the capsule, at 32.6% +/- 8.4%. The strain energy density was 7.8 +/- 3.1 MPa for the ALL, 2.1 +/- 1.3 MPa for the capsule, and 7.1 +/- 3.1 MPa for the IGHL (P < .001). The ALL and IGHL consisted of collagen bundles aligned in a parallel manner, containing elastin bundles, which was in contrast to the random collagen architecture noted in capsule samples. CONCLUSIONS: The ALL has similar tensile and histologic properties to the IGHL. The tensile properties of the ALL are significantly greater than those observed in the knee capsule. CLINICAL RELEVANCE: The ALL is not just a thickening of capsular tissue and should be considered a distinct ligamentous structure comparable to the IGHL in the shoulder. The tensile behavior of the ALL is similar to the IGHL, and treatment strategies should take this into account. PMID- 28359669 TI - Anatomic Anterior Cruciate Ligament Reconstruction via Independent Tunnel Drilling: A Systematic Review of Randomized Controlled Trials Comparing Patellar Tendon and Hamstring Autografts. AB - PURPOSE: To collect the highest level of evidence comparing anatomic anterior cruciate ligament (ACL) reconstruction via independent tunnel drilling using bone patellar tendon-bone (BTB) and hamstring tendon (HT) autografts in terms of clinical outcome and failure rate. METHODS: We performed a systematic review of clinical trials that randomized patients to ACL reconstruction with either BTB or HT autografts with a minimum 2-year follow-up. Only trials using independent tunnel drilling, including outside-in and anteromedial portal techniques, for both autografts were eligible for inclusion, whereas all transtibial studies were excluded. Study design, demographics, surgical technique, rehabilitation protocol, and clinical outcomes were compiled. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Quality assessment was performed using the Coleman Methodological Scale (CMS). RESULTS: Six published studies reporting on 5 randomized controlled trials (RCTs) met the inclusion criteria. No study reported a difference in rerupture rate between BTB and HT. BTB-reconstructed knees experienced a greater incidence of anterior knee pain or crepitus in 2/7 trials and radiographic evidence of degenerative change in 3/7 trials. HT-reconstructed knees had increased instrumented laxity in 2/7 trials and less knee flexion strength postoperatively. CONCLUSIONS: This study collects all available Level I and II evidence for anatomic ACL reconstruction using BTB and HT grafts. According to the data presented in these studies, clinical outcome scores and failure rates showed no differences for anatomic reconstruction using either autograft. However, in some studies, BTB reconstructed knees experienced a greater incidence of anterior knee pain and radiographic evidence of degenerative change, and in others, HT-reconstructed knees had increased laxity and less knee flexion strength. In our opinion, both BTB and HT autografts remain valid options for ACL reconstruction when using anatomic drilling techniques, providing a stable knee with reliable return to activity. LEVEL OF EVIDENCE: Level II, systematic review of Level I and II studies. PMID- 28359671 TI - Biosimilars and drug development in allergic and immunologic diseases. PMID- 28359670 TI - Electron-beam-induced-current and active secondary-electron voltage-contrast with aberration-corrected electron probes. AB - The ability to map out electrostatic potentials in materials is critical for the development and the design of nanoscale electronic and spintronic devices in modern industry. Electron holography has been an important tool for revealing electric and magnetic field distributions in microelectronics and magnetic-based memory devices, however, its utility is hindered by several practical constraints, such as charging artifacts and limitations in sensitivity and in field of view. In this article, we report electron-beam-induced-current (EBIC) and secondary-electron voltage-contrast (SE-VC) with an aberration-corrected electron probe in a transmission electron microscope (TEM), as complementary techniques to electron holography, to measure electric fields and surface potentials, respectively. These two techniques were applied to ferroelectric thin films, multiferroic nanowires, and single crystals. Electrostatic potential maps obtained by off-axis electron holography were compared with EBIC and SE-VC to show that these techniques can be used as a complementary approach to validate quantitative results obtained from electron holography analysis. PMID- 28359672 TI - Cloning and expression analysis of a Toll-like receptor 21 (TLR21) gene from turbot, Scophthalmus maximus. AB - Toll-like receptor 21 (TLR21) is a non-mammalian TLR recognizing unmethylated CpG DNA and considered as a functional homolog of mammalian TLR9. In the present study, a TLR21 gene was cloned from turbot, Scophthalmus maximus, its immune responsive expression was subsequently studied in vivo. The turbot (Sm)TLR21 gene is an intronless gene with a length of 3527 bp and encodes a peptide of 984 amino acids. The deduced protein possesses a signal peptide sequence, a leucine-rich repeat (LRR) domain composed of 16 LRR motifs, a transmembrane (TM) region and a Toll/interleukin-1 receptor (TIR) domain. Phylogenetic analysis grouped it with other teleost TLR21s. Quantitative real-time PCR (qPCR) analysis demonstrated the constitutive expression of SmTLR21 mRNA in all twelve examined tissues with higher levels in the lymphomyeloid-rich tissues like spleen and head kidney. Further, upon stimulation with polyinosinic: polycytidylic acid [poly(I:C)], turbot reddish body iridovirus (TRBIV) and CpG oligodeoxynucleotides (CpG-ODN) 2395, the SmTLR21 mRNA expression was up-regulated in the gills, head kidney, spleen and muscle. The maximum increases of SmTLR21 transcript levels ranged from 1.3 to 8.1-fold and appeared at 3 h to 5 day post-injection depending on different organs and stimuli. These findings suggest that SmTLR21 may play an important role in the immune responses to the infections of a broad range of pathogens that include RNA and DNA viruses and bacteria. PMID- 28359674 TI - Design and synthesis of bicyclic acetals as Beta Secretase (BACE1) inhibitors. AB - Taking advantage of the structural similarity between aspartic proteases, small molecule peptidomimetic inhibitors that already showed activity towards Secreted Aspartic Protease 2 as anti-Candida agents and HIV protease inhibitors were exploited as potential BACE1 inhibitors. A focused library of 6,8-dioxa-3 azabicyclo[3.2.1]-octane peptidomimetic scaffolds was synthesized and assayed towards BACE1 enzyme, resulting in the identification of a thiolactam-containing hit compound possessing IC50 in the low micromolar range, and confirming the bicyclic acetal portion as a potential transition state analogue in the interaction with catalytic aspartic acid residues. PMID- 28359675 TI - Measuring Marrow Density and Area Using Peripheral Quantitative Computed Tomography at the Tibia: Precision in Young and Older Adults and Individuals With Spinal Cord Injury. AB - The objective of this study was to compare the test-retest precision error for peripheral quantitative computed tomography (pQCT)-derived marrow density and marrow area segmentation at the tibia using 3 software packages. A secondary analysis of pQCT data in young adults (n = 18, mean +/- standard deviation 25.4 +/- 3.2 yr), older adults (n = 47, 71.8 +/- 8.2 yr), and individuals with spinal cord injury (C1-T12 American Spinal Injury Association Impairment Scale, classes A-C; n = 19, 43.5 +/- 8.6 yr) was conducted. Repeat scans of the tibial shaft (66%) were performed using pQCT (Stratec XCT2000). Test-retest precision errors (root mean square standard deviation and root mean square coefficient of variation [RMSCV%]) for marrow density (mg/cm3) and marrow area (mm2) were reported for the watershed-guided manual segmentation method (SliceOmatic version 4.3 [Sliceo-WS]) and the 2 threshold-based edge detection methods (Stratec version 6.0 [Stratec-TB] and BoneJ version 1.3.14 [BoneJ-TB]). Bland-Altman plots and 95% limits of agreement were computed to evaluate test-retest discrepancies within and between methods of analysis and subgroups. RMSCV% for marrow density segmentation was >5% for all methods across subgroups (Stratec-TB: 12.2%-28.5%, BoneJ-TB: 14.5%-25.2%, and Sliceo-WS: 10.9%-23.0%). RMSCV% for marrow area segmentation was within 5% for all methods across subgroups (Stratec-TB: 1.9% 4.4%, BoneJ-TB: 2.6%-5.1%, and Sliceo-WS: 2.4%-4.5%), except using BoneJ-TB in older adults. Intermethod discrepancies in marrow density appeared to be present across the range of marrow density values and did not differ by subgroup. Intermethod discrepancies varied to a greater extent for marrow area and were found to be more frequently at mid- to higher-range values for those with spinal cord injury. Precision error for pQCT-derived marrow density segmentation exceeded 5% for all methods of analysis across a range of bone mineral densities and fat infiltration, whereas precision error for marrow area segmentation ranged from 2% to 5%. Further investigation is necessary to determine alternative acquisition and analysis methods for pQCT-derived marrow segmentation. PMID- 28359673 TI - Indole-TEMPO conjugates alleviate ischemia-reperfusion injury via attenuation of oxidative stress and preservation of mitochondrial function. AB - Mitochondrial oxidative damage contributes to a wide range of pathologies including ischemia/reperfusion injury. Accordingly, protecting mitochondria from oxidative damage should possess therapeutic relevance. In the present study, we have designed and synthesized a series of novel indole-TEMPO conjugates that manifested good anti-inflammatory properties in a murine model of xylene-induced ear edema. We have demonstrated that these compounds can protect cells from simulated ischemia/reperfusion (s-I/R)-induced reactive oxygen species (ROS) overproduction and mitochondrial dysfunction. Furthermore, we have demonstrated that indole-TEMPO conjugates can attenuate organ damage induced in rodents via intestinal I/R injury. We therefore propose that the pharmacological profile and mechanism of action of these indole-TEMPO conjugates involve convergent roles, including the ability to decrease free radical production via lipid peroxidation which couples to an associated decrease in ROS-mediated activation of the inflammatory process. We further hypothesize that the protective effects of indole-TEMPO conjugates partially reside in maintaining optimal mitochondrial function. PMID- 28359676 TI - Transplantation of the decellularized tracheal allograft in animal model (rabbit). AB - BACKGROUND: It has been difficult to perform tracheal allotransplantation without immunosuppression. To determine whether decellularized trachea can be used in tracheal replacement, we evaluated the viability of decellularized tracheal allografts in a rabbit model of immunosuppressant-free transplantation. METHOD: Half allograft (Group 1, n = 7) was harvested from adult New Zealand white rabbits, subjected to a detergent-enzymatic method (containing sodium deoxycholate/DNase lavations) of decellularization for as many cycles as needed, and the other half was stored in phosphate-buffered saline at 4 degrees C as a control (Group 2, n = 7). Bioengineered and control tracheas were then implanted in 14 age-matched rabbits. RESULTS: In Group 1 (decellularized), all rabbits survived, whereas in Group 2(control), all rabbits died of airway obstruction between 20 days and 45 days after operation. Histologically, the decellularized allografts displayed complete regeneration of epithelium and cartilage, but the fresh allografts showed inflammatory changes, no epithelium, and no cartilage. CONCLUSIONS: Complete regeneration of epithelium and cartilage tracheal rings occurred after the implantation of decellularized tracheal allografts without immunosuppression. We demonstrate that the decellularized process reduces the allogeneic response to the trachea. Therefore, we believe that the decellularized tracheal allograft is an excellent choice for tracheal replacement. To our knowledge, this is the first study to observe the long-term (1 year) prognosis of this transplanted trachea. PMID- 28359677 TI - Paclitaxel dimers assembling nanomedicines for treatment of cervix carcinoma. AB - Poor water solubility and adverse side effects pose a challenge for clinical application of paclitaxel (PTX). In this work, a series of PTX dimers are synthesized by coupling two PTX molecules with dicarboxylic acids. As-synthesized PTX dimers form stable nanoparticles in aqueous solution without using any surfactants or adjuvants, and the solubility of PTX in water increases by 2500 fold compared to that of free PTX. These nanoparticles with high content of PTX are internalized by cancer cells and exhibit comparable cytotoxicity with Taxol. Furthermore, when the PTX dimers are incorporated into methoxypoly(ethylene glycol)2K-block-poly(d, l-lactide)2K (PEG-PDLLA) micelles, the loading content of PTX dimers is as high as 85wt%. The formed nanoparticles possess the high stability in biological conditions. Both in vitro and in vivo experiments show that these (PTX dimer)/PEG-PDLLA formulations possess effective cellular uptake and potent cytotoxicity, and exhibit reduced systemic toxicity and enhanced antitumor efficacy towards human cervical tumor. We believe these PTX dimers based nanoparticles would be an alternative formulation for PTX, and such drug dimer assembling behaviors could be extended to other therapeutic agents. PMID- 28359678 TI - Bodyguards: Pathogen-Derived Decoys That Protect Virulence Factors. AB - Recent studies on plant-pathogen interactions have exposed a new strategy used by plant pathogens: decoy effectors that protect virulence factors. Examples of these "bodyguards" include the recently discovered PsXLP1 from Phytophthora sojae and truncated TALEs from Xanthomonas oryzae. These examples suggest important roles for seemingly non-functional effector proteins in distracting the host. PMID- 28359679 TI - Activation of Wnt Signaling Increases Numbers of Enteric Neurons Derived From Neonatal Mouse and Human Progenitor Cells. AB - BACKGROUND & AIMS: Neural stem and progenitor cells from the enteric nervous system (ENS) might serve as a source of cells for treatment of neurogastrointestinal disorders. Before we can use these cells, we must increase our understanding of the signaling mechanisms that regulate proliferation and differentiation. We systematically evaluated the effects of canonical Wnt signaling on proliferation and differentiation of cultured ENS progenitor cells from neonatal mice and humans. METHODS: We isolated ENS progenitors from tunica muscularis of the small intestine of newborn (postnatal day 0) wild-type C57BL/6 mice as well as from Wnt1-Cre2 reporter mice. We also obtained intestinal tissue samples from infants (2 and 7 months old) undergoing surgery for imperforate anus or focal intestinal perforation and isolated ENS cells. ENS cells were cultured under proliferation conditions leading to formation of 3-dimensional spheres, which we activated with Wnt3a and SB216763 in order to activate the beta-catenin dependent canonical Wnt pathway. We used immunoblot and quantitative polymerase chain reaction to evaluate the molecular response to Wnt stimuli and immunohistochemistry, proliferation, and cell death assays to identify new neurons. RESULTS: In proliferating enterospheres derived from ENS progenitor cells, we verified the expression of Wnt receptors frizzled 1-10 and the co receptors low-density lipoprotein receptor-related proteins 5 and 6. Pharmacologic stimulation with Wnt agonists led to intracellular accumulation of Wnt-dependent beta-catenin and up-regulated expression of known Wnt target genes axin2, lef1, and lgr5. Activation of the canonical Wnt pathway promoted growth of ENS cell spheres during cell expansion and increased the number of newborn neurons derived from mouse and human progenitor cells. CONCLUSIONS: In studies of human and mouse ENS progenitors, we found activation of the Wnt signaling pathway to promote neurogenesis of the ENS in vitro. The neurogenic effect of Wnt agonists on ENS progenitors supports their use in generation of cell pools for autologous cell replacement therapies. PMID- 28359680 TI - Assessment of "YouTube" Content for Distal Radius Fracture Immobilization. AB - OBJECTIVE: Distal radius fractures (DRFs) are the most common orthopedic fractures, with >70% of cases treated by closed immobilization using a short arm cast or a sugar tong splint. However, inadequate immobilization is a risk factor for loss of reduction requiring repeat reduction or surgical treatment. Therefore, education of clinical skills for appropriate immobilization of DRFs is important. With the increasing use of web-based information by medical learners, our aim was to assess the quality and quantity of videos regarding closed immobilization of DRFs on YouTube. DESIGN: Retrospective review of YouTube videos on distal radius fracture immobilization using specific search terms. SETTING: Identified videos were analyzed for their educational value, quality of the technical skill demonstrated, and overall metrics. Educational value was scored on a 5-point scale, with "1" indicative of low quality and "5" of high quality. PARTICIPANTS: Not applicable. RESULTS: Among the 68,366 videos identified, 16 met our inclusion criteria of being in English; performed by a health care professional or institution; and with casting being the major theme of the educational information provided. Of these 16 videos, 6 had an educational value score of 4 or 5, with the remaining 10 having a score <=3. Although immobilization was demonstrated by cast technician specialized in orthopedics, skills were also performed by orthopedic attendants, urgent care physicians, orthopedic residents, and nurse practitioners. The credentials of the performer in 3 videos were not identified. CONCLUSION: There is a need to promote high quality educational videos produced by established medical school faculty members on open, web-based, portals. PMID- 28359682 TI - Anticipatory representations of reward and threat in perceptual areas from preadolescence to late adolescence. AB - This study examined whether changes in perceptual processes can partially account for the increase in reward-orientated behaviour during adolescence. This was investigated by examining reinforcement-dependent potentiation to discriminative stimuli (SD) that predicted rewarding or threatening outcomes. To that end, perceptual event-related potentials that are modulated by motivationally salient stimuli, the N170 and Late Positive Potential (LPP), were recorded from 30 preadolescents (9-12 years), 30 adolescents (13-17 years), and 34 late adolescents (18-23 years) while they completed an instrumental task in which they emitted or omitted a motor response to obtain rewards and avoid losses. The LPP, but not the N170, showed age, but not gender, differences in reinforcement dependent potentiation; preadolescents, adolescents, and late adolescents showed potentiation to SD that predicted a threat, whereas only preadolescents showed potentiation to SD that predicted a reward. Notably, the magnitude of threat related LPP reinforcement-dependent potentiation decreased during the course of adolescence. In addition, greater sensation seeking was associated with greater LPP amplitudes in preadolescent males, but smaller LPP amplitudes in late adolescent males. Critically, these findings provide initial evidence for developmental differences in value-related coding in perceptual areas, where adolescents show greater perceptual biases to avoidance-related cues than to reward-related cues. PMID- 28359681 TI - Evaluation of Plaque Morphology by 64-Slice Coronary Computed Tomographic Angiography Compared to Intravascular Ultrasound in Nonocclusive Segments of Coronary Arteries. AB - RATIONALE AND OBJECTIVES: Although intravascular ultrasound (IVUS) is the current gold standard for plaque characterization, noninvasive coronary computed tomographic angiography (CCTA) requires further evaluation. The ability to detect plaque morphology by CCTA remains unclear. The purpose of this study was to evaluate the diagnostic accuracy of CCTA for plaque detection and morphology. MATERIALS AND METHODS: Thirty-one patients underwent cardiac catheterization with IVUS and CCTA. The presence of plaque was evaluated by both modalities in nonocclusive segments (<50% stenosis) of the left anterior descending artery, left circumflex artery, and right coronary artery. Plaque morphology was classified as (1) normal, (2) soft or fibrous, (3) fibrocalcific, or (4) calcific. Results by IVUS and CCTA were compared blindly on a segment-to-segment basis with subgroup analysis based on CCTA tube voltage. RESULTS: Among the 31 patients (mean age 56.2 +/- 8.6 years, 27% female), 152 segments were analyzed. Of these segments, 42% were in the left anterior descending artery, 32% were in the left circumflex artery, and 26% were in the right coronary artery. Plaque morphology by IVUS identified 103 segments as fibrous (68%), 31 as fibrocalcific (20%), and 6 as calcific (4.0%); 12 segments were normal (8.0%). To evaluate for the presence of plaque, CCTA had an overall sensitivity and specificity of 99% and 75%, respectively. In patients who underwent CCTA with a tube voltage of 100 kV, both sensitivity and specificity were 100%. The sensitivity and specificity of CCTA to identify plaque as calcified (fibrocalcific or calcific) vs noncalcified (soft or fibrous) were 87% and 96%, respectively. Overall, the accuracy of CCTA to detect the presence of plaque was 97%; the accuracy to detect plaque calcification was 94%. CONCLUSIONS: CCTA offers excellent sensitivity and accuracy for plaque detection and morphology characterization in nonocclusive coronary segments. In addition, diagnostic accuracy is preserved with a reduced tube voltage protocol. PMID- 28359683 TI - [Detection of severe hemophilia A during neonatal screening]. PMID- 28359684 TI - [Giant mesenteric lipoma in children: A case-report]. AB - Mesenteric lipoma is an extremely rare disease in children. Fewer than 50 cases have been reported in the literature. Diagnosis is based on clinical examination, ultrasound, and computed tomography (CT). However, only the histological study of the specimen during laparotomy or laparoscopy can confirm the diagnosis. Thus, surgery, be it by laparotomy or laparoscopic, is both a means of exploration and treatment in mesenteric lipoma. We report on a case of giant lipoma of the mesentery in a 7-year-old girl presenting paroxysmal abdominal pain with a subocclusive syndrome lasting 1 week. PMID- 28359685 TI - Professor Arto Urtti -A northern light from the land of the midnight sun. PMID- 28359686 TI - SLM, a novel carbazole-based fluorophore attenuates okadaic acid-induced tau hyperphosphorylation via down-regulating GSK-3beta activity in SH-SY5Y cells. AB - Phosphorylated tau dissociates from microtubules and aggregates to form neurofibrillary tangles resulting in neuronal toxicity and cognitive deficits. Attenuating tau hyperphosphorylation is considered as an effective therapeutic approach for Alzheimer's disease (AD). From our previous study, SLM, a carbazole based fluorophore prevents Abeta aggregation, reduced glycogen synthase kinase 3beta (GSK-3beta) activity and tau hyperphosphorylation in triple transgenic mouse model of AD. However, the mechanism by which SLM attenuates tau hyperphosphorylation warrants further investigation. In the current study, we intend to evaluate the effects of SLM against okadaic acid (OA)-induced tau hyperphosphorylation and microtubules instability in human neuroblastoma (SH SY5Y) cells. The results showed that, SLM reduced the OA-induced cell neurotoxicity and tau hyperphosphorylation in SH-SY5Y cells. SLM treatment down regulated GSK-3beta activity. However, in the presence of GSK-3beta inhibitor (SB216763, 10MUM), SLM treatment could not reduce GSK-3beta activity and tau hyperphosphorylation as compared with SB216763 treatment alone. Furthermore, SLM treatment also ameliorated OA-induced microtubules instability and cytoskeleton damage. Collectively, SLM attenuated OA-induced tau hyperphosphorylation via down regulating GSK-3beta activity in SH-SY5Y cells. Therefore, this study supports SLM as a potential compound for AD and other tau pathology-related neurodegenerative disorders. PMID- 28359687 TI - Comparison of the adult three-dimensional craniofacial features of patients with unilateral craniofacial microsomia with and without early mandible distraction. AB - This study was conducted to analyze the long-term facial growth of patients with craniofacial microsomia (CFM) after early mandible distraction osteogenesis (DO), and compared adult three-dimensional (3D) craniofacial features of patients with and without early mandibular DO for Pruzansky grade II deformities. The study included 20 patients: 9 with early mandible DO (the DO group) and 11 without previous treatment (the NDO group). Longitudinal radiographs were measured for growth changes after DO. The 3D craniofacial images were constructed to compare the craniofacial forms between the two groups. The patients with early DO presented 8 to 9mm forward and downward maxillary growth and 4.6mm limited forward and 17.3mm substantial downward mandibular growth. The ramus length ratio (affected/nonaffected) was 90.8% at DO completion and decreased to 69.5% at growth completion during 13 years of follow-up. Both groups showed obvious craniofacial asymmetry, as indicated by occlusal plane canting, chin deviation, transverse and vertical condyle positions, and mandibular contours. Although all the bilateral differences were higher in the NDO group than in the DO group, no statistical differences were found. Early mandible distraction could not alter the inherent facial growth pattern in patients with grade II CFM. Limited changes are derived for definitive facial correction with early DO. PMID- 28359688 TI - Evaluation of hyaluronic matrix efficacy in sinus augmentation: a randomized controlled histomorphometric and micro-computed tomography analysis. AB - The objective of the present study was to test the hypothesis that the addition of hyaluronic acid-based matrix to collagenated heterologous bone graft for sinus augmentation would enhance bone formation compared to collagenated heterologous bone graft alone in the early healing period, by micro-computed tomography and histomorphometry. Thirteen systemically healthy patients requiring bilateral two stage maxillary sinus augmentation (residual crest height<=4mm) were enrolled in this split-mouth prospective randomized controlled study. One sinus side as a control group was grafted with only collagenated heterologous bone graft; the other region as a test group was grafted with hyaluronic matrix and collagenated heterologous bone graft. Bone biopsy samples were taken after 4 months during the dental implant surgery and analyzed using micro-computed tomography and histomorphometric parameters. According to the micro-computed tomography and histomorphometric results, a significantly higher percentage of new bone was observed in the test group when compared to the control group after 4 months of healing. This study confirmed the hypothesis that the addition of hyaluronic matrix to collagenated heterologous bone graft for sinus augmentation enhances bone formation compared to collagenated heterologous bone graft alone in the early healing period. PMID- 28359689 TI - Frailty measure is more predictive of outcomes after curative therapy for endometrial cancer than traditional risk factors in women 60 and older. AB - OBJECTIVES: To determine if readily obtainable markers of frailty predict disease free survival (DFS) in elderly women with endometrial cancer treated with curative intent. METHODS: 88 consecutive women>=age 60 treated with surgery, chemotherapy and radiation for stage I-IV endometrial cancer were included. We considered the following health deficits as markers of "frailty": albumin <3.5mg/dL, hemoglobin <10mg/dL, BMI<20kg/m,2 unintentional weight loss, ECOG performance status >=2, history of osteopenia or osteoporosis and Charlson comorbidity score. Kaplan-Meier estimates and Cox proportional hazards models of DFS were calculated. RESULTS: The median age was 68.5 (range 60-88years). The majority of women (65/88) had at least one frailty factor at baseline and 23/88 had two or more. All women received radiation and chemotherapy. Treatment was delayed, modified or truncated in 46% (40/88) of women due to treatment-related toxicity. Age (< 70 vs. >=70 y) did not independently predict toxicity or recurrence risk. Women with at least one baseline frailty factor had twice the risk of disease recurrence (HR=2.21;95% CI:1.02-4.80) when adjusted for age, stage, grade and Charlson score. The 3-year DFS was 77% in those with no frailty markers and 48% in those with at least one (p=0.02). The presence of a frailty marker also predicted shortened overall survival (HR=2.34;95% CI:1.08-5.03) irrespective of treatment administered and stage of disease. CONCLUSIONS: A combined frailty measure was a more robust predictor of DFS and OS than patient age, tumor characteristics and comorbidities in this cohort of older women with very good functional status. PMID- 28359690 TI - Prognostic significance of peritoneal cytology in low-intermediate risk endometrial cancer. AB - OBJECTIVES: There is uncertainty surrounding the prognostic value and clinical utility of peritoneal cytology in endometrial cancer. Our primary objective was to determine if positive cytology is associated with disease-free and overall survival in women treated surgically for endometrial cancer, specifically those with low or intermediate risk disease. METHODS: This was a retrospective population-based cohort study of British Columbia Cancer Registry patients who underwent surgery with peritoneal washings for endometrioid-type endometrial cancer from 2003 to 2009. Low risk was defined as Stage IA grade 1 or 2, and intermediate risk defined as Stage IA grade 3, or Stage IB grade 1 or 2 tumours. Five-year overall and disease free-survival were assessed using Kaplan-Meier estimation. Potential covariates including peritoneal cytology, grade, depth of myometrial invasion, LVSI, age, and adjuvant therapy were evaluated in a multivariable Cox proportional hazards model. RESULTS: There were 849 patients, of whom 370 (43.6%) and 298 (35.1%) had low- and intermediate-risk disease, respectively. Overall, forty-nine (5.8%) patients had positive cytology, including 6 and 9 with low- and intermediate-risk respectively (2.2% within low and intermediate risk combined). Positive peritoneal cytology was not significantly associated with disease-free (HR 3.17, 95% CI 0.91-11.03) or overall survival (HR 1.33, 95% CI 0.47-3.76) in low and intermediate risk patients. Only age and extensive LVSI were associated with lower overall survival (HR 1.10, 95% CI 1.08-1.13, and HR 2.39, 95% CI 1.02-5.61, respectively). CONCLUSIONS: Positive peritoneal cytology was not associated with disease-free and overall survival in women with low and intermediate risk endometrial cancer. PMID- 28359691 TI - Ablation of supraventricular arrhythmias in adult congenital heart disease: A contemporary review. AB - Supraventricular arrhythmias are an important and increasing cause of morbidity in adults with congenital heart disease, requiring specific management strategies. Pharmacological treatment has limited efficacy, and is often associated with some side-effects. Major improvements in catheter ablation techniques have opened new opportunities to better understand underlying mechanisms of supraventricular arrhythmias, offer better therapy, and eventually improve symptoms and quality of life in these patients. An array of tools and techniques are necessary to access relevant anatomical areas to address the arrhythmogenic substrate. The mechanism of these arrhythmias is mostly related to macroreentry around surgical scars or cavotricuspid isthmus-dependent flutter. The efficacy of catheter ablation is mainly dependent on the underlying congenital heart condition, with the most complex cases typically being associated with atrial switch and Fontan surgeries. Although relatively high rates of recurrence are seen after a single procedure, additional attempts are often helpful to decrease recurrences and improve symptoms. Catheter ablation in such patients continues to present many unique challenges that are best addressed by experienced multidisciplinary teams, at centres equipped with the proper catheters, imaging capabilities, mapping systems and support staff needed to maximize safety and success. Consensus indications have emerged that often support ablation as first-line therapy in these patients. In this comprehensive review, we aim to describe the specific issues associated with ablation of supraventricular arrhythmias in adult congenital heart disease, assess the results in contemporary practice and, finally, review the current indications. PMID- 28359692 TI - Disentangling a Bad Reputation: Changing Perceptions of Amyloids. AB - Historically, amyloids were perceived as toxic/irreversible protein aggregates associated with neurodegenerative disorders including Alzheimer's and Parkinson's diseases. Recent papers are challenging this perception by uncovering widespread cellular roles for physiological amyloidogenesis. These findings suggest that the amyloid-fold should be considered, alongside the native-fold and unfolded configurations, as a physiological and reversible protein organization. PMID- 28359693 TI - Low-grade infections in nonarthroplasty shoulder surgery. AB - BACKGROUND: Recent studies have identified the diagnostic challenge of low-grade infections after shoulder arthroplasty surgery. Infections after nonarthroplasty procedures have not been reported. This study assessed patient-related risk factors, outcomes, and clinical presentation of low-grade infection after open and arthroscopic nonarthroplasty shoulder surgery. METHODS: The cases of 35 patients presenting with suspected low-grade infection were reviewed. Biopsy specimens taken at revision surgery were cultured in the sterile environment of a class II laminar flow cabinet and incubated for a minimum of 14 days at a specialist orthopedic microbiology laboratory. Patient-related factors (age, occupation, injection), index surgery, and infection characteristics (onset of symptoms, duration to diagnosis, treatment) were analyzed. RESULTS: Positive cultures were identified in 21 cases (60.0%), of which 15 were male patients (71%). Of all patients with low-grade infection, 47.6% were male patients between 16 and 35 years of age. Propionibacterium acnes and coagulase-negative staphylococcus were the most common organisms isolated (81.1% [n = 17] and 23.8% [n = 5], respectively). Of 14 negative culture cases, 9 were treated with early empirical antibiotics (64.3%); 7 patients reported symptomatic improvement (77.8%). Of 5 patients treated with late empirical antibiotics, 4 stated improvement. Patients presented with symptoms akin to resistant postoperative frozen shoulder (persistent pain and stiffness, unresponsive to usual treatments). CONCLUSION: Young male patients are at greatest risk for low-grade infections after arthroscopic and open nonarthroplasty shoulder surgery. P. acnes was the most prevalent organism. Patients presented with classic postoperative frozen shoulder symptoms, resistant to usual treatments. Interestingly, 78.6% of patients with negative cultures responded positively to empirical treatment. PMID- 28359694 TI - Long-term clinical results in patients treated for recurrent posterolateral elbow joint instability using an ipsilateral triceps tendon graft. AB - BACKGROUND: The aim was to report the long-term functional and radiologic outcomes in patients treated for recurrent posterolateral elbow joint instability using an ipsilateral triceps tendon graft. METHODS: We included 18 patients previously treated for posterolateral elbow joint instability and evaluated for clinical results in 2003. Fifteen patients were examined with a mean follow-up period of 19 years (range, 17-22 years). We performed the clinical follow-up with clinical examination of stability, range of motion, pain score on a visual analog scale, Mayo Elbow Performance Score, and Danish version of Oxford Elbow Score. Furthermore, conventional anteroposterior and side-view radiographs of the elbow were obtained to evaluate osteoarthritis, calcifications in the ligaments, and joint subluxation. We evaluated the radiographs by the size of osteophytes, joint space narrowing, and subchondral sclerosis and classified the findings into 3 categories: no osteoarthritis, osteoarthritis, and severe osteoarthritis. RESULTS: All patients had a clinically stable elbow. None had pain while inactive or locking of the joint, and 4 had decreased range of motion. Two patients had a positive pivot-shift stress test, indicating laxity. The mean Mayo Elbow Performance Score was 93 (range, 70-100). The mean Oxford Elbow Score was 45. We observed 5 patients with osteoarthritis and 1 patient with severe osteoarthritis. CONCLUSION: The technique reported by Olsen and Sojbjerg in 2003 gives good long term results in the treatment of symptomatic posterolateral elbow joint instability, though the development of elbow joint osteoarthritis may decrease the surgical result in the coming years. PMID- 28359695 TI - Use of a shorter humeral stem in revision reverse shoulder arthroplasty. AB - BACKGROUND: The purpose of this study was to examine the outcomes of revision reverse arthroplasty using short bone-preserving humeral components in revising a long-stemmed component. METHODS: During a 7-year period, 39 patients who underwent revision reverse shoulder arthroplasty using the long to short humeral component technique were included. The mean age was 72 years. Prior implants used in the primary setting included anatomic (n = 26), hemiarthroplasty (n = 11), and reverse (n = 2). RESULTS: At a follow-up of 3 years (2-5), 5 shoulders (13%) required revision surgery, including 1 for a periprosthetic humerus fracture and 4 for glenoid component loosening. The survival free of revision for any reason and revision for humeral disease was 84% and 94%, respectively. One patient experienced a nondisplaced greater tuberosity fracture at 18 months postoperatively that healed without operative intervention. There were no dislocations or infections. Overall, patients experienced excellent overall improvements in their pain levels and shoulder motion (P < .001), with a postoperative 91% satisfaction rate as well as postoperative American Shoulder and Elbow Surgeons score of 68 and Simple Shoulder Test score of 6.7. At most recent radiographic follow-up, 1 (5%) patient had grade 3 humeral lucency. CONCLUSIONS: Preserving bone stock through conversion to a shorter reverse humeral stem in the revision setting is a reasonable option with good short- to intermediate-term results and low rates of humeral complications. Using the shorter stem components provides adequate stability and high rates of humeral component ingrowth. PMID- 28359696 TI - Partial-thickness tears involving the rotator cable lead to abnormal glenohumeral kinematics. AB - HYPOTHESIS: The objective of this study was to determine the biomechanical function of the rotator cable when a partial-thickness (>50%) tear is present. We compared intact specimens with partial tears of the anterior cable followed by partial anterior and posterior tears in regard to glenohumeral kinematics and translation. The hypothesis was that partial-thickness tears will lead to abnormal glenohumeral biomechanics, including glenohumeral translation and path of glenohumeral articulation. METHODS: Five fresh frozen cadaveric shoulders with intact labrum, rotator cuff, and humerus were tested using a custom shoulder testing system in the scapular plane. Glenohumeral translation was measured after applying an anterior load of 30 N at different angles of external rotation. The path of glenohumeral articulation was measured by calculating the humeral head center with respect to the glenoid articular surface at 30 degrees , 60 degrees , 90 degrees , and 120 degrees of external rotation. RESULTS: With an anterior force of 30 N, there was a significant increase in anterior and total translation at 30 degrees of external rotation after the anterior cable was cut (P < .05). When the tear was extended to the posterior cable, there was a significant increase in anterior, inferior, and total translation at 30 degrees and 120 degrees of external rotation (P < .05). With respect to the path of glenohumeral articulation , the humeral head apex was shifted superiorly at 90 degrees and 120 degrees of external rotation after the posterior cable was cut (P < .05). CONCLUSION: Partial-thickness articular-sided rotator cuff tears with a thickness >50% involving the rotator cable increased glenohumeral translation and changed kinematics in our cadaveric biomechanical model. PMID- 28359697 TI - A comparison of onlay versus inlay glenoid component loosening in total shoulder arthroplasty. AB - BACKGROUND: Glenoid component loosening is common in total shoulder arthroplasty (TSA), often resulting from the mechanical interaction of glenohumeral components. This cadaveric study was performed to evaluate and to compare commercially available onlay and inlay glenoid prosthetic designs with respect to loading characteristics and loosening. METHODS: Sixteen prescreened cadaveric shoulders (8 matched pairs) underwent either onlay or inlay TSA. We created a custom glenohumeral loading model and used cycles of 5 mm anterior-posterior humeral translation to simulate a rocking-horse loosening mechanism for all testing. Articular TekScan measurements were performed with 9.1 kg (88.9 N) of glenohumeral compression before and after TSA. Fatigue testing was performed with 34.0 kg (333.6 N) of glenohumeral compression using high-definition video to document gross glenoid loosening. Testing ended with gross loosening or a maximum of 4000 cycles. Mean contact area, pressure, and joint reaction force were used to compare the 2 glenoid designs. RESULTS: In both implant types, contact area decreased and pressure increased after TSA (P < .0001). Force increased at the onlay component edge only (P = .0012) compared with native glenoid testing. Force was greater in the onlay vs. the inlay implants (P < .0001). During fatigue testing, all onlay glenoid components exhibited gross loosening at a mean of 1126 cycles (range, 749-1838), whereas none of the inlay glenoid components exhibited gross loosening (P < .0001). CONCLUSION: The inlay glenoid implant exhibited biomechanical characteristics favoring stability and decreased loosening compared with the onlay glenoid implant in this cadaveric model. PMID- 28359698 TI - Refuting the lipstick sign. AB - BACKGROUND: Arthroscopic examination of the tendon has been described as the "gold standard" for diagnosis of tendinitis of the long head of the biceps (LHB). An arthroscopic finding of an inflamed and hyperemic LHB within the bicipital groove has been described as the "lipstick sign." Studies evaluating direct visualization in diagnosis of LHB tendinitis are lacking. METHODS: During a 1 year period, 363 arthroscopic shoulder procedures were performed, with 16 and 39 patients prospectively selected as positive cases and negative controls, respectively. All positive controls had groove tenderness, positive Speed maneuver, and diagnostic ultrasound-guided bicipital injection. Negative controls had none of these findings. Six surgeons reviewed randomized deidentified arthroscopic pictures of enrolled patients The surgeons were asked whether the images demonstrated LHB tendinitis and if the lipstick sign was present. RESULTS: Overall sensitivity and specificity were 49% and 66%, respectively, for detecting LHB tendinitis and 64% and 31%, respectively, for erythema. The nonweighted kappa score for interobserver reliability ranged from 0.042 to 0.419 (mean, 0.215 +/- 0.116) for tendinitis and from 0.486 to 0.835 (mean, 0.680 +/- 0.102) for erythema. The nonweighted kappa score for intraobserver reliability ranged from 0.264 to 0.854 (mean, 0.615) for tendinitis and from 0.641 to 0.951 (mean, 0.783) for erythema. CONCLUSIONS: The presence of the lipstick sign performed only moderately well in a rigorously designed level III study to evaluate its sensitivity and specificity. There is only fair agreement among participating surgeons in diagnosing LHB tendinitis arthroscopically. Consequently, LHB tendinitis requiring tenodesis remains a clinical diagnosis that should be made before arthroscopic examination. PMID- 28359699 TI - The role age plays in the outcomes and complications of shoulder arthroplasty. AB - BACKGROUND: This investigation used age as a continuous variable to estimate implant survival and the risk of complications. METHODS: Prospectively collected data were used to analyze 5494 consecutive shoulder arthroplasties performed from 1970 to 2012. Patients were a mean age of 67 years. The association between the age at the index procedure and the risk for each outcome was assessed using Cox regression and smoothing spline analysis. RESULTS: Older age was associated with a decreased risk of revision surgery, revision for mechanical failure, and reoperation but with a higher risk for thromboembolic events. Reoperation rates also decreased in a linear fashion with older ages (P < .001). The risk of revision surgery decreased in a linear fashion between the ages of 40 and 85, with a 3% decreased risk of revision per 1-year increase in age (P < .01). This association held true in a multivariate model and when specific procedures were separated out. Compared with patients aged <50 years, patients aged from 50 to 65 years (P < .001) and those >65 years (P < .001) have decreased risks of revision surgery. The risk of a revision surgery in a patient aged >50 years was significantly decreased (~13% reduction in risk for each year; P < .001). There was a subtle association between older age and decreased rates of infection (P = .01). CONCLUSIONS: There is a strong association between older age and decreased rates of revision surgery and reoperation after shoulder arthroplasty, with a striking association with decreased rates of mechanical failure. These are important considerations when counseling younger patients regarding their risks. PMID- 28359700 TI - The effect of first and second premolar extractions on third molars: A retrospective longitudinal study. AB - OBJECTIVES: To analyse the effect of first and second premolar extractions on eruption space for upper and lower third molars and on third molar position and angulation during orthodontic treatment. METHODS: The sample consisted of 296 patients of which 218 patients were orthodontically treated without extraction and 78 patients with extraction of first or second premolars. The eruption space for third molars was measured on pre- and posttreatment lateral cephalograms, whereas the angulation, vertical position, the relation with the mandibular canal and the mineralization status of third molars were evaluated using pre- and posttreatment panoramic radiographs. All data were statistically analyzed. RESULTS: The increase in eruption space and the change in vertical position of upper and lower third molars significantly differed between patients treated with and without premolar extractions, whereas the change in angulation, relationship with the mandibular canal and mineralization status of the third molars did not significantly differ between patients treated with and without premolar extractions. CONCLUSIONS: The retromolar space and the position of third molars significantly change during orthodontic treatment in growing patients. Premolar extractions have a positive influence on the eruption space and vertical position of third molars, whereas they do not influence the angular changes of third molars. Due to the retrospective character of the study, these conclusions should be carefully considered. Further prospective research is necessary for better insights into this complex topic. CLINICAL SIGNIFICANCE: This study stresses the importance of considering the possible effects of orthodontic treatment on third molars during treatment planning. PMID- 28359701 TI - The Power (and Misery) of Incremental Changes. PMID- 28359702 TI - Educational Crowdsourcing: Developing RadExam. PMID- 28359703 TI - Exploring the mediating role of energy balance-related behaviours in the association between sleep duration and obesity in European adults. The SPOTLIGHT project. AB - Sleep restriction is a risk factor for weight gain and obesity. Few studies have formally investigated the mediating role of energy balance-related behaviours in the sleep - obesity association. The aim of this study was to explore the mediating role of physical activity, sedentary behaviours and dietary habits in the association of sleep duration with obesity in adults in five European urban regions. Data on self-reported sleep duration, energy balance-related behaviours, height and weight and other covariates were collected between February and September 2014 from participants to the SPOTLIGHT survey (N=5900, mean age 52years). Participants were recruited from 60 urban neighbourhoods in Belgium, France, Hungary, the Netherlands and the United Kingdom. Multilevel logistic regression analyses were used to assess the associations of sleep duration, energy balance-related behaviours and obesity and mediating effects were calculated using MacKinnon's product-of-coefficients method. Results indicated that a 1h increase in sleeping time was associated with a 14% lower likelihood of being obese (OR=0.86, 95%CI=0.80; 0.93). Only work-related sedentary behaviour was identified as a statistically significant mediator in the association between sleep duration and obesity for the total sample, and youngest and oldest age group. We did not find evidence for a mediating role of dietary habits and physical activities. PMID- 28359704 TI - Myopia among schoolchildren in East Asia and Singapore. AB - Myopia is highly prevalent among schoolchildren in East Asia and Singapore; however, its prevalence has been gradually increasing, and the number of population-based and non-population-based studies assessing this trend has increased in the past 10 years. Although the causes of this high prevalence in East Asia and Singapore remain poorly identified, related studies have discussed the associated risk factors. We summarize the data concerning the prevalence rates reported in related studies and discuss the most crucial risk factors among these schoolchildren. PMID- 28359705 TI - Manipulation of GES and ERG20 for geraniol overproduction in Saccharomyces cerevisiae. AB - Manipulation of monoterpene synthases to maximize flux towards targeted products from GPP (geranyl diphosphate) is the main challenge for heterologous monoterpene overproduction, in addition to cell toxicity from compounds themselves. In our study, by manipulation of the key enzymes geraniol synthase (GES) and farnesyl diphosphate synthase (Erg20), geraniol (a valuable acyclic monoterpene alcohol) overproduction was achieved in Saccharomyces cerevisiae with truncated 3-hydroxy 3-methylglutaryl-coenzyme reductase (tHMGR) and isopentenyl diphosphate isomerase (IDI1) overexpressed. The expressions of all above engineered genes were under the control of Gal promoter for alleviating product toxicity. Geraniol production varied from trace amount to 43.19mg/L (CrGES, GES from Catharanthus roseus) by screening of nine GESs from diverse species. Further through protein structure analysis and site-directed mutation in CrGES, it was firstly demonstrated that among the high-conserved amino acid residues located in active pocket, Y436 and D501 with strong affinity to diphosphate function group, were critical for the dephosphorylation (the core step for geraniol formation). Moreover, the truncation position of the transit peptide from the N-terminus of CrGES was found to influence protein expression and activity significantly, obtaining a titer of 191.61mg/L geraniol in strain with CrGES truncated at S43 (t3CrGES). Furthermore, directed by surface electrostatics distribution of t3CrGES and Erg20WW (Erg20F96W N127W), co-expression of the reverse fusion of Erg20ww/t3CrGES and another copy of Erg20WW promoted the geraniol titer to 523.96mg/L at shakes flask level, due to enhancing GPP accessibility led by protein interaction of t3CrGES-Erg20WW and the free Erg20WW. Eventually, a highest reported titer of 1.68g/L geraniol in eukaryote cells was achieved in 2.0L fed-batch fermentation under carbon restriction strategy. Our research opens large opportunities for other microbial production of monoterpenes. It also sets a good reference for desired compounds overproduction in microorganisms in terms of manipulation of key enzymes by protein engineering and metabolic engineering. PMID- 28359706 TI - Discovery of a new Mycobacterium tuberculosis thymidylate synthase X inhibitor with a unique inhibition profile. AB - Tuberculosis (TB), mainly caused by Mycobacterium tuberculosis (Mtb), is an infection that is responsible for roughly 1.5 million deaths per year. The situation is further complicated by the wide-spread resistance to the existing first- and second-line drugs. As a result of this, it is urgent to develop new drugs to combat the resistant bacteria as well as have lower side effects, which can promote adherence to the treatment regimens. Targeting the de novo synthesis of thymidylate (dTMP) is an important pathway to develop drugs for TB. Although Mtb carries genes for two families of thymidylate synthases (TS), ThyA and ThyX, only ThyX is essential for its normal growth. Both enzymes catalyze the conversion of uridylate (dUMP) to dTMP but employ a different catalytic approach and have different structures. Also, ThyA is the only TS found in humans. This is the rationale for identifying selective inhibitors against ThyX. We exploited the NADPH oxidation to NADP+ step, catalyzed by ThyX, to develop a spectrophotometric biochemical assay. Success of the assay was demonstrated by its effectiveness (average Z'=0.77) and identification of selective ThyX inhibitors. The most potent compound is a tight-binding inhibitor with an IC50 of 710nM. Its mechanism of inhibition is analyzed in relation to the latest findings of ThyX mechanism and substrate and cofactor binding order. PMID- 28359707 TI - Evidence-Based Practice: Video-Discharge Instructions in the Pediatric Emergency Department. AB - PROBLEM: While a high quality discharge from a Pediatric Emergency Department helps caregivers feel informed and prepared to care for their sick child at home, poor adherence to discharge instructions leads to unnecessary return visits, negative health outcomes, and decreased patient satisfaction. Nurses at the Inova Loudoun Pediatric ED utilized the Johns Hopkins Model of Evidence Based Practice to answer the following question: Among caregivers who have children discharged from the ED, does the addition of video discharge instructions (VDI) to standard written/verbal discharge instructions (SDI) result in improved knowledge about the child's diagnosis, treatment, illness duration, and when to seek further medical care? METHODS: A multidisciplinary team reviewed available evidence and created VDI for three common pediatric diagnoses: gastroenteritis, bronchiolitis, and fever. Knowledge assessments were collected before and after delivery of discharge instructions to caregivers for both the SDI and VDI groups. RESULTS: Analysis found that the VDI group achieved significantly higher scores on the post test survey (P < .001) than the SDI group, particularly regarding treatment and when to seek further medical care. After integrating the best evidence with clinical expertise and an effective VDI intervention, the team incorporated VDI into the discharge process. IMPLICATIONS FOR PRACTICE: VDI offer nurses an efficient, standardized method of providing enhanced discharge instructions in the ED. Future projects will examine whether VDI are effective for additional diagnoses and among caregivers for whom English is not the primary language. PMID- 28359708 TI - The Effect of Pneumatic Tube Systems on the Hemolysis of Biochemistry Blood Samples. AB - : Pneumatic tube systems (PTSs) are widely used in many hospitals because they lead to reduced turnaround times and cost efficiency. However, PTSs may affect the quality of the blood samples transported to the laboratory. The aim of this study was to investigate the effect of the PTS used in our hospital on the hemolysis of the biochemical blood samples transported to the laboratory. METHODS: A total of 148 samples were manually transported to the laboratory by hospital staff, 148 samples were transported with the PTS, and 113 were transported with the PTS without use of sponge-rubber inserts (PTSws). Hemolysis rates and the levels of biochemical analytes for the different transportation methods were compared. RESULTS: No significant difference was found between the samples transported manually and with the PTS with regard to hemolysis rate and the levels of biochemical analytes. However, the samples transported with the PTSws showed a significant difference compared with the samples transported manually and with the PTS with regard to hemolysis rate and potassium and lactate dehydrogenase levels. The percentages of the samples that exceeded the permissible threshold for the hemolysis among the samples transported manually, with the PTS, and with the PTSws were 10%, 8%, and 47%, respectively. DISCUSSION: A PTS can be used safely for transporting biochemistry blood samples to the laboratory. However, a sponge-rubber insert that holds sample tubes must be used with the PTS to prevent the hemolysis of blood samples. PMID- 28359709 TI - Nurse Participation in Continuing Education in Disaster Nursing in Taiwan. PMID- 28359710 TI - National Institutes of Health Stroke Scale in Plain English Is Reliable for Novice Nurse Users with Minimal Training. AB - : The National Institutes of Health Stroke Scale (NIHSS) is commonly used in Comprehensive Stroke Centers, but it has not been easily implemented in smaller centers. The aim of this study was to assess whether nurse providers who were naive to stroke assessment scales could obtain accurate stroke severity scores using our previously validated NIH Stroke Scale in Plain English (NIHSS-PE) with minimal or no training. METHODS: We randomly assigned 122 nursing students who were naive to stroke assessment scales to 1 of 4 groups: trained on the NIHSS, untrained on the NIHSS, trained on the NIHSS-PE, or untrained on the NIHSS-PE. The Trained/NIHSS and Trained/NIHSS-PE groups watched assessment scale-specific training DVDs. All 4 study groups scored the same 3 patients from the National Institute of Neurological Disorders and Stroke certification DVD, in randomly assigned order. Two-way repeated measures analysis of variance was used to compare group scores with those obtained by a consensus panel of NIHSS-certified expert users, and with each other. RESULTS: NIHSS-PE users had scores significantly closer to the expert scores compared with NIHSS users (F(1,118) = 4.656, P = .033). Trained users had scores significantly closer to the expert scores than untrained users (F(1,118) = 6.607, P = .011). Scores from untrained users of the NIHSS-PE did not differ from those of trained users of the NIHSS (F(1,59) = 0.08, P = .780). DISCUSSION: With minimal or no training, novice nurse users of the NIHSS-PE can do as well as, if not better than, novice users of the NIHSS, making this tool useful for facilities pursuing Acute Stroke-Ready certification. PMID- 28359711 TI - Painful Discrimination in the Emergency Department: Risk Factors for Underassessment of Patients' Pain by Nurses. AB - INTRODUCTION: Unrelieved acute musculoskeletal pain continues to be a reality of major clinical importance, despite advancements in pain management. Accurate pain assessment by nurses is crucial for effective pain management. Yet inaccurate pain assessment is a consistent finding worldwide in various clinical settings, including the emergency department. In this study, pain assessments between nurses and patients with acute musculoskeletal pain after extremity injury will be compared to assess discrepancies. A second aim is to identify patients at high risk for underassessment by emergency nurses. METHODS: The prospective PROTACT study included 539 adult patients who were admitted to the emergency department with musculoskeletal pain. Data on pain assessment and characteristics of patients including demographics, pain, and injury, psychosocial, and clinical factors were collected using questionnaires and hospital registry. RESULTS: Nurses significantly underestimated patients' pain with a mean difference of 2.4 and a 95% confidence interval of 2.2-2.6 on an 11-points numerical rating scale. Agreement between nurses' documented and patients' self-reported pain was only 27%, and 63% of the pain was underassessed. Pain was particularly underassessed in women, in persons with a lower educational level, in patients who used prehospital analgesics, in smokers, in patients with injury to the lower extremities, in anxious patients, and in patients with a lower urgency level. DISCUSSION: Underassessment of pain by emergency nurses is still a major problem and might result in undertreatment of pain if the emergency nurses rely on their assessment to provide further pain treatment. Strategies that focus on awareness among nurses of which patients are at high risk of underassessment of pain are needed. PMID- 28359712 TI - Voluntary Medication Error Reporting by ED Nurses: Examining the Association With Work Environment and Social Capital. AB - INTRODUCTION: Medication errors are one of the most frequently occurring errors in health care settings. The complexity of the ED work environment places patients at risk for medication errors. Most hospitals rely on nurses' voluntary medication error reporting, but these errors are under-reported. The purpose of this study was to examine the relationship among work environment (nurse manager leadership style and safety climate), social capital (warmth and belonging relationships and organizational trust), and nurses' willingness to report medication errors. METHODS: A cross-sectional descriptive design using a questionnaire with a convenience sample of emergency nurses was used. Data were analyzed using descriptive, correlation, Mann-Whitney U, and Kruskal-Wallis statistics. RESULTS: A total of 71 emergency nurses were included in the study. Emergency nurses' willingness to report errors decreased as the nurses' years of experience increased (r = -0.25, P = .03). Their willingness to report errors increased when they received more feedback about errors (r = 0.25, P = .03) and when their managers used a transactional leadership style (r = 0.28, P = .01). DISCUSSION: ED nurse managers can modify their leadership style to encourage error reporting. Timely feedback after an error report is particularly important. Engaging experienced nurses to understand error root causes could increase voluntary error reporting. PMID- 28359713 TI - Child Passenger Safety: An Assessment of Emergency Nurses' Knowledge and Provision of Information in the Emergency Department. AB - : Each year, more than 130,000 children younger than 13 years are treated in the emergency department after evaluation of injuries sustained from motor vehicle crashes (MVCs). Many of these injuries can be prevented with use of child restraints. In this study we sought to assess emergency nurses' knowledge of child passenger safety (CPS) and its use to keep children safe while traveling in motor vehicles. METHODS: A cross-sectional anonymous study was distributed electronically to 530 emergency nurses who were asked to forward the survey link to other emergency nurses through snowball sampling. The target population included full-time and part-time emergency nurses, including nurse practitioners caring for pediatric patients. Emergency nurses' CPS knowledge, attitudes, and practices were ascertained. RESULTS: Nine hundred eighty-four emergency nurses completed a Web-based survey. All 6 CPS knowledge and scenario-based items were answered correctly by only 18.8% of the sample; these respondents were identified as the "high knowledge" group. Similarly, ED nurses rarely addressed CPS during ED visits in the prior 6 months. Those with high knowledge were more likely to be confident about providing recommendations for CPS topics. DISCUSSION: Emergency nurses can improve their knowledge and provision of CPS in the emergency department, particularly for children presenting for care following MVCs. These results identify opportunities to increase the knowledge and confidence of emergency nurses in providing CPS information to parents seen in the emergency department, especially those involved in MVCs. The gap in knowledge can be overcome by providing the nurses with increased CPS-focused educational opportunities. PMID- 28359714 TI - Influencing factors of sac shrinkage after endovascular aneurysm repair. AB - OBJECTIVE: Sac shrinkage is considered a reliable surrogate marker of success after endovascular aneurysm repair (EVAR). Whereas sac shrinkage is the best expected outcome, predictive factors of sac shrinkage remain unclear. The aim of this study was to identify the role of preoperative and postoperative influencing factors of sac reduction after EVAR. METHODS: Online searches across MEDLINE, Embase, and Cochrane Library medical databases were simultaneously performed. Study effects were pooled using a random-effects model, and forest plots were generated for every potential influencing factor. RESULTS: A total of 24 studies with 14,754 patients were included (mean age, 73.4 years; 76% male). At a mean follow-up of 24 months, the pooled shrinkage proportion was 47%. Random-effects meta-analysis revealed that renal impairment (odds ratio [OR], 0.74; 95% confidence interval [CI], 0.57-0.96), type I endoleaks (OR, 0.17; 95% CI, 0.08 0.39), type II endoleaks (OR, 0.21; 95% CI, 0.14-0.33), and combined type I and type II endoleaks (OR, 0.32; 95% CI, 0.22-0.47) were found to prevent sac shrinkage, whereas hypercholesterolemia (OR, 1.24; 95% CI, 1.02-1.51) and smoking (OR, 1.32; 95% CI, 1.17-1.49) have a significant positive impact on sac shrinkage. In addition, there was a trend toward the association between shrinkage and statin therapy (OR, 4.07; 95% CI, 1.02-16.32) and nearly significant negative impacts of coronary artery disease (OR, 0.84; 95% CI, 0.70 1.01), diabetes (OR, 0.79; 95% CI, 0.60-1.04), and sac thrombus (OR, 0.88; 95% CI, 0.77-1.01) on sac shrinkage. CONCLUSIONS: In this large meta-analysis of patients undergoing EVAR, we found that several comorbidity and postoperative factors were associated with postoperative sac shrinkage. These findings may contribute to a better understanding of the shrinkage process of patients undergoing EVAR. PMID- 28359715 TI - Simplified total aortic arch replacement with an in situ stent graft fenestration technique for acute type A aortic dissection. AB - OBJECTIVE: Total arch replacement combined with stented elephant trunk implantation in the descending aorta has successfully improved the outcomes of acute type A aortic dissection (AAAD). However, the optimal surgical strategy for the left subclavian artery (LSA) during the procedure remains a challenge. This study aimed to present our new technique of in situ stent graft fenestration to simplify the surgical procedure for suitable cases of AAAD. METHODS: From August 2008 to December 2015, a total of 106 patients underwent simplified total aortic arch replacement with an in situ stent graft fenestration technique. The mean age of the patients was 50.71 +/- 11.54 years (range, 24-78 years). Both perioperative variables and postoperative follow-up outcome of the procedure were assessed. RESULTS: The in-hospital mortality rate was 7.5%. The mean cardiopulmonary bypass time was 162.73 +/- 68.49 minutes, cross-clamp time was 93.13 +/- 22.29 minutes, and circulatory arrest time was 23.28 +/- 5.56 minutes. Transient neurologic dysfunction was observed in five patients. No permanent neurologic dysfunction was observed, and no stroke or left arm ischemia occurred. During the follow-up period (mean, 43.4 +/- 21.53 months), the survival rates of patients were 90.6%, 85.5%, and 78.8% at 1 year, 2 years, and 7 years, respectively. No stroke or left limb ischemia was observed. The LSA perfusion was well preserved in all surviving patients, and there was no endoleak or dissection around the LSA. All patients were free from reoperation. CONCLUSIONS: The in situ graft fenestration technique could simplify the procedure of LSA reconstruction during total arch replacement, provide a good surgical view for anastomosis and hemostasis, shorten the operation time, and yield satisfactory early and midterm results. It is a safe and effective alternative approach for suitable patients with AAAD. However, the long-term results of this technique need further evaluation. PMID- 28359716 TI - Pretreatment with and ongoing use of omega-3 fatty acid ethyl esters reduce the slow-flow phenomenon and prevent in-stent restenosis in patients undergoing carotid artery stenting. AB - OBJECTIVE: Carotid artery stenting (CAS) is a less invasive alternative to carotid endarterectomy, but it is essential to prevent thromboembolic complications during CAS and to suppress in-stent restenosis (ISR) after CAS because of the relatively high risk of periprocedural and follow-up stroke events. Clinical trials have demonstrated the strong relationship of carotid plaque vulnerability with the subsequent risk of ipsilateral ischemic stroke and thromboembolic complications during CAS. Recent studies demonstrated that both low eicosapentaenoic acid (EPA) and low docosahexaenoic acid (DHA) levels were significantly associated with lipid-rich coronary and carotid plaques, but little is known about the effect of administration of omega-3 fatty acids (O-3FAs) containing EPA and DHA before and after CAS for stabilizing carotid plaque, preventing thromboembolic complications, and suppressing ISR. In this study, the efficacy of pretreatment with and ongoing daily use of O-3FA in addition to statin treatment was evaluated in patients undergoing CAS. METHODS: This study was a nonrandomized prospective trial with retrospective analysis of historical control data. From 2012 to 2015, there were 100 consecutive patients with hyperlipidemia undergoing CAS for carotid artery stenosis who were divided into two groups. Between 2012 and 2013 (control period), 47 patients were treated with standard statin therapy. Between 2014 and 2015 (O-3FA period), patients were treated with statin therapy and add-on oral O-3FA ethyl esters containing 750 mg/d DHA and 1860 mg/d EPA from 4 weeks before CAS, followed by ongoing daily use for at least 12 months. In all patients, the plaque morphology by virtual histology intravascular ultrasound, the incidence of new ipsilateral ischemic lesions on the day after CAS, the slow-flow phenomenon during CAS, and ISR within 12 months after CAS were compared between the periods. RESULTS: The slow-flow phenomenon during CAS with filter-type embolic protection devices decreased in the O-3FA period (1 of 53 patients [2%]) compared with the control period (7 of 47 patients [15%]; P = .02). Furthermore, ISR for 12 months after CAS was significantly decreased in the O-3FA period (1 of 53 patients [2%]) compared with the control period (10 of 47 patients [21%]; P = .01). On virtual histology intravascular ultrasound analysis, the fibrofatty area was significantly smaller and the fibrous area was significantly greater in the O-3FA period. On multivariate logistic regression analysis, a low EPA/arachidonic acid ratio and a symptomatic lesion were the factors related to vulnerable plaque (P = .01 [odds ratio, 5.24; 95% confidence interval, 1.65-16.63] and P = .01 [odds ratio, 11.72; 95% confidence interval, 2.93-46.86], respectively). CONCLUSIONS: Pretreatment with O-3FA reduces the slow-flow phenomenon generated by plaque vulnerability during CAS, and on-going daily use of O-3FA suppresses ISR after CAS. PMID- 28359717 TI - "In situ" endografting in the treatment of arterial and graft infections. AB - OBJECTIVE: Endografts (eg, aortic aneurysm device or covered stent) are increasingly being used to temporize or treat arterial and graft infections in inaccessible areas, in patients with compromised anatomy, or in the presence of active bleeding or rupture. This summary examines the evidence for "in situ" endografting in the treatment these conditions. METHODS: A two-level search strategy of the literature (MEDLINE, PubMed, Google Scholar, and The Cochrane Library) was performed for relevant articles listed between January 2000 and December 2015. The review was confined to patients with primary and secondary bacterial or viral arterial infections, with or without fistulization and infection of bypass grafts and arteriovenous accesses. For the purposes of this summary, endografts can be considered to be an aortic aneurysm device or a covered stent. RESULTS: There are no societal guidelines. Endografts have been successfully applied to mycotic arterial aneurysms, aortoenteric, aortobronchial, and arterioureteric fistulae, and to anastomotic bleeds secondary to infection. Multiple reports indicate success at the control of hemorrhage in all locations. Short-term outcomes are good, but fatal infection-related complications, especially if antibiotic therapy is halted, are well reported and necessitate a more definitive plan for the long term. CONCLUSIONS: Stent grafts remain an important and viable option for the treatment of mycotic aneurysms, aortoesophageal and aortobronchial fistulae, and infected pseudoaneurysms in anatomically or technically inaccessible locations. In patients with a short life span (<6 months), no further intervention is generally required. In patients with a predicted life span >6 months, careful consideration should be given to a more definitive procedure. Life-long appropriate antibiotic therapy is strongly recommended for any patient receiving an endograft in an infected field. PMID- 28359718 TI - Impact of surgeon and hospital experience on outcomes of abdominal aortic aneurysm repair in New York State. AB - OBJECTIVE: This study aimed to assess the impact of the surgeon's and hospital's experience on the outcomes of open surgical repair (OSR) and endovascular aneurysm repair (EVAR) of intact and ruptured abdominal aortic aneurysms (AAAs) in New York State. METHODS: New York Statewide Planning and Research Cooperative System data were used to identify patients undergoing AAA repair from 2000 to 2011. Characteristics of the provider and hospital were determined by linkage to the New York Office of Professions and National Provider Identification databases. Distinct hierarchical logistic regression models for EVAR and OSR for intact and ruptured AAAs were created to adjust for the patient's comorbidities and to evaluate the impact of the surgeon's and hospital's experience on outcomes. The provider's years since medical school graduation as well as annual volume of the facility and provider are examined in tertiles. Adjusted odds ratios and 95% confidence intervals are presented. RESULTS: A total of 18,842 patients underwent AAA repair by a vascular surgeon. For intact AAAs (n = 17,118), 26.2% of patients underwent OSR and 73.8% underwent EVAR. For ruptured AAAs (n = 1724), 63.9% underwent OSR and 36.1% underwent EVAR. After intact AAA repair, OSR adjusted outcomes were significantly influenced by the surgeon's annual volume but not by the facility's volume or the surgeon's age. The lowest volume providers (1-4 OSRs) had higher in-hospital mortality rates than high volume (>11 OSRs) surgeons (adjusted odds ratio, 1.87 [95% confidence interval, 1.1-3.17]). Low-volume providers also had higher odds of major complications (1.23 [1-1.51]). For patients with intact AAA undergoing EVAR, mortality was higher at low-volume facilities (2.6 [1.3-5.3] and 2.7 [1.5-4.8] for <33 EVARs and 34-81 EVARs, respectively). After OSR for ruptured AAA, treatment at a low volume facility (<9 OSRs for ruptured AAA) was associated with greater mortality than at high-volume (>27 OSRs for ruptured AAA) centers (1.56 [1.02-2.39]), whereas low-volume physicians (<4 OSRs for ruptured AAA) had higher odds of major complications (1.58 [1.04-2.41]). In the case of EVAR for rupture, there were no characteristics of the hospital or surgeon significantly associated with poorer outcomes. CONCLUSIONS: For intact AAA, the surgeon's volume was an important factor for OSR outcomes, whereas low facility volume was associated with worse outcomes after EVAR. For ruptured AAA, low-volume surgeons and low-volume facilities had worse outcomes after OSR but not after EVAR. The interaction between the surgeon's volume and the hospital's volume is complex and varies on the basis of the acuity of presentation and treatment modality. PMID- 28359720 TI - The sequential catheterization amid progressive endograft deployment technique for fenestrated endovascular aortic aneurysm repair. AB - Fenestrated endovascular aneurysm repair (FEVAR) is an alternative to open repair of complex aortic aneurysms. Despite promising short-term results, the technical complexities of this procedure remain a considerable challenge. The risk of technical failure with loss of visceral or renal arteries is ubiquitous even in the most experienced hands, and thus many patients with unfavorable anatomy are frequently denied FEVAR. We have adopted a new technique for FEVAR that involves retrograde brachial artery access and stepwise deployment of the endograft during target vessel catheterization, overcoming many anatomic limitations encountered from a transfemoral approach. This technique, termed sequential catheterization amid progressive endograft deployment, has become our preferred approach for FEVAR and is described in this article. Of note, currently available Food and Drug Administration-approved fenestrated endografts may not be amenable to sequential catheterization amid progressive endograft deployment as this technique requires preloaded wires incorporated into the endografts. PMID- 28359719 TI - Regional variation in patient selection and treatment for carotid artery disease in the Vascular Quality Initiative. AB - OBJECTIVE: Previous studies involving large administrative data sets have revealed regional variation in the demographics of patients selected for carotid endarterectomy (CEA) and carotid artery stenting (CAS) but lacked clinical granularity. This study aimed to evaluate regional variation in patient selection and operative technique for carotid artery revascularization using a detailed clinical registry. METHODS: All patients who underwent CEA or CAS from 2009 to 2015 were identified in the Vascular Quality Initiative (VQI). Deidentified regional groups were used to evaluate variation in patient selection, operative technique, and perioperative management. chi2 analysis was used to identify significant variation across regions. RESULTS: A total of 57,555 carotid artery revascularization procedures were identified. Of these, 49,179 patients underwent CEA (asymptomatic: median, 56%; range, 46%-69%; P < .01) and 8376 patients underwent CAS (asymptomatic: median, 36%; range, 29%-51%; P < .01). There was significant regional variation in the proportion of asymptomatic patients being treated for carotid stenosis <70% in CEA (3%-9%; P < .01) vs CAS (3%-22%; P < .01). There was also significant variation in the rates of intervention for asymptomatic patients older than 80 years (CEA, 12%-27% [P < .01]; CAS, 8%-26% [P < .01]). Preoperative computed tomography angiography or magnetic resonance angiography in the CAS cohort also varied widely (31%-83%; P < .01), as did preoperative medical management with combined aspirin and statin (CEA, 53%-77% [P < .01]; CAS, 62%-80% [P < .01]). In the CEA group, the use of shunt (36%-83%; P < .01), protamine (32%-89%; P < .01), and patch (87%-99%; P < .01) varied widely. Similarly, there was regional variation in frequency of CAS done without a protection device (1%-8%; P < .01). CONCLUSIONS: Despite clinical benchmarks aimed at guiding management of carotid disease, wide variation in clinical practice exists, including the proportion of asymptomatic patients being treated by CAS and preoperative medical management. Additional intraoperative variables, including the use of a patch and protamine during CEA and use of a protection device during CAS, displayed similar variation in spite of clear guidelines. Quality improvement projects could be directed toward improved adherence to benchmarks in these areas. PMID- 28359721 TI - Western Osteoporosis Alliance Clinical Practice Series: Evaluating the Balance of Benefits and Risks of Long-Term Osteoporosis Therapies. AB - Osteoporosis is a chronic disease that requires life-long strategies to reduce fracture risk. Few trials have investigated the balance of benefits and risk with long-term use of osteoporosis therapies, and fewer still have investigated the consequences of treatment discontinuation. The best available evidence suggests that up to 10 years of treatment with an oral bisphosphonate maintains the degree of fracture risk reduction observed in the 3-year registration trials. With denosumab, 10 years of therapy appears to provide fracture risk reduction similar to or better than that observed in the 3-year registration trial. Available data suggest an increasing but low risk of fractures with atypical features with increasing duration of bisphosphonate therapy. Published data linking duration of therapy to osteonecrosis of the jaw are lacking for bisphosphonates and denosumab. Other side effects associated with denosumab or bisphosphonates do not appear to be related to therapy duration. The antifracture benefits of long-term therapy with bisphosphonates and denosumab in appropriately selected patients outweigh the low risk of serious side effects. PMID- 28359722 TI - Urine Tests for Chronic Hypokalemia: When in Doubt, Check Urine-Sodium-to Chloride Ratio. PMID- 28359723 TI - Apoptotic effect of demethoxyfumitremorgin C from marine fungus Aspergillus fumigatus on PC3 human prostate cancer cells. AB - Demethoxyfumitremorgin C, a secondary metabolite of the marine fungus, Aspergillus fumigatus, had been reported to demonstrate cytotoxic effect on mouse tsFT210 cells. However, no information is available regarding its functional mechanism and the chemo-sensitization effects on different kinds of human cancer cells. We found that treatment of demethoxyfumitremorgin C inhibited the cell viability of PC3 human advanced prostate cancer cells, induced apoptosis as determined by Annexin V/propidium iodide double staining, and decreased mitochondrial membrane potential. Demethoxyfumitremorgin C induced apoptosis was associated with downregulation of anti-apoptotic proteins: Ras, PI3K, Akt, Bcl xL, and Bcl-2, and upregulation of pro-apoptotic Bax. Demethoxyfumitremorgin C activated caspase-3, -8, and -9, leading to PARP cleavage. Additionally, caspase inhibitors blocked demethoxyfumitremorgin C-induced apoptosis of PC3 cells. These results suggest that demethoxyfumitremorgin C from Aspergillus fumigatus inhibits the proliferation of PC3 human prostate cancer cells via the intrinsic (mitochondrial) and extrinsic pathway, followed by downstream events leading to apoptotic cell death. Demethoxyfumitremorgin C could therefore, serve as a useful agent to treat human advanced prostate cancer. PMID- 28359724 TI - Tutor-led teaching of procedural skills in the skills lab: Complexity, relevance and teaching competence from the medical teacher, tutor and student perspective. AB - BACKGROUND: In current medical curricula, the transfer of procedural skills has received increasing attention. Skills lab learning and tutor-led teaching have become an inherent part of all medical curricula at German medical faculties. In 2011, the initial basis for the classification of clinical skills in medical school was created by the German Association for Medical Education (GMA) Committee's consensus statement on procedural skills. As a recommendation for medical curricula, the National Competency-based Catalogue of Learning Objectives (NKLM, 2015) lists procedural skills according to their curriculum integration and competency level. However, classification in regard to the perceived complexity, relevance, or teaching competency is still lacking. OBJECTIVE: The present study aimed to investigate procedural skills taught at the Medical Faculty of Heidelberg in regard to their complexity, relevance, and required teaching skills. To achieve this aim (1) the specific procedural skills in terms of complexity, that is, the degree of difficulty, and (2) the perceived relevance of taught procedural skills for studying and subsequent medical profession as well as (3) the personal preparation and required teaching skills were assessed in medical teachers, tutors and students. METHOD: During the winter semester 2014/2015, the evaluations of all medical teachers, student tutors, and medical students in the skills lab teaching departments of internal medicine, surgery, pediatrics, gynecology, and otorhinolaryngology at the Medical Faculty of Heidelberg were assessed via a quantitative cross-sectional questionnaire survey using 7-point Likert scales. The questionnaire comprised four item sets concerning 1) demographic details, 2) procedural skill complexity, 3) practical relevance, and 4) required preparation and teaching skills. Descriptive, quantitative analysis was used for questionnaire data. RESULTS: The survey included the data from 17 of 20 physicians (return rate: 85 %), 10 of 10 student tutors (return rate: 100 %) and a total of 406 of 691 students (return rate: 58.8 %). In terms of complexity and relevance, no major differences between medical teachers, tutors, and students were found. Procedural skills, assigned to the competence level of final year medical education in the NKLM, were also perceived as more complex than other skills. All skills were considered equally relevant, and student tutors were seen to have equally competent teaching skills as experienced medical teachers. CONCLUSION: This study largely underpins the NKLM's classification of procedural skills. The complexity assessment allows for conclusions to be drawn as to which skills are perceived to require particularly intensive training. Finally, our study corroborates extant findings that student tutors are apt at teaching procedural skills if they have been properly trained. PMID- 28359725 TI - Dysfunctional Skin-Derived Glucocorticoid Synthesis Is a Pathogenic Mechanism of Psoriasis. AB - Glucocorticoids (GC) are the primary steroids that regulate inflammation and have been exploited therapeutically in inflammatory skin diseases. Despite the broad spectrum therapeutic use of GC, the biochemical rationale for locally treating inflammatory skin conditions is poorly understood, as systemic GC production remains largely functional in these patients. GC synthesis has been well characterized in healthy skin, but the pathological consequence has not been examined. Here we show de novo GC synthesis, and GC receptor expression is dysfunctional in both nonlesional and lesional psoriatic skin. Use of GC receptor epidermal knockout mice with adrenalectomy allowed for the distinction between local (keratinocyte) and systemic GC activity. Compensation exhibited by adult GC receptor epidermal knockout mice demonstrated that keratinocyte-derived GC synthesis protected skin from topical phorbol 12-myristate 13-acetate-induced inflammatory assault. Thus, localized de novo GC synthesis in skin is essential for controlling inflammation, and loss of the GC pathway in psoriatic skin represents an additional pathological process in this complex inflammatory skin disease. PMID- 28359726 TI - Migraine: A look down the nose. AB - BACKGROUND: Studies have suggested that contact between opposing mucosal surfaces in the nasal wall and cavity can be a target of the surgical treatment of migraines. Unfortunately, not enough is known about the role of nasal pathology in the pathogenesis of this condition. The co-existence of further rhinological disorders can be an impediment to defining the cause and effect of anatomical variants. The authors compared the MRI scans of migraine- and non-migraine patients (MPs and NMPs, respectively) to determine the prevalence of such mucosal contact points in order to extrapolate whether there is a significant association with migraines. METHODS: Coronal and axial MRI brain scans of 522 patients (412 migraineurs and 110 non-migraineurs) were analysed for the prevalence of anatomical variations of the nasal cavity, e.g. concha bullosa, septal deviations, mucosal swelling and contact points. RESULTS: The results showed no significant difference between MPs and NMPs patients for any of the parameters examined. Moreover, 87% MPs and 79% NMPs had at least one contact point. The most frequent contact point was between the middle turbinate and the septum, observed in 54% of MPs and 45% of NMPs. CONCLUSIONS: Contact points with the nasal mucosa are highly prevalent in both MPs and NMPs. Although a contact point does not cause a migraine in the absence of the disease, the concomitant presence of migraine and contact points can trigger an attack, and therefore, it is necessary to differentiate or exclude a rhinological disorder in these patients. PMID- 28359727 TI - The medial femoral condyle flap to re-vitalise the femoral head for calcaneal reconstruction. PMID- 28359728 TI - Enriching consumer health vocabulary through mining a social Q&A site: A similarity-based approach. AB - The widely known vocabulary gap between health consumers and healthcare professionals hinders information seeking and health dialogue of consumers on end user health applications. The Open Access and Collaborative Consumer Health Vocabulary (OAC CHV), which contains health-related terms used by lay consumers, has been created to bridge such a gap. Specifically, the OAC CHV facilitates consumers' health information retrieval by enabling consumer-facing health applications to translate between professional language and consumer friendly language. To keep up with the constantly evolving medical knowledge and language use, new terms need to be identified and added to the OAC CHV. User-generated content on social media, including social question and answer (social Q&A) sites, afford us an enormous opportunity in mining consumer health terms. Existing methods of identifying new consumer terms from text typically use ad-hoc lexical syntactic patterns and human review. Our study extends an existing method by extracting n-grams from a social Q&A textual corpus and representing them with a rich set of contextual and syntactic features. Using K-means clustering, our method, simiTerm, was able to identify terms that are both contextually and syntactically similar to the existing OAC CHV terms. We tested our method on social Q&A corpora on two disease domains: diabetes and cancer. Our method outperformed three baseline ranking methods. A post-hoc qualitative evaluation by human experts further validated that our method can effectively identify meaningful new consumer terms on social Q&A. PMID- 28359730 TI - The Changing Role of Vacuum-assisted Biopsy of the Breast: A New Prototype of Minimally Invasive Breast Surgery. PMID- 28359731 TI - Acute submaxillitis: Etiological data and etiological management. AB - OBJECTIVES: The objective of the present study was to test the hypothesis that acute submaxillitis involves salivary duct obstruction. Obstacle characteristics and treatment were analyzed. MATERIAL AND METHODS: Patients presenting with an episode of acute submaxillitis between 2009 and 2015 were retrospectively included. All underwent salivary duct imaging and/or sialendoscopy, with pathologic examination if the salivary gland was removed for etiologic diagnosis. For etiological treatment, if the causal lesion could not be treated by isolated sialendoscopy, surgery used a direct approach assisted by sialendoscope. In case of failure of these procedures, submaxillectomy was indicated. RESULTS: Twenty nine patients were included, 28 of whom showed salivary duct abnormality. At least 1 calculus was found in 27 patients; calculi were usually single (n=20), situated in the mid-third (n=21), and large (mean 7.7mm). Ten patients showed stenosis, associated with salivary calculus in 9 cases. Twenty-five patients with salivary duct obstruction underwent sialendoscopy. Isolated sialendoscopy was used in 5 cases, and a combined approach in 13 cases. CONCLUSION: An episode of submaxillitis requires salivary duct exploration by sialendoscopy, to enable early treatment given the prevalence of associated calculi and high success rate of conservative management by sialendoscopy. PMID- 28359729 TI - DL-3-n-butylphthalide induced neuroprotection, regenerative repair, functional recovery and psychological benefits following traumatic brain injury in mice. AB - Previous investigations suggest that DL-3-n-butylphthalide (NBP) is a promising multifaceted drug for the treatment of stroke. It is not clear whether NBP can treat traumatic brain injury (TBI) and what could be the mechanisms of therapeutic benefits. To address these issues, TBI was induced by a controlled cortical impact in adult male mice. NBP (100 mg/kg) or saline was intraperitoneally administered within 5 min after TBI. One day after TBI, apoptotic events including caspase-3/9 activation, cytochrome c release from the mitochondria, and apoptosis-inducing factor (AIF) translocation into the nucleus in the pericontusion region were attenuated in NBP-treated mice compared to TBI saline controls. In the assessment of the nuclear factor kappa-light-chain enhancer of activated B (NF-kappaB) pathway, NBP ameliorated the p65 expression and the p-IkappaB-alpha/IkappaB-alpha ratio, indicating reduced NF-kappaB activation. Consistently, NBP reduced the upregulation of proinflammatory cytokines such as tumor necrotizing factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta) after TBI. In sub-acute treatment experiments, NBP was intranasally delivered once daily for 3 days. At 3 days after TBI, this repeated NBP treatment significantly reduced the contusion volume and cell death in the pericontusion region. In chronic experiments up to 21 days after TBI, continues daily intranasal NBP treatment increased neurogenesis, angiogenesis, and arteriogenesis in the post-TBI brain, accompanied with upregulations of regenerative genes including brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), endothelial-derived nitric oxide synthase (eNOS), and matrix metallopeptidase 9 (MMP-9). The NBP treatment significantly improved sensorimotor functional recovery and reduced post-TBP depressive behavior. These new findings demonstrate that NBP shows multiple therapeutic benefits after TBI. PMID- 28359732 TI - Outpatient hemithyroidectomy: A retrospective feasibility analysis. AB - BACKGROUND: Outpatient surgery is a major public health policy issue. It is controversial for total thyroidectomy, which raises the question of hemithyroidectomy. The present study assessed our experience in outpatient hemithyroidectomy. OBJECTIVES: To evaluate the rates of postoperative hematoma and unscheduled hospital admission. MATERIAL AND METHODS: A multicenter retrospective analysis was conducted in two hospital centers between January 2009 and December 2013. Exclusion criteria for outpatient hemithyroidectomy comprised: ASA score >2, anticoagulant therapy, risk of completion procedure, and associated procedure requiring >12 hours' surveillance. Data were collated for age, gender, weight, postoperative complications, and unscheduled hospital admission. RESULTS: During the study period, 294 hemithyroidectomies were performed, 130 of which on an outpatient basis (44%). There were no medical contraindications to outpatient surgery in 64% of patients operated on under conventional admission. In the outpatient group, mean age was 44 years. Eight completion thyroidectomies were performed in the outpatient group, and only two patients required admission for surveillance, with no revision surgeries. All patients were satisfied or very satisfied with outpatient management. CONCLUSION: In our experience, outpatient hemithyroidectomy was safe and reliable. PMID- 28359733 TI - Right ethmoid eosinophilic angiocentric fibrosis with orbital extension. AB - INTRODUCTION: Eosinophilic angiocentric fibrosis (EAF) is a slowly progressive, benign disease involving the mucosa of the upper airways or, more rarely, the orbit. It belongs to the spectrum of IgG4-related disease. CASE REPORT: The authors report the case of a 61-year-old man who presented with orbital involvement (visual loss, pain, proptosis, and eyelid oedema), headache and nasal obstruction. Imaging revealed a right ethmoido-orbital mass infiltrating the periorbital fat and enveloping the optic nerve. Histological examination concluded on a diagnosis of EAF in the presence of perivascular infiltration by inflammatory cells, predominantly eosinophils, and zones of "onion skin" fibrosis. Immunohistochemistry attributed these lesions to IgG4-related disease. Initial treatment with corticosteroids followed by dapsone failed to control the disease and resulted in severe steroid dependence. Surgical ethmoidectomy with resection of the lamina papyracea was performed to allow displacement of the eyeball into the nasal cavity in the event of another episode. DISCUSSION: The combination of surgery and rituximab achieved lasting pain relief with no recurrence of exophthalmos. PMID- 28359734 TI - Complications After Metastasectomy for Renal Cell Carcinoma-A Population-based Assessment. AB - : Metastasectomy has long been considered a valid treatment option for patients with oligometastatic renal cell carcinoma (oligo-mRCC). However, the literature on complications in this setting is scarce. Our objective was to describe in hospital complications after metastasectomy in a contemporary cohort of patients with mRCC. Using the National Inpatient Sample database (2000-2011), 45 279 mRCC patients were identified. Of those, 1102 underwent metastasectomies. The metastatic sites were the lungs, bone, liver, lymph nodes, adrenal glands, and brain in, respectively, 52%, 29%, 19%, 14%, 11%, and 3.4% of patients. The overall complication rate was 45.7%. Major complications (Clavien III-V) constituted 27.5%. Resections of hepatic lesions were significantly associated with higher odds of overall complications compared with any other site (odds ratio 2.59, 95% confidence interval 1.84-3.62, p<0.001). While metastasectomy remains a potential treatment option in RCC with oligometastatic disease, the associated complication rates are non-negligible; therefore, careful patient selection is warranted. PATIENT SUMMARY: We studied outcomes of patients with metastatic kidney cancer treated with metastasectomy. While metastasectomy is a treatment option for metastatic renal cell carcinoma, complications are not insignificant and our results may guide preoperative counseling. PMID- 28359735 TI - The Influence of Deferred Action for Childhood Arrivals on Undocumented Asian and Pacific Islander Young Adults: Through a Social Determinants of Health Lens. AB - PURPOSE: There is an urgent need to provide evidence-based policies to address the health of the 11.7 million undocumented immigrants in the United States. Deferred Action for Childhood Arrivals (DACA) offers temporary relief to qualified undocumented immigrants. Asians and Pacific Islanders (APIs), in particular, are the fastest growing immigrant population; yet, little is known about their health challenges. This article examines the influence of DACA on the health of API undocumented young adults. METHODS: In total, 32 unique participants participated in 24 in-depth interviews and four focus group discussions. Participants were aged 18-31 years and identified as undocumented API. RESULTS: DACA potentially improves health outcomes through four potential social determinants: economic stability, educational opportunities, social and community contexts, and access to health care. These determinants improve the mental health and sense of well-being among undocumented young adults. CONCLUSIONS: Targeted outreach and education in communities should be informed by these research findings with an eye toward promoting the economic, education, and health benefits of enrolling in DACA. Social policies that address the social determinants of health have significant potential to address health inequities. PMID- 28359736 TI - HLA-A, B, DRB1, DQA1, DQB1 alleles and haplotype frequencies in Dene and Cree cohorts in Manitoba, Canada. AB - BACKGROUND: First Nations in the Canadian province of Manitoba have disproportionately high rates of epidemic and endemic TB. Gene polymorphisms that modulate HLA Class I and II antigens are among the risk markers for TB, along with other biologic, and social determinants of health. HLA-A, B, DRB1, DQA1, DQB1 were typed in two Manitoba First Nation indigenous groups to identify and compare the frequency of gene polymorphisms that may influence susceptibility or resistance to TB. METHODS: Participants who self-identified as either Dene or Cree enrolled into the study from two First Nation communities in Manitoba, Canada. Genomic DNA was extracted from blood samples collected with informed consent from Dene (N=63) and Cree (N=42) First Nation study participants. Participants self-reported having treated active TB, treated latent TB or no TB. HLA Class I and II molecules were typed using sequence-specific oligonucleotide (SSO) probes from commercially available kits. RESULTS: The rates of treated active and latent TB were marginally higher among the Dene than the Cree participants (p=0.112). Class I and II HLA loci were in Hardy-Weinberg equilibrium in both the Dene and Cree groups. In this exploratory analysis of TB and HLA allele frequencies in Dene and Cree cohorts HLA-A*03 and HLA-DQB1*05:03 were significantly associated with TB. CONCLUSIONS: The high incidence of TB in both Dene and Cree populations in Canada requires both biomedical and socioeconomic prevention and control measures. Among the former, an understanding of HLA diversity among First Nations groups may aid the development of new effective vaccine and therapeutic modalities that depend on the interaction between small molecules and specific HLA epitopes. PMID- 28359738 TI - Development of a multiplex real-time PCR assay for phylogenetic analysis of Uropathogenic Escherichia coli. AB - Uropathogenic Escherichia coli (UPEC) is among major pathogens causing 80-90% of all episodes of urinary tract infections (UTIs). Recently, E. coli strains are divided into eight main phylogenetic groups including A, B1, B2, C, D, E, F, and clade I. This study was aimed to develop a rapid, sensitive, and specific multiplex real time PCR method capable of detecting phylogenetic groups of E. coli strains. This study was carried out on E. coli strains (isolated from the patient with UTI) in which the presence of all seven target genes had been confirmed in our previous phylogenetic study. An EvaGreen-based singleplex and multiplex real-time PCR with melting curve analysis was designed for simultaneous detection and differentiation of these genes. The primers were selected mainly based on the production of amplicons with melting temperatures (Tm) ranging from 82 degrees C to 93 degrees C and temperature difference of more than 1.5 degrees C between each peak.The multiplex real-time PCR assays that have been developed in the present study were successful in detecting the eight main phylogenetic groups. Seven distinct melting peaks were discriminated, with Tm value of 93+/ 0.8 for arpA, 89.2+/-0.1for chuA, 86.5+/-0.1 for yjaA, 82.3+/-0.2 for TspE4C2, 87.8+/-0.1for trpAgpC, 85.4+/-0.6 for arpAgpE genes, and 91+/-0.5 for the internal control. To our knowledge, this study is the first melting curve-based real-time PCR assay developed for simultaneous and discrete detection of these seven target genes. Our findings showed that this assay has the potential to be a rapid, reliable and cost-effective alternative for routine phylotyping of E. coli strains. PMID- 28359737 TI - A flow-cytometric method to evaluate eosinophil-mediated uptake of probiotic Lactobacillus reuteri. AB - Eosinophils are resident leukocytes of gut mucosa. Here we present a combined flow cytometric-antibiotic protection assay to identify mouse eosinophils capable of bacterial uptake, specifically, Gram-positive Lactobacillus reuteri, in studies performed ex vivo. The assay may be adapted for use in vivo. PMID- 28359739 TI - 2,4 DNP improves motor function, preserves medium spiny neuronal identity, and reduces oxidative stress in a mouse model of Huntington's disease. AB - Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the first exon of the gene huntingtin. There is no treatment to prevent or delay the disease course of HD currently. Oxidative stress and mitochondrial dysfunction have emerged as key determinants of the disease progression in HD. Therefore, counteracting mutant huntingtin (mHtt)-induced oxidative stress and mitochondrial dysfunction appears as a new approach to treat this devastating disease. Interestingly, mild mitochondrial uncoupling improves neuronal resistance to stress and facilitates neuronal survival. Mild mitochondrial uncoupling can be induced by the proper dose of 2,4-dinitrophenol (DNP), a proton ionophore that was previously used for weight loss. In this study, we evaluated the effects of chronic administration of DNP at three doses (0.5, 1, 5mg/kg/day) on mHtt-induced behavioral deficits and cellular abnormalities in the N171-82Q HD mouse model. DNP at a low dose (1mg/kg/day) significantly improved motor function and preserved medium spiny neuronal marker DARPP32 and postsynaptic protein PSD95 in the striatum of HD mice. Further mechanistic study suggests that DNP at this dose reduced oxidative stress in HD mice, which was indicated by reduced levels of F2-isoprostanes in the brain of HD mice treated with DNP. Our data indicated that DNP provided behavioral benefit and neuroprotective effect at a weight neutral dose in HD mice, suggesting that the potential value of repositioning DNP to HD treatment is warranted in well controlled clinical trials in HD. PMID- 28359740 TI - Bilateral tactile hypersensitivity and neuroimmune responses after spared nerve injury in mice lacking vasoactive intestinal peptide. AB - Vasoactive intestinal peptide (VIP) is one of the neuropeptides showing the strongest up-regulation in the nociceptive pathway after peripheral nerve injury and has been proposed to support neuropathic pain. Nevertheless, the story may be more complicated considering the known suppressive effects of the peptide on the immune reactivity of microglial cells, which have been heavily implicated in the onset and maintenance of pain after nerve injury. We here used mice deficient in VIP and the model of spared nerve injury, characterized by persistent tactile hypersensitivity. While tactile hypersensitivity developed similarly to wild type mice for the ipsilateral hindpaw, only transgenic mice showed a mirror-image tactile hypersensitivity in the contralateral hindpaw. This exacerbated neuropathic pain phenotype appeared to be mediated through a local mechanism acting at the level of the lumbar spinal cord as a distant nerve lesion in the front limb did not lead to hindpaw hypersensitivity in VIP-deficient mice. Innocuous tactile hindpaw stimulation was found to increase a neuronal activation marker in the bilateral superficial laminae of the lumbar dorsal horn of VIP deficient, but not wild type mice, after SNI. A deeper study into the immune responsiveness to the nerve lesion also proved that VIP-deficient mice had a stronger early pro-inflammatory cytokine response and a more pronounced microglial reactivity compared to wild type controls. The latter was also observed at four weeks after spared nerve injury, a time at which bilateral tactile hypersensitivity persisted in VIP-deficient mice. These data suggest an action of VIP in neuropathic states that is more complicated than previously assumed. Future research is now needed for a deeper understanding of the relative contribution of receptors and fiber populations involved in the VIP-neuropathic pain link. PMID- 28359742 TI - Increased vasopressin expression in the BNST accompanies paternally induced territoriality in male and female California mouse offspring. AB - While developmental consequences of parental investment on species-typical social behaviors has been extensively characterized in same-sex parent-offspring interactions, the impact of opposite-sex relationships is less clear. In the bi parental California mouse (Peromyscus californicus), paternal retrieval behavior induces territorial aggression and the expression of arginine vasopressin (AVP) in adult male offspring. Although similar patterns of territorially emerge among females, the sexually dimorphic AVP system has not been considered since it is generally thought to regulate male-typical behavior. However, we recently demonstrated that male and female P. californicus offspring experience increases in plasma testosterone following paternal retrieval. Since AVP expression is androgen-dependent during development, we postulate that increases in AVP expression may accompany territoriality in female, as well as male offspring. To explore this aim, adult P. californicus offspring that received either high or low levels of paternal care (retrievals) during early development were tested for territoriality and immunohistochemical analysis of AVP within the bed nucleus of the stria terminalis (BNST), paraventricular nucleus (PVN), and supraoptic nucleus (SON). Consistent with previous studies, high care offspring were more aggressive than low care offspring. Moreover, high care offspring had significantly more AVP immunoreactive (AVP-ir) cells within the BNST than low care offspring. This pattern was observed within female as well as male offspring, suggesting an equally salient role for paternal care on female offspring physiology. Regardless of early social experience, sex differences in AVP persisted in the BNST, with males having greater expression than females. PMID- 28359743 TI - Ejaculatory frequency and the risk of aggressive prostate cancer: Findings from a case-control study. AB - OBJECTIVES: Recent literature reports inverse associations with ejaculator frequency and prostate cancer (PC). We sought to explore the relationship between ejaculatory frequency from ages 20 to 50 and subsequent development of aggressive PC. MATERIAL AND METHODS: We conducted a case-control study sampling 2,141 men from private urology practices in Victoria, Australia. Cases were defined as men with high grade or high stage PC and controls being biopsy negative men. Ejaculation frequency recalled at age decades 20, 30, and 40 second was assessed by questionnaire. Unconditional multivariable logistic regression models were used to generate odds ratios (ORs). RESULTS: An inverse association with ejaculatory frequency at age 30 to 39 was observed (OR per 5-unit increase per week = 0.83, 95% CI: 0.72-0.96) but not at ages 20 to 29 (OR = 1.01, 95% CI: 0.89 1.14) or ages 40 to 49 (OR = 0.95, 95% CI: 0.81-1.12). This result differed between men with new sexual partners after age 30 (OR = 0.77, P = 0.009) and those with no new partners (OR = 0.97, P = 0.8) though the test for a difference between these estimates was not significant (P = 0.11). CONCLUSION: We found only weak evidence of an inverse association between ejaculatory frequency in the fourth decade of life and advanced PC, which was not significantly modified by number of new sexual partners. No relationship was found for ejaculatory frequency in the third and fifth decades of life. PMID- 28359745 TI - Laparoscopic cryoablation for renal cell carcinoma: 100-Month oncologic outcomes. Caputo PA, Ramirez D, Zargar H, Akca O, Andrade HS, O'Malley C, Remer EM, Kaouk JH. J Urol. 2015 Oct;194(4):892-896. [Epub 2015 April 23]. doi: 10.1016/j.juro.2015.03.128. AB - PURPOSE: With the incidence of renal cell carcinoma on the rise treatment options for the small renal mass have broadened. Cryoablation is increasingly used as a therapeutic option for renal tumors in select cases. However, studies with long term oncologic outcomes are sparse. We evaluated the long-term oncologic outcomes of laparoscopic renal mass cryoablation. MATERIALS AND METHODS: We reviewed our laparoscopic cryoablation database for patients treated with laparoscopic cryoablation from October 1997 to February 2005. Patients with less than 3 months of followup were excluded from study. Patient and tumor characteristics, and perioperative outcomes, including complications, were recorded. Recurrence-free, cancer specific and overall survival was analyzed using Kaplan-Meier curves. RESULTS: A total of 142 tumors in 138 consecutive patients were treated with laparoscopic cryoablation. Mean age of the cohort was 66.35 years. Of the patients 99 (71.7%) were male and 39 (28.3%) were female. Mean body mass index was 29.15kg/m(2) and median ASA score was 3. A solitary kidney was present in 23 patients (16.2%). Mean tumor size on cross-sectional imaging was 2.4cm. The mean preoperative and postoperative estimated glomerular filtration rate was 66.72 and 61.00ml per minute, respectively. The postoperative estimated glomerular filtration rate was determined at a mean+/-SD of 15.17+/-10.99 months of followup. The median R.E.N.A.L. nephrometry score was 5. Of the 142 tumors 100 were diagnosed as renal cell carcinoma after histopathological examination of the biopsy specimen. At 3, 5, and 10 years in patients diagnosed with renal cell carcinoma estimated recurrence-free survival was 91.4%, 86.5%, and 86.5%, estimated cancer specific survival was 96.8%, 96.8%, and 92.6%, and estimated overall survival was 88.7%, 79.1%, and 53.8%, respectively. Mean followup was 98.8+/-54.2 months in those diagnosed with renal cell carcinoma. Mean time to recurrence was 2.3 years. The latest experienced recurrence was 4.4 years after laparoscopic cryoablation. There was a postoperative complication rate of 10.6% with a total of 15 complications. CONCLUSIONS: Laparoscopic cryoablation achieves good long-term oncologic outcomes for localized small renal masses. It can safely be used in patients who cannot undergo or are unwilling to accept the risks of partial nephrectomy. Mean time to recurrence was 2.3 years and all recurrences developed within 4.4 years of initial treatment. PMID- 28359744 TI - Activation of the kynurenine pathway predicts poor outcome in patients with clear cell renal cell carcinoma. AB - OBJECTIVE: To investigate the expression of the kynurenine (KYN) pathway components and the prognostic role of the KYN-to-tryptophan ratio (KTR) in a cohort of patients with clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS: The expression of KYN pathway components was investigated by tissue microarray-based immunohistochemistry, indirect immunofluorescence, and confocal microscopy analysis in 100 ccRCC cases and 30 normal renal samples. The role of this pathway in sustaining cancer cell proliferation, migration, and chemoresistance was evaluated. In addition, tryptophan and KYN concentrations and their ratio were measured in serum of 195 patients with ccRCC using a sandwich enzyme-linked immunosorbent assay. The role of KTR as a prognostic factor for ccRCC cancer-specific survival (CSS) and progression-free survival (PFS) was assessed. RESULTS: Tissue microarray-based immunohistochemistry and indirect immunofluorescence staining showed an increased signal for KYN pathway components in ccRCC. Kaplan-Meier curves showed significant differences in CSS and PFS among groups of patients with high vs. low KTR. In particular, patients with high KTR values had a 5-year survival rate of 76.9% as compared with 92.3% for subjects with low levels (P < 0.0001). Similar findings were observed for PFS (72.8% vs. 96.8% at 5y). At multivariate analysis, KTR was an independent adverse prognostic factor for CSS (hazard ratio = 1.24, P = 0.001), and PFS (hazard ratio = 1.14, P = 0.001). CONCLUSIONS: The involvement of the KYN pathway enzymes and catabolites in ccRCC occurs via both immune and nonimmune mechanisms. Our data suggest that KTR could serve as a marker of ccRCC aggressiveness and as a prognostic factor for CSS and PFS. PMID- 28359741 TI - Targeting the mercapturic acid pathway and vicenin-2 for prevention of prostate cancer. AB - Prostate cancer (CaP) is often androgen-sensitive malignancy and regresses upon inhibition of androgen signaling. However, CaP, nearly always develops androgen resistance and progresses to aggressive and lethal androgen-independent CaP, which lacks satisfactory therapy. For metastatic CaP, patients are often treated with Taxotere (docetaxel), a cytoskeleton-targeted chemotherapy drug, that provides transient palliative benefit but to which patients rapidly develop drug resistance. Combination chemotherapy may be used instead, but is more toxic and adds little clinically relevant benefit over docetaxel. Therefore, novel strategies to enhance docetaxel efficacy are needed to effectively treat patients with metastatic CaP. The mercapturic acid pathway, which metabolizes genotoxic and pro-apoptotic toxins, is over-expressed in CaP and plays an important role in carcinogenesis, metastasis and therapy-resistance of CaP. Vicenin-2, a flavonoid derived from Tulsi (holy basil) as an active compound, inhibits the growth of CaP and increases the anti-tumor activity of docetaxel in-vitro and in-vivo. Taken together, the combination of vicenin-2 and docetaxel could be highly effective in the treatment of advanced and metastatic CaP due to their multi-targeting anti tumor potential. PMID- 28359746 TI - Are all grade group 4 prostate cancers created equal? Implications for the applicability of the novel grade grouping. AB - BACKGROUND: According to the novel prostate cancer (PCa) grade grouping, men with Gleason score 8 should be included in the grade group 4 regardless of primary and secondary scores. We aimed at evaluating the effect of Gleason patterns on the risk of recurrence in men with grade group 4 PCa. PATIENTS AND METHODS: Overall, 1,089 patients treated with radical prostatectomy with grade group 4 PCa at final pathology were identified. Biochemical recurrence (BCR) was defined as 2 consecutive prostate-specific antigen values>=0.2ng/ml and rising. Clinical recurrence (CR) was defined as positive imaging after BCR. Kaplan-Meier analyses assessed time to BCR and CR. Multivariable Cox regression analyses assessed the impact of Gleason patterns on the risk of BCR and CR. RESULTS: Overall, 295 (27.1%), 651 (59.8%), and 143 (13.1%) patients had pathologic Gleason pattern 3+5, 4+4, and 5+3. Overall, 435 (39.9%) patients had positive margins and 439 (30.2%), 300 (27.5%), 350 (32.1%), and 216 (19.8%) had pT2, pT3a, pT3b/4, and pN1 disease. Median follow-up was 83 months. Overall, 536 and 221 patients experienced BCR and CR. The 10-year BCR- and CR-free survival rates were 42.9% and 67.5% vs. 38.3% and 59.7% vs. 40.6% and 50.4% for patients with pathologic Gleason pattern 3+5 vs. 4+4 vs. 5+3, respectively (all P<=0.005). In multivariable analyses, patients with Gleason pattern 3+5 were at lower risk of BCR compared to those with 4+4 (P = 0.002). Men with Gleason pattern 3+5 were at lower risk of CR compared to those with 4+4 and 5+3 (all P<= 0.01). CONCLUSIONS: Patients with a primary Gleason score 3 are at reduced risk of recurrence as compared to their counterparts with 4 or 5. Primary and secondary Gleason scores should be considered to stratify the risk of recurrence after surgery in patients with grade group 4 PCa. PMID- 28359747 TI - Influence of previous breast surgery in sentinel lymph node biopsy in patients with breast cancer. AB - AIM: The aim of this study was to review the feasibility of selective sentinel lymph node biopsy in patients with previous surgery for breast cancer, as well as to examine the factors that may interfere with sentinel node detection. MATERIAL AND METHODS: A retrospective review was performed on 91 patients with breast cancer and previous breast surgery, and who underwent sentinel lymph node biopsy. Patients were divided into two groups according to their previous treatment: aesthetic breast surgery in 30 patients (group I) and breast-conserving surgery in 61 (group II). Lymphoscintigraphy was performed after an intra-tumour injection in 21 cases and a peri-areolar injection in 70 cases. An analysis was made of lymphatic drainage patterns and overall sentinel node detection according to clinical, pathological and surgical variables. RESULTS: The overall detection of the sentinel lymph node in the lymphoscintigraphy was 92.3%, with 7.7% of extra-axillary drainages. The identification rate was similar after aesthetic breast surgery (93.3%) and breast-conserving surgery (91.8%). Sentinel lymph nodes were found in the contralateral axilla in two patients (2.2%), and they were included in the histopathology study. The non-identification rate in the lymphoscintigraphy was 7.7%. There was a significantly higher non-detection rate in the highest histological grade tumours (28.6% grade III, 4.5% grade I and 3.6% grade II). CONCLUSION: Sentinel lymph node biopsy in patients with previous breast surgery is feasible and deserves further studies to assess the influence of different aspects in sentinel node detection in this clinical scenario. A high histological grade was significantly associated with a lower detection. PMID- 28359748 TI - Persistent sciatic artery aneurysm as a rare cause of radiculopathy. PMID- 28359750 TI - Can lifestyle changes prevent cognitive impairment? PMID- 28359751 TI - The influence of abiotic and biotic factors on the invasion of Ixodes scapularis in Ontario, Canada. AB - In northeastern North America, the blacklegged tick, Ixodes scapularis, is the vector of numerous tick-borne pathogens, including the agent of Lyme disease, Borrelia burgdorferi sensu stricto. Since 1990, there has been a rapid spread of I. scapularis northward into the province of Ontario, Canada. Climate change has been implicated as one of the driving factors for the spread of this vector. Other ecological factors also influence survival of I. scapularis populations and may facilitate invasion. The objective of this study was to identify local abiotic and biotic factors of significance for the invasion of I. scapularis in Ontario. The presence of ticks was determined by drag sampling at 154 sites in southern, eastern and central Ontario from May to October in 2014 and 2015. At each site, data on site aspect, forest cover, understory density and composition, soil moisture and composition, and the depth of litter layer were collected. Cumulative degree days above zero degrees C, total precipitation and elevation were attributed to each site using a geographic information system. A mixed multi variable logistic regression model was created to assess the impact of the ecological factors on the presence of I. scapularis. In total, I. scapularis was found at 29 sites (18.8%) across the study area. The density of the understory, the presence of shrubs and the interaction of these two ecological factors were statistically significant, as well as longitude and cumulative degree days above zero. Our findings illustrate that local ecological factors are of importance for the invasion of I. scapularis into Ontario, and may be used to enhance local public health interventions and current predictive models and risk maps for I. scapularis. PMID- 28359752 TI - Development of a Model of Holistic Reflection to facilitate transformative learning in student midwives. AB - BACKGROUND: Reflective practice is considered an essential aspect of personal and professional development, and critical reflection is considered the cornerstone of being an accountable and autonomous practitioner. Tertiary education should lay the foundations of lifelong learning by ensuring students develop into critically reflective and reflexive practitioners, who demonstrate self-awareness and an ability to reflect on personal values and beliefs and their impact on the wider healthcare system. This level of reflective practice is essential to effect change at both an individual and societal level. Reflection should therefore be embedded into education programs as a learning, teaching and assessment strategy. AIM: The aim of this paper is to describe a structured Model of Holistic Reflection embedded within an Australian Bachelor of Midwifery Program. The paper firstly outlines the theoretical and conceptual underpinnings of the newly developed model. Secondly describes the six integrated and inter-dependant phases of the model. DISCUSSION AND CONCLUSION: The aim of developing the Holistic Reflective Model was to produce a sound educational tool to assist midwifery students to progressively build reflexivity and reflective practice. Furthermore, provide midwifery academics with an educational resource to facilitate development of reflective and critical thinking skills in students. The specific intention was to promote deep personal and transformative learning across an entry to practice program. This paper highlights a number of ways the model can be embedded within the curriculum to support the scaffolded development of critical reflection and reflexivity required to facilitate transformative learning. While evaluation is required the model may have transferability to other disciplines. PMID- 28359753 TI - "The right help at the right time": Positive constructions of peer and professional support for breastfeeding. AB - Problem or issue: Support during the early establishment phase of breastfeedingis important but women report that health professionalscan undermine their confidence with breastfeeding. What is already known: Breastfeeding support provided in fragmented hospitalbased models of care predominantly reflect authoritativeexpert advice-giving which women describe as conflictingand unsupportive. Women show a preference for supportfrom a known midwife, or a peer supporter, or a combinationof the two. What this paper adds: Peer support counsellors and privately practicing midwivesapproached breastfeeding support in a similar way. Theyinteracted with women as a 'knowledgeable friend' andnormalised breastfeeding challenges which enhanced women'sconfidence with breastfeeding. PMID- 28359754 TI - "Better safe than sorry"-Reasons for consulting care due to decreased fetal movements. AB - BACKGROUND: Experience of reduced fetal movements is a common reason for consulting health care in late pregnancy. There is an association between reduced fetal movements and stillbirth. AIM: To explore why women decide to consult health care due to reduced fetal movements at a specific point in time and investigate reasons for delaying a consultation. METHODS: A questionnaire was distributed at all birth clinics in Stockholm during 2014, to women seeking care due to reduced fetal movements. In total, 3555 questionnaires were collected, 960 were included in this study. The open-ended question; "Why, specifically, do you come to the clinic today?" was analyzed using content analysis as well as the complementary question "Are there any reasons why you did not come to the clinic earlier?" RESULTS: Five categories were revealed: Reaching dead line, Receiving advice from health care professionals, Undergoing unmanageable worry, Contributing external factors and Not wanting to jeopardize the health of the baby. Many women stated that they decided to consult care when some time with reduced fetal movements had passed. The most common reason for not consulting care earlier was that it was a new experience. Some women stated that they did not want to feel that they were annoying, or be perceived as excessively worried. Not wanting to burden health care unnecessarily was a reason for prehospital delay. CONCLUSION: Worry about the baby is the crucial reason for consulting care as well as the time which has passed since the women first experienced decreased fetal movements. PMID- 28359749 TI - Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial. AB - BACKGROUND: No large trials have been done to investigate the efficacy of an intervention combining a specific compound and several lifestyle interventions compared with placebo for the prevention of cognitive decline. We tested the effect of omega 3 polyunsaturated fatty acid supplementation and a multidomain intervention (physical activity, cognitive training, and nutritional advice), alone or in combination, compared with placebo, on cognitive decline. METHODS: The Multidomain Alzheimer Preventive Trial was a 3-year, multicentre, randomised, placebo-controlled superiority trial with four parallel groups at 13 memory centres in France and Monaco. Participants were non-demented, aged 70 years or older, and community-dwelling, and had either relayed a spontaneous memory complaint to their physician, limitations in one instrumental activity of daily living, or slow gait speed. They were randomly assigned (1:1:1:1) to either the multidomain intervention (43 group sessions integrating cognitive training, physical activity, and nutrition, and three preventive consultations) plus omega 3 polyunsaturated fatty acids (ie, two capsules a day providing a total daily dose of 800 mg docosahexaenoic acid and 225 mg eicosapentaenoic acid), the multidomain intervention plus placebo, omega 3 polyunsaturated fatty acids alone, or placebo alone. A computer-generated randomisation procedure was used to stratify patients by centre. All participants and study staff were blinded to polyunsaturated fatty acid or placebo assignment, but were unblinded to the multidomain intervention component. Assessment of cognitive outcomes was done by independent neuropsychologists blinded to group assignment. The primary outcome was change from baseline to 36 months on a composite Z score combining four cognitive tests (free and total recall of the Free and Cued Selective Reminding test, ten Mini-Mental State Examination orientation items, Digit Symbol Substitution Test, and Category Naming Test) in the modified intention-to-treat population. The trial was registered with ClinicalTrials.gov (NCT00672685). FINDINGS: 1680 participants were enrolled and randomly allocated between May 30, 2008, and Feb 24, 2011. In the modified intention-to-treat population (n=1525), there were no significant differences in 3-year cognitive decline between any of the three intervention groups and the placebo group. Between-group differences compared with placebo were 0.093 (95% CI 0.001 to 0.184; adjusted p=0.142) for the combined intervention group, 0.079 (-0.012 to 0.170; 0.179) for the multidomain intervention plus placebo group, and 0.011 (-0.081 to 0.103; 0.812) for the omega 3 polyunsaturated fatty acids group. 146 (36%) participants in the multidomain plus polyunsaturated fatty acids group, 142 (34%) in the multidomain plus placebo group, 134 (33%) in the polyunsaturated fatty acids group, and 133 (32%) in the placebo group had at least one serious emerging adverse event. Four treatment-related deaths were recorded (two in the multidomain plus placebo group and two in the placebo group). The interventions did not raise any safety concerns and there were no differences between groups in serious or other adverse events. INTERPRETATION: The multidomain intervention and polyunsaturated fatty acids, either alone or in combination, had no significant effects on cognitive decline over 3 years in elderly people with memory complaints. An effective multidomain intervention strategy to prevent or delay cognitive impairment and the target population remain to be determined, particularly in real-world settings. FUNDING: French Ministry of Health, Pierre Fabre Research Institute, Gerontopole, Exhonit Therapeutics, Avid Radiopharmaceuticals. PMID- 28359755 TI - A novel staphylococcal enterotoxin B subunit vaccine candidate elicits protective immune response in a mouse model. AB - Staphylococcal enterotoxin B (SEB), produced by the gram-positive bacterium Staphylococcus aureus, is responsible for food poisoning and toxic shock syndrome, and is considered a potential bioterrorism agent. Unfortunately, still now no approved vaccines are available against SEB. In this study, we constructed a series of nontoxic SEB mutants (mSEBs) and examined whether these mSEBs provide protective immunity against SEB challenge. These mSEB vaccine candidates did not demonstrate superantigen activity in mouse splenocyte cultures. Immunization with the vaccine candidates triggered the production of IgG-antibodies with neutralizing activity. In addition, increased production of IgG1 and IgG3 was observed after immunization, which signifies both Th1- and Th2-induced immune responses. Among the vaccine candidates tested, S9, a double mutant (N23A and Y90A) and S19, a quadruple mutant (N23A, Y90A, R110A, and F177A), demonstrated complete protection against a lethal SEB challenge. Altogether, our results strongly suggest that these mSEBs could be an effective recombinant SEB vaccine candidates for further/future preclinical and clinical studies. PMID- 28359756 TI - iTRAQ proteomic analysis of the hippocampus in a rat model of nicotine-induced conditioned place preference. AB - Repeated exposures to nicotine are known to result in persistent changes in proteins expression in addiction-related brain regions, such as the striatum, nucleus accumbens and prefrontal cortex, but the changes induced in the protein content of the hippocampus remain poorly studied. This study established a rat model of nicotine-induced conditioned place preference (CPP), and screened for proteins that were differentially expressed in the hippocampus of these rats using isobaric tags for relative and absolute quantitation labeling (iTRAQ) coupled with 2D-LC MS/MS. The nicotine-induced CPP was established by subcutaneously injecting rats with 0.2 mg/kg nicotine. Relative to the control (saline) group, the nicotine group showed 0.67- and 1.5-fold changes in 117 and 10 hippocampal proteins, respectively. These differentially expressed proteins are mainly involved in calcium-mediated signaling, neurotransmitter transport, GABAergic synapse function, long-term synaptic potentiation and nervous system development. Furthermore, RT-PCR was used to confirmed the results of the proteomic analysis. Our findings identify several proteins and cellular signaling pathways potentially involved in the molecular mechanisms in the hippocampus that underlie nicotine addiction. These results provide insights into the mechanisms of nicotine treatment in hippocampus. PMID- 28359757 TI - Pyridoxamine scavenges protein carbonyls and inhibits protein aggregation in oxidative stress-induced human HepG2 hepatocytes. AB - Introduction of carbonyl groups into amino acid residues is a hallmark for oxidative damage to proteins by reactive oxygen species (ROS). Protein carbonylation can have deleterious effects on cell function and viability, since it is generally unrepairable by cells and can lead to protein dysfunction and to the production of potentially harmful protein aggregates. Meanwhile, pyridoxamine (PM) is known to scavenge various toxic carbonyl species derived from either glucose or lipid degradation through nucleophilic addition. PM is also demonstrated to catalyze non-enzymatic transamination reactions between amino and alpha-keto acids. Here, we found that PM scavenges protein carbonyls in oxidized BSA with concomitant generation of pyridoxal and recovers oxidized lysozyme activity. Moreover, we demonstrated that the treatment of H2O2-exposed HepG2 hepatocytes with PM significantly reduced levels of cellular carbonylated proteins and aggregated proteins, and also improved cell survival rate. Our results suggest that PM may have potential efficacy in ameliorating ROS-mediated cellular dysfunction. PMID- 28359758 TI - Melanoma growth and lymph node metastasis is independent of host CD169 expression. AB - Metastasis to the lymph node is a frequent and early event in tumour dissemination. Tumour soluble factors, including extracellular vesicles, condition host organs for metastatic tumour spread, thereby facilitating tumour cell migration and survival. In the peripheral lymphatics, extracellular vesicles are captured via their sialic acids by lymph node macrophages expressing the CD169 (sialoadhesin) molecule, thereby suppressing the immune response. We hypothesised that the CD169 molecule could modulate primary tumour growth and invasion into the regional lymph node by altering the immune response to tumour extracellular vesicles, or by directly interacting with invading tumour cells. No significant difference was noted in primary tumour growth between wild-type and CD169-/- mice, and protection against tumour challenge with tumour extracellular vesicle immunisation was similar between the strains. Subcutaneous implantation of B16 (F1 or F10) into the ventral-carpal aspect of forelimb resulted in melanoma infiltration into the axillary and brachial lymph nodes. CD169-/- mice displayed a lower level of metastatic lymph node lesions, however this failed to reach statistical significance. Although CD169 participates in the immune response to tumour antigen and appears to be a positive prognostic marker for human cancers, its role in modulating melanoma growth and metastasis is less clear. PMID- 28359759 TI - A vesicle trafficking protein alphaSNAP regulates Paneth cell differentiation in vivo. AB - A soluble N-ethylmaleimide-sensitive factor-attachment protein alpha (alphaSNAP) is a multifunctional scaffolding protein that regulates intracellular vesicle trafficking and signaling. In cultured intestinal epithelial cells, alphaSNAP has been shown to be essential for cell survival, motility, and adhesion; however, its physiologic functions in the intestinal mucosa remain unknown. In the present study, we used a mouse with a spontaneous hydrocephalus with hop gait (hyh) mutation of alphaSNAP to examine the roles of this trafficking protein in regulating intestinal epithelial homeostasis in vivo. Homozygous hyh mice demonstrated decreased expression of alphaSNAP protein in the intestinal epithelium, but did not display gross abnormalities of epithelial architecture in the colon and ileum. Such alphaSNAP depletion attenuated differentiation of small intestinal epithelial enteroids ex vivo. Furthermore, alphaSNAP-deficient mutant animals displayed reduced formation of lysozyme granules in small intestinal crypts and decreased expression of lysozyme and defensins in the intestinal mucosa, which is indicative of defects in Paneth cell differentiation. By contrast, development of Goblet cells, enteroendocrine cells, and assembly of enterocyte apical junctions was not altered in hyh mutant mice. Our data revealed a novel role of alphaSNAP in the intestinal Paneth cell differentiation in vivo. PMID- 28359760 TI - Effect of p62/SQSTM1 polyubiquitination on its autophagic adaptor function and cellular survival under oxidative stress induced by arsenite. AB - Oxidative stress induced by arsenite [As(III)] affects protein folding and results in increased levels of misfolded proteins or protein aggregates. Accumulation of misfolded protein aggregates may act as a cue signal for the oligomerization of the autophagic adaptor protein p62, which facilitates recognition of misfolded protein aggregates that are polyubiquitinated with K63 linkages. However, as the autophagic flux is impaired under exposure to As(III), p62 oligomers cannot be cleared by autophagy and accumulate as aggregates with Keap1. This results in the sequestration of Keap1 and the stabilization of Nrf2, which activates the non-canonical Nrf2-Keap1 pathway as an antioxidant response. In this study, we found that polyubiquitination of p62 itself increased upon exposure to As(III) to prevent further oligomerization of p62 and to increase the availability of functional free monomeric p62. We also found that monomeric p62 could also interact with ubiquitinated proteins and that the forced dimerization of p62 was sufficient to increase the interactions with ubiquitinated proteins, probably polyubiquitinated with K63 linkages. Upon exposure to As(III), (1) inability to form oligomeric p62 because of a mutation in the PB1 dimerization domain, or (2) reduced capability to generate monomeric p62 owing to diminished polyubiquitination of p62 itself, resulted in reduced viability of cells. Therefore, upon exposure to As(III), p62 initially needs to form oligomers to activate an antioxidant response pathway. Subsequently, p62 is polyubiquitinated to prevent further oligomerization and ensure the availability of free p62 monomers. We propose that the polyubiquitination of p62 under exposure to As(III) plays an important role in overcoming the impaired autophagic flux by regulating the oligomerization status of p62. PMID- 28359761 TI - Aspirin suppresses the abnormal lipid metabolism in liver cancer cells via disrupting an NFkappaB-ACSL1 signaling. AB - Abnormal lipid metabolism is a hallmark of tumorigenesis. Hence, the alterations of metabolism enhance the development of hepatocellular carcinoma (HCC). Aspirin is able to inhibit the growth of cancers through targeting nuclear factor kappaB (NF-kappaB). However, the role of aspirin in disrupting abnormal lipid metabolism in HCC remains poorly understood. In this study, we report that aspirin can suppress the abnormal lipid metabolism of HCC cells through inhibiting acyl-CoA synthetase long-chain family member 1 (ACSL1), a lipid metabolism-related enzyme. Interestingly, oil red O staining showed that aspirin suppressed lipogenesis in HepG2 cells and Huh7 cells in a dose-dependent manner. In addition, aspirin attenuated the levels of triglyceride and cholesterol in the cells, respectively. Strikingly, we identified that aspirin was able to down-regulate ACSL1 at the levels of mRNA and protein. Moreover, we validated that aspirin decreased the nuclear levels of NF-kappaB in HepG2 cells. Mechanically, PDTC, an inhibitor of NF-kappaB, could down-regulate ACSL1 at the levels of mRNA and protein in the cells. Functionally, PDTC reduced the levels of lipid droplets, triglyceride and cholesterol in HepG2 cells. Thus, we conclude that aspirin suppresses the abnormal lipid metabolism in HCC cells via disrupting an NFkappaB-ACSL1 signaling. Our finding provides new insights into the mechanism by which aspirin inhibits abnormal lipid metabolism of HCC. Therapeutically, aspirin is potentially available for HCC through controlling abnormal lipid metabolism. PMID- 28359762 TI - Visual deprivation induce cross-modal enhancement of olfactory perception. AB - The underlying mechanisms responsible for enhanced olfactory perception of congenital blind humans remain elusive so far. Here, animal behavioral test showed that congenital visual deprivation (from postnatal day 0-28) or one-week visual deprivation during juvenile stage (from postnatal day 21-28) could reduce the latency time of food-seeking but increase the odor discrimination performance of rodents. The enhanced olfactory perception induced by one-week visual deprivation could be returned to base level when visual input was recovered. Accordingly, local field potential (LFP) oscillation recording in vivo showed that the power of high-frequency beta and gamma oscillations were increased in olfactory bulb (OB) and anterior piriform cortex (aPC) of vision deprived animals. This research discovered the enhancement of olfactory perception and adaptive plasticity of oscillations in olfactory system of rodents induced by visual deprivation, which may facilitate better understanding of mechanisms underlying cross-modal plasticity. PMID- 28359764 TI - Neuroimmunological response in neuro-Behcet's. AB - Behcet's disease is a chronic, multisystem, autoimmune vasculitis characterized by a triad of key signs. We report the case of a 16-year-old Caucasian girl, who complained of headache, dizziness and paresis of the left side of her body. After physical examination and ancillary tests, she was diagnosed with Behcet's disease with neurological manifestations (neuro-Behcet's disease). She had a good response to treatment. IgG, IgA, IgM and albumin were quantified in serum and cerebrospinal fluid by single radial immunodiffusion. Intrathecal synthesis was found for the 3 classes of immunoglobulins. This is the first case in which the Reibergram was used to evaluate the neuroimmunological response in a patient with Behcet's disease, suggesting the use of this diagnostic means for the active phase of the disease. PMID- 28359763 TI - Overcome the limitation of hypoxia against photodynamic therapy to treat cancer cells by using perfluorocarbon nanodroplet for photosensitizer delivery. AB - The low oxygen concentration limits the therapeutic efficacy of photodynamic therapy in treating cancer cells in hypoxia, since the cytotoxic 1O2 can't be effectively generated in this condition. To overcome this, we load photosensitizer into perfluorocarbon nanodroplet, which has a high oxygen capacity to enrich O2 for photodynamic consumption. Under the well-controlled hypoxic condition, we test its efficacy both in vitro and in vivo. This method can be successfully used for destroying cancer cells in hypoxic condition. PMID- 28359765 TI - Nephrocalcinosis in a patient with rheumatoid arthritis and secondary Sjogren's syndrome. PMID- 28359766 TI - Interstitial granulomatous dermatitis associated with lupus: A case report. PMID- 28359767 TI - Bilateral subacute lacrimal gland enlargement mimicking dacryoadenitis in a 7 year-old boy: a rare adverse effect of valproic acid (sodium valproate). AB - A healthy 7-year-old boy presented with bilateral symmetrical lacrimal gland enlargement; a week later salivary gland enlargement was also noted. Clinical investigations suggested no diagnosis, and surgical biopsy was considered. Valproic acid (sodium valproate), which he was taking for absence seizures, has been reported to cause salivary gland swelling in adults. Suspecting that a similar mechanism could be causal, the drug was discontinued. Complete resolution of the lacrimal and salivary gland enlargement rapidly ensued. This is the first report of lacrimal gland enlargement caused by valproic acid. PMID- 28359768 TI - On the Science of Consciousness: Epistemological Reflections and Clinical Implications. AB - Consciousness has been one of the most important and tantalizing issues ever since the origin of philosophy and medicine. The concept of consciousness and the so-called "hard problem" (i.e., the mind-brain relationship) are highly complex topics that have yet to be elucidated, involving the realms of both science and philosophy with profound epistemological implications. In the lively debate on the foundations of the science of consciousness there are several potential biases of an essentially philosophical nature, such as those related to the paradigm and axioms adopted, and the ostensible logical contradiction between monism and dualism. Their origin dates back largely to Descartes' thinking and the birth of the new sciences as a compromise with the Inquisition, but they have been handed down through the Enlightenment and Positivism. A proper investigation of consciousness and the world of subjectivity demands a careful reflection on the paradigm of scientific medicine to identify possible flaws and overcome the limits of the mechanistic-reductionist approach. PMID- 28359769 TI - Regular in-situ simulation training of paediatric Medical Emergency Team leads to sustained improvements in hospital response to deteriorating patients, improved outcomes in intensive care and financial savings. AB - AIM OF THE STUDY: The introduction of a paediatric Medical Emergency Team (pMET) was accompanied by weekly in-situ simulation team training. Key ward staff participated in team training, focusing on recognition of the deteriorating child, teamwork and early involvement of senior staff. Following an earlier study [1], this investigation aimed to evaluate the long-term impact of ongoing regular team training on hospital response to deteriorating ward patients, patient outcome and financial implications. METHODS: Prospective cohort study of all deteriorating in-patients in a tertiary paediatric hospital requiring admission to paediatric intensive care (PICU) the year before, 1year after and 3 years after the introduction of pMET and team training. RESULTS: Deteriorating patients were recognised more promptly (before/1year after/3years after pMET; median time 4/1.5/0.5h, p<0.001), more often reviewed by consultants (45%/76%/81%, p<0.001) and more rapidly escalated to PICU (median time 10.5/5/3.5h, p=0.02). There was a significant reduction in associated PICU admissions (56/51/32, p=0.02) and PICU bed days (527/336/193, p<0.001). The total annual cost of training (L74,250) was more than offset by savings from reduced PICU bed days (L801,600 per annum). Introduction of pMET coincided with significantly reduced hospital mortality (p<0.001). CONCLUSION: These results indicate that lessons learnt by ward staff during team training led to sustained improvements in the hospital response to critically deteriorating in-patients, significantly improved patient outcomes and substantial savings. Integration of regular in-situ simulation training of medical emergency teams, including key ward staff, in routine clinical care has potential application in all acute specialties. PMID- 28359771 TI - Hydrogen-rich saline attenuates anxiety-like behaviors in morphine-withdrawn mice. AB - Hydrogen therapy is a new medical approach for a wide range of diseases. The effects of hydrogen on central nervous system-related diseases have recently become increasingly appreciated, but little is known about whether hydrogen affects the morphine withdrawal process. This study aims to investigate the potential effects of hydrogen-rich saline (HRS) administration on naloxone precipitated withdrawal symptoms and morphine withdrawal-induced anxiety-like behaviors. Mice received gradually increasing doses (25-100 mg/kg, i.p.) of morphine over 3 days. In the naloxone-precipitated withdrawal procedure, the mice were treated with three HRS (20 MUg/kg, i.p.) injections, and naloxone (1 mg/kg, i.p.) was given 30 min after HRS administration. Body weight, jumping behavior and wet-dog shakes were immediately assessed. In the spontaneous withdrawal procedure, the mice were treated with HRS (20 MUg/kg, i.p.) every 8-h. Mice underwent naloxone-precipitated or spontaneous withdrawal were tested for anxiety like behaviors in the elevated plus-maze (EPM) and light/dark box (L/D box) paradigm, respectively. In addition, the levels of plasma corticosterone were measured. We found that HRS administration significantly reduced body weight loss, jumping behavior and wet-dog shakes in mice underwent naloxone-precipitated withdrawal, and attenuated anxiety-like behaviors in the EPM and L/D box tests after naloxone-precipitated withdrawal or a 2-day spontaneous withdrawal period. Hypo-activity or motor impairment after HRS administration was not observed in the locomotion tests. Furthermore, HRS administration significantly decreased the levels of corticosterone in morphine-withdrawn mice. These are the first findings to indicate that hydrogen might ameliorate withdrawal symptoms and exert an anxiolytic-like effect in morphine-withdrawal mice. PMID- 28359770 TI - Evaluation of cell viability dyes in antiviral assays with RNA viruses that exhibit different cytopathogenic properties. AB - Studies were conducted to determine the performance of four dyes in assessing antiviral activities of compounds against three RNA viruses with differing cytopathogenic properties. Dyes included alamarBlue(r) measured by absorbance (ALB-A) and fluorescence (ALB-F), neutral red (NR), Viral ToxGloTM (VTG), and WST 1. Viruses were chikungunya, dengue type 2, and Junin, which generally cause 100, 80-90, and 50% maximal cytopathic effect (CPE), respectively, in Vero or Vero 76 cells Compounds evaluated were 6-azauridine, BCX-4430, 3-deazaguanine, EICAR, favipiravir, infergen, mycophenolic acid (MPA), ribavirin, and tiazofurin. The 50% virus-inhibitory (EC50) values for each inhibitor and virus combination did not vary significantly based on the dye used. However, dyes varied in distinguishing the vitality of virus-infected cultures when not all cells were killed by virus infection. For example, VTG uptake into dengue-infected cells was nearly 50% when visual examination showed only 10-20% cell survival. ALB-A measured infected cell viability differently than ALB-F as follows: 16% versus 32% (dengue-infected), respectively, and 51% versus 72% (Junin-infected), respectively. Cytotoxicity (CC50) assays with dyes in uninfected proliferating cells produced similar CC50 values for EICAR (1.5-8.9MUM) and MPA (0.8-2.5MUM). 6 Azauridine toxicity was 6.1-17.5MUM with NR, VTG, and WST-1, compared to 48-92MUM with ALB-A and ALB-F (P<0.001). Curiously, the CC50 values for 3-deazaguanine were 83-93MUM with ALB-F versus 2.4-7.0MUM with all other dyes including ALB-A (P<0.001). Overall, ALB minimized the toxicities detected with these two inhibitors. Because the choice of dyes affected CC50 values, this impacted on the resulting in vitro selectivity indexes (calculated as CC50/EC50 ratio). PMID- 28359772 TI - GCK, GCKR, FADS1, DGKB/TMEM195 and CDKAL1 Gene Polymorphisms in Women with Gestational Diabetes. AB - OBJECTIVES: Gestational diabetes mellitus (GDM) is the carbohydrate intolerance that can occur in pregnancy. Genetic polymorphisms associated with type 2 diabetes could be considered as genetic determinants of GDM. The aim of this study was to examine the association between GCK, GCKR, FADS1, DGKB/TMEM195 and CDKAL1 gene polymorphisms and the development of gestational diabetes. These genetic polymorphisms are involved in glucose and lipid metabolism and are associated with increased risk for diabetes type 2. METHODS: This case-control study included 204 pregnant women with GDM and 207 pregnant women with normal glucose tolerance. The diagnosis of GDM was based on a 75-gram oral glucose tolerance test at 24 to 28 weeks' gestation. RESULTS: There was a statistically significant association between FADS1 rs174550 gene polymorphism and GDM. Among women with GDM, a predominance of C-allele carriers (CC and TC genotypes) was observed (CC+TC vs. TT; p=0.00065; OR=1.97, 95% CI, 1.33 to 2.92), and this association remained significant after correction for multiple testing. In the case of the GCK rs1799884 polymorphism, there was a predominance of the T allele in women with GDM; however, this association reached only borderline statistical significance (p=0.08). Women with higher numbers of GCK rs1799884 T alleles more commonly required insulin treatment; likewise, the CDKAL1 rs10946398 CC genotype was associated with the need for insulin therapy. However, these associations do not pass the statistical significance threshold after correction for multiple testing. CONCLUSIONS: The results of our study suggest an association between the rs174550 FADS1 polymorphism and GDM risk. PMID- 28359773 TI - Impact of Egg Consumption on Cardiovascular Risk Factors in Individuals with Type 2 Diabetes and at Risk for Developing Diabetes: A Systematic Review of Randomized Nutritional Intervention Studies. AB - Observational studies have reported inconclusive results regarding the relationship between egg consumption (and dietary cholesterol) and the risk for cardiovascular diseases (CVDs) in individuals with type 2 diabetes, which has led to inconsistent recommendations to patients. We reviewed the evidence of egg consumption on major CVD risk factors in individuals with or at risk for type 2 diabetes (prediabetes, insulin resistance or metabolic syndrome). We performed a systematic search in the databases PubMed, MEDLINE, EMBASE and Web of Science in January 2016. Inclusion criteria included randomized controlled trials in which the amount of egg consumed was manipulated and compared to a control group that received no-egg or low-egg diets (<2 eggs/week). We found 10 articles (6 original trials) that met our inclusion criteria. The majority of studies found that egg consumption did not affect major CVD risk factors. Consumption of 6 to 12 eggs per week had no impact on plasma concentrations of total cholesterol, low-density lipoprotein-cholesterol, triglycerides, fasting glucose, insulin or C-reactive protein in all studies that reported these outcomes in comparison with control groups. An increase in high-density lipoprotein-cholesterol with egg consumption was observed in 4 of 6 studies. Results from randomized controlled trials suggest that consumption of 6 to 12 eggs per week, in the context of a diet that is consistent with guidelines on cardiovascular health promotion, has no adverse effect on major CVD risk factors in individuals at risk for developing diabetes or with type 2 diabetes. However, heterogeneities in study design, population included and interventions prevent firm conclusions from being drawn. PMID- 28359774 TI - TRPV4 regulates insulin mRNA expression and INS-1E cell death via ERK1/2 and NO dependent mechanisms. AB - TRPV4 is a Ca2+-permeable, nonselective cation channel. Recently, TRPV4 was implicated in controlling peripheral insulin sensitivity, insulin secretion and apoptosis of pancreatic beta cells. Here, we characterize the role and potential mechanisms of TRPV4 in regulating insulin mRNA expression and cell death in insulin producing INS-1E cells and rat pancreatic islets. TRPV4 protein production was downregulated by siRNA. Intracellular calcium level was measured using Fluo-3 AM. Gene expression was studied by real-time PCR. Phosphorylation of extracellular signal-regulated kinase (ERK1 and ERK2) was detected by Western blot. Nitric oxide (NO) production was assessed by chemiluminescent reaction. Reactive oxygen species (ROS) level was analysed using a fluorogenic dye (DCFDA). Cell death was evaluated by determination of cytoplasmic histone-associated DNA fragments. Downregulation of TRPV4 neither affected insulin mRNA expression nor INS-1E cell growth. By contrast, pharmacological TRPV4 activation by 100nmol/l GSK1016790A increased Ca2+ levels in INS-1E cells and enhanced insulin mRNA expression after 1 and 3h, whereas a suppression of insulin mRNA expression was detected after 24h incubation. GSK1016790A increased ERK1/2 phosphorylation and NO production but not ROS production. Pharmacological blockade of ERK1/2 attenuated GSK1016790A-induced insulin mRNA expression. Inhibition of NO synthesis by l-NAME failed to affect insulin mRNA expression in GSK1016790A treated INS-1E cells. Furthermore, inhibition of NO production attenuated GSK1016790A-induced INS-1E cell death. In pancreatic islets, 100nmol/l GSK1016790A increased insulin mRNA levels after 3h without inducing cytotoxicity after 24h. In conclusion, TRPV4 differently regulates insulin mRNA expression in INS-1E cells via ERK1/2 and NO-dependent mechanisms. PMID- 28359776 TI - Cross-species comparison of the gut: Differential gene expression sheds light on biological differences in closely related tenebrionids. AB - The gut is one of the primary interfaces between an insect and its environment. Understanding gene expression profiles in the insect gut can provide insight into interactions with the environment as well as identify potential control methods for pests. We compared the expression profiles of transcripts from the gut of larval stages of two coleopteran insects, Tenebrio molitor and Tribolium castaneum. These tenebrionids have different life cycles, varying in the duration and number of larval instars. T. castaneum has a sequenced genome and has been a model for coleopterans, and we recently obtained a draft genome for T. molitor. We assembled gut transcriptome reads from each insect to their respective genomes and filtered mapped reads to RPKM>1, yielding 11,521 and 17,871 genes in the T. castaneum and T. molitor datasets, respectively. There were identical GO terms in each dataset, and enrichment analyses also identified shared GO terms. From these datasets, we compiled an ortholog list of 6907 genes; 45% of the total assembled reads from T. castaneum were found in the top 25 orthologs, but only 27% of assembled reads were found in the top 25 T. molitor orthologs. There were 2281 genes unique to T. castaneum, and 2088 predicted genes unique to T. molitor, although improvements to the T. molitor genome will likely reduce these numbers as more orthologs are identified. We highlight a few unique genes in T. castaneum or T. molitor that may relate to distinct biological functions. A large number of putative genes expressed in the larval gut with uncharacterized functions (36 and 68% from T. castaneum and T. molitor, respectively) support the need for further research. These data are the first step in building a comprehensive understanding of the physiology of the gut in tenebrionid insects, illustrating commonalities and differences that may be related to speciation and environmental adaptation. PMID- 28359775 TI - Origin of alpha-mannosidase activity in CSF. AB - The alpha-mannosidase activity in human frontal gyrus, cerebrospinal fluid and plasma has been analyzed by DEAE-cellulose chromatography to investigate the origin of the alpha-mannosidase activity in cerebrospinal fluid (CSF). The profile of alpha-mannosidase isoenzymes obtained in CSF was similar to that in the frontal gyrus but different from that in human plasma. In particular the two characteristic peaks of lysosomal alpha-mannosidase, A and B, which have a pH optimum of 4.5 and are found in human tissues, were present in both the frontal gyrus and CSF. In contrast the majority of alpha-mannosidase activity in human plasma was due to the so called intermediate form, which has a pH-optimum of 5.5. The results suggest that the intermediate form of alpha-mannosidase in plasma does not cross the blood-brain barrier and that the alpha-mannosidase activity present in the cerebrospinal fluid is of lysosomal type and of brain origin. Thus the alpha-mannosidase activity in cerebrospinal fluid might mirror the brain pathological changes linked to neurodegenerative disorders such as Parkinson's disease. PMID- 28359777 TI - Kidney transplantation in children weighing 15 kg or less is challenging but associated with good outcome. AB - OBJECTIVE: Pediatric kidney transplantation (KT) in small children is assumed to be related to potential surgical complications that may cause severe morbidity and graft loss. The aim of our study was to analyze the outcome of KT recipients weighing <=15 kg, focusing on surgical complications, associated morbidity and mortality, as well as allograft loss. METHODS: We reviewed our retrospective institutional database for recipients of KT between January 2000 and December 2014 with body weight <=15 kg. RESULTS: Forty-four children weighing <=15 kg, out of a total of 164 children (26.8%), received a deceased donor KT at our center during the study period. Mean weight was 10.10 +/- 2.9 kg (3-15 kg), and weight was <=10 kg in 23 patients (52.3%). The allograft was implanted intraperitoneally in two cases (4.5%) and extraperitoneally in the remaining 42 (95.5%). Two patients received a simultaneous double liver-kidney transplant. Postoperative complications appeared in 10 patients (22.7%) and eight required reintervention. Five allografts (11.4%) were lost secondary to surgical complications. No statistically significant differences in surgical complications were observed when compared with patients weighing >15 kg. Actuarial graft survival was 81% and 73% at 1 and 5 years, respectively. No significant differences in graft survival were observed compared with patients >15 kg. Mean follow-up was 84.95 +/- 50 months (1-190 months). CONCLUSIONS: Our results demonstrate that KT in children weighing <=15 kg is challenging but not associated with increased risk of surgical complications or early graft loss. PMID- 28359778 TI - One-stage repair of proximal hypospadias with severe chordee by in situ tubularization of the transverse preputial island flap. AB - INTRODUCTION: To investigate a modified transverse preputial island flap repair which is performed in an attempt to reduce the complications following one-stage repair of proximal hypospadias with chordee. METHODS: Briefly, the two ends of the flap were trimmed into V shape and anastomosed with the spatulated urethra proximally and urethral plate distally before tubularization. Then the in situ tubularization of the flap was performed. The procedure was performed in our hospital on 32 patients (mean age = 11 months). They were followed for 12-38 months. RESULTS: The length of the urethral defect ranged from 4.0-6.0 cm after chordee correction. Urethrocutaneous fistulae occurred in 6 (18.7%) cases. No urethral strictures or meatal stenoses were observed. 29/32 families were satisfied with the cosmetic results. CONCLUSION: This procedure seems straightforward and reliable, leading to good result after a short-term follow up. PMID- 28359779 TI - "Trident" preputial plasty for phimosis in childhood. AB - OBJECTIVE: To evaluate the functional and cosmetic result of modified-triple incision preputial plasty for surgical management of phimosis in children. MATERIALS AND METHODS: This prospective study involved all consecutive children (age 3-15) with phimosis, managed at our Institution in a one-year period. All patients unable to retract the foreskin and symptomatic with episodes of posthitis or balanoposthitis or ballooning of the foreskin with voiding were initially included. After a two-month trial of topic corticosteroids treatment, for patients refractory to conservative ointment treatment, "trident" preputial plasty was offered. This procedure combines two lateral Z-plasty and one middle Y V plasty. All the procedures were performed as a day care, in general anaesthesia by two senior surgeons. Outpatient follow-up controls were scheduled at 1 and 2 week, 1, 6 and 12 months after surgery, respectively. RESULTS: A total of 41 patient were enrolled. Mean operative time was 24 minutes (range 15-43). At 12 month follow-up, all but one patients (97.6%) was able to retract the prepuce. Cosmetic and functional results were satisfactory. CONCLUSION: In selected group of children with phimosis, the "trident" preputial plasty provided excellent cosmetic and functional result. Adequate retraction of the prepuce by the patients soon after surgery is mandatory. PMID- 28359780 TI - Potential role of retinoids in ovarian physiology and pathogenesis of polycystic ovary syndrome. AB - Retinoids (retinol and its derivatives) are required for maintaining vision, immunity, barrier function, reproduction, embryogenesis, cell proliferation and differentiation. Furthermore, retinoid signaling plays a key role in initiating meiosis of germ cells of the mammalian fetal ovary. Recently, studies indicated that precise retinoid level regulation in the ovary provides a molecular control of ovarian development, steroidogenesis and oocyte maturation. Besides, abnormal retinoid signaling may be involved in the pathogenesis of polycystic ovary syndrome (PCOS), one of the most common ovarian endocrinopathies in reproductive aged women worldwide. This review primarily summarizes recent advancements made in investigating the action of retinoid signaling in ovarian physiology as well as the abnormal retinoid signaling in PCOS. PMID- 28359781 TI - Why do Dutch people use dietary supplements? Exploring the role of socio cognitive and psychosocial determinants. AB - BACKGROUND: In the Netherlands, the prevalence of dietary supplement use has doubled (from 17 to 40 per cent) since the 1980s. Yet, limited data is available on which socio-cognitive factors are associated with dietary supplement use. Therefore, the purpose of the study is to explain dietary supplement use with determinants deriving from the Integrated Change Model (ICM) and from formative research. METHOD/DESIGN: Socio-cognitive and psychosocial factors were measured among users and non-users of dietary supplements in a longitudinal survey study, with measurements at baseline (N = 1448) and at one-month follow-up (N = 1161). Negative binomial regression analysis was applied to de data. RESULTS: Intention emerged as the main predictor of dietary supplement use (OR = 1.99). Further predictors of dietary supplement use with smaller effect-sizes were: health regulatory focus (promotion, OR = 1.46), social modelling (OR = 1.44), attitude (pros, OR = 1.37), attitude (cons, OR = 0.87), health locus of control (OR = 0.77), and risk perception (chance of getting ill, OR = 1.22). CONCLUSIONS: Individuals tend to use dietary supplements if they are promotion oriented, notice dietary supplement users in their social environment, estimate their chances of getting ill higher, and have positive attitudes towards dietary supplements. In contrast, non-users believe that external factors affect their health, and hold negative attitudes towards dietary supplements. PRACTICAL IMPLICATIONS: Mapping out individuals' socio-cognitive profile may contribute to the development of online health communication. Based on socio-cognitive and demographical factors, personalised advice can be given about dietary supplement use. PMID- 28359782 TI - In vivo IL-4 prevents allo-antigen driven CD8+ CTL development. AB - IL-4 has been shown to suppress acute graft vs. host disease (GVHD) in irradiated hosts. Here we evaluated whether IL-4 suppresses acute GVHD in the un-irradiated parent-into-F1 GVHD model with relevance to renal allograft rejection. IL-4 completely suppressed CD8 CTL when administered with donor cells however this effect was lost if its administration was delayed 3days. IL-4 did not inhibit donor CD8+ T cell homing to the host spleen but rather prevented donor CD8+ T cell differentiation into CTLs. Studies with IL-4Ralpha-deficient donor cells or recipient mice demonstrated that IL-4 effects on the host, rather than, or in addition to IL-4 effects on donor cells, were critical for suppression of CTL. Because IL-4 decreased all splenic dendritic cell populations and increased neutrophil and CD8+ T cells, IL-4 may suppress donor CD8+ CTL by decreasing Ag presentation and/or increasing host myeloid and CD8+ T cell suppression of donor T cells. PMID- 28359785 TI - Optimum dosing of ipilimumab in melanoma: too little, too late? PMID- 28359783 TI - Systematic analysis of splicing defects in selected primary immunodeficiencies related genes. AB - Both variants affecting splice sites and those in splicing regulatory elements (SREs) can impair pre-mRNA splicing, eventually leading to severe diseases. Despite the availability of many prediction tools, prognosis of splicing affection is not trivial, especially when SREs are involved. Here, we present data on 92 in silico-/55 minigene-analysed variants detected in genes responsible for the primary immunodeficiencies development (namely BTK, CD40LG, IL2RG, SERPING1, STAT3, and WAS). Of 20 splicing-affecting variants, 16 affected splice site while 4 disrupted potential SRE. The presence or absence of splicing defects was confirmed in 30 of 32 blood-derived patients' RNAs. Testing prediction tools performance, splice site disruptions and creations were reliably predicted in contrast to SRE-affecting variants for which just ESRseq, DeltaHZEI-scores and EX SKIP predictions showed promising results. Next, we found an interesting pattern in cryptic splice site predictions. These results might help PID-diagnosticians and geneticists cope with potential splicing-affecting variants. PMID- 28359784 TI - Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. AB - BACKGROUND: A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3-4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit-risk profile of ipilimumab 10 mg/kg versus 3 mg/kg. METHODS: This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov, number NCT01515189. FINDINGS: Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14.5 months (IQR 4.6-42.3) for the ipilimumab 10 mg/kg group and 11.2 months (4.9 29.4) for the ipilimumab 3 mg/kg group. Median overall survival was 15.7 months (95% CI 11.6-17.8) for ipilimumab 10 mg/kg compared with 11.5 months (9.9-13.3) for ipilimumab 3 mg/kg (hazard ratio 0.84, 95% CI 0.70-0.99; p=0.04). The most common grade 3-4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two (<1%) patients died from treatment-related adverse events. INTERPRETATION: In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment. FUNDING: Bristol-Myers Squibb. PMID- 28359786 TI - The Looming Maladaptive Style Questionnaire: Measurement invariance and relations to anxiety and depression across 10 countries. AB - The Looming Maladaptive Style Questionnaire (LMSQ) is a self-report measure designed to assess the looming cognitive style, a tendency to interpret threats as rapidly approaching and increasing in magnitude. To date, no systematic evaluation on the psychometric properties of the LMSQ across diverse cultural contexts has been done. In the present research, the measurement invariance of the LMSQ test scores was examined in 10 countries (N=4000). Confirmatory factor analysis suggested that a two-factor model (i.e., physical looming and social looming) fitted the data well across countries. Partial measurement invariance was established for the LMSQ scores across the countries whereas full measurement invariance was achieved across gender. Meta-analytic structural equation modeling was applied to examine the unique contributions of the two looming factors to anxiety and depression symptoms. Results indicated that the test scores underlying two looming factors were crucial and valid predictors of symptoms. The LMSQ shows promise as a measure with cross-cultural generalizability and opens new avenues for its use in diverse cultural settings. PMID- 28359787 TI - Tips on the analysis of phosphatidic acid by the fluorometric coupled enzyme assay. AB - The fluorometric coupled enzyme assay to measure phosphatidic acid (PA) involves the solubilization of extracted lipids in Triton X-100, deacylation, and the oxidation of PA-derived glycerol-3-phosphate to produce hydrogen peroxide for conversion of Amplex Red to resorufin. The enzyme assay is sensitive, but plagued by high background fluorescence from the peroxide-containing detergent and incomplete heat inactivation of lipoprotein lipase. These problems affecting the assay reproducibility were obviated by the use of highly pure Triton X-100 and by sufficient heat inactivation of the lipase enzyme. The enzyme assay could accurately measure the PA content from the subcellular fractions of yeast cells. PMID- 28359788 TI - Extended hybrid-space SENSE for EPI: Off-resonance and eddy current corrected joint interleaved blip-up/down reconstruction. AB - INTRODUCTION: Geometric distortions along the phase encode direction caused by off-resonant spins are still a major issue in EPI based functional and diffusion imaging. If the off-resonance map is known it is possible to correct for distortions. Most correction methods operate as a post-processing step on the reconstructed magnitude images. THEORY AND METHODS: Here, we present an algebraic reconstruction method (hybrid-space SENSE) that incorporates a physics based model of off-resonances, phase inconsistencies between k-space segments, and T2* decay during the acquisition. The method can be used to perform a joint reconstruction of interleaved acquisitions with normal (blip-up) and inverted (blip-down) phase encode direction which results in reduced g-factor penalty. RESULTS: A joint blip-up/down simultaneous multi slice (SMS) reconstruction for SMS-factor 4 in combination with twofold in-plane acceleration leads to a factor of two decrease in maximum g-factor penalty while providing off-resonance and eddy-current corrected images. CONCLUSION: We provide an algebraic framework for reconstructing diffusion weighted EPI data that in addition to the general applicability of hybrid-space SENSE to 2D-EPI, SMS-EPI and 3D-EPI with arbitrary k-space coverage along z, allows for a modeling of arbitrary spatio-temporal effects during the acquisition period like off-resonances, phase inconsistencies and T2*-decay. The most immediate benefit is a reduction in g-factor penalty if an interleaved blip-up/down acquisition strategy is chosen which facilitates eddy current estimation and ensures no loss in k-space encoding in regions with strong off-resonance gradients. PMID- 28359789 TI - Anti-leishmanial and cytotoxic activities of amino acid-triazole hybrids: Synthesis, biological evaluation, molecular docking and in silico physico chemical properties. AB - According to WHO, leishmaniasis is a major tropical disease, ranking second after malaria. Significant efforts have been therefore invested into finding potent inhibitors for the treatment. In this work, eighteen novel 1,2,3-triazoles appended with l-amino acid (Phe/Pro/Trp) tail were synthesized via azide-alkyne click chemistry with moderate to good yield, and evaluated for their anti leishmanial activity against promastigote form of Leishmania donovani (Dd8 strain). Among all, compounds 40, 43, and 53 were identified with promising anti leishmanial activity with IC50=88.83+/-2.93, 96.88+/-12.88 and 94.45+/-6.51MUM respectively and displayed no cytotoxicity towards macrophage cells. Moreover, compound 43 showed highest selectivity index (SI=8.05) among all the tested compounds. Supported by docking studies, the lead inhibitors (40, 43 and 53) showed interactions with key residues in the catalytic site of trypanothione reductase. The results of pharmacokinetic parameters suggest that these selected inhibitors can be carried forward for further structural optimization and pharmacological investigation. PMID- 28359790 TI - Design, synthesis and optimization of 7-substituted-pyrazolo[4,3-b]pyridine ALK5 (activin receptor-like kinase 5) inhibitors. AB - A series of potent ALK5 inhibitors were designed using a SBDD approach and subsequently optimized to improve drug likeness. Starting with a 4-substituted quinoline screening hit, SAR was conducted using a ALK5 binding model to understand the binding site and optimize activity. The resulting inhibitors displayed excellent potency but were limited by high in vitro clearance in rat and human microsomes. Using a scaffold morphing strategy, these analogs were transformed into a related pyrazolo[4,3-b]pyridine series with improved ADME properties. PMID- 28359792 TI - 4-Anilino-pyrimidine, novel aldosterone synthase (CYP11B2) inhibitors bearing pyrimidine structures. AB - 2,2,2-Trifluoro-1-{4-[(4-fluorophenyl)amino]pyrimidin-5-yl}-1-[1 (methylsulfonyl)piperidin-4-yl]ethanol 1 was identified as a novel potent aldosterone synthase inhibitor. Despite large species differences, compound 1 inhibits both human and rodent CYP11B2 in a nano-molar range. PMID- 28359791 TI - Plumbagin reduces osteopontin-induced invasion through inhibiting the Rho associated kinase signaling pathway in A549 cells and suppresses osteopontin induced lung metastasis in BalB/c mice. AB - Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer deaths in both men and women in the United States. It has been recently demonstrated that osteopontin (OPN) effectively inhibits cofilin activity through the focal adhesion kinase (FAK)/AKT/Rho-associated kinase (ROCK) pathway to induce the invasion of human non-small cell lung cancer (NSCLC) cells. Plumbagin was isolated from the roots of the medicinal plant Plumbago zeylanica L. and has been reported to possess anticancer activities. However, the molecular mechanisms by which plumbagin inhibits the invasion of cancer cells is still unclear. In this study, the anti-invasive and anti-metastatic mechanisms of plumbagin were investigated in OPN-treated NSCLC A549 cells. OPN effectively induced the motility and invasion of NSCLC A549 cells and H1299 cells, which was strongly suppressed by plumbagin with no evidence of cytotoxicity. In addition, lamellipodia formation at the leading edge of cells by OPN was dramatically decreased in plumbagin-treated cells. Plumbagin caused an effective inhibition in OPN-induced the expression of ROCK1 as well as the phosphorylation of LIM kinase 1 and 2 (LIMK1/2), and cofilin. OPN-induced the phosphorylation of FAK and AKT was impaired without affecting their total forms by plumbagin treatment. OPN facilitated metastatic lung colonization, which was effectively suppressed in plumbagin-treated mice. Taken together, these results suggest that plumbagin reduces OPN-induced the invasion of NSCLC A549 cells, which resulted from inhibiting the ROCK pathway mediated by the FAK/AKT pathway and suppresses lung metastasis in vivo. PMID- 28359793 TI - Preoperative Hypoalbuminemia is a Risk Factor for Early and Late Mortality in Patients Undergoing Endovascular Juxtarenal and Thoracoabdominal Aortic Aneurysm Repair. AB - BACKGROUND: Advances in endovascular aneurysm repair now allow surgeons to treat high-risk patients with complex aortic aneurysms. Stringent selection criteria for repair exist from an anatomic and technical perspective; however, there is a paucity of literature examining frailty in patients being evaluated for fenestrated and branched endovascular aortic repair (FEVAR). As a marker of frailty well supported in the literature, we hypothesized that preoperative hypoalbuminemia would increase risk for short-term mortality after endovascular juxtarenal and thoracoabdominal aortic aneurysm repair. METHODS: One thousand eighty nine consecutive patients with juxtarenal and thoracoabdominal aortic aneurysms considered high risk for open surgery from a single institution who underwent FEVAR from 2001 to 2014 were included in the study. Risk factors for all-cause mortality were identified via a Cox regression model on time to death. RESULTS: The patients with severe hypoalbuminemia (albumin <2.4 g/dL) had significantly increased 30-day mortality (P = 0.025, odds ratio [OR]: 4.967 (95% CI: 1.385-17.814, normal versus severe) and 2-year mortality P = 0.006, OR: 2.4, 95% CI: 1.05-5.73, normal versus severe), as well as increased 30-day complication rates P = 0.026, OR: 1.91, 95% CI: 0.9-4.17, normal versus severe). A univariate analysis for 30-day mortality revealed no significant difference in median age: 75.1 vs. 72.5 years (alive at 30 days (Q1, Q3: 69.8, 80.1) versus expired (Q1, Q3: 69.3, 77.8), P = 0.24. CONCLUSIONS: Patients with hypoalbuminemia have significantly increased mortality risk. Albumin level is regulated by nutritional intake and inflammation due to chronic disease, which make it a useful part of a preoperative frailty assessment. Further studies are needed to identify whether optimizing nutrition status will affect albumin levels or decrease mortality. PMID- 28359794 TI - Multilayered Parallel Endografting for Urgent Endovascular Repair of a Severely Angulated Thoracoabdominal Aortic Aneurysm. AB - Total endovascular repair of TAAA using branched, fenestrated stent grafts have been performed with promising midterm results. However, severe angulation of the aorta as well as close proximity of the visceral and renal artery ostia pose a significant technical challenge in designing and implanting branched, fenestrated stent grafts. Parallel grafting offers an alternative technique, allowing an urgent, or emergent total endovascular repair of symptomatic, or ruptured TAAA. We describe a technique of 4-vessel incorporation in a total endovascular repair of TAAA, using multilayered parallel endografting via bilateral femoral and unilateral brachial access. A 76-year-old male with severe chronic obstructive pulmonary disease and coronary artery disease presented with a symptomatic 9 cm extent IV thoracoabdominal aortic aneurysm. The thoracic, and paravisceral segments of his aorta, as well as the iliac arteries were severely angulated, whereas the superior mesenteric and the celiac arteries had a common origin. An urgent total endovascular aortic repair was performed. The aorta and the iliac arteries were straightened by placing stiff wires from bilateral femoral arteries in a "buddy" fashion. In addition, a brachiofemoral "body-floss" wire was established. Over this body-floss wire, thoracic stent grafts were deployed in multiple layers, alternating with parallel branch stents into visceral and renal arteries. Distally, a bifurcated modular stent graft was deployed down to the common iliacs, achieving complete aneurysm exclusion. Patient recovered well without complications and was discharged home in 5 days. Postoperative computed tomography scan showed patent visceral and renal stents and complete exclusion of the aneurysm without evidence of endoleak. PMID- 28359795 TI - Estimation of V-POSSUM and E-PASS Scores in Prediction of Acute Kidney Injury in Patients after Elective Open Abdominal Aortic Aneurysm Surgery. AB - BACKGROUND: V-POSSUM and E-PASS scoring systems are usually used to predict morbidity and early mortality in surgical patients. We conducted this study to assess the validity of the V-POSSUM and E-PASS scores in predicting risk of acute kidney injury (AKI) development in patients undergoing elective open abdominal aortic aneurysm (AAA) repair. METHODS: We studied a consecutive series of 171 patients with AAA, qualified for elective open infrarenal repair. Patients underwent a thorough examination, and the physiological and surgical stress components of the V-POSSUM and E-PASS scores were calculated. The classification of patients in terms of postoperative AKI was performed in accordance with KDIGO criteria. RESULTS: AKI was recognized in 62 patients. In these patients, we found significantly higher physiological and surgical stress components of V-POSSUM and E-PASS scores in relation to patients without AKI. ROC analysis showed that the E PASS score with a cutoff point >=0.796 and the V-POSSUM score (morbidity) with a cutoff point >=77.2% with sensitivity of 75.8% and 74.2%, respectively, and with specificity of 83.5% for both, identified patients with postoperative AKI. CONCLUSIONS: V-POSSUM and E-PASS scores have similar good properties in predicting postoperative AKI in patients undergoing elective open AAA repair. PMID- 28359796 TI - Trends in Treatment and Mortality for Mesenteric Ischemia in the United States from 2000 to 2012. AB - BACKGROUND: It is unknown whether increased endovascular treatment of chronic mesenteric ischemia has led to decreases in open surgery, acute mesenteric ischemia, or overall mortality. The present study evaluates the trends in endovascular and open treatment over time for chronic and acute mesenteric ischemia. METHODS: We identified patients with chronic or acute mesenteric ischemia in the Nationwide Inpatient Sample and Center for Disease Control and Prevention database from 2000 to 2012. Trends in revascularization, mortality, and total deaths were evaluated over time. Data were adjusted to account for population growth. RESULTS: There were 14,810 revascularizations for chronic mesenteric ischemia (10,453 endovascular and 4,358 open) and 11,294 revascularizations for acute mesenteric ischemia (4,983 endovascular and 6,311 open). Endovascular treatment increased for both chronic (0.6-4.5/million, P < 0.01) and acute mesenteric ischemia (0.6-1.8/million, P < 0.01). However, concurrent declines in open surgery did not occur (chronic: 1-1.1/million, acute: 1.8-1.7/million). Among patients with acute mesenteric ischemia, the proportion with atrial fibrillation (18%) and frequency of embolectomy (1/million per year) remained stable. In-hospital mortality rates decreased for both endovascular (chronic: 8-3%, P < 0.01; acute: 28-17%, P < 0.01) and open treatment (chronic: 21-9%, P < 0.01; acute: 40-25%, P < 0.01). Annual population-based mortality remained stable for chronic mesenteric ischemia (0.7-0.6 deaths per million/year), but decreased for acute mesenteric ischemia (12.9-5.3 deaths per million/year, P < 0.01). CONCLUSIONS: Population mortality from acute mesenteric ischemia declined from 2000 to 2012, correlated with dramatic increases in endovascular intervention for chronic mesenteric ischemia, and in spite of a stable rate of embolization. However, open surgery for both chronic and acute ischemia remained stable. PMID- 28359797 TI - The future of paediatric pneumococcal conjugate vaccines. PMID- 28359798 TI - Effect of high-valency pneumococcal conjugate vaccines on invasive pneumococcal disease in children in SpIDnet countries: an observational multicentre study. AB - BACKGROUND: The Streptococcus pneumoniae Invasive Disease network (SpIDnet) actively monitors populations in nine sites in seven European countries for invasive pneumococcal disease. Five sites use 13-valent pneumococcal conjugate vaccine (PCV13) alone and four use the ten-valent PCV (PCV10) and PCV13. Vaccination uptake is greater than 90% in six sites and 67-78% in three sites. We measured the effects of introducing high-valency PCVs on the incidence of invasive pneumococcal disease in children younger than 5 years. METHODS: We compared the incidence of invasive pneumococcal disease in each of the 4 years after the introduction of PCV13 alone or PCV10 and PCV13 with the average incidence during the preceding period of heptavalent PCV (PCV7) use, overall and by serotype category. We calculated incidence rate ratios (IRRs) and 95% CIs for each year and pooled the values for all sites in a random effects meta-analysis. FINDINGS: 4 years after the introduction of PCV13 alone or PCV10 and PCV13, the pooled IRR was 0.53 (95% CI 0.43-0.65) for invasive pneumococcal disease in children younger than 5 years caused by any serotype, 0.16 (0.07-0.40) for disease caused by PCV7 serotypes, 0.17 (0.07-0.42) for disease caused by 1, 5, and 7F serotypes, and 0.41 (0.25-0.69) for that caused by 3, 6A and 19A serotypes. We saw a similar pattern when we restricted the analysis to sites where only PCV13 was used. The pooled IRR for invasive pneumococcal disease caused by non-PCV13 serotypes was 1.62 (1.09-2.42). INTERPRETATION: The incidence of invasive pneumococcal disease caused by all serotypes decreased due to a decline in the incidence of vaccine serotypes. By contrast, that of invasive pneumococcal disease caused by non-PCV13 serotypes increased, which suggests serotype replacement. Long-term surveillance will be crucial to monitor the further effects of PCV10 and PCV13 vaccination programmes in young children. FUNDING: European Centre for Disease Prevention and Control, Czech National Institute of Public Health, French National Agency for Public Health, Irish Health Services Executive, Norwegian Institute of Public Health, Public Health Agency of Catalonia, Public Health Department of Community of Madrid, Navarra Hospital Complex, Public Health Institute of Navarra, CIBER Epidemiology and Public Health, Institute of Health Carlos III, Public Health Agency of Sweden, and NHS Scotland. PMID- 28359801 TI - Hybrid optimal descriptors as a tool to predict skin sensitization in accordance to OECD principles. AB - Skin sensitization (allergic contact dermatitis) is a widespread problem arising from the contact of chemicals with the skin. The detection of molecular features with undesired effect for skin is complex task owing to unclear biochemical mechanisms and unclearness of conditions of action of chemicals to skin. The development of computational methods for estimation of this endpoint in order to reduce animal testing is recommended (Cosmetics Directive EC regulation 1907/2006; EU Regulation, Regulation, 1223/2009). The CORAL software (http://www.insilico.eu/coral) gives good predictive models for the skin sensitization. Simplified molecular input-line entry system (SMILES) together with molecular graph are used to represent the molecular structure for these models. So-called hybrid optimal descriptors are used to establish quantitative structure-activity relationships (QSARs). The aim of this study is the estimation of the predictive potential of the hybrid descriptors. Three different distributions into the training (~70%), calibration (~15%), and validation (~15%) sets are studied. QSAR for these three distributions are built up with using the Monte Carlo technique. The statistical characteristics of these models for external validation set are used as a measure of predictive potential of these models. The best model, according to the above criterion, is characterized by nvalidation=29, r2validation=0.8596, RMSEvalidation=0.489. Mechanistic interpretation and domain of applicability for these models are defined. PMID- 28359799 TI - Paxillin and embryonic PolyAdenylation Binding Protein (ePABP) engage to regulate androgen-dependent Xenopus laevis oocyte maturation - A model of kinase-dependent regulation of protein expression. AB - Steroid-triggered Xenopus laevis oocyte maturation is an elegant physiologic model of nongenomic steroid signaling, as it proceeds completely independent of transcription. We previously demonstrated that androgens are the main physiologic stimulator of oocyte maturation in Xenopus oocytes, and that the adaptor protein paxillin plays a crucial role in mediating this process through a positive feedback loop in which paxillin first enhances Mos protein translation, ensued by Erk2 activation and Erk-dependent phosphorylation of paxillin on serine residues. Phosphoserine-paxillin then further augments Mos protein translation and downstream Erk2 activation, resulting in meiotic progression. We hypothesized that paxillin enhances Mos translation by interacting with embryonic PolyAdenylation Binding Protein (ePABP) on polyadenylated Mos mRNA. Knockdown of ePABP phenocopied paxillin knockdown, with reduced Mos protein expression, Erk2 and Cdk1 activation, as well as oocyte maturation. In both Xenopus oocytes and mammalian cells (HEK-293), paxillin and ePABP constitutively interacted. Testosterone (Xenopus) or EGF (HEK-293) augmented ePABP-paxillin binding, as well as ePABP binding to Mos mRNA (Xenopus), in an Erk-dependent fashion. Thus, ePABP and paxillin work together in an Erk-dependent fashion to enhance Mos protein translation and promote oocyte maturation. PMID- 28359802 TI - Low level arsenite exposures suppress the development of bone marrow erythroid progenitors and result in anemia in adult male mice. AB - Epidemiological studies report an association between chronic arsenic (As) exposure and anemia in men, and women who are predisposed to anemia. The purpose of these studies was to determine whether a 60 d drinking water exposure of adult male C57BL/6J mice to 0, 100, and 500ppb arsenite (As+3) results in anemia due to alterations in erythroid progenitor cell development in the bone marrow. Exposure to 500ppb As+3 for 60 d resulted in a reduction of mean corpuscular hemoglobin (MCH) levels, but did not significantly alter red blood cell (RBC) counts, hemoglobin (Hgb) levels, mean corpuscular Hgb concentrations (MCHC), or mean corpuscular volumes (MCV). Attenuation of burst-forming unit-erythroid (BFU-E) colony formation was observed in bone marrow cells of mice exposed to 500ppb As+3. The differentiation of late-stage bone marrow erythroblasts as defined by CD71 and Ter119 surface marker expression was reduced with the 500ppb As+3 exposure. Mice exposed to 500ppb As+3 also had elevated serum levels of erythropoietin (EPO). Collectively, these results show that exposure to low levels of As+3 attenuate the development of early BFU-E cells and reduce the differentiation of late-stage erythroblasts. This suppression of bone marrow erythropoiesis may be a contributing factor to the mild hypochromic anemia observed in 500ppb As+3 exposed mice. PMID- 28359800 TI - Baicalin against obesity and insulin resistance through activation of AKT/AS160/GLUT4 pathway. AB - Obesity may cause several metabolic complications, including insulin resistance and type 2 diabetes mellitus. Despite great advances in medicine, people still keep exploring novel and effective drugs for treatment of obesity and insulin resistance. The aim of this study was to survey if baicalin might ameliorate obesity-induced insulin resistance and to explore its signal mechanisms in skeletal muscles of mice. Diet-induced obese (DIO) mice were given 50 mg/kg baicalin intraperitoneally (i.p.) once a day for 21 days, and C2C12 myotubes were treated with 100, 200, 400 MUM baicalin for 12 h in this study. Then insulin resistance indexes and insulin signal protein levels in skeletal muscles were examined. We discovered that administration of baicalin decreased food intake, body weight, HOMA-IR and NT-PGC-1alpha levels, but enhanced GLUT4, PGC-1alpha, pP38MAPK, pAKT and pAS160 contents, as well as GLUT4 mRNA, PGC-1alpha mRNA, PPARgamma mRNA, GLUT1 mRNA expression in skeletal muscles of obese mice and myotubes of C2C12 cells, and reversed high fat diet-induced glucose and insulin intolerance, hyperglycemia and insulin resistance in the mice. These results suggest that baicalin is a powerful and promising agent for treatment of obesity and insulin resistance via Akt/AS160/GLUT4 and P38MAPK/PGC1alpha/GLUT4 pathway. PMID- 28359804 TI - [Genomic medicine for every patient: Dream or reality?] PMID- 28359803 TI - [Outcomes of patients with breast cancer in function of their body mass index]. AB - OBJECTIVE: The aim of this study was to evaluate outcomes of patients with breast cancer in function of the body mass index (BMI). METHODS: The study cohort consisted of consecutive women undergoing surgery for breast cancer in our institution between January 2009, and September 2013. Individual records of all patients were reviewed and analyzed. Patient BMI was categorized as underweight, normal, overweight and obese. RESULTS: A total of 1599 patients were evaluated. Patients were followed for one to 265months with a mean of 36.4months. The number of patients in each of the BMI categories was 66, 779, 463 and 291 for underweight, normal, overweight and obese women respectively. Women with higher BMI were more frequently affected by hypertension (18, 21, 35 and 47% respectively, P<0.0001) and diabetes (3, 2, 7 and 7% respectively, P<0.0001). Obese women had more frequently an inflammatory presentation (P=0.006), larger tumour size (P=0.038) and axillary lymph node involvement (P=0.03) with much more positive lymph nodes (P=0.02). Patients had the same protocols of treatment (surgery and adjuvant treatment). There was no statistically significant difference in overall 5-years survival between groups (P=0.30). CONCLUSIONS: Our study demonstrate a more aggressive clinical and histological presentation for obese women with breast cancer. PMID- 28359806 TI - Causes of low neonatal T-cell receptor excision circles: A systematic review. PMID- 28359805 TI - [Specific folic-acid targeted photosensitizer. The first step toward intraperitoneal photodynamic therapy for epithelial ovarian cancer]. AB - OBJECTIVE: Epithelial ovarian cancer (EOC) management remains association of debulking surgery in combination with platinum-based chemotherapy. Sixty percent of women with EOC considered in remission will develop recurrent disease. An option to improve the completion of cytoreductive surgery may be the use of photodynamic therapy to induce necrosis of peritoneal metastases. A limit of this technique was the toxicity induced by the lack of specificity of old-generation photosensitizer (PS) for tumor tissue if the light could not be specifically applied. To solve this problem, a solution is the design of selective PS. Folate receptor is a promising target for EOC targeted therapy. We present preclinical results concerning properties of a folic-acid targeted photosensitizer. METHOD: Preclinical studies have been performed in vitro on murine and human cell lines of EOC and in vivo with a preclinical model of peritoneal carcinomatosis (Fisher F344 rat/NuTu-19 cell line). They aimed to precise the ability of PS to target specifically tumor tissue, to emit specific fluorescence, and to obtain cell death. RESULTS: Tissue quantification of the PS showed specific incorporation of the folate-targeted PS within tumor tissue. Specificity for ovarian cancer metastases is better than previously reported with others photosensitizers (tumor to-normal tissue ratio 9.6). We could detect specific fluorescence in vitro and in vivo on peritoneal metastases. Folic-acid targeted PDT allows to obtain human EOC cells death. CONCLUSION: Specific PS may allow the development of efficient and safe intraperitoneal PDT procedure, which could play a role in the prevention of EOC peritoneal recurrences. PMID- 28359807 TI - The heterochronic gene Lin28 regulates amphibian metamorphosis through disturbance of thyroid hormone function. AB - Metamorphosis is a classic example of developmental transition, which involves important morphological and physiological changes that prepare the organism for the adult life. It has been very well established that amphibian metamorphosis is mainly controlled by Thyroid Hormone (TH). Here, we show that the heterochronic gene Lin28 is downregulated during Xenopus laevis metamorphosis. Lin28 overexpression before activation of TH signaling delays metamorphosis and inhibits the expression of TH target genes. The delay in metamorphosis is rescued by incubation with exogenous TH, indicating that Lin28 works upstream or parallel to TH. High-throughput analyses performed before any delay on metamorphosis or change in TH signaling showed that overexpression of Lin28 reduces transcript levels of several hormones secreted by the pituitary, including the Thyroid Stimulating Hormone (TSH), and regulates the expression of proteins involved in TH transport, metabolism and signaling, showing that Lin28 disrupts TH function at different levels. Our data demonstrates that the role of Lin28 in controlling developmental transitions is evolutionary conserved and establishes a functional interaction between Lin28 and thyroid hormone function introducing a new regulatory step in perinatal development with implications for our understanding of endocrine disorders. PMID- 28359808 TI - Asymmetrically reduced expression of hand1 homeologs involving a single nucleotide substitution in a cis-regulatory element. AB - During vertebrate evolution, whole genome duplications resulted in a number of duplicated genes, some of which eventually changed their expression patterns and/or levels via alteration of cis-regulatory sequences. However, the initial process involved in such cis-regulatory changes remains unclear. Therefore, we investigated this process by analyzing the duplicated hand1 genes of Xenopus laevis (hand1.L and hand1.S), which were generated by allotetraploidization 17-18 million years ago, and compared these with their single ortholog in the ancestral type diploid species X. tropicalis. A dN/dS analysis indicated that hand1.L and hand1.S are still under purifying selection, and thus, their products appear to retain ancestral functional properties. RNA-seq and in situ hybridization analyses revealed that hand1.L and hand1.S have similar expression patterns to each other and to X. tropicalis hand1, but the hand1.S expression level was much lower than the hand1.L expression level in the primordial heart. A comparative sequence analysis, luciferase reporter analysis, ChIP-PCR analysis, and transgenic reporter analysis showed that a single nucleotide substitution in the hand1.S promoter was responsible for the reduced expression in the heart. These findings demonstrated that a small change in the promoter sequence can trigger diversification of duplicated gene expression prior to diversification of their encoded protein functions in a young duplicated genome. PMID- 28359809 TI - Wnt8a expands the pool of embryonic kidney progenitors in zebrafish. AB - During zebrafish embryogenesis the pronephric kidney arises from a small population of posterior mesoderm cells that then undergo expansion during early stages of renal organogenesis. While wnt8 is required for posterior mesoderm formation during gastrulation, it is also transiently expressed in the post gastrula embryo in the intermediate mesoderm, the precursor to the pronephros and some blood/vascular lineages. Here, we show that knockdown of wnt8a, using a low dose of morpholino that does not disrupt early mesoderm patterning, reduces the number of kidney and blood cells. For the kidney, wnt8a deficiency decreases renal progenitor growth during early somitogenesis, as detected by EdU incorporation, but has no effect on apoptosis. The depletion of the renal progenitor pool in wnt8a knockdown embryos leads to cellular deficits in the pronephros at 24 hpf that are characterised by a shortened distal-most segment and stretched proximal tubule cells. A pulse of the canonical Wnt pathway agonist BIO during early somitogenesis is sufficient to rescue the size of the renal progenitor pool while longer treatment expands the number of kidney cells. Taken together, these observations indicate that Wnt8, in addition to its well established role in posterior mesoderm patterning, also plays a later role as a factor that expands the renal progenitor pool prior to kidney morphogenesis. PMID- 28359810 TI - An approach for chemical stability during melt extrusion of a drug substance with a high melting point. AB - Poorly water-soluble drug substances that exhibit high melting points are difficult to process by melt extrusion due to chemical instability at high temperatures required for processing. The purpose of this study was to extrude meloxicam (melting point 255 degrees C) by optimizing processing parameters and formulation composition. Five extrusion studies were performed: 1) design space, 2) impact of moisture, 3) impact of melt residence time, 4) specific energy optimization, and 5) altered microenvironment pH. Powder X-ray diffraction and polarized light microscopy were used to confirm amorphous conversion. Liquid chromatography-mass spectrometry was used to characterize the extrusion degradation pathway. The formulation consisted of 10% meloxicam and 90% copovidone. When processed above 140 degrees C, significant chemical degradation was observed. The minimum energy input to convert meloxicam was 1.8kWh/kg. Degradation of meloxicam during extrusion was identified as hydrolysis. Barrel configuration and screw design were designed to drive-off moisture and reduce melt residence time. With optimized parameters, the purity of the extrudate was 96.7%. To further enhance chemical stability, meglumine was added to provide a stabilizing basic microenvironment resulting in 100% purity. By process parameter optimization and formulation modification, we successfully extruded a meloxicam amorphous solid dispersion. PMID- 28359811 TI - Delivery of doxorubicin-loaded PLGA nanoparticles into U87 human glioblastoma cells. AB - The paramount problem in the therapy of brain tumors is the inability of most drugs to cross the blood-brain barrier. PLGA nanoparticles overcoated with poloxamer 188 could overcome this problem and enabled a high anti-tumoral effect against the very aggressive intracranial 101.8 glioblastoma in rats that closely resembles human grade IV glioblastomas. The basis for the transport of these particles across the blood-brain barrier appears to be adsorption of blood apolipoproteins (ApoE or ApoA-I) on the nanoparticle surface caused by the poloxamer 188-coating, followed by receptor-mediated transcytosis of the nanoparticles. The objective of the present study is the elucidation of the mechanism by which the poloxamer 188-coated nanoparticles then enter the brain tumor cells. Their intracellular fate, therefore, was investigated using the U87 human glioma cell line. The main mechanism of the PLGA nanoparticle internalization by U87 cells was clathrin-mediated endocytosis. Within 1h free doxorubicin was released from late endosomes and could reach its target site, i.e. the DNA in the nuclei without degradation, whereas the PLGA nanoparticles, which were labeled with Cy5.5, still were observed in the endo-lysosomal compartment. These results demonstrate that the underlying mechanism of action in the brain cells is by diffusive doxorubicin release from the nanoparticles rather than by their intracellular degradation. PMID- 28359812 TI - Deferoxamine-conjugated AgInS2 nanoparticles as new nanodrug for synergistic therapy for hepatocellular carcinoma. AB - Herein, a new nanodrug that exhibits multi-therapeutic modalities for synergistic treatment of hepatocellular carcinoma is reported. The nanodrug is composed of carboxymethyl cellulose modified silver indium sulfide nanoparticle (CMC-AgInS2 NP, served as a source of reactive oxygen species) covalently linked with deferoxamine (DFO, served as iron chelating agent). The DFO/CMC-AgInS2 nanodrug was taken up by the HepG2 cell and accumulated within the cytosol as well as the nucleus, leading to induction of cell arrest in the G2/M phase and subsequent apoptosis cell death. Compared to DFO, the DFO/CMC-AgInS2 nanodrug demonstrated better anti-proliferative activity against the HepG2 cell. As they were cultured in a medium supplemented with ferric ions, the HepG2 cells were induced to grow faster as compared to the cells without the addition of ferric ions. Fortunately, our nanodrug was found to inhibit the cell growth induced by ferric ions. Our results indicate that the nanodrug has synergistic effect for treatment of HepG2 cells via the intrinsic therapeutic property of CMC-AgInS2 NP and the iron chelating capability of DFO. PMID- 28359813 TI - Gaining insight into tablet capping tendency from compaction simulation. AB - Capping or lamination is an unsolved common problem in tablet manufacturing. Knowledge gaps remain despite an enormous amount of effort made in the past to better understand the tablet capping/lamination phenomenon. Using acetaminophen - containing formulations, we examined the potential use of a compaction simulator as a material-sparing tool to predict capping occurrence under commercial tableting conditions. Systematical analyses of the in-die compaction data led to insight on the potential mechanism of tablet capping/lamination. In general, capping strongly correlates with high in-die elastic recovery, high Poisson's ratio, low tensile strength, and radial die-wall pressure. Such insight can be used to guide the formulation design of high quality tablet products that are free from capping problems for challenging active pharmaceutical ingredients. PMID- 28359814 TI - Targeted delivery of anticancer drugs to tumor vessels by use of liposomes modified with a peptide identified by phage biopanning with human endothelial progenitor cells. AB - As tumor angiogenic vessels are critical for tumor growth and express different molecules on their surface from those on normal vessels, these vessels are expected to be an ideal target for anticancer drug delivery systems. It was previously reported that endothelial progenitor cells (EPCs) are involved in angiogenesis, tumor growth, and metastasis, and that EPCs show gene expression patterns similar to those of tumor endothelial cells. In the present study, a tumor vessel-targeting peptide, ASSHN, was identified from a phage-display peptide library by in vitro biopanning with human EPCs (hEPCs) and in vivo biopanning using angiogenesis model mice prepared by the dorsal air sac method. Phage clones displaying ASSHN peptide showed a marked affinity for hEPCs in vitro, and also for tumor vessels in vivo. PEGylated liposomes modified with the ASSHN peptide (ASSHN-Lip) were designed and prepared for the delivery of anticancer agents. Confocal images showed that ASSHN-Lip clearly bound to hEPCs in vitro and tumor vessels, and also showed extravasation from the vessels. The administration of doxorubicin-encapsulated ASSHN-Lip into Colon26 NL-17-bearing mice significantly suppressed tumor growth compared with doxorubicin-encapsulated PEGylated liposomes. These results suggest that the delivery of anticancer agents with ASSHN-Lip could be useful for targeted cancer therapy. PMID- 28359815 TI - Insight into the role of dual-ligand modification in low molecular weight heparin based nanocarrier for targeted delivery of doxorubicin. AB - Low molecular weight heparin nanoparticles (LMWH) modified by glycyrrhetinic acid (GA) (LMWH-GA) and further decorated by lactobionic acid (LA) (LA-LMWH-GA) were reported as novel hepatocellular carcinoma (HPC)-targeted carriers to overcome multidrug resistance (MDR) of doxorubicin (DOX). The drug-loaded nanoparticles had negative charge of around -25mV and average size range of 70-170nm. These nanoparticles performed sustained drug release in vitro and prolonged DOX residence time in blood circulation in vivo. Compared to free DOX, DOX-loaded nanoparticles demonstrated increased DOX accumulation in drug-resistance HepG2/ADR cells and enhanced in vitro therapeutic efficacy. However, DOX/LA-LMWH GA with dual ligands didn't show higher cellular uptake and cytotoxicity than single GA modified DOX/LMWH-GA, although both GA-mediated and LA-mediated endocytosis were involved in their cell internalization. Uptake pathway inhibition study revealed the less efficacy of DOX/LA-LMWH-GA in cellular level could be attributed to the reduced effect of micropinocytosis and caveolae mediated endocytosis in cellular uptake. Interestingly, the DOX-loaded nanoparticles developed from lower drug/carrier feeding ratio possessed higher performance in cell internalization and in vitro efficacy compared to those developed from higher drug/carrier feeding ratio, which could highlight the role of carrier in drug delivery process. PMID- 28359816 TI - Design and evaluation of surface functionalized superparamagneto-plasmonic nanoparticles for cancer therapeutics. AB - Designing a multifunctional nanomaterial is always considered as a biggest concern in the field of nanomedicine which aims to promote versatile action in a single use from tracking to therapeutics. Therefore, metallic nanoparticles are well exploited as a major platform with the assemblage of surface modifications which can be effectively engaged for plenty of applications. Here, in this work, we have successfully amalgamated gold coated magnetite core-shell nanoparticles along with bio-functionalization of folic acid and doxorubicin to explore its possibility as a distinct nanocargo for cancer nanotheranostics. This unique combination of both magnetic and optical properties makes its function to be more precise. For example, in case of in-vitro drug-release studies more than 75% of drug moieties are released at acidic pH 5.4 and exactly fitting in first order rate kinetics. As gold shell retains the superparamagnetic nature of the core it exhibited high r2 values, and because of large relaxivities (r2/r1) ratio, they are confirmed as T2-weighted contrast agent by MRI. Finally, under microwave of 2.45GHz exhibited enough heat which can induce both apoptosis & necrosis leading to cell death. Thus, we conclude that our nanoparticle can be a multitool for diagnosis and therapeutics for various human diseases. PMID- 28359817 TI - Solubility and thermodynamics of apremilast in different mono solvents: Determination, correlation and molecular interactions. AB - The solubility data of recently launched poorly soluble antipsoriatic drug apremilast (APM) in any mono solvent or cosolvent mixtures with respect to temperature are not available in literature. Hence, in this research work, the solubility of APM in twelve different mono solvents namely "water, methanol, ethanol, isopropanol (IPA), ethylene glycol (EG), propylene glycol (PG), 1 butanol, 2-butanol, ethyl acetate (EA), dimethyl sulfoxide (DMSO), polyethylene glycol-400 (PEG-400) and Transcutol(r)" was determined at temperatures "T=298.2K to 318.2K" and pressure "p=0.1 MPa". Eexperimental solubilities of APM in mole fraction were determined by a static equilibrium method using high performance liquid chromatography at 254nm. Experimental solubilities of APM in mole fraction were correlated well with "Van't Hoff and Apelblat models". The solubilities of APM in mole fraction were recorded highest in DMSO (9.91*10-2), followed by EA (2.54*10-2), Transcutol (2.51*10-2), PEG-400 (2.16*10-2),PG (4.01*10-3), EG (1.61*10-3), IPA (4.96*10-4), 1-butanol (4.18*10-4), 2-butanol (3.91*10-4), methanol (2.25*10-4), ethanol (2.20*10-4) and water (1.29*10-6) at "T=318.2K" and similar results were also obtained at each temperature evaluated. The molecular interactions between solute and solvent molecules were evaluated by the determination of activity coefficients. Based on activity coefficients, the higher solute-solvents molecular interactions were recorded in APM-DMSO, APM-EA, APM-Transcutol and APM-PEG-400 in comparison with other combination of solute and solvents. "Apparent standard thermodynamic parameters" of APM indicated an "endothermic and entropy-driven dissolution" of APM in all mono solvents evaluated. Based on these results, APM was proposed as freely soluble in DMSO, EA and Transcutol, sparingly soluble in PEG0-400, slightly soluble in methanol, ethanol, IPA, EG, PG, 1-butanol and 2-butanol and practically insoluble in water. Hence, DMSO, EA and Transcutol were selected as the best solvents and water and ethanol were selected as the anti-solvents for APM. PMID- 28359818 TI - Ganoderma lucidum polysaccharide loaded sodium alginate micro-particles prepared via electrospraying in controlled deposition environments. AB - Ganoderma lucidum polysaccharide (GLP) is a functional food source deployed in preventative medicine. However, applications utilizing GLP are limited due to oxidative and acidic environmental damage. Advances in preserving GLP structure (and therefore function), in situ, will diversify their applications within biomedical fields (drug and antibacterial active delivery via the enteral route). In this study, GLP loaded sodium alginate (NaAlg) micro-particles (size range 225 355MUm) were generated using the electrospray (ES) process. The loading capacity and encapsulation efficiency of GLP for composite particles (collected at different temperatures) were ~23% and 71%, respectively. The collection substrate (CaCl2, 1-20w/v%) concentration was explored and preliminary findings indicated a 10w/v% solution to be optimal. The process was further modified by manipulating the collection environment temperature (~25 to 50 degrees C). Based on this, NaAlg/GLP micro-particles were engineered with variable surface morphologies (porous and crinkled), without effecting the chemical composition of either material (GLP and NaAlg). In-vitro release studies demonstrated pH responsive release rates. Modest release of GLP from micro-particles in simulated gastric fluid (pH ~1.7) was observed, while rapid release was exhibited under simulated intestinal conditions (pH ~7.4). Release of GLP from NaAlg beads was the greatest from samples prepared at elevated environmental temperatures. These findings demonstrate a facile route to fabricate GLP-NaAlg loaded micro-particles with various shapes, surface topographies and release characteristics via a one-step ES process. PMID- 28359819 TI - Effects of amine modification of mesoporous magnesium carbonate on controlled drug release. AB - (3-Aminopropyl)triethoxysilane (APTES) was used to modify the surface of mesoporous magnesium carbonate (MMC). The as-synthesized MMC had an average pore diameter of ~5nm, but amine grafting occurred preferentially on the walls of the largest MMC pores. Analysis of ibuprofen (IBU) loading and release showed that IBU remained stable in the amorphous phase in all the MMC and modified MMC samples. The kinetics of IBU release from the modified MMC were assessed and used to evaluate the effects of the different functional groups. The release rate showed that the release of IBU could be controlled by adjusting the amine surface coverage of MMC and also by changing the surface groups. It was concluded that the interaction between the grafted functional groups in the modified MMC and the OH in the carboxyl groups of IBU was the most important factor for prolonging the release of the drug. These results are expected to lead to investigation of other as yet unexplored applications for MMC, including using it as a plastic additive and for gas separation. PMID- 28359820 TI - Development of medicated foams that combine incompatible hydrophilic and lipophilic drugs for psoriasis treatment. AB - The focus was on the development of medicated foam for incorporation of two incompatible active agents for psoriasis treatment; i.e., lipophilic cholecalciferol, and hydrophilic salicylic acid. Emphasis was given to formulation of a propellant-free foam, with sufficient foaming properties, physical and chemical stability, and low irritancy potential to maintain relevance for later translation into clinical practice. Various excipients and concentrations were examined to achieve suitable foam stability parameters, viscoelasticity, and bubble-size, which relate to foamability and spreadability. The major positive impact on these properties was through a combination of surfactants, and by inclusion of a viscosity-modifying polymer. Incorporation of the incompatible drugs was then examined, noting the instability of cholecalciferol in an acidic environment, with the design aim to separate the drug distributions among the different foam phases. Cholecalciferol was stabilized in the emulsion-based foam, with at least a 30-fold lower degradation rate constant compared to its aqueous solution. The composition of the emulsion based foam itself protected cholecalciferol from degradation, as well as the addition of the radical-scavenging antioxidant tocopheryl acetate to the oil phase. With the patient in mind, the irritancy potential was also examined, which was below the set limit that defines a non-irritant dermal product. PMID- 28359822 TI - Computational and experimental approaches for development of methotrexate nanosuspensions by bottom-up nanoprecipitation. AB - Development of nanosuspensions offers a promising tool for formulations involving poorly water-soluble drugs. In this study, methotrexate (MTX) nanosuspensions were prepared using a bottom-up process based on acid-base neutralization reactions. Computational studies were performed to determine structural and electronic properties for isolated molecules and molecular clusters in order to evaluate the mechanism of MTX nanoparticle formation. Computational results indicated that the clusters in zwitterionic and cationic states presented larger dimensions and higher energies of interaction between MTX molecules, which favored aggregation. In contrast, the clusters in the anionic state exhibited lower energies of interaction, indicating aggregation was less likely to occur. Experimental results indicated that the higher the HCl proportion during drug precipitation, the greater the particle size, resulting in micrometric particles (2874-7308nm) (cationic and zwitterionic forms). However, MTX nanoparticles ranging in size from 132 to 186nm were formed using the lowest HCl proportion during drug precipitation (anionic form). In vitro release profiles indicated that the drug release rate from nanosuspension was increased (approximately 2.6 times) over that of the raw material. Overall, computational modeling and experimental analysis were complementary and assisted in the rational design of the nanosuspension based on acid-base reactions. PMID- 28359821 TI - Rapamycin nanoparticles localize in diseased lung vasculature and prevent pulmonary arterial hypertension. AB - Vascular remodeling resulting from pulmonary arterial hypertension (PAH) leads to endothelial fenestrations. This feature can be exploited by nanoparticles (NP), allowing them to extravasate from circulation and accumulate in remodeled pulmonary vessels. Hyperactivation of the mTOR pathway in PAH drives pulmonary arterial smooth muscle cell proliferation. We hypothesized that rapamycin (RAP) loaded NPs, an mTOR inhibitor, would accumulate in diseased lungs, selectively targeting vascular mTOR and preventing PAH progression. RAP poly(ethylene glycol) block-poly(epsilon-caprolactone) (PEG-PCL) NPs were fabricated. NP accumulation and efficacy were examined in a rat monocrotaline model of PAH. Following intravenous (IV) administration, NP accumulation in diseased lungs was verified via LC/MS analysis and confocal imaging. Pulmonary arteriole thickness, right ventricular systolic pressures, and ventricular remodeling were determined to assess the therapeutic potential of RAP NPs. Monocrotaline-exposed rats showed increased NP accumulation within lungs compared to healthy controls, with NPs present to a high extent within pulmonary perivascular regions. RAP, in both free and NP form, attenuated PAH development, with histological analysis revealing minimal changes in pulmonary arteriole thickness and no ventricular remodeling. Importantly, NP-treated rats showed reduced systemic side effects compared to free RAP. This study demonstrates the potential for nanoparticles to significantly impact PAH through site-specific delivery of therapeutics. PMID- 28359823 TI - Tandem-multimeric F3-gelonin fusion toxins for enhanced anti-cancer activity for prostate cancer treatment. AB - Despite significant progress in prostate cancer treatment, yet, it remains the leading diagnosed cancer and is responsible for high incidence of cancer related deaths in the U.S. Because of the insufficient efficacy of small molecule anti cancer drugs, significant interest has been drawn to more potent macromolecular agents such as gelonin, a plant-derived ribosome inactivating protein (RIP) that efficiently inhibits protein translation. However, in spite of the great potency to kill tumor cells, gelonin lacks ability to internalize tumor cells and furthermore, cannot distinguish between tumor and normal cells. To address this challenge, we genetically engineered gelonin fusion proteins with varied numbers of F3 peptide possessing homing ability to various cancer cells and angiogenic blood vessels. The E. coli produced F3-gelonin fusion proteins possessed equipotent activity to inhibit protein translation in cell-free protein translation systems to unmodified gelonin; however, they displayed higher cell uptake that led to significantly augmented cytotoxicity. Compared with gelonin fusion with one F3 peptide (F3-Gel), tandem-multimeric F3-gelonins showed even greater cell internalization and tumor cell killing ability. Moreover, when tested against LNCaP s.c. xenograft tumor bearing mice, more significant tumor growth inhibition was observed from the mice treated with tandem-multimeric F3 gelonins. Overall, this research demonstrated the potential of utilizing tandem multimeric F3-modified gelonin as highly effective anticancer agents to overcome the limitations of current chemotherapeutic drugs. PMID- 28359825 TI - Bilateral simultaneous infective keratitis. AB - AIM: To analyze the demographics, risk factors, clinical and microbiological characteristics of cases of bilateral simultaneous infective keratitis. METHODS: In this retrospective case series, patients with clinical evidence of bilateral simultaneous infective keratitis were identified from January 1, 2011 to August 31, 2016. Demographics, risk factors, clinical and microbiological characteristics, and treatment outcomes were analyzed. RESULTS: Five patients (ten eyes) with bilateral simultaneous infective keratitis were identified. The mean age was 32.8 years (SD,+/-8.8; range, 24-44). All the patients were disposable soft contact lens wearers before presentation. The average size of the infiltrate was 4.76mm2 (SD+/-9.0; range, 0.2-31.34). A total of 4 types of bacteria were isolated, with Pseudomonas aeruginosa being the most frequently isolated bacteria involving 5 eyes of four patients. Infection resolved with medical treatment in 9 eyes, 1 patient required therapeutic corneal transplantation for impending corneal perforation. The average time taken for infection to resolve was 6.7days (SD+/-4.5; range, 2-16). CONCLUSIONS: In this case series, the most common risk factor of bilateral simultaneous microbial keratitis was use of soft disposable contact lens and the most commonly isolated bacteria was Pseudomonas aeruginosa. Bilateral simultaneous infective keratitis is uncommon and is a serious complication of contact lens use in immunocompetent adult patients. PMID- 28359824 TI - Development of biomonitoring equivalents for barium in urine and plasma for interpreting human biomonitoring data. AB - The objectives of the present work were: (1) to assemble population-level biomonitoring data to identify the concentrations of urinary and plasma barium across the general population; and (2) to derive biomonitoring equivalents (BEs) for barium in urine and plasma in order to facilitate the interpretation of barium concentrations in the biological matrices. In population level biomonitoring studies, barium has been measured in urine in the U.S. (NHANES study), but no such data on plasma barium levels were identified. The BE values for plasma and urine were derived from U.S. EPA's reference dose (RfD) of 0.2 mg/kg bw/d, based on a lower confidence limit on the benchmark dose (BMDL05) of 63 mg/kg bw/d. The plasma BE (9 MUg Ba/L) was derived by regression analysis of the near-steady-state plasma concentrations associated with the administered doses in animals exposed to barium chloride dihydrate in drinking water for 2 years in a NTP study. Using a human urinary excretion fraction of 0.023, a BE for urinary barium (0.19 mg/L or 0.25 mg/g creatinine) was derived for US EPA's RfD. The median and the 95th percentile barium urine concentrations of the general population in U.S. are below the BE determined in this study, indicating that the population exposure to inorganic barium is expected to be below the exposure guidance value of 0.2 mg/kg bw/d. PMID- 28359826 TI - Response to: Socio-political prescriptions for latent tuberculosis infection are required to prevent reactivation of tuberculosis. AB - The importance of addressing the conditions that predispose individuals and populations to develop tuberculosis is increasingly being recognized. Accurate quantification of the protective effect of preventive therapy and the provision of pragmatic guidance for clinical care and public health interventions is important. However, this approach must be nested within a socio-political context that addresses associated disadvantage and inequality. PMID- 28359827 TI - Rickettsia parkeri in Amblyomma dubitatum ticks in a spotted fever focus from the Brazilian Pampa. AB - Spotted fever is an acute febrile illness, which is considered severely underreported and misdiagnosed in the Brazilian Pampa, caused by tick-borne Rickettsiae. Here, we report an eco-epidemiological investigation of Rickettsia spp. in ticks from a spotted fever focus in Toropi, southern Brazil. Ticks were collected from capybara carcasses and processed individually to obtain genomic DNA. Rickettsia was investigated using PCR that amplified the rickettsial fragments of the gltA, ompA and htrA genes. DNA from Rickettsia parkeri was found in four of 14 Amblyomma dubitatum ticks collected from capybara carcasses in Toropi and the nearby municipality of Quevedos. We also tested 210A. dubitatum ticks obtained from road-killed capybaras of other localities from the Pampa biome; none of them were positive for Rickettsiae. Thus, in Rio Grande do Sul, two Rickettsia species can be potentially associated to spotted fever: Rickettsia sp. strain Atlantic Rainforest, associated with Amblyomma ovale ticks in the Atlantic Rainforest biome, and R. parkeri, associated both with Amblyomma tigrinum and A. dubitatum ticks in the Pampa biome. Our results reinforce that R. parkeri may be the agent associated with spotted fever in the Brazilian Pampa. PMID- 28359828 TI - TsPKA-r: a potential immunodiagnostic antigen for the detection of porcine cysticercosis. AB - Cysticercosis, caused by metacestodes of Taenia solium, has a significant soci economic impact and is of considerable importance in public health. However, there are no specific diagnostic antigens to distinguish between T. solim and Taenia hydatigena. In the present study, cAMP-dependent protein kinase regulatory subunit (TsPKA-r), an excretory/secretary (ES) antigen of T. solium, was used to establish a specific and sensitive diagnostic tool for detection of porcine cysticercosis. The full-length sequence encoding TsPKA-r was amplified by PCR, sequenced and then identified by bioinformatics. The fusion protein with 6*His tags was expressed in E. coli, purified by Ni SepharoseTM 6 Fast Flow and used to test reactionogenicity by immunoblotting. TsPKA-r based indirect enzyme-linked immunosorbent assays (iELISA) showed good performance in recognition of sera of pigs experimentally infected with T. solium metacestodes, with 93.88% sensitivity and 96.40% specificity. There were no cross-reactions against the sera from pigs experimentally infected with T. hydatigena, Toxoplasma gondii or Trichinella spiralis. These results indicate that the TsPKA-r is a promising immunodiagnostic antigen for detection of porcine cysticercosis. PMID- 28359829 TI - Feeding behavior of Mimomyia (Etorleptiomyia) luzonensis (Ludlow, 1905) (Diptera, Culicidae) in Peninsular Malaysia. AB - Mosquitoes are vectors of various human diseases in the tropics including yellow fever, dengue, malaria and West Nile virus. Mosquitoes can act as vectors between wildlife and humans, which is particularly important for diseases where wild animals serve as reservoirs of parasites in the absence of human infections. Research has mainly focused on the medical impacts of Anopheles, Aedes, Mansonia and Culex, however, very little attention has been directed towards other mosquito genera, especially those which act as vectors of diseases of wildlife. We have observed adults of Mimomyia (Etorleptiomyia) luzonensis (Ludlow, 1905) feeding on a toad, Ingerophrynus parvus, near an oil palm plantation settlement in Setia Alam, Selangor state, Peninsular Malaysia. Mimomyia is known to feed on reptiles and amphibians, and is a documented vector of several arboviruses, including West Nile virus. The observation of Mimomyia feeding on a common toad near a human settlement highlights a need to understand the relationships between mosquitoes, toads and humans from an ecological perspective. We report on-site observations of the feeding habit of Mimomyia; the first records from Malaysia. PMID- 28359830 TI - Taxonomy and polytene chromosomes of the Neotropical black fly Simulium perplexum (Diptera: Simuliidae). AB - Simulium perplexum Shelley, Maia-Herzog, Luna Dias & Couch is structurally similar in the pupal stage to Simulium guianense Wise, the main vector in the onchocerciasis foci of Amazonian Brazil and Venezuela. We report S. perplexum for the first time beyond its type locality (Guyana, Potaro River), describe its larva, redescribe its pupa, and provide a chromosomal comparison with S. guianense and other morphologically similar species. We collected it in two rivers in Ruropolis municipality, Para state, Brazil. The larvae can be distinguished from those of related species by having body cuticle with microscopic, translucent, and lanceolate setae. Chromosomal comparisons of S. perplexum and similar Brazilian species with available chromosome information (S. guianense, S. hirtipupa Lutz, and S. litobranchium Hamada, Pepinelli, Mattos Gloria & Luz), using S. guianense Cytoform A as the standard, show that S. perplexum has the nucleolar organizer uniquely in the middle of the short arm of chromosome I, whereas the other three species have this marker at the base of the long arm of chromosome I. All chromosome arms, except IIS and IIIS, of S. perplexum are rearranged, compared with S. guianense Cytoform A, suggesting that it is not closely related to this species or to S. litobranchium, as suggested by some authors, based on morphological features. PMID- 28359832 TI - RE: Incidence and risk factors for secondary malignancy in patients with neuroblastoma after treatment with 131-I-metaiodobenzylguanidine. Huibregtse K et al. European Journal of Cancer 2016. 66:144-152. PMID- 28359831 TI - Seizure induced by repetitive transcranial magnetic stimulation for central pain: Adapted guidelines for post-stroke patients. PMID- 28359833 TI - First report in Africa of two clinical isolates of Proteus mirabilis carrying Salmonella genomic island (SGI1) variants, SGI1-PmABB and SGI1-W. AB - Two Proteus mirabilis strains, designated PmTAN59 and PmKAF126, were isolated from two different Egyptian cities in 2014 and 2015, respectively. PmTAN59 was isolated from a sputum swab from a pneumonia patient in Tanta University Teaching Hospital. PmKAF126 was isolated from a patient with a diabetic foot infection in a hospital in the city of Kafr El-Sheikh. The two isolates were identified with bacterial small ribosomal RNA (16S rRNA) gene amplification and sequencing and tested for antimicrobial sensitivity with a Kirby-Bauer disk diffusion assay. The two strains were resistant to amoxicillin/clavulante, ampicillin, cefotaxime, cefoxitin, ceftriaxone, chloramphenicol, ciprofloxacin, colistin, gentamicin, kanamycin, nalidixic acid, spectinomycin, streptomycin, sulfamethoxazole/trimethoprime, and tetracycline, but sensitive to aztreonam, imipenem, and meropenem. Molecular characterization was used to map the entire backbone, including the multiple antibiotic resistance (MDR) region, of Salmonella genomic island 1 (SGI1). Both isolates carried a structure similar to SGI1, with two different MDR regions corresponding to SGI1-PmABB in PmTAN59 and SGI1-W in PmKAF126. SGI1-PmABB carried an integron of ~1.5kb with a two-gene cassette, aacCA5-aadA7, which confers resistance to gentamicin, streptomycin, and spectinomycin, whereas SGI1-W carried an integron of ~1.9kb containing aadA2 lnuF, which confers resistance to spectinomycin, streptomycin, and lincosamides. PmKAF126 carried the entire SGI1 sequence, however PmTAN59 carried a SGI1 structure with a deletion in the region from ORF S005 to ORF S009 and accompanied by insertion of IS1359 (1258bp). Furthermore, PmTAN59 carried class 2 integron of ~2.2kb containing dfrA1-sat2-aadA1. An ERIC-PCR analysis detected no clonal relationship between the two strains. Molecular screening for other antimicrobial resistance genes and a plasmid analysis indicated that PmTAN59 carried an IncFIB plasmid type. This strain also carried blaTEM-1 and the plasmid-mediated quinolone-resistance gene qnrA1. However, PmKAF126 carried no plasmids and no resistance gene other than that contained in the MDR region of SGI1 and floR gene conferring resistance to florfenicol. To the best of our knowledge, this is the first report of an SGI1-positive P. mirabilis strain in Egypt or on the entire African continent. PMID- 28359834 TI - Novel antigenic shift in HA sequences of H1N1 viruses detected by big data analysis. AB - The influenza virus H1N1 has been prevalent all over the world for nearly a century. Many studies on its evolutionary history, substitution rate and antigenicity-associated sites have been done with small datasets. To have a complete view, we analysed 3171 full-length HA sequences from human H1N1 viruses sampled from 1918 to 2016, and discovered a new clade has formed with sequences isolated in Iran. Based on genetic distance calculations, we revealed an uneven evolutionary rate among sequences isolated in different years. We also found that the HA1 fragment of the new clade is like that of viruses that existed in the 1930s, while the HA2 fragment is closely associated with strains isolated after the 2009 pandemic. This new, "mixed" HA sequence indicates a cryptic antigenic shift event occurred, and it should draw more attention to the new clade identified from sequences from Iran. PMID- 28359835 TI - Noninitiation and Noncompletion of HPV Vaccine Among English- and Spanish Speaking Parents of Adolescent Girls: A Qualitative Study. AB - OBJECTIVE: The Advisory Committee on Immunization Practices recommends routine human papillomavirus (HPV) vaccination for female adolescents aged 11 to 12 years, yet vaccination rates remain low. We conducted a qualitative study to understand English- and Spanish-speaking parents' reasons for noninitiation or noncompletion of the HPV vaccine series for their daughters. METHODS: Parents of female adolescents aged 12 to 15 years who had not initiated or not completed the HPV vaccine series were identified through administrative data in 2 large urban safety net health care systems in Colorado. Focus groups and in-depth interviews were conducted with English-speaking parents and in-depth interviews were conducted with Spanish-speaking parents. All data were recorded, transcribed, and analyzed for thematic content by experienced analysts using established qualitative content analysis techniques. RESULTS: Forty-one parents participated in the study. Thirty parents participated in individual interviews and 11 parents participated in 1 of 2 focus groups. The most common reasons for noninitiation and noncompletion among English-speaking parents included a low perceived risk of HPV infection, vaccine safety concerns, and distrust of government and/or medicine. In contrast, Spanish-speaking parents most often reported that providers had either not encouraged initiation of the HPV vaccine series or had not explained the necessity of completing the series. Some noninitiating parents, particularly Spanish-speaking ones, also cited concerns that vaccination would encourage sexual activity. CONCLUSIONS: The reasons for noninitiation and noncompletion of the HPV vaccine series differed substantially between English- and Spanish-speaking parents. To maximize uptake of HPV vaccine, varying approaches might be needed to effectively target specific populations. PMID- 28359837 TI - Symptoms from masked acrolein exposure suggest altered trigeminal reactivity in chemical intolerance. AB - BACKGROUND: Chemical intolerance (CI) is a widespread occupational and public health problem characterized by symptoms that reportedly result from low-levels of chemical exposure. The mechanisms behind CI are unknown, however modifications of the chemical senses (rather than toxic processes) have been suggested as key components. The aim of this study was to investigate whether individuals with self-reported CI report more sensory irritation during masked acrolein exposure compared to controls without CI. METHODS: Individuals with CI (n=18) and controls without CI (n=19) were exposed in an exposure chamber. Each participant took part in two exposure conditions - one with heptane (the masking compound), and one with heptane and acrolein at a dose below previously reported sensory irritation thresholds. The exposures lasted for 60min. Symptoms and confidence ratings were measured continuously throughout the exposure as were measurements of electrodermal activity and self-reported tear-film break-up time. Participants were blind to exposure condition. RESULTS: Individuals with CI, compared with controls reported greater sensory irritation in the eyes, nose and throat when exposed to acrolein masked with heptane. There was no difference during exposure to heptane. CONCLUSIONS: Masked exposure to acrolein at a concentration below the previously reported detection threshold is perceived as more irritating by individuals with CI compared with controls. The results indicate that there is altered trigeminal reactivity in those with CI compared to controls. PMID- 28359836 TI - Development and Pilot Implementation of a Trauma-Informed Care Curriculum for Pediatric Residents. PMID- 28359838 TI - Graphene oxide nanosheets induced genotoxicity and pulmonary injury in mice. AB - : Graphene and graphene-related materials have broadly applied in biomedical purposes due to their unique properties, thus safety evaluation of them is crucial. This study was performed to explore the genotoxic and pulmonary toxic potential of different doses of graphene oxide nanosheets' (GOs) in mice.A total of 90 male mature mice were randomly divided into six groups of fifteen mice per each, five groups were intraperitoneally injected by GO at doses of 10, 50, 100, 250 and 500MUg/kg b.w once weekly in addition to the control group that was injected intraperitoneally with 0.2ml saline solution. Five animals from each group were euthanized after 7, 28 and 56days post treatment. Evaluation of genotoxicity was performed through detection of chromosomal aberrations in bone marrow while assessment of lung injury was made by determination of DNA fragmentation in lung specimens using the alkali Comet assay, pulmonary oxidative markers estimation and finally histopathological investigations. Results revealed that GOs induced variable structural chromosomal aberrations (SCA) in bone marrow and DNA damage of lung cells that were time and dose dependent and represented by increase in%DNA in comet tail, tail moment and tail length and decrease in% head DNA in nuclei of lung of GOs-treated mice versus control groups in addition, GOs induced various changes in pulmonary oxidative stress parameters that were affected by dose and duration of treatment compared with the control as well as various pulmonary histopathological alterations were detected indicating lung injury. CONCLUSION: GO potentiate the induction of genotoxicity and pulmonary injury in mice in time and dose dependent manner. PMID- 28359839 TI - A novel flexible drill device enabling arthroscopic transosseous repair of Bankart lesions. AB - : We have developed a flexible drill device that makes arthroscopic transosseous repair possible, and report preliminary results. Twelve patients with post traumatic anterior inferior glenohumeral instability were selected. SURGICAL TECHNIQUE: the flexible drill device is inserted into the shoulder joint through the posterior portal and the guide pipe unit is placed 5mm posterior to the margin of the anterior glenoid rim. The flexible drill is driven through the glenoid with the power drill, creating a hole in the glenoid. A non-absorbable suture is passed through the hole and a sliding knot tying is performed over the capsule and labrum after completing stitches with the suture hook loaded. The same procedures are repeated in the 2, 3 and 4 o'clock positions of the glenoid. There was no recurrence of dislocation at the mean follow-up period of 52.3 months. The mean Rowe score was 89.5. PMID- 28359840 TI - SAMHD1 is active in cycling cells permissive to HIV-1 infection. AB - SAMHD1 is a triphosphohydrolase that restricts HIV-1 by limiting the intracellular dNTP pool required for reverse transcription. Although SAMHD1 is expressed and active/unphosphorylated in most cell lines, its restriction activity is thought to be relevant only in non-cycling cells. However, an in depth evaluation of SAMHD1 function and relevance in cycling cells is required. Here, we show that SAMHD1-induced degradation by HIV-2 Vpx affects the dNTP pool and HIV-1 replication capacity in the presence of the 3'-azido-3'-deoxythymidine (AZT) in cycling cells. Similarly, in SAMHD1 knockout cells, HIV-1 showed increased replicative capacity in the presence of nucleoside inhibitors, especially AZT, that was reverted by re-expression of wild type SAMHD1. Sensitivity to non-nucleoside inhibitors (nevirapine and efavirenz) or the integrase inhibitor raltegravir was not affected by SAMHD1. Combination of three mutations (S18A, T21A, T25A) significantly prevented SAMHD1 phosphorylation but did not significantly affect HIV-1 replication in the presence of AZT. Our results demonstrate that SAMHD1 is active in HIV-1 permissive cells, does not modify susceptibility to HIV-1 infection but strongly affects sensitivity to nucleoside inhibitors. PMID- 28359841 TI - Harnessing cAMP signaling in musculoskeletal regenerative engineering. AB - This paper reviews the most recent findings in the search for small molecule cyclic AMP analogues regarding their potential use in musculoskeletal regenerative engineering. PMID- 28359842 TI - History of traumatic brain injury in prison populations: A systematic review. AB - : Traumatic brain injury (TBI) can lead to cognitive, behavioural and social impairments. The relationship between criminality and a history of TBI has been addressed on several occasions. OBJECTIVE: The objective of this review was to present an update on current knowledge concerning the existence of a history of TBI in prison populations. METHODS: PubMed and PsycINFO databases were searched for relevant papers, using the PRISMA guidelines. We selected papers describing TBI prevalence among incarcerated individuals and some that also discussed the validity of such studies. RESULTS: Thirty-three papers were selected. The majority of the papers were on prison populations in Australia (3/33), Europe (5/33) and the USA (22/33). The selected studies found prevalence rates of the history of TBI ranging from 9.7% and 100%, with an average of 46% (calculated on a total population of 9342). However, the level of evidence provided by the literature was poor according to the French national health authority scale. The majority of the prisoners were males with an average age of 37. In most of the papers (25/33), prevalence was evaluated using a questionnaire. The influence of TBI severity on criminality could not be analysed because of a lack of data in the majority of papers. Twelve papers mentioned that several comorbidities (mental health problems, use of alcohol...) were frequently found among prisoners with a history of TBI. Two papers established the validity of the use of questionnaires to screen for a history of TBI. CONCLUSION: These results confirmed the high prevalence of a history of TBI in prison populations. However, they do not allow conclusions to be drawn about a possible link between criminality and TBI. Specific surveys need to be performed to study this issue. The authors suggest ways of improving the screening and healthcare made available to these patients. PMID- 28359844 TI - Sequencing of the Hepatitis D Virus RNA WHO International Standard. AB - BACKGROUND: Well-characterized, stable calibration materials are essential to standardize quantitative viral reporting. The preferred calibration materials are the WHO International Standards and secondary standards derived from them. In 2013, the 1st WHO International Standard for Hepatitis D Virus (HDV) RNA became available. During the course of assay development in our laboratory, differences between the published sequence (GenBank ID: HQ005371) and sequence we generated from the WHO HDV Standard were identified. OBJECTIVES: We sought to sequence the entire genome of the WHO HDV Standard and compare the results to the published sequence. STUDY DESIGN: RNA extracted from the WHO HDV Standard was used to generate five overlapping PCR products, including one covering the entire HDV genome, which were Sanger sequenced using standard dye-terminator chemistry. Total RNA from the WHO HDV Standard was also converted to a cDNA library generating 2.1 million sequencing reads on a NextSeq500 instrument. RESULTS: Sanger sequencing produced 32 overlapping, partial sequences of the HDV genome. RNA-seq resulted in 8100 HDV sequences covering the viral genome an average of 645-fold. Sanger and RNA-seq consensus sequences had 100% agreement and showed 89.0% nucleotide identity with the published WHO HDV Standard sequence. BLAST analysis revealed HQ005369 as the closest match with 99.2% nucleotide identity. CONCLUSIONS: HQ005369 was deposited in GenBank along with HQ005371 and seven others from a study of nine Turkish patients. A sample mix-up or clerical error may have resulted in the incorrect association of identifier and sequence. The correct nucleic acid sequence for standards is critical for test accuracy, optimization, calibration, and troubleshooting. PMID- 28359845 TI - Detection of cytomegalovirus drug resistance mutations in solid organ transplant recipients with suspected resistance. AB - BACKGROUND: Current guidelines recommend that treatment of resistant cytomegalovirus (CMV) in solid organ transplant (SOT) recipients must be based on genotypic analysis. However, this recommendation is not systematically followed. OBJECTIVES: To assess the presence of mutations associated with CMV resistance in SOT recipients with suspected resistance, their associated risk factors and the clinical impact of resistance. STUDY DESIGN: Using Sanger sequencing we prospectively assessed the presence of resistance mutations in a nation-wide prospective study between September 2013-August 2015. RESULTS: Of 39 patients studied, 9 (23%) showed resistance mutations. All had one mutation in the UL 97 gene and two also had one mutation in the UL54 gene. Resistance mutations were more frequent in lung transplant recipients (44% p=0.0068) and in patients receiving prophylaxis >=6 months (57% vs. 17%, p=0.0180). The mean time between transplantation and suspicion of resistance was longer in patients with mutations (239 vs. 100days, respectively, p=0.0046) as was the median treatment duration before suspicion (45 vs. 16days, p=0.0081). There were no significant differences according to the treatment strategies or the mean CMV load at the time of suspicion. Of note, resistance-associated mutations appeared in one patient during CMV prophylaxis and also in a seropositive organ recipient. Incomplete suppression of CMV was more frequent in patients with confirmed resistance. CONCLUSIONS: Our study confirms the need to assess CMV resistance mutations in any patient with criteria of suspected clinical resistance. Early confirmation of the presence of resistance mutations is essential to optimize the management of these patients. PMID- 28359843 TI - It takes a village to raise a branch: Cellular mechanisms of the initiation of axon collateral branches. AB - The formation of axon collateral branches from the pre-existing shafts of axons is an important aspect of neurodevelopment and the response of the nervous system to injury. This article provides an overview of the role of the cytoskeleton and signaling mechanisms in the formation of axon collateral branches. Both the actin filament and microtubule components of the cytoskeleton are required for the formation of axon branches. Recent work has begun to shed light on how these two elements of the cytoskeleton are integrated by proteins that functionally or physically link the cytoskeleton. While a number of signaling pathways have been determined as having a role in the formation of axon branches, the complexity of the downstream mechanisms and links to specific signaling pathways remain to be fully determined. The regulation of intra-axonal protein synthesis and organelle function are also emerging as components of signal-induced axon branching. Although much has been learned in the last couple of decades about the mechanistic basis of axon branching we can look forward to continue elucidating this complex biological phenomenon with the aim of understanding how multiple signaling pathways, cytoskeletal regulators and organelles are coordinated locally along the axon to give rise to a branch. PMID- 28359847 TI - Abeta propagation and strains: Implications for the phenotypic diversity in Alzheimer's disease. AB - The progressive nature of Alzheimer's disease (AD) is thought to occur, at least in part, by the self-replication and spreading of Abeta and Tau aggregates through a prion mechanism. Evidence now exists that structural variants of Abeta prions can propagate their distinct conformations through template-directed folding of naive Abeta peptides. This notion implicates that the first self propagating Abeta assembly to emerge in the brain dictates the conformation, anatomical spread and pace of subsequently formed deposits. It is hypothesized that a prion mechanism defines the molecular basis underlying the diverse clinicopathologic phenotypes observed across the spectrum of AD patients. Thus, distinct AD strains might require further sub-classification based on biochemical and structural characterization of aggregated Abeta. Here, we review the evidence for distinct, self-propagating Abeta strains, and discuss potential cellular mechanisms that might contribute to their manifestation. From this perspective, we also explore the implications of Abeta strains for current FDA-approved medical imaging probes and therapies for amyloid. Ultimately, the discovery of new molecular tools to differentiate Abeta strains and dissect the heterogeneity of AD may lead to the development of more informative diagnostics and strain specific therapeutics. PMID- 28359848 TI - Traditional Chinese medicine therapy reduces the catheter indwelling risk in dementia patients with difficult voiding symptoms. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Dementia is an international health issue in elder people. Indwelling catheters to address voiding problems in patients with dementia introduce risks of urinary tract infection or urethral trauma. Traditional Chinese medicine (TCM) is widely used to treat difficult voiding symptoms in Taiwan. We investigated the long-term clinical effects of TCM for reducing the risk of indwelling catheterization in dementia patients with difficult voiding symptoms. MATERIALS AND METHODS: We used National Health Insurance Research Database to conduct a retrospective study of dementia patients with difficult voiding symptoms between 1997 and 2012 in Taiwan. We collected medical data from the onset of dementia to post-catheter insertion. Cox regression proportional hazards model and cumulative incidence of the urinal catheterization curve were used to determine the association between catheter indwelling risk and TCM use. RESULTS: Data from 11069 patients with dementia was assessed, and 3982 participants who received medication for relief voiding symptoms were categorized into 2 groups: 2121 (53.3%) were TCM users and 1861 (46.7%) were TCM non-users with a mean follow-up period of 7.25 years. Cox regression demonstrated that using TCM may decrease the need for indwelling catheterization in patients with dementia (adjusted hazards ratio (aHR) =0.58, 95% confidence interval (95% CI): 0.52-0.66) compared to TCM non-users. A relationship between longer TCM use and reduced urinary retention with indwelling catheter use was observed, especially in patients who used TCM for >=200 days (aHR =0.46, 95% CI: 0.39-0.55). Ji-Sheng-Shen-Qi-Wan (aHR =0.44, 95% CI: 0.21 0.88), Wu-Ling-San (aHR =0.47, 95% CI: 0.16-0.92), Zhi-Bai-Di-Huang-Wan (aHR =0.50, 95% CI: 0.26-0.94), were the most 3 beneficial TCM formulae. CONCLUSIONS: The results of this study suggest that TCM is associated with a reduced risk of indwelling catheterization in patients with dementia, with enhanced benefits from longer durations of TCM use. PMID- 28359846 TI - Long-term effect of neonatal inhibition of APP gamma-secretase on hippocampal development in the Ts65Dn mouse model of Down syndrome. AB - Neurogenesis impairment is considered a major determinant of the intellectual disability that characterizes Down syndrome (DS), a genetic condition caused by triplication of chromosome 21. Previous evidence obtained in the Ts65Dn mouse model of DS showed that the triplicated gene APP (amyloid precursor protein) is critically involved in neurogenesis alterations. In particular, excessive levels of AICD (amyloid precursor protein intracellular domain) resulting from APP cleavage by gamma-secretase increase the transcription of Ptch1, a Sonic Hedgehog (Shh) receptor that keeps the mitogenic Shh pathway repressed. Previous evidence showed that neonatal treatment with ELND006, an inhibitor of gamma-secretase, reinstates the Shh pathway and fully restores neurogenesis in Ts65Dn pups. In the framework of potential therapies for DS, it is extremely important to establish whether the positive effects of early intervention are retained after treatment cessation. Therefore, the goal of the current study was to establish whether early treatment with ELND006 leaves an enduring trace in the brain of Ts65Dn mice. Ts65Dn and euploid pups were treated with ELND006 in the postnatal period P3-P15 and the outcome of treatment was examined at ~one month after treatment cessation. We found that in treated Ts65Dn mice the pool of proliferating cells in the hippocampal dentate gyrus (DG) and total number of granule neurons were still restored as was the number of pre- and postsynaptic terminals in the stratum lucidum of CA3, the site of termination of the mossy fibers from the DG. Accordingly, patch-clamp recording from field CA3 showed functional normalization of the input to CA3. Unlike in field CA3, the number of pre- and postsynaptic terminals in the DG of treated Ts65Dn mice was no longer fully restored. The finding that many of the positive effects of neonatal treatment were retained after treatment cessation provides proof of principle demonstration of the efficacy of early inhibition of gamma-secretase for the improvement of brain development in DS. PMID- 28359849 TI - A review on traditional uses, phytochemistry, pharmacology, pharmacokinetics and toxicology of the genus Peganum. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The plants of the genus Peganum have a long history as a Chinese traditional medicine for the treatment of cough, hypertension, diabetes, asthma, jaundice, colic, lumbago, and many other human ailments. Additionally, the plants can be used as an amulet against evil-eye, dye and so on, which have become increasingly popular in Asia, Iran, Northwest India, and North Africa. AIM OF THE REVIEW: The present paper reviewed the ethnopharmacology, phytochemistry, analytical methods, biological activities, metabolism, pharmacokinetics, toxicology, and drug interaction of the genus Peganum in order to assess the ethnopharmacological use and to explore therapeutic potentials and future opportunities for research. MATERIALS AND METHODS: Information on studies of the genus Peganum was gathered via the Internet (using Google Scholar, Baidu Scholar, Elsevier, ACS, Pudmed, Web of Science, CNKI and EMBASE) and libraries. Additionally, information was also obtained from some local books, PhD and MS's dissertations. RESULTS: The genus Peganum has played an important role in traditional Chinese medicine. The main bioactive metabolites of the genus include alkaloids, flavonoids, volatile oils, etc. Scientific studies on extracts and formulations revealed a wide range of pharmacological activities, such as cholinesterase and monoamine oxidase inhibitory activities, antitumor, anti-hypertension, anticoagulant, antidiabetic, antimicrobial, insecticidal, antiparasidal, anti-leishmaniasis, antioxidant, and anti-inflammatory. CONCLUSIONS: Based on this review, there is some evidence for extracts' pharmacological effects on Alzheimer's and Parkinson's diseases, cancer, diabetes, hypertension. Some indications from ethnomedicine have been confirmed by pharmacological effects, such as the cholinesterase, monoamine oxidase and DNA topoisomerase inhibitory activities, hypoglycemic and vasodilation effects of this genus. The available literature showed that most of the activities of the genus Peganum can be attributed to the active alkaloids. Data regarding many aspects of the genus such as mechanisms of actions, metabolism, pharmacokinetics, toxicology, potential drug interactions with standard-of-care medications is still limited which call for additional studies particularly in humans. Further assessments and clinical trials should be performed before it can be integrated into medicinal practices. PMID- 28359850 TI - Cancer chemopreventive activity of compounds isolated from Waltheria indica. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Waltheria indica L. is traditionally used in several countries against inflammatory related diseases and cancer, mainly as a decoction of the aerial parts. AIM OF THE STUDY: The transcription factor NF kappaB is known to induce tumor promotion and progression and is considered a major player in inflammation-driven cancers. Therefore, inhibitors of this pathway possess cancer chemopreventive and chemotherapeutic activities. This study aimed first to confirm the use of Waltheria indica as a traditional anti inflammatory remedy by assessing the NF-kappaB inhibitory activity and then to identify the major bioactive compounds. The isolated compounds were also tested for their QR inducing property, a complementary strategy in cancer chemoprevention able to target tumor initiation. Finally, the relevance of in vitro results was examined by investigating the occurrence of the active compounds in traditional preparations. MATERIALS AND METHODS: Compounds were isolated from the dichloromethane extract of the aerial parts using flash chromatography and semi-preparative HPLC. NF-kappaB inhibitory activity of pure compounds from Waltheria indica was assessed using a luciferase reporter assay in HEK293 cells. Their QR inducing activity was also assessed in Hepa1c1c7 cells. RESULTS: Twenty-nine compounds, of which 5 are new, were obtained from the dichloromethane extract and tested for their cancer chemoprevention activity. Eleven compounds inhibited NF-kappaB and/or induced QR in the low to mid uM range. Chrysosplenol E (20) was active in both tests. Two of the most potent NF kappaB inhibitors, waltherione A (4) and waltherione C (5), as well as 20 were found in the traditional decoction, in which 4 and 5 were major compounds. CONCLUSION: The presence of potent NF-kappaB inhibitors and QR inducing compounds in the decoction of the aerial parts of Waltheria indica supports its traditional use in inflammatory-related diseases and cancer chemoprevention. PMID- 28359851 TI - Characterization of a protein-bound polysaccharide from Herba Epimedii and its metabolic mechanism in chronic fatigue syndrome. AB - OBJECTIVES: Herba Epimedii is one of the famous Traditional Chinese Medicines used to treat the chronic fatigue syndrome (CFS). The polysaccharides are the main active components in H. epimedii. The aim of this study is to discover the therapeutic effect and metabolic mechanism of H. epimedii polysaccharides against CFS. METHODS: The polysaccharide conjugates named HEP2-a were isolated from the leaves of H. epimedii using a water extraction method, and the general physicochemical properties of HEP2-a were analysed. In addition, a CFS rat model was established, and then, urinary metabonomic studies were performed using gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) in combination with multivariate statistical analysis. RESULTS: The physicochemical properties revealed that HEP2-a had an average molecular weight of 13.6*104Da and consisted of mannose (4.41%), rhamnose (5.43%), glucose (31.26%), galactose (27.07%), arabinose (23.43%), and galacturonic acid (8.40%). The amino acids in HEP2-a include glutamate, cysteine, leucine, tyrosine, lysine, and histidine. Molecular morphology studies revealed many highly curled spherical particles with diameters of 5-10um in solids and 100-200nm for particles in water. Five metabolites in the HEP2-a group were oppositely and significantly changed compared to the CFS model group. CONCLUSION: Two metabolic pathways were identified as significant metabolic pathways involved with HEP2-a. The therapeutic effects of HEP2-a on CFS were partially due to the restoration of these disturbed pathways. PMID- 28359852 TI - Lithium and memantine improve spatial memory impairment and neuroinflammation induced by beta-amyloid 1-42 oligomers in rats. AB - Alzheimer's disease (AD) is the most common cause of dementia in the elderly. The main hallmarks of this disease include progressive cognitive dysfunction and an accumulation of soluble oligomers of beta-amyloid (Abeta) 1-42 peptide. In this research, we show the effects of lithium and memantine on spatial memory and neuroinflammation in an Abeta1-42 oligomers-induced animal model of dementia in rats. Abeta 1-42 oligomers were administered intrahippocampally to male wistar rats to induce dementia. Oral treatments with memantine (5mg/kg), lithium (5mg/kg), or both drugs in combination were performed over a period of 17days. 14days after the administration of the Abeta1-42 oligomers, the radial arm-maze task was performed. At the end of the test period, the animals were euthanized, and the frontal cortex and hippocampus were removed for use in our analysis. Our results showed that alone treatments with lithium or memantine ameliorate the spatial memory damage caused by Abeta1-42. The animals that received combined doses of lithium and memantine showed better cognitive performance in their latency time and total errors to find food when compared to the results from alone treatments. Moreover, in our study, lithium and/or memantine were able to reverse the decreases observed in the levels of interleukin (IL)-4 that were induced by Abeta1-42 in the frontal cortex. In the hippocampus, only memantine and the association of memantine and lithium were able to reverse this effect. Alone doses of lithium and memantine or the association of lithium and memantine caused reductions in the levels of IL-1beta in the frontal cortex and hippocampus, and decreased the levels of TNF-alpha in the hippocampus. Taken together, these data suggest that lithium and memantine might be a potential therapy against cognitive impairment and neuroinflammation induced by Abeta1-42, and their association may be a promising alternative to be investigated in the treatment of AD-like dementia. PMID- 28359853 TI - Adult neurogenesis reduction by a cytostatic treatment improves spatial reversal learning in rats. AB - Adult neurogenesis in the dentate gyrus adds a substantial number of new functional neurons to the hippocampus network in rodents. To date, however, the function of these new granule cells remains unclear. We conducted an experiment to assess the contribution of adult neurogenesis in the dentate gyrus to acquisition and reversal learning in a task that predominantly requires generalization of a rule. Young adult male Long-Evans rats were repeatedly administered either a cytostatic temozolomide or saline for a period of four weeks (3 injections per week). Post treatment, animals were injected with bromodeoxyuridine to quantify adult neurogenesis in the dentate gyrus. For behavioral assessment we used hippocampus-dependent active place avoidance with reversal in a Carousel maze. Animals first learned to avoid a 60 degrees sector on the rotating arena. Afterwards, sector was relocated to the opposite side of the rotating arena (reversal). The administration of temozolomide significantly improved the reversal performance compared to saline-treated rats. Our results suggest a significant, level-dependent, improvement of reversal learning in animals with reduced adult neurogenesis in hippocampus. PMID- 28359854 TI - Optimizing culture conditions for production of intra and extracellular inulinase and invertase from Aspergillus niger ATCC 20611 by response surface methodology (RSM). AB - The aim of this study was obtain a model that maximizes growth and production of inulinase and invertase by Aspergillus niger ATCC 20611, employing response surface methodology (RSM). The RSM with a five-variable and three-level central composite design (CCD) was employed to optimize the medium composition. Results showed that the experimental data could be appropriately fitted into a second order polynomial model with a coefficient of determination (R2) more than 0.90 for all responses. This model adequately explained the data variation and represented the actual relationships between the parameters and responses. The pH and temperature value of the cultivation medium were the most significant variables and the effects of inoculum size and agitation speed were slightly lower. The intra-extracellular inulinase, invertase production and biomass content increased 10-32 fold in the optimized medium condition (pH 6.5, temperature 30 degrees C, 6% (v/v), inoculum size and 150rpm agitation speed) by RSM compared with medium optimized through the one-factor-at-a-time method. The process development and intensification for simultaneous production of intra extracellular inulinase (exo and endo inulinase) and invertase from A. niger could be used for industrial applications. PMID- 28359855 TI - Draft genome sequence of Streptomyces sp. strain F1, a potential source for glycoside hydrolases isolated from Brazilian soil. AB - Here, we show the draft genome sequence of Streptomyces sp. F1, a strain isolated from soil with great potential for secretion of hydrolytic enzymes used to deconstruct cellulosic biomass. The draft genome assembly of Streptomyces sp. strain F1 has 69 contigs with a total genome size of 8,142,296bp and G+C 72.65%. Preliminary genome analysis identified 175 proteins as Carbohydrate-Active Enzymes, being 85 glycoside hydrolases organized in 33 distinct families. This draft genome information provides new insights on the key genes encoding hydrolytic enzymes involved in biomass deconstruction employed by soil bacteria. PMID- 28359857 TI - Effect of e-beam sterilization on the in vivo performance of conventional UHMWPE tibial plates for total knee arthroplasty. AB - : Although the introduction of highly cross-linked polyethylene is effective in reducing the amount of wear, there are still major concerns regarding the use of this material in total knee arthroplasty (TKA), essentially due to the reduction of fatigue resistance and toughness. Monitoring the in vivo performance of different types of UHMWPE is a much needed task to tackle the lack of information on which should be the most reliable choice for TKA. The present study was aimed at investigating the mid-term degradation of electron beam sterilized conventional UHMWPE tibial plates. Visual inspection enabled to grade the surface damage of 12 retrievals according to the Hood's score: the total wear damage correlates to the in vivo time (Spearman's rho=0.681, p<0.05) and BMI (rho=0.834, p<0.001). Surface degradation was less severe than that quantified in similar studies on gamma-sterilized UHMWPE. Raman and infra-red spectroscopies were utilized to unfold the microstructural modifications. In the load zone, polyethylene whitened damage regions were noticed in the inserts implanted longer than 1year, in which oxidation index (OI) is clearly higher than 1 (max 8). The maximum OI (rho=0.802, p<0.005) and alphac (rho=0.816, p<0.005) correlate to the implantation time in the load zone. The crystallinity increased along with the extent of oxidation. Concentration of absorbed species from synovial fluid is higher in the contact zone and correlates to maximum OI (Spearman's rho=0.699, p=0.011). Absorption was promoted in the contact area by the mechanical action of the femoral counterpart and it exacerbated the oxidative degradation in retrievals with high concentration of absorbed species. In the non-load zone, mild but detectable oxidation was observed, probably due to free radicals trapped after sterilization. STATEMENT OF SIGNIFICANCE: Although several clinical studies on retrieved tibial bearings have been published so far, monitoring and comparing the in vivo performance of different types of UHMWPE is still a much needed task. The present study reports for the first time results on the effect of sterilization by electron beam on the mid-term in vivo performance of conventional UHMWPE tibial plates. In the present investigation, visual inspection of wear damage based on the Hood's scoring method, Raman micro spectroscopy and Fourier-transformed infrared spectroscopy were utilized to unveil the damage, the microstructural modifications and the oxidation occurred during implantation. The findings of this investigation have been discussed and compared to previous clinical studies on gamma-air sterilized, gamma-inert sterilized tibial bearings. PMID- 28359856 TI - Evaluation of short-chain-length polyhydroxyalkanoate accumulation in Bacillus aryabhattai. AB - This study was focused on the polyhydroxybutyrate (PHB) accumulation property of Bacillus aryabhattai isolated from environment. Twenty-four polyhydroxyalkanoate (PHA) producers were screened out from sixty-two environmental bacterial isolates based on Sudan Black B colony staining. Based on their PHA accumulation property, six promising isolates were further screened out. The most productive isolate PHB10 was identified as B. aryabhattai PHB10. The polymer production maxima were 3.264g/L, 2.181g/L, 1.47g/L, 1.742g/L and 1.786g/L in glucose, fructose, maltose, starch and glycerol respectively. The bacterial culture reached its stationary and declining phases at 18h and 21h respectively and indicated growth-associated PHB production. Nuclear Magnetic Resonance (NMR) spectra confirmed the material as PHB. The material has thermal stability between 30 and 140 degrees C, melting point at 170 degrees C and maximum thermal degradation at 287 degrees C. The molecular weight and poly dispersion index of the polymer were found as 199.7kDa and 2.67 respectively. The bacterium B. aryabhattai accumulating PHB up to 75% of cell dry mass utilizing various carbon sources is a potential candidate for large scale production of bacterial polyhydroxybutyrate. PMID- 28359858 TI - Surface immobilized antibody orientation determined using ToF-SIMS and multivariate analysis. AB - : Antibody orientation at solid phase interfaces plays a critical role in the sensitive detection of biomolecules during immunoassays. Correctly oriented antibodies with solution-facing antigen binding regions have improved antigen capture as compared to their randomly oriented counterparts. Direct characterization of oriented proteins with surface analysis methods still remains a challenge however surface sensitive techniques such as Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) provide information-rich data that can be used to probe antibody orientation. Diethylene glycol dimethyl ether plasma polymers (DGpp) functionalized with chromium (DGpp+Cr) have improved immunoassay performance that is indicative of preferential antibody orientation. Herein, ToF SIMS data from proteolytic fragments of anti-EGFR antibody bound to DGpp and DGpp+Cr are used to construct artificial neural network (ANN) and principal component analysis (PCA) models indicative of correctly oriented systems. Whole antibody samples (IgG) test against each of the models indicated preferential antibody orientation on DGpp+Cr. Cross-reference between ANN and PCA models yield 20 mass fragments associated with F(ab')2 region representing correct orientation, and 23 mass fragments associated with the Fc region representing incorrect orientation. Mass fragments were then compared to amino acid fragments and amino acid composition in F(ab')2 and Fc regions. A ratio of the sum of the ToF-SIMS ion intensities from the F(ab')2 fragments to the Fc fragments demonstrated a 50% increase in intensity for IgG on DGpp+Cr as compared to DGpp. The systematic data analysis methodology employed herein offers a new approach for the investigation of antibody orientation applicable to a range of substrates. STATEMENT OF SIGNIFICANCE: Controlled orientation of antibodies at solid phases is critical for maximizing antigen detection in biosensors and immunoassays. Surface-sensitive techniques (such as ToF-SIMS), capable of direct characterization of surface immobilized and oriented antibodies, are under utilized in current practice. Selection of a small number of mass fragments for analysis, typically pertaining to amino acids, is commonplace in literature, leaving the majority of the information-rich spectra unanalyzed. The novelty of this work is the utilization of a comprehensive, unbiased mass fragment list and the employment of principal component analysis (PCA) and artificial neural network (ANN) models in a unique methodology to prove antibody orientation. This methodology is of significant and broad interest to the scientific community as it is applicable to a range of substrates and allows for direct, label-free characterization of surface bound proteins. PMID- 28359859 TI - Raman spectroscopy of biomedical polyethylenes. AB - With the development of three-dimensional Raman algorithms for local mapping of oxidation and plastic strain, and the ability to resolve molecular orientation patterns with microscopic spatial resolution, there is an opportunity to re examine many of the foundations on which our understanding of biomedical grade ultra-high molecular weight polyethylenes (UHMWPEs) are based. By implementing polarized Raman spectroscopy into an automatized tool with an improved precision in non-destructively resolving Euler angles, oxidation levels, and microscopic strain, we become capable to make accurate and traceable measurements of the in vitro and in vivo tribological responses of a variety of commercially available UHMWPE bearings for artificial hip and knee joints. In this paper, we first review the foundations and the main algorithms for Raman analyses of oxidation and strain of biomedical polyethylene. Then, we critically re-examine a large body of Raman data previously collected on different polyethylene joint components after in vitro testing or in vivo service, in order to shed new light on an area of particular importance to joint orthopedics: the microscopic nature of UHMWPE surface degradation in the human body. A complex scenario of physical chemistry appears from the Raman analyses, which highlights the importance of molecular-scale phenomena besides mere microstructural changes. The availability of the Raman microscopic probe for visualizing oxidation patterns unveiled striking findings related to the chemical contribution to wear degradation: chain breaking and subsequent formation of carboxylic acid sites preferentially occur in correspondence of third-phase regions, and they are triggered by emission of dehydroxylated oxygen from ceramic oxide counterparts. These findings profoundly differ from more popular (and simplistic) notions of mechanistic tribology adopted in analyzing joint simulator data. Statement of Significance This review was dedicated to the theoretical and experimental evaluation of the commercially available biomedical polyethylene samples by Raman spectroscopy with regard to their molecular textures, oxidative patterns, and plastic strain at the microscopic level in the three dimensions of the Euclidean space. The main achievements could be listed, as follow: (i) visualization of molecular patterns at the surface of UHMWPE bearings operating against metallic components; (ii) differentiation between wear and creep deformation in retrievals; (iii) non destructive mapping of oxidative patterns; and, (iv) the clarification of chemical interactions between oxide/non-oxide ceramic heads and advanced UHMWPE liners. PMID- 28359861 TI - Corrections. PMID- 28359863 TI - Ketamine and ECT: better alone than together? PMID- 28359862 TI - Ketamine augmentation of electroconvulsive therapy to improve neuropsychological and clinical outcomes in depression (Ketamine-ECT): a multicentre, double-blind, randomised, parallel-group, superiority trial. AB - BACKGROUND: The use of electroconvulsive therapy (ECT) is limited by concerns about its cognitive adverse effects. Preliminary evidence suggests that administering the glutamate antagonist ketamine with ECT might alleviate cognitive adverse effects and accelerate symptomatic improvement; we tested this in a randomised trial of low-dose ketamine. METHODS: In this multicentre, randomised, parallel-group study in 11 ECT suites serving inpatient and outpatient care settings in seven National Health Service trusts in the North of England, we recruited severely depressed patients, who were diagnosed as having unipolar or bipolar depressive episodes defined as moderate or severe by DSM-IV criteria, aged at least 18 years, and were able and willing to provide written consent to participate in the study. Patients were randomly assigned (1:1) to ketamine (0.5 mg/kg intravenous bolus) or saline adjunctive to the anaesthetic for the duration of their ECT course. Patients and assessment and ECT treatment teams were masked to treatment allocation, although anaesthetists administering the study medication were not. We analysed the primary outcome, Hopkins Verbal Learning Test-Revised delayed verbal recall (HVLT-R-DR) after four ECT treatments, using a Gaussian repeated measures model in all patients receiving the first ECT treatment. In the same population, safety was assessed by adverse effect monitoring. This trial was registered with International Standard Randomised Controlled Trial Number, number ISRCTN14689382. FINDINGS: Between early December, 2012, and mid-June, 2015, 628 patients were screened for eligibility, of whom 79 were randomly assigned to treatment (40 in the ketamine group vs 39 in the saline group). Ketamine (mean 5.17, SD 2.92), when compared with saline (5.54, 3.42), had no benefit on the primary outcome (HVLT-R-DR; difference in means -0.43 [95% CI -1.73 to 0.87]). 15 (45%) of 33 ketamine treated patients compared with 10 (27%) of 37 patients receiving saline experienced at least one adverse event which included two (6%) of 33 patients who had ketamine-attributable transient psychological effects. Psychiatric adverse events were the most common in both groups (six [27%] of 22 adverse events in the ketamine group vs seven [54%] of 13 in the saline group). INTERPRETATION: No evidence of benefit for ketamine was found although the sample size used was small; however, the results excluded greater than a small to moderate benefit with 95% confidence. The results do not support the use of adjunctive low-dose ketamine in routine ECT treatment. FUNDING: National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme, an MRC and NIHR partnership. PMID- 28359864 TI - Reduction in adolescent depression after contact with mental health services: a longitudinal cohort study in the UK. PMID- 28359860 TI - Factors affecting increased risk for substance use disorders following traumatic brain injury: What we can learn from animal models. AB - Recent studies have helped identify multiple factors affecting increased risk for substance use disorders (SUDs) following traumatic brain injury (TBI). These factors include age at the time of injury, repetitive injury and TBI severity, neurocircuits, neurotransmitter systems, neuroinflammation, and sex differences. This review will address each of these factors by discussing 1) the clinical and preclinical data identifying patient populations at greatest risk for SUDs post TBI, 2) TBI-related neuropathology in discrete brain regions heavily implicated in SUDs, and 3) the effects of TBI on molecular mechanisms that may drive substance abuse behavior, like dopaminergic and glutamatergic transmission or neuroimmune signaling in mesolimbic regions of the brain. Although these studies have laid the groundwork for identifying factors that affect risk of SUDs post TBI, additional studies are required. Notably, preclinical models have been shown to recapitulate many of the behavioral, cellular, and neurochemical features of SUDs and TBI. Therefore, these models are well suited for answering important questions that remain in future investigations. PMID- 28359865 TI - Transcriptomic analysis of two Beauveria bassiana strains grown on cuticle extracts of the silkworm uncovers their different metabolic response at early infection stage. AB - Beauveria bassiana is an important entomopathogenic fungus which not only widely distributes in the environment but also shows phenotypic diversity. However, the mechanism of pathogenic differences among natural B. bassiana strains has not been revealed at transcriptome-wide level. In the present study, in order to explore the mechanism, two B. bassiana strains with different pathogenicity were isolated from silkworms (Bombyx mori L.) and selected to analyze the gene expression of early stage by culturing on cuticle extracts of the silkworm and using RNA-sequencing technique. A total of 2108 up-regulated and 1115 down regulated genes were identified in B. bassiana strain GXsk1011 (hyper-virulent strain) compared with B. bassiana strain GXtr1009 (hypo-virulent strain), respectively. The function categorization of differential expressed genes (DEGs) showed that most of them involved in metabolic process, biosynthesis of secondary metabolites, catalytic activity, and some involved in nutrition uptake, adhesion and host defense were also noted. Based on our data, distinct pathogenicity among different strains of B. bassiana may largely attribute to unique gene expression pattern which differed at very early infection process. Most of the genes involved in conidia adhesion, cuticle degradation and fungal growth were up regulated in hyper-virulent B. bassiana strain GXsk1011. Furthermore, in combination with fungal growth analysis, our research provided a clue that fungal growth may also play an important role during early infection process. The results will help to explain why different B. bassiana strains show distinct pathogenicity on the same host even under same condition. Moreover, the transcriptome data were also useful for screening potential virulence factors. PMID- 28359866 TI - mRNA imaging in the chloroplast of Chlamydomonas reinhardtii using the light-up aptamer Spinach. AB - Light-up aptamers are practical tools to image RNA localization in vivo. A now classical light-up aptamer system is the combination of the 3,5-difluoro-4 hydroxybenzylidene (DFHBI) fluorogen and the RNA aptamer Spinach, which has been successfully used in bacterial and mammalian cells. However, light-up aptamers have not been used in algae. Here, we show that a simple vector, carrying Spinach, transcriptionally fused to the aphA-6 gene, can be effectively used to generate a functional light-up aptamer in the chloroplast of Chlamydomonas reinhardtii. After incubation with DFHBI, lines expressing the aphA-6/Spinach mRNA were observed with laser confocal microscopy to evaluate the functionality of the light-up aptamer in the chloroplast of C. reinhardtii. Clear and strong fluorescence was localized to the chloroplast, in the form of discrete spots. There was no background fluorescence in the strain lacking Spinach. Light-up aptamers could be further engineered to image RNA or to develop genetically encoded biosensors in algae. PMID- 28359867 TI - Plant tissue cultures as sources of new ene- and ketoreductase activities. AB - While many redox enzymes are nowadays available for synthetic applications, the toolbox of ene-reductases is still limited. Consequently, the screening for these enzymes from diverse sources in the search of new biocatalyst suitable for green chemistry approaches is needed. Among 13 plant tissue cultures, Medicago sativa and Tessaria absinthioides calli, as well as Capsicum annuum hairy roots, were selected due to their ability to hydrogenate the CC double bond of the model substrate 2-cyclohexene-1-one. The three axenic plant cultures showed more preference toward highly activated molecules such as nitrostyrene and maleimide rather than the classical substrates of the well-known Old Yellow Enzymes, resembling the skills of the NAD(P)H-dependent flavin-independent enzymes. When the three biocatalytic systems were applied in the reduction of chalcones, T. absinthioides showed high chemoselectivity toward the CC double bond whereas the other two demonstrated abilities to biohydrogenate the CC double bounds and the carbonyl groups in a sequential fashion. PMID- 28359868 TI - Heterologous expression of the Halothiobacillus neapolitanus carboxysomal gene cluster in Corynebacterium glutamicum. AB - Compartmentalization represents a ubiquitous principle used by living organisms to optimize metabolic flux and to avoid detrimental interactions within the cytoplasm. Proteinaceous bacterial microcompartments (BMCs) have therefore created strong interest for the encapsulation of heterologous pathways in microbial model organisms. However, attempts were so far mostly restricted to Escherichia coli. Here, we introduced the carboxysomal gene cluster of Halothiobacillus neapolitanus into the biotechnological platform species Corynebacterium gluta-micum. Transmission electron microscopy, fluorescence microscopy and single molecule localization microscopy suggested the formation of BMC-like structures in cells expressing the complete carboxysome operon or only the shell proteins. Purified carboxysomes consisted of the expected protein components as verified by mass spectrometry. Enzymatic assays revealed the functional production of RuBisCO in C. glutamicum both in the presence and absence of carboxysomal shell proteins. Furthermore, we could show that eYFP is targeted to the carboxysomes by fusion to the large RuBisCO subunit. Overall, this study represents the first transfer of an alpha-carboxysomal gene cluster into a Gram-positive model species supporting the modularity and orthogonality of these microcompartments, but also identified important challenges which need to be addressed on the way towards biotechnological application. PMID- 28359869 TI - Spondylodiskitis after Dilatation of Esophageal Radiation Stenosis: A Suspect for Metastasis. PMID- 28359870 TI - Adsorption of emerging contaminant metformin using graphene oxide. AB - The occurrence of emerging contaminants in our water resources poses potential threats to the livings. Due to the poor treatment in wastewater management, treatment technologies are needed to effectively remove these products for living organism safety. In this study, Graphene oxide (GO) was tested for the first time for its capacity to remove a kind of emerging wastewater contaminants, metformin. The research was conducted by using a series of systematic adsorption and kinetic experiments. The results indicated that GO could rapidly and efficiently reduce the concentration of metformin, which could provide a solution in handling this problem. The uptake of metformin on the graphene oxide was strongly dependent on temperature, pH, ionic strength, and background electrolyte. The adsorption kinetic experiments revealed that almost 80% removal of metformin was achieved within 20 min for all the doses studied, corresponding to the relatively high k1 (0.232 min-1) and k2 (0.007 g mg-1 min-1) values in the kinetic models. It indicated that the highest adsorption capacity in the investigated range (qm) of GO for metformin was at pH 6.0 and 288 K. Thermodynamic study indicated that the adsorption was a spontaneous (DeltaG0 < 0) and exothermic (DeltaH0 < 0) process. The adsorption of metformin increased when the pH values changed from 4.0 to 6.0, and decreased adsorption were observed at pH 6.0-11.0. GO still exhibited excellent adsorption capacity after several desorption/adsorption cycles. Besides, both so-called pi-pi interactions and hydrogen bonds might be mainly responsible for the adsorption of metformin onto GO. PMID- 28359871 TI - Evaluation of functional parameters in the occlusion of complete denture wearers before and after prosthetic treatment. AB - PURPOSE: The aim of the study was to evaluate functional parameters of the occlusion in complete denture wearers before and after prosthetic treatment. METHODS: The sample used as the basis for the present study consisted of 50 healthy Caucasian patients (35 women and 15 men), aged from 44 to 86 years (mean=69.18+/-10), with a total deficiency of teeth. All patients received new complete dentures. Each patient underwent lateral radiograph with the presence of complete dentures, both before (initially existing dentures) and after the prosthetic treatment (new restorations). Cephalometric analysis was based on the Ricketts and McNamara criteria. In order to assess the functional parameters of the occlusion T-scan III analysis was conducted. The following parameters were measured: occlusion - and disclusion time. RESULTS: Statistically significant differences of functional parameters obtained before and 3 months after the treatment were noted in the whole study group. Both before and after therapy occlusion time was longer in women than in men. No statistically significant link was noted between functional parameters in occlusion and age of the patients, denture wearing time, and edentulous period. Some relationships were noted between occlusion time and cephalometric parameters associated with anterior facial height. CONCLUSION: Reconstruction of the surface of artificial teeth and vertical occlusal dimension affects the sustainability of parameters of occlusion and balance of forces in centric occlusion. The progressive shortening of occlusion time during the period of monitoring may be considered as a sign of progressive adaptation. PMID- 28359872 TI - Microbial colonization at the implant-abutment interface and its possible influence on periimplantitis: A systematic review and meta-analysis. AB - PURPOSE: The aim of this systematic review and meta-analysis was to evaluate the microbial colonization at the implant-abutment interfaces (IAI) on bone-level implants and to identify possible association with peri-implant conditions. STUDY SELECTION: The focus question aimed to answer whether two-piece osseointegrated implants, in function for at least 1 year, in human, relate to higher bacterial count and the onset of periimplantitis, compared to healthy peri-implant conditions. Search strategy encompassed the on-line (MedLine, Google scholar, Cochrane library) literature from 1990 up to March 2015 published in English using combinations of MeSH (Medical Subject Headings) and search terms. Quality assessment of selected full-text articles was performed according to the ARRIVE and CONSORT statement guidelines. For data analysis, the total bacterial count of Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Prevotella intermedia, and Fusobacterium nucleatum was calculated and compared to IAI with or without peri-implant pathology. RESULTS: A total of 14 articles, reporting data from 1126 implants, fulfilled the inclusion criteria and subjected to quality assessment. The selected studies revealed contamination of the IAI, in patients who received two-piece implant systems. Meta-analysis indicated significant difference in total bacterial count between implants affected by periimplantitis versus healthy peri-implant tissues (0.387+/-0.055; 95% CI 0.279 0.496). Less bacterial counts were identified in the healthy IAI for all the investigated gram-negative bacteria except for T. forsythia. CONCLUSIONS: Significantly higher bacterial counts were found for periodontal pathogenic bacteria within the IAI of implants in patients with periimplantitis compared to those implants surrounded by healthy peri-implant tissues. PMID- 28359873 TI - Neural correlates of emotional inhibitory control in autism spectrum disorders. AB - Atypical inhibitory function is often present in individuals with autism spectrum disorder (ASD), who may have difficulty suppressing context-inappropriate behaviors. We investigated the neural correlates of inhibition in ASD in response to both emotional and non-emotional stimuli using an fMRI Go/NoGo inhibition task with human faces and letters. We also related neural activation to behavioral dysfunction in ASD. Our sample consisted of 19 individuals with ASD (mean age=25.84) and 22 typically developing (TD) control participants (mean age=29.03). As expected, no group differences in task performance (inhibition accuracy and response time) were found. However, adults with ASD exhibited greater angular gyrus activation in face response inhibition blocks, as well as greater fusiform gyrus activation than controls, in a condition comparing face inhibition to letter inhibition. In contrast, control participants yielded significantly greater anterior cingulate cortex (ACC) activation in letter inhibition blocks. A positive relationship between communication and language impairment and angular gyrus activation during face inhibition was also found. Group activation differences during inhibition tasks in the context of comparable task performance and the relationship between activation and dysfunction highlight brain regions that may be related to ASD-specific dysfunction. PMID- 28359874 TI - In silico analysis of nonsynonymous single nucleotide polymorphisms of the human adiponectin receptor 2 (ADIPOR2) gene. AB - Polymorphisms of the ADIPOR2 gene are frequently linked to a higher risk of developing diseases including obesity, type 2 diabetes and cardiovascular diseases. Though mutations of the ADIPOR2 gene are detrimental, there is a lack of comprehensive in silico analyses of the functional and structural impacts at the protein level. Considering the involvement of ADIPOR2 in glucose uptake and fatty acid oxidation, an in silico functional analysis was conducted to explore the possible association between genetic mutations and phenotypic variations. A genomic analysis of 82 nonsynonymous SNPs in ADIPOR2 was initiated using SIFT followed by the SNAP2, nsSNPAnalyzer, PolyPhen-2, SNPs&GO, FATHMM and PROVEAN servers. A total of 10 mutations (R126W, L160Q, L195P, F201S, L235R, L235P, L256R, Y328H, E334K and Q349H) were predicted to have deleterious effects on the ADIPOR2 protein and were therefore selected for further analysis. Theoretical models of the variants were generated by comparative modeling via MODELLER 9.16. A protein structural analysis of these amino acid variants was performed using SNPeffect, I-Mutant, ConSurf, Swiss-PDB Viewer and NetSurfP to explore their solvent accessibility, molecular dynamics and energy minimization calculations. In addition, FTSite was used to predict the ligand binding sites, while NetGlycate, NetPhos2.0, UbPerd and SUMOplot were used to predict post translational modification sites. All of the variants showed increased free energy, though F201S exhibited the highest energy increase. The root mean square deviation values of the modeled mutants strongly indicated likely pathogenicity. Remarkably, three binding sites were detected on ADIPOR2, and two mutations at positions 328 and 201 were found in the first and second binding pockets, respectively. Interestingly, no mutations were found at the post-translational modification sites. These genetic variants can provide a better understanding of the wide range of disease susceptibility associated with ADIPOR2 and aid the development of new molecular diagnostic markers for these diseases. The findings may also facilitate the development of novel therapeutic elements for associated diseases. PMID- 28359875 TI - Seasonal variation of Brazilian red propolis: Antibacterial activity, synergistic effect and phytochemical screening. AB - The aim of this study was to investigate the effect of the dry and rainy season on the antibacterial activity and chemical composition of the Brazilian red propolis. The samples were collected in rainy (RP-PER) and dry (RP-PED) seasons and analyzed by HPLC-DAD. The extracts were tested alone and in association with antibiotics against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. The HPLC analysis identified luteolin and quercetin as the main compounds. Seasonal variation was observed according to concentrations of the compounds. The MIC values against E. coli ranged from 128 MUg/mL to 512 MUg/mL (EC 06 and EC ATCC). The red propolis showed MIC values of 512 MUg/mL against both strains of P. aeruginosa used in our study (PA03 and PA24) and against strains of Gram-positive bacteria S. aureus the MICs ranged from 64 MUg/mL to >=1024 MUg/mL (SA10). A synergistic effect was observed when we combined the RP PED with gentamicin against all the strains tested. When we combined the RP-PED with Imipenem, we only observed synergistic effect against P. aeruginosa. According to our synergistic activity results, the utilization of red propolis collected in the drier periods can be used as an adjuvant against multiresistant bacterial infections. PMID- 28359876 TI - Production, purification and characterization of an aspartic protease from Aspergillus foetidus. AB - An acidic thermostable protease was extracellularly produced either in shake flask or in stirred tank bioreactor by an Aspergillus foetidus strain isolated from the Brazilian savanna soil using different nitrogen sources. Its maximum activity (63.7 U mL-1) was obtained in a medium containing 2% (w/v) peptone. A cultivation carried out in a 5.0 L stirred-tank bioreactor provided a maximum protease activity 9% lower than that observed in Erlenmeyer flasks, which was obtained after a significantly shorter (by 16-29%) time. Protease purification by a combination of gel-filtration chromatography resulted in a 16.9-fold increase in specific activity (248.1 U g-1). The estimated molecular weight of the purified enzyme was 50.6 kDa, and the optimal pH and temperature were 5.0 and 55 degrees C, respectively. The enzyme was completely inhibited by pepstatin A, and its activity enhanced by some metals. According to the inhibition profiles, it was confirmed that the purified acid protease belongs to the aspartic protease type. These results are quite promising for future development of large-scale production of such protease, which can be useful in biotechnological applications requiring high enzyme activity and stability under acidic conditions. PMID- 28359877 TI - A new method of screening for latent tuberculosis infection: Results from army recruits in Beijing in 2014. AB - Latent tuberculosis infection (LTBI) lacks diagnostic gold method. Effective method is important to the control of tuberculosis. IFN-gamma responses in 600 military recruits were tested by ELISA using whole blood incubation with latent protein Rv2029c, Rv2659c and recombinant protein CFP10-ESAT6 (rCE) respectively. They also received tuberculin skin test. Their BCG vaccination status was recorded. When 30.7% (184/600) of recruits gave higher IFN-gamma responses (>=470pg/mL) to rCE as LTBI, the rests as healthy control, the AUC of rRv2029c was 0.856 and rRv2659c was 0.827 for LTBI diagnosis. IFN-gamma responses to rCE were higher in PPD-positive group (>=5mm) than negative group (<5mm) (p<0.05), while for rRv2029c and rRv2659c were not (p>0.05). IFN-gamma responses induced by rRv2029c and rRv2659c were higher in the moderately-positive group (>=5, <15mm) than the strongly-positive group (>=15mm) (p<0.05), while for rCE were not (p>0.05). IFN-gamma levels to three antigens were not related to BCG vaccination status (p>0.05). Rv2659c and Rv2029c are good candidate antigens to complement the role of rCE for LTBI diagnosis, which provide a basis for developing cost effective LTBI screening methods in the army. PMID- 28359878 TI - Formulation and biopharmaceutical evaluation of bitter taste masking microparticles containing azithromycin loaded in dispersible tablets. AB - The objective of this study was to prepare and evaluate some physiochemical and biopharmaceutical properties of bitter taste masking microparticles containing azithromycin loaded in dispersible tablets. In the first stage of the study, the bitter taste masking microparticles were prepared by solvent evaporation and spray drying method. When compared to the bitter threshold (32.43ug/ml) of azithromycin (AZI), the microparticles using AZI:Eudragit L100=1:4 and having a size distribution of 45-212um did significantly mask the bitter taste of AZI. Fourier transform infrared spectroscopy (FTIR), and proton nuclear magnetic resonance spectroscopy (1H NMR) proved that the taste masking of microparticles resulted from the intermolecular interaction of the amine group in AZI and the carbonyl group in Eudragit L100. Differential scanning calorimeter (DSC) analysis was used to display the amorphous state of AZI in microparticles. Images obtaining from optical microscopy and scanning electron microscopy (SEM) indicated the existence of microparticles in regular cube shape with many layers. In the second stage, dispersible tablets containing microparticles (DTs-MP) were prepared by direct compression technique. Stability study was conducted to screen pH modulators for DTs-MP, and a combination of alkali agents (CaCO3:NaH2PO4, 2:1) was added into DTs-MP to create microenvironment pH of 5.0-6.0 for the tablets. The disintegration time of optimum DTs-MP was 53+/-5.29s and strongly depended on the kinds of lubricant and diluent. The pharmacokinetic study in the rabbit model using liquid chromatography tandem mass spectrometry showed that the mean relative bioavailability (AUC) and mean maximum concentration (Cmax) of DTs-MP were improved by 2.19 and 2.02 times, respectively, compared to the reference product (Zithromax(r), Pfizer). PMID- 28359879 TI - A comparison of fat-soluble antioxidants in wild and farm-reared chukar partridges (Alectoris chukar). AB - This study assessed differences in antioxidant (carotenoid, retinol, retinol ester, vitamin E and coenzyme Q10) composition of egg yolk and tissue in chukar partridges (Alectoris chukar) newly hatched from eggs of birds maintained in captivity on commercial maize-soybean based diets and birds from the wild whose diet was obtained from the natural environment. All eggs were incubated in a commercial hatchery. Day-old chicks from both groups were sacrificed and dissected for antioxidant analysis. Fat soluble antioxidant concentrations of egg yolk and tissues were determined by HPLC. Total carotenoids, retinol, alpha tocopherol, and total vitamin E concentration of wild egg yolks were significantly higher compared to yolks from farm-reared birds (p<0.05). However, gamma tocopherol, and coenzyme Q10 were not significantly different in the yolks of either wild or farmed birds (p>0.05). The concentration of total carotenoids in all tissues of wild chukar one-day old partridges was significantly higher than in farmed one-day old chukar partridge tissues (p<0.05). Alpha tocopherol, free-retinol, retinol-esters and total vitamin A were significantly higher in most tissues of wild chukar when compared to farmed chicks (p<0.05). Coenzyme Q10 concentrations of heart, kidney and brain tissues of farm-reared chukar day old chicks were significantly higher than tissues from wild birds, although leg and breast tissues of wild chicks were significantly higher than in farmed birds (p<0.05). These findings suggest that maternal access to antioxidants in the diet of farmed chukar partridges could positively influence fat soluble antioxidant concentrations in the egg yolk and tissues of day old chicks. PMID- 28359880 TI - Coordinated movement is influenced by prenatal light experience in bobwhite quail chicks (Colinus virginianus). AB - Sensory-motor development begins early during embryogenesis and is influenced by sensory experience. Little is known about the prenatal factors that influence the development of motor coordination. Here we investigated whether and to what extent prenatal light experience can influence the development of motor coordination in bobwhite quail hatchlings. Quail embryos were incubated under four light conditions: no light (dark), 2h of total light (2HR), 6h of total light (6HR), and diffused sunlight (controls). Hatchlings were video recording walking down a runway at three developmental ages (12, 24, and 48h). Videos were assessed for forward locomotion, a measurement of motor coordination, falls, a measurement of motor instability, and motivation to complete the task. We anticipated a linear decline of coordination with a reduction in prenatal light experience and improved coordination with age. Furthermore, as motor coordination becomes more laborious we anticipated motivation to complete the task would decline. However, our findings revealed hatchlings did not uniformly improve with age as expected, nor did the reduction of light result in a linear reduction in motor coordination. Instead, we found a more complex relationship with 6HR and 2HR hatchlings showing distinct patterns of stability and instability. Similarly, we found a reduction in motivation within the 6HR light condition. It appears that prenatal light exposure influences the development of postnatal motor coordination and we discuss these finding in light of neurodevelopmental processes influenced by light experience. PMID- 28359881 TI - KU32 prevents 5-fluorouracil induced cognitive impairment. AB - Chemotherapy induced cognitive impairment (i.e. chemobrain) involves acute and long-term deficits in memory, executive function, and processing speed. Animal studies investigating these cognitive deficits have had mixed results, potentially due to variability in the complexity of behavioral tasks across experiments. Further, common chemotherapy treatments such as 5-fluorouracil (5 FU) break down myelin integrity corresponding to hippocampal neurodegenerative deficits and mitochondrial dysfunction. There is little evidence, however, of pharmacological treatments that may target mitochondrial dysfunction. Using a differential reinforcement of low rates (DRL) task combining spatial and temporal components, the current study evaluated the preventative effects of the pharmacological agent KU32 on the behavior of rats treated with 5-FU (5-FU+Saline vs. 5FU+KU32). DRL performance was analyzed the day after the first set of injections (D1), the day after the second set of injections (D7) and the last day of the experiment (D14). The 5FU+KU32 group earned significantly more reinforcers on the DRL task at D7 and D14 than the 5FU+Saline group. Further, the 5FU+KU32 group showed significantly better temporal discrimination. The 5FU+KU32 showed within-group improvement in temporal discrimination from D7 to D14. No significant differences were observed in spatial discrimination, however, those in the 5FU+Saline group responded more frequently on T3 compared to the 5FU+KU32 group, highlighting temporal discrimination differences between groups. The current data suggest that KU32 shows promise in the prevention of chemotherapy induced impairments in temporal discrimination. PMID- 28359882 TI - Re-examining the factors affecting choice in the light-dark preference test in zebrafish. AB - The light-dark preference test has been extensively used to screen anxiolytic drugs and investigate mechanisms of anxiety with rodents. Recently, this task has been adapted to zebrafish, but a number of inconsistent findings have emerged. For example, some found zebrafish to avoid and others to prefer dark. Given the translational relevance of the zebrafish, its utility in high throughput drug screens, and that anxiety still represents a large unmet medical need, there is an urgent need to resolve these inconsistencies. We propose these inconsistencies are due to lack of distinction between two separate factors: background shade and level of illumination. Here, we systematically manipulated background shade (black vs. white) while keeping the illumination level constant (uniformly illuminated). We also manipulated the level of illumination (illuminated vs. not illuminated) while keeping the background constant (either uniformly black or white). We examined the time-course of numerous behavioural responses under these conditions, and found zebrafish to exhibit a significant preference for the black side of the tank within the first 3min of the test when the illumination level was constant. We found this response, along with other anxiety-like behaviours, to diminish over time. In contrast, we found zebrafish did not exhibit a preference for the unilluminated (dark) side of the tank when the background shade was kept constant. Our results demonstrate a dissociation between illumination level and background shade, shown by a preference for black to white, but not for dark to light, confirming the importance of differentiating these two distinct factors. PMID- 28359884 TI - Administration of riluzole into the basolateral amygdala has an anxiolytic-like effect and enhances recognition memory in the rat. AB - It is widely thought that inactivation of the glutamatergic system impairs recognition memory in rodents. However, we previously demonstrated that systemic administration of riluzole, which blocks the glutamatergic system, enhances recognition memory in the rat novel object recognition (NOR) test. The mechanisms underlying this paradoxical effect of riluzole on recognition memory remain unclear. In the present study, adult male Wistar rats were bilaterally cannulated in the basolateral amygdala (BLA) to examine the effects of intra-BLA administration of riluzole. We also compared the effects of riluzole with those of d-cycloserine, a partial agonist at the glycine binding site on the N-methyl-d aspartate (NMDA) receptor. The BLA plays a critical role not only in recognition memory, but also in the regulation of anxiety. In the present study, intra-BLA administration of riluzole or d-cycloserine enhanced recognition memory in the NOR test. It was previously suggested that recognition memory can be strongly affected by the state of anxiety in rodents. Interestingly, intra-BLA administration of riluzole, but not d-cycloserine, produced a potent anxiolytic like effect in the elevated plus-maze test. Thus, the enhancement of recognition memory by riluzole might be an indirect effect resulting from the anxiolytic-like action of the intra-BLA administration of the drug, and may not be directly related to inhibition of the glutamatergic system. Further studies are needed to clarify the mechanisms underlying the memory enhancing effect of riluzole. PMID- 28359885 TI - Sex differences in the acute locomotor response to methamphetamine in BALB/c mice. AB - Women use methamphetamine more frequently than men and are more vulnerable to its negative psychological effects. Rodent models have been an essential tool for evaluating the sex-dependent effects of psychostimulants; however, evidence of sex differences in the behavioral responses to methamphetamine in mice is lacking. In the present study, we investigated acute methamphetamine-induced (1mg/kg and 4mg/kg) locomotor activation in female and male BALB/c mice. We also evaluated whether basal locomotor activity was associated with the methamphetamine-induced locomotor response. The results indicated that female BALB/c mice displayed enhanced methamphetamine-induced locomotor activity compared to males, while basal locomotor activity was positively correlated with methamphetamine-induced activity in males, but not females. This study is the first to show sex-dependent locomotor effects of methamphetamine in BALB/c mice. Our observations emphasize the importance of considering sex when assessing behavioral responses to methamphetamine. PMID- 28359883 TI - The BDNF Val66Met polymorphism is associated with structural neuroanatomical differences in young children. AB - The brain-derived neurotrophic factor (BDNF) Val66Met single nucleotide polymorphism (SNP) has been associated with individual differences in brain structure and function, and cognition. Research on BDNF's influence on brain and cognition has largely been limited to adults, and little is known about the association of this gene, and specifically the Val66Met polymorphism, with developing brain structure and emerging cognitive functions in children. We performed a targeted genetic association analysis on cortical thickness, surface area, and subcortical volume in 78 children (ages 6-10) who were Val homozygotes (homozygous Val/Val carriers) or Met carriers (Val/Met, Met/Met) for the Val66Met locus using Atlas-based brain segmentation. We observed greater cortical thickness for Val homozygotes in regions supporting declarative memory systems (anterior temporal pole/entorhinal cortex), consistent with adult findings. Met carriers had greater surface area in the prefrontal and parietal cortices and greater cortical thickness in lateral occipital/parietal cortex in contrast to prior adult findings that may relate to performance on cognitive tasks supported by these regions in Met carriers. Finally, we found larger right hippocampal volume in Met carriers, although inconsistent with adult findings (generally reports larger volumes for Val homozygotes), is consistent with a recent finding in children. Gene expression levels vary across different brain regions and across development and our findings highlight the need to consider this developmental change in explorations of BDNF-brain relationships. The impact of the BDNF Val66Met polymorphism on the structure of the developing brain therefore reflects regionally-specific developmental changes in BDNF expression and cortical maturation trajectories. PMID- 28359886 TI - Sex differences in the strategies of spatial learning in prenatally-exposed rats treated with various drugs in adulthood. AB - In the present study we investigated the sex differences in the effect of adult long-term drug treatment on cognitive functions of Wistar rats, which were prenatally exposed to MA (5mg/kg) or saline. Cognitive functions were tested as an ability of spatial learning in the Morris Water Maze (MWM), which consisted of three types of tests: "Place Navigation Test"; "Probe Test", and "Memory Recall Test". Adult animals were injected daily, after completion of the last trial, either with saline or cocaine (COC; 5mg/kg), MDMA (3,4-methylenedioxy methamphetamine; 5mg/kg), morphine (MOR; 5mg/kg), or delta-9-tetrahydrocannabinol (THC; 2mg/kg). Results revealed worsened MWM performance in female rats after drug treatment in adulthood. Not only were traditionally investigated parameters affected by drug treatment (latency of platform acquisition, search strategy, distance traveled), but also strategies used by animals (thigmotaxis, scanning). Analyses of search strategies observed in the Place Navigation Test, as well as in the Memory Recall Test, demonstrated variations in the percentage of time spent in thigmotaxis and scanning in females after treatment with COC, MDMA, MOR, and THC. Although we did not see a sensitizing effect of prenatal MA, in some cases the effect of drug treatment in adulthood differed depending on the prenatal drug exposure. The data presented in this study demonstrates that exposure to drugs with various mechanisms of action alters spatial abilities of female rats in the MWM. Alterations in the effect of adult drug treatment with reference to prenatal drug exposure were also found in the present study. PMID- 28359888 TI - Characterisation of the fumarate hydratase repertoire in Trypanosoma cruzi. AB - Nifurtimox and benznidazole represent the only treatments options available targeting Chagas disease, the most important parasitic infection in the Americas. However, use of these is problematic as they are toxic and ineffective against the more severe stages of the disease. In this work, we used a multidisciplinary approach to characterise the fumarases from Trypanosoma cruzi, the causative agent of Chagas Disease. We showed this trypanosome expresses cytosolic and mitochondrial fumarases that via an iron-sulfur cluster mediate the reversible conversion of fumarate to S-malate. Based on sequence, biochemical properties and co-factor binding, both T. cruzi proteins share characteristics with class I fumarases, enzymes found in bacteria and some other protozoa but absent from humans, that possess class II isoforms instead. Gene disruption suggested that although the cytosolic or mitochondrial fumarase activities are individually dispensable their combined activity is essential for parasite viability. Finally, based on the mechanistic differences with the human (host) fumarase, we designed and validated a selective inhibitor targeting the parasite enzyme. This study showed that T. cruzi fumarases should be exploited as targets for the development of new chemotherapeutic interventions against Chagas disease. PMID- 28359887 TI - Preparation and characterization of aminoethyl hydroxypropyl starch modified with collagen peptide. AB - The preparation of aminoethyl hydroxypropyl starch collagen peptide (AEHPS-COP) was via an enzyme-catalyzed reaction between amino groups in aminoethyl hydroxypropyl starch (AEHPS) and gamma-carboxamide groups in collagen peptide (COP) by using microbial transglutaminase (MTGase) as biocatalyst. As an intermediate reactant, AEHPS was synthesized from hydroxypropyl starch (HPS) and 2-chloroethylamine hydrochloride (CEH). The chemical structures of HPS, AEHPS and AEHPS-COP were characterized by Fourier transform infrared spectroscopy (FT-IR) and 13C nuclear magnetic resonance (13C NMR). The reaction conditions that influenced the degree of substitution (DS) of AEHPS-COP were optimized, which included the reaction temperature, the reaction time, the mass ratio of collagen peptide to aminoethyl hydroxypropyl starch and the pH value. In addition, in vitro antioxidant activities of AEHPS-COP were evaluated through the scavenging activity of hydroxyl and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical. Furthermore, the methylthiazol tetrazolium (MTT) assay was applied to investigate the cell viability of AEHPS-COP. The results indicated that the AEHPS-COP exhibited better cell viability to L929 mouse fibroblast cells. Therefore, the AEHPS-COP showed a promising potential application in cosmetic, biomedical and pharmaceutical fields. PMID- 28359889 TI - Characterization of four arginine kinases in the ciliate Paramecium tetraurelia: Investigation on the substrate inhibition mechanism. AB - The ciliate Paramecium tetraurelia contains four arginine kinase genes (AK1-4). We detected cDNA for only three of the AKs (AK1-3) via PCR. Recombinant AK1-4 were expressed in Escherichia coli and their kinetics parameters determined. AK3 showed typical substrate inhibition toward arginine, and enzymatic activity markedly decreased when arginine concentration increased. This is the first example of substrate inhibition in wild-type phosphagen kinases. To explore the substrate inhibition mechanism, site-directed mutations were generated, targeting the amino acid sequence D-D-S-Q-V at positions 77-81 in P. tetraurelia AK3. Among the mutants, substrate inhibition was lost remarkably in the S79A mutant. In spite of high amino acid sequence identity (91%) between P. tetraurelia AK3 and AK4, the enzymatic activity of AK4 was less by 3% than that of AK3. We noticed that the conservative G298 was unusually replaced by R in P. tetraurelia AK4, and we constructed two mutants, R298G/AK4 and G298R/AK3. Enzymatic activity of the former mutant was comparable with that of the wild-type AK3, whereas that of the latter mutant was dramatically reduced. Thus, we concluded that the significantly low activity of P. tetraurelia AK4 is due to the residue R298. PMID- 28359890 TI - Artemisinin loaded chitosan magnetic nanoparticles for the efficient targeting to the breast cancer. AB - Artemisinin, a natural anti-malarial agent, also possesses anti-proliferative and anti-angiogenic activity in cancer cells with very low toxicity to normal healthy cells. Drug loaded magnetic nanoparticles by using external magnetic field could selectively accumulate the drug at the target site and thereby reduce the doses required to achieve therapeutic concentration which may otherwise produce serious side effects on healthy cells. In the present study the artemisinin magnetic nanoparticles were successfully formulated using chitosan by ionic-gelation method. The developed magnetic nanoparticles of artemisinin were smooth and spherical in nature and their size was in the range of 349-445nm. The polydispersity index (PDI) and zeta potential of the formulated nanoparticles were in the range of 0.373-0.908 and -9.34 to -33.3 respectively. They showed 55% to 62.5% of drug encapsulation efficiency and 20% to 25% drug loading capacity. Around 62% to 78% of artemisinin was released from the artemisinin magnetic nanoparticles over the period of 48h. On application of physiologically acceptable external magnetic field, FITC conjugated artemisinin magnetic nanoparticles showed an enhanced accumulation of nanoparticles in the 4T1 breast tumour tissues of BALB/c mice model. PMID- 28359891 TI - Synthesis, characterization and antibacterial activity of hybrid chitosan-cerium oxide nanoparticles: As a bionanomaterials. AB - The hybrid chitosan cerium oxide nanoparticles were prepared for the first time by green chemistry approach using plant leaf extract. The intense peak observed around 292nm in the UV-vis spectrum indicate the formation of cerium oxide nanoparticles. The XRD pattern revealed that the hybrid chitosan-cerium oxide nanoparticles have a polycrystalline structure with cubic fluorite phase. The FTIR spectrum of prepared samples showed the formation of Ce-O bonds and chitosan main chains COC and CO. The FESEM image of hybrid chitosan cerium oxide nanoparticles revealed that the particles are spherical in shape with grains size varying from 23.12nm to 89.91nm. EDAX analysis confirmed the presence of Ce, O, C and N elements in the prepared sample. TEM images showed that the prepared hybrid chitosan-cerium oxide nanoparticles are predominantly uniform in size and most of the particles are spherical in shape with less agglomeration and the particles size varies from 3.61nm to 24.40nm. The prepared chitosan cerium oxide nanoparticles of 50MUL concentration showed good antibacterial properties against test pathogens, which was confirmed by the FESEM analysis. The prepared small particle size facilitate that these hybrid ChiCO2 NPs could effectively be used in biomedical applications. PMID- 28359892 TI - Bamboo leaf extract ameliorates diabetic nephropathy through activating the AKT signaling pathway in rats. AB - Diabetic nephropathy (DN) is one of the most severe diabetic complication and it is becoming become a worldwide epidemic, accounting for approximately one-third of all case of end-stage renal disease. However, the underlying mechanism and strategy to alleviate renal injury remain unclear. In the present study, we assessed the protective effect of bamboo leaf extract on the DN, and investigated the underlying mechanism by which bamboo leaf extract ameliorating DN. Diabetic rats were induced by 4 weeks high sugar and high fat diet, and then injected a single dose of STZ (35mg/kg) into abdominal cavity. Different dose of bamboo extract (50mg/kg, 100mg/kg and 200mg/kg) were orally administered every day for a period of 12 weeks. Body weight, blood glucose, glycosylated hemoglobin A1c (HbAlc), blood urea nitrogen (BUN), serum creatinine (Scr), and 24-hour urinary protein (24 h-UP) were assessed. Total superoxide dismutase (T-SOD) activity and MDA (methane dicarboxylic aldehyde, MDA) level were tested by assay kit. Microstructural changes were observed by hematoxylin-eosin (HE) staining and electron microscopy. Expression of phosphorylated ser/thr protein kinase (P-AKT), phosphorylated glycogen synthase kinase-3 beta (P-GSK-3beta), B cell lymphoma/leukemia 2-associated X protein (BAX) and cleaved-cysteinyl aspartate specific proteinase-3 (Cleaved Caspase-3) were measured by Western-Blotting (WB). Results showed that diabetic rats had weight loss, high blood glucose, HbAlc, BUN, Scr and 24-UP and T-SOD activity were increased and MDA level was decreased in diabetic rats. Moreover, hyperglycemia could injury renal tissue ultrastructure, inhibit P-AKT level and increase P-GSK-3beta, BAX and Cleaved Caspase-3 levels in rats. However, bamboo leaf extract treatment could reduce body weight loss, BUN, Scr, 24 h-UP and MDA level, improve T-SOD activity and alleviate renal injury in diabetic rats. Furthermore, bamboo leaf extract increased P-AKT level, decreased P-GSK-3beta, BAX and Cleaved Caspase-3 levels in STZ-diabetic rats. In conclusion, our study suggested that bamboo leaf extract ameliorated DN in diabetic rats, and this protective effect is possibly related to suppressing oxidative stress through activating AKT signaling pathway. Bamboo leaf extract treatment may be a potential promising therapy for DN. PMID- 28359893 TI - Spectroscopic studies on the gemini surfactant mediated refolding of human serum albumin. AB - Refolding of guanidinium hydrochloride (GdCl) denatured human serum albumin (HSA) using a combination of cationic gemini surfactants; pentanediyl-alpha,omega bis(cetyldimethylammonium bromide) (C16H33(CH3)2N+-(CH2)5-N+(CH3)2C16H33)2Br- designated as G5 and methyl- beta-cyclodextrin, is attempted in the present study. The studies were carried out in an aqueous medium (pH 7.4) using dynamic light scattering (DLS), circular dichroism (CD) and fluorescence spectroscopy. A careful study of the DLS data indicates that against the hydrodynamic radius (Rh) of 3.5nm in native human serum albumin (HSA), hydrodynamic radius after attempting refolding by simple dilution increases to 33.8nm. The large Rh values of the diluted protein sample is associated with the formation of aggregates as dilution is an aggregation prone pathway. Hydrodynamic radii equal to 5.4nm, that is very near to the native protein (3.5nm), is obtained on the sequential addition of G5 and methyl- beta-cyclodextrin to the denatured protein. The results obtained from the multi-technique approach are associated with the presence of two charged head-groups and two hydrocarbon tails in the gemini surfactants resulting in very strong electrostatic and hydrophobic interactions.The present study suggests that gemini surfactants may be utilised in the protein refolding studies and may prove to be inexpensive and efficient folding agents. PMID- 28359894 TI - Characterisation and solution properties of a galactomannan from Bauhinia monandra seeds. AB - This study reports on the chemical and physicochemical properties of the polysaccharide isolated from Bauhinia monandra seeds. The seeds were found to contain 17.8% polysaccharide which consisted predominantly of galactose and mannose. The Man/Gal ratio was found to be approximately 4:1and the average molar mass was 2.54*105g/mol. The extracted material was also found to contain a small amount of protein (5.35%). The galactomannan produced highly viscous solution; the viscosity-shear rate profile was best described by the Williamson model. The mechanical spectrum of a 0.5wt% solution showed that G" was greater than G' over the frequency range employed while at higher concentrations G' became greater than G" above a critical frequency. The solutions obeyed the Cox-Merz rule at low concentrations, but there was some deviation at higher concentrations. Viscosity measurements were undertaken over a range of temperatures and the activation energy of viscous flow was found to be 20.75kJ/mol. The rheological properties of solutions of B. monandra galactomannan indicate that it has comparable characteristics to other commercially important galactomannans such as guar gum and locust bean gum and hence has potential as a thickener in the formulation of food and other related products. PMID- 28359895 TI - Multi-scale structure, pasting and digestibility of heat moisture treated red adzuki bean starch. AB - The pasting and digestibility of a red adzuki bean starch were simultaneously modulated by heat-moisture treatment (HMT) through altering the multi-scale structure. HMT, especially at high moisture content, could disrupt the granule integrity, semicrystalline lamellae, molecular order (crystallites) and molecular chains. Also, certain rearrangement of starch molecules occurred to form ordered structures with increased thermal stability as shown by DSC. This concomitant disordering and reassembly in the multi-scale structure converted the fractions of resistant starch (RS) and rapidly digestible starch (RDS) into that of slowly digestible starch (SDS). Furthermore, the emergence of thermally-stable orders increased the pasting temperature but suppressed the swelling of granules during heating. Hence, HMT-modified red adzuki starch may serve as a potential thickener/gelling agent with slow digestion rate for various foods. PMID- 28359896 TI - Yield study with the release property of polysaccharide-based physical hydrogels. AB - Water-release from kappa-Carrageenan (kC) hydrogels (syneresis) has been studied by two experimental methods (1) one in which the exudate is enabled to surround the gel and (2) one in which the exudate is continuously removed from the gel surfaces. The pressures Pg caused by the gel weight decrease from 1Pa for method (1) and 500Pa for method (2). The syneresis of the gels at 2g/L kC with 40mM KCl has been observed to decrease with Pg for the highest pressures. However, for the lowest pressures, the pressure-dependence of the syneresis has not been found, although this gel shrank remarkably. This gel exhibits yielding at approximately 0.15Pa during rheological testing and exhibits creep at stress well below its yield stress. The result is consistent in demonstrating that similar gels in the conditions of method (1) or (2) yield while releasing fluid. The release kinetics have been fitted with a sum of two exponential decay functions, one for shrinkage and the other for yielding. The kinetic rate, k1 for shrinkage, is almost 0.035+/ 0.005h-1 for all of the gels studied, except for very soft and stiff gels; for that of yielding, k2 increases in the range of 0.07-0.33+/-0.01h-1 when the gel is modulated from soft to stiff. PMID- 28359897 TI - Chitosan-hyaluronic acid hydrogel for cartilage repair. AB - The current study investigates the potential of chitosan-hyaluronic acid dialdehyde hydrogels for in vivo cartilage regeneration following two different approaches: Gel alone for cartilage regeneration or combination of chondrocytes and gel for cartilage repair. Critical size osteochondral defects were created in knee joints of Newzealand White rabbits. Allogenic rabbit chondrocytes were encapsulated in hydrogels and gel or gel+cells were implanted in defects aseptically. The regenerated cartilage was analyzed after 12 weeks of implantation. The morphological scoring indicates that repair tissue was formed in all the animals by 12 weeks irrespective of whether they were sham, received gel, or gel with cells as implant. However the repair tissue formed in sham appeared fibrous and opaque, where as those that received gel had texture similar to the surrounding native cartilage and animals with gel+cells showed varied response. Histology staining, score distribution and immunostaining for collagen Type II showed animals that received gel alone as the implant had a mixture of hyaline and fibro cartilage. The animals with cell encapsulated gels had more fibrous cells with weak staining for collagen type II. There was no significant enhancement in the quality of regenerated cartilage in presence of encapsulated chondrocytes. PMID- 28359898 TI - Chitosan mediated enhancement of hydrolysable tannin in Phyllanthus debilis Klein ex Willd via plant cell suspension culture. AB - Phyllanthus debilis Klein ex Willd. is wild medicinal plant used in the traditional system of medicine. This plant has been actively used for hepatoprotection and to cure many diseases including jaundice and so on; which leads to complete extinction of this particular species. Therefore, the chitosan mediated cost effective cell suspension method has been developed for the production of hydrolysable tannin. The hydrolysable tannins are the main therapeutically active constituents with antioxidant, anticancer, and antimicrobial properties. An in vitro cell suspension culture was optimized by adding chitosan for production of hydrolysable tannin. According to the growth kinetics, a maximum biomass of 4.46+/-0.06g fresh cell weight and 1.33+/-0.04g dry cell weight were obtained from the optimal suspension medium consisted of MS medium+0.5mgL-1 BAP+1.5mgL-1 NAA. Chitosan was treated at the stationary phase which leads to the highest accumulation of hydrolysable tannin compared to the untreated control. Hydrolysable tannin was observed and compared using HPLC at the Rt of 4.91 in both chitosan treated and untreated cells. This is the first ever report where use of chitosan has been done to enhance the production of the hydrolysable tannin in P. debilis using cell suspension culture technique. PMID- 28359899 TI - IL-33/ST2 contributes to severe symptoms in Plasmodium chabaudi-infected BALB/c mice. AB - It has been reported that IL-33 contributes to potentiation of Th2 inflammatory diseases and protection against helminth infection. Increased plasma IL-33 levels have been observed in patients with severe falciparum malaria, however, the role of IL-33 in malaria remains unclear. Here we report that IL-33 enhances inflammatory responses in malaria infection. ST2-deficiency altered severity of inflammation in the liver and serum levels of pro-inflammatory cytokines such as TNF-alpha and IL-6, and IL-13 that is a Th2 cytokine during Plasmodium chabaudi infection. IL-13-deficient mice have similar phenotype with ST2-deficient mice during P. chabaudi infection. Furthermore, ST2- and IL-13-deficiency reduced mortality from P. chabaudi infection. These results indicate that IL-33/ST2 can induce production of proinflammatory cytokines, such as TNF-alpha and IL-6, through production of IL-13 in P. chabaudi-infected BALB/c mice, suggesting that IL-33/ST2 play a critical role in inflammatory responses to malaria infection. Thus, these findings may define a novel therapeutic target for patients with severe malaria. PMID- 28359900 TI - Phylogenetic position of the genus Gonocerca Manter, 1925 (Trematoda, Hemiuroidea), based on partial sequences of 28S rRNA gene and a reconsideration of taxonomic status of Gonocercinae Skrjabin et Guschanskaja, 1955. AB - Adult trematodes of the genus Gonocerca Manter, 1925, are parasites of marine fishes. Identification of the phylogenetic positions and a revision of the taxonomic status of the subfamily Gonocercinae Skrjabin et Guschanskaja, 1955 (Derogenidae) are the main purposes of this research article. Four Gonocerca species were used in the study, including the type-species G. phycidis Manter, 1925. Molecular phylogenetic analysis, based on partial sequences of 28S rRNA gene, revealed that Gonocerca spp. are phylogenetically distant from other hemiuroid trematodes, including Derogenes varicus (Muller, 1784), representative of the type-genus of the family Derogenidae. The taxonomic rank of Gonocercinae should be raised to the family level. The generic composition of the family Gonocercidae Skrjabin et Guschanskaja, 1955 stat. nov., requires further clarification as the molecular data do not support the inclusion of the genus Hemipera Nicoll, 1913, in this family. PMID- 28359901 TI - Model-based structural and functional characterization of the Rice stripe tenuivirus nucleocapsid protein interacting with viral genomic RNA. AB - Rice stripe tenuivirus (RSV) is a filamentous, negative-strand RNA virus causing severe diseases on rice in Asian countries. The viral particle is composed predominantly of a nucleocapsid protein (NP) and genomic RNA. However, the molecular details of how the RSV NP interacts with genomic RNA during particle assembly remain largely unknown. Here, we modeled the NP-RNA complex and show that polar amino acids within a predicted groove of NP are critical for RNA binding and protecting the RNA from RNase digestion. RSV NP formed pentamers, hexamers, heptamers, and octamers. By modeling the higher-order structures, we found that oligomer formation was driven by the N-terminal amino arm of the NP. Deletion of this arm abolished oligomerization; the N-terminally truncated NP was less able to interact with RNA and protect RNA than was the wild type. These findings afford valuable new insights into molecular mechanism of RSV NPs interacting with genomic RNA. PMID- 28359903 TI - First derivative spectrofluorimetric determination of zopiclone and its degradation product, 2-amino-5-chloropyridine, in pharmaceutical formulations with preliminary tool in biological fluids for clinical evidence of zopiclone intake. AB - A simple, fast, sensitive and stability-indicating derivative spectrofluorimetric method is presented for the assay of zopiclone (ZOP), a drug with hypnotic effect, and its main degradation product and major contaminant, 2-amino-5 chloropyridine (ACP). The method is based on measuring the inherent fluorescence intensity of both drugs at lambdaex=300nm in methanol, then differentiation using D1 (first derivative technique). The developed method was found to be rectilinear over a range of 0.2-4MUg/mL of ZOP and 4-100ng/mL of ACP. The limits of detection were 0.05MUg/mL of ZOP and 0.2ng/mL of ACP with the limit of quantitation of 0.17MUg/mL of ZOP and 0.7ng/mL of ACP. The outcoming results of the proposed method were compared to those obtained by a reference method showing no significant statistical difference between them concerning precision and accuracy. Additionally, the developed method was applied for detecting ACP in spiked human urine and plasma specimens as a tool of clinical evidence of zopiclone intake that can be easily implemented in forensic laboratories. The proposed method was validated as per ICH guidelines. PMID- 28359902 TI - On the catalytic mechanism of bacteriophage HK97 capsid crosslinking. AB - During maturation of the phage HK97 capsid, each of the 415 capsid subunits forms covalent bonds to neighboring subunits, stabilizing the capsid. Crosslinking is catalyzed not by a separate enzyme but by subunits of the assembled capsid in response to conformational rearrangements during maturation. This report investigates the catalytic mechanism. Earlier work established that the crosslinks are isopeptide (amide) bonds between side chains of a lysine on one subunit and an asparagine on another subunit, aided by a catalytic glutamate on a third subunit. The mature capsid structure suggests that the reaction may be facilitated by the arrival of a valine with the lysine to complete a hydrophobic pocket surrounding the glutamate, lysine and asparagine. We show that this valine has an essential role for efficient crosslinking, and that any of six other amino acids can successfully substitute for valine. Evidently none of the remaining 13 amino acids will work. PMID- 28359904 TI - Quantum mechanical, spectroscopic and docking studies of 2-Amino-3-bromo-5 nitropyridine by Density Functional Method. AB - Experimental and theoretical investigations on the molecular structure, electronic and vibrational characteristics of 2-Amino-3-bromo-5-nitropyridine are presented. The vibrational frequencies were obtained by DFT/B3LYP calculations employing 6-311++G (d, p) basis set. This was compared with experimental FT-IR and FT-Raman spectral data. Simulated FT-IR (4000-400cm-1) and FT-Raman spectra (4000-100cm-1) showed good agreement with the observed spectra. The molecular equilibrium geometry of the title compound was fully optimized. Quantum chemical calculations of the equilibrium geometry and the complete vibrational assignments of wavenumbers using potential energy distribution (PED) were calculated with scaled quantum mechanics. HOMO-LUMO energies, energy gap (DeltaE), electronegativity (chi), chemical potential (MU), global hardness (eta), softness (S) and the Fukui function were calculated for the title molecule. The title compound has a low softness value (0.239) and the calculated value of electrophilicity index (5.905) describes the biological activity. The stability and charge delocalization of the title molecule were studied by Natural Bond Orbital (NBO) analysis, Non-Linear Optical (NLO) behaviour in terms of first order hyperpolarizability, dipole moment and anisotropy of polarizability and Molecular Electrostatic Potential (MEP) were accounted. The computed values of MU, alpha and beta for the title molecule are 1.851 Debye, 1.723*10-23esu and 7.428*10-30esu respectively. The high beta value and non-zero value of MU indicate that the title compound might be a good candidate for NLO material. Thermodynamic properties of the title molecule were studied for different temperatures thereby revealing the correlations between heat capacity (C), entropy (S) and enthalpy changes (H) with temperatures. Docking studies of the title compound were scrutinized to predict the preferred binding orientation, affinity and activity of the given compound. The title compound was docked into the active site of the protein 5FCT which belongs to the class of proteins exhibiting the property as a Dihydrofolate synthase inhibitor. A minimum binding energy of -5.9kcal/mol and intermolecular energy of -6.5kcal/mol is seen in the interaction. PMID- 28359905 TI - Effects of TiO2 crystal structure on the luminescence quenching of [Ru(bpy)2(dppz)]2+-intercalated into DNA. AB - The intercalation of [Ru(bpy)2(dppz)]2+ labeled as Ru(II) (bpy=2,2'-bipyridine and dppz=dipyrido[3,2,-a:2',3'-c]phenazine) into herring sperm DNA leads to the formation of emissive Ru(II)-DNA dyads, which can be quenched by TiO2 nanoparticles (NPs) and sol-gel silica matrices at heterogeneous interfaces. The calcinations temperature exhibits a remarkable influence on the luminescence quenching of the Ru(II)-DNA dyads by TiO2 NPs. With increasing calcinations temperature in the range from 200 to 850 degrees C, the anatase-to-rutile TiO2 crystal structure transformation increases the average particle size and hydrodynamic diameter of TiO2 and DNA@TiO2. The anatase TiO2 has the stronger ability to unbind the Ru(II)-DNA dyads than the rutile TiO2 at room temperature. The TiO2 NPs and sol-gel silica matrices can quench the luminescence of the Ru(II) complex intercalated into DNA by selectively capturing the negatively DNA and positively charged Ru(II) complex to unbind the dyads, respectively. This present results provide new insights into the luminescence quenching and competitive binding of dye-labeled DNA dyads by inorganic NPs. PMID- 28359906 TI - Patient-perceived surgical indication influences patient expectations of surgery for degenerative spinal disease. AB - OBJECTIVE: Patients frequently have misconceptions regarding diagnosis, surgical indication, and expected outcome following spinal surgery for degenerative spinal disease. In this study, we sought to understand the relationship between patient perceived surgical indications and patient expectations. We hypothesized that patients reporting appendicular symptoms as a primary surgical indication would report a higher rate of having expectations met by surgery compared to those patients reporting axial symptoms as a primary indication. METHODS: Questionnaires were administered to patients who had undergone surgery for degenerative spinal disease at 2 tertiary care institutions. Questions assessed perception of the primary indication for undergoing surgery (radicular versus axial), whether the primary symptom improved after surgery, and whether patient expectations were met with surgery. Outcomes of interest included patient reported symptomatic improvement following surgery and expectations met by surgery. Various factors were assessed for their relationship to these outcomes of interest. RESULTS: There were 151 unique survey respondents. Respondents were nearly split between having a patient-perceived indication for surgery as appendicular symptoms (55.6%) and axial symptoms (44.4%). Patient-perceived surgical indication being appendicular symptoms was the only factor predictive of patient-reported symptomatic improvement in our logistic regression model (OR 2.614; 95% CI 1.218-5.611). Patient-perceived surgical indication being appendicular symptoms (OR 3.300; 95% CI 1.575-6.944) and patient-reported symptomatic improvement (OR 33.297; 95% CI 12.186-90.979) were predictive of patients reporting their expectations met with surgery in both univariate and multivariate logistic regression modeling. CONCLUSIONS: We found that patient reported appendicular symptoms as the primary indication for surgery were associated with a higher rate of both subjective improvement following surgery and having expectations met by surgery. Studies such as ours point to the fact that while performing technically superlative operations is paramount, it may be equally important to address other factors that help determine patient perception of the surgery experience. PMID- 28359907 TI - Anxiety in the preoperative phase of awake brain tumor surgery. AB - OBJECTIVE: Awake surgery emerges as a standard of care for brain tumors located in or near eloquent areas. Levels of preoperative anxiety in patients are important, because anxiety can influence cognitive performance and participation, hence altering the outcome of the procedure. In this study we analyzed the prevalence and potential clinical predictors of anxiety in the pre-operative phase of an awake brain tumor surgery. PATIENTS AND METHODS: Seventy consecutive candidates for an awake brain tumor surgery were included. All patients received a neuropsychological pre-operative work-up. The Hospital Anxiety and Depression Scale (HADS) was administrated to investigate symptoms of anxiety. Demographic and medical data were extracted from patients' charts. Linear regression analyses, multiple regression analyses, t-tests for parametric and Mann-Whitney U tests for non-parametric data were used to analyze the relation between demographic and medical variables and pre-operative anxiety. RESULTS: Mean score on the anxiety scale of the HADS was 6.1 (SD=4.2, range 1-19) and 25% of the patients scored on or above the cut-off for anxiety symptoms (score >7). Women reported higher levels of anxiety than men (p<0.01). Furthermore, younger patient were more anxious than older patients (p<0.05). No other variables were significantly related to pre-operative anxiety. CONCLUSIONS: Merely, one in every four patients reported significant anxiety symptoms in the pre-operative phase. Besides gender and age, none of the other demographic or medical factors were significantly associated with the level of anxiety. PMID- 28359908 TI - Perception of safety is a prerequisite for the association between neighbourhood green qualities and physical activity: Results from a cross-sectional study in Sweden. AB - In this study, we assess how the Scania Green Score (SGS5), and the five distinct perceived neighbourhood green dimensions within this area-aggregated index (1km2 squares), is associated with self-reported physical activity and general health, and if perceived safety and social coherence has a moderating effect. Two independent surveys, both conducted in Scania, Sweden, was used for data on SGS5 and health outcomes (N=28 198 and N=23 693), respectively. SGS5 was more clearly associated with physical activity (OR 1.06; 95% CI 1.02-1.10) than with general health (OR 1.02; 95% CI 1.00-1.04). This association was moderated by safety (p for interaction <0.001); SGS5 was positively associated with physical activity only among individuals who perceived high safety in their neighbourhood (OR 1.07; 95% CI 1.02-1.11). No moderating effect was seen for social coherence. Among specific dimensions, cultural history was positively associated with both physical activity and general health. Our results suggest that perception of safety is a prerequisite for the positive effects of neighbourhood green qualities. PMID- 28359909 TI - Worries, 'weirdos', neighborhoods and knowing people: a qualitative study with children and parents regarding children's independent mobility. AB - This qualitative study involved focus groups with 132 children and 12 parents in primary and secondary schools in metropolitan and regional areas of Victoria, Australia, to explore experiences and perceptions of children's independent mobility. The study highlights the impact of family routines, neighborhood characteristics, social norms and reference points for decision making. Children reported a wider range of safety concerns than parents, including harm from strangers or traffic, bullying, or getting lost. Children expressed great delight in being independent, often seeking to actively influence parents' decision making. Children's independent mobility is a developmental process, requiring graduated steps and skill building. PMID- 28359910 TI - Cost-Effectiveness of Defibrotide in the Prophylaxis of Veno-Occlusive Disease after Pediatric Allogeneic Stem Cell Transplantation. AB - Veno-occlusive disease (VOD) remains a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Prophylactic use of defibrotide (DF) might further reduce VOD rates but has no impact on the incidence of severe VOD or VOD-associated mortality. We investigated the cost-effectiveness of prophylactic DF according to the British Committee for Standards in Haematology/British Society for Blood and Marrow Transplantation guidelines in 348 children who underwent transplantation between 2001 and 2014 in our hospital, 138 of whom were at risk for VOD. The VOD incidence was 7.4% for the total cohort. Patients at risk had a higher incidence of VOD compared with patients without risk factors (15.2% versus 2.4%, P < .0001). VOD occurred more often in patients after busulfan-based myeloablative conditioning than in patients after total body irradiation (11.2% versus 3.5%, P = .001). Donor types or the transplantation-related mortality (TRM) risk score did not correlate with VOD incidence. In 81% of patients who responded to therapeutic DF, VOD resolved completely. Overall VOD-associated mortality was .3% for the complete cohort, 3.7% for patients diagnosed with VOD, and 20% for patients with severe VOD. Neither the cumulative incidence of TRM (19% +/- 8% versus 17% +/- 2%, P = .706) nor the median length of hospitalization differed between patients with VOD and patients without. The median costs per HSCT in patients with VOD were about one third higher than the overall median costs per transplantation at our institution. The calculated total costs of prophylactic DF treatment for 138 patients at risk was almost 6 times as high as the incremental costs for patients with VOD. We conclude that prophylactic DF for children at risk for VOD is not cost-effective with respect to TRM and length of hospital stay. PMID- 28359911 TI - Visceral larvae as a predictive index of the overall level of fish batch infection in European anchovies (Engraulis encrasicolus): A rapid procedure for Food Business Operators to assess marketability. AB - The European anchovy (Engraulis encrasicolus), one of the most important pelagic fish resources in the Mediterranean Sea, is frequently infected by anisakid larvae. Food Business Operators (FBOs) should use appropriate sampling plans and analytical methods to avoid commercialization of massively infected batches and reduce the risk of transmission of viable zoonotic larvae. In this study, performed at FishLab (Department of Veterinary Sciences of the University of Pisa) during 2016, an official sampling plan was associated with a digestion protocol for the inspection of anchovies. Considering that anisakid larvae are usually located in the fish visceral cavity and in the adjacent muscles (VM), this part was analyzed. In particular, we assessed the reliability of the digestion of a subsample of 150g (+/-30g) of VM, randomly collected from 29 specimens, in estimating the marketability of the anchovies' batch. Fifty-seven samples of 29 anchovies were collected. Each anchovy was sectioned to separate VM. All the subsamples were digested, and visible larvae counted. A high correlation between the number of larvae in VM regions and in the total batch was observed, indicating a very significant contribution of the VM region on total number of parasites. The Mean Abundance (MA) was used to assess the batch marketability according to a threshold calculated on the basis of the maximum number of nematodes tolerated per sample. Considering that the MA can be calculated only when the number of examined specimens is known, the number of visible Larvae per gram of tissue (LpG) was calculated on 150g (+/-30g) of VM subsamples. A LpG marketability threshold was calculated dividing the maximum number of tolerated nematodes by the average weight of a sample of 29 anchovies calculated considering data available in literature. To evaluate the diagnostic performance of the LpG threshold, the marketability of 57 batches assessed on the basis of the MA threshold was assumed as the gold standard. The proposed LpG showed very high Specificity and Sensitivity. These findings suggest that the analysis of VM is representative of the overall infestation of the batch, both when considering the absolute number of parasites and the LpG, and may represent a valid alternative to the whole anchovy digestion. In particular, the use of an automated digestive method, coupled with the aforesaid sampling plan, could allow the procedure to be used by FBOs in operational conditions. PMID- 28359912 TI - Diffusion tensor imaging and tractography of the white matter in normal aging: The rate-of-change differs between segments within tracts. AB - Knowledge concerning the normal aging of cerebral white matter will improve our understanding of abnormal changes in neurodegenerative diseases. The microstructural basis of white matter maturation and aging can be investigated using diffusion tensor imaging (DTI). Generally, diffusion anisotropy increases during childhood and adolescence followed by a decline in middle age. However, this process is subject to spatial variations between tracts. The aim of this study was to investigate to what extent age-related variations also occur within tracts. DTI parameters were compared between segments of two white matter tracts, the cingulate bundle (CB) and the inferior fronto-occipital fasciculus (IFO), in 257 healthy individuals between 13 and 84years of age. Segments of the CB and the IFO were extracted and parameters for each segment were averaged across the hemispheres. The data was analysed as a function of age. Results show that age related changes differ both between and within individual tracts. Different age trajectories were observed in all segments of the analysed tracts for all DTI parameters. In conclusion, aging does not affect white matter tracts uniformly but is regionally specific; both between and within white matter tracts. PMID- 28359914 TI - Starving for survival-how catabolic metabolism fuels immune function. AB - Infections disturb homeostasis and often induce a switch to catabolic organismal metabolism. During catabolism, increased systemic availability of glucose, fatty acids and ketone bodies is observed, and recent evidence indicates that these metabolites might serve an immunomodulatory function. However, whereas our understanding of direct pathogen recognition by the host immune system is quite detailed, much less is known about the immunobiology of the metabolic host response to infection. In this review article we briefly discuss how pathogens induce 'dys-homeostasis' systemically, locally, and within cells, and provide examples of how such changes can shape immune-functionality during the course of an infection. PMID- 28359913 TI - Obesity altered T cell metabolism and the response to infection. AB - An epidemic of obesity over the past three decades increases the risk of chronic and infectious diseases for adults and children alike. Within the past few years, obesity has been shown to impair the adaptive immune response to infection through alterations in T cell functioning. Growing evidence suggests that perturbations in T cell metabolism drives this stunted immune response, stemming from nutrient, hormone and adipokine dysregulation in the obese. In this review, recent findings in the fields of obesity and T cell mediated immunity demonstrate a unique relationship between altered mechanisms of T cell metabolic homeostasis and plasticity of adaptive immune responses in the obese setting. PMID- 28359915 TI - Sp3 controls fibroblast growth factor receptor 4 gene activity during myogenic differentiation. AB - Fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling is a critical component in the regulation of myoblast proliferation and differentiation. The transient FGFR4 gene expression during the transition from proliferating myoblasts to differentiated myotubes indicates that FGFR4 regulates this critical phase of myogenesis. The Specificity Protein (SP) family of transcription factors controls FGFR family member gene activity. We sought to determine if members of the Sp family regulate mouse FGFR4 gene activity during myogenic differentiation. RT-PCR and western blot analysis of FGFR4 mRNA and protein revealed transient expression over 72h, with peak expression between 24 and 36h after addition of differentiation medium to C2C12 myogenic cultures. Sp3 also displayed a transient expression pattern with peak expression occurring after 6h of differentiation. We cloned a 1527bp fragment of the mouse FGFR4 promoter into a luciferase reporter. This FGFR4 promoter contains eight putative Sp binding sites and directed luciferase gene activity comparable to native FGFR4 expression. Overexpression of Sp1 and Sp3 showed that Sp1 repressed FGFR4 gene activity, and Sp3 activated FGFR4 gene activity during myogenic differentiation. Mutational analyses of multiple Sp binding sites within the FGFR4 promoter revealed that three of these sites were transcriptionally active. Electromobility shift assays and chromatin immunoprecipitation of the area containing the activator sites showed that Sp3 bound to this promoter location. PMID- 28359917 TI - The identities of stop codon reassignments support ancestral tRNA stop codon decoding activity as a facilitator of gene duplication and evolution of novel function. AB - Stop codon reassignments are widely distributed in prokaryotic, eukaryotic and organellar genomes, but are remarkably convergent in terms of the stop codons and amino acids reassigned. Strikingly, the identities of stop codon reassignments are closely matched to the properties of naturally occurring nonsense suppressor (NONS) tRNAs, suggesting that pre-existing nonsense suppression in an ancestral tRNA facilitated the occurrence of stop codon reassignments. Here this idea is expanded, by exploring the mechanism by which the gene duplication of tRNAs has occurred, leading to the reassignment of stop codons. Two types of stop codon reassignment are identified: those that necessitate a tRNA gene duplication, and those that do not because a single tRNA can recognize the reassigned stop codon and the canonical codon(s) for the cognate amino acid. Where tRNA gene duplication has occurred, this implies a multi-functional ancestral NONS tRNA, followed by adaptive mutation in the anticodon of one of the gene duplicates to become complementary to the stop codon, constituting a clear example of escape from adaptive conflict. The best exemplar is the UAA+UAG ->gln reassignment, which has occurred 9 times independently in a diverse range of genomes, and appears to reflect the widespread occurrence of naturally occurring nonsense suppression of the UAA+UAG stop codons by glutamine tRNAs. Consideration of pre existing tRNA functionality and the mechanism of gene duplication provide new insights into the process of stop codon reassignment. PMID- 28359916 TI - Identification of microRNA biomarkers in the blood of breast cancer patients based on microRNA profiling. AB - Accumulating evidence indicates that human circulating microRNAs (miRNAs) could serve as diagnostic and prognostic biomarkers in various cancers. We aimed to explore novel miRNA biomarkers in the blood of breast cancer patients based on miRNA profiling. A miRCURYTM LNA Array was used to identify differentially altered miRNAs in the whole blood of breast cancer patients (n=6) and healthy controls (n=6). Levels of candidate miRNAs were quantified by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in whole blood specimens of 15 breast cancer patients and 13 age-matched healthy control individuals. The miRWalk database was used to predict miRNA targets and the DAVID tool was used to identify significant enrichment pathways. A total of 171 differentially expressed miRNAs were identified by microarray, including 169 upregulated and 2 downregulated miRNAs in breast cancer. Five upregulated miRNAs (miR-30b-5p, miR-96-5p, miR-182-5p, miR-374b-5p, and miR-942-5p) were confirmed by qRT-PCR. The areas under the receiver operating characteristic curve of miR 30b-5p, miR-96-5p, miR-182-5p, miR-374b-5p, and miR-942-5p were 0.9333, 0.7692, 0.7590, 0.8256, and 0.8128, respectively. Importantly, upregulation of these five miRNAs was observed even in patients with very early-stage breast cancer. A total of 855 genes were predicted to be targeted by the five miRNAs, and the one cut domain family member 2 gene (ONECUT2) was a shared target of the five miRNAs. Analysis of publicly available data revealed that these dysregulated miRNAs and the target genes were associated with the survival of breast cancer patients. Furthermore, the five miRNAs were significantly enriched in numerous cancer related pathways, including "MicroRNAs in cancer", "Pathways in cancer", "FoxO signaling pathway", "Ras signaling pathway", "Rap1 signaling pathway", "MAPK signaling pathway", and "PI3K-Akt signaling pathway". Our data support the potential of the five identified miRNAs as novel biomarkers for the detection of breast cancer, and indicate that they may be involved in breast cancer development and progression. PMID- 28359918 TI - The effects of desipramine, fluoxetine, or tianeptine on changes in bulbar BDNF levels induced by chronic social instability stress and inflammation. AB - BACKGROUND: Stress is a major predisposing factor in the development of psychiatric disorders and potential source of augmented inflammatory processes in the brain. Increasing body of evidence shows an important role of alterations in the olfactory bulbs (OBs) function in stress-related disorders. The aim of the present study was to investigate the impact of antidepressants on the alterations of brain-derived neurotrophic factor (BDNF) induced by lipopolysaccharide (LPS) in female rats subjected to chronic social instability stress (CSIS). METHODS: 9 weeks old female rats were subjected to CSIS and injected ip once daily with desipramine (10mg/kg), fluoxetine (5mg/kg), or tianeptine (10mg/kg) for 4 weeks. On the last day of the experiment, rats being at the estrus phase of cycle were injected ip with LPS (1mg/kg) or saline. RESULTS: The BDNF mRNA and protein levels were evaluated in the olfactory bulbs. and the BDNF protein levels were measured in plasma. A single LPS administration in the stressed rats resulted in significant decrease in the bulbar BDNF mRNA, but not in the protein level. Chronic administration of desipramine, fluoxetine, or tianeptine increased the BDNF mRNA expression and protein levels in the LPS-injected stressed rats. There was no effect of the studied antidepressants on the reduction of the plasma BDNF protein level induced by CSIS and LPS. CONCLUSIONS: These results suggest that studied antidepressants were effective in inhibiting the impact of LPS on BDNF expression in the stressed rats what may be significant for beneficial action of this drugs. PMID- 28359919 TI - The role of transient receptor potential vanilloid type 1 in unimodal and multimodal object recognition task in rats. AB - BACKGROUND: The role of transient receptor potential vanilloid type 1 (TRPV1) channels in learning and memory processes has recently been recognized. In the present study, the role of this receptor in the multisensory integration process was investigated. METHODS: This study was done using 96 male Wistar rats, which were kept in a reverse 12-12h dark/light cycle. Unimodal and multimodal object recognition task was performed by four variations of the spontaneous object recognition (SOR) test including standard SOR, tactile SOR, visual SOR, and cross modal visual-tactile SOR (CMOR). AMG9810 (selective TRPV1 antagonist) was injected into the right lateral cerebral ventricle prior to sample and choice phases of SOR. A discrimination ratio was calculated to assess the preference of the animal for the novel object. RESULTS: Results demonstrated that administration of AMG9810 prior to the sample phase, as encoding phase, and prior to the choice phase, as retrieval phase, impaired discrimination between the novel and the familiar objects in all standard SOR, tactile SOR, visual SOR, and CMOR tasks (all p<0.05). CONCLUSION: The results of this study showed that TRPV1 receptors might be implicated in both unimodal and cross-modal encoding of information in rats. PMID- 28359920 TI - HCV core antigen as an alternate test to HCV RNA for assessment of virologic responses to all-oral, interferon-free treatment in HCV genotype 1 infected patients. AB - In light of the advances in HCV therapy, simplification of diagnosis confirmation, pre- treatment diagnostic workup and treatment monitoring is required to ensure broad access to interferon-free therapies. HCV core antigen (HCV cAg) testing is rapid, giving results in approximately 60min, and less expensive than HCV RNA methods. While extensive data on the analytical performance of HCV cAg relative to RNA or comparisons in longitudinal studies of patients on interferon based (response guided) therapy there is very limited data on the relative performance of HCV cAg in diagnosis and monitoring patients receiving all-oral interferon free regimens. Furthermore, there is no data in the literature that describes the specificity of HCV cAg in patients with resolved HCV infection i.e. anti-HCV positive/HCV RNA negative. In this study a total of 1201 plasma samples from the 411 HCV genotype 1 subjects with a HCV RNA viral load >50,000IU/ml who enrolled in a clinical trial with ombitasvir, ritonavir boosted paritaprevir and dasabuvir, with or without ribavirin were retrospectively tested in a blinded fashion with HCV cAg test and results were compared to HCV RNA levels. The specificity of the HCV cAg test was also evaluated in anti-HCV positive but HCV RNA negative samples. Overall concordance between HCV cAg and HCV RNA was 98.6% while concordance in pre-treatment samples was 99.5% (409/411; n=2 HCV RNA pos. with viral loads>3 Mill IU/ml but HCV cAg neg.) and 99.24% in post treatment week 12 samples (391/394; n=2 HCV RNA pos.<25IU/ml and n=1 HCV RNA pos. 2180IU/ml). Specificity in anti-HCV positive HCV RNA negative samples tested was 100%. PMID- 28359921 TI - Increased 30-Day Complication Rates Associated with Laminectomy in 874 Adult Patients with Spinal Deformity Undergoing Elective Spinal Fusion: A Single Institutional Study. AB - OBJECTIVE: Recent studies have reported that decompression with fusion leads to superior outcomes in correction of spinal deformity. The aim of this study was to determine if there is a difference in intraoperative and 30-day postoperative complication rates in patients undergoing spinal fusion with and without decompression. METHODS: Medical records of 874 adult (>=18 years old) patients with spinal deformity undergoing elective spinal fusion at a major academic institution from 2005 to 2015 were reviewed; 374 (42.8%) patients underwent laminectomy in addition to spinal fusion. The primary outcome investigated was the rate of intraoperative and 30-day complications. RESULTS: Patient demographics and comorbidities were similar between groups. The laminectomy cohort had significantly higher estimated blood loss (P < 0.0001), incidence of allogeneic blood transfusions (P = 0.0001), and rate of intraoperative durotomies (laminectomy cohort 10.4% vs. no-laminectomy cohort 3.1%; P < 0.0001). The laminectomy cohort had a significantly higher proportion of patients in the intensive care unit (28.6% vs. 17.7%; P < 0.001). There was no significant difference in 30-day readmission rate between cohorts (laminectomy cohort 13.0% vs. no-laminectomy cohort 9.8%; P = 0.13). Within 30 days after initial discharge, the laminectomy cohort had significantly higher rates of altered mental status (3.2% vs. 1.2%; P = 0.05), urinary tract infection (4.3% vs. 1.4%; P = 0.009), wound drainage (7.2% vs. 3.1%; P = 0.007), and instrumentation failure (1.1% vs. 0.0%; P = 0.03). CONCLUSIONS: Patients undergoing spinal fusion with laminectomy may have higher complication rates than patients undergoing spinal fusion alone. PMID- 28359923 TI - Overlapped Stenting Combined with Coiling for Blood Blister-Like Aneurysms: Comparison of Low-Profile Visualized Intraluminal Support (LVIS) Stent and Non LVIS Stent. AB - OBJECTIVE: To evaluate the safety and efficacy of overlapped stenting for blood blister-like aneurysms (BBAs) and to compare the outcomes between Low-profile Visualized Intraluminal Support (LVIS) and non-LVIS stents. METHODS: A retrospective review of the aneurysm database identified 37 patients with intracranial carotid artery BBAs treated by overlapped stenting in our institution from June 2013 to June 2016. The clinical characteristics and angiographic results were reviewed. RESULTS: Overlapped stenting combined with coiling were applied in 37 BBAs, including LVIS stents in 18 cases and non-LVIS stents in 19. For the LVIS group, angiographic results at 3-24 months were complete occlusion in 15 cases (83.3%), improved in 2 cases (11.1%), and recanalized in 1 case (5.6%). The modified Rankin Scale scores at 3-36 months' follow-up were 0-2 in 15 cases (83.3%) and 3-6 in 3 cases (16.7%). For the non LVIS group, angiographic results at 3-46 months were complete occlusion in 12 cases (63.2%) and recanalized in 7 cases (36.8%). Clinical outcomes at 6-58 months were modified Rankin Scale scores of 0-2 in 17 cases (89.5%) and 3-6 in 2 cases (10.5%). Use of the LVIS stent was less likely to result in recanalization (odds ratio 0.10, 95% confidence interval 0.01-0.93, P = 0.042) than the non-LVIS stent. The LVIS group had a lower average number of stents than did the non-LVIS group (2.2 vs. 2.6, P = 0.016). In terms of complication rate (11.1% vs. 5.3%, P = 0.604), good outcome rate (83.3% vs. 89.5%, P = 0.660), and immediate angiographic result (P = 0.424), no statistically significant difference between the 2 groups was found. CONCLUSIONS: Overlapped LVIS stenting combined with coiling is feasible and safe for BBAs. Overall, the LVIS stent provided less risk of BBA recurrence compared with the non-LVIS stent and did not increase the risk of procedure-related complications. PMID- 28359922 TI - First Application of 7-T Magnetic Resonance Imaging in Endoscopic Endonasal Surgery of Skull Base Tumors. AB - BACKGROUND: Successful endoscopic endonasal surgery for the resection of skull base tumors is reliant on preoperative imaging to delineate pathology from the surrounding anatomy. The increased signal-to-noise ratio afforded by 7-T MRI can be used to increase spatial and contrast resolution, which may lend itself to improved imaging of the skull base. In this study, we apply a 7-T imaging protocol to patients with skull base tumors and compare the images with clinical standard of care. METHODS: Images were acquired at 7 T on 11 patients with skull base lesions. Two neuroradiologists evaluated clinical 1.5-, 3-, and 7-T scans for detection of intracavernous cranial nerves and internal carotid artery (ICA) branches. Detection rates were compared. Images were used for surgical planning and uploaded to a neuronavigation platform and used to guide surgery. RESULTS: Image analysis yielded improved detection rates of cranial nerves and ICA branches at 7 T. The 7-T images were successfully incorporated into preoperative planning and intraoperative neuronavigation. CONCLUSIONS: Our study represents the first application of 7-T MRI to the full neurosurgical workflow for endoscopic endonasal surgery. We detected higher rates of cranial nerves and ICA branches at 7-T MRI compared with 3- and 1.5-T MRI, and found that integration of 7 T into surgical planning and guidance was feasible. These results suggest a potential for 7-T MRI to reduce surgical complications. Future studies comparing standardized 7-, 3-, and 1.5-T MRI protocols in a larger number of patients are warranted to determine the relative benefit of 7-T MRI for endonasal endoscopic surgical efficacy. PMID- 28359924 TI - Prolonged Cerebral Hyperperfusion and Subcortical Low Intensity on Fluid Attenuated Inversion Recovery Images: Unusual Manifestation After Removal of Organized Chronic Subdural Hematoma. AB - BACKGROUND: Cerebral hyperperfusion sometimes occurs after removal of chronic subdural hematoma (CSH) and usually resolves within a few days without any symptoms. Subcortical low intensity (SCLI) on fluid-attenuated inversion recovery (FLAIR) magnetic resonance images is rare and has been reported in some diseases other than CSH. A case of organized CSH who suffered prolonged neurologic deterioration, SCLI, and cerebral hyperperfusion postoperatively is described. CASE DESCRIPTION: An 81-year-old man, presenting with left hemiparesis, underwent craniotomy for right organized CSH after 2 burr-hole surgeries. After the craniotomy, the symptoms improved, but on postoperative day 2, left hemiparesis, hemispatial neglect, and hemiasomatognosia developed. Magnetic resonance imaging revealed SCLI on FLAIR images, and single-photon emission computed tomography with N-isopropyl-p-[123I]-iodoamphetamine revealed cerebral hyperperfusion in the right hemispheric cortex. Antihypertensive treatment improved the symptoms gradually, which resolved completely 1 month postsurgery. CONCLUSIONS: A case of organized CSH, which showed postoperative neurologic deterioration associated with prolonged cerebral hyperperfusion and SCLI on FLAIR images, is reported. Prolonged cerebral hyperperfusion could be a cause of postoperative neurologic deterioration in organized CSH. PMID- 28359925 TI - Results of Proactive Surgical Clipping in Poor-Grade Aneurysmal Subarachnoid Hemorrhage: Pattern of Recovery and Predictors of Outcome. AB - BACKGROUND: The outcome associated with the treatment of poor-grade aneurysmal subarachnoid hemorrhage is rather discouraging. Even then, some patients may survive; however, the long-term outcomes and the patterns of recovery of these survivors have not received much attention in the literature. METHODS: A total of 85 patients (mean age 53.3 years, male/female = 34:51, 98 aneurysms) with post resuscitation Hunt and Hess grades 4 and 5 subarachnoid hemorrhage were studied. Modified Rankin Scale score was used to determine the functional outcome. Different factors were analyzed with uni- and multivariate models for their effect on the functional outcomes after surgery. RESULTS: A total of 23 patients died in the 30-day perioperative period, whereas 8 patients died at follow-up (n = 31, 36.5%). Nearly 35% and 51% of the survivors obtained favorable short- and long-term functional outcomes, respectively. The presence of a space-occupying hematoma (P = 0.014) and the functional status at discharge significantly affected the long-term functionality (P = 0.004) in our patients. The functional improvement was steady with time (the probability of good outcome at about 2 months of discharge was around 65%, about 55% at 1 year, and 40% at 2 years and then achieved a plateau). Marked improvement occurred in 11% survivors even after 18 months. CONCLUSIONS: If operated at the earliest opportunity after admission, meaningful survival may be provided to a significant number of patients with poor grade subarachnoid hemorrhage. The recovery process in the survivors is a dynamic process and considering the late improvements in some, it is advisable be follow them beyond the conventional end points. PMID- 28359926 TI - Therapy Decisions for Patients with High-Grade Glioma and Their Families. PMID- 28359928 TI - The attentional demands of ambulating with an assistive device in older adults with Alzheimer's disease. AB - Ambulation with a mobility aid is a unique real-life situation of multi-tasking. These simultaneous motor tasks place increased demands on executive function in healthy young and older adults, but the demands have not been evaluated in people with Alzheimer's disease (AD). Mobility problems are common among adults with AD, leading to provision of a mobility aid to optimize independent activity. The study objectives were: (i) to determine the dual-task cost (DTC) associated with the use of a mobility aid in straight and complex path walking, and (ii) to evaluate the association between executive function and ambulation with a mobility aid in older adults with AD and age-sex matched cognitively normal controls. Fourteen people (mean age+/-SD, 72.6+/-9.9years) with a diagnosis of probable AD (MMSE range 12-25) and controls (mean age+/-SD, 72.9+/-9.5) walked at a self-selected pace and using a 4-wheeled walker in a 6m straight path and a Figure of 8 Test. Ambulation with the walker in a straight path produced a low DTC that was not different between the groups. Ambulation with the 4-wheeled walker in the complex path produced a significantly different DTC in the group with AD at -38.1+/-23.5% compared to -19.7+/-21.4% (p=0.041). Lower scores on executive function were associated with longer times across test conditions. Ambulation with a 4-wheeled walker, in particular maneuvering around obstacles, requires greater attentional costs in dementia. Future research should explore the timing for safely introducing mobility aids in AD and the role of improving executive function. PMID- 28359929 TI - Asymptomatic radiographic hip osteoarthritis is associated with gait differences, especially in women: A population-based study. AB - BACKGROUND: Hip and knee osteoarthritis (OA) are debilitating diseases that impair gait at severe stages. Although associations between OA and gait are established for normal walking, little is known about its relation with turning and tandem (heel-to-toe) walking. Furthermore, it is unknown how asymptomatic OA associates with gait, and whether associations differ by sex. We investigated how symptomatic and asymptomatic hip and knee OA associate with gait in community dwelling individuals. METHODS: In 2706 participants of a population-based cohort study, gait was assessed by electronic walkway and summarised into seven gait domains. Hip and knee radiographs were graded for radiographic OA (ROA) using the Kellgren and Lawrence (K&L) score. Linear regression was used to investigate associations between ROA and gait. Analyses were repeated including only participants with asymptomatic ROA, defined as a K&L-score of 2 without pain. RESULTS: In total, 177 participants (6.5%) had hip ROA and 441 (16.3%) knee ROA. We found no associations of knee ROA with gait. Hip ROA associated with Rhythm, Tandem, and Turning. Furthermore, unilateral hip ROA associated with larger gait asymmetry and gait differences in osteoarthritic and non-osteoarthritic leg, when compared to people without hip ROA. Associations between hip ROA and gait were generally stronger for women than men. Associations for hip ROA remained after restricting to asymptomatic ROA. CONCLUSION: Hip ROA, but not knee ROA, associates with gait differences in normal walking, turning, and tandem walking in community-dwelling individuals. These associations differ between the sexes, and are already present for asymptomatic ROA. PMID- 28359927 TI - Ultrasonography During Surgery to Approach Cerebral Metastases: Effect on Karnofsky Index Scores and Tumor Volume. AB - BACKGROUND: The goals of treating a cerebral metastasis (CM) are to achieve local control of the disease and to improve patient quality of life. The aim of this study was to analyze the effect of conventional surgery supported by intraoperative ultrasound (IOUS) to approach a CM. To perform this analysis, we determined the postoperative Karnofsky Performance Status Scale (KPS) scores and tumor resection grades. METHODS: Patients with a CM diagnosis were included in this study. Surgical treatment was either supported or not by IOUS. Pre- and postoperative KPS scores were determined by the oncology team, and cerebral tumor volume was estimated through pre- and postoperative magnetic resonance imaging. The surgical team determined whether it was possible to perform a total CM resection. RESULTS: There were 78 patients treated using surgical management (35 with and 43 without IOUS). In the IOUS group, the postoperative KPS scores were higher (80 vs. 70, respectively; P = 0.045) and the KPS evolution was superior (P = 0.036), especially in the following subgroups: difficulty of tumor resection ranking score <4 (P = 0.037), tumor in an eloquent area (P = 0.043), tumor not associated with vessels or nerves (P = 0.007), and solitary lesions (P = 0.038). The residual tumor volume was lower in the IOUS group (9.5% and 1.6 mm3 vs. 30.8% and 9 mm3, respectively; P = 0.05). In patients with a KPS score >=70, 62% of them had <10% residual tumors (76% in the IOUS group and 45% in the non-IOUS group; P = 0.032; odds ratio, 3.8). CONCLUSIONS: IOUS may improve postoperative KPS scores and decrease residual tumor volumes in CM surgeries. These findings should be confirmed in future studies. PMID- 28359930 TI - Wiedemann-Steiner syndrome: Novel pathogenic variant and review of literature. AB - Wiedemann-Steiner syndrome (WDSTS) is a very rare genetic disorder characterized by short stature, intellectual disability and distinctive facial appearance. We present a five-year-old boy who was diagnosed with WDSTS based on identification of a novel de novo pathogenic variant in the KMT2A gene (OMIM: 159555) by Whole Exome Sequencing and supported by some characteristic clinical features. Genotype and phenotype of the patient is compared with the earlier reported patients in the literature, in an attempt to broaden our knowledge of this rare syndrome. PMID- 28359931 TI - Transplanting mouse induced pluripotent stem cells into mouse otocysts in vivo. AB - The otocyst is an attractive target for studying treatment strategies for genetic hearing loss and for understanding inner ear development. We have previously reported that trans-uterine supplemental gene therapy in vivo into the otocysts of mice, which had a loss of function mutation in a causative gene of deafness, was able to prevent putative hearing loss. We herein set out to clarify the feasibility of allogenic cell transplantation into the mouse otocysts in vivo. We transplanted naive mouse-derived induced pluripotent stem cells (miPSCs) into the otocysts of wild type mice or connexin (Cx) 30 deficient mice, at embryonic day 11.5 (E11.5). The transplanted m-iPSCs survived in the lumens of the inner ears at E13.5 and E15.5 in wild type mice. In the Cx30 deficient mouse, the transplanted cells survived similarly, with some of the transplanted cells migrating into the lining cells of the lumens of the inner ears at E13.5 and showing tumorigenic cell proliferation at E15.5. In addition, engrafted cells appear to be able to differentiate after the cell transplantation. Our results suggest that otocyst transplanted cells survived and differentiated. A Cx30 deficiency may facilitate cell migration. These findings may offer some hope for cell transplantation therapy for profound genetic hearing loss caused by a Cxs deficiency. PMID- 28359932 TI - Increased abundance of myeloid-derived suppressor cells and Th17 cells in peripheral blood of newly-diagnosed Parkinson's disease patients. AB - Parkinson's disease (PD) is a neurodegenerative disease that is often associated with corresponding neuroinflammation. In the present study, flow cytometry was used to detect T-helper 17 (Th17) cells and myeloid-derived suppressor cells (MDSCs) in 18 patients newly diagnosed with PD as well as 18 normal controls. Results showed that Th17 cells and MDSCs were significantly higher in peripheral blood of PD patients compared to controls (P<0.001). Furthermore, there was no correlation between Th17 cells and MDSCs in peripheral blood of PD patients. Our findings suggest that Th17 cells and MDSCs may be important factors related to the occurrence and progression of PD, as well as the development of PD-related neuroinflammation. PMID- 28359933 TI - Recombinant human erythropoietin offers neuroprotection through inducing endogenous erythropoietin receptor and neuroglobin in a neonatal rat model of periventricular white matter damage. AB - Recombinant human erythropoietin (rh-EPO) has been reported to have protective effects against brain injury. The purpose of this study was to evaluate the levels of erythropoietin receptor (EPOR) and neuroglobin (Ngb) in a neonatal rat model of periventricular white matter damage (PWMD), and to identify the relationship between the two proteins. On postnatal day 3 (P3), rats underwent permanent ligation of the right common carotid artery followed by 6% O2 for 4h (HI) or sham operation and normoxic exposure (sham). Immediately after HI, rats received a single intraperitoneal injection of rh-EPO (5U/g) or saline. We assessed the expression level of Ngb and EPOR on postnatal days 5, 7, 10 and 14. EPOR in the HI rats was initially increased as compared to the sham rats at P5. Subsequently, EPOR expression decreased, but was maintained at a higher level than in sham rats from P7 to P14. In rh-EPO treated rats, the increase in EPOR was greater than in HI rats at P5. However, EPOR levels decreased sharply from P7 to P14. In HI rats, Ngb was increased compared to the sham rats from P5 to P14. Ngb levels were further upregulated after rh-EPO administration from P5 to P10 compared to HI rats. However, this upregulation decreased at P14. In conclusion, this study shows that EPOR and Ngb were upregulated, and both of them act as important coordinated neuroprotectors in rh-EPO treatment of PWMD. However, the two proteins exhibit different expression patterns. PMID- 28359934 TI - CXCL13 regulates the trafficking of GluN2B-containing NMDA receptor via IL-17 in the development of remifentanil-induced hyperalgesia in rats. AB - BACKGROUND: This study aimed to investigate whether CXCL13 modulated the trafficking of NMDA receptor via interleukin (IL)-17 in a rat model of remifentanil-induced hyperalgesia (RIH).Although chemokines are crucial regulators of neuroinflammation, spinal N-methyl-d-aspartate (NMDA) receptor activation, and development of hypernociceptive process, little is known about specific pathogenesis and effective treatment. Inflammatory mediators are required for excitatory synaptic transmission in pathologic pain. METHODS: A neutralizing antibody against CXCL13 (anti-CXCL13), antiserum against IL-17 (anti IL-17), and recombinant CXCL13 and IL-17 were administered intrathecally to explore the roles of CXCL13, IL-17, and NMDA receptor, as well as the prevention of hyperalgesia. Paw withdrawal threshold and paw withdrawal latency were employed to record mechanical allodynia and thermal hyperalgesia. Reverse transcriptase quantitative polymerase chain reaction was used to evaluate the levels of CXCL13/CXCR5 and IL-17/IL-17RA in the spinal dorsal horn. The trafficking of spinal GluN2B-containing NMDA receptor was assessed by Western blot after nociceptive testing. RESULTS: This study found mechanical allodynia and thermal hyperalgesia with a remarkable increase in the expression of spinal CXCL13/CXCR5 and IL-17/IL-17RA and trafficking of GluN2B-containing NMDA receptor after remifentanil exposure. Behavioral RIH and elevated GluN2B trafficking were dampened by intrathecal anti-CXCL13 and anti-IL-17, respectively. The delivery of exogenous CXCL13 dose-dependently generated a rapid nociceptive hypersensitivity in naive rats, which was prevented by coadministering anti-IL-17. CXCL13-induced IL-17RA overproduction and GluN2B trafficking were reversed by anti-IL-17 treatment. GluN2B antagonist also blocked CXCL13, and IL-17 directly induced hyperalgesia. CONCLUSION: This study highlighted the contribution of IL-17 pathway in the trafficking of CXCL13-induced GluN2B-containing NMDA receptor in the pathogenesis of RIH. PMID- 28359935 TI - A large increase of sour taste receptor cells in Skn-1-deficient mice does not alter the number of their sour taste signal-transmitting gustatory neurons. AB - The connections between taste receptor cells (TRCs) and innervating gustatory neurons are formed in a mutually dependent manner during development. To investigate whether a change in the ratio of cell types that compose taste buds influences the number of innervating gustatory neurons, we analyzed the proportion of gustatory neurons that transmit sour taste signals in adult Skn-1a /- mice in which the number of sour TRCs is greatly increased. We generated polycystic kidney disease 1 like 3-wheat germ agglutinin (pkd1l3-WGA)/Skn-1a+/+ and pkd1l3-WGA/Skn-1a-/- mice by crossing Skn-1a-/- mice and pkd1l3-WGA transgenic mice, in which neural pathways of sour taste signals can be visualized. The number of WGA-positive cells in the circumvallate papillae is 3 fold higher in taste buds of pkd1l3-WGA/Skn-1a-/- mice relative to pkd1l3-WGA/Skn 1a+/+ mice. Intriguingly, the ratio of WGA-positive neurons to P2X2-expressing gustatory neurons in nodose/petrosal ganglia was similar between pkd1l3-WGA/Skn 1a+/+ and pkd1l3-WGA/Skn-1a-/- mice. In conclusion, an alteration in the ratio of cell types that compose taste buds does not influence the number of gustatory neurons that transmit sour taste signals. PMID- 28359936 TI - Selective photoinactivation of Histoplasma capsulatum by water-soluble derivatives chalcones. AB - Histoplasmosis is a respiratory and systemic disease caused by the dimorphic fungus Histoplasma capsulatum. The clinical features may vary from asymptomatic infections to disseminated severe form depending of patient immunity. The treatment of histoplasmosis can be performed with itraconazole, fluconazole, and in the disseminated forms is used amphotericin B. However, the critical side effects of amphotericin B, the cases of itraconazole therapy failure and the appearance of fluconozole-resistant strains makes necessary the search of new strategies to treat this disease. Antimicrobial photodynamic therapy (aPDT) seems to be a potential candidate once have been show efficacy to inhibit others dimorphic fungi. Although the photosensitizer (PS) chalcone aggregates in biological medium, it has antifungal activity and show a high quantum yield of ROS formation. So, the aim of this study was to obtain the experimental parameters to achieve an acceptable selective chalcone water-soluble derivatives photoinactivation of H. capsulatum comparing with fibroblastic and keratinocytes cells which are the constituents of some potential host tissues. Yeast and cells were incubated with the same chalchones concentrations and short incubation time followed by irradiation with equal dose of light. The best conditions to kill H. capsulatum selectively were very low photosensitizers concentration (1.95MUgmL-1) incubated by 15min and irradiated with LED 450nm with 24Jcm-2. Key words: chalcone, Histoplasma capsulatum, aPDT, selectivity. PMID- 28359937 TI - Pilot study on laser propagation in maxillary and mandibular bone: Grey level image analysis for optical measurements. AB - BACKGROUND: Bone tissue anatomy, density and porosity vary among subjects in different phases of life and even within areas of a single specimen. The optical characteristics of changes in bone tissue are analyzed based on these properties. Photobiomodulation has been used to improve bone healing after surgery or fractures. Thus, knowledge on light propagation is of considerable importance to the obtainment of successful clinical outcomes. OBJECTIVE: This study determines light penetration and distribution in human maxillary and mandibular bones in three different regions (anterior, middle, and posterior). METHODS: A HeNe laser (633nm) irradiated maxillary and mandibular bones in the cervical-apical direction. The light propagation and scattering pattern were acquired and the grey level of the images was analyzed. Three-dimensional plots of the intensity profile and attenuation profiles were created. RESULTS: Differences in optical properties were found between the mandibular and maxillary bones. The maxilla attenuated more light than the mandible at all sites, leading to a shallower penetration depth. CONCLUSION: Our results provide initial information on the behavior of the propagation of red laser on alveolar bone using an optical method. PMID- 28359938 TI - Effect of antimicrobial photodynamic therapy on the counts of salivary Streptococcus mutans in children with severe early childhood caries. AB - BACKGROUND: Antimicrobial photodynamic therapy (aPDT) is a novel technique for reduction of pathogenic microorganisms in dentistry. The aim of this study was to evaluate the effects of aPDT on Streptococcus mutans reduction in children with severe early childhood caries. METHODS: Twenty-two children with severe early childhood caries aged 3-6 years were treated with toluoidine blue O (TBO) for 1min and irradiated by a Light Emitting Diode (LED; FotoSan, CMS Dental, Denmark) with the exposure time of 150s. Saliva samples were collected at baseline, 1h and 7 days after treatment. S. mutans counts were determined using the Dentocult SM Strip mutans. RESULTS: The counts of S. mutans in saliva decreased significantly after 1h (P<0.001). However, the difference in reduction of S. mutans counts in saliva was not significant between the baseline and 7 days after treatment (P>0.05). CONCLUSION: aPDT seems to be efficient to reduce salivary S. mutans immediately after treatment in children with severe early childhood caries. However, further research is needed to evaluate different doses and frequency of irradiation in combination with restoring carious teeth to find more durable results. PMID- 28359940 TI - Oval gradient coils for an open magnetic resonance imaging system with a vertical magnetic field. AB - Existing open magnetic resonance imaging (MRI) systems use biplanar gradient coils for the spatial encoding of signals. We propose using novel oval gradient coils for an open vertical-field MRI. We designed oval gradients for a 0.3T open MRI system and showed that such a system could outperform a traditional biplanar gradient system while maintaining adequate gradient homogeneity and subject accessibility. Such oval gradient coils would exhibit high efficiency, low inductance and resistance, and high switching capability. Although the designed oval Y and Z coils showed more heat dissipation and less cooling capability than biplanar coils with the same gap, they showed an efficient heat-dissipation path to the surrounding air, which would alleviate the heat problem. The performance of the designed oval-coil system was demonstrated experimentally by imaging a human hand. PMID- 28359941 TI - Maternal cigarette smoking during pregnancy and the trajectory of externalizing and internalizing symptoms across childhood: Similarities and differences across parent, teacher, and self reports. AB - Maternal smoking during pregnancy (MSDP) has been associated with symptoms of externalizing (e.g., hyperactivity) and internalizing (e.g., emotional) disorders in childhood. The present research addresses two new questions about the nature of this relation: (1) Do the associations between MSDP and externalizing and internalizing symptoms vary by who reports the symptoms? and (2) Is MSDP associated with changes in symptomatology across childhood? We address these questions with two cohorts from the Longitudinal Study of Australian Children (LSAC). Parents and teachers completed the Strengths and Difficulties Questionnaire up to six times every two years between child ages 4 and 14 in the older cohort (N = 3841) and up to four times between child ages 4 and 10 in the younger cohort (N = 3714); the study children also completed the same questionnaire up to three times starting at age 10. Across the two cohorts, MSDP was associated with more externalizing symptoms as reported by parents, teachers, and self. MSDP was also associated with increases in externalizing symptoms across childhood when teachers assessed the symptoms but not when parents assessed them. Finally, MSDP was not consistently associated with the average level of internalizing symptoms, but it was associated with increases in these symptoms across childhood. The present research indicates a robust association between MSDP and the average level of externalizing symptoms in childhood regardless of who reports the symptoms. It also indicates that whether MSDP is associated with the trajectory of externalizing symptomatology depends on who reports on the symptoms. PMID- 28359939 TI - Tropomyosin 1: Multiple roles in the developing heart and in the formation of congenital heart defects. AB - Tropomyosin 1 (TPM1) is an essential sarcomeric component, stabilising the thin filament and facilitating actin's interaction with myosin. A number of sarcomeric proteins, such as alpha myosin heavy chain, play crucial roles in cardiac development. Mutations in these genes have been linked to congenital heart defects (CHDs), occurring in approximately 1 in 145 live births. To date, TPM1 has not been associated with isolated CHDs. Analysis of 380 CHD cases revealed three novel mutations in the TPM1 gene; IVS1+2T>C, I130V, S229F and a polyadenylation signal site variant GATAAA/AATAAA. Analysis of IVS1+2T>C revealed aberrant pre-mRNA splicing. In addition, abnormal structural properties were found in hearts transfected with TPM1 carrying I130V and S229F mutations. Phenotypic analysis of TPM1 morpholino-treated embryos revealed roles for TPM1 in cardiac looping, atrial septation and ventricular trabeculae formation and increased apoptosis was seen within the heart. In addition, sarcomere assembly was affected and altered action potentials were exhibited. This study demonstrated that sarcomeric TPM1 plays vital roles in cardiogenesis and is a suitable candidate gene for screening individuals with isolated CHDs. PMID- 28359942 TI - Production, characterization and application of monoclonal antibody against immunoglobulin D heavy chain of flounder (Paralichthys olivaceus). AB - Immunoglobulin D (IgD) is considered to be an enigmatic Ig molecule because of the lack understanding of its immunological functions. In the present study, a partial delta region of the flounder IgD was recombinantly expressed, purified and used as an immunogen to produce monoclonal antibodies (MAbs) against the H chain of flounder IgD. After fusion, a total of 97 hybridomas were generated and observed under an inverted microscope One of the hybridomas, designated 5G7, gave strong positive results in an indirect enzyme-linked immunosorbent assay (ELISA) and was cloned and subcloned by limiting dilution. Western blot analysis showed that MAb 5G7 could specifically recognize a 118 kDa protein from peripheral blood lymphocytes (PBLs), which was identified to be the H chain of flounder IgD by mass spectrometric analysis. Indirect immunofluorescence assay tests (IIFAT) showed that specific fluorescence signals were observed on the membranes of the PBLs, which suggests that MAb 5G7 could recognize the membrane-bound IgD molecule. Moreover, only the subset of IgD+/IgM + B cells were observed in the PBLs of healthy flounder when tested by flow cytometry analysis. Consistent with the results of flow cytometry, a double immunofluorescence assay test (DIFAT) showed that the positive lymphocytes were stained with both green and red fluorescence signals, which represent the IgM+/IgD + lymphocytes subset. These results demonstrate that the produced MAb 5G7 could specifically recognize the flounder IgD, which provides a useful tool to study the functions of flounder IgD. PMID- 28359943 TI - BNIP3, a cell pro-apoptotic protein, involved in response to viral infection in orange spotted grouper, Epinephelus coioides. AB - BNIP3 is a kind of BH3-only protein that induces both cell death and autophagy. Here, a BNIP3 gene (EcBNIP3) was identified from orange spotted grouper, Epinephelus coioides. EcBNIP3 possessed 236 amino acids residues, contained a conservative BNIP3 domain and a transmembrane region. Besides, EcBNIP3 expressed at a relative high level in heart and spleen. EcBNIP3 transcript was up-regulated after SGIV infection in vitro. Subcellular localization analysis revealed that EcBNIP3 was predominantly localized in the cytoplasm and co-localized with mitochondria. In addition, overexpression EcBNIP3 accelerated SGIV infection induced cell death but inhibited viral genes transcription. Taken together, these results provided new evidence that fish BNIP3 might involved in response to virus infection. PMID- 28359944 TI - Dietary dehydrated lemon peel improves the immune but not the antioxidant status of gilthead seabream (Sparus aurata L.). AB - Lemon (Citrus limon) is the third most important species of citrus in the world, while Spain is the major producer in Europe. Numerous beneficial effects of lemon are known, which explains their use in traditional medicine. The paper describes the effect of dietary dehydrated lemon peel (a sub-product of the lemon industry) on the growth, immune and antioxidant status of gilthead seabream (Sparus aurata L.) over a period of 30 days. Fish fed diets enriched with dehydrated lemon peel (1.5% and 3%) for 15 days showed improved growth and both humoral (seric immunoglobulin M) and cellular (peroxidase activity and phagocytic ability of head kidney leucocytes) immunity, as well as the expression of some immune related genes (nkefa, il1beta, igth and csfr1). However, decreases growth promotion was observed after thirty days of trial. Neither the anti-oxidant enzymes activity nor the expression of several anti-oxidants and anti-stress genes in liver was improved by the diet. The possible inclusion of dehydrated lemon peel in fish diets for its immunostimulant effects is discussed. PMID- 28359945 TI - Supplementation of arachidonic acid rich oil in European sea bass juveniles (Dicentrarchus labrax) diets: Effects on leucocytes and plasma fatty acid profiles, selected immune parameters and circulating prostaglandins levels. AB - The main objective of this study was to assess the effects of graded levels of dietary arachidonic acid (ARA), supplemented from alternative sources, on fatty acid composition of plasma and head kidney leucocytes of European sea bass (Dicentrarchus labrax). For that purpose, sea bass juveniles were fed four diets containing graded levels of ARA as follows: 0.5% (ARA0.5), 1% (ARA1), 2% (ARA2) and 4% (ARA4) during 60 days. At the end of the feeding trial fatty acid profiles of plasma and head kidney leucocytes were analyzed. Besides, plasma prostaglandins levels, head kidney leucocytes respiratory burst activity; peroxidase activity and phagocytic index were assayed. Reducing dietary ARA levels below 1% markedly reduced European sea bass growth performance. However, fish fed diet ARA0.5 tried to compensate this dietary ARA deficiency by a selective deposition of ARA on plasma and head kidney leucocytes, reaching similar levels to those fish fed diet ARA1 after 60 days of feeding. Nevertheless, head kidney phagocytic capacity was reduced as dietary ARA content in relation not only to variations on membrane composition but also to changes on fish basal prostaglandins levels. Results obtained demonstrated the importance to supply the necessary quantity n-6 LC-PUFA, and not only n-3 LC-PUFA levels, in European sea bass diets, in relation to not only growth performance but also immune system function. PMID- 28359946 TI - Use of in vivo induced technology to identify antigens expressed by Photobacterium damselae subsp. piscicida during infection of Senegalese sole (Solea senegalensis). AB - Photobacterium damselae subsp. piscicida (Phdp), the causative agent of photobacteriosis, is an important pathogen in marine aquaculture that affects many different fish species worldwide, including Solea senegalensis, an important fish species for aquaculture in the south of Europe. Bacteria express different repertoires of proteins in response to environmental conditions and when invading a host, sense in vivo environment and adapt by changing the expression of specific proteins. In the case of pathogens, identification of genes with up regulated expression in vivo compared to in vitro conditions might give an insight into the genes relevant to the bacterial virulence. In the present work, in vivo induced antigen technology (IVIAT) has been used to search for Phdp genes only expressed or up-regulated in infected S. senegalensis. An expression library from Phdp was assayed against pooled sera from convalescent S. senegalensis specimens and 18 clones were positive, indicating that proteins encoded are expressed by Phdp during S. senegalensis infection and are immunogenic for this fish species. In addition, five proteins were reactive against adsorbed sera, indicating their in vivo induced character. Inosine-5'-monophosphate dehydrogenase, serine hydroxy methyltransferase and alanyl-tRNA synthethase, involved in aminoacid and nucleotide metabolism, the protein with antioxidant activity alkyl hydroperoxide reductase and a non-ribosomal peptide synthetase responsible for the synthesis of the siderophore piscibactin have been identified as antigens induced in Phdp during S. senegalensis infection. Proteins induced during in vivo growth of Phdp represent promising targets for the development of novel antimicrobial or prophylactic agents in the treatment and prevention of photobacteriosis. PMID- 28359947 TI - The hot-water extract of leaves of noni, Morinda citrifolia, promotes the immunocompetence of giant freshwater prawn, Macrobrachium rosenbergii. AB - The hot-water Morinda citrifolia leaf extract (HMLE) was prepared for in vitro assessment on phenoloxidase (PO) activity, respiratory bursts (RBs), and phagocytic activity (PA). Furthermore, the HMLE was administrated in the diet at 0.6, 3, and 6 g (kg diet)-1 for Macrobrachium rosenbergii, and the potential effects on the immunocompetence of prawns were evaluated. PO activity, RBs, and PA in hemocytes incubated with the HMLE at 140, 20, 20, and 140 mg l-1 significantly increased. The immune parameters of the total hemocyte count (THC), differential hemocyte count (DHC), RBs, PO activity, superoxide dismutase (SOD) activity, PA, transglutaminase (TG) activity and hemolymph clotting time were evaluated before and after 1, 3, 5, 7, and 9 weeks of the feeding trial. During 9 weeks of the feeding trial, higher THCs, DHCs, RBs, PO, and TG as well as accelerated clotting times were observed in prawns fed HMLE-containing diets at 0.6 g kg-1. The mRNA expressions of prophenoloxidase, TG, crustin, and lysozyme of prawns fed HMLE-containing diets at 0.6 g kg-1 for 9 weeks of the feeding trial significantly increased. The susceptibility of prawns fed the HMLE at 0.6 g kg-1 to Lactococcus garvieae infection significantly decreased, and the relative survival percentage was 23.1%. We therefore found that HMLE administrated through the diet at 0.6 g kg-1 was capable of enhancing the immunity and resistance against L. garvieae in M. rosenbergii. PMID- 28359948 TI - Effect of dietary Clostridium butyricum on growth, intestine health status and resistance to ammonia stress in Pacific white shrimp Litopenaeus vannamei. AB - The present study evaluated the effect of dietary Clostridium butyricum (CB) on growth, intestine microstructure, intestine digestive and immune function, intestine short-chain fatty acids (SCFA) content and body composition of Pacific white shrimp Litopenaeus vannamei. The shrimp was fed for 56 d with diets containing different levels of C. butyricum (1 * 109 cfu/g): 0% (Control), 0.25% (CB1), 0.5% (CB2) and 1.0% (CB3) as treatment groups, followed by an acute ammonia stress test for 72 h. The results indicated that dietary supplementation of C. butyricum decreased the feed conversion rate (FCR) and increased the growth performance of shrimp. Compared with the control group, after shrimp fed with C. butyricum 56 d, intestine amylase and protease activity in the three C. butyricum group increased, while lipase activity was only affected in the CB1 and CB2 group. Total antioxidant capacity (T-AOC) content, lysozyme (LSZ) activity, and the relative expression level of Toll and immune deficiency (Imd) gene all increased in three C. butyricum groups. Inducible nitric oxide synthase (iNOS) activity increased in the CB2 and CB3 group, heat shock protein 70 (HSP70) gene expression level increased in the CB3 group, while nitric oxide (NO) content was not affected by C. butyricum. After shrimp exposed to ammonia stress, intestine immune biochemical parameters (T-AOC, LSZ, iNOS and NO) and genes (HSP70, Toll and Imd) expression level of C. butyricum group was higher than that of the control. HE stain showed that C. butyricum increased the intestine epithelium height of L. vannamei. These results revealed that C. butyricum could improve the growth performance, increased intestine SCFA content and body crude protein content, modulated intestine digestive capacity, and enhanced intestine immune function of L. vannamei against ammonia stress. PMID- 28359950 TI - Whole transcriptome expression of trigeminal ganglia compared to dorsal root ganglia in Rattus Norvegicus. AB - The trigeminal ganglia (TG) subserving the head and the dorsal root ganglia (DRG) subserving the rest of the body are homologous handling sensory neurons. Differences exist, as a number of signaling substances cause headache but no pain in the rest of the body. To date, very few genes involved in this difference have been identified. We aim to reveal basal gene expression levels in TG and DRG and detect genes that are differentially expressed (DE) between TG and DRG. RNA Sequencing from six naive rats describes the whole transcriptome expression profiles of TG and DRG. Differential expression analysis was followed by pathway analysis to identify DE processes between TG and DRG. In total, 64 genes had higher and 55 genes had lower expressed levels in TG than DRG. Higher expressed genes, including S1pr5 and Gjc2, have been related to phospholipase activity. The lower expressed genes, including several Hox genes and Slc5a7, have been related to tyrosine and phenylalanine metabolism. Tissue-specific expression was identified for Gabra6 and Gabrd in TG, and for several Hox genes in DRG. Furthermore, genes that were known to be associated with headache/migraine were mostly moderately to highly expressed in one or both tissues. We present a comprehensive overview of the expression profiles of whole tissue comparison of TG and DRG. Further, we showed DE genes/pathways between TG and DRG, including several known migraine-associated genes. This study provides a basis for further pain-related studies using TG and DRG in rats. PMID- 28359949 TI - Establishment of lysozyme gene RNA interference systemand its involvement in salinity tolerance in sea cucumber (Apostichopus japonicus). AB - The lysozyme gene was silenced using RNA interference (RNAi) to analyze the function of lysozyme in sea cucumber under salt stress. The interfering efficiency of four lysozyme RNAi oligos ranged from 0.55 to 0.70. From the four oligos, p-miR-L245 was used for further interfering experiments because it had the best silencing efficiency. Peristomial film injection of p-miR-L245 (10 MUg) was used for further interfering experiments. The lowest gene expression, determined by RT-PCR assay, in muscle, coelomic fluid, and parapodium occurred 48 h after p-miR-L245 injection, while that of body wall and tube foot was 96 h and 24 h, respectively. Lysozyme activity in muscle and body wall was significantly lower than the controls. The lowest lysozyme activity in muscle, body wall and parapodium, was found at 48, 72, and 48 h, respectively, which was consistent with the transcription expression of lysozyme. The lowest point of lysozyme activity was at 96 h in coelomic fluid and tube foot, which was laid behind lysozyme expression in transcription level. The expression profile of the lysozyme transcription level and lysozyme activity in the body wall and tube foot increased at 12 h after p-miR-L245 injection before the interference effect appeared. NKA gene expression was expressed at a high level in the positive control (PC) and negative control (NC) groups at 12, 24, and 48 h, while NKA was expressed at low levels in the lysozyme RNAi injection group at 12 and 24 h. The level of NKA gene expression recovered to the level of the PC and NC group at 48, 72, and 96 h after the lysozyme RNAi injection. NKCC1 gene expression was high in the PC and NC groups at 96 h, while the NKCC1 was expressed at a low level 96 h after lysozyme RNAi injection. The results suggest that lysozyme decay involves NKA and NKCC1 gene expression under salinity 18 psMU. The K+ and Cl- concentration after lysozyme RNAi injection was lower than in the PC and NC group. PMID- 28359951 TI - Acute stress regulates phosphorylation of N-methyl-d-aspartate receptor GluN2B at S1284 in hippocampus. AB - Exposure to acute stress leads to diverse changes, which include either beneficial or deleterious effects on molecular levels that are implicated in stress-related disorders. N-methyl-d-aspartate receptor (NMDAR)-mediated signalings, are thought to be vital players in stress-related mental disorders as well as attractive therapeutic targets for clinical treatment. In the present study, we utilized acute stress models in mice to explore regulation of phosphorylation level of S1284 in GluN2B subunit of NMDAR. We found out that forced swimming and acute restraint stress increased phosphorylation level of S1284, while phosphorylation level of S1284 was unaltered after brief exposure to open field. Moreover, phosphorylation change of S1284 was negated by treatment of roscovitine which is believed to be a Cyclin-dependent kinase inhibitor. Besides, we showed well correlation of phosphorylation change of S1284 and immobility time during forced swimming. Collectively, our results demonstrated that phosphorylation level of S1284 in GluN2B was regulated by acute stress. PMID- 28359952 TI - Low testosterone levels are related to oxidative stress, mitochondrial dysfunction and altered subclinical atherosclerotic markers in type 2 diabetic male patients. AB - INTRODUCTION: Low testosterone levels in men are associated with type 2 diabetes and cardiovascular risk. However, the role of testosterone in mitochondrial function and leukocyte-endothelium interactions is unknown. Our aim was to evaluate the relationship between testosterone levels, metabolic parameters, oxidative stress, mitochondrial function, inflammation and leukocyte-endothelium interactions in type 2 diabetic patients. MATERIALS AND METHODS: The study was performed in 280 male type 2 diabetic patients and 50 control subjects. Anthropometric and metabolic parameters, testosterone levels, reactive oxygen species (ROS) production, mitochondrial membrane potential, TNFalpha, adhesion molecules and leukocyte-endothelium cell interactions were evaluated. RESULTS: Testosterone levels were lower in diabetic patients. Total and mitochondrial ROS were increased and mitochondrial membrane potential, SOD and GSR expression levels were reduced in diabetic patients. TNFalpha, ICAM-1 and VCAM-1 levels, leukocyte rolling flux and adhesion were all enhanced in diabetic patients, while rolling velocity was reduced. Testosterone levels correlated negatively with glucose, HOMA-IR, HbA1c, triglycerides, nonHDL-c, ApoB, hs-CRP and AIP, and positively with HDL-c and ApoA1. The multivariable regression model showed that HDL-c, HOMA-IR and age were independently associated with testosterone. Furthermore, testosterone levels correlated positively with membrane potential and rolling velocity and negatively with ROS production, VCAM-1, rolling flux and adhesion. CONCLUSIONS: Our data highlight that low testosterone levels in diabetic men are related to impaired metabolic profile and mitochondrial function and enhanced inflammation and leukocyte-endothelium cell interaction, which leaves said patients at risk of cardiovascular events. PMID- 28359953 TI - Cigarette smoke extract induced exosome release is mediated by depletion of exofacial thiols and can be inhibited by thiol-antioxidants. AB - INTRODUCTION: Airway epithelial cells have been described to release extracellular vesicles (EVs) with pathological properties when exposed to cigarette smoke extract (CSE). As CSE causes oxidative stress, we investigated whether its oxidative components are responsible for inducing EV release and whether this could be prevented using the thiol antioxidants N-acetyl-l-cysteine (NAC) or glutathione (GSH). METHODS: BEAS-2B cells were exposed for 24h to CSE, H2O2, acrolein, 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB), bacitracin, rutin or the anti-protein disulfide isomerase (PDI) antibody clone RL90; with or without NAC or GSH. EVs in media were measured using CD63+CD81+ bead-coupled flow cytometry or tunable resistive pulse sensing (TRPS). For characterization by Western Blotting, cryo-transmission electron microscopy and TRPS, EVs were isolated using ultracentrifugation. Glutathione disulfide and GSH in cells were assessed by a GSH reductase cycling assay, and exofacial thiols using Flow cytometry. RESULTS: CSE augmented the release of the EV subtype exosomes, which could be prevented by scavenging thiol-reactive components using NAC or GSH. Among thiol-reactive CSE components, H2O2 had no effect on exosome release, whereas acrolein imitated the NAC-reversible exosome induction. The exosome induction by CSE and acrolein was paralleled by depletion of cell surface thiols. Membrane impermeable thiol blocking agents, but not specific inhibitors of the exofacially located thiol-dependent enzyme PDI, stimulated exosome release. SUMMARY/CONCLUSION: Thiol-reactive compounds like acrolein account for CSE induced exosome release by reacting with cell surface thiols. As acrolein is produced endogenously during inflammation, it may influence exosome release not only in smokers, but also in ex-smokers with chronic obstructive pulmonary disease. NAC and GSH prevent acrolein- and CSE-induced exosome release, which may contribute to the clinical benefits of NAC treatment. PMID- 28359954 TI - Comparison of the effects of commercial coated and uncoated ZnO nanomaterials and Zn compounds in kidney bean (Phaseolus vulgaris) plants. AB - Bean (Phaseolus vulgaris) plants were grown for 45 days in soil amended with either uncoated (Z-COTE(r)) and coated (Z-COTE HP1(r)) ZnO nanomaterials (NMs), bulk ZnO and ZnCl2, at 0-500mg/kg. At harvest, growth parameters, chlorophyll, and essential elements were determined. None of the treatments affected germination and pod production, and only ZnCl2 at 250 and 500mg/kg reduced relative chlorophyll content by 34% and 46%, respectively. While Z-COTE(r) did not produce phenotypic changes, Z-COTE HP1(r), at all concentrations, increased root length (~44%) and leaf length (~13%) compared with control. Bulk ZnO reduced root length (53%) at 62.5mg/kg and ZnCl2 reduced leaf length (16%) at 125mg/kg. Z COTE(r), at 125mg/kg, increased Zn by 203%, 139%, and 76% in nodules, stems, and leaves, respectively; while at the same concentration, Z-COTE HP1(r) increased Zn by 89%, 97%, and 103% in roots, stems, and leaves, respectively. At 125mg/kg, Z COTE HP1(r) increased root S (65%) and Mg (65%), while Z-COTE(r) increased stem B (122%) and Mn (73%). Bulk ZnO and ZnCl2 imposed more toxicity to kidney bean than the NMs, since they reduced root and leaf elongation, respectively, and the concentration of several essential elements in tissues. PMID- 28359955 TI - Does preoperative depression predict post-operative surgical pain: A systematic review. AB - BACKGROUND: As surgical procedures have been developed and refined, determining which factors predict rapid and successful surgical outcomes has become a priority. Significant psychosocial influences on surgical outcomes have been found with numerous procedures. The objective of this study is to perform a systematic review of randomized-control trials and observational studies to examine the relationships between pre-operative depression and post-operative (<6 weeks) pain outcomes. MATERIALS AND METHODS: Pubmed/MEDLINE, EMBASE, CINAHL and Web of Science were searched for studies published from January 1, 2006 and August 31, 2016. Two independent reviewers assessed the eligibility of each report based on predefined inclusion criteria (study design, measure of pre operative depression, and post-operative pain). Participants included adult patients undergoing surgical procedures diagnosed with depression pre operatively. Patients were assessed for post-operative pain via pain scales and use of post-operative pain medications. Data was summarized qualitatively due to limitations of comparability and transformation. Significant clinical and statistical heterogeneity of the included studies was identified. RESULTS: Of 1091 abstracts reviewed, 18 studies met the inclusion criteria. Due to the significant clinical and statistical heterogeneity, a meta-analysis was not performed. 8 studies (comprising a total of 1314 patients) reported a statistically significant effect of pre-operative depression on post-operative pain. 10 studies encompassing a total 1226 patients failed to demonstrate a statistically significant effect of depression on postoperative pain. CONCLUSION: The analysis of results was limited to a systematic review and qualitative analysis of the eligible studies. Based on this systematic review we identified 8 studies reporting a statistically significant effect of pre-operative depression on post-operative pain and 10 studies reporting no statistically significant effect of pre-operative depression on post-operative pain. Therefore, the quality of presented data is poor and makes it challenging to answer further questions. Large epidemiologic studies in this field are needed to provide further evidence. PMID- 28359956 TI - Ab initio study of the energy loss near sulfur K and L2,3 edges of layered MS2 (M=Ta, Nb and V) in trigonal prismatic and octahedral structures. AB - This study set out to calculate the full-potential linearized augmented plane wave (FPLAPW)-based energy loss near sulfur K and L2,3 edge structures of group V layered transition metal disulfides MS2 (M=Ta, Nb, and V) in octahedral (1T) as well as trigonal prismatic (2H) structures. The calculations showed that, consistent with other calculations, all the studied materials were metallic due to the partially filled d bands in their configurations. Furthermore, the calculated ELNES spectra revealed a good agreement with the available experimental XANES analogues. The d-like and p-like transitions of M and sulfur atoms were the dominant electron transitions in K edge spectra. Spectrum characteristics of the sulfur L2,3 edge of ELNES indicated the transition of sulfur-p electrons to the unoccupied s or d states. These spectra reflect the electronic band structures of materials, as well. As the focus shifts from bulk to monolayer, substrate hybridization becomes stronger. In 2H phases, the dominant peaks of sulfur K edge spectra originate from unoccupied d bands. Further, the broad peaks at higher energy ranges are due to the transitions to sulfur p hybridized with M-s and p states. For energies below 7eV, M-d state is the target state of most of the transitions in both 1T and 2H phases. For above 10eV energies, however, sulfur-d is the target state. Moreover, density of states of sulfur-p (d) is very similar in shape to that of sulfur K (L2,3) edges spectra. For the sulfur L2,3 edges, from 2H-TaS2 to 2H-VS2 and also from bulk to monolayer, the number of transitions to M-d state increases. PMID- 28359957 TI - Structure and components of the globular and filamentous viroplasms induced by Rice black-streaked dwarf virus. AB - Viroplasms of members of the family Reoviridae are considered to be viral factories for genome replication and virion assembly. Globular and filamentous phenotypes have different components and probably have different functions. We used transmission electron microscopy and electron tomography to examine the structure and components of the two viroplasm phenotypes induced by Rice black streaked dwarf virus (RBSDV). Immuno-gold labeling was used to localize each of the 13 RBSDV encoded proteins as well as double-stranded RNA, host cytoskeleton actin-11 and alpha-tubulin. Ten of the RBSDV proteins were localized in one or both types of viroplasm. P5-1, P6 and P9-1 were localized on both viroplasm phenotypes but P5-1 was preferentially associated with filaments and P9-1 with the matrix. Structural analysis by electron tomography showed that osmiophilic granules 6-8nm in diameter served as the fundamental unit for constructing both of the viroplasm phenotypes but were more densely packed in the filamentous phenotype. PMID- 28359958 TI - Atom probe study of B2 order and A2 disorder of the FeCo matrix in an Fe-Co-Mo alloy. AB - The physical and mechanical properties of intermetallic alloys can be tailored by controlling the degree of order of the solid solution by means of heat treatments. FeCo alloys with an appropriate composition exhibit an A2-disorder< >B2-order transition during continuous cooling from the disordered bcc region. The study of atomic order in intermetallic alloys by diffraction and its influence on the material properties is well established, however, investigating magnetic FeCo-based alloys by conventional methods such as X-ray diffraction is quite challenging. Thus, the imaging of ordered FeCo-nanostructures needs to be done with high resolution techniques. Transmission electron microscopy investigations of ordered FeCo domains are difficult, due to the chemical and physical similarity of Fe and Co atoms and the ferromagnetism of the samples. In this work it will be demonstrated, that the local atomic arrangement of ordered and disordered regions in an industrial Fe-Co-Mo alloy can be successfully imaged by atom probe measurements supported by field ion microscopy and transmission Kikuchi diffraction. Furthermore, a thorough atom probe parameter study will be presented and field evaporation artefacts as a function of crystallographic orientation in Fe-Co-samples will be discussed. PMID- 28359959 TI - Designing new surfactant peptides for binding to carbon nanotubes via computational approaches. AB - The non-covalent interaction between single-walled carbon nanotube and surfactant peptides makes them soluble in biological media to be used in nano-medicine, drug delivery and gene therapy. Pervious study has shown that two important parameters in binding peptides into nanotubes are hydrophobic effect and the number of aromatic amino acids. Ten surfactant peptides with the length of eight residue, including Lys, Trp, Tyr, Phe and Val, were designed to investigate the important parameters in binding peptides to a (6, 6) carbon nanotube. 500ns MD simulation was performed for free surfactant peptides in water or near to a nanotube. Our results have indicated that the binding affinity of peptides to nanotube increases with the increase of aromatic residue content. Also, among aromatic residues, the peptides containing Trp residues have higher binding affinity to nanotube compared to the peptides with Phe or Tyr residue. Steric hindrance between bulky aromatic residues in peptide sequence has negative influence in binding peptide to nanotube, and in designing a surfactant peptide, the number and distance of aromatic residue and polarity of them should be taken into account. Our results also show that in docking peptides to nanotube, full flexible docking leads to incorrect results. PMID- 28359960 TI - Optimization of cell seeding in a 2D bio-scaffold system using computational models. AB - The cell expansion process is a crucial part of generating cells on a large-scale level in a bioreactor system. Hence, it is important to set operating conditions (e.g. initial cell seeding distribution, culture medium flow rate) to an optimal level. Often, the initial cell seeding distribution factor is neglected and/or overlooked in the design of a bioreactor using conventional seeding distribution methods. This paper proposes a novel seeding distribution method that aims to maximize cell growth and minimize production time/cost. The proposed method utilizes two computational models; the first model represents cell growth patterns whereas the second model determines optimal initial cell seeding positions for adherent cell expansions. Cell growth simulation from the first model demonstrates that the model can be a representation of various cell types with known probabilities. The second model involves a combination of combinatorial optimization, Monte Carlo and concepts of the first model, and is used to design a multi-layer 2D bio-scaffold system that increases cell production efficiency in bioreactor applications. Simulation results have shown that the recommended input configurations obtained from the proposed optimization method are the most optimal configurations. The results have also illustrated the effectiveness of the proposed optimization method. The potential of the proposed seeding distribution method as a useful tool to optimize the cell expansion process in modern bioreactor system applications is highlighted. PMID- 28359961 TI - Natural and artificial protein cages: design, structure and therapeutic applications. AB - Advanced electron microscopy techniques have been used to solve many viral capsid structures. The resulting detailed structural knowledge contributes to understanding of the mechanisms of self-assembly, maturation pathways and virion host cell interactions. It also acts as inspiration for design and production of capsid-like artificial protein cages. Both natural and artificial cages have potential uses in medicine including as vaccines and in drug delivery. For vaccines, virus-like particles formed only from outer virion shells, lacking genetic material, offer the simplest basis for development, while encapsulation of target molecules inside protein cages is potentially more challenging. Here we review advances in cryo-electron microscopy with particular reference to viral capsid structures. We then consider why knowledge of these structures is useful, giving examples of their utilization as encapsulation and vaccine agents. Finally we look at the importance of structural techniques including cryo-EM in the rapidly progressing field of designed protein cages. PMID- 28359962 TI - Quantitative analysis of binary polymorphs mixtures of fusidic acid by diffuse reflectance FTIR spectroscopy, diffuse reflectance FT-NIR spectroscopy, Raman spectroscopy and multivariate calibration. AB - Vibrational spectroscopic techniques such as infrared, near-infrared and Raman spectroscopy have become popular in detecting and quantifying polymorphism of pharmaceutics since they are fast and non-destructive. This study assessed the ability of three vibrational spectroscopy combined with multivariate analysis to quantify a low-content undesired polymorph within a binary polymorphic mixture. Partial least squares (PLS) regression and support vector machine (SVM) regression were employed to build quantitative models. Fusidic acid, a steroidal antibiotic, was used as the model compound. It was found that PLS regression performed slightly better than SVM regression in all the three spectroscopic techniques. Root mean square errors of prediction (RMSEP) were ranging from 0.48% to 1.17% for diffuse reflectance FTIR spectroscopy and 1.60-1.93% for diffuse reflectance FT-NIR spectroscopy and 1.62-2.31% for Raman spectroscopy. The results indicate that diffuse reflectance FTIR spectroscopy offers significant advantages in providing accurate measurement of polymorphic content in the fusidic acid binary mixtures, while Raman spectroscopy is the least accurate technique for quantitative analysis of polymorphs. PMID- 28359963 TI - Determination of AB-CHMINACA and its metabolites in human hair and their deposition in hair of abusers. AB - Despite global efforts to control the abuse of synthetic cannabinoids, the high level of turnover from the market impedes regulation, endangering public health. N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-1-(cyclohexylmethyl)-1H-indazole-3 carboxamide (AB-CHMINACA) is the most popular synthetic cannabinoid in South Korea since its introduction in 2014. Nonetheless, few studies have been carried out on AB-CHMINACA and its metabolites, and its deposition in human hair. The purpose of this study was to develop and validate an analytical method for detection of AB-CHMINACA and its six metabolites in hair using a liquid chromatography tandem mass spectrometry (LC-MS/MS) system, for forensic applications. The methanol extracts of hair samples were evaporated, filtered, and analyzed by LC-MS/MS with electrospray ionization in positive ion mode. The limits of detection and quantification ranged from 0.5 to 10pg/mg and 2 to 50pg/mg, respectively. Good linearity was achieved within the range of 5 1000pg/mg or 10-1000pg/mg depending on the analyte. Intra- and inter-assay precision and accuracy values were below 15%. No significant variation was observed using different sources of hair matrices. These validation results proved the selectivity, accuracy and reproducibility of the method. The established method was applied to 37 authentic samples from suspected synthetic cannabinoid users. AB-CHMINACA and its two metabolites, AB-CHMINACA M2 and AB CHMINACA M4, were detected. The concentration of the parent drug was much higher than those of its metabolites, and the amount of AB-CHMINACA M2 was greater than that of AB-CHMINACA M4 in all samples. No other metabolites were detected in the samples. PMID- 28359964 TI - Development of a new chlorogenic acid certified reference material for food and drug analysis. AB - This paper reports the preparation and characterization of a new chlorogenic acid (CHA) certified reference material (CRM), which is unavailable commercially. CHA is an active ingredient found in many geo-authentic Chinese medicinal materials and developed as an anti-cancer drug. In this work, trace impurities were isolated and identified through various techniques. CHA CRM was quantified with two analytical methods, and their results were in good agreement with each other. The certified value and corresponding expanded uncertainty of CHA CRM reached 99.4%+/-0.2%, which was calculated by multiplying the combined standard uncertainty by the coverage factor (k=2), at a confidence level of 95%. This CRM can be used to calibrate measurement system, evaluate or validate measurement procedures, assign traceable property values to non-CRMs, and conduct quality control assays. PMID- 28359965 TI - Detailed analysis of cortisol, cortisone and their tetrahydro- and allo tetrahydrometabolites in human urine by LC-MS/MS. AB - Cortisol (F) and cortisone (E) are metabolized to A-ring reduced metabolites in the reactions catalyzed by 5alpha- and 5beta-reductase. 5alpha-tetrahydrocortisol (alloTHF) and 5beta-tetrahydrocortisol (THF) are produced from F. The metabolism of E takes place in analogy to form alloTHE and THE. Up to now, the analysis of endogenous glucocorticoids did not consider alloTHE, limiting the metabolism of E to THE only. Nevertheless, such simplification can generate inaccuracy in the assessment of the function of enzymes crucial for glucocorticoids metabolism: 11beta-hydroxysteroid dehydrogenase type 1 and type 2 (11beta-HSD1 and 11beta HSD2), as well as 5alpha- and 5beta-reductase. The paper presents the new LC MS/MS method for the simultaneous analysis of F and E with their tetrahydro- (THF and THE) and allo-tetrahydrometabolites (alloTHF and alloTHE) in urine. The method was fully validated and allows determining both the unconjugated and total concentrations of urinary glucocorticoids. The method meets the EMA's recommendations and was proved to be useful in the analysis of clinical samples. The LLOQ of 1ng/mL allows the determination of free urinary F, E, THF and THE, but not alloTHF and alloTHE, in samples obtained from pregnant women. The range of concentrations is wide enough for the analysis of total levels of F, E, THF, alloTHF, THE and alloTHE. The undisputed advantage of the method, distinguishing it among others, is the ability to determine F and E and their both 5alpha- and 5beta-metabolites. Taking alloTHE into consideration enables the thorough analysis of the glucocorticoid equilibrium in human. PMID- 28359966 TI - Synchronous determination with double-wavelength by RP-HPLC-UV and optimization of ultrasound-assisted extraction of phenolic acids from Caragana species using response surface methodology. AB - The utilization of Caragana korshinskii Kom. (CK) is currently concentrated on its ecological and fuel functions. Little attention has been devoted to the analysis of their phenolic acid (PA) components. To obtain more data for further utilization of CK, a new analysis protocol was tested to determine PAs synchronously by RP-HPLC-UV with double-wavelength (280nm and 320nm) detection. Specifically, separation of PA components was performed on a Hypersil Gold C18 reverse phase column with gradient elution. A four-factor-three-level Box-Behnken design was implemented for optimization of PA extraction. The results demonstrated that CK were rich primarily in chlorogenic acid, vanillic acid, caffeic acid and rosmarinic acid. The total content of PAs in CK leaves was the highest compared with its other parts. The distribution of total flavonoid content of CK was leaves>flowers>bark, while that of the total phenolic content of CK was flowers>leaves>bark. PMID- 28359967 TI - Alcohol-related serious road traffic injuries between 2000 and 2010: A new perspective to deal with administrative data in Australia. AB - BACKGROUND: According to the most recent statistics from the World Health Organization, 1.2 million people die or are injured on the world's roads every year. Drink-driving continues to be a major risk factor for road traffic crashes, with 22% of serious road injuries (SRIs) in Victoria involving a blood alcohol concentration (BAC) equal to or above the legal driving limit of 0.05g/mL. Use of police and hospital data to determine alcohol involvement in SRIs is not reliable, with researchers using proxy measures such as high alcohol hours (HAH). This paper examines patterns of alcohol-related SRIs based on reported BAC versus the surrogate HAH measure. METHODS: Trends over a 10year period (2000-2010) were examined, comparing four different SRI rates (low alcohol hours (LAH), LAH with positive BAC, HAH, HAH with positive BAC). Discontinuities in the data series were also examined. SRI data were drawn from the Road Networks Database of VicRoads containing information on all reported road crashes in Victoria. RESULTS: For the 10year period there were 52,286 reported SRIs relating to the driver. Of the incidents where a driver's reading was recorded, 44% had a recorded BAC exceeding Victoria's legal limit of 0.05% and a further 23% had a BAC below the legal limit. During the period over 17,000 (or 34%) SRIs occurred during HAH. Where a BAC had been recorded during HAH, almost 60% exceeded the legal limit and a further 20% had some positive recording of BAC. Where SRI drivers had a recorded BAC during LAH, 58% had a positive BAC (31% with a BAC over the legal limit). While it is likely that an SRI occurring during HAH will be associated with a positive BAC (80%), of which 60% will be above the legal limit, almost 60% of SRIs during LAH had a positive BAC, with 31% above the legal limit. CONCLUSION: There was no significant change in overall alcohol-related SRI rates between 2000 and 2010, suggesting that policies and procedures implemented to decrease drink-driving have not reduced alcohol-related SRI rates. In the absence of a reliable direct measure (i.e., BAC readings) this paper demonstrated the utility of the surrogate HAH measure for determining changes in alcohol related serious road injuries. Further, the unmet need for routine BAC testing in SRIs occurring during LAH requires further exploration given the significant proportion of SRIs involving positive BAC during these times. PMID- 28359968 TI - The mortality reducing effect of aspirin in colorectal cancer patients: Interpreting the evidence. AB - In 1971 the first study appeared that suggested a relationship between aspirin and cancer. Currently publications on the subject of aspirin and cancer are numerous, with both a beneficial effect of aspirin on cancer incidence and a beneficial effect on cancer survival. This review focusses on the relation between the use of aspirin and improved survival in colorectal cancer patients. Various study designs have been used, with the main part being observational studies and post hoc meta-analyses of cancer outcomes in cardiovascular prevention trials. The results of these studies are unambiguously pointing towards an effect of aspirin on colorectal cancer survival, and several randomised controlled trials are currently ongoing. Some clinicians feel that the current evidence is conclusive and that the time has come for aspirin to be prescribed as adjuvant therapy. However, until this review, not much attention has been paid to the specific types of bias associated with these studies. One of these biases is confounding by indication, because aspirin is indicated for patients as secondary prevention for cardiovascular disease. This review aims to provide perspective on these biases and provide tools for the interpretation of the current evidence. Albeit promising, the current evidence is not sufficient to already prescribe aspirin as adjuvant therapy for colorectal cancer. PMID- 28359969 TI - Simulation study of the backward-scattering effect in Compton imager. AB - In the field of nuclear medicine, nuclear security and astrophysics, Compton imaging is a promising technique for gamma-ray source imaging. We are developing a Compton imager using two layers of CdZnTe pixel array detectors. In this paper, the backward-scattering effect within such imagers is numerically studied using Geant4 Monte Carlo Package. From images reconstructed based on forward-scattering and backward-scattering imaging events, the imaging precision was investigated in a comparative analysis, in regard to energy resolution and position resolution. Furthermore, to establish a method to use backward-scattering imaging events properly so that the imaging efficiency can be significantly improved, the difference between reconstruction from forward-scattering and backward-scattering imaging events was analyzed to uncover a causal mechanism. PMID- 28359970 TI - Aryl- or heteroaryl-based hydrazinylphthalazine derivatives as new potential antitrypanosomal agents. AB - A series of twenty phthalazinyl-hydrazones were synthesized and tested as potential anti-Trypanosoma cruzi agents. The phthalazines containing 5 nitroheteroaryl moiety 3l and 3m displayed an excellent in vitro antitrypanosomal profile, exhibiting low micromolar EC50 values against proliferative epimastigote of T. cruzi and minimal toxicity toward Vero cells. These derivatives were more potent than the reference drug benznidazole against the epimastigote stage of the parasite. Structure-property analysis indicates that the highly conjugated 5 nitroheteroaryl moiety connected to the phthalazin scaffold play an important role in the antichagasic activity of these phthalazines. The decrease on the mitochondrial dehydrogenase activity and significant ROS production found for the parasites treated with 3l and 3m suggest that both nitro-derivatives can act through an oxidative stress mechanism. PMID- 28359971 TI - Emotion dysregulation explains the relation between insomnia symptoms and negative reinforcement smoking cognitions among daily smokers. AB - INTRODUCTION: Insomnia co-occurs with smoking. However, mechanisms that may explain their comorbidity are not well known. METHOD: The present study tested the hypothesis that insomnia would exert an indirect effect on negative reinforcement smoking processes via emotion dysregulation among 126 adult non treatment seeking daily smokers (55 females; Mage=44.1years, SD=9.72). Negative reinforcement smoking processes included negative reinforcement smoking outcome expectancies, negative reinforcement smoking motives, and two negative expectancies from brief smoking abstinence (somatic symptoms and harmful consequences). RESULTS: Insomnia symptoms yielded a significant indirect effect through emotion dysregulation for negative reinforcement smoking outcome expectancies, negative reinforcement smoking motives, and harmful consequences expectancies from brief smoking abstinence. In contrast to prediction, however, insomnia was not associated with somatic symptom expectancies from brief smoking abstinence through emotion dysregulation. CONCLUSIONS: These data may suggest that the indirect effect of emotion dysregulation is more relevant to cognitive affective negative reinforcement processes rather than somatic states. Overall, the present findings contribute to a growing body of literature linking emotion dysregulation as an explanatory mechanism for insomnia and smoking and uniquely extend such work to an array of clinically significant negative reinforcement smoking processes. PMID- 28359973 TI - Comments to special issue geogenic radiation and its potential use for developing the geogenic radon map. PMID- 28359972 TI - Descriptive drinking norms in Native American and non-Hispanic White college students. AB - OBJECTIVE: College students tend to overestimate how much their peers drink, which is associated with higher personal alcohol use. However, research has not yet examined if this phenomenon holds true among Native American (NA) college students. This study examined associations between descriptive norms and alcohol use/consequences in a sample of NA and non-Hispanic White (NHW) college students. METHOD: NA (n=147, 78.6% female) and NHW (n=246, 67.8% female) undergraduates completed an online survey. RESULTS: NAs NHWs showed similar descriptive norms such that the "typical college student," "typical NA student," and "typical NHW student" were perceived to drink more than "best friends." "Best friends" descriptive norms (i.e., estimations of how many drinks per week were consumed by participants' best friends) were the most robust predictors of alcohol use/consequences. Effect size estimates of the associations between drinking norms and participants' alcohol use were consistently positive and ranged from r=0.25 to r=0.51 across the four reference groups. Negative binomial hurdle models revealed that all descriptive norms tended to predict drinking, and "best friends" drinking norms predicted alcohol consequences. Apart from one interaction effect, likely due to familywise error rate, these associations were not qualified by interactions with racial/ethnic group. CONCLUSIONS: We found similar patterns between NAs and NHWs both in the pattern of descriptive norms across reference groups and in the strength of associations between descriptive norms and alcohol use/consequences. Although these results suggest that descriptive norms operate similarly among NAs as other college students, additional research is needed to identify whether other norms (e.g., injunctive norms) operate similarly across NA and NHW students. PMID- 28359974 TI - Purifying, cloning and characterizing a novel dehalogenase from Bacillus sp. GZT to enhance the biodegradation of 2,4,6-tribromophenol in water. AB - 2,4,6-Tribromophenol (TBP), an intermediate of brominated flame retardants, can easily release to environment and recalcitrant to degradation. Previously, Bacillus sp. GZT, a pure aerobic strain capable of simultaneously debrominating and mineralizing TBP, was successfully isolated by us. To further obtain a practical application and dig up its TBP degradation mechanism, a total of 46.7 fold purification of a novel dehalogenase with a final specific activity of 18.9 U mg-1 and a molecular mass of 63.4 kDa was achieved. Under optimal conditions (35 degrees C and 200 rpm), up to 80% degradation efficiencies were achieved within 120 min. Adding H2O2, NADPH, Mn2+ and Mg2+ promoted enzyme reaction effectively; while EDTA, methyl viologen, Ni2+, Cu2+, Ca2+ and Fe2+ strongly inhibited reaction activities. The debromination of TBP was catalyzed by the enzyme at a Km of 78 MUM and a Vmax of 0.65 min-1 mg protein-1, which indicated that this dehalogenase could specifically eliminate TBP with a high efficiency and stability. Based on MALDI-TOF/TOF analysis, the dehalogenase shared 98% identity with peptide ABC transporter substrate-binding protein. One open reading frame (ORF) encoding this peptide was found in Strain GZT genome, subjected to clone and expressed in Escherichia coli (E. coli) to characterize the encoding gene. Result showed that this recombinant strain could also remove as similar amount of TBP as Bacillus sp. GZT under the identical condition. Based on these results, we suggest that this newly-isolated TBP dehalogenase highlights a new approach for remediating TBP pollution. PMID- 28359975 TI - Mono-2-ethylhexyl phthalate associated with insulin resistance and lower testosterone levels in a young population. AB - Phthalates are commonly used as plasticizers and are reported to associate with testicular dysfunction or insulin resistance in different studies, but the concurrent relationship between phthalate exposure, testosterone levels, and insulin resistance in the young population is not well understood. We recruited 786 subjects aged 12-30 years from a population-based sample of Taiwanese adolescents and young adults from 2006 to 2008. Generalized additive models were used to evaluate glucose homeostasis and testicular function in relation to seven urinary phthalate metabolites among adolescents (aged 12-20) and young adults (aged 20-30) in Taiwan. We observed a trend toward a decrease in male testosterone and an increase in urinary mono-2-ethylhexyl phthalate (MEHP) levels across four quartiles of homeostasis model assessment of insulin resistance (HOMA IR). After adjusting for potential covariates, generalized additive models further showed that log-transformed insulin and HOMA-IR were raised by 0.055 [95% confidence interval (CI), 0.027-0.082] and 0.056 (95% CI, 0.027-0.084), respectively, with a one-unit increase in log-transformed MEHP in young adults. In male adults (aged 22-30), the log-testosterone levels were reduced by 0.018 (95% CI, 0.001-0.036), with a one-unit of increase in log-transformed MEHP. Such relationships were not observed in adolescents. In conclusion, this study demonstrated age-related associations of urinary MEHP metabolites with impaired metabolic homeostasis of glucose that were only observed in young adults. In addition, MEHP exposure was concurrently associated with lower testosterone levels in young, male adults. PMID- 28359976 TI - TRIM36 hypermethylation is involved in polycyclic aromatic hydrocarbons-induced cell transformation. AB - Long term exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with the increasing risk of lung cancer. To identify differentially hypermethylated genes associated with PAHs-induced carcinogenicity, we performed genome-wide DNA methylation analysis in 20 MUM benzo(a)pyrene (BaP)-transformed human bronchial epithelial (HBE) cells at different stages of cell transformation. Several methylated genes (CNGA4, FLT1, GAREM1, SFMBT2, TRIM36) were differentially hypermethylated and their mRNA was suppressed in cells at both pre-transformed and transformed stages. Similar results were observed in HBE cells transformed by 20 MUg/mL coke oven emissions (COEs) mixture collected from a coking manufacturing facility. In particular, hypermethylation of TRIM36 and suppression of TRIM36 expression were gradually enhanced over the time of COEs treatment. We developed bisulfite pyrosequencing assay and assessed TRIM36 methylation quantitatively. We found that hypermethylation of TRIM36 and reduced gene expression was prevalent in several types of human cancers. TRIM36 hypermethylation appeared in 90.0% (23/30) of Non-Small Cell Lung Cancer (NSCLCs) tissues compared to their paired adjacent tissues with an average increase of 1.32 fold. Furthermore, an increased methylation rate (5.90% v.s 7.38%) and reduced levels of TRIM36 mRNA were found in peripheral lymphocytes (PBLCs) of 151 COEs-exposed workers. In all subjects, TRIM36 hypermethylation was positively correlated with the level of urinary 1-hydroxypyrene (P < 0.001), an internal exposure marker of PAHs, and the DNA damage (P = 0.013). These findings suggest that aberrant hypermethylation of TRIM36 might be involved in the acquisition of malignant phenotype and could be served as a biomarker for risk assessment of PAHs exposure. PMID- 28359977 TI - Report of novel H105R, D29N, V27A mutations in the methyltransferase region of the HEV genome in patients with acute liver failure. AB - BACKGROUND: The Hepatitis E virus (HEV) has been responsible for major outbreaks in the developing countries affecting millions of people and acute sporadic hepatitis worldwide. The HEV methyltransferase is important for capping the 5' end of the viral pregenomic RNA which is critical for viral infection. OBJECTIVES: We aimed to assess the substitutional profile in the HEV methyltransferase region in patients with acute liver failure (ALF) and acute viral hepatitis (AVH) from North Indian population and associate the substitutions with the poor outcome of the disease. STUDY DESIGN: HEV RNA was detected and partial region encoding the Methyltransferase domain in the HEV genome was amplified by Reverse Transcriptase(RT-PCR). Viral load of HEV was quantified utilizing Real time PCR.32 representative samples consisting of 16 AVH and 16 ALF were directly sequenced and amino acid changes were compared using Fischer's exact (two-tailed) test. RESULTS: Novel mutations Valine27Alanine (V27A), Aspartate29Asparagine (D29N) and Histidine105Arginine (H105R) mutation corresponding to 107T>C, 115G>A and 341 A>G substitutions respectively were significantly (p<0.0001) obtained in 16/16(100%) ALF patients compared to none (0/16) of the AVH patients. HEV viral load and disease severity parameters corresponding to the samples with D29N and V27A mutations were significantly higher compared to the isolates lacking these mutations while the H105R mutation was associated with decreased viremia. CONCLUSION: The D29N and V27A mutations had significant association with the poor outcome in ALF patients suggesting key role in enhancing HEV replication while the association of H105R mutation with decreased viremia creates interest on its antiviral aspects. PMID- 28359979 TI - Variation in selection criteria and approaches to surgery for Lumbar Spinal Stenosis among patients treated in Boston and Norway. AB - OBJECTIVES: There are no uniform guidelines regarding when to operate or the ideal surgical intervention in Lumbar Spinal Stenosis (LSS). Understanding the presence of practice-based variation between different localities is critical. We sought to compare patient-reported pre-operative pain, disability, and health related quality of life as indications for surgery between Boston and Norway, and the use of decompression alone vs. decompression and arthrodesis. PATIENTS AND METHODS: This study included 3826 patients; 1886 from Boston and 1940 from Norway. Eligible patients were 50 years or older who received surgery for the diagnosis of LSS. Data were retrieved from a centralized clinical database in Boston and a national spine registry in Norway based on reported diagnosis and procedure. We evaluated patient-reported pre-operative pain, disability, and health-related quality of life as indications for surgery. A propensity score match was performed for the generation of comparable cohorts. RESULTS: There were no significant differences in demographics between the unadjusted cohorts. The rates of obesity (39.4% vs. 25.4%; p<0.001) and patients with ASA >=3 (34.8% vs. 22.1%; p<0.001) were higher in the Boston cohort, while smokers were less frequent (9.6% vs. 19.3%; p<0.001). These differences were accounted for in the propensity score matching. Pre-operative ODI was slightly higher among patients in Boston (43.3 [95% CI 41.5, 45.1] vs. 40.7 [95% CI 40.0, 41.4]; p=0.005), but did not reach the minimal clinically important difference. No statistical difference was encountered between pre-operative EQ-5D (0.339 [95% CI 0.304, 0.374] vs. 0.366 [95% CI 0.351, 0.381]; p=0.16). Fifty-one percent of patients treated in Boston received a decompression and arthrodesis, as compared to only 13.9% of those in Norway (p<0.001). In the matched cohort, counting 294 in each group, the overall conclusions were the same. CONCLUSIONS: The results demonstrate that indications for intervention were very similar in comparable patient populations with LSS in Boston and Norway. The use of supplemental arthrodesis was significantly greater in Boston. The etiology behind this finding is likely multifactorial but may represent medico-legal concerns in the US, or the phenomenon of provider inducement. PMID- 28359980 TI - Number needed to treat for stroke thrombectomy based on a systematic review and meta-analysis. AB - The positive results of recent clinical trials examining endovascular treatment of acute stroke were the culmination of nearly two decades of studies of endovascular stroke treatment. We systematically reviewed this body of work, evaluated the strength of evidence, and performed a meta-analysis to define the clinical impact of these investigations. Terms were entered into search engines in a systematic fashion. Articles were reviewed independently by study authors, graded for level of evidence, and combined in a meta-analysis. The overall body of evidence was evaluated using GRADE criteria. Our search yielded 948 articles. Twenty-five met predefined inclusion criteria. We identified 12 grade I, 1 grade II, 5 grade III, and 7 grade IV studies (kappa=0.86). Meta-analysis for independence at 90days showed a benefit of endovascular treatment (grade I studies OR 1.58 [1.20-2.07]). When limiting the analysis to studies using stent retriever, the OR increased to 2.44 (1.77-3.36). The number needed to treat (NNT) was 8. Endovascular treatment was not associated with increased symptomatic intracranial hemorrhage, and forgoing endovascular treatment was associated with death at 90 days. The quality of evidence according to GRADE criteria was "moderate." In summary, we found impressive evidence for a benefit of endovascular treatment of acute stroke, particularly when using stent retriever devices. Our meta-analysis is unique in that it includes all studies related to this topic and defines the clinical impact of the data, providing NNT. We show that thrombectomy is among the most effective stroke treatments currently available. PMID- 28359978 TI - Transcription factor-DNA binding: beyond binding site motifs. AB - Sequence-specific transcription factors (TFs) regulate gene expression by binding to cis-regulatory elements in promoter and enhancer DNA. While studies of TF-DNA binding have focused on TFs' intrinsic preferences for primary nucleotide sequence motifs, recent studies have elucidated additional layers of complexity that modulate TF-DNA binding. In this review, we discuss technological developments for identifying TF binding preferences and highlight recent discoveries that elaborate how TF interactions, local DNA structure, and genomic features influence TF-DNA binding. We highlight novel approaches for characterizing functional binding site motifs that promise to inform our understanding of how TF binding controls gene expression and ultimately contributes to phenotype. PMID- 28359981 TI - Increased aortic intima-media thickness following Kawasaki disease. AB - BACKGROUND AND AIMS: The cardiovascular risk following Kawasaki disease (KD), especially in those without coronary artery changes or with regressed coronary artery lesions, is unclear. We assessed markers of early atherosclerosis in individuals following KD, including those with and without coronary artery abnormalities. METHODS: We performed a cross-sectional case-control study of 60 patients (25 with always normal coronary arteries and 35 with abnormalities) and 60 controls, at least two years after KD. Non-invasive assessment of arterial structure (carotid and aortic intima-media thickness (IMT)) and function (pulse wave velocity, carotid artery distensibility and diameter compliance) was done. Analyses were adjusted for traditional cardiovascular risk factors. RESULTS: Kawasaki disease patients had increased aortic IMT compared to controls (0.53 mm (95% CI 0.51-0.56) versus 0.49 (95% CI 0.47-0.52), p = 0.04), largely driven by those with abnormal coronary arteries. There were no differences in carotid IMT. Kawasaki disease patients with coronary artery abnormalities had reduced carotid distensibility compared to controls (15.16% (95% CI 13.67-16.65) versus 17.50 (95% CI 16.43-18.58), p = 0.02). CONCLUSIONS: Patients with KD have increased aortic IMT and reduced carotid distensibility, indicating heightened cardiovascular risk, especially in those with coronary artery abnormalities. In our study, we used validated surrogates for cardiovascular disease risk. Our findings, therefore, warrant follow-up investigations in KD patients. PMID- 28359982 TI - Bidirectional association between Bell's palsy and anxiety disorders: A nationwide population-based retrospective cohort study. AB - OBJECTIVE: Bell's palsy and anxiety disorders share numerous risk factors (e.g., immune response, ischemia, and psychological stress). However, there have been no studies on the bidirectional temporal association between the two illnesses. In this study, we used the Taiwan National Health Insurance Research Database (NHIRD) to test the bidirectional association between Bell's palsy and anxiety disorders. We hypothesized that patients with Bell's palsy would have an increased risk of subsequent anxiety disorders later in life and that, conversely, those with anxiety disorders would have an increased likelihood of developing Bell's palsy later in life. METHODS: We conducted two retrospective cohort studies using Taiwan's National Health Insurance Research Database (NHIRD). Study 1 included 8070 patients diagnosed with anxiety disorders and 32,280 controls without anxiety disorders who were matched with sex, age, and enrollment date to analyze the following risk of Bell's palsy among both groups. Study 2 included 4980 patients with Bell's palsy and 19,920 controls without Bell's palsy who were matched with sex, age, and enrollment date to analyze the following risk of anxiety disorders among both groups. The patient records selected for the studies were dated between January 1, 2000, and December 31, 2004. All subjects were observed until their outcomes of interest, death or December 31, 2009. RESULTS: After adjustment for age, sex, comorbidities, urbanization, and income, the hazard ratio (HR) for patients with anxiety disorders to contract Bell's palsy was 1.53 (95% CI, 1.21-1.94, P<.001), and the HR for patients with Bell's palsy to develop an anxiety disorder was 1.59 (95% CI, 1.23-2.06, P<.001). CONCLUSION: This study found a bidirectional temporal association between Bell's palsy and anxiety disorders. After one of these conditions develops, the morbidity rate for the other significantly increases. Additional studies are required to determine whether these two conditions share the same pathogenic mechanisms, and whether successfully treating one will reduce the morbidity rate for the other. PMID- 28359983 TI - Prolactin, a potential mediator of reduced social interactive behavior in newborn infants following maternal perinatal depressive symptoms. AB - BACKGROUND: The hormone prolactin (PRL) plays a crucial role for the initiation and maintenance of maternal behavior, and is also associated with the etiology of mood disorders in women, especially for depression. The present study aimed to determine whether maternal peripheral prolactin would be associated with newborn behavior disorders following maternal perinatal depressive symptoms, and further to explore the efficacy of the Newborn Behavioral Observations (NBO) in improving newborn social interactive behavior. METHODS: Interview and the 24-item Hamilton Rating Scale for Depression (HAMD) were used to assess the hospitalized pregnant women waiting for delivery at 37-42weeks of gestation. A total of 255 subjects were recruited, diagnosed with depression (n=135), and control group (n=120). Within 2 weeks postpartum, mothers were asked to fill with Maternal Attachment Inventory (MAI) to measure maternal care. Neonatal Behavioral Assessment Scale (NBAS) were used to evaluate newborn behavior. The depressed mother-newborns dyad was randomly assigned to NBO intervention and control group. Serum prolaction in mothers and cortisol in mothers and newborns were measured. RESULTS: The newborns of mothers exposed to maternal perinatal depressive symptoms displayed the reduced newborn social interactive behavior accompanied by decreased maternal serum PRL as well as increased maternal and neonatal serum cortisol. The NBO could be an effective intervention tool. LIMITATIONS: Our study could not be double-blind. The mothers knew which group their infant were in. CONCLUSIONS: Maternal peripheral PRL had the potential to be a mediator in reduced social interactive behavior in newborn infants following maternal perinatal depressive symptoms. PMID- 28359984 TI - A selective HPLC-MS/MS method for quantification of SND-117 in rat plasma and its application to a pharmacokinetic study. AB - Rheumatoid arthritis (RA), a chronic systemic inflammatory disorder affects many adults. Sinomenine, a natural product, has been clinically available for the treatment of RA in China. SND-117, a sinomenine derivative with much more potent activity, might serve as a candidate for anti-arthritis. The aim of the present study was to develop a sensitive and rapid high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method for quantification of SND-117 in rat plasma and to understand its absolute bioavailability. The HPLC-MS/MS method was developed and fully validated for determination of SND-117 in rat plasma, and the pharmacokinetic differences were investigated after different administration routes. The pharmacokinetics parameters were calculated by non-compartment model with DAS 3.0 software. After the oral or intravenous administration of different doses of SND-117, the time to peak is 1.5h, half-life time is 8-10h. The absolute oral bioavailability of SND-117 in rats was 9.60%. The results showed that SND 117 in rats was quickly absorbed, slowly eliminate, and the kinetics were linear. This method was suitable for pharmacokinetic studies of SNA-117 in rats. PMID- 28359985 TI - An on-line HPLC system for detection of antioxidant compounds in some plant extracts by comparing three different methods. AB - Echinacea (Echinacea purpurea), green tea (Camellia sinensis) and yaylacayi (Thymus praecox OPIZ subsp. grossheimii (Ronniger) Jalas) are herbs used in traditional medicine because of their beneficial health effects. A high performance liquid chromatography (HPLC) post-column method was developed by coupling HPLC with on-line antioxidant assays using diode array (DAD) and ultraviolet (UV) detectors. Thus antioxidant compounds and fifteen phenolic standards were detected in echinacea, green tea and yaylacayi methanol extracts simultaneously. Later on, the developed on-line HPLC coupled system was used to compare three different antioxidant methods, ABTS [2,2'-Azino-bis-(3 ethylbenzothiazoline-6-sulfonic acid)], DPPH (2,2-diphenyl-1-picrylhydrazyl and FRAP (Ferric reducing antioxidant power). Eight compounds with antioxidant activity were identified as gallic acid, protocatechuic aldehyde, p-OH benzoic acid, chlorogenic acid, caffeic acid, vanillin, ferulic acid, and rosmarinic acid. For validation purposes, LOD (limit of detection) (0.36-14.68MUg/mL) and LOQ (limit of quantification) (1.35-48.92MUg/mL) values were calculated for six standards. The results showed that while the post-column ABTS and FRAP assays were repeatable, sensitive and supportive of each other, the post-column DPPH assay did not provide reliable results. Also due to the base-line noise and drifts in post-column DPPH assay, identification and quantitation of analytes could not be done accurately. PMID- 28359986 TI - Diagnostic accuracy of ultrasonography for detecting nasogastric tube (NGT) placement in adults: A systematic review and meta analysis. AB - OBJECTIVE: To review the evidence on diagnostic accuracy of ultrasonography for detecting correct nasogastric tube (NGT) placement in adults compared to X-ray as the reference standard. METHODS: This is a systematic review and meta-analysis of observational studies, searched in the literature between 1961 and 2015. We included studies which compared the diagnostic accuracy of ultrasonography detection for NGT placement with X-ray in adult patients who were undergoing NGT placement for any reason in any care setting. We searched published studies in the following electronic databases: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, Web of Science, WanFang Data, China Journal Net, and the Chinese Biomedical Literature Database. Both English and non-English language articles were retrieved. Risk of bias was assessed using a standard procedure according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) criteria. RESULTS: We included five studies involving a total of 420 adult patients undergoing nasogastric tube placement: three trials were undertaken in mechanically ventilated patients in prehospital settings and two involved participants with comma or severe trauma in emergency room or intensive care unit (ICU). Pooled results showed that ultrasonography had a sensitivity of 0.93 (95% CI 0.87 to 0.97), and specificity of 0.97 (95% CI 0. 23 to 1.00), suggesting that diagnostic performance of ultrasound is useful to confirm correct NGT placement, but not optimal to detect incorrect NGT position. This was confirmed through a summary receiver operator characteristics (SROC) curve that showed the area under the curve was 0.96 (95% CI 0.94 to 0.98). DISCUSSION: The main limitation of the review is the relatively moderate level of heterogeneity of included studies which may partially undermine the reliability and reproducibility of results. The insufficient studies included did not allow identification of possible sources of heterogeneity and exploration of reporting bias. Due to heterogeneity of studies, the diagnostic performance of ultrasonography could only be drawn cautiously. Physicians and nurses should perform routine X-ray if visualization of NGT is not possible. More well designed studies exploring ultrasound as a diagnostic tool for accuracy of NGT placement are needed to strengthen the current evidence. PMID- 28359987 TI - Developmental options and functional plasticity of innate lymphoid cells. AB - Innate lymphoid cells (ILCs) are lineage- and antigen receptor-negative lymphocytes including natural killer (NK) cells and at least three distinguishable cell subsets (ILC1, ILC2, ILC3) that rapidly produce cytokines (IFN-gamma, IL-5, IL-13, IL-17A, IL-22) upon activation. As such, ILCs can act as first-line defenders in the context of infection, inflammation and cancer. Because of the strong conservation between the expression of key transcription factors that can drive signature cytokine outputs in ILCs and differentiated helper T cells, it has been proposed that ILCs represent innate counterparts of the latter. Several distinct ILC precursors (ILCP) with pan-ILC (giving rise to all ILCs) or subset-restricted potentials have been described in both mouse and man. How and where these different ILCP give rise to more mature tissue-resident ILCs remains unclear. Recently, environmental signals have been shown to epigenetically influence canonical ILC differentiation pathways, generating substantial functional plasticity. These new results suggest that while ILC differentiation may be 'fixed' in principle, it remains 'flexible' in practice. A more comprehensive knowledge in the molecular mechanisms that regulate ILC development and effector functions may allow for therapeutic manipulation of ILCs for diverse disease conditions. PMID- 28359988 TI - Regulation of CRISPR-Cas adaptive immune systems. AB - CRISPR-Cas systems are prokaryotic immune systems that allow defense against invasion by foreign genetic elements. Through the acquisition of genetic memory representing prior exposure, the CRISPR-Cas machinery identifies complementary nucleic acids and mediates their destruction. Since their discovery, CRISPR-Cas research has exploded, with major progress into their mechanism and biotechnological application. In contrast, we are only beginning to understand how CRISPR-Cas activity is regulated. Recent studies have uncovered both conserved regulatory pathways, in addition to more specific mechanisms. Identifying the stimuli linking invasion with CRISPR-Cas activation will be essential in unraveling their ecological roles, evolutionary success and might offer strategies to control immunity for particular applications. We highlight factors impinging on CRISPR-Cas regulation across diverse bacterial and archaeal species. PMID- 28359989 TI - Benzophenone-type UV filters in surface waters: An assessment of profiles and ecological risks in Shanghai, China. AB - Benzophenone-type UV filters (BP-UV filters) are frequently introduced into aquatic environment from several sources. The occurrence and fate of select BP-UV filters and their metabolites were investigated in this study. All target compounds were detected in water samples, except for 2, 3, 4 trihydroxybenzophenone (2, 3, 4-OH-BP). The concentration reached up 131ngL-1 for 5-benzoyl-4-hydroxy-2-ethoxybenzenesulfonic acid (BP-4), 30.0ngL-1 for 2-hydroxy 4-methoxybenzophenone (BP-3), and mean value of 158ngL-1 for benzophenone (BP). Concentrations of BP-UV filters were not related to recreational waters but with high population frequencies. In addition, five BP-UV filters, namely 2,2',4,4' tetrahydroxybenzophenone (BP-2), 2,3,4-OH-BP, 2,4-dihydroxybenzophenone (BP-1), 4 hydroxybenzophenone (4-OH-BP) and BP were investigated for probable sources, and found that they originate from BP-3 metabolism. There is a similar source for BP 3, BP-4, BP-1, 4-OH-BP and BP. Environmental risk assessment (ERA) showed that risk quotients (RQs) of BP-4, BP-3 and BP were 2.7, 0.8 and 0.5, respectively. PMID- 28359990 TI - Morphoanatomical and physiological changes in Bauhinia variegata L. as indicators of herbicide diuron action. AB - The wide use of the herbicide diuron has compromised surrounding uncultivated areas, resulting in acute and/or chronic damage to non-target plants. Thus, the aim of this research was to evaluate physiological and morphoanatomical responses in Bauhinia variegata L. plants to different doses of diuron. Seedlings of 90-day old B. variegata were transplanted into 10liter pots. After an acclimation period (about 30 days), treatments consisting of different diuron doses were applied: 0 (control), 400, 800, 1600, and 2400g ai ha-1. The experiment was conducted in a randomized block design in a 5*5 factorial scheme with five doses of diuron five evaluation times, and five replicates per treatment. Anatomical and physiological injuries were observed in leaves of Bauhina variegata 10h after diuron application. Disruption of waxes was observed on both sides of the leaves of plants exposed since the lowest dose. Plasmolysis in cells were observed in treated leaves; more severe damage was observed in plants exposed to higher doses, resulting in rupture of epidermis. The diuron herbicide also caused gradual reduction in the gas exchange and chlorophyll fluorescence variables. Among the morphoanatomical and physiological variables analyzed, the non-invasive ones (e.g., ETR, YII, and Fv/Fm) may be used as biomarkers of diuron action in association with visible symptoms. In addition, changes in leaf blade waxes and chlorophyll parenchyma damage may also be considered additional leaf biomarkers of diuron herbicide action. PMID- 28359992 TI - Bioassays for toxicological risk assessment of landfill leachate: A review. AB - Landfilling is the most common solid waste management practice. However, there exist a potential environmental risk to the surface and ground waters due to the possible leaching of contaminants from the landfill leachates. Current municipal solid waste landfill regulatory approaches consider physicochemical characterization of the leachate and do not assess their potential toxicity. However, assessment of toxic effects of the leachates using rapid, sensitive and cost-effective biological assays is more useful in assessing the risks as they measure the overall toxicity of the chemicals in the leachate. Nevertheless, more research is needed to develop an appropriate matrix of bioassays based on their sensitivity to various toxicants in order to evaluate leachate toxicity. There is a need for a multispecies approach using organisms representing different trophic levels so as to understand the potential impacts of leachate on different trophic organisms. The article reviews different bioassays available for assessing the hazard posed by landfill leachates. From the review it appears that there is a need for a multispecies approach to evaluate leachate toxicity. PMID- 28359991 TI - Synergic use of chemical and ecotoxicological tools for evaluating multi contaminated soils amended with iron oxides-rich materials. AB - Abandoned waste piles from ancient mining activities are potential hot spots for the pollution of the surrounding areas. A pot experiment was carried out to check the potential toxicity of the dumping material present in one of these scenarios, and several amendments were tested to attenuate the spread of the contamination events. The waste material had an acid pH and a large total concentration of As and Cu. A dose-response experiment was performed with this material following OCDE 208 test. A proportion 90:10 uncontaminated soil: dumping material (% w/w) was selected for the following experiment, in order to surpass the amount of dumping material that caused 50% reduction in plant growth. Pots were filled with the 90:10 mixture, planted with seeds of Brassica napus and amended with the following materials: three iron oxides of Bayoxide(r) E33 series, iron (II) sulphate in combination with de-inking paper sludge (Fe+PS), iron oxide-rich rolling mill scale (ROL) and iron oxide-rich cement waste (CEM). Amendment effectiveness evaluation was based on chemical and biological assays: extractable trace element concentration, soil enzymatic activities, inhibition of light emission of V. fischeri and Anabaena sp., B. napus L. fresh weight and screening test for emergence of B. napus L. seedlings. Amendments E33HCF and Fe+PS were the most effective in reducing extractable As and Zn concentration. B. napus weight and dehydrogenase and beta-glucosidase activities were positively increased with the two above mentioned treatments but they triggered more toxic effects for V. fischeri luminescence. E33P treatment was the only in which the EC50 was higher than in the control. Anabaena sp. was less sensitive than V. fischeri as its luminescence was not hampered by any treatment. Trace element concentration did not significantly affect the failure in seed emergence. E33HCF and Fe+PS could act as proper amendments as they decreased extractable As and Zn. Further, plant fresh weight, enzymatic activities and some of the bioassays identified the latter treatments as the best ones among those tested here to this type of multi contaminated soil. PMID- 28359994 TI - Population genetic structure and hybridization patterns in the cryptic sister species Chironomus riparius and Chironomus piger across differentially polluted freshwater systems. AB - Chironomids are an integral and functionally important part of many freshwater ecosystems. Yet, to date, there is limited understanding of their microevolutionary processes under chemically polluted natural environments. In this study, we investigated the genetic variation within populations of the ecotoxicological model species Chironomus riparius and its cryptic sister species Chironomus piger at 18 metal-contaminated and reference sites in northwestern Portugal. Microsatellite analysis was conducted on 909 samples to answer if metal contamination affects genetic variation in natural chironomid populations as previously suggested from controlled laboratory experiments. Similarly high levels of genetic diversity and significant but weak genetic substructuring were found across all sites and temporal replicates, with no effects of metal contamination on the genetic variation or species' abundance, although C. piger tended to be less frequent at highly contaminated sites. Our results indicate that high levels of gene flow and population dynamic processes may overlay potential pollutant effects. At least for our study species, we conclude that the "genetic erosion hypothesis", which suggests that chemical pollution will reduce genome-wide genetic variability in affected populations, does not hold under natural conditions. Interestingly, our study provides evidence of successful hybridization between the two sister species under natural conditions. PMID- 28359993 TI - Chronic exposure to the beta-blocker metoprolol reduces growth and alters gene expression of gonadotropins and vitellogenin in Nile tilapia (Oreochromis niloticus). AB - Knowledge of the occurrence and impacts of human pharmaceuticals in the aquatic environment is increasing since many years. Ecotoxicological studies mainly focus on acute effects though; chronic exposure studies are still rare. beta-adrenergic receptor antagonists (beta-blockers) are widely detected in the aquatic environment and likely alter the physiology of aquatic vertebrates due to a well conserved adrenergic system. In this study, Nile tilapia (Oreochromis niloticus) were exposed to four different concentrations (4*10-10M, 4*10-9M, 4*10-8M and 4*10-7M) of metoprolol (beta1-blocker) from fertilized egg until 80 days post hatch. Hatching and survival were not affected but growth was reduced almost dose dependently after 30 and 80 days post-hatch. Histopathological evaluation of the gills revealed the tendency of mild alterations with proliferation of mucous/chloride cells and infiltration by leucocytes as the main findings. The transcriptional responses of both pituitary gonadotropins (luteinizing hormone and follicle stimulating hormone) as well as the estrogenic biomarker vitellogenin indicated moderately altered endocrine processes due to metoprolol exposure at the concentrations chosen. In contrast, hepatic detoxification mechanisms displayed only little to no effects. Based on this study, the overall toxicity of metoprolol in fish at environmentally relevant concentrations seems to be rather low. PMID- 28359995 TI - Cognitive advantages of immersion education after 1year: Effects of amount of exposure. AB - Previous studies with bilingual children have shown that the nature of their second-language instruction has an effect on the development of their cognitive abilities. The aim of this study was to determine whether children who acquire a second language in two different immersion programs for a period of 1year show advantages in executive functions and to examine how the amount of daily exposure affects executive functions. A group of Serbian-speaking second-grade children exposed to the second language for about 5h each day (high exposure group, HEG) and a low-exposure group (LEG) exposed to the second language for about 1.5h each day were compared with an age-matched control group (CG) of monolingual peers on working memory, inhibition, and shifting. Significant group differences were found for working memory, with the HEG performing better than the CG and LEG even after controlling for individual differences in terms of age and intelligence. The three groups did not differ in terms of inhibition and overall shifting abilities, although the control group had a marginally significant advantage on one of the two shifting tasks. Our findings extend previous research by demonstrating that the amount of daily exposure is a significant factor affecting executive functions in early immersion programs for second-language acquisition. In addition, they show that early intensive second-language acquisition can be advantageous for performance on tasks that require a higher level of executive control. PMID- 28359996 TI - Treatment of recurrent aphthous stomatitis with Er,Cr:YSGG laser irradiation: A randomized controlled split mouth clinical study. AB - The present randomized controlled split mouth clinical study aimed to investigate the efficacy of Er,Cr:YSGG laser irradiation on pain reduction and healing rate of recurrent aphthous stomatitis. 40 patients with RAS were recruited for this study and RAS ulcerations of each patient were randomly assigned to the control or test group. In the test group, Er,Cr:YSGG laser with non-contact mode was used to irradiate RAS lesions. In the placebo group, RAS lesions were irradiated with the same device without laser emission. Pain was evaluated with visual analog scale (VAS) while a clinician graded healing of RAS (HRAS). In the placebo group at immediate; scores of VAS presented no statistically significance; in the test group, laser application showed significant pain reducing, at 1st day control. In the test group, a significantly healing effect at 1st day control was observed and this effect was maintained throughout the study. In the placebo group, scores of HRAS were statistically significant at controls on 3, 7, 10days. Statistically significant difference between the scores of VAS and HRAS was found for all control days except day 10 according to the intergroup comparisons. Based on these findings, Er,Cr:YSGG laser application at 0.25W without water may be appropriate to reduce pain and also accelerate the healing of RAS. PMID- 28359997 TI - Impacts of sanitation improvement on reduction of nitrogen discharges entering the environment from human excreta in China. AB - Identifying the sanitation efficacy in reducing contaminations entering the environment is an important step for water pollution controls and developing management strategies to further improve sanitation conditions. With continuous efforts in sanitation improvement during the past decade, reductions in discharges of aquatic nutrients are expected in China. In this study, we estimated the aquatic nitrogen discharges from human excreta in 31 provinces in China during 2006-2014. The results indicated that the nitrogen discharges entering the environment from human excreta are largely determined by both local population and sanitation conditions. In 2014, the nitrogen discharges from human excreta in the rural areas (2118(1219-3140) Gg per year) (median and 95% confidence interval) are higher than those in the urban areas (1485(626-2495) Gg per year). The significant relationship (R2=0.38, n=29) between the total nitrogen concentrations in lakes and corresponding local nitrogen discharges indicated that, the lakes might be potentially affected by the contaminant inputs from human excreta. The further calculations under two policy scenarios showed that through sanitation improvement, further reduction of nitrogen discharges from human excreta in the developed regions might be limited. The sanitation improvement in the less-developed regions, such as Tibet, Qinghai, and Ningxia, should be considered a priority due to the larger reduction potentials. PMID- 28359998 TI - Too much to handle? Pesticide dependence of smallholder vegetable farmers in Southeast Asia. AB - This study aimed to understand farmers' knowledge, attitudes, and practices regarding agricultural pest management and synthetic pesticide use in Southeast Asia. Data were used from 900 farm households producing leaf mustard (Brassica juncea (L.) Czern. et Coss.) and yard-long bean (Vigna unguiculata subsp. sesquipedalis (L.) Verdc.) in Cambodia, Laos and Vietnam. Farmers heavily depended on synthetic pesticides as their main method of pest control. Most farmers were aware of the adverse health effects associated with pesticide use and covered body parts while spraying, but also considered pesticides to be highly effective and indispensable farm inputs. Farmers were largely unable to distinguish between common beneficial and harmful arthropods. Greater knowledge about this was associated with less pesticide use while greater awareness of pesticide health risks was associated with fewer observed poisoning symptoms. For the average farm and while controlling for other factors, farmers who sought advice from friends and neighbors used 45% less pesticide, but those who sought advice from pesticide shopkeepers used 251% more pesticide. Pesticide use was 42% less when a woman was in charge of pest management and 31% less when farmers had adopted biopesticides. These findings suggest relevant entry points for interventions aimed at reducing pesticide dependence. PMID- 28359999 TI - Potency of (doped) rare earth oxide particles and their constituent metals to inhibit algal growth and induce direct toxic effects. AB - Use of rare earth elements (REEs) has increased rapidly in recent decades due to technological advances. It has been accompanied by recurring rare earth element anomalies in water bodies. In this work we (i) studied the effects of eight novel doped and one non-doped rare earth oxide (REO) particles (aimed to be used in solid oxide fuel cells and gas separation membranes) on algae, (ii) quantified the individual adverse effects of the elements that constitute the (doped) REO particles and (iii) attempted to find a discernible pattern to relate REO particle physicochemical characteristics to algal growth inhibitory properties. Green algae Raphidocelis subcapitata (formerly Pseudokirchneriella subcapitata) were used as a test species in two different formats: a standard OECD201 algal growth inhibition assay and the algal viability assay (a 'spot test') that avoids nutrient removal effects. In the 24h 'spot' test that demonstrated direct toxicity, algae were not viable at REE concentrations above 1mgmetal/L. 72-hour algal growth inhibition EC50 values for four REE salts (Ce, Gd, La, Pr) were between 1.2 and 1.4mg/L, whereas the EC50 for REO particles ranged from 1 to 98mg/L. The growth inhibition of REEs was presumably the result of nutrient sequestration from the algal growth medium. The adverse effects of REO particles were at least in part due to the entrapment of algae within particle agglomerates. Adverse effects due to the dissolution of constituent elements from (doped) REO particles and the size or specific surface area of particles were excluded, except for La2NiO4. However, the structure of the particles and/or the varying effects of oxide composition might have played a role in the observed effects. As the production rates of these REO particles are negligible compared to other forms of REEs, there is presumably no acute risk for aquatic unicellular algae. PMID- 28360000 TI - Spatial distribution of organic contaminants in three rivers of Southern England bound to suspended particulate material and dissolved in water. AB - The spatial distribution of pharmaceuticals, personal care products (PPCPs) and other emerging contaminants (ECs) such as plasticisers, perflourinated compounds (PFCs) and illicit drug metabolites in water and bound to suspended particulate material (SPM) is not well-understood. Here, we quantify levels of thirteen selected contaminants in water (n=88) and their partition to suspended particulate material (SPM, n=16) in three previously-unstudied rivers of Greater London and Southern England during a key reproduction/spawning period. Analysis was conducted using an in-house validated method for Solid Phase Extraction followed by High-Performance Liquid Chromatography-Tandem Mass-Spectrometry. Analytes were extracted from SPM using an optimised method for ultrasonic assisted solvent extraction. Detection frequencies of contaminants dissolved in water ranged from 3% (ethinylestradiol) to 100% (bisphenol-A). Overall mean concentrations in the aqueous-phase ranged from 14.7ng/L (benzoylecgonine) to 159ng/L (bisphenol-A). Sewage treatment works (STW) effluent was the predominant source of pharmaceuticals, while plasticisers/perfluorinated compounds may additionally enter rivers via other sources. In SPM, detection frequencies ranged from 44% (PFOA) to 94% (hydroxyacetophenone). Mean quantifiable levels of analytes bound to SPM ranged from 13.5ng/g dry SPM (0.33ng bound/L water) perfluorononanoic acid to 2830ng/g dry SPM (14.3ng bound/L water) perfluorooctanesulfonic acid. Long chain (>C7) amphipathic and acidic PFCs were found to more preferentially bind to SPM than short chain PFCs and other contaminants (Kd=34.1-75.5 vs <5 respectively). Per capita daily contributions of studied contaminants entering rivers ranged from 0.157MUg/person/day of benzoylecgonine (cocaine metabolite) to 58.6MUg/person/day of bisphenol-A. The large sample size of this work (n=104) enabled ANOVA followed by Tukey HSD post hoc tests to establish significant trends in PPCP/EC spatial distribution from headwaters through downstream stretches of studied rivers. Novel findings include environmental Kd calculations, the occurrence of contaminants in river headwaters, increases in contaminant metabolite concentrations downstream of STW effluents revealing possible in-river degradation or de-conjugation, the influence of polarity and acidity in the partition of contaminants to particulate material, among others. PMID- 28360001 TI - Assessment of urban stream sediment pollutants entering estuaries using chemical analysis and multiple bioassays to characterise biological activities. AB - Stormwater contaminants are a major source of often neglected environmental stressors because of the emphasis placed on the management of municipal and industrial wastewaters. Stormwater-derived pollutants in sediments from two New Zealand estuaries was characterised by analytical chemistry and bioassays. Contaminants were extracted from sediment using accelerated solvent extraction (ASE), recovered and concentrated by solid phase extraction (SPE), and analysed for polycyclic aromatic hydrocarbons (PAHs), selected metals, and musk fragrances. The concentrations of PAHs were below the ANZECC Interim Sediment Quality Guideline values while those of lead and zinc exceeded them in some samples. The sediment extracts containing organic contaminants exhibited acute toxicity in the zebrafish fish embryo toxicity (FET) and teratogenicity, induction of biotransformation (EROD activity), and genotoxicity (comet assay) in zebrafish. The potential of the extracts to interact with endocrine signalling processes was assessed by GeneBLAzer reporter gene bioassays and they exhibited estrogenic, androgenic, and anti-progestagenic activities. PMID- 28360002 TI - A monsoon-related 174-year relative humidity record from tree-ring delta18O in the Yaoshan region, eastern central China. AB - The authors present a time series of tree-ring cellulose stable oxygen isotope ratios (delta18O) constructed using a numerical mixing method, from five Pinus tabulaeformis from Yaoshan, eastern central China. The time series is synchronous with the observed April-to-September precipitation delta18O time series records from surrounding stations, implying that the tree-ring delta18O signals reflect Asian summer monsoon-related precipitation. Moreover, significant correlations were detected between the tree-ring delta18O records and central-eastern Pacific sea surface temperature (SSTs)/Asian summer monsoon indices. This suggests that the Yaoshan tree-ring delta18O time series offers a promising means to study past Asian summer monsoons and ENSO variability. The time series is significantly correlated with the mean relative humidity from April to September (RHAS) (r= 0.638, n=52, p<0.0001) over the Yaoshan region. The authors assign a transfer function to the reconstruct the RHAS time series from 1835 to 2008. The mean value of RHAS over the period 1870-1890 is the lowest observed value during the past 174years, implying severe drought at that time. From 1930 to 2008, an obvious drying trend in the Yaoshan region is observed. Particularly from 1985 to 2008, frequent, extremely dry years occurred, with few extremely wet years. The drying trend is consistent with decreasing Asian summer monsoon precipitation over the Loess Plateau over the past 60years. The acidification implied by this data extends well beyond the vicinity of Yaoshan and may be expected to impact the entire monsoonal region in northern China. A multi-taper spectral analysis and an ensemble empirical mode decomposition EEMD of the time series indicate 14.6-12.4 and 6.4-2.3 year cycles in the reconstructed RHAS time series during the past 174years, which correspond with solar cycles and ENSO cycles, respectively. PMID- 28360003 TI - ZnO nanoparticle effects on hormonal pools in Arabidopsis thaliana. AB - At present, nanoparticles have been more and more used in a wide range of areas. However, very little is known about the mechanisms of their impact on plants, as both positive and negative effects have been reported. As plant interactions with the environment are mediated by plant hormones, complex phytohormone analysis has been performed in order to characterize the effect of ZnO nanoparticles (mean size 30nm, concentration range 0.16-100mgL-1) on Arabidopsis thaliana plants. Taking into account that plant hormones exhibit high tissue-specificity as well as an intensive cross-talk in the regulation of growth and development as well as defense, plant responses were followed by determination of the content of five main phytohormones (cytokinins, auxins, abscisic acid, salicylic acid and jasmonic acid) in apices, leaves and roots. Increasing nanoparticle concentration was associated with gradually suppressed biosynthesis of the growth promoting hormones cytokinins and auxins in shoot apical meristems (apices). In contrast, cis-zeatin, a cytokinin associated with stress responses, was elevated by 280% and 590% upon exposure to nanoparticle concentrations 20 and 100mgL-1, respectively, in roots. Higher ZnO nanoparticle doses resulted in up-regulation of the stress hormone abscisic acid, mainly in apices and leaves. In case of salicylic acid, stimulation was found in leaves and roots. The other stress hormone jasmonic acid (as well as its active metabolite jasmonate isoleucine) was suppressed at the presence of nanoparticles. The earliest response to nanoparticles, associated with down-regulation of growth as well as of cytokinins and auxins, was observed in apices. At higher dose, up-regulation of abscisic acid, was detected. This increase, together with elevation of the other stress hormone - salicylic acid, indicates that plants sense nanoparticles as severe stress. Gradual accumulation of cis-zeatin in roots may contribute to relatively higher stress resistance of this tissue. PMID- 28360004 TI - Outdoor and indoor particle characterization from a large and uncontrolled combustion of a tire landfill. AB - A large and uncontrolled fire of a tire landfill started in Sesena (Toledo, Spain) on May 13, 2016. An experimental deployment was immediately launched in the area for measuring regulated and non-standard air quality parameters to assess the potential impact of the plume at local and regional levels. Outdoor and indoor measurements of different parameters were carried out at a near school, approximately 700m downwind the burning tires. Real time measurements of ambient black carbon (BC) and total number particle concentrations were identified as good tracers of the smoke plume. Simultaneous peaks allowed us to characterize situations of the plume impact on the site. Outdoor total particle number concentrations reached in these occasions 3.8*105particlescm-3 (on a 10min resolution) whereas the indoor concentration was one order of magnitude lower. BC mass concentrations in ambient air were in the range of 2 to 7MUgm-3, whereas concentrations<2MUgm-3 were measured indoor. Indoor and outdoor deposited inhalable dust was sampled and chemically characterized. Both indoor and outdoor dust was enriched in tire components (Zn, sulfate) and PAHs associated to the tire combustion process. Infiltration processes have been documented for BC and particle number concentrations causing increases in indoor concentrations. PMID- 28360005 TI - Origin of hexavalent chromium in groundwater: The example of Sarigkiol Basin, Northern Greece. AB - Hexavalent chromium constitutes a serious deterioration factor for the groundwater quality of several regions around the world. High concentrations of this contaminant have been also reported in the groundwater of the Sarigkiol hydrological basin (near Kozani city, NW Greece). Specific interest was paid to this particular study area due to the co-existence here of two important factors both expected to contribute to Cr(VI) presence and groundwater pollution; namely the area's exposed ophiolitic rocks and its substantial fly ash deposits originating from the local lignite burning power plant. Accordingly, detailed geochemical, mineralogical, hydro-chemical, geophysical and hydrogeological studies were performed on the rocks, soils, sediments and water resources of this basin. Cr(VI) concentrations varied in the different aquifers, with the highest concentration (up to 120MUgL-1) recorded in the groundwater of the unconfined porous aquifer situated near the temporary fly ash disposal site. Recharge of the porous aquifer is related mainly to precipitation infiltration and occasional surface run-off. Nevertheless, a hydraulic connection between the porous and neighboring karst aquifers could not be delineated. Therefore, the presence of Cr(VI) in the groundwater of this area is thought to originate from both the ophiolitic rock weathering products in the soils, and the local leaching of Cr(VI) from the diffused fly ash located in the area surrounding the lignite power plant. This conclusion was corroborated by factor analysis, and the strongly positively fractionated Cr isotopes (delta53Cr up to 0.830/00) recorded in groundwater, an ash leachate, and the bulk fly ash. An anthropogenic source of Cr(VI) that possibly influences groundwater quality is especially apparent in the eastern part of the Sarigkiol basin. PMID- 28360006 TI - Do mosses exist outside of Europe? A biomonitoring reflection. AB - The passive moss biomonitoring technique has been proved a useful environmental tool for the study of the air quality. However, after more than 40years of its discovery, it has not been used yet in decision making when dealing with atmospheric pollution. Scientific efforts and funding are wasted when these sort of findings do not have a meaningful impact on society. Thus, the aim of this review is to showcase the reasons preventing the worldwide application of the moss technique. The results showed that the possible reasons underlying this problem are the lack of standardization of the technique, transmission of a false idea of robustness, and the lack of a theoretical background. Knowing and accepting these problems is the first step to encourage scientists and funding bodies to invest their efforts in really improving the technique for its application in environmental policies and not only in scientific circles. PMID- 28360007 TI - Biofilm structures (EPS and bacterial communities) in drinking water distribution systems are conditioned by hydraulics and influence discolouration. AB - High-quality drinking water from treatment works is degraded during transport to customer taps through the Drinking Water Distribution System (DWDS). Interactions occurring at the pipe wall-water interface are central to this degradation and are often dominated by complex microbial biofilms that are not well understood. This study uses novel application of confocal microscopy techniques to quantify the composition of extracellular polymeric substances (EPS) and cells of DWDS biofilms together with concurrent evaluation of the bacterial community. An internationally unique, full-scale, experimental DWDS facility was used to investigate the impact of three different hydraulic patterns upon biofilms and subsequently assess their response to increases in shear stress, linking biofilms to water quality impacts such as discolouration. Greater flow variation during growth was associated with increased cell quantity but was inversely related to EPS-to-cell volume ratios and bacterial diversity. Discolouration was caused and EPS was mobilised during flushing of all conditions. Ultimately, biofilms developed under low-varied flow conditions had lowest amounts of biomass, the greatest EPS volumes per cell and the lowest discolouration response. This research shows that the interactions between hydraulics and biofilm physical and community structures are complex but critical to managing biofilms within ageing DWDS infrastructure to limit water quality degradation and protect public health. PMID- 28360009 TI - Occurrence and fate of parabens and their metabolites in five sewage treatment plants in India. AB - Parabens (p-hydroxy benzoic acid esters) are antimicrobial agents, used widely as preservatives in personal care products (PCPs), pharmaceuticals, foods, and beverages. PCPs that contain parabens are a major source of these chemicals in sewage treatment plants (STPs). Very few studies have demonstrated the occurrence of parabens in wastewater. In this study, the occurrence and fate of six parabens, methyl-(MeP), ethyl-(EtP), propyl-(PrP), butyl-(BuP), hepty-(HpP) and benzyl-(BzP) parabens, and five of their metabolites (4-HB, 3,4-DHB, OH-MeP, OH EtP and BA) were studied in five STPs in India. The concentrations of parent parabens (?6parent parabens) in five STPs ranged between 131 and 920ng/L in influent; 16 and 67ng/L in effluent; and 104 and 1090ng/g, dry weight, in sludge samples. The sum concentrations of five paraben metabolites (?5paraben metabolites) in five STPs ranged between 4110 and 34,600ng/L in influent; 2560 and 3800ng/L in effluent; and 1220 and 35,900ng/g, dry weight, in sludge samples. These values were higher than those reported for many industrialized countries. We calculated the mass loadings, removal efficiencies, and environmental emissions of parabens based on the measured concentrations in influents, effluents, and sludge. The mean removal efficiencies of parent parabens and their metabolites ranged from 80% to 100% and 28% to 76%, respectively. PMID- 28360008 TI - Stress acclimation and particulate matter accumulation in Pinus sylvestris saplings affected by moderate combinations of urban stressors. AB - To predict how the function of urban vegetation and the provision of ecosystem services respond to combinations of natural and anthropogenic drivers, a better understanding of multiple stress interactions is required. This study tested combined effects of moderate levels of drought, soil salinity and exposure to diesel exhaust on parameters of physiology, metabolism, morphology and growth of Pinus sylvestris L. saplings. We found that plant responses were primarily dominated by single stressors and a few two-way interactions. Stressor combinations did not have considerable additional negative effects on plant performance compared to single stressors. Hence, synergistic and antagonistic interactions were rare and additive effects frequent. Drought cycles caused most negative effects, from chlorophyll a fluorescence and epicuticular wax content to growth responses, while soil salinity caused fewer negative effects but contributed to reduction in fine root growth and fluorescence parameters at low air contamination. Interestingly, the air contamination alone had only marginal effects on plant morphology and growth, but contributed an antagonistic effect, dampening the negative effect of drought and salinity on the maximum quantum efficiency of PSII photochemistry (Fv/Fm) and fine root biomass. Although, these effects were moderate, it appears that exhaust exposure had a cross-acclimation effect on plant responses to drought and salinity. We also found that salinity had a negative effect on the accumulation of particulate matter on shoots, illustrating that the plant stress situation can affect the provisioning of certain ecosystem services like pollution attenuation. These findings have implications for the understanding of the complex natural and anthropogenic stress situation of urban, and how to maintain the ecological functions and delivery of ecosystem services. PMID- 28360010 TI - Food as a social determinant of mental health among household heads in the Upper West Region of Ghana. AB - According to the World Health Organization, mental distress and related illnesses are becoming leading causes of morbidity and mortality in developing countries. Despite the influence of food insecurity on mental health, empirical understanding of this relationship in sub-Saharan Africa, where incidence of food insecurity is relatively high, is almost non-existent. This study contributes to the literature by examining the association between food insecurity and mental health in the Upper West Region of Ghana. We used Ordinary Least Square (OLS) to analyze cross-sectional data collected on household heads (n = 1438) in 2014 using the Household Food Insecurity Access Scale and the DUKE Health Profile. The results show that heads of severely food insecure (beta = 0.934, p <= 0.001) and moderately food secure households (beta = 0.759, p <= 0.001) were more likely to report elevated mental distress compared to those from food secure households. We also found that female household heads were more likely to report elevated mental distress (beta = 0.164, p <= 0.05) compared to their male counterparts. Our findings suggest the need to improve food security as a strategy targeted at improving overall mental health in the Ghanaian context. PMID- 28360011 TI - A modified 3D algorithm for road traffic noise attenuation calculations in large urban areas. AB - The primary objective of this study is the development and application of a 3D road traffic noise attenuation calculation algorithm. First, the traditional empirical method does not address problems caused by non-direct occlusion by buildings and the different building heights. In contrast, this study considers the volume ratio of the buildings and the area ratio of the projection of buildings adjacent to the road. The influence of the ground affection is analyzed. The insertion loss due to barriers (infinite length and finite barriers) is also synthesized in the algorithm. Second, the impact of different road segmentation is analyzed. Through the case of Pearl River New Town, it is recommended that 5 degrees is the most appropriate scanning angle as the computational time is acceptable and the average error is approximately 3.1 dB. In addition, the algorithm requires only 1/17 of the time that the beam tracking method requires at the cost of more imprecise calculation results. Finally, the noise calculation for a large urban area with a high density of buildings shows the feasibility of the 3D noise attenuation calculation algorithm. The algorithm is expected to be applied in projects requiring large area noise simulations. PMID- 28360012 TI - Assessment of Olea europaea L. fruit extracts: Phytochemical characterization and anticancer pathway investigation. AB - Olea europaea L. has been widely used as an advantageous rich source of bioactive compounds of high economic value leading to its use in pharmaceutical, cosmetic, and agriculture industries. Ethanolic extracts of olive fruits from three different cultivars (OFE) were studied for their phytochemical contents and were investigated for antioxidant activities and anticancer potential. Major polyphenols detected in these extracts were tyrosol, hydroxytyrosol, oleuropein, rutin, quercetin and glucoside forms of luteolin and apigenin. All these compounds have shown to significantly contribute to the antioxidant activity of OFE, which was evaluated by DPPH and ABTS assays. Proliferation of hepatic and colon cancer cells, HepG2 and Caco-2, were shown to be sensitive to OFE with IC50 less than 1.6mg/ml for all tested extracts. Moreover, flow cytometry analysis showed that OFE induced cell cycle arrest in the S-phase within both HepG2 and Caco-2 cells. This has triggered a cell death mechanism as shown by DNA fragmentation, expression of p53 and phosphorylation level of Akt and Erk proteins. Interestingly, these extracts could be further used as a potential source of natural compounds with both antioxidant and anticancer effects. PMID- 28360013 TI - A review of the role of orexin system in pain modulation. AB - The roles of orexinergic system (orexin-A, orexin-B) and their receptors (orexin receptor type-1, orexin receptor type-2) in various physiological processes such as arousal, reward seeking behavior, energy homeostasis, sensory modulation, stress processing, cognition, endocrine functions, visceral functions and pain modulation have been established. This review summarizes the studies investigating orexin antinociceptive effects and their cellular mechanisms in various types of pain including neuropathic pain, migraine and cluster headache, visceral and orofacial pains. Moreover, the role of orexins in stress induced analgesia and on the development of morphine analgesic tolerance has been discussed. The antinociceptive effects of orexins have been shown in several pain models including thermal, mechanical and chemical induced nociception. Orexins modulate pain perception at both spinal and supraspinal levels. The periaqueductal gray (PAG) is one important supraspinal sites of orexin pain modulation. A possible involvement of endocannabinoids in supraspinal orexin induced analgesia has been proposed. This review suggests a potential role of orexins in the management of pain. PMID- 28360014 TI - Concurrent versus sequential adjuvant chemo-endocrine therapy in hormone-receptor positive early stage breast cancer patients: a systematic review and meta analysis. AB - BACKGROUND: Although in clinical practice adjuvant chemotherapy (CT) and endocrine therapy (ET) are administered sequentially in patients with hormone receptor positive breast cancer, the optimal timing, i.e. concurrent or sequential administration, of these treatments has been scarcely investigated. To better clarify this issue we conducted a systematic review and meta-analysis of randomized studies comparing these two modalities of administrations in terms of disease-free survival (DFS) and overall survival (OS). METHODS: Relevant studies were identified by searching PubMed, Web of Knowledge and the proceedings of the major conferences with no date restriction up to March 2016. The summary risk estimates (pooled hazard ratio [HR] and 95% confidence intervals [CI]) for DFS and OS were calculated using random effect models (DerSimonian and Laird method). RESULTS: A total of three randomized studies were eligible including 2021 breast cancer patients. Overall, 755 DFS events were observed, 365 in the sequential arm and 390 in the concomitant arm, with a pooled HR of 0.95 (95% CI = 0.76 to 1.18, P = 0.643). No association between timing of treatment and OS was observed (HR = 0.95; 95% CI = 0.80 to 1.12, P = 0.529). CONCLUSION: Our pooled analysis showed no association between the timing of administration of adjuvant CT and ET and DFS and OS in breast cancer patients candidates for both adjuvant treatments. Because of the small number of published trials, the lack of data on the timing with modern adjuvant treatments, i.e. taxane-containing CT and aromatase inhibitors, this topic remain still controversial and requires further studies to be clarified. PMID- 28360016 TI - FcgammaRIIb expression on B cells is associated with treatment efficacy for acute rejection after kidney transplantation. AB - BACKGROUND: Fcgamma receptors (FcgammaR) play a role in the acute rejection (AR) of organ transplants. FcgammaRIIB is an inhibitory FcgammaR expressed on B cells. Intravenous IgG (IVIG) and CD28 monoclonal antibody (mAb) have been shown to have immunomodulatory properties against AR. AIM: To examine the association between FcgammaRIIB expression on B cell subpopulations and AR treatment efficacy. METHODS: Male F344 rats were used as kidney donors and Lewis rats as recipients to establish models of renal transplantation. Rats were divided into five groups: sham, AR-PBS, AR-IVIG, AR-PNGase F-IVIG, and AR-CD28. Serum creatinine (Scr), blood urea nitrogen (BUN), and urine protein content were determined. Inflammatory markers were measured by ELISA, FcgammaR by western blotting, and spleen B cell activation by flow cytometry. RESULTS: Scr, BUN, urinary protein content, levels of CRP, IL-10, TNF-alpha, IL-6, IL-8, and IgG were all increased in the AR-PBS group compared with the sham group (all P<0.01); these increases were partly reversed in the AR-IVIG, AR-PNGase F IVIG, and AR-CD28 groups (all P<0.01), with IVIG showing the better efficacy than PNGase F IVIG. Furthermore, blood and spleen FcgammaRIA and FcgammaRIIIA were increased by AR, while FcgammaRIIB expressions in splenic activated B cells and regulatory B cells were decreased; these changes were partly alleviated by all three treatments, with IVIG having the better effect than PNGase F IVIG. CONCLUSION: We observed an association between B cell FcgammaRIIB expression and treatment efficacy for AR after kidney transplantation in rats. PMID- 28360015 TI - Health-related quality of life in patients with locally recurrent or metastatic breast cancer treated with etirinotecan pegol versus treatment of physician's choice: Results from the randomised phase III BEACON trial. AB - BACKGROUND: Health-related quality of life (HRQoL) enhances understanding of treatment effects that impact clinical decision-making. Although the primary end point was not achieved, the BEACON (BrEAst Cancer Outcomes with NKTR-102) trial established etirinotecan pegol, a long-acting topoisomerase-1 (TOP1) inhibitor, as a promising therapeutic for patients with advanced/metastatic breast cancer (MBC) achieving clinically meaningful benefits in median overall survival (OS) for patients with stable brain metastases, with liver metastases or >= 2 sites of metastatic disease compared to treatment of physician's choice (TPC). Reported herein are the findings from the preplanned secondary end-point of HRQoL. PATIENTS AND METHODS: HRQoL, assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) (version 3.0) supplemented by the breast cancer-specific Quality of Life Questionnaire (QLQ-BR23), was evaluated post randomisation in 733 of 852 patients with either anthracycline-, taxane- and capecitabine-pretreated locally recurrent or MBC randomised to etirinotecan pegol (n = 378; 145 mg/m2 every 3 weeks (q3wk)) or single-agent TPC (n = 355). Patients completed assessments at screening, every 8 weeks (q8wk) during treatment, and end-of-treatment. Changes from baseline were analysed, and the proportions of patients achieving differences (>=5 points) in HRQoL scores were compared. RESULTS: Differences were seen favouring etirinotecan pegol up to 32 weeks for global health status (GHS) and physical functioning scales (P < 0.02); numerical improvement was reported in other functional scales. The findings from HRQoL symptom scales were consistent with adverse event profiles; etirinotecan pegol was associated with worsening gastrointestinal symptoms whereas TPC was associated with worsened dyspnoea and other systemic side-effects. Analysis of GHS and physical functioning at disease progression showed a decline in HRQoL in both treatment arms, with a mean change from baseline of -9.4 and -10.8 points, respectively. CONCLUSION: There was evidence of benefit associated with etirinotecan pegol compared with current standard of care agents in multiple HRQoL measurements, including global health status and physical functioning, despite worse gastrointestinal symptoms (e.g. diarrhoea). Patients in both arms had a decline in HRQoL at disease progression. STUDY NUMBER: NCT01492101. PMID- 28360017 TI - Modification of cytokine-induced killer cells with folate receptor alpha (FRalpha)-specific chimeric antigen receptors enhances their antitumor immunity toward FRalpha-positive ovarian cancers. AB - Folate receptor alpha (FRalpha) is aberrantly expressed in ovarian cancers but largely absent in normal tissues, and therefore represents an attractive target for immunotherapy. In recent years, modification of T cells with chimeric antigen receptor (CAR) targeting FRalpha has been reported to improve antitumor immunity of T cells. However, there are limited data regarding CAR-modified cytokine induced killer (CAR-CIK) cells. In the present study, we modified CIK cells with FRalpha-specific CARs and investigated their antitumor immunity against ovarian cancers. We found that both non-transduced and mock CAR-transduced CIK cells showed only low antitumor activity against either FRalpha-positive (FRalpha+) or FRalpha-negative (FRalpha-) targets. However, all three generations of CAR modified CIK cells showed enhanced antitumor activity against FRalpha+ targets, but not FRalpha- targets. First-generation zeta-CAR-CIK cells increased production of IFN-gamma, enhanced short-term cytotoxicity against FRalpha+ ovarian cancer cells, and showed modest and short-term suppression of established tumors; while second-generation 28zeta- and third-generation 28BBzeta-CAR-CIK cells showed significant proliferation, enhanced secretion of IL-2, eliminated the FRalpha+ ovarian cancer cells in long-term co-culture, and showed dramatic and long-term inhibition of tumor growth and prolonged survival of xenograft bearing mice. It is noteworthy that the 28BBzeta-CAR was more potent in the modification of CIK cells than 28zeta-CAR both in vitro and in vivo. Moreover, CAR-CIK cells showed more efficient anticancer activity compared with CAR-T cells in vitro, but less efficient than CAR-T cells in vivo. According to these results, we conclude that modification of CIK cells with FRalpha-specific CARs enhances their antitumor immunity to FRalpha+ ovarian cancers. The third generation 28BB-zeta CAR containing 4-1BB co-stimulation was more efficient in modification of CIK cells than either first-generation zeta-CAR or second generation CD28-zeta-CAR. PMID- 28360018 TI - Microwave-assisted inorganic salt pretreatment of sugarcane leaf waste: Effect on physiochemical structure and enzymatic saccharification. AB - This paper presents a method to pretreat sugarcane leaf waste using microwave assisted (MA) inorganic salt to enhance enzymatic saccharification. The effects of process parameters of salt concentration, microwave power intensity and pretreatment time on reducing sugar yield from sugarcane leaf waste were investigated. Pretreatment models based on MA-NaCl, MA-ZnCl2 and MA-FeCl3 were developed with high coefficients of determination (R2 >0.8) and optimized. Maximum reducing sugar yield of 0.406g/g was obtained with 2M FeCl3 at 700W for 3.5min. Scanning electron microscopy (SEM), Fourier Transform Infrared analysis (FTIR) and X-ray diffraction (XRD) showed major changes in lignocellulosic structure after MA-FeCl3 pretreatment with 71.5% hemicellulose solubilization. This regime was further assessed on sorghum leaves and Napier grass under optimal MA-FeCl3 conditions. A 2-fold and 3.1-fold increase in sugar yield respectively were observed compared to previous reports. This pretreatment was highly effective for enhancing enzymatic saccharification of lignocellulosic biomass. PMID- 28360019 TI - Effects of biochar on nitrogen transformation and heavy metals in sludge composting. AB - Composting is regarded as an effective treatment to suppress pathogenic organisms and stabilize the organic material in sewage sludge. This study investigated the use of biochar as an amendment to improve the composting effectiveness and reduce the bioavailability of heavy metals and loss of nitrogen during composting. Biochar of 0%, 1%, 3%, 5% and 7% were added into a mixture of sludge and straw, respectively. The use of biochar, even in small amounts, altered the composting process and the properties of the end products. Biochar addition resulted in a higher pile temperature (66 degrees C) and could reduce nitrogen loss by transforming ammonium into nitrite. In the 5% biochar group, the final product from sludge composting, ammonia nitrogen, decreased by 22.4% compared to the control, and nitrate nitrogen increased by 310.6%. Considering temperature and N transformation, the treatment with 5% biochar is suggested for sludge composting. PMID- 28360020 TI - Strain rate influence on human cortical bone toughness: A comparative study of four paired anatomical sites. AB - Bone fracture is a major health issue worldwide and consequently there have been extensive investigations into the fracture behavior of human cortical bone. However, the fracture properties of human cortical bone under fall-like loading conditions remains poorly documented. Further, most published research has been performed on femoral diaphyseal bone, whereas it is known that the femoral neck and the radius are the most vulnerable sites to fracture. Hence, the aim of this study is to provide information on human cortical bone fracture behavior by comparing different anatomical sites including the radius and the femoral neck acquired from 32 elderly subjects (50 - 98 y.o.). In order to investigate the intrinsic fracture behavior of human cortical bone, toughness experiments were performed at two different strain rates: standard quasi-static conditions, and a higher strain rate representative of a fall from a standing position. The tests were performed on paired femoral neck, femoral, tibial and radius diaphyseal samples. Linear elastic fracture toughness and the non-linear J-integral method were used to take into account both the elastic and non-elastic behavior of cortical bone. Under quasi-static conditions, the radius presents a significantly higher toughness than the other sites. At the higher strain rate, all sites showed a significantly lower toughness. Also, at the high strain rate, there is no significant difference in fracture properties between the four anatomical sites. These results suggest that regardless of the anatomical site (femur, femoral neck, tibia and radius), the bone has the same fracture properties under fall loading conditions. This should be considered in biomechanical models under fall-like loading conditions. PMID- 28360021 TI - The morbidly adherent placenta: when and what association of signs can improve MRI diagnosis? Our experience. AB - PURPOSE: We aimed to verify whether combination of specific signs improves magnetic resonance imaging (MRI) accuracy in morbidly adherent placenta (MAP). METHODS: MRI findings for MAP were retrospectively evaluated in 27 women. Histopathology was the reference standard, showing MAP in eight of 27 cases. Specificity, sensitivity, positive predictive value, and negative predictive value were calculated for all MRI signs. Two skilled radiologists analyzed MRI findings, resolving discrepancies by consensus, using three alternative diagnostic criteria during three consecutive sections. First criterion: at least one of reported MRI signs indicates MAP and the absence of any sign is normal; second criterion: at least one statistically significant sign indicates MAP and no sign or nonsignificant sign is normal; third criterion: at least two statistically significant signs indicate MAP and no sign, nonsignificant sign, or only one significant sign is normal. RESULTS: Using the first criterion yielded an unacceptable rate of false positive results (78.9%). Using the second criterion there were less false positive results (31.5%), and diagnostic accuracy of the second criterion was significantly higher than the first; the third criterion correctly classified 100% of cases. CONCLUSION: Only specific MRI signs can correctly predict MAP at histopathology, particularly when multiple (at least two) specific signs are observed together. PMID- 28360022 TI - Patient Portals as a Tool for Health Care Engagement: A Mixed-Method Study of Older Adults With Varying Levels of Health Literacy and Prior Patient Portal Use. AB - BACKGROUND: Growing evidence that patient engagement improves health outcomes and reduces health care costs has fueled health providers' focus on patient portals as the primary access point for personal health information and patient-provider communication. Whereas much attention has been given to identifying characteristics of older adults who do and do not adopt patient portals and necessary adaptions to portal design, little is known about their attitudes and perceptions regarding patient portal use as a tool for engagement in their health care within the context of health literacy, experience navigating Web-based health information, and previous patient portal use. OBJECTIVE: The specific aims of this study were to explore attitudes toward portal adoption and its perceived usefulness as a tool for health care engagement among adults (65 years and older) who have varying levels of health literacy and degrees of prior patient portal use. METHODS: A phone survey of 100 community dwelling adults gathered sociodemographic, health, and technology related information. Older adults were purposefully selected for 4 follow-up focus groups based on survey responses to health literacy and previous patient portal use. A mixed-method approach was used to integrate phone survey data with thematic analysis of 4 focus groups. Due to variability in attitudes between focus group participants, an individual case analysis was performed and thematic patterns were used as the basis for subgroup formation. RESULTS: Differences in health literacy, comfort navigating health information on the Web, and previous portal experience explained some but not all differences related to the 7 themes that emerged in the focus groups analysis. Individual cases who shared attitudes were arranged into 5 subgroups from least to most able and willing to engage in health care via a patient portal. The subgroups' overall portal adoption attitudes were: (1) Don't want to feel pushed into anything, (2) Will only adopt if required, (3) Somebody needs to help me, (4) See general convenience of the portal for simple tasks and medical history, but prefer human contact for questions, and (5) Appreciates current features and excited about new possibilities . CONCLUSIONS: Most of the older adults are interested in using a patient portal regardless of health literacy level, previous patient portal adoption, or experience navigating health information on the Web. Research targeting informal caregivers of older adults who are unable or unwilling to engage with information technology in health care on their own is warranted. Health care organizations should consider tailored strategies to meet the needs of older adults (and their informal caregivers) and explore alternative workflows that integrate patient portal information into phone conversations and face-to-face contact with health care providers. PMID- 28360023 TI - Continuing Professional Development via Social Media or Conference Attendance: A Cost Analysis. AB - BACKGROUND: Professional development is essential in the health disciplines. Knowing the cost and value of educational approaches informs decisions and choices about learning and teaching practices. OBJECTIVE: The primary aim of this study was to conduct a cost analysis of participation in continuing professional development via social media compared with live conference attendance. METHODS: Clinicians interested in musculoskeletal care were invited to participate in the study activities. Quantitative data were obtained from an anonymous electronic questionnaire. RESULTS: Of the 272 individuals invited to contribute data to this study, 150 clinicians predominantly from Australia, United States, United Kingdom, India, and Malaysia completed the outcome measures. Half of the respondents (78/150, 52.0%) believed that they would learn more with the live conference format. The median perceived participation costs for the live conference format was Aus $1596 (interquartile range, IQR 172.50-2852.00). The perceived cost of participation for equivalent content delivered via social media was Aus $15 (IQR 0.00-58.50). The majority of the clinicians (114/146, 78.1%, missing data n=4) indicated that they would pay for a subscription-based service, delivered by social media, to the median value of Aus $59.50. CONCLUSIONS: Social media platforms are evolving into an acceptable and financially sustainable medium for the continued professional development of health professionals. When factoring in the reduced costs of participation and the reduced loss of employable hours from the perspective of the health service, professional development via social media has unique strengths that challenge the traditional live conference delivery format. PMID- 28360024 TI - With Some Help From My Network: Supplementing eHealth Literacy With Social Ties. AB - BACKGROUND: eHealth literacy is defined as the ability to seek, find, understand, and appraise health information from electronic sources and apply knowledge gained to addressing or solving a health problem. Previous research has shown high reliance on both online and face-to-face interpersonal sources when sharing and receiving health information. OBJECTIVE: In this paper, we examine these interpersonal sources and their interplay with respondents' eHealth literacy and perceived health outcomes. Specifically, we look at how the relationship between eHealth literacy and health outcomes is moderated by (1) finding help while performing online activities, (2) finding others with similar health concerns online, and (3) the importance of finding others with similar health concerns for people from ethnic minorities, specifically Palestinian citizens of Israel versus Israeli Jews. METHODS: We used a nationally representative random-digit dial telephone household survey of an Israeli adult population (age >=21 years, N=819). The collected data were analyzed using two regression models. The first examined how the correlation between eHealth literacy and perceived outcomes was moderated by the availability of help. The second examined how the correlation between eHealth literacy and perceived outcomes was moderated by finding others with similar health concerns and by ethnicity. RESULTS: Respondents with low eHealth literacy who were able to recruit help when performing online activities demonstrated higher perceived health outcomes compared to similar respondents who did not find help. Respondents with low eHealth literacy, who were able to find others with similar health concerns (online), demonstrated higher perceived health outcomes when compared to similar respondents who did not find others with similar health concerns. Finally, finding similar others online was more helpful in enhancing health outcomes for ethnic minorities; Palestinian citizens of Israel gained more health benefits by finding similar others compared to Israeli Jews. CONCLUSIONS: Although the availability of help and the notion of ethnicity have been discussed extensively within the context of social capital and health, our findings offer initial evidence for the relevancy of these concepts when studying individuals' eHealth literacy. Specifically, our findings enable a better understanding of the role of social ties and ethnicity in moderating the interplay between eHealth literacy and perceived health outcomes. Given the increased importance of eHealth information, our findings enhance understanding of how social ties can potentially compensate for low eHealth literacy. PMID- 28360025 TI - Design and Implementation of a Novel Web-Based E-Learning Tool for Education of Health Professionals on the Antibiotic Vancomycin. AB - BACKGROUND: Traditional approaches to health professional education are being challenged by increased clinical demands and decreased available time. Web-based e-learning tools offer a convenient and effective method of delivering education, particularly across multiple health care facilities. The effectiveness of this model for health professional education needs to be explored in context. OBJECTIVES: The study aimed to (1) determine health professionals' experience and knowledge of clinical use of vancomycin, an antibiotic used for treatment of serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and (2) describe the design and implementation of a Web-based e-learning tool created to improve knowledge in this area. METHODS: We conducted a study on the design and implementation of a video-enhanced, Web-based e-learning tool between April 2014 and January 2016. A Web-based survey was developed to determine prior experience and knowledge of vancomycin use among nurses, doctors, and pharmacists. The Vancomycin Interactive (VI) involved a series of video clips interspersed with question and answer scenarios, where a correct response allowed for progression. Dramatic tension and humor were used as tools to engage users. Health professionals' knowledge of clinical vancomycin use was obtained from website data; qualitative participant feedback was also collected. RESULTS: From the 577 knowledge survey responses, pharmacists (n=70) answered the greatest number of questions correctly (median score 4/5), followed by doctors (n=271; 3/5) and nurses (n=236; 2/5; P<.001). Survey questions on target trough concentration (75.0%, 433/577) and rate of administration (64.9%, 375/577) were answered most correctly, followed by timing of first level (49%, 283/577), maintenance dose (41.9%, 242/577), and loading dose (38.0%, 219/577). Self reported "very" and "reasonably" experienced health professionals were also more likely to achieve correct responses. The VI was completed by 163 participants during the study period. The rate of correctly answered VI questions on first attempt was 65% for nurses (n=63), 68% for doctors (n=86), and 82% for pharmacists (n=14; P<.001), reflecting a similar pattern to the knowledge survey. Knowledge gaps were identified for loading dose (39.2% correct on first attempt; 64/163), timing of first trough level (50.3%, 82/163), and subsequent trough levels (47.9%, 78/163). Of the 163 participants, we received qualitative user feedback from 51 participants following completion of the VI. Feedback was predominantly positive with themes of "entertaining," "engaging," and "fun" identified; however, there were some technical issues identified relating to accessibility from different operating systems and browsers. CONCLUSIONS: A novel Web-based e-learning tool was successfully developed combining game design principles and humor to improve user engagement. Knowledge gaps were identified that allowed for targeting of future education strategies. The VI provides an innovative model for delivering Web-based education to busy health professionals in different locations. PMID- 28360026 TI - Experiences of Older Adults With Mobile Phone Text Messaging as Reminders of Home Exercises After Specialized Manual Therapy for Recurrent Low Back Pain: A Qualitative Study. AB - BACKGROUND: Clinical experience of manual therapy for musculoskeletal pain is that patients often suffer from recurrent pain and disorders, but that they do not continue to perform their physical home exercises when they are free from symptoms. The chance of positive long-term effects of manual therapy would probably increase if patients were reminded that they are to continue to perform their exercises. Mobile phone text messaging (short messaging service, SMS) is increasingly used as an innovative intervention to remind patient to exercise. However, there are only a few studies on such interventions in the field of low back pain (LBP). Qualitative studies of patients' experiences of receiving text messages as reminders of home exercises after manual treatment for recurrent LBP have to the best of our knowledge never been published. OBJECTIVES: The aim of this study was to explore older persons' common experiences of receiving reminders of home exercises through mobile phone text messaging after specialized manual therapy for recurrent LBP. METHODS: A total of 7 men and 8 women (67-86 years), who had sought specialized manual therapy (Naprapathic manual therapy) for recurrent LBP were included in the study. Individual one-way text messages as reminders of home exercises (to be performed on a daily basis) were sent to each patient every third day for 3 weeks, then once a week for another 2 weeks. Semistructured interviews with 2 broad, open-ended questions were held and data were analyzed with systematic text condensation, based on Giorgi's principles of psychological phenomenological analysis. RESULTS: The participants appreciated the messages, which were perceived as timely and usable, and also stimulated memorizing. The messages made the participants reflect on the aim of the exercise, value of being reminded, and on their improvement in pain. During the interviews, the participants created their own routines for continued adherence to the exercises. CONCLUSIONS: It seems plausible that mobile phone text messaging may serve as a useful tool for patient empowerment with regard to recurrent LBP in older persons. Further studies are needed to explore whether future compliance with the exercises will be as large if the participants are not being interviewed. PMID- 28360027 TI - Relative effectiveness of insulin pump treatment over multiple daily injections and structured education during flexible intensive insulin treatment for type 1 diabetes: cluster randomised trial (REPOSE). AB - Objective To compare the effectiveness of insulin pumps with multiple daily injections for adults with type 1 diabetes, with both groups receiving equivalent training in flexible insulin treatment.Design Pragmatic, multicentre, open label, parallel group, cluster randomised controlled trial (Relative Effectiveness of Pumps Over MDI and Structured Education (REPOSE) trial).Setting Eight secondary care centres in England and Scotland.Participants Adults with type 1 diabetes who were willing to undertake intensive insulin treatment, with no preference for pumps or multiple daily injections. Participants were allocated a place on established group training courses that taught flexible intensive insulin treatment ("dose adjustment for normal eating," DAFNE). The course groups (the clusters) were then randomly allocated in pairs to either pump or multiple daily injections.Interventions Participants attended training in flexible insulin treatment (using insulin analogues) structured around the use of pump or injections, followed for two years.Main outcome measures The primary outcomes were a change in glycated haemoglobin (HbA1c) values (%) at two years in participants with baseline HbA1c value of >=7.5% (58 mmol/mol), and the proportion of participants achieving an HbA1c value of <7.5%. Secondary outcomes included body weight, insulin dose, and episodes of moderate and severe hypoglycaemia. Ancillary outcomes included quality of life and treatment satisfaction.Results 317 participants (46 courses) were randomised (156 pump and 161 injections). 267 attended courses and 260 were included in the intention to treat analysis, of which 235 (119 pump and 116 injection) had baseline HbA1c values of >=7.5%. Glycaemic control and rates of severe hypoglycaemia improved in both groups. The mean change in HbA1c at two years was -0.85% with pump treatment and -0.42% with multiple daily injections. Adjusting for course, centre, age, sex, and accounting for missing values, the difference was -0.24% (-2.7 mmol/mol) in favour of pump users (95% confidence interval -0.53 to 0.05, P=0.10). Most psychosocial measures showed no difference, but pump users showed greater improvement in treatment satisfaction and some quality of life domains (dietary freedom and daily hassle) at 12 and 24 months.Conclusions Both groups showed clinically relevant and long lasting decreases in HbA1c, rates of severe hypoglycaemia, and improved psychological measures, although few participants achieved glucose levels currently recommended by national and international guidelines. Adding pump treatment to structured training in flexible intensive insulin treatment did not substantially enhance educational benefits on glycaemic control, hypoglycaemia, or psychosocial outcomes in adults with type 1 diabetes. These results do not support a policy of providing insulin pumps to adults with poor glycaemic control until the effects of training on participants' level of engagement in intensive self management have been determined.Trial registration Current Controlled Trials ISRCTN61215213. PMID- 28360029 TI - Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon. AB - Ward JB, Lajczak NK, Kelly OB, O'Dwyer AM, Giddam AK, Ni Gabhann J, Franco P, Tambuwala MM, Jefferies CA, Keely S, Roda A, Keely SJ. Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon. Am J Physiol Gastrointest Liver Physiol 312: G550-G558, 2017. First published March 30, 2017; doi:10.1152/ajpgi.00256.2016.-Inflammatory bowel diseases (IBD) comprise a group of common and debilitating chronic intestinal disorders for which currently available therapies are often unsatisfactory. The naturally occurring secondary bile acid, ursodeoxycholic acid (UDCA), has well-established anti-inflammatory and cytoprotective actions and may therefore be effective in treating IBD. We aimed to investigate regulation of colonic inflammatory responses by UDCA and to determine the potential impact of bacterial metabolism on its therapeutic actions. The anti-inflammatory efficacy of UDCA, a nonmetabolizable analog, 6alpha-methyl-UDCA (6-MUDCA), and its primary colonic metabolite lithocholic acid (LCA) was assessed in the murine dextran sodium sulfate (DSS) model of mucosal injury. The effects of bile acids on cytokine (TNF-alpha, IL-6, Il-1beta, and IFN gamma) release from cultured colonic epithelial cells and mouse colonic tissue in vivo were investigated. Luminal bile acids were measured by gas chromatography mass spectrometry. UDCA attenuated release of proinflammatory cytokines from colonic epithelial cells in vitro and was protective against the development of colonic inflammation in vivo. In contrast, although 6-MUDCA mimicked the effects of UDCA on epithelial cytokine release in vitro, it was ineffective in preventing inflammation in the DSS model. In UDCA-treated mice, LCA became the most common colonic bile acid. Finally, LCA treatment more potently inhibited epithelial cytokine release and protected against DSS-induced mucosal inflammation than did UDCA. These studies identify a new role for the primary metabolite of UDCA, LCA, in preventing colonic inflammation and suggest that microbial metabolism of UDCA is necessary for the full expression of its protective actions.NEW & NOTEWORTHY On the basis of its cytoprotective and anti-inflammatory actions, the secondary bile acid ursodeoxycholic acid (UDCA) has well-established uses in both traditional and Western medicine. We identify a new role for the primary metabolite of UDCA, lithocholic acid, as a potent inhibitor of intestinal inflammatory responses, and we present data to suggest that microbial metabolism of UDCA is necessary for the full expression of its protective effects against colonic inflammation. PMID- 28360030 TI - Old and new models for studying host-microbe interactions in health and disease: C. difficile as an example. AB - There has been an explosion of interest in studying the indigenous microbiota, which plays an important role in human health and disease. Traditionally, the study of microbes in relationship to human health involved consideration of individual microbial species that caused classical infectious diseases. With the interest in the human microbiome, an appreciation of the influence that complex communities of microbes can have on their environment has developed. When considering either individual pathogenic microbes or a symbiotic microbial community, researchers have employed a variety of model systems with which they can study the host-microbe interaction. With the use of studies of infections with the toxin-producing bacterium Clostridium difficile as a model for both a pathogen and beneficial bacterial communities as an example, this review will summarize and compare various model systems that can be used to gain insight into the host-microbe interaction. PMID- 28360028 TI - Detection of human elastase isoforms by the ScheBo Pancreatic Elastase 1 Test. AB - Determination of fecal pancreatic elastase content by ELISA is a reliable, noninvasive clinical test for assessing exocrine pancreatic function. Despite the widespread use of commercial tests, their exact molecular targets remain poorly characterized. This study was undertaken to clarify which human pancreatic elastase isoforms are detected by the ScheBo Pancreatic Elastase 1 Stool Test and whether naturally occurring genetic variants influence the performance of this test. Using recombinantly expressed and purified human pancreatic proteinases, we found that the test specifically measured chymotrypsin-like elastases (CELA) 3A and 3B (CELA3A and CELA3B), while CELA2A was not detected. Inactive proelastases, active elastases, and autolyzed forms were detected with identical efficiency. CELA3B elicited approximately four times higher ELISA signal than CELA3A, and we identified Glu154 in CELA3B as the critical determinant of detection. Common genetic variants of CELA3A and CELA3B had no effect on test performance, with the exception of the CELA3B variant W79R, which increased detection by 1.4-fold. Finally, none of the human trypsin and chymotrypsin isoforms were detected. We conclude that the ScheBo Pancreatic Elastase 1 Stool Test is specific for human CELA3A and CELA3B, with most of the ELISA signal attributable to CELA3B.NEW & NOTEWORTHY The ScheBo Pancreatic Elastase 1 Stool Test is widely used to assess pancreatic exocrine function, yet its molecular targets have been poorly defined. We demonstrate that, among the human pancreatic proteinases, the test measures the elastase isoform CELA3B and, to a lesser extent, CELA3A. Genetic variants of the human CELA3 isoforms have no significant effect on test performance. PMID- 28360033 TI - GP numbers drop despite government pledge to boost workforce. PMID- 28360034 TI - Ages and Stages Questionnaire at 3 Years for Predicting IQ at 5-6 Years. AB - OBJECTIVES: To assess the predictive value of the 36-month Ages & Stages Questionnaire (ASQ) score for IQ score at age 5 to 6 years in the general population and to identify factors associated with IQ <85 once the ASQ score is taken into account. METHODS: Data were collected from 939 children enrolled in a population-based prospective cohort study. Developmental outcomes at 36 months were assessed via the ASQ and at 5 to 6 years via the Wechsler Preschool and Primary Scale of Intelligence. The ASQ threshold was identified via the receiver operating characteristic curve. Additional predictive factors to obtain an IQ <85 were investigated, and their interaction with ASQ score was studied. RESULTS: Sixty-nine children (7.3%) had an IQ <85. A 36-month ASQ score threshold of 270 was optimal to identify children with an IQ <85 at 5 to 6 years, with a 0.77 +/- 0.11 sensitivity and 0.68 +/- 0.03 specificity. Maternal educational level and occupational activity at the time of ASQ completion were associated with the risk of an IQ <85 at a given ASQ level. In the multivariate model, no interaction between the studied factors and ASQ score reached significance. CONCLUSIONS: In the general pediatric population, 36-month ASQ parental reports could be used to identify children at later risk of cognitive delay. Low maternal education level should also be considered as a major risk factor for lower IQ in preschool children regardless of ASQ score. PMID- 28360031 TI - Intermediate filament proteins of digestive organs: physiology and pathophysiology. AB - Intermediate filament proteins (IFs), such as cytoplasmic keratins in epithelial cells and vimentin in mesenchymal cells and the nuclear lamins, make up one of the three major cytoskeletal protein families. Whether in digestive organs or other tissues, IFs share several unique features including stress-inducible overexpression, abundance, cell-selective and differentiation state expression, and association with >80 human diseases when mutated. Whereas most IF mutations cause disease, mutations in simple epithelial keratins 8, 18, or 19 or in lamin A/C predispose to liver disease with or without other tissue manifestations. Keratins serve major functions including protection from apoptosis, providing cellular and subcellular mechanical integrity, protein targeting to subcellular compartments, and scaffolding and regulation of cell-signaling processes. Keratins are essential for Mallory-Denk body aggregate formation that occurs in association with several liver diseases, whereas an alternate type of keratin and lamin aggregation occurs upon liver involvement in porphyria. IF-associated diseases have no known directed therapy, but high-throughput drug screening to identify potential therapies is an appealing ongoing approach. Despite the extensive current knowledge base, much remains to be discovered regarding IF physiology and pathophysiology in digestive and nondigestive organs. PMID- 28360035 TI - Prognostic value of early response assessment using (18F)FDG-PET in patients with advanced non-small cell lung cancer treated with tyrosine-kinase inhibitors. AB - The purpose of this meta-analysis was to determine the prognostic value of early response assessment using (18F)fluorodeoxyglucose (FDG)-positron emission thermography (PET) in patients with advanced non-small cell lung cancer (NSCLC) treated with tyrosine-kinase inhibitors (TKIs). MEDLINE, PubMed, Cochrane, EMBASE, and Google Scholar databases were searched until August 1, 2016 using the keywords non-small cell lung carcinoma, positron-emission tomography, fluorodeoxyglucose, prognosis, disease progression, survival, erlotinib, gefitinib, and afatinib. Inclusion criteria were studies of patients with stage III or IV NSCLC treated with a TKI and had response assessed by FDG-PET. Outcome measures were overall survival (OS) and progression-free survival (PFS). Of the 167 articles identified, 10 studies including 302 patients were included in the analysis. In 8 studies, patients were treated with erlotinib, and in 2 they were treated with gefitinib. The overall analysis revealed that early metabolic response was statistically associated with improved OS (HR=0.54; 95% CI 0.46 to 0.63; p<0.001), and with longer PFS (HR=0.23; 95% CI 0.17 to 0.33; p<0.001). Early response of patients with NSCLC treated with TKIs identified on FDG-PET is associated with improved OS and PFS. PMID- 28360032 TI - Multimodality Strategy for Cardiovascular Risk Assessment: Performance in 2 Population-Based Cohorts. AB - BACKGROUND: Current strategies for cardiovascular disease (CVD) risk assessment among adults without known CVD are limited by suboptimal performance and a narrow focus on only atherosclerotic CVD (ASCVD). We hypothesized that a strategy combining promising biomarkers across multiple different testing modalities would improve global and atherosclerotic CVD risk assessment among individuals without known CVD. METHODS: We included participants from MESA (Multi-Ethnic Study of Atherosclerosis) (n=6621) and the Dallas Heart Study (n=2202) who were free from CVD and underwent measurement of left ventricular hypertrophy by ECG, coronary artery calcium, N-terminal pro B-type natriuretic peptide, high-sensitivity cardiac troponin T, and high-sensitivity C-reactive protein. Associations of test results with the global composite CVD outcome (CVD death, myocardial infarction, stroke, coronary or peripheral revascularization, incident heart failure, or atrial fibrillation) and ASCVD (fatal or nonfatal myocardial infarction or stroke) were assessed over >10 years of follow-up. Multivariable analyses for the primary global CVD end point adjusted for traditional risk factors plus statin use and creatinine (base model). RESULTS: Each test result was independently associated with global composite CVD events in MESA after adjustment for the components of the base model and the other test results (P<0.05 for each). When the 5 tests were added to the base model, the c-statistic improved from 0.74 to 0.79 (P=0.001), significant integrated discrimination improvement (0.07, 95% confidence interval [CI] 0.06-0.08, P<0.001) and category free net reclassification improvement (0.47; 95% CI, 0.38-0.56; P=0.003) were observed, and the model was well calibrated (chi2=12.2, P=0.20). Using a simple integer score counting the number of abnormal tests, compared with those with a score of 0, global CVD risk was increased among participants with a score of 1 (adjusted hazard ratio, 1.9; 95% CI, 1.4-2.6), 2 (hazard ratio, 3.2; 95% CI, 2.3-4.4), 3 (hazard ratio, 4.7; 95% CI, 3.4-6.5), and >=4 (hazard ratio, 7.5; 95% CI, 5.2 10.6). Findings replicated in the Dallas Health Study were similar for the ASCVD outcome. CONCLUSIONS: Among adults without known CVD, a novel multimodality testing strategy using left ventricular hypertrophy by ECG, coronary artery calcium, N-terminal pro B-type natriuretic peptide, high-sensitivity cardiac troponin T, and high-sensitivity C-reactive protein significantly improved global CVD and ASCVD risk assessment. PMID- 28360036 TI - Disseminated MRSA infection with purulent pericarditis. AB - The risk of developing pericarditis secondary to Methicillin-Resistant Staphylococcus aureus (MRSA) infection in the absence of preceding surgical procedure is extremely low. We present a case report of a 36-year-old woman who developed disseminated MRSA infection leading to purulent pericarditis. PMID- 28360037 TI - Mitochondrial DNA Integrity Is Maintained by APE1 in Carcinogen-Induced Colorectal Cancer. AB - Changes in mitochondrial DNA (mtDNA) integrity have been reported in many cancers; however, the contribution of mtDNA integrity to tumorigenesis is not well understood. We used a transgenic mouse model that is haploinsufficient for the apurinic/apyrimidinic endonuclease 1 (Apex1+/-) gene, which encodes the base excision repair (BER) enzyme APE1, to determine its role in protecting mtDNA from the effects of azoxymethane (AOM), a carcinogen used to induce colorectal cancer. Repair kinetics of AOM-induced mtDNA damage was evaluated using qPCR after a single AOM dose and a significant induction in mtDNA lesions in colonic crypts from both wild-type (WT) and Apex1+/-animals were observed. However, Apex1+/- mice had slower repair kinetics in addition to decreased mtDNA abundance. Tumors were also induced using multiple AOM doses, and both WT and Apex1+/-animals exhibited significant loss in mtDNA abundance. Surprisingly, no major differences in mtDNA lesions were observed in tumors from WT and Apex1+/- animals, whereas a significant increase in nuclear DNA lesions was detected in tumors from Apex1+/- mice. Finally, tumors from Apex1+/- mice displayed an increased proliferative index and histologic abnormalities. Taken together, these results demonstrate that APE1 is important for preventing changes in mtDNA integrity during AOM induced colorectal cancer.Implications: AOM, a colorectal cancer carcinogen, generates damage to the mitochondrial genome, and the BER enzyme APE1 is required to maintain its integrity. Mol Cancer Res; 15(7); 831-41. (c)2017 AACR. PMID- 28360040 TI - Vitamin B12 deficiency from the perspective of a practicing hematologist. AB - B12 deficiency is the leading cause of megaloblastic anemia, and although more common in the elderly, can occur at any age. Clinical disease caused by B12 deficiency usually connotes severe deficiency, resulting from a failure of the gastric or ileal phase of physiological B12 absorption, best exemplified by the autoimmune disease pernicious anemia. There are many other causes of B12 deficiency, which range from severe to mild. Mild deficiency usually results from failure to render food B12 bioavailable or from dietary inadequacy. Although rarely resulting in megaloblastic anemia, mild deficiency may be associated with neurocognitive and other consequences. B12 deficiency is best diagnosed using a combination of tests because none alone is completely reliable. The features of B12 deficiency are variable and may be atypical. Timely diagnosis is important, and treatment is gratifying. Failure to diagnose B12 deficiency can have dire consequences, usually neurological. This review is written from the perspective of a practicing hematologist. PMID- 28360039 TI - How I treat autoimmune hemolytic anemia. AB - Autoimmune hemolytic anemia (AIHA) is an uncommon entity that presents diagnostic, prognostic, and therapeutic dilemmas despite being a well-recognized entity for over 150 years. This is because of significant differences in the rates of hemolysis and associated diseases and because there is considerable clinical heterogeneity. In addition, there is a lack of clinical trials required to refine and update standardized and evidence-based therapeutic approaches. To aid the clinician in AIHA management, we present four vignettes that represent and highlight distinct clinical presentations with separate diagnostic and therapeutic pathways that we use in our clinical practice setting. We also review the parameters present in diagnostic testing that allow for prognostic insight and present algorithms for both diagnosis and treatment of the AIHA patient in diverse situations. This is done in the hope that this review may offer guidance in regard to personalized therapy recommendations. A section is included for the diagnosis of suspected AIHA with negative test results, a relatively infrequent but challenging situation, in order to assist in the overall evaluation spectrum for these patients. PMID- 28360041 TI - Securing the Future. PMID- 28360042 TI - Not 'just' a GP: a call for action. PMID- 28360038 TI - Insulin Receptor and GPCR Crosstalk Stimulates YAP via PI3K and PKD in Pancreatic Cancer Cells. AB - We examined the impact of crosstalk between the insulin receptor and G protein coupled receptor (GPCR) signaling pathways on the regulation of Yes-associated protein (YAP) localization, phosphorylation, and transcriptional activity in the context of human pancreatic ductal adenocarcinoma (PDAC). Stimulation of PANC-1 or MiaPaCa-2 cells with insulin and neurotensin, a potent mitogenic combination of agonists for these cells, promoted striking YAP nuclear localization and decreased YAP phosphorylation at Ser127 and Ser397 Challenging PDAC cells with either insulin or neurotensin alone modestly induced the expression of YAP/TEAD regulated genes, including connective tissue growth factor (CTGF), cysteine-rich angiogenic inducer 61 (CYR61), and CXCL5, whereas the combination of neurotensin and insulin induced a marked increase in the level of expression of these genes. In addition, siRNA-mediated knockdown of YAP/TAZ prevented the increase in the expression of these genes. A small-molecule inhibitor (A66), selective for the p110alpha subunit of PI3K, abrogated the increase in phosphatidylinositol 3,4,5 trisphosphate production and the expression of CTGF, CYR61, and CXCL5 induced by neurotensin and insulin. Furthermore, treatment of PDAC cells with protein kinase D (PKD) family inhibitors (CRT0066101 or kb NB 142-70) or with siRNAs targeting the PKD family prevented the increase of CTGF, CYR61, and CXCL5 mRNA levels in response to insulin and neurotensin stimulation. Thus, PI3K and PKD mediate YAP activation in response to insulin and neurotensin in pancreatic cancer cells.Implications: Inhibitors of PI3K or PKD disrupt crosstalk between insulin receptor and GPCR signaling systems by blocking YAP/TEAD-regulated gene expression in pancreatic cancer cells. Mol Cancer Res; 15(7); 929-41. (c)2017 AACR. PMID- 28360043 TI - General practice: the heart of the NHS. PMID- 28360044 TI - Can innovation help us deliver an NHS for the 21st century? PMID- 28360045 TI - Opioid analgesic dependence: where do we go from here? PMID- 28360046 TI - 'MUS' or 'DEN'? PMID- 28360047 TI - MUS: continuing challenges for primary care. PMID- 28360048 TI - The recipe for general practice. PMID- 28360049 TI - Clinical and cultural conflicts. PMID- 28360050 TI - Discharge summary information: more than DVT warnings needed. PMID- 28360051 TI - The role of general practice in surgical trials. PMID- 28360052 TI - Do primary care chaplains need training in mental health issues? PMID- 28360053 TI - Incorporating cancer risk information into general practice: a qualitative study using focus groups with health professionals. PMID- 28360054 TI - The wrong paradigm may be driving drug glucose control in the face of the evidence. PMID- 28360055 TI - Medically unexplained symptoms. PMID- 28360056 TI - Giving patients choice of appointment length. PMID- 28360057 TI - Bad medicine: red drugs. PMID- 28360058 TI - Viewpoint: Redundant subjectivity? PMID- 28360059 TI - The chronotherapy of hypertension: or the benefit of taking blood pressure tablets at bedtime. PMID- 28360060 TI - Nature works: why don't we? How living systems can inform the design of effective primary care. PMID- 28360062 TI - Bad Medicine: Medical student numbers. PMID- 28360063 TI - Yonder: Physician assistants, timewasting, nursing homes, and social media. PMID- 28360061 TI - Every home should have one: the critical role of the research librarian. PMID- 28360064 TI - Can compassion help cure health-related disorders? PMID- 28360065 TI - Books: A Layman's Guide to Psychiatry and Psychoanalysis: Not a Wasted Word. PMID- 28360066 TI - Books: His Bloody Project. Documents Relating to the Case of Roderick Macrae: Mad or Bad? PMID- 28360067 TI - Fakery and science. PMID- 28360068 TI - Are we stripping the care out of care plans? PMID- 28360069 TI - Overdiagnosis of COPD: precise definitions and proposals for improvement. PMID- 28360070 TI - Recognition, diagnosis, and early management of sepsis: NICE guideline. PMID- 28360071 TI - Primary care management of overactive bladder symptoms: evaluation and treatment. PMID- 28360072 TI - Attitudes of newly qualified doctors towards a career in general practice: a qualitative focus group study. AB - BACKGROUND: A key element of the NHS is universal access to a GP. Recently, UK general practice has been described as being in crisis, with training places unfilled and multiple practices reporting vacancies or facing closure. The recruitment of GPs continues to be a key focus for both the Royal College of General Practitioners (RCGP) and the government. AIM: To understand the attitudes of newly qualified doctors towards a career in general practice, to appreciate potential reasons for the crisis in GP recruitment, and to recommend ways to improve recruitment. DESIGN AND SETTING: A qualitative study comprising five focus groups with 74 Foundation Year 1 (FY1) doctors from one Yorkshire deanery. METHOD: Audio recordings were transcribed verbatim and thematic analysis undertaken. RESULTS: Foundation Year 1 doctors' thoughts towards a career in general practice were summarised in four themes: quality of life, job satisfaction, uncertainty surrounding the future of general practice, and the lack of respect for GPs among both doctors and the public. Participants felt that general practice could provide a good work-life balance, fair pay, and job stability. Job satisfaction, with the ability to provide care from the cradle to the grave, and to work within a community, was viewed positively. Uncertainties around future training, skill levels, pay, and workload, together with a perceived stigma experienced in medical schools and hospitals, were viewed as a deterrent to a career in general practice. CONCLUSION: This study has gathered the opinions of doctors at a critical point in their careers, before they choose a future specialty. Findings highlight areas of concern and potential deterrents to a career in general practice, together with recommendations to address these issues. PMID- 28360073 TI - Patient participation in general practice based undergraduate teaching: a focus group study of patient perspectives. AB - BACKGROUND: Patients make a crucial contribution to undergraduate medical education. Although a national resource is available for patients participating in research, none is as yet available for education. AIM: This study aimed to explore what information patients would like about participation in general practice based undergraduate medical education, and how they would like to obtain this information. DESIGN AND SETTING: Two focus groups were conducted in London based practices involved in both undergraduate and postgraduate teaching. METHOD: Patients both with and without teaching experience were recruited using leaflets, posters, and patient participation groups. An open-ended topic guide explored three areas: perceived barriers that participants anticipated or had experienced; patient roles in medical education; and what help would support participation. Focus groups were audiorecorded, transcribed, and analysed thematically. RESULTS: Patients suggested ways of professionalising the teaching process. These were: making information available to patients about confidentiality, iterative consent, and normalising teaching in the practice. Patients highlighted the importance of relationships, making information available about their GPs' involvement in teaching, and initiating student-patient interactions. Participants emphasised educational principles to maximise exchange of information, including active participation of students, patient identification of student learner needs, and exchange of feedback. CONCLUSION: This study will inform development of patient information resources to support their participation in teaching and access to information both before and during general practice based teaching encounters. PMID- 28360076 TI - Reuben Frederick Payne. PMID- 28360075 TI - Alexander Ross Kerr Mitchell. PMID- 28360074 TI - Predicting the onset of hazardous alcohol drinking in primary care: development and validation of a simple risk algorithm. AB - BACKGROUND: Little is known about the risk of progressing to hazardous alcohol use in abstinent or low-risk drinkers. AIM: To develop and validate a simple brief risk algorithm for the onset of hazardous alcohol drinking (HAD) over 12 months for use in primary care. DESIGN AND SETTING: Prospective cohort study in 32 health centres from six Spanish provinces, with evaluations at baseline, 6 months, and 12 months. METHOD: Forty-one risk factors were measured and multilevel logistic regression and inverse probability weighting were used to build the risk algorithm. The outcome was new occurrence of HAD during the study, as measured by the AUDIT. RESULTS: From the lists of 174 GPs, 3954 adult abstinent or low-risk drinkers were recruited. The 'predictAL-10' risk algorithm included just nine variables (10 questions): province, sex, age, cigarette consumption, perception of financial strain, having ever received treatment for an alcohol problem, childhood sexual abuse, AUDIT-C, and interaction AUDIT-C*Age. The c-index was 0.886 (95% CI = 0.854 to 0.918). The optimal cutoff had a sensitivity of 0.83 and specificity of 0.80. Excluding childhood sexual abuse from the model (the 'predictAL-9'), the c-index was 0.880 (95% CI = 0.847 to 0.913), sensitivity 0.79, and specificity 0.81. There was no statistically significant difference between the c-indexes of predictAL-10 and predictAL-9. CONCLUSION: The predictAL-10/9 is a simple and internally valid risk algorithm to predict the onset of hazardous alcohol drinking over 12 months in primary care attendees; it is a brief tool that is potentially useful for primary prevention of hazardous alcohol drinking. PMID- 28360077 TI - Assessment and treatment of persistent pain in nursing home residents should be implemented systematically to prevent suffering. PMID- 28360078 TI - Health, psychosocial and workplace characteristics may identify nurses and midwives at risk of high absenteeism. PMID- 28360079 TI - BMA urges government to grant permanent residence to European doctors working in UK. PMID- 28360080 TI - Michael J Scott. PMID- 28360081 TI - Resolution of glucose intolerance in long-term high-fat, high-sucrose-fed mice. AB - The high-fat, high-sucrose diet (HFSD)-fed C57Bl/6 mouse is a widely used model of prediabetes. However, studies typically implement a relatively short dietary intervention lasting between 4 and 16 weeks; as a result, little is known about how a long-term HFSD influences the metabolic profile of these mice. Therefore, the aim of this investigation was to examine the effects of consuming a HFSD for 42 weeks on the development of hyperinsulinaemia and glucose intolerance in male C57Bl/6 mice. Two cohorts of HFSD mice were studied at independent institutes and they underwent an oral glucose tolerance test (OGTT) with measures of plasma insulin and free fatty acids (FFA). Age-matched chow-fed control mice were also studied. The HFSD-fed mice were hyperinsulinaemic and grossly obese, being over 25 g heavier than chow-fed mice, which was due to a marked expansion of subcutaneous adipose tissue. This was associated with a 3-fold increase in liver lipid content. Glucose tolerance, however, was either the same or better than control mice due to the preservation of glucose disposal as revealed by a dynamic stable isotope-labelled OGTT. In addition, plasma FFAs were suppressed to lower levels in HFSD mice during the OGTT. In conclusion, we have made the paradoxical observation that long-term HFSD feeding results in the resolution of glucose intolerance in the C57Bl/6 mouse. Mechanistically, we propose that the gross expansion of subcutaneous adipose tissue increases the glucose disposal capacity of the HFSD-fed mouse, which overcomes the prevailing insulin resistance to improve glucose tolerance. PMID- 28360083 TI - Posterior condylar offset is an independent predictor of functional outcome after revision total knee arthroplasty. AB - OBJECTIVES: Preservation of posterior condylar offset (PCO) has been shown to correlate with improved functional results after primary total knee arthroplasty (TKA). Whether this is also the case for revision TKA, remains unknown. The aim of this study was to assess the independent effect of PCO on early functional outcome after revision TKA. METHODS: A total of 107 consecutive aseptic revision TKAs were performed by a single surgeon during an eight-year period. The mean age was 69.4 years (39 to 85) and there were 59 female patients and 48 male patients. The Oxford Knee Score (OKS) and Short-form (SF)-12 score were assessed pre operatively and one year post-operatively. Patient satisfaction was also assessed at one year. Joint line and PCO were assessed radiographically at one year. RESULTS: There was a significant improvement in the OKS (10.6 points, 95% confidence interval (CI) 8.8 to 12.3) and the SF-12 physical component score (5.9, 95% CI 4.1 to 7.8). PCO directly correlated with change in OKS (p < 0.001). Linear regression analysis confirmed the independent effect of PCO on the OKS (p < 0.001) and the SF-12 physical score (p = 0.02). The overall rate of satisfaction was 85% and on logistic regression analysis improvement in the OKS (p = 0.002) was a significant predictor of patient satisfaction, which is related to PCO; although this was not independently associated with satisfaction. CONCLUSION: Preservation of PCO should be a major consideration when undertaking revision TKA. The option of increasing PCO to balance the flexion gap while maintaining the joint line should be assessed intra-operatively.Cite this article: N. D. Clement, D. J. MacDonald, D. F. Hamilton, R. Burnett. Posterior condylar offset is an independent predictor of functional outcome after revision total knee arthroplasty. Bone Joint Res 2017;6:172-178. DOI: 10.1302/2046 3758.63.BJR-2015-0021.R1. PMID- 28360082 TI - Adipose tissue supports normalization of macrophage and liver lipid handling in obesity reversal. AB - Adipose tissue inflammation and dysfunction are considered central in the pathogenesis of obesity-related dysmetabolism, but their role in the rapid metabolic recovery upon obesity reversal is less well defined. We hypothesized that changes in adipose tissue endocrine and paracrine mechanisms may support the rapid improvement of obesity-induced impairment in cellular lipid handling. C57Bl 6J mice were fed ad libitum either normal chow (NC) or high-fat diet (HFF) for 10 weeks. A dietary obesity reversal group was fed HFF for 8 weeks and then switched to NC for 2 weeks (HFF->NC). Whole-body glucose homeostasis rapidly nearly normalized in the HFF->NC mice (fasting glucose and insulin fully normalized, glucose and insulin tolerance tests reversed 82% to the NC group levels). During 2 weeks of the dietary reversal, the liver was significantly cleared from ectopic fat, and functionally, glucose production from pyruvate, alanine or fructose was normalized. In contrast, adipose tissue inflammation (macrophage infiltration and polarization) largely remained as in HFF, though obesity-induced adipose tissue macrophage lipid accumulation decreased by ~50%, and adipose tissue MAP kinase hyperactivation was reversed. Ex vivo, mild changes in adipose tissue adipocytokine secretion profile were noted. These corresponded to partial or full reversal of the excess cellular lipid droplet accumulation induced by HFF adipose tissue conditioned media in hepatoma or macrophage cells, respectively. We propose that early after initiating reversal of nutritional obesity, rapid metabolic normalization largely precedes resolution of adipose tissue inflammation. Nevertheless, we demonstrate a hitherto unrecognized contribution of adipose tissue to the rapid improvement in lipid handling by the liver and by macrophages. PMID- 28360084 TI - The revitalisation of flexor tendon allografts with bone marrow stromal cells and mechanical stimulation: An ex vivo model revitalising flexor tendon allografts. AB - OBJECTIVES: The present study describes a novel technique for revitalising allogenic intrasynovial tendons by combining cell-based therapy and mechanical stimulation in an ex vivo canine model. METHODS: Specifically, canine flexor digitorum profundus tendons were used for this study and were divided into the following groups: (1) untreated, unprocessed normal tendon; (2) decellularised tendon; (3) bone marrow stromal cell (BMSC)-seeded tendon; and (4) BMSC-seeded and cyclically stretched tendon. Lateral slits were introduced on the tendon to facilitate cell seeding. Tendons from all four study groups were distracted by a servohydraulic testing machine. Tensile force and displacement data were continuously recorded at a sample rate of 20 Hz until 200 Newton of force was reached. Before testing, the cross-sectional dimensions of each tendon were measured with a digital caliper. Young's modulus was calculated from the slope of the linear region of the stress-strain curve. The BMSCs were labeled for histological and cell viability evaluation on the decellularized tendon scaffold under a confocal microscope. Gene expression levels of selected extracellular matrix tendon growth factor genes were measured. Results were reported as mean +/ SD and data was analyzed with one-way ANOVAs followed by Tukey's post hoc multiple-comparison test. RESULTS: We observed no significant difference in cross sectional area or in Young's modulus among the four study groups. In addition, histological sections showed that the BMSCs were aligned well and viable on the tendon slices after two-week culture in groups three and four. Expression levels of several extracellular matrix tendon growth factors, including collagen type I, collagen type III, and matrix metalloproteinase were significantly higher in group four than in group three (p < 0.05). CONCLUSION: Lateral slits introduced into de-cellularised tendon is a promising method of delivery of BMSCs without compromising cell viability and tendon mechanical properties. In addition, mechanical stimulation of a cell-seeded tendon can promote cell proliferation and enhance expression of collagen types I and III in vitro.Cite this article: J. H. Wu, A. R. Thoreson, A. Gingery, K. N. An, S. L. Moran, P. C. Amadio, C. Zhao. The revitalisation of flexor tendon allografts with bone marrow stromal cells and mechanical stimulation: An ex vivo model revitalising flexor tendon allografts. Bone Joint Res 2017;6:179-185. DOI: 10.1302/2046-3758.63.BJR-2016-0207.R1. PMID- 28360085 TI - Silencing of translation initiation factor eIF3b promotes apoptosis in osteosarcoma cells. AB - OBJECTIVES: Eukaryotic translation initiation factor 3 (eIF3) is a multi-subunit complex that plays a critical role in translation initiation. Expression levels of eIF3 subunits are elevated or decreased in various cancers, suggesting a role for eIF3 in tumorigenesis. Recent studies have shown that the expression of the eIF3b subunit is elevated in bladder and prostate cancer, and eIF3b silencing inhibited glioblastoma growth and induced cellular apoptosis. In this study, we investigated the role of eIF3b in the survival of osteosarcoma cells. METHODS: To investigate the effect of eIF3b on cell viability and apoptosis in osteosarcoma cells, we first examined the silencing effect of eIF3b in U2OS cells. Cell viability and apoptosis were examined by the Cell Counting Kit-8 (CCK-8) assay and Western blot, respectively. We also performed gene profiling to identify genes affected by eIF3b silencing. Finally, the effect of eIF3b on cell viability and apoptosis was confirmed in multiple osteosarcoma cell lines. RESULTS: eIF3b silencing decreased cell viability and induced apoptosis in U2OS cells, and by using gene profiling we discovered that eIF3b silencing also resulted in the upregulation of tumour necrosis factor receptor superfamily member 21 (TNFRSF21). We found that TNFRSF21 overexpression induced cell death in U2OS cells, and we confirmed that eIF3b silencing completely suppressed cell growth in multiple osteosarcoma cell lines. However, eIF3b silencing failed to suppress cell growth completely in normal fibroblast cells. CONCLUSION: Our data led us to conclude that eIF3b may be required for osteosarcoma cell proliferation by regulating TNFRSF21 expression.Cite this article: Y. J. Choi, Y. S. Lee, H. W. Lee, D. M. Shim, S. W. Seo. Silencing of translation initiation factor eIF3b promotes apoptosis in osteosarcoma cells. Bone Joint Res 2017;6:186-193. DOI: 10.1302/2046 3758.63.BJR-2016-0151.R2. PMID- 28360086 TI - Potential Impact and Study Considerations of Metabolomics in Cardiovascular Health and Disease: A Scientific Statement From the American Heart Association. AB - Through the measure of thousands of small-molecule metabolites in diverse biological systems, metabolomics now offers the potential for new insights into the factors that contribute to complex human diseases such as cardiovascular disease. Targeted metabolomics methods have already identified new molecular markers and metabolomic signatures of cardiovascular disease risk (including branched-chain amino acids, select unsaturated lipid species, and trimethylamine N-oxide), thus in effect linking diverse exposures such as those from dietary intake and the microbiota with cardiometabolic traits. As technologies for metabolomics continue to evolve, the depth and breadth of small-molecule metabolite profiling in complex systems continue to advance rapidly, along with prospects for ongoing discovery. Current challenges facing the field of metabolomics include scaling throughput and technical capacity for metabolomics approaches, bioinformatic and chemoinformatic tools for handling large-scale metabolomics data, methods for elucidating the biochemical structure and function of novel metabolites, and strategies for determining the true clinical relevance of metabolites observed in association with cardiovascular disease outcomes. Progress made in addressing these challenges will allow metabolomics the potential to substantially affect diagnostics and therapeutics in cardiovascular medicine. PMID- 28360087 TI - Impairment of the Ability of HDL From Patients With Metabolic Syndrome but Without Diabetes Mellitus to Activate eNOS: Correction by S1P Enrichment. AB - OBJECTIVE: High-density lipoprotein (HDL) from nondiabetic patients with metabolic syndrome (MetS) displays abnormalities in their lipidome, such as triglyceride enrichment and sphingosine-1-phosphate depletion. We hypothesized that these abnormalities could impair the ability of HDL to stimulate endothelial nitric oxide synthase (eNOS). APPROACH AND RESULTS: Compared with HDL from control subjects, HDL from normoglycemic patients with MetS was 39% richer in triglycerides (P<0.01) and 15% poorer in sphingosine-1-phosphate (P<0.05; n=23 in each group). eNOS activity, assessed by the conversion of L-[3H]arginine to L [3H]citrulline, was 69% lower in human umbilical vein endothelial cells incubated with HDL from MetS patients than in cells incubated with HDL from controls (P<0.0001). In addition, the activating phosphorylation of eNOS at serine (Ser) 1177 and of Akt (protein kinase B) at Ser473 was 37% (P<0.001) and 39% (P<0.05) lower, respectively, with HDL from MetS patients. Sphingosine-1-phosphate enrichment of HDL from MetS patients restored their ability to stimulate eNOS activity (P<0.05), in relation with a significant increase in eNOS phosphorylation at Ser1177 (P<0.05) and in Akt phosphorylation at Ser473 (P=0.05). By contrast, triglyceride enrichment of HDL from control subjects did not modify eNOS activity (P=0.90) and phosphorylation at Ser1177 (P=0.87). CONCLUSIONS: We provide evidence that the activation of eNOS by HDL is decreased in MetS patients before the appearance of diabetes mellitus and that sphingosine 1-phosphate depletion of HDL is the main factor responsible for this defect. This has important consequences on the impairment of HDL functionality and antiatherogenic properties in these patients. PMID- 28360088 TI - VEGF-A Regulates Cellular Localization of SR-BI as Well as Transendothelial Transport of HDL but Not LDL. AB - OBJECTIVE: Low- and high-density lipoproteins (LDL and HDL) must pass the endothelial layer to exert pro- and antiatherogenic activities, respectively, within the vascular wall. However, the rate-limiting factors that mediate transendothelial transport of lipoproteins are yet little known. Therefore, we performed a high-throughput screen with kinase drug inhibitors to identify modulators of transendothelial LDL and HDL transport. APPROACH AND RESULTS: Microscopy-based high-content screening was performed by incubating human aortic endothelial cells with 141 kinase-inhibiting drugs and fluorescent-labeled LDL or HDL. Inhibitors of vascular endothelial growth factor (VEGF) receptors (VEGFR) significantly decreased the uptake of HDL but not LDL. Silencing of VEGF receptor 2 significantly decreased cellular binding, association, and transendothelial transport of 125I-HDL but not 125I-LDL. RNA interference with VEGF receptor 1 or VEGF receptor 3 had no effect. Binding, uptake, and transport of HDL but not LDL were strongly reduced in the absence of VEGF-A from the cell culture medium and were restored by the addition of VEGF-A. The restoring effect of VEGF-A on endothelial binding, uptake, and transport of HDL was abrogated by pharmacological inhibition of phosphatidyl-inositol 3 kinase/protein kinase B or p38 mitogen-activated protein kinase, as well as silencing of scavenger receptor BI. Moreover, the presence of VEGF-A was found to be a prerequisite for the localization of scavenger receptor BI in the plasma membrane of endothelial cells. CONCLUSIONS: The identification of VEGF as a regulatory factor of transendothelial transport of HDL but not LDL supports the concept that the endothelium is a specific and, hence, druggable barrier for the entry of lipoproteins into the vascular wall. PMID- 28360092 TI - Marie Driver. PMID- 28360090 TI - Testosterone Prevents Cutaneous Ischemia and Necrosis in Males Through Complementary Estrogenic and Androgenic Actions. AB - OBJECTIVE: Chronic nonhealing wounds are a substantial medical concern and are associated with morbidity and mortality; thus, new treatment strategies are required. The first step toward personalized/precision medicine in this field is probably in taking sex differences into account. Impaired wound healing is augmented by ischemia, and we previously demonstrated that 17beta-estradiol exerts a major preventive effect against ischemia-induced skin flap necrosis in female mice. However, the equivalent effects of testosterone in male mice have not yet been reported. We then investigated the role of steroid hormones in male mice using a skin flap ischemia model. APPROACH AND RESULTS: Castrated male mice developed skin necrosis after ischemia, whereas intact or castrated males treated with testosterone were equally protected. Testosterone can (1) activate the estrogen receptor after its aromatization into 17beta-estradiol or (2) be reduced into dihydrotestosterone, a nonaromatizable androgen that activates the androgen receptor. We found that dihydrotestosterone protected castrated wild-type mice by promoting skin revascularization, probably through a direct action on resistance arteries, as evidenced using a complementary model of flow-mediated outward remodeling. 17beta-estradiol treatment of castrated male mice also strongly protected them from ischemic necrosis through the activation of estrogen receptor alpha by increasing skin revascularization and skin survival. Remarkably, 17beta estradiol improved skin survival with a greater efficiency than dihydrotestosterone. CONCLUSIONS: Testosterone provides males with a strong protection against cutaneous necrosis and acts through both its estrogenic and androgenic derivatives, which have complementary effects on skin survival and revascularization. PMID- 28360091 TI - Transcriptional response to hepatitis C virus infection and interferon-alpha treatment in the human liver. AB - Hepatitis C virus (HCV) is widely used to investigate host-virus interactions. Cellular responses to HCV infection have been extensively studied in vitro However, in human liver, interferon (IFN)-stimulated gene expression can mask direct transcriptional responses to infection. To better characterize the direct effects of HCV infection in vivo, we analyze the transcriptomes of HCV-infected patients lacking an activated endogenous IFN system. We show that expression changes observed in these patients predominantly reflect immune cell infiltrates rather than cell-intrinsic pathways. We also investigate the transcriptomes of patients with endogenous IFN activation, which paradoxically cannot eradicate viral infection. We find that most IFN-stimulated genes are induced by both recombinant IFN therapy and the endogenous IFN system, but with lower induction levels in the latter, indicating that the innate immune response in chronic hepatitis C is too weak to clear the virus. We show that coding and non-coding transcripts have different expression dynamics following IFN treatment. Several microRNA primary transcripts, including that of miR-122, are significantly down regulated in response to IFN treatment, suggesting a new mechanism for IFN induced expression fine-tuning. PMID- 28360094 TI - Identification and Structure-Function Study of Positive Allosteric Modulators of Kainate Receptors. AB - Kainate receptors (KARs) consist of a class of ionotropic glutamate receptors, which exert diverse pre- and postsynaptic functions through complex signaling regulating the activity of neural circuits. Whereas numerous small-molecule positive allosteric modulators of the ligand-binding domain of (S)-2-amino-3-(3 hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMPA) receptors have been reported, no such ligands are available for KARs. In this study, we investigated the ability of three benzothiadiazine-based modulators to potentiate glutamate-evoked currents at recombinantly expressed KARs. 4-cyclopropyl-7-fluoro-3,4-dihydro-2H 1,2,4-benzothiadiazine 1,1-dioxide (BPAM344) potentiated glutamate-evoked currents of GluK2a 21-fold at the highest concentration tested (200 MUM), with an EC50 of 79 MUM. BPAM344 markedly decreased desensitization kinetics (from 5.5 to 775 ms), whereas it only had a minor effect on deactivation kinetics. 4 cyclopropyl-7-hydroxy-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (BPAM521) potentiated the recorded peak current amplitude of GluK2a 12-fold at a concentration of 300 MUM with an EC50 value of 159 MUM, whereas no potentiation of the glutamate-evoked response was observed for 7-chloro-4-(2-fluoroethyl)-3,4 dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (BPAM121) at the highest concentration of modulator tested (300 MUM). BPAM344 (100 MUM) also potentiated the peak current amplitude of KAR subunits GluK3a (59-fold), GluK2a (15-fold), GluK1b (5-fold), as well as the AMPA receptor subunit GluA1i (5-fold). X-ray structures of the three modulators in the GluK1 ligand-binding domain were determined, locating two modulator-binding sites at the GluK1 dimer interface. In conclusion, this study may enable the design of new positive allosteric modulators selective for KARs, which will be of great interest for further investigation of the function of KARs in vivo and may prove useful for pharmacologically controlling the activity of neuronal networks. PMID- 28360089 TI - ATVB Distinguished Scientist Award: How Costimulatory and Coinhibitory Pathways Shape Atherosclerosis. AB - OBJECTIVE: Immune cells play a critical role in atherosclerosis. Costimulatory and coinhibitory molecules of the tumor necrosis factor receptor and CD28 immunoglobulin superfamilies not only shape T-cell and B-cell responses but also have a major effect on antigen-presenting cells and nonimmune cells. APPROACH AND RESULTS: Pharmacological inhibition or activation of costimulatory and coinhibitory molecules and genetic deletion demonstrated their involvement in atherosclerosis. This review highlights recent advances in understanding how costimulatory and coinhibitory pathways shape the immune response in atherosclerosis. CONCLUSIONS: Insights gained from costimulatory and coinhibitory molecule function in atherosclerosis may inform future therapeutic approaches. PMID- 28360096 TI - The microbiome of professional athletes differs from that of more sedentary subjects in composition and particularly at the functional metabolic level. AB - OBJECTIVE: It is evident that the gut microbiota and factors that influence its composition and activity effect human metabolic, immunological and developmental processes. We previously reported that extreme physical activity with associated dietary adaptations, such as that pursued by professional athletes, is associated with changes in faecal microbial diversity and composition relative to that of individuals with a more sedentary lifestyle. Here we address the impact of these factors on the functionality/metabolic activity of the microbiota which reveals even greater separation between exercise and a more sedentary state. DESIGN: Metabolic phenotyping and functional metagenomic analysis of the gut microbiome of professional international rugby union players (n=40) and controls (n=46) was carried out and results were correlated with lifestyle parameters and clinical measurements (eg, dietary habit and serum creatine kinase, respectively). RESULTS: Athletes had relative increases in pathways (eg, amino acid and antibiotic biosynthesis and carbohydrate metabolism) and faecal metabolites (eg, microbial produced short-chain fatty acids (SCFAs) acetate, propionate and butyrate) associated with enhanced muscle turnover (fitness) and overall health when compared with control groups. CONCLUSIONS: Differences in faecal microbiota between athletes and sedentary controls show even greater separation at the metagenomic and metabolomic than at compositional levels and provide added insight into the diet-exercise-gut microbiota paradigm. PMID- 28360095 TI - HNRNPLL, a newly identified colorectal cancer metastasis suppressor, modulates alternative splicing of CD44 during epithelial-mesenchymal transition. AB - OBJECTIVE: Despite the recent advances in treatment of colon cancer, the prognosis is unfavourable for patients with distant metastases. The aim of this study was to identify targets for prevention and/or therapy of colon cancer metastasis. DESIGN: CMT93 cells, a murine rectal cancer cell line with poor metastasising activity, were transduced with lentiviral shRNA library and transplanted into the rectum of syngeneic C57BL/6 mice. Genomic DNA was collected from metastatic lesions, and the integrated shRNA were retrieved by PCR for sequencing, followed by identification of the candidate genes targeted by the shRNA. RESULTS: The genome-wide shRNA library screen identified Hnrnpll (heterogeneous nuclear ribonucleoprotein L-like) encoding a pre-mRNA splicing factor as a candidate metastasis suppressor gene. Knockdown of Hnrnpll enhanced matrigel invasion activity of colon cancer cells in vitro, as well as their metastatic ability in vivo. An RNA-immunoprecipitation analysis showed Hnrnpll binding to Cd44 pre-mRNAs, and the level of Cd44 variable exon 6 (Cd44v6), a poor prognosis marker of colorectal cancer, was increased by knocking down Hnrnpll. A neutralising Cd44v6 antibody suppressed the matrigel invasion ability induced by Hnrnpll knockdown. HNRNPLL expression was downregulated when colon cancer cells were induced to undergo epithelial-mesenchymal transition (EMT). Immunohistochemistry of clinical samples indicated that colorectal cancer cells with low E-cadherin expression at the invasion front exhibited decreased HNRNPLL expression. CONCLUSIONS: HNRNPLL is a novel metastasis suppressor of colorectal cancer, and modulates alternative splicing of CD44 during EMT. PMID- 28360097 TI - CHK2 overexpression and mislocalisation within mitotic structures enhances chromosomal instability and hepatocellular carcinoma progression. AB - OBJECTIVE: Chromosomal instability (CIN) is the most common form of genomic instability, which promotes hepatocellular carcinoma (HCC) progression by enhancing tumour heterogeneity, drug resistance and immunity escape. CIN per se is an important factor of DNA damage, sustaining structural chromosome abnormalities but the underlying mechanisms are unknown. DESIGN: DNA damage response protein checkpoint kinase 2 (Chk2) expression was evaluated in an animal model of diethylnitrosamine-induced HCC characterised by DNA damage and elevated mitotic errors. Chk2 was also determined in two discrete cohorts of human HCC specimens. To assess the functional role of Chk2, gain on and loss-of-function, mutagenesis, karyotyping and immunofluorescence/live imaging were performed by using HCT116, Huh7 and human hepatocytes immortalised with hTERT gene (HuS). RESULTS: We demonstrate that mitotic errors during HCC tumorigenesis cause lagging chromosomes/DNA damage and activation of Chk2. Overexpression/phosphorylation and mislocalisation within the mitotic spindle of Chk2 contributes to induce lagging chromosomes. Lagging chromosomes and mitotic activity are reversed by knockdown of Chk2. Furthermore, upregulated Chk2 maintains mitotic activity interacting with Aurora B kinase for chromosome condensation and cytokinesis. The forkhead-associated domain of Chk2 is required for Chk2 mislocalisation to mitotic structures. In addition, retinoblastoma protein phosphorylation contributes to defective mitoses. A cohort and independent validation cohort show a strong cytoplasm to nuclear Chk2 translocation in a subset of patients with HCC. CONCLUSIONS: The study reveals a new mechanistic insight in the coinvolvement of Chk2 in HCC progression. These findings propose Chk2 as a putative biomarker to detect CIN in HCC providing a valuable support for clinical/therapeutical management of patients. PMID- 28360098 TI - Fatal outcome due to CO2 emboli during direct cholangioscopy. PMID- 28360099 TI - Humanisation of a claudin-1-specific monoclonal antibody for clinical prevention and cure of HCV infection without escape. AB - OBJECTIVE: HCV infection is a leading cause of chronic liver disease and a major indication for liver transplantation. Although direct-acting antivirals (DAAs) have much improved the treatment of chronic HCV infection, alternative strategies are needed for patients with treatment failure. As an essential HCV entry factor, the tight junction protein claudin-1 (CLDN1) is a promising antiviral target. However, genotype-dependent escape via CLDN6 and CLDN9 has been described in some cell lines as a possible limitation facing CLDN1-targeted therapies. Here, we evaluated the clinical potential of therapeutic strategies targeting CLDN1. DESIGN: We generated a humanised anti-CLDN1 monoclonal antibody (mAb) (H3L3) suitable for clinical development and characterised its anti-HCV activity using cell culture models, a large panel of primary human hepatocytes (PHH) from 12 different donors, and human liver chimeric mice. RESULTS: H3L3 pan-genotypically inhibited HCV pseudoparticle entry into PHH, irrespective of donor. Escape was likely precluded by low surface expression of CLDN6 and CLDN9 on PHH. Co treatment of a panel of PHH with a CLDN6-specific mAb did not enhance the antiviral effect of H3L3, confirming that CLDN6 does not function as an entry factor in PHH from multiple donors. H3L3 also inhibited DAA-resistant strains of HCV and synergised with current DAAs. Finally, H3L3 cured persistent HCV infection in human-liver chimeric uPA-SCID mice in monotherapy. CONCLUSIONS: Overall, these findings underscore the clinical potential of CLDN1-targeted therapies and describe the functional characterisation of a humanised anti-CLDN1 antibody suitable for further clinical development to complement existing therapeutic strategies for HCV. PMID- 28360100 TI - trans-Fatty acids promote proinflammatory signaling and cell death by stimulating the apoptosis signal-regulating kinase 1 (ASK1)-p38 pathway. AB - Food-borne trans-fatty acids (TFAs) are mainly produced as byproducts during food manufacture. Recent epidemiological studies have revealed that TFA consumption is a major risk factor for various disorders, including atherosclerosis. However, the underlying mechanisms in this disease etiology are largely unknown. Here we have shown that TFAs potentiate activation of apoptosis signal-regulating kinase 1 (ASK1) induced by extracellular ATP, a damage-associated molecular pattern leaked from injured cells. Major food-associated TFAs such as elaidic acid (EA), linoelaidic acid, and trans-vaccenic acid, but not their corresponding cis isomers, dramatically enhanced extracellular ATP-induced apoptosis, accompanied by elevated activation of the ASK1-p38 pathway in a macrophage-like cell line, RAW264.7. Moreover, knocking out the ASK1-encoding gene abolished EA-mediated enhancement of apoptosis. We have reported previously that extracellular ATP induces apoptosis through the ASK1-p38 pathway activated by reactive oxygen species generated downstream of the P2X purinoceptor 7 (P2X7). However, here we show that EA did not increase ATP-induced reactive oxygen species generation but, rather, augmented the effects of calcium/calmodulin-dependent kinase II-dependent ASK1 activation. These results demonstrate that TFAs promote extracellular ATP induced apoptosis by targeting ASK1 and indicate novel TFA-associated pathways leading to inflammatory signal transduction and cell death that underlie the pathogenesis and progression of TFA-induced atherosclerosis. Our study thus provides insight into the pathogenic mechanisms of and proposes potential therapeutic targets for these TFA-related disorders. PMID- 28360101 TI - Phospholipase C-related but catalytically inactive proteins regulate ovarian follicle development. AB - Phospholipase C-related but catalytically inactive proteins PRIP-1 and -2 are inositol-1,4,5-trisphosphate binding proteins that are encoded by independent genes. Ablation of the Prip genes in mice impairs female fertility, which is manifested by fewer pregnancies, a decreased number of pups, and the decreased and increased secretion of gonadal steroids and gonadotropins, respectively. We investigated the involvement of the PRIPs in fertility, focusing on the ovaries of Prip-1 and -2 double-knock-out (DKO) mice. Multiple cystic follicles were observed in DKO ovaries, and a superovulation assay showed a markedly decreased number of ovulated oocytes. Cumulus-oocyte complexes showed normal expansion, and artificial gonadotropin stimulation regulated the ovulation-related genes in a normal fashion, suggesting that the ovulation itself was probably normal. A histological analysis showed atresia in fewer follicles of the DKO ovaries, particularly in the secondary follicle stages. The expression of luteinizing hormone receptor (LHR) was aberrantly higher in developing follicles, and the phosphorylation of extracellular signal-regulated protein kinase, a downstream target of LH-LHR signaling, was higher in DKO granulosa cells. This suggests that the up-regulation of LH-LHR signaling is the cause of impaired follicle development. The serum estradiol level was lower, but estradiol production was unchanged in the DKO ovaries. These results suggest that PRIPs are positively involved in the development of follicles via their regulation of LH-LHR signaling and estradiol secretion. Female DKO mice had higher serum levels of insulin, testosterone, and uncarboxylated osteocalcin, which, together with reduced fertility, are reminiscent of polycystic ovary syndrome in humans. PMID- 28360102 TI - The activity of cGMP-dependent protein kinase Ialpha is not directly regulated by oxidation-induced disulfide formation at cysteine 43. AB - The type I cGMP-dependent protein kinases (PKGs) are key regulators of smooth muscle tone, cardiac hypertrophy, and other physiological processes. The two isoforms PKGIalpha and PKGIbeta are thought to have unique functions because of their tissue-specific expression, different cGMP affinities, and isoform-specific protein-protein interactions. Recently, a non-canonical pathway of PKGIalpha activation has been proposed, in which PKGIalpha is activated in a cGMP independent fashion via oxidation of Cys43, resulting in disulfide formation within the PKGIalpha N-terminal dimerization domain. A "redox-dead" knock-in mouse containing a C43S mutation exhibits phenotypes consistent with decreased PKGIalpha signaling, but the detailed mechanism of oxidation-induced PKGIalpha activation is unknown. Therefore, we examined oxidation-induced activation of PKGIalpha, and in contrast to previous findings, we observed that disulfide formation at Cys43 does not directly activate PKGIalpha in vitro or in intact cells. In transfected cells, phosphorylation of Ras homolog gene family member A (RhoA) and vasodilator-stimulated phosphoprotein was increased in response to 8 CPT-cGMP treatment, but not when disulfide formation in PKGIalpha was induced by H2O2 Using purified enzymes, we found that the Cys43 oxidation had no effect on basal kinase activity or Km and Vmax values; however, PKGIalpha containing the C43S mutation was less responsive to cGMP-induced activation. This reduction in cGMP affinity may in part explain the PKGIalpha loss-of-function phenotype of the C43S knock-in mouse. In conclusion, disulfide formation at Cys43 does not directly activate PKGIalpha, and the C43S-mutant PKGIalpha has a higher Ka for cGMP. Our results highlight that mutant enzymes should be carefully biochemically characterized before making in vivo inferences. PMID- 28360103 TI - Mutations in valosin-containing protein (VCP) decrease ADP/ATP translocation across the mitochondrial membrane and impair energy metabolism in human neurons. AB - Mutations in the gene encoding valosin-containing protein (VCP) lead to multisystem proteinopathies including frontotemporal dementia. We have previously shown that patient-derived VCP mutant fibroblasts exhibit lower mitochondrial membrane potential, uncoupled respiration, and reduced ATP levels. This study addresses the underlying basis for mitochondrial uncoupling using VCP knockdown neuroblastoma cell lines, induced pluripotent stem cells (iPSCs), and iPSC derived cortical neurons from patients with pathogenic mutations in VCP Using fluorescent live cell imaging and respiration analysis we demonstrate a VCP mutation/knockdown-induced dysregulation in the adenine nucleotide translocase, which results in a slower rate of ADP or ATP translocation across the mitochondrial membranes. This deregulation can explain the mitochondrial uncoupling and lower ATP levels in VCP mutation-bearing neurons via reduced ADP availability for ATP synthesis. This study provides evidence for a role of adenine nucleotide translocase in the mechanism underlying altered mitochondrial function in VCP-related degeneration, and this new insight may inform efforts to better understand and manage neurodegenerative disease and other proteinopathies. PMID- 28360105 TI - Demethylation of induced pluripotent stem cells from type 1 diabetic patients enhances differentiation into functional pancreatic beta cells. AB - Type 1 diabetes (T1D) can be managed by transplanting either the whole pancreas or isolated pancreatic islets. However, cadaveric pancreas is scarcely available for clinical use, limiting this approach. As such, there is a great need to identify alternative sources of clinically usable pancreatic tissues. Here, we used induced pluripotent stem (iPS) cells derived from patients with T1D to generate glucose-responsive, insulin-producing cells (IPCs) via 3D culture. Initially, T1D iPS cells were resistant to differentiation, but transient demethylation treatment significantly enhanced IPC yield. The cells responded to high-glucose stimulation by secreting insulin in vitro The shape, size, and number of their granules, as observed by transmission electron microscopy, were identical to those found in cadaveric beta cells. When the IPCs were transplanted into immunodeficient mice that had developed streptozotocin-induced diabetes, they promoted a dramatic decrease in hyperglycemia, causing the mice to become normoglycemic within 28 days. None of the mice died or developed teratomas. Because the cells are derived from "self," immunosuppression is not required, providing a much safer and reliable treatment option for T1D patients. Moreover, these cells can be used for drug screening, thereby accelerating drug discovery. In conclusion, our approach eliminates the need for cadaveric pancreatic tissue. PMID- 28360104 TI - The lysosomal Ca2+ release channel TRPML1 regulates lysosome size by activating calmodulin. AB - Intracellular lysosomal membrane trafficking, including fusion and fission, is crucial for cellular homeostasis and normal cell function. Both fusion and fission of lysosomal membrane are accompanied by lysosomal Ca2+ release. We recently have demonstrated that the lysosomal Ca2+ release channel P2X4 regulates lysosome fusion through a calmodulin (CaM)-dependent mechanism. However, the molecular mechanism underlying lysosome fission remains uncertain. In this study, we report that enlarged lysosomes/vacuoles induced by either vacuolin-1 or P2X4 activation are suppressed by up-regulating the lysosomal Ca2+ release channel transient receptor potential mucolipin 1 (TRPML1) but not the lysosomal Na+ release channel two-pore channel 2 (TPC2). Activation of TRPML1 facilitated the recovery of enlarged lysosomes/vacuoles. Moreover, the effects of TRPML1 on lysosome/vacuole size regulation were eliminated by Ca2+ chelation, suggesting a requirement for TRPML1-mediated Ca2+ release. We further demonstrate that the prototypical Ca2+ sensor CaM is required for the regulation of lysosome/vacuole size by TRPML1, suggesting that TRPML1 may promote lysosome fission by activating CaM. Given that lysosome fission is implicated in both lysosome biogenesis and reformation, our findings suggest that TRPML1 may function as a key lysosomal Ca2+ channel controlling both lysosome biogenesis and reformation. PMID- 28360106 TI - Ca2+ and calpain mediate capsaicin-induced ablation of axonal terminals expressing transient receptor potential vanilloid 1. AB - Capsaicin is an ingredient in spicy peppers that produces burning pain by activating transient receptor potential vanilloid 1 (TRPV1), a Ca2+-permeable ion channel in nociceptors. Capsaicin has also been used as an analgesic, and its topical administration is approved for the treatment of certain pain conditions. The mechanisms underlying capsaicin-induced analgesia likely involve reversible ablation of nociceptor terminals. However, the mechanisms underlying these effects are not well understood. To visualize TRPV1-lineage axons, a genetically engineered mouse model was used in which a fluorophore is expressed under the TRPV1 promoter. Using a combination of these TRPV1-lineage reporter mice and primary afferent cultures, we monitored capsaicin-induced effects on afferent terminals in real time. We found that Ca2+ influx through TRPV1 is necessary for capsaicin-induced ablation of nociceptive terminals. Although capsaicin-induced mitochondrial Ca2+ uptake was TRPV1-dependent, dissipation of the mitochondrial membrane potential, inhibition of the mitochondrial transition permeability pore, and scavengers of reactive oxygen species did not attenuate capsaicin-induced ablation. In contrast, MDL28170, an inhibitor of the Ca2+-dependent protease calpain, diminished ablation. Furthermore, overexpression of calpastatin, an endogenous inhibitor of calpain, or knockdown of calpain 2 also decreased ablation. Quantitative assessment of TRPV1-lineage afferents in the epidermis of the hind paws of the reporter mice showed that EGTA and MDL28170 diminished capsaicin-induced ablation. Moreover, MDL28170 prevented capsaicin-induced thermal hypoalgesia. These results suggest that TRPV1/Ca2+/calpain-dependent signaling plays a dominant role in capsaicin-induced ablation of nociceptive terminals and further our understanding of the molecular mechanisms underlying the effects of capsaicin on nociceptors. PMID- 28360107 TI - Electrostatic attraction of weak monoacid anions increases probability for protonation and passage through aquaporins. AB - A positive electrostatic field emanating from the center of the aquaporin (AQP) water and solute channel is responsible for the repulsion of cations. At the same time, however, a positive field will attract anions. In this regard, l lactate/lactic acid permeability has been shown for various isoforms of the otherwise highly water and neutral substrate selective AQP family. The structural requirements rendering certain AQPs permeable for weak monoacids and the mechanism of conduction have remained unclear. Here, we show by profiling pH dependent substrate permeability, measurements of media alkalization, and proton decoupling that AQP9 acts as a channel for the protonated, neutral monocarboxylic acid species. Intriguingly, the obtained permeability rates indicate an up to 10 times higher probability of passage via AQP9 than given by the fraction of the protonated acid substrate at a certain pH. We generated AQP9 point mutants showing that this effect is independent from properties of the channel interior but caused by the protein surface electrostatics. Monocarboxylic acid-conducting AQPs thus employ a mechanism similar to the family of formate-nitrite transporters for weak monoacids. On a more general basis, our data illustrate semiquantitatively the contribution of surface electrostatics to the interaction of charged molecule substrates or ligands with target proteins, such as channels, transporters, enzymes, or receptors. PMID- 28360111 TI - The effects of electronic cigarette aerosol exposure on inflammation and lung function in mice. AB - Electronic cigarette usage is increasing worldwide, yet there is a paucity of information on the respiratory health effects of electronic cigarette aerosol exposure. This study aimed to assess whether exposure to electronic cigarette (e cigarette) aerosol would alter lung function and pulmonary inflammation in mice and to compare the severity of any alterations with mice exposed to mainstream tobacco smoke. Female BALB/c mice were exposed for 8 wk to tobacco smoke, medical air (control), or one of four different types of e-cigarette aerosol. E-cigarette aerosols varied depending on nicotine content (0 or 12 mg/ml) and the main excipient (propylene glycol or glycerin). Twenty-four hours after the final exposure, we measured pulmonary inflammation, lung volume, lung mechanics, and responsiveness to methacholine. Mice exposed to tobacco cigarette smoke had increased pulmonary inflammation and responsiveness to methacholine compared with air controls. Mice exposed to e-cigarette aerosol did not have increased inflammation but did display decrements in parenchymal lung function at both functional residual capacity and high transrespiratory pressures. Mice exposed to glycerin-based e-cigarette aerosols were also hyperresponsive to methacholine regardless of the presence or absence of nicotine. This study shows, for the first time, that exposure to e-cigarette aerosol during adolescence and early adulthood is not harmless to the lungs and can result in significant impairments in lung function. PMID- 28360112 TI - Apoptotic cell death in rat lung following mustard gas inhalation. AB - To investigate apoptosis as a mechanism of sulfur mustard (SM) inhalation injury in animals, we studied different caspases (caspase-8, -9, -3, and -6) in the lungs from a ventilated rat SM aerosol inhalation model. SM activated all four caspases in cells obtained from bronchoalveolar lavage fluid (BALF) as early as 6 h after exposure. Caspase-8, which is known to initiate the extrinsic Fas mediated pathway of apoptosis, was increased fivefold between 6 and 24 h, decreasing to the unexposed-control level at 48 h. The initiator, caspase-9, in the intrinsic mitochondrial pathway of apoptosis as well as the executioner caspases, caspase-3 and -6, all peaked (P < 0.01) at 24 h; caspase-3 and -6 remained elevated, but caspase-9 decreased to unexposed-control level at 48 h. To study further the Fas pathway, we examined soluble as well as membrane-bound Fas ligand (sFas-L and mFas-L, respectively) and Fas receptor (Fas-R) in both BALF cells and BALF. At 24 h after SM exposure, sFas-L increased significantly in both BALF cells (P < 0.01) and BALF (P < 0.05). However, mFas-L increased only in BALF cells between 24 and 48 h (P < 0.1 and P < 0.001, respectively). Fas-R increased only in BALF cells by 6 h (P < 0.01) after SM exposure. Apoptosis in SM-inhaled rat lung specimens was also confirmed by both immunohistochemical staining using cleaved caspase-3 and -9 antibodies and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining as early as 6 h in the proximal trachea and bronchi, but not before 48 h in distal airways. These findings suggest pathogenic mechanisms at the cellular and molecular levels and logical therapeutic target(s) for SM inhalation injury in animals. PMID- 28360109 TI - Focal adhesion kinase signaling determines the fate of lung epithelial cells in response to TGF-beta. AB - Alveolar epithelial cell (AEC) injury and apoptosis are prominent pathological features of idiopathic pulmonary fibrosis (IPF). There is evidence of AEC plasticity in lung injury repair response and in IPF. In this report, we explore the role of focal adhesion kinase (FAK) signaling in determining the fate of lung epithelial cells in response to transforming growth factor-beta1 (TGF-beta1). Rat type II alveolar epithelial cells (RLE-6TN) were treated with or without TGF beta1, and the expressions of mesenchymal markers, phenotype, and function were analyzed. Pharmacological protein kinase inhibitors were utilized to screen for SMAD-dependent and -independent pathways. SMAD and FAK signaling was analyzed using siRNA knockdown, inhibitors, and expression of a mutant construct of FAK. Apoptosis was measured using cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. TGF-beta1 induced the acquisition of mesenchymal markers, including alpha-smooth muscle actin, in RLE 6TN cells and enhanced the contraction of three-dimensional collagen gels. This phenotypical transition or plasticity, epithelial-myofibroblast plasticity (EMP), is dependent on SMAD3 and FAK signaling. FAK activation was found to be dependent on ALK5/SMAD3 signaling. We observed that TGF-beta1 induces both EMP and apoptosis in the same cell culture system but not in the same cell. While blockade of SMAD signaling inhibited EMP, it had a minimal effect on apoptosis; in contrast, inhibition of FAK signaling markedly shifted to an apoptotic fate. The data support that FAK activation determines whether AECs undergo EMP vs. apoptosis in response to TGF-beta1 stimulation. TGF-beta1-induced EMP is FAK- dependent, whereas TGF-beta1-induced apoptosis is favored when FAK signaling is inhibited. PMID- 28360113 TI - Directional preference of airway smooth muscle mass increase in human asthmatic airways. AB - Airway smooth muscle (ASM) orientation and morphology determine the ability of the muscle to constrict the airway. In asthma, ASM mass is increased, but it is unknown whether ASM orientation and morphology are altered as well or whether the remodeling at the source of the mass increase is ongoing. We dissected human airway trees from asthmatic and control lungs. Stained, intact airway sections were imaged in axial projection to show ASM bundle orientation, whereas cross sectional histological slides were used to assess ASM area, bundle thickness, and ASM bundle-to-basement membrane distance. We also used these slides to assess cell size, proliferation, and apoptosis. We showed that ASM mass increase in cartilaginous airways is primarily the result of an increase of ASM bundle thickness (as measured radially in an airway cross section) and coincides with an increased distance of the ASM bundles to the airway perimeter. ASM orientation was unchanged in all airways. Apoptosis markers and cell size did not show differences between asthmatics and controls. Our findings show that ASM mass increase likely contributes to the airway-constricting capacity of the muscle. Both the increased bundle thickness and increased thickness of the airway wall inwards of the ASM bundles could further enhance this capacity. Turnover of ASM appears to be the same in airways and biopsies, but the lack of correlation between different markers of proliferation casts doubt on the specificity of markers generally used to assess proliferation. PMID- 28360110 TI - The CFTR trafficking mutation F508del inhibits the constitutive activity of SLC26A9. AB - Several members of the SLC26A family of anion transporters associate with CFTR, forming complexes in which CFTR and SLC26A functions are reciprocally regulated. These associations are thought to be facilitated by PDZ scaffolding interactions. CFTR has been shown to be positively regulated by NHERF-1, and negatively regulated by CAL in airway epithelia. However, it is unclear which PDZ-domain protein(s) interact with SLC26A9, a SLC26A family member found in airway epithelia. We have previously shown that primary, human bronchial epithelia (HBE) from non-CF donors exhibit constitutive anion secretion attributable to SLC26A9. However, constitutive anion secretion is absent in HBE from CF donors. We examined whether changes in SLC26A9 constitutive activity could be attributed to a loss of CFTR trafficking, and what role PDZ interactions played. HEK293 coexpressing SLC26A9 with the trafficking mutant F508del CFTR exhibited a significant reduction in constitutive current compared with cells coexpressing SLC26A9 and wt CFTR. We found that SLC26A9 exhibits complex glycosylation when coexpressed with F508del CFTR, but its expression at the plasma membrane is decreased. SLC26A9 interacted with both NHERF-1 and CAL, and its interaction with both significantly increased with coexpression of wt CFTR. However, coexpression with F508del CFTR only increased SLC26A9's interaction with CAL. Mutation of SLC26A9's PDZ motif decreased this association with CAL, and restored its constitutive activity. Correcting aberrant F508del CFTR trafficking in CF HBE with corrector VX-809 also restored SLC26A9 activity. We conclude that when SLC26A9 is coexpressed with F508del CFTR, its trafficking defect leads to a PDZ motif-sensitive intracellular retention of SLC26A9. PMID- 28360115 TI - CD163 Expression in Neurons After Experimental Intracerebral Hemorrhage. AB - BACKGROUND AND PURPOSE: CD163, a receptor for hemoglobin, is involved in hemoglobin clearance after intracerebral hemorrhage (ICH). In contrast to microglial/macrophage CD163, neuronal CD163 hemoglobin has not been well studied. This study examined the expression of neuronal CD163 in a pig model of ICH and in vitro rat cortical neurons and the impact of deferoxamine on that expression. METHODS: There were 2 parts to this study. In the in vivo part, piglets had injection of autologous blood into the right frontal lobe. The time course of CD163 expression and the effect of deferoxamine on the expression of CD163 after ICH were determined in the grey matter. In the in vitro part, the levels of CD163 and neuronal death and the effect of deferoxamine were examined in rat cortical neurons culture treated with hemoglobin. RESULTS: CD163-positive cells were found, and the CD163 protein levels were upregulated in the ipsilateral grey matter after ICH. The CD163 levels peaked at days 1 and 3. The CD163-positive cells were colocated with NeuN-positive, heme oxygenase-2-positive, and terminal deoxynucleatidyl transferase dUTP nick end labeling-positive cells. Deferoxamine treatment attenuated ICH-induced CD163 upregulation and significantly reduced both brain CD163 and hemoglobin levels at day 3. Treating neuronal cultures with hemoglobin for 24 hours resulted in CD163 upregulation and increased cell death. Deferoxamine significantly attenuated the hemoglobin-induced neuronal death and CD163 upregulation. CONCLUSIONS: CD163 is expressed in neurons and upregulated after ICH. Deferoxamine reduced ICH-induced CD163 upregulation and brain cell death in vivo and hemoglobin-induced CD163 upregulation and neuronal death in vitro. PMID- 28360114 TI - RORalpha-dependent type 2 innate lymphoid cells are required and sufficient for mucous metaplasia in immature mice. AB - Early-life wheezing-associated respiratory tract infection by rhinovirus (RV) is considered a risk factor for asthma development. We have shown that RV infection of 6-day-old BALB/c mice, but not mature mice, induces an asthmalike phenotype that is associated with an increase in the population of type 2 innate lymphoid cells (ILC2s) and dependent on IL-13 and IL-25. We hypothesize that ILC2s are required and sufficient for development of the asthmalike phenotype in immature mice. Mice were infected with RV1B on day 6 of life and treated with vehicle or a chemical inhibitor of retinoic acid receptor-related orphan receptor-alpha (RORalpha), SR3335 (15 mg.kg-1.day-1 ip for 7 days). We also infected Rorasg/sg mice without functional ILC2s. ILC2s were identified as negative for lineage markers and positive for cluster of differentiation 25 (CD25)/IL-2Ralpha and CD127/IL-7Ralpha. Effects of SR3335 on proliferation and function of cultured ILC2s were determined. Finally, sorted ILC2s were transferred into naive mice, and lungs were harvested 14 days later for assessment of gene expression and histology. SR3335 decreased the number of RV-induced lung lineage-negative, CD25+, CD127+ ILC2s in immature mice. SR3335 also attenuated lung mRNA expression of IL-13, Muc5ac, and Gob5 as well as mucous metaplasia. We also found reduced expansion of ILC2s in RV-infected Rorasg/sg mice. SR3335 also blocked IL-25 and IL-33-induced ILC2 proliferation and IL-13 production ex vivo. Finally, adoptive transfer of ILC2s led to development of asthmalike phenotype in immature and adult mice. RORalpha-dependent ILC2s are required and sufficient for type 2 cytokine expression and mucous metaplasia in immature mice. PMID- 28360117 TI - Are babies conceived during Ramadan born smaller and sooner than babies conceived at other times of the year? A Born in Bradford Cohort Study. AB - BACKGROUND: It is not known whether infants exposed to intermittent maternal fasting at conception are born smaller or have a higher risk of premature birth than those who are not. Doctors are therefore unsure about what advice to give women about the safety of Ramadan fasting. This cohort study aimed to investigate these questions in Muslim mother-infant pairs to inform prenatal care. METHODS: Routinely collected data accessed from maternity records were the source for information. Mothers were considered exposed if they were Muslim and Ramadan overlapped with their infant conception date, estimated to be 14 days after the last menstrual period. Infants were included as exposed if their estimated conception date was in the first 21 days of Ramadan or 7 days prior to Ramadan. RESULTS: After adjusting for gestational age, maternal age, infant gender, maternal body mass index at booking, smoking status, gestational diabetes, parity and year of birth, there was no significant difference in birth weight between infants born to Muslim mothers who were conceived during Ramadan (n=479) and those who were not (n=4677) (adjusted mean difference =24.3 g, 95% CI -16.4 to 64.9). There was no difference in rates of premature births in exposed and unexposed women (5.2% vs 4.9%; OR=1.08, 95% CI 0.71 to 1.65). CONCLUSIONS: Healthy Muslim women considering becoming pregnant prior to, or during Ramadan, can be advised that fasting does not seem to have a detrimental effect on the size (weight) of their baby and it appears not to increase the likelihood of giving birth prematurely. PMID- 28360116 TI - Homocysteine and Stroke Risk: Modifying Effect of Methylenetetrahydrofolate Reductase C677T Polymorphism and Folic Acid Intervention. AB - BACKGROUND AND PURPOSE: Elevated blood homocysteine concentration increases the risk of stroke, especially among hypertensive individuals. Homocysteine is largely affected by the methylenetetrahydrofolate reductase C677T polymorphism and folate status. Among hypertensive patients, we aimed to test the hypothesis that the association between homocysteine and stroke can be modified by the methylenetetrahydrofolate reductase C677T polymorphism and folic acid intervention. METHODS: We analyzed the data of 20 424 hypertensive adults enrolled in the China Stroke Primary Prevention Trial. The participants, first stratified by methylenetetrahydrofolate reductase genotype, were randomly assigned to receive double-blind treatments of 10-mg enalapril and 0.8-mg folic acid or 10-mg enalapril only. The participants were followed up for a median of 4.5 years. RESULTS: In the control group, baseline log-transformed homocysteine was associated with an increased risk of first stroke among participants with the CC/CT genotype (hazard ratio, 3.1; 1.1-9.2), but not among participants with the TT genotype (hazard ratio, 0.7; 0.2-2.1), indicating a significant gene homocysteine interaction (P=0.008). In the folic acid intervention group, homocysteine showed no significant effect on stroke regardless of genotype. Consistently, folic acid intervention significantly reduced stroke risk in participants with CC/CT genotypes and high homocysteine levels (tertile 3; hazard ratio, 0.73; 0.55-0.97). CONCLUSIONS: In Chinese hypertensive patients, the effect of homocysteine on the first stroke was significantly modified by the methylenetetrahydrofolate reductase C677T genotype and folic acid supplementation. Such information may help to more precisely predict stroke risk and develop folic acid interventions tailored to individual genetic background and nutritional status. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885. PMID- 28360118 TI - Raising the pressure: Hemodynamic effects of splanchnic nerve stimulation. AB - A number of cardiovascular and neurological diseases are characterized by a dysregulation of intravascular volume distribution. The veins and arteries of the visceral organs form the so-called splanchnic vascular compartment and are the largest reservoir for intravascular blood. The blood localized in the splanchnic compartment can be mobilized in and out of the compartment via passive compression or active neurohormonal recruitment. We studied the hemodynamic effects of splanchnic nerve stimulation during five cases of irreversible electroporation (IRE) in patients with pancreatic cancer. In IRE, repeated bursts of high-voltage electrical fields are applied to visceral beds for >1 min, which induces rapid increase in blood pressure, heart rate, and cardiac output. We present the first analysis into the hemodynamic changes with splanchnic nerve stimulation and explore potential mechanisms of the hyperdynamic state. Our analysis presents the first human report of splanchnic nerve stimulation to induce hypertension and volume redistribution, introducing the splanchnic nerves as a key component of cardiovascular regulation.NEW & NOTEWORTHY Our case series provides the first detailed description of human hemodynamic effects with splanchnic nerve stimulation. Splanchnic nerve stimulation results in profound hemodynamic alteration with rapid onset of hypertension and blood mobilization. PMID- 28360119 TI - Optical clearing: impact of optical and dielectric properties of clearing solutions on pulmonary tissue mechanics. AB - Optical clearing allows tissue visualization under preservation of organ integrity. Optical clearing of organs with a physiological change in three dimensional geometry (such as the lung) would additionally allow visualization of macroscopic and microscopic tissue geometry. A prerequisite, however, is the preservation of the native tissue mechanics of the optically cleared lung tissue. We investigated the impact of optical and dielectric properties of clearing solutions on biomechanics and clearing potency in porcine tissue strips of healthy lungs. After fixation, bleaching, and rehydration, four methods of optical clearing were investigated using eight different protocols. The mechanical and optical properties of the cleared lung tissue strips were investigated by uniaxial tensile testing and by analyzing optical transparency and translucency for red, green, and blue light before, during, and after the biochemical optical clearing process. Fresh tissue strips were used as controls. Best balance between efficient clearing and preserved mechanics was found for clearing with a 1:1 mixture of dimethyl sulfoxide (DMSO) and aniline. Our findings show that 1) the degree of tissue transparency and translucency correlated with the refractive index of the clearing solution index (r = 0.976, P = 0.0004; and r = 0.91, P = 0.0046, respectively), 2) tissue mechanics were affected by dehydration and the type of clearing solution, and 3) tissue biomechanics and geometry correlated with the dielectric constant of the clearing solution (r = -0.98, P < 0.00001; and r = 0.69, P = 0.013, respectively). We show that the lower the dielectric constant of the clearing solutions, the larger the effect on tissue stiffness. This suggests that the dielectric constant is an important measure in determining the effect of a clearing solution on lung tissue biomechanics. Optimal tissue transparency requires complete tissue dehydration and a refractive index of 1.55 of the clearing solution.NEW & NOTEWORTHY Investigating optical clearing in porcine lung tissue strips, we found that refractive index and dielectric constant of the clearing solution affected tissue clearing and biomechanics. By documenting the impact of the composition of the clearing solution on clearing potency and preservation of tissue mechanics, our results help to compose optimal clearing solutions. In addition, the results allow conclusions on the molecular interaction of solvents with collagen fibers in tissue, thereby consolidating existing theories about the functionality of collagen. PMID- 28360121 TI - Prosthetic model, but not stiffness or height, affects the metabolic cost of running for athletes with unilateral transtibial amputations. AB - Running-specific prostheses enable athletes with lower limb amputations to run by emulating the spring-like function of biological legs. Current prosthetic stiffness and height recommendations aim to mitigate kinematic asymmetries for athletes with unilateral transtibial amputations. However, it is unclear how different prosthetic configurations influence the biomechanics and metabolic cost of running. Consequently, we investigated how prosthetic model, stiffness, and height affect the biomechanics and metabolic cost of running. Ten athletes with unilateral transtibial amputations each performed 15 running trials at 2.5 or 3.0 m/s while we measured ground reaction forces and metabolic rates. Athletes ran using three different prosthetic models with five different stiffness category and height combinations per model. Use of an Ottobock 1E90 Sprinter prosthesis reduced metabolic cost by 4.3 and 3.4% compared with use of Freedom Innovations Catapult [fixed effect (beta) = -0.177; P < 0.001] and Ossur Flex-Run (beta = 0.139; P = 0.002) prostheses, respectively. Neither prosthetic stiffness (P >= 0.180) nor height (P = 0.062) affected the metabolic cost of running. The metabolic cost of running was related to lower peak (beta = 0.649; P = 0.001) and stance average (beta = 0.772; P = 0.018) vertical ground reaction forces, prolonged ground contact times (beta = -4.349; P = 0.012), and decreased leg stiffness (beta = 0.071; P < 0.001) averaged from both legs. Metabolic cost was reduced with more symmetric peak vertical ground reaction forces (beta = 0.007; P = 0.003) but was unrelated to stride kinematic symmetry (P >= 0.636). Therefore, prosthetic recommendations based on symmetric stride kinematics do not necessarily minimize the metabolic cost of running. Instead, an optimal prosthetic model, which improves overall biomechanics, minimizes the metabolic cost of running for athletes with unilateral transtibial amputations.NEW & NOTEWORTHY The metabolic cost of running for athletes with unilateral transtibial amputations depends on prosthetic model and is associated with lower peak and stance average vertical ground reaction forces, longer contact times, and reduced leg stiffness. Metabolic cost is unrelated to prosthetic stiffness, height, and stride kinematic symmetry. Unlike nonamputees who decrease leg stiffness with increased in-series surface stiffness, biological limb stiffness for athletes with unilateral transtibial amputations is positively correlated with increased in-series (prosthetic) stiffness. PMID- 28360120 TI - Voluntary upregulation of reflex cough is possible in healthy older adults and Parkinson's disease. AB - Cough is an airway-protective mechanism that serves to detect and forcefully eject aspirate material. Existing research has identified the ability of healthy young adults to suppress or modify cough motor output based on external cueing. However, no study has evaluated the ability of people with Parkinson's disease (PD) and healthy older adults (HOAs) to upregulate cough motor output. The goal of this study was to evaluate the ability of people with PD and healthy age matched controls (HOAs) to upregulate reflex and voluntary cough function volitionally with verbal instruction and visual biofeedback of airflow targets. Sixteen participants with PD and twenty-eight HOAs (56-83 yr old) were recruited for this study. Experimental procedures used spirometry to evaluate 1) baseline reflex cough (evoked with capsaicin) and voluntary sequential cough and 2) reflex and voluntary cough with upregulation biofeedback. Cough airflow was recorded and repeated-measures ANOVA was used to analyze differences in cough airflow parameters. Cough peak expiratory airflow rate and cough expired volume were significantly greater in the cueing condition for both induced reflex (P < 0.001) and voluntary cough (P < 0.001) compared with baseline measures. This is the first study to demonstrate the ability of people with PD and HOAs to upregulate induced reflex and voluntary cough motor output volitionally. These results support the development of studies targeting improved cough effectiveness in patients with airway-protective deficits.NEW & NOTEWORTHY Aspiration pneumonia is a leading cause of death in Parkinson's disease (PD) and results from concurrent dysphagia and dystussia (cough dysfunction). This is the first study to demonstrate that people with PD and healthy age-matched controls can volitionally upregulate induced reflex and voluntary cough effectiveness when presented with novel cueing strategies. Thus targeting upregulation of cough effectiveness via biofeedback may be a viable way to enhance airway protection in people with PD. PMID- 28360122 TI - Increased cerebral blood volume pulsatility during head-down tilt with elevated carbon dioxide: the SPACECOT Study. AB - Astronauts aboard the International Space Station (ISS) have exhibited hyperopic shifts, posterior eye globe flattening, dilated optic nerve sheaths, and even optic disk swelling from spaceflight. Elevated intracranial pressure (ICP) consequent to cephalad fluid shifts is commonly hypothesized as contributing to these ocular changes. Head-down tilt (HDT) is frequently utilized as an Earth based analog to study similar fluid shifts. Sealed environments like the ISS also exhibit elevated CO2, a potent arteriolar vasodilator that could further affect cerebral blood volume (CBV) and cerebral blood flow, intracranial compliance, and ICP. A collaborative pilot study between the National Space Biomedical Research Institute and the German Aerospace Center tested the hypotheses that 1) HDT and elevated CO2 physiologically interact and 2) cerebrovascular pulsatility is related to HDT and/or elevated CO2 In a double-blind crossover study (n = 6), we measured CBV pulsatility via near-infrared spectroscopy, alongside noninvasive ICP and intraocular pressure (IOP) during 28-h -12 degrees HDT at both nominal (0.04%) and elevated (0.5%) ambient CO2 In our cohort, CBV pulsatility increased significantly over time at cardiac frequencies (0.031 +/- 0.009 MUM/h increase in total hemoglobin concentration pulsatility amplitude) and Mayer wave frequencies (0.019 +/- 0.005 MUM/h increase). The HDT-CO2 interaction on pulsatility was not robust but rather driven by one individual. Significant differences between atmospheres were not detected in ICP or IOP. Further work is needed to determine whether individual differences in pulsatility responses to CO2 relate to visual changes in space.NEW & NOTEWORTHY Cerebral blood volume (CBV) pulsatility-as measured by near-infrared spectroscopy-increases over time during -12 degrees head-down tilt at both cardiac and Mayer wave frequencies. CBV pulsatility appeared to increase more under elevated (0.5%) CO2 at Mayer wave frequencies in some individuals. If similar dynamic pulsatility increases occur in astronauts, there is the potential to initiate vascular and possibly other remodeling processes that lead to symptoms associated with sustained increases in intracranial pressure. PMID- 28360123 TI - Impact of positive pressure ventilation on mean systemic filling pressure in critically ill patients after death. AB - Mean systemic filling pressure (Pms) defines the pressure measured in the venous arterial system when the cardiac output is nil. Its estimation has been proposed in patients with beating hearts by building the venous return curve, using different pairs of right atrial pressure/cardiac output during mechanical ventilation. We raised the hypothesis according to which the Pms is altered by tidal ventilation and positive end-expiratory pressure (PEEP), which would challenge this extrapolation method based on cardiopulmonary interactions. We conducted a two-center, noninterventional, observational, and prospective study, using an arterial and a venous catheter to measure the pressure in the circulatory system at the time of death in critically ill, mechanically ventilated patients with a PEEP. Arterial (Part) and venous pressures (Pra) were recorded in five conditions: at end expiration and end inspiration with and without PEEP and finally once the ventilator was disconnected. Part and Pra did not differ in any experimental conditions. Tidal ventilation increased Pra and Part by 2.4 and 1.9 mmHg, respectively, whereas PEEP increased both values by 1.2 and 1 mmHg, respectively. After disconnection of the ventilator, Pra and Part were 10.0 +/- 4.2 and 9.9 +/- 4.2 mmHg, respectively. Pms increases during mechanical ventilation, with an effect of tidal ventilation and PEEP. This calls into question the validity of its evaluation in heart-beating patients using cardiopulmonary interactions during mechanical ventilation.NEW & NOTEWORTHY The physiology of the mean systemic filling pressure (Pms) is not well understood in human beings. This study is the first report of a tidal ventilation- and positive end-expiratory pressure-related increase in Pms in critically ill patients. The results challenge the utility and the value estimating Pms in heart-beating patients by reconstruction of the venous return curve using varying inflation pressures. PMID- 28360124 TI - Genetic mutations linked to Parkinson's disease differentially control nucleolar activity in pre-symptomatic mouse models. AB - Genetic mutations underlying neurodegenerative disorders impair ribosomal DNA (rDNA) transcription suggesting that nucleolar dysfunction could be a novel pathomechanism in polyglutamine diseases and in certain forms of amyotrophic lateral sclerosis/frontotemporal dementia. Here, we investigated nucleolar activity in pre-symptomatic digenic models of Parkinson's disease (PD) that model the multifactorial aetiology of this disease. To this end, we analysed a novel mouse model mildly overexpressing mutant human alpha-synuclein (hA53T-SNCA) in a PTEN-induced kinase 1 (PINK1/PARK6) knockout background and mutant mice lacking both DJ-1 (also known as PARK7) and PINK1. We showed that overexpressed hA53T SNCA localizes to the nucleolus. Moreover, these mutants show a progressive reduction of rDNA transcription linked to a reduced mouse lifespan. By contrast, rDNA transcription is preserved in DJ-1/PINK1 double knockout (DKO) mice. mRNA levels of the nucleolar transcription initiation factor 1A (TIF-IA, also known as RRN3) decrease in the substantia nigra of individuals with PD. Because loss of TIF-IA, as a tool to mimic nucleolar stress, increases oxidative stress and because DJ-1 and PINK1 mutations result in higher vulnerability to oxidative stress, we further explored the synergism between these PD-associated genes and impaired nucleolar function. By the conditional ablation of TIF-IA, we blocked ribosomal RNA (rRNA) synthesis in adult dopaminergic neurons in a DJ-1/PINK1 DKO background. However, the early phenotype of these triple knockout mice was similar to those mice exclusively lacking TIF-IA. These data sustain a model in which loss of DJ-1 and PINK1 does not impair nucleolar activity in a pre symptomatic stage. This is the first study to analyse nucleolar function in digenic PD models. We can conclude that, at least in these models, the nucleolus is not as severely disrupted as previously shown in DA neurons from PD patients and neurotoxin-based PD mouse models. The results also show that the early increase in rDNA transcription and nucleolar integrity may represent specific homeostatic responses in these digenic pre-symptomatic PD models. PMID- 28360125 TI - Cellular levels of Grb2 and cytoskeleton stability are correlated in a neurodegenerative scenario. AB - Alzheimer's disease (AD) manifests as neuronal loss. On the premise of Grb2 overexpression in AD mouse brain and brain tissues of AD patients, our study primarily focuses on the stability of cytoskeletal proteins in the context of degenerative AD-like conditions. Two predominant molecular features of AD, extracellular accumulation of beta-amyloid oligomers and intracellular elevation of amyloid precursor protein intracellular domain levels, have been used to closely inspect the series of signalling events. In their presence, multiple signalling pathways involving ROCK and PAK1 proteins lead to disassembly of the cytoskeleton, and Grb2 partially counterbalances the cytoskeletal loss. Increased Grb2-NOX4 interactions play a preventive role against cytoskeletal disassembly, in turn blocking the activity of nitrogen oxides and decreasing the expression of slingshot homolog 1 (SSH-1) protein, a potent inducer of cytoskeleton disassembly. This study unravels a unique role of Grb2 in protecting the cytoskeletal architecture in AD-like conditions and presents a potential new strategy for controlling neurodegeneration. PMID- 28360126 TI - The Evolving Definition of the Term "Gene". AB - This paper presents a history of the changing meanings of the term "gene," over more than a century, and a discussion of why this word, so crucial to genetics, needs redefinition today. In this account, the first two phases of 20th century genetics are designated the "classical" and the "neoclassical" periods, and the current molecular-genetic era the "modern period." While the first two stages generated increasing clarity about the nature of the gene, the present period features complexity and confusion. Initially, the term "gene" was coined to denote an abstract "unit of inheritance," to which no specific material attributes were assigned. As the classical and neoclassical periods unfolded, the term became more concrete, first as a dimensionless point on a chromosome, then as a linear segment within a chromosome, and finally as a linear segment in the DNA molecule that encodes a polypeptide chain. This last definition, from the early 1960s, remains the one employed today, but developments since the 1970s have undermined its generality. Indeed, they raise questions about both the utility of the concept of a basic "unit of inheritance" and the long implicit belief that genes are autonomous agents. Here, we review findings that have made the classic molecular definition obsolete and propose a new one based on contemporary knowledge. PMID- 28360127 TI - Mitochondrial Replacement Therapy: Are Mito-nuclear Interactions Likely To Be a Problem? AB - It has been suggested that deleterious interactions between the mitochondrial and nuclear genomes could pose a problem for mitochondrial replacement therapy (MRT). This is because the mitochondrial genome is placed in a novel nuclear environment using this technique. In contrast, it is inherited with half the mother's genome during normal reproduction, a genome that it is relatively compatible with, since the mother is alive. Here, I review the evidence of whether mito-nuclear interactions are likely to pose a problem for MRT. The majority of the available experimental evidence, both in humans and other species, suggests that MRT is not harmful. These results are consistent with population genetic theory, which predicts that deleterious mito-nuclear interactions are unlikely to be much more prevalent in individuals born to MRT than normal reproduction, particularly in a species such as humans with low population differentiation. This is because selection is unlikely to be strong enough to establish significant linkage disequilibrium between the mitochondrial and nuclear genomes. These results are supported by a meta-analysis of 231 cases, from a variety of animals, in which the mitochondrial DNA (mtDNA) from one strain has been introgressed into the nuclear background of another strain of the same species. Overall, there is little tendency for introgression of mtDNA to be harmful. PMID- 28360129 TI - Corrigendum. PMID- 28360131 TI - A small-molecule screen reveals that HSP90beta promotes the conversion of induced pluripotent stem cell-derived endoderm to a hepatic fate and regulates HNF4A turnover. AB - We have previously shown that the transcription factor HNF4A is required for the formation of hepatic progenitor cells from endoderm that has been derived from human induced pluripotent stem cells (iPSCs). We reasoned that we could uncover regulatory pathways with new roles in hepatocyte differentiation by identifying cellular processes that regulate HNF4A. We therefore performed a screen of 1120 small molecules with well-characterized mechanisms of action to detect those that affect the abundance of HNF4A in iPSC-derived hepatic progenitor cells. This approach uncovered several small molecules that depleted HNF4A. Of those, we chose to focus on an inhibitor of heat shock protein 90 beta (HSP90beta). We show that mutation of the gene encoding HSP90beta represses hepatocyte differentiation during the formation of hepatocytes from iPSCs. We reveal that HSP90beta, although dispensable for expression of HNF4A mRNA, directly interacts with HNF4A protein to regulate its half-life. Our results demonstrate that HSP90beta has an unappreciated role in controlling hepatic progenitor cell formation and highlight the efficiency of using small-molecule screens during the differentiation of iPSCs to reveal new molecular mechanisms that control hepatocyte formation. PMID- 28360132 TI - Dose-dependent transduction of Hedgehog relies on phosphorylation-based feedback between the G-protein-coupled receptor Smoothened and the kinase Fused. AB - Smoothened (SMO) is a G-protein-coupled receptor-related protein required for the transduction of Hedgehog (HH). The HH gradient leads to graded phosphorylation of SMO, mainly by the PKA and CKI kinases. How thresholds in HH morphogen regulate SMO to promote switch-like transcriptional responses is a central unsolved issue. Using the wing imaginal disc model in Drosophila, we identified new SMO phosphosites that enhance the effects of the PKA/CKI kinases on SMO accumulation, its localization at the plasma membrane and its activity. Surprisingly, phosphorylation at these sites is induced by the kinase Fused (FU), a known downstream effector of SMO. In turn, activation of SMO induces FU to act on its downstream targets. Overall, our data provide evidence for a SMO/FU positive regulatory loop nested within a multikinase phosphorylation cascade. We propose that this complex interplay amplifies signaling above a threshold that allows high HH signaling. PMID- 28360134 TI - Colloidally prepared La-doped BaSnO3 electrodes for efficient, photostable perovskite solar cells. AB - Perovskite solar cells (PSCs) exceeding a power conversion efficiency (PCE) of 20% have mainly been demonstrated by using mesoporous titanium dioxide (mp-TiO2) as an electron-transporting layer. However, TiO2 can reduce the stability of PSCs under illumination (including ultraviolet light). Lanthanum (La)-doped BaSnO3 (LBSO) perovskite would be an ideal replacement given its electron mobility and electronic structure, but LBSO cannot be synthesized as well-dispersible fine particles or crystallized below 500 degrees C. We report a superoxide colloidal solution route for preparing a LBSO electrode under very mild conditions (below 300 degrees C). The PSCs fabricated with LBSO and methylammonium lead iodide (MAPbI3) show a steady-state power conversion efficiency of 21.2%, versus 19.7% for a mp-TiO2 device. The LBSO-based PSCs could retain 93% of their initial performance after 1000 hours of full-Sun illumination. PMID- 28360133 TI - Numb regulates somatic cell lineage commitment during early gonadogenesis in mice. AB - During early gonadogenesis, proliferating cells in the coelomic epithelium (CE) give rise to most of the somatic cells in both XX and XY gonads. Previous dye labeling experiments showed that a single CE cell could give rise to additional CE cells and to both supporting and interstitial cell lineages, implying that cells in the CE domain are multipotent progenitors, and suggesting that an asymmetric division is involved in the acquisition of gonadal cell fates. We found that NUMB is asymmetrically localized in CE cells, suggesting that it might be involved. To test this hypothesis, we conditionally deleted Numb on a Numbl mutant background just prior to gonadogenesis. Mutant gonads showed a loss of cell polarity in the surface epithelial layers, large interior cell patches expressing the undifferentiated cell marker LHX9, and a loss of differentiated cells in somatic cell lineages. These results indicate that NUMB is necessary for establishing polarity in CE cells, and that asymmetric divisions resulting from CE polarity are required for commitment to differentiated somatic cell fates. Surprisingly, germ cells, which do not arise from the CE, were also affected in mutants, which may be a direct or indirect effect of loss of Numb. PMID- 28360128 TI - Circadian Rhythms and Sleep in Drosophila melanogaster. AB - The advantages of the model organism Drosophila melanogaster, including low genetic redundancy, functional simplicity, and the ability to conduct large-scale genetic screens, have been essential for understanding the molecular nature of circadian (~24 hr) rhythms, and continue to be valuable in discovering novel regulators of circadian rhythms and sleep. In this review, we discuss the current understanding of these interrelated biological processes in Drosophila and the wider implications of this research. Clock genes period and timeless were first discovered in large-scale Drosophila genetic screens developed in the 1970s. Feedback of period and timeless on their own transcription forms the core of the molecular clock, and accurately timed expression, localization, post transcriptional modification, and function of these genes is thought to be critical for maintaining the circadian cycle. Regulators, including several phosphatases and kinases, act on different steps of this feedback loop to ensure strong and accurately timed rhythms. Approximately 150 neurons in the fly brain that contain the core components of the molecular clock act together to translate this intracellular cycling into rhythmic behavior. We discuss how different groups of clock neurons serve different functions in allowing clocks to entrain to environmental cues, driving behavioral outputs at different times of day, and allowing flexible behavioral responses in different environmental conditions. The neuropeptide PDF provides an important signal thought to synchronize clock neurons, although the details of how PDF accomplishes this function are still being explored. Secreted signals from clock neurons also influence rhythms in other tissues. SLEEP is, in part, regulated by the circadian clock, which ensures appropriate timing of sleep, but the amount and quality of sleep are also determined by other mechanisms that ensure a homeostatic balance between sleep and wake. Flies have been useful for identifying a large set of genes, molecules, and neuroanatomic loci important for regulating sleep amount. Conserved aspects of sleep regulation in flies and mammals include wake-promoting roles for catecholamine neurotransmitters and involvement of hypothalamus-like regions, although other neuroanatomic regions implicated in sleep in flies have less clear parallels. Sleep is also subject to regulation by factors such as food availability, stress, and social environment. We are beginning to understand how the identified molecules and neurons interact with each other, and with the environment, to regulate sleep. Drosophila researchers can also take advantage of increasing mechanistic understanding of other behaviors, such as learning and memory, courtship, and aggression, to understand how sleep loss impacts these behaviors. Flies thus remain a valuable tool for both discovery of novel molecules and deep mechanistic understanding of sleep and circadian rhythms. PMID- 28360135 TI - Enhancement of Zika virus pathogenesis by preexisting antiflavivirus immunity. AB - Zika virus (ZIKV) is spreading rapidly into regions around the world where other flaviviruses, such as dengue virus (DENV) and West Nile virus (WNV), are endemic. Antibody-dependent enhancement has been implicated in more severe forms of flavivirus disease, but whether this also applies to ZIKV infection is unclear. Using convalescent plasma from DENV- and WNV-infected individuals, we found substantial enhancement of ZIKV infection in vitro that was mediated through immunoglobulin G engagement of Fcgamma receptors. Administration of DENV- or WNV convalescent plasma into ZIKV-susceptible mice resulted in increased morbidity including fever, viremia, and viral loads in spinal cord and testes-and increased mortality. Antibody-dependent enhancement may explain the severe disease manifestations associated with recent ZIKV outbreaks and highlights the need to exert great caution when designing flavivirus vaccines. PMID- 28360137 TI - The applied value of public investments in biomedical research. AB - Scientists and policy-makers have long argued that public investments in science have practical applications. Using data on patents linked to U.S. National Institutes of Health (NIH) grants over a 27-year period, we provide a large-scale accounting of linkages between public research investments and subsequent patenting. We find that about 10% of NIH grants generate a patent directly but 30% generate articles that are subsequently cited by patents. Although policy makers often focus on direct patenting by academic scientists, the bulk of the effect of NIH research on patenting appears to be indirect. We also find no systematic relationship between the "basic" versus "applied" research focus of a grant and its propensity to be cited by a patent. PMID- 28360136 TI - High-performance light-emitting diodes based on carbene-metal-amides. AB - Organic light-emitting diodes (OLEDs) promise highly efficient lighting and display technologies. We introduce a new class of linear donor-bridge-acceptor light-emitting molecules, which enable solution-processed OLEDs with near-100% internal quantum efficiency at high brightness. Key to this performance is their rapid and efficient utilization of triplet states. Using time-resolved spectroscopy, we establish that luminescence via triplets occurs within 350 nanoseconds at ambient temperature, after reverse intersystem crossing to singlets. We find that molecular geometries exist at which the singlet-triplet energy gap (exchange energy) is close to zero, so that rapid interconversion is possible. Calculations indicate that exchange energy is tuned by relative rotation of the donor and acceptor moieties about the bridge. Unlike other systems with low exchange energy, substantial oscillator strength is sustained at the singlet-triplet degeneracy point. PMID- 28360138 TI - Mathematical Modeling Links Pregnancy-Associated Changes and Breast Cancer Risk. AB - Recent debate has concentrated on the contribution of bad luck to cancer development. The tight correlation between the number of tissue-specific stem cell divisions and cancer risk of the same tissue suggests that bad luck has an important role to play in tumor development, but the full extent of this contribution remains an open question. Improved understanding of the interplay between extrinsic and intrinsic factors at the molecular level is one promising route to identifying the limits on extrinsic control of tumor initiation, which is highly relevant to cancer prevention. Here, we use a simple mathematical model to show that recent data on the variation in numbers of breast epithelial cells with progenitor features due to pregnancy are sufficient to explain the known protective effect of full-term pregnancy in early adulthood for estrogen receptor positive (ER+) breast cancer later in life. Our work provides a mechanism for this previously ill-understood effect and illuminates the complex influence of extrinsic factors at the molecular level in breast cancer. These findings represent an important contribution to the ongoing research into the role of bad luck in human tumorigenesis. Cancer Res; 77(11); 2800-9. (c)2017 AACR. PMID- 28360140 TI - New approaches to measurement and management for high integrity health systems. PMID- 28360139 TI - A Pyrrole-Imidazole Polyamide Is Active against Enzalutamide-Resistant Prostate Cancer. AB - The LREX' prostate cancer model is resistant to the antiandrogen enzalutamide via activation of an alternative nuclear hormone receptor, glucocorticoid receptor (GR), which has similar DNA-binding specificity to the androgen receptor (AR). Small molecules that target DNA to interfere with protein-DNA interactions may retain activity against enzalutamide-resistant prostate cancers where ligand binding domain antagonists are ineffective. We reported previously that a pyrrole imidazole (Py-Im) polyamide designed to bind the consensus androgen response element half-site has antitumor activity against hormone-sensitive prostate cancer. In enzalutamide-resistant LREX' cells, Py-Im polyamide interfered with both AR- and GR-driven gene expression, whereas enzalutamide interfered with only that of AR. Genomic analyses indicated immediate interference with the AR transcriptional pathway. Long-term treatment with Py-Im polyamide demonstrated a global decrease in RNA levels consistent with inhibition of transcription. The polyamide was active against two enzalutamide-resistant xenografts with minimal toxicity. Overall, our results identify Py-Im polyamide as a promising therapeutic strategy in enzalutamide-resistant prostate cancer. Cancer Res; 77(9); 2207-12. (c)2017 AACR. PMID- 28360141 TI - Sofosbuvir faces fresh patent challenge in Europe. PMID- 28360142 TI - Do Functional Movement Screen (FMS) composite scores predict subsequent injury? A systematic review with meta-analysis. AB - AIM: This paper aims to systematically review studies investigating the strength of association between FMS composite scores and subsequent risk of injury, taking into account both methodological quality and clinical and methodological diversity. DESIGN: Systematic review with meta-analysis. DATA SOURCES: A systematic search of electronic databases was conducted for the period between their inception and 3 March 2016 using PubMed, Medline, Google Scholar, Scopus, Academic Search Complete, AMED (Allied and Complementary Medicine Database), CINAHL (Cumulative Index to Nursing and Allied Health Literature), Health Source and SPORTDiscus. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Inclusion criteria: (1) English language, (2) observational prospective cohort design, (3) original and peer-reviewed data, (4) composite FMS score, used to define exposure and non exposure groups and (5) musculoskeletal injury, reported as the outcome. EXCLUSION CRITERIA: (1) data reported in conference abstracts or non-peer reviewed literature, including theses, and (2) studies employing cross-sectional or retrospective study designs. RESULTS: 24 studies were appraised using the Quality of Cohort Studies assessment tool. In male military personnel, there was 'strong' evidence that the strength of association between FMS composite score (cut-point <=14/21) and subsequent injury was 'small' (pooled risk ratio=1.47, 95% CI 1.22 to 1.77, p<0.0001, I2=57%). There was 'moderate' evidence to recommend against the use of FMS composite score as an injury prediction test in football (soccer). For other populations (including American football, college athletes, basketball, ice hockey, running, police and firefighters), the evidence was 'limited' or 'conflicting'. CONCLUSION: The strength of association between FMS composite scores and subsequent injury does not support its use as an injury prediction tool. TRIAL REGISTRATION NUMBER: PROSPERO registration number CRD42015025575. PMID- 28360144 TI - 'There is nothing more deceptive than an obvious fact': more evidence for the prescription of exercise during haemodialysis (intradialytic exercise) is still required. PMID- 28360143 TI - Return to play after hamstring injuries in football (soccer): a worldwide Delphi procedure regarding definition, medical criteria and decision-making. AB - There are three major questions about return to play (RTP) after hamstring injuries: How should RTP be defined? Which medical criteria should support the RTP decision? And who should make the RTP decision? The study aimed to provide a clear RTP definition and medical criteria for RTP and to clarify RTP consultation and responsibilities after hamstring injury. The study used the Delphi procedure. The results of a systematic review were used as a starting point for the Delphi procedure. Fifty-eight experts in the field of hamstring injury management selected by 28 FIFA Medical Centres of Excellence worldwide participated. Each Delphi round consisted of a questionnaire, an analysis and an anonymised feedback report. After four Delphi rounds, with more than 83% response for each round, consensus was achieved that RTP should be defined as 'the moment a player has received criteria-based medical clearance and is mentally ready for full availability for match selection and/or full training'. The experts reached consensus on the following criteria to support the RTP decision: medical staff clearance, absence of pain on palpation, absence of pain during strength and flexibility testing, absence of pain during/after functional testing, similar hamstring flexibility, performance on field testing, and psychological readiness. It was also agreed that RTP decisions should be based on shared decision-making, primarily via consultation with the athlete, sports physician, physiotherapist, fitness trainer and team coach. The consensus regarding aspects of RTP should provide clarity and facilitate the assessment of when RTP is appropriate after hamstring injury, so as to avoid or reduce the risk of injury recurrence because of a premature RTP. PMID- 28360145 TI - Preliminary evidence that high levels of nicotine on children's hands may contribute to overall tobacco smoke exposure. AB - BACKGROUND: Dust and surfaces are important sources of lead and pesticide exposure in young children. The purpose of this pilot study was to investigate if third-hand smoke (THS) pollutants accumulate on the hands of children who live in environments where tobacco is used and if hand nicotine levels are associated with second-hand smoke (SHS), as measured by salivary cotinine. METHODS: Participants were parents and children (n=25; age mean (SD)=5.4 (5.3) years) presenting to the emergency department with a potentially SHS-related illness. A convenience sample of participants were recruited at baseline from an ongoing two group, randomised controlled trial of a SHS reduction and tobacco cessation intervention. Parents were current smokers; thus, all children were at risk of SHS and THS exposure to varying extents. Primary outcome measures, which were assessed in child participants only, were hand nicotine and salivary cotinine. Parents reported sociodemographics and smoking patterns; children's medical records were abstracted for chief complaint, medical history and discharge diagnosis. RESULTS: All children had detectable hand nicotine (range=18.3-690.9 ng/wipe). All but one had detectable cotinine (range=1.2-28.8 ng/mL). Multiple linear regression results showed a significant positive association between hand nicotine and cotinine (p=0.009; semipartial r2=0.24), independent of child age. DISCUSSION: The higher-than-expected nicotine levels and significant association with cotinine indicate that THS may play a role in the overall exposure of young children to tobacco smoke toxicants and that hand wipes could be a useful marker of overall tobacco smoke pollution and a proxy for exposure. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT02531594. PMID- 28360150 TI - Public health interventions are highly cost saving, review finds. PMID- 28360146 TI - Resistin induces multidrug resistance in myeloma by inhibiting cell death and upregulating ABC transporter expression. AB - Despite advances in therapy, multiple myeloma remains incurable, with a high frequency of relapse. This suggests the need to identify additional factors that contribute to drug resistance. Our previous studies revealed that bone marrow adipocytes promote resistance to chemotherapy in myeloma through adipocyte secreted adipokines, but the mechanism underlying this effect and the specific adipokines involved are not well understood. We proposed to determine the role of resistin, an adipokine that is secreted by adipocytes, in chemotherapy resistance in myeloma. We found that resistin abrogated chemotherapy-induced apoptosis in established myeloma cell lines and primary myeloma samples. Resistin inhibited chemotherapy-induced caspase cleavage through the NF-kappaB and PI3K/Akt pathways. Resistin also increased the expression and drug efflux function of ATP binding cassette (ABC) transporters in myeloma cells through decreasing the expression of both DNA methyltransferases DNMT1 and DNMT3a and the methylation levels of ABC gene promoters. In vivo studies further demonstrated the protective effect of resistin in chemotherapy-induced apoptosis. Our study thus reveals a new biological function of resistin in the pathogenesis of myeloma, with the implication that targeting resistin could be a potential strategy to prevent or overcome multidrug resistance in myeloma. PMID- 28360148 TI - Sphingosine kinase 1 participates in the activation, proliferation and survival of chronic lymphocytic leukemia cells. PMID- 28360151 TI - Trump's order on climate policy threatens public health, say US doctors. PMID- 28360147 TI - A three-dimensional ex vivo tri-culture model mimics cell-cell interactions between acute myeloid leukemia and the vascular niche. AB - Ex vivo studies of human disease, such as acute myeloid leukemia, are generally limited to the analysis of two-dimensional cultures which often misinterpret the effectiveness of chemotherapeutics and other treatments. Here we show that matrix metalloproteinase-sensitive hydrogels prepared from poly(ethylene glycol) and heparin functionalized with adhesion ligands and pro-angiogenic factors can be instrumental to produce robust three-dimensional culture models, allowing for the analysis of acute myeloid leukemia development and response to treatment. We evaluated the growth of four leukemia cell lines, KG1a, MOLM13, MV4-11 and OCI AML3, as well as samples from patients with acute myeloid leukemia. Furthermore, endothelial cells and mesenchymal stromal cells were co-seeded to mimic the vascular niche for acute myeloid leukemia cells. Greater drug resistance to daunorubicin and cytarabine was demonstrated in three-dimensional cultures and in vascular co-cultures when compared with two-dimensional suspension cultures, opening the way for drug combination studies. Application of the C-X-C chemokine receptor type 4 (CXCR4) inhibitor, AMD3100, induced mobilization of the acute myeloid leukemia cells from the vascular networks. These findings indicate that the three-dimensional tri-culture model provides a specialized platform for the investigation of cell-cell interactions, addressing a key challenge of current testing models. This ex vivo system allows for personalized analysis of the responses of patients' cells, providing new insights into the development of acute myeloid leukemia and therapies for this disease. PMID- 28360149 TI - NOTCH1 mutation, TP53 alteration and myeloid antigen expression predict outcome heterogeneity in children with first relapse of T-cell acute lymphoblastic leukemia. PMID- 28360152 TI - Complete Genome Sequence of Carbapenem-Resistant Klebsiella pneumoniae Strain 1756, Isolated from a Pus Specimen. AB - Carbapenem-resistant Klebsiella pneumoniae strain 1756 was isolated from a pus specimen from a Taiwanese patient. Here, the complete genome sequence of strain 1756 is presented. PMID- 28360153 TI - Whole-Genome Sequence and Fosfomycin Resistance of Bacillus sp. Strain G3(2015) Isolated from Seawater off the Coast of Malaysia. AB - Bacillus sp. is a Gram-positive bacterium that is commonly found in seawater. In this study, the genome of marine Bacillus sp. strain G3(2015) was sequenced using MiSeq. The fosfomycin resistant gene fosB was identified upon bacterial genome annotation. PMID- 28360154 TI - Draft Genome Sequences of 12 Feline Bartonella henselae Isolates. AB - Bartonella henselae is the main causative agent of cat scratch disease. In this report, we present the draft genome sequences of 12 strains of Bartonella henselae originating from the United States, Denmark, and France. These strains were isolated from cats and belonged to either 16S rRNA genotype I or 16S rRNA genotype II. PMID- 28360155 TI - Draft Genome Sequence of Bacillus thuringiensis INTA Fr7-4. AB - We report here the complete annotated 6,035,547-bp draft genome sequence of Bacillus thuringiensis INTA Fr7-4. This strain contains three cry8 and two vip1 and vip2 insecticidal toxin genes. PMID- 28360156 TI - Draft Genome Sequences of Tersicoccus phoenicis DSM 30849T, Isolated from a Cleanroom for Spacecraft Assembly, and Tersicoccus sp. Strain Bi-70, Isolated from a Freshwater Lake. AB - Here, we report the draft genome sequences of Tersicoccus phoenicis DSM 30849T, isolated from a spacecraft assembly cleanroom at the National Aeronautics and Space Administration (NASA), and Tersicoccus sp. strain Bi-70, isolated from Lake Biwa, the largest lake in Japan. These genome sequences facilitate our understanding of the adaptation of these closely related strains to different habitats. PMID- 28360157 TI - Draft Genome Sequence of Streptococcus caviae Strain Cavy grass 6T, Isolated from Domesticated Guinea Pig Fecal Samples. AB - Streptococcus caviae strain Cavy grass 6T, isolated from fecal samples of pet guinea pigs, can metabolize a range of plant mono- and disaccharides, as well as polymeric carbohydrates. Here, we report the draft genome sequence of this strain, which comprises 2.11 Mb. PMID- 28360158 TI - Draft Genome Sequence of Corynebacterium pseudotuberculosis Strain PA05 Isolated from an Ovine Host in Para State, Brazil. AB - We report here the draft genome sequence of Corynebacterium pseudotuberculosis PA05, isolated from an ovine host in Para State, Brazil. C. pseudotuberculosis is an etiological agent of diseases with veterinary and medical importance. The genome contains 2,435,137 bp, a G+C content of 52.2%, 2,295 coding sequences, five pseudogenes, 53 tRNAs, and six rRNAs. PMID- 28360159 TI - Draft Genome Sequence of Corynebacterium pseudotuberculosis Strain PA06 Isolated from a Subauricular Abscess in an Ovine Host. AB - We report here the draft genome sequence of Corynebacterium pseudotuberculosis PA06, isolated from a subauricular abscess in an ovine host. C. pseudotuberculosis is a worldwide pathogen of small and large ruminants. The genome comprises 2,320,074 bp, with a G+C content of 52.2%, 2,195 coding sequences, 48 tRNAs, and three rRNAs. PMID- 28360160 TI - First Complete Genome Sequence of Corynebacterium riegelii. AB - Here, we report the first complete genome sequence of Corynebacterium riegelii strain PUDD_83A45, isolated from the urine of a patient with urinary tract infection. The genome measured 2.56 Mb and contained no plasmid. PMID- 28360162 TI - Draft Genome Sequence of Pseudomonas putida Strain GM4FR, an Endophytic Bacterium Isolated from Festuca rubra L. AB - Pseudomonas putida GM4FR is an endophytic bacterium isolated from aerial plant tissues of Festuca rubra L. Functional annotation of the draft genome (7.1 Mb) revealed 6,272 predicted protein-encoding genes. The genome provides insights into the biocontrol and plant growth-promoting potential of P. putida GM4FR. PMID- 28360161 TI - Draft Genome Sequence of Bacillus pumilus Strain GM3FR, an Endophyte Isolated from Aerial Plant Tissues of Festuca rubra L. AB - Here, we report the draft genome sequence of Bacillus pumilus GM3FR, an endophytic bacterium isolated from aerial plant tissues of Festuca rubra L. The draft genome consists of 3.5 Mb and harbors 3,551 predicted protein-encoding genes. The genome provides insights into the biocontrol potential of B. pumilus GM3FR. PMID- 28360163 TI - Complete Genome Sequence of Staphylococcus aureus Strain Wood 46. AB - Here, we report the first complete genome sequence of the Staphylococcus aureus strain Wood 46. Wood 46 has played an important role in understanding the virulence and pathogenesis of S. aureus infections. This report will assist efforts in vaccine development against methicillin-resistant S. aureus (MRSA) infections. PMID- 28360164 TI - Draft Genome Sequence of Caenibacillus caldisaponilyticus B157T, a Thermophilic and Phospholipase-Producing Bacterium Isolated from Acidulocompost. AB - Caenibacillus caldisaponilyticus B157T (= NBRC 111400T = DSM 101100T), in the family Sporolactobacillaceae, was isolated from acidulocompost as a thermophilic and phospholipid-degrading bacterium. Here, we report the 3.36-Mb draft genome sequence, with a G+C content of 51.8%, to provide the genetic information coding for phospholipases. PMID- 28360165 TI - Complete Genome Sequence of Lactobacillus fermentum MTCC 25067 (Formerly TDS030603), a Viscous Exopolysaccharide-Producing Strain Isolated from Indian Fermented Milk. AB - Lactobacillus fermentum MTCC 25067 (formerly TDS030603) is capable of producing a highly viscous slime exopolysaccharide. We report here the complete genome sequence of the strain, which was deciphered by using PacBio single-molecule real time sequencing technology. PMID- 28360166 TI - Draft Genome Sequences of 14 Staphylococcus aureus Sequence Type 5 Isolates from California, USA. AB - Staphylococcus aureus is part of the human epithelial microbiota; however, it is also a pathogen. The acquisition of mobile genetic elements plays a role in the virulence of S. aureus isolates and contributes to treatment failures. This report details the draft genome sequences of 14 clinical S. aureus isolates. PMID- 28360167 TI - Complete Genome Sequences of Two Staphylococcus aureus Sequence Type 5 Isolates from California, USA. AB - Staphylococcus aureus causes a variety of human diseases ranging in severity. The pathogenicity of S. aureus can be partially attributed to the acquisition of mobile genetic elements. In this report, we provide two complete genome sequences from human clinical S. aureus isolates. PMID- 28360168 TI - Draft Genome Sequence of Streptomyces specialis Type Strain GW41-1564 (DSM 41924). AB - Here, we report the draft genome sequence of Streptomyces specialis type strain GW41-1564, which was isolated from soil. This 5.87-Mb genome exhibits a high G+C content of 72.72% and contains 5,486 protein-coding genes. PMID- 28360169 TI - Complete Genome Sequences of Two Genotype A2 Small Ruminant Lentiviruses Isolated from Infected U.S. Sheep. AB - Two distinct subgroups of genotype A2 small ruminant lentiviruses (SRLVs) have been identified in the United States that infect sheep with specific host transmembrane protein 154 (TMEM154) diplotypes. Here, we report the first two complete genome sequences of SRLV strains infecting U.S. sheep belonging to genotype A2, subgroups 1 and 2. PMID- 28360170 TI - Draft Genome Sequence of Saccharomyces cerevisiae Barra Grande (BG-1), a Brazilian Industrial Bioethanol-Producing Strain. AB - Here, we present the draft genome sequence of Saccharomyces cerevisiae BG-1, a Brazilian industrial strain widely used for bioethanol production from sugarcane. The 11.7-Mb genome sequence consists of 216 scaffolds and harbors 5,607 predicted protein-coding genes. PMID- 28360171 TI - Draft Genome Sequence of the Root-Colonizing Fungus Trichoderma harzianum B97. AB - Trichoderma harzianum is one of the most beneficial microorganisms applied on diverse crops against biotic and abiotic stresses and acts also as a plant growth promoting fungus. Here, we report the genome of T. harzianum B97, originating from a French agricultural soil and used as a biofertilizer that can tolerate abiotic stresses. PMID- 28360172 TI - Complete Genome Sequences of Two Escherichia coli Phages, vB_EcoM_ ESCO5 and vB_EcoM_ESCO13, Which Are Related to phAPEC8. AB - We report here the complete genome sequences of two Myoviridae phages that infect various avian-pathogenic Escherichia coli strains and that are closely related to phage phAPEC8. PMID- 28360173 TI - Genome Sequence of Escherichia coli Tailed Phage Utah. AB - Escherichia coli bacteriophage Utah is a member of the chi-like tailed phage cluster in the Siphoviridae family. We report here the complete 59,024-bp sequence of the genome of phage Utah. PMID- 28360175 TI - Draft Genome Sequence of the Pelagic Photoferrotroph Chlorobium phaeoferrooxidans. AB - Here, we report the draft genome sequence of Chlorobium phaeoferrooxidans, a photoferrotrophic member of the genus Chlorobium in the phylum Chlorobi This genome sequence provides insight into the metabolic capacity that underpins photoferrotrophy within low-light-adapted pelagic Chlorobi. PMID- 28360174 TI - Complete Genome Sequences of Isolates of Enterococcus faecium Sequence Type 117, a Globally Disseminated Multidrug-Resistant Clone. AB - The emergence of nosocomial infections by multidrug-resistant sequence type 117 (ST117) Enterococcus faecium has been reported in several European countries. ST117 has been detected in Spanish hospitals as one of the main causes of bloodstream infections. We analyzed genome variations of ST117 strains isolated in Madrid and describe the first ST117 closed genome sequences. PMID- 28360176 TI - Complete Genome Sequence of a Novel Human Betapapillomavirus Isolated from a Skin Sample. AB - We report the genetic characterization of a new papillomavirus (HPV_MTS1) isolated and fully cloned from a skin swab. The L1 open reading frame of HPV_MTS1 was 85% identical to its closest human papillomavirus (HPV) type 80, which belongs to the species beta-2 of the genus Betapapillomavirus, hence qualifying it as a new HPV type. PMID- 28360177 TI - Draft Genome Sequences of 24 Lactococcus lactis Strains. AB - The lactic acid bacterium Lactococcus lactis is widely used for the production of fermented dairy products. Here, we present the draft genome sequences of 24 L. lactis strains isolated from different environments and geographic locations. PMID- 28360178 TI - Draft Genome Sequences of Pseudomonas moraviensis UCD-KL30, Vibrio ostreicida UCD KL16, Colwellia sp. Strain UCD-KL20, Shewanella sp. Strain UCD-KL12, and Shewanella sp. Strain UCD-KL21, Isolated from Seagrass. AB - Here, we present the draft genome sequences for five bacterial strains. These strains were all isolated from seagrass (Zostera marina) collected from Bodega Bay, CA, as a part of an undergraduate research project focused on seagrass associated microbes. PMID- 28360179 TI - Whole-Genome Sequence of Pseudomonas fluorescens EK007-RG4, a Promising Biocontrol Agent against a Broad Range of Bacteria, Including the Fire Blight Bacterium Erwinia amylovora. AB - Here, we report the first draft whole-genome sequence of Pseudomonas fluorescens strain EK007-RG4, which was isolated from the phylloplane of a pear tree. P. fluorescens EK007-RG4 displays strong antagonism against Erwinia amylovora, the causal agent for fire blight disease, in addition to several other pathogenic and non-pathogenic bacteria. PMID- 28360180 TI - First Whole-Genome Sequence of a Haemophilus influenzae Type e Strain Isolated from a Patient with Invasive Disease in Italy. AB - In the present era of conjugate vaccines against Haemophilus influenzae type b, non-vaccine-preventable strains are of concern. Here, we report the first whole genome sequence of an invasive H. influenzae type e strain. This genomic information will enable further investigations on encapsulated non-type b H. influenzae strains. PMID- 28360181 TI - Draft Genome Sequences of Three Cellulolytic Bacillus licheniformis Strains Isolated from Imperial Geyser, Amphitheater Springs, and Whiterock Springs inside Yellowstone National Park. AB - Novel cellulolytic microorganisms are becoming more important for rapidly growing biofuel industries. This paper reports the draft genome sequences of Bacillus licheniformis strains YNP2-TSU, YNP3-TSU, and YNP5-TSU. These cellulolytic isolates were collected from several hydrothermal features inside Yellowstone National Park. PMID- 28360183 TI - NHS will publish national list of "low value" drugs to curb GPs' prescribing costs. PMID- 28360182 TI - Simultaneous mapping of active DNA demethylation and sister chromatid exchange in single cells. AB - To understand mammalian active DNA demethylation, various methods have been developed to map the genomic distribution of the demethylation intermediates 5 formylcysotine (5fC) and 5-carboxylcytosine (5caC). However, the majority of these methods requires a large number of cells to begin with. In this study, we describe low-input methylase-assisted bisulfite sequencing (liMAB-seq ) and single-cell MAB-seq (scMAB-seq), capable of profiling 5fC and 5caC at genome scale using ~100 cells and single cells, respectively. liMAB-seq analysis of preimplantation embryos reveals the oxidation of 5mC to 5fC/5caC and the positive correlation between chromatin accessibility and processivity of ten-eleven translocation (TET) enzymes. scMAB-seq captures the cell-to-cell heterogeneity of 5fC and 5caC and reveals the strand-biased distribution of 5fC and 5caC. scMAB seq also allows the simultaneous high-resolution mapping of sister chromatid exchange (SCE), facilitating the study of this type of genomic rearrangement. Therefore, our study not only establishes new methods for the genomic mapping of active DNA demethylation using limited numbers of cells or single cells but also demonstrates the utilities of the methods in different biological contexts. PMID- 28360184 TI - Myeloid-derived suppressor cells and T regulatory cells in tumors: unraveling the dark side of the force. AB - Important conceptual advances in tumor immunology over the last years have shifted the paradigm from focusing on the malignant cell to the importance of host immune components in the design of successful immunotherapies. The immune system, through sophisticated innate and adaptive immune surveillance mechanisms, inhibits the growth and establishment of tumors. However, despite immune surveillance, tumors still escape and grow, mainly as a result of endowed tumor induced immunosuppressive circuits. Regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs) are the major components of these regulatory networks that facilitate tumor immune escape and significantly compromise the efficacy of current immunotherapies. A better understanding of the induction, function, and expansion of these powerful regulatory compartments represents a major challenge on the clinical benefit of current treatments and may foster the design of novel cancer immunotherapies. PMID- 28360185 TI - Neutrophil, quo vadis? AB - Neutrophils were traditionally considered to be a homogeneous population of terminally differentiated cells with very defined roles in inflammation and fighting infections. However, recent advances in neutrophil research challenge this limited view and demonstrate that neutrophils are highly versatile, play different roles in various pathologic scenarios, and are heterogeneous. With this, it is becoming clear that one term-"neutrophil"-is too general, and more precise nomenclature is urgently required. In this mini review, we discuss the knowns and unknowns in neutrophil terminology and highlight the critical questions that should be addressed for the establishment of clear neutrophil nomenclature. PMID- 28360186 TI - Family Chores: TRAF Family Proteins Help Recycle Cellular Rubbish by Regulating Autophagy Dynamics. PMID- 28360188 TI - Rapid detection of cfiA metallo-beta-lactamase-producing Bacteroides fragilis by the combination of MALDI-TOF MS and CarbaNP. AB - AIMS: Carbapenem resistance in Bacteroides fragilis is emerging and is mainly attributed to insertion sequence (IS)-mediated activation of the carbapenemase gene cfiA. We investigated the use of matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS) and the CarbaNP assay for the rapid identification of these strains. METHODS: This study used the Bruker MALDI Biotype system and the mass spectra models generated by 20 B. fragilis reference strains (10 cfiA-positive and 10 cfiA-negative) in the ClinProTools software to identify 404 B. fragilis (71 cfiA-positive and 333 cfiA-negative) clinical isolates. The ability of the CarbaNP assay to detect IS-mediated activation of the cfiA gene was assessed and the results obtained by molecular analysis were used as reference methods. RESULTS: The support vector machine model generated by ClinProTools was found to be the most reliable algorithm for differentiation of cfiA-positive and cfiA-negative B. fragilis subgroups. Using the direct transfer method, all but one cfiA-negative isolates were correctly identified to the two subgroups by the model. The correct identification of the cfiA-negative isolate was obtained upon retesting by the extraction method. Of the 81 cfiA-positive isolates, PCR and sequencing showed that 30 had an IS element providing the promoter for activation of cfiA. With regard to the presence of the IS element, the CarbaNP test in the cfiA upstream region had 100% sensitivity, 80.4% specificity, 75.0% positive predictive value and 100% negative predictive value. CONCLUSIONS: The combination of MALDI-TOF MS and the CarbaNP assay can be applied in diagnostic clinical laboratory for rapid identification of B. fragilis with IS element-activated cfiA gene. PMID- 28360187 TI - Growth throughout childhood of children born growth restricted. AB - OBJECTIVE: Many studies that examine growth in growth-restricted children at birth do not discriminate between fetal growth restriction (FGR) and small for gestational age (SGA). These terms however are not synonymous. In SGA, stunting and increased weight gain have been reported. We do not know if this holds true for FGR. Our aim was to study postnatal growth until age 12.5 years in a cohort of children born FGR due to early onset placental insufficiency, and its relation to FGR severity. DESIGN: Prospective cohort study, follow-up of an antenatal randomised controlled trial in two tertiary centres. PATIENTS: Children aged 12.5 years born after FGR, with mothers who had severe early onset hypertensive pregnancy disorders (N=96). MAIN OUTCOME MEASURES: Anthropometry at age 12.5 years in SD scores (SDS). RESULTS: Mean height SDS (SD) corrected for target height was -0.09 (0.94), mean body mass index (BMI) SDS was 0.00 (1.16) and mean head circumference SDS was -0.37 (1.11). Catch-up growth was at fastest rate between term age and 3 months and similar for height (0.55 SDS/months) and weight (0.49 SDS/months). Neither FGR severity nor gestational age was related to height and BMI at age 12.5 years. CONCLUSIONS: Children born growth restricted due to early onset placental insufficiency have height and BMI scores comparable to their age-matched peers at age 12.5 years. FGR severity was not related to height and BMI at age 12.5 years. These reassuring results differ from most studies that examine SGA children. PMID- 28360189 TI - Biobanking strategy and sample preprocessing for integrative research in monoclonal gammopathies. AB - AIMS: Some types of monoclonal gammopathies are typified by a very limited availability of aberrant cells. Modern research use high throughput technologies and an integrated approach for detailed characterisation of abnormal cells. This strategy requires relatively high amounts of starting material which cannot be obtained from every diagnosis without causing inconvenience to the patient. The aim of this methodological paper is to reflect our long experience with laboratory work and describe the best protocols for sample collection, sorting and further preprocessing in terms of the available number of cells and intended downstream application in monoclonal gammopathies research. Potential pitfalls are also discussed. METHODS: Comparison and optimisation of freezing and sorting protocols for plasma cells in monoclonal gammopathies, followed by testing of various nucleic acid isolation and amplification techniques to establish a guideline for sample processing in haemato-oncology research. RESULTS: We show the average numbers of aberrant cells that can be obtained from various monoclonal gammopathies (monoclonal gammopathy of undetermined significance/light chain amyloidosis/multiple myeloma (MM)/MM circulating plasma cells/ minimal residual disease MM-10 123/22 846/305 501/68 641/4000 aberrant plasma cells of 48/30/10/16/37*106 bone marrow mononuclear cells) and the expected yield of nucleic acids provided from multiple isolation kits (DNA/RNA yield from 1 to 200*103 cells was 2.14-427/0.12-123 ng). CONCLUSIONS: Tested kits for parallel isolation deliver outputs comparable with kits specialised for just one type of molecule. We also present our positive experience with the whole genome amplification method, which can serve as a very powerful tool to gain complex information from a very small cell population. PMID- 28360191 TI - miR-10b is a prognostic marker in clear cell renal cell carcinoma. AB - AIMS: Clear cell renal cell carcinoma (ccRCC) is the most common adult kidney cancer. It is an aggressive tumour with unpredictable outcome. The currently used clinical parameters are not always accurate for predicting disease behaviour. miR 10b is dysregulated in different malignancies including RCC. METHODS: We assessed the clinical utility of miR-10b as a prognostic marker in 250 patients with primary ccRCC. We examined the correlation between miR-10b and clinicopathological parameters. We compared miR-10b expression among different RCC subtypes and normal kidney tissue. RESULTS: We observed a stepwise decrease of miR-10b expression from normal kidney to primary ccRCC and a further decrease from primary to metastatic RCC. miR-10b expression was significantly lower in stages III/IV compared with stages I/II (p=0.038). Using a binary cut-off, miR 10b-positive patients had significantly longer disease-free survival (HR=0.47, CI 0.28 to 0.79, p=0.004). In the subgroup of patients with tumour size >4 cm, higher miR-10b expression was associated with significant longer disease-free and overall survival (p=0.001 and p=0.036, respectively). miR-10b was significantly downregulated in ccRCC compared with normal kidney (p<0.0001), and oncocytoma (p=0.031). It was also downregulated in chromophobe RCC. In addition, we identified a number of miR-10b-predicted targets and pathways that are involved in tumourigenesis. CONCLUSIONS: Our data point to miR-10b as a promising prognostic marker in ccRCC with potential therapeutic applications. PMID- 28360192 TI - Exploring thoughts of suicide. PMID- 28360190 TI - Release of urinary extracellular vesicles in prostate cancer is associated with altered urinary N-glycosylation profile. AB - AIM: Nowadays, extracellular vesicles are of great interest in prostate cancer (PCa) research. Asparagine (N)-linked glycosylation could play a significant role in the pathological mechanism of these vesicles. We investigated if prostatic protein N-glycosylation profiles were related to urinary vesicle-associated prostate-specific antigen (PSA) extractability and if this parameter showed diagnostic potential for PCa. METHODS: Urinary extracellular vesicles were visualised using transmission electron microscopy. Urinary extracellular vesicles extraction by means of n-butanol allowed determination of urinary vesicle associated PSA extractability. Diagnostic value was assessed between benign prostate hyperplasia (BPH; n=122) and patients with PCa (n=85). Additionally, correlation with urine N-glycosylation was assessed. RESULTS: Urinary extracellular vesicles with a diameter of approximately 100 nm were more abundantly present in urine of patients with PCa versus patients with BPH resulting in a higher vesicle-associated PSA extraction ratio (p<0.001). Next, vesicle-associated PSA extraction ratio was correlated to biantennary core fucosylation (p=0.003). Finally, vesicle-associated PSA extraction ratio proved beneficial in PCa diagnosis, next to serum PSA and the urinary glycosylation marker (p=0.021). CONCLUSIONS: The urinary vesicle-associated PSA extraction ratio is increased in PCa which is a direct result of the abundant presence of extracellular vesicles in urine of patients with PCa. The urinary vesicle associated PSA extraction ratio was associated with changes in N-glycoforms and showed diagnostic potential. Further research is warranted to unravel the pathological link between N-glycosylation and extracellular vesicles in cancer, as well as to assess the prognostic value of this biomarker. PMID- 28360193 TI - A role for galectin-3 in the development of early molecular alterations in short term aortic stenosis. AB - Aortic stenosis (AS) is characterized by pressure overload and causes left ventricular (LV) fibrosis and inflammation, two mechanisms that eventually lead to cardiac dysfunction. Galectin-3 (Gal-3), a beta-galactoside-binding lectin, promotes cardiac remodelling. In the present study, we investigated the role of Gal-3 in LV remodelling in patients with AS and the effects of Gal-3 blockade in rats subjected to short-term (6-week) supravalvular aortic banding (AS group). Myocardial biopsies were obtained from 25 patients with severe AS referred for aortic valve replacement and from necropsies of 11 cardiovascular disease-free control individuals. Gal-3 was up-regulated in myocardial biopsies from AS patients compared with controls. Gal-3 directly correlated with parameters assessing myocardial fibrosis and inflammation in AS patients. Normotensive AS animals presented decreased LV diastolic diameter compared with controls. At the histological level, AS rats exhibited a slight increase in LV cross-sectional area and LV wall thickness, and augmented cardiomyocyte width and cross-sectional area. AS animals presented enhanced cardiac Gal-3 expression, which paralleled higher myocardial fibrosis and inflammation. Cardiac Gal-3 was associated with fibrosis and inflammatory markers. Gal-3 pharmacological inhibition prevented the increase in cardiac Gal-3 and normalized histological and molecular alterations in AS rats. In short-term AS, the increase in myocardial Gal-3 expression was associated with cardiac fibrosis and inflammation, alterations that were prevented by Gal-3 blockade. These data suggest that Gal-3 inhibition could be a novel therapeutic approach in the prevention of AS-associated early pathological cardiac remodelling. PMID- 28360194 TI - Neuronal nitric oxide synthase-derived hydrogen peroxide effect in grafts used in human coronary bypass surgery. AB - Recently, H2O2 has been identified as the endothelium-dependent hyperpolarizing factor (EDHF), which mediates flow-induced dilation in human coronary arteries. Neuronal nitric oxide synthase (nNOS) is expressed in the cardiovascular system and, besides NO, generates H2O2 The role of nNOS-derived H2O2 in human vessels is so far unknown. The present study was aimed at investigating the relevance of nNOS/H2O2 signaling in the human internal mammary artery (IMA) and saphenous vein (SV), the major conduits used in coronary artery bypass grafting. In the IMA, but not in the SV, ACh (acetylcholine)-induced vasodilatation was decreased by selective nNOS inhibition with TRIM or Inhibitor 1, and by catalase, which specifically decomposes H2O2 Superoxide dismutase (SOD), which generates H2O2 from superoxide, decreased the vasodilator effect of ACh on SV. In the IMA, SOD diminished phenylephrine-induced contraction in endothelium-containing, but not in endothelium-denuded vessels. Importantly, while exogenous H2O2 produced vasodilatation in IMA, it constricted SV. ACh increased H2O2 production in both sets of vessels. In the IMA, the increase in H2O2 was inhibited by catalase and nNOS blockade. In SV, H2O2 production was abolished by catalase and reduced by nNOS inhibition. Immunofluorescence experiments showed the presence of nNOS in the vascular endothelium and smooth muscle cells of both the IMA and SV. Together, our results clearly show that H2O2 induced endothelium-dependent vascular relaxation in the IMA, whereas, in the SV, H2O2 was a vasoconstrictor. Thus, H2O2 produced in the coronary circulation may contribute to the susceptibility to accelerated atherosclerosis and progressive failure of the SV used as autogenous graft in coronary bypass surgery. PMID- 28360195 TI - G1/S phase progression is regulated by PLK1 degradation through the CDK1/betaTrCP axis. AB - Polo-like kinase 1 (PLK1) is a serine/threonine kinase involved in several stages of the cell cycle, including the entry and exit from mitosis, and cytokinesis. Furthermore, it has an essential role in the regulation of DNA replication. Together with cyclin A, PLK1 also promotes CDH1 phosphorylation to trigger its ubiquitination and degradation, allowing cell cycle progression. The PLK1 levels in different type of tumors are very high compared to normal tissues, which is consistent with its role in promoting proliferation. Therefore, several PLK1 inhibitors have been developed and tested for the treatment of cancer. Here, we further analyzed PLK1 degradation and found that cytoplasmic PLK1 is ubiquitinated and subsequently degraded by the SCFbetaTrCP/proteasome. This procedure is triggered when heat shock protein (HSP) 90 is inhibited with geldanamycin, which results in misfolding of PLK1. We also identified CDK1 as the major kinase involved in this degradation. Our work shows for the first time that HSP90 inhibition arrests cell cycle progression at the G1/S transition. This novel mechanism inhibits CDH1 degradation through CDK1-dependent PLK1 destruction by the SCFbetaTrCP/proteasome. In these conditions, CDH1 substrates do not accumulate and cell cycle arrests, providing a novel pathway for regulation of the cell cycle at the G1-to-S boundary.-Giraldez, S., Galindo-Moreno, M., Limon Mortes, M. C., Rivas, A. C., Herrero-Ruiz, J., Mora-Santos, M., Saez, C., Japon, M. A., Tortolero, M., Romero, F. G1/S phase progression is regulated by PLK1 degradation through the CDK1/betaTrCP axis. PMID- 28360197 TI - Donor Quality in the Eye of the Beholder: Interactions between Nonimmunologic Recipient and Donor Factors as Determinants of Graft Survival. PMID- 28360196 TI - Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4. AB - The chemokine receptor, CXC chemokine receptor 4 (CXCR4), is selective for CXC chemokine ligand 12 (CXCL12), is broadly expressed in blood and tissue cells, and is essential during embryogenesis and hematopoiesis. CXCL14 is a homeostatic chemokine with unknown receptor selectivity and preferential expression in peripheral tissues. Here, we demonstrate that CXCL14 synergized with CXCL12 in the induction of chemokine responses in primary human lymphoid cells and cell lines that express CXCR4. Combining subactive concentrations of CXCL12 with 100 300 nM CXCL14 resulted in chemotaxis responses that exceeded maximal responses that were obtained with CXCL12 alone. CXCL14 did not activate CXCR4-expressing cells (i.e., failed to trigger chemotaxis and Ca2+ mobilization, as well as signaling via ERK1/2 and the small GTPase Rac1); however, CXCL14 bound to CXCR4 with high affinity, induced redistribution of cell-surface CXCR4, and enhanced HIV-1 infection by >3-fold. We postulate that CXCL14 is a positive allosteric modulator of CXCR4 that enhances the potency of CXCR4 ligands. Our findings provide new insights that will inform the development of novel therapeutics that target CXCR4 in a range of diseases, including cancer, autoimmunity, and HIV. Collins, P. J., McCully, M. L., Martinez-Munoz, L., Santiago, C., Wheeldon, J., Caucheteux, S., Thelen, S., Cecchinato, V., Laufer, J. M., Purvanov, V., Monneau, Y. R., Lortat-Jacob, H., Legler, D. F., Uguccioni, M., Thelen, M., Piguet, V., Mellado, M., Moser, B. Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4. PMID- 28360199 TI - Y chromosome's roles in sex differences in disease. PMID- 28360198 TI - Donor-Recipient Weight and Sex Mismatch and the Risk of Graft Loss in Renal Transplantation. AB - BACKGROUND AND OBJECTIVES: Relatively smaller kidney donor to recipient size is proposed to result in higher graft loss due to nephron underdosing and hyperfiltration injury, but the potentially additive effect of sex and weight mismatch has not been explored in detail. The purpose of this study was to determine if concurrent donor and recipient absolute weight and sex mismatch was associated with graft loss in a cohort of deceased donor kidney transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The association of kidney donor and recipient absolute weight and sex difference with death-censored graft loss was explored using a cohort of United States deceased donor recipients between 2000 and 2014 through the Scientific Registry of Transplants Recipients. Donor-recipient sex pairings (male donor-male recipient; female donor-female recipient; male donor-female recipient; female donor-male recipient) were further stratified by donor and recipient absolute weight difference (>30 or 10-30 kg [donorrecipient] or <10 kg [donor=recipient]) resulting in 20 weight and sex pairings. Time to death-censored graft loss for each pairing was evaluated using multivariable Cox proportional hazards models adjusting for donor, immunologic, surgical, and recipient predictors of graft loss compared with the reference group of male donor-male recipients with no weight mismatch (<10 kg difference). RESULTS: Of 115,124 kidney transplant recipients, 21,261 developed death-censored graft failure (median graft survival time was 3.8 years; quartile 1 to 3, 0.0 to 14.8 years). After multivariable adjustment, the highest relative hazards for graft failure were observed for female recipients of male donor kidneys and male recipients of female donor kidneys in situations where the recipient was >30 kg larger than donor (hazard ratio, 1.50; 95% confidence interval, 1.32 to 1.70; hazard ratio, 1.35; 95% confidence interval, 1.25 to 1.45, respectively). CONCLUSIONS: A concurrent mismatch in donor-recipient weight (donor 0.2). Ex vivo tumor analysis confirmed the presence of hypoxic tumor regions that nevertheless exhibited relatively lower 18F-FMISO uptake. Conclusion:18F-FMISO kinetic modeling reveals a more detailed response to antiangiogenic treatment than a single static image is able to reveal. The reduced mean K1 reflects a reduction in tumor vascular perfusion, whereas the increased k3 reflects a rise in hypoxia-mediated entrapment of the radiotracer. However, if only late static images are analyzed, the observed reduction in 18F-FMISO uptake after treatment with cediranib may be mistakenly interpreted as a global decrease, rather than an increase, in tumor hypoxia. These findings support the use of 18F-FMISO kinetic modeling to more accurately characterize the response to treatments that have a direct effect on tumor vascularization and perfusion. PMID- 28360210 TI - Learning from Failure; Hypoxia Is an Evil Foe. PMID- 28360208 TI - Prediction of Response to Immune Checkpoint Inhibitor Therapy Using Early-Time Point 18F-FDG PET/CT Imaging in Patients with Advanced Melanoma. AB - The purpose of this study was to evaluate 18F-FDG PET/CT scanning as an early predictor of response to immune checkpoint inhibitors (ICIs) in patients with advanced melanoma. Methods: Twenty patients with advanced melanoma receiving ICI prospectively underwent 18F-FDG PET/CT at 3 scan intervals: before treatment initiation (SCAN-1), at days 21-28 (SCAN-2), and at 4 mo (SCAN-3). This study was approved by the institutional review board, and informed consent was received from all patients who were enrolled between April 2012 and December 2013. Tumor response at each posttreatment time point was assessed according to RECIST 1.1, immune-related response criteria, PERCIST (PERCIST 1.0), and European Organization for Research and Treatment of Cancer (EORTC) criteria. Performance characteristics of each metric to predict best overall response (BOR) at >= 4 mo were assessed. Results: Twenty evaluable patients were treated with ipilimumab (n = 16), BMS-936559 (n = 3), or nivolumab (n = 1). BOR at >= 4 mo included complete response (n = 2), partial response (n = 2), stable disease (n = 1), and progressive disease (n = 15). Response evaluations at SCAN-2 using RECIST 1.1, immune-related response criteria, PERCIST, and EORTC criteria demonstrated accuracies of 75%, 70%, 70%, and 65%, respectively, to predict BOR at >= 4 mo. Interestingly, the optimal PERCIST and EORTC threshold values at SCAN-2 to predict BOR were >15.5% and >14.7%, respectively. By combining anatomic and functional imaging data collected at SCAN-2, we developed criteria to predict eventual response to ICI with 100% sensitivity, 93% specificity, and 95% accuracy. Conclusion: Combining functional and anatomic imaging parameters from 18F-FDG PET/CT scans performed early in ICI appears predictive for eventual response in patients with advanced melanoma. These findings require validation in larger cohorts. PMID- 28360209 TI - Preclinical Evaluation of RYM1, a Matrix Metalloproteinase-Targeted Tracer for Imaging Aneurysm. AB - Matrix metalloproteinases (MMPs) play a key role in abdominal aortic aneurysm (AAA) development. Accordingly, MMP-targeted imaging provides important information regarding vessel wall biology in the course of aneurysm development. Given the small size of the vessel wall and its proximity with blood, molecular imaging of aneurysm optimally requires highly sensitive tracers with rapid blood clearance. To this end, we developed a novel hydrosoluble zwitterionic MMP inhibitor, RYM, on the basis of which a pan-MMP tracer, RYM1, was designed. Here, we describe the development and preclinical evaluation of RYM1 in comparison with RP805, a commonly used pan-MMP tracer in murine models of aneurysm. Methods: The macrocyclic hydroxamate-based pan-MMP inhibitor coupled with 6 hydrazinonicotinamide, RYM1, was synthesized and labeled with 99mTc. Radiochemical stability of 99mTc-RYM1 was evaluated by radio-high-performance liquid chromatography analysis. Tracer blood kinetics and biodistribution were compared with 99mTc-RP805 in C57BL/6J mice (n = 10). 99mTc-RYM1 binding to aneurysm and specificity were evaluated by quantitative autoradiography in apolipoprotein E-deficient (apoE-/-) mice with CaCl2-induced carotid aneurysm (n = 11). Angiotensin II-infused apoE-/- (n = 16) mice were used for small-animal SPECT/CT imaging. Aortic tissue MMP activity and macrophage marker CD68 expression were assessed by zymography and reverse-transcription polymerase chain reaction. Results: RYM1 showed nanomolar range inhibition constants for several MMPs. 99mTc-RYM1 was radiochemically stable in mouse blood for 5 h and demonstrated rapid renal clearance and lower blood levels in vivo compared with 99mTc-RP805. 99mTc-RYM1 binding to aneurysm and its specificity were shown by autoradiography in carotid aneurysm. Angiotensin II infusion in apoE-/- mice for 4 wk resulted in AAA formation in 36% (4/11) of surviving animals. In vivo 99mTc RYM1 small-animal SPECT/CT images showed higher uptake of the tracer in AAA than nondilated aortae. Finally, aortic uptake of 99mTc-RYM1 in vivo correlated with aortic MMP activity and CD68 expression. Conclusion: The newly developed pan-MMP inhibitor-based tracer 99mTc-RYM1 displays favorable pharmacokinetics for early vascular imaging and enables specific detection of inflammation and MMP activity in aneurysm. PMID- 28360211 TI - Quantitation of Cancer Treatment Response by 18F-FDG PET/CT: Multicenter Assessment of Measurement Variability. AB - The aim of this study was to assess the interobserver variability of quantitative 18F-FDG PET/CT parameters used in assessments of treatment response across multiple sites and readers. Methods: Paired pre- and posttreatment 18F-FDG PET/CT images of 30 oncologic patients were distributed to 22 readers across 15 U.S. and international sites. One reader was aware of the full medical history (readreference) of the patients, whereas the 21 other readers were unaware. The readers selected the single hottest tumor from each study, and made SUV measurements from this target lesion and the liver. Descriptive statistics, percentage changes in the measurements, and their agreements were obtained. Results: The intraclass correlation coefficient for the percentage change in SUVmax (%DeltaSUVmax) of the hottest tumor was 0.894 (95% confidence interval [CI], 0.813-0.941), and the individual equivalence coefficient was 1.931 (95% CI, 0.568-6.449) when all reads were included (n = 638). When only the measurements that selected the same target tumor as the readreference (n = 486) were included, the intraclass correlation coefficient for the %DeltaSUVmax was 0.944 (95% CI, 0.841-0.989), and the individual equivalence coefficient was -0.688 (95% CI, 1.810 to -0.092). The absolute change in SUVmean of liver corrected for lean body mass showed upper and lower limits of agreement (average bias +/- 2 SDs) of 0.13 and -0.13 g/mL. Conclusion: The quantitative tumor SUV changes measured across multiple sites and readers show a high correlation. Selection of the same tumor target among readers further increased the degree of correlation. PMID- 28360212 TI - Correlation of 18F-FDG PET and MRI Apparent Diffusion Coefficient Histogram Metrics with Survival in Diffuse Intrinsic Pontine Glioma: A Report from the Pediatric Brain Tumor Consortium. AB - The purpose of this study was to describe baseline 18F-FDG PET voxel characteristics in pediatric diffuse intrinsic pontine glioma (DIPG) and to correlate these metrics with baseline MRI apparent diffusion coefficient (ADC) histogram metrics, progression-free survival (PFS), and overall survival. Methods: Baseline brain 18F-FDG PET and MRI scans were obtained in 33 children from Pediatric Brain Tumor Consortium clinical DIPG trials. 18F-FDG PET images, postgadolinium MR images, and ADC MR images were registered to baseline fluid attenuation inversion recovery MR images. Three-dimensional regions of interest on fluid attenuation inversion recovery MR images and postgadolinium MR images and 18F-FDG PET and MR ADC histograms were generated. Metrics evaluated included peak number, skewness, and kurtosis. Correlation between PET and MR ADC histogram metrics was evaluated. PET pixel values within the region of interest for each tumor were plotted against MR ADC values. The association of these imaging markers with survival was described. Results: PET histograms were almost always unimodal (94%, vs. 6% bimodal). None of the PET histogram parameters (skewness or kurtosis) had a significant association with PFS, although a higher PET postgadolinium skewness tended toward a less favorable PFS (hazard ratio, 3.48; 95% confidence interval [CI], 0.75-16.28 [P = 0.11]). There was a significant association between higher MR ADC postgadolinium skewness and shorter PFS (hazard ratio, 2.56; 95% CI, 1.11-5.91 [P = 0.028]), and there was the suggestion that this also led to shorter overall survival (hazard ratio, 2.18; 95% CI, 0.95-5.04 [P = 0.067]). Higher MR ADC postgadolinium kurtosis tended toward shorter PFS (hazard ratio, 1.30; 95% CI, 0.98-1.74 [P = 0.073]). PET and MR ADC pixel values were negatively correlated using the Pearson correlation coefficient. Further, the level of PET and MR ADC correlation was significantly positively associated with PFS; tumors with higher values of ADC-PET correlation had more favorable PFS (hazard ratio, 0.17; 95% CI, 0.03-0.89 [P = 0.036]), suggesting that a higher level of negative ADC-PET correlation leads to less favorable PFS. A more significant negative correlation may indicate higher-grade elements within the tumor leading to poorer outcomes. Conclusion:18F-FDG PET and MR ADC histogram metrics in pediatric DIPG demonstrate different characteristics with often a negative correlation between PET and MR ADC pixel values. A higher negative correlation is associated with a worse PFS, which may indicate higher-grade elements within the tumor. PMID- 28360215 TI - Correction for Arl13b regulates Shh signaling from both inside and outside the cilium. PMID- 28360213 TI - Forty years on: clathrin-coated pits continue to fascinate. AB - Clathrin-mediated endocytosis (CME) is a fundamental process in cell biology and has been extensively investigated over the past several decades. Every cell biologist learns about it at some point during his or her education, and the beauty of this process has led many of us to go deeper and make it the topic of our research. Great progress has been made toward elucidating the mechanisms of CME, and the field is becoming increasingly complex, with several hundred new publications every year. This makes it easy to get lost in the vast amount of literature and forget about the fundamentals of the field, which are based on the careful interpretation of simple observations made >40 years ago, as exemplified by a study performed by Anderson, Brown, and Goldstein in 1977. We examine how this seminal study was pivotal to our understanding of CME and its progression into ever-increasing complexity over the past four decades. PMID- 28360217 TI - Bilateral Lung Transplantation for Bleomycin-Associated Lung Injury. AB - This report details the successful use of bilateral lung transplantation for the management of severe postoperative bleomycin-associated lung injury. This case highlights that the extremely favorable prognosis of advanced testicular germ cell tumors after systemic chemotherapy (>90% cure rate) should not preclude lung transplant consideration in all cases, despite current guidance that considers an advanced malignancy to be a contraindication for lung transplant listing. The Oncologist 2017;22:620-622. PMID- 28360218 TI - A productive NHS. PMID- 28360216 TI - Prolonged Temozolomide Maintenance Therapy in Newly Diagnosed Glioblastoma. AB - BACKGROUND: The impact of prolonging temozolomide (TMZ) maintenance beyond six cycles in newly diagnosed glioblastoma (GBM) remains a topic of discussion. We investigated the effects of prolonged TMZ maintenance on progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: In this retrospective single-center cohort study, we included patients with GBM who were treated with radiation therapy with concomitant and adjuvant TMZ. For analysis, patients were considered who either completed six TMZ maintenance cycles (group B), continued with TMZ therapy beyond six cycles (group C), or stopped TMZ maintenance therapy within the first six cycles (group A). Patients with progression during the first six TMZ maintenance cycles were excluded. RESULTS: Clinical data from 107 patients were included for Kaplan-Meier analyses and 102 for Cox regressions. Median PFS times were 8.1 months (95% confidence interval [CI] 6.1-12.4) in group A, 13.7 months (95% CI 10.6-17.5) in group B, and 20.9 months (95% CI 15.2-43.5) in group C. At first progression, response rates of TMZ/lomustine rechallenge were 47% in group B and 13% in group C. Median OS times were 12.7 months (95% CI 10.3-16.8) in group A, 25.2 months (95% CI 17.7-55.5) in group B, and 28.6 months (95% CI 24.4-open) in group C. Nevertheless, multivariate Cox regression for patients in group C compared with group B that accounted for imbalances of other risk factors showed no different relative risk (RR) for OS (RR 0.77, p = .46). CONCLUSION: Our data do not support a general extension of TMZ maintenance therapy beyond six cycles. The Oncologist 2017;22:570-575 IMPLICATIONS FOR PRACTICE: Radiation therapy with concomitant and adjuvant temozolomide (TMZ) maintenance therapy is still the standard of care in patients below the age of 65 years in newly diagnosed glioblastoma. However, in clinical practice, many centers continue TMZ maintenance therapy beyond six cycles. The impact of this continuation is controversial and has not yet been addressed in prospective randomized clinical trials. We compared the effect of more than six cycles of TMZ in comparison with exactly six cycles on overall survival (OS) and progression-free survival (PFS) by multivariate analysis and found a benefit in PFS but not OS. Thus, our data do not suggest prolonging TMZ maintenance therapy beyond six cycles, which should be considered in neurooncological practice. PMID- 28360214 TI - Genetically encoded fluorescent tags. AB - Genetically encoded fluorescent tags are protein sequences that can be fused to a protein of interest to render it fluorescent. These tags have revolutionized cell biology by allowing nearly any protein to be imaged by light microscopy at submicrometer spatial resolution and subsecond time resolution in a live cell or organism. They can also be used to measure protein abundance in thousands to millions of cells using flow cytometry. Here I provide an introduction to the different genetic tags available, including both intrinsically fluorescent proteins and proteins that derive their fluorescence from binding of either endogenous or exogenous fluorophores. I discuss their optical and biological properties and guidelines for choosing appropriate tags for an experiment. Tools for tagging nucleic acid sequences and reporter molecules that detect the presence of different biomolecules are also briefly discussed. PMID- 28360219 TI - A new mechanism of voltage-dependent gating exposed by KV10.1 channels interrupted between voltage sensor and pore. AB - Voltage-gated ion channels couple transmembrane potential changes to ion flow. Conformational changes in the voltage-sensing domain (VSD) of the channel are thought to be transmitted to the pore domain (PD) through an alpha-helical linker between them (S4-S5 linker). However, our recent work on channels disrupted in the S4-S5 linker has challenged this interpretation for the KCNH family. Furthermore, a recent single-particle cryo-electron microscopy structure of KV10.1 revealed that the S4-S5 linker is a short loop in this KCNH family member, confirming the need for an alternative gating model. Here we use "split" channels made by expression of VSD and PD as separate fragments to investigate the mechanism of gating in KV10.1. We find that disruption of the covalent connection within the S4 helix compromises the ability of channels to close at negative voltage, whereas disconnecting the S4-S5 linker from S5 slows down activation and deactivation kinetics. Surprisingly, voltage-clamp fluorometry and MTS accessibility assays show that the motion of the S4 voltage sensor is virtually unaffected when VSD and PD are not covalently bound. Finally, experiments using constitutively open PD mutants suggest that the presence of the VSD is structurally important for the conducting conformation of the pore. Collectively, our observations offer partial support to the gating model that assumes that an inward motion of the C-terminal S4 helix, rather than the S4-S5 linker, closes the channel gate, while also suggesting that control of the pore by the voltage sensor involves more than one mechanism. PMID- 28360220 TI - The Use of Sildenafil for Glomerular Disease. PMID- 28360222 TI - Novel imaging detailing the origins of a pneumothorax. AB - This is a prospective clinical study aimed at introducing a method to visualise the location of an air leak and to identify the bulla responsible on three dimensional (3-D) cine CT. In 10 patients with spontaneous pneumothorax, dynamic 320-detector row CT was performed with injection of 0.9% saline into the affected pleural cavity via a preplaced chest tube. In eight cases, 3-D cine CT thoracography revealed the location of the air leak and the bulla responsible (7 cases: air stream sign; 1 case: repeated collapse and expansion of a bulla with the patient's breathing). PMID- 28360223 TI - Risk stratification based on screening history: the NELSON lung cancer screening study. AB - BACKGROUND: Debate about the optimal lung cancer screening strategy is ongoing. In this study, previous screening history of the Dutch-Belgian Lung Cancer Screening trial (NELSON) is investigated on if it predicts the screening outcome (test result and lung cancer risk) of the final screening round. METHODS: 15 792 participants were randomised (1:1) of which 7900 randomised into a screening group. CT screening took place at baseline, and after 1, 2 and 2.5 years. Initially, three screening outcomes were possible: negative, indeterminate or positive scan result. Probability for screening outcome in the fourth round was calculated for subgroups of participants. RESULTS: Based on results of the first three rounds, three subgroups were identified: (1) those with exclusively negative results (n=3856; 73.0%); (2) those with >=1 indeterminate result, but never a positive result (n=1342; 25.5%); and (3) with >=1 positive result (n=81; 1.5%). Group 1 had the highest probability for having a negative scan result in round 4 (97.2% vs 94.8% and 90.1%, respectively, p<0.001), and the lowest risk for detecting lung cancer in round 4 (0.6% vs 1.6%, p=0.001). 'Smoked pack-years' and 'screening history' significantly predicted the fourth round test result. The third round results implied that the risk for detecting lung cancer (after an interval of 2.5 years) was 0.6% for those with negative results compared with 3.7% of those with indeterminate results. CONCLUSIONS: Previous CT lung cancer screening results provides an opportunity for further risk stratifications of those who undergo lung cancer screening. TRIAL REGISTRATION NUMBER: Results, ISRCTN63545820. PMID- 28360224 TI - Ultrasound evaluation of diaphragm function in mechanically ventilated patients: comparison to phrenic stimulation and prognostic implications. AB - RATIONALE: In intensive care unit (ICU) patients, diaphragm dysfunction is associated with adverse clinical outcomes. Ultrasound measurements of diaphragm thickness, excursion (EXdi) and thickening fraction (TFdi) are putative estimators of diaphragm function, but have never been compared with phrenic nerve stimulation. Our aim was to describe the relationship between these variables and diaphragm function evaluated using the change in endotracheal pressure after phrenic nerve stimulation (Ptr,stim), and to compare their prognostic value. METHODS: Between November 2014 and June 2015, Ptr,stim and ultrasound variables were measured in mechanically ventilated patients <24 hours after intubation ('initiation of mechanical ventilation (MV)', under assist-control ventilation, ACV) and at the time of switch to pressure support ventilation ('switch to PSV'), and compared using Spearman's correlation and receiver operating characteristic curve analysis. Diaphragm dysfunction was defined as Ptr,stim <11 cm H2O. RESULTS: 112 patients were included. At initiation of MV, Ptr,stim was not correlated to diaphragm thickness (p=0.28), EXdi (p=0.66) or TFdi (p=0.80). At switch to PSV, TFdi and EXdi were respectively very strongly and moderately correlated to Ptr,stim, (r=0.87, p<0.001 and 0.45, p=0.001), but diaphragm thickness was not (p=0.45). A TFdi <29% could reliably identify diaphragm dysfunction (sensitivity and specificity of 85% and 88%), but diaphragm thickness and EXdi could not. This value was associated with increased duration of ICU stay and MV, and mortality. CONCLUSIONS: Under ACV, diaphragm thickness, EXdi and TFdi were uncorrelated to Ptr,stim. Under PSV, TFdi was strongly correlated to diaphragm strength and both were predictors of remaining length of MV and ICU and hospital death. PMID- 28360225 TI - Biomarker Profiles in Heart Failure Patients With Preserved and Reduced Ejection Fraction. AB - BACKGROUND: Biomarkers may help us to unravel differences in the underlying pathophysiology between heart failure (HF) patients with a reduced ejection fraction (HFrEF) and a preserved ejection fraction (HFpEF). Therefore, we compared biomarker profiles to characterize pathophysiological differences between patients with HFrEF and HFpEF. METHODS AND RESULTS: We retrospectively analyzed 33 biomarkers from different pathophysiological domains (inflammation, oxidative stress, remodeling, cardiac stretch, angiogenesis, arteriosclerosis, and renal function) in 460 HF patients (21% HFpEF, left ventricular ejection fraction >=45%) measured at discharge after hospitalization for acute HF. The association between these markers and the occurrence of all-cause mortality and/or HF-related rehospitalizations at 18 months was compared between patients with HFrEF and HFpEF. Patients were 70.6+/-11.4 years old and 37.4% were female. Patients with HFpEF were older, more often female, and had a higher systolic blood pressure. Levels of high-sensitive C-reactive protein were significantly higher in HFpEF, while levels of pro-atrial-type natriuretic peptide and N terminal pro-brain natriuretic peptide were higher in HFrEF. Linear regression followed by network analyses revealed prominent inflammation and angiogenesis associated interactions in HFpEF and mainly cardiac stretch-associated interactions in HFrEF. The angiogenesis-specific marker, neuropilin and the remodeling-specific marker, osteopontin were predictive for all-cause mortality and/or HF-related rehospitalizations at 18 months in HFpEF, but not in HFrEF (P for interaction <0.05). CONCLUSIONS: In HFpEF, inflammation and angiogenesis mediated interactions are predominantly observed, while stretch-mediated interactions are found in HFrEF. The remodeling marker osteopontin and the angiogenesis marker neuropilin predicted outcome in HFpEF, but not in HFrEF. PMID- 28360226 TI - Dual Function for Mature Vascular Smooth Muscle Cells During Arteriovenous Fistula Remodeling. AB - BACKGROUND: The arteriovenous fistula (AVF) is the preferred form of hemodialysis access for patients with chronic kidney disease. However, AVFs are associated with significant problems including high incidence of both early and late failures, usually attributed to inadequate venous arterialization and neointimal hyperplasia, respectively. Understanding the cellular basis of venous remodeling in the setting of AVF could provide targets for improving AVF patency rates. METHODS AND RESULTS: A novel vascular smooth muscle cell (VSMC) lineage tracing reporter mouse, Myh11-Cre/ERT2-mTmG, was used to track mature VSMCs in a clinically relevant AVF mouse model created by a jugular vein branch end to carotid artery side anastomosis. Prior to AVF surgery, differentiated medial layer VSMCs were labeled with membrane green fluorescent protein (GFP) following tamoxifen induction. Four weeks after AVF surgery, we observed medial VSMC layer thickening in the middle region of the arterialized vein branch. This thickened medial VSMC layer was solely composed of differentiated VSMCs that were GFP+/MYH11+/Ki67-. Extensive neointimal hyperplasia occurred in the AVF region proximal to the anastomosis site. Dedifferentiated VSMCs (GFP+/MYH11-) were a major cellular component of the neointima. Examination of failed human AVF samples revealed that the processes of VSMC phenotypic modulation and intimal hyperplasia, as well as medial VSMC layer thickening, also occurred in human AVFs. CONCLUSIONS: We demonstrated a dual function for mature VSMCs in AVF remodeling, with differentiated VSMCs contributing to medial wall thickening towards venous maturation and dedifferentiated VSMCs contributing to neointimal hyperplasia. These results provide valuable insights into the mechanisms underlying venous adaptations during AVF remodeling. PMID- 28360221 TI - NFAT5 and SLC4A10 Loci Associate with Plasma Osmolality. AB - Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at P<5.0 * 10-6 Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis (P=3.1 * 10-5), with combined stages 1 and 2 genome-wide significance of P=5.6 * 10-10 Transethnic meta-analysis further supported the association at rs9980 (P=5.9 * 10-12). Additionally, rs16846053 at SLC4A10 showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (P=6.7 * 10-8). NFAT5 encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. SLC4A10 encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for NFAT5 and SLC4A10 are cis expression quantitative trait loci in tissues of the central nervous system and relevant to transcriptional regulation. Thus, genetic variation in NFAT5 and SLC4A10 expression and function in the central nervous system may affect the regulation of systemic water balance. PMID- 28360227 TI - Increased Arterial Stiffness is an Independent Predictor of Renal Function Decline in Patients With Type 2 Diabetes Mellitus Younger Than 60 Years. AB - BACKGROUND: The objective of this study was to evaluate whether aortic pulse wave velocity (Ao-PWV) predicts estimated glomerular filtration rate (eGFR) decline in patients with type 2 diabetes mellitus. METHODS AND RESULTS: This prospective single-center cohort study investigated 211 type 2 diabetes mellitus patients with eGFR >=45 mL/min with a baseline mean age of 60.1 years (range, 30-82 years). The mean+/-SD baseline eGFR was 85+/-26.1 mL/min. We divided the cohort into 2 groups above (n=117, "older") and below (n=94, "younger") the mean age to evaluate whether Ao-PWV predicted progression of kidney disease differentially in older and younger patients. The primary end point was reaching a final eGFR below the median for the age group and an eGFR fall >=1 mL/min per year. Median follow up was 9 years (range, 3-11 years) and ~50% of patients in both groups reached the primary end point. In older patients, Ao-PWV was similar in those who did and did not reach the primary end point. By contrast, younger patients who reached the primary end point had a higher Ao-PWV at baseline compared with those who did not (10.8 m/s versus 9.5 m/s, respectively; mean difference of 1.36 m/s [95% CI, 0.38-2.33], P=0.007). Ao-PWV was an independent predictor of the primary end point (incident risk ratio, 1.09; 95% CI, 1.02-1.18) after adjustment for traditional risk factors only in younger patients (P=0.02). A 1m/s increase in Ao PWV was associated with a mean fall in eGFR of 2.1 mL/min per year (95% CI, 0.09 4.1) independent of other risk factors in younger patients (P=0.04). CONCLUSIONS: Ao-PWV predicts eGFR decline, before the onset of advanced renal dysfunction, and is a potential target for renoprotection in younger patients with type 2 diabetes mellitus. PMID- 28360228 TI - Echocardiographic Pulmonary Artery Systolic Pressure in the Coronary Artery Risk Development in Young Adults (CARDIA) Study: Associations With Race and Metabolic Dysregulation. AB - BACKGROUND: The determinants of pulmonary artery systolic pressure (PASP) are not fully understood. It is unknown whether racial differences in PASP exist or if other population characteristics are associated with pulmonary pressure in humans. We examined echocardiographically estimated PASP in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a middle-aged, biracial community-based cohort. METHODS AND RESULTS: At the CARDIA year-25 examination, 3469 participants underwent echocardiography, including measurement of tricuspid regurgitant jet velocity to estimate PASP. Clinical features, laboratory values, pulmonary function tests, and measurement of adipose depot volume were analyzed for association with PASP. PASP was estimated in 1311 individuals (61% female, 51% white). Older age, higher blood pressure, and higher body mass index were associated with higher PASP. Black race was associated with higher PASP after adjustment for demographics and left and right ventricular function (beta 0.94, 95% CI 0.24-1.64; P=0.009), but this association was no longer significant after further adjustment for lung volume (beta 0.42, 95% CI -0.68 to 0.96; P=0.74). Insulin resistance, inflammation (C-reactive protein and interleukin-6), and visceral adipose volume were independently associated with higher PASP after adjustment for relevant covariates. PASP rose with worsening diastolic function (ratio of early transmitral Doppler velocity to average mitral annular tissue Doppler velocity [E/e'] and left atrial volume index). CONCLUSIONS: In a large biracial cohort of middle-aged adults, we identified associations among black race, insulin resistance, and diastolic dysfunction with higher echocardiographically estimated PASP. Further studies are needed to examine racial differences in PASP and whether insulin resistance directly contributes to pulmonary vascular disease in humans. PMID- 28360229 TI - Aortic Calcification Onset and Progression: Association With the Development of Coronary Atherosclerosis. AB - BACKGROUND: Thoracic aortic calcification (TAC) and coronary artery calcification (CAC) are markers of subclinical atherosclerosis and are associated with incident major cardiovascular events. We investigated major determinants for incidence and progression of TAC and the association between TAC and CAC incidence and progression. METHODS AND RESULTS: In a population-based cohort study, 3270 participants (aged 45-74 years, 53.1% women) received cardiac computed tomography at baseline and after a mean follow-up of 5.1+/-0.3 years for quantification of calcification of the ascending (ATAC) and descending thoracic aorta (DTAC) and CAC. Multivariable relative risk regression analysis was used to investigate associations of cardiovascular risk factors with incident TAC, of baseline TAC with incident CAC, and of baseline CAC with incident TAC. Of 1243 participants with baseline TAC of 0, 517 (41.6%) revealed incident TAC after 5 years. Incidence of descending TAC was higher (34.5%) than ascending TAC (23.3%). Incident TAC after 5 years was associated with age (relative risk 1.26 [95% CI 1.21-1.33], per 5 years), blood pressure (relative risk 1.06 [95% CI 1.03-1.10], per 10 mm Hg), low-density lipoprotein cholesterol (relative risk 1.08 [95% CI 1.04-1.12], per 20 mg/dL), and smoking (relative risk 1.28 [95% CI 1.07-1.53]). Among the 1185 participants without CAC at baseline, the risk of developing CAC was 28.3% when baseline TAC was present compared with 22.2% among those without baseline TAC (excess risk 6.1% [95% CI 1.2-11.0%]). The point estimate of excess risk for incident CAC was higher for ascending TAC (10.8% [95% CI 4.8-16.7%]) and low for descending TAC (1.8% [95% CI -3.2% to 6.7%]). Excess risk for developing ascending and descending TAC with present baseline CAC was 16.4% (95% CI 12.7 20.0%) and 15.6% (95% CI 10.8-20.4%), respectively. CONCLUSION: TAC and CAC share similar major determinants for incident calcification. Participants with TAC, especially ascending TAC, are at elevated risk for development of CAC. PMID- 28360230 TI - Sequences of 95 human MHC haplotypes reveal extreme coding variation in genes other than highly polymorphic HLA class I and II. AB - The most polymorphic part of the human genome, the MHC, encodes over 160 proteins of diverse function. Half of them, including the HLA class I and II genes, are directly involved in immune responses. Consequently, the MHC region strongly associates with numerous diseases and clinical therapies. Notoriously, the MHC region has been intractable to high-throughput analysis at complete sequence resolution, and current reference haplotypes are inadequate for large-scale studies. To address these challenges, we developed a method that specifically captures and sequences the 4.8-Mbp MHC region from genomic DNA. For 95 MHC homozygous cell lines we assembled, de novo, a set of high-fidelity contigs and a sequence scaffold, representing a mean 98% of the target region. Included are six alternative MHC reference sequences of the human genome that we completed and refined. Characterization of the sequence and structural diversity of the MHC region shows the approach accurately determines the sequences of the highly polymorphic HLA class I and HLA class II genes and the complex structural diversity of complement factor C4A/C4B It has also uncovered extensive and unexpected diversity in other MHC genes; an example is MUC22, which encodes a lung mucin and exhibits more coding sequence alleles than any HLA class I or II gene studied here. More than 60% of the coding sequence alleles analyzed were previously uncharacterized. We have created a substantial database of robust reference MHC haplotype sequences that will enable future population scale studies of this complicated and clinically important region of the human genome. PMID- 28360232 TI - Genome graphs and the evolution of genome inference. AB - The human reference genome is part of the foundation of modern human biology and a monumental scientific achievement. However, because it excludes a great deal of common human variation, it introduces a pervasive reference bias into the field of human genomics. To reduce this bias, it makes sense to draw on representative collections of human genomes, brought together into reference cohorts. There are a number of techniques to represent and organize data gleaned from these cohorts, many using ideas implicitly or explicitly borrowed from graph-based models. Here, we survey various projects underway to build and apply these graph-based structures-which we collectively refer to as genome graphs-and discuss the improvements in read mapping, variant calling, and haplotype determination that genome graphs are expected to produce. PMID- 28360231 TI - Combination of short-read, long-read, and optical mapping assemblies reveals large-scale tandem repeat arrays with population genetic implications. AB - Accurate and contiguous genome assembly is key to a comprehensive understanding of the processes shaping genomic diversity and evolution. Yet, it is frequently constrained by constitutive heterochromatin, usually characterized by highly repetitive DNA. As a key feature of genome architecture associated with centromeric and subtelomeric regions, it locally influences meiotic recombination. In this study, we assess the impact of large tandem repeat arrays on the recombination rate landscape in an avian speciation model, the Eurasian crow. We assembled two high-quality genome references using single-molecule real time sequencing (long-read assembly [LR]) and single-molecule optical maps (optical map assembly [OM]). A three-way comparison including the published short read assembly (SR) constructed for the same individual allowed assessing assembly properties and pinpointing misassemblies. By combining information from all three assemblies, we characterized 36 previously unidentified large repetitive regions in the proximity of sequence assembly breakpoints, the majority of which contained complex arrays of a 14-kb satellite repeat or its 1.2-kb subunit. Using whole-genome population resequencing data, we estimated the population-scaled recombination rate (rho) and found it to be significantly reduced in these regions. These findings are consistent with an effect of low recombination in regions adjacent to centromeric or subtelomeric heterochromatin and add to our understanding of the processes generating widespread heterogeneity in genetic diversity and differentiation along the genome. By combining three different technologies, our results highlight the importance of adding a layer of information on genome structure that is inaccessible to each approach independently. PMID- 28360233 TI - A Plant Cryptochrome Controls Key Features of the Chlamydomonas Circadian Clock and Its Life Cycle. AB - Cryptochromes are flavin-binding proteins that act as blue light receptors in bacteria, fungi, plants, and insects and are components of the circadian oscillator in mammals. Animal and plant cryptochromes are evolutionarily divergent, although the unicellular alga Chlamydomonas reinhardtii (Chlamydomonas throughout) has both an animal-like cryptochrome and a plant cryptochrome (pCRY; formerly designated CPH1). Here, we show that the pCRY protein accumulates at night as part of a complex. Functional characterization of pCRY was performed based on an insertional mutant that expresses only 11% of the wild-type pCRY level. The pcry mutant is defective for central properties of the circadian clock. In the mutant, the period is lengthened significantly, ultimately resulting in arrhythmicity, while blue light-based phase shifts show large deviations from what is observed in wild-type cells. We also show that pCRY is involved in gametogenesis in Chlamydomonas pCRY is down-regulated in pregametes and gametes, and in the pcry mutant, there is altered transcript accumulation under blue light of the strictly light-dependent, gamete-specific gene GAS28 pCRY acts as a negative regulator for the induction of mating ability in the light and for the loss of mating ability in the dark. Moreover, pCRY is necessary for light dependent germination, during which the zygote undergoes meiosis that gives rise to four vegetative cells. In sum, our data demonstrate that pCRY is a key blue light receptor in Chlamydomonas that is involved in both circadian timing and life cycle progression. PMID- 28360234 TI - Linking medical and dental health record data: a partnership with the Rochester Epidemiology Project. AB - PURPOSE: The purpose of this project was to expand the Rochester Epidemiology Project (REP) medical records linkage infrastructure to include data from oral healthcare providers. The goal of this linkage is to facilitate research studies examining the role of oral health in overall health and quality of life. PARTICIPANTS: Eight dental practices joined the REP between 2011 and 2015. The REP study team has linked oral healthcare information with medical record information from local healthcare providers for 31 750 participants who have resided in Olmsted County, Minnesota. Overall, 17 718 (56%) participants are women, 14 318 (45%) are 40 years of age or older and 26 090 (82%) are white. FINDINGS TO DATE: A first study using this new information was recently completed. This resource was used to determine whether the 2007 guidelines from the American Heart Association affected prescription rates of antibiotics to patients with moderate-risk cardiac conditions prior to dental procedures. The REP infrastructure was used to identify a series of patients diagnosed with moderate-risk cardiac conditions by the local healthcare providers (n=1351), and to abstract antibiotic prescriptions from dental records both pre-2007 and post 2007. Antibiotic prescriptions prior to dental procedures declined from 62% to 7% following the change in guidelines. FUTURE PLANS: Dental data from participating practitioners will be updated on an annual basis, and new dental data will be linked to patient medical records. In addition, we will continue to invite new dental practices to participate in the REP. Finally, we will continue to use this research infrastructure to investigate associations between oral and medical health, and will present findings at conferences and in the scientific literature. PMID- 28360236 TI - Spin in RCTs of anxiety medication with a positive primary outcome: a comparison of concerns expressed by the US FDA and in the published literature. AB - OBJECTIVES: This study aimed to determine the presence of spin in papers on positive randomised clinical trials (RCTs) of antidepressant medication for anxiety disorders by comparing concerns expressed in the Food and Drug Administration (FDA) reviews with those expressed in the published paper. METHODS: For every positive anxiety medication trial with a matching publication (n=41), two independent reviewers identified the concerns raised in the US FDA reviews and those in the published literature. Spin was identified when concerns or limitations were expressed by the FDA (about the efficacy of the study drug) but not in the corresponding published paper. Concerns mentioned in the papers but not by the FDA were scored as 'non-FDA' concerns. FINDINGS: Only six out of 35 (17%) of the FDA concerns pertaining to drug efficacy were reported in the papers. Two papers mentioned a concern that fit the FDA categories, but was not mentioned in the corresponding FDA review. Eighty-seven non-FDA concerns were counted, which often reflected general concerns or concerns related to the study design. CONCLUSIONS: Results indicate the presence of substantial spin in the clinical trial literature on drugs for anxiety disorders. In papers describing RCTs on anxiety medication, the concerns raised by the authors differed from those raised by the FDA. Published papers mentioned a large number of generic concerns about RCTs, such as a lack of long-term research and limited generalisability, while they mentioned few concerns about drug efficacy. These results warrant the promotion of independent statistical review, reporting of patient-level data, more study of spin, and an increased expectation that authors report FDA concerns. PMID- 28360237 TI - Developing a national dental education research strategy: priorities, barriers and enablers. AB - OBJECTIVES: This study aimed to identify national dental education research (DER) priorities for the next 3-5 years and to identify barriers and enablers to DER. SETTING: Scotland. PARTICIPANTS: In this two-stage online questionnaire study, we collected data with multiple dental professions (eg, dentistry, dental nursing and dental hygiene) and stakeholder groups (eg, learners, clinicians, educators, managers, researchers and academics). Eighty-five participants completed the Stage 1 qualitative questionnaire and 649 participants the Stage 2 quantitative questionnaire. RESULTS: Eight themes were identified at Stage 1. Of the 24 DER priorities identified, the top three were: role of assessments in identifying competence; undergraduate curriculum prepares for practice and promoting teamwork. Following exploratory factor analysis, the 24 items loaded onto four factors: teamwork and professionalism, measuring and enhancing performance, dental workforce issues and curriculum integration and innovation. Barriers and enablers existed at multiple levels: individual, interpersonal, institutional structures and cultures and technology. CONCLUSIONS: This priority setting exercise provides a necessary first step to developing a national DER strategy capturing multiple perspectives. Promoting DER requires improved resourcing alongside efforts to overcome peer stigma and lack of valuing and motivation. PMID- 28360235 TI - Venous thromboembolism in adults screened for sickle cell trait: a population based cohort study with nested case-control analysis. AB - OBJECTIVE: To determine whether sickle cell carriers ('sickle cell trait') have an increased risk of venous thromboembolism (VTE). DESIGN: Cohort study with nested case-control analysis. SETTING: General population with data from 609 UK general practices in the Clinical Practice Research Datalink (CPRD). PARTICIPANTS: All individuals registered with a CPRD general practice between 1998 and 2013, with a medical record of screening for sickle cell between 18 and 75 years of age. MAIN OUTCOMES MEASURES: Incidence of VTE per 10 000 person-years (PY) among sickle cell carriers and non-carriers; and adjusted OR for VTE among sickle cell carriers compared with non-carriers. RESULTS: We included 30 424 individuals screened for sickle cell, with a follow-up time of 179 503 PY, identifying 55 VTEs in 6758 sickle cell carriers and 125 VTEs in 23 666 non carriers. VTE incidence among sickle cell carriers (14.9/10 000 PY; 95% CI 11.4 to 19.4) was significantly higher than non-carriers (8.8/10 000 PY; 95% CI 7.4 to 10.4). Restricting analysis to confirmed non-carriers was non-significant, but performed on a small sample. In the case-control analysis (180 cases matched to 1775 controls by age and gender), sickle cell carriers remained at increased risk of VTE after adjusting for body mass index, pregnancy, smoking status and ethnicity (OR 1.78, 95% CI 1.18 to 2.69, p=0.006), with the greatest risk for pulmonary embolism (PE) (OR 2.27, 95% CI 1.17 to 4.39, p=0.011). CONCLUSIONS: Although absolute numbers are small, in a general population screened for sickle cell, carriers have a higher incidence and risk of VTE, particularly PE, than non carriers. Clinicians should be aware of this elevated risk in the clinical care of sickle cell carriers, or when discussing carrier screening, and explicitly attend to modifiable risk factors for VTE in these individuals. More complete primary care coding of carrier status could improve analysis. PMID- 28360238 TI - Psychological and behavioural patterns of stigma among patients with type 2 diabetes: a cross-sectional study. AB - OBJECTIVES: The aim of this study was to test the psychological and behavioural patterns of stigma (self-esteem and social participation) and their relationship to self-stigma, patient activation for engaging in self-care and glycaemic control among patients with type 2 diabetes mellitus (T2DM). DESIGN: A cross sectional study. SETTING: 2 tertiary-level hospitals and 2 secondary-level hospitals in Japan. PARTICIPANTS: A consecutive sample of 209 outpatients with T2DM. Inclusion criteria were as follows: presence of T2DM, age 20-74 years, no diagnosis of dementia and/or psychosis, and no need for urgent medical procedures. OUTCOME MEASURES: Study measures included a self-administered questionnaire to assess the Rosenberg Self-Esteem Scale (SES), the 3 subscales of 36-question Short Form Health Survey (SF-36; Social Function, Role Physical, Role Emotional), Self-Stigma Scale and Patient Activation Measure (PAM-13). Glycated haemoglobin was obtained from same day blood work. In our previous qualitative study, we found that psychological and behavioural patterns of stigma varied according to patients' levels of illness-related self-esteem as well as attitudes towards social participation. For quantitative consistency, we used the SES scale to measure self-esteem and the SF-36 subscales to measure social participation. We then divided participants into 4 groups by exhibited psychological and behavioural patterns: group A (high SES/high SF-36), group B (high SES/low SF 36), group C (low SES/high SF-36) and group D (low SES/low SF-36). RESULTS: Using analysis of covariance after controlling for age and sex, there was a significant difference in self-stigma levels between the four groups (F[3203]=15.70, p<0.001). We observed the highest mean self-stigma levels in group D. Group D also had significantly lower PAM-13 scores than those of groups A (p<0.001) and B (p=0.02). CONCLUSIONS: The psychological and behavioural pattern of group D was found to be associated with higher levels of self-stigma and poorer patient activation for self-care. PMID- 28360239 TI - Instruments measuring the disease-specific quality of life of family carers of people with neurodegenerative diseases: a systematic review. AB - OBJECTIVE: Neurodegenerative diseases, such as dementia, have a profound impact on those with the conditions and their family carers. Consequently, the accurate measurement of family carers' quality of life (QOL) is important. Generic measures may miss key elements of the impact of these conditions, so using disease-specific instruments has been advocated. This systematic review aimed to identify and examine the psychometric properties of disease-specific outcome measures of QOL of family carers of people with neurodegenerative diseases (Alzheimer's disease and other dementias; Huntington's disease; Parkinson's disease; multiple sclerosis; and motor neuron disease). DESIGN: Systematic review. METHODS: Instruments were identified using 5 electronic databases (PubMed, PsycINFO, Web of Science, Scopus and the International Bibliography of the Social Sciences (IBSS)) and lateral search techniques. Only studies which reported the development and/or validation of a disease-specific measure for adult family carers, and which were written in English, were eligible for inclusion. The methodological quality of the included studies was evaluated using the COnsensus based Standards for the selection of health Measurement Instruments (COSMIN) checklist. The psychometric properties of each instrument were examined. RESULTS: 676 articles were identified. Following screening and lateral searches, a total of 8 articles were included; these reported 7 disease-specific carer QOL measures. Limited evidence was available for the psychometric properties of the 7 instruments. Psychometric analyses were mainly focused on internal consistency, reliability and construct validity. None of the measures assessed either criterion validity or responsiveness to change. CONCLUSIONS: There are very few measures of carer QOL that are specific to particular neurodegenerative diseases. The findings of this review emphasise the importance of developing and validating psychometrically robust disease-specific measures of carer QOL. PMID- 28360240 TI - Meta-analysis of the effectiveness of psychological and medical treatments for binge-eating disorder (MetaBED): study protocol. AB - INTRODUCTION: Binge-eating disorder (BED) was included as its own diagnostic entity in the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). An increasing number of treatment studies have been published, but an up-to-date comprehensive meta-analysis on diverse treatment approaches for BED is lacking. In an updated and extension of a previous meta-analysis, the goals of this study are to assess the short-term and long-term effectiveness of psychological and medical treatments for BED. METHODS AND ANALYSIS: We will search bibliographic databases and study registries, including manual searches for studies published before January 2016. The search strategy will include terms relating to binge eating and diverse forms of psychological and medical interventions. Language will be restricted to English. The studies included will be treatment studies, that is, randomised-controlled trials, and non-randomised and non-controlled studies, for individuals with BED (DSM-IV or DSM-5), and studies that provided a pre-treatment and at least one post-treatment or follow up assessment of binge eating. The primary outcomes will be the number of binge eating episodes, abstinence from binge eating and diagnosis of BED at post treatment and/or follow-up(s), and changes from pre-treatment to post-treatment and/or follow-up(s). Likewise, as secondary outcomes, eating disorder and general psychopathology, quality of life, and body weight will be analysed and adverse events and treatment drop-out will be examined. Study search, selection and data extraction, including risk of bias assessment, will be independently performed by 2 reviewers and consensus will be sought. Moderator analyses will be conducted, and equity aspects will be considered. Sensitivity analyses will be conducted to determine the robustness of the results. ETHICS AND DISSEMINATION: Ethical approval is not required for this meta-analysis. Published in a peer-reviewed journal and disseminated electronically and in print, this meta-analysis will form the basis of the renewal of the German evidence-based S3 Guidelines of Diagnosis and Treatment of Eating Disorders, specifically BED. TRIAL REGISTRATION NUMBER: CRD42016043604. PMID- 28360241 TI - Protocol for validating cardiovascular and cerebrovascular ICD-9-CM codes in healthcare administrative databases: the Umbria Data Value Project. AB - INTRODUCTION: Administrative healthcare databases can provide a comprehensive assessment of the burden of diseases in terms of major outcomes, such as mortality, hospital readmissions and use of healthcare resources, thus providing answers to a wide spectrum of research questions. However, a crucial issue is the reliability of information gathered. Aim of this protocol is to validate International Classification of Diseases, 9th Revision-Clinical Modification (ICD 9-CM) codes for major cardiovascular diseases, including acute myocardial infarction (AMI), heart failure (HF), atrial fibrillation (AF) and stroke. METHODS AND ANALYSIS: Data from the centralised administrative database of the entire Umbria Region (910 000 residents, located in Central Italy) will be considered. Patients with a first hospital discharge for AMI, HF, AF or stroke, between 2012 and 2014, will be identified in the administrative database using the following groups of ICD-9-CM codes located in primary position: (1) 410.x for AMI; (2) 427.31 for AF; (3) 428 for HF; (4) 433.x1, 434 (excluding 434.x0), 436 for ischaemic stroke, 430 and 431 for haemorrhagic stroke (subarachnoid haemorrhage and intracerebral haemorrhage). A random sample of cases, and of non cases, will be selected, and the corresponding medical charts retrieved and reviewed for validation by pairs of trained, independent reviewers. For each condition considered, case adjudication of disease will be based on symptoms, laboratory and diagnostic tests, as available in medical charts. Divergences will be resolved by consensus. Sensitivity and specificity with 95% CIs will be calculated. ETHICS AND DISSEMINATION: Research protocol has been granted approval by the Regional Ethics Committee. Study results will be disseminated widely through peer-reviewed publications and presentations at national and international conferences. PMID- 28360242 TI - Northern Shanghai Study: cardiovascular risk and its associated factors in the Chinese elderly-a study protocol of a prospective study design. AB - INTRODUCTION: Cardiovascular (CV) diseases are the leading cause of death and disability in the world. Increasing lifespans and ageing populations also contribute to an increasing CV burden. However, in China, there were few well designed cohort studies focusing on the elderly population, let alone an established CV risk score. The objective of this study is to establish a CV risk score based on a community-dwelling Chinese elderly population, determining the profile of the associated CV risk factors and target organ damages (TODs), so as to guide the later intervention. METHODS AND ANALYSIS: The Northern Shanghai Study is an ongoing prospective community-based study. After enrolment, clinical examination, anthropometric measurement and a questionnaire will be administered to each participant at baseline and after every 2 years in the follow-up. Our tests and examinations include: blood/urine sample and biochemical measurements, office blood pressure recording, carotid ultrasonograph, echocardiograph, pulse wave velocity, pulse wave analysis, 4-limb blood pressure recording, body mass index, etc. Baseline measurement will also include the assessments on TODs and the conventional CV risk factors. In the follow-up, the incidence of CV events and mortality will be recorded. The Northern Shanghai Risk Score will be calculated, with considerations on CV risk factors and TODs. ETHICS AND DISSEMINATION: This study was approved by the Shanghai Tenth People's Hospital Institutional Review Board. All participants signed a written consent form. TRIAL REGISTRATION NUMBER: NCT02368938; Pre-results. PMID- 28360244 TI - Evaluation of an alternative care provider clinic for severe sleep-disordered breathing: a study protocol for a randomised controlled trial. AB - INTRODUCTION: Despite the high prevalence of sleep-disordered breathing (SDB) and the significant health consequences associated with untreated disease, access to diagnosis and treatment remains a challenge. Even patients with severe SDB (severe obstructive sleep apnoea or hypoventilation), who are at particularly high risk of adverse health effects, are subject to long delays. Previous research has demonstrated that, within a sleep clinic, management by alternative care providers (ACPs) is effective for patients with milder forms of SDB. The purpose of this study is to compare an ACP-led clinic (ACP Clinic) for patients with severe SDB to physician-led care, from the perspective of clinical outcomes, health system efficiency and cost. METHODS AND ANALYSIS: The study is a randomised, controlled, non-inferiority study in which patients who are referred with severe SDB are randomised to management by a sleep physician or by an ACP. ACPs will be supervised by sleep physicians for safety. The primary outcome is positive airway pressure (PAP) adherence after 3 months of therapy. Secondary outcomes include: long-term PAP adherence; clinical response to therapy; health related quality of life; patient satisfaction; healthcare usage; wait times from referral to treatment initiation and cost-effectiveness. The economic analysis will be performed using the perspective of a publicly funded healthcare system. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Conjoint Health Research Ethics Board (ID: REB13-1280) at the University of Calgary. Results from this study will be disseminated through presentations at scientific conferences and publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02191085; Pre-results. PMID- 28360246 TI - Evidence on health-promoting lifestyle practices and information and communication technologies: scoping review protocol. AB - INTRODUCTION: Information and communication technologies (ICTs) play a key role in improving health and maintaining health promoting behaviours. ICTs are therefore one potential solution for promoting healthy lifestyles. In addition, they can assist in the reduction and control of the menace of both communicable and non-communicable diseases. This study will map evidence of interventions that demonstrate the effect of ICTs on health-promoting lifestyle practices that can prevent and control diseases. It is anticipated that this study will help identify areas where there is need for primary research. METHODS AND ANALYSIS: The following electronic databases will be searched: PsycArticle (EBSCO), PsycINFO (EBSCO), Science direct, PubMed, Medline (EBSCO) and Google Scholar. The study will be conducted in two stages: the first stage will map out the studies descriptively while the second stage will map the additional inclusion criteria of quality assessment. Two independent reviewers will undertake the data extraction. Relevant outcomes of the studies will be analysed thematically using NVIvo computer software. The authors will code all evidence independently. Thereafter the authors will critically cross-examine the relationship of the research questions to the emerging themes from the selected articles. The authors hope to find a large number of studies on health-promoting lifestyles that encompass six-subscales of health-promoting activities (nutrition, stress management, interpersonal relation, self-actualisation, health responsibility, physical activity) and ICT. DISSEMINATION: This study will be presented in conferences related to health promotion and health-promoting lifestyles. It will also be disseminated in print and electronically. TRIAL REGISTRATION NUMBER: CRD42016042568. PMID- 28360243 TI - Incidence and prevalence of type 2 diabetes mellitus with HIV infection in Africa: a systematic review and meta-analysis. AB - OBJECTIVES: This systematic review aims to investigate the incidence and prevalence of type 2 diabetes mellitus (T2DM) in patients with HIV infection in African populations. SETTING: Only studies reporting data from Africa were included. PARTICIPANTS: A systematic search was conducted using four databases for articles referring to HIV infection and antiretroviral therapy, and T2DM in Africa. Articles were excluded if they reported data on children, animals or type 1 diabetes exclusively. MAIN OUTCOME MEASURES: Incidence of T2DM and prevalence of T2DM. Risk ratios were generated for pooled data using random effects models. Bias was assessed using an adapted Cochrane Collaboration bias assessment tool. RESULTS: Of 1056 references that were screened, only 20 were selected for inclusion. Seven reported the incidence of T2DM in patients with HIV infection, eight reported the prevalence of T2DM in HIV-infected versus uninfected individuals and five reported prevalence of T2DM in HIV-treated versus untreated patients. Incidence rates ranged from 4 to 59 per 1000 person years. Meta analysis showed no significant differences between T2DM prevalence in HIV infected individuals versus uninfected individuals (risk ratio (RR) =1.61, 95% CI 0.62 to 4.21, p=0.33), or between HIV-treated patients versus untreated patients (RR=1.38, 95% CI 0.66 to 2.87, p=0.39), and heterogeneity was high in both meta analyses (I2=87% and 52%, respectively). CONCLUSIONS: Meta-analysis showed no association between T2DM prevalence and HIV infection or antiretroviral therapy; however, these results are limited by the high heterogeneity of the included studies and moderate-to-high risk of bias, as well as, the small number of studies included. There is a need for well-designed prospective longitudinal studies with larger population sizes to better assess incidence and prevalence of T2DM in African patients with HIV. Furthermore, screening for T2DM using gold standard methods in this population is necessary. TRIAL REGISTRATION NUMBER: PROSPERO42016038689. PMID- 28360245 TI - Listening to paediatric primary care nurses: a qualitative study of the potential for interprofessional oral health practice in six federally qualified health centres in Massachusetts and Maryland. AB - OBJECTIVES: To explore the opportunities for interprofessional collaboration (IPC) to improve paediatric oral health in federally qualified health centres (FQHCs), to identify challenges to IPC-led integration of oral health prevention into the well-child visit and to suggest strategies to overcome barriers. SAMPLE: Nurse managers (NMs), nurse practitioners (NPs), paediatric clinical staff and administrators in six FQHCs in two states were interviewed using a semistructured format. DESIGN: Grounded theory research. Topics included feasibility of integration, perceived barriers and strategies for incorporating oral health into paediatric primary care. MEASUREMENTS: Qualitative data were coded and analysed using NVivo 10 to generate themes iteratively. RESULTS: Nurses in diverse roles recognised the importance of oral health prevention but were unaware of professional guidelines for incorporating oral health into paediatric encounters. They valued collaborative care, specifically internal communication, joint initiatives and training and partnering with dental schools or community dental practices. Barriers to IPC included inadequate training, few opportunities for cross-communication and absence of charting templates in electronic health records. CONCLUSIONS: NMs, NPs and paediatric nursing staff all value IPC to improve patients' oral health, yet are constrained by lack of oral health training and supportive charting and referral systems. With supports, they are willing to take on responsibility for introducing oral health preventive measures into the well-child visit, but will require IPC approaches to training and systems changes. IPC teams in the health centre setting can work together, if policy and administrative supports are in place, to provide oral health assessments, education, fluoride varnish application and dental referrals, decrease the prevalence of early childhood caries and increase access to a dental home for low-income children. PMID- 28360247 TI - Economic evaluation of aerobic exercise training in older adults with vascular cognitive impairment: PROMoTE trial. AB - BACKGROUND/OBJECTIVES: Evidence suggests that aerobic exercise may slow the progression of subcortical ischaemic vascular cognitive impairment (SIVCI) by modifying cardiovascular risk factors. Yet the economic consequences relating to aerobic training (AT) remain unknown. Therefore, our primary objective was to estimate the incremental cost per quality-adjusted life years (QALYs) gained of a thrice weekly AT intervention compared with usual care. DESIGN: Cost-utility analysis alongside a randomised trial. SETTING: Vancouver, British Columbia, Canada. PARTICIPANTS: 70 adults (mean age of 74 years, 51% women) who meet the diagnostic criteria for mild SIVCI. INTERVENTION: A 6-month, thrice weekly, progressive aerobic exercise training programme compared with usual care (CON; comparator) with a follow-up assessment 6 months after formal cessation of aerobic exercise training. MEASUREMENTS: Healthcare resource usage was estimated over the 6-month intervention and 6-month follow-up period. Health status (using the EQ-5D-3L) at baseline and trial completion and 6-month follow-up was used to calculate QALYs. The incremental cost-utility ratio (cost per QALY gained) was calculated. RESULTS: QALYs were both modestly greater, indicating a health gain. Total healthcare costs (ie, 1791+/-1369 {2015 $CAD} at 6 months) were greater, indicating a greater cost for the thrice weekly AT group compared with CON. From the Canadian healthcare system perspective, the incremental cost-utility ratios for thrice weekly AT were cost-effective compared with CON, when using a willingness to pay threshold of $CAD 20 000 per QALY gained or higher. CONCLUSIONS: AT represents an attractive and potentially cost-effective strategy for older adults with mild SIVCI. TRIAL REGISTRATION NUMBER: NCT01027858. PMID- 28360248 TI - Transfusion of red blood cells in patients with traumatic brain injuries admitted to Canadian trauma health centres: a multicentre cohort study. AB - BACKGROUND: Optimisation of healthcare practices in patients sustaining a traumatic brain injury is of major concern given the high incidence of death and long-term disabilities. Considering the brain's susceptibility to ischaemia, strategies to optimise oxygenation to brain are needed. While red blood cell (RBC) transfusion is one such strategy, specific RBC strategies are debated. We aimed to evaluate RBC transfusion frequency, determinants of transfusions and associated clinical outcomes. METHODS: We conducted a retrospective multicentre cohort study using data from the National Trauma Registry of Canada. Patients admitted with moderate or severe traumatic brain injury to participating hospitals between April 2005 and March 2013 were eligible. Patient information on blood products, comorbidities, interventions and complications from the Discharge Abstract Database were linked to the National Trauma Registry data. Relative weights analyses evaluated the contribution of each determinant. We conducted multivariate robust Poisson regression to evaluate the association between potential determinants, mortality, complications, hospital-to-home discharge and RBC transfusion. We also used proportional hazard models to evaluate length of stay for time to discharge from ICU and hospital. RESULTS: Among the 7062 patients with traumatic brain injury, 1991 patients received at least one RBC transfusion during their hospital stay. Female sex, anaemia, coagulopathy, sepsis, bleeding, hypovolemic shock, other comorbid illnesses, serious extracerebral trauma injuries were all significantly associated with RBC transfusion. Serious extracerebral injuries altogether explained 61% of the observed variation in RBC transfusion. Mortality (risk ratio (RR) 1.23 (95% CI 1.13 to 1.33)), trauma complications (RR 1.38 (95% CI 1.32 to 1.44)) and discharge elsewhere than home (RR 1.88 (95% CI 1.75 to 2.04)) were increased in patients who received RBC transfusion. Discharge from ICU and hospital were also delayed in transfused patients. CONCLUSIONS: RBC transfusion is common in patients with traumatic brain injury and associated with unfavourable outcomes. Trauma severity is an important determinant of RBC transfusion. Prospective studies are needed to further evaluate optimal transfusion strategies in traumatic brain injury. PMID- 28360251 TI - The incidence of delirium after cardiac surgery in the elderly: protocol for a systematic review and meta-analysis. AB - INTRODUCTION: Delirium is one of the most common complications after cardiac surgery in the elderly. Future studies aimed at preventing postoperative delirium will need an accurate estimate of incidence. However, there are no available systematic reviews on the incidence, and reports of incidence of postoperative delirium after a cardiac operation vary widely with significant heterogeneity. Therefore, we aim to perform a systematic review and meta-analysis to determine the most accurate incidence possible of postoperative delirium in individuals aged >65 years after cardiac surgery. METHODS AND ANALYSES: We will undertake a comprehensive literature search among PubMed, EMBASE, the Cochrane Library, PsycINFO and CINAHL, from their inception to January 2017. Prospective cohort and cross sectional studies that described the incidence of delirium will be eligible for inclusion. The primary outcome will be the incidence of delirium. Risk of bias and methodological quality for the included studies will be assessed using a risk of bias tool for prevalence studies and the Cochrane guidelines. Heterogeneity of the estimates across studies will be assessed. Incidence data will be pooled by selective or emergency surgery. This systematic review will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). ETHICS AND DISSEMINATION: This proposed systematic review and meta-analysis is based on published data, and thus there is no requirement for ethics approval. The study will provide an up to date and accurate incidence of postoperative delirium among the older population after cardiac surgery, which is necessary for future research in this area. The findings of this study will be presented at conferences and disseminated through publication in a peer reviewed journal. TRIAL REGISTRATION NUMBER: CRD42016047773. PMID- 28360249 TI - Understanding the acceptability and adherence to paediatric antiretroviral treatment in the new formulation of pellets (LPV/r): the protocol of a realist evaluation. AB - BACKGROUND: Improving access to paediatric HIV treatment requires both large scale treatment programmes and medication that is adapted to infants and children's needs. The WHO recommends lopinavir/ritonavir as first-line antiretroviral therapy for all HIV-infected children younger than 3 years. There is currently little evidence on the acceptability of, and adherence to, a formulation of this combination treatment if given in the form of pellets. This protocol presents how we will carry a realist evaluation to assess the factors that contribute to the acceptability and adherence to the new pellets formulation in 3 hospitals in Kenya. METHODS: We structured the protocol along the realist evaluation cycle following 4 steps: (1) the initial programme theory, (2) the study design, (3) the data collection methods and (4) the data analysis plan. Theories of behavioural sciences were reviewed for frames that could provide insights into how using such new formulations may contribute to better acceptability and adherence. ETHICS AND DISSEMINATION: This study was approved by the Institutional Review Board of the Institute of Tropical Medicine, the Ethical Committee of the University Hospital Antwerp and the Kenyatta National Hospital/University of Nairobi Ethics and Research Committee. We aim to disseminate the findings through international conferences and peer-reviewed journals and to share them with Drugs for Neglected Diseases initiative's (DNDi) programme managers and with the Kenyan healthcare providers. DISCUSSION: In developing this study, we encountered some challenges. First, methods to measure the acceptability of any formulation and adherence to it are not standardised. The second challenge is common in realist evaluation and relates to how to choose from different potentially interesting theoretical frameworks. We identified relevant and empirically tested theories from behavioural science that may be helpful in our study. We will test them in 3 settings by exploring the multilevel factors that influence acceptability and adherence of this new paediatric Antiretroviral (ARV) formulation. PMID- 28360250 TI - Development of the Brussels Infant and Toddler Stool Scale ('BITSS'): protocol of the study. AB - INTRODUCTION: The Bristol Stool Form Scale (BSS) which consists of 7 photographs of different stool forms allows assessment of stool consistency (scale 1 for hard lumps to scale 7 for watery stools), in an objective manner in adults. The BSS is also sometimes used to characterise the stools of infants and young children. Despite its use, there is general agreement among paediatric gastroenterologists that the BSS is not adequate to be used in infants and young children who wear diapers; thus, a new scale specifically designed for this population is needed. Our aim is to develop a paediatric stool scale, the Brussels Infant and Toddler Stool Scale ('BITSS'), and to evaluate the interobserver agreement of stool assessment with the BITSS between the patient's parent and healthcare providers (physicians and nurses). METHODS AND ANALYSIS: This study has two phases. In the first phase, 11 key-opinion leaders in the field of paediatric gastroenterology representing different areas of the world selected seven coloured photographs of infants and/or young children wearing diapers to match the original descriptors of the BSS. The selected photographs were used to create a new scale in which the drawings of stools of the BSS were replaced by infant/toddlers stool photographs. In phase II, we aim at demonstrating that parents, nurses and primary healthcare physicians interpret the stool-pictures of the BITSS with a high degree of consensus and that the agreement is independent of whether it is a parent or a healthcare provider. Interobserver variability of stool assessment with the BITSS between the patient's parent and healthcare providers will be assessed. ETHICS AND DISSEMINATION: The study will be approved by the Ethics Committee of the participating centres. The findings of this study will be submitted to a peer reviewed journal. Abstracts will be submitted to national and international conferences. TRIAL REGISTRATION NUMBER: NCT02913950. PMID- 28360253 TI - To dialyse or delay: a qualitative study of older New Zealanders' perceptions and experiences of decision-making, with stage 5 chronic kidney disease. AB - BACKGROUND: Issues related to renal replacement therapy in elderly people with end stage kidney disease (ESKD) are complex. There is inadequate empirical data related to: decision-making by older populations, treatment experiences, implications of dialysis treatment and treatment modality on quality of life, and how these link to expectations of ageing. STUDY POPULATION: Participants for this study were selected from a larger quantitative study of dialysis and predialysis patients aged 65 years or older recruited from three nephrology services across New Zealand. All participants had reached chronic kidney disease (CKD) stage 5 and had undergone dialysis education but had not started dialysis or recently started dialysis within the past 6 months. METHODOLOGY: Serial qualitative interviews were undertaken to explore the decision-making processes and subsequent treatment experiences of patients with ESKD.Analytical approach: A framework method guided the iterative process of analysis. Decision-making codes were generated within NVivo software and then compared with the body of the interviews. RESULTS: Interviews were undertaken with 17 participants. We observed that decision-making was often a fluid process, rather than occurring at a single point in time, and was heavily influenced by perceptions of oneself as becoming old, social circumstances, life events and health status. LIMITATIONS: This study focuses on participants' experiences of decision-making about treatment and does not include perspectives of their nephrologists or other members of the nephrology team. CONCLUSIONS: Older patients often delay dialysis as an act of self-efficacy. They often do not commit to a dialysis decision following predialysis education. Delaying decision-making and initiating dialysis were common. This was not seen by participants as a final decision about therapy. Predialysis care and education should be different for older patients, who will delay decision-making until the time of facing obvious uraemic symptoms, threatening blood tests or paternalistic guidance from their nephrologist. TRIAL REGISTRATION NUMBER: Australasian Clinical Trials Registry ACTRN 12611000024943; results. PMID- 28360252 TI - State of reporting of primary biomedical research: a scoping review protocol. AB - INTRODUCTION: Incomplete or inconsistent reporting remains a major concern in the biomedical literature. Incomplete or inconsistent reporting may yield the published findings unreliable, irreproducible or sometimes misleading. In this study based on evidence from systematic reviews and surveys that have evaluated the reporting issues in primary biomedical studies, we aim to conduct a scoping review with focuses on (1) the state-of-the-art extent of adherence to the emerging reporting guidelines in primary biomedical research, (2) the inconsistency between protocols or registrations and full reports and (3) the disagreement between abstracts and full-text articles. METHODS AND ANALYSES: We will use a comprehensive search strategy to retrieve all available and eligible systematic reviews and surveys in the literature. We will search the following electronic databases: Web of Science, Excerpta Medica Database (EMBASE), MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL). Our outcomes are levels of adherence to reporting guidelines, levels of consistency between protocols or registrations and full reports and the agreement between abstracts and full reports, all of which will be expressed as percentages, quality scores or categorised rating (such as high, medium and low). No pooled analyses will be performed quantitatively given the heterogeneity of the included systematic reviews and surveys. Likewise, factors associated with improved completeness and consistency of reporting will be summarised qualitatively. The quality of the included systematic reviews will be evaluated using AMSTAR (a measurement tool to assess systematic reviews). ETHICS AND DISSEMINATION: All findings will be published in peer-reviewed journals and relevant conferences. These results may advance our understanding of the extent of incomplete and inconsistent reporting, factors related to improved completeness and consistency of reporting and potential recommendations for various stakeholders in the biomedical community. PMID- 28360254 TI - Hospital admissions for respiratory system diseases in adults with intellectual disabilities in Southeast London: a register-based cohort study. AB - BACKGROUND: Intellectual disability (ID) carries a high impact on need for care, health status and premature mortality. Respiratory system diseases contribute a major part of mortality among people with ID, but remain underinvestigated as consequent morbidities. METHODS: Anonymised electronic mental health records from the South London and Maudsley Trust (SLaM) were linked to national acute medical care data. Using retrospective cohort and matched case-control study designs, adults with ID receiving SLaM care between 1 January 2008 and 31 March 2013 were identified and compared with local catchment residents for respiratory system disease admissions. Standardised admission ratios (SARs) were first calculated, followed by a comparison of duration of hospitalisation with respiratory system disease between people with ID and age-matched and gender-matched random counterparts modelled using linear regression. Finally, the risk of readmission for respiratory system disease was analysed using the Cox models. RESULTS: For the 3138 adults with ID identified in SLaM, the SAR for respiratory system disease admissions was 4.02 (95% CI 3.79 to 4.26). Compared with adults without ID, duration of hospitalisation was significantly longer by 2.34 days (95% CI 0.03 to 4.64) and respiratory system disease readmission was significantly elevated (HR=1.35; 95% CI 1.17 to 1.56) after confounding adjustment. CONCLUSIONS: Respiratory system disease admissions in adults with ID are more frequent, of longer duration and have a higher likelihood of recurring. Development and evaluation of potential interventions to the preventable causes of respiratory diseases should be prioritised. PMID- 28360256 TI - Predicting late-onset sepsis by routine neonatal screening for colonisation by gram-negative bacteria in neonates at intensive care units: a protocol for a systematic review. AB - INTRODUCTION: Hospitals conduct extensive screening procedures to assess colonisation of the body surface of neonates by gram-negative bacteria to avoid complications like late-onset sepsis. However, the benefits of these procedures are controversially discussed. Until now, no systematic review has investigated the value of routine screening for colonisation by gram-negative bacteria in neonates for late-onset sepsis prediction. METHODS AND ANALYSIS: We will conduct a systematic review, considering studies of any design that include infants up to an age of 12 months. We will search MEDLINE and EMBASE (inception to 2016), reference lists and grey literature. Screening of titles, abstracts and full texts will be conducted by two independent reviewers. We will extract data on study characteristics and study results. Risk of bias will be assessed using Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) and Quality in Prognosis Studies (QUIPS) tools. Subgroup analyses are planned according to characteristics of studies, participants, index tests and outcome. For quantitative data synthesis on prognostic accuracy, sensitivity and specificity of screening to detect late-onset sepsis will be calculated. If sufficient data are available, we will calculate summary estimates using hierarchical summary receiver operating characteristics and bivariate models. Applying a risk factor approach, pooled summary estimates will be calculated as relative risk or OR, using fixed-effects and random-effects models. I-squared will be used to assess heterogeneity. All calculations will be performed in Stata V14.1 (College Station, Texas, USA). The results will be used to calculate positive and negative predictive value and number needed to be screened to prevent one case of sepsis. Grading of Recommendations Assessment, Development and Evaluation (GRADE) will be used to assess certainty in the evidence. The protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guideline. ETHICS AND DISSEMINATION: This study will not require ethical approval since it is not carried out in humans. The systematic review will be published in an open-access peer-reviewed journal. TRIAL REGISTRATION NUMBER: CRD42016036664. PMID- 28360255 TI - Public health surveillance of automated external defibrillators in the USA: protocol for the dynamic automated external defibrillator registry study. AB - INTRODUCTION: Lay use of automated external defibrillators (AEDs) before the arrival of emergency medical services (EMS) providers on scene increases survival after out-of-hospital cardiac arrest (OHCA). AEDs have been placed in public locations may be not ready for use when needed. We describe a protocol for AED surveillance that tracks these devices through time and space to improve public health, and survival as well as facilitate research. METHODS AND ANALYSIS: Included AEDs are installed in public locations for use by laypersons to treat patients with OHCA before the arrival of EMS providers on scene. Included cases of OHCA are patients evaluated by organised EMS personnel and treated for OHCA. Enrolment of 10 000 AEDs annually will yield precision of 0.4% in the estimate of readiness for use. Enrolment of 2500 patients annually will yield precision of 1.9% in the estimate of survival to hospital discharge. Recruitment began on 21 Mar 2014 and is ongoing. AEDs are found by using multiple methods. Each AED is then tagged with a label which is a unique two-dimensional (2D) matrix code; the 2D matrix code is recorded and the location and status of the AED tracked using a smartphone; these elements are automatically passed via the internet to a secure and confidential database in real time. Whenever the 2D matrix code is rescanned for any non-clinical or clinical use of an AED, the user is queried to answer a finite set of questions about the device status. The primary outcome of any clinical use of an AED is survival to hospital discharge. Results are summarised descriptively. ETHICS AND DISSEMINATION: These activities are conducted under a grant of authority for public health surveillance from the Food and Drug Administration. Results are provided periodically to participating sites and sponsors to improve public health and quality of care. PMID- 28360257 TI - Three-year outcomes after acute kidney injury: results of a prospective parallel group cohort study. AB - OBJECTIVES: Using a prospective study design, we aimed to characterise the effect of acute kidney injury (AKI) on long-term changes in renal function in a general hospital population. PARTICIPANTS: Hospitalised patients with AKI (exposed) and hospitalised patients without AKI (non-exposed), recruited at 3 months after hospital admission. DESIGN: Prospective, matched parallel group cohort study, in which renal function and proteinuria were measured at 3 months, 1 year and 3 years. SETTING: Single UK centre. CLINICAL END POINTS: Clinical end points at 3 years were comparison of the following variables between exposed and non-exposed groups: renal function, prevalence of proteinuria and albuminuria and chronic kidney disease (CKD) progression/development at each time point. CKD progression was defined as a decrease in the estimated glomerular filtration rate (eGFR) of >=25% associated with a decline in eGFR stage. RESULTS: 300 exposed and non exposed patients were successfully matched 1:1 for age and baseline renal function; 70% of the exposed group had AKI stage 1. During follow-up, the AKI group had lower eGFR than non-exposed patients at each time point. At 3 years, the mean eGFR was 60.7+/-21 mL/min/1.73 m2 in the AKI group compared with 68.4+/ 21 mL/min/1.73 m2 in the non-exposed group, p=0.003. CKD development or progression at 3 years occurred in 30 (24.6%) of the AKI group compared with 10 (7.5%) of the non-exposed group, p<0.001. Albuminuria was more common in the AKI group, and increased with AKI severity. Factors independently associated with CKD development/progression after AKI were non-recovery at 90 days, male gender, diabetes and recurrent AKI. CONCLUSIONS: AKI is associated with deterioration in renal function to 3 years, even in an unselected population with predominantly AKI stage 1. Non-recovery from AKI is an important factor determining long-term outcome. PMID- 28360258 TI - Impact of maternal antibodies and infant gut microbiota on the immunogenicity of rotavirus vaccines in African, Indian and European infants: protocol for a prospective cohort study. AB - INTRODUCTION: Gastroenteritis is the leading cause of morbidity and mortality among young children living in resource-poor settings, majority of which is attributed to rotavirus. Rotavirus vaccination can therefore have a significant impact on infant mortality. However, rotavirus vaccine efficacy in Sub-Saharan Africa and Southeast Asia is significantly lower than in high-income countries. Maternally derived antibodies, infant gut microbiota and concomitant oral polio vaccination have been proposed as potential reasons for poor vaccine performance in low-income settings. The overall aim of this study is to compare the role of maternally derived antibodies and infant gut microbiota in determining immune response to rotavirus vaccine in high-income and low-income settings, using the same vaccine and a similar study protocol. METHODS AND ANALYSIS: The study is an observational cohort in three countries-Malawi, India and UK. Mothers will be enrolled in third trimester of pregnancy and followed up, along with infants after delivery, until the infant completes two doses of oral rotavirus vaccine (along with routine immunisation). The levels of prevaccination maternally derived rotavirus-specific antibodies (IgG) will be correlated with infant seroconversion and antibody titres, 4 weeks after the second dose of rotavirus vaccine. Both within-country and between-country comparisons of gut microbiome will be carried out between children who seroconvert and those who do not. The impact of oral polio vaccine coadministration on rotavirus vaccine response will be studied in Indian infants. ETHICS AND DISSEMINATION: Ethical approvals have been obtained from Integrated Research Application System (IRAS, NHS ethics) in UK, College of Medicine Research and Ethics Committee (COMREC) in Malawi and Institutional Review Board (IRB), Christian Medical College, Vellore in India. Participant recruitment and follow-up is ongoing at all three sites. Analysis of data, followed by publication of the results, is expected in 2018. PMID- 28360259 TI - Influence of Left Atrial Function on Exercise Capacity and Left Ventricular Function in Patients With Heart Failure and Preserved Ejection Fraction. AB - BACKGROUND: Although left atrial (LA) dysfunction is common in heart failure with preserved ejection fraction (HFpEF), its functional implications beyond the reflection of left ventricular (LV) pathology are not well understood. The aim of this study was to further characterize LA function in HFpEF patients. METHODS AND RESULTS: We performed cardiac magnetic resonance myocardial feature tracking in 22 patients with HFpEF and 12 patients without HFpEF. LA reservoir strain, LA conduit strain, and LA booster pump strain were quantified. Peak oxygen uptake (VO2max) was determined. Invasive pressure-volume loops were obtained to evaluate LV diastolic properties. LV early filling was determined from LV volume-time curves as derived from cardiac magnetic resonance. LA reservoir and conduit strain were significantly lower in HFpEF (LA reservoir strain, 22+/-7% versus 29+/-6%, P=0.04; LA conduit strain, -9+/-5% versus -15+/-4%, P<0.01). Patients with HFpEF showed lower oxygen uptake (17+/-6 versus 29+/-8 mL/(kg min); P<0.01). Strain measurement for LA conduit function was strongly associated with VO2max (r=0.80; P<0.01). On multivariable regression analysis, LA conduit strain emerged as strongest predictor for VO2max even after inclusion of LV stiffness and relaxation time (beta=0.80; P<0.01). LA conduit strain correlated with the volume of early ventricular filling (r=0.67; P<0.01), but not LV stiffness constant beta (-0.34; P=0.051) or relaxation constant tau (r=-0.33; P=0.06). CONCLUSIONS: Cardiac magnetic resonance myocardial feature tracking-derived conduit strain is significantly impaired in HFpEF and associated with exercise intolerance. Impaired conduit function is associated with impaired early ventricular filling, as potential mechanism leading to impaired oxygen uptake. Our results propose that impaired LA conduit function represents a distinct feature of HFpEF, independent of LV stiffness and relaxation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02459626. PMID- 28360260 TI - Multiparametric Imaging of Organ System Interfaces. AB - Cardiovascular diseases are a consequence of genetic and environmental risk factors that together generate arterial wall and cardiac pathologies. Blood vessels connect multiple systems throughout the entire body and allow organs to interact via circulating messengers. These same interactions facilitate nervous and metabolic system's influence on cardiovascular health. Multiparametric imaging offers the opportunity to study these interfacing systems' distinct processes, to quantify their interactions, and to explore how these contribute to cardiovascular disease. Noninvasive multiparametric imaging techniques are emerging tools that can further our understanding of this complex and dynamic interplay. Positron emission tomography/magnetic resonance imaging and multichannel optical imaging are particularly promising because they can simultaneously sample multiple biomarkers. Preclinical multiparametric diagnostics could help discover clinically relevant biomarker combinations pivotal for understanding cardiovascular disease. Interfacing systems important to cardiovascular disease include the immune, nervous, and hematopoietic systems. These systems connect with classical cardiovascular organs, such as the heart and vasculature, and with the brain. The dynamic interplay between these systems and organs enables processes, such as hemostasis, inflammation, angiogenesis, matrix remodeling, metabolism, and fibrosis. As the opportunities provided by imaging expand, mapping interconnected systems will help us decipher the complexity of cardiovascular disease and monitor novel therapeutic strategies. PMID- 28360264 TI - Changing the Paradigm in Type B Acute Aortic Dissection: Combining Clinical and Imaging Markers of Risk. PMID- 28360263 TI - Stepping Out of the Left Ventricle's Shadow: Time to Focus on the Left Atrium in Heart Failure With Preserved Ejection Fraction. PMID- 28360262 TI - Accuracy of Echocardiography to Estimate Pulmonary Artery Pressures With Exercise: A Simultaneous Invasive-Noninvasive Comparison. AB - BACKGROUND: Exercise echocardiography is often applied as a noninvasive strategy to screen for abnormal pulmonary hemodynamic response, but it is technically challenging, and limited data exist regarding its accuracy to estimate pulmonary arterial pressure during exercise. METHODS AND RESULTS: Among 65 patients with exertional intolerance undergoing upright invasive exercise testing, tricuspid regurgitation (TR) Doppler estimates and invasive measurement of pulmonary arterial pressure at rest and peak exercise were simultaneously obtained. TR Doppler envelopes were assessed for quality. Correlation, Bland-Altman, and receiver-operating characteristic curve analyses were performed to evaluate agreement and diagnostic accuracy. Mean age was 62+/-13 years, and 31% were male. High-quality (grade A) TR Doppler was present in 68% at rest and 34% at peak exercise. For grade A TR signals, echocardiographic measures of systolic pulmonary arterial pressure correlated reasonably well with invasive measurement at rest (r=0.72, P<0.001; bias, -2.9+/-8.0 mm Hg) and peak exercise (r=0.75, P<0.001; bias, -1.9+/-15.6 mm Hg). Lower quality TR signals (grade B and C) correlated poorly with invasive measurements overall. In patients with grade A TR signals, mean pulmonary arterial pressure-to-workload ratio at a threshold of 1.4 mm Hg/10 W was able to identify abnormal pulmonary hemodynamic response during exercise (>3.0 mm Hg/L per minute increase), with 91% sensitivity and 82% specificity (area under the curve, 0.90; 95% confidence interval, 0.77-1.0; P=0.001). CONCLUSIONS: Agreement between echocardiographic and invasive measures of pulmonary pressures during upright exercise is good among the subset of patients with high-quality TR Doppler signal. While the limits of agreement are broad, our results suggest that in those patients, sensitivity is adequate to screen for abnormal pulmonary hemodynamic response during exercise. PMID- 28360265 TI - Pulmonary Vascular Function During Exercise: Progressing Toward Routine Clinical Use. PMID- 28360261 TI - Computed Tomography Imaging Features in Acute Uncomplicated Stanford Type-B Aortic Dissection Predict Late Adverse Events. AB - BACKGROUND: Medical treatment of initially uncomplicated acute Stanford type-B aortic dissection is associated with a high rate of late adverse events. Identification of individuals who potentially benefit from preventive endografting is highly desirable. METHODS AND RESULTS: The association of computed tomography imaging features with late adverse events was retrospectively assessed in 83 patients with acute uncomplicated Stanford type-B aortic dissection, followed over a median of 850 (interquartile range 247-1824) days. Adverse events were defined as fatal or nonfatal aortic rupture, rapid aortic growth (>10 mm/y), aneurysm formation (>=6 cm), organ or limb ischemia, or new uncontrollable hypertension or pain. Five significant predictors were identified using multivariable Cox regression analysis: connective tissue disease (hazard ratio [HR] 2.94, 95% confidence interval [CI]: 1.29-6.72; P=0.01), circumferential extent of false lumen in angular degrees (HR 1.03 per degree, 95% CI: 1.01-1.04, P=0.003), maximum aortic diameter (HR 1.10 per mm, 95% CI: 1.02 1.18, P=0.015), false lumen outflow (HR 0.999 per mL/min, 95% CI: 0.998-1.000; P=0.055), and number of intercostal arteries (HR 0.89 per n, 95% CI: 0.80-0.98; P=0.024). A prediction model was constructed to calculate patient specific risk at 1, 2, and 5 years and to stratify patients into high-, intermediate-, and low risk groups. The model was internally validated by bootstrapping and showed good discriminatory ability with an optimism-corrected C statistic of 70.1%. CONCLUSIONS: Computed tomography imaging-based morphological features combined into a prediction model may be able to identify patients at high risk for late adverse events after an initially uncomplicated type-B aortic dissection. PMID- 28360266 TI - Gene bivalency at Polycomb domains regulates cranial neural crest positional identity. AB - The cranial neural crest cells are multipotent cells that provide head skeletogenic mesenchyme and are crucial for craniofacial patterning. We analyzed the chromatin landscapes of mouse cranial neural crest subpopulations in vivo. Early postmigratory subpopulations contributing to distinct mouse craniofacial structures displayed similar chromatin accessibility patterns yet differed transcriptionally. Accessible promoters and enhancers of differentially silenced genes carried H3K27me3/H3K4me2 bivalent chromatin marks embedded in large enhancer of zeste homolog 2-dependent Polycomb domains, indicating transcriptional poising. These postmigratory bivalent chromatin regions were already present in premigratory progenitors. At Polycomb domains, H3K27me3 antagonized H3K4me2 deposition, which was restricted to accessible sites. Thus, bivalent Polycomb domains provide a chromatin template for the regulation of cranial neural crest cell positional identity in vivo, contributing insights into the epigenetic regulation of face morphogenesis. PMID- 28360269 TI - Science for life. PMID- 28360270 TI - News at a glance. PMID- 28360268 TI - Biodiversity redistribution under climate change: Impacts on ecosystems and human well-being. AB - Distributions of Earth's species are changing at accelerating rates, increasingly driven by human-mediated climate change. Such changes are already altering the composition of ecological communities, but beyond conservation of natural systems, how and why does this matter? We review evidence that climate-driven species redistribution at regional to global scales affects ecosystem functioning, human well-being, and the dynamics of climate change itself. Production of natural resources required for food security, patterns of disease transmission, and processes of carbon sequestration are all altered by changes in species distribution. Consideration of these effects of biodiversity redistribution is critical yet lacking in most mitigation and adaptation strategies, including the United Nation's Sustainable Development Goals. PMID- 28360271 TI - Science funders plunge into publishing. PMID- 28360272 TI - U.N. biodiversity group confronts cash crunch. PMID- 28360273 TI - HIV infections are spiking among young gay Chinese. PMID- 28360274 TI - Enzymes offer waste-to-energy solution. PMID- 28360267 TI - Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq. AB - Tumor subclasses differ according to the genotypes and phenotypes of malignant cells as well as the composition of the tumor microenvironment (TME). We dissected these influences in isocitrate dehydrogenase (IDH)-mutant gliomas by combining 14,226 single-cell RNA sequencing (RNA-seq) profiles from 16 patient samples with bulk RNA-seq profiles from 165 patient samples. Differences in bulk profiles between IDH-mutant astrocytoma and oligodendroglioma can be primarily explained by distinct TME and signature genetic events, whereas both tumor types share similar developmental hierarchies and lineages of glial differentiation. As tumor grade increases, we find enhanced proliferation of malignant cells, larger pools of undifferentiated glioma cells, and an increase in macrophage over microglia expression programs in TME. Our work provides a unifying model for IDH mutant gliomas and a general framework for dissecting the differences among human tumor subclasses. PMID- 28360275 TI - Is the cell's garbage disposal sending messages? PMID- 28360276 TI - Dengue may bring out the worst in Zika. PMID- 28360277 TI - Circular RNAs hint at new realm of genetics. PMID- 28360278 TI - Deadly chemistry. PMID- 28360279 TI - Can we protect island flying foxes? PMID- 28360280 TI - Breathing to inspire and arouse. PMID- 28360281 TI - How Cyanobacteria went green. PMID- 28360282 TI - Costimulation, a surprising connection for immunotherapy. PMID- 28360283 TI - Looking backward to move regulations forward. PMID- 28360284 TI - Harnessing legal complexity. PMID- 28360286 TI - Cresting a gravitational wave. PMID- 28360285 TI - Mechanized creatures. PMID- 28360287 TI - Never Out of Season: How Having the Food We Want When We Want It Threatens Our Food Supply and Our Future. PMID- 28360288 TI - Global roadless areas: Hidden roads. PMID- 28360289 TI - Global roadless areas: Consider terrain. PMID- 28360290 TI - Global roadless areas-Response. PMID- 28360291 TI - Comment on "Outburst flood at 1920 BCE supports historicity of China's Great Flood and the Xia dynasty". AB - Wu et al (Reports, 5 August 2016, p. 579) reported geological and archaeological evidence about an earthquake-induced landslide dam outburst flood around 1920 BCE and claimed a support to the historicity of China's legendary Great Flood and Xia dynasty. We argue that the physical evidence is unreliable and their arguments are unconvincing. PMID- 28360292 TI - Comment on "Outburst flood at 1920 BCE supports historicity of China's Great Flood and the Xia dynasty". AB - By analyzing the data and methodology of Wu et al (Reports, 5 August 2016, p. 579), I find that their conclusions about the scale of the dammed lake, the dating of the lake, and the peak discharge at the point of dam failure and at the Lajia site cannot be validated. The conjecture of the supposed Great Flood and its impact on the formation of the early Chinese dynasty is not substantiated. PMID- 28360293 TI - Comment on "Outburst flood at 1920 BCE supports historicity of China's Great Flood and the Xia dynasty". AB - Wu et al (Reports, 5 August 2016, p. 579) reported an enormous flood in the upper Yellow River that destroyed the Lajia Ruins. However, published research shows that the Ruins were destroyed at 3950 years before the present (B.P.) by earthquakes accompanied with mudflows, whereas the landslide-dammed lake terminated about 5650 years B.P. Various kinds of sediments with different ages were taken as evidence to verify an outburst flood. PMID- 28360295 TI - AAAS seeks to uphold science's role in policy-making. PMID- 28360296 TI - Video games: The bad, the ugly, and the (potentially) good. PMID- 28360297 TI - Small molecules to target parasite organelle. PMID- 28360294 TI - Response to Comments on "Outburst flood at 1920 BCE supports historicity of China's Great Flood and the Xia dynasty". AB - Wu et al, Han, and Huang et al question our reconstruction of a large outburst flood and its possible relationship to China's Great Flood and the Xia dynasty. Here, we clarify misconceptions concerning geologic evidence of the flood, its timing and magnitude, and the complex social-cultural response. We also further discuss how this flood may be related to ancient accounts of the Great Flood and origins of the Xia dynasty. PMID- 28360298 TI - CD28 is a critical target for PD-1 blockade. PMID- 28360299 TI - Digging deeper into soils. PMID- 28360300 TI - The changing surface of a comet. PMID- 28360301 TI - The calming effect of breathing. PMID- 28360302 TI - Aging and variability among immune cells. PMID- 28360303 TI - Predicting the shape of crystals to come. PMID- 28360305 TI - Mapping a path to HIV elimination. PMID- 28360304 TI - Knowing a name promotes cooperation. PMID- 28360306 TI - Consequences of shifting species distributions. PMID- 28360308 TI - Effects of the tumor microenvironment. PMID- 28360307 TI - The epigenetics of face-making. PMID- 28360309 TI - Most of Mars' atmosphere has been lost. PMID- 28360310 TI - Turning benzene into a C-H bond cleaver. PMID- 28360311 TI - Photosynthesis evolution in Cyanobacteria. PMID- 28360313 TI - Flying foxes in peril. PMID- 28360314 TI - Vitamin C prevents microglia activation. PMID- 28360312 TI - Mtb faces sirtuin death. PMID- 28360316 TI - Common antibiotic hurts bee survival. PMID- 28360317 TI - Metastatic cells feed off a complement. PMID- 28360315 TI - Supported gold ions. PMID- 28360319 TI - Manipulating the fly conditionally. PMID- 28360318 TI - Separating chemistry from mechanics. PMID- 28360320 TI - Gut churning controls inflammation. PMID- 28360322 TI - 3D assessment: The future is here. PMID- 28360321 TI - Neon nudges clusters toward bulk liquid. PMID- 28360323 TI - Controlled growth and form of precipitating microsculptures. AB - Controlled self-assembly of three-dimensional shapes holds great potential for fabrication of functional materials. Their practical realization requires a theoretical framework to quantify and guide the dynamic sculpting of the curved structures that often arise in accretive mineralization. Motivated by a variety of bioinspired coprecipitation patterns of carbonate and silica, we develop a geometrical theory for the kinetics of the growth front that leaves behind thin walled complex structures. Our theory explains the range of previously observed experimental patterns and, in addition, predicts unexplored assembly pathways. This allows us to design a number of functional base shapes of optical microstructures, which we synthesize to demonstrate their light-guiding capabilities. Overall, our framework provides a way to understand and control the growth and form of functional precipitating microsculptures. PMID- 28360324 TI - Identification of single-site gold catalysis in acetylene hydrochlorination. AB - There remains considerable debate over the active form of gold under operating conditions of a recently validated gold catalyst for acetylene hydrochlorination. We have performed an in situ x-ray absorption fine structure study of gold/carbon (Au/C) catalysts under acetylene hydrochlorination reaction conditions and show that highly active catalysts comprise single-site cationic Au entities whose activity correlates with the ratio of Au(I):Au(III) present. We demonstrate that these Au/C catalysts are supported analogs of single-site homogeneous Au catalysts and propose a mechanism, supported by computational modeling, based on a redox couple of Au(I)-Au(III) species. PMID- 28360325 TI - Arylation of hydrocarbons enabled by organosilicon reagents and weakly coordinating anions. AB - Over the past 80 years, phenyl cation intermediates have been implicated in a variety of C-H arylation reactions. Although these examples have inspired several theoretical and mechanistic studies, aryl cation equivalents have received limited attention in organic methodology. Their high-energy, promiscuous reactivity profiles have hampered applications in selective intermolecular processes. We report a reaction design that overcomes these challenges. Specifically, we found that beta-silicon-stabilized aryl cation equivalents, generated via silylium-mediated fluoride activation, undergo insertion into sp3 and sp2 C-H bonds. This reaction manifold provides a framework for the catalytic arylation of hydrocarbons, including simple alkanes such as methane. This process uses low loadings of Earth-abundant initiators (1 to 5 mole percent) and occurs under mild conditions (30 degrees to 100 degrees C). PMID- 28360326 TI - Mars' atmospheric history derived from upper-atmosphere measurements of 38Ar/36Ar. AB - The history of Mars' atmosphere is important for understanding the geological evolution and potential habitability of the planet. We determine the amount of gas lost to space through time using measurements of the upper-atmospheric structure made by the Mars Atmosphere and Volatile Evolution (MAVEN) spacecraft. We derive the structure of 38Ar/36Ar between the homopause and exobase altitudes. Fractionation of argon occurs as a result of loss of gas to space by pickup-ion sputtering, which preferentially removes the lighter atom. The measurements require that 66% of the atmospheric argon has been lost to space. Thus, a large fraction of Mars' atmospheric gas has been lost to space, contributing to the transition in climate from an early, warm, wet environment to today's cold, dry atmosphere. PMID- 28360327 TI - Breathing control center neurons that promote arousal in mice. AB - Slow, controlled breathing has been used for centuries to promote mental calming, and it is used clinically to suppress excessive arousal such as panic attacks. However, the physiological and neural basis of the relationship between breathing and higher-order brain activity is unknown. We found a neuronal subpopulation in the mouse preBotzinger complex (preBotC), the primary breathing rhythm generator, which regulates the balance between calm and arousal behaviors. Conditional, bilateral genetic ablation of the ~175 Cdh9/Dbx1 double-positive preBotC neurons in adult mice left breathing intact but increased calm behaviors and decreased time in aroused states. These neurons project to, synapse on, and positively regulate noradrenergic neurons in the locus coeruleus, a brain center implicated in attention, arousal, and panic that projects throughout the brain. PMID- 28360330 TI - On the origins of oxygenic photosynthesis and aerobic respiration in Cyanobacteria. AB - The origin of oxygenic photosynthesis in Cyanobacteria led to the rise of oxygen on Earth ~2.3 billion years ago, profoundly altering the course of evolution by facilitating the development of aerobic respiration and complex multicellular life. Here we report the genomes of 41 uncultured organisms related to the photosynthetic Cyanobacteria (class Oxyphotobacteria), including members of the class Melainabacteria and a new class of Cyanobacteria (class Sericytochromatia) that is basal to the Melainabacteria and Oxyphotobacteria All members of the Melainabacteria and Sericytochromatia lack photosynthetic machinery, indicating that phototrophy was not an ancestral feature of the Cyanobacteria and that Oxyphotobacteria acquired the genes for photosynthesis relatively late in cyanobacterial evolution. We show that all three classes independently acquired aerobic respiratory complexes, supporting the hypothesis that aerobic respiration evolved after oxygenic photosynthesis. PMID- 28360328 TI - Inhibitors of PEX14 disrupt protein import into glycosomes and kill Trypanosoma parasites. AB - The parasitic protists of the Trypanosoma genus infect humans and domestic mammals, causing severe mortality and huge economic losses. The most threatening trypanosomiasis is Chagas disease, affecting up to 12 million people in the Americas. We report a way to selectively kill Trypanosoma by blocking glycosomal/peroxisomal import that depends on the PEX14-PEX5 protein-protein interaction. We developed small molecules that efficiently disrupt the PEX14-PEX5 interaction. This results in mislocalization of glycosomal enzymes, causing metabolic catastrophe, and it kills the parasite. High-resolution x-ray structures and nuclear magnetic resonance data enabled the efficient design of inhibitors with trypanocidal activities comparable to approved medications. These results identify PEX14 as an "Achilles' heel" of the Trypanosoma suitable for the development of new therapies against trypanosomiases and provide the structural basis for their development. PMID- 28360332 TI - Creating our own community. PMID- 28360333 TI - Detailed Characterization of the In Vitro Pharmacological and Pharmacokinetic Properties of N-(2-Hydroxybenzyl)-2,5-Dimethoxy-4-Cyanophenylethylamine (25CN NBOH), a Highly Selective and Brain-Penetrant 5-HT2A Receptor Agonist. AB - Therapeutic interest in augmentation of 5-hydroxytryptamine2A (5-HT2A) receptor signaling has been renewed by the effectiveness of psychedelic drugs in the treatment of various psychiatric conditions. In this study, we have further characterized the pharmacological properties of the recently developed 5-HT2 receptor agonist N-2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine (25CN NBOH) and three structural analogs at recombinant 5-HT2A, 5-HT2B, and 5-HT2C receptors and investigated the pharmacokinetic properties of the compound. 25CN NBOH displayed robust 5-HT2A selectivity in [3H]ketanserin/[3H]mesulergine, [3H]lysergic acid diethylamide and [3H]Cimbi-36 binding assays (Ki2C/Ki2A ratio range of 52-81; Ki2B/Ki2A ratio of 37). Moreover, in inositol phosphate and intracellular Ca2+ mobilization assays 25CN-NBOH exhibited 30- to 180-fold 5 HT2A/5-HT2C selectivities and 54-fold 5-HT2A/5-HT2B selectivity as measured by Deltalog(Rmax/EC50) values. In an off-target screening 25CN-NBOH (10 MUM) displayed either substantially weaker activity or inactivity at a plethora of other receptors, transporters, and kinases. In a toxicological screening, 25CN NBOH (100 MUM) displayed a benign acute cellular toxicological profile. 25CN-NBOH displayed high in vitro permeability (Papp = 29 * 10-6 cm/s) and low P glycoprotein-mediated efflux in a conventional model of cellular transport barriers. In vivo, administration of 25CN-NBOH (3 mg/kg, s.c.) in C57BL/6 mice mice produced plasma and brain concentrations of the free (unbound) compound of ~200 nM within 15 minutes, further supporting that 25CN-NBOH rapidly penetrates the blood-brain barrier and is not subjected to significant efflux. In conclusion, 25CN-NBOH appears to be a superior selective and brain-penetrant 5 HT2A receptor agonist compared with (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI), and thus we propose that the compound could be a valuable tool for future investigations of physiologic functions mediated by this receptor. PMID- 28360336 TI - Meet the First Authors. PMID- 28360329 TI - Aging increases cell-to-cell transcriptional variability upon immune stimulation. AB - Aging is characterized by progressive loss of physiological and cellular functions, but the molecular basis of this decline remains unclear. We explored how aging affects transcriptional dynamics using single-cell RNA sequencing of unstimulated and stimulated naive and effector memory CD4+ T cells from young and old mice from two divergent species. In young animals, immunological activation drives a conserved transcriptomic switch, resulting in tightly controlled gene expression characterized by a strong up-regulation of a core activation program, coupled with a decrease in cell-to-cell variability. Aging perturbed the activation of this core program and increased expression heterogeneity across populations of cells in both species. These discoveries suggest that increased cell-to-cell transcriptional variability will be a hallmark feature of aging across most, if not all, mammalian tissues. PMID- 28360337 TI - Trainees in the Spotlight: Yet Another Addition to Our Portfolio. PMID- 28360338 TI - Novel Lipoprotein(a) Catabolism Pathway via Apolipoprotein(a) Recycling: Adding the Plasminogen Receptor PlgRKT to the List. PMID- 28360334 TI - A Genomic DNA Reporter Screen Identifies Squalene Synthase Inhibitors That Act Cooperatively with Statins to Upregulate the Low-Density Lipoprotein Receptor. AB - Hypercholesterolemia remains one of the leading risk factors for the development of cardiovascular disease. Many large double-blind studies have demonstrated that lowering low-density lipoprotein (LDL) cholesterol using a statin can reduce the risk of having a cardiovascular event by approximately 30%. However, despite the success of statins, some patient populations are unable to lower their LDL cholesterol to meet the targeted lipid levels, due to compliance or potency issues. This is especially true for patients with heterozygous familial hypercholesterolemia who may require additional upregulation of the low-density lipoprotein receptor (LDLR) to reduce LDL cholesterol levels below those achievable with maximal dosing of statins. Here we identify a series of small molecules from a genomic DNA reporter screen that upregulate the LDLR in mouse and human liver cell lines at nanomolar potencies (EC50 = 39 nM). Structure activity relationship studies carried out on the lead compound, OX03771 [(E)-N,N dimethyl-3-(4-styrylphenoxy)propan-1-amine], led to the identification of compound OX03050 [(E)-3-(4-styrylphenoxy)propan-1-ol], which had similar potency (EC50 = 26 nM) but a much-improved pharmacokinetic profile and showed in vivo efficacy. Compounds OX03050 and OX03771 were found to inhibit squalene synthase, the first committed step in cholesterol biosynthesis. These squalene synthase inhibitors were shown to act cooperatively with statins to increase LDLR expression in vitro. Overall, we demonstrated here a novel series of small molecules with the potential to be further developed to treat patients either alone or in combination with statins. PMID- 28360339 TI - Biological Age and Circulating Progenitor Cell Levels as Predictors Heart Disease Events. PMID- 28360340 TI - Route TESI: Main Street for MSC? PMID- 28360341 TI - Inorganic Nitrates: Qi for Heart Failure With Preserved Ejection Fraction? PMID- 28360343 TI - Catherine Makarewich: Collaboration of Diligence and Luck. PMID- 28360342 TI - Clinical Progress in Cell Therapy for Single Ventricle Congenital Heart Disease. PMID- 28360344 TI - The Davis Heart and Lung Research Institute: Building a Sustainable Platform for Translation. PMID- 28360345 TI - The Unraveling of the Matryoshka Doll. PMID- 28360346 TI - Individualized Knowledge Graph: A Viable Informatics Path to Precision Medicine. PMID- 28360347 TI - Adapt or Perish: Updating the Predoctoral Training Model. PMID- 28360351 TI - Correction to: Novel Risk Markers and Risk Assessments for Cardiovascular Disease. PMID- 28360350 TI - Myocardial Viability: Survival Mechanisms and Molecular Imaging Targets in Acute and Chronic Ischemia. AB - Myocardial responses to acute ischemia/reperfusion and to chronic ischemic conditions have been studied extensively at all levels of organization. These include subcellular (eg, mitochondria in vitro); intact, large animal models (eg, swine with chronic coronary stenosis); as well as human subjects. Investigations in humans have used positron emission tomographic metabolic and myocardial blood flow measurements, assessment of gene expression and anatomic description of myocardium obtained at the time of coronary artery revascularization, ventricular assist device placement, or heart transplantation. A multitude of genetic, molecular, and metabolic pathways have been identified, which may promote either myocyte survival or death or, most interestingly, both. Many of these potential mediators in both acute ischemia/reperfusion and adaptations to chronic ischemic conditions involve the mitochondria, which play a central role in cellular energy production and homeostasis. The present review is focused on operative survival mechanisms and potential myocardial viability molecular imaging targets in acute and chronic ischemia, especially those which impact mitochondrial function. PMID- 28360348 TI - Contemporary Approaches to Modulating the Nitric Oxide-cGMP Pathway in Cardiovascular Disease. AB - Endothelial cells lining the vessel wall control important aspects of vascular homeostasis. In particular, the production of endothelium-derived nitric oxide and activation of soluble guanylate cyclase promotes endothelial quiescence and governs vasomotor function and proportional remodeling of blood vessels. Here, we discuss novel approaches to improve endothelial nitric oxide generation and preserve its bioavailability. We also discuss therapeutic opportunities aimed at activation of soluble guanylate cyclase for multiple cardiovascular indications. PMID- 28360352 TI - Intracranial venous pressures under conscious sedation and general anesthesia. AB - INTRODUCTION: Venous outflow obstruction has been implicated in the pathophysiology of a subset of patients with idiopathic intracranial hypertension (IIH), and venous sinus stenting (VSS) has emerged as an effective treatment. However, the effect of anesthesia on venous sinus pressure measurements is unpredictable. A more thorough understanding of the effect of the level of anesthesia on intracranial venous pressures might help to better define patients who might benefit most from stent placement. OBJECTIVE: To compare, in a retrospective cohort study, intracranial venous pressures measured under conscious (CS) sedation versus general anesthesia (GA) and to assess the relationship between anesthetic-dependent venous pressures and outcomes after VSS. METHODS: We performed a retrospective review of a prospectively maintained database to identify patients undergoing angiographic evaluation and VSS for intracranial venous stenosis. Mean venous pressures (MVPs) and trans-stenosis pressure gradients obtained under CS were compared with those measured under GA. RESULTS: The maximal MVP was significantly lower under GA (19.8 mm Hg) than CS (21.9 mm Hg; p=0.029). The MVPs in the superior sagittal sinus, torcula, and transverse sinus were lower under GA, but were significantly higher in the sigmoid sinus and jugular bulb under GA (p<0.001). The mean trans-stenosis pressure gradient was also significantly lower under GA (8.6 mm Hg) than CS (12.1 mm Hg; p<0.001). Patients with a larger difference between maximum MVP under GA versus CS were more likely to have normalization of the MVP after VSS (p=0.0008). CONCLUSIONS: Intracranial venous pressures are markedly affected by GA. In order to obtain an accurate measurement of MVPs and trans-stenosis gradients, patients undergoing investigation for IIH should undergo cerebral angiography and venous manometry under CS, which provides more reliable data for outcomes after VSS. PMID- 28360349 TI - Gut Microbiota in Cardiovascular Health and Disease. AB - Significant interest in recent years has focused on gut microbiota-host interaction because accumulating evidence has revealed that intestinal microbiota play an important role in human health and disease, including cardiovascular diseases. Changes in the composition of gut microbiota associated with disease, referred to as dysbiosis, have been linked to pathologies such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity, and type 2 diabetes mellitus. In addition to alterations in gut microbiota composition, the metabolic potential of gut microbiota has been identified as a contributing factor in the development of diseases. Recent studies revealed that gut microbiota can elicit a variety of effects on the host. Indeed, the gut microbiome functions like an endocrine organ, generating bioactive metabolites, that can impact host physiology. Microbiota interact with the host through many pathways, including the trimethylamine/trimethylamine N-oxide pathway, short chain fatty acids pathway, and primary and secondary bile acids pathways. In addition to these metabolism-dependent pathways, metabolism-independent processes are suggested to also potentially contribute to cardiovascular disease pathogenesis. For example, heart failure-associated splanchnic circulation congestion, bowel wall edema, and impaired intestinal barrier function are thought to result in bacterial translocation, the presence of bacterial products in the systemic circulation and heightened inflammatory state. These are thought to also contribute to further progression of heart failure and atherosclerosis. The purpose of the current review is to highlight the complex interplay between microbiota, their metabolites, and the development and progression of cardiovascular diseases. We will also discuss the roles of gut microbiota in normal physiology and the potential of modulating intestinal microbial inhabitants as novel therapeutic targets. PMID- 28360353 TI - Optical coherence tomography evaluation of tissue prolapse after carotid artery stenting using closed cell design stents for unstable plaque. AB - BACKGROUND AND PURPOSE: During carotid artery stenting (CAS) with the use of closed cell design stents for unstable plaques, tissue prolapse between stent struts was evaluated by optical coherence tomography (OCT). METHODS: 14 carotid stenosis lesions diagnosed as unstable plaques by MRI were evaluated by OCT imaging during CAS using closed cell stents. Cross sectional OCT images within the stented segment were evaluated at 1 mm intervals. The slice rate for the presence of tissue prolapse between the struts was calculated. RESULTS: No intra procedural complications occurred. After single stent placement, plaque prolapse was observed in all cases. Slices with any and >500 um tissue prolapse were seen in 30% and 7.8% of cases, respectively. In 5 of 7 lesions with tissue prolapse >500 um, additional stents were overlapped. In cases with overlapping stents, slices with any tissue prolapse were significantly decreased from 26% to 16% (p=0.008); in particular, the occurrence of tissue prolapse >500 um was significantly decreased from 15% to 2.3% (p<0.001). In one case of >500 um tissue prolapse without an overlapping stent, delayed embolization due to an in-stent thrombus occurred 9 months after the procedure. CONCLUSIONS: OCT during CAS using closed cell stent for unstable plaques frequently revealed tissue prolapse between struts. Placement of overlapping stents significantly reduced tissue prolapse, particularly tissue prolapse >500 um. However, closed cell stents used for unstable plaques may not solve the problem of tissue prolapse. PMID- 28360355 TI - Predicting APL lethal bleeding in the ATRA era. PMID- 28360354 TI - Predictors of false-positive stroke thrombectomy transfers. AB - BACKGROUND: Most patients with large vessel occlusion (LVO) stroke need to be transferred to receive thrombectomy. To save time, the decision to transfer often relies on clinical scales as a surrogate for LVO rather than imaging. However, clinical scales have been associated with high levels of diagnostic error. The aim of this study is to define the susceptibility to overdiagnosis of our current transfer decision process by measuring the rate of non-treatment transfers, the most common reasons for no treatment and potential predictors. METHODS: Clinical and transfer data on consecutive patients transferred to a single endovascular capable centre for possible thrombectomy via stroke code activation were retrospectively reviewed. Whether patients underwent the procedure, why they did not undergo the procedure, and other clinical and logistical predictors were recorded. chi2 tests and multivariate logistic regression analysis were performed. RESULTS: From 2015 to 2016, 105/192 transferred patients (54%) did not undergo thrombectomy and the most common reason was absence of a LVO found on CTA after transfer (71/104 (68%)). 14/16 (88%) with a National Institutes of Health Stroke Scale (NIHSS) score <10 did not undergo thrombectomy while 41/78 (52%) with a NIHSS>20 underwent thrombectomy (p<0.001). Helicopter use was associated with no treatment (p=0.004) while arrival within 5 hours was associated with treatment (p<0.001). CONCLUSIONS: Clinical scales appear to overdiagnose LVO and may be responsible for the majority of our stroke code transfers not undergoing thrombectomy. Primary stroke centres therefore have reason to develop the capability to rapidly acquire and interpret a CTA in patients with suspected LVO prior to transfer. Such efforts may reduce the costs associated with unnecessary thrombectomy transfers. PMID- 28360356 TI - Toward autophagy-targeted therapy in lymphoma. PMID- 28360357 TI - Risking thromboembolism: podoplanin and glioma. PMID- 28360358 TI - APL: Oh! What a tangled web we weave. PMID- 28360359 TI - The classical nature of distinctive CMML monocytes. PMID- 28360361 TI - Peripheral T-cell lymphoma with EBV-infected "anaplastic" B-cell proliferation confined to sinuses. PMID- 28360360 TI - Clusters of paracortical plasmacytoid dendritic cells in lupus lymphadenitis. PMID- 28360362 TI - Rising to the Challenge of Antimicrobial Resistance. PMID- 28360363 TI - The Importance of Continuous Quality Improvement in Peritoneal Dialysis Units. PMID- 28360364 TI - The Future of Peritoneal Dialysis in a Moving Landscape of Bacterial Resistance. PMID- 28360365 TI - ISPD Catheter-Related Infection Recommendations: 2017 Update. PMID- 28360366 TI - Peritoneal Dialysis to Treat Patients with Acute Kidney Injury-The Saving Young Lives Experience in West Africa: Proceedings of the Saving Young Lives Session at the First International Conference of Dialysis in West Africa, Dakar, Senegal, December 2015. AB - In December 2015, as part of the First African Dialysis Conference organized in Dakar, Senegal, 5 physicians from West African countries who have participated in the Saving Young Lives Program reviewed their experiences establishing peritoneal dialysis (PD) programs to treat patients with acute kidney injury (AKI). Thus far, nearly 200 patients have received PD treatment in these countries. The interaction and discussion amongst the participants at the meeting was meaningful and informative. The presentations highlighted the creativity, conviction, and determination of the physicians in overcoming the various barriers and challenges they encountered to establish PD/AKI programs. Hopefully, these successes and the increased awareness of the importance of early diagnosis and treatment of AKI will inspire much needed support from government, hospital, and international organizations. PMID- 28360367 TI - Peritoneal Dialysis: A Scoping Review of Strategies to Maximize PD Utilization. AB - The percentage of end-stage renal disease (ESRD) patients treated with peritoneal dialysis (PD) has declined in many countries since the mid-1990s. Barriers to PD have been reviewed extensively in the literature, but evidence about strategies to address these barriers and maximize the safe and effective use of PD is lacking. We therefore decided to conduct a scoping review identifying strategies to maximize PD use in adults with ESRD. Our search strategy included the following online databases: MEDLINE (OVID), EMBASE, PubMed, Cochrane Controlled Trials Register, Current Controlled Trials, and Cochrane Database of Systematic Reviews for articles published from 1974 to November 2013. Experts in the field were contacted for information about other ongoing or unpublished studies. A complementary search was conducted in the gray literature. Websites of national, provincial or regional agencies were searched for documents regarding policies surrounding the use of PD. Individual dialysis centers need to identify barriers to increasing PD in their program and direct targeted strategies to maximize PD utilization. Our review highlights some effective strategies that may be used. Our review also highlights the need for further research into strategies to maximize PD utilization. PMID- 28360368 TI - The 'Pull' Technique for Removal of Peritoneal Dialysis Catheters: A Call for Re Evaluation of Practice Standards. AB - ? BACKGROUND: The most commonly used peritoneal dialysis (PD) catheters have silicon tubing with attached Dacron cuffs. The current standard of care for PD catheter removal is by complete surgical dissection, withdrawing both the tubing and the cuffs. The intention is to avoid infection of any residual part of the catheter. We retrospectively analyzed our results with the alternative 'pull' technique, by which the silicon tube is pulled out, leaving the Dacron cuffs within the abdominal wall. This technique never gained popularity due to concern that the retained cuffs would get infected. ? METHODS: We reviewed our experience from an 18-month period, between January 2014 and June 2015. There were 46 catheter removals in 40 patients. All the catheters were of the double-cuffed coiled Tenckhoff type (Covidien, Dublin, Ireland). ? RESULTS: Of the 46 catheter removals by the 'pull' technique, there was only 1 case of retained cuff infection. ? CONCLUSIONS: The 'pull' technique is a safe method for Tenckhoff catheter removal with low risk of infection. We strongly recommend it as the procedure of choice. PMID- 28360369 TI - Significant Decreasing Incidence of Encapsulating Peritoneal Sclerosis in the Dutch Population of Peritoneal Dialysis Patients. AB - The Dutch Encapsulating Peritoneal Sclerosis (EPS) Registry was started in 2009. Cases were identified by contacting all Dutch nephrologists twice yearly. The predefined criteria for EPS allowed for inclusion of patients with diagnosed and suspected EPS. Cases registered between January 2009 and January 2015 were analyzed with follow-up until September 2015. Fifty-three EPS cases were identified, of which 28.3% were post-transplantation EPS cases. Fourteen patients were initially categorized as suspected EPS, of whom 13 developed EPS. A remarkable 6-fold decrease in the yearly incidence of EPS was observed, from 0.85% in 2009 to 0.14% in 2014. This decrease could not be explained by a decrease in the number of PD patients or average duration of PD treatment in this period. Two-year survival of EPS patients was 52%. The use of tamoxifen and surgical interventions increased significantly over the years. Tamoxifen-treated cases showed a trend to better patient survival and post-transplantation EPS had a significantly favorable outcome. In conclusion, the incidence of EPS has declined significantly in the Netherlands from 2009 to 2014. PMID- 28360370 TI - Barriers to Increasing Use of Peritoneal Dialysis in Bangladesh: A Survey of Patients and Providers. AB - Despite a lower requirement for technology and equipment than hemodialysis (HD), peritoneal dialysis (PD) is an underutilized modality in low- and middle-income countries (LMICs). Bangladesh has the lowest use of PD in the world (fewer than 2% of prevalent patients). We evaluated nephrologists' attitudes toward PD and examined differences between patients on HD and PD in Dhaka. We asked nephrologists to fill out an English-language questionnaire. Using convenience sampling but targeting both public and private hospitals in Dhaka, we asked trained nurses to administer a Bangla-language questionnaire to patients on HD (n = 116) and PD (n = 41). We validated the questionnaires on a sub-sample (n = 10 for each group). Of the 43 nephrologists surveyed, 27 (63%) had patients on PD. When compared with nephrologists without patients on PD, those with patients on PD were less likely to believe that survival and quality of life on PD was worse than on HD (odds ratio [OR] = 0.21, 95% confidence interval [CI] 0.05 - 0.83 and OR = 0.11, 95% CI 0.02 - 0.67 respectively) but were not more likely to have received training for PD. Nephrologists named cost of PD as the predominant barrier to increasing use of PD, followed by concerns about patient hygiene and lack of trained nurses. Fifty-two HD patients (45%) did not know about a home based modality. When compared with patients on HD, patients on PD were more likely to have been educated by non-nephrologists about dialysis, to be "forewarned" about the need for dialysis, to be paying fully, and to be living in a permanent home with a non-communal water source. Some barriers to increasing access to PD-i.e., patient living conditions and cost-are unique to LMICs. Our study also highlights that issues encountered in high-income countries-i.e., nephrologists' subjective preference and lack of patient knowledge about an alternate modality to HD-may play a role as well. PMID- 28360371 TI - CAPD Catheter Exit-Site and Tunnel Infection with Fungal Etiology-Treatment and Catheter Reinsertion for an Extremely Rare Complication. AB - Fungal infection is an extremely rare etiology of exit-site and tunnel infection in patients on continuous ambulatory peritoneal dialysis (CAPD). There are few data available regarding its management-especially choice of antifungals, duration of therapy, and removal of catheter. There are no guidelines pertaining to reinsertion of the CAPD catheter following fungal exit-site and tunnel infection. This case report highlights Candida albicans as a rare cause of exit site and tunnel infection of the CAPD catheter. The catheter was removed and the patient received appropriate antifungal therapy followed by reinsertion of the CAPD catheter and re-initiation on CAPD. PMID- 28360372 TI - Peritonitis as the First Presentation of Disseminated Listeriosis in a Patient on Peritoneal Dialysis-a Case Report. AB - Infections with Listeria monocytogenes are uncommon but serious, with mortality rate approaching 30% in cases of systemic involvement despite first-line therapy. They are usually caused by ingestion of contaminated foods, but spontaneous infections have also been described. Listeria monocytogenes is a rare cause of peritonitis, and most of the published cases are in patients with cirrhosis and ascites. There are a few reported cases of Listeria peritonitis associated with peritoneal dialysis (PD), primarily isolated peritonitis.If detected early, Listeria peritonitis can be successfully treated with ampicillin, alone or in combination with gentamicin. Vancomycin has been listed as a second-line agent. However, it has been associated with treatment failure.In this case report, we present a patient who developed disseminated listeriosis, with peritonitis as the first manifestation of disseminated infection. This case illustrates the importance of having a high index of suspicion for L. monocytogenes if patients deteriorate despite empiric therapy for PD-associated peritonitis and serves as a further example demonstrating the inadequate coverage of vancomycin for L. monocytogenes. PMID- 28360374 TI - The Phrene Asunder: The Unrelenting Puzzle of Psychosis. PMID- 28360373 TI - Successful Treatment of PD Peritonitis Due to Morganella morganii Resistant to Third-Generation Cephalosporins - A Case Report. AB - Morganella morganii is a rare cause of peritonitis in patients on peritoneal dialysis (PD). Most of the reported cases have resorted to a switch to hemodialysis. We herein report a case of peritonitis due to M. morganii resistant to third-generation cephalosporins, which was treated successfully with intraperitoneal (IP) tobramycin followed by oral ciprofloxacin. Early microbiologic diagnosis is essential in the treatment of peritonitis from rare microorganisms such as Morganella morganii, and appropriate antibiotic therapy is the key to avoiding catheter loss and subsequent switch to hemodialysis. PMID- 28360377 TI - Erratum. PMID- 28360375 TI - The Path to New Therapies for Schizophrenia and Bipolar Illness. AB - Schizophrenia and bipolar illness are two of the most serious forms of mental illness. Until relatively recently, almost nothing was known about the molecular pathogenesis of either illness. The single largest risk factor that predisposes people to schizophrenia or bipolar illness is genetic risk. Heritability is high, and the incidence is significantly higher in identical twins than in nonidentical twins. Despite decades of work aimed at identifying the genes involved in these two illnesses, virtually no progress had been made until the past decade. With the knowledge and technologies that have been gained from the Human Genome Project, it has been possible to begin to understand the underlying genetics and to use the new information to begin the effort to discover new and better medicines to treat these illnesses. This article will describe the past decade of work toward this goal and articulate both the promise that now exists and what is still needed to bring dramatic and tangible change to patients.-Scolnick, E. M. The path to new therapies for schizophrenia and bipolar illness. PMID- 28360378 TI - A systematic review and appraisal of the quality of practice guidelines for the management of Neisseria gonorrhoeae infections. AB - BACKGROUND: Clinical guidelines help ensure consistent care informed by current evidence. As shifts in antimicrobial resistance continue to influence first-line treatment, up-to-date guidelines are important for preventing treatment failure. A guideline's development process will influence its recommendations and users' trust. OBJECTIVE: To assess the quality of current gonorrhoea guidelines' development processes. DATA SOURCES: Multiple databases. STUDY ELIGIBILITY CRITERIA: Original and current English-language guidelines targeting health professionals and containing treatment recommendations for uncomplicated gonorrhoea in the general adult population. STUDY APPRAISAL AND SYNTHESIS METHODS: Two appraisers assessed the guidelines independently using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool. Scores were combined as per the AGREE II users' manual. RESULTS: We identified 10 guidelines meeting the inclusion criteria. The quality of the gonorrhoea treatment guidelines varied. Most scored poorly on Rigour of Development; information on the evidence review process and methods for formulating recommendations was often missing. The WHO Guidelines for the Treatment of Neisseria gonorrhoeae and UK National Guideline for the Management of Gonorrhoea in Adults scored the highest on Rigour of Development. Methods to address conflicts of interest were often not described in the materials reviewed. Implementation of recommendations was often not addressed. LIMITATIONS: By limiting our study to English-language guidelines, a small number of guidelines we identified were excluded. Our analysis was limited to either published or online materials that were readily available to users. We could not differentiate between items addressed in the development process but not documented from items that were not addressed. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Gonorrhoea treatment guidelines may slow antimicrobial resistance. Many current guidelines are not in line with the current guideline development best practices; this might undermine the perceived trustworthiness of guidelines. By identifying current limitations, this study can help improve the quality of future guidelines. PMID- 28360379 TI - Prevalence and characteristics of gastrointestinal infections in men who have sex with men diagnosed with rectal chlamydia infection in the UK: an 'unlinked anonymous' cross-sectional study. AB - INTRODUCTION: Gastrointestinal infections (GII) can cause serious ill health and morbidity. Although primarily transmitted through faecal contamination of food or water, transmission through sexual activity is well described, especially among men who have sex with men (MSM). METHODS: We investigated the prevalence of GIIs among a convenience sample of MSM who were consecutively diagnosed with rectal Chlamydia trachomatis (CT) at 12 UK genitourinary medicine clinics during 10 weeks in 2012. Residual rectal swabs were coded, anonymised and tested for Shigella, Campylobacter, Salmonella, shiga toxin-producing Escherichia coli and enteroaggregative E. coli (EAEC) using a real-time PCR. Results were linked to respective coded and anonymised clinical and demographic data. Associations were investigated using Fisher's exact tests. RESULTS: Of 444 specimens tested, overall GII prevalence was 8.6% (95% CI 6.3% to 11.6%): 1.8% (0.9% to 3.6%) tested positive for Shigella, 1.8% (0.9% to 3.6%) for Campylobacter and 5.2% (3.5% to 7.7%) for EAEC. No specimens tested positive for Salmonella or other diarrhoeagenic E. coli pathotypes. Among those with any GII, 14/30 were asymptomatic (2/7 with Shigella, 3/6 with Campylobacter and 9/17 with EAEC). Shigella prevalence was higher in MSM who were HIV-positive (4.7% (2.1% to 10.2%) vs 0.5%(0.1% to 3.2%) in HIV-negative MSM; p=0.01). CONCLUSIONS: In this small feasibility study, MSM with rectal CT appeared to be at appreciable risk of GII. Asymptomatic carriage may play a role in sexual transmission of GII. PMID- 28360380 TI - Genetic diversity of Echinococcus multilocularis in red foxes in Poland: the first report of a haplotype of probable Asian origin. AB - The aim of the present study was to estimate the genetic diversity of the cestode Echinococcus multilocularis Leuckart, 1863 in Poland based on sequence analysis of the mitochondrial genes of worms isolated from red foxes, Vulpes vulpes (Linnaeus). Overall, 83 adults of E. multilocularis from the same number of foxes in different parts of Poland were used for analysis. Sequences of the three mitochondrial genes, cytochrome b (cob), NADH dehydrogenase subunit 2 (nad2) and cytochrome c oxidase subunit 1 (cox1), were analysed. Seventy-four individual biological samples were successfully sequenced. Combined sequence analysis of these three genes exhibited fifteen Polish haplotypes (EmPL1-EmPL15). Most isolates (n = 29; 39%) were classified to the EmPL1 haplotype, which occurred mainly in the east, north and centre of Poland. Haplotype EmPL4 (n = 14; 19%) and other haplotypes appeared predominantly in the south and west area. Fourteen haplotypes were grouped in the European clade. One Polish haplotype (EmPL9) (n = 7, 10%) was assigned to the Asian clade with haplotypes from Japan and Kazakhstan. This haplotype was found only in northeast Poland and this is the westernmost report of haplotype of E. multilocularis belonging to the Asian clade in Europe. The investigation demonstrated that populations of E. multilocularis in Poland (and probably also in eastern Europe) included not only different European haplotypes but also those of the Asian origin. PMID- 28360381 TI - Microsatellite development and characterization for Saurogobio dabryi Bleeker, 1871 in a Yangtze river-connected lake, China. PMID- 28360382 TI - Genetic diversity in Satureja species determined by sequence-related amplified polymorphism markers. PMID- 28360383 TI - Cloning and expression analysis of zygote arrest 1 (Zar1) in New Zealand white rabbits. AB - Zygote arrest 1 (Zar1) is an oocyte-specific maternal-effect gene. Previous studies indicate that Zar1 plays important role in early embryo development, but little is known about its function in rabbit. The objectives of this study were to clone the New Zealand white rabbit Zar1 gene and to investigate its expression in various organs in groups of animals with different reproductive traits.We obtained a 709-bp Zar1 cDNA fragment consisting of an 8-bp exon 1, 161-bp exon 2, 75-bp exon 3, 271-bp exon 4 and 194-bp 3'sequences. The rabbit Zar1 nucleotide sequence showed per cent identities of 91, 88, 88, 87, 86, 87, 76 and 82% with Zar1 orthologues in human, cattle, sheep, pig, mouse, rat, zebrafish and Xenopus laevis, respectively, indicating a high homology with other species and evolutionary conservation. Quantitative real-time polymerase chain reaction analyses revealed nonoocyte-specific Zar1 expression, with expression in spleen, lung, ovary, uterus, heart, liver and kidney. The expression level was highest in the lung. This study may lay the theoretical foundation for the study of ZAR1's biological function. PMID- 28360384 TI - Sequence variants of the LCORL gene and its association with growth and carcass traits in Qinchuan cattle in China. AB - Molecular marker-assisted selection is a better way to satisfy the growing customer requirement with the development of beef cattle growth and breeding research. For now, quantitative trait locus (QTL) for cattle growth and carcass traits, just like body height, body length and carcass weight have been detected on bovine chromosome 6. In this study, ligand-dependent nuclear receptor corepressor-like (LCORL) was selected as the potential positional candidate gene located in chromosome 6 which is closely connected with the bovine growth and carcass traits. A total of 450 Qinchuan beef cattle were used to detect mutations in exon and its neighbouring region, and the promoter region of the bovine LCORL gene. The methods for SNPs detection were polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and created restriction site PCR (CRSPCR), and the results of this study show that there were two variations in intron regions, the other four variations were located in the promoter region. Linkage disequilibrium analysis and haplotype analysis indicated that L78-Q4 had strong linkage disequilibrium, A T G C G C (16.2%) and G C G C A T (16.7%) had higher haplotype frequencies, G C A C A C (0.8%) and G T A C A T (0.7%) had lower haplotype frequencies. Correlation analysis indicated that SNP g. INT+52098A>G was significantly associated with slaughter weight and carcass weight. Based on the research, we selected LCORL as the candidate gene that can contribute to improved marker-assisted selection for the meat performance of Qinchuan beef cattle. PMID- 28360385 TI - Molecular analysis of glycogen storage disease type Ia in Iranian Azeri Turks: identification of a novel mutation. AB - Glycogen storage diseases (GSDs) are caused by abnormalities in enzymes that are involved in the regulation of gluconeogenesis and glycogenolysis. GSD I, an autosomal recessive metabolic disorder, is the most common GSD and has four subtypes. Here, we examined GSD Ia caused by the defective glucose-6-phosphatase catalytic (G6PC) gene. We investigated the frequency of GSD Ia and clarified its molecular aspect in patients with the main clinical and biochemical characteristics of GSD, including 37 unrelated patients with a mean age of three years at the time of diagnosis. All patients belonged to the Azeri Turkish population. Hypoglycaemia and hypertriglyceridaemia were the most frequent laboratory findings. Mutations were detected by performing direct sequencing. Mutation analysis of the G6PC gene revealed that GSD Ia accounted for 11% in GSD patients with involvement of liver. Three patients were homozygous for R83C mutation. In addition, a novel stop mutation, Y85X, was identified in a patient with the typical features of GSD Ia. PMID- 28360386 TI - Cloning and expression analysis of a new anther-specific gene CaMF4 in Capsicum annuum. AB - Our previous study on the genic male sterile-fertile line 114AB of Capsicum annuum indicated a diversity of differentially expressed cDNA fragments in fertile and sterile lines. In this study, a transcript-derived fragment (TDF), male fertile 4 (CaMF4) was chosen for further investigation to observe that this specific fragment accumulates in the flower buds of the fertile line. The full genomic DNA sequence of CaMF4 was 894 bp in length, containing two exons and one intron, and the complete coding sequence encoded a putative 11.53 kDa protein of 109 amino acids. The derived protein of CaMF4 shared similarity with the members of PGPS/D3 protein family. The expression of CaMF4 was detected in both the flower buds at stage 8 and open flowers of the male fertile line. In contrast to this observation, expression of CaMF4 was not detected in any organs of the male sterile line. Further analysis revealed that CaMF4 was expressed particularly in anthers of the fertile line. Our results suggest that CaMF4 is an anther-specific gene and might be indispensable for anther or pollen development in C. annuum. PMID- 28360387 TI - Genetic structure of Pseudococcus microcirculus (Hemiptera: Pseudococcidae) populations on epiphytic orchids in south Florida. AB - In 2012, the orchid mealy bug Pseudococcus microcirculus was first detected in situ in North America's more diverse orchid region, the Big Cypress Basin (Collier Co FL). A follow-up survey showed that the mealy bug is more widespread and found on epiphytic orchids in two locations, in both the Fakahatchee Strand State Preserve (sites B and F) and the Florida Panther National Wildlife Refuge (sites M and C). There, we collected mealy bugs (n = 54) from 35 orchid individuals and screened allelic variation at seven microsatellite loci. We estimated genetic diversity and differentiation among all sites and compared the variation among individuals collected on the same plant. Genetic differentiation between sites M and C (FST = 0.03, P < 0.01) and,Mand B (FST = 0.04, P < 0.01) was detected.We also detected significantly lower mean pairwise relatedness among individuals from site B compared to all the other locations, and this population had the lowest inbreeding coefficient. Genetic diversity and mean pairwise relatedness were highly variable among plants with multiple individuals; however, plants from sites F and M tend to have collections of individuals with higher mean pairwise relatedness compared to sites B and C. Our results indicate that there is genetic diversity and differentiation among mealy bugs in these locations, and that collections of individuals on the same plant are genetically diverse. As such, the mealy bugs throughout these areas are likely to be genetically diverse and exist in multiple distinct populations. PMID- 28360388 TI - Transiently expressed pattern during myogenesis and candidate miRNAs of Tmem8C in goose. AB - Transmembrane protein 8C (Tmem8C) is a muscle-specific membrane protein that controls myoblast fusion, which is essential for the formation of multinucleated muscle fibres. As most of the birds can fly, they have enormous requirement for the muscle, but there are only a few studies of Tmem8C in birds. In this study, we obtained the coding sequence (CDS) of Tmem8C in goose, predicted miRNAs that can act on the 3'UTR, analysed expression profiles of this gene in breast and leg muscles (BM and LM) during the embryonic period and neonatal stages, and identified miRNAs that might affect the targeted gene. The results revealed a high homology between Tmem8C in goose and other animals (indicated by sequence comparisons and phylogenetic trees), some conservative characteristics (e.g., six transmembrane domains and two E-boxes in the 5'UTR might be the potential binding sites of muscle regulatory factors (MRFs)), and the dN/dS ratio indicated purifying selection acting on this gene, facilitating conservatism in vertebrates. Q-PCR indicated Tmem8C had a peak expression pattern, reaching its highest expression levels in stage E15 in LM and E19 in BM, and then dropping transiently in E23 (P < 0.05). We examined 13 candidate miRNAs, and negative relationships were detected both in BM and LM (mir-125b-5p, mir-15a, mir-16-1 and mir-n23). Notably, mir-16-1 significantly decreased luciferase activity in dual luciferase reporter gene (LRG) assay, suggesting that it can be identified as potential factors affecting Tmem8C. This study investigated Tmem8C in water bird for the first time, and provided useful information about this gene and its candidate miRNAs in goose. PMID- 28360389 TI - Potential emigration of Siberian cattle germplasm on Chirikof Island, Alaska. AB - Feral cattle residing in Chirikof Island, Alaska, are relatively distinct from breeds used in commercial production in North America. However, preliminary evidence suggested that they exhibit substantial genetic relationship with cattle from Yakutian region of Siberia. Thus, our objective was to further elucidate quantify the origins, admixture and divergence of the Chirikof Island cattle relative to cattle from Siberia and USA. Subject animals were genotyped at 15 microsatellite loci. Compared with Turano-Mongolian and North American cattle, Chirikof Island cattle had similar variation, with slightly less observed heterozygosity, fewer alleles per locus and a positive fixation index. Analysis of the genetic distances revealed two primary clusters; one that contained the North American breeds and the Kazakh White head, and a second that contained the Yakutian and Kalmyk breeds, and the Chirikof population. Thus, it is suggested that Chirikof Island cattle may be a composite of British breeds emanating from North America and Turano-Mongolian cattle. A potential founder effect, consistent with historical records of the Russian-American period, may contribute to the adaptation of the Chirikof Island cattle to their harsh high-latitude environment. Further study of adaptive mechanisms manifest by these cattle is warranted. PMID- 28360391 TI - Complement component 3: characterization and association with mastitis resistance in Egyptian water buffalo and cattle. AB - Mastitis is an infectious disease of the mammary gland that leads to reduced milk production and change in milk composition. Complement component C3 plays a major role as a central molecule of the complement cascade involving in killing of microorganisms, either directly or in cooperation with phagocytic cells. C3 cDNA were isolated, from Egyptian buffalo and cattle, sequenced and characterized. The C3 cDNA sequences of buffalo and cattle consist of 5025 and 5019 bp, respectively. Buffalo and cattle C3 cDNAs share 99% of sequence identity with each other. The 4986 bp open reading frame in buffalo encodes a putative protein of 1661 amino acids-as in cattle-and includes all the functional domains. Further, analysis of the C3 cDNA sequences detected six novel single-nucleotide polymorphisms (SNPs) in buffalo and three novel SNPs in cattle. The association analysis of the detected SNPs with milk somatic cell score as an indicator of mastitis revealed that the most significant association in buffalo was found in the C>A substitution (ss: 1752816097) in exon 27, whereas in cattle it was in the C>T substitution (ss: 1752816085) in exon 12. Our findings provide preliminary information about the contribution of C3 polymorphisms to mastitis resistance in buffalo and cattle. PMID- 28360390 TI - Association of IL-10 gene (-1082A>G, -819C>T and -592C>A) polymorphism and its serum level with metabolic syndrome of north Indian subjects. AB - Metabolic syndrome (MetS) is an inflammatory disorder, in which various cytokines play important role in tilting balance towards disease state. Interleukin-10 (IL 10) is an important antiinflammatory cytokine, but its genetic polymorphisms and serum levels in Indian MetS subjects are unknown. Three IL-10 gene polymorphisms (-1082A>G (rs1800896), -819C>T (rs1800872) and -592C>A (rs1800871)) were genotyped with PCR-RFLP in MetS subjects (n = 384) and age/sex matched control subjects (n = 386). Serum IL-10 was measured using enzyme-linked immunosorbent assay. Serum IL-10 level was significantly low in MetS subject and significantly correlated with clinicobiochemical parameters of MetS. Of three investigated promoter polymorphisms, IL-10 -819C> T and -592C>A were significantly associated with risk of MetS. The mutant alleles -819T and -592A of IL-10 gene polymorphism were significantly higher in MetS subjects compared to controls. Of the four different haplotypes obtained, common ACC haplotype and rare GTA haplotype of IL 10 polymorphisms were associated with MetS. The mean of fasting insulin and HOMA IR were significantly different between the genotypes of both -819 C>T and 592C>A polymorphisms of IL-10 in MetS subjects. These results suggested that polymorphisms in IL-10 gene (-819C>T and -592C>A), haplotypes (ACC and GTA) and serum level are significantly associated with risk of MetS. IL- 10 -819C>T and 592C>A polymorphic variants are also significantly associated with insulin level and homeostasis model assessment-insulin resistance in north Indian MetS subjects. PMID- 28360393 TI - Single-nucleotide polymorphism of INS, INSR, IRS1, IRS2, PPAR-G and CAPN10 genes in the pathogenesis of polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is the most common and a complex female endocrine disorder, and is one of the leading cause of female infertility. Here, we aimed to investigate the association of single-nucleotide polymorphism of INS, INSR, IRS1, IRS2, PPAR-G and CAPN10 gene in the pathogenesis of PCOS. A hospital based, observational case-control study was carried on 169 PCOS and 169 control women in the southern region of India. Genotype was carried out by real-time polymerase chain reaction. A chi-square (chi2) test was performed and the genotypes were verified to comply with the Hardy- Weinberg equilibrium. Odds ratio and 95% confidence interval were calculated to assess the relative risk. Comparison of clinical characteristics of women with PCOS and controls reveal an increase in body mass index (BMI), luteinizing hormone / follicle stimulating hormone (LH/FSH) ratio, glucose levels, insulin, testosterone, hirsutism and antral follicular count in PCOS women. The variant rs1801278 (P = 0.002; OR = 2.88; 95% CI = 1.43, 5.80) show an association with PCOS. In the genotypic (P = 0.0002) and allelic models (P = 0.000), significance persisted even after Bonferroni correction. The genotypes of SNPs strongly influence BMI, LH, LH/FSH ratio, ovarian volume and antral follicular count in PCOS women. The study results were suggestive of a positive association between Gly972Arg of IRS1 and PCOS in the south Indian population, while INS, IRS2, PPAR-G and CAPN10 failed to show any association with PCOS in our studied population. Further studies focussing the role of IRS1 are warranted to delineate its implication towards PCOS. PMID- 28360392 TI - Transcript variations, phylogenetic tree and chromosomal localization of porcine aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT) genes. AB - Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor best known for mediating xenobiotic-induced toxicity. AhR requires aryl hydrocarbon receptor nuclear translocator (ARNT) to form an active transcription complex and promote the activation of genes which have dioxin responsive element in their regulatory regions. The present study was performed to determine the complete cDNA sequences of porcine AhR and ARNT genes and their chromosomal localization. Total RNA from porcine livers were used to obtain the sequence of the entire porcine transcriptome by next-generation sequencing (NGS; lllumina HiSeq2500). In addition, both, in silico analysis and fluorescence in situ hybridization (FISH) were used to determine chromosomal localization of porcine AhR and ARNT genes. In silico analysis of nucleotide sequences showed that there were two transcript variants of AhR and ARNT genes in the pig. In addition, computer analysis revealed that AhR gene in the pig is located on chromosome 9 and ARNT on chromosome 4. The results of FISH experiment confirmed the localization of porcine AhR and ARNT genes. In the present study, for the first time, the full cDNAs of AhR and ARNT were demonstrated in the pig. In future, it would be interesting to determine the tissue distribution of AhR and ARNT transcript variants in the pig and to test whether these variants are associated with different biological functions and/or different activation pathways. PMID- 28360394 TI - The Drosophila bipectinata species complex: phylogenetic relationship among different members based on chromosomal variations. AB - Making interspecific hybridizations, where possible remains an unparalleled option for studying the intricacies of speciation. In the Drosophila bipectinata species complex comprising of four species, namely D. bipectinata, D. parabipectinata, D. malerkotliana and D. pseudoananassae, interspecific hybrids can be obtained in the laboratory, thus bequeathing an ideal opportunity for studying speciation and phylogeny. With the view of investigating the degree of divergence between each species pair, we planned to study the polytene chromosomes of the F1 hybrids, as it would mirror the level of compatibility between the genomes of the parental species. Two sets of crosses were made, one involving homozygous strains of all four species from India and the other including homozygous strains from different places across the globe. Polytene chromosomes of F1 larvae from both sets of crosses had similar configurations. In F1 larvae from crosses involving D. bipectinata, D. parabipectinata and D. malerkotliana, complex configurations (depicting overlapping inversions) could be detected in different arms. However, they were fairly synapsed, indicating that the differences are only at the level of gene arrangements. The polytene chromosomes of larvae obtained by crossing D. pseudoananassae with the other three species were very thin with gross asynapsis in all the arms, demonstrating that the genome of D. pseudoananassae is widely diverged from rest of the species. The overlapping inversions (reflected in complex configuration), are inferred in the light of earlier chromosomal studies performed in this complex. PMID- 28360395 TI - Cooverexpression of EpCAM and c-myc genes in malignant breast tumours. AB - The overexpression of epithelial cell adhesion molecule (EpCAM), a proto oncogene, affects progression, treatment, and diagnosis of many adenocarcinomas. C-myc has been shown to be a downstream target of EpCAM and is also one of the most important proto-oncogenes routinely overexpressed in breast cancer. However, cooverexpression of EpCAM and c-myc genes has not been investigated in breast cancer tissues, particularly in Iranian population. The aim of this study was to assess the expression of EpCAM and c-myc genes in malignant breast cancer tissues using reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) followed by analyses of the association between the outcomes. In this study, 122 fresh tissues, including 104 malignant and 18 benign samples, were disrupted by mortar and pestle, and then the RNA was isolated from the samples and converted to cDNA. The relative expression levels of EpCAM and c-myc genes were measured by 2-DeltaDeltaCt method using RT-qPCR. EpCAM protein level was also assessed in 66 cases using Western blot technique. Using RT-qPCR method, our results showed that EpCAM was overexpressed in 48% of malignant and 11.1% of benign samples. Evaluating EpCAM protein overexpression in a portion of samples depicted the fully concordance rate between Western blot and RT-qPCR techniques. C-myc expression was first evaluated by RT-qPCR method, showing the overexpression rate of 39% and 28% in malignant and benign samples, respectively. These data were also quite concordant with the clinically available immunohistochemistry reports of the same samples studied in this study. Importantly, overexpression of EpCAM and c-myc was significantly associated and showed an agreement of 57.3%. This study demonstrated the cooverexpression of EpCAM and c-myc in breast tumours collected from breast cancer patients of the Iranian population. EpCAM and c-myc positive cases were significantly associated with reduced and enhanced risk of ER/PR positivity respectively. However, both were associated with grade III of breast cancer. PMID- 28360396 TI - Phylogenetic analysis of Tibetan mastiffs based on mitochondrial hypervariable region I. AB - Recently, the number of Tibetan mastiffs, which is a precious germplasm resource and cultural heritage, is decreasing sharply. Therefore, the genetic diversity of Tibetan mastiffs needs to be studied to clarify its phylogenetics relationships and lay the foundation for resource protection, rational development and utilization of Tibetan mastiffs. We sequenced hypervariable region I of mitochondrial DNA (mtDNA) of 110 individuals from Tibet region and Gansu province. A total of 12 polymorphic sites were identified which defined eight haplotypes of which H4 and H8 were unique to Tibetan population with H8 being identified first. The haplotype diversity (Hd: 0.808), nucleotide diversity (Pi: 0.603%), the average number of nucleotide difference (K: 3.917) of Tibetan mastiffs from Gansu were higher than those from Tibet region (Hd: 0.794; Pi: 0.589%; K: 3.831), which revealed higher genetic diversity in Gansu. In terms of total population, the genetic variation was low. The median-joining network and phylogenetic tree based on the mtDNA hypervariable region I showed that Tibetan mastiffs originated from grey wolves, as the other domestic dogs and had different history of maternal origin. The mismatch distribution analysis and neutrality tests indicated that Tibetan mastiffs were in genetic equilibrium or in a population decline. PMID- 28360397 TI - Ubiquitous distribution of fluorescent protein in muscles of four species and two subspecies of eel (genus Anguilla). AB - In this study, the localization of fluorescent protein (FP) was characterized in the muscles of four species and two subspecies of eels Anguilla anguilla, A. australis, A. bicolor bicolor (b.), A. bicolor pacifica (p.) and A. mossambica in addition to the previously reported A. japonica. The open reading frame of each eel FP was 417 bp encoding 139 amino acid residues. The deduced amino acid sequences among the four species and two subspecies exhibited 91.4-100% identity, and belonged to the fatty-acid-binding protein (FABP) family. The gene structure of eel FPs in A. japonica, A. anguilla, A. australis, A. bicolor b., A. bicolor p. and A. mossambica have four exons and three introns, and were common to that of FABP family. The apo eel FPs expressed by Escherichia coli with recombinant eel FP genes were analysed for the fluorescent properties in the presence of bilirubin. The excitation and emission spectra of holo eel FPs had the maximum wavelengths of 490-496 and 527-530 nm, respectively. The holo eel FPs indicated that the fluorescent intensities were stronger in A. japonica and A. bicolor than in A. mossambica, A. australis and A. anguilla. The comparison of amino acid sequences revealed two common substitutions in A. mossambica, A. australis and A. anguilla with weak fluorescent intensity. PMID- 28360398 TI - Nucleotide diversity and phylogenetic relationships among Gladiolus cultivars and related taxa of family Iridaceae. AB - The plastid genome regions of two intergenic spacers, psbA-trnH and trnL-trnF, were sequenced to study the nucleotide diversity and phylogenetic relationships among Gladiolus cultivars. Nucleotide diversity of psbA-trnH region was higher than trnL-trnF region of chloroplast. We employed Bayesian, maximum parsimony (MP) and neighbour-joining (NJ) approaches for phylogenetic analysis of Gladiolus and related taxa using combined datasets from chloroplast genome. The psbA-trnH and trnL-trnF intergenic spacers of Gladiolus and related taxa-like Babiana, Chasmanthe, Crocus, Iris, Moraea, Sisyrinchium, Sparaxis and two out group species (Hymenocallis littoralis and Asphodeline lutea) were used in the present investigation. Results showed that subfamily Iridoideae have sister lineage with subfamily Ixioideae and Crocoideae. H. littoralis and A. lutea were separately attached at the base of tree as the diverging Iridaceae relative's lineage. Present study revealed that psbA-trnH region are useful in addressing questions of phylogenetic relationships among the Gladiolus cultivars, as these intergenic spacers are more variable and have more phylogenetically informative sites than the trnL-trnF spacer, and therefore, are suitable for phylogenetic comparison on a lower taxonomic level. Gladiolus cultivars are extensively used as an ornamental crop and showed high potential in floriculture trade. Gladiolus cultivation still needs to generate new cultivars with stable phenotypes. Moreover, one of the most popular methods for generating new cultivars is hybridization. Hence, information on phylogenetic relationships among cultivars could be useful for hybridization programmes for further improvement of the crop. PMID- 28360399 TI - Genetic analyses for deciphering the status and role of photoperiodic and maturity genes in major Indian soybean cultivars. AB - Allelic combinations of major photoperiodic (E1, E3, E4) and maturity (E2) genes have extended the adaptation of quantitative photoperiod sensitive soybean crop from its origin (China ~35?N latitude) to both north (up to ~50?N) and south (up to 40?S) latitudes, but their allelic status and role in India (6-35?N) are unknown. Loss of function and hypoactive alleles of these genes are known to confer photoinsensitivity to long days and early maturity. Early maturity has helped to adapt soybean to short growing season of India. We had earlier found that all the Indian cultivars are sensitive to incandescent long day (ILD) and could identify six insensitive accessions through screening 2071 accessions under ILD. Available models for ILD insensitivity suggested that identified insensitive genotypes should be either e3/e4 or e1 (e1-nl or e1-fs) with either e3 or e4. We found that one of the insensitive accessions (EC 390977) was of e3/e4 genotype and hybridized it with four ILD sensitive cultivars JS 335, JS 95-60, JS 93-05, NRC 37 and an accession EC 538828. Inheritance studies and marker-based cosegregation analyses confirmed the segregation of E3 and E4 genes and identified JS 93-05 and NRC 37 as E3E3E4E4 and EC 538828 as e3e3E4E4. Further, genotyping through sequencing, derived cleaved amplified polymorphic sequences (dCAPS) and cleaved amplified polymorphic sequences (CAPS) markers identified JS 95-60 with hypoactive e1-as and JS 335 with loss of function e3-fs alleles. Presence of photoperiodic recessive alleles in these two most popular Indian cultivars suggested for their role in conferring early flowering and maturity. This observation could be confirmed in F2 population derived from the cross JS 95 60 * EC 390977, where individuals with e1-as e1-as and e4e4 genotypes could flower 7 and 2.4 days earlier, respectively. Possibility of identification of new alleles ormechanism for ILD insensitivity and use of photoinsensitivity in Indian conditions have been discussed. PMID- 28360401 TI - Mutational analysis of the GLA gene in Mexican families with Fabry disease. AB - Fabry disease (FD) is a lysosomal storage disorder, which develops due to a deficiency in the hydrolytic enzyme, alpha-galactosidase A (alpha-Gal A). Alpha Gal A hydrolyzes glycosphingolipid globotriaosylceramide (Gb3), and an alpha-Gal A deficiency leads to Gb3 accumulation in tissues and cells in the body. This pathology is likely to involve multiple systems, but it is generally considered to affect primarily vascular endothelium. In this study, we investigated mutations in the GLA gene, which encodes alpha-Gal A, in Mexican families with FD. We included seven probands with FD that carried known mutations. We analysed pedigrees of the probands, and performed molecular screening in 65 relatives with the potential of carrying a GLA mutation. Five mutations (P40S, IVS4+4, G328V, R363H, R404del) were detected in seven unrelated Mexican families with the classic FD phenotype. Of the 65 relatives examined, 42 (64.6%) had a GLA gene mutation. In summary, among seven Mexican probands with FD, 65 relatives were at risk of carrying a known GLA mutation, and molecular screening identified 42 individuals with the mutation. Thus, our findings showed that it is important to perform molecular analysis in families with FD to detect mutations and to provide accurate diagnoses for individuals that could be affected. PMID- 28360400 TI - CDKN2A and MC1R variants found in Cypriot patients diagnosed with cutaneous melanoma. AB - The prevalence of genetic variants associated to cutaneous melanoma (CM) has never been determined within Cypriot melanomas. This study evaluates the frequency of variants in cyclin-dependent kinase inhibitor 2A (CDKN2A) and melanocortin-1 receptor (MC1R) in 32 patients diagnosed with CM. Other characteristics and risk factors were also assessed. CDKN2A p.Ala148Thr was detected in three of 32 patients, while the control group revealed no variations within CDKN2A. MC1R screening in 32 patients revealed the following variations: p.Val60Leu in 11 patients, p.Arg142His in four patients, p.Thr314Thr in one patient, p.Arg160Trp in one patient, p.Val92Met/p.Thr314Thr in one patient and p.Val92Met/p.Arg142His/p.Thr314Thr in one patient. The control group revealed only p.Val60Leu (in 10 of 45 individuals), which is frequently found in general populations. Two unrelated patients carried CDKN2A p.Ala148Thr in combination with MC1R p.Arg142His, suggesting digenic inheritance that may provide evidence of different gene variants acting synergistically to contribute for CM development. This study confirms the presence of CDKN2A and MC1R variants among Cypriot melanomas and supports existing evidence of a role for these variants in susceptibility to melanoma. PMID- 28360402 TI - Molecular cytogenetic identification of a wheat-Thinopyrum ponticum translocation line resistant to powdery mildew. AB - Thinopyrum ponticum (2n = 70) serves as a valuable gene pool for wheat improvement. Line SN0224, derived from crosses between Th. ponticum and the common wheat cultivar Yannong15, was identified in the present study. Cytogenetic observations showed that SN0224 contains 42 chromosomes in the root-tip cells and 21 bivalents in the pollen mother cells, thereby demonstrating its cytogenetic stability. Genomic in situ hybridization, probed with the total genomic DNA of Th. ponticum, produced hybridization signals in the distal region of two wheat chromosome arms. After inoculation with the Blumeria graminis f. sp. tritici (Bgt) isolates, SN0224 exhibited immunity. Segregation in F1s and F2s from the cross SN0224/cv. Huixianhong indicated that SN0224 carries a single dominant gene for powdery mildew (Pm) resistance, which was temporarily designated PmSn0224. Three markers Barc212, Xwmc522 and Xbarc1138 were detected to be linked with PmSn0224. Based on the locations of the markers, PmSn0224 was located on the chromosome 2A. None of the three markers above is linked with the previously reported PM resistance genes on chromosome 2A, and none of the previously reported PM resistance genes on chromosome 2A is related to Th. ponticum. Therefore, PmSn0224 is likely a novel gene putatively from Th. ponticum. PMID- 28360403 TI - A universal, rapid, and inexpensive method for genomic DNA isolation from the whole blood of mammals and birds. AB - There is no 'one' procedure for extracting DNA from the whole blood of both mammals and birds, since each species has a unique property that require different methods to release its own DNA. Therefore, to obtain genomic DNA, a universal, rapid, and noncostly method was developed. A very simple biological basis is followed in this procedure, in which, when the blood is placed in water, it rapidly enters the RBCs by osmosis and causes cells to burst by hemolysis. The validity of extracting genomic DNA was confirmed by several molecular biological experiments. It was found that this method provides an efficient and versatile alternative for extracting bulk amounts of highly-qualified DNA from the blood of a wide range of species. This is the first manuscript that describes use of distilled water as the only eliminator of RBCs among all other known DNA extraction techniques. PMID- 28360404 TI - Genomewide association study for seeding emergence and tiller number using SNP markers in an elite winter wheat population. AB - Seeding emergence and tiller number are the most important traits for wheat (Triticum aestivum L.) yield, but the inheritance of seeding emergence and tillering is poorly understood. We conducted a genomewide association study focussing on seeding emergence and tiller number at different growth stages with a panel of 205 elite winter wheat accessions. The population was genotyped with a high-density Illumina iSelect 90K SNPs assay. A total of 31 loci were found to be associated with seeding emergence rate (SER) and tiller number in different growth stages. Loci distributed among 12 chromosomes accounted for 5.35 to 11.33% of the observed phenotypic variation. With this information, 10 stable SNPs were identified for eventual development of cleaved amplified polymorphic sequence markers for SER and tiller number in different growth stages. Additionally, a set of elite alleles were identified, such as Ra_c14761_1348-T, which may increase SER by 13.35%, and Excalibur_c11045_236-A and BobWhite_c8436_391-T, which may increase the rate of available tillering by 14.78 and 8.47%, respectively. These results should provide valuable information for marker-assisted selection and parental selection in wheat breeding programmes. PMID- 28360406 TI - Noncoding RNAs in protein clearance pathways: implications in neurodegenerative diseases. AB - The importance of noncoding genome has become more evident in recent years. Before genome sequencing, the most well studied portion of our genome was protein coding genes. Interestingly, this coding portion accounted only for 1.5% of the genome, the rest being the noncoding sequences. Noncoding RNAs (ncRNAs) are involved in normal cell physiology, stress, and disease states. A class of small ncRNAs and miRNAs has gained much importance because of its involvement in human diseases such as cancer. Involvement of long ncRNAs have also been acknowledged in other human diseases, especially in neurodegenerative diseases. Neurodegenerative diseases are characterized by the presence of abnormally folded proteins that are toxic to the cell. Several studies from model organisms suggest upregulation of pathways that clear this toxic protein may provide protection against neurodegeneration. In this review, I summarize the importance of ncRNAs in protein quality control system of cell that is implicated in this fatal group of neurodegenerative diseases. PMID- 28360405 TI - CYP/PON genetic variations as determinant of organophosphate pesticides toxicity. AB - In the present scenario of increased accumulation of pesticides in the environment, it is important to understand its impact on human health. The focus is on gene-environment interaction, highlighting the consequences and factors that may halt the biotransformation of some pesticides and change their actual dose response curve due to mixed exposure to pesticides. The paraoxonase and cytochrome P450 gene families are involved in the metabolism of oxon derivate (toxic than its parent compound) of organophosphate pesticides, thus, mutations in these genes may impact the metabolic outcome of pesticides and subsequent health hazards. The complex multi gene-environment interaction and one gene - one risk factor are two different aspects to understand the potential health effect related to environmental exposure studies. The genetic polymorphisms are associated with varying levels of risk within the population, as gene products of varied genotype alter the biotransformation of exogenous/endogenous substrates. This paper is aimed to review the impact of endogenous and exogenous factors on a mechanistic pathway of organophosphate pesticide biotransformation and various risk associated with it among the human population. Understanding the genetic polymorphism of genes involved in pesticide metabolism and highlighting the gene isoform dependent interindividual differences to metabolize particular pesticides may help us to unravel the reasons behind differential toxicity for pesticides exposure than expected. PMID- 28360408 TI - Senescence of Pancreas in Middle-Aged Rats with Normal Vascular Function. AB - BACKGROUND In organ transplantation, particularly pancreas transplantation, donor age is a determinant factor for graft survival. Physiological aging is crucial in the progressive deterioration of organs in adulthood. We compared the senescence and function features of pancreas and vascular tissues in young rats and middle aged rats. MATERIAL AND METHODS Islet morphology and the area of cells secreting insulin or glucagon was investigated using immunohistology in young rats (12 weeks) and middle-aged rats (52 weeks) (n=8). Senescence markers, oxidative stress (ROS), and tissue factor (TF) were measured in the rat pancreases. Circulating microparticles (MPs) were measured as surrogates of vascular cell injury. Vascular function was studied in mesenteric arterial rings. RESULTS Larger islets were twice as frequent in young rats versus middle-aged rats. In middle-aged rats there was a significant decrease of the beta-cells/islet area ratio. Western blot analysis showed an increased expression of p53, p21, and p16 senescence markers (2-, 7- and 3-fold respectively) with no modification in caspase-3 activation. A 30% decrease of endothelial nitric oxide synthase (eNOS) was observed together with a 4-fold increase in TF expression. ROS formation increased significantly (2-fold) in middle-aged rats and their main source, determined by pharmacological inhibition, was NADPH oxidase and uncoupled nitric oxide (NO) synthase. No sign of vascular injury (microparticles) or dysfunction was evidenced. CONCLUSIONS Modification in islet morphology and function were detected in middle-aged rats before any measurement of macro-vascular dysfunction. The data indicate a pancreatic senescence in the process of aging associated with uncontrolled accumulation of oxidative species that suggests a determining role of donor age in transplantation. PMID- 28360410 TI - A Case with Recurrent Free-Floating Ball Thrombi in Left Atrium. AB - BACKGROUND A free-floating ball thrombus in the left atrium is a rare clinical condition. However, the diagnosis of this condition has been facilitated by the advent and development of echocardiography and multi-detector row computed tomography (MDCT) and several cases have been reported. CASE REPORT We report a case of a 75-year-old woman who had recurrent giant spherical thrombi in the left atrium. She was diagnosed with chronic atrial fibrillation at 52 years of age. A pacemaker implantation was performed at 54 years of age because of a complete atrioventricular block; and mitral valve replacement was performed for severe mitral regurgitation at 62 years of age. She had a history of cerebral infarction and she was under treatment for chronic heart failure. Despite intensive anticoagulant therapy, she developed ball thrombi in the left atrium three times in six months. During hospitalization for acute myocardial infarction treated with percutaneous catheter intervention, transthoracic echocardiography and computed tomography (CT) revealed a free-floating giant spherical thrombus in the left atrium. She was treated with intensive anticoagulation therapy and the left atrial ball thrombus disappeared; however, two ball thrombi in the left atrium and left atrial appendage recurred after three months. Surgical removal of the thrombi and closure of the left atrial appendage were performed. Unfortunately, a ball thrombus in the left atrium recurred again after a further three months. CONCLUSIONS The present case highlights the difficulty of treating refractory thrombi in the left atrium. PMID- 28360407 TI - Predictive Role of Coagulation, Fibrinolytic, and Endothelial Markers in Patients with Atrial Fibrillation, Stroke, and Thromboembolism: A Meta-Analysis, Meta Regression, and Systematic Review. AB - BACKGROUND The pathophysiological mechanism associated with the higher prothrombotic tendency in atrial fibrillation (AF) is complex and multifactorial. However, the role of prothrombotic markers in AF remains inconclusive. MATERIAL AND METHODS We conducted a meta-analysis of observational studies evaluating the association of coagulation activation, fibrinolytic, and endothelial function with occurrence of AF and clinical adverse events. A comprehensive subgroup analysis and meta-regression was performed to explore potential sources of heterogeneity. RESULTS A literature search of major databases retrieved 1703 studies. After screening, a total of 71 studies were identified. Pooled analysis showed the association of coagulation markers (D-dimer (weighted mean difference (WMD) =197.67 and p<0.001), fibrinogen (WMD=0.43 and p<0.001), prothrombin fragment 1-2 (WMD=0.53 and p<0.001), antithrombin III (WMD=23.90 and p=0.004), thrombin-antithrombin (WMD=5.47 and p=0.004)); fibrinolytic markers (tissue-type plasminogen activator (t-PA) (WMD=2.13 and p<0.001), plasminogen activator inhibitor (WMD=11.44 and p<0.001), fibrinopeptide-A (WMD=4.13 and p=0.01)); and endothelial markers (von Willebrand factor (WMD=27.01 and p<0.001) and soluble thrombomodulin (WMD=3.92 and p<0.001)) with AF. CONCLUSIONS The levels of coagulation, fibrinolytic, and endothelial markers have been reported to be significantly higher in AF patients than in SR patients. PMID- 28360412 TI - Thermoelectric and phonon transport properties of two-dimensional IV-VI compounds. AB - We explore the thermoelectric and phonon transport properties of two-dimensional monochalcogenides (SnSe, SnS, GeSe, and GeS) using density functional theory combined with Boltzmann transport theory. We studied the electronic structures, Seebeck coefficients, electrical conductivities, lattice thermal conductivities, and figures of merit of these two-dimensional materials, which showed that the thermoelectric performance of monolayer of these compounds is improved in comparison compared to their bulk phases. High figures of merit (ZT) are predicted for SnSe (ZT = 2.63, 2.46), SnS (ZT = 1.75, 1.88), GeSe (ZT = 1.99, 1.73), and GeS (ZT = 1.85, 1.29) at 700 K along armchair and zigzag directions, respectively. Phonon dispersion calculations confirm the dynamical stability of these compounds. The calculated lattice thermal conductivities are low while the electrical conductivities and Seebeck coefficients are high. Thus, the properties of the monolayers show high potential toward thermoelectric applications. PMID- 28360409 TI - Vascularization Potential of Electrospun Poly(L-Lactide-co-Caprolactone) Scaffold: The Impact for Tissue Engineering. AB - BACKGROUND Electrospun nanofibers have widespread putative applications in the field of regenerative medicine and tissue engineering. When compared to naturally occurring collagen matrices, electrospun nanofiber scaffolds have two distinct advantages: they do not induce a foreign body reaction and they are not at risk for biological contamination. However, the exact substrate, structure, and production methods have yet to be defined. MATERIAL AND METHODS In the current study, tubular-shaped poly(L-lactide-co-caprolactone) (PLCL) constructs produced using electrospinning technology were evaluated for their potential application in the field of tissue regeneration in two separate anatomic locations: the skin and the abdomen. The constructs were designed to have an internal diameter of 3 mm and thickness of 200 MUm. Using a rodent model, 20 PLCL tubular constructs were surgically implanted in the abdominal cavity and subcutaneously. The constructs were then evaluated histologically using electron microscopy at 6 weeks post-implantation. RESULTS Histological evaluation and analysis using scanning electron microscopy showed that pure scaffolds by themselves were able to induce angiogenesis after implantation in the rat model. Vascularization was observed in both tested groups; however, better results were obtained after intraperitoneal implantation. Formation of more and larger vessels that migrated inside the scaffold was observed after implantation into the peritoneum. In this group no evidence of inflammation and better integration of scaffold with host tissue were noticed. Subcutaneous implantation resulted in more fibrotic reaction, and differences in cell morphology were also observed between the two tested groups. CONCLUSIONS This study provides a standardized evaluation of a PLCL conduit structure in two different anatomic locations, demonstrating the excellent ability of the structure to achieve vascularization. Functional, histological, and mechanical data clearly indicate prospective clinical utilization of PLCL in critical size defect regeneration. PMID- 28360411 TI - Interplay of DNA methyltransferase 1 and EZH2 through inactivation of Stat3 contributes to beta-elemene-inhibited growth of nasopharyngeal carcinoma cells. AB - beta-elemene, a compound extracted from Curcuma wenyujin plant, exhibits anticancer activity in many cancer types. However, the detailed mechanism by which beta-elemene inhibits growth of nasopharyngeal carcinoma (NPC) cells remains unknown. We showed that beta-elemene reduced phosphorylation of signal transducer and activator of transcription 3 (Stat3), and protein expressions of DNA methyltransferase 1 (DNMT1) and enhancer of zeste homolog 2 (EZH2). Exogenously expressed Stat3 antagonized the effect of beta-elemene on DNMT1 and EZH2 expressions. Furthermore, overexpressions of DNMT1 and EZH2 reversed the effect of beta-elemene on phosphorylation of Stat3 and cell growth inhibition. Intriguingly, exogenously expressed DNMT1 overcame beta-elemene-inhibited EZH2 protein expression and promoter activity. On the contrary, silencing of EZH2 and DNMT1 genes feedback strengthened the effect of beta-elemene on phosphorylation of Stat3. Consistent with this, beta-elemene inhibited tumor growth, phosphorylation of Stat3, expressions of DNMT1 and EZH2 in a mouse xenograft model. Collectively, this study shows that beta-elemene inhibits NPC cell growth via inactivation of Stat3, and reduces DNMT1 and EZH2 expressions. The interplay of DNMT1 and EZH2, and the mutual regulations among Stat3, EZH2 and DNMT1 contribute to the overall responses of beta-elemene. This study uncovers a novel mechanism by which beta-elemene inhibits growth of NPC cells. PMID- 28360414 TI - Chromosomal integration of HHV-6A during non-productive viral infection. AB - Human herpesvirus 6A (HHV-6A) and 6B (HHV-6B) are two different species of betaherpesviruses that integrate into sub-telomeric ends of human chromosomes, for which different prevalence rates of integration have been reported. It has been demonstrated that integrated viral genome is stable and is fully retained. However, study of chromosomally integrated viral genome in individuals carrying inherited HHV-6 (iciHHV-6) showed unexpected number of viral DR copies. Hence, we created an in vitro infection model and studied retention of full or partial viral genome over a period of time. We observed an exceptional event where cells retained viral direct repeats (DRs) alone in the absence of the full viral genome. Finally, we found evidence for non-telomeric integration of HHV-6A DR in both cultured cells and in an iciHHV-6 individual. Our results shed light on several novel features of HHV-6A chromosomal integration and provide valuable information for future screening techniques. PMID- 28360417 TI - Circadian rhythms: Astrocytes keep time. PMID- 28360416 TI - Heterodimerization of AML1/ETO with CBFbeta is required for leukemogenesis but not for myeloproliferation. AB - The AML1/Runx1 transcription factor and its heterodimerization partner CBFbeta are essential regulators of myeloid differentiation. The chromosomal translocation t(8;21), fusing the DNA binding domain of AML1 to the corepressor eight-twenty-one (ETO), is frequently associated with acute myeloid leukemia and generates the AML1/ETO (AE) fusion protein. AE represses target genes usually activated by AML1 and also affects the endogenous repressive function of ETO at Notch target genes. In order to analyze the contribution of CBFbeta in AE mediated leukemogenesis and deregulation of Notch target genes, we introduced two point mutations in a leukemia-initiating version of AE in mice, called AE9a, that disrupt the AML1/CBFbeta interaction (AE9aNT). We report that the AE9a/CBFbeta interaction is not required for the AE9a-mediated aberrant expression of AML1 target genes, while upregulation/derepression of Notch target genes does require the interaction with CBFbeta. Using retroviral transduction to express AE9a in murine adult bone marrow-derived hematopoietic progenitors, we observed that both AE9a and AE9aNT lead to increased myeloproliferation in vivo. However, both development of leukemia and long-term replating capacity are only observed with AE9a but not with AE9aNT. Thus, deregulation of both AML1 and Notch target genes is required for the development of AE9a-driven leukemia. PMID- 28360415 TI - HIV Tat induces a prolonged MYC relocalization next to IGH in circulating B cells. AB - With combined antiretroviral therapy (cART), the risk for HIV-infected individuals to develop a non-Hodgkin lymphoma is diminished. However, the incidence of Burkitt lymphoma (BL) remains strikingly elevated. Most BL present a t(8;14) chromosomal translocation which must take place at a time of spatial proximity between the translocation partners. The two partner genes, MYC and IGH, were found colocalized only very rarely in the nuclei of normal peripheral blood B-cells examined using 3D-FISH while circulating B-cells from HIV-infected individuals whose exhibited consistently elevated levels of MYC-IGH colocalization. In vitro, incubating normal B-cells from healthy donors with a transcriptionally active form of the HIV-encoded Tat protein rapidly activated transcription of the nuclease-encoding RAG1 gene. This created DNA damage, including in the MYC gene locus which then moved towards the center of the nucleus where it sustainably colocalized with IGH up to 10-fold more frequently than in controls. In vivo, this could be sufficient to account for the elevated risk of BL-specific chromosomal translocations which would occur following DNA double strand breaks triggered by AID in secondary lymph nodes at the final stage of immunoglobulin gene maturation. New therapeutic attitudes can be envisioned to prevent BL in this high risk group. PMID- 28360423 TI - Immunometabolism in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease mediated by pathogenic autoantibodies directed against nucleoprotein complexes. Beyond the activation of autoreactive B cells, this process involves dysregulation in many other types of immune cells, including CD4+ T cells, dendritic cells, macrophages and neutrophils. Metabolic substrate utilization and integration of cues from energy sensors are critical checkpoints of effector functions in the immune system, with common as well as cell-specific programmes. Patients with SLE and lupus-prone mice present with activated metabolism of CD4+ T cells, and the use of metabolic inhibitors to normalize these features is associated with therapeutic effects. Far less is known about the metabolic requirements of B cells and myeloid cells in SLE. This article reviews current knowledge of the alterations in metabolism of immune cells in patients with SLE and mouse models of lupus in the context of what is known about the metabolic regulation of these cells during normal immune responses. How these alterations might contribute to lupus pathogenesis and how they can be targeted therapeutically are also discussed. PMID- 28360422 TI - Immunometabolism in early and late stages of rheumatoid arthritis. AB - One of the fundamental traits of immune cells in rheumatoid arthritis (RA) is their ability to proliferate, a property shared with the joint-resident cells that form the synovial pannus. The building of biomass imposes high demands for energy and biosynthetic precursors, implicating metabolic control as a basic disease mechanism. During preclinical RA, when autoreactive T cells expand and immunological tolerance is broken, the main sites of disease are the secondary lymphoid tissues. Naive CD4+ T cells from patients with RA have a distinct metabolic signature, characterized by dampened glycolysis, low ATP levels and enhanced shunting of glucose into the pentose phosphate pathway. Equipped with high levels of NADPH and depleted of intracellular reactive oxygen species, such T cells hyperproliferate and acquire proinflammatory effector functions. During clinical RA, immune cells coexist with stromal cells in the acidic milieu of the inflamed joint. This microenvironment is rich in metabolic intermediates that are released into the extracellular space to shape cell-cell communication and the functional activity of tissue-resident cells. Increasing awareness of how metabolites regulate signalling pathways, guide post-translational modifications and condition the tissue microenvironment will help to connect environmental factors with the pathogenic behaviour of T cells in RA. PMID- 28360419 TI - Algorithms for survival: a comparative perspective on emotions. AB - The nature and neural implementation of emotions is the subject of vigorous debate. Here, we use Bayesian decision theory to address key complexities in this field and conceptualize emotions in terms of their relationship to survival relevant behavioural choices. Decision theory indicates which behaviours are optimal in a given situation; however, the calculations required are radically intractable. We therefore conjecture that the brain uses a range of pre programmed algorithms that provide approximate solutions. These solutions seem to produce specific behavioural manifestations of emotions and can also be associated with core affective dimensions. We identify principles according to which these algorithms are implemented in the brain and illustrate our approach by considering decision making in the face of proximal threat. PMID- 28360420 TI - Lifespan Gyrification Trajectories of Human Brain in Healthy Individuals and Patients with Major Psychiatric Disorders. AB - Cortical gyrification of the brain represents the folding characteristic of the cerebral cortex. How the brain cortical gyrification changes from childhood to old age in healthy human subjects is still unclear. Additionally, studies have shown regional gyrification alterations in patients with major psychiatric disorders, such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ). However, whether the lifespan trajectory of gyrification over the brain is altered in patients diagnosed with major psychiatric disorders is still unknown. In this study, we investigated the trajectories of gyrification in three independent cohorts based on structural brain images of 881 subjects from age 4 to 83. We discovered that the trajectory of gyrification during normal development and aging was not linear and could be modeled with a logarithmic function. We also found that the gyrification trajectories of patients with MDD, BD and SCZ were deviated from the healthy one during adulthood, indicating altered aging in the brain of these patients. PMID- 28360424 TI - The emerging safety profile of JAK inhibitors in rheumatic disease. PMID- 28360418 TI - Not just amyloid: physiological functions of the amyloid precursor protein family. AB - Amyloid precursor protein (APP) gives rise to the amyloid-beta peptide and thus has a key role in the pathogenesis of Alzheimer disease. By contrast, the physiological functions of APP and the closely related APP-like proteins (APLPs) remain less well understood. Studying these physiological functions has been challenging and has required a careful long-term strategy, including the analysis of different App-knockout and Aplp-knockout mice. In this Review, we summarize these findings, focusing on the in vivo roles of APP family members and their processing products for CNS development, synapse formation and function, brain injury and neuroprotection, as well as ageing. In addition, we discuss the implications of APP physiology for therapeutic approaches. PMID- 28360421 TI - Muscle-specific downregulation of GR levels inhibits adipogenesis in porcine intramuscular adipocyte tissue. AB - Intramuscular adipose is conducive to good pork quality, whereas subcutaneous adipose is considered as waste in pig production. So uncovering the regulation differences between these two adiposes is helpful to tissue-specific control of fat deposition. In this study, we found the sensitivity to glucocorticoids (GCs) was lower in intramuscular adipocytes (IMA) compared with subcutaneous adipocytes (SA). Comparison of glucocorticoid receptor (GR) revealed that IMA had lower GR level which contributed to its reduced GCs sensitivity. Higher methylation levels of GR promotor 1-C and 1-H were detected in IMA compared with SA. GR expression decrease was also found in adipocytes when treated with muscle conditioned medium (MCM) in vitro, which resulted in significant inhibition of adipocytes proliferation and differentiation. Since abundant myostatin (MSTN) was detected in MCM by ELISA assay, we further investigated the effect of this myokine on adipocytes. MSTN treatment suppressed adipocytes GR expression, cell proliferation and differentiation, which mimicked the effects of MCM. The methylation levels of GR promotor 1-C and 1-H were also elevated after MSTN treatment. Our study reveals the role of GR in muscle fiber inhibition on intramuscular adipocytes, and identifies myostatin as a muscle-derived modulator for adipose GR level. PMID- 28360426 TI - Bracing for the biosimilar wave. PMID- 28360425 TI - Rapid breeding of parthenocarpic tomato plants using CRISPR/Cas9. AB - Parthenocarpy in horticultural crop plants is an important trait with agricultural value for various industrial purposes as well as direct eating quality. Here, we demonstrate a breeding strategy to generate parthenocarpic tomato plants using the CRISPR/Cas9 system. We optimized the CRISPR/Cas9 system to introduce somatic mutations effectively into SlIAA9-a key gene controlling parthenocarpy-with mutation rates of up to 100% in the T0 generation. Furthermore, analysis of off-target mutations using deep sequencing indicated that our customized gRNAs induced no additional mutations in the host genome. Regenerated mutants exhibited morphological changes in leaf shape and seedless fruit-a characteristic of parthenocarpic tomato. And the segregated next generation (T1) also showed a severe phenotype associated with the homozygous mutated genome. The system developed here could be applied to produce parthenocarpic tomato in a wide variety of cultivars, as well as other major horticultural crops, using this precise and rapid breeding technique. PMID- 28360427 TI - Novel insights into the interaction of UBA5 with UFM1 via a UFM1-interacting sequence. AB - The modification of proteins by ubiquitin-fold modifier 1 (UFM1) is implicated in many human diseases. Prior to conjugation, UFM1 undergoes activation by its cognate activating enzyme, UBA5. UBA5 is a non-canonical E1 activating enzyme that possesses an adenylation domain but lacks a distinct cysteine domain. Binding of UBA5 to UFM1 is mediated via an amino acid sequence, known as the UFM1 interacting sequence (UIS), located outside the adenylation domain that is required for UFM1 activation. However, the precise boundaries of the UIS are yet not clear and are still under debate. Here we revisit the interaction of UFM1 with UBA5 by determining the crystal structure of UFM1 fused to 13 amino acids of human UBA5. Using binding and activity assays, we found that His 336 of UBA5, previously not reported to be part of the UIS, occupies a negatively charged pocket on UFM1's surface. This His is involved in UFM1 binding and if mutated perturbs activation of UFM1. Surprisingly, we also found that the interaction between two UFM1 molecules mimics how the UIS binds UFM1. Specifically, UFM1 His 70 resembles UBA5 His336 and enters a negatively charged pocked on the other UFM1 molecule. Our results refine our understanding of UFM1-UBA5 binding. PMID- 28360429 TI - Interleukin-20 targets podocytes and is upregulated in experimental murine diabetic nephropathy. AB - Interleukin (IL)-20, a proinflammatory cytokine of the IL-10 family, is involved in acute and chronic renal failure. The aim of this study was to elucidate the role of IL-20 during diabetic nephropathy development. We found that IL-20 and its receptor IL-20R1 were upregulated in the kidneys of mice and rats with STZ induced diabetes. In vitro, IL-20 induced MMP-9, MCP-1, TGF-beta1 and VEGF expression in podocytes. IL-20 was upregulated by hydrogen peroxide, high-dose glucose and TGF-beta1. In addition, IL-20 induced apoptosis in podocytes by activating caspase-8. In STZ-induced early diabetic nephropathy, IL-20R1 deficient mice had lower blood glucose and serum BUN levels and a smaller glomerular area than did wild-type controls. Anti-IL-20 monoclonal antibody (7E) treatment reduced blood glucose and the glomerular area and improved renal functions in mice in the early stage of STZ-induced diabetic nephropathy. ELISA showed that the serum IL-20 level was higher in patients with diabetes mellitus than in healthy controls. The findings of this study suggest that IL-20 induces cell apoptosis of podocytes and plays a role in the pathogenesis of early diabetic nephropathy. PMID- 28360428 TI - Molecular checkpoints controlling natural killer cell activation and their modulation for cancer immunotherapy. AB - Natural killer (NK) cells have gained considerable attention as promising therapeutic tools for cancer therapy due to their innate selectivity against cancer cells over normal healthy cells. With an array of receptors evolved to sense cellular alterations, NK cells provide early protection against cancer cells by producing cytokines and chemokines and exerting direct cytolytic activity. These effector functions are governed by signals transmitted through multiple receptor-ligand interactions but are not achieved by engaging a single activating receptor on resting NK cells. Rather, they require the co-engagement of different activating receptors that use distinct signaling modules, due to a cell-intrinsic inhibition mechanism. The redundancy of synergizing receptors and the inhibition of NK cell function by a single class of inhibitory receptor suggest the presence of common checkpoints to control NK cell activation through different receptors. These molecular checkpoints would be therapeutically targeted to harness the power of NK cells against diverse cancer cells that express heterogeneous ligands for NK cell receptors. Recent advances in understanding the activation of NK cells have revealed promising candidates in this category. Targeting such molecular checkpoints will facilitate NK cell activation by lowering activation thresholds, thereby providing therapeutic strategies that optimize NK cell reactivity against cancer. PMID- 28360431 TI - Chilli consumption and the incidence of overweight and obesity in a Chinese adult population. AB - BACKGROUND: The frequency of spicy food intake has recently been associated with a reduced risk of mortality in the Chinese population. This study aimed to prospectively examine the association between chilli intake and the incidence of overweight/obesity in a Chinese adult population. METHODS: Adults aged 20-75 years in the China Health and Nutrition Survey were followed between 1991 and 2011. Dietary data were collected during home visits using a 3-day food record in 1991, 1993, 1997, 2000, 2004, 2006, 2009 and 2011. Cox regression was used in the analysis. Overweight/obesity was defined as body mass index ?25 kg m-2. RESULTS: A total 12 970 adults were followed for a median of 9 years. During 126 884 person-years of follow-up, 3203 subjects developed overweight/obesity. The absolute incidence rate of overweight/obesity was 26.4, 22.3, 24.4 and 20.5 per 1000 person-years among those who consumed no chilli or 1-20, 20.1-50, ?50.1 g per day, respectively. Chilli consumption was therefore inversely associated with the incidence of overweight/obesity. After adjusting for age, gender, energy and fat intake, smoking, alcohol drinking and physical activity, those whose cumulative average chilli intake was 0, 1-20, 20.1-50 and ?50.1 g per day had a hazard ratio for overweight/obesity of 1.00, 0.81 (95% confidence interval=0.73 0.89), 0.77 (0.69-0.86) and 0.73 (0.63-0.84); P for trend <0.001, respectively. There was no interaction between chilli intake and gender, income, education and residence (urban/rural) in relation to the risk of overweight/obesity. CONCLUSIONS: Chilli intake is inversely associated with the risk of becoming overweight/obese in Chinese adults. PMID- 28360430 TI - Sex differences in the influence of body mass index on anatomical architecture of brain networks. AB - BACKGROUND/OBJECTIVES: The brain has a central role in regulating ingestive behavior in obesity. Analogous to addiction behaviors, an imbalance in the processing of rewarding and salient stimuli results in maladaptive eating behaviors that override homeostatic needs. We performed network analysis based on graph theory to examine the association between body mass index (BMI) and network measures of integrity, information flow and global communication (centrality) in reward, salience and sensorimotor regions and to identify sex-related differences in these parameters. SUBJECTS/METHODS: Structural and diffusion tensor imaging were obtained in a sample of 124 individuals (61 males and 63 females). Graph theory was applied to calculate anatomical network properties (centrality) for regions of the reward, salience and sensorimotor networks. General linear models with linear contrasts were performed to test for BMI and sex-related differences in measures of centrality, while controlling for age. RESULTS: In both males and females, individuals with high BMI (obese and overweight) had greater anatomical centrality (greater connectivity) of reward (putamen) and salience (anterior insula) network regions. Sex differences were observed both in individuals with normal and elevated BMI. In individuals with high BMI, females compared to males showed greater centrality in reward (amygdala, hippocampus and nucleus accumbens) and salience (anterior mid-cingulate cortex) regions, while males compared to females had greater centrality in reward (putamen) and sensorimotor (posterior insula) regions. CONCLUSIONS: In individuals with increased BMI, reward, salience and sensorimotor network regions are susceptible to topological restructuring in a sex-related manner. These findings highlight the influence of these regions on integrative processing of food-related stimuli and increased ingestive behavior in obesity, or in the influence of hedonic ingestion on brain topological restructuring. The observed sex differences emphasize the importance of considering sex differences in obesity pathophysiology. PMID- 28360434 TI - Locally advanced breast cancer in elderly patients. AB - BACKGROUND: Although locally advanced breast cancer (LABC) is more common in the elderly population, there is little data on the clinical characteristics and survival of these patients. The aim of the present study was to compare different factors affecting survival in elderly patients with LABC. METHODS: Retrospective analysis was carried out on a cohort of 80 patients aged 70 to 96 years, diagnosed with LABC defined as T3 N1, T4 N0, any N2 or N3, and M0. The prognostic impact of selected clinical parameters including age, comorbidities, tumour grade, HER2 status, tumour stage, local therapies, and systemic treatments was studied. RESULTS: The median age of the patients was 79 years. The majority (n=53; 66%) had at least one significant comorbidity according to the Charlson score evaluation. The median overall survival was 50.6 months. As expected, hormonal therapy was the dominant mode of systemic treatment, but 24% also received at least one line of chemotherapy. Local therapies including surgery and/or radiotherapy were applied in 58% of patients. CONCLUSIONS: The diagnosis of LABC in the elderly is associated with poor prognosis. Age and serious comorbidities were negative prognostic factors. PMID- 28360433 TI - Use of near-infrared spectroscopy (NIRS) in cerebral tissue oxygenation monitoring in neonates. AB - Near-infrared spectroscopy (NIRS) is a technology capable of non-invasive, continuous measuring of regional tissue oxygen saturation (StO2). StO2 represents a state of hemodynamic stability, which is influenced by many factors. Extensive research has been done in the field of measuring StO2 of various organs. The current clinical availability of several NIRS-based devices reflects an important development in prevention, detection and correction of discrepancy in oxygen delivery to the brain and vital organs. Managing cerebral ischemia remains a significant issue in the neonatal intensive care units (NICU). Cerebral tissue oxygenation (cStO2) and cerebral fractional tissue extraction (cFTOE) are reported in a large number of clinical studies. This review provides a summary of the concept of function, current variability of NIRS-based devices used in neonatology, clinical applications in continuous cStO2 monitoring, limitations, disadvantages, and the potential of current technology. PMID- 28360435 TI - Effect of water on the fluorine and chlorine partitioning behavior between olivine and silicate melt. AB - Halogens show a range from moderate (F) to highly (Cl, Br, I) volatile and incompatible behavior, which makes them excellent tracers for volatile transport processes in the Earth's mantle. Experimentally determined fluorine and chlorine partitioning data between mantle minerals and silicate melt enable us to estimate Mid Ocean Ridge Basalt (MORB) and Ocean Island Basalt (OIB) source region concentrations for these elements. This study investigates the effect of varying small amounts of water on the fluorine and chlorine partitioning behavior at 1280 degrees C and 0.3 GPa between olivine and silicate melt in the Fe-free CMAS+F-Cl Br-I-H2O model system. Results show that, within the uncertainty of the analyses, water has no effect on the chlorine partitioning behavior for bulk water contents ranging from 0.03 (2) wt% H2O (DClol/melt = 1.6 +/- 0.9 * 10-4) to 0.33 (6) wt% H2O (DClol/melt = 2.2 +/- 1.1 * 10-4). Consequently, with the effect of pressure being negligible in the uppermost mantle (Joachim et al. Chem Geol 416:65-78, 2015), temperature is the only parameter that needs to be considered for the determination of chlorine partition coefficients between olivine and melt at least in the simplified iron-free CMAS+F-Cl-Br-I-H2O system. In contrast, the fluorine partition coefficient increases linearly in this range and may be described at 1280 degrees C and 0.3 GPa with (R2 = 0.99): [Formula: see text]. The observed fluorine partitioning behavior supports the theory suggested by Crepisson et al. (Earth Planet Sci Lett 390:287-295, 2014) that fluorine and water are incorporated as clumped OH/F defects in the olivine structure. Results of this study further suggest that fluorine concentration estimates in OIB source regions are at least 10% lower than previously expected (Joachim et al. Chem Geol 416:65-78, 2015), implying that consideration of the effect of water on the fluorine partitioning behavior between Earth's mantle minerals and silicate melt is vital for a correct estimation of fluorine abundances in OIB source regions. Estimates for MORB source fluorine concentrations as well as chlorine abundances in both mantle source regions are within uncertainty not affected by the presence of water. PMID- 28360436 TI - Conditional Sure Independence Screening. AB - Independence screening is powerful for variable selection when the number of variables is massive. Commonly used independence screening methods are based on marginal correlations or its variants. When some prior knowledge on a certain important set of variables is available, a natural assessment on the relative importance of the other predictors is their conditional contributions to the response given the known set of variables. This results in conditional sure independence screening (CSIS). CSIS produces a rich family of alternative screening methods by different choices of the conditioning set and can help reduce the number of false positive and false negative selections when covariates are highly correlated. This paper proposes and studies CSIS in generalized linear models. We give conditions under which sure screening is possible and derive an upper bound on the number of selected variables. We also spell out the situation under which CSIS yields model selection consistency and the properties of CSIS when a data-driven conditioning set is used. Moreover, we provide two data-driven methods to select the thresholding parameter of conditional screening. The utility of the procedure is illustrated by simulation studies and analysis of two real datasets. PMID- 28360432 TI - Dose-response effects of aerobic exercise on energy compensation in postmenopausal women: combined results from two randomized controlled trials. AB - BACKGROUND/OBJECTIVES: Despite the clear health benefits of exercise, exercised induced weight loss is often less than expected. The term 'exercise energy compensation' is used to define the amount of weight loss below what is expected for the amount of exercise energy expenditure. We examined the dose-response effects of exercise volume on energy compensation in postmenopausal women. PARTICIPANTS/METHODS: Data from Alberta Physical Activity and Breast Cancer Prevention (ALPHA) and Breast Cancer and Exercise Trial in Alberta (BETA) were combined for the present analysis. The ALPHA and BETA trials were two-centred, two-armed, 12-month randomized controlled trials. The ALPHA trial included 160 participants randomized to 225 min per week of aerobic exercise, and the BETA trial randomized 200 participants to each 150 and 300 min per week of aerobic exercise. All participants were aged 50-74 years, moderately inactive (<90 min per week of exercise), had no previous cancer diagnosis and a body mass index between 22 and 40 kg m-2. Energy compensation was based on changes in body composition (dual-energy X-ray absorptiometry scan) and estimated exercise energy expenditure from completed exercise volume. Associations between Deltaenergy intake, DeltaVO2peak and Deltaphysical activity time with energy compensation were assessed. RESULTS: No differences in energy compensation were noted between interventions. However, there were large inter-individual differences in energy compensation between participants; 9.4% experienced body composition changes that were greater than expected based on exercise energy expenditure, 64% experienced some degree of energy compensation and 26.6% experienced weight gain based on exercise energy expenditure. Increases in VO2peak were associated with reductions in energy compensation (beta=-3.44 ml kg-1 min-1, 95% confidence interval for beta=-4.71 to -2.17 ml kg-1 min-1; P=0.0001). CONCLUSIONS: Large inter-individual differences in energy compensation were noted, despite no differences between activity doses. In addition, increases in VO2peak were associated with lower energy compensation. Future studies are needed to identify behavioral and metabolic factors that may contribute to this large inter-individual variability in energy compensation. PMID- 28360437 TI - Introducing New Antimalarial Analogues of Chloroquine and Amodiaquine: A Narrative Review. AB - Antimalarial drugs with the 4-aminoquinoline scaffold such as the important drugs, chloroquine (CQ) and amodiaquine (AQ), have been used to prevent and treat malaria for many years. The importance of these drugs is related to their simple usage, high efficacy, affordability, and cost-effectiveness of their synthesis. In recent years, with the spread of parasite resistance to CQ and cross resistance to its other analogues have decreased their consumption in many geographical areas. On the other hand, AQ is an effective antimalarial drug which its usage has been restricted due to hepatic and hematological toxicities. The significance of the quinoline ring at quinoline-based antimalarial drugs has prompted research centers and pharmaceutical companies to focus on the design and synthesis of new analogues of these drugs, especially CQ and AQ analogues. Accordingly, various derivatives have been synthesized and evaluated in vitro and in vivo against the resistant strains of the malaria parasite to solve the problem of drug resistance. Also, the pharmacokinetic properties of these compounds have been evaluated to augment their efficacy and diminish their toxicity. Some of these analogues are currently in clinical and preclinical development. Consequently, the recent researches showed yet 4-aminoquinoline scaffold is active moiety in new compounds with antiplasmodial activity. Hence, the aim of this review article is to introduce of the novel synthetic analogues of CQ and AQ, which may constitute the next generation of antimalarial drugs with the 4-aminoquinoline scaffold. PMID- 28360438 TI - Comparing Adrenaline with Tranexamic Acid to Control Acute Endobronchial Bleeding: A Randomized Controlled Trial. AB - BACKGROUND: Hemoptysis occurs due to either pulmonary diseases or bronchoscopy interventions. The aim of the present study was to compare the efficacy of the endobronchial instillation of adrenaline with that of tranexamic acid. METHODS: Fifty patients were randomly selected as 2 double-blinded sample groups (n=25). In these patients, bleeding could not be controlled with cold saline lavage during bronchoscopy and they, therefore, required prescription of another medicine. Adrenaline (1 mg) in one group and tranexamic acid (500 mg) in the other group were diluted in 20 mL of normal saline and instilled through the bronchoscope. This technique was repeated 3 times at 90-second intervals, if necessary. In the case of persistent bleeding, 90 seconds after the last dose, a second medicine was given for bleeding control. Observation of clot through the bronchoscope meant that the bleeding had stopped. The efficacy of tranexamic acid and adrenaline was evaluated and then compared using the Mann-Whitney test. RESULTS: The time of bleeding control had no significant difference between tranexamic acid and adrenaline (P=0.908). Another analysis was done to evaluate bleeding control with a second medicine; the results showed that 1 (4%) patient in the tranexamic acid and 8 (32%) in the adrenaline group needed the second medicine and there was no significant difference between the 2 groups (P=0.609). CONCLUSION: Our results suggested that tranexamic acid by endobronchial instillation was as efficient as adrenaline in controlling hemoptysis and required less frequent use of a second medicine. Trial Registration Number: IRCT2014120220188. PMID- 28360439 TI - Baricity of Bupivacaine on Maternal Hemodynamics after Spinal Anesthesia for Cesarean Section: A Randomized Controlled Trial. AB - BACKGROUND: After spinal anesthesia, patients undergoing cesarean section are more likely to develop hemodynamic changes. The baricity of local anesthetic has an important role on spinal blockade effects. The aim of this study was to compare the isobar and hyperbaric bupivacaine 0.5% plus fentanyl on maternal hemodynamics after spinal anesthesia for C/S. METHODS: In this double-blind study, 84 healthy pregnant women undergoing C/S using bupivacaine 0.5% isobar (study group, n=42) or hyperbaric (control group, n=42) for spinal anesthesia were scheduled. The study was conducted from 21 April 2014 to 21 November 2014 at Al-Zahra Hospital, Tabriz, Iran. Parameters such as maternal hemodynamics, block characteristics, side effects, and neonatal Apgar scores were recorded. Data were analyzed using the SPSS software by performing chi-square test, Fisher's exact test, one-way ANOVA, Mann-Whitney U-test, and student's t test. RESULTS: The incidence of hypotension in the isobar group was lower than the hyperbaric group, although it was not statistically significant (40.47% vs. 61.9%, P=0.08). The duration of hypotension was shorter in the study group (1.6+/-7.8 min vs. 7.4+/ 12.5 min, P=0.004). The dose of ephedrine was lower in the study group (2.4+/-6.6 mg vs. 5.3+/-10.7 mg, P=0.006). The main maternal side effect is sustained hypotension that was seen in 0 patients of the isobar and 7 (16.66%) of hyperbaric groups (P=0.006). None of the neonates had Apgar score<=7 at 5 min of delivery (P=1.0). Sensory and motor block duration was shorter in the study group (P=0.01). CONCLUSION: Isobaric bupivacaine is associated with more hemodynamic stability and shorter sensory and motor blockade in mothers under spinal anesthesia for C/S. Trial Registration Number: IRCT201401287013N7. PMID- 28360440 TI - Effect of Poor Glycemic Control in Newly Diagnosed Patients with Smear-Positive Pulmonary Tuberculosis and Type-2 Diabetes Mellitus. AB - BACKGROUND: There is growing evidence that diabetes mellitus (DM) is an important risk factor for tuberculosis (TB). A significant number of DM patients have poor glycemic control. This study was carried out to find the impact of poor glycemic control on newly diagnosed smear-positive pulmonary tuberculosis patients with type-2 diabetes mellitus in a tertiary care hospital. METHODS: In a hospital based prospective study, newly diagnosed smear-positive pulmonary TB with DM patients were classified as poorly controlled diabetes (HBA1C>=7%) and optimal control diabetics (HbA1c<7%). Patients were started on anti-TB treatment and followed for 2 years for severity and treatment outcome. ANOVA was used for numerical variables in the univariable analysis. Logistic regression analysis was used for multivariable analysis of treatment outcome. The significance level was kept at a P<=0.05. RESULTS: A total of 630 individuals who met the inclusion criteria were analyzed; of which 423 patients had poor glycemic control (PGC) and 207 patients had optimal glycemic control (OGC). The average HbA1c was 10+/-2.6 and 5+/-1.50 in the PGC and OGC groups, respectively. The mean symptom score was significantly higher in the PGC group compared with patients in the OGC group (4.55+/-0.80 vs. 2.70+/-0.82, P<0.001). PGC was associated with more extensive lung disease, lung cavitation, and positive sputum smear at the baseline. In PGC, sputum smears were significantly more likely to remain positive after 2 months of treatment. PGC patients had significantly higher rates of treatment failure (adj. OR 0.72, 95% CI 0.58-0.74, P<0.001) and relapse (adj. OR 2.83, 95% CI 2.60-2.92, P<0.001). CONCLUSION: Poor glycemic control is associated with an increased risk of advanced and more severe TB disease in the form of lung cavitations, positive sputum smear, and slower smear conversion. It has a profound negative effect on treatment completion, cure, and relapse rates in patients with pulmonary tuberculosis. PMID- 28360441 TI - Neutralizing Antibody Response and Efficacy of Novel Recombinant Tetravalent Dengue DNA Vaccine Comprising Envelope Domain III in Mice. AB - BACKGROUND: Dengue is a global arboviral threat to humans; causing 390 million infections per year. The availability of safe and effective tetravalent dengue vaccine is a global requirement to prevent epidemics, morbidity, and mortality associated with it. METHODS: Five experimental groups (6 mice per group) each of 5-week-old BALB/c mice were immunized with vaccine and placebo (empty plasmid) (100 ug, i.m.) on days 0, 14 and 28. Among these, four groups (one group per serotype) of each were subsequently challenged 3 weeks after the last boost with dengue virus (DENV) serotypes 1-4 (100 LD50, 20 ul intracerebrally) to determine vaccine efficacy. The fifth group of each was used as a control. The PBS immunized group was used as mock control. Serum samples were collected before and after subsequent immunizations. EDIII fusion protein expression was determined by Western blot. Total protein concentration was measured by Bradford assay. Neutralizing antibodies were assessed by TCID50-CPE inhibition assay. Statistical analysis was performed using Stata/IC 10.1 software for Windows. One-way repeated measures ANOVA and Mann-Whitney test were used for neutralizing antibody analysis and vaccine efficacy, respectively. RESULTS: The recombinant EDIII fusion protein was expressed adequately in transfected 293T cells. Total protein concentration was almost 3 times more than the control. Vaccine candidate induced neutralizing antibodies against all four DENV serotypes with a notable increase after subsequent boosters. Vaccine efficacy was 83.3% (DENV-1, -3, -4) and 50% (DENV 2). CONCLUSION: Our results suggest that vaccine is immunogenic and protective; however, further studies are required to improve the immunogenicity particularly against DENV-2. PMID- 28360443 TI - Protective Effect of Edaravone Against Cyclosporine-Induced Chronic Nephropathy Through Antioxidant and Nitric Oxide Modulating Pathways in Rats. AB - BACKGROUND: Cyclosporine A (CsA) is an immunosuppressant with therapeutic indications in various immunological diseases; however, its use is associated with chronic nephropathy. Oxidative stress has a crucial role in CsA-induced nephrotoxicity. The present study evaluates the protective effect of edaravone on CsA-induced chronic nephropathy and investigates its antioxidant and nitric oxide modulating property. METHODS: Male Sprague-Dawley rats (n=66) were distributed into nine groups, including a control (group 1) (n=7). Eight groups received CsA (15 mg/kg) for 28 days while being treated. The groups were categorized as: Group 2: Vehicle (n=10)Groups 3, 4, and 5: Edaravone (1, 5, and 10 mg/kg) (n=7 each)Group 6: Diphenyliodonium chloride, a specific endothelial nitric oxide synthase (eNOS) inhibitor (n=7)Group 7: Aminoguanidine, a specific inducible nitric oxide synthase (iNOS) inhibitor (n=7)Group 8: Edaravone (10 mg/kg) plus diphenyliodonium chloride (n=7)Group 9: Edaravone (10 mg/kg) plus aminoguanidine (n=7) Blood urea nitrogen and serum creatinine levels, malondialdehyde, superoxide dismutase, and glutathione reductase enzyme activities were measured using standard kits. Renal histopathological evaluations and measurements of eNOS and iNOS gene expressions by RT-PCR were also performed. Data were analyzed using one-way analysis of variance (ANOVA) followed by Tukey's test (SPSS software version 18.0). RESULTS: Edaravone (10 mg/kg) significantly attenuated CsA-induced oxidative stress, renal dysfunction, and kidney tissue injury. Aminoguanidine improved the renoprotective effect of edaravone. Edaravone reduced the elevated mRNA level of iNOS, but could not alter the level of eNOS mRNA significantly. CONCLUSION: Edaravone protects against CsA-induced chronic nephropathy using antioxidant property and probably through inhibiting iNOS gene expression. PMID- 28360444 TI - Nepeta Dschuparensis Bornm Extract Moderates COX-2 and IL-1beta Proteins in a Rat Model of Cerebral Ischemia. AB - BACKGROUND: Nepeta dschuparensis Bornm (NP) is used as a medicinal herb in Iran. In traditional medicine, this herb is extensively employed for curing ailments such as cardiovascular diseases. NP has antioxidant and anti-inflammatory properties. This project examined the effects of the NP extract on cyclooxygenase 2 (COX-2) and interleukin-1beta (IL-1beta) protein levels and its efficacy in neuroprotection in a cerebral ischemia-reperfusion model. METHODS: Twenty-six male rats were randomly divided into 3 groups: 1) sham (n=6): no middle cerebral artery occlusion (MCAO) procedure, 2) control (n=10): MCAO procedure and treatment with normal saline, and 3) NP extract (n=10): MCAO procedure and treatment with the NP extract (20 mg/kg, i.p.) at the beginning of reperfusion. To examine the injury caused by cerebral ischemia, we measured motor coordination and the infarct area using the rotarod test and triphenyl tetrazolium chloride staining, respectively. IL-1beta and COX-2 protein levels, as inflammatory markers, were measured by immunoblotting assay. The statistical analyses were performed using SPSS, version 16, and the data are expressed as means+/-SEMs. Statistical difference was evaluated using the one-way ANOVA, followed by the post hoc LSD test (P<0.01). RESULTS: Treatment with the NP extract significantly diminished the infarct volume and alleviated the motor coordination disorder induced by cerebral ischemia. The NP extract administration significantly attenuated the increase in IL-1beta and COX-2 protein levels too (P<0.01). CONCLUSION: The beneficial effects of the NP extract are related to its ability to decrease the levels of IL-1beta and COX-2. PMID- 28360442 TI - Effects of Maternal Isocaloric Diet Containing Different Amounts of Soy Oil and Extra Virgin Olive Oil on Weight, Serum Glucose, and Lipid Profile of Female Mice Offspring. AB - BACKGROUND: Health status of offspring is programmed by maternal diet throughout gestation and lactation. The present study investigates the lasting effects of maternal supplementation with different amounts of soy oil or extra virgin olive oil (EVOO) on weight and biochemical parameters during gestation and lactation of female mice offspring. METHODS: Eight weeks old female C57BL/6 mice (n=40) were assigned through simple randomization into four isocaloric dietary groups (16% of calories as soy oil (LSO) or EVOO (LOO) and 45% of calories as soy oil (HSO) or EVOO (HOO)) during three weeks of gestation and lactation. After weaning (at 3 weeks), all offspring received a diet containing 16% of calories as soy oil and were sacrificed at 6 weeks. Two-way ANOVA was used to adjust for confounding variables and repeated measures test for weight gain trend. Statistical analyses were performed with the IBM SPSS package. RESULTS: At birth and adolescence, the weight of offspring was significantly higher in the soy oil than the olive oil groups (P<0.001 and P<0.001, respectively). Adolescence weight was significantly higher in the offspring born to mothers fed with 16% oil than those with 45% oil (P=0.001). Serum glucose, triglyceride and total cholesterol were significantly higher in the LSO than LOO (P<0.001, P<0.001 and P<0.001), LSO than HSO (P<0.001, P=0.03 and P<0.001), and LOO than HOO (P<0.001, P<0.001 and P<0.001) dietary groups, respectively. Serum triglyceride and total cholesterol were significantly higher in the offspring of HSO than HOO fed mothers (P<0.001 and P<0.001, respectively). CONCLUSION: A maternal diet containing EVOO has better effects on birth weight, as well as weight and serum biochemical parameters in offspring at adolescence. PMID- 28360445 TI - Effect of Motivational Interviewing on Weight Efficacy Lifestyle among Women with Overweight and Obesity: A Randomized Controlled Trial. AB - : Obesity and overweight have become increasingly a major public health problem across the world. This study aimed at exploring the effects of motivational interviewing on weight efficacy lifestyle among women with obesity and overweight. A single-blind randomized clinical trial study was conducted on 100 overweight and obese women who attended a nutrition clinic. The samples were selected based on the clinical records and assigned into two groups, namely motivational interviewing arm (50 samples) and nutrition education arm (50 samples). Data were collected using a standard validated questionnaire entitled "weight efficacy lifestyle". The intervention was designed according to five motivation sessions and four nutrition education programs, such that the participants of the nutrition education arm were also provided with the nutrition pamphlets related to weight control. Data were finally analyzed using the SPSS statistical software by performing the independent t-test, chi-square, LSD and repeated measures ANOVA tests. P<0.05 were considered statistically significant. The mean age of women was 39.9+/-9.1 and 36.3+/-8.9 years in the control and motivational interviewing arms, respectively. Compared with the control group, the score of the motivational interviewing group was statistically significant in terms of weight efficacy lifestyle P=0.0001) and all subscales including social pressure (P=0.0001), physical discomfort (P=0.005), food accessibility (P=0.0001), positive and entertainment activities (P=0.0001), as well as negative emotions (P=0.003). Motivational interviewing appeared to be effective in increasing weight efficacy lifestyle among women with overweight and obesity. TRIAL REGISTRATION NUMBER: IRCT2014051817736N1. PMID- 28360447 TI - Botulism Outbreak in a Family after Ingestion of Locally Produced Cheese. AB - Botulism is one of the most important foodborne diseases and is caused by Clostridium botulinum toxin. The main manifestations are flaccid muscle paralysis and cranial nerve palsies. Botulism is an essential health problem because of its high mortality. The diagnosis of botulism, especially in sporadic cases, is a medical challenge and a high clinical suspicion is necessary for early recognition. So, every physician should be familiar with its signs and symptoms for early detection and treatment. We describe a family with dysphasia and acute paralysis after the ingestion of locally made cheese. The clinical presentations of the 1st patient were similar to myasthenic crisis and she, therefore, received plasma exchange. After the appearance of similar symptoms in the other family members, they were treated with polyvalent botulinum antitoxin and diagnosis was confirmed by toxicology and detection of serotype A botulinum toxin in cheese and stool samples. Uncommon clinical presentations and unusual sources of botulinum toxin should be kept in mind because of the importance of early diagnosis and treatment. PMID- 28360446 TI - Surface Electromyographic Assessment of Swallowing Function. AB - The reliability of surface electromyographic (sEMG) variables during swallowing determines the potential usefulness of these measures in swallowing assessment and treatment. This study aimed to establish the reliability of the sEMG measures of the swallowing function of muscles during different swallowing conditions in healthy young and old volunteers. Two groups of volunteers (24 older adults, 10 younger adults) participated in this cross-sectional study during 2014. The activity of masseter, submental, and infrahyoid groups were measured using sEMG during three repetitions of different swallowing tasks. Both the relative and absolute reliability (characterized respectively by ICC, SEM%, and SRD%) were calculated for the sEMG indices of muscle activity during swallowing events. Statistical analyses were performed by the SPSS 19.0 and Microsoft Excel 2007 software packages. Statistical significance was set at P<=0.05. The relative reliability calculations showed significant agreements between repetitions for the mean and peak amplitude and the average of median frequency (MDF) of the studied muscles function during most swallowing types in both groups. However, the duration and particularly the time to peak of muscle activity showed significant agreements during fewer swallowing conditions. Excluding MDF, we found high SEM% and SRD% for the studied measures (particularly timing measures) of muscles function during most swallowing types in both groups. The reliability of sEMG measures was influenced by the age and swallowing types. Our findings suggest that the MDF of muscle function during almost all studied swallowing types can be a reliable measure for the sEMG assessment of swallowing function in both younger and older adults. PMID- 28360448 TI - Tumefactive Fibroinflammatory Lesion: A Diagnostic Dilemma. AB - Tumefactive fibroinflammatory lesions (TFLs) are rare idiopathic benign fibrosclerosing lesions that clinically simulate a malignancy. TFLs are seen more frequently in males between 10 and 74 years of age. The usual site of involvement is the head and neck region, but rarely the extremities may be involved. Coexisting fibrosclerotic processes have been reported including retroperitoneal fibrosis, sclerosing cholangitis, sclerosing mediastinal fibrosis, and orbital pseudotumors. The etiology of this poorly understood entity remains unknown. Possible suggestions include exaggerated responses or autoimmune reactions to any chronic infection. The clinical and radiological appearance of TFLs is that of malignancy, but histopathology reveals them to be a benign process broadly classified under non-neoplastic, fibroinflammatory proliferations. The treatment strategies for these lesions are not well defined and variable and include steroids, surgery, and radiotherapy either alone or in combination. TFLs, albeit not fatal, have a high recurrence rate; patients should, therefore, be kept on long-term follow-up. We describe a young female patient presenting with a rapidly developing cheek swelling, which was diagnosed histopathologically as a TFLs. PMID- 28360449 TI - Balanced Reciprocal Translocation t(X;1) in a Girl with Tall Stature and Primary Amenorrhea. AB - Chromosomal translocations constitute one of the most important, yet uncommon, causes of primary amenorrhea and gonadal dysgenesis. Although X-autosome translocations are frequently associated with streak gonads and clinical features of the Turner syndrome, the majority of X-autosome carriers may present with a variable phenotype, developmental delay, and recognizable X-linked syndrome due to nonrandom X-inactivation. In this article, we describe a healthy 15.5-year-old girl with primary amenorrhea, gonadal dysgenesis, and tall stature without other manifestations of the Turner syndrome. Relevant clinical, biochemical, endocrinological, and cytogenetical evaluations were performed. Initial investigations revealed hypergonadotropic hypogonadism (FSH=134 mIU/mL [normal=10 15 mIU/mL], LH=47.5 [normal=10-15 mIU/mL], and estradiol=24.3 pmol/L). On ultrasound examination of the pelvis, streak ovaries with a hypoplastic uterus were noted. Chromosome study, performed according to routine procedures, revealed an apparently balanced reciprocal translocation involving the short arm of chromosome 1(p2) and the long arm of the X chromosome (q2) in all the cells with the following karyotype: 46,X,t(1;X)(p13;q22). She was placed on hormone replacement therapy. In our patient, X-autosome translocation was associated with gonadal dysgenesis and tall stature. We conclude that t(X;1) may be associated with gonadal dysgenesis without other congenital abnormalities. To our knowledge, normal phenotype with gonadal dysgenesis and tall stature in association with t(X;1) translocation has not been previously reported. PMID- 28360450 TI - Renal Medullary Carcinoma; A Rare Entity. AB - Renal medullary carcinoma (RMC) is an uncommon aggressive neoplasm of the kidney. RMC is biologically aggressive with a very poor prognosis, and metastasis is seen in up to 95% of the patients at diagnosis or shortly thereafter. The common sites of metastasis are respectively lymph nodes, lungs, livers, and adrenal glands in order of frequency. The presence of poorly differentiated eosinophilic cells in a characteristic fibro-inflammatory stroma is seen in histological examination. The origin and pathogenesis of RMC are unclear. The radiographical and pathological findings suggest that RMC probably originates in the calyceal epithelium in or near the renal papillae, which could be the result of chronic ischemic damage in the renal papillae epithelium by sickled erythrocytes. Positivity of VEGF and HIF 1alpha supports the chronic hypoxia that may be caused in the pathogenesis of RMC. Other factors such as genetic or environmental factors are important. Although hemoglobinopathy is very common, RMC is very rare. An understanding of the molecular and genetic factors of this rare disease is important for its prevention and treatment. We herein describe an adult Turkish patient, who presented with hematuria. The diagnosis was RMC after pathological examination. PMID- 28360451 TI - Effects of Mutational Combinations on Philadelphia-Negative Myeloproliferative Neoplasms. PMID- 28360452 TI - Cobra-Head Stone in Single-System Ureterocele. PMID- 28360453 TI - Long-term analysis on the variance of extra-group paternities in rhesus macaques. AB - ABSTRACT: Extra-group paternity (EGP) has been described in various mammalian species; however, little is known about which factors contribute to the variation in EGP, as the majority of studies were restricted in time and the number of groups considered. Using longitudinal demographic and genetic data, we aim to investigate which factors predict rates of EGP in the free-ranging rhesus macaque population of Cayo Santiago, Puerto Rico (USA). Of the 1649 infants considered which were born into six social groups over 9 years, we identified an average of 16% of infants resulting from EGPs. We tested the influence of group size, breeding group sex ratio, female reproductive synchrony, and group instability on the occurrence of EGPs. Our results suggest a tendency for EGPs to increase as the proportion of females increased in larger groups, but no such effect in smaller groups. Furthermore, as group instability and female reproductive synchrony decreased, the number of EGPs tended to increase. Our results support the hypothesis that group structure affects the occurrence of EGPs, which might be mediated by male mating opportunities, male monopolization potential, and/or female choice. SIGNIFICANCE STATEMENT: In several species, both sexes seek alternative reproductive strategies to enhance their reproductive success. For instance, females may pursue EGPs to potentially increase genetic compatibility with males, or males may seek EGPs to improve their mating opportunities. Our longitudinal analysis, including demographic and genetic data over 9 years of six social groups of rhesus macaques, revealed high variation in the occurrence of EGPs across groups and years, and this variation tended to depend on group characteristics such as breeding group size, sex ratio, female synchrony, and group instability. The data suggest that group structure affects the number of EGPs in this group-living primate. Our results show that EGPs can affect the distribution of paternity within social groups and should be taken into account when assessing reproductive success. PMID- 28360454 TI - MAIN ETHICAL BREACHES IN MULTICENTER CLINICAL TRIALS REGULATIONS OF TURKEY. AB - Turkey has been a growing market for multicenter clinical trials for the last ten years and is considered among the top ten countries in terms of potential study subject populations. The objective of increasing the share of Turkey in multicenter clinical trials is strongly supported. This ambitious goal of Turkey raises the need to have regulations in compliance with other leading countries conducting clinical trials. The latest published Turkish regulations on clinical trials are structured in compliance with the International Conference on Harmonization (ICH) Guidelines and in harmony with the regulations of other leading countries in clinical research, such as the US. There are still flaws in Turkish regulation with the risk of violating human subjects' rights and issues with responsible conduct of research. The aim of this article is to compare Turkish clinical trials regulations with those of the US, to determine if there exists any incompatibility between the countries' regulations and, if so, how to ameliorate these. The main flaws in Turkish clinical trials regulations are identified as follows: lack of definition of the term "human subject; absence of explicit referral to the unacceptability of Conflict of Interest (COI) and taking measures to avoid it; exiguity of emphasis on plurality of the IRB members; nonexistence of a clear expression that this is research; and clinical equipoise, regarding the treatment of the existing clinical problem and lack of integration with international accreditation systems for Institutional Review Boards. PMID- 28360456 TI - Nonsmoker COPD: Is it a reality? PMID- 28360455 TI - A Feasibility Study of High-Strength Bi-2223 Conductor for High-Field Solenoids. AB - We performed a feasibility study on a high-strength Bi2-x Pb x Sr2Ca2Cu3O10-x (Bi 2223) tape conductor for high-field solenoid applications. The investigated conductor, DI-BSCCO Type HT-XX, is a pre-production version of Type HT-NX, which has recently become available from Sumitomo Electric Industries (SEI). It is based on their DI-BSCCO Type H tape, but laminated with a high-strength Ni-alloy. We used stress-strain characterizations, single- and double-bend tests, easy- and hard-way bent coil-turns at various radii, straight and helical samples in up to 31.2 T background field, and small 20-turn coils in up to 17 T background field to systematically determine the electro-mechanical limits in magnet-relevant conditions. In longitudinal tensile tests at 77 K, we found critical stress- and strain-levels of 516 MPa and 0.57%, respectively. In three decidedly different experiments we detected an amplification of the allowable strain with a combination of pure bending and Lorentz loading to >= 0.92% (calculated elastically at the outer tape edge). This significant strain level, and the fact that it is multi-filamentary conductor and available in the reacted and insulated state, makes DI-BSCCO HT-NX highly suitable for very high-field solenoids, for which high current densities and therefore high loads are required to retain manageable magnet dimensions. PMID- 28360457 TI - India's fight against tuberculosis: How can chest physicians help? PMID- 28360458 TI - Prevalence and etiological profile of chronic obstructive pulmonary disease in nonsmokers. AB - BACKGROUND: Tobacco smoking has been recognized as the most important risk factor for chronic obstructive pulmonary disease (COPD) for a long time, but recent studies have shown that nonsmokers also contribute to a significant proportion of COPD. This study was performed to find out the proportion of nonsmoker individuals among COPD patients and to determine various etiologies in nonsmoker COPD patients. MATERIALS AND METHODS: This study was an observational cross sectional study conducted in Department of Pulmonary Medicine, MLN Medical College, Allahabad. A total of 200 COPD patients, aged >18 years of either gender with COPD, diagnosed by clinical and spirometric criteria (GOLD guideline) were included in the study. RESULTS: Of the 200 COPD patients, the proportion of nonsmoker patients was 56.5%, and the smoker was 43.5%. Among 113 nonsmoker COPD patients, maximum number of patients (69.03%) belonged to low socioeconomic status but most important and statistically significant risk factor was exposure to biomass smoke (53.98%), other significant risk factors were treated pulmonary tuberculosis (32.74%), and long-standing asthma (14.16%). Risk factors that were not statistically significant were occupational exposure (9.73%), exposure to outdoor air pollution (3.54%), and lower respiratory tract infection during childhood (1.77%). The patients who were exposed to more than one risk factors, developed COPD at an earlier age. CONCLUSIONS: This study revealed that nonsmokers contribute a significant proportion of COPD patients. Multiple risk factors other than smoking also play a major role in the development of COPD, particularly exposure to biomass smoke, treated pulmonary tuberculosis, and long standing asthma. PMID- 28360459 TI - Correlation of pollen counts and number of hospital visits of asthmatic and allergic rhinitis patients. AB - AIMS AND OBJECTIVES: Environmental pollens are known to cause exacerbation of symptoms of patients with allergic rhinitis (AR) and asthma. During pollen months, number of patients visiting hospital has been shown to increase in some studies. However, in India, such studies are lacking. Therefore, we aimed to study pollen counts and to find its correlation with number of new patients attending Asthma Bhawan for 2 years. MATERIALS AND METHODS: Aerobiological sampling was done using Burkard 24 h spore trap system. The site selected for the entrapment of the air spore was the building of Asthma Bhawan situated at Vidhyadhar Nagar, Jaipur. New patients coming with problems of respiratory allergy such as AR or asthma were recruited in the study. Skin prick tests (SPTs) were carried out after obtaining consent in these patients. Monthly pollen counts of trees, weeds and grasses were correlated with the number of new patients. Pollen calendar was prepared for 2 years. RESULTS: Average annual pollen count during 2011 and 2012 were 14,460.5. In the analysis, 37 types of species or families were identified. Pollen count showed two seasonal peaks during March April and from August to October. January and June showed the lowest pollen counts in 2 years. Average monthly count of grass pollens showed significant correlation with number of new patients (r = 0.59). However, monthly pollen count of trees and weeds did not correlate. The correlation of the pollen count of individual pollen with the SPT positivity to that pollen showed significant correlation with Chenopodium album only. CONCLUSIONS: It can be concluded that there were two peaks of pollen count in a year during March-April and August October. Average monthly pollen counts of grass were significantly correlated with the number of hospital visits of new patients. PMID- 28360460 TI - Fractional exhaled nitric oxide is a useful adjunctive modality for monitoring bronchial asthma. AB - BACKGROUND AND OBJECTIVE: To evaluate the utility of fractional exhaled nitric oxide (FeNO) in monitoring asthma control. MATERIALS AND METHODS: Steroid naive nonsmoking asthmatics were recruited and followed for 6-8 weeks on standard treatment. Serial measurements of FeNO, peak expiratory flow rate (PEFR) variability, forced expiratory volume in 1 s (FEV1), bronchodilator reversibility (BDR), and asthma control test (ACT) score were measured at baseline and after 6 8 weeks of treatment. RESULTS: One hundred and fifty-one patients were recruited over an 18-month period. These comprised 79 males (52.3%) with mean (standard deviation) age of 34.2 (11.6). Mean (SD) FeNO levels at baseline and after therapy were 45.4 (35.9) and 38.4 (23.7) ppb, respectively (P = 0.01). Baseline FeNO correlated strongly with FEV1 (r = -0.78, P < 0.001), ACT score (r = -0.76, P < 0.001), PEFR variability (r = -0.74, P < 0.001), and moderately with BDR (r = 0.50, P < 0.001). After treatment with inhaled steroids, the correlation remained strong with ACT score (r = -0.68, P < 0.001) but weakened with PEFR variability (r = -0.34, P = 0.01) and FEV1 (r = -0.36, P = 0.01). CONCLUSIONS: FeNO may be useful as an adjunctive noninvasive modality to assess asthma control in both steroid naive asthmatics and asthmatics on treatment. However, the suboptimal sensitivity and specificity may limit its utility as a point-of-care single monitoring tool. PMID- 28360462 TI - Cotton dust exposure: Analysis of pulmonary function and respiratory symptoms. AB - BACKGROUND: Cotton industry workers are exposed to various hazards in the different departments of textile factories. The major health problems associated with cotton dust are respiratory problems, byssinosis, bronchitis and asthma. OBJECTIVE: To study the effect of cotton dust exposure on pulmonary function and respiratory symptoms. SETTINGS AND DESIGN: This cross-sectional observational study was conducted at cotton mill in the Ahmedabad city. MATERIALS AND METHODS: One hundred cotton mill workers of the weaving and spinning area participated in this study while 100 age- and gender-matched male subjects living in the residential area served as the control group. A questionnaire was used to inquire about respiratory symptoms and spirometry was done in both the groups. STATISTICAL ANALYSIS USED: Student's t-test was used to find the difference between spirometric parameters, and Chi-square test was used to find the difference between respiratory symptoms. RESULTS: Respiratory symptoms were statistically significantly more common in the cotton mill workers compared to control group. Cotton mill workers group also showed significant (P < 0.0001) decrease in forced expiratory volume in 1 s (FEV1), ratio of FEV1 and forced vital capacity (FVC) and peak expiratory flow rate, and no significant difference of FVC between groups. There was an association of duration of exposure and symptoms with spirometric abnormality. CONCLUSION: Cotton mill workers showed a significant decrease in spirometric parameters and increase in respiratory symptoms. As the duration of exposure and symptoms increased, spirometric abnormality increased. PMID- 28360461 TI - Study the association of chronic obstructive pulmonary disease with early endothelial dysfunction and its impact on cardiovascular system by estimating urinary albumin creatinine ratio. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) attribute to systemic inflammation which is responsible for microalbuminuria reflecting endothelial dysfunction, could be a significant surrogate marker of potential cardiovascular morbidity. OBJECTIVE: The aim of our study was to find out the possible association of COPD with early cardiovascular changes in the form of renal endothelial dysfunction. SETTINGS AND DESIGN: Case-control, multi-group, cross sectional hospital-based study was designed and conducted in the Department of Respiratory Medicine of BPS Government Medical College for Women, Khanpur Kalan, Sonipat, Haryana. SUBJECTS AND METHODS: The study included 150 subjects, comprising of three groups with each having 50 subjects: Group 1 - acute exacerbation of COPD, Group 2 - stable COPD patients, Group 3 - asymptomatic smokers. Pulmonary function test, urine albumin creatinine ratio (UACR) and brachio-ankle pulse wave velocity were measured in all the subjects. STATISTICAL ANALYSIS: Data were analyzed using SPSS ver 20 (IBM, USA) software. Continuous variables were compared by unpaired Student's t-test while correlation was measured by Pearson correlation test, P < 0.05 was considered statistically significant. RESULTS: The mean urine albumin creatinine ratio UACR value in acute exacerbation of COPD (283.30 mg/g; standard deviation [SD] +/-871.98) was found significantly higher compare to control subjects (24.17 mg/g; SD +/- 32.105;) P = 0.038. Besides this COPD patients with Type 2 respiratory failure having robust positive correlation in between UACR and arterial blood pH (r = 0.559; P = 0.030) while it was inverse and moderate with partial pressure of arterial oxygen (r = 0.470; P = 0.077). CONCLUSIONS: Acute state of COPD with or without Type 2 respiratory failure is having a significant impact on cardiovascular system in the form of early microvascular changes. PMID- 28360463 TI - Prevalence of Aspergillus hypersensitivity and allergic bronchopulmonary aspergillosis in patients with bronchial asthma at a tertiary care center in North India. AB - BACKGROUND: The prevalence of Aspergillus hypersensitivity (AH) and allergic bronchopulmonary aspergillosis (ABPA) has been variably reported. Systematic data regarding Aspergillus sensitization and ABPA are lacking from this part of the country. OBJECTIVES: The aim of this study was to evaluate the prevalence of AH and ABPA in Uttar Pradesh. SETTING AND DESIGN: This was prospective observational study. All patients attending outpatient Department of Pulmonary Medicine of our institute were included in the study. SUBJECTS AND METHODS: Consecutive asthmatic patients underwent screening for ABPA using Aspergillus skin test (AST). Those showing a positive response to AST were further evaluated for ABPA. RESULTS: During the study, 350 patients (192 males, 158 females, mean +/- standard deviation age: 38.3 +/- 12.8) were screened with AST. One hundred and twenty three patients (35.1%) were tested positive for AST and 21.7% of patients were diagnosed as ABPA. CONCLUSIONS: A high prevalence rate of ABPA was observed at our chest clinic. Although comparable with published data from other tertiary centers, it does not represent the true prevalence rates in asthmatics because of high chances of referral bias. PMID- 28360464 TI - Assess drug resistance pattern and genetic profile of Mycobacterium tuberculosis clinical isolates by molecular typing methods using direct repeats and IS6110 in pulmonary tuberculosis cases. AB - BACKGROUND: Tuberculosis (TB), a highly contagious disease that sees no gender, age, or race is mainly a disease of lungs. According to World Health Organization, a TB patient can be completely cured with 6-9 months of anti-TB treatment under directly observed treatment short course. OBJECTIVES: The aim of this study was to check the mono, multi- and triple-drug resistance to first line drugs (FLDs) among TB patients and to access their genetic profile using DR 3074, DR 0270, DR 0642, DR 2068, and DR 4110 using molecular techniques. MATERIAL AND METHODS: To gain a better understanding of drug resistant TB, we characterized 121 clinical isolates recovered from 159 drug resistant pulmonary tuberculosis patients by IS6110 genotyping. MTB isolates recovered from HIV- negative, and smear positive cases of both genders, age varied from 18 to 70 years with drug resistant-TB that was refractory to chemotherapy given for > 12 months. Of a total of 159 sputum smear positive patients sum number of male and female patients was 121 (76.10%) and 38 (23.89%), respectively. Among these patients, number of literate and illiterate patients were 123 (77.3%) and 36 (22.6%). 25 (15.7%) patients had farming as their occupation, 80 (50.3%) had nonagricultural occupation and 54 (33.9%) women were housewives. RESULTS: Mono drug resistant, multi-drug resistant, and totally drug resistant (TDR) cases of TB were calculated as 113.83%, 125.1%, and 67.9%. Isoniazid showed the highest percentage of resistance among the patients. CONCLUSION: Any noncompliance to TB medications, lack of knowledge, and poor management in health centers, etc., results in the emergence of deadly direct repeat forms of TB, which are further complicated and complex to treat. PMID- 28360466 TI - Rare cause of paradoxical worsening of pleural effusion in a patient with tuberculosis. AB - A 33-year-old patient, Known case of chronic kidney disease on maintenance dialysis presented with complaints of low-grade fever and weight loss of 2 months duration. Computed tomography (CT) revealed bilateral mild pleural effusion with significant mediastinal and abdominal adenopathy. CT-guided fine-needle aspiration cytology of abdominal lymph nodes and bone marrow culture was suggestive of tuberculosis. The patient was started on four drug anti-tubercular therapy, post 6 weeks of initiation he developed new onset fever and chest X-ray revealed moderate right pleural effusion. Diagnostic thoracocentesis was suggestive of chylothorax. To the best of our knowledge, this is the first case report of chylothorax due to the paradoxical reaction in the HIV-negative tuberculous patient. PMID- 28360465 TI - Diagnosis and management options in malignant pleural effusions. AB - Malignant pleural effusion (MPE) denotes an advanced malignant disease process. Most of the MPE are metastatic involvement of the pleura from primary malignancy at lung, breast, and other body sites apart from lymphomas. The diagnosis of MPE has been traditionally made on cytological examination of pleural fluid and/or histological examination of pleural biopsy tissue that still remains the initial approach in these cases. There has been tremendous advancement in the diagnosis of MPE now a day with techniques i.e. characteristic Ultrasound and computed tomography features, image guided biopsies, fluorodeoxyglucose-positron emission tomography imaging, thoracoscopy with direct biopsy under vision, tumor marker studies and immunocytochemical analysis etc., that have made possible an early diagnosis of MPE. The management of MPE still remains a challenge to pulmonologist and oncologist. Despite having various modalities with better tolerance such as pleurodesis and indwelling pleural catheters etc., for long term control, all the management approaches remain palliative to improve the quality of life and reduce symptoms. While choosing an appropriate management intervention, one should consider the clinical status of the patient, life expectancy, overall cost, availability and comparative institutional outcomes, etc. PMID- 28360467 TI - Curious case of extraskeletal myxoid chondrosarcoma. AB - Extraskeletal myxoid chondrosarcomas (EMC) are a rare entity of soft tissue tumors that have slow growth with metastatic potential. We discuss here a case of EMC presenting with right upper extremity pain and hemoptysis. Computed tomography scans chest showed diffuse metastatic numerous lung nodules bilaterally. Biopsy confirmed the diagnosis of the tumor. Chemotherapy was a bigger challenge for our patient due to sparse research and data in the literature about the disease. PMID- 28360468 TI - Air leak: An unusual manifestation of organizing pneumonia secondary to bleomycin. AB - Organizing pneumonia (OP) is a less common interstitial lung disease with varying clinical picture. The development of pulmonary air leak in a case of OP is an extremely rare complication. Here, we report the case of a 46-year-old female with carcinoma ovary, postchemotherapy who developed respiratory distress with pneumomediastinum, and subcutaneous emphysema. Lung biopsy showed evidence of OP. This turned out to be a rare case of OP, secondary to bleomycin chemotherapy, presenting with pulmonary air leak. PMID- 28360469 TI - Myelomatous pleural effusion: A rare case entity reported from a tertiary care cancer center in South India. AB - Multiple myeloma (MM) is a plasma cell neoplasm and constitutes 10% of hematologic malignancies. Malignant myelomatous pleural effusions are very rare and occur in <1% of cases of MM. In this article, we report a rare case of a patient who initially presented with pleural effusion and was subsequently found to be secondary to MM with an underlying raised IgG paraprotein. The patient symptomatically improved and was in partial remission with palliative radiotherapy, VTD chemotherapy, and bisphosphonates. PMID- 28360470 TI - Pulmonary mucormycosis diagnosed by convex probe endobronchial ultrasound-guided fine needle aspiration of cavity wall. AB - Pulmonary mucormycosis is an opportunistic fungal infection in immunocompromised individuals. It is difficult to diagnose as it requires tissue biopsy, and generally these patients are unfit to undergo invasive lung biopsies. We describe a novel technique in a case with uncontrolled diabetes mellitus with nonresolving pulmonary cavitary disease where convex probe endobronchial ultrasound (EBUS) guided aspiration of lung cavity wall showed classical histopathological picture establishing the diagnosis of mucorale infection. EBUS being real-time, minimally invasive technique with minimal risk of complications, led to early diagnosis, and prompt treatment. This appears to be a novel diagnostic modality in pulmonary mucormycosis with minimal complications as compared with other biopsy methods with very high complication risk. PMID- 28360471 TI - Thoracoscopic foreign body removal and repair of bronchus intermedius following injury during failed bronchoscopic retrieval. AB - Aspiration of foreign body (FB) into the airways is common in children and continues to be a cause for morbidity and mortality. We report herein, successful thoracoscopic management of a child who aspirated a large magnetic FB into his right bronchus and developed a tear of bronchus intermedius (BI) during an attempt at bronchoscopic retrieval using rigid bronchoscope. The impacted FB was successfully removed thoracoscopically followed by thoracoscopic BI repair. PMID- 28360472 TI - Management of locally advanced primary mediastinal synovial sarcoma. AB - Primary mediastinal synovial sarcoma (PMSS) is a relatively rare disease, and patients are treated predominantly with surgery for resectable disease. Management of locally advanced borderline resectable and unresectable PMSS is not only challenging but also lacks standard guidelines. We present three patients with PMSS, who were unresectable or borderline resectable at presentation and were treated with neoadjuvant chemotherapy followed by surgery and postoperative radiotherapy. PMID- 28360473 TI - Recurrent endobronchial actinomycosis following an interventional procedure. AB - Actinomycosis is an indolent, slowly progressive infection caused by anaerobic or microaerophilic bacteria, primarily from the genus Actinomyces. Thoracic involvement is observed in approximately 15% of cases of infection with actinomycosis. Here, we present a case of a 61-year-old male who presented with recurrent endobronchial actinomycosis. The case is being presented because of its rarity on three counts - endobronchial involvement, which is uncommon, recurrence in different sites in the bronchial tree, which is even rarer and development of the disease following an endobronchial procedure. PMID- 28360474 TI - An intra-thoracic follicular carcinoma of thyroid: An uncommon presentation. AB - Follicular carcinoma of thyroid is the second most common type of carcinoma of thyroid, and it may metastasize to bone, lung, brain, and skin. However, the initial presentation of follicular carcinoma of the thyroid as a large intrathoracic mass without any symptoms of thyroid gland enlargement and dysfunction is very rare. We hereby report a case of a 50-year-old male who presented with chief complaints of chest and low back pain. Preliminary evaluation led to the provisional diagnosis of left-sided intrathoracic mass with vertebral metastasis which was suspected to be a case of bronchogenic carcinoma with distant metastasis. Surprisingly, transthoracic biopsy and histopathology revealed metastasis from follicular carcinoma of thyroid. This prompted us for a retrograde evaluation for a primary thyroid malignancy for which an ultrasound and contrast enhanced computed tomography (CECT) of the neck was done which confirmed the presence of a solitary thyroid nodule. Ultrasonography-guided fine needle aspiration cytology of the nodule revealed follicular carcinoma of thyroid. Histopathological evaluation subsequent to total thyroidectomy revealed follicular carcinoma thyroid, further confirming the diagnosis. The patient was then referred to Department of Nuclear Medicine and Radiotherapy for radionuclide ablation and chemotherapy. We chose to report this case because of its rare presentation as a large intrathoracic mass and the retrograde diagnosis of follicular carcinoma of thyroid. To the best of our knowledge, this is the first report of such a rare case. PMID- 28360475 TI - Intrathoracic Castleman's disease: "An important clinical mimicker". PMID- 28360477 TI - Bronchoscopic management of critical central airway obstruction by thyroid cancer: Combination airway stenting using tracheal and inverted-Y carinal self expanding metallic stents. AB - Central airway obstruction (CAO) can result from various benign and malignant etiologies. Anaplastic thyroid cancer (ATC) is the most aggressive form of thyroid cancer. Rapid airway compromise is the main cause of death in ATC. We report a patient with ATC who presented with a large neck mass leading to CAO with long segment tracheal and right main bronchial compression and respiratory failure. Urgent Rigid Bronchoscopy was performed for airway stabilization and patient was managed with a combination airway stenting approach. A combination of self expanding, metallic, covered inverted Y and straight tracheal stents was used to stabilize the near complete airway structure. We herein highlight the role of therapeutic rigid bronchoscopy with airway stenting as an efficacious treatment modality for management of malignant CAO. PMID- 28360476 TI - Eggshell calcification. PMID- 28360478 TI - Hereditary hemorrhagic telangiectasia with hemothorax in pregnancy. PMID- 28360479 TI - Bronchoscopic instillation of liposomal amphotericin B in management of nonresponding endobronchial mucormycosis. PMID- 28360480 TI - Pulmonary inflammatory pseudotumor with jaundice and anemia: A case report. PMID- 28360481 TI - Hoarseness of voice as presenting complaint of idiopathic pulmonary arterial hypertension. PMID- 28360482 TI - Mapleson D continuous positive airway pressure system for weaning of mechanical ventilation in pediatric patients. PMID- 28360484 TI - Author's reply to concern on excessive dynamic airway collapse and wheeze. PMID- 28360483 TI - Mapleson D continuous positive airway pressure system for weaning of mechanical ventilation in pediatric patients: In response. PMID- 28360485 TI - Methodological issues in article titled, "Prevalence and correlates of nicotine dependence among construction site workers: A cross-sectional study in Delhi". PMID- 28360486 TI - Erratum: Mechanisms of hypoxemia. AB - [This corrects the article on p. 47 in vol. 34, PMID: 28144061.]. PMID- 28360487 TI - All-inside ACL reconstruction: How does it compare to standard ACL reconstruction techniques? AB - The all-inside ACL reconstruction technique is a relatively new development in ACL surgery. Some features of this technique include closed-socket tunnels, dual suspensory graft fixation, decreased bone removal, and smaller skin incisions. The purpose of this review was to compare the unique features of the all-inside ACL versus standard ACL techniques using biomechanical and clinical studies. The all-inside ACL appears to have similar overall results on subjective and objective outcomes studies compared to standard ACL techniques and may be associated with decreased post-operative pain. There is also a concern for a higher graft failure rate with the all-inside ACL. PMID- 28360488 TI - Musculoskeletal colloquialisms based on weapons. AB - Eponyms and colloquialisms are commonly used in orthopaedic literature and convey a great deal of information in a concise fashion. Several orthopaedic conditions have characteristic clinical or radiologic appearances, mimicking the appearance of certain arms or weapons. Most of these are easy to memorise and recognise, provided the orthopaedic surgeon is aware of the colloquialism and familiar with the appearance of the weapon on which it is based. Unfortunately, many such colloquialisms are based on traditional weapons no longer in current use, and their appearances are not familiar to most orthopaedists, creating confusion and difficulty in understanding them. In this paper, we have reviewed the musculoskeletal colloquialisms based on weapons, including a brief description of the weapon with illustrations, highlighting the importance of the colloquialism in diagnosis or treatment of musculoskeletal conditions. PMID- 28360490 TI - Postoperative outcomes of initial varus versus initial valgus proximal humerus fracture: A systematic review and meta-analysis. AB - OBJECTIVES: Our objective was to perform a systematic review of the literature and conduct a meta-analysis to investigate the effect of initial varus or valgus displacement of proximal humerus on the outcomes of patients with proximal humerus fractures treated with open reduction and internal fixation. METHODS: In accordance with Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) statement standards, we performed a systematic review. Electronic databases MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched to identify randomised and non randomised studies comparing postoperative outcomes associated with initial varus versus initial valgus displacement of proximal humerus fracture. The Newcastle Ottawa scale was used to assess the methodological quality and risk of bias of the selected studies. Fixed-effect or random-effects models were applied to calculate pooled outcome data. RESULTS: We identified two retrospective cohort studies and one retrospective analysis of a prospective database, enrolling a total of 243 patients with proximal humerus fractures. Our analysis showed that initial varus displacement was associated with a higher risk of overall complication (RR 2.28, 95% CI 1.12-4.64, P = 0.02), screw penetration (RR 2.30, 95% CI 1.06-5.02, P = 0.04), varus displacement (RR 4.38, 95% CI 2.22-8.65, P < 0.0001), and reoperation (RR 3.01, 95% CI 1.80-5.03, P < 0.0001) compared to valgus displacement. There was no significant difference in avascular necrosis (RR 1.43, 95% CI 0.62-3.27, P = 0.40), infection (RR 1.49, 95% CI 0.46-4.84, P = 0.51), and non-union or malunion (RR 1.37, 95% CI 0.37-5.04, P = 0.64). CONCLUSIONS: The best available evidence demonstrates that initial varus displacement of proximal humerus fractures is associated with higher risk of overall complication, screw penetration, varus displacement, and reoperation compared to initial valgus displacement. The best available evidence is not adequately robust to make definitive conclusions. Further high quality studies, that are adequately powered, are required to investigate the outcomes of initial varus and valgus displacement in specific fracture types. LEVEL OF EVIDENCE: Level II. PMID- 28360489 TI - Unicondylar knee arthroplasty: Key concepts. AB - The concept of unicondylar knee arthroplasty (UKA) has been described as early as 1950s following the introduction of the MacIntosh and McKeever hemiarthroplasty. With improvements in implant design, patient selection, and surgical technique, there has been an increase in utilization of UKA as a less-invasive alternative to total joint arthroplasty for the treatment of localized symptomatic osteoarthritis. The purpose of this review article is to highlight five trending concepts in UKA based on current evidence: bearing design, fixation technique, medial vs. lateral UKA, implant survivorship, and revision surgery. PMID- 28360491 TI - Remote physiotherapy monitoring using the novel D+R Therapy iPhone application. AB - BACKGROUND: Patient compliance to physiotherapy after surgical intervention is key to optimal functional outcome. This has been recognised by published literature over a number of decades. Improving and monitoring patient compliance remains a challenge. This paper explores the use of a website linked iPhone application that may be used to address this issue. PURPOSE: The purpose of this case study was to assess if the D+R Therapy application was of benefit to a patient and to assess the advantages and disadvantages of such a system. METHOD: One patient who underwent knee cartilage resurfacing surgery was followed up in the post-operative period. RESULTS/CONCLUSION: The D+R Therapy platform may provide a timely and cost effective method of managing patients undergoing musculoskeletal physiotherapy. Costs may be reduced by exploiting the hardware patients already own, and identifying non-compliant patients who may be of interest to both healthcare providers and insurers. LEVEL OF EVIDENCE: Level IV. PMID- 28360492 TI - Social media and Internet usage of orthopaedic surgeons. AB - INTRODUCTION: The main objective of this study was to identify the prevalence of social media and Internet usage of orthopaedists and to determine its effects on patient-physician communication. METHODS: Data were collected by e-mail from 321 orthopaedists who filled out the questionnaire. The questionnaire consists of a total 25 items pertaining to personal information, which social media tool they use, their overall views of and expectations from social media, the effects of social media on patient-physician relationship and communication. RESULTS: The rates of keeping in contact with patients and "often" helping patients to manage their treatments over social media increased with age (p < 0.05). It was found that the rate of helping patients to manage their treatments over social media was significantly higher in academicians compared to that in specialist physicians (p = 0.040). The rates of having a personal website and being a member of online physician platform and social-networking sites were higher in participants working in the private sector than participants working in the public sector (p = 0.001). It was found that the rate of finding it useful to be in contact with patients over social media was higher in physicians working in the private sector compared to that in those working in the public sector (p < 0.01). CONCLUSION: Social media tools and Internet are commonly used by orthopaedists to communicate with their patients. Even though there are beneficial effects in patient-physician relationship, effective standards and regulations should be developed to enable a safe communication and to resolve ethical and legal uncertainties. PMID- 28360493 TI - Vitamin D levels among pediatric tuberculosis patients - Does it alter following antitubercular treatment? A prospective study in 19 children. AB - OBJECTIVES: It is still unknown whether altered vitamin D levels observed with osteoarticular tuberculosis change during treatment in a child or modify the disease course. To find a possible answer to the above query, we investigated serial serum 25 hydroxy vitamin D concentrations in children suffering from osteoarticular tuberculosis treated with multidrug antitubercular drugs. METHODS: The prospective study enrolled 19 untreated immunocompetent children with an established diagnosis of osteoarticular tuberculosis. None of the patients were offered any therapeutic vitamin D supplementation at initiation or during the treatment. The patients were followed for response to multidrug antitubercular therapy (DOTS) at 2 months interval. Mean values of vitamin D were calculated at 0, 2, and 6 months and statistically compared. The following laboratory references for defining the vitamin D status were used: <30 nmol/L = deficiency; 30-75 nmol/L = insufficiency; >75 nmol/L = sufficiency. RESULTS: All the patients responded to antitubercular therapy. Out of the enrolled children, 73.67% had low vitamin D levels at initial presentation. There was no statistically significant difference in vitamin D levels in affected children at either 0-2 (p = 0.452), 2 6 (p = 0.240), or 0-6 months (p = 0.854) following antitubercular treatment. Although the mean vitamin D levels were higher in male patients when compared to female patients at all times, there was no statistically significant difference in vitamin D levels during treatment stages in either sex. CONCLUSIONS: Vitamin D levels were low at initiation of treatment and did not significantly improve during multidrug antitubercular treatment. Further, tuberculosis healed well with antitubercular therapy despite persistence of low serum levels of vitamin D. PMID- 28360494 TI - Vitamin D status and adult fracture healing. AB - INTRODUCTION: The effect of vitamin D on maintaining bone health is well researched and its role in the various metabolic stages of fracture healing has become evident, the clinical effects of a vitamin D deficiency in human fracture healing are less well described. Considering today's high prevalence of vitamin D deficiency, the aim of this present study was to investigate the effect of vitamin D status on human adult fracture healing. METHODS: The serum calcidiol concentration was measured in a cohort of adult patients with a fracture in the upper or lower extremity between September 2012 and October 2013. Deficient patients (serum calcidiol <50 nmol/L) were treated with vitamin D. Clinical and radiological consolidation was determined. RESULTS: Vitamin D concentration was measured in 617 patients; 249 (40%) were vitamin D deficient, they subsequently received vitamin D supplements. In 141 patients with a deficiency vitamin D was measured again after 4 months; 111 patients (78.7%) were no longer vitamin D deficient, and 30 remained vitamin D deficient. In six patients of the entire cohort, a clinical delayed union was described. The incidence of delayed union was higher in the group that remained vitamin D deficient (9.7%) compared to the patients who were not initially deficient (0.3%) and those who were no longer deficient after supplementation (1.7%; p < 0.001). The incidence of radiological delayed union did not differ between these three groups (p = 0.67). CONCLUSION: The results of this research suggest that the vitamin D status at time of fracture affects fracture healing. Further research is needed to confirm these results. PMID- 28360495 TI - The incidence of deep vein thrombosis and pulmonary embolism after fracture of the tibia: An analysis of the National Trauma Databank. AB - Controversy exists regarding the routine use of chemical prophylaxis in isolated lower extremity fractures. The incidence of VTE in specific fracture locations in the lower extremity is largely unknown, and represents key information necessary to determine the need for prophylaxis. A large cross-sectional study using the National Trauma Databank was performed evaluating for the incidence and risk factors of VTE in isolated tibia fractures. The overall incidence of DVT and PE are extremely low in cases of isolated tibia fractures, which brings into doubt a role for routine use of chemical prophylaxis for these fractures. PMID- 28360496 TI - Drivers of hospital length of stay in 56,000 orthopaedic trauma patients: The impact of postoperative cardiac events. AB - PURPOSE: To determine whether postoperative cardiac complications following orthopaedic trauma treatment are associated with longer lengths of stay. METHODS: This was a retrospective cohort study. We analyzed orthopaedic trauma patients in the United States for whom data was collected in the ACS-NSQIP database between the years of 2006 and 2013. The patient population included 56,217 orthopaedic trauma patients meeting any 1 of the 89 CPT codes selected in the ACS-NSQIP database. The main outcome measure was hospital length of stay following orthopaedic trauma treatment. RESULT: Of the 56,217 orthopaedic trauma patients, 749 (1.3%) developed postoperative adverse cardiac events. There was a significant difference in total length of stay (p < 0.001): patients with cardiac complications on average stayed 10.6 days compared to 5.2 days for patients who did not experience such cardiac complications. This amounted to a difference of $24,316 in total hospital costs. Through multiple linear regression modeling controlling for multiple patient and surgical factors, the presence of cardiac complications significantly added 1.5 days in total hospital stay (p < 0.05). CONCLUSION: Orthopaedic trauma patients sustaining postoperative cardiac events have significantly longer hospital lengths of stay when compared to those who do not develop cardiac complications. This difference amounts to significantly higher health care costs. PMID- 28360498 TI - Arthroscopic assisted ankle arthrodesis: A retrospective study of 32 cases. AB - PURPOSE: The arthroscopic assisted ankle arthrodesis (AAAA) is a minimally invasive procedure for end-stage ankle arthritis with numerous benefits like faster time of union, insignificant blood loss, less morbidity, less infection rate, and less soft tissue complications. A shorter hospital stay decreases the cost and results in early mobilization compared to open methods. We present a retrospective series of 32 patients, who underwent AAAA during a period of 8 years. METHODS: Thirty-two patients were reviewed retrospectively from 2008 to 2015. We calculated the Karlsson and Peterson ankle function scoring system pre operatively and at 3 and 12 months after the surgery, in all the patients. All the patients were operated using arthroscopic denuding of degenerated cartilage followed by percutaneous criss-cross screw fixation through the tibia crossing the ankle joint into the talus. RESULTS: The mean age at operation time was 43.7 years. Four patients were excluded from the study. 18 were male, and 10 were female patients. All the 28 cases were followed up for a minimum of 1 year (mean 1.7 years). The average time to union was 14 weeks. The complications included four cases requiring removal of a screw for prominence, and one superficial infection. There were 20 (71.4%) patients with excellent, 4 (14.2%) with good, 3 (10.7%) with fair and 1 (3.5%) with poor clinical outcome. The average tourniquet time for the surgery was 70 min. The mean hospital stay was 2 days. The average Karlsson and Peterson's scoring was 32.71 pre-operatively and 74.10 and 89.00 postoperatively measured at 3 months and 1-year follow-up. CONCLUSION: With the high incidence of soft-tissue problems and the young age of onset of post traumatic arthritis, AAAA remains the treatment of choice in most cases with numerous advantages over open technique. PMID- 28360497 TI - Operative repair of proximal humerus fractures in septuagenarians and octogenarians: Does chronologic age matter? AB - BACKGROUND: With an expected doubling of the geriatric population within the next thirty years it is becoming increasingly important to determine who among the elderly population benefit from orthopaedic interventions. This study assesses post-operative outcomes in patients aged seventy or greater who sustained a proximal humerus fracture and were treated surgically as compared to a younger geriatric cohort to determine if there is a chronologic age after which post operative outcomes significantly decline. METHODS: A retrospective chart review was conducted for 201 patients who sustained fractures of the proximal humerus (OTA 11A-C) and were treated operatively by open reduction and internal fixation. Data from 132 independent, active patients aged fifty-five or older was identified and analyzed. Forty-seven patients age 70 or older were compared to 78 patients aged 55-69. Average length of follow-up was 19.5 months. All complications were recorded. Univariate and multivariate analysis was conducted to assess for differences between groups. RESULTS: 95% of patients achieved fracture union within 6 months. No significant differences were found between cohorts with regard to gender, fracture severity, or CCI (p = 0.197, p = 0.276, p = 0.084, respectively). Functional outcome scores, shoulder range of motion, and complications rates for patients aged 70 and older were not significantly different from patients aged 55-69. There were 10 complications in the older elderly cohort (21%), 6 of which required re-operation and 13 complications in the young elderly cohort (17%), 8 of which required re-operation. CONCLUSIONS: Operative fracture repair using locked plating of the proximal humerus in septuagenarians and octogenarians can provide for excellent long-term outcomes in appropriately selected patients. These patients tend to have long term functional outcome scores, post-operative range of motion, and complication rates that are comparable to younger geriatric patients. Physicians should not exclude patients for repair of proximal humerus fractures based on chronological age cutoffs. PMID- 28360499 TI - Long-term safety and efficacy of human bone morphogenetic protein (HBMP) in the treatment of resistant non-unions and failed arthrodesis. AB - The bone morphogenetic protein (BMP) has emerged as a suitable alternative to autogenous cancellous bone grafting and despite current knowledge about its mechanism; few studies provide evidence about the long-term safety of BMP. The aim of this investigation is to determine if BMP implantation is a safe and effective agent in a long-term setting for the treatment of patients with resistant non-unions and failed arthrodesis. This study is a retrospective case series study that was conducted on 55 patients who had received BMP. Collected data included all related surgical history, and clinical and X-ray data both pre operatively and post-operatively. All patients were scheduled for follow-up evaluations at one week and 1, 3, 6, and 12 months post-operatively. Seven patients (13%) experienced adverse events related to their surgery with hBMP. Six patients (11%) experienced persistent non-union; five of these underwent further revision surgery. One patient (2%) developed an infected non-union. No patients experienced tumor induction, allergic reaction to hBMP. The remaining 48 patients achieved osseous union within six months of hBMP implantation. This study differs from previous studies that the use of hBMP is a safe and efficacious treatment method for resistant non-unions and failed arthrodesis in the long-term setting. PMID- 28360500 TI - Outcome after internal fixation of intraarticular distal humerus (AO type B & C) fractures: Preliminary results with anatomical distal humerus LCP system. AB - PURPOSE: The treatment of intraarticular fractures of the distal humerus is challenging and involves the risk of complications and bad functional results. Anatomical and stable internal fixation with early postoperative mobilization is expected to improve the functional outcomes. The objective of this study was to evaluate the functional and radiological results, along with the complications associated, of open reduction and internal fixation using precontoured anatomical locking LCP plate system for intraarticular distal humerus fractures in adult patients. METHODS: This prospective study consist of 31 patients with a mean age of 41.2 years (range 19-62) were treated with open reduction and angular stable internal fixation. All underwent posterior transolecranon surgical approach. Mean follow-up to the final interview was 10 months (from 6 to 20 months). All operated patients were available at the time of last followup. AO classification showed 26 C-fractures (9*13C 1, 12*13C2,5* 13C3) and 5 B-fracture (1* 13B1,1* 13B2,3* 13B3). There were 25 closed fractures and 6 open grade 1 fractures. The clinical followup using Mayo elbow performance score (MEPS) and radiographic follow up with elbow anterior-posterior and lateral view X-rays were performed postoperatively. RESULTS: The mean MEPS was 87.9 points out of 100 (range 55-100) with 61% Excellent, 29% good and 10% fair and poor scores. Mean elbow flexion of 115.8 degrees (range 85 degrees -150 degrees ). The mean deficit in extension was 19 degrees (range 5 degrees -35 degrees ). All olecranon osteotomy were united .Nonunion of distal humerus fracture occurred in 2 cases. Other complications were hardware prominence in 3 cases, superficial infection in 4 cases and Ulnar nerve neuropraxia in 1 case which was recovered uneventfully. Revision surgery was not required in any complication. CONCLUSION: Open reduction and internal fixation with precontoured distal humerus anatomical locking plate system is a good method of treatment for complex Supra- intercondylar fracture of distal humerus with good functional outcome and low rates of complications. Even though early results are promising, longer term investigations and larger patient groups are necessary to confirm the presented data. PMID- 28360501 TI - Can TAD and CalTAD predict cut-out after extra-medullary fixation with new generation devices of proximal femoral fractures? A retrospective study. AB - BACKGROUND: Intramedullary and extramedullary strategies of pertrochanteric fracture fixation are still controversial, but new percutaneous devices may give advantages regarding operative time, blood loss and rate of cardiovascular complications. We retrospectively analyze our cases regarding Anteversa(r) plate (Intrauma, Turin, Italy) fixation of pertrochanteric femoral fractures, focusing on the correlation between two radiographical parameters (tip-apex distance "TAD" and calcar referenced tip-apex distance "CalTAD") and the occurrence of cut-out. The purpose of this study was to determine if these predicting factors of cut-out are reliable in the treatment of proximal femoral fractures with the Anteversa plate. METHODS: A series of 77 patients with 53 31-A1 fracture types and 24-A2 fractures completed a 12-month-follow-up. Clinical outcomes were evaluated according to Parker-Palmer Mobility Score at the final follow-up. TAD and CalTAD were considered to determine their correlation with cut-out events. RESULTS: The mean Parker-Palmer Score was 6.94 in A1 group and 7.41 in A2 group (p = 0.47). Mean value of TAD index was 29.58, 29.81 in the A1 group and 29.08 in the A2 group, and mean value of CalTAD index was 30.87, 31.03 in the A1 group and 30.50 in the A2 group. We observed 3 cases of implant cut-out. We shared our sample in two groups, one group with TAD and CalTAD indices lower than 25 mm and another group higher than 25 mm to evaluate how the Palmer Parker score changed and no statistical differences were found between the two groups. CONCLUSIONS: Taking into consideration that good clinical results were obtained for TAD and CalTAD values superior to 25 mm, the prognostic value of 25 mm of TAD and CalTAD indices might not be appropriate to this new percutaneous plate. PMID- 28360502 TI - Citation analysis of the 100 most common articles regarding distal radius fractures. AB - PURPOSE: Bibliometric studies are increasingly being utilized as a tool for gauging the impact of different literature within a given field. The purpose of this study was to identify the most cited articles related to the management of distal radius fractures to better understand how the evidence of this topic has been shaped and changed over time. METHODS: We utilized the ISI web of science database to conduct a search for the term "distal radius fracture" under the "orthopaedics" research area heading, and sorted the results by number of times cited. The 100 most cited articles published in orthopedic journals were then analyzed for number of citations, source journal, year of publication, number of authors, study type, level of evidence, and clinical outcomes utilized. RESULTS: The 100 most cited articles identified were published between 1951 and 2009. Total number of citations ranged between 525 and 67, and came from ten different orthopedic journals. The largest number of articles came from J Hand Surg Am and J Bone Joint Surg Am, each with 32. Consistent with previous analyses of orthopedic literature, the articles were primarily clinical, and of these, 53/76 were case series. The vast majority were evidence level IV. Only a small percentage of articles utilized patient reported outcome measures. CONCLUSIONS: These data show that despite distal radius fractures being a common fracture encountered by physicians, very few of the articles were high quality studies, and only a low proportion of the studies include patient reported outcome measures. Surgeons should take this lack of high-level evidence into consideration when referencing classic papers in this field. CLINICAL RELEVANCE: Analysis of the 100 most cited distal radius fracture articles allows for delineation of which articles are most common in the field and if a higher level of evidence correlates positively with citation quantity. PMID- 28360503 TI - The role of copy and paste function in orthopedic trauma progress notes. AB - INTRODUCTION: The electronic medical record (EMR) is standard in institutions. While there is not concern for legibility of notes and access to charts, there is an ease of copy and paste for daily notes. This may not lead to accurate portrayal of patient's status. Our purpose was to evaluate the use of copy and paste functions in daily notes of patients with injuries at high risk for complications. METHODS: IRB approval was obtained for a retrospective review. Inclusion criteria included patients aged 18 and older treated at our Level 1 Trauma Center after implementation of Epic Systems Corporation, Verona, WI, USA. Those who were surgically treated for bicondylar tibial plateau fracture, or open tibial shaft fracture type I or II were included. Manual comparison of daily progress to the previous day's note was carried out. Comparisons were made by evaluating the subjective, objective, and plan portions of the notes, coded nominally using 1 for a change 0 for remaining the same. RESULTS: 38 patients' charts were reviewed during a 10-month (July 2012-April 2013) period, and the average length of stay was 12 days (range: 2-35). A total of 418 notes were compared. The overall average of copied data was 85% daily. In the subjective portion, 85-97% of the data was copied on a daily basis and 71-92% of the data was copied within the objective portion of the notes. There were 15 medical complications necessitating intervention. Of these medical complications, the note the day after the complication reflected the event in 10 out of 15, or 70%, of the complications. Thus 5, or 30%, of the patients did not have notes reflecting the complication (p < 0.05). There were 7 complications related to the injuries: 4 cases of compartment syndrome, 1 case of foot drop, representing a change in neurologic status, an amputation, and a wound infection treated with antibiotics. Four of the 7 complications (57%) were not reflected in the notes the following day after the complication (p < 0.05). There were 54 planned returns to the operating room for procedures, yet 30 of the 54 (56%) notes regarding planned surgical procedures notes did not accurately report the plan for surgery (p < 0.05). There were 4 patients with unplanned trips to the operating room and 3 of the notes (75%) did not reflect this (p < 0.05). Twelve patients (32%) did not have notes accurately reflecting discharge plans and/or destination (p < 0.05). DISCUSSION/CONCLUSION: Our results demonstrated widespread use of copy and paste function. We encourage evaluation of the charts by comparing notes to check and a plan to minimize this practice. There needs to be consistent note writing guidelines and appropriate templates used. This will decrease the inaccuracies in the chart and provide a clear picture of the patient, their injuries, and current status. PMID- 28360504 TI - Lateral facetectomy decreased patellofemoral contact pressure in total knee replacement: A cadaveric study. AB - BACKGROUND: To study the patellofemoral contact pressure in patellar non resurfacing total knee replacement after lateral facetectomy in different amounts of bone removal. METHODS: Eight knees from four fresh-frozen whole body cadavers were used for this study. Total knee replacement of all knees was performed by the same surgical technique. The contact pressure was measured and recorded when the knee performed passive motion from full extension to full flexion in native patella, lateral retinacular junction release, 10% lateral facetectomy, and 20% lateral facetectomy. RESULTS: Peak patellofemoral contact pressure decreased progressively from native patellar, junctional release of the patella, 10% facetectomy, and 20% facetectomy. The peak patellofemoral contact pressures were statistically significantly different in each patellar condition (p = 0.025). CONCLUSION: In the experimental study, lateral facetectomy can reduce the peak patellofemoral contact pressure in patellar non-resurfacing total knee arthroplasty. PMID- 28360505 TI - Intra-articular hyaluronic acid is superior to steroids in knee osteoarthritis: A comparative, randomized study. AB - BACKGROUND: To compare the short and mid-term results of intraarticular triamcinolone hexacetonide and hyaluronic acid (HA) in knee osteoarthritis. METHODS: A prospective randomized study including 40 patients in steroid and 42 patients in HA group. The outcome was evaluated with Knee Society Score (KSS) and Visual Analog Scale (VAS). RESULT: On KSS function and VAS score, there was no difference till four weeks. On KSS pain there was no difference till 12 weeks (P > 0.05) after that score of steroid group deteriorated rapidly. At six months HA was significantly better than a steroid. CONCLUSION: The HA seems to be better for pain relief and functionality in the short and mid-term periods. PMID- 28360506 TI - Current trends of microorganisms and their sensitivity pattern in paediatric septic arthritis: A prospective study from tertiary care level hospital. AB - PURPOSE: Early treatment of septic arthritis is essential before irreversible damage to the articular cartilage occurs. Clinicians often start empirical antibiotic therapy for symptomatic relief while awaiting a definitive culture report. In present day parlance with variations in different centres in the private and public sector and rampant antibiotic abuse, a lot of resistance is being seen in the flora and their sensitivity patterns. Hence it is imperative to document and analyze these changing trends. METHODS: The authors conducted a retrospective analysis of prospectively gathered data of 60 patients under 14 years of age. Joint arthrotomy was performed as a standard therapeutic protocol and the drained pus or synovial fluid was sent for gram stain and culture by 2 different methods: conventional agar plate method and BACTEC Peds Plus/F bottle method. Antibiotic susceptibility tests were done by the disc diffusion method of Clinical Laboratory Standards Institute (CLSI). RESULTS: The commonest presenting age group was below 1 year (80% patients) including 24 neonates. There were 19 hospital and 41 community acquired cases of septic arthritis. The hip (56%) was the commonest affected joint followed by knee (28%), shoulder joint (11%) and elbow (5%). Microorganism was isolated in 53% isolates of joint fluid only (36 culture positive patients). Conventional agar methods of culture showed positive report in only 42% patients (15/36 patients) while with the BACTEC method the yield was 71%. In the Community acquired septic arthritis, methicillin sensitive Staphylococcus aureus was isolated as commonest microbe while resistant variety of gram negative bacilli including E. coli and Klebsiella were found as predominant organism causing hospital acquired nosocomial infection of joints. The results strikingly differ in terms of response to treatment as most patients (11/19 patients) showed significant resistance to the most commonly practiced empirical antibiotic regimen of ampicillin-cloxacillin group in routine practice. When cefazolin was used as empirical antibiotic, it has shown good response and better sensitivity in 82% patients (27/33 patients). CONCLUSION: S. aureus is still the most common organism in septic arthritis. The BACTEC system was found to improve the yield of clinically significant isolates. Though a significant resistance to common antibiotic regimen is noticed, the strain is susceptible to cephalosporin group of antibiotics. We recommend the use of cephalosporine antibiotics as an empirical therapy till culture and sensitivity report are available. PMID- 28360508 TI - New applications of Schrodinger type inequalities to the existence and uniqueness of Schrodingerean equilibrium. AB - As new applications of Schrodinger type inequalities appearing in Jiang (J. Inequal. Appl. 2016:247, 2016), we first investigate the existence and uniqueness of a Schrodingerean equilibrium. Next we propose a tritrophic Hastings-Powell model with two different Schrodingerean time delays. Finally, the stability and direction of the Schrodingerean Hopf bifurcation are also investigated by using the center manifold theorem and normal form theorem. PMID- 28360507 TI - Clear cell chondrosarcoma proximal femur with secondary aneurysmal component - A rarity. PMID- 28360509 TI - Influence on ocular surface after cataract surgery and effect of topical diquafosol on postoperative dry eye: a multicenter prospective randomized study. AB - PURPOSE: To investigate influences of 3% diquafosol sodium ophthalmic solution (DQS) on ocular surface after cataract surgery and effects on postoperative dry eye. DESIGN: This study had two consecutive prospective study phases. The former was an observational study from before cataract surgery to 4 weeks after surgery and the latter was a randomized open-label study from 4 to 8 weeks after surgery. METHODS: Subjects were 433 eyes of 433 patients undergoing cataract surgery with intraocular lens implantation. Dry eye examination of tear breakup time (BUT), corneal and conjunctival fluorescein staining scores, total subjective symptom score (12 symptoms), and Schirmer I test were conducted before surgery and 4 weeks after surgery. Patient demographics and these examination results were used to analyze risk factors to predict postoperative dry eye. In a randomized study, 154 eyes diagnosed with dry eye postoperatively were applied either DQS or artificial tears (AT) six times daily for 4 weeks. The data of the examinations were compared. RESULTS: At 4 weeks after surgery, BUT was shortened significantly (P=0.036), fluorescein staining score increased significantly (P=0.012), but total subjective symptom score was significantly improved (P<0.001). The majority of postoperative dry eye was shortened BUT type (53.1%). The dry eye prevalence after surgery decreased (55.7%) compared with before surgery (69.7%). Females and the patient with dry eye symptoms before surgery had significant risk factors for postoperative dry eye. In a randomized study, BUT was significantly prolonged in the DQS group (P=0.015), but not in the AT group. Fluorescein staining score was significantly improved in both groups (P<0.001). Total subjective symptom score was significantly decreased in the AT group (P<0.001), but not in the DQS group. CONCLUSION: Our study suggests that cataract surgery has harmful effects on tear film stability and ocular surface, and DQS has a capability to improve them. PMID- 28360510 TI - Efficacy of cytokine-induced killer cell infusion as an adjuvant immunotherapy for hepatocellular carcinoma: a systematic review and meta-analysis. AB - This study was designed to evaluate the efficacy and safety of cytokine-induced killer (CIK) cell-based immunotherapy as an adjuvant therapy for hepatocellular carcinoma (HCC). Published studies were identified by searching Medline, Cochrane, EMBASE, and Google Scholar databases with the keywords: cytokine induced killer cell, hepatocellular carcinoma, and immunotherapy. The outcomes of interest were overall survival, progression-free survival, and disease-free survival. Eight randomized controlled trials (RCTs), six prospective studies, and three retrospective studies were included. The overall analysis revealed that patients in the CIK cell-treatment group had a higher survival rate (pooled hazard ratio (HR) =0.594, 95% confidence interval [CI] =0.501-0.703, P<0.001). Patients treated with CIK cells in non-RCTs had a higher progression-free survival rate (pooled HR =0.613, 95% CI =0.510-0.738, P<0.001). However, CIK cell treated patients in RCTs had progression-free survival rates similar to those of the control group (pooled HR =0.700, 95% CI =0.452-1.084, P=0.110). The comparison between pooled results of RCTs and non-RCTs regarding the progression free survival rate did not reach statistical significance. Patients in the CIK cell-treatment group had lower rates of relapse in RCTs (pooled HR =0.635, 95% CI =0.514-0.784, P<0.001). Similar results were found when non-RCT and RCTs were pooled (pooled HR =0.623, 95% CI =0.516-0.752, P<0.001). Adjuvant CIK cell-based immunotherapy is a promising therapeutic approach that can improve overall survival and reduce recurrence in patients with HCC. PMID- 28360511 TI - Health-related quality of life, visual function and treatment satisfaction following intravitreal dexamethasone implant for diabetic macular edema. AB - PURPOSE: The aim of this study was to explore and describe quantitatively patient reported outcome measures (PROMs), ie, health-related quality of life (QoL), visual function and treatment satisfaction, in patients with diabetic macular edema (DME) receiving two different regimens of Ozurdex (intravitreal dexamethasone implant). METHODS: In this multicenter, prospective study, 100 patients with center-involving refractory DME were randomized 1:1 to either five monthly fixed dosing or optical coherence tomography (OCT)-guided pro re nata (PRN) regimen of dexamethasone intravitreal implant therapy. The primary outcome was the difference between arms in change in PROMs and health-related QoL from baseline to 12 months, as measured by the Retinopathy-Dependent Quality of Life (RetDQoL) questionnaire, Visual Function Questionnaire-25 (VFQ-25) and Retinopathy Treatment Satisfaction Questionnaire (RetTSQ). RESULTS: There was no statistically significant difference in the RetDQoL score and VFQ-25 score at month 12 compared to those at baseline, whereas the total mean RetTSQ score increased significantly at the exit visit. The two treatment arms did not differ significantly regarding the change in PROMs and health-related QoL questionnaires. Logistic regression analysis showed that visual acuity (VA) of >=55 letters, central foveal thickness <300 MUm and macular volume <9.2 mm3 at the exit visit (month 12) predicted a higher change in RetTSQ. CONCLUSION: This study showed that there is a statistically significant improvement in treatment satisfaction, as measured by RetTSQ, in patients with DME treated with dexamethasone intravitreal implant, independent of the dose regimen, namely, fixed or PRN. However, it should be noted that the clinically meaningful change could not be assessed accurately, since no thresholds for clinically meaningful change currently exist for the RetTSQ. On the other hand, there was no significant change in health-related QoL, as measured using VFQ-25 and RetDQoL. Factors affecting the patients' treatment satisfaction were the final VA, the central foveal thickness and the macular volume. PMID- 28360512 TI - Treatment adherence in patients with type 2 diabetes mellitus correlates with different coping styles, low perception of self-influence on disease, and depressive symptoms. AB - BACKGROUND: Insulin analogs are regarded as more convenient to use than human insulin; however, they require a different administration scheme due to their unique pharmacokinetic and pharmacodynamic properties. This study aimed to assess difficulties with adherence to treatment with insulin analogs in patients with type 2 diabetes mellitus (T2DM), who had previously been treated with human insulin. The associations between difficulties with adherence and clinical, demographic, and psychological characteristics were also evaluated. PATIENTS AND METHODS: The study was conducted on 3,467 consecutively enrolled patients with T2DM (54.4% women), mean age 63.9 years (SD =9.57), who had recently undergone a physician-directed change in treatment from human insulin to insulin analogs. The questionnaires addressed difficulties with switching the therapy, coping styles, well-being, and perception of self-influence on the disease. RESULTS: No adherence problems in switching therapy were reported in 56.6% of patients. Specific moderate difficulties were reported in 10.4%-22.1% of patients, major difficulties in 0.7%-6.9% of patients, and very significant difficulties in 0.03% 1.3% of patients. Overall, remembering to modify the insulin dose in the case of additional meals was the most frequently reported difficulty, and problems with identifying hypoglycemic symptoms were the least frequently reported. The increased risk of difficulties was moderately related to low perception of self influence on diabetes and poor well-being. The intensity of problems was higher among those who were less-educated, lived in rural areas, had complications, and/or reported maladaptive coping styles. CONCLUSION: Switching from human insulin to an insulin analog did not cause adherence problems in more than half of the patients. In the remaining patients, difficulties in adherence correlated with maladaptive coping styles, low perception of self-influence on disease course, and depressive symptoms. PMID- 28360513 TI - Evaluation of the efficacy of randomized controlled trials of sensory stimulation interventions for sleeping disturbances in patients with dementia: a systematic review. AB - OBJECTIVE: The current review aims to evaluate the sensory stimulation interventions in terms of reducing sleeping disturbances in patients with dementia. The nonpharmacological interventions seem to be an efficient, inexpensive, and easy tool for family caregivers. Moreover, sleeping disorders increase caregivers' distress and may lead to hospitalization. METHODS: A systematic literature search was performed. Eleven randomized controlled trials have been found. Among these eleven trials, one referred to massage therapy and acupuncture, and the other ten studies referred to bright light therapy. RESULTS: The results demonstrated that there are no relevant randomized controlled trials of music therapy, aromatherapy, and multisensory environment/Snoezelen referring to sleeping disturbances. Several studies have been conducted about the effect of the bright light therapy, and there is also another study that combines massage therapy and acupuncture therapy. CONCLUSION: Sensory stimulation interventions are inexpensive and practical for dementia caregivers; however, only bright light therapy seems to be useful to reduce sleeping problems in dementia. The other sensory stimulation interventions lack evidence, and there is a strong need for further research. PMID- 28360514 TI - LABA/LAMA combinations versus LAMA monotherapy or LABA/ICS in COPD: a systematic review and meta-analysis. AB - BACKGROUND: Randomized controlled trials (RCTs) indicate that long-acting bronchodilator combinations, such as beta2-agonist (LABA)/muscarinic antagonist (LAMA), have favorable efficacy compared with commonly used COPD treatments. The objective of this analysis was to compare the efficacy and safety of LABA/LAMA with LAMA or LABA/inhaled corticosteroid (ICS) in adults with stable moderate-to very-severe COPD. METHODS: This systematic review and meta-analysis (PubMed/MEDLINE, Embase, Cochrane Library and clinical trial/manufacturer databases) included RCTs comparing >=12 weeks' LABA/LAMA treatment with LAMA and/or LABA/ICS (approved doses only). Eligible studies were independently selected by two authors using predefined data fields; the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. RESULTS: Eighteen studies (23 trials) were eligible (N=20,185). LABA/LAMA significantly improved trough forced expiratory volume in 1 second (FEV1) from baseline to week 12 versus both LAMA and LABA/ICS (0.07 L and 0.08 L, P<0.0001), with patients more likely to achieve clinically important improvements in FEV1 of >100 mL (risk ratio [RR]: 1.33, 95% confidence interval [CI]: [1.20, 1.46] and RR: 1.44, 95% CI: [1.33, 1.56], respectively, the number needed to treat being eight and six, respectively). LABA/LAMA improved transitional dyspnea index and St George's Respiratory Questionnaire scores at week 12 versus LAMA (both P<0.0001), but not versus LABA/ICS, and reduced rescue medication use versus both (P<0.0001 and P=0.001, respectively). LABA/LAMA significantly reduced moderate/severe exacerbation rate compared with LABA/ICS (RR 0.82, 95% CI: [0.75, 0.91]). Adverse event (AE) incidence was no different for LABA/LAMA versus LAMA treatment, but it was lower versus LABA/ICS (RR 0.94, 95% CI: [0.89, 0.99]), including a lower pneumonia risk (RR 0.59, 95% CI: [0.43, 0.81]). LABA/LAMA presented a lower risk for withdrawals due to lack of efficacy versus LAMA (RR: 0.66, 95% CI: [0.51, 0.87]) and due to AEs versus LABA/ICS (RR: 0.83, 95% CI: [0.69, 0.99]). CONCLUSION: The greater efficacy and comparable safety profiles observed with LABA/LAMA combinations versus LAMA or LABA/ICS support their potential role as first-line treatment options in COPD. These findings are of direct relevance to clinical practice because we included all currently available LABA/LAMAs and comparators, only at doses approved for clinical use. PMID- 28360515 TI - A review of general pain measurement tools and instruments for consideration of use in COPD clinical practice. AB - BACKGROUND: The experience of pain can have a significant impact on the everyday life of individuals including those with COPD. Recently, pain has emerged as an area in COPD research. When considering pain measurement in COPD studies, it is important to consider the validity, reliability, responsiveness and interpretability of instruments and tools. This review sought to assess these domains of general pain instruments and tools using the consensus-based standards for the selection of health measurement instruments (COSMIN). METHODS: Three separate analyses were used to assess general pain measurement tools and instruments. These comprise COSMIN's, 1) methodological quality assessment with dichotomous responses, 2) the 4-point rating scale, and 3) overall quality criteria using an assessment scale for clinimetric properties by Terwee. RESULTS: Overall Pain Sensitivity Questionnaire (PSQ) was found to have the highest rating in all domains of validity, reliability, responsiveness and interpretability. In the first analysis, PSQ and Geriatric Pain Measure (GPM) scored highest in four of the six domains. In the second analysis, using the 4-point rating, the PSQ scored highest in three of four domains. In the third analysis, the GPM scored the highest in all four domains. Overall the PSQ, GPM and Defense and Veterans Pain Rating Scale scores were consistently high in the three separate analyses in this review. CONCLUSION: This review found variability in the domains of validity, reliability, responsiveness and interpretability in general pain tools and instruments. The PSQ was found to be the most valid and reliable general pain measurement instrument for adult populations. PMID- 28360518 TI - Erratum: Current asthma contributes as much as smoking to chronic bronchitis in middle age: a prospective population-based study [Corrigendum]. AB - [This corrects the article on p. 1911 in vol. 11, PMID: 27574415.]. PMID- 28360516 TI - Association between RTEL1 gene polymorphisms and COPD susceptibility in a Chinese Han population. AB - OBJECTIVE: We investigated the association between single-nucleotide polymorphisms in regulation of telomere elongation helicase 1 (RTEL1), which has been associated with telomere length in several brain cancers and age-related diseases, and the risk of chronic obstructive pulmonary disease (COPD) in a Chinese Han population. METHODS: In a case-control study that included 279 COPD cases and 290 healthy controls, five single-nucleotide polymorphisms in RTEL1 were selected and genotyped using the Sequenom MassARRAY platform. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression after adjusting for age and gender. RESULTS: In the genotype model analysis, we determined that rs4809324 polymorphism had a decreased effect on the risk of COPD (CC versus TT: OR =0.28; 95% CI =0.10-0.82; P=0.02). In the genetic model analysis, we found that the "C/C" genotype of rs4809324 was associated with a decreased risk of COPD based on the codominant model (OR =0.33; 95% CI =0.13-0.86; P=0.022) and recessive model (OR =0.32; 95% CI =0.12-0.80; P=0.009). CONCLUSION: Our data shed new light on the association between genetic polymorphisms of RTEL1 and COPD susceptibility in the Chinese Han population. PMID- 28360517 TI - Greater dyspnea is associated with lower health-related quality of life among European patients with COPD. AB - OBJECTIVE: Dyspnea is a defining symptom in the classification and treatment of chronic obstructive pulmonary disease (COPD). However, the degree of variation in burden among symptomatic COPD patients and the possible correlates of burden remain unclear. This study was conducted to characterize patients in Europe currently being treated for COPD according to the level of dyspnea in terms of sociodemographics, health-related quality of life, work productivity impairment, and health care resource use assessed by patient reports. METHODS: Data were derived from the 5-EU 2013 National Health and Wellness Survey (N=62,000). Respondents aged >=40 years who reported currently using a prescription for COPD were grouped according to their level of dyspnea as per the Global Initiative for Chronic Obstructive Lung Disease guidelines and compared on health status (revised Short Form 36 [SF-36]v2), work impairment (Work Productivity and Activity Impairment questionnaire), and number of health care visits in the past 6 months using generalized linear models with appropriate distributions and link functions. RESULTS: Of the 768 respondents who met the inclusion criteria, 245 (32%) were considered to have higher dyspnea (equivalent to modified Medical Research Council score >=2). Higher dyspnea was associated with decrements ranging from 3.9 to 8.2 points in all eight domains of the SF-36 health profile after adjustment for sociodemographics, general health characteristics, and length of COPD diagnosis; mental component summary scores and Short Form-6D health utility scores were lower by 3.5 and 0.06 points, respectively. Adjusted mean activity impairment (55% vs 37%, P<0.001) and number of emergency room visits (0.61 vs 0.40, P=0.030) were higher in patients with greater dyspnea. CONCLUSION: Many European patients with COPD continue to experience dyspnea despite treatment and at levels associated with notable impairments in the patients' ability to function across a multitude of domains. These patients may benefit from more intense treatment of their symptoms. PMID- 28360519 TI - Intratracheal transplantation of endothelial progenitor cells attenuates smoking induced COPD in mice. AB - BACKGROUND: Endothelial progenitor cells (EPCs) might play a protective role in COPD. The aim of this study was to investigate whether intratracheal allogeneic transplantation of bone-marrow-derived EPCs would attenuate the development of smoking-induced COPD in mice. METHODS: Isolated mononuclear cells from the bone marrow of C57BL/6J mice were cultured in endothelial cell growth medium-2 for 10 days, yielding EPCs. A murine model of COPD was established by passive 90-day exposure of cigarette smoke. On day 30, EPCs or phosphate-buffered saline alone was administered into the trachea. On day 90, EPCs or 30 MUL phosphate-buffered saline alone was administered into the trachea, and on day 120, inflammatory cells, antioxidant activity, apoptosis, matrix metalloproteinase (MMP)-2, and MMP 9 were measured. RESULTS: After EPC treatment, the lung function of the mice had improved compared with the untreated mice. Mean linear intercept and destructive index were reduced in the EPCs-treated group compared with the untreated group. In addition, the EPCs-treated mice exhibited less antioxidant activity in bronchoalveolar lavage fluid compared with the untreated mice. Moreover, decreased activities of MMP-2, MMP-9, and TUNEL-positive cells in lung tissues were detected in EPCs-treated mice. CONCLUSION: Intratracheal transplantation of EPCs attenuated the development of pulmonary emphysema and lung function disorder probably by alleviating inflammatory infiltration, decelerating apoptosis, inhibiting proteolytic enzyme activity, and improving antioxidant activity. PMID- 28360521 TI - Rapamycin modulated brain-derived neurotrophic factor and B-cell lymphoma 2 to mitigate autism spectrum disorder in rats. AB - The number of children suffered from autism spectrum disorder (ASD) is increasing dramatically. However, the etiology of ASD is not well known. This study employed mammalian target of rapamycin inhibitor rapamycin to explore its effect on ASD and provided new therapeutic strategies for ASD. ASD rat model was constructed and valproic acid (VPA) was injected intraperitoneally into rats on pregnancy day 12.5. Offspring from VPA group were divided into ASD group and ASD + rapamycin (ASD + RAPA) group. Compared with normal group, the frequency and duration of social behavior and straight times of ASD group were shortened, but the grooming times were extended. Meanwhile, in ASD group, the average escape latency and the frequency of crossing plates were decreased, the apoptotic index (AI) detected by TUNEL assay was increased, and the expression of brain-derived neurotrophic factor (BDNF) and B-cell lymphoma 2 (Bcl-2) analyzed was decreased with great difference compared with normal group (P<0.01). However, rapamycin treatment in ASD rats mitigated the ASD-like social behavior, such as the frequencies of straight and grooming. Furthermore, rapamycin shortened the average escape latency, but increased the frequency of crossing plates of ASD rats. In hippocampus, rapamycin decreased the AI, but increased the levels of BDNF and Bcl 2 (P<0.01) of ASD rats. These findings revealed that rapamycin significantly mitigated the social behavior by enhancing the expression of BDNF and Bcl-2 to suppress the hippocampus apoptosis in VPA-induced ASD rats. PMID- 28360522 TI - Long-term efficacy and safety of lamotrigine for all types of bipolar disorder. AB - BACKGROUND: We investigated whether the long-term efficacy and safety of lamotrigine (LTG) for bipolar disorder (BP) differs between disease types (BP-I, BP-II, or BP not otherwise specified [BP-NOS]), and the efficacy of the concomitant use of antidepressants (ADs). METHODS: For >1 year, we observed 445 outpatients with BP (diagnosed by DSM-IV criteria) who initiated LTG treatment between July 1 and October 31, 2011, using the Himorogi Self-rating Depression (HSDS) and Anxiety Scales and the Clinical Global Impression-Improvement scale and also recorded adverse events. RESULTS: Treatment efficacy was observed at week 4, with the improved HSDS scores sustained until week 52 for all types of BP; 50% of the patients with any type of BP could be treated with LTG for 1 year, whereas ~40% could be treated for >1.5 years. However, 25% of the patients were withdrawn within the first 4 weeks. The overall incidence of adverse events was 22.9% (104/455): 34.1% (14/41) for BP-I, 22.7% (15/66) for BP-II, and 22.2% (75/338) for BP-NOS. The most common adverse event was skin rash: 22.0% for BP-I, 16.7% for BP-II, and 12.1% for BP-NOS. LIMITATIONS: There was no control group. Data were collected retrospectively. CONCLUSION: With careful and adequate titration, long-term treatment with LTG is possible for any type of BP, with BP NOS patients, the largest population in clinical practice, responding particularly well. Symptoms can improve with or without ADs. Large-scale prospective studies of the efficacy of ADs in bipolar treatment are warranted. PMID- 28360520 TI - Human cytotoxic T-lymphocyte membrane-camouflaged nanoparticles combined with low dose irradiation: a new approach to enhance drug targeting in gastric cancer. AB - Cell membrane-derived nanoparticles are becoming more attractive because of their ability to mimic many features of their source cells. This study reports on a biomimetic delivery platform based on human cytotoxic T-lymphocyte membranes. In this system, the surface of poly-lactic-co-glycolic acid nanoparticles was camouflaged using T-lymphocyte membranes, and local low-dose irradiation (LDI) was used as a chemoattractant for nanoparticle targeting. The T-lymphocyte membrane coating was verified using dynamic light scattering, transmission electron microscopy, and confocal laser scanning microscopy. This new platform reduced nanoparticle phagocytosis by macrophages to 23.99% (P=0.002). Systemic administration of paclitaxel-loaded T-lymphocyte membrane-coated nanoparticles inhibited the growth of human gastric cancer by 56.68% in Balb/c nude mice. Application of LDI at the tumor site significantly increased the tumor growth inhibition rate to 88.50%, and two mice achieved complete remission. Furthermore, LDI could upregulate the expression of adhesion molecules in tumor vessels, which is important in the process of leukocyte adhesion and might contribute to the localization of T-lymphocyte membrane-encapsulated nanoparticles in tumors. Therefore, this new drug-delivery platform retained both the long circulation time and tumor site accumulation ability of human cytotoxic T lymphocytes, while local LDI could significantly enhance tumor localization. PMID- 28360523 TI - Type D personality as a predictor of self-efficacy and social support in patients with type 2 diabetes mellitus. AB - OBJECTIVE: The aim of this study was to estimate the prevalence of Type D personality and assess the relationship between this personality type and self efficacy/social support in Chinese patients with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: From January 1, 2014, to July 31, 2014, 532 consecutive patients with T2DM were recruited from two hospitals in Guangzhou, China. The participants completed questionnaires containing questions about sociodemographic characteristics, Type D personality, self-efficacy, and social support scales, and their medical records were reviewed for additional data. RESULTS: Of the 532 patients, 18.2% had Type D personality. Patients with this personality type reported significantly lower levels of self-efficacy (P<0.001), total social support (P<0.001), subjective support (P<0.001), and support utilization (P=0.003), but similar level of objective support (P=0.314), compared to those of patients without Type D personality. Negative affectivity and social inhibition, two intrinsic traits of Type D personality, negatively correlated with self efficacy and social support scores. Type D personality was significantly associated with less self-efficacy and social support (P<0.001), controlling for other sociodemographic factors. Glycosylated hemoglobin (HbA1c) levels were significantly higher in T2DM patients with Type D personality than in patients with non-Type D personality. CONCLUSION: This study provides new evidence linking Type D personality with self-efficacy, social support, and poor glycemic control, highlighting the special need for care among T2DM patients with Type D personality. PMID- 28360525 TI - The importance of a multidisciplinary approach to hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. The rising incidence, genetic heterogeneity, multiple etiologies, and concurrent chronic liver diseases make diagnosis, staging, and selection of treatment options challenging in patients with HCC. The best approach to optimize the management of HCC is one that utilizes a core multidisciplinary liver tumor board, consisting of hepatologists, pathologists, interventional radiologists, oncologists, hepatobiliary and transplant surgeons, nurses, and general practitioners. In most cases, HCC is diagnosed by abdominal imaging studies, preferably with a triphasic computed tomography scan of the abdomen or magnetic resonance imaging of the abdomen. Histopathological diagnosis using a guided liver biopsy may be needed in noncirrhotic patients or when radiological diagnostic criteria are not fulfilled in the setting of cirrhosis. The Barcelona Clinic Liver Cancer staging system facilitates a standardized therapeutic strategy based on the tumor burden, extent of metastasis, severity of hepatic decompensation, comorbid medical illnesses, functional status of patient, HCC-related symptoms, and preference of the patient. Treatment options include curative surgery (hepatic resection and liver transplantation) and palliative measures (radiofrequency ablation, transarterial chemoembolization, and chemotherapy with sorafenib). The role of the multidisciplinary team is crucial in promptly reconfirming the diagnosis, staging the HCC, and formulating an individualized treatment plan. In potential liver transplant candidates, timely liver transplant evaluation and coordinating bridging/downsizing treatment modalities, such as radiofrequency ablation and transarterial chemoembolization, can be time-consuming. In summary, a multidisciplinary team approach provides a timely, individualized treatment plan, which can vary from curative surgery in patients with early-stage HCC to palliative/hospice care in patients with metastatic HCC. In most tertiary care centers in the US, a multidisciplinary liver tumor board has become the standard of care and a key component of best practice protocol for patients with HCC. PMID- 28360524 TI - Antistress effects of Kampo medicine "Yokukansan" via regulation of orexin secretion. AB - OBJECTIVE: Various stressors induce stress responses through the hypothalamic pituitary-adrenal and the sympathetic-adrenal-medullary axes, which are regulated, in part, by orexin. For example, secretion of orexin in the hypothalamus is increased in rats exposed to the stress of social isolation for 1 week. In this study, the antistress effects of Kampo medicine Yokukansan (YKS) via the regulation of orexin secretion were investigated using a rat model. METHODS AND RESULTS: The administration of 300 mg/kg per day of YKS to rats for 1 week significantly decreased the plasma orexin levels compared with non-treated rats, whereas the administration of 1,000 mg/kg of YKS had no effect on orexin levels. Therefore, 300 mg/kg of YKS was an effective dose for controlling orexin secretion. Subsequently, rats were divided into group-housed control (Con), individually housed stress (Stress), and individually housed YKS (300 mg/kg) treated stress (Stress + YKS) groups. After 1 week, a resident-intruder aggression test was performed, and the plasma levels of orexin and corticosterone were measured. In the Stress group, aggressive behavior and the levels of corticosterone and orexin significantly increased compared with the Con group; however, these effects were inhibited in the Stress + YKS group. Further, an orexin receptor antagonist (TCS 1102; 10 mg/kg) was intraperitoneally administered to rats exposed to isolation stress to determine whether orexin was involved in stress responses. Under these conditions, aggressive behavior and the level of corticosterone significantly decreased compared with the Stress group. CONCLUSION: These results suggest that orexin is involved in the control of stress response and that YKS exerts an antistress effect via the regulation of orexin secretion. PMID- 28360526 TI - Human omental adipose-derived mesenchymal stem cell-conditioned medium alters the proteomic profile of epithelial ovarian cancer cell lines in vitro. AB - Mesenchymal stem cells (MSCs) have been reported to participate in the formation of supportive tumor stroma. The abilities of proliferation and invasion of human epithelial ovarian cancer (EOC) cells were significantly enhanced when indirectly cocultured with human omental adipose-derived MSCs (O-ADSCs) in vitro. However, the underlying mechanisms remain poorly understood. In this study, EOC cells were cultured with conditioned medium (CM) from O-ADSCs (O-ADSC), and the effect of O ADSC CM on the proteomic profile of EOC cells was assessed by two-dimensional gel electrophoresis (2-DE), followed by liquid chromatography and tandem mass spectrometry. The 2-DE assays revealed a global increase in protein expression in the EOC cells treated with CM. Nine proteins were identified from 11 selected protein spots with differential expression after treatment with CM from O-ADSCs. All the nine proteins have been linked to carcinoma and apoptosis, and the migration ability of tumor cells can be regulated by these proteins. Moreover, the upregulation of prohibitin and serine/arginine-rich splicing factor 1 in EOC cells treated with CM was further confirmed by quantitative real-time polymerase chain reaction. These results suggest that O-ADSCs affect the proteomic profile of EOC cells via paracrine mechanism in favor of EOC progression. PMID- 28360528 TI - The association of weight loss with patient experience and outcomes in a population of patients with type 2 diabetes mellitus prescribed canagliflozin. AB - OBJECTIVE: Type 2 diabetes mellitus (T2DM) is a chronic condition complicated by being overweight or obese. This study used a patient survey to assess health, satisfaction, and diabetes self-management in relation to weight management. METHODS: A survey including the Current Health Satisfaction Questionnaire, Diabetes Distress Scale, and Diabetes Treatment Satisfaction Questionnaire was administered using an online platform to a sample of 205 patients with T2DM prescribed canagliflozin. Patients were placed into 5 groups based on their self reported weight change since initiation of canagliflozin: Lost >10 lbs, Lost 5-10 lbs, Lost <5 lbs, No Change, and Gained Weight. One-way ANOVAs, Kruskall-Wallis tests, and multivariable regression were used to explore differences between weight loss groups. RESULTS: The majority of patients (66.8%) reported losing weight. Compared to other groups, patients who lost >10 lbs were more likely to be engaged in a weight loss program for at least 6 months. Patients in the Lost >10 lbs and Lost 5-10 lbs groups reported the greatest satisfaction with canagliflozin (p<0.05 for both). Multivariable analyses controlling for patient demographic and treatment characteristics revealed that losing >10 lbs was associated with reduced diabetes distress, improved A1c and blood glucose levels, and decreased perceived frequency of hyperglycemia (p<0.05). CONCLUSION: Increased positive patient outcomes, engagement in diabetes self-management, and medication satisfaction were observed among patients who reported weight loss. These findings suggest that a T2DM regimen that includes canagliflozin as part of a weight loss regimen can help improve patient outcomes and experiences with T2DM. PMID- 28360527 TI - Role of cytokines and chemokines in alcohol-induced tumor promotion. AB - Excessive chronic alcohol consumption has become a worldwide health problem. The oncogenic effect of chronic alcohol consumption is one of the leading concerns. The mechanisms of alcohol-induced tumorigenesis and tumor progression are largely unknown, although many factors have been implicated in the process. This review discusses the recent progress in this research area with concentration on alcohol induced dysregulation of cytokines and chemokines. Based on the available evidence, we propose that alcohol promotes tumor progression by the dysregulation of the cytokine/chemokine system. In addition, we discuss specific transcription factors and signaling pathways that are involved in the action of these cytokines/chemokines and the oncogenic effect of alcohol. This review provides novel insight into the mechanisms of alcohol-induced tumor promotion. PMID- 28360530 TI - Treatment application of rivaroxaban in Chinese patients with livedoid vasculopathy. AB - Livedoid vasculopathy (LV) is a chronic prothrombotic disease of cutaneous micro circulation resulting in cutaneous ischemia and infarction. As a rare disease, LV has an estimated incidence of ten cases per million. Not only correct diagnosis but also effective treatments are very difficult for patients with LV. Due to the lack of large-scale studies in this rare disease, LV poses a great challenge to the doctors, and existing treatment has always been an individual attempt with off-label application. The main goals in the treatment of patients with LV are to avoid the repeated occurrence of active cutaneous lesions and prevent painful ulceration and irreversible scarring. The current report describes the cases of three Chinese patients with LV receiving rivaroxaban treatment, an oral direct inhibitor of factor Xa inhibitor, and observes the treatment effect of rivaroxaban during the follow-up. As an injection-free alternative to low molecular-weight heparin (LMWP) and monitoring-free alternative to warfarin, rivaroxaban improves the quality of life and enhances the compliance of patients. All patients consider rivaroxaban as more tolerable than previous drugs and, therefore, continue the application of rivaroxaban, effectively improving the treatment effect of drugs and successfully avoiding the repeated occurrence of active cutaneous lesions. Treatment application of rivaroxaban in Chinese patients with LV successfully avoids the recurrence of active cutaneous lesions and prevents the progressive ulceration and scarring. PMID- 28360529 TI - Association of self-reported symptoms with serum levels of vitamin D and multivariate cytokine profile in healthy women. AB - BACKGROUND: Although a large number of studies have investigated possible relationships among serum levels of vitamin D or cytokines with disease progress and prognosis, similar studies on self-reported symptoms are still controversial. The overall objective of this study was to look into the association between serum levels of vitamin D or cytokines with self-reported symptoms related to musculoskeletal pain, sleep disorders, and premenstrual syndrome (PMS) in healthy adult women. SUBJECTS AND METHODS: Venous blood samples were collected from 117 healthy adult women, and serum levels of vitamin D, pro-inflammatory cytokines (IL-1beta, IL-6, IL-8, IL-17, IFN-gamma, and TNF-alpha) and anti-inflammatory cytokines (IL-4, IL-10, and IL-13) were measured. Groups were tested for differences in single parameters, pro-:anti-inflammatory cytokine ratios, and differences in multivariate patterns. RESULTS: There were no significant associations between serum levels of vitamin D and any of the self-reported symptoms studied. However, serum levels of certain pro-inflammatory cytokines were significantly higher in subjects with musculoskeletal pain (IL-8, P=0.008), sleep disorders (IFN-gamma, P=0.02), and PMS (IL-8 and TNF-alpha, P=0.009 and 0.002, respectively) compared to subjects who reported no symptoms. The pro-:anti inflammatory cytokine ratios showed pro-inflammatory cytokine dominance in subjects with self-reported symptoms, particularly in the groups with deficient levels of vitamin D. However, the multivariate cytokine-pattern analysis was significantly different between PMS groups only. CONCLUSION: These data point to a possible role of pro-inflammatory cytokines as a contributing factor in self reported symptoms related to musculoskeletal pain, sleep disorders, and PMS. PMID- 28360531 TI - A review and survey of policies utilized for interventional pain procedures: a need for consensus. AB - BACKGROUND: Other than the newly published anticoagulation guidelines, there are currently few recommendations to assist pain medicine physicians in determining the safety parameters to follow when performing interventional pain procedures. Little information exists regarding policies for oral intake, cumulative steroid dose limits, driving restrictions with and without sedation, and routine medication use for interventional procedures. METHODS: A 16-question survey was developed on common policies currently in use for interventional pain procedures. The questionnaire was distributed through the American Society of Regional Anesthesia and Pain Medicine and American Academy of Pain Medicine. We sought to statistically analyze the range of policies being used by pain medicine physicians and to determine if there are any commonly accepted standards. RESULTS: A total of 337 physicians out of 4037 members responded to our survey with a response rate of 8.4%. A total of 82% of these respondents used a sedative agent while performing an interventional pain procedure. The majority of respondents required drivers after procedures, except after trigger points. A total of 47% indicated that they have an nil per os (NPO) policy for procedures without sedation. A total of 98% reported that they had an anticoagulation policy before an interventional procedure. A total of 17% indicated that the interval between steroid doses was <2 weeks, while 53% indicated that they waited 2-4 weeks between steroid doses. CONCLUSION: Our study has clearly demonstrated a wide variation in the current practice among physicians regarding sedation, NPO status, steroid administration, and the need for designated drivers. There was much higher endorsement of policies regarding anticoagulation. There is an obvious need for evidence-based guidelines for these aspects of interventional pain care to improve patient safety and minimize the risk of adverse events. PMID- 28360532 TI - Bottlenecks in the development of topical analgesics: molecule, formulation, dose finding, and phase III design. AB - Topical analgesics can be defined as topical formulations containing analgesics or co-analgesics. Since 2000, interest in such formulations has been on the rise. There are, however, four critical issues in the research and development phases of topical analgesics: 1) The selection of the active pharmaceutical ingredient. Analgesics and co-analgesics differ greatly in their mechanism of action, and it is required to find the most optimal fit between such mechanisms of action and the pathogenesis of the targeted (neuropathic) pain. 2) Issues concerning the optimized formulation. For relevant clinical efficacy, specific characteristics for the selected vehicle (eg, cream base or gel base) are required, depending on the physicochemical characteristics of the active pharmaceutical ingredient(s) to be delivered. 3) Well-designed phase II dose-finding studies are required, and, unfortunately, such trials are missing. In fact, we will demonstrate that underdosing is one of the major hurdles to detect meaningful and statistically relevant clinical effects of topical analgesics. 4) Selection of clinical end points and innovatively designed phase III trials. End point selection can make or break a trial. For instance, to include numbness together with tingling as a composite end point for neuropathic pain seems stretching the therapeutic impact of an analgesic too far. Given the fast onset of action of topical analgesics (usually within 30 minutes), enrichment designs might enhance the chances for success, as the placebo response might decrease. Topical analgesics may become promising inroads for the treatment of neuropathic pain, once sufficient attention is given to these four key aspects. PMID- 28360533 TI - Effects of decompression on behavioral, electrophysiologic, and histomorphologic recovery in a chronic sciatic nerve compression model of streptozotocin-induced diabetic rats. AB - PURPOSE: To determine susceptibility to decompression surgery in diabetic and nondiabetic peripheral neuropathy using a chronic compression neuropathy model. MATERIALS AND METHODS: Twenty-four streptozotocin-induced diabetic rats were randomly divided into three groups: group I, chronic compression of the left sciatic nerve for 4 weeks with decompression; group II, similar without decompression; and group III, sham exposing the sciatic nerve only. The other 24 nondiabetic rats were assigned to groups IV-VI, which received compression decompression, compression, and the sham operation, respectively. Mixed-nerve elicited somatosensory evoked potentials (M-SSEPs) and compound muscle action potentials (CMAPs) were measured to verify the compression neuropathy in the posttreatment follow-up. Behavioral observations in thermal hyperalgesia tests were quantified before electrophysiologic examinations. Treated and contralateral nerves were harvested for histomorphologic analysis. RESULTS: Chronic compression of sciatic nerve induced significant reduction of amplitude and increment of latency of M-SSEP and CMAP in both diabetic and nondiabetic rats. Diabetic group changes were more susceptible. Decompression surgery significantly improved both sensory and motor conduction, thermal hyperalgesia, and the mean myelin diameter of the rat sciatic nerve in both diabetic and nondiabetic groups. Near full recovery of motor and sensory function occurred in the nondiabetic rats, but not in the diabetic rats 8 weeks postdecompression. CONCLUSION: Behavioral, electrophysiologic, and histomorphologic findings indicate that decompression surgery is effective in both diabetic and nondiabetic peripheral neuropathy. PMID- 28360535 TI - Assessment of risk factors for postdural puncture headache in women undergoing cesarean delivery in Jordan: a retrospective analytical study. AB - PURPOSE: Postdural puncture headache (PDPH) is one of the most recognized complications after spinal anesthesia in women undergoing cesarean delivery. This study aimed to investigate the incidence of PDPH and its associated risk factors in women undergoing cesarean delivery in Jordan. PATIENTS AND METHODS: This study included all women who underwent cesarean delivery at King Abdullah University Hospital in Jordan during 2015. Patient characteristics including age, weight, occurrence of PDPH, needle type, repeated puncture attempt, history of spinal anesthesia and PDPH, presence of tension headache, preeclampsia, migraine, sinusitis, and caffeine withdrawal were collated from hospital records. Statistical analyses were performed to assess the association of these characteristics with PDPH. RESULTS: The study cohort consisted of 680 women. Among these, only 43 (6.3%) had developed PDPH. The only factors that showed significant association (P<0.01) with PDPH were repeated puncture attempt and presence of tension headache. The repeated puncture attempt increased the risk of PDPH 2.55-fold, while presence of tension headache increased the risk 4.60-fold. Furthermore, the use of the traumatic 27 G Spinostar needle increased the risk of repeated puncture attempt 28.45-fold (P<0.01) compared with the use of the pencil point 25 G Whitacre needle. CONCLUSION: The major risk factors associated with the incidence of PDPH in women undergoing cesarean delivery in Jordan are repeated puncture attempt and presence of tension headache. The use of the pencil point 25 G Whitacre needle is recommended since this was associated with a substantially reduced risk of repeated spinal puncture than the traumatic 27 G Spinostar needle. PMID- 28360534 TI - Involvement of endoplasmic reticulum stress in formalin-induced pain is attenuated by 4-phenylbutyric acid. AB - BACKGROUND: Endoplasmic reticulum (ER) stress is involved in many neurological and inflammatory responses. Peripheral inflammatory responses can induce central sensitization and trigger inflammatory pain. However, there is little research on the relationship between ER stress and inflammatory pain. In this study, we examined whether the ER stress response is involved in peripheral inflammatory pain using a formalin-induced rat pain model. METHODS: Rats were divided into the following five groups: control, formalin, formalin + vehicle, formalin + 4 phenylbutyric acid (4-PBA) (40 mg/kg) and formalin + 4-PBA (100 mg/kg). Formalin induced pain was assessed behaviorally by recording licking activity. The expression levels of immunoglobulin-binding protein (BIP), activating transcription factor-6 (ATF6), phosphorylated inositol-requiring enzyme-1 (p IRE1), phosphorylated protein kinase RNA-like ER kinase (p-PERK) and c-fos were quantitatively assessed by Western blot, and the distribution of BIP, ATF6 and c fos in the lumbar enlargement of spinal cord were identified by immunohistochemistry in spinal dorsal horn slices. In addition, the concentrations of nitric oxide (NO) and prostaglandin E2 (PGE2) in the spinal cord were tested by biochemical measurement and enzyme-linked immunosorbent assay (ELISA), respectively. RESULTS: Intraperitoneal injection of 4-PBA at the dose of 100 mg/kg before formalin injection significantly decreased nociceptive behavior in the second phase compared with control, formalin, formalin + vehicle and formalin + 4-PBA (40 mg/kg) (P<0.05). Western blot showed that formalin injection significantly upregulated the expression of BIP, ATF6, p-PERK and c-fos in the spinal cord. This upregulation was reduced by peritoneal injection of 4-PBA (P<0.05), while expression of p-IRE1 was not altered by formalin treatment. Immunohistochemistry revealed markedly increased staining density for BIP, ATF6 and c-fos in the superficial spinal dorsal horn after formalin injection. This was significantly decreased by administration of 4-PBA (P<0.05). Compared with the formalin + vehicle group, 4-PBA inhibited the release of NO and PGE2 in the spinal cord (P<0.05). CONCLUSION: These results suggest that ER stress is involved in formalin-induced inflammatory pain and that inhibition of ER stress may attenuate central sensitization induced by peripheral inflammatory stimulation. PMID- 28360536 TI - Intensity-modulated radiation therapy for early-stage breast cancer: is it ready for prime time? AB - Whole breast external beam radiotherapy (WBEBRT) is commonly used as an essential arm in the treatment management of women with early-stage breast cancer. Dosimetry planning for conventional WBEBRT typically involves a pair of tangential fields. Advancement in radiation technology and techniques has the potential to improve treatment outcomes with clinically meaningful long-term benefits. However, this advancement must be balanced with safety and improved efficacy. Intensity-modulated radiation therapy (IMRT) is an advanced technique that shows promise in improving the planning process and radiation delivery. Early data on utilizing IMRT for WBEBRT demonstrate more homogenous dose distribution with reduction in organs at risk doses. This translates to toxicities reduction. The two common descriptors for IMRT are forward-planning "fields in field" and inverse planning. Unlike IMRT for other organs, the aim of IMRT for breast planning is to achieve dose homogeneity and not organ conformality. The aim of this paper was to evaluate whether IMRT is ready for prime time based on these three points: 1) workload impact, 2) the clinical impact on the patient's quality of life, and 3) the appropriateness and applicability to clinical practice. PMID- 28360537 TI - Successful treatment of Chrysosporium keratitis with voriconazole. AB - OBJECTIVE: To report a patient with severe Chrysosporium keratitis successfully treated by voriconazole. METHOD: Case report. RESULTS: A 37-year-old healthy male presented with irritation, pain and reduced vision in his left eye after mud contamination. Examination demonstrated corneal stromal infiltration, endothelial plaque and hypopyon. Corneal scrapings demonstrated numerous septate hyphae, and specimen cultures were positive for Chrysosporium sp. The lesion did not respond to aggressive topical 5% natamycin, 0.15% topical amphotericin B and oral itraconazole. The patient was then treated by topical 1% voriconazole every hour. Intracameral and intrastromal voriconazole injections (50 MUg/0.1 mL) were also undertaken. The keratitis was significantly improved after voriconazole. CONCLUSION: To the best of the authors' knowledge, this is the first report on the use of voriconazole for Chrysosporium keratitis. Voriconazole may be an effective alternative to conventional antifungal agents in some cases of fungal keratitis. It should be considered before shifting to therapeutic keratoplasty. PMID- 28360538 TI - Antidiabetic and gastric emptying inhibitory effect of herbal Melia azedarach leaf extract in rodent models of diabetes type 2 mellitus. AB - Diabetes type 2 is associated with impaired insulin production and increased insulin resistance. Treatment with antidiabetic drugs and insulin strives for normalizing glucose homeostasis. In Ethiopian traditional medicine, plant extracts of Melia azedarach are used to control diabetes mellitus and various gastrointestinal disorders. The objective of this study was to clarify the antidiabetic effects of M. azedarach leaf extracts in diabetic type 2 experimental animals. In this study, mice were injected with Melia extract intraperitoneally. Plasma glucose was studied by using tail vein sampling in acute experiments over 4 h and chronic experiments over 21 days with concurrent insulin and body weight assessments. Glucose tolerance was studied by using intraperitoneal glucose (2 mg/g) tolerance test over 120 min. Gastric emptying of a metabolically inert meal was studied by the gastric retention of a radioactive marker over 20 min. Melia extracts displayed acute, dose-dependent antidiabetic effects in ob/ob mice similar to glibenclamide (p<0.05-0.001). Long-term administration of Melia extract reduced plasma glucose (p<0.001) and insulin (p<0.01-0.001) levels over 21 days, concurrent with body weight loss. Glucose tolerance test showed reduced basal glucose levels (p<0.05-0.01), but no difference was found in glucose disposal after long-term treatment with Melia extract. In addition, the Melia extract at 400 mg/kg slowed gastric emptying rate of normal Sprague-Dawley (p<0.001) and diabetic Goto-Kakizaki rats (p<0.001) compared with controls. It is concluded that the M. azedarach leaf extract elicits diabetic activity through a multitargeted action. Primarily an increased insulin-sensitizing effect is at hand, resulting in blood glucose reduction and improved peripheral glucose disposal, but also through reduced gastric emptying and decreased insulin demand. PMID- 28360539 TI - Alternative remedies for insomnia: a proposed method for personalized therapeutic trials. AB - Insomnia is a common symptom, with chronic insomnia being diagnosed in 5-10% of adults. Although many insomnia patients use prescription therapy for insomnia, the health benefits remain uncertain and adverse risks remain a concern. While similar effectiveness and risk concerns exist for herbal remedies, many individuals turn to such alternatives to prescriptions for insomnia. Like prescription hypnotics, herbal remedies that have undergone clinical testing often show subjective sleep improvements that exceed objective measures, which may relate to interindividual heterogeneity and/or placebo effects. Response heterogeneity can undermine traditional randomized trial approaches, which in some fields has prompted a shift toward stratified trials based on genotype or phenotype, or the so-called n-of-1 method of testing placebo versus active drug in within-person alternating blocks. We reviewed six independent compendiums of herbal agents to assemble a group of over 70 reported to benefit sleep. To bridge the gap between the unfeasible expectation of formal evidence in this space and the reality of common self-medication by those with insomnia, we propose a method for guided self-testing that overcomes certain operational barriers related to inter- and intraindividual sources of phenotypic variability. Patient-chosen outcomes drive a general statistical model that allows personalized self assessment that can augment the open-label nature of routine practice. The potential advantages of this method include flexibility to implement for other (nonherbal) insomnia interventions. PMID- 28360541 TI - Students' perceptions of lecturing approaches: traditional versus interactive teaching. AB - BACKGROUND: There is an increasing trend toward transcending from traditional teaching to student-centered methodologies that actively engage students. We aimed to analyze students' perceptions of effective interactive teaching using PollEverywhere Audience Response System (ARS) as a worthwhile teaching methodology. It can be of great help in maintaining students' attention and in facilitating the lecturer to pick up students' misunderstandings and correct them. MATERIALS AND METHODS: This system was introduced to the undergraduate dental curriculum to increase student's motivation and attention, giving immediate feedback on student understanding during an anatomy module. Computer science (CS) students who were more familiar with the use of this technology were also involved in the study for comparison and validation of the findings. The lecturer strategically inserted questions using PollEverywhere ARS. Students' perception of the effective interactive teaching using this technology was evaluated statistically using a questionnaire and focus groups. RESULTS: It promoted interactivity, focused attention, and provided feedback on comprehension. A total of 95% reported that it increased their participation and found that it clarified their thinking and helped to focus on key points. Another 81.7% mentioned that it increased their motivation to learn. Students regarded it as a useful method for giving real-time feedback, which stimulated their performance and participation. Data from CS students echoed the findings from the dental students. Reports from focus groups demonstrated that this strategy was helpful in focusing students' attention and in clarifying information. DISCUSSION: PollEverywhere encouraged all students to participate during the learning process. This has proven to be an effective tool for improving students' understanding and critical thinking. CONCLUSION: Students regarded PollEverywhere as an effective teaching innovation that encouraged deeper ongoing retention of information. It was found to be an effective teaching aid in monitoring students' progress and identifying deficiencies. This is of benefit in a module where interactivity is considered important. PMID- 28360540 TI - Medical students' perception of the learning environment at King Saud University Medical College, Saudi Arabia, using DREEM Inventory. AB - BACKGROUND: The students' perception of the learning environment is an important aspect for evaluation and improvement of the educational program. The College of Medicine at King Saud University (KSU) reformed its curriculum in 2009 from a traditional to a system-oriented hybrid curriculum. OBJECTIVE: The objective of the present study was to determine the perception of the second batch (reformed curriculum) of medical graduates about the educational environment at the College of Medicine, KSU, using the Dundee Ready Education Environment Measure (DREEM) scale. METHODS: The fifth year medical students were asked to evaluate the educational program after graduation in May 2014. The questionnaire was distributed to the graduate students electronically. The DREEM questionnaire consisted of 50 items based on Likert's scale; and five domains, namely, students' perceptions of learning, perceptions of teachers, academic self perceptions, perceptions of atmosphere, and social self-perceptions. Data were analyzed using SPSS. RESULTS: A total of 62 students participated in the study. The score for students' perception of learning among medical students ranged from 2.93 to 3.64 (overall mean score: 40.17). The score for students' perception of teachers ranged from 2.85 to 4.01 (overall mean score: 33.35). The score for students' academic self-perceptions ranged from 3.15 to 4.06 (overall mean score: 28.4). The score for students' perception of atmosphere ranged from 2.27 to 3.91 (overall mean score: 41.32). The score for students' social self-perceptions ranged from 2.85 to 4.33 (overall mean score: 24.33). The general perceptions of the students in all five sub-scales were positive. CONCLUSION: The overall student's perception about the educational environment was satisfactory. This study was important to evaluate the students' perception of the learning environment among medical graduates of the reformed curriculum and provided guidance on areas of improvement in the curriculum. PMID- 28360542 TI - Self-regulated learning: why is it important compared to traditional learning in medical education? AB - Self-regulated learning has played an increasingly significant role in medical education over the last one to two decades. Medical educators have endeavored to ensure that the students are equipped to face the challenges of continued growth of medical knowledge. Here we enquire and reflect on various aspects of self regulated learning including its strengths and weaknesses. We investigate how it could be incorporated with traditional teaching to bring the best out of the students and what students think about it. PMID- 28360543 TI - Examination of Attention Level in Nurses Working Night Shifts in terms of the Relationship between Electrodermal Activity and Sex Hormones. AB - INTRODUCTION: Electrodermal activity (EDA) is an electrical activity of eccrine sweat gland stimulated by the sympathetic nervous system. Skin conductance level (SCL) is measured with EDA. SCL and sweat gland activity increase in emotional situations, such as high activation, attention or stress. In this study, we investigated whether working in shifts affects attention level of nurses with EDA and explored the relationship between EDA and sex hormones. METHOD: The study was carried out on nurses working night shifts (16.00-08.00 h) (n=22) and nurses working without a shift (08.00-16.00 h) (n=20). Firstly, The Epworth Sleepiness Scale which evaluates a person's daytime sleepiness was applied to the subjects. For EDA measurement, Ag/AgCl electrodes were put on two fingers of their dominant hand. SCL was measured via MP30 system and GSR connection. The blood samples were analyzed for cortisol and ACTH hormone levels to investigate the changes in sleep and circadian rhythm. RESULT: It was found that there was no statistically significant difference in skin conductance levels between the groups. Moreover, in the comparison of hormone values between the groups, the cortisol levels in night shift nurses were higher than in those working without a shift. CONCLUSION: Night shift had no significant effect on the attention levels in the nurses. This situation is thought to be related to the fact that the nurses responsible for the night service raise their attention level to the highest point. The reason for higher level of cortisol in nurses working shifts may reflect that cortisol has no effect on the breadth of attention but reflects a high level of stress. PMID- 28360544 TI - Body Image and Self-Esteem in Patients with Rheumatoid Arthritis. AB - INTRODUCTION: The study was conducted in order to investigate the effect of disease-related variables such as socio-demographic characteristics, disease complaints and use of necrosis factor (anti-TNF) on the body image and self esteem in patients with rheumatoid arthritis. METHOD: The data was collected by an Introductory Information Form, Body Image Scale (PfP) BIS and the Coopersmith Self-Esteem Inventory (SEI) in 120 patients with rheumatoid arthritis and in 120 healthy controls. One-way analysis of variance, Tukey HDS analysis, t-test, Kruskal-Wallis test, the Mann-Whitney U test, and Pearson's and Spearman's correlation coefficients were used to compare the data. RESULT: 60% of the control group were in the 20-44 year-age group, 75% were women and 30.8% had a bachelor's degree or above, while 60% of patient group were in the 20-44 year-age group, 71.7% were women and 36.7% had a bachelor's degree or higher education level. We observed that the body satisfaction and self-esteem levels were higher in the 20-44 age group, in those with a bachelor's degree or higher education and in the patients who had no additional disease and who did not use anti-TNF. The body satisfaction and self-esteem levels were lower in those who had been receiving treatment for longer than 5 years, who had changes in hands and body, who had gait disturbance and who had changes in family and working life. CONCLUSION: The assessment of the psychosocial needs with a holistic approach and training programs for body image and self-esteem would be advisable for patients with rheumatoid arthritis who are aged 45-59 years, who have low self-esteem, who have additional diseases, who use anti-TNF, who have changes in hands and body and who have primary-school education. PMID- 28360546 TI - Sociodemographic and Clinical Characteristics of Psychiatric Inpatients Hospitalized Involuntarily and Voluntarily in a Mental Health Hospital. AB - INTRODUCTION: In this study, we aimed to investigate and compare the sociodemographic and clinical characteristics of psychiatric inpatients hospitalized involuntarily and voluntarily. To our knowledge, there is no study analyzing involuntary psychiatric hospitalization in our country. METHOD: In this retrospective study, we included a total of 504 patients who were involuntarily or voluntarily hospitalized in Bolu Izzet Baysal Mental Health Hospital between 1st of May and 31st October 2010. The data were obtained from the hospital records. RESULT: In the 6-month period, 13.1% of 504 inpatients were hospitalized involuntarily. The number of male patients who were involuntarily hospitalized was higher than the number of female patients. Most of the patients in the involuntary hospitalized group were graduates of primary school, were not married and were not working at the time of hospitalization. Schizophrenia was the most common diagnosis in the involuntarily hospitalized psychiatric patients and these patients needed longer stay in the hospital. The next hospitalization of the involuntarily hospitalized patients was mostly involuntary. CONCLUSION: Most of the involuntarily hospitalized psychiatric inpatients were male, were not working and had the diagnosis of schizophrenia. These general psychiatric risk factors were more important in involuntary hospitalization compared to voluntary hospitalization. We concluded that the high prevalence of involuntary hospitalizations deserved further studies. PMID- 28360545 TI - Psychiatric and Neurocognitive Evaluation Focused on Frontal Lobe Functions in Rolandic Epilepsy. AB - INTRODUCTION: In this study, we aimed to assess the behavioral problems, psychiatric disorders and neurocognitive functions focusing on frontal lobe functions in children with rolandic epilepsy (RE) and compare them with a control group. METHOD: 31 children with RE, aged between 8 and 13,5 years were compared with a control group matched for age, sex and socioeconomic status. Behavioral problems were assessed by the Child Behavior Checklist (CBCL) and psychiatric diagnoses were established by using the Kiddie Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version. The Wechsler Intelligence Scale for Children-Revised (WISC-R), Wisconsin Card Sorting Test (WCST) and the Stroop Color and Word Test (SCWT) were applied in both groups of children. RESULT: The RE group presented more psychiatric disorders than the control group. Verbal and total IQ scores in the RE group were lower than in the control group. Although the groups did not differ from each other in WCST scores, children with RE displayed lower performance in SCWT. The RE group had a higher externalizing score and higher total scores in CBCL. CONCLUSION: It was concluded that RE did not affect basic frontal lobe functions significantly, had negative effects on attention and IQ performance and increased behavioral problems and psychiatric disorders. PMID- 28360547 TI - Evaluation of the Relation between Deliberate Self-Harm Behavior and Childhood Trauma Experiences in Patients Admitted to a Secondary-Care Psychiatric Outpatient Clinic for Adolescents and Young Adults. AB - INTRODUCTION: The aim of this study was to determine the prevalence and the features of deliberate self-harm (DSH) behavior in patients admitted to the psychiatric outpatient clinic for adolescents and young adults and also to detect the association between the act of DSH and childhood traumas. METHOD: In this study, we included all patients who were admitted to the secondary-care psychiatric outpatient clinic for adolescents and young adults in Bakirkoy Research and Training Hospital Psychiatry, Neurology and Neurosurgery throughout a month. A sociodemographic data form, the Childhood Trauma Questionnaire (CTQ 28), Childhood Abuse and Neglect Question List and the Deliberate Self-Harm and Intent Screening Form were applied to three hundred participants. RESULT: The prevalence of DSH was 50.0% among the participants (56.8% for females and 28.8% for males). Childhood abuse was detected in 57.0% of all participants (60.4% of females and 46.6% of males). Among patients with act of DSH, the rate of childhood abuse was 71.3%, while it was 42.7% in the subjects without act of DSH. CONCLUSION: DSH is a common behavior among adolescent psychiatric patients. It is more common in females than in males. The prevalence of experience of childhood abuse and neglect is remarkably high and is associated with self-harm behavior. PMID- 28360548 TI - Mental Findings in Trauma Victims. AB - INTRODUCTION: In medico-legal evaluation of trauma patients, the bio psychological effects of the trauma and the severity of the injuries require to be evaluated. In this study, assuming the fact that psychiatric assessment is not taken into consideration in physical trauma cases, we planned to show the presence of psychological trauma in our medico-legally evaluated patients who presented with different types of traumas and to review the mental findings and diagnoses in trauma victims. METHOD: We retrospectively analyzed the hospital records of 1975 patients aged 18 years or older who presented to the Department of Forensic Medicine at Dokuz Eylul University School of Medicine for medico legal evaluation between 1999 and 2009. Psychiatric assessment was performed in 142 patients by the Department of Psychiatry. The data contained in medico-legal reports and patient records were then examined with respect to patients' age, gender, nature of traumatic events, psychiatric diagnoses, descriptive characteristics of the patients, severity of trauma and past history of mental disorder and trauma experience. Results of the medicolegal evaluations were also analyzed. RESULT: Of the 142 patients, 80 (56.3%) were female and their average age was 40.30+/-17.17 years. The most frequent traumatic events were traffic accidents (29.6%) and violence-related blunt force trauma (28.9%). When the distribution of the most common psychiatric diagnoses was examined, it was found that anxiety disorders were found in 69 cases (48.6%), adjustment disorders were found in 16 cases (11.3%) and mood disorders were found in 12 cases (8.5%). Among anxiety disorders, acute stress disorder (n=39) and post-traumatic stress disorder (PTSD) (n=27) were the most common ones. In 27 cases of the 142, it was determined that, psychiatric symptoms and findings did not meet the diagnostic criteria of any psychiatric disorder. Diagnosis of psychiatric disorder was not significantly related with traumatic experiences, comorbidity, marriage status, education level or lack of health insurance. CONCLUSION: We assume elucidating the presence of a psychological trauma is crucial not only for the health benefit but also for legal rights of the patient. The necessity of considering merely the international diagnostic criteria in determining the existence of psychiatric trauma and its severity level can bring forth some difficulties in medico-legal evaluation. PMID- 28360550 TI - The Effectiveness of an Interpersonal Cognitive Problem-Solving Strategy on Behavior and Emotional Problems in Children with Attention Deficit Hyperactivity. AB - INTRODUCTION: This study was designed to evaluate the effectiveness of the "I Can Problem Solve" (ICPS) program on behavioral and emotional problems in children with attention deficit hyperactivity disorder (ADHD). METHODS: The subjects were 33 children with ADHD aged between 6 to 11 years. The study used a pre- and post test quasi-experimental design with one group. The researchers taught 33 children with ADHD how to apply ICPS over a period of 14 weeks. The Child Behavior Checklist for Ages 6-18 (Teacher Report Form) and the Diagnostic and Statistical Manual of Mental Disorders, 4th edition Text Revision (DSM-IV-TR) Based Disruptive Behavior Disorders Screening and Rating Scale (parents' and teacher's forms) were used to evaluate the efficacy of the program. The scales were applied to parents and teachers of the children before and after the ICPS program. RESULT: The findings indicated that the measured pre-training scores for behavioral and emotional problems (attention difficulties, problems, anxious/depressed, withdrawn/depressed, oppositional defiant problems, rule breaking behaviors, and aggressive behaviors) were significantly decreased in all children post-training. In addition, children's total competence scores increased (working, behaving, learning and happy) after the ICPS program. CONCLUSION: According to the results, it is likely that, ICPS would be a useful program to decrease certain behavioral and emotional problems associated with ADHD and to increase the competence level in children with ADHD. An additional benefit of the program might be to empower children to deal with problems associated with ADHD such as attention difficulties, hyperactivity-impulsivity, and oppositional defiant problems. PMID- 28360549 TI - Use of Complementary and Alternative Medicine in Children with Autism Spectrum Disorders: A Multicenter Study. AB - INTRODUCTION: This study examined the prevalence of the use of different complementary and alternative medicine (CAM) strategies, families' attitudes and belief systems about the use of these strategies, and the economic burden of these strategies placed on family income in families of children with autism spectrum disorders (ASD). METHOD: A questionnaire survey concerning the use of CAM in children with ASD was administered to parents in the five different geographic locations in Turkey. RESULT: Of the 172 respondents, 56% had used at least one CAM therapy. The most frequently used CAM intervention was spiritual healing. Among the most reported reasons for seeking CAM were dissatisfaction with conventional interventions and a search for ways to enhance the effectiveness of conventional treatments. The most frequently reported source of recommendation for CAM was advice from family members. The mean economic burden of the CAM methods was a total of 4,005 Turkish lira ($2,670) in the sample using CAM. The CAM usage rate was lower in parents who suspected genetic/congenital factors for the development of ASD. CONCLUSION: This study observed the importance of socioeconomic and cultural factors as well as parents' beliefs about the etiology of ASD in treatment decisions about CAM. PMID- 28360551 TI - Comparison of Polysomnography and Multiple Sleep Latency Test Findings in Subjects with Narcolepsy and Idiopathic Hypersomnia. AB - INTRODUCTION: Both narcolepsy and idiopathic hypersomnia are the main causes of excessive daytime sleepiness. In this study, we aimed to compare polysomnography (PSG) and multiple sleep latency test (MSLT) findings in narcolepsy and idiopathic hypersomnia patients. METHODS: The files of patients with narcolepsy and hypersomnia who were admitted between 1995 and 2009 were reviewed. We evaluated data from 94 patients with narcolepsy with cataplexy, 49 with narcolepsy without cataplexy and 140 patients with idiopathic hypersomnia. RESULT: Sleep latency and REM latency were longer in idiopathic hypersomnia group than in narcolepsy with and without cataplexy group. Mean sleep latency in MSLT was the shortest in narcolepsy with cataplexy group. There was no difference in sleep efficiency, percentage of sleep stage and number of awakenings in PSG between three groups. CONCLUSION: The findings of the study indicated that narcolepsy patients differ from idiopathic hypersomnia patients in terms of sleep latency and REM latency in PSG. PMID- 28360552 TI - Clinical, Neurocognitive, Structural Imaging and Dermatogliphics in Schizophrenia According to Kraepelin Criteria. AB - INTRODUCTION: A century ago, Kraepelin stated that the distinctive feature of schizophrenia was progressive deterioration. Kraepelin criteria for schizophrenia are: (1) continuous hospitalization or complete dependence on others for obtaining basic necessities of life, (2) unemployment and (3) no remission for the past five years. We aimed to determine the clinical appearance and structural biological features of Kraepelinian schizophrenia. METHODS: The sample consisted of 17 Kraepelinian patients, 30 non-Kraepelinian schizophrenic patients and 43 healthy controls. The Clinical Global Impressions (CGI) and the Positive and Negative Syndrome Scales (PANSS) were used for clinical assessment. The Frontal Assessment Battery (FAB) and the Verbal Fluency and Color Trail Test (CTT) were included in the cognitive battery. Brain magnetic resonance imaging and dermatoglyphic measurements were performed for structural features. RESULT: Duration of illness, hospitalization, suicide attempts, admission type, presence of a stressor and treatment choice were similar between the two patient groups. Treatment resistance and family history of schizophrenia were more common in Kraepelinian patients. PANSS and CGI subscales scores were also higher in this group. Only the category fluency and CTT-I were different in Kraepelinian patients in comparison to the other patient group. Structural findings were not different between the three groups. CONCLUSION: Category fluency, which was lower in Kraepelinian patients, is an important marker of a degenerative process. The collection of severe clinical symptoms, family history of psychiatric illness and nonresponse to treatment in this particular group of patients points to the need to conduct further studies including cluster analysis in methodology. PMID- 28360553 TI - Post-Traumatic Stress Disorder in Migraine Patients: Migraine, Trauma and Alexithymia. AB - INTRODUCTION: In recent studies, it has been suggested that there is a relationship between migraine headaches and post-traumatic stress disorder (PTSD). The PTSD has not been diagnosed by a clinician in these studies; the evaluation has been carried out by the screening scales. Besides, it has also been asserted that there was relationship of alexithymia with migraine and other chronic painful disorders. In this study, our aim was to investigate the prevalence of clinically-diagnosed PTSD and alexithymic features among migraine patients. METHODS: Sixty consecutive migraine patients sent from neurology clinic and 60 healthy controls having similar features constituted the sample of this study. SCID-I/CV PTSD module and the Clinician-Administered PTSD Scale (CAPS) was administered to the sample. The subjects also filled in the socio-demographic data form and the Toronto Alexithymia Scale (TAS). The level of pain perceived by the migraine patients was evaluated using a Visual Analog Scale (VAS). RESULT: 17 subjects (28%) in the migraine group and 5 individuals (8.3%) in the control group were diagnosed with PTSD. Hence, PTSD was found to be statistically significantly higher in the migraine group. 25 persons in the migraine group (41.6%) and 12 in the control group (20%) scored above the TAS cutoff score in terms of alexithymic features. Alexithymia was found to be statistically significantly higher in the migraine group). In the migraine group, VAS scores of the ones with PTSD were statistically significantly higher compared to that in ones without PTSD. 94% of the persons diagnosed with PTSD in the migraine group reported that their migraine headaches started after a traumatic experience. In the migraine group, no statistically significant correlation was detected between CAPS and VAS scores in subjects with PTSD. CONCLUSION: In migraine patients, PTSD and alexithymic features have been found higher than in the healthy controls. Further studies are needed to search whether the practices aimed at treating the PTSD and alexithymic features can contribute to the treatment of migraine headaches or not. PMID- 28360554 TI - Injuries in Patients with Epilepsy and Some Factors Associated with Injury. AB - INTRODUCTION: The aim of the study was to evaluate injuries in patients with epilepsy and some factors associated with injury. METHODS: This study included 126 epileptic patients who attended a neurology outpatient clinic of a hospital between March 2009 and March 2010. Data were collected using a patient information form and an injury evaluation form. The data were evaluated using percentage, mean and the Chi square test. RESULT: 82.5% of patients have sustained injury due to an epileptic seizure. Soft tissue injuries were the most common (70.2%), followed by head injury (61.5%), dental and tongue injury (%58.6), burns (24%), and orthopaedic injury (21.2%). The most common site of burns were the upper extremities and the face (36% and 24%, respectively). Burns occurred during cooking in 32% of cases. Five patients had upper extremity fractures. Four patients faced the risk of bathtub drowning. The injuries usually occurred at home. The significant risk factors for injury were generalized tonic clonic seizures and high frequency of seizures. Twenty-six patients were taken to the emergency unit due to an injury. CONCLUSION: Injury is a common problem in patients with epilepsy. Dental and tongue injury was the most common seizure related injury. The risk factors were generalized tonic-clonic seizures, and high frequency of seizures. Patients with epilepsy can lead normal lives but certain precautions are needed to prevent seizure-related injuries. PMID- 28360556 TI - An Unusual Case: The Comorbidity of Mood Disorder and 17-alpha-Hydroxylase Deficiency. AB - 17-alpha-hydroxylase enzyme has a crucial role in the steroid biosynthesis and, deficiency of this enzyme is an autosomal recessive monogenic disorder which is one of the two hypertensive form of congenital adrenal hyperplasia. It is characterized with the deficiency in glucocorticoid, adrenal androgen, and sex steroid synthesis with concomitant mineralocorticoid excess due to genetic defect in steroid biosynthesis. The relationship of hormone system physiology with psychiatric signs and syndromes are complex. Any problem in the hypothalamo pituitary axis may cause psychiatric syndromes. On the other hand, many psychiatric disorders, such as mood-anxiety symptoms, depression, mania, psychosis, and delirium can be seen secondary to the treatment of hormone deficiency. We present the case of a male patient with pseudohermaphroditism who has been followed and treated in Rasit Tahsin Mood Clinic with the diagnosis of mood disorder not otherwise specified and was diagnosed with 46, XY karyotype and 17-alpha-hydroxylase deficiency after referring to a hospital with delayed puberty. Considering the medical literature, 17-alpha-hydroxylase deficiency has been evaluated from the aspects of gender-related behavioral disorders, psychological developmental and anxiety disorders. To the best of our knowledge, in the medical literature, this is the first case of 17-alpha-hydroxylase deficiency associated with mood disorder. Here, the relationship between mood disorders and hypothalamo-pituitary axis is discussed in the light of the literature. PMID- 28360555 TI - Endothelial Nitric Oxide Synthase and Angiotensin Converting Enzyme Gene Polymorphisms in Migraine Patients. AB - INTRODUCTION: In this study, we investigated the association of migraine with the Variable Number of Tandem Repeats (VNTR), repeated as 27 base pair, gene polymorphism in intron 4 of the endothelial nitric oxide synthase (eNOS) and the insertion/deletion of angiotensin converting enzyme (ACE) gene polymorphisms. METHODS: One hundred and five migraine and ninety seven healthy female control subjects were enrolled in the study. The patients were subdivided as migraine with aura and without aura, and the frequency and severity of migraine headaches were recorded. The eNOS VNTR (eNOS 4 a/b) and ACE insertion/deletion gene polymorphisms (ACE I/D) were assessed by polymerase chain reactions. RESULT: The allele and genotype frequencies of eNOS 4 a/b gene polymorphism showed no difference between the migraine and control groups. The genotypic distribution of the ACE I/D gene polymorphism in the migraine group significantly differed from that in the control group. The DD and ID genotype increased the risk of migraine as much as 2.571 (95% CI-1.138-5.811) and 4.453 (95% CI-2.006-9.883) compared to the II genotype. The same increased risk sustained for both genotypes in the migraine with aura subgroup, but only the ID genotype remained as the risk factor in the migraine without aura subgroup (OR-3.750, 95% CI-1.493-9.420). No association of gene polymorphisms with migraine frequency and severity was observed. CONCLUSION: Our findings support the relationship between migraine and the ACE I/D gene polymorphism. However, no association was found between migraine and the eNOS 4 a/b gene polymorphism. PMID- 28360558 TI - Clinical and Polysomnographic Features of Kleine-Levin Syndrome: Case Series. AB - Kleine-Levin Syndrome (KLS) is a rare disorder characterized intermittent hypersomnia, hyperphagia, hypersexuality, abnormal behaviors, and confusion. Patients are asymptomatic between episodes. The aim of this case series study was to determine the clinical features of patients with KLS and to compare the polysomnography (PSG) findings between symptomatic and asymptomatic periods. We compared the results of PSG investigations performed in symptomatic and asymptomatic periods in six patients diagnosed with KLS at Gulhane Military Medical Faculty Sleep Research Center between 1998 and 2005. The age at onset of KLS was approximately 18 years, the diagnosis delayed 2.67 years, hypersomnia episodes lasted approximately 11.5 days, until the correct diagnosis, the patients had experienced on average 5 episodes. Total sleep time in KLS patients during symptomatic period and stage 2 sleep percent was higher than in asymptomatic period. REM latency was shorter and stage 3 and REM percent was lower in asymptomatic period. The clinical features including the age of onset and episode duration are compatible with those from the previous studies. It was observed that the sleep architecture during symptomatic period was different from that in asymptomatic period. PMID- 28360557 TI - The Effect of Balance Training by Tetraks Interactive Balance System on Balance and Fall Risk in Parkinson's Patients: A Report of Four Cases. AB - This pilot study aimed to investigate the effect of balance training by Tetraks Interactive Balance System (TIBS) on balance and fall risk in patients with mild to moderate Parkinson's disease. Four patients with Parkinson's disease between the ages of 56 and 70 years (61.25+/-6.70) were applied balance training for 3 weeks by TIBS. Sociodemographic features and physical properties of the subjects were recorded. Their motor performance was evaluated by the Unified Parkinson's Disease Rating Scale (UPDRS), balance was measured using the Berg Balance Scale (BBS), Functional Reach Test (FRT), Timed Up and Go Test (TUG), and the Standing on One Leg Balance Test (SOL) and, their fall risks were evaluated by TIBS. Evaluations were performed twice, before and after treatment. Following training, Parkinson's patients showed improvements in UPDRS, TUG, BBS, FRT, SOL and fall risk. Balance training by TIBS has positive effects on balance and decreases fall risk in Parkinson's disease patients. PMID- 28360559 TI - Epilepsy, Psychogenic Seizure, Trauma in the Developmental Process. AB - An epileptic seizure, can cause trauma for its sudden emergence, leading to functional impairment, accidents and injuries, and fear of death. The seizure can be traumatizing itself, besides, an head trauma that may occur during the seizure can also cause epilepsy. As the severity and duration of epilepsy increases, disturbances in development and traumatic effects occur. Conversion (psychogenic) seizures may be added over the years in epileptic patients. The comorbidity of trauma-related dissociative disorder and psychogenic seizures is observed in approximately half of the cases. Dissociative disorders are known to occur in children with chronic diseases due to the traumatic effect of the disease. Conversion disorder and psychogenic seizures are frequently seen in dissociative disorders. Posttraumatic stress disorder, dissociative disorders, and psychogenic seizures are often comorbid diagnoses in epilepsy. For this reason, traumatic effect and associated dissociative disorder dimension should be kept in mind in the psychiatric approach when handling with cases of epilepsy. PMID- 28360560 TI - The Relationship of Symptoms of Anxiety and Depression with Disease Severity and Treatment Modality in Myasthenia Gravis: A Cross-sectional Study. AB - INTRODUCTION: Findings about the relationship between psychopathology and severity of myasthenia gravis (MG) seem scarce and conflicting. The aim of this study was to investigate the relationship of depressive and anxiety symptoms with disease severity and treatment modalities among a cohort of patients with MG. METHODS: Sixty-seven patients, who presented to the neuromuscular outpatient clinic, at a neuropsychiatry hospital in Istanbul, Turkey in a two-month period, were recruited consecutively. A total of 42 patients with MG were invited to participate in the study. None of the patients refused to participate. Severity of MG was assessed according to the Osserman and Genkins classification. The participants were evaluated by a sociodemographic form, the Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Hamilton Depression Rating Scale 17-item version (HAM-D), and the Hamilton Anxiety Rating Scale (HAM-A). RESULTS: The patients with stage IIB MG had significantly higher scores on the BAI, HAM-D, HAM-A total and somatic anxiety than those with stage I and IIA MG (p<0.05). Likewise, the patients taking a combination of prednisolone+pyridostigmine/azathioprine had significantly higher scores on the BAI, HAM-D, HAM-A total and somatic anxiety than those taking only prednisolone (p<0.05). Linear regression analysis revealed that disease severity and stressful life events were the factors associated with the HAM-D scores. Disease severity, treatment modalities, and gender were the factors associated with the HAM-A scores. CONCLUSION: The results of the present study may suggest that patients with relatively more severe MG or those taking a combination of immunosupressive and anticholinesterase medications need psychiatric/psychological evaluation. PMID- 28360561 TI - Comparison between Camberwell Family Interview and Expressed Emotion Scale in Determining Emotions of Caregivers of Schizophrenic Patients. AB - INTRODUCTION: The aim of the study was to compare the Camberwell Family Interview (CFI) and the Expressed Emotion Scale (EES) in determining the level of expressed emotion in caregivers of patients with schizophrenia. METHOD: The study sample included caregivers of 22 schizophrenic patients followed in two psychiatric clinics. The level of expressed emotion in the caregivers was assessed by the CFI and the EES. CFI was applied to caregivers of the inpatients and the procedure was audio recorded. These records were later used for the ratings. EES was completed by the caregivers. Total EES scores were used to determine the level of expressed emotion in the caregivers. RESULTS: Forty point nine percent and 50% of the caregivers had high level of expressed emotion based on the analysis of the data obtained from the CFI and EES. Fifty-nine percent and 50% of the caregivers had low level of expressed emotion based on the data obtained from the CFI and EES. The proportion of the caregivers with high level of expressed emotion as measured by the CFI and the EES were not statistically significantly different within the sample (chi2= 0.727). CONCLUSION: The CFI and the EES were similar in determining the level of expressed emotion in caregivers of schizophrenic patients. It can be suggested that the EES, a user friendly tool, may be preferred to determine the level of expressed emotion in caregivers of patients with schizophrenia. However, further studies with larger samples are needed to obtain more reliable results. PMID- 28360562 TI - Sporadic Creutzfeldt-Jacob Disease: An 8-Year Experience from a Single Center in Turkey. AB - INTRODUCTION: Our aim was to conduct a retrospective review to demonstrate the clinical, radiological, and electrophysiological features of patients with sporadic Creutzfeldt-Jacob disease (sCJD). METHOD: A total of 10 patients (5 female and 5 male, with a mean age of 45 years from a range of 40 to 67 years) out of 8.259 adult patients hospitalized from January 2000 to December 2008 were diagnosed with sCJD. RESULTS: Eight of the patients were diagnosed on the basis of clinical, radiological, electroencephalography (EEG), and cerebrospinal fluid (CSF) findings. Two other patients also had a pathological diagnosis. The most common signs and symptoms were behavioral disturbances, movement disorders, cognitive decline, myoclonus, psychosis, focal neurological deficit, and aphasia. Nine of the patients had periodic sharp wave discharges on EEG. Seven patients were positive for the 14.3.3 protein in the CSF. Five patients had pulvinar signs a bilateral increased signal in the pulvinar thalami-on cranial magnetic resonance imaging. Eight patients were diagnosed with probable sCJD; two were diagnosed with definite sCJD. All of the patients died as a result of the disease within 24 months after the onset of symptoms. DISCUSSION: sCJD should be considered in the diagnosis of patients who present with rapidly progressive dementia. Clinical and radiological data appear to be sufficient for the diagnosis. However, detailed molecular examinations of the subtypes of the disease may be required for early diagnosis of cases given the wide spectra of CJD. PMID- 28360563 TI - The Turkish Adaptation of the Ten-Item Personality Inventory. AB - INTRODUCTION: Personality is one of the important domains of psychology, and it is an integration of emotional, cognitive, social and physical properties. In this study, we aimed to assess the applicability of the "Ten-Item Personality Inventory (TIPI)" which measures five basic personality traits in Turkish young people. METHOD: Data from a total of 420 participants - 208 male (49.1%) and 212 female (50.9%) - were employed for the validity and reliability analyses. Of the participants, 230 (54,8%; mean age: 23.2 years; sd=1.6) were university students and the rest were not (n=190; 45.2%; mean age: 23.4 years; df=1.7). The mean age of the participants was 22.1 years (df=1.3), ranging from 18 to 25 years. RESULTS: Language validity (correlations between 0.92 and 0.97), exploratory factor analysis yielded 10 items and five-factor model explaining 65.21% of the variance. Confirmatory factor analyses (chi2/df: 2.20, GFI=0.95, AGFI=0.92, CFI=0.93, NNFI=0.91, RMR=0.04, and RMSEA=0.03), item analysis, and convergent validity results indicated that a five-factor solution with 10 items met the criteria standards for adequacy of fit among Turkish young people. The internal consistency (Openness to Experiences 0.83, Agreeableness 0.81, Emotional Stability 0.83, Conscientiousness 0.84, and Extraversion 0.86) and test-retest stability (=54; Openness to Experiences 0.89, Agreeableness 0.87, Emotional Stability 0.89, Conscientiousness 0.87, and Extraversion 0.88) revealed a moderate to acceptable reliabilities. CONCLUSION: The results demonstrated that the TIPI could be used in studies that evaluate personality in Turkish young people. PMID- 28360564 TI - Self-Esteem, Social Phobia and Depression Status in Patients with Epilepsy. AB - INTRODUCTION: The increased risk for psychiatric disorders in epilepsy can be related to a number of clinical, psychosocial and biological factors. Due to the unpredictability of seizures and the possibility that they may occur at any time and in any place, patients with epilepsy may develop social phobia and may have feelings of worthlessness and stigma. These factors decrease their psychosocial function, self-efficacy, and quality of life and even increase the suicide rate. Considering the above-mentioned scientific data, the present study was designed to investigate phobia, self-esteem and depression status in patients with epilepsy. METHODS: One hundred thirty-two patients (aged 21-52 years) and age- and gender-matched control group of 61 subjects (aged 25-60 years) were included in this study. All patients in both groups were administered the Liebowitz Social Anxiety Scale (LSAS), Coopersmith Self-Esteem Inventory (CSEI), and the Beck Depression Inventory (BDI). RESULTS: The mean ages of the patient group and the healthy controls were 29.66+/-11.3 and 32.16+/-7.99, respectively. There was no statistical significance between the two groups in terms of age and sex (p>0.05). BDI, LSAS and CSEI scores in the patient group were statistically significantly different than in the control group (p<0.05). DISCUSSION: Our results showed that social phobia, lower self-esteem and depression are important comorbid conditions in epileptic patients. Psychiatric disorders are usually underrecognized and undertreated in patients with epilepsy. Therefore, it is very important to identify and treat the psychiatric comorbid conditions in epilepsy because of their significant burden on patients' quality of life. PMID- 28360565 TI - Reliability and Validity of the Turkish Version of the Health Anxiety Inventory. AB - INTRODUCTION: Health anxiety is seen in the clinical presentation of both somatoform disorders, especially hypochondriasis and anxiety disorders. In this study, we aimed to perform the reliability and validity analyses of the Turkish version of the Health Anxiety Inventory which is used in the assessment of health anxiety. METHOD: Translation and back-translation of the Health Anxiety Inventory was done. Study groups consisted of in- or out-patients with somatoform disorder (n=65), panic disorder (n=55), major depressive disorder (n=22), and healthy volunteers (n=114). In the assessment, beside the Health Anxiety Inventory, the Hamilton Rating Scale for Depression, Somatosensory Amplification Scale and the Trait Anxiety Inventory were used. RESULTS: In reliability analyses, Cronbach's alpha internal consistency coefficient was 0.918 and item-total score correlation coefficients were between 0.405 and 0.769. Test-retest correlation coefficient was r=0.572. In construct validity, two factors that representing 54.5 percent of the total variance were obtained and they represented sensitivity to somatic symptoms and anxiety towards organic diseases. In concurrent validity, it had moderate to good correlation with the other study scales. In the comparison of study groups, the groups of somatoform disorder and anxiety disorder had significantly higher level of health anxiety than the groups with major depressive disorder and of healthy controls. CONCLUSION: The Turkish version of the Health Anxiety Inventory can be reliably and validly used both in clinical practice and in research. PMID- 28360566 TI - Temperament and Character Differences in Patients with Premature Ejaculation. AB - INTRODUCTION: The debate on the etiology of premature ejaculation is still ongoing although there was huge amount of biological and psychological theories. We aimed to investigate the personality structure of patients with premature ejaculation via temperament and character inventory. METHODS: Forty patients with premature ejaculation and a matched number of healthy people were included. Participants were asked to fill out a questionnaire booklet with separate sections for general demographic information and the temperament and character inventory. RESULTS: Total novelty seeking scores and subscale 1 (exploration excitability) scores in premature ejaculation patients were significantly higher than in control groups (p<0.05). Total harm avoidance scores and harm avoidance subscale 2 (fear of uncertainty) scores in premature ejaculation patients was found significantly lower than in control group (p<0.05). Beck depression score was significantly higher in patients with premature ejaculation than in control groups. DISCUSSION: Men with premature ejaculation are more impulsive (excitant), more tempered, more excitable and less prone to harmful behavior. Current findings tend to reinforce premature ejaculation based upon combination of neurobiological and psychological reasons. PMID- 28360567 TI - Differences in Affective Temperaments in Anxiety Disorders: Comparison of Panic Disorder and Obsessive Compulsive Disorder. AB - INTRODUCTION: In this study, probable differences in affective temperament among anxiety disorders were investigated via a comparison of panic disorder (PD) and obsessive-compulsive disorder (OCD). METHOD: 44 patients with OCD and 42 patients with PD, who were admitted to Bakirkoy Prof. Dr. Mazhar Osman Research and Training Hospital for Psychiatry, Neurology and Neurosurgery outpatient clinics with complaints of OCD and PD and were diagnosed according to DSM IV criteria, were consecutively included in the study after informed consent was taken. A sociodemographic form, the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID I), Hamilton Depression Rating Scale (HAM-D), Beck Anxiety Inventory, Panic and Agoraphobia Scale, Yale-Brown Obsessive-Compulsive Scale (Y BOCS) and the temperament evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A) were given to the patients. PD and OCD patients were compared in terms of affective temperament characteristics. RESULTS: Mean age, educational status and gender distribution of OCD and PD patients were similar (p>0.05). Dominant depressive temperament was more prominent in OCD group than in PD group (p=0.021). Hyperthymic temperament scores were higher in PD group than in OCD group (p=0.002). Dominant hyperthymic temperament was not encountered in either group. CONCLUSION: Dominant depressive temperament was more prominent in OCD group whereas hyperthymic temperament scores were higher in PD group. These findings should be evaluated in studies with larger sample sizes. PMID- 28360568 TI - The Prevalence of Psychiatric Disorders Distribution of Subjects Gender and its Relationship with Psychiatric Help-Seeking. AB - INTRODUCTION: The aim of this study was to investigate the prevalance of psychiatric disorders and psychiatric help-seeking behaviours in central Eskisehir according to sociodemographic variables. METHOD: In this study, for the purpose of revealing the psychiatric disorder profile of Eskisehir city and evaluating the prevalance of psychiatric disorders according to gender differences and psychiatric help-seeking behaviours; The Primary Care Evaluation of Mental Disorders (PRIME-MD) scale and psychiatric help questionnaire were administered to 1475 subjects who were randomly selected from 24 primary health care centers in Eskisehir. RESULTS: The prevalence of psychiatric disorders was as follows: at least one mood disorder 37%, anxiety disorders 29%, somatoform disorders - 8.6% and, possible alcohol abuse 7.7%. All diagnoses except possible alcohol abuse were found to be more frequent in women than men. Also It was found that in subjects who were thougth to have a psychiatric disorder, 64% of mood disorder patients, 67% of anxiety disorder patients, 70% of somatoform disorder patients and, 61% of possible alcohol abuse patients can receive appropriate treatment. DISCUSSION: Since psychiatric disorders are common, it is important to direct such patients to appropriate treatment. Therefore, new studies are necessary to find out the prevalance of psychiatric disorders and risky groups as well as to identify the reasons that why such people do not seek for help in different regions of our country. PMID- 28360569 TI - Investigation of Social, Emotional, and Cognitive Factors with Effect on Suicidal Behaviour in Adolescents with Depression. AB - INTRODUCTION: Our study aimed at investigating social, emotional, and cognitive factors playing a role in the development of suicidal ideation in depressed adolescents and its turning into a suicide attempt. METHOD: Sixty-three adolescents (48 female, 15 male) aged 12 to 18 years were included in the study. In face-to-face interviews, suicide ideation, suicide plans, and previous suicide attempts were evaluated, sociodemographic data were collected. Additionally, the Children's Depression Inventory, State-Trait Anxiety Inventory (STAI-I, II), Beck Hopelessness Scale, Coopersmith Self-Esteem Inventory, Multidimensional Scale of Perceived Social Support, Strengths and the Difficulties Questionnaire (SDQ) parent forms were applied. SPSS version 13.0 for Windows was used for statistical analysis. RESULTS: It has been established that in the last six months, 71.4% of cases (n=45) had suicidal ideation and 27% (n=17) attempted suicide. Factors associated with suicidal ideation in depressed adolescents were: high depression and anxiety levels, hopelessness and low self-esteem (p<0.05). Factors associated with suicide attempts were: separated family background, lower perceived family support and high rates of conduct difficulties (p<0.05). Patients with suicide attempt differed from patients with suicidal ideation but without suicide attempt in lower perceived family support only (p<0.05). DISCUSSION: It is thought that keeping in mind the factors associated with the development of suicidal ideation and its turning into a suicide attempt, will help clinicians in preventing suicide attempts in depressed adolescents. PMID- 28360570 TI - The Relationship of White Matter Hyperintensities with Depressive Symptoms and Daily Living Activities in Early-Stage Alzheimer's Disease Patients. AB - INTRODUCTION: Cerebral white matter hyperintensities (WMHs) detected on magnetic resonance imaging scans are frequently seen in both Alzheimer's disease (AD) and depression patients and believed to play an important role in cognition and mood. Depressive symptoms and depression may accompany AD in all stages of the disease. The aim of the study was to evaluate the relationship of regional WMHs with depressive symptoms, cognitive status, medial temporal lobe atrophy, and daily living activities in early-stage AD patients. METHOD: Forty-five patients with very mild or mild AD were examined. All subjects underwent MRI and were assessed by the Geriatric Depression Scale (GDS) and the Addenbrooke's Cognitive Examination-Revised (ACE-R) for the evaluation of depressive symptom severity and cognitive status, respectively. The patients were divided into two groups based on the selected cut-off point in the GDS. CDR sum of the boxes (CDR-sb) scores were calculated as a measure of activities of daily living (ADLs). MRI T2-FLAIR slices were used to rate the white-matter lesions according to the Age-Related White Matter Changes Rating Scale, assessing the WMHs in frontal, parietooccipital, temporal, infratentorial and basal ganglia areas individually. Medial temporal lobe atrophy was assessed with high-resolution T1 images using visual rating scale. RESULTS: In the depressive group, frontal WMH scores were found to be higher than in the non-depressive group (p=0.006). ACE-r, CDR-sb and medial temporal lobe atrophy scores did not differ among the groups. CDR-sb scores showed a significant correlation with frontal WMH scores (left frontal WMH r=0.439, p=0.003, right frontal AMH r=0.459, p=0.001). Linear regression models revealed the effect of WMHs on depressive symptoms among the other factors including age, functionality and atrophy in the medial temporal areas. DISCUSSION: Our findings underscore the potential role of regional, particularly frontal AMHs in depressive symptoms and functionality of the early AD patients. PMID- 28360571 TI - Expected and Experienced Pain Levels in Electromyography. AB - INTRODUCTION: The aim of the present study was to assess pain using a visual analogue scale (VAS) in patients awaiting an EMG procedure (i.e., expected VAS) and after an EMG procedure (i.e., experienced VAS). METHODS: Expected and experienced pain in response to nerve conduction studies (NCS) and needle EMG were assessed in 108 patients (61 females, 47 males; mean age 43.2+/-11.6) using a VAS. RESULTS: No significant correlations were noted between the expected or the experienced VAS in response to EMG and demographic features of the patients. The expected VAS was significantly higher than the experienced VAS in response to needle EMG (p=0.005). The highest VAS level was noted in the expected VAS in response to needle EMG (4.7+/-2.2). The lowest VAS level was noted in the experienced VAS in response to NCS (3.6+/-2.5). CONCLUSION: The present study demonstrated that neither the expected nor the experienced pain associated with EMG exceeded a moderate level. Interestingly, we found that expected pain levels in response to needle EMG were significantly higher than experienced pain levels. Therefore, it may be possible to increase compliance if patients are provided with this information before undergoing electrophysiological procedures. PMID- 28360572 TI - Cerebellar Mutism Syndrome After Posterior Fossa Surgery: A Report of Two Cases of Pilocytic Astrocytoma. AB - Cerebellar mutism is a type of syndrome including decreased speech, hypotonia, ataxia and emotional instability which occurs after posterior fossa surgery. It has been first reported by Rekate et al. and Yonemasu in 1985. It is well known that long tract signs and lower cranial nerve involvement are not seen with this syndrome and understanding is preserved. However, the pathophysiology of cerebellar mutism has not been well clarified yet. It is mainly seen in patients with medulloblastoma and brainstem involvement. In this report, we present two extraordinary cases of cerebellar mutism after posterior fossa surgery. They were considered extraordinary because their hystopathological analysis results yielded pilocytic astrocytoma which is out of the predefined risk factors. PMID- 28360573 TI - Late-life Onset Mania After Varenicline Use: A Case Report. AB - Late-life onset manic attacks generally occur secondary to general medical conditions or drug use. Varenicline is an alpha4beta2 nicotinic acetylcholine receptor partial agonist, used for the cessation of smoking. In this case report, we present a 67-year-old male patient with a new-onset manic episode following varenicline treatment. The patient's manic symptoms started on the seventh day of varenicline treatment. His symptoms started on the 7th day of treatment. He was admitted to the psychiatric outpatient clinic since his symptoms did not improve despite discontinuing varenicline treatment. In the initial mental status examination, he scored 35/60 on the Young Mania Rating Scale (YMRS). On the twenty-fifth day of the hospitalization, the patient was discharged since his YMRS score improved (5/60). Varenicline may cause manic episodes in patients with bipolar disorder and in healthy individuals. An increasing number of serious psychiatric disorders are being reported due to varenicline treatment. Mental state examination before and during varenicline treatment seems necessary. PMID- 28360574 TI - Chorea-Ballismus Associated with Hyperglycemia. AB - Chorea-ballismus which is a rare complication of nonketotic hyperglycemia may be the first symptom of type 2 diabetes mellitus. In this paper, we present two patients, who had involuntary movements and were diagnosed as having ballismus chorea associated with nonketotic hyperglycemia. While one of the patients was not diagnosed with diabetes mellitus, the other one did not administer insulin therapy for a long time which was prescribed. The patients were investigated by cranial imaging and biochemical tests. The symptoms improved in one of them within hours, however, it took days to improve for the other one. This clinical situation, which is thought to be caused by hyperglycemia, cerebral ischemia and failure of gamma-aminobutyric acid (GABA) and which probably improves with regulation of blood glucose levels, should be kept in mind by emergency physicians, because it can be the first presentation of type 2 diabetes mellitus. PMID- 28360575 TI - Agomelatine-Induced Maculopapular Rash: A Case Report. PMID- 28360577 TI - Critical Evaluation of Headache Classifications. AB - Transforming a subjective sense like headache into an objective state and establishing a common language for this complaint which can be both a symptom and a disease all by itself have kept the investigators busy for years. Each recommendation proposed has brought along a set of patients who do not meet the criteria. While almost the most ideal and most comprehensive classification studies continued at this point, this time criticisims about withdrawing from daily practice came to the fore. In this article, the classification adventure of scientists who work in the area of headache will be summarized. More specifically, 2 classifications made by the International Headache Society (IHS) and the point reached in relation with the 3rd classification which is still being worked on will be discussed together with headache subtypes. It has been presented with the wish and belief that it will contribute to the readers and young investigators who are interested in this subject. PMID- 28360576 TI - Pathophysiology of Migraine. AB - Migraine is a serious health problem which impair quality of life. It is the second most common primary headache that affects approximately more than %10 people in general population. Migraine pathophysiology is still unclear. Increasing results of studies suggest to migraine pathophysiology is related with primary neuronal mechanisms. Migraine pain starts in which region of brain and what brain regions are activated in different stages is unenlightened. There is evidences that growing number of studies which using new imaging techniques as positron emission tomography (PET) and functional magnetic resonans imaging (fMRI) show that migraine and cluster headaches are related with neuronal structures and vasodilatation. There are four phases to a migraine. The prodrome phase, aura, the attack, and the postdrome phase. Some datas obtained from last ten years indicate that cortical excitability has increased in interictal phase too. For many years, studies in rodents show trgimenial nerve is activated and it leads to vasodilatation and neurogenic inflammation in the headache phase. Although the majority of patients encountered in clinical practice are migraine without aura or chronic migraine, experimental studies of the migraine pathophysiology are focusing on the aura model which is used cortical spreading depression. PMID- 28360580 TI - Acute Treatment of Migraine. AB - Migraine is one of the most frequent disabling neurological conditions with a major impact on the patient's quality of life. Migraine has been described as a chronic disorder that characterized with attacks. Attacks are characterized by moderate-severe, often unilateral, pulsating headache attacks, typically lasting 4 to 72 hours. Migraine remains underdiagnosed and undertreated despite advances in the understanding of its pathophysiology. This article reviews management of migraine acute pharmacological treatment. Currently, for the acute treatment of migraine attacks, non-steroidal anti-inflammatory drugs (NSAIDs) and triptans (serotonin 5HT1B/1D receptor agonists) are recommended. Before intake of NSAID and triptans, metoclopramide or domperidone is useful. In very severe attacks, subcutaneous sumatriptan is first choice. The patient should be treated early in the attack, use an adequate dose and formulation of a medication. Ideally, acute therapy should be restricted to no more than 2 to 3 days per week to avoid medication overuse. PMID- 28360579 TI - The Face of Chronic Migraine Which Has Started to be Clarified. AB - Recently, information about migraine which is generally characterized with attacks has gradually increased. In some patients with migraine, progression may be observed such that the frequency and time of the attacks are increased and an attack lasts for days. This condition is called chronic migraine (CM). According to the last classification, chronic migraine is defined as headache which occurs 15 days a month or more frequently at least 8 of which show the characteristic properties of migraine or response to migraine-specific treatment. The diagnostic cirteria of chronic migraine, its differences from other chronic daily headaches and the question if it is a migraine form with a high frequency which transforms from episodic migraine or a completely different pathophysiological picture are still contradictory. Clarifying these issues is possible with clinical studies as well as increasing the studies directed to investigate the pathophysiological mechanisms. PMID- 28360578 TI - Comorbidity of Migraine. AB - Migraine is a common neurological disorder and can be severely disabling during attacks. The highest prevalence occurs between the ages of 25 and 55 years. Prior studies have found that migraine occurs together with other illnesses at a greater coincidental rate than is seen in the general population. These occurrences are called "comorbidities". To delineate the comorbidities of migraine is important, because it can help improve treatment strategies and the understanding of the possible pathophysiology of migraine. PMID- 28360581 TI - Prophylactic Treatment of Migraine. AB - Migraine is a common chronic neurological disease characterized by episodic attacks of headache and associated symptoms. The pharmacological treatment of migraine may be acute or prophylactic, and patients with frequent, severe headaches often require both approaches. Prophylactic treatment is used to reduce the frequency, duration, or severity of attacks, to enhance the benefits of acute treatments, and to improve patient's ability to function normally. Prophylactic treatment may also prevent progression from episodic migraine to chronic migraine and may result in reductions in health-care cost. The currently available pharmacological options for migraine prophylaxis include a wide array of medications. The major medication groups for prophylactic treatment include beta blockers, anticonvulsant, drugs such as topiramate and valproate, antidepressant drugs, such as amitriptyline and selective serotonin and selective serotonin norepinephrine reuptake inhibitors (SNRIs), calcium channel antagonists and neurotoxins. The agent for prophylactic treatment should be chosen based on the efficacy and side-effect profile of the drug, and the patient's coexistent and comorbid conditions. PMID- 28360582 TI - Botulinum Toxin in Migraine Treatment. AB - Since botulinum toxin might have a therapeutic effect on pain, many studies investigating the efficiency of botulinum toxin in headache treatment have been done. The most satisfying results were achieved by botulinum toxin type A (BoNT/A) in the treatment of chronic migraine. In this paper, we reviewed the clinical effectiveness of BoNT/A in migraine and included our clinical experience. In our ongoing pilot study, where we have repeated BoNT/A injections every 12 weeks, The difference in the Migraine Disability Assessment (MIDAS) scores between the first and the second injections was 61.1%; and between the first and the 3rd injections was found to be 65.72%. PMID- 28360584 TI - Medication Overuse Headache: The Reason of Headache That Common and Preventable. AB - Medication overuse headache (MOH) is well-defined clinically and is one of the common reasons of chronic daily headache, but its pathophysiology has not been elucidated yet. MOH has varying clinical features in regard to regional, psychosocial, medical and economic factors. Even though, the studies have shown that many factors may play a role, MOH is likely to occur in patients who are prone to primary headaches. Mainstay of the treatment is to withdraw the excessively used analgesic drugs. The primary prevention with education of the patients as well as early diagnosis and treatment of MOH will reduce its increasing financial burden on both patients and countries. Meticulous and multifactorial evaluation of the disease besides the diagnosis and treatment of the comorbid diseases will reduce the risk of recurrences. PMID- 28360583 TI - The Use of Complementary and Alternative Medicine in Patients with Migraine. AB - Although many patients with migraine get positive benefits from conventional pharmacological treatments, many others do not benefit sufficiently or experience adverse effects from these treatments. For that reason, these patients usually seek complementary and/or alternative medical (CAM) treatments all over the world. In general, although CAM therapies are not recommended by neurologist in Turkey, most of migraine patients, who do not respond conventional medicine treatments, seek alternative therapy. Acupuncture, botulinum toxin, mind-body interventions, and nutraceutical options are the most popular treatments. In this review, the available evidence for all these treatments will be discussed. PMID- 28360585 TI - Syndrome of Headache Accompanied with Transient Neurologic Deficits and Cerebrospinal Fluid Lymphocytosis. AB - The syndrome of headache accompanied with transient neurologic deficits and cerebrospinal fluid lymphocytosis (HaNDL), is a rare, benign and self limiting syndrome. In the 2nd Edition of the International Classification of Headache Disorders, HaNDL syndrome was defined in secondary headache group as "Headache attributed to non-vascular intracranial disorder". The etiology of HaNDL is still unknown. In recent years, some authors have shown that ion channel autoimmunity might at least partially contribute to HaNDL pathogenesis. In this paper, the definition of HaNDL syndrome, clinical picture and epidemiology of HaNDL syndrome, etiopathogenesis, differential diagnosis and treatment will be reviewed with the recent literature. PMID- 28360586 TI - Vestibular Migraine. AB - The co-occurrence between migraine and vertigo has been noticed for a long time ago. In recent years, however, growing numbers of epidemiological and clinical studies have definitely shown the significant relation between these two diseases. Recently, the term "vestibular migraine" is used commonly in studies. Vestibular migraine has taken place in appendix in the latest International Headache Society Classification. In this review, epidemiology, clinical features, diagnostic criteria and treatment of vesti-bular migraine will be discussed. PMID- 28360587 TI - Assessment of Quality of Life in Migraine. AB - Quality of life is the perception of an individual's position in life associated with his objectives, expectations, interests, and standard's of life. Health related quality of life, on the other hand, includes satisfaction with his health and emotional reaction to his state of health. Primary headaches are encountered commonly in adults during their most productive years like end of puberty and at the beginning of 50's. Migraine alone is responsible for 1.3% of years with disability in the world, all headaches together being responsible for twice of this load. Headaches both worsen quality of life of individuals and place a significant burden on the society. This review will focus on the effects of primary headaches, especially migraine, on quality of life and tools used to evaluate these effects. PMID- 28360588 TI - The Effect of Violence on the Diagnoses and the Course of Illness Among Female Psychiatric Inpatients. AB - INTRODUCTION: The aim of the study was to determine the rate of exposure to domestic violence among female inpatients at any period of their lives; to investigate the effect of different forms of violence on the diagnoses and the course of the illness. METHOD: The study was conducted on 102 female inpatients treated at Bakirkoy Research and Training Hospital for Psychiatry, Neurology and Neurosurgery. The Structured Clinical Interview for DSM-IV Axis I Disorders (SCID I) was administered and socio-demographic and clinical data was collected. A form designed for the assessment of violence was used to evaluate domestic violence. RESULTS: Ninety patients reported that they had been subjected to some kind of violence at some period of their lives. The parents or husbands were the most frequently reported persecutors. Seventy-three patients reported that they had been subjected to violence before the onset of their illness. Seventy-one had been subjected to physical, 79 to verbal, 42 to sexual, 52 to economic violence, and 49 to constraints on social relationship formation. Comorbid diagnosis of post traumatic stress disorder (PTSD) was related to all types of violence. The rate of suicide attempt was found to be significantly related to verbal-emotional violence. Only 12 patients had previously reported being subjected to domestic violence to their psychiatrist. CONCLUSION: Domestic violence, an often overlooked phenomenon, is prevalent among women with psychiatric disorders. Subjection to domestic violence is found to be correlated with PTSD and suicidal attempt. PMID- 28360589 TI - Risk Factors For Diabetic Polyneuropathy. AB - INTRODUCTION: The aim of this study was to investigate the risk factors for distal symmetric sensory-motor polyneuropathy (DSP) in patients with type 2 diabetes mellitus (DM). METHOD: Sixty seven patients with type 2 DM (33 males and 34 females) were included in the study. In addition to a detailed neurological examination, the Michigan Neuropathy Screening Instrument was administered to all patients and their total neuropathy scores were calculated. Nerve conduction examinations were performed for all patients. RESULTS: The mean age of the patients was 52.83+/-.87 years. The mean glycosylated hemoglobin (HbA1C) value was 8.56+/-2.07% (normal: 3-6.5%). The total neuropathy score significantly correlated with diabetes duration, hypertension, retinopathy, and HbA1C. CONCLUSION: This study confirms the previous reports regarding the association of neuropathy with poor glycaemic control and duration of the disease. The association of neuropathy with retinopathy and hypertension is important. PMID- 28360590 TI - Validation of the Turkish Version of the Obsessive-Compulsive Inventory-Revised (OCI-R) in Clinical and Non-Clinical Samples. AB - INTRODUCTION: The Obsessive-Compulsive Inventory-Revised (OCI-R) is a widely used self-report instrument developed to overcome the problems with the available instruments. The aim of this study was to assess the psychometric properties of the revised Obsessive Compulsive Inventory (OCI-R) in Turkish sample. METHODS: The psychometric properties of the Turkish version of the Obsessive-Compulsive Inventory-Revised (OCI-R) were assessed in clinical samples (n=44 for patients with obsessive-compulsive disorder (OCD), and n=44 for patients with major depression (MD) and a non-clinical student sample (n=287). RESULTS: The confirmatory factor analysis demonstrated that the original six-factor structure was valid in the Turkish sample. The overall and each of the subscales showed moderate to good internal consistency and convergent validity as well as test retest reliability. However, the Cronbach's alpha was excessively low for the hoarding subscale in the OCD group. The total and subscale scores of the OCI-R satisfied at discriminating patients with OCD from both patients with MD and healthy controls, with an exception of the neutralizing subscale. CONCLUSION: The Turkish version of the OCI-R did not reveal sound psychometric properties. Findings are discussed in the light of current theoretical considerations. PMID- 28360591 TI - Possible Risk Factors for Acute Stress Disorder and Post-Traumatic Stress Disorder After an Industrial Explosion. AB - INTRODUCTION: There have been deaths and injuries after an explosion which happened in an industrial region in Ankara in February 2011. The aim of this study was to determine the prevalence of acute stress disorder (ASD) and posttraumatic stress disorder (PTSD), and to determine the variables which can be the risk factors for PTSD. METHODS: In this study, we included a total of 197 subjects who were present at the factory building and at the four offices nearby when the disaster occurred. All the participants were assessed one month after the explosion and 157 of them were reassessed six months after the explosion. Socio-demographic information forms were given and the Clinician-Administered PTSD Scale (CAPS) was administered to the participants one month after the explosion. Psychiatric assessments were done using the structured clinical interview for DSM-IV axis-I disorders (SCID-I). The CAPS was re-applied six month after the disaster. RESULTS: At the first-month assessments, ASD was detected in 37.1% of participants and PTSD in 13.7%, whereas PTSD was observed in 16.6% of subjects at the sixth month of the accident. According to the first month data, having any psychiatric disorder before the incident, physical injury, acquaintances among the dead and the injured people, being involved in the incident and seeing dead people were detected as the risk factors for PTSD. At the sixth month assessment, physical injury, acquaintances among the dead and the injured, being involved in the incident were seen as risk factors for PTSD. CONCLUSION: ASD and PTSD can be seen after an explosion. Having a previous psychiatric disorder and being directly affected by trauma and being injured are the risk factors for PTSD. This study implies that preventive mental health care services should include the management of current psychiatric condition and employee safety issues. PMID- 28360593 TI - Submissive Behaviour, Depression, and Suicide Probability in Male Arrestees and Convicts. AB - INTRODUCTION: The aim of this study was to determine the relationship of suicide probability with submissive behaviors and the levels of depression in male arrestees and convicts staying in penal institutions. METHODS: The study consisted of 326 male participants from five different prisons. A personal information form was used to collect the socio-demographic data, The Suicide Probability Scale (SPS), Beck Depression Inventory (BDI) and the Submissive Behaviour Scala (SBS) were used to determine the related psychological characteristics. RESULTS: The results showed that depression was determined in 69% of the inmates (convicts and arrestees), while the suicide probability rate was found to be in the proportion of 88% which is higher than in the general population. Regarding the examination in terms of crime types, it was found that the suicide ideation rate of sex offenders or sex offender arrestees (x=18.33; ss=7.28) and the hostility rate of bulglary offenders (x=16.63; ss=4.75) were much higher than that of the other types of offenders. According to the findings of the Hierarchical Regression Analysis conducted in order to define the variables predicting the subscale rates of SPS, while previous suicide attempt(s) and depression predict hopelessness rate; self-attempted suicide, witnessing suicide attempts, self-harm and depression predict suicide ideation rate. Furthermore, education status and depression symptoms predict negative self evaluation rate, and lastly education level, witnessing suicide attempts, self harm and depression symptoms predict hostility subscale rate. CONCLUSION: Factors such as social isolation, mislearning, etc. were considered to cause increased feelings of hopelessness, suicide ideation, negative sense of self and feelings of hostility in convicts and arrestees staying indoors. PMID- 28360592 TI - The Effect of Sertraline on the Quality of Life for Children and Adolescents with Anxiety Disorder. AB - INTRODUCTION: In this study, we aimed to determine the changes in quality of life of children/adolescents with anxiety disorders during six months of sertraline treatment, to investigate parent-child/adolescent concordance in perception of quality of life and to examine the effect of treatment on children/adolescents. METHODS: In this study, 30 patients with anxiety disorders according to criteria specified in Diagnostic and Statistical Manual of Mental Disorders, 4th. Edition (DSM-IV) were assigned to sertraline treatment. The patients were evaluated using the Pediatric Quality of Life Inventory (PedsQL), State-Trait Anxiety Inventory for Children, Clinical Global Impression Scale (CGI) and the Children's Global Assessment Scale (CGAS) at 0th, 2nd and 6th months. RESULTS: PedsQL total scores increased significantly with the treatment in children and adolescents (p<.001), however, no differences were observed in parent proxy report (p=.326). The mean CGAS score was 59.85+/-7.73 at the beginning of treatment and 73.70+/-7.01 at the end of treatment (p<.001). The average CGI score decreased from 4.68+/-.96 to 2.27+/-.84. CONCLUSION: It was observed that perception of quality of life in children and adolescents with anxiety disorders increased with the treatment. PMID- 28360594 TI - Coping Strategies in Patients Who Had Suicide Attempts. AB - INTRODUCTION: The aim of this study was to investigate coping strategies suggested to be a determinant of suicide attempt and to compare them with coping strategies of healthy volunteers. METHODS: This study was conducted on 50 patients who had suicide attempts within the past two months and 52 healthy volunteers who did not have any suicide attempt. They were evaluated with the Turkish version of COPE inventory. The results were analyzed using SPSS version 15.0 for Windows. RESULTS: In the suicide attempt group, 'active coping', 'planning', 'positive reinterpretation and growth' scores were found to be lower than that in the control group. On the other hand, 'restraint coping', 'acceptance', 'focus on and venting of emotions', 'behavioral disengagement', 'substance use' and nonfunctional coping total points were significantly higher in the suicide attempt group. The patients with depression in the suicide group were found less of the 'positive reinterpretation and growth' but more of the 'substance use' compared to the healthy group. Subjects who attempted suicide more than once tended to 'substance use' rather than 'active coping'. 'Focus on and venting of emotions' scores in suicide attempters were higher in women than in males. CONCLUSION: We observed that individuals who attempted suicide have fewer functional coping strategies and more nonfunctional coping strategies than who do not attempt suicide. It was determined that under stressful situations, individuals with depression tended to alcohol and substance abuse instead of positive reinterpretation and growth. In subjects who had recurrent suicidal attempts, alcohol and substance abuse was more common than active coping. Women were using focusing on and venting of emotions techniques much more than men. We assume that to monitor, and in case of necessity, to change the coping strategies in suicide attempters are vitally important for preventing suicide attempts. PMID- 28360595 TI - Alterations of Lipid-Lipoprotein and Leptin in Bipolar Disorder Associated with Clinic Process. AB - INTRODUCTION: Obesity is more common among patients with bipolar disorder as compared to normal population. There are studies showing increased leptin levels in obese patients. The aim of the present study was to investigate the alterations in leptin levels, body mass index (BMI), and lipid-lipoprotein levels during manic period, as well as during euthymic period, after one month in patients with bipolar disorder. METHODS: Thirty-one adult patients, who had been hospitalized in the psychiatry clinic because of manic period of bipolar disorder, were included in the present study. Serum leptin and lipid-lipoprotein levels and BMI of the patients were analyzed both on the first day and 30th day of hospitalization after they became euthymic. RESULTS: Total cholesterol and triglyceride levels significantly increased in male patients (p<.05). The increase in total cholesterol and LDL-C levels was not significant in female patients (p=.066 and p=.056, respectively). BMI was significantly, but slightly increased in both genders (.56+/-.14 kg/m2), however, such a change was not observed in serum leptin levels. CONCLUSION: Results of the present study demonstrated that clinical improvement in bipolar patients showed different association in each gender with the alterations in BMI and serum lipid and/or lipoprotein levels. Such an alteration might have resulted from direct or indirect effect of drugs, as well as from lifestyle changes. PMID- 28360596 TI - Assessment of Relation Between Subjective Memory Complaints and Objective Cognitive Performance of Elderly Over 55 Years Old Age. AB - INTRODUCTION: This study investigated the frequency of forgetfulness in elderly individuals over 55 years of age and examined the association of subjective memory complaints (SMCs) with objective cognitive functions,, depression and other risk factors. METHODS: We recruited 405 patients over 55 years of age who were referred to Neurology, Cardiology, or Physical Therapy and Rehabilitation outpatient clinics. All subjects were questioned regarding forgetfulness and then were administered the Subjective Memory Complaint (SMC) Scale, Mini Mental Test (MMT), Verbal Fluency Test (VFT), Clock Drawing Test (CDT) and the Geriatric Depression Scale (GDS). Subjects with SMC were compared with those without SMC in terms of cognition, depression and some laboratory parameters. RESULTS: Of the patients, 42.5% complained of forgetfulness. None of these patients had been admitted to hospital for this complaint. Women and patients with low education had more forgetfulness as well as poorer results on the SMC Scale, MMT, VFT, and GDS. Patients with SMC had lower hemoglobin, ferritin and free T4 levels. Female gender and depression was found to be a risk factor for SMCs. CONCLUSION: SMCs are common in people over 55 years of age. Being a woman as well as depression was found to be a risk factor for SMC. Since depression is a treatable condition, these people should be assessed carefully in terms of depressive symptoms. Laboratory parameters, such as hemoglobin, ferritin and free T4 levels should be investigated in patients with SMC. Unlike the other cognitive tests, CDT performance is independent of subjective memory complaints. Elderly patients rarely visit hospital with complaint of SMC, therefore, clinicians should be watchful for this problem. PMID- 28360597 TI - Therapeutic Plasma Exchange in Neurologic Diseases: An Experience with 91 Patients in Seven Years. AB - INTRODUCTION: In this study, we report the results of our experience of therapeutic plasma exchange (TPE) for neuroimmunologic disorders performed at our hospital over a seven-year period. METHODS: We retrospectively reviewed the medical records of 91 patients (53 male, 38 female) who had been treated at our center with TPE. RESULTS: 60 patients with Guillain-Barre syndrome (GBS), 23 with myasthenia gravis (MG), 4 with chronic inflammatory demyelinating polyneuropathy (CIDP) and 1 patient each with polymyositis, septic encephalopathy, acute disseminated encephalomyelitis (ADEM) and Opsoclonus-Myoclonus syndrome (OMS) received TPE. 26.7% of GBS patient's made complete recovery, 61.7% had partial recovery and 11.7% patients died due to respiratory failure. Despite our best efforts and effective TPE treatments, 13.4% of MG patients deceased, however, 78% had full recovery. Three patients with CIDP were discharged with full and 1 patient with partial recovery. The patient with ADEM had partial recovery with TPE at first, but deceased 2 months later due to pneumonia-related respiratory insufficiency. While, patient with polymyositis had slight-partial recovery, we obtained full recovery with TPE in septic encephalopathy and OMS patients. The side effects and complications of treatments with TPE, which included hypotension, hypocalcaemia and anemia, were mild and manageable. CONCLUSION: The improvement rates were encouraging and we concluded that significant benefit can be achieved with TPE for the treatment of neuroimmunological disorders. PMID- 28360600 TI - A Case of Acute Psychosis Following Energy Drink Consumption. AB - Interest in energy drinks is increasing every day. Energy drink consumption is increasing proportionally. Users often utilize these drinks in order to enjoy, have fun and to increase performance and attention. However, consumption of the energy drinks sometimes may also cause adverse physical and psychological consequences. Unwanted physical results are in the more foreground, noticeable and visible but the data about psychological problems caused by energy drinks is accumulated over the years in the literature. In this case report, we describe the case of a young man with no psychiatric history who was hospitalized for psychotic symptoms following excessive consumption of energy drinks. PMID- 28360599 TI - Inflammatory Demyelinating Diseases of Childhood: Case Report and Literature Review. AB - Multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM) are demyelinating inflammatory diseases, considered to have a striking pathophysiological resemblance. However, due to the differences in both clinical course and clinical approaches, it is important to differentiate between the two conditions, to plan further investigations and therapy protocols. These diseases have similar but also distinct clinical, radiological and cerebrospinal fluid (CSF) findings. ADEM is typically a monophasic disease of children. MS occurs generally in adult age, but uncommonly may develop in childhood with variable features. Our case is a 14 year-old-girl, presented with a three-month history of left hemiparesis, followed by right hemiparesis, cerebellar signs, myelitis and cortical visual disturbances. Based on the clinical follow-up, MR and CSF findings, our patient was diagnosed with relapsing tumefactive multiple sclerosis. Steroid treatment was not significantly effective, however the patient has benefited from plasmapheresis clinically and radiologically. Our patient is still being followed under the disease modifying therapy without any relapse. PMID- 28360598 TI - Genetic Susceptibility to Multiple Sclerosis: The Role of FOXP3 Gene Polymorphism. AB - INTRODUCTION: It is well recognized that both genetic and environmental factors play an important role in the pathogenesis of multiple sclerosis (MS). Immune pathogenesis of MS focuses on pathogenic CD4+ T lymphocytes. CD4+CD25+ regulatory T cells have suppressive function in this cell group. FOXP3 (forkhead boxP3) transcription factor is a key structure in the development and function of regulatory cells. Functional alterations in FOXP3 gene expression have been observed in various autoimmune diseases. METHODS: We screened a non-synonymous coding single nucleotide polymorphism (exon +2710 C/T) (rs2232369) of human FOXP3 gene in 148 MS patients (118 with Relapsing Remitting MS, 30 with Secondary Progressive MS) and 102 age- and sex-matched healthy controls. The association of polymorphisms with susceptibility, and course of the disease was evaluated. RESULTS: We could not detect any single nucleotide polymorphism in MS patients, however, polymorphic allele was detected in 3% of the control group. Consequently, a genetic association between the FOXP3 gene polymorphism and MS was not revealed. CONCLUSION: The distribution of this polymorphism has not been screened in any other MS populations before. Although we could not succeed to find any association between susceptibility to MS and screened FOXP3 gene polymorphisms, we suggest that this particular polymorphism is not appropriate for these kind of studies in the future. PMID- 28360601 TI - Acute Motor Conduction Block Neuropathy: Another Distinct Variant of Guillain Barre Syndrome. AB - We describe a patient who developed progressive weakness in all limbs without sensory symptoms 4 weeks after upper respiratory system infection. Electrophysiological findings suggested a new variant of Guillain-Barre syndrome named "acute motor conduction block neuropathy". Electrophysiological studies were performed at admission, 12th and 28th weeks. At the 28th week, the clinical examination and electrophysiological findings showed complete recovery. PMID- 28360602 TI - A Case of ADEM Mimicking Cerebral Adrenoleukodystrophy Based on Supratentorial MRI Findings. AB - A 9-year-old male admitted for syncope also had the complains of pain and numbness in his legs and frequent falling down. There was a history of upper respiratory tract infection 10 days before. On neurologic examination, paraparesia and fall a sleep were identified. On magnetic resonance imaging, the symetric signal increases were seen in biparieto-occipital white matter intented to corpus callosum at T2-weighted sequences and cytotoxic edema was seen at diffusion-weighted images. Heterogeneous contrast enhancement was seen on these areas. In addition, at the C7-Th5 vertebrae levels, spinal cord had diffuse increased signal intensity and contrast enhancement. Acute disseminated encephalomyelitis was thought based on clinical and radiological findings. Steroid therapy was started. Significant improvement was shown after treatment. On 2-year follow-up, there was no recurrence. In conclusion, it must be kept in mind that acute disseminated encephalomyelitis can rarely present with biparieto occipital involvement which extends to corpus callosum and can mimic adrenoleukodystrophy. For the differential diagnosis butterfly glioma, tumefactive demyelinating lesions or multiple sclerosis should be considered. PMID- 28360603 TI - Cognitive Impairment in Patients with Multiple Sclerosis. PMID- 28360604 TI - Supranuclear Gaze Abnormality in Sporadic-Creutzfeldt Jacob Disease. PMID- 28360605 TI - Cluster-Like Headache Associated with Symptomatic Chiari Type 1 Malformation. PMID- 28360606 TI - Could Hemiplegia Vegetativa Alterna be a Cerebral Sign of Heart Valve Disease? PMID- 28360607 TI - Comorbidity of Adult Attention Deficit and Hyperactivity Disorder in Bipolar Patients: Prevalence, Sociodemographic and Clinical Correlates. AB - INTRODUCTION: The aims of this study were to determine the frequency of adult attention deficit and hyperactivity disorder (ADHD) comorbidity in bipolar patients and to investigate the influence of this comorbidity on the clinical characteristics of bipolar disorder (BD). METHOD: A total of 135 patients with BD type I and II and BD not otherwise specified were included in this study. First, the Adult ADD/ADHD DSM-IV-Based Diagnostic Screening and Rating Scale (ADHD scale) was administered to all patients, and all of the patients were also interviewed for the diagnosis. Patients who were diagnosed as having ADHD comorbidity (n=23) on the basis of DSM-IV and those who were not diagnosed to have ADHD comorbidity (n=32) were compared in terms of sociodemographic and clinical correlates. RESULTS: Twenty-three of 135 patients (17%) were found to have ADHD comorbidity. In the ADHD comorbidity group, the level of education and the number of suicide attempts were higher (p=.011 and .043, respectively). Although not significant, subthreshold depressive symptoms in interepisodic periods, the lifetime history of antidepressant use and the total number of lifetime depressive episodes tended to be more frequent in bipolar disorder with ADHD comorbidity group than in the control group. CONCLUSION: Bipolar disorder has a frequent comorbidity with ADHD, and contrary to expectations, it might be related to the depressive aspect, rather than the manic aspect, of bipolar disorder. Early diagnosis of ADHD comorbidity in bipolar patients might help to prevent serious risk factors. PMID- 28360608 TI - Does Illness Perception Predict Posttraumatic Stress Disorder in Patients with Myocardial Infarction? AB - INTRODUCTION: Myocardial infarction (MI) as a life-threatening event, carrying high risk of recurrence and chronic disabling complications, increases the risk of developing acute stress disorder (ASD), posttraumatic stress disorder (PTSD), or both. The aim of this study was to investigate the relationship between illness perceptions and having ASD, PTSD, or both in patients after MI. METHOD: Seventy-six patients diagnosed with acute MI were enrolled into our prospective study. We evaluated patients during the first week and six months after MI. Patients were assessed by using the Clinician Administered PTSD Scale (CAPS), the Hamilton Depression Rating Scale (HDRS), the Hamilton Anxiety Rating Scale (HARS), the Brief Illness Perception Questionnaire (BIPQ), and a semi-structured interview for socio-demographic characteristics during both the first and second evaluations. RESULTS: Acute stress disorder (ASD) developed in 9.2% of patients and PTSD developed in 11.9% of patients with MI. Illness perception factors of 'consequences, identity and concern' predicted the occurrence of both ASD and PTSD, whereas 'emotion' predicted only PTSD. CONCLUSION: The factors of illness perceptions predicted the induction of ASD and PTSD in patients who had acute MI. PMID- 28360609 TI - Coping with Stress and Body Image in Patients with Ankylosing Spondylitis. AB - INTRODUCTION: The aim of this study was to determine coping with stress and body image in patients with ankylosing spondylitis (AS) and to investigate the correlation between these two characteristics together and also between them and disease activity/functional capacity. METHOD: Fourty healthy controls and 40 patients with AS who were diagnosed on the basis of Modified New York Criteria were included in the study. The exclusion criteria were another medical disease or comorbid psychiatric disorder. All participants were administered the Coping Orientations to Problems Experienced (COPE) questionnaire in order to evaluate attitudes to coping with stress and the Multidimensional Body-Self Relations Questionnaire (MBSRQ) to evaluate body image. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) were used to evaluate AS patients' disease activities and functional capacities. RESULTS: There was no difference between the two groups in terms of COPE scores. The MBSRQ 'health evaluation' subscale scores were lower and the 'fitness orientation' scores higher in the AS group. The COPE active coping subscale had a weak, positive correlation with MBSRQ total score and a weak, negative correlation with BASFI score. MBRSQ total score had a moderate, negative correlation with BASFI score, and a weak, negative correlation with BASDAI score. CONCLUSION: The attitudes to coping with stress in AS patients with no accompanying medical disease or psychiatric disorder may not differ from that in healthy controls. Negative health evaluation and fitness orientation must be characteristics considered in psychotherapeutic interventions applied to these patients. In addition, psychotherapeutic interventions directed toward coping with stress and body image may be especially useful in active stages of the disease and in patients with limited functional capacity. PMID- 28360610 TI - Attachment Characteristics and Behavioral Problems in Children and Adolescents with Congenital Blindness. AB - INTRODUCTION: This study aimed to assess the behavioral problems and the attachment characteristics of children and adolescents with congenital blindness (CB). METHOD: Forty children and adolescents aged 11-14 years with CB were included as the case group. Forty healthy children and adolescents who were matched for age, gender, and socioeconomic status with the case group served as the comparison group. Behavioral problems were assessed by the Child Behavior Checklist for ages 4-18 (CBCL 4/18). Attachment characteristics were assessed via the Short Form of Inventory of Parent and Peer Attachment (s-IPPA). RESULTS: The case group had lower CBCL total problems scores as well as anxiety/depression, withdrawal/depression, and attention problems subscales scores with respect to the comparison group. There were no significant differences between the two groups in s-IPPA scores. CONCLUSION: Children and adolescents with CB did not differ from the comparison group in terms of attachment, whereas, they had lower scores on behavioral problems than the comparison group. Although previous studies indicate that children and adolescents with CB may be at the risk of insecure attachment, our study suggested that adaptive mechanisms of their families together with professional help from specialized teachers and services provided by schools for children and adolescents with CB may play compensatory roles. PMID- 28360611 TI - Association Between Internet Use and Sleep Problems in Adolescents. AB - INTRODUCTION: Sleep problems are commonly encountered in adolescents. It has been shown that electronic media have a negative influence on the sleep quality and daytime functioning in adolescents. This study aims to investigate the association between internet use and sleep problems in adolescents. METHOD: A total of 1212 adolescents were recruited to the study. Self-report study questionnaire included two main parts: Young's Internet Addiction Scale (IAS) and a semi-structured inquiry on sleep habits/problems. RESULTS: Of the study sample, 16% (n=198) reported their sleep quality as bad or very bad. One-fourth of the sample reported using internet everyday and 27% of them reported spending more than one hour when online. The mean IAS total score was 35.56+/-13.87. Adolescents with a higher IAS score reported getting to bed later in the night, needing more time to fall asleep and having an increased number of awakenings in the night than the adolescents with lower IAS score (p=.001). They were also found to have higher frequencies of several sleep problems including difficulty in initiating and sustaining sleep, difficulty in waking up and feelings of sleepiness in day. In addition, sleep quality of them was worse when compared to the adolescents with a lower IAS score (p=.001). CONCLUSION: Problematic sleep habits and sleep problems were found to be more frequent in adolescents with a higher IAS total score. Health care providers must be aware of the possible negative impact of excessive and uncontrolled internet use on adolescents' sleep habits. PMID- 28360612 TI - Body Image, Self-Esteem and Depressive Symptomatology in Women with Polycystic Ovary Syndrome. AB - INTRODUCTION: In the current study we aimed to determine body image, self-esteem and depressive symptomatology in women with Polycystic ovary syndrome (PCOS) and compare with healthy controls. METHOD: This study was conducted among the patients with untreated PCOS who admitted to the Outpatient Clinic of Gynecology and Obstetrics of Faculty of Medicine of Selcuk University. A total 83 consecutive women with PCOS met the criteria of present study were included in the study. Age matched healthy controls (n=64) were recruited from employees at Selcuk University Hospital. PCOS was defined according to Rotterdam criteria. After socio-demographic characteristics of the participants were recorded, Body Image Scale, Rosenberg Self-Esteem Scale and Beck Depression Inventory were completed by the participants. RESULTS: Patients with PCOS and healthy controls did not differ in some sociodemographic variables, including age, education and economic status (p>.05). Previous psychiatric history was more prevalent among the PCOS group (p<. 05). Body mass index (BMI) was <=25 kg/m2 in both groups. BMI values in the PCOS group were significantly higher than in the controls (p<.05). BDI scores were significantly higher in the PCOS group compared to that in the healthy controls (p<.05). There was no significant difference between the PCOS group and healthy controls in BIS and RSES scores (p>.05). CONCLUSION: The present study suggests that PCOS seems to be associated with depressive symptomatology. Furthermore, rising BMI values of these women may be an indicator for the onset of PCOS. However, these results should be confirmed by prospective studies. PMID- 28360613 TI - The Relationship of Childhood Abuse and Neglect with Suicide Attempts in an Adult Unipolar Depression Sample. AB - INTRODUCTION: Unipolar depression is an important psychiatric disorder that leads to an increased risk of suicide. However, not all depression patients attempt suicide. This reflects the presence of other factors that may be related to suicide other than the sole presence of psychopathology. Drawing upon the clinical evidence linking childhood abuse and neglect experiences with suicide; this study aimed at investigating the relationship of childhood abuse and neglect experiences with suicide attempts in patients with unipolar depression. METHOD: One hundred six unipolar depressed patients between the ages of 18 and 65 were included in the study. Patients with comorbid psychiatric disorders, neurological disorders, alcohol-substance abuse problems, and a Beck Depression Inventory (BDI) score of <17 were excluded from the study. The BDI, Childhood Trauma Questionnaire (CTQ-28), State-Trait Anger Expression Inventory (STAXI), and the Suicide Behavior Questionnaire (SBQ) were administered to all patients. Suicidal and non-suicidal cases were determined according to clinic interviews and the patients' responses in the SBQ. RESULTS: Sixty-four patients have previously attempted suicide. Although there was no significant difference between unipolar depression patients with a history of suicide attempts and patients with no history of suicide attempts in terms of average age, education and marital status, however, female/male ratio in the former group was determined to be significantly higher. BDI, STAXI continuous anger and outward anger average scores, and average CTQ-28 emotional abuse, physical abuse and total scores were significantly higher in the group with a history of suicide attempts. The predictors of suicide attempts were higher BDI and CTQ-28 physical abuse scores and female gender. The predictors for average SBQ scores were determined as higher BDI, CTQ-28 sexual abuse, and STAXI outward anger and continuous anger scores. CONCLUSION: Childhood physical and sexual abuse experiences are important factors in evaluating the presence of suicide attempts and risk of suicide in patients with unipolar depression. Careful questioning of traumatic childhood experiences during psychiatric examinations and monitoring of depression patients is crucial in determining treatment protocols and preventing suicide attempts. PMID- 28360614 TI - The Presence of Autoantibodies Against Vascular and Nervous Tissue in Sera From Patients with Neuro-Behcet's Disease. AB - INTRODUCTION: Behcet's disease is a chronic inflammatory disease of unknown aetiology that affects multiple organ systems. Since the diagnosis of this disease mainly relies on clinical criteria, a diagnostic laboratory test is required especially for neuro-Behcet's patients without systemic involvement. METHOD: In this study, we searched for the presence of autoantibodies against brain tissue, by means of indirect immunofluorescent staining technique in sera obtained from patients with neuro-Behcet's disease, based on reports that humoral immune dysregulation may play a role in susceptibility to Behcet's disease. After pre-absorbtion of sera with guinea pig liver powder to reduce nonspecific staining, serum samples were applied to mouse brain sections and immunoreactivity was detected with fluorescein (FITC)-conjugated goat antibody against human IgG. RESULTS: Ten sera from neuro-Behcet's patients and 10 age-matched control sera were screened for immunoreactivity. We detected specific immunoreactivity to both parenchymal and vascular brain structures in the patients' sera. Parenchymal vessel immunopositivity was detected in 8 of 10 patients, whereas only two of control sera showed no significant parenchymal vascular immunoreactivity (p=.025). In addition to vascular immunoreactivity, filamentous and reticular immunopositive structures were detected in brain sections of 5 out of 10 patients. No such immunoreactivity was detected in sections incubated with control sera (p=.016). CONCLUSION: We detected a specific immunoreactivity against vascular and parenchymal filamentous structures in neuro-Behcet patients' sera. Humoral autoimmunity may play a role in the pathogenesis of neuro-Behcet's disease in addition to cellular immune response. Findings of this preliminary study will be evaluated with a large number of patients and controls, to determine whether it is the cause or the result and, further studies are underway to disclose the nature of epitope to which the immunoreactivity was directed against and to develop a diagnostic laboratory method for investigating central nervous system involvement in Behcet's patients. PMID- 28360615 TI - If Neurologists Establish The Diagnosis of Primary Sjogren's Syndrome? AB - INTRODUCTION: Neurological involvements were shown in 20% of patients with Primary Sjogren's Syndrome (pSS). Neurological symptoms may be the first signs of pSS in 57% of the cases. In addition, early diagnosis and treatment of neurological disorders may save or improve the quality of life of these cases. There have been reports about the neurologic manifestations of pSS but little is known about the details of neurologically presented cases. METHOD: In this study, we described 11 pSS patients who presented with neurological manifestations. RESULTS: Central nervous system (CNS) involvement was recorded in 7 (63.7%) and peripheric nervous system (PNS) involvement in 4 cases (36.4%). CONCLUSION: Our findings regarding the cases with neurological manifestations leading to the diagnosis of pSS suggest that: 1) The frequency of CNS involvement was higher than that of PNS, and the most frequent clinical pictures of CNS involvement are Multiple Sclerosis (MS)-like illnesses and optic neuritis, 2) Guillain Barre Syndrome (GBS) was the most frequent disease of PNS involvement; 3) Mononeuropathy multiplex (MM) might be the first sign of pSS; 4) Neurologists should consider pSS in the differential diagnosis of cases with MS, optic neuritis, GBS and neuropathies of unknown causes including MM; 5) There is an urgent need of therapeutical guidelines for the cases with neurological involvement associated with pSS. PMID- 28360616 TI - The Effect of Vitamin D Treatment On Nerve Growth Factor (NGF) Release From Hippocampal Neurons. AB - INTRODUCTION: Vitamin D, the main function of which is thought to be the maintenance of calcium and phosphate homeostasis and bone structure, has been shown in recent studies to have important roles in brain development as well. A certain vitamin D receptor (VDR) gene haplotype was reported, for the first time by our group, to increase the risk of developing Alzheimer's disease. Our studies also showed that vitamin D prevents beta amyloid-induced calcium elevation and toxicity that target nerve growth factor (NGF) release in cortical neurons; beta amyloid suppresses VDR expression and the disruption of vitamin D-VDR pathway mimics beta amyloid-induced neurodegeneration. In this study, our aim was to investigate the effects of vitamin D on the NGF release from hippocampal neurons. METHOD: Primary hippocampal neuron cultures that were prepared from 18-day-old Sprague-Dawley rat embryos were treated with vitamin D for 48 hours. The alteration in the NGF release was determined with ELISA. Cytotoxicity tests were also performed for all groups. RESULTS: The NGF release in vitamin D-treated group was significantly higher than in untreated control group. The protective effect of vitamin D against cytotoxicity was also observed. CONCLUSION: Our results indicated that vitamin D regulates the release of NGF, a very important molecule for neuronal survival of hippocampal neurons as well as cortical neurons. PMID- 28360618 TI - Paliperidone: As a Possible Cause of Pericardial Effusion. AB - Paliperidone which is the active metabolite of risperidon is one of the novel antipsychotics. Controlled clinical studies proved its effectiveness on decreasing the positive and negative symptoms of schizophrenia. Some studies and case reports, reported its cardiovascular and cardiometabolic side effects. Cardiac tamponade, that may be mortal, wasn't reported as a side effect with paliperidone usage before. We present a 40 years old female with catatonic schizophrenia for eighteen years, whom was on 6 mg/day paliperidon for 3 years and presented with pericardial tamponade. We suggest that paliperdione may have cardiovascular and cardiometabolic side effects also in therapeutic doses. PMID- 28360617 TI - The Influence of Vitamin D Treatment on the Inducible Nitric Oxide Synthase (INOS) Expression in Primary Hippocampal Neurons. AB - INTRODUCTION: Neurodegeneration is a process that is characterized by the loss of neuronal structure and function and eventually ends with neuronal death. An elevated level of inducible nitric oxide synthase (iNOS) is suggested to accompany this process by inducing oxidative and nitrosative damage. Vitamin D is reported to protect glial cells against neurotoxicity via suppressing iNOS synthesis. Though there was no data about whether iNOS is regulated by vitamin D in hippocampal neurons. In this study our aim was to determine any alteration in iNOS expression of hippocampal neurons in response to vitamin D treatment. METHOD: Twenty four and 48 hours of vitamin D treatments were performed on primary hippocampal neuron cultures that were prepared from Sprague dawley rat embryos (E18). The alterations in the iNOS mRNA expression were determined with quantative real time polymerase chain reaction (qRT-PCR). The cytotoxicity levels of each group were investigated by the measurement of lactate dehydrogenase (LDH) that is released to culture medium. RESULTS: No difference was observed between groups in 24 hours of treatment regarding the iNOS expression. Though the iNOS mRNA level of vitamin D treated group was significantly lower than that of control group on the 48th hours of treatment (p<.001). Vitamin D treatment also attenuated the LDH release which is an indicator of cytotoxicity (p<.001). CONCLUSION: Our results indicated that vitamin D has the potential to prevent oxidative damage by suppressing iNOS expression. PMID- 28360619 TI - A Case of Carbonic Anhydrase Type 2 Deficiency Syndrome with Autistic Disorder. AB - Carbonic Anhydrase Type II Deficiency Syndrome (CADS) is a disease with an autosomal recessive inheritance that mainly includes characteristics of osteopetrosis, renal tubular acidosis and cerebral calcification. Pathological fractures, poor vision due to cranial nerve pressure, wide forehead, disproportionate mouth and jaw, physical and mental developmental delay are other features. In this paper, we present the case of a patient who was referred to our department with a diagnosis of CADS and diagnosed with autistic disorder after a psychiatric evaluation. We performed a detailed literature search, however, we did not find any report of co-existence of CADS (osteopetrosis intermediate type) and autistic disorder. PMID- 28360620 TI - Fibromuscular Dysplasia and Intravenous Thrombolytic Treatment. AB - Fibromuscular dysplasia (FMD), which usually affects middle-aged and older women, is a non-atheromatous and non-inflammatory angiopathy. Definitive diagnosis is made only by angiography showing classic string-of-beads appearance. In this article, we present a patient with acute ischemic stroke due to FMD who was successfully treated with thrombolytic therapy as well as to revise the approach to FMD in the light of the literature. PMID- 28360621 TI - Are the Comments on HaNDL Syndrome in the ICHD-II Sufficient? AB - A 33-year-old man was admitted to our emergency department for severe frontal headache followed by a state of consciousness disturbance and right-sided hemiparesis. No previous febrile disease, head trauma, vascular risk factor, and medication for any systemic disease were defined in his history. He had experienced a similar disorder three years ago and had recovered completely. Cerebrospinal fluid (CSF) analysis revealed pleocytosis and electroencephalography (EEG) showed diffuse slow wave activity. Hyperintense foci on T2 and FLAIR sequences representing bilateral cortical ischemia, prominent on the right hemisphere, were seen on MRI. Contrast-enhanced T1 images showed marked leptomeningeal thickening with enhancement. The patient was considered as having CSF lymphocytosis (HaNDL syndrome) due to temporary headache with neurologic deficit and CSF pleocytosis. Diagnostic criteria have been identified for this syndrome according to the International Classification of Headache Disorders, 2nd edition (ICHD-II). According to these criteria, neuroimaging should be normal. Positive neuroimaging findings and impairment of consciousness have been reported in a limited number of HaNDL cases so far. Diversity of neurological signs, duration and distinctness from migraine headache have been described in comment section under the diagnostic criteria. Comments are inadequate in this regard. PMID- 28360623 TI - He who Sleeps with a Blind Man Will Wake Up Cross-Eyed: Wernicke's Encephalopathy. PMID- 28360622 TI - Spontaneous Rupture of Intracranial Dermoid Cyst Mimicking a Primary Psychiatric Disorder. AB - We discussed the case of a 14-year-old patient with acute onset of psychiatric symptoms for two months who had been examined and different antipsychotic drugs had been prescribed by several psychiatrists without any neuroradiological imaging. Because of unresponsiveness to the antipsychotic drugs, computed tomography and magnetic resonance imaging were performed which revealed a ruptured intracranial dermoid cyst. The patient underwent surgery and antipsychotic medications were withdrawn in short time. The emphasis of this case is that intracranial lesions can present with neuropsychiatric symptoms and findings only without any neurological deficit or signs. PMID- 28360624 TI - Rheumatoid Arthritis, Depressive Symptoms and Inflammation. PMID- 28360625 TI - State of the Art Approach to the Classification of Epileptic Seizures and Epilepsies. AB - In the light of the latest knowledge acquired from clinical and laboratory research dealing with genetic, molecular biology and neuroimaging, existing classifications were successively revised by the International League Against Epilepsy (ILAE) in 2001, 2006, and 2010. In the latest classification established in 2010, proposals articulated radical changes in terms of concepts and definitions of the previously published classifications and put forward new classifications for epileptic seizures, epilepsies and electroclinical syndromes. This review refers to the changes of the new classification with their reasons and criticisms. PMID- 28360626 TI - A Comparison between School and Home Rating Scales and Reliability-Validity of the Scales-the Scales for Diagnosing Attention-Deficit/Hyperactivity Disorder. AB - INTRODUCTION: The purpose of the present research is to compare the Turkish translations of school and home versions of the Scales for Diagnosing Attention Deficit/Hyperactivity Disorder (SCALES) developed by Ryser and McConnell with respect to age and gender and to examine the correlation between the two scales. METHOD: The research was conducted with 102 teachers and parents of 891 children aged between 5.0 and 14.11 years. 656 scale forms of parents returned to us were included in the study. The teachers filled in teacher information form, child information form, SCALES-School Rating Scale and the Turkish version of Conners' Teacher Rating Scale. The parents filled in family information form, child information form and SCALES-Home Rating Scale and the Turkish version of the Conners' Home Rating Scale. RESULTS: When SCALES-Home Rating Scale and SCALES School Rating Scale scores of each age group were compared using t-test, it was observed that the difference in all sub-scale scores in the 5-9 age group was significant and it was also observed that in the 10-13 and 13+ age groups, the difference was significant only in the hyperactivity field. The correlation between SCALES-School Rating Scale and SCALES-Home Rating Scale was investigated. The correlation between sub-scales measuring the same abilities was found to be between 0.1 and 0.26. CONCLUSION: We assume that the Turkish version of the SCALES is a valid and reliable instrument for diagnosing ADHD. Since SCALES-Home Rating Scale scores were higher than SCALES-School Rating Scale scores and the correlation between the two scales was low, we assume that the objectivity of parents' ratings was limited. Future validity studies on diagnosed children are needed. PMID- 28360627 TI - The Effects of Prolactin-Raising and Prolactin-Sparing Antipsychotics on Prolactin Levels and Bone Mineral Density in Schizophrenic Patients. AB - INTRODUCTION: We aimed to investigate the effects of antipsychotics on prolactin levels in patients diagnosed with schizophrenia and the effects of hyperprolactinemia on bone mineral density (BMD) in patients on long-term antipsychotics. METHOD: In this study, we included eighty consecutive patients who were diagnosed with schizophrenia according to DSM-IV, had been using the same antipsychotic for the last ten months, and fulfilled the inclusion criteria. Data on sociodemographic characteristics of the patients were collected through an information sheet. The Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS) were used to rate positive and negative symptoms of the patients. In addition, their body mass indices (BMI) were calculated. Prolactin levels were measured through luminescence immune assay and BMD measurements were made at lumbar and femoral sites using dual-energy x-ray absorbtiometry. Haloperidol (n=20) and risperidone (n=20) were assigned to prolactin-raising antipsychotic group, and olanzapine (n=20) and quetiapine (n=20) were assigned to prolactin-sparing antipsychotic group for this study. The effects of antipsychotics on BMD were compared among these groups. RESULTS: Hyperprolactinemia was determined in 60% of haloperidol using patients, 90% of risperidone using patients, 25% of olanzapine using patients and 10% of quetiapine using patients. Mean prolactin levels were found to be significantly higher in prolactin-raising antipsychotic using group (p<0.001). There were no statistically significant differences in BMD values between the two groups, for the sites where the measurement was done. Lumbar spine and femoral neck T-scores and Z-scores in the prolactin-raising group significantly negatively correlated with the treatment durations and chlorpromazineequivalent doses (p<0.05). BMI and BMD values of both groups also displayed statistically significant positive correlations (p<0.05). CONCLUSION: The statistically significant differences in mean prolactin levels and numbers of patients with hyperprolactinemia between the treatment groups support the validity of classifying the antipsychotics as prolactin-raising and prolactin sparing". The relationship of BMD with the treatment duration and doses in the prolactin-raising antipsychotic using group was deemed to be important, since it indicated that a decrease in BMD was to be expected in long-term antipsychotic treatment. PMID- 28360628 TI - Association Between Age at Onset of Schizophrenia and Age at Menarche. AB - INTRODUCTION: Increasing evidence from clinical practice, as well as from epidemiological and basic research shows that there are gender differences in clinical features of schizophrenia, and this may be related to estrogens. There may be a relationship between earlier puberty and later onset of the disease, because of the protective effects of estrogens in women with schizophrenia. In this study, our aim was to analyze the correlation between age of menarche and age of onset of schizophrenia and to investigate the protective effects of estrogens in schizophrenia. METHOD: In this study, we included 289 patients who were diagnosed with schizophrenia. Those with mental deficiency or organic brain disorders were excluded from the study. All subjects were given a socio demographic form to determine their personal information, age at menarche, age at first odd behavior, age at onset of the disease and first hospitalization. Data on factors which may affect the association between age at onset of schizophrenia and age at menarche such as family history, head or birth trauma etc. were recorded on the information form. RESULTS: We found out that age at menarche was negatively associated with age at first odd behavior and age at first psychotic symptoms. CONCLUSION: Our study verifies the protective effects of estrogens and shows that the earlier puberty may be the cause of later onset of schizophrenia. A gender-sensitive approach in psychiatry improves our understanding of mental illness and our therapeutic strategies. PMID- 28360629 TI - Reliability and Validity of the Turkish Version of the Addiction Severity Index in Male Alcohol Dependents. AB - INTRODUCTION: We aimed to evaluate the psychometric characteristics of the Turkish translation of the Addiction Severity Index (ASI) in 115 male alcohol dependent patients. METHOD: The reliability of the instrument was assessed by measuring test-retest, interrater and internal reliabilities. In the validity analysis, the correlation coefficients between corresponding severity ratings and composite scores of each subscale and concurrent validity were assessed. Moreover, the discriminant validity and concurrent validity scores were calculated. RESULTS: The test-retest reliability of the ASI scores ranged from .79 to .91. The interrater reliability assigned by three raters was high (.74 to .99). Cronbach's alpha coefficient for internal consistency was .85 for all scales, and it varied between .64 and .77 for the subscales. The Beck Depression Inventory moderately correlated with the Psychatric status, and the MacAndrew Alcoholism Scale correlated with the Alcohol and Drug Use subscales of the Addiction Severity Index (ASI). The correlation coefficient was .91 for the alcohol use subscale. CONCLUSION: The results obtained in this study suggest that the Turkish version of the ASI could be used as a reliable and valid instrument in alcohol-dependent patients. PMID- 28360630 TI - Youth Sexual Health: Sexual Knowledge, Attitudes, and Behavior Among Students at a University in Turkey. AB - INTRODUCTION: To determine sexual attitudes, behavior, and knowledge of Namik Kemal University (NKU) students about sexual health and sexually transmitted infections (STIs). METHOD: A sample representing 10% of the undergraduate population of NKU in 2009-2010, was studied. Of 1,500 questionnaires distributed, 1,314 (87.6%) were filled out. RESULTS: The mean age of the respondents (52.9% male) was 20.07+/-1.75 years. The rate of students who had received sexual health education was 32.0%, and 15.3% had previously used a sexual health service. Eleven percent of the female students and 50.3% of the male students had had sexual intercourse. The average age of initial sexual intercourse was 16.83+/ 2.07 years. Of the students who had had sexual intercourse, 46.6% reported that they did not use any contraception method. The most preferred method was condoms (37.6%). The rate of contraceptive use was 58.7% in sexually educated students and 43.9% in those not educated (p=.004). The most well-known STI was AIDS (96.5%), with sexually educated students giving higher rates of correct answers about STIs (p<.05). CONCLUSION: The students who had received sexual health education were more knowledgeable about vital consequences of STI's, even though it is not sufficient, than sexually active students. Awareness of safe sexual practices and changes in behavior, in particular, promoting condom use should be established in higher risk youths. Deficiencies in knowledge could be addressed by adding a sexual healthtraining component to the university curriculum, and unmet requirements could be met by reorganizing medico-social centers in universities. PMID- 28360631 TI - Are Uric Acid Levels Different from Healthy Subjects in Bipolar Affective Disorder and Schizophrenia?: Relationship Between Clinical Improvement and Episode Severity in Male Patients. AB - INTRODUCTION: Purinergic system dysfunction has been shown both in patients with bipolar disorder (BD) and those with schizophrenia. The aim of this study was to evaluate whether uric acid levels in male BD patients with manic episode and schizophrenia patients with psychotic relapse differ from healthy male subjects. Secondly to assess whether uric acid levels in both patient groups correlate with episode severity and if a decrease in uric acid levels correlate with clinical improvement. METHOD: A total of 55 BD patients with manic episode and 59 schizophrenic patients with psychotic relapse were evaluated at baseline and at weeks 1, 2, 3 using the Young Mania Rating Scale (YMRS) and the Positive and Negative Syndrome Scale (PANSS), and their plasma uric acid levels were measured. 60 age-matched healthy males without history of any previous or current psychiatric diagnosis and treatment constituted the control group. In order to determine plasma uric acid levels, blood samples were centrifuged at 3000 * g for 15 minutes, stored at -80 degrees C and measured in milligrams per deciliter. RESULTS: Uric acid levels in both patient groups with manic episode and psychotic relapse were found higher than in healthy controls (f=6.122, p=.027). The difference between repeated measurements of uric acid levels in BD patient group was found to be between baseline and first week measurements (after Bonferroni correction) (p<.001). No correlation was found between YMRS and PANSS scores and uric acid levels at 4 assessment times. CONCLUSION: Uric acid levels in male BD and schizophrenia patients with manic episode and psychotic relapse were similar with each other, and higher than in healthy males. No correlation was found between uric acid levels and episode severity in both groups. However, for patients with BD, a decrease in uric acid levels between baseline and first week seems to be correlated with clinical improvement. PMID- 28360632 TI - Effects of Dimensional and Categorical Classification on the Clinical Manifestation of Major Depressive Disorder. AB - INTRODUCTION: The aim of this study was to combine the dimensional concept with the categorical system in major depressive disorder (MDD) to reduce the complexity of the diagnosis. Furthermore, it was aimed to match categorical and dimensional approaches in a clear and simple manner. METHOD: The study included a patient group of 131 consecutive outpatients diagnosed with MDD according to the DSM-IV diagnosis criteria, and a control group of 99 people that is matched with the patient group by gender, age and education level. All subjects completed the Beck Depression Inventory, the Beck Anxiety Inventory and the Toronto Alexithymia Scale (TAS). RESULTS: Cronbach's alpha values for the analysis of the internal consistency of the scale for the patients group, control group and the total participants were determined as .94-.97, .87-.92 and .93-.96, respectively. Nine factors were obtained from the results of exploratory factor analysis. According to the Scree-plot, it was decided that the two-factor structure represents best. Although depression and anxiety are two distinct dimensions, the relationship between them was found to be significantly significant. This was valid for both patient and control groups. When the relationship between the DSM-IV diagnosis criteria and all variables (depression and its sub-dimensions, anxiety and its sub-dimensions and the number of symptoms) was evaluated, the number of symptoms was found to be significantly related with all of the criteria. CONCLUSION: The number of symptoms and the severity of illness are found to be important in the clinical manifestation of MDD. The relationship of the severity of the illness with sleep and appetite seems weaker. While loss of interest was mainly predicting the disorder, weight changes, psychomotor changes, difficulty in concentration, fatigue, and worthlessness were determined not to be predictors of the manifestations. According to dimensional approach, somatic anxiety and deterioration in performance predict the presence of the disorder. According to categorical and dimensional approaches, some of the DSM-IV criteria (#2, #1, #9, #4, number of symptoms, severity of symptoms, somatic anxiety, performance deterioration) are seen to contribute to the matchability between the approaches. PMID- 28360633 TI - Comparison of Sexual Function and Hormonal Parameters Between Mood Stabilizer Treatment Modalities in Bipolar Disorder. AB - INTRODUCTION: The aim of this study was to determine the differences between lithium and atypical antipsychotics (quetiapine and olanzapine) with regard to their effects on sexual functions and hormonal variables and to assess the findings in term of gender differences, in patients with bipolar disorder. METHOD: 28 female and 29 male patients diagnosed as having bipolar disorder type I according to the DSM-IV, using lithium or quetiapine and quetiapine+lithium or olanzapine and olanzapine+lithium were evaluated consecutively. Being in remission period and given informed consent were set as inclusion criteria in these cases. Interviews with the patients were carried out using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and SKIP-TURK. Sexual functions and satisfaction were evaluated with the Arizona Sexual Experiences Scale (ASEX) and the Golombok Rust Inventory of Sexual Satisfaction (GRISS). Blood samples of the patients were taken in order to determine prolactin (PRL), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and free testosterone (T) levels. RESULTS: GRISS scores in male patients were higher than in female patients (p=.001). The number of manic, depressive and total episodes, and functionality levels were similar between the treatment groups, both in female and male patients. No differences were found between treatment modalities in terms of hormone levels both in female and male patients. Among females, ASEX scores of the patients treated with lithium monotherapy were less than the ones treated with quetiapine and olanzapine. Among patients with quetiapine monotherapy, GRISS scores in male patients were higher than in female patients. CONCLUSION: There are some evidences showing gender-based differences in the side effects of atypical antipsychotic drugs. Future studies with a specific focus on this topic are needed in order to have a better understanding of the basic mechanisms of gender differences. PMID- 28360634 TI - Triage of Patients in the Child and Adolescent Psychiatry Outpatient Clinic. AB - INTRODUCTION: The aim of this study was to evaluate and describe the three-stage triage method used in a child and adolescent psychiatry outpatient clinic. METHOD: The study investigated the new allocation process of 1482 children and adolescents who were assessed using this triage system for the duration of one year, in the year 2005. Data of 1423 children and adolescents who presented in 2003 regarding the waiting time for the first appointment and the rate of nonattendance at the first appointment were used for the comparison. In triage system, new patients presenting to the outpatient clinic in the morning four days a week were assessed by a three-stage procedure: An initial Strengths and Difficulties Questionnaire screening and a structured interview administered by an intern was then followed by a clinical interview. RESULTS: Of the 1482 children and adolescents who presented to the outpatient clinic during the study period, 1291 were given further appointments. Among patients who presented in 2005, the 207 non-attendant patients were significantly more likely to have longer waiting times than the 1084 attendant patients. When compared to year 2003, it was found that there was a significant decrease in the median waiting time for the first appointment and the rate of nonattendance at the first appointment among patients who presented in 2005. CONCLUSION: The triage procedure used in this study may constitute a model for developing countries with limited health care resources. PMID- 28360635 TI - Dissociative Experiences are Associated with Obsessive-Compulsive Symptoms in a Non-clinical Sample: A Latent Profile Analysis. AB - INTRODUCTION: There has been a burgeoning literature considering the significant associations between obsessive-compulsive symptoms and dissociative experiences. In this study, the relationsips between dissociative symtomotology and dimensions of obsessive-compulsive symptoms were examined in homogeneous sub-groups obtained with latent class algorithm in an undergraduate Turkish sample. METHOD: Latent profile analysis, a recently developed classification method based on latent class analysis, was applied to the Dissociative Experiences Scale (DES) item response data from 2976 undergraduates. Differences in severity of obsessive compulsive symptoms, anxiety and depression across groups were evaluated by running multinomial logistic regression analyses. Associations between latent class probabilities and psychological variables in terms of obsessive-compulsive sub-types, anxiety, and depression were assessed by computing Pearson's product moment correlation coefficients. RESULTS: The findings of the latent profile analysis supported further evidence for discontinuity model of dissociative experiences. The analysis empirically justified the distinction among three sub groups based on the DES items. A marked proportion of the sample (42%) was assigned to the high dissociative class. In the further analyses, all sub-types of obsessive-compulsive symptoms significantly differed across latent classes. Regarding the relationships between obsessive-compulsive symptoms and dissociative symptomatology, low dissociation appeared to be a buffering factor dealing with obsessive-compulsive symptoms; whereas high dissociation appeared to be significantly associated with high levels of obsessive-compulsive symptoms. CONCLUSION: It is concluded that the concept of dissociation can be best understood in a typological approach that dissociative symptomatology not only exacerbates obsessive-compulsive symptoms but also serves as an adaptive coping mechanism. PMID- 28360636 TI - Affective Temperament Profiles of Overactive Bladder Patients. AB - INTRODUCTION: Overactive bladder (OAB) is generally characterized by urinary urgency with or without incontinence and increased frequency of voiding and nocturia. Although animal studies have demonstrated the relationship between defective serotonergic neurotransmission and OAB, its etiology is still unclarified. Temperament profiles are hypothesized to be related with serotonergic activity and are studied in many psychosomatic disorders. Thus, we assume that OAB is related with a certain type of temperament. METHOD: 29 patients, who were admitted to the urology outpatient clinic at Kocaeli University and clinically diagnosed with OAB syndrome, were recruited for the study. Temperament profiles were evaluated with the Temperament Evaluation of Memphis Pisa Paris and San Diego Autoquestionnaire (TEMPS-A). Depressive, hyperthymic, cyclothymic, anxious and irritable temperament scores in patients were compared with those in 25 healthy controls. RESULTS: Patient and control groups were similar in terms of age (p=.65), sex (p=.64) and educational level (p=.90). Anxious temperament scores were higher (p=.02) and hyperthymic temperament scores were lower (p=.02) in patients with OAB compared to controls. Depressive, cyclothymic and irritable temperament scores were similar in both groups. There was no significant differences between men and women in both groups in terms of different temperament profile scores. CONCLUSION: Hypothetically, there might be an association between anxious temperament and OAB syndrome reflecting serotonergic dysfunction. However, OAB syndrome must be considered from the aspect of the interdependence of psychosomatic implications in a narrow sense and psychosomatic dimensions due to the psychological predisposition in the individual case. PMID- 28360637 TI - Relationship of Cognitive Functions with Daily Living Activities, Depression, Anxiety and Clinical Variables in Hospitalized Elderly Patients. AB - INTRODUCTION: Cognitive impairment in elderly patients, which may be a sign of dementia, depression, anxiety or medical diseases, has been determined as a risk factor for functional loss. In this study, we aimed to investigate the frequency of cognitive impairment and to investigate the relationship of cognitive status with sociodemographic variables, daily living activities, anxiety and depression in elderly inpatients. METHOD: The sample of this cross-sectional and descriptive study consists of 243 patients aged 65 years and older who were hospitalized in Bulent Ecevit University Hospital. A sociodemographic questionnaire,, the Mini Mental State Examination (MMSE), Activities of Daily Living Scale, Lawton-Brody Instrumental Daily Activities Scale, Geriatric Depression Scale (GDS) and the Beck Anxiety Inventory were used for data collection. RESULTS: One hundred and six (43.6%) patients were female and 137 (56.4%) were male. The patients were divided into two groups according to the Mini-Mental State Examination (MMSE) 23/24 cut-off score. The cognitive decline was statistically significantly more frequent in patients who were older, female, less educated, low socioeconomic status, and living in rural areas. There were more problems in the basic and instrumental activities of daily living and nutrition in patients with cognitive decline. Anxiety and depression scores were higher in this group. In our study, although the frequency of cognitive decline and depression according to GDS were 56% and 48%, respectively; we found that only 10.5% of patients applied to the psychiatrist, and 9.3% of patients received psychiatric treatment. CONCLUSION: Cognitive decline may cause deterioration in the daily living activities, nutrition and capacity for independent functioning. Older age, female, low education, low socioeconomic status and living in rural area are important risk factors for cognitive impairment. Cognitive decline in older age may be associated with depression and anxiety. We assume that when cognitive decline, depression and other psychiatric problems are unidentified, it may contribute to deterioration of mental health in medically ill elderly. PMID- 28360638 TI - Analysis of Suicide Notes: An experience in Eskisehir City. AB - INTRODUCTION: It is estimated that a million people around the world die by suicide each year. It has been reported that a note was left in 5%-43% of the suicides. In this study, it we aimed to evaluate and discuss suicide notes in our city which is situated in Western Anatolia and where several universities are located. METHOD: All forensic deaths in Eskisehir in 10-year period between 2001 and 2011 were evaluated. Forensic investigation files were assessed. After investigation, Out of 399 cases, 168 (42.1%) cases, who were determined to have left a suicide letter, telephone message (sms) or message via social network sites, were included in the scope of the study. RESULTS: It was found that 95 (56.5%) of all cases had left a suicide letter, 69 (41.1%) cases had sent a telephone message to a person or more than one person, 4 (2.4%) cases had written notes about suicide and death in social networking sites. CONCLUSION: A suicide note is an important finding in suicide cases to clarify the case. However, the note should be confirmed by investigation to be accepted as evidence. PMID- 28360639 TI - Two Cases of Excessive Internet Use with Comorbid Family Relationship Problems. AB - Although the internet is used effectively and beneficially in every aspect of life, several users have been experiencing some problems due to excessive and uncontrolled use. While the term "internet addiction" still remains controversial, disturbed family relationships are considered to be a diagnostic criterion. The use of the internet, even in non-excessive levels, is associated with disturbance in family and social life. As considering from systemic point of view; while family relationships may be disturbed with internet addiction, people who have problems with their family relationships also may use internet excessively. This case report is composed of both the cases with excessive internet usage and those who had problems in complying with the changes in their family systems following the decrease in duration of internet usage during the treatment process. PMID- 28360640 TI - Cases of Narcolepsy-Cataplexy Syndrome Following H1N1 Vaccination. AB - Narcolepsy-Cataplexy syndrome is a rare sleep disorder related with human leukocyte antigens (HLA-DQB1*0602) caused by the loss of hypothalamic hypocretin/orexin producing neurons. Recently, in European countries, Narcolepsy Cataplexy syndrome developing following H1N1 vaccination has attracted attention. Our first patient was a 9-year-old boy, who was referred to our clinic with the complaint of daytime sleepiness developed 1.5 month after H1N1 vaccination. After a couple of weeks, weakness of the upper extremities while laughing was added to the clinical picture. He also developed hypnopompic hallucinations and nightmares. Multiple sleep latency test (MSLT) following full-night polysomnography (PSG) showed that the mean sleep latency was 0.6 minutes; and all of the naps had sleep-onset REM periods. Our second patient was a 50 year-oldman, who presented to our clinic complaining of sleep paralysis and REM sleep behavior disorder developed 4 months after H1N1 vaccination. He developed daytime sleepiness 6 months after and cataplexy 8 months after H1N1 vaccination. He was also diagnosed as having Narcolepsy-Cataplexy syndrome upon PSG and MSLT. We investigated HLA-DRB1/ DQB1 locus with Polymerase Chain Reaction-Sequence Specific Primer technique. The first patient had HLA-DQB1*0602.47 and DQB1*03.01 heterozygous loci; and the second patient had HLA-DQB1*0602.47 and DQB1*02.01 heterozygous loci. These patients are the first reported cases of Narcolepsy Cataplexy syndrome related with H1N1 vaccination in Turkey. Although there is no specific marker, temporal relationship between vaccination and onset of disease symptoms suggests a possible causal relationship. In the presence of an underlying genetic predisposition, it was thought that H1N1 vaccination could trigger Narcolepsy-Cataplexy syndrome. PMID- 28360641 TI - Guillain-Barre Syndrome in a Patient with Primary Extranodal Intestinal Non Hodgkin's Lymphoma: Paraneoplastic, Drug Induced or Coincidental? AB - Neurological involvement is observed in 5%-25% of patients with lymphoma being either the first presentation of the disease or emerging during its course. However, Guillain-Barre syndrome is rarely reported. In this article, we present a case with intestinal lymphoma developing Guillain-Barre syndrome during the course of the disease. A 66-year-old male patient with primary extranodal intestinal lymphoma developed quadriparesis, sensory deficits and autonomic dysfunction while receiving chemotherapy. The findings of clinical, electrophysiological and laboratory examinations were consistent with Guillain Barre syndrome. Guillain-Barre syndrome can potentially be fatal and mimic chemotherapy-induced neurotoxicity, especially in patients with lymphoma, and therefore, must be considered in the differential diagnosis. PMID- 28360642 TI - Other Possible Methods in the Differential Diagnosis of Epileptic and Non Epileptic Seizures. PMID- 28360643 TI - Coexistence of Migraine Headache and Red Ear Syndrome. PMID- 28360644 TI - Paroxysmal Dystonia as the First Manifestation of Multiple Sclerosis with Internal Capsular Plaque. PMID- 28360645 TI - New Nightmare "Synthetic Cannabinoids". PMID- 28360646 TI - Social Cognition or Towards a Mental Psychology/Neurology as a Dialectical Synthesis of Faculty Psychology. PMID- 28360648 TI - Language Disorders due to Posterior System Strokes - An Ignored Dysfunction. AB - The anterior system is primarily responsible for the clinical picture in a patient that presents with clinical aphasia. However, recent reports have shown that injuries to posterior structures, the cerebellum in particular, may have a role in language processing. Herein, we will look first at the linguistic role of the cerebellum in light of the literature, then of the thalamus and some described clinical syndromes, and finally, specific syndromes resulting from occipital lobe lesions, all of which are supported by the posterior vascular system. The human brain is such a complex organization that in addition to the thalamus and occipital cortex, we can see the involvement of the cerebellum in high cognitive functions. Posterior system strokes may lead to clinical findings of cognitive deficits, including neurolinguistic components. Determining these defects in stroke patients may precipitate changes in current management strategies. PMID- 28360647 TI - Management of Behavioral and Psychological Symptoms of Dementia. AB - Symptoms of disturbed perception, thought content, mood, or behavior that frequently occur in patients with dementia are defined as the term "Behavioral and Psychological Symptoms of Dementia (BPSD)." The behavioral symptoms of dementia include physical/verbal aggression, agitation, disinhibition, restlessness, wandering, culturally inappropriate behaviors, sexual disinhibition, and hoarding, and the psychological symptoms of dementia are anxiety, depressive mood, hallucinations and delusions, apathy, and misidentification syndrome. With the cognitive decline in Alzheimer's Dementia (AD), the frequency of neuropsychiatric symptoms increases. Apathy, depression, irritability, agitation, and anxiety are the most frequently detected neuropsychiatric symptoms of AD. In the mild stage of AD, affective symptoms are more likely to occur; agitated and psychotic behaviors are frequent in patients with moderately impaired cognitive function. When neuropsychiatric symptoms are first detected, medical conditions, such as delirium, infection, dehydration, diarrhea, and drug interactions, must be ruled out. The treatment of mild BPSD must be started with psychosocial approaches, such as behavioral management, caregiver education, and physical activity. Medications are indicated for BPSD symptoms that are refractory to non-pharmacological interventions or severe or jeopardizing the safety of a patient or others, often in conjunction with non pharmacological interventions. PMID- 28360649 TI - Psychometric Properties of Difficulties of Working with Patients with Personality Disorders and Attitudes Towards Patients with Personality Disorders Scales. AB - INTRODUCTION: In this study, we aimed to develop two reliable and valid assessment instruments for investigating the level of difficulties mental health workers experience while working with patients with personality disorders and the attitudes they develop tt the patients. METHODS: The research was carried out based on the general screening model. The study sample consisted of 332 mental health workers in several mental health clinics of Turkey, with a certain amount of experience in working with personality disorders, who were selected with a random assignment method. In order to collect data, the Personal Information Questionnaire, Difficulty of Working with Personality Disorders Scale (PD-DWS), and Attitudes Towards Patients with Personality Disorders Scale (PD-APS), which are being examined for reliability and validity, were applied. To determine construct validity, the Adjective Check List, Maslach Burnout Inventory, and State and Trait Anxiety Inventory were used. Explanatory factor analysis was used for investigating the structural validity, and Cronbach alpha, Spearman-Brown, Guttman Split-Half reliability analyses were utilized to examine the reliability. Also, item reliability and validity computations were carried out by investigating the corrected item-total correlations and discriminative indexes of the items in the scales. RESULTS: For the PD-DWS KMO test, the value was .946; also, a significant difference was found for the Bartlett sphericity test (p<.001). The computed test-retest coefficient reliability was .702; the Cronbach alpha value of the total test score was .952. For PD-APS KMO, the value was .925; a significant difference was found in Bartlett sphericity test (p<.001); the computed reliability coefficient based on continuity was .806; and the Cronbach alpha value of the total test score was .913. Analyses on both scales were based on total scores. CONCLUSION: It was found that PD-DWS and PD-APS have good psychometric properties, measuring the structure that is being investigated, are compatible with other scales, have high levels of internal reliability between their items, and are consistent across time. Therefore, it was concluded that both scales are valid and reliable instruments. PMID- 28360650 TI - Depression, Anxiety, and Anger in Patients with Polycystic Ovary Syndrome. AB - INTRODUCTION: Polycystic Ovary Syndrome (PCOS) is a syndrome of heterogeneous nature, affecting multiple systems, particularly the endocrine system. We propose to investigate the possible relationships among hormonal changes, levels of anxiety, depression, and anger in patients with PCOS. METHOD: Forty-four female patients with PCOS and 44 body mass index (BMI )-matched healthy women participated in this study. We measured the sociodemographic features, some serum hormonal levels (insulin, gonadotropins, prolactin, dehydroepiandrosterone sulfate (DHEAS), thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), 17 OH-progesterone, and total and free testosterone), and some other biochemical parameters of the participants. Also, all participants completed the Trait Anger-Anger Expression Scale (STAS), Beck Depression, and Beck Anxiety Inventories. We evaluated the psychiatric scale scores obtained from PCOS patients and control subjects. We used the independent-samples t-test for parametric data to evaluate normal distribution, and Mann-Whitney U-test was used for both abnormally distributed and nonparametric data. We used Pearson correlation analysis to evaluate the potential connection between the two groups' data. RESULTS: The mean ages of the patients with PCOS and control subjects who participated in this study were 27.3+/-5.6 and 27.4+/-6.1 years, respectively. The measures of BMI, insulin, luteinizing hormone (LH), DHEAS, and total testosterone serum levels in the patient group were significantly higher than in the control group (p<.05). There was a statistically significant positive correlation between Beck anxiety scores and serum DHEAS levels (Pearson r=.4366, P=.0001). We found significant differences between the two groups in terms of trait anger, anger control, outward and inward anger, anxiety level, and depression scores (P<.05). CONCLUSION: Anxiety symptoms indicate a stronger relationship compared to depression with DHEAS serum levels via the autonomic nervous system, considering the gamma-aminobutyric acid (GABA)-antagonistic effect of DHEAS. Obesity, hirsutism, and infertility may reduce self-confidence and create depressive symptoms in patients with PCOS. In addition, changes in hormonal levels may lead to anxiety directly. Possibly, depressive symptoms are a secondary reflection of these changes. PMID- 28360651 TI - Neuropsychological and Clinical Profiles of Children and Adolescents Diagnosed with Childhood Obsessive Compulsive Disorder. AB - INTRODUCTION: The differential features of childhood-onset obsessive compulsive disorder (OCD) compared to adult-onset OCD are being more of a focus of attention in recent years. The aim of this study was to determine the clinical and neuropsychological profiles of children and adolescents diagnosed with childhood onset OCD and to investigate the association between the duration, severity, comorbidity, and family history of the disorder and clinical and neuropsychological functional impairments. METHODS: Thirty-five OCD patients (patient group) and 35 healthy control subjects (control group) between 8-15 years of age were included. To investigate the neuropsychological profiles, the Wisconsin Card Sorting Test (WCST), Stroop Test, and Continuous Performance Test (CPT) were applied. To assess the clinical and behavioral profiles, the Children's Depression Inventory (CDI), Conner's Parent Rating Scale (CPRS-48), and the Yale Brown Obsessive Compulsive Scale (YB-OCS) and Yale Global Tic Severity Rating Scale (YGTSRS) were given. RESULTS: Based on the performance in the WCST, Stroop Test, and SPT, the results of the study reveal that childhood onset OCD patients have statistically significant worse performance compared to healthy controls in terms of executive functions, sustained attention, and motor inhibition tasks. Excluding the comorbid diagnoses, childhood-onset OCD patients did not show a difference in behavioral problems, but they had higher levels of anxiety compared to healthy controls. CONCLUSION: The findings of this study reveal that independent of the duration, severity, comorbid problems, and anxiety levels, the disorder itself is associated with worse performance in executive functions, attention, and motor inhibition processes, and a positive family history of OCD is an important risk factor. Long-term follow-up studies with patients diagnosed with childhood-onset OCD would be a logical next step in order to determine the cause-effect relation between the disorder and cognitive impairments. PMID- 28360652 TI - Childhood Traumatic Experiences, Anxiety, and Depression Levels in Fibromyalgia and Rheumatoid Arthritis. AB - INTRODUCTION: The close relationship between chronic pain, anxiety, depression, and childhood traumatic experiences is well known. The aim of this study is to investigate childhood traumatic experiences, anxiety, and depression levels in patients with fibromyalgia and rheumatoid arthritis, which are diseases that cause chronic pain. METHOD: A total of 30 patients with fibromyalgia, 30 patients with rheumatoid arthritis, and 30 healthy controls, matched with patients with respect to gender, age, and education, were included in the study (90 participants in total). All participants were given a form for sociodemographic characteristics, the Childhood Trauma Questionnaire (CTQ), and Hospital Anxiety and Depression Scale (HAD). Patients were also asked to complete a numeric pain scale (NPS). RESULTS: Patients with fibromyalgia reported significantly higher scores for CTQ emotional abuse and HAD depression compared with healthy controls. Patients with fibromyalgia reported significantly higher scores for HAD anxiety than both healthy controls and patients with rheumatoid arthritis. Patients with rheumatoid arthritis reported significantly higher scores for CTQ emotional abuse and HAD depression compared with healthy controls. Pain scores of patients with fibromyalgia were higher than in patients with rheumatoid arthritis. Participants who had scores over the threshold on HAD anxiety and depression had significantly higher scores on CTQ sexual abuse. CONCLUSION: Both patients with fibromyalgia and patients with rheumatoid arthritis have high levels of childhood traumatic experiences and depression. Patients with pain-related disorders should be examined for childhood traumatic experiences, anxiety, and depression for better treatment outcomes. PMID- 28360653 TI - Alexithymia and Self-Esteem in Patients with Ankylosing Spondylitis. AB - INTRODUCTION: Ankylosing spondylitis (AS), which has an unknown etiology, inflammatory disorder, characterized by inflammation of the spinal joints and adjacent structures. It has a negatif effect on all aspects of a patients's life: Physcally, psychologically and socially. The purpose of this study was to determine the effect of AS on self-esteem and alexithymia. METHOD: In this study, 50 patients from the department of physical therapy and rehabilitation with the diaognosis of AS who were under traetment and follow-up and 50 healty volunteers who matched for age and gender were taken. Toronto Alexithymia Scale (TAS), Beck Depression Inventory (BDI), Rosenberg Self-Esteem Scale (RSES), Beck Anxiety Inventory (BAI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were performed to both patients and control group. RESULTS: Compared to the control group, the anxiety and depression scores were higher in the patient group and the alexithymic characteristics were significantly higher, self-esteem scores were significantly lower in the patient group (p<.05). CONCLUSION: Like all the other inflammatory chronic diseases, depression and anxiety are commonly seen in AS patients. Alexithymai and self-esteem of these patients should be considered carefully. More studies are needed on this regard. PMID- 28360655 TI - Comparison of Temperamental Features, Anxiety, and Depression Levels Between Non Cardiac Angina and Acute Coronary Syndrome. AB - INTRODUCTION: In many studies that are aimed to determine the psychological profile of patients admitted to the emergency unit with non-cardiac angina (NCA), it was indicated that psychiatric problems, less effective problem-solving, and alexithymia are more common in NCA compared with acute coronary syndrome (ACS) patients. In this study, aiming to find predictive psychological clinical features, we compared the temperament, anxiety, and depression scores of patients with NCA and ACS. METHODS: Sociodemographic variables of 63 patients (n=41 NCA, n=22 ACS) who were admitted to the emergency unit with chest pain were recorded. TEMPS-A scale was used for defining temperamental features, and Hospital Anxiety and Depression Scale (HADS) was used to measure anxiety and depression levels of patients in both groups. Sociodemographic variables and TEMPS-A and HADS scores were compared with chi2 and independent-groups t-test between the NCA and ACS groups. RESULTS: The NCA and ACS groups were similar in terms of sociodemographic variables. There was no statistical difference between groups in HDS (p=.12) and HAS (p=.39) scores and TEMPS-A scale depressive (p=.41), cyclothymic (p=.08), hyperthymic (p=.06), and anxious (p=.29) temperament scores. But, irritable temperament scores were significantly higher in the NCS group (p=.04). CONCLUSION: We believe that our findings will provide a basis for further studies in the diagnosis and treatment of NCA by contributing to the definition of NCA patients' psychological profiles. PMID- 28360654 TI - Development of a Psychometric Instrument Based on the Inference-Based Approach to Obsessive-Compulsive Disorder: The Obsessional Probabilistic Inference Scale. AB - INTRODUCTION: The current article addresses the validation of the construct of obsessional probabilistic inference in clinical and non-clinical samples. Obsessional probabilistic inference or obsessional doubt refers to a type of inferential process resulting in the belief that a state of affairs "maybe" causes development of a maladaptive cognitive coping style in terms of obsessing. METHODS: The latent structure of the Obsessional Probabilistic Inference Scale (OPIS) was evaluated with confirmatory factor analysis. RESULTS: Explanatory and confirmatory factor analyses indicated that a one-factor solution was satisfactory for the instrument, assessing a unidimensional psychological construct. The OPIS was shown to have high internal consistency in all samples, as well as temporal stability, relying on predominantly non-clinical individuals. The scale exhibited high convergent validity and successfully discriminated patients with obsessive-compulsive disorder from both depressive patients and controls. CONCLUSION: The findings replicated and extended the role of reasoning process in the development and maintenance of obsessive compulsive symptoms. The results are discussed in regard to assumptions of the inference-based approach to obsessive-compulsive disorder. PMID- 28360656 TI - Night Eating Syndrome in Major Depression and Anxiety Disorders. AB - INTRODUCTION: The purpose of this study is to investigate the prevalence and the clinical features of night eating syndrome (NES) in patients with depression and anxiety disorders. METHOD: The study was conducted at Bakirkoy State Hospital for Mental Health and Neurological Disorders. Three-hundred out-patients who had major depression (MD), panic disorders (PD), general anxiety disorders (GAD) and obsessive-compulsive disorders (OCD) participated in the study. The semi structured socio-demographic form, the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), Night Eating Questionnaire, and NES Evaluation Questionnaire were implemented. RESULTS: In our sample, the prevalence of the NES was 15.7% (n=47). NES frequency was significantly higher in the patients diagnosed with major depression (MD 22%, GAD 7.8%, OCD 12.5%, PD 14%). Smoking, presence of past suicide attempts, rates of antipsychotic drugs use, and average scores of body mass index (BMI) were significantly higher in the patients who had NES. In this sample, depression, BMI, and smoking were found to be determinants of NES. CONCLUSION: This study shows that NES may be frequently observed in patients admitted to psychiatric clinics, especially in those with major depression. Evaluation of NES in psychiatric patients may help the treatment of the primary psychopathology and prevent the adverse effects, like weight gain, which may reduce the quality of life. PMID- 28360657 TI - Role of CRP, TNF-a, and IGF-1 in Delirium Pathophysiology. AB - INTRODUCTION: Delirium is a common and life-threatening neuropsychiatric syndrome. Diagnosing delirium can be challenging, which increases mortality and mortality rates and health care costs. The biologic model of delirium is not definite yet, but evidence supports a cholinergic deficiency model. Delirium may be the result of processes and drugs that trespass a compromised blood-brain barrier. We aimed to evaluate the possible diagnostic utilization and the role of certain biomarkers, such as C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), and insulin like growth factor-1 (IGF-1), in delirium etiology. METHODS: A total of 93 inpatients that planned to undergo cardiovascular surgery were informed; 35 of them completed the study. Medical history and current cognitive status were evaluated pre-operatively. Participants were followed using Delirium Rating Scale-Revised-98 Turkish (DRS-R98-T) for delirium symptoms, and blood samples were collected post-operatively. RESULTS: Delirium was developed more in participants who had worse pre-operative cognitive status. Also, low pre operative IGF-1 levels were detected in the delirium group. Pre-operative CRP and TNF-alpha levels were not different between groups. CONCLUSION: Low IGF-1 levels can be used to predict delirium after surgery. However, the complex nature of cytokines and delirium itself make it difficult to utilize cytokines to predict delirium instead of psychometric tools. PMID- 28360658 TI - Clinical Characteristics and Response to Long-Term Botulinum Toxin Type A Therapy in Patients with Cervical Dystonia at a Neurology Clinic. AB - INTRODUCTION: To determine the demographic and clinical characteristics and response to botulinum toxin type A (BoNT-A) therapy in patients with cervical dystonia (CD). METHOD: A retrospective analysis of the detailed medical records of the patients with CD, followed up at our Botulinum Toxin Outpatient Clinic from 1998 to 2012, was performed. The treatment data were compared between the patients with primary CD and those with secondary CD; between patients receiving BoNT-A treatment for more than 5 years and less than five years, and between first applications and last applications. RESULTS: Fifty-seven patients (56.15% women) with CD were included in this study. The mean age was 41.01+/-13.42 years, the mean age at symptom onset was 32.93+/-15.45 years, and the mean dystonia duration was 8.10+/-8.5 years. The interval between onset of symptom and first BoNT-A treatment was 5.94+/-9.06 years, the duration of BoNT-A treatment was 36.13+/-29.17 months, and the number of applications was 8.48+/-6.23 in 45 patients with CD who were under treatment with BoNT-A for more than 1 year and had received at least three injections before. There was no difference between the patients with primary and secondary CD in terms of treatment results. The injection interval of the patients receiving BoNT-A treatment for more than 5 years and less than 5 years was 18.37+/-5.10 and 14.43+/-2.36 weeks, respectively (p=.001). There were no differences in the other treatment values. The mean doses were 559.00+/-147.60 vs. 681.66+/-188.09 units (p=.0001), the durations of improvement were 11.82+/-2.71 vs. 13.00+/-4.00 weeks (p=.014), the response scores were 2.71+/-.3 vs. 3.02+/-.5 (p=.002), the response ratings were 64.66%+/ 16.18 vs. 71.22%+/-17.29 (p=.001), and the numbers of muscles applied were 3.15+/ 1.16 vs. 3.51+/-0.99 (p=.012) in the first and last applications, respectively. CONCLUSION: There were no differences between the response of the patients with primary and secondary CD. Our results showed a statistically significant increase in the mean dose of BoNT-A, the response rating, the number of muscles applied, the duration of improvement, and the injection interval over time. PMID- 28360659 TI - Relation between Olfactory Dysfunction and Episodic Verbal Memory in Early Parkinson's Disease. AB - INTRODUCTION: Olfactory dysfunction is an early and common symptom in idiopathic Parkinson's disease (IPD). Recently, the relation between olfactory dysfunction and cognitive loss in IPD has been reported. In our study, we aimed to investigate the relation between olfactory dysfunction and cognitive impairments in early IPD related with this theory. METHODS: In this study, we included 28 patients with stage 1 and stage 2 IPD according to the Hoehn-Yahr (H-Y) scale and 19 healthy participants. The University of Pennsylvania Smell Identification Test (UPSIT) was performed for evaluating olfactory function. For cognitive investigation in participants, the clock drawing test, Stroop test, verbal fluency test, Benton face recognition test (BFR), Benton line judgment orientation test (BLO), and Auditory Verbal Learning Test (AVLT) were performed. RESULTS: We found significantly lower UPSIT scores in the patient group compared to controls (p=.018). In the neuropsychological investigation, only Stroop test and BLOT test scores were significantly lower in the patient group compared to controls (p=.003, p=.002, respectively). We found a negative correlation between UPSIT scores and Stroop time (p=.033) and Stroop error (p=.037) and a positive correlation between UPSIT scores and SBST long-term memory scores (p=.016) in patients. CONCLUSION: In our study, we found mild cognitive impairment related with visuospatial and executive functions in early-stage IPD compared to controls. But, in the patient group, we detected a different impairment pattern of memory and frontal functions that correlated with hyposmia. This different pattern might be indicating a subgroup of IPD characterized by low performance in episodic verbal memory, with accompanying olfactory dysfunction in the early stage. PMID- 28360661 TI - Idiopathic Hypoparathyroidism (IHP) Presenting as "Schizophrenia:" A Case Report. AB - Idiopathic hypoparathyroidism (IHP) with the onset of psychosis is a rare case in the psychiatric clinic. In this case report, we summarize the three facets of IHP, which contains the clinical, biochemical, and radiological features. Besides, the differential diagnosis of this case is supposed to be a highlight that IHP could have the main complaints of psychotic symptoms and featured signs on neuroimaging manifestation. PMID- 28360660 TI - The Relationship of Serum S100B Levels with Infarction Size and Clinical Outcome in Acute Ischemic Stroke Patients. AB - INTRODUCTION: S100B protein, which helps nerve development and differentiation, is produced by astrocytes and can be detected in peripheral circulation after brain damage. In this study, we aimed to investigate the relationship between the serum S100B protein level and the infarction volume and clinical outcome and also the early prognostic role of serum S100B protein in patients with ischemic stroke. METHOD: Fifty patients admitted in the first 24-hour period of acute ischemic stroke were evaluated prospectively, and the findings were compared to those of the controls (n=26). S100B levels of the patients and neurological findings on days 1, 3, and 5 and their functional outcomes on the discharge day and at the first month were recorded by the same examiner. RESULTS: S100B levels were not affected by sex, age, or concomitant systemic diseases. The maximum levels of S100B were recorded on the 3rd day, and there was a correlation between infarct size and S100B levels. No correlation between the severity of stroke and S100B level was found. There was a poor correlation between the functional outcomes of the patients at the 1st month and S100B levels and on the 3rd day. CONCLUSION: The detection of high S100B levels in peripheral circulation after acute ischemic stroke and the correlations of S100B levels with infarct size (good) and disability (poor) imply that S100B protein may be used as a peripheral marker in acute ischemic stroke patients. PMID- 28360662 TI - A Case of Risperidone Induced Stuttering as a Paradox. AB - The main feature of stuttering is the disturbance in terms of both timing and fluency of speech inappropriate with the age. This disturbance is characterized with the repetition and prolongation of sounds and syllables. There are two types of stuttering as acquired and developmental. Acquired stuttering may begin suddenly at any age and may be seen rarely due to the adverse effects of drugs. Stuttering induced by antipsychotics may develop very rarely. Risperidone is a strong antagonist of dopamin 2 (D2) and serotonin 2A (5 HT2A) and shows a high affinity for alpha1 and alpha2 noradrenaline receptors. It's used in a wide spectrum including psychotic disorders, mood disorders, and behavioral disorders, even for the treatment of stuttering. Risperidone treats the symptoms of stuttering by the antagonism of D2 receptors with an increase in striatal metabolism. In literature, we haven't observed any other case reports except the two stuttering cases with psychotic disorders due to the short term and high-dose risperidone treatment. In our case, stuttering adverse effect of chronic low-dose risperidone treatment is remarkable that is discussed for the first time. As well as the use of risperidone for the treatment of stuttering, stuttering adverse effect seems to be interesting as a paradox. PMID- 28360663 TI - Remission of Episodic Sweating Attacks and Comorbid Depression in Shapiro Syndrome: Case Report. AB - Shapiro syndrome, a rare disorder originally described by Shapiro and Plum in 1967, is characterized by episodic hypothermia and hyperhydrosis associated with agenesis of the corpus callosum. Proposed hypotheses to explain the clinical features of this syndrome include changes in the set point of the hypothalamic thermostat, increased norepinephrine (NE) release, and decreased plasma NE clearance. It was emphasized that the recognition of Shapiro syndrome in the evaluation of episodic hyperhydrosis is important. Here, we described a case with Shapiro syndrome who presented to our psychiatry clinic with recurrent episodic profuse sweating and depression. Sweating attacks and depression remitted after successful treatment with amitriptyline. PMID- 28360664 TI - A Case of Cortical Multiple Sclerosis. PMID- 28360665 TI - An Unusual Case of Corticobasal Syndrome. PMID- 28360666 TI - Recovery as a Process in Severe Mental Illnesses. PMID- 28360667 TI - Attentional Bias and Training in Social Anxiety Disorder. AB - Cognitive behavioral therapy (CBT) is one of the most effective treatment modalities for social anxiety disorder (SAD), showing a high level of clinical evidence supporting its effectiveness. On the other hand, lack of the desired benefit from this treatment in some patients causes continuation of the search for new techniques. Recent research studies have focused on attentional bias and attention training in SAD. Attention processes in SAD have been a major target of interest and investigation since the introduction of the first cognitive models explaining SAD. In the first model, it was highlighted that attention was self focused. The relationship between threatening stimuli and attention was considered in the subsequent models. Attentional bias towards threat may take place in several ways, such as facilitated processing of threat, difficulty in disengaging attention from the threat and avoidance of attention from the threat. After these descriptions regarding the phenomenology of the disorder, treatments to modify attention, processes were developed. In spite of conflicting results, investigations on attentional training are promising. Attention processes, attentional bias and attentional training in SAD are discussed in this review. PMID- 28360669 TI - Evaluation of Early Postoperative Neurological Complications Following Living Donor Liver Transplantation. AB - INTRODUCTION: Liver transplantation is one of the best treatment options for end stage liver disease. In Turkey, living donor liver transplantation (LDLT) is performed more frequently than cadaveric transplantation, because organ donation is unpopular in our country. Neurological complications contribute to poor postoperative outcomes after liver transplantation. In the present study, we aimed to evaluate the outcomes of LDLT patients in whom such complications developed early during postoperative follow-up in the intensive care unit. METHODS: Of 217 LDLTs performed between August 2011 and August 2012, neurology consultations were arranged for 29 patients (13.36%) because of development of new-onset neurological symptoms and/or findings in patients with neurologically uneventful preoperative histories. We retrospectively collected data on age, gender, primary disease, Model for End-Stage Liver Disease (MELD) score, and postoperative hospitalization duration of those who survived. The indications for neurological consultation and diagnoses were categorized into acute confusion/encephalopathy, epileptic seizures, leukoencephalopathy, and focal neurological deficits. The immunosuppressive treatment regimens prescribed were also considered. The outcomes of the 2 groups (with and without neurological complications) were compared. RESULTS: The mean patient age was 44.52+/-16.24 years, and males predominated (65.5%, n=19). Acute confusion/encephalopathy was the most frequent complication (62.1%, n=18), followed by epileptic seizures (27.6%, n=8), cerebrovascular disease (6.9%, n=2), and leukoencephalopathy (3.4%, n=1). Statistically significant between-group differences in age (44.5+/-16.2 vs. 34.33+/-20.98 years; p<0.001), and proportions of patients with a disease of viral etiology (55.17% vs. 35.63%, p<0.05), were evident. Mortality was significantly higher in the group with neurological complications (65.5% vs. 37.32%, p<0.05). The duration of postoperative hospitalization was also significantly longer in this group (29.80+/-15.04 vs. 10.00+/-5.47 days; p<0.05). CONCLUSION: Mortality was significantly higher and the duration of postoperative hospitalization significantly longer in LDLT patients with new-onset neurological complications than in those without such complications. PMID- 28360668 TI - The Relationship between Childhood Maltreatment and Emotional Dysregulation in Self Mutilation: An Investigation among Substance Dependent Patients. AB - INTRODUCTION: The present study aims to examine the role of emotion dysregulation and childhood maltreatment in self mutilation (SM) of substance dependent patients. Specifically, the present study examined whether emotion dysregulation and its dimensions, and childhood maltreatment and its dimensions were associated with SM. The relationship between emotion dysregulation and childhood maltreatment was also investigated. METHODS: The sample of study consisted of 55 alcohol dependent and 24 opiate dependent patients (n=79). Substance dependence was diagnosed by means of the Structured Clinical Interview for DSM-IV-TR (SCID I), Turkish version. Childhood Trauma Questionnaire (CTQ) and Difficulties in Emotion Regulation Scale (DERS) were used. RESULTS: Findings indicated that substance dependents with SM and without SM were differentiated in terms of overall emotion dysregulation. Results also suggest the relevance of three specific dimensions of emotion dysregulation to SM: Difficulties engaging in goal directed behaviors when experiencing negative emotions, difficulties controlling impulsive behaviors when experiencing negative emotions, and limited access to effective emotion regulation strategies. These dimensions were predicted from childhood emotional maltreatment and neglect. It is also revealed that substance dependents with SM had higher points than those without SM on emotional childhood maltreatment and neglect, physical childhood maltreatment. CONCLUSION: Results were supported by the literature suggested that self-mutilation functions as a emotional regulation strategy. Findings also suggested that self- mutilation is related to early relationships take place in family environment in which individuals grow up. PMID- 28360670 TI - Effects of Parental Attitudes Among a Group of High School Students in Istanbul. AB - INTRODUCTION: Current study aimed to investigate the possible relations between parental attitudes and depression in a sample of mid-pubertal, high-school students under the light of several sociodemographic variables. METHODS: With the permission of Ministry of National Education, a total of 391 students from second and third grades in a state high school and occupational high school in Sisli area included in the study. Sociodemographic Questionnaire, The Parental Bonding Instrument (PBI), and Beck Depression Inventory (BDI) were administered. RESULTS: Among the students in the sample, 25.6% (n=100) had significantly higher depression scores and girls had significanltly higher mean BDI scores than boys (p=0.001) reflecting the presence of depression. Adolescents with depression also had higher scores of maternal protection than adolescents without depression (p=0.02). On the other hand, adolescents with depression had lower scores of both maternal and paternal interest than adolescents without depression (p=0.02 and p=0.03, respectively). We also found that boys had higher levels of nicotine - alcohol and substance abuse where girls had higher levels for suicidal attempts and self harming behaviors (p<0.05). CONCLUSION: Depression onset was found to be associated with parental attitude which does not promote autonomy and independency. Warm, accepting and concerned parental attitude that promotes secure attachment was found to be protective against depression. Parental attitudes must be of concern when working with adolescents and dealing with the problems seen in this vulnerable phase of the life. PMID- 28360672 TI - Substance and Alcohol use in Young Adults in Turkey as Indicated by the CAGE Questionnaire and Drinking Frequency. AB - INTRODUCTION: The purpose of this study was to determine drinking problems and to analyze the socio-demographic factors associated with problematic alcohol use in young adults. METHODS: The study included 262 students who were surveyed for substance use problems in a postgraduate program using the Cut down, Annoyed, Guilty, Eye opener (CAGE) Questionnaire. The relationships between socio demographic variables and alcohol use were assessed using both univariate and multivariate analyses. RESULTS: Of the whole sample, 56.11% reported that they had tried drinking alcohol and 1.91% had tried cannabis. The prevalence of problematic alcohol use was 15.3% and 29.7% according to CAGE1+ and past-year drinking frequency, respectively. Alcohol use by mothers was an important differentiating factor for alcohol use by their daughters. Graduating from a university located in the Eastern/Southeastern Anatolia regions, graduating from a private high school, and having average academic performance levels were determinants of problematic alcohol use according to CAGE1+ and frequency of drinking. CONCLUSION: This study suggests there is need for early intervention to prevent exposure to the risk factors for problematic alcohol use in young adults, emphasizing that probable presence of an alcohol use disorder and high frequency of drinking are related to socio-demographic factors (high school type, geographical location of the university, and family structure). PMID- 28360671 TI - Neuropathy and Dysautonomia in Patients with Obstructive Sleep Apnea Syndrome. AB - INTRODUCTION: The aim of our study is to search for the existence of neuropathy, dysautonomia and to identify the correlations of sickness level of patients with Obstructive Sleep Apnea Syndrome (OSAS). METHODS: The research is based on the real cases at Dokuz Eylul University of Medicine Sleep and Epilepsy Center, observed during September 2008-May 2009. The patients were selected by polysomnography samples based on 20 persons at same ages with following criteria; high leveled OSAS (AHI>=30), low OSAS (5<=AHI<30) and healthy participants. Classical ENMG protocol, symphatic skin response and R-R interval variation test were performed on these samples. RESULTS: High and low leveled OSAS patients had a statistically significant (p<0.05) decrease in the average velocity of motor conduction in right tibialis posterior when compared to the control group. Besides we observed an statistically significant (p<0.05) increase in the average amplitud of symphatic skin responses in high leveled OSAS patients than control group. CONCLUSION: OSAS indicates a risk of possible peripheral neuropathy and autonomic dysfunction risk increases in positive correlation with level of OSAS. PMID- 28360673 TI - The Relationships Between Dissociation, Attention, and Memory Dysfunction. AB - INTRODUCTION: Dissociation is a disruption in the integrated functions of consciousness, memory, identity, and perception. Dissociative symptoms include derealization/depersonalization, absorption, and amnesia. These experiences can cause a loss of control over mental processes, including memory and attention. In literature, there is a paucity of research concerning the relationships between dissociation and memory performance. In this study, our aim was to investigate the relationships between dissociative experiences, attention, and memory performance in a non-clinical community sample. METHODS: In this study, we examined the relationship between dissociation and cognitive dysfunction among 60 healthy volunteers. We administered the Wechsler Memory Scale-Revised, Auditory Verbal Learning Test, Stroop Color Word Interference Test, and Dissociative Experience Scale. Here we examined the relationships between the subtypes of dissociation and memory performance as assessed by neuropsychological tests. RESULTS: We found that verbal memory was negatively associated with dissociative experiences. Pathological dissociation, particularly amnesia and depersonalization/derealization, was reversely linked to general memory performance and long-term memory. Moreover, low dissociators reported higher scores on verbal memory, general memory performance, and long-term memory but lower scores on recognition than high dissociators. CONCLUSION: The results of our study suggested that there are significant linkages between dissociative experiences and memory performance. PMID- 28360675 TI - Validity and Reliability of the Seizure Self-Efficacy Scale for Children with Epilepsy. AB - INTRODUCTION: This study aims to adapt the Seizure Self-Efficacy Scale for Children (SSES-C) into Turkish and then assess its validity and reliability in children with epilepsy. METHODS: The study sample consisted of 166 children (aged 9-17 years) with epilepsy who attended of Akdeniz University Hospital, Antalya Training and Research Hospital, and Bursa Dortcelik Children's Hospital Pediatric Neurology Clinics between July 2012 and March 2013. All research data were collected by a researcher in face-to-face interviews using Child Information Form, Seizure Self-Efficacy Scale for Children and Children's Depression Scale. The Seizure Self-Efficacy Scale for Children is a 15-item, 5-point Likert scale designed by Caplin et al. (2002). RESULTS: The linguistic adaptation and validation of the scale was conducted by seven experts. To evaluate the content validity of the scale, we elicited judgments from a panel of 10 content experts. The expert judgments showed that the correlation between the items on the scale was fairly good (Kendall's W=0.411, p<0.001, ki-kare: 57.495). Load factor of 40% and a large factor analysis included analysis of substances and two factors accounting for 49.67% of the total variance explained. We calculated Cronbach's alpha coefficient for the internal consistency and the full-scale score showed good internal consistency (alpha 0.89). Within the context of reliability studies, it was found correlations varying between 0,98-0,74 for the two sub factors of the scale. Test/retest correlation coefficients were significant (p<0,01) and high (r=0.99). In parallel forms reliability, the correlations between the Seizure Self-Efficacy Scale for Children and Children's Depression Rating Scale were found to be negative, moderate and statistically significant (r=-0.58, p<0.001). CONCLUSION: The measurements conducted on the Turkish version of the Seizure Self-Efficacy Scale for Children showed that it is consistent with the original scale, valid and reliable for Turkish society. PMID- 28360674 TI - Psychological Symptoms in Obesity and Related Factors. AB - INTRODUCTION: This study aimed to investigate the relationship between levels of depression and anxiety symptoms and quality of life, self-esteem in obesity. METHODS: Fifty-two subjects whose Body Mass Index (BMI) is 30 kg/m2 and over and 43 control whose BMI is normal were recruited for this study. The socio demographic data form, Hamilton Depression Rating Scale (HAM-D17), Hamilton Anxiety Rating Scale (HAM-A), Quality of Life Scale Short Form (WHOQOL-Brief-TR), Coopersmith Self Esteem Scale (CSES), The Eating Attitudes (EAT), were applied to the participants. RESULTS: In this study most of the patients are women, married, postgraduated and live in urban areas. It was determined to scores of HAM-D17, HAM-A and EAT are higher in obese group than control group; WHOQOL-Brief-TR physical field scores was lower in obese group than control group. CSES scores wasn't difference between obese and control group. In obese group, there was HAM D17 and HAM-A scores a negative correlation between quality of life physical field score, negative correlation between CSES score, positive correlation between EAT scale score. There is no correlation between scores of HAM-D17 and HAM-A and BMI. CONCLUSION: Our results suggest that depressive and anxiety levels are high in induvidual with obesity. They have problems in eating attitudes and their quality of life especially physical field is poor. The psychological symptoms have negative effects on the quality of life, self-esteem, and eating attitudes. Our results suggest that psychiatric support to improving positive effects quality of life and self-esteem in individual with obesity. PMID- 28360676 TI - Relationship between Obsessive Beliefs and Symptoms in Patients with Obsessive Compulsive Disorder. AB - INTRODUCTION: Misinterpretation of intrusive thoughts because of obsessive beliefs has been thought to be important in the development of obsessive compulsive symptoms. In current study, (I) the difference between OCD patients and healthy controls in regard of obsessive beliefs and (II) the relation of obsesive beliefs with the prevelance and severity of obsessive compulsive symptoms was investigated. METHODS: The current study included 47 OCD patients and 44 healthy controls who have same properties with regard to age, sex and duration of education. All subjects were applied to Obsessive Beliefs Scale, Maudsley Obsessive Compulsive Scale, Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale. OCD patients were applied to Yale Brown Obsessive Compulsive Scale as well as the other scales. RESULTS: In analyses by controlling depression and anxiety scores, OCD patients had significantly higher scores than controls, with regard to all subscales of Obsessive Beliefs Scale. Also, prevalence of obsessive compulsive symptoms other than cleaning were correlated with obsessive beliefs about "responsibility and threat estimation" and "perfectionism and need for certainty". Hovewer, there was no correlation in between severity of obsessive compulsive symptoms and subscale scores of Obsessive Beliefs Scale. CONCLUSION: Excluding the effects of depression and anxiety, generally the results suggests that obsessive beliefs have an important role for development of obsessive compulsive symptoms. Future studies of seperated OCD subgroup with regard to obsessive compulsive symptoms will be helpful in determinig the difference among these subgroups in regard of obsessive beliefs. PMID- 28360677 TI - Vascular Ischemia as a Cause of Transient Global Amnesia: A Patient Series. AB - INTRODUCTION: Epileptic, migrainous, and vascular pathologies may cause transient global amnesia (TGA); however, the mechanism of causation remains unclear. We investigated possible vascular causes of TGA. METHODS: We retrospectively evaluated the clinical and radiologic studies of 13 patients with TGA. On admission, patients underwent diffusion-weighted imaging (DWI) and intra- and extracranial magnetic resonance angiography (MRA); vascular risk factor profiles for diabetes, hypertension, and hyperlipidemia; electroencephalography; and neuropsychological tests. Seven patients underwent control DWIs 24 h after symptom onset. RESULTS: One patient had two punctiform acute infarcts in the left hippocampus, and one had a left pontine paramedian acute infarct. In the second patient, control DWI showed additional left hippocampal and right frontal acute infarcts. None of the patients had electroencephalographic evidence of epileptic activity. All patients except for one had at least one vascular risk factor. The second patient was shown to have paroxsysmal atrial fibrillation during follow up. CONCLUSION: Minor posterior circulation ischemic stroke appears to cause TGA in some patients. Evaluations such as DWI and vascular risk factor assessment may be helpful in making the diagnosis. PMID- 28360678 TI - Relationship between Antidepressant Prescription Rates and Features of Schizophrenic Patients and Its Outcome in Schizophrenia Treatment. AB - INTRODUCTION: Comorbid depression in schizophrenia is associated with poor outcome, increased risk of relapse and a high rate of suicide. Identification of depressive symptoms and their appropriate treatment is crucial for depressed schizophrenic patients. The aim of this study is to investigate the rates of antidepressant prescription and their outcomes. METHODS: The records of the schizophrenic outpatients, who were consulted at Psychosis Unit of Psychiatry Department between January 2007 and September 2012, were evaluated retrospectively. Enrolled schizophrenic patients' antidepressant medications were at their minimal effective doses and effective duration. RESULTS: The present study demonstrates that 39 of the 101 patients during their follow-ups were prescribed antidepressants. The mean follow-up period was 6.3 (+/-4.2) years; the mean age at onset was 22 (+/-6.5) years; the mean duration of illness was 14.7 (+/-7.3) years and the mean number of psychotic exacerbation was 5 (+/-3.7). The most prescribed antidepressants were; sertraline (36.9%), venlefaxine (23.8%) and essitalopram (20.2%). SSRI's were prescribed 57 (73.1%), where as SNRI's 21 times (26.9%). There was no significant difference between SSRI (78.6%) and SNRI (21.4%) treatments in terms of psychotic exacerbation under antidepressant medication. Full remission of depressive symptoms was achieved in 21 patients (53.8%). Remission rates were significantly higher (p<0.01) in SNRI treated depressed schizophrenic patients (85.7%) compared to SSRI treated patients (50.9%). In 8 of the 39 patients (20.5%) antidepressant treatment was terminated due to side effects. CONCLUSION: This study demonstrates that SSRI's were more often prescribed compared to other classes of antidepressants in emerging depressive symptoms in schizophrenic patients despite full remission with SNRI's is more common. There was no significant difference between SSRI and SNRI treatment in terms of psychotic exacerbation. PMID- 28360679 TI - Effects of Repeated Botulinum Toxin Treatment for Sialorrhea in Patients with Parkinson's Disease. AB - INTRODUCTION: To evaluate the efficacy and adverse effects of repeated onabotulinumtoxinA (BoNT-A) treatment in patients suffering from Parkinson's disease (PD) with sialorrhea. METHODS: A retrospective analysis of 16 patients with sialorrhea treated with BoNT-A at our movement disorders outpatient clinic was conducted from February 2009 to September 2013. A patient with adult cerebral palsy and a patient with PD who received only a single application were excluded. BoNT-A was injected into the parotid glands without ultrasound guidance. Pre treatment sialorrhea severity was quantified according to the Drooling Frequency and Severity Scale (DFSS). The efficacy was evaluated four weeks after BoNT-A injections using DFSS and according to the subjective assessment of the patients and/or caregivers. RESULTS: The mean age of the patients was 70.00+/-9.82 years and the mean follow-up duration was 18.78+/-10.37 months. Totally, 37 applications were performed. The mean BoNT-A total dose was 34.35+/-6.41 units. The mean scores of DFSS before and after injections were 7.00+/-1.03 and 3.21+/ 0.89, respectively (p<0.001). Efficacy was 100%, and the mean experienced sialorrhea improvement was 71.78+/-12.95%. We found a significant difference between the first and last application in the mean duration of efficacy (17.28+/ 9.21 weeks and 18.03+/-9.02 weeks, respectively, p=0.001). We did not observe side effects in this study group. CONCLUSION: Repeated injections of BoNT-A are safe and effective in treating sialorrhea in patients with PD. Based on our results, it seems that there is a maintenance of efficacy after a three-year period and an increase in the mean duration of efficacy with the number of injections. Further prospective clinical studies with larger number of patients and more longer duration of follow-up are needed to confirm our results. PMID- 28360680 TI - Cortical Excitability and Agressive Behavior in Post-Traumatic Stress Disorder. AB - INTRODUCTION: Hyperarousal and alertness play an important role in the clinical presentation of Post-traumatic stress disorder (PTSD). Strenuous effort has been made to shed light on the mechanisms that cause these symptoms of patients. Based on the claim that there is a relationship between some subtypes of hyperarousal symptoms and aggression in patients with PTSD, we aimed to examine the relationship between electrophysiological measurements that was measured through transcranial magnetic stimulation (TMS) and aggression scale scores of PTSD patients in this study. METHODS: The study included 37 patients with a diagnosis of PTSD according to DSM-IV criteria and 25 healthy volunteers. Electrophysiological measurements of participants were made with TMS. The Buss Perry Aggression Questionnaires was administered to patients and control group. RESULTS: In the patient group, a positive correlation was found between scores of aggression and arousal symptoms. Motor excitability threshold, one of TMS measurements, which is a sign of cortical excitability, was significantly lower in the patient group than the control group. There was a negative correlation between aggression scale scores and the parameters of motor excitability threshold and cortical silent period which both shows cortical excitability of the patients. CONCLUSION: We concluded that there was an increase in cortical excitability in PTSD patients and we suggest that this increase might be associated with hyperarousal symptoms and aggressive behavior. PMID- 28360681 TI - Analysis of the Maternal Filicide in Terms of Forensic Medicine in Turkey: A Clinical Research. AB - INTRODUCTION: In the literature, 15% of the victims of homicide consists of children under 16 years of age; children under the age has been proved that they have the maximum risk. The vast majority of the victims were killed by their mothers. Thus, if mothers are the perpetrators of crime child murders are discussed in different ways, so it is conceptualized under the name of maternal filicide in the literature. This study has been performed for, in Turkey, women who killed their own children between 0-6 years old, victims of crimes, and to determine features of crime regarding on forensic medicine, eventually in order to provide a basis for taking necessary precautions and measures. METHODS: This research includes 74 reports of maternal filicide cases came to IV. Board of Specialization at the Council of Forensic Medicine in Istanbul, Ministry of Justice of Republic of Turkey between 1996-2006 years. In the light of data came from these reports, the socio-demographic characteristics of mothers who attempted filicide and children who were killed, and crime occurrence methods and mothers' criminal legal responsibility were examined. RESULTS: Mothers, suspected of the filicide crime, are often at a young age, and did not desire pregnancy, 73 of mother's do not have criminal history, and 48 of mothers confessed the crime. Found that 71 of child victims are biological kids, 38 of them were killed around age, and 20 of them were girls, 35 of them were boys. The study group, seven of defendants killed or attempted to kill more than one child at the same time. The majority of mothers committed the crime during the daylight. When filicide methods were examined strangling or throwing up the child from higher were seen the most. The majority of mothers committed crime wiithout weapon or other objects, just by their hands. Based on decisions of IV. Board of Specialization, no significant difference was observed between the the mothers with criminal liability and mothers with non-criminal liability. CONCLUSION: In this study, important data procured from the demographic characteristics of the mothers, findings on conditions during the crime and the method of the crime, and mothers' psychosocial stressors, but it has been discerned that this data is limited to define the crime of filicide. At the end of the study, besides studied the parameters that directed people to commit this crime, other factors, like mental status and/or motives should be probed. PMID- 28360682 TI - The Effects of Sleep Deprivation on Dissociation and Profiles of Mood, and Its Association with Biochemical Changes. AB - INTRODUCTION: Sleep deprivation is a method, which has being used in order to comprehend the functions of sleep both in healthy individuals and for the patients of depression with in treatment, for a long time. The objective of our present study is to examine the relation between hormonal values, which are known for being related to the effects of these said changes determined in the mood, dissociation and thought suppression in healthy individuals after one night of sleep deprivation implementation. METHODS: One night sleep deprivation was performed on a total of thirty-two healthy volunteers (16 males and 16 females) who were included in the study. Blood samples were taken from the individuals before and after sleep deprivation implementation in order to determine cortisol, dehydroepiandrosterone-sulfate (DHEA-S) and Thyroid Functions' Levels tests. In order to evaluate the effects of the sleep deprivation on moods, "White Bear Suppression Inventory (WBSI)" has been conducted, with an aim of evaluating thought suppression, "Profile of Mood States (POMS)", "Dissociative Experiences Scale (DES)" with a purpose of realizing any dissociation tendency. RESULTS: On the individuals who have been implemented for sleep deprivation, a decrease on depression and vigor-activity sub-scales values was detected, and an increase was determined on fatigue sub-scales values of "POMS". While the values of DES were found to have been statistically increased after sleep deprivation, also a significant decrease was determined on WBSI values. Even if there hasn't been any significant statistical change determined on cortisol levels after sleep deprivation, yet there had been some significant changes detected on Thyroid Stimulating Hormone (TSH), fT3, fT4, and DHEA-S levels. Decrease in "POMS" depression sub-scale values and increase on fatigue sub-scale values were determined on the individuals whose sT4 levels were found to be increased significantly in statistic manner after the sleep deprivation. CONCLUSION: According to the results of our study, sleep deprivation for one night was determined to cause decrease on depressive mood, increase on dissociative symptoms and to lower the tendency of suppressing the unwanted thoughts, consciously. The fact of being obtained lower depression values, on the individuals with the increased DHEA-S levels after the sleep deprivation meets with the information claiming that the high DHEA-S levels may be deemed as protectors against the negative effects of the stress. PMID- 28360683 TI - Reliability and Validity Study of the Turkish Version of the Clinical Opiate Withdrawal Scale. AB - INTRODUCTION: The aim of the present study was to perform reliability and validity analyses of the Turkish version of the Clinical Opiate Withdrawal Scale which is used to determine the severity of opiate withdrawal. METHODS: Initially, the Clinical Opiate Withdrawal Scale (COWS) was translated into Turkish and subsequently back-translated into English. The originality of the back-translated version was approved by the author who developed the scale. After the translation was completed, the scale was used to assess the withdrawal symptoms of 100 patients with opiate withdrawal and 41 patients with alcohol withdrawal. Cronbach's alpha was used in the reliability assessment; explanatory and confirmatory factor analyses were used in structural validity assessment; and in scale validity, ROC analysis was used among diagnosis groups. RESULTS: The Cronbach's alpha internal consistency coefficient was calculated as 0.74 in reliability analyses. The correlation coefficient was found to be 0.975 (p<0.001) for inter-rater reliability. Factor analysis was conducted for the structural validity of the scale and findings that support the unidimensional structure of the scale were observed. In the confirmatory factor analysis, CFI, GFI and RMSEA values were found to be 0.905, 0.905 and 0.079, respectively. It was detected that COWS was successful in distinguishing between opiate and alcohol withdrawal symptoms and the area under the ROC curve was 0.878. CONCLUSION: This study showed that the Turkish version of COWS can be used reliably and validly for assessing opiate withdrawal. PMID- 28360684 TI - Longitudinal Analysis of Female Authorship of Psychiatry Articles in Turkey. AB - INTRODUCTION: The number of women with careers in medicine and with academic positions at medical schools has increased substantially since the 1980s; however, women remain underrepresented in medical academia, which may be because of the fewer research publications authored by women. This study aimed to determine the gender distribution among Turkish authors of psychiatry articles published in international scientific journals during a 30-year period. METHODS: The ISI Web of Science database was searched for all psychiatry publications between 1980 and 2009 using the search term Turkey. All articles were classified according to publication period (1980-1989, 1990-1999, 2000-2004, and 2005-2009), gender of the first and last authors, first author title, total number of authors, and type of article. RESULTS: In all, 1961 articles meet the study criteria. The first author of 36.5% of the articles and 34.9% of last authors were women. The percentage of female first and last authors did not differ according to publication period (p=0.57). CONCLUSION: To the best of our knowledge this is the first study to examine gender and authorship of psychiatric research in Turkey. In total, 33% of academic positions in Turkish university psychiatry departments were occupied by women, which is comparable to the percentage of female first authors of psychiatric research papers from Turkey. It could be concluded that women academics in psychiatry departments from state universities are as reproductive as their male counterparts, but there is still a "gender gap" in psychiatry field in our country. PMID- 28360685 TI - Modafinil-Induced Psychosis: A Case Report. AB - Modafinil is used in the treatment of excessive day time sleepiness associated with several clinical conditions. It can also be used for affective stimulation for working late and/or concentrating for a long time. The reported cases of psychosis associated with modafinil use in the literature, have medical or psychiatric diorders. There is only one reported case without medical or psychiatric disorder but developed modafinil related psychosis, which is a case under simulated shift work in laboratory conditions. The cases in the literature are reported to develop mania or psychosis with 200-400 mg/day or higher doses. The case reported in this manuscript develop psychosis with 100 mg/day dosage. This case has no previous psychiatric and medical disorder history and not being on a shift work. The aim of modafinil use in this case was reported as increasing the concentration and performance while studying. Modafinil using patients must be psychiatrically monitored for its potential psychotic effect even in previously healthy individuals and low doses. PMID- 28360687 TI - Glomus Tumor as a Rare Cause of Dizziness. PMID- 28360686 TI - Diagnosis and Treatment in Neurosarcoidosis. AB - Sarcoidosis is an inflammatory multisystem disorder, affecting many systems such as lung, lymph nodes, skin and eye involvement. Nervous system involvement is often seen in 5-15% of patients with systemic sarcoidosis in the first two years. Preceding to systemic involvement the initial symptom as neurological complaints has been rarely reported. Lacking of any specific, clinical and / or radiological findings for neurosarcoidosis in these cases, it could be difficult to make an accurate diagnosis and histopathological evaluation may be required. Due to rarity and complexity diagnosis of the neurosarcoidosis, in this study, clinical, radiological and / or histopathological features, treatment modalities of the 7 neurosarcoidosis patients to be presented with detailed investigations of different neurological symptoms were evaluated. PMID- 28360688 TI - Up-to-date Critical Review of the Classification of Epilepsies and Epileptic Seizures. AB - The classification of epileptic seizures and epilepsies is a subject of interest in various medical disciplines (such as neurology, pediatric neurology, molecular biology and genetics, neurosurgery, pharmacology, radiology, histopathology), and each of them requires a different approach in their practice. In last 15 years, enormous amount of debate in which irrelevant to actual level of knowledge, were ongoing in the literature. Epilepsy classification is a fundamental tool that impacts not only daily clinical practice but also research era and education. The current lack of consensus in this field causes a serious obstacle in patient management, student and resident education, and information sharing among different scientific interest groups. The comparison of different classification proposals by means of positive and negative aspects is beyond the scope of discussion in this article; therefore, I will try to give a brief summary of our current level of understanding. Main issues regarding the classifications proposal are as follows: Concepts of epileptic seizure/epilepsy/syndromeFocal & generalized epilepsy conceptIdiopathic, genetic, cryptogenic, and symptomatic (structural/metabolic) concepts. PMID- 28360689 TI - From Poster Presentation to Publication: National Congress of Child and Adolescent Psychiatry. AB - INTRODUCTION: The aims of this study were as follows: 1) to determine publication rate, time to publication, and study design of poster presentations accepted at the National Congress of Child and Adolescent Psychiatry (NCCAP) and converted to publication and the degree of first author in a published article and journal index and 2) to investigate the relationship of these data with each other. METHODS: The poster presentations of four congresses organized between 2005 and 2008 were investigated separately. The presentations were screened by taking into account the title and the first and second author in English and Turkish languages via PubMed and Google Academic databases. Published studies, time between presentation and publishing date, study design, degree of first author, and journal index of these studies were recorded. RESULTS: Fifty-four (25.2%) of 214 poster presentations were published in international and national peer reviewed journals. Of the published articles, 74.1% (n=40) were research type and 61.1% (n=33) were found in the Science Citation Index (SCI) and Science Citation Index-Expanded (SCI-E) peer-reviewed journals. The first author in 42.6% (n=23) of published articles were assistant professors. The average time between presentation and publishing date was 30.72+/-18.89 months. Statistical differences were not determined between publication rate and study design; between time to publication and study type/study design, degree of first author, and journal index; and between journal index and study design and degree of first author (p>0.05). It was found that research articles were published significantly more by teaching staff than experts and other researchers (p<0.05). CONCLUSION: Compared with literature data, it was found that the time to publication was longer while the publication rate was similar for poster presentations in our congresses. Based on these results, it is important to create necessary conditions and encourage the researchers to publish the poster presentations presented in NCCAP. PMID- 28360690 TI - What are the Predictors of Death in Patients With Cranio-Cervical Artery Dissection? AB - INTRODUCTION: Few studies have reported the predictive factors related to mortality in patients with cranio-cervical artery dissections (CCAD). Our aim was to investigate the predictors related to in-hospital mortality in patients with CCAD and its subgroups. METHODS: Sixty-seven patients diagnosed with carotid artery dissection (CAD) or vertebral artery dissection (VAD), admitted to our clinic between 2000 and 2013, were retrospectively reviewed. Age, gender, modified Rankin Scale scores (pre-stroke and at admission), clinical presentation type, location of the dissection, risk factors, and treatments were analyzed as mortality-related prognostic factors. Of the 67 patients, 12 (17.9%) died, five (7.46%) with CAD and seven (10.44%) with VAD. We compared the prognostic characteristics of the surviving versus deceased patients with CCAD and in the subgroups with CAD and VAD. RESULTS: Age above 45 years, severe disability at admission, presentation with stroke, and intracranial VAD occurred more frequently in deceased patients and were independent variables related to mortality in patients with CCAD and its subgroup with VAD. Severe disability at admission alone was related to mortality in patients with CAD. Hypertension and hypercholesterolemia were independent variables related to mortality in patients with CCAD. CONCLUSION: Severe disability at admission was a mortality predictor in both CAD and VAD. Although the initial severity of stroke is reportedly related to poor outcomes in patients with CCAD, it has not previously been directly identified as a predictor of mortality in patients with CAD or VAD. PMID- 28360691 TI - The Polymorphisms of Ser49Gly and Gly389Arg in Beta-1-Adrenergic Receptor Gene in Major Depression. AB - INTRODUCTION: It was reported that the genetic susceptibility of major depressive disorder (MDD) is related with genetic polymorphisms. The aim of this study was to investigate the possible association of the genotype and allele frequencies of Ser49Gly and Arg389Gly polymorphisms in MDD by comparing them with healthy subjects. METHODS: A total of 144 patients with MDD diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria and 105 healthy controls were included in the study. Polymerase chain reaction (PCR) with restriction fragment length polymorphism (RFLP) was used for genotyping. RESULTS: Of the 144 participants in the MDD group, 77 (53.5%) had homozygous wild type (AA), 57 (39.6%) had heterozygous type (AG), and 10 (6.9%) had mutant (GG) genotype for Ser49Gly, whereas 75 (52.1%) had homozygous wild type (GG), 59 (41.0%) had heterozygous (GC) type, and 10 (6.9%) had mutant homozygous (CC) genotype for Gly386Arg. There were no significant difference in the allele and genotype frequencies of the beta-1-adrenergic receptor (ADRB1) gene for Ser49Gly and Arg389Gly polymorphisms after comparing with healthy controls (p=0.626; p=0.863 and p=0.625; p=0.914). CONCLUSION: The results of our study did not reveal a major effect of the polymorphism of Ser49Gly and Gly389Arg in the ADRB1 gene in MDD. Further studies with larger sample size are required to elucidate the role of other beta-1 adrenergic gene polymorphisms in MDD. PMID- 28360692 TI - Turkish Version Study of "Parkinson's Disease Quality of Life Questionnaire" (PDQL). AB - INTRODUCTION: This study aimed to evaluate Turkish transcultural adaptation, reliability, and validity of "Parkinson's Disease Quality of Life Questionnaire" (PDQL), which has been developed to assess the quality of life of patients with Parkinson's disease. METHODS: Eighty-nine patients who were included in the study were diagnosed with Parkinson's disease. They were presented to the outpatient clinic of the Istanbul Faculty of Medicine, Physical Medicine and Rehabilitation department between July 2005 and April 2008. The Turkish translated version of PDQL (PDQL-TR), "Unified Parkinson's Disease Rating Scale" (UPDRS), and Hoehn & Yahr (HY) were used as the main outcome measures. RESULTS: The calculated Pearson correlation coefficient for PDQL, H&Y, and UPDRS ranged between -0.36 and -0.80. Cronbach's alpha coefficients of the PDQL-TR complete questionnaire and subdomains were higher than 0.80. The absolute value of item-total score correlation coefficients by Pearson fluctuated between 0.40 (question 4-total score) and 0.88 (question 26-total score), whereas the subdomain-total score correlation coefficients ranged between 0.81 and 0.96. PDQL-TR showed high stability according to the ICC results, ranging between 0.75 (Emotional Function) and 0.88 (Parkinsonian Symptoms). CONCLUSION: The psychometric features of PDQL TR are satisfactory, and our results are consistent with the previous literature findings. PDQL-TR is a valid and reliable tool to measure health-related quality of life in patients with Parkinson's disease. PMID- 28360693 TI - Assessment of Psychopathology, Quality of Life, and Parental Attitudes in Adolescents with Type 1 Diabetes Mellitus. AB - INTRODUCTION: The aim of the present study was to identify psychopathology, parental attitudes, perceptions of quality of life, and relationships between these factors in adolescents with type 1 diabetes mellitus (DM). METHODS: Fifty adolescents (12-18 years old) with type 1 diabetes mellitus and 50 healthy adolescents and their parents were recruited for the study. Clinical interviews with the diabetic adolescents were performed using "Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL)." Both groups completed the "Depression Scale for Children," "State Trait Anxiety Inventory," and "Health Related Quality of Life Scale for Children," while their parents completed the "Parental Attitude Research Instrument," "The Coping Strategy Indicator," and "Health Related Quality of Life Scale for Children-Parent Form." RESULTS: The psychological disorder ratio in diabetic adolescents was 68%. No significant difference was found regarding perceptions of quality of life between the diabetic group and control group. However, diabetic adolescents with psychological disorder had reduced perception of quality of life than those without psychological disorder. Among parental attitudes, an authoritarian attitude was found to be more common in the diabetic group. It was found that among coping strategies, parents in the diabetic group use avoidance more commonly. CONCLUSION: In the present study, a high rate of psychopathology was detected among adolescents with type 1 DM. In addition, no clear impairment in quality of life was reported in patients with type 1 DM; however, there was worsening in the perception of quality of life in the presence of psychiatric disorders accompanying diabetes. It was found that parents of diabetic children use inappropriate coping strategies and negative parental attitudes more often than those of healthy controls. PMID- 28360694 TI - Recurrent Ischemic Stroke Characteristics and Assessment of Sufficiency of Secondary Stroke Prevention. AB - INTRODUCTION: Disabilities due to stroke lead to a serious individual and socioeconomic burden. In this presented hospital-based study, we aimed to evaluate recurrent ischemic stroke (RIS) characteristics and the sufficiency of secondary prevention regarding the most common modifiable risk factors. METHODS: The records of patients with a diagnosis of ischemic stroke between November 2009 and November 2011 in our unit were retrospectively investigated. RESULTS: Ninety one (18%) out of 500 patients with ischemic stroke had RIS. Hypertension, diabetes mellitus, ischemic heart disease, hyperlipidemia, atrial fibrillation, and smoking were found in 88%, 43%, 36%, 30%, 11%, and 14% of the patients, respectively. Thirty-eight percent of the patients had more than two risk factors. While 14% of the hypertensive patients did not use antihypertensive medications, antihypertensive treatment was insufficient in 39% of those who already used antihypertensive medications. Twenty-three percent of the patients received no prophylactic agents. Sixty percent of the patients with a history of atrial fibrillation were on oral anticoagulant therapy (warfarin), and the international normalized ratio was <2.0 in 73% of them. Of the diabetic patients, 87% had an HgbA1C level above 6%. The LDL level was higher than 100 mg/dL in 72% of the patients. CONCLUSION: The incidence of RIS and risk factors in our retrospective study was compatible with the results of those in literature. Secondary prophylactic treatment and modification of risk factors in the stroke patients were not satisfactory. The improvement of the patients' adherence to treatment is also very important in addition to the optimal treatment and follow up strategy for decreasing the incidence of RIS. A multidisciplinary outpatient model of stroke care may be beneficial for decreasing the incidence of RIS. PMID- 28360695 TI - Antipsychotic Use Pattern in People with Psychotic Disorder Living in Board and Care Facilities. AB - INTRODUCTION: The aim of this survey is to determine the pattern of antipsychotic drug use in patients with psychotic disorders, living in board and care facilities and to investigate the related factors. METHODS: We evaluated the antipsychotic drug use pattern in outpatients with psychotic disorders according to DSM-IV, living in board and care facilities. Patients using polypharmacy at least one month were compared with patients using monotherapy in terms of clinical and demographic characteristics. RESULTS: Antipsychotic polypharmacy (with two: 34%, with more than two: 28%) was identified in 62% of the patients. The most frequently prescribed combination was olanzapine+quetiapine (13%), the rate of first and second generation combination was 50%, the rate of second generation antipsychotic combination was 44%, and the rate of first generation anytipsychotic combination was 4% in the two antipsychotic drug combination group. The rate of clozapine use was 3%. Use of polypharmacy was associated with the diagnosis of schizophrenia and schizoaffective disorder, young age, suicidal behavior, multiple hospitalizations, clinical severity, and the need of anticholinergic drug. CONCLUSION: The ratio of using more than two antipsychotic drug combination is high (28%) in psychotic patients living in board and care, and rate of clozapine use is low, which shows that clinical practice is inconsistent with the treatment guidelines recommendations. It appears that further education to rationale antipsychotic drug use in psychiatric practices is required. PMID- 28360696 TI - Sympathetic Skin Responses from the Neck Area in Patients with Unilateral Migraine. AB - INTRODUCTION: In this study, in patients with unilateral migraine headache and in normal controls, it was aimed to assess the sympathetic function during attack, post attack, and interval periods and to compare these findings by recording sympathetic skin responses from the neck area, which was not studied before. METHODS: A total of 37 unilateral patients with migraine (30 women, seven men) who fulfilled the criteria of International Headache Society (2004) were recruited from our outpatient clinic. The control group consisted of 21 healthy individuals (16 women, five men) who are employees or students of our Medical Faculty. Mean latency and maximum amplitude values of sympathetic skin responses obtained from neck areas of the patients during attack, post attack, and interval periods were calculated. We compared the mean latency and the maximum amplitude values of the symptomatic side with the data of the asymptomatic side and with the data of the control group. We also compared the responses of the patients with right-sided headache with the responses of the patients with left-sided headache. All statistical analyses were performed using SPSS. RESULTS: On the neck area, we observed sympathetic hypo-function in the attack and interval periods and a relative hyper-function in the post attack period bilaterally, regardless of the symptomatic side. CONCLUSION: These findings suggest that there is ongoing bilateral sympathetic hypo-function in the neck area and there occurs a temporary increase in the function of sympathetic sudomotor activity in the recovery period of headaches. PMID- 28360697 TI - Mother-Child Interactions of Preterm Toddlers. AB - INTRODUCTION: We aimed to investigate the mother-toddler relationship in preterm toddlers. METHODS: The sample consisted of 18 mothers and their preterm toddlers (group 1) and 20 mothers and their fullterm toddlers (group 2). Anxiety and depressive symptom levels, attachment pattern, and parental attitudes of mothers and social-emotional problems and developmental level of the toddlers were explored to assess possible confounding factors in the mother-toddler relationship. Two researchers rated the Parent Infant Relationship Global Assessment Scales (PIRGAS). RESULTS: Both the mothers in group 1 and group 2 had similar Beck Depression Inventory (BDI) and State and Trait Anxiety Inventory (STAI) scores. However, the mothers who gave birth before 32 weeks of gestation had higher trait anxiety scores than others (46+/-2.4 vs. 42.3+/-5.4, p=0.01). The groups had similar Brief Infant Toddler Social Emotional Assessment Scale (BITSEA) problem and competency scores. The parenting style of group 1 revealed that they had higher scores on the Parenting Attitude Research Instrument (PARI) subscale 5 (excessive discipline) (39.6 vs. 32.1; p=0.02). CONCLUSION: Mother toddler interaction and attachment security were found to be similar in fullterm and moderately preterm healthy toddlers. Our findings suggest that not the preterm birth itself but the medical, developmental, and/or neurological consequences of prematurity may affect the mother-toddler interaction. To explore the independent effect of prematurity in mother-toddler dyadic relationship, longitudinally designed studies are warranted. PMID- 28360698 TI - Comparison of Cognitive Impairment between Patients having Epilepsy and Psychogenic Nonepileptic Seizures. AB - INTRODUCTION: The aim of this study was to evaluate cognitive impairment in patients having epilepsy or psychogenic nonepileptic seizures (PNESs) using selected neuropsychological tests at different time periods related to the seizure. METHODS: In this study, selected neurocognitive tests were administered to the patients. Within 24 h, the previously applied neurocognitive tests were repeated within 24 h following the observation of typical seizures when monitoring and normalizing electroencephalography (EEG) activity. Basal neurocognitive tests were also administered to the healthy control group, and repeat neurocognitive evaluation was performed within 24-96 h. RESULTS: The basal neurocognitive evaluation revealed that verbal learning and memory scores as well as Stroop test interference time were significantly lower in the PNES group compared with those in the controls. In the basal cognitive tests administered to the patients with epilepsy, verbal learning and memory scores, long-term memory, and total recognition test scores were significantly lower than those of the controls. Following the repeat cognitive tests, significant progress was found in the verbal categorical fluency score of the PNES group. No significant difference was determined in the epilepsy group. Significant contraction was determined in the Stroop interference time in the control group, but no similar change was recorded in the epilepsy or PNES groups. CONCLUSION: While memory problems seemed to be most prominent in the assessed patients with epilepsy, attention and executive function problems were more dominant in the patients with PNESs. These findings are probably related to numerous factors such duration of disease, mood disorders, and specific drug use. No deterioration in attention and executive functions was reported in the early post-seizure period in either patient group. PMID- 28360699 TI - Relationship Suicide, Cognitive Functions, and Depression in Patients with Schizophrenia. AB - INTRODUCTION: The aim of this study was to compare schizophrenic patients with and without a suicide attempt history in terms of sociodemographic and clinical features and cognitive functions and to determine the predictive factors for suicide attempt history. METHODS: In this study, we assessed and compared 70 patients with schizophrenia, 27 patients with a suicide attempt history, and 43 patients without a suicide attempt history. The cognitive functions of patients were assessed by the Stroop test, Wisconsin Card Sorting Test (WCST), and Rey Auditory Verbal Learning Test. In order to evaluate clinical symptoms, the Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS) were used. RESULTS: In this study, the number of hospitalizations, PANSS general psychopathology subscale score, CDSS total score, suicide item score, and WCST total number of responses (WCST1) were significantly higher among the patients with a suicide attempt history. The WCST1 and CDSS total scores were predicted using the suicide attempt history. CONCLUSION: Revealing the factors related to suicidal behavior in patients with schizophrenia contributes to the prevention of suicide. Studies with long-term follow-up and with a larger sample group are required for the investigation of relationship suicide, cognitive impairment, which is one of the core symptoms of schizophrenia, and depression. PMID- 28360700 TI - The Effects of Cognitive Rehabilitation on Relapsing Remitting Multiple Sclerosis Patients. AB - INTRODUCTION: The aims of this study were to determine the severity of cognitive impairment with Brief Repeatable Battery Neuropsychology (BRB-N) and to show the benefits of cognitive rehabilitation programs to develop coping strategies for the retardation of cognitive losses in relapsing remitting multiple sclerosis (RRMS) patients. METHODS: The cognitive screening with BRB-N was performed in RRMS patients who had applied to the MS outpatient clinic of Bakirkoy Psychiatric and Neurological Diseases Hospital, had an Expanded Disability Status Scale (EDSS) score between 1.0 and 5.5, and had no other cognitive disease or used drugs that effected the cognitive status. Thirty two patients with cognitive impairment underwent consecutive computer-assisted cognitive rehabilitation program once a week for 8 weeks conducted by psychologists. The effects of the program were evaluated with the tests repeated every 4 weeks. RESULTS: The mean age of the patients was 36.09+/-7.19 years. Their initial and control test scores were found to be paced auditory serial addition test (PASAT) 29.21+/-17.97; 42.43+/-15.43, Selective Reminding Test-Total Learning (SRT-TL) 8.03+/-2.36; 10.09+/-1.77, Selective Reminding Test-Long-term Memory (SRT-DR) 6.72+/-2.74; 9+/ 2.29, Spatial Recall Test-Total Learning (SPART-TL) 4.72+/-2.02; 4.22+/-1.74, Spatial Recall Test-Long-term Memory (SPART-DR) 5.94+/-2.54; 5.16+/-2.23, Symbol Digit Modalities Test (SDMT) 40.44+/-17.04; 46.47+/-17.94, Word Fluency Test (WLG) 32.88+/-9.87; 40.44+/-9.95 respectively. There was no significant statistical difference between Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ) and SPART values of preface, 1st control and 2nd control (p>0.05). There was significant statistical difference between PASAT, WLG, SDMT, SRT-TL, SRT-DR values of Preface, 1st control, and 2nd control (p=0.0001). CONCLUSION: It was determined that on distinctive improvement on sustaining attention, working memory and information processing speed, and verbal fluency and verbal learning with cognitive rehabilitation, no changes were observed on visuospatial learning. This approach is hopeful and further comprehensive studies are needed. PMID- 28360702 TI - Anxiety Disorders Comorbidity in Children and Adolescents with Attention Deficit Hyperactivity Disorder. AB - INTRODUCTION: Our aim is to investigate the prevalence of comorbidity of anxiety disorders (AD) among patients newly diagnosed with attention deficit hyperactivity disorder (ADHD) and to compare symptom severity of ADHD and sociodemographic parameters between patients with and without AD. METHODS: Among 1683 children and adolescents admitted to Kocaeli University Medical Faculty, Child and Adolescent Mental Health Outpatient Clinic, 447 children and adolescents, who were preliminarily diagnosed as ADHD by clinical interview based on Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), were invited to participate in the second phase of the study. Kiddie Schedule for Affective Disorder and Schizophrenia, Present and Lifetime-Turkish Version were applied to children and adolescents with ADHD and one of their parents to support the diagnoses of both ADHD and AD. Mothers, fathers, and teachers of the children were asked to complete DSM-IV-Based Child and Adolescent Behavior Disorders Screening and Rating Scale. RESULTS: Our study group comprised 170 children and adolescents diagnosed with ADHD of whom 19.4% were girls and 80.6% were boys; 27.6% of patients diagnosed with ADHD showed AD comorbidity. Age of the parents at birth of the patients with AD was significantly lower than that of patients without AD. CONCLUSION: In line with the previous studies, the comorbidity rate of AD was found to be higher among patients with ADHD than general population and clinical sample without ADHD. The possibility of comorbidity of AD in patients with ADHD should be considered because higher rates of AD are observed in ADHD and comorbidities of AD. PMID- 28360701 TI - Denver Developmental Test Findings and their Relationship with Sociodemographic Variables in a Large Community Sample of 0-4-Year-Old Children. AB - INTRODUCTION: The aim of this study was to investigate the prevalence of developmental problems and relationship with sociodemographic variables in a community sample of young children. METHODS: Participants included 1000 children (558 males, 442 females, age range 1-48 months, mean 18.4 months, SD 7.8 months). Children were referred generally by their parents for developmental evaluation and consultation in response to a public announcement in a district area in Istanbul, Turkey. An interview form and the Denver Developmental Screening Test II (DDST) were used for sociodemographic data and developmental evaluation. The chi2 test and Pearson's correlation test were used for data analysis. RESULTS: Seven hundred forty-one out of 1000 children (74.1%) had normal, 140 (14%) had risky, and 119 (11.9%) had abnormal findings on the DDST results. The probability of abnormal findings on the DDST results was significantly higher in males (p=0.003), the 2-4-year-old group (p<0.05), families with more than one child (p=0.001), consanguineous marriages (p<0.01), low parental educational levels and low household income (p<0.01), and in children without a history of breastfeeding (p=0.000). Immigration status and delivery mode did not have a significant effect on the probability of abnormal findings on the DDST results (p>0.05). CONCLUSION: Sociodemographic factors have a noteworthy impact on development. Determining these factors is important especially during the first years of life. PMID- 28360703 TI - Electroencephalography Spectral Power Density in First-Episode Mania: A Comparative Study with Subsequent Remission Period. AB - INTRODUCTION: Our aim in this study was to investigate spectral power density (PSD) in first-episode mania and subsequent remission period and to evaluate their difference. METHODS: Sixty-nine consecutive cases referring to our hospital within the previous 1 year, who were evaluated as bipolar disorder manic episode according to The Diagnostic and Statistical Manual of Mental Disorders-IV (DSM IV) at the first episode and had the informed consent form signed by first degree relatives, were included in this study. Exclusion criteria included having previous depressive episode, using drugs which could influence electroencephalographic activity before electroencephalography (EEG), and having previous neurological disease, particularly epilepsy, head trauma, and/or loss of consciousness. EEG records were obtained using a digital device in 16 channels; 23 surface electrodes were placed according to the International 10-20 system. Spectral power density (dbMUV/Hz) of EEG signal provided information on the power carried out by EEG waves in defined frequancy range per unit frequency in the present study. RESULTS: A peak power value detected on the right with FP2P4 and on the left with F7T3 electrodes were found to be higher in the manic episode than in the remission period (p=0.018 and 0.025). In the remission period, in cases with psychotic symptoms during the manic period, F4C4 peak power value was found to be lower than that in cases with no psychotic findings during the manic period (p=0.027). There was no relation was found between YMRS scores and peak power scores. CONCLUSION: Electrophysiological corollary of mood episode is present from the onset of the disease, and it differs between the manic and remission periods of bipolar disorder. In the remission period, peak power values of PSD distinguish cases with psychotic findings from cases without psychotic findings when they were manic. PMID- 28360704 TI - The Phenomenology of Delusions in a Patient with Disorders of Sex Development. AB - Abnormal development of the external and internal genital organs and male pseudohermaphrodite-type disorders of sex development is one of the conditions that creates problem in determination of gender. In this case report, our aim is to discuss how disorders with psychotic symptoms may affect different cultural life styles, circumstances, experience, delusion contents of identification and acceptance in a patient diagnosed with bipolar affective disorder, and with male pseudohermaphroditism during adulthood. PMID- 28360705 TI - Neuro-Behcet's Disease with Chorea. AB - Behcet's disease (BD) was described as a three-symptom complex comprising uveitis, oral aphthae, and genital ulcerations. It is a multisystemic, recurrent, inflammatory disorder and it is of unknown cause. Neuro-Behcet (NB) is present in 5%-7% of BD. Movement disorders have rarely been reported in NB. Here, we report a case of chronic parenchymal NB presenting with chorea. PMID- 28360706 TI - Sertraline Induced Galactorrhea. AB - There is limited literature reporting galactorrhea with antidepressants, including selective serotonin reuptake inhibitors. In this case report, a patient with adjustment disorder who developed galactorrhea with sertraline was presented. PMID- 28360707 TI - Treatment Approach to Sleep Terror: Two Case Reports. AB - Parasomnias are a group of disorders characterized by abnormal behaviors, physical activities, and autonomic arousal symptoms while transition to sleep or continuation of sleep. Sleep terror (ST) is classified under parasomnias characterized by sudden fear attacks beginning with crying attacks or high frequency screams and continuing with increased autonomic symptoms. ST occurs in the first few hours of sleep during the delta phase. Further, the lifetime prevalence of ST in adults is less than 1%. It is important to obtain; anamnesis from patients' bed partner for a clinical evaluation of ST. Methods, such as evaluating sleep diaries and video recordings, can help ST diagnosis. It is also important to evaluate patients' medical history, history of substance or alcohol abuse, psychological traumatic experiences, primary or secondary incomes, and detailed neurological aspects. Physician can select some serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCADs) as medical treatment if patients have a high frequency of attacks. Because of addiction and relapse of ST episodes, benzodiazepines are not preferred as the first-line treatment. In this study, we will discuss ST, which is rare in adulthood, and use of long-acting benzodiazepine based on two cases. PMID- 28360709 TI - The Effects of Antipsychotics on Prolactin and Bone Mineral Density. PMID- 28360708 TI - Tardive Blepharospasm and Meige Syndrome during Treatment with Quetiapine and Olanzapine. AB - Meige syndrome, which has been presented in tardive syndromes, is a form of blepharospasm accompanied by oromandibular dystonia with manifestations over the face, jaw, and neck. A blepharospasm can be induced by antihistamines, dopaminomimetic or sympathomimetic drugs, or long-term exposure to dopamine antagonists. Atypical antipsychotics have less extrapyramidal side effects because of a weak dopamine D2 receptor binding affinity or a strong antagonistic effect to serotonin 5-HT2a receptor and have been known to cause less tardive dyskinesia than typical antipsychotics. Thus, in literature, atypical antipsychotics are recommended for the treatment of psychosis in cases of tardive dyskinesia. The potential risk factors associated with the development of tardive dyskinesia are extrapyramidal symptoms' history, diabetes mellitus, affective disorder, female gender, older age, and long-term therapy with neuroleptics at higher dosages. As reported below, a patient with an affective disorder who had quetiapine-induced oromandibular dystonia and olanzapine-induced Meige syndrome after antipsychotic augmentation in different stages of the disease process was presented. PMID- 28360710 TI - Reversible Anorgasmia with Acetazolamide Treatment for Idiopathic Intracranial Hypertension. PMID- 28360711 TI - Erratum. AB - [This corrects the article on p. 4 in vol. 52.]. PMID- 28360712 TI - The Challenge Behind the Facade: Substance Abuse and Comorbidities. PMID- 28360713 TI - Pregnancy-Onset Panic Disorder: Incidence, Comorbidity and Associated Factors. AB - INTRODUCTION: The present study aimed to investigate the incidence rate of pregnancy-onset panic disorder (POPD) among Turkish pregnant women using a diagnostic interview. Additionally, we examined whether the independent socio demographic or clinical risk factors were associated with the risk of panic disorder in these women. METHODS: The study sample comprised 1475 consecutive pregnant women who presented to the obstetric outpatient clinics of two research centers. The rate of POPD in these participants was 1.3% (Group 1, n=20). The 20 women with POPD were compared with 250 pregnant women without pregnancy-onset depression or anxiety (Group 2; controls). Panic disorder and other anxiety or mood disorders were determined by means of the Structured Clinical Interview for DSM-IV. Comorbid Axis II disorders were diagnosed with the Structured Clinical Interview for DSM-III-R Personality Disorders. RESULTS: The incidence rate of panic disorder was 1.3% (n=20). In group 1, 55% (n=11) of the women with POPD had an additional mood or anxiety disorder. In addition, the prevalence rate of any cluster C personality disorder, including avoidant, passive-aggressive and obsessive-compulsive personality disorders, were significantly greater in the group 1 women with POPD than the control pregnant women without a panic disorder (group 2). CONCLUSION: The women with POPD were more likely than the controls to have a cluster C Axis II disorder and a history of a pre-existing anxiety or mood disorder. PMID- 28360714 TI - Investigation of the Plasma Nitrite Levels and Oxidant-Antioxidant Status in Obstructive Sleep Apnea Syndrome. AB - INTRODUCTION: Obstructive sleep apnea (OSA) is one of the most prevalent sleep disorders. In the present study, we assessed the nitrite level, which is an indirect indicator of nitric oxide (NO), total oxidant status (TOS), total antioxidant status (TAS) and oxidative stress index (OSI), which may be associated with endotel dysfunction. We investigated the difference between the groups and the relationship among the severity of comorbid conditions. METHODS: This study was conducted in 39 OSA patients confirmed by polysomnography and 40 healthy subjects (controls). The OSA group consisted of 10 women and 29 men and the control group consisted of 20 women and 20 men. Polysomnographic revealed mild OSA in two, moderate in 7 and severe in 30 cases. We measured plasma TAS, TOS and nitrite levels from venous blood. The OSI value was obtained by dividing the TOS and TAS values. Values were compared with the control group and between patient groups. RESULTS: A high body mass index (BMI), cardiovasculer diseases (CVD) and the use of medication for co-morbid diseases were more prevalent in the OSA group (p=.001, p=.029 and p=.006, respectively). The median plasma TOS level and OSI in the obstructive sleep apnea syndrome (OUA) group were significantly higher than those in the control group (p=.001 and p=.001, respectively). The plasma median nitrite level and TAS did not show any significant difference between the OSA and the control groups. None of the parameters revealed a significant difference between severe and moderate OSA cases. CONCLUSION: Our findings in the present study revealed that the oxidant-antioxidant balance shifted toward the oxidant side in OSA cases; however, the NO level did not change. These findings together may point out that some molecules other than NO may have a role in the pathophysiology of endothelial dysfunction and also in the disturbed oxidant-antioxidant balance in OSA. PMID- 28360715 TI - Relationships between Childhood Traumatic Experiences, Early Maladaptive Schemas and Interpersonal Styles. AB - INTRODUCTION: Cognitive theories of psychopathology have generally proposed that early experiences of childhood abuse and neglect may result in the development of early maladaptive self-schemas. Maladaptive core schemas are central in the development and maintenance of psychological symptoms in a schema-focused approach. Psychosocial dysfunction in individuals with psychological problems has been consistently found to be associated with symptom severity. However, till date, linkages between psychosocial functioning, early traumatic experiences and core schemas have received little attention. The aim of the present study was to explore the relations among maladaptive interpersonal styles, negative experiences in childhood and core self-schemas in non-clinical adults. METHODS: A total of 300 adults (58% women) participated in the study. The participants completed a socio-demographic questionnaire, Young Schema Questionnaire, Childhood Trauma Questionnaire and Interpersonal Style Scale. RESULTS: Hierarchical regression analyses revealed that the Disconnection and Rejection and Impaired Limits schema domains were significant antecedents of maladaptive interpersonal styles after controlling for demographic characteristics and childhood abuse and neglect. Associations of child sexual abuse with Emotionally Avoidant, Manipulative and Abusive interpersonal styles were mediated by early maladaptive schemas. Early maladaptive schemas mediated the relations of emotional abuse with Emotionally Avoidant and Avoidant interpersonal styles as well as the relations of physical abuse with Avoidant and Abusive interpersonal styles. CONCLUSION: Interpersonal styles in adulthood are significantly associated with childhood traumatic experiences. Significant relations between early traumatic experiences and maladaptive interpersonal styles are mediated by early maladaptive schemas. PMID- 28360716 TI - Correlation Between Life Events and Quality of Life in Patients with Medication Overuse Headache. AB - INTRODUCTION: The present study aimed to determine (a) the correlation between type and number of stressful life events and quality of life in patients with medication-overuse headache (MOH) and (b) whether stressful life events could be attributed to medication overuse and the conversion of headache to a chronic type. METHODS: The present study included 114 patients aged between 15 and 65 years who met the criteria for headache classification of International Headache Society (IHS). The patients were divided into three groups according to the revised 2004 IHS classification; MOH (n=64), chronic migraine (n=25) and episodic migraine (n=25). Detailed data on clinical and sociodemographic characteristics were recorded. Neurological and physical examinations were performed for differential diagnosis. The patients underwent structured clinical interviews for DSM-IV Inventory (SCID-I), Beck Anxiety Inventory, Beck Depression Inventory, Short Form-36 (SF-36) and Life Events List. Scores of these inventories were statistically compared. RESULTS: Comparing MOH group with episodic migraine group via SF-36, statistically significant decreases were observed in the subscales of physical role limitation (p=.024), pain (p=.0001), general health (p=.043) and social functioning (p=.004). There was a statistically significant correlation between the number of life events and the time the disease became chronic in the patient group with non-MOH chronic migraine (p=.027). Moreover, a statistically significant correlation was observed between stressful family life events and the body pain subscale of quality of life scale (p=.038). CONCLUSION: The present study demonstrates that stressful life events impair quality of life in patients with MOH. It was also found that number of stressful life events could be attributed to the conversion of headache to a chronic type. PMID- 28360718 TI - Correlation of Fatigue with Depression, Disability Level and Quality of Life in Patients with Multiple Sclerosis. AB - INTRODUCTION: Fatigue is a subjective and non-specific symptom; therefore, evaluation of fatigue is quite difficult. Fatigue has been reported in 75%-87% of patients with multiple sclerosis (MS) and two-thirds of these patients indicated fatigue as one of the worst three common symptoms that they experienced. This study was conducted to measure the intensity, frequency and the characteristics of fatigue in patients with MS. Moreover, the effect of fatigue on the quality of life and its association with depression and disability were evaluated. METHODS: One hundred and twenty patients with multiple sclerosis (84 women and 36 men) were included in our study. The patients' sociodemographic characteristics and their experiences on symptoms of fatigue were questioned. Presence and degree of fatigue were assessed using the fatigue severity scale (FSS). Disability status was detected with expanded disability status scale (EDSS). The Multiple Sclerosis Quality of Life (MSQoL-54) survey was conducted to evaluate the quality of life of patients and Beck Depression Inventory (BDI) was used to determine the current depression status. Patients were grouped into fatigue and non-fatigue groups based on FSS. Both groups were compared according to their age, sex, MS clinical types, course of the disease and scores of EDSS, BDI and MSQoL-54. RESULTS: Seventy percent of patients reported fatigue and 38% of these patients defined fatigue as their most disabling symptom. There was no correlation of fatigue with age, sex and disease duration. The correlation of fatigue and educational level was negative and weak (p<.05, r=-.214) and the correlation between fatigue and MS clinical types were significant but weak (p<.01, r=.228). Patients with fatigue had higher EDSS and BDI scores. In addition, FSS scores were found to be statistically meaningful and positively correlated with both EDSS and BDI scores (r=.404, r=.476, p<.01). Furthermore, our findings revealed that the quality of life in patients with MS and fatigue was poor (r=-.58 p<.01). Similarly, a negative connection was found between MSQoL-54 sub-scales and fatigue. CONCLUSION: This study proved that fatigue has a positive correlation with depression and disability and a negative significant relation with the quality of life of patients with MS. PMID- 28360717 TI - Relationship between Symptoms of Disruptive Behavior Disorders and Unsafe Internet Usage in Early Adolescence. AB - INTRODUCTION: Children and adolescents are at the highest risk for negative effects of internet usage. Risk taking and erroneous decision making have been described as major behavioral characteristics of patients with attention deficit hyperactivity disorder (ADHD). ADHD and its association particularly with oppositional defiant disorder/conduct disorder are correlated with risk-taking behaviors. This study was conducted to evaluate how disruptive behavior disorder symptoms are associated with internet usage, particularly unsafe internet usage, in early adolescents. METHODS: A sample of 1389 secondary school students was invited to the survey. All children were given an invitation letter and Conners' Parent Rating Scale (CPRS) forms were sent to their parents. The accepted participants filled in questionnaire forms, which consisted of questions interrogating demographic information and internet usage habits. RESULTS: Responses indicated that 27.4% (n=249) of the participants encountered unwanted content unintentionally and nearly one-third (n=280, 30.4%) had chatted online with people they did not know. Additionally, respondents who had more severe ADHD symptoms were more likely to report surfing online mainly for the purpose of chatting than respondents with milder ADHD symptoms. Students with comparatively higher attention deficit scores were also significantly more likely to report meeting in person with strangers they knew only from internet chatting. Analyses have demonstrated the presence of a significant difference between study participants with and without conduct disorder as for internet overusage or meeting with their internet acquaintances. CONCLUSION: This study suggests that there may be a significant relation between ADHD symptoms, conduct disorder and pathological and unsafe internet usage. Evaluating adolescents with ADHD and conduct disorder with this risk in mind is important in the development of both preventive and interventional strategies. PMID- 28360719 TI - Relations between Post-traumatic Stress Disorder, Dissociation and Attention Deficit/Hyperactivity Disorder among Earthquake Survivors. AB - INTRODUCTION: There is a burgeoning interest in relations between post-traumatic stress disorder (PTSD) and attention-deficit/hyperactivity disorder (ADHD). Although few studies were conducted, weak evidence was found supporting the hypothesis that ADHD may be a risk factor for the development of PTSD. In addition, there is a paucity of research addressing the relations between dissociation and ADHD. In this study, our aim was to examine the relations between PTSD and ADHD combined with the mediating effect of dissociative psychopathology. METHODS: The participants were 317 undergraduate students, a greater proportion of whom experienced the 2011 Van earthquake (66%). The participants were administered the Posttraumatic Diagnostic Scale, Dissociative Experiences Scale, Adult ADHD Self-Report Scale, Beck Depression Inventory and Beck Anxiety Inventory. RESULTS: We found that ADHD symptoms and dissociation were significantly associated with PTSD. Considering the multivariate relations between ADHD, PTSD and dissociation, significant associations between PTSD and ADHD resulted from symptom overlaps. However, pathological dissociation mediated the relations between PTSD and ADHD. CONCLUSION: We concluded that ADHD comorbidity was not a predominant vulnerability factor for the development of post-traumatic stress response but may be an exacerbating factor after the development of PTSD. PMID- 28360720 TI - Electroneuromyographic Features in Fabry Disease: A Retrospective Review. AB - INTRODUCTION: Fabry disease (FD) is an X-linked recessive inherited disorder characterized by lysosomal alpha-galactosidase deficiency. The purpose of our study was to assess and compare the electroneuromyographic (ENMG) findings of 15 patients with Fabry disease and the electroneurographic (ENG) findings of 15 healthy controls. We have not encountered any similar study in the medical literature of our country. Therefore, we believe that our study will contribute to national literature. METHODS: Fifteen patients with Fabry disease, 13 females and 2 males and 15 healthy controls, 13 females and 2 males, were included in the study. The definite diagnosis of patients with Fabry disease was made based on the enzyme level and genetic mutation. The patients with Fabry disease were examined with ENMG, while the healthy control group was examined with ENG. In the patients with a normal ENMG examination, neuropathic pain was attributed to the small fiber involvement. RESULTS: Patients with Fabry disease had neuropathic pain (LANSS score>=12). While neurological examination was normal in eight patients, glove- and stocking-type hypoesthesia and decreased deep tendon reflexes were observed in five and two patients, respectively. Axonal polyneuropathy was detected in one patient. The ENMG examinations of the other patients were normal. Enzyme replacement therapy could not be initiated in one patient because of pregnancy. The neurological examination of the healthy control group was normal. There was no statistically significant difference between the ENMG features of both groups (p>.05). As in other studies, a routine ENMG examination was normal in our patients with early-stage Fabry disease. Neuropathic pain, seen in patients with Fabry disease in literature, is thought to be due to small fiber involvement. CONCLUSION: Fabry disease should be considered in the differential diagnosis of patients with neuropathic pain at young ages. It should be kept in mind that ENMG examination can be normal at the early stages. Quantitative sensory test, autonomic tests (R-R interval and sympathetic skin response) and skin biopsy should be performed in such cases. In our country, pediatric physicians work on Fabry disease more than physicians dealing with Fabry disease in adults. Therefore, in this retrospective study, we aimed to draw adult and pediatric neurologists' attention to Fabry disease. PMID- 28360721 TI - Risk among Combat Veterans with Post-traumatic Stress Disorder: The Impact of Psychosocial Factors on the Escalation of Suicidal Risk. AB - INTRODUCTION: The purpose of this study was to (a) evaluate the influence of post traumatic stress disorder (PTSD) and other comorbid disorders on suicidal risk among combat veterans and (b) evaluate the impact of psychosocial factors on the escalation of suicidal risk. METHODS: Data were gathered from a random and representative sample of 215 Kosovo War veterans. Subjects were assessed for the presence of lifetime and current psychiatric disorders according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Revision (DSM-IV TR) using the following questionnaires: Harvard Trauma Questionnaire (HTQ), Beck's Depression Inventory (BDI) and Beck's Suicide Intent Scale (BSIS). RESULTS: Suicidal ideations were observed in 44 (20.5%) of the 215 subjects. High suicide risk was found in 31.8% veterans diagnosed with PTSD and comorbid major depressive disorder. In addition, high suicide risk was also observed in the group of unemployed veterans, veterans dissatisfied with social/economic attainment and veterans dissatisfied with living conditions. CONCLUSION: Our study showed that socioeconomic factors contributes to the deterioration of symptoms of major depression, PTSD and other comorbid disorders, with a direct impact of worsening suicidal ideations and suicidal behavior among war veterans. PMID- 28360722 TI - Evaluation of Relationship Between Childhood Maltreatment and Medication Overuse Headache. AB - INTRODUCTION: We aimed to evaluate the prevalence and relationship between childhood maltreatment (CMT) among patients with medication overuse headache (MOH) and to investigate whether CMT is associated with medication overuse in patients having headaches or with headaches that become chronic. Epidemiological studies report a relationship between childhood abuse and headache. There is growing knowledge about the evidence that childhood maltreatment leads to neurobiological sequel. Medication overuse is the most important problem for migraine to become chronic. But in the literature, there was no information about the role of childhood abuse in MOH and for migraine to become chronic. METHODS: A total of 116 patients with headache, aged from 15 to 65 years, were included in the study. Patients having chronic migraine (CM), MOH and episodic migraine (EM) were selected out of patients presented to the headache outpatient clinic. Types of headache were determined according to the revised International Headache Society (IHS) criteria published in 2004. The Childhood Trauma Questionnaire, Beck Depression Inventory and Beck Anxiety Inventory were performed. Presence of psychiatric co-morbidities was evaluated by a clinician using Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, the Fourth Edition. RESULTS: A total of 116 patients with headache were included in the study. Of patients, 64 had MOH, 25 had CM and 27 had EM. The prevalence of CMT, particularly emotional neglect (62%), physical neglect (44%) and emotional abuse (36.2%), was determined higher in all headache groups. There was no statistically significant difference in prevalence of childhood maltreatment between MOH, CM and EM groups. No statistically significant difference was detected between educational status, psychiatric co-morbidities and childhood trauma, except for physical neglect. CONCLUSION: Childhood maltreatment was observed in MOH as in other forms of migraine and headache. However, no significant difference was observed between the three groups of patients with headache. PMID- 28360723 TI - Exploring the Role of Social Anhedonia in the Positive and Negative Dimensions of Schizotypy in a Non-Clinical Sample. AB - INTRODUCTION: The present study aimed to investigate the role of social anhedonia, defined as the lack of ability to feel pleasure from interpersonal relationship, in a multidimensional model of schizotypy and to determine the psychometric properties of the Turkish version of Chapman's Revised Social Anhedonia Scale (SAS) in a non-clinical sample. METHODS: Second-grade students of Ankara University Medical Faculty were recruited (n=266, Mage=20.28). Confirmatory factor analysis was performed to test schizotypy dimensions. The Cronbach's alpha internal consistency value, test-retest reliability and congruent validity of SAS were calculated. RESULTS: The model in which social anhedonia was allowed to load on both schizotypy dimensions fit the data set better than the model in which social anhedonia was allowed to load on negative dimension alone. The internal consistency assessed with Cronbach's alpha was .84, test-retest reliability was r=.76 and the congruent validity of SAS was r=.55. CONCLUSION: The results of current study were consistent with those of earlier studies showing that social anhedonia was related to both schizotypy dimensions. Furthermore, the psychometric properties of the Turkish Version of SAS revealed that it is a reliable and valid measurement to assess social anhedonia in a non clinical population. PMID- 28360724 TI - The Activation of RAGE and NF-KB in Nerve Biopsies of Patients with Axonal and Vasculitic Neuropathy. AB - INTRODUCTION: The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor expressed in tissues and cells, which plays a role in immunity. The activation of RAGE results in the translocation of nuclear factor kappa B (NF-kappaB) to the nucleus for expression of proinflammatory molecules. The role of the RAGE pathway in the pathogenesis of diabetic complications is well determined. We aimed to investigate the role of the RAGE pathway in axonal and vasculitic neuropathy. METHODS: We immunoreacted nerve biopsy samples from 17 axonal neuropathy (AN), 11 vasculitic neuropathy (VN) and 12 hereditary neuropathy (as a control group) with liability to pressure palsy (HNPP) patients with antibodies to NF-kappaB and RAGE. Subsequently, we performed double staining with the antibodies to NF-kappaB or RAGE and T cells, macrophages and Schwann cells. RESULTS: RAGE and NF-kappaB immunoreactivities were higher in the perivascular cuff and in endoneurial cells in VN than in AN and HNPP. Although there is no significant difference, nerve biopsies with AN showed higher NFkappaB and RAGE immunoreactivities than HNPP. The colocalization study showed that most of the NFkappaB- and RAGE-positive cells were CD8 (+) T cells in VN. In AN, all NFkappaB- and RAGE-positive cells were macrophages, whereas all NFkappaB- and RAGE-positive cells were Schwann cells in HNPP. CONCLUSION: The activation of the RAGE pathway predominant in CD8 (+) T cells underscores its role in VN. In AN patients, the immunoreactivity to NFkappaB and RAGE in macrophages may support their role in axonal degeneration without inflammatory milieu. PMID- 28360725 TI - Relationship of Suicidal Ideation and Behavior to Attachment Style in Patients with Major Depression. AB - INTRODUCTION: The attachment theory aims to understand close relationships in adulthood based on the relationship of a child with the caregiver. Attachment styles are classified as secure, preoccupied, fearful and dismissing, which are the subtypes of insecure attachment style. Insecure attachment is suggested to be related to depression and suicide. In this study, the relationship of suicidal ideation and behavior to attachment style is investigated in patients diagnosed with major depression. METHODS: Sixty-two patients diagnosed with major depressive disorder according to the DSM-IV-TR criteria were taken and divided into two groups, 31 patients with and 31 patients without a past suicide attempt. Sixty healthy volunteers matched with the patients for age, gender and education and comprised the control group. Sociodemographic and clinical data form, Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), Hamilton Depression Rating Scale (HDRS), Experiences in Close Relationships Scale (ECR), Scale of Suicidal Ideation and Suicidal Behavior Scale were applied to the groups. RESULTS: In the patients with depression, ECR anxiety and avoidance scores were found to be higher compared with those in the control group. There were no differences in the anxiety and avoidance scores between the patients with and without suicide attempt. The rate of participants who showed secure attachment style in the control group was higher than that of those with depression. In the patients with fearful attachment style, the suicide attempt rate was found to be higher than the other groups. A positively significant relationship was detected between ECR anxiety score and scores of HDRS suicide item, Scale of Suicidal Ideation and Suicidal Behavior Scale. CONCLUSION: Patients with depression were more anxious and more avoidant and showed more insecure attachment. In patients with depression with fearful attachment style, suicide attempts were more common. PMID- 28360726 TI - Validity and Reliability of the Quality of Life in Epilepsy Inventory (QOLIE-31) for Turkey. AB - INTRODUCTION: The purpose of this study was to evaluate reliability and validity of the 31-item Quality of Life in Epilepsy Inventory (QOLIE-31) in Turkish epileptic patients. METHODS: This study was performed methodologically. To standardize the inventory, using a standard "forward-backward" translation and cultural adaptation procedure the English version of the QOLIE-31 was translated to Turkish. Language equivalence of the scale was provided. The opinions of experts were considered regarding the content validity of the scale. Reliability of the scale was determined with the test-retest reliability, item-total correlation and internal consistency analysis. For the construct validity, QOLIE 31 was compared with Nottingham Health Profile (NHP) scale and pre validity was determined. RESULTS: One hundred and forty-eight epileptic patients (62 females, 86 males), with a mean age of 32.5 (SD: 10.71) years were enrolled in the study. Content Validity Index of instrument was .85. Alpha reliability was .91. Item total correlations were between .46 and .74 (p=.001). The mean score for the quality of life of epileptic patients was found to be moderate level (56.4; SD: 17.3). The mean score of Seizure Worry subscale was the lowest (48.9, SD: 29.82), while social function subscale (60.1, SD: 20.12) was found to be highest. As expected, correlations between QOLIE-31 and NHP subscales were fairly strong, particularly between those subscales with close or interdependent content. Thus, Emotional Well-Being correlated with NHP Emotional Reactions, Social Isolation and Pain; Social Function with NHP Social Isolation and Physical Mobility; Seizure Worry with NHP Social Isolation and Emotional Reactions; and Cognitive Function with NHP Energy, Emotional Reactions and Pain. CONCLUSION: The Turkish version of the QOLIE-31 questionnaire has good structural characteristics, is a reliable and valid instrument and can be used for measuring the effect of epilepsy on the quality of life. PMID- 28360727 TI - The Validity and Reliability of the Turkish Version of Miller Forensic Assessment of Symptoms Test (M-FAST). AB - INTRODUCTION: The aim of this study was to show the validity and reliability of the M-FAST Turkish Version. METHODS: Translation and back-translation of the M FAST was done, then the M-FAST Turkish Version was created with linguistic equivalence. The study was performed with 97 detainees and convicts sent from penal institutions who were internalized at our hospital forensic psychiatry service. M-FAST Turkish Version was applied to evaluees and as a result of clinical interview according to DSM-IV-TR diagnostic criteria and various data explorations the evaluee was examined for malingering. To investigate the internal consistency of the scale, Cronbach's alpha and test-retest methods were used. In order to check the validity of the scale, in addition to the clinician's diagnosis, participants were requested to fill the Minnesota Multiphasic Personality Inventory (MMPI) F and K validity scales. RESULTS: The mean age of participants was 31.8+/-9.3 (SD) years. 47 evaluees (48.5%) were diagnosed as malingering. In the internal consistency analysis, Cronbach's alpha Coefficient was found to be .93. Test-retest relationship that was applied to 22 evaluees was found to be highly significant and strong (r=.89, p<.001). M-FAST scores were significantly high at the malingering group (n=47) (z=-8.02, p<.001). ROC curve analysis suggested a score of >=7 points as the optimal cut-off for a malingering level for the M-FAST. Kappa coefficients of malingering +/- groups were found to be, M-FAST>=7 Kappa: .83; F>16 Kappa: .29; F-K>16 Kappa: .30. For diagnosis of malingering, M-FAST Scale and the MMPI inventory scales were evaluated with the Binary Logistic Regression analysis and only M-FAST scores were found to be significant in prediction of malingering. CONCLUSION: The findings of this study support that, M-FAST Turkish Form represents the structure of the original scale and can be used as a reliable and valid instrument. PMID- 28360728 TI - Premorbid Personality Disorders in Male Schizophrenic Patients with or without Comorbid Substance Use Disorder: Is Dual Diagnosis Mediated by Personality Disorder? AB - INTRODUCTION: Although substance abuse is an important clinical problem in schizophrenic patients, very little evidence explains why these patients use drugs and alcohol. This study therefore aimed to examine whether premorbid personality disorders affect substance abuse. METHODS: The sample included 40 male schizophrenic patients with and 40 male schizophrenic patients without substance use disorder comorbidity who had applied to Ankara Numune Research and Training Hospital. Each participant and a family member were interviewed in a structured clinical interview that addressed premorbid personality disorders. RESULTS: Altogether, 32 patients (80%) in the group with comorbidity and 28 (70%) in the group without comorbidity had a premorbid personality disorder. Antisocial (35% vs. 0%; p<.001) and borderline (37.5% vs. 5%; p=.001) personality disorders were more often detected in the group with comorbidity, while avoidant (10% vs. 35%; p=.014) and obsessive-compulsive (0% vs. 15%; p=.026) personality disorders were less frequently found in this group. Comparing the group with comorbidity with premorbid personality types, schizophrenic patients with premorbid antisocial personality disorder were more frequently unemployed and hospitalized as well as had an earlier onset age of schizophrenia (p=.034, p=.038 and p=.035, respectively). Schizophrenic patients with premorbid borderline personality disorder had a significantly earlier onset age of substance use (19+/-5; p=.028). CONCLUSION: Schizophrenic patients with substance use comorbidity variously differ from those without comorbidity and some of these differences may be associated with premorbid personality disorders. PMID- 28360729 TI - Repetitive Transcranial Magnetic Stimulation (rTMS)-Induced Trigeminal Autonomic Cephalalgia. AB - Repetitive transcranial magnetic stimulation (rTMS) is an effective and novel treatment method that has been approved for the treatment of refractory depression by the U.S. Food and Drug Administration. The most common side effects of rTMS are a transient headache that usually responds to simple analgesics, local discomfort in the stimulation area, dizziness, ipsilateral lacrimation and, very rarely, generalized seizure. TMS is also regarded as a beneficial tool for investigating mechanisms underlying headache. Although rTMS has considerable benefits in terms of headache, there is the potential for rare side effects. In this report, we present the case of a patient with no history of autonomic headache who underwent a course of rTMS for refractory unipolar depression caused by an inadequate response to pharmacotherapy. After his fourth rTMS session, the patient developed sudden headaches with characteristics of trigeminal autonomic cephalalgia on the stimulated side, representing a noteworthy example of the potential side effects of rTMS. PMID- 28360730 TI - An Alternative Approach to the Effects of Multiple Traumas: Complex Post Traumatic Stress Disorder. AB - Exposure to multiple traumatic events, particularly in childhood, has been shown to result in more complex symptoms than those seen after exposure to a single traumatic event. In case of overlooking the link between trauma and psychopathology, patients with multiple traumatic experiences receive a variety of different diagnoses that are unable to completely cover the clinical picture. Misdiagnoses of genuine cases inevitably lead to mistreatment. A diagnosis of complex post-traumatic stress disorder has been proposed to cover the emerging psychopathology in survivors of multiple traumas. This present report aimed to discuss the construct and to increase the awareness of complex post-traumatic stress disorder diagnosis among mental health professionals. PMID- 28360732 TI - A Methodological Criticism to Diagnostic and Statistical Manual of Mental Disorders. PMID- 28360731 TI - Association of Demyelinating and Inflammatory Bowel Diseases: A Case Series and Overview of the Literature. AB - Neurological complications of inflammatory bowel diseases (i.e., ulcerative colitis and Crohn's disease) can be summarized as a combination of neuromuscular manifestations, cerebrovascular and demyelinating diseases that can be seen in approximately 3% of patients. In addition, asymptomatic cerebral white matter lesions may be detected in these patients. Clustering of diseases within families may be explained by the exposure to similar environmental factors, shared genes, or complex interactions between genetic and environmental factors. Here we report an epileptic patient with Crohn's disease and cerebral white matter lesions, a family with ulcerative colitis and multiple sclerosis and two patients who have both multiple sclerosis and Crohn's disease. PMID- 28360733 TI - Thirty Years of Magnetic Stimulation: Is it Still Only for the Purpose of Research? PMID- 28360734 TI - Prevalence of Intimate Partner Violence and Associated Factors. AB - INTRODUCTION: The aim of the present cross-sectional study was to investigate the prevalence of intimate partner physical violence among depressive Turkish women, as well as the association of intimate partner physical violence with attachment patterns, childhood traumas, and socio-demographic factors. METHODS: The study included 100 women diagnosed with depressive disorder and 30 healthy women. The Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders-IV axis I disorders, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Adult Attachment Style Questionnaire (AASQ), and Childhood Trauma Questionnaire (CTQ) were used for clinical assessment. RESULTS: It was found that 64% of the women diagnosed with depression were suffering from intimate partner physical violence. In these women, the severity of depression and anxiety symptoms was higher, suicidal ideation and suicide attempts were more common, and the diagnosis of double depression was more prevalent. These women also achieved higher scores in the avoidant and ambivalent subscales of AASQ and higher total scores and higher scores in the physical abuse subscale of CTQ. The partner's and the woman's experiences of physical violence in their families during their childhood predicted intimate partner physical violence for women suffering from depression. CONCLUSION: The investigation of domestic violence contributes to the treatment of depression and also to the recognition and prevention of domestic violence that has profound effects on successive generations. PMID- 28360735 TI - Neurological Complications after Renal Transplantation: A Retrospective Clinical Study. AB - INTRODUCTION: The aim of this study was to evaluate the incidence and types of neurological complications (NCs) and associated factors in renal transplantation (RT) patients. METHODS: Three hundred and forty-four patients who had RT performed at our institution between January 2005 and July 2014 were retrospectively evaluated. RESULTS: File records of the patients revealed 19 who experienced a total of 22 episodes of NCs, of whom three had more than one episode. The mean age of 19 patients included in the study, of whom eight were female, was 37.52+/-13.08 (range, 18-65) years. NCs were classified into central or peripheral depending on the location of involvement of the central nervous system (CNS). CNS involvement was found in 16 (84.2%) of the 19 patients. Tremor (36.8%) was the most common CNS complication in these patients. Encephalopathy, generalized tonic-clonic seizures, and status epilepticus were observed in two patients (10.5%). Delirium and dementia were observed in one patient (5.2%). Headache was experienced by one patient, and agitated depression was observed in one patient. Six patients (26.3%) had the peripheral nervous system involvement. One patient had the numbness of hands with normal electromyography findings, and four patients had polyneuropathy. In one patient, lumbar plexopathy was observed. Seventeen of the 22 NCs were considered to be caused by immunosuppressive agents. Each incidence of amyloidosis, infection, septic emboli, and hypoglycemia caused a neurological episode. The etiology of one episode was unknown. CONCLUSION: Different neurological disorders can be seen after RT, and most of them are caused by immunosuppressive drugs. NCs seen after RT can be treated by decreasing the dose or changing the immunosuppressive drug. PMID- 28360736 TI - Psychiatric Features in Neurotic Excoriation Patients: The Role of Childhood Trauma. AB - INTRODUCTION: Neurotic excoriation is a psychodermatological disease of primary psychological/psychiatric genesis, responsible for self-induced dermatological disorders. Childhood traumatic events are closely related with self-injurious behaviors. The aim of this study is to evaluate the psychiatric features of neurotic excoriation and to investigate the effect of childhood traumatic events on the disease. METHODS: Thirty-eight neurotic excoriation patients who did not receive any psychiatric treatment within the past year and 40 healthy individuals having similar sociodemographic features were included in the study. For clinical evaluation, the Structured Clinical Interview for DSM-IV Axis I Disorders, Beck Depression Inventory, Beck Anxiety Inventory, and Childhood Trauma Questionnaire Short Form were applied to all the individuals. RESULTS: In this study, we observed that 78.9% of neurotic excoriation patients were diagnosed with at least one Axis I psychiatric disorder, the most frequent diagnoses of which were major depressive disorders and anxiety disorders. The anxiety and depression levels were significantly higher in the patient group than in the healthy individuals. Regarding the Childhood Trauma Questionnaire, emotional neglect, emotional abuse, and physical abuse subscales and weighted average total scores were found to be significantly higher in the patient group (p<.05). CONCLUSION: Our study has shown a close relationship between neurotic excoriation and childhood traumatic events as well as the accompanying psychiatric problems. We suppose that early interventions by both dermatologists and psychiatrists and especially a detailed investigation of childhood traumatic events by establishing a therapeutic collaboration are highly important and that using psychotherapeutic interventions can result in better treatment outcomes in many patients. PMID- 28360737 TI - Risk Factors for Hemorrhagic Transformation in Patients with Acute Middle Cerebral Artery Infarction. AB - INTRODUCTION: Hemorrhagic transformation (HT) after acute ischemic stroke (AIS) can be seen at any time following ischemic stroke. Although HT usually occurs as a complication of antithrombotic, anticoagulant, or thrombolytic treatments, it can also occur spontaneously. We aimed to investigate the occurrence of early HT and its relevant risk factors in patients diagnosed with acute middle cerebral artery (MCA) infarction who were not treated with thrombolytic agents. METHODS: We recruited 171 patients with acute MCA infarction between January 2011 and July 2012 who were not treated with thrombolytic agents and were suitable to our inclusion criteria. Controlled neuroimaging was performed immediately in patients with deterioration, otherwise on day 7 following stroke. All patients were investigated for AIS risk factors and biochemical analyses were performed. Patients with HT in controlled neuroimaging were grouped both clinically (i.e., symptomatic or asymptomatic) and radiologically, according to "European Cooperative Acute Stroke Radiological Study" (ECASS), and risk factors were examined. RESULTS: We enrolled 171 patients [94 men (55%) and 77 women (45%)] in the study. HT developed in 37 patients (21.63%). In terms of risk factor analysis, the most frequent etiological factor was atherosclerosis in AIS patients (50.3%). National Institutes of Health Stroke Scale scores were significantly higher both in sHT patients according to asHT patients and in HT patients on day 7 compared with their initial scores. Serum low-density lipoprotein (LDL-C), triglycerides (TG), and total cholesterol (TC) levels were significantly lower in patients with HT (p<.001). CONCLUSION: HT is a major complication in AIS that considerably increases the morbidity and mortality. To reduce the occurrence of HT, risk factors for each patient population should be determined. Acute thrombolytic therapy should be used cautiously in high-risk patients, and appropriate alternative therapies should be revised in them. PMID- 28360739 TI - Survey on Smoking, Consuming Alcohol, and using Illicit Drugs in Patients with Epilepsy. AB - INTRODUCTION: Addiction can be defined as the continuous consumption of addictive substances or repetition of certain behaviors despite adverse consequences. Epilepsy is associated with an increased risk of psychiatric disorders. However, to the best of our knowledge, there is no published data regarding addictions in patients with epilepsy. Considering the high incidence of psychopathology, we planned a survey using a self-report questionnaire to study some of the addictive behaviors in patients with epilepsy and in control subjects. METHODS: Patients from our outpatient epilepsy clinic (n=106) and control subjects (n=96) aged between 18 and 65 years took the 20-question questionnaire that screened for smoking, consuming alcohol, or using other illicit drugs. RESULTS: Fifty-three percent of patients with epilepsy were male (n=57) and in the control group, 52% were male (n=50) (p=.062). The mean age was 32.66+/-2.23 years for patients with epilepsy and 35.70+/-0.59 years for the control group (p=.810). Mean duration of epilepsy was found to be 14.33+/-11.26 (1-46) years. Majority of patients with epilepsy (84%) had focal epilepsy. Alcohol intake was found to be significantly lower in patients with epilepsy (p=.0001). There was no difference regarding smoking (p=.530) or using illicit drugs between the groups (p=.262). Smoking cigarettes was lower in new onset epilepsies (<5 years) compared with epilepsies of longer duration (p=.031). CONCLUSION: Recent studies connote to some common substrates in the pathophysiology of epilepsy and addiction. Therefore, we wanted to evaluate some addictive behaviors in patients with epilepsy. Although this study did not show significant differences other than low frequency of alcohol use in patients with epilepsy and low rate of smoking in patients with epilepsy duration of <5 year, further studies among homogeneous epilepsy subgroups with larger scale along with their neuropsychological profiles may still be required. PMID- 28360740 TI - Persistent Depression as a Novel Diagnostic Category: Results from the Menderes Depression Study. AB - INTRODUCTION: Persistent depressive disorder (PDD) introduced in the Diagnostic and Statistical Manual of Mental Disorders (DSM) 5 as a novel diagnostic category represents a consolidation of two separate DSM-IV categories, chronic major depressive disorder (MDD) and dysthymic disorder. The present study aims to investigate the frequency and clinical as well as socio-demographic correlates of PDD in comparison with those of episodic MDD among patients seeking treatment for depressive symptoms. METHODS: Participants were 140 depressive out-and in patients under treatment at the psychiatry clinic of the Adnan Menderes University Research Hospital. Each patient was assessed by means of a structured clinical interview (SCID-I) and relevant psychometric instruments including the Hamilton Depression Inventory and Eskin Suicidal Behavior Inventory. RESULTS: Among the depressive patients, 61% fulfilled the criteria for PDD and 39% for episodic MDD. As compared with patients with episodic MDD, the PDD patients were older (d=.54), lower in educational attainment (d=.55), more likely to have comorbid generalized anxiety disorder (OR=3.7), and more prone to report symptoms of anxiety, hopelessness, pessimism, and somatic complaints. Nevertheless, the PDD patients displayed heterogeneous characteristics with respect to clinical severity and suicidal behavior. CONCLUSION: Our findings suggest that majority of depressive patients, including those fulfilling the criteria for MDD, have been suffering from a persistent ailment rather than an episodic disorder. Clinicians with a cross-sectional perspective are more likely to diagnose MDD, whereas those with a longitudinal perspective are more likely to identify PDD in the majority of depressive patients. The incorporation of both of these perspectives into DSM 5 in a complementary manner will possibly enhance our insight into depressive disorders and improve our treatment results. PMID- 28360738 TI - Factors Associated with Depression in Obsessive-Compulsive Disorder: A Cross Sectional Study. AB - INTRODUCTION: Major depressive disorder (MDD) is the most frequent comorbid psychiatric condition associated with obsessive-compulsive disorder (OCD). This study aimed to evaluate the prevalence of current depression in OCD, differences in socio-demographic and clinical characteristics, and obsessive-compulsive symptoms between OCD patients with and without depression. Additionally, factors associated with comorbid depression were investigated in our study. METHODS: In total, 140 OCD patients, of which 63 were OCD patients with MDD (OCD+MDD, n=63) and 77 were OCD patients without depression (OCD-MDD, n=77) were included in the study. All patients were diagnosed with OCD using the Structured Clinical Interview for DSM-IV. The Yale-Brown Obsessive-Compulsive Scale, Beck Anxiety Scale, and Beck Depression Scale were administered to all patients. After the socio-demographic and clinical variables and scales were accomplished, the OCD patients divided into two groups as OCD with or without depression and we compared their mean scores of the variables and scales. Univariate analyses were followed by logistic regression. RESULTS: There were no significant differences in age, gender, marital status, period without treatment, profession, medical and family history, and social support between the two groups. Anxiety, depression, and obsession and compulsion scores were significantly higher in the OCD+MDD group. The avoidance, insight, instability, and retardation scores of the OCD+MDD group were also significantly higher than those of the OCD-MDD group. CONCLUSION: Our study suggests that many factors are strongly associated with depression in OCD. Positive correlations between poor insight, severity of obsession and compulsion, and stressful life events during the last six months increased the risk of depression in OCD. Our study suggests that high level of avoidance, instability and retardation, history of suicidal attempt, and delayed treatment are other notable factors associated with the development of depression in OCD. PMID- 28360741 TI - Evaluation of Eating Attitude in Patients with Migraine. AB - INTRODUCTION: This study aimed to investigate the eating attitudes in patients with migraine. METHODS: Fifty-nine patients (mean age: 32.54+/-8.47 years) diagnosed with migraine according to the International Classification of Headache Disorder, 2004, and 47 age-, gender- and education-matched healthy controls (mean age: 31.85+/-7.14 years) were enrolled for this study. Sociodemographic data were recorded, and the body mass index was calculated as kilograms per meter squared. Data regarding the duration of illness and attack, frequency of migraine attacks, and the presence of aura were recorded. Migraine severity was assessed by Migraine Disability Assessment Score (MIDAS). Eating Attitudes Test (EAT), Beck Depression Inventory (BDI), and Beck Anxiety Inventory were applied to all participants. RESULTS: The patients with migraine had significantly higher EAT scores, levels of anxiety, and depression than controls (p<.01). Furthermore, 11.9% of patients with migraine had an EAT score of 30 or higher, which is suggestive of a disordered eating attitude, whereas this rate was 2.1% in healthy controls (p<.05). The scores of EAT and BDI had positive correlation with the scores of MIDAS in patients with migraine (r=.298, p<.05; r=.332, p=.01, respectively). CONCLUSION: In our study, disordered eating attitudes and the levels of anxiety and depression were high in patients with migraine than controls. Our study is important to demonstrate the connection between migraine and disordered eating attitudes. PMID- 28360742 TI - Reliability and Validity of the Turkish Version of Abdel-Khalek's Death Anxiety Scale among College Students. AB - INTRODUCTION: Although death anxiety is considered a universal phenomenon, attitudes toward death may vary across populations that differ in terms of religion and culture. Abdel-Khalek's Death Anxiety Scale (ASDA) was developed on the basis of the rationale that there are specific concepts related to death and after death in Muslim populations. This study aims to translate and adapt ASDA in the Turkish population, examine its validity and reliability, and to compare its psychometric properties with the widely used Templer's Death Anxiety Scale (DAS). METHODS: A total of 220 medical students were included in the study. The Turkish version of ASDA, DAS, and Hospital Anxiety and Depression Scale were used for data collection. RESULTS: Cronbach's alpha coefficients were .86 for ASDA and .66 for DAS. Analysis by principal components with varimax rotation produced five factors for ASDA that explained 65.6% of total variance. ASDA and DAS were highly correlated with each other (r=.68, p<.001). CONCLUSION: The results of this study indicate that the Turkish version of Abdel-Khalek's Death Anxiety Scale is a reliable and valid instrument. The Turkish version of ASDA revealed better psychometric properties than DAS. This finding may reflect specific cultural and religious attitudes toward death or may result from more comprehensible language use in ASDA. PMID- 28360743 TI - Evaluation of the Adherence to Immunmodulatory Treatment in Patients with Multiple Sclerosis. AB - INTRODUCTION: In this article, we report the data regarding treatment adherence of a group of patients with multiple sclerosis (MS) and relapsing-remitting or secondary progressive disease who were followed in the MS outpatient clinic of Bozyaka Education and Research Hospital, Izmir. METHODS: We collected the demographic data of 219 patients with MS who were treated with immunomodulatory drugs and the documentary data on the disease characteristics from the patient' files. Each patient was provided a detailed questionnaire regarding treatment adherence in addition to the Beck depression scale (BDS) and Paced Auditory Serial Addition Test (PASAT). Nonadherence was defined as the discontinuation of the drug, i.e., more than one dose a month for intramuscular interferon, six doses a month for glatiramer acetate, and four doses a month for subcutaneous interferons. Statistical analyses were performed using Medcalc statistics package. For those parameters with an even distribution, the paired samples t test was used to compare the results. RESULTS: Of the 219 [183 relapsing remitting multiple sclerosis (RRMS) and 36 secondary progressive multiple sclerosis (SPMS)] patients included in the study, 143 patients were women and 76 were men. The mean age of the patients was 40.77+/-10.36 years. The mean expanded disability status scale (EDSS) score was 2.90+/-1.88, and mean annualized attack rate (ARR) was .65+/-.55. Of the 219 patients, 75.1% continued the immunomodulatory treatment. Thirty-three patients in the RRMS group and 23 patients in the SPMS group abandoned the immunomodulatory treatment. Treatment adherences were similar between patients with RRMS and SPMS (53%). Adherence revealed no correlation with age, ARR, PASAT score, and disease duration. However, higher EDSS and depression scores had significant positive correlation with adherence. Moreover, treatment adherence was noted to be lower in the group with higher education levels. Treatment discontinuation did not correlate with age, ARR, BDS, or PASAT scores. The disease duration and EDSS scores were found to be significantly correlated with treatment discontinuation. CONCLUSION: In this extensively followed up patients' group with multiple sclerosis, the ones with extended disease duration, higher disability, and more educated had higher rates of treatment discontinuation and lower levels of treatment adherence. The patient-reported outcomes and well-documented treatment adherence data will contribute to the neurologists' understanding of the patients' inclinations regarding the injectable treatments and help in better management of the immunomodulatory treatments. PMID- 28360744 TI - The Effect of Dressing Styles and Attitudes of Psychiatrists on Treatment Preferences: Comparison between Patients and Psychiatrists. AB - INTRODUCTION: Recently, different dressing styles and attitudes of psychiatrists have been proposed to enhance the interaction between patients and the physician. The aim of the present study was to investigate the preferences of dressing style and attitudes of a psychiatrist of the patients referred to an outpatient psychiatry clinic and the perception of psychiatrists regarding the preferences of the patients. METHODS: One hundred and fifty-three patients referred to the outpatient psychiatry clinic of the Bulent Ecevit University School of Medicine, and 94 psychiatrists have been included in the present study. RESULTS: When the images of psychiatrists were evaluated in terms of referral for treatment, trust in treatment, and willingness to share their confidential matters, both groups gave minimum scores to causal/sports dress style. While psychiatrists preferred to dress in a suit, casuals, and white coat, the preference order was white coat, casual dress, and suit in the patient group. There was a significant difference between the groups with respect to three dressing styles. CONCLUSION: It can be suggested that psychiatrists assume that patients are traditional in terms of their preference of the dressing style of a doctor and doctor-patient relationship, and a white coat is important to enhance the treatment adherence of patients. PMID- 28360745 TI - Executive Functioning in Subtypes of Attention Deficit Hyperactivity Disorder. AB - INTRODUCTION: This study aims to evaluate executive functions (EF), such as inhibition, planning, working memory, and set shifting, in children with attention deficit hyperactivity disorder (ADHD) by comparing three ADHD subtype groups (ADHD-Inattentive, ADHD-Combined, and ADHD-Comorbid) and a normal control group. METHODS: Participants included 147 children. In total, 111 children were assigned to the ADHD groups of the study. Each child was matched according to the WISC-R Full-Scale IQ-score, sex, and age and was grouped as follows: ADHD Inattentive group (ADHD-I; n=37), ADHD-Combined (ADHD-C; n=37), ADHD-Comorbid group (ADHD-Comorbid with oppositional defiant disorder and/or conduct disorder; n=37), and control group (n=36). The tests used to assess the children were Conners' Parent and Teacher Rating Scales; Wechsler Intelligence Scale-Revised; Tower of London test; Wisconsin Card Sorting Test; Stroop Color-Word Test, and verbal fluency test. The data were analyzed by one-way ANOVA between subjects for all dependent variables. RESULTS: Children in the ADHD-I group had significantly better performances in verbal working memory and verbal category shifting than children in the ADHD-C group. There was no significant difference between the ADHD-I and ADHD-C groups in terms of inhibition, set shifting, verbal fluency, cognitive flexibility, and planning. The ADHD-Comorbid group displayed more severe impairments in EF measures than the ADHD-C group; however, the severity was not statistically significant. EF performances of children in the control group were similar to children in the ADHD-I group but better than children in the ADHD-C and ADHD-Comorbid groups. CONCLUSION: The outcome of the study indicated that subjects in the ADHD-Comorbid and ADHD-C groups had more severe EF deficits than subjects in the ADHD-I and control groups. PMID- 28360747 TI - Intolerance of Uncertainty and Coping Mechanisms in Nonclinical Young Subjects. AB - INTRODUCTION: We aimed to explore the relationship between intolerance of uncertainty (IU) and coping mechanisms in a nonclinical sample with the same age and educational level. METHODS: The Coping Orientations to Problems Experienced (COPE) scale was used to evaluate the coping mechanisms. The IU scale was used to evaluate IU situations. RESULTS: We found that the negative impact of uncertainty on the action in female students was greater than males. While female students used more planning, instrumental support, reinterpretation, religion, emotional support, venting, and mental disengagement coping styles, male students used more humor, denial, and alcohol/drug abuse coping styles. Subjects with psychological problems had higher IU scores and used some more coping mechanisms (restraint, acceptance, behavioral disengagement, and alcohol/drug abuse) than the others. CONCLUSION: Our results suggest that healthy subjects use different coping styles and respond differently to uncertainty in both genders. PMID- 28360746 TI - The Psychiatric Consequences of Child and Adolescent Sexual Abuse. AB - INTRODUCTION: The purpose of this study was to investigate the psychiatric consequences of sexual abuse and its associated factors in children and adolescents referred to our child and adolescent psychiatry clinic from official medico-legal units. METHODS: All victims of sexual abuse (n=590) aged 1-18 (mean: 13.56+/-3.38) referred from forensic units to Ondokuz Mayis University Child and Adolescent Psychiatry Clinic over a period of 2 years [boys: 83 (14.1%); girls: 507 (85.9%)] were included. Child and adolescent psychiatry and forensic medicine specialists evaluated all the cases. The Wechsler Intelligence Scale for Children Revised Form (WISC-R) and the Schedule for Affective Disorders and Schizophrenia for School Age Children-Present and Lifetime Version-Turkish Version (K-SADS-PL T) were applied. RESULTS: Abuse-related psychiatric diagnoses (of which 45.9% were major depressive disorder and 31.7% were post-traumatic stress disorder cases) were made in 75.2% of the cases. In 80.3% of the cases, the perpetrators were known to their victims [incest, n=91 (15.1%)], and intercourse took place in 48.8%. Although gender and age were not significantly associated with the appearance of any psychiatric disorders, severity of abuse (e.g., intercourse; p=.006), additional physical assault (p<.001), and incest (p<.001) had a significant correlation with psychiatric disorders. To explore the predictive value of multiple factors in the appearance of any sexual assault-related psychiatric disorder, a logistic regression model was used to determine the best linear combination of age, gender, abuse severity, incest, involvement of any other victim, additional physical assault, and length of time from first abuse to first psychiatric evaluation. This combination of variables (occurrence of incest, additional physical assault, and a long duration from first abuse to first psychiatric evaluation) significantly predicted the appearance of a psychiatric disorder of any kind (chi2=55.42; df=7; n=522; p<.001). CONCLUSION: Our findings reveal that the occurrence of incest, additional physical assault, and a long duration from first abuse to first psychiatric evaluation predict higher rates of sexual abuse-related psychiatric disorders. PMID- 28360748 TI - Extreme Appraisals of Internal States and Duration of Remission in Remitted Bipolar Patients. AB - INTRODUCTION: To identify dysfunctional attitudes seen in bipolar disorder (BPD) is important for the cognitive theories of BPD and corresponding psychosocial interventions. Cognitions are seen as vulnerability factors in the development and maintenance of BPD. The present study aims to contribute to the cognitive literature on BPD by examining depressive and hypomanic attitudes and their contribution to the prediction of BPD diagnosis as well as by exploring the relationship between dysfunctional cognitions and clinical features (types of episodes experienced, duration of illness, and duration of remission). METHODS: One hundred and eighteen remitted bipolar patients and 103 healthy controls completed the Mood Disorder Questionnaire (MDQ), Turkish Brief-Hypomanic Interpretations and Positive Predictions Inventory (HAPPI), and Dysfunctional Attitudes Scale. RESULTS: The bipolar group had significantly higher depressive and hypomanic attitudes than the control group. No significant differences were found regarding the types of episodes experienced and duration of illness. However, both types of attitudes decreased as the duration of remission increased. They were also found to contribute to the prediction of bipolar diagnosis together with the screening of the MDQ. CONCLUSION: The results pointed out that dysfunctional cognitions may be utilized as possible indicators for the risk of relapse in clinical groups and vulnerability for BPD among other populations. PMID- 28360749 TI - Effects of Depression on Treatment Motivation in Male Alcohol Dependence. AB - INTRODUCTION: Treatment motivation in alcohol dependents is usually viewed as a strong predictor of seeking treatment and treatment success. The conditions affecting motivation in alcohol dependence, however, has not been clarified. In this study, it is aimed to determine the effects of depression on treatment motivation in male alcohol dependence. METHODS: The present study included 34 male alcohol dependents presenting to outpatient clinics in Manisa Hospital of Mental Disorders and Hospital of Celal Bayar University. The patients underwent evaluation using the socio-demographic and clinical information form, DSM-IV SCID I Clinical Version, Treatment Motivation Questionnaire (TMQ), and Hamilton Depression Rating Scale (HDRS). RESULTS: A significant relationship was found between the total score of TMQ and HDRS (p=.039). CONCLUSION: We believe that the present study, in which we examined the relationship between treatment motivation in male alcohol dependence and depression, would provide a significant contribution to literature. It is also important to investigate other factors that may affect treatment motivation in male alcohol dependence. Studies with larger samples are needed on this topic. PMID- 28360752 TI - Pregabalin Use Disorder. PMID- 28360750 TI - Menstrual Cycle in Schizophrenic Patients: Review with a Case. AB - There are not enough studies about the relationship between menstrual psychosis and schizophrenia exacerbation during the menstrual cycle. In patients diagnosed with schizophrenia, it is important to examine the psychotic symptoms and depression and anxiety symptoms during the menstrual cycle and to adjust the treatment according to these symptoms. If depression and anxiety symptoms are present, selective serotonin reuptake inhibitors can be used. In patients with exacerbated psychotic symptoms, it may be effective to increase the dose of an antipsychotic drug, which has no effect on prolactin release, 3-5 days prior to menstruation. In addition, hormonal therapy or menstrual cycle suppression is an alternative option. In this article, a case of a schizophrenic patient whose psychotic symptoms exacerbated with the menstrual cycle is presented. PMID- 28360751 TI - Dopamine Dysregulation Syndrome after Deep Brain Stimulation of the Subthalamic Nucleus. PMID- 28360753 TI - Steroid-Responsive Late Symptomatic Perihematomal Edema In Intracerebral Hemorrhage. PMID- 28360754 TI - Clinically Isolated Syndromes: Clinical Characteristics, Differential Diagnosis, and Management. AB - Clinically isolated syndrome (CIS) is a term that describes the first clinical onset of potential multiple sclerosis (MS). The term CIS is typically applied to young adults with episodes of acute or subacute onset, which reaches a peak quite rapidly within 2-3 weeks. In 85% of young adults who develop MS, onset occurs with an acute, CIS of the optic nerves, brainstem, or spinal cord. When clinically silent brain lesions are seen on MRI, the likelihood of developing MS is high. Because no single clinical feature or diagnostic test is sufficient for the diagnosis of CIS, diagnostic criteria have included a combination of both clinical and paraclinical studies. Diagnostic criteria from the International Panel of McDonald and colleagues incorporate MRI evidence of dissemination in time and space to allow a diagnosis of definite MS in patients with CIS. As CIS is typically the earliest clinical expression of MS, research on patients with CIS may provide new insights into early pathological changes and pathogenetic mechanisms that might affect the course of the disorder. With recent improvements in diagnosis and the advent of disease-modifying treatments for MS, there has been growing interest and research in patients with CIS. PMID- 28360755 TI - Cognitive Impairment in Multiple Sclerosis: Historical Aspects, Current Status, and Beyond. AB - Although the cognitive symptoms of multiple sclerosis (MS) were acknowledged in the 1800s, until the latter part of the 20th century, these symptoms were poorly recognized. Cognitive impairment associated with MS has a profound impact on many aspects of daily life, including employment, academic life, and social functioning. The cognitive reserve can be protected in MS patients to a certain limit, and prevention might be linked to early treatment. The analyses of historical and contemporary data can help researchers gain a clear vision of the direction in which to proceed in the future for better insight into cognitive issues in MS. PMID- 28360757 TI - Community Mental Health Services: Quo Vadis? PMID- 28360756 TI - Magnetic Resonance Imaging as a Major Milestone in Multiple Sclerosis Diagnosis and Treatment. AB - Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Magnetic resonance imaging (MRI) has played a unique role in the diagnosis and management of patients with MS. In recent years, there have been considerable changes in the diagnostic criteria for MS as MRI-based studies have demonstrated their power in the earlier and more accurate diagnosis of the disease. Moreover, MRI metrics have become key supportive outcome measures for evaluating the efficacy of experimental treatments in randomized controlled trials. MRI can also be used as a prognostic tool in patients with clinically isolated syndrome (CIS). Conventional MR techniques including proton density, T1/T2-weighted images, and FLAIR sequences are now accepted in standard protocols for diagnostic and treatment outcome measures in clinical trials for MS. Radiological features may show a similarity between radiologically isolated syndrome and MS. Approximately two-thirds of individuals with RIS exhibit radiological progression and one-third develop neurological symptoms during mean follow-up times of up to five years. However, a current challenge in the global application of established criteria for RIS involves the accurate classification of subjects with incidentally identified anomalies that are highly characteristic of MS, in comparison to those categorized in medical parlance as possessing "unidentified bright objects" or nonspecific T2-hyperintensities, which are commonly identified in patients with migraine headache who fulfill the spatial dissemination requirements for MS. The need for systematically acquired data for improvements in the classification of radiologically isolated syndrome (RIS) and the generation of risk algorithms are critically important, providing a basis for scientifically supported management and most importantly, minimizing the number of improperly classified subjects exposed to unnecessary medical testing, MS treatments, and psychological harm. In addition, brain atrophy is a common finding that can now be quantitatively assessed by MR volumetric measures. Further, integrated strategies that combine MRI and clinical markers in scoring systems have provided a potentially useful approach for the management of patients with MS. PMID- 28360758 TI - Prevalence of Substance Use in Patients Diagnosed with Schizophrenia. AB - INTRODUCTION: Substance abuse among schizophrenic patients is a growing clinical concern. Substance use disorders and their effects on the course of schizophrenia have made the identification and treatment of schizophrenic patients a high priority. This study aimed to investigate the prevalence of substance use, preferred types of substances, sociodemographic characteristics and clinical features of schizophrenia, and substance use impact in schizophrenic patients. METHODS: Hundred patients who were consecutively admitted to the psychiatry clinic and were diagnosed with schizophrenia according to the DSM-IV criteria were enrolled in this study. Individual interviews were conducted during the patients. In order to evaluate substance abuse disorder (SAD) as per DSM-IV criteria, the substance use disorder section of the structured clinical interview for DSM disorders-II (SCID-II) form was used. In addition, the following were applied to schizophren-ic patients: sociodemographic data form, medical history form, Brief Disability Questionnaire (BDQ), UKU Side Effect Rating Scale (UKUSERS), Insight Rating Scale (IRS), Alcohol Use Dis-orders Identification Test (AUDIT), Fagerstrom Nicotine Dependence Test (FNDT), Global As-sessment of Functioning Scale (GAF), Scale for the Assessment of Positive Symptoms (SAPS), Scale for the Assessment of Negative Symptoms (SANS), and Calgary Depression Scale (CDS). RESULTS: Schizophrenia and alcohol and drug use were more common in males, and younger age was found to have no association with substance use. Unemployment, low education levels, rural survival rates, age at disease onset, the doctor first age of the applicant, the first inpatient years, legal issues, harm caused by others and suicidal behavior, SAPS, SANS, CDS received from their scores significant difference was detected. Schizophrenic patients with substance use had higher side effects of drugs, disability, and psychopathology scores than schizophrenic patients without substance use. The functioning of schizophrenic patients with substance use was worse, and the total length of stay was longer. Nicotine, alcohol, biperiden, cannabis, and volatile substances were the preferred materials most commonly used by schizophrenic patients. CONCLUSION: In our country, limited research has been conducted on the prevalence of substance use in schizophrenic patients. Therefore, we believe that this study will contribute to the literature on the subject. More sample groups and first-episode patients as well as follow-up studies will contribute to a better understanding of the effect of substance use on the clinical course of schizophrenia. PMID- 28360759 TI - Antinociceptive Effect of Mirtazapine in Rats with Diabetic Neuropathy. AB - INTRODUCTION: To evaluate the antinociceptive effect of mirtazapine and the mechanisms mediating this effect in neuropathic pain in rats with diabetes. METHODS: The experiments were performed in Sprague Dawley rats using a hot-plate device. Streptozotocin (STZ) was administered to the rats after taking control measurements. Rats with a blood glucose level of 240 mg/dL or above in the blood specimen obtained from the tail vein 3 days after STZ administration were considered as being diabetic. Three weeks after STZ administration, the hot-plate test was performed. Compared with the control measurements, rats that exhibited >20% decrease in the second hot-plate test measurements were considered to have developed neuropathy. Drugs [mirtazapine, naloxone (opioidergic antagonist), metergoline (serotonergic antagonist), and BRL44408 (adrenergic antagonist)] and drug combinations were administered to those rats that developed neuropathy. After administrating the drugs or drug combinations, the third hot-plate test was performed. RESULTS: Mirtazapine at doses of 10 and 15 mg/kg exhibited a significant antinociceptive effect. Naloxone, metergoline, or BRL44408 alone did not cause an antinociceptive effect. However, combinations of these drugs with mirtazapine (15 mg/kg) significantly decreased the antinociceptive effect of mirtazapine. CONCLUSION: It is suggested that mirtazapine has a significant antinociceptive effect in diabetic neuropathy and that opioidergic, serotonergic, and adrenergic systems have roles to play in this effect. PMID- 28360760 TI - Evaluation of Interoceptive Awareness in Alcohol-Addicted Patients. AB - INTRODUCTION: Interoceptive awareness (IA) is defined as an ability to accurately perceive interoceptive processes, which comprise receiving, processing, and integrating body-relevant signals together with external stimuli. Interoceptive processes affect the motivated approach or avoidance behavior toward stimuli. Alcohol and other substances have effects on the autonomic system that result in altered interoceptive processes. Individuals who have disturbed IA may be at a higher risk of addiction because they are not able to utilize sufficiently body relevant signals to guide their decision-making. The hypothesis that IA in alcohol-addicted patients would be affected and that the disturbed IA would be associated with alcohol craving was tested in this study. METHODS: The study was conducted with 55 patients diagnosed with alcohol addiction according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria and who had been sober for at least two weeks and 52 non-addicted healthy controls. IA measurements were performed using the heartbeat perception performance method, which determines participants' awareness of their own heartbeat by comparing the number of subjectively perceived heartbeats with an objective heart rate measure recorded with ECG during four separate intervals. In addition, the Alcohol Use Disorders Identification Test (AUDIT), Penn Alcohol Craving Scale (PACS), and Obsessive Compulsive Drinking Scale (OCDS) were performed on the alcohol-addicted patient group. RESULTS: IA scores were significantly lower in the alcohol-addicted patients than the control subjects. IA scores of alcohol-addicted patients were negatively correlated with the levels of alcohol craving sensations according to the PACS results. CONCLUSION: Our results corroborate the suggestion that IA in alcohol-addicted patients would be affected and that poor IA would be associated with alcohol craving and could be a maintaining factor for drinking behavior. PMID- 28360762 TI - Electroacupuncture Therapy in Nicotine Dependence: A Double Blind, Sham Controlled Study. AB - INTRODUCTION: The number of non-pharmacological controlled studies is insufficient in the treatment of nicotine dependence (ND). Nevertheless, non pharmacological treatments, such as electroacupuncture (EA), are becoming increasingly popular in the treatment of ND. The aims of this study were to determine the efficacy and safety of "true EA therapy" (TEAT) compared to those of "sham EA therapy" (SEAT) in ND treatment. METHODS: Eligible patients who met the DSM-IV criteria for ND (n=450) were included in the study. This study was a double-blinded, sham-controlled clinical trial with a 4-week treatment period and 4-week follow-up conducted between June and December 2009 at a psychiatry outpatient clinic. One hundred and sixty four adult (>=18 years; 44 men, 120 women) cigarette smokers out of 450 patients who met the inclusion and exclusion criteria were enrolled in the study in a ratio of 1:1 to receive TEAT (n=84) or SEAT (n=80). Routine biochemical and hematological tests, chest X-Ray, and ECG were carried out; end-expired carbon monoxide (CO) levels were measured too. Clinical characteristics were obtained through the Fagerstrom Nicotine Dependence Test (FNDT), Hamilton Rating Scale for Depression (HRSD), and Hamilton Anxiety Scale (HAS). EA was carried out by a trademark device, Antismoke 3000(r). Efficacy analyses were performed on "intent-to-treat analysis." Primary outcome was the differences from baseline to endpoint in mean FNDT, number of cigarettes smoked per day, and CO levels at week 4. Secondary outcomes were the same variables at week 8. These variables were assessed via analysis of covariance (ANCOVA). RESULTS: Mean baseline FNDT, HRSD, HAS, and CO levels of the groups were statistically similar. TEAT and SEAT groups demonstrated no significant changes in the outcome variables and smoking cessation rates (35.7% and 30%, respectively). Of those remaining outside of the study, 8.3% were from the TEAT group and 8.7% were from the SEAT group; there was no statistical difference between the groups. The rate of treatment discontinuation was similar between the TEAT (44%) and SEAT (43.7%) groups (p>0.05). The rates of adverse events were not similar too. CONCLUSION: This study showed that both TEAT and SEAT have similar efficacy and safety profiles in patients with ND. PMID- 28360761 TI - Screening for Electrophysiological Abnormalities in Chronic Hepatitis C Infection: Peripheral Neuropathy and Optic Neuropathy. AB - INTRODUCTION: To investigate the existence of peripheral and optic neuropathies in asymptomatic individuals with hepatitis C infection. METHODS: Thirty consecutive patients who were followed in a hepatitis C outpatient clinic were recruited for electrophysiological evaluation together with 30 age- and gender compatible healthy controls. All patients had a detailed neurological examination. The information regarding the disease duration and management with interferons were collected. Nerve conduction studies and visual evoked potentials (VEP) were recorded in all subjects. The results of the patient and control groups were statistically compared. RESULTS: Of the patients with hepatitis C infection, 16 were females and 14 males. The mean age was 57.5 years, and the average disease duration was 6.43 years. The P100 latencies in the patient group were within normal limits, while the amplitudes were meaningfully small by comparison with the controls. There were some abnormalities in the nerve conduction studies of 15 patients. Sensorial neuropathy was detected in two patients, sensorimotor polyneuropathy in four, carpal tunnel syndrome in seven, and carpal tunnel syndrome and sensorimotor polyneuropathy as comorbid states in another two patients. The nerve conduction studies and VEP parameters were entirely normal in the control group. CONCLUSION: Hepatitis C-related neurological abnormalities may occur both in the central and peripheral nervous system. Mononeuritis multiplex, sensorial axonal neuropathy, and multiple mononeuropathies are some of the presentations of the peripheral nervous system involvement. The mode of infection is considered to be via vasculitic mechanisms. In addition, optic neuropathy is a known complication of interferon treatment. Autoantibodies, cytokines, chemokines, and cryoglobulins are accused to play roles in the pathogenesis. In this study, we investigated the involvement of the peripheral nervous system and optic nerves in a group of patients with hepatitis C. The results were in favor of peripheral nerve injury of various types and optic neuropathy of the axonal type. PMID- 28360763 TI - Vitamin D Deficiency in Obsessive-Compulsive Disorder Patients with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections: A Case Control Study. AB - INTRODUCTION: Previous studies have indicated that vitamin D deficiency is common in psychiatric patients, particularly in those with neuropsychiatric disorders such as autism and schizophrenia. Vitamin D is an important neurosteroid hormone and immunomodulatory agent that also has bone metabolic effects. There has been an increasing interest in immune-related neuropsychiatric symptoms that are triggered by group A beta-hemolytic streptococcal infections. In this study, we aimed to compare the serum levels of vitamin D between obsessive-compulsive disorder (OCD) patients with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and control subjects. METHODS: Thirty-three OCD patients with PANDAS and 20 healthy controls were enrolled in the study. Serum 25-hydroxyvitamin D (25-(OH) D), calcium, phosphorus, alkaline phosphatase, and parathormone levels of the two groups were compared. Serum 25 (OH) D levels of <15 ng/mL were classified as vitamin D deficiency. The children's Yale-Brown Obsessive Compulsive Scale (YBOCS) and Clinical Global Impression (CGI) were used to assess the severity of OCD symptoms. RESULTS: There was no significant difference in serum 25-(OH) D levels between the patient and control groups. However, vitamin D deficiency was significantly more frequent in the patient group than in the control group (48.5% vs. 20.0%; p=0.038). Moreover, OCD patients with vitamin D deficiency had higher rates of comorbid ADHD than those without vitamin D deficiency (87.5% vs. 52.6%; p=0.027). While serum phosphorus levels were negatively correlated with age as well as alkaline phosphatase and ASO levels, they were positively correlated with the YBOCS total score and global severity score. Serum parathormone levels were positively correlated with the YBOCS total score, compulsion score, obsession score, and global severity score. CONCLUSION: This study supports the hypothesis that an association between vitamin D metabolism and PANDAS-related OCD exists. We suggest that biochemical parameters predicting metabolic bone diseases are more common in PANDAS patients. There is a need for prospective studies to show a clear association between PANDAS and bone metabolic turnover based on autoimmune mechanisms. PMID- 28360764 TI - The Assessment of Family Functions, Dyadic Adjustment, and Parental Attitude in Adolescents with Substance Use Disorder. AB - INTRODUCTION: Family structure and family attitudes have been reported to be important factors in the development of substance use disorders. In this study, we aimed to assess the relationship between substance use and family functions, parental attitude, and parental dyadic adjustment of adolescents with substance use disorder. METHODS: The study was conducted on 50 patients, comprising 9 female and 41 male adolescents between the ages of 14 and 18 years, treated at Bakirkoy Mental Health Hospital, Substance Abuse Research, Treatment and Education Center for Children Adolescents (CEMATEM), Turkey, with the diagnosis of substance use disorder according to DSM-5 and their parents and a control group comprising 50 healthy adolescents without any psychopathology or substance use disorder and their parents. The study was designed as a matched case-control study for age and gender. Sociodemographic Data Form (SDF), Parental Attitude Scale (PAS), Dyadic Adjustment Scale (DAS), and Family Assessment Device (FAD) were applied to both groups. RESULTS: When the study and control groups were compared with regard to the PAS, the study group scores determined for "involvement-acceptance," "psychological autonomy," and "control-supervision" dimensions were significantly lower than the control group scores. Compared with the control group, dyadic adjustment was lower in terms of "dyadic cohesion," "dyadic consensus," and "affectional expression." Living with biological parents and the togetherness of parents were lower in the study group. "Problem solving," "communication," "roles," "affective responsiveness," "affective involvement," "behavior control," and "general functioning" dimension scores according to FAD were also significantly higher in the study group. CONCLUSION: Compared with togetherness of the controls, the dyadic adjustment of their parents was lower and family functions as perceived by the parents and adolescents were unhealthier in the adolescents using substances. These findings indicate that the family functions, dyadic adjustment, and parental attitude styles need to be assessed in the risk groups to determine familial risk factors and to structure protective measures. These assessments may guide clinicians and policy-makers toward good clinical practice and help build protective measures. PMID- 28360765 TI - Effectiveness of Greater Occipital Nerve Blocks in Migraine Prophylaxis. AB - INTRODUCTION: Peripheral nerve blocks have been used in primary headache treatment since a long time. In this study, we aimed to examine the efficiency of greater occipital nerve (GON) block in migraine prophylaxis. METHODS: Data from migraine without aura patients who had GON block were collected and divided into two groups: Group PGON (n=25), which included patients who were under medical prophylaxis and had GON block, and Group GON (n=53), which included patients who had only GON blocks. Migraine was diagnosed using International Headache Society (IHS) classification. Data of 78 patients were analyzed. Headache attack frequency, headache duration, and severity were compared between and within groups in a 3-month follow-up period. RESULTS: The decrease in headache parameters after GON block in both groups was significantly similar. Headache attack frequency decreased from 15.73+/-7.21 (pretreatment) to 4.52+/-3.61 (3rd month) in Group GON and from 13.76+/-8.07 to 3.28+/-2.15 in Group PGON (p<0.05). Headache duration decreased from 18.51+/-9.43 to 8.02+/-5.58 at 3rd month in Group GON and from 15.20+/-9.16 to 7.20+/-4.16 in Group PGON (p<0.05). Headache severity decreased from 8.26+/-1.32 to 5.16+/-2.64 in Group GON and from 8.08+/ 0.90 to 5.96+/-1.20 in Group PGON (p<0.05). There was no statistically significant difference between the groups in 3rd month after treatment (p>0.05). CONCLUSION: This study showed significant decreases in headache parameters in both groups. As GON blocks were performed in patients unresponsive to medical prophylaxis, a decrease in the headache parameters in Group PGON similar to that in Group GON can be attributed to GON blocks. Consequently, these results show that repeated GON blocks with local anesthetic can be an effective alternative treatment in migraine patients who are unresponsive to medical prophylaxis or who do not prefer to use medical prophylaxis. PMID- 28360766 TI - Impact of Symptoms of Maternal Anxiety and Depression on Quality of Life of Children with Cerebral Palsy. AB - INTRODUCTION: Cerebral palsy (CP) interferes with the quality of life (QOL) of children with CP, and given that parents report having to often guide their children's decision making, it is important to understand the psychosocial factors that have a potential influence on parent-proxy reports. The purpose of this study was to investigate the impact of maternal anxiety and depression symptoms on parent proxy-reported health-related QOL (HRQOL) for children with CP, while controlling other clinical and demographical variables that may have affect HRQOL. METHODS: The HRQOL scores of 97 outpatients with CP, aged 7-18 years, were assessed using the Pediatric QOL Inventory, Parent version (PedsQL P). Each patient's type of CP, gross and fine motor function levels, severity of intellectual disability (ID), and other clinical variables were recorded. The levels of depression symptoms in each mother were assessed using the Beck Depression Inventory (BDI), and the levels of anxiety symptoms were assessed with the Beck Anxiety Inventory (BAI). RESULTS: According to regression analyses, male gender, severity of ID, and higher mothers' BAI scores had negative effects on the PedsQL-P physical scores, and severity of ID and higher mothers' BDI scores had negative effects on the PedsQL-P psychosocial scores. Regarding the determinants of total HRQOL, severity of ID, GMFCS score, and higher mothers' BDI scores negatively impacted the PedsQL-P total scores. CONCLUSION: Our findings show significant predictor effects of the mothers' anxiety and depressive symptoms, independent from other clinical variables, on the mother-rated HRQOL scores in children with CP. PMID- 28360767 TI - Head Circumference Charts for Turkish Children Aged Five to Eighteen Years. AB - INTRODUCTION: Most head circumference growth references are useful during the first years of life, but they are also useful for older children when screening for developmental, neurological, and genetic disorders. We aimed to develop head circumference growth reference charts for age, height, and waist circumference for Turkish children aged 5-18 years. METHODS: Head circumference, height, and waist circumference measurements were obtained from 5079 students aged 5-18 years from Izmit, Kocaeli Province, Turkey. The LMS method was used to construct reference centile curves. RESULTS: Head circumference measurements were strongly correlated with height (r=0.74), weight (r=0.76), and waist circumference (r=0.68). The mean head circumference values for boys were larger than those for girls at all ages. Compared with data from the United States, the World Health Organization, and other studies from Turkey, our data showed a decrease in head circumference at all ages for both sexes. CONCLUSION: Local growth charts can be used to evaluate head circumference growth in older Turkish children and adolescents. PMID- 28360768 TI - The Role of Patent Foramen Ovale in Cryptogenic Stroke. AB - INTRODUCTION: Almost one-third of ischemic strokes has an unknown etiology and are classified as cryptogenic stroke. Paradoxical embolism because of a patent foramen ovale (PFO) is detected in 40%-50% of these patients. Recently, PFO has been reported as a risk factor for patients of all age groups. METHODS: In this study, 1080 ischemic stroke patients admitted to our clinic (2011-2013) were retrospectively evaluated. Age, sex, risk factors, complete blood count, vasculitis, biochemical and hypercoagulability tests, magnetic resonance imaging, magnetic resonance angiography, transthoracic echocardiography, transeosophageal echocardiography (TEE) findings, and therapeutic approaches were evaluated. RESULTS: The age range of the participants (seven male and four female patients) was 20-60 years (mean=43.09+/-11.13 years). Hemiparesis (n=10), diplopia (n=2), hemianopsia (n=2), and dysarthria (n=2) were the main findings of the neurological examinations. Patient medical history revealed hypertension (n=3), asthma (n=1), deep venous thrombosis (n=1), and smoking (n=4). Diffusion-weighted imaging showed middle cerebral artery (n=8) and posterior cerebral artery (n=3) infarctions. In one case, symptomatic severe carotid stenosis was detected. In eight cases, TEE showed PFO without any other abnormalities, but PFO was associated with atrial septal aneurysm in two cases, and in one case it was associated with ventricular hypokinesia and pulmonary arterial hypertension. Antiplatelet therapy was applied to nine patients and percutaneous PFO closure operation to two patients. In a 2-year follow-up, no recurrent ischemic stroke was recorded. CONCLUSION: PFO, especially in terms of the etiology of cryptogenic stroke in young patients, should not be underestimated. We want to emphasize the importance of TEE in identifying potential cardioembolic sources not only in young but also in all ischemic stroke patients with unknown etiology; we also discuss the controversial management options of PFO. PMID- 28360769 TI - SUDEP: The First Case Series in Turkey. AB - INTRODUCTION: Sudden unexpected death in epilepsy (SUDEP) is defined as the sudden, unexpected, witnessed or unwitnessed, non-traumatic, and non-drowning death of patients with epilepsy with or without evidence of a seizure, excluding documented status epilepticus, and in whom postmortem examinations do not reveal a toxicological or anatomic cause for death. In this study, data on patients who passed away under observation in the epilepsy clinic due to sudden, unexpected death have been compiled, and we also aim to emphasize the importance of SUDEP in Turkey. METHODS: This study was performed with a total of nine cases. Data were obtained from hospital records, information given by the families of patients, the database of the General Directorate for Civil Services of the Ministry of Internal Affairs of Turkey, and from the Ankara Metropolitan Municipality Cemetery Information System. As the basis of classification and definition, the proposals suggested by Nashef et al., which were made to the International League Against Epilepsy (ILAE) in 2011, were taken into consideration. RESULTS: Eight of the patients were classified as probable SUDEP and one of them as possible SUDEP; the mean age at SUDEP was 33 years, and the average follow-up period was 19.7 years. In these cases, except for known risk factors (generalized tonic-clonic seizures, nocturnal seizures, severe epilepsy, more frequent seizures, younger age at the onset of epilepsy, unwitnessed seizures, polytherapy, and mental handicap), a different risk factor was not identified. CONCLUSION: This study is the first case series on SUDEP in Turkey. Postmortem studies are the most important shortcoming of the study. However, the importance of the topic is highlighted by presenting the available data. SUDEP deserves more attention during the daily practice of neurologists, pediatric neurologists, forensic physicians, and family physicians. If death is sudden and unexpected in a patient with epilepsy, SUDEP should be considered, regardless of the clear causes of death. PMID- 28360771 TI - A Case in the Bipolar Spectrum. AB - It has been reported that the correct diagnosis and treatment are delayed when subsyndromal bipolar mood disorder symptoms are overlooked. Patients in this spectrum are reported to have a diminished level of functioning, and these patients fail to accept their diagnosis; therefore, there is a low level of treatment adherence. This case report focuses on the diagnosis and treatment of a patient in the bipolar spectrum. PMID- 28360770 TI - One Size Does Not Fit All in Psychotherapy: Understanding Depression Among Patients of Turkish Origin in Europe. AB - Over the last decades, Europe has become an immigration country hosting an estimated 56 million international immigrants. Yet, a large amount of literature suggests that migration is associated with a higher risk of common mental disorders, such as depression and anxiety. As representatives of one of the largest immigrant groups in Europe, various studies have shown that Turkish immigrants exhibit a higher prevalence of depression and anxiety disorders than do the background population. Nevertheless, it is also well demonstrated that this particular patient group is more likely to terminate treatment prematurely and displays lower rates of treatment compliance than their native counterparts. This reluctance for service utilization might be partially because of the fact that people from non-Western ethno-cultural backgrounds (e.g., Turkey) often have a different notion and comprehension of mental health and illness as compared with those of the people from Western societies. Such mismatch often results in discrepancies between the needs and expectations of immigrant patients and clinicians, which attenuate the communication and effectiveness of treatment and lead to unexplained high dropout rates. To provide continued provision of culture sensitive, high quality, evidence-based mental health care, the advancement of researches exploring such sociocultural differences between the patients' and the clinicians' notions of mental health must occur. In response to these problems, the current review aims to explore the interplay between culture and mental processes that associate with the etiology, maintenance, and management of depression among Turkish immigrant patients. This is to inform clinicians regarding culture-specific correlates of depression among Turkish patients to enable them to present interventions that fit the needs and expectations of this particular patient group. PMID- 28360772 TI - Copycat Suicides Without an Intention to Die After Watching TV Programs: Two Cases at Five Years of Age. AB - Suicide is an intentional self-destructive act. As conceptualization of death as an irreversible end occurs at approximately 8-10 years, attempted and completed suicides are rare before 7 years of age. Studies have suggested that media may contribute to increased suicides in adolescents through social learning. Effects of media on suicides were thoroughly evaluated in children and adolescents who committed suicide after identifying with the subject of a TV program, movie, or book. We present 2 cases at 5 years of age who committed suicide by hanging themselves after watching a TV program. These cases differed from copycat suicides reported in the literature that are performed mostly by adolescents because victims are very young children and because they died without an actual intent to die while they were imitating suicides. By presenting these cases, we want to emphasize that destructive effects of media may involve not only adults and adolescents but also very young children who do not have a completely developed concept of death. PMID- 28360773 TI - Spontaneous Ejaculations Associated with Aripiprazole. AB - Sexual side effects are common with antipsychotic use. Spontaneous ejaculations without sexual arousal have been previously described with several typical and atypical antipsychotics. We report the case of a man who had spontaneous ejaculations after stopping risperidone and starting 30 mg/day aripiprazole. Spontaneous ejaculations ceased 3 days after decreasing the aripiprazole dose to 15 mg/day. He denied sexual fantasies or increased sexual desire during the period in which he had spontaneous ejaculations. The partial agonistic effect of aripiprazole on D2 receptors may have augmented the mesolimbic dopaminergic pathway, which was suppressed by risperidone, causing spontaneous ejaculations in this patient. Serotoninergic effects of aripiprazole should also be considered. This unusual side effect should be questioned, particularly in patients who recieve aripiprazole after D2-blocking antipsychotics; otherwise, this side effect may cause embarrassement and noncompliance. PMID- 28360774 TI - Leukocytosis after Clozapine Treatment in a Patient with Chronic Schizophrenia. AB - Clozapine is an atypical antipsychotic drug that is approved by the US Food and Drug Administration (FDA) for the treatment of psychotic disorders. Agranulocytosis is a well-established side effect of clozapine; clozapine has also been associated with other blood dyscrasias like leukocytosis, albeit rarely. In this paper, we aim to report a case of possible clozapine-associated leukocytosis in a 41-year-old woman. PMID- 28360775 TI - A Rare Cause of Neuropathic Pain in the Back: Notalgia Paresthetica. PMID- 28360776 TI - Frequently Seen But Rarely Diagnosed: Musical Ear Syndrome. PMID- 28360777 TI - Late Onset Tremor and Ataxia Syndrome: FXTAS and its Ignored Peripheral Nervous System Findings in Diagnostic Criteria. PMID- 28360778 TI - Multiple Sclerosis and Panuveitis: A Rare Association. PMID- 28360779 TI - Burden on Caregivers of Patients with Schizophrenia and Related Factors. AB - INTRODUCTION: Caregivers of patients with schizophrenia are under the burden of continuous and difficult processes. Determination of the factors related to caregiver burden in schizophrenia may help find strategies to decrease the burden. This study aimed at investigating the factors associated with caregiver burden among relatives of patients with schizophrenia. METHODS: Eighty-eight caregivers of patients under treatment for schizophrenia for at least 1 year were included in the study. The Zarit Caregiver Burden Interview was used for the assessment of caregiver burden. Sociodemographical data, the level of knowledge about schizophrenia, clinical impression scale, and global assessment of functioning were used to evaluate the related factors. RESULTS: Caregiver burden was negatively correlated with income level and functionality of the patient and was positively correlated with the age of the caregiver, the daily time spent with the patient, and the number of hospitalizations of the patient (p<0.05). There was no significant correlation between the caregivers' knowledge about schizophrenia and caregiver burden (p<0.05). Living in the same house with the patient was a positive predictor, whereas functionality and income level of the patient and education level of the caregiver were negative predictors (p<0.05). CONCLUSION: This study highlighted the importance of setting targets for improving the functionality of patients in the design and implementation of rehabilitation and support programs for patients with schizophrenia. Additionally, providing higher income for patients, creating conditions for an independent life, and increasing incentives for younger caregivers with a higher educational level may help decrease caregiver burden. PMID- 28360780 TI - Effect of Sleep Quality on Psychiatric Symptoms and Life Quality in Newspaper Couriers. AB - INTRODUCTION: Working at unusual hours has been found to be related to sleep problems, psychiatric symptoms, and low quality of life. This study aimed to investigate the effect of sleep quality on psychiatric symptoms and the quality of life in newspaper couriers who permanently wake up at early morning hours. METHODS: Thirty-five newspaper couriers who worked for a media company in Ankara and 35 healthy individuals who worked at usual hours and who were matched according to age, gender, and work duration were included in the study. All individuals were evaluated using the demographic forms, Symptom Checklist (SCL) 90-R, Pittsburg Sleep Quality Index (PSQI), and Short Form-36 (SF-36). RESULTS: The somatization subscale of SCL-90-R and the sleep duration sub-component scores of PSQI were significantly higher and the physical role functioning domain score of SF-36 was significantly lower in newspaper couriers compared with the scores in healthy individuals. There were significantly positive correlations between the PSQI total and sub-component scores and the SCL-90-R subscale and global symptom index scores. There were significantly negative correlations between the PSQI total and sub-component scores and the SF-36 domain scores. CONCLUSION: This study demonstrates that waking up permanently at early morning hours may be related to sleep disturbances, psychiatric symptoms, and low quality of life. Measures to increase sleep quality in individuals working at unusual hours may improve their mental health and quality of life. Future studies should investigate the effects of interventions toward sleep disturbances on mental health and quality of life in different occupational groups. PMID- 28360781 TI - Evaluation of the Relationship between Major Depressive Disorder and Bereavement Symptoms in Elderly Patients Who Present Either to Psychiatry or Family Medicine. AB - INTRODUCTION: We aimed to determine the level of bereavement and depression symptoms among elderly patients who experience the loss of a significant other and the relationship between depressive symptoms and bereavement symptoms. METHODS: The study sample consisted of elderly adults who lost a significant other at least 6 months prior to the submission time. Participants were recruited from patients who presented to either the psychiatry or family medicine outpatient unit of a Training and Research Hospital. Cognitive functions were assessed using Standardized Mini Mental Examinations for Educated and Uneducated People (SMME/SMME-U). Participants were excluded from the study if their SMME or SMME-U scores were lower than 23 points. To assess the severity of depressive and bereavement symptoms, the Geriatric Depression Scale (GDS) and Core Bereavement Items (CBI) scales were used, respectively. RESULTS: Overall, 33 out of 67 individuals (49.2%) who presented to the psychiatry unit and 7 out of the 43 individuals (16.3%) who presented to the family medicine unit were diagnosed with major depressive disorder (MDD). CBI scale score means were higher in the MDD groups than in the non-depressive groups (p=0.012 and p=0.001, respectively). CBI scores were significantly correlated to acute (p=0.047) and chronic stress (p=0.007) in the psychiatry group and to chronic stress in the family medicine group (p=0.001). CONCLUSION: Probing loss experiences and reactions to them can be important to understand depression, to evaluate its symptoms, and to help manage the relevant symptoms. Considering the significant contributions of bereavement to depressive symptom severity in elders, interventions specific to bereavement symptoms should not be ignored. PMID- 28360782 TI - Determination of Genotypic and Phenotypic Characteristics of Friedreich's Ataxia and Autosomal Dominant Spinocerebellar Ataxia Types 1, 2, 3, and 6. AB - INTRODUCTION: This study aimed to analyze the genotypic characteristics of Friedreich's ataxia (FA) and autosomal dominant ataxias [such as spinocerebellar ataxia (SCA) types 1, 2, 3, and 6] using molecular and biological methods in hereditary cerebellar ataxia considering both clinical and electrophysiological findings. METHODS: The study included 129 indexed cases, who applied to the neurology department and were diagnosed with hereditary cerebellar ataxia through clinical, laboratory, and electrophysiological findings, and 15 sibling patients who were diagnosed through family scanning (144 cases in total); their genetic analyses were also performed. Detailed physical and neurological examinations, pedigree analyses, electroneurography, evoked potentials, cerebral-spinal magnetic resonance imaging, and echocardiographic analyses were performed for all cases. Blood samples were collected from patients, and the genotypic characteristics of autosomal dominant SCA types 1, 2, 3, and 6 were investigated. Statistical analyses were performed with the Statistical Package for the Social Sciences (SPSS Inc; Chicago, IL, USA) 17.0. RESULTS: Almost 50% of patients were defined as FA. Moreover, two SCA1 cases and one SCA6 case were detected. CONCLUSION: In our study, 47.2% of patients with FA had developed hereditary cerebellar ataxia. Ground and autosomal dominant-linked SCA1 and SCA6 were each detected in one family. These data suggest that patients with cerebellar ataxia of hereditary origin should be primarily examined for FA. PMID- 28360783 TI - The Relationship between Aggression and Serum Thyroid Hormone Level in Individuals Diagnosed with Antisocial Personality Disorder. AB - INTRODUCTION: Aggression is one of the leading clinical characteristics of antisocial personality disorder (APD). Studies aiming to clarify and control the biological basis of aggression are ongoing. Thyroid hormones have been indicated to play a role in the development of aggression. The aim of this study was to examine the level of aggression and serum thyroid hormone in a sample of APD and to make contributions to this field with the current findings. METHODS: The sample consisted of 96 subjects with a diagnosis of APD and 97 subjects as a control group. Structured Clinical Interview for DSM-IV Axis (SCID) 1 and 2 were used for the diagnosis, and the Buss-Perry Aggression Questionnaire was administered. Based on criminal patterns, the APD group was then divided into two subgroups: "criminal" and "noncriminal" APD groups. The day after the interview, after one night of fasting, blood was collected from the subjects between 7:00 a.m. and 9:00 a.m.. Thyroid function tests and other biochemical analyses related to the confounding variables were also administered. The study group and the control group were compared in terms of their aggression scores and thyroid hormone levels. RESULTS: The mean score of free T3 level in the criminal APD group was found to be significantly higher than that in the noncriminal APD group. APD subjects with higher free T3 levels also had higher aggression scores. In the noncriminal APD group, as serum free T3 and T4 levels increased, there was also an increment in the aggression scores. However, in the criminal APD group, there was no significant correlation between thyroid hormone levels and aggression. CONCLUSION: The findings of this study indicated that criminal and noncriminal APD groups actually show different properties. PMID- 28360784 TI - Jitter Values on Voluntary Active Periocular Muscles of Healthy Subjects with Conventional (37 mm) Concentric Needle Electrode. AB - INTRODUCTION: The aim of this study was to re-evaluate jitter values of healthy subjects in whom pairs of single-fiber-like potentials were recorded from voluntary activated periocular muscles using a disposable 37-mm concentric needle electrode (CNE) with 2-kHz low-cut filtering. METHODS: We reviewed the recordings of 129 subjects (85 women; 44 men; mean age, 43.8+/-15.3 years). The m. frontalis group included 116 subjects, and the m. orbicularis oculi group included 18 subjects. Jitter values were expressed as the mean consecutive difference (MCD) of 20 different pairs. RESULTS: The mean MCD (n=2680) was 22.5+/-9.7 MUs (range, 5-121 MUs), and the upper 95% confidence limit (CL) was 39 MUs. The mean of 134 MCD values for each subject was 22.5+/-3.7 MUs (range, 15-33 MUs), and the upper 95% CL was 30 MUs. The outer limit of the 18th highest MCD values out of 20 recordings for each subject was 31.3+/-6.5 MUs (range, 18-53 MUs), with an upper 95% CL of 43.3 MUs. CONCLUSION: Using a conventional 37-mm CNE with 2-kHz low-cut filtering may be a cost effective alternative to a single-fiber electrode in periocular muscles if strict criteria are used for acceptable signals. Jitter values of >44 MUs that were calculated from single-fiber-like action potential pairs should alert the physician regarding the possibility of neuromuscular junction disorders and constitute an indication for a further diagnostic investigation. PMID- 28360785 TI - Determination of Clinical and Socio-demographical Differences of Adolescents Applying to a Treatment Center with Family Encouragement or the Decision of the Probation Office and Determination of Predictive Factors in Maintaining Soberness among Probation Cases. AB - INTRODUCTION: This study has two objectives. The first objective of this study was the determination of some basic clinical and socio-demographical differences among the adolescents with substance abuse who apply to a treatment center with support from their family or by order of the probation office. The other objective of this study was the determination of the predictive factors in maintaining soberness among adolescents who successfully complete the probation treatment process. METHODS: The target population of this study is young adults under 19 years of age who apply to a substance addiction center for adolescents as a result of encouragement from their family or ordered by the Probation Office between 2005 and 2013. These two groups were analyzed in terms of socio demographical characteristics such as age, the age at which they tried the substance, the age at which they applied to the treatment center, sex, substances they used, education period, employment history, and street life experience. The Statistical Package for the Social Sciences (SPSS) 18.0 software was used for the statistical analysis. RESULTS: It was detected that among the cases who applied to the treatment center with family support, their education period was longer than probation (PR) cases (p<0.0001), and the rates of previous treatment, their mother being alive, and having street life experiences were more frequent (p values: <0.0001; =0.010; =0.027; <0.0001, respectively) and employment history was higher among PR cases (p<0.0001). In terms of the substances used, ecstasy, alcohol, inhalants, and volatile substances are more common among those applying with family support (p=0.018; 0.001; <0.0001, respectively). However, use of cannabis was found to be more common among PR cases (p<0.0001). It was found that PR cases who successfully completed their treatment process had married parents (p=0.008) and had more years of education (p=0.004). It can be predicted that if the subject is well educated and does not use multiple substances or have an alcohol history, the treatment process for PR cases can be successfully completed. (R2=0.176; p<0.0001). CONCLUSION: The rates of completing the treatment among cases analyzed in this study were higher than those among cases from adults. In the studies conducted, the results of the treatment efficiency among PR cases were inconsistent. This inconsistency may result from, except for legal obligations, having different circumstances such as socio-economic factors during the treatment period. PMID- 28360786 TI - Interaction of Cocaine- and Amphetamine-regulated Transcript and Neuropeptide Y on Behavior in the Central Nervous System. AB - INTRODUCTION: In the central nervous system, cocaine- and amphetamine-regulated transcript (CART) 55-102 peptide is localized in areas, such as the ventral tegmental area, amygdala, hypothalamus, and hippocampus, where emotional activity is regulated. Studies on the effects of the intracerebroventricular (ICV) administration of CART peptide on behavior remain limited. The findings from these studies suggest that this neuropeptide has anxiogenic-like effects. In the central nervous system, neuropeptide Y (NPY) has similar localization as CART. Previous behavioral studies have demonstrated that the ICV administration of NPY has anxiolytic-like effects. METHODS: In our study, we established five experimental groups of male Wistar rats to study the competitive effects of NPY and CART peptide. These groups were sham (n=10), CART (n=10), NPY (n=10), CART NPY (n=10), and NPY-CART (n=10). The open field test, elevated plus maze test, and Porsolt swim test were performed for behavioral analyses. Moreover, the rats were decapitated after the behavioral tests, and the amount of these two peptide in their brains was quantified. RESULTS: Our study revealed that the ICV administration of CART peptide is anxiogenic and inhibits animals undergoing learned helplessness in the Porsolt swim test. When we evaluated the results of our study with respect to NPY, we observed its anxiolytic-like effects; in the Porsolt swim test, although it reduced the duration of immobilization, it did not affect the period of struggle. CONCLUSION: Our results revealed that during the competitive interaction of these two peptides, anxiogenic CART peptide suppressed the anxiolytic effects of NPY. PMID- 28360787 TI - Using Neuropsychometric Measurements in the Differential Diagnosis of Specific Learning Disability. AB - INTRODUCTION: The aim of this study was to develop a neuropsychometric battery for the differential diagnosis of specific learning disability (SLD), with specific respect to attention deficit hyperactivity disorder (ADHD), and to help resolve the conflicting results in the literature by an integrative utilization of scores on both the Bannatyne categories and neuropsychological tests. METHODS: The sample included 168 primary school boys who were assigned to SLD (n=21), ADHD (n=45), SLD and ADHD (n=57), and control groups (n=45). The exclusion criteria were a neurological or psychiatric comorbidity other than ADHD, a level of anxiety and/or depression above the cutoff score, medication affecting cognitive processes, visual and/or auditory disorders, and an intelligence level outside the IQ range of 85-129. Psychometric scores were obtained from the SLD Battery and Wechsler Intelligence Scale for Children-Revised in the form of Bannatyne category scores. Neuropsychological scores were from the Visual-Aural Digit Span Test-Form B, Serial Digit Learning Test, Judgment of Line Orientation, and Mangina Test. The battery was called the Integrative Battery of SLD. RESULTS: The correctness of estimation for classifying cases into the diagnostic dyads (SLD/ADHD, SLD/SLD+ADHD, and SLD+ADHD/ADHD) by an integrative utilization of both the Bannatyne category scores (n=4) and scores from the four neuropsychological tests (n=10) was 92.4%, 81.4%, and 71.8%, respectively. These proportions were generally higher than those obtained using the Bannatyne category scores alone (86.4%, 75.5%, and 73.1%, respectively). The same trend was seen in the classification of children into diagnostic and control groups. However, the proportion of the correctness of estimation was higher than that obtained for the diagnostic dyads. CONCLUSION: When conducted using appropriately chosen research designs and statistical techniques and if confounding variables are sufficiently controlled, a neuropsychometric battery that includes capacities that relate to intelligence (Bannatyne categories) and those that relate to neurocognitive processes (neuropsychological tests) can be useful in the differential diagnosis of SLD. PMID- 28360788 TI - Determinants of Antenatal Psychological Distress in Pakistani Women. AB - INTRODUCTION: An increasing number of evidence has demonstrated that poor antenatal psychological health can lead to adverse pregnancy outcomes. Studies conducted in various countries demonstrated a wide range of factors associated with psychological distress during pregnancy. METHODS: A cross-sectional study was conducted between September 2011 and December 2012 in Peshawar, north-west Pakistan. A total of 230 women in their third trimester of pregnancy fulfilled the inclusion criteria. The antenatal psychological health status of women was measured using the Depression Anxiety Stress Scale. Relevant data regarding health and demographic-socioeconomic status were collected through personal interviews using standardized questionnaires. RESULTS: Overall, 45% (n=104) of women exhibited symptoms for composite depression, anxiety, and stress (composite DAS). In the univariate analysis, maternal age, husband support, monthly income, family size, stressful life events, lack of confidence, domestic violence, and pregnancy-related concerns were strongly associated with antenatal composite DAS (p<0.01). The association of maternal composite DAS symptoms with age, monthly income, family size, and lack of confidence remained significant in the multivariate analysis (p<0.01). CONCLUSION: A major proportion of women exhibited symptoms of antenatal composite DAS, and various factors were found to be related to their psychological distress. A young maternal age, low husband support, low income, large family size, adverse life events, lack of confidence, pregnancy related concerns, and domestic violence were stronger determinants of poor antenatal psychological status. The study findings concluded that policymakers at the government level should launch special intervention programs to improve maternal perinatal mental and psychological health at the community level. PMID- 28360789 TI - Social Aspect of Functioning Deteriorates More Than Individual Aspect in Patients with Remitted Bipolar Disorder. AB - INTRODUCTION: Many studies have demonstrated that patients with bipolar disorder (BD) suffer from significant functional impairment, even during remission periods. This study aimed to assess the levels of overall functioning and specific areas of functioning in remitted patients with BD compared with those in healthy controls. METHODS: Eighty completely remitted patients with BD and 80 healthy controls were included in the study. The Bipolar Disorder Functioning Questionnaire (BDFQ), Young Mania Rating Scale, and Beck Depression Inventory were used. RESULTS: There were fewer married and employed cohorts in the BD group than in the control group. Compared with healthy controls, patients with BD exhibited a worse functioning in terms of intellectual and sexual functioning, feelings of stigmatization, social withdrawal, household relationships, relationships with friends, and participation in social activities. There was no difference between the groups in terms of emotional functioning, daily activities and hobbies, taking initiative and self-sufficiency, and occupation. The total BDFQ scores of patients were lower than those of healthy controls. A better functionality was observed in patients using only a mood stabilizer than in patients using three or more drugs. CONCLUSION: Remarkably, remitted patients with BD tended to perform daily activities well when these activities were not in a social context. Stigma-oriented interpersonal approaches can be particularly beneficial for these patients. PMID- 28360790 TI - Alcohol and Psychoactive Substance Use among University Students in Edirne and Related Parameters. AB - INTRODUCTION: Alcohol and psychoactive substance use and their effects are an important issue among adolescents and young adults. Different results have been reported about the frequency of alcohol and psychoactive substance use among university students in studies conducted both in Turkey and in different places worldwide. METHODS: The frequency of alcohol and psychoactive substance use among Trakya University students (n=1385) and the related parameters were studied cross sectionally using a self-reporting questionnaire. RESULTS: Alcohol was the most common substance used (30%), followed by tobacco (29.9%) and marijuana (3.1%). The frequency of alcohol and psychoactive substance use was found to be higher among males with higher amounts of pocket money, whose parents experienced more conflict in their relationship, and who belong to families with a higher education and income level. CONCLUSION: The frequency of alcohol and psychoactive substance use among Trakya University students was found to be lower than other regions in Turkey and particularly lower than the levels reported in studies conducted in other countries. PMID- 28360791 TI - Familial Adult-onset Alexander Disease: Clinical and Neuroradiological Findings of Three Cases. AB - The adult-onset Alexander disease (AOAD) dramatically differs from the early onset AD with respect to clinical and neuroradiological findings. Herein we report the detailed clinical and neuroradiological findings of a Turkish family with AOAD. In all three cases, magnetic resonance imaging revealed marked atrophy of the mesencephalon, bulbus, and cervical spinal cord accompanied with signal abnormalities in the same regions along with supratentorial white matter. Basal ganglia were affected in two cases. Molecular genetic analysis revealed heterozygous mutation in the 8th exon of the glial fibrillary acidic protein gene M451I (c.1245G>A), leading to the diagnosis of AOAD in all cases. PMID- 28360792 TI - Orbital Myositis: Evaluating Five New Cases Regarding Clinical and Radiological Features. AB - Orbital myositis (OM) is an inflammatory disorder of the extraocular muscles. The signs and symptoms of OM are periorbital pain, eyelid swelling and redness, restricted ocular motility, and strabismus. There are at least two major forms, described by Benedikt GH Schoser, a limited oligosymptomatic ocular myositis (LOOM), which is associated with conjunctival injection only, and severe exophthalmic ocular myositis (SEOM), which presents with additional ptosis, chemosis, and proptosis. We report the clinical and radiological features of five patients with OM who were recently followed in our clinic. Three patients, one man and two women, were placed in the LOOM group, and the other two patients, both women, were in the SEOM group. In both groups, the initial complaints were pain worsening with eye movements and double vision, with only one patient in the SEOM group having pain worsening secondary to Crohn's disease. The most affected muscles were the medial and lateral recti. All the patients were treated with corticosteroids, resulting in rapid improvement. Only one patient in the SEOM group experienced a relapse. Orbital magnetic resonance imaging of all the patients revealed enlargement and contrast enhancement of the involved muscles. Although clinical and radiological features are quite consistent, delayed diagnosis in some patients demonstrates the importance of the awareness of OM. PMID- 28360794 TI - A Case of Skin Picking Disorder of a Patient with a History of Childhood Abuse. AB - Skin picking (excoriation) disorder is the recurrent excoriation of one's own skin, resulting in noticeable skin damage. People pick their skin for different reasons. For the majority of patients, first skin picking is associated with a history of childhood abuse and personal problems. Subjects who moderately to severely cause injurious self-harm are more likely to have a history of exposure to domestic violence and childhood abuse than those who do not self-harm. At the same time, these conditions could be related to the etiology for majority of other psychiatric disorders. We report herein, a case of a patient with skin picking disorder who had a history of childhood physical and emotional abuse with borderline personality disorder. PMID- 28360793 TI - Withdrawal-Emergent Dyskinesia and Supersensitivity Psychosis Due to Olanzapine Use. AB - Tardive dyskinesia (TD) usually appears after years of antipsychotic drug use and appears to be related to the total lifetime medication dose. In withdrawal emergent dyskinesia (WE-D), which is considered to be a subtype of TD, dyskinetic symptoms often appear shortly after a rapid reduction in antipsychotic drug dose or sudden discontinuation of the drug. Supersensitivity psychosis, which is frequently observed along with TD and is considered to have a similar etiology as TD, is a psychotic relapse phenomenon that occurs after the withdrawal of an antipsychotic drug or a rapid reduction in the drug dosage. In general, atypical antipsychotics tend to be associated with less propensity to cause TD when compared with typical antipsychotics. Furthermore, olanzapine and clozapine may have a therapeutic potential in improving or totally curing TD. In this study, a case of WE-D because of discontinuing olanzapine use and supersensitivity psychosis is discussed. PMID- 28360795 TI - Herpes Zoster Ophthalmicus That Mimics the SUNCT Syndrome. PMID- 28360796 TI - Can Priapism Occur as an Idiosyncratic Reaction to Risperidone? PMID- 28360797 TI - Stiff Person Syndrome with Pyramidal Signs. PMID- 28360798 TI - Epicrania Fugax. PMID- 28360799 TI - Affective Temperament Profiles of Overactive Bladder Patients. PMID- 28360800 TI - Higher Relability? Higher Validity? PMID- 28360801 TI - Relationship between Impulsivity and Serum Oxytocin in Male Children and Adolescents with Attention-Deficit and Hyperactivity Disorder: A Preliminary Study. AB - INTRODUCTION: Here we aimed to determine the relationship between oxytocin levels and impulsivity, which is an important aspect at Attention Deficit Hyperactivity Disorder (ADHD) clinics. METHODS: The study population comprised 40 ADHD patients diagnosed based on the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version, without other psychiatric disorders and chronic diseases aged between 8 and 15 years. The control group comprised 40 healthy, age-matched, male children and adolescents who voluntarily participated in the study. Patients and controls filled the Barratt impulsivity scale-11 (BIS-11). Ten cubic centimeters of blood was collected at 8 am for determining serum oxytocin levels. ELISA kits were used to measure serum oxytocin levels in a biochemistry laboratory. The obtained data were evaluated using appropriate statistical methods. RESULTS: In this study, compared with the control group, the impulsivity scores were significantly higher and serum oxytocin levels were lower in the ADHD group (52.5+/-18.1 and 37.62+/-9.0, respectively, p<0.001). Serum oxytocin levels showed a negative correlation with impulsivity and attention subscale scores of BIS-11 in the ADHD group. CONCLUSION: ADHD and impulsivity, which comprise an aspect of ADHD, may be associated with oxytocin. Serum oxytocin levels may contribute to inattention subtypes of impulsivity observed in ADHD. PMID- 28360802 TI - Validity and Reliability of the Turkish Adaptation of the Dream Reflective Awareness Questionnaire (DRAQ). AB - INTRODUCTION: The aim of this research was to adapt the Dream Reflective Awareness Questionnaire (DRAQ) to Turkish and to examine its psychometric properties. METHODS: In total, 378 college students participated in the study. The average age of the participants was 20.4 years; 56% of participants were women and 44% were men. After the scale linguistic equivalence was completed, the validity and reliability analyses were checked. Exploratory factor analysis and confirmatory factor analysis were utilized for the construct validity, and Cronbach's alpha coefficient was used for internal consistency reliability. RESULTS: In the exploratory factor analysis of the scale, unlike the original form, a 5-factor structure for 15 items was obtained, explaining the 71% of the total variance. The factor loads were between 0.61 and 0.88. Confirmatory factor analysis results confirmed the structure that was obtained from the exploratory factor analysis. The Cronbach's alpha internal consistency coefficient, which was derived from the reliability analysis of the scale, ranged between 0.74 and 0.78. CONCLUSION: Based on the results obtained, we can conclude that the scale is a valid and reliable tool with sufficient psychometric properties. PMID- 28360803 TI - Exposure of Students to Emotional and Physical Violence in the School Environment. AB - INTRODUCTION: While peer abuse or physical violence in school is emphasized more, the physical and emotional violence caused by school staff has been emphasized less. The purpose of this study was to investigate the variables related to emotional and physical violence that students are exposed to in the school environment. METHODS: This cross-sectional and descriptive study was conducted by applying a questionnaire to 434 fifth-grade students receiving education in the primary schools in Konak district of Izmir province. Being prepared by the researchers of this study, the questionnaire consisted of questions about the socio-demographic features of the child and the family, the place where the child has been raised, family income, average grade, and the emotional and physical violence of teachers, parents, and peers s/he has been exposed to within the last year. The Chi-square test, Mann-Whitney U test, and logistic regression analysis were used for statistical analyses. RESULTS: The study group consisted of 214 (49.3%) female and 220 (50.7%) male students. Students reported that they were exposed to at least one type of emotional violence from 59.4% of teachers, 52.8% of parents, and 61.8% of children at school; they were exposed to at least one type of physical violence from 42.9% of teachers, 33.6% of parents, and 24.9% of children at school. While the rate of encountering with the beating of another child was 53%, the rate of watching this in television/cinema was 52.8%. Regarding exposure to at least one type of violence, males were found to be significantly more exposed to emotional and physical violence from male teachers, female teachers, and fathers and physical violence from children at school. The factors regarding the exposure to emotional and physical violence by teachers were evaluated using logistic regression analysis, and it was determined that the physical violence from teachers, emotional violence from children in school, and emotional violence from parents could predict the emotional violence from teachers. For males, physical violence from children in school and emotional violence from teachers could predict the physical violence from teachers. CONCLUSION: In this study, the determination of the tendency of togetherness of different types of violence applied to students from different people groups like teachers, parents, and children in school makes us think about the possibility of common risk factors in terms of violence exposure. The risk factors determined in this study may guide us in planning protective interventions aimed at violence. PMID- 28360804 TI - Affective Temperament Profiles in Patients with Multiple Sclerosis: Association with Mood Disorders. AB - INTRODUCTION: The aim of the present study was to screen for bipolarity and to investigate the affective temperaments of patients with multiple sclerosis (MS) and the possible association between the clinical and demographic characteristics of MS patients and temperament profiles. METHODS: A total of 65 patients with MS and 66 healthy volunteers completed the 32-item hypomania checklist (HCl-32), the Mood Disorder Questionnaire (MDQ), and the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Autoquestionnaire (TEMPS-A) tests. The HCl-32, MDQ, and TEMPS-A scores were compared between the patients and healthy volunteers. RESULTS: MS patients had significantly higher scores for the depressive, cyclothymic, irritable, and anxious domains of the TEMPS-A scale than the control group, whereas relapsing remitting MS (RRMS) patients had higher MDQ and TEMPS-A hyperthymia scores than secondary progressive MS patients. MS patients who were being treated with interferon beta 1-b therapy had significantly higher MDQ scores than those being treated with interferon beta 1-a, glatiramer acetate, or who were without medication. Expanded Disability Status Scale (EDSS) scores were positively correlated with TEMPS-A depressive and hyperthymic temperaments. CONCLUSION: Our results suggest that higher scores for affective temperament in MS patients indicate subclinical manifestations of mood disorders. Higher hyperthymia scores and manic symptoms detected in the RRMS group could shed light on the relationship between bipolarity and MS. Thus, the screening of bipolarity and affective temperament profiles in MS patients could help clinicians predict future mood episodes and decrease their impact on disease severity. PMID- 28360805 TI - Effect of Increased Neutrophil-to-Lymphocyte Ratio (NLR) and Decreased Mean Platelet Volume (MPV) Values on Inflammation in Acute Mania. AB - INTRODUCTION: The neutrophil-to-lymphocyte ratio (NLR) and mean platelet volume (MPV) are simple, low-cost, and useful inflammatory markers detected in routine complete blood count (CBC), and their use has recently become widespread. In this study, we aimed to investigate the presence of an inflammatory state in manic patients on the basis of NLR and MPV values. METHODS: This retrospective study was performed on 76 patients with acute mania who were admitted to the Inpatients Psychiatry Clinic of Afyon Kocatepe University Hospital in Turkey. Diagnoses were based on Diagnostic and Statistical Manuel of Mental disorder (DSM-IV). The control group consisted of 74 healthy individuals recruited from the community. They were age- and sex-matched with the study group. RESULTS: NLR values of the manic patient group were 2.2+/-1.4 and those of the control group were 1.6+/-0.5. NLR values were significantly higher (p=0.004) and MPV values were significantly lower in the manic patient group than in the control group (10.0+/-1.2 vs. 10.9+/ 2.3, p=0.027). CONCLUSION: Increased NLR and decreased MPV levels may reflect inflammation in manic patients, and inflammation may play a role in the complex pathophysiology of acute mania. PMID- 28360806 TI - Possible Effects of Copper and Ceruloplasmin Levels on Auditory Event Potentials in Boys with Attention Deficit Hyperactivity Disorder. AB - INTRODUCTION: The aims of the present study were to investigate the relationship between levels of plasma copper (Cu) and ceruloplasmin (Cp) and amplitudes and latencies of P1, N2, and P3 in the parietal and frontal areas of children with attention deficit hyperactivity disorder (ADHD) as well as to compare these Cu levels and event-related potentials (ERPs) indices in controls. METHODS: Boys (n=41) with ADHD were divided into two subgroups according to a median split of plasma Cu and Cp levels, separately. ERP indices from the parietal and frontal regions were recorded in children with ADHD and 24 normal boys (control group) using an auditory oddball paradigm. RESULTS: Parietal P3 latency was significantly longer, and parietal P3 amplitude, frontal P3 amplitude, and frontal N2 amplitudes were smaller in children with ADHD than in controls (all p values <0.017). Parietal P1 and frontal P1 latencies were significantly shorter in the higher Cu group than in the lower Cu group (both p values <0.017). Decreased latency of parietal P1 was dependent on plasma levels of Cu (p<0.05). Frontal N2 and parietal N2 amplitudes were significantly lower in the ADHD group with lower Cp levels than in the ADHD group with higher Cp levels (both p values <0.017). Decreased frontal N2 and parietal N2 amplitudes were dependent on plasma levels of Cp (both p values <0.05). CONCLUSION: Plasma Cu and Cp levels may have an effect on ERPs in ADHD, thus indicating the existence of effects on information processing. Cu levels may have a negative effect on the neuronal encoding of sound, whereas Cp levels may have a positive effect on the processes of cognitive control, conflict monitoring, and stimulus discrimination in children with ADHD. PMID- 28360807 TI - Symptomatic Remission Determines Functional Improvement and Quality of Life in Schizophrenia. AB - INTRODUCTION: Schizophrenia is a chronic illness that negatively affects the quality of life and psychosocial functions. Defined criteria to assess remission in schizophrenia are considered to be useful in the long-term follow-up of patients and in discriminating diagnostic factors. This study investigated the quality of life and functionality in schizophrenia patients in symptomatic remission (R-Sch) and not in remission (Non-R-Sch). METHODS: Sociodemographic data were collected for 40 R-Sch and 40 Non-R-Sch patients, and the following scales were administered: the Clinical Global Impression-Severity (CGI-S) Scale; Positive and Negative Syndrome Scale (PANSS), World Health Organization Quality of Life Questionnaire-Short Form, Turkish Version (WHOQOL-BREF-TR), Quality of Life Scale for Schizophrenia Patients (QLS), and Global Assessment of Functioning Scale (GAF). RESULTS: The total and all subscale scores of PANSS and the CGI-S score were significantly lower in the R-Sch group than in the Non-R-Sch group, whereas the GAF scores and all subscales of QLS and WHOQOL-BREF-TR were significantly higher. CONCLUSION: This study demonstrates that improvement in symptoms in schizophrenia patients improves quality and functionality in all areas of life, suggesting that an improvement in symptoms is the most important determinant of functional recovery in the treatment of schizophrenia. PMID- 28360808 TI - Ischemic Stroke in the Elderly: Septuagenarians Versus Octogenarians. AB - INTRODUCTION: Stroke prevalence is known to increase with age. Approximately 50% of acute ischemic stroke patients are aged between 70 and 89 years. METHODS: In this study, records of 770 ischemic stroke patients who were 70-89 years old were retrospectively examined (407 septuagenarians and 363 octogenarians). The demographics, comorbid conditions, ischemic stroke type, and stroke outcome for the two age groups were analyzed. RESULTS: Comorbid hypertension, diabetes mellitus, and HbA1c levels of >=6.5% more frequently occurred in septuagenarians than in octogenarians (80.6% versus 70.8%, p=0.002; 32.2% versus 21.8%, p=0.001; and 35% versus 23.2%, p=0.003, respectively), whereas atrial fibrillation was significantly higher in octogenarians (49.3% versus 41.5%, p=0.03). Hypercholesterolemia, previous stroke history, and antiaggregant and/or anticoagulant use were not significantly different between the two age groups. Based on the Oxfordshire Community Stroke Project classification, the most common stroke subtype in the septuagenarian group was a lacunar infarction and in the octogenarian group, it was a partial anterior circulation infarct. According to the Modified Ranking Score, the number of patients living independently was higher for septuagenarians (42.8% versus 27.8%, p<0.001). CONCLUSION: The present findings indicate that the clinical characteristics of ischemic stroke differed between septuagenarians and octogenarians. Therefore, elderly stroke patients cannot be accepted as a homogeneous group. Because this is a hospital-based study, our findings need to be tested via additional epidemiological studies. PMID- 28360809 TI - Social Cognition in Schizophrenia Patients and Their First-Degree Relatives. AB - INTRODUCTION: Social cognition is a person's ability to configure the designs of relationships between themselves and others and to use these designs to guide social behaviors in a flexible manner. The models that are the most studied and describe social cognition are the theory of mind (ToM) and emotion recognition. This study was aimed to detect ToM and emotion recognition disorders in schizophrenia patients and their first-degree relatives. METHODS: Thirty schizophrenia patients in remission, the first-degree relatives of schizophrenia patients (n=30), and 30 healthy volunteers who were paired with the patients in terms of age and duration of education were included in the study. The Positive and Negative Symptom Scale (PANSS), Dokuz-Eylul Theory of Mind Scale (DEToMS), Reading the Mind in the Eyes test, Facial Emotion Identification Test (FEIT), and Facial Emotion Discrimination Test (FEDT) were performed by the patients participating in this study. RESULTS: ToM and emotion recognition were found to be defective in the schizophrenia patients and their relatives. The performances of ToM and emotion recognition were ranked as the schizophrenia group, family group, and control group, from the worst to the best. The schizophrenia group showed poor performance in all sub-components except irony. In the family group, the empathy subcomponent showed similar performance with the control group, whereas the subcomponents of the second-order false belief, metaphor, and faux pas tests showed similar performance with the patient group. There were differences among the three groups in the first-order false belief subscale as well as the total DEToMS. The patient and family groups showed the poorest performances, whereas the control group showed the best performance. CONCLUSION: The detection of ToM and emotion recognition disorders in the remission period, regardless of the attack period and asymptomatic first-degree relatives, may support the view that the period of schizophrenia is an independent continuous variable. PMID- 28360810 TI - Brain Infiltration of Immune Cells in CASPR2-Antibody Associated Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis. AB - INTRODUCTION: Antibodies directed against neuronal surface antigens have recently been identified in patients with focal temporal lobe epilepsy (TLE) of unknown cause and mesial TLE with hippocampal sclerosis (MTLE-HS), thereby emphasizing the role of autoimmunity in TLE. Antibodies to contactin-associated protein-like 2 (CASPR2) are prevalent in MTLE-HS patients. We aimed to find out whether anti neuronal autoimmunity might be involved in CASPR2 antibody-related MTLE-HS. METHODS: Surgically resected medial temporal lobe specimens of seropositive and seronegative MTLE-HS patients were examined with hematoxylin and eosin and immunohistochemical staining using specific immune cell markers. RESULTS: Two of 5 CASPR2 antibody-positive MTLE-HS patients showed polymorphonuclear and mononuclear cells infiltrating the subarachnoidal region. One of these patients also showed mononuclear cell infiltration in the parenchyma of the temporal lobe cortex. Subarachnoidal and parenchymal infiltrates contained CD3+, CD8+, and CD68+ cells. None of the 13 seronegative MTLE-HS patients displayed cellular infiltrates in their brain samples, and all MTLE-HS patients showed marked neuronal cell loss but no immune cell infiltration in their hippocampi. CONCLUSION: Our results show that CASPR2 antibody-associated MTLE-HS can present with central nervous system inflammation; thus, this subtype of MTLE-HS might have an autoimmune origin. PMID- 28360812 TI - Serum Prolactin Levels in Multiple Sclerosis, Neuromyelitis Optica, and Clinically Isolated Syndrome Patients. AB - INTRODUCTION: Prolactin has been discussed as a factor likely to play a mediating role in multiple sclerosis (MS). Our aim was to investigate the possible association between prolactin production and clinical features of autoimmune demyelinating central nervous system disorders. METHODS: Serum prolactin levels of 255 MS patients, 19 neuromyelitis optica (NMO) patients, 15 clinically isolated syndrome (CIS) patients, and 240 healthy controls were measured by a heterogeneous sandwich magnetic separation assay. RESULTS: MS and NMO cohorts had a significantly higher number of patients with hyperprolactinemia than healthy controls. Sera obtained during attacks of both MS and NMO patients displayed higher prolactin levels than those collected during remission. Prolactin level elevations were found to be more prominent in myelitis attacks in MS. No significant correlation was found between prolactin levels and age, disease duration, disability status, number of attacks, and oligoclonal band positivity. CIS patients who converted to MS had higher prolactin levels than those who did not. CONCLUSION: Our findings support the possible mediating role of prolactin in the immunopathogenesis of MS, NMO, and conversion from CIS to MS. PMID- 28360811 TI - Evaluation of the Relationship between Brain-Derived Neurotropic Factor Levels and the Stroop Interference Effect in Children with Attention-Deficit Hyperactivity Disorder. AB - INTRODUCTION: Brain-derived neurotropic factor (BDNF) has been suggested to play a role in the pathogenesis of attention-deficit hyperactivity disorder (ADHD). In addition, impairment in executive functions has been reported in children with ADHD. This study investigated the presence of a relationship between Stroop test scores and BDNF levels in children with ADHD. METHODS: The study was conducted in the Department of Child Psychiatry at Dicle University. The study included 49 children between 6 and 15 years of age (M/F: 42/7), who were diagnosed with ADHD according to DSM-IV, and who did not receive previous therapy. Similar in terms of age and gender to the ADHD group, 40 children were selected in the control group. The Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime version was administered to all participants. Parents and teachers were administered Turgay DSM-IV-based Child and Adolescent Behavior Disorders Screening and Rating Scale to measure symptom severity in children with ADHD. Children with ADHD underwent the Stroop test. BDNF levels were evaluated in serum by ELISA. RESULTS: The ADHD and control groups did not differ in terms of BDNF levels. BDNF levels did not differ between ADHD subtypes. There was also no relationship between the Stroop test interference scores and BDNF levels. CONCLUSION: The findings of the present study are in line with those in studies that demonstrated no significant role of BDNF in the pathogenesis of ADHD. PMID- 28360814 TI - Long-acting Injectable Risperidone Use in an 11-Years-Old Bipolar Child. AB - Early-onset bipolar disorder is difficult for child psychiatrists in terms of both diagnosis and treatment. The proper diagnostic evaluation is negatively impacted by the atypical clinical manifestation and rapid cycling pattern of the disease, together with common comorbidity with attention-deficit hyperactivity disorder and anxiety disorder. In addition to poor insight, nonadherence to treatment, poor family coping skills, and insufficient child psychiatric inpatient units make clinicians unsuccessful in following up and treating such patients. Risperidone is a commonly used atypical antipsychotic it has been approved for the treatment of manic and mixed episodes of bipolar disorder even in 10-17-year-old patients, and it is commonly used. It has a long-acting injectable formulation. Studies on its long-acting form in younger children are limited. In this case presentation, the diagnostic procedure in an 11-year old child with bipolar disorder will be presented. Long-acting injectable risperidone use in the case of nonadherence to treatment and observed side effects will be discussed. PMID- 28360813 TI - Effect of 72 h of Sleep Deprivation on the Iowa Gambling Task. AB - INTRODUCTION: Sleep deprivation has detrimental effects on cognitive processes, including decision making. The present study investigated how 72 h of sleep deprivation influenced individual neural performance in the Iowa gambling task using event-related potential technology. METHODS: Eleven healthy male adults who participated in our study were randomized to be either in group with 72 h of social isolation condition or 72 h of sleep deprivation condition. RESULTS: Results showed that, in the feedback stage, the N250-400 amplitude was smaller in post-test than in pre-test for the sleep deprivation condition, especially in the frontal cortex. No significant difference between the pre-test and post-test condition was found in the social isolation condition. CONCLUSION: These results suggested that 72 h of sleep deprivation affected an individual's response to feedback stimuli, causing the individual to evaluate the stimuli slowly. PMID- 28360815 TI - Epileptic Seizures with Mirthful Laughter. PMID- 28360816 TI - Relationship Between the Clinical and Biochemical Findings of Polycystic Ovary Syndrome and Depression and Anxiety. PMID- 28360817 TI - Carcinoid Tumor-Associated Paraneoplastic Polyneuropathy that Mimics Guillain Barre Syndrome. PMID- 28360818 TI - Geometric auxetics. AB - We formulate a mathematical theory of auxetic behaviour based on one-parameter deformations of periodic frameworks. Our approach is purely geome- tric, relies on the evolution of the periodicity lattice and works in any dimension. We demonstrate its usefulness by predicting or recognizing, without experiment, computer simulations or numerical approximations, the auxetic capabilities of several well-known structures available in the literature. We propose new principles of auxetic design and rely on the stronger notion of expansive behaviour to provide an infinite supply of planar auxetic mechanisms and several new three-dimensional structures. PMID- 28360819 TI - Surface-initiated ring-opening metathesis polymerization (SI-ROMP) to attach a tethered organic corona onto CdSe/ZnS core/shell quantum dots. AB - Core-shell CdSe/ZnS quantum dots (QDs) are useful as tunable photostable fluorophores for multiple applications in industry, biology, and medicine. However, to achieve the optimum optical properties, the surface of the QDs must be passivated to remove charged sites that might bind extraneous substances and allow aggregation. Here we describe a method of growing an organic polymer corona onto the QD surface using the bottom-up approach of surface-initiated ring opening metathesis polymerization (SI-ROMP) with Grubbs catalyst. CdSe/ZnS QDs were first coated with mercaptopropionic acid by displacing the original trioctylphosphine oxide layer, and then reacted with 7-octenyl dimethyl chlorosilane. The resulting octenyl double bonds allowed the attachment of ruthenium alkylidene groups as a catalyst. A subsequent metathesis reaction with strained bicyclic monomers (norbornene-dicarbonyl chloride (NDC), and a mixture of NDC and norbornenylethylisobutyl-polyhedral oligomeric silsesquioxane (norbornoPOSS)) allowed the construction of tethered organic homo-polymer or co polymer layers onto the QD. Compounds were characterized by FT-IR, 1H-NMR, X-ray photoelectron spectroscopy, differential scanning calorimetry, and transmission electron microscopy. Atomic force microscopy showed that the coated QDs were separate and non-aggregated with a range of diameter of 48-53 nm. PMID- 28360820 TI - The effect of tetrandrine combined with cisplatin on proliferation and apoptosis of A549/DDP cells and A549 cells. AB - BACKGROUND: Non-small cell lung cancer comprises the majority of lung cancer cases and is insensitive to chemotherapy. Most patients develop drug resistance. Recently, tetrandrine (TET), a bis-benzylisoquinoline alkaloid, was identified as a novel anti-cancer agent. However, the effect of tetrandrine combined with cisplatin on lung cancer has not yet been studied. We aimed to identify a possible synergistic effect between tetrandrine and cisplatin, besides, to investigate the effects of TET in combination with DDP on proliferation and apoptosis in cisplatin-resistant and cisplatin-sensitive A549 cell lines, and to study the underlying mechanism. METHODS: Cell viability was confirmed with CCK8 assays, and the IC50 values for each treatment group were calculated. The synergistic interaction of these drugs was evaluated using an isobolographic analysis. Proliferation was assessed by EDU staining. Hoechst staining and flow cytometry were used to assess apoptosis. Apoptosis- and autophagy-associated proteins were analyzed by western blot. Transmission electron microscopy was used to detect autophagy, RFP-GFP-LC3 lentivirus was used to perform autophagic flux assay. RESULTS: Tetrandrine and cisplatin exerted synergistic cytotoxic effects on both cisplatin-resistant and cisplatin-sensitive A549 cell lines. The combination of tetrandrine and cisplatin induced apoptosis and inhibited proliferation in a synergistic manner. The formation of autophagosomes was evident by transmission electron microscopy. The autophagic flux of combination treatment was increased. CONCLUSIONS: Tetrandrine synergized with cisplatin to reduce the viability of cisplatin-resistant and cisplatin-sensitive A549 cells, tetrandrine could reverse the resistance of A549 cells to cisplatin. Tetrandrine combined with cisplatin could induce autophagy. Therefore, tetrandrine is a potent autophagy agonist and may be a promising drug for the treatment of non small cell lung cancer. PMID- 28360821 TI - Combined EphB2 receptor knockdown with radiation decreases cell viability and invasion in medulloblastoma. AB - BACKGROUND: Medulloblastoma is one of the most common types of pediatric brain tumor characterized by the subpopulation of cells that exhibit high invasive potential and radioresistant properties. In addition, dysregulated function and signaling by Eph family of receptors have been shown to impart pro-tumorigenic characteristics in this brain malignancy. In the current study, we investigated whether EphB2 knockdown in combination with radiation can alter invasiveness and decrease medulloblastoma tumor growth or viability in vitro. METHODS: The expression of EphB2 receptor was analyzed by immunohistochemistry and Western blotting. Microarray analysis and mRNA analysis was performed on medulloblastoma patient datasets and compared to the normal cerebellum. The radiosensitization effect following EphB2 knockdown was determined by clonogenic assay in human medulloblastoma cells. Effects of EphB2-siRNA in absence or presence of radiation on cell cycle distribution, cell viability, and invasion were analyzed by flow cytometry, MTT assay, trypan blue exclusion assay, xcelligence system, and Western blotting. RESULTS: We observed that EphB2 is expressed in both medulloblastoma cell lines and patient samples and its downregulation sensitized these cells to radiation as evident by decreased clonogenic survival fractions. EphB2 expression was also high across different medulloblastoma subgroups compared to normal cerebellum. The radiosensitization effect observed following EphB2 knockdown was in part mediated by enhanced G2/M cell cycle arrest. We also found that the combined approach of EphB2 knockdown and radiation exposure significantly reduced overall cell viability in medulloblastoma cells compared to control groups. Similar results were obtained in the xcelligence-based invasion assay. Western blot analysis also demonstrated changes in the protein expression of cell proliferation, cell survival, and invasion molecules in the combination group versus others. CONCLUSIONS: Overall, our findings indicate that specific targeting of EphB2 receptor in combination with radiation may serve as an effective therapeutic strategy in medulloblastoma. Future studies are warranted to test the efficacy of this approach in in vivo preclinical models. PMID- 28360822 TI - Impact of blood hypercoagulability on in vitro fertilization outcomes: a prospective longitudinal observational study. AB - BACKGROUND: Blood coagulation plays a crucial role in the blastocyst implantation process and its alteration may be related to in vitro fertilization (IVF) failure. We conducted a prospective observational longitudinal study in women eligible for IVF to explore the association between alterations of coagulation with the IVF outcome and to identify the biomarkers of hypercoagulability which are related with this outcome. METHODS: Thirty-eight women eligible for IVF (IVF group) and 30 healthy, age-matched women (control group) were included. In the IVF-group, blood was collected at baseline, 5-8 days after administration of gonadotropin-releasing hormone agonist (GnRH), before and two weeks after administration of human follicular stimulating hormone (FSH). Pregnancy was monitored by measurement of betaHCG performed 15 days after embryo transfer. Thrombin generation (TG), minimal tissue factor-triggered whole blood thromboelastometry (ROTEM(r)), procoagulant phospholipid clotting time (Procoag PPL(r)), thrombomodulin (TMa), tissue factor activity (TFa), factor VIII (FVIII), factor von Willebrand (FvW), D-Dimers and fibrinogen were assessed at each time point. RESULTS: Positive IVF occurred in 15 women (40%). At baseline, the IVF group showed significantly increased TG, TFa and TMa and significantly shorter Procoag-PPL versus the control group. After initiation of hormone treatment TG was significantly higher in the IVF-positive as compared to the IVF-negative group. At all studied points, the Procoag-PPL was significantly shorter and the levels of TFa were significantly higher in the IVF-negative group compared to the IVF-positive one. The D-Dimers were higher in the IVF negative as compared to IVF positive group. Multivariate analysis retained the Procoag-PPL and TG as predictors for the IVF outcome. CONCLUSIONS: Diagnosis of women with hypercoagulability and their stratification to risk of IVF failure using a model based on the Procoag-PPL and TG is a feasible strategy for the optimization of IVF efficiency that needs to be validated in prospective trials. PMID- 28360824 TI - Interrelations Between Maternal Smoking During Pregnancy, Birth Weight and Sociodemographic Factors in the Prediction of Early Cognitive Abilities. AB - Maternal prenatal smoking, birth weight and sociodemographic factors were investigated in relation to cognitive abilities of 1544 children (aged 3.5 years) participating in the Quebec Longitudinal Study of Children's Development. The Peabody Picture Vocabulary Test (PPVT) was used to assess verbal ability, the Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R) block design test to assess visuospatial ability, and the Visually Cued Recall (VCR) task to assess short-term memory. Prenatal smoking was related to performance on the WPPSI-R, the PPVT, and the VCR, although it did not independently predict any cognitive ability after maternal education was taken into account. Birth weight was a more robust predictor of all outcome measures and independently predicted VCR-performance. Birth weight interacted significantly with family income and maternal education in predicting visuospatial ability, indicating a greater influence of birth weight under relatively poor socio-economic conditions. Parenting and family functioning mediated associations between maternal education/family income and cognitive task performance under different birth weight conditions, although there were indications for stronger effects under relatively low birth weight. We conclude that investigations of moderating and mediating effects can provide insights into which children are most at risk of cognitive impairment and might benefit most from interventions. PMID- 28360825 TI - Ingestion of oxygenated water enhances lactate clearance kinetics in trained runners. AB - BACKGROUND: Drinks with higher dissolved oxygen concentrations have in recent times gained popularity as a potential ergogenic aid, despite a lack of evidence regarding their efficacy. The aim of this study was to assess effects of ingestion of an oxygen supplement (OS) on exercise performance and post-exercise recovery in a group of trained runners. METHODS: Trained male runners (n = 25, mean +/- SD; age 23 +/- 6 years, mass 70 +/- 9 kg, BMI 21.9 +/- 2.7 kg.m-2 VO2max 64 +/- 6mL.kg-1.min-1), completed a randomised double blinded, crossover study to assess the effect of ingestion of OS solution on exercise performance and recovery. Trials consisted of a 30min rest period, 5min warm-up, a 5000m treadmill time-trial, and a 30min passive recovery. Participants ingested 6x15mL of either OS or a taste matched placebo during the trials (3 during the rest phase, 1 during exercise and 2 during the recovery). Muscle tissue O2 saturation was measured via near infrared spectroscopy. Blood lactate concentrations were measured prior to, mid-way and directly after the finish of the 5000m time trials and every 3-min during the post-exercise recovery. RESULTS: Ingestion of OS did not improve exercise performance. No significant differences were observed for muscle tissue O2 saturation at any time-points. However, lactate clearance was significantly improved during recovery in the OS trials. Both AUC (109 +/- 32 vs. 123 +/- 38 mmol.min, P < 0.05, d = 0.40) and lactate half-life (lambda) (1127 +/- 272 vs. 1223 +/- 334 s, P < 0.05, d = 0.32) were significantly reduced. CONCLUSIONS: Despite no evidence of improved exercise performance, ingestion of OS did enhance post-exercise recovery via increased lactate clearance. PMID- 28360826 TI - Glycated lysine-141 in haptoglobin improves the diagnostic accuracy for type 2 diabetes mellitus in combination with glycated hemoglobin HbA1c and fasting plasma glucose. AB - BACKGROUND: Recent epidemiological studies indicate that only 30-50% of undiagnosed type 2 diabetes mellitus (T2DM) patients are identified using glycated hemoglobin (HbA1c) and elevated fasting plasma glucose (FPG) levels. Thus, novel biomarkers for early diagnosis and prognosis are urgently needed for providing early and personalized treatment. METHODS: Here, we studied the glycation degrees of 27 glycation sites representing nine plasma proteins in 48 newly diagnosed male T2DM patients and 48 non-diabetic men matched for age (range 35-65 years). Samples were digested with trypsin and enriched for glycated peptides using boronic acid affinity chromatography. Quantification relied on mass spectrometry (multiple reaction monitoring) using isotope-labelled peptides as internal standard. RESULTS: The combination of glycated lysine-141 of haptoglobin (HP K141) and HbA1c provided a sensitivity of 94%, a specificity of 98%, and an accuracy of 96% to identify T2DM. A set of 15 features considering three glycation sites in human serum albumin, HP K141, and 11 routine laboratory measures of T2DM, metabolic syndrome, obesity, inflammation, and insulin resistance provided a sensitivity of 98%, a specificity of 100%, and an accuracy of 99% for newly diagnosed T2DM patients. CONCLUSIONS: Our studies demonstrated the great potential of glycation sites in plasma proteins providing an additional diagnostic tool for T2DM and elucidating that the combination of these sites with HbA1c and FPG could improve the diagnosis of T2DM. PMID- 28360827 TI - Property-Guided Synthesis of Aza-Tricyclic Indolines: Development of Gold Catalysis En Route. AB - Antibiotic resistance is a worldwide public health threat that needs to be addressed by improved antibiotic stewardship and continuing development of new chemical entities to treat resistant bacterial infections. Compounds that work alongside known antibiotics as combination therapies offer an efficient and sustainable approach to counteract antibiotic resistance in bacteria. Guided by property-based analysis, a series of aza-tricyclic indolines (ATIs) were synthesized to optimize their physiochemical properties as novel combination therapies with beta-lactams to treat methicillin-resistant S. aureus (MRSA) infections. A novel and highly efficient gold-catalyzed tandem cyclization was developed to facilitate the synthesis of these ATIs. One guanidine-containing ATI was discovered to possess both improved anti-MRSA activity and lower mammalian toxicity both in vitro and in vivo. In addition, it also showed significantly enhanced aqueous solubility and metabolic stability. These results indicated that the ATIs are a novel class of anti-MRSA agents suitable for further evaluations as adjuvant therapy in animal model studies. PMID- 28360828 TI - Economic evaluation of an exercise-counselling intervention to enhance smoking cessation outcomes: The Fit2Quit trial. AB - BACKGROUND: In the Fit2Quit randomised controlled trial, insufficiently-active adult cigarette smokers who contacted Quitline for support to quit smoking were randomised to usual Quitline support or to also receive <=10 face-to-face and telephone exercise-support sessions delivered by trained exercise facilitators over the 24-week trial. This paper aims to determine the cost-effectiveness of an exercise-counselling intervention added to Quitline compared to Quitline alone in the Fit2Quit trial. METHODS: Within-trial and lifetime cost-effectiveness were assessed. A published Markov model was adapted, with smokers facing increased risks of lung cancer and cardiovascular disease. RESULTS: Over 24 weeks, the incremental programme cost per participant in the intervention was NZ$428 (US$289 or ?226; purchasing power parity-adjusted [PPP]). The incremental cost effectiveness ratio (ICER) for seven-day point prevalence measured at 24-week follow-up was NZ$31,733 (US$21,432 or ?16,737 PPP-adjusted) per smoker abstaining. However, for the 52% who adhered to the intervention (>=7 contacts), the ICER for point prevalence was NZ$3,991 (US$2,695 or ?2,105 PPP-adjusted). In this adherent subgroup, the Markov model estimated 0.057 and 0.068 discounted quality-adjusted life-year gains over the lifetime of 40-year-old males (ICER: NZ$4,431; US$2,993 or ?2,337 PPP-adjusted) and females (ICER: NZ$2,909; US$1,965 or ?1,534 PPP-adjusted). CONCLUSIONS: The exercise-counselling intervention will only be cost-effective if adherence is a minimum of >=7 intervention calls, which in turn leads to a sufficient number of quitters for health gains. TRIAL REGISTRATION: Australasian Clinical Trials Registry Number ACTRN12609000637246. PMID- 28360829 TI - Activation and Functional Connectivity of the Left Inferior Temporal Gyrus during Visual Speech Priming in Healthy Listeners and Listeners with Schizophrenia. AB - Under a "cocktail-party" listening condition with multiple-people talking, compared to healthy people, people with schizophrenia benefit less from the use of visual-speech (lipreading) priming (VSP) cues to improve speech recognition. The neural mechanisms underlying the unmasking effect of VSP remain unknown. This study investigated the brain substrates underlying the unmasking effect of VSP in healthy listeners and the schizophrenia-induced changes in the brain substrates. Using functional magnetic resonance imaging, brain activation and functional connectivity for the contrasts of the VSP listening condition vs. the visual non speech priming (VNSP) condition were examined in 16 healthy listeners (27.4 +/- 8.6 years old, 9 females and 7 males) and 22 listeners with schizophrenia (29.0 +/- 8.1 years old, 8 females and 14 males). The results showed that in healthy listeners, but not listeners with schizophrenia, the VSP-induced activation (against the VNSP condition) of the left posterior inferior temporal gyrus (pITG) was significantly correlated with the VSP-induced improvement in target-speech recognition against speech masking. Compared to healthy listeners, listeners with schizophrenia showed significantly lower VSP-induced activation of the left pITG and reduced functional connectivity of the left pITG with the bilateral Rolandic operculum, bilateral STG, and left insular. Thus, the left pITG and its functional connectivity may be the brain substrates related to the unmasking effect of VSP, assumedly through enhancing both the processing of target visual speech signals and the inhibition of masking-speech signals. In people with schizophrenia, the reduced unmasking effect of VSP on speech recognition may be associated with a schizophrenia-related reduction of VSP-induced activation and functional connectivity of the left pITG. PMID- 28360831 TI - A 4-fJ/Spike Artificial Neuron in 65 nm CMOS Technology. AB - As Moore's law reaches its end, traditional computing technology based on the Von Neumann architecture is facing fundamental limits. Among them is poor energy efficiency. This situation motivates the investigation of different processing information paradigms, such as the use of spiking neural networks (SNNs), which also introduce cognitive characteristics. As applications at very high scale are addressed, the energy dissipation needs to be minimized. This effort starts from the neuron cell. In this context, this paper presents the design of an original artificial neuron, in standard 65 nm CMOS technology with optimized energy efficiency. The neuron circuit response is designed as an approximation of the Morris-Lecar theoretical model. In order to implement the non-linear gating variables, which control the ionic channel currents, transistors operating in deep subthreshold are employed. Two different circuit variants describing the neuron model equations have been developed. The first one features spike characteristics, which correlate well with a biological neuron model. The second one is a simplification of the first, designed to exhibit higher spiking frequencies, targeting large scale bio-inspired information processing applications. The most important feature of the fabricated circuits is the energy efficiency of a few femtojoules per spike, which improves prior state-of-the-art by two to three orders of magnitude. This performance is achieved by minimizing two key parameters: the supply voltage and the related membrane capacitance. Meanwhile, the obtained standby power at a resting output does not exceed tens of picowatts. The two variants were sized to 200 and 35 MUm2 with the latter reaching a spiking output frequency of 26 kHz. This performance level could address various contexts, such as highly integrated neuro-processors for robotics, neuroscience or medical applications. PMID- 28360830 TI - Transthyretin and BRICHOS: The Paradox of Amyloidogenic Proteins with Anti Amyloidogenic Activity for Abeta in the Central Nervous System. AB - Amyloid fibrils are physiologically insoluble biophysically specific beta-sheet rich structures formed by the aggregation of misfolded proteins. In vivo tissue amyloid formation is responsible for more than 30 different disease states in humans and other mammals. One of these, Alzheimer's disease (AD), is the most common form of human dementia for which there is currently no definitive treatment. Amyloid fibril formation by the amyloid beta-peptide (Abeta) is considered to be an underlying cause of AD, and strategies designed to reduce Abeta production and/or its toxic effects are being extensively investigated in both laboratory and clinical settings. Transthyretin (TTR) and proteins containing a BRICHOS domain are etiologically associated with specific amyloid diseases in the CNS and other organs. Nonetheless, it has been observed that TTR and BRICHOS structures are efficient inhibitors of Abeta fibril formation and toxicity in vitro and in vivo, raising the possibility that some amyloidogenic proteins, or their precursors, possess properties that may be harnessed for combating AD and other amyloidoses. Herein, we review properties of TTR and the BRICHOS domain and discuss how their abilities to interfere with amyloid formation may be employed in the development of novel treatments for AD. PMID- 28360832 TI - A Life without Hunger: The Ups (and Downs) to Modulating Melanocortin-3 Receptor Signaling. AB - Melanocortin neurons conserve body mass in hyper- or hypo-caloric conditions by conveying signals from nutrient sensors into areas of the brain governing appetite and metabolism. In mice, melanocortin-3 receptor (MC3R) deletion alters nutrient partitioning independently of hyperphagia, promoting accumulation of fat over muscle mass. Enhanced rhythms in insulin and insulin-responsive metabolic genes during hypocaloric feeding suggest partial insulin resistance and enhanced lipogenesis. However, exactly where and how MC3Rs affect metabolic control to alter nutrient partitioning is not known. The behavioral phenotypes exhibited by MC3R-deficient mice suggest a contextual role in appetite control. The impact of MC3R-deficiency on feeding behavior when food is freely available is minor. However, homeostatic responses to hypocaloric conditioning involving increased expression of appetite-stimulating (orexigenic) neuropeptides, binge-feeding, food anticipatory activity (FAA), entrainment to nutrient availability and enhanced feeding-related motivational responses are compromised with MC3R deficiency. Rescuing Mc3r transcription in hypothalamic and limbic neurons improves appetitive responses during hypocaloric conditioning while having minor effects on nutrient partitioning, suggesting orexigenic functions. Rescuing hypothalamic MC3Rs also restores responses of fasting-responsive hypothalamic orexigenic neurons in hypocaloric conditions, suggesting actions that sensitize fasting-responsive neurons to signals from nutrient sensors. MC3R signaling in ventromedial hypothalamic SF1(+ve) neurons improves metabolic control, but does not restore appetitive responses or nutrient partitioning. In summary, desensitization of fasting-responsive orexigenic neurons may underlie attenuated appetitive responses of MC3R-deficient mice in hypocaloric situations. Further studies are needed to identify the specific location(s) of MC3Rs controlling appetitive responses and partitioning of nutrients between fat and lean tissues. PMID- 28360833 TI - Efficient Binding of the NOS1AP C-Terminus to the nNOS PDZ Pocket Requires the Concerted Action of the PDZ Ligand Motif, the Internal ExF Site and Structural Integrity of an Independent Element. AB - Neuronal nitric oxide synthase is widely regarded as an important contributor to a number of disorders of excitable tissues. Recently the adaptor protein NOS1AP has emerged as a contributor to several nNOS-linked conditions. As a consequence, the unexpectedly complex mechanisms of interaction between nNOS and its effector NOS1AP have become a particularly interesting topic from the point of view of both basic research and the potential for therapeutic applications. Here we demonstrate that the concerted action of two previously described motif regions contributing to the interaction of nNOS with NOS1AP, the ExF region and the PDZ ligand motif, efficiently excludes an alternate ligand from the nNOS-PDZ ligand binding pocket. Moreover, we identify an additional element with a denaturable structure that contributes to interaction of NOS1AP with nNOS. Denaturation does not affect the functions of the individual motifs and results in a relatively mild drop, ~3-fold, of overall binding affinity of the C-terminal region of NOS1AP for nNOS. However, denaturation selectively prevents the concerted action of the two motifs that normally results in efficient occlusion of the PDZ ligand binding pocket, and results in 30-fold reduction of competition between NOS1AP and an alternate PDZ ligand. PMID- 28360834 TI - An Aberrant Phosphorylation of Amyloid Precursor Protein Tyrosine Regulates Its Trafficking and the Binding to the Clathrin Endocytic Complex in Neural Stem Cells of Alzheimer's Disease Patients. AB - Alzheimer's disease (AD) is the most common cause of dementia and is likely caused by defective amyloid precursor protein (APP) trafficking and processing in neurons leading to amyloid plaques containing the amyloid-beta (Abeta) APP peptide byproducts. Understanding how APP is targeted to selected destinations inside neurons and identifying the mechanisms responsible for the generation of Abeta are thus the keys for the advancement of new therapies. We previously developed a mouse model with a mutation at tyrosine (Tyr) 682 in the C-terminus of APP. This residue is needed for APP to bind to the coating protein Clathrin and to the Clathrin adaptor protein AP2 as well as for the correct APP trafficking and sorting in neurons. By extending these findings to humans, we found that APP binding to Clathrin is decreased in neural stem cells from AD sufferers. Increased APP Tyr phosphorylation alters APP trafficking in AD neurons and it is associated to Fyn Tyr kinase activation. We show that compounds affecting Tyr kinase activity and counteracting defects in AD neurons can control APP location and compartmentalization. APP Tyr phosphorylation is thus a potential therapeutic target for AD. PMID- 28360835 TI - Hemifusion in Synaptic Vesicle Cycle. AB - In the neuron, early neurotransmitters are released through the fusion pore prior to the complete vesicle fusion. It has been thought that the fusion pore is a gap junction-like structure made of transmembrane domains (TMDs) of soluble N ethylmaleimide-sensitive-factor attachment protein receptor (SNARE) proteins. However, evidence has accumulated that lipid mixing occurs prior to the neurotransmitter release through the fusion pore lined predominantly with lipids. To explain these observations, the hemifusion, a membrane structure in which two bilayers are partially merged, has emerged as a key step preceding the formation of the fusion pore. Furthermore, the hemifusion appears to be the bona fide intermediate step not only for the synaptic vesicle cycle, but for a wide range of membrane remodeling processes, such as viral membrane fusion and endocytotic membrane fission. PMID- 28360836 TI - Genetic Tracing of Cav3.2 T-Type Calcium Channel Expression in the Peripheral Nervous System. AB - Characterizing the distinct functions of the T-type ion channel subunits Cav3.1, 3.2 or 3.3 has proven difficult due to their highly conserved amino-acid sequences and the lack of pharmacological blockers specific for each subunit. To precisely determine the expression pattern of the Cav3.2 channel in the nervous system we generated two knock-in mouse strains that express EGFP or Cre recombinase under the control of the Cav3.2 gene promoter. We show that in the brains of these animals, the Cav3.2 channel is predominantly expressed in the dentate gyrus of the hippocampus. In the peripheral nervous system, the activation of the promoter starts at E9.5 in neural crest cells that will give rise to dorsal root ganglia (DRG) neurons, but not sympathetic neurons. As development progresses the number of DRG cells expressing the Cav3.2 channel reaches around 7% of the DRG at E16.5, and remains constant until E18.5. Characterization of sensory neuron subpopulations at E18.5 showed that EGFP+ cells are a heterogeneous population consisting mainly of TrkB+ and TrkC+ cells, while only a small percentage of DRG cells were TrkA+. Genetic tracing of the sensory nerve end-organ innervation of the skin showed that the activity of the Cav3.2 channel promoter in sensory progenitors marks many mechanoreceptor and nociceptor endings, but spares slowly adapting mechanoreceptors with endings associated with Merkel cells. Our genetic analysis reveals for the first time that progenitors that express the Cav3.2 T-type calcium channel, defines a sensory specific lineage that populates a large proportion of the DRG. Using our Cav3.2-Cre mice together with AAV viruses containing a conditional fluorescent reporter (tdTomato) we could also show that Cre expression is largely restricted to two functionally distinct sensory neuron types in the adult ganglia. Cav3.2 positive neurons innervating the skin were found to only form lanceolate endings on hair follicles and are probably identical to D-hair receptors. A second population of nociceptive sensory neurons expressing the Cav3.2 gene was found to be positive for the calcitonin-gene related peptide but these neurons are deep tissue nociceptors that do not innervate the skin. PMID- 28360837 TI - New Insights into the Crosstalk between NMDARs and Iron: Implications for Understanding Pathology of Neurological Diseases. AB - Both iron dyshomeostasis and N-methyl-D-aspartate receptors (NMDARs)-mediated neurotoxicity have been shown to have an important role in neurological diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). Evidence proved that activation of NMDARs could promote iron overload and iron-induced neurotoxicity by enhancing iron importer divalent metal transporter 1 (DMT1) mediated iron uptake and iron releasing from lysosome. Also, iron overload could regulate NMDARs-mediated synaptic transmission. This indicates that there might be a possible relationship between iron and activation of NMDARs in neurological diseases. Understanding this interaction between iron and activation of NMDARs may provide new therapeutic avenues for a more targeted neurotherapeutic strategy for these diseases. Therefore, in this review article, we will describe the dysfunction of iron metabolism and NMDARs in neurological diseases including PD and AD, and summarize the new insight into the mechanisms underlying the interaction between iron and activation of NMDARs. PMID- 28360838 TI - Planar Supported Membranes with Mobile SNARE Proteins and Quantitative Fluorescence Microscopy Assays to Study Synaptic Vesicle Fusion. AB - Synaptic vesicle membrane fusion, the process by which neurotransmitter gets released at the presynaptic membrane is mediated by a complex interplay between proteins and lipids. The realization that the lipid bilayer is not just a passive environment where other molecular players like SNARE proteins act, but is itself actively involved in the process, makes the development of biochemical and biophysical assays particularly challenging. We summarize in vitro assays that use planar supported membranes and fluorescence microscopy to address some of the open questions regarding the molecular mechanisms of SNARE-mediated membrane fusion. Most of the assays discussed in this mini-review were developed in our lab over the last 15 years. We emphasize the sample requirements that we found are important for the successful application of these methods. PMID- 28360839 TI - Emerging Roles for Glycogen in the CNS. AB - The ability of glycogen, the depot into which excess glucose is stored in mammals, to act as a source of rapidly available energy substrate, has been exploited by several organs for both general and local advantage. The liver, expressing the highest concentration of glycogen maintains systemic normoglycemia ensuring the brain receives a supply of glucose in excess of demand. However the brain also contains glycogen, although its role is more specialized. Brain glycogen is located exclusively in astrocytes in the adult, with the exception of pathological conditions, thus in order to benefit neurons, and energy conduit (lactate) is trafficked inter-cellularly. Such a complex scheme requires cell type specific expression of a variety of metabolic enzymes and transporters. Glycogen supports neural elements during withdrawal of glucose, but once the limited buffer of glycogen is exhausted neural function fails and irreversible injury ensues. Under physiological conditions glycogen acts to provide supplemental substrates when ambient glucose is unable to support function during increased energy demand. Glycogen also supports learning and memory where it provides lactate to neurons during the conditioning phase of in vitro long-term potentiation (LTP), an experimental correlate of learning. Inhibiting the breakdown of glycogen or intercellular transport of lactate in in vivo rat models inhibits the retention of memory. Our current understanding of the importance of brain glycogen is expanding to encompass roles that are fundamental to higher brain function. PMID- 28360841 TI - Single Neuron Optimization as a Basis for Accurate Biophysical Modeling: The Case of Cerebellar Granule Cells. AB - In realistic neuronal modeling, once the ionic channel complement has been defined, the maximum ionic conductance (Gi-max) values need to be tuned in order to match the firing pattern revealed by electrophysiological recordings. Recently, selection/mutation genetic algorithms have been proposed to efficiently and automatically tune these parameters. Nonetheless, since similar firing patterns can be achieved through different combinations of Gi-max values, it is not clear how well these algorithms approximate the corresponding properties of real cells. Here we have evaluated the issue by exploiting a unique opportunity offered by the cerebellar granule cell (GrC), which is electrotonically compact and has therefore allowed the direct experimental measurement of ionic currents. Previous models were constructed using empirical tuning of Gi-max values to match the original data set. Here, by using repetitive discharge patterns as a template, the optimization procedure yielded models that closely approximated the experimental Gi-max values. These models, in addition to repetitive firing, captured additional features, including inward rectification, near-threshold oscillations, and resonance, which were not used as features. Thus, parameter optimization using genetic algorithms provided an efficient modeling strategy for reconstructing the biophysical properties of neurons and for the subsequent reconstruction of large-scale neuronal network models. PMID- 28360840 TI - Impaired NGF/TrkA Signaling Causes Early AD-Linked Presynaptic Dysfunction in Cholinergic Primary Neurons. AB - Alterations in NGF/TrkA signaling have been suggested to underlie the selective degeneration of the cholinergic basal forebrain neurons occurring in vivo in AD (Counts and Mufson, 2005; Mufson et al., 2008; Niewiadomska et al., 2011) and significant reduction of cognitive decline along with an improvement of cholinergic hypofunction have been found in phase I clinical trial in humans affected from mild AD following therapeutic NGF gene therapy (Tuszynski et al., 2005, 2015). Here, we show that the chronic (10-12 D.I.V.) in vitro treatment with NGF (100 ng/ml) under conditions of low supplementation (0.2%) with the culturing serum-substitute B27 selectively enriches the basal forebrain cholinergic neurons (+36.36%) at the expense of other non-cholinergic, mainly GABAergic (-38.45%) and glutamatergic (-56.25%), populations. By taking advantage of this newly-developed septo-hippocampal neuronal cultures, our biochemical and electrophysiological investigations demonstrate that the early failure in excitatory neurotransmission following NGF withdrawal is paralleled by concomitant and progressive loss in selected presynaptic and vesicles trafficking proteins including synapsin I, SNAP-25 and alpha-synuclein. This rapid presynaptic dysfunction: (i) precedes the commitment to cell death and is reversible in a time-dependent manner, being suppressed by de novo external administration of NGF within 6 hr from its initial withdrawal; (ii) is specific because it is not accompanied by contextual changes in expression levels of non synaptic proteins from other subcellular compartments; (ii) is not secondary to axonal degeneration because it is insensible to pharmacological treatment with known microtubule-stabilizing drug such paclitaxel; (iv) involves TrkA-dependent mechanisms because the effects of NGF reapplication are blocked by acute exposure to specific and cell-permeable inhibitor of its high-affinity receptor. Taken together, this study may have important clinical implications in the field of AD neurodegeneration because it: (i) provides new insights on the earliest molecular mechanisms underlying the loss of synaptic/trafficking proteins and, then, of synapes integrity which occurs in vulnerable basal forebrain population at preclinical stages of neuropathology; (ii) offers prime presynaptic-based molecular target to extend the therapeutic time-window of NGF action in the strategy of improving its neuroprotective in vivo intervention in affected patients. PMID- 28360843 TI - MagR Alone Is Insufficient to Confer Cellular Calcium Responses to Magnetic Stimulation. AB - Magnetic manipulation of cell activity offers advantages over optical manipulation but an ideal tool remains elusive. The MagR protein was found through its interaction with cryptochrome (Cry) and the protein in solution appeared to respond to magnetic stimulation (MS). After we initiated an investigation on the specific role of MagR in cellular response to MS, a subsequent study claimed that MagR expression alone could achieve cellular activation by MS. Here we report that despite systematically testing different ways of measuring intracellular calcium and different MS protocols, it was not possible to detect any cellular or neuronal responses to MS in MagR-expressing HEK cells or primary neurons from the dorsal root ganglion and the hippocampus. By contrast, in neurons co-expressing MagR and channelrhodopin, optical but not MS increased calcium influx in hippocampal neurons. Our results indicate that MagR alone is not sufficient to confer cellular magnetic responses. PMID- 28360844 TI - Recurrent Network Dynamics; a Link between Form and Motion. AB - To discriminate visual features such as corners and contours, the brain must be sensitive to spatial correlations between multiple points in an image. Consistent with this, macaque V2 neurons respond selectively to patterns with well-defined multipoint correlations. Here, we show that a standard feedforward model (a cascade of linear-non-linear filters) does not capture this multipoint selectivity. As an alternative, we developed an artificial neural network model with two hierarchical stages of processing and locally recurrent connectivity. This model faithfully reproduced neurons' selectivity for multipoint correlations. By probing the model, we gained novel insights into early form processing. First, the diverse selectivity for multipoint correlations and complex response dynamics of the hidden units in the model were surprisingly similar to those observed in V1 and V2. This suggests that both transient and sustained response dynamics may be a vital part of form computations. Second, the model self-organized units with speed and direction selectivity that was correlated with selectivity for multipoint correlations. In other words, the model units that detected multipoint spatial correlations also detected space time correlations. This leads to the novel hypothesis that higher-order spatial correlations could be computed by the rapid, sequential assessment and comparison of multiple low-order correlations within the receptive field. This computation links spatial and temporal processing and leads to the testable prediction that the analysis of complex form and motion are closely intertwined in early visual cortex. PMID- 28360845 TI - Surround-Masking Affects Visual Estimation Ability. AB - Visual estimation of numerosity involves the discrimination of magnitude between two distributions or perceptual sets that vary in number of elements. How performance on such estimation depends on peripheral sensory stimulation is unclear, even in typically developing adults. Here, we varied the central and surround contrast of stimuli that comprised a visual estimation task in order to determine whether mechanisms involved with the removal of unessential visual input functionally contributes toward number acuity. The visual estimation judgments of typically developed adults were significantly impaired for high but not low contrast surround stimulus conditions. The center and surround contrasts of the stimuli also differentially affected the accuracy of numerosity estimation depending on whether fewer or more dots were presented. Remarkably, observers demonstrated the highest mean percentage accuracy across stimulus conditions in the discrimination of more elements when the surround contrast was low and the background luminance of the central region containing the elements was dark (black center). Conversely, accuracy was severely impaired during the discrimination of fewer elements when the surround contrast was high and the background luminance of the central region was mid level (gray center). These findings suggest that estimation ability is functionally related to the quality of low-order filtration of unessential visual information. These surround masking results may help understanding of the poor visual estimation ability commonly observed in developmental dyscalculia. PMID- 28360842 TI - Neuroplastic Changes Following Brain Ischemia and their Contribution to Stroke Recovery: Novel Approaches in Neurorehabilitation. AB - Ischemic damage to the brain triggers substantial reorganization of spared areas and pathways, which is associated with limited, spontaneous restoration of function. A better understanding of this plastic remodeling is crucial to develop more effective strategies for stroke rehabilitation. In this review article, we discuss advances in the comprehension of post-stroke network reorganization in patients and animal models. We first focus on rodent studies that have shed light on the mechanisms underlying neuronal remodeling in the perilesional area and contralesional hemisphere after motor cortex infarcts. Analysis of electrophysiological data has demonstrated brain-wide alterations in functional connectivity in both hemispheres, well beyond the infarcted area. We then illustrate the potential use of non-invasive brain stimulation (NIBS) techniques to boost recovery. We finally discuss rehabilitative protocols based on robotic devices as a tool to promote endogenous plasticity and functional restoration. PMID- 28360847 TI - Effects of Different Exercise Strategies and Intensities on Memory Performance and Neurogenesis. AB - It is well established that physical exercise affects both hippocampal neurogenesis and memory functions. Until now, distinctive effects of controlled and voluntary training (VT) on behavior and neurogenesis as well as interactions between exercise intensity, neurogenesis and memory performance are still elusive. The present study tested the impact of moderate controlled and VT on memory formation and hippocampal neurogenesis and evaluated interactions between exercise performance, learning efficiency and proliferation of progenitor cells in the hippocampus. Our data show that both controlled and VT augmented spatial learning and promoted hippocampal neurogenesis. Regression analysis revealed a significant linear increase of the amount of new hippocampal neurons with increased exercise intensity. Regression analysis of exercise performance on retention memory performance revealed a quadratic, inverted u-shaped relationship between exercise performance and retention of spatial memory. No association was found between the amount of newborn neurons and memory performance. Our results demonstrate that controlled training (CT), if performed with an appropriate combination of speed and duration, improves memory performance and neurogenesis. Voluntary exercise elevates neurogenesis dose dependently to high levels. Best cognitive improvement was achieved with moderate exercise performance. PMID- 28360848 TI - Response-Modality-Specific Encoding of Human Choices in Upper Beta Band Oscillations during Vibrotactile Comparisons. AB - Perceptual decisions based on the comparison of two vibrotactile frequencies have been extensively studied in non-human primates. Recently, we obtained corresponding findings from human oscillatory electroencephalography (EEG) activity in the form of choice-selective modulations of upper beta band amplitude in medial premotor areas. However, the research in non-human primates as well as its human counterpart was so far limited to decisions reported by button presses. Thus, here we investigated whether the observed human beta band modulation is specific to the response modality. We recorded EEG activity from participants who compared two sequentially presented vibrotactile frequencies (f1 and f2), and decided whether f2 > f1 or f2 < f1, by performing a horizontal saccade to either side of a computer screen. Contrasting time-frequency transformed EEG data between both choices revealed that upper beta band amplitude (~24-32 Hz) was modulated by participants' choices before actual responses were given. In particular, "f2 > f1" choices were always associated with higher beta band amplitude than "f2 < f1" choices, irrespective of whether the choice was correct or not, and independent of the specific association between saccade direction and choice. The observed pattern of beta band modulation was virtually identical to our previous results when participants responded with button presses. In line with an intentional framework of decision making, the most likely sources of the beta band modulation were now, however, located in lateral as compared to medial premotor areas including the frontal eye fields. Hence, we could show that the choice-selective modulation of upper beta band amplitude is on the one hand consistent across different response modalities (i.e., same modulation pattern in similar frequency band), and on the other hand effector specific (i.e., modulation originating from areas involved in planning and executing saccades). PMID- 28360850 TI - Exercise-Induced Fitness Changes Correlate with Changes in Neural Specificity in Older Adults. AB - Neural specificity refers to the degree to which neural representations of different stimuli can be distinguished. Evidence suggests that neural specificity, operationally defined as stimulus-related differences in functional magnetic resonance imaging (fMRI) activation patterns, declines with advancing adult age, and that individual differences in neural specificity are associated with individual differences in fluid intelligence. A growing body of literature also suggests that regular physical activity may help preserve cognitive abilities in old age. Based on this literature, we hypothesized that exercise induced improvements in fitness would be associated with greater neural specificity among older adults. A total of 52 adults aged 59-74 years were randomly assigned to one of two aerobic-fitness training regimens, which differed in intensity. Participants in both groups trained three times a week on stationary bicycles. In the low-intensity (LI) group, the resistance was kept constant at a low level (10 Watts). In the high-intensity (HI) group, the resistance depended on participants' heart rate and therefore typically increased with increasing fitness. Before and after the 6-month training phase, participants took part in a functional MRI experiment in which they viewed pictures of faces and buildings. We used multivariate pattern analysis (MVPA) to estimate the distinctiveness of neural activation patterns in ventral visual cortex (VVC) evoked by face or building stimuli. Fitness was also assessed before and after training. In line with our hypothesis, training-induced changes in fitness were positively associated with changes in neural specificity. We conclude that physical activity may protect against age-related declines in neural specificity. PMID- 28360852 TI - Self-Organized Behavior Generation for Musculoskeletal Robots. AB - With the accelerated development of robot technologies, control becomes one of the central themes of research. In traditional approaches, the controller, by its internal functionality, finds appropriate actions on the basis of specific objectives for the task at hand. While very successful in many applications, self organized control schemes seem to be favored in large complex systems with unknown dynamics or which are difficult to model. Reasons are the expected scalability, robustness, and resilience of self-organizing systems. The paper presents a self-learning neurocontroller based on extrinsic differential plasticity introduced recently, applying it to an anthropomorphic musculoskeletal robot arm with attached objects of unknown physical dynamics. The central finding of the paper is the following effect: by the mere feedback through the internal dynamics of the object, the robot is learning to relate each of the objects with a very specific sensorimotor pattern. Specifically, an attached pendulum pilots the arm into a circular motion, a half-filled bottle produces axis oriented shaking behavior, a wheel is getting rotated, and wiping patterns emerge automatically in a table-plus-brush setting. By these object-specific dynamical patterns, the robot may be said to recognize the object's identity, or in other words, it discovers dynamical affordances of objects. Furthermore, when including hand coordinates obtained from a camera, a dedicated hand-eye coordination self organizes spontaneously. These phenomena are discussed from a specific dynamical system perspective. Central is the dedicated working regime at the border to instability with its potentially infinite reservoir of (limit cycle) attractors "waiting" to be excited. Besides converging toward one of these attractors, variate behavior is also arising from a self-induced attractor morphing driven by the learning rule. We claim that experimental investigations with this anthropomorphic, self-learning robot not only generate interesting and potentially useful behaviors, but may also help to better understand what subjective human muscle feelings are, how they can be rooted in sensorimotor patterns, and how these concepts may feed back on robotics. PMID- 28360849 TI - Embodied Medicine: Mens Sana in Corpore Virtuale Sano. AB - Progress in medical science and technology drastically improved physicians' ability to interact with patient's physical body. Nevertheless, medicine still addresses the human body from a Hippocratic point of view, considering the organism and its processes just as a matter of mechanics and fluids. However, the interaction between the cognitive neuroscience of bodily self-consciousness (BSC), fundamentally rooted in the integration of multisensory bodily inputs, with virtual reality (VR), haptic technologies and robotics is giving a new meaning to the classic Juvenal's latin dictum "Mens sana in corpore sano" (a healthy mind in a healthy body). This vision provides the basis for a new research field, "Embodied Medicine": the use of advanced technologies for altering the experience of being in a body with the goal of improving health and well-being. Up to now, most of the research efforts in the field have been focused upon how external bodily information is processed and integrated. Despite the important results, we believe that existing bodily illusions still need to be improved to enhance their capability to effectively correct pathological dysfunctions. First, they do not follow the suggestions provided by the free energy and predictive coding approaches. More, they lacked to consider a peculiar feature of the human body, the multisensory integration of internal inputs (interoceptive, proprioceptive and vestibular) that constitute our inner body dimension. So, a future challenge is the integration of simulation/stimulation technologies also able to measure and modulate this internal/inner experience of the body. Finally, we also proposed the concept of "Sonoception" as an extension of this approach. The core idea is to exploit recent technological advances in the acoustic field to use sound and vibrations to modify the internal/inner body experience. PMID- 28360851 TI - Neuroimaging, Genetics, and Clinical Data Sharing in Python Using the CubicWeb Framework. AB - In neurosciences or psychiatry, the emergence of large multi-center population imaging studies raises numerous technological challenges. From distributed data collection, across different institutions and countries, to final data publication service, one must handle the massive, heterogeneous, and complex data from genetics, imaging, demographics, or clinical scores. These data must be both efficiently obtained and downloadable. We present a Python solution, based on the CubicWeb open-source semantic framework, aimed at building population imaging study repositories. In addition, we focus on the tools developed around this framework to overcome the challenges associated with data sharing and collaborative requirements. We describe a set of three highly adaptive web services that transform the CubicWeb framework into a (1) multi-center upload platform, (2) collaborative quality assessment platform, and (3) publication platform endowed with massive-download capabilities. Two major European projects, IMAGEN and EU-AIMS, are currently supported by the described framework. We also present a Python package that enables end users to remotely query neuroimaging, genetics, and clinical data from scripts. PMID- 28360846 TI - Stress and the Emerging Roles of Chromatin Remodeling in Signal Integration and Stable Transmission of Reversible Phenotypes. AB - The influence of early life experience and degree of parental-infant attachment on emotional development in children and adolescents has been comprehensively studied. Structural and mechanistic insight into the biological foundation and maintenance of mammalian defensive systems (metabolic, immune, nervous and behavioral) is slowly advancing through the emerging field of developmental molecular (epi)genetics. Initial evidence revealed that differential nurture early in life generates stable differences in offspring hypothalamic-pituitary adrenal (HPA) regulation, in part, through chromatin remodeling and changes in DNA methylation of specific genes expressed in the brain, revealing physical, biochemical and molecular paths for the epidemiological concept of gene environment interactions. Herein, a primary molecular mechanism underpinning the early developmental programming and lifelong maintenance of defensive (emotional) responses in the offspring is the alteration of chromatin domains of specific genomic regions from a condensed state (heterochromatin) to a transcriptionally accessible state (euchromatin). Conversely, DNA methylation promotes the formation of heterochromatin, which is essential for gene silencing, genomic integrity and chromosome segregation. Therefore, inter-individual differences in chromatin modifications and DNA methylation marks hold great potential for assessing the impact of both early life experience and effectiveness of intervention programs-from guided psychosocial strategies focused on changing behavior to pharmacological treatments that target chromatin remodeling and DNA methylation enzymes to dietary approaches that alter cellular pools of metabolic intermediates and methyl donors to affect nutrient bioavailability and metabolism. In this review article, we discuss the potential molecular mechanism(s) of gene regulation associated with chromatin modeling and programming of endocrine (e.g., HPA and metabolic or cardiovascular) and behavioral (e.g., fearfulness, vigilance) responses to stress, including alterations in DNA methylation and the role of DNA repair machinery. From parental history (e.g., drugs, housing, illness, nutrition, socialization) to maternal-offspring exchanges of nutrition, microbiota, antibodies and stimulation, the nature of nurture provides not only mechanistic insight into how experiences propagate from external to internal variables, but also identifies a composite therapeutic target, chromatin modeling, for gestational/prenatal stress, adolescent anxiety/depression and adult-onset neuropsychiatric disease. PMID- 28360854 TI - Refining Pharmacologic Research to Prevent and Treat Spontaneous Preterm Birth. PMID- 28360853 TI - White Matter Integrity Declined Over 6-Months, but Dance Intervention Improved Integrity of the Fornix of Older Adults. AB - Degeneration of cerebral white matter (WM), or structural disconnection, is one of the major neural mechanisms driving age-related decline in cognitive functions, such as processing speed. Past cross-sectional studies have demonstrated beneficial effects of greater cardiorespiratory fitness, physical activity, cognitive training, social engagement, and nutrition on cognitive functioning and brain health in aging. Here, we collected diffusion magnetic resonance (MRI) imaging data from 174 older (age 60-79) adults to study the effects of 6-months lifestyle interventions on WM integrity. Healthy but low active participants were randomized into Dance, Walking, Walking + Nutrition, and Active Control (stretching and toning) intervention groups (NCT01472744 on ClinicalTrials.gov). Only in the fornix there was a time * intervention group interaction of change in WM integrity: integrity declined over 6 months in all groups but increased in the Dance group. Integrity in the fornix at baseline was associated with better processing speed, however, change in fornix integrity did not correlate with change in processing speed. Next, we observed a decline in WM integrity across the majority of brain regions in all participants, regardless of the intervention group. This suggests that the aging of the brain is detectable on the scale of 6-months, which highlights the urgency of finding effective interventions to slow down this process. Magnitude of WM decline increased with age and decline in prefrontal WM was of lesser magnitude in older adults spending less time sedentary and more engaging in moderate-to-vigorous physical activity. In addition, our findings support the anterior-to-posterior gradient of greater to-lesser decline, but only in the in the corpus callosum. Together, our findings suggest that combining physical, cognitive, and social engagement (dance) may help maintain or improve WM health and more physically active lifestyle is associated with slower WM decline. This study emphasizes the importance of a physically active and socially engaging lifestyle among aging adults. PMID- 28360856 TI - East Indian Sandalwood Oil (EISO) Alleviates Inflammatory and Proliferative Pathologies of Psoriasis. AB - Psoriasis, a chronic inflammatory skin disease marked by hyper proliferation and aberrant differentiation of keratinocytes, affects 2-3% of the world's population. Research into the pathogenesis of psoriasis has been hampered by the lack of models that accurately reflect the biology of the psoriatic phenotype. We have previously reported that East Indian Sandalwood oil (EISO) has significant anti-inflammatory properties in skin models and hypothesized that EISO might provide therapeutic benefit to psoriasis patients due to its anti-inflammatory and anti-proliferative properties. Here we present interim results from an on going proof-of-concept Phase 2 clinical trial in which topically applied EISO is demonstrating to be well tolerated and helpful in alleviating mild to moderate psoriasis symptoms. This led us to evaluate the ability of EISO to affect the psoriatic phenotype using MatTek Corporation reconstituted organotypic psoriatic and normal human skin models. EISO had no impact on the phenotype of the normal skin tissue model, however, EISO treatment of the psoriasis tissue model reverted psoriatic pathology as demonstrated by histologic characterization and expression of keratinocyte proliferation markers, Ki67 and psoriasin. These phenotypic affects correlated with suppressed production of ENA-78, IL-6, IL-8, MCP-1, GM CSF, and IL-1beta. Demonstration of the ability of EISO to abrogate these psoriasis symptoms in well-characterized in vitro psoriatic tissue models, supports the hypothesis that the clinically observed symptom alleviation is due to suppression of intrinsic tissue inflammation reactions in afflicted lesions. This study presents a systematic approach to further study the underlying mechanisms that cause psoriasis, and presents data supporting the potential of EISO as a new ethnobotanical therapeutic concept to help direct and accelerate the development of more effective therapies. PMID- 28360855 TI - The P2X7 Receptor-Interleukin-1 Liaison. AB - Interleukin-1beta (IL-1beta) plays a central role in stimulation of innate immune system and inflammation and in several chronic inflammatory diseases. These include rare hereditary conditions, e.g., auto-inflammatory syndromes, as well as common pathologies, such as type II diabetes, gout and atherosclerosis. A better understanding of IL-1beta synthesis and release is particularly relevant for the design of novel anti-inflammatory drugs. One of the molecules mainly involved in IL-1beta maturation is the P2X7 receptor (P2X7R), an ATP-gated ion channel that chiefly acts through the recruitment of the NLRP3 inflammasome-caspase-1 complex. In this review, we will summarize evidence supporting the key role of the P2X7R in IL-1beta production, with special emphasis on the mechanism of release, a process that is still a matter of controversy. Four different models have been proposed: (i) exocytosis via secretory lysosomes, (ii) microvesicles shedding from plasma membrane, (iii) release of exosomes, and (iv) passive efflux across a leaky plasma membrane during pyroptotic cell death. All these models involve the P2X7R. PMID- 28360857 TI - Hydrogen Sulfide Inhibits High-Salt Diet-Induced Myocardial Oxidative Stress and Myocardial Hypertrophy in Dahl Rats. AB - The study aimed to examine the protective effect of hydrogen sulfide (H2S) on high-salt-induced oxidative stress and myocardial hypertrophy in salt-sensitive (Dahl) rats. Thirty male Dahl rats and 40 SD rats were included in the study. They were randomly divided into Dahl control (Dahl + NS), Dahl high salt (Dahl + HS), Dahl + HS + NaHS, SD + NS, SD + HS, SD + HS + NaHS, and SD + HS + hydroxylamine (HA). Rats in Dahl + NS and SD + NS groups were given chow with 0.5% NaCl and 0.9% normal saline intraperitoneally daily. Myocardial structure, alpha-myosin heavy chain (alpha-MHC) and beta-myosin heavy chain (beta-MHC) expressions were determined. Endogenous myocardial H2S pathway and oxidative stress in myocardial tissues were tested. Myocardial H2S pathway was downregulated with myocardial hypertrophy featured by increased heart weight/body weight and cardiomyocytes cross-sectional area, decreased alpha-MHC and increased beta-MHC expressions in Dahl rats with high-salt diet (all P < 0.01), and oxidative stress in myocardial tissues was significantly activated, demonstrated by the increased contents of hydroxyl radical, malondialdehyde and oxidized glutathione and decreased total antioxidant capacity, carbon monoxide, catalase, glutathione, glutathione peroxidase, superoxide dismutase (SOD) activities and decreased SOD1 and SOD2 protein expressions (P < 0.05, P < 0.01). However, H2S reduced myocardial hypertrophy with decreased heart weight/body weight and cardiomyocytes cross-sectional area, increased alpha-MHC, decreased beta-MHC expressions and inhibited oxidative stress in myocardial tissues of Dahl rats with high-salt diet. However, no significant difference was found in H2S pathway, myocardial structure, alpha-MHC and beta-MHC protein and oxidative status in myocardial tissues among SD + NS, SD + HS, and SD + HS + NaHS groups. HA, an inhibitor of cystathionine beta-synthase, inhibited myocardial H2S pathway (P < 0.01), and stimulated myocardial hypertrophy and oxidative stress in SD rats with high-salt diet. Hence, H2S inhibited myocardial hypertrophy in high salt stimulated Dahl rats in association with the enhancement of antioxidant capacity, thereby inhibiting oxidative stress in myocardial tissues. PMID- 28360858 TI - Saponins from Sanguisorba officinalis Improve Hematopoiesis by Promoting Survival through FAK and Erk1/2 Activation and Modulating Cytokine Production in Bone Marrow. AB - Radix Sanguisorbae, the root of Sanguisorba officinalis L. is used as traditional Chinese medicine. In recent decades, it has been reported to be clinically effective against myelosuppression induced by chemotherapy and/ or radiotherapy. However, the underlining mechanism has not been well studied. In this work, we evaluated the hematopoietic effect of total saponins from S. officinalis L. on myelosuppressive mice induced by cyclophosphamide and by60Co-gamma-irradiation and confirmed the therapeutic effect. Then, we found total saponins and their characteristic constituents Ziyuglycoside I and Ziyuglycoside II can inhibit apoptosis of TF-1 cells caused by cytokine deprivation, and promote survival of mouse bone marrow nuclear cells through focal adhesion kinase (FAK) and extracellular signal-regulated kinase 1/2 (Erk1/2) activation in vitro. In addition, they can down-regulate macrophage inflammatory protein 2 (MIP-2), platelet factor 4 (PF4) and P-selectin secretion, which are reported to be suppressive to hematopoiesis, both in vitro and in vivo. These results suggest that promotion of survival through FAK and Erk1/2 activation and inhibition of suppressive cytokines in the bone marrow is likely to be the pharmacological mechanism underlying the hematopoietic effect of saponins from S. officinalis L. PMID- 28360859 TI - Dexamethasone Pretreatment Alleviates Isoniazid/Lipopolysaccharide Hepatotoxicity: Inhibition of Inflammatory and Oxidative Stress. AB - Isoniazid (INH) remains a cornerstone key constitute of the current tuberculosis management strategy, but its hepatotoxic potentiality remains a significant clinical problem. Our previous findings succeed to establish a rat model of INH hepatotoxicity employing the inflammatory stress theory in which non-injurious doses of inflammatory-mediating agent bacterial lipopolysaccharides (LPS) augmented the toxicity of INH that assist to uncover the mechanisms behind INH hepatotoxicity. Following LPS exposure, several inflammatory cells are activated and it is likely that the consequences of this activation rather than direct hepatocellular effects of LPS underlie the ability of LPS to augment toxic responses. In this study, we investigated the potential protective role of the anti-inflammatory agent dexamethasone (DEX), a potent synthetic glucocorticoid, in INH/LPS hepatotoxic rat model. DEX pre-treatment successfully eliminates the components of the inflammatory stress as shown through analysis of blood biochemistry and liver histopathology. DEX potentiated hepatic anti-oxidant mechanisms while serum and hepatic lipid profiles were reduced. However, DEX administration was not able to revoke the principal effects of cytochrome P450 2E1 (CYP2E1) in INH/LPS-induced liver damage. In conclusion, this study illustrated the DEX-preventive capabilities on INH/LPS-induced hepatotoxicity model through DEX-induced potent anti-inflammatory activity whereas the partial toxicity seen in the model could be attributed to the expression of hepatic CYP2E1. These findings potentiate the clinical applications of DEX co administration with INH therapy in order to reduce the potential incidences of hepatotoxicity. PMID- 28360860 TI - Acanthoic Acid Can Partially Prevent Alcohol Exposure-Induced Liver Lipid Deposition and Inflammation. AB - Aims: The present study aims to detect the effect of acanthoic acid (AA) on alcohol exposure-induced liver lipid deposition and inflammation, and to explore the mechanisms. Methods: C57BL/6 mice were pretreated with single dose of AA (20 and 40 mg/kg) by oral gavage or equal volume of saline, and then exposed to three doses of ethanol (5 g/kg body weight, 25%, w/v) by gavage within 24 h. The mice were sacrificed at 6 h after the last ethanol dosing. Serum and hepatic indexes were detected by western blot, RT-PCR, and histopathological assay. AML-12 cells were pretreated with AA (5, 10, 20 MUM), or AICAR (500 MUM), GW3965 (1 MUM), SRT1720 (6 MUM), Nicotinamide (20 mM) for 2 h, respectively, and then following treated with EtOH (200 mM) and lipopolysaccharide (LPS) (10 ng/ml) for additional 48 h. Cell protein and mRNA were collected for western blot and RT-PCR. Cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) release were detected by ELISA assay. Results: It was found that AA significantly decreased acute ethanol-induced increasing of the serum ALT/AST, LDH, ALP levels, and hepatic and serum triglyceride levels, and reduced fat droplets accumulation in mice liver. AA significantly suppressed the levels of sterol regulatory element binding protein 1 (SREBP-1), cytochrome P4502E1 (CYP2E1), IL-1beta, and caspase-1 induced by ethanol. Furthermore, a significant decline of sirtuin 1 (Sirt1) and liver X receptors (LXRs) levels was observed in EtOH group, compared with normal group mice. And AA pretreatment increased the Sirt1 and LXRs levels, and also ameliorated phosphorylation of liver kinase B-1 (LKB-1), adenosine monophosphate-activated protein kinase (AMPK), acetyl CoA carboxylase (ACC) proteins, compared with EtOH group. However, the levels of peroxisome proliferator activated receptor -alpha or -gamma (PPAR-alpha or PPAR-gamma) induced by acute ethanol were reversed by AA. In EtOH/LPS cultivated AML-12 cells, AA decreased IL-1beta and TNF-alpha levels, lipid droplets, and SREBP-1 and CYP2E1 expressions, compared with EtOH/LPS treatment. AA also significantly increased protein expressions of Sirt1, p-LKB1, p-ACC, PPARalpha, and decreased protein expression of PPARgamma, compared with EtOH/LPS treatment. Conclusion: Acanthoic acid can partially prevent alcohol exposure-induced liver lipid deposition and inflammation via regulation of LKB1/Sirt1/AMPK/ACC and LXRs pathways. PMID- 28360861 TI - Odor, Not Performance, Dictates Bemisia tabaci's Selection between Healthy and Virus Infected Plants. AB - Although, insect herbivores are generally thought to select hosts that favor the fitness of their progeny, this "mother-knows-best" hypothesis may be challenged by the presence of a plant virus. Our previous study showed that the whitefly, Bemisia tabaci, the obligate vector for transmitting Tomato yellow leaf curl virus (TYLCV), preferred to settle and oviposit on TYLCV-infected rather than healthy host plant, Datura stramonium. The performances of B. tabaci larvae and adults were indeed improved on virus-infected D. stramonium, which is consistent with "mother-knows-best" hypothesis. In this study, B. tabaci Q displayed the same preference to settle and oviposit on Tomato spotted wilt virus (TSWV) infected host plants, D. stramonium and Capsicum annuum, respectively. As a non vector of TSWV, however, insect performance was impaired since adult body size, longevity, survival, and fecundity were reduced in TSWV infected D. stramonium. This appears to be an odor-mediated behavior, as plant volatile profiles are modified by viral infection. Infected plants have reduced quantities of o-xylene and alpha-pinene, and increased levels of phenol and 2-ethyl-1-hexanol in their headspace. Subsequent behavior experiments showed that o-xylene and alpha-pinene are repellant, while phenol and 2-ethyl-1-hexanol are attractive. This indicates that the preference of B. tabaci for virus-infected plants is modulated by the dynamic changes in the volatile profiles rather than the subsequent performances on virus-infected plants. PMID- 28360862 TI - Iodixanol as a Contrast Agent in a Fibrin Hydrogel for Endodontic Applications. AB - The application of biomaterials used in regenerative endodontics should be traceable. In this study, we checked some basic effects of rendering a fibrin hydrogel radiopaque using an iodine-based contrast agent (iodixanol) approved for systemic application. Fibrin hydrogels were prepared from a fibrin sealant (Tisseel) using either an isotonic iodixanol solution (Visipaque 320, test) or Tris buffer (control) as a diluent. Gelation kinetics, radiopacity, and swelling of lyophilized hydrogels were tested using standard methods. Hydrogel structure was evaluated using scanning electron microscopy (SEM). Furthermore, iodixanol release from the test gels was assessed using spectrophotometry, and tissue compatibility was compared between test and control hydrogels using the chick chorioallantoic membrane (CAM) assay. Results were compared using pairwise t test, p < 0.05. Iodixanol caused a 70-fold delay in gelation to 26 min in the test compared to the control hydrogels (22 +/- 1 s). Radiopacity of the test gels was 1.9 +/- 0.2 mm Al/mm, compared to zero in the control hydrogels. Lyophilized hydrogel swelling was strongly reduced when iodixanol was added to the hydrogel (p < 0.05). Test hydrogels had an altered SEM appearance compared to controls, and exhibited a reduced porosity. Iodixanol release from the test hydrogels reached 14.5 +/- 0.5% after 120 h and then ceased. This release did not have any apparent toxic effect and neither affected the viability, nor the physiology or vascularization of the CAM of fertilized chicken eggs. Iodixanol can render a fibrin hydrogel radiopaque and maintains its tissue compatibility, yet impacts gelation kinetics and hydrogel porosity. PMID- 28360863 TI - Differences in Oral Structure and Tissue Interactions during Mouse vs. Human Palatogenesis: Implications for the Translation of Findings from Mice. AB - Clefting of the secondary palate is one of the most common human birth defects and results from failure of the palatal shelves to fuse during embryonic development. Palatogenesis is traditionally considered to be a highly conserved developmental process among mammalian species. However, cleft palate phenotypes in humans are considerably more variable than those seen in mice, the most common animal model for studying palatal development and pathogenesis of cleft palate. In this investigation, we utilized macroscopic observations, histology and 3D imaging techniques to directly compare palate morphology and the oral-nasal cavity during palate closure in mouse embryos and human conceptuses. We showed that mouse and human palates display distinct morphologies attributable to the structural differences of the oral-nasal cavity. We further showed that the palatal shelves interact differently with the primary palate and nasal septum in the hard palate region and with pharyngeal walls in the soft palate region during palate closure in mice and humans. Knowledge of these morphological differences is important for improved translation of findings in mouse models of human cleft lip/palate and, as such, should ultimately enhance our understanding of human palatal morphogenesis and the pathogenesis of cleft lip/palate in humans. PMID- 28360864 TI - Isometric Stretch Alters Vascular Reactivity of Mouse Aortic Segments. AB - Most vaso-reactive studies in mouse aortic segments are performed in isometric conditions and at an optimal preload, which is the preload corresponding to a maximal contraction by non-receptor or receptor-mediated stimulation. In general, this optimal preload ranges from about 1.2 to 8.0 mN/mm, which according to Laplace's law roughly correlates with transmural pressures of 10-65 mmHg. For physiologic transmural pressures around 100 mmHg, preloads of 15.0 mN/mm should be implemented. The present study aimed to compare vascular reactivity of 2 mm mouse (C57Bl6) aortic segments preloaded at optimal (8.0 mN/mm) vs. (patho) physiological (10.0-32.5 mN/mm) preload. Voltage-dependent contractions of aortic segments, induced by increasing extracellular K+, and contractions by alpha1 adrenergic stimulation with phenylephrine (PE) were studied at these preloads in the absence and presence of L-NAME to inhibit basal release of NO from endothelial cells (EC). In the absence of basal NO release and with higher than optimal preload, contractions evoked by depolarization or PE were attenuated, whereas in the presence of basal release of NO PE-, but not depolarization induced contractions were preload-independent. Phasic contractions by PE, as measured in the absence of external Ca2+, were decreased at higher than optimal preload suggestive for a lower contractile SR Ca2+ content at physiological preload. Further, in the presence of external Ca2+, contractions by Ca2+ influx via voltage-dependent Ca2+ channels were preload-independent, whereas non selective cation channel-mediated contractions were increased. The latter contractions were very sensitive to the basal release of NO, which itself seemed to be preload-independent. Relaxation by endogenous NO (acetylcholine) of aortic segments pre-contracted with PE was preload-independent, whereas relaxation by exogenous NO (diethylamine NONOate) displayed higher sensitivity at high preload. Results indicated that stretching aortic segments to higher than optimal preload depolarizes the SMC and causes Ca2+ unloading of the contractile SR, making them extremely sensitive to small changes in the basal release of NO from EC as can occur in hypertension or arterial stiffening. PMID- 28360865 TI - Bosutinib Therapy Ameliorates Lung Inflammation and Fibrosis in Experimental Silicosis. AB - Silicosis is an occupational lung disease for which no effective therapy exists. We hypothesized that bosutinib, a tyrosine kinase inhibitor, might ameliorate inflammatory responses, attenuate pulmonary fibrosis, and thus improve lung function in experimental silicosis. For this purpose, we investigated the potential efficacy of bosutinib in the treatment of experimental silicosis induced in C57BL/6 mice by intratracheal administration of silica particles. After 15 days, once disease was established, animals were randomly assigned to receive DMSO or bosutinib (1 mg/kg/dose in 0.1 mL 1% DMSO) by oral gavage, twice daily for 14 days. On day 30, lung mechanics and morphometry, total and differential cell count in alveolar septa and granuloma, levels of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, IL-4, transforming growth factor (TGF)-beta, and vascular endothelial growth factor in lung homogenate, M1 and M2 macrophages, total leukocytes, and T cells in BALF, lymph nodes, and thymus, and collagen fiber content in alveolar septa and granuloma were analyzed. In a separate in vitro experiment, RAW264.7 macrophages were exposed to silica particles in the presence or absence of bosutinib. After 24 h, gene expressions of arginase-1, IL-10, IL-12, inducible nitric oxide synthase (iNOS), metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1, and caspase-3 were evaluated. In vivo, in silicotic animals, bosutinib, compared to DMSO, decreased: (1) fraction area of collapsed alveoli, (2) size and number of granulomas, and mononuclear cell granuloma infiltration; (3) IL-1beta, TNF-alpha, IFN-gamma, and TGF-beta levels in lung homogenates, (4) collagen fiber content in lung parenchyma, and (5) viscoelastic pressure and static lung elastance. Bosutinib also reduced M1 cell counts while increasing M2 macrophage population in both lung parenchyma and granulomas. Total leukocyte, regulatory T, CD4+, and CD8+ cell counts in the lung-draining lymph nodes also decreased with bosutinib therapy without affecting thymus cellularity. In vitro, bosutinib led to a decrease in IL-12 and iNOS and increase in IL-10, arginase-1, MMP-9, and TIMP-1. In conclusion, in the current model of silicosis, bosutinib therapy yielded beneficial effects on lung inflammation and remodeling, therefore resulting in lung mechanics improvement. Bosutinib may hold promise for silicosis; however, further studies are required. PMID- 28360866 TI - From Toxoplasmosis to Schizophrenia via NMDA Dysfunction: Peptide Overlap between Toxoplasma gondii and N-Methyl-d-Aspartate Receptors As a Potential Mechanistic Link. AB - The present work aims at investigating how Toxoplasma gondii (T. gondii) infection may be linked to N-methyl-d-aspartate receptor (NMDAR) dysfunction in schizophrenia and related disorders and puts forward the hypothesis that immune responses against T. gondii may involve NMDARs. Indeed, the analysis of the protozoan proteome and NMDAR subunits for peptide commonalities shows a massive peptide overlap and supports the possibility that anti-T. gondii immune responses raised during active protozoan infection may cross-react with host NMDARs, determining disruption of neural circuits and cognitive deficits. In particular, the NMDA 2D subunit, which is mainly expressed in parvalbumin-positive interneurons, appears to be a hotspot for potential T. gondii-induced cross reactive immune attacks. PMID- 28360868 TI - Gendered Expectations: Examining How Peers Shape Female Students' Intent to Pursue STEM Fields. AB - Building on prior psychological and sociological research on the power of local environments to shape gendered outcomes in STEM fields, this study focuses on the critical stage of adolescence to explore the potential negative impact of exposure to exclusionary messages from peers within girls' science classrooms, as well as the positive potential impact of inclusionary messages. Specifically, utilizing longitudinal data from a diverse sample of adolescent youth, analyses examine how the presence of biased male peers, as well as confident female peers, shape girls' subsequent intentions to pursue different STEM fields, focusing specifically on intentions to pursue the male-dominated fields of computer science and engineering, as well as more gender equitable fields. Results reveal that exposure to a higher percentage of 8th grade male peers in the classroom who endorsed explicit gender/STEM stereotypes significantly and negatively predicted girls' later intentions to pursue a computer science/engineering (CS/E) major. Yet results also reveal that exposure to a higher percentage of confident female peers in the science classroom positively predicted such intentions. These results were specific to CS/E majors, suggesting that peers are an important source of messages regarding whether or not girls should pursue non-traditional STEM fields. This study calls attention to the importance of examining both positive and negative sources of influence within the local contexts where young people live and learn. Limitations and directions for future research are also discussed. PMID- 28360867 TI - Focal and Ambient Processing of Built Environments: Intellectual and Atmospheric Experiences of Architecture. AB - Neuroscience has well established that human vision divides into the central and peripheral fields of view. Central vision extends from the point of gaze (where we are looking) out to about 5 degrees of visual angle (the width of one's fist at arm's length), while peripheral vision is the vast remainder of the visual field. These visual fields project to the parvo and magno ganglion cells, which process distinctly different types of information from the world around us and project that information to the ventral and dorsal visual streams, respectively. Building on the dorsal/ventral stream dichotomy, we can further distinguish between focal processing of central vision, and ambient processing of peripheral vision. Thus, our visual processing of and attention to objects and scenes depends on how and where these stimuli fall on the retina. The built environment is no exception to these dependencies, specifically in terms of how focal object perception and ambient spatial perception create different types of experiences we have with built environments. We argue that these foundational mechanisms of the eye and the visual stream are limiting parameters of architectural experience. We hypothesize that people experience architecture in two basic ways based on these visual limitations; by intellectually assessing architecture consciously through focal object processing and assessing architecture in terms of atmosphere through pre-conscious ambient spatial processing. Furthermore, these separate ways of processing architectural stimuli operate in parallel throughout the visual perceptual system. Thus, a more comprehensive understanding of architecture must take into account that built environments are stimuli that are treated differently by focal and ambient vision, which enable intellectual analysis of architectural experience versus the experience of architectural atmosphere, respectively. We offer this theoretical model to help advance a more precise understanding of the experience of architecture, which can be tested through future experimentation. (298 words). PMID- 28360869 TI - The Influence of State Anxiety on Fear Discrimination and Extinction in Females. AB - Formal theories have linked pathological anxiety to a failure in fear response inhibition. Previously, we showed that aberrant response inhibition is not restricted to anxiety patients, but can also be observed in anxiety-prone adults. However, less is known about the influence of currently experienced levels of anxiety on inhibitory learning. The topic is highly important as state anxiety has a debilitating effect on cognition, emotion, and physiology and is linked to several anxiety disorders. In the present study, healthy female volunteers performed a fear conditioning task, after being informed that they will have to perform the Trier Social Stress Test task (n = 25; experimental group) or a control task (n = 25; control group) upon completion of the conditioning task. The results showed that higher levels of state anxiety corresponded with a reduced discrimination between a stimulus (CS+) typically followed by an aversive event and a stimulus (CS-) that is never followed by an aversive event both during the acquisition and the extinction phase. No effect of state anxiety on the skin conductance response associated with CS+ and CS- was found. Additionally, higher levels of state anxiety coincided with more negative valence ratings of the CSs. The results suggest that increased stress-induced state anxiety might lead to stimulus generalization during fear acquisition, thereby impairing associative learning. PMID- 28360870 TI - The Faculty of Language Integrates the Two Core Systems of Number. AB - Only humans possess the faculty of language that allows an infinite array of hierarchically structured expressions (Hauser et al., 2002; Berwick and Chomsky, 2015). Similarly, humans have a capacity for infinite natural numbers, while all other species seem to lack such a capacity (Gelman and Gallistel, 1978; Dehaene, 1997). Thus, the origin of this numerical capacity and its relation to language have been of much interdisciplinary interest in developmental and behavioral psychology, cognitive neuroscience, and linguistics (Dehaene, 1997; Hauser et al., 2002; Pica et al., 2004). Hauser et al. (2002) and Chomsky (2008) hypothesize that a recursive generative operation that is central to the computational system of language (called Merge) can give rise to the successor function in a set-theoretic fashion, from which capacities for discretely infinite natural numbers may be derived. However, a careful look at two domains in language, grammatical number and numerals, reveals no trace of the successor function. Following behavioral and neuropsychological evidence that there are two core systems of number cognition innately available, a core system of representation of large, approximate numerical magnitudes and a core system of precise representation of distinct small numbers (Feigenson et al., 2004), I argue that grammatical number reflects the core system of precise representation of distinct small numbers alone. In contrast, numeral systems arise from integrating the pre-existing two core systems of number and the human language faculty. To the extent that my arguments are correct, linguistic representations of number, grammatical number, and numerals do not incorporate anything like the successor function. PMID- 28360871 TI - The Role of Autonomous and Controlled Motivation in Exercise Intentions of Participants in a Mass Cycling Event. AB - Purpose: This study used self-determination theory to examine the role of participants' autonomous and controlled motivation to exercise and to participate in a challenging mass cycling event and investigated whether the event enhanced intended and actual exercise behavior among the participants. Method: Two hundred and twenty-eight subjects, having participated in the cycling event, completed a questionnaire shortly after the event and again 4 months later. The questionnaire measured self-reported cycling and exercise activity, training in preparation of the event, motivation to participate in the event, motivation to exercise, and future exercise intentions due to the event. Results: Results showed that most participants were very active in cycling and other sports. The expected positive effect of autonomous motivation on exercise intentions and behavior could not be confirmed in our study. Multiple regression analyses revealed that the event had an enhancing effect on exercise intentions shortly after the event among participants that scored higher on controlled motivation to exercise (beta = 0.15) and to participate (beta = 0.15); also, participants were more satisfied with the event (beta = 0.19) and had followed a preparation program before the event (beta = 0.15). However, intentions and exercise behavior distinctively dropped 4 months after the event. Conclusions: Events aiming to enhance their participants' exercise behavior need to attract less active participants and need to make additional efforts to prevent relapse in intentions and exercise behavior. PMID- 28360872 TI - Integrative Priming of Compositional and Locative Relations. AB - Integrative priming refers to the facilitated recognition of a target word (bench) as a real word following a prime (park). Prior integrative priming studies have used a wide variety of integrative relations including temporal (summer rain), topical (travel book), locative (forest river), and compositional (peach pie) relations. Yet differences in the types of integrative relations may yield differences in the underlying explanatory processes of integrative priming. In this study, we compared the magnitude, time course, and three theoretically based correlates of integrative priming for compositional (stone table) and locative (patio table) pairs in a lexical decision task across four stimulus onset asynchronies (SOAs; 50, 300, 800, and 1,600 ms). Based on the Complementary Role Activation theory, integrative ratings (the extent to which the prime and target can be combined into a meaningful phrase) were predicted to facilitate target RTs. Based on the Embodied Conceptual Combination (ECCo) theory, the local co-occurrence of the prime and target, and the ability to perceptually simulate (visually experience) the prime-target pair were tested as predictors. In comparison to unrelated pairs (nose table), target RTs were faster for the compositional and locative pairs, though did not differ between these relations. In support of the Complementary Role Activation theory, integrative ratings predicted target RTs above and beyond our control variables. In support of the ECCo theory, co-occurrence emerged as an early predictor of target RTs, and visual experience ratings was a reliable predictor at the 300 ms SOA, though only for the compositional relations. PMID- 28360873 TI - Second Language Use Facilitates Implicit Emotion Regulation via Content Labeling. AB - Previous studies reported that negative stimuli induced less affect in bilinguals when stimuli were presented in bilinguals' second, weaker language (L2) than when they were presented in their native language (L1). This effect of L2 use was attributed to increased emotional distance as well as to increased levels of cognitive control during L2 use. Here we investigated how explicit (cognitive reappraisal, i.e., reinterpreting the meaning of the emotional stimulus to alter its emotional impact) and implicit (content labeling, i.e., categorizing the content of the image; and emotion labeling, i.e., naming the emotion induced by the emotional stimulus) emotion regulation strategies are altered in an L2 (English) context in German native speakers with medium to high proficiency in their L2. While previous studies used linguistic stimuli, such as words, to induce affect, here we used images to test whether reduced affect could also be observed for non-linguistic stimuli when presented in an L2 context. We hypothesized that the previously implicated increase in emotional distance and cognitive control in an L2 would result in an L2 advantage in emotion regulation (i.e., leading to less negative emotions compared to an L1 context), by strengthening the effect of linguistic re-evaluation on the evoked emotions. Using a classic emotion regulation paradigm, we examined changes in subjective emotional state ratings during reappraisal, emotion labeling and content labeling in a L1 and L2 context. We found that the strength of evoked affective responses did not depend on the language context in which an image was presented. Crucially, content labeling in L2 was more effective than in L1, whereas emotion labeling did not differ between languages. Overall, evoked responses were regulated most effectively through explicit emotion regulation (reappraisal) in L1 and L2 context. These results demonstrate an L2 advantage effect for emotion regulation through content labeling and suggest that L2 context alters sub processes implicated in content labeling but not emotion labeling. PMID- 28360874 TI - Online Control of Prehension Predicts Performance on a Standardized Motor Assessment Test in 8- to 12-Year-Old Children. AB - Goal-directed hand movements are guided by sensory information and may be adjusted 'online,' during the movement. If the target of a movement unexpectedly changes position, trajectory corrections can be initiated in as little as 100 ms in adults. This rapid visual online control is impaired in children with developmental coordination disorder (DCD), and potentially in other neurodevelopmental conditions. We investigated the visual control of hand movements in children in a 'center-out' double-step reaching and grasping task, and examined how parameters of this visuomotor control co-vary with performance on standardized motor tests often used with typically and atypically developing children. Two groups of children aged 8-12 years were asked to reach and grasp an illuminated central ball on a vertically oriented board. On a proportion of trials, and at movement onset, the illumination switched unpredictably to one of four other balls in a center-out configuration (left, right, up, or down). When the target moved, all but one of the children were able to correct their movements before reaching the initial target, at least on some trials, but the latencies to initiate these corrections were longer than those typically reported in the adult literature, ranging from 211 to 581 ms. These later corrections may be due to less developed motor skills in children, or to the increased cognitive and biomechanical complexity of switching movements in four directions. In the first group (n = 187), reaching and grasping parameters significantly predicted standardized movement scores on the MABC-2, most strongly for the aiming and catching component. In the second group (n = 85), these same parameters did not significantly predict scores on the DCDQ'07 parent questionnaire. Our reaching and grasping task provides a sensitive and continuous measure of movement skill that predicts scores on standardized movement tasks used to screen for DCD. PMID- 28360875 TI - An Exploratory Investigation of the Role of Openness in Relationship Quality among Emerging Adult Chinese Couples. AB - This study tested emerging adult couples' openness and its fit effect on their romantic relationship quality using quadratic polynomial regression and response surface analysis. Participants were 260 emerging adult dyads. Both dyads' openness and relationship quality were measured. The result showed that (1) female and male openness contribute differently to relationship quality; (2) couples with similar high openness could experience better relationship quality than those with similar low openness traits; and (3) when dyadic openness is dissimilar, it is better to be either relatively high or relatively low than to be moderate. These findings highlight the role of openness in emerging adults' romantic relationships from a dyadic angle. PMID- 28360876 TI - Groupness in Preverbal Infants: Proof of Concept. AB - Infant sociability is generally conceived in terms of dyadic capacities and behaviors. Recently, quantitative evidence has been published to support arguments that infants achieve a criterion for groupness: the capacity to interact simultaneously with two others. Such studies equate this capacity with alternating dyadic acts to the two other members of an interacting trio. Here we propose a stricter threefold criterion for infant groupness, of which the crux is whether the social behavior of an infant at time B is shown to be influenced by what two or more group-members were previously doing at time A. We test the viability of this conceptualization: (a) through its justification of the novel laboratory procedure of studying infant sociability in infant-peer quartets (rather than trios); and, (b) in an analysis of a pilot study of gaze-behavior recorded in 5-min interactions among two quartets of infants aged 6-9 months. We call this a 'proof of concept' because our aim is to show that infants are capable of groupness, when groupness is conceptualized in a supra-dyadic way-not that all infants will manifest it, nor that all conditions will produce it, nor that it is commonplace in infants' everyday lives. We found that both quartets did achieve the minimum criterion of groupness that we propose: mutual gaze predicting coordinated gaze (where two babies, A and B, are looking at each other, and B is then looked at by C, and sometimes D) more strongly than the reverse. There was a significant absence of 'parallel mutual gaze,' where the four babies pair off. We conclude that, under specific conditions, preverbal infants can manifest supra-dyadic groupness. Infants' capacities to exhibit groupness by 9 months of age, and the paucity of parallel mutual gaze in our data, run counter to the assumption that infant sociability, when in groups, is always generated by a dyadic program. Our conceptualization and demonstration of groupness in 8-month-olds thus opens a host of empirical, theoretical, and practical questions about the sociability and care of young babies. PMID- 28360877 TI - Social Discounting under Risk. AB - As a measure of how prosocial behavior depends on social distance, social discounting is defined as the decrease in generosity between the decision maker and the recipient as the social distance increases. While risk is a ubiquitous part of modern life, there is limited research on the relationship between risk and prosocial behavior. In the present experiment, we empirically test whether risk has an influence on social discounting. We use the choice titration procedure to examine this effect. Our data show that independent of risk, participants are less eager to forego money and exhibit more selfishness toward a specific person when the social distance increases; these findings are reflected in the hyperbolic model. Interestingly, risk influences the shape of the social discounting function, which is reflected in the notable different discount rates. Individuals who make decisions under risk yield a smaller discount rate than those who make decisions without risk, i.e., under risk subjects reduce less their generosity as a function of the social distance. Furthermore, this distinct type of generosity occurs typically among individuals with 10-distance recipients but not with the closest- and furthest-social-distance recipients. PMID- 28360878 TI - Task Integration Facilitates Multitasking. AB - The aim of this study was to investigate multi-task integration in a continuous tracking task. We were particularly interested in how manipulating task structure in a dual-task situation affects learning of a constant segment embedded in a pursuit-tracking task. Importantly, we examined if dual-task effects could be attributed to task integration by varying the structural similarity and difficulty of the primary and secondary tasks. In Experiment 1 participants performed a pursuit tracking task while counting high-pitched tones and ignoring low-pitched tones. The tones were either presented randomly or structurally 250 ms before each tracking turn. Experiment 2 increased the motor load of the secondary tasks by asking participants to tap their feet to the tones. Experiment 3 further increased motor load of the primary task by increasing its speed and having participants tracking with their non-dominant hand. The results show that dual-task interference can be moderated by secondary task conditions that match the structure of the primary task. Therefore our results support proposals of task integration in continuous tracking paradigms. We conclude that multi-tasking is not always detrimental for motor learning but can be facilitated through task integration. PMID- 28360879 TI - Resilience Protected against Suicidal Behavior for Men But Not Women in a Community Sample of Older Adults in Korea. AB - Suicide prevention efforts in reducing risk factors have been found to be more beneficial to older women than men, suggesting potential gender differences in effective prevention. The study aimed to examine gender difference in resilience for suicidal behavior in a community sample of older adults in Korea. A community based survey was conducted to investigate resilience and risk factors of suicidal behavior using the Suicidal Behaviors Questionnaire-Revised, Connor-Davidson Resilience Scale, Center for Epidemiologic Studies Depression Scale (CES-D), as well as questions regarding physical illness and depression history. After accounting for well-known risk factors, resilience was inversely associated with suicidal behavior, but this protective role of resilience was applicable to men only. The findings of this study indicated gender difference in resilience against suicidal behavior in the elderly population. Gender-specific preventive intervention strategies need to be developed for community-based suicide prevention for older adults. PMID- 28360880 TI - (Mal)Adaptive Psychological Functioning of Students Utilizing University Counseling Services. AB - Background: University students confront psychological difficulties that can negatively influence their academic performance. The present study aimed to assess several areas of adaptive and maladaptive psychological functioning among university students who request counseling services. Method: One hundred eighty four young female students seeking professional psychological help (Counseling seekers) and 185 young female students who have never asked for psychological help (Non-counseling seekers) were asked to complete the Adult Self-Report (ASR) to evaluate both their internalizing and externalizing problems through DSM oriented scales as well as their adaptive functioning. Results: ANOVA results indicated worse psychological functioning for the students who sought counseling. They reported lower score in ASR Adaptive Functioning Scales (i.e., friends, jobs, family, education), and higher scores in DSM-oriented scales (i.e., Depressive, Anxiety, Somatic, Avoidant Personality, Attention Deficit/Hyperactivity symptoms) than the students who never asked psychological help. Furthermore, discriminant analysis successfully discriminated between the two groups of students on the basis of the ASR's adaptive and DSM-oriented scales. Conclusion: The study findings could be useful to guide university counseling services in their screening activities as well as useful for clinical practice. PMID- 28360882 TI - Vestibular Activation Habituates the Vasovagal Response in the Rat. AB - Vasovagal syncope is a significant medical problem without effective therapy, postulated to be related to a collapse of baroreflex function. While some studies have shown that repeated static tilts can block vasovagal syncope, this was not found in other studies. Using anesthetized, male Long-Evans rats that were highly susceptible to generation of vasovagal responses, we found that repeated activation of the vestibulosympathetic reflex (VSR) with +/-2 and +/-3 mA, 0.025 Hz sinusoidal galvanic vestibular stimulation (sGVS) caused incremental changes in blood pressure (BP) and heart rate (HR) that blocked further generation of vasovagal responses. Initially, BP and HR fell ~20-50 mmHg and ~20-50 beats/min (bpm) into a vasovagal response when stimulated with Sgv?S in susceptible rats. As the rats were continually stimulated, HR initially rose to counteract the fall in BP; then the increase in HR became more substantial and long lasting, effectively opposing the fall in BP. Finally, the vestibular stimuli simply caused an increase in BP, the normal sequence following activation of the VSR. Concurrently, habituation caused disappearance of the low-frequency (0.025 and 0.05 Hz) oscillations in BP and HR that must be present when vasovagal responses are induced. Habituation also produced significant increases in baroreflex sensitivity (p < 0.001). Thus, repeated low-frequency activation of the VSR resulted in a reduction and loss of susceptibility to development of vasovagal responses in rats that were previously highly susceptible. We posit that reactivation of the baroreflex, which is depressed by anesthesia and the disappearance of low-frequency oscillations in BP and HR are likely to be critically involved in producing resistance to the development of vasovagal responses. SGVS has been widely used to activate muscle sympathetic nerve activity in humans and is safe and well tolerated. Potentially, it could be used to produce similar habituation of vasovagal syncope in humans. PMID- 28360883 TI - Continuous Monitoring of Essential Tremor Using a Portable System Based on Smartwatch. AB - INTRODUCTION: Essential tremor (ET) shows amplitude fluctuations throughout the day, presenting challenges in both clinical and treatment monitoring. Tremor severity is currently evaluated by validated rating scales, which only provide a timely and subjective assessment during a clinical visit. Motor sensors have shown favorable performances in quantifying tremor objectively. METHODS: A new highly portable system was used to monitor tremor continuously during daily lives. It consists of a smartwatch with a triaxial accelerometer, a smartphone, and a remote server. An experiment was conducted involving eight ET patients. The average effective data collection time per patient was 26 (+/-6.05) hours. Fahn Tolosa-Marin Tremor Rating Scale (FTMTRS) was adopted as the gold standard to classify tremor and to validate the performance of the system. Quantitative analysis of tremor severity on different time scales is validated. RESULTS: Significant correlations were observed between neurologist's FTMTRS and patient's FTMTRS auto-assessment scores (r = 0.84; p = 0.009), between the device quantitative measures and the scores from the standardized assessments of neurologists (r = 0.80; p = 0.005) and patient's auto-evaluation (r = 0.97; p = 0.032), and between patient's FTMTRS auto-assessment scores day-to-day (r = 0.87; p < 0.001). A graphical representation of four patients with different degrees of tremor was presented, and a representative system is proposed to summarize the tremor scoring at different time scales. CONCLUSION: This study demonstrates the feasibility of prolonged and continuous monitoring of tremor severity during daily activities by a highly portable non-restrictive system, a useful tool to analyze efficacy and effectiveness of treatment. PMID- 28360881 TI - Hemostasis in Intracranial Hemorrhage. AB - Spontaneous non-traumatic intracerebral hemorrhage (ICH) is associated with high morbidity and mortality throughout the world with no proven effective treatment. Majority of hematoma expansion occur within 4 h after symptom onset and is associated with early deterioration and poor clinical outcome. There is a vital role of ultra-early hemostatic therapy in ICH to limit hematoma expansion. Patients at risk for hematoma expansion are with underlying hemostatic abnormalities. Treatment strategy should include appropriate intervention based on the history of use of antithrombotic use or an underlying coagulopathy in patients with ICH. For antiplatelet-associated ICH, recommendation is to discontinue antiplatelet agent and transfuse platelets to those who will undergo neurosurgical procedure with moderate quality of evidence. For vitamin K antagonist-associated ICH, administration of 3-factor or 4-factor prothrombin complex concentrates (PCCs) rather than fresh frozen plasma to patients with INR >1.4 is strongly recommended. For patients with novel oral anticoagulant associated ICH, administering activated charcoal to those who present within 2 h of ingestion is recommended. Idarucizumab, a humanized monoclonal antibody fragment against dabigatran (direct thrombin inhibitor) is approved by FDA for emergency situations. Administer activated PCC (50 U/kg) or 4-factor PCC (50 U/kg) to patients with ICH associated with direct thrombin inhibitors (DTI) if idarucizumab is not available or if the hemorrhage is associated with a DTI other than dabigatran. For factor Xa inhibitor-associated ICH, administration of 4 factor PCC or aPCC is preferred over recombinant FVIIa because of the lower risk of adverse thrombotic events. PMID- 28360885 TI - Circadian Rhythm Influences the Promoting Role of Pulsed Electromagnetic Fields on Sciatic Nerve Regeneration in Rats. AB - Circadian rhythm (CR) plays a critical role in the treatment of several diseases. However, the role of CR in the treatment of peripheral nerve defects has not been studied. It is also known that the pulsed electromagnetic fields (PEMF) can provide a beneficial microenvironment to quicken the process of nerve regeneration and to enhance the quality of reconstruction. In this study, we evaluate the impact of CR on the promoting effect of PEMF on peripheral nerve regeneration in rats. We used the self-made "collagen-chitosan" nerve conduits to bridge the 15-mm nerve gaps in Sprague-Dawley rats. Our results show that PEMF stimulation at daytime (DPEMF) has most effective outcome on nerve regeneration and rats with DPEMF treatment achieve quickly functional recovery after 12 weeks. These findings indicate that CR is an important factor that determines the promoting effect of PEMF on peripheral nerve regeneration. PEMF exposure in the daytime enhances the functional recovery of rats. Our study provides a helpful guideline for the effective use of PEMF mediations experimentally and clinically. PMID- 28360886 TI - Increased Circulating T Follicular Helper Cells Are Inhibited by Rituximab in Neuromyelitis Optica Spectrum Disorder. AB - Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune disease of the central nervous system. The existence of autoantibody targeting aquaporin-4 (AQP4-Ab) indicates the involvement of humoral immunity in the pathogenesis of this disease. Rituximab (RTX), a monoclonal antibody against CD20, has been used to treat NMOSD by depleting circulating B cells and overall satisfactory outcome has been achieved. Although T follicular helper cells have been proved to regulate B cell activation and antibody production, the role of these cells in NMOSD and the impact of RTX treatment on these cells remain less understood. In this study, we found that frequencies of circulating T follicular helper (cTfh) cells and B cells together with the related cytokines, IL-21 and IL-6, were closely correlated with disease activity of NMOSD. Furthermore, B cell depletion with RTX treatment inhibited the expansion of cTfh cells, and these effects were achieved through eliminating IL-6-producing B cells and blocking the direct contact between cTfh cells and B cells. These findings imply the complicated cross talk between cTfh cells and B cells and may provide a novel therapeutic target for NMOSD. PMID- 28360887 TI - Oxidative Stress Function in Women over 40 Years of Age, Considering Their Lifestyle. AB - Aging is dependent on biological processes that determine the aging of the organism at the cellular level. The Oxidative Stress Theory of Aging might explain some of the age-related changes in cell macromolecules. Moreover, exposome and lifestyle may also induce changes in cell damage induced by oxidative stress. The aim of the present study was to analyze the related redox changes in lymphocyte function of healthy women over 40 years old. Three groups: younger (YG: 40-49 years), middle aged (MAG: 50-59 years), and older (OG: >=60 years) were evaluated on anthropometric variables, blood pressure, cardiovascular fitness, lifestyle habits, perceived stress, DNA damage, malondialdehyde, catalase activity, and total antioxidant capacity. Physical activity and cardiovascular fitness were significantly higher in YG and MAG as compared to the OG. Systolic blood pressure increased significantly with group age. Frequency and total amount of alcohol intake were lower in the OG and higher in the MAG. No significant differences were observed between the three groups in oxidative stress parameters. Only alcohol consumption was associated with the higher DNA FPG-sensitive sites, and only in the YG (p < 0.05). Healthy lifestyle is critical to avoiding major ailments associated with aging. This may be inferred from the lack of significant differences in the various oxidative stress parameters measured in the healthy women over the age of 40 who took part in the study. Conscious lifestyle behaviors (decrease in alcohol and smoking habits) could have impaired the expected age-related oxidative stress increase. PMID- 28360884 TI - Clock-Enhancing Small Molecules and Potential Applications in Chronic Diseases and Aging. AB - Normal physiological functions require a robust biological timer called the circadian clock. When clocks are dysregulated, misaligned, or dampened, pathological consequences ensue, leading to chronic diseases and accelerated aging. An emerging research area is the development of clock-targeting compounds that may serve as drug candidates to correct dysregulated rhythms and hence mitigate disease symptoms and age-related decline. In this review, we first present a concise view of the circadian oscillator, physiological networks, and regulatory mechanisms of circadian amplitude. Given a close association of circadian amplitude dampening and disease progression, clock-enhancing small molecules (CEMs) are of particular interest as candidate chronotherapeutics. A recent proof-of-principle study illustrated that the natural polymethoxylated flavonoid nobiletin directly targets the circadian oscillator and elicits robust metabolic improvements in mice. We describe mood disorders and aging as potential therapeutic targets of CEMs. Future studies of CEMs will shed important insight into the regulation and disease relevance of circadian clocks. PMID- 28360888 TI - The Absence of the Transcription Factor Yrr1p, Identified from Comparative Genome Profiling, Increased Vanillin Tolerance Due to Enhancements of ABC Transporters Expressing, rRNA Processing and Ribosome Biogenesis in Saccharomyces cerevisiae. AB - Enhancing the tolerance of Saccharomyces cerevisiae to inhibitors derived from lignocellulose is conducive to producing biofuel and chemicals using abundant lignocellulosic materials. Vanillin is a major type of phenolic inhibitor in lignocellulose hydrolysates for S. cerevisiae. In the present work, the factors beneficial to vanillin resistance in yeast were identified from the vanillin resistant strain EMV-8, which was derived from strain NAN-27 by adaptive evolution. We found 450 SNPs and 44 genes with InDels in the vanillin-tolerant strain EMV-8 by comparing the genome sequences of EMV-8 and NAN-27. To investigate the effects of InDels, InDels were deleted in BY4741, respectively. We demonstrated that the deletion of YRR1 improved vanillin tolerance of strain. In the presence of 6 mM vanillin, deleting YRR1 increase the maximum specific growth rate and the vanillin consumption rate by 142 and 51%, respectively. The subsequent transcriptome analysis revealed that deleting YRR1 resulted in changed expression of over 200 genes in the presence of 5 mM vanillin. The most marked changes were the significant up-regulation of the dehydrogenase ADH7, several ATP binding cassette (ABC) transporters, and dozens of genes involved in ribosome biogenesis and rRNA processing. Coincidently, the crude enzyme solution of BY4741(yrr1Delta) exhibited higher NADPH-dependent vanillin reduction activity than control. In addition, overexpressing the ABC transporter genes PDR5, YOR1, and SNQ2, as well as the RNA helicase gene DBP2, increased the vanillin tolerance of strain. Interestingly, unlike the marked changes we mentioned above, under vanillin-free conditions, there are only limited transcriptional differences between wildtype and yrr1Delta. This indicated that vanillin might act as an effector in Yrr1p-related regulatory processes. The new findings of the relationship between YRR1 and vanillin tolerance, as well as the contribution of rRNA processing and ribosome biogenesis to enhancing S. cerevisiae vanillin tolerance, provide novel targets for genetic engineering manipulation to improve microbes' tolerance to lignocellulose hydrolysate. PMID- 28360889 TI - Small Luggage for a Long Journey: Transfer of Vesicle-Enclosed Small RNA in Interspecies Communication. AB - In the evolutionary arms race, symbionts have evolved means to modulate each other's physiology, oftentimes through the dissemination of biological signals. Beyond small molecules and proteins, recent evidence shows that small RNA molecules are transferred between organisms and transmit functional RNA interference signals across biological species. However, the mechanisms through which specific RNAs involved in cross-species communication are sorted for secretion and protected from degradation in the environment remain largely enigmatic. Over the last decade, extracellular vesicles have emerged as prominent vehicles of biological signals. They can stabilize specific RNA transcripts in biological fluids and selectively deliver them to recipient cells. Here, we review examples of small RNA transfers between plants and bacterial, fungal, and animal symbionts. We also discuss the transmission of RNA interference signals from intestinal cells to populations of the gut microbiota, along with its roles in intestinal homeostasis. We suggest that extracellular vesicles may contribute to inter-species crosstalk mediated by small RNA. We review the mechanisms of RNA sorting to extracellular vesicles and evaluate their relevance in cross-species communication by discussing conservation, stability, stoichiometry, and co occurrence of vesicles with alternative communication vehicles. PMID- 28360890 TI - Driving HIV-1 into a Vulnerable Corner by Taking Advantage of Viral Adaptation and Evolution. AB - Anti-retroviral therapy (ART) is crucial for controlling human immunodeficiency virus type-1 (HIV-1) infection. Recently, progress in identifying and characterizing highly potent broadly neutralizing antibodies has provided valuable templates for HIV-1 therapy and vaccine design. Nevertheless, HIV-1, like many RNA viruses, exhibits genetically diverse populations known as quasispecies. Evolution of quasispecies can occur rapidly in response to selective pressures, such as that exerted by ART and the immune system. Hence, rapid viral evolution leading to drug resistance and/or immune evasion is a significant barrier to the development of effective HIV-1 treatments and vaccines. Here, we describe our recent investigations into evolutionary pressure exerted by anti-retroviral drugs and monoclonal neutralizing antibodies (NAbs) on HIV-1 envelope sequences. We also discuss sensitivities of HIV-1 escape mutants to maraviroc, a CCR5 inhibitor, and HIV-1 sensitized to NAbs by small-molecule CD4-mimetic compounds. These studies help to develop an understanding of viral evolution and escape from both anti-retroviral drugs and the immune system, and also provide fundamental insights into the combined use of NAbs and entry inhibitors. These findings of the adaptation and evolution of HIV in response to drug and immune pressure will inform the development of more effective antiviral therapeutic strategies. PMID- 28360892 TI - Enhancement of Non-photochemical Quenching as an Adaptive Strategy under Phosphorus Deprivation in the Dinoflagellate Karlodinium veneficum. AB - Intensified water column stratification due to global warming has the potential to decrease nutrient availability while increasing excess light for the photosynthesis of phytoplankton in the euphotic zone, which together will increase the need for photoprotective strategies such as non-photochemical quenching (NPQ). We investigated whether NPQ is enhanced and how it is regulated molecularly under phosphorus (P) deprivation in the dinoflagellate Karlodinium veneficum. We grew K. veneficum under P-replete and P-depleted conditions, monitored their growth rates and chlorophyll fluorescence, and conducted gene expression and comparative proteomic analyses. The results were used to characterize NPQ modulation and associated gene expression dynamics under P deprivation. We found that NPQ in K. veneficum was elevated significantly under P deprivation. Accordingly, the abundances of three light-harvesting complex stress related proteins increased under P-depleted condition. Besides, many proteins related to genetic information flow were down-regulated while many proteins related to energy production and conversion were up-regulated under P deprivation. Taken together, our results indicate that K. veneficum cells respond to P deprivation by reconfiguring the metabolic landscape and up-tuning NPQ to increase the capacity to dissipate excess light energy and maintain the fluency of energy flow, which provides a new perspective about what adaptive strategy dinoflagellates have evolved to cope with P deprivation. PMID- 28360893 TI - Diversity of Cultivable Protease-Producing Bacteria in Laizhou Bay Sediments, Bohai Sea, China. AB - Protease-producing bacteria are widespread in ocean sediments and play important roles in degrading sedimentary nitrogenous organic materials. However, the diversity of the bacteria and the proteases involved in such processes remain largely unknown especially for communities in enclosed sea bays. Here, we investigated the diversity of the extracellular protease-producing bacteria and their protease types in Laizhou Bay. A total of 121 bacterial isolates were obtained from sediment samples in 7 sites and their protease types were characterized. The abundance of cultivable protease-producing bacteria was about 104 CFU g-1 of sediment. Phylogenetic analysis based on 16S rRNA gene sequences suggest that the isolates belonged to 17 genera from 4 phyla including Firmicutes, Actinobacteria, Proteobacteria and Bacteroidetes, and mainly dominated by the genera Pseudoalteromonas (40.5%), Bacillus (36.3%), and Photobacterium (5.8%). The diversity and community structure varied among different sampling sites but no significant correlation was observed with soil sediment's characteristics. Enzyme activity and inhibition tests further revealed that all isolates secreted proteases that were inhibited by serine and/or metalloprotease inhibitors, and a smaller proportion was inhibited by inhibitors of cysteine and/or aspartic proteases. Furthermore, all isolates effectively degraded casein and/or gelatin with only a few that could hydrolyze elastin, suggesting that the bacteria were producing different kinds of serine proteases or metalloproteases. This study provided novel insights on the community structure of cultivable protease-producing bacteria near the Yellow River estuary of an enclosed sea bay. PMID- 28360891 TI - Cloning and Heterologous Expression of a Large-sized Natural Product Biosynthetic Gene Cluster in Streptomyces Species. AB - Actinomycetes family including Streptomyces species have been a major source for the discovery of novel natural products (NPs) in the last several decades thanks to their structural novelty, diversity and complexity. Moreover, recent genome mining approach has provided an attractive tool to screen potentially valuable NP biosynthetic gene clusters (BGCs) present in the actinomycetes genomes. Since many of these NP BGCs are silent or cryptic in the original actinomycetes, various techniques have been employed to activate these NP BGCs. Heterologous expression of BGCs has become a useful strategy to produce, reactivate, improve, and modify the pathways of NPs present at minute quantities in the original actinomycetes isolates. However, cloning and efficient overexpression of an entire NP BGC, often as large as over 100 kb, remain challenging due to the ineffectiveness of current genetic systems in manipulating large NP BGCs. This mini review describes examples of actinomycetes NP production through BGC heterologous expression systems as well as recent strategies specialized for the large-sized NP BGCs in Streptomyces heterologous hosts. PMID- 28360894 TI - Plasmids Carrying blaCMY -2/4 in Escherichia coli from Poultry, Poultry Meat, and Humans Belong to a Novel IncK Subgroup Designated IncK2. AB - The blaCMY -2/4-carrying IncB/O/K-like plasmids of seven Escherichia coli strains from poultry, poultry meat and human urine samples were examined using comparative analysis of whole plasmid sequences. The incompatibility group was determined by analysis of the incRNAI region and conjugation assays with strains containing the IncK and IncB/O reference plasmids. Strains were additionally characterized using MLST and MIC determination. The complete DNA sequences of all plasmids showed an average nucleotide identity of 91.3%. Plasmids were detected in E. coli sequence type (ST) 131, ST38, ST420, ST1431, ST1564 and belonged to a new plasmid variant (IncK2) within the IncK and IncB/O groups. Notably, one E. coli from poultry meat and one from human contained the same plasmid. The presence of a common recently recognized IncK2 plasmid in diverse E. coli from human urine isolates and poultry meat production suggests that the IncK2 plasmids originated from a common progenitor and have the capability to spread to genetically diverse E. coli in different reservoirs. This discovery is alarming and stresses the need of rapidly introducing strict hygiene measures throughout the food chain, limiting the spread of such plasmids in the human settings. PMID- 28360896 TI - Comparative Genomics of Four Isosphaeraceae Planctomycetes: A Common Pool of Plasmids and Glycoside Hydrolase Genes Shared by Paludisphaera borealis PX4T, Isosphaera pallida IS1BT, Singulisphaera acidiphila DSM 18658T, and Strain SH PL62. AB - The family Isosphaeraceae accommodates stalk-free planctomycetes with spherical cells, which can be assembled in short chains, long filaments, or aggregates. These bacteria inhabit a wide variety of terrestrial environments, among those the recently described Paludisphaera borealis PX4T that was isolated from acidic boreal wetlands. Here, we analyzed its finished genome in comparison to those of three other members of the Isosphaeraceae: Isosphaera pallida IS1BT, Singulisphaera acidiphila DSM 18658T, and the uncharacterized planctomycete strain SH-PL62. The complete genome of P. borealis PX4T consists of a 7.5 Mb chromosome and two plasmids, 112 and 43 kb in size. Annotation of the genome sequence revealed 5802 potential protein-coding genes of which 2775 could be functionally assigned. The genes encoding metabolic pathways common for chemo organotrophic bacteria, such as glycolysis, citrate cycle, pentose-phosphate pathway, and oxidative phosphorylation were identified. Several genes involved in the synthesis of peptidoglycan as well as N-methylated ornithine lipids were present in the genome of P. borealis PX4T. A total of 26 giant genes with a size >5 kb were detected. The genome encodes a wide repertoire of carbohydrate-active enzymes (CAZymes) including 44 glycoside hydrolases (GH) and 83 glycosyltransferases (GT) affiliated with 21 and 13 CAZy families, respectively. The most-represented families are GH5, GH13, GH57, GT2, GT4, and GT83. The experimentally determined carbohydrate utilization pattern agrees well with the genome-predicted capabilities. The CAZyme repertoire in P. borealis PX4T is highly similar to that in the uncharacterized planctomycete SH-PL62 and S. acidiphila DSM 18658T, but different to that in the thermophile I. pallida IS1BT. The latter strain has a strongly reduced CAZyme content. In P. borealis PX4T, many of its CAZyme genes are organized in clusters. Contrary to most other members of the order Planctomycetales, all four analyzed Isosphaeraceae planctomycetes have plasmids in numbers varying from one to four. The plasmids from P. borealis PX4T display synteny to plasmids from other family members, providing evidence for their common evolutionary origin. PMID- 28360895 TI - Genetic Diversity of Brucella Reference and Non-reference Phages and Its Impact on Brucella-Typing. AB - Virulent phages have been used for many years to type Brucella isolates, but until recently knowledge about the genetic makeup of these phages remains limited. In this work the host specificity and genomic sequences of the original set (deposited in 1960) of VLA Brucella reference phages Tb, Fi, Wb, Bk2, R/C, and Iz were analyzed and compared with hitherto described brucellaphages. VLA phages turned out to be different from homonymous phages in other laboratories. The host range of the phages was defined by performing plaque assays with a wide selection of Brucella strains. Propagation of the phages on different strains did not alter host specificity. Sequencing of the phages TbV, FiV, WbV, and R/CV revealed nucleotide variations when compared to same-named phages previously described by other laboratories. The phages Bk2V and IzV were sequenced for the first time. While Bk2V exhibited the same deletions as WbV, IzV possesses the largest genome of all Brucella reference phages. The duplication of a 301 bp sequence in this phage and the large deletion in Bk2V, WbV, and R/CV may be a result of recombination caused by repetitive sequences located in this DNA region. To identify new phages as potential candidates for lysotyping, the host range and Single Nucleotide Polymorphisms (SNPs) of 22 non-reference Brucella phages were determined. The phages showed lysis patterns different from those of the reference phages and thus represent novel valuable candidates in the typing set. PMID- 28360897 TI - Classification of Isolates from the Pseudomonas fluorescens Complex into Phylogenomic Groups Based in Group-Specific Markers. AB - The Pseudomonas fluorescens complex of species includes plant-associated bacteria with potential biotechnological applications in agriculture and environmental protection. Many of these bacteria can promote plant growth by different means, including modification of plant hormonal balance and biocontrol. The P. fluorescens group is currently divided into eight major subgroups in which these properties and many other ecophysiological traits are phylogenetically distributed. Therefore, a rapid phylogroup assignment for a particular isolate could be useful to simplify the screening of putative inoculants. By using comparative genomics on 71 P. fluorescens genomes, we have identified nine markers which allow classification of any isolate into these eight subgroups, by a presence/absence PCR test. Nine primer pairs were developed for the amplification of these markers. The specificity and sensitivity of these primer pairs were assessed on 28 field isolates, environmental samples from soil and rhizosphere and tested by in silico PCR on 421 genomes. Phylogenomic analysis validated the results: the PCR-based system for classification of P. fluorescens isolates has a 98.34% of accuracy and it could be used as a rapid and simple assay to evaluate the potential of any P. fluorescens complex strain. PMID- 28360898 TI - Archaea Dominate the Ammonia-Oxidizing Community in Deep-Sea Sediments of the Eastern Indian Ocean-from the Equator to the Bay of Bengal. AB - Ammonia-oxidizing Archaea (AOA) and ammonia-oxidizing Bacteria (AOB) oxidize ammonia to nitrite, and therefore play essential roles in nitrification and global nitrogen cycling. To better understand the population structure and the distribution of AOA and AOB in the deep Eastern Indian Ocean (EIO), nine surface sediment samples (>3,300 m depth) were collected during the inter-monsoon Spring 2013. One sediment sample from the South China Sea (SCS; 2,510 m) was also included for comparison. The community composition, species richness, and diversity were characterized by clone libraries (total 1,238 clones), and higher diversity of archaeal amoA genes than bacterial amoA genes was observed in all analyzed samples. Real time qPCR analysis also demonstrated higher abundances (gene copy numbers) of archaeal amoA genes than bacterial amoA genes, and the ratios of AOA/AOB ranged from 1.42 to 8.49 among sites. In addition, unique and distinct clades were found in both reconstructed AOA and AOB phylogeny, suggesting the presence of niche-specific ammonia-oxidizing microorganisms in the EIO. The distribution pattern of both archaeal and bacterial amoA genes revealed by NMDS (non-metric multidimensional scaling) showed a distinct geographic separation of the sample from the SCS and most of the samples from the EIO following nitrogen gradients. Higher abundance and diversity of archaeal amoA genes indicated that AOA may play a more important role than AOB in the deep Indian Ocean. Environmental parameters shaping the distribution pattern of AOA were different from that of AOB, indicating distinct metabolic characteristics and/or adaptation mechanisms between AOA and AOB in the EIO, especially in deep sea environments. PMID- 28360899 TI - Members of the Oral Microbiota Are Associated with IL-8 Release by Gingival Epithelial Cells in Healthy Individuals. AB - The triggers for the onset of oral diseases are still poorly understood. The aim of this study was to characterize the oral bacterial community in healthy humans and its association with nutrition, oral hygiene habits, and the release of the inflammatory marker IL-8 from gingival epithelial cells (GECs) with and without stimulation by bacterial endotoxins to identify possible indicator operational taxonomic units (OTUs) associated with inflammatory marker status. GECs from 21 healthy participants (13 females, 8 males) were incubated with or without addition of bacterial lipopolysaccharides (LPSs), and the oral microbiota was profiled using 16S rRNA gene-targeted sequencing. The basal IL-8 release after 6 h was between 9.9 and 98.2 pg/ml, and bacterial communities were characteristic for healthy oral microbiota. The composition of the oral microbiota was associated with basal IL-8 levels, the intake of meat, tea, white wine, sweets and the use of chewing gum, as well as flossing habits, allergies, gender and body mass index. Additionally, eight OTUs were associated with high basal levels of IL-8 and GEC response to LPS, with high basal levels of IL-8, and 1 with low basal levels of IL8. The identification of indicator bacteria in healthy subjects with high levels of IL-8 release is of importance as they may be promising early warning indicators for the possible onset of oral diseases. PMID- 28360900 TI - Oral Immunization with Recombinant Lactobacillus acidophilus Expressing espA-Tir M Confers Protection against Enterohemorrhagic Escherichia coli O157:H7 Challenge in Mice. AB - Enterohemorrhagic Escherichia coli O157:H7 (EHEC O157:H7) causes hemorrhagic colitis and the formation of characteristic attaching and effacing (A/E) lesions in humans. Given the severe sequelae of EHEC O157:H7 infection, it is critical to develop effective vaccines for human use. However, for achieving this goal many hurdles need to be addressed, such as the type or subset of antigens, adjuvant, and the delivery route. We developed a candidate vaccine by inserting the bivalent antigen espA-Tir-M composed of espA and the Tir central domain into Lactobacillus acidophilus. The recombinant L. acidophilus (LA-ET) was safe in a cell model and excluded EHEC O157:H7 from LoVo cells at rates of nearly 94 and 60% in exclusion and competition assays, respectively. LA-ET inhibited the induction of A/E lesions by EHEC O157:H7 cells in vitro. Oral immunization with LA-ET induced higher levels of specific mucosal and systemic antibody responses in mice. Moreover, LA-ET enhanced interferon-gamma and interleukin-4 and -10 production, which was associated with mixed helper T (Th1/Th2) cell responses, and protected against EHEC O157:H7 colonization and infection in mice at a rate of 80%. Histopathological analyses revealed that orally administered LA-ET reduced or inhibited A/E lesions and toxin-induced systemic injury. These findings demonstrate that LA-ET induces both humoral and cellular immune responses in mice and is therefore a promising vaccine against EHEC O157:H7 infection. PMID- 28360901 TI - An Efficient Multiplex PCR-Based Assay as a Novel Tool for Accurate Inter-Serovar Discrimination of Salmonella Enteritidis, S. Pullorum/Gallinarum and S. Dublin. AB - Salmonella enterica serovars Enteritidis, Pullorum/Gallinarum, and Dublin are infectious pathogens causing serious problems for pig, chicken, and cattle production, respectively. Traditional serotyping for Salmonella is costly and labor-intensive. Here, we established a rapid multiplex PCR method to simultaneously identify three prevalent Salmonella serovars Enteritidis, Pullorum/Gallinarum, and Dublin individually for the first time. The multiplex PCR-based assay focuses on three genes tcpS, lygD, and flhB. Gene tcpS exists only in the three Salmonella serovars, and lygD exists only in S. Enteritidis, while a truncated region of flhB gene is only found in S. Pullorum/Gallinarum. The sensitivity and specificity of the multiplex PCR assay using three pairs of specific primers for these genes were evaluated. The results showed that this multiplex PCR method could accurately identify Salmonella Enteritidis, Pullorum/Gallinarum, and Dublin from eight non-Salmonella species and 27 Salmonella serovars. The least concentration of genomic DNA that could be detected was 58.5 pg/MUL and the least number of cells was 100 CFU. Subsequently, this developed method was used to analyze clinical Salmonella isolates from one pig farm, one chicken farm, and one cattle farm. The results showed that blinded PCR testing of Salmonella isolates from the three farms were in concordance with the traditional serotyping tests, indicating the newly developed multiplex PCR system could be used as a novel tool to accurately distinguish the three specific Salmonella serovars individually, which is useful, especially in high-throughput screening. PMID- 28360902 TI - The Potential of Systems Biology to Discover Antibacterial Mechanisms of Plant Phenolics. AB - Drug resistance of bacterial pathogens is a growing problem that can be addressed through the discovery of compounds with novel mechanisms of antibacterial activity. Natural products, including plant phenolic compounds, are one source of diverse chemical structures that could inhibit bacteria through novel mechanisms. However, evaluating novel antibacterial mechanisms of action can be difficult and is uncommon in assessments of plant phenolic compounds. With systems biology approaches, though, antibacterial mechanisms can be assessed without the bias of target-directed bioassays to enable the discovery of novel mechanism(s) of action against drug resistant microorganisms. This review article summarizes the current knowledge of antibacterial mechanisms of action of plant phenolic compounds and discusses relevant methodology. PMID- 28360903 TI - Cooperative Actions of CRP-cAMP and FNR Increase the Fosfomycin Susceptibility of Enterohaemorrhagic Escherichia coli (EHEC) by Elevating the Expression of glpT and uhpT under Anaerobic Conditions. AB - Bacterial infections to anaerobic site are often hard to be treated because the activity of most of antimicrobials decreases under anaerobic conditions. However, fosfomycin rather provides a greater activity under anaerobic conditions than aerobic conditions. Previously, we found that expression of glpT and uhpT, fosfomycin symporters in enterohaemorrhagic Escherichia coli (EHEC) was upregulated by FNR, a global regulator during the anaerobiosis of the bacterium, which led to increased uptake and susceptibility to this drug. In this study, we showed that expression of glpT and uhpT is induced by CRP-cAMP, the regulator complex under both aerobic and anaerobic conditions. The activity of CRP-cAMP in EHEC was elevated under anaerobic conditions because levels of both CRP and cAMP were higher in the cells when grown anaerobically than those when grown aerobically. Results of expression study using mutants indicated that CRP-cAMP is indispensable for expression of glpT but not uhpT-whereas that of uhpT requires UhpA that is the response regulator composing of two-component system with the sensor kinase, UhpB. The CRP-cAMP protein bound to a region that overlaps RNA polymerase binding site for glpT and region upstream of UhpA binding site for uhpT. FNR bound to a region further upstream of CRP-cAMP binding site on region upstream of the glpT gene. These combined results suggested that increased antibacterial activity of fosfomycin to EHEC under anaerobic conditions is due to activation of FNR and increment of CRP-cAMP activity. Then, FNR enhances the expression of glpT activated by CRP-cAMP while CRP-cAMP and FNR cooperatively aids the action of UhpA to express uhpT to maximum level. PMID- 28360905 TI - Improvement of the Process Stability of Arylmalonate Decarboxylase by Immobilization for Biocatalytic Profen Synthesis. AB - The enzyme arylmalonate decarboxylase (AMDase) enables the selective synthesis of enantiopure (S)-arylpropinates in a simple single-step decarboxylation of dicarboxylic acid precursors. However, the poor enzyme stability with a half-life time of about 1.2 h under process conditions is a serious limitation of the productivity, which results in a need for high catalyst loads. By immobilization on an amino C2 acrylate carrier the operational stability of the (S)-selective AMDase variant G74C/M159L/C188G/V43I/A125P/V156L was increased to a half-life of about 8.6 days, which represents a 158-fold improvement. Further optimization was achieved by simple immobilization of the cell lysate to eliminate the cost- and time intensive enzyme purification step. PMID- 28360904 TI - Host Factors in the Infection Cycle of Bamboo mosaic virus. AB - To complete the infection cycle efficiently, the virus must hijack the host systems in order to benefit for all the steps and has to face all the defense mechanisms from the host. This review involves a discussion of how these positive and negative factors regulate the viral RNA accumulation identified for the Bamboo mosaic virus (BaMV), a single-stranded RNA virus. The genome of BaMV is approximately 6.4 kb in length, encoding five functional polypeptides. To reveal the host factors involved in the infection cycle of BaMV, a few different approaches were taken to screen the candidates. One of the approaches is isolating the viral replicase-associated proteins by co-immunoprecipitation with the transiently expressed tagged viral replicase in plants. Another approach is using the cDNA-amplified fragment length polymorphism technique to screen the differentially expressed genes derived from N. benthamiana plants after infection. The candidates are examined by knocking down the expression in plants using the Tobacco rattle virus-based virus-induced gene silencing technique following BaMV inoculation. The positive or negative regulators could be described as reducing or enhancing the accumulation of BaMV in plants when the expression levels of these proteins are knocked down. The possible roles of these host factors acting on the accumulation of BaMV will be discussed. PMID- 28360906 TI - Efficacy of Resistance to Francisella Imparted by ITY/NRAMP/SLC11A1 Depends on Route of Infection. AB - Natural resistance-associated macrophage protein (NRAMP) encoded by the Slc11a1 gene is a membrane-associated transporter of divalent metal ions. Murine Slc11a1 has two known alleles, a functional Slc11a1Gly169, which is found in DBA2/J, NOD/LtJ, and 129p3/J and related mouse strains, and a non-functional Slc11a1Asp169, that is found in C56Bl/6J (B6) and BALB/cJ mice. B6 mice congenic for Slc11a1Gly169 (B6-Slc11a1G169 ) are markedly resistant to the intracellular pathogens Salmonella, Leishmania, and Mycobacterium tuberculosis. We examined the host cell response and replication of Francisella in B6-Slc11a1G169 mice. Bone marrow-derived macrophages from either B6-Slc11a1G169 or B6 mice were both effectively invaded by Francisella live vaccine strain (LVS). However, at 16 hours post-infection (hpi), the number of LVS bacteria recovered from B6 macrophages had increased roughly 100-fold, while in B6-Slc11a1G169 mice the number decreased 10-fold. When the mice were challenged intranasally (i.n.) B6 mice lost significant amounts (~15%) of weight, where as B6-Slc11a1G169 mice lost no weight. Three days after infection in B6-Slc11a1G169 mice, we failed to recover viable Francisella from the lungs, livers, or spleens. By contrast, B6 mice had bacterial burdens approaching 1 * 106 CFU/organ in all three organs. To further examine the degree of resistance imparted by Slc11a1Gly169 expression, we challenged mice deficient in TLR2, TLR4, and TLR9, but expressing the functional Slc11a1 (B6-Slc11a1G169Tlr2/4/9-/- ). Surprisingly, B6-Slc11a1G169Tlr2/4/9-/- mice had no notable weight loss. Eighty percent of B6-Slc11a1G169Tlr2/4/9-/- mice yielded no detectable Francisella in any organ tested. Additionally, Slc11a1G169 produced little detectable cytokine either in the lung or serum compared to B6 mice. Mice expressing Slc11a1Gly169 survived even high doses (~80 LD50) of LVS inoculation. These data taken together serve to highlight that functional Slc11a1Gly169 can compensate the lack of TLR2/4/9. Thus Slc11a1 is a critical player in murine resistance to pulmonary Francisella infection, but not footpad infection. PMID- 28360907 TI - Aspirin: The Mechanism of Action Revisited in the Context of Pregnancy Complications. AB - Aspirin is one of the most frequently used and cheapest drugs in medicine. It belongs to the non-steroidal anti-inflammatory drugs with a wide range of pharmacological activities, including analgesic, antipyretic, and antiplatelet properties. Currently, it is accepted to prescribe a low dose of aspirin to pregnant women who are at high risk of preeclampsia (PE) because it reduces the onset of this complication. Another pregnancy alteration in which a low dose of aspirin is recommended is the obstetric antiphospholipid syndrome (APS). The most recognized mechanism of action of aspirin is to inhibit the synthesis of prostaglandins but this by itself does not explain the repertoire of anti inflammatory effects of aspirin. Later, another mechanism was described: the induction of the production of aspirin-triggered lipoxins (ATLs) from arachidonic acid by acetylation of the enzyme cyclooxygenase-2. The availability of a stable analog of ATL has stimulated investigations on the use of this analog and it has been found that, similar to endogenously produced lipoxins, ATL resolves inflammation and acts as antioxidant and immunomodulator. If we consider that in PE and in the obstetric APS, there is an underlying inflammatory process, aspirin might be used based on the induction of ATL. The objective of this review is to revisit the old and new mechanisms of action of aspirin. In particular, it intends to show other potential uses of this drug to prevent certain pregnancy complications in the light of its ability to induce anti-inflammatory and pro resolving lipid-derived mediators. PMID- 28360908 TI - Fasciola hepatica Immune Regulates CD11c+ Cells by Interacting with the Macrophage Gal/GalNAc Lectin. AB - Fasciolosis, caused by Fasciola hepatica and Fasciola gigantica, is a trematode zoonosis of interest in public health and livestock production. Like other helminths, F. hepatica modulates the host immune response by inducing potent polarized Th2 and regulatory T cell immune responses and by downregulating the production of Th1 cytokines. In this work, we show that F. hepatica glycans increase Th2 immune responses by immunomodulating TLR-induced maturation and function of dendritic cells (DCs). This process was mediated by the macrophage Gal/GalNAc lectin (MGL) expressed on DCs, which recognizes the Tn antigen (GalNAc Ser/Thr) on parasite components. More interestingly, we identified MGL-expressing CD11c+ cells in infected animals and showed that these cells are recruited both to the peritoneum and the liver upon F. hepatica infection. These cells express the regulatory cytokines IL-10, TNFalpha and TGFbeta and a variety of regulatory markers. Furthermore, MGL+ CD11c+ cells expand parasite-specific Th2/regulatory cells and suppress Th1 polarization. The results presented here suggest a potential role of MGL in the immunomodulation of DCs induced by F. hepatica and contribute to a better understanding of the molecular and immunoregulatory mechanisms induced by this parasite. PMID- 28360911 TI - Swine Leukocyte Antigen Diversity in Canadian Specific Pathogen-Free Yorkshire and Landrace Pigs. AB - The highly polymorphic swine major histocompatibility complex (MHC), termed swine leukocyte antigen (SLA), is associated with different levels of immunologic responses to infectious diseases, vaccines, and transplantation. Pig breeds with known SLA haplotypes are important genetic resources for biomedical research. Canadian Yorkshire and Landrace pigs represent the current specific pathogen-free (SPF) breeding stock maintained in the isolation environment at the Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences. In this study, we identified 61 alleles at five polymorphic SLA loci (SLA-1, SLA-2, SLA 3, DRB1, and DQB1) representing 17 class I haplotypes and 11 class II haplotypes using reverse transcription-polymerase chain reaction (RT-PCR) sequence-based typing and PCR-sequence specific primers methods in 367 Canadian SPF Yorkshire and Landrace pigs. The official designation of the alleles has been assigned by the SLA Nomenclature Committee of the International Society for Animal Genetics and released in updated Immuno Polymorphism Database-MHC SLA sequence database [Release 2.0.0.3 (2016-11-03)]. The submissions confirmed some unassigned alleles and standardized nomenclatures of many previously unconfirmed alleles in the GenBank database. Three class I haplotypes, Hp-37.0, 63.0, and 73.0, appeared to be novel and have not previously been reported in other pig populations. One crossover within the class I region and two between class I and class II regions were observed, resulting in three new recombinant haplotypes. The presence of the duplicated SLA-1 locus was confirmed in three class I haplotypes Hp-28.0, Hp 35.0, and Hp-63.0. Furthermore, we also analyzed the functional diversities of 19 identified frequent SLA class I molecules in this study and confirmed the existence of four supertypes using the MHCcluster method. These results will be useful for studying the adaptive immune response and immunological phenotypic differences in pigs, screening potential T-cell epitopes, and further developing the more effective vaccines. PMID- 28360910 TI - Antifungal Immunological Defenses in Newborns. AB - Newborns are prone to fungal infections, largely due to Candida species. The immunological basis for this vulnerability is not yet fully understood. However, useful insights can be gained from the knowledge of the maturation of immune pathways during ontogeny, particularly when placed in context with how rare genetic mutations in humans predispose to fungal diseases. In this article, we review these most current data on immune functions in human newborns, highlighting pathways most relevant to the response to Candida. While discussing these data, we propose a framework of why deficiencies in these pathways make newborns particularly vulnerable to this opportunistic pathogen. PMID- 28360912 TI - Exosomes Isolated from Ascites of T-Cell Lymphoma-Bearing Mice Expressing Surface CD24 and HSP-90 Induce a Tumor-Specific Immune Response. AB - Extracellular vesicles (EVs), including endosome-derived nanovesicles (exosomes), are involved in cell-cell communication. Through transfer of their molecular contents, extracellular nanovesicles can alter the function of recipient cells. Due to these characteristics, EVs have shown potential as a new alternative for cancer immunotherapy. Tumor exosomes isolated from malignant ascites can activate dendritic cells, thereby priming the immune system to recognize and kill cancer cells. However, a suppressive role on tumor immune response has also been reported, suggesting that the neoplastic stage of carcinogenesis and the microenvironment where tumor cells grow may influence the amount of EVs released by the cell. This neoplastic stage and microenvironment may also impact EVs' components such as proteins and miRNA, determining their biological behavior. Most T-cell lymphomas have an aggressive clinical course and poor prognosis. Consequently, complementary alternative therapies are needed to improve the survival rates achieved with conventional treatments. In this work, we have characterized EVs isolated from ascites of mice bearing a very aggressive murine T-cell lymphoma and have studied their immunogenic properties. Small EVs were isolated by differential centrifugation, ultrafiltration, and ultracentrifugation at 100,000 * g on a sucrose cushion. The EVs were defined as exosomes by their morphology and size analyzed by electron microscopy, their floating density on a sucrose gradient, as well as their expression of endosome marker proteins ALIX, TSG-101; the tetraspanins CD63, CD9, and CD81. In addition, they contain tumor antigens, the marker for malignancy CD24, the heat shock protein HSP-70, and an unusual surface expression of HSP-90 was demonstrated. The administration of EVs isolated from ascites (EVs A) into naive-syngeneic mice induced both humoral and cellular immune responses that allowed the rejection of subsequent tumor challenges. However, the immunization had no effect on a non-related mammary adenocarcinoma, demonstrating that the immune response elicited was specific and also it induced immune memory. In vitro analysis demonstrated that T-cells from EVs A-immunized mice secrete IFN-gamma in response to tumor stimulation. Furthermore, tumor-specific CD4+ and CD8+ IFN-gamma secreting cells could be efficiently expanded from mice immunized with EVs A, showing that a T helper 1 response is involved in tumor rejection. Our findings confirm exosomes as promising defined acellular tumor antigens for the development of an antitumor vaccine. PMID- 28360909 TI - Inflammasomes in Inflammation-Induced Cancer. AB - The inflammasome is an important multiprotein complex that functions during inflammatory immune responses. The activation of inflammasome will lead to the autoactivation of caspase-1 and subsequent cleavage of proIL-1beta and proIL-18, which are key sources of inflammatory manifestations. Recently, the roles of inflammasomes in cancers have been extensively explored, especially in inflammation-induced cancers. In different and specific contexts, inflammasomes exhibit distinct and even contrasting effects in cancer development. In some cases, inflammasomes initiate carcinogenesis through the extrinsic pathway and maintain the malignant cancer microenvironment through the intrinsic pathway. On the contrary, inflammasomes also exert anticancer effects by specialized programmed cell death called pyroptosis and immune regulatory functions. The phases and compartments in which inflammasomes are activated strongly influence the final immune effects. We systemically summarize the functions of inflammasomes in inflammation-induced cancers, especially in gastrointestinal and skin cancers. Besides, information about the current therapeutic use of inflammasome-related products and potential future developing directions are also introduced. PMID- 28360913 TI - Lectin Pathway of Complement Activation Is Associated with Vulnerability of Atherosclerotic Plaques. AB - Inflammatory mechanisms may be involved in atherosclerotic plaque rupture. By using a novel histology-based method to quantify plaque instability here, we assess whether lectin pathway (LP) of complement activation, a major inflammation arm, could represent an index of plaque instability. Plaques from 42 consecutive patients undergoing carotid endarterectomy were stained with hematoxylin-eosin and the lipid core, cholesterol clefts, hemorrhagic content, thickness of tunica media, and intima, including or not infiltration of cellular debris and cholesterol, were determined. The presence of ficolin-1, -2, and -3 and mannose binding lectin (MBL), LP initiators, was assessed in the plaques by immunofluorescence and in plasma by ELISA. LP activation was assessed in plasma by functional in vitro assays. Patients presenting low stenosis (<=75%) had higher hemorrhagic content than those with high stenosis (>75%), indicating increased erosion. Increased hemorrhagic content and tunica media thickness, as well as decreased lipid core and infiltrated content were associated with vulnerable plaques and therefore used to establish a plaque vulnerability score that allowed to classify patients according to plaque vulnerability. Ficolins and MBL were found both in plaques' necrotic core and tunica media. Patients with vulnerable plaques showed decreased plasma levels and intraplaque deposition of ficolin-2. Symptomatic patients experiencing a transient ischemic attack had lower plasma levels of ficolin-1. We show that the LP initiators are present within the plaques and their circulating levels change in atherosclerotic patients. In particular, we show that decreased ficolin-2 levels are associated with rupture-prone vulnerable plaques, indicating its potential use as marker for cardiovascular risk assessment in atherosclerotic patients. PMID- 28360914 TI - Macrophage Metabolism As Therapeutic Target for Cancer, Atherosclerosis, and Obesity. AB - Macrophages are not only essential components of innate immunity that contribute to host defense against infections, but also tumor growth and the maintenance of tissue homeostasis. An important feature of macrophages is their plasticity and ability to adopt diverse activation states in response to their microenvironment and in line with their functional requirements. Recent immunometabolism studies have shown that alterations in the metabolic profile of macrophages shape their activation state and function. For instance, to fulfill their respective functions lipopolysaccharides-induced pro-inflammatory macrophages and interleukin-4 activated anti-inflammatory macrophages adopt a different metabolism. Thus, metabolic reprogramming of macrophages could become a therapeutic approach to treat diseases that have a high macrophage involvement, such as cancer. In the first part of this review, we will focus on the metabolic pathways altered in differentially activated macrophages and link their metabolic aspects to their pro- and anti-inflammatory phenotype. In the second part, we will discuss how macrophage metabolism is a promising target for therapeutic intervention in inflammatory diseases and cancer. PMID- 28360917 TI - Ubiquitin-Proteasome-Dependent Regulation of Bidirectional Communication between Plastids and the Nucleus. AB - Plastids are DNA-containing organelles and can have unique differentiation states depending on age, tissue, and environment. Plastid biogenesis is optimized by bidirectional communication between plastids and the nucleus. Import of nuclear encoded proteins into plastids serves as anterograde signals and vice versa, plastids themselves send retrograde signals to the nucleus, thereby controlling de novo synthesis of nuclear-encoded plastid proteins. Recently, it has become increasingly evident that the ubiquitin-proteasome system regulates both the import of anterograde plastid proteins and retrograde signaling from plastids to the nucleus. Targets of ubiquitin-proteasome regulation include unimported chloroplast precursor proteins in the cytosol, protein translocation machinery at the chloroplast surface, and transcription factors in the nucleus. This review will focus on the mechanism through which the ubiquitin-proteasome system optimizes plastid biogenesis and plant development through the regulation of nuclear-plastid interactions. PMID- 28360916 TI - B Cell-Activating Factor Regulates Different Aspects of B Cell Functionality and Is Produced by a Subset of Splenic B Cells in Teleost Fish. AB - In mammals, B cell functionality is greatly influenced by cytokines released by innate cells, such as macrophages or dendritic cells, upon the early recognition of common pathogen patterns through invariant receptors. B cell-activating factor (BAFF) is one of these innate B cell-helper signals and plays a key role in the survival and differentiation of B cells. Although, evolutionarily, teleost fish constitute the first animal group in which adaptive immunity based on Ig receptors is present, fish still rely greatly on innate responses. In this context, we hypothesized that BAFF would play a key role in the control of B cell responses in fish. Supporting this, our results show that teleost BAFF recapitulates mammalian BAFF stimulating actions on B cells, upregulating the expression of membrane MHC II, improving the survival of fish naive B cells and antibody-secreting cells, and increasing the secretion of IgM. Surprisingly, we also demonstrate that BAFF is not only produced in fish by myeloid cells but is also produced by a subset of splenic B cells. Thus, if this B cell-produced BAFF proves to be actively regulating this same B cell subset, our findings point to an ancient mechanism to control B cell differentiation and survival in lower vertebrates, which has been silenced in mammals in physiological conditions, but reemerges under pathological conditions, such as B cell lymphomas and autoimmune diseases. PMID- 28360915 TI - Role of Distinct Natural Killer Cell Subsets in Anticancer Response. AB - Natural killer (NK) cells, the prototypic member of innate lymphoid cells, are important effectors of anticancer immune response. These cells can survey and control tumor initiation due to their capability to recognize and kill malignant cells and to regulate the adaptive immune response via cytokines and chemokines release. However, several studies have shown that tumor-infiltrating NK cells associated with advanced disease can have profound functional defects and display protumor activity. This evidence indicates that NK cell behavior undergoes crucial alterations during cancer progression. Moreover, a further level of complexity is due to the extensive heterogeneity and plasticity of these lymphocytes, implying that different NK cell subsets, endowed with specific phenotypic and functional features, may be involved and play distinct roles in the tumor context. Accordingly, many studies reported the enrichment of selective NK cell subsets within tumor tissue, whereas the underlying mechanisms are not fully elucidated. A malignant microenvironment can significantly impact NK cell activity, by recruiting specific subpopulations and/or influencing their developmental programming or the acquisition of a mature phenotype; in particular, neoplastic, stroma and immune cells, or tumor-derived factors take part in these processes. In this review, we will summarize and discuss the recently acquired knowledge on the possible contribution of distinct NK cell subsets in the control and/or progression of solid and hematological malignancies. Moreover, we will address emerging evidence regarding the role of different components of tumor microenvironment on shaping NK cell response. PMID- 28360918 TI - The Unfolded Protein Response Supports Plant Development and Defense as well as Responses to Abiotic Stress. AB - The unfolded protein response (UPR) is a stress response conserved in eukaryotic organisms and activated by the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Adverse environmental conditions disrupt protein folding in the ER and trigger the UPR. Recently, it was found that the UPR can be elicited in the course of plant development and defense. During vegetative plant development, the UPR is involved in normal root growth and development, the effect of which can be largely attributed to the influence of the UPR on plant hormone biology. The UPR also functions in plant reproductive development by protecting male gametophyte development from heat stress. In terms of defense, the UPR has been implicated in virus and microbial defense. Viral defense represents a double edge sword in that various virus infections activate the UPR, however, in a number of cases, the UPR actually supports viral infections. The UPR also plays a role in plant immunity to bacterial infections, again through the action of plant hormones in regulating basal immunity responses. PMID- 28360919 TI - Reconsideration of Plant Morphological Traits: From a Structure-Based Perspective to a Function-Based Evolutionary Perspective. AB - This opinion article proposes a novel alignment of traits in plant morphogenesis from a function-based evolutionary perspective. As a member species of the ecosystem on Earth, we human beings view our neighbor organisms from our own sensing system. We tend to distinguish forms and structures (i.e., "morphological traits") mainly through vision. Traditionally, a plant was considered to be consisted of three parts, i.e., the shoot, the leaves, and the root. Based on such a "structure-based perspective," evolutionary analyses or comparisons across species were made on particular parts or their derived structures. So far no conceptual framework has been established to incorporate the morphological traits of all three land plant phyta, i.e., bryophyta, pteridophyta and spermatophyta, for evolutionary developmental analysis. Using the tenets of the recently proposed concept of sexual reproduction cycle, the major morphological traits of land plants can be aligned into five categories from a function-based evolutionary perspective. From this perspective, and the resulting alignment, a new conceptual framework emerges, called "Plant Morphogenesis 123." This framework views a plant as a colony of integrated plant developmental units that are each produced via one life cycle. This view provided an alternative perspective for evolutionary developmental investigation in plants. PMID- 28360920 TI - Study of Commercially Available Lobelia chinensis Products Using Bar-HRM Technology. AB - There is an unmet need for herbal medicine identification using a fast, sensitive, and easy-to-use method that does not require complex infrastructure and well-trained technicians. For instance, the detection of adulterants in Lobelia chinensis herbal product has been challenging, since current detection technologies are not effective due to their own limits. High Resolution Melting (HRM) has emerged as a powerful new technology for clinical diagnosis, research in the food industry and in plant molecular biology, and this method has already highlighted the complexity of species identification. In this study, we developed a method of species specific detection of L. chinensis using HRM analysis combined with internal transcribed spacer 2. We then applied this method to commercial products purporting to contain L. chinensis. Our results demonstrated that HRM can differentiate L. chinensis from six common adulterants. HRM was proven to be a fast and accurate technique for testing the authenticity of L. chinensis in herbal products. Based on these results, a HRM approach for herbal authentication is provided. PMID- 28360921 TI - The Involvement of Heat Shock Proteins in the Establishment of Tomato Yellow Leaf Curl Virus Infection. AB - Tomato yellow leaf curl virus (TYLCV), a begomovirus, induces protein aggregation in infected tomatoes and in its whitefly vector Bemisia tabaci. The interactions between TYLCV and HSP70 and HSP90 in plants and vectors are necessity for virus infection to proceed. In infected host cells, HSP70 and HSP90 are redistributed from a soluble to an aggregated state. These aggregates contain, together with viral DNA/proteins and virions, HSPs and components of the protein quality control system such as ubiquitin, 26S proteasome subunits, and the autophagy protein ATG8. TYLCV CP can form complexes with HSPs in tomato and whitefly. Nonetheless, HSP70 and HSP90 play different roles in the viral cell cycle in the plant host. In the infected host cell, HSP70, but not HSP90, participates in the translocation of CP from the cytoplasm into the nucleus. Viral amounts decrease when HSP70 is inhibited, but increase when HSP90 is downregulated. In the whitefly vector, HSP70 impairs the circulative transmission of TYLCV; its inhibition increases transmission. Hence, the efficiency of virus acquisition by whiteflies depends on the functionality of both plant chaperones and their cross talk with other protein mechanisms controlling virus-induced aggregation. PMID- 28360922 TI - Sub-high Temperature and High Light Intensity Induced Irreversible Inhibition on Photosynthesis System of Tomato Plant (Solanum lycopersicum L.). AB - High temperature and high light intensity is a common environment posing a great risk to organisms. This study aimed to elucidate the effects of sub-high temperature and high light intensity stress (HH, 35 degrees C, 1000 MUmol?m-2?s 1) and recovery on the photosynthetic mechanism, photoinhibiton of photosystem II (PSII) and photosystem I (PSI), and reactive oxygen (ROS) metabolism of tomato seedlings. The results showed that with prolonged stress time, net photosynthetic rate (Pn), Rubisco activity, maximal photochemistry efficiency (Fv/Fm), efficient quantum yield and electron transport of PSII [Y(II) and ETR(II)] and PSI [Y(I) and ETR(I)] decreased significantly whereas yield of non-regulated and regulated energy dissipation of PSII [Y(NO) and Y(NPQ)] increased sharply. The donor side limitation of PSI [Y(ND)] increased but the acceptor side limitation of PSI [Y(NA)] decreased. Content of malondialdehyde (MDA) and hydrogen peroxide (H2O2) were increased while activity of superoxide dismutase (SOD) and peroxidase (POD) were significantly inhibited compared with control. HH exposure affected photosynthetic carbon assimilation, multiple sites in PSII and PSI, ROS accumulation and elimination of Solanum lycopersicum L. PMID- 28360923 TI - Adaptation Mechanisms in the Evolution of Moss Defenses to Microbes. AB - Bryophytes, including mosses, liverworts and hornworts are early land plants that have evolved key adaptation mechanisms to cope with abiotic stresses and microorganisms. Microbial symbioses facilitated plant colonization of land by enhancing nutrient uptake leading to improved plant growth and fitness. In addition, early land plants acquired novel defense mechanisms to protect plant tissues from pre-existing microbial pathogens. Due to its evolutionary stage linking unicellular green algae to vascular plants, the non-vascular moss Physcomitrella patens is an interesting organism to explore the adaptation mechanisms developed in the evolution of plant defenses to microbes. Cellular and biochemical approaches, gene expression profiles, and functional analysis of genes by targeted gene disruption have revealed that several defense mechanisms against microbial pathogens are conserved between mosses and flowering plants. P. patens perceives pathogen associated molecular patterns by plasma membrane receptor(s) and transduces the signal through a MAP kinase (MAPK) cascade leading to the activation of cell wall associated defenses and expression of genes that encode proteins with different roles in plant resistance. After pathogen assault, P. patens also activates the production of ROS, induces a HR-like reaction and increases levels of some hormones. Furthermore, alternative metabolic pathways are present in P. patens leading to the production of a distinct metabolic scenario than flowering plants that could contribute to defense. P. patens has acquired genes by horizontal transfer from prokaryotes and fungi, and some of them could represent adaptive benefits for resistance to biotic stress. In this review, the current knowledge related to the evolution of plant defense responses against pathogens will be discussed, focusing on the latest advances made in the model plant P. patens. PMID- 28360926 TI - Commentary: A "Source" of Error: Computer Code, Criminal Defendants, and the Constitution. PMID- 28360924 TI - Molecular Genetic Influences on Normative and Problematic Alcohol Use in a Population-Based Sample of College Students. AB - Background: Genetic factors impact alcohol use behaviors and these factors may become increasingly evident during emerging adulthood. Examination of the effects of individual variants as well as aggregate genetic variation can clarify mechanisms underlying risk. Methods: We conducted genome-wide association studies (GWAS) in an ethnically diverse sample of college students for three quantitative outcomes including typical monthly alcohol consumption, alcohol problems, and maximum number of drinks in 24 h. Heritability based on common genetic variants (h2SNP) was assessed. We also evaluated whether risk variants in aggregate were associated with alcohol use outcomes in an independent sample of young adults. Results: Two genome-wide significant markers were observed: rs11201929 in GRID1 for maximum drinks in 24 h, with supportive evidence across all ancestry groups; and rs73317305 in SAMD12 (alcohol problems), tested only in the African ancestry group. The h2SNP estimate was 0.19 (SE = 0.11) for consumption, and was non significant for other outcomes. Genome-wide polygenic scores were significantly associated with alcohol outcomes in an independent sample. Conclusions: These results robustly identify genetic risk for alcohol use outcomes at the variant level and in aggregate. We confirm prior evidence that genetic variation in GRID1 impacts alcohol use, and identify novel loci of interest for multiple alcohol outcomes in emerging adults. These findings indicate that genetic variation influencing normative and problematic alcohol use is, to some extent, convergent across ancestry groups. Studying college populations represents a promising avenue by which to obtain large, diverse samples for gene identification. PMID- 28360925 TI - Jmjd6, a JmjC Dioxygenase with Many Interaction Partners and Pleiotropic Functions. AB - Lysyl hydroxylation and arginyl demethylation are post-translational events that are important for many cellular processes. The jumonji domain containing protein 6 (JMJD6) has been reported to catalyze both lysyl hydroxylation and arginyl demethylation on diverse protein substrates. It also interacts directly with RNA. This review summarizes knowledge of JMJD6 functions that have emerged in the last 15 years and considers how a single Jumonji C (JmjC) domain-containing enzyme can target so many different substrates. New links and synergies between the three main proposed functions of Jmjd6 in histone demethylation, promoter proximal pause release of polymerase II and RNA splicing are discussed. The physiological context of the described molecular functions is considered and recently described novel roles for JMJD6 in cancer and immune biology are reviewed. The increased knowledge of JMJD6 functions has wider implications for our general understanding of the JmjC protein family of which JMJD6 is a member. PMID- 28360927 TI - Stakeholder views of breastfeeding education in schools: a systematic mixed studies review of the literature. AB - BACKGROUND: Breastfeeding provides numerous health benefits for mothers and infants, but worldwide breastfeeding rates fall below recommendations. As part of efforts to increase breastfeeding initiation and duration, the World Health Organization and UNICEF UK recommend educational interventions to increase awareness and positive attitudes towards breastfeeding beginning during the school years. Breastfeeding education in the school setting offers the opportunity to improve the knowledge base, address misconceptions, and positively influence beliefs and attitudes for students from a wide range of socioeconomic and cultural backgrounds. The purpose of this paper is to present a comprehensive narrative review of the literature regarding student and teacher (stakeholder) views of breastfeeding and breastfeeding education programs in schools to inform future research in the area. METHODS: Articles were located through a systematic search of online databases and journals using the following keywords in various combinations: (1) breastfeeding, lactation, breast-feeding, "bottle feeding", "infant feeding" (2) student, educator, teacher, "school administrator" and (3) schools, "secondary education", "primary education", "K-12", "high school", "middle school", "elementary school", education, adolescents, curriculum, and a manual search of article references. Studies were screened for inclusion against specific criteria and included papers were assessed using the Mixed Methods Appraisal Tool (MMAT). RESULTS: This review suggests that adolescents have a deficit in breastfeeding knowledge and express negative conceptions about breastfeeding. Breastfeeding is being discussed in some school environments, but the extent of lessons and the specific messages that teachers communicate have not been explored. Students appear to be interested in receiving more information about breastfeeding, especially if delivered by health professionals or breastfeeding mothers. The majority of teachers are supportive of incorporating breastfeeding education in family and consumer sciences, sexual education, and health classes; however, time constraints and limited knowledge of infant feeding recommendations may be barriers to implementation of appropriate lesson plans. CONCLUSIONS: Students generally support and are receptive to breastfeeding education; however, research on educator attitudes, knowledge, and experiences are necessary for appropriate implementation of breastfeeding education in varying school settings around the world. PMID- 28360928 TI - A new kymogram-based method reveals unexpected effects of marker protein expression and spatial anisotropy of cytoskeletal dynamics in plant cell cortex. AB - BACKGROUND: Cytoskeleton can be observed in live plant cells in situ with high spatial and temporal resolution using a combination of specific fluorescent protein tag expression and advanced microscopy methods such as spinning disc confocal microscopy (SDCM) or variable angle epifluorescence microscopy (VAEM). Existing methods for quantifying cytoskeletal dynamics are often either based on laborious manual structure tracking, or depend on costly commercial software. Current automated methods also do not readily allow separate measurements of structure lifetime, lateral mobility, and spatial anisotropy of these parameters. RESULTS: We developed a new freeware-based, operational system-independent semi manual technique for analyzing VAEM or SDCM data, QuACK (Quantitative Analysis of Cytoskeletal Kymograms), and validated it on data from Arabidopsis thaliana fh1 formin mutants, previously shown by conventional methods to exhibit altered actin and microtubule dynamics compared to the wild type. Besides of confirming the published mutant phenotype, QuACK was used to characterize surprising differential effects of various fluorescent protein tags fused to the Lifeact actin probe on actin dynamics in A. thaliana cotyledon epidermis. In particular, Lifeact-YFP slowed down actin dynamics compared to Lifeact-GFP at marker expression levels causing no macroscopically noticeable phenotypic alterations, although the two fluorophores are nearly identical. We could also demonstrate the expected, but previously undocumented, anisotropy of cytoskeletal dynamics in elongated epidermal cells of A. thaliana petioles and hypocotyls. CONCLUSIONS: Our new method for evaluating plant cytoskeletal dynamics has several advantages over existing techniques. It is intuitive, rapid compared to fully manual approaches, based on the free ImageJ software (including macros we provide here for download), and allows measurement of multiple parameters. Our approach was already used to document unexpected differences in actin mobility in transgenic A. thaliana expressing Lifeact fusion proteins with different fluorophores, highlighting the need for cautious interpretation of experimental results, as well as to reveal hitherto uncharacterized anisotropy of cytoskeletal mobility in elongated plant cells. PMID- 28360929 TI - TALEN-mediated genome-editing approaches in the liverwort Marchantia polymorpha yield high efficiencies for targeted mutagenesis. AB - BACKGROUND: The liverwort Marchantia polymorpha occupies a crucial position in land plant evolution and provides the opportunity to investigate adaptations to a terrestrial plant life style. Marchantia reverse genetic analyses have thus far been conducted by employing a homologous recombination approach, which yields an efficiency of around 3%. Availability of the characterized and suitable endogenous MpEF1alpha promoter prompted us to establish the TALEN gene targeting technique for Marchantia. RESULTS: Here, two different TALEN techniques, using custom and self-assembled TALEN constructs, were applied and compared. The MpNOP1 gene was selected as a candidate gene, as the respective knockout mutant has been shown to lack air chamber formation, representing an easily traceable phenotype. We demonstrate that both TALEN approaches are successful in Marchantia yielding high gene targeting efficiencies of over 20%. Investigation of selected G1 up to G4 generations proved the stability of the knockout mutants. In 392 analyzed T1 plants, no additional phenotypes were observed and only one chimeric knockout plant was detected after an extended cultivation period. Interestingly, two out of the 24 sequenced mutants harbored indels causing in-frame mutations and revealed novel Mpnop1-related phenotypes. This demonstrates the potential to detect crucial amino acids and motives of targeted proteins, which is of special interest for essential genes where full knockouts are lethal. The FastTALETM TALEN assembly kit enables the rapid assembly and ligation of the TALEN arms within half a day. For transformations, custom and assembled constructs were subcloned into Marchantia binary vectors possessing the MpEF1alpha promoter. CONCLUSION: Considering time, costs and practicability, the assembly TALEN approach represents a rapid and highly efficient gene targeting system to generate Marchantia knockout mutants, which can be further adapted for future advanced genome-editing applications. PMID- 28360930 TI - Performance of new adjustments to the TRISS equation model in developed and developing countries. AB - BACKGROUND: The Trauma and Injury Severity Score (TRISS) has been criticized for being based on data from the USA and Canada-high-income countries-and therefore, it may not be applicable to low-income and middle-income countries. The present study evaluated the accuracy of three adjustments to the TRISS equation model (NTRISS-like; TRISS SpO2; NTRISS-like SpO2) in a high-income and a middle-income country to compare their performance when derived and applied to different groups. METHODS: This was a retrospective study of trauma patients admitted to two institutions: a university medical center in Sao Paulo, Brazil (a middle income country), and a level 1 university trauma center in San Diego, USA (a high income country). Patients were admitted between January 1, 2006, and December 31, 2010. The subjects were 2416 patients from Brazil and 8172 patients from the USA. All equations had adjusted coefficients for Sao Paulo and San Diego and for blunt and penetrating trauma. Receiver operating characteristic (ROC) curves were used to evaluate performance of the models. RESULTS: Regardless of the population where the equation was generated, it performed better when applied to patients in the USA (AUC from 0.911 to 0.982) compared to patients in Brazil (AUC from 0.840 to 0.852). When the severity was considered and homogenized, the performance of equations were similar to both application in the USA and Brazil. CONCLUSIONS: Survival probability models showed better performance when applied in data collected in the high-income countries (HIC) regardless the country they were derived. The severity is an important factor to consider when using non-adjusted survival probability models for the local population. Adjusted models for severely traumatized patients better predict survival probability in less severely traumatized populations. Other factors besides physiological and anatomical data may impact final outcomes and should be identified in each environment if they are to be used in the development of the trauma care performance improvement process in middle-income countries. PMID- 28360933 TI - Extraction, purification, characterization and antioxidant activities of polysaccharides from Ramaria botrytis (Pers.) Ricken. AB - BACKGROUND: Ramaria botrytis (Pers.) Ricken, a member of the family Clavariaceae, has been widely prescribed for anti-aging and improving immunity. To extract and purify the polysaccharides, the main constituent of the fruiting-body, from R. botrytis and explore antioxidant activities was great significant. RESULTS: Ramaria botrytis polysaccharides (RBP) was extracted with water at 88.47 degrees C for 1.42 h with a solution to sample ratio of 10.94 mL g-1 employing response surface methodology. Four purified fractions, RBP-1, RBP-2, RBP-3, and RBP-4, were obtained from column chromatography of DEAE-52 and Sephadex G-100. Among these four purified fractions, RBP-1, RBP-2, RBP-4 were mainly composed of glucose, while RBP-3 contained 41.36% mannose and 28.96% glucose. The molecular weights of RBP-1, RBP-2, RBP-3 and RBP-4 were 6.48, 36.12, 96.72 and 8.34 kDa, respectively. These four fractions are also tested for antioxidant activities in vitro, RBP-4 exhibited strong assay of reducing power and high scavenging activity on DPPH radical, while RBP-3 showed the stronger ability of hydroxyl radical scavenging activity. CONCLUSIONS: Response surface methodology was successfully applied to optimize the ultrasonic extraction of polysaccharides from R. botrytis. RBP is an efficient natural antioxidant. PMID- 28360931 TI - Mechanisms for the anti-obesity actions of bofutsushosan in high-fat diet-fed obese mice. AB - BACKGROUND: The Kampo medicine bofutsushosan (BTS; Pulvis ledebouriellae compositae; Fang Feng Tong Sheng San) has been used as an anti-obesity treatment in overweight patients. In this study, we assessed the underlying physiological changes induced by BTS in obese mice maintained on a high-fat diet. METHODS: Male ICR mice were fed a 60% kcal fat diet for 5 weeks starting at 4 weeks of age and then fed the same diet with administration of water (control) or aqueous BTS extract (1.0-2.0 g/kg) for 25 days. Body weight, wet weight of isolated white adipose tissue, and obesity-related serum parameters (glucose, lipids, leptin, adiponectin) were measured after treatment. The mRNA expression levels of leptin, adiponectin, and UCP1 in the adipose tissues were determined by quantitative real time polymerase chain reaction after the first 5 days of treatment. RESULTS: Bofutsushosan (1.5-2.0 g/kg) significantly decreased total body weight and total wet weight of white adipose tissue isolated from subcutaneous (retroperitoneal) and visceral regions (epididymal, mesenteric, and perirenal). At 2.0 g/kg, BTS also decreased total fat mass, visceral fat mass, and ratio of fat mass to body weight as measured by computed tomography, and significantly decreased epididymal adipocyte size after 14 and 25 days' treatment. Twenty-five days' treatment lowered serum glucose, insulin, leptin, and triglycerides, and reduced homeostasis model assessment-insulin resistance. Alternatively, 2.0 g/kg BTS significantly increased mRNA levels of adiponectin, leptin, and UCP1 in interscapular brown adipose tissue but not epididymal white adipose tissue after 5 days' administration. CONCLUSION: In the early administration period, BTS increased mRNA expression levels of leptin, adiponectin, and UCP1 in brown adipose tissues. With longer administration, BTS improved insulin resistance, and subsequently reduced serum levels of leptin and triglyceride in parallel with decreased visceral white adipose tissue volume and adipocyte size. PMID- 28360932 TI - Synthesis and in vitro antitumor activity of (1E,4E)-1-aryl-5-(2-((quinazolin-4 yl)oxy)phenyl)-1,4-pentadien-3-one derivatives. AB - BACKGROUND: Cancer is one of the leading causes of death and only second to heart diseases. Recently, preclinical studies have demonstrated that curcumin had a number of anticancer properties. Thus, we planned to synthesize a series of curcumin analogs to assess their antiproliferation efficacy. RESULTS: A series of (1E,4E)-1-aryl-5-(2-((quinazolin-4-yl)oxy)phenyl)-1,4-pentadien-3-one derivatives (curcumin analogs) were synthesized and characterized by IR, NMR, and elemental analysis techniques. All of the prepared compounds were screened for antitumor activities against MGC-803, PC3, and Bcap-37 cancer cell lines. A significant inhibition for cancer cells were observed with compound 5f and also less toxic on NIH3T3 normal cells. The mechanism of cell death induced by compound 5f was further investigated by acridine orange/ethidium bromide staining, Hoechst 33,258 staining, TUNEL assay, and flow cytometry cytometry, which revealed that the compound can induce cell apoptosis in MGC-803 cells. CONCLUSIONS: This study suggests that most of the derivatives could inhibit the growth of human cancer cell lines. In addition, compound 5f could induce apoptosis of cancer cells, and it should be subjected to further investigation as a potential anticancer drug candidate. PMID- 28360934 TI - Sleep disturbances and mental strain in university students: results from an online survey in Luxembourg and Germany. AB - OBJECTIVES: This study examined the prevalence of sleep disturbances and mental strain in students from two European countries, Luxembourg and Germany. METHODS: A total of 2831 students took part in an online survey, with 2777 students from Germany and 184 students from Luxembourg. Sleep disturbances were assessed with the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale, and aspects of mental strain using the Patient Health Questionnaire, the Social-Interactive Anxiety Scale, the self-efficacy questionnaire and the test anxiety questionnaire. In addition, we also assessed students' chronotypes. RESULTS: Across the whole sample mean scores on the sleep questionnaires were above the cut-off for clinically relevant sleep problems, indicating an increased prevalence of sleep disturbances in students from both countries. Sleep quality was impaired in 42.8%, and 17.9% showed clinically relevant scores. Overall 25.5% reported elevated depression and 13.3% social phobia symptoms, while 45% indicated elevated stress levels. Sleep quality, daytime sleepiness, chronotype, depression scores, stress levels, test anxiety, and self-efficacy differed significantly between men and women, but there were no differences between countries. CONCLUSIONS: Sleep disturbances and mental strain in students are common, with the current results replicating previous findings. Students from Luxembourg and Germany are affected equally. PMID- 28360935 TI - Portable nuclear magnetic resonance biosensor and assay for a highly sensitive and rapid detection of foodborne bacteria in complex matrices. AB - BACKGROUND: Nuclear magnetic resonance (NMR) technique is a powerful analytical tool in determining the presence of bacterial contaminants in complex biological samples. In this paper, a portable NMR-based (pNMR) biosensor and assay to detect the foodborne bacteria Escherichia coli O157:H7 is reported. It uses antibody functionalized polymer-coated magnetic nanoparticles as proximity biomarker of the bacteria which accelerates NMR resonance signal decay. RESULTS: The pNMR biosensor operates at 0.47 Tesla of magnetic strength and consists of a high power pulsed RF transmitter and an ultra-low noise sensing circuitry capable of detecting weak NMR signal at 0.1 MUV. The pNMR biosensor assay and sensing mechanism is used in detecting E. coli O157:H7 bacteria in drinking water and milk samples. Experimental results demonstrate that by adding a filtration step in the assay, the pNMR biosensor is able to detect E. coli O157:H7 as low as 76 CFU/mL in water samples and as low as 92 CFU/mL in milk samples in about one min. CONCLUSION: The pNMR biosensor assay and sensing system is innovative for foodborne bacterial detection in food matrices. The lowest detection level for E. coli O157:H7 in water and milk samples is essentially 101 CFU/mL. Although the linear range of detection is only from 101 to 104 CFU/mL, the wider detection range spans from 101 CFU/mL to 107 CFU/mL. Existing pNMR biosensors have detection limits at 103-104 CFU/mL only. The detection technique can be extended to other microbial or viral organisms by merely changing the specificity of the antibodies. Besides food safety, the pNMR biosensor described in this paper has potential to be applied as a rapid detection device in biodefense and healthcare diagnostic applications. PMID- 28360938 TI - Citrobacter amalonaticus Y19 for constitutive expression of carbon monoxide dependent hydrogen-production machinery. AB - BACKGROUND: Citrobacter amalonaticus Y19 is a good biocatalyst for production of hydrogen (H2) from oxidation of carbon monoxide (CO) via the so-called water-gas shift reaction (WGSR). It has a high H2-production activity (23.83 mmol H2 g-1 cell h-1) from CO, and can grow well to a high density on various sugars. However, its H2-production activity is expressed only when CO is present as an inducer and in the absence of glucose. RESULTS: In order to avoid dependency on CO and glucose, in the present study, the native CO-inducible promoters of WGSR operons (CO dehydrogenase, CODH, and CODH-dependent hydrogenase, CO-hyd) in Y19 were carefully analyzed and replaced with strong and constitutive promoters screened from Y19. One engineered strain (Y19-PR1), selected from three positive ones after screening ~10,000 colonies, showed a similar CO-dependent H2 production activity to that of wild-type Y19, without being affected by glucose and/or CO. Compared with wild-type Y19, transcription of the CODH operon in Y19 PR1 increased 1.5-fold, although that of the CO-hyd operon remained at a similar level. To enhance the activity of CO-Hyd in Y19-PR1, further modifications, including an increase in gene copy number and engineering of the 5' untranslated region, were attempted, but without success. CONCLUSIONS: Convenient recombinant Y19-PR1 that expresses CO-dependent H2-production activity without being limited by CO and glucose was obtained. PMID- 28360937 TI - Enhanced fermentative performance under stresses of multiple lignocellulose derived inhibitors by overexpression of a typical 2-Cys peroxiredoxin from Kluyveromyces marxianus. AB - BACKGROUND: Bioethanol from lignocellulosic materials is of great significance to the production of renewable fuels due to its wide sources. However, multiple inhibitors generated from pretreatments represent great challenges for its industrial-scale fermentation. Despite the complex toxicity mechanisms, lignocellulose-derived inhibitors have been reported to be related to the levels of intracellular reactive oxygen species (ROS), which makes oxidoreductase a potential target for the enhancement of the tolerance of yeasts to these inhibitors. RESULTS: A typical 2-Cys peroxiredoxin from Kluyveromyces marxianus Y179 (KmTPX1) was identified, and its overexpression was achieved in Saccharomyces cerevisiae 280. Strain TPX1 with overexpressed KmTPX1 gene showed an enhanced tolerance to oxidative stresses. Serial dilution assay indicated that KmTPX1 gene contributed to a better cellular growth behavior, when the cells were exposed to multiple lignocellulose-derived inhibitors, such as formic acid, acetic acid, furfural, ethanol, and salt. In particular, KmTPX1 expression also possessed enhanced tolerance to a mixture of formic acid, acetic acid, and furfural (FAF) with a shorter lag period. The maximum glucose consumption rate and ethanol generation rate in KmTPX1-expressing strain were significantly improved, compared with the control. The mechanism of improved tolerance to FAF depends on the lower level of intracellular ROS for cell survival under stress. CONCLUSION: A new functional gene KmTPX1 from K. marxianus is firstly associated with the enhanced tolerance to multiple lignocellulose-derived inhibitors in S. cerevisiae. We provided a possible detoxification mechanism of the KmTPX1 for further theoretical research; meanwhile, we provided a powerful potential for application of the KmTPX1 overexpressing strain in ethanol production from lignocellulosic materials. PMID- 28360939 TI - Techno-economic assessment of hybrid extraction and distillation processes for furfural production from lignocellulosic biomass. AB - BACKGROUND: Lignocellulosic biomass is one of the most promising alternatives for replacing mineral resources to overcome global warming, which has become the most important environmental issue in recent years. Furfural was listed by the National Renewable Energy Laboratory as one of the top 30 potential chemicals arising from biomass. However, the current production of furfural is energy intensive and uses inefficient technology. Thus, a hybrid purification process that combines extraction and distillation to produce furfural from lignocellulosic biomass was considered and investigated in detail to improve the process efficiency. This effective hybrid process depends on the extracting solvent, which was selected based on a comprehensive procedure that ranged from solvent screening to complete process design. RESULTS: Various solvents were first evaluated in terms of their extraction ability. Then, the most promising solvents were selected to study the separation feasibility. Eventually, processes that used the three best solvents (toluene, benzene, and butyl chloride) were designed and optimized in detail using Aspen Plus. Sustainability analysis was performed to evaluate these processes in terms of their energy requirements, total annual costs (TAC), and carbon dioxide (CO2) emissions. The results showed that butyl chloride was the most suitable solvent for the hybrid furfural process because it could save 44.7% of the TAC while reducing the CO2 emissions by 45.5% compared to the toluene process. In comparison with the traditional purification process using distillation, this suggested hybrid extraction/distillation process can save up to 19.2% of the TAC and reduce 58.3% total annual CO2 emissions. Furthermore, a sensitivity analysis of the feed composition and its effect on the performance of the proposed hybrid system was conducted. CONCLUSIONS: Butyl chloride was found to be the most suitable solvent for the hybrid extraction/distillation process of furfural production. The proposed hybrid sequence was more favorable than the traditional distillation process when the methanol fraction of the feed stream was <3% and more benefit could be obtained when that fraction decreased. PMID- 28360936 TI - Hybridization and adaptive evolution of diverse Saccharomyces species for cellulosic biofuel production. AB - BACKGROUND: Lignocellulosic biomass is a common resource across the globe, and its fermentation offers a promising option for generating renewable liquid transportation fuels. The deconstruction of lignocellulosic biomass releases sugars that can be fermented by microbes, but these processes also produce fermentation inhibitors, such as aromatic acids and aldehydes. Several research projects have investigated lignocellulosic biomass fermentation by the baker's yeast Saccharomyces cerevisiae. Most projects have taken synthetic biological approaches or have explored naturally occurring diversity in S. cerevisiae to enhance stress tolerance, xylose consumption, or ethanol production. Despite these efforts, improved strains with new properties are needed. In other industrial processes, such as wine and beer fermentation, interspecies hybrids have combined important traits from multiple species, suggesting that interspecies hybridization may also offer potential for biofuel research. RESULTS: To investigate the efficacy of this approach for traits relevant to lignocellulosic biofuel production, we generated synthetic hybrids by crossing engineered xylose-fermenting strains of S. cerevisiae with wild strains from various Saccharomyces species. These interspecies hybrids retained important parental traits, such as xylose consumption and stress tolerance, while displaying intermediate kinetic parameters and, in some cases, heterosis (hybrid vigor). Next, we exposed them to adaptive evolution in ammonia fiber expansion pretreated corn stover hydrolysate and recovered strains with improved fermentative traits. Genome sequencing showed that the genomes of these evolved synthetic hybrids underwent rearrangements, duplications, and deletions. To determine whether the genus Saccharomyces contains additional untapped potential, we screened a genetically diverse collection of more than 500 wild, non engineered Saccharomyces isolates and uncovered a wide range of capabilities for traits relevant to cellulosic biofuel production. Notably, Saccharomyces mikatae strains have high innate tolerance to hydrolysate toxins, while some Saccharomyces species have a robust native capacity to consume xylose. CONCLUSIONS: This research demonstrates that hybridization is a viable method to combine industrially relevant traits from diverse yeast species and that members of the genus Saccharomyces beyond S. cerevisiae may offer advantageous genes and traits of interest to the lignocellulosic biofuel industry. PMID- 28360940 TI - Comprehensive characterization of non-cellulosic recalcitrant cell wall carbohydrates in unhydrolyzed solids from AFEX-pretreated corn stover. AB - BACKGROUND: Inefficient carbohydrate conversion has been an unsolved problem for various lignocellulosic biomass pretreatment technologies, including AFEX, dilute acid, and ionic liquid pretreatments. Previous work has shown 22% of total carbohydrates are typically unconverted, remaining as soluble or insoluble oligomers after hydrolysis (72 h) with excess commercial enzyme loading (20 mg enzymes/g biomass). Nearly one third (7 out of 22%) of these total unconverted carbohydrates are present in unhydrolyzed solid (UHS) residues. The presence of these unconverted carbohydrates leads to a considerable sugar yield loss, which negatively impacts the overall economics of the biorefinery. Current commercial enzyme cocktails are not effective to digest specific cross-linkages in plant cell wall glycans, especially some of those present in hemicelluloses and pectins. Thus, obtaining information about the most recalcitrant non-cellulosic glycan cross-linkages becomes a key study to rationally improve commercial enzyme cocktails, by supplementing the required enzyme activities for hydrolyzing those unconverted glycans. RESULTS: In this work, cell wall glycans that could not be enzymatically converted to monomeric sugars from AFEX-pretreated corn stover (CS) were characterized using compositional analysis and glycome profiling tools. The pretreated CS was hydrolyzed using commercial enzyme mixtures comprising cellulase and hemicellulase at 7% glucan loading (~20% solid loading). The carbohydrates present in UHS and liquid hydrolysate were evaluated over a time period of 168 h enzymatic hydrolysis. Cell wall glycan-specific monoclonal antibodies (mAbs) were used to characterize the type and abundance of non cellulosic polysaccharides present in UHS over the course of enzymatic hydrolysis. 4-O-methyl-d-glucuronic acid-substituted xylan and pectic arabinogalactan were found to be the most abundant epitopes recognized by mAbs in UHS and liquid hydrolysate, suggesting that the commercial enzyme cocktails used in this work are unable to effectively target those substituted polysaccharide residues. CONCLUSION: To our knowledge, this is the first report using glycome profiling as a tool to dynamically monitor recalcitrant cell wall carbohydrates during the course of enzymatic hydrolysis. Glycome profiling of UHS and liquid hydrolysates unveiled some of the glycans that are not cleaved and enriched after enzyme hydrolysis. The major polysaccharides include 4-O-methyl-d-glucuronic acid substituted xylan and pectic-arabinogalactan, suggesting that enzymes with glucuronidase and arabinofuranosidase activities are required to maximize monomeric sugar yields. This methodology provides a rapid tool to assist in developing new enzyme cocktails, by supplementing the existing cocktails with the required enzyme activities for achieving complete deconstruction of pretreated biomass in the future. PMID- 28360942 TI - Comparing the speed of irrigation between pulsatile lavage versus gravity irrigation: an Ex-vivo experimental investigation. AB - BACKGROUND: The need for reoperation or wound infection treatments between pulsatile and gravity irrigation are statistically equivalent, however, it is unclear which method maximizes operative efficiency and expeditious irrigation. In this study we set out to determine the differences in irrigation rate between these various treatment methods. METHODS: This was an ex-vivo experimental laboratory study not involving human subjects. Irrigation rates were tested based on the time in seconds required to empty a three-liter bag of normal saline hanging at either 6 or 9 ft. Three forms of irrigation were tested: gravity irrigation (GI6, GI9), low-pressure pulsatile irrigation (LP6, LP9) and high pressure pulsatile irrigation. One-way ANOVA and Student's t-test were used to compare rates based on height and form of irrigation. RESULTS: Significant differences in irrigation rates were noted at 6 ft between all three forms of irrigation with gravity irrigation the fastest followed by high-pressure and low pressure pulsatile irrigation (GI6, mean 142 s +/- 3.2; HP6, mean 189 s +/- 10.2; LP6, mean 323 s +/- 22.5; p < 0.001). This difference was also found at 9 ft (GI9, mean 114 s +/- 1.5; HP9, mean 186 s +/- 10.5; LP9, mean 347 s +/- 3.5; p < 0.001). Gravity irrigation was significantly faster (p < 0.001) at an increased height, whereas the high and low-pressure irrigation rates were unaffected by height. List price comparison found pulsatile irrigation to cost approximately 3.3 times more than gravity lavage. CONCLUSIONS: Gravity irrigation provided the most rapid rate of irrigation tested, regardless of the height. With existing literature demonstrating equivalent clinical outcomes between methods, gravity lavage offers a faster and potentially more cost-effective form of irrigation. PMID- 28360941 TI - Co-production of hydrogen and ethanol from glucose in Escherichia coli by activation of pentose-phosphate pathway through deletion of phosphoglucose isomerase (pgi) and overexpression of glucose-6-phosphate dehydrogenase (zwf) and 6-phosphogluconate dehydrogenase (gnd). AB - BACKGROUND: Biologically, hydrogen (H2) can be produced through dark fermentation and photofermentation. Dark fermentation is fast in rate and simple in reactor design, but H2 production yield is unsatisfactorily low as <4 mol H2/mol glucose. To address this challenge, simultaneous production of H2 and ethanol has been suggested. Co-production of ethanol and H2 requires enhanced formation of NAD(P)H during catabolism of glucose, which can be accomplished by diversion of glycolytic flux from the Embden-Meyerhof-Parnas (EMP) pathway to the pentose phosphate (PP) pathway in Escherichia coli. However, the disruption of pgi (phosphoglucose isomerase) for complete diversion of carbon flux to the PP pathway made E. coli unable to grow on glucose under anaerobic condition. RESULTS: Here, we demonstrate that, when glucose-6-phosphate dehydrogenase (Zwf) and 6-phosphogluconate dehydrogenase (Gnd), two major enzymes of the PP pathway, are homologously overexpressed, E. coli Deltapgi can recover its anaerobic growth capability on glucose. Further, with additional deletions of DeltahycA, DeltahyaAB, DeltahybBC, DeltaldhA, and DeltafrdAB, the recombinant Deltapgi mutant could produce 1.69 mol H2 and 1.50 mol ethanol from 1 mol glucose. However, acetate was produced at 0.18 mol mol-1 glucose, indicating that some carbon is metabolized through the Entner-Doudoroff (ED) pathway. To further improve the flux via the PP pathway, heterologous zwf and gnd from Leuconostoc mesenteroides and Gluconobacter oxydans, respectively, which are less inhibited by NADPH, were overexpressed. The new recombinant produced more ethanol at 1.62 mol mol-1 glucose along with 1.74 mol H2 mol-1 glucose, which are close to the theoretically maximal yields, 1.67 mol mol-1 each for ethanol and H2. However, the attempt to delete the ED pathway in the Deltapgi mutant to operate the PP pathway as the sole glycolytic route, was unsuccessful. CONCLUSIONS: By deletion of pgi and overexpression of heterologous zwf and gnd in E. coli DeltahycA DeltahyaAB DeltahybBC DeltaldhA DeltafrdAB, two important biofuels, ethanol and H2, could be successfully co-produced at high yields close to their theoretical maximums. The strains developed in this study should be applicable for the production of other biofuels and biochemicals, which requires supply of excessive reducing power under anaerobic conditions. PMID- 28360943 TI - Age-related reduction and independent predictors of toe flexor strength in middle aged men. AB - BACKGROUND: Toe flexor muscles play an important role in posture and locomotion, and poor toe flexor strength is a risk factor for falls. In this cross-sectional study, we estimated the age-related change in toe flexor strength and compared it with that of handgrip strength. Independent factors predicting toe flexor and handgrip strength were also determined. METHODS: A total of 1401 male (aged 35-59 years) study participants were divided into five groups according to their chronological age; 35-39, 40-44, 45-49, 50-54, and 55-59 years. Toe flexor and handgrip strength, anthropometry, and resting blood pressure were measured. Fasting blood samples were collected to measure blood glucose, triglycerides, high- and low-density lipoprotein-cholesterols, and albumin. A self-administered lifestyle questionnaire was conducted. RESULTS: Decline in absolute toe flexor and handgrip strength began in the age groups 50-55 and 55-59 years, respectively. In comparison to the mean values of the youngest group, relative toe flexor strength (87.0 +/- 26.6%) was significantly lower than handgrip strength (94.4 +/- 13.1%) for the oldest group. Multiple regression analyses showed that independent factors predicting both toe flexor and handgrip strength were lean body mass, age, serum albumin, drinking habit, and fat mass. Additionally, fasting blood glucose, diastolic blood pressure, sleeping time and exercise habit were predicting factors of toe flexor strength but not of handgrip strength. CONCLUSIONS: Age-related reduction in toe flexor strength was earlier and greater than handgrip strength, and toe flexor strength reflects body composition and metabolic status. PMID- 28360944 TI - Multiaxial Polarity Determines Individual Cellular and Nuclear Chirality. AB - Intrinsic cell chirality has been implicated in the left-right (LR) asymmetry of embryonic development. Impaired cell chirality could lead to severe birth defects in laterality. Previously, we detected cell chirality with an in vitro micropatterning system. Here, we demonstrate for the first time that chirality can be quantified as the coordination of multiaxial polarization of individual cells and nuclei. Using an object labeling, connected component based method, we characterized cell chirality based on cell and nuclear shape polarization and nuclear positioning of each cell in multicellular patterns of epithelial cells. We found that the cells adopted a LR bias the boundaries by positioning the sharp end towards the leading edge and leaving the nucleus at the rear. This behavior is consistent with the directional migration observed previously on the boundary of micropatterns. Although the nucleus is chirally aligned, it is not strongly biased towards or away from the boundary. As the result of the rear positioning of nuclei, the nuclear positioning has an opposite chirality to that of cell alignment. Overall, our results have revealed deep insights of chiral morphogenesis as the coordination of multiaxial polarization at the cellular and subcellular levels. PMID- 28360945 TI - Epigenetic signatures of gestational diabetes mellitus on cord blood methylation. AB - BACKGROUND: Intrauterine exposure to gestational diabetes mellitus (GDM) confers a lifelong increased risk for metabolic and other complex disorders to the offspring. GDM-induced epigenetic modifications modulating gene regulation and persisting into later life are generally assumed to mediate these elevated disease susceptibilities. To identify candidate genes for fetal programming, we compared genome-wide methylation patterns of fetal cord bloods (FCBs) from GDM and control pregnancies. METHODS AND RESULTS: Using Illumina's 450K methylation arrays and following correction for multiple testing, 65 CpG sites (52 associated with genes) displayed significant methylation differences between GDM and control samples. Four candidate genes, ATP5A1, MFAP4, PRKCH, and SLC17A4, from our methylation screen and one, HIF3A, from the literature were validated by bisulfite pyrosequencing. The effects remained significant after adjustment for the confounding factors maternal BMI, gestational week, and fetal sex in a multivariate regression model. In general, GDM effects on FCB methylation were more pronounced in women with insulin-dependent GDM who had a more severe metabolic phenotype than women with dietetically treated GDM. CONCLUSIONS: Our study supports an association between maternal GDM and the epigenetic status of the exposed offspring. Consistent with a multifactorial disease model, the observed FCB methylation changes are of small effect size but affect multiple genes/loci. The identified genes are primary candidates for transmitting GDM effects to the next generation. They also may provide useful biomarkers for the diagnosis, prognosis, and treatment of adverse prenatal exposures. PMID- 28360946 TI - Associations of LEP, CRH, ICAM-1, and LINE-1 methylation, measured in saliva, with waist circumference, body mass index, and percent body fat in mid-childhood. AB - BACKGROUND: Genetics explains a small proportion of variance in body mass index at the population level. Epigenetics, commonly measured by gene methylation, holds promise for understanding obesity risk factors and mechanisms. METHODS: Participants were 431 adolescents aged 10-15 years. BMI z-score, waist circumference z-score, and percent body fat were measured. Saliva samples were collected and methylation of promoter regions of four candidate genes or sequences (LEP, ICAM-1, CRH, and LINE-1) were measured in 3-4 CpG sites each. Linear regression was used to identify associations of methylation with obesity related outcomes. RESULTS: After adjusting for age, in sex-stratified analysis, the three obesity-related outcomes were negatively associated with LEP methylation in obese boys only. There were no associations of methylation of the other genes or sequences and the obesity-related outcomes. CONCLUSIONS: Our results are consistent with prior studies that reported sex differences in associations of obesity-related outcomes with LEP methylation, and also as would be expected in adipose tissue, the source of circulating leptin. The findings suggest that saliva might be an acceptable tissue for epigenetics studies in adolescents. PMID- 28360947 TI - A novel method for isolation of histones from serum and its implications in therapeutics and prognosis of solid tumours. AB - BACKGROUND: Dysregulation in post-translational modifications of histones and their modifiers are now well-recognized as a hallmark of cancer and can be used as biomarkers and potential therapeutic targets for disease progression and prognosis. In most solid tumours, a biopsy is challenging, costly, painful or potentially risky for the patient. Therefore, non-invasive methods like 'liquid biopsy' for analysis of histone modifications and their modifiers if possible will be helpful in the better clinical management of cancer patients. METHODS: Here, we have developed a cost-effective and time-efficient protocol for isolation of circulating histones from serum of solid tumor, HCC, called Dual Acid Extraction (DAE) protocol and have confirmed by mass spectrometry. Also, we measured the activity of HDACs and HATs in serum samples. RESULTS: The serum purified histones were profiled for changes in histone PTMs and have shown a comparable pattern of modifications like acetylation (H4K16Ac), methylation (H4K20Me3, H3K27Me3, H3K9Me3) and phosphorylation (gamma-H2AX and H3S10P) to paired cancer tissues. Profiling for the histone PTM changes in various other organs of normal and tumor bearing animal suggests that the changes in the histone PTMs observed in the tumor serum is indeed due to changes in the tumor tissue only. Further, we demonstrate that the observed hypo-acetylation of histone H4 in tissue and serum samples of tumor bearing animals corroborated with the elevated HDAC activity in both samples compared to normal. Interestingly, human normal and tumor serum samples also showed elevated HDAC activity with no significant changes in HAT activity. CONCLUSIONS: Our study provides the first evidence in the context of histone PTMs and modifiers that liquid biopsy is a valuable predictive tool for monitoring disease progression. Importantly, with the advent of drugs that target specific enzymes involved in the epigenetic regulation of gene expression, liquid biopsy-based 'real time' monitoring will be useful for subgrouping of the patients for epi-drug treatment, predicting response to therapy, early relapse and prognosis. PMID- 28360948 TI - Are Mindfulness and Self-Compassion Related to Psychological Distress and Communication in Couples Facing Lung Cancer? A Dyadic Approach. AB - Lung cancer patients and their spouses report high rates of distress. Due to the increasing popularity of and evidence for mindfulness-based interventions in cancer, mindfulness and self-compassion have been identified as potentially helpful skills when coping with cancer. This dyadic study examined how mindfulness and self-compassion are related to psychological distress and communication about cancer in couples facing lung cancer. Using the actor-partner interdependence model, self-reported mindfulness, self-compassion, psychological distress and communication about cancer were analyzed in a cross-sectional sample of 88 couples facing lung cancer. Regarding psychological distress, no difference was found between patients and spouses. In both partners, own levels of mindfulness (B = -0.19, p = .002) and self-compassion (B = -0.45, p < .001) were negatively related to own distress levels. At a dyadic level, own self-compassion was less strongly associated with distress if the partner reported high self compassion (B = 0.03, p = .049). Regarding communication about cancer, patients reported to communicate more openly with their partner than with spouses. However, after controlling for gender, this difference was no longer significant. In both partners, own self-compassion (B = 0.03, p = .010) was significantly associated with own communication while mindfulness was not. A trend showed that mindfulness of the partner was related to more open communication in the individual (B = 0.01, p = .080). These findings give a first indication that mindfulness and self-compassion skills may go beyond the individual and could impact couple functioning. Future research should examine whether couples facing (lung) cancer may benefit from programs in which mindfulness and self-compassion are cultivated. PMID- 28360950 TI - Management of pelvic fracture-associated urethral injuries: A survey of Canadian urologists. AB - INTRODUCTION: The management of pelvic fracture-associated urethral injuries (PFUI) is not standardized and optimal management is controversial. We surveyed Canadian urologists about their experiences and opinions regarding optimal management of PFUI. METHODS: Canadian urologists were surveyed via an anonymous, bilingual, web-based, 12-item questionnaire. A total of 735 Canadian urologists were invited to participate via email distributed by the Canadian Urological Association. RESULTS: Of the 146 urologists who participated (19.9% response rate), the majority practice at a trauma centre (53.2%), but manage only 1-5 PFUI/year (71.5%). Most participants (82.6%) favour primary realignment compared to suprapubic (SP) tube with delayed repair (15.3%) and immediate reconstruction (2.1%). Compared to SP diversion and delayed repair, the majority of participants believe primary realignment is associated with equivocal incontinence (61.2%) and erectile dysfunction rates (75.8%), but has lower stricture rates (73.0%). Among respondents who perform primary realignment, 45.4% concurrently place a SP tube, while 54.6% do not. While 91% believe SP tubes do not increase the risk of pelvic hardware infections, 31.6% report that orthopedic surgeons alter their management of pelvic fractures in the presence of a SP tube. CONCLUSIONS: Most Canadian urologist respondents - even those practicing at trauma centres - manage very few PFUIs/year. There is reasonable consensus among respondents that primary realignment is favourable to delayed or immediate reconstruction, but discordance on whether or not to place concurrent SP tubes. The urological and orthopedic consequences of SP tubes in the management of traumatic urological injuries warrant further investigation. PMID- 28360951 TI - Intravesical formalin for hemorrhagic cystitis: A contemporary cohort. AB - INTRODUCTION: Hemorrhagic cystitis presents a difficult clinical challenge, yet data regarding treatment options is sparse. Here, we sought to evaluate outcomes of a contemporary cohort of patients treated with intravesical formalin for hemorrhagic cystitis. METHODS: We identified a retrospective cohort of eight patients managed with formalin for hemorrhagic cystitis from 2000-2014. All patients failed prior measures, including bladder irrigation, clot evacuation, and other intravesical agents. Treatment success was defined as hematuria resolution during the given hospitalization without use of additional invasive therapies. We also evaluated treatment complications and additional treatments following hospital dismissal. RESULTS: Etiology of cystitis was radiation for malignancy in all cases. The formalin concentration ranged from 1-4%, with escalation used in treatment failures. Five patients (62.5%) received a single dose of 1% formalin, two patients received two doses, and one patient received three doses. Notably, intraoperative cystography identified vesicoureteral reflux (VUR) in 50.0% of patients. Six patients (75.0%) achieved treatment success, with a median time to resolution of four days (range 1-17 days). Of those refractory to formalin, one was managed with indwelling nephrostomy tubes and one underwent cystectomy. Median followup was eight months. Of the responders, two eventually required cystectomy, one for recurrent hematuria and one for recalcitrant bladder neck contracture and bladder dysfunction. The remaining four patients (50%) required no additional therapy. CONCLUSIONS: Formalin remains an important tool for treating refractory hemorrhagic cystitis, with roughly 75.0% of patients requiring no additional therapy prior to hospital discharge. Notably, there is a risk of bladder dysfunction following formalin. PMID- 28360949 TI - CUA guideline on the management of cystic renal lesions. PMID- 28360953 TI - Diabetes and elevated urea level predict for uretero-ileal stricture after radical cystectomy and ileal conduit formation. AB - INTRODUCTION: Benign uretero-ileal anastomotic stricture is a significant complication following radical cystectomy and ileal conduit urinary diversion after radical cystectomy. We examined risk factors for stricture formation to predict those at greatest stricture risk. METHODS: A retrospective chart review was conducted for patients undergoing radical cystectomy and ileal conduit diversion between 2002 and 2012. Demographic data and patient variables were analyzed to determine risk factors for uretero-ileal stricture using multivariate logistic regression. RESULTS: Over the study period, 133 patients underwent cystectomy and ileal conduit formation, with 14 (10.5%) developing uretero-ileal anastomotic stricture. Diabetes and elevated serum urea level (defined as >7.1 mmol/L) were associated with increased risk for development of uretero-ileal stricture (odds ratio 4.31 and 4.28, respectively; p<0.05 for each). CONCLUSIONS: In this patient cohort, diabetes and elevated serum urea level were predictive for the development of uretero-ileal anastomotic stricture. Further prospective study with larger patient samples is required. PMID- 28360952 TI - Urogynecological conditions associated with overactive bladder symptoms in women. AB - INTRODUCTION: Overactive bladder symptoms (OAB) affect 9-43% of women and are associated with underlying disorders, including pelvic organ prolapse (POP) and stress urinary incontinence (SUI). The aim of this study is to identify urogynecological conditions associated with OAB symptoms. METHODS: This prospective, institutional review board-approved study included women referred to a tertiary centre with lower urinary tract symptoms (LUTS). All women completed the self-administered OAB questionnaire (OABSS). Those with an OABSS >=8, the cutoff, were considered to have OAB symptoms. Patients underwent a history and physical examination (including Baden-Walker prolapse grading and stress test), 24-hour voiding diary, pad test (for urinary incontinence), urinalysis, and uroflow with post-void residual volume. Patients were classified clinically into the following: idiopathic OAB, SUI, POP, bladder outlet obstruction (BOO) neurogenic bladder (NGB), recurrent urinary tract infection (UTI), and miscellaneous. RESULTS: In total, 148 women met the inclusion criteria with a mean age of 67 years. Only 27% had no comorbid conditions and were considered idiopathic OAB. Associated urogynecological conditions included SUI in 37%, POP in 26%, miscellaneous conditions in 18%, recurrent UTI in 11%, NGB in 9%, and BOO in 8%. Some patients met criteria for more than one category, thus the total is greater than 100%. CONCLUSIONS: In a tertiary care setting, a significant proportion of women with OAB symptoms have underlying conditions that may cause or contribute to their symptoms. Appropriate evaluation is desirable to enhance our understanding of the relationship of these conditions to the diagnosis, treatment, outcomes, and pathophysiology of OAB. PMID- 28360954 TI - Impact of preoperative and postoperative membranous urethral length measured by 3 Tesla magnetic resonance imaging on urinary continence recovery after robotic assisted radical prostatectomy. AB - INTRODUCTION: We sought to investigate the impact of preoperative and postoperative membranous urethral length (MUL) on urinary continence using 3 Tesla (3T) magnetic resonance imaging (MRI) after robotic-assisted radical prostatectomy (RARP). METHODS: Between 2008 and 2013, 190 men with RARP underwent preoperative and postoperative MRI. Patients who received adjuvant radiotherapy or who were lost to followup were excluded, leaving 186 patients eligible for analysis. Preoperative MUL was estimated from the prostate apex to the penile bulb, while postoperative MUL was estimated from the bladder neck to penile bulb. Patients with no pads or protection were considered to have complete continence. Logistic regression analysis was used to identify predictors associated with urinary incontinence at six and 12 months. RESULTS: Age was commonly associated with urinary incontinence at six and 12 months. In addition, diabetes mellitus (DM) was another factor associated with urinary incontinence at 12 months. When adjusting these variables, preoperative MUL <=16 mm (95% confidence interval [CI] 1.01-1.14; p=0.022), postoperative MUL <=14 mm (95% CI 1.16-9.80; p=0.025) and percent change of MUL >18% (95% CI 1.17-7.23; p=0.021) were significantly associated with urinary incontinence at six months. However, at 12 months, preoperative MUL <=13.5 mm (95% CI 1.85-19.21; p=0.003) and postoperative MUL <=13 mm (95% CI 1.24-13.84; p=0.021) had impacts on urinary incontinence, but not percent change of MUL. CONCLUSIONS: Preoperative and postoperative MUL were significantly associated with urinary continence recovery after RARP. Therefore, efforts to preserve MUL are highly recommended during surgery for optimal continence outcomes after RARP. PMID- 28360955 TI - Is testis-sparing surgery safe in small testicular masses? Results of a multicentre study. AB - INTRODUCTION: Our goal was to evaluate benign and malignant lesions and testicular intraepithelial neoplasia (TIN) in the neighbouring normal-appearing testis tissue in men who underwent radical orchiectomy for testicular mass with a pathologic tumour size of <=3cm. METHODS: In this retrospective, multicentre study, data of 252 patients from 11 different institutions were included. Patients were divided into three groups based on tumour size: Group 1 (0-1 cm; n=35), Group 2 (1.1-2cm; n=99), and Group 3 (2.1-3 cm; n=118). Benign lesions and TIN were sought in the neighbouring testicular tissue and compared between groups. RESULTS: Mean patient age was 32.3 years. Benign lesions were reported in 54.3%, 33.3%, and 14.4% of Groups 1, 2, and 3, respectively (p<0.05 between groups). TIN was detected in 20%, 42.4%, and 41.5% of Groups 1, 2, and 3, respectively (p<0.05 for Group 1 vs. Groups 2 and 3; p>0.05 for Groups 2 vs. 3). Multifocality was detected in 8.6%, 4%, and 0% of Groups 1, 2, and 3, respectively (p<0.05 for both Group 1 vs. Group 3 and for Group 2 vs. Group 3; p>0.05 for Group 1 vs. Group 2). A tumour cutoff size of 1.5 cm was found to be significant for detecting benign tumour. TIN and multifocality rates were similar in patients with a tumour size of <=1.5 vs. >1.5 cm (p>0.05). CONCLUSIONS: Benign lesions and TIN in the neighbouring testis were significantly decreased and multifocality was increased in patients with a tumour mass size of <=1 cm. Testis sparing surgery should be performed with caution and a safety rim of normal tissue should also be excised. PMID- 28360956 TI - Shock due to urosepsis: A multicentre study. AB - INTRODUCTION: Urosepsis is a severe infection that can cause shock afterwards. The purpose of this study is to investigate the clinical and bacterial risk factors for shock in those cases with urosepsis caused by urinary tract infection in a multicentre study. METHODS: Our study included 77 consecutive urosepsis cases from four hospitals. We examined factors such as patient characteristics, underlying disease, serum white blood cell (WBC) count, platelet count, C reactive protein (CRP) level at the time of diagnosis of urosepsis, urinary tract occlusion, causative bacteria, and bacterial antibiotic susceptibilities. Statistical analyses were performed to assess the potential risk factors for shock during the clinical course of urosepsis by a multivariate analysis. RESULTS: We had 38 male and 39 female patients aged 25-104 (median 73). Underlying diseases included cancers (n=22, 28.6 %) and diabetes mellitus (n=17, 22.1 %). Positive blood culture was seen in 74 cases; these involved 88 bacterial strains, of which Escherichia coli was the most common (34 strains, 38.6 %). There were 31 cases with shock (40.3 %) and multivariate analyses demonstrated that serum CRP was the only clinical risk factor for shock due to urosepsis. CONCLUSIONS: Our study demonstrated that serum CRP was a risk factor for shock during urosepsis in a multicentre analysis. Further prospective studies with a greater number of patients are needed to draw more definitive conclusions. PMID- 28360958 TI - Rare complication of needleless mini-sling procedure: Case report. AB - The mini-sling procedure is a widely used, minimally invasive treatment for stress urinary incontinence. While bladder perforation and stone formation over the mesh is not an expected complication of the mini-sling procedure, in this case, we report on the management of bladder calculi formed over the mesh, which was passed through the bladder while applying the mini-sling procedure, and was eventually removed using holmium laser. Performing cystoscopy in patients with irritative and obstructive symptoms after the sling procedure will help confirm bladder perforation, and an endoscopic approach using holmium laser is an effective treatment. PMID- 28360957 TI - Treatment of lower urinary tract symptoms in multiple sclerosis patients: Review of the literature and current guidelines. AB - Multiple sclerosis (MS) is a unique neurological disease with a broad spectrum of clinical presentations that are time- and disease course-related. Lower urinary tract symptoms (LUTS) are highly prevalent in this patient population, with approximately 90% showing some degree of voiding dysfunction and/or incontinence 6-8 years after the initial MS diagnosis. Major therapeutic goals include quality of life improvement and the avoidance of urological complications Owing to the wide divergence of clinical symptoms and disease course, evaluation and treatment differ between patients. Treatment must be customized for each patient based on disease phase, patient independence, manual dexterity, social support, and other medical- or MS-related issues. Ablative or irreversible therapies are indicated only when the disease course is stable. In most cases of "safe" bladder, behavioural treatment is considered first-line defense. Antimuscarinic drugs, alone or in combination with intermittent self-catheterization, are currently the mainstay of conservative treatment, and several other medications may help in specific disease conditions. Second-line treatment includes botulinum toxin A injection, neuromodulation, indwelling catheters, and surgery in well-selected cases. PMID- 28360959 TI - A case of epidermoid median raphe cyst traversing the corpora cavernosa. AB - Median raphe cysts are congenital lesions that typically have a superficial appearance. We present a very unusual case of a deep perineal mass in a six-year old boy. The lesion extends into the corpus cavernosum, suggesting that the anomaly was an early embryological event. Histopathological features are consistent with an epidermoid type of median raphe cyst. PMID- 28360960 TI - Clomiphene citrate rescue of spermatogenesis in men with infertility while remaining on finasteride: A case report. PMID- 28360961 TI - Flexible cystoscope retrieval of detached resectoscope sheath beak. PMID- 28360963 TI - Assessing eosinophilic cationic protein as a biomarker for monitoring patients with eosinophilic esophagitis treated with specific exclusion diets. AB - BACKGROUND: Eosinophilic esophagitis (EoE) is a complex pathology. Attempts have been made in order to relate EoE with the intake of certain food. The problem is to establish which foods are really involved in the pathophysiology of this condition and to objectify a reliable inflammation biomarker for the follow-up of patients undergoing pharmacological treatment and/or diets. Our aim is to assess the food sensitization profile of patients with objective diagnosis of EoE and objectify the utility of ECP as an inflammation biomarker for the follow-up of patients with EoE treated with specific diets, based on the hypothesis that we will observe a decrease and clinical improvement after maintenance of these diets. METHODS: A total of 19 subjects were included between 1 January 2012 and 30 June 2015. Diets based on allergy testing were established. Prior to the initiation of the diets, baseline ECP was determined. Appointments were arranged for the patients between 4 and 6 months later to assess the clinical response to the specific diets and to request a second blood sample for blood counts and serum ECP levels to compare with the previous baseline. RESULTS: 19 patients diagnosed with EoE (12 males and 7 females) between January 2012 and June 2015, aged between 17 and 68 (33.52; SD 13.67 years), were included consecutively, 15 of whom showed optimum response to specific diets based on allergy testing. A statistically significant difference ECP decrease was observed in our patients. DISCUSSION: Until now most of the studies previously published in reference to the use of ECP as a biomarker for monitoring patients on treatment with diets show consistent but insignificant decreases in ECP levels. However, ECP seems to be a good marker of inflammation if the determinations are performed avoiding confounding factors. CONCLUSION: The serial determination of ECP is useful when monitoring patients with EoE treated with specific diets. PMID- 28360964 TI - Picosecond Lasers: A New and Emerging Therapy for Skin of Color, Minocycline induced Pigmentation, and Tattoo Removal. PMID- 28360965 TI - A Closer Look at Seborrheic Keratoses: Patient Perspectives, Clinical Relevance, Medical Necessity, and Implications for Management. AB - The author sought to discover why seborrheic keratoses that are not symptomatic or clinically suspicious are not considered therapeutically important to most clinicians. The author conducted an office-based, observational study examining how the diagnosis of asymptomatic seborrheic keratoses personally affects patients and what these patients think concerning treatment. Many patients reported being bothered by the diagnosis of seborrheic keratoses, even when told it's not cancerous, and indicated an interest in its treatment. Lack of insurance coverage for the treatment of non-symptomatic seborrheic keratoses may be the primary reason clinicians do not consider seborrheic keratoses therapeutically important, as clinicians often find the discussion of "self payment" with their patients to be awkward. Furthermore, patients may not understand the implications that "lack of medical necessity" may have on their treatment options. The author describes a clinical approach that may better serve patients and clinicians through the compartmentalization of asymptomatic seborrheic keratoses treatment as a cosmetic procedure within the clinical practice model. PMID- 28360962 TI - Novel Immune Mechanisms in Hypertension and Cardiovascular Risk. AB - PURPOSE OF REVIEW: Hypertension is a common disorder with substantial impact on public health due to highly elevated cardiovascular risk. The mechanisms still remain unclear and treatments are not sufficient to reduce risk in majority of patients. Inflammatory mechanisms may provide an important mechanism linking hypertension and cardiovascular risk. We aim to review newly identified immune and inflammatory mechanisms of hypertension with focus on their potential therapeutic impact. RECENT FINDINGS: In addition to the established role of the vasculature, kidneys and central nervous system in pathogenesis of hypertension, low-grade inflammation contributes to this disorder as indicated by experimental models and GWAS studies pointing to SH2B3 immune gene as top key driver of hypertension. Immune responses in hypertension are greatly driven by neoantigens generated by oxidative stress and modulated by chemokines such as RANTES, IP-10 and microRNAs including miR-21 and miR-155 with other molecules under investigation. Cells of both innate and adoptive immune system infiltrate vasculature and kidneys, affecting their function by releasing pro-inflammatory mediators and reactive oxygen species. SUMMARY: Immune and inflammatory mechanisms of hypertension provide a link between high blood pressure and increased cardiovascular risk, and reduction of blood pressure without attention to these underlying mechanisms is not sufficient to reduce risk. PMID- 28360966 TI - Recurrent Aphthous Stomatitis: A Review. AB - Aphthous stomatitis is a painful and often recurrent inflammatory process of the oral mucosa that can appear secondary to various well-defined disease processes. Idiopathic recurrent aphthous stomatitis is referred to as recurrent aphthous stomatitis. The differential diagnosis for recurrent aphthous ulcerations is extensive and ranges from idiopathic benign causes to inherited fever syndromes, to connective tissue disease, or even inflammatory bowel diseases. A thorough history and review of systems can assist the clinician in determining whether it is related to a systemic inflammatory process or truly idiopathic. Management of aphthous stomatitis is challenging. For recurrent aphthous stomatitis or recalcitrant aphthous stomatitis from underlying disease, first-line treatment consists of topical medications with use of systemic medications as necessary. Herein, the authors discuss the differential diagnosis and treatment ladder of aphthous stomatitis as described in the literature. PMID- 28360968 TI - Molluscum Contagiosum Treated with Dilute Povidone-Iodine: A Series of Cases. AB - Objective: To report our experience using a broad spectrum antimicrobial, povidone-iodine, as a novel at-home prescription treatment for molluscum contagiosum. Design/Setting: A systematic review of cases presenting to one of the author's private dermatology clinics from January to July of 2015 identified 12 patients with molluscum contagiosum seeking treatment. Participants: The population was pediatric, with six males and six female patients included (age range 2-17 years, mean age 6 years). Measurements: Patients were evaluated at baseline and returned to the office for evaluation at four-week intervals until resolution or failure to show for appointments, with number and location of lesions being recorded at each visit. Adverse effects were evaluated at each visit. Results: All 12/12 (100%) patients demonstrated complete or partial resolution. There were a total of 115 lesions treated in the case series, and 103/115 (90%) resolved. Complete resolution occurred in 8/12 (67%) patients. Of the 8/12 with complete resolution, 4/8 (50%) patients showed complete resolution at the four-week follow-up visit and 4/8 (50%) showed complete resolution at the eight-week follow-up. Of the 4/12 (33%) patients who failed to demonstrate complete resolution, 4/4 (100%) showed partial resolution. Conclusion: This case series demonstrates considerable success for treatment of molluscum contagiosum with a dilute povidone-iodine preparation. The treatment was well-tolerated, with minimal side effects. PMID- 28360967 TI - Azelaic Acid Topical Formulations: Differentiation of 15% Gel and 15% Foam. AB - In this article, the author reviews topical formulations of azelaic acid used to treat papulopustular rosacea. Emphasis is placed on differences in vehicle technology and potential clinical impact of the possibility for neurosensory cutaneous tolerability reactions. PMID- 28360969 TI - Ticks and Tick Bites Presenting as "Funny Moles": A Review of Different Presentations and a Focus on Tick-borne Diseases. AB - Purpose: To describe a man with an adherent tick mimicking a melanoma, summarize the salient features of this condition, and review other cases of ticks mistaken for dermatoses. Background: Ticks are obligatory ectoparasites. Disease-causing ticks belong to two families: Ixodidae (hard ticks) and Argasidae (soft ticks). Ticks thrive by consuming blood from animal hosts, and the transfer of infected blood from one host to the next is the method by which ticks spread disease. Materials and methods: The authors describe a man who presented to their dermatology clinic in New York with an unusual black pigmented lesion on the right zygomatic region of his face. He was worried about how rapidly the lesion had developed and the tingling of the skin surrounding it. Since the patient had a history of nonmelanoma skin cancer, he was concerned that the lesion was a melanoma. An excisional biopsy of the lesion revealed a non-Ixodes tick with a surrounding tick-bite reaction. Results: Ticks cause cutaneous manifestations through physical trauma and their salivary contents. A number of reports describe a similar phenomenon of a persistent tick being mistaken for a nodule or tumor. Management includes complete removal of a tick, either mechanically or surgically, along with the appropriate work-up for tick-borne diseases in the relevant geographic location. The decision to test for systemic disease depends on the clinical presentation of the patient and geographic location of the tick bite. Conclusion: A patient presented to the authors' dermatology clinic with a pigmented lesion suspicious for a melanoma, but the lesion was actually an adherent non-Ixodes tick. This case illustrates the importance of keeping insects and arthropods in the differential diagnosis of a sudden- and recent-onset pigmented skin lesion. PMID- 28360970 TI - Pediatric Dermatology. AB - Skin changes are common in children. Common concerns are birthmarks (e.g., hemangiomas and port wine stains), atopic and contact dermatitis, acne, and alopecia areata. The authors review advances in common and not so common skin changes in pediatric patients. PMID- 28360971 TI - Psoriasis and Psoriatic Arthritis. AB - Psoriasis is a dynamic systemic disease that can have a profound affect on a patient's self-esteem. Fortunately, numerous therapeutic advances have been made over the last 10 years. In order to help patients manage their disease, healthcare providers should be aware of the modifiable risk factors that may exacerbate psoriasis. Additionally, exploring the impact the disease has on a patient and how it may change over their lifespan will help ensure appropriate therapies are used. Patients are unique so one medication will not fit all of our patients' needs. In this paper, the authors look at available treatment options for psoriasis and psoriatic arthritis. Educating psoriasis patients, in addition to collaborating with patients and other healthcare providers, may help initiate therapies that will result in patients living their lives to the fullest. PMID- 28360972 TI - Dermatology Roundup: The Latest Tips, Techniques, and Technologies for Busy Clinicians. AB - Rapid advances in use of technology and discovery of innovative therapeutic tips or clinically relevant epidemiological clues are discussed. Much of the literature-based review was drawn from somewhat non-traditional sources of dermatological information. PMID- 28360975 TI - Clipping prevents perforation in large, flat polyps. AB - AIM: To determine if prophylactic clipping of post-polypectomy endoscopic mucosal resection (EMR) mucosal defects of large, flat, right sided polyps prevents perforations. METHODS: IRB approved review of all colonoscopies, and prospective data collection of grasp and snare EMR performed by 2 endoscopists between January 1, 2010 and March 31, 2014 in a community ambulatory endoscopy center. The study consisted of two phases. In the first phase, all right-sided, flat polyps greater than or equal to 1.2 cm in size were removed using the grasp and snare technique. Clipping was done at the discretion of the endoscopist. In the second phase, all mucosal defects were closed using resolution clips. Phase 2 of the study was powered to detect a statistically significant difference in perforation rate with 148 EMRs, if less than or equal to 2 perforations occurred. RESULTS: In phase 1 of the study, 2121 colonoscopies were performed. Seventy-five patients had 95 large polyps removed. There were 4 perforations in 95 polypectomies (4.2%). The perforations occurred in polyps ranging in size from 1.5 cm to 2.5 cm. In phase 2, there were 2464 colonoscopies performed. One hundred and sixteen patients had 151 large polyps removed, and all mucosal defects were clipped. There were no perforations (P = 0.0016). There were no post polypectomy hemorrhages in either phase. An average of 2.15 clips were required to close the mucosal defects. The median time to perform the polypectomy and clipping was 13 min, and the median procedure duration was 40 min. Five percent of all patients undergoing colonoscopy in our community based, ambulatory endoscopy center had flat, right sided polyps greater than or equal to 1.2 cm in size. CONCLUSION: Prophylactic clipping of the mucosal resection defect of large, right-sided, flat polyps reduces the incidence of perforation. PMID- 28360974 TI - Utility of endoscopic retrograde cholangiopancreatography on biliopancreatic diseases in patients with Billroth II-reconstructed stomach. AB - AIM: To examine the utility of endoscopic retrograde cholangiopancreatography (ERCP) on biliopancreatic diseases in the patients with Billroth II-reconstructed stomach. METHODS: For 26 cases of biliopancreatic diseases in patients with Billroth II-reconstructed stomach, ERCP was conducted using a straight-view scope or a retrograde oblique-viewing endoscope. All the cases were patients aiming at selective insertion into the bile duct. One patient aimed at diagnosis, and 25 patients aimed at treatment. The cases in which the endoscope reached the duodenal papilla and anastomosis, and insertion into the bile duct became possible, were considered successful. RESULTS: The rate of reaching the duodenal papilla and anastomosis was 84.7% (22/26 patients). Among the cases without reaching the duodenal papilla and anastomosis, there were 2 in which the endoscope did not pass due to tumor-induced duodenal infiltration. In 1 case, the fiber did not reach the duodenal papilla due to long afferent loop. The success rate of insertion into the bile duct in patients in which the endoscope reached the duodenal papilla and anastomosis was 90.9% (20/22 patients), and the success rate of procedures including treatment was 86.3% (19/22 patients). After treatment, mild cholangitis was observed in 1 patient (4.5%, 1/22 patients) but relieved conservatively. No other accidental symptom was observed. CONCLUSION: It was considered that the ERCP for biliopancreatic diseases in patients with Billroth II-reconstructed stomach will become a less invasive, safe and useful examination and treatment approach. PMID- 28360976 TI - Langerhans cell histiocytosis masquerading as acute appendicitis: Case report and review. AB - Langerhans cell histiocytosis (LCH) is a rare syndrome characterized by unifocal, multifocal unisystem, or disseminated/multi-system disease that commonly involves the bone, skin, lymph nodes, pituitary, or sometimes lung (almost exclusively in smokers) causing a variety of symptoms from rashes and bone lesions to diabetes insipidus or pulmonary infiltrates. We present a previously unreported case of gastrointestinal LCH as well as a novel characteristic lesion affecting the colon of a young woman who presented with signs and symptoms mimicking acute on chronic appendicitis. Immunohistochemical analysis of appendectomy specimen and nodular specimens on colonoscopy demonstrated S-100, CD1a, and langerin reactivity. The patient underwent systemic chemotherapy with cytarabine and demonstrated excellent response to therapy. PMID- 28360977 TI - Endoscopic retrograde cholangiopancretography in modified double tracks anastomosis with anastomotic stenosis. AB - A 63-year-old man presented at our hospital with right upper abdomen pain and fever for 4 d. The patient's magnetic resonance cholangiopancreatography revealed dilated common bile duct and choledocholithiasis. In his past history, he received proximal gastrectomy and modified double tracks anastomosis. Endoscopic retrograde cholangiopancretography in modified double tracks anastomosis, especially accompanied with anastomotic stenosis, has been rarely reported. In the present case, the duodenoscope was successfully introduced over the guidewire and the stone taken out using a basket. The patient had good palliation of his symptoms after removal of the stone. PMID- 28360978 TI - Shift Work and Health Problems. PMID- 28360973 TI - Endoluminal solutions to bariatric surgery complications: A review with a focus on technical aspects and results. AB - Obesity is a growing problem in developed countries, and surgery is the most effective treatment in terms of weight loss and improving medical comorbidity in a high proportion of obese patients. Despite the advances in surgical techniques, some patients still develop acute and late postoperative complications, and an endoscopic evaluation is often required for diagnosis. Moreover, the high morbidity related to surgical reintervention, the important enhancement of endoscopic procedures and technological innovations introduced in endoscopic equipment have made the endoscopic approach a minimally-invasive alternative to surgery, and, in many cases, a suitable first-line treatment of bariatric surgery complications. There is now evidence in the literature supporting endoscopic management for some of these complications, such as gastrointestinal bleeding, stomal and marginal ulcers, stomal stenosis, leaks and fistulas or pancreatobiliary disorders. However, endoscopic treatment in this setting is not standardized, and there is no consensus on its optimal timing. In this article, we aim to analyze the secondary complications of the most expanded techniques of bariatric surgery with special emphasis on those where more solid evidence exists in favor of the endoscopic treatment. Based on a thorough review of the literature, we evaluated the performance and safety of different endoscopic options for every type of complication, highlighting the most recent innovations and including comparative data with surgical alternatives whenever feasible. PMID- 28360979 TI - Shift Work Is Associated with Metabolic Syndrome in Young Female Korean Workers. AB - BACKGROUND: Shift work is associated with health problems, including metabolic syndrome. This study investigated the association between shift work and metabolic syndrome in young workers. METHODS: A total of 3,317 subjects aged 20 40 years enrolled in the 2011-2012 Korean National Health and Nutrition Examination Survey were divided into shift and day workers. We conducted a cross sectional study and calculated odds ratios using multivariate logistic regression analysis in order to examine the association between shift work and metabolic syndrome. RESULTS: The prevalence of metabolic syndrome was 14.3% and 7.1% among male and female shift workers, respectively. After adjusting for confounding factors, shift work was associated with metabolic syndrome in female workers (odds ratio, 2.53; 95% confidence interval, 1.12 to 5.70). CONCLUSION: Shift work was associated with metabolic syndrome in young women. Timely efforts are necessary to manage metabolic syndrome in the workplace. PMID- 28360980 TI - Mental Health of the People with Hearing Impairment in Korea: A Population-Based Cross-Sectional Study. AB - BACKGROUND: The prevalence of hearing impairment is increasing and an association between hearing impairment and mental health has been reported. Our study aimed to determine the association between hearing impairment and mental health in Korea. METHODS: This was a cross-sectional study of data from the Korean National Health and Nutrition Examination Survey 2010-2013, with a sample size of 18,563 individuals (6,395 with hearing impairment and 12,168 without hearing impairment), aged >=20 years. RESULTS: The female group with hearing impairment tended to have a higher rate of stress (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.11 to 1.56). The association between hearing impairment and depressive symptoms was higher in elderly males (OR, 1.60; 95% CI, 1.10 to 2.32), while the association of hearing impairment with suicide ideation was higher in elderly females (OR, 1.32; 95% CI, 1.00 to 1.75). CONCLUSION: Elderly individuals with hearing impairment are easily susceptible to poor mental health status. Early targeted intervention to address mental health problems is recommended for people with hearing impairment. PMID- 28360981 TI - Association Between the Awareness of Dyslipidemia and Health Behavior for Control of Lipid Levels Among Korean Adults with Dyslipidemia. AB - BACKGROUND: Dyslipidemia is a major risk factor contributing to cardiovascular disease and its prevalence is steadily rising. Although screening tests are readily accessible, dyslipidemia remains undertreated. Evaluating health behavior patterns after diagnosis may help improve lifestyle interventions for the management of dyslipidemia. METHODS: Data from the fifth Korean National Health and Nutrition Examination Survey 2010-2012 were used. A total of 6,624 dyslipidemia patients over 20 years old were included according to National Cholesterol Education Program-Adult Treatment Panel III guidelines. Logistic regression analysis was completed using a weighted method to determine whether awareness of dyslipidemia was associated with health behavior. Health behavior was divided into two categories: behavioral factors (smoking, alcohol consumption, exercise) and nutritional factors (adequate intake of fiber, carbohydrate, fat, protein). RESULTS: There were no significant differences in health behavior among dyslipidemia patients according to awareness after adjustment for covariates, diabetes and hypertension. Awareness in women was associated with decreased smoking (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.32 to 0.94), but when adjusted for diabetes and hypertension the result was not significant (OR, 0.61; 95% CI, 0.35 to 1.06). The same pattern applied to intake of carbohydrate in men (OR, 1.28; 95% CI, 0.99 to 1.67) and protein in women (OR, 1.22; 95% CI, 0.98 to 1.50). In subgroup analysis, awareness of dyslipidemia in men without hypertension or diabetes was associated with adequate intake of carbohydrate (OR, 1.70; 95% CI, 1.06 to 2.72). CONCLUSION: Increasing awareness alone may not be enough to improve healthy behavior in patients with dyslipidemia. Efforts including patient education and counseling through a multi team approach may be required. PMID- 28360982 TI - Joint Effect of Cigarette Smoking and Body Mass Index on White Blood Cell Count in Korean Adults. AB - BACKGROUND: White blood cell count is an independent risk factor for cardiovascular disease. Several lifestyle and metabolic factors such as cigarette smoking and obesity are known to be associated with an elevated white blood cell count. However, the joint effect of cigarette smoking and obesity on white blood cell count has not yet been fully described. METHODS: We explored the joint effect of cigarette smoking and obesity on white blood cell count using multiple logistic regression analyses after adjusting for confounding variables in a population-based, cross-sectional study of 416,065 Korean adults. RESULTS: Cigarette smoking and body mass index have a dose-response relationship with a higher white blood cell count, but no synergistic interaction is observed between them (men, P for interaction=0.797; women, P for interaction=0.311). Cigarette smoking and body mass index might have an additive combination effect on high white blood cell count. Obese male smokers were 2.36 times more likely and obese female smokers 2.35 times more likely to have a high white blood cell count when compared with normal body mass index non-smokers. CONCLUSION: Cigarette smoking and body mass index are independently associated with an elevated white blood cell count in both men and women. PMID- 28360983 TI - Association Between Serum 25-Hydroxyvitamin D Levels and Dry Eye in Korean Adults: A Study Based on Korean National Health and Nutrition Examination Survey, 2010-2011. AB - BACKGROUND: Dry eye is a common disease. Many patients continue to experience residual symptoms despite optimal treatment. Thus, new treatment options are required. The purpose of this study was to evaluate the association between serum 25-hydroxyvitamin D [25(OH)D] levels and dry eye. METHODS: This study was performed using data from the fifth Korean National Health and Nutrition Examination Survey, which is a cross-sectional study of the Korean population that was conducted from 2010 to 2011. We included adults aged >19 years who underwent ophthalmologic interviews and examinations. We excluded subjects who had comorbid conditions (rheumatoid arthritis, thyroid disease, chronic kidney disease, or depression) that are associated with dry eye. The subjects were divided into normal and dry eye groups. The dry eye group consisted of those who had clinically diagnosed dry eye syndrome or symptoms. Multiple logistic regression analysis was conducted to determine the association between serum 25(OH)D levels and dry eye. RESULTS: In the univariate model, the 25(OH)D levels were lower in the dry eye group than in the normal group (P=0.01). A significant association was found between severe vitamin D deficiency (<10 ng/mL) and dry eye (P=0.04). However, after multivariate adjustment, the statistical significance of the association disappeared (P-values= 0.49, vitamin D insufficiency; P=0.33, vitamin D deficiency; P=0.18, severe vitamin D deficiency). CONCLUSION: Severe vitamin D deficiency was associated with dry eye in an unadjusted model, but the association was not statistically significant after adjustment. PMID- 28360984 TI - The Association Between Shift Work and Health Behavior: Findings from the Korean National Health and Nutrition Examination Survey. AB - BACKGROUND: Shift workers are increasing worldwide, and various negative health effects of shift work have been reported. This study aimed to evaluate the relationship between shift work and health behavior. METHODS: This cross sectional study included a total of 11,680 Korean adults (6,061 men and 5,619 women) aged >=20 years old who participated in the Fifth Korean National Health and Nutrition Examination Survey, 2010-2012. Multiple logistic regression analysis was performed to evaluate the association between shift work and health behavior after adjusting for covariates. RESULTS: In men, shift work was associated with an increased risk of inadequate sleep (odds ratio [OR], 1.18; 95% confidence interval [CI], 1.00 to 1.40) compared to day work. In women, shift work was associated with an increased risk of smoking (OR, 1.73; 95% CI, 1.34 to 2.22) and inadequate sleep (OR, 1.24; 95% CI, 1.05 to 1.47) compared to day work. In an age-stratified subgroup analysis, female shift workers aged >=50 years old demonstrated an increased risk of smoking (OR, 5.55; 95% CI, 3.60 to 8.55), alcohol consumption (OR, 2.22; 95% CI, 1.53 to 3.23), and inadequate sleep (OR, 1.50; 95% CI, 1.10 to 2.05) compared to female day workers. CONCLUSION: Shift work is associated with worse health behavior, and this is most evident in women aged >=50 years. Targeted strategies to reduce the negative health effects of shift work should be implemented, with consideration of shift workers' demographic characteristics. PMID- 28360986 TI - Confusion, Faciobrachial Dystonic Seizures, and Critical Hyponatremia in a Patient with Voltage-Gated Potassium Channel Encephalitis. AB - Autoimmune limbic encephalitis is a rare cause of encephalitic disease. It is associated with various target antigens and is difficult to diagnose, and experience with its treatment is limited. This case report describes a 69-year old man, who presented with life-threatening hyponatremia and confusion, following several months of gradually worsening faciobrachial dystonic seizures. Faciobrachial dystonic seizures are a well-described feature classically observed in voltage-gated potassium channel autoimmune encephalitis. The presence of chronic hyponatremia without cognitive dysfunction, eventually culminating in an acute episode of encephalopathy and severe hyponatremia, is a pattern of natural history not previously documented in this condition. PMID- 28360985 TI - Relationship Between Alcohol Consumption and Prostatic Hyperplasia According to Facial Flushing After Drinking in Korean Men. AB - BACKGROUND: The purpose of this study was to examine whether facial flushing after drinking influences the relationship between alcohol consumption and prostatic hyperplasia among Korean men. METHODS: The subjects were 957 Korean men (180 non-drinkers, 389 with drinking-related facial flushing, 388 without facial flushing) in the 40-69 age group, who underwent prostate ultrasound at the health promotion center of Chungnam National University Hospital between 2008 and 2014. Alcohol consumption and alcohol-related facial flushing were assessed through a questionnaire. In terms of the amount consumed, 14 g of alcohol was considered a standard drink. With the non-drinker group as reference, logistic regression was used to analyze the relationship between weekly alcohol intake and prostatic hyperplasia in the flushing and non-flushing groups, with adjustment for confounding factors such as age, body mass index, smoking, and exercise patterns. RESULTS: Individuals aged 50-59 years who experienced drinking-related facial flushing had a significantly lower risk of prostatic hyperplasia than the non drinker group, depending on alcohol consumption: <=4 standard drinks (adjusted odds ratio [OR], 0.38; 95% confidence interval [CI], 0.16 to 0.86); >4 <=8 standard drinks (OR, 0.35; 95% CI, 0.13 to 0.95); >8 standard drinks (OR, 0.33; 95% CI, 0.13 to 0.84). However, no significant relationship was observed between the number of drinks consumed and the risk of prostate hyperplasia in the non flushing group. CONCLUSION: The risk of prostatic hyperplasia appears to be reduced by alcohol consumption among Korean men aged 50-59 years who exhibit drinking-related facial flushing. PMID- 28360987 TI - A Diagnosis to Consider in an Adult Patient with Facial Features and Intellectual Disability: Williams Syndrome. AB - Williams syndrome (OMIM #194050) is a rare, well-recognized, multisystemic genetic condition affecting approximately 1/7,500 individuals. There are no marked regional differences in the incidence of Williams syndrome. The syndrome is caused by a hemizygous deletion of approximately 28 genes, including ELN on chromosome 7q11.2. Prenatal-onset growth retardation, distinct facial appearance, cardiovascular abnormalities, and unique hypersocial behavior are among the most common clinical features. Here, we report the case of a patient referred to us with distinct facial features and intellectual disability, who was diagnosed with Williams syndrome at the age of 37 years. Our aim is to increase awareness regarding the diagnostic features and complications of this recognizable syndrome among adult health care providers. Williams syndrome is usually diagnosed during infancy or childhood, but in the absence of classical findings, such as cardiovascular anomalies, hypercalcemia, and cognitive impairment, the diagnosis could be delayed. Due to the multisystemic and progressive nature of the syndrome, accurate diagnosis is critical for appropriate care and screening for the associated morbidities that may affect the patient's health and well-being. PMID- 28360988 TI - Validity of Alcohol Use Disorder Identification Test: Methodological Issues. PMID- 28360989 TI - Authors' Reply to the Letter to the Editor "Validity of an Alcohol Use Disorder Identification Test: Methodological Issues". PMID- 28344770 TI - Aspiration in injections: should we continue or abandon the practice? AB - Aspiration during any kind of injection is meant to ensure that the needle tip is at the desired location during this blind procedure. While aspiration appears to be a simple procedure, it has generated a lot of controversy concerning the perceived benefits and indications. Advocates and opponents of aspiration both make logically sound claims. However, due to scarcity of available data, there is no evidence that this procedure is truly beneficial or unwarranted. Keeping in view the huge number of injections given worldwide, it is important that we draw attention to key questions regarding aspiration that, up till now, remain unanswered. In this review, we have attempted to gather and present literature on aspiration both from published and non-published sources in order to provide not only an exhaustive review of the subject, but also a starting point for further studies on more specific areas requiring clarification. A literature review was conducted using the US National Institute of Health's PubMed service (including Medline), Google Scholar and Scopus. Guidelines provided by the World Health Organization, Safe Injection Global Network, International Council of Nursing, Center for Disease Control, US Federal Drug Agency, UK National Health Services, British Medical Association, Europe Nursing and Midwifery Council, Public Health Agency Canada, Pakistan Medical Association and International Organization of Standardization recommendations 7886 parts 1-4 for sterile hypodermics were reviewed for relevant information. In addition, curricula of several medical/ nursing schools from India, Nigeria and Pakistan, the US pharmacopeia Data from the WHO Program for International Drug Monitoring network in regard to adverse events as a result of not aspirating prior to injection delivery were reviewed. Curricula of selected major medical/nursing schools in India, Nigeria and Pakistan, national therapeutic formularies, product inserts of most commonly used drugs and other possible sources of information regarding aspiration and injections were consulted as well. PMID- 28360990 TI - Sex differences in the association of phospholipids with components of the metabolic syndrome in young adults. AB - BACKGROUND: There are differences in the prevalence and severity of diseases between males, females not taking hormonal contraceptives (non-HC females) and females taking hormonal contraceptives (HC females). The aim of this study was to identify sex-specific differences in the metabolome and its relation to components of the metabolic syndrome in a young adult population. METHODS: The subjects analysed are from the 20-year follow-up of the Western Australian Pregnancy Cohort (Raine) Study. Two hundred fifteen plasma metabolites were analysed in 1021 fasted plasma samples by a targeted liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) metabolomics approach. Principal component analysis between males (n = 550), non-HC females (n = 199) and HC females (n = 269) was applied. Regression analysis with a sex * metabolite concentration interaction was performed on components of the MetS, namely waist circumference, systolic blood pressure, and plasma HDL-C, triglycerides and glucose concentration, as outcome to select the significant metabolites of the interaction. Those selected metabolites were used as predictors in a sex group stratified analysis to compare the different beta coefficients and therefore the sex group-dependent associations. RESULTS: Principal component analysis between males, non-HC females, and HC females showed a general discriminating trend between males and HC females. One hundred twenty-seven metabolites were significantly different between males and non-HC females, whereas 97 differed between non-HC females and HC females. Males and non-HC females mainly differed in sphingomyelin, lyso-phosphatidylcholine, acyl-carnitine and amino acid species, whilst non-HC females and HC females mainly differed in phosphatidylcholine, lyso-phosphatidylcholine and acyl-carnitine concentrations. Forty-one metabolites (phosphatidylcholines, sphingomyelines, lyso phosphatidylcholine) were significantly differently associated with the MetS factors in the different groups. CONCLUSIONS: We have shown clear differences between plasma metabolite concentrations in males, and HC or non-HC females, especially in lyso-phosphatidylcholine, sphingomyelin and phosphatidylcholine, which have been shown to associate with obesity in other studies. The association of these metabolites differed between sexes with components of the metabolic syndrome, which means that development of diseases like obesity and diabetes may differ between the sexes. Our findings highlight the importance of considering sex differences when conducting a metabolomics study and the need to account for the effect of HC usage in females in future studies. PMID- 28344770 TI - Aspiration in injections: should we continue or abandon the practice? AB - Aspiration during any kind of injection is meant to ensure that the needle tip is at the desired location during this blind procedure. While aspiration appears to be a simple procedure, it has generated a lot of controversy concerning the perceived benefits and indications. Advocates and opponents of aspiration both make logically sound claims. However, due to scarcity of available data, there is no evidence that this procedure is truly beneficial or unwarranted. Keeping in view the huge number of injections given worldwide, it is important that we draw attention to key questions regarding aspiration that, up till now, remain unanswered. In this review, we have attempted to gather and present literature on aspiration both from published and non-published sources in order to provide not only an exhaustive review of the subject, but also a starting point for further studies on more specific areas requiring clarification. A literature review was conducted using the US National Institute of Health's PubMed service (including Medline), Google Scholar and Scopus. Guidelines provided by the World Health Organization, Safe Injection Global Network, International Council of Nursing, Center for Disease Control, US Federal Drug Agency, UK National Health Services, British Medical Association, Europe Nursing and Midwifery Council, Public Health Agency Canada, Pakistan Medical Association and International Organization of Standardization recommendations 7886 parts 1-4 for sterile hypodermics were reviewed for relevant information. In addition, curricula of several medical/nursing schools from India, Nigeria and Pakistan, the US pharmacopeia Data from the WHO Program for International Drug Monitoring network in regard to adverse events as a result of not aspirating prior to injection delivery were reviewed. Curricula of selected major medical/nursing schools in India, Nigeria and Pakistan, national therapeutic formularies, product inserts of most commonly used drugs and other possible sources of information regarding aspiration and injections were consulted as well. PMID- 28360993 TI - Risk factors for Clostridium difficile infection in surgical patients hospitalized in a tertiary hospital in Belgrade, Serbia: a case-control study. AB - BACKGROUND: The objective of this study was to investigate independent risk factors (RFs) connected with healthcare-associated (HA) Clostridium difficile infection (CDI) in surgical patients, its frequency per surgical wards and in hospital-mortality at a single hospital. METHODS: Risk factors for the infection were prospectively assessed among surgical patients with laboratory confirmed HA CDI and compared with a control group without HA CDI. RESULTS: The overall incidence rate of HA CDI was 2.6 per 10000 patient-days. Significant independent RFs for HA CDI were the use of carbapenems (P = 0.007, OR: 10.62, 95% CI: 1.93 58.4), the admission to intensive care unit (P = 0.004, OR:3.00, 95% CI:1.41 6.40), and the administration of 3rd generation cephalosporins (P = 0.014, OR:2.27, 95% CI:1.18-4.39). Patients with HA CDI had significantly higher in hospital mortality compared to controls (P: 0.007; OR: 8.95; 95% CI: 1.84-43.43). CONCLUSIONS: CDI is an important HA infection in population of surgical patients and this study emphasizes the importance of the wise use of antibiotics, and other infection control strategies in order to prevent HA CDI, and to decrease the incidence and in-hospital mortality rate. PMID- 28360994 TI - MRSA decolonization failure-are biofilms the missing link? AB - BACKGROUND: Device-associated infections due to biofilm-producing methicillin resistant Staphylococcus aureus (MRSA) have been recently associated with the failure of antibiotic treatment and decolonization measures. The goal of our study was to evaluate the extent to which the formation of biofilms influenced the efficacy of topical decolonization agents or disinfectants such as mupirocin (MUP), octenidine (OCT), chlorhexidine (CHG), polyhexanide (POL), and chloroxylenol (CLO). METHODS: Bacterial killing in biofilms by the disinfectants and MUP was determined as the reduction [%] in metabolic activity determined by a biofilm viability assay that uses kinetic analysis of metabolic activity. The test substances were diluted in water with standardized hardness (WSH) at 25 degrees C at the standard concentration as well as half the standard concentration to demonstrate the dilution effects in a practical setting. The tested concentrations were: CHG 1%, 2%; OCT 0.1%, 0.05%; PH 0.04%, 0.02%; and CLO 0.12%, 0.24%. A test organism suspension, 1 mL containing ~1 * 109 bacterial cells/mL, and 1 mL of sterile WSH were mixed and incubated for six different exposure times (15 s, 1, 3, 5, 10 and 20 min) after the test substance was added. Additionally, the bactericidal effects of all substances were tested on planktonic bacteria and measured as the log10 reduction. RESULTS: The disinfectants OCT and CHG showed good efficacy in inhibiting MRSA in biofilms with reduction rates of 94 +/- 1% and 91 +/- 1%, respectively. POL, on the other hand, had a maximum efficacy of only 81 +/- 7%. Compared to the tested disinfectants, MUP showed a significantly lower efficacy with <20% inhibition (p < .05). Bactericidal effects were the greatest for CHG (log10 reduction of 9.0), followed by OCT (7.7), POL (5.1), and CLO (6.8). MUP, however, showed a very low bactericidal effect of only 2.1. Even when the exposure time was increased to 24 h, 2% MUP did not show sufficient bactericidal effect. CONCLUSIONS: Our data provide evidence that OCT and CHG are effective components for disinfection of MRSA-biofilms. On the other hand, exposure to MUP at the standard concentrations in topical preparations did not effectively inhibit MRSA-biofilms and also did not show adequate bactericidal effects. Combining an MUP-based decolonization regimen with a disinfectant such as OCT or CHG could decrease decolonization failure. PMID- 28360995 TI - Inappropriate prescribing in outpatient healthcare: an evaluation of respiratory infection visits among veterans in teaching versus non-teaching primary care clinics. AB - A recent study led by the Centers for Disease Control and Prevention (CDC) revealed at least 30% of antibiotic prescriptions in the outpatient setting were inappropriate. In this study of all ages, among adult patients, results were similar to the overall population, with the majority of inappropriate prescribing relating to respiratory infections. We applied the same methodology to investigate rates of antibiotic prescribing for respiratory tract infections in outpatient primary care clinics at the Providence Veterans Affairs Medical Center. The results of our evaluation reflected comparable rates of inappropriate prescribing, but when stratified by teaching versus non-teaching primary care clinics, inappropriate prescribing was significantly higher in non-teaching clinics (17.6% vs 44.0%, p < .0001). Respiratory infection visits in non-teaching outpatient clinics may be a pragmatic target for antimicrobial stewardship programs. PMID- 28360998 TI - Protective factors against disordered eating in family systems: a systematic review of research. AB - OBJECTIVE: This systematic review aims to identify and evaluate the literature investigating protective factors and eating disorders (EDs), to establish what is known about factors in family systems that could be considered protective against the development of ED/disordered eating. METHODS: A systematic review of the literature was conducted on five databases, using search terms related to ED/disordered eating and protective factors. Studies were systematically screened and included if they made reference to a protective factor within the family system and explored associations with a quantitative measure of ED/disordered eating behaviours. All included studies were evaluated for study quality. RESULTS: Twenty-five studies met criteria for inclusion. Ten papers made use of longitudinal or prospective designs appropriate to identify factors potentially protecting against the development of disordered eating difficulties, while a further 15 papers report cross-sectional associations between family factors and disordered eating outcomes. Studies looked at aspects of family relationships and family practices around food or eating. There was a particular research focus on the potential protective role of regular family meals. CONCLUSIONS AND IMPLICATIONS: Many of the potential protective factors identified, such as family support and connectedness, may be non-specific to eating difficulties, promoting general adaptive development and a range of positive development outcomes. Factors in the family environment around food, eating and weight, such as frequent family meals and avoiding comments about weight, may be more specific to ED and disordered eating. Issues with the methodologies used severely impact on the ability to draw conclusions about whether factors are 'protective'. PMID- 28360999 TI - Stress response to handling is short lived but may reflect personalities in a wild, Critically Endangered tortoise species. AB - We investigated the acute stress response associated with animal personalities by measuring plasma glucocorticoids throughout handling and collected ~2 years of movement and behavioural data in a wild, Critically Endangered animal, Astrochelys radiata (radiated tortoise). To determine whether our standard, brief conscientious handling procedures induce a stress response in our target species, we applied a stressor by way of initial animal processing and deployment of telemetry equipment. During surveys and processing, we sampled animals immediately upon detection, again after completing transmitter attachment and processing, and a final time the following day. We then used radiotelemetry to follow a subset of the animals for 22 months while collecting behavioural, climatic and location data. We found that brief and conscientious handling did not illicit consistent changes in plasma concentrations of the stress hormone corticosterone (CORT) but did reveal tremendous individual variation in response. The CORT concentration ranged more than 200-fold after imposing the stressor and returned to near-baseline values by the following day. When we accounted for the wide variation by calculating the degree of each individual's stress response relative to its baseline over its processing time, we discovered two non overlapping physiological response types; those in which CORT concentrations increased dramatically in response to handling (219 +/- 89.8 pg/ml/min) and those in which CORT varied only slightly (5.3 +/- 8.9 pg/ml/min). The response types (strong vs. mild) also predicted body condition, home range size, activity, and behavioural tendencies. The degree of the individual's stress response in this species may be one component of correlated physiological and behavioural traits (animal personalities), which have previously been obscured in other chelonian studies by the use of mean values and should be considered in future conservation management applications for chelonian species. PMID- 28361000 TI - Rethinking the approach to viability monitoring in seed genebanks. AB - Seed viability monitoring, usually through a germination test, is a key aspect of genebank management; a low viability result triggers the regeneration of an accession in order to ensure that the genetic diversity of the accession is conserved and available for distribution. However, regular viability monitoring of large collections is costly in terms of seeds, labour and other resources. Genebanks differ in how they conduct their viability monitoring and how they collect, manage and store the data that are generated. In this article, we propose alternatives to the current norm of conducting an initial germination test soon after arrival at the genebank and then testing after regular, set storage intervals, as recommended in the Food and Agriculture Organization's Genebank Standards for Plant Genetic Resources for Food and Agriculture. We use real data from the International Rice Genebank (held at the International Rice Research Institute) to illustrate some of the issues regarding the accuracy and reliability of germination test results, in particular when they are used to predict the longevity of a seed lot in storage and to set viability monitoring intervals. We suggest the use of seed storage experiments on samples of seeds to identify which seed lots from a particular crop season to test first. We also give advice on the use of sequential testing schemes potentially to reduce the number of seeds used for viability testing; the use of tolerance tables to identify unlikely results when samples are subdivided into replicates; and what data to include in a genebank management database to improve the management of seed collections. PMID- 28360996 TI - The role of cognitive activity in cognition protection: from Bedside to Bench. AB - BACKGROUND: Cognitive decline poses a great concern to elderly people and their families. In addition to pharmacological therapies, several varieties of nonpharmacological intervention have been developed. Most training trials proved that a well-organized task is clinically effective in cognition improvement. MAIN BODY: We will first review clinical trials of cognitive training for healthy elders, MCI and AD patients, respectively. Besides, potential neuroprotective and compensatory mechanisms in animal models of AD are discussed. Despite controversy, cognitive training has promising effect on cognitive ability. In animal model of AD, environmental enrichment showed beneficial effect for cognitive ability, as well as neuronal plasticity. Neurotrophin, neurotransmitter and neuromodulator signaling pathway were also involved in the process. Well designed cognitive activity could benefit cognitive function, and thus life quality of patients and their families. CONCLUSION: The positive effects of cognitive activity is closely related with neural plasticity, neurotrophin, neurotransmitter and neuromodulator signaling pathway changes. PMID- 28361001 TI - Effects of ambient oxygen and size-selective mortality on growth and maturation in guppies. AB - Growth, onset of maturity and investment in reproduction are key traits for understanding variation in life-history strategies. Many environmental factors affect variation in these traits, but for fish, hypoxia and size-dependent mortality have become increasingly important because of human activities, such as increased nutrient enrichment (eutrophication), climate warming and selective fishing. Here, we study experimentally the effect of oxygen availability on maturation and growth in guppies (Poecilia reticulata) from two different selected lines, one subjected to positive and the other negative size-dependent fishing. This is the first study to assess the effects of both reduced ambient oxygen and size-dependent mortality in fish. We show that reduced ambient oxygen led to stunting, early maturation and high reproductive investment. Likewise, lineages that had been exposed to high mortality of larger-sized individuals displayed earlier maturation at smaller size, greater investment in reproduction and faster growth. These life-history changes were particularly evident for males. The widely reported trends towards earlier maturation in wild fish populations are often interpreted as resulting from size-selective fishing. Our results highlight that reduced ambient oxygen, which has received little experimental investigation to date, can lead to similar phenotypic changes. Thus, changes in ambient oxygen levels can be a confounding factor that occurs in parallel with fishing, complicating the causal interpretation of changes in life history traits. We believe that better disentangling of the effects of these two extrinsic factors, which increasingly affect many freshwater and marine ecosystems, is important for making more informed management decisions. PMID- 28361002 TI - A case of lung abscess successfully treated by transbronchial drainage using a guide sheath. AB - A 51-year-old man was diagnosed with colon cancer in September 2011, and a solitary pulmonary nodule was detected by computed tomography (CT) scan. We performed a transbronchial biopsy with endobronchial ultrasonography using a guide sheath (GS) and diagnosed lung metastasis of colon cancer. The patient experienced remittent fever after the biopsy in spite of intravenous antibiotic therapies. Moreover, his CT scan showed a large lung abscess at the biopsy site. We performed transbronchial drainage using a GS as salvage therapy. The bloody pus was successfully aspirated, and chest X-ray following the procedure showed dramatic shrinkage of the abscess. PMID- 28360997 TI - Imaging biomarkers in Parkinson's disease and Parkinsonian syndromes: current and emerging concepts. AB - Two centuries ago in 1817, James Parkinson provided the first medical description of Parkinson's disease, later refined by Jean-Martin Charcot in the mid-to-late 19th century to include the atypical parkinsonian variants (also termed, Parkinson-plus syndromes). Today, Parkinson's disease represents the second most common neurodegenerative disorder with an estimated global prevalence of over 10 million. Conversely, atypical parkinsonian syndromes encompass a group of relatively heterogeneous disorders that may share some clinical features with Parkinson's disease, but are uncommon distinct clinicopathological diseases. Decades of scientific advancements have vastly improved our understanding of these disorders, including improvements in in vivo imaging for biomarker identification. Multimodal imaging for the visualization of structural and functional brain changes is especially important, as it allows a 'window' into the underlying pathophysiological abnormalities. In this article, we first present an overview of the cardinal clinical and neuropathological features of, 1) synucleinopathies: Parkinson's disease and other Lewy body spectrum disorders, as well as multiple system atrophy, and 2) tauopathies: progressive supranuclear palsy, and corticobasal degeneration. A comprehensive presentation of well established and emerging imaging biomarkers for each disorder are then discussed. Biomarkers for the following imaging modalities are reviewed: 1) structural magnetic resonance imaging (MRI) using T1, T2, and susceptibility-weighted sequences for volumetric and voxel-based morphometric analyses, as well as MRI derived visual signatures, 2) diffusion tensor MRI for the assessment of white matter tract injury and microstructural integrity, 3) proton magnetic resonance spectroscopy for quantifying proton-containing brain metabolites, 4) single photon emission computed tomography for the evaluation of nigrostriatal integrity (as assessed by presynaptic dopamine transporters and postsynaptic dopamine D2 receptors), and cerebral perfusion, 5) positron emission tomography for gauging nigrostriatal functions, glucose metabolism, amyloid and tau molecular imaging, as well as neuroinflammation, 6) myocardial scintigraphy for dysautonomia, and 7) transcranial sonography for measuring substantia nigra and lentiform nucleus echogenicity. Imaging biomarkers, using the 'multimodal approach', may aid in making early, accurate and objective diagnostic decisions, highlight neuroanatomical and pathophysiological mechanisms, as well as assist in evaluating disease progression and therapeutic responses to drugs in clinical trials. PMID- 28361003 TI - Case report: primary osteonecrosis associated with thrombophilia-hypofibrinolysis and worsened by testosterone therapy. AB - BACKGROUND: Familial and acquired thrombophilia are often etiologic for idiopathic hip and jaw osteonecrosis (ON), and testosterone therapy (TT) can interact with thrombophilia, worsening ON. CASE PRESENTATION: Case 1: A 62-year old Caucasian male (previous deep venous thrombosis), on warfarin 1 year for atrial fibrillation (AF), had non-specific right hip-abdominal pain for 2 years. CT scan revealed bilateral femoral head ON without collapse. Coagulation studies revealed Factor V Leiden (FVL) heterozygosity, 4G/4G plasminogen activator inhibitor (PAI) homozygosity, high anti-cardiolipin (ACLA) IgM antibodies, and endothelial nitric oxide (NO) synthase (eNOS) T786C homozygosity (reduced conversion of L-arginine to NO, required for bone health). Apixaban 5 mg twice daily was substituted for warfarin; and L-arginine 9 g/day was started to increase NO. On Apixaban for 8 months, he became asymptomatic. Case 2: A 32-year old hypogonadal Caucasian male had 10 years of unexplained tooth loss, progressing to primary jaw ON with cavitation 8 months after starting TT gel 50 mg/day. Coagulation studies revealed FVL heterozygosity, PAI 4G/4G homozygosity, and the lupus anticoagulant. TT was discontinued. Jaw pain was sharply reduced within 2 months. CONCLUSIONS: Idiopathic ON, often caused by thrombophilia hypofibrinolysis, is worsened by TT, and its progression may be slowed or stopped by discontinuation of TT and, thereafter, anticoagulation. Recognition of thrombophilia-hypofibrinolysis before joint collapse facilitates anticoagulation which may stop ON, preserving joints. PMID- 28361004 TI - How to use composite indicator and linear programming model for determine sustainable tourism. AB - BACKGROUND: The tourism industry which is one of the most dynamic economic activities in today's world plays a significant role in the sustainable development. Therefore, in addition to paying attention to tourism, sustainable tourism must be taken into huge account; otherwise, the environment and its health will be damaged irreparably. METHODS: To determine the level of sustainability in this study, indicators of sustainable tourism were first presented in three environmental health, economic and social aspects. Then, the levels of sustainable tourism and environmental sustainability were practically measured in different cities of Kerman Province using a composite indicator, a linear programming model, Delphi method and the questionnaire technique. Finally, the study cities (tourist attractions) were ranked. RESULTS: Result of this study showed that unfortunately the tourism opportunities were not used appropriately in these cities and tourist destinations, and that environmental aspect (health and environmental sustainability) had very bad situations compared to social and economic aspects. In other words, environmental health had the lowest levels of sustainability. CONCLUSIONS: The environment is a place for all human activities like tourism, social and economic issues; therefore, its stability and health is of great importance. Thus, it is necessary to pay more attention to sustainability of activities, management and environmental health in planning sustainable development in regional and national policy. PMID- 28361005 TI - Respiratory symptoms and illnesses related to the concentration of airborne particulate matter among brick kiln workers in Kathmandu valley, Nepal. AB - BACKGROUND: Bricks have been manufactured in Nepal for hundreds of years and are seen as a component of Nepalese sculpture and architecture. Large quantities of hazardous materials including high concentrations of particulate matter are emitted on a daily basis from brick kilns. Exposure to these hazardous materials can lead to adverse consequences on the environment and human health. This study was conducted to estimate the prevalence of respiratory symptoms/illnesses and the magnitude of respirable and total dust exposures among Nepalese brick kiln workers. METHODS: Respiratory symptoms/illnesses were evaluated by questionnaire among brickfield workers (n = 400) and a referent group of grocery workers (n = 400) in Kathmandu valley. Work zones (WZs): green brick molding (GBM), green brick stacking/carrying (GBS/C), red brick loading/carrying (RBL/C), coal preparation (CP) and firemen (FM) were the similar exposure groups (SEGs) from where personal air samples and interviews were taken. Among brickfield workers, personal monitoring was conducted across SEGs for total (n = 89) and respirable (n = 72) dust during February-March 2015 and March-April 2016. Applying multi stage probability proportionate to size sampling technique, 16 kilns and 400 brick workers for interview were selected. Proportions, means, medians and ranges were calculated for the demographics, samples and respiratory symptoms/illnesses. One-way ANOVA was applied to compare the significance differences of the level of particulate matter among SEGs. Bivariate and multivariate logistic regression analysis were performed to evaluate association between respiratory symptoms/illnesses and participants groups, and SEGs among brick kiln workers at 0.05 level. Statistical analyses were performed using IBM SPSS Statistics 21. RESULTS: Chronic cough (14.3%), phlegm (16.6%) and bronchitis (19.0%) were higher (P < 0.05) among brickfield compared with grocery workers (6.8, 5.8 and 10.8%). Mean respirable (5.888 mg/m3) and total (20.657 mg/m3) dust exposures were highest for red brick loading tasks. The prevalence of chronic cough, chronic phlegm, chronic bronchitis, wheezing and asthma were significantly higher for other WZs workers (p < 0.05) compared with CP; for GBM: 22.9, 34.6, 15.0 and 7.5%; for GBS/C: 13.5, 15.8, 10.0, 8.8 and 7.5%; for RBL/C: 11.1, 17.1, 27.4, 19.0 and 11.9%; for FM: 18.4, 12.5, 28.4, 4.9 and 0.0%; and for CP: 4.9, 6.3, 13.3, 9.3 and 4.0% respectively. CONCLUSION: High dust exposures identified in this study may explain the increased prevalence of respiratory symptoms/illnesses among Nepalese brickfield workers, warranting action to reduce exposures. PMID- 28361007 TI - Association of angiotensinogen gene SNPs and haplotypes with risk of hypertension in eastern Indian population. AB - BACKGROUND: Angiotensinogen (AGT) enzyme comprises a vital module of RAAS system that effectively controls the blood pressure and related cardiovascular functions. Ample association studies have reported the importance of AGT variants in cardiovascular and non-cardiovascular adversities. But lately, owing to the complexity of the many anomalies, the haplotype based examination of genetic variation that facilitates the identification of polymorphic sites which are located in the vicinity of the causative polymorphic site, gets greater appreciation. METHODS: In the present study, we have done genotype and haplotype analysis of AGT gene in reference to hypertension to confirm the association of the two in an Indian population. To accomplish this, we performed candidate SNPs analysis and construct possible haplotypes across the AGT promoter and gene region in 414 subjects (256 Hypertensive cases and 158 controls). RESULTS: We found four SNPs (rs11568020: A-152G and rs5050: A-20C in promoter; rs4762 and rs699 in exon2) and 3 haplotypes (H4, H7 and H8) that showed a stronger positive association with hypertension. The haplotype H2 was showing protective association with hypertension. CONCLUSION: The results of the present study confirmed and reestablished the role of AGT gene variants and their haplotypes in the causation of hypertension in Indian population and showed that haplotypes can provide stronger evidence of association. PMID- 28361008 TI - Chameleon: Dynamic Color Mapping for Multi-Scale Structural Biology Models. AB - Visualization of structural biology data uses color to categorize or separate dense structures into particular semantic units. In multiscale models of viruses or bacteria, there are atoms on the finest level of detail, then amino-acids, secondary structures, macromolecules, up to the compartment level and, in all these levels, elements can be visually distinguished by color. However, currently only single scale coloring schemes are utilized that show information for one particular scale only. We present a novel technology which adaptively, based on the current scale level, adjusts the color scheme to depict or distinguish the currently best visible structural information. We treat the color as a visual resource that is distributed given a particular demand. The changes of the color scheme are seamlessly interpolated between the color scheme from the previous views into a given new one. With such dynamic multi-scale color mapping we ensure that the viewer is able to distinguish structural detail that is shown on any given scale. This technique has been tested by users with an expertise in structural biology and has been overall well received. PMID- 28361009 TI - Analysis of Intonation Patterns in Cantonese Aphasia Speech. AB - This paper presents a study on intonation patterns in Cantonese aphasia speech. The speech materials were spontaneous discourse recorded from seven pairs of aphasic and unimpaired speakers. Hidden Markov model based forced alignment was applied to obtain syllable-level time alignments. The pitch level of each syllable was determined and normalized according to the given tone identity of the syllable. Linear regression of the normalized pitch levels was performed to describe the intonation patterns of sentences. It was found that aphasic speech has a higher percentage of sentences with increasing pitch. This trend was found to be more prominent in story-telling than descriptive discourses. PMID- 28361010 TI - Verrucoid Variant of Invasive Squamous Cell Carcinoma in Oral Submucous Fibrosis: A Clinicopathological Challenge. AB - Verrucous carcinoma (VC) is an exophytic, low-grade, well-differentiated variant of squamous cell carcinoma. It is described as a lesion appearing in the sixth or seventh decade of life that has minimal aggressive potential and, in long standing cases, has been shown to transform into squamous cell carcinoma. Oral submucous fibrosis (OSMF) is a potentially malignant disorder, and about one third of the affected population develop oral squamous cell carcinoma. The histopathological diagnosis of verrucous carcinoma is challenging, and the interpretation of early squamous cell carcinoma requires immense experience. Here we present a rare case of a 24-year-old male with OSMF transforming to verrucous carcinoma with invasive squamous cell carcinoma. Even though the case had a straightforward clinical diagnosis, the serial sectioning done for pathological diagnosis disclosed the squamous cell carcinoma. PMID- 28361011 TI - Severe Dumping Syndrome in a 6-year-old Girl with Congenital Microgastria Treated by Hunt-Lawrence Pouch. AB - Microgastria is a rare congenital condition often associated with other anomalies. In the present report we describe the case of a 6-year-old girl with isolated CM who presented with dumping syndrome successfully treated by a Hunt Lawrence pouch. PMID- 28361006 TI - Regulatory mechanisms, prophylaxis and treatment of vascular leakage following severe trauma and shock. AB - Vascular leakage, or increased vascular permeability, is a common but important pathological process for various critical diseases, including severe trauma, shock, sepsis, and multiple organ dysfunction syndrome (MODS), and has become one of the most important causes of death for intensive care units (ICU) patients. Currently, although there has been some progress in knowledge of the pathogenesis of these vascular disorders, the detailed mechanisms remain unclear, and effective prophylaxis and treatment are still lacking. In this study, we aimed to provide a review of the literature regarding the regulatory mechanisms and prophylaxis as well as the treatment of vascular leakage in critical diseases such as severe trauma and shock, which could be beneficial for the overall clinical treatment of vascular leakage disorders. PMID- 28361012 TI - Surveillance and prayer - comparing Muslim prison chaplaincy in Germany's federal states. AB - Moving beyond approaches that emphasise the influence of national ideologies and transnational frameworks on the governance of religious diversity in Western Europe, recent scholarship has underlined the importance of analysing the impact of concrete institutional settings such as hospitals, schools and prisons on the public incorporation of religious minorities. Building on this approach, the present article analyses the emergence of Muslim prison chaplaincies in three German federal states by focussing on how framing strategies of state- and religious actors accommodate the national state-church framework and prison related norms. The article thus shows how national ideologies of diversity regulation and prison norms are mutually shaped in the process of the local governance of Islam. The comparative perspective of the article highlights subnational variations regarding actor constellations and strategies and thereby emphasises a multidimensional process of negotiating the national regime of diversity governance. PMID- 28361013 TI - Anterior cruciate ligament reconstruction and knee osteoarthritis. AB - Anterior cruciate ligament (ACL) injury is a traumatic event that can lead to significant functional impairment and inability to participate in high-level sports-related activities. ACL reconstruction is considered the treatment of choice for symptomatic ACL-deficient patients and can assist in full functional recovery. Furthermore, ACL reconstruction restores ligamentous stability to normal, and, therefore, can potentially fully reinstate kinematics of the knee joint. As a consequence, the natural history of ACL injury could be potentially reversed via ACL reconstruction. Evidence from the literature is controversial regarding the effectiveness of ACL reconstruction in preventing the development of knee cartilage degeneration. This editorial aims to present recent high-level evidence in an attempt to answer whether ACL injury inevitably leads to osteoarthritis and whether ACL reconstruction can prevent this development or not. PMID- 28361014 TI - Fix and replace: An emerging paradigm for treating acetabular fractures in older patients. AB - Acetabular fractures in older patients are challenging to manage. The "fix and replace" construct may present a new paradigm for the management of these injuries. We present the current challenge of acetabular fractures in older patients. We present this in the context of the current literature. This invited editorial presents early results from our centre and the ongoing challenges are discussed. PMID- 28361015 TI - Development of an internally braced prosthesis for total talus replacement. AB - Total loss of talus due to trauma or avascular necrosis, for example, still remains to be a major challenge in foot and ankle surgery with severely limited treatment options. Implantation of a custom made total talar prosthesis has shown promising results so far. Most important factors for long time success are degree of congruence of articular surfaces and ligamentous stability of the ankle. Therefore, our aim was to develop an optimized custom made prosthesis for total talus replacement providing a high level of primary stability. A custom made hemiprosthesis was developed using computed tomography and magnetic resonance imaging data of the affected and contralateral talus considering the principles and technology for the development of the S.T.A.R. prosthesis (Stryker). Additionally, four eyelets for fixation of artificial ligaments were added at the correspondent footprints of the most important ligaments. Two modifications can be provided according to the clinical requirements: A tri-articular hemiprosthesis or a bi-articular hemiprosthesis combined with the tibial component of the S.T.A.R. total ankle replacement system. A feasibility study was performed using a fresh frozen human cadaver. Maximum range of motion of the ankle was measured and ligamentous stability was evaluated by use of standard X rays after application of varus, valgus or sagittal stress with 150 N. Correct implantation of the prosthesis was technically possible via an anterior approach to the ankle and using standard instruments. Malleolar osteotomies were not required. Maximum ankle dorsiflexion and plantarflexion were measured as 22-0-28 degrees. Maximum anterior displacement of the talus was 6 mm, maximum varus tilt 3 degrees and maximum valgus tilt 2 degrees. Application of an internally braced prosthesis for total talus replacement in humans is technically feasible and might be a reasonable procedure in carefully selected cases with no better alternatives left. PMID- 28361017 TI - Lower limb stress fractures in sport: Optimising their management and outcome. AB - Stress fractures in sport are becoming increasing more common, comprising up to 10% of all of sporting injuries. Around 90% of such injuries are located in the lower limb. This articles aims to define the optimal management of lower limb stress fractures in the athlete, with a view to maximise return rates and minimise return times to sport. Treatment planning of this condition is specific to the location of the injury. However, there remains a clear division of stress fractures by "high" and "low" risk. "Low risk" stress fractures are those with a low probability of fracture propagation, delayed union, or non-union, and so can be managed reliably with rest and exercise limitation. These include stress fractures of the Postero-Medial Tibial Diaphysis, Metatarsal Shafts, Distal Fibula, Medial Femoral Neck, Femoral Shaft and Calcaneus. "High risk" stress fractures, in contrast, have increased rates of fracture propagation, displacement, delayed and non-union, and so require immediate cessation of activity, with orthopaedic referral, to assess the need for surgical intervention. These include stress fractures of the Anterior Tibial Diaphysis, Fifth Metatarsal Base, Medial Malleolus, Lateral Femoral Neck, Tarsal Navicular and Great Toe Sesamoids. In order to establish the optimal methods for managing these injuries, we present and review the current evidence which guides the treatment of stress fractures in athletes. From this, we note an increased role for surgical management of certain high risk stress fractures to improve return times and rates to sport. Following this, key recommendations are provided for the management of the common stress fracture types seen in the athlete. Five case reports are also presented to illustrate the application of sport-focussed lower limb stress fracture treatment in the clinical setting. PMID- 28361016 TI - Prevention and management of post-instability glenohumeral arthropathy. AB - Post-instability arthropathy may commonly develop in high-risk patients with a history of recurrent glenohumeral instability, both with and without surgical stabilization. Classically related to anterior shoulder instability, the incidence and rates of arthritic progression may vary widely. Radiographic arthritic changes may be present in up to two-thirds of patients after primary Bankart repair and 30% after Latarjet procedure, with increasing rates associated with recurrent dislocation history, prominent implant position, non-anatomic reconstruction, and/or lateralized bone graft placement. However, the presence radiographic arthrosis does not predict poor patient-reported function. After exhausting conservative measures, both joint-preserving and arthroplasty surgical options may be considered depending on a combination of patient-specific and anatomic factors. Arthroscopic procedures are optimally indicated for individuals with focal disease and may yield superior symptomatic relief when combined with treatment of combined shoulder pathology. For more advanced secondary arthropathy, total shoulder arthroplasty remains the most reliable option, although the clinical outcomes, wear characteristics, and implant survivorship remains a concern among active, young patients. PMID- 28361018 TI - Spinal alignment evolution with age: A prospective gait analysis study. AB - AIM: To describe, using gait analysis, the development of spinal motion in the growing child. METHODS: Thirty-six healthy children aged from 3 to 16 years old were included in this study for a gait analysis (9 m-walk). Various kinematic parameters were recorded and analyzed such as thoracic angle (TA), lumbar angle (LA) and sagittal vertical axis (SVA). The kinetic parameters were the net reaction moments (N.m/kg) at the thoracolumbar and lumbosacral junctions. RESULTS: TA and LA curves were not statistically correlated to the age (respectively, P = 0.32 and P = 0.41). SVA increased significantly with age (P < 0.001). Moments in sagittal plane at the lumbosacral junction were statistically correlated to the age (P = 0.003), underlining the fact that sagittal mechanical constraints at the lumbosacral junction increase with age. Moments in transversal plane at the thoracolumbar and lumbosacral junctions were statistically correlated to the age (P = 0.0002 and P = 0.0006), revealing that transversal mechanical constraints decrease with age. CONCLUSION: The kinetic analysis showed that during growth, a decrease of torsional constraint occurs while an increase of sagittal constraint is observed. These changes in spine biomechanics are related to the crucial role of the trunk for bipedalism acquisition, allowing stabilization despite lower limbs immaturity. With the acquisition of mature gait, the spine will mainly undergo constraints in the sagittal plane. PMID- 28361019 TI - Results of single stage exchange arthroplasty with retention of well fixed cement less femoral component in management of infected total hip arthroplasty. AB - AIM: To investigate success of one stage exchange with retention of fixed acetabular cup. METHODS: Fifteen patients treated by single stage acetabular component exchange with retention of well-fixed femoral component in infected total hip arthroplasty (THA) were retrospectively reviewed. Inclusion criteria were patients with painful chronic infected total hip. The patient had radiologically well fixed femoral components, absence of major soft tissue or bone defect compromising, and infecting organism was not poly or virulent micro organism. The organisms were identified preoperatively in 14 patients (93.3%), coagulase negative Staphylococcus was the infecting organism in 8 patients (53.3%). RESULTS: Mean age of the patients at surgery was 58.93 (+/- 10.67) years. Mean follow-up was 102.8 mo (36-217 mo, SD 56.4). Fourteen patients had no recurrence of the infection; one hip (6.7%) was revised for management of infection. Statistical analysis using Kaplan Meier curve showed 93.3% survival rate. One failure in our series; the infection recurred after 14 mo, the patient was treated successfully with surgical intervention by irrigation, and debridement and liner exchange. Two complications: The first patient had recurrent hip dislocation 12 years following the definitive procedure, which was managed by revision THA with abductor reconstruction and constrained acetabular liner; the second complication was aseptic loosening of the acetabular component 2 years following the definitive procedure. CONCLUSION: Successful in management of infected THA when following criteria are met; well-fixed stem, no draining sinuses, non-immune compromised patients, and infection with sensitive organisms. PMID- 28361020 TI - Role of dynamic computed tomography scans in patients with congenital craniovertebral junction malformations. AB - AIM: To evaluate the role of dynamic computed tomography (CT) scan imaging in diagnosing craniovertebral junction (CVJ) instability in patients with congenital CVJ malformations. METHODS: Patients with symptomatic congenital CVJ malformations who underwent posterior fossa decompression and had a preoperative dynamic CT scan in flexion and extended position were included in this study. Measurements of the following craniometrical parameters were taken in flexed and extended neck position: Atlanto-dental interval (ADI), distance of the odontoid tip to the Chamberlain's line, and the clivus-canal angle (CCA). Assessment of the facet joints congruence was also performed in both positions. Comparison of the values obtained in flexion and extension were compared using a paired Student's t-test. RESULTS: A total of ten patients with a mean age of 37.9 years were included. In flexion imaging, the mean ADI was 1.76 mm, the mean CCA was 125.4 degrees and the mean distance of the odontoid tip to the Chamberlain's line was + 9.62 mm. In extension, the mean ADI was 1.46 mm (P = 0.29), the mean CCA was 142.2 degrees (P < 0.01) and the mean distance of the odontoid tip to the Chamberlain's line was + 7.11 mm (P < 0.05). Four patients (40%) had facetary subluxation demonstrated in dynamic imaging, two of them with mobile subluxation (both underwent CVJ fixation). The other two patients with a fixed subluxation were not initially fixed. One patient with atlantoaxial assimilation and C23 fusion without initial facet subluxation developed a latter CVJ instability diagnosed with a dynamic CT scan. Patients with basilar invagination had a lower CCA variation compared to the whole group. CONCLUSION: Craniometrical parameters, as well as the visualization of the facets location, may change significantly according to the neck position. Dynamic imaging can provide additional useful information to the diagnosis of CVJ instability. Future studies addressing the relationship between craniometrical changes and neck position are necessary. PMID- 28361022 TI - Hip resurfacing arthroplasty complicated by mismatched implant components. AB - Metal-on-metal hip resurfacing has gained popularity as a feasible treatment option for young and active patients with hip osteoarthritis and high functional expectations. This procedure should only be performed by surgeons who have trained specifically in this technique. Preoperative planning is essential for hip resurfacing in order to execute a successful operation and preview any technical problems. The authors present a case of a man who underwent a resurfacing arthroplasty for osteoarthritis of the left hip that was complicated by mismatched implant components that were revised three days afterwards for severe pain and leg length discrepancy. Such mistakes, although rare, can be prevented by educating operating room staff in the size and colour code tables provided by the companies on their prostheses or implant boxes. PMID- 28361021 TI - Relationship between biological factors and catastrophizing and clinical outcomes for female patients with knee osteoarthritis. AB - AIM: To investigate the correlations between clinical outcomes and biopsychological variables in female patients with knee osteoarthritis (OA). METHODS: Seventy-seven patients with symptomatic knee OA were enrolled in this study. We investigated the age, body mass index (BMI), pain catastrophizing scale (PCS) and radiographic severity of bilateral knees using a Kellgren-Lawrence (K L) grading system of the subjects. Subsequently, a multiple linear regression was conducted to determine which variables best correlated with main outcomes of knee OA, which were pain severity, moving capacity by measuring timed-up-and-go test and Japanese Knee Osteoarthritis Measure (JKOM). RESULTS: We found that the significant contributor to pain severity was PCS (beta = 0.555) and BMI (beta = 0.239), to moving capacity was K-L grade (beta = 0.520) and to PCS (beta = 0.313), and to a JKOM score was PCS (beta = 0.485) and K-L grade (beta = 0.421), respectively. CONCLUSION: The results suggest that pain catastrophizing as well as biological factors were associated with clinical outcomes in female patients with knee OA, irrespective of radiographic severity. PMID- 28361023 TI - Pharyngeal airway dimensions in skeletal class II: A cephalometric growth study. AB - PURPOSE: This retrospective study aimed to evaluate the nasopharyngeal and oropharyngeal dimensions of individuals with skeletal class II, division 1 and division 2 patterns during the pre-peak, peak, and post-peak growth periods for comparison with a skeletal class I control group. MATERIALS AND METHODS: Totally 124 lateral cephalograms (47 for skeletal class I; 45 for skeletal class II, division 1; and 32 for skeletal class II, division 2) in pre-peak, peak, and post peak growth periods were selected from the department archives. Thirteen landmarks, 4 angular and 4 linear measurements, and 4 proportional calculations were obtained. The ANOVA and Duncan test were applied to compare the differences among the study groups during the growth periods. RESULTS: Statistically significant differences were found between the skeletal class II, division 2 group and other groups for the gonion-gnathion/sella-nasion angle. The sella nasion-B-point angle was different among the groups, while the A-point-nasion-B point angle was significantly different for all 3 groups. The nasopharyngeal airway space showed a statistically significant difference among the groups throughout the growth periods. The interaction among the growth periods and study groups was statistically significant regarding the upper oropharyngeal airway space measurement. The lower oropharyngeal airway space measurement showed a statistically significant difference among the groups, with the smallest dimension observed in the skeletal class II, division 2 group. CONCLUSION: The naso-oropharyngeal airway dimensions showed a statistically significant difference among the class II, division 1; class II, division 2; and class I groups during different growth periods. PMID- 28361024 TI - Intraobserver and interobserver reproducibility in linear measurements on axial images obtained by cone-beam computed tomography. AB - PURPOSE: This study was performed to investigate the intra- and inter-observer variability in linear measurements with axial images obtained by PreXion (PreXion Inc., San Mateo, USA) and i-CAT (Imaging Sciences International, Xoran Technologies Inc., Hatfield, USA) CBCT scanners, with different voxel sizes. MATERIALS AND METHODS: A cylindrical object made from nylon with radiopaque markers (phantom) was scanned by i-CAT and PreXion 3D devices. For each axial image, measurements were taken twice in the horizontal (distance A-B) and vertical (distance C-D) directions, randomly, with a one-week interval between measurements, by four oral radiologists with five years or more experience in the use of these measuring tools. RESULTS: All of the obtained linear measurements had lower values than those of the phantom. The statistical analysis showed high intra- and inter-observer reliability (p=0.297). Compared to the real measurements, the measurements obtained using the i-CAT device and PreXion tomography, on average, revealed absolute errors ranging from 0.22 to 0.59 mm and from 0.23 to 0.63 mm, respectively. CONCLUSION: It can be concluded that both scanners are accurate, although the linear measurements are underestimations, with no significant differences between the evaluators. PMID- 28361025 TI - Detection of furcation involvement using periapical radiography and 2 cone-beam computed tomography imaging protocols with and without a metallic post: An animal study. AB - PURPOSE: The purpose of this study was to assess the accuracy, sensitivity, and specificity of the diagnosis of incipient furcation involvement with periapical radiography (PR) and 2 cone-beam computed tomography (CBCT) imaging protocols, and to test metal artifact interference. MATERIALS AND METHODS: Mandibular second molars in 10 macerated pig mandibles were divided into those that showed no furcation involvement and those with lesions in the furcation area. Exams using PR and 2 different CBCT imaging protocols were performed with and without a metallic post. Each image was analyzed twice by 2 observers who rated the absence or presence of furcation involvement according to a 5-point scale. Receiver operating characteristic (ROC) curves were used to evaluate the accuracy, sensitivity, and specificity of the observations. RESULTS: The accuracy of the CBCT imaging protocols ranged from 67.5% to 82.5% in the images obtained with a metallic post and from 72.5% to 80% in those without a metallic post. The accuracy of PR ranged from 37.5% to 55% in the images with a metallic post and from 42.5% to 62.5% in those without a metallic post. The area under the ROC curve values for the CBCT imaging protocols ranged from 0.813 to 0.802, and for PR ranged from 0.503 to 0.448. CONCLUSION: Both CBCT imaging protocols showed higher accuracy, sensitivity, and specificity than PR in the detection of incipient furcation involvement. Based on these results, CBCT may be considered a reliable tool for detecting incipient furcation involvement following a clinical periodontal exam, even in the presence of a metallic post. PMID- 28361026 TI - Cone-beam computed tomography versus digital periapical radiography in the detection of artificially created periapical lesions: A pilot study of the diagnostic accuracy of endodontists using both techniques. AB - PURPOSE: The aim of this study was to compare the diagnostic accuracy of previously trained endodontists in the detection of artificially created periapical lesions using cone-beam computed tomography (CBCT) and digital periapical radiography (DPR). MATERIALS AND METHODS: An ex vivo model using dry skulls was used, in which simulated apical lesions were created and then progressively enlarged using #1/2, #2, #4, and #6 round burs. A total of 11 teeth were included in the study, and 110 images were obtained with CBCT and with an intraoral digital periapical radiographic sensor (Instrumentarium dental, Tuusula, Finland) initially and after each bur was used. Specificity and sensitivity were calculated. All images were evaluated by 10 previously trained, certified endodontists. Agreement was calculated using the kappa coefficient. The accuracy of each method in detecting apical lesions was calculated using the chi square test. RESULTS: The kappa coefficient between examiners showed low agreement (range, 0.17-0.64). No statistical difference was found between CBCT and DPR in teeth without apical lesions (P=.15). The accuracy for CBCT was significantly higher than for DPR in all corresponding simulated lesions (P<.001). The correct diagnostic rate for CBCT ranged between 56.9% and 73.6%. The greatest difference between CBCT and DPR was seen in the maxillary teeth (CBCT, 71.4%; DPR, 28.6%; P<.01) and multi-rooted teeth (CBCT, 83.3%; DPR, 33.3%; P<.01). CONCLUSION: CBCT allowed higher accuracy than DPR in detecting simulated lesions for all simulated lesions tested. Endodontists need to be properly trained in interpreting CBCT scans to achieve higher diagnostic accuracy. PMID- 28361027 TI - Cone-beam computed tomography analysis of accessory maxillary ostium and Haller cells: Prevalence and clinical significance. AB - PURPOSE: This study aimed to evaluate the prevalence of Haller cells and accessory maxillary ostium (AMO) in cone-beam computed tomography (CBCT) images, and to analyze the relationships among Haller cells, AMO, and maxillary sinusitis. MATERIALS AND METHODS: Volumetric CBCT scans from 201 patients were retrieved from our institution's Digital Imaging and Communications in Medicine archive folder. Two observers evaluated the presence of Haller cells, AMO, and maxillary sinusitis in the CBCT scans. RESULTS: AMO was observed in 114 patients, of whom 27 (23.7%) had AMO exclusively on the right side, 26 (22.8%) only on the left side, and 61 (53.5%) bilaterally. Haller cells were identified in 73 (36.3%) patients. In 24 (32.9%) they were present exclusively on the right side, in 17 (23.3%) they were only present on the left side, and in 32 (43.8%) they were located bilaterally. Of the 73 (36.3%) patients with Haller cells, maxillary sinusitis was also present in 50 (68.5%). On using chi-square test, a significant association was observed between AMO and maxillary sinusitis in the presence of Haller cells. CONCLUSION: Our results showed AMO and Haller cells to be associated with maxillary sinusitis. This study provides evidence for the usefulness of CBCT in imaging the bony anatomy of the sinonasal complex with significantly higher precision and a smaller radiation dose. PMID- 28361028 TI - Prevalence and location of the posterior superior alveolar artery using cone-beam computed tomography. AB - PURPOSE: Insufficient knowledge of the anatomy of the maxillary sinuses prior to sinus graft surgery may lead to perioperative or postoperative complications. This study sought to characterize the position of the posterior superior alveolar artery (PSAA) within the maxillary sinuses using cone-beam computed tomography (CBCT). MATERIALS AND METHODS: A total of 300 patients with edentulous posterior maxillae, including 138 females and 162 males with an age range of 33-86 years, who presented to a radiology clinic between 2013 and 2015 were enrolled in this retrospective cross-sectional study. The distance from the inferior border of the PSAA to the alveolar crest according to the residual ridge classification by Lekholm and Zarb, the distance from the PSAA to the nasal septum and zygomatic arch, and the diameter and position of the PSAA were all assessed on patients' CBCT scans. The data were analyzed using the Mann-Whitney test and the t-test. RESULTS: The PSAA was detected on the CBCT scans of 87% of the patients; it was located beneath the sinus membrane in 47% of cases and was intraosseous in 47% of cases. The diameter of the artery was between 1 and 2 mm in most patients (72%). The mean diameter of the artery was 1.29+/-0.39 mm, and the mean distances from the PSAA to the zygomatic arch, nasal septum, and alveolar crest were 22.59+/ 4.89 mm, 26.51+/-3.52 mm, and 16.7+/-3.96 mm, respectively. CONCLUSION: The likelihood of detecting the PSAA on CBCT scans is high; its location is intraosseous or beneath the sinus membrane in most patients. Determining the exact location of the PSAA on CBCT scans preoperatively can help prevent it from being damaged during surgery. PMID- 28361029 TI - Risk factors of osteonecrosis of the jaw after tooth extraction in osteoporotic patients on oral bisphosphonates. AB - PURPOSE: The aim of this study was to investigate the incidence of bisphosphonate related osteonecrosis of the jaw (BRONJ) after tooth extraction in patients with osteoporosis on oral bisphosphonates in Korea and to evaluate local factors affecting the development of BRONJ. MATERIALS AND METHODS: The clinical records of 320 patients who underwent dental extraction while receiving oral bisphosphonates were reviewed. All patients had a healing period of more than 6 months following the extractions. Each patient's clinical record was used to assess the incidence of BRONJ; if BRONJ occurred, a further radiographic investigation was carried out to obtain a more definitive diagnosis. Various local factors including age, gender, extraction site, drug type, duration of administration, and C-terminal telopeptide (CTx) level were retrieved from the patients' clinical records for evaluating their effect on the incidence of BRONJ. RESULTS: Among the 320 osteoporotic patients who underwent tooth extraction, 11 developed BRONJ, reflecting an incidence rate of 3.44%. Out of the local factors that may affect the incidence of BRONJ, gender, drug type, and CTx level showed no statistically significant effects, while statistically significant associations were found for age, extraction site, and duration of administration. The incidence of BRONJ increased with age, was greater in the mandible than the maxilla, and was associated with a duration of administration of more than 3 years. CONCLUSION: Tooth extraction in patients on oral bisphosphonates requires careful consideration of their age, the extraction site, and the duration of administration, and close postoperative follow-up should be carried out to facilitate effective early management. PMID- 28361030 TI - The development of a learning management system for dental radiology education: A technical report. AB - PURPOSE: This study was conducted to suggest the development of a learning management system for dental radiology education using the Modular Object Oriented Dynamic Learning Environment (Moodle). MATERIALS AND METHODS: Moodle is a well-known and verified open-source software-learning management system (OSS LMS). The Moodle software was installed on a server computer and customized for dental radiology education. The system was implemented for teaching undergraduate students to diagnose dental caries in panoramic images. Questions were chosen that could assess students' diagnosis ability. Students were given several questions corre-sponding to each of 100 panoramic images. RESULTS: The installation and customization of Moodle was feasible, cost-effective, and time saving. By having students answer questions repeatedly, it was possible to train them to examine panoramic images sequentially and thoroughly. CONCLUSION: Based on its educational efficiency and efficacy, the adaptation of an OSS-LMS in dental school may be highly recommended. The system could be extended to continuing education for dentists. Further studies on the objective evaluation of knowledge acquisition and retention are needed. PMID- 28361031 TI - Recurrent osteochondroma of the mandibular condyle: A case report. AB - A 21-year-old woman presented with facial asymmetry. Crepitus and clicking of the temporomandibular joint were noted. The midline deviated 5.5 mm to the left, and secondary malocclusion was observed. Panoramic and cone-beam computed tomographic images showed an irregular and exophytic bony mass on the anteromedial surface of the right mandibular condyle. A 3-phase bone scan revealed increased tracer uptake on the affected side. The lesion was treated with excision and reshaping under the diagnosis of osteochondroma confirmed by a histopathological examination. The lesion recurred after 3 years, and the patient underwent condylectomy. Mandibular condylar osteochondroma is often resected because it causes functional and aesthetic problems, but it rarely recurs. To the best of our knowledge, only 2 cases of recurrent osteochondromas of the mandibular condyle have been reported previously. Surgical treatment of the osteochondroma should be performed considering the possibility of recurrence, and long-term follow-up is recommended. PMID- 28361032 TI - Radiographic and computed tomography monitoring of a fractured needle fragment in the mandibular branch. AB - Some complications can arise with the usage of local anesthesia for dental procedures, including the fracture of needles in the patient. This is a rare incident, usually caused by the patient's sudden movements during anesthetic block. Its complications are not common, but can include pain, trismus, inflammation in the region, difficulty in swallowing, and migration of the object, which is the least common but has the ability to cause more serious damage to the patient. This report describes a case in which, after the fracture of the anesthetic needle used during alveolar nerve block for exodontia of the left mandibular third molar, the fragment moved significantly in the first 2 months, before stabilizing after the third month of radiographic monitoring. PMID- 28361033 TI - Clinical Implications of ESR1 Mutations in Hormone Receptor-Positive Advanced Breast Cancer. AB - Hormone receptor-positive breast cancer is the most frequent breast cancer subtype. Endocrine therapy (ET) targeting the estrogen receptor (ER) pathway represents the main initial therapeutic approach. The major strategies include estrogen deprivation and the use of selective estrogen modulators or degraders, which show efficacy in the management of metastatic and early-stage disease. However, clinical resistance associated with progression of disease remains a significant therapeutic challenge. Mutations of the ESR1 gene, which encodes the ER, have been increasingly recognized as an important mechanism of ET resistance, with a prevalence that ranges from 11 to 39%. The majority of these mutations are located within the ligand-binding domain and result in an estrogen-independent constitutive activation of the ER and, therefore, resistance to estrogen deprivation therapy such as aromatase inhibition. ESR1 mutations, most often detected from liquid biopsies, have been consistently associated with a worse outcome and are being currently evaluated as a potential biomarker to guide therapeutic decisions. At the same time, targeted therapy directed to ESR1 mutated clones is an appealing concept with preclinical and clinical work in progress. PMID- 28361034 TI - Combinatorial Ranking of Gene Sets to Predict Disease Relapse: The Retinoic Acid Pathway in Early Prostate Cancer. AB - BACKGROUND: Quantitative high-throughput data deposited in consortia such as International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) present opportunities and challenges for computational analyses. METHODS: We present a computational strategy to systematically rank and investigate a large number (210-220) of clinically testable gene sets, using combinatorial gene subset generation and disease-free survival (DFS) analyses. This approach integrates protein-protein interaction networks, gene expression, DNA methylation, and copy number data, in association with DFS profiles from patient clinical records. RESULTS: As a case study, we applied this pipeline to systematically analyze the role of ALDH1A2 in prostate cancer (PCa). We have previously found this gene to have multiple roles in disease and homeostasis, and here we investigate the role of the associated ALDH1A2 gene/protein networks in PCa, using our methodology in combination with PCa patient clinical profiles from ICGC and TCGA databases. Relationships between gene signatures and relapse were analyzed using Kaplan-Meier (KM) log-rank analysis and multivariable Cox regression. Relative expression versus pooled mean from diploid population was used for z-statistics calculation. Gene/protein interaction network analyses generated 11 core genes associated with ALDH1A2; combinatorial ranking of the power set of these core genes identified two gene sets (out of 211 - 1 = 2,047 combinations) with significant correlation with disease relapse (KM log rank p < 0.05). For the more significant of these two sets, referred to as the optimal gene set (OGS), patients have median survival 62.7 months with OGS alterations compared to >150 months without OGS alterations (p = 0.0248, hazard ratio = 2.213, 95% confidence interval = 1.1-4.098). Two genes comprising OGS (CYP26A1 and RDH10) are strongly associated with ALDH1A2 in the retinoic acid (RA) pathways, suggesting a major role of RA signaling in early PCa progression. Our pipeline complements human expertise in the search for prognostic biomarkers in large-scale datasets. PMID- 28361035 TI - Mitochondrial and Oxidative Stress-Mediated Activation of Protein Kinase D1 and Its Importance in Pancreatic Cancer. AB - Due to alterations in their metabolic activity and decreased mitochondrial efficiency, cancer cells often show increased generation of reactive oxygen species (ROS), but at the same time, to avoid cytotoxic signaling and to facilitate tumorigenic signaling, have mechanism in place that keep ROS in check. This requires signaling molecules that convey increases in oxidative stress to signal to the nucleus to upregulate antioxidant genes. Protein kinase D1 (PKD1), the serine/threonine kinase, is one of these ROS sensors. In this mini-review, we highlight the mechanisms of how PKD1 is activated in response to oxidative stress, so far known downstream effectors, as well as the importance of PKD1 initiated signaling for development and progression of pancreatic cancer. PMID- 28361036 TI - A Salmonella Regulator Modulates Intestinal Colonization and Use of Phosphonoacetic Acid. AB - Many microorganisms produce phosphonates, molecules characterized by stable carbon-phosphorus bonds that store phosphorus or act as antimicrobials. The role of phosphonates in the marine biosphere is well characterized but the role of these molecules in the intestine is poorly understood. Salmonella enterica uses its virulence factors to influence the host immune response to compete with the host and normal microflora for nutrients. Salmonella cannot produce phosphonates but encodes the enzymes to use them suggesting that it is exposed to phosphonates during its life cycle. The role of phosphonates during enteric salmonellosis is unexplored. We have previously shown that STM3602, encoding a putative regulator of phosphonate metabolism, is needed for colonization in calves. Here, we report that the necessity of STM3602 in colonization of the murine intestine results from multiple factors. STM3602 is needed for full activation of the type-3 secretion system-1 and for optimal invasion of epithelial cells. The DeltaSTM3602 mutant grows poorly in phosphonoacetic acid (PA) as the sole phosphorus source, but can use 2-aminoethylphosphonate. PhnA, an enzyme required for PA breakdown, is not controlled by STM3602 suggesting an additional mechanism for utilization of PA in S. Typhimurium. Finally, the requirement of STM3602 for intestinal colonization differs depending on the composition of the microflora. Our data suggest that STM3602 has multiple regulatory targets that are necessary for survival within the microbial community in the intestine. Determination of the members of the STM3602 regulon may illuminate new pathways needed for colonization of the host. PMID- 28361037 TI - Either fadD1 or fadD2, Which Encode acyl-CoA Synthetase, Is Essential for the Survival of Haemophilus parasuis SC096. AB - In Haemophilus parasuis, the genes HAPS_0217 and HAPS_1695 are predicted to encode long-chain fatty acid-CoA ligases (FACSs). These proteins contain ATP/AMP signature motifs and FACS conserved motifs that are homologous to those in Escherichia coli FadD (EcFadD). In this study, we demonstrate that HAPS_0217 and HAPS_1695 can functionally replace EcFadD in the E. coli fadD mutant JW1794, and were thus designated fadD1 and fadD2, respectively. An evaluation of kinetic parameters indicated that FadD1 and FadD2 have a substrate preference for long chain fatty acids. Moreover, FadD2 exhibited substrate inhibition in the presence of high concentrations of oleic acid. Single mutants of each of the fadD genes were easily constructed, whereas double mutants were not. These results were further confirmed using genomic site-directed mutagenesis, which supported the idea that H. parasuis requires either fadD1 or fadD2 for survival. The fadD1 mutant exhibited slower growth than the wild-type strain SC096, and its complementation resulted in a restored phenotype. The wild-type strain did not grow on chemically defined medium without the addition of oleic acid, indicating that lipids are a vital nutrient for this bacterium. Additionally, strains with a disrupted fadD1 gene also exhibited increased sensitivity to quinolone antibiotics, including levofloxacin, enrofloxacin, ciprofloxacin and nalidixic acid. PMID- 28361038 TI - Tick Thioester-Containing Proteins and Phagocytosis Do Not Affect Transmission of Borrelia afzelii from the Competent Vector Ixodes ricinus. AB - The present concept of the transmission of Lyme disease from Borrelia-infected Ixodes sp. ticks to the naive host assumes that a low number of spirochetes that manage to penetrate the midgut epithelium migrate through the hemocoel to the salivary glands and subsequently infect the host with the aid of immunomodulatory compounds present in tick saliva. Therefore, humoral and/or cellular immune reactions within the tick hemocoel may play an important role in tick competence to act as a vector for borreliosis. To test this hypothesis we have examined complement-like reactions in the hemolymph of the hard tick Ixodes ricinus against Borrelia afzelii (the most common vector and causative agent of Lyme disease in Europe). We demonstrate that I. ricinus hemolymph does not exhibit borreliacidal effects comparable to complement-mediated lysis of bovine sera. However, after injection of B. afzelii into the tick hemocoel, the spirochetes were efficiently phagocytosed by tick hemocytes and this cellular defense was completely eliminated by pre-injection of latex beads. As tick thioester containing proteins (T-TEPs) are components of the tick complement system, we performed RNAi-mediated silencing of all nine genes encoding individual T-TEPs followed by in vitro phagocytosis assays. Silencing of two molecules related to the C3 complement component (IrC3-2 and IrC3-3) significantly suppressed phagocytosis of B. afzelii, while knockdown of IrTep (insect type TEP) led to its stimulation. However, RNAi-mediated silencing of T-TEPs or elimination of phagocytosis by injection of latex beads in B. afzelii-infected I. ricinus nymphs had no obvious impact on the transmission of spirochetes to naive mice, as determined by B. afzelii infection of murine tissues following tick infestation. This result supports the concept that Borrelia spirochetes are capable of avoiding complement-related reactions within the hemocoel of ticks competent to transmit Lyme disease. PMID- 28361039 TI - CD4 T Cell Dependent Colitis Exacerbation Following Re-Exposure of Mycobacterium avium ssp. paratuberculosis. AB - Mycobacterium avium ssp. paratuberculosis (MAP) is the causative agent of Johne's disease (JD), a chronic inflammatory bowel disease of cattle characterized by intermittent to chronic diarrhea. In addition, MAP has been isolated from Crohn's disease (CD) patients. The impact of MAP on severity of clinical symptoms in JD as well as its role in CD are yet unknown. We have previously shown that MAP is able to colonize inflamed enteric tissue and to exacerbate the inflammatory tissue response (Suwandi et al., 2014). In the present study, we analyzed how repeated MAP administration influences the course of dextran sulfate sodium (DSS) induced colitis. In comparison to mice exposed to DSS or MAP only, repeated exposure of DSS-treated mice to MAP (DSS/MAP) revealed a significantly enhanced clinical score, reduction of colon length as well as severe CD4+ T cell infiltration into the colonic lamina propria. Functional analysis identified a critical role of CD4+ T cells in the MAP-induced disease exacerbation. Additionally, altered immune responses were observed when closely related mycobacteria species such as M. avium ssp. avium and M. avium ssp. hominissuis were administered. These data reveal the specific ability of MAP to aggravate intestinal inflammation and clinical symptoms. Overall, this phenotype is compatible with similar disease promoting capabilites of MAP in JD and CD. PMID- 28361040 TI - Different Phenotypes of Mature Biofilm in Flavobacterium psychrophilum Share a Potential for Virulence That Differs from Planktonic State. AB - Flavobacterium psychrophilum is the etiological agent of bacterial coldwater disease and the rainbow trout fry syndrome in salmonid aquaculture worldwide. However, there have been few studies into the capacity of F. psychrophilum to form biofilms and how these cellular accretions differ from planktonic cells or how they affect potential virulence. We evaluated the biofilm formation by three Chilean isolates of F. psychrophilum (LM-02-Fp, LM-06-Fp, and LM-13-Fp) and two non-Chilean strains (JIP02/86 and NCMB1947T), and compared biofilm and planktonic states to obtain insights into expression differences of virulence- and biofilm related genes (VBRGs). Our findings are based on scanning confocal laser microscopy (SCLM) and LIVE/DEAD staining, enzymatic reactions, reverse transcription-quantitative PCR (RT-qPCR) of genes encoding putative virulence factors, and transcriptomes (RNA-Seq). The LM-02-Fp and NCMB1947T strains were the strongest and weakest biofilm producers, respectively. The strong-biofilm producer showed different physiological cell states distributed in different layers of mature biofilms, whereas the NCMB1947T biofilms consisted of cells arranged in a monolayer. WGA-binding exopolysaccharides would be the main components of their corresponding extracellular matrices. Transcriptomes of F. psychrophilum NCMB1947T and LM-02-Fp were clustered by state (biofilm vs. planktonic) rather than by strain, indicating important state-dependent differences in gene expression. Analysis of differentially expressed genes between states identified putative VBRGs involved in polysaccharide biosynthesis, lateral gene transfer, membrane transport (e.g., for drugs and Fe3+), sensory mechanisms, and adhesion, and indicated that about 60-100% of VBRGs involved in these processes was significantly upregulated in the biofilm state. Conversely, upregulated motility-related genes in the biofilm state were not identified, whereas a lower fraction of proteolysis-related genes (33%) was upregulated in biofilms. In summary, F. psychrophilum strains that produce different biofilm phenotypes show global transcriptional activity in the mature biofilm state that differs significantly from their planktonic counterparts. Also, different biofilm phenotypes share a genetic potential for virulence that is transcriptionally enhanced with respect to free-living cells. Our results suggest that the F. psychrophilum biofilm lifestyle acts as a reservoir for a given set of putative virulence factors, and recommend a deeper understanding of which could help prevent recurring infections in salmonid farms. PMID- 28361041 TI - Decrease of Staphylococcus aureus Virulence by Helcococcus kunzii in a Caenorhabditis elegans Model. AB - Social bacterial interactions are considered essential in numerous infectious diseases, particularly in wounds. Foot ulcers are a common complication in diabetic patients and these ulcers become frequently infected. This infection is usually polymicrobial promoting cell-to-cell communications. Staphylococcus aureus is the most prevalent pathogen isolated. Its association with Helcococcus kunzii, commensal Gram-positive cocci, is frequently described. The aim of this study was to assess the impact of co-infection on virulence of both H. kunzii and S. aureus strains in a Caenorhabditis elegans model. To study the host response, qRT-PCRs targeting host defense genes were performed. We observed that H. kunzii strains harbored a very low (LT50: 5.7 days +/- 0.4) or an absence of virulence (LT50: 6.9 days +/- 0.5). In contrast, S. aureus strains (LT50: 2.9 days +/- 0.4) were significantly more virulent than all H. kunzii (P < 0.001). When H. kunzii and S. aureus strains were associated, H. kunzii significantly reduced the virulence of the S. aureus strain in nematodes (LT50 between 4.4 and 5.2 days; P < 0.001). To evaluate the impact of these strains on host response, transcriptomic analysis showed that the ingestion of S. aureus led to a strong induction of defense genes (lys-5, sodh-1, and cyp-37B1) while H. kunzii did not. No statistical difference of host response genes expression was observed when C. elegans were infected with either S. aureus alone or with S. aureus + H. kunzii. Moreover, two well-characterized virulence factors (hla and agr) present in S. aureus were down-regulated when S. aureus were co-infected with H. kunzii. This study showed that H. kunzii decreased the virulence of S. aureus without modifying directly the host defense response. Factor(s) produced by this bacterium modulating the staphylococci virulence must be investigated. PMID- 28361042 TI - Sodium Octanoate Modulates the Innate Immune Response of Bovine Mammary Epithelial Cells through the TLR2/P38/JNK/ERK1/2 Pathway: Implications during Staphylococcus aureus Internalization. AB - Bovine mammary epithelial cells (bMECs) contribute to mammary gland defense against invading pathogens, such as Staphylococcus aureus (intracellular facultative), which is recognized by TLR2. In a previous report, we showed that sodium octanoate [NaO, a medium chain fatty acid (C8)] induces (0.25 mM) or inhibits (1 mM) S. aureus internalization into bMECs and differentially regulates the innate immune response (IIR). However, the molecular mechanisms have not been described, which was the aim of this study. The results showed that alpha5beta1 integrin membrane abundance (MA) was increased in 0.25 mM NaO-treated cells, but TLR2 or CD36 MA was not modified. When these receptors were blocked individually, 0.25 mM NaO-increased S. aureus internalization was notably reduced. Interestingly, in this condition, the IIR of the bMECs was impaired because MAPK (p38, JNK, and ERK1/2) phosphorylation and the activation of transcription factors related to these pathways were decreased. In addition, the 1 mM NaO treatment induced TLR2 MA, but neither the integrin nor CD36 MA was modified. The reduction in S. aureus internalization induced by 1 mM NaO was increased further when TLR2 was blocked. In addition, the phosphorylation levels of the MAPKs increased, and 13 transcriptional factors related to the IIR were slightly activated (CBF, CDP, c-Myb, AP-1, Ets-1/Pea-3, FAST-1, GAS/ISRE, AP-2, NFAT-1, OCT-1, RAR/DR-5, RXR/DR-1, and Stat-3). Moreover, the 1 mM NaO treatment up regulated gene expression of IL-8 and RANTES and secretion of IL-1beta. Notably, when 1 mM NaO-treated bMECs were challenged with S. aureus, the gene expression of IL-8 and IL-10 increased, while IL-1beta secretion was reduced. In conclusion, our results showed that alpha5beta1 integrin, TLR2 and CD36 are involved in 0.25 mM NaO-increased S. aureus internalization in bMECs. In addition, 1 mM NaO activates bMECs via the TLR2 signaling pathways (p38, JNK, and ERK1/2), which improves IIR before S. aureus invasion. Additionally, NaO (1 mM) might exert anti inflammatory effects after bacterial internalization. PMID- 28361043 TI - Cleavage of Grb2-Associated Binding Protein 2 by Viral Proteinase 2A during Coxsackievirus Infection. AB - Coxsackievirus type B3 (CV-B3), an enterovirus associated with the pathogenesis of several human diseases, subverts, or employs the host intracellular signaling pathways to support effective viral infection. We have previously demonstrated that Grb2-associated binding protein 1 (GAB1), a signaling adaptor protein that serves as a platform for intracellular signaling assembly and transduction, is cleaved upon CV-B3 infection, resulting in a gain-of-pro-viral-function via the modification of GAB1-mediated ERK1/2 pathway. GAB2 is a mammalian homolog of GAB1. In this study, we aim to address whether GAB2 plays a synergistic role with GAB1 in the regulation of CV-B3 replication. Here, we reported that GAB2 is also a target of CV-B3-encoded viral proteinase. We showed that GAB2 is cleaved at G238 during CV-B3 infection by viral proteinase 2A, generating two cleaved fragments of GAB2-N1-237 and GAB2-C238-676. Moreover, knockdown of GAB2 significantly inhibits the synthesis of viral protein and subsequent viral progeny production, accompanied by reduced levels of phosphorylated p38, suggesting a pro-viral function for GAB2 linked to p38 activation. Finally, we examined whether the cleavage of GAB2 can promote viral replication as observed for GAB1 cleavage. We showed that expression of neither GAB2-N1-237 nor GAB2-C238 676 results in enhanced viral infectivity, indicating a loss-of-function, rather than a gain-of-function of GAB2 cleavage in mediating virus replication. Taken together, our findings in this study suggest a novel host defense machinery through which CV-B3 infection is limited by the cleavage of a pro-viral protein. PMID- 28361044 TI - [Family background influence on adolescents' smoking on mures, harghita and covasna sample]. AB - Cigarette consumption might be considered as a lifestyle model. The formation of this lifestyle model in childhood and adolescence is considerable due to the socio-cultural environment in which socialization take part. The aim of this study was to analyze adolescents' smoking behavior, and family-related factors that may influence it. The self-reported questionnaire-based study was done in Mures, Harghita and Covasna counties among 7th and 8th grades students. The prevalence of smoking was 5.9% in the total sample. The results showed significant associations between smoking behavior of young people and their family background (e.g. education of parents, smoking bans at home). PMID- 28361045 TI - Phase I clinical trial of sipuleucel-T combined with escalating doses of ipilimumab in progressive metastatic castrate-resistant prostate cancer. AB - BACKGROUND: Sipuleucel-T (SIP-T), which functions by stimulating cancer-specific dendritic cells, prolongs survival in men with prostate cancer. Ipilimumab (IPI) achieved a borderline survival advantage in a large randomized trial. SIP-T and IPI are potentially synergistic. PATIENTS AND METHODS: Nine men with progressive metastatic castrate-resistant prostate cancer (mCRPC) were treated prospectively with SIP-T followed immediately by IPI with one of the following doses of IPI: 1 mg/kg at 1 week after SIP-T; 1 mg/kg at 1 and 4 weeks after SIP-T; or 1 mg/kg at 1, 4, and 7 weeks after SIP-T. Three patients were evaluated at each level. Cancer-specific immunoglobulins directed at granulocyte-macrophage-colony stimulating factor/prostatic acid phosphatase (PAP) fusion protein (PA2024) and PAP were measured prior to SIP-T, after SIP-T, 1 week after IPI, every other month for 5 months, then every 3 months for an additional 12 months. RESULTS: Adverse events of SIP-T were consistent with previous reports. IPI only caused a transient grade 1 rash in one patient. Median age, Gleason score, and number of previous hormonal interventions were 77 years, 8, and 3, respectively. Eight men had bone metastases and one had lymph node metastasis. Statistically significant increases in serum immunoglobulin G (IgG) and IgG-IgM specific for PA2024 and PAP occurred after SIP-T. An additional statistically significant increase in the aforementioned immunoglobulins - above the levels achieved by SIP-T - occurred after IPI. Median clinical follow-up was 36 months (range: 26-40). Three patients died from progressive disease after 9, 18, and 20 months. Out of the remaining six patients, five of them needed further treatment that included abiraterone acetate, enzalutamide, radium-223 dichloride, and spot radiation. One patient had an undetectable PSA, who did not receive any other treatment except spot radiation. Median PSA at last follow-up for the surviving patients was 3.8 (range: 0.6-7.47). CONCLUSION: In this small trial, the addition of IPI to SIP-T was well tolerated. IPI increased immunoglobulins specific for the PA2024 protein and PAP above the level achieved with SIP-T alone. PMID- 28361046 TI - Endothelial Progenitor Cells of the Human Placenta and Fetoplacental Circulation: A Potential Link to Fetal, Neonatal, and Long-term Health. AB - The fetoplacental circulation plays a key role in both short- and long-term outcomes, and aberrant flow indices as manifested by abnormal fetal Doppler velocimetry within this compartment have been associated with significant adverse consequences. These include fetal growth restriction, which often coexists with preeclampsia, and long-lasting medical issues as a result of both the underlying pathology and prematurity such as bronchopulmonary dysplasia, chronic lung disease, and neurodevelopmental delay. Furthermore, it is also clear that exposure to an abnormal in utero environment increases risk for long-term, adulthood issues such as cardiovascular disease. Endothelial progenitor cells (EPCs) have been implicated in vasculogenesis and angiogenesis, and they have been isolated from both human placenta and umbilical cord blood. This review outlines the extensive nomenclature of EPCs, summarizes existing literature surrounding human placental and umbilical cord blood EPCs, explores their potential role in pregnancy complications and adverse perinatal outcome, and highlights key areas where future investigations are needed. PMID- 28361048 TI - Screening for Hypertension in Children and Adolescents: Methodology and Current Practice Recommendations. AB - Hypertension (HTN) requires urgent, uniform, and consistent attention across all frontiers of pediatric health care not only because of established links between the onset of HTN during one's youth and its sustenance throughout adulthood but also because of the sequelae associated with the disease's trajectory, such as cardiovascular disease, end organ damage, and decreased quality of life. Although national guidelines for the diagnosis and management of pediatric HTN have been available for nearly 40 years, knowledge and recognition of the problem by clinicians remain poor due to a host of influencing factors. The purpose of this article is to explicate key issues contributing to the inaccurate measurement of blood pressure and misclassification of HTN among children and to present strategies to address these issues. PMID- 28361047 TI - Dynamic Akt/mTOR Signaling in Children with Autism Spectrum Disorder. AB - Autism spectrum disorder (ASD) is a behaviorally defined disorder affecting 1 in 68 children. Currently, there is no known cause for the majority of ASD cases nor are there physiological diagnostic tools or biomarkers to aid behavioral diagnosis. Whole-genome linkage studies, genome-wide association studies, copy number variation screening, and SNP analyses have identified several ASD candidate genes, but which vary greatly among individuals and family clusters, suggesting that a variety of genetic mutations may result in a common pathology or alter a common mechanistic pathway. The Akt/mammalian target of rapamycin (mTOR) pathway is involved in many cellular processes including synaptic plasticity and immune function that can alter neurodevelopment. In this study, we examined the activity of the Akt/mTOR pathway in cells isolated from children with ASD and typically developing controls. We observed higher activity of mTOR, extracellular receptor kinase, and p70S6 kinase and lower activity of glycogen synthase kinase 3 (GSK3)alpha and tuberin (TSC2) in cells from children with ASD. These data suggest a phosphorylation pattern indicative of higher activity in the Akt/mTOR pathway in children with general/idiopathic ASD and may suggest a common pathological pathway of interest for ASD. PMID- 28361049 TI - Programs and Place: Risk and Asset Mapping for Fall Prevention. AB - Identifying ways to measure access, availability, and utilization of health-care services, relative to at-risk areas or populations, is critical in providing practical and actionable information to key stakeholders. This study identified the prevalence and geospatial distribution of fall-related emergency medical services (EMS) calls in relation to the delivery of an evidence-based fall prevention program in Tarrant County, Texas over a 3-year time period. It aims to educate public health professionals and EMS first respondents about the application of geographic information system programs to identify risk-related "hot spots," service gaps, and community assets to reduce falls among older adults. On average, 96.09 (+/-108.65) calls were received per ZIP Code (ranging from 0 calls to 386 calls). On average, EMS calls per ZIP Code increased from 30.80 (+/-34.70) calls in 2009 to 33.75 (+/-39.58) calls in 2011, which indicate a modest annual call increase over the 3-year study period. The percent of ZIP Codes offering A Matter of Balance/Volunteer Lay Leader Model (AMOB/VLL) workshops increased from 27.3% in 2009 to 34.5% in 2011. On average, AMOB/VLL workshops were offered in ZIP Codes with more fall-related EMS calls over the 3 year study period. Findings suggest that the study community was providing evidence-based fall prevention programming (AMOB/VLL workshops) in higher-risk areas. Opportunities for strategic service expansion were revealed through the identification of fall-related hot spots and asset mapping. PMID- 28361050 TI - Conceptual DFT Descriptors of Amino Acids with Potential Corrosion Inhibition Properties Calculated with the Latest Minnesota Density Functionals. AB - Amino acids and peptides have the potential to perform as corrosion inhibitors. The chemical reactivity descriptors that arise from Conceptual DFT for the twenty natural amino acids have been calculated by using the latest Minnesota family of density functionals. In order to verify the validity of the calculation of the descriptors directly from the HOMO and LUMO, a comparison has been performed with those obtained through DeltaSCF results. Moreover, the active sites for nucleophilic and electrophilic attacks have been identified through Fukui function indices, the dual descriptor Deltaf(r) and the electrophilic and nucleophilic Parr functions. The results could be of interest as a starting point for the study of large peptides where the calculation of the radical cation and anion of each system may be computationally harder and costly. PMID- 28361051 TI - On the Role of Additional [4Fe-4S] Clusters with a Free Coordination Site in Radical-SAM Enzymes. AB - The canonical CysXXXCysXXCys motif is the hallmark of the Radical-SAM superfamily. This motif is responsible for the ligation of a [4Fe-4S] cluster containing a free coordination site available for SAM binding. The five enzymes MoaA, TYW1, MiaB, RimO and LipA contain in addition a second [4Fe-4S] cluster itself bound to three other cysteines and thus also displaying a potentially free coordination site. This review article summarizes recent important achievements obtained on these five enzymes with the main focus to delineate the role of this additional [4Fe-4S] cluster in catalysis. PMID- 28361052 TI - CaMKII Signaling Stimulates Mef2c Activity In Vitro but Only Minimally Affects Murine Long Bone Development in vivo. AB - The long bones of vertebrate limbs form by endochondral ossification, whereby mesenchymal cells differentiate into chondrogenic progenitors, which then differentiate into chondrocytes. Chondrocytes undergo further differentiation from proliferating to prehypertrophic, and finally to hypertrophic chondrocytes. Several signaling pathways and transcription factors regulate this process. Previously, we and others have shown in chicken that overexpression of an activated form of Calcium/calmodulin-dependent kinase II (CaMKII) results in ectopic chondrocyte maturation. Here, we show that this is not the case in the mouse. Although, in vitro Mef2c activity was upregulated by about 55-fold in response to expression of an activated form of CaMKII (DACaMKII), transgenic mice that expressed a dominant-active form of CaMKII under the control of the Col2a1 regulatory elements display only a very transient and mild phenotype. Here, only the onset of chondrocyte hypertrophy at E12.5 is accelerated. It is also this early step in chondrocyte differentiation that is temporarily delayed around E13.5 in transgenic mice expressing the peptide inhibitor CaM-KIIN from rat (rKIIN) under the control of the Col2a1 regulatory elements. Yet, ultimately DACaMKII, as well as rKIIN transgenic mice are born with completely normal skeletal elements with regard to their length and growth plate organization. Hence, our in vivo analysis suggests that CaMKII signaling plays a minor role in chondrocyte maturation in mice. PMID- 28361053 TI - T1 Mapping for Myocardial Fibrosis by Cardiac Magnetic Resonance Relaxometry-A Comprehensive Technical Review. AB - Cardiac magnetic resonance (CMR) imaging has been widely used to assess myocardial perfusion and scar and is the non-invasive gold standard for identification of focal myocardial fibrosis. However, the late gadolinium enhancement technique is limited in its accuracy for absolute quantification and assessment of diffuse myocardial fibrosis by technical and pathophysiological features. CMR relaxometry, incorporating T1 mapping, has emerged as an accurate, reproducible, highly sensitive, and quantitative technique for the assessment of diffuse myocardial fibrosis in a number of disease states. We comprehensively review the physics behind CMR relaxometry, the evidence base, and the clinical applications of this emerging technique. PMID- 28361054 TI - Validation and Utilization of a Clinical Next-Generation Sequencing Panel for Selected Cardiovascular Disorders. AB - The development of high-throughput technologies such as next-generation sequencing (NGS) has allowed for thousands of DNA loci to be interrogated simultaneously in a fast and economical method for the detection of clinically deleterious variants. Whenever a clinical diagnosis is known, a targeted NGS approach involving the use of disease-specific gene panels can be employed. This approach is often valuable as it allows for a more specific and clinically relevant interpretation of results. Here, we describe the customization, validation, and utilization of a commercially available targeted enrichment platform for the scalability of clinical diagnostic cardiovascular genetic tests, including the design of the gene panels, the technical parameters for the quality assurance and quality control, the customization of the bioinformatics pipeline, and the post-bioinformatics analysis procedures. Regions of poor base coverage were detected and targeted by Sanger sequencing as needed. All panels were successfully validated using genotype-known DNA samples either commercially available or from research subjects previously tested in outside clinical laboratories. In our experience, utilizing several of the sub-panels in a clinical setting with 33 real-life cardiovascular patients, we found that 20% of tests requested were reported to have at least one pathogenic or likely pathogenic variant that could explain the patient phenotype. For each of these patients, the positive results may aid the clinical team and the patients in best developing a disease management plan and in identifying relatives at risk. PMID- 28361055 TI - Changes in Circulating Monocyte Subsets (CD16 Expression) and Neutrophil-to Lymphocyte Ratio Observed in Patients Undergoing Cardiac Surgery. AB - BACKGROUND: The characteristics of circulating inflammatory cells (leukocytes) in patients undergoing heart surgery remains poorly understood. Recently, neutrophil to-lymphocyte ratio (NLR) and specific monocyte subsets (based on CD14/CD16 expression) have been suggested as markers of inflammation and predictors of outcomes. The present study aims to characterize the influence cardiac surgery with cardiopulmonary bypass has on specific circulating leukocytes. METHODS: All enrolled patients had blood samples taken pre- (0 days), early post- (5 days), and late post- (90 days) surgery. Complete blood counts were performed and whole leukocyte isolations were obtained from blood samples and analyzed with flow cytometry. Fluorophore-linked antibodies (CD45, CD11b, CD14, and CD16) were added to the blood cell isolations and later assessed by flow cytometry. RESULTS: Seventeen patients were enrolled and samples obtained at 0, 5, and 90 days. We demonstrated a significant increase in NLR (2.2-fold; p = 0.0028) and CD16 mean fluorescence index (MFI-measure fluorescence intensity shift of CD16 in a gated cell population) early at day 5 (2.0-fold; p = 0.0051). Both NLR and CD16 MFI levels generally returned to normal by day 90. There was a significant positive correlation between NLR and CD16 MFI (r2 = 0.29; p = 0.0064). Adverse cardiovascular event (AE) was defined as prolonged length of hospitalization or readmission to hospital for cardiac reasons after discharge was seen in 59% of patients (no deaths occurred). In an unadjusted analysis of AE, we identified NLR as a likely predictor of AE, which meant that patients developing AE had a significantly higher baseline NLR (p = 0.0065), something that was not observed with CD16 MFI (p = 0.2541). CONCLUSION: Cardiac surgery is associated with a significant increase in NLR and CD16 MFI (non-classical monocytes) early after surgery corresponding to the early inflammatory phase after surgery. Furthermore, we have, for the first time, identified a significant correlation between NLR and CD16 MFI. While the mechanism for this relationship remains unclear, our findings support the use of a simple test of NLR as a biomarker of inflammation for predicting outcomes in cardiac surgery patients. PMID- 28361056 TI - Eliminating Dog-Mediated Rabies in Sikkim, India: A 10-Year Pathway to Success for the SARAH Program. AB - A third of the world rabies burden is in India. The Sikkim Anti-Rabies and Animal Health (SARAH) program is the first state-wide rabies program in India and demonstrates a successful One Health model of dog-mediated rabies elimination. The SARAH program was created in 2006 as a collaboration between the Government of Sikkim and international non-government organizations-Vets Beyond Borders and Fondation Brigitte Bardot. Activities are directed to canine rabies vaccination, humane dog population control, community education, and treatment of sick and injured animals. In 2005, there were 0.74 human rabies deaths per 100,000 (4 deaths) within Sikkim, and from 2006 to 2015, there were no human rabies deaths. In 2016, two human rabies deaths were reported near the West Bengal border region. From 2005 to 2010, the incidence of animal rabies is unknown; from 2010 to 2016, eight cases of animal rabies were reported. Major challenges for the program are continued commitment to rabies control in the face of 0 to low human rabies incidence and the risk of rabies incursions. Effective intersectoral communication between Health, Veterinary, Forestry, and Police officers is essential to enable rapid response to animal bite incidents and possible rabies incursions. An integrated One Health approach needs to be maintained with enhanced active rabies surveillance. Other states must establish similar programs if India is ever to achieve a goal of eliminating dog-mediated human rabies. PMID- 28361057 TI - Effect of Skull Type on the Relative Size of Cerebral Cortex and Lateral Ventricles in Dogs. AB - Volume measurements of the brain are of interest in the diagnosis of brain pathology. This is particularly so in the investigation hydrocephalus and canine cognitive dysfunction (CCD), both of which result in thinning of the cerebral cortex and enlarged ventricles. Volume assessment can be made using computed tomography or more usually magnetic resonance imaging (MRI). There is, however, some uncertainty in the interpretation of such volume data due to the great variation in skull size and shape seen in dog. In this retrospective study, we examined normal MRI images from 63 dogs <6 years of age. We used a continuous variable, the cranial index (CrI) to indicate skull shape and compared it with MRI volume measurements derived using Cavalieri's principle. We found a negative correlation between CrI and the ratio of cortical to ventricular volume. Breeds with a high CrI (large laterolateral compared to rostrocaudal cranial cavity dimension) had a smaller ratio of cortical to ventricular volume (low C:V ratio) than breeds with lower CrI skull types. It is important to consider this effect of skull shape on the relative volume estimates of the cerebral cortex and ventricles when trying to establish if pathology is present. PMID- 28361058 TI - "Don't Just Do Something ... Stand There!" Emergency Responders' Peri-Incident Perceptions of Animal Owners in Bushfire. AB - INTRODUCTION: Narrowing the awareness-preparedness gap in bushfires (wildfires) means that new strategies and tactics will be needed to improve human safety and survival in this increasingly frequent and severe globally significant natural hazard. One way to do this is to explore the peri-event experiences of novel demographic groups living and working in at-risk areas to determine how best to strengthen a collaborative, mutually beneficial interface with emergency responders. Thus, this study included participants from one novel demographic, animal owners, in combination with emergency responders. Animal owners themselves are a large, diverse group whose preparedness and response behavior has not been assessed with respect to their potential contribution to contemporary natural hazard management. METHOD: Data were collected using semi-structured interviews and focus group discussions from four emergency responder classifications who were asked about their perceptions of animal owners in bushfire. Thematic analysis was used for data analysis because of its flexibility and suitability to this pragmatic qualitative study. Results from the first of 10 themes, chosen for its "overview" properties, are discussed in this paper, and indicate that exploring the animal owner-emergency responder interface has the potential to generate useful additions to public policy and expansion of social theory. CONCLUSION: Analysis of these data in this paper supports the potential for positive outcomes gained by reciprocal collaboration between animal owners and emergency responders. Some simple practical solutions are evident and two major outcome streams are identified. These are (1) policy development and implementation and (2) etiology of decision-making. Considerations and recommendations for research examining the efficacy of these streams and solutions are provided. PMID- 28361059 TI - In vitro prediction of breast cancer therapy toxicity. AB - BACKGROUND: Understanding the basis of clinical radiosensitivity is a key goal of radiation research. In this study, we used the limiting dilution assay (LDA) to analyze in vitro radiosensitivity of cell lines from individuals with breast and other cancers, who had been treated with ionizing radiation, and who either had a non-radiosensitive (RS) radiation response or who were clinically RS. METHODS: Lymphoblastoid cell lines (LCLs) were created from 29 cancer patients including 19 RS patients, 10 controls who had not developed severe normal tissue reactions, and 1 ataxia telangiectasia RS control cell line. The clinically RS patients had grade 3 or grade 4 reactions; one had a grade 2 reaction. All cells were exposed to graded doses of gamma-radiation in vitro and cell survival assessed via LDA. Cell survival was expressed on non-linear regression analysis-fitted survival curves and also as the surviving fraction at 2 Gray (Gy) (SF2). RESULTS: Our LDA analysis yielded two notable positive results. Firstly, it could distinguish control cells from cells from pooled breast cancer cases with severe reactions of all types (acute reactors, consequential late reactors and late reactors). Secondly, two radiosensitivity outliers were detected on the fitted curves, corresponding clinically to grade 3 and 4 late radiation reactions in breast and head and neck cancer cases respectively. The assay showed considerable cell survival heterogeneity. CONCLUSIONS: The LDA as used here may provide unique clinical utility in detecting potential RS breast cancer patients prior to radiotherapy (RT), a form of personalized medicine. The assay may be especially useful in situations where its results can be temporally available prior to therapy initiation (e.g., those patients not undergoing RT until some months after surgery, typically those having adjuvant chemotherapy prior to RT). Two LCLs from RS outliers could potentially yield insight into the cellular and/or genetic basis of radiosensitivity, for example by undertaking genomic analyses on these cell lines. PMID- 28361060 TI - Bioaerosols in the lungs of subjects with different ages-Part 2: clearance modeling. AB - BACKGROUND: The present contribution deals with theoretical aspects regarding biogenic particle clearance from various lung structures of probands with different ages (1, 5, 15, 20 y). With reference to part 1 of the study, particles varying in size and shape are subject to a detailed analysis. The main goal of the investigation consists in an increase of our knowledge concerning the clearance behaviour of bioparticles and its dependence upon various physiological and anatomical factors. METHODS: Theoretical clearance of biogenic particles was subdivided into four main phases, namely fast bronchial clearance, slow bronchial clearance, fast alveolar clearance, and slow alveolar clearance. All of these phases were simulated by using a well validated stochastic modeling approach, where the main focus is set on the randomly varied particle mass transfer between main compartments of the human respiratory tract. Whilst effects of particle geometry on clearance were approximated by application of the projective-diameter concept, age dependence of the particle removal process was expressed by the experimentally proven relationship between bronchial mucus velocities and morphometry of the airway tree. RESULTS: According to the results of the theoretical simulations efficiency of fast bronchial clearance, expressed by the 24-h-retention value, exhibits a negative correlation with proband's age, whereas the other clearance phases are characterized by a rather conservative behaviour among the different age categories. Highest clearance rates may be observed for very fine (<0.01 um) and very coarse particles (>5 um) preferentially deposited in the upper bronchial airways, whilst large particles accumulated in the alveoli may be stored there for several months to years. CONCLUSIONS: The study comes to the conclusion that infants and children dispose of an enhanced bronchial clearance efficiency with respect to adolescents and adults, which results in a faster removal of particulate substances accumulated in the upper bronchial regions. Particles escaping from the natural filtering process in the upper airways and undergoing alveolar deposition are subject to identical clearance scenarios among the age groups and may represent remarkable health hazards. PMID- 28361061 TI - Non-homologous end-joining protein expression screen from radiosensitive cancer patients yields a novel DNA double strand break repair phenotype. AB - BACKGROUND: Clinical radiosensitivity is a significant impediment to tumour control and cure, in that it restricts the total doses which can safely be delivered to the whole radiotherapy population, within the tissue tolerance of potentially radiosensitive (RS) individuals. Understanding its causes could lead to personalization of radiotherapy. METHODS: We screened tissues from a unique bank of RS cancer patients for expression defects in major DNA double-strand break repair proteins, using Western blot analysis and subsequently reverse transcriptase polymerase chain reaction and pulsed-field gel electrophoresis. RESULTS: We hypothesized that abnormalities in expression of these proteins may explain the radiosensitivity of some of our cancer patients. The cells from one patient showed a reproducibly consistent expression reduction in two complex forming DNA double-strand break repair protein components (DNA Ligase IV and XRCC4). We also showed a corresponding reduction in both gene products at the mRNA level. Additionally, the mRNA inducibility by ionizing radiation was increased for one of the proteins in the patient's cells. We confirmed the likely functional significance of the non-homologous end-joining (NHEJ) expression abnormalities with a DNA double strand break (DNA DSB) repair assay. CONCLUSIONS: We have identified a novel biological phenotype linked to clinical radiosensitivity. This is important in that very few molecular defects are known in human radiotherapy subjects. Such knowledge may contribute to the understanding of radiation response mechanisms in cancer patients and to personalization of radiotherapy. PMID- 28361062 TI - Is the SenseWear Armband accurate enough to quantify and estimate energy expenditure in healthy adults? AB - BACKGROUND: The SenseWear Armband (SWA) is a monitor that can be used to estimate energy expenditure (EE); however, it has not been validated in healthy adults. The objective of this paper was to study the validity of the SWA for quantifying EE levels. METHODS: Twenty-three healthy adults (age 40-55 years, mean: 48+/-3.42 years) performed different types of standardized physical activity (PA) for 10 minutes (rest, walking at 3 and 5 km.h-1, running at 7 and 9 km.h-1, and sitting/standing at a rate of 30 cycle.min-1). Participants wore the SWA on their right arm, and their EE was measured by indirect calorimetry (IC) the gold standard. RESULTS: There were significant differences between the SWA and IC, except in the group that ran at 9 km.h-1 (>9 METs). Bland-Altman analysis showed a BIAS of 1.56 METs (+/-1.83 METs) and limits of agreement (LOA) at 95% of -2.03 to 5.16 METs. There were indications of heteroscedasticity (R2 =0.03; P<0.05). Analysis of the receiver operating characteristic (ROC) curves showed that the SWA seems to be not sensitive enough to estimate the level of EE at highest intensities. CONCLUSIONS: The SWA is not as precise in estimating EE as IC, but it could be a useful tool to determine levels of EE at low intensities. PMID- 28361063 TI - Survival of primary lung cancer patients in Brunei Darussalam, 1987-2012. AB - BACKGROUND: In 2009 to 2011, the commonest cause of death was by cancer in Brunei Darussalam, and 16.5% and 19.5% of cancer deaths were due to lung cancer in 2004 and 2011 respectively. This study was to investigate the survival of lung cancer patients in Brunei Darussalam. METHODS: This retrospective cohort study was conducted in 2013 & 2014 for those who were diagnosed as primary lung cancer in the period of 1987 to 2012. Data were retrieved from patients' medical records and death certificates using pretested data collection form. Survival analyses namely Kaplan-Meier method, and log-rank test to compare survival between groups. RESULTS: We retrieved 630 primary lung cancer records. Majority was diagnosed at the late stages, 42.5% at Stage IV & 33.4% at Stage III. The overall median survival time was 6.1 months whereas 2.6 and 79.1 months for Stage IV and Stage I respectively. The overall 6-month, 1-, 3- and 5-year survival rates were 50.2%, 32.1%, 14.5% and 8.8% respectively. Survival duration had significantly improved from 1987-1999 to 2000-2012 (P=0.001) although significant higher proportion of Stage IV was diagnosed in the second period (P=0.008). CONCLUSIONS: Overall survival rates and duration of primary lung cancer in Brunei Darussalam were comparable with some developed countries. However, through effective public intervention such as increase awareness, early case detection, and effective anti smoking strategies, survival of lung cancer patients can certainly be improved and the burden of disease can be reduced. PMID- 28361064 TI - The effect of financial crisis on the profile of the patients examined at the surgical emergencies of an academic institution in Greece. AB - BACKGROUND: Greece is suffering an economic recession of enormous magnitude, but whether its health has deteriorated as a result, has not yet been well established. We aim to present and analyze differences in demographics and clinical distribution of patients examined at the emergency room (ER) in the era of financial crisis. METHODS: A retrospective data analysis of all patients that were examined to surgical ER, between January 1st 2008 and December 31st 2014, was conducted. We only analyzed and evaluated data for the years 2008, 2011 and 2014. We evaluated the etiology of the examination (main complaint of the patient), the gender, the ethnic origin, the age and the severity of the disease, whenever it was feasible. The diseases that presented differences that were statistically significant were analyzed in terms of medical, social and financial aspects. RESULTS: The number of patients being examined in the ER in 2011 was higher compared with that of 2014 and to 2008 respectively (P<0.05). Throughout the years, there was a decline in vascular emergencies (veins, arteries, AAA; P<0.05). An increased incidence of soft tissue infections (STIs) was also found (P<0.05). Finally, an increased incidence of anal diseases and patients with abdominal pain was also noted (P<0.05). CONCLUSIONS: Financial crisis seems to have a multivariable effect on epidemiology and clinical diversity of patients being examined in the ER. PMID- 28361065 TI - Surgical prophylaxis with gentamicin and acute kidney injury: a systematic review and meta-analysis. AB - BACKGROUND: Gentamicin has been increasingly used instead of cephalosporins for surgical prophylaxis in an attempt to reduce the rate of "Clostridium difficile" infection. There are limited data regarding nephrotoxicity related to gentamicin in these patients. METHODS: We have conducted a systematic review and meta analysis to evaluate the risk of acute kidney injury (AKI) in gentamicin containing surgical prophylactic regimens, compared to regimens without gentamicin, in several types of surgery. Electronic searches were performed using PubMed and Embase, including terms for "AKI, gentamicin, and surgical prophylaxis" with and without MeSH/EMTREE functions. Statistical analysis was then performed using a random-effect model; risk ratios (RR), risk differences (RD) and heterogeneity (I2) were calculated. Funnel plot was used for assessment of publication bias. RESULTS: Eleven studies with fifteen cohorts with 18,354 patients were included in the analysis. Subgroup analysis was performed according to surgery type. We have found that antibiotic prophylaxis with gentamicin containing regimen has significant risk for developing postoperative AKI in orthopedic surgery (RR 2.99; 95% CI: 1.84, 4.88). The results were inconclusive in other types of surgery. Funnel plot indicates potential publication bias. CONCLUSIONS: Gentamicin-induced AKI is significant in patients undergoing orthopedic surgery. Physicians should consider risks and benefits of using this regimen in individual patients. PMID- 28361066 TI - Emerging treatments for hemophilia: patients and their treaters spoilt for choice, but laboratories face a difficult path? PMID- 28361067 TI - Structural equation modeling in the context of clinical research. AB - Structural equation modeling (SEM) has been widely used in economics, sociology and behavioral science. However, its use in clinical medicine is quite limited, probably due to technical difficulties. Because SEM is particularly suitable for analysis of complex relationships among observed variables, it must have potential applications to clinical medicine. The article introduces basic ideas of SEM in the context of clinical medicine. A simulated dataset is employed to show how to do model specification, model fit, visualization and assessment of goodness-of-fit. The first example fits a SEM with continuous outcome variable using sem() function, and the second explores the binary outcome variable using lavaan() function. PMID- 28361068 TI - Use of distal perfusion in peripheral extracorporeal membrane oxygenation. AB - Extra corporeal membrane oxygenation (ECMO) is a life-saving technique to manage refractory cardiopulmonary failure. Its usage and indication continue to increase. Femoral venoarterial ECMO (VA ECMO) is relatively less invasive and the cardiac support may be more rapidly instituted in in these extremely tenuous patients. Vascular injuries and limb ischemia unfortunately occur in these emergent access settings. Here we will discuss the optimal techniques of preventing this complication which might affect patient survival and impact the patient quality of life. PMID- 28361069 TI - Posterior reversible encephalopathy syndrome associated with left horizontal gaze palsy. AB - Posterior reversible encephalopathy syndrome (PRES) is characterized by rapid onset of symptoms including headache, seizures, altered consciousness, and visual disturbance, as well as radiologic findings of focal reversible vasogenic edema. Multiple visual disturbances have been described in PRES, such as hemianopia, visual neglect, auras, visual hallucinations, and cortical blindness. However, horizontal gaze palsy has not been previously reported. We report a 72-year-old female who presented with blurred vision, severe headache, lethargy, and later developed seizures. She was found to have left horizontal gaze palsy with intact vestibulo-ocular reflex. Brain magnetic resonance imaging (MRI) showed severe edema throughout the subcortical white matter, and signal in the posterior parietal and occipital lobes. She was diagnosed with PRES associated with supranuclear gaze palsy. PMID- 28361070 TI - Primary psoas sarcoma causing malignant psoas syndrome: favourable response to radiotherapy. AB - Malignant psoas syndrome (MPS) is an uncommon condition first described by Stevens et al. MPS is caused by malignant infiltration of the psoas muscle and adjacent nerves and is characterised by (fixed) flexion deformity of the ipsilateral hip and proximal lumbosacral plexopathy. It has previously been described in relation to metastatic carcinoma, melanoma and liposarcoma, as well as non-Hodgkins lymphoma. We present the case of a 68-year-old woman with a sarcoma arising in the left psoas muscle at the level of L4 who presented with symptoms of MPS. To the authors' knowledge this is the first case of MPS arising from a primary sarcoma of the iliopsoas compartment. The patient underwent presurgical radiotherapy, with a significant improvement in pain control without an increase in analgesic medications. We discuss the aetiology of MPS and the role of radiotherapy in the treatment of this rare syndrome. PMID- 28361071 TI - A brother and sister with breast cancer, BRCA2 mutations and bilateral supernumerary nipples. AB - We describe a 54-year-old man with breast cancer and a BRCA2 mutation who was also found to have bilateral supernumerary nipples. His sister, also with a BRCA2 mutation, was diagnosed with breast cancer in her late forties; she also had bilateral supernumerary nipples. We address the significance of breast cancer arising in breast tissue underlying supernumerary nipples; the known association between supernumerary nipples and genitourinary malignancies/malformations and the possible link between BRCA2 and supernumerary nipple development. We believe that this is the first described case of the latter. We then outline an approach to further management for supernumerary nipple cases. PMID- 28361072 TI - High-flow nasal cannula is superior to noninvasive ventilation to prevent reintubation? PMID- 28361073 TI - Is there a benefit to locally consolidative therapy for oligometastatic non-small cell lung cancer? PMID- 28361074 TI - Neonatal Ebstein repair-where are we now? PMID- 28361075 TI - Liposteroid therapy for juvenile and adult dermatomyositis: efficacy and side effects. PMID- 28361076 TI - Not all extracellular vesicles were created equal: clinical implications. PMID- 28361077 TI - Extra corporeal membrane oxygenation support: ethical dilemmas. AB - The vast expansion of patients treated with of extra corporeal membrane oxygenation (ECMO) emerge novel ethical questions about the use of this new technology. In regard the indications, duration of support and timing of withdrawal of support, these questions sometimes create disagreement among surrogates, between health care team and surrogates, and even disagreement among health care team, these disagreements occurs because of the extreme emergency of support initiation, the ambiguity of the outcome as well as lack of clarity on the intended treatment direction, whether it is ineffective, bridge to recovery or bridge to lifetime mechanical support or transplant. In this article we discuss these questions through patients' scenarios. PMID- 28361078 TI - Targeting the seeds of small cell lung cancer. AB - The concept of antibody drug conjugates (ADCs), which includes the delivery of cytotoxic drugs to antigen-expressing tumor cells by harnessing the antigen selectivity of a monoclonal antibody, has the potential to redefine the landscape of translational medicine. With the advent of patient derived xenograft (PDX) models and sophisticated genomic technologies, the identification of a selective antigen can be accurately validated within the appropriate tumor milieu. However, a major biological hurdle in cancer translational medicine is the inherent tumoral heterogeneity, underscoring the importance of targeting the 'right' sub population of cancer cells. Herein, we review a seminal work highlighting the ability to target a key 'stem-like' cancer sub-population called tumor initiating cells (TICs) using engineered ADCs. While the promise of this approach needs to be validated in the clinical setting, TIC-targeted ADCs offer great hope for circumventing current limitations with conventional ADC therapy. PMID- 28361079 TI - Ultrasound to assess diaphragmatic function in the critically ill-a critical perspective. AB - Ultrasound of the diaphragm in critically ill patients has become a diagnostic technique of emerging interest among clinicians and scientists. The advantages include that it is widely available, non-invasive and examination can be performed after relatively short training and at low costs. It is used to estimate muscle mass by measurement of muscle thickness and diagnose weakness by the assessment of diaphragm movement during unassisted breathing. Thickening of the muscle during inspiration has been used to quantify force generation. The enthusiasm that surrounds this topic is shared by many clinicians and we agree that ultrasound is a valuable tool to screen for diaphragm dysfunction in intensive care unit (ICU) patients. However, in our opinion much more studies are required to validate ultrasound as a tool to quantify breathing effort. More sophisticated ultrasound techniques, such as speckle tracking imaging are promising techniques to evaluate respiratory muscle function in patients, including the critically ill. PMID- 28361081 TI - On vs. off pump coronary artery bypass grafting: the next chapter. PMID- 28361080 TI - Future directions of extracellular vesicle-associated miRNAs in metastasis. AB - Numerous studies have demonstrated the dynamic cell-to-cell communication mediated by extracellular vesicles (EV) in cancer cell survival and metastasis development. EV content includes proteins, lipids, DNA, and RNA like microRNAs. Non-protein coding microRNAs play a very active role in almost all cellular processes targeting mRNAs for silencing. Different miRNA profiles have been found in different cancer types, and clarification of miRNAs packed in EV from different types of cancers will allow the understanding of metastasis and the application of miRNAs as biomolecules in diagnostic, prognostic and therapeutic approaches to fight cancer. The profound review of Dhondt et al., 2016, provides a wide view of EV miRNAs involved in various steps of the metastasis process to illustrate how the cancer cell interaction with the near and long distance microenvironment allows metastasis. These studies will surely conduce to additional patient studies to prove the relevance of EV miRNAs in metastasis in vivo. It remains to be elucidated how the tumoral cell sorts the miRNAs for secretion to send a message, and to well recognize the type of EV performing this message delivering. It will be very useful to identify whether miRNAs are delivered with post-transcriptional modifications since this is an important feature for miRNAs activity and stability. PMID- 28361082 TI - Is the exosome a potential target for cancer immunotherapy? PMID- 28361083 TI - Next steps to improve disparities in lung cancer treatment clinical trial enrollment. PMID- 28361084 TI - Meta-analysis on extracorporeal life support during cardiac arrest: do not compare apples and oranges. PMID- 28361085 TI - Human stem memory T cells (TSCM) as critical players in the long-term persistence of immune responses. PMID- 28361086 TI - Asymmetric cell division regulates the transcriptional balance controlling memory fate decisions in T cells. PMID- 28361087 TI - Proper selection of sedative drugs improves outcomes: volatile anesthetics are surgeons' best friends. PMID- 28361088 TI - Residency training in Greece: job dissatisfaction paves the way to brain drain. PMID- 28361089 TI - Truth behind hypokalemia. PMID- 28361090 TI - Prof. Stefanie Dimmeler: long non-coding RNAs-why it is important in cardiovascular disease. PMID- 28361091 TI - The highlights in the Digestive Disease Institute Week 2017. PMID- 28361092 TI - Erratum to Isolated idiopathic aortitis with an unusually thickened aortic wall: case report. AB - [This corrects the article DOI: 10.21037/atm.2016.11.14.]. PMID- 28361093 TI - A Systematic Review of the Management of Incidental Findings in Genomic Research. AB - Information empowerment has been the greatest gain of genomics, yet it also poses serious threat to its survival, especially when the information is incidental. There may be an emerging consensus that actionable incidental findings be returned. But this has not been supported by any systematic review. Future directions are equally missing. These are significant gaps. To fill these gaps, an online search on PubMed and Genetics in Medicine website was conducted between 20th of August to 23rd of October, 2013; combining certain filters and phrases, such as 'return incidental findings'. Nineteen (19) articles were selected from an avalanche of results, and reviewed. The review confirms a majority support for return of clinically actionable findings. The result also shows that the support represents views of Northern Americans. Critical contributions of Africans, Asians and Europeans are missing in this discourse. I recommended studies in this direction. PMID- 28361095 TI - Genetics and genomic medicine in Indonesia. AB - Genetics and genomic medicine in Indonesia. PMID- 28361094 TI - Genetic contributions to stuttering: the current evidence. AB - Evidence for genetic factors in persistent developmental stuttering has accumulated over the past four decades, and the genes that underlie this disorder are starting to be identified. The genes identified to date, all point to deficits in intracellular trafficking in this disorder. PMID- 28361096 TI - Clinical dose effect and functional consequences of R92Q in two families presenting with a TRAPS/PFAPA-like phenotype. AB - BACKGROUND: TNF receptor-associated syndrome (TRAPS) is a dominantly inherited autoinflammatory condition caused by mutations in the TNFRSF1A gene. The mechanism underlying the variable expressivity of the common variant R92Q (rs4149584; c.362G>A; p.Arg121Gln) is unclear and is of critical importance for patient care and genetic counseling. This study evaluated the impact of the number of R92Q mutations in two unique unrelated families. METHODS: Two patients with undefined but clear autoinflammatory symptoms were referred for genetic diagnosis. Blood samples were collected from the available family members to screen autoinflammatory genes and assess key steps of the TNFR1-mediated signaling pathway using flow cytometry and ex vivo culture. RESULTS: R92Q homozygosity was demonstrated for the two probands. In family 1, the segregation analysis revealed TRAPS-like symptoms in all carriers, with a more severe presentation in the proband, whereas in family 2, the heterozygous parents were totally asymptomatic, suggesting recessive transmission. Functional studies revealed a nonclassical pathogenesis of TRAPS in the two probands and suggested a compensatory mechanism without clear dose effect. CONCLUSION: We observed for the first time a possible clinical dose effect of R92Q. This work highlights the importance of familial studies to reconcile the contradictory reports published on the pathogenicity of this variant. PMID- 28361097 TI - Independent variant analysis of TEAD1 and OCEL1 in 38 Aicardi syndrome patients. AB - BACKGROUND: Aicardi syndrome is a severe neurodevelopmental disorder characterized by infantile spasms, typical chorioretinal lacunae, agenesis of the corpus callosum, and other neuronal migration defects. It has been reported recently that de novo variants in TEAD1 and OCEL1 each may cause Aicardi syndrome in a single individual of a small cohort of females with this clinical diagnosis. These data were interpreted to suggest that the clinical diagnosis of Aicardi syndrome may be genetically heterogeneous. METHODS: To investigate this further, we sequenced TEAD1 and OCEL1 coding regions using DNA from 38 clinically well characterized girls with Aicardi syndrome. RESULTS: We did not detect the previously reported or any other deleterious variants in any of the analyzed samples. CONCLUSIONS: This suggests that the published variants represent either an extremely rare cause of Aicardi syndrome or an incidental finding. PMID- 28361098 TI - Building a family network from genetic testing. AB - BACKGROUND: Genetic testing has multigenerational and familial repercussions. However, the "trickle-down effect" of providing genetic counseling and testing to family members at risk after an initial identification of a pathogenic variant in a medically actionable gene has been poorly understood. METHODS: Three probands were identified during the pharmacogenetics research phase of eMERGEII (electronic MEdical Record and Genomics, phase II) to have variants in genes associated with autosomal dominant adult-onset disorders determined to be actionable by the American College of Medical Genetics (ACMG). Two of the three probands had variants that were classified as pathogenic and the third proband had a variant ultimately classified of uncertain significance, but of concern due to the proband's own phenotype. All probands had additional family members at risk for inheriting the variant. Two of the three probands had family members who received their medical care from the same health care system, Group Health Cooperative (GHC). It was recommended that the proband contact their family members at risk to be referred to genetic counseling for consideration of genetic testing. RESULTS: The two probands with pathogenic variants contacted some of their family members at risk. Individuals contacted included children and adult grandchildren, particularly if they received their medical care at GHC. To the best of our knowledge, siblings and more distant relatives at risk were not informed by the proband of their genetic risk. CONCLUSIONS: Establishing a family network is essential to disseminate knowledge of genetic risk. These three initial cases describe our experience of contacting eMERGE participants with identified variants, providing the probands with appropriate genetic counseling and care coordination, and recommendations for contacting family members at risk. Greater challenges were observed for coordinating genetics care for family members and extending the family network to include other relatives at risk. PMID- 28361100 TI - A novel de novo frameshift deletion in EHMT1 in a patient with Kleefstra Syndrome results in decreased H3K9 dimethylation. AB - BACKGROUND: Kleefstra Syndrome (KS) (MIM# 610253) is an autosomal dominant disorder caused by haploinsufficiency of euchromatic histone methyltransferase-1 (EHMT1, GLP). EHMT1 (MIM# 607001) encodes a histone methyltransferase that heterodimerizes with EHMT2 (also known as G9a, MIM# 604599), which together are responsible for mono- and dimethylation of H3 lysine 9 (H3K9me1 and -me2), resulting in transcriptional repression of target genes. METHODS: This report describes an 18-year-old woman with intellectual disability, severely limited speech, hypotonia, microcephaly, and facial dysmorphisms, who was found to have a novel de novo single-base frameshift deletion in EHMT1. RESULTS: Functional studies using patient fibroblasts showed decreased H3K9me2 compared to wild-type control cells, thus providing a rapid confirmatory test that complements molecular studies. CONCLUSION: Whole exome sequencing revealed a novel frameshift deletion in EHMT1 after a lengthy diagnostic odyssey in this patient. Functional testing using this patient's fibroblasts provides proof-of-concept for the analysis of variants of uncertain significance that are predicted to impact EHMT1 enzymatic activity. PMID- 28361099 TI - A de novo splice site mutation in EHMT1 resulting in Kleefstra syndrome with pharmacogenomics screening and behavior therapy for regressive behaviors. AB - BACKGROUND: Kleefstra syndrome (KS) is a rare autosomal dominant developmental disability, caused by microdeletions or intragenic mutations within the epigenetic regulator gene EHMT1 (euchromatic histone lysine N-methyltransferase 1). In addition to common features of autism, young adult regressive behaviors have been reported. However, the genetic downstream effects of the reported deletions or mutations on KS phenotype have not yet been completely explored. While genetic backgrounds affecting drug metabolism can have a profound effect on therapeutic interventions, pharmacogenomic variations are seldom considered in directing psychotropic therapies. METHODS: In this report, we used next generation sequencing (exome sequencing and high-throughput RNA sequencing) in a patient and his parents to identify causative genetic variants followed by pharmacogenomics-guided clinical decision-making for making positive changes toward his treatment strategies. The patient had an early autism diagnosis and showed significant regressive behaviors and physical aberrations at age 23. RESULTS: Exome sequencing identified a novel, de novo splice site variant NM_024757.4: c.2750-1G>T in EHMT1, a candidate gene for Kleefstra syndrome, in the patient that results in exon skipping and downstream frameshift and termination. Gene expression results from the patient showed, when compared to his parents, there was a significant decreased expression of several reported gene variants associated with autism risk. Further, using a pharmacogenomics genotyping panel, we discovered that the patient had the CYP2D6 nonfunctioning variant genotype *4/*4 that results in very low metabolic activity on a number of psychotropic drugs, including fluvoxamine which he was prescribed. As reported here, a change in psychotropic drugs and intense behavior therapies resulted in a significant reversal of the regressive behaviors and physical aberrations. CONCLUSION: These results demonstrate an individualized approach that integrated genetic information and behavior therapies, resulting in a dramatic improvement in regressive behaviors associated with KS. PMID- 28361102 TI - Gene-centric analysis implicates nuclear encoded mitochondrial protein gene variants in migraine susceptibility. AB - BACKGROUND: Migraine is a common neurological disorder which affects a large proportion of the population. The Norfolk Island population is a genetically isolated population and is an ideal discovery cohort for genetic variants involved in complex disease susceptibility given the reduced genetic and environmental heterogeneity. Given that the majority of proteins responsible for mitochondrial function are nuclear encoded, this study aimed to investigate the role of Nuclear Encoded Mitochondrial Protein (NEMP) genes in relation to migraine susceptibility. METHODS: A gene-centric association analysis of NEMP genes was undertaken in the most related individuals (n = 315) within the genetically isolated Norfolk Island population. The discovery phase included genes with three or more SNP associations (P < 0.005), which were investigated further in a replication phase using an unrelated migraine case-control cohort (544 patients and 584 controls). RESULTS: The discovery phase of the study implicated SNPs in 5 NEMP genes to be associated with migraine susceptibility (P < 0.005). Replication analysis validated some of these implicated genes with SNPs in three NEMP genes shown to be associated with migraine in the replication cohort. These were CSNK1G3 (P = 0.00037), ELOVL6 (P = 0.00035) and SARDH (P = 0.00081), which are involved in phosphorylation, fatty acid metabolism, and oxidative demethylation, respectively. CONCLUSION: Here we provide evidence that variation in NEMP genes is associated with migraine susceptibility. This study provides evidence for a link between mitochondrial function and migraine susceptibility. PMID- 28361101 TI - A molecular analysis of the GBA gene in Caucasian South Africans with Parkinson's disease. AB - BACKGROUND: The molecular basis of Parkinson's disease in South African population groups remains elusive. To date, substitutions in the GBA gene are the most common large-effect genetic risk factor for Parkinson's disease. The primary objective of this study was to determine the prevalence of GBA substitutions in South Africans with idiopathic Parkinson's disease. METHODS: Participants were recruited from tertiary hospitals in the Gauteng Province in South Africa. All participants were screened for substitutions in GBA exon 8-11 and the full coding region was analysed in 20 participants. Peripheral beta-glucocerebrosidase enzymatic activity of GBA-carriers was measured in mixed leukocytes. RESULTS: Of 105 Caucasian Parkinson's disease participants (82.7% Afrikaner) with an average age of disease onset of 61.9 +/- 12.2 years and 40 controls (age 73.4 +/- 12.4 years) were included. Heterozygous GBA substitutions were identified in 12.38% of affected participants (p.G35A, p.E326K, p.I368T, p.T369M, p.N370S, p.P387L and p.K441N) and 5.00% of controls (p.E326K and p.T369M). The substitutions ranged from predicted benign to moderately damaging; with p.E326K and p.T369M most prevalent, followed by the Afrikaner Gaucher disease substitution p.P387L. Severe Gaucher disease mutations, like p.L444P, were absent in this cohort. Enzyme activity analysis revealed a nonsignificant reduction in the GBA-Parkinson's disease individuals (14.49 +/- 2.30 nmol/h/mg protein vs. 15.98 +/- 3.06 nmol/h/mg in control samples). GBA substitutions occur in both young-onset and late-onset Parkinson's cases in the cohort. CONCLUSION: Mild GBA substitutions that may not cause Gaucher disease were a common risk factor for Parkinson's disease in the participant group. PMID- 28361104 TI - Discordance in selected designee for return of genomic findings in the event of participant death and estate executor. AB - BACKGROUND: Legal and ethical questions arise regarding disseminating genetic research results to family members in the event of a research participant's death; failure to return or return to legal next of kin or estate executor may not reflect participant desires. We sought to determine participant preferences for whether and to whom they would like their data released in the case of their death prior to receiving genomic results, focusing on whether the person selected was also their estate executor. METHODS: The University of Washington NEXT Medicine Study of the Clinical Sequencing Exploratory Research program previously reported participant preferences regarding designating an individual to receive genomic results in the event of death, including whether they want results shared, and if so, with what person. Participants were also asked whether this designee is executor of their will or estate. RESULTS: To date, 61 individuals were asked about the concordance of their study designee and legal representative: 42 (69%) reported having a will or estate plan and of these, 14 (33%) chose someone other than their executor to receive their results. For the 14 who chose someone other than their estate executor to receive genetic results, 12 (86%) chose a family member, typically a biological relative, as their designee. Those with a different genomic designee than their executor were less likely to be partnered (P = 0.0024). For those partnered participants without an estate plan, spouses were not always chosen for return of genomic results. CONCLUSION: For one-third of our participants, the individual deemed most appropriate by the participant to receive their genomic results was not the executor. In the absence of an explicit designation, HIPAA may prohibit access to genomic results to persons other than the executor; hence asking for designation at the time of study enrollment (or initiation of clinical testing) is important. PMID- 28361103 TI - The prevalence, penetrance, and expressivity of etiologic IRF6 variants in orofacial clefts patients from sub-Saharan Africa. AB - BACKGROUND: Orofacial clefts are congenital malformations of the orofacial region, with a global incidence of one per 700 live births. Interferon Regulatory Factor 6 (IRF6) (OMIM:607199) gene has been associated with the etiology of both syndromic and nonsyndromic orofacial clefts. The aim of this study was to show evidence of potentially pathogenic variants in IRF6 in orofacial clefts cohorts from Africa. METHODS: We carried out Sanger Sequencing on DNA from 184 patients with nonsyndromic orofacial clefts and 80 individuals with multiple congenital anomalies that presented with orofacial clefts. We sequenced all the nine exons of IRF6 as well as the 5' and 3' untranslated regions. In our analyses pipeline, we used various bioinformatics tools to detect and describe the potentially etiologic variants. RESULTS: We observed that potentially etiologic exonic and splice site variants were nonrandomly distributed among the nine exons of IRF6, with 92% of these variants occurring in exons 4 and 7. Novel variants were also observed in both nonsyndromic orofacial clefts (p.Glu69Lys, p.Asn185Thr, c.175 2A>C and c.1060+26C>T) and multiple congenital anomalies (p.Gly65Val, p.Lys320Asn and c.379+1G>T) patients. Our data also show evidence of compound heterozygotes that may modify phenotypes that emanate from IRF6 variants. CONCLUSIONS: This study demonstrates that exons 4 and 7 of IRF6 are mutational 'hotspots' in our cohort and that IRF6 mutants-induced orofacial clefts may be prevalent in the Africa population, however, with variable penetrance and expressivity. These observations are relevant for detection of high-risk families as well as genetic counseling. In conclusion, we have shown that there may be a need to combine both molecular and clinical evidence in the grouping of orofacial clefts into syndromic and nonsyndromic forms. PMID- 28361105 TI - Single-nucleotide substitution T to A in the polypyrimidine stretch at the splice acceptor site of intron 9 causes exon 10 skipping in the ACAT1 gene. AB - BACKGROUND: beta-ketothiolase (T2, gene symbol ACAT1) deficiency is an autosomal recessive disorder, affecting isoleucine and ketone body metabolism. We encountered a patient (GK03) with T2 deficiency whose T2 mRNA level was <10% of the control, but in whom a previous routine cDNA analysis had failed to find any mutations. Genomic PCR-direct sequencing showed homozygosity for c.941-9T>A in the polypyrimidine stretch at the splice acceptor site of intron 9 of ACAT1. Initially, we regarded this variant as not being disease-causing by a method of predicting the effect of splicing using in silico tools. However, based on other findings of exon 10 splicing, we eventually hypothesized that this mutation causes exon 10 skipping. METHODS: cDNA analysis was performed using GK03's fibroblasts treated with/without cycloheximide (CHX), since exon 10 skipping caused a frameshift and nonsense-mediated mRNA decay (NMD). Minigene splicing experiment was done to confirm aberrant splicing. RESULTS: cDNA analysis using fibroblasts cultured with cycloheximide indeed showed the occurrence of exon 10 skipping. A minigene splicing experiment clearly showed that the c.941-9T>A mutant resulted in transcripts with exon 10 skipping. There are few reports describing that single-nucleotide substitutions in polypyrimidine stretches of splice acceptor sites cause aberrant splicing. CONCLUSION: We showed that c.941 9T>A induces aberrant splicing in the ACAT1 gene. Our ability to predict the effects of mutations on splicing using in silico tools is still limited. cDNA analysis and minigene splicing experiments remain useful alternatives to reveal splice defects. PMID- 28361106 TI - Fluorescence spectroscopy of roGFP2-based redox probes responding to various physiologically relevant oxidant species in vitro. AB - This article contains representative fluorescence excitation spectra of roGFP2 based probes used for ratiometric analysis of redox changes as presented in the article "Systematic in vitro assessment of responses of roGFP2-based probes to physiologically relevant oxidant species" [1]. The recombinant probes roGFP2, roGFP2-Orp1, and Grx1-roGFP2 were exposed to various oxidative and nitrosative species, including hydrogen peroxide (H2O2), aldrithiol-2 (AT-2), glutathione disulfide (GSSG), hypochlorous acid (HOCl), S-nitrosoglutathione (GSNO), peroxynitrite (ONOO-), potassium polysulfide (K2Sx), spermine NONOate (SperNO), and diethyl amino NONOate (DeaNO) at different molar ratios. Fluorescence excitation spectra of the probes were recorded in the excitation wavelength range between 350 and 500 nm and for a total of 60 min. Analysis and interpretation of the data is presented in an associated article [1]. PMID- 28361108 TI - A generalized fixed drug eruption associated with mycophenolate. PMID- 28361107 TI - Remission of subcutaneous panniculitis-like T-cell lymphoma in a pregnant woman after treatment with oral corticosteroids as monotherapy. AB - Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of cutaneous T-cell lymphoma characterized by neoplastic alpha/beta T cells infiltrating subcutaneous tissues in a lobular pattern. Few data support the optimal treatment regimen for patients, given the rarity of this condition, and even fewer data describe treatment when diagnosed during pregnancy. We describe a case of SPTCL in a pregnant patient who achieved clinical remission after treatment with corticosteroid monotherapy. Our case suggests that corticosteroids should be considered as first-line treatment in pregnant patients with SPTCL. PMID- 28361109 TI - Trousseau syndrome presenting with penile gangrene. PMID- 28361110 TI - Patterns of Care and Outcomes in Cardiovascular Disease After Kidney Transplantation in the United States. AB - BACKGROUND: Cardiovascular disease (CVD) is an important driver of mortality after kidney transplantation. Its broader impact on posttransplant health care utilization in US hospitals is unknown. METHODS: We used administrative claims data from the Nationwide Inpatient Sample and the American Hospital Association Annual Survey to identify hospitalizations for kidney transplant patients with a cardiovascular diagnosis from 2005 to 2011. CVD hospitalizations were stratified by transplant hospital status to characterize patterns in inpatient health care utilization and outcomes. Based on these analyses, the domestic burden of treatment for posttransplant CVD (myocardial infarction, stroke, congestive heart failure, dysrhythmia, cardiac arrest, malignant hypertension) was estimated. RESULTS: The total domestic burden of post-kidney transplant hospitalization between 2005 and 2011 is estimated at 389 138 of which 26.5% of episodes were related to CVD (n = 103 118). CVD was responsible for a growing proportion of post-transplant hospitalizations over time (24.4%-30.4%, P < 0.001). Compared with nontransplant hospitals, transplant hospitals had similar length of stay (median length of stay, 3.7 days), higher median costs per hospitalization (US $10 364 vs US $8606, overall US $9324), and lower adjusted mortality (3.2% vs 3.9%, overall 3.6%; P = 0.003). CONCLUSIONS: Inpatient CVD care is increasing over time for kidney transplant patients, accounting for 30% of all post transplant hospitalizations. Variation exists in the inpatient care, outcomes, and costs between by hospital type. Further studies are needed to better understand the mechanisms behind these phenomena. PMID- 28361111 TI - Perspectives of Patients, Caregivers and Researchers on Research Priorities in Donation and Transplantation in Canada: A Pilot Workshop. AB - BACKGROUND: It is vitally important to seek input from key stakeholders to increase the quality and relevance of health-related research and accelerate its adoption into practice. Patients and caregivers have rarely been involved in setting research priorities in the transplantation and donation field. The objectives of this explorative study are: (i) to discuss research priorities within the Canadian National Transplant Research Program during a priority setting exercise with patients, caregivers, organ donors and researchers and (ii) to compare the identified priorities with research published in 2 prestigious transplantation journals. METHODS: A pilot workshop attended by 10 patients and caregivers and 5 researchers was held in Montreal (Quebec, Canada) in August 2014 to identify research priorities. Priorities were identified using a thematic analysis of the workshop transcription conducted by multiple coders. These priorities were compared with the topics of research articles published in 2 major transplantation journals between 2012 and 2014. RESULTS: The themes of the 10 research priorities identified by study participants were related to different research domains: social, cultural, and environmental health factors (4); biomedical or clinical (4); and research about health systems and services (2). 26.7% of the research articles published were related to the identified priorities. Thirteen percent looked at ways to improve graft survival and 8.5% looked at the development of tolerance, 2 priorities identified by participants. Fewer than 5% examined the other 8 research priorities identified as important by workshop participants. CONCLUSIONS: This is the first study reporting patients' and researchers' priorities in the field of transplantation and donation in Canada. There is a discrepancy between topics that key stakeholders find important and research published in 2 major transplantation journals. The research priorities identified during our initial workshop will be validated through a national survey and workshop. PMID- 28361112 TI - 5 Years Experience With Drug Eluting and Bare Metal Stents as Primary Intervention in Transplant Renal Artery Stenosis. AB - BACKGROUND: Transplant renal artery stenosis (TRAS) is a common vascular complication after kidney transplantation and is associated with refractory hypertension, volume overload, and graft injury or loss. This article describes 5 year outcomes of endovascular intervention for TRAS with bare metal and drug eluting stents (DES). METHODS: We investigated, as a prospective cohort study, patient and graft outcomes after the targeted use of DES for vessel diameter less than 5 mm and bare metal stents (BMS) for vessel diameter greater than 5 mm as the primary management for TRAS. RESULTS: From March 2008 to November 2014, 57 patients were stented for hemodynamically significant TRAS; 29 received DES, 26 received BMS, and 2 patients received both stent types. They were followed up for a mean of 35.1 +/- 22.8 months; a subset of these patients who all received DES were followed up for 61.7 +/- 17.5 months. Mean serum creatinine declined from 2.87 +/- 1.5 mg/dL at the time of intervention to 1.98 +/- 0.76 mg/dL (P < 0.001) at one month follow-up and was 1.96 +/-0.92 mg/dL (P < 0.001) at 35.1 +/- 22.8 months. Mean systolic blood pressure declined from 159.05 +/- 19.68 mm Hg at time of intervention to 135.65 +/- 15.10 mm Hg (P < 0.001) at most recent visit. Clinically driven restenosis requiring repeat revascularization occurred in 15.7% of patients. CONCLUSIONS: Primary stenting with DES and BMS is both successful in the initial treatment of TRAS and also produced an immediate and long-term reduction in serum creatinine and systolic blood pressure. PMID- 28361113 TI - Overweight Kidney Transplant Recipients Are at Risk of Being Overdosed Following Standard Bodyweight-Based Tacrolimus Starting Dose. AB - BACKGROUND: Bodyweight-based dosing of tacrolimus (Tac) is considered standard care, even though the available evidence is thin. An increasing proportion of transplant recipients is overweight, prompting the question if the starting dose should always be based on bodyweight. METHODS: For this analysis, data were used from a randomized-controlled trial in which patients received either a standard Tac starting dose or a dose that was based on CYP3A5 genotype. The hypothesis was that overweight patients would have Tac overexposure following standard bodyweight-based dosing. RESULTS: Data were available for 203 kidney transplant recipients, with a median body mass index (BMI) of 25.6 (range, 17.2-42.2). More than 50% of the overweight or obese patients had a Tac predose concentration above the target range. The CYP3A5 nonexpressers tended to be above target when they weighed more than 67.5 kg or had a BMI of 24.5 or higher. Dosing guidelines were proposed with a decrease up to 40% in Tac starting doses for different BMI groups. The dosing guideline for patients with an unknown genotype was validated using the fixed-dose versus concentration controlled data set. CONCLUSIONS: This study demonstrates that dosing Tac solely on bodyweight results in overexposure in more than half of overweight or obese patients. PMID- 28361114 TI - En Bloc Cadaver Kidney Transplantation From a 9-Month-Old Donor to an Adult Recipient: Maturation of Glomerular Size and Podocyte in the Recipient. AB - BACKGROUND: Favorable outcomes of en bloc pediatric donor kidney transplantation to adult recipients are attributed primarily to grafting of twice the nephron mass of a single kidney. METHODS: The kidneys of a 9-month-old male infant were transplanted en bloc in a 56-year-old man. Biopsies were performed 1 hour postreperfusion, 6 months and 3.5 years posttransplant. RESULTS: Warm and cold ischemia times were 21 and 426 minutes, respectively. The recipient was released from hemodialysis 10 days posttransplant and discharged 91 days posttransplant when serum creatinine was 0.9 mg/dL. At 4 years and 9 months posttransplant, serum creatinine was 1.0 mg/dL, and estimated glomerular filtration rate was 58.0 mL/min per 1.73 m2. The grafts increased in size until they reached adult size by 3 months posttransplant. The glomerular area and volume, respectively, increased from 5.9 * 103 MUm2 and 0.34 * 106 MUm3 at 1 hour postreperfusion to 14.9 * 103 MUm2 and 1.27 * 106 MUm3 at 3.5 years posttransplant, both of which were less than half of adult size. At 1 hour postreperfusion, podocytes were structurally immature. At 6 months posttransplant, podocyte immaturity was still evident. At 3.5 years posttransplant, podocytes were mature. CONCLUSIONS: These findings suggest that podocytes and glomerular size of pediatric donor kidneys can continue to mature in adult recipients at rates appropriate for donor age when transplanted en bloc. The maturational levels of podocytes and glomeruli may also be a factor involved in favorable outcomes of en bloc pediatric donor kidney transplantation. PMID- 28361115 TI - Detection of Donor-Derived Microparticles in the Peripheral Blood of a Hand Transplant Recipient During Rejection. AB - BACKGROUND: Microparticles (MPs) are released from the plasma membrane of activated or dying cells and bear surface molecules from those cells. We examined whether donor-derived MPs in the peripheral blood of the recipient could serve as a marker of tissue damage due to rejection of a transplanted hand. METHODS: Platelet-free plasma from the recipient of the transplanted hand was analyzed for MPs bearing the donor-specific HLA molecule A*02 using flow cytometry. Rejection status of the transplanted hand was monitored by histopathology of skin punch biopsies. RESULTS: Donor-specific MPs expressing HLA A*02 were quantifiable in the peripheral blood of the recipient. Levels of these MPs increased with worsening rejection of the transplanted hand. CONCLUSIONS: These findings demonstrate the ability to detect donor specific MPs through staining of graft cell-specific HLA and promote further investigation into the potential utility of flow cytometry for donor-derived MPs as a noninvasive tool to assess rejection in solid organ transplantation patients. PMID- 28361116 TI - Development and Validation of the Kidney Transplant Understanding Tool (K-TUT). AB - BACKGROUND: Several educational interventions have been designed to improve patient knowledge before and after kidney transplantation. However, evaluation of such interventions has been difficult because validated instruments to measure knowledge-based outcomes in this population have not been developed. OBJECTIVE: To create a tool to measure patient knowledge of kidney transplantation and to evaluate its validity. METHODS: The Kidney Transplant Understanding Tool (K-TUT) was created using a stepwise iterative process. Experts in the field and transplant recipients were consulted to establish content validity. The K-TUT consists of 9 true/false and 13 multiple-choice questions, and scores are based on the number correct answers [YES/NO format] of 69 items. The questionnaire was piloted in a study that also measured health literacy (via the Short Test of Functional Health Literacy) in transplant candidates, whereas the main survey was mailed to transplant recipients. Test-retest was performed, and completed surveys were analyzed for internal consistency, construct validity, floor and ceiling effects, and reproducibility. RESULTS: Surveys were offered to 106 pretransplant patients and 235 in the posttransplant period, and response rates were 38.7% (41/106) and 63.4% (149/235), respectively. The mean corrected scores were 53.1 +/- 8.5 (77%) and 56.2 +/- 6.3 (81%), respectively. Test-retest was performed over 20% of both cohorts and percent agreement ranged between 70% and 100% in the pretransplant group and 66% and 100% in the posttransplant group. Cronbach alpha ranged from 0.794 to 0.875 in all cohorts indicating favorable internal consistency. Increased health literacy in the pretransplant group was significantly associated with increased knowledge (r = 0.52; P < 0.001), suggestive of construct validity, and the absence of floor and ceiling effects was positive. The majority of transplant recipients (98/148, 67%) believed the questionnaire adequately assessed transplant knowledge, about a quarter (36/148, 24.3%) were "unsure," and 85% (126/148) agreed that no questions should be removed. CONCLUSIONS: Although more study is warranted to further assess psychometric properties, the K-TUT appears to be a promising tool to measure transplant knowledge. PMID- 28361117 TI - The Privilege of Induction Avoidance and Calcineurin Inhibitors Withdrawal in 2 Haplotype HLA Matched White Kidney Transplantation. AB - BACKGROUND: White recipients of 2-haplotype HLA-matched living kidney transplants are perceived to be of low immunologic risk. Little is known about the safety of induction avoidance and calcineurin inhibitor withdrawal in these patients. METHODS: We reviewed our experience at a single center and compared it to Organ Procurement and Transplantation Network (OPTN) registry data and only included 2 haplotype HLA-matched white living kidney transplants recipients between 2000 and 2013. RESULTS: There were 56 recipients in a single center (where no induction was given) and 2976 recipients in the OPTN. Among the OPTN recipients, 1285 received no induction, 903 basiliximab, 608 thymoglobulin, and 180 alemtuzumab. First-year acute rejection rates were similar after induction-free transplantation among the center and induced groups nationally. Compared with induction-free transplantation in the national data, there was no decrease in graft failure risk over 13 years with use of basiliximab (adjusted hazard ratio [aHR], 0.86; confidence interval [CI], 0.68-1.08), Thymoglobulin (aHR, 0.92; CI, 0.7-1.21) or alemtuzumab (aHR, 1.18; CI, 0.72-1.93). Among induction-free recipients at the center, calcineurin inhibitor withdrawal at 1 year (n = 27) did not significantly impact graft failure risk (HR,1.62; CI, 0.38-6.89). CONCLUSIONS: This study may serve as a foundation for further studies to provide personalized, tailored, immunosuppression for this very low-risk population of kidney transplant patients. PMID- 28361118 TI - A Case Report of Paradoxical Air Embolism Caused by Intrapulmonary Shunting During Liver Transplantation. AB - Supplemental digital content is available in the text. PMID- 28361119 TI - Evaluation of Carotid Ultrasonography Screening Among Kidney Transplant Candidates: A Single-Center, Retrospective Study. AB - BACKGROUND: Kidney transplant candidates undergo rigorous testing prior to clearance for transplantation. Because kidney transplant candidates may be at increased risk for carotid artery stenosis because of arteriosclerosis and atherosclerosis secondary to hypertension, vascular calcification, and diabetes, carotid ultrasound is often performed with the intent of preventing a cerebrovascular accident in the perioperative or posttransplant period. To our knowledge, there has not been a study investigating the utility of screening carotid ultrasonography in pretransplant candidates. The purpose of the present study was to investigate the yield of carotid ultrasonography in end-stage renal disease patients, at high risk for having clinically significant vascular disease evaluated at our center for kidney transplantation during the years 2009 to 2014. METHODS: Data for carotid ultrasound findings and risk factors for carotid artery disease were extracted from the medical records. RESULTS: A total of 882 patients were included in our study of which only 13 patients (1.47% of the cohort) had significant carotid artery stenosis (>70%) on ultrasound testing. Using multiple logistic regression on the outcome of carotid stenosis, congestive heart failure (adjusted odds ratio, 5.2), and peripheral vascular disease (adjusted odds ratio, 4.4) were positively associated with carotid stenosis. CONCLUSIONS: The prevalence of significant carotid artery stenosis was only 1.47% in our cohort of kidney transplant candidates, and the routine use of carotid ultrasound testing in this population may not be an efficient use of clinical resources. Use of risk factors, such as congestive heart failure or peripheral vascular disease, may identify patients who are more likely to benefit from carotid ultrasonography screening. PMID- 28361121 TI - A Systematic Review and Meta-Analysis of the Data Behind Current Recommendations for Corticosteroids in Non-HIV-Related PCP: Knowing When You Are on Shaky Foundations. AB - BACKGROUND: Randomized trials show a mortality benefit to adjunctive corticosteroids for human immunodeficiency virus (HIV)-related Pneumocystis jiroveci pneumonia (HIV-PCP). Guidelines for non-HIV PCP (NH-PCP) recommend adjunctive corticosteroids based on expert opinion. We conducted a systematic review and meta-analysis characterizing adjunctive corticosteroids for NH-PCP. METHODS: We searched MEDLINE from 1966 through 2015. Data on clinical outcomes from NH-PCP were extracted with a standardized instrument. Heterogeneity was assessed with the I2 index. Pooled odds ratios and 95% confidence interval were calculated using a fixed effects model. RESULTS: Our search yielded 5044 abstracts, 277 articles were chosen for full review, and 6 articles described outcomes in moderate to severe NH-PCP. Studies were limited by variable definitions, treatment selection bias, concomitant infections and small sample size. Individual studies reported shorter intensive care unit stay and duration of mechanical ventilation of patients given adjunctive corticosteroids. There was no association between corticosteroids and survival in NH-PCP (odds ratio, 0.66; 95% confidence interval, 0.38-1.15; P = 0.14). CONCLUSIONS: The literature does not support an association between adjunctive corticosteroids and survival from NH-PCP but data are limited and findings should not be considered conclusive. Further research with improved methodology is needed to better understand the role of adjunctive corticosteroids for NH-PCP. PMID- 28361120 TI - Acute Rejection Phenotypes in the Current Era of Immunosuppression: A Single Center Analysis. AB - BACKGROUND: Besides 'definitive rejection', the Banff classification includes categories for 'suspicious for rejection' phenotypes. The aim of this study was to determine the frequency and phenotypes of rejection episodes in 316 consecutive renal transplants from 2009 to 2014 grouped into patients without/with pretransplant HLA-DSA (ptDSAneg, n = 251; ptDSApos, n = 65). METHODS: All adequate indication (n = 125) and surveillance biopsies (n = 538) performed within the first year posttransplant were classified according to the current Banff criteria. RESULTS: 'Suspicious for rejection' phenotypes were 3 times more common than 'definitive rejection' phenotypes in biopsies from ptDSAneg patients (35% vs 11%) and equally common in biopsies from ptDSApos patients (25% vs 27%). In both groups, 'suspicious for rejection' phenotypes were more frequent in surveillance than in indication biopsies (28% vs 16% in ptDSAneg patients, and 37% vs 29% in ptDSApos patients). 'Borderline changes: 'Suspicious' for acute T-cell mediated rejection' (91%) were the dominant 'suspicious for rejection' phenotype in ptDSAneg patients, whereas 'borderline changes' (58%) and 'suspicious for acute/active antibody-mediated rejection' (42%) were equally frequent in biopsies from ptDSApos patients. Inclusion of 'suspicious for rejection' phenotypes increased the 1-year incidence of clinical (ptDSAneg patients: 18% vs 8%, P = 0.0005; ptDSApos patients: 24% vs 18%, P = 0.31) and (sub)clinical rejection (ptDSAneg patients: 59% vs 22%, P < 0.0001; ptDSApos patients: 68% vs 40%, P = 0.004). CONCLUSIONS: 'Suspicious for rejection' phenotypes are very common in the current era and outnumber the frequency of 'definitive rejection' within the first year posttransplant. PMID- 28361122 TI - Risk Factors for Intractable Ascites After Adult-to-Adult Living Donor Liver Transplantation Using Left Lobe. AB - BACKGROUND: Intractable ascites is one of the causes of graft loss after adult-to adult living donor liver transplantation (LDLT) using a small graft. Identification of factors associated with increasing posttransplant ascites has important implications for prevention and treatment. METHODS: All 59 consecutive adult patients who underwent left lobe LDLT without portal inflow modulation between October 2002 and February 2016 were prospectively enrolled. Factors associated with the average daily amount of ascites for 2 weeks after LDLT were assessed. RESULTS: The median daily amount of ascites during the 2 weeks was 1052 mL (range, 52-3480 mL). Although 16 of the 59 patients developed intractable ascites, exceeding 1500 mL daily (massive ascites group), the remaining 43 patients produced less than 1500 mL of ascites daily (nonmassive ascites group). The presence of pretransplant ascites (P = 0.001), albumin (P = 0.011), albumin/globulin ratio (P = 0.026), cold ischemia time (P = 0.004), operation time (P = 0.022), and pretransplant portal vein pressure (PVP) (P = 0.047) differed significantly between the 2 groups. Neither posttransplant PVP nor portal vein flow differed between the 2 groups. The variables associated with intractable ascites that remained significant after logistic regression analysis were pretransplant PVP (P = 0.047) and cold ischemia time (P = 0.049). After appropriate fluid resuscitation for intractable ascites, 58 (98%) of the 59 recipients were discharged from hospital after removal of the indwelling drains. CONCLUSIONS: It is important to shorten the scold ischemia time to reduce massive ascites after LDLT. Pretransplant portal hypertension is more closely associated with ascites production than posttransplant hemodynamic status. PMID- 28361123 TI - Tocilizumab (Anti-IL-6R) Suppressed TNFalpha Production by Human Monocytes in an In Vitro Model of Anti-HLA Antibody-Induced Antibody-Dependent Cellular Cytotoxicity. AB - BACKGROUND: We previously demonstrated that natural killer (NK) cells activated via FcgammaRIIIa (CD16) interactions with anti-HLA antibodies binding to peripheral blood mononuclear cells (PBMCs) in the in vitro antibody-dependent cellular cytotoxicity (ADCC) assay produced IFNgamma. Here we investigate if other CD16 bearing cells are responsive to alloantigen via alloantibody in the in vitro ADCC and if the ADCC-induced cytokine reactions and cytotoxicity can be modified by the anti-interleukin 6 receptor (IL-6R) monoclonal antibody, Tocilizumab (TCZ). METHODS: Whole blood from a normal individual was incubated overnight with irradiated allo-PBMCs pretreated with anti-HLA antibody positive (in vitro ADCC) or negative sera (mixed lymphocyte reaction [MLR]), with or without TCZ or control IgG. IFNgamma+, TNFalpha+ or IL-6+ cell% in NK cells, monocytes and CD8+ T cells were enumerated by cytokine flow cytometry. ADCC using PBMCs (effector) and Farage B cells (FB, target) with anti-HLA antibody positive sera, with or without TCZ, was measured by flow cytometry. RESULTS: IFNgamma+ and/or TNFalpha+ cell% in NK cells, monocytes and CD8+ T cells were elevated in the ADCC compared to the MLR condition. IL-6+ cells were significantly increased in ADCC versus MLR (10.2 +/- 4.8% vs 2.7 +/- 1.5%, P = 0.0003), but only in monocytes. TCZ treatment significantly reduced TNFalpha+ cell% in monocytes in ADCC, but had no effect on other cytokine+ cells. TCZ showed no effect on cytotoxicity in ADCC. CONCLUSIONS: IFNgamma, TNFalpha, and IL-6 production induced by HLA antibody-mediated CD16 bearing cell activation in NK cells, monocytes, and CD8+ T cells suggests a potential role for ADCC and these inflammatory cytokines in mediation of antibody-mediated rejection. TCZ suppressed TNFalpha production in monocytes in the ADCC condition, suggesting a role of IL-6/IL-6R pathway in monocytes activation. Inhibition of this pathway could reduce the inflammatory cascade induced by alloantibody, although the inhibitory effect on cytotoxicity is minimal. PMID- 28361124 TI - Lowering Perfusate Temperature From 37 degrees C to 32 degrees C Diminishes Function in a Porcine Model of Ex Vivo Kidney Perfusion. AB - BACKGROUND: Ex vivo perfusion (EVP) is a novel method of preservation. However, optimal perfusion conditions remain undetermined. Reducing the temperature of the perfusate to subnormothermia may be beneficial during EVP and improve early graft function. The aim of this study was to investigate whether subnormothermia would influence the conditioning effect of EVP when compared with normothermic perfusion, and standard cold static storage (CS). METHODS: Porcine kidneys underwent static CS for 23 hours followed by 1 hour of EVP using leukocyte depleted blood at a mean temperature of 32 degrees C or 37 degrees C. After this, kidneys were reperfused with whole autologous blood at 37 degrees C for 3 hours to assess renal function and injury. These were compared with a control group that underwent 24 hours CS. RESULTS: During EVP, kidneys perfused at 37 degrees C had a higher level of renal blood flow and oxygen consumption compared with EVP at 32 degrees C (P = 0.001, 0.002). During reperfusion, 32 degrees C EVP kidneys had lower creatinine clearance and urine output than control (P = 0.023, 0.011) and a higher fractional excretion of sodium, serum potassium, and serum aspartate transaminase than 37 degrees C EVP kidneys (P = 0.01, 0.023, 0.009). CONCLUSIONS: Tubular and renal functions were better preserved by a near-physiological temperature of 37 degrees C during 1 hour of EVP, when compared to EVP at 32 degrees C or cold storage. PMID- 28361126 TI - Pressure sensitivity and phenotypic changes in patients with suspected opioid induced hyperalgesia being withdrawn from full mu agonists. AB - OBJECTIVES: To assess changes in phenotype and pressure sensitivity in patients with suspected opioid-induced-hyperalgesia (OIH) after transitioning to buprenorphine. METHODS: Twenty patients with suspected OIH were enrolled to transition to buprenorphine therapy. Patients completed validated self-report measures at baseline and at 1, 4, 8 weeks, and 6 months after initiation of buprenorphine along with quantitative sensory testing including measures of pressure pain threshold, pain tolerance and Pain 50 (a pain intensity rating). RESULTS: 20 patients were enrolled, 17 were treated with buprenorphine and 11 completed all assessment points. We found that after transitioning to buprenorphine, patients on higher opioid doses (>=100mg oral morphine equivalents) had significant improvements for some measures including decreased pain severity and fibromyalgia survey scores, fewer neuropathic pain features, less catastrophizing, fewer depressive symptoms, and improved functioning 1-week after transitioning to buprenorphine with an eventual return back to baseline. Although not statistically significant, patients on high dose opioids (>=100mg OME) also showed a trend of decreased pressure sensitivity 1-week after transitioning to buprenorphine with a gradual return back to baseline. CONCLUSIONS: Our study is the first to look at pressure pain sensitivity in patients who were taking opioids and transitioned to buprenorphine. These results suggest that the patients most likely to benefit from buprenorphine therapy are those on higher doses. In addition, the eventual return back to baseline on measures of pain phenotype and pressure sensitivity suggests that buprenorphine may over time result in a return of the hyperalgesic effects of a full mu agonist. PMID- 28361125 TI - Thiol-ene click hydrogels for therapeutic delivery. AB - Hydrogels are of growing interest for the delivery of therapeutics to specific sites in the body. For use as a delivery vehicle, hydrophilic precursors are usually laden with bioactive moieties and then directly injected to the site of interest for in situ gel formation and controlled release dictated by precursor design. Hydrogels formed by thiol-ene click reactions are attractive for local controlled release of therapeutics owing to their rapid reaction rate and efficiency under mild aqueous conditions, enabling in situ formation of gels with tunable properties often responsive to environmental cues. Herein, we will review the wide range of applications for thiol-ene hydrogels, from the prolonged release of anti-inflammatory drugs in the spine to the release of protein-based therapeutics in response to cell-secreted enzymes, with a focus on their clinical relevance. We will also provide a brief overview of thiol-ene click chemistry and discuss the available alkene chemistries pertinent to macromolecule functionalization and hydrogel formation. These chemistries include functional groups susceptible to Michael type reactions relevant for injection and radically mediated reactions for greater temporal control of formation at sites of interest using light. Additionally, mechanisms for the encapsulation and controlled release of therapeutic cargoes are reviewed, including i) tuning the mesh size of the hydrogel initially and temporally for cargo entrapment and release and ii) covalent tethering of the cargo with degradable linkers or affinity binding sequences to mediate release. Finally, myriad thiol-ene hydrogels and their specific applications also are discussed to give a sampling of the current and future utilization of this chemistry for delivery of therapeutics, such as small molecule drugs, peptides, and biologics. PMID- 28361128 TI - Design of dual multiple aperture devices for dynamical fluence field modulated CT. AB - A Multiple Aperture Device (MAD) is a novel x-ray beam modulator that uses binary filtration on a fine scale to spatially modulate an x-ray beam. Using two MADs in series enables a large variety of fluence profiles by shifting the MADS relative to each other. This work details the design and control of dual MADs for a specific class of desired fluence patterns. Specifically, models of MAD operation are integrated into a best fit objective followed by CMA-ES optimization. To illustrate this framework we demonstrate the design process for an abdominal phantom with the goal of uniform detected signal. Achievable fluence profiles show good agreement with target fluence profiles, and the ability to flatten projections when a phantom is scanned is demonstrated. Simulated data reconstruction using traditional tube current modulation (TCM) and MAD filtering with TCM are investigated with the dual MAD system demonstrating more uniformity in noise and illustrating the potential for dose reduction under a maximum noise level constraint. PMID- 28361127 TI - Longterm maintenance of human naive T cells through in situ homeostasis in lymphoid tissue sites. AB - Naive T cells develop in the thymus and coordinate immune responses to new antigens; however, mechanisms for their long-term persistence over the human lifespan remain undefined. Here, we investigated human naive T cell development and maintenance in primary and secondary lymphoid tissues obtained from individual organ donors aged 3 months-73 years. In the thymus, the frequency of double-positive thymocytes declined sharply in donors over age 40 coincident with reduced recent thymic emigrants (RTE) in lymphoid tissues, while naive T cells were functionally maintained predominantly in lymph nodes (LN). Analysis of TCR clonal distribution by CDR3 sequencing of naive CD4+ and CD8+ T cells in spleen and LNs reveal site-specific clonal expansions of naive T cells from individuals >40 years of age with minimal clonal overlap between lymphoid tissues. We also identified biased naive T cell clonal distribution within specific lymph nodes based on VJ usage. Together these results suggest prolonged maintenance of naive T cells through in situ homeostasis and retention in lymphoid tissue. PMID- 28361129 TI - Modeling Shift-Variant X-Ray Focal Spot Blur for High-Resolution Flat-Panel Cone Beam CT. AB - Flat-panel cone-beam CT (CBCT) has been applied clinically in a number of high resolution applications. Increasing geometric magnification can potentially improve resolution, but also increases blur due to an extended x-ray focal-spot. We present a shift-variant focal-spot blur model and incorporate it into a model based iterative-reconstruction algorithm. We apply this algorithm to simulation and CBCT test-bench data. In a trabecular bone simulation study, we find traditional reconstruction approaches without a blur model exhibit shift-variant resolution properties that depend greatly on the acquisition protocol (e.g. short vs. full scans) and the anode angles of the rays used to reconstruct a particular region. For physical CBCT experiments focal spot blur was characterized and a spatial resolution phantom was scanned and reconstructed. In both experiments image quality using the shift-variant model was significantly improved over approaches that modeled no blur or only a shift-invariant blur, suggesting a potential means to overcome traditional CBCT spatial resolution and system design limitations. PMID- 28361130 TI - A luminogenic lanthanide-based probe for the highly selective detection of nanomolar sulfide levels in aqueous samples. AB - A bimetallic terbium(iii)/copper(ii) complex (Tb-1.Cu2+) for the time-gated luminescent detection of hydrogen sulfide in aqueous samples is reported. The probe shows excellent selectivity towards HS- over various anions and cations, including the ions common to natural waterways and waste water samples, displaying a 73-fold increase in luminescence in the presence of sulfide. The probe exhibits extremely fast reaction times and a low limit of detection (130 nM). The probe was used to quantify sulfide in an industrial "sour water" sample, with the result in excellent agreement with those from two independent assay methods (methylene blue and AzMC). PMID- 28361131 TI - A mixed-valence metallogrid [CoCo] with an unusual electronic structure and single-ion-magnet characterization. AB - The reaction of the multisite coordination ligand (H2L) with Co(Ac)2.4H2O in the absence of any base affords a homometallic tetranuclear mixed-valence complex, [Co4(L)4(CH3CO2)2(CH3OH)2].Et2O (1). This mixed-valence metallogrid [Co4(L)4(CH3CO2)2 (CH3OH)2].Et2O (1) has been theoretically and experimentally analyzed to assign the valence and spin state in the form of trans-[Co-Co-Co-Co]. HF-EPR reveals the presence of axial anisotropy (D = -34.4 cm-1) with a significant transverse component (E = 9.5 cm-1) in the local high spin cobalt centers. Slow magnetic relaxation effects were observed in the presence of a dc field, demonstrating field-induced single ion magnetic behavior, which is associated with the unusual electronic structure of Co(ii) within the metallogrid. PMID- 28361132 TI - Anionic and cationic Hofmeister effects are non-additive for guanidinium salts. AB - To understand specific ion effects on a molecular level we explore the effect of salts on the rotational mobility of a model amide using dielectric spectroscopy. Based on our previous studies on the effect of strong denaturing anions or cations, here we study the additivity of the anionic and cationic effect. Using salts consisting of denaturing spherical anions and spherical cations we find such salts to affect the amide according to what one expects based on the additive activity of the individual ions. The guanidinium (Gdm+) cation appears to be a notable exception, as our results suggest that GdmI (and accordingly GdmSCN) is less efficient in hindering the rotation of the amide than KI or GdmCl. PMID- 28361133 TI - Glycolipid-based nanostructures with thermal-phase transition behavior functioning as solubilizers and refolding accelerators for protein aggregates. AB - The self-assembly of synthetic glycolipids produced nanostructures such as vesicles and nanotubes consisting of bilayer membranes, which underwent a gel-to liquid crystalline thermal phase transition. Vesicles formed at temperatures above the thermal phase transition temperatures (Tg-l) could solubilize aggregates of denatured proteins by trapping them in the fluid bilayer membranes. Cooling to temperatures below Tg-l caused a morphological transformation into nanotubes that accompanied the thermal phase transition from the fluid to the solid state. This phenomenon allowed the trapped proteins to be quickly released into the bulk solution and simultaneously facilitated the refolding of the proteins. The refolding efficiency strongly depended on the electrostatic attraction between the bilayer membranes of the nanostructures and the proteins. Because of the long shape (>400 nm) of the nanotubes, simple membrane filtration through a pore size of 200 nm led to complete separation and recovery of the refolded proteins (3-9 nm sizes). PMID- 28361134 TI - Selective mono-alkylation of N-methoxybenzamides. AB - We report our latest discovery of norbornene derivative modulated highly mono selective ortho-C-H activation alkylation reactions on arenes bearing simple mono dentate coordinating groups. The reaction features the use of readily available benzamides and alkyl halides. During the study, we prepared 30 mono-alkylated aryl amides in good yields with good mono-selectivity. We have also demonstrated that structurally rigid alkenes such as norbornene and its derivatives are a good class of ligand and could be used for future direct C-H functionalizations. The utilization of norbornene type ligands for assistance in C-H activation processes has opened a new window for future molecular design using direct C-H functionalization strategies. PMID- 28361135 TI - Programmable self-assembly of water-soluble organo-heterometallic cages [M12M'4L12] using 3-(3,5-dimethyl-1H-pyrazol-4-yl)pentane-2,4-dione (H2L). AB - A bifunctional ligand H2L featuring primary (pyrazole) and secondary (acetylacetone) coordination sites was preferentially reacted with dimetallic [M2(NO3)2](NO3)2 linkers at the pyrazolyl end of H2L, giving rise to dimetallic corners. Subsequently, the corners serve as the secondary site with M' to form water-soluble organo-heterometallic [M12M'4L12] cages in a stepwise mode. PMID- 28361136 TI - A family of 'windmill'-like {Cu6Ln12} complexes exhibiting single-molecule magnetism behavior and large magnetic entropy changes. AB - A family of nanosized {Cu6Ln12} clusters with a 'windmill'-like topology was prepared from the employment of 2,6-diacetylpyridine dioxime, in conjunction with bridging N3-, in 3d/4f-metal chemistry; the octadecanuclear compounds exhibit single-molecule magnetism behavior and large magnetic entropy changes, depending on the 4f-metal ion present. PMID- 28361137 TI - The metalation of hen egg white lysozyme impacts protein stability as shown by ion mobility mass spectrometry, differential scanning calorimetry, and X-ray crystallography. AB - Metalation of hen egg white lysozyme (HEWL) with organometallics was studied with physicochemical methods in solid state, solution and the gas phase. While metalation did not affect the crystal structure of HEWL significantly, protein destabilisation was detected in gas phase and solution. PMID- 28361138 TI - Fully convolutional neural network for removing background in noisy images of uranium bearing particles. AB - A fully convolutional neural network (FCN) was developed to supersede automatic or manual thresholding algorithms used for tabulating SIMS particle search data. The FCN was designed to perform a binary classification of pixels in each image belonging to a particle or not, thereby effectively removing background signal without manually or automatically determining an intensity threshold. Using 8000 images from 28 different particle screening analyses, the FCN was trained to accurately predict pixels belonging to a particle with near 99% accuracy. Background eliminated images were then segmented using a watershed technique in order to determine isotopic ratios of identified particles. A comparison of the isotopic distributions of an independent data set segmented using the neural network with a commercially available automated particle measurement (APM) program developed by CAMECA was performed. This comparison highlighted the necessity for effective background removal to ensure that resulting particle identification is not only accurate, but preserves valuable signal that could be lost due to improper segmentation. The FCN approach improves the robustness of current state-of-the-art particle searching algorithms by reducing user input biases, resulting in an improved absolute signal per particle and decreased uncertainty of the determined isotope ratios. PMID- 28361139 TI - Controlling transmembrane protein concentration and orientation in supported lipid bilayers. AB - The trans-membrane protein - proteorhodopsin (pR) has been incorporated into supported lipid bilayers (SLB). In-plane electric fields have been used to manipulate the orientation and concentration of these proteins, within the SLB, through electrophoresis leading to a 25-fold increase concentration of pR. PMID- 28361140 TI - Magnetic zeolites: novel nanoreactors through radiofrequency heating. AB - Many catalytic applications use conventional heating to increase the temperature to allow the desired reaction. A novel methodology is presented for the preparation of magnetic zeolite-based catalysts, allowing more efficient radiofrequency heating. These nanoreactors are tested in the isomerisation of citronellal with successful results and without any apparent deactivation. PMID- 28361141 TI - A backbone design principle for covalent organic frameworks: the impact of weakly interacting units on CO2 adsorption. AB - Covalent organic frameworks are designed to have backbones with different yet discrete contents of triarylamine units that interact weakly with CO2. Adsorption experiments indicate that the triarylamine units dominate the CO2 adsorption process and the CO2 uptake increases monotonically with the triarylamine content. These profound collective effects reveal a principle for designing backbones targeting for CO2 capture and separation. PMID- 28361142 TI - Textures and shapes in nematic elastomers under the action of dopant concentration gradients. AB - We explore a novel strategy of patterning nematic elastomers that does not require inscribing the texture directly. It is based on varying the dopant concentration that, beside shifting the phase transition point, affects the nematic director field via coupling between the gradients of concentration and nematic order parameter. Rotation of the director around a point dopant source causes topological modification manifesting itself in a change of the number of defects. A variety of shapes, dependent on the dopant distribution, are obtained by anisotropic deformation following the nematic-isotropic transition. PMID- 28361143 TI - Automatic generation of reaction energy databases from highly accurate atomization energy benchmark sets. AB - In this contribution, we discuss how reaction energy benchmark sets can automatically be created from arbitrary atomization energy databases. As an example, over 11 000 reaction energies derived from the W4-11 database, as well as some relevant subsets are reported. Importantly, there is only very modest computational overhead involved in computing >11 000 reaction energies compared to 140 atomization energies, since the rate-determining step for either benchmark is performing the same 140 quantum chemical calculations. The performance of commonly used electronic structure methods for the new database is analyzed. This allows investigating the relationship between the performances for atomization and reaction energy benchmarks based on an identical set of molecules. The atomization energy is found to be a weak predictor for the overall usefulness of a method. The performance of density functional approximations in light of the number of empirically optimized parameters used in their design is also discussed. PMID- 28361144 TI - Borane-catalysed postpolymerisation modification of the Si-H bonds in poly(phenylsilane). AB - B(C6F5)3-catalysed hydrosilation, heterodehydrocoupling, and demethanative coupling reactions of the Si-H bonds in poly(phenylsilane) allow the introduction of 10-40% new sidechains in this polymer. The resulting new polymers contain an unusually wide variety of functionalities including Si-C, Si-O, Si-N, and Si-S bonds, whose presence is confirmed by NMR and IR spectroscopies. Gel permeation chromatography (GPC) and thermogravimetric analysis (TGA) are consistent with conservation of the all-silicon backbones in these modified polymers, a result of the high chemoselectivity of the borane-catalysed reactions for Si-H versus Si-Si bonds. UV-visible spectroscopy is sensitive to the presence of new functional groups in the modified polysilanes, although the high proportion of residual Si-H groups attenuates the changes in the sigma-delocalized chromophores. Limitations in substrate scope, arising from issues of borane-substrate complexation or competing catalytic over-reduction chemistry, have been identified, and the potential for achieving greater degrees of sidechain substitution at higher reaction temperatures has been demonstrated for the hydrosilation of 1-hexene. PMID- 28361145 TI - Substrate effects on cell-envelope deformation during early-stage Staphylococcus aureus biofilm formation. AB - Bacterial adhesion to a surface is the first step in biofilm formation, and adhesive forces between the surface and a bacterium are believed to give rise to planktonic-to-biofilm phenotypic changes. Here we use Focused-Ion-Beam (FIB) tomography with backscattered scanning electron microscopy (SEM) to image Staphyolococcus aureus (S. aureus) biofilms grown on Au-coated polystyrene (PS) and Au-coated PS modified by mixed thiols of triethylene glycol mono-11 mercaptoundecyl ether (EG3) and 1-dodecanethiol (CH3). The FIB-SEM technique enables a direct measurement of the contact area between individual bacteria and the substrate. The area of adhesion is effectively zero on the EG3 substrate. It is nonzero on all of the other substrates and increases with increasing hydrophobicity. The fact that the contact area is highest on the unmodified gold, however, indicates that other forces beyond hydrophobicity are significant. The magnitude of bacterial deformation suggests that the adhesive forces are on the order of a few nN, consistent with AFM force measurements reported in the literature. The resolution afforded by electron microscopy furthermore enables us to probe changes in the cell-envelope thickness, which decreases within and near the contact area relative to other parts of the same bacterium. This finding supports the idea that mechanosensing due to stress-induced membrane thinning plays a role in the planktonic-to-biofilm transition associated with bacterial adhesion. PMID- 28361146 TI - Local collection, reaction and analysis with theta pipette emitters. AB - A mobile nanofluidic device based on theta pipettes was developed for "collect react-analyze" measurements of small volumes of a sample collected locally from biological samples. Specifically, we demonstrate execution of local reactions inside single cells and on Pseudomonas aeruginosa biofilms for targeted analysis of metabolites. Nanoliter volumes of the sample, post-reaction, were delivered to a mass spectrometer via electrospray ionization (ESI) for chemical analysis. A new strategy was developed where the additional barrel of a theta pipette was utilized both to enable chemical manipulations after sample collection and to electrospray the nanoliter sample volumes collected directly from the pipette tip. This strategy proved a robust method for ESI from nanometer sized tips without clogging or degradation of the emitter and obviated the need to coat glass pipettes with a conductive metal coating. Chemical reactions investigated include acid catalyzed degradation of oligosaccharides inside the pipette tip to increase the detection sensitivity of minor metabolites found in Allium cepa cells. Additionally, phenylboronic acid complexation of carbohydrates from single cells and liposaccharides from biofilms was also performed inside the pipette tip for selective detection of carbohydrates and liposaccharides with cis-diols. PMID- 28361147 TI - Enantioselective construction of quaternary tetrahydropyridines by palladium catalyzed vinylborylation of alkenes. AB - Here, the highly enantioselective construction of 3,3-disubstituted tetrahydropyridines via Pd(0)-catalyzed asymmetric vinylborylation of (Z)-1-iodo dienes and B2pin2 in the presence of a (S)-p-CF3-BnPHOX ligand is reported. This process is supposed to be initiated by oxidative addition of Pd(0) to vinyl iodide, followed by transmetallation with B2pin2, insertion of the pendant alkene and reductive elimination of alkyl-Pd(ii)-Bpin. PMID- 28361148 TI - Chemical states of 3d transition metal impurities in a liquid lead-bismuth eutectic analyzed using first principles calculations. AB - Steels are easily corroded in a liquid lead-bismuth eutectic (LBE) because their components, such as Fe, Cr and Ni, exhibit a high solubility in the liquid LBE. To understand the reason for such a high solubility of these 3d transition metals, we have performed first-principles molecular dynamics calculations and analyzed the pair-correlation functions, electronic densities of states, and Bader charges and volumes of the 3d transition metals dissolved in the liquid LBE as impurities. The calculations show that the 4s and 3d orbitals of the 3d impurity atoms largely interact with the 6p band of the LBE, which generates bonding orbitals. We suggest that the high stability of 3d metals in the liquid LBE is caused by the interactions of the 4s and 3d orbitals with the 6p band. Spin polarization is induced by V, Cr, Mn, Fe and Co impurity atoms in a similar manner to the Slater-Pauling curve of solid transition metals, which exhibits a downward shift in the atomic number by approximately two. Based on the degree of spin polarization and the shifted trend of the Slater-Pauling curve, we suggest that Ni exhibits a higher solubility than Cr and Fe because of the differences in their interaction strengths between their 3d orbitals and the 6p band. In addition, the 4s and 3d orbitals of the 3d impurity atoms were found to interact more favorably with the Bi 6p band than the Pb 6p band, which is consistent with the fact that liquid Bi is more corrosive to steels than is liquid Pb. PMID- 28361149 TI - Encapsulation of a compartmentalized cytoplasm mimic within a lipid membrane by microfluidics. AB - There is growing interest in analyzing the effect of microenvironments, which may be mimicked through liquid-liquid phase separation (LLPS), on the reactivity of biological macromolecules. We report the encapsulation by microfluidics of the division protein FtsZ and a LLPS system inside microdroplets and their conversion into permeable vesicles (allowing ligand uptake), with higher yield, homogeneity and biomolecular compatibility than those previously described. PMID- 28361150 TI - Ab initio calculation of the attempt frequency of oxygen diffusion in pure and samarium doped ceria. AB - The rate of oxygen ion jumps in a solid oxide depends not only on the activation energy but also on the pre-exponential factor of diffusion. In order to allow a fully ab initio prediction of the oxygen ion conductivity in pure and samarium doped ceria, we calculated the attempt frequency for an oxygen ion jump from first principles combining DFT+U, the NEB method, phonon calculations and the transition state theory. Different definitions of the jump attempt frequency are presented. The equivalence of the Eyring and the Vineyard method is shown without restriction to the Gamma point. Convergence checks of the phonon mesh reveal that the common reduction to the Gamma point is not sufficient to calculate the attempt frequency. Calculations of Sm doped ceria revealed an increase of the prefactor. The attempt frequency for the constant pressure case in quasi-harmonic approximation is larger than the attempt frequency at constant volume in harmonic approximation. The calculated electronic energies, enthalpies and entropies of migration are in agreement with the experimental diffusion coefficients and activation energies. PMID- 28361151 TI - High-performance nanocomposite membranes realized by efficient molecular sieving with CuBDC nanosheets. AB - Two-dimensional (2-D) CuBDC nanosheets (ns-CuBDC) with high-aspect-ratios were deliberately paired with polymers possessing high free volumes to fabricate high performance gas separation membranes. Owing to the molecular sieving effect of the filler, a small ns-CuBDC loading (2-4 wt%) could significantly improve the CO2/CH4 selectivities of membranes, resulting in performances that surpass the upper bound limit for polymer membranes. PMID- 28361152 TI - New pressure-induced polymorphic transitions of anhydrous magnesium sulfate. AB - The effects of pressure on the crystal structure of the three known polymorphs of magnesium sulfate (alpha-MgSO4, beta-MgSO4, and gamma-MgSO4) have been theoretically studied by means of density-functional theory calculations up to 45 GPa. We determined that under ambient conditions gamma-MgSO4 is an unstable polymorph, which decomposes into MgO + SO3, and that the response of the other two polymorphs to hydrostatic pressure is non-isotropic. Additionally, we found that at all pressures beta-MgSO4 has a larger enthalpy than alpha-MgSO4. This indicates that beta-MgSO4 is thermodynamically unstable versus alpha-MgSO4 and predicts the occurrence of a beta-alpha phase transition under moderate compression. Our calculations also predict the existence under pressure of additional phase transitions to two new polymorphs of MgSO4, which we named delta MgSO4 and epsilon-MgSO4. The alpha-delta transition is predicted to occur at 17.5 GPa, and the delta-epsilon transition at 35 GPa, pressures that nowadays can be experimentally easily achieved. All the predicted structural transformations are characterized as first-order transitions. This suggests that they can be non reversible, and therefore the new polymorphs could be recovered as metastable polymorphs under ambient conditions. The crystal structure of the two new polymorphs is reported. In them, the coordination number of sulfur is four as in the previously known polymorphs, but the coordination number of magnesium is eight instead of six. In this article we will report the axial and bond compressibility for the four polymorphs of MgSO4. The pressure-volume equation of state of each phase is also given, which is described by a third-order Birch Murnaghan equation. The values obtained for the bulk modulus are 62 GPa, 57 GPa, 102 GPa, and 119 GPa for alpha-MgSO4, beta-MgSO4, delta-MgSO4, and epsilon-MgSO4, respectively. Finally, the electronic band structure of these four polymorphs of MgSO4 has been calculated for the first time. The obtained results will be presented and discussed. PMID- 28361153 TI - Optimized synthesis of pi-extended squaraine dyes relevant to organic electronics by direct (hetero)arylation and Sonogashira coupling reactions. AB - This study reports on the synthesis and characterization of four molecular pi extended squaraine compounds relevant to the field of organic electronics. The compounds each consist of a bis-indole squaraine core end-capped with indoloquinoxaline units employing three different bridging units, namely thiophene, thiazole, and acetylene. Compound 10 bears a thiophene bridge, 11 consists of a thiophene bridge and fluorinated indoloquinoxaline terminal units, and compounds 12 and 13 are bridged by thiazole and acetylene, respectively. The final compounds are constructed using the atom economical direct (hetero)arylation or the classic Sonogashira carbon-carbon bond formation protocols. Each carbon-carbon bond forming reaction employing thiophene bridges (i.e. synthesis of compounds 10 and 11) has been optimized using the stable and reusable silica supported Pd catalyst, SiliaCat(r) DPP-Pd, streamlining the synthetic procedure. While compounds 12 and 13 were also accessible using the SiliaCat(r) DPP-Pd catalyst, the use of Herrmann-Beller and Pd(PPh3)4 catalysts, respectively, lead to improved isolated yields of the final materials. Compounds 10-13 were characterized by thermal gravimetric analysis, cyclic voltammetry, optical absorption spectroscopy, photoluminescence spectroscopy, and each structure was analysed using density functional theory. All compounds exhibit high thermal stability and good solubility in common organic solvents, including in the greener alternative 2-methyl tetrahydrofuran. The reported compounds display stable ambipolar redox behaviour, furthermore, we have demonstrated that the frontier molecular energy levels can be effectively tuned by changing the bridging unit as predicted by density functional theory. Most striking is the drastic optical absorption profile changes observed from this class of materials upon post-deposition film annealing, suggesting molecular rearrangement in the solid-state. The induced changes and fine structure observed upon post-deposition annealing is unique to these pi-extended squaraines with nothing like it reported in the literature for related squaraine based materials. PMID- 28361154 TI - Capillary fracture of ultrasoft gels: variability and delayed nucleation. AB - A droplet of surfactant spreading on an ultrasoft (E ? 100 Pa) gel substrate will produce capillary fractures at the gel surface; these fractures originate at the contact-line and propagate outwards in a starburst pattern. There is an inherent variability in both the number of fractures formed and the time delay before fractures form. In the regime where single fractures form, we observe a Weibull like distribution of delay times, consistent with a thermally-activated process. The shape parameter is close to 1 for softer gels (a Poisson process), and larger for stiffer gels (indicative of aging). For single fractures, the characteristic delay time is primarily set by the elastocapillary length of the system, calculated from the differential in surface tension between the droplet and the substrate, rather than the elastic modulus as for stiffer systems. For multiple fractures, all fractures appear simultaneously and long delay times are suppressed. The experimental protocol provides a new technique for probing the energy landscape and fracture toughness of ultrasoft materials through measurement of the delay time distribution. PMID- 28361155 TI - A stochastic method for asphaltene structure formulation from experimental data: avoidance of implausible structures. AB - This work presents a stochastic procedure designed to formulate a discrete set of molecular structures that, as a whole, adjust properly to experimental asphaltene data. This algorithm incorporates the pentane effect concept and Clar's sextet rule to the formulation process. The set of viable structures was constructed based on probability distribution functions obtained from experimental information and an isomer database containing all plausible configurations for a given number of rings, avoiding high-energy structures. This procedure was applied to a collection of experimental data from the literature. Ten sets, consisting of 5000 structures each, were obtained. Each set was then optimized. For the most accurate representation, four molecules were sufficient to properly reproduce the experimental input. The asphaltene system obtained is consistent with the reported molecular weight, number of aromatic rings and heteroatom content. Molecular dynamic simulations showed that the asphaltene representation adequately reproduced asphaltene aggregation behavior in toluene and n-heptane. In toluene, a single three-molecule aggregate was observed, and the majority of asphaltene molecules remained in a monomeric state. In n-heptane, aggregates containing up to four molecules were observed; both porous and compact aggregates were found. The asphaltene molecular representation obtained, which allows researchers to avoid inappropriate torsions in the molecule, is able to reproduce interplanar distances between aromatic cores of 4 A or less for the aggregation state, as supported by experimental results. PMID- 28361157 TI - Integration of Hospital Information and Clinical Decision Support Systems to Enable the Reuse of Electronic Health Record Data. AB - BACKGROUND: The efficiency and acceptance of clinical decision support systems (CDSS) can increase if they reuse medical data captured during health care delivery. High heterogeneity of the existing legacy data formats has become the main barrier for the reuse of data. Thus, we need to apply data modeling mechanisms that provide standardization, transformation, accumulation and querying medical data to allow its reuse. OBJECTIVES: In this paper, we focus on the interoperability issues of the hospital information systems (HIS) and CDSS data integration. MATERIALS AND METHODS: Our study is based on the approach proposed by Marcos et al. where archetypes are used as a standardized mechanism for the interaction of a CDSS with an electronic health record (EHR). We build an integration tool to enable CDSSs collect data from various institutions without a need for modifications in the implementation. The approach implies development of a conceptual level as a set of archetypes representing concepts required by a CDSS. RESULTS: Treatment case data from Regional Clinical Hospital in Tomsk, Russia was extracted, transformed and loaded to the archetype database of a clinical decision support system. Test records' normalization has been performed by defining transformation and aggregation rules between the EHR data and the archetypes. These mapping rules were used to automatically generate openEHR compliant data. After the transformation, archetype data instances were loaded into the CDSS archetype based data storage. The performance times showed acceptable performance for the extraction stage with a mean of 17.428 s per year (3436 case records). The transformation times were also acceptable with 136.954 s per year (0.039 s per one instance). The accuracy evaluation showed the correctness and applicability of the method for the wide range of HISes. These operations were performed without interrupting the HIS workflow to prevent the HISes from disturbing the service provision to the users. CONCLUSIONS: The project results have proven that archetype based technologies are mature enough to be applied in routine operations that require extraction, transformation, loading and querying medical data from heterogeneous EHR systems. Inference models in clinical research and CDSS can benefit from this by defining queries to a valid data set with known structure and constraints. The standard based nature of the archetype approach allows an easy integration of CDSSs with existing EHR systems. PMID- 28361156 TI - Mapping Acute Coronary Syndrome Registries to SNOMED CT. A Comparative Study between Malaysia and Sweden. AB - BACKGROUND: Malaysia and Sweden have mapped their acute coronary syndrome registries using SNOMED CT. Since similar-purposed patient registries can be expected to collect similar data, these data should be mapped to the same SNOMED CT codes despite the different languages used. Previous studies have however shown variations in mapping between different mappers but the reasons behind these variations and the influence of different mapping approaches are still unknown. OBJECTIVES: To analyze similar-purposed registries and their registry-to SNOMED CT maps, using two national acute coronary syndrome registries as examples, to understand the reasons for mapping similarities and differences as well as their implications. METHODS: The Malaysian National Cardiovascular Disease - Acute Coronary Syndrome (NCVD-ACS) registry was compared to the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA). The structures of NCVD-ACS and RIKS-HIA registry forms and their distributions of headings, variables and values were studied. Data items with equivalent meaning (EDIs) were paired and their mappings were categorized into match, mismatch, and non-comparable mappings. Reasons for match, mismatch and non-comparability of each paired EDI were seen as factors that contributed to the similarities and differences between the maps. RESULTS: The registries and their respective maps share a similar distribution pattern regarding the number of headings, variables and values. The registries shared 101 EDIs, whereof 42 % (42) were mapped to SNOMED CT. 45 % (19) of those SNOMED CT coded EDIs had matching codes. The matching EDIs occurred only in pre-coordinated SNOMED CT expressions. Mismatches occurred due to challenges arising from the mappers themselves, limitations in SNOMED CT, and complexity of the registries. Non comparable mappings appeared due to the use of other coding systems, unmapped data items, as well as requests for new SNOMED CT concepts. CONCLUSIONS: To ensure reproducible and reusable maps, the following three actions are recommended: (i) develop a specific mapping guideline for patient registries; (ii) openly share maps; and (iii) establish collaboration between clinical research societies and the SNOMED CT community. PMID- 28361158 TI - A Machine Learning-based Method for Question Type Classification in Biomedical Question Answering. AB - BACKGROUND AND OBJECTIVE: Biomedical question type classification is one of the important components of an automatic biomedical question answering system. The performance of the latter depends directly on the performance of its biomedical question type classification system, which consists of assigning a category to each question in order to determine the appropriate answer extraction algorithm. This study aims to automatically classify biomedical questions into one of the four categories: (1) yes/no, (2) factoid, (3) list, and (4) summary. METHODS: In this paper, we propose a biomedical question type classification method based on machine learning approaches to automatically assign a category to a biomedical question. First, we extract features from biomedical questions using the proposed handcrafted lexico-syntactic patterns. Then, we feed these features for machine learning algorithms. Finally, the class label is predicted using the trained classifiers. RESULTS: Experimental evaluations performed on large standard annotated datasets of biomedical questions, provided by the BioASQ challenge, demonstrated that our method exhibits significant improved performance when compared to four baseline systems. The proposed method achieves a roughly 10 point increase over the best baseline in terms of accuracy. Moreover, the obtained results show that using handcrafted lexico-syntactic patterns as features' provider of support vector machine (SVM) lead to the highest accuracy of 89.40 %. CONCLUSION: The proposed method can automatically classify BioASQ questions into one of the four categories: yes/no, factoid, list, and summary. Furthermore, the results demonstrated that our method produced the best classification performance compared to four baseline systems. PMID- 28361159 TI - Evaluation of Adjusted and Unadjusted Indirect Comparison Methods in Benefit Assessment. A Simulation Study for Time-to-event Endpoints. AB - BACKGROUND: With the Act on the Reform of the Market for Medicinal Products (AMNOG) in Germany, pharmaceutical manufacturers are obliged to submit a dossier demonstrating added benefit of a new drug compared to an appropriate comparator. Underlying evidence was planned for registration purposes and therefore often does not meet the appropriate comparator as defined by the Federal Joint Committee (G-BA). For this reason AMNOG allows indirect comparisons to assess the extent of added benefit. OBJECTIVES: The aim of this study is to evaluate the characteristics and applicability of adjusted indirect comparison described by Bucher and Matching-Adjusted Indirect Comparison (MAIC) in various situations within the early benefit assessment according to S35a Social Code Book 5. In particular, we consider time-to-event endpoints. METHODS: We conduct a simulation study where we consider three different scenarios: I) similar study populations, II) dissimilar study populations without interactions and III) dissimilar study populations with interactions between treatment effect and effect modifiers. We simulate data from a Cox model with Weibull distributed survival times. Desired are unbiased effect estimates. We compare the power and the proportion of type 1 errors of the methods. RESULTS: I) Bucher and MAIC perform equivalently well and yield unbiased effect estimates as well as proportions of type 1 errors below the significance level of 5 %. II) Both Bucher and MAIC yield unbiased effect estimates, but Bucher shows a higher power for detection of true added benefit than MAIC. III) Only MAIC, but not Bucher yields unbiased effect estimates. When using robust variance estimation MAIC yields a proportion of type 1 error close to 5 %. In general, power of all methods for indirect comparisons is low. An increasing loss of power for the indirect comparisons can be observed as the true treatment effects decrease. CONCLUSION: Due to the great loss of power and the potential bias for indirect comparisons, head-to-head trials using the appropriate comparator as defined by the Federal Joint Committee should be conducted whenever possible. However, indirect comparisons are needed if no such direct evidence is available. To conduct indirect comparisons in case of a present common comparator and similar study populations in the trials to be compared, both Bucher and MAIC can be recommended. In case of using adjusted effect measures (such as Hazard Ratio), the violation of the similarity assumption has no relevant effect on the Bucher approach as long as interactions between treatment effect and effect modifiers are absent. Therefore Bucher can still be considered appropriate in this specific situation. In the authors' opinion, MAIC can be considered as an option (at least as sensitivity analysis to Bucher) if such interactions are present or cannot be ruled out. Nevertheless, in practice MAIC is potentially biased and should always be considered with utmost care. PMID- 28361160 TI - Ministry of Health Clinical Practice Guidelines: Lipids. AB - The Ministry of Health (MOH) has updated the Clinical Practice Guidelines on Lipids to provide doctors and patients in Singapore with evidence-based treatment for lipids. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the MOH Clinical Practice Guidelines on Lipids, for the information of SMJ readers. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website: http://www.moh.gov.sg/content/moh_web/healthprofessionalsportal/doctors/guideline /cpg_medical.html. PMID- 28361162 TI - Comment on: The joy of parenting: infant sleep intervention to improve maternal emotional well-being and infant sleep. PMID- 28361163 TI - Authors' reply. PMID- 28361161 TI - Steroids in traditional Chinese medicine: what is the evidence? AB - Local healthcare providers often question the possible steroidal activity of traditional Chinese medicine (TCM) herbs or herbal products and implicate them as a cause for adrenal insufficiency or Cushing's syndrome in patients with a history of TCM intake. We conducted a comprehensive database search for evidence of potential glucocorticoid, mineralocorticoid, androgenic or oestrogenic activity of herbs or herbal products. Overall, there are not many herbs whose steroidal activity is well established; among these, most cases were based on preclinical studies. Liquorice root may cause pseudoaldosteronism through interference with the steroidogenesis pathway. Although ginseng and cordyceps have some in vitro glucocorticoid activities, the corroborating clinical data is lacking. Deer musk and deer antler contain androgenic steroids, while epimedium has oestrogenic activity. On the other hand, adulteration of herbal products with exogenous glucocorticoids is a recurrent problem encountered locally in illegal products masquerading as TCM. Healthcare providers should stay vigilant and report any suspicion to the relevant authorities for further investigations. PMID- 28361164 TI - Clinics in diagnostic imaging (175). Corpus callosum glioblastoma multiforme (GBM): butterfly glioma. AB - A 54-year-old man presented with change in behaviour, nocturnal enuresis, abnormal limb movement and headache of one week's duration. The diagnosis of butterfly glioma (glioblastoma multiforme) was made based on imaging characteristics and was further confirmed by biopsy findings. As the corpus callosum is usually resistant to infiltration by tumours, a mass that involves and crosses the corpus callosum is suggestive of an aggressive neoplasm. Other neoplastic and non-neoplastic conditions that may involve the corpus callosum and mimic a butterfly glioma, as well as associated imaging features, are discussed. PMID- 28361166 TI - [The first Mental Health Act in China 2013 : An historical step towards human rights]. AB - In the past, the mentally ill used to be relentlessly stigmatized and their basic needs grossly neglected in China. Only the coastal cities with their Western oriented universities provided Western type mental healthcare. In general, traditional Chinese medicine (TCM) embracing medicinal herbs and acupuncture was practiced. Mental hospitals were non-existent before 1889 and care of the chronically mentally ill rested with their families and the community; however, the prevalence and spectrum of mental disorders were similar to those in Western countries. After the establishment of the People's Republic of China old fashioned mental hospitals were founded. The "Great Leap Forward" starting in 1958 envisaged the creation of a mental healthcare system based on Soviet Union standards. Psychiatry had a strong biological orientation, and psychotherapy did not exist. Psychology was rejected as not being science and was not taught at universities before 1978. With the Reform and Opening Policy in 1978 the education of psychology was stepped up. Psychology was introduced as an academic discipline in 1978 and psychotherapy and psychosomatic medicine were established in mental healthcare. The current mental healthcare in China resembles the standard in Germany before the "Psychiatrie-Enquete" (expert commission official report). With the Mental Health Act adopted in 2013 after 27 years of planning, China has laid the legal foundation for planning and establishing a humane system of mental healthcare. The Act safeguards patients' human and individual rights and increases trust in psychiatric institutions. It guarantees the right to optimal treatment and provides legal protection in cases of malpractice. PMID- 28361165 TI - Accuracy of stereolithographically printed digital models compared to plaster models. AB - OBJECTIVE: This study compared the accuracy of plaster models from alginate impressions and printed models from intraoral scanning. MATERIALS AND METHODS: A total of 28 volunteers were selected and alginate impressions and intraoral scans were used to make plaster models and digital models of their dentition, respectively. The digital models were printed using a stereolithographic (SLA) 3D printer with a horseshoe-shaped design. Two calibrated examiners measured distances on the plaster and printed models with a digital caliper. The paired t test was used to determine intraobserver error and compare the measurements. The Pearson correlation coefficient was used to evaluate the reliability of measurements for each model type. RESULTS: The measurements on plaster models and printed models show some significant differences in tooth dimensions and interarch parameters, but these differences were not clinically relevant, except for the transversal measurements. The upper and lower intermolar distances on the printed models were statistically significant and clinically relevant smaller. CONCLUSIONS: Printed digital models with the SLA 3D printer studied, with a horseshoe-shaped base made from intraoral scans cannot replace conventional plaster models from alginate impressions in orthodontics for diagnosis and treatment planning because of their clinically relevant transversal contraction. PMID- 28361167 TI - Potential drug-drug interactions with abiraterone in metastatic castration resistant prostate cancer patients: a prevalence study in France. AB - PURPOSE: Abiraterone acetate combined with prednisone improves survival in metastatic castration-resistant prostate cancer (mCRPC) patients. This oral anticancer agent may result in drug-drug interactions (DDI). We aimed to evaluate the prevalence of DDI with abiraterone and the possible determinants for the occurrence of these DDI. METHODS: We performed a single centre retrospective review from electronic medical records of mCRPC patients treated with abiraterone from 2011 to 2015. Potential DDI with abiraterone were identified using Micromedex and were categorized by a 4-point scale severity. RESULTS: Seventy-two out of ninety-five mCRPC pts (median age: 77 years [68-82]) had comorbidities. The median number of drugs used per patient was 7 [5-9]. 66 potential DDI with abiraterone were detected in 49 patients (52%): 39 and 61% were classified as major and moderate DDI, respectively. In the univariate analysis, pain (p < 0.0001), hypo-albuminemia (p = 0.032), and higher ECOG performance status (PS) (p = 0.013) were significantly associated with a higher risk of DDI with abiraterone. Pain (p < 0.0001) and PS (p = 0.018) remained significant in the multivariate analysis. CONCLUSIONS: Polypharmacy is an issue among mCRPC patients. In our study, half of the patients have potential DDI with abiraterone. Patients with pain and poor PS are at higher risk of DDI with abiraterone. A medication review by a pharmacist is of crucial importance to prevent DDI with abiraterone. PMID- 28361168 TI - Influence of leptin and GABAB-receptor agonist and antagonist on neurons of the hypothalamic infundibular nucleus in the chicken. AB - In birds and mammals, the neuroendocrine regulation of energy balance is conserved in many aspects. Despite significant similarities between the two groups, differences in the regulatory mechanisms were detected. The present study was performed to carry out investigations of the influence of human leptin and GABAB-receptor agonist and antagonist on the firing rate of neurons of the Nucleus infundibuli hypothalami in brain slices from juvenile chickens. For the first time, we demonstrated a clear, dose-related change in the firing rate of hypothalamic neurons in juvenile chickens after the acute application of recombinant human leptin (1, 10, and 100 nM). All investigated neurons increased their subsequent firing rate. Application of GABAB-receptor agonist baclofen (1 uM) blocked, while antagonist CGP 35348 (10 uM) increased the spontaneous neuronal activity. Simultaneous application of baclofen and leptin reduced the effect observed from single leptin application. This was not found after simultaneously application of leptin and CGP. Altogether, our results indicate that in bird brain slices, and exemplarily in those of the chicken, hypothalamic neurons show mammalian-like responsiveness after acute leptin and GABA application. GABAB-mechanisms involved in GABA release play a likely important role in the leptin-mediated effects on NI neurons via functional leptin receptors. PMID- 28361170 TI - Bilateral chorea-ballism and diabetic ketoacidosis as the initial presentation of a case with maternally inherited diabetes and deafness. PMID- 28361169 TI - Magnetic activation in the brain of the migratory northern wheatear (Oenanthe oenanthe). AB - Behavioural and neurobiological evidence suggests the involvement of the visual and trigeminal sensory systems in avian magnetoreception. The constantly growing array of new genetic approaches becoming available to scientists would bear great potential to contribute to a generally accepted understanding of the mechanisms underlying this ability, but would require to breed migratory birds in captivity. Here we show that the transcontinental night-migratory Northern Wheatear (Oenanthe oenanthe), which is currently the only migratory songbird successfully being bred in reasonable numbers in captivity, shows magnetic-field-induced neuronal activation in the trigeminal brainstem areas receiving their input through the ophthalmic branch of the trigeminal nerve. In addition, preliminary data indicate night vision-triggered activation in the anterior visual forebrain. This brain area could represent the same brain region, which has previously been named "Cluster N" and shown to be involved in processing magnetic compass information in European Robins. Thus, based on brain activation data, both visually and trigeminally mediated magnetic senses known from other birds seem to exist in Northern Wheatears. This makes this species a potentially excellent model species for future genetic research on magnetoreception in migratory birds. PMID- 28361172 TI - Letter to the Editor regarding "Analysis of recombinant human follicle stimulating hormone by mass spectrometric approaches". PMID- 28361173 TI - [Medical examination: Preparation for ENT specialisation : Part 29]. PMID- 28361171 TI - Reducing dentine hypersensitivity with nano-hydroxyapatite toothpaste: a double blind randomized controlled trial. AB - OBJECTIVES: The present randomized double-blind clinical trial aimed to compare the efficacy in reducing dentin hypersensitivity of a dentifrice formulation containing nano-hydroxyapatite with a fluoride dentifrice and a placebo. METHODS AND MATERIALS: One hundred and five subjects were recruited to participate in the study. A computer-generated random table with blocking to one of the three study treatments was used in order to have 35 subjects per group: (1) nano hydroxyapatite 2% gel toothpaste fluoride free; (2) fluoride gel toothpaste; (3) placebo. Groups 1, 2, and 3 were instructed to treat their teeth for 10 min twice a day with the provided toothpaste gel. The participant's dentin hypersensitivity was evaluated at baseline and after 2 and 4 weeks using airblast and tactile tests. In addition, a subjective evaluation using a visual analogue scale was used. RESULTS: Significant lower values of cold air sensitivity and tactile sensitivity (p < 0.05) were found for the test group at 2 weeks and 4 weeks. In addition, statistically significant (p < 0.05) lower values of sensitivity were reported for group 1 compared to those for groups 2 and 3 at 2 and 4 weeks, respectively. The VAS scores were significantly lower (p < 0.05) in the test group at 2 and 4 weeks compared to those at baseline and in the control groups. CONCLUSION: The application of nano-hydroxyapatite in gel toothpaste fluoride free is an effective desensitizing agent providing relief from symptoms after 2 and 4 weeks. PMID- 28361174 TI - Eustachian tuboplasty and shrinkage of ostial mucosa with new devices : Including a proposal of a classification system. AB - OBJECTIVE: A new combined approach to Eustachian tube dysfunction (ETD) employing new minimally invasive devices is described. STUDY DESIGN: An anatomoclinical classification of ETD was conceived to allow correct categorization of patients and enable comparative studies to be performed. Herein, the authors report on their experience with a consecutive series of obstructive ETD patients treated by balloon dilation of the Eustachian tube using AERA (Acclarent, Menlo Park, CA, USA), combined with a quantic molecular resonance (QMR)-mediated rhinopharyngeal tubal ostial mucosa shrinkage technique with a dedicated "Mitto" hand piece (Telea, Sandrigo-Vicenza, Italy). METHODS: A prospective study was conducted in 102 patients with ETD. Medical history, complete clinical ENT evaluation and oto functional examinations were performed in all patients. In all cases, balloon dilatation of the Eustachian tube was performed via the transnasal approach under video-endoscopic control. This was followed by decongestion of the torus tubarius and the inferior turbinate by QMR, with immediate shrinkage of the mucosa of the turbinate and a reduction of the prolapse of the mucosal plica on the tubal ostium. RESULTS: Comparison of pre- and postoperative oto-functional examinations revealed a significant improvement. The postoperative hearing symptoms were reduced in a statistically significant manner on the visual analog scale (VAS). It was possible to perform the postoperative "swallowing-opening-Toynbee Valsalva" (SOTV) test in a significant percentage of cases compared to the preoperative test. CONCLUSION: The combined surgical procedure of balloon tubodilation with simultaneous QMR-mediated shrinkage of the tubal ostial mucosa and reduction of the posterior portion of the inferior turbinate was found to be an effective, safe, and complete treatment for tubal dysfunction in the majority of patients. PMID- 28361175 TI - Letter of response: Small-incision lenticule extraction (SMILE): Outcomes of 722 eyes treated for myopia and myopic astigmatism. PMID- 28361176 TI - Electrophysiological assessment for early detection of retinal dysfunction in beta-thalassemia major patients. AB - PURPOSE: The purpose of this study was to assess the role of various diagnostic tests in early detection of retinal changes in beta-thalassemia major patients. METHODS: Thirty-eight visually asymptomatic beta-thalassemia major patients receiving regular blood transfusions and iron-chelation therapy with deferoxamine (group A, n = 13), deferasirox (group B, n = 11) or deferoxamine with deferiprone (group C, n = 14) and fourteen age- and sex- matched healthy individuals were included in the study. All participants underwent ophthalmoscopy, full-field electroretinography (ERG), visual evoked potentials (VEP), multifocal electroretinography (mfERG), fundus autofluorescence (FAF) imaging and optical coherence tomography (OCT) scans. RESULTS: Retinal pigment epithelium changes were present in two cases. Scotopic ERG demonstrated decreased a-wave amplitude in groups A, B and C (p = 0.03, p = 0.002 and p = 0.002, respectively) and decreased b-wave amplitude in groups B and C (p = 0.002 and p = 0.01, respectively) compared to controls. Photopic ERG showed delayed b-wave latency in groups A and C (p = 0.03 and p = 0.03, respectively) ERG maximal combined response and VEP response did not differ between groups. MfERG showed reduced retinal response density in ring 1 in groups A, B, C (p < 0.001, p < 0.001, p = 0.001, respectively) and ring 2 in group B (p = 0.02) and delayed latency in ring 5 in groups A and B (p = 0.04 and p = 0.04, respectively). Abnormal FAF images appeared in three cases and OCT abnormalities in one case, whereas no changes were observed in controls (p = 0.55 and p = 1.00, respectively). CONCLUSIONS: Full-field ERG and mfERG are more sensitive tools for detecting early retinal changes in beta-thalassemia patients compared with ophthalmoscopy, VEP, FAF imaging and OCT scans. PMID- 28361177 TI - Chronic thromboembolic pulmonary hypertension: Evaluation of 2D-perfusion angiography in patients who undergo balloon pulmonary angioplasty. AB - OBJECTIVE: To evaluate the feasibility of 2D-perfusion angiography (2D-PA) in order to quantify perfusion changes of the lung parenchyma pre- and post-balloon pulmonary angioplasty (BPA). METHODS: Thirty consecutive interventions in 16 patients with 99 treated pulmonary artery segments were included. To quantify changes in pulmonary blood flow using 2D-PA, the acquired digital subtraction angiographies (DSA) pre- and post-BPA were post-processed. A reference ROI in the treated pulmonary artery and a distal target ROI in the lung parenchyma were placed in corresponding areas on DSA pre- and post-BPA. Time to peak (TTP), peak density (PD) and area under the curve (AUC) were assessed. The ratios reference ROI to target ROI (TTPparenchyma/TTPinflow; PDparenchyma/PDinflow; AUCparenchyma/AUCinflow) were calculated. Relative differences of the 2D-PA parameters were correlated to changes in the pulmonary-flow-grade-score. RESULTS: The pulmonary-flow-grade-score improved after BPA (p<0.0001). Likewise, the ratio TTPparenchyma/TTPinflow shortened by 10% (p=0.0002), the PDparenchyma/PDinflow increased by 46% (p<0.0001) and the AUCparenchyma/AUCinflow increased by 36% (p<0.0001). A significant correlation between changes in the pulmonary-flow-grade score and changes in PDparenchyma/PDinflow (rho=0.48, p<0.0001) and AUCparenchyma/AUCinflow (rho=0.31, p=0.0018) was observed. CONCLUSION: Quantification of pulmonary perfusion pre- and post-BPA using 2D-PA is feasible and has the potential to improve monitoring of BPA. KEY POINTS: * Quantification of BPA results by use of 2D-PA is feasible. * 2D-PA allows objective assessment of changes in lung parenchymal perfusion. * 2D-PA has the potential to optimize BPA. PMID- 28361179 TI - [Frequency and doses of diagnostic and interventional X-ray applications : Trends between 2007 and 2014]. AB - BACKGROUND: In Germany, approximately 95% of man-made radiation exposure of the population results from diagnostic and interventional X-ray procedures. Thus, radiation protection of patients in this field of application is of great importance. OBJECTIVE: Quantification and evaluation of current data on the frequency and doses of X-ray procedures as well as temporal trends for the years 2007-2014. MATERIAL AND METHODS: For outpatients the frequency of X-ray procedures was estimated using reimbursement data from health insurances and for inpatients by means of hospital statistics. For the years under review, representative values for the effective dose per X-ray application were determined mainly from data reported by X-ray departments to the competent authorities. RESULTS: In 2014 approximately 140 million X-ray procedures were performed in Germany with some 40% from dental examinations. On average 1.7 procedures per inhabitant and year were almost constantly carried out between 2007 and 2014. Besides dental diagnostics, X-ray examinations of the skeleton and thorax were performed most frequently. The number of computed tomography (CT) examinations increased by approximately 40%. The increase in magnetic resonance imaging (MRI) was even more pronounced with approximately 55% but overall CT examinations were still performed more often than MRI. The doses per X-ray procedure were only slightly reduced, despite the various dose reduction approaches established in recent years; therefore, the mean effective dose per inhabitant increased from approximately 1.4 mSv in 2007 to 1.6 mSv in 2014, mainly due to the increasing frequency of CT examinations. CONCLUSION: The principles of justification and optimization of radiological procedures are to be consistently applied in each individual instance, especially in the case of CT examinations. PMID- 28361178 TI - Nitrogen-regulated changes in total amino acid profile of maize genotypes having contrasting response to nitrogen deficit. AB - Sustainable development of cellular organisms depends on a precise coordination between the carbon and nitrogen metabolisms within the living system. Inorganic N is assimilated into amino acids which serve as an important N source for various regulatory metabolic pathways in plants. This study investigates the role of amino acids in C/N balance by examining changes in amino acid profile in the leaves and roots of low-N-tolerant (PHEM-2) and low-N-sensitive (HM-4) maize genotypes grown hydroponically under N-sufficient (4.5 mM), N-deficient (0.05 mM) and N-restoration conditions. N application effectively altered the level of cysteine, methionine, asparagine, arginine, phenylalanine, glycine, glutamine, aspartate and glutamate in both genotypes. Under low N (0.05 mM), the asparagine and glutamine contents increased, while those of glutamate, phenylalanine and aspartate decreased in both genotypes. However, serine content increased in PHEM 2 but decreased in HM-4. Resupply of N to low-N-grown plants of both genotypes restored the amino acids level to that in the control; the restoration was quicker and more consistent in PHEM-2 than in HM-4. Based on alteration of amino acid level, a strategy can be developed to improve the ability of maize to adapt to low-N environments by way of an improved N utilization. PMID- 28361180 TI - Evaluation of Endothelial Function by Flow-Mediated Dilation: a Comprehensive Review in Rheumatic Disease. AB - Flow-mediated dilation (FMD) represents a non-invasive marker of endothelial function to evaluate vascular homeostasis, which reflects the effects of several mechanisms, including vessel tone regulation, cell proliferation, and inflammatory responses. Beyond classical atherosclerotic risk factors such as arterial hypertension, diabetes mellitus, smoking, obesity, and dyslipidemia, chronic inflammation contributes to the endothelial dysfunction causing plaque formation and there is growing evidence of a significantly higher cardiovascular morbidity associated with autoimmune diseases. The endothelium reacts to several endogenous and exogenous stimuli, through surface receptors and intracellular signalling, and releases numerous vasoactive substances, including endothelins, prostacyclins, and nitric oxide (NO). Chronic inflammatory rheumatic diseases are commonly associated with decreased endothelial NO production, vascular damage, and premature atherosclerosis. Despite partially eclipsed by pulse wave velocity measure in the modern scientific literature, we provide a comprehensive overview and critically discuss the available data supporting FMD as a surrogate marker of endothelial function and, therefore, its potential role in predicting early atherosclerosis in patients with rheumatic diseases. PMID- 28361182 TI - Stiffness of Protease Sensitive and Cell Adhesive PEG Hydrogels Promotes Neovascularization In Vivo. AB - Materials that support the assembly of new vasculature are critical for regenerative medicine. Controlling the scaffold's mechanical properties may help to optimize neovascularization within implanted biomaterials. However, reducing the stiffness of synthetic hydrogels usually requires decreasing polymer densities or increasing chain lengths, both of which accelerate degradation. We synthesized enzymatically-degradable poly(ethylene glycol) hydrogels with compressive moduli from 2 to 18 kPa at constant polymer density, chain length, and proteolytic degradability by inserting an allyloxycarbonyl functionality into the polymer backbone. This group competes with acrylates during photopolymerization to alter the crosslink network structure and reduce the hydrogel's stiffness. Hydrogels that incorporated (soft) or lacked (stiff) this group were implanted subcutaneously in rats to investigate the role of stiffness on host tissue interactions. Changes in tissue integration were quantified after 4 weeks via the hydrogel area replaced by native tissue (tissue area fraction), yielding 0.136 for softer vs. 0.062 for stiffer hydrogels. Including soluble FGF 2 and PDGF-BB improved these responses to 0.164 and 0.089, respectively. Softer gels exhibited greater vascularization with 8.6 microvessels mm-2 compared to stiffer gels at 2.4 microvessels mm-2. Growth factors improved this to 11.2 and 4.9 microvessels mm-2, respectively. Softer hydrogels tended to display more sustained responses, promoting neovascularization and tissue integration in synthetic scaffolds. PMID- 28361183 TI - Handheld Electrical Impedance Myography Probe for Assessing Carpal Tunnel Syndrome. AB - Electrical impedance myography (EIM) is a novel, noninvasive, and painless technique for quantitatively assessing muscle health as well as disease status and progression. The preparatory work for commercial adhesive electrodes used in previous EIM measurements is tedious, as the electrodes need to be cut, repeatedly applied, and removed. Moreover, the electrode distances need to be measured many times. To overcome these problems, we developed a convenient and practical handheld EIM probe for assessing carpal tunnel syndrome (CTS) in the small hand muscles. To reduce the electrode-skin contact impedance (ESCI), the micropillared and microholed stainless steel electrodes (SSEs) contained in the probe were fabricated using a laser processing technique. When covered with saline, these electrodes showed lower ESCIs than a smooth SSE and Ag/AgCl electrode. The probe was shown to have excellent test-retest reproducibility in both healthy subjects and CTS patients, with intraclass correlation coefficients exceeding 0.975. The reactance and phase values of the abductor pollicis brevis (affected muscle) for CTS patients were consistently lower than those for healthy subjects, with a 50-kHz difference of 37.1% (p < 0.001) and 31.0% (p < 0.001), respectively. Further, no significant differences were detected in the case of the abductor digiti minimi (unaffected muscle). These results indicate that EIM has considerable potential for CTS assessment and hence merits further investigation. PMID- 28361181 TI - Putting a brake on synaptic vesicle endocytosis. AB - In chemical synapses, action potentials evoke synaptic vesicle fusion with the presynaptic membrane at the active zone to release neurotransmitter. Synaptic vesicle endocytosis (SVE) then follows exocytosis to recapture vesicle proteins and lipid components for recycling and the maintenance of membrane homeostasis. Therefore, SVE plays an essential role during neurotransmission and is one of the most precisely regulated biological processes. Four modes of SVE have been characterized and both positive and negative regulators have been identified. However, our understanding of SVE regulation remains unclear, especially the identity of negative regulators and their mechanisms of action. Here, we review the current knowledge of proteins that function as inhibitors of SVE and their modes of action in different forms of endocytosis. We also propose possible physiological roles of such negative regulation. We believe that a better understanding of SVE regulation, especially the inhibitory mechanisms, will shed light on neurotransmission in health and disease. PMID- 28361184 TI - Impact of Fiber Structure on the Material Stability and Rupture Mechanisms of Coronary Atherosclerotic Plaques. AB - The rupture of an atherosclerotic plaque in the coronary circulation remains the main cause of heart attack. As a fiber-oriented structure, the fiber structure, in particular in the fibrous cap (FC), may affect both loading and material strength in the plaque. However, the role of fiber orientation and dispersion in plaque rupture is unclear. Local orientation and dispersion of fibers were calculated for the shoulder regions, mid FC, and regions with intimal thickening (IT) from histological images of 16 human coronary atherosclerotic lesions. Finite element analysis was performed to assess the effect of these properties on mechanical conditions. Fibers in shoulder regions had markedly reduced alignment (Median [interquartile range] 12.9 degrees [6.6, 18.0], p < 0.05) compared with those in mid FC (6.1 degrees [5.5, 9.0]) and IT regions (6.7 degrees [5.1, 8.6]). Fiber dispersion was highest in shoulders (0.150 [0.121, 0.192]), intermediate in IT (0.119 [0.103, 0.144]), and lowest in mid FC regions (0.093 [0.081, 0.105], p < 0.05). When anisotropic properties were considered, stresses were significantly higher for the mid FC (p = 0.030) and IT regions (p = 0.002) and no difference was found for the shoulder or global regions. Shear (sliding) stress between fibers in each region and their proportion of maximum principal stress were: shoulder (25.8 kPa [17.1, 41.2], 12.4%), mid FC (13.9 kPa [5.8, 29.6], 13.8%), and IT (36.5 kPa [25.9, 47.3], 15.5%). Fiber structure within the FC has a marked effect on principal stresses, resulting in considerable shear stress between fibers. Fiber structure including orientation and dispersion may determine mechanical strength and thus rupture of atherosclerotic plaques. PMID- 28361186 TI - Soret coefficient of the n-dodecane-n-hexane binary mixture under high pressure. AB - In the present work, the Soret coefficient has been determined at high pressure for a binary hydrocarbon mixture by combining the thermogravitational column and the dynamic near-field imaging techniques. The analyzed mixture is an iso-massic n -dodecane-n -hexane mixture at 298.15K. The molecular diffusion coefficient has been measured up to 20MPa by means of the dynamic analysis of the light scattered by non-equilibrium concentration fluctuations. With a cylindrical thermogravitational column the thermodiffusion coefficient was determined from 0.1MPa to 10MPa. Density, as well as, mass expansion and thermal expansion have been measured with a high pressure densimeter. Dynamic viscosity at up to 20MPa has been determined with a high pressure viscometer. This work shows the decreasing tendency of both the molecular diffusion and the thermodiffusion coefficient with increasing pressure. PMID- 28361185 TI - Assessment of pharmacokinetics for microvessel proliferation by DCE-MRI for early detection of physeal bone bridge formation in an animal model. AB - OBJECTIVES: Bone bridge formation occurs after physeal lesions and can lead to growth arrest if not reversed. Previous investigations on the underlying mechanisms of this formation used histological methods. Therefore, this study aimed to apply a minimally invasive method using dynamic contrast-enhanced MRI (DCE-MRI). MATERIALS AND METHODS: Changes in functional parameters related to the microvessel system were assessed in a longitudinal study of a cohort of an animal model applying a reference region model. The development of morphology of the injured physis was investigated with 3D high-resolution MRI. To acquire complementary information for MRI-related findings qRT-PCR and immunohistochemical data were acquired for a second cohort of the animal model. RESULTS: The evaluation of the pharmacokinetic parameters showed a first rise of the transfer coefficient 7 days post-lesion and a maximum 42 days after operation. The analysis of the complementary data showed a connection of the first rise to microvessel proliferation while the maximum value was linked to bone remodeling. CONCLUSION: The pharmacokinetic analysis of DCE-MRI provides information on a proliferation of microvessels during the healing process as a sign for bone bridge formation. Thereby, DCE-MRI could identify details, which up to now required analyses of highly invasive methods. PMID- 28361187 TI - Polycyclic Aromatic Hydrocarbons (PAHs) in Exposed-Lawn Soils from 28 Urban Parks in the Megacity Guangzhou: Occurrence, Sources, and Human Health Implications. AB - Polycyclic aromatic hydrocarbons (PAHs) in urban soils may pose a serious threat to human health via oral ingestion, dermal absorption, and particulate inhalation, especially in public parks and playgrounds, with children and senior citizens showing the highest susceptibility. Several studies have been undertaken identifying PAHs in urban soils, but no studies to date have assessed PAHs in urban parks, in particular in exposed-lawn soils. In recent decades, unprecedented rates of urbanization and industrialization in China have resulted in significant levels of urban environmental pollution. However, concentrations, sources, and the health risk associated with PAH exposure via urban park lawn soils in China remain unknown. The concentrations, sources, and health risk of exposure to 16 PAHs in surface-exposed lawn soils were studied in 28 urban parks in Guangzhou. Concentrations of Sigma16PAHs ranged from 76.44 to 890.85 ng/g with a mean of 286.11 ng/g. PAH composition was mostly characterized by 2- and 4-ring PAHs in most sampling parks; Nap, Flua, Pyr, Phe, and Chr were the dominant constituents. Principle component analysis coupled with multivariate linear regression indicated that vehicular and coal combustion emissions contributed to 50.53 and 49.46% of PAHs in Guangzhou's urban park soils, respectively. Total cancer risk (TCR) analysis found that 22 parks (accounting for 78.57% total parks) designed for children's use and general-use park areas presented a potentially high risk (>1 * 10-4) for all users. PMID- 28361188 TI - Evaluating tumor response with FDG PET: updates on PERCIST, comparison with EORTC criteria and clues to future developments. AB - Eighteen years ago, the EORTC PET criteria standardized for the first time response assessment by FDG PET. Response assessment by FDG PET has been further developed and refined by PERCIST (PET response criteria in solid tumors). This review describes the data underlying these two systems for assessing tumor response on FDG PET/CT. It also summarizes recent clinical studies that have compared EORTC criteria and PERCIST with each other as well as with the anatomically based "response criteria in solid tumors" (RECIST). These studies have shown that response assessment by EORTC criteria and PERCIST leads to very similar response classifications. In contrast, there are significant differences between response assessment by PERCIST and RECIST. Preliminary data also suggest that response assessment by PERCIST is better correlated with patient outcome and may be a better predictor for the effectiveness of new anti-cancer therapies than RECIST. If correct, this could have a significant impact on oncologic drug development. However, confirmation of the better predictive value of response assessment by PERCIST by data from randomized trials is still lacking. PMID- 28361189 TI - Personalized 177Lu-octreotate peptide receptor radionuclide therapy of neuroendocrine tumours: a simulation study. AB - PURPOSE: Peptide receptor radionuclide therapy (PRRT) with 177Lu-octreotate is commonly administered at empiric, fixed amounts of injected radioactivity (IA). This results in highly variable absorbed doses to critical organs and suboptimal treatment of most patients. The primary aims of this study were to design a personalized PRRT (P-PRRT) protocol based on dosimetry, and to perform a simulation of this protocol in a retrospective cohort of patients with neuroendocrine tumours, in order to assess the potential of P-PRRT to safely increase the absorbed dose to the tumour during a four-cycle induction course. METHODS: Thirty-six patients underwent 122 fixed-IA 177Lu-octreotate PRRT cycles with quantitative SPECT/CT-based dosimetry. Twenty-two patients completed a four cycle induction course (29.6 +/- 2.4 GBq cumulative IA), with kidney, bone marrow and maximum tumour absorbed doses of 16.2 +/- 5.5, 1.3 +/- 0.8, and 114 +/- 66 Gy, respectively. We simulated a P-PRRT regime in which the renal absorbed dose per IA was predicted by the body surface area and glomerular filtration rate for the first cycle, and by renal dosimetry of the previous cycle(s) for the following cycles. Personalized IA was adjusted at each cycle in order to reach the prescribed renal absorbed dose of 23 Gy over four cycles (with a 25-50% reduction when renal or bone marrow function was impaired). Simulated IA and absorbed doses were based on actual patient characteristics, laboratory values and absorbed doses per IA delivered at each cycle. RESULTS: In the P-PRRT regime, cumulative IA could have been increased to 43.7 +/- 16.5 GBq over four induction cycles (10.9 +/- 5.0 GBq per cycle), yielding cumulative kidney, bone marrow and maximum tumour absorbed doses of 21.5 +/- 2.5, 1.63 +/- 0.61, and 163.4 +/- 85.9 Gy, respectively. This resulted in an average 1.48-fold increase in cumulative maximum tumour absorbed dose over empiric PRRT (range, 0.68-2.64-fold; P = 0.0013). CONCLUSION: By standardizing the renal absorbed dose delivered during the induction course, P-PRRT has the potential to significantly increase tumour absorbed dose, thus to augment the therapeutic benefit while limiting toxicity. PMID- 28361190 TI - [The fibrous skeleton of the hand : Changes with Dupuytren's contracture]. AB - The exact knowledge of the anatomy of the fibrous skeleton of the hand is an absolute prerequisite for any treatment of Dupuytren's disease. The fibrous skeleton does not only include the palmar aponeurosis, but also numerous retinacula cutis, which are not found in current anatomy books. Here, eponyms facilitate the otherwise difficult and over-pronounced names of the fiber systems. Skoog, Legueu and Juvara, Gosset, Grapow, Grayson, Cleland, Thomine, and Barton are the most important. This systematic review of the fibers and strands is designed to help reduce iatrogenic complications. PMID- 28361192 TI - [Malalignment of the first ray : Clinical and radiological diagnostics]. AB - Clinical and radiological examination of the foot are mandatory before surgical correction of the forefoot. The clinical examination includes leg axis, position of the hind foot, deformity of the first ray as well as skin conditions, pulse status and possible sensitive deficits. A shortening of the gastrocnemius muscle can be identified using the Silfverskiold test. Discomfort in the midfoot can indicate pathologies of the tarsometatarsal joint and the same applies for osteophyte infiltration around the Lisfranc joint line, whereby the second tarsometatarsal joint often shows more advanced degenerative arthritis than the first tarsometatarsal joint. Callosities under the second and third metatarsal heads correlate with a faulty load transmission of the first ray. A limitation of the range of movement of the first metatarsophalangeal joint is usually associated with degenerative arthritis in X-ray imaging. Under weight bearing, X rays of the foot in two planes represent the standard imaging examination. In addition to the intermetatarsal angle, the hallux valgus angle and the interphalangeal angle as well as the width of the first metatarsal bone influence the therapy decision. The same applies to degenerative changes or an obvious instability of the first tarsometatarsal joint. In many cases, initial signs of degenerative arthritis can be found in the metatarsophalangeal joint and around the sesamoid bones, although these often do not correlate to clinical symptoms. PMID- 28361191 TI - [Bone void fillers in osteotomies : If, when, and which type?] AB - Medial opening wedge high tibial osteotomy (HTO) is an established procedure for treating medial osteoarthritis of the knee. In order to achieve the desired amount of correction, the osteotomy gap is opened, which creates a bone void in the medial aspect of the proximal tibia. The resulting bone void can either be left alone or be addressed by interposing a variety of different bone void fillers. Autologous and allogenic fillers can be distinguished from synthetic materials. Up to now, few studies have dealt with the usefulness and necessity for bone void fillers in HTO. The following article provides an overview on the currently used bone void fillers, their specific advantages and disadvantages and their influence on clinical and radiographic outcome after HTO. PMID- 28361193 TI - Return to sports and work after partial shoulder replacement surgery. AB - BACKGROUND: Shoulder hemiarthroplasty is a particularly attractive treatment option in young active patients, where revision surgery is an issue and a glenoid replacement might be necessary in the long run. These patients often ask about the possibility of returning to sport and work after surgery. OBJECTIVE: The purpose of this investigation was to analyze whether patients undergoing shoulder hemiarthroplasty (HSA) are able to successfully return to sports activities and work after surgery. MATERIALS AND METHODS: This study included 42 patients treated with HSA. Two subgroups were built: patients who had participated in sports less than 5 years prior to surgery (group A: n = 29, 69%) and those who had not done so (group B: n = 13, 31%). Evaluation was based on a questionnaire asking about types of sports, frequency of sports activity, and the time taken to return to sports and work, as well as about limitations in occupational life. RESULTS: Patients' mean age at the time of surgery was 56.3 +/- 12.7 years in group A and 66.9 +/- 13.8 years in group B. Mean follow-up was 5.5 years (range 2.5-12 years). In group A, 18 patients (62%) had participated in sports up to the time of surgery and 12 (41%) had returned to the same level of sports activity at final follow-up. The rate of return to preoperative sports activity was 67%. Swimming was one of the most favorable sports (92%). Of the cohort patients, 2 (5%) had to change their profession due to surgery. Most patients were retired at follow-up. CONCLUSION: Patients who were sportingly active prior to HSA were able to return to sports after surgery in 67% of cases. This study confirms that patients treated by hemiarthroplasty of the shoulder joint can return to sports and work, even at medium-term follow-up. PMID- 28361194 TI - [Lapidus arthrodesis]. AB - The tarso-metatarsal 1 joint (TMT-I) arthrodesis is a treatment option or moderate to severe hallux valgus (HV) deformities. Instability of the TMT1 joint is still a debatable indication. Using stable osteosynthesis techniques allows early postoperative weight bearing. Plantar plating combined with a lag screw is the biomechanical most stable construct. An additional intermetatarsal screw can improve the horizontal stability. Clinical results are good and radiological parameters stay constant, even in the long term. PMID- 28361195 TI - Percutaneous Image-Guided Cryoablation as Second-Line Therapy of Soft-Tissue Venous Vascular Malformations of Extremities: A Prospective Study of Safety and 6 Month Efficacy. AB - PURPOSE: To report the safety and short-term efficacy of percutaneous image guided cryoablation performed as second-line therapy of venous vascular malformations (VVM) of extremities. MATERIALS AND METHODS: In this non-blinded, no-randomized trial, cryoablation was proposed in 14 patients presenting with symptomatic VVM for recurrences after treatment. Eligibility criteria were: cryoablation feasible, localization at least 5 mm from skin and nerves, absence of contra-indication for anesthesia. Safety was evaluated by the common terminology criteria for adverse events (AE). Clinical response was assessed by evaluating pain at day 7, month 2 and 6 using visual analog scale; quality of life before cryoablation and at 2 and 6 months after using questionnaire. Evolution of volume was evaluated by MRI at 6 months. Comparison was performed using the Wilcoxon test. RESULTS: A technical success was observed in all cases. While 11 patients (78.6%) presented AE (13 grade 1-2 and 3 grade 3), only two severe AE (grade 3) related to cryoablation occurred in two patients (14.3%) during the 6-month follow-up: one immediate sciatic paralysis and one delayed paresthesia. A clinical response was observed in 12 patients (85.7%) at 6 months. Pain decreased significantly from 42.5 +/- 14.2 mm before the intervention to 11.8 +/- 17.9 mm at 6 months (P = 0.002). A significant decrease in the mean volume from 12.8 +/- 14.3 to 3 +/- 2.7 cm3 was observed at 6 months (P = 0.002). CONCLUSION: Percutaneous cryoablation is a promising alternative treatment for sclerotherapy-resistant venous malformations. However, to improve safety, careful patient selection and treatment planning will be mandatory. PMID- 28361196 TI - Gender Identity Disparities in Bathroom Safety and Wellbeing among High School Students. AB - By examining the relationship between trans identity, bathroom safety and wellbeing among high school students, this article empirically investigates how educational institutions operate as sites through which gender is negotiated in ways that are consequential for trans youth. We draw cross-sectional survey data, from a multi-school climate survey (n = 1046) conducted in the Midwestern United States, to examine three aspects of high school students' wellbeing: safety at school, self-esteem, and grades. The sample included students in 9th-12th grade who identified as trans (9.2%) and cisgender (41.2% boys, 49.6% girls), as well as LGBQ (21.6%) and heterosexual (78.4%). Most respondents were monoracial white (65.8%), monoracial Black (12.4%), and multiracial (14.1%). Using mediation and moderation linear regression models, we show that feeling safe using school facilities helps to explain widespread inequalities between trans and cisgender students. Based on these results, we suggest that in order to address disparities in educational outcomes between trans and cisgender students, as well as to improve student wellbeing in general, policies and practices need to ensure that all students have the right to safely access bathrooms and school facilities. PMID- 28361197 TI - Aspirations, Expectations and Delinquency: The Moderating Effect of Impulse Control. AB - Although prior research finds a robust link between delinquent behavior and expectations, or an adolescent's perceived likelihood of obtaining one's future goals, fewer studies have evaluated aspirations, or the perceived importance of achieving one's goals. In addition, few studies consider how individual traits such as impulsivity affect the degree to which expectations and aspirations motivate or deter delinquent behavior. We contribute to this body of research by evaluating the independent effects of expectations and aspirations, and the aspiration-expectation gap (i.e., strain) on delinquent behavior during the year following an adolescent's first arrest using a large (N = 1117), racially/ethnically diverse sample of male adolescents (46.55% Latino, 35.81% Black, 14.95% White, and 2.69% Other race). In addition, we considered how impulse control interacts with expectations, aspirations, and strain to motivate behavior. Our results indicated that both aspirations, expectations and strain uniquely influence criminal behavior. Importantly, aspirations interacted with impulse control, such that aspirations affected delinquency only among youth with higher impulse control. Our findings suggest that aspirations may only influence behavior if youth also have the psychosocial capabilities to consider their future aspirations when behaving in the present. PMID- 28361198 TI - Peer Influence, Peer Selection and Adolescent Alcohol Use: a Simulation Study Using a Dynamic Network Model of Friendship Ties and Alcohol Use. AB - While studies suggest that peer influence can in some cases encourage adolescent substance use, recent work demonstrates that peer influence may be on average protective for cigarette smoking, raising questions about whether this effect occurs for other substance use behaviors. Herein, we focus on adolescent drinking, which may follow different social dynamics than smoking. We use a data calibrated Stochastic Actor-Based (SAB) Model of adolescent friendship tie choice and drinking behavior to explore the impact of manipulating the size of peer influence and selection effects on drinking in two school-based networks. We first fit a SAB Model to data on friendship tie choice and adolescent drinking behavior within two large schools (n = 2178 and n = 976) over three time points using data from the National Longitudinal Study of Adolescent to Adult Health. We then alter the size of the peer influence and selection parameters with all other effects fixed at their estimated values and simulate the social systems forward 1000 times under varying conditions. Whereas peer selection appears to contribute to drinking behavior similarity among adolescents, there is no evidence that it leads to higher levels of drinking at the school level. A stronger peer influence effect lowers the overall level of drinking in both schools. There are many similarities in the patterning of findings between this study of drinking and previous work on smoking, suggesting that peer influence and selection may function similarly with respect to these substances. PMID- 28361199 TI - The #Tamojunto Drug Prevention Program in Brazilian Schools: a Randomized Controlled Trial. AB - A randomized controlled trial was conducted in 2014 with 7th and 8th grade students from 72 public schools in 6 Brazilian cities. This trial aimed to evaluate the effects of an adapted European school-based drug prevention program Unplugged, called #Tamojunto in Brazil, which was implemented by the Ministry of Health as part of public policy. The experimental group (n = 3340) attended 12 classes in the #Tamojunto program, and the control group (n = 3318) did not receive a school prevention program. Baseline data were collected prior to program implementation, and follow-up data were collected 9 months later, allowing a matching of 4213 adolescents in both waves. The substances examined were alcohol, tobacco, marijuana, inhalants, cocaine, and crack. Multilevel analyses were used to evaluate the changes in consumption of each drug between time points and between groups. The intervention and control groups had similar baseline characteristics. The mean age of the adolescents was 12.5 +/- 0.7 years, and 51.3% were female. The program seemed to increase alcohol use initiation (first alcohol use); students in the experimental group had a 30% increased risk of initiating alcohol use during the 9-month follow-up (aRR = 1.30, 95% confidence interval (95%CI) 1.13-1.49, p < 0.001) compared to the control group. The opposite was found for the first inhalant use: the risk of using inhalants for the first time after baseline was lower in the experimental group (aRR = 0.78, 95%CI 0.63-0.96, p = 0.021) than the control group. The results of the #Tamojunto program suggest that the content and lessons regarding alcohol may enhance curiosity about its use among adolescents. We suggest a re-evaluation of the expansion of the #Tamojunto program in schools while analyzing why the program's effects were inconsistent with those of previous European studies. PMID- 28361200 TI - Utilization of Liver Microsomes to Estimate Hepatic Intrinsic Clearance of Monoamine Oxidase Substrate Drugs in Humans. AB - PURPOSE: Monoamine oxidases (MAOs) are non-CYP enzymes that contribute to systemic elimination of therapeutic agents, and localized on mitochondrial membranes. The aim of the present study was to validate quantitative estimation of metabolic clearance of MAO substrate drugs using human liver microsomes (HLMs). METHODS: Three MAO substrate drugs, sumatriptan, rizatriptan and phenylephrine, as well as four CYP substrates were selected, and their disappearance during incubation with HLMs or mitochondria (HLMt) was measured. Metabolic clearance (CL) was then calculated from the disappearance curve. RESULTS: CL obtained in HLMs for sumatriptan and a typical MAO substrate serotonin was correlated with that obtained in HLMt among ten human individual livers. Hepatic intrinsic clearance (CLint,vitro) estimated from CL in HLMs was 14-20 and 2-5 times lower than in vivo hepatic intrinsic clearance (CLint,vivo) obtained from literature for MAO and CYP substrates, respectively. Utilization of HLMs for quantitatively assessing metabolic clearance of MAO substrates was further validated by proteomics approach which has revealed that numerous proteins localized on inner and outer membranes of mitochondria were detected in both HLMs and HLMt. CONCLUSION: CLint,vitro values of MAO substrate drugs can be quantitatively estimated with HLMs and could be used for semi-quantitative prediction of CLint,vivo values. PMID- 28361201 TI - Swallowing Function After Continuous Neuromuscular Electrical Stimulation of the Submandibular Region Evaluated by High-Resolution Manometry. AB - Although neuromuscular electrical stimulation (NMES) is increasingly used in dysphagia therapy, patient responses to NMES are inconsistent and conflicting results have been reported. This, together with a lack of information about the effects of NEMS on the swallowing process, has led to an ongoing debate about its impact on swallowing function. In order to address this, we set out to (i) collect baseline information on the physiological effects of NMES on the complex pharyngeal phase of swallowing and (ii) to compare two different stimulation protocols. In doing so, we provide information useful for evaluating the therapeutic effectiveness of NMES on the swallowing process. In a prospective study, 29 healthy participants performed water swallows after receiving continuous NMES for 10 min. The stimulus was applied in the submandibular region using one of two different stimulation protocols: low-frequency stimulation (LFS) and mid-frequency stimulation (MFS). Swallowing parameters of the pharynx and UES were measured using high-resolution manometry. Maximum tongue base pressure increased by 8.4% following stimulation with the MFS protocol. Changes in UES function were not found. LFS stimulation did not result in any significant changes in the parameters examined. The MFS protocol enhances tongue base retraction during swallowing in healthy volunteers. The magnitude of the effect, however, was small, possibly due to the ability of healthy subjects to compensate for external influences, such as NMES, and may actually prove to be much greater in patients with diminished tongue base retraction. Thus, further studies are needed to determine whether a similar effect is also achievable in dysphagic patients with impaired bolus propulsion, possibly allowing MFS stimulation of the tongue base region to be used as an additional treatment tool. PMID- 28361203 TI - Physiotherapy and behavior therapy for the treatment of overactive bladder syndrome: a prospective cohort study. AB - PURPOSE: To determine the efficacy of physiotherapy and behavior therapy and to find specific subgroups of women with overactive bladder syndrome that might gain increased benefit from this therapy. METHODS: Women with >=10 micturitions per 24 h period were included. Six to nine therapy sessions were held within a 14-day interval. Efficacy end point was a reduction in micturitions and in episodes of nocturia. Secondary outcomes included ICIQ-OAB, ICIQ-OABqol and visual analog scales. Follow-up was 6 months. Levene test, Student's t test, Pearson's and Spearman's correlations were utilized as well as the Friedman test and a multivariable-multilevel model. RESULTS: 32 women were included. Mean age was 51 +/- 15.9 (years +/- standard deviation, sd). Mean body mass index (BMI) was 24.4 +/- 4.8 (kg/m2 +/- sd). There was a 22.9% reduction in the number of micturitions per 24 h (11.7 +/- 1.6 vs. 9.0 +/- 1.3 p < 0.001), a 21.3% reduction during the day (10.3 +/- 1.4 vs. 8.1 +/- 1.1 p < 0.001) and a 34.7% reduction in episodes of nocturia (1.5 +/- 1.0 vs. 1.0 +/- 0.8 p = 0.026). Both ICIQ-OAB (8.7 +/- 2.3 vs. 5.8 +/- 2.7 vs. 6.3 +/- 3.3 p < 0.001) and ICIQ-OABqol (73.4 +/- 25.9 vs. 47.5 +/ 14.5 vs. 47.7 +/- 18.6 p < 0.001) questionnaires as well as VAS (7.5 +/- 1.4 vs. 4.1 +/- 2.4 vs. 4.2 +/- 2.7 p < 0.001) showed significant improvement persisting in the 6-month follow-up. In addition, in a multivariable model controlling for age, women who were overactive bladder syndrome therapy naive responded significantly better than those who had already been under therapy (p < 0.001). CONCLUSIONS: This study shows the efficacy of physiotherapy and behavior therapy in women with overactive bladder syndrome with a post-therapy effect especially for women with no prior treatment. PMID- 28361204 TI - Genetic stability of ectomycorrhizal fungi is not affected by cryopreservation at -130 degrees C or cold storage with repeated sub-cultivations over a period of 2 years. AB - Cryopreservation is considered the most reliable method for storage of filamentous fungi including ectomycorrhizal (ECM) fungi. A number of studies, however, have reported genetic changes in fungus cultures following cryopreservation. In the present study, the genetic stability of six ECM fungus isolates was analyzed using amplified fragment length polymorphism (AFLP). The isolates were preserved for 2 years either by cryopreservation (at -130 degrees C) or by storage at 4 degrees C with regular sub-cultivation. A third preservation treatment consisting of isolates maintained on Petri dishes at 22-23 degrees C for 2 years (i.e., without any sub-cultivation) was included and used as a control. The differences observed in AFLP patterns between the three preservation methods remained within the range of the total error generated by the AFLP procedure (6.85%). Therefore, cryopreservation at -130 degrees C and cold storage with regular sub-cultivation did not affect the genetic stability of the ECM fungus isolates, and both methods can be used for the routine storage of ECM fungus isolates over a period of 2 years. PMID- 28361202 TI - Swallowing Preparation and Execution: Insights from a Delayed-Response Functional Magnetic Resonance Imaging (fMRI) Study. AB - The present study sought to elucidate the functional contributions of sub-regions of the swallowing neural network in swallowing preparation and swallowing motor execution. Seven healthy volunteers participated in a delayed-response, go, no-go functional magnetic resonance imaging study involving four semi-randomly ordered activation tasks: (i) "prepare to swallow," (ii) "voluntary saliva swallow," (iii) "do not prepare to swallow," and (iv) "do not swallow." Results indicated that brain activation was significantly greater during swallowing preparation, than during swallowing execution, within the rostral and intermediate anterior cingulate cortex bilaterally, premotor cortex (left > right hemisphere), pericentral cortex (left > right hemisphere), and within several subcortical nuclei including the bilateral thalamus, caudate, and putamen. In contrast, activation within the bilateral insula and the left dorsolateral pericentral cortex was significantly greater in relation to swallowing execution, compared with swallowing preparation. Still other regions, including a more inferior ventrolateral pericentral area, and adjoining Brodmann area 43 bilaterally, and the supplementary motor area, were activated in relation to both swallowing preparation and execution. These findings support the view that the preparation, and subsequent execution, of swallowing are mediated by a cascading pattern of activity within the sub-regions of the bilateral swallowing neural network. PMID- 28361206 TI - Three-dimensional replica of corrected transposition of the great arteries for successful heart transplantation. AB - A 59-year-old man who had been previously diagnosed with congenitally corrected transposition of the great arteries at the age of 35 years became a candidate for heart transplantation. At the age of 57 years, he was referred to our hospital and underwent implantation of a left ventricular assist device (EVAHEART; Sun Medical Technology Research Corp., Suwa City, Japan) because of worsening ventricular function and was listed as a heart transplant candidate. A donor appeared when the patient was 59 years. A three-dimensional replica was made using data from computed tomography angiography. The three-dimensional replica was made of soft rubber (crossMedical, Inc., Kyoto, Japan), which enabled the surgeons to understand the relationship between the great arteries and chambers. After repeated dry laboratories using this replica, the patient underwent successful heart transplantation. PMID- 28361205 TI - Caspase-Cleaved Cytokeratin 18 Fragment M30 as a Potential Biomarker of Macrovascular Invasion in Hepatocellular Carcinoma. AB - BACKGROUND AND AIM: Extremely poor prognosis in hepatocellular carcinoma (HCC) patients with progressing disease was denoted by vascular invasion. Cytokeratin 18 (CK18) has been shown to be overexpressed in hepatocellular carcinoma so it is a valuable tumor marker; however, its role in vascular invasion is still unclear. This study aimed to predict CK18 as a predictive marker for macrovascular malignant invasion. METHODS: The present study was conducted on three groups of patients: group I included 91 HCC patients without macrovascular invasion, group II included 34 HCC patients with radiological evidence of vascular invasion, and group III included 110 control individuals subdivided into IIIA as healthy blood donors and IIIB as post-HCV cirrhotic patients without HCC. RESULTS: ROC curve of M30 fragments of CK18 was constructed for discrimination between HCC with and without macrovascular invasion. Optimum cutoff value was 304.5 ng/mL (AUC = 0.997, P < 0.001), sensitivity (100%) and specificity (98.8%). Regression analysis was conducted for prediction of macrovascular invasion within HCC patients. The following variables: higher levels of AST, M30, bilirubin, and AFP, lower levels of serum albumin, larger tumor size, child B score, and multiple lesions were associated with vascular invasion in univariate analysis. While in multivariate analysis, higher levels of AST and bilirubin and elevated levels of M30 and AFP serum were considered independent predictors for macrovascular invasion in HCC patients. CONCLUSION: The present study suggests that increased M30 fragments of CK18 levels may be useful as a possible marker of early tumor invasiveness. PMID- 28361208 TI - The use of warmed, humidified CO2 during open abdominal surgery: a modified delivery technique. PMID- 28361207 TI - Antibody Response to Paramyxoviruses in Paget's Disease of Bone. AB - Paget's disease of bone (PDB) is a common skeletal disorder characterised by focal abnormalities of increased and disorganised bone turnover. Genetic factors play a central role in the pathogenesis of PDB but environmental factors also contribute. Measles virus (MV), respiratory syncytial virus (RSV) and canine distemper virus (CDV) have all been implicated as potential disease triggers but the data are conflicting. Since chronic paramyxovirus infection with measles is known to be accompanied by increased production of antiviral antibodies, we have analysed circulating concentrations of antibodies to MV, CDV, and RSV as well as mumps, rubella and varicella zoster virus (VZV) in 463 patients with PDB and 220 aged and gender-matched controls. We also studied the relation between viral antibody concentrations and various markers of disease severity and extent in 460 PDB patients. A high proportion of cases and controls tested positive for antiviral antibodies but there was no significant difference in circulating antibody concentrations between PDB cases and controls for MV, CDV, RSV, rubella or VZV. However, mumps virus antibody levels were significantly higher in the PDB cases (mean +/- SD = 3.1 +/- 0.84 vs. 2.62 +/- 0.86. p < 0.001). There was no association between disease severity and circulating antibody concentrations to any of the viruses. In conclusion, we found no evidence to suggest that PDB is associated with abnormalities of immune response to measles or other paramyxoviruses, although there was evidence of a greater antibody response to mumps. The results do not support that hypothesis that PDB is associated with a persistent infection with measles or other paramyxoviruses. PMID- 28361209 TI - Correlation between clinical symptoms and striatal DAT uptake in patients with DLB. AB - OBJECTIVE: It is widely known that there is low striatal 123I-FP-CIT dopamine transporter-single photon emission tomography (DAT-SPECT) uptake in patients with dementia with Lewy bodies (DLB). We assessed the correlation between symptom and regional low DAT uptake in the striatum. METHODS: Patients with Alzheimer's disease (AD) (n = 95) and patients with DLB (n = 133) who underwent DAT-SPECT were enrolled. We examined the correlation between symptoms [cognitive function decline, fluctuations, visual hallucinations, parkinsonism, and REM sleep behavior disorder (RBD)] and regional striatal DAT uptake in the patients with DLB. RESULTS: When comparing the DLB patients with or without fluctuations, visual hallucinations, or RBD, there were no significant differences in DAT uptake in any regions of the striatum. DLB patients with parkinsonism had significantly lower DAT uptake in entire striatum, entire putamen, and anterior putamen compared to DLB patients without parkinsonism. Moreover, there was weak but significant correlation between severity of parkinsonism and DAT uptake in entire regions of the striatum in patients with DLB. There was no significant correlation between cognitive function and DAT uptake in any regions of the striatum in patients with DLB. CONCLUSIONS: In patients with DLB, only parkinsonism is associated with a reduction in striatal DAT uptake. PMID- 28361212 TI - Catheter ablation of a left posterior fascicular ventricular tachycardia guided by a novel high-resolution multipolar mapping catheter. PMID- 28361210 TI - The Treatment of Advanced Thyroid Cancer in the Age of Novel Targeted Therapies. AB - Until recently, patients with advanced thyroid cancers had limited options for systemic treatment. With the introduction of tyrosine kinase inhibitors (TKIs) as a promising new class of targeted therapies for thyroid cancer, suddenly patients with advanced disease were given new options to extend survival. Guidelines worldwide have been updated to include general indications for these newer agents, but questions remain regarding which agent(s) to select, when to begin treatment, and how long therapy should continue. Additionally, the true impact of TKIs on overall survival and quality-of-life in thyroid cancer patients needs further clarification. As familiarity with approved agents and longer-term data become available, better strategies for implementation of these targeted drugs will evolve to optimize benefit for patients living with metastatic disease. PMID- 28361211 TI - Efficacy and Safety of Quinolone-Containing Rescue Therapies After the Failure of Non-Bismuth Quadruple Treatments for Helicobacter pylori Eradication: Systematic Review and Meta-Analysis. AB - BACKGROUND: Anti-Helicobacter pylori eradication treatment fails in a significant percentage of cases. Although this percentage has been reduced to 5-15% with the use of non-bismuth quadruple therapies, limited data exist regarding rescue after failure of these treatments. AIM: The aim of this study was to systematically review the efficacy and safety of quinolone-containing therapies after the failure of non-bismuth quadruple regimens. METHODS: Studies evaluating the efficacy of second-line quinolone-containing therapies after the failure of non bismuth sequential or concomitant regimens were selected. Efficacy (by intention to treat) was analyzed using the inverse variance method; safety data were recorded as the occurrence of any adverse event. The risk of bias of each primary study was evaluated using the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) tool. The quality of the evidence was summarized using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. RESULTS: Sixteen studies were included. The 10-day levofloxacin/amoxicillin/proton pump inhibitor (PPI) triple therapy (LT) achieved eradication rates of 80% (95% CI 71-88). Regarding the moxifloxacin/amoxicillin/PPI triple therapy (MT), its efficacy was higher when administered for 14 days instead of 7 days (80 vs 63%). Two studies investigated the levofloxacin/bismuth-containing quadruple therapies (LBQ) obtaining eradication rates over 90%. Safety was similar in all treatments. The sensitivity analyses showed that results for LT were robust, but MT had weak evidence. CONCLUSIONS: Quinolone-containing triple therapies reported eradication rates <=80%, but LBQ therapies showed encouraging rates. However, the strength of the evidence was very low. The efficacy of LBQ should be corroborated in more studies, and the usefulness of quinolones needs to be evaluated in areas with moderate to high bacterial resistances. PMID- 28361213 TI - Food addiction as a proxy for eating disorder and obesity severity, trauma history, PTSD symptoms, and comorbidity. AB - PURPOSE: Food addiction (FA) is a newly defined yet still controversial condition that has important etiological, developmental, treatment, prevention, and social policy implications. In this review, the case is made that FA (or high scores on the Yale Food Addiction Scale) may be used as a proxy measure for a matrix of interrelated clinical features, including greater eating disorder severity, greater obesity severity, more severe trauma histories, greater symptoms of posttraumatic stress disorder (PTSD), greater psychiatric comorbidity, as well as greater medical morbidity and mortality. METHODS: A Medline search was undertaken using the following terms: food addiction cross-referenced with eating disorders (anorexia nervosa, bulimia nervosa, binge eating disorder, and binge eating), obesity, trauma, posttraumatic stress disorder, and comorbidity. RESULTS: The thesis is that the identification and acknowledgment of the concept of FA, when integrated into an overall, trauma-focused and transdiagnostic treatment approach, are supported and can be useful in understanding clinically the "big picture." CONCLUSIONS: Food addiction (FA) may be used as a proxy for (1) bulimic eating disorder severity, (2) complex trauma histories, (3) severity of PTSD and PTSD symptoms, (4) intensity of psychiatric comorbidity, (5) severity of obesity, as well as (6) their combination. Implications for developing treatment strategies are discussed. The case for a comprehensive management that requires careful attention to medical and psychiatric assessment and integrated care that incorporates trauma-focused treatment is made. PMID- 28361214 TI - Adolescent pregnancy and eating disorders: a minireview and case report. AB - BACKGROUND: Despite the fact that eating disorders (EDs) during pregnancy and early child bearing can both individually increase risk to mother and child, there is a paucity of research exploring pregnancy in adolescence and concomitant EDs. CASE: We report the case of a 16-year-old female with atypical anorexia nervosa, who experiences a remission of her ED behavior during pregnancy, followed by a severe relapse in the post-partum period. CONCLUSION: In this case, pregnancy functioned as a motivator for remission in our patient with concomitant ED. Further research is needed to identify risks of EDs in adolescent pregnancy, to explore the trajectory of pre-existing EDs during pregnancy and to identify effective interventions for prolonging remission into the post-partum period. PMID- 28361215 TI - The Categorical Stability of Gambling Motives Among Community-Recruited Gamblers: A Longitudinal Assessment. AB - Over the past decade, several motivational models have been proposed to explain the role of motives in gambling disorder. In the model captured by the four factor Gambling Motives Questionnaire Financial (GMQ-F), gamblers are described as being primarily motivated to gamble for 'coping', 'enhancement', 'social', and 'financial' reasons. Although this model has received significant empirical support; to date, research assessing the role of motives in gambling disorder has been primarily cross-sectional in nature. Thus, the extent to which gambling motives remain stable over time has yet to be explored. In the current study, the stability versus fluidity of self-assessed gambling motives was investigated using the Quinte Longitudinal Study, a longitudinal dataset of gambling behaviour collected over 5 years. Gambling motives of 2795 gamblers were examined over all five annual assessments. The total proportion of gamblers who stayed in the same primary motive category across each of the 5 consecutive assessments was 22%, indicating substantial fluidity in category membership. Substantial movement between categories was seen for each GMQ-F group, as well as an additional group of non-classified motives. Logistic regression analyses suggest that greater resistance to gambling fallacies significantly predicted stability between the baseline assessment and a follow-up 1 year later, but gambling severity did not. Potential limitations in the study design and opportunities for future research are discussed. PMID- 28361216 TI - Combined hepatic arterial resection in pancreatic resections for locally advanced pancreatic cancer. AB - PURPOSE: Arterial involvement in advanced pancreatic cancer generally defines local unresectability. This study was aimed to evaluate the clinical outcomes of combined common hepatic arterial resection with pancreaticoduodenectomy or total pancreatectomy in patients with locally advanced pancreatic cancer involving the hepatic artery. METHODS: Of 348 patients with pancreatic head cancers who underwent surgical resection between June 1999 and September 2015, 21 underwent combined common hepatic arterial resection with pancreaticoduodenectomy (17) or total pancreatectomy (4). Preoperative common hepatic arterial embolization was performed in 12 patients. Preoperative CT findings of hepatic arterial involvement, postoperative complications, survival rates, and prognostic factors for survival were analyzed. Twenty-one unresectable patients with locally advanced pancreatic cancer who underwent laparotomy in this study period were selected as the control group. RESULTS: Rates of pathological arterial invasion were significantly higher in patients with level III (>1800) CT findings (90%,9/10) than in patients with levels I and II (<1800) (27%, 3/11) (p < 0.01). No surgical deaths occurred. Survival after surgical resection in all 21 patients was 47.6%, 6.6%, and 6.6% at 1, 3, and 5 years, and median survival was 11 months. The preoperative serum CA19-9 level was a significant prognostic factor for overall survival, median survivals were 21.5 and 8.3 months in the low CA19-9 and high CA19-9 groups, respectively. No significant difference in survival between the high-CA19-9 group and the unresectable group was found. CONCLUSIONS: Combined common hepatic arterial resection in pancreaticoduodenectomy or total pancreatectomy might be feasible with an acceptable rate of surgical complications, and may have a beneficial effect on the prognosis only in patients with low preoperative serum CA19-9 levels. PMID- 28361218 TI - Intramedullary nailing of tibial shaft fractures in the semi-extended position using a suprapatellar portal technique. AB - Intramedullary nail fixation remains the standard treatment for displaced tibial shaft fractures. Establishing an appropriate starting point remains a crucial step in the surgical procedure. Tibial nailing using an infrapatellar starting point with the knee flexed over a radiolucent triangle has been established as a widely-used standard technique. Tibial nail insertion with the knee in the semi extended position was introduced with the goal to counteract post-operative procurvatum deformities that frequently have been reported as a common problem in proximal third tibial shaft fractures. Early reports on tibial nailing in the semi-extended position used a knee arthrotomy in order to establish the proximal tibial starting point. Recent technological advances have provided the surgical community with instrumentation systems that allow for tibial nailing in the semi extended position using a suprapatellar portal with nail insertion through the patellofemoral joint. Preliminary clinical studies have suggested favorable outcomes that can be achieved with this technique. This article provides a description of the surgical technique and a review of the currently available evidence. PMID- 28361217 TI - The push-through total femoral prosthesis offers a functional alternative to total femoral replacement: a case series. AB - PURPOSE: Oncologic resections or complications of segmental femoral prostheses can result in severe bone loss of the femur for which a total femoral prosthesis (TFP) is required. This study assesses whether the loss of stability and function caused by the loss of muscle attachments can be improved by using a push-through total femoral endoprosthesis (PTTF), because it saves parts of the femur and its muscle attachments. METHODS: In this retrospective case series, ten patients aged 25-77 (mean 54) who received a PTTF between 2005 and 2014 were included for baseline, complications and survival analysis with a mean follow-up of 5.3 (1.1 9.6) years. Functional outcome was assessed in six patients using the Musculoskeletal Tumor Society (MSTS) score, WHO performance scale, Toronto Extremity Salvage Score (TESS), SF36, EQ-5D, NRS pain score, fatigue score and satisfaction score. RESULTS: The mean MSTS score was 64% (23-93%). Five patients had a WHO performance scale of 1, one patient of 3. Mean TESS was 69% (13-90%). SF36 was most notably limited by physical functioning (mean 48), vitality (68) and general health (67). NRS score was 1.9, 1.8 and 8.3 for pain, fatigue and satisfaction, respectively. There were four failures: two infections (one resulting in amputation and one in a minor revision) and two mechanical failures (which required one revision to a TFP and one minor revision). Patient survival was 100%, limb survival 90%, and prosthesis survival 80%. CONCLUSION: The push through total femoral endoprosthesis allows preservation of muscle attachments and offers a good alternative to total femoral prostheses. PMID- 28361219 TI - Shoulder arthroplasty for locked anterior shoulder dislocation: a role for the reversed design. AB - INTRODUCTION: Locked anterior shoulder dislocation (LASD) is an uncommon condition associated with bone, articular cartilage, and soft tissue damage. In selected cases, shoulder arthroplasty (SA) may be the best treatment. The purpose of this study was to assess outcomes of SA for LASD. MATERIALS AND METHODS: Between 1976 and 2013, 19 SAs [three hemiarthroplasties (HA), seven total shoulder arthroplasties (TSA), and nine reverse shoulder arthroplasties (RSA), mean age 62 years] were performed for LASD. Shoulders were followed for at least two years (range, 2-30 years, mean 7.1). Clinical and radiographic outcomes were studied. RESULTS/DISCUSSION: Three SAs required re-operation, two TSAs for early redislocation and one HA for late, painful glenoid arthrosis. Four additional shoulders (two TSA, two HA) were unstable at most recent follow-up. Pain improved from 4.7 to 2.2 (p < 0.0001) out of 5, elevation from 51 to 94 degrees (p = 0.004), and external rotation from 1 to 34 degrees (p = 0.01). There were two excellent, seven satisfactory, and ten unsatisfactory modified Neer ratings. Compared to TSA/HA, RSA experienced fewer re-operations (0 vs. 3, hazard ratio, 2.03*10^-9, p = 0.0844) and instability (0 vs. 6, p = 0.0108). Similar post operative pain (p = 0.2192), range of motion (p = 0.2432-0.5299), strength (p = 0.2099), satisfaction (p = 0.6563), outcomes scores (p = 0.0683-0.0933), and complication rate (p = 0.3698) were seen with RSA vs. TSA/HA. CONCLUSIONS: RSA for the treatment of chronic LASD provides greater pain relief, and improvement in range of motion (ROM) compared to TSA/HA. Anatomic SA is associated with a high rate of instability not seen with RSA. Therefore, anatomic SA (TSA/HA) is likely not indicated in these difficult circumstances. LEVEL OF EVIDENCE: IV. PMID- 28361220 TI - Disease severity and treatment requirements in familial inflammatory bowel disease. AB - PURPOSE: Several studies demonstrate an increased prevalence and concordance of inflammatory bowel disease among the relatives of patients. Other studies suggest that genetic influence is over-estimated. The aims of this study are to evaluate the phenotypic expression and the treatment requirements in familial inflammatory bowel disease, to study the relationship between number of relatives and degree of kinship with disease severity and to quantify the impact of family aggregation compared to other environmental factors. METHODS: Observational analytical study of 1211 patients followed in our unit. We analyzed, according to the existence of familial association, number and degree of consanguinity, the phenotypic expression, complications, extraintestinal manifestations, treatment requirements, and mortality. A multivariable analysis considering smoking habits and non-steroidal-anti-inflammatory drugs was performed. RESULTS: 14.2% of patients had relatives affected. Median age at diagnosis tended to be lower in the familial group, 32 vs 29, p = 0.07. In familial ulcerative colitis, there was a higher proportion of extraintestinal manifestations: peripheral arthropathy (OR = 2.3, p = 0.015) and erythema nodosum (OR = 7.6, p = 0.001). In familial Crohn's disease, there were higher treatment requirements: immunomodulators (OR = 1.8, p = 0.029); biologics (OR = 1.9, p = 0.011); and surgery (OR = 1.7, p = 0.044). The abdominal abscess increased with the number of relatives affected: 5.1% (sporadic), 7.0% (one), and 14.3% (two or more), p=0.039. These associations were maintained in the multivariate analysis. CONCLUSIONS: Familial aggregation is considered a risk factor for more aggressive disease and higher treatment requirements, a tendency for earlier onset, more abdominal abscess, and extraintestinal manifestations, remaining a risk factor analyzing the influence of some environmental factors. PMID- 28361221 TI - Eighth edition of AJCC staging for differentiated thyroid cancer: Is stage I appropriate for T4/N1b patients aged 45-55 years? PMID- 28361222 TI - Philadelphia-Like Acute Lymphoblastic Leukemia in Adults. AB - PURPOSE OF REVIEW: This study aims to provide an overview of the classification, incidence, genomic alterations, and clinical implications of Philadelphia-like Acute Lymphoblastic Leukemia (Ph-like ALL) in adults. RECENT FINDINGS: Ph-like ALL is a high-risk subtype of B cell precursor ALL with characteristic genomic alterations in children and adults. A standard approach for diagnosis is missing and currently mainly based on gene expression analysis. The incidence is age depended and highest in adolescents and younger adults (age 16-39) where 19-28% of patients belong to this subtype. Ph-like ALL is associated with persistence of minimal residual disease (MRD) and inferior prognosis. Some genomic alterations respond to specific treatment approaches and provide hope for tailored therapies. Ph-like ALL in adults is an aggressive and high-risk subtype of B cell precursor ALL. Without consensus definition, diagnosis is difficult and current publications highlight the importance of stringent MRD monitoring to guide risk adapted treatment strategies. PMID- 28361225 TI - Abdominal imaging ordering patterns by referring provider specialty. AB - PURPOSE: Prior work has demonstrated marked growth in the volume of abdominal imaging performed by radiologists. However, decisions to pursue imaging are largely driven by referring providers. In this study, we take the novel approach of investigating abdominal imaging utilization patterns by referring provider specialty. METHODS: Data on imaging services were obtained from the 2014 DocGraph Medicare Referring Provider Utilization for Procedures (MrPUP) public use file. MrPUP contains aggregated transaction data for combinations of unique referring provider and service code. Imaging services were classified by modality and body region using the Neiman Institute Types of Service (NITOS). Each referring provider's specialty was determined using Medicare Physician Compare. Abdominal imaging ordering patterns were summarized by referring specialty. RESULTS: The final dataset included 5,824,754 abdominal imaging transactions. The most common ordering specialties of abdominal imaging were as follows: (1) internal medicine; (2) urology; (3) emergency medicine; (4) family practice; and (5) gastroenterology. The most common ordering specialties by abdominal imaging modality were emergency medicine for CT; gastroenterology for MRI and nuclear medicine; and internal medicine for ultrasound and radiography. While numerous specialties commonly ordered abdominal radiography and CT, urologists also commonly ordered retroperitoneal ultrasound and retrograde urography, and gastroenterologists also commonly ordered abdominal ultrasound, abdominal MRI, and esophagrams. Internal medicine, family practice, and emergency medicine providers ordered a much broader mix of imaging, including many non-abdominal imaging examinations. CONCLUSION: Referring specialty abdominal imaging ordering patterns are varied but distinct. Awareness of these patterns may facilitate focused educational and policy initiatives to improve abdominal imaging appropriateness and utilization. PMID- 28361224 TI - Immunotherapy for Esophageal Squamous Cell Carcinoma. AB - Esophageal squamous cell carcinoma have been frustrating to treat, with slow progress made on extending survival. Immunotherapy targeting immune checkpoints, T cells, and infiltrating lymphocytes has shown promise in early studies. The efficacy of pembrolizumab and nivolumab is encouraging. Anti-chemokine receptors and oncolytic viruses are also making headway against these stubborn tumors; improved results when immune checkpoint inhibitors are combined with radiation therapy are eagerly anticipated. Adoptive T cell therapy and vaccines are also under development. The importance of a multidisciplinary approach cannot be emphasized enough. PMID- 28361223 TI - Emerging Variants of Castration-Resistant Prostate Cancer. AB - Metastatic castration-resistant prostate cancer (CRPC) is associated with substantial clinical, pathologic, and molecular heterogeneity. Most tumors remain driven by androgen receptor (AR) signaling, which has clinical implications for patient selection for AR-directed approaches. However, histologic and clinical resistance phenotypes can emerge after AR inhibition, in which the tumors become less dependent on the AR. In this review, we discuss prostate cancer variants including neuroendocrine (NEPC) and aggressive variant (AVPC) prostate cancers and their clinical implications. Improvements in the understanding of the biologic mechanisms and molecular features underlying prostate cancer variants may help prognostication and facilitate the development of novel therapeutic approaches for subclasses of patient with CRPC. PMID- 28361226 TI - Bending percutaneous drainage catheters to facilitate CT-guided insertion using curved trocar technique. AB - PURPOSE: To assess the safety and efficacy of placing thoraco-abdominal drainage catheters under CT-guidance using a curved trocar technique. METHODS: A retrospective study of 182 CT/CT-fluoroscopy-guided thoraco-abdominal catheter drainages was conducted; half were performed by residents or fellows under the supervision of one radiologist (Group 1) and the other half under the supervision of 10 other radiologists (Group 2). Group 1 procedures employed a curved catheter assembly placed using trocar technique (n = 44) or straight catheters placed with Seldinger technique (n = 47). Group 2 procedures employed a straight catheter placed using trocar technique (n = 16) or straight catheters placed with Seldinger technique (n = 75). Technical success, procedure time, radiation dose (CT Dose Index CTDIvol), and adverse events (Common Terminology Criteria for Adverse Events, 4.0) were compared between techniques and groups using Student's t test, Fisher's exact test or Chi-square analysis. RESULTS: All procedures in groups 1 and 2 were technically successful. Mean procedure time for Group 1 curved trocar technique (28 +/- 8 min) was shorter than groups 1 and 2 Seldinger technique (37 +/- 11 min, p = .00002). Mean CTDIvol for Group 1 curved trocar technique (107.8 +/- 54.2 mGy) was lower than groups 1 and 2 Seldinger technique (136.1 +/- 99.7 mGy, p = 0.032). Adverse event rates for curved trocar, straight trocar, and Seldinger techniques were 2.3% (1/44), 0% (0/16), and 3.3% (4/122), respectively (p = 1); all were grade 1 or 2, and no catheter malfunctions occurred. CONCLUSIONS: The curved catheter trocar technique is a safe and effective modification of the standard trocar technique that may facilitate CT guided procedures impeded by CT gantry size limitations. PMID- 28361227 TI - Light use efficiency of a warm-temperate mixed plantation in north China. AB - Light use efficiency (LUE) is one of the important parameters on calculating terrestrial gross primary productivity (GPP) and net primary productivity (NPP). Based on 5-year (2006-2010) carbon flux and climatic variable data of a mixed plantation in north China, the seasonal and interannual variation of LUE was investigated and the biophysical controls were examined. Our results show that LUE had a distinct seasonal course, and peaked in the vigorous growing season with a value of 0.92-1.27 g C MJ-1. During the period of 2006-2010, annual mean LUE ranged between 0.54 and 0.62 g C MJ-1, and it was linearly correlated with annual GPP. In the growing season, LUE was significantly linked with the water availability variables (including monthly mean vapor pressure deficit (VPD), precipitation, evaporative fraction (EF), and the ratio of precipitation to evapotranspiration (P/ET)) and canopy conductance (g c). However, EF was a better estimator of LUE compared with other biophysical variables. LUE decreased with an increase of the clearness index (CI), indicating that LUE was higher under cloudy sky conditions than that under sunny sky conditions in the mixed plantation. PMID- 28361228 TI - Cancer patients' preferences for therapy decisions can be grouped into categories and separated by demographic factors. AB - PURPOSE: Shared decision-making is based on comparable understanding of decision criteria on both sides that requires knowledge about preferences, reception/prioritization of benefits and covariates influencing these criteria. We addressed identification of cancer patients' preferences for treatment decisions and covariates for preference patterns in certain patient cohorts. DESIGN: Using preference surveys ordinal ranking of decisional preferences in life (PL) and during therapy (PT) were obtained and aggregated by factorial analysis. Demographic and clinical data enabled clustering of patient groups including non-malignant control group with distinct preference patterns. Covariates for these patterns were determined by multivariate ANOVA. RESULTS: 1777 cancer and 367 non-oncological patients (>=18 years) were evaluable (response 56.0%). Patient-reported PT was grouped into distinctive categories: immediate treatment effectivity, long-term effects and survival, empathy, easy treatment and employability/healing. Gender, parenthood, family status, age and educational level mainly determine importance of PL (52.1% variance) and PT (55.1% variance) enabling discrimination of specific preference patterns in patients: older males, non-single, younger males, non-single female with children and young, single patients without children that mainly significantly differed from non-cancer patients (p < 0.001). CONCLUSION: Relevance of decisional PL/PT appears to be cancer-specific and distinct between cancer patient groups. If patients recognize direct social responsibility, immediate treatment effects gain importance accompanied by reduced impact of employability, rehabilitation and financial security. For young and independent patients empathy has similar impact as treatment effects. Consequently, clinical research should consider age specific endpoints and distinct decisional preferences to match patients' perspective by specific evidence. PMID- 28361231 TI - [Infectiology in intensive care medicine]. PMID- 28361229 TI - Obesity in pediatric kidney transplant recipients and the risks of acute rejection, graft loss and death. AB - BACKGROUND: Obesity is prevalent in children with chronic kidney disease (CKD), but the health consequences of this combination of comorbidities are uncertain. The aim of this study was to evaluate the impact of obesity on the outcomes of children following kidney transplantation. METHODS: Using data from the ANZDATA Registry (1994-2013), we assessed the association between age-appropriate body mass index (BMI) at the time of transplantation and the subsequent development of acute rejection (within the first 6 months), graft loss and death using adjusted Cox proportional hazards models. RESULTS: Included in our analysis were 750 children ranging in age from 2 to 18 (median age 12) years with a total of 6597 person-years of follow-up (median follow-up 8.4 years). Overall, at transplantation 129 (17.2%) children were classified as being overweight and 61 (8.1%) as being obese. Of the 750 children, 102 (16.2%) experienced acute rejection within the first 6 months of transplantation, 235 (31.3%) lost their allograft and 53 (7.1%) died. Compared to children with normal BMI, the adjusted hazard ratios (HR) for graft loss in children who were underweight, overweight or diagnosed as obese were 1.05 [95% confidence interval (CI) 0.70-1.60], 1.03 (95% CI 0.71-1.49) and 1.61 (95% CI 1.05-2.47), respectively. There was no statistically significant association between BMI and acute rejection [underweight: HR 1.07, 95% CI 0.54-2.09; overweight: HR 1.42, 95% CI 0.86-2.34; obese: HR 1.83, 95% CI 0.95-3.51) or patient survival (underweight: HR 1.18, 95% CI 0.54-2.58, overweight: HR 0.85, 95% CI 0.38-1.92; obese: HR 0.80, 95% CI 0.25 2.61). CONCLUSIONS: Over 10 years of follow-up, pediatric transplant recipients diagnosed with obesity have a substantially increased risk of allograft failure but not acute rejection of the graft or death. PMID- 28361230 TI - Acute kidney injury and fluid overload in infants and children after cardiac surgery. AB - Acute kidney injury is a common and serious complication after congenital heart surgery, particularly among infants. This comorbidity has been independently associated with adverse outcomes including an increase in mortality. Postoperative acute kidney injury has a complex pathophysiology with many risk factors, and therefore no single medication or therapy has been demonstrated to be effective for treatment or prevention. However, it has been established that the associated fluid overload is one of the major determinants of morbidity, particularly in infants after cardiac surgery. Therefore, in the absence of an intervention to prevent acute kidney injury, much of the effort to improve outcomes has focused on treating and preventing fluid overload. Early renal replacement therapy, often in the form of peritoneal dialysis, has been shown to be safe and beneficial in infants with oliguria after heart surgery. As understanding of the pathophysiology of acute kidney injury and the ability to confidently diagnose it earlier continues to evolve, it is likely that novel preventative and therapeutic interventions will be available in the future. PMID- 28361233 TI - RNA Seq analysis for transcriptome profiling in response to classical swine fever vaccination in indigenous and crossbred pigs. AB - In present investigation, differential expression of transcriptome after classical swine fever (CSF) vaccination has been explored at the cellular level in crossbred and indigenous (desi) piglets. RNA Sequencing by Expectation Maximization (RSEM) package was used to quantify gene expression from RNA Sequencing data, and differentially expressed genes (DEGs) were identified using EBSeq, DESeq2, and edgeR softwares. After analysis, 5222, 6037, and 6210 common DEGs were identified in indigenous post-vaccinated verses pre-vaccinated, crossbred post-vaccinated verses pre-vaccinated, and post-vaccinated crossbred verses indigenous pigs, respectively. Functional annotation of these DEGs showed enrichment of antigen processing-cross presentation, B cell receptor signaling, T cell receptor signaling, NF-kappaB signaling, and TNF signaling pathways. The interaction network among the immune genes included more number of genes with greater connectivity in vaccinated crossbred than the indigenous piglets. Higher expression of IRF3, IL1beta, TAP1, CSK, SLA2, SLADM, and NF-kB in crossbred piglets in comparison to indigenous explains the better humoral response observed in crossbred piglets. Here, we predicted that the processed CSFV antigen through the T cell receptor signaling cascade triggers the B cell receptor-signaling pathway to finally activate MAPK kinase and NF-kappaB signaling pathways in B cell. This activation results in expression of genes/transcription factors that lead to B cell ontogeny, auto immunity and immune response through antibody production. Further, immunologically important genes were validated by qRT-PCR. PMID- 28361234 TI - Aseptic meningitis in relapsing polychondritis: a case report and literature review. AB - Aseptic meningitis is an extremely rare neurologic complication of relapsing polychondritis (RP). We reported a case of a 58-year-old Chinese female with intractable headache, puffy ears, pleocytosis, and cranial magnetic resonance imaging (MRI) showing thickened and enhanced meninges. She was finally diagnosed of aseptic meningitis due to RP after full exclusion of infectious causes. She gradually developed neurosensory hearing loss, vertigo, and saddle nose while glucocorticosteroid therapy and combined cyclophosphamide could not control her headache. Ultimately, cyclosporin A was tried showing a good response. Only 18 previous cases were found in the literature and the clinical manifestation, cerebrospinal fluid (CSF) characteristics, imaging features, and therapy considerations of RP-related aseptic meningitis were summarized by reviewing the literature. Aseptic meningitis due to RP is a rare condition of undetermined pathoetiology. Its diagnosis is primarily based on clinical manifestations combined with CSF and MRI examinations plus adequate exclusion of possible infections. Corticosteroid is the basic therapy but choice of protocol should be individualized. PMID- 28361236 TI - Efficient synthesis of tyrosol galactosides by the beta-galactosidase from Enterobacter cloacae B5. AB - In this work, the beta-galactosidase from Enterobacter cloacae B5 (BgaB5) exhibited excellent transglycosylation activity toward tyrosol (p hydroxyphenethyl alcohol) when using lactose as the glycosyl donor, generating a series of tyrosol glycosides with potential pharmacological properties. The effects of substrate concentration, temperature, pH, and reaction time on the transglycosylation reaction catalyzed by the enzyme BgaB5 were studied in detail. Three tyrosol derivatives were produced in a total high yield of 50.0% when incubating the enzyme with 250 mM tyrosol and 1000 mM lactose (pH 7.5) at 50 degrees C for 5 min. These derivatives were subsequently purified by column chromatography and preparative thin-layer chromatography. MS analysis of the purified compounds suggested one monogalactoside (M r 300) and two digalactoside derivatives (M r 462). The following NMR analysis further identified them to be p hydroxyphenethyl beta-D-galactopyranoside, p-hydroxyphenethyl beta-D- galactopyranosyl-(1 -> 3')-beta-D-galactopyranoside, and p-hydroxyphenethyl beta D- galactopyranosyl-(1 -> 6')-beta-D-galactopyranoside, respectively. The yield of the tyrosol monogalactoside which was known to possess potent bioactivities reached 39.4%, higher than other enzymatic yields reported so far. The two digalactosides, which were expected to have potential applications for novel drug screening and discovery, were artificially obtained with 10.6% yield for the first time. PMID- 28361237 TI - Valorization of spent oyster mushroom substrate and laccase recovery through successive solid state cultivation of Pleurotus, Ganoderma, and Lentinula strains. AB - Spent mushroom substrate (SMS) of Pleurotus ostreatus was supplemented with wheat bran and soybean flour in various proportions to obtain C/N ratios of 10, 20, and 30, and their effect was evaluated in successive cultivation of Pleurotus ostreatus, Pleurotus pulmonarius, Ganoderma adspersum, Ganoderma resinaceum, and Lentinula edodes strains with respect to mycelium growth rate, biomass concentration, recovery of the enzyme laccase and crude exopolysaccharides, and also with additional fruiting body production. All fungi showed the highest growth rate on unamended SMS (C/N 30), with G. resinaceum being the fastest colonizer (Kr = 9.84 mm day-1), while biomass concentration maximized at C/N 10. Moreover, supplementation affected positively laccase activity, with P. pulmonarius furnishing the highest value (44,363.22 U g-1) at C/N 20. On the contrary, L. edodes growth, fruiting, and laccase secretion were not favored by SMS supplementation. Fruiting body formation was promoted at C/N 30 for Ganoderma and at C/N 20 for Pleurotus species. Exopolysaccharide production of further studied Pleurotus strains was favored at a C/N 20 ratio, at the initial stage of SMS colonization. The obtained results support the potential effective utilization of supplemented SMS for laccase production from Ganoderma spp. and for new fruiting body production of Pleurotus spp. PMID- 28361235 TI - DASH diet and change in serum uric acid over time. AB - The Dietary Approaches to Stop Hypertension (DASH) diet lowers serum uric acid (SUA) levels compared to the typical American (control) diet. However, the time required for the DASH diet to take effect is unknown. We analyzed data from a parallel arm, randomized-controlled trial in pre-hypertensive or hypertensive adults (N = 103), comparing the effects of DASH or a control diet on SUA measured at 30, 60, and 90 days. Effects were examined overall and within stratified subgroups based on baseline SUA status (SUA >=6 mg/dL vs <6 mg/dL). The mean age of participants was 51.5 +/- 9.7 years, 55% were women, 75% were black, 42% were obese, and 34% had hypertension. Twenty-four of the 103 (23%) participants had a baseline SUA >=6 mg/dL. Overall, compared to the control, DASH lowered SUA by 0.5 mg/dL at 30 and 90 days. Among participants with baseline SUA >=6 mg/dL, DASH lowered SUA by 0.8 and 1.0 mg/dL at 30 and 90 days, respectively. These findings demonstrate that the DASH diet reduces SUA within 30 days, with a sustained effect at 90 days, which is informative for healthcare providers counseling patients on time course expectations for uric acid reduction in response to dietary modification. PMID- 28361238 TI - A novel genetic tool for metabolic optimization of Corynebacterium glutamicum: efficient and repetitive chromosomal integration of synthetic promoter-driven expression libraries. AB - Fine-tuning the expression level of multiple genes is usually pivotal for metabolic optimization. We have developed a tool for this purpose for the important industrial workhorse Corynebacterium glutamicum that allows for the introduction of synthetic promoter-driven expression libraries of arbitrary genes. We first devised a method for introducing genetic elements into the chromosome repeatedly, relying on site-specific recombinases and the vector pJS31 serving as the carrier. The pJS31 vector contains a synthetic cassette including a phage attachment site attP for integration, a bacterial attachment site attB for subsequent integration, a multiple cloning site, and two modified loxP sites to facilitate easy removal of undesirable vector elements. Meanwhile, we constructed a derivative of the wild-type strain ATCC 13032 carrying an attB site in its chromosome (JS34) and demonstrated that pJS31 readily could integrate into the attB site in this strain providing expression of the corresponding integrase. Subsequent expression of the Cre recombinase promoted recombination between the modified loxP sites, resulting in a strain only retaining the target insertions and an attB site. To simplify the procedure, non-replicating circular expression units for the phage integrase and the Cre recombinase were used. As a showcase, we used the tool to construct a battery of strains simultaneously expressing the two reporter genes, lacZ (encoding beta-galactosidase) and gusA (encoding beta glucuronidase), to arbitrary levels. In principle, an unlimited number of genes, whether native, heterologous, or synthetic, can be introduced using the developed approach, and this should greatly facilitate metabolic optimization of this important platform organism. PMID- 28361239 TI - Implications of molecular diversity of chitin and its derivatives. AB - Chitin is a long unbranched polysaccharide, made up of beta-1,4-linked N acetylglucosamine which forms crystalline fiber-like structure. It is present in the fungal cell walls, insect and crustacean cuticles, nematode eggshells, and protozoa cyst. We provide a critical appraisal on the chemical modifications of chitin and its derivatives in the context of their improved efficacy in medical applications without any side effect. Recent advancement in nanobiotechnology has helped to synthesize several chitin derivatives having significant biological applications. Here, we discuss the molecular diversity of chitin and its applications in enzyme immobilization, wound healing, packaging material, controlled drug release, biomedical imaging, gene therapy, agriculture, biosensor, and cosmetics. Also, we highlighted chitin and its derivatives as an antioxidant, antimicrobial agent, anticoagulant material, food additive, and hypocholesterolemic agent. We envisage that chitin and chitosan-based nanomaterials with their potential applications would augment nanobiotechnology and biomedical industries. PMID- 28361232 TI - Cancer immunotherapy: how low-level ionizing radiation can play a key role. AB - The cancer immunoediting hypothesis assumes that the immune system guards the host against the incipient cancer, but also "edits" the immunogenicity of surviving neoplastic cells and supports remodeling of tumor microenvironment towards an immunosuppressive and pro-neoplastic state. Local irradiation of tumors during standard radiotherapy, by killing neoplastic cells and generating inflammation, stimulates anti-cancer immunity and/or partially reverses cancer promoting immunosuppression. These effects are induced by moderate (0.1-2.0 Gy) or high (>2 Gy) doses of ionizing radiation which can also harm normal tissues, impede immune functions, and increase the risk of secondary neoplasms. In contrast, such complications do not occur with exposures to low doses (<=0.1 Gy for acute irradiation or <=0.1 mGy/min dose rate for chronic exposures) of low LET ionizing radiation. Furthermore, considerable evidence indicates that such low-level radiation (LLR) exposures retard the development of neoplasms in humans and experimental animals. Here, we review immunosuppressive mechanisms induced by growing tumors as well as immunomodulatory effects of LLR evidently or likely associated with cancer-inhibiting outcomes of such exposures. We also offer suggestions how LLR may restore and/or stimulate effective anti-tumor immunity during the more advanced stages of carcinogenesis. We postulate that, based on epidemiological and experimental data amassed over the last few decades, whole- or half-body irradiations with LLR should be systematically examined for its potential to be a viable immunotherapeutic treatment option for patients with systemic cancer. PMID- 28361240 TI - [Psychological pain modulation]. PMID- 28361241 TI - Novel Silicon Phthalocyanines Bearing Triethylene Glycol Groups: Photophysical and Photochemical Properties as well as pH-Induced Spectral Behaviour. AB - Herein, novel silicon (IV) phthalocyanines peripherally substituted by triethylene glycol groups and bearing axial hydroxyl groups were synthesized and fully characterized by using different analyses techniques. The photophysical and photochemical properties of octa (2a) and tetra (2b) derivatives were investigated in DMF and DMSO. The effect of octa or tetra substitution on fluorescence quantum yield, singlet oxygen generation and photodegradation were examined, and the differences were evaluated regarding their potential efficiency in photodynamic therapy (PDT). Their pH-responses were investigated to determine the influence of protonation of azomethine nitrogen atoms on singlet oxygen generation efficiencies. Dramatic optical changes were observed by protonation of azomethine bridges of 2a and 2b. They exhibited signal decrease from pH 4.0 to 1.0 for 2a (pKa = 2.6) and pH 3.0 to 1.0 for 2b (pKa = 1.8). Besides, the compounds exhibited no aggregation tendency, moderate fluorescence quantum yield, solubility in common organic solvents, high singlet oxygen quantum yield and high photostability in DMF and in DMSO, these favorable properties making them good candidates as photosensitizer for PDT. PMID- 28361242 TI - Optimal resource allocation enables mathematical exploration of microbial metabolic configurations. AB - Central to the functioning of any living cell, the metabolic network is a complex network of biochemical reactions. It may also be viewed as an elaborate production system, integrating a diversity of internal and external signals in order to efficiently produce the energy and the biochemical precursors to ensure all cellular functions. Even in simple organisms like bacteria, it shows a striking level of coordination, adapting to very different growth media. Constraint-based models constitute an efficient mathematical framework to compute optimal metabolic configurations, at the scale of a whole genome. Combining the constraint-based approach "Resource Balance Analysis" with combinatorial optimization techniques, we propose a general method to explore these configurations, based on the inference of logical rules governing the activation of metabolic fluxes in response to diverse extracellular media. Using the concept of partial Boolean functions, we notably introduce a novel tractable algorithm to infer monotone Boolean functions on a minimal support. Monotonicity seems particularly relevant in this context, since the orderliness exhibited by the metabolic network's dynamical behavior is expected to give rise to relatively simple rules. First results are promising, as the application of the method on Bacillus subtilis central carbon metabolism allows to recover known regulations as well as to investigate lesser known parts of the global regulatory network. PMID- 28361243 TI - Asexual Identity in a New Zealand National Sample: Demographics, Well-Being, and Health. AB - Academic interest in asexuality has increased in recent years; however, there is yet to be a national probability study exploring the correlates of self identifying as asexual. Here, we utilized data from the 2014/15 New Zealand Attitudes and Values Study. Past research has typically used attraction-based measures; however, we asked participants to describe their sexual orientation using a self-generated, open-ended item, and 0.4% (n = 44) self-identified as asexual. We then compared self-identified asexual participants with a heterosexual reference group (n = 11,822) across a large number of demographic, psychological, and health variables. Relative to heterosexuals, self-identified asexual participants were (1) more likely to be women, and (2) substantially less likely to be cisgender, (3) in a serious romantic relationship, or (4) a parent. No deleterious mental or physical health effects were associated with asexuality when compared to heterosexuality. This study provides the first attempt at measuring self-identification as asexual in a national sample and highlights core similarities and differences between those who identify as asexual and heterosexual. PMID- 28361244 TI - Condition-dependent virulence of slow bee paralysis virus in Bombus terrestris: are the impacts of honeybee viruses in wild pollinators underestimated? AB - Slow bee paralysis virus (SBPV)-previously considered an obligate honeybee disease-is now known to be prevalent in bumblebee species. SBPV is highly virulent in honeybees in association with Varroa mites, but has been considered relatively benign otherwise. However, condition-dependent pathogens can appear asymptomatic under good, resource abundant conditions, and negative impacts on host fitness may only become apparent when under stressful or resource-limited conditions. We tested whether SBPV expresses condition-dependent virulence in its bumblebee host, Bombus terrestris, by orally inoculating bees with SBPV and recording longevity under satiated and starvation conditions. SBPV infection resulted in significant virulence under starvation conditions, with infected bees 1.6 times more likely to die at any given time point (a median of 2.3 h earlier than uninfected bees), whereas there was no effect under satiated conditions. This demonstrates clear condition-dependent virulence for SBPV in B. terrestris. Infections that appear asymptomatic in non-stressful laboratory assays may nevertheless have significant impacts under natural conditions in the wild. For multi-host pathogens such as SBPV, the use of sentinel host species in laboratory assays may further lead to the underestimation of pathogen impacts on other species in nature. In this case the impact of 'honeybee viruses' on wild pollinators may be underestimated, with detrimental effects on conservation and food security. Our results highlight the importance of multiple assays and multiple host species when testing for virulence, in order for laboratory studies to accurately inform conservation policy and mitigate disease impacts in wild pollinators. PMID- 28361245 TI - Detoxification of Sap from Felled Oil Palm Trunks for the Efficient Production of Lactic Acid. AB - The availability of fermentable sugars in high concentrations in the sap of felled oil palm trunks and the thermophilic nature of the recently isolated Bacillus coagulans strain 191 were exploited for lactic acid production under non sterile conditions. Screening indicated that strain 191 was active toward most sugars including sucrose, which is a major component of sap. Strain 191 catalyzed a moderate conversion of sap sugars to lactic acid (53%) with a productivity of 1.56 g/L/h. Pretreatment of oil palm sap (OPS) using alkaline precipitation improved the sugar fermentability, providing a lactic acid yield of 92% and productivity of 2.64 g/L/h. To better characterize potential inhibitors in the sap, phenolic, organic, and mineral compounds were analyzed using non-treated sap and saps treated with activated charcoal and alkaline precipitation. Phthalic acid, 3,4-dimethoxybenzoic acid, aconitic acid, syringic acid, and ferulic acid were reduced in the sap after treatment. High concentrations of Mg, P, K, and Ca were also precipitated by the alkaline treatment. These results suggest that elimination of excess phenolic and mineral compounds in OPS can improve the fermentation yield. OPS, a non-food resource that is readily available in bulk quantities from plantation sites, is a promising source for lactic acid production. PMID- 28361246 TI - Multidrug-resistant Mycoplasma genitalium infections in Europe. AB - In Japan and Australia, multidrug-resistant Mycoplasma genitalium infections are reported with increasing frequency. Although macrolide-resistant M. genitalium strains are common in Europe and North America, fluoroquinolone-resistant strains are still exceptional. However, an increase of multidrug-resistant M. genitalium in Europe and America is to be expected. The aim of this paper is to increase awareness on the rising number of multidrug-resistant M. genitalium strains. Here, one of the first cases of infection with a genetically proven multidrug resistant M. genitalium strain in Europe is described. The patient was a native Dutch 47-year-old male patient with urethritis. Mycoplasma genitalium was detected, but treatment failed with azithromycin, doxycycline and moxifloxacin. A urogenital sample was used to determine the sequence of the 23S rRNA, gyrA, gyrB and parC genes. The sample contained an A2059G single nucleotide polymorphism (SNP) in the 23S rRNA gene and an SNP in the parC gene, resulting in an amino acid change of Ser83 -> Ile, explaining both azithromycin and moxifloxacin treatment failure. The SNPs associated with resistance were probably generated de novo, as a link with high-prevalence areas was not established. It is, thus, predictable that there is going to be an increase of multidrug-resistant M. genitalium strains in Europe. As treatment options for multidrug-resistant M. genitalium are limited, the treatment of M. genitalium infections needs to be carefully considered in order to limit the rapid increase of resistance to macrolides and fluoroquinolones. PMID- 28361249 TI - Does trajectory matter? A study looking into the relationship of trajectory with target engagement and error accommodation in subthalamic nucleus deep brain stimulation. AB - BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is now a key treatment choice for advanced Parkinson's disease. The optimum target area within the STN is well established. However, no emphasis on the impact of trajectory exists. The ellipsoid shape of the STN and the off-centre traditional target point mean that variation in the electrode inclination should affect STN engagement. Understanding of this relationship could inform trajectory selection during planning by improving STN engagements and margins for error. METHOD: We simulated electrode placement at the clinical target through a set of trial trajectories. Twelve three-dimensionally reconstructed STNs were created from magnetic resonance imaging data of six patients. An appropriate target within each STN was then chosen. Each STN was approached through 56 simulated trajectories arranged in a grid covering a quadrant of skull around and in front of the coronal suture. A subset of 20 viable trajectories was reassessed for depth of engagement in each STN whilst approaching the chosen target. RESULTS: Group averages for each trajectory are presented as traffic light maps and as an overlaid skull mask illustrating recommended electrode entry sites. Trajectories under 30 degrees anterior to the bregma and between 10 to 30 degrees off the midline accommodated over 2.4 degrees of wobble. A mean engagement of 6 mm was possible in half of the subset. The longest engagements are on trajectories which saddle the coronal suture, extending to 40 degrees lateral. Microelectrode tracts of 14 additional STNs were collated using the above protocol and engagement exceeded 5 mm in all central trajectories without capsular side effects, suggesting placement away from STN borders. CONCLUSIONS: Trajectory selection influences engagement and flexibility to accommodate electrode wobble or brain shift whilst approaching a chosen STN target. We recommend having the first trial trajectory 20 degrees anterior to the bregma, moving postero-laterally in successive trials to balance both error and engagement. When wider margins for error are beneficial (e.g. second side during bilateral procedures), trajectories nearer the coronal suture and around 25 degrees off the midline are advised. PMID- 28361248 TI - Increased risk of critical CBF levels in SAH patients with actual CPP below calculated optimal CPP. AB - BACKGROUND: Cerebral pressure autoregulation can be quantified with the pressure reactivity index (PRx), based on the correlation between blood pressure and intracranial pressure. Using PRx optimal cerebral perfusion pressure (CPPopt) can be calculated, i.e., the level of CPP where autoregulation functions best. The relation between cerebral blood flow (CBF) and CPPopt has not been examined. The objective was to assess to which extent CPPopt can be calculated in SAH patients and to investigate CPPopt in relation to CBF. METHODS: Retrospective study of prospectively collected data. CBF was measured bedside with Xenon-enhanced CT (Xe CT). The difference between actual CPP and CPPopt was calculated (CPP?). Correlations between CPP? and CBF parameters were calculated with Spearman's rank order correlation coefficient (rho). Separate calculations were done using all patients (day 0-14 after onset) as well as in two subgroups (day 0-3 and day 4 14). RESULTS: Eighty-two patients with 145 Xe-CT scans were studied. Automated calculation of CPPopt was possible in adjunct to 60% of the Xe-CT scans. Actual CPP < CPPopt was associated with higher numbers of low-flow regions (CBF <10 ml/100 g/min) in both the early phase (day 0-3, n = 39, Spearman's rho = -0.38, p = 0.02) and late acute phase of the disease (day 4-14, n = 35, Spearman's rho = 0.39, p = 0.02). CPP level per se was not associated with CBF. CONCLUSIONS: Calculation of CPPopt is possible in a majority of patients with severe SAH. Actual CPP below CPPopt is associated with low CBF. PMID- 28361247 TI - The potential curative effect of rebamipide in hepatic ischemia/reperfusion injury. AB - Rebamipide (Reba), a gastroprotective drug, has signified its hepatoprotective activity; however, its possible post-therapeutic intervention in hepatic ischemia/reperfusion (I/R) remains elusive. Consequently, the intent of this study was to test Reba modulatory effect on nuclear factor (NF)-kappaB signaling in hepatic I/R model. Rats were randomized into sham, I/R, Reba 60, and Reba100 (60 and 100 mg/kg, respectively) groups. Ischemia was induced for 30 min followed by 3-day reperfusion to set up a model of partial (70%) warm hepatic ischemia. Post-treatment with Reba reduced the serum level of alanine transaminase, improved histopathological alterations of the liver, and elevated hepatic adenosine triphosphate. It also lowered hepatic lipid peroxides and increased both total antioxidant capacity and nitric oxide. Besides, Reba decreased tumor necrosis factor-alpha, interferon-gamma, intercellular adhesion molecule-1, myeloperoxidase, prostaglandin E2, cyclooxygenase-2 expression/content, and caspase-3 activity. Reba also upregulated the gene expression/content of sirtuin 1 (SIRT-1), while it downregulated that of high mobility group box (HMGB)1 and reduced the expression/content of NF-kappaB p65/pS536-NF-kappaB and the content of pT180/Y182-p38MAPK. Reba provided tenable hepato-therapeutic mechanisms to mitigate events concomitant with hepatic I/R via inhibition of NF-kappaB p65 and modulation of its influential signals (SIRT-1, HMGB1, p38MAPK) associated with its antiinflammatory, antioxidant, and antiapoptotic impacts. PMID- 28361250 TI - Influence of Co-57 and CT Transmission Measurements on the Quantification Accuracy and Partial Volume Effect of a Small Animal PET Scanner. AB - PURPOSE: Non-invasive in vivo positron emission tomography (PET) provides high detection sensitivity in the nano- to picomolar range and in addition to other advantages, the possibility to absolutely quantify the acquired data. The present study focuses on the comparison of transmission data acquired with an X-ray computed tomography (CT) scanner or a Co-57 source for the Inveon small animal PET scanner (Siemens Healthcare, Knoxville, TN, USA), as well as determines their influences on the quantification accuracy and partial volume effect (PVE). A special focus included the impact of the performed calibration on the quantification accuracy. PROCEDURES: Phantom measurements were carried out to determine the quantification accuracy, the influence of the object size on the quantification, and the PVE for different sphere sizes, along the field of view and for different contrast ratios. RESULTS: An influence of the emission activity on the Co-57 transmission measurements was discovered (deviations up to 24.06 % measured to true activity), whereas no influence of the emission activity on the CT attenuation correction was identified (deviations <3 % for measured to true activity). The quantification accuracy was substantially influenced by the applied calibration factor and by the object size. The PVE demonstrated a dependency on the sphere size, the position within the field of view, the reconstruction and correction algorithms and the count statistics. Depending on the reconstruction algorithm, only ~30-40 % of the true activity within a small sphere could be resolved. The iterative 3D reconstruction algorithms uncovered substantially increased recovery values compared to the analytical and 2D iterative reconstruction algorithms (up to 70.46 % and 80.82 % recovery for the smallest and largest sphere using iterative 3D reconstruction algorithms). The transmission measurement (CT or Co-57 source) to correct for attenuation did not severely influence the PVE. CONCLUSIONS: The analysis of the quantification accuracy and the PVE revealed an influence of the object size, the reconstruction algorithm and the applied corrections. Particularly, the influence of the emission activity during the transmission measurement performed with a Co-57 source must be considered. To receive comparable results, also among different scanner configurations, standardization of the acquisition (imaging parameters, as well as applied reconstruction and correction protocols) is necessary. PMID- 28361251 TI - [Singular skin-colored nodule on the trunk of an 18-month-old girl]. PMID- 28361253 TI - Effects of photoinitiator on electro-optical properties of polymerization-induced phase separation blue-phase liquid crystals. AB - We have reported polymer-dispersed blue-phase (PDBP) liquid-crystal films via polymerization-induced phase separation. PDBP films are prepared by photochemical polymerization of curable crosslinking agent, monomer and blue-phase liquid crystal under an ultraviolet (UV) light. The influences of photoinitiator and weight ratio between monomer/crosslinking agent and blue phase on the electro optical properties of PDBP liquid-crystal samples are investigated. The electro optical (E-O) properties of PDBP films are determined in the top-down electro optical cell. PDBP liquid-crystal films show good E-O properties with high contrast ratio and fast response time. PMID- 28361252 TI - [Single center analysis of the dermatosurgical patient cohort of a tumor center in Germany]. AB - BACKGROUND: The incidence of skin cancer continues to increase. However, little is known about the dermatosurgical characteristics of the patients. PATIENTS AND METHODS: In this single center, retrospective study, dermatosurgical reports of all patients treated because of basal cell carcinomas (BCC), squamous cell carcinomas (SCC), and malignant melanoma (MM) between 2004 and 2013 were analyzed. RESULTS: During the observed period, the number of operated BCC rose by a factor of 1.86 and the number of MM by a factor of 2.3. In comparison to BCC/MM, there was a disproportionately high increase of SCC by a factor of 4.02. The average age was 71.5 +/- 13.4 years (minimum: 14 years; maximum: 104 years), whereupon a significant increase of male age and a significant decrease of female age occurred. Almost 70% of all tumors were located in the head and neck area. The nose was most commonly treated. CONCLUSIONS: During the last 10 years, the cohort of dermatosurgical patients changed in the tumor center. This should be verified in multicenter studies. PMID- 28361255 TI - Novel WDR45 mutation causing beta-propeller protein associated neurodegeneration (BPAN) in two monozygotic twins. PMID- 28361254 TI - Vestibular cognition: the effect of prior belief on vestibular perceptual decision making. AB - Vestibular cognition is a growing field of interest and relatively little is known about the underlying mechanisms. We tested the effect of prior beliefs about the relative probability (50:50 vs. 80:20) of motion direction (yaw rotation) using a direction discrimination task. We analyzed choices individually with a logistic regression model and together with response times using a cognitive process model. The results show that self-motion perception is altered by prior belief, leading to a shift of the psychometric function, without a loss of sensitivity. Hierarchical drift diffusion analysis showed that at the group level, prior belief manifests itself as an offset to the drift criterion. However, individual model fits revealed that participants vary in how they use cognitive information in perceptual decision making. At the individual level, the response bias induced by a prior belief resulted either in a change in starting point (prior to evidence accumulation) or drift rate (during evidence accumulation). Participants incorporate prior belief in a self-motion discrimination task, albeit in different ways. PMID- 28361256 TI - Computational Approaches and Related Tools to Identify MicroRNAs in a Species: A Bird's Eye View. AB - MicroRNAs (miRNAs) are a family of non-coding RNAs that play a central role in fine-tuning gene expression regulation. Over the past decade, identification and annotation of miRNAs have become a major focus in epigenomics research. However, detection and characterization of miRNA are challenging due to its small size (~22 nucleotide-long) and susceptibility to degradation. The difficulties involved in experimental prediction and characterization of miRNA coding genes have led to the development of in silico-based approaches. Although several algorithms have been developed in recent years, a comprehensive assessment of the principles, methodological insights, and estimate of the strengths and weaknesses of computational methods are limited. The present review is dealt with the detailed methodological insights of different tools used for identifying miRNA coding genes falling under four computational approaches. The parameters considered in these tools along with their specificity are also delineated. Furthermore, the strengths and weaknesses of these four computational approaches, and the bioinformatics resources pertaining to target identification, expression analysis, regulatory network analysis, and SNP identification are stated in this review. The methodological details of miRNA prediction methods and bioinformatics resources related to miRNA research in one platform would facilitate the miRNA research community to develop efficient tools for uncovering novel miRNAs and understanding their role in regulatory networks. PMID- 28361257 TI - Induction of anthocyanin in the inner epidermis of red onion leaves by environmental stimuli and transient expression of transcription factors. AB - KEY MESSAGE: Novel imaging approaches have allowed measurements of the anthocyanin induction in onion epidermal cells that can be induced through water stress or transient expression of exogenous transcription factors. Environmental and genetic mechanisms that allow the normally colourless inner epidermal cells of red onion (Allium cepa) bulbs to accumulate anthocyanin were quantified by both absorbance ratios and fluorescence. We observed that water-stressing excised leaf segments induced anthocyanin formation, and fluorescence indicated that this anthocyanin was spectrally similar to the anthocyanin in the outer epidermal cells. This environmental induction may require a signal emanating from the leaf mesophyll, as induction did not occur in detached epidermal peels. Exogenous transcription factors that successfully drive anthocyanin biosynthesis in other species were also tested through transient gene expression using particle bombardment. Although the petunia R2R3-MYB factor AN2 induced anthocyanin in both excised leaves and epidermal peels, several transcription factors including maize C1 and Lc inhibited normal anthocyanin development in excised leaves. This inhibition may be due to moderate levels of conservation between the exogenous transcription factors and endogenous Allium transcription factors. The over expressed exogenous transcription factors cannot drive anthocyanin biosynthesis themselves, but bind to the endogenous transcription factors and prevent them from driving anthocyanin biosynthesis. PMID- 28361259 TI - The role of weight teasing and weight bias internalization in psychological functioning: a prospective study among school-aged children. AB - Weight-related teasing is a widespread phenomenon in childhood, and might foster the internalization of weight bias. The goal of this study was to examine the role of weight teasing and weight bias internalization as mediators between weight status and negative psychological sequelae, such as restrained eating and emotional and conduct problems in childhood. Participants included 546 female (52%) and 501 (48%) male children aged 7-11 and their parents, who completed surveys assessing weight teasing, weight bias internalization, restrained eating behaviors, and emotional and conduct problems at two points of measurement, approximately 2 years apart. To examine the hypothesized mediation, a prospective design using structural equation modeling was applied. As expected, the experience of weight teasing and the internalization of weight bias were mediators in the relationship between weight status and psychosocial problems. This pattern was observed independently of gender or weight status. Our findings suggest that the experience of weight teasing and internalization of weight bias is more important than weight status in explaining psychological functioning among children and indicate a need for appropriate prevention and intervention approaches. PMID- 28361258 TI - Effects of neonatal excitotoxic lesions in ventral thalamus on social interaction in the rat. AB - The role of the thalamus in schizophrenia has increasingly been studied in recent years. Deficits in the ventral thalamus have been described in only few postmortem and neuroimaging studies. We utilised our previously introduced neurodevelopmental animal model, the neonatal excitotoxic lesion of the ventral thalamus of Sprague-Dawley rats (Wolf et al., Pharmacopsychiatry 43:99-109, 22). At postnatal day (PD7), male pubs received bilateral thalamic infusions with ibotenic acid (IBA) or artificial cerebrospinal fluid (control). In adulthood, social interaction of two animals not familiar to each other was studied by a computerised video tracking system. This study displays clear lesion effects on social interaction of adult male rats. The significant reduction of total contact time and the significant increase in distance between the animals in the IBA group compared to controls can be interpreted as social withdrawal modelling a negative symptom of schizophrenia. The significant increase of total distance travelled in the IBA group can be hypothesised as agitation modelling a positive symptom of schizophrenia. Using a triple concept of social interaction, the percentage of no social interaction (Non-SI%) was significantly larger, and inversely, the percentage of passive social interaction (SI-passive%) was significantly smaller in the IBA group when compared to controls. In conclusion, on the background of findings in schizophrenic patients, the effects of neonatal ventral thalamic IBA lesions in adult male rats support the hypothesis of face and construct validity as animal model of schizophrenia. PMID- 28361260 TI - Gadolinium retention in the body: what we know and what we can do. AB - Gadolinium-based contrast agents (GBCA), widely used in Magnetic Resonance Imaging (MRI) for almost 30 years, were recently shown to be deposited in the brain and to induce persistent T1 shortening in deep gray matter structures in subjects with normal renal function. The aim of the present study is to summarize the evidence derived from the rapidly growing scientific literature on Gadolinium retention in the brain and in the rest of the body. To this end, the original articles that described imaging and pathology findings in humans and animals exposed to GBCA were reviewed. The main aspects that emerged were the different effects of linear and macrocyclic GBCA on brain MRI appearance, the evidence of Gadolinium tissue retention in multiple organs, and the debated issue of the possible clinical consequences. Although no adverse health effects have been documented so far, updated information about GBCA build-up in the body is necessary for health professionals, also in view of the increasing concern in the general population. To date, our knowledge about the mechanisms of Gadolinium tissue deposition and, above all, its long-term consequences is still largely incomplete. However, while official guidelines are eagerly awaited, some advices may already be given, to help our radiological daily practice. PMID- 28361261 TI - Diabetic brain or retina? Visual psychophysical performance in diabetic patients in relation to GABA levels in occipital cortex. AB - Visual impairment is one of the most feared complications of Type 2 Diabetes Mellitus. Here, we aimed to investigate the role of occipital cortex gamma aminobutyric acid (GABA) as a predictor of visual performance in type 2 diabetes. 18 type 2 diabetes patients were included in a longitudinal prospective one-year study, as well as 22 healthy age-matched controls. We collected demographic data, HbA1C and used a novel set of visual psychophysical tests addressing color, achromatic luminance and speed discrimination in both groups. Psychophysical tests underwent dimension reduction with principle component analysis into three synthetic variables: speed, achromatic luminance and color discrimination. A MEGA PRESS magnetic resonance brain spectroscopy sequence was used to measure occipital GABA levels in the type 2 diabetes group. Retinopathy grading and retinal microaneurysms counting were performed in the type 2 diabetes group for single-armed correlations. Speed discrimination thresholds were significantly higher in the type 2 diabetes group in both visits; mean difference (95% confidence interval), [0.86 (0.32-1.40) in the first visit, 0.74 (0.04-1.44) in the second visit]. GABA from the occipital cortex predicted speed and achromatic luminance discrimination thresholds within the same visit (r = 0.54 and 0.52; p = 0.02 and 0.03, respectively) in type 2 diabetes group. GABA from the occipital cortex also predicted speed discrimination thresholds one year later (r = 0.52; p = 0.03) in the type 2 diabetes group. Our results suggest that speed discrimination is impaired in type 2 diabetes and that occipital cortical GABA is a novel predictor of visual psychophysical performance independently from retinopathy grade, metabolic control or disease duration in the early stages of the disease. PMID- 28361263 TI - Serum Biomarkers of Myocardial Remodeling and Coronary Dysfunction in Early Stages of Hypertrophic Cardiomyopathy in the Young. AB - Hypertrophic cardiomyopathy (HCM) remains the leading cause of sudden cardiac death in the young. Early markers for HCM are important to identify individuals at risk. The aim of this study was to investigate novel serum biomarkers reflecting myocardial remodeling, microfibrosis, and vascular endotheliopathy in the early stages of familial HCM in young patients. Twenty-three HCM patients, 16 HCM-risk individuals, and 66 controls (median 15 years) underwent echocardiography and serum analysis for cathepsin S, endostatin, myostatin, type I collagen degradation marker (ICTP), matrix metalloproteinase (MMP)-9, vascular endothelial growth factor receptor (VEGFR)-1, and vascular and intercellular adhesion molecules (VCAM, ICAM). In a subset of the population, global myocardial perfusion was performed by magnetic resonance imaging. Cathepsin S (p = 0.0009), endostatin (p < 0.0001), MMP-9 (p = 0.008), and VCAM (p = 0.04) were increased in the HCM group and correlated to left ventricular mass index and mitral E/e' (p < 0.01). In the HCM-risk group, myostatin was decreased (p = 0.004), whereas ICAM was increased (p = 0.002). Global perfusion was decreased in the HCM group (p < 0.05) versus controls. Endostatin and mitral E/e' correlated inversely to myocardial perfusion (p <= 0.05). This is the first study demonstrating adverse changes in biomarkers reflecting myocardial matrix remodeling, microfibrosis, and vascular endotheliopathy in early stage of hypertrophic cardiomyopathy in the young. PMID- 28361262 TI - The interrelationship of metabolic syndrome and neurodegenerative diseases with focus on brain-derived neurotrophic factor (BDNF): Kill two birds with one stone. AB - The brain-derived neurotrophic factor (BDNF) is involved in metabolic syndrome (MetS) and neurodegenerative diseases (NDD) like Alzheimer's disease, Huntington's disease, Parkinson's disease and depression. If one factor plays an essential role in the pathogenesis of two diseases, it can be concluded that there might be a common root in these two diseases, as well. This review was aimed to highlight the crucial roles of BDNF in the pathogenesis of MetS and NDD and to introduce sole prophylactic or therapeutic applications, BDNF gene therapy and BDFN administration, in controlling MetS and NDD. PMID- 28361264 TI - Social context has differential effects on acquisition of nicotine self administration in male and female rats. AB - RATIONAL: Smoking typically begins during adolescence or early adulthood in a social context, yet the role of social context in animal models is poorly understood. OBJECTIVES: The present study examined the effect of social context on acquisition of nicotine self-administration. METHODS: Sixty-day-old male and female Sprague-Dawley rats were trained to press a lever for nicotine (0.015 mg/kg, IV) or saline infusions (males only) on a fixed ratio (FR1) schedule of reinforcement across nine sessions in duplex chambers that were conjoined with either a solid wall or a wall containing wire mesh creating a social context between rat dyads (social visual, auditory, and olfactory cues). In a subsequent experiment, sex differences and dose-dependent effects of nicotine [0 (saline), 0.015 or 0.03 mg/kg, IV] were directly compared in rats trained in the isolated or social context on a schedule progressing from FR1 to FR3. These rats were given 20 sessions followed by 3 extinction sessions. RESULTS: We consistently found transient social facilitation of low-dose nicotine self-administration in males during the first session. However, across training overall, we found social suppression of nicotine intake that was most prominent in females during later sessions. CONCLUSIONS: Collectively, these findings suggest that at the age of transition from adolescence to adulthood, a social context enhances the initial reinforcing effects of nicotine in males, but protects against nicotine intake during later sessions especially in females. These findings highlight the importance of sex and social context in studying neural mechanisms involved in initiation of nicotine use. PMID- 28361265 TI - Diversity, Antimicrobial Activity, and Biosynthetic Potential of Cultivable Actinomycetes Associated with Lichen Symbiosis. AB - Lichens are structured associations of a fungus with a cyanobacteria and/or green algae in a symbiotic relationship, which provide specific habitats for diverse bacterial communities, including actinomycetes. However, few studies have been performed on the phylogenetic relationships and biosynthetic potential of actinomycetes across lichen species. In the present study, a total of 213 actinomycetes strains were isolated from 35 lichen samples (22 lichen genera) collected in Yunnan Province, China. 16S rRNA gene sequence analysis revealed an unexpected level of diversity among these isolates, which were distributed into 38 genera, 19 families, and 9 orders within the Actinobacteria phylum. The detailed taxa of isolates had no clear relationship to the taxonomic affiliations of the associated lichens. To the best of our knowledge, this is the first report to describe the isolation of Actinophytocola, Angustibacter, Herbiconiux, Kibdelosporangium, Kineosporia, Kitasatospora, Nakamurella, Nonomuraea, Labedella, Lechevalieria, Lentzea, Schumannella, and Umezawaea species from lichens. At least 40 isolates (18.78%) are likely to represent novel actinomycetes taxa within 15 genera. In addition, all 213 isolates were tested for antimicrobial activity and screened for genes associated with secondary metabolite production to evaluate their biosynthetic potential. These results demonstrate that the lichens of Yunnan Province represent an extremely rich reservoir for the isolation of a significant diversity of actinomycetes, including novel species, which are potential source for discovering biologically active compounds. PMID- 28361266 TI - Genomic Epidemiology and Management of Salmonella in Island Ecosystems Used for Takahe Conservation. AB - Translocation and isolation of threatened wildlife in new environments may have unforeseen consequences on pathogen transmission and evolution in host populations. Disease threats associated with intensive conservation management of wildlife remain speculative without gaining an understanding of pathogen dynamics in meta-populations and how location attributes may determine pathogen prevalence. We determined the prevalence and population structure of an opportunistic pathogen, Salmonella, in geographically isolated translocated sub populations of an endangered New Zealand flightless bird, the takahe (Porphyrio hochstetteri). Out of the nine sub-populations tested, Salmonella was only isolated from takahe living on one private island. The apparent prevalence of Salmonella in takahe on the private island was 32% (95% CI 13-57%), with two serotypes, Salmonella Mississippi and Salmonella houtenae 40:gt-, identified. Epidemiological investigation of reservoirs on the private island and another island occupied by takahe identified environmental and reptile sources of S. Mississippi and S. houtenae 40:gt- on the private island. Single nucleotide polymorphism analysis of core genomes revealed low-level diversity among isolates belonging to the same serotype and little differentiation according to host and environmental source. The pattern observed may be representative of transmission between sympatric hosts and environmental sources, the presence of a common unsampled source, and/or evidence of a recent introduction into the ecosystem. This study highlights how genomic epidemiology can be used to ascertain and understand disease dynamics to inform the management of disease threats in endangered wildlife populations. PMID- 28361269 TI - [Drainages in abdominal surgery: (in)dispensable?] AB - BACKGROUND: Prophylactic placement of intraperitoneal drains in elective abdominal surgery is still subject to scrutiny. OBJECTIVE: Do currently available data enable the practice of routine placement of abdominal drainages to be abandoned? METHODS: The databases of MEDLINE, PubMed and the Cochrane Library were systematically searched for clinical trials concerning the practice of routine drainage placement in elective abdominal surgery. The available evidence was summarized for cholecystectomy, colorectal surgery, gastrectomy and pancreatic surgery, as well as for liver resection. A total of 6 Cochrane reviews including 65 randomized controlled trials (RCTs) and 9 retrospective analyses, as well as 1 more recent RCT and 3 retrospective analyses that were not included in a meta-analysis were reviewed. CONCLUSION: There is evidence that drains should not be routinely used in elective abdominal surgery, such as cholecystectomy, colorectal resection and gastrectomy. Even for some cases of pancreatic and liver resection, there is growing evidence that routine placement of drains is not mandatory. In conclusion, there is a need for more prospective randomized controlled trials. PMID- 28361270 TI - [Lugol's solution for preoperative pretreatment in Grave's disease]. PMID- 28361268 TI - Resveratrol Attenuates Abeta-Induced Early Hippocampal Neuron Excitability Impairment via Recovery of Function of Potassium Channels. AB - Alzheimer's disease (AD) is an age-related neurodegenerative disease. Amyloid beta (Abeta) is not only the morphological hallmark but also the initiator of the pathology process of AD. As a natural compound found in grapes, resveratrol shows a protective effect on the pathophysiology of AD, but the underlying mechanism is not very clear. This study was to investigate whether resveratrol could attenuate Abeta-induced early impairment in hippocampal neuron excitability and the underlying mechanism. The excitability and voltage-gated potassium currents were examined in rat hippocampal CA1 pyramidal neurons by using whole-cell patch-clamp technique. It was found that Abeta25-35 increased the excitability of neurons. Resveratrol could reverse the Abeta25-35-induced increase in the frequency of repetitive firing and the spike half-width of action potential (AP). Moreover, resveratrol can attenuate Abeta25-35-induced decreases in transient potassium channel (I A ) and delay rectifier potassium channel (I K(DR)) of neurons. It was also found that resveratrol could decline the increase of protein kinase A (PKA) and inhibit the activation of PI3K/Akt signaling pathway induced by Abeta25-35. The results suggest that resveratrol alleviates Abeta25-35-induced dysfunction in hippocampal CA1 pyramidal neurons via recovery of the function of I A and I K(DR) by inhibiting the increase of PKA and the activation of PI3K/Akt signaling pathway. PMID- 28361267 TI - Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy? AB - Angiogenesis is defined as the formation of new blood vessels from preexisting vessels and has been characterized as an essential process for tumor cell proliferation and viability. This has led to the development of pharmacological agents for anti-angiogenesis to disrupt the vascular supply and starve tumor of nutrients and oxygen, primarily through blockade of VEGF/VEGFR signaling. This effort has resulted in 11 anti-VEGF drugs approved for certain advanced cancers, alone or in combination with chemotherapy or other targeted therapies. But this success had only limited impact on overall survival of cancer patients and rarely resulted in durable responses. Given the recent success of immunotherapies, combinations of anti-angiogenics with immune checkpoint blockers have become an attractive strategy. However, implementing such combinations will require a better mechanistic understanding of their interaction. Due to overexpression of pro-angiogenic factors in tumors, their vasculature is often tortuous and disorganized, with excessively branched leaky vessels. This enhances vascular permeability, which in turn is associated with high interstitial fluid pressure, and a reduction in blood perfusion and oxygenation. Judicious dosing of anti angiogenic treatment can transiently normalize the tumor vasculature by decreasing vascular permeability and improving tumor perfusion and blood flow, and synergize with immunotherapy in this time window. However, anti-angiogenics may also excessively prune tumor vessels in a dose and time-dependent manner, which induces hypoxia and immunosuppression, including increased expression of the immune checkpoint programmed death receptor ligand (PD-L1). This review focuses on revisiting the concept of anti-angiogenesis in combination with immunotherapy as a strategy for cancer treatment. PMID- 28361272 TI - Sterilization of blow fly eggs, Chrysomya megacephala and Lucilia cuprina, (Diptera: Calliphoridae) for maggot debridement therapy application. AB - Maggot debridement therapy (MDT) is an application of sterile laboratory-reared blow fly larvae to remove necrotic tissue and disinfect wounds for medical conditions. For effective application, the blow fly larvae used in the wound treatment are required to be in aseptic condition. Here, we report the results of a detailed assessment of bacteria and fungi isolated from the eggs of two blow fly species, Chrysomya megacephala (F.) and Lucilia cuprina (Wiedemann) before and after sterilization by disinfectants Chlorhex-C, povidone-iodine, and sodium hypochlorite. We also assess the survival ability of larvae and their sterility after the cleansing process. The results indicate that the isolated microorganisms from the control group of both the species consisted of 10 species of gram-positive bacteria, 21 species of gram-negative bacteria, and 4 species of yeast. As for sterility testing, the eggs and the larvae of C. megacephala were found to have been completely sterilized after being subjected to thioglycollate medium for 5 days, leading to aseptic larvae. By contrast, some microorganisms from the bacterial culture were still detected in the L. cuprina larvae treated with Chlorhex-C and povidone-iodine. The survival ability of the larvae in both the species was not significantly different between the treated and the control groups. Due to its high disinfection efficacy in destroying microorganisms in both the blow fly eggs, sodium hypochlorite is recommended for preparing sterile larvae before using MDT. PMID- 28361273 TI - Widespread 5-methylcytosine in the genomes of avian Coccidia and other apicomplexan parasites detected by an ELISA-based method. AB - To date, little is known about cytosine methylation in the genomic DNA of apicomplexan parasites, although it has been confirmed that this important epigenetic modification exists in many lower eukaryotes, plants, and animals. In the present study, ELISA-based detection demonstrated that low levels of 5 methylcytosine (5-mC) are present in Eimeria spp., Toxoplasma gondii, Cryptosporidium spp., and Neospora caninum. The proportions of 5-mC in genomic DNA were 0.18 +/- 0.02% in E tenella sporulated oocysts, 0.19 +/- 0.01% in E. tenella second-generation merozoites, 0.22 +/- 0.04% in T. gondii tachyzoites, 0.28 +/- 0.03% in N. caninum tachyzoites, and 0.06 +/- 0.01, 0.11 +/- 0.01, and 0.09 +/- 0.01% in C. andersoni, C. baileyi, and C. parvum sporulated oocysts, respectively. In addition, we found that the percentages of 5-mC in E. tenella varied considerably at different life stages, with sporozoites having the highest percentage of 5-mC (0.78 +/- 0.10%). Similar stage differences in 5-mC were also found in E. maxima, E. necatrix, and E. acervulina, the levels of 5-mC in their sporozoites being 4.3-, 1.8-, 2.5-, and 2.0-fold higher than that of sporulated oocysts, respectively (p < 0.01). Furthermore, a total DNA methyltransferase-like activity was detected in whole cell extracts prepared from E. tenella sporozoites. In conclusion, genomic DNA methylation is present in these apicomplexan parasites and may play a role in the stage conversion of Eimeria. PMID- 28361271 TI - The Development of Translational Biomarkers as a Tool for Improving the Understanding, Diagnosis and Treatment of Chronic Neuropathic Pain. AB - Chronic neuropathic pain (CNP) is one of the most significant unmet clinical needs in modern medicine. Alongside the lack of effective treatments, there is a great deficit in the availability of objective diagnostic methods to reliably facilitate an accurate diagnosis. We therefore aimed to determine the feasibility of a simple diagnostic test by analysing differentially expressed genes in the blood of patients diagnosed with CNP of the lower back and compared to healthy human controls. Refinement of microarray expression data was performed using correlation analysis with 3900 human 2-colour microarray experiments. Selected genes were analysed in the dorsal horn of Sprague-Dawley rats after L5 spinal nerve ligation (SNL), using qRT-PCR and ddPCR, to determine possible associations with pathophysiological mechanisms underpinning CNP and whether they represent translational biomarkers of CNP. We found that of the 15 potential biomarkers identified, tissue inhibitor of matrix metalloproteinase-1 (TIMP1) gene expression was upregulated in chronic neuropathic lower back pain (CNBP) (p = 0.0049) which positively correlated (R = 0.68, p = <=0.05) with increased plasma TIMP1 levels in this group (p = 0.0433). Moreover, plasma TIMP1 was also significantly upregulated in CNBP than chronic inflammatory lower back pain (p = 0.0272). In the SNL model, upregulation of the Timp1 gene was also observed (p = 0.0058) alongside a strong trend for the upregulation of melanocortin 1 receptor (p = 0.0847). Our data therefore highlights several genes that warrant further investigation, and of these, TIMP1 shows the greatest potential as an accessible and translational CNP biomarker. PMID- 28361274 TI - The patient's experience of primary ciliary dyskinesia: a systematic review. AB - BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by progressive sinopulmonary disease, with symptoms starting soon after birth. The aim of this study is to critically review, analyse, and synthesise the literature in order to understand the experiences of patients with primary ciliary dyskinesia (PCD) and the impact on health-related quality of life. METHOD: MEDLINE, EBSCO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO and EMBASE were searched according to the inclusion criteria. A qualitative analysis of 14 studies was conducted. RESULTS: Fourteen studies were included in the review, five with qualitative methodologies. Studies originated from the UK, USA, Italy, Denmark and Belgium, one study included a survey distributed internationally. Significant relationships were found between age and worsening of respiratory symptoms, physical, and mental domains of health related quality of life, with a greater decline compared with reference populations. Variations between the UK and Italy were found for health-related quality of life and its correlation with time since diagnosis. PCD was found to have a physical impact in all age groups: patients found it difficult to keep up with others, and found energy levels were easily depleted compared to family or peers. In terms of social impact, symptoms lead to embarrassment and a sense of isolation, with patients concealing symptoms and/or their diagnosis. In turn, isolation was also linked with the lack of public and medical knowledge. In relation to emotional impact, anxiety was reported in a number of qualitative studies; patients were anxious about getting sick or when thinking about their future health. The burden of treatment and factors influencing adherence were also discussed in depth. CONCLUSION: Health-related quality of life decreases with age in patients with PCD. For all age groups, PCD was found to greatly impact physical, emotional, social functioning, and treatment burden. More research is needed on the psychosocial impact of the illness, disease burden and its effect on quality of life. PMID- 28361275 TI - Effects of spinal stabilization exercises in women with benign joint hypermobility syndrome: a randomized controlled trial. AB - The aim of this study was to investigate the effects of an 8-week lumbar spinal stabilization exercise program on pain, trunk muscle endurance, and postural stability in women with benign joint hypermobility syndrome (BJHS). Women with BJHS were randomly allocated into exercise (n = 20) and control (n = 18) groups. The lumbar spinal stabilization exercise program was carried out 3 days a week for 8 weeks. BJHS with Brighton criteria, musculoskeletal pain intensity with Visual Analog Scale, trunk muscle endurance with McGill's trunk muscle endurance tests, and postural stability as static and dynamic while eyes open and closed with Biodex Balance System SD were evaluated. Chi-square test, independent sample t test, Mann-Whitney U test, and Wilcoxon test were used for statistical analysis. It was shown that most of the patients with BJHS had low back (exercise group 40.0%; control group 22.2%) and knee pain (exercise group 15.0%; control group 22.2%). After the program, pain intensity, and static and dynamic stability scores (eyes closed) decreased, and trunk muscle endurance scores increased in the exercise group. There was no difference for all parameters in the control group. Pain intensity, trunk muscle endurance, and only dynamic stability (eyes open) improved in the exercise group in comparison to the control group. The lumbar spinal stabilization exercise program improved pain complaints, postural stability, and trunk muscle endurance of women with BJHS. The program can be used for general pain relief, trunk muscle weakness, and postural impairment in women with BJHS. PMID- 28361276 TI - Aplastic anemia in a lung adenocarcinoma patient receiving pemetrexed. AB - Pemetrexed (PEM) is an antimetabolite drug that interferes with enzymes involved in DNA synthesis and also the folate-dependent metabolic processes necessary for DNA replication and homocysteine homeostasis. Continuation maintenance with PEM after induction therapy with PEM plus cisplatin has been the standard form of first-line chemotherapy for advanced non-squamous non-small cell lung cancer. The regimen has a low incidence of bone marrow suppression, and the incidences of anemia, leukopenia, neutropenia and thrombocytopenia exceeding grade 3 are less than 5%. Here we report a 68-year-old Japanese man with stage IIIB (cT4N3M0) lung adenocarcinoma who received 4 cycles of chemotherapy with PEM 500 mg/m2 and cisplatin 75 mg/m2 every three weeks, which resulted in a partial response, and then continued to receive maintenance PEM monotherapy. After 11 cycles of PEM maintenance therapy, the patient's platelet count decreased, and progressed to pancytopenia within two months. A bone marrow puncture revealed replacement with fatty marrow. As other diseases possibly responsible for pancytopenia were ruled out, we diagnosed the patient as having aplastic anemia. This is the first reported case of aplastic anemia to have occurred during PEM therapy. Clinicians should bear in mind that PEM can potentially trigger severe pancytopenia, including aplastic anemia. PMID- 28361277 TI - The effect of a dynamic PCL brace on patellofemoral compartment pressures in PCL and PCL/PLC-deficient knees. AB - BACKGROUND: The natural history of posterior cruciate ligament (PCL) deficiency includes the development of arthrosis in the patellofemoral joint (PFJ). The purpose of this biomechanical study was to evaluate the hypothesis that dynamic bracing reduces PFJ pressures in PCL- and combined PCL/posterolateral corner (PLC)-deficient knees. STUDY DESIGN: Controlled Laboratory Study. METHODS: Eight fresh frozen cadaveric knees with intact cruciate and collateral ligaments were included. PFJ pressures and force were measured using a pressure mapping system via a lateral arthrotomy at knee flexion angles of 30 degrees , 60 degrees , 90 degrees , and 120 degrees in intact, PCL-deficient, and PCL/PLC-deficient knees under a combined quadriceps/hamstrings load of 400 N/200 N. Testing was then repeated in PCL- and PCL/PLC-deficient knees after application of a dynamic PCL brace. RESULTS: Application of a dynamic PCL brace led to a reduction in peak PFJ pressures in PCL-deficient knees. In addition, the brace led to a significant reduction in peak pressures in PCL/PLC-deficient knees at 60 degrees , 90 degrees , and 120 degrees of flexion. Application of the dynamic brace also led to a reduction in total PFJ force across all flexion angles for both PCL- and PCL/PLC deficient knees. CONCLUSION: Dynamic bracing reduces PFJ pressures in PCL- and combined PCL/PLC-deficient knees, particularly at high degrees of knee flexion. PMID- 28361278 TI - Cost Effectiveness of Gastroprotection with Proton Pump Inhibitors in Older Low Dose Acetylsalicylic Acid Users in the Netherlands. AB - PURPOSE: The present study aimed to assess the cost effectiveness of concomitant proton pump inhibitor (PPI) treatment in low-dose acetylsalicylic acid (LDASA) users at risk of upper gastrointestinal (UGI) adverse effects as compared with no PPI co-medication with attention to the age-dependent influence of PPI-induced adverse effects. METHODS: We used a Markov model to compare the strategy of PPI co-medication with no PPI co-medication in older LDASA users at risk of UGI adverse effects. As PPIs reduce the risk of UGI bleeding and dyspepsia, these risk factors were modelled together with PPI adverse effects for LDASA users 60 69, 70-79 (base case) and 80 years and older. Incremental cost-utility ratios (ICURs) were calculated as cost per quality-adjusted life-year (QALY) gained per age category. Furthermore, a budget impact analysis assessed the expected changes in expenditure of the Dutch healthcare system following the adoption of PPI co treatment in all LDASA users potentially at risk of UGI adverse effects. RESULTS: PPI co-treatment of 70- to 79-year-old LDASA users, as compared with no PPI, resulted in incremental costs of ?100.51 at incremental effects of 0.007 QALYs with an ICUR of ?14,671/QALY. ICURs for 60- to 69-year-old LDASA users were ?13,264/QALY and ?64,121/QALY for patients 80 years and older. Initiation of PPI co-treatment for all Dutch LDASA users of 60 years and older at risk of UGI adverse effects but not prescribed a PPI (19%) would have cost ?1,280,478 in the first year (year 2013 values). CONCLUSIONS: PPI co-medication in LDASA users at risk of UGI adverse effects is generally cost effective. However, this strategy becomes less cost effective with higher age, particularly in patients aged 80 years and older, mainly due to the increased risks of PPI-induced adverse effects. PMID- 28361279 TI - Outcomes after hand and upper extremity transplantation. AB - Hand and upper extremity transplantation (HUET) has emerged as the most frequently performed reconstructive procedure in the burgeoning field of vascularized composite allotransplantation (VCA). VCA refers to a form of transplant with multiple tissue types that represents a viable treatment option for devastating injuries where conventional reconstruction would be unable to restore form and function. As hand transplantation becomes increasingly more common, discussions on advantages and disadvantages of the procedure seem to intensify. Despite encouraging functional outcomes, current immunosuppressive regimens with their deleterious side-effect profile remain a major concern for a life-changing but not life-saving type of transplant. In addition, a growing number of recipients with progressively longer follow-up prompt the need to investigate potential long-term sequelae, such as chronic rejection. This review will discuss the current state of HUET, summarizing outcome data on graft survival, motor and sensory function, as well as immunosuppressive treatment. The implications of these findings for VCA in terms of achievements and challenges ahead will then be discussed. PMID- 28361280 TI - Temporary skin grafts based on hybrid graphene oxide-natural biopolymer nanofibers as effective wound healing substitutes: pre-clinical and pathological studies in animal models. AB - In recent years, temporary skin grafts (TSG) based on natural biopolymers modified with carbon nanostructures have received considerable attention for wound healing. Developments are required to improve physico-mechanical properties of these materials to match to natural skins. Additionally, in-deep pre-clinical examinations are necessary to ensure biological performance and toxicity effect in vivo. In the present work, we show superior acute-wound healing effect of graphene oxide nanosheets embedded in ultrafine biopolymer fibers (60 nm) on adult male rats. Nano-fibrous chitosan-based skin grafts crosslinked by Genepin with physico-mechanical properties close to natural skins were prepared by electrospinning of highly concentrated chitosan- polyvinylpyrrolidone solutions containing graphene oxide (GO) nanosheets. No surfactants and organic solvents were utilized to ensure high biocompatibility of the fibrous structure. In vitro evaluations by human skin fibroblast cells including live and dead assay and MTT results show that GO promote cell viability of porous nanofibrous membrane while providing enhanced bactericidal capacity. In vivo studies on rat's skin determine accelerated healing effect, i.e. a large open wound (1.5 * 1.5 cm2) is fully regenerated after 14-day of post operation while healing is observed for sterile gauze sponge (as the control). Pathological studies support thick dermis formation and complete epithelialization in the presence of 1.5 wt% GO nanosheets. Over 99% wound healing occurs after 21 days for the injury covered with TSG containing 1.5 wt% GO while this would takes weeks for the control. Therefore, the developed materials have a high potential to be used as TSG as pre clinical testing has shown. PMID- 28361281 TI - Europium-phenolic network coated BaGdF5 nanocomposites for tri-modal computed tomography/magnetic resonance/luminescence imaging. AB - Multifunctional nanocomposites based on BaGdF5 nanoparticles (NPs) and metal phenolic network (MPN) have been engineered as novel contrast agents for potential applications in X-ray computed tomography, magnetic resonance and luminescence imaging. The BaGdF5@MPN nanocomposites were synthesized at room temperature by coating BaGdF5 NPs with europium-phenolic network, which was obtained by the coordination of europium (III) with tannic acid (TA). The in vitro cytotoxicity assays against HepG2 cells revealed that the BaGdF5@MPN nanocomposites presented better cytocompatibility and lower cytotoxity than pure BaGdF5 NPs. In addition, vivid red and green luminescence can be observed by confocal laser scanning microscope (CLSM) from the BaGdF5@MPN nanocomposites laden HepG2 cells under the excitation of UV (390 nm) and visible light (440 nm), respectively. The longitudinal relaxivity value (r1) of the nanocomposites was 2.457 mM-1s-1. Moreover, the nanocomoposites exhibited X-ray computed tomography (CT) and T1-weighted magnetic resonance (MR) imaging capacities, and the intensities of the enhanced signals of in vitro CT and MR images were proportional to the concentrations of the nanocomposites. These results indicated that the as-prepared BaGdF5@MPN nanocomposites are promising contrast agents for CT/MR/luminescence imaging. PMID- 28361282 TI - Prenatal maternal distress seems to be associated with the infant's temperament and motor development: an explorative study. AB - According to the concept of fetal programming, prenatal distress has long-lasting consequences on the offspring's health later in life. The hypothalamic-pituitary adrenal axis is considered a mediating system by which maternal distress is transferred to the fetus in intrauterine environment. In this longitudinal explorative study on 30 mother-child-dyads, reported maternal distress and salivary cortisol were collected during pregnancy. Infant temperament, motor and cognitive development were assessed at 16 months. Additionally, infant cortisol levels throughout the day and in reaction to a psycho-social stressor where measured. As expected, infants whose mothers had experienced higher prenatal distress expressed a more difficult temperament and lower fine motor development at 16 months. No association could be shown between prenatal maternal distress and infant salivary cortisol. PMID- 28361283 TI - CORR Insights(r): Have the Causes of Revision for Total and Unicompartmental Knee Arthroplasties Changed During the Past Two Decades? PMID- 28361284 TI - CORR Insights(r): The 2017 ABJS Nicolas Andry Award: Advancing Personalized Medicine for Clubfoot Through Translational Research. PMID- 28361285 TI - Evaluation of lower limb kinetics during gait, sprint and hop tests before and after anterior cruciate ligament reconstruction. AB - BACKGROUND: The purpose of this study was to evaluate the functional status prior to and at different times after anterior cruciate ligament reconstruction (ACLR), and to analyze the changes in the kinetic patterns of the involved and uninvolved lower limb during gait, sprint and three hop tests. MATERIALS AND METHODS: Seventy-four male patients with an ACL injury were included in the study. All patients performed a standardized kinetic protocol including gait, sprint and three hop tests (single-leg hop, drop vertical jump and vertical jump tests), preoperatively and at 3, 6, and 12 months after ACLR with a semitendinosus gracilis tendon autograft. Measurements were performed with two force plates. The lower limb symmetry index (LSI) was calculated to determine whether a side-to side leg difference was classified as normal (LSI >90%) or abnormal (LSI <90%). RESULTS: The LSI presented high values (>90%) at almost all times before and after ACLR in gait, sprint and single-leg hop tests (p < 0.005), with a tendency to increase postoperatively. A lower LSI was observed (<90%) in tests where both extremities were tested simultaneously, such as the drop vertical jump and vertical hop tests (p < 0.05). CONCLUSION: We observed a tendency to increase symmetry restoration in the kinetics of the involved and uninvolved limb up to twelve months after ACLR, especially in those tests, in which, both limbs were tested individually (gait analysis, sprint and single-leg hop tests). Therefore, the isolation of the involved and uninvolved limb seems to be a critical component in the functional rehabilitation and evaluation of patients before and after ACLR. LEVEL OF EVIDENCE: level III. PMID- 28361287 TI - Characteristics of far eastern strains of tick-borne encephalitis virus. AB - A comparative study of biological, molecular and genetic characteristics of a collection of ten strains of tick-borne encephalitis virus (TBEV) isolated in Primorsky Krai before 1960 and stored in a lyophilized state for a prolonged period (over 65 years) is presented. The collection includes the Sofjin strain isolated from the brain of a fatal case in Primorsky Krai in 1937 and transferred to the Scientific Research Institute of Epidemiology and Microbiology (Vladivostok) in 1953. All lyophilized viral strains demonstrated great preservation and high infectious activity in the model of 2-day-old non-inbred mice. Whole-genome sequencing showed that all strains belong to the Far East TBEV subtype, comprising three clusters of Sofjin-, Oshima- and Senzhang-like strains. We show that SofjinPYB, Sofjin (Vector) and Sofjin-HO strains form a separate branch of the phylogenetic tree and are closely related to Khabarovsk-Obor-4, but not to the original Sofjin strain. The Sofjin-1953, Sofijin-Chumakov, SofjinKSY and SofjinCDC strains are genetically close to each other and can be used as reference strains for comparative analysis of the tick-borne encephalitis virus population. PMID- 28361286 TI - Quasispecies evolution of the prototypical genotype 1 porcine reproductive and respiratory syndrome virus early during in vivo infection is rapid and tissue specific. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is a major infectious threat to the pig industry worldwide. Increasing evidence suggests that microevolution within a quasispecies population can give rise to high sequence heterogeneity in PRRSV; potentially impacting the pathogenicity of the virus. Here, we report on micro-evolutionary events taking place within the viral quasispecies population in lung and lymph node 3 days post infection (dpi) following experimental in vivo infection with the prototypical Lelystad PRRSV (LV). Sequence analysis revealed 16 high frequency single nucleotide variants (SNV) or differences from the reference LV genome which are assumed to be representative of the consensus inoculum genome. Additionally, 49 other low frequency SNVs were also found in the inoculum population. At 3 dpi, a total of 9 and 10 SNVs of varying frequencies could already be detected in the LV population infecting the lung and lymph nodes, respectively. Interestingly, of these, three and four novel SNVs emerged independently in the two respective tissues when compared to the inoculum. The remaining variants, though already present at lower frequencies in the inoculum, were positively selected and their frequency increased within the quasispecies population. Hence, we were able to determine directly from tissues infected with PRRSV the repertoire of genetic variants within the viral quasispecies population. Our data also suggest that microevolution of these variants is rapid and some may be tissue-specific. PMID- 28361288 TI - Evolution of H5 highly pathogenic avian influenza: sequence data indicate stepwise changes in the cleavage site. AB - The genetic composition of an H5 subtype hemagglutinin gene quasispecies, obtained from ostrich tissues that had been infected with H5 subtype influenza virus was analysed using a next generation sequencing approach. The first evidence for the reiterative copying of a poly (U) stretch in the connecting peptide region in the haemagglutinin cleavage site (HACS) by the viral RNA dependent RNA polymerase (RdRp) is provided. Multiple non-consensus species of RNA were detected in the infected host, corresponding to likely intermediate sequences between the putative low pathogenic precursor nucleotide sequence of the H5 influenza strain and the highly pathogenic avian influenza virus gene sequence. In silico analysis of the identified RNA sequences predicted that the intermediary H5 sequence PQREKRGLF plays an important role in subsequent mutational events that relocate the HACS coding region from stable base-paired RNA regions to a single-stranded bulge, thereby priming the connecting peptide coding region for RdRp slippage. PMID- 28361289 TI - Exposure to cold impairs interferon-induced antiviral defense. AB - It is commonly believed that exposure to low temperature increases susceptibility to viral infection in the human respiratory tract, but a molecular mechanism supporting this belief has yet to be discovered. In this study, we investigated the effect of low temperature on viral infection and innate defense in cell lines from the human respiratory tract and found that interferon-induced antiviral responses were impaired at low temperatures. Cells maintained at 25 degrees C and 33 degrees C expressed lower levels of myxovirus resistance protein 1 (MxA) and 2'5'-oligoadenylate synthetase 1 (OAS1) mRNAs when compared to cells maintained at 37 degrees C after infection by seasonal influenza viruses. Exogenous beta interferon treatment reduced the viral replication at 37 degrees C, but not at 25 degrees C. Our results suggest that the impairment of interferon-induced antiviral responses by low temperature is one of several mechanisms that could explain an increase in host susceptibility to respiratory viruses after exposure to cold temperature. PMID- 28361291 TI - Belgian Neurological Society (BNS) and Belgian Dementia Council (BeDeCo) Joint Scientific Meeting University of Antwerp, Belgium, December 10th, 2016. PMID- 28361290 TI - Efficacy and safety of atazanavir/ritonavir-based antiretroviral therapy for HIV 1 infected subjects: a systematic review and meta-analysis. AB - Atazanavir (ATZ) is a well-tolerated protease inhibitor that can be boosted with ritonavir (r) to treat infection with resistant strains of human immunodeficiency virus 1 (HIV-1). The aim of this meta-analysis was to compare the efficacy, safety, and metabolic effects of ATZ/r regimen versus commonly used antiretroviral drugs such as lopinavir (LPV) and darunavir (DRV) in HIV-1 infected patients. We searched PubMed, Scopus, Embase and Cochrane CENTRAL, using relevant keywords. Data were extracted from eligible randomized trials and pooled as risk ratios (RR) or standardized mean differences (SMD) in a meta-analysis model using RevMan software. Nine randomized controlled trials (RCTs) (3292 patients) were eligible for the final analysis. After 96 weeks of treatment, the pooled effect estimate did not favor either ATZ/r or LPV/r in terms of virological failure rate (RR 1.11, 95% CI [0.74, 1.66]). However, ATZ/r was marginally superior to LPV/r in terms of increasing the proportion of patients with HIV RNA <50 copies/ml (RR 1.09, 95% CI [1.01, 1.17]). The pooled effect estimate did not favor ATZ/r over DRV/r regarding the change in plasma levels of total cholesterol, triglycerides, or high-density lipoprotein at 24, 48, and 96 weeks. Moreover, no significant difference was found between the two regimens (ATZ/r and DRV/r) in terms of change in visceral (SMD -0.06, 95%CI [-0.33, 0.21]) or subcutaneous adipose tissue (SMD 0.12, 95% CI [-0.15, 0.39]). The ATZ/r regimen was generally as effective and well-tolerated as the LPV/r regimen for the treatment of HIV-1 patients. Compared to the DRV/r regimen, ATZ/r has no favorable effect on the plasma lipid profile or adipose tissue distribution. PMID- 28361292 TI - Evidence of social deprivation on the spatial patterns of excess winter mortality. AB - OBJECTIVES: The aims of this study are to identify the patterns of excess winter mortality (due to diseases of the circulatory system) and to analyse the association between the excess winter deaths (EWD) and socio-economic deprivation in Portugal. METHODS: The number of EWD in 2002-2011 was estimated by comparing the number of deaths in winter months with the average number in non-winter months. The EWD ratio of each municipality was calculated by following the indirect standardization method and then compared with two deprivation indexes (socio-material and housing deprivation index) through ecological regression models. RESULTS: This study found that: (1) the EWD ratio showed considerable asymmetry in its geography; (2) there are significant positive associations between the EWD ratio and both deprivation indexes; and (3) at the higher level of deprivation, housing conditions have a stronger association with EWD than socio-material conditions. CONCLUSIONS: The significant association between two deprivation dimensions (socio-material and housing deprivation) and EWDs suggests that EWD geographical pattern is influenced by deprivation. PMID- 28361295 TI - Hearing sub-Saharan African voices in bioethics. PMID- 28361293 TI - Activation of liver X receptor alpha protects amyloid beta1-40 induced inflammatory and senescent responses in human retinal pigment epithelial cells. AB - OBJECTIVE: To investigate whether activation of the liver X receptors (LXRs) inhibits amyloid beta1-40 (Abeta1-40) induced inflammatory and senescent responses in human retinal pigment epithelial (RPE) cells. MATERIALS AND METHODS: Confluent cultures of human primary RPE and ARPE-19 cells pretreated with 5 MUMU of TO901317 (TO90), a synthetic agonist of LXR, or vehicle were incubated with 1 MUMU of Abeta1-40 or Abeta40-1. The optimum concentrations of Abeta1-40 and TO90 were determined by cell viability assay. Pro-inflammatory cytokines IL-6, IL-8, MCP-1 were detected by real-time polymerase chain reaction (PCR) and enzyme linked immunosorbent assay (ELISA). Expression and localization of an aging protein p16INK4a (p16) were analyzed by western blotting and immunofluorescence. Expressions of LXRs and one of their target genes ATP-binding cassette transporter A1 (ABCA1) were examined by real-time PCR and western blotting. Phosphorylated transcription inhibition factor-kappaB-alpha (p-IkappaB-alpha) was assessed by western blotting. RESULTS: A negative linear relationship between the Abeta1-40 concentration and the cell viability was evident, indicating Abeta1-40 decreased ARPE-19 cell viability in a dose-dependent manner. Abeta1-40 enhanced the expression of IL-6, IL-8, MCP-1 as well as p16 in both RPE cell lines at both mRNA and protein levels, whereas TO90 counteracted the detrimental effects. TO90 upregulated the expression of LXRalpha and its target gene ABCA1, but it did not affect the expression of LXRbeta. Meanwhile, TO90 inhibited the phosphorylation of IkappaB-alpha mediated by Abeta1-40 stimulation. CONCLUSION: Activation of the LXRalpha-ABCA1 axis may alleviate Abeta1-40 induced inflammatory and senescent responses in RPE cells. The beneficial effect appears associated with the inhibition of the NF-kappaB signaling pathway. PMID- 28361294 TI - Image-based multiscale mechanical modeling shows the importance of structural heterogeneity in the human lumbar facet capsular ligament. AB - The lumbar facet capsular ligament (FCL) primarily consists of aligned type I collagen fibers that are mainly oriented across the joint. The aim of this study was to characterize and incorporate in-plane local fiber structure into a multiscale finite element model to predict the mechanical response of the FCL during in vitro mechanical tests, accounting for the heterogeneity in different scales. Characterization was accomplished by using entire-domain polarization sensitive optical coherence tomography to measure the fiber structure of cadaveric lumbar FCLs ([Formula: see text]). Our imaging results showed that fibers in the lumbar FCL have a highly heterogeneous distribution and are neither isotropic nor completely aligned. The averaged fiber orientation was [Formula: see text] ([Formula: see text] in the inferior region and [Formula: see text] in the middle and superior regions), with respect to lateral-medial direction (superior-medial to inferior-lateral). These imaging data were used to construct heterogeneous structural models, which were then used to predict experimental gross force-strain behavior and the strain distribution during equibiaxial and strip biaxial tests. For equibiaxial loading, the structural model fit the experimental data well but underestimated the lateral-medial forces by [Formula: see text]16% on average. We also observed pronounced heterogeneity in the strain field, with stretch ratios for different elements along the lateral-medial axis of sample typically ranging from about 0.95 to 1.25 during a 12% strip biaxial stretch in the lateral-medial direction. This work highlights the multiscale structural and mechanical heterogeneity of the lumbar FCL, which is significant both in terms of injury prediction and microstructural constituents' (e.g., neurons) behavior. PMID- 28361296 TI - Women with homozygous AT deficiency type II heparin-binding site (HBS) are at high risk of pregnancy loss and pregnancy complications. AB - Data regarding outcome and therapy of pregnancies in patients with homozygous antithrombin (AT) deficiency are very rare. We conducted a retrospective, descriptive investigation with emphasis on the obstetric history of eight women with homozygous AT deficiency heparin-binding site (HBS), who had at least one pregnancy. The aim of the study was to get a better insight into the outcome and identify suitable management procedures of pregnancy in this rare disease. All patients suffered from homozygous AT deficiency caused by the mutation c.391C>T p.Leu131Phe in the AT gene (SERPINC1). The women reported in total 23 pregnancies; one pregnancy was excluded because of induced abortion. We found that only seven out of the 22 analyzed pregnancies ended with a live infant, all of them were born preterm. Among the 15 negative outcomes, seven were early pregnancy losses and eight were intrauterine fetal deaths. We found no clear association between treatment protocols and outcome. Eight pregnancies were not treated at all; all of them ended with pregnancy loss. We conclude that homozygous AT deficiency HBS, a form of severe thrombophilia, is associated with high risk of pregnancy loss and preterm delivery. Rigorous anticoagulation and/or replacement of AT during pregnancy may improve the outcome. PMID- 28361297 TI - Neuropathic pain in patients with sickle cell disease: a cross-sectional study assessing teens and young adults. AB - Chronic pain conditions are little studied and may be underestimated in sickle cell disease (SCD). The aim of this study was to identify the occurrence and characteristics of neuropathic pain (NP) in SCD patients. A sample of 56 patients was chosen from a total of 554 patients submitted to the inclusion criteria between 2015 and 2016. The Leeds assessment of neuropathic symptoms and signs scale was used for detecting NP. The groups with and without NP were compared by sex, age, use of hydroxyurea, and sensory changes through Chi-square, Fisher's exact, ANOVA, and Kruskal-Wallis tests. The average age was 20.6 years (SD +/- 4.6), 51.8% of the patients were male, and 14 patients (25%) suffered from NP. Most commonly, the pain was reported to be in the lower back area (53.6%). Age was positively related to NP: the average age in the group with NP was 22.7 years (SD +/- 4.1) and in the group without NP was 19.8 years (SD +/- 4.5), p < 0.05. Higher rates of NP occurred in patients aged 19 years or older, compared with that in teens (p < 0.01). There was a positive association between NP and the use of hydroxyurea (p < 0.05). An association was found between NP and sensitive neurological changes (p < 0.01). Therefore, screening for NP may result in faster and more effective diagnoses and consequently initiate appropriate treatment. PMID- 28361298 TI - Multidisciplinary Approach to the Management of Esophageal Malignancies. AB - INTRODUCTION: A multidisciplinary approach in the management of complex malignancies is becoming more common, and likewise, adopting such an approach to the care of patients with locally advanced esophageal is recommended in order to optimize clinical outcomes. METHODS: In this review, we discuss both the surgical and medical oncology perspectives in the management of patients with locally advanced esophageal cancer. We review the data supporting the current standard-of care approach, namely trimodality therapy with neoadjuvant chemo-radiotherapy followed by surgery. Other aspects of managing these patients including the control of dysphagia and pain as well as nutritional support are discussed. Finally, we review data that support the importance of incorporating a multidisciplinary streamlined approach in the management of these patients. RESULTS: Rather than having patients see each provider separately, a multidisciplinary approach to esophageal cancer allows for the seamless flow of communication and proactive management of the patient's symptoms. These benefits include increasing the likelihood of evidence-based decision making, shorter time to treatment, and increased patient quality of life, all of which can result in improved patient outcomes. CONCLUSION: The use of a multidisciplinary team can lead to a more accurate staging paradigm and thereby, better management decisions that translate to improved clinical outcomes. Therefore, optimizing the multidisciplinary approach for the care of patients with locally advanced esophageal cancer is essential for successful and individualized patient care. PMID- 28361300 TI - Treatment of chronic hepatitis C genotype 3 with Sofosbuvir-based therpy: a real life study. AB - BACKGROUND AND AIMS: Recently, Sofosbuvir was launched in India at affordable cost. We conducted a real-life study to determine the efficacy and safety of Sofosbuvir plus Ribavirin, with and without peginterferon-alfa 2a, in patients with chronic hepatitis C (CHC) genotype 3, the commonest genotype in South Asia. METHODS: This study included data of CHC patients from 11 sites in northern India between March 2015 and December 2015 (n = 1203). Patients with CHC genotype 3 (n = 931), who were treated with either Sofosbuvir 400 mg plus weight-based Ribavirin, daily *24 weeks (n = 432) (dual therapy), or Peginterferon-alpha2a 180 mcg weekly, Sofosbuvir 400 mg plus weight-based Ribavirin, daily *12 weeks (n = 499) (triple therapy) were included for analysis. Primary outcome was the proportion of patients achieving sustained viral response at 12 weeks post therapy. RESULTS: The overall SVR rates were 91 and 92% in the dual and triple therapy arms, respectively. The SVR rates in treatment experienced were 67 and 74% versus 93 and 96% in naive patients, on the dual and triple therapy arms, respectively. The SVR rates of cirrhotics were 73 and 75% on the dual and triple treatment arms, respectively. The SVR rates were low in the experienced cirrhotic patients: 44% (dual therapy) and 58% (triple therapy). Common adverse events were fatigue, headache, and myalgia. CONCLUSION: Both dual and triple therapy regimes resulted in SVR rates of >95% in CHC genotype 3 who were naive non-cirrhotics. However, the SVR rates were low in treatment-experienced cirrhotics. PMID- 28361301 TI - Anoxic and Oxic Oxidation of Rocks Containing Fe(II)Mg-Silicates and Fe(II) Monosulfides as Source of Fe(III)-Minerals and Hydrogen. Geobiotropy. AB - In this article, anoxic and oxic hydrolyses of rocks containing Fe (II) Mg silicates and Fe (II)-monosulfides are analyzed at 25 degrees C and 250-350 degrees C. A table of the products is drawn. It is shown that magnetite and hydrogen can be produced during low-temperature (25 degrees C) anoxic hydrolysis/oxidation of ferrous silicates and during high-temperature (250 degrees C) anoxic hydrolysis/oxidation of ferrous monosulfides. The high-T (350 degrees C) anoxic hydrolysis of ferrous silicates leads mainly to ferric oxides/hydroxides such as the hydroxide ferric trihydroxide, the oxide hydroxide goethite/lepidocrocite and the oxide hematite, and to Fe(III)-phyllosilicates. Magnetite is not a primary product. While the low-T (25 degrees C) anoxic hydrolysis of ferrous monosulfides leads to pyrite. Thermodynamic functions are calculated for elementary reactions of hydrolysis and carbonation of olivine and pyroxene and E-pH diagrams are analyzed. It is shown that the hydrolysis of the iron endmember is endothermic and can proceed within the exothermic hydrolysis of the magnesium endmember and also within the exothermic reactions of carbonations. The distinction between three products of the iron hydrolysis, magnetite, goethite and hematite is determined with E-pH diagrams. The hydrolysis/oxidation of the sulfides mackinawite/troilite/pyrrhotite is highly endothermic but can proceed within the heat produced by the exothermic hydrolyses and carbonations of ferromagnesian silicates and also by other sources such as magma, hydrothermal sources, impacts. These theoretical results are confirmed by the products observed in several related laboratory experiments. The case of radiolyzed water is studied. It is shown that magnetite and ferric oxides/hydroxides such as ferric trihydroxide, goethite/lepidocrocite and hematite are formed in oxic hydrolysis of ferromagnesian silicates at 25 degrees C and 350 degrees C. Oxic oxidation of ferrous monosulfides at 25 degrees C leads mainly to pyrite and ferric oxides/hydroxides such as ferric trihydroxide, goethite/lepidocrocite and hematite and also to sulfates, and at 250 degrees C mainly to magnetite instead of pyrite, associated to the same ferric oxides/hydroxides and sulfates. Some examples of geological terrains, such as Mawrth Vallis on Mars, the Tagish Lake meteorite and hydrothermal venting fields, where hydrolysis/oxidation of ferromagnesian silicates and iron(II)-monosulfides may occur, are discussed. Considering the evolution of rocks during their interaction with water, in the absence of oxygen and in radiolyzed water, with hydrothermal release of H2 and the plausible associated formation of components of life, geobiotropic signatures are proposed. They are mainly Fe(III)-phyllosilicates, magnetite, ferric trihydroxide, goethite/lepidocrocite, hematite, but not pyrite. PMID- 28361299 TI - Invasive and non-invasive assessment of portal hypertension. AB - Portal hypertension is the central driver of complications in patients with chronic liver diseases and cirrhosis. The diagnosis of portal hypertension has important prognostic and clinical implications. In particular, screening for varices in patients with portal hypertension can effectively reduce the morbidity and mortality of variceal bleeding. In this article, we review the invasive and non-invasive methods to assess portal hypertension. Hepatic venous pressure gradient remains the gold standard to measure portal pressure but is invasive and seldom performed outside expert centers and research settings. In recent years, a number of non-invasive tests of fibrosis have shown good correlation with liver histology. They also show promise in identifying patients with portal hypertension and large varices. As a result, the latest Baveno VI consensus guidelines endorse the use of liver stiffness measurement by transient elastography and platelet count as initial assessment to select patients for varices screening. On the other hand, the performance of non-invasive tests in assessing the response to non-selective beta-blockers or transjugular intrahepatic portosystemic shunting is either suboptimal or unclear. PMID- 28361302 TI - Transfer of Asymmetry between Proteinogenic Amino Acids under Harsh Conditions. AB - The heating above 400 degrees C of serine, cysteine, selenocysteine and threonine leads to a complete decomposition of the amino acids and to the formation in low yields of alanine for the three formers and of 2-aminobutyric acid for the latter. At higher temperature, this amino acid is observed only when sublimable alpha-alkyl-alpha-amino acids are present, and with an enantiomeric excess dependent on several parameters. Enantiopure or enantioenriched Ser, Cys, Sel or Thr is not able to transmit its enantiomeric excess to the amino acid formed during its decomposition. The presence during the sublimation decomposition of enantioenriched valine or isoleucine leads to the enantioenrichment of all sublimable amino acids independently of the presence of many decomposition products coming from the unstable derivative. All these studies give information on a potentially prebiotic key-reaction of abiotic transformations between alpha-amino acids and their evolution to homochirality. PMID- 28361303 TI - Macrophage type modulates osteogenic differentiation of adipose tissue MSCs. AB - Since the reconstruction of large bone defects remains a challenge, knowledge about the biology of bone healing is desirable to develop novel strategies for improving the treatment of bone defects. In osteoimmunology, macrophages are the central component in the early stage of physiological response after bone injury and bone remodeling in the late stage. During this process, a switch of macrophage phenotype from pro-inflammatory (M1) to anti-inflammatory (M2) is observed. An appealing option for bone regeneration would be to exploit this regulatory role for the benefit of osteogenic differentiation of osteoprogenitor cells (e.g., mesenchymal stem cells; MSCs) and to eventually utilize this knowledge to improve the therapeutic outcome of bone regenerative treatment. In view of this, we focused on the in vitro interaction of different macrophage subtypes with adipose tissue MSCs to monitor the behavior (i.e. proliferation, differentiation and mineralization) of the latter in dedicated co-culture models. Our data show that co-culture of MSCs with M2 macrophages, but not with M1 macrophages or M0 macrophages, results in significantly increased MSC mineralization caused by soluble factors. Specifically, M2 macrophages promoted the proliferation and osteogenic differentiation of MSCs, while M0 and M1 macrophages solely stimulated the osteogenic differentiation of MSCs in the early and middle stages during co-culture. Secretion of the soluble factors oncostatin M (OSM) and bone morphogenetic protein 2 (BMP-2) by macrophages showed correlation with MSC gene expression levels for OSM-receptor and BMP-2, suggesting the involvement of both signaling pathways in the osteogenic differentiation of MSCs. PMID- 28361304 TI - Parietal cells-new perspectives in glomerular disease. AB - In normal glomeruli, parietal epithelial cells (PECs) line the inside of Bowman's capsule and form an inconspicuous sheet of flat epithelial cells in continuity with the proximal tubular epithelial cells (PTECs) at the urinary pole and with the podocytes at the vascular pole. PECs, PTECs and podocytes have a common mesenchymal origin and are the result of divergent differentiation during embryogenesis. Podocytes and PTECs are highly differentiated cells with well established functions pertaining to the maintenance of the filtration barrier and transport, respectively. For PECs, no specific function other than a structural one has been known until recently. Possible important functions for PECs in the fate of the glomerulus in glomerular disease have now become apparent: (1) PECs may be involved in the replacement of lost podocytes; (2) PECs form the basis of extracapillary proliferative lesions and subsequent sclerosis in glomerular disease. In addition to the acknowledgement that PECs are crucial in glomerular disease, knowledge has been gained regarding the molecular processes driving the phenotypic changes and behavior of PECs. Understanding these molecular processes is important for the development of specific therapeutic approaches aimed at either stimulation of the regenerative function of PECs or inhibition of the pro sclerotic action of PECs. In this review, we discuss recent advances pertaining to the role of PECs in glomerular regeneration and disease and address the major molecular processes involved. PMID- 28361306 TI - Generation of Various Telencephalic Regions from Human Embryonic Stem Cells in Three-Dimensional Culture. AB - In the developing embryo, telencephalon arises from the rostral portion of the neural tube. The telencephalon further subdivides into distinct brain regions along the dorsal-ventral (DV) axis by exogenous patterning signals. Here, we describe a protocol for in vitro generation of various telencephalic regions from human embryonic stem cells (ESCs). Dissociated human ESCs are reaggregated in a low-cell-adhesion 96-well plate and cultured as floating aggregates. Telencephalic neural progenitors are efficiently generated when ESC aggregates are cultured in serum-free medium containing TGFbeta inhibitor and Wnt inhibitor. In long-term culture, the telencephalic neural progenitors acquire cortical identities and self-organize a stratified cortical structure as seen in human fetal cortex. By treatment with Shh signal, the telencephalic progenitors acquire ventral (subpallial) identities and generate lateral ganglionic eminence (LGE) and medial ganglionic eminence (MGE). In contrast, by treatment with Wnt and BMP signals, their regional identities shift to more dorsal side that generates choroid plexus and medial palllium (hippocampal primordium). PMID- 28361307 TI - Generation of a Three-Dimensional Retinal Tissue from Self-Organizing Human ESC Culture. AB - A three-dimensional (3D) tissue generated in vitro is a promising source to study developmental biology and regenerative medicine. In the last decade, Yoshiki Sasai's group have developed a 3D stem cell culture technique known as SFEBq and demonstrated that embryonic stem cells (ESCs) have an ability to self-organize stratified neural tissue including 3D-retina. Furthermore, we have reported that ESC-derived retinal tissue can form an optic cup and a ciliary margin, which are unique structures in the developing retina. In this review, we focus on self organizing culture technique to generate 3D-retina from human ESCs. PMID- 28361308 TI - 3D Culture for Self-Formation of the Cerebellum from Human Pluripotent Stem Cells Through Induction of the Isthmic Organizer. AB - Pluripotent stem cells (PSCs) possess self-organizing abilities in 3D culture. This property has been demonstrated in recent studies, including the generation of various neuroectodermal and endodermal tissues. For example, PSCs are able to differentiate into specific type of neural tissues, such as the neocortex and the optic cup, in response to local positional information brought about by signals during embryogenesis. In contrast, the generation of cerebellar tissue from PSCs requires a secondary induction by a signaling center, called the isthmic organizer, which first appears in the cell aggregate in 3D culture. Such developmental complexity of cerebellum has hampered establishment of effective differentiation culture system from PSCs, thus far.We recently reported that cerebellar neurons are generated from human PSCs (hPSCs). In this chapter, we describe an efficient protocol for differentiation of 3D cerebellar neuroepithelium from hPSCs. We also describe the protocols for further differentiation into specific neurons in the cerebellar cortex, such as Purkinje cells and the granule cells. PMID- 28361305 TI - Role of primary cilia in non-dividing and post-mitotic cells. AB - The essential role of primary (non-motile) cilia during the development of multi cellular tissues and organs is well established and is underlined by severe disease manifestations caused by mutations in cilia-associated molecules that are collectively termed ciliopathies. However, the role of primary cilia in non dividing and terminally differentiated, post-mitotic cells is less well understood. Although the prevention of cells from re-entering the cell cycle may represent a major chore, primary cilia have recently been linked to DNA damage responses, autophagy and mitochondria. Given this connectivity, primary cilia in non-dividing cells are well positioned to form a signaling hub outside of the nucleus. Such a center could integrate information to initiate responses and to maintain cellular homeostasis if cell survival is jeopardized. These more discrete functions may remain undetected until differentiated cells are confronted with emergencies. PMID- 28361309 TI - Reconstitution of a Patterned Neural Tube from Single Mouse Embryonic Stem Cells. AB - The recapitulation of tissue development and patterning in three-dimensional (3D) culture is an important dimension of stem cell research. Here, we describe a 3D culture protocol in which single mouse ES cells embedded in Matrigel under neural induction conditions clonally form a lumen containing, oval-shaped epithelial structure within 3 days. By Day 7 an apicobasally polarized neuroepithelium with uniformly dorsal cell identity forms. Treatment with retinoic acid at Day 2 results in posteriorization and self-organization of dorsal-ventral neural tube patterning. Neural tube organoid growth is also supported by pure laminin gels as well as poly(ethylene glycol) (PEG)-based artificial extracellular matrix hydrogels, which can be fine-tuned for key microenvironment characteristics. The rapid generation of a simple, patterned tissue in well-defined culture conditions makes the neural tube organoid a tractable model for studying neural stem cell self-organization. PMID- 28361310 TI - Functional Pituitary Tissue Formation. AB - The adenohypophysis, which mainly consists of anterior pituitary, plays important roles for endocrine systems by secreting several hormones indispensable for maintaining homeostasis. During early mouse development, the pituitary primordium (called Rathke's pouch) develops from oral ectoderm adjacent to ventral hypothalamus by interaction between these two tissues. By using mouse embryonic stem cells (ESCs), we recapitulated this in vivo micro-environment of the pituitary development and demonstrated that Rathke's pouch-like structures were self-formed from three-dimensional (3D) floating culture. The mouse ESC-derived Rathke's pouch-like structures subsequently differentiated into hormone-producing cells such as corticotrophs and somatotrophs. We have modified this technique for human pluripotent stem cells and recently reported that pituitary placodes can also be generated from human ESCs through a similar process. Here, we describe a protocol for human ESC culture for in vitro generation of 3D pituitary tissue. PMID- 28361311 TI - Directed Differentiation of Mouse Embryonic Stem Cells Into Inner Ear Sensory Epithelia in 3D Culture. AB - The inner ear sensory epithelium harbors mechanosensory hair cells responsible for detecting sound and maintaining balance. This protocol describes a three dimensional (3D) culture system that efficiently generates inner ear sensory epithelia from aggregates of mouse embryonic stem (mES) cells. By mimicking the activations and repressions of key signaling pathways during in vivo inner ear development, mES cell aggregates are sequentially treated with recombinant proteins and small molecule inhibitors for activating or inhibiting the Bmp, TGFbeta, Fgf, and Wnt signaling pathways. These stepwise treatments promote mES cells to sequentially differentiate into epithelia representing the non-neural ectoderm, preplacodal ectoderm, otic placodal ectoderm, and ultimately, the hair cell-containing sensory epithelia. The derived hair cells are surrounded by a layer of supporting cells and are innervated by sensory neurons. This in vitro inner ear organoid culture system may serve as a valuable tool in developmental and physiological research, disease modeling, drug testing, and potential cell based therapies. PMID- 28361312 TI - Generation of Functional Thyroid Tissue Using 3D-Based Culture of Embryonic Stem Cells. AB - During the last decade three-dimensional (3D) cultures of pluripotent stem cells have been intensively used to understand morphogenesis and molecular signaling important for the embryonic development of many tissues. In addition, pluripotent stem cells have been shown to be a valid tool for the in vitro modeling of several congenital or chronic human diseases, opening new possibilities to study their physiopathology without using animal models. Even more interestingly, 3D culture has proved to be a powerful and versatile tool to successfully generate functional tissues ex vivo. Using similar approaches, we here describe a protocol for the generation of functional thyroid tissue using mouse embryonic stem cells and give all the details and references for its characterization and analysis both in vitro and in vivo. This model is a valid approach to study the expression and the function of genes involved in the correct morphogenesis of thyroid gland, to elucidate the mechanisms of production and secretion of thyroid hormones and to test anti-thyroid drugs. PMID- 28361313 TI - Functional Tooth Regeneration. AB - Three-dimensional organogenesis in vivo is principally regulated by the spatiotemporal developmental process that relies on the cellular behavior such as cell growth, migration, differentiation, and cell-to-cell interaction. Organ development and morphogenesis have been elucidated to be regulated by the proper transient expression of various signaling molecules including cytokines, extracellular matrix, and adhesion molecules based on the epithelial and mesenchymal interactions. Current bioengineering technology for regenerating three-dimensional organ has progressed to the replication of organogenesis, thereby enabling the development of fully functional bioengineered organs using bioengineered organ germs that are generated from immature stem cells via tissue engineering technology in vitro.To achieve precise replication of organogenesis, we have developed a novel three-dimensional cell manipulation method designated the organ germ method, and enabled the generation of a structurally correct and fully functional bioengineered tooth in vivo. This method is also expected to be utilized for analyzing gene and protein functions during organogenesis. Here, we describe protocols for the tooth germ reconstitution by using the organ germ method and for the functional analysis of tooth development in vitro and in vivo. PMID- 28361314 TI - Functional Hair Follicle Regeneration by the Rearrangement of Stem Cells. AB - Hair follicles develop from the ectoderm in embryos and cyclically regenerate using proper spatiotemporal signaling molecules, which are conserved in organogenesis during adulthood. Previously, we demonstrated that bioengineered hair follicle germs could regenerate functional hair follicles via a three dimensional cell manipulation technique, which we named the "organ germ method ." We could also regulate the type of hair follicle and pigmentation with correct structures by rearranging the source of the cells. In this article, we describe a detailed protocol for the regeneration of functional hair follicles and their stem cell niches by the rearrangement of embryonic or adult hair follicle-derived epithelial and mesenchymal cells. PMID- 28361315 TI - Functional Salivary Gland Regeneration. AB - The salivary gland plays important roles in maintaining the health and homeostasis of the oral cavity by regulating functions, such as chewing, digestion, cleaning, and swallowing. Salivary gland dysfunction causes dry mouth syndrome, which includes many oral problems, such as dental caries, bacterial infection, mastication dysfunction, and swallowing dysfunction. Therefore, salivary gland regeneration is expected, and we attempted to establish a method by manual approaches. Previously, a novel three-dimensional cell manipulation technique, the "organ germ method," to create a bioengineered organ germ enabled the regeneration of structurally correct and fully functional bioengineered organs, including the teeth, hair follicles, and secretory glands, in vivo. Here, we describe the protocol for salivary gland germ regeneration using this method and the functional analysis of the regenerated salivary gland. PMID- 28361316 TI - Generation of a Bioengineered Lacrimal Gland by Using the Organ Germ Method. AB - In organogenesis including lacrimal gland development, cell arrangement within a tissue plays an important role. The lacrimal gland develops from embryonic ocular surface epithelium through reciprocal epithelial and mesenchymal interaction, which is organized by interactive regulation of various pathways of signaling molecules. Current development of an in vitro three-dimensional cell manipulation procedure to generate a bioengineered organ germ, named as the organ germ method, has shown the regeneration of a histologically correct and fully functional bioengineered lacrimal gland after engraftment in vivo. This method demonstrated a possibility of lacrimal gland organ replacement to treat dry eye disease, which has been a public health problem leading reduction of visual function. Here, we describe protocols for lacrimal gland germ regeneration using the organ germ method and methods for analyzing the function of the bioengineered lacrimal gland after its transplantation in vivo. PMID- 28361317 TI - Generation of Gastrointestinal Organoids from Human Pluripotent Stem Cells. AB - Over the past several decades, developmental biologists have discovered fundamental mechanisms by which organs form in developing embryos. With this information it is now possible to generate human "organoids" by the stepwise differentiation of human pluripotent stem cells using a process that recapitulates organ development. For the gastrointestinal tract, one of the first key steps is the formation of definitive endoderm and mesoderm, a process that relies on the TGFb molecule Nodal. Endoderm is then patterned along the anterior posterior axis, with anterior endoderm forming the foregut and posterior endoderm forming the mid and hindgut. A-P patterning of the endoderm is accomplished by the combined activities of Wnt, BMP, and FGF. High Wnt and BMP promote a posterior fate, whereas repressing these pathways promotes an anterior endoderm fate. The stomach derives from the posterior foregut and retinoic acid signaling is required for promoting a posterior foregut fate. The small and large intestine derive from the mid and hindgut, respectively.These stages of gastrointestinal development can be precisely manipulated through the temporal activation and repression of the pathways mentioned above. For example, stimulation of the Nodal pathway with the mimetic Activin A, another TGF-beta superfamily member, can trigger the differentiation of pluripotent stem cells into definitive endoderm (D'Amour et al., Nat Biotechnol 23:1534-1541, 2005). Exposure of definitive endoderm to high levels of Wnt and FGF promotes the formation of posterior endoderm and mid/hindgut tissue that expresses CDX2. Mid-hindgut spheroids that are cultured in a three-dimensional matrix form human intestinal organoids (HIOs) that are small intestinal in nature Spence et al., Nature 2011. In contrast, activation of FGF and Wnt in the presence of the BMP inhibitor Noggin promotes the formation of anterior endoderm and foregut tissues that express SOX2. These SOX2-expressing foregut spheroids can be further patterned into posterior foregut by addition of retinoic acid. Once formed, these posterior foregut spheroids can be grown in three-dimensional human gastric organoids (HGOs) that have all of the cell types of antral part of the stomach (Mc Cracken et al. 2014).Here, we describe the detailed methods for generating stomach/human gastric organoids (HGOs) and human intestinal organoids (HIOs) from human pluripotent stem cells. We first present a method for generating definitive endoderm from pluripotent stem cells followed by differentiation of definitive endoderm into either posterior foregut spheroids or mid-hindgut spheroids. We then describe how three dimensional culturing of these spheroids results in the formation of HGOs and HIOs, respectively. PMID- 28361318 TI - Generation of a Three-Dimensional Kidney Structure from Pluripotent Stem Cells. AB - The kidney is a vital organ that has an important role in the maintenance of homeostasis by fluid volume regulation and waste product excretion. This role cannot be performed without the three-dimensional (3D) structure of the kidney. Therefore, it is important to generate the 3D structure of the kidney when inducing functional kidney tissue or the whole organ from pluripotent stem cells. In this chapter, we describe the detailed methods to induce kidney progenitor cells from pluripotent stem cells, which are based on embryological development. We also provide a method to generate 3D kidney tissue with vascularized glomeruli upon transplantation. PMID- 28361319 TI - Making a Kidney Organoid Using the Directed Differentiation of Human Pluripotent Stem Cells. AB - An organoid can be defined as a three-dimensional organ-like structure formed from organ-specific progenitor cells. Organ progenitor cells were empirically found to self-organize three-dimensional tissues when they were aggregated and cultivated in vitro. While this nature power of progenitor cells has an amazing potential to recreate artificial organs in vitro, there had been difficulty to apply this technology to human organs due to the inaccessibility to human progenitor cells until human-induced pluripotent stem cell (hiPSC) was invented by Takahashi and Yamanaka in 2007. As embryonic stem cells do, hiPSCs also have pluripotency to give rise to any organs/tissues cell types, including the kidney, via directed differentiation. Here, we provide a detailed protocol for generating kidney organoids using human pluripotent stem cells. The protocol differentiates human pluripotent stem cells into the posterior primitive streak. This is followed by the simultaneous induction of posterior and anterior intermediate mesoderm that are subsequently aggregated and undergo self-organization into the kidney organoid. Such kidney organoids are comprised of all anticipated kidney cell types including nephrons segmented into the glomerulus, proximal tubule, loop of Henle, and distal tubule as well as the collecting duct, endothelial network, and renal interstitium. PMID- 28361320 TI - Liver Regeneration Using Cultured Liver Bud. AB - Here, we describe a protocol to develop a three-dimensional (3D) liver bud-like tissue from human iPSCs in vitro. This method mainly consists of two parts: (1) hepatic endoderm (HE) differentiation from human iPSCs in 2D culture and (2) co culturing iPSC-HE with endothelial and mesenchymal cells. First, iPSCs were differentiated into definitive endoderm (DE) cells, and the DE cells were differentiated into HE cells, which were then co-cultured with endothelial cells and mesenchymal cells on Matrigel-coated plastic plates or micropattern plates. The cells rapidly condensed to generate 3D tissue masses. We named these iPSC liver buds (iPSC-LBs) because they resemble the developing liver bud from the perspective of gene expression, cell proliferation, and cell proportion. This liver bud culture system provides a novel approach for future clinical applications, for drug development, and as a tool for studying human development. PMID- 28361321 TI - Formation of Stomach Tissue by Organoid Culture Using Mouse Embryonic Stem Cells. AB - In this chapter, we describe a method for the induction of stomach organoids from mouse embryonic stem (ES) cells. We used an embryoid body-based differentiation method to induce gastric primordial epithelium covered with mesenchyme and further differentiate it in Matrigel by 3D culture. The differentiated organoid contains both corpus- and antrum-specific mature gastric tissue cells. This protocol may be useful for a variety of studies in developmental biology and disease modeling of the stomach. PMID- 28361322 TI - In Vivo Model of Small Intestine. AB - The utilization of human pluripotent stem cells (hPSCs) offers new avenues in the generation of organs and opportunities to understand development and diseases. The hPSC-derived human intestinal organoids (HIOs) provide a new tool to gain insights in small intestinal development, physiology, and associated diseases. Herein, we provide a method for orthotropic transplantation of HIOs in immunocompromised mice. This method highlights the specific steps to successful engraftment and provides insight into the study of bioengineered human small intestine. PMID- 28361323 TI - SLIDE: automatic spine level identification system using a deep convolutional neural network. AB - PURPOSE: Percutaneous spinal needle insertion procedures often require proper identification of the vertebral level to effectively and safely deliver analgesic agents. The current clinical method involves "blind" identification of the vertebral level through manual palpation of the spine, which has only 30% reported accuracy. Therefore, there is a need for better anatomical identification prior to needle insertion. METHODS: A real-time system was developed to identify the vertebral level from a sequence of ultrasound images, following a clinical imaging protocol. The system uses a deep convolutional neural network (CNN) to classify transverse images of the lower spine. Several existing CNN architectures were implemented, utilizing transfer learning, and compared for adequacy in a real-time system. In the system, the CNN output is processed, using a novel state machine, to automatically identify vertebral levels as the transducer moves up the spine. Additionally, a graphical display was developed and integrated within 3D Slicer. Finally, an augmented reality display, projecting the level onto the patient's back, was also designed. A small feasibility study [Formula: see text] evaluated performance. RESULTS: The proposed CNN successfully discriminates ultrasound images of the sacrum, intervertebral gaps, and vertebral bones, achieving 88% 20-fold cross-validation accuracy. Seventeen of 20 test ultrasound scans had successful identification of all vertebral levels, processed at real-time speed (40 frames/s). CONCLUSION: A machine learning system is presented that successfully identifies lumbar vertebral levels. The small study on human subjects demonstrated real-time performance. A projection-based augmented reality display was used to show the vertebral level directly on the subject adjacent to the puncture site. PMID- 28361324 TI - Coffee: the key to safer image-guided surgery-a granular jamming cap for non invasive, rigid fixation of fiducial markers to the patient. AB - PURPOSE: Accurate image guidance requires a rigid connection between tracked fiducial markers and the patient, which cannot be guaranteed by current non invasive attachment techniques. We propose a new granular jamming approach to firmly, yet non-invasively, connect fiducials to the patient. METHODS: Our granular jamming cap surrounds the head and conforms to the contours of the patient's skull. When a vacuum is drawn, the device solidifies in a manner conceptually like a vacuum-packed bag of ground coffee, providing a rigid structure that can firmly hold fiducial markers to the patient's skull. By using the new Polaris Krios optical tracker, we can also use more fiducials in advantageous configurations to reduce registration error. RESULTS: We tested our new approach against a clinically used headband-based fiducial fixation device under perturbations that could reasonably be expected to occur in a real-world operating room. In bump testing, we found that the granular jamming cap reduced average TRE at the skull base from 2.29 to 0.56 mm and maximum TRE at the same point from 7.65 to 1.30 mm. Clinically significant TRE reductions were also observed in head repositioning and static force testing experiments. CONCLUSION: The granular jamming cap concept increases the robustness and accuracy of image guided sinus and skull base surgery by more firmly attaching fiducial markers to the patient's skull. PMID- 28361325 TI - Intravascular endoscopy improvement through narrow-band imaging. AB - PURPOSE: Recent advances in endoscopy have led to new technologies with significant optical imaging improvements. Since its development a few years ago, narrow-band imaging (NBI) has already been proved useful in detecting malignant lesions and carcinoma in clinical settings of urology, gastroenterology and ENT. The potential of this technology for imaging applications of the arterial vessel wall has not been properly analysed yet, but with the observed benefits could prove valuable for this clinical use as well. METHODS: In order to assess the efficacy of NBI, defects such as burns and mechanical tears were created on the walls of an arterial vessel sample. Ex vivo imaging using NBI and white light imaging (WLI) were performed with rigid and flexible fibre endoscopes. RESULTS: A thorough comparison of the images proved that NBI enhances the visualisation of lesions and defects on the artery walls compared to normal WLI. CONCLUSION: WLI provides a direct image of the vessel lumen and its anatomical shape. It is suitable for observation and documentation of intravascular therapies. NBI images are more distinct and have more contrast. This helps to detect even small defects or changes on the inner vessel wall that could provide additional information and lead to more precise and personalised therapies. PMID- 28361326 TI - Translation, validation, and cross-cultural adaption of the Western Ontario Meniscal Evaluation Tool (WOMET) into German. AB - PURPOSE: The Western Ontario Meniscal Evaluation Tool (WOMET) was developed in order to investigate the health-related quality of life of patients with meniscal pathologies. The aim of the present study was to translate and validate the WOMET into German. METHODS: A standardized forward backward translation of the WOMET into German was first performed. One hundred ninety-two patients with isolated meniscal tears completed the German version of the WOMET as well as the Western Ontario McMasters University Arthritis Index, and the Knee Osteoarthritis Outcome Score. Furthermore, reliability, construct validity, feasibility, internal consistency, ceiling, and floor effects were then calculated. RESULTS: Excellent feasibility (85.4% fully complete questionnaire), internal consistency (Cronbach's alpha = 0.92), and test-retest reliability (ICC, r = 0.90) were found. The standard error of measurement and the minimal detectable change were +/-4.6 and 12.7 points, respectively. All predefined hypothesises were confirmed. No floor or ceiling effects were found. CONCLUSIONS: The presented German version of the WOMET is a valid and reliable tool for investigating the health-related quality of life of German-speaking patients with meniscal pathologies. LEVEL OF EVIDENCE: Cross-sectional study, Level II. PMID- 28361327 TI - How Much Rugby is Too Much? A Seven-Season Prospective Cohort Study of Match Exposure and Injury Risk in Professional Rugby Union Players. AB - INTRODUCTION: Numerous studies have documented the incidence and nature of injuries in professional rugby union, but few have identified specific risk factors for injury in this population using appropriate statistical methods. In particular, little is known about the role of previous short-term or longer-term match exposures in current injury risk in this setting. OBJECTIVES: Our objective was to investigate the influence that match exposure has upon injury risk in rugby union. METHOD: We conducted a seven-season (2006/7-2012/13) prospective cohort study of time-loss injuries in 1253 English premiership professional players. Players' 12-month match exposure (number of matches a player was involved in for >=20 min in the preceding 12 months) and 1-month match exposure (number of full-game equivalent [FGE] matches in preceding 30 days) were assessed as risk factors for injury using a nested frailty model and magnitude-based inferences. RESULTS: The 12-month match exposure was associated with injury risk in a non-linear fashion; players who had been involved in fewer than ~15 or more than ~35 matches over the preceding 12-month period were more susceptible to injury. Monthly match exposure was linearly associated with injury risk (hazard ratio [HR]: 1.14 per 2 standard deviation [3.2 FGE] increase, 90% confidence interval [CI] 1.08-1.20; likely harmful), although this effect was substantially attenuated for players in the upper quartile for 12-month match exposures (>28 matches). CONCLUSION: A player's accumulated (12-month) and recent (1-month) match exposure substantially influences their current injury risk. Careful attention should be paid to planning the workloads and monitoring the responses of players involved in: (1) a high (>~35) number of matches in the previous year, (2) a low (<~15) number of matches in the previous year, and (3) a low-moderate number of matches in previous year but who have played intensively in the recent past. These findings make a major contribution to evidence-based policy decisions regarding match workload limits in professional rugby union. PMID- 28361328 TI - The past, present and future of the postanesthesia care unit (PACU) in Japan. AB - The postanesthesia care unit (PACU), which is run and coordinated by anesthesiologists, delivers general medical supervision as well as close and constant care to patients who have just undergone a surgical procedure under anesthesia. Although PACU management has been considered a standard procedure in many developed countries since the 1940s, Japanese hospitals have tended to cease their management, and only 16.1% of hospitals in Japan currently have PACUs. In today's efficiency-required atmosphere in Japan, we need to consider a better postoperative management method, including facilities similar to the PACU, to prevent serious adverse events and improve the postoperative outcomes and quality of life. Nevertheless, the way postoperative patients are treated and cared for, and the location in which they receive such attention, will likely need to be modified to fit the Japanese style due to Japan's unique medical systems and traditions. Here, we describe the past, present and future of the PACU and postanesthesia care in Japan compared with other countries. PMID- 28361329 TI - Implementation of safeguards to improve patient safety in chemotherapy. AB - PURPOSE: To evaluate the effectiveness of safeguards introduced in the process of using cytostatic agents for increasing the safety of oncology patients. METHODS: Prospective hospital study conducted in two stages, before and after the implementation of safeguards: staff training, standardized procedures, computerized prescription, pharmaceutical validation, implementation of bar codes, and a new manual on drug interactions. Medication errors (MEs) were actively recorded during the process of administering chemotherapy in the Medical Oncology Department. The study classified MEs by the stage of the medication process in which they occurred and assessed their severity. RESULTS: 500 patients, 250 before implementing safeguards and 250 afterward, were included in this study . Out of all patients included before, 43.1% had at least 1 error, compared to 27% of those included later. The number of MEs detected before and after was 144 vs. 95: 125 vs. 55 prescription errors, 2 vs. 5 validation errors, 14 vs. 4 preparation errors, 3 vs. 1 dispensation errors and 0 vs. 30 administration errors. The number of MEs that reached the patient before and after safeguard implementation was 16.7% vs. 6.3%. After the safeguards were introduced, all MEs that could have caused harm or required monitoring of some kind were prevented. CONCLUSIONS: Implementing safeguards in the hospital's cytostatic treatment cycle is useful for preventing MEs. Computerized prescription, pharmaceutical validation, and the creation/dissemination of proper work procedures are effective barriers that keep MEs from reaching the patient. Administering chemotherapy with a bar-code system facilitates detection error detection at this stage of the cycle and prevents them from reaching the patient. PMID- 28361331 TI - ANCA-Associated Vasculitis Pathogenesis: A Commentary. AB - PURPOSE OF REVIEW: The ANCA-associated vasculitides are a group of small vessel vasculitides characterized by autoantibodies recognizing the neutrophil cytoplasmic antigens PR3 and MPO. We examine the current clinical and molecular immunology understanding of ANCA-associated vasculitides and discuss the current needs in our understanding of the pathogenic mechanisms of these rare diseases. RECENT FINDINGS: The majority of efforts to understand the pathogenesis of these diseases have focused on dissecting neutrophil biology because the neutrophil is the primary expressor of ANCA autoantigens. However, a number of important genetic, clinical, and cellular biology observations suggest that attempts to understand the pathogenesis of ANCA vasculitides should move away from emphasis on the role of the neutrophil and instead re-focus on the potential role of other immune cell mediators. Whether or not neutrophils are the key determinant of ANCA associated vasculitis pathogenesis should be revisited in detail. A neutrophil centric view of the pathogenesis of these diseases cannot fully account for important genetic, clinical, and cellular biology observations that implicate important and under-appreciated roles for monocytes and T cells. Refocusing on these findings will likely lead to new discovery of novel therapeutic targets and the identification of clinically useful biomarkers for disease activity. PMID- 28361330 TI - The Paradox of Bone Formation and Bone Loss in Ankylosing Spondylitis: Evolving New Concepts of Bone Formation and Future Trends in Management. AB - PURPOSE OF REVIEW: The purpose of the study is to briefly review the molecular mechanisms that leads to structural damage in ankylosing spondylitis (AS), defined as new bone formation resulting in complete or incomplete ankylosis of the spine, and the impact of treatment with biologics to retard this process. RECENT FINDINGS: The understanding of molecular mechanisms leading to new bone formation in AS has significantly improved but is still incomplete. Availability of biologics has greatly enhanced the treatment of patients with AS, but its impact on slowing the structural damage is still a matter of debate, although a few observational studies have shown that long term use of TNF-alpha blockers may slow radiographic progression. The availability of newer biologics targeting IL 17/1L23 has shown some promising results in slowing radiographic progression in AS. Although the availability of TNF-inhibitors has greatly enhanced the treatment options for patients with AS, their impact on slowing the structural damage is still not clearly established. However, preliminary results using newer biologics targeting IL-17/1L23 axis are more encouraging but longer follow-up is needed. PMID- 28361332 TI - Managing Cardiovascular Disease Risk in Rheumatoid Arthritis: Clinical Updates and Three Strategic Approaches. AB - : ?: The increase in cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) is well known; however, appropriate management of this elevated risk in rheumatology clinics is less clear. PURPOSE OF REVIEW: By critically reviewing literature published within the past 5 years, we aim to clarify current knowledge and gaps regarding CVD risk management in RA. RECENT FINDINGS: We examine recent guidelines, recommendations, and evidence and discuss three approaches: (1) RA specific management including treat-to-target and medication management, (2) assessment of comprehensive individual risk, and (3) targeting traditional CVD risk factors (hypertension, smoking, hyperlipidemia, diabetes, obesity, and physical inactivity) at a population level. Considering that 75% of US RA visits occur in specialty clinics, further research is needed regarding evidence-based strategies to manage and reduce CVD risk in RA. This review highlights clinical updates including US cardiology and international professional society guidelines, successful evidence-based population approaches from primary care, and novel opportunities in rheumatology care to reduce CVD risk in RA. PMID- 28361333 TI - In the Pursuit of Methotrexate Treatment Response Biomarker in Juvenile Idiopathic Arthritis-Are We Getting Closer to Personalised Medicine? AB - PURPOSE OF REVIEW: Methotrexate (MTX) is the most widely used disease-modifying antirheumatic drug (DMARD) in paediatric rheumatology and the mainstay in the therapy of juvenile idiopathic arthritis (JIA). Despite its common use, about 30% of children fail to respond to this medicine that results in potentially irreversible joint damage. RECENT FINDINGS: No clinical biomarker that would predict the outcome of MTX therapy exists. Results of several studies focused on gene polymorphisms and outcome of this DMARD therapy have been published, but no reliable genetic marker useful to tailor the therapy has been discovered so far. The results of the first genome-wide association study in this field have recently revealed new genetic candidates from outside the metabolic pathway of MTX that may be associated with the efficacy of treatment. However promising, those outcomes need validation in independent prospective cohorts before we can claim that clinically useful biomarker predicting MTX treatment response is discovered. PMID- 28361334 TI - Chronic Recurrent Multifocal Osteomyelitis and Related Diseases-Update on Pathogenesis. AB - PURPOSE OF REVIEW: We focus on recent advances in the understanding of the genetic, molecular, immunologic, and environmental factors implicated in the pathogenesis of autoinflammatory bone diseases including the syndromic and non syndromic forms of chronic recurrent multifocal osteomyelitis (CRMO). RECENT FINDINGS: Evidence implicating the IL-1 pathway in the pathogenesis of the Mendelian forms of CRMO is growing. LIPIN2 can regulate the NLRP3 inflammasome by affecting P2X7 receptor activation, and intracellular cholesterol can modulate P2X7R currents. Work in a mouse model of CRMO demonstrates that dietary manipulation can alter the microbiome and protect these mice from the development of sterile osteomyelitis in vivo. Although the genetic and immunologic basis of non-syndromic CRMO remains only partially understood, the IL-1 pathway is central to the pathogenesis in the syndromic autoinflammatory bone disorders. Recent work implicates lipids and the microbiome in sterile osteomyelitis. PMID- 28361336 TI - Setting the light conditions for measuring root transparency for age-at-death estimation methods. AB - Age-at-death estimation is one of the main goals in forensic identification, being an essential parameter to determine the biological profile, narrowing the possibility of identification in cases involving missing persons and unidentified bodies. The study of dental tissues has been long considered as a proper tool for age estimation with several age estimation methods based on them. Dental age estimation methods can be divided into three categories: tooth formation and development, post-formation changes, and histological changes. While tooth formation and growth changes are important for fetal and infant consideration, when the end of dental and skeletal growth is achieved, post-formation or biochemical changes can be applied. Lamendin et al. in J Forensic Sci 37:1373 1379, (1992) developed an adult age estimation method based on root transparency and periodontal recession. The regression formula demonstrated its accuracy of use for 40 to 70-year-old individuals. Later on, Prince and Ubelaker in J Forensic Sci 47(1):107-116, (2002) evaluated the effects of ancestry and sex and incorporated root height into the equation, developing four new regression formulas for males and females of African and European ancestry. Even though root transparency is a key element in the method, the conditions for measuring this element have not been established. The aim of the present study is to set the light conditions measured in lumens that offer greater accuracy when applying the Lamendin et al. method modified by Prince and Ubelaker. The results must be also taken into account in the application of other age estimation methodologies using root transparency to estimate age-at-death. PMID- 28361337 TI - Chronic Stressors and Adolescents' Externalizing Problems: Genetic Moderation by Dopamine Receptor D4. The TRAILS Study. AB - The existing literature does not provide consistent evidence that carriers of the Dopamine D4 Receptor 7-repeat allele are more sensitive to adverse environmental influences, resulting in enhanced externalizing problems, compared to noncarriers. One explanation is that the adverse influences examined in prior studies were not severe, chronic, or distressing enough to reveal individual differences in sensitivity reflected by DRD4-7R. This study examined whether the 7-repeat allele moderated the association between chronic stressors capturing multiple stressful aspects of individuals' lives and externalizing problems in adolescence. We expected that chronic stressor levels would be associated with externalizing levels only in 7-repeat carriers. Using Linear Mixed Models, we analyzed data from 1621 Dutch adolescents (52.2% boys), obtained in three measurement waves (mean age approximately 11, 13.5, and 16 years) from the TRacking Adolescents' Individual Lives Survey (TRAILS) population-based birth cohort and the parallel clinic-referred cohort. Across informants, we found that higher levels of chronic stressors were related to higher externalizing levels in 7-repeat carriers but not in noncarriers, as hypothesized. Although previous studies on the 7-repeat allele as a moderator of environmental influences on adolescents' externalizing problems have not convincingly demonstrated individual differences in sensitivity to adverse environmental influences, our findings suggest that adolescent carriers of the Dopamine D4 Receptor 7-repeat allele are more sensitive to chronic, multi-context stressors than noncarriers. PMID- 28361335 TI - Endosomal Redox Signaling in the Antiphospholipid Syndrome. AB - PURPOSE OF REVIEW: It is well established that the antiphospholipid syndrome (APS) is caused by antiphospholipid antibodies (aPL). While several underlying mechanisms have been described in the past, many open questions remain. Here, we will review data on endosomal signaling and, in particular, redox signaling in APS. RECENT FINDINGS: Endosomal redox signaling has been implicated in several cellular processes including signaling of proinflammatory cytokines. We have shown that certain aPL can activate endosomal NADPH-oxidase (NOX) in several cell types followed by induction of proinflammatory and procoagulant cellular responses in vitro. Involvement of endosomes in aPL signaling has also been reported by others. In wild-type mice but not in NOX-deficient mice, aPL accelerate venous thrombus formation underscoring the relevance of endosomal NOX. Furthermore, hydroxychloroquine (HCQ) inhibits activation of endosomal NOX and prevents thrombus formation in aPL-treated mice. Endosomal redox signaling is an important novel mechanism involved in APS pathogenesis. This makes endosomes a potential target for future treatment approaches of APS. PMID- 28361338 TI - Maternal Executive Functioning and Scaffolding in Families of Children with and without Parent-Reported ADHD. AB - Parental scaffolding robustly predicts child developmental outcomes, including improved self-regulation and peer relationships and fewer externalizing behaviors. However, few studies have examined parental characteristics associated with a parent's ability to scaffold. Executive functioning (EF) may be an important individual difference factor associated with maternal scaffolding that has yet to be examined empirically. Scaffolding may be particularly important for children with attention-deficit/hyperactivity disorder (ADHD) and disruptive behavior disorder (DBD) symptoms due to their core difficulties with inattention, disorganization, EF, and self-regulation, their need for greater parental structure, and higher-than-average rates of parental EF deficits. Yet, little research has examined child ADHD in relation to parental scaffolding. This cross sectional study examined: (1) the association between maternal EF (as measured by the Hotel Test, Barkley's Deficits in Executive Functioning Scale, and Digit Span) and observed scaffolding, (2) the association between parent-reported child ADHD/DBD symptoms and scaffolding, and (3) the interaction between child ADHD/DBD symptoms and maternal EF in predicting scaffolding. In a sample of 84 mothers and their 5-10 year-old biological children (62% male) with and without parent reported ADHD, we found that maternal EF, as measured by Digit Span and the Hotel Test, predicted observed maternal scaffolding. However, child ADHD/DBD symptoms did not significantly predict maternal scaffolding controlling for child age, maternal education, and maternal EF, nor did the interaction of maternal EF and parent-reported child ADHD/DBD symptoms. Working memory and task shifting may be key components of parental EF that could be targeted in interventions to improve parental scaffolding. PMID- 28361339 TI - Use of Antihypertensive Drugs in Neoplastic Patients. AB - The introduction of Vascular Endothelial Growth Factor (VEGF) signaling pathway inhibitor treatment has highlighted the role of the baseline activity of the VEFG system for blood pressure regulation. VEGF signaling pathway is associated with hypertension and proteinuria. Activation of the endothelin system, endothelial dysfunction and capillary rarefaction are among the underlying mechanisms possibly explaining the rise in blood pressure and, to some extent, also the renal injury. The hypertension induced by VEGF signaling pathway inhibition is, usually, responsive to treatment. Recommendations about the management of cardiovascular toxicity in patients receiving VEGF signaling pathway inhibitors include a formal cardiovascular risk assessment before initiation of VEGF signaling pathway inhibitor treatment, active monitoring of blood pressure and cardiac toxicity throughout treatment, with more frequent monitoring during the first cycles of therapy, given that marked and unpredictable blood pressure rises can occur early after treatment with a VEGF signaling pathway inhibitor, and aggressive management of blood pressure elevations and early symptoms and signs of cardiac toxicity to prevent clinically limiting complications. In patients with preexisting hypertension, the blood pressure target for initiating VEGF signaling pathway inhibitor treatment should be <140/90 mmHg. Blockers of the renin-angiotensin system and calcium channel antagonists are among the drugs to be preferably used in these clinical conditions. PMID- 28361340 TI - Overall survival and prognostic factors in patients with spinal metastases from lung cancer treated with and without epidermal growth factor receptor tyrosine kinase inhibitors. AB - BACKGROUND: Evaluation of the prognosis in patients with spinal metastases is important in decision making regarding surgical treatment. The purpose of this study was to investigate overall survival in patients with spinal metastases from lung cancer by histological subtype, and to investigate prognostic factors in patients treated with and without epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). METHODS: The data from 135 patients diagnosed with spinal metastases from lung cancer were retrospectively evaluated. The 88 patients with adenocarcinoma were divided into two groups according to whether the lung cancer was treated with or without EGFR-TKIs-the EGFR-TKI group (n = 43) and the non-EGFR-TKI group (n = 45). RESULTS: The overall median survival time was 11.3 months for those with adenocarcinoma, 5.3 months for squamous cell carcinoma, and 3.9 months for small cell carcinoma. Overall survival in the EGFR TKI group (median 21.4 months) was significantly longer than in the non-EGFR-TKI group (median 6.1 months). In univariate analysis, poor performance status was a poor prognostic factor in the non-EGFR-TKI group. However, performance status and other variables were not significant prognostic factors in the EGFR-TKI group. CONCLUSIONS: Median overall survival was longer in patients with spinal metastases from lung cancer treated with EGFR-TKIs compared with those treated without EGFR-TKIs. Poor performance status or other prognostic factors were not associated with poor overall survival in the group treated with EGFR-TKIs. PMID- 28361341 TI - Cot kinase plays a critical role in Helicobacter pylori-induced IL-8 expression. AB - Helicobacter pylori is a major pathogen causing various gastric diseases including gastric cancer. Infection of H. pylori induces pro-inflammatory cytokine IL-8 expression in gastric epithelial cells in the initial inflammatory process. It has been known that H. pylori can modulate Ras-Raf-Mek-Erk signal pathway for IL-8 induction. Recently, it has been shown that another signal molecule, cancer Osaka thyroid oncogene/tumor progression locus 2 (Cot/Tpl2) kinase, activates Mek and Erk and plays a role in the Erk pathway, similar to MAP3K signal molecule Raf kinase. Therefore, the objective of this study was to determine whether Cot kinase might be involved in IL-8 induction caused by H. pylori infection. AGS gastric epithelial cells were infected by H. pylori strain G27 or its isogenic mutants lacking cagA or type IV secretion system followed by treatment with Cot kinase inhibitor (KI) or siRNA specific for Cot kinase. Activation of Erk was assessed by Western blot analysis and expression of IL-8 was measured by ELISA. Treatment with Cot KI reduced both transient and sustained Erk activation. It also reduced early and late IL-8 secretion in the gastric epithelial cell line. Furthermore, siRNA knockdown of Cot inhibited early and late IL-8 secretion induced by H. pylori infection. Taken together, these results suggest that Cot kinase might play a critical role in H. pylori type IV secretion apparatus-dependent early IL-8 secretion and CagA-dependent late IL-8 secretion as an alternative signaling molecule in the Erk pathway. PMID- 28361343 TI - Erratum to: A computationally simplistic poly-phasic approach to explore microbial communities from the Yucatan aquifer as a potential sources of novel natural products. PMID- 28361344 TI - Cerebral aneurysms and metastases occurring as a delayed complication of resected atrial Myxoma: Imaging findings including high resolution Vessel Wall MRI. PMID- 28361342 TI - Potential use of lactic acid bacteria Leuconostoc mesenteroides as a probiotic for the removal of Pb(II) toxicity. AB - It has been demonstrated that certain lactic acid bacteria (LAB) can sequester metal ions by binding them to their surfaces. In the present study, lead (Pb) resistant LAB were isolated from kimchi, a Korean fermented food. A total of 96 different LAB strains were isolated, and 52 strains showed lead resistance. Among them, an LAB strain-96 (L-96) identified as Leuconostoc mesenteroides showed remarkable Pb resistance and removal capacity. The maximum adsorption capacity of this strain calculated using the Langmuir isotherm was 60.6 mg Pb/g. In an in vivo experiment, young male mice were provided with water (A), Pb-water (B), or Pb-water+ L-96 (C) during puberty. Lower glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) levels in Pb-exposed male mice that received strain L-96 as a probiotic were suggestive of reduced hepatotoxicity. Moreover, feces from mice treated with L-96 contained more Pb than feces from untreated mice. Increased Pb elimination likely reduced internal accumulation, and this hypothesis was supported by significantly lower Pb concentrations in kidneys and testes of the mice treated with strain L-96. The motility and ATP content of epididymal spermatozoa were partially restored if strain L-96 was administered. In conclusion, isolated L-96 LAB had lead biosorption activity and efficiently detoxified lead-poisoned male mice, resulting in recovering male reproductive function. These results suggest the potential use of LAB as a probiotic to protect humans from the adverse effects of Pb exposure. PMID- 28361346 TI - Redesigning the diagnostic pathway for chest pain patients in emergency departments. AB - Patients presenting with chest pain at an emergency department in the United Kingdom receive troponin tests to assess the likelihood of an acute myocardial infarction (AMI). Until recently, serial testing with two blood samples separated by at least six hours was necessary in order to analyse the change in troponin levels over time. New high-sensitivity troponin tests, however, allow the inter test time to be shortened from six to three hours. Recent evidence also suggests that the new generation of troponin tests can be used to rule out AMI on the basis of a single test if patients at low risk of AMI present with very low cardiac troponin levels more than three hours after onset of worst pain. This paper presents a discrete event simulation model to assess the likely impact on the number of hospital admissions if emergency departments adopt strategies for serial and single testing based on the use of high-sensitivity troponin. Data sets from acute trusts in the South West of England are used to quantify the resulting benefits. PMID- 28361345 TI - Altered structural connectivity of pain-related brain network in burning mouth syndrome-investigation by graph analysis of probabilistic tractography. AB - PURPOSE: Burning mouth syndrome (BMS) is a chronic intraoral pain syndrome featuring idiopathic oral pain and burning discomfort despite clinically normal oral mucosa. The etiology of chronic pain syndrome is unclear, but preliminary neuroimaging research has suggested the alteration of volume, metabolism, blood flow, and diffusion at multiple brain regions. According to the neuromatrix theory of Melzack, pain sense is generated in the brain by the network of multiple pain-related brain regions. Therefore, the alteration of pain-related network is also assumed as an etiology of chronic pain. In this study, we investigated the brain network of BMS brain by using probabilistic tractography and graph analysis. METHODS: Fourteen BMS patients and 14 age-matched healthy controls underwent 1.5T MRI. Structural connectivity was calculated in 83 anatomically defined regions with probabilistic tractography of 60-axis diffusion tensor imaging and 3D T1-weighted imaging. Graph theory network analysis was used to evaluate the brain network at local and global connectivity. RESULTS: In BMS brain, a significant difference of local brain connectivity was recognized at the bilateral rostral anterior cingulate cortex, right medial orbitofrontal cortex, and left pars orbitalis which belong to the medial pain system; however, no significant difference was recognized at the lateral system including the somatic sensory cortex. A strengthened connection of the anterior cingulate cortex and medial prefrontal cortex with the basal ganglia, thalamus, and brain stem was revealed. CONCLUSION: Structural brain network analysis revealed the alteration of the medial system of the pain-related brain network in chronic pain syndrome. PMID- 28361347 TI - Testing the influence of gravity on flower symmetry in five Saxifraga species. AB - Flower symmetry is considered a species-specific trait and is categorized in asymmetry, actinomorphic symmetry, bisymmetry and zygomorphic symmetry. Here we report on the intra-individual variation of flower symmetry in the genus Saxifraga and the influence of light, gravity and intrinsic factors on the development of flower symmetry. We tested five species-Saxifraga cuneifolia, Saxifraga imparilis, Saxifraga rotundifolia, Saxifraga stolonifera and Saxifraga umbrosa-concerning six flower parameters-angles between petals, petal length, petal pigmentation, angular position of carpels, movement of stamens and (only for S. imparilis and S. stolonifera) the length of the two lower elongated petals in regard to their position towards the stem. Specimens of all species were tested on a vertical clinostat as a gravity compensator, on a horizontal clinostat as a light incidence compensator and on a stationary control. The results show that the angle of incident light has no apparent impact on flower symmetry, whereas gravity affects the angular position of petals in S. cuneifolia and S. umbrosa and the petal colouration in S. rotundifolia. In S. cuneifolia and S. umbrosa, the absence of directional gravity resulted in the development of actinomorphic flowers, whereas the corresponding control flowers were zygomorphic. The development of flowers in S. rotundifolia was not altered by this treatment. The length of the two elongated petals in S. stolonifera and S. imparilis was not affected by gravity, but rather was determined by position of the flower within the inflorescence and resulted in asymmetrical flowers. PMID- 28361348 TI - Controlling enzymatic activity by immobilization on graphene oxide. AB - In this study, graphene oxide (GO) has been applied as a matrix for enzyme immobilization. The protein adsorption capacity of GO is much higher than of other large surface area carbonaceous materials. Its structure and physicochemical properties are reported beneficial also for enzymatic activity modifications. The experimental proof was done here that GO-based biocatalytic systems with immobilized catalase are modifiable in terms of catalyzed reaction kinetic constants. It was found that activity and stability of catalase, considered here as model enzyme, closely depend on enzyme/GO ratio. The changes in kinetic parameters can be related to secondary structure alterations. The correlation between enzyme/GO ratio and kinetic and structure parameters is reported for the first time and enables the conscious control of biocatalytic processes and their extended applications. The biological activity of obtained biocatalytic systems was confirmed in vitro by the use of functional test. The addition of immobilized catalase improved the cells' viability after they were exposed to hydrogen peroxide and tert-butyl-hydroperoxide used as source of reactive oxygen species. PMID- 28361349 TI - Impact of the EARL harmonization program on automatic delineation of metabolic active tumour volumes (MATVs). AB - BACKGROUND: The clinical validation of the EARL harmonization program for standardised uptake value (SUV) metrics is well documented; however, its potential for defining metabolic active tumour volume (MATV) has not yet been investigated. We aimed to compare delineation of MATV on images reconstructed using conventional ordered subset expectation maximisation (OSEM) with those reconstructed using point spread function modelling (PSF-reconstructed images), and either optimised for diagnostic potential (PSF) or filtered to meet the EANM/EARL harmonising standards (PSF7). METHODS: Images from 18 stage IIIA-IIIB lung cancer patients were reconstructed using all the three methods. MATVs were then delineated using both a 40% isocontour and a gradient-based method. MATVs were compared by means of Bland-Altman analyses, and Dice coefficients and concordance indices based on the unions and intersections between each pair of reconstructions (PSF vs OSEM, PSF7 vs PSF and PSF7 vs OSEM). RESULTS: Using the 40% isocontour method and taking the MATVs delineated on OSEM images as a reference standard, the use of PSF7 images led to significantly higher Dice coefficients (median value = 0.96 vs 0.77; P < 0.0001) and concordance indices (median value = 0.92 vs 0.64; P < 0.0001) than those obtained using PSF images. The gradient-based methodology was less sensitive to reconstruction variability than the 40% isocontour method; Dice coefficients and concordance indices were superior to 0.8 for both PSF reconstruction methods. However, the use of PSF7 images led to narrower interquartile ranges and significantly higher Dice coefficients (median value = 0.96 vs 0.94; P = 0.01) and concordance indices (median value = 0.89 vs 0.85; P = 0.003) than those obtained with PSF images. CONCLUSION: This study demonstrates that automatic contouring of lung tumours on EARL-compliant PSF images using the widely adopted automatic isocontour methodology is an accurate means of overcoming reconstruction variability in MATV delineation. Although gradient-based methodology appears to be less sensitive to reconstruction variability, the use of EARL-compliant PSF images significantly improved the Dice coefficients and concordance indices, demonstrating the importance of harmonised-images, even when more advanced contouring algorithms are used. PMID- 28361350 TI - FOXM1 transcriptionally regulates expression of integrin beta1 in triple-negative breast cancer. AB - PURPOSE: Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer and associated with early metastasis, drug resistance, and poor patient survival. Fork head box M1 (FOXM1) is considered as an emerging molecular target due to its oncogenic role and high overexpression profile in 85% in TNBC. However, molecular mechanisms by which FOXM1 transcription factor mediate its oncogenic effects are not fully understood. Integrin beta1 is often upregulated in invasive breast cancers and associated with poor clinical outcome and shorter overall patient survival in TNBC. However, the mechanisms regulating integrin beta1 (ITGB1) gene expression have not been well elucidated. METHODS: Normal breast epithelium (MCF10A) and TNBC cells (i.e., MDA-MB-231, BT-20 MDA-MB436) were used for the study. Small interfering RNA (siRNA)-based knockdown was used to inhibit Integrin beta1 gene (mRNA) and protein expressions, which are detected by RT-PCR and Western blot, respectively. Chromatin immunoprecipitation (ChiP) and gene reporter (Luciferase) assays were used to demonstrate that FOXM1 transcription factor binds to the promoter of Integrin beta1 gene and drives its expression. RESULTS: We demonstrated that FOXM1 directly binds to the promoter of integrin beta1 gene and transcriptionally regulates its expression and activity of focal adhesion kinase (FAK) in TNBC cells. CONCLUSION: Our study suggests that FOXM1 transcription factor regulates Integrin beta1 gene expression and that FOXM1/ Integrin-beta1/FAK axis may play an important role in the progression of TNBC. PMID- 28361351 TI - Glenohumeral position during CT arthrography with arthroscopic correlation: optimization of diagnostic yield. AB - OBJECTIVE: To evaluate the diagnostic yield of two acquisitions of single contrast CT arthrography (CTA) of the shoulder in internal, neutral, or external glenohumeral rotation with arthroscopic correlation. MATERIALS AND METHODS: The CT study was obtained using two acquisitions (first the humerus positioned in maximum tolerated external rotation with the arm along the body and the second with the humerus in internal rotation with the palm placed flat on the table). Two independent readers blinded to the arthroscopic results evaluated the CTA images for labral tears, glenoid bone loss/fractures, and cartilage loss. For each CTA acquisition, sensitivity and specificity for detection of the aforementioned pathology were assessed. Inter-reader agreement was quantified by weighted K statistics. RESULTS: Sensitivity and specificity for detecting anteroinferior or posterior labral tears was highest with neutral rotation (sensitivity 91-100%, specificity 61-100%). For glenoid fracture, sensitivity (67%) was highest with external rotation and specificity (100%) was highest with internal rotation. For cartilage loss, sensitivity (64%) and specificity (89%) was highest with external rotation and neutral rotation, respectively. Neutral rotation showed high sensitivity and specificity for glenoid fractures and cartilage loss. Inter-reader agreement ranged from fair to very good. CONCLUSIONS: Neutral glenohumeral position in shoulder CT arthrography was adequately sensitive and specific for the detection of intra-articular pathology, avoiding the use of more than one acquisition. PMID- 28361352 TI - Small, superficial, indeterminate soft-tissue lesions as suspected sarcomas: is primary excision biopsy suitable? AB - OBJECTIVE: Suspected soft-tissue sarcomas are typically investigated using magnetic resonance imaging (MRI), with a view to planning image-guided core needle biopsy for confirmation of the histological diagnosis. Indeterminate superficial lesions may be small and therefore potentially difficult to biopsy safely, such lesions possibly being more amenable to primary excision biopsy. The aim of this study is to determine the suitability of this practice in the setting of a specialist sarcoma service. MATERIALS AND METHODS: All patients referred over a 12-month period to the sarcoma service with a small (<3-cm), indeterminate, superficial soft-tissue mass according to MRI criteria, or a small lesion of the hand or foot deemed unsafe for percutaneous biopsy, and who underwent primary excision biopsy were included. The histology results were categorized into neoplastic and non-neoplastic lesions, and assessed for resection completeness. RESULTS: Fifty-eight patients fulfilled the inclusion criteria from all patients referred to the sarcoma service in a 12-month period. Of these, 42 out of 58 (72.4%) had benign neoplasms, 4 out of 58 (6.9%) had malignant tumours, 2 out of 58 (3.4%) an intermediate grade lesion, while 10 out of 58 (17.2%) were non-neoplastic. All 4 malignant lesions were completely excised at the time of excision biopsy. CONCLUSIONS: Primary excision biopsy of small, indeterminate soft-tissue masses within the setting of a specialist sarcoma service is a suitable management option. Only a small proportion of small superficial soft-tissue lesions with indeterminate MRI features are malignant tumours. PMID- 28361353 TI - Erratum to: Neurobiology of local and intercellular BDNF signaling. PMID- 28361354 TI - The diagnosis of neglected tropical diseases (NTDs) in Italy: comment. PMID- 28361355 TI - Redox status alterations during the competitive season in elite soccer players: focus on peripheral leukocyte-derived ROS. AB - It is well known that exercise training can deeply affect redox homeostasis by enhancing antioxidant defenses. However, exhaustive exercise can induce excessive reactive oxygen species (ROS) production, leading to oxidative stress-related tissue injury and impaired muscle contractility. Hence, ROS represent important signaling molecules whose level has to be maintained to preserve normal cellular function, but which can also accumulate in response to repetitive muscle contraction. In fact, low levels of oxidants have been suggested to be essential for muscle contraction. Both aerobic and anaerobic exercise induce ROS production from several sources (mitochondria, NADPH oxidases and xanthine oxidases); however, the exact mechanisms underlying exercise-induced oxidative stress remain undefined. Professional athletes show a high risk for oxidative stress, and consequently muscle injury or decreased performance. Based on this background, we investigated leukocyte redox homeostasis alterations during the soccer season in elite soccer players. Overall blood redox status was investigated in twenty-seven male soccer players from primary division (Italian "Serie A" team) at four critical time points during the soccer season: T0: just before the first team training session; T1: at the beginning of the season; T2: in the middle of the season and T3: at the end of the season. The main markers of muscular damage (CK, myoglobin, LDH), assessed by standard routine methods, are significantly altered at the considered time points (T0 vs T1 P < 0.01). In peripheral leukocyte subpopulations, ROS production shows significant alterations at the considered time points during the soccer season, and strictly and significantly correlates with CK values at every considered time point. Our experimental data indicate that deep redox homeostasis alterations are evident during the soccer season in elite soccer players, and that oxidative stress can be easily monitored, besides using the standard plasma biochemical parameters, by leukocyte ROS production analysis. PMID- 28361358 TI - [Compression of the median nerve by chronic palmar dislocation of the lunate due to carpal collapse]. AB - Carpal tunnel syndrome is among the most frequently diagnosed forms of peripheral nerve compression. Carpal tunnel syndrome due to carpal collapse that had progressed over decades, with a palmarly dislocated lunate, is rare. Hints of past trauma to the wrist going back decades should prompt further radiological examination in case of recurrent median nerve compression. With sufficient preoperative evaluation, the causes can be accurately detected and treated. Therefore, precise and complete history-taking is mandatory. Conclusions on further diagnostics that can be drawn from the latter must be consistently implemented to enable adequate therapy. PMID- 28361356 TI - [Pathophysiology of atopic blepharokeratoconjunctivitis]. AB - Atopic dermatitis (AD) is a systemic inflammatory disease, which is characterized by pronounced eczema and pruritus. In addition to the involvement of the entire integument, the periocular lid skin and the surface of the eye are frequently involved. Ocular involvement may occur solely without dermatitis of facial or body skin. Pathophysiologically, besides a dysregulated immune response, genetic changes can occur in various dermal structural proteins which will lead to a disturbed skin barrier. Furthermore, there is a regular colonization with bacterial pathogens and an increased susceptibility for viral skin infections. The lid margin reveals a loss of Meibomian glands whereas the conjunctiva shows reduced goblet cells. Consecutively, eye surface defects and recurrent conjunctival and corneal defects can be found. Increased mechanical manipulation in atopia-associated pruritus is seen as a cause of increased comorbidity with keratoconus. In addition, individual cases are reported of various malignomas of the eye surface, which are present in patients with AD. Understanding of the pathophysiological connections is essential for the correct diagnosis and therapy of this clinically very complex disease picture. PMID- 28361357 TI - Increasing accuracy of pulse transit time measurements by automated elimination of distorted photoplethysmography waves. AB - Photoplethysmography (PPG) is a widely available non-invasive optical technique to visualize pressure pulse waves (PWs). Pulse transit time (PTT) is a physiological parameter that is often derived from calculations on ECG and PPG signals and is based on tightly defined characteristics of the PW shape. PPG signals are sensitive to artefacts. Coughing or movement of the subject can affect PW shapes that much that the PWs become unsuitable for further analysis. The aim of this study was to develop an algorithm that automatically and objectively eliminates unsuitable PWs. In order to develop a proper algorithm for eliminating unsuitable PWs, a literature study was conducted. Next, a '7Step PW Filter' algorithm was developed that applies seven criteria to determine whether a PW matches the characteristics required to allow PTT calculation. To validate whether the '7Step PW-Filter' eliminates only and all unsuitable PWs, its elimination results were compared to the outcome of manual elimination of unsuitable PWs. The '7Step PW-Filter' had a sensitivity of 96.3% and a specificity of 99.3%. The overall accuracy of the '7Step PW-Filter' for detection of unsuitable PWs was 99.3%. Compared to manual elimination, using the '7Step PW Filter' reduces PW elimination times from hours to minutes and helps to increase the validity, reliability and reproducibility of PTT data. PMID- 28361359 TI - Medical Student Oncology Congress: Designed and Implemented by Brazilian Medical Students. AB - Oncology is an essential field of medicine; however, its teaching is occasionally underemphasized and uncoordinated during medical school. An alternative method of providing additional oncological information to medical students is through extracurricular activities, such as congresses and medical student associations. The aim of this paper is to describe a Medical Student Oncology Congress entirely designed and organized by medical students. Three medical students from oncology study and research groups identified the gap in oncology training at universities and decided to organize a congress for students. They selected representatives from 26 universities in Brazil for onsite registration and created a website for online registration and promotion of the congress. To determine the topics of the lectures, they searched the medical literature for the most commonly occurring cancers in adults and children. Extrapolating the academic content of oncology, they organized lectures by non-governmental organizations (NGOs), talks on career guidance and research in this field as well as a role-playing workshop to train future doctors on how to deliver news to patients. There were a total of 609 attendees, with 590 students from 26 different universities in Brazil. Approximately 82% were medical students, and among the participants there were also 15 medical educators. A total of 80.75% of the participants were extremely satisfied with the congress, and 99.17% would recommend it to a colleague. Most of the overall cost of the congress, 96%, was covered by registration fees. There was a 6% positive net balance, which was donated to the NGOs participating in the congress. This successful experience proves that it is possible to have a congress fully designed, organized and managed by students. It demonstrates how students can be active participants in their own education, as opposed to a classic approach through which only professors are responsible for instruction. PMID- 28361360 TI - Feasibility of Providing Web-Based Information to Breast Cancer Patients Prior to a Surgical Consult. AB - Patients facing decisions for breast cancer surgery commonly search the internet. Directing patients to high-quality websites prior to the surgeon consultation may be one way of supporting patients' informational needs. The objective was to test an approach for delivering web-based information to breast cancer patients. The implementation strategy was developed using the Replicating Effective Programs framework. Pilot testing measured the proportion that accepted the web-based information. A pre-consultation survey assessed whether the information was reviewed and the acceptability to stakeholders. Reasons for declining guided refinement to the implementation package. Eighty-two percent (309/377) accepted the web-based information. Of the 309 that accepted, 244 completed the pre consultation survey. Participants were a median 59 years, white (98%), and highly educated (>50% with a college degree). Most patients who completed the questionnaire reported reviewing the website (85%), and nearly all found it helpful. Surgeons thought implementation increased visit efficiency (5/6) and would result in patients making more informed decisions (6/6). The most common reasons patients declined information were limited internet comfort or access (n = 36), emotional distress (n = 14), and preference to receive information directly from the surgeon (n = 7). Routine delivery of web-based information to breast cancer patients prior to the surgeon consultation is feasible. High stakeholder acceptability combined with the low implementation burden means that these findings have immediate relevance for improving care quality. PMID- 28361361 TI - In vitro antioxidant and antidiabetic activities of zinc oxide nanoparticles synthesized using different plant extracts. AB - Phytofabricated green synthesis of zinc oxide (ZnO) nanoparticles using different plant extracts of Azadirachta indica, Hibiscus rosa-sinensis, Murraya koenigii, Moringa oleifera, and Tamarindus indica for biological applications has been reported. ZnO nanoparticles were also synthesized by chemical method to compare the efficiency of the green synthesized nanoparticles. FT-IR spectra confirmed the functional groups involved in the green synthesis of ZnO nanoparticles and the powder XRD patterns of the ZnO nanoparticles revealed pure wurtzite structure with preferred orientation at (100) reflection plane. SEM and TEM analysis revealed the spherical shape of the synthesized ZnO nanoparticles with the particle size between 54 and 27 nm. The antioxidant activity was evaluated by five different free radical scavenging assays. The present study also intends to screen alpha-amylase and alpha-glucosidase activity of ZnO nanoparticles synthesized using natural sources, which may minimize the toxicity and side effects of the inhibitors used to control diabetes. The ZnO nanoparticles synthesized using T. indica extract displayed remarkable antioxidant and antidiabetic activities. PMID- 28361362 TI - Functional disruption of peroxiredoxin by bismuth antiulcer drugs attenuates Helicobacter pylori survival. AB - Bismuth drugs have been used clinically to treat infections from Helicobacter pylori, a pathogen that is strongly related to gastrointestinal diseases even stomach cancer. Despite extensive studies, the mechanisms of action of bismuth drugs are not fully understood. Alkyl hydroperoxide reductase subunit C (AhpC) is the most abundant 2-cysteine peroxiredoxin, crucial for H. pylori survival in the host by defense of oxidative stress. Herein we show that a Bi(III) antiulcer drug (CBS) binds to the highly conserved cysteine residues (Cys49 and Cys169) with a dissociation constant (K d) of Bi(III) to AhpC of 3.0 (+/-1.0) * 10-24 M. Significantly the interaction of CBS with AhpC disrupts the peroxiredoxin and chaperone activities of the enzyme both in vitro and in bacterial cells, leading to attenuated bacterial survival. Moreover, using a home-made fluorescent probe, we demonstrate that Bi(III) also perturbs AhpC relocation between the cytoplasm and membrane region in decomposing the exogenous ROS. Our study suggests that disruption of redox homeostasis by bismuth drugs via interaction with key enzymes such as AhpC contributes to their antimicrobial activity. PMID- 28361363 TI - Fine mapping and candidate gene analysis of qFL-chr1, a fiber length QTL in cotton. AB - KEY MESSAGE: A fiber length QTL, qFL-chr1, was fine mapped to a 0.9 cM interval of cotton chromosome 1. Two positional candidate genes showed positive correlation between gene expression level and fiber length. Prior analysis of a backcross-self mapping population derived from a cross between Gossypium hirsutum L. and G. barbadense L. revealed a QTL on chromosome 1 associated with increased fiber length (qFL-chr1), which was confirmed in three independent populations of near-isogenic introgression lines (NIILs). Here, a single NIIL, R01-40-08, was used to develop a large population segregating for the target region. Twenty-two PCR-based polymorphic markers used to genotype 1672 BC4F2 plants identified 432 recombinants containing breakpoints in the target region. Substitution mapping using 141 informative recombinants narrowed the position of qFL-chr1 to a 1.0-cM interval between SSR markers MUSS084 and CIR018. To exclude possible effects of non-target introgressions on fiber length, different heterozygous BC4F3 plants introgressed between SSR markers NAU3384 and CGR5144 were selected to develop sub NILs. The qFL-chr1 was further mapped at 0.9-cM interval between MUSS422 and CIR018 by comparisons of sub-NIL phenotype, and increased fiber length by ~1 mm. The 2.38-Mb region between MUSS422 and CIR018 in G. barbadense contained 19 annotated genes. Expression levels of two of these genes, GOBAR07705 (encoding 1 aminocyclopropane-1-carboxylate synthase) and GOBAR25992 (encoding amino acid permease), were positively correlated with fiber length in a small F2 population, supporting these genes as candidates for qFL-chr1. PMID- 28361364 TI - Spontaneous and complete regeneration of a vertebra plana after surgical curettage of an eosinophilic granuloma. AB - PURPOSE: The eosinophilic granuloma is a unifocal or multifocal Langerhans cell histiocytosis characterized by an expanding proliferation of Langerhans cells in bones. Skeletal LCH is a rare condition, and vertebral regeneration in cases of vertebral body collapse is even rarer. We report the case of a girl with spontaneous complete healing. METHODS AD RESULTS: A 3-year-old girl was referred for nighttime back pain, with no fever and no neurologic signs. Within a few days, she developed sudden painful restriction of all spine movements. X-ray and computed tomography (CT) of the spine showed reduced T7 vertebral body height (vertebra plana).The patient underwent T7 curettage and the histopathological exam was suggestive of LCH. Two additional skull lesions were found and therefore she underwent chemotherapy. After 7 years of follow-up, total vertebral reconstruction was observed. CONCLUSIONS: Despite the rarity of the condition and despite the rarity of vertebral body lesion resolution, total vertebral body reconstruction was observed over a 7-year period. Long-term follow-up is necessary for a better understanding of the final outcome of patients with EG. PMID- 28361365 TI - Acute non-traumatic idiopathic spinal subdural hematoma: radiographic findings and surgical results with a literature review. AB - PURPOSE: Intraspinal hematoma is a serious condition, and early diagnosis is necessary to permit emergency treatment. Among such hematomas, non-traumatic spinal subdural hematoma is a rare occurrence. We have experienced three patients with surgically proven subdural spinal hematoma, and here we report these cases with a review of their clinical and imaging characteristics. METHODS: All three cases were idiopathic with no history of disease, no coagulopathy, and no trauma. All had acute onset that brought about paralysis of the lower limbs with severe pain. Early surgery was performed, based on a relatively early diagnosis using thoracolumbar MRI and CT. RESULTS: Since the epidural fat is not affected by bleeding, the normal structure remains and the boundary between hematoma and fat is a significant feature in MRI and CT. Partial Gd enhancement in MRI and ring enhancement in contrast CT were also apparent. Two of the cases had subarachnoid hematomas. CONCLUSIONS: Preoperative diagnosis of spinal subarachnoid hematoma is difficult because there are no specific radiological findings and confirmation can only occur intraoperatively. In particular, one case had a massive hematoma causing canal stenosis, and it was difficult to distinguish between intradural and extradural hematoma. In all cases of subarachnoid or subdural hematoma, decompression was performed within 24 h after onset, and consequently, the patients had relatively good outcomes. PMID- 28361366 TI - A rare invasive hemangioma in cauda equina. AB - PURPOSE: Typical hemangioma of cauda equina with relative clear margin has been described in some case reports, but atypical hemangioma with invasion, infiltration, and augmentation of all nerve roots in the cauda equina area has never been reported. In this paper, we reported a rare case with invasive hemangioma in cauda equina, and analyzed its radiological appearance and treatment. METHODS: We described an atypical case of hemangioma, which was revealed by MR and intraoperative photograph without clear margin and confirmed by histopathologic diagnosis. RESULTS: The patient was received radiotherapy (5400 cGy/25f/5w) and continued to be clinically in good condition with follow-up MR after 24 months without further surgery. CONCLUSIONS: Surgery may be the first management modality for hemangiomas with severe or progressive neurologic deficits, and radiotherapy may be an alternative therapy to treat hemangiomas according to accurate histopathologic diagnosis. PMID- 28361368 TI - Multiple intradural-extramedullary spinal ependymomas including tumors with different histological features. AB - INTRODUCTION: We report a rare case with multiple intradural-extramedullary spinal ependymomas with different histological features. CASE REPORT: A 26-year old female presented to our hospital because of difficulty in walking due to progressive paresis. Magnetic resonance imaging of the thoracic spinal cord showed multiple spinal cord tumors. Surgical resection of these tumors was performed and a different histological diagnosis including World Health Organization Grade III anaplastic ependymoma and Grade II ependymoma was obtained using the resected specimen. Additional radiotherapy and chemotherapy were also performed, and a successful outcome has been maintained for at least 3 years after surgery. CONCLUSION: Surgical resections and subsequent radiotherapy and chemotherapy for cases with multiple intradural-extramedullary ependymomas can result in a good postoperative course. PMID- 28361370 TI - Expert's comment concerning Grand Rounds case entitled "Floating lumbar spine: proposed mechanism with review of literature" (K. Das et al., Eur Spine J. doi:10.1007/s00586-016-4690-2). PMID- 28361367 TI - Three-column osteotomy for correction of cervical and cervicothoracic deformities: alignment changes and early complications in a multicenter prospective series of 23 patients. AB - PURPOSE: Three-column osteotomy (3CO), including pedicle subtraction osteotomy (PSO) and vertebral column resection (VCR), can provide powerful alignment correction for adult cervical deformity (ACD). Our objective was to assess alignment changes and early complications associated with 3CO for ACD. METHODS: ACD patients treated with 3CO with minimum 90-day follow-up were identified from a prospectively collected multicenter ACD database. Complications within 90-days of surgery and pre- and postoperative radiographs were collected. RESULTS: All 23 ACD patients treated with 3CO (14 PSO/9 VCR) had minimum 90-day follow-up (mean age 62.3 years, previous cervical/cervicothoracic instrumentation in 52.2% and thoracic/thoracolumbar instrumentation in 47.8%). The primary diagnosis was kyphosis in 91.3% and coronal deformity in 8.7%. The mean number of fusion levels was 12 (range 6-18). The most common 3CO levels were T1 (39.1%), T2 (30.4%) and T3 (21.7%). Eighteen (12 major/6 minor) complications affected 13 (56.5%) patients. The most common complications were neurologic deficit (17.4%), wound infection (8.7%), distal junctional kyphosis (DJK 8.7%), and cardiorespiratory failure (8.7%). Three (13.0%) patients required re-operation within 90-days (1 each for nerve root motor deficit, DJK, and implant pain/prominence). Cervical alignment improved significantly following 3CO, including cervical lordosis (-2.8 degrees to -12.9 degrees , p = 0.036), C2-7 sagittal vertical axis (64.6-42.3 mm, p < 0.001), and T1 slope minus cervical lordosis (46.4 degrees -27.0 degrees , p < 0.001). CONCLUSIONS: Among 23 ACD patients treated with 3CO, cervical alignment improved significantly following surgery. Thirteen (56.5%) patients had at least one complication. The most common complications were neurologic deficit, infection, DJK, and cardiorespiratory failure. PMID- 28361369 TI - Lack of improvement in health-related quality of life (HRQOL) scores 6 months after surgery for adult spinal deformity (ASD) predicts high revision rate in the second postoperative year. AB - PURPOSE: ASD is assessed radiologically with the spinopelvic parameters and clinically with HRQOL scores. The revision rate after ASD surgery is high and usually occurs during the first or second postoperative year. The aim of this study is to find clinical or radiological factors that could predict revision surgery in the second postoperative year. MATERIALS AND METHODS: Inclusion criterion: ASD patients operated on by instrumented posterior fusion with more than 2 years follow-up were enrolled prospectively. Additional criterion was no revision surgery during the first postoperative year. From a multicenter database of 560 operated ASD patients, 164 patients met these criteria. The patients were divided into two groups depending on the need of revision surgery during the second postoperative year. Preoperative, 6-month, 1-year and 2-year data were collected and compared for both groups. RESULTS: A total of 22 patients needed revision surgery and 142 did not. All revisions were for mechanical complications (non-fusion and implant related). Preoperatively, there was a significant difference between the groups (no revision vs. revision) for age (48 vs. 60 years), ODI (37 vs. 53), and SVA (29 vs. 76 mm), respectively. At 6 months, a significant difference in sagittal alignment was found, though HRQOL scores were similar. At 1 year, the no revision group scores improved, whereas the revision group scores remained stable or worsened. At 2 years, the no revision group scores remained stable. Comparing 6- and 12-month data, patients with improved, stable and worsened HRQOL scores had 8, 15 and 28% revision rates, respectively. CONCLUSION: The revision rate at the second-year post-surgery (13.4%) remains high and demonstrated that a 2-year follow-up is mandatory. In addition to usual risk factors for mechanical complications in ASD surgery, stabilization or worsening of the HRQOL scores between the 6th and 12th month postop was highly predictive of revision rate. This observation is beneficial for ASD patient follow-up as clinical symptoms clearly precede mechanical failure. PMID- 28361371 TI - Regional differences in health-related quality of life in elderly heart failure patients: results from the CIBIS-ELD trial. AB - AIM: Patient-reported outcomes such as health-related quality of life (HRQoL) are main treatment goals for heart failure (HF) and therefore endpoints in multinational therapy trials. However, little is known about country-specific differences in HRQoL and in treatment-associated HRQoL improvement. The present work sought to examine those questions. METHODS AND RESULTS: We analysed data from the Cardiac Insufficiency Bisoprolol Study in Elderly (CIBIS-ELD) trial, in which patients from central and south-eastern Europe completed the HRQoL questionnaire SF-36 at baseline and the end of a 12-week beta-blocker up titration (follow-up). 416 patients from Serbia (mean age 72.21 years, 69% NYHA class I-II, 27.4% women) and 114 from Germany (mean age 73.64 years, 78.9% NYHA class I-II, 47.4% women) were included. Controlling for clinical variables, the change in mental HRQoL from baseline to follow-up was modulated by Country: Serbian patients, M baseline = 37.85 vs. M follow-up = 40.99, t(526) = 5.34, p < .001, reported a stronger increase than Germans, M baseline = 37.66 vs. M follow up = 38.23, t(526) = 0.68, ns. For physical HRQoL, we observed a main effect of Country, M Serbia = 39.28 vs. M Germany = 35.29, t(526) = 4.24, p < .001. CONCLUSION: We observed significant differences in HF patients from Germany and Serbia and country-specific differences between Serbian and German patients in mean physical HRQoL. Changes in mental HRQoL were modulated by country. Those results may reflect psychological, sociocultural, aetiological differences or regional differences in phenotype prevalence. More importantly, they suggest that future multinational trials should consider such aspects when designing a trial in order to avoid uncertainties aligned to data interpretation and to improve subsequent treatment optimisation. PMID- 28361372 TI - State-of-the-Art: a Review of Cardiovascular Effects of Testosterone Replacement Therapy in Adult Males. AB - PURPOSE OF REVIEW: According to an Endocrine Society Clinical Practice Guideline published in June 2010, testosterone replacement therapy (TRT) should be administered only to men who are hypogonadal with documented low testosterone level on two morning measurements. This recommendation was based on previous studies that did not show an increased risk in cardiovascular events with TRT. In contrast, recent studies did show an increased risk which prompted the FDA to investigate further. RECENT FINDINGS: Multiple studies suggested an increased risk in cardiovascular events among groups of men prescribed TRT. There is recent evidence that TRT can be associated with higher cardiovascular risks, while these risks are still not well established, and more well-designed trials are needed. Physicians should always be cautious when prescribing TRT to their patients. Potential risks should be discussed with each patient, and TRT requires regular monitoring to help minimize side effects. PMID- 28361373 TI - Methylmercury Exposure Reduces the Auditory Brainstem Response of Zebra Finches (Taeniopygia guttata ). AB - Mercury contamination from mining and fossil fuel combustion causes damage to humans and animals worldwide. Mercury exposure has been implicated in mammalian hearing impairment, but its effect on avian hearing is unknown. In this study, we examined whether lifetime dietary mercury exposure affected hearing in domestic zebra finches (Taeniopygia guttata) by studying their auditory brainstem responses (ABRs). Zebra finches exposed to mercury exhibited elevated hearing thresholds, decreased amplitudes, and longer latencies in the ABR, the first evidence of mercury-induced hearing impairment in birds. Birds are a more appropriate model for the human auditory spectrum than most mammals because of similarities in frequency discrimination, vocal learning, and communication behavior. When mercury is considered in combination with other anthropogenic stressors such as noise pollution and habitat alteration, the hearing impairments we document here could substantially degrade avian auditory communication in wild birds. PMID- 28361375 TI - Impaired Recognition of Basic Emotions from Facial Expressions in Young People with Autism Spectrum Disorder: Assessing the Importance of Expression Intensity. AB - It has been proposed that impairments in emotion recognition in ASD are greater for more subtle expressions of emotion. We measured recognition of 6 basic facial expressions at 8 intensity levels in young people (6-16 years) with ASD (N = 63) and controls (N = 64) via an Internet platform. Participants with ASD were less accurate than controls at labelling expressions across intensity levels, although differences at very low levels were not detected due to floor effects. Recognition accuracy did not correlate with parent-reported social functioning in either group. These findings provide further evidence for an impairment in recognition of basic emotion in ASD and do not support the idea that this impairment is limited solely to low intensity expressions. PMID- 28361374 TI - Spatial Gradients in the Size of Inner Hair Cell Ribbons Emerge Before the Onset of Hearing in Rats. AB - The size and locations of pre-synaptic ribbons and glutamate receptors within and around inner hair cells are correlated with auditory afferent response features such as the spontaneous discharge rate (SR), threshold, and dynamic range of sound intensity representation (the so-called SR-groups). To test if the development of these spatial gradients requires experience with sound intensity, we quantified the size and spatial distribution of synaptic ribbons from the inner hair cells of neonatal rats before and after the onset of hearing (from post-natal day (P) 3 to P33). To quantify ribbon size, we used high resolution fluorescence confocal microscopy and 3-D reconstructions of immunolabeled ribbons. The size, density, and spatial distribution of ribbons changed during development. At P3, ribbons were densely clustered near the basal/modiolar face of the hair cell where low SR-groups preferentially contact adult hair cells. By P12, the disparity in ribbon count was less striking and ribbons were equally likely to occupy both faces. At all ages before P12, ribbons were larger on the modiolar face than on the pillar face. These differences initially grew larger with age but collapsed around the onset of hearing. Between P12 and P33, the spatial gradients remained small and began to re-emerge around P33. Even by P12, we did not find spatial gradients in the size of the post-synaptic glutamate receptors as is found on afferent terminals contacting adult inner hair cells. These results suggest that spatial gradients in ribbon size develop in the absence of sensory experience. PMID- 28361376 TI - Treatment with teriparatide for advanced bisphosphonate-related osteonecrosis of the jaw around dental implants: a case report. AB - We report a case of a 66-year-old severely osteoporotic woman with bisphosphonate related osteonecrosis of the jaw (BRONJ) around her dental implants, who was treated successfully with teriparatide and sequestrectomy of the mandible. After 5 months of teriparatide therapy, the sequestrum separation had progressed and a sequestrectomy was performed under general anesthesia. Five months after the operation, new bone formation was observed around the bone defect in the region of the sequestrectomy. A repeat computed tomographic image revealed improvement in the bone defect in the mandible. These results suggest that teriparatide provides beneficial effects in the treatment of advanced BRONJ around dental implants. PMID- 28361377 TI - Alveolar ridge preservation with autologous particulated dentin-a case series. AB - INTRODUCTION: Ridge preservation can be performed with autologous bone, alloplastic bone substitute material or a combination of both. Dentin is similar to bone in its chemical composition. In its use as bone substitute material, it undergoes a remodelling process and transforms to bone. The presented case report introduces a technique in which the extraction socket is augmented with autologous, particulated dentin. MATERIAL AND METHODS: The fractured, non-savable mesial incisor of the upper jaw was carefully extracted in axial direction. After the extraction, the tooth was cleared from remaining periodontal tissue. The vital pulp tissue or a root canal filling, enamel and cementum were also removed. Following the particulation of the remaining dentin in a bone mill, the dentin particles were immediately filled orthotope into the alveolar socket. The soft tissue closure was performed with a free gingival graft of the palate. RESULTS: After an observation period of 4 months, an implant was placed in the augmented area, which osseointegrated successfully and could be restored prosthodontically in the following. The results of this method showed a functional and aesthetic success. CONCLUSION: The pre-implantological, autologous ridge preservation with dentin could be performed successfully. For the establishment of dentin as augmentation material for jaw augmentation procedures, a prospective, clinical trial is now necessary. PMID- 28361378 TI - Evaluation of corneal topographic changes and surgically induced astigmatism after transconjunctival 27-gauge microincision vitrectomy surgery. AB - PURPOSE: To evaluate the corneal topographic changes and postvitrectomy astigmatism after 27-gauge (g) microincision vitrectomy surgery (MIVS) by using Pentacam HR-Scheimpflug imaging system. METHODS: This prospective descriptive study included 30 eyes of 30 patients who underwent 27-g MIVS. All eyes underwent a Pentacam HR examination preoperatively and on the first week, first month and third month postoperatively. The power of the corneal astigmatism, mean keratometry (K m), K 1 and K 2 values and corneal asphericity (Q value) values for the both front and back surfaces of the cornea, index of surface variance (ISV), index of vertical asymmetry (IVA), index of height asymmetry (IHA), index of height decentration (IHD) and higher-order aberrations including coma, trefoil, spherical aberration, higher-order root-mean-square and total RMS were recorded. Additionally, the mean induced astigmatism was estimated by vector analysis. RESULTS: No statistically significant changes were observed in the mean power of corneal astigmatism, mean keratometry, K 1 and K 2 values, corneal asphericity values, ISV, IVA, IHA, IHD and higher-order aberrations on the first week, first month and third month after the operation. The mean surgically induced astigmatism was calculated as 0.23 +/- 0.11 D on the first week, 0.19 +/- 0.10 D on the first month and 0.19 +/- 0.08 D on the third month postoperatively. CONCLUSION: Minor corneal surface and induced astigmatic changes are expected to result in rapid visual rehabilitation after pars plana vitrectomy with the 27-g MIVS system. PMID- 28361379 TI - Bevacizumab for treatment of choroidal neovascularization secondary to candida chorioretinitis. AB - PURPOSE: To report a case of juxtafoveal choroidal neovascularization in a patient with candida chorioretinitis successfully treated with intravitreal bevacizumab. METHODS: Case report. RESULTS: A 45-year-old woman previously treated for candida chorioretinitis was presented with reduced vision in the left eye. The patient was investigated with ophthalmoscopy, fluorescein angiography, and optical coherence tomography (OCT). Following initial treatment, fundus examination, fluorescein angiography, and OCT of the right eye revealed a secondary juxtafoveal classic choroidal neovascularization. Following a single intravitreal injection of bevacizumab, the patient had excellent visual recovery, with absence of subretinal or intraretinal fluid in the OCT. CONCLUSIONS: Bevacizumab was effective in treatment of choroidal neovascularization associated with candida chorioretinitis. PMID- 28361380 TI - A challenged case of Vogt-Koyanagi-Harada syndrome: when dermatological manifestations came first. AB - INTRODUCTION: Vogt-Koyanagi-Harada syndrome (VKHS) is an inflammatory systemic autoimmune disease principally affecting pigmented tissues in the ocular, auditory, integumentary and central nervous systems. Patients are generally women in the fourth decade of life. The prognosis is correlated mainly with the time between diagnosis and the start of treatment and number of recurrent episodes of inflammation. Most complications are mainly ocular. The purpose of this paper is to describe a clinical case of VKHS. MATERIAL AND METHODS: A child with a challenging clinical presentation in which the dermatological symptoms occurred before ocular manifestations. DISCUSSION AND CONCLUSION: VKHS is rare in children and can be a diagnostic challenge. It seemed interesting to share this case as an opportunity to expand our knowledge of the clinical spectrum of diseases and reflect about current diagnostic criteria. PMID- 28361381 TI - Prospective Evaluation of Predictive DNA Testing for Huntington's Disease in a Large German Center. AB - We present a prospective study of counselees seeking predictive testing for Huntington's disease at the Huntington Center North Rhine-Westphalia (Bochum, Germany) between 2010 and 2012. The aim was to observe the decision-making process of at-risk individuals and explore their experiences following the decision as well as the impacts of positive and negative mutation results. Data were collected using two standardized questionnaires as well as via a semi standardized telephone interview one year after the initial counseling session. Seventy-two individuals participated in at least one of the three phases of the survey, including 31 individuals in the telephone interview. Sociodemographic data were in accordance with previous reports. The process of predictive testing was generally perceived in a positive manner, with almost all interviewees reporting a balanced emotional state one year after initial counseling, regardless of the decision for or against the test. The most important reasons named in favor of or against testing were assembled as well as different aspects regarding the satisfaction with the reached decision. In line with and expanding previous observations on gender-related differences in decision-making, our results suggest that gender-related aspects should be more strongly taken into account in genetic counseling during the predictive testing and counseling processes. PMID- 28361382 TI - Pointing movements both impair and improve visuospatial working memory depending on serial position. AB - Two experiments investigated the effects of pointing movements on the item and order recall of random, horizontal, and vertical arrays consisting of 6 and 7 squares (Experiment 1) or 8 and 9 squares (Experiment 2). In the encoding phase, participants either viewed the items passively (passive-view condition) or pointed towards them (pointing condition). Then, after a brief interval, they were requested to recall the locations of the studied squares in the correct order of presentation. The critical result was that, for all types of arrays, the effects of the encoding condition varied as a function of serial position: for the initial and central positions accuracy was higher in the passive-view than in the pointing condition (confirming the standard inhibitory effect of pointing movements on visuospatial working memory), whereas the reverse pattern occurred in the final positions-showing a significant advantage of the pointing condition over the passive-view condition. Findings are interpreted as showing that pointing can have two simultaneous effects on the recall of spatial locations, a positive one due to the addition of a motor code and a negative one due to the attentional requirements of hand movements, with the net impact on serial recall depending on the amount of attention resources needed for the encoding of each position. Implications for the item-order hypothesis and the perceptual-gestural account of working memory are also discussed. PMID- 28361383 TI - "Does this Look Infected to You?" Social Network Predictors of Dental Help Seeking Among Mexican Immigrants. AB - Compared to U.S. born Latinos, Mexican immigrants (MAs) have diminished health care access and face substantial barriers to accessing needed dental health services. However, little research has examined how MAs social networks shape their use of dental health services. Using data from 332 Mexican immigrants to the Midwest, this research examines the significance of individual and egocentric network characteristics on two measures of dental health service utilization. Findings reveal that network size, network dental service utilization, and the frequency with which MAs discuss acute problems with network ties, positively correspond to use of oral health services. Conversely, embeddedness in networks where ties hassle egos about dental issues and have low levels of dental health knowledge correspond to lower odds of using these services. This research is among the first to use ego network data and methods to examine the ways network characteristics shape oral health behaviors among this underserved population. PMID- 28361384 TI - Formation of Pyrylium from Aromatic Systems with a Helium:Oxygen Flowing Atmospheric Pressure Afterglow (FAPA) Plasma Source. AB - The effects of oxygen addition on a helium-based flowing atmospheric pressure afterglow (FAPA) ionization source are explored. Small amounts of oxygen doped into the helium discharge gas resulted in an increase in abundance of protonated water clusters by at least three times. A corresponding increase in protonated analyte signal was also observed for small polar analytes, such as methanol and acetone. Meanwhile, most other reagent ions (e.g., O2+., NO+, etc.) significantly decrease in abundance with even 0.1% v/v oxygen in the discharge gas. Interestingly, when analytes that contained aromatic constituents were subjected to a He:O2-FAPA, a unique (M + 3)+ ion resulted, while molecular or protonated molecular ions were rarely detected. Exact-mass measurements revealed that these (M + 3)+ ions correspond to (M - CH + O)+, with the most likely structure being pyrylium. Presence of pyrylium-based ions was further confirmed by tandem mass spectrometry of the (M + 3)+ ion compared with that of a commercially available salt. Lastly, rapid and efficient production of pyrylium in the gas phase was used to convert benzene into pyridine. Though this pyrylium-formation reaction has not been shown before, the reaction is rapid and efficient. Potential reactant species, which could lead to pyrylium formation, were determined from reagent-ion mass spectra. Thermodynamic evaluation of reaction pathways was aided by calculation of the formation enthalpy for pyrylium, which was found to be 689.8 kJ/mol. Based on these results, we propose that this reaction is initiated by ionized ozone (O3+.), proceeds similarly to ozonolysis, and results in the neutral loss of the stable CHO2. radical. Graphical Abstract ?. PMID- 28361385 TI - MALDI Orbitrap Mass Spectrometry Profiling of Dysregulated Sulfoglycosphingolipids in Renal Cell Carcinoma Tissues. AB - Matrix-assisted laser desorption/ionization coupled with Orbitrap mass spectrometry (MALDI-Orbitrap-MS) is used for the clinical study of patients with renal cell carcinoma (RCC), as the most common type of kidney cancer. Significant changes in sulfoglycosphingolipid abundances between tumor and autologous normal kidney tissues are observed. First, sulfoglycosphingolipid species in studied RCC samples are identified using high mass accuracy full scan and tandem mass spectra. Subsequently, optimization, method validation, and statistical evaluation of MALDI-MS data for 158 tissues of 80 patients are discussed. More than 120 sulfoglycosphingolipids containing one to five hexosyl units are identified in human RCC samples based on the systematic study of their fragmentation behavior. Many of them are recorded here for the first time. Multivariate data analysis (MDA) methods, i.e., unsupervised principal component analysis (PCA) and supervised orthogonal partial least square discriminant analysis (OPLS-DA), are used for the visualization of differences between normal and tumor samples to reveal the most up- and downregulated lipids in tumor tissues. Obtained results are closely correlated with MALDI mass spectrometry imaging (MSI) and histologic staining. Important steps of the present MALDI Orbitrap-MS approach are also discussed, such as the selection of best matrix, correct normalization, validation for semiquantitative study, and problems with possible isobaric interferences on closed masses in full scan mass spectra. Graphical Abstract ?. PMID- 28361386 TI - Human Immune Monitoring Techniques during Food Allergen Immunotherapy. AB - PURPOSE OF REVIEW: Encouraging results from recent food allergen immunotherapy clinical trials indicate that the immune system plays an essential role in peripheral tolerance to food allergen. Thus, the monitoring of changes in immune responses and their possible correlation with clinical outcome in allergic patients receiving immunotherapies could theoretically serve as surrogate markers and be harnessed as rationale for food allergen immunotherapy development. RECENT FINDINGS: A shift towards antigen specificity in recent assays has provided a solid foundation for the elucidation of cellular mechanisms involved in food allergen immunotherapy as well as the tracking of allergen-specific immune cells. In this review, we overview the current challenges and technologies used in immune monitoring during immunotherapy in allergic patients with a focus on cell mediated immunity. We also discuss critical steps involved in some of the cellular immune assays utilized in clinical trials. PMID- 28361387 TI - Excess Manganese-Induced Apoptosis in Chicken Cerebrums and Embryonic Neurocytes. AB - There were many studies about the effect of excess manganese (Mn) on nervous system apoptosis; however, Mn-induced apoptosis in chicken cerebrums and embryonic neurocytes was unclear. The purpose of this study was to investigate the effect of excess Mn on chicken cerebrum and embryonic neurocyte apoptosis. Seven-day-old Hyline male chickens were fed either a commercial diet or three levels of manganese chloride (MnCl2)-added commercial diets containing 600-, 900 , and 1800-mg/kg-Mn diet, respectively. On the 30th, 60th, and 90th days, cerebrums were collected. Fertilized Hyline chicken eggs were hatched for 6-8 days and were selected. Embryonic neurocytes with 0, 0.5, 1, 1.5, 2, 2.5, and 3 mM Mn were collected and were cultured for 12, 24, 36, and 48 h, respectively. The following research contents were performed: superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) activities; tumor protein p53 (p53), B cell lymphoma-2 (Bcl-2), B cell lymphoma extra large (Bcl-x), Bcl-2-associated X protein (Bax), Bcl-2 homologous antagonist/killer (Bak), fas, and caspase-3 messenger RNA (mRNA) expression; and morphologic observation. The results indicated that excess Mn inhibited SOD and T-AOC activities; induced p53, Bax, Bak, fas, and caspase-3 mRNA expression; and inhibited Bcl-2 and Bcl-x mRNA expression in chicken cerebrums and embryonic neurocytes. There were dose dependent manners on all the above factors at all the time points and time dependent manners on SOD activity of 1800-mg/kg-Mn group, T-AOC activity, and apoptosis-related gene mRNA expression in all the treatment groups in chicken cerebrums. Excess Mn induced chicken cerebrum and embryonic neurocyte apoptosis. PMID- 28361389 TI - Improving trial design in cancer anesthesia (onco-anesthesia) research. PMID- 28361388 TI - Effects of Ag Nanoparticles on Growth and Fat Body Proteins in Silkworms (Bombyx mori). AB - Ag nanoparticles (AgNPs), a widely used non-antibiotic, antibacterial material, have shown toxic and other potentially harmful effects in mammals. However, the deleterious effects of AgNPs on insects are still unknown. Here, we studied the effects of AgNPs on the model invertebrate organism Bombyx mori. After feeding silkworm larvae different concentrations of AgNPs, we evaluated the changes of B. mori body weights, survival rates, and proteomic differences. The results showed that low concentrations (<400 mg/L) of AgNPs promoted the growth and cocoon weights of B. mori. Although high concentrations (>=800 mg/L) of AgNPs also improved B. mori growth, they resulted in silkworm death. An analysis of fat body proteomic differences revealed 13 significant differences in fat body protein spots, nine of which exhibited significantly downregulated expression, while four showed significantly upregulated expression. Reverse transcription-polymerase chain reaction results showed that at an AgNP concentration of 1600 mg/L, the expression levels of seven proteins were similar to the transcription levels of their corresponding genes. Our results suggest that AgNPs lowered the resistance to oxidative stress, affected cell apoptosis, and induced cell necrosis by regulating related protein metabolism and metabolic pathways in B. mori. PMID- 28361390 TI - Effect of magnesium sulfate on oxytocin-induced contractility in human myometrium: an in vitro study. AB - PURPOSE: The purpose of this study was to determine the contractile patterns induced by oxytocin in myometrium exposed to magnesium sulfate (MgSO4). We hypothesized that MgSO4 pretreatment would reduce oxytocin-induced myometrial contractions in both oxytocin-naive and oxytocin-desensitized myometrium. METHODS: In this prospective in vitro study, myometrial samples were obtained from 26 women undergoing elective Cesarean deliveries. Samples were divided into six groups. Four groups were apportioned to no pretreatment (control group), oxytocin 10-5 M pretreatment (desensitization group), MgSO4 3.5 mM pretreatment, and MgSO4 3.5 mM + oxytocin 10-5M pretreatment. This was followed by dose response testing to oxytocin 10-10 to 10-5M in all four groups. Two additional groups included MgSO4 3.5 mM pretreatment and MgSO4 3.5 mM + oxytocin 10-5 M pretreatment, followed by dose-response testing to oxytocin along with MgSO4 3.5 mM. The outcomes were motility index (MI), as defined by the amplitude (g) * frequency of myometrial contractions (c) over ten minutes, and area under the curve (AUC). RESULTS: In oxytocin-naive myometrium, the mean (standard error [SE]) MI was not affected by MgSO4 pretreatment [3.31 (0.20) ?g?c/10 min] as compared with control (P = 0.88), even when MgSO4 was continued during dose response testing [2.50 (0.19) ?g?c/10 min; P = 0.41]. In the oxytocin desensitized model, mean (SE) MI was not affected by MgSO4 pretreatment [2.60 (0.21) ?g?c/10 min; P = 0.68], but when MgSO4 was continued during the dose response period, the MI was significantly reduced compared with control [1.89 (0.13) ?g?c/10 min; P < 0.001]. The results for AUC were similar to MI, except for a significant reduction in oxytocin-naive myometrium when MgSO4 was continued during dose-response testing (P = 0.02). CONCLUSION: Magnesium sulfate pretreatment does not impair oxytocin-induced myometrial contractility in oxytocin-naive or desensitized myometrium unless it is continued during oxytocin dose-response testing. These results suggest that its tocolytic effect is likely dependent on an extracellular mechanism. The study was registered with ClinicalTrials.gov, number NCT02647268. PMID- 28361391 TI - Relation between bispectral index measurements of anesthetic depth and postoperative mortality: a meta-analysis of observational studies. AB - INTRODUCTION: The association between anesthesia depth and mortality is still controversial. There are a number of narrative reviews on this topic that affirm this association, but their conclusions were based only on qualitative analyses. The aim of this meta-analysis of observational studies was to examine the potential association between depth of anesthesia as a low bispectral index (BIS) and mortality using appropriate quantitative methods. METHODS: The literature was systematically reviewed in three main electronic databases (MEDLINE, EMBASE, Google Scholar) to identify all articles from inception through December 2015 regarding the association between depth of anesthesia and mortality. Inclusion criteria were restricted to observational studies that used multivariable Cox proportional regression methodology and reported adjusted hazard ratios (aHR). Pooled effect size was measured using a random effects model. Subgroup analysis was performed post hoc based on follow-up duration (30 days and >= one year). RESULTS: Eight observational studies that included 40,317 patients were evaluated in this meta-analysis. The results showed a statistically significant association between the depth of anesthesia as measured by low BIS (< 40-45), and mortality (pooled aHR, 1.21; 95% CI, 1.07 to 1.38; P = 0.003). Subgroup analysis showed that the association between depth of anesthesia (measured by low BIS) and mortality was significant for studies with a follow-up duration of >= one year (n = 23,347; pooled aHR, 1.10; 95% CI, 1.00 to 1.21; P = 0.04) but was not significant for studies with a follow-up duration of 30 days (n = 16,970; pooled aHR, 1.38; 95% CI = 0.81 to 2.36; P = 0.24). CONCLUSION: Existing observational studies support a significant association between depth of anesthesia (as measured by BIS) and long-term mortality (>= one year), although it was without statistical significance at 30 days. Larger prospective, randomized trials are necessary to establish a definitive conclusion about whether this association represents true causality or is an epiphenomenon. PMID- 28361393 TI - Limited evidence of individual differences in holistic processing in different versions of the part-whole paradigm. AB - The part-whole paradigm was one of the first measures of holistic processing and it has been used to address several topics in face recognition, including its development, other-race effects, and more recently, whether holistic processing is correlated with face recognition ability. However the task was not designed to measure individual differences and it has produced measurements with low reliability. We created a new holistic processing test designed to measure individual differences based on the part-whole paradigm, the Vanderbilt Part Whole Test (VPWT). Measurements in the part and whole conditions were reliable, but, surprisingly, there was no evidence for reliable individual differences in the part-whole index (how well a person can take advantage of a face part presented within a whole face context compared to the part presented without a whole face) because part and whole conditions were strongly correlated. The same result was obtained in a version of the original part-whole task that was modified to increase its reliability. Controlling for object recognition ability, we found that variance in the whole condition does not predict any additional variance in face recognition over what is already predicted by performance in the part condition. PMID- 28361392 TI - Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features: Historical Context, Diagnosis, and Future Challenges. AB - The encapsulated/well-demarcated non-invasive form of follicular variant of papillary thyroid carcinoma (FVPTC) that occurs annually in 45,000 patients worldwide was thought for 30 years to be a carcinoma. Many studies have now shown almost no recurrence in these non-invasive tumors, even in patients treated by surgery without radioactive iodine therapy. The categorization of the tumor as cancer has led to aggressive forms of treatment, with their side effects, financial costs, and the psychological and social impact of a cancer diagnosis. Recently, the encapsulated/well-demarcated non-invasive, FVPTC was renamed as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) by an international group of experts. The new terminology lacks the carcinoma label enabling clinicians to avoid aggressive therapy. By taking the reader through the history of FVPTC, this article explains how diagnostic criteria for thyroid carcinoma of follicular cells have evolved over the last 60 years. It discusses the steps that led to the labeling of FVPTC as cancer and highlights the various studies that helped reclassify and rename this tumor. It also sheds light on the impact of this reclassification on cytologic diagnosis and focuses on the studies needed to refine and expand the histologic criteria of NIFTP. By understanding the history of this change in nomenclature, future classification of tumors will be greatly improved. PMID- 28361394 TI - Financial feasibility of end-user designed rainwater harvesting and greywater reuse systems for high water use households. AB - Water availability pressures, competing end-uses and sewers at capacity are all drivers for change in urban water management. Rainwater harvesting (RWH) and greywater reuse (GWR) systems constitute alternatives to reduce drinking water usage and in the case of RWH, reduce roof runoff entering sewers. Despite the increasing popularity of installations in commercial buildings, RWH and GWR technologies at a household scale have proved less popular, across a range of global contexts. For systems designed from the top-down, this is often due to the lack of a favourable cost-benefit (where subsidies are unavailable), though few studies have focused on performing full capital and operational financial assessments, particularly in high water consumption households. Using a bottom-up design approach, based on a questionnaire survey with 35 households in a residential complex in Bucaramanga, Colombia, this article considers the initial financial feasibility of three RWH and GWR system configurations proposed for high water using households (equivalent to >203 L per capita per day). A full capital and operational financial assessment was performed at a more detailed level for the most viable design using historic rainfall data. For the selected configuration ('Alt 2'), the estimated potable water saving was 44% (equivalent to 131 m3/year) with a rate of return on investment of 6.5% and an estimated payback period of 23 years. As an initial end-user-driven design exercise, these results are promising and constitute a starting point for facilitating such approaches to urban water management at the household scale. PMID- 28361395 TI - Bioaccumulation of gadolinium in freshwater bivalves. AB - In this study, the presence of anthropogenic gadolinium (Gd) was evaluated in rivers, close to wastewater treatment plant outputs. Then, one site was selected for in situ experiments to assess the bioaccumulation of Gd in the digestive gland and in the gills of two bivalves (Dreissena rostriformis bugensis and Corbicula fluminea). For both organisms, the results suggested that the bioaccumulation of Gd can be observed when organisms are exposed in a geogenic and anthropogenic Gd mixture. In order to observe if Gd can bioaccumulate in tissues of bivalves when the ion is only present as the main anthropogenic speciation of Gd, i.e., Gd-contrast agents (Gd-CAs), the gadoteric acid was used for a laboratory experiment. In this case, the presence of Gd was clearly detected in a significant amount in the digestive glands of D. rostriformis bugensis and C. fluminea while low concentrations are measured in the gills. For the first time, these results clearly showed that Gd can bioaccumulate in bivalve tissues even when it is only present as Gd-CAs. Biochemical activities were measured in the digestive gland and in the gills of the bivalves to assess the effects of Gd-CA bioaccumulation. No significant variations were observed in the gills. Concerning the digestive gland, after 7 days of exposure at 10 MUg L-1 of Gd as Gd-CA speciation, GST activity in D. rostriformis bugensis and lipid hydroperoxide and mitochondrial electron transfer system in C. fluminea had increased. The results suggest an acclimation of the organisms to the presence of Gd-CAs in the medium within less than 21 days. PMID- 28361396 TI - Synthesis and photocatalytic performance of reduced graphene oxide-TiO2 nanocomposites for orange II degradation under UV light irradiation. AB - To enhance the photocatalytic activity of TiO2, reduced graphene oxide-TiO2 (RGO TiO2) composites with sandwich-like structure were synthesized using a simple solvothermal method. The morphology, crystalline information, and structural property of the photocatalyst were characterized by field emission scanning electron microscopy, transmission electron microscopy, X-ray diffraction, and Fourier transmission infrared spectroscopy. The photocatalytic performances of the RGO-TiO2 composites were evaluated by the degradation of orange II (AO7) in water under UV light irradiation. The results showed that the RGO-TiO2 composites exhibited much higher photocatalytic activity than TiO2 and that the removal efficiency of AO7 could reach above 95% only after 20 min of UV light irradiation under the optimum condition. The improved photocatalytic activity might be attributed to the improved charge transfer and significant separation of the photoinduced electrons and holes in the presence of a two-dimensional graphene network. The results of recycling experiments show that RGO-TiO2 composites have a high photostability, which is expected in the practical application. Radical trapping experiments indicated that .OH plays a crucial role in the process of AO7 degradation. PMID- 28361398 TI - A two-stage fuzzy chance-constrained water management model. AB - In this study, an inexact two-stage fuzzy gradient chance-constrained programming (ITSFGP) method is developed and applied to the water resources management in the Heshui River Basin, Jiangxi Province, China. The optimization model is established by incorporating interval programming, two-stage stochastic programming, and fuzzy gradient chance-constrained programming within an optimization framework. The hybrid model can address uncertainties represented as fuzzy sets, probability distributions, and interval numbers. It can effectively tackle the interactions between pre-regulated economic targets and the associated environmental penalties attributed to water allocation schemes and reflect the tradeoffs between economic revenues and system-failure risk. Furthermore, uncertainties associated with the decision makers' preferences are considered in decision-making processes. The obtained results can provide decision support for the local sustainable economic development and water resources allocation strategies under multiple uncertainties. PMID- 28361397 TI - Integration of coagulation and adsorption for removal of N-nitrosodimethylamine (NDMA) precursors from biologically treated municipal wastewater. AB - This study investigated the N-nitrosodimethylamine (NDMA) formation potential of various dissolved organic matter (DOM) fractions in biologically treated municipal wastewater by UF fractionation, XAD-8 resin adsorption isolation, and excitation and emission matrix (EEM) fluorescence spectroscopy. Removal of various NDMA precursor fractions was also analyzed to evaluate the efficiency of traditional water treatment processes (coagulation, adsorption, and coagulation adsorption). Results showed that NDMA were mainly formed by low molecular weight (MW) fractions (<30 kDa) and hydrophilic fractions (HiS) in biologically treated municipal wastewater. Integrated coagulation-adsorption treatments showed the highest reduction capacity for NDMA formation potential (57%), followed by isolated adsorption treatment (50%) and isolated coagulation treatment (28%). The powdered activated carbon (PAC) adsorption process could reduce the high MW precursors (>30 kDa) by 48%, which was higher than other treatments. In contrast, the highest uptake (66%) of low MW precursors (<30 kDa) was achieved by the coagulation-adsorption process. All treatments preferentially removed the hydrophobic acids (HoA) fraction compared to other fractions. Coagulation could remove more fulvic acid-like substances and adsorption could remove more microbial by-products and aromatic proteins. PMID- 28361399 TI - The potential DNA toxic changes among workers exposed to antimony trioxide. AB - Occupational exposure to antimony has gained much interest when specific toxic effects were noticed among workers processing antimony. Thus, the aim of the present work was to investigate the potential DNA oxidative damage occurring among Egyptian workers occupationally exposed to antimony trioxide. The study was conducted on 25 subjects exposed to antimony trioxide while working in the polymerization process of polyester in Misrayon and Polyester Fiber Company, KafrEldawwar, Beheira, Egypt. Urinary antimony levels were assessed using inductive coupled plasma-optical emission spectrometry (ICP-OES) and considered as a biological exposure index. DNA damage and total oxidant capacity (TOC) were assessed using ELISA. DNA damage was detected in the form of increased apurinic/apyrimidinic (AP) sites among antimony trioxide-exposed workers compared to control subjects, but it could not be explained by oxidative mechanisms due to lack of significant correlation between DNA damage and measured TOC. Antimony trioxide might have a genotoxic impact on occupationally exposed workers which could not be attributed to oxidative stress in the studied cases. PMID- 28361400 TI - Comparison of two modified coal ash ferric-carbon micro-electrolysis ceramic media for pretreatment of tetracycline wastewater. AB - Application of modified sintering ferric-carbon ceramics (SFC) and sintering-free ferric-carbon ceramics (SFFC) based on coal ash and scrap iron for pretreatment of tetracycline (TET) wastewater was investigated in this article. Physical property, morphological character, toxic metal leaching content, and crystal component were studied to explore the application possibility of novel ceramics in micro-electrolysis reactors. The influences of operating conditions including influent pH, hydraulic retention time (HRT), and air-water ratio (A/W) on the removal of tetracycline were studied. The results showed that SFC and SFFC were suitable for application in micro-electrolysis reactors. The optimum conditions of SFC reactor were pH of 3, HRT of 7 h, and A/W of 10. For SFFC reactor, the optimum conditions were pH of 2, HRT of 7 h, and A/W of 15. In general, the TET removal efficiency of SFC reactor was better than that of SFFC reactor. However, the harden resistance of SFFC was better than that of SFC. Furthermore, the biodegradability of TET wastewater was improved greatly after micro-electrolysis pretreatment for both SFC and SFFC reactors. PMID- 28361401 TI - Rosmarinus officinalis L. ameliorates titanium dioxide nanoparticles and induced some toxic effects in rats' blood. AB - Titanium dioxide nanoparticles (TiO2 NPs) have been widely used as a white pigment in food and drugs. The most important route of human exposure to TiO2 is through food and drug products containing TiO2 additives. This study investigates the efficacy of an oral traditional use of rosemary extract in ameliorating some toxic effects induced on blood of TiO2 NP-intoxicated rats. Rats were given rosemary extract via intragastric administration 1 h before the intragastric administration of 100 mg/kg/day TiO2 NPs (10 nm) for 60 days. TiO2 NPs significantly increased serum cholesterol, glucose, and triglyceride levels of rats. They also induced significant oxidative stress and inflammatory and caused DNA damage in peripheral blood leukocytes. The rosemary extract appears to have a significant protective effect by lowering glucose level properties, restoring the lipid profile and showing an antioxidative, anti-inflammatory, and antigenotoxic properties against TiO2 NPs toxicity. In conclusion, this study gives an encouraging scientific basis for consumers of rosemary leaves to keep on with this culinary habit. PMID- 28361402 TI - Response of low-molecular-weight organic acids in mangrove root exudates to exposure of polycyclic aromatic hydrocarbons. AB - Low-molecular-weight organic acids (LMWOAs) represent an important component of root exudates. They play a pivotal role in the degradation of polycyclic aromatic hydrocarbons (PAHs) in sediments as they influence PAH bioavailability and degrader colonization. This study examined variations of LMWOAs in mangrove root exudates (Aegiceras corniculatum and Kandelia obovata) after exposure in phenanthrene and pyrene solution for 7 and 40 days, respectively. After 7 days of treatment, total root exudates and six types of LMWOA in root exudates from both mangrove species were enhanced. The largest increase was found in oxalic acid, i.e., the dominant component in determined LMWOAs. Coupled with the enhancement in LMWOA exudation rates, root metabolism intensities, measured as the dehydrogenase activity, increased. In contrast, after 40 days of exposure, the exudation rate of total LMWOAs had dropped markedly in PAH-contaminated groups compared to the control, indicating that PAHs negatively impacted root metabolism and activities due to their toxicity. The largest decrease was also found in oxalic acid, suggesting that the biological reactions related with oxalic acid are vulnerable under PAH stresses. PMID- 28361403 TI - Impact of highway traffic and the acoustic screen on the content and spatial distribution of heavy metals in soils. AB - Recent years have witnessed intensification of road traffic and, with it, the amount of substances emitted by vehicles. Such emissions need to be monitored for public health purposes. The aim of this study was to evaluate the impact of the highway traffic on the total content and bioavailability of Zn, Cu, Ni, Cd, Cr and Pb in nearby soils as well as influence of an acoustic screen on spatial distribution of the metals. The material included 40 soil samples collected from 15 research points located 5, 10, 25 and 50 m away from the road acoustic screen and from 4 points between the screen and the highway. Additionally, 5 research points were located next to the metal barrier. Selected physicochemical properties of soils were determined: soil texture, soil pH, TOC and CaCO3 content. The total content of heavy metals in the soils was determined by AAS after digestion in aqua regia and bioavailable forms in 1 M diethylenetriaminepentaacetic acid. The research found low impact of the highway traffic on the content of heavy metals in soils; however, due to a very short period of this potential impact (5 years), the moderately polluted category of geo-accumulation index of cadmium and high bioavailability of lead indicate the need of repeating the research within the next several years. Furthermore, the road acoustic screen significantly influenced spatial distribution of the metals in soils. PMID- 28361404 TI - Antibacterial mode of action of violacein from Chromobacterium violaceum UTM5 against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA). AB - Violacein, violet pigment produced by Chromobacterium violaceum, has attracted much attention recently due to its pharmacological properties including antibacterial activity. The present study investigated possible antibacterial mode of action of violacein from C. violaceum UTM5 against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) strains. Violet fraction was obtained by cultivating C. violaceum UTM5 in liquid pineapple waste medium, extracted, and fractionated using ethyl acetate and vacuum liquid chromatography technique. Violacein was quantified as major compound in violet fraction using HPLC analysis. Violet fraction displayed bacteriostatic activity against S. aureus ATCC 29213 and methicillin-resistant S. aureus ATCC 43300 with minimum inhibitory concentration (MIC) of 3.9 MUg/mL. Fluorescence dyes for membrane damage and scanning electron microscopic analysis confirmed the inhibitory effect by disruption on membrane integrity, morphological alternations, and rupture of the cell membranes of both strains. Transmission electron microscopic analysis showed membrane damage, mesosome formation, and leakage of intracellular constituents of both bacterial strains. Mode of action of violet fraction on the cell membrane integrity of both strains was shown by release of protein, K+, and extracellular adenosine 5'-triphosphate (ATP) with 110.5 MUg/mL, 2.34 MUg/mL, and 87.24 ng/MUL, respectively, at 48 h of incubation. Violet fraction was toxic to human embryonic kidney (HEK293) and human fetal lung fibroblast (IMR90) cell lines with LC50 value of 0.998 +/- 0.058 and 0.387 +/- 0.002 MUg/mL, respectively. Thus, violet fraction showed a strong antibacterial property by disrupting the membrane integrity of S. aureus and MRSA strains. This is the first report on the possible mode of antibacterial action of violet fraction from C. violaceum UTM5 on S. aureus and MRSA strains. PMID- 28361405 TI - Impact of Safety-Related Regulations on Codeine Use in Children: A Quasi Experimental Study Using Taiwan's National Health Insurance Research Database. AB - INTRODUCTION: Safety concerns regarding potential life-threatening adverse events associated with codeine have resulted in policy decisions to restrict its use in pediatrics. However, whether these drug safety communications have had an immediate and strong impact on codeine use remains in question. OBJECTIVE: We aimed to investigate the impact of the two implemented safety-related regulations (label changes and reimbursement regulations) on the use of codeine for upper respiratory infection (URI) or cough. METHODS: A quasi-experimental study was performed using Taiwan's National Health Insurance Research Database. Quarterly data of codeine prescription rates for URI/cough visits were reported, and an interrupted time series design was used to assess the impact of the safety regulations on the uses of codeine among children with URI/cough visits. Multivariable logistic regression models were used to explore patient and provider characteristics associated with the use of codeine. RESULTS: The safety related regulations were associated with a significant reduction in codeine prescription rates of -4.24% (95% confidence interval [CI] -4.78 to -3.70), and the relative reduction compared with predicted rates based on preregulation projections was 60.4, 56.6, and 53.2% in the first, second, and third year after the regulations began, respectively. In the postregulation period, physicians specializing in otolaryngology (odds ratio [OR] 1.47, 95% CI 1.45-1.49), practicing in district hospitals (OR 6.84, 95% CI 5.82-8.04) or clinics (OR 6.50, 95% CI 5.54-7.62), and practicing in the least urbanized areas (OR 1.60, 95% CI 1.55-1.64) were more likely to prescribe codeine to children than their counterparts. CONCLUSIONS: Our study provides a successful example of how to effectively reduce the codeine prescriptions in children in the 'real-world' settings, and highlights areas where future effort could be made to improve the safety use of codeine. Future research is warranted to explore whether there was a simultaneous decrease in the incidence rates of codeine-related adverse events following the safety-related regulations. PMID- 28361406 TI - "Vesica Patavina" (lat.). AB - After the initial simulation, we started performing Ves.Pa. on human patients. We can confirm that the technique is more rapid than others, and easy to perform with a totally intracorporeal robotic approach. PMID- 28361407 TI - Erratum to: Modern Approaches to Studies of New Osteogenic Biomaterials on the Model of Regeneration of Critical-Size Cranial Defects in Rats. PMID- 28361408 TI - Correction of Abnormalities Provoked by Long-Term Alcoholization with Hypoxic Hyperoxic Training. AB - Free radical oxidation in the liver and skeletal muscles as well as stress behavior were examined in rats subjected to a gradual long-term alcoholization with elevated ethanol content from 10 to 40% followed by correction of alcohol induced disturbances with hypoxic-hyperoxic training. The elevated plus-maze test revealed increased anxiety and appearance of risky behavior in alcoholized rats in the absence of changes in motor and orientation activity. In the liver and skeletal muscles of alcoholized rats, free radical oxidation processes were decompensated despite activation of antioxidant enzymes. Adaptation to intermittent hypoxia-hyperoxia during last two weeks of alcoholization exerted a protective effect against ethanol-induced oxidative stress: reduced anxious and risk behavior, normalized tissue tolerance of free radical oxidation processes, and restored the level of protective proteins. PMID- 28361409 TI - Albumin in the Vitreous Body, Retina and Lens of Human Fetal Eye. AB - The content of serum albumin was evaluated in the vitreous body, retina, and lens of human fetuses of 14, 16, 17, 18 and 24 weeks of gestation. Albumin was detected in these tissues. PCR analysis revealed no albumin mRNA in the retina or in the lens, while in fetal liver (control) mRNA for this protein was expressed. These findings suggest that serum albumin is not synthesized by cells of retina and lens, but is captured by them. The presence of serum albumin in human eye tissues suggests its involvement in the metabolism, maintenance of tissue volume, and antioxidant reactions. PMID- 28361410 TI - Effect of Selank on Spontaneous Synaptic Activity of Rat Hippocampal CA1 Neurons. AB - Application of anxiolytic drug Selank to hippocampal slices increased the amplitude and discharge rate of spontaneous inhibitory postsynaptic currents in rat hippocampal pyramidal CA1 neurons. In some neurons, Selank-induced up regulation of spontaneous inhibitory postsynaptic currents was preceded by a transient decrease in this activity. In the examined concentration range (1-8 MUM), Selank demonstrated no significant dose-dependence. PMID- 28361411 TI - Study of SMAD-Dependent Signal Pathway in the Development of Early Pulmonary Fibrosis in Mice Infected with Influenza A/H1N1 Virus. AB - Early fibrosis of the visceral organs is one of the main complications of infection caused by influenza A virus. Structural manifestations and molecular regulators of the epithelialmesenchymal transformation as a possible mechanism of fibrosis progression were studied in mice infected with influenza A/H1N1 A/Tomsk/13/2010 virus. We found early fibrosis of the lungs against the background of minor changes in fibroblast count. However, enhanced expression of TGF-beta and SMAD-2 by macrophages and alveolocytes attested to possible development of epithelial-mesenchymal transformation and its contribution to activation of fibrogenesis process in the lungs. PMID- 28361412 TI - Study of MU- and delta-Opioid Activities in Agents with Various kappa-Receptor Selectivity. AB - A putative opioid agonist RU-1205 was ineffective within in vitro model of electrically induced contractions of rat ileum assessing the MU- and delta-opioid receptor pathways, while morphine inhibited these contractions in a dose dependent and naloxone-reversible manners with EC50=2.6*10-7 M. In vivo experiments revealed no significant effects of RU-1205 on respiration and gastrointestinal tract contractile activity. In contrast, butorphanol decreased respiration rate by 25% (25-100 mg/kg) and slowed down the transit of labeled particles along the small intestine by 77.1% (1 mg/kg) and by 45.5% (10 mg/kg). Morphine-induced inhibition of peristalsis was dose-dependent with maximum effect (by 68.6%) observed in the dose of 10 mg/kg. It was concluded that the effects of RU-1205 are not related to activation MU- and delta-opioid receptors known to mediate the effects of non-selective opioid agonist morphine and agonist antagonist butorphanol. PMID- 28361413 TI - Structural Reorganization of the Thyroid Gland in Males of the Republic of Sakha (Yakutia) Depending on Ethnicity and Climate. AB - Histomorphometric and immunohistochemical analyses showed season-dependent changes in the morphofunctional parameters of the structural components of the thyroid gland in males of indigenous (Yakuts, Evens, and Evenkis) and non indigenous (Russian and Ukrainians) populations of the Republic of Sakha (Yakutia) in different seasons. External and internal diameters of follicles and area of the colloid in the thyroid gland was higher in non-indigenous than in non indigenous individuals both in summer and in winter. The height of thyroid epithelium, areas of thyrocytes and their nuclei, and nucleocytoplasmic index of the thyroid gland were lower in men from non-indigenous population in summer, and higher in winter than in non-indigenous inhabitants. Transition of a part of follicular apparatus of the thyroid gland to enhanced activity during winter was less pronounced in indigenous males in comparison with non-indigenous subjects. PMID- 28361414 TI - Cytophysiological Changes in the Follicular Epithelium of the Thyroid Gland after Long-Term Exposure to Low Doses of Dichlorodiphenyltrichloroethane (DDT). AB - Exposure to endocrine disruptors is considered as a risk factor thyroid gland diseases. We analyzed cytophysiological changes in rat thyroid follicular epithelium after long-term exposure to low doses of the most widespread disruptor DDT. Analysis of thyroid hormone production and light and electron microscopy of thyroid gland samples revealed cytophysiological changes in thyroid epithelium related to impaired transport through the apical membrane, suppressed Golgi complex activity, and impaired thyrotrophic hormone regulation of the secretory functions of thyroid cells, which led to compensatory transition from merocrine to microapocrine secret release. PMID- 28361415 TI - Role of Vascular Endothelial Growth Factor and Transforming Growth Factor-beta2 in Rat Bone Tissue after Bone Fracture and Placement of Titanium Implants with Bioactive Bioresorbable Coatings. AB - The study established enhanced expression of vascular endothelial growth factor (VEGF) in the subpopulation of osteoblasts located in the regeneration region of femoral bone fracture near the titanium implants with bioactive calcium phosphate and hydroxyapatite coatings and suppressed activity of transforming growth factor beta2 (TGF-beta2) in chondroblasts during the two weeks after surgery. In the delayed posttraumatic period, the distribution of TGF-beta2 inversely related to its maximal activity. The data revealed the up-regulating effect of bioresorbable coatings on expression of VEGF and TGF-beta2 and their implication in the control over various stages of reparative osteogenesis. PMID- 28361416 TI - Characteristics of Depressive-Like Behavior of Prenatally Stressed Male Rats with Androgen Deficiency. AB - Characteristics of depressive-like behavior of male rats with androgen deficiency born by mothers subjected to prenatal stress during pregnancy were assessed by using Porsolt tests and open-field tests. The level of depression-like behavior in prenatally stressed males increased more intensively than in non-stressed gonadectomized males. Chronic administration of testosterone propionate (0.5 mg/kg, intramuscularly, for 14 days) increased depressive behavior in prenatally stressed gonadectomized males in contrast to its antidepressant effect in nonstressed gonadectomized rats. Prenatal stress considerably exacerbated depressive behavior of male rats under conditions of androgen deficiency and abolished the antidepressant effect of exogenously administered testosterone propionate. PMID- 28361417 TI - Participation of Purinergic P2X Receptors in the Thermoregulatory Response to Cooling. AB - We studied the role of purinergic P2X receptors in the body response to cooling. In experiments on rats, P2X receptor antagonist PPADS was administered in different modes, which resulted in changes of different characteristics of the thermoregulatory response to cold. Iontophoresis of P2X antagonist into the skin decreased the thermal thresholds of all thermoregulatory responses to cooling, which can attest to a modulating effect of P2X receptors on peripheral thermosensitive afferents. Intraperitoneal administration of P2X antagonist suppressed thermoregulatory activity of skeletal muscles (shivering) developing during cooling without changing the thresholds of thermoregulatory responses. The findings suggest that ATP and P2X receptors play an important role in the formation of the response to cooling. PMID- 28361418 TI - Proteomic Characteristics of Blood Serum in Rats with Different Behavioral Parameters after Acute Stress. AB - We studied proteome profile of blood serum of Wistar rats with different behavioral activity immediately and in 1 and 3 days after acute stress on the model of 12-h immobilization during the nighttime. Comparative analysis of 2D electrophoretograms revealed differences in the expression of serum proteins in non-stressed (control) and stressed (experimental) rats. We found 22 protein spots that characterized the proteomic features of blood serum in rats with different prognostic resistance to stress. Mass-spectrometry of isolated spots identified 6 functional proteins. Persistent proteome changes in the blood of animals at different stages after acute stress were determined. The specificity of proteomic characteristics of blood serum was shown in behaviorally passive and active rats during the post-stress period. These data extend the concept on specific protein markers for the formation of a negative emotional state and adaptive-and-compensatory processes in mammals with different sensitivity to stressogenic factors. PMID- 28361419 TI - Association of Glu298Asp Polymorphism of Endothelial NO Synthase Gene with Metabolic Syndrome Development: a Pilot Study. AB - We studied association of single nucleotide polymorphism Glu298Asp (rs1799983) of the NOS3 gene with the risk of metabolic syndrome in the Slavic population. Blood samples were obtained from 128 patients with metabolic syndrome and 100 healthy individuals. Polymorphism Glu298Asp of the NOS3 gene was genotyped by allele specific PCR. Allele Asp (OR=1.95, 95%CI 1.29-2.95, p=0.007) and genotype Asp/Asp (OR=2.56, 95%CI 0.98-6.72, p=0.04) were associated with the risk of metabolic syndrome in Slavic population. Patients with metabolic syndrome carrying genotype Asp/Asp had higher serum endothelin-1 level in comparison with Glu/Asp and Glu/Glu carriers. PMID- 28361421 TI - Dynamics of Interaction of Neural Networks in the Course of EEG Alpha Biofeedback. AB - Brain EEG-fMRI activity was studied in subjects, who had successfully completed the EEG alpha stimulating training course (20 sessions): for 14 healthy men (20 35 years) three records were obtained in the feedback loop (biofeedback with EEG alpha rhythm with sound reinforcement): in the beginning, middle and at the end of the course. During alpha training, increased functional connectivity was revealed between precuneus network and anterior salience network, left executive control network, default mode network, primary visual network; anterior salience network and executive control network, visual-spatial network. The most prominent changes were found for precuneus network and anterior salience network, which could be due to their key role in the biofeedback phenomenon. Significant changes in functional connectivity were recorded for anterior salience network and precuneus network (synchronicity increased from the first to the third trial) and right and left executive control networks (weakening from the first to the second session. PMID- 28361420 TI - Effect of Purine Co-Transmitters on Automatic Activity Caused by Norepinephrine in Myocardial Sleeves of Pulmonary Veins. AB - We studied the effect of extracellular purine nucleotides (NAD+ and ATP) on spontaneous arrhythmogenic activity caused by norepinephrine in myocardial sleeves of pulmonary veins. In pulmonary veins, NAD+ and ATP reduced the frequency of action potentials and their duration at regular type of spontaneous activity caused by norepinephrine. NAD+ and ATP lengthened the intervals between spike bursts at periodic (burst) type of spontaneous activity. In addition, ATP shortened the duration of spike bursts and the number of action potentials in the "bursts" caused by norepinephrine in the pulmonary veins. It was hypothesized that NAD+ and ATP attenuate the effects of sympathetic stimulation and when released together with norepinephrine from sympathetic endings in vivo, probably, reduce arrhythmogenic activity in myocardial sleeves of pulmonary veins. PMID- 28361422 TI - Effect of Metal-Containing Nanocomposites on Functional Status of the Thymus in Experimental Animals. AB - The effects of nanostructurized composites argentogalactomannan and argento-poly 1-vinyl-1,2,4-triasole on the kinetics of T cell maturation in the thymus of albino mice were studied. These nanocomposites stimulated the formation of CD3+CD4+CD8- and CD3+CD4-CD8+ cells from CD3-CD4-CD8- cells, the effect of argentogalactomannan was more potent. The efficiency of these compounds as agents improving the defense potential deserves special studies. PMID- 28361423 TI - Effects of Growth Factors on Mobilization of Mesenchymal Stem Cells. AB - We studied mobilization of bone marrow stem cells the under conditions of boost therapy with granulocytic CSF and erythropoietin. Immunophenotyping of the peripheral blood was carried out in patients after transplantation of tissue engineered trachea during the perioperative period. We observed an increase in hemopoietic stem cell pool and appearance of multipotent mesenchymal stromal cells in systemic circulation, their maximum concentration being recorded on days 10-14 after surgery. These data indicated a positive effect of growth factors on mobilization of stem cells. PMID- 28361424 TI - Role of Prolactin in the Regulation of Bicarbonates Biodynamics in Female Rat Model of Cholestasis of Pregnancy. AB - We studied possible involvement of prolactin in the regulation of bicarbonate biodynamics using female rat model of cholestasis of pregnancy induced by transplantation of the donor pituitary under the renal capsule of a recipient (hyperprolactinemia) and bile duct ligation (cholestasis). The concentration of bicarbonates in the bile and blood, their excretion, clearance, and reabsorption, as well as glomerular filtration rate and excretion of sodium ions were assessed. It was found that the main effect of prolactin was directed to the kidney regulated pool of bicarbonates and consisted in stimulation of their clearance and inhibition of reabsorption, which led to a decrease in bicarbonate blood concentration. Parallel influence of prolactin on the clearance of bicarbonates and sodium ions was observed. PMID- 28361425 TI - Anxiolytic Properties of Trimetazidine in Experimental Models of Increased Anxiety. AB - Effect of trimetazidine (20 and 30 mg/kg) on elevated plus maze behavior of rodents was assessed in the genetic and pharmacological anxiety models. Single intraperitoneal injection of trimetazidine in a dose of 20 mg/kg prevented anxiety development in highly emotional male BALB/c mice and increased the time spent in open arms of the maze. In outbred male rats receiving 10% ethanol solution for 20 weeks, trimetazidine administered intraperitoneally in a dose of 20 mg/kg for 28 days abolished ethanol withdrawal-induced anxiogenesis developed against the background of 4-week alcohol deprivation: it increased the time spent in open arms, the number of entries into open arms, and total locomotor activity in the maze. Anxiolytic properties of trimetazidine were not inferior to those of the non-benzodiazepine anxiolytic Afobazole (fabomotizole) in acute and chronic administration. PMID- 28361426 TI - Antithrombotic Activity of DAB-15, a Novel Diazepinobenzimidazole Compound. AB - Antithrombotic activity of a new orally administered antiplatelet compound DAB-15 was compared to that of acetylsalicylic acid, ticlopidine, and clopidogrel in the experimental model of arterial thrombosis in rats caused by surface application of 50% ferric chloride (III) on the carotid artery. Compound DAB-15 exerted a dose-dependent antithrombotic effect and was superior to acetylsalicylic acid, ticlopidine and clopidogrel by 5, 7, and 4.9 times, respectively (by ED50). This necessitates studying of the action mechanism of this antiplatelet compound with consideration of its influence on different stages of the pathogenesis of platelet aggregation. PMID- 28361428 TI - Experimental Validation of the Efficiency of Gamalant-paste-FORTE Plus, a Russian Osteoinductive Material, in Oral Surgery. AB - For evaluation of the efficiency of bone substitute, nanostructurized Gamalant paste-FORTEPlus was placed into a mandibular defect in rats. Bone tissue reparation was evaluated after 30 days by histological methods under a microscope. Use of bone substitute in experimental mandibular defect ensured more complete and rapid restructuring of the bone tissue in comparison with the control (natural healing). PMID- 28361427 TI - Age-Specific Characteristics of CO-Mediated Reaction of the Pial Arteries of Various Diameters in Rats. AB - First-fourth order pial branches of the median cerebral artery were studied by biomicroscopy in male Wistar rats aged 1 and 12 months. Irrespective of age, CO mediated mechanisms are involved in the regulation of the basal tone of pial vessels of various diameters (more so of arteries with well-developed muscular tunic). Injection of hemin confirmed that endogenous production of CO maintained vasodilatation and this effect was most pronounced in large pial branches of young animals, while zinc protoporphyrin IX blocked this effect in all cases. On the other hand, zinc IX protoporphyrin did not modify NO-mediated reaction caused by injection of L-arginine, while hemin compensated (though not completely) vasoconstriction induced by NO synthase blocker L-NAME. In contrast to NO, the effect of CO on blood vessels was not so rapid and potent, but more lasting. Other targets for CO were arteries with well-developed muscular tunic, while targets for NO were small vessels. The vasomotor effects of both gas transmitters were more pronounced in young animals. PMID- 28361429 TI - Possible Role of Polymorphisms in TNFA, NFKB1, and CASP8 Gene Promoter Areas in the Development of Chronic Lymphocytic Leukemia. AB - We studied the relationship between polymorphisms rs1800629 (-308G>A), rs28362491 (-94ins>del), and rs3834129 (-652ins>del) in the promoter regions of TNFA, NFKB1, and CASP8 genes, respectively, encoding TNF-alpha, nuclear transcription factor kappaB1 (NF-kappaB1), and caspase 8 (CASP8), and the risk and stages of chronic lymphocytic leukemia in ethnic Russians, residents of the Vyatka region of Russia. Allele -308A, genotype -308AA, and -308A genotypes (-308AA/-308AG) were associated with the risk of this pathology (OR=1.64, 95%CI 1.14-2.37, p=0.007; OR=4.48, 95%CI 1.20-16.80, p=0.02, and OR=1.57, 95%CI 1.05-2.36, p=0.03). In addition, NFKB1 allele -94del and genotype -94del/del were associated with advanced stages of the disease at the time of diagnosis (OR=0.66, 95%CI 0.46 0.97, p=0.03 and OR=0.43, 95%CI 0.20-0.92, p=0.03). These data suggest that 308G>A and -94ins>del polymorphisms of genes TNFA and NFKB1, respectively, can be involved in the pathogenesis of chronic lymphocytic leukemia. PMID- 28361430 TI - Changes in the Structure of the Thymus under Conditions of Various Treatments for Experimental Mammary Tumor. AB - Morphological changes in the thymus of female Wistar rats with experimental mammary gland carcinomas were studied. After adjuvant therapy, the area of the cortical matter and density of parenchymal cells in the thymus decreased, while areas of the medulla, connective tissue, and content of immunoblasts and macrophages increased. In the thymuses of rats receiving exogenous DNA, morphological signs of activation of the lymphoid and epithelial components were found: areas of the cortex and medulla, glandular and connective tissue corresponded to the values in intact animals, the counts of lymphocytes in the central part of the cortical matter and of macrophages in all zones of the thymus increased, and lymphocyte migration from the thymus increased (in comparison with the chemotherapy group). PMID- 28361431 TI - Modification of Rat Lung Decellularization Protocol Based on Dynamic Conductometry of Working Solution. AB - We modified the protocol of obtaining of biological scaffolds of rat lungs based on dynamic recording of specific resistivity of working detergent solution (conductometry) during perfusion decellularization. Termination of sodium deoxycholate exposure after attaining ionic equilibrium plateau did not impair the quality of decellularization and preserved structural matrix components, which was confirmed by morphological analysis and quantitative assay of residual DNA. PMID- 28361432 TI - Prediction of Intraoperative Blood Loss during Total Knee Arthroplasty in HCV+ and HCV- Patients with Hemophilia A. AB - We examined HCV+ and HCV- hemophilia A patients with knee arthropathy and hematocrit above 38.5%. The mean density of erythrocytes was studied by the phthalate method, intraoperative blood loss was assessed gravimetrically. The volume of blood loss in HCV+ patients with manifest adhesive process and chronic synovitis varied from 300 to 1900 ml, in patients with moderate adhesive process from 400 to 1500 ml. The volume of blood loss in HCV- patients was 300-800 ml. A positive correlation between the blood loss volume and mean density of erythrocytes was detected. Blood loss >1000 ml during total knee arthroplasty can be expected in patients with hemophilia A with HCV and high mean density of erythrocytes. Blood loss >1000 ml is unlikely in HCV- and HCV+ patients with the mean density of erythrocytes not surpassing the normal values. PMID- 28361433 TI - Ultrastructural Characteristics of Placental Telocytes. AB - Telocytes of placental villi were studied by electronic microscopy during physiological pregnancy. Ultrastructural features of telocytes indicating their heterogeneity and presence of at least three types of villi depending on their localization and kind were observed. All placental telocytes were characterized by small amount of organelles including mitochondria. Presence of long thin processes, which generated a branching network by contacting with each other, served as a typical feature of telocytes including telocytes of the stroma and intermediate villi. Telocytes were absent in the terminal villi. PMID- 28361434 TI - Comparative Analysis of Structural Responses of Rat Subcutaneous Fat on the Implantation of Samples of Polymethyl Methacrylate with Hydrophobic and Hydrophilic Surface. AB - Morphological analysis of the subcutaneous fat was performed in rats after subcutaneous implantation of basic dental plastic materials with different hydrophobic and hydrophilic properties. It was shown that subcutaneous implantation of dental plastics with mostly hydrophobic surface and low biocompatibility induced destructive and inflammatory processes of various intensities, sometimes with allergic component; morphological signs of processes persisted for 6 weeks. Modification of basic plastics using glow-discharge plasma and enhancement of their hydrophilicity and biocompatibility significantly reduced the intensity of destructive and inflammatory processes and ensured more rapid (in 2 weeks) repair of the destroyed tissues with the formation of fibrous capsule around the implant. PMID- 28361435 TI - The time course of morphological processing during spoken word recognition in Chinese. AB - We investigated the time course of morphological processing during spoken word recognition using the printed-word paradigm. Chinese participants were asked to listen to a spoken disyllabic compound word while simultaneously viewing a printed-word display. Each visual display consisted of three printed words: a semantic associate of the first constituent of the compound word (morphemic competitor), a semantic associate of the whole compound word (whole-word competitor), and an unrelated word (distractor). Participants were directed to detect whether the spoken target word was on the visual display. Results indicated that both the morphemic and whole-word competitors attracted more fixations than the distractor. More importantly, the morphemic competitor began to diverge from the distractor immediately at the acoustic offset of the first constituent, which was earlier than the whole-word competitor. These results suggest that lexical access to the auditory word is incremental and morphological processing (i.e., semantic access to the first constituent) that occurs at an early processing stage before access to the representation of the whole word in Chinese. PMID- 28361436 TI - The effect of character contextual diversity on eye movements in Chinese sentence reading. AB - Chen, Huang, et al. (Psychonomic Bulletin & Review, 2017) found that when reading two-character Chinese words embedded in sentence contexts, contextual diversity (CD), a measure of the proportion of texts in which a word appears, affected fixation times to words. When CD is controlled, however, frequency did not affect reading times. Two experiments used the same experimental designs to examine whether there are frequency effects of the first character of two-character words when CD is controlled. In Experiment 1, yoked triples of characters from a control group, a group matched for character CD that is lower in frequency, and a group matched in frequency with the control group, but higher in character CD, were rotated through the same sentence frame. In Experiment 2 each character from a larger set was embedded in a separate sentence frame, allowing for a larger difference in log frequency compared to Experiment 1 (0.8 and 0.4, respectively). In both experiments, early and later eye movement measures were significantly shorter for characters with higher CD than for characters with lower CD, with no effects of character frequency. These results place constraints on models of visual word recognition and suggest ways in which Chinese can be used to tease apart the nature of context effects in word recognition and language processing in general. PMID- 28361437 TI - Effect of Preventive and Curative Fingolimod Treatment Regimens on Microglia Activation and Disease Progression in a Rat Model of Multiple Sclerosis. AB - Fingolimod was the first oral drug approved for multiple sclerosis treatment. Its principal mechanism of action is blocking of lymphocyte trafficking. In addition, recent studies have shown its capability to diminish microglia activation. The effect of preventive and curative fingolimod treatment on the time-course of neuroinflammation was investigated in the experimental autoimmune encephalomyelitis rat model for multiple sclerosis. Neuroinflammatory progression was followed in Dark Agouti female rats after immunization. Positron-Emission tomography (PET) imaging with (R)-[11C]PK11195 was performed on day 11, 15, 19, 27, 29 and 34 during normal disease progression, preventive and curative treatments with fingolimod (1 mg/kg/day). Additionally, bodyweight and clinical symptoms were determined. Preventive treatment diminished bodyweight loss and inhibited the appearance of neurological symptoms. In non-treated rats, PET showed that neuroinflammation peaked in the brainstem at day 19, whereas the imaging signal was decreased in cortical regions. Both preventive and curative treatment reduced neuroinflammation in the brainstem at day 19. Eight days after treatment withdrawal, neuroinflammation had flared-up, especially in cortical regions. Preventive treatment with fingolimod suppressed clinical symptoms and neuroinflammation in the brainstem. After treatment withdrawal, clinical symptoms reappeared together with neuroinflammation in cortical regions, suggesting a different pathway of disease progression. PMID- 28361438 TI - Drug Utilization of Japanese Patients Diagnosed with Schizophrenia: An Administrative Database Analysis. AB - BACKGROUND AND OBJECTIVE: Patient characteristics require consideration for optimal treatment in order to achieve clinical remission for an improved quality of life and social functioning. Prior evidence supports long-acting injectable antipsychotics (LAIs) in the relapse prevention of schizophrenia. This study aimed to characterize Japanese patients diagnosed with schizophrenia and to compare the outcomes of LAIs and oral antipsychotics (AP) in re-hospitalization or emergency room visit rates. METHODS: Diagnostic Procedure Combination (DPC) designated hospital data in Japan with ICD-10 code F20x between July 2013 and June 2015 were obtained from the Medical Data Vision Co. Ltd. Patients were divided into sub-groups in order to filter co-diagnostic conditions. Differences across sub-groups were assessed using a Chi square test or ANOVA. The incidence rate ratio (IRR) was calculated to compare the re-hospitalization (30 days post discharge) or emergency room visit rates between pharmacotherapy groups of oral versus LAI or typical versus atypical within LAI patients. Adjusted estimates were provided by propensity scores that were assigned for age, gender, and Charlson co-morbidity index (CCI) scores. RESULTS: A quarter of the data sourced were attributed to co-diagnosis with dementia/delirium with antipsychotic prescriptions despite reported risks of antipsychotic use. After adjusting for age, gender, and co-morbidity, LAI reduced re-hospitalization and emergency (ER) visit rates more than oral APs (LAI vs. oral IRR = 0.38 (95% CI 0.17-0.74), IRR = 0.56 (95% CI 0.34-0.91), respectively). CONCLUSION: The study findings demonstrate usage of DPC hospital data in schizophrenia pharmacotherapy based on classification of co-diagnoses. In comparison with oral APs only, LAI utilization can provide an opportunity for reduced re-hospitalization and ER visit rates among patients with schizophrenia. PMID- 28361439 TI - Cost-Effectiveness Analysis of Regorafenib for Gastrointestinal Stromal Tumour (GIST) in Germany. AB - BACKGROUND: No study has compared the cost-effectiveness of active treatment options for unresectable or metastatic gastrointestinal stromal tumours in patients who progressed on or are intolerant to prior treatment with imatinib and sunitinib. The aim of this study was to estimate the cost-effectiveness of regorafenib compared to imatinib rechallenge in this setting in Germany. METHODS: Hazard ratios for progression-free (PFS) and overall survival (OS) with regorafenib versus imatinib rechallenge were estimated by indirect comparison. A state distribution model was used to simulate progression, mortality and treatment costs over a lifetime horizon. Drug acquisition costs and utilities were derived from clinical trial data and published literature; non-drug costs were not included. The outcomes measured were treatment costs, life-years (LYs) and quality-adjusted life-years (QALYs). RESULTS: The indirect comparison suggested that median PFS and OS were longer with regorafenib compared to imatinib but results were not statistically significant. Regorafenib versus imatinib rechallenge was estimated to have hazard ratios of 0.58 (95% CI 0.31 1.11) for PFS and 0.77 (95% CI 0.34-1.77) for OS, with substantial uncertainty due to the rarity of the disease and small number of patients within the trials. Regorafenib treatment per patient over a lifetime horizon provided an additional 0.61 LYs and 0.42 QALYs over imatinib rechallenge, with additional direct drug costs of ?8,773. The incremental cost-effectiveness ratio was ?21,127 per QALY gained. At a cost-effectiveness threshold of ?50,000 per QALY, regorafenib had a 67% probability of being cost-effective. CONCLUSION: Based on the currently available clinical data, this analysis suggests that regorafenib is cost effective compared with imatinib rechallenge in Germany. PMID- 28361441 TI - The effect of a telephone-based cognitive behavioral therapy on quality of life: a randomized controlled trial. AB - Health-related quality of life (HRQoL) has emerged as a major public health concern in perinatal care. The purpose of this study was to examine the effect of telephone-based cognitive behavioral therapy (T-CBT) on HRQoL among Chinese mothers at risk of postnatal depression at 6 weeks and 6 months postpartum. A multi-center randomized controlled trial was conducted at the postnatal units of three regional hospitals. Three hundred and ninety-seven women at risk of postnatal depression were recruited and were randomly assigned to the T-CBT (n = 197) or usual care (n = 200). Assessment was conducted at baseline, 6 weeks and 6 months postpartum for HRQoL. Women in the T-CBT experienced greater improvement in the physical component of HRQoL from baseline to 6 weeks and 6 months postpartum than the usual care group. At 6 months postpartum, the T-CBT group also experienced better HRQoL in the mental component of HRQoL than the usual care group. The T-CBT appears to be feasible and effective in improving HRQoL in women at risk of postnatal depression in the primary care practice. PMID- 28361442 TI - Natural polyprenylated benzophenone: keto-enol tautomerism from density functional calculations and the AIM theory. AB - The quantum theory of atoms in molecules (QTAIM) and density functional theory (DFT) calculations were employed to investigate the structure and tautomeric equilibrium of epiclusianone, a polyisoprenylated benzophenone with interesting biological activities. Two different exchange-correlation functionals were employed, namely omegaB97x-D and M06-2x, including implicit solvent models (benzene and DMSO). Our results for the thermodynamic properties show that the isomer in which the H atom is bonded to the oxygen away from the benzene ring is the most stable tautomer form of the epiclusianone, thus confirming previous charge density analysis from X-ray diffraction data (Martins et al. J Braz Chem Soc 18(8):1515-1523, 22). PMID- 28361443 TI - Gaining insight into crizotinib resistance mechanisms caused by L2026M and G2032R mutations in ROS1 via molecular dynamics simulations and free-energy calculations. AB - ROS1 fusion kinase-highly expressed in a variety of human cancers-has emerged as an important and attractive target for anticancer drug design. Crizotinib, a well known drug approved by the FDA as an ALK inhibitor to treat advanced NSCLC, also shows potent inhibitoy activity against ROS1. However, the development of serious resistance due to secondary mutations has been observed in clinical studies. To provide insight into the mechanisms of this drug resistance, molecular dynamics simulations and free-energy calculations were carried out for complexes of crizotinib with wild-type (WT) ROS1 as well as the mutated L2026M and G2032R forms. MD simulations indicated that the L2026M and G2032R systems are slightly less flexible than the WT system. Binding free energy calculations showed that the L2026M and G2032R mutations significantly reduce the binding affinity of crizotinib for ROS1, and that the resistance to crizotinib caused by the L2026M and G2032R mutations arises mostly from increases in entropic terms. Furthermore, calculations of per-residue binding free energies highlighted increased and decreased contributions of some residues in the L2026M and G2032R systems relative to those in the WT system. The present study therefore yielded detailed insight into the mechanisms of resistance to crizotinib caused by the L2026M and G2032R mutations, which should provide the basis for rational drug design to combat crizotinib resistance. Graphical Abstract Superposition of the average structures obtained from the last 10 ns of the molecular dynamics simulation trajectoriy for WT (green) and mutated ROS1 (cyan). PMID- 28361444 TI - Functional roles of T3.37 and S5.46 in the activation mechanism of the dopamine D1 receptor. AB - The activation mechanism of dopamine receptors is unknown. The amino acids S5.42, S5.43, and S5.46 located in helix 5 appear to be crucial, but their specific roles in receptor activation have not been studied. We modeled the D1 dopamine receptor using the crystal structures of the D3 dopamine and beta2 adrenergic receptors. Molecular dynamics simulations show that the interaction of dopamine with the D1 receptor leads to the formation of a hydrogen-bond network with its catechol group and helices 3, 5, and 6, including water molecules. The para hydroxyl group of dopamine binds directly to S5.42 and N6.55, the latter also interacting with S5.43. Unexpectedly, S5.46 does not interact directly with the catechol; instead, it interacts through a water molecule with S5.42 and directly with T3.37. The formation of this hydrogen-bond network, part of which was previously observed in docking studies with dopamine agonists, triggers the opening of the E6.30-R3.60 ionic lock associated with the activation of GPCRs. These changes do not occur in the unbonded (apo) receptor or when it is in a complex with the antagonist 3-methoxy-5,6,7,8,9,14-hexahydrodibenz[d,g]azecine. Our results provide valuable insight into the T3.37-S5.46-water-S5.43-ligand interaction, which may be crucial to the activation of the D1 dopamine receptor and should be considered during the design of novel agonists. Graphical Abstract General representation of the relationship between the formation of the HBN and the opening of the R3.50-E6.30 ionic lock. PMID- 28361445 TI - Roles of Probiotic Lactobacilli Inclusion in Helping Piglets Establish Healthy Intestinal Inter-environment for Pathogen Defense. AB - The gastrointestinal tract of pigs is densely populated with microorganisms that closely interact with the host and with ingested feed. Gut microbiota benefits the host by providing nutrients from dietary substrates and modulating the development and function of the digestive and immune systems. An optimized gastrointestinal microbiome is crucial for pigs' health, and establishment of the microbiome in piglets is especially important for growth and disease resistance. However, the microbiome in the gastrointestinal tract of piglets is immature and easily influenced by the environment. Supplementing the microbiome of piglets with probiotic bacteria such as Lactobacillus could help create an optimized microbiome by improving the abundance and number of lactobacilli and other indigenous probiotic bacteria. Dominant indigenous probiotic bacteria could improve piglets' growth and immunity through certain cascade signal transduction pathways. The piglet body provides a permissive habitat and nutrients for bacterial colonization and growth. In return, probiotic bacteria produce prebiotics such as short-chain fatty acids and bacteriocins that benefit piglets by enhancing their growth and reducing their risk of enteric infection by pathogens. A comprehensive understanding of the interactions between piglets and members of their gut microbiota will help develop new dietary interventions that can enhance piglets' growth, protect piglets from enteric diseases caused by pathogenic bacteria, and maximize host feed utilization. PMID- 28361448 TI - Variability of aggregation extent of light-harvesting pigments in peripheral antenna of Chloroflexus aurantiacus. AB - The stationary ground state and femtosecond time-resolved absorption spectra as well as spectra of circular dichroism were measured at room temperature using freshly prepared samples of chlorosomes isolated from fresh cultures of the green bacterium Chloroflexus aurantiacus. Cultures were grown by using as inoculum the same seed culture but under different light conditions. All measured spectra clearly showed the red shift of BChl c Qy bands (up to 5 nm) for low-light chlorosomes as compared to high-light ones, together with concomitant narrowing of these bands and increasing of their amplitudes. The sizes of the unit BChl c aggregates of the high-light-chlorosomes and the low-light ones were estimated. The fit of all experimental spectra was obtained within the framework of our model proposed before (Fetisova et al., Biophys J 71:995-101, 1996). The model assumes that a unit building block of the BChl c antenna has a form of a tubular aggregate of L = 6 linear single or double exciton-coupled pigment chains within a rod element, with the pigment packing density, approximating that in vivo. The simultaneous fit of all experimental spectra gave the number of pigments in each individual linear pigment chain N = 4 and N = 6 for the high-light and the low light BChl c unit building blocks, respectively. The size of a unit building block in the BChl c antenna was found to vary from L * N = 24 to L * N = 36 exciton-coupled BChl c molecules being governed by the growth-light intensity. All sets of findings for Chloroflexus aurantiacus chlorosomes demonstrated the biologically expedient light-controlled variability, predicted by us, of the extent of BChl c aggregation within a unit building block in this antenna. PMID- 28361447 TI - Reproductive factors and incidence of endometrial cancer in U.S. black women. AB - PURPOSE: Previous studies have shown that reproductive history is a strong determinant of endometrial cancer risk among white women. Less is known about how reproductive history affects endometrial cancer risk among black women, whose incidence and mortality differ from white women. We investigated the associations of age at menarche, parity, timing of births, and menopausal age with endometrial cancer in the Black Women's Health Study, a prospective cohort study. METHODS: Every 2 years from 1995 to 2013, 47,555 participants with intact uteri at baseline in 1995 completed questionnaires on reproductive and medical history, and lifestyle factors. Self-reported cases of endometrial cancer were confirmed by medical record, cancer registry, or death certificate when available. Cox proportional hazards regression was used to estimate multivariable incidence rate ratios (IRR) and 95% confidence intervals (CI). RESULTS: During 689,501 person years of follow-up, we identified 300 incident cases of endometrial cancer. The strongest associations with endometrial cancer were found for early age at menarche (<11 vs. 12-13 years: IRR 1.82, 95% CI 1.31, 2.52), and later age at first birth (>=30 vs. <20 years: IRR 0.26, 95% CI 0.13, 0.50). Parous women were less likely than nulliparous women to develop endometrial cancer (IRR 0.77, 95% CI 0.57, 1.05), but there was little evidence of a dose-response relationship for number of births. CONCLUSION: Associations between reproductive factors and endometrial cancer among black women were generally consistent with those in studies of white women. PMID- 28361446 TI - Does milk intake promote prostate cancer initiation or progression via effects on insulin-like growth factors (IGFs)? A systematic review and meta-analysis. AB - PURPOSE: To establish whether the association between milk intake and prostate cancer operates via the insulin-like growth factor (IGF) pathway (including IGF I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3). METHODS: Systematic review, collating data from all relevant studies examining associations of milk with IGF, and those examining associations of IGF with prostate cancer risk and progression. Data were extracted from experimental and observational studies conducted in either humans or animals, and analyzed using meta-analysis where possible, with summary data presented otherwise. RESULTS: One hundred and seventy-two studies met the inclusion criteria: 31 examining the milk-IGF relationship; 132 examining the IGF prostate cancer relationship in humans; and 10 animal studies examining the IGF prostate cancer relationship. There was moderate evidence that circulating IGF-I and IGFBP-3 increase with milk (and dairy protein) intake (an estimated standardized effect size of 0.10 SD increase in IGF-I and 0.05 SD in IGFBP-3 per 1 SD increase in milk intake). There was moderate evidence that prostate cancer risk increased with IGF-I (Random effects meta-analysis OR per SD increase in IGF I 1.09; 95% CI 1.03, 1.16; n = 51 studies) and decreased with IGFBP-3 (OR 0.90; 0.83, 0.98; n = 39 studies), but not with other growth factors. The IGFBP-3 202A/C single nucleotide polymorphism was positively associated with prostate cancer (pooled OR for A/C vs. AA = 1.22; 95% CI 0.84, 1.79; OR for C/C vs. AA = 1.51; 1.03, 2.21, n = 8 studies). No strong associations were observed for IGF II, IGFBP-1 or IGFBP-2 with either milk intake or prostate cancer risk. There was little consistency within the data extracted from the small number of animal studies. There was additional evidence to suggest that the suppression of IGF-II can reduce tumor size, and contradictory evidence with regards to the effect of IGFBP-3 suppression on tumor progression. CONCLUSION: IGF-I is a potential mechanism underlying the observed associations between milk intake and prostate cancer risk. PMID- 28361449 TI - Interaction and electron transfer between ferredoxin-NADP+ oxidoreductase and its partners: structural, functional, and physiological implications. AB - Ferredoxin-NADP+ reductase (FNR) catalyzes the last step of linear electron transfer in photosynthetic light reactions. The FAD cofactor of FNR accepts two electrons from two independent reduced ferredoxin molecules (Fd) in two sequential steps, first producing neutral semiquinone and then the fully anionic reduced, or hydroquinone, form of the enzyme (FNRhq). FNRhq transfers then both electrons in a single hydride transfer step to NADP+. We are presenting the recent progress in studies focusing on Fd:FNR interaction and subsequent electron transfer processes as well as on interaction of FNR with NADP+/H followed by hydride transfer, both from the structural and functional point of views. We also present the current knowledge about the physiological role(s) of various FNR isoforms present in the chloroplasts of higher plants and the functional impact of subchloroplastic location of FNR. Moreover, open questions and current challenges about the structure, function, and physiology of FNR are discussed. PMID- 28361452 TI - Great Expectations: HIV Risk Behaviors and Misperceptions of Low HIV Risk among Incarcerated Men. AB - Incarcerated populations have relatively high HIV prevalence but little has been reported about their aggregate HIV risk behaviors or perceptions of risk. A random selection of HIV-negative men (n = 855) entering a US state prison system were surveyed to assess five risk behaviors and his self-perceived HIV risk. Using multivariate logistic regression, we identified factors associated with having elevated actual but low perceived risk (EALPR). Of the 826 men with complete data, 88% were at elevated risk. While 64% of the sample had risk perceptions concordant with their actual risk, 14% had EALPR (with the remainder at low actual but high perceived risk). EALPR rates were lower in those with a pre-incarceration HIV test but higher for those with a negative prison entry HIV test. HIV testing counseling should assess for discordance between actual and perceived risk and communicate the continued risk of HIV despite a negative result. PMID- 28361451 TI - Long-term Duration of First-Line Axitinib Treatment in Advanced Renal Cell Carcinoma. AB - OBJECTIVE: We conducted a retrospective analysis of two clinical trials in treatment-naive patients (n = 402) with advanced renal cell carcinoma (RCC) treated with axitinib. Our objective was to compare duration of treatment (DT) and clinical outcome in patients who achieved DT >18 months (longer DT) versus <=18 months (shorter DT). PATIENTS AND METHODS: DT, objective response rate (ORR), tumor shrinkage, and overall survival (OS) were summarized for patients with longer and shorter DT. RESULTS: Overall, 152 patients (37.8%) had longer DT and 250 (62.2%) had shorter DT (median, 34.7 vs. 6.5 months, respectively). ORR in all 402 patients with advanced RCC was 43.5%. ORR was 75% for longer DT versus 24.4% for shorter DT (p < 0.0001). More patients with longer DT versus shorter DT had >=10% tumor shrinkage at first scan (74.8% vs. 55.3%; p = 0.0001) and maximum on-study tumor shrinkage was greater in longer-DT versus shorter-DT group (-51.8% vs. -22.1%; p < 0.0001). Median OS was 32.6 months in the overall population while in the patients with longer DT the median was not reached. Treatment related adverse events (AEs) grade >=3 were more frequent in longer-DT versus shorter-DT and included hypertension (25.7% vs. 18.8%), diarrhea (15.1% vs. 4.4%), and weight decrease (11.2% vs. 3.2%); however, these AEs decreased over time in both groups. Eastern Cooperative Oncology Group performance status 0, favorable hematology values, no bone or liver metastases, and baseline tumor burden below the overall median were associated with longer DT. CONCLUSIONS: Longer duration (>18 months) of axitinib treatment was associated with increased frequency of early tumor shrinkage, greater magnitude of tumor shrinkage, and a favorable OS. PMID- 28361454 TI - Self-Report and Dry Blood Spot Measurement of Antiretroviral Medications as Markers of Adherence in Pregnant Women in Rural South Africa. AB - Antiretroviral (ARV) adherence is essential to prevent mother-to-child transmission of HIV. This study compared self-reported adherence versus ARV detection in dried blood spots (DBS) among N = 392 HIV-infected pregnant women in South Africa (SA). Women completed two self-reported adherence measures [visual analog scale (VAS), AIDS Clinical Trials Group Adherence (ACTG)]. Adherence was 89% (VAS), 80% (ACTG), and 74% (DBS). Self-report measures marginally agreed with DBS (VAS: Kappa = 0.101, Area under the ROC curve (AUROC) = 0.543; ACTG: Kappa = 0.081, AUROC = 0.538). Self-reported adherence was overestimated and agreement with DBS was poor. Validation of self-reported ARV adherence among pregnant HIV+ women in SA is needed. PMID- 28361455 TI - Development of Albumin Coupled, Cholesterol Stabilized, Lipid Nanoemulsion of Methotrexate, and TNF-alpha Inhibitor for Improved In Vivo Efficacy Against Rheumatoid Arthritis. AB - Methotrexate (MTX; an anti-folate) and etanercept (ET; a TNF-alpha inhibitor) are used against arthritis; however, limitations like short biological half-life, low cutaneous absorption, and acidic instability limit their clinical relevance. Therefore, the aim of the investigation was to develop albumin coupled lipid nanoemulsion of MTX and ET for improved efficacy by virtue of their controlled release and specificity at the arthritic site. This emulsion was prepared by high speed homogenization and stabilized using cholesterol. Lipid nanoemulsion of MTX and ET (MTX+ET-LNE) was coupled with albumin (MTX+ET-ALNE). MTX+ET-ALNE was characterized on the basis of particle size (410 +/- 25.4 nm), PDI (0.160), and zeta potential (+38.6 +/- 5.6 mV) and evaluated for pH (6.15), drug content (97.7 +/- 2.17%), entrapment efficiency (76 +/- 4.6%), in vitro release, and in vitro cytotoxicity. About 82.6 +/- 9.60% release of MTX+ET was observed in 24 h from the developed MTX+ET-ALNE which may help maintain therapeutic level of drugs in blood at least for one day. No toxicity was observed when Raw 264.7 cells were treated with MTX+ET-ALNE, and no causalities of mice were observed at experimental in vivo dose (10 mg/kg BW) of MTX+ET in MTX+ET-ALNE-treated group. MTX+ET-ALNE treatment has alleviated arthritic scores and inflammatory cytokines level in a very significant manner when compared with MTX+ET-LNE and MTX+ET solutions. MTX+ET-ALNE-treated group restored histological alterations (cartilage/bone erosion, inflammatory cell infiltration, synovial hyperplasia, and narrower joint space) as observed in diseased treated groups. In conclusion, MTX+ET-ALNE can be opted as efficacious and clinically pertinent option to the current medication systems of arthritis. PMID- 28361458 TI - In remembrance of Professor Mario Andreoli (1929-2016). PMID- 28361456 TI - Transition of stable patients from traditional anticoagulation clinic services to telephonic management. AB - Background Outpatient warfarin dosing and monitoring with telephonic anticoagulation management (TAM) could be an effective alternative to other more labor intensive management models. Objectives To evaluate the time in therapeutic range (TTR) and number of extreme INR values (<1.5 or >4.5) of a telephonic system of warfarin management for stable patients who currently utilized traditional anticoagulation management services (AMSs). Method A retrospective, observational cohort with three groups (1) patients transitioned from an office based anticoagulation clinic to TAM, (2) patients continuously enrolled in office based AMS, (3) patients continuously managed by usual physician care without specialized anticoagulation services (UPC). Data was collected for six months before and six months after transition. Results All groups demonstrated decreased TTR from baseline to active phase, with the TAM and AMS groups showing similar magnitude of reduction (-10.61 and -12.66% respectively) but UPC group producing a greater drop (-20.08%). The TAM and AMS groups had similar rates of extreme INR levels; UPC had higher numbers of extreme INRs in three of the four measurements. Conclusion Stable patients transitioned from office-based anticoagulation clinic to a telephonic model of management performed equally as well as those who continued traditional enrollment. PMID- 28361457 TI - Myxobolus lepomis n. sp. (Cnidaria: Myxobolidae), a gill myxozoan infecting Lepomis marginatus Holbrook and Lepomis miniatus Jordan (Perciformes: Centrarchidae), in the Big Thicket National Preserve, Texas, USA. AB - A parasitological survey of freshwater fishes in the Big Thicket National Preserve in southeast Texas revealed myxozoan infections in two species of sunfish, Lepomis marginatus Holbrook and Lepomis miniatus Jordan (Perciformes: Centrarchidae). Pseudocysts were elongate-oval, 988 * 485 um (ex L. marginatus) and 800 * 606 um (ex L. miniatus) and demonstrated a predilection to the edge of the primary gill lamellae. Myxospores consistent with the genus Myxobolus were oblong, 16.8-21.3 (19.0 +/- 0.9) um long, 7.0-8.8 (7.9 +/- 0.5) um wide and 5.3 6.1 (5.8 +/- 0.3) um thick (ex L. marginatus) and 17.2-20.3 (18.8 +/- 0.7) um long, 7.5-9.9 (8.7 +/- 0.6) um wide, and 6.8-7.2 (7.0 +/- 0.2) um thick (ex L. miniatus); with 2 pyriform polar capsules 8.3-9.8 (9.0 +/- 0.5) um long, 2.2-2.7 (2.5 +/- 0.2) um wide (ex L. marginatus) and 9.2-10.5 (10.0 +/- 0.4) um long, 2.2 3.0 (2.8 +/- 0.2) um wide (ex L. miniatus). Statistically, the measurements of spore body width, polar capsule length, and polar capsule width were significantly different between myxospores from L. marginatus and L. miniatus. However, intraspecific genetic variability between isolates at the 18S rRNA gene was negligible, with < 0.8% variability across > 2,000 bp of sequence. The isolates shared no significant sequence similarity with any myxozoan deposited in the GenBank nucleotide database. Phylogenetic analysis inferred from the 18S rRNA gene from both L. marginatus and L. miniatus placed the isolates within a clade of myxozoan parasites of perciform fishes. Based on shared tissue and host family tropism, overlapping morphological characters and high degrees of sequence conservation at the 18S rRNA gene, we propose these isolates as morphologically distinct, genetically conspecific representatives of M. lepomis n. sp. from the gills of L. marginatus and L. miniatus in the Big Thicket National Preserve in Texas, USA. PMID- 28361460 TI - Influence of Long Term Application of Butachlor on its Dissipation and Harvest Residues in Soil and Rice. AB - The study delineates the effect of repeated application of butachlor to rice crop from 1997 onwards. Additionally, in 2014 and 2015, dissipation kinetics of butachlor in soil was studied under field and laboratory conditions. The average recovery of butachlor for soil, rice grain and rice straw ranged between 80.3% 93.2% and 82.8%-96.5% with quantification limit of 0.01 and 0.003 ug g-1 for HPLC and GC-MS/MS, respectively. The dissipation of butachlor followed first order kinetics and half-life under long term field trials in rice soil varied from 15.2 to 19.29 days and 25.94 to 29.79 days under field and laboratory conditions, respectively. The residue of butachlor in soil, rice grain and straw samples at harvest over the years was below the quantification limit and no quantifiable amount of metabolites were present in soil at harvest suggestive of its safe application. PMID- 28361459 TI - Distribution and antifungal susceptibility of yeasts isolates from intensive care unit patients. AB - Yeasts frequently colonize non-sterile sites in the body. The aim of the study was to determine distribution in clinical samples and antifungal susceptibility to five antifungals. From January 2013 through June 2015, 800 isolates were obtained from intensive care unit patients. Candida albicans (58.9%), Candida glabrata (20.4%), Candida krusei (8.6%), and Candida parapsilosis (3.6%) were the leading species. Majority of the C. albicans isolates were susceptible to the fluconazole. Elevated voriconazole minimal inhibitory concentrations (MICs) were observed in isolates exhibiting high fluconazole MICs, most frequently in C. glabrata. Isolates with echinocandins MICs suggesting reduced susceptibility were only sporadic cases with the exception of Trichosporon spp. The amphotericin B MICs were slightly higher for some C. krusei. PMID- 28361453 TI - The Benefits of Psychosocial Interventions for Mental Health in People Living with HIV: A Systematic Review and Meta-analysis. AB - In this systematic review and meta-analysis we investigated the effectiveness of different psychosocial treatments for people living with HIV (PLWH) and mental health problems. Additionally, characteristics that may influence the effectiveness of a treatment (e.g., treatment duration) were studied. PubMed, PsycINFO and Embase were searched for randomized controlled trials on psychosocial interventions for PLWH. Depression, anxiety, quality of life, and psychological well-being were investigated as treatment outcome measures. Sixty two studies were included in the meta-analysis. It was found that psychosocial interventions for PLWH had a small positive effect on mental health (g = 0.19, 95% CI [0.13, 0.25]). Furthermore, there was evidence for publication bias. Six characteristics influenced the effectiveness of a treatment for depression. For example, larger effects were found for studies with psychologists as treatment providers. To conclude, this systematic review and meta-analysis suggests that psychosocial interventions have a beneficial effect for PLWH with mental health problems. PMID- 28361461 TI - Bisphenol A Removal by Submerged Macrophytes and the Contribution of Epiphytic Microorganisms to the Removal Process. AB - Bisphenol A (BPA), a typical endocrine disruptor, has been found in global aquatic environments, causing great concern. The capabilities of five common submerged macrophytes to remove BPA from water and the contributions of epiphytic microorganisms were investigated. Macrophytes removed 62%-100% of total BPA (5 mg/L) over 12 days; much higher rates than that observed in the control (2%, F = 261.511, p = 0.000). Ceratophyllum demersum was the most efficient species. C. demersum samples from lakes with different water qualities showed no significant differences in BPA removal rates. Moreover, removal, inhibition or re colonization of epiphytic microorganisms did not significantly change the BPA removal rates of C. demersum. Therefore, the contributions of epiphytic microorganisms to the BPA removal process were negligible. The rate of BPA accumulation in C. demersum was 0.1%, indicating that BPA was mainly biodegraded by the macrophyte. Hence, submerged macrophytes, rather than epiphytic microorganisms, substantially contribute to the biodegradation of BPA in water. PMID- 28361462 TI - PPAR-alpha Agonist Fenofibrate Reduces Insulin Resistance in Impaired Glucose Tolerance Patients with Hypertriglyceridemia: A Cross-Sectional Study. AB - INTRODUCTION: Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonists can regulate metabolism and protect the cardiovascular system. This study investigated the effects of PPAR-alpha agonist fenofibrate on insulin resistance in patients with impaired glucose tolerance (IGT). METHODS: This research evaluated cross-sectional and interventional studies. 191 subjects with IGT were divided into a hypertriglyceridemia group (HTG group, n = 118) and a normal triglyceride (TG) group (NTG group, n = 73). 79 subjects with normal glucose tolerance were recruited as a control group. The HTG group was treated with fenofibrate (200 mg/day) for 12 weeks. The homeostatic model assessment index 2 (HOMA2) and the McAuley index (McA) were calculated. RESULTS: HOMA2 for beta-cell function (HOMA2-%B) was 93.47 +/- 26.28, 68.47 +/- 21.29, and 79.92 +/- 23.15 in HTG, NTG, and control groups, respectively. HOMA2 for insulin sensitivity (HOMA2-%S) was 48.40 (39.70, 68.70), 110.20 (62.55, 141.95), and 101.20 (79.90, 140.10) in HTG, NTG, and control groups, respectively. HOMA2 for insulin resistance (HOMA2-IR) was 2.09 (1.46, 2.52), 0.92 (0.70, 1.61), and 0.99 (0.71, 1.25) in HTG, NTG, and control groups, respectively. McA was 5.05 +/- 0.76, 7.99 +/- 1.79, and 8.34 +/- 1.55 in HTG, NTG, and control groups, respectively. The HTG group had higher HOMA2-%B and HOMA2-IR, and lower HOMA2-%S and McA than NTG and control groups (P < 0.001 for all). Fenofibrate decreased HOMA2-%B and HOMA2-IR and increased HOMA2-%S and McA in the HTG group (HOMA2-%B: from 93.47 +/- 26.28 to 89.34 +/- 23.53, P = 0.018; HOMA2-%S: from 48.40 (39.70, 68.70) to 56.75 (44.88, 72.53), P < 0.001; HOMA2-IR: from 2.07 (1.46, 2.52) to 1.76 (1.38, 2.30), P < 0.001; McA: from 5.05 +/- 0.76 to 9.34 +/- 0.88, P < 0.001). CONCLUSION: PPAR-alpha agonists improve parameters of glucoregulation in IGT patients with hypertriglyceridemia. PMID- 28361463 TI - Clinical Outcomes of Patients with Diabetes Who Exhibit Upper-Quartile Insulin Antibody Responses After Treatment with LY2963016 or Lantus(r) Insulin Glargine. AB - INTRODUCTION: We compared insulin antibody response (IAR) profiles in patients with type 1 diabetes (T1D) or type 2 diabetes (T2D) who received LY2963016 insulin glargine (LY IGlar) or Lantus(r) insulin glargine (IGlar) and evaluated the potential relationship between higher IARs and clinical and safety outcomes with a focus on patients who exhibited antibody responses in the upper quartile. METHODS: Data from ELEMENT-1 (52-week open-label in T1D) and ELEMENT-2 (24-week, double-blind study in T2D) were analyzed. Maximum postbaseline IAR levels and proportions of patients in the upper quartile of maximum antibody percent binding (UQMAPB; patients with maximum postbaseline percent binding in the highest 25% of maximum values observed) were compared for differential treatment effects on clinical efficacy outcomes and incidence of adverse events. Continuous outcomes were analyzed by analysis of covariance. Categorical data were analyzed by the Cochran-Mantel-Haenszel or Breslow-Day test. RESULTS: In both studies (N = 532 evaluable patients with T1D; N = 730 with T2D), no statistically significant differences between LY IGlar and IGlar were observed for maximum antibody percent binding (MAPB) levels or for proportions of patients in the respective UQMAPB. No statistically significant differential treatment effects were observed in the relationship between MAPB and clinical efficacy and safety outcomes. CONCLUSIONS: Maximum postbaseline IAR levels and the proportion of patients with high IAR levels were similar for LY IGlar and IGlar. High antibody levels did not affect clinical outcomes. These results add further evidence supporting similar IARs of LY IGlar and IGlar. FUNDING: Eli Lilly and Company and Boehringer-Ingelheim. PMID- 28361464 TI - Healthcare Resource Use, Costs, and Disease Progression Associated with Diabetic Nephropathy in Adults with Type 2 Diabetes: A Retrospective Observational Study. AB - INTRODUCTION: Diabetic nephropathy (DN) is a progressive kidney disease resulting as a complication of diabetes mellitus. This study evaluated the disease progression and economic burden of DN among commercially insured patients with type 2 diabetes in the USA. METHODS: The research design was a retrospective observational study based on healthcare claims data. The Truven MarketScan Databases (2004-2014) were queried for adults with type 2 diabetes with at least one urine albumin test (index, randomly selected) after diagnosis and at least one test after the index. On the basis of the index test, patients were classified into normoalbuminuria, microalbuminuria, or macroalbuminuria groups. Nephropathy-related treatment use was measured in the 6 months after the index, disease progression was assessed from the index to the end of data availability, and annual all-cause and nephropathy-related costs and healthcare resource use (HRU) were assessed up to 2 years from the index. Outcomes were compared between any two groups, controlling for baseline demographics. RESULTS: A total of 23,235 patients were identified and classified into normoalbuminuria (N = 18,409), microalbuminuria (N = 3863), or macroalbuminuria (N = 963) groups. Patients with albuminuria were more likely to be older, male, and have a higher burden of baseline comorbidities and HRU. Within 6 months following the index, 12-20% of patients with albuminuria were not treated with any relevant recommended treatment. Compared to the normoalbuminuria group, patients with macroalbuminuria had a significantly greater risk of disease progression (hazard ratio [HR] = 1.44), and both albuminuria groups were more likely to require dialysis (HR = 4.23 and 40.14 for micro- and macroalbuminuria, respectively; all p < 0.05). Annual all-cause (2016 US dollars, $3580 and $12,830 higher for micro- and macroalbuminuria vs. normoalbuminuria, respectively) and nephropathy-related ($362 and $3716) costs increased significantly with increasing nephropathy severity, consistent with the trend in increased HRU. CONCLUSIONS: Diabetic nephropathy may be undertreated or inappropriately treated. It was also associated with significantly higher costs, HRU, and risk of disease progression among commercially insured patients with type 2 diabetes in the USA. FUNDING: Takeda Development Center Americas, Inc. PMID- 28361440 TI - Acid-Suppressive Therapy and Risk of Infections: Pros and Cons. AB - This narrative review summarises the benefits, risks and appropriate use of acid suppressing drugs (ASDs), proton pump inhibitors and histamine-2 receptor antagonists, advocating a rationale balanced and individualised approach aimed to minimise any serious adverse consequences. It focuses on current controversies on the potential of ASDs to contribute to infections-bacterial, parasitic, fungal, protozoan and viral, particularly in the elderly, comprehensively and critically discusses the growing body of observational literature linking ASD use to a variety of enteric, respiratory, skin and systemic infectious diseases and complications (Clostridium difficile diarrhoea, pneumonia, spontaneous bacterial peritonitis, septicaemia and other). The proposed pathogenic mechanisms of ASD associated infections (related and unrelated to the inhibition of gastric acid secretion, alterations of the gut microbiome and immunity), and drug-drug interactions are also described. Both probiotics use and correcting vitamin D status may have a significant protective effect decreasing the incidence of ASD associated infections, especially in the elderly. Despite the limitations of the existing data, the importance of individualised therapy and caution in long-term ASD use considering the balance of benefits and potential harms, factors that may predispose to and actions that may prevent/attenuate adverse effects is evident. A six-step practical algorithm for ASD therapy based on the best available evidence is presented. PMID- 28361466 TI - Research with and about user participation: potentials and challenges. PMID- 28361467 TI - Effectiveness of decompression alone versus decompression plus fusion for lumbar spinal stenosis: a systematic review and meta-analysis. AB - INTRODUCTION: The debate on efficacy of fusion added to decompression for lumbar spinal stenosis (LSS) is ongoing. No meta-analysis has compared the effectiveness of decompression versus decompression plus fusion in treating patients with LSS. METHODS: A literature search was performed in the Web of Science, PubMed, Embase, and Springer databases from 1970 to 2016. Relevant references were selected and the included studies were manually reviewed. We included trials evaluating decompression surgery compared to decompression plus fusion surgery in treating patients with LSS. The primary outcomes analyzed were back pain, leg pain, Oswestry Disability Index scores (ODI), the quality-of-life EuroQol-5 Dimensions (EQ-5D), duration of operation, intraoperative blood loss, length of hospital stay, major complications, walking ability, number of reoperation, and finally clinically excellent and good rates. Data analysis was conducted using the Review Manager 5.2 software. RESULTS: Fifteen studies involving 17,785 patients with LSS were included. The overall effect mean difference (MD) (95% CI) in the differences between pre- and post-operative back pain, leg pain, operative time, intraoperative blood loss, and length of stay were 0.04 (-0.36, 0.44), 0.69 ( 0.38, 1.76), -2.04 (-3.12, -0.96), -3.96 (-6.64, -1.27) and -4.21 (-10.03, 1.62) (z = 0.18, 1.26, 3.71, 2.89 and 1.41, respectively; P = 0.86, 0.55, 0.0002, 0.004 and 0.16, respectively) in random effects models. The overall effect MD (95% CI) in ODI, EQ-5D, and walking ability were 0.43 (-1.15, 2.00), 0.01 (-0.01, 0.03) and 0.04 (-0.49, 0.57) (z = 0.52, 1.16 and 0.15, respectively; P = 0.59, 0.24 and 0.88, respectively) in fixed effects models. The overall effect odds ratio (OR) (95% CI) of major complications, number of reoperations, and clinically excellent and good rates between the two groups were 0.70 (0.60, 0.81), 1.04 (0.90, 1.19) and 0.31 (0.06, 1.59) (z = 4.63, 0.53 and 1.40, respectively; P < 0.00001, 0.60 and 0.16, respectively). Our study reveals no difference in the effectiveness between the two surgical techniques. CONCLUSIONS: The additional fusion in the management of LSS yielded no clinical improvements over decompression alone within a 2-year follow-up period. But fusion resulted in a longer duration of operation, more blood loss, and a higher risk of complications. Therefore, the appropriate surgical protocol for LSS should be discussed further. PMID- 28361465 TI - Antibody-Drug Conjugates (ADCs) for Personalized Treatment of Solid Tumors: A Review. AB - Attaching a cytotoxic "payload" to an antibody to form an antibody-drug conjugate (ADC) provides a mechanism for selective delivery of the cytotoxic agent to cancer cells via the specific binding of the antibody to cancer-selective cell surface molecules. The first ADC to receive marketing authorization was gemtuzumab ozogamicin, which comprises an anti-CD33 antibody conjugated to a highly potent DNA-targeting antibiotic, calicheamicin, approved in 2000 for treating acute myeloid leukemia. It was withdrawn from the US market in 2010 following an unsuccessful confirmatory trial. The development of two classes of highly potent microtubule-disrupting agents, maytansinoids and auristatins, as payloads for ADCs resulted in approval of brentuximab vedotin in 2011 for treating Hodgkin lymphoma and anaplastic large cell lymphoma, and approval of ado trastuzumab emtansine in 2013 for treating HER2-positive breast cancer. Their success stimulated much research into the ADC approach, with >60 ADCs currently in clinical evaluation, mostly targeting solid tumors. Five ADCs have advanced into pivotal clinical trials for treating various solid tumors-platinum-resistant ovarian cancer, mesothelioma, triple-negative breast cancer, glioblastoma, and small cell lung cancer. The level of target expression is a key parameter in predicting the likelihood of patient benefit for all these ADCs, as well as for the approved compound, ado-trastuzumab emtansine. The development of a patient selection strategy linked to target expression on the tumor is thus critically important for identifying the population appropriate for receiving treatment. PMID- 28361468 TI - Impact of Participation in the Adalimumab (Humira) Patient Support Program on Rheumatoid Arthritis Treatment Course: Results from the PASSION Study. AB - INTRODUCTION: Patients with rheumatoid arthritis (RA) who are treated with adalimumab (ADA) are offered a proprietary patient support program (PSP, AbbVie Care(r)). The main objective of this study was to examine the effectiveness of ADA on RA treatment course over time in the context of PSP utilization. METHODS: PASSION was a 78-week post-marketing observational study of RA patients with an insufficient response to >=1 DMARD newly initiating ADA in routine clinical care that was conducted in Europe, Israel, Mexico, Puerto Rico, and Australia. One prior biologic DMARD was allowed. The primary endpoint was percentage of patients achieving the minimal clinically important difference (MCID; improvement of >=0.22 compared to baseline) in Health Assessment Questionnaire (HAQ) Disability Index (HAQ-DI) at week 78. Additionally, multiple clinical and patient-reported outcomes (PROs) were evaluated over time. Patients were categorized based on their participation in the PSP: ever (PSP users) vs. never (PSP non-users). Safety events were monitored throughout the study. RESULTS: Overall, 42.8% of PSP users achieved the MCID in HAQ-DI at week 78 (improvement of at least 0.22 compared to baseline). From 1025 enrolled, 48.7% of patients were PSP users while treated with ADA. The percentage of patients achieving MCID in the HAQ-DI was higher in PSP users vs. PSP non-users (48.1 vs. 37.8%) at week 78 (p < 0.001, NRI). Most of the studied clinical outcomes and PROs showed significant improvements (p < 0.05) from baseline to week 78 favoring PSP users over PSP non users. CONCLUSIONS: In patients with moderate-to-severe RA who initiated ADA, improvements in clinical, functional, and PROs were achieved in real-world settings with significantly greater improvements among PSP users in comparison with PSP non-users. FUNDING: AbbVie. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01383421. PMID- 28361469 TI - Supracostal access for miniaturized percutaneous nephrolithotomy: comparison of supracostal and infracostal approaches. AB - In this study, we aimed to evaluate the efficiency and safety of supracostal and subcostal approaches during miniaturized percutaneous nephrolithotomy (mPNL). In two tertiary academic centers, we retrospectively analyzed the charts of patients who had undergone mPNL between January 2011 and June 2015 for the treatment of renal stones. Enrolled in the study were 49 patients who had access through the supracostal area (Group 1) and, to serve as controls, 49 patients who were accessed through the subcostal area (Group 2). To avoid potential bias between the groups, the patients were retrospectively matched one-on-one with respect to age, gender, body mass index, ASA score, and size and number of stones. The presence of upper calyx stones and distorted lower calyx anatomy were the most common reasons for performing supracostal access (57.1 and 28.6%, respectively). Access through 11-12 intercostal space was performed in 46 patients (93.9%), and the other three supracostal accesses (6.1%) were performed through the 10-11 intercostal area. The complication rates were 14.3% in Group 1 and 16.3% in Group 2 (p = 0.952). Final stone-free status had increased to 89.8 and 87.8% in Groups 1 and 2, respectively (p = 0.942). Our study demonstrated that mPNL resulted in acceptable stone-free rates whether accessed through either the supracostal or subcostal areas. Moreover, the supracostal approach with mPNL had no negative effect on any intraoperative and postoperative parameters, nor did it increase complication rates. PMID- 28361472 TI - A Global Perspective of Fine Particulate Matter Pollution and Its Health Effects. AB - Fine particulate matter (PM) in the ambient air is implicated in a variety of human health issues throughout the globe. Regulation of fine PM in the atmosphere requires information on the dimension of the problem with respect to variations in concentrations and sources. To understand the current status of fine particles in the atmosphere and their potential harmful health effects in different regions of the world this review article was prepared based on peer-reviewed scientific papers, scientific reports, and database from government organizations published after the year 2000 to evaluate the global scenario of the PM2.5 (particles <2.5 MUm in aerodynamic diameter), its exceedance of national and international standards, sources, mechanism of toxicity, and harmful health effects of PM2.5 and its components. PM2.5 levels and exceedances of national and international standards were several times higher in Asian countries, while levels in Europe and USA were mostly well below the respective standards. Vehicular traffic has a significant influence on PM2.5 levels in urban areas; followed by combustion activities (biomass, industrial, and waste burning) and road dust. In urban atmosphere, fine particles are mostly associated with different health effects with old aged people, pregnant women, and more so children being the most susceptible ones. Fine PM chemical constituents severely effect health due to their carcinogenic or mutagenic nature. Most of the research indicated an exceedance of fine PM level of the standards with a diverse array of health effects based on PM2.5 chemical constituents. Emission reduction policies with epidemiological studies are needed to understand the benefits of sustainable control measures for fine PM mitigation. PMID- 28361470 TI - Pathogenesis of calcium oxalate urinary stone disease: species comparison of humans, dogs, and cats. AB - Idiopathic calcium oxalate nephrolithiasis is a highly recurrent disease that is increasing in prevalence. Decades of research have not identified effective methods to consistently prevent the formation of nephroliths or induce medical dissolution. Idiopathic calcium oxalate nephroliths form in association with renal papillary subepithelial calcium phosphate deposits called Randall's plaques (RPs). Rodent models are commonly used to experimentally induce calcium oxalate crystal and stone formation, but a rodent model that conclusively forms RPs has not been identified. Both dogs and cats form calcium oxalate uroliths that can be recurrent, but the etiopathologic mechanisms of stone formation, especially renal pathologic findings, are a relatively unexploited area of study. A large animal model that shares a similar environment to humans, along with a shorter lifespan and thus shorter time to recurrence, might provide an excellent means to study preventative and therapeutic measures, along with enhancing the concepts of the one health initiative. This review article summarizes and compares important known features of idiopathic calcium oxalate stone disease in humans, dogs, and cats, and emphasizes important knowledge gaps and areas for future study in the quest to discover a naturally occurring animal model of idiopathic calcium oxalate stone disease. PMID- 28361473 TI - Extending the Quality and Reach of IPS. PMID- 28361471 TI - Perceiver as polar planimeter: Direct perception of jumping, reaching, and jump reaching affordances for the self and others. AB - Runeson (Scandanavian Journal of Psychology 18:172-179, 1977) suggested that the polar planimeter might serve as an informative model system of perceptual mechanism. The key aspect of the polar planimeter is that it registers a higher order property of the environment without computational mediation on the basis of lower order properties, detecting task-specific information only. This aspect was posited as a hypothesis for the perception of jumping and reaching affordances for the self and another person. The findings supported this hypothesis. The perception of reaching while jumping significantly differed from an additive combination of jump-without-reaching and reach-without-jumping perception. The results are consistent with Gibson's (The senses considered as perceptual systems, Houghton Mifflin, Boston, MA; Gibson, The senses considered as perceptual systems, Houghton Mifflin, Boston, MA, 1966; The ecological approach to visual perception, Houghton Mifflin, Boston, MA; Gibson, The ecological approach to visual perception, Houghton Mifflin, Boston, MA, 1979) theory of information-that aspects of the environment are specified by patterns in energetic media. PMID- 28361475 TI - Factors affecting appearance of a normal myocardial perfusion scan. PMID- 28361474 TI - Metabolic syndrome is predictive of lower urinary tract symptom improvement after holmium laser enucleation of the prostate for benign prostatic obstruction. AB - PURPOSE: To investigate the effect of metabolic syndrome (MS) on patient outcomes who underwent holmium laser enucleation of the prostate (HoLEP) for benign prostatic obstruction. MATERIALS AND METHODS: Data from 151 patients who underwent HoLEP by a single surgeon between March 2012 and March 2016 were retrospectively analyzed. Patients with MS were assigned to group 1 (n = 33) and patients without MS in group 2 (n = 118). Clinical characteristics and the International Prostate Symptom Score (IPSS), including quality of life (QoL), peak urinary flow rate (Qmax), and postvoid residual urine (PVR), before surgery and 3 months afterward were compared between groups. Additionally, predictors of total IPSS improvement after HoLEP were assessed. RESULTS: Compared with group 2 patients, group 1 patients were older (70.3 vs. 65.2 years old, p = 0.001). Preoperative data, which included prostate volume, QoL, Qmax, and PVR, were not different between groups. For all patients, both the storage subscore and voiding subscore significantly decreased after surgery (p < 0.001). Postoperative total IPSS and voiding subscore improvement in group 1 were lower than in group 2 (total IPSS improvement 9.2 vs. 12.5, p = 0.042; voiding subscore improvement 6.6 vs. 8.8, p = 0.048). Multivariate analysis showed preoperative total IPSS (beta = 0.79, CI 0.71-0.94, p < 0.001) and number of MS components (beta = -0.15, CI 2.04 to -0.29, p = 0.009) were independently associated with total IPSS improvement. CONCLUSIONS: We found that MS was associated with decreased postoperative symptom improvement. Thus, lower urinary tract symptoms after surgery may be a systemic disorder due to multiple metabolic risk factors. PMID- 28361476 TI - Left-ventricular mechanical dyssynchrony in the prognosis of dilated cardiomyopathy: Which parameter is more useful? PMID- 28361477 TI - Effect of patient positioning on the evaluation of myocardial perfusion SPECT. AB - BACKGROUND: ECG-gated SPECT myocardial perfusion imaging is usually acquired in supine position. However, some patients are not comfortable in this position for a variety of personal or medical reasons. Our aim was to investigate the effect of patient positioning on quantitative SPECT imaging results using normal supine database. METHODS: 55 patients (mean age 58.5 +/- 8.3 years) were enrolled in this prospective study. Each patient had a pair of ECG-gated stress SPECT myocardial perfusion images acquired on two gamma cameras: one in supine position and the other in upright sitting position. Left ventricular (LV) ejection fraction (EF), end-diastolic (ED), and end-systolic (ES) left ventricular volumes (V), LV mass, summed stress perfusion defect score (SSS), and total severity score (TSS) were calculated automatically relative to a supine normal reference database. RESULTS: There were no significant differences in LVEF using the two cameras (0.65 +/- 0.08 vs. 0.66 +/- 0.10; P > 0.1). However, EDV, ESV, and LV mass were significantly smaller in sitting position than in supine position (89 vs. 80 ml; 33 vs. 29 ml and 115 vs. 109 ml, respectively, all P < 0.0001). On the other hand, SSS and TSS were significantly higher in sitting position than in supine position (5.16 vs. 8.73 and 166.82 vs. 288.27, both P < 0.0001). Overall, more studies in sitting position were interpreted as abnormal than in supine position (P < 0.05). CONCLUSION: Patient positioning has a significant impact on quantitative gated SPECT imaging results. Using a supine normal reference database, SSS and TSS were larger in sitting position than in supine position. Thus, for imaging in sitting position, separate normal limits are required. PMID- 28361478 TI - Commissioning a hobby cutting device for radiochromic film preparation. AB - In addition to a high spatial resolution and well characterised dose response, one of the major advantages of radiochromic film as a dosimeter is that sheets of film can be cut into pieces suitable for use as calibration films, and for in vivo and phantom measurements. The cutting of film is typically done using scissors or a guillotine, and this process can be time-consuming, limited in precision, requires extensive handling and does not allow holes to be cut from the film without cutting from an existing edge. This study investigated the use of a Brother ScanNCut hobby cutting system for EBT3 film preparation. The optimal operating parameters (blade size, pressure, speed) that resulted in precise cuts with minimal delamination at cut edges were identified using test cutting patterns. These parameters were then used to cut a large film insert for a stereotactic head phantom for comparison against an insert cut with scissors. While the hobby cutting system caused a wider region of delamination at the film edge (1.8 mm) compared to scissors (1 mm), the hobby cutting system was found to be able to produce reproducible cuts more efficiently and more accurately than scissors. The use of the hobby cutting system is recommended for complex phantom inserts (containing sharp corners or holes for alignment rods) or in situations where large numbers of film pieces need to be prepared. PMID- 28361479 TI - A Simple Method of Generating 3D Brain Organoids Using Standard Laboratory Equipment. AB - 3D brain organoids are a powerful tool with prospective application for the study of neural development and disease. Here we describe the growth factor-free method of generating cerebral organoids from feeder-dependent or feeder-free human pluripotent stem cells using standard laboratory equipment. The protocol outlined below allows generation of 3D tissues, which replicate human early in vivo brain development up to the end of the first trimester, both in terms of morphology and gene expression pattern. PMID- 28361480 TI - Human Intestinal Enteroids: New Models to Study Gastrointestinal Virus Infections. AB - Human rotavirus (HRV) and human norovirus (HuNoV) infections are recognized as the most common causes of epidemic and sporadic cases of gastroenteritis worldwide. The study of these two human gastrointestinal viruses is important for understanding basic virus-host interactions and mechanisms of pathogenesis and to establish models to evaluate vaccines and treatments. Despite the introduction of live-attenuated vaccines to prevent life-threatening HRV-induced disease, the burden of HRV illness remains significant in low-income and less-industrialized countries, and small animal models or ex vivo models to study HRV infections efficiently are lacking. Similarly, HuNoVs remained non-cultivatable until recently. With the advent of non-transformed human intestinal enteroid (HIE) cultures, we are now able to culture and study both clinically relevant HRV and HuNoV in a biologically relevant human system. Methods described here will allow investigators to use these new culture techniques to grow HRV and HuNoV and analyze new aspects of virus replication and pathogenesis. PMID- 28361481 TI - Sphingosine-1-Phosphate (S1P) Signaling in Neural Progenitors. AB - Sphingosine-1-phosphate (S1P) and its receptors are important in nervous system development. Reliable in vitro human model systems are needed to further define specific roles for S1P signaling in neural development. We have described S1P regulated signaling, survival, and differentiation in a human embryonic stem cell derived neuroepithelial progenitor cell line (hNP1) that expresses functional S1P receptors. These cells can be further differentiated to a neuronal cell type and therefore represent a good model system to study the role of S1P signaling in human neural development. The following sections describe in detail the culture and differentiation of hNP1 cells and two assays to measure S1P signaling in these cells. PMID- 28361482 TI - Induction of PINK1/Parkin-Mediated Mitophagy. AB - PINK1/Parkin mitophagy is a key mechanism to contribute mitochondrial quality control, and the defects are thought to be a cause of those Parkinson's disease onsets. Upon loss of mitochondrial membrane potential, PINK1 and Parkin are activated to promote the proteasomal degradation of mitochondrial outer membrane proteins and selective elimination of damaged mitochondria by autophagy. In this chapter, we describe the methods for induction of PINK1/Parkin-mediated mitophagy in tissue culture cell lines. PMID- 28361483 TI - Immunocytochemical Monitoring of PINK1/Parkin-Mediated Mitophagy in Cultured Cells. AB - Both PINK1 and parkin are the responsible genes (PARK6 and PARK2, respectively) for familial early-onset Parkinson's disease (PD). Several lines of evidences have suggested that mitochondrial dysfunction would be associated with PD pathogenesis. Lewy body, one of PD pathological hallmarks, contains alpha synuclein, a familial PD (PARK1/4)-gene product, which is eliminated by macroautophagy, while PINK1 and parkin coordinately mediate mitophagy (hereafter called as PINK1/parkin-mediated mitophagy) reported firstly by Youle's group. The mitochondrial quality control system is specific for elimination of damaged mitochondria especially in the loss of mitochondrial membrane potential induced by treatment with mitochondrial uncoupler like CCCP or FCCP. In this chapter, we summarized immunocytochemical methods to monitor the PINK1/parkin-mediated mitophagy using cultured cells. PMID- 28361484 TI - A Cleanup Method for Mass Spectrometric Analysis of Sphingosine- and Ceramide-1 Phosphate in Blood and Solid Tissue Using a Phosphate Capture Molecule. AB - Cleanup technology and mass spectrometric determination of sphingosine-1 phosphate (S1P) using a phosphate capture molecule are shown. The protocol is rapid, requires neither thin-layer chromatography nor liquid chromatography, and is applicable to both blood and solid tissue samples. The mass spectrometric method is also applicable to ceramide-1-phosphate. PMID- 28361485 TI - The Use of Correlative Light-Electron Microscopy (CLEM) to Study PINK1/Parkin Mediated Mitophagy. AB - In this chapter we describe the use of correlative light-electron microscopy (CLEM) to study, in cultured cells, the turnover of damaged mitochondria by PINK1/Parkin-dependent mitophagy. CLEM combines the advantages of light microscopy, which allows to image and rapidly screen a large number of the cells, while electron microscopy provides high-resolution imaging of these selected cells and a detailed structural analysis of their cellular organelles. We describe in detail how to prepare the cell cultures for optimum preservation of their cellular ultrastructure for CLEM using the most suitable buffers, fixatives, and embedding resins. These protocols are applicable for detailed ultrastructural analysis in a wide variety of organisms and cells, ranging from prokaryotic bacteria to mammalian cells. PMID- 28361486 TI - Size effect on the mineralogy and chemistry of Mytilus trossulus shells from the southern Baltic Sea: implications for environmental monitoring. AB - Mussels have the ability to control biomineral production and chemical composition, producing shells with a range of functions. In addition to biological control, the environment also seems to influence the process of biomineralization; thus, shells can be used as archives of ambient water parameters during the calcium carbonate deposition. Past and present environmental conditions are recorded in the shells in the form of various proxies including Mg/Ca or Sr/Ca ratios. For such proxies to be accurate and robust, the influence of biological effects including the size of studied organism must be examined and eliminated or minimized, so that the environmental signal can be efficiently extracted. This study considers mineralogy and elemental composition of shells representing four size classes of Mytilus trossulus from the Baltic Sea. Obtained results suggest that mineralogy and chemical composition change throughout the shell development due to most likely a combination of environmental and biological factors. The content of aragonite increases with increasing shell size, while the bulk concentrations of Na, Cd, Cu, U, V, Zn and Pb were found to decrease with increasing height of the shells. Therefore, using mussels for environmental monitoring requires analysis of individuals in the same size range. PMID- 28361487 TI - Simultaneous spectrophotometric determination of crystal violet and malachite green in water samples using partial least squares regression and central composite design after preconcentration by dispersive solid-phase extraction. AB - In this paper, a simple, fast, and inexpensive method is introduced for the simultaneous spectrophotometric determination of crystal violet (CV) and malachite green (MG) contents in aquatic samples using partial least squares regression (PLS) as a multivariate calibration technique after preconcentration by graphene oxide (GO). The method was based on the sorption and desorption of analytes onto GO and direct determination by ultraviolet-visible spectrophotometric techniques. GO was synthesized according to Hummers method. To characterize the shape and structure of GO, FT-IR, SEM, and XRD were used. The effective factors on the extraction efficiency such as pH, extraction time, and the amount of adsorbent were optimized using central composite design. The optimum values of these factors were 6, 15 min, and 12 mg, respectively. The maximum capacity of GO for the adsorption of CV and MG was 63.17 and 77.02 mg g 1, respectively. Preconcentration factors and extraction recoveries were obtained and were 19.6, 98% for CV and 20, 100% for MG, respectively. LOD and linear dynamic ranges for CV and MG were 0.009, 0.03-0.3, 0.015, and 0.05-0.5 (MUg mL 1), respectively. The intra-day and inter-day relative standard deviations were 1.99 and 0.58 for CV and 1.69 and 3.13 for MG at the concentration level of 50 ng mL-1, respectively. Finally, the proposed DSPE/PLS method was successfully applied for the simultaneous determination of the trace amount of CV and MG in the real water samples. PMID- 28361488 TI - Adaptive nitrogen and integrated weed management in conservation agriculture: impacts on agronomic productivity, greenhouse gas emissions, and herbicide residues. AB - Increasing nitrogen (N) immobilization and weed interference in the early phase of implementation of conservation agriculture (CA) affects crop yields. Yet, higher fertilizer and herbicide use to improve productivity influences greenhouse gase emissions and herbicide residues. These tradeoffs precipitated a need for adaptive N and integrated weed management in CA-based maize (Zea mays L.)-wheat [Triticum aestivum (L.) emend Fiori & Paol] cropping system in the Indo-Gangetic Plains (IGP) to optimize N availability and reduce weed proliferation. Adaptive N fertilization was based on soil test value and normalized difference vegetation index measurement (NDVM) by GreenSeekerTM technology, while integrated weed management included brown manuring (Sesbania aculeata L. co-culture, killed at 25 days after sowing), herbicide mixture, and weedy check (control, i.e., without weed management). Results indicated that the 'best-adaptive N rate' (i.e., 50% basal + 25% broadcast at 25 days after sowing + supplementary N guided by NDVM) increased maize and wheat grain yields by 20 and 14% (averaged for 2 years), respectively, compared with whole recommended N applied at sowing. Weed management by brown manuring (during maize) and herbicide mixture (during wheat) resulted in 10 and 21% higher grain yields (averaged for 2 years), respectively, over the weedy check. The NDVM in-season N fertilization and brown manuring affected N2O and CO2 emissions, but resulted in improved carbon storage efficiency, while herbicide residuals in soil were significantly lower in the maize season than in wheat cropping. This study concludes that adaptive N and integrated weed management enhance synergy between agronomic productivity, fertilizer and herbicide efficiency, and greenhouse gas mitigation. PMID- 28361489 TI - Estimation of underwater visibility in coastal and inland waters using remote sensing data. AB - An optical method is developed to estimate water transparency (or underwater visibility) in terms of Secchi depth (Z sd ), which follows the remote sensing and contrast transmittance theory. The major factors governing the variation in Z sd , namely, turbidity and length attenuation coefficient (1/(c + K d ), c = beam attenuation coefficient; K d = diffuse attenuation coefficient at 531 nm), are obtained based on band rationing techniques. It was found that the band ratio of remote sensing reflectance (expressed as (R rs (443) + R rs (490))/(R rs (555) + R rs (670)) contains essential information about the water column optical properties and thereby positively correlates to turbidity. The beam attenuation coefficient (c) at 531 nm is obtained by a linear relationship with turbidity. To derive the vertical diffuse attenuation coefficient (K d ) at 531 nm, K d (490) is estimated as a function of reflectance ratio (R rs (670)/R rs (490)), which provides the bio-optical link between chlorophyll concentration and K d (531). The present algorithm was applied to MODIS-Aqua images, and the results were evaluated by matchup comparisons between the remotely estimated Z sd and in situ Z sd in coastal waters off Point Calimere and its adjoining regions on the southeast coast of India. The results showed the pattern of increasing Z sd from shallow turbid waters to deep clear waters. The statistical evaluation of the results showed that the percent mean relative error between the MODIS-Aqua derived Z sd and in situ Z sd values was within +/-25%. A close agreement achieved in spatial contours of MODIS-Aqua-derived Z sd and in situ Z sd for the month of January 2014 and August 2013 promises the model capability to yield accurate estimates of Z sd in coastal, estuarine, and inland waters. The spatial contours have been included to provide the best data visualization of the measured, modeled (in situ), and satellite-derived Z sd products. The modeled and satellite-derived Z sd values were compared with measurement data which yielded RMSE = 0.079, MRE = -0.016, and R 2 = 0.95 for the modeled Z sd and RMSE = 0.075, MRE = 0.020, and R 2 = 0.95 for the satellite-derived Z sd products. PMID- 28361490 TI - Managed aquifer recharge by a check dam to improve the quality of fluoride-rich groundwater: a case study from southern India. AB - In many regions around the globe, including India, degradation in the quality of groundwater is of great concern. The objective of this investigation is to determine the effect of recharge from a check dam on quality of groundwater in a region of Krishnagiri District of Tamil Nadu State, India. For this study, water samples from 15 wells were periodically obtained and analysed for major ions and fluoride concentrations. The amount of major ions present in groundwater was compared with the drinking water guideline values of the Bureau of Indian Standards. With respect to the sodium and fluoride concentrations, 38% of groundwater samples collected was not suitable for direct use as drinking water. Suitability of water for agricultural use was determined considering the electrical conductivity, sodium adsorption ratio, sodium percentage, permeability index, Wilcox and United States Salinity Laboratory diagrams. The influence of freshwater recharge from the dam is evident as the groundwater in wells nearer to the check dam was suitable for both irrigation and domestic purposes. However, the groundwater away from the dam had a high ionic composition. This study demonstrated that in other fluoride-affected areas, the concentration can be reduced by dilution with the construction of check dams as a measure of managed aquifer recharge. PMID- 28361491 TI - Response to: Letter to the Editor: Long-Term Results of Laparoscopic Sleeve Gastrectomy for Morbid Obesity: 5 to 8-Year Results. PMID- 28361492 TI - Pregnancy After Bariatric Surgery: National Survey of Obstetrician's Comfort, Knowledge, and Practice Patterns. AB - OBJECTIVE: The objective of this study is to survey a nationally representative sample of obstetricians regarding comfort, knowledge, and practice patterns of caring for pregnant women after bariatric surgery. MATERIALS AND METHODS: We conducted an online survey of US obstetricians and describe obstetrician's demographics, practice settings, and practice patterns. We assessed respondent's knowledge and recommended practices. We compared provider knowledge by years since completing residency, scope of practice (generalist or specialist), and practice setting (academic setting or other). Statistical significance was set at p < 0.05. RESULTS: A total of 106 completed the survey (response rate of 54%). Respondents had a median age of 47 and median 17 years in practice. Sixty-two percent were generalists. Nearly all of the respondents (94%) had some experience with caring for pregnant women after bariatric surgery and 83% reported feeling "very comfortable" (48%) or "somewhat comfortable" (35%) providing care for this population. Most (74%) were aware of increased risk of small for gestational age after surgery. Only 13% were able to correctly identify all recommended nutritional labs and 20% reported that they "did not know" which labs are recommended. There were no differences in comfort, experience, knowledge, and practice patterns by physician characteristics and practice settings. CONCLUSION: While most obstetricians are aware of perinatal risks after bariatric surgery, a substantial percentage of obstetricians are unaware of recommended practices regarding nutrition and nutritional monitoring. As bariatric surgery becomes increasingly prevalent among reproductive age women, educational interventions to increase obstetricians' knowledge of optimal care of pregnant women after bariatric surgery are urgently needed. PMID- 28361493 TI - Understanding Objections to One Anastomosis (Mini) Gastric Bypass: A Survey of 417 Surgeons Not Performing this Procedure. AB - BACKGROUND: Despite published experience with thousands of patients, the uptake of One Anastomosis/Mini Gastric Bypass (OAGB/MGB) has been less than enthusiastic and many surgeons still harbour objections to this procedure. The purpose of this study was to understand these objections scientifically. METHODS: Bariatric surgeons from around the world were invited to participate in a questionnaire based survey on SurveyMonkey(r). Surgeons already performing this procedure were excluded. RESULTS: Four hundred seventeen bariatric surgeons (from 42 countries) not currently performing OAGB/MGB took the survey. There were 211/414 (50.97%) and 188/414 (45.41%) respondents who expressed concerns that it will lead to an increased risk of gastric and oesophageal cancers respectively. A total of 62/416 (14.9%) and 201/413 (n = 48.6%) surgeons respectively felt that OAGB/MGB was associated with a higher early (30-day) and late complication rate compared to the RYGB. Moreover, 7.8% (n = 32/411) and 16.26% (n = 67/412) of the respondents were concerned that OAGB/MGB carried a higher early (30-day) and late mortality, respectively, in comparison with the RYGB. There were 79/410 (19.27%) and 88/413 (21.3%) respondents who were concerned that OAGB/MGB was not an effective procedure for weight loss and co-morbidity resolution, respectively. A total of 258/411 (62.77%) respondents reported that OAGB/MGB was not approved by their national society as a mainstream bariatric procedure; 51.0% of these surgeons would start performing this procedure if it was. CONCLUSIONS: Surgeons not performing OAGB/MGB cite a number of concerns for not performing this operation. This survey is the first scientific attempt to understand these objections scientifically. PMID- 28361494 TI - Management Options for Twisted Gastric Tube after Laparoscopic Sleeve Gastrectomy. AB - PURPOSE: This study aims to determine the incidence, etiology, and management options for symptomatic gastric obstruction caused by axially twisted sleeve gastrectomy. METHODS: In this retrospective study, we reviewed medical charts of all morbidly obese patients who underwent laparoscopic sleeve gastrectomy. Patients who developed gastric obstruction symptoms and were diagnosed with twisted sleeve gastrectomy were identified and included in this study. RESULTS: From October 2005 to December 2015, there are 3634 morbidly obese patients who underwent laparoscopic sleeve gastrectomy (LSG). Eighty-six (2.3%) patients developed symptoms of gastric obstruction. Forty-five (1.23%) patients were included in this study. The mean time of presentation was 59.8 days after surgery. Upper GI contrast study was done routinely, and it was positive for axial twist in 37 (82%) patients. Abdominal CT with oral and IV contrast was done in eight (18%) when swallow study was equivocal. Endoscopic treatment was successful in 43 patients (95.5%). Sixteen patients were successfully managed by endoscopic stenting, and 29 patients had balloon dilation. The average numbers of dilation sessions were 1.7. Out of these 29 patients, 18 responded well to a single session of dilatation and did not require any further dilatation sessions. Two patients who failed to respond to three subsequent sessions of balloon dilation underwent laparoscopic adhesiolysis and gastropexy. CONCLUSIONS: Endoscopic stenting is an effective tool in management of axial rotation of sleeved stomach. Balloon dilation can also be effective in selected cases. Few cases might require laparoscopic adhesiolysis and gastropexy. PMID- 28361495 TI - On the tragedy of the commons: When predation and livestock loss may improve the economic lot of herders. AB - This paper studies the practice of semi-domestic reindeer (Rangifer t. tarandus) herding in Finnmark county in northern Norway. In this area, the Saami reindeer herders compete for space and grazing areas and keep large herds, while at the same time, the reindeer population is heavily exposed to carnivore predation by the lynx (Lynx lynx), the wolverine (Gulo gulo), and the golden eagle (Aquila chrysaetos). It is demonstrated that predation actually may improve the economic lot of livestock holders in this unmanaged local common setting. There are ecological as well as economic reasons as to why this happens. The ecological reason is that predation compensates for natural mortality; that is, increased predation reduces natural mortality, indicating that the net loss due to predation actually may be quite small. When predation reduces livestock density, the feeding conditions of the animals will improve, resulting in increased livestock weight and higher per animal slaughter value. At the same time, a smaller stock reduces the operating costs of the herders. PMID- 28361496 TI - Individual behavioural counselling for smoking cessation. AB - BACKGROUND: Individual counselling from a smoking cessation specialist may help smokers to make a successful attempt to stop smoking. OBJECTIVES: The review addresses the following hypotheses:1. Individual counselling is more effective than no treatment or brief advice in promoting smoking cessation.2. Individual counselling is more effective than self-help materials in promoting smoking cessation.3. A more intensive counselling intervention is more effective than a less intensive intervention. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group Specialized Register for studies with counsel* in any field in May 2016. SELECTION CRITERIA: Randomized or quasi-randomized trials with at least one treatment arm consisting of face-to-face individual counselling from a healthcare worker not involved in routine clinical care. The outcome was smoking cessation at follow-up at least six months after the start of counselling. DATA COLLECTION AND ANALYSIS: Both authors extracted data in duplicate. We recorded characteristics of the intervention and the target population, method of randomization and completeness of follow-up. We used the most rigorous definition of abstinence in each trial, and biochemically-validated rates where available. In analysis, we assumed that participants lost to follow-up continued to smoke. We expressed effects as a risk ratio (RR) for cessation. Where possible, we performed meta-analysis using a fixed-effect (Mantel-Haenszel) model. We assessed the quality of evidence within each study using the Cochrane 'Risk of bias' tool and the GRADE approach. MAIN RESULTS: We identified 49 trials with around 19,000 participants. Thirty-three trials compared individual counselling to a minimal behavioural intervention. There was high-quality evidence that individual counselling was more effective than a minimal contact control (brief advice, usual care, or provision of self-help materials) when pharmacotherapy was not offered to any participants (RR 1.57, 95% confidence interval (CI) 1.40 to 1.77; 27 studies, 11,100 participants; I2 = 50%). There was moderate-quality evidence (downgraded due to imprecision) of a benefit of counselling when all participants received pharmacotherapy (nicotine replacement therapy) (RR 1.24, 95% CI 1.01 to 1.51; 6 studies, 2662 participants; I2 = 0%). There was moderate-quality evidence (downgraded due to imprecision) for a small benefit of more intensive counselling compared to brief counselling (RR 1.29, 95% CI 1.09 to 1.53; 11 studies, 2920 participants; I2 = 48%). None of the five other trials that compared different counselling models of similar intensity detected significant differences. AUTHORS' CONCLUSIONS: There is high-quality evidence that individually-delivered smoking cessation counselling can assist smokers to quit. There is moderate quality evidence of a smaller relative benefit when counselling is used in addition to pharmacotherapy, and of more intensive counselling compared to a brief counselling intervention. PMID- 28361497 TI - Group behaviour therapy programmes for smoking cessation. AB - BACKGROUND: Group therapy offers individuals the opportunity to learn behavioural techniques for smoking cessation, and to provide each other with mutual support. OBJECTIVES: To determine the effect of group-delivered behavioural interventions in achieving long-term smoking cessation. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group Specialized Register, using the terms 'behavior therapy', 'cognitive therapy', 'psychotherapy' or 'group therapy', in May 2016. SELECTION CRITERIA: Randomized trials that compared group therapy with self-help, individual counselling, another intervention or no intervention (including usual care or a waiting-list control). We also considered trials that compared more than one group programme. We included those trials with a minimum of two group meetings, and follow-up of smoking status at least six months after the start of the programme. We excluded trials in which group therapy was provided to both active therapy and placebo arms of trials of pharmacotherapies, unless they had a factorial design. DATA COLLECTION AND ANALYSIS: Two review authors extracted data in duplicate on the participants, the interventions provided to the groups and the controls, including programme length, intensity and main components, the outcome measures, method of randomization, and completeness of follow-up. The main outcome measure was abstinence from smoking after at least six months follow up in participants smoking at baseline. We used the most rigorous definition of abstinence in each trial, and biochemically-validated rates where available. We analysed participants lost to follow-up as continuing smokers. We expressed effects as a risk ratio for cessation. Where possible, we performed meta-analysis using a fixed-effect (Mantel-Haenszel) model. We assessed the quality of evidence within each study and comparison, using the Cochrane 'Risk of bias' tool and GRADE criteria. MAIN RESULTS: Sixty-six trials met our inclusion criteria for one or more of the comparisons in the review. Thirteen trials compared a group programme with a self-help programme; there was an increase in cessation with the use of a group programme (N = 4395, risk ratio (RR) 1.88, 95% confidence interval (CI) 1.52 to 2.33, I2 = 0%). We judged the GRADE quality of evidence to be moderate, downgraded due to there being few studies at low risk of bias. Fourteen trials compared a group programme with brief support from a health care provider. There was a small increase in cessation (N = 7286, RR 1.22, 95% CI 1.03 to 1.43, I2 = 59%). We judged the GRADE quality of evidence to be low, downgraded due to inconsistency in addition to risk of bias. There was also low quality evidence of benefit of a group programme compared to no-intervention controls, (9 trials, N = 1098, RR 2.60, 95% CI 1.80 to 3.76 I2 = 55%). We did not detect evidence that group therapy was more effective than a similar intensity of individual counselling (6 trials, N = 980, RR 0.99, 95% CI 0.76 to 1.28, I2 = 9%). Programmes which included components for increasing cognitive and behavioural skills were not shown to be more effective than same-length or shorter programmes without these components. AUTHORS' CONCLUSIONS: Group therapy is better for helping people stop smoking than self-help, and other less intensive interventions. There is not enough evidence to evaluate whether groups are more effective, or cost-effective, than intensive individual counselling. There is not enough evidence to support the use of particular psychological components in a programme beyond the support and skills training normally included. PMID- 28361499 TI - Supporting people living with HIV in serodiscordant partnerships to attempt a desired pregnancy by integrating sexual and reproductive health and HIV interventions. PMID- 28361498 TI - Disclosure of sexual orientation to health professionals in China: results from an online cross-sectional study. AB - BACKGROUND: Many men who have sex with men (MSM) in China are "in the closet." The low rate of disclosure may impact sexual behaviours, testing for HIV and other sexually transmitted infections (STIs), and diseases transmission. This study examines factors associated with overall sexual orientation disclosure and disclosure to healthcare professionals. METHODS: A nationwide cross-sectional online survey was conducted from September 2014 to October 2014 in China. Participants completed questions covering socio-demographic information, sexual behaviours, HIV/STI testing history, and self-reported HIV status. We defined healthcare professional disclosure as disclosing to a doctor or other medical provider. RESULTS: A total of 1819 men started the survey and 1424 (78.3%) completed it. Among the 1424 participants, 62.2% (886/1424) reported overall disclosure, and 16.3% (232/1424) disclosed to healthcare professionals. In multivariate analyses, the odds of sexual orientation disclosure were 56% higher among MSM who used smartphone-based, sex-seeking applications [adjusted odds ratio (aOR) = 1.56, 95% CI: 1.25-2.95], but were lower among MSM reporting sex while drunk or recreational drug use. The odds of disclosure to a healthcare professional were greater among MSM who had ever tested for HIV or STIs (aOR = 3.36, 95% CI: 2.50-4.51 for HIV, and aOR = 4.92, 95% CI: 3.47-6.96 for STIs, respectively) or self-reported as living with HIV (aOR = 1.59, 95% CI: 0.93 2.72). CONCLUSION: Over 80% of MSM had not disclosed their sexual orientation to health professionals. This low level of disclosure likely represents a major obstacle to serving the unique needs of MSM in clinical settings. Further research and interventions to facilitate MSM sexual orientation disclosure, especially to health professionals, are urgently needed. PMID- 28361501 TI - Fertility care interventions should be provided as the first line options for HIV+ serodiscordant couples who desire children in settings with affordable access to care, regardless of their fertility status. AB - INTRODUCTION: With increasing life expectancy, couples with at least one partner afflicted with HIV are more commonly pursuing the opportunity to have biologic offspring. Currently, there are no universally accepted recommendations regarding first line reproductive treatments for HIV serodiscordant couples lacking a history of infertility. We strongly believe that fertility care intervention should be the first line treatment, when affordably accessible, over natural conception for HIV serodiscordant couples to achieve pregnancy in a safe and efficacious manner. Discussion: In the era of highly active anti-retroviral therapy, in combination with timed intercourse and pre-exposure prophylaxis for the HIV negative partner, some members of the medical community are arguing in favour of natural conception as a means of achieving pregnancy in this patient population. In our opinion, laboratory assisted fertility methods, including intrauterine insemination, in vitro fertilization, and intracytoplasmic sperm injection with semen washing should be the first line treatment recommendation for HIV serodiscordant couples desiring pregnancy for the following reasons: (1) abundance of evidence in the medical literature supporting the safety profile and efficacy of fertility care intervention in couples with HIV; paucity of data addressing safety of natural conception in comparison to fertility intervention techniques (2) unknown public health impact of promoting natural conception as a safe means of achieving pregnancy (3) ethical implications: patients should be offered the available and accessible treatment option posing the lowest possible known risk to the uninfected partner. Conclusions: We believe that physician assisted fertility care, when affordably accessible, should be the treatment of choice over natural conception. While the preliminary data on natural conception in couples using highly active anti-retroviral therapy/pre-exposure prophylaxis/timed intercourse appears promising, we believe that this approach should be limited to patients in resource poor settings where more sophisticated measures do not exist or for patients that simply cannot afford subspecialty care. There are likely to be unknown psychological and behavioural factors impacted by promoting natural conception and diminishing the importance of safe sex practices. Additionally, it is our moral obligation to patients to offer the affordably accessible treatment interventions that pose the least known risk when considering reproductive options. PMID- 28361500 TI - The role of family planning in achieving safe pregnancy for serodiscordant couples: commentary from the United States government's interagency task force on family planning and HIV service integration. AB - INTRODUCTION: People living with HIV (PLHIV) have the right to exercise voluntary choices about their health, including their reproductive health. This commentary discusses the integral role that family planning (FP) plays in helping PLHIV, including those in serodiscordant relationships, achieve conception safely. The United States (US) President's Emergency Plan for AIDS Relief (PEPFAR) is committed to meeting the reproductive health needs of PLHIV by improving their access to voluntary FP counselling and services, including prevention of unintended pregnancy and counselling for safer conception. DISCUSSION: Inclusion of preconception care and counselling (PCC) as part of routine HIV services is critical to preventing unintended pregnancies and perinatal infections among PLHIV. PLHIV not desiring a current pregnancy should be provided with information and counselling on all available FP methods and then either given the method onsite or through a facilitated referral process. PLHIV, who desire children should be offered risk reduction counselling, support for HIV status disclosure and partner testing, information on safer conception options to reduce the risk of HIV transmission to the partner and the importance of adhering to antiretroviral treatment during pregnancy and breastfeeding to reduce the risk of vertical transmission to the infant. Integration of PCC, HIV and FP services at the same location is recommended to improve access to these services for PLHIV. Other considerations to be addressed include the social and structural context, the health system capacity to offer these services, and stigma and discrimination of providers. CONCLUSION: Evaluation of innovative service delivery models for delivering PCC services is needed, including provision in community-based settings. The US Government will continue to partner with local organizations, Ministries of Health, the private sector, civil society, multilateral and bilateral donors, and other key stakeholders to strengthen both the policy and programme environment to ensure that all PLHIV and serodiscordant couples have access to FP services, including prevention of unintended pregnancy and safer conception counselling. PMID- 28361502 TI - Achieving pregnancy safely for HIV-serodiscordant couples: a social ecological approach. AB - The recognition and fulfilment of the sexual and reproductive health and rights (SRHR) of all individuals and couples affected by HIV, including HIV serodiscordant couples, requires intervention strategies aimed at achieving safe and healthy pregnancies and preventing undesired pregnancies. Reducing risk of horizontal and vertical transmission and addressing HIV-related infertility are key components of such interventions. In this commentary, we present challenges and opportunities for achieving safe pregnancies for serodiscordant couples through a social ecological lens. At the individual level, knowledge (e.g. of HIV status, assisted reproductive technologies) and skills (e.g. adhering to antiretroviral therapy or pre-exposure prophylaxis) are important. At the couple level, communication between partners around HIV status disclosure, fertility desires and safer pregnancy is required. Within the structural domain, social norms, stigma and discrimination from families, community and social networks influence individual and couple experiences. The availability and quality of safer conception and fertility support services within the healthcare system remains essential, including training for healthcare providers and strengthening integration of SRHR and HIV services. Policies, legislation and funding can improve access to SRHR services. A social ecological framework allows us to examine interactions between levels and how interventions at multiple levels can better support HIV-serodiscordant couples to achieve safe pregnancies. Strategies to achieve safer pregnancies should consider interrelated challenges at different levels of a social ecological framework. Interventions across multiple levels, implemented concurrently, have the potential to maximize impact and ensure the full SRHR of HIV-serodiscordant couples. PMID- 28361504 TI - Ask women living with HIV what's needed to achieve safe pregnancies in serodifferent relationships. PMID- 28361505 TI - Men living with HIV in serodiscordant relationships who desire a child/children. PMID- 28361503 TI - Offering pre-exposure prophylaxis for HIV prevention to pregnant and postpartum women: a clinical approach. AB - INTRODUCTION: HIV prevention during pregnancy and lactation is critical for both maternal and child health. Pregnancy provides a critical opportunity for clinicians to elicit women's vulnerabilities to HIV and offer HIV testing, treatment and referral and/or comprehensive HIV prevention options for the current pregnancy, the postpartum period and safer conception options for future pregnancies. In this commentary, we review the safety of oral pre-exposure prophylaxis with tenofovir/emtricitabine in pregnant and lactating women and suggest opportunities to identify pregnant and postpartum women at substantial risk of HIV. We then describe a clinical approach to caring for women who both choose and decline pre-exposure prophylaxis during pregnancy and postpartum, highlighting areas for future research. DISCUSSION: Evidence suggests that pre exposure prophylaxis with tenofovir/emtricitabine is safe in pregnancy and lactation. Identifying women vulnerable to HIV and eligible for pre-exposure prophylaxis is challenging in light of the myriad of individual, community, and structural forces impacting HIV acquisition. Validated risk calculators exist for specific populations but have not been used to screen and offer HIV prevention methods. Partner testing and engagement of men living with HIV are additional means of reaching at-risk women. However, women's vulnerabilities to HIV change over time. Combining screening for HIV vulnerability with HIV and/or STI testing at standard intervals during pregnancy is a practical way to prompt providers to incorporate HIV screening and prevention counselling. We suggest using shared decision-making to offer women pre-exposure prophylaxis as one of multiple HIV prevention strategies during pregnancy and postpartum, facilitating open conversations about HIV vulnerabilities, preferences about HIV prevention strategies, and choosing a method that best meets the needs of each woman. CONCLUSION: Growing evidence suggests that pre-exposure prophylaxis with tenofovir/emtricitabine during pregnancy and lactation is safe and effective. Shared decision-making provides one approach to identify at-risk women and offers pre-exposure prophylaxis but requires implementation research in diverse clinical settings. Including pregnant and breastfeeding women in future HIV prevention research is critical for the creation of evidence-driven public health policies and clinical guidelines. PMID- 28361506 TI - Supporting HIV prevention and reproductive goals in an HIV-endemic setting: taking safer conception services from policy to practice in South Africa. AB - INTRODUCTION: Safer conception care encompasses HIV care, treatment and prevention for persons living with HIV and their partners who desire children. In 2012, South Africa endorsed a progressive safer conception policy supporting HIV affected persons to safely meet reproductive goals. However, aside from select research-supported clinics, widespread implementation has not occurred. Using South Africa as a case study, we identify key obstacles to policy implementation and offer recommendations to catalyse expansion of these services throughout South Africa and further afield. DISCUSSION: Four key implementation barriers were identified by combining authors' safer conception service delivery experiences with available literature. First, strategic implementation frameworks stipulating where, and by whom, safer conception services should be provided are needed. Integrating safer conception services into universal test-and-treat (UTT) and elimination-of-mother-to-child-transmission (eMTCT) priority programmes would support HIV testing, ART initiation and management, viral suppression and early antenatal/eMTCT care engagement goals, reducing horizontal and vertical transmissions. Embedding measurable safer conception targets into these priority programmes would ensure accountability for implementation progress. Second, facing an organizational clinic culture that often undermines clients' reproductive rights, healthcare providers' (HCP) positive experiences with eMTCT and enthusiasm for UTT provide opportunities to shift facility-level and individual attitudes in favour of safer conception provision. Third, safer conception guidelines have not been incorporated into HCP training. Combining safer conception with "test-and-treat" training would efficiently ensure that providers are better equipped to discuss clients' reproductive goals and support safer conception practices. Lastly, HIV-affected couples remain largely unaware of safer conception strategies. HIV-affected populations need to be mobilized to engage with safer conception options alongside other HIV-related healthcare services. CONCLUSION: Key barriers to widespread safer conception service provision in South Africa include poor translation of policy into practical and measurable implementation plans, inadequate training and limited community engagement. South Africa should leverage the momentum and accountability associated with high priority UTT and eMTCT programmes to reinvigorate implementation efforts by incorporating safer conception into implementation and monitoring frameworks and associated HCP training and community engagement activities. South Africa's experiences should be used to inform policy development and implementation processes in other HIV high-burden countries. PMID- 28361507 TI - Client uptake of safer conception strategies: implementation outcomes from the Sakh'umndeni Safer Conception Clinic in South Africa. AB - INTRODUCTION: Implementation of safer conception services for HIV-affected couples within primary healthcare clinics in resource-limited settings remains limited. We review service utilization and safer conception strategy uptake during the first three years of Sakh'umndeni, which is a safer conception clinic in South Africa. METHODS: Sakh'umndeni is located at Witkoppen Health and Welfare Centre, a high-volume primary healthcare clinic in northern Johannesburg. Men and women desiring to conceive in less than or equal to six months and in relationships in which one or both partners are living with HIV are eligible for safer conception services. Clients receive a baseline health assessment and counselling around periconception HIV risk reduction strategies and choose which strategies they plan to use. Clients are followed-up monthly. We describe client service utilization and uptake and continuation of safer conception methods. Factors associated with male partner attendance are assessed using robust Poisson regression. RESULTS: Overall 440 individuals utilized the service including 157 couples in which both partners attended (55%) and 126 unaccompanied female partners. Over half of the couples (55%) represented were in serodiscordant/unknown status relationships. Higher economic status and HIV negative status of the women increased male partner involvement, while HIV negative status of the men decreased male involvement. Regarding safer conception strategies, uptake of antiretroviral therapy initiation (90%), vaginal self insemination among partnerships with HIV-negative men (75%) and timed condomless intercourse strategies (48%) were variable, but generally high. Overall uptake of pre-exposure prophylaxis (PrEP) was 23% and was lower among HIV-negative men than women (7% vs. 44%, p < 0.001). Male medical circumcision (MMC) was used by 28% of HIV-negative men. Over 80% of clients took up at least one recommended safer conception strategy. Continuation of selected strategies over attempted conception attempts was >60%. CONCLUSIONS: Safer conception strategies are generally used by clients per recommendations. High uptake of strategies suggests that the proposed combination prevention methods are acceptable to clients and appropriate for scale-up; however, low uptake of PrEP and MMC among HIV-negative men needs improvement. Targeted community-based efforts to reach men unlinked to safer conception services are needed, alongside streamlined approaches for service scale-up within existing HIV and non-HIV service delivery platforms. PMID- 28361509 TI - A Clinician's Perspective on the Mechanism of beta3-Adrenoceptor Agonists in the Bladder. PMID- 28361508 TI - Delivering safer conception services to HIV serodiscordant couples in Kenya: perspectives from healthcare providers and HIV serodiscordant couples. AB - INTRODUCTION: For HIV serodiscordant couples in resource-limited settings, pregnancy is common despite the risk of sexual and/or perinatal HIV transmission. Some safer conception strategies to reduce HIV transmission during pregnancy attempts are available but often not used for reasons including knowledge, accessibility, preference and others. We sought to understand Kenyan health providers' and HIV serodiscordant couples' perspectives and experiences with safer conception. METHODS: Between August 2015 and March 2016, we conducted key informant interviews (KIIs) with health providers from public and private HIV care and fertility clinics and in-depth interviews (IDIs) and focus group discussions (FGDs) with HIV serodiscordant couples participating in an open-label study of integrated pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART) for HIV prevention (the Partners Demonstration Project). An inductive analytic approach identified a number of themes related to experiences with and perceptions of safer conception strategies. RESULTS: We conducted 20 KIIs with health providers, and 21 IDIs and 4 FGDs with HIV serodiscordant couples. HIV clinic providers frequently discussed timed condomless sex and antiretroviral medications while providers at private fertility care centres were more comfortable recommending medically assisted reproduction. Couples experienced with ART and PrEP reported that they were comfortable using these strategies to reduce HIV risk when attempting pregnancy. Timed condomless sex in conjunction with ART and PrEP was a preferred strategy, often owing to them being available for free in public and research clinics, as well as most widely known; however, couples often held inaccurate knowledge of how to identify days with peak fertility in the upcoming menstrual cycle. CONCLUSIONS: Antiretroviral-based HIV prevention is acceptable and accessible to meet the growing demand for safer conception services in Kenya, since medically assisted interventions are currently cost prohibitive. Cross-disciplinary training for health providers would expand confidence in all prevention options and foster the tailoring of counselling to couples' preferences. PMID- 28361510 TI - Broaden and Build Up Knowledge Based on Investigative and Clinical Research. PMID- 28361511 TI - Therapeutic Efficacy of a New Procedure for Male Urinary Incontinence Combining a Suburethral Polypropylene Mesh and Cardiovascular Patch. AB - PURPOSE: Stress urinary incontinence (SUI) in men is a complication secondary to prostatectomy or resulting from neurological lesions. This study presents our experiences with male suburethral slings over the past decade. METHODS: In this study, we considered patients who presented with SUI and were diagnosed with an intrinsic sphincteric deficiency due to postprostatectomy incontinence (PPI) or other causes (non-PPI). Patients who underwent the suburethral sling procedure using a polypropylene mesh and a cardiovascular patch were retrospectively included. An urodynamic study was performed before and after the operation. Global response assessment (GRA) and SUI grading were used for surgical outcome. The revision rate and the infection rate were also evaluated. RESULTS: A total 31 patients were enrolled in this study; the mean patient age was 59.5+/-18.9 years, and the mean follow-up period was 36.9+/-29.4 months. Fourteen patients comprised the non-PPI group and 17 were in the PPI group. The preoperative SUI of all patients were categorized as a moderate to severe problem according to the SUI grade, with a mean score of 2.32+/-0.48 before the operation and 0.48+/-0.57 after the operation. With a mean score of 2.35+/-0.71, GRA showed that the patients were satisfied with the treatment. After the sling procedure, 4 patients (13%) reported a mild improvement, 12 (38.7%) a moderate improvement, while 15 (48.4%) reported an excellent improvement. Six patients (19.4%), including 5 from the non-PPI group (35.7%) and 1 (5.9%) from the PPI group (P=0.037), underwent sling removal because of infection. CONCLUSIONS: The male suburethral sling procedure using a polypropylene mesh and a cardiovascular patch is a safe, efficacious, and inexpensive surgical procedure for PPI. In cases of neurological incontinence, however, the higher infection rate in non-PPI patients means that they should be carefully managed. PMID- 28361512 TI - Comparison of Surgical Outcomes Between Holmium Laser Enucleation and Transurethral Resection of the Prostate in Patients With Detrusor Underactivity. AB - PURPOSE: Currently, holmium laser enucleation of the prostate (HoLEP) and transurethral resection of the prostate (TURP) are the standard surgical procedures used to treat benign prostatic hyperplasia (BPH). Several recent studies have demonstrated that the surgical management of BPH in patients with detrusor underactivity (DU) can effectively improve voiding symptoms, but comparative data on the efficacy of HoLEP and TURP are insufficient. Therefore, we compared the short-term surgical outcomes of HoLEP and TURP in patients with DU. METHODS: From January 2010 to May 2015, 352 patients underwent HoLEP or TURP in procedures performed by a single surgeon. Of these patients, 56 patients with both BPH and DU were enrolled in this study (HoLEP, n=24; TURP, n=32). Surgical outcomes were retrospectively compared between the 2 groups. DU was defined as a detrusor pressure at maximal flow rate of <40 cm H2O as measured by a pressure flow study. RESULTS: The preoperative characteristics of patients and the presence of comorbidities were comparable between the 2 groups. The TURP group showed a significantly shorter operative time than the HoLEP group (P=0.033). The weight of the resected prostate was greater in the HoLEP group, and postoperative voiding parameters, including peak flow rate and postvoid residual urine volume were significantly better in the HoLEP group than in the TURP group. CONCLUSIONS: HoLEP can be effectively and safely performed in patients with DU and can be expected to have better surgical outcomes than TURP in terms of the improvement in lower urinary tract symptoms. PMID- 28361513 TI - Surgical Outcomes and Safety of Robotic Sacrocolpopexy in Women With Apical Pelvic Organ Prolapse. AB - PURPOSE: This study aimed to investigate the surgical outcomes and safety of robotic sacrocolpopexy (RSC) in patients with uterine/vaginal vault prolapse. METHODS: Between January 2009 and June 2015, 16 women with apical prolapse underwent RSC. Pelvic organ prolapse quantification (POP-Q) examination was performed, and treatment success was defined as the presence of grade 0 or I apical prolapse upon POP-Q examination at the final follow-up. Pelvic floor distress inventory-short form 20 (PFDI-SF 20) was administered at every follow up. A treatment satisfaction questionnaire was administered by telephone to evaluate patient satisfaction with the operation. RESULTS: Median age was 65 years (interquartile range [IQR], 56-68 years), and follow-up duration was 25.3 months (IQR, 5.4-34.0 months). Thirteen women (81.3%) had >=grade III apical prolapse. Operation time was 251 minutes (IQR, 236-288 minutes), and blood loss was 75 mL (IQR, 50-150 mL). Median hospital stay was 4 days (IQR, 3-5 days). At the final follow-up, treatment success was reported in all patients, who presented grade 0 (n=8, 57.1%) and grade I (n=6, 42.9%) apical prolapse. Dramatic improvements in PFDI-SF 20 scores were noted after RSC (from 39 to 4; P=0.001). Most patients (12 of 13) were satisfied with RSC. An intraoperative complication (sacral venous plexus injury) was reported in 1 patient, and there was no conversion to open surgery. Mesh erosion was not reported. CONCLUSIONS: RSC is an efficient and safe surgical option for apical prolapse repair. Most patients were satisfied with RSC. Thus, RSC might be one of the best treatment options for apical prolapse in women. PMID- 28361514 TI - Treatment of Stress Urinary Incontinence in Neurological Patients With an Injectable Elastomer Prosthesis: Preliminary Results. AB - Many treatment options for stress urinary incontinence are difficult to apply to neurological patients. Urolastic is a new agent that is primarily indicated for women with mild stress urinary incontinence or men after prostate surgery. In this report, we present a series of 5 cases describing the first use of Urolastic to treat neurological patients. All patients were evaluated with a voiding diary and the use of auxiliary devices as the main indicators of continence. The median operative time was 30.8 minutes, and no complications were observed. Of the 5 patients, 4 reported improved incontinence: 2 switched from diapers to small pads, while the other 2 patients were able to discontinue urinary condom use. The only instance of treatment failure occurred in a patient with a low-compliance bladder. The advantages of this procedure appear to include a soft-cuff effect, reversibility, and minimal invasiveness. However, a future randomized study would be necessary to validate this treatment option. PMID- 28361515 TI - Efficacy and Adverse Events Associated With Use of OnabotulinumtoxinA for Treatment of Neurogenic Detrusor Overactivity: A Meta-Analysis. AB - PURPOSE: OnabotulinumtoxinA is used widely for the treatment of neurogenic detrusor overactivity. We conducted a systematic review and meta-analysis to assess its efficacy and safety for neurogenic detrusor overactivity treatment. METHODS: A systematic literature review was performed to identify all published randomized double-blind, placebo-controlled trials of onabotulinumtoxinA for neurogenic detrusor overactivity treatment. MEDLINE, Embase, and the CENTRAL were employed. Reference lists of retrieved studies were reviewed carefully. RESULTS: Six publications involving 871 patients, which compared onabotulinumtoxinA with a placebo were analyzed. Efficacy of onabotulinumtoxinA treatment was shown as a reduction of the mean number of urinary incontinence episodes per day (mean difference, -1.41; 95% confidence interval [CI], -1.70 to -1.12; P<0.00001), maximum cystometric capacity (135.48; 95% CI, 118.22-152.75; P<0.00001), and maximum detrusor pressure (-32.98; 95% CI, -37.33 to -28.62; P<0.00001). Assessment of adverse events revealed that complications due to onabotulinumtoxinA injection were localized primarily to the urinary tract. CONCLUSIONS: This meta-analysis suggests that onabotulinumtoxinA is an effective treatment for neurogenic detrusor overactivity with localized advent events. PMID- 28361516 TI - Evaluation of Overactive Bladder in Male Antidepressant Users: A Prospective Study. AB - PURPOSE: In this study, we investigated overactive bladder (OAB) functions in male patients who used antidepressant drugs (ADs) that were previously examined in female patients, based on conflicting data in literature regarding the effects of AD on OAB and the differences between male and female urinary system physiologies (anatomical and hormonal). METHODS: The study included 202 male patients (a control group of 90 healthy subjects, and an experimental group of 112 patients taking ADs for different disorders). All the patients completed the overactive bladder-validated 8 (OAB-V8) questionnaire, the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), and the Beck Depression Inventory (BDS). RESULTS: The OAB-V8, ICIQ-SF, and BDS scores for the antidepressant users were significantly higher than those of the control group. The highest prevalence of OAB symptoms was observed in patients taking venlafaxine (68.2%), and the lowest prevalence was in patients taking sertraline (28.0%). Moreover, the frequency of OAB between the antidepressant groups was statistically significant. The univariate logistic regression analyses showed a significant relationship between the presence of OAB, antidepressant usage, BDS score, and the age of a patient. In the multivariate logistic regression analyses, the association between the presence of OAB and antidepressant usage was statistically significant. CONCLUSIONS: The present study showed that the incidence of OAB and the severity of OAB symptoms increased in males using antidepressants for various disorders. This may have been due to unique pharmacological effects, on a molecular or individual level, of serotonin norepinephrine reuptake inhibitors. PMID- 28361517 TI - Structural Changes of the Urinary Bladder After Chronic Complete Spinal Cord Injury in Minipigs. AB - PURPOSE: The aim of this study was to determine the structural changes of the urinary bladder after chronic spinal cord injury (SCI) in minipigs with the primary focus on the analysis of urinary bladder wall proteins and their quantitative distribution. METHODS: Seven Gottingen minipigs (adult, female) underwent a complete spinal cord transection. Follow-up time was 4 months during which the bladder was drained by frequent single catheterisation and data from the bladder diary and daily urine strip test were collected. Samples from the urinary bladder were taken, fixed in 4% paraformaldehyde and stained for histological analyses. Bladder wall thickness, single tissue quantities/distributions, types I and III collagen, and elastin quantifications were performed. Comparisons to healthy urinary bladder tissue of age-matched minipigs were performed for statistical analyses. RESULTS: No urinary tract infections were observed in our SCI minipig collective during follow-up. A trend towards a reduction in bladder volumes and an increase in incontinence periods were seen. The bladder wall thickness significantly increased after chronic SCI. Furthermore, bladder wall composition was severely altered by a significant loss of smooth muscle tissue and a significant increase in connective tissue. Elastic fibres were reduced in number and altered in their structural appearance after SCI. Type I collagen was significantly increased, while type III collagen was significantly decreased after SCI. CONCLUSIONS: Chronic SCI highlighted that the urinary bladder wall undergoes fibrotic events with reduced contractile and elastic properties due to changes of the bladder wall protein composition. These changes show in detail how SCI severely influences the urinary bladder wall composition and depicts the similarities between minipigs and humans. PMID- 28361518 TI - Ketanserin and Naftopidil Enhance the Potentiating Effect of Alpha-Methyl Serotonin on the Neurally-Induced Contraction of Human Isolated Urinary Bladder Muscle Strips. AB - PURPOSE: The aim of this study was to assess the potential involvement of a specific subtype of 5-hydroxytryptamine (5-HT), 5HT2 receptors in neurally induced contractions of the human detrusor. METHODS: Contractile responses to electrical field stimulation (EFS) were examined in human isolated urinary bladder muscle strips. The potentiation of EFS-induced detrusor contraction was examined by adding cumulative concentrations of a 5-HT and 5-HT2 receptor agonist, alpha-methyl-serotonin (alpha-Me-5-HT) (1nM-100MUM) in the presence or absence of a 5-HT2 antagonist, ketanserin (5-HT2A>5-HT2C) or naftopidil (5-HT2B>5 HT2A) (0.3-3MUM). RESULTS: 5-HT and alpha-Me-5-HT potentiated EFS-induced contraction with a maximal effect (Emax) of 37.6% and 38.6%, respectively, and with pEC50 (negative logarithm of the concentration required for a half-maximal response to an agonist) values of 8.3 and 6.8, respectively. Neither ketanserin nor naftopidil at any concentration produced a rightward displacement of the alpha-Me-5-HT concentration response curve. Instead, the Emax of alpha-Me-5-HT increased in the presence of ketanserin at 0.3-1MUM and in the presence of naftopidil at 1MUM to 51% and 56%, respectively, while the Emax in the presence of vehicle alone was 36%. The highest concentration (3MUM) of either drug, however, fully reversed the enhancement. CONCLUSIONS: The potentiating effect of alpha-Me-5-HT on neurally-induced contraction of human urinary bladder muscle strips was not found to be mediated via any 5-HT2 receptor subtypes. The underlying mechanism for the enhancement of the alpha-Me-5-HT potentiating effect on detrusor contractility by ketanserin and naftopidil remains unknown; however, our results suggest that these drugs may be useful for treating contractile dysfunction of the detrusor, as manifested in conditions such as underactive bladder. PMID- 28361519 TI - Evidence Is Enough?: A Systematic Review and Network Meta-Analysis of the Efficacy of Tamsulosin 0.2 mg and Tamsulosin 0.4 mg as an Initial Therapeutic Dose in Asian Benign Prostatic Hyperplasia Patients. AB - PURPOSE: We compared the efficacy of tamsulosin between 0.2 mg and 0.4 mg in Asian prostatic hyperplasia (BPH) patients using network meta-analysis due to lack of studies with direct comparison. METHODS: The literature search was conducted using the MEDLINE, Embase, and Cochrane Library. Keywords used were "BPH," "tamsulosin," "placebo." Experimental groups were defined as tamsulosin 0.2 mg (Tam 0.2) and 0.4 mg (Tam 0.4) and common control group was defined as placebo for indirect treatment comparison. Mixed treatment comparison was performed including one direct comparison study. RESULTS: Seven studies met the eligible criteria. Indirect treatment comparison revealed that total International Prostate Symptoms Score (IPSS) and quality of life score of IPSS were not significantly different in Tam 0.2 and Tam 0.4 (P>0.05). There was no significant difference of maximal flow rate and postvoid residual urine volume in Tam 0.2 and Tam 0.4 (P>0.05). Mixed treatment comparison including one direct comparison study showed inconsistency (P<0.001). Therefore, analysis using direct treatment comparison effect sizes of Tam 0.2 vs. placebo and Tam 0.4 vs. placebo was done and there was no significant difference. CONCLUSIONS: Network meta analysis showed no difference of efficacy between tamsulosin 0.2 mg and 0.4 mg and the evidence of tamsulosin 0.4 mg as initial dose for Asian BPH patient seems to be insufficient. Therefore, initial dose of tamsulosin for Asian BPH patient should be 0.2 mg. PMID- 28361520 TI - On the Site and Mechanism of Action of beta3-Adrenoceptor Agonists in the Bladder. AB - The clinical success of mirabegron as the first beta3-adrenoceptor (AR) agonist for treatment of the overactive bladder (OAB) syndrome, has resulted in substantial interest in its site and mechanism of action. Even if the adrenergic innervation of the bladder and urethra has been well studied, the location(s) of beta3-ARs in different structures within the bladder wall and urethra, and the mode(s) of action of beta3-AR stimulation have still not been established. The recent demonstration of beta3-ARs on cholinergic nerve terminals with no immunoreactivity in urothelium or detrusor smooth muscle, is not in agreement with previous morphological studies, and functional data strongly suggest that beta3-ARs can be found these structures. However, recent studies suggest that the beta3-ARs on detrusor smooth muscle may not be the functionally most relevant. The assumption that beta3-AR activation during bladder filling inhibits acetylcholine release from parasympathetic neurons by a prejunctional mechanism and that this decreases bladder micromotions that generate afferent activity, is an attractive hypothesis. It does not exclude that other mechanisms may be contributing, and supports combined approaches to reduce afferent activity for treatment of the OAB syndrome. PMID- 28361521 TI - Gemcitabine and Docetaxel Combination for Advanced Soft Tissue Sarcoma: A Nationwide Retrospective Study. AB - PURPOSE: This nationwide retrospective study was conducted to evaluate the efficacy and safety of combined gemcitabine and docetaxel (GD) as an off-label therapy for advanced soft tissue sarcoma, which has limited treatment options owing to its rare occurrence. MATERIALS AND METHODS: A total of 228 patients received GD therapy for advanced soft tissue sarcoma from 2009 to 2014 in Korea. We retrospectively reviewed the clinical medical records and claims data of these patients. RESULTS: A total of 218 patients in 20 medical centers were included in the final analysis (median age, 50.0 years). The objective response rate was 15.1% (34/218, in the leiomyosarcoma subgroup; 26.3%). The median overall survival and progression-free survival were 10.3 months (95% confidence interval [CI], 8.4 to 12.2) and 3.3 months (95% CI, 2.8 to 4.7), respectively. The treatment was discontinued in 7.8% of patients owing to adverse events; however, there was no adverse event-related death. Neutropenia (35.7%) and anemia (15.1%) were the most frequent grade 3/4 toxicities. Univariate analysis for identifying the predictors of the progression-free survival period revealed that patients aged <= 50 years had a hazard ratio of 1.388 (95% CI, 1.027 to 1.875; p < 0.05) relative to those aged > 50 years, and the group with leiomyosarcoma had a hazard ratio of 0.693 (95% CI, 0.493 to 0.975; p < 0.05) relative to the group with other histopathological subtypes. CONCLUSION: GD therapy was tolerable and effective for Korean patients with soft tissue sarcoma. In conclusion, for patients with advanced soft tissue sarcoma, especially leiomyosarcoma, GD therapy could be an important therapeutic option. PMID- 28361522 TI - Strategic Distributional Cost-Effectiveness Analysis for Improving National Cancer Screening Uptake in Cervical Cancer: A Focus on Regional Inequality in South Korea. AB - PURPOSE: The purpose of this study was to conduct a cost effectiveness analysis of strategies designed to improve national cervical cancer screening rates, along with a distributional cost effectiveness analysis that considers regional disparities. MATERIALS AND METHODS: Cost effectiveness analysis was conducted using a Markov cohort simulation model, with quality adjusted life years as the unit of effectiveness. The strategies considered were current (biennial Papanicolaou smear cytology of females aged 20 or above), strong screening recommendation by mail to target regions (effect, 12% increase in screening uptake; cost, 1,000 Korean won per person), regular universal screening recommendation by mail (effect, 6% increase in screening uptake; cost, 500 Korean won per person), and strong universal screening recommendation by mail (effect, 12% increase in screening uptake; cost, 1,000 Korean won per person). Distributional cost effectiveness analysis was conducted by calculating the cost effectiveness of strategies using the Atkinson incremental cost effectiveness ratio. RESULTS: All strategies were under the threshold value, which was set as the Korean gross domestic product of $25,990. In particular, the 'strong screening recommendation to target regions' strategy was found to be the most cost effective (incremental cost effectiveness ratio, 7,361,145 Korean won). This was also true when societal inequality aversion increased in the distributional cost effectiveness analysis. CONCLUSION: The 'strong screening recommendation to target regions' strategy was the most cost effective approach, even when adjusting for inequality. As efficiency and equity are objectives concurrently sought in healthcare, these findings imply a need to develop appropriate economic evaluation methodologies to assess healthcare policies. PMID- 28361524 TI - Validation of the Korean Version of the Quality of Life-Cancer Survivors (QOL-CS K) Questionnaire in Lymphoma Survivors. AB - PURPOSE: The objective of this study was to validate the Korean version of the Quality of Life-Cancer Survivors (QOL-CS-K) in a sample of lymphoma survivors. MATERIALS AND METHODS: We conducted a cross-sectional survey of lymphoma survivors who had survived for at least 24 months since diagnosis. Participants were recruited at the outpatient clinics and at a hospital event in a tertiary hospital in Seoul, Korea. Survivors were asked to complete the QOL-CS-K and the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) questionnaires. To determine test-retest reliability, a second questionnaire was sent to participants who completed the first questionnaire adequately. Exploratory factor analysis and Pearson's correlations were used for evaluating reliability and validity of the QOL-CS-K. RESULTS: Among 257 survivors, 245 (95.3%) completed all questionnaires and had no missing data. The mean age of study participants was 52.2 years, 54.9% were men, and the mean time since diagnosis was 4.0+/-1.6 years. The Cronbach's alpha for the overall QOL-CS-K was 0.90, and the alpha coefficients for each subscale ranged from 0.73 to 0.83. The test and retest reliability was 0.88. Moderate correlations were found between comparable subscales of the QOL-CS-K and subscales of the EORTC QLQ-C30 (r=0.51-0.55) except for the spiritual well-being subscale of the QOL-CS-K, which did not correlate with any of the EORTC QLQ-C30 subscales (-0.08 to 0.16). CONCLUSION: The QOL-CS-K is a reliable and valid scale for measuring the QOL in long-term lymphoma survivors. PMID- 28361525 TI - A rapid validated UV-HPLC method for the simultaneous determination of the antiretroviral compounds darunavir and raltegravir in their dosage form. AB - OBJECTIVE: A rapid, simple and sensitive high-performance liquid chromatography (HPLC) method with ultraviolet detection has been developed for quantification of darunavir and raltegravir in their pharmaceutical dosage form. METHODS: The assay enables the measurement of both drugs with a linear calibration curve (R2= 0.999) over the concentration range 5-100 mg/L. The determination was performed on an analytical Tracer Excel 120 ODSB (15x0.4.6 cm) column at 35oC. The selected wavelength was 254 nm. The mobile phase was a mixture of 0.037 M sodium dihydrogen phosphate buffer, acetonitrile and methanol (40:50:10, v/v/v) at a flow rate of 2.0 mL/min Nevirapine (50 mg/L) was used as internal standard. RESULTS: Accuracy, intra-day repeatability (n = 5), and inter-day precision (n = 3) were found to be satisfactory, being the accuracy from -4.33 to 3.88% and precisions were intra-day and inter-day, 0.25% and 4.42% respectively in case of darunavir. Raltegravir intra-day and inter-day precisions lower of 1.01 and 2.36%, respectively and accuracy values bet from -4.02 to 1.06%. CONCLUSIONS: Determination of the darunavir and raltegravir in their dosage form was done with a maximum deviation of 4%. This analytical method is rapid, easily implantable and offers good results. PMID- 28361523 TI - Nationwide Statistical Analysis of Lymphoid Malignancies in Korea. AB - PURPOSE: Regional differences in the incidence of lymphoid malignancies have been reported worldwide, but there has been no large-scale epidemiologic analysis in Korea. The aim of this study was to provide a nationwide population-based statistical analysis of Korean patients with lymphoid malignancies. MATERIALS AND METHODS: The Korea Central Cancer Registry analyzed the incidence and survival of patients with lymphoid malignancies from the Korean National Cancer Incidence Database. Diseases were grouped by clinically relevant categories based on the 2008 World Health Organization classification. RESULTS: Overall 65,948 lymphoid diseases were identified between 1999 and 2012. The incidence of most subtypes increased with age, except for precursor cell neoplasms. Male predominance (male:female ratio=1.28:1) was observed. In 2012, annual age-standardized incidence rates per 100,000 persons of Hodgkin's lymphoma, mature B-cell neoplasm, mature T/natural killer (NK)-cell neoplasm, and precursor cell neoplasm were 0.46, 6.60, 0.95, and 1.50, respectively, and they increased yearly from 1999. Composite Hodgkin's and non-Hodgkin's lymphomas were extremely rare. Survival improvement estimated using 5-year relative survival rate was observed in patients with Hodgkin's lymphoma (71.1%-83.0%), diffuse large B-cell lymphoma (49.5%-61.5%), plasma cell neoplasms (20.2%-36.9%), and lymphoblastic lymphoma/leukemia (41.5%-56.3%) between 1993 and 2012. However, survival rates of T/NK-cell lymphoma (excluding cutaneous T-cell lymphoma) ranged from 40.5%-43.5% during the study period. Survival rates decreased with age in most subtypes. CONCLUSION: This report presented the subtype-specific statistical analysis of lymphoid malignancies in the Korean population, showing increasing incidences and survival rates in most subtypes. PMID- 28361526 TI - Ceftolozane-tazobactam for the treatment of ventilator-associated infections by colistin-resistant Pseudomonas aeruginosa. AB - The use of colistin for the treatment of multiresistant bacteria has led to the emergence of colistin-resistant strains of Gram-negative bacilli. Treatment of infections caused by these pan-drug-resistant bacteria is difficult owing to the paucity of effective antibiotics. We report two cases of ventilator-associated respiratory infection caused by pan-drug-resistant, colistin-resistant Pseudomonas aeruginosa that were successfully treated with ceftolozane tazobactam. PMID- 28361527 TI - Clinical presentation of candidaemia in elderly patients: experience in a single institution. AB - OBJECTIVE: To analyse the clinical presentation of candidaemia in elderly patients. METHODS: A comparison of clinical presentation of candidaemia cases was carried out in a Spanish tertiary hospital between January 2010 and September 2015. RESULTS: Forty-five cases (32%) corresponded to elderly patients (>= 75 years) and 95 cases (68%) to non-elderly patients (16-74 years). A higher proportion of elderly patients presented solid tumour (51% versus 32%, p=0.026) and a lower proportion had undergone solid or hematopoietic transplantation (0% versus 28%, p<0.001). Fewer elderly patients (16 patients, 36%) had a central venous line inserted than non-elderly patients (81 patients, 85%, p<0.001). Isolation of Candida parapsilosis was significantly lower among elderly (13.3%) than among non-elderly patients (32%, p=0.015). Fundoscopy was carried out in 20 elderly (44%) and in 64 younger patients (67%, p=0.009). The proportion of patients who underwent echocardiography was similar in both groups (56% vs 66%, respectively; p=0.218). Adequate antifungal treatment within the first 48 hours was administered in16 elderly patients (36%) and 58 younger patients (61%, p=0.005). Catheter removal was carried out in 9 elderly patients (68.1%) and in 40 non-elderly patients (49%, p=0.544). Mortality was higher among elderly patients (55.6%) than non-elderly patients (36.8%; p=0.037). CONCLUSIONS: Elderly patients account for a substantial proportion of patients suffering from candidaemia in recent years. The clinical management of these patients was less appropriate than in younger patients with respect to fundus examination and the prescription of appropriate antifungal treatment. Mortality in elderly patients was higher than in younger patients. PMID- 28361528 TI - Epidemic meningitis control in countries of the African meningitis belt, 2016. PMID- 28361529 TI - Ensuring the timely supply and management of medicines for preventive chemotherapy against neglected tropical diseases. PMID- 28361530 TI - Enhanced Efficiency and Stability of an Aqueous Lead-Nitrate-Based Organometallic Perovskite Solar Cell. AB - We investigate the stability of an active organometallic perovskite layer prepared from a two-step solution procedure, including spin coating of aqueous lead nitrate (Pb(NO3)2) as a Pb2+ source and sequential dipping into a methylammonium iodide (CH3NH3I) solution. The conversion of CH3NH3PbI3 from a uniform Pb(NO3)2 layer generates PbI2-free and large-grain perovskite crystallites owing to an intermediate ion-exchange reaction step, resulting in improved humidity resistance and, thereby, improved long-term stability with 93% of the initial power conversion efficiency (PCE) after a period of 20 days. The conventional fast-converted PbI2-dimethylformamide solution system leaves small amounts of intrinsic PbI2 residue on the resulting perovskite and MAPbI3 crystallites with uncontrollable sizes. This accelerates the generation of PbI2 and the decomposition of the perovskite layer, resulting in poor stability with less than 60% of the initial PCE after a period of 20 days. PMID- 28361531 TI - Photocatalytic Anatase TiO2 Thin Films on Polymer Optical Fiber Using Atmospheric Pressure Plasma. AB - Due to the undeniable industrial advantages of low-temperature atmospheric pressure plasma processes, such as low cost, low temperature, easy implementation, and in-line process capabilities, they have become the most promising next-generation candidate system for replacing thermal chemical vapor deposition or wet chemical processes for the deposition of functional coatings. In the work detailed in this article, photocatalytic anatase TiO2 thin films were deposited at a low temperature on polymer optical fibers using an atmospheric pressure plasma process. This method overcomes the challenge of forming crystalline transition metal oxide coatings on polymer substrates by using a dry and up-scalable method. The careful selection of the plasma source and the titanium precursor, i.e., titanium ethoxide with a short alkoxy group, allowed the deposition of well-adherent, dense, and crystalline TiO2 coatings at low substrate temperature. Raman and XRD investigations showed that the addition of oxygen to the precursor's carrier gas resulted in a further increase of the film's crystallinity. Furthermore, the films deposited in the presence of oxygen exhibited a better photocatalytic activity toward methylene blue degradation assumedly due to their higher amount of photoactive {101} facets. PMID- 28361532 TI - Fused Deposition Modeling Enables the Low-Cost Fabrication of Porous, Customized Shape Sorbents for Small-Molecule Extraction. AB - Fused deposition modeling, one of the most common techniques in three-dimensional printing and additive manufacturing, has many practical applications in the fields of chemistry and pharmacy. We demonstrate that a thermoplastic elastomer poly(vinyl alcohol) (PVA) composite material (LAY-FOMM 60), which presents porous properties after PVA removal, is useful for the extraction of small-molecule drug like compounds from water samples. The usefulness of the proposed approach is demonstrated by the extraction of glimepiride from a water sample, followed by LC MS analysis. The recovery was 82.24%, with a relative standard deviation of less than 5%. The proposed approach can change the way of thinking about extraction and sample preparation due to a shift to the use of sorbents with customizable size, shape, and chemical properties that do not rely on commercial suppliers. PMID- 28361533 TI - Synthesis and Reactivity of 1-Allenyltriazenes. AB - 1-Aryl-3,3-dialkyltriazenes have received considerable attention in the context of synthetic and medicinal chemistry. In contrast, the chemistry of other unsaturated triazenes is largely unexplored. The synthesis of 1-allenyltriazenes is described. This new class of compounds can be obtained by base-induced isomerization of 1-alkynyltriazenes. The latter are accessible by reaction of alkynyl Grignard reagents with lithium amides and nitrous oxide. 1 Allenyltriazenes were found to be thermally labile, but they can be stored without degradation at lower temperatures. In the presence of ZnCl2, 1 allenyltriazenes rearrange into N-aminopyrazoles. PMID- 28361534 TI - Ultrathin Broadband Germanium-Graphene Hybrid Photodetector with High Performance. AB - Germanium-based photodetector is a key component in silicon based photonics because of its unique properties of response at telecommunication band and compatibility with CMOS techniques. However, the limitations of low quantum efficiency and high surface recombination in ultrathin germanium film, especially in the near-infrared range, put huge obstructions on the road toward applications. Nowadays, practical applications require more nanoscale devices with lower power consumption as well as higher responsivity and response speed. In this work, we first demonstrate a germanium-graphene hybrid structure photodetector that consists of an ultrathin 20 nm germanium layer and a monolayer graphene. The photodetector can achieve a broadband detection from ultraviolet to near-infrared range. A conductive gain of 155 and a responsivity of 66.2 A W-1 are achieved, which is about 3 orders of magnitude higher than pure graphene photodetectors and about 4 times larger than pure germanium photodetectors. Such enhancement owes to effective generation, separation and transfer of photogenerated carriers at material interface. The photodetector based on germanium--graphene hybrid structure presents a new paradigm for the realization of small but high performance device in the process of integration in silicon based optical chips. And it offers new opportunities for imaging, sensing, and other optoelectronic field applications. PMID- 28361535 TI - Detecting Ligand-Binding Events and Free Energy Landscape while Imaging Membrane Receptors at Subnanometer Resolution. AB - Force-distance curve-based atomic force microscopy has emerged into a sophisticated technique for imaging cellular membranes and for detecting specific ligand-binding events of native membrane receptors. However, so far the resolution achieved has been insufficient to structurally map ligand-binding sites onto membrane proteins. Here, we introduce experimental and theoretical approaches for overcoming this limitation. To establish a structurally and functionally well-defined reference sample, we engineer a ligand-binding site to the light-driven proton pump bacteriorhodopsin of purple membrane. Functionalizing the AFM stylus with an appropriate linker-system tethering the ligand and optimizing the AFM conditions allows for imaging the engineered bacteriorhodopsin at subnanometer resolution while structurally mapping the specific ligand-receptor binding events. Improved data analysis allows reconstructing the ligand-binding free energy landscape from the experimental data, thus providing thermodynamic and kinetic insight into the ligand-binding process. The nanoscopic method introduced is generally applicable for imaging receptors in native membranes at subnanometer resolution and for systematically mapping and quantifying the free energy landscape of ligand binding. PMID- 28361536 TI - Semipolar (2021) GaN and InGaN Light-Emitting Diodes Grown on Sapphire. AB - We have demonstrated growing uniform and purely nitrogen polar semipolar (2021) GaN epilayers on 2 in. patterned sapphire substrates. The as-grown surface of (2021) GaN is composed of two stable facets: (1010) and (1011). A chemical mechanical polishing process was further used to planarize the surface with a final surface root-mean-square roughness of less than 1.5 nm over an area of 10 * 10 MUm2. InGaN light-emitting diodes were grown on a polished (2021) GaN/sapphire template with an electroluminescence emission at around 490 nm. Our work exhibits the potential to produce high-quality nitrogen-polar semipolar GaN templates and optoelectronic devices on large-area sapphire substrates with economical feasibility. PMID- 28361537 TI - Integration of Chemical, Genetic, and Bioinformatic Approaches Delineates Fungal Polyketide-Peptide Hybrid Biosynthesis. AB - To identify natural products and their associated biosynthetic genes from underutilized, difficult-to-manipulate microbes, chemical screening and bioinformatic analysis were employed to identify secondary metabolites and a potentially associated biosynthetic gene cluster. Subsequently, a heterologous expression system was used to confirm the identity of the gene cluster and the proposed biosynthetic mechanism. This approach successfully identified the curvupallide and spirostaphylotrichin biosynthetic pathways in endophytic fungus Curvularia pallescens and the short-chain pyranonigrin biosynthetic pathway in Aspergillus niger. PMID- 28361538 TI - Light-Controlled Membrane Mechanics and Shape Transitions of Photoswitchable Lipid Vesicles. AB - Giant unilamellar vesicles (GUVs) represent a versatile model system to emulate the fundamental properties and functions associated with the plasma membrane of living cells. Deformability and shape transitions of lipid vesicles are closely linked to the mechanical properties of the bilayer membrane itself and are typically difficult to control under physiological conditions. Here, we developed a protocol to form cell-sized vesicles from an azobenzene-containing phosphatidylcholine (azo-PC), which undergoes photoisomerization on irradiation with UV-A and visible light. Photoswitching within the photolipid vesicles enabled rapid and precise control of the mechanical properties of the membrane. By varying the intensity and dynamics of the optical stimulus, controlled vesicle shape changes such as budding transitions, invagination, pearling, or the formation of membrane tubes were achieved. With this system, we could mimic the morphology changes normally seen in cells, in the absence of any molecular machines associated with the cytoskeleton. Furthermore, we devised a mechanism to utilize photoswitchable lipid membranes for storing mechanical energy and then releasing it on command as locally usable work. PMID- 28361539 TI - Direct Observation of Charge Collection at Nanometer-Scale Iodide-Rich Perovskites during Halide Exchange Reaction on CH3NH3PbBr3. AB - Organolead halide perovskites MAPbX3 (MA = CH3NH3+, X = Cl-, Br-, or I-) are known to undergo reversible halide exchange reactions, enabling bandgap tuning over the visible light region. Using single-particle photoluminescence (PL) imaging for in situ observation, we have studied the structure-dependent charge dynamics during halide exchange with iodide ions on an MAPbBr3 crystal. In particular, we optically detected nanometer-scale iodide-rich domains (i.e., MAPbBrI2) and found that their lifetimes of several tens of milliseconds are limited by reaction with diffusing vacancies. Furthermore, it was discovered that these domains effectively collect the charge carriers from the bulk crystal, thus resulting in amplified spontaneous emission (ASE) under continuous-wave laser irradiation. Our findings will provide direction for development of perovskite heterostructures with enhanced charge utilization. PMID- 28361540 TI - Exciton-Induced Degradation of Carbazole-Based Host Materials and Its Role in the Electroluminescence Spectral Changes in Phosphorescent Organic Light Emitting Devices with Electrical Aging. AB - We investigate the origins of the long-wavelength bands that appear in the emission spectra of carbazole-based host materials and play a role in the electroluminescence (EL) spectral changes of phosphorescent organic light emitting devices (PhOLEDs) with electrical aging. 4,4'-Bis(carbazol-9-yl)biphenyl (CBP) is used as a model carbazole host material and is studied using photoluminescence, EL, and atomic force microscopy measurements under various stress scenarios in both single and bilayer devices and in combination with various electron transport layer (ETL) materials. Results show that exciton induced morphological aggregation of CBP is behind the appearance of those long wavelength bands and that complexation between the aggregated CBP molecules and ETL molecules plays a role in this phenomenon. Comparisons between the effects of exciton and thermal stress suggest that exciton-induced aggregation may be limited to short-range molecular ordering or pairing (e.g., dimer or trimer species formation) versus longer-range ordering (crystallization) in the case of thermal stress. The findings provide new insights into exciton-induced degradation in wide band gap host materials and its role in limiting the stability of PhOLEDs. PMID- 28361541 TI - Characterization of Polyphenol Effects on Inhibition and Promotion of Iron Uptake by Caco-2 Cells. AB - Polyphenolic compounds present in the seed coat of common bean (Phaseolus vulgaris L.) are known to act collectively as inhibitors of iron bioavailability. Recent research identified specific polyphenols as being potent Fe uptake inhibitors. That research also identified other polyphenols as being promoters of Fe uptake. The present study extends that work using a Caco-2 cell model to characterize the effects of 43 additional polyphenols on Fe uptake. In addition, this study indicates that the inhibitory compounds have a more potent effect that outweighs the ability of promoting compounds to increase Fe uptake. For example, a ratio of 100:0 epicatechin (a promoter)/myricetin (an inhibitor) produced 78.5 +/- 6.7 ng ferritin/mg protein, 90:10 yielded 27.4 +/- 3.0, 50:50 yielded 3.42 +/ 0.54, and 0:100 yielded 2.26 +/- 0.25 ng ferritin/mg protein. A simulation of the relative concentrations of eight major polyphenols (four inhibitors, four promoters) present in a sample of black bean seed coats demonstrated that most of the inhibitory compounds would need to be removed to reduce the negative effect on Fe uptake. In vivo studies are now warranted to confirm the above in vitro effects. Such work would be significant as other bean color classes exist that are likely to have polyphenolic profiles that are more favorable to Fe bioavailability. PMID- 28361542 TI - Wafer Scale Fabrication of Dense and High Aspect Ratio Sub-50 nm Nanopillars from Phase Separation of Cross-Linkable Polysiloxane/Polystyrene Blend. AB - We demonstrated a simple and effective approach to fabricate dense and high aspect ratio sub-50 nm pillars based on phase separation of a polymer blend composed of a cross-linkable polysiloxane and polystyrene (PS). In order to obtain the phase-separated domains with nanoscale size, a liquid prepolymer of cross-linkable polysiloxane was employed as one moiety for increasing the miscibility of the polymer blend. After phase separation via spin-coating, the dispersed domains of liquid polysiloxane with sub-50 nm size could be solidified by UV exposure. The solidified polysiloxane domains took the role of etching mask for formation of high aspect ratio nanopillars by O2 reactive ion etching (RIE). The aspect ratio of the nanopillars could be further amplified by introduction of a polymer transfer layer underneath the polymer blend film. The effects of spin speeds, the weight ratio of the polysiloxane/PS blend, and the concentration of polysiloxane/PS blend in toluene on the characters of the nanopillars were investigated. The gold-coated nanopillar arrays exhibited a high Raman scattering enhancement factor in the range of 108-109 with high uniformity across over the wafer scale sample. A superhydrophobic surface could be realized by coating a self-assembled monolayers (SAM) of fluoroalkyltrichlorosilane on the nanopillar arrays. Sub-50 nm silicon nanowires (SiNWs) with high aspect ratio of about 1000 were achieved by using the nanopillars as etching mask through a metal-assisted chemical etching process. They showed an ultralow reflectance of approximately 0.1% for wavelengths ranging from 200 to 800 nm. PMID- 28361543 TI - Inhibition of Myeloperoxidase- and Neutrophil-Mediated Hypochlorous Acid Formation in Vitro and Endothelial Cell Injury by (-)-Epigallocatechin Gallate. AB - Myeloperoxidase (MPO) plays important roles in various diseases through its unique chlorinating activity to catalyze excess hypochlorous acid (HOCl) formation. Epidemiological studies indicate an inverse correlation between plant polyphenol consumption and the incidence of cardiovascular diseases. Here we showed that (-)-epigallocatechin gallate (EGCG), the main flavonoid present in green tea, dose-dependently inhibited MPO-mediated HOCl formation in vitro (chlorinating activities of MPO: 50.2 +/- 5.7% for 20 MUM EGCG versus 100 +/- 5.6% for control, P < 0.01). UV-vis spectral and docking studies indicated that EGCG bound to the active site (heme) of MPO and resulted in the accumulation of compound II, which was unable to produce HOCl. This flavonoid also effectively inhibited HOCl generation in activated neutrophils (HOCl formation: 65.0 +/- 5.6% for 20 MUM EGCG versus 100 +/- 6.2% for control, P < 0.01) without influencing MPO and Nox2 release and superoxide formation, suggesting that EGCG specifically inhibited MPO but not NADPH oxidase activity in activated neutrophils. Moreover, EGCG inhibited MPO (or neutrophil)-mediated HOCl formation in human umbilical vein endothelial cells (HUVEC) culture and accordingly protected HUVEC from MPO (or neutrophil)-induced injury (P < 0.05, all cases), although it did not induce cytotoxicity to HUVEC (P > 0.05, all cases). Our results indicate that dietary EGCG is an effective and specific inhibitor of MPO activity and may participate in the regulation of immune responses at inflammatory sites. PMID- 28361544 TI - Response to: "Mammographic density as a risk factor: to go out of a 30-year fog". PMID- 28361545 TI - Progressive massive fibrosis in patients with pneumoconiosis: utility of MRI in differentiating from lung cancer. AB - Background It is occasionally difficult to distinguish progressive massive fibrosis (PMF) from lung cancer on computed tomography (CT) in patients with pneumoconiosis. Purpose To evaluate the magnetic resonance imaging (MRI) features of PMF and to assess its ability to differentiate PMF from lung cancer. Material and Methods Between 2000 and 2014, 40 pulmonary lesions suspected to be lung cancer on the basis of CT in 28 patients with known pneumoconiosis were evaluated. Twenty-four of the 40 lesions were pathologically or clinically diagnosed as PMF. The signal pattern on T2-weighted (T2W) images, post-contrast enhancement pattern on T1-weighted (T1W) images, and the pattern of the time intensity curve (TIC) on contrast-enhanced dynamic studies were evaluated. All images were analyzed independently by two chest radiologists. Results All 24 PMF lesions showed low signal intensity (SI) on T2W images (sensitivity, 100%), while 15 of 16 lung cancer lesions showed intermediate or high SI on T2W images (specificity, 94%) when PMF was regarded as a positive result. Six of 17 PMF lesions showed a homogeneous enhancement pattern (sensitivity, 35%), and 4/9 lung cancer lesions showed an inhomogeneous or a ring-like enhancement pattern (specificity, 44%). Six of 16 PMF lesions showed a gradually increasing enhancement pattern (sensitivity, 38%), and 7/9 lung cancer lesions showed rapid enhancement pattern (specificity, 78%). Conclusion When differentiation between PMF and lung cancer in patients with pneumoconiosis is difficult on CT, an additional MRI study, particularly the T2W imaging sequence, may help differentiate between the two. PMID- 28361546 TI - Clinical feasibility of simultaneous multi-slice imaging with blipped-CAIPI for diffusion-weighted imaging and diffusion-tensor imaging of the brain. AB - Background Simultaneous multi-slice (SMS) imaging is starting to be used in clinical situation, although evidence of clinical feasibility is scanty. Purpose To prospectively assess the clinical feasibility of SMS diffusion-weighted imaging (DWI) and diffusion-tensor imaging (DTI) with blipped-controlled aliasing in parallel imaging for brain lesions. Material and Methods The institutional review board approved this study. This study included 156 hyperintense lesions on DWI from 32 patients. A slice acceleration factor of 2 was applied for SMS scans, which allowed shortening of the scan time by 41.3%. The signal-to-noise ratio (SNR) was calculated for brain tissue of a selected slice. The contrast-to-noise ratio (CNR), apparent diffusion coefficient (ADC), and fractional anisotropy (FA) were calculated in 36 hyperintense lesions with a diameter of three pixels or more. Visual assessment was performed for all 156 lesions. Tractography of the corticospinal tract of 29 patients was evaluated. The number of tracts and averaged tract length were used for quantitative analysis, and visual assessment was evaluated by grading. Results The SMS scan showed no bias and acceptable 95% limits of agreement compared to conventional scans in SNR, CNR, and ADC on Bland Altman analyses. Only FA of the lesions was higher in the SMS scan by 9% ( P = 0.016), whereas FA of the surrounding tissues was similar. Quantitative analysis of tractography showed similar values. Visual assessment of DWI hyperintense lesions and tractography also resulted in comparable evaluation. Conclusion SMS imaging was clinically feasible for imaging quality and quantitative values compared with conventional DWI and DTI. PMID- 28361547 TI - Esential oils extraction: a 24-hour steam distillation systematic methodology. AB - Steam distillation is known to be the most prevalent method of essential oil extraction. Despite many studies on extraction methods, there is no report about the impact of distillation process duration on the yield and oil quality. A new 24-h steam distillation process for extraction of plant essential oils is presented. For improving the total yield, prolonged and continued isolation was used. A selection of plant species from Lamiaceae and Apiaceae families was subjected to direct steam distillation and essential oils were collected at different times (1, 2, 3, 6, 12 and 24 h). The analysis included either annual or perennial species monitored in terms of different harvesting time. From these studies, it is conclusively that there is no rule about appropriate extraction time, and different plants need different periods for the essential oils to achieve the desired quality or quantity of extract. Thus, extraction duration is directly dependent on what the study is conducted for. PMID- 28361548 TI - Bloody technology: the sphygmograph in asylum practice. AB - The sphygmograph, an instrument to measure and visually chart the pulse, was used by a number of asylum researchers in the late nineteenth century in an attempt to better understand mental disease. In charting the use of such a medical technology in the asylum, this article explores the utility of a practice oriented approach in the history of psychiatry - as a window onto the alienist profession and as a means of investigating how new medical technologies were assimilated into everyday practice. PMID- 28361549 TI - Antimicrobial sesquiterpene lactones from Artemisia sieberi. AB - Two new sesquiterpene lactones 3R, 8R-dihydroxygermacr-4(15),9(10)-dien 6S,7S,11RH,12,6-olide (1) and 1R, 8S-dihydroxy-11R,13-dihydrobalchanin(2), together with two known compounds 11-epiartapshin (3) and 3'-hydroxygenkwanin (4), were isolated from Artemisia sieberi. Their structures were elucidated by 1D, 2D NMR, MS, and X-ray diffraction. Compound 4 inhibited Gram-positive bacteria Bacillus subtilis and Staphylococcus aureus with Minimal inhibitory concentration values of 50 and 25 MUg/disk, respectively. All the isolated compounds exhibited moderate antifungal activities. PMID- 28361550 TI - Mercury in fish products: what's the best for consumers between bluefin tuna and yellowfin tuna? AB - A total of 205 bluefin and yellowfin tuna samples were examined for mercury detection in order to verify possible differences and have a detailed risk assessment of the two tuna species. The results showed significant higher mercury concentration in muscle tissue of bluefin tuna respect yellowfin tuna (p < 0.001) with mean concentration of 0.84 mg/kg and maximum value of 1.94 mg/kg. These differences can be due the different biological and ecological aspects of the two tuna species and to different oceanographic aspects between Atlantic Ocean and Mediterranean sea. The results obtained in this study suggest an advisable containment of the sources of pollution and further studies on the closed-loop farming of bluefin tuna, in order to ensure the product safety. PMID- 28361551 TI - Antioxidant phenolic compounds from the rhizomes of Astilbe rivularis. AB - The rhizomes of Astilbe rivularis, commonly known as 'Thulo Okhati' are widely used in Nepal as tonic for uterine and menstrual disorders. In our preliminary study, the 70% MeOH extract of the rhizomes showed potent antioxidant activity. Hence, present study was aimed for the isolation of potent antioxidant constituents. Bergenin (1), 11-O-galloylbergenin (2), (+)-catechin (3), (-) catechin (4), (-)-afzelechin (5), (-)-epiafzelechin (6) and 2-(beta-D glucopyranosyloxy)-4-hydroxylbenzenacetonitrile (7) were isolated from the rhizomes. Structures of these compounds were elucidated on the basis of spectroscopic methods. All these isolated compounds were evaluated for their in vitro antioxidant activity by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay. 11-O-Galloylbergenin (2), (+)-catechin (3), (-)-catechin (4), ( )-afzelechin (5) and (-)-epiafzelechin (6) showed potent antioxidant activity. PMID- 28361552 TI - Serum levels of nesfatin-1 are increased in gestational diabetes mellitus. AB - OBJECTIVE: To analyze the concentrations of nesfatin-1 in maternal and cord serum, to evaluate the expression of nesfatin-1 in subcutaneous adipose tissue (SAT) from pregnant women with gestational diabetes mellitus (GDM) and those with normal glucose tolerance (NGT). METHODS: We studied a total of 50 GDM and 50 NGT subjects. The clinical features, serum nesfatin-1, homeostasis model assessment of insulin resistance (HOMA-IR), lipid profiles were measured at the third trimester of pregnancy. The expression of nesfatin-1 in the SAT was determined by western blot. RESULTS: Compared with the NGT group, the GDM group showed greater levels of serum nesfatin-1, adipocyte fatty acid binding protein (AFABP), and leptin; a greater level of cord blood nesfatin-1; and a higher level of expression in SAT (p < 0.05 or p < 0.01). Fasting insulin (FI) (b = 0.317, p= 0.022) and body mass index (BMI) before delivery (b = 0.367, p=0.008) were independently associated with serum nesfatin-1. Nesfatin-1 was the independent risk factor for GDM. CONCLUSIONS: The GDM group had higher levels of maternal serum and cord blood nesfatin-1, and greater nesfatin-1 expression in SAT. Nesfatin-1 is closely related to obesity and IR in pregnancy. PMID- 28361553 TI - Phytochemical analysis and antioxidant activity of the seed of Telfairia occidentalis Hook (Cucurbitaceae). AB - The 2,2-diphenyl-1-picryl hydrazyl (DPPH) radical, nitric oxide, reducing power, hydrogen peroxide scavenging, and total antioxidant activities of the methanol extract, n-hexane, dichloromethane, ethyl acetate, butanol and aqueous fractions of the seed of Telfairia occidentalis were evaluated. Total phenolic content was determined using the Folin-Ciocalteu method. The dichloromethane fraction exhibited the highest DPPH radical scavenging, reducing power and total antioxidant activities. Two pure compounds which were identified by FTIR, H-and 2D NMR and Mass spectroscopy as 9-octadecenoic acid (TOS B) and 10 hydroxyoctadecanoic acid (TOS C) and four oily isolates, TOS A, TOS D, TOS E and TOS F were obtained from the dichloromethane fraction. TOS E had the highest DPPH radical scavening activity comparable to that of ascorbic acid. GC-MS analysis revealed the major compounds in TOS E as 4-(2,2-Dimethyl-6-methylene cyclohexylidene)-2-butanol; 3-(3-hydroxybutyl)-2,4,4-trimethyl-2-cyclohexene-1 one and 1,2-Benzenedicarboxylic acid disooctyl ester. Thus, the seed of T. occidentalis can be consumed for its antioxidant property. PMID- 28361554 TI - Molecular antibiogram in diagnostic clinical microbiology: advantages and challenges. PMID- 28361555 TI - Life-threatening endocrine emergencies during pregnancy - management and therapeutic features. AB - Endocrine emergencies during pregnancy may be life-threatening events for both mother and fetus. Besides pregnancy-associated endocrine disorders, several pre existing endocrinopathies such as type-1 diabetes and Grave's disease or adrenal failure may acutely deteriorate during pregnancy. Since "classical" signs are often modified by pregnancy, early diagnosis and management may be hampered. In addition, laboratory tests show altered physiologic ranges and pharmacologic options are limited while therapeutic goals are mostly tighter than in the non pregnant patient. Though subclinical endocrinopathies are more frequent and worth consideration due to their related adverse sequelae, this article focuses on endocrine emergencies complicating pregnancy. PMID- 28361556 TI - Fungicide Xylaria sp. BCC 1067 extract induces reactive oxygen species and activates multidrug resistance system in Saccharomyces cerevisiae. AB - AIM: To investigate antifungal potential of Xylaria sp. BIOTEC culture collection (BCC) 1067 extract against the model yeast Saccharomyces cerevisiae. MATERIALS & METHODS: Antifungal property of extract, reactive oxygen species levels and cell survival were determined, using selected deletion strains. RESULTS: Extract showed promising antifungal effect with minimal inhibitory concentration100 and minimal fungicidal concentration of 500 and 1000 mg/l, respectively. Strong synergy was observed with fractional inhibitory concentration index value of 0.185 for the combination of 60.0 and 0.5 mg/l of extract and ketoconazole, respectively. Extract-induced intracellular reactive oxygen species levels in some oxidant-prone strains and mediated plasma membrane rupture. Antioxidant regulator Yap1, efflux transporter Pdr5 and ascorbate were pivotal to protect S. cerevisiae from extract cytotoxicity. CONCLUSION: Xylaria sp. BCC 1067 extract is a potentially valuable source of novel antifungals. PMID- 28361557 TI - Protective effect of alpha-lipoic acid in methotrexate-induced ovarian oxidative injury and decreased ovarian reserve in rats. AB - To determine whether the possible oxidative effect of methotrexate (Mtx) on ovary and to evaluate the effectiveness of alpha lipoic acid (ALA), which may be useful in many oxidative stress models. Thirty-two female Wistar-albino rats were randomly divided into four groups; control group, alpha lipoic acid group (ALA 100 mg/kg, 10 days), multiple dose Mtx group (Mtx 1 mg/kg 1, 3, 5, 7 days) and Mtx and ALA group (Mtx 1 mg/kg 1, 3, 5, 7 days and ALA 100 mg/kg, 10 days). Serum total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI), tumor necrosis factor-alpha (TNF-alpha), tissue malondialdehyde (MDA) and activities of glutathione peroxidase (GSH-Px) and catalase (CAT) and anti-Mullerian hormone (AMH) and total ovarian follicle count were evaluated. Mtx administration caused a significant decrease in TAS, a significant increase in TOS and OSI, a significant increase in MDA levels and a decrease in GSH-Px and CAT activity. Moreover the proinflammatory cytokine (TNF-alpha) was increased in the Mtx group. And AMH values and total follicle count were significantly decreased in Mtx group. However, ALA treatment reversed biochemical results and AMH levels and total follicle count. Alpha lipoic acid ameliorates methotrexate induced oxidative damage of ovarian in rats. PMID- 28361558 TI - Mining the fecal proteome: from biomarkers to personalised medicine. AB - INTRODUCTION: Fecal proteomics has gained increased prominence in recent years. It can provide insights into the diagnosis and surveillance of many bowel diseases by both identifying potential biomarkers in stool samples and helping identify disease-related pathways. Fecal proteomics has already shown its potential for the discovery and validation of biomarkers for colorectal cancer screening, and the analysis of fecal microbiota by MALDI-MS for the diagnosis of a range of bowel diseases is gaining clinical acceptance. Areas covered: Based on a comprehensive analysis of the current literature, we introduce the range of sensitive and specific proteomics methods which comprise the current 'Proteomics Toolbox', explain how the integration of fecal proteomics with data processing/bioinformatics has been used for the identification of potential biomarkers for both CRC and other gut-related pathologies and analysis of the fecal microbiome, outline some of the current fecal assays in current clinical practice and introduce the concept of personalised medicine which these technologies will help inform. Expert commentary: Integration of fecal proteomics with other proteomics and genomics strategies as well as bioinformatics is paving the way towards personalised medicine, which will bring with it improved global healthcare. PMID- 28361560 TI - After phrenology: neural reuse and the interactive brain. PMID- 28361559 TI - A new immunosuppressive pregnane glycoside from aqueous fraction of Epigynum cochinchinensis. AB - Chemical investigation on the aqueous fraction of the stems of Epigynum cochinchinensis led to the isolation of a new pregnane glycoside named as epigycoside A (1) along with three known analogues (2-4). The structure of compound 1 was elucidated by means of spectroscopic techniques, including HRESIMS, and 1D and 2D NMR experiments. The immunosuppressive activity of 1 was evaluated by an in vitro model of concanavalin A-induced mice splenocytes proliferation. Compound 1 showed significant inhibitory activity in a dose dependent manner, closer to the efficacy of positive control, dexamethasone, at a concentration of 50 MUM. PMID- 28361561 TI - Positive events protect children from causal false memories for scripted events. AB - Adults produce fewer inferential false memories for scripted events when their conclusions are emotionally charged than when they are neutral, but it is not clear whether the same effect is also found in children. In the present study, we examined this issue in a sample of 132 children aged 6-12 years (mean 9 years, 3 months). Participants encoded photographs depicting six script-like events that had a positively, negatively, or a neutral valenced ending. Subsequently, true and false recognition memory of photographs related to the observed scripts was tested as a function of emotionality. Causal errors-a type of false memory thought to stem from inferential processes-were found to be affected by valence: children made fewer causal errors for positive than for neutral or negative events. Hypotheses are proposed on why adults were found protected against inferential false memories not only by positive (as for children) but also by negative endings when administered similar versions of the same paradigm. PMID- 28361563 TI - What makes a space invader? Passenger perceptions of personal space invasion in aircraft travel. AB - The invasion of personal space is often a contributory factor to the experience of discomfort in aircraft passengers. This paper presents a questionnaire study which investigated how air travellers are affected by invasions of personal space and how they attempt to adapt to, or counter, these invasions. In support of recent findings on the factors influencing air passenger comfort, the results of this study indicate that the invasion of personal space is not only caused by physical factors (e.g. physical contact with humans or objects), but also other sensory factors such as noise, smells or unwanted eye contact. The findings of this study have implications for the design of shared spaces. Practitioner Summary: This paper presents a questionnaire study which investigated personal space in an aircraft environment. The results highlight the factors which affect the perception of personal space invasion in aircraft and can therefore inform the design of aircraft cabin environments to enhance the passenger experience. PMID- 28361562 TI - Age-related similarities and differences in monitoring spatial cognition. AB - Spatial cognitive performance is impaired in later adulthood but it is unclear whether the metacognitive processes involved in monitoring spatial cognitive performance are also compromised. Inaccurate monitoring could affect whether people choose to engage in tasks that require spatial thinking and also the strategies they use in spatial domains such as navigation. The current experiment examined potential age differences in monitoring spatial cognitive performance in a variety of spatial domains including visual-spatial working memory, spatial orientation, spatial visualization, navigation, and place learning. Younger and older adults completed a 2D mental rotation test, 3D mental rotation test, paper folding test, spatial memory span test, two virtual navigation tasks, and a cognitive mapping test. Participants also made metacognitive judgments of performance (confidence judgments, judgments of learning, or navigation time estimates) on each trial for all spatial tasks. Preference for allocentric or egocentric navigation strategies was also measured. Overall, performance was poorer and confidence in performance was lower for older adults than younger adults. In most spatial domains, the absolute and relative accuracy of metacognitive judgments was equivalent for both age groups. However, age differences in monitoring accuracy (specifically relative accuracy) emerged in spatial tasks involving navigation. Confidence in navigating for a target location also mediated age differences in allocentric navigation strategy use. These findings suggest that with the possible exception of navigation monitoring, spatial cognition may be spared from age-related decline even though spatial cognition itself is impaired in older age. PMID- 28361564 TI - Superior episodic memory in inconsistent-handers: a replication and extension using fNIRS. AB - A large body of evidence supports the existence of a robust handedness difference in episodic memory retrieval, with inconsistent-handedness being associated with superior memory across a wide variety of paradigms, including superior retrieval of lab-based and real world memories. Despite superior episidoc memory in inconsistent-handers, and despite neuroanatomical and neurophysiological differences in cortical regions between inconsistent- and consistent-handers, we are aware of no studies to date that have examined physiological activity in the brains of inconsistent- versus consistent-handers while engaged in memory tasks. The purpose of this paper, therefore, is to present a first look at this issue, using functional near-infrared spectroscopy (fNIRS) as a simple, non-invasive measure of frontal lobe activity during encoding and recall of list words in inconsistent- and consistent-handers. Behaviourally, we replicated prior studies, finding a significant inconsistent-handed advantage in free recall. Using fNIRS derived oxygenated haemoglobin (O2Hb) as a measure of frontal lobe activity, we found the first evidence for handedness differences in brain activity that are associated with the handedness differences in episodic retrieval. Specifically, the primary finding was that increased O2Hb in the right hemisphere during recall was associated with better retrieval, but for consistent-handers only. PMID- 28361565 TI - Education, training, and practice among nordic neuropsychologists. Results from a professional practices survey. AB - OBJECTIVE: To investigate sociodemographic characteristics, clinical and academic training, work setting and salary, clinical activities, and salary and job satisfaction among practicing neuropsychologists in four Nordic countries. METHODS: 890 neuropsychologists from Denmark, Finland, Norway, and Sweden participated in an internet-based survey between December 2013 and June 2015. RESULTS: Three-fourths (76%) of the participants were women, with a mean age of 47 years (range 24-79). In the total sample, 11% earned a PhD and 42% were approved as specialists in neuropsychology (equivalent to board certification in the U.S.). Approximately 72% worked full-time, and only 1% were unemployed. Of the participants, 66% worked in a hospital setting, and 93% had conducted neuropsychological assessments during the last year. Attention deficit hyperactivity disorder, learning disability, and intellectual disability were the most common conditions seen by neuropsychologists. A mean income of 53,277 Euros was found. Neuropsychologists expressed greater job satisfaction than income satisfaction. Significant differences were found between the Nordic countries. Finnish neuropsychologists were younger and worked more hours every week. Fewer Swedish neuropsychologists had obtained specialist approval and fewer worked full time in neuropsychology positions. Danish and Norwegian neuropsychologists earned more money than their Nordic colleagues. CONCLUSION: This is the first professional practice survey of Nordic neuropsychologists to provide information about sociodemographic characteristics and work setting factors. Despite the well established guidelines for academic and clinical education, there are relevant differences between the Nordic countries. The results of the study offer guidance for refining the development of organized and highly functioning neuropsychological specialty practices in Nordic countries. PMID- 28361567 TI - Corrigendum. PMID- 28361566 TI - Evaluation of the ACR and SLICC classification criteria in juvenile-onset systemic lupus erythematosus: a longitudinal analysis. AB - Objectives The Systemic Lupus International Collaborating Clinics (SLICC) group proposed revised classification criteria for systemic lupus erythematosus (SLICC 2012 criteria). This study aimed to compare these criteria with the well established American College of Rheumatology classification criteria (ACR-1997 criteria) in a national cohort of juvenile-onset systemic lupus erythematosus (JSLE) patients and evaluate how patients' classification criteria evolved over time. Methods Data from patients in the UK JSLE Cohort Study with a senior clinician diagnosis of probable evolving, or definite JSLE, were analyzed. Patients were assessed using both classification criteria within 1 year of diagnosis and at latest follow up (following a minimum 12-month follow-up period). Results A total of 226 patients were included. The SLICC-2012 was more sensitive than ACR-1997 at diagnosis (92.9% versus 84.1% p < 0.001) and after follow up (100% versus 92.0% p < 0.001). Most patients meeting the SLICC-2012 criteria and not the ACR-1997 met more than one additional criterion on the SLICC 2012. Conclusions The SLICC-2012 was better able to classify patients with JSLE than the ACR-1997 and did so at an earlier stage in their disease course. SLICC 2012 should be considered for classification of JSLE patients in observational studies and clinical trial eligibility. PMID- 28361568 TI - Heterogeneous impact of body mass index on in-hospital mortality in acute heart failure syndromes: An analysis from the ATTEND Registry. AB - BACKGROUND: Although the obesity paradox may vary depending upon clinical background factors such as age, gender, aetiology of heart failure and comorbidities, the reasons underlying the heterogeneous impact of body mass index (BMI) on in-hospital cardiac mortality under various conditions in patients with acute heart failure syndromes (AHFSs) remain unclear. METHODS: Among 4617 hospitalised patients with AHFSs enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, the patient characteristics and in-hospital cardiac mortality rates in those with low BMI (BMI <25 kg/m2, n = 3263) were compared to those with high BMI (BMI ?25 kg/m2, n = 1354). RESULTS: Compared to the high-BMI group, the low-BMI group was significantly older, less likely to be male and to have hypertensive or idiopathic dilated aetiologies and more likely to have valvular aetiologies and a history of prior hospitalisation for AHFS. The low-BMI group also had lower prevalence rates of diabetes, dyslipidaemia, hypertension and atrial fibrillation and higher prevalence rates of anaemia and chronic obstructive pulmonary disease. In addition, cardiac mortality was significantly higher in the low-BMI group than in the high-BMI group (5.5 vs. 1.5%, p < 0.001). Logistic regression analysis demonstrated that low BMI was a predictor of cardiac mortality (odds ratio: 3.89, 95% confidence interval: 2.44 6.21). In subgroup analyses, the impact of BMI on cardiac mortality differed depending on the presence of hypertensive aetiology, hypertension, chronic obstructive pulmonary disease and hyponatremia (all p < 0.05), although there were no interactions between the impacts of BMI and age, gender, other aetiologies, prior hospitalisation, diabetes, anaemia, cardio-renal function and in-hospital management. CONCLUSION: It is necessary to appreciate the obesity paradox in AHFS patients, and a patient's heterogeneous background should also be considered. PMID- 28361569 TI - Processes of change in a school-based mindfulness programme: cognitive reactivity and self-coldness as mediators. AB - The underlying mechanisms of the effectiveness of mindfulness-based interventions for emotional well-being remain poorly understood. Here, we examined the potential mediating effects of cognitive reactivity and self-compassion on symptoms of depression, anxiety and stress using data from an earlier randomised controlled school trial. A moderated time-lagged mediation model based on multilevel modelling was used to analyse the data. The findings showed that post treatment changes in cognitive reactivity and self-coldness, an aspect of self compassion, mediated subsequent changes in symptoms of depression, anxiety and stress. These results suggest that cognitive reactivity and self-coldness may be considered as transdiagnostic mechanisms of change of a mindfulness-based intervention programme for youth. PMID- 28361570 TI - The acute muscular response to two distinct blood flow restriction protocols. AB - The purpose of this study was to determine acute physiological and perceptual responses to two commonly implemented blood flow restriction protocols. Using a within-subject design, 15 participants (age ~25) performed four sets of unilateral elbow flexion with each arm. One arm exercised using a 3-cm elastic cuff inflated to 160 mmHg, whereas the other arm exercised using a 5-cm nylon cuff inflated to 40% of the individual's arterial occlusion pressure. While both protocols elicited increases in acute muscle thickness [pre: 4.5 (0.2) cm, post: 5.0 (0.2) cm; p < 0.001] and electromyography amplitude [first 3 reps: 55 ( 5 ) %MVC; last 3 reps: 87 ( 10 ) %MVC], there were no differences between conditions. Both protocols produced decreases in post-exercise strength (pre: 70 Nm, post: 51 Nm; p < 0.001) with no difference between conditions. The nylon protocol resulted in more repetitions during sets 2 [13 ( 2 ) vs. 9 ( 4 ); p = 0.001] and 3 [10 ( 2 ) vs. 7 ( 4 ); p = 0.05], while producing lower levels of discomfort following each set (average 3 vs. 4; p < 0.05). In conclusion, both protocols produced similar acute responses thought to be important for promoting muscle growth. However, the use of arbitrary pressures may place some individuals under complete arterial occlusion which may increase the potential risk of an adverse event. PMID- 28361571 TI - Correlation between ECG changes and early left ventricular remodeling in preadolescent footballers. AB - The aim of this study was to assess the early electrocardiogram (ECG) changes induced by physical training in preadolescent elite footballers. This study included 94 preadolescent highly trained male footballers (FG) competing in Serbian Football League (minimum of 7 training hours/week) and 47 age-matched healthy male controls (less than 2 training hours/week) (CG). They were screened by ECG and echocardiography at a tertiary referral cardio center. Sokolow-Lyon index was used as a voltage electrocardiographic criterion for left ventricular hypertrophy diagnosis. Characteristic ECG intervals and voltage were compared and reference range was given for preadolescent footballers. Highly significant differences between FG and CG were registered in all ECG parameters: P-wave voltage (p < 0.001), S-wave (V1 or V2 lead) voltage (p < 0.001), R-wave (V5 and V6 lead) voltage (p < 0.001), ECG sum of S V1-2 + R V5-6 (p < 0.001), T-wave voltage (p < 0.001), QRS complex duration (p < 0.001), T-wave duration (p < 0.001), QTc interval duration (p < 0.001), and R/T ratio (p < 0.001). No differences were found in PQ interval duration between these two groups (p > 0.05). During 6-year follow-up period, there was no adverse cardiac event in these footballers. None of them expressed pathological ECG changes. Benign ECG changes are presented in the early stage of athlete's heart remodeling, but they are not related to pathological ECG changes and they should be regarded as ECG pattern of LV remodeling. PMID- 28361572 TI - Characterization of the thrombin generation profile in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a multisystemic inflammatory autoimmune disorder. Thrombotic events occur at a higher incidence among SLE patients. The investigation of thrombin generation (TG) with calibrated automated thrombogram (CAT) test as a global hemostasis assay is applicable for the overall functional assessment of the hemostasis. The aim of this study was to characterize the hemostatic alterations observed in SLE by CAT assay. In this study, CAT parameters and basic coagulation parameters of SLE patients (n = 22) and healthy control subjects (n = 34) were compared. CAT area under the curve (i.e., endogenous thrombin potential) was lower than normal in SLE (807 vs. 1,159 nM*min, respectively), whereas other CAT parameters (peak, lag time, time to peak, and velocity index) and the basic coagulation tests were within the normal range. The presence of anti-phospholipid antibodies and the applied therapy was not associated with hemostasis parameters in SLE. We concluded that the reported high risk of thrombosis is not related to TG potential. PMID- 28361573 TI - Effects of time-of-day on oxidative stress, cardiovascular parameters, biochemical markers, and hormonal response following level-1 Yo-Yo intermittent recovery test. AB - The aim of this study was to investigate the effect of time-of-day on oxidative stress, cardiovascular parameters, muscle damage parameters, and hormonal responses following the level-1 Yo-Yo intermittent recovery test (YYIRT). A total of 11 healthy subjects performed an intermittent test (YYIRT) at two times-of-day (i.e., 07:00 h and 17:00 h), with a recovery period of >=36 h in-between, in a randomized order. Blood samples were taken at the rest (baseline) and immediately (post-YYIRT) after the YYIRT for measuring oxidative stress, biochemical markers, and hormonal response. Data were statistically analyzed using one-way and two-way repeated measures ANOVA and Bonferroni test at p < 0.05. Observed power (alpha = 0.05) and partial eta-squared were used. Our results showed that oxygen uptake (VO2max), maximal aerobic speed, and the total distance covered tended to be higher in the evening (17:00 h). There was also a main effect of time-of-day for cortisol and testosterone concentration, which were higher after the YYIRT in the morning (p < 0.05). The heart rate peak and the rating of perceived exertion scales were lower in the morning (p < 0.05). However, the plasma glucose (p < 0.01), malondialdehyde, creatine kinase (p < 0.01), lactate dehydrogenase (p < 0.05), high-density lipoprotein (p < 0.01), total cholesterol (p < 0.01), and triglycerides (p < 0.05) were higher after the YYIRT in the evening. Low-density lipoprotein, systolic blood pressure, diastolic blood pressure, and lactate levels (p > 0.05) were similar for the morning and evening test. In conclusion, our findings suggest that aerobic performance presents diurnal variation with great result observed in the evening accompanied by an improvement of hormonal, metabolic, and oxidative responses. These data may help to guide athletes and coaches and contribute to public health recommendations on exercise and muscle damage particularly in the competitive periods. PMID- 28361574 TI - Influence of testosterone on mean arterial pressure: A physiological study in male and female normotensive WKY and hypertensive SHR rats. AB - Introduction Testosterone plays an important role in the blood pressure regulation. However, information with regard to the effect of this hormone on blood pressure in normotensive and hypertensive conditions is limited. Therefore, in this study, the relationship between plasma testosterone level and mean arterial pressure (MAP) was investigated under these conditions. Methods Normotensive Wistar-Kyoto (WKY) and hypertensive Spontaneous Hypertensive (SHR) male and female rats were gonadectomized with female rats treated with testosterone. Estrous cycle stages of intact female rats of both strains were identified by vaginal smear. Pressure in the carotid artery of anesthetized rats was measured via direct cannulation technique. The blood was withdrawn for plasma testosterone level measurement by enzyme-linked immunosorbent assay. Results Treatment of ovariectomized female WKY and SHR rats with testosterone for 6-week duration has resulted in MAP to increase (P < 0.05). In male WKY and SHR rats, MAP and plasma testosterone levels decreased by orchidectomy (P < 0.05). No significant differences in MAP and plasma testosterone levels were observed in intact female WKY and SHR rats between stages of the estrous cycle. Conclusions The effects seen in testosterone-treated ovariectomized female rats and in orchidectomized male rats suggested that testosterone could play an important role in causing the blood pressure to increase. PMID- 28361575 TI - Obesity and kidney disease: Hidden consequences of the epidemic. AB - Obesity has become a worldwide epidemic, and its prevalence has been projected to grow by 40% in the next decade. This increasing prevalence has implications for the risk of diabetes, cardiovascular disease, and also for chronic kidney disease (CKD). A high body mass index is one of the strongest risk factors for new-onset CKD. In individuals affected by obesity, a compensatory hyperfiltration occurs to meet the heightened metabolic demands of the increased body weight. The increase in intraglomerular pressure can damage the kidneys and raise the risk of developing CKD in the long-term. The incidence of obesity-related glomerulopathy has increased tenfold in recent years. Obesity has also been shown to be a risk factor for nephrolithiasis, and for a number of malignancies including kidney cancer. This year the World Kidney Day promotes education on the harmful consequences of obesity and its association with kidney disease, advocating healthy lifestyle, and health policy measures that makes preventive behaviors an affordable option. PMID- 28361576 TI - The effect of 8-week different-intensity walking exercises on serum hepcidin, IL 6, and iron metabolism in pre-menopausal women. AB - Objective Hepcidin may be an important mediator in exercise-induced iron deficiency. Despite the studies investigating acute exercise effects on hepcidin and markers of iron metabolism, we found no studies examining the chronic effects of walking exercises (WE) on hepcidin and markers of iron metabolism in premenopausal women. The chronic effects of two 8-week different-intensity WE on hepcidin, interleukin 6 (IL-6), and markers of iron metabolism in pre-menopausal women were examined. Methods Exercise groups (EG) [moderate tempo walking group (MTWG), n = 11; brisk walking group (BWG), n = 11] walked 3 days/week, starting from 30 to 51 min. Control group (CG; n = 8) did not perform any exercises. BWG walked at ~70%-75%; MTWG at ~50%-55% of HRRmax. VO2max, hepcidin, IL-6, and iron metabolism markers were determined before and after the intervention. Results VO2max increased in both EGs, favoring the BWG. Hepcidin increased in the BWG (p < 0.01) and CG (p < 0.05). IL-6 decreased in the BWG and the MTWG (p < 0.05; p < 0.01). While iron, ferritin, transferrin, and transferrin saturation levels did not change in any group, total iron binding capacity (p < 0.05), red blood cells (p < 0.05), and hematocrit (p < 0.01) increased only in the BWG. Conclusion Both WE types may be useful to prevent inflammation. However, brisk walking is advisable due to the positive changes in VO2max and some iron metabolism parameters, which may contribute to prevent iron deficiency. The increase in hepcidin levels remains unclear and necessitates further studies. PMID- 28361577 TI - Effects of Nigella sativa seeds and certain species of fungi extracts on number and activation of dural mast cells in rats. AB - In this study, we aimed to investigate the effects of Nigella sativa seeds and certain species of fungi extracts on the number and degranulation states of dural mast cells in rats. Rats were fed ad libitum with normal tap water or tap water with extract of N. sativa seed, Ramaria condensata, Lactarius salmonicolor, Lactarius piperatus, and Tricholoma terreum for 3 days. Mast cells in dura mater were counted and evaluated in terms of granulation and degranulation states. Compound 48/80, a mast cell degranulating agent, and T. terreum significantly increased the percent of degranulated mast cells in dura mater, respectively (p < 0.01 and p < 0.05). Moreover, T. terreum causes a significant increase in the total number of mast cells (p < 0.05). N. sativa significantly inhibited mast cell degranulation induced by both the compound 48/80 and T. terreum (p < 0.05), and significantly decreased the mast cell numbers increased by T. terreum (p < 0.05). Our results suggested that T. terreum following ingestion can contribute to headaches like migraine via dural mast cell degranulation and N. sativa may be able to exert analgesic and anti-inflammatory effects by stabilizing dural mast cells. However, investigation is needed to determine the ingredients of N. sativa that may be responsible for these beneficial effects. PMID- 28361578 TI - Perceived social determinants of health among older, rural-dwelling adults with early-stage cognitive impairment. AB - Limited access to resources and delayed detection of subtle cognitive changes may negatively impact the long-term cognitive health of rural-dwelling adults. This study explored perceived social determinants of health among older, rural dwelling adults with early-stage cognitive impairment. Semi-structured interviews were conducted with older, rural-dwelling adults with early-stage cognitive impairment and their care partners. Thematic content analysis was performed. Participants ( n = 9) were 73.7 +/- 6.0 years of age with 14.2 +/- 3.1 years of education; care partners ( n = 10) were 70.9 +/- 7.4 years of age with 15.6 +/- 2.3 years of education. Data analysis revealed six themes: Staying active, Eating well, Living with cognitive changes, Living rural, Connecting with neighbors and community, and Relying on children. Dyads' depictions of perceived social determinants of health focused on the adoption of a healthy lifestyle, description of relationships, and advantages of living in a rural area. Emergent themes may be used to promote adoption of self-management and prevention behaviors, particularly lifestyle changes. PMID- 28361579 TI - Dementia and clinical interaction in frontline radiography: Mapping the practical experiences of junior clinicians in the UK. AB - This paper reports findings from a study of the practical experiences of junior diagnostic radiographers in the UK when managing patients with dementia. Extended semi-structured interviews with six participants (mean experience in diagnostic radiography = 3.5 years) were analysed using interpretative phenomenological analysis. Findings highlight that participants' recurrently cited lack of confidence around their knowledge of dementia, and regular treatment of the condition as a 'generic' thing in practice, had sometimes damaged clinical interaction, particularly when the participant was feeling institutional time pressures. Education for new professionals was seen as lacking in both quantity and context-relevance, with implications for professional confidence and ethical practice. Carers and family members were viewed by participants as potentially positive and negative forces within an examination context, and technological advances in radiography were taken to be clinically advantageous but also actively detrimental to the effective interpersonal care of their patients. PMID- 28361580 TI - Rapid-deployment or transcatheter aortic valves in intermediate-risk patients? AB - Background Transcatheter aortic valve implantation and rapid-deployment aortic valve replacement represent two emerging therapies for patients with intermediate surgical risk and severe aortic stenosis. However, head-to-head comparisons between such novel therapies are lacking. Methods Severe aortic stenosis patients with intermediate surgical risk treated with rapid-deployment valve replacement at our institution were identified and compared with a propensity-matched population of patients who underwent transcatheter aortic valve replacement. Postoperative echocardiographic findings, in-hospital and midterm clinical outcomes were compared. Results We identified 60 patients who received transcatheter ( n = 30) or rapid-deployment ( n = 30) valve replacement. On postoperative echocardiography, freedom from paravalvular regurgitation was higher in the rapid-deployment valve group ( p < 0.001), while postoperative mean transprosthetic gradient was lower in the transcatheter valve group ( p = 0.03). Permanent pacemaker implantation was required more frequently in transcatheter valve patients ( p = 0.01). Postoperative atrial fibrillation was more common in the rapid-deployment valve group ( p = 0.03). Hospital mortality was similarly low in both groups ( p = 0.33). At midterm follow-up, mortality was comparable ( p = 0.42) but the rapid-deployment valve group still had a lower degree of paravalvular regurgitation. Conclusions Transcatheter and rapid-deployment valve replacement are promising treatment options for patients with intermediate surgical risk. These two techniques are associated with specific patterns of prosthesis function and postoperative complications. Further evaluation of the clinical impact of these therapies in this patient population is needed. PMID- 28361581 TI - Biatrial connection of partial anomalous pulmonary venous return. AB - We describe an extremely rare case of partial anomalous pulmonary venous return in a 3-year-old boy with an abnormal connection between the right upper pulmonary vein and the right middle pulmonary vein, which created biatrial communication hemodynamically. Patch closure on the orifice of the right upper pulmonary vein was performed to avoid distortion or kinking of the right pulmonary veins and the connection. PMID- 28361582 TI - HEART score performance in Asian and Caucasian patients presenting to the emergency department with suspected acute coronary syndrome. AB - BACKGROUND: The HEART score is a simple and effective tool to predict short-term major adverse cardiovascular events in patients suspected of acute coronary syndrome. Patients are assigned to three risk categories using History, ECG, Age, Risk factors and Troponin (HEART). The purpose is early rule out and discharge is considered safe for patients in the low risk category. Its performance in patients of Asian ethnicity is unknown. We evaluated the performance of the HEART score in patients of Caucasian, Chinese, Indian and Malay ethnicity. METHODS: The HEART score was assessed retrospectively in 3456 patients presenting to the emergency department with suspected acute coronary syndrome (1791 Caucasians, 1059 Chinese, 344 Indians, 262 Malays), assigning them into three risk categories. RESULTS: The incidence of major adverse cardiovascular events within six weeks after presentation was similar between the ethnic groups. A smaller proportion of Caucasians was in the low risk category compared with Asians (Caucasians 35.8%, Chinese 43.5%, Indians 45.3%, Malays 44.7%, p<0.001). The negative predictive value of a low HEART score was comparable across the ethnic groups, but lower than previously reported (Caucasians 95.3%, Chinese 95.0%, Indians 96.2%, Malays 96.6%). Also the c-statistic for the HEART score was not significantly different between the groups. CONCLUSIONS: These results show that the overall performance of the HEART score is equal among Caucasian and Asian ethnic groups. The event rate in the low risk group, however, was higher than reported in previous studies, which queries the safety of early discharge of patients in the low risk category. PMID- 28361583 TI - Two new unsaturated fatty acids from the whole plant of Pothos chinensis. AB - Two new unsaturated fatty acids, (Z)-octadec-13-en-11-ynoic acid (1) and (Z) octadec-16-en-12,14-diynoic acid (2), along with six known compounds were isolated from the whole plant of Pothos chinensis. The structures of these compounds were elucidated by detailed spectroscopic analysis, including 1D and 2D NMR data. Compound 2 showed moderate antibacterial activity against Staphylococcus aureus. PMID- 28361584 TI - "Paintings Fade Like Flowers": Pigment Analysis and Digital Reconstruction of a Faded Pink Lake Pigment in Vincent van Gogh's Undergrowth with Two Figures. AB - Color fading in Vincent van Gogh's Undergrowth with Two Figures was studied chemically to facilitate the creation of a digital reconstruction of fugitive colors . The painting contains a field of white, green, orange, and yellow flowers under a canopy of poplar trees with two central figures-a man and a woman, arms entwined. From Van Gogh's letters, however, it is known that he painted the picture with some pink flowers, which appear to have altered, presumably to white. Raman spectroscopy was applied to microsamples of paint to identify the faded pigment as geranium lake, which in this painting consists of the dye, eosin (2',4',5',7'-tetrabromofluorescein). For the first time, lead(II) sulfate has been specifically identified as the likely inorganic substrate for a geranium lake used by Van Gogh in the last months of his life. Microfocus X-ray fluorescence (MXRF) spectroscopy was subsequently used in situ to analyze the white flowers to identify bromine as a proxy for eosin, thus indicating an original pink coloration. Of the 387 white flowers analyzed, 37.7% contained measurable bromine and were, therefore, originally pink. Several cross-sections from these formerly pink areas were assessed using a combination of visual inspection and microcolorimetry to create a colored mask in Adobe Photoshop to digitally reconstruct a suggestion of the original appearance of the painting with regard to the faded flowers. Additionally, microfadeometry was undertaken for the first time on a painting cross-section sample to understand the actual fading kinetics of the underlying bright pink geranium lake used by Van Gogh. A combination of Raman microspectroscopy, MXRF, and scanning electron microscopy energy dispersive spectroscopy (SEM-EDS) were utilized in situ and on paint microsamples to identify the complete palette used to create Undergrowth with Two Figures. PMID- 28361586 TI - Determination and application of the permitted daily exposure (PDE) for topical ocular drugs in multipurpose manufacturing facilities. AB - Limits for the carry-over of product residues should be based on toxicological evaluation such as described in the "Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities". The toxicological evaluation should be performed also for locally administered drugs to ensure patient safety. Currently, there is no guidance on setting PDE for ocular drug substances in particular. The purpose of this investigation was to identify and describe a method for calculating a PDE value for topical ocular drugs (PDEocular). As an alternative method, extrapolation of a PDE for systemically administered drugs to a PDEocular is presented. These methods may be applied in cross-contamination risk assessments for manufacturing of topical ocular drugs. Similarly, the methods apply to systemically administered drugs, if their production precedes manufacturing of a topical ocular drug. We have examined pharmacokinetic (PK) properties of topical ocular drugs and compared them to the PK parameters of systemically administered drugs. Furthermore, we examined possible adverse effects of the carry-over in topical ocular drugs at therapeutic doses. PMID- 28361585 TI - Featured Article: Pyruvate preserves antiglycation defenses in porcine brain after cardiac arrest. AB - Cardiac arrest (CA) and cardiocerebral resuscitation (CCR)-induced ischemia reperfusion imposes oxidative and carbonyl stress that injures the brain. The ischemic shift to anaerobic glycolysis, combined with oxyradical inactivation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), provokes excessive formation of the powerful glycating agent, methylglyoxal. The glyoxalase (GLO) system, comprising the enzymes glyoxalase 1 (GLO1) and GLO2, utilizes reduced glutathione (GSH) supplied by glutathione reductase (GR) to detoxify methylglyoxal resulting in reduced protein glycation. Pyruvate, a natural antioxidant that augments GSH redox status, could sustain the GLO system in the face of ischemia-reperfusion. This study assessed the impact of CA-CCR on the cerebral GLO system and pyruvate's ability to preserve this neuroprotective system following CA. Domestic swine were subjected to 10 min CA, 4 min closed-chest CCR, defibrillation and 4 h recovery, or to a non-CA sham protocol. Sodium pyruvate or NaCl control was infused (0.1 mmol/kg/min, intravenous) throughout CCR and the first 60 min recovery. Protein glycation, GLO1 content, and activities of GLO1, GR, and GAPDH were analyzed in frontal cortex biopsied at 4 h recovery. CA-CCR produced marked protein glycation which was attenuated by pyruvate treatment. GLO1, GR, and GAPDH activities fell by 86, 55, and 30%, respectively, after CA-CCR with NaCl infusion. Pyruvate prevented inactivation of all three enzymes. CA-CCR sharply lowered GLO1 monomer content with commensurate formation of higher molecular weight immunoreactivity; pyruvate preserved GLO1 monomers. Thus, ischemia reperfusion imposed by CA-CCR disabled the brain's antiglycation defenses. Pyruvate preserved these enzyme systems that protect the brain from glycation stress. Impact statement Recent studies have demonstrated a pivotal role of protein glycation in brain injury. Methylglyoxal, a by-product of glycolysis and a powerful glycating agent in brain, is detoxified by the glutathione-catalyzed glyoxalase (GLO) system, but the impact of cardiac arrest (CA) and cardiocerebral resuscitation (CCR) on the brain's antiglycation defenses is unknown. This study in a swine model of CA and CCR demonstrated for the first time that the intense cerebral ischemia-reperfusion imposed by CA-resuscitation disabled glyoxalase-1 and glutathione reductase (GR), the source of glutathione for methylglyoxal detoxification. Moreover, intravenous administration of pyruvate, a redox-active intermediary metabolite and antioxidant in brain, prevented inactivation of glyoxalase-1 and GR and blunted protein glycation in cerebral cortex. These findings in a large mammal are first evidence of GLO inactivation and the resultant cerebral protein glycation after CA-resuscitation, and identify novel actions of pyruvate to minimize protein glycation in postischemic brain. PMID- 28361587 TI - Stimulus-evoked changes in cerebral vessel diameter: A study in healthy humans. AB - The high metabolic demand of neuronal tissue, coupled with its relatively low energy storage capacity, requires that increases in neuronal activation are quickly matched with increased blood flow to ensure efficient supply of oxygen and nutrients to the tissue. For this to occur, dilation of nearby arterioles must be coordinated with the dilation of larger upstream feeding arteries. As it stands, the exact spatial extent of such dilation in humans is unknown. Using non invasive time-of-flight magnetic resonance angiography in healthy participants, we developed an automatic methodology for reconstructing cerebral arterial vessels and quantifying their diameter on a voxel-by-voxel basis. Specifically, we isolated the posterior cerebral artery (PCA) supplying each occipital lobe and quantified its vasodilation induced by visual stimulation. Stimulus-induced changes were strongest (~30%) near primary visual cortex and progressively decreased in a non-linear fashion as a function of distance. Surprisingly, weak - albeit significant - changes (~2%) were observed ~70 mm from the visual cortex. This demonstrates that visual stimulation modulates vascular tone along the bulk of the PCA segment, and thus may have important implications for our understanding of functional hyperemia in healthy and diseased states. PMID- 28361588 TI - First Report of Hb Limassol [beta8(A5)Lys->Asn; HBB: c.27G>C] from Odisha, India. AB - In this short report, we describe the clinical presentation of a rare hemoglobin (Hb) variant, Hb Limassol [beta8(A5)Lys->Asn; HBB: c.27G>C] with a faster electrophoretic mobility than Hb A and that elutes in the P3 window on cation exchange high performance liquid chromatography (HPLC). This sequence variation at codon 8 (AAG>AAC) of the HBB gene was found in the four heterozygous cases, all of whom were clinically asymptomatic. PMID- 28361589 TI - Detection of the Unstable Hb Koln (HBB: c.295G>A) by a Capillary Electrophoresis Method. AB - Hb Koln (HBB: c.295G>A) is an unstable beta-globin gene variant with a GTG>ATG substitution at codon 98. This variant is quite frequent in Europe and the USA but rare in China. It can easily be misdiagnosed as Hb Constant Spring (Hb CS; HBA2: c.427T>C) by high performance liquid chromatography (HPLC), but detection and quantification of both Hb Koln and degraded Hb Koln by capillary electrophoresis (CE) are possible. Thus, we concluded that CE was the preferred method for Hb Koln detection. PMID- 28361590 TI - Hb Alesha [beta67(E11)Val->Met (GTG>ATG); HBB: c.202G > A] Found in a Chinese Girl. AB - Mutations that cause destabilization of the hemoglobin (Hb) tetramer are a rare cause of hemolytic anemia. In contrast to the hemolytic anemia caused by enzyme deficiencies, a dominant mode of inheritance characterizes the unstable Hbs. Hb Alesha [beta67(E11)Val->Met; HBB: c.202G>A] is caused by a G>A mutation at codon 67 of the beta-globin gene, resulting in a valine to methionine substitution at helix E11. This replacement disrupts the apolar bonds between valine and the heme group, producing an unstable Hb and severe hemolysis. We report this rare hemoglobinopathy in a Chinese girl with severe hemolytic anemia, splenomegaly and frequent requirement for red blood cell (RBC) transfusions. PMID- 28361591 TI - Genetic Variants at BCL11A and HBS1L-MYB loci Influence Hb F Levels in Chinese Zhuang beta-Thalassemia Intermedia Patients. AB - Increased Hb F levels can ameliorate the symptoms of beta-thalassemia (beta thal). Due to the genetic heterogenicity of beta-thal, the relationship between genetic variants in modifier genes and Hb F level has been studied in different populations. The Chinese Zhuang has the second largest population in China and has 6.78% prevalence of beta-thal. However, the effects of these single nucleotide polymorphism (SNP) variants on the Hb F levels of beta-thal intermedia (beta-TI) patients in this population have not been reported. To explore the association between modifier loci (beta-globin gene cluster, HBS1L-MYB intergenic region and BCL11A) and Hb F levels in Chinese Zhuang beta-TI patients, 96 unrelated beta-TI patients (50 males and 46 females) with different Hb F levels were recruited and genotyped by mass spectrometry. A total of 13 SNPs were confirmed to be in a significant relationship with Hb F levels in this population. Of these, high-risk genotypes of six Hb F-associated SNPs, rs9376090, rs7776054, rs9399137, rs9389268, rs9402685 in the HBS1L-MYB intergenic region and rs189984760 in the BCL11A locus, showed association with high Hb F levels, especially for SNPs in linkage disequilibrium. One novel Hb F-associated SNP, rs189984760, was identified in our study. Our findings will be of valuable reference for correlation between modifier genes and Hb F in Chinese Zhuang populations and may lead to better understand the modifying mechanisms for beta thal. PMID- 28361592 TI - Lactate Dehydrogenase: A Marker of the Severity of Vaso-Occlusive Crisis in Children with Sickle Cell Disease Presenting at the Emergency Department. AB - The aim of this study was to describe the characteristics of vaso-occlusive crises (VOC) in children with sickle cell disease and to identify factors associated with greater severity. We performed a prospective observational study from August 2012 to January 2014. The study population comprised patients with sickle cell disease who consulted at the emergency department (ED) for VOC. We recorded demographic variables, history of complications related to the disease, and data on usual treatment. We also assessed pain, analgesia at home, need for admission, length of stay, and analgesia during admission. Analytical parameters were collected. A total of 29 patients with VOC were included. The patient's usual treatment was hydroxyurea (HU) in 69.0%, and 7.0% required chronic transfusions. In the ED, 90.0% had moderate or severe pain, even though 86.0% had received analgesia at home (41.4% minor opioids). Overall, 27 of the 29 patients were admitted, and 56.0% needed major opioids. Higher lactate dehydrogenase (LDH) levels were related to the use of major opioids during admission (p = 0.038). A significant difference was recorded between the median number of days of admission for patients receiving non-steroidal anti-inflammatory drugs and for those requiring intravenous opioids (p = 0.005). Most patients with VOC were admitted to hospital. Lactate dehydrogenase level in the ED was a predictor of severity and was associated with the need for major opioids during admission and more days of admission. PMID- 28361593 TI - First Report of a Chinese Family Carrying a Double Heterozygosity for Hb Q Thailand and Hb J-Bangkok. AB - The double heterozygosity for alpha and beta chain variants leads to the formation of abnormal heterodimer hybrids, which could render laboratory diagnostics in a routine setting difficult. The following is the first report of a double heterozygosity for Hb Q-Thailand [alpha74(EF3)Asp->His; HBA1: c.223G>C] with alpha+-thalassemia (alpha+-thal) and Hb J-Bangkok [beta56(D7)Gly->Asp; HBB: c.170G>A] found in a Chinese family. Both subjects were healthy with normal or borderline hematological parameters. Hemoglobin (Hb) analyses showed a novel variant, Hb Q-Thailand and Hb J-Bangkok. Family studies helped in the initial recognition and in making presumptive diagnoses, but definitive diagnoses of these cases with complex alpha and beta chain variants could only be obtained after DNA analysis. PMID- 28361594 TI - An Unusual Hydrops Fetalis Associated with Compound Heterozygosity for Kruppel like Factor 1 mutations. AB - Hydrops fetalis is commonly due to Hb Bart's (gamma4) disease in South East Asia. Here, we report an unusual case of hydrops fetalis due to congenital dyserythropoietic anemia (CDA) associated with compound heterozygosity for Kruppel-like factor 1 (KLF1) gene mutations. Fetal cardiomegaly was first detected on routine mid-trimester scan in a pregnant woman with normal mean corpuscular volume (MCV) and Rhesus positive status. The fetus subsequently developed hydrops fetalis, and cordocentesis showed severe fetal anemia with a hemoglobin (Hb) level of 3.4 g/dL. Common causes of fetal anemia including Hb Bart's disease, parvovirus infection, and red cell antibodies were excluded. In view of the marked increase in erythroblasts at various stages of erythropoiesis, the diagnosis of CDA was suspected. We screened the couple for previously reported KLF1 gene mutations, showing that the mother was heterozygous for the c.525_526insCGGCGCC, p.Gly176Argfs*179 mutation, and her husband heterozygous for c.1012C>A, p.Pro338Thr mutation. The fetus was a compound heterozygote for these two KLF1 mutations. After counseling, repeated intrauterine transfusions were given at 27, 29, and 34 weeks' gestation; the hydrops fetalis was resolved. The baby was delivered at 34 weeks' gestation and required monthly blood transfusions but was otherwise thriving. Bone marrow aspiration at 10 months of age showed the features of ineffective erythropoiesis, compatible with CDA. In conclusion, hydrops fetalis can rarely be due to CDA associated with a compound heterozygous mutation for KLF1 gene mutations, and be managed by repeated intrauterine transfusions. Our present report adds to the wide clinical spectrum of KLF1 mutations. PMID- 28361595 TI - The Molecular Spectrum of beta- and alpha-Thalassemia Mutations in Non-Endemic Umbria, Central Italy. AB - The aim of this study was to describe the mutational spectrum of hemoglobinopathies during the period 1988-2015 in Umbria, Central Italy, which has never been considered endemic for these conditions. Twenty-four different beta-globin gene mutations were identified in 188 patients and eight different alpha-globin gene mutations in 74 patients. Sixty percent beta-thalassemia (beta thal), 85.0% sickle cell disease, 44.0% Hb S (HBB: c.20A>T)/beta-thal and 85.0% compound heterozygotes for hemoglobin (Hb) variant-carrying patients were diagnosed or molecularly characterized in the last 3 years. Moreover, most homozygous or compound heterozygous patients (84.5%) came from foreign countries, while only 15.5% were of Italian origin. These data are in accordance with the increasing foreign resident population in Umbria, which has nearly doubled in 10 years (2004-2014). Different from beta-globin gene variations, no increasing trend in alpha defects was observed in our study cohort. Consistently, 58.0% of patients have an Italian origin, suggesting no broad influence of foreign migration in the alpha-globin genes genetic background. As few defects are prevalent in each country of origin or ethnic group, their knowledge may provide a proper strategy for the identification of mutations in immigrant individuals in a non-endemic region and be important for carrier identification and prenatal screening. PMID- 28361596 TI - A Case of Fatal Agranulocytosis That Developed in a Patient with beta-Thalassemia Major Treated with Deferiprone. AB - A 29-year-old male with transfusion-dependent beta-thalassemia major (beta-TM), splenectomized and on chelation therapy with deferiprone (DFP or L1) due to heart and liver hemosiderosis, presented with high fever and agranulocytosis. Deferiprone was discontinued and a broad spectrum antibiotic therapy was started intravenously. The patient remained febrile and showed no recovery of neutrophil count even after the initiation of granulocyte colony-stimulation factor (G-CSF). After 12 days at the hospital, he developed respiratory failure and was transferred to the intensive care unit (ICU) where he developed multi-organ failure and died 3 days later. To investigate the mechanism of agranulocytosis, bone marrow mononuclear cells of a healthy volunteer were plated on culture dishes, with or without the patient's serum. The observation of colony forming units of progenitor cells in dishes that contained the patient's serum, provided inconclusive explanation of the possible mechanism of DFP-induced agranulocytosis. This is a case of fatal agranulocytosis developing in a patient being treated with DFP, a well recognized but rare complication of this drug. Further studies are required in order to elucidate the possible pathogenic mechanism of agranulocytosis due to DFP and to provide clear guidelines in order to best care for the patient. PMID- 28361597 TI - Regional recurrence in early stage I-II oral tongue cancer: a single institutional study and review of the literature. AB - CONCLUSIONS: There is a high propensity for locoregional and isolated regional failure in stage II patients, even though treated with combined therapy. In stage I patients the risk of isolated regional failure was moderate, at levels below 10%. BACKGROUND: The neck treatment of early stages of oral tongue squamous cell carcinoma (OTSCC) are still debatable, considering that previous studies have produced diverting results. The purpose of this study is to report on the outcome of patients with stages I-II, with special respect to regional outcome. MATERIALS AND METHODS: All patients treated for OTSCC at Karolinska University Hospital between 2008-2014 were included. Patient demographics, intention of treatment, treatment modality, time of follow-up and status at follow-up, recurrence, and place of recurrence were recorded. RESULTS: Of 230 patients, 149 presented within stages I and II. Of those, 105 were electively treated to the neck. In stage I, the risk of presence of disease in the neck specimen was four out of 63 (6%), whereas 17 out of 41 (41%) were positive in stage II patients. The overall risk of isolated regional failure at any time in stage I patients was six out of 89 and in stage II 25 out of 60. PMID- 28361598 TI - Topical and Transdermal Formulation and Drug Delivery. PMID- 28361599 TI - Antianginal Therapy for Stable Ischemic Heart Disease: A Contemporary Review. AB - Chronic angina pectoris is associated with considerable morbidity and mortality, especially if treated suboptimally. For many patients, aggressive pharmacologic intervention is necessary in order to alleviate anginal symptoms. The optimal treatment of stable ischemic heart disease (SIHD) should be the prevention of angina and ischemia, with the goal of maximizing both quality and quantity of life. In addition to effective risk factor modification with lifestyle changes, intensive pharmacologic secondary prevention is the therapeutic cornerstone in managing patients with SIHD. Current guidelines recommend a multifaceted therapeutic approach with beta-blockers as first-line treatment. Another important pharmacologic intervention for managing SIHD is nitrates. Nitrates can provide both relief of acute angina and can be used prophylactically before exposure to known triggers of myocardial ischemia to prevent angina. Additional therapeutic options include calcium channel blockers and ranolazine, an inhibitor of the late inward sodium current, that can be used alone or in addition to nitrates or beta-blockers when these agents fail to alleviate symptoms. Ranolazine appears to be particularly effective for patients with microvascular angina and endothelial dysfunction. In addition, certain antianginal therapies are approved in Europe and have been shown to improve symptoms, including ivabradine, nicorandil, and trimetazidine; however, these have yet to be approved in the United States. Ultimately, there are several different medications available to the physician for managing the patient with SIHD having chronic angina, when either used alone or in combination. The purpose of this review is to highlight the most important therapeutic approaches to optimizing contemporary treatment in response to individual patient needs. PMID- 28361600 TI - Application of DRIFTS, 13C NMR, and py-MBMS to Characterize the Effects of Soil Science Oxidation Assays on Soil Organic Matter Composition in a Mollic Xerofluvent. AB - Chemical oxidations are routinely employed in soil science to study soil organic matter (SOM), and their interpretation could be improved by characterizing oxidation effects on SOM composition with spectroscopy. We investigated the effects of routinely employed oxidants on SOM composition in a Mollic Xerofluvent representative of intensively managed agricultural soils in the California Central Valley. Soil samples were subjected to oxidation by potassium permanganate (KMnO4), sodium hypochlorite (NaOCl), and hydrogen peroxide (H2O2). Additionally, non-oxidized and oxidized soils were treated with hydrofluoric acid (HF) to evaluate reduction of the mineral component to improve spectroscopy of oxidation effects. Oxidized non-HF and HF-treated soils were characterized by diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), 13C cross polarization magic angle spinning (CP-MAS) nuclear magnetic resonance (NMR) spectroscopy, and pyrolysis molecular beam mass spectrometry (py-MBMS), and for particle size distribution (PSD) using laser diffractometry (LD). Across the range of soil organic carbon (OC) removed by oxidations (14-72%), aliphatic C-H stretch at 3000-2800 cm-1 (DRIFTS) decreased with OC removal, and this trend was enhanced by HF treatment due to significant demineralization in this soil (70%). Analysis by NMR spectroscopy was feasible only after HF treatment, and did not reveal trends between OC removal and C functional groups. Pyrolysis-MBMS did not detect differences among oxidations, even after HF treatment of soils. Hydrofluoric acid entailed OC loss (13-39%), and for H2O2 oxidized soils increased C:N and substantially decreased mean particle size. This study demonstrates the feasibility of using HF to improve characterizations of SOM composition following oxidations as practiced in soil science, in particular for DRIFTS. Since OC removal by oxidants, mineral removal by HF, and the interaction of oxidants and HF observed for this soil may differ for soils with different mineralogies, future work should examine additional soil and land use types to optimize characterizations of oxidation effects on SOM composition. PMID- 28361602 TI - Sex differences in pharyngeal airway morphology in adults with skeletal Class III malocclusion. AB - OBJECTIVES: To compare the pharyngeal airway dimensions in adults with skeletal Class III malocclusion and well-balanced faces, to ascertain whether sex can influence such measurements and to correlate skeletal pattern with pharyngeal dimensions. METHODOLOGY: Fifty adults were recruited and assigned to two groups: skeletal Class III (n = 25; 12 males and 13 females, mean age = 26.1 years), and skeletal Class I (n = 25; 11 males and 14 females, mean age = 26.0 years), with well-balanced faces. Pharyngeal measurements were made using cone beam computed tomography and analyzed with Dolphin Imaging software 11.5. RESULTS: Pharyngeal sagittal area, length, retroglossal area and width were statistically greater for males. Pharyngeal volume was greater for Class III patients (p = .0245), due to enlarged male dimensions. A significant but moderate correlation was observed between pharyngeal airway volume and ANB angle (r = -.4917) and effective mandibular length (Co-Gn, r = .5181). CONCLUSION: There is sexual differentiation in the pharyngeal airway morphology for Class III adults. As females present similar pharynx volume compared to a normal skeletal pattern, mandibular setback surgery should be carefully planned because of the risk of airway constriction. PMID- 28361601 TI - Prospective validation of a novel renal activity index of lupus nephritis. AB - Objectives The renal activity index for lupus (RAIL) score was developed in children with lupus nephritis as a weighted sum of six urine biomarkers (UBMs) (neutrophil gelatinase-associated lipocalin, monocyte chemotactic protein 1, ceruloplasmin, adiponectin, hemopexin and kidney injury molecule 1) measured in a random urine sample. We aimed at prospectively validating the RAIL in adults with lupus nephritis. Methods Urine from 79 adults was collected at the time of kidney biopsy to assay the RAIL UBMs. Using receiver operating characteristic curve analysis, we evaluated the accuracy of the RAIL to discriminate high lupus nephritis activity status (National Institutes of Health activity index (NIH-AI) score >10), from low/moderate lupus nephritis activity status (NIH-AI score <=10). Results In this mixed racial cohort, high lupus nephritis activity was present in 15 patients (19%), and 71% had proliferative lupus nephritis. Use of the identical RAIL algorithm developed in children resulted in only fair prediction of lupus nephritis activity status of adults (area under the receiver operating characteristic curve (AUC) 0.62). Alternative weightings of the six RAIL UBMs as suggested by logistic regression yielded excellent accuracy to predict lupus nephritis activity status (AUC 0.88). Accuracy of the model did not improve with adjustment of the UBMs for urine creatinine or albumin, and was little influenced by concurrent kidney damage. Conclusions The RAIL UBMs provide excellent prediction of lupus nephritis activity in adults. Age adaption of the RAIL is warranted to optimize its discriminative validity to predict high lupus nephritis activity status non-invasively. PMID- 28361603 TI - Repeatability of electromyography normalization of the neck and shoulder muscles in symptomatic office workers. AB - PURPOSE: The purpose of the study was to examine the repeatability of electromyography (EMG) normalization in office workers with neck and shoulder symptoms. METHODS: Fifteen female office workers with neck/shoulder symptoms were recruited to participate in two separate days of testing. Maximum voluntary isometric contraction (MVIC) was used for the normalization of EMG data on the following muscles: cervical erector spinae, upper trapezius, lower trapezius and anterior deltoid. Repeatability was calculated using the intra-class correlation (ICC), relative standard error of measurement (%SEM) and relative coefficient of variation (%CV). RESULTS: Peak root mean square (rms) and median frequency (MF) showed good to high repeatability in the UT, AD and CES (ICC = 0.87-0.95, %SEM= 2.65-9.48, %CV= 0.2-5.9). The repeatability of peak rms was good (ICC = 0.87, %SEM = 12.56, %CV = 3.3) and the MF of the LT was fair (ICC = 0.76, %SEM = 5.71, %CV = 2.9). CONCLUSION: Peak rms and MF from the MVIC normalization method can be measured with sufficient repeatability in symptomatic office workers. PMID- 28361604 TI - Caregiver-proxy reliability of the Igbo-culture adapted Maleka Stroke Community Reintegration Measure: a validation study. AB - OBJECTIVES: This study was designed to determine the caregiver-proxy reliability of the Igbo-culture adapted urban version of the Maleka Stroke Community Reintegration Measure (I-MSCRIM). METHODS: This was a validation study involving 74 consenting stroke survivors and their 74 primary informal caregivers consecutively recruited from selected tertiary hospitals in South-East Nigeria (Igboland). The I-MSCRIM was researcher-administered to the participants. Obtained data was analyzed using frequency counts, percentages, range, mean, standard deviation, Spearman rank order correlation, Mann-Whitney U test, Kruskal Wallis test and Intra-class Correlation Coefficient. Alpha level was set at 0.05. RESULTS: The mean ages of the stroke survivors (55.4% males) and their primary informal caregivers (41.9% males) were 50.14 +/- 12.24 and 31.93 +/- 10.9 years respectively. There was no significant difference in the community reintegration (CR) scores as rated by stroke survivors and their primary informal caregivers (p > 0.05). The correlations between stroke survivors' and primary informal caregivers' rated CR scores were all adequate and acceptable (ICC = 0.602-0.917). The discrepancy in the total CR scores between the two ratings was significantly influenced by primary informal caregivers' educational attainment (k = 13.15; p < 0.01). CONCLUSION: The I-MSCRIM has acceptable caregiver-proxy reliability among Igbo stroke survivors in South-East Nigeria. This suggests that primary informal caregivers of stroke survivors can reliably estimate the CR of their care recipients when I-MSCRIM is administered to them. This will be useful when a stroke survivor cannot respond to I-MSCRIM. PMID- 28361605 TI - Development of microemulsions for ocular delivery. AB - Microemulsions (MEs) are thermodynamic stable dispersion of oily phase and aqueous phase stabilized by surfactants and co-surfactants, and are a small droplet size of less than 100 nm. MEs are appropriate systems for ocular drug delivery because they improve ocular drug retention, extended duration of action, high ocular absorption, permeation of loaded drugs and effortlessness of preparation and administration. This review is an effort to summarize the recent development in the area of MEs, self-emulsifying drug delivery systems, which are examined in relation to their uses in ocular drug delivery. The noteworthy patent, toxicity and stability issues related to these ME systems are also explored here. PMID- 28361606 TI - Targeting active cancer cells with smart bullets. AB - Paul Ehrlich's 'magic bullet' concept has stimulated research for therapeutic agents with the capability to go straight to their intended targets. The 'magic bullet' concept is still considered the ultimate approach to maximize the therapeutic effects of a given therapeutic agent without affecting nontargeted tissues. But so far, there has never been a therapeutic agent or a delivery system that goes straight to the target in the body, and no approach has provided anything better than just a few percents of the total administered dose reaching the intended target sites. But engineering principles can transform systematically circulating vectors that so far were based primarily on physical characteristics and biochemical principles alone, as smart therapeutic agents with the required propulsion-navigation-homing capabilities to enable them to go straight to their intended targets. PMID- 28361607 TI - Fabrication, characterization and application of sugar microneedles for transdermal drug delivery. AB - AIM: This study aimed to fabricate, characterize and use maltose microneedles for transdermal delivery of doxorubicin. MATERIALS & METHODS: Microneedles were fabricated by micromolding technique and evaluated for dimensions, mechanical properties and in situ dissolution. Microporation of human cadaver skin was confirmed by dye binding, histology, pore uniformity, confocal laser microscopy and skin integrity measurement. In vitro permeation studies were performed on vertical Franz diffusion cells. RESULTS: Maltose microneedles were sharp, mechanically uniform and rapidly dissolvable. Microneedle insertion resulted in a marked decrease in lag time and a significant increase in the permeation across and into human skin (p < 0.05). The skin delivery profile was used to predict the steady-state plasma concentration. CONCLUSION: Maltose microneedles are a promising physical technique to increase skin delivery. PMID- 28361608 TI - Biomimetic and bioinspired nanoparticles for targeted drug delivery. AB - In drug targeting, the urgent need for more effective and less iatrogenic therapies is pushing toward a complete revision of carrier setup. After the era of 'articles used as homing systems', novel prototypes are now emerging. Newly conceived carriers are endowed with better biocompatibility, biodistribution and targeting properties. The biomimetic approach bestows such improved functional properties. Exploiting biological molecules, organisms and cells, or taking inspiration from them, drug vector performances are now rapidly progressing toward the perfect carrier. Following this direction, researchers have refined carrier properties, achieving significant results. The present review summarizes recent advances in biomimetic and bioinspired drug vectors, derived from biologicals or obtained by processing synthetic materials with a biomimetic approach. PMID- 28361609 TI - Skin cancer: symptoms, mechanistic pathways and treatment rationale for therapeutic delivery. AB - Cancer is a group of diseases categorized by abandoning escalation and multiplication of abnormal cells. Current topical treatments for skin cancer are mainly in the semisolid dosage forms of 5-fluorouracil, imiquimod, etc. Many surgical treatments are also available these days for the treatment of skin cancer, for example, photodynamic therapy, which is approved by the US FDA. The stratum corneum is the main barrier against permeation of topical formulations developed for skin cancer treatment. Liposomes, thermosensitive stealth liposomes, nanoemulsions and polymeric lipid nanoparticles have been used by several researchers to increase skin permeability. In the present paper, major aspects of formulations developed for skin cancer, various types of skin cancer, its etiology and pathogenesis have been emphasized. PMID- 28361610 TI - An industry update: the latest developments in therapeutic delivery. AB - The present industry update covers the period 1-31 January 2017, with information sourced from company press releases, regulatory and patent agencies as well as the scientific literature. With a new year come new resolutions, annual operation plans but also reports and outlooks for the years(s) to come. A number of the latter have been published in January forecasting various spaces in drug delivery (Market and Research). Also a number of financing deals were closed being fresh into the year such as Ossianix and Ocular Therapeutix and contract manufacturers will show their offerings at the 2017 MD&M West Medtech event (Lubrizol, Trelleborg). The US FDA released some new (draft) guidelines for combination products to regulate standards and disputes in this increasingly important field. Recent advances in artificial pancreas technology demonstrates that while the age of nanotechnology and gene therapy (Bluebird Bio) has arrived, implantable, closed-loop delivery systems (Medtronic) are just to pass successfully the clinic and come in reach of patients. PMID- 28361611 TI - High failure rate of transungal drug delivery: need for new strategies. PMID- 28361612 TI - Targeting therapeutics to the plasma membrane: opportunities for nanoparticle mediated delivery abound. PMID- 28361613 TI - Synergistic efficacy of ultrasound, sonosensitizers and chemotherapy: a review. AB - Chemotherapeutic agents, either in the form of systemically injected free drug or encapsulated in nanoparticles transport vehicles, must overcome three main obstacles prior to reaching and interacting with their intended target inside tumor cells. Drugs must leave the circulation, overcome the tissue-tumor barrier and penetrate the cell's plasma membrane. Since, many agents enter the cell by endocytosis, they must avoid entrapment and degradation by the intracellular endolysosome complex. Ultrasound has demonstrated potential to enhance the efficacy of chemotherapy by reducing these barriers. The purpose of this review is to highlight the potential of ultrasound in combination with sonosensitizers to enhance the efficacy of chemotherapy by optimizing the anticancer agent's intracellular ability to engage and interact with its target. PMID- 28361614 TI - Therapeutic approaches for the delivery of TNF-alpha siRNA. AB - Immune-mediated diseases are emerging as a major healthcare concern in the present era. TNF-alpha, a proinflammatory cytokine, plays a major role in the manifestation of these diseases by mediating different pathways and inducing the expression of other cytokines. In last decades, monoclonal antibodies and extracellular portion of human TNF-alpha receptors are explored in this area; however, the risk of immunological response and undesired effects urge a need to develop more effective therapies to control TNF-alpha levels. siRNA therapeutic strategies are emerging for the treatment of myriad of diseases, but the delivery challenges associated with siRNA require the development of suitable delivery vectors. For delivery of TNF-alpha siRNA, both viral and nonviral vectors are explored. This review attempts to describe different delivery approaches for TNF alpha siRNA with special focus on nonviral delivery vectors. PMID- 28361615 TI - Unclear-onset intracerebral hemorrhage: Clinical characteristics, hematoma features, and outcomes. AB - Background and purpose Although unclear-onset ischemic stroke, including wake-up ischemic stroke, is drawing attention as a potential target for reperfusion therapy, acute unclear-onset intracerebral hemorrhage has been understudied. Clinical characteristics, hematoma features, and outcomes of patients who developed intracerebral hemorrhage during sleep or those with intracerebral hemorrhage who were unconscious when witnessed were determined. Methods Consecutive intracerebral hemorrhage patients admitted within 24 hours after onset or last-known normal time were classified into clear-onset intracerebral hemorrhage and unclear-onset intracerebral hemorrhage groups. Outcomes included initial hematoma volume, initial National Institutes of Health Stroke Scale score, hematoma growth on 24-hour follow-up computed tomography, and vital and functional prognoses at 30 days. Results Of 377 studied patients (122 women, 69 +/- 11 years old), 147 (39.0%) had unclear-onset intracerebral hemorrhage. Patients with unclear-onset intracerebral hemorrhage had larger hematoma volumes (p = 0.044) and higher National Institutes of Health Stroke Scale scores (p < 0.001) than those with clear-onset intracerebral hemorrhage after multivariable adjustment for risk factors and comorbidities. Hematoma growth was similarly common between the two groups (p = 0.176). There were fewer patients with modified Rankin Scale (mRS) scores of 0-2 (p = 0.033) and more patients with mRS scores of 5-6 (p = 0.009) and with fatal outcomes (p = 0.049) in unclear-onset intracerebral hemorrhage group compared with clear-onset intracerebral hemorrhage as crude values, but not after adjustment. Conclusions Patients with unclear onset intracerebral hemorrhage presented with larger hematomas and higher National Institutes of Health Stroke Scale scores at emergent visits than those with clear-onset intracerebral hemorrhage, independent of underlying characteristics. Unclear-onset intracerebral hemorrhage patients showed poorer 30 day vital and functional outcomes than clear-onset intracerebral hemorrhage patients; these differences seem to be mainly due to initial hematoma volumes and National Institutes of Health Stroke Scale scores. PMID- 28361616 TI - Acute basilar artery occlusion: Endovascular Interventions versus Standard Medical Treatment (BEST) Trial-Design and protocol for a randomized, controlled, multicenter study. AB - Rationale Endovascular treatment plus standard medical therapy is superior to standard medical therapy alone for acute anterior proximal intracranial large artery occlusion strokes. The benefit of endovascular treatment in acute ischemic stroke caused by basilar artery occlusion remains unproven. Aim This study compares the safety and efficacy of endovascular treatment plus standard medical therapy versus standard medical therapy alone in acute ischemic stroke due to basilar artery occlusion. Design The study is a multicenter randomized control trial with blinded outcome assessment. A projected total 344 subjects with acute basilar arterial occlusion within 8 h of estimated occlusion time will be enrolled over three years in China. Patients will be assigned to endovascular treatment plus standard medical therapy and standard medical therapy alone group in 1:1 ratio for study centers. Study outcomes The primary outcome measure is a favorable functional outcome, defined as a modified Rankin Score of 0-3 at 90 days. The primary safety measure is mortality at 90 days. Trial registration ClinicalTrials.gov (NCT 02441556). Summary The BEST trial will provide valuable insights into the safety and efficacy of endovascular treatment for acute ischemic stroke patients with basilar artery occlusion. PMID- 28361617 TI - Optimal testing time for suppression of competitors during interference resolution. AB - Interference between competing memory traces is a common cause of memory failure. Recent research has demonstrated a suppression mechanism that operates at retrieval to resolve interference. Using an adaptation of the suppression paradigm in Healey, Ngo, and Hasher [(2014). Below-baseline suppression of competitors during interference resolution by younger but not older adults. Psychological Science, 25(1), 145-151. doi: 10.1177/0956797613501169 ], we tested whether the ability to suppress competing memory traces varies with the synchrony between optimal arousal period and time of testing. We replicate the below baseline suppression effect for young adults tested at optimal times of day, and present novel evidence that they do not show competitor suppression during non optimal times of day. In fact, competitors are actually strengthened at non optimal times. Our results suggest that the ability to resolve interference by suppression varies with circadian arousal. PMID- 28361618 TI - Erratum. PMID- 28361619 TI - Classification of long bone fractures in children. PMID- 28361620 TI - Practice improvement as a result of an end of life care programme for care homes. AB - This article explores practice outcomes from a Six Steps+ programme for end of life care (EoLC) delivered in care homes in the south of England. The education programme aims to increase staff's knowledge, skills and confidence to counter balance their anxiety about EoLC. The Six Steps+ programme promotes a culture of high quality, compassionate, person-centred and dignified holistic care to meet the needs of residents who may have increasing complex requirements throughout their last year or more of life. Through integrated working and a reduction in avoidable hospital admissions, residents are enabled to die in their place of choice where possible. Case studies show that participating in the Six Steps+ programme increases care home staff's knowledge, skills and confidence and enhances the quality of EoLC for residents. With the cost of the education and support required essentially covered by six avoided hospital admissions throughout the one-year course, the Six Steps+ programme is an attractive and cost-effective approach to improving EoLC. PMID- 28361621 TI - Deprivation of Liberty: Collected Guidance The Law Society Deprivation of Liberty: Collected Guidance 400 pages L29.95 Law Society Publishing 9781784460433 1784460435 [Formula: see text]. AB - Deprivation of liberty (DoL) can be a difficult subject, partly due to the complexity of regulations and variety of guidance sources. It can be challenging to find specific information. PMID- 28361622 TI - Nurse-led team commended for specialist Parkinson's disease service. AB - A nurse-led team that offers support for people with complex Parkinson's needs in nursing homes has been highly commended in the first UK Parkinson's Excellence Network Awards. PMID- 28361623 TI - Story in numbers. AB - Facts and figures about dementia in the UK. PMID- 28361624 TI - Nutritional standards needed for ready meals to avoid micronutrient deficiencies. AB - Micronutrient deficiencies contribute to many age-related disorders, although initial effects may be mild and easily missed. For example, B vitamin deficiency may result in mild cognitive decline, thiamine deficiency can contribute to development of type 2 diabetes and lack of vitamin D changes immune function. PMID- 28361625 TI - 'Long way to go' for high quality end of life care. AB - NHS England recently called on its Twitter followers to share their views about end of life care. It highlighted best practice examples in a bid to show progress on the government's six commitments to end of life care. PMID- 28361626 TI - 'Nurses need to find a voice to challenge the status quo'. AB - What is your job? I have recently taken up a new and exciting role as director of health and well-being at the Royal Hospital Chelsea. I will lead the social care and health team, including the nursing team, who care for the 320 pensioners living at the hospital. PMID- 28361627 TI - Challenges in implementing an advance care planning programme in long-term care. AB - This study explores the effectiveness of an education programme, Let Me Decide, designed to support the development of advance care planning (ACP) for people with cognitive impairment and frailty. PMID- 28361628 TI - Dementia Care at a Glance Jenkins Catharine Ginesi Laura and Keenan Bernie Dementia Care at a Glance 176pp L26.99 Wiley-Blackwell 9781118859988 1118859987 [Formula: see text]. AB - This book adds to Wiley's critically acclaimed 'at a glance' series with an overview of dementia care for all grades of healthcare providers, including healthcare assistants. PMID- 28361629 TI - Healthcare decision-making: past, present and future, in light of a diagnosis of dementia. AB - This study explores experiences of and views of healthcare decision-making in the past, present and future among people with dementia and their family carers. PMID- 28361630 TI - Obstructive sleep apnoeahypopnoea syndrome and cognitive impairments. AB - Obstructive sleep apnoea-hypopnoea is a common condition involving apnoea (absence of breath) and hypopnoea (reduced airflow). It causes intermittent hypoxia and poor quality, fragmented sleep. As a result, daytime functioning is significantly impaired with excessive sleepiness, fatigue and mood problems. PMID- 28361631 TI - Vitamin D supplementation effective in preventing acute respiratory tract infections. AB - Studies have consistently shown low levels of vitamin D make people more susceptible to respiratory infections. Acute respiratory infections are a major cause of ill health and mortality. Observational studies have shown that people with low levels of 25-hydroxyvitamin D, the major circulating vitamin D metabolite, are susceptible to respiratory infection. PMID- 28361632 TI - Advance care planning for people with dementia. AB - UK policy and guidance state that people should have their preferences and priorities for end of life care recorded in the form of an advance care plan. However, for people with dementia and their families, issues of reduced capacity, difficulties with discussing end of life preferences and staff understanding can make this process challenges. This research focus summarises two studies that explore these issues. PMID- 28361634 TI - Pressure ulcer prevention in care home settings. AB - Pressure ulcer prevention in the care home setting can be challenging and is often compromised by a lack of access to education and resources. There are measures that have been shown to consistently improve outcomes in pressure ulcer prevention including assessment of the patient and their individual risks, delivery of a consistent plan of care that meets patients' needs, and regular evaluation to identify shortfalls. In addition, there should be a robust approach to investigating events that lead to a person developing a pressure ulcer and that information should be used to improve future practice. Pressure ulcer prevention in care homes is achievable and nurses should all be aware of the necessary measures detailed in this article. PMID- 28361636 TI - Writing can seriously improve your health. AB - Laughter rings out in the dining room of a care home where residents try on a range of different hats and invent characters who might wear them. PMID- 28361637 TI - ANPs can improve older people's care. AB - Advanced and specialist nurses have the potential to improve older patients' experiences of GP services in Wales, according to independent older people's commissioner for Wales Sarah Rochira in her latest guidance to health boards. PMID- 28361638 TI - This year's award finalists revealed. AB - The names of the finalists for nursing older people category at RCNi Nurse Awards 2017 have been revealed. PMID- 28361639 TI - Nurses need access to high-quality education in end of life care. AB - End of life care is often explored in the pages of Nursing Older People, including in an article on the development, implementation and evaluation of an end of life care intervention in care homes that appeared in our February edition ( Cox et al 2017 ). PMID- 28361640 TI - Sight loss charity calls for nurse training in care homes. AB - A sight loss charity has called for more training for nurses in care homes so that they can intervene early to prevent residents' vision deteriorating. PMID- 28361641 TI - Correct use of inhalers is our responsibility. AB - Despite the fact that inhaled medications have been the basis for treating patients with respiratory diseases for more than 60 years, we are repeatedly reminded that many individuals cannot use their inhaler devices correctly ( Capstick and Clifton 2012 , Scullion and Holmes 2013 , Sanchis et al 2016 ).This is often because healthcare professionals cannot use the devices correctly either and they teach less than optimum techniques to patients. This in turn results in poor control and, potentially, death. PMID- 28361642 TI - Nursing care for people with delirium superimposed on dementia. AB - Nursing and healthcare is changing in response to an ageing population. There is a renewed need for holistic nursing to provide clinically competent, appropriate and timely care for patients who may present with inextricably linked mental and physical health requirements. This article explores the dichotomy in healthcare provision for 'physical' and 'mental' health, and the unique role nurses have when caring for people with delirium superimposed on dementia (DSD). Delirium is prevalent in older people and recognised as 'acute brain failure'. As an acute change in cognition, it presents a unique challenge when occurring in a person with dementia and poses a significant risk of mortality. In this article, dementia is contrasted with delirium and subtypes of delirium presentation are discussed. Nurses can recognise DSD through history gathering, implementation of appropriate care and effective communication with families and the multidisciplinary team. A simple mnemonic called PINCH ME (Pain, INfection, Constipation, deHydration, Medication, Environment) can help identify potential underlying causes of DSD and considerations for care planning. The mnemonic can easily be adapted to different clinical settings and a fictitious scenario is presented to show its application in practice. PMID- 28361643 TI - Ask dying adults about their spiritual beliefs. AB - Essential facts Religion should be included in the vital discussions about the care people and those close to them want to receive in the last two to three days of life, according to the National Institute for Health and Care Excellence (NICE). PMID- 28361646 TI - Correction to: Exposure to methyl tert-butyl ether (MTBE) is associated with mitochondrial dysfunction in rat. PMID- 28361645 TI - An unusual cause of epidemic thyrotoxicosis. AB - We describe the case of four patients consulting for headache and tachycardia of brutal onset. Their biological data were compatible with primary hyperthyroidism with low TSH and high T4 serum levels. Serum thyroglobulin level was low and Tc scintigraphy showed decreased uptake with a homogenous pattern. These results allowed to conclude a thyrotoxicosis caused by thyroid hormones intake. History taking revealed consumption of beef neck meat containing all or parts of the bovine thyroid gland. Evolution was favourable with beta-blockers. A literature review of " hamburger thyrotoxicosis " is presented. PMID- 28361647 TI - Effects of Photo-Depicted Pupil Diameter on Judgments of Others' Attentiveness and on Facial Recognition Memory. AB - Occasionally, individuals perceive that someone is no longer paying attention to the discussion at hand even when there are no overt cues of inattentiveness. As a preliminary study of this phenomenon, we examined whether pupil diameter might be implicitly used to infer others' attentiveness. Forty participants (27 women, 13 men, M age = 19.7 year, SD = 2.8) were presented with images of male faces with either large or small pupils, and, in the context of a personnel selection scenario, participants then judged the attentiveness of the person in the image. Images of faces with large pupils were judged as more attentive, compared with images of faces with small pupils. Face recognition memory performance was not affected by depicted pupil size. Our results are consistent with the proposal that pupillary fluctuations can be an index of perceived attention, and they provide preliminary evidence that pupil dilation may be implicitly relied upon to infer attentional states. PMID- 28361648 TI - Can Eye Fixation During the Grooved Pegboard Test Distinguish Between Planning and Online Correction? AB - The Grooved Pegboard Test, in its standard use, has well-documented utility. However, a revised methodology needs further study, leading us to investigate whether duration of eye fixation could predict performance on different task conditions of the Grooved Pegboard Test (place and remove pegs) with the preferred and nonpreferred hands. Fifty-two right-handed undergraduate students (33 male and 19 female), with a mean age of 22.22 (+/-3.57) years, performed the Grooved Pegboard Test. SensoMotoric eye-tracking glasses with a binocular time resolution of 30 Hz were used to measure eye fixation. The videos were recorded in iView software, and data were analyzed using BeGaze software. The number and duration of eye fixations were statistically different with preferred and nonpreferred hands and also differed across tasks. Simple linear regression showed eye fixation duration to predict movement time in the place task (preferred hand: R2 = 31%; nonpreferred hand: R2 = 41%) and in the remove task (preferred hand: R2 = 11%; nonpreferred hand: R2 = 25%). Thus, duration of eye fixation during the Grooved Pegboard Test differentially predicted performance with each hand and on preferred and different subtests of this instrument. PMID- 28361649 TI - Self-Regulation in Language Learning. AB - Self-regulated learning has been a widely researched subject for decades in educational psychology. Different instruments have been developed to understand learners' self-regulated learning in a specific subject domain. This study developed a measurement scale to assess English-as-a-foreign-language learners' self-regulatory capacity in English language learning and further examined the effects of gender on English-as-a-foreign-language learners' self-regulatory capacity. A series of psychometric analyses including exploratory factor analysis, confirmatory factor analysis, and full structural equation modeling were undertaken to answer the research questions raised. The findings suggest that the scale can attain high reliability and strong validity in two different samplings, and the underlying construct of self-regulation in English language learning is shown to be multidimensional with a significant impact by gender. Theoretical and pedagogical implications are further put forward in light of the research findings. PMID- 28361650 TI - Exploring the Interaction of Motor and Social Skills With Autism Severity Using the SFARI Dataset. AB - Social communicative deficits and stereotyped or repetitive interests or behaviors are the defining features of autism spectrum disorder (ASD). A growing body of research suggests that gross motor deficits are also present in most children with ASD. This study sought to understand how pediatric ASD severity is related to motor skills and social skills. A multivariate analysis of variance analysis of 483 children with autism ( N = 444) and ASD ( N = 39) revealed a nonsignificant difference between groups. Results suggest little difference between severity groups on gross motor and social skills within the limited age range of the participants (about 5.6 years of age). PMID- 28361651 TI - Interrelationships among Jumping Power, Sprinting Power and Pubertal Status after Controlling for Size in Young Male Soccer Players. AB - This study examined power output on jumping and sprinting tests in young soccer players of differing pubertal status, while controlling for body size with allometric scaling exponents. A total of 46 males aged 12-18 years (14.17 years) were divided into three groups: pre-pubescent ( n = 12), pubescent ( n = 22), and post-pubescent ( n = 12). Participants performed a series of tests, including the squat jump (SJ), countermovement jump (CMJ), and 10-meter and 30-meter sprint test protocols. The Post-PUB group was older ( F = 112.411, p < 0.001), more experienced in competitive soccer ( F = 8.055, p = 0.001), taller ( F = 28.940, p < 0.001), and heavier ( F = 20.618, p < 0.001), when compared to peers in the other groups. Mean differences in jumping and sprinting performances suggested a significant effect for pubertal status on performance in the 10-meter sprint (large effect size, F = 8.191, p < 0.001) and 30-meter sprint (large effect size, F = 8.093, p < 0.001) after allometric scaling. Power output derived from SJ (small effect size, F = 0.536, p = 0.001) and CMJ (small effect size, F = 1.058, p = 0.356) showed no significant differences across players of varying pubertal status. Biological maturation showed a large effect on maximal power output for sprints, but not for jumps, when the effect of body size was adjusted by statistically derived allometric exponents in young male soccer players. PMID- 28361652 TI - Electrical Activity of Powerhouse Muscles During the Teaser Exercise of Pilates Using Different Types of Apparatus. AB - We compared the electrical activity of certain powerhouse muscles-External Oblique, Multifidus, Adductor Longus, and Gluteus Medius-during the teaser exercise of the Pilates Method, performed on various types of apparatus-the Mat, Reformer, and Wall Unit. Fifteen female practitioners of the Classic Pilates Method (32.6 +/- 7.7 years old; 21.9 +/- 1.9 body mass index) performed the teaser in each situation while electromyographic (EMG) and kinematic data were collected. Root mean square values of the flexion phase were compared. All muscles showed higher EMG activity in Reformer compared with Wall Unit, and Multifidus, Adductor Longus, and Gluteus Medius showed higher EMG activity in Mat compared with Wall Unit. No difference was found between Reformer and Mat. PMID- 28361653 TI - Hand Function in Muscular Dystrophies. AB - The aim of this study was to investigate the relationship between Performance of Upper Limb (PUL) and Jebsen-Taylor Test (JTT) to assess and monitor upper limb function progression in patients with muscular dystrophy. Thirty patients diagnosed with Duchenne muscular dystrophy, limb-girdle muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy Type 1, and fascioscapulohumeral dystrophy were submitted to the shoulder, elbow, and wrist domains of PUL, and to JTT subtests. Spearman tests investigated the relationships between PUL and JTT total scores and domains. Correlations were classified as strong ( r >= 0.70), moderate (0.40 <= r < 0.70), or weak ( r <= 0.40). There were strong correlations between the PUL and JTT total scores ( r = -0.706). Although JTT measures time and PUL provides kinesiologic scores, these measures were related. Therefore, muscle synergies, which control the compensatory movements and motor functions involving mainly shoulder, elbow, wrist, and finger movements, are related to timed performance in patients with muscular dystrophies. PMID- 28361654 TI - Effect of a 6-Week Active Play Intervention on Fundamental Movement Skill Competence of Preschool Children. AB - This study examined the effectiveness of an active play intervention on fundamental movement skills of 3- to 5-year-old children from deprived communities. In a cluster randomized controlled trial design, six preschools received a resource pack and a 6-week local authority program involving staff training with help implementing 60-minute weekly sessions and postprogram support. Six comparison preschools received a resource pack only. Twelve skills were assessed at baseline, postintervention, and at a 6-month follow-up using the Children's Activity and Movement in Preschool Study Motor Skills Protocol. One hundred and sixty-two children (Mean age = 4.64 +/- 0.58 years; 53.1% boys) were included in the final analyses. There were no significant differences between groups for total fundamental movement skill, object-control skill or locomotor skill scores, indicating a need for program modification to facilitate greater skill improvements. PMID- 28361655 TI - The Effect of Variability of Practice at Execution Redundancy Level in Skilled and Novice Basketball Players. AB - We investigated the effect of practice variability through execution redundancy in skilled and novice basketball players on free throw skills. Twelve skilled basketball players and 12 novices (mean age = 25.4 years, SD = 4.3) were divided into four groups (skilled constant, skilled variable, novice constant, and novice variable). After a pretest, participants practiced free throw action. The variable groups threw the ball over an obstacle of varying heights on each trial in random order, whereas the obstacle's height was fixed for the constant groups. After 7 and 14 consecutive days of practice, participants performed two posttests with constant and variable distances from the basket. The results showed that practicing different solutions of a task did not affect the performance of skilled players but had an immediate negative effect on the performance of novice players. Learning a complex task is the result of learning task-related parameters, and practice variability can create a mismatch between task difficulty and new learner skill levels. PMID- 28361656 TI - Motor Skills and Free-Living Physical Activity Showed No Association Among Preschoolers in 2012 U.S. National Youth Fitness Survey. AB - Albeit limited, some emerging work, using convenience-based samples, has demonstrated that greater motor skill development is associated with higher physical activity among preschool-aged children. The purpose of this study was to evaluate this topic using data from the 2012 National Youth Fitness Survey that included 329 preschool-aged children (3-5 years). Parents proxy-reported their child's physical activity, with motor skill level assessed from the Test of Gross Motor Development-Second Edition (TGMD2). Motor skill levels (Gross Motor Quotient, locomotor or object control) were not associated with preschool free living physical activity in any analytic model. Thus, in this large sample of preschoolers, contrary to research with older children, motor skill level was not associated with physical activity. Findings are discussed in terms of study limitations of (a) a reliance on parent report of children's physical activity levels and (b) the possibility that physical activity data within the national survey were too limited in range to show possible associations to motor skill development with higher levels of free-living physical activity in preschoolers. PMID- 28361657 TI - Attention Deficit Hyperactivity Disorder and Motor Impairment. AB - Attention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral disorder during childhood, affecting approximately 3-6% of school aged children; its cardinal symptoms of high activity, impulsivity, and behavioral distractibility might be assumed to have close relationships to interferences with motor skills. A separate body of literature attests to ways that motor problems can severely impact children's daily lives, as motor problems may occur in 30-50% of children with ADHD. This article critically reviews research on motor impairment in children with ADHD, notable differences in motor performance of individuals with ADHD compared with age-matched controls, and possible neural underpinnings of this impairment. We discuss the highly prevalent link between ADHD and developmental coordination disorder (DCD) and the lack of a clear research consensus about motor difficulties in ADHD. Despite increasing evidence and diagnostic classifications that define DCD by motor impairment, the role of ADHD symptoms in DCD has not been delineated. Similarly, while ADHD may predispose children to motor problems, it is unclear whether any such motor difficulties observed in this population are inherent to ADHD or are mediated by comorbid DCD. Future research should address the exact nature and long-term consequences of motor impairment in children with ADHD and elucidate effective treatment strategies for these disorders together and apart. PMID- 28361658 TI - Roles of Perceived Motivational Climates Created by Coach, Peer, and Parent on Dispositional Flow in Young Athletes. AB - We investigated the contribution of perceived motivational climates created by coach, peer, and parent on the dispositional flow experience of young athletes. Eighty-six female ( Mage = 14.24, SD = 1.38 years) and 134 male ( Mage = 16.28, SD = 1.17 years) athletes completed questionnaires of perceived motivational climates created by coach, peer, and parent and the Dispositional Flow Scale-2. Results of hierarchical multiple regression analyses indicated that perceived task-involving coach (beta = .40, p < .001) and peer (beta = .28, p < .002) motivational climates were the only significant predictors of dispositional flow. These findings suggest that task-involving motivational climates should be strengthened to increase experience of flow. PMID- 28361659 TI - Ratings of Perceived Exertion and Physiological Parameters of Muscle Metabolism in Postmenopausal Women. AB - We compared responses from postmenopausal women living a sedentary lifestyle ( n = 15; Mean age= 59; SD = 4.2) to a single bout of water- or land-based exercise with respect to ratings of perceived exertion (RPE), lactate concentration, and muscle oxygen saturation. Each participant was randomly assigned to a single water- or land-based 50-minute bout of combined aerobic and resistance exercise. Blood samples were collected to detect pre- and post-exercise lactate concentration. Total hemoglobin, deoxidized hemoglobin, and the percentage change in the total oxygen saturation index (TSI%) of the rectus femoris were detected by means of near-infrared spectroscopy. We found similar RPE at various stages of land- and water-based exercise, and a similar change in lactate concentration in these environments (in water: 4.35 +/- 1.49 mol/L; on land: 3.62 +/- 1.18 mol/L). However, the reduction in HHb response was less pronounced after water-based exercise, and TSI% increased on land but decreased in water, with the magnitude of this change much higher on land. For similar RPE and lactate concentration, the oxygen saturation in the exercising muscles decreased in water, suggesting higher oxygen consumption in water than on land. PMID- 28361660 TI - Effects of Auditory and Visual Priming on the Identification of Spoken Words. AB - This study examined the effects of preceding contextual stimuli, either auditory or visual, on the identification of spoken target words. Fifty-one participants (29% males, 71% females; mean age = 24.5 years, SD = 8.5) were divided into three groups: no context, auditory context, and visual context. All target stimuli were spoken words masked with white noise. The relationships between the context and target stimuli were as follows: identical word, similar word, and unrelated word. Participants presented with context experienced a sequence of six context stimuli in the form of either spoken words or photographs. Auditory and visual context conditions produced similar results, but the auditory context aided word identification more than the visual context in the similar word relationship. We discuss these results in the light of top-down processing, motor theory, and the phonological system of language. PMID- 28361661 TI - Personality, Motivation, and Math Achievement Among Turkish Students. AB - Using the Turkish portion of the Programme for International Student Assessment dataset ( N = 4,848; 51% boys, 49% girls; age, M = 15.81 years, SD = 0.28), this study investigated factors associated with mathematics achievement among Turkish students. Three different models were estimated using the method of balanced repeated replication with Fay's method and taking into account the presence of five plausible values of the dependent variable. Results showed that male students and older students had better mathematics proficiency. Socio-economic status and school resources also played a significant role in explaining student achievement in mathematics. Finally, students who were more open to problem solving, who attributed their failure to external factors, and who were intrinsically motivated to learn mathematics achieved higher scores. Policy implications are provided. PMID- 28361662 TI - Throwing Skills. AB - Traditionally, motor learning scientists have evaluated the process of learning a new motor skill by considering the skill as a whole. Yet, motor skills comprise various phases, and in the motor learning literature, it is not clear whether new learners show similar or different learning across various phases. We provide exploratory data on learning movement phases by novices, using baseball pitching as the learning task. Eight participants (four male, four female, M age = 23.7 years, SD = 2.4) performed five trials each in the pretest followed by three blocks of 10 trials each in the acquisition phase. Finally, two retention tests of five trials were conducted by each participant 10 minutes and seven days after the last acquisition block, respectively. Intra- and interlimb coordination of upper and lower body segments were measured as dependent variables. We found significant differences between the stride phase and the other phases at pretest, during the acquisition phase, and on both retention tests across all kinematic variables. Participants experienced more trouble coordinating the stride phase than the other phases of pitching, perhaps because the stride phase is the only phase in which the participants had to move their upper and lower body parts simultaneously. We discuss implications for motor learning generally. PMID- 28361663 TI - Sex and Ability Differences in Neural Strategy for Piaget's Water Level Test. AB - To explore brain activation differences between the sexes and between high and low performers on spatial perception performance, 43 college students (20 males and 23 females) performed the Piaget's Water Level Test (WLT) while their electroencephalogram signals were recorded. A 2 (Sex) * 2 (Group: high performing vs. low performing) * 2 (Hemisphere: left vs. right) * 3 (Region: frontal, parietal, and temporal) mixed analysis of variance on beta power data showed that females more significantly activated the left hemisphere when performing the WLT, suggesting their application of an analytic strategy. In contrast, males showed a bilateral activation pattern, suggesting their use of an analytic- or holistic combined strategy. Moreover, superior performance on the WLT was associated with enhanced temporal lobe functioning, suggesting that a superior analytic skill is key to successful performance on the WLT. There is likely modulating impact of both cognitive style and specific task properties on spatial perception strategy preferences. PMID- 28361664 TI - Network-based analysis of transcriptional profiles from chemical perturbations experiments. AB - BACKGROUND: Methods for inference and comparison of biological networks are emerging as powerful tools for the identification of groups of tightly connected genes whose activity may be altered during disease progression or due to chemical perturbations. Connectivity-based comparisons help identify aggregate changes that would be difficult to detect with differential analysis methods comparing individual genes. METHODS: In this study, we describe a pipeline for network comparison and its application to the analysis of gene expression datasets from chemical perturbation experiments, with the goal of elucidating the modes of actions of the profiled perturbations. We apply our pipeline to the analysis of the DrugMatrix and the TG-GATEs, two of the largest toxicogenomics resources available, containing gene expression measurements for model organisms exposed to hundreds of chemical compounds with varying carcinogenicity and genotoxicity. RESULTS: Starting from chemical-specific transcriptional networks inferred from these data, we show that the proposed comparative analysis of their associated networks identifies groups of chemicals with similar functions and similar carcinogenicity/genotoxicity profiles. We also show that the in-silico annotation by pathway enrichment analysis of the gene modules with a significant gain or loss of connectivity for specific groups of compounds can reveal molecular pathways significantly associated with the chemical perturbations and their likely modes of action. CONCLUSIONS: The proposed pipeline for transcriptional network inference and comparison is highly reproducible and allows grouping chemicals with similar functions and carcinogenicity/genotoxicity profiles. In the context of drug discovery or drug repositioning, the methods presented here could help assign new functions to novel or existing drugs, based on the similarity of their associated network with those built for other known compounds. Additionally, the method has broad applicability beyond the uses here described and could be used as an alternative or as a complement to standard approaches of differential gene expression analysis. PMID- 28361665 TI - A computational method for estimating the PCR duplication rate in DNA and RNA-seq experiments. AB - BACKGROUND: PCR amplification is an important step in the preparation of DNA sequencing libraries prior to high-throughput sequencing. PCR amplification introduces redundant reads in the sequence data and estimating the PCR duplication rate is important to assess the frequency of such reads. Existing computational methods do not distinguish PCR duplicates from "natural" read duplicates that represent independent DNA fragments and therefore, over-estimate the PCR duplication rate for DNA-seq and RNA-seq experiments. RESULTS: In this paper, we present a computational method to estimate the average PCR duplication rate of high-throughput sequence datasets that accounts for natural read duplicates by leveraging heterozygous variants in an individual genome. Analysis of simulated data and exome sequence data from the 1000 Genomes project demonstrated that our method can accurately estimate the PCR duplication rate on paired-end as well as single-end read datasets which contain a high proportion of natural read duplicates. Further, analysis of exome datasets prepared using the Nextera library preparation method indicated that 45-50% of read duplicates correspond to natural read duplicates likely due to fragmentation bias. Finally, analysis of RNA-seq datasets from individuals in the 1000 Genomes project demonstrated that 70-95% of read duplicates observed in such datasets correspond to natural duplicates sampled from genes with high expression and identified outlier samples with a 2-fold greater PCR duplication rate than other samples. CONCLUSIONS: The method described here is a useful tool for estimating the PCR duplication rate of high-throughput sequence datasets and for assessing the fraction of read duplicates that correspond to natural read duplicates. An implementation of the method is available at https://github.com/vibansal/PCRduplicates . PMID- 28361666 TI - Towards targeted combinatorial therapy design for the treatment of castration resistant prostate cancer. AB - BACKGROUND: Prostate cancer is one of the most prevalent cancers in males in the United States and amongst the leading causes of cancer related deaths. A particularly virulent form of this disease is castration-resistant prostate cancer (CRPC), where patients no longer respond to medical or surgical castration. CRPC is a complex, multifaceted and heterogeneous malady with limited standard treatment options. RESULTS: The growth and progression of prostate cancer is a complicated process that involves multiple pathways. The signaling network comprising the integral constituents of the signature pathways involved in the development and progression of prostate cancer is modeled as a combinatorial circuit. The failures in the gene regulatory network that lead to cancer are abstracted as faults in the equivalent circuit and the Boolean circuit model is then used to design therapies tailored to counteract the effect of each molecular abnormality and to propose potentially efficacious combinatorial therapy regimens. Furthermore, stochastic computational modeling is utilized to identify potentially vulnerable components in the network that may serve as viable candidates for drug development. CONCLUSION: The results presented herein can aid in the design of scientifically well-grounded targeted therapies that can be employed for the treatment of prostate cancer patients. PMID- 28361667 TI - Combination therapy design for maximizing sensitivity and minimizing toxicity. AB - BACKGROUND: Design of personalized targeted therapies involve modeling of patient sensitivity to various drugs and drug combinations. Majority of studies evaluate the sensitivity of tumor cells to targeted drugs without modeling the effect of the drugs on normal cells. In this article, we consider the individual modeling of drug responses to tumor and normal cells and utilize them to design targeted combination therapies that maximize sensitivity over tumor cells and minimize toxicity over normal cells. RESULTS: The problem is formulated as maximizing sensitivity over tumor cell models while maintaining sensitivity below a threshold over normal cell models. We utilize the constrained structure of tumor proliferation models to design an accelerated lexicographic search algorithm for generating the optimal solution. For comparison purposes, we also designed two suboptimal search algorithms based on evolutionary algorithms and hill-climbing based techniques. Results over synthetic models and models generated from Genomics of Drug Sensitivity in Cancer database shows the ability of the proposed algorithms to arrive at optimal or close to optimal solutions in significantly lower number of steps as compared to exhaustive search. We also present the theoretical analysis of the expected number of comparisons required for the proposed Lexicographic search that compare favorably with the observed number of computations. CONCLUSIONS: The proposed algorithms provide a framework for design of combination therapy that tackles tumor heterogeneity while satisfying toxicity constraints. PMID- 28361668 TI - GATK hard filtering: tunable parameters to improve variant calling for next generation sequencing targeted gene panel data. AB - BACKGROUND: NGS technology represents a powerful alternative to the standard Sanger sequencing in the context of clinical setting. The proprietary software that are generally used for variant calling often depend on preset parameters that may not fit in a satisfactory manner for different genes. GATK, which is widely used in the academic world, is rich in parameters for variant calling. However the self-adjusting parameter calibration of GATK requires data from a large number of exomes. When these are not available, which is the standard condition of a diagnostic laboratory, the parameters must be set by the operator (hard filtering). The aim of the present paper was to set up a procedure to assess the best parameters to be used in the hard filtering of GATK. This was pursued by using classification trees on true and false variants from simulated sequences of a real dataset data. RESULTS: We simulated two datasets, with different coverages, including all the sequence alterations identified in a real dataset according to their observed frequencies. Simulated sequences were aligned with standard protocols and then regression trees were built up to identify the most reliable parameters and cutoff values to discriminate true and false variant calls. Moreover, we analyzed flanking sequences of region presenting a high rate of false positive calls observing that such sequences present a low complexity make up. CONCLUSIONS: Our results showed that GATK hard filtering parameter values can be tailored through a simulation study based-on the DNA region of interest to ameliorate the accuracy of the variant calling. PMID- 28361669 TI - Interpretive time-frequency analysis of genomic sequences. AB - BACKGROUND: Time-Frequency (TF) analysis has been extensively used for the analysis of non-stationary numeric signals in the past decade. At the same time, recent studies have statistically confirmed the non-stationarity of genomic non numeric sequences and suggested the use of non-stationary analysis for these sequences. The conventional approach to analyze non-numeric genomic sequences using techniques specific to numerical data is to convert non-numerical data into numerical values in some way and then apply time or transform domain signal processing algorithms. Nevertheless, this approach raises questions regarding the relative magnitudes under numeric transforms, which can potentially lead to spurious patterns or misinterpretation of results. RESULTS: In this paper, using the notion of interpretive signal processing (ISP) and by redefining correlation functions for non-numeric sequences, a general class of TF transforms are extended and applied to non-numerical genomic sequences. The technique has been successfully evaluated on synthetic and real DNA sequences. CONCLUSION: The proposed framework is fairly generic and is believed to be useful for extracting quantitative and visual information regarding local and global periodicity, symmetry, (non-) stationarity and spectral color of genomic sequences. The notion of interpretive time-frequency analysis introduced in this work can be considered as the first step towards the development of a rigorous mathematical construct for genomic signal processing. PMID- 28361670 TI - Prediction of virus-host infectious association by supervised learning methods. AB - BACKGROUND: The study of virus-host infectious association is important for understanding the functions and dynamics of microbial communities. Both cellular and fractionated viral metagenomic data generate a large number of viral contigs with missing host information. Although relative simple methods based on the similarity between the word frequency vectors of viruses and bacterial hosts have been developed to study virus-host associations, the problem is significantly understudied. We hypothesize that machine learning methods based on word frequencies can be efficiently used to study virus-host infectious associations. METHODS: We investigate four different representations of word frequencies of viral sequences including the relative word frequency and three normalized word frequencies by subtracting the number of expected from the observed word counts. We also study five machine learning methods including logistic regression, support vector machine, random forest, Gaussian naive Bayes and Bernoulli naive Bayes for separating infectious from non-infectious viruses for nine bacterial host genera with at least 45 infecting viruses. Area under the receiver operating characteristic curve (AUC) is used to compare the performance of different machine learning method and feature combinations. We then evaluate the performance of the best method for the identification of the hosts of contigs in metagenomic studies. We also develop a maximum likelihood method to estimate the fraction of true infectious viruses for a given host in viral tagging experiments. RESULTS: Based on nine bacterial host genera with at least 45 infectious viruses, we show that random forest together with the relative word frequency vector performs the best in identifying viruses infecting particular hosts. For all the nine host genera, the AUC is over 0.85 and for five of them, the AUC is higher than 0.98 when the word size is 6 indicating the high accuracy of using machine learning approaches for identifying viruses infecting particular hosts. We also show that our method can predict the hosts of viral contigs of length at least 1kbps in metagenomic studies with high accuracy. The random forest together with word frequency vector outperforms current available methods based on Manhattan and [Formula: see text] dissimilarity measures. Based on word frequencies, we estimate that about 95% of the identified T4-like viruses in viral tagging experiment infect Synechococcus, while only about 29% of the identified non-T4-like viruses and 30% of the contigs in the study potentially infect Synechococcus. CONCLUSIONS: The random forest machine learning method together with the relative word frequencies as features of viruses can be used to predict viruses and viral contigs for specific bacterial hosts. The maximum likelihood approach can be used to estimate the fraction of true infectious associated viruses in viral tagging experiments. PMID- 28361671 TI - Using the entrapment sequence method as a standard to evaluate key steps of proteomics data analysis process. AB - BACKGROUND: The mass spectrometry based technical pipeline has provided a high throughput, high-sensitivity and high-resolution platform for post-genomic biology. Varied models and algorithms are implemented by different tools to improve proteomics data analysis. The target-decoy searching strategy has become the most popular strategy to control false identification in peptide and protein identifications. While this strategy can estimate the false discovery rate (FDR) within a dataset, it cannot directly evaluate the false positive matches in target identifications. RESULTS: As a supplement to target-decoy strategy, the entrapment sequence method was introduced to assess the key steps of mass spectrometry data analysis process, database search engines and quality control methods. Using the entrapment sequences as the standard, we evaluated five database search engines for both the origanal scores and reprocessed scores, as well as four quality control methods in term of quantity and quality aspects. Our results showed that the latest developed search engine MS-GF+ and percolator embeded quality control method PepDistiller performed best in all tools respectively. Combined with efficient quality control methods, the search engines can improve the low sensitivity of their original scores. Moreover, based on the entrapment sequence method, we proved that filtering the identifications separately could increase the number of identified peptides while improving the confidence level. CONCLUSION: In this study, we have proved that the entrapment sequence method could be an useful strategy to assess the key steps of the mass spectrometry data analysis process. Its applications can be extended to all steps of the common workflow, such as the protein assembling methods and data integration methods. PMID- 28361672 TI - Improving the accuracy of high-throughput protein-protein affinity prediction may require better training data. AB - BACKGROUND: One goal of structural biology is to understand how a protein's 3 dimensional conformation determines its capacity to interact with potential ligands. In the case of small chemical ligands, deconstructing a static protein ligand complex into its constituent atom-atom interactions is typically sufficient to rapidly predict ligand affinity with high accuracy (>70% correlation between predicted and experimentally-determined affinity), a fact that is exploited to support structure-based drug design. We recently found that protein-DNA/RNA affinity can also be predicted with high accuracy using extensions of existing techniques, but protein-protein affinity could not be predicted with >60% correlation, even when the protein-protein complex was available. METHODS: X-ray and NMR structures of protein-protein complexes, their associated binding affinities and experimental conditions were obtained from different binding affinity and structural databases. Statistical models were implemented using a generalized linear model framework, including the experimental conditions as new model features. We evaluated the potential for new features to improve affinity prediction models by calculating the Pearson correlation between predicted and experimental binding affinities on the training and test data after model fitting and after cross-validation. Differences in accuracy were assessed using two-sample t test and nonparametric Mann-Whitney U test. RESULTS: Here we evaluate a range of potential factors that may interfere with accurate protein-protein affinity prediction. We find that X-ray crystal resolution has the strongest single effect on protein-protein affinity prediction. Limiting our analyses to only high-resolution complexes (<=2.5 A) increased the correlation between predicted and experimental affinity from 54 to 68% (p = 4.32x10-3). In addition, incorporating information on the experimental conditions under which affinities were measured (pH, temperature and binding assay) had significant effects on prediction accuracy. We also highlight a number of potential errors in large structure-affinity databases, which could affect both model training and accuracy assessment. CONCLUSIONS: The results suggest that the accuracy of statistical models for protein-protein affinity prediction may be limited by the information present in databases used to train new models. Improving our capacity to integrate large-scale structural and functional information may be required to substantively advance our understanding of the general principles by which a protein's structure determines its function. PMID- 28361673 TI - AfterQC: automatic filtering, trimming, error removing and quality control for fastq data. AB - BACKGROUND: Some applications, especially those clinical applications requiring high accuracy of sequencing data, usually have to face the troubles caused by unavoidable sequencing errors. Several tools have been proposed to profile the sequencing quality, but few of them can quantify or correct the sequencing errors. This unmet requirement motivated us to develop AfterQC, a tool with functions to profile sequencing errors and correct most of them, plus highly automated quality control and data filtering features. Different from most tools, AfterQC analyses the overlapping of paired sequences for pair-end sequencing data. Based on overlapping analysis, AfterQC can detect and cut adapters, and furthermore it gives a novel function to correct wrong bases in the overlapping regions. Another new feature is to detect and visualise sequencing bubbles, which can be commonly found on the flowcell lanes and may raise sequencing errors. Besides normal per cycle quality and base content plotting, AfterQC also provides features like polyX (a long sub-sequence of a same base X) filtering, automatic trimming and K-MER based strand bias profiling. RESULTS: For each single or pair of FastQ files, AfterQC filters out bad reads, detects and eliminates sequencer's bubble effects, trims reads at front and tail, detects the sequencing errors and corrects part of them, and finally outputs clean data and generates HTML reports with interactive figures. AfterQC can run in batch mode with multiprocess support, it can run with a single FastQ file, a single pair of FastQ files (for pair-end sequencing), or a folder for all included FastQ files to be processed automatically. Based on overlapping analysis, AfterQC can estimate the sequencing error rate and profile the error transform distribution. The results of our error profiling tests show that the error distribution is highly platform dependent. CONCLUSION: Much more than just another new quality control (QC) tool, AfterQC is able to perform quality control, data filtering, error profiling and base correction automatically. Experimental results show that AfterQC can help to eliminate the sequencing errors for pair-end sequencing data to provide much cleaner outputs, and consequently help to reduce the false-positive variants, especially for the low-frequency somatic mutations. While providing rich configurable options, AfterQC can detect and set all the options automatically and require no argument in most cases. PMID- 28361674 TI - BATVI: Fast, sensitive and accurate detection of virus integrations. AB - BACKGROUND: The study of virus integrations in human genome is important since virus integrations were shown to be associated with diseases. In the literature, few methods have been proposed that predict virus integrations using next generation sequencing datasets. Although they work, they are slow and are not very sensitive. RESULTS AND DISCUSSION: This paper introduces a new method BatVI to predict viral integrations. Our method uses a fast screening method to filter out chimeric reads containing possible viral integrations. Next, sensitive alignments of these candidate chimeric reads are called by BLAST. Chimeric reads that are co-localized in the human genome are clustered. Finally, by assembling the chimeric reads in each cluster, high confident virus integration sites are extracted. CONCLUSION: We compared the performance of BatVI with existing methods VirusFinder and VirusSeq using both simulated and real-life datasets of liver cancer patients. BatVI ran an order of magnitude faster and was able to predict almost twice the number of true positives compared to other methods while maintaining a false positive rate less than 1%. For the liver cancer datasets, BatVI uncovered novel integrations to two important genes TERT and MLL4, which were missed by previous studies. Through gene expression data, we verified the correctness of these additional integrations. BatVI can be downloaded from http://biogpu.ddns.comp.nus.edu.sg/~ksung/batvi/index.html . PMID- 28361675 TI - A statistical method for the conservative adjustment of false discovery rate (q value). AB - BACKGROUND: q-value is a widely used statistical method for estimating false discovery rate (FDR), which is a conventional significance measure in the analysis of genome-wide expression data. q-value is a random variable and it may underestimate FDR in practice. An underestimated FDR can lead to unexpected false discoveries in the follow-up validation experiments. This issue has not been well addressed in literature, especially in the situation when the permutation procedure is necessary for p-value calculation. RESULTS: We proposed a statistical method for the conservative adjustment of q-value. In practice, it is usually necessary to calculate p-value by a permutation procedure. This was also considered in our adjustment method. We used simulation data as well as experimental microarray or sequencing data to illustrate the usefulness of our method. CONCLUSIONS: The conservativeness of our approach has been mathematically confirmed in this study. We have demonstrated the importance of conservative adjustment of q-value, particularly in the situation that the proportion of differentially expressed genes is small or the overall differential expression signal is weak. PMID- 28361676 TI - Selecting high-quality negative samples for effectively predicting protein-RNA interactions. AB - BACKGROUND: The identification of Protein-RNA Interactions (PRIs) is important to understanding cell activities. Recently, several machine learning-based methods have been developed for identifying PRIs. However, the performance of these methods is unsatisfactory. One major reason is that they usually use unreliable negative samples in the training process. METHODS: For boosting the performance of PRI prediction, we propose a novel method to generate reliable negative samples. Concretely, we firstly collect the known PRIs as positive samples for generating positive sets. For each positive set, we construct two corresponding negative sets, one is by our method and the other by random method. Each positive set is combined with a negative set to form a dataset for model training and performance evaluation. Consequently, we get 18 datasets of different species and different ratios of negative samples to positive samples. Secondly, sequence based features are extracted to represent each of PRIs and protein-RNA pairs in the datasets. A filter-based method is employed to cut down the dimensionality of feature vectors for reducing computational cost. Finally, the performance of support vector machine (SVM), random forest (RF) and naive Bayes (NB) is evaluated on the generated 18 datasets. RESULTS: Extensive experiments show that comparing to using randomly-generated negative samples, all classifiers achieve substantial performance improvement by using negative samples selected by our method. The improvements on accuracy and geometric mean for the SVM classifier, the RF classifier and the NB classifier are as high as 204.5 and 68.7%, 174.5 and 53.9%, 80.9 and 54.3%, respectively. CONCLUSION: Our method is useful to the identification of PRIs. PMID- 28361677 TI - Predicting protein-binding regions in RNA using nucleotide profiles and compositions. AB - BACKGROUND: Motivated by the increased amount of data on protein-RNA interactions and the availability of complete genome sequences of several organisms, many computational methods have been proposed to predict binding sites in protein-RNA interactions. However, most computational methods are limited to finding RNA binding sites in proteins instead of protein-binding sites in RNAs. Predicting protein-binding sites in RNA is more challenging than predicting RNA-binding sites in proteins. Recent computational methods for finding protein-binding sites in RNAs have several drawbacks for practical use. RESULTS: We developed a new support vector machine (SVM) model for predicting protein-binding regions in mRNA sequences. The model uses sequence profiles constructed from log-odds scores of mono- and di-nucleotides and nucleotide compositions. The model was evaluated by standard 10-fold cross validation, leave-one-protein-out (LOPO) cross validation and independent testing. Since actual mRNA sequences have more non-binding regions than protein-binding regions, we tested the model on several datasets with different ratios of protein-binding regions to non-binding regions. The best performance of the model was obtained in a balanced dataset of positive and negative instances. 10-fold cross validation with a balanced dataset achieved a sensitivity of 91.6%, a specificity of 92.4%, an accuracy of 92.0%, a positive predictive value (PPV) of 91.7%, a negative predictive value (NPV) of 92.3% and a Matthews correlation coefficient (MCC) of 0.840. LOPO cross validation showed a lower performance than the 10-fold cross validation, but the performance remains high (87.6% accuracy and 0.752 MCC). In testing the model on independent datasets, it achieved an accuracy of 82.2% and an MCC of 0.656. Testing of our model and other state-of-the-art methods on a same dataset showed that our model is better than the others. CONCLUSIONS: Sequence profiles of log-odds scores of mono- and di-nucleotides were much more powerful features than nucleotide compositions in finding protein-binding regions in RNA sequences. But, a slight performance gain was obtained when using the sequence profiles along with nucleotide compositions. These are preliminary results of ongoing research, but demonstrate the potential of our approach as a powerful predictor of protein binding regions in RNA. The program and supporting data are available at http://bclab.inha.ac.kr/RBPbinding . PMID- 28361678 TI - DIGNiFI: Discovering causative genes for orphan diseases using protein-protein interaction networks. AB - BACKGROUND: An orphan disease is any disease that affects a small percentage of the population. Orphan diseases are a great burden to patients and society, and most of them are genetic in origin. Unfortunately, our current understanding of the genes responsible for inherited orphan diseases is still quite limited. Developing effective computational algorithms to discover disease-causing genes would help unveil disease mechanisms and may enable better diagnosis and treatment. RESULTS: We have developed a novel method, named as DIGNiFI (Disease causIng GeNe FInder), which uses Protein-Protein Interaction (PPI) network-based features to discover and rank candidate disease-causing genes. Specifically, our approach computes topologically similar genes by taking into account both local and global connected paths in PPI networks via Direct Neighbors and Local Random Walks, respectively. Furthermore, since genes with similar phenotypes tend to be functionally related, we have integrated PPI data with gene ontology (GO) annotations and protein complex data to further improve the performance of this approach. Results of 128 orphan diseases with 1184 known disease genes collected from the Orphanet show that our proposed methods outperform existing state-of-the art methods for discovering candidate disease-causing genes. We also show that further performance improvement can be achieved when enriching the human-curated PPI network data with text-mined interactions from the biomedical literature. Finally, we demonstrate the utility of our approach by applying our method to identifying novel candidate genes for a set of four inherited retinal dystrophies. In this study, we found the top predictions for these retinal dystrophies consistent with literature reports and online databases of other retinal dystrophies. CONCLUSIONS: Our method successfully prioritizes orphan disease-causative genes. This method has great potential to benefit the field of orphan disease research, where resources are scarce and greatly needed. PMID- 28361679 TI - Stochastic modeling and simulation of reaction-diffusion system with Hill function dynamics. AB - BACKGROUND: Stochastic simulation of reaction-diffusion systems presents great challenges for spatiotemporal biological modeling and simulation. One widely used framework for stochastic simulation of reaction-diffusion systems is reaction diffusion master equation (RDME). Previous studies have discovered that for the RDME, when discretization size approaches zero, reaction time for bimolecular reactions in high dimensional domains tends to infinity. RESULTS: In this paper, we demonstrate that in the 1D domain, highly nonlinear reaction dynamics given by Hill function may also have dramatic change when discretization size is smaller than a critical value. Moreover, we discuss methods to avoid this problem: smoothing over space, fixed length smoothing over space and a hybrid method. CONCLUSION: Our analysis reveals that the switch-like Hill dynamics reduces to a linear function of discretization size when the discretization size is small enough. The three proposed methods could correctly (under certain precision) simulate Hill function dynamics in the microscopic RDME system. PMID- 28361680 TI - Inferring microbial interaction networks from metagenomic data using SgLV-EKF algorithm. AB - BACKGROUND: Inferring the microbial interaction networks (MINs) and modeling their dynamics are critical in understanding the mechanisms of the bacterial ecosystem and designing antibiotic and/or probiotic therapies. Recently, several approaches were proposed to infer MINs using the generalized Lotka-Volterra (gLV) model. Main drawbacks of these models include the fact that these models only consider the measurement noise without taking into consideration the uncertainties in the underlying dynamics. Furthermore, inferring the MIN is characterized by the limited number of observations and nonlinearity in the regulatory mechanisms. Therefore, novel estimation techniques are needed to address these challenges. RESULTS: This work proposes SgLV-EKF: a stochastic gLV model that adopts the extended Kalman filter (EKF) algorithm to model the MIN dynamics. In particular, SgLV-EKF employs a stochastic modeling of the MIN by adding a noise term to the dynamical model to compensate for modeling uncertainties. This stochastic modeling is more realistic than the conventional gLV model which assumes that the MIN dynamics are perfectly governed by the gLV equations. After specifying the stochastic model structure, we propose the EKF to estimate the MIN. SgLV-EKF was compared with two similarity-based algorithms, one algorithm from the integral-based family and two regression-based algorithms, in terms of the achieved performance on two synthetic data-sets and two real data sets. The first data-set models the randomness in measurement data, whereas, the second data-set incorporates uncertainties in the underlying dynamics. The real data-sets are provided by a recent study pertaining to an antibiotic-mediated Clostridium difficile infection. The experimental results demonstrate that SgLV EKF outperforms the alternative methods in terms of robustness to measurement noise, modeling errors, and tracking the dynamics of the MIN. CONCLUSIONS: Performance analysis demonstrates that the proposed SgLV-EKF algorithm represents a powerful and reliable tool to infer MINs and track their dynamics. PMID- 28361681 TI - An integrated approach with new strategies for QSAR models and lead optimization. AB - BACKGROUND: Computational drug design approaches are important for shortening the time and reducing the cost for drug discovery and development. Among these methods, molecular docking and quantitative structure activity relationship (QSAR) play key roles for lead discovery and optimization. Here, we propose an integrated approach with core strategies to identify the protein-ligand hot spots for QSAR models and lead optimization. These core strategies are: 1) to generate both residue-based and atom-based interactions as the features; 2) to identify compound common and specific skeletons; and 3) to infer consensus features for QSAR models. RESULTS: We evaluated our methods and new strategies on building QSAR models of human acetylcholinesterase (huAChE). The leave-one-out cross validation values q 2 and r 2 of our huAChE QSAR model are 0.82 and 0.78, respectively. The experimental results show that the selected features (resides/atoms) are important for enzymatic functions and stabling the protein structure by forming key interactions (e.g., stack forces and hydrogen bonds) between huAChE and its inhibitors. Finally, we applied our methods to arthrobacter globiformis histamine oxidase (AGHO) which is correlated to heart failure and diabetic. CONCLUSIONS: Based on our AGHO QSAR model, we identified a new substrate verified by bioassay experiments for AGHO. These results show that our methods and new strategies can yield stable and high accuracy QSAR models. We believe that our methods and strategies are useful for discovering new leads and guiding lead optimization in drug discovery. PMID- 28361682 TI - Identifying miRNA sponge modules using biclustering and regulatory scores. AB - BACKGROUND: MicroRNA (miRNA) sponges with multiple tandem miRNA binding sequences can sequester miRNAs from their endogenous target mRNAs. Therefore, miRNA sponge acting as a decoy is extremely important for long-term loss-of-function studies both in vivo and in silico. Recently, a growing number of in silico methods have been used as an effective technique to generate hypotheses for in vivo methods for studying the biological functions and regulatory mechanisms of miRNA sponges. However, most existing in silico methods only focus on studying miRNA sponge interactions or networks in cancer, the module-level properties of miRNA sponges in cancer is still largely unknown. RESULTS: We propose a novel in silico method, called miRSM (miRNA Sponge Module) to infer miRNA sponge modules in breast cancer. We apply miRSM to the breast invasive carcinoma (BRCA) dataset provided by The Cancer Genome Altas (TCGA), and make functional validation of the computational results. We discover that most miRNA sponge interactions are module conserved across two modules, and a minority of miRNA sponge interactions are module-specific, existing only in a single module. Through functional annotation and differential expression analysis, we also find that the modules discovered using miRSM are functional miRNA sponge modules associated with BRCA. Moreover, the module-specific miRNA sponge interactions among miRNA sponge modules may be involved in the progression and development of BRCA. Our experimental results show that miRSM is comparable to the benchmark methods in recovering experimentally confirmed miRNA sponge interactions, and miRSM outperforms the benchmark methods in identifying interactions that are related to breast cancer. CONCLUSIONS: Altogether, the functional validation results demonstrate that miRSM is a promising method to identify miRNA sponge modules and interactions, and may provide new insights for understanding the roles of miRNA sponges in cancer progression and development. PMID- 28361684 TI - NEArender: an R package for functional interpretation of 'omics' data via network enrichment analysis. AB - BACKGROUND: The statistical evaluation of pathway enrichment, i.e. of gene profiles' confluence to the pathway level, allows exploring molecular landscapes using functionally annotated gene sets. However, pathway scores can also be used as predictive features in machine learning. That requires, firstly, increasing statistical power and biological relevance via a network enrichment analysis (NEA) and, secondly, a fast and convenient procedure for rendering the original data into a space of pathway scores. However, previous implementations of NEA involved multiple runs of network randomization and were therefore slow. RESULTS: Here, we present a new R package NEArender which can transform raw 'omics' features of experimental or clinical samples into matrices describing the same samples with many fewer NEA-based pathway scores. This is done via a parametric estimation of the null binomial distribution and is thus much faster and less biased than randomization procedures. Further, we compare estimates from these two alternative procedures and demonstrate that the summarization of individual genes to pathways increases the statistical power compared to both the default differential expression analysis on individual genes and the state-of-the-art gene set enrichment analysis. The package also contains functions for preparing input, modeling null distributions, and evaluating alternative versions of the global network. CONCLUSIONS: Beyond the state-of-the-art exploration of molecular data through pathway enrichment, score matrices produced by NEArender can be used in larger bioinformatics pipelines as input for phenotype modeling, predicting disease outcomes etc. This approach is often more sensitive and robust than using the original data. The package NEArender is complementary to the online NEA tool EviNet ( https://www.evinet.org ) and, unlike of the latter, enables high performance of computations off-line. The R package NEArender version 1.4 is available at CRAN repository https://cran.r-project.org/web/packages/NEArender/. PMID- 28361683 TI - Comparative network stratification analysis for identifying functional interpretable network biomarkers. AB - BACKGROUND: A major challenge of bioinformatics in the era of precision medicine is to identify the molecular biomarkers for complex diseases. It is a general expectation that these biomarkers or signatures have not only strong discrimination ability, but also readable interpretations in a biological sense. Generally, the conventional expression-based or network-based methods mainly capture differential genes or differential networks as biomarkers, however, such biomarkers only focus on phenotypic discrimination and usually have less biological or functional interpretation. Meanwhile, the conventional function based methods could consider the biomarkers corresponding to certain biological functions or pathways, but ignore the differential information of genes, i.e., disregard the active degree of particular genes involved in particular functions, thereby resulting in less discriminative ability on phenotypes. Hence, it is strongly demanded to develop elaborate computational methods to directly identify functional network biomarkers with both discriminative power on disease states and readable interpretation on biological functions. RESULTS: In this paper, we present a new computational framework based on an integer programming model, named as Comparative Network Stratification (CNS), to extract functional or interpretable network biomarkers, which are of strongly discriminative power on disease states and also readable interpretation on biological functions. In addition, CNS can not only recognize the pathogen biological functions disregarded by traditional Expression-based/Network-based methods, but also uncover the active network-structures underlying such dysregulated functions underestimated by traditional Function-based methods. To validate the effectiveness, we have compared CNS with five state-of-the-art methods, i.e. GSVA, Pathifier, stSVM, frSVM and AEP on four datasets of different complex diseases. The results show that CNS can enhance the discriminative power of network biomarkers, and further provide biologically interpretable information or disease pathogenic mechanism of these biomarkers. A case study on type 1 diabetes (T1D) demonstrates that CNS can identify many dysfunctional genes and networks previously disregarded by conventional approaches. CONCLUSION: Therefore, CNS is actually a powerful bioinformatics tool, which can identify functional or interpretable network biomarkers with both discriminative power on disease states and readable interpretation on biological functions. CNS was implemented as a Matlab package, which is available at http://www.sysbio.ac.cn/cb/chenlab/images/CNSpackage_0.1.rar . PMID- 28361685 TI - Sparse feature selection for classification and prediction of metastasis in endometrial cancer. AB - BACKGROUND: Metastasis via pelvic and/or para-aortic lymph nodes is a major risk factor for endometrial cancer. Lymph-node resection ameliorates risk but is associated with significant co-morbidities. Incidence in patients with stage I disease is 4-22% but no mechanism exists to accurately predict it. Therefore, national guidelines for primary staging surgery include pelvic and para-aortic lymph node dissection for all patients whose tumor exceeds 2cm in diameter. We sought to identify a robust molecular signature that can accurately classify risk of lymph node metastasis in endometrial cancer patients. 86 tumors matched for age and race, and evenly distributed between lymph node-positive and lymph node negative cases, were selected as a training cohort. Genomic micro-RNA expression was profiled for each sample to serve as the predictive feature matrix. An independent set of 28 tumor samples was collected and similarly characterized to serve as a test cohort. RESULTS: A feature selection algorithm was designed for applications where the number of samples is far smaller than the number of measured features per sample. A predictive miRNA expression signature was developed using this algorithm, which was then used to predict the metastatic status of the independent test cohort. A weighted classifier, using 18 micro RNAs, achieved 100% accuracy on the training cohort. When applied to the testing cohort, the classifier correctly predicted 90% of node-positive cases, and 80% of node-negative cases (FDR = 6.25%). CONCLUSION: Results indicate that the evaluation of the quantitative sparse-feature classifier proposed here in clinical trials may lead to significant improvement in the prediction of lymphatic metastases in endometrial cancer patients. PMID- 28361686 TI - DTL reconciliation repair. AB - BACKGROUND: Maximum parsimony phylogenetic tree reconciliation is an important technique for reconstructing the evolutionary histories of hosts and parasites, genes and species, and other interdependent pairs. Since the problem of finding temporally feasible maximum parsimony reconciliations is NP-complete, current methods use either exact algorithms with exponential worst-case running time or heuristics that do not guarantee optimal solutions. RESULTS: We offer an efficient new approach that begins with a potentially infeasible maximum parsimony reconciliation and iteratively "repairs" it until it becomes temporally feasible. CONCLUSIONS: In a non-trivial number of cases, this approach finds solutions that are better than those found by the widely-used Jane heuristic. PMID- 28361688 TI - Pysim-sv: a package for simulating structural variation data with GC-biases. AB - BACKGROUND: Structural variations (SVs) are wide-spread in human genomes and may have important implications in disease-related and evolutionary studies. High throughput sequencing (HTS) has become a major platform for SV detection and simulation serves as a powerful and cost-effective approach for benchmarking SV detection algorithms. Accurate performance assessment by simulation requires the simulator capable of generating simulation data with all important features of real data, such GC biases in HTS data and various complexities in tumor data. However, no available package has systematically addressed all issues in data simulation for SV benchmarking. RESULTS: Pysim-sv is a package for simulating HTS data to evaluate performance of SV detection algorithms. Pysim-sv can introduce a wide spectrum of germline and somatic genomic variations. The package contains functionalities to simulate tumor data with aneuploidy and heterogeneous subclones, which is very useful in assessing algorithm performance in tumor studies. Furthermore, Pysim-sv can introduce GC-bias, the most important and prevalent bias in HTS data, in the simulated HTS data. CONCLUSIONS: Pysim-sv provides an unbiased toolkit for evaluating HTS-based SV detection algorithms. PMID- 28361687 TI - PINTnet: construction of condition-specific pathway interaction network by computing shortest paths on weighted PPI. AB - BACKGROUND: Identifying perturbed pathways in a given condition is crucial in understanding biological phenomena. In addition to identifying perturbed pathways individually, pathway analysis should consider interactions among pathways. Currently available pathway interaction prediction methods are based on the existence of overlapping genes between pathways, protein-protein interaction (PPI) or functional similarities. However, these approaches just consider the pathways as a set of genes, thus they do not take account of topological features. In addition, most of the existing approaches do not handle the explicit gene expression quantity information that is routinely measured by RNA-sequecing. RESULTS: To overcome these technical issues, we developed a new pathway interaction network construction method using PPI, closeness centrality and shortest paths. We tested our approach on three different high-throughput RNA-seq data sets: pregnant mice data to reveal the role of serotonin on beta cell mass, bone-metastatic breast cancer data and autoimmune thyroiditis data to study the role of IFN- alpha. Our approach successfully identified the pathways reported in the original papers. For the pathways that are not directly mentioned in the original papers, we were able to find evidences of pathway interactions by the literature search. Our method outperformed two existing approaches, overlapping gene-based approach (OGB) and protein-protein interaction-based approach (PB), in experiments with the three data sets. CONCLUSION: Our results show that PINTnet successfully identified condition-specific perturbed pathways and the interactions between the pathways. We believe that our method will be very useful in characterizing biological mechanisms at the pathway level. PINTnet is available at http://biohealth.snu.ac.kr/software/PINTnet/ . PMID- 28361689 TI - AVC: Selecting discriminative features on basis of AUC by maximizing variable complementarity. AB - BACKGROUND: The Receiver Operator Characteristic (ROC) curve is well-known in evaluating classification performance in biomedical field. Owing to its superiority in dealing with imbalanced and cost-sensitive data, the ROC curve has been exploited as a popular metric to evaluate and find out disease-related genes (features). The existing ROC-based feature selection approaches are simple and effective in evaluating individual features. However, these approaches may fail to find real target feature subset due to their lack of effective means to reduce the redundancy between features, which is essential in machine learning. RESULTS: In this paper, we propose to assess feature complementarity by a trick of measuring the distances between the misclassified instances and their nearest misses on the dimensions of pairwise features. If a misclassified instance and its nearest miss on one feature dimension are far apart on another feature dimension, the two features are regarded as complementary to each other. Subsequently, we propose a novel filter feature selection approach on the basis of the ROC analysis. The new approach employs an efficient heuristic search strategy to select optimal features with highest complementarities. The experimental results on a broad range of microarray data sets validate that the classifiers built on the feature subset selected by our approach can get the minimal balanced error rate with a small amount of significant features. CONCLUSIONS: Compared with other ROC-based feature selection approaches, our new approach can select fewer features and effectively improve the classification performance. PMID- 28361690 TI - Revealing common disease mechanisms shared by tumors of different tissues of origin through semantic representation of genomic alterations and topic modeling. AB - BACKGROUND: Cancer is a complex disease driven by somatic genomic alterations (SGAs) that perturb signaling pathways and consequently cellular function. Identifying patterns of pathway perturbations would provide insights into common disease mechanisms shared among tumors, which is important for guiding treatment and predicting outcome. However, identifying perturbed pathways is challenging, because different tumors can have the same perturbed pathways that are perturbed by different SGAs. Here, we designed novel semantic representations that capture the functional similarity of distinct SGAs perturbing a common pathway in different tumors. Combining this representation with topic modeling would allow us to identify patterns in altered signaling pathways. RESULTS: We represented each gene with a vector of words describing its function, and we represented the SGAs of a tumor as a text document by pooling the words representing individual SGAs. We applied the nested hierarchical Dirichlet process (nHDP) model to a collection of tumors of 5 cancer types from TCGA. We identified topics (consisting of co-occurring words) representing the common functional themes of different SGAs. Tumors were clustered based on their topic associations, such that each cluster consists of tumors sharing common functional themes. The resulting clusters contained mixtures of cancer types, which indicates that different cancer types can share disease mechanisms. Survival analysis based on the clusters revealed significant differences in survival among the tumors of the same cancer type that were assigned to different clusters. CONCLUSIONS: The results indicate that applying topic modeling to semantic representations of tumors identifies patterns in the combinations of altered functional pathways in cancer. PMID- 28361691 TI - Improving prediction of burial state of residues by exploiting correlation among residues. AB - BACKGROUND: Residues in a protein might be buried inside or exposed to the solvent surrounding the protein. The buried residues usually form hydrophobic cores to maintain the structural integrity of proteins while the exposed residues are tightly related to protein functions. Thus, the accurate prediction of solvent accessibility of residues will greatly facilitate our understanding of both structure and functionalities of proteins. Most of the state-of-the-art prediction approaches consider the burial state of each residue independently, thus neglecting the correlations among residues. RESULTS: In this study, we present a high-order conditional random field model that considers burial states of all residues in a protein simultaneously. Our approach exploits not only the correlation among adjacent residues but also the correlation among long-range residues. Experimental results showed that by exploiting the correlation among residues, our approach outperformed the state-of-the-art approaches in prediction accuracy. In-depth case studies also showed that by using the high-order statistical model, the errors committed by the bidirectional recurrent neural network and chain conditional random field models were successfully corrected. CONCLUSIONS: Our methods enable the accurate prediction of residue burial states, which should greatly facilitate protein structure prediction and evaluation. PMID- 28361692 TI - Active module identification in intracellular networks using a memetic algorithm with a new binary decoding scheme. AB - BACKGROUND: Active modules are connected regions in biological network which show significant changes in expression over particular conditions. The identification of such modules is important since it may reveal the regulatory and signaling mechanisms that associate with a given cellular response. RESULTS: In this paper, we propose a novel active module identification algorithm based on a memetic algorithm. We propose a novel encoding/decoding scheme to ensure the connectedness of the identified active modules. Based on the scheme, we also design and incorporate a local search operator into the memetic algorithm to improve its performance. CONCLUSION: The effectiveness of proposed algorithm is validated on both small and large protein interaction networks. PMID- 28361693 TI - Protein complex-based analysis is resistant to the obfuscating consequences of batch effects --- a case study in clinical proteomics. AB - BACKGROUND: In proteomics, batch effects are technical sources of variation that confounds proper analysis, preventing effective deployment in clinical and translational research. RESULTS: Using simulated and real data, we demonstrate existing batch effect-correction methods do not always eradicate all batch effects. Worse still, they may alter data integrity, and introduce false positives. Moreover, although Principal component analysis (PCA) is commonly used for detecting batch effects. The principal components (PCs) themselves may be used as differential features, from which relevant differential proteins may be effectively traced. Batch effect are removable by identifying PCs highly correlated with batch but not class effect. However, neither PC-based nor existing batch effect-correction methods address well subtle batch effects, which are difficult to eradicate, and involve data transformation and/or projection which is error-prone. To address this, we introduce the concept of batch-effect resistant methods and demonstrate how such methods incorporating protein complexes are particularly resistant to batch effect without compromising data integrity. CONCLUSIONS: Protein complex-based analyses are powerful, offering unparalleled differential protein-selection reproducibility and high prediction accuracy. We demonstrate for the first time their innate resistance against batch effects, even subtle ones. As complex-based analyses require no prior data transformation (e.g. batch-effect correction), data integrity is protected. Individual checks on top-ranked protein complexes confirm strong association with phenotype classes and not batch. Therefore, the constituent proteins of these complexes are more likely to be clinically relevant. PMID- 28361694 TI - An empirical fuzzy multifactor dimensionality reduction method for detecting gene gene interactions. AB - BACKGROUND: Detection of gene-gene interaction (GGI) is a key challenge towards solving the problem of missing heritability in genetics. The multifactor dimensionality reduction (MDR) method has been widely studied for detecting GGIs. MDR reduces the dimensionality of multi-factor by means of binary classification into high-risk (H) or low-risk (L) groups. Unfortunately, this simple binary classification does not reflect the uncertainty of H/L classification. Thus, we proposed Fuzzy MDR to overcome limitations of binary classification by introducing the degree of membership of two fuzzy sets H/L. While Fuzzy MDR demonstrated higher power than that of MDR, its performance is highly dependent on the several tuning parameters. In real applications, it is not easy to choose appropriate tuning parameter values. RESULT: In this work, we propose an empirical fuzzy MDR (EF-MDR) which does not require specifying tuning parameters values. Here, we propose an empirical approach to estimating the membership degree that can be directly estimated from the data. In EF-MDR, the membership degree is estimated by the maximum likelihood estimator of the proportion of cases(controls) in each genotype combination. We also show that the balanced accuracy measure derived from this new membership function is a linear function of the standard chi-square statistics. This relationship allows us to perform the standard significance test using p-values in the MDR framework without permutation. Through two simulation studies, the power of the proposed EF-MDR is shown to be higher than those of MDR and Fuzzy MDR. We illustrate the proposed EF MDR by analyzing Crohn's disease (CD) and bipolar disorder (BD) in the Wellcome Trust Case Control Consortium (WTCCC) dataset. CONCLUSION: We propose an empirical Fuzzy MDR for detecting GGI using the maximum likelihood of the proportion of cases(controls) as the membership degree of the genotype combination. The program written in R for EF-MDR is available at http://statgen.snu.ac.kr/software/EF-MDR . PMID- 28361695 TI - SILVA, RDP, Greengenes, NCBI and OTT - how do these taxonomies compare? AB - BACKGROUND: A key step in microbiome sequencing analysis is read assignment to taxonomic units. This is often performed using one of four taxonomic classifications, namely SILVA, RDP, Greengenes or NCBI. It is unclear how similar these are and how to compare analysis results that are based on different taxonomies. RESULTS: We provide a method and software for mapping taxonomic entities from one taxonomy onto another. We use it to compare the four taxonomies and the Open Tree of life Taxonomy (OTT). CONCLUSIONS: While we find that SILVA, RDP and Greengenes map well into NCBI, and all four map well into the OTT, mapping the two larger taxonomies on to the smaller ones is problematic. PMID- 28361697 TI - Selected research articles from the 2016 International Workshop on Computational Network Biology: Modeling, Analysis, and Control (CNB-MAC). PMID- 28361696 TI - P-Hint-Hunt: a deep parallelized whole genome DNA methylation detection tool. AB - BACKGROUND: The increasing studies have been conducted using whole genome DNA methylation detection as one of the most important part of epigenetics research to find the significant relationships among DNA methylation and several typical diseases, such as cancers and diabetes. In many of those studies, mapping the bisulfite treated sequence to the whole genome has been the main method to study DNA cytosine methylation. However, today's relative tools almost suffer from inaccuracies and time-consuming problems. RESULTS: In our study, we designed a new DNA methylation prediction tool ("Hint-Hunt") to solve the problem. By having an optimal complex alignment computation and Smith-Waterman matrix dynamic programming, Hint-Hunt could analyze and predict the DNA methylation status. But when Hint-Hunt tried to predict DNA methylation status with large-scale dataset, there are still slow speed and low temporal-spatial efficiency problems. In order to solve the problems of Smith-Waterman dynamic programming and low temporal spatial efficiency, we further design a deep parallelized whole genome DNA methylation detection tool ("P-Hint-Hunt") on Tianhe-2 (TH-2) supercomputer. CONCLUSIONS: To the best of our knowledge, P-Hint-Hunt is the first parallel DNA methylation detection tool with a high speed-up to process large-scale dataset, and could run both on CPU and Intel Xeon Phi coprocessors. Moreover, we deploy and evaluate Hint-Hunt and P-Hint-Hunt on TH-2 supercomputer in different scales. The experimental results illuminate our tools eliminate the deviation caused by bisulfite treatment in mapping procedure and the multi-level parallel program yields a 48 times speed-up with 64 threads. P-Hint-Hunt gain a deep acceleration on CPU and Intel Xeon Phi heterogeneous platform, which gives full play of the advantages of multi-cores (CPU) and many-cores (Phi). PMID- 28361698 TI - A clustering-based approach for efficient identification of microRNA combinatorial biomarkers. AB - BACKGROUND: MicroRNAs (miRNAs) have great potential serving as tumor biomarkers and therapeutic targets. As the rapid development of high-throughput experimental technology, gene expression experiments have become more and more specialized and diversified. The complex data structure has brought great challenge for the identification of biomarkers. In the meantime, current statistical and machine learning methods for detecting biomarkers have the problem of low reliability and biased criteria. RESULTS: This study aims to select combinatorial miRNA biomarkers, which have higher sensitivity and specificity than single-gene biomarkers. In order to avoid exhaustive search and redundant information, miRNAs are firstly clustered, then the combinations of representative cluster members are assessed as potential biomarkers. Both the criteria for the partition of clusters and selection of representative members are based on Fisher linear discriminant analysis (FDA). The FDA-based criterion has been demonstrated to be superior to three other criteria in selecting representative members, and also good at refining clusters. In the comparison with eight common feature selection methods, this clustering-based method performs the best with regard to the discriminative ability of selected biomarkers. CONCLUSIONS: Our experimental results demonstrate that the clustering-based method can identify microRNA combinatorial biomarkers with high accuracy and efficiency. Our method and data are available to the public upon request. PMID- 28361699 TI - Prior knowledge guided active modules identification: an integrated multi objective approach. AB - BACKGROUND: Active module, defined as an area in biological network that shows striking changes in molecular activity or phenotypic signatures, is important to reveal dynamic and process-specific information that is correlated with cellular or disease states. METHODS: A prior information guided active module identification approach is proposed to detect modules that are both active and enriched by prior knowledge. We formulate the active module identification problem as a multi-objective optimisation problem, which consists two conflicting objective functions of maximising the coverage of known biological pathways and the activity of the active module simultaneously. Network is constructed from protein-protein interaction database. A beta-uniform-mixture model is used to estimate the distribution of p-values and generate scores for activity measurement from microarray data. A multi-objective evolutionary algorithm is used to search for Pareto optimal solutions. We also incorporate a novel constraints based on algebraic connectivity to ensure the connectedness of the identified active modules. RESULTS: Application of proposed algorithm on a small yeast molecular network shows that it can identify modules with high activities and with more cross-talk nodes between related functional groups. The Pareto solutions generated by the algorithm provides solutions with different trade-off between prior knowledge and novel information from data. The approach is then applied on microarray data from diclofenac-treated yeast cells to build network and identify modules to elucidate the molecular mechanisms of diclofenac toxicity and resistance. Gene ontology analysis is applied to the identified modules for biological interpretation. CONCLUSIONS: Integrating knowledge of functional groups into the identification of active module is an effective method and provides a flexible control of balance between pure data-driven method and prior information guidance. PMID- 28361700 TI - Plant miRNAs found in human circulating system provide evidences of cross kingdom RNAi. AB - BACKGROUND: Emerging evidence indicates that plant miRNAs can present within human circulating system through dietary intake and regulate human gene expression. Hence we deduced that comestible plants miRNAs can be identified in the public available small RNA sequencing data sets. RESULTS: In this study, we identified abundant plant miRNAs sequences from 410 human plasma small RNA sequencing data sets. One particular plant miRNA miR2910, conserved in fruits and vegetables, was found to present in high relative amount in the plasma samples. This miRNA, with same 6mer and 7mer-A1 target seed sequences as hsa-miR-4259 and hsa-miR-4715-5p, was predicted to target human JAK-STAT signaling pathway gene SPRY4 and transcription regulation genes. CONCLUSIONS: Through analysis of public available plasma small RNA sequencing data, we found the supporting evidence for the plant miRNAs cross kingdom RNAi within human circulating system. PMID- 28361701 TI - In silico prediction of lncRNA function using tissue specific and evolutionary conserved expression. AB - BACKGROUND: In recent years long non coding RNAs (lncRNAs) have been the subject of increasing interest. Thanks to many recent functional studies, the existence of a large class of lncRNAs with potential regulatory functions is now widely accepted. Although an increasing number of lncRNAs is being characterized and shown to be involved in many biological processes, the functions of the vast majority lncRNA genes is still unknown. Therefore computational methods able to take advantage of the increasing amount of publicly available data to predict lncRNA functions could be very useful. RESULTS: Since coding genes are much better annotated than lncRNAs, we attempted to project known functional information regarding proteins onto non coding genes using the guilt by association principle: if a gene shows an expression profile that correlates with those of a set of coding genes involved in a given function, that gene is probably involved in the same function. We computed gene coexpression for 30 human tissues and 9 vertebrates and mined the resulting networks with a methodology inspired by the rank product algorithm used to identify differentially expressed genes. Using different types of reference data we can predict putative new annotations for thousands of lncRNAs and proteins, ranging from cellular localization to relevance for disease and cancer. CONCLUSIONS: New function of coding genes and lncRNA can be profitably predicted using tissue specific coexpression, as well as expression of orthologous genes in different species. The data are available for download and through a user-friendly web interface at www.funcpred.com . PMID- 28361702 TI - A sequence-based method to predict the impact of regulatory variants using random forest. AB - BACKGROUND: Most disease-associated variants identified by genome-wide association studies (GWAS) exist in noncoding regions. In spite of the common agreement that such variants may disrupt biological functions of their hosting regulatory elements, it remains a great challenge to characterize the risk of a genetic variant within the implicated genome sequence. Therefore, it is essential to develop an effective computational model that is not only capable of predicting the potential risk of a genetic variant but also valid in interpreting how the function of the genome is affected with the occurrence of the variant. RESULTS: We developed a method named kmerForest that used a random forest classifier with k-mer counts to predict accessible chromatin regions purely based on DNA sequences. We demonstrated that our method outperforms existing methods in distinguishing known accessible chromatin regions from random genomic sequences. Furthermore, the performance of our method can further be improved with the incorporation of sequence conservation features. Based on this model, we assessed importance of the k-mer features by a series of permutation experiments, and we characterized the risk of a single nucleotide polymorphism (SNP) on the function of the genome using the difference between the importance of the k-mer features affected by the occurrence of the SNP. We conducted a series of experiments and showed that our model can well discriminate between pathogenic and normal SNPs. Particularly, our model correctly prioritized SNPs that are proved to be enriched for the binding sites of FOXA1 in breast cancer cell lines from previous studies. CONCLUSIONS: We presented a novel method to interpret functional genetic variants purely base on DNA sequences. The proposed k-mer based score offers an effective means of measuring the impact of SNPs on the function of the genome, and thus shedding light on the identification of genetic risk factors underlying complex traits and diseases. PMID- 28361703 TI - Mathematical modelling for variations of inbreeding populations fitness with single and polygenic traits. AB - BACKGROUND: Inbreeding mating has been widely accepted as the key mechanism to enhance homozygosity which normally will decrease the fitness of the population. Although this result has been validated by a large amount of biological data from the natural populations, a mathematical proof of these experimental discoveries is still not complete. A related question is whether we can extend the well established result regarding the mean fitness from a randomly mating population to inbreeding populations. A confirmative answer may provide insights into the frequent occurrence of self-fertilization populations. RESULTS: This work presents a theoretic proof of the result that, for a large inbreeding population with directional relative genotype fitness, the mean fitness of population increases monotonically. However, it cannot be extended to the case with over dominant genotype fitness. In addition, by employing multiplicative intersection hypothesis, we prove that inbreeding mating does decrease the mean fitness of polygenic population in general, but does not decrease the mean fitness with mixed dominant-recessive genotypes. We also prove a novel result that inbreeding depression depends on not only the mating pattern but also genetic structure of population. CONCLUSIONS: For natural inbreeding populations without serious inbreeding depression, our theoretical analysis suggests the majority of its genotypes should be additive or dominant-recessive genotypes. This result gives a reason to explain why many hermaphroditism populations do not show severe inbreeding depression. In addition, the calculated purging rate shows that inbreeding mating purges the deleterious mutants more efficiently than randomly mating does. PMID- 28361704 TI - Comparison of tissue/disease specific integrated networks using directed graphlet signatures. AB - BACKGROUND: Analysis of integrated genome-scale networks is a challenging problem due to heterogeneity of high-throughput data. There are several topological measures, such as graphlet counts, for characterization of biological networks. RESULTS: In this paper, we present methods for counting small sub-graph patterns in integrated genome-scale networks which are modeled as labeled multidigraphs. We have obtained physical, regulatory, and metabolic interactions between H. sapiens proteins from the Pathway Commons database. The integrated network is filtered for tissue/disease specific proteins by using a large-scale human transcriptional profiling study, resulting in several tissue and disease specific sub-networks. We have applied and extended the idea of graphlet counting in undirected protein-protein interaction (PPI) networks to directed multi-labeled networks and represented each network as a vector of graphlet counts. Graphlet counts are assessed for statistical significance by comparison against a set of randomized networks. We present our results on analysis of differential graphlets between different conditions and on the utility of graphlet count vectors for clustering multiple condition specific networks. CONCLUSIONS: Our results show that there are numerous statistically significant graphlets in integrated biological networks and the graphlet signature vector can be used as an effective representation of a multi-labeled network for clustering and systems level analysis of tissue/disease specific networks. PMID- 28361705 TI - SNP by SNP by environment interaction network of alcoholism. AB - BACKGROUND: Alcoholism has a strong genetic component. Twin studies have demonstrated the heritability of a large proportion of phenotypic variance of alcoholism ranging from 50-80%. The search for genetic variants associated with this complex behavior has epitomized sequence-based studies for nearly a decade. The limited success of genome-wide association studies (GWAS), possibly precipitated by the polygenic nature of complex traits and behaviors, however, has demonstrated the need for novel, multivariate models capable of quantitatively capturing interactions between a host of genetic variants and their association with non-genetic factors. In this regard, capturing the network of SNP by SNP or SNP by environment interactions has recently gained much interest. RESULTS: Here, we assessed 3,776 individuals to construct a network capable of detecting and quantifying the interactions within and between plausible genetic and environmental factors of alcoholism. In this regard, we propose the use of first-order dependence tree of maximum weight as a potential statistical learning technique to delineate the pattern of dependencies underpinning such a complex trait. Using a predictive based analysis, we further rank the genes, demographic factors, biological pathways, and the interactions represented by our SNP [Formula: see text]SNP[Formula: see text]E network. The proposed framework is quite general and can be potentially applied to the study of other complex traits. PMID- 28361706 TI - Comprehensive evaluation of RNA-seq quantification methods for linearity. AB - BACKGROUND: Deconvolution is a mathematical process of resolving an observed function into its constituent elements. In the field of biomedical research, deconvolution analysis is applied to obtain single cell-type or tissue specific signatures from a mixed signal and most of them follow the linearity assumption. Although recent development of next generation sequencing technology suggests RNA seq as a fast and accurate method for obtaining transcriptomic profiles, few studies have been conducted to investigate best RNA-seq quantification methods that yield the optimum linear space for deconvolution analysis. RESULTS: Using a benchmark RNA-seq dataset, we investigated the linearity of abundance estimated from seven most popular RNA-seq quantification methods both at the gene and isoform levels. Linearity is evaluated through parameter estimation, concordance analysis and residual analysis based on a multiple linear regression model. Results show that count data gives poor parameter estimations, large intercepts and high inter-sample variability; while TPM value from Kallisto and Salmon shows high linearity in all analyses. CONCLUSIONS: Salmon and Kallisto TPM data gives the best fit to the linear model studied. This suggests that TPM values estimated from Salmon and Kallisto are the ideal RNA-seq measurements for deconvolution studies. PMID- 28361708 TI - SEQUOIA: significance enhanced network querying through context-sensitive random walk and minimization of network conductance. AB - BACKGROUND: Network querying algorithms provide computational means to identify conserved network modules in large-scale biological networks that are similar to known functional modules, such as pathways or molecular complexes. Two main challenges for network querying algorithms are the high computational complexity of detecting potential isomorphism between the query and the target graphs and ensuring the biological significance of the query results. RESULTS: In this paper, we propose SEQUOIA, a novel network querying algorithm that effectively addresses these issues by utilizing a context-sensitive random walk (CSRW) model for network comparison and minimizing the network conductance of potential matches in the target network. The CSRW model, inspired by the pair hidden Markov model (pair-HMM) that has been widely used for sequence comparison and alignment, can accurately assess the node-to-node correspondence between different graphs by accounting for node insertions and deletions. The proposed algorithm identifies high-scoring network regions based on the CSRW scores, which are subsequently extended by maximally reducing the network conductance of the identified subnetworks. CONCLUSIONS: Performance assessment based on real PPI networks and known molecular complexes show that SEQUOIA outperforms existing methods and clearly enhances the biological significance of the query results. The source code and datasets can be downloaded from http://www.ece.tamu.edu/~bjyoon/SEQUOIA . PMID- 28361707 TI - Investigation and identification of protein carbonylation sites based on position specific amino acid composition and physicochemical features. AB - BACKGROUND: Protein carbonylation, an irreversible and non-enzymatic post translational modification (PTM), is often used as a marker of oxidative stress. When reactive oxygen species (ROS) oxidized the amino acid side chains, carbonyl (CO) groups are produced especially on Lysine (K), Arginine (R), Threonine (T), and Proline (P). Nevertheless, due to the lack of information about the carbonylated substrate specificity, we were encouraged to develop a systematic method for a comprehensive investigation of protein carbonylation sites. RESULTS: After the removal of redundant data from multipe carbonylation-related articles, totally 226 carbonylated proteins in human are regarded as training dataset, which consisted of 307, 126, 128, and 129 carbonylation sites for K, R, T and P residues, respectively. To identify the useful features in predicting carbonylation sites, the linear amino acid sequence was adopted not only to build up the predictive model from training dataset, but also to compare the effectiveness of prediction with other types of features including amino acid composition (AAC), amino acid pair composition (AAPC), position-specific scoring matrix (PSSM), positional weighted matrix (PWM), solvent-accessible surface area (ASA), and physicochemical properties. The investigation of position-specific amino acid composition revealed that the positively charged amino acids (K and R) are remarkably enriched surrounding the carbonylated sites, which may play a functional role in discriminating between carbonylation and non-carbonylation sites. A variety of predictive models were built using various features and three different machine learning methods. Based on the evaluation by five-fold cross validation, the models trained with PWM feature could provide better sensitivity in the positive training dataset, while the models trained with AAindex feature achieved higher specificity in the negative training dataset. Additionally, the model trained using hybrid features, including PWM, AAC and AAindex, obtained best MCC values of 0.432, 0.472, 0.443 and 0.467 on K, R, T and P residues, respectively. CONCLUSION: When comparing to an existing prediction tool, the selected models trained with hybrid features provided a promising accuracy on an independent testing dataset. In short, this work not only characterized the carbonylated substrate preference, but also demonstrated that the proposed method could provide a feasible means for accelerating preliminary discovery of protein carbonylation. PMID- 28361709 TI - Staged heterogeneity learning to identify conformational B-cell epitopes from antigen sequences. AB - BACKGROUND: The broad heterogeneity of antigen-antibody interactions brings tremendous challenges to the design of a widely applicable learning algorithm to identify conformational B-cell epitopes. Besides the intrinsic heterogeneity introduced by diverse species, extra heterogeneity can also be introduced by various data sources, adding another layer of complexity and further confounding the research. RESULTS: This work proposed a staged heterogeneity learning method, which learns both characteristics and heterogeneity of data in a phased manner. The method was applied to identify antigenic residues of heterogenous conformational B-cell epitopes based on antigen sequences. In the first stage, the model learns the general epitope patterns of each kind of propensity from a large data set containing computationally defined epitopes. In the second stage, the model learns the heterogenous complementarity of these propensities from a relatively small guided data set containing experimentally determined epitopes. Moreover, we designed an algorithm to cluster the predicted individual antigenic residues into conformational B-cell epitopes so as to provide strong potential for real-world applications, such as vaccine development. With heterogeneity well learnt, the transferability of the prediction model was remarkably improved to handle new data with a high level of heterogeneity. The model has been tested on two data sets with experimentally determined epitopes, and on a data set with computationally defined epitopes. This proposed sequence-based method achieved outstanding performance - about twice that of existing methods, including the sequence-based predictor CBTOPE and three other structure-based predictors. CONCLUSIONS: The proposed method uses only antigen sequence information, and thus has much broader applications. PMID- 28361710 TI - A framework for space-efficient read clustering in metagenomic samples. AB - BACKGROUND: A metagenomic sample is a set of DNA fragments, randomly extracted from multiple cells in an environment, belonging to distinct, often unknown species. Unsupervised metagenomic clustering aims at partitioning a metagenomic sample into sets that approximate taxonomic units, without using reference genomes. Since samples are large and steadily growing, space-efficient clustering algorithms are strongly needed. RESULTS: We design and implement a space efficient algorithmic framework that solves a number of core primitives in unsupervised metagenomic clustering using just the bidirectional Burrows-Wheeler index and a union-find data structure on the set of reads. When run on a sample of total length n, with m reads of maximum length l each, on an alphabet of total size sigma, our algorithms take O(n(t+logsigma)) time and just 2n+o(n)+O(max{l sigmalogn,K logm}) bits of space in addition to the index and to the union-find data structure, where K is a measure of the redundancy of the sample and t is the query time of the union-find data structure. CONCLUSIONS: Our experimental results show that our algorithms are practical, they can exploit multiple cores by a parallel traversal of the suffix-link tree, and they are competitive both in space and in time with the state of the art. PMID- 28361712 TI - A program to compute the soft Robinson-Foulds distance between phylogenetic networks. AB - BACKGROUND: Over the past two decades, phylogenetic networks have been studied to model reticulate evolutionary events. The relationships among phylogenetic networks, phylogenetic trees and clusters serve as the basis for reconstruction and comparison of phylogenetic networks. To understand these relationships, two problems are raised: the tree containment problem, which asks whether a phylogenetic tree is displayed in a phylogenetic network, and the cluster containment problem, which asks whether a cluster is represented at a node in a phylogenetic network. Both the problems are NP-complete. RESULTS: A fast exponential-time algorithm for the cluster containment problem on arbitrary networks is developed and implemented in C. The resulting program is further extended into a computer program for fast computation of the Soft Robinson-Foulds distance between phylogenetic networks. CONCLUSIONS: Two computer programs are developed for facilitating reconstruction and validation of phylogenetic network models in evolutionary and comparative genomics. Our simulation tests indicated that they are fast enough for use in practice. Additionally, the distribution of the Soft Robinson-Foulds distance between phylogenetic networks is demonstrated to be unlikely normal by our simulation data. PMID- 28361713 TI - The joint NETTAB/Integrative Bioinformatics 2015 Meeting: aims, topics and outcomes. AB - The 15th International NETTAB workshop and the 11th Integrative Bioinformatics Symposium were held together in Bari, on October 14-16, 2016, as Joint NETTAB/IB 2015 Meeting. A special topic for the meeting was "Bioinformatics for ncRNA", but the traditional topics of both meetings series were also included in the event.About 60 scientific contributions were presented, including six keynote lectures, one special guest lecture, and many oral communications and posters. A "Two-Day Hands-on Tutorial" event was organised before the workshop.Selected full papers from some of the best works presented in Bari were submitted either to the Journal of Integrative Bioinformatics or to a purpose Call for a Supplement of BMC Bioinformatics.Here, we provide an overview of meeting aims and scope. We also shortly introduce selected papers that have been either accepted for publication in this Supplement or published in the Journal of Integrative Bioinformatics, for a more complete presentation of the outcomes of the meeting. PMID- 28361711 TI - Receptor-guided 3D-QSAR studies, molecular dynamics simulation and free energy calculations of Btk kinase inhibitors. AB - BACKGROUND: Bruton tyrosine kinase (Btk) plays an important role in B-cell development, differentiation, and signaling. It is also found be in involved in male immunodeficiency disease such as X-linked agammaglobulinemia (XLA). Btk is considered as a potential therapeutic target for treating autoimmune diseases and hematological malignancies. RESULTS: In this work, a combined molecular modeling study was performed on a series of thieno [3,2-c] pyridine-4-amine derivatives as Btk inhibitors. Receptor-guided COMFA (q 2 = 0.574, NOC = 3, r 2 = 0.924) and COMSIA (q 2 = 0.646, NOC = 6, r 2 = 0.971) models were generated based on the docked conformation of the most active compound 26. All the developed models were tested for robustness using various validation techniques. Furthermore, a 5-ns molecular dynamics (MD) simulation and binding free energy calculations were carried out to determine the binding modes of the inhibitors and to identify crucial interacting residues. The rationality and stability of molecular docking and 3D-QSAR results were validated by MD simulation. The binding free energies calculated by the MM/PBSA method showed the importance of the van der Waals interaction. CONCLUSIONS: A good correlation between the MD results, docking studies, and the contour map analysis were observed. The study has identified the key amino acid residues in Btk binding pocket. The results from this study can provide some insights into the development of potent, novel Btk inhibitors. PMID- 28361714 TI - Finding low-conductance sets with dense interactions (FLCD) for better protein complex prediction. AB - BACKGROUND: Intuitively, proteins in the same protein complexes should highly interact with each other but rarely interact with the other proteins in protein protein interaction (PPI) networks. Surprisingly, many existing computational algorithms do not directly detect protein complexes based on both of these topological properties. Most of them, depending on mathematical definitions of either "modularity" or "conductance", have their own limitations: Modularity has the inherent resolution problem ignoring small protein complexes; and conductance characterizes the separability of complexes but fails to capture the interaction density within complexes. RESULTS: In this paper, we propose a two-step algorithm FLCD (Finding Low-Conductance sets with Dense interactions) to predict overlapping protein complexes with the desired topological structure, which is densely connected inside and well separated from the rest of the networks. First, FLCD detects well-separated subnetworks based on approximating a potential low conductance set through a personalized PageRank vector from a protein and then solving a mixed integer programming (MIP) problem to find the minimum-conductance set within the identified low-conductance set. At the second step, the densely connected parts in those subnetworks are discovered as the protein complexes by solving another MIP problem that aims to find the dense subnetwork in the minimum conductance set. CONCLUSION: Experiments on four large-scale yeast PPI networks from different public databases demonstrate that the complexes predicted by FLCD have better correspondence with the yeast protein complex gold standards than other three state-of-the-art algorithms (ClusterONE, LinkComm, and SR-MCL). Additionally, results of FLCD show higher biological relevance with respect to Gene Ontology (GO) terms by GO enrichment analysis. PMID- 28361717 TI - Guest Editorial: Yet Another Emerging Technology: Old and New Questions Posed by Synthetic Biology. PMID- 28361716 TI - Visualization of consensus genome structure without using a reference genome. AB - BACKGROUND: Standard graphical tools for whole genome comparison require a reference genome. However, any reference is also subject to annotation biases and rearrangements, and may not serve as the standard except for those of extensively studied model species. To fully exploit the rapidly accumulating sequence data from the recent sequencing technologies, genome comparison without any reference has been anticipated. RESULTS: We introduce a circular genome visualizer to compare complete genomes of closely related species. This tool visualizes the position of orthologous gene clusters rather than actual sequences or their features, thereby achieving the comparative view without using a single reference genome. The essential information is the matrix of orthologous gene clusters whose positions (not sequences) are color-coded in circular graphics. As a demonstration, comparison of 14 Lactobacillus paracasei strains and one L. casei strain revealed not only large-scale rearrangements but also genomic islands that are strain-specific. Comparison of 73 Helicobacter pylori strains confirmed their genetic consistency and also revealed the three general patterns of large-scale genome inversions. CONCLUSIONS: From the ample sequence information in the GenBank/ENA/DDBJ repository, we can reconstruct a genomic consensus for particular species. By visualizing multiple strains at a glance, we can identify conserved as well as strain-specific regions in multiply sequenced genomes. Positional consistency for orthologous genes provides information orthogonal to major sequence features such as the GC content or sequence similarity of marker genes. The positional comparison is therefore useful for identifying large-scale genome rearrangements or gene transfers. PMID- 28361719 TI - Consequentialism and the Synthetic Biology Problem. AB - This article analyzes the ethics of synthetic biology (synbio) from a consequentialist perspective, examining potential effects on food and agriculture, and on medicine, fuel, and the advancement of science. The issues of biosafety and biosecurity are also examined. A consequentialist analysis offers an essential road map to policymakers and regulators as to how to deal with synbio. Additionally, the article discusses the limitations of consequentialism as a tool for analysing synbioethics. Is it possible to predict, with any degree of plausibility, what the consequences of synthetic biology will be in 50 years, or in 100, or in 500? Synbio may take humanity to a place of radical departure from what is known or knowable. PMID- 28361718 TI - Synthetic Biology and Ethics: Past, Present, and Future. AB - This article explores the ethical issues that have been identified in emerging technologies, from early genetic engineering to synthetic biology. The scientific advances in the field form a continuum, and some ethical considerations can be raised time and again when new developments occur. An underlying concern is the cumulative effect of scientific advances and ensuing technological innovation that can change our understanding of life and humanity. PMID- 28361720 TI - The Bioethicist Who Cried "Synthetic Biology": An Analysis of the Function of Bioterrorism Predictions in Bioethics. AB - This article analyzes a specter that has haunted bioethics almost since its inception, namely the specter of the misuse of biotechnology by maleficent agents bent on mass destruction, or the complete eradication of human kind and life as we know it. The article provides a general account of why bioethicists cry "catastrophic bioterrorism potential" when new biotechnologies emerge, and an analysis of the arguments that flow from the prediction, especially in relation to synthetic biology. PMID- 28361721 TI - Finding Hope in Synthetic Biology. AB - For some, synthetic biology represents great hope in offering possible solutions to many of the world's biggest problems, from hunger to sustainable development. Others remain fearful of the harmful uses, such as bioweapons, that synthetic biology can lend itself to, and most hold that issues of biosafety are of utmost importance. In this article, I will evaluate these points of view and conclude that although the biggest promises of synthetic biology are unlikely to become reality, and the probability of accidents is fairly substantial, synthetic biology could still be seen to benefit humanity by enhancing our ethical understanding and by offering a boost to world economy. PMID- 28361722 TI - Synthetic Biology between Self-Regulation and Public Discourse: Ethical Issues and the Many Roles of the Ethicist. AB - This article discusses the roles of ethicists in the governance of synthetic biology. I am particularly concerned with the idea of self-regulation of bioscience and its relationship to public discourse about ethical issues in bioscience. I will look at the role of philosophical ethicists at different levels and loci, from the "embedded ethicist" in the laboratory or research project, to ethicists' impact on policy and public discourse. In a democratic society, the development of governance frameworks for emerging technologies, such as synthetic biology, needs to be guided by a well-informed public discourse. In the case of synthetic biology, the public discourse has to go further than merely considering technical issues of biosafety and biosecurity, or risk management, to consider more philosophical issues concerning the meaning and value of "life" between the natural and the synthetic. I argue that ethicists have moral expertise to bring to the public arena, which consists not only in guiding the debate but also in evaluating arguments and moral positions and making normative judgments. When ethicists make normative claims or moral judgments, they must be transparent about their theoretical positions and basic moral standpoints. PMID- 28361723 TI - Synthetic Biology: The Response of the Commission of the (Catholic) Bishops' Conferences of the European Community. AB - The Commission of the (Catholic) Bishops' Conferences of the European Community (COMECE) has issued an opinion on the ethics of synthetic biology (synbio). Examining synbio from religious and more general ethical perspectives, it examines synbio's potential pros and cons, as well as whether it is ethical in and of itself. Its conclusions mirror those of the ethical mainstream; namely, that synbio may present humanity with opportunities for both great advancement and great destruction. It suggests a prudent approach, and calls for regulation to be used to encourage positive outcomes while reducing the likelihood of negative ones. PMID- 28361724 TI - Sex before the State: Civic Sex, Reproductive Innovations, and Gendered Parental Identity. AB - Certain changes in the way that states classify people by sex as well as certain reproductive innovations undercut the rationale for state identification of people as male or female in signifying gendered parental relationships to children. At present, people known to the state as men may be genetic mothers to their children; people known to the state as women may be genetic fathers to their children. Synthetic gametes would make it possible for transgender men to be genetically related to children as fathers and transgender women to be genetically related to children as mothers, even if they have otherwise relied on naturally-occurring gametes to be genetic mothers and genetic fathers of children respectively. Synthetic gametes would presumably make it possible for any person to be the genetic father or genetic mother of children, even in a mix-and-match way. Other reproductive innovations will also undercut existing expectations of gendered parental identity. Uterus transplants would uncouple the maternal function of gestation from women, allowing men to share in maternity that way. Extracorporeal gestation ((ExCG)-gestation outside anyone's body-would also undercut the until-now absolute connection between female sex and maternity. In kind, effects such as these-undoing conventionally gendered parenthood-undercut the state's interest in knowing whether parents are male or female in relation to a given child, as against knowing simply whether someone stands in a parental relationship to that child, as a matter of rights and duties. PMID- 28361725 TI - Resource Allocation, Treatment, Disclosure, and Mitochondrial Replacement Techniques. PMID- 28361726 TI - From What Kind of Research Can They Dissent? PMID- 28361727 TI - Beyond an Open Future. AB - Discussions about the ethical permissibility of pediatric cognitive enhancement frequently revolve around arguments about welfare, and often include an appeal to the child's right to an open future. Both proponents and opponents of cognitive enhancement claim that their respective positions best serve the interests of the child by promoting an open future. This article argues that this right to an open future argument only captures some of the risks to the welfare of children, therefore requiring a broader ethical approach. Further, it suggests that a thorough moral assessment of the ends pursued is needed before concluding on the moral permissibility of cognitive enhancement in children, which ultimately hinges on the effect on the overall welfare of the child, beyond an open future. PMID- 28361728 TI - The Electronic Medical Record and the Loss of Narrative. AB - The use of the electronic medical record (EMR) facilitates many aspects of patient care as well as clinical and outcomes research. However, our thought processes are directed differently when collecting data to be entered into a structured database compared with when collecting data to construct a narrative of the patient and his or her complaints. While recognizing that the EMR will improve overall patient care, it is worthwhile examining aspects of patient doctor interaction that may be sacrificed. PMID- 28361729 TI - The Electronic Health Record and Patient Portals in HIV Medicine. AB - The electronic medical record provides an exciting opportunity to support the coordination of care by medical and social providers. Many of these systems include patient portals that allow providers to share clinical information with patients in real time. These "patient portals" provide a unique opportunity for clients and patients to access and use HIV and sexually transmitted infection information for communication with healthcare providers, with potential or actual sex partners, and for tracking their own clinical course and progress. A concerted effort to develop these should include a high level of transparency and adequate support for both patient and provider. PMID- 28361730 TI - Safeguarding Confidentiality in Electronic Health Records. AB - Electronic health records (EHRs) offer significant advantages over paper charts, such as ease of portability, facilitated communication, and a decreased risk of medical errors; however, important ethical concerns related to patient confidentiality remain. Although legal protections have been implemented, in practice, EHRs may be still prone to breaches that threaten patient privacy. Potential safeguards are essential, and have been implemented especially in sensitive areas such as mental illness, substance abuse, and sexual health. Features of one institutional model are described that may illustrate the efforts to both ensure adequate transparency and ensure patient confidentiality. Trust and the therapeutic alliance are critical to the provider-patient relationship and quality healthcare services. All of the benefits of an EHR are only possible if patients retain confidence in the security and accuracy of their medical records. PMID- 28361715 TI - SheddomeDB: the ectodomain shedding database for membrane-bound shed markers. AB - BACKGROUND: A number of membrane-anchored proteins are known to be released from cell surface via ectodomain shedding. The cleavage and release of membrane proteins has been shown to modulate various cellular processes and disease pathologies. Numerous studies revealed that cell membrane molecules of diverse functional groups are subjected to proteolytic cleavage, and the released soluble form of proteins may modulate various signaling processes. Therefore, in addition to the secreted protein markers that undergo secretion through the secretory pathway, the shed membrane proteins may comprise an additional resource of noninvasive and accessible biomarkers. In this context, identifying the membrane bound proteins that will be shed has become important in the discovery of clinically noninvasive biomarkers. Nevertheless, a data repository for biological and clinical researchers to review the shedding information, which is experimentally validated, for membrane-bound protein shed markers is still lacking. RESULTS: In this study, the database SheddomeDB was developed to integrate publicly available data of the shed membrane proteins. A comprehensive literature survey was performed to collect the membrane proteins that were verified to be cleaved or released in the supernatant by immunological-based validation experiments. From 436 studies on shedding, 401 validated shed membrane proteins were included, among which 199 shed membrane proteins have not been annotated or validated yet by existing cleavage databases. SheddomeDB attempted to provide a comprehensive shedding report, including the regulation of shedding machinery and the related function or diseases involved in the shedding events. In addition, our published tool ShedP was embedded into SheddomeDB to support researchers for predicting the shedding event on unknown or unrecorded membrane proteins. CONCLUSIONS: To the best of our knowledge, SheddomeDB is the first database for the identification of experimentally validated shed membrane proteins and currently may provide the most number of membrane proteins for reviewing the shedding information. The database included membrane-bound shed markers associated with numerous cellular processes and diseases, and some of these markers are potential novel markers because they are not annotated or validated yet in other databases. SheddomeDB may provide a useful resource for discovering membrane-bound shed markers. The interactive web of SheddomeDB is publicly available at http://bal.ym.edu.tw/SheddomeDB/ . PMID- 28361731 TI - Health Information Technology as a Universal Donor to Bioethics Education. AB - Health information technology, sometimes called biomedical informatics, is the use of computers and networks in the health professions. This technology has become widespread, from electronic health records to decision support tools to patient access through personal health records. These computational and information-based tools have engendered their own ethics literature and now present an opportunity to shape the standard medical and nursing ethics curricula. It is suggested that each of four core components in the professional education of clinicians-privacy, end-of-life care, access to healthcare and valid consent, and clinician-patient communication-offers an opportunity to leverage health information technology for curricular improvement. Using informatics in ethics education freshens ethics pedagogy and increases its utility, and does so without additional demands on overburdened curricula. PMID- 28361732 TI - Bioethicsing. AB - This article describes the components of a unique 9 month required course in bioethics for 3rd year medical students at the American University of Beirut. The blended (hybrid) learning format emphasizes three innovative learning activities: the bioethics documentary, edutainment games, and the bioethics log book. Sample student responses are included as well as an outline of limitations. PMID- 28361733 TI - Emerging Fungal Threats to Plants and Animals Challenge Agriculture and Ecosystem Resilience. AB - While fungi can make positive contributions to ecosystems and agro-ecosystems, for example, in mycorrhizal associations, they can also have devastating impacts as pathogens of plants and animals. In undisturbed ecosystems, most such negative interactions will be limited through the coevolution of fungi with their hosts. In this article, we explore what happens when pathogenic fungi spread beyond their natural ecological range and become invasive on naive hosts in new ecosystems. We will see that such invasive pathogens have been problematic to humans and their domesticated plant and animal species throughout history, and we will discuss some of the most pressing fungal threats of today. PMID- 28361734 TI - Tuberculosis in Enclosed Populations. AB - Transmission of tuberculosis (TB) is most effective in close contact indoor environments in various congregate settings including health care facilities, homeless shelters, correctional facilities, long-term care facilities, as well as community settings such as homes, schools, workplaces, and various modes of transportation. Outbreaks are fueled by numerous factors including the HIV epidemic, ease of global travel, unstable socio-economic and/or political situations, and lapses in response to potentially infectious patients. Organized approaches to TB control include an appropriate index of suspicion, identification and isolation of contagious patients in appropriate facilities, use of environmental controls, and personal protective equipment in accordance to national and international published guidelines. These all require tailoring to the various settings where TB is encountered using a determination of risk. Concerted efforts at the local, regional, national, and international levels at identifying patients with active disease, enforcing completion of treatment, and testing and fully treating patients with latent TB infection are paramount in reducing TB burden and continued transmission. PMID- 28361735 TI - Key Ecological Roles for Zoosporic True Fungi in Aquatic Habitats. AB - The diversity and abundance of zoosporic true fungi have been analyzed recently using fungal sequence libraries and advances in molecular methods, such as high throughput sequencing. This review focuses on four evolutionary primitive true fungal phyla: the Aphelidea, Chytridiomycota, Neocallimastigomycota, and Rosellida (Cryptomycota), most species of which are not polycentric or mycelial (filamentous), rather they tend to be primarily monocentric (unicellular). Zoosporic fungi appear to be both abundant and diverse in many aquatic habitats around the world, with abundance often exceeding other fungal phyla in these habitats, and numerous novel genetic sequences identified. Zoosporic fungi are able to survive extreme conditions, such as high and extremely low pH; however, more work remains to be done. They appear to have important ecological roles as saprobes in decomposition of particulate organic substrates, pollen, plant litter, and dead animals; as parasites of zooplankton and algae; as parasites of vertebrate animals (such as frogs); and as symbionts in the digestive tracts of mammals. Some chytrids cause economically important diseases of plants and animals. They regulate sizes of phytoplankton populations. Further metagenomics surveys of aquatic ecosystems are expected to enlarge our knowledge of the diversity of true zoosporic fungi. Coupled with studies on their functional ecology, we are moving closer to unraveling the role of zoosporic fungi in carbon cycling and the impact of climate change on zoosporic fungal populations. PMID- 28361737 TI - Therapy of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis. AB - The global epidemic of multidrug-resistant tuberculosis (MDR-TB) caused by Mycobacterium tuberculosis strains resistant to at least isoniazid and rifampin was recently reported as larger than previously estimated, with at least 580,000 new cases reported in 2015. Extensively drug-resistant tuberculosis (XDR-TB), MDR TB with additional resistance to a second-line fluoroquinolone and injectable, continues to account for nearly 10% of MDR cases globally. Cases in India, China, and the Russian Federation account for >45% of the cases of MDR-TB. Molecular testing helps identify MDR more quickly, and treatment options have expanded across the globe. Despite this, only 20% are in treatment, and treatment is challenging due to the toxicity of medications and the long duration. In 2016 the World Health Organization updated guidelines for the treatment of MDR-TB. A new short-course regimen is an option for those who qualify. Five effective drugs, including pyrazinamide (PZA) when possible, are recommended during the initial treatment phase and four drugs thereafter. Revised drug classifications include the use of linezolid and clofazimine as key second-line drugs and the option to use bedaquiline and delamanid to complete a five-drug regimen when needed due to poor medication tolerance or extensive resistance. Despite multiple drugs and long-duration treatment regimens, the outcomes for MDR and especially XDR-TB are much worse than for drug-susceptible disease. Better management of toxicity, prevention of transmission, and identification and appropriate management of infected contacts are important challenges for the future. PMID- 28361739 TI - Ghrelin activation and neuropeptide Y elevation in response to medium chain triglyceride administration in anorexia nervosa patients. AB - BACKGROUND & AIMS: Ghrelin, a peptide found in the stomach, increases appetite and fat-free mass while suppressing energy expenditure. Ghrelin requires modification by medium-chain triglycerides (MCTs) to exert its physiological effects. In this study, we investigated ghrelin activation and the resulting physiological changes following MCT administration. METHODS: Thirty participants were selected from among inpatients diagnosed with anorexia nervosa (AN). The patients were randomly divided into three groups by the MCT content of their nutritional supplement: (1) 'MCT high' (>6 g/day), (2) 'MCT moderate' (1-6 g/day), and (3) 'MCT low' (<1 g/day). Physical factors such as body weight and composition, as well as levels of nutrition-related serum factors such as acylated (active form) and desacyl (inactive form) ghrelin, leptin, growth hormone, insulin-like growth factor, and neuropeptide Y (NPY) were measured at weeks 0, 2, 4, and 6 of the treatment protocol. RESULTS: Significantly higher ghrelin activation was found in the 'MCT high' than in the 'MCT low' group (P < 0.05). The amount of consumed MCT had a curvilinear relationship with the active ghrelin level (P = 0.00). NPY levels in the 'MCT high' group were significantly more elevated than in the 'MCT low' group (P < 0.05). MCT administration did not significantly affect the remaining factors. CONCLUSIONS: This study clearly demonstrated that MCT activates ghrelin and increases NPY, suggesting that nutritional supplementation with MCT may be effective for the treatment of AN patients in an emaciated state. PMID- 28361740 TI - Association between adductor pollicis muscle thickness, anthropometric and immunological parameters in HIV-positive patients. AB - BACKGROUNDS AND AIMS: Involuntary weight loss and muscle mass loss among HIV positive patients are only detectable in late stages, leading poor life quality. The reduction of adductor pollicis muscle thickness (APMT) can be easily and earlier uncovered in those cases. The purpose was to estimate APMT and compare it with immunological and anthropometric parameters of HIV-infected people. METHODS: A crosssectional study was carried out in an University Hospital including 103 HIV-infected outpatients by subjective global assessment (SGA). Data were compared to APMT for the whole sample and between gender in univariate analysis. Besides that, simple correlation and multiple linear regression were done to check the APMT relation with gender, age, weight body, body mass index, arm circumference, CD4, CD8 and viral load. RESULTS: The APMT average values of the dominant hand (16.2 +/- 4.2 mm) and non-dominant hand (14.8 +/- 4.3 mm) were lower than in the healthy population. Through stratified analysis by gender, it was found significant difference in weight, arm muscle circumference, arm muscle area, triceps skinfold thickness and arm fat area (p < 0,01 for each). In any age group, men had significantly higher dominant and non-dominant APMT values than women (p < 0.001). Although the fair correlation among cited variables and APMT of both hands, there were no correlation and no difference between the genders in regards to immunological markers (CD4, CD8 and viral load). In a prediction model to APMT values, gender was determinant in multiple linear regression. CONCLUSIONS: In a well-nourished HIV sample by SGA with adequate CD4 counts, APMT measures of both hands were lower than in healthy people. In both hands, APMT were positively correlated with weight and male, regardless of other anthropometric data and immunologic factors. PMID- 28361738 TI - Simplifying study of fever's dramatic relief of autistic behavior. AB - Dramatic relief of autistic behavior by infectious fever continues to tantalize parents and practitioners, yet researchers still hesitate to study its physiology/biochemistry, fearing stress and heat of brain imaging, contagion, and fever's complexity. Yet what could be more revealing than a common event that virtually 'normalizes' autistic behavior for a time? This paper proposes study of three simplified scenarios: (1) improvements appearing hours before fever, (2) return of autistic behavior soon after fever, (3) improvements persisting long after fever. Each scenario limits some risk - and some explanation - inviting triangulation of decisive factor(s) in relief and recurrence. Return of autistic behavior after fever may be most revealing. The complex mechanisms that generated fever have all abated; simpler cooling mechanisms prevail - how many plausible explanations can there be? The decisive factor in fever's benefit is concluded to be water drawn/carried from brain myelin and astrocytes by osmolytes glutamine and taurine released from muscles and brain; the decisive factor in return of autistic behavior after fever is return of water. PMID- 28361736 TI - DNA Replication in Mycobacterium tuberculosis. AB - Faithful replication and maintenance of the genome are essential to the ability of any organism to survive and propagate. For an obligate pathogen such as Mycobacterium tuberculosis that has to complete successive cycles of transmission, infection, and disease in order to retain a foothold in the human population, this requires that genome replication and maintenance must be accomplished under the metabolic, immune, and antibiotic stresses encountered during passage through variable host environments. Comparative genomic analyses have established that chromosomal mutations enable M. tuberculosis to adapt to these stresses: the emergence of drug-resistant isolates provides direct evidence of this capacity, so too the well-documented genetic diversity among M. tuberculosis lineages across geographic loci, as well as the microvariation within individual patients that is increasingly observed as whole-genome sequencing methodologies are applied to clinical samples and tuberculosis (TB) disease models. However, the precise mutagenic mechanisms responsible for M. tuberculosis evolution and adaptation are poorly understood. Here, we summarize current knowledge of the machinery responsible for DNA replication in M. tuberculosis, and discuss the potential contribution of the expanded complement of mycobacterial DNA polymerases to mutagenesis. We also consider briefly the possible role of DNA replication-in particular, its regulation and coordination with cell division-in the ability of M. tuberculosis to withstand antibacterial stresses, including host immune effectors and antibiotics, through the generation at the population level of a tolerant state, or through the formation of a subpopulation of persister bacilli-both of which might be relevant to the emergence and fixation of genetic drug resistance. PMID- 28361741 TI - How to measure energy and protein intake in a geriatric department - A comparison of three visual methods. AB - BACKGROUND & AIMS: Sufficient energy and protein intake are essential to treatment and recovery of hospitalized older adults. The food intake should be assessed in order to detect patients in need of nutritional intervention. The aim of this study was to compare the accuracy of three visual methods for assessing energy and protein intake as compared to weighing food items. METHODS: We conducted assessment of 103 lunch meals served to geriatric inpatients. Lunch meals were assessed by the nursing staff using three visual methods: 1. Meal Portions (MP): Consumption of each meat/fish, vegetables, potatoes, and sauce 2. Plate Method (PM): Consumption of 100%, 75%, 50%, 25%, or 0% 3. Reduced Plate Method (RPM): All, half, quarter, or nothing Separate weighing of all food items pre- and post-serving was used as reference method. Wilcoxon Signed Rank Test was used comparing the accuracy of the three visual methods. Bland-Altman analysis was used to test the degree of agreement. Results are given as median estimates [25%>, 75%> percentiles]. The Alpha level was set to 0.05. RESULTS: The total energy served pr. lunch meal was 893.6 kJ [830.4, 1034.3] and the weighed intake 676.6 kJ [421.4, 870.0]. The median intake was 663.0 kJ [389.0, 873.0] (p = 0.044), 636.0 kJ [436.5, 873.0] (p < 0.001), and 487.8 kJ [316.5, 873.0] (p < 0.001) assessed by MP, PM, and RPM respectively. The weighted protein content pr. served meal was 13.0 g [11.4, 15.4] with a weighted intake of 10.3 g [5.3, 13.1]. The median intake was 10.7 g [5.3, 11.7] (P = 0.045), 9.3 g [5.8, 11.7] (p < 0.001), and 8.0 g [4.8, 11.7] (p < 0.001) assessed by MP, PM, and RPM respectively. CONCLUSIONS: All visual methods underestimated energy intake. PM and RPM underestimated protein intake whereas MP overestimated protein intake. However, visual assessment by MP was found to be most accurate. PMID- 28361743 TI - The role of nutritional assessment and early enteral nutrition for combined pancreas and kidney transplant candidates. AB - BACKGROUND: Early post-operative enteral nutrition is an important part of perioperative management and is strongly supported by ESPEN Guidelines. However, there is limited evidence into the use of Early Enteral Nutrition (EEN) after combined Pancreas and Kidney Transplantation (PKT). We know malnutrition in type 1 diabetics with end stage renal failure (ESRF) is a common problem and a significant risk factor. Therefore, we introduced EEN in our patients. METHOD: We monitored and recorded nutritional data on 29 PKT recipients who underwent transplantation between Oct 2007 and Jan 2010 without a nutritional assessment or EEN [Monitored Group (MG)] and on 30 PKT recipients between Feb 2010 and Dec 2013 who received a nutritional assessment and EEN (Naso-jejunal feed or oral intake with supplementation, according to their nutritional status) [Fed Group (FG)]. The end-point was to assess patients' daily post-transplant nutritional intake. This was calculated as a percentage of estimated nutritional requirements using the Schofield equation with a 25% added stress factor and relevant activity factor. Following a literature search and realistic targets our aim was to reach >60% requirements: achievement of >=60% energy requirements by day-7 (7d-60%) and at the time of discharge (total-60%) [13,14]. RESULTS: There was no significant difference between MG and FG patients in cold ischemic time (CIT), recipient-age and donor-age, Length of Stay and donor-creatinine. In contrast, FG patients were less frequently in predialysis status 41.4% vs. 26.7%, p = 0.001; and had higher incidence of BMI <22.5 kg/m2 63.3% vs. 48.3%, p = <0.005. In outcomes, FG patients more frequently achieved a higher average % of nutritional requirements in the first week 39.69% vs. 22.37%, p = <0.005; as well as during whole in patient stay 57.24% vs. 44.43%, p = <0.005 (Table 3, Figs. 1 and 2). The FG spent a greater proportion during the first week 66.7% vs. 31%, p = <0.005; and of whole their admission 93.3% vs. 75.9%, p = <0.005; meeting more than 60% of nutritional requirements. Most important, the need for parenteral nutrition within the FG was significantly lower, 7.1% vs. 20.7%, p < 0.005 (Table 3). CONCLUSION: Our results show that these patients benefit from planned EEN and receive better nutritional support when compared to the patients managed with the historic, reactive approach to nutritional care. Nutritional intake in the first week as well as during the whole admission was superior in patients receiving active EEN despite a more difficult post-operative course due to higher incidence of re-operations compared to the control group. Also the need for parenteral nutrition was significantly lower in this group. In addition, pre-transplant nutritional assessment is beneficial and accurately highlights those who may be at risk of malnutrition pre and post-operatively. PMID- 28361742 TI - Coffee consumption and calcified atherosclerotic plaques in the coronary arteries: The NHLBI Family Heart Study. AB - BACKGROUND & AIMS: While a recent meta-analysis of prospective studies reported that coffee consumption is associated with a lower risk of cardiovascular disease mortality, limited and inconsistent data are available on the relation of coffee intake with subclinical disease. Thus, the aim of the present study was to see the association of coffee consumption with the prevalence of atherosclerotic plaque in the coronary arteries in NHLBI Family Heart Study. METHODS: In a cross sectional design, we studied 1929 participants of the NHLBI Family Heart Study without known coronary heart disease. Coffee consumption was assessed by a semi quantitative food frequency questionnaire and coronary-artery calcium (CAC) was measured by cardiac computed tomography. We defined prevalent CAC as an Agatston score of >=100 and used generalized estimating equations to calculate prevalence ratios of CAC as well as a sensitivity analysis at a range of cutpoints for CAC. RESULTS: Mean age was 56.7 years and 59% of the study subjects were female. In adjusted analysis for age, sex, BMI, smoking, alcohol, physical activity, field center, and energy intake, prevalence ratio (95% CI) for CAC was 1.0 (reference), 0.92 (0.57-1.49), 1.34 (0.86-2.08), 1.30 (0.84-2.02), and 0.99 (0.60-1.64) for coffee consumption of almost never, <1/day, 1/day, 2-3/day, and >=4 cups/day, respectively. In a sensitivity analysis, there was no evidence of association between coffee consumption and prevalent CAC when CAC cut points of 0, 50, 150, 200, and 300 were used. CONCLUSIONS: These data do not provide evidence for an association between coffee consumption and prevalent CAC in adult men and women. PMID- 28361744 TI - Admission handgrip strength predicts functional decline in hospitalized patients. AB - PROBLEM: Up to 35% of hospitalized patients may experience functional decline during or after hospitalization. Subjective Global Assessment (SGA) and handgrip strength at admission, have been proposed as simple and accessible tools to predict functional decline, but there are few studies in hospitalized patients to confirm these findings. OBJECTIVE: To assess the predictive value of handgrip strength at hospital admission, on functional decline after 30 days. METHODS: 125 non-critical patients hospitalized for medical and surgical conditions, were studied in El Pino hospital in Santiago, Chile. Upon admission, nutritional status was assessed by SGA, functional status through the Karnofsky index (KI), and handgrip strength by dynamometry. Change in functionality was assessed by the difference between KI at admission and 30 days later. Multivariate logistic regression models were used to establish associations between the variables at hospital admission, and subsequent functional decline. RESULTS: Thirty days post hospital admission, 28.8% of the sample showed functional decline. In a multivariate analysis, only handgrip strength was associated with this decline (beta = -0.025, OR = 0.974 (CI 0.956-0.992), p = 0.007). CONCLUSIONS: Handgrip strength upon hospital admission can be a useful independent and early method to predict deterioration of functional status during hospitalization. PMID- 28361745 TI - Short-term impact of a classical ketogenic diet on gut microbiota in GLUT1 Deficiency Syndrome: A 3-month prospective observational study. AB - BACKGROUND&AIMS: The classical ketogenic diet (KD) is a high-fat, very low carbohydrate normocaloric diet used for drug-resistant epilepsy and Glucose Transporter 1 Deficiency Syndrome (GLUT1 DS). In animal models, high fat diet induces large alterations in microbiota producing deleterious effects on gut health. We carried out a pilot study on patients treated with KD comparing their microbiota composition before and after three months on the diet. METHODS: Six patients affected by GLUT1 DS were asked to collect fecal samples before and after three months on the diet. RT - PCR analysis was performed in order to quantify Firmicutes, Bacteroidetes, Bifidobacterium spp., Lactobacillus spp., Clostridium perfringens, Enterobacteriaceae, Clostridium cluster XIV, Desulfovibrio spp. and Faecalibacterium prausnitzii. RESULTS: Compared with baseline, there were no statistically significant differences at 3 months in Firmicutes and Bacteroidetes. However fecal microbial profiles revealed a statistically significant increase in Desulfovibrio spp. (p = 0.025), a bacterial group supposed to be involved in the exacerbation of the inflammatory condition of the gut mucosa associated to the consumption of fats of animal origin. CONCLUSIONS: A future prospective study on the changes in gut microbiota of all children with epilepsy started on a KD is warranted. In patients with dysbiosis demonstrated by fecal samples, it my be reasonable to consider an empiric trial of pre or probiotics to potentially restore the "ecological balance" of intestinal microbiota. PMID- 28361746 TI - Short-term effects of Mediterranean-type diet intervention on soluble cellular adhesion molecules in subjects with abdominal obesity. AB - BACKGROUND & AIMS: Abdominal obesity (AO) is associated with increased risk for cardiovascular disease and with increased production of adhesion molecules. The present work examined the effect of a Mediterranean-style diet on soluble cellular adhesion molecules in individuals with AO. METHODS: Ninety subjects with AO without cardiovascular disease or diabetes mellitus were randomly allocated to the intervention or control group and were instructed to follow a Mediterranean style diet for two months. Intervention group followed a specific relevant food plan with close dietetic supervision and provision of basic foods. Soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), sP and sE-selectin, C-reactive protein (CRP) and interleukin-6 (IL-6) were measured. RESULTS: Subjects in the intervention group increased their intake of total fat, monounsaturated fatty acids, dietary fiber, vitamin C, and alcohol compared to controls, while decreased their intake of saturated fat. Although there was a significant decrease in CRP, sP-selectin and in sE-selectin in the intervention group, and an increase in sVCAM-1 in the control group, between-group analysis showed no statistically significant differences. There were also no significant changes in sICAM-1, and IL-6 levels after intervention. CONCLUSIONS: Mediterranean-type diet for two months combined with close dietetic supervision showed a beneficial tendency towards the down regulation of some markers of vascular inflammation, although the comparison between groups after the intervention did not reach statistical significance. A longer period of dietary intervention may be required to further support these changes. PMID- 28361747 TI - Dietary counseling adherence during tuberculosis treatment: A longitudinal study. AB - BACKGROUND: The World Health Organization (WHO) recommends the use of dietary counseling to overcome malnutrition for patients with tuberculosis, with or without HIV, however the response to nutritional treatment depends on patient's adherence to nutritional counseling. OBJECTIVE: Identify the degree of adherence to dietary counseling and predictors of adherence among patients undergoing tuberculosis treatment. DESIGN: Observational prospective follow-up study conducted in adults treating for tuberculosis with or without HIV. Self-reported adherence and 24-h diet recall were checked. Diet counseling according to WHO strategy was offered at each visit for all patients. The endpoint was the adherence to the recommended dietary allowance (RDA) and total calories consumed during tuberculosis treatment. Data were mainly analyzed with marginal models to estimate adjusted trajectories. RESULTS: Sixty-eight patients were included in the study. The maximum probability of total calories consumption of at least one RDA was 80%. The adherence to dietary counseling was low regardless of HIV infection. The negative determinants of adherence were the presence of loss of appetite and nausea/vomiting. For patients with loss of appetite and nausea/vomiting, the probability of total calories consumption of at least one RDA is less than 20% at any time. CONCLUSION: The loss of appetite and nausea/vomiting are highly prevalents and were the main causes of non-adherence to dietary counseling. PMID- 28361748 TI - Erythrocyte concentrations of B1, B2, B6 but not plasma C and E are reliable indicators of nutrition status in the presence of systemic inflammation. AB - BACKGROUND & AIM: There is increasing evidence that the plasma concentration of vitamin D, carotenoids, zinc and selenium are associated with the magnitude of the systemic inflammatory response. In order to examine whether other vitamins may be affected and whether red cell concentrations are less affected by systemic inflammation the aim of the present study was to examine the effect of the systemic inflammatory response on red cell measurements of vitamins B1, B2 and B6, and plasma concentration of vitamin C and E in a large cohort of patients referred for a nutritional screen. METHODS: Patients referred for nutritional assessment of B1 (n = 551), B2 (n = 251), B6 (n = 313), ascorbic acid (n = 494) and alpha-tocopherol (n = 395) concentrations. These vitamins were measured using routine laboratory methods. RESULTS: The median concentrations of vitamin B1 grouped according to C-reactive protein concentrations <=10, 11-80 and >80 mg/L were 543, 664 and 766 ng/g Hb respectively (p < 0.001, 41% higher). The median concentration of vitamin B1 grouped according to albumin concentrations >=35, 25 34 and <25 g/l were 547, 664 and 701 ng/g Hb respectively (p < 0.001, 28% higher). The median concentrations of red cell vitamin B2 grouped according to CRP concentrations <=10, 11-80 and >80 mg/L were 2.2, 2.3 and 2.4 nmol/g Hb respectively (p < 0.001, 9% higher). The median red cell concentrations of vitamin B2 grouped according to albumin concentrations >=35, 25-34 and <25 g/l were 2.1, 2.4 and 2.3 nmol/g Hb respectively (p < 0.001, 14% higher). The median concentrations of red cell vitamin B6 grouped according to CRP concentrations <=10, 11-80 and >80 mg/L were 534, 548 and 767 pmol/g Hb respectively (p < 0.001, 44% higher). The median red cell concentrations of vitamin B6 grouped according to albumin concentrations >=35, 25-34 and <25 g/l were 462, 644 and 840 pmol/g Hb respectively (p < 0.001, 82% higher). In contrast, the median plasma concentrations of ascorbic acid grouped according to CRP concentrations <=10, 11 80 and >80 mg/L were 25.0, 15.0 and 6.0 MUmol/l respectively (78% lower, p < 0.001). The median plasma concentrations of ascorbic acid grouped according to albumin concentrations >=35, 25-34 and <25 g/l were 32.0, 13.0 and 5.0 MUmol/l respectively (84% lower, p < 0.001). The median alpha-tocopherol/cholesterol grouped according to CRP concentrations <=10, 11-80 and >80 mg/L were 5.9, 4.6 and 2.1 MUmol/l respectively (64% lower, p < 0.001). The median alpha tocopherol/cholesterol grouped according to albumin concentrations >=35, 25-34 and <25 g/l were 6.0, 5.5 and 2.1 MUmol/l respectively (65% lower, p < 0.001). CONCLUSION: Red cell concentrations of vitamins B1, B2 and B6 were not lower with an increasing systemic inflammatory response. In contrast, plasma concentrations of vitamin C and E were lower. Therefore, compared with plasma concentration, red cell concentrations of B1, B2 and B6 are likely to be more reliable measures of status in the presence of a systemic inflammatory response. PMID- 28361749 TI - Malnutrition Inflammation Score cut-off predicting mortality in maintenance hemodialysis patients. AB - BACKGROUND: Malnutrition is a strong predictor of mortality on hemodialysis patients, especially when it is associated with inflammation. Malnutrition Inflammation Score (MIS) is a simple and low cost tool which assesses the presence of malnutrition associated with inflammation. Therefore, the aim is to evaluate if MIS is associated with mortality in patients on maintenance hemodialysis and establish a cut-off to predict mortality at different follow-up periods. METHODS: Observational retrospective cohort study including 215 patients on hemodialysis between July 2012 and June 2014, censored until November 2015. MIS was used to assess patient's nutritional status at the moment they were enrolled in the study. They were followed for at least 18 months. RESULTS: At the end of 18 months, 38 (17.7%) deaths, 20 renal transplants (9.3%), four facilities transference (1.9%), three dialysis method change (1.4%) and one renal function recovery (0.5%) were observed. One hundred seventy one patients completed at least 24 months of follow-up, and during this additional period, there were five deaths and one renal transplant more. Score higher than 7 points was able to predict mortality for both follow-up periods using sensitivity and specificity analysis and ROC curves. Using this cut-off on Kaplan-Meier survival curve, it was possible to confirm the association of MIS with all-cause mortality at 18 months and 24 or more months of follow-up. Finally, Cox multivariate analysis adjusted for demographic, clinical and nutritional variables showed MIS as the only significant predictor of mortality. CONCLUSION: MIS is an independent predictor of mortality in hemodialysis patients. PMID- 28361750 TI - Nutritional status and the performance of multiple bedside tools for nutrition assessment among patients waiting for liver transplantation: A Canadian experience. AB - BACKGROUND: Malnutrition is an important predictor of morbidity and mortality among cirrhotic patients. Our objectives were to assess protein-calorie malnutrition (PCM) in cirrhotic pre-liver transplant patients and to study the correlation between subjective global assessment (SGA) and other objective measures of malnutrition. METHODS: We recruited pre-liver transplant adult patients at our center between October 2012 and Oct 2015. Nutrition status was assessed via SGA. PCM was assessed by comparing recommended to actual protein and calorie intake. SGA was correlated with body mass index (BMI), dry BMI, handgrip strength by calibrated dynometer (HGS), and mid-arm circumference (MAC). We used non-parametric statistical methods in our analysis. RESULTS: Seventy patients were included in this study. Majority were males (n = 46, 66%) with a median age of 58 years (IQR: 50-61). Moderate to severe malnutrition was prevalent in our cohort (SGA-A: n = 15 (21.4%), SGA-B: n = 30 (42.9%) and SGA-C: n = 25 (35.7%). There was a significant difference in the recommended calories consumed between SGA groups (A 98.5% vs. C 79.2%, P = 0.03). A similar trend was observed for the recommended protein consumed (A 85.4%, C 62.5%; P = 0.09). SGA correlated with BMI (A = 26.4, C = 22.4; P<0.01), Dry BMI (A = 25.9, C = 20.4; P<0.01), HGS (A = 67.0, C = 47.0 PSI; P = 0.03), and MAC (A = 29.5 cm, C = 22.0 cm; P<0.01). HGS and MAC were strongly correlated (Spearman correlation 0.49, P<0.01). CONCLUSIONS: Cirrhotic patients have significant protein-calorie malnutrition. Multiple malnutrition tools including BMI, dry BMI, HGS and MAC were precisely able to assess malnutrition. PMID- 28361751 TI - Glutamine dipeptide-supplemented parenteral nutrition improves the clinical outcomes of critically ill patients: A systematic evaluation of randomised controlled trials. AB - BACKGROUND & AIMS: Early randomised controlled trials (RCTs) testing whether parenteral nutrition regimens that include glutamine dipeptides improves the outcomes of critically ill patients demonstrated convincingly that this regimen associates with reduced mortality, infections, and hospital stays. However, several new RCTs on the same question challenged this. To resolve this controversy, the present meta-analysis was performed. Stringent eligibility criteria were used to select only those RCTs that tested the outcomes of critically ill adult patients without hepatic and/or renal failure who were haemodynamically and metabolically stabilised and who were administered glutamine dipeptide strictly according to current clinical guidelines (via the parenteral route at 0.3-0.5 g/kg/day; max. 30% of the prescribed nitrogen supply) in combination with adequate nutrition. METHODS: The literature research (PubMed, Embase, Cochrane Central Register of Controlled Trials) searched for English and German articles that had been published in peer-review journals (last entry March 31, 2015) and reported the results of RCTs in critically ill adult patients (major surgery, trauma, infection, or organ failure) who received parenteral glutamine dipeptide as part of an isoenergetic and isonitrogenous nutrition therapy. The following data were extracted: infectious complications, lengths of stay (LOS) in the hospital and intensive care unit (ICU), duration of mechanical ventilation, days on inotropic support, and ICU and hospital mortality rates. The selection of and data extraction from studies were performed by two independent reviewers. RESULTS: Fifteen RCTs (16 publications) fulfilled all selection criteria. They involved 842 critically ill patients. None had renal and/or hepatic failure. The average study quality (Jadad score: 3.8 points) was well above the predefined cut-off of 3.0. Common effect estimates indicated that parenteral glutamine dipeptide supplementation significantly reduced infectious complications (relative risk [RR] = 0.70, 95% CI 0.60, 0.83, p < 0.0001), ICU LOS (common mean difference [MD] -1.61 days, 95% CI -3.17, -0.05, p = 0.04), hospital LOS (MD -2.30 days, 95% CI -4.14, -0.45, p = 0.01), and mechanical ventilation duration (MD -1.56 days, 95% CI -2.88, -0.24, p = 0.02). It also lowered the hospital mortality rate by 45% (RR = 0.55, 95% CI 0.32, 0.94, p = 0.03) but had no effect on ICU mortality. Visual inspection of funnel plots did not reveal any potential selective reporting of studies. CONCLUSIONS: This meta-analysis clearly confirms that when critically ill patients are supplemented with parenteral glutamine dipeptide according to clinical guidelines as part of a balanced nutrition regimen, it significantly reduces hospital mortality, infectious complication rates, and hospital LOS. The latter two effects indicate that glutamine dipeptide supplementation also confers economic benefits in this setting. The present analysis indicates the importance of delivering glutamine dipeptides together with adequate parenteral energy and nitrogen so that the administered glutamine serves as precursor in various biosynthetic pathways rather than simply as a fuel. PMID- 28361753 TI - Handgrip strength and weight predict long-term mortality in acute kidney injury patients. AB - INTRODUCTION: Surviving acute kidney (AKI) patients have a higher late mortality compared with those admitted without AKI. The negative impact of malnutrition on the early outcome of AKI patients has recently been confirmed by various studies. However, its impact after hospital discharge has not been studied. The objective of the study was to determine the role of anthropometric measurements and handgrip strength as predictors of mortality 180 days after discharge. METHODOLOGY: Eighty-two survivors AKI patients who were older than 18 y old and followed by AKI team were prospectively evaluated. Patient's characteristics were recorded, anthropometric measurements were taken, handgrip strength (HGS) was measured, subjective global assessment and bioimpedance were applied and blood samples were collected during hospitalization at first and last nephrologist evaluation and in after hospital discharge at 1 month, 3 and 6 months. Multivariable logistic regression was used to adjust confounding and selection bias. RESULTS: Age was 62.3 +/- 14.7 years, prevalence of hospitalization in medical wards of 71.6%, index of severity of AKI (ATN-ISS) was 28% and late mortality rates was 25.6%. Risk factors associated with late mortality were the number of comorbidities (HR = 1.79, 95% CI = 1.45-2.46, p = 0.04), cancer (HR = 1.89, 95 CI% = 1.48-3.16, p = 0.01), sepsis (HR = 1.47, 95% CI = 1.18-2.38, p = 0.03), no recovery of renal function at hospital discharge (HR = 1.46, 95% CI = 1.02-2.16, p = 0.03), malnutrition at first evaluation (HR = 1.58, 95% CI = 1.14 2.94, p = 001), the HGS value at the moment of last evaluation by nephrologist (HR = 1.81, 95% CI = 1.17-2.31, p = 0.04) and gain weigh < 1 kg between the moment at first evaluation by nephrologist and one month after hospital discharge (HR = 1.95, 95 CI% = 1.29-3.3, p = 0.02). CONCLUSION: HGS and gain weight were identified as predictors of late mortality. Simple and ease methods can be applied in AKI patients during and after hospitalization to diagnose nutritionally patients who are at higher risk for poor prognosis and, consequently intervention measures can be performed to improve survival in long term. PMID- 28361752 TI - An empirically derived dietary pattern associated with breast cancer risk is validated in a nested case-control cohort from a randomized primary prevention trial. AB - BACKGROUND & AIMS: We reported an association between cytologic atypia, a reversible biomarker of breast cancer risk, and lower omega-3/omega-6 fatty acid ratio in blood and breast tissue. Our goal was to develop and validate a dietary pattern index in this high-risk sample of U.S. women, and test its capacity to predict incidence in a nested case-control cohort of Canadian women from a randomized trial of a low-fat dietary intervention for primary prevention of breast cancer. METHODS: Food intake was measured by food frequency questionnaire in the U.S. sample (n = 65) and multiple dietary recalls in the Canadian sample (n = 220 cases; 440 controls). Principal component analysis identified a dietary pattern associated with atypia. We measured differences among dietary pattern tertiles in (a) fatty acid composition in blood lipids and breast tissue in the U.S. sample, and (b) risk of breast cancer subtypes in the Canadian cohort. Registered under ClinicalTrials.gov Identifier: NCT00148057. RESULTS: A Modern diet was characterized as consuming more grains, dairy, and sugar and less vegetables, fish and poultry; these women had lower tissue omega-3 fatty acids and higher omega-6 and trans fatty acids. The low-fat intervention increased the likelihood of a Modern diet after randomization. A Modern diet at baseline and post-randomization was associated with estrogen-receptor negative (ER-) breast cancer risk among those at least 160 cm tall. A Traditional diet (the reciprocal of Modern) at baseline was associated with lower ER-positive (ER+) risk in the comparison group, but not the low-fat intervention group. CONCLUSIONS: A Modern diet (high in grains, dairy, and sugar and low in vegetables, fish, and poultry) is associated with ER- breast cancer risk among taller women. Recommending dietary fat reduction may have untoward effects on breast cancer risk. PMID- 28361754 TI - The medical risks of severe anorexia nervosa during initial re-feeding and medical stabilisation. AB - BACKGROUND & AIMS: Objective evidence about the risks associated with anorexia nervosa and how to manage them, is limited. The aim of this study is to describe the medical risk profile, management and outcomes of a cohort of patients with severe anorexia nervosa (sAN) during medical stabilisation treatment. METHODS: Retrospective analysis of case records gathered medical risk data for a 90 day high risk period, on 65 patients with sAN admitted to two specialist services. Prospectively established definitions of medical risk variables and significant complications were applied to the data to describe the risk profiles and outcomes. RESULTS: Amongst this population with an average initial BMI of 12.8 kg/m2, 74% developed no significant medical complications. Oral re-feeding over 60 days achieved an increase in mean BMI to 14.4 kg/m2 and mean weight gain of 4 kg. No patients developed severe hypophosphatemia (<0.45 mmol/L) or any other indicators of a re-feeding syndrome. All the medical complications that arose were temporary. CONCLUSIONS: Initial re-feeding and medical stabilisation of patients with severe AN can be managed safely in specialist inpatient and community settings with slow re-feeding. Although the prevalence of complications was shown to be low, slight worsening of medical risk markers and increased incidence of complications did occur during initial re-feeding. The limited comparable published data appears to support slower rates of re-feeding, showing fewer abnormal results and complications. There is however a need for a definitive prospective multi-centre observational cohort study to investigate risks factors, and the effects of treatment on medical outcomes, in a large sample with varied rates of re-feeding. PMID- 28361755 TI - Plasma pro-inflammatory markers in chronic neuropathic pain: A multivariate, comparative, cross-sectional pilot study. AB - BACKGROUND: Caused by a lesion or disease of the somatosensory system, neuropathic pain is notoriously difficult to treat with conventional analgesics. It has been suggested that inflammatory cytokines play a role in the development and maintenance of neuropathic pain. But human studies of these substances are relatively few and partly contradictory. OBJECTIVES: To simultaneously investigate the plasma levels of chemokine interleukin 8 (IL-8) and the cytokines IL-6, IL-1beta, and Granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with peripheral neuropathic pain (most of whom due to failed back surgery syndrome) (n=14) compared to controls (n=17). RESULTS: IL-6 was significantly higher in patients than in controls (0.92+/-0.12pg/ml vs. 0.57+/ 0.08pg/ml, p=0.012). IL-1beta, IL-8, and GM-CSF levels did not differ between the two groups. A multivariate analysis showed a tendency for patients also to have higher GM-CSF plasma levels than controls. CONCLUSIONS: This study found an increased level of IL-6 in plasma in patients with neuropathic pain, but not for the other pro-inflammatory substances investigated. There are several possible confounders not registered or controlled for in this and other studies of neuropathic pain. IMPLICATIONS: Larger studies that take several possible confounders into consideration are needed to further investigate the levels of plasma cytokines in different pain conditions. PMID- 28361756 TI - The obesity epidemic makes life difficult for patients with herniated lumbar discs - and for back-surgeons: Increased risk of complications. PMID- 28361757 TI - Multimodal Rehabilitation Programs (MMRP) for patients with longstanding complex pain conditions - The need for quality control with follow-up studies of patient outcomes. PMID- 28361758 TI - Mechanisms of cognitive impairment in chronic pain patients can now be studied preclinically by inducing cognitive deficits with an experimental animal model of chronic neuropathic pain. PMID- 28361759 TI - Complex Regional Pain Syndrome (CRPS) after viper-bite in a pregnant young woman: Pathophysiology and treatment options. PMID- 28361760 TI - Finnish version of the fear-avoidance-beliefs questionnaire (FABQ) and the importance of validated questionnaires on FAB in clinical praxis and in research on low-back pain. PMID- 28361761 TI - Translation and validation of the Finnish version of the Fear-Avoidance Beliefs Questionnaire (FABQ). AB - BACKGROUND AND AIM: Low back pain (LBP) is a debilitating problem worldwide causing disability and reducing quality of life. The Fear Avoidance Beliefs Questionnaire (FABQ) was developed on the basis of the assumption that fear avoidance beliefs play a major role in LBP-related disability. It comprises 16 items scored by the patient and includes sub-scores for fear-avoidance beliefs regarding work and physical activity. This study aimed to translate and validate the Finnish version of the FABQ and to measure its properties among Finnish patients with LBP. MATERIAL AND METHODS: A forward-backward translation procedure was used based on modified recommended guidelines. The FABQ was applied to 66 Finnish patients with LBP. Patients answered the FABQ at baseline and again approximately two weeks later. The test-re-test reliability between the baseline and follow-up FABQ was evaluated by calculating intraclass correlation coefficients (ICC). Internal consistency between the items within total and sub scores was evaluated by calculating Cronbach's alpha. The items of the baseline FABQ were grouped using factor analysis and the correlations between the FABQ, pain intensity in visual analogue scale (VAS) and Oswestry Disability Index (ODI) were assessed using linear regression analysis. RESULTS: The Finnish version of the FABQ was successfully adapted. The mean age of patients was 46. Almost all patients (97%) reported LBP, most patients (76%) had chronic pain lasting more than 3 months and the mean intensity of LBP was 58mm on VAS. The follow-up time between the first and second questionnaire ranged from 2 days to 59 days with the median of 16 days. The ICC value for reliability between the baseline and follow up questionnaires was excellent for the total score (0.91) and work sub-score (0.89), and good for the physical activity sub-score (0.73). The items regarding work showed high or excellent reliability throughout, with ICC values ranging from 0.63 to 0.89. The ICC values for the items related to physical activity ranged from 0.43 to 0.66, displaying moderate to good reliability. Cronbach's alpha for internal consistency was excellent for the total score (0.92) and work (0.89), and good for physical activity (0.71). The best factor analysis solution yielded three factors characterized by the fear that pain aggravates due to (1) work or (2) physical activity, and (3) fear-avoidance beliefs concerning work. Higher total FABQ score was associated significantly with higher VAS (p-value 0.021) and ODI (<0.001). CONCLUSIONS AND IMPLICATIONS: The expert committee successfully created an applicable Finnish version of the FABQ. The Finnish FABQ is a valid and reliable instrument for assessing LBP patients' fear avoidance behaviour and has similar properties to those found in other validation studies of the FABQ. Thus it can be used for assessing the risk of disability due to fear avoidance behaviour in Finnish-speaking patients with LBP for both clinical and scientific purposes. PMID- 28361762 TI - Pain, sleep and catastrophizing: The conceptualization matters: Comment on Wilt JA et al. "A multilevel path model analysis of the relations between sleep, pain, and pain catastrophizing in chronic pain rehabilitation patients". PMID- 28361763 TI - A multilevel path model analysis of the relations between sleep, pain, and pain catastrophizing in chronic pain rehabilitation patients. AB - BACKGROUND AND AIM: Pain catastrophizing is linked to heightened pain and poorer coping among individuals with chronic pain, yet little is known about how pain catastrophizing associates with sleep and pain over the course of treatment for chronic pain. Previous research employing a cross-sectional design suggests that sleep mediates the association between pain catstrophizing and pain, but there have been no longitudinal studies examining the directionality of these associations. Thus, the aim of this study was to test two competing theoretical models. The first model specified that pain catastrophizing leads to increased pain via poor sleep. The second model specified that poor sleep leads to increased pain catastrophizing via increased pain. METHODS: This study examined the relations between pain catastrophizing, sleep, and pain among 50 consecutive patients (36 female, 14 male) ages 20-80 (M=45.96, SD=13.94) with chronic, non malignant pain who were admitted to the Cleveland Clinic, Chronic Pain Rehabilitation Programme (CPRP). The CPRP, within the Neurological Centre for Restoration, Neurologic Institute at the Cleveland Clinic, is a comprehensive, interdisciplinary programme designed to treat patients with disabling chronic pain. As part of their daily, morning update with their case manager, patients completed self-report ratings of their previous night's sleep time (TST), and their current pain, anxiety, and depression. Pain catastrophizing was assessed at admission and discharge. RESULTS: Over the course of treatment, daily TST increased from approximately 5h and 20min per night to nearly 6h and 30min per night, and average daily pain, daily depression, and daily anxiety decreased over the course of treatment. As the data in this study has a multilevel structure, with daily reports nested with in patients, we conducted multilevel path models to examine the longitudinal relations between pain catastrophizing, sleep, and pain. Multilevel path analysis permits the analysis of interdependent data without violating the assumptions of standard multiple regression. Models were conducted for pain catastrophizing and each of its subscales: rumination, magnification and helplessness. The findings were uniform across the composite pain catastrophizing scale and its subscales. There was an indirect path from sleep to pain catastrophizing (post-treatment) via pain, but not from pain catastrophizing (pre-treatment) to pain via sleep. There were also direct effects of sleep on pain and from pain to pain catastrophizing (post-treatment). Additionally, decreases in pain over the course of treatment were related to lower pain catastrophizing post-treatment. CONCLUSION AND IMPLICATIONS: These results call into question previous evidence that pain catastrophizing indirectly affects pain by way of its impact on sleep. Rather, our findings suggest that pain mediates the relationship between sleep and levels of pain catastrophizing. These results therefore underscore importance and value in collecting longitudinal data and potential influence on the conclusions gained with regards to sleep, pain and psychological variables. These findings may be of clinical importance when tailoring interventions for individuals with chronic pain and perhaps even more so for those with comorbid pain and sleep disturbance; prioritizing the treatment of sleep difficulties could result in improvements to pain-related outcomes. PMID- 28361764 TI - Genetic variability of pain - A patient focused end-point. PMID- 28361765 TI - Complex regional pain syndrome following viper-bite. AB - BACKGROUND: Complex regional pain syndrome (CRPS) may occur following fractures, surgery or different trauma. Development of CRPS following snake-bite has only been published in three reports (from Turkey, Nepal and Korea), although snake bites occur frequently world-wide. There has been no report from Western Europe. Vipera Berus is a common snake in European countries and the only venomous snake in Norway. We here describe the development of CRPS in a young woman as a consequence of a viper bite (Vipera Berus) in the right arm. METHODS: We performed a clinical investigation (inspection, measurement of skin temperatures, sensory and motor evaluation) of the patient six months following the viper-bite, measurement of thermal thresholds (quantitative sensory testing, QST), measurement of resting sweat output (RSO) and quantitative sudomotor axon reflex (QSART) from both arms. RESULTS: The patient fulfilled the Budapest criteria for a CRPS-condition, with continuous pain and symptoms and findings of autonomic dysfunction. In addition, we found elevated thresholds of warmth and cold, evidence of an affection of afferent A-delta and C-fibres as well as an affection of the efferent sympathetic sudomotor C-fibres by QSART. An increased RSO-volume was in inverse relationship to the decreased QSART result. CONCLUSION AND IMPLICATIONS: It is important to be aware of viper-bite as a possible eliciting event for CRPS for early diagnosis and treatment of a patient. As long-lasting pain and oedema are known complications, it is probable that CRPS after viper bites previously may have been underdiagnosed. As many patients are unaware of being bit, viper bite should be considered in cases of unexplained sudden pain and swelling of a limb. PMID- 28361766 TI - An investigation into enlarging and reducing the size of mirror reflections of the hand on experimentally-induced cold-pressor pain in healthy human participants. AB - BACKGROUND AND AIMS: Mirror visual feedback may be a useful clinical tool for reducing pain. Research suggests that reducing the size of a non-painful reflected hand can alleviate complex regional pain syndrome in the affected hand that is out of view. In contrast, research on healthy humans exposed to experimentally induced pain suggests that reducing the appearance of the size of a reflected body part can increase pain. The aim of this study was to investigate the effect of enlarging and reducing the visual appearance of the size of a hand using mirror visual feedback on pain threshold, intensity and tolerance in healthy human participants exposed to cold-pressor pain. METHODS: Participants were a convenience sample of 20 unpaid, healthy pain free volunteers aged 18 years or above. Each participant took part in one experiment where they completed cold-pressor pain tests whilst observing normal, enlarged and reduced size reflections of a hand congruent to a hand immersed in the ice cold water. A 4*2 factorial repeated measures analysis of variance (ANOVA) was performed on time to pain threshold and pain tolerance, and pain intensity with Condition (four levels: no reflection, reduced reflection, normal reflection, enlarged reflection) being the within-subject factors and Sex (two levels: female, male) between-subject factors. RESULTS: There were no significant effects for Condition, Sex, or Condition*Sex interaction for pain threshold, intensity or tolerance (p>0.05). There were no significant differences between the 3 mirror reflection conditions for agreement with the statements: "It felt like I was looking directly at my hand rather than at a mirror image"; "It felt like the hand I was looking at was my hand"; and "Did it seem like the hand you saw was a right hand or a left hand?". CONCLUSION: Enlarging or reducing the size of a hand using mirror visual feedback did not alter pain perception in healthy human participants exposed to cold-pressor pain. The different sizes of hands generated by mirror visual feedback created an illusion of looking at their own hand but this was not as strong as looking directly at the hand. IMPLICATIONS: In future, investigators and clinicians using mirror visual feedback may consider including an adaptive phase to ensure the reflection has been perceptually embodied. Reasons for the lack of effects are explored to inspire further research in the field. PMID- 28361767 TI - An investigation into enlarging and reducing the size of mirror reflections of the hand on experimentally induced cold-pressor pain in healthy volunteers. PMID- 28361768 TI - Structural and functional characterization of nerve fibres in polyneuropathy and healthy subjects. AB - OBJECTIVES: Quantification of intraepidermal nerve fibre density (IENFD) is an important small fibre measure in distal symmetric polyneuropathies (DSP), but quantitative evaluation of additional structural and functional factors may help in elucidating the underlying mechanisms, and in improving the diagnostic accuracy in DSP. The literature reports a weak or moderate relationship between IENFD and spontaneous and evoked pain in neuropathies, but the relationship between functional and structural small fibre parameters in patients with DSP is unclear. The objectives of the current study, therefore, were to determine morphological and functional parameters related to small nerve fibres in subjects with distal symmetric polyneuropathy (DSP) and healthy controls, and to characterize the interplay among these parameters in these two groups. MATERIALS AND METHODS: 17 patients with painful DSP (>=4 on 0-10 numerical rating scale) and with symptoms and signs of small fibre abnormality (with or without large fibre involvement) and 19 healthy control subjects underwent comprehensive functional and structural small fibre assessments that included quantitative sensory testing, response to 30min topical application of 10% capsaicin and analysis of skin biopsy samples taken from the distal leg (IENFD, epidermal and dermal nerve fibre length densities (eNFLD, dNFLD) using global spatial sampling and axonal swelling ratios (swellings/IENFD and swellings/NFLD)). RESULTS: DSP patients had reduced sensitivity to cold (median -11.07 degrees C vs. -2.60, P<=0.001) and heat (median 46.7 vs. 37.70, P<=0.001), diminished neurovascular (median 184 vs. 278 mean flux on laser Doppler, P=0.0003) and pain response to topical capsaicin (median 10 vs. 35 on 0-100 VAS, P=0.0002), and lower IENFD, eNFLD and dNFLD values combined with increased swelling ratios (all P<0.001) compared to healthy controls. The correlation between structural and functional parameters was poor in DSP patients, compared with healthy controls. In healthy controls eNFLD and dNFLD, IENFD and eNFLD, IENFD and dNFLD all correlated well with each other (r=0.81; P<=0.001, r=0.58; P=0.009, r=0.60; P=0.007, respectively). In DSP, on the other hand, only eNFLD and dNFLD showed significant correlation (r=0.53, P=0.03). A diagnostic approach of combined IENFD and eNFLD utilization increased DSP diagnostic sensitivity from 82.0% to 100% and specificity from 84.0% to 89.5%. CONCLUSIONS: This study presents a rigorous comparison between functional and morphological parameters, including parameters such as eNFDL and dNFLD that have not been previously evaluated in this context. The correlation pattern between functional and structural small fibre parameters is different in patients with DSP when compared to healthy controls. The findings suggest a more direct relationship between structure and function of nerve fibres in healthy controls compared to DSP. Furthermore, the findings suggest that combining IENFD with measurement of NFLD improves the diagnostic sensitivity and specificity of DSP. IMPLICATIONS: Combining small fibre parameters may improve the diagnostic accuracy of DSP. PMID- 28361769 TI - Patients with chronic pain: One-year follow-up of a multimodal rehabilitation programme at a pain clinic. AB - BACKGROUND AND AIMS: Multimodal rehabilitation (MMR) programmes, including, physical training, educational and psychological interventions by an interdisciplinary team are found to be more successful for patients with disabling chronic pain compared with less comprehensive treatments. MMR programmes are based on the biopsychosocial model and the goal is usually to improve function, quality of life and facilitate and enable return to work. As pain clinics traditionally offer conventional medical pain treatment, there is limited knowledge about MMR given in this context. The aim of our study was to describe characteristics of patients with chronic pain, treated with a MMR programme at a conventional pain clinic, to evaluate patient-reported outcome measures (PROM) from start to one year after, and to study possibly associated factors for the improvement of health-related quality of life after one year. METHODS: A prospective, observational study with a one-year follow-up was performed. SUBJECTS: A total of 42 individuals (38 females, age 44.0+/-12.3 years and 4 men age 40+/-8.5 years) with different pain diagnoses were included. After a team assessment, the patients began a programme that lasted about three months. The MMR programme contained coordinated, individually adapted treatments administered individually or in groups, and was based on cognitive behavioural principles. Questionnaires regarding health-related quality of life (HRQoL) (EQ 5D), insomnia (ISI), mental health (HADS), pain-related disability (PDI), kinesiophobia (TSK), current pain intensity (VAS) and sense of coherence (SOC) were used at the start of the MMR and at follow-up. Demographic data were collected from the patient records. RESULTS: The PROM at baseline showed substantial pain problems with low HRQoL (EQ-5D index of 0.1+/-0.282, and EQ VAS of 32.67+/-20.1), moderate insomnia (ISI 18.95+/-6.7), doubtful cases of depression and anxiety (HADS-depression 9.35+/-4.1 and HADS-anxiety 9.78+/-3.95), presence of pain-related disability (PDI 39.48 +/-12.64), kinesiophobia (TSK 40.8+/-9.8), as well as moderate current pain (VAS 61.31+/-20.4). The sense of coherence was weak (SOC of 51.37+/-14). At one-year follow-up, significant (p<=0.05) improvement occurred on the EQ-5D index, EQ VAS, ISI, PDI and TSK. In the logistic regression analysis, no significant associations could be identified. CONCLUSIONS: MMR for patients with complex pain problems can be a successful treatment alternative at conventional pain clinics. IMPLICATIONS: Since access to rehabilitation clinics in Sweden may be limited, the availability of MMR can increase by providing this type of intervention in pain clinics. Increased knowledge of MMR in different settings can also contribute to increased understanding and collaboration between pain clinics and rehabilitation units. PMID- 28361771 TI - Plasma pro-inflammatory markers in chronic neuropathic pain: Why elevated levels may be relevant for diagnosis and treatment of patients suffering chronic pain. PMID- 28361770 TI - Stimulation-induced expression of immediate early gene proteins in the dorsal horn is increased in neuropathy. AB - BACKGROUND AND AIMS: Peripheral neuropathic pain is described as a pain state caused by an injury or dysfunction of the nervous system, and could have clinical manifestations such as hyperalgesia, allodynia and spontaneous pain. The development of neuropathic pain may depend on long-term forms of neuronal plasticity in the spinal cord (SC). Expression of the immediate early gene proteins (IEGPs) Arc, Zif268, and c-Fos are implicated in establishment of long term potentiation (LTP) induced by conditioning stimulation (CS) of primary afferent fibres. However, the impact of the neuropathic state (Bennett's model) on CS-induced expression of IEGPs has not been studied. The aim of this study was to compare the levels of Arc, c-Fos and Zif268 immunoreactivity prior to and after conditioning stimulation in animals with developed neuropathic pain, with sham operated, non-ligated controls. METHODS: Twenty-four animals were divided equally into the neuropathic and non-neuropathic groups. Neuropathic pain was induced in all animals by conducting a loose ligation of the sciatic nerve with Chromic Catgut 4.0 sutures 7 days prior to conditioning stimulation or sham operation. The loose ligation was performed by placing sutures around the sciatic nerve compressing the nerve slightly just enough to reduce but not completely diminish the perineural circulation. A state of neuropathy was confirmed by a significant decrease in mechanical withdrawal threshold measured by von Frey's fibres. Immunohistochemical analysis was performed on transverse sections obtained from the L3-L5 segments of the SC at 2 and 6h post-CS and IEGP positive cells were counted in lamina I and II of the dorsal horn. During statistical analyses, the groups were compared by means of analysis of variance (univariate general linear model). If significant differences were found, each set of animals was compared with the sham group with post hoc Tukey's multiple comparison test. RESULTS: Strikingly, all IEGPs exhibited a significant increase in immunoreactivity at both time points compared to time-matched, sham operated controls. Maximal IEGP expression was found 2h after CS in neuropathic rats, and there was a smaller but still significant increase 6h after CS. The unstimulated side of the dorsal horn in stimulated animals did not show any significant change of the number of IEGP positive cells and was approximately at the same level as sham operated animals. The number of IEGP positive cells in sham operated controls (non-neuropathic and non-stimulated animals) showed same immunoreactivity in 2 and 6h post sham operation. CONCLUSIONS AND IMPLICATIONS: The neurophysiological process of neuropathic pain development is complex and needs to be studied further in order to clarify its nature and components. This present study is meant to reveal a step towards further understanding the role of Arc, c-Fos and Zif268 in neuropathic pain. Moreover, this study might contribute to the knowledge base for further research on better therapeutic possibilities for neuropathic pain. PMID- 28361772 TI - Advancing methods for characterizing structure and functions of small nerve fibres in neuropathic conditions. PMID- 28361773 TI - Stimulation-induced expression of immediate early gene proteins in the dorsal horn is increased in neuropathy. PMID- 28361774 TI - Targeting glial dysfunction to treat post-surgical neuropathic pain. PMID- 28361775 TI - Impaired recognition memory and cognitive flexibility in the rat L5-L6 spinal nerve ligation model of neuropathic pain. AB - BACKGROUND AND AIMS: Although neuropathic pain is known to negatively affect cognition, the neural mechanisms involved are poorly understood. Chronic pain is associated with changes in synaptic plasticity in the brain which may impact on cognitive functioning. The aim of this study was to model neuropathic pain in mid aged rats using spinal nerve ligation (SNL). Following establishment of allodynia and hyperalgesia, behaviour was assessed in a battery of cognitive tests. Expression of the presynaptic protein, synaptophysin, and its colocalisation with the vesicular GABA and glutamate transporters (vGAT and vGLUT, respectively), was investigated in the medial prefrontal cortex (mPFC) and hippocampus. METHODS: Nine month old male Sprague Dawley rats underwent L5-L6 spinal nerve ligation or a sham procedure. Mechanical and cold allodynia and thermal hyperalgesia were assessed using von Frey, acetone and Hargreaves tests, respectively. Cognition was assessed in the novel-object recognition, air-puff passive avoidance and Morris water maze behavioural tasks. Immunohistochemistry was used to examine the expression of synaptophysin in the mPFC and CA1 region of the hippocampus and double labelling of synaptophysin and the vesicular transporters vGAT and vGlut was used to investigate the distribution of synaptophysin on GABAergic and glutamatergic neurons. RESULTS: SNL rats displayed impaired performance in the novel-object recognition task. Passive-avoidance responding, and spatial learning and memory in the Morris water maze, were unaffected by SNL surgery. However, in the water maze reversal task, pain-related impairments were evident during training and probe trials. SNL surgery was not associated with any differences in the expression of synaptophysin or its colocalisation with vGAT or vGLUT in the mPFC or the hippocampal CA1 region. CONCLUSIONS: These results suggest that the SNL model of neuropathic pain is associated with deficits in recognition memory and cognitive flexibility, but these deficits are not associated with altered synaptophysin expression or distribution in the mPFC and CA1. IMPLICATIONS: Cognitive complaints are common amongst chronic pain patients. Here we modelled cognitive impairment in a well-established animal model of neuropathic pain and investigated the neural mechanisms involved. A better understanding of this phenomenon is an important prerequisite for the development of improved treatment of patients affected. PMID- 28361776 TI - Glial dysfunction and persistent neuropathic postsurgical pain. AB - BACKGROUND: Acute pain in response to injury is an important mechanism that serves to protect living beings from harm. However, persistent pain remaining long after the injury has healed serves no useful purpose and is a disabling condition. Persistent postsurgical pain, which is pain that lasts more than 3 months after surgery, affects 10-50% of patients undergoing elective surgery. Many of these patients are affected by neuropathic pain which is characterised as a pain caused by lesion or disease in the somatosensory nervous system. When established, this type of pain is difficult to treat and new approaches for prevention and treatment are needed. A possible contributing mechanism for the transition from acute physiological pain to persistent pain involves low-grade inflammation in the central nervous system (CNS), glial dysfunction and subsequently an imbalance in the neuron-glial interaction that causes enhanced and prolonged pain transmission. AIM: This topical review aims to highlight the contribution that inflammatory activated glial cell dysfunction may have for the development of persistent pain. METHOD: Relevant literature was searched for in PubMed. RESULTS: Immediately after an injury to a nerve ending in the periphery such as in surgery, the inflammatory cascade is activated and immunocompetent cells migrate to the site of injury. Macrophages infiltrate the injured nerve and cause an inflammatory reaction in the nerve cell. This reaction leads to microglia activation in the central nervous system and the release of pro inflammatory cytokines that activate and alter astrocyte function. Once the astrocytes and microglia have become activated, they participate in the development, spread, and potentiation of low-grade neuroinflammation. The inflammatory activated glial cells exhibit cellular changes, and their communication to each other and to neurons is altered. This renders neurons more excitable and pain transmission is enhanced and prolonged. Astrocyte dysfunction can be experimentally restored using the combined actions of a MU-opioid receptor agonist, a MU-opioid receptor antagonist, and an anti-epileptic agent. To find these agents we searched the literature for substances with possible anti inflammatory properties that are usually used for other purposes in medicine. Inflammatory induced glial cell dysfunction is restorable in vitro by a combination of endomorphine-1, ultralow doses of naloxone and levetiracetam. Restoring inflammatory-activated glial cells, thereby restoring astrocyte-neuron interaction has the potential to affect pain transmission in neurons. CONCLUSION: Surgery causes inflammation at the site of injury. Peripheral nerve injury can cause low-grade inflammation in the CNS known as neuroinflammation. Low-grade neuroinflammation can cause an imbalance in the glial-neuron interaction and communication. This renders neurons more excitable and pain transmission is enhanced and prolonged. Astrocytic dysfunction can be restored in vitro by a combination of endomorphin-1, ultralow doses of naloxone and levetiracetam. This restoration is essential for the interaction between astrocytes and neurons and hence also for modulation of synaptic pain transmission. IMPLICATIONS: Larger studies in clinical settings are needed before these findings can be applied in a clinical context. Potentially, by targeting inflammatory activated glial cells and not only neurons, a new arena for development of pharmacological agents for persistent pain is opened. PMID- 28361777 TI - Pain treatment with intrathecal corticosteroids: Much ado about nothing? But epidural corticosteroids for radicular pain is still an option. PMID- 28361778 TI - Obesity has an impact on outcome in lumbar disc surgery. AB - PURPOSE: To investigate the effect of obesity on outcome in lumbar discectomy. METHODS: A cross-sectional postal survey; a self-made questionnaire, Beck depression inventory IA (BDI IA) and the Oswestry low back disability questionnaire (ODI) were sent to the patients, who had undergone lumbar disc surgery in the Oulu University Hospital between June 2005 and May 2008. Patients were divided into three groups according to BMI: normal, pre-obese and obese. The ODI was also examined in the framework of the international classification of functioning, disability and health (ICF) to investigate its ability to describe various dimensions of functioning (body structure and functions, activities and participation). RESULTS: The postal survey was sent to 642 patients, of whom 355 (55%) replied. Males dominated in the pre-obese (66%) and obese (62%) groups (p=0.01). Normal-weighted and pre-obese patients had lower BDI scores compared to obese patients (mean BDI: 8.0, 7.6, 11.2, respectively, p=0.035). Total ODI score was highest in the obese group compared to normal-weighted or pre-obese (20.3, 18.6, 26.4, respectively, p=0.011). When ODI was linked to the ICF there were significant differences in all activity domains (mobility, self-care and interpersonal interactions and relationships) and the mobility component of the participation domain between the weight groups. CONCLUSIONS AND IMPLICATIONS: Obesity has an impact on outcome in lumbar discectomy. Obese patients had higher scores in BDI and ODI indicating mild mood disturbances and moderate functional disability. According to ICF, functional disability of obese patients was observed to some extent in all activity domains. Obese patients will be more frequently present for disc surgery and increased morbidity risk must be recognized. We need a strategy to rehabilitate and activate obese patients pre- and postoperatively. PMID- 28361779 TI - Analgesic properties of intrathecal glucocorticoids in three well established preclinical pain models. AB - BACKGROUND AND AIMS: Glucocorticoids, a group of anti-inflammatory agents, are frequently administered in pain medicine. Of interest is the reported activity after intrathecal delivery in patients with neuropathic pain syndromes such as postherpetic neuralgia, though its efficacy is controversial. After the publication of two randomized clinical trials in postherpetic neuralgia patients treated with similar intrathecal methylprednisolone acetate (MPA) dosing regimes with conflicting results; one showing significant pain reduction (Kotani N, Kushikata T, Hashimoto H, Kimura F, Muraoka M, Yodono M, Asai M, Matsuki A: Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med 2000;23: 1514-9), the other increased pain sensations (Rijsdijk M, van Wijck AJ, Meulenhoff PC, Kavelaars A, van der Tweel I, Kalkman CJ: No beneficial effect of intrathecal methylprednisolone acetate in postherpetic neuralgia patients. Eur J Pain 2013;38: 175-200), we decided additional research was warranted. Present study sought to determine effects of intrathecally delivered methylprednisolone on pain-like behaviour and pain-associated markers in three well established rodent pain models: (1) intraplantar carrageenan, (2) intraplantar formalin, and (3) ligation of L5/L6 spinal nerves (SNL model). METHODS: Male rats with intrathecal catheters were examined for (1) tactile allodynia after unilateral hindpaw intraplantar carrageenan injection (2%), (2) flinching and subsequent long term tactile allodynia after unilateral hindpaw intraplantar formalin injection (2.5%) or (3) tactile allodynia after unilateral ligation of the L5 and L6 spinal nerves. Rats were treated with the maximum tolerable intrathecal dose of the soluble methylprednisolone sodium succinate (MP) or the particulate methylprednisolone acetate (MPA). Dorsal root ganglia and spinal cords were harvested for immunohistochemistry to assess markers of neuronal damage (ATF3) and glial activation (GFAP, Iba1). RESULTS: During dose finding, severe generalized allodynia was observed with high intrathecal doses of both MPA and MP in naive rats. MPA had no effect upon tactile allodynia after carrageenan. MP and MPA did not reverse tactile allodynia in the SNL model, and did not reduce flinching in the formalin model. MP and MPA prevented the delayed (7-day) tactile allodynia otherwise observed in the formalin-injected paw. Systemic MP or perineural MP or MPA did not reduce pain-like behaviour in the SNL model. No reduction of neuronal injury (ATF3) in the dorsal root ganglion or astrocyte activation (GFAP) in the spinal dorsal horn with intrathecal MP or MPA was observed. There was a decrease in microglial activation (Iba1) in the spinal dorsal horn with MPA after SNL. CONCLUSION: Severe generalized allodynia was observed after high intrathecal doses of MP and MPA in naive rats. No acute analgesic effects with intrathecal glucocorticoids were observed in three well established pain models. Only a late antiallodynic effect was present in the formalin model, 7 days after formalin injection and drug treatment. IMPLICATIONS: Our results do not support use of intrathecal methylprednisolone in the treatment of pain. PMID- 28361780 TI - A candidate reference method for serum potassium measurement by inductively coupled plasma mass spectrometry. AB - BACKGROUND: Potassium is an important serum ion that is frequently assayed in clinical laboratories. Quality assurance requires reference methods; thus, the establishment of a candidate reference method for serum potassium measurements is important. METHODS: An inductively coupled plasma mass spectrometry (ICP-MS) method was developed. Serum samples were gravimetrically spiked with an aluminum internal standard, digested with 69% ultrapure nitric acid, and diluted to the required concentration. The 39K/27Al ratios were measured by ICP-MS in hydrogen mode. The method was calibrated using 5% nitric acid matrix calibrators, and the calibration function was established using the bracketing method. RESULTS: The correlation coefficients between the measured 39K/27Al ratios and the analyte concentration ratios were >0.9999. The coefficients of variation were 0.40%, 0.68%, and 0.22% for the three serum samples, and the analytical recovery was 99.8%. The accuracy of the measurement was also verified by measuring certified reference materials, SRM909b and SRM956b. Comparison with the ion selective electrode routine method and international inter-laboratory comparisons gave satisfied results. CONCLUSIONS: The new ICP-MS method is specific, precise, simple, and low-cost, and it may be used as a candidate reference method for standardizing serum potassium measurements. PMID- 28361782 TI - Laboratory testing in the emergency department: an Italian Society of Clinical Biochemistry and Clinical Molecular Biology (SIBioC) and Academy of Emergency Medicine and Care (AcEMC) consensus report. PMID- 28361781 TI - Serum complexed and free prostate-specific antigen (PSA) for the diagnosis of the polycystic ovarian syndrome (PCOS). AB - BACKGROUND: Polycystic ovarian syndrome (PCOS) is a common cause of reproductive and metabolic dysfunction. We hypothesized that serum prostate-specific antigen (PSA) may constitute a new biomarker for hyperandrogenism in PCOS. METHODS: We conducted a cross-sectional study of 45 women with PCOS and 40 controls. Serum from these women was analyzed for androgenic steroids and for complexed PSA (cPSA) and free PSA (fPSA) with a novel fifth- generation assay with a sensitivity of ~10 fg/mL for cPSA and 140 fg/mL for fPSA. RESULTS: cPSA and fPSA levels were about three times higher in PCOS compared to controls. However, in PCOS, cPSA and fPSA did not differ according to waist-to-hip ratio, Ferriman Gallwey score, or degree of hyperandrogenemia or oligo-ovulation. In PCOS and control women, serum cPSA and fPSA levels were highly correlated with each other, and with free and total testosterone levels, but not with other hormones. Adjusting for age, body mass index (BMI) and race, cPSA was significantly associated with PCOS, with an odds ratio (OR) of 5.67 (95% confidence interval [CI]: 1.86, 22.0). The OR of PCOS for fPSA was 7.04 (95% CI: 1.65, 40.4). A multivariate model that included age, BMI, race and cPSA yielded an area-under the-receiver-operating-characteristic curve of 0.89. CONCLUSIONS: Serum cPSA and fPSA are novel biomarkers for hyperandrogenism in PCOS and may have value for disease diagnosis. PMID- 28361783 TI - A Theorem at the Core of Colliding Bias. AB - Conditioning on a shared outcome of two variables can alter the association between these variables, possibly adding a bias component when estimating effects. In particular, if two causes are marginally independent, they might be dependent in strata of their common effect. Explanations of the phenomenon, however, do not explicitly state when dependence will be created and have been largely informal. We prove that two, marginally independent, causes will be dependent in a particular stratum of their shared outcome if and only if they modify each other's effects, on a probability ratio scale, on that value of the outcome variable. Using our result, we also qualify the claim that such causes will "almost certainly" be dependent in at least one stratum of the outcome: dependence must be created in one stratum of a binary outcome, and independence can be maintained in every stratum of a trinary outcome. PMID- 28361784 TI - Obituary - Edward Ogata (1945-2017). PMID- 28361785 TI - Whither National Medical Commission (NMC) Bill? PMID- 28361786 TI - What Predicts Intergenerational Change in Anthropometry? PMID- 28361787 TI - IAP Guidelines on Rickettsial Diseases in Children. AB - OBJECTIVE: To formulate practice guidelines on rickettsial diseases in children for pediatricians across India. JUSTIFICATION: Rickettsial diseases are increasingly being reported from various parts of India. Due to low index of suspicion, nonspecific clinical features in early course of disease, and absence of easily available, sensitive and specific diagnostic tests, these infections are difficult to diagnose. With timely diagnosis, therapy is easy, affordable and often successful. On the other hand, in endemic areas, where healthcare workers have high index of suspicion for these infections, there is rampant and irrational use of doxycycline as a therapeutic trial in patients of undifferentiated fevers. Thus, there is a need to formulate practice guidelines regarding rickettsial diseases in children in Indian context. PROCESS: A committee was formed for preparing guidelines on rickettsial diseases in children in June 2016. A meeting of consultative committee was held in IAP office, Mumbai and scientific content was discussed. Methodology and results were scrutinized by all members and consensus was reached. Textbook references and published guidelines were also used in few instances to make recommendations. Various Indian and international publications pertinent to present study were collated and guidelines were approved by all committee members. Future updates in these guidelines will be dictated by new scientific data in the field of rickettsial diseases in children. RECOMMENDATIONS: Indian tick typhus and scrub typhus are commonly seen rickettsial diseases in India. It is recommended that practicing pediatricians should be well conversant with compatible clinical scenario, suggestive epidemiological features, differential diagnoses and suggestive laboratory features to make diagnosis and avoid over diagnosis of these infections, as suggested in these guidelines. Doxycycline is the drug of choice and treatment should begin promptly without waiting for confirmatory laboratory results. PMID- 28361788 TI - Indian Childhood Cirrhosis - A Forgotten Entity. PMID- 28361789 TI - Vaccine Associated Paralytic Poliomyelitis Unmasking Common Variable Immunodeficiency. AB - BACKGROUND: Oral polio vaccine can rarely lead to Vaccine-associated paralytic poliomyelitis (VAPP). CASE CHARACTERISTICS: A 2-year-old child with asymmetric paralysis of lower limbs following first booster of oral polio vaccine; type 2 Vaccine-derived poliovirus (VDPV) isolated. Subsequently, the child was diagnosed to have common variable immunodeficiency. OUTCOME: Paralysis gradually improved on follow-up; monthly intravenous immunoglobulin therapy started for primary immunodeficiency. MESSAGE: We need to evaluate children with VAPP for underlying immunodeficiency. PMID- 28361790 TI - Neurological Manifestations of Chikungunya in Children. PMID- 28361791 TI - Acute Generalized Exanthematous Pustulosis. PMID- 28361792 TI - Calcinosis Cutis. PMID- 28361794 TI - Fabrication of beta-tricalcium phosphate composite ceramic sphere-based scaffolds with hierarchical pore structure for bone regeneration. AB - Polymer sphere-based scaffolds, which are prepared by bonding the adjacent spheres via sintering the randomly packed spheres, feature uniform pore structure, full three-dimensional (3D) interconnection, and considerable mechanical strength. However, bioceramic sphere-based scaffolds fabricated by this method have never been reported. Due to high melting temperature of bioceramic, only limited diffusion rate can be achieved when sintering the bioceramic spheres, which is far from enough to form robust bonding between spheres. In the present study, for the first time we fabricated 3D interconnected beta-tricalcium phosphate ceramic sphere-based (PG/TCP) scaffolds by introducing phosphate-based glass (PG) as sintering additive and placing uniaxial pressure during the sintering process. The sintering mechanism of PG/TCP scaffolds was unveiled. The PG/TCP scaffolds had hierarchical pore structure, which was composed by interconnected macropores (>200 MUm) among spheres, pores (20-120 MUm) in the interior of spheres, and micropores (1-3 MUm) among the grains. During the sintering process, partial PG reacted with beta-TCP, forming beta Ca2P2O7; metal ions from PG substituted to Ca2+ sites of beta-TCP. The mechanical properties (compressive strength 2.8-10.6 MPa; compressive modulus 190-620 MPa) and porosity (30%-50%) of scaffolds could be tailored by manipulating the sintering temperatures. The introduction of PG accelerated in vitro degradation of scaffolds, and the PG/TCP scaffolds showed good cytocompatibility. This work may offer a new strategy to prepare bioceramic scaffolds with satisfactory physicochemical properties for application in bone regeneration. PMID- 28361796 TI - Why research on Endocrine Disrupting Chemicals is still worthwhile. Editorial. PMID- 28361793 TI - Modeling the response of small myelinated axons in a compound nerve to kilohertz frequency signals. AB - OBJECTIVE: There is growing interest in electrical neuromodulation of peripheral nerves, particularly autonomic nerves, to treat various diseases. Electrical signals in the kilohertz frequency (KHF) range can produce different responses, including conduction block. For example, EnteroMedics' vBloc(r) therapy for obesity delivers 5 kHz stimulation to block the abdominal vagus nerves, but the mechanisms of action are unclear. APPROACH: We developed a two-part computational model, coupling a 3D finite element model of a cuff electrode around the human abdominal vagus nerve with biophysically-realistic electrical circuit equivalent (cable) model axons (1, 2, and 5.7 um in diameter). We developed an automated algorithm to classify conduction responses as subthreshold (transmission), KHF evoked activity (excitation), or block. We quantified neural responses across kilohertz frequencies (5-20 kHz), amplitudes (1-8 mA), and electrode designs. MAIN RESULTS: We found heterogeneous conduction responses across the modeled nerve trunk, both for a given parameter set and across parameter sets, although most suprathreshold responses were excitation, rather than block. The firing patterns were irregular near transmission and block boundaries, but otherwise regular, and mean firing rates varied with electrode-fibre distance. Further, we identified excitation responses at amplitudes above block threshold, termed 're excitation', arising from action potentials initiated at virtual cathodes. Excitation and block thresholds decreased with smaller electrode-fibre distances, larger fibre diameters, and lower kilohertz frequencies. A point source model predicted a larger fraction of blocked fibres and greater change of threshold with distance as compared to the realistic cuff and nerve model. SIGNIFICANCE: Our findings of widespread asynchronous KHF-evoked activity suggest that conduction block in the abdominal vagus nerves is unlikely with current clinical parameters. Our results indicate that compound neural or downstream muscle force recordings may be unreliable as quantitative measures of neural activity for in vivo studies or as biomarkers in closed-loop clinical devices. PMID- 28361795 TI - Native extracellular matrix/fibroin hydrogels for adipose tissue engineering with enhanced vascularization. AB - Adipose tissue engineering is a promising field for regeneration of soft tissue defects. However, vascularization is needed since nutrients and oxygen cannot reach cells in thick implants by diffusion. Obtaining a biocompatible scaffold with good mechanical properties is another problem. In this study, we aimed to develop thick and vascularized adipose tissue constructs supporting cell viability and adipose tissue regeneration. Hydrogels were prepared by mixing rat decellularized adipose tissue (DAT) and silk fibroin (Fib) at different v/v ratios (3:1, 1:1 and 1:3) and vortexing. Gelation times decreased with increasing fibroin ratio Among hydrogel groups 1:3-DAT:Fib ratio group showed similar mechanical properties with adipose tissue. Both pre-adipocytes and pre endothelial cells, pre-differentiated from adipose derived stem cells (ASCs), were encapsulated in hydrogels at a 1: 3 ratio. In vitro analyses showed that hydrogels with 1:3 (v/v) DAT:Fib ratio supported better cell viability. Pre adipocytes had lipid vesicles, and pre-endothelial cells formed tubular structures inside hydrogels only after 3 days in vitro. When endothelial and adipogenic pre-differentiated ASCs (for 7 days before encapsulation) were encapsulated together into 1:3-DAT:Fib hydrogels both cell types continued to differentiate into the committed cell lineage. Vascularization process in the hydrogels implanted with adipogenic and endothelial pre-differentiated ASCs took place between the first and second week after implantation which was faster than observed in the empty hydrogels. ASCs pre-differentiated towards adipogenic lineage inside hydrogels had begun to accumulate lipid vesicles after 1 week of subcutaneous implantation Based on these results, we suggest that 1:3-DAT:Fib hydrogels with enhanced vascularization hold promise for adipose tissue engineering. PMID- 28361797 TI - Knowledge and participation. Moving towards scientific citizenship. Editorial. PMID- 28361798 TI - Research on biological materials of human origin. Jurists and scientists face to face. Commentary. AB - On 3rd October 2016 a convention was held in the Aldo Moro room of the Chamber of Deputies on "Research on biological materials of human origin. Jurists and scientists face to face". The convention was organised by the Bioethics Unit of the Istituto Superiore di Sanita (ISS, Italian National Institute of Health) in conjunction with the Italian Academy of the Internet Code (IAIC) and the Fondazione Centro di Iniziativa Giuridica Piero Calamandrei. The present contribution reports the topics discussed and the key conclusions reached. As a follow-up to the discussion, the scientists, jurists and institutions concerned are resolved to take further steps towards the formulation of operational proposals intended to facilitate research using human biological materials within a framework of precise and strict regulations. PMID- 28361799 TI - Do I need training in public health ethics? A survey on Italian residents' beliefs, knowledge and curricula. AB - INTRODUCTION: Ethics is needed to support the decision-making process in public health and to face moral issues during practice. However, professionals are often not adequately trained. OBJECTIVES: In 2015, the National Conference of Public Health Medical Residents of the Italian Society of Public Health started the "Public Health Ethics" workgroup to evaluate how the Italian Schools of Public Health train their residents in ethics, and which are residents' beliefs, knowledge and attitudes about public health ethics. METHODS: A survey was built and emailed to the Italian public health residents. RESULTS: Residents are interested in ethics/bioethics (83.2%) and are aware of its importance for professional practice (97.2%). However, few of them (19.6%) evaluated their competence above a satisfactory level. They believe that a training in ethics should be offered during residency (92.1%). Nonetheless, in Italy only two schools required a course on bioethics, and one a course in public health ethics. According to residents, a public health ethics trainer should be a public health professional (23.2%) or a social scientist (22.8%). CONCLUSIONS: In Italy, Schools of Public Health do not train future professionals in ethics or public health ethics during residency. Training should be implemented in curricula, and trainers should have a strong competence in both public health and ethics. PMID- 28361800 TI - The product of the human AHI-1 (Abelson helper integration site) gene: experimental in vitro data point to its involvement in tumor cell invasion. AB - INTRODUCTION: Each of the steps involved in invasion of tumors requires specific molecular program in which the modulation of adhesive and migratory properties of disseminating cells plays an essential role. The improvement in the knowledge of these mechanisms can lead to discovery of new target candidates in drug development. In this study we focused attention on the product of the human AHI-1 (Abelson helper integration site) gene Jouberin (Jbn). METHODS: In particular, we explore by in vitro invasion assay, AHI-1 knockdown and electron microscopy, if Jbn is involved in the signaling machinery that regulates tumor invasion. To this purpose tumor cells of different histological derivation (brain, breast, skin) were employed. RESULTS: We found that Jbn expression correlates with the proliferation, invasive potential and invasion strategy of the tested tumor cells, and that its downregulation reduces their capability of migrating and invading the extracellular matrix. CONCLUSIONS: The results obtained in this study for the first time point to Jbn as a new candidate involved in the invasion process of tumor cells, and as potential molecular target in anticancer therapy. PMID- 28361801 TI - Uterus transplants and their ethical implications. AB - Early experiments in womb transplants have increased interest in the possibility of performing this procedure in women who have no womb, usually for congenital reasons. The present article describes past experiments and summarises the most relevant reference documents before indicating the key ethical implications involved in womb transplants. PMID- 28361802 TI - Molecular characterization of Babesia and Theileria species in ticks collected in the outskirt of Monte Romano, Lazio Region, Central Italy. AB - BACKGROUND: In 2012-2013, an investigation was carried out in the Viterbo province, Lazio region, on ticks and tick-borne Apicomplexan protozoa of the Babesia and Theileria genera. This followed the reporting of high density of ticks by soldiers operating in a military shooting range, and the signaling by owners and local veterinary authorities of several cases of babesiosis among cattle. METHODS: A total of 422 ticks were collected from 35 heads, whereas 96 ticks were collected by dragging. Ticks were identified as Rhipicephalus (Boophilus) annulatus Say (n = 373), Rhipicephalus bursa Canestrini & Fanzago (n = 63), Rhipicephalus sanguineus/turanicus (n = 32), Hyalomma marginatum Koch (n = 49) and Dermacentor marginatus Sulzer, 1776 (n = 1). A randomly selected sample of ticks (235 from animals and 36 by dragging) was analyzed using molecular methods to detect species of Babesia and Theileria. RESULTS: In total, 11 ticks collected from animals (4.7%) and two ticks (5.5%) collected by dragging were positive. Sequencing of PCR products of the small subunit ribosomal RNA gene revealed Babesia caballi (n = 2), Babesia bigemina (n = 3), Theileria sergenti/buffeli/orientalis (n = 7) and Theileria equi (n = 1). None of the detected species has been associated with human infection. PMID- 28361803 TI - Illicit drugs in Emergency Department patients injured in road traffic accidents. AB - Urine and blood samples from 1730 drivers involved in road accidents (July 2012 - December 2015) were analyzed for the evaluation of driving under influence of drug of abuse according to the Lombardia Region guideline. The 22.5% (95% CI 20.5 to 24.5) of urine screenings tested positive for at least one class of drugs. 10.6% (95% CI 9.2 to 12.1) of the 1730 drivers were under the influence of drug, being blood concentration above the cut-off limit for at least one active substance; the proportion of illicit drugs in blood was cocaine 5.7 % (95% CI 4.7 to 6.9), cannabinoids 3.7 % (95% CI 2.9 to 4.7), opiates 1.4% (95% CI 0.9 to 2.1), methadone 1.4% (95% CI 0.9 to 2.1), amphetamines 0.2% (95% CI 0.04 to 0.5). Trend in proportion showed similar percentage (about 5%) of cocaine and cannabinoids consumption in the last two years. Poly-drug of abuse consumption emerged in the 10.4% (95% CI 6.4 to 15.7) of the positive blood and alcohol was above the legal limit in 47% (95% CI 39.6 to 54.5) of the subjects driving under the influence of drugs. PMID- 28361804 TI - Risk adjusted mortality after hip replacement surgery: a retrospective study. AB - INTRODUCTION: Hip replacement (HR) operations are increasing. Short term mortality is an indicator of quality; few studies include risk adjustment models to predict HR outcomes. We evaluated in-hospital and 30-day mortality in hospitalized patients for HR and compared the performance of two risk adjustment algorithms. MATERIALS AND METHODS: A retrospective cohort study on hospital discharge records of patients undergoing HR from 2000 to 2005 in Tuscany Region, Italy, applied All-Patient Refined Diagnosis Related Groups (APR-DRG) and Elixhauser Index (EI) risk adjustment models to predict outcomes. Logistic regression was used to analyse the performance of the two models; C statistic (C) was used to define their discriminating ability. RESULTS: 25 850 hospital discharge records were studied. In-hospital and 30-day crude mortality were 1.3% and 3%, respectively. Female gender was a significant (p < 0.001) protective factor under both models and had the following Odds Ratios (OR): 0.64 for in hospital and 0.51 for 30-day mortality using APR-DRG and 0.55 and 0.48, respectively, with EI. Among EI comorbidities, heart failure and liver disease were associated with in-hospital (OR 9.29 and 5.60; p < 0.001) and 30-day (OR 6.36 and 3.26; p < 0.001) mortality. Increasing age and APR-DRG risk class were predictive of all the outcomes. Discriminating ability for in-hospital and 30-day mortality was reasonable with EI (C 0.79 and 0.68) and good with APR-DRG (C 0.86 and 0.82). CONCLUSIONS: Our study found that gender, age, EI comorbidities and APR-DRG risk of death are predictive factors of in-hospital and 30-day mortality outcomes in patients undergoing HR. At least one risk adjustment algorithm should always be implemented in patient management. PMID- 28361805 TI - Hospital efficiency: how to spend less maintaining quality? AB - INTRODUCTION: The recent global economic crisis is pushing governments worldwide to obtain a more explicit and urgent rationing of resources. The purpose of this study is to provide, through Data Envelopment Analysis (DEA), a methodological framework useful for investigating technical efficiency of hospital care. METHODS: To validate such framework, we compared 50 Italian public hospital trusts (AOs) to identify relative efficient using inputs and outputs from national databases. We also evaluated if, and how, efficiency is affected by various exogenous factors. RESULTS: On average, Italian AOs had an efficiency score of 77% (SD 0.12). Tobit regression model identified a positive association between efficiency and a lower case-mix index, being in the north of Italy, in a region with fiscal autonomy, with a higher public and a lower private expenditure on health as percentage of GDP. CONCLUSIONS: DEA may provide useful and especially objective information regarding the technical efficiency of hospital care and support hospital management and policy makers' decisions. PMID- 28361806 TI - Association between serum vitamin D and metabolic syndrome in middle-aged and older adults and role of supplementation therapy with vitamin D. AB - OBJECTIVES: To evaluate i) the correlation between vitamin D (vit. D) serum concentrations and metabolic syndrome (MetS); ii) the efficacy of 6 months supplementation therapy with vit. D. METHOD: 200 patients were enrolled. Blood analyses and anthropometric measurements were carried out. Patients with hypovitaminosis D received an oral supplement therapy. RESULTS: 81% of the sample shows vit. D levels < 30 ng/mL. Rate of MetS was significantly higher in vit. D deficiency group than in vit D insufficiency (p = 0.009) and sufficiency (p = 0.002) groups. Vit. D shows a significant negative correlation with both waist circumference (WC) (rho - 0.202 p = 0.004) and glycaemia values (FBG) (rho -0.185 p = 0.009). After the supplementation therapy in a group of 60 subjects a significant increase in vit. D levels (p = 0.001) and a significant reduction in WC values (p = 0.001) were observed. CONCLUSIONS: MetS, WC and FBG appeared to be associated vit. D status and it is well-known that central obesity, with the inflammatory alterations thereto correlated that determine insulin resistance, can be considered the "primum movens" for the development of MetS. PMID- 28361807 TI - The Italian reference sites of the European innovation partnership on active and healthy ageing: Progetto Mattone Internazionale as an enabling factor. AB - BACKGROUND: Ageing population implies an increasing demand for health care services and resources, unsustainable according to current previsions. The European Commission is tackling this challenge throughout initiatives such as the European Innovation Partnership on Active and Healthy Ageing (EIP-AHA), where all the efforts are aligned to the common goal of adding two active and healthy years to the life of European Union (EU) citizens. METHOD: We presented the collaborative efforts of Italian Reference Site Collaborative Network 2012-2015. RESULTS: Italian regions joined forces through the "Progetto Mattone Internazionale" of the Ministry of Health developing several national and international collaborations. Activities from all five Italian reference sites are presented with different good practices and scale-up approaches for improving health in ageing population. DISCUSSION: The simultaneous development of these activities allowed the strengthening of the coordination of Italian stakeholders in the European arena fostering collaboration and supporting the streamlining of the Italian regions still outside these projects. PMID- 28361808 TI - Appropriateness and efficacy of Spa therapy for musculoskeletal disorders. A Delphi method consensus initiative among experts in Italy. AB - OBJECTIVE: The aim of the study was to identify the main aspects concerning appropriateness and efficacy of Spa therapy for musculoskeletal pathologies. METHODS: A committee of 8 experts from Italian universities, public hospitals, territorial services, research institutes and patient associations was set up. Clinicians from Italian medical centers specialized in rheumatology, rehabilitation and thermal medicine took part in a Delphi process aimed at obtaining consensus statements among the participants. RESULTS: Large consensus was obtained for statements grouped under the following main themes: treatment indications; choice of treatment modality and treatment efficacy. CONCLUSIONS: The experts developed a number of consensus statements which may be used as a practical reference to guide the choice of physicians to treat musculoskeletal diseases with Spa therapy. PMID- 28361809 TI - Association of non-alcoholic fatty liver disease and cardiometabolic risk factors with early atherosclerosis in an adult population in Southern Italy. AB - AIM: The prevalence of risk factors for cardiovascular and metabolic diseases was investigated in an adult population of the city of Cittanova, Southern Italy. METHODS: The study was conducted among 992 randomly selected adults aged 18-75 years, between April 2009 and January 2011. RESULTS: Prevalence rates of non alcoholic fatty liver disease (NAFLD), overweight, obesity, and metabolic syndrome (MS) were 24.8%, 41.5%, 27.1%, and 34.4%, respectively. For the components of MS, prevalence of central obesity was 47.4%, impaired fasting glucose (IFG) 34.7%; hypertension 53.7%, low high-density lipoprotein (HDL) cholesterol 34.2%, and hypertriglyceridemia 27.2%. CONCLUSIONS: Hypertension, central obesity, IFG, low HDL cholesterol, hypertriglyceridemia, MS, and increased carotid artery intima-media thickness (IMT) were significantly associated with NAFLD after adjustment for age and sex. With additional adjustment for body mass index (BMI), IMT and MS (depending on the prevalence ratio that was investigated), the positive association between the NAFLD and increased IMT lost statistical significance, while that with body mass index (BMI) and MS remained significant. PMID- 28361810 TI - Educational action in the rehabilitation of severe acquired brain injuries: the role of self-awareness. AB - Severe acquired brain injuries (ABI) cause a range of short-or long-term limitations in physical and neuropsychological abilities. The aim of rehabilitation is to promote the harmonious development of the individual through collaboration between medical and educational sciences, involved in the educability of the whole person, in which the aim is not only functional recovery but also social-reintegration. This "functional synergy" permits the development of the person, and establishes an indissoluble link between functions and attitudes, thus allowing the achievement of the greater possible autonomy. In this way classical and pedagogical rehabilitation may be combined in a single concept of educational action. To realize this integrated educational process it is important to evaluate and promote awareness development, based on the possibilities of brain plasticity and on the presence of multiple intelligences skillfully intertwined each other. Therefore, self-awareness plays a prime role in educational actions for the rehabilitation of persons with severe ABI. PMID- 28361811 TI - Predictive value of FSH, testicular volume, and histopathological findings for the sperm retrieval rate of microdissection TESE in nonobstructive azoospermia: a meta-analysis. AB - We performed this meta-analysis to evaluate the predictive value of different parameters in the sperm retrieval rate (SRR) of microdissection testicular sperm extraction (TESE) in patients with nonobstructive azoospermia (NOA). All relevant studies were searched in PubMed, Web of Science, EMBASE, Cochrane Library, and EBSCO. We chose three parameters to perform the meta-analysis: follicle stimulating hormone (FSH), testicular volume, and testicular histopathological findings which included three patterns: hypospermatogenesis (HS), maturation arrest (MA), and Sertoli-cell-only syndrome (SCOS). If there was a threshold effect, only the area under the summary receiver operating characteristic curve (AUSROC) was calculated. Otherwise, the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and the diagnostic odds ratio (DOR) were also calculated. Twenty-one articles were included in our study finally. There was a threshold effect among studies investigating FSH and SCOS. The AUSROCs of FSH, testicular volume, HS, MA, and SCOS were 0.6119, 0.6389, 0.6758, 0.5535, and 0.2763, respectively. The DORs of testicular volume, HS, and MA were 1.98, 16.49, and 1.26, respectively. The sensitivities of them were 0.80, 0.30, and 0.27, while the specificities of them were 0.35, 0.98, and 0.76, respectively. The PLRs of them were 1.49, 10.63, and 1.15, respectively. And NLRs were 0.73, 0.72, and 0.95, respectively. All the investigated factors in our study had limited predictive value. However, the histopathological findings were helpful to some extent. Most patients with HS could get sperm by microdissection TESE. PMID- 28361812 TI - Validity of premature ejaculation diagnostic tool and its association with International Index of Erectile Function-15 in Chinese men with evidence-based defined premature ejaculation. AB - The premature ejaculation diagnostic tool (PEDT) is a brief diagnostic measure to assess premature ejaculation (PE). However, there is insufficient evidence regarding its validity in the new evidence-based-defined PE. This study was performed to evaluate the validity of PEDT and its association with IIEF-15 in different types of evidence-based-defined PE. From June 2015 to January 2016, a total of 260 men complaining of PE and defined as lifelong PE (LPE)/acquired PE (APE) according to the evidence-based definition from Andrology Clinic of the First Affiliated Hospital of Anhui Medical University, along with 104 male healthy controls without PE from a medical examination center, were enrolled in this study. All individuals completed questionnaires including demographics, medical and sexual history, as well as PEDT and IIEF-15. After statistical analysis, it was found that men with PE reported higher PEDT scores (14.28 +/- 3.05) and lower IIEF-15 (41.26 +/- 8.20) than men without PE (PEDT: 5.32 +/- 3.42, IIEF-15: 52.66 +/- 6.86, P < 0.001 for both). It was suggested that a score of >=9 indicated PE in both LPE and APE by sensitivity and specificity analyses (sensitivity: 0.875, 0.913; specificity: 0.865, 0.865, respectively). In addition, IIEF-15 were higher in men with LPE (42.64 +/- 8.11) than APE (39.43 +/ 7.84, P < 0.001). After adjusting for age, IIEF-15 was negatively related to PEDT in men with LPE (adjust r = -0.225, P < 0.001) and APE (adjust r = -0.378, P < 0.001). In this study, we concluded that PEDT was valid in the diagnosis of evidenced-based-defined PE. Furthermore, IIEF-15 was negatively related to PEDT in men with different types of PE. PMID- 28361813 TI - Childhood diabetes mellitus: Advances & challenges. PMID- 28361815 TI - Understanding of skeletal deformities in Parkinson's disease. PMID- 28361814 TI - Macronutrient intake, insulin secretion, oxidative stress & inflammation: Clinico pathological implications. PMID- 28361816 TI - Need for power in genetic explorations of alcoholism in India. PMID- 28361817 TI - Epilepsy: Is there hope? AB - Epilepsy is a highly prevalent chronic neurologic disorder and leads to social, behavioural, health and economic consequences. 'Treatment gap' varies from 10 per cent in developed countries to 75 per cent in low-income countries. Stigma and discrimination related to epilepsy are prevalent worldwide. Electroencephalography (EEG) is considered the most important tool for evaluating the patient with epilepsy. Video-EEG monitoring is an important tool for confirming the seizure type and estimating the epileptogenic zone in the brain. Neuroimaging evaluation is important to determine the aetiology of the epilepsies. Genetic testing has increased the probability of identifying the causes of some types of epilepsies. Epilepsy can be treated in an affordable way with low-cost medications. Refractory epilepsies occur in approximately one-third of recently diagnosed patients with epilepsy. For this group of patients, there are options of surgical treatment, diets and neurostimulation to improve seizure control and quality of life. In poorly organized societies, there is a lack of prioritization of epilepsy in national health policies, limited resources for trained personnel and a shortage of basic antiepileptic medications. There is evidence of improvement in the understanding of epilepsy and a clear progress in the management of epileptic seizures in recent times. PMID- 28361818 TI - Current status of Mycobacterium avium subspecies paratuberculosis infection in animals & humans in India: What needs to be done? AB - Mycobacterium avium subspecies paratuberculosis (MAP) has emerged as a major health problem for domestic livestock and human beings. Reduced per animal productivity of domestic livestock seriously impacts the economics of dairy farming globally. High to very high bioload of MAP in domestic livestock and also in the human population has been reported from north India. Presence of live MAP bacilli in commercial supplies of raw and pasteurized milk and milk products indicates its public health significance. MAP is not inactivated during pasteurization, therefore, entering into human food chain daily. Recovery of MAP from patients with inflammatory bowel disease or Crohn's disease and animal healthcare workers suffering with chronic gastrointestinal problems indicate a close association of MAP with a number of chronic and other diseases affecting human health. Higher bioload of MAP in the animals increases the risk of exposure to the human population with MAP. This review summarizes the current status of MAP infection in animals as well as in human beings and also highlights the prospects of effective management and control of disease in animals to reduce the risk of exposure to human population. PMID- 28361819 TI - Pioglitazone utilization, efficacy & safety in Indian type 2 diabetic patients: A systematic review & comparison with European Medicines Agency Assessment Report. AB - BACKGROUND & OBJECTIVES: With pioglitazone ban and subsequent revoking in India along with varying regulatory decisions in other countries, it was decided to carry out a systematic review on its safety, efficacy and drug utilization in patients with type 2 diabetes mellitus (T2DM) in India and compare with the data from the European Medicines Agency Assessment Report (EMA-AR). METHODS: Systematic review was performed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching Medline/PubMed, Google Scholar and Science Direct databases using 'pioglitazone AND India AND human' and 'pioglitazone AND India AND human AND patient' and compared with EMA-AR. Spontaneous reports in World Health Organization VigiBase from India were compared with VigiBase data from other countries. RESULTS: Sixty six publications, 26 (efficacy), 32 (drug utilization) and eight (safety), were retrieved. In India, pioglitazone was used at 15-30 mg/day mostly with metformin and sulphonylurea, being prescribed to 26.7 and 8.4 per cent patients in north and south, respectively. The efficacy in clinical trials (CTs) was similar to those in EMA-AR. Incidence of bladder cancer in pioglitazone exposed and non exposed patients was not significantly different in an Indian retrospective cohort study. There were two cases and a series of eight cases of bladder cancer published but none reported in VigiBase. INTERPRETATION & CONCLUSIONS: In India, probably due to lower dose, lower background incidence of bladder cancer and smaller sample size in epidemiological studies, association of bladder cancer with pioglitazone was not found to be significant. Reporting of CTs and adverse drug reactions to Clinical Trials Registry of India and Pharmacovigilance Programme of India, respectively, along with compliance studies with warning given in package insert and epidemiological studies with larger sample size are needed. PMID- 28361820 TI - Assessment of striatal & postural deformities in patients with Parkinson's disease. AB - BACKGROUND & OBJECTIVES: Though striatal and postural deformities are known to occur commonly in atypical Parkinsonism patients, these may also be seen in patients with Parkinson's disease (PD). These are frequently misdiagnosed as joint or orthopaedic pathology leading to unnecessary investigations. This study was conducted to observe the various striatal and postural deformities among patients with PD in India. METHODS: This study was conducted at a tertiary care teaching institute in north# India. Seventy consecutive patients with PD diagnosed as per the modified UK Brain Bank criteria were included. Various striatal (hand & foot) and postural (antecollis, camptocormia, scoliosis & Pisa syndrome) deformities and their relation with the duration of disease, severity [measured by the Unified Parkinson's Disease Rating Scale (UPDRS)] and levodopa intake were analyzed. RESULTS: Of the 70 patients with PD, 34 (48.57%) had either striatal or postural deformities. Striatal foot was the most common deformity observed (25.71%). Camptocormia was the second most common deformity (20%). Striatal and postural deformities were seen in more advanced PD as suggested by significantly higher UPDRS and Hoehn and Yahr scale (P<0.001). Striatal deformities were more ipsilateral to PD symptom onset side (agreement 94.44%). Pisa and scoliosis concavity were more on contralateral side to PD symptoms onset side (66.67%). INTERPRETATION & CONCLUSIONS: Our results showed that striatal and postural deformities were common and present in about half of the patients with PD. These deformities we more common in patients with advanced stage of PD. PMID- 28361821 TI - Candidate genes for alcohol dependence: A genetic association study from India. AB - BACKGROUND & OBJECTIVES: Search for candidate genes for alcohol dependence (AD) has been inconsistent and inconclusive. Moreover, most of the research has been confined to a few specific ethnic groups. Hence, the aim of our study was to explore specific candidate genes for AD in north Indian male population. METHODS: In this clinic-based genetic association study, 210 males with AD and 200 controls matched for age, gender and ethnicity were recruited from the clinic and the general population, respectively. Cases were diagnosed with Semi-structured Assessment for Genetics of Alcoholism-II (SSAGA-II). Single-nucleotide polymorphism genotyping was done by real-time quantitative-polymerase chain reaction (PCR) using Taq Man assay (ABI 7500) fast real-time PCR system. RESULTS: Both at the genotypic level and at allelic frequency, Met158 variant of catechol O-methyl transferase (COMT) showed significant increase in cases as compared to controls. The frequency of heterozygous genotype (A/G) of gamma-aminobutyric acid receptor A1 (GABRA1) was significantly lower in cases as compared to controls. Likewise, for GABRA2, the frequency of homozygous recessive genotype (G/G) was significantly higher in the control group. With respect to the 5 hydroxytryptamine (5HT) transporter long promoter region (5HTTLPR), cholinergic receptor muscarinic (CHRM2) and alcohol dehydrogenase 1B (ADH1B) genes, there was no significant difference between the cases and the controls. Aldehyde dehydrogenase (ALDH2) gene was found to be monomorphic in our study population. INTERPRETATION & CONCLUSIONS: Our study findings showed COMT polymorphism conferring risk and GABRA polymorphism as a protective genotype for Indian male with AD. Genes for alcohol metabolism, serotonin transporter and cholinergic receptor gene polymorphism were perhaps not contributory to AD for Indian population. PMID- 28361823 TI - Prevalence & correlates of tobacco use among adolescents in Kerala, India. AB - BACKGROUND & OBJECTIVES: Most tobacco users who initiate its use during adolescence are likely to continue the use into adulthood and contribute to the 90 per cent of premature deaths among tobacco users. In this context the prevalence, patterns and correlates of tobacco use were studied among adolescent school students in Kerala, India. METHODS: Total 7560 students from classes 8, 10 and 12, within the age group of 12-19 yr, across 73 schools in Ernakulam district, Kerala, India, selected by cluster random sampling, completed a self administered questionnaire incorporating standardized instruments. RESULTS: Of the 7350 valid questionnaires, the overall lifetime prevalence of tobacco use was 6.9 per cent (12.5% males and 1.2% females). The prevalence of tobacco use increased from 3.1 per cent at 12-13 yr to 15.1 per cent at 18-19 yr. The mean age of onset of tobacco use was 14.0+/-2.2 yr. The prevalence was higher among students from urban backgrounds, lower socio-economic status and those with part time jobs. Tobacco users had significantly higher rates of use of alcohol (67.8 vs. 11%) and illicit drugs (33 vs. 6.1%). They had poorer academic performance (24.7 vs. 9.1%), more severe psychological distress (10.8 vs. 4.5%), suicidal attempts (10.2 vs. 3.5%), higher scores of ratings of attention deficit hyperactivity disorder (8.3 vs. 2.5%) and history of sexual abuse (12.5 vs. 3.8%). INTERPRETATION & CONCLUSIONS: The prevalence of tobacco use in adolescents reported in this study was relatively lower than those reported from other Indian States. However, it correlates with multiple negative outcomes suggesting a need to promote specific interventions to prevent adolescent tobacco use. PMID- 28361822 TI - Comparative study of clozapine versus risperidone in treatment-naive, first episode schizophrenia: A pilot study. AB - BACKGROUND & OBJECTIVES: Clozapine may be more useful in treatment-naive patients with first-episode schizophrenia for better symptoms control and improving quality of life. The current study was carried out to compare the efficacy and tolerability of clozapine versus risperidone in treatment-naive, first-episode patients of schizophrenia. METHODS: This was a comparative, open-label, six months prospective study of treatment-naive, first-episode patients with schizophrenia between the age group of 18 and 40 yr diagnosed as per the International Classification of Diseases-10 (ICD-10) criteria. A total of 63 patients were recruited and randomly assigned to clozapine group or risperidone group using computer-generated random number tables. Eight patients were lost to follow up. The dosages of the respective drugs were kept in therapeutic range of 200-600 mg/day and 4-8 mg/day orally for clozapine and risperidone, respectively. RESULTS: On general psychopathology score, after six months of intervention, clozapine led to 60.32 per cent mean reduction in Positive and Negative Syndrome Scale (PANSS) for Schizophrenia total score while risperidone led to 56.35 per cent mean reduction in PANSS total score, which meant more improvement with clozapine. Clozapine group was found to have significant improvement in quality of life (P = 0.04339). On Glasgow Antipsychotic Side-effect Scale, clozapine was superior to risperidone. The most common side effects observed in clozapine group were oversedation (78.96%) and dizziness (55.23%), and in risperidone group, common side effects were rigidity (62.36%), sedation (38.69%), tremors (65.69%) and menstrual irregularities in 80.25 per cent of female patients. INTERPRETATION & CONCLUSIONS: The findings of this preliminary study showed clozapine as a better choice than risperidone in terms of efficacy, tolerability and better quality of life in treatment-naive, first-episode schizophrenia. However, further studies need to be done on a larger group of patients to confirm the findings. PMID- 28361824 TI - Postprandial glycaemic response of foxtail millet dosa in comparison to a rice dosa in patients with type 2 diabetes. AB - BACKGROUND & OBJECTIVES: Millets are rich source of dietary fibre and non-starchy polysaccharides with low glycaemic index (GI), hence can be used as a therapeutic diet. This study was conducted to estimate the effects of a millet-based dosa (foxtail dosa) compared to a rice dosa for breakfast on postprandial glucose levels in patients with type 2 diabetes mellitus (T2DM). METHODS: The GI of rice dosa and foxtail millet dosa was estimated. A total of 105 T2DM participants were randomly selected for the study. The participants were on oral hypoglycaemic agents (OHA) and not on insulin. In this study, each individual served as their own control and experimental group. The postprandial increase in blood glucose was compared after a breakfast of rice dosa and millet dosa. Single and paired t test was used to note the change in blood glucose levels and the level of the significance. RESULTS: The GI of foxtail millet dosa was 59.25 and rice dosa was 77.96. There was a significant reduction (P<0.001) in the postprandial glucose level of patients who consumed a millet-based dosa when compared to those who consumed a rice-based dosa. No significant reduction was observed in the fasting glucose levels. INTERPRETATION & CONCLUSIONS: The results suggested that replacing a rice-based breakfast item with a millet-based breakfast item lowers the postprandial blood glucose levels in T2DM patients. Thus, millets may have a protective role in the management of hyperglycaemia. Further studies need to be done in a systematic manner to confirm these findings. PMID- 28361825 TI - Evidence of apoptosis in right ventricular dysfunction in rheumatic mitral valve stenosis. AB - BACKGROUND & OBJECTIVES: Right ventricular (RV) dysfunction is one of the causes of morbidity and mortality in valvular heart disease. The phenomenon of apoptosis, though rare in cardiac muscle may contribute to loss of its function. Role of apoptosis in RV in patients with rheumatic valvular heart disease is investigated in this study. METHODS: Patients with rheumatic mitral valve stenosis formed two groups based on RV systolic pressure (RVSP) as RVSP <40 mmHg (group I, n=9) and RVSP >=40 mmHg (group II, n=30). Patients having atrial septal defect (ASD) with RVSP <40 mmHg served as control (group III, n=15). Myocardial performance index was assessed for RV function. Real-time polymerase chain reaction was performed on muscle biopsy procured from RV to assess expression of pro-apoptotic genes (Bax, cytochrome c, caspase 3 and Fas) and anti-apoptotic genes (Bcl-2). Apoptosis was confirmed by histopathology and terminal deoxynucleotide-transferase-mediated dUTP nick end labelling. RESULTS: Group II had significant RV dysfunction compared to group I (P=0.05) while caspase 3 (P=0.01) and cytochrome c (P=0.03) were expressed excessively in group I. When group I was compared to group III (control), though there was no difference in RV function, a highly significant expression of pro-apoptotic genes was observed in group I (Bax, P=0.02, cytochrome c=0.001 and caspase 3=0.01). There was a positive correlation between pro-apoptotic genes. Nuclear degeneration was present conforming to apoptosis in valve disease patients (groups I and II) while it was absent in patients with ASD. INTERPRETATION & CONCLUSION: Our findings showed evidence of apoptosis in RV of patients with valvular heart disease. Apoptosis was set early in the course of rheumatic valve disease even with lower RVSP, followed by RV dysfunction; however, expression of pro-apoptotic genes regressed. PMID- 28361826 TI - Preventive role of carvedilol in adriamycin-induced cardiomyopathy. AB - BACKGROUND & OBJECTIVES: Adriamycin though considered as an effective anticancer drug, leads to irreversible cardiomyopathy (CMP) and congestive heart failure (CHF). The aim of this study was to determine the protective effect of carvedilol in adriamycin (ADR)-induced cardiomyopathy (CMP) in cancer patients. METHODS: Patients with lymphoreticular malignancy in whom ADR therapy was planned were randomized into two groups: carvedilol and control. Twenty seven patients each were enrolled in carvedilol and control groups. In the carvedilol group, 12.5 mg once daily oral carvedilol was given during six months. The patients were evaluated by echocardiography before and after chemotherapy. Left ventricular ejection fraction (EF) and systolic and diastolic diameters were calculated. RESULTS: At six months of follow up, six patients in the carvedilol group and five in the control group had died. The mean EF (63.19 vs. 63.88%) and fraction shortening (FS) (34 vs. 34.6) of the carvedilol group were similar at follow up, but in the control group, the mean EF (67.27 vs. 60.82%, P =0.003) and FS (38.48 vs. 34.6, P<0.05) at control echocardiography were significantly lower. In carvedilol group, both systolic and diastolic diameters were not changed, but in control group, systolic diameters were significantly increased compared with basal measures (left ventricular end systolic diameter = 28.26+/-5.50 mm vs. 31.25+/- 6.50 mm; P< 0.05). INTERPRETATION & CONCLUSIONS: Prophylactic use of carvedilol in patients receiving anthracycline protected systolic functions of the left ventricle. Carvedilol can be a potential drug which can ameliorate ADR induced CMP. PMID- 28361827 TI - Comparative antinociceptive effect of arachidonylcyclopropylamide, a cannabinoid 1 receptor agonist & lignocaine, a local anaesthetic agent, following direct intrawound administration in rats. AB - BACKGROUND & OBJECTIVES: Treatment of inflammatory pain with opioids is accompanied by unpleasant and, at times, life-threatening side effects.Cannabis produces antinociception as well as psychotropic effects. It was hypothesized that peripheral cannabinoid receptors outside the central nervous system could be selectively activated for relief of pain. This study was undertaken to measure the antinociceptive effect of type 1 cannabinoid receptor (CB1r) agonist arachidonylcyclopropylamide (ACPA) in a rat model of inflammatory pain after intrawound administration and the effects were compared with lignocaine. METHODS: Wounds were produced under controlled conditions by an incision in the right hind paw in rats. ACPA (10, 30 or 100 MUg/10 MUl) was administered directly into the wound. Antinociception was evaluated by guarding, allodynia and thermal hyperalgesia. This was compared to lignocaine (30 MUg/10 MUl). Reversal of ACPA (30 MUg)-mediated antinociceptive effect was attempted by intrawound AM251 (100 MUg), a CB1r antagonist. Antinociception was also evaluated after contralateral administration of ACPA (30 MUg). Primary afferent nociceptive input to the spinal cord was investigated by c-Fos expression after ACPA treatment (100 MUg). RESULTS: ACPA, but not lignocaine, inhibited guarding behaviour, which was locally mediated. Conversely, lignocaine, but not ACPA, inhibited thermal hyperalgesia and mechanical allodynia. ACPA-mediated inhibitory effect was reversible and dose dependent. It was associated with a decreased c-Fos expression. Locomotor activity was unaffected following ACPA (100 MUg) treatment. INTERPRETATION & CONCLUSIONS: Lignocaine attenuated evoked pain behaviour whereas ACPA decreased guarding score. This difference was likely due to blockade of sodium ion channels and the activation of peripheral CB1r, respectively. Central side effects were absent after ACPA treatment. Further studies need to be done to assess the effect of ACPA treatment in clinical conditions. PMID- 28361828 TI - Knowledge, attitude & practice on human papillomavirus vaccination: A cross sectional study among healthcare providers. AB - BACKGROUND & OBJECTIVES: Cervical cancer is a major health problem and a leading cause of death among women in India. Of all the associated risk factors, high risk human papillomavirus (HPV) infections being the principal aetiologic agent, two HPV vaccines are in use for the control of cervical cancer. The present study was undertaken to explore the knowledge, attitude and practice (KAP) on HPV vaccination among the healthcare providers in India. METHODS: A cross-sectional study was conducted among 590 healthcare professionals from 232 hospitals and 80 PHCs of nine districts of Delhi-NCR (National Capital Region). A total of 590 (526 female, 64 male) healthcare providers were surveyed. RESULTS: Only 47 per cent of respondents recommended young women to get vaccinated against HPV. Majority of respondents (81%) were found to be aware about the existence of vaccines for cervical cancer prevention. District-wise, highest (88.3%) awareness about the existence of vaccines against HPV was reported from Gautam Budh Nagar and lowest (64%) in Faridabad. Although 86 per cent of gynaecologists were aware about the names of HPV vaccines available in the market, only 27 per cent of paramedical staff had this knowledge. There was a significant difference between the respondents from government and private sectors regarding their awareness about HPV vaccines. Lack of awareness about the principal cause, risk factors and symptoms for cervical cancer and HPV vaccination was significantly (P< 0.05) reported in the respondents from paramedical staff category. INTERPRETATION & CONCLUSIONS: The findings reinforce continued medical education of healthcare providers, particularly those from the government sector on HPV vaccination for cervical cancer prevention. Public education is also pertinent for a successful HPV vaccination programme in the country. PMID- 28361829 TI - Genetic characterization of human herpesvirus type 1: Full-length genome sequence of strain obtained from an encephalitis case from India. AB - BACKGROUND & OBJECTIVES: Human herpes simplex virus 1 (HSV-1) is the most common cause of sporadic encephalitis in humans that contributes to >10 per cent of the encephalitis cases occurring worldwide. Availability of limited full genome sequences from a small number of isolates resulted in poor understanding of host and viral factors responsible for variable clinical outcome. In this study genetic relationship, extent and source of recombination using full-length genome sequence derived from a newly isolated HSV-1 isolate was studied in comparison with those sampled from patients with varied clinical outcome. METHODS: Full genome sequence of HSV-1 isolated from cerebrospinal fluid (CSF) of a patient with acute encephalitis syndrome (AES) by inoculation in baby hamster kidney-21 (BHK-21) cells was determined using next-generation sequencing (NGS) technology. Phylogenetic analysis of the newly generated sequence in comparison with 33 additional full-length genomes defined genetic relationship with worldwide distributed strains. The bootscan and similarity plot analysis defined recombination crossovers and similarities between newly isolated Indian HSV-1 with six Asian and a total of 34 worldwide isolated strains. RESULTS: Mapping of 376,332 reads amplified from HSV-1 DNA by NGS generated full-length genome of 151,024 bp from newly isolated Indian HSV-1. Phylogenetic analysis classified worldwide distributed strains into three major evolutionary lineages correlating to their geographic distribution. Lineage 1 containing strains were isolated from America and Europe; lineage 2 contained all the strains from Asian countries along with the North American KOS and RE strains whereas the South African isolates were distributed into two groups under lineage 3. Recombination analysis confirmed events of recombination in Indian HSV-1 genome resulting from mixing of different strains evolved in Asian countries. INTERPRETATION & CONCLUSIONS: Our results showed that the full-length genome sequence generated from an Indian HSV 1 isolate shared close genetic relationship with the American KOS and Chinese CR38 strains which belonged to the Asian genetic lineage. Recombination analysis of Indian isolate demonstrated multiple recombination crossover points throughout the genome. This full-length genome sequence amplified from the Indian isolate would be helpful to study HSV evolution, genetic basis of differential pathogenesis, host-virus interactions and viral factors contributing towards differential clinical outcome in human infections. PMID- 28361830 TI - Synergism in dual functionality of cryptdin-2 in conjunction with antibiotics against Salmonella. AB - BACKGROUND & OBJECTIVES: The emergence of multidrug-resistant Salmonella over the last two decades poses a major health risk. In this context, antimicrobial peptides have found a strategic place in the therapeutic armamentarium. Previously, we found that cryptdin-2 has the potential to augment the activity of conventional second- and third-generation anti-Salmonella antibiotics as evident by in vitro assays. In continuation to this, the present study was designed to evaluate the in vivo synergistic effects, if any, of cryptdin-2 in combination with ciprofloxacin and ceftriaxone against murine salmonellosis. METHODS: Scanning electron microscopy (SEM) studies along with in vivo synergistic studies were performed using cryptdin- 2 and antibiotic combinations. In addition, peroxidative liver damage, levels of nitric oxide (NO) and antioxidant enzymes along with tumour necrosis factor-alpha (TNF-alpha) levels were also measured. RESULTS: The SEM results revealed marked changes on the outer membrane of the bacterial cells treated with various combinations. Both the tested combinations demonstrated synergistic in vivo potency against S. Typhimurium as evident by reduction in the number of Salmonellae in the liver, spleen and intestine. Analysis of peroxidative liver damage, levels of NO and antioxidant enzymes along with TNF-alpha and nuclear factor-kappa B levels revealed that the tested combinations restored their levels to near normal. The most potent combination was found to be that of cryptdin-2 and ciprofloxacin in terms of direct killing and immunomodulatory potential. INTERPRETATION & CONCLUSIONS: These findings suggest that cryptdin-2 may act in conjunction with conventional antibiotics indicating the possibility of developing these combinations as additional therapeutic agents to combat Salmonella infections. PMID- 28361831 TI - Evolving management of insulinoma: Experience at a tertiary care centre. AB - BACKGROUND & OBJECTIVES: Since our previous study in 2006, several new modalities for localization of cause of endogenous hyperinsulinemic hypoglycaemia such as multiphasic computed tomography (CT), multiphasic magnetic resonance imaging (MRI), endoscopic ultrasound (EUS), intraoperative ultrasound, and intra-arterial calcium infusion with arterial stimulation venous sampling (ASVS) have become available. Therefore, to evaluate the relative usefulness of various imaging modalities to guide future management in terms of diagnosis and patient care, we analyzed presentation and management of patients of endogenous hyperinsulinemic hypoglycaemia. METHODS: In this retrospective study, medical records of patients admitted with endogenous hyperinsulinemic hypoglycaemia were retrieved. Data pertaining to clinical features, diagnosis, imaging, surgery and patient outcome were extracted. The localization of insulinoma by preoperative imaging techniques was compared with the findings at surgery to assess the accuracy of localization. RESULTS: Fasting hypoglycaemia was present in all, and post-prandial hypoglycaemia (plasma glucose <=50 mg/dl within four hours of meal) in 25.8 per cent. Mean duration of symptoms before reaching a diagnosis of hyperinsulinemic hypoglycaemia was 3.9 years. Mean duration of provocative fast was 21.8 h (range 6-48 h). Among the currently used imaging modalities, the sensitivity of localizing tumour was 79.3 per cent for multiphasic CT, 85 per cent for multiphasic MRI and 95 per cent for EUS. EUS detected tumour missed by both CT and MRI. All, except one of the operated patients, were cured by surgery. INTERPRETATION & CONCLUSIONS: Our results suggest that patients with insulinoma have a varied presentation. Multiphasic contrast-enhanced MRI/CT scan, EUS and ASVS may be complimentary in pre-operative localization. PMID- 28361832 TI - Safety of yellow fever vaccine in Indian travellers: A prospective observational study. PMID- 28361833 TI - Carbapenem resistance in a rural part of southern India: Escherichia coli versus Klebsiella spp. PMID- 28361834 TI - Metastatic skull swelling secondary to neuroblastoma in a child. PMID- 28361835 TI - Unilateral submandibular gland agenesis. PMID- 28361836 TI - The choice of myotomy in achalasia cardia: Heller's or per-oral endoscopic myotomy. PMID- 28361838 TI - Comparison of diagnostic efficacy between AFI, NBI, and AFI combined with NBI for colonic cancers: A meta-analysis. AB - BACKGROUND/AIMS: Advanced endoscopic imaging technologies have been used for the early detection and differentiation of colonic cancers recently. We aim to evaluate the diagnostic efficacy of autofluorescence imaging (AFI), narrow-band imaging (NBI), and AFI combined with NBI for colonic cancers. MATERIALS AND METHODS: We searched Medline/PubMed, Embase, Web of Science, and Cochrane Library databases for relevant articles. A random-effects model was used to assess diagnostic efficacy. Heterogeneity was tested by the I2 statistic and Chi-square test. Meta-regression was used to analyze the sources of heterogeneity. RESULTS: The pooled sensitivities for AFI, NBI, and AFI plus NBI were 0.84 (95% confidence interval (CI) 0.82-0.87), 0.84 (95% CI 0.81-0.86), and 0.93 (95% CI 0.90-0.95), respectively. The pooled specificities were 0.44 (95% CI 0.40-0.48), 0.69 (95% CI 0.65-0.72), and 0.69 (95% CI 0.64-0.74), respectively. The sensitivity estimate was significantly higher for AFI plus NBI than AFI or NBI alone (P = 0.041), and the specificity estimates were significantly higher for NBI and AFI plus NBI than AFI (P = 0.031).The pooled diagnostic odds ratio for AFI, NBI, and AFI plus NBI were 8.71 (95% CI 2.90-26.16), 16.02 (95% CI 7.05-36.39), and 57.55 (95% CI 9.82 337.33), respectively. Furthermore, the summary receiver operating characteristic curve area under the curve for AFI, NBI, and AFI plus NBI were 0.8125 with Q* =0.7469, 0.8696 with Q* =0.8001, and 0.9447 with Q* =0.8835, respectively. The Q* index for AFI plus NBI was significantly higher than AFI or NBI alone (P = 0.048). CONCLUSION: The combination of AFI and NBI was associated with increased diagnostic value for colonic cancers compared with AFI and NBI alone. PMID- 28361837 TI - Early squamous neoplasia of the esophagus: The endoscopic approach to diagnosis and management. AB - Considerable focus has been placed on esophageal adenocarcinoma in the last 10 years because of its rising incidence in the West. However, squamous cell cancer (SCC) continues to be the most common type of esophageal cancer in the rest of the world. The detection of esophageal SCC (ESCC) in its early stages can lead to early endoscopic resection and cure. The increased incidence of ESCC in high-risk groups, such as patients with head and neck squamous cancers, highlights the need for screening programs. Lugol's iodine chromoendoscopy remains the gold standard technique in detecting early ESCC, however, safer techniques such as electronic enhancement or virtual chromoendoscopy would be ideal. In addition to early detection, these new "push-button" technological advancements can help characterize early ESCC, thereby further aiding the diagnostic accuracy and facilitating resection. Endoscopic resection (ER) of early ESCC with negligible risk of lymph node metastases has been widely accepted as an effective therapeutic strategy because it offers similar success rates when compared to esophagectomy, but carries lesser morbidity and mortality. Endoscopic submucosal dissection (ESD) is the preferred technique of ER in lesions larger than 15 mm because it provides higher rates of en bloc resections and lower local recurrence rates when compared to endoscopic mucosal resection (EMR). PMID- 28361839 TI - Peroral endoscopic myotomy achieves similar clinical response but incurs lesser charges compared to robotic heller myotomy. AB - BACKGROUND/AIM: Several uncontrolled studies comparing peroral endoscopic myotomy (POEM) and Heller myotomy have demonstrated equivalent short-term efficacy and safety. However, no data exists rergarding the cost of POEM and how it compares to that of robotic Heller myotomy (RHM). The primary aim of this study was to compare the inpatient charges incurred in patients who underwent POEM or RHM for the treatment of achalasia. PATIENTS AND METHODS: A retrospective single center review was conducted among 52 consecutive POEM patients (2012-2014) and 52 consecutive RHM patients (2009-2014). All RHM procedures included a Toupet fundoplication and were performed via a transabdominal approach. All POEM procedures were performed by a gastroenterologist in the endoscopy unit. Clinical response was defined by improvement of symptoms and decrease in Eckardt stage to <=I. All procedural and facility charges were obtained from review of the hospital finance records. RESULTS: There was no difference between POEM and RHM with regards to age, gender, symptom duration, achalasia subtype, manometry findings, or Eckardt symptom stage. There was no significant difference in the rate of adverse events (19.2% vs 9.6%, P = 0.26) or the length of stay (1.9 vs. 2.3, P = 0.18) between both groups. Clinical response rate of patients in the POEM groups was similar to that in the RHM group (94.3% vs. 88.5%, P = 0.48). POEM incurred significantly less total charges compared to LHM ($14481 vs. $17782, P = 0.02). CONCLUSIONS: POEM when performed in an endoscopy unit was similar in efficacy and safety to RHM. However, POEM was associated with significant cost savings ($3301/procedure). PMID- 28361840 TI - Patient-perceived barriers to lifestyle interventions in cirrhosis. AB - BACKGROUND/AIMS: Sarcopenia, muscle weakness, and physical frailty are independent predictors of mortality in cirrhosis. These adverse prognostic factors are potentially modifiable with lifestyle interventions, including adequate nutritional intake and physical activity. Our aim was to identify patient-perceived barriers and enablers to these interventions. PATIENTS AND METHODS: Adult patients with cirrhosis were prospectively recruited from two tertiary care liver clinics. Patients were excluded if they had hepatocellular carcinoma beyond transplant criteria, other active malignancy, or advanced chronic disease. RESULTS: A total of 127 patients (mean age: 60 +/- 9 years, 58% males, and 48% with Child-Pugh-B/C (CP-B/C) disease) were included. Two-thirds of the patients had cirrhosis related to alcohol or hepatitis C. CP-B/C patients were more likely to take oral nutritional supplements (56% vs 29%) and less likely to consume animal protein daily (66% vs 85%) when compared to CP-A patients. Early satiety, altered taste, and difficulty in buying/preparing meals were more common in CP-B/C patients and even present in 20-30% of CP-A patients. Most patients reported adequate funds to purchase food. As quantified by the International Physical Activity Questionnaire-Short Form, 47% reported low activity levels, with no significant differences between groups. CP-B/C patients were more fatigued with exercise, however, overall Exercise Benefits/Barriers Scale scores were similar across groups. CONCLUSIONS: Barriers to nutritional intake and physical activity are common in cirrhosis and should be evaluated and treated in all patients. Asking simple screening questions in clinic and referring at-risk patients to expert multidisciplinary providers is a reasonable strategy to address these barriers. Future research should evaluate techniques to overcome modifiable barriers and enhance enablers. PMID- 28361841 TI - Effects of humanin on experimental colitis induced by 2,4,6-trinitrobenzene sulphonic acid in rats. AB - BACKGROUND/AIM: The excessive apoptosis of intestinal epithelial cells (IECs) partly accounts for the development of colonic inflammation and eventually results in ulcerative colitis (UC). Humanin, an endogenous anti-apoptotic peptide, has previously been shown to protect against Alzheimer's disease and a variety of cellular insults. The present study aimed to investigate the effects of glysin variant of humanin (HNG) on 2,4,6-trinitrobenzene sulphonic acid (TNBS) induced colitis in rats. MATERIALS AND METHODS: Rats were divided into four groups as follows: Group 1 (n = 8): control; isotonic saline solution 0.1 ml/rat rectally, Group 2 (n = 8): TNBS colitis; 0.1 ml of a 2.5% (w/v) TNBS solution in 50% ethanol rectally, Group 3 (n = 8): 10 MUM HNG, and Group 4 (n = 8): 20 MUM HNG intraperitoneal (ip) on day 2 and 6 after rectal TNBS administration. Rats were sacrificed 7 days after the induction of colitis. Blood and tissue samples were harvested for biochemical and histopathological analysis. RESULTS: HNG treatment significantly ameliorated weight loss and macroscopic and microscopic scores. TNBS-induced colitis significantly increased the colonic mRNA expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and caspase-3 activities in group II in comparison to the group I. HNG treatment was associated with an inhibition of mRNA expression of TNF-alpha and IL-1beta, and a decrease in caspase-3 activities in colon tissues in group III and IV when compared to group II. CONCLUSION: The results of this study indicate that HNG treatment may exert beneficial effects in UC by decreasing inflammatory reactions and apoptosis. PMID- 28361842 TI - Quality of life in dyspepsia and its subgroups using EQ-5D (EuroQol) questionnaire. AB - BACKGROUND/AIM: Dyspepsia has a significant impact on the quality of life. Health related quality of life (HRQoL) can be assessed by disease-specific and generic HRQoL instruments. The present study evaluated HRQoL and compared it among dyspepsia subgroups by using EQ (Euro QoL)-5D questionnaire. PATIENTS AND METHODS: Patients with abnormal findings on upper gastrointestinal endoscopy were classified to have organic dyspepsia, whereas those with normal endoscopy were classified as functional dyspepsia if they met the ROME III criteria or as endoscopy negative recent dyspepsia if symptom duration was <6 months. HRQoL was assessed using the EQ-5D questionnaire, and the overall health status on a visual analogue scale (VAS); and the frequency of impairment in each dimension were compared between the dyspepsia subgroups. RESULTS: The overall health status was affected equally in all three dyspepsia subgroups. Impairment in HRQoL was commonly seen in the dimensions of pain (98.4%), usual activities (66.20%), and anxiety/depression (70.60%), however, much less so in mobility (22.70%) and self care (10.9%). Any impairment in HRQoL was not significantly different between the three subgroups in the dimensions of mobility and usual activities. Self-care was more commonly affected in organic dyspepsia, anxiety/depression was more common with functional dyspepsia, while pain, though significantly different among various subgroups, was very common in all three subgroups. CONCLUSION: HRQoL was equally affected in all three subgroups of dyspepsia but variably so in the different domains of EQ-5D. These differences need to be studied further to improve the management of different etiological subgroups of dyspepsia. PMID- 28361843 TI - Does combining liraglutide with intragastric balloon insertion improve sustained weight reduction? AB - BACKGROUND/AIM: Intragastric balloon (IGB) is an effective and safe method of weight reduction. However, IGBs have been associated with a high rate of weight regain post removal. Accordingly, ways to improve sustained weight reduction including concomitant treatment with Glucagon-like peptide 1 (GLP-1) agonists have been proposed. This study aims to evaluate the effect of adding Liraglutide to IGB insertion on sustained weight reduction. PATIENTS AND METHODS: A retrospective analysis of all cases treated with IGB with or without Liraglutide was performed. Outcomes were statistically compared. RESULTS: A total of 108 patients were included; 64 were treated with IGB alone and 44 with IGB + Liraglutide. Six months after removing IGB, patients treated with IGB + Liraglutide had a higher mean weight loss post treatment completion (10.2 +/- 6.7 vs. 18.5 +/- 7.6, P = <0.0001) than those treated with IGB alone. After adjusting for covariates, patients treated with IGB alone demonstrated a higher mean body weight loss at the time of IGB removal (coefficient 7.71, 95% CI = 4.78-10.63), and a higher odds of treatment success 6 months post IGB removal (OR = 5.74, 95% CI = 1.79-188.42). Baseline body mass index appeared to be a significant predictor of mean body weight loss at the time of balloon removal. CONCLUSIONS: Adding Liraglutide to IGB does not appear to decrease the risk of weight regain 6 months post IGB removal. PMID- 28361844 TI - New mutations of EpCAM gene for tufting enteropathy in Saudi Arabia. AB - BACKGROUND/AIM: Tufting enteropathy (TE) is a rare cause of congenital intractable diarrhea in children. It often results in an irreversible intestinal failure and total parenteral nutrition (TPN) dependency; eventually, intestinal transplantation may be necessary. Data on TE from the Middle East are scarce; therefore, our aim of conducting this study was to clarify the clinical, histopathologic, and molecular features of TE in Saudi children. PATIENTS AND METHODS: This was a retrospective chart review of four children with TE who presented between January 2011 and December 2013 to King Fahad Specialist Hospital-Dammam (KFSH-D). The diagnosis of TE was suspected based on characteristic histopathologic intestinal biopsy findings and confirmed by EpCAM gene testing. RESULTS: Molecular testing identified two novel mutations in the EpCAM gene in our patients. These mutations were associated with severe phenotype of the disease characterized by very early onset (median of 2 weeks of life), TPN dependency, and death during early childhood. Two patients died due to central line-related complications. Two patients were referred for intestinal transplantation due to loss of intravenous access in one and progressive liver disease in the other. CONCLUSION: Mutations in EpCAM gene in Saudi children are characterized by severe phenotype and poor outcome. PMID- 28361845 TI - Finally, it is bismuth's time. PMID- 28361846 TI - Is solitary rectal ulcer syndrome uncommon in Saudi Arabia? PMID- 28361847 TI - Is solitary rectal ulcer syndrome uncommon in Saudi Arabia? Response to letter. PMID- 28361848 TI - Erratum: efficacy of proton pump inhibitors for patients with duodenal ulcers: A pairwise and network meta-analysis of randomized controlled trials. AB - [This corrects the article DOI: 10.4103/1319-3767.199117.]. PMID- 28361849 TI - Effect of antitumor drugs in low concentrationson the biological, immunophenotypic and cytogenetic characteristics of human colon cancer cells in vitro. AB - OBJECTIVE: To estimate the impact of the low-dose anticancer drugs (ACD) with the different mechanisms of action and human interferon (IFN) alpha 2b on the biological properties, immunophenotypic and cytogenetic characteristics of colon cancer cells in vitro. MATERIALS AND METHODS: The study was performed on human colon cancer cell lines COLO 205, HT-29 and 3C-P treated with ACD and IFN in subtoxic concentrations. Expression of CD44, N-cadherin, vimentin, beta-catenin, ERCC1 and Slug was assessed by immunocytochemical method. Using cytogenetic analysis, the numbers of mitoses, cells with micronuclei, apoptotic cells and cells with nuclear protrusions were studied. RESULTS: The prolonged exposure (up to 30 days) of colon cancer cells to low-dose ACD (0.2-0.5 ug/ml cisplatin and 0.1-0.2 ug/ml irinotecan) in combination with IFN (500-1000 IU/ml) led to 37-fold decreased colony-forming activity of these cell and 10-fold reduction of the number of cells expressing mesenchymal protein markers (N-cadherin, vimentin). Also, in COLO 205 cells treated with ACD and IFN the number of SLUG- and CD44 positive cells decreased by 92 and by 85%, respectively. Long-term cultivation of HT-29 cells in the presence of cisplatin and IFN resulted in 5-fold suppression of ERCC1 expression. The cytogenetic analysis has shown that the ACD, IFN and their combinations in subtoxic concentrations caused significant genotoxic effect, suppression of cell proliferation and accumulation of cells with micronuclei. The sensitivity of colon cancer cells to ACD in standard cytotoxic concentrations did not change after prolonged low-dose exposure. CONCLUSION: The data showed that the prolonged action of the low doses of ACD on human colon cancer cells resulted in the suppression of cell proliferation, colony-forming activity in soft agar, expression of epithelial-mesenchymal transition-associated markers and significant cytogenetic changes. PMID- 28361850 TI - Prognostic value of the bone turnover markers in multiple myeloma. AB - BACKGROUND: Multiple myeloma (MM) is characterized by osteolytic bone disease resulting from increased osteoclast activity and reduced osteoblast function. AIM: The aim of our research was to determine connection between bone turnover markers and presence of bone lesions, their degree of severity, to monitor MM bone disease and to assess effectiveness of anti-myeloma treatment. MATERIALS AND METHODS: Serum samples and clinical data from 123 patients with newly diagnosed MM were collected at Riga East Clinical University Hospital (Riga, Latvia) from June 2014 to June 2016. Bone lesions detected by radiography, CT scans, MRI, and PET/CT were divided into degrees from 0 to 3 (0 - no bone involvement, 1 - <= 3 bone lesions, 2 - >= 3 bone lesions, 3 - fracture). Staging was performed applying Durie/Salmon (DS) and International Staging System classifications. Progressive disease was defined as development of one or more new bone lesions. The levels of bone metabolic markers beta-isomerized C-terminal telopeptide of collagen type I (beta-CTX) and bone-specific alkaline phosphatase (bALP) were monitored regularly in the year. RESULTS: Bone lesions were found in 86 (69%) patients. From these 6 (4%) patients had 1st degree, 11 (9%) had 2nd degree and 69 (56%) had 3rd degree bone lesions. Level of the bone resorption marker beta CTX in the control group was 0.41 ng/ml, which is lower than in MM patients (p < 0.001). Spearman correlation coefficient analysis found a positive and statistically significant correlation (rs = 0.51, p < 0.001) between bone lesions degree and beta-CTX levels. Mean beta-CTX for patients without bone lesions was 0.72 ng/ml (SD = 0.64), but for patients with 3rd degree bone lesions it was 1.34 ng/ml (SD = 0.65) difference being 38% (p < 0.001). In patients who responded to therapy after 6 months of treatment reduction of beta-CTX was found compared to baseline values (M = -0.65). In contrast, in patients who did not respond to therapy, there was a statistically significant (p < 0.001) increase in beta-CTX values after six months of treatment compared to baseline values (M = 0.42). Exact cutoff value of beta-CTX is 0.79. When analyzing mean bALP, no significant difference between MM patients and control group was found. ANOVA statistical analysis showed no statistically significant differences in bALP levels at different degrees of bone lesions (p = 0.95) in MM patients. Analysis of bALP suitability as MM diagnostic marker using receiver operating characteristics curve showed that bALP is not applicable for clinical diagnosis of MM (AUC 0.5, p > 0.05). However, beta-CTX was found to be an excellent diagnostic marker for MM (AUC 0.91; 95% confidence interval, 0.88-0.94; p < 0.001). CONCLUSIONS: Patients with MM and bone lesions have increased value of bone resorption marker beta-CTX. There is a correlation between bone resorption marker and degree of bone lesions. Changes in beta-CTX levels may be used to monitor the effectiveness of myeloma treatment. PMID- 28361851 TI - Significance of iodine symporter for prognosis of the disease course and efficacy of neoadjuvant chemotherapy in patients with breast cancer of luminal and basal subtypes. AB - The aim of the research was to study the relation between expression of Na. PMID- 28361852 TI - EPR spectroscopy studies of changes in erythrocyte membranes in patients with laryngeal cancer. AB - AIM: To evaluate microviscosity and sorption capacity of erythrocyte membranes (SCEM) from patients with laryngeal cancer (LC). MATERIALS AND METHODS: Samples from 35 patients with LC of stages II and III and 20 healthy volunteers were investigated by electron paramagnetic resonance with Bis(1-oxyl-2,2,6,6 tetramethylpiperidinyl-4)-ester of 5,7-dimethyladamantane-1,3-dicarbonic acid (AdTEMPO) probe. SCEM was evaluated by amount of unabsorbed methylene blue. RESULTS: Microviscosity of erythrocyte membranes was determined by the effective rotational diffusion correlation times (taueff) and a decrease in radical spectrum signal intensity per hour. The most apparent decrease in mobility of the AdTEMPO in erythrocytes was observed prior to washing of erythrocytes with 0.9% NaCl for 5 min after probe insertion. The deceleration after 60 min was observed only in stage II LC. taueff was at control values after washing of erythrocytes of stage II LC 5 min after probe insertion and was significantly reduced in stage III LC in comparison to control. Radical spectrum signal intensity per hour in samples of stage II and III patients prior to and after washing of erythrocytes was on average 1.5-fold higher than that of control. SCEM in samples of stage II and III LC was found in 40 and 33% cases, respectively and was on average significantly reduced in comparison to control. CONCLUSIONS: The initial interaction of AdTEMPO with erythrocyte membranes of stage II and III LC patients is accompanied by an increase in taueff, indicating deceleration of probe rotation. taueff of the probe in membranes remains unchanged in 60 min, indicating changes in the structural organization of lipid bilayer and its associated proteins in particular. The similarity of SCEM for both studied groups reflects the pathological changes in function of erythrocyte membranes. PMID- 28361854 TI - Anti-histone H1 IgGs possess proliferative activity towards human T-leukaemia CEM cells. AB - : The aim of this study was to characterize the proliferative activity of the anti-histone H1 IgGs towards human T-leukaemia CEM cells. MATERIALS AND METHODS: Anti-histone H1 IgGs were purified from blood serum of systemic lupus erythematosus patients by precipitation of serum proteins with 50% ammonium sulfate followed by a sequential affinity chromatography on Protein G-Sepharose and histone H1-Sepharose columns. To avoid contamination with other proteins, anti-histone H1 IgGs were subjected to strongly acidic pH 2.0 during gel filtration through HPLC column. The effects of the anti-histone H1 IgGs on cell viability and cell cycle were tested by MTS-assay and flow cytometry, correspondingly. The cross-reactivity of the anti-histone H1 antibodies towards heterogenetic and cellular antigens was evaluated by Western-blot analysis. RESULTS: It was found that incubation of CEM cells with the HPLC-purified anti histone H1 IgGs resulted in significant stimulation of cell growth by 46% after 48 h of incubation. These IgGs possess an antigenic poly-specificity to positively charged heterogenetic antigens and different cellular antigens. FITC labeled and biotinylated anti-histone H1 IgGs are internalized by CEM cells and preferentially accumulated in the cytoplasm. CONCLUSION: The anti-histone H1 IgGs are shown to internalize human T-leukemia CEM and stimulate their proliferation. These IgGs are polyspecific toward cellular antigens. PMID- 28361853 TI - Anticancer effect and immunologic response to xenogeneic embryonic proteins in mice bearing Ehrlich solid carcinoma. AB - AIM: To investigate anticancer and immunologic effects of chicken embryonic proteins (CEP) in mice bearing Ehrlich solid carcinoma. MATERIALS AND METHODS: The study was carried out on male Balb/c mice bearing Ehrlich solid carcinoma. The immunizations were performed after the tumor transplantation. The immune status was assessed on days 7, 14, 21 and 28 after the tumor challenge. Cytotoxic activity (CAT) of macrophages (Mph), natural killer cells (NK), cytotoxic T lymphocytes (CTL) and blood serum, as well as the influence of the blood serum on immune cells activity was checked in MTT-assay; Mph's cytochemical activity was tested in NBT-assay; Ehrlich antigen-specific or CEP-specific antibodies were detected in ELISA-assay; medium size circulating immune complexes (CIC) were detected in reaction of 4.5% polyethylene glycol precipitation. RESULTS: The immunization resulted in tumor growth suppression and significant 25.64% prolongation of the survival time. In both control and immunized mice with transplanted tumors antibodies specific to Ehrlich carcinoma antigens and to CEP were detected, but antibody response was more balanced in the treatment group. In the treatment group both cytochemical and CAT of Mph was moderately activated and well preserved until late stages of tumor development; CAT of NK and CTL remained in the range of the intact mice until day 28 after the tumor transplantation. The immunized mice were well protected from accumulation of CIC and suppressive activity of autologous blood serum. CONCLUSION: Collectively, our data indicate that CEP can elicit immunomodulating and immunoprotecting effects sufficient to provide tumor growth inhibition. The further elaboration of a xenogeneic anticancer vaccine based on CEP is warranted. PMID- 28361855 TI - Parthenolide reduces gene transcription of prosurvival mediators in U937 cells. AB - : In acute myeloid leukemia (AML) the functional abnormalities of osteopontin (OPN), NF-kB, PI3K/AKT/mTOR/PTEN pathway or beta-catenin have been considered. AIM: To analyze the response of U937 cells to parthenolide (PTL) through the involvement of expression of OPN protein, RelB, AKT1, mTOR, PTEN and beta-catenin genes. MATERIALS AND METHODS: The U937 cells were treated with PTL at concentrations of 4 MUM (IC25) or 6 MUM (IC50) and with OPN siRNA for MTT assay and colony forming assay. Western blot analysis using antibodies against OPN was performed with lysates of PTL-treated cells. Quantitative real-time polymerase chain reaction was performed using primers for OPN siRNA, RelB, AKT1, mTOR, PTEN and beta-catenin. RESULTS: PTL reduces OPN protein level and down-regulates RelB mRNA in U937 cell line. Suppression of OPN with siRNA increases the cytotoxic effects of PTL. Also, mRNA expression of AKT1, mTOR, PTEN, and beta-catenin decreases with PTL or OPN siRNA. CONCLUSION: Sensitivity of U937 cells to PTL can be associated with the reduction in expression of prosurvival mediators. PMID- 28361856 TI - Aberrant promoter hypermethylation of selected apoptotic genes in childhood acute lymphoblastic leukemia among North Indian population. AB - : Promoter hypermethylation mediates gene silencing in many neoplasms. Acute leukemia has been reported to harbor multiple genes aberrantly silenced by hypermethylation. AIM: In present study, we investigated the prevalence of hypermethylation of caspase-8 (CASP8), TMS1 and DAPK genes in correlation with clinicopathological factors in childhood acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: A case-control study has been conducted based on bone marrow and peripheral blood samples from 125 ALL patients and 100 sex-age matched healthy controls. Methylation specific polymerase chain reaction (PCR) and bisulfite sequencing PCR was performed to analyze the methylation status of these genes. Reverse transcription PCR and real time PCR was carried out to determine changes in the mRNA expression level of the genes due to hypermethylation. RESULTS: Hypermethylation of the 5'CpG islands of the CASP8, TMS1 and DAPK gene promoters was found in 3.2, 6.4, and 13.6% of 125 childhood ALL samples from north Indian population, respectively. There were significant differences in pattern of hypermethylation of TMS1 (p = 0.045) and DAPK (p < 0.001) between patients and healthy controls. Down-regulation of mRNA expression was found in cases in which CASP8, TMS1 and DAPK were hypermethylated. CONCLUSIONS: The present study indicated the impact of hypermethylation-mediated inactivation of CASP8, TMS1 and DAPK genes, which is associated with risk of childhood ALL. This abnormality occurs in leukemogenesis and it may be used as a biomarker and for predicting the prognosis of ALL. PMID- 28361857 TI - Artemisinin modulating effect on human breast cancer cell lines with different sensitivity to cytostatics. AB - AIM: To explore effects of Artemisinin on a series of breast cancer cells with different sensitivity to typical cytotoxic drugs (doxorubicin - Dox; cisplatin - DDP) and to investigate possible artemisinin-induced modification of the mechanisms of drug resistance. MATERIALS AND METHODS: The study was performed on wild-type breast cancer MCF-7 cell line (MCF-7/S) and its two sublines MCF-7/Dox and MCF-7/DDP resistant to Dox and DDP, respectively. The cells were treated with artemisinin and iron-containing magnetic fluid. The latter was added to modulate iron levels in the cells and explore its role in artemisinin-induced effects. The MTT assay was used to monitor cell viability, whereas changes of expression of selected proteins participating in regulation of cellular iron homeostasis were estimated using immunocytochemical methods. Finally, relative expression levels of miRNA-200b, -320a, and -34a were examined by using qRT-PCR. RESULTS: Artemisinin affects mechanisms of the resistance of breast cancer cells towards both Dox and DDP at sub-toxic doses. The former drug induces changes of expression of iron-regulating proteins via different mechanisms, including epigenetic regulation. Particularly, the disturbances in ferritin heavy chain 1, lactoferrin, hepcidin (decrease) and ferroportin (increase) expression (r <= 0.05) were established. The most enhanced increase of miRNA expression under artemisinin influence were found for miRNA-200b in MCF-7/DDP cells (7.1 +/- 0.98 fold change), miRNA-320a in MCF-7/Dox cells (2.9 +/- 0.45 fold change) and miRNA 34a (1.7 +/- 0.15 fold change) in MCF-7/S cells. It was observed that the sensitivity to artemisinin can be influenced by changing iron levels in cells. CONCLUSIONS: Artemisinin can modify iron metabolism of breast cancer cells by its cytotoxic effect, but also by inducing changes in expression of iron-regulating proteins and microRNAs (miRNAs), involved in their regulation. This modification affects the mechanisms that are implicated in drug-resistance, that makes artemisinin a perspective modulator of cell sensitivity towards chemotherapeutic agents in cancer treatment. PMID- 28361858 TI - Impact of single nucleotide polymorphism in chemical metabolizing genes and exposure to wood smoke on risk of cervical cancer in North-Indian women. AB - AIM: In the present study, we investigated the hypothesis whether exposure to wood smoke increases the risk of cervical cancer (CC) in North-Indian women who inherit different polymorphic forms of chemical metabolizing genes (GSTM1, GSTT1, GSTP1 and CYP1A1). MATERIALS AND METHODS: One hundred fifty histologically confirmed CC patients and equal number of cancer-free age and ethnicity matched controls were genotyped for genetic polymorphism in chemical metabolizing genes by using polymerase chain reaction/restriction fragment length polymorphism method. The association of the different genotypes and exposure to wood smoke with the risk of CC in North-Indian women was estimated by doing statistical analysis using Statistical Package for the Social Science. RESULTS: It was observed that the variant genotypes of GSTM1, GSTT1, GSTP1 and CYP1A1 did not significantly increase the risk of CC. However, statistically significant increased risk (odds ratio 3.6; 95% confidence interval, 1.34-9.78; p = 0.008) was observed for women who used wood for cooking and had GSTM1 (null) genotype. CONCLUSIONS: The present study suggests that genetic differences in the metabolism of wood smoke carcinogens, particularly by GSTM1, may increase the risk of CC. PMID- 28361859 TI - The impact of locoregional treatment on survival of patients with primary metastatic breast cancer. AB - : The aim of the study was to investigate the impact of primary tumor locoregional treatment (surgery or/and radiotherapy) on overall survival in patients with primary metastatic breast cancer (PMBC). MATERIALS AND METHODS: This retrospective study included 295 wo-men aged from 23 to 76 years with PMBC. Among the 295 patients, the effect of locoregional treatment of primary tumor on survival outcomes was evaluated in 177 women with distant metastases at diagnosis of breast cancer. 35 patient received breast surgery (group 1), 95 patients with PMBC - radiotherapy (group 2) and 47 patients - combination of breast surgery and radiation (group 3). The remaining 118 patients didn't receive surgery or/and radiotherapy (group 4). All patients received systemic cytotoxic chemotherapy. RESULTS: The groups of patients with PMBC did not differ significantly by age, menstrual function, ER status, Her2 receptor status, site of metastasis and number of metastatic lesions. 2- and 5-year overall survival in patients of group 1 was 54 and 32%, group 2 - 47 and 8%, group 3 - 73 and 18%, whereas in patients from group 4 - 26 and 9%, respectively. The median survival of patients who underwent surgery was 36 months, patients with PMBC who received radiotherapy - 24 months, patients who obtained combination of breast surgery and radiation - 30 months vs 18 months in patients who did not undergo primary tumor locoregional treatment. CONCLUSIONS: The results of this study showed a favourable effect of locoregional treatment in patients with PMBC. PMID- 28361860 TI - Do MRPS18-2 and RB proteins cooperate to control cell stemness and differentiation, preventing cancer development? AB - In childhood tumors, including retinoblastoma, osteosarcoma, and neuroblastoma, the RB-E2F1 pathway is inactivated, as a rule. These tumors arise from precursor cells that fail to undergo the terminal differentiation. Noteworthy, the RB1 encoded protein (RB) does not control the cell cycle in embryonic stem cells. It has not been yet well understood how RB controls cell stemness and differentiation. The question arises why "inactive" RB is required for the survival and stemness of cells? Recently, we have found that overexpression of the RB-binding protein MRPS18-2 (S18-2) in primary fibroblasts leads to their immortalization, which is accompanied by the induction of embryonic stem cell markers and, eventually, malignant transformation. We suggest that cell stemness may be associated with high expression levels of both proteins, RB and S18-2. There must be a strict regulation of the expression levels of S18-2 and RB during embryogenesis. Disturbances in the expression of these proteins would lead to the abnormalities in development. We think that the S18-2 protein, together with the RB, plays a crucial role in the control on cell stemness and differentiation. We hope to uncover the new mechanisms of the cell fate determination. The S18-2 may serve as a new target for anticancer medicines, which will help to improve human health. PMID- 28361861 TI - Diagnostic challenges with intraoral myeloid sarcoma: report of two cases & review of world literature. AB - BACKGROUND: Myeloid sarcomas (MS) are rare extramedullary tumors composed of blasts of myeloid lineage that either precede, follow or present concomitantly with acute myeloid leukaemia (AML) or myeloproliferative neoplasms. The diagnosis of MS is especially challenging in patients without an antecedent history of leukemia. METHODS: We present 2 cases of intraoral MS that presented as de novo lesions. A detailed review of cases of intraoral MS that either preceded or presented along with leukemia has been done with emphasis on diagnostic criteria used. RESULTS: Two male patients aged 28 and 5 years presented with MS with one patient presenting with concomitant AML. A combination of morphological and immunohistochemical methods was used for diagnosis. A thorough review of world literature revealed 44 cases of intraoral MS that presented as de novo lesions. CONCLUSION: Intraoral MS is a rare tumor with poor prognosis. It may be diagnostically challenging due to its protean clinical manifestations and histological overlap with other tumors. PMID- 28361864 TI - Materials of International VACTRAIN/3-rd Swedish-Ukrainian Conference on Cancer Diseases, January 16-17, 2017, Stockholm, Sweden. PMID- 28361862 TI - Circulating tumor cells in breast cancer: functional heterogeneity, pathogenetic and clinical aspects. AB - Each patient has a unique history of cancer ecosystem development, resulting in intratumor heterogeneity. In order to effectively kill the tumor cells by chemotherapy, dynamic monitoring of driver molecular alterations is necessary to detect the markers for acquired drug resistance and find the new therapeutic targets. To perform the therapeutic monitoring, frequent tumor biopsy is needed, but it is not always possible due to small tumor size or its regression during the therapy or tumor inaccessibility in advanced cancer patients. Liquid biopsy appears to be a promising approach to overcome this problem, providing the testing of circulating tumor cells (CTC) and/or tumor-specific circulating nucleic acids. Their genomic characteristics make it possible to assess the clonal dynamics of tumors, comparing it with the clinical course and identification of driver mutation that confer resistance to therapy. The main attention in this review is paid to CTC. The biological behavior of the tumor is determined by specific cancer-promoting molecular and genetic alterations of tumor cells, and by the peculiarities of their interactions with the microenvironment that can result in the presence of wide spectrum of circulating tumor clones with various properties and potentialities to contribute to tumor progression and response to chemotherapy and prognostic value. Indeed, data on prognostic or predictive value of CTC are rather contradictory, because there is still no standard method of CTC identification, represented by different populations manifesting various biological behavior as well as different potency to metastasis. Circulating clasters of CTC appear to have essentially greater ability to metastasize in comparison with single CTC, as well as strong association with worse prognosis and chemoresistance in breast cancer patients. The Food and Drug Administration (USA) has approved the CTC-based prognostic test for clinical application in patients with advanced breast cancer. Prospective clinical trials have demonstrated that measuring changes in CTC numbers during treatment is useful for monitoring therapy response in breast cancer patients. Molecular and genetic analysis of CTC gives the opportunity to have timely information on emergence of resistant tumor clones and may shed light on the new targets for pathogenetic antitumor therapy. PMID- 28361863 TI - Trichilemmal cystis in metastatic melanoma: a case report. AB - The malignant melanoma is a neoplasm associated with a wide variety of cutaneous paraneoplastic syndromes, as dermatomyositis, systemic sclerosis, paraneoplastic pemphigus. We describe a case of four multiple trichilemmal cystis arising on frontal region in the same patient with brain metastasis and unknown primary melanoma and discuss their relationship. PMID- 28361865 TI - Workshop with International Participation ''New Trends in Cancer Research and Innovative Tumor Vaccines'', May 11-12, 2017, Kyiv, Ukraine. PMID- 28361866 TI - International Scientific Conference ''Normal and Cancer Stem Cells: Discovery, Diagnosis and Therapy'' October 5-6, 2017 Kyiv, Ukraine. PMID- 28361867 TI - Integrated arrays of air-dielectric graphene transistors as transparent active matrix pressure sensors for wide pressure ranges. AB - Integrated electronic circuitries with pressure sensors have been extensively researched as a key component for emerging electronics applications such as electronic skins and health-monitoring devices. Although existing pressure sensors display high sensitivities, they can only be used for specific purposes due to the narrow range of detectable pressure (under tens of kPa) and the difficulty of forming highly integrated arrays. However, it is essential to develop tactile pressure sensors with a wide pressure range in order to use them for diverse application areas including medical diagnosis, robotics or automotive electronics. Here we report an unconventional approach for fabricating fully integrated active-matrix arrays of pressure-sensitive graphene transistors with air-dielectric layers simply formed by folding two opposing panels. Furthermore, this realizes a wide tactile pressure sensing range from 250 Pa to ~3 MPa. Additionally, fabrication of pressure sensor arrays and transparent pressure sensors are demonstrated, suggesting their substantial promise as next-generation electronics. PMID- 28361868 TI - A recent deep earthquake doublet in light of long-term evolution of Nazca subduction. AB - Earthquake faulting at ~600 km depth remains puzzling. Here we present a new kinematic interpretation of two Mw7.6 earthquakes of November 24, 2015. In contrast to teleseismic analysis of this doublet, we use regional seismic data providing robust two-point source models, further validated by regional back projection and rupture-stop analysis. The doublet represents segmented rupture of a ~30-year gap in a narrow, deep fault zone, fully consistent with the stress field derived from neighbouring 1976-2015 earthquakes. Seismic observations are interpreted using a geodynamic model of regional subduction, incorporating realistic rheology and major phase transitions, yielding a model slab that is nearly vertical in the deep-earthquake zone but stagnant below 660 km, consistent with tomographic imaging. Geodynamically modelled stresses match the seismically inferred stress field, where the steeply down-dip orientation of compressive stress axes at ~600 km arises from combined viscous and buoyant forces resisting slab penetration into the lower mantle and deformation associated with slab buckling and stagnation. Observed fault-rupture geometry, demonstrated likelihood of seismic triggering, and high model temperatures in young subducted lithosphere, together favour nanometric crystallisation (and associated grain boundary sliding) attending high-pressure dehydration as a likely seismogenic mechanism, unless a segment of much older lithosphere is present at depth. PMID- 28361869 TI - Strained in Planning Your Mouse Background? Using the HPA Stress Axis as a Biological Readout for Backcrossing Strategies. PMID- 28361871 TI - A tipping point in refreezing accelerates mass loss of Greenland's glaciers and ice caps. AB - Melting of the Greenland ice sheet (GrIS) and its peripheral glaciers and ice caps (GICs) contributes about 43% to contemporary sea level rise. While patterns of GrIS mass loss are well studied, the spatial and temporal evolution of GICs mass loss and the acting processes have remained unclear. Here we use a novel, 1 km surface mass balance product, evaluated against in situ and remote sensing data, to identify 1997 (+/-5 years) as a tipping point for GICs mass balance. That year marks the onset of a rapid deterioration in the capacity of the GICs firn to refreeze meltwater. Consequently, GICs runoff increases 65% faster than meltwater production, tripling the post-1997 mass loss to 36+/-16 Gt-1, or ~14% of the Greenland total. In sharp contrast, the extensive inland firn of the GrIS retains most of its refreezing capacity for now, buffering 22% of the increased meltwater production. This underlines the very different response of the GICs and GrIS to atmospheric warming. PMID- 28361870 TI - Associations Between Daily Affective Instability and Connectomics in Functional Subnetworks in Remitted Patients with Recurrent Major Depressive Disorder. AB - Remitted patients with major depressive disorder (rMDD) often report more fluctuations in mood as residual symptomatology. It is unclear how this affective instability is associated with information processing related to the default mode (DMS), salience/reward (SRS), and frontoparietal (FPS) subnetworks in rMDD patients at high risk of recurrence (rrMDD). Sixty-two unipolar, drug-free rrMDD patients (?2 MDD episodes) and 41 healthy controls (HCs) were recruited. We used experience sampling methodology to monitor mood/cognitions (10 times a day for 6 days) and calculated affective instability using the mean adjusted absolute successive difference. Subsequently, we collected resting-state functional magnetic resonance imaging data and performed graph theory to obtain network metrics of integration within (local efficiency) the DMS, SRS, and FPS, and between (participation coefficient) these subnetworks and others. In rrMDD patients compared with HCs, we found that affective instability was increased in most negative mood/cognition variables and that the DMS had less connections with other subnetworks. Furthermore, we found that rrMDD patients, who showed more instability in feeling down and irritated, had less connections between the SRS and other subnetworks and higher local efficiency coefficients in the FPS, respectively. In conclusion, rrMDD patients, compared with HCs, are less stable in their negative mood and these dynamics are related to differences in information processing within- and between-specific functional subnetworks. These results are a first step to gain a better understanding of how mood fluctuations in real life are represented in the brain and provide insights into the vulnerability profile of MDD. PMID- 28361872 TI - Evidence for a bi-partition of the Younger Dryas Stadial in East Asia associated with inversed climate characteristics compared to Europe. AB - The Younger Dryas Stadial (YDS) was an episode of northern hemispheric cooling which occurred within the Last Glacial Interglacial Transition (LGIT). A major driver for the YDS climate was a weakening of the Atlantic Meridional Overturning Circulation (AMOC). It has been inferred that the AMOC began to strengthen mid YDS, producing a bipartite structure of the YDS in records from continental Europe. These records imply that the polar front and westerlies shifted northward, producing a warmer second phase of the YDS in Europe. Here we present multi-proxy data from the sediments of Lake Suigetsu (Japan), as evidence that a related bi-partition of the YDS also occurred in East Asia. Besides showing for the first time that the bi-partition was not limited to the North Atlantic/European region, the data also imply a climatic dipole between Europe and East Asia since the cold-warm characteristics are reversed at Lake Suigetsu. We suggest that changes in eastward moisture transport from the North Atlantic are the primary mechanism by which the teleconnection can be explained. PMID- 28361873 TI - Erratum: PARP1 promotes gene expression at the post-transcriptional level by modulating the RNA-binding protein HuR. PMID- 28361876 TI - A novel method for non-destructive determination of hair photo-induced damage based on multispectral imaging technology. AB - Extended exposure to sunlight may give rise to chemical and physical damages of human hairs. In this work, we report a novel method for non-destructive quantification of hair photodamage via multispectral imaging (MSI) technology. We show that the multispectral reflectance value in near-infrared region has a strong correlation with hair photodamage. More specifically, the hair segments with longer growing time and the same hair root segment after continuous ultraviolet (UV) irradiation displaying more severe photodamage observed via scanning electron microscopy (SEM) micrographs showed significantly higher multispectral reflectance value. Besides, the multispectral reflectance value of hair segments with different growing time was precisely reproduced by exposing the same hair root segment to specific durations of UV irradiation, suggesting that MSI can be adequately applied to determine the sunlight exposure time of the hair. The loss of cystine content of photodamaged hairs was identified to be the main factor that physiologically contributed to the morphological changes of hair surface fibers and hence the variation of their multispectral reflectance spectra. Considering the environmental information recording nature of hairs, we believe that MSI for non-destructive evaluation of hair photodamage would prove valuable for assessing sunlight exposure time of a subject in the biomedical fields. PMID- 28361875 TI - Label-free quantification of calcium-sensor targeting to photoreceptor guanylate cyclase and rhodopsin kinase by backscattering interferometry. AB - Quantification of protein binding to membrane proteins is challenging and a limited set of methods is available to study such systems. Here we employed backscattering interferometry (BSI), a free-solution label-free method with high sensitivity, to quantify the interaction of neuronal Ca2+-Sensor proteins with their targets operating in phototransduction. We tested direct binding of guanylate cyclase-activating proteins (GCAP1 and GCAP2) to their membrane target guanylate cyclase 1. The regulatory mechanism of GCAPs including their binding interface in the target is unresolved. Here we used a label-free, free-solution assay method based on BSI to determine binding constants of GCAP1 and GCAP2 to the full-length membrane-bound guanylate cyclase type 1. GCAP1 and GCAP2 bound to different regions on the target guanylate cyclase with submicromolar affinity (apparent KD-values of 663 +/- 121 nM and 231 +/- 63 nM for Ca2+-free GCAP1 and GCAP2, respectively). A guanylate cyclase construct containing the juxta-membrane and kinase homology domain harbored an exclusive binding site for GCAP1 with similar affinities as the full-length protein, whereas GCAP2 did not bind to this region. We provide a model in which GCAP1 and GCAP2 do not share a single binding site to the target, thus cannot exchange upon fluctuating Ca2+ levels. PMID- 28361874 TI - IL-15 sustains IL-7R-independent ILC2 and ILC3 development. AB - The signals that maintain tissue-resident innate lymphoid cells (ILC) in different microenvironments are incompletely understood. Here we show that IL-7 receptor (IL-7R) is not strictly required for the development of any ILC subset, as residual cells persist in the small intestinal lamina propria (siLP) of adult and neonatal Il7ra-/- mice. Il7ra-/- ILC2 primarily express an ST2- phenotype, but are not inflammatory ILC2. CCR6+ ILC3, which express higher Bcl-2 than other ILC3, are the most abundant subset in Il7ra-/- siLP. All ILC subsets are functionally competent in vitro, and are sufficient to provide enhanced protection to infection with C. rodentium. IL-15 equally sustains wild-type and Il7ra-/- ILC survival in vitro and compensates for IL-7R deficiency, as residual ILCs are depleted in mice lacking both molecules. Collectively, these data demonstrate that siLP ILCs are not completely IL-7R dependent, but can persist partially through IL-15 signalling. PMID- 28361877 TI - Unacylated ghrelin promotes adipogenesis in rodent bone marrow via ghrelin O-acyl transferase and GHS-R1a activity: evidence for target cell-induced acylation. AB - Despite being unable to activate the cognate ghrelin receptor (GHS-R), unacylated ghrelin (UAG) possesses a unique activity spectrum that includes promoting bone marrow adipogenesis. Since a receptor mediating this action has not been identified, we re-appraised the potential interaction of UAG with GHS-R in the regulation of bone marrow adiposity. Surprisingly, the adipogenic effects of intra-bone marrow (ibm)-infused acylated ghrelin (AG) and UAG were abolished in male GHS-R-null mice. Gas chromatography showed that isolated tibial marrow adipocytes contain the medium-chain fatty acids utilised in the acylation of UAG, including octanoic acid. Additionally, immunohistochemistry and immunogold electron microscopy revealed that tibial marrow adipocytes show prominent expression of the UAG-activating enzyme ghrelin O-acyl transferase (GOAT), which is located in the membranes of lipid trafficking vesicles and in the plasma membrane. Finally, the adipogenic effect of ibm-infused UAG was completely abolished in GOAT-KO mice. Thus, the adipogenic action of exogenous UAG in tibial marrow is dependent upon acylation by GOAT and activation of GHS-R. This suggests that UAG is subject to target cell-mediated activation - a novel mechanism for manipulating hormone activity. PMID- 28361878 TI - Structural mechanisms for alpha-conotoxin activity at the human alpha3beta4 nicotinic acetylcholine receptor. AB - Nicotinic acetylcholine receptors (nAChR) are therapeutic targets for a range of human diseases. alpha-Conotoxins are naturally occurring peptide antagonists of nAChRs that have been used as pharmacological probes and investigated as drug leads for nAChR related disorders. However, alpha-conotoxin interactions have been mostly characterised at the alpha7 and alpha3beta2 nAChRs, with interactions at other subtypes poorly understood. This study provides novel structural insights into the molecular basis for alpha-conotoxin activity at alpha3beta4 nAChR, a therapeutic target where subtype specific antagonists have potential to treat nicotine addiction and lung cancer. A co-crystal structure of alpha conotoxin LsIA with Lymnaea stagnalis acetylcholine binding protein guided the design and functional characterisations of LsIA analogues that identified the minimum pharmacophore regulating alpha3beta4 antagonism. Interactions of the LsIA R10F with beta4 K57 and the conserved -NN- alpha-conotoxin motif with beta4 I77 and I109 conferred alpha3beta4 activity to the otherwise inactive LsIA. Using these structural insights, we designed LsIA analogues with alpha3beta4 activity. This new understanding of the structural basis of protein-protein interactions between alpha-conotoxins and alpha3beta4 may help rationally guide the development of alpha3beta4 selective antagonists with therapeutic potential. PMID- 28361879 TI - Synthesizing topological structures containing RNA. AB - Though knotting and entanglement have been observed in DNA and proteins, their existence in RNA remains an enigma. Synthetic RNA topological structures are significant for understanding the physical and biological properties pertaining to RNA topology, and these properties in turn could facilitate identifying naturally occurring topologically nontrivial RNA molecules. Here we show that topological structures containing single-stranded RNA (ssRNA) free of strong base pairing interactions can be created either by configuring RNA-DNA hybrid four-way junctions or by template-directed synthesis with a single-stranded DNA (ssDNA) topological structure. By using a constructed ssRNA knot as a highly sensitive topological probe, we find that Escherichia coli DNA topoisomerase I has low RNA topoisomerase activity and that the R173A point mutation abolishes the unknotting activity for ssRNA, but not for ssDNA. Furthermore, we discover the topological inhibition of reverse transcription (RT) and obtain different RT-PCR patterns for an ssRNA knot and circle of the same sequence. PMID- 28361880 TI - Genomic structure of the horse major histocompatibility complex class II region resolved using PacBio long-read sequencing technology. AB - The mammalian Major Histocompatibility Complex (MHC) region contains several gene families characterized by highly polymorphic loci with extensive nucleotide diversity, copy number variation of paralogous genes, and long repetitive sequences. This structural complexity has made it difficult to construct a reliable reference sequence of the horse MHC region. In this study, we used long read single molecule, real-time (SMRT) sequencing technology from Pacific Biosciences (PacBio) to sequence eight Bacterial Artificial Chromosome (BAC) clones spanning the horse MHC class II region. The final assembly resulted in a 1,165,328 bp continuous gap free sequence with 35 manually curated genomic loci of which 23 were considered to be functional and 12 to be pseudogenes. In comparison to the MHC class II region in other mammals, the corresponding region in horse shows extraordinary copy number variation and different relative location and directionality of the Eqca-DRB, -DQA, -DQB and -DOB loci. This is the first long-read sequence assembly of the horse MHC class II region with rigorous manual gene annotation, and it will serve as an important resource for association studies of immune-mediated equine diseases and for evolutionary analysis of genetic diversity in this region. PMID- 28361881 TI - Wave-particle energy exchange directly observed in a kinetic Alfven-branch wave. AB - Alfven waves are fundamental plasma wave modes that permeate the universe. At small kinetic scales, they provide a critical mechanism for the transfer of energy between electromagnetic fields and charged particles. These waves are important not only in planetary magnetospheres, heliospheres and astrophysical systems but also in laboratory plasma experiments and fusion reactors. Through measurement of charged particles and electromagnetic fields with NASA's Magnetospheric Multiscale (MMS) mission, we utilize Earth's magnetosphere as a plasma physics laboratory. Here we confirm the conservative energy exchange between the electromagnetic field fluctuations and the charged particles that comprise an undamped kinetic Alfven wave. Electrons confined between adjacent wave peaks may have contributed to saturation of damping effects via nonlinear particle trapping. The investigation of these detailed wave dynamics has been unexplored territory in experimental plasma physics and is only recently enabled by high-resolution MMS observations. PMID- 28361882 TI - Rapid electron transfer by the carbon matrix in natural pyrogenic carbon. AB - Surface functional groups constitute major electroactive components in pyrogenic carbon. However, the electrochemical properties of pyrogenic carbon matrices and the kinetic preference of functional groups or carbon matrices for electron transfer remain unknown. Here we show that environmentally relevant pyrogenic carbon with average H/C and O/C ratios of less than 0.35 and 0.09 can directly transfer electrons more than three times faster than the charging and discharging cycles of surface functional groups and have a 1.5 V potential range for biogeochemical reactions that invoke electron transfer processes. Surface functional groups contribute to the overall electron flux of pyrogenic carbon to a lesser extent with greater pyrolysis temperature due to lower charging and discharging capacities, although the charging and discharging kinetics remain unchanged. This study could spur the development of a new generation of biogeochemical electron flux models that focus on the bacteria-carbon-mineral conductive network. PMID- 28361883 TI - Migration phenology and breeding success are predicted by methylation of a photoperiodic gene in the barn swallow. AB - Individuals often considerably differ in the timing of their life-cycle events, with major consequences for individual fitness, and, ultimately, for population dynamics. Phenological variation can arise from genetic effects but also from epigenetic modifications in DNA expression and translation. Here, we tested if CpG methylation at the poly-Q and 5'-UTR loci of the photoperiodic Clock gene predicted migration and breeding phenology of long-distance migratory barn swallows (Hirundo rustica) that were tracked year-round using light-level geolocators. Increasing methylation at Clock poly-Q was associated with earlier spring departure from the African wintering area, arrival date at the European breeding site, and breeding date. Higher methylation levels also predicted increased breeding success. Thus, we showed for the first time in any species that CpG methylation at a candidate gene may affect phenology and breeding performance. Methylation at Clock may be a candidate mechanism mediating phenological responses of migratory birds to ongoing climate change. PMID- 28361884 TI - AT-RvD1 Promotes Resolution of Inflammation in NOD/ShiLtJ mice. AB - Sjogren's syndrome (SS) is a chronic inflammatory autoimmune disease characterized by diminished secretory function of the exocrine glands. Treatments for hyposalivation are limited to the use of saliva substitutes and medications that provide only temporary relief. In light of the high degree of need and the limitations of current therapies, development of alternative treatments to restore functioning is essential. Resolvins (Rv), which are highly potent lipid mediators, offer a viable alternative for better treating inflammatory diseases such as SS. The goal of this study was to determine whether systemic preventive treatment with Aspirin-triggered RvD1 (AT-RvD1) reduces inflammation and preserves secretory functioning in NOD/ShiLtJ SS-like mice. Our results indicate that systemic treatment with AT-RvD1 diminishes the progression of the disease in salivary epithelium from female mice as follows: (a) improves secretory function, (b) reduces pro-inflammatory molecule gene expression, (c) increases anti inflammatory molecule gene expression and (d) induces M2 macrophage polarization. Finally, AT-RvD1 decreases lymphocytic infiltration into the salivary glands when used with small doses of the steroid, dexamethasone, and promotes the tissue healing process. PMID- 28361885 TI - Exposure to Ambient Particulate Matter Induced COPD in a Rat Model and a Description of the Underlying Mechanism. AB - While the health effects of air pollution have been an international public health concern since at least the 1950s, recent research has focused on two broad sources of air pollution, namely, biomass fuel (BMF) and motor vehicle exhaust (MVE). Many studies have shown associations between air pollution PM and exacerbations of pre-existing COPD, but the role of air pollution PM in the development and progression of COPD is still uncertain. The current study indicates that rats can develop pronounced COPD following chronic exposure to air pollution PM (BMF and MVE), as characterized by lung function reduction, mucus metaplasia, lung and systemic inflammation, emphysema, and small airway remodeling. Comparative analyses demonstrate that both BMF and MVE activate similar pathogenesis that are linked to the development of COPD. These findings also show that some differences are found in the lungs of rats exposed to BMF or MVE, which might result in different phenotypes of COPD. PMID- 28361887 TI - Mechanisms of social buffering of fear in zebrafish. AB - Some humans thrive whereas others resign when exposed to threatening situations throughout life. Social support has been identified as an important modulator of these discrepancies in human behaviour, and other social animals also exhibit phenomena in which individuals recover better from aversive events when conspecifics are present - aka social buffering. Here we studied social buffering in zebrafish, by exposing focal fish to an aversive stimulus (alarm substance - AS) either in the absence or presence of conspecific cues. When exposed to AS in the presence of both olfactory (shoal water) and visual (sight of shoal) conspecific cues, focal fish exhibited a lower fear response than when tested alone, demonstrating social buffering in zebrafish. When separately testing each cue's effectiveness, we verified that the visual cue was more effective than the olfactory in reducing freezing in a persistent threat scenario. Finally, we verified that social buffering was independent of shoal size and coincided with a distinct pattern of co-activation of brain regions known to be involved in mammalian social buffering. Thus, this study suggests a shared evolutionary origin for social buffering in vertebrates, bringing new evidence on the behavioural, sensory and neural mechanisms underlying this phenomenon. PMID- 28361888 TI - Control strategy of hand movement depends on target redundancy. AB - Reaching toward a point target has been intensively studied in human motor control. However, little is known about reaching toward a redundant target, such as grasping a bar, in which the grasping point is irrelevant to the achievement of a task. We examined whether humans could solve the target-redundancy and control problems in a serial fashion or control their body without solving the target-redundancy problem. We equalized the target ranges between two reaching tasks: a point-to-point reaching task without target-redundancy and a point-to bar reaching task with target-redundancy. In the both tasks, we measured hand viscoelasticity at movement end as parameters that reflect the adopted control strategy. As a result, the hand viscoelasticity in the point-to-bar reaching task was smaller than that in the point-to-point reaching task, even under the same kinematics. These results indicate that the hand viscoelasticity was modulated depending on the target-redundancy. Moreover, it is suggested that a human reaches toward a redundant target by effectively utilizing information of target redundancy rather than explicitly solving the target-redundancy problem. PMID- 28361886 TI - Enzyme-dependent fluorescence recovery of NADH after photobleaching to assess dehydrogenase activity of isolated perfused hearts. AB - Reduction of NAD+ by dehydrogenase enzymes to form NADH is a key component of cellular metabolism. In cellular preparations and isolated mitochondria suspensions, enzyme-dependent fluorescence recovery after photobleaching (ED FRAP) of NADH has been shown to be an effective approach for measuring the rate of NADH production to assess dehydrogenase enzyme activity. Our objective was to demonstrate how dehydrogenase activity could be assessed within the myocardium of perfused hearts using NADH ED-FRAP. This was accomplished using a combination of high intensity UV pulses to photobleach epicardial NADH. Replenishment of epicardial NADH fluorescence was then imaged using low intensity UV illumination. NADH ED-FRAP parameters were optimized to deliver 23.8 mJ of photobleaching light energy at a pulse width of 6 msec and a duty cycle of 50%. These parameters provided repeatable measurements of NADH production rate during multiple metabolic perturbations, including changes in perfusate temperature, electromechanical uncoupling, and acute ischemia/reperfusion injury. NADH production rate was significantly higher in every perturbation where the energy demand was either higher or uncompromised. We also found that NADH production rate remained significantly impaired after 10 min of reperfusion after global ischemia. Overall, our results indicate that myocardial NADH ED-FRAP is a useful optical non-destructive approach for assessing dehydrogenase activity. PMID- 28361891 TI - Integrated Design and Simulation of Tunable, Multi-State Structures Fabricated Monolithically with Multi-Material 3D Printing. AB - Multi-material 3D printing has created new opportunities for fabricating deployable structures. We design reversible, deployable structures that are fabricated flat, have defined load bearing capacity, and multiple, predictable activated geometries. These structures are designed with a hierarchical framework where the proposed bistable actuator serves as the base building block. The actuator is designed to maximise its stroke length, with the expansion ratio approaching one when serially connected. The activation force of the actuator is parameterised through its joint material and joint length. Simulation and experimental results show that the bistability triggering force can be tuned between 0.5 and 5.0 N. Incorporating this bistable actuator, the first group of hierarchical designs demonstrate the deployment of space frame structures with a tetrahedron module consisting of three active edges, each containing four serially connected actuators. The second group shows the design of flat structures that assume either positive or negative Gaussian curvature once activated. By flipping the initial configuration of the unit actuators, structures such as a dome and an enclosure are demonstrated. A modified Dynamic Relaxation method is used to simulate all possible geometries of the hierarchical structures. Measured geometries differ by less than 5% compared to simulation results. PMID- 28361889 TI - The histone H3K9 methyltransferase SUV39H links SIRT1 repression to myocardial infarction. AB - Myocardial infarction (MI) dampens heart function and poses a great health risk. The class III deacetylase sirtuin 1 (SIRT1) is known to confer cardioprotection. SIRT1 expression is downregulated in the heart by a number of stress stimuli that collectively drive the pathogenesis of MI, although the underlying mechanism remains largely obscure. Here we show that in primary rat neonatal ventricular myocytes (NRVMs), ischaemic or oxidative stress leads to a rapid upregulation of SUV39H, the mammalian histone H3K9 methyltransferase, paralleling SIRT1 downregulation. Compared to wild-type littermates, SUV39H knockout mice are protected from MI. Likewise, suppression of SUV39H activity with chaetocin attenuates cardiac injury following MI. Mechanistically, SUV39H cooperates with heterochromatin protein 1 gamma (HP1gamma) to catalyse H3K9 trimethylation on the SIRT1 promoter and represses SIRT1 transcription. SUV39H augments intracellular ROS levels in a SIRT1-dependent manner. Our data identify a previously unrecognized role for SUV39H linking SIRT1 trans-repression to myocardial infarction. PMID- 28361890 TI - Development of the macaque face-patch system. AB - Face recognition is highly proficient in humans and other social primates; it emerges in infancy, but the development of the neural mechanisms supporting this behaviour is largely unknown. We use blood-volume functional MRI to monitor longitudinally the responsiveness to faces, scrambled faces, and objects in macaque inferotemporal cortex (IT) from 1 month to 2 years of age. During this time selective responsiveness to monkey faces emerges. Some functional organization is present at 1 month; face-selective patches emerge over the first year of development, and are remarkably stable once they emerge. Face selectivity is refined by a decreasing responsiveness to non-face stimuli. PMID- 28361892 TI - An Inter-comparison of Three Heat Wave Types in China during 1961-2010: Observed Basic Features and Linear Trends. AB - Using observed daily temperatures in China, three independent types of heat waves (HWs), including daytime HWs, nighttime HWs, and compound HWs (with both extreme daily maxima and minima), were defined. Different types of HWs showed distinctive preferences in occurrence locations and timing. However, spatial patterns of accompanying relative humidity were generally independent of categorization, except for closer association of nighttime events with high humidity level. Compound HWs and nighttime HWs experienced significant increases in frequency, participating days, mean duration, intensity and areal extent. Conversely, significant decreasing trends of above indicators prevailed in daytime HWs, especially in central-eastern China. Tendency of relative humidity changes didn't vary with HW types. Instead it caused an interesting phenomenon that dry HWs in the west became more humid and humid events in the east got dryer, as manifested most obviously in compound type. Thorough comparisons highlight the evolutionary dominance of HW types. Specifically, previously-dominating independent daytime HWs have been increasingly replaced by independent nighttime events in central eastern China, and by compound HWs in southern China. That's the very reason for negative trends of independent daytime HWs in eastern China, even in a warming climate. PMID- 28361893 TI - Shock-Resistibility of MEMS-Based Inertial Microswitch under Reverse Directional Ultra-High g Acceleration for IoT Applications. AB - This paper presents a novel MEMS-based inertial microswitch design with multi directional compact constraint structures for improving the shock-resistibility. Its shock-resistibility in the reverse-sensitive direction to ultra-high g acceleration (~hunderds of thousands) is simulated and analyzed. The dynamic response process indicates that in the designed inertial microswitch the proof mass weight G, the whole system's stiffness k and the gap x2 between the proof mass and reverse constraint blocks have significant effect on the shock resistibility. The MEMS inertial microswitch micro-fabricated by surface micromachining has been evaluated using the drop hammer test. The maximum allowable reverse acceleration, which does not cause the spurious trigger, is defined as the reverse acceleration threshold (athr). Test results show that athr increases with the decrease of the gap x2, and the proposed microswitch tends to have a better shock-resistibility under smaller gap. The measured responses of the microswitches with and without constraint structure indicates that the device without constraint structure is prone to spurious trigger, while the designed constraint structures can effectively improve the shock-resistibility. In this paper, the method for improving the shock-resistibility and reducing the spurious trigger has been discussed. PMID- 28361895 TI - Cell fate conversion: a chromatin remodeling checkpoint revealed. AB - In a new paper in Cell Research, Ji et al. find that transcription factor instigated opening of chromatin, during cell reprogramming, can be sensed by the Baf60b-containing chromatin remodeling complex, which then activates the ATM-p53 pathway, leading to cell death. These findings from reprogramming studies unveil what I term a "chromatin remodeling checkpoint" whereby extensive, inappropriate chromatin opening events lead to cell elimination, thus preventing cell fate conversion that might occur upon tissue damage; if unchecked, such conversion could lead to metaplasia and cancer. PMID- 28361896 TI - Tissue-resident memory T cells live off the fat of the land. AB - The consumption of exogenous free fatty acids by tissue-resident memory T (Trm) cells is critical for their long-term survival and antiviral function, and appears to be a conserved feature of Trm cells in both mouse and man, a recent paper published in Nature demonstrates. PMID- 28361894 TI - The antimicrobial effects of the alginate oligomer OligoG CF-5/20 are independent of direct bacterial cell membrane disruption. AB - Concerns about acquisition of antibiotic resistance have led to increasing demand for new antimicrobial therapies. OligoG CF-5/20 is an alginate oligosaccharide previously shown to have antimicrobial and antibiotic potentiating activity. We investigated the structural modification of the bacterial cell wall by OligoG CF 5/20 and its effect on membrane permeability. Binding of OligoG CF-5/20 to the bacterial cell surface was demonstrated in Gram-negative bacteria. Permeability assays revealed that OligoG CF-5/20 had virtually no membrane-perturbing effects. Lipopolysaccharide (LPS) surface charge and aggregation were unaltered in the presence of OligoG CF-5/20. Small angle neutron scattering and circular dichroism spectroscopy showed no substantial change to the structure of LPS in the presence of OligoG CF-5/20, however, isothermal titration calorimetry demonstrated a weak calcium-mediated interaction. Metabolomic analysis confirmed no change in cellular metabolic response to a range of osmolytes when treated with OligoG CF 5/20. This data shows that, although weak interactions occur between LPS and OligoG CF-5/20 in the presence of calcium, the antimicrobial effects of OligoG CF 5/20 are not related to the induction of structural alterations in the LPS or cell permeability. These results suggest a novel mechanism of action that may avoid the common route in acquisition of resistance via LPS structural modification. PMID- 28361897 TI - Spontaneous DNA damage propels tumorigenicity. AB - High levels of endogenously generated DNA damage drive oncogenesis, sustain malignant progression and increase therapy resistance. In a paper recently published in Cell Research, Liu and colleagues added additional insights into this topic by uncovering a novel intrinsic source of double-strand breaks that fosters the aggressiveness and stemness of malignant cells. PMID- 28361898 TI - Atomic resolution structure of serine protease proteinase K at ambient temperature. AB - Atomic resolution structures (beyond 1.20 A) at ambient temperature, which is usually hampered by the radiation damage in synchrotron X-ray crystallography (SRX), will add to our understanding of the structure-function relationships of enzymes. Serial femtosecond crystallography (SFX) has attracted surging interest by providing a route to bypass such challenges. Yet the progress on atomic resolution analysis with SFX has been rather slow. In this report, we describe the 1.20 A resolution structure of proteinase K using 13 keV photon energy. Hydrogen atoms, water molecules, and a number of alternative side-chain conformations have been resolved. The increase in the value of B-factor in SFX suggests that the residues and water molecules adjacent to active sites were flexible and exhibited dynamic motions at specific substrate-recognition sites. PMID- 28361899 TI - Towards a Humanized Mouse Model of Liver Stage Malaria Using Ectopic Artificial Livers. AB - The malaria liver stage is an attractive target for antimalarial development, and preclinical malaria models are essential for testing such candidates. Given ethical concerns and costs associated with non-human primate models, humanized mouse models containing chimeric human livers offer a valuable alternative as small animal models of liver stage human malaria. The best available human liver chimeric mice rely on cellular transplantation into mice with genetically engineered liver injury, but these systems involve a long and variable humanization process, are expensive, and require the use of breeding-challenged mouse strains which are not widely accessible. We previously incorporated primary human hepatocytes into engineered polyethylene glycol (PEG)-based nanoporous human ectopic artificial livers (HEALs), implanted them in mice without liver injury, and rapidly generated human liver chimeric mice in a reproducible and scalable fashion. By re-designing the PEG scaffold to be macroporous, we demonstrate the facile fabrication of implantable porous HEALs that support liver stage human malaria (P. falciparum) infection in vitro, and also after implantation in mice with normal liver function, 60% of the time. This proof-of concept study demonstrates the feasibility of applying a tissue engineering strategy towards the development of scalable preclinical models of liver stage malaria infection for future applications. PMID- 28361901 TI - Parental Exposure to Dim Light at Night Prior to Mating Alters Offspring Adaptive Immunity. AB - Exposure to dim light at night (dLAN) disrupts natural light/dark cycles and impairs endogenous circadian rhythms necessary to maintain optimal biological function, including the endocrine and immune systems. We have previously demonstrated that white dLAN compromises innate and cell mediated immune responses in adult Siberian hamsters (Phodopus sungorus). We hypothesized that dLAN has transgenerational influences on immune function. Adult male and female Siberian hamsters were exposed to either dark nights (DARK) or dLAN (~5 lux) for 9 weeks, then paired in full factorial design, mated, and thereafter housed under dark nights. Offspring were gestated and reared in dark nights, then tested as adults for cell-mediated and humoral immunity. Maternal exposure to dLAN dampened delayed type hypersensitivity (DTH) responses in male offspring. Maternal and paternal exposure to dLAN reduced DTH responses in female offspring. IgG antibodies to a novel antigen were elevated in offspring of dams exposed to dLAN. Paternal exposure to dLAN decreased splenic endocrine receptor expression and global methylation in a parental sex-specific manner. Together, these data suggest that exposure to dLAN has transgenerational effects on endocrine-immune function that may be mediated by global alterations in the epigenetic landscape of immune tissues. PMID- 28361900 TI - MicroRNAs Associated with Caste Determination and Differentiation in a Primitively Eusocial Insect. AB - In eusocial Hymenoptera (ants, bees and wasps), queen and worker adult castes typically arise via environmental influences. A fundamental challenge is to understand how a single genome can thereby produce alternative phenotypes. A powerful approach is to compare the molecular basis of caste determination and differentiation along the evolutionary trajectory between primitively and advanced eusocial species, which have, respectively, relatively undifferentiated and strongly differentiated adult castes. In the advanced eusocial honeybee, Apis mellifera, studies suggest that microRNAs (miRNAs) play an important role in the molecular basis of caste determination and differentiation. To investigate how miRNAs affect caste in eusocial evolution, we used deep sequencing and Northern blots to isolate caste-associated miRNAs in the primitively eusocial bumblebee Bombus terrestris. We found that the miRNAs Bte-miR-6001-5p and -3p are more highly expressed in queen- than in worker-destined late-instar larvae. These are the first caste-associated miRNAs from outside advanced eusocial Hymenoptera, so providing evidence for caste-associated miRNAs occurring relatively early in eusocial evolution. Moreover, we found little evidence that miRNAs previously shown to be associated with caste in A. mellifera were differentially expressed across caste pathways in B. terrestris, suggesting that, in eusocial evolution, the caste-associated role of individual miRNAs is not conserved. PMID- 28361902 TI - Corticosterone activity during early weaning reprograms molecular markers in rat gastric secretory cells. AB - Gastric epithelial cells differentiate throughout the third postnatal week in rats, and become completely functional by weaning time. When suckling is interrupted by early weaning (EW), cell proliferation and differentiation change in the gastric mucosa, and regulatory mechanisms might involve corticosterone activity. Here we used EW and RU486 (glucocorticoid receptor antagonist) to investigate the roles of corticosterone on differentiation of mucous neck (MNC) and zymogenic cells (ZC) in rats, and to evaluate whether effects persisted in young adults. MNC give rise to ZC, and mucin 6, Mist1, pepsinogen a5 and pepsinogen C are produced to characterize these cells. We found that in pups, EW augmented the expression of mucins, Mist1 and pepsinogen C at mRNA and protein levels, and it changed the number of MNC and ZC. Corticosterone regulated pepsinogen C expression, and MNC and ZC distributions. Further, the changes on MNC population and pepsinogen C were maintained until early- adult life. Therefore, by using EW as a model for altered corticosterone activity in rats, we demonstrated that the differentiation of secretory epithelial cells is sensitive to the type of nutrient in the lumen. Moreover, this environmental perception activates corticosterone to change maturation and reprogram cellular functions in adulthood. PMID- 28361903 TI - Steviol glycosides enhance pancreatic beta-cell function and taste sensation by potentiation of TRPM5 channel activity. AB - Steviol glycosides (SGs), such as stevioside and rebaudioside A, are natural, non caloric sweet-tasting organic molecules, present in extracts of the scrub plant Stevia rebaudiana, which are widely used as sweeteners in consumer foods and beverages. TRPM5 is a Ca2+-activated cation channel expressed in type II taste receptor cells and pancreatic beta-cells. Here we show that stevioside, rebaudioside A and their aglycon steviol potentiate the activity of TRPM5. We find that SGs potentiate perception of bitter, sweet and umami taste, and enhance glucose-induced insulin secretion in a Trpm5-dependent manner. Daily consumption of stevioside prevents development of high-fat-diet-induced diabetic hyperglycaemia in wild-type mice, but not in Trpm5-/- mice. These results elucidate a molecular mechanism of action of SGs and identify TRPM5 as a potential target to prevent and treat type 2 diabetes. PMID- 28361905 TI - Changes in temporomandibular joint spaces after arthroscopic disc repositioning: a self-control study. AB - Disc repositioning is a common procedure for patients with anterior disc displacement (ADD). The purpose of this retrospective record-based study was to evaluate changes in the widths of joint spaces and condylar position changes in patients with unilateral ADD following arthroscopic disc repositioning, with the healthy sides as self-control, using magnetic resonance images (MRI).Widths of anterior, superior, and posterior joint spaces (AS, SS, and PS) were measured. The condylar position was described as anterior, centric or posterior, expressed as . Paired-t test and Chi-square test were used to analyze the data. Fifty-four records conformed to the inclusion criteria (mean age of 21.02 years). Widths of SS and PS increased significantly after surgery (P < 0.001) on the operative sides, while joint spaces of healthy sides and AS of operative sides had no significant changes. Dominant location of condyles of operative sides changed from a posterior position to an anterior position, while healthy sides were mostly centric condylar position no matter preoperatively or postoperatively. Therefore, the results of this study indicate that unilateral arthroscopic disc repositioning significantly increases the posterior and superior spaces of the affected joints, without affecting spaces of the healthy sides. PMID- 28361904 TI - IgE binds asymmetrically to its B cell receptor CD23. AB - The antibody IgE plays a central role in allergic disease mechanisms. Its effector functions are controlled through interactions between the Fc region and two principal cell surface receptors FcepsilonRI and CD23. The interaction with FcepsilonRI is primarily responsible for allergic sensitization and the inflammatory response, while IgE binding to CD23 is involved in the regulation of IgE synthesis and allergen transcytosis. Here we present the crystal structure of a CD23/IgE-Fc complex and conduct isothermal titration calorimetric binding studies. Two lectin-like "head" domains of CD23 bind to IgE-Fc with affinities that differ by more than an order of magnitude, but the crystal structure reveals only one head bound to one of the two identical heavy-chains in the asymmetrically bent IgE-Fc. These results highlight the subtle interplay between receptor binding sites in IgE-Fc and their affinities, the understanding of which may be exploited for therapeutic intervention in allergic disease. PMID- 28361907 TI - Wide-Range Probing of Dzyaloshinskii-Moriya Interaction. AB - The Dzyaloshinskii-Moriya interaction (DMI) in magnetic objects is of enormous interest, because it generates built-in chirality of magnetic domain walls (DWs) and topologically protected skyrmions, leading to efficient motion driven by spin orbit torques. Because of its importance for both potential applications and fundamental research, many experimental efforts have been devoted to DMI investigation. However, current experimental probing techniques cover only limited ranges of the DMI strength and have specific sample requirements. Thus, there are no versatile methods to quantify DMI over a wide range of values. Here, we present such an experimental scheme, which is based on the angular dependence of asymmetric DW motion. This method can be used to determine values of DMI much larger than the maximum strength of the external magnetic field strength, which demonstrates that various DMI strengths can be quantified with a single measurement setup. This scheme may thus prove essential to DMI-related emerging fields in nanotechnology. PMID- 28361906 TI - Herbicidal properties of antimalarial drugs. AB - The evolutionary relationship between plants and the malarial parasite Plasmodium falciparum is well established and underscored by the P. falciparum apicoplast, an essential chloroplast-like organelle. As a result of this relationship, studies have demonstrated that herbicides active against plants are also active against P. falciparum and thus could act as antimalarial drug leads. Here we show the converse is also true; many antimalarial compounds developed for human use are highly herbicidal. We found that human antimalarial drugs (e.g. sulfadiazine, sulfadoxine, pyrimethamine, cycloguanil) were lethal to the model plant Arabidopsis thaliana at similar concentrations to market herbicides glufosinate and glyphosate. Furthermore, the physicochemical properties of these herbicidal antimalarial compounds were similar to commercially used herbicides. The implications of this finding that many antimalarial compounds are herbicidal proffers two novel applications: (i) using the genetically tractable A. thaliana to reveal mode-of-action for understudied antimalarial drugs, and (ii) co-opting antimalarial compounds as a new source for much needed herbicide lead molecules. PMID- 28361909 TI - Rational mutagenesis by engineering disulphide bonds improves Kluyveromyces lactis beta-galactosidase for high-temperature industrial applications. AB - Kluyveromyces lactis beta-galactosidase (Kl-beta-Gal) is one of the most important enzymes in the dairy industry. The poor stability of this enzyme limits its use in the synthesis of galactooligosaccharides (GOS) and other applications requiring high operational temperature. To obtain thermoresistant variants, a rational mutagenesis strategy by introducing disulphide bonds in the interface between the enzyme subunits was used. Two improved mutants, R116C/T270C and R116C/T270C/G818C, had increased half-lives at 45 degrees C compared to Kl-beta Gal (2.2 and 6.8 fold increases, respectively). Likewise, Tm values of R116C/T270C and R116C/T270C/G818C were 2.4 and 8.5 degrees C, respectively, higher than Kl-beta-Gal Tm. Enrichment in enzymatically active oligomeric forms in these mutant variants also increased their catalytic efficiency, due to the reinforcement of the interface contacts. In this way, using an artificial substrate (p-nitrophenyl-beta-D-galactopyranoside), the Vmax values of the mutants were ~1.4 (R116C/T270C) and 2 (R116C/T270C/G818C) fold higher than that of native Kl-beta-Gal. Using the natural substrate (lactose) the Vmax for R116C/T270C/G818C almost doubled the Vmax for Kl-beta-Gal. Validation of these mutant variants of the enzyme for their use in applications that depend on prolonged incubations at high temperatures was achieved at the laboratory scale by monitoring their catalytic activity in GOS synthesis. PMID- 28361908 TI - Sustained delivery of calcium and orthophosphate ions from amorphous calcium phosphate and poly(L-lactic acid)-based electrospinning nanofibrous scaffold. AB - The purpose of this study is to investigate electrospinning poly(L-lactic acid) (PLLA) nanofibrous scaffold with different contents of amorphous calcium phosphate (ACP), which is suitable for using in bone regeneration through sustained release of calcium and orthophosphate ions. Three groups of nanofibrous scaffolds, ACP-free PLLA, ACP-5 wt%/PLLA and ACP-10 wt%/PLLA, are developed and characterized by scanning electron microscopy and gel permeation chromatography. Calcium and phosphate colorimetric assay kits are used to test ions released from scaffold during hydrolytic degradation. The results show ACP-5 wt%/PLLA and ACP 10 wt%/PLLA scaffolds have relatively high degradation rates than ACP-free PLLA group. The bioactivity evaluation further reveals that ACP-5 wt%/PLLA scaffold presents more biocompatible feature with pre-osteoblast cells and significant osteogenesis ability of calvarial bone defect. Due to the facile preparation method, sustained calcium and orthophosphate release behavior, and excellent osteogenesis capacity, the presented ACP/PLLA nanofibrous scaffold has potential applications in bone tissue engineering. PMID- 28361911 TI - Land cover changes induced by the great east Japan earthquake in 2011. AB - The east Japan earthquake that occurred on March 11, 2011 was a big natural disaster, comprising the large earthquake shock, tsunami, and Fukushima Daiichi Nuclear Power Plant (FDNPP) accident. These disasters caused changes in the land use and land cover (LULC) in Japan's Tohoku district. While the LULC map created before the disaster is available, as yet there is no precise LULC map of the district after the disaster. In this study, we created a precise LULC map for the years 2013-2015 post-disaster with 30-m spatial resolution using the Landsat-8 with the Operational Land Imager (OLI) to evaluate the changes in LULC induced by the disaster. Our results indicate many changes in areas categorized as rice paddies primarily into grass categories along the coast damaged by the tsunami and in the evacuation zone around the FDNPP. Since there is a possibility of future LULC changes according to the change of the evacuation zone and implementation of reconstruction and revitalization efforts, we recommend continual monitoring of the changes in LULC by the use of satellite data in order to evaluate the long-term effects of the disaster. PMID- 28361910 TI - Her-2 expression regulated by downregulation of miR-9 and which affects chemotherapeutic effect in breast cancer. AB - This study aimed to identify microRNAs (miRs), the deregulated expression of which leads to the activation of oncogenic pathways in human breast cancer (BC). miRs are classes of endogenous, small, noncoding RNAs that regulate gene expression aberrantly in human tumor tissues. A total of 39 out of 123 tumoral and matched uninvolved peritumoral breast specimens from 3 independent subsets of patients were analyzed for the expression of 851 human miRs using an Agilent platform. The remaining 84 samples were used to validate miRs differentially expressed between tumoral and matched peritumoral specimens by quantitative polymerase chain reaction. Animal assay was further used to test the role of miR 9 and Her-2 in the pathogenesis of BC. All 39 matched samples were analyzed by unsupervised cluster analysis. This analytical approach identified a signature of miRs (miR-9, miR-148a, miR-31, miR-375, miR-21, miR-135b, miR-196a and miR-196b) that were significantly modulated between tumoral and peritumoral tissues in both subsets of patients. Her-2 protein staining increased in tumoral specimens when miR-9 downregulation correlated with the prognostic value. The ectopic expression of miR-9 inhibited the colony-forming ability, migration and tumor engraftment of BC cells. miR-9 targeted the Her-2 messenger RNA and increased responsiveness of BC cells to docetaxel (DOC) or cyclophosphamide treatment. The ectopic expression of Her-2 protein counteracted the miR-9 proapoptotic activity in response to DOC. These findings suggested that the modulation of aberrant expression of miR-9, which in turn induces oncogenic Her-2 protein activity, might hold promise for preventive and therapeutic management of BC. PMID- 28361912 TI - Polymorphisms of RAD51B are associated with rheumatoid arthritis and erosion in rheumatoid arthritis patients. AB - Rheumatoid arthritis (RA) is a common, chronic autoimmune disease affecting 0.5 1.0% of adults worldwide, including approximately 4.5-5.0 million patients in China. The genetic etiology and pathogenesis of RA have not yet been fully elucidated. Recently, one new RA susceptibility gene (RAD51B) has been identified in Korean and European populations. In this study, we designed a two-stage case control study to further assess the relationship of common variants in the RAD51B gene with increased risk of RA in a total of 965 RA patients and 2,511 unrelated healthy controls of Han Chinese ancestry. We successfully identified a common variant, rs911263, as being significantly associated with the disease status of RA (P = 4.8 * 10-5, OR = 0.64). In addition, this SNP was shown to be related to erosion, a clinical assessment of disease severity in RA (P = 2.89 * 10-5, OR = 0.52). These findings shed light on the role of RAD51B in the onset and severity of RA. More research in the future is needed to clarify the underlying functional link between rs911263 and the disease. PMID- 28361914 TI - Soft and wrinkled carbon membranes derived from petals for flexible supercapacitors. AB - Biomass materials are promising precursors for the production of carbonaceous materials due to their abundance, low cost and renewability. Here, a freestanding wrinkled carbon membrane (WCM) electrode material for flexible supercapacitors (SCs) was obtained from flower petal. The carbon membrane was fabricated by a simple thermal pyrolysis process and further activated by heating the sample in air. As a binder and current collector-free electrode, the activated wrinkled carbon membrane (AWCM) exhibited a high specific capacitance of 332.7 F/g and excellent cycling performance with 92.3% capacitance retention over 10000 cycles. Moreover, a flexible all-solid supercapacitor with AWCM electrode was fabricated and showed a maximum specific capacitance of 154 F/g and great bending stability. The development of this flower petal based carbon membrane provides a promising cost-effective and environmental benign electrode material for flexible energy storage. PMID- 28361913 TI - Multi-scale radiomic analysis of sub-cortical regions in MRI related to autism, gender and age. AB - We propose using multi-scale image textures to investigate links between neuroanatomical regions and clinical variables in MRI. Texture features are derived at multiple scales of resolution based on the Laplacian-of-Gaussian (LoG) filter. Three quantifier functions (Average, Standard Deviation and Entropy) are used to summarize texture statistics within standard, automatically segmented neuroanatomical regions. Significance tests are performed to identify regional texture differences between ASD vs. TDC and male vs. female groups, as well as correlations with age (corrected p < 0.05). The open-access brain imaging data exchange (ABIDE) brain MRI dataset is used to evaluate texture features derived from 31 brain regions from 1112 subjects including 573 typically developing control (TDC, 99 females, 474 males) and 539 Autism spectrum disorder (ASD, 65 female and 474 male) subjects. Statistically significant texture differences between ASD vs. TDC groups are identified asymmetrically in the right hippocampus, left choroid-plexus and corpus callosum (CC), and symmetrically in the cerebellar white matter. Sex-related texture differences in TDC subjects are found in primarily in the left amygdala, left cerebellar white matter, and brain stem. Correlations between age and texture in TDC subjects are found in the thalamus-proper, caudate and pallidum, most exhibiting bilateral symmetry. PMID- 28361916 TI - Seeing elements by visible-light digital camera. AB - A visible-light digital camera is used for taking ordinary photos, but with new operational procedures it can measure the photon energy in the X-ray wavelength region and therefore see chemical elements. This report describes how one can observe X-rays by means of such an ordinary camera - The front cover of the camera is replaced by an opaque X-ray window to block visible light and to allow X-rays to pass; the camera takes many snap shots (called single-photon-counting mode) to record every photon event individually; an integrated-filtering method is newly proposed to correctly retrieve the energy of photons from raw camera images. Finally, the retrieved X-ray energy-dispersive spectra show fine energy resolution and great accuracy in energy calibration, and therefore the visible light digital camera can be applied to routine X-ray fluorescence measurement to analyze the element composition in unknown samples. In addition, the visible light digital camera is promising in that it could serve as a position sensitive X-ray energy detector. It may become able to measure the element map or chemical diffusion in a multi-element system if it is fabricated with external X-ray optic devices. Owing to the camera's low expense and fine pixel size, the present method will be widely applied to the analysis of chemical elements as well as imaging. PMID- 28361915 TI - Evolution of multi-drug resistant HCV clones from pre-existing resistant associated variants during direct-acting antiviral therapy determined by third generation sequencing. AB - Resistance-associated variant (RAV) is one of the most significant clinical challenges in treating HCV-infected patients with direct-acting antivirals (DAAs). We investigated the viral dynamics in patients receiving DAAs using third generation sequencing technology. Among 283 patients with genotype-1b HCV receiving daclatasvir + asunaprevir (DCV/ASV), 32 (11.3%) failed to achieve sustained virological response (SVR). Conventional ultra-deep sequencing of HCV genome was performed in 104 patients (32 non-SVR, 72 SVR), and detected representative RAVs in all non-SVR patients at baseline, including Y93H in 28 (87.5%). Long contiguous sequences spanning NS3 to NS5A regions of each viral clone in 12 sera from 6 representative non-SVR patients were determined by third generation sequencing, and showed the concurrent presence of several synonymous mutations linked to resistance-associated substitutions in a subpopulation of pre existing RAVs and dominant isolates at treatment failure. Phylogenetic analyses revealed close genetic distances between pre-existing RAVs and dominant RAVs at treatment failure. In addition, multiple drug-resistant mutations developed on pre-existing RAVs after DCV/ASV in all non-SVR cases. In conclusion, multi-drug resistant viral clones at treatment failure certainly originated from a subpopulation of pre-existing RAVs in HCV-infected patients. Those RAVs were selected for and became dominant with the acquisition of multiple resistance associated substitutions under DAA treatment pressure. PMID- 28361917 TI - The low affinity glucose transporter HxtB is also involved in glucose signalling and metabolism in Aspergillus nidulans. AB - One of the drawbacks during second-generation biofuel production from plant lignocellulosic biomass is the accumulation of glucose, the preferred carbon source of microorganisms, which causes the repression of hydrolytic enzyme secretion by industrially relevant filamentous fungi. Glucose sensing, subsequent transport and cellular signalling pathways have been barely elucidated in these organisms. This study therefore characterized the transcriptional response of the filamentous fungus Aspergillus nidulans to the presence of high and low glucose concentrations under continuous chemostat cultivation with the aim to identify novel factors involved in glucose sensing and signalling. Several transcription factor- and transporter-encoding genes were identified as being differentially regulated, including the previously characterized glucose and xylose transporter HxtB. HxtB was confirmed to be a low affinity glucose transporter, localizing to the plasma membrane under low- and high-glucose conditions. Furthermore, HxtB was shown to be involved in conidiation-related processes and may play a role in downstream glucose signalling. A gene predicted to encode the protein kinase PskA was also identified as being important for glucose metabolism. This study identified several proteins with predicted roles in glucose metabolic processes and provides a foundation for further investigation into the response of biotechnologically important filamentous fungi to glucose. PMID- 28361918 TI - Single-cell RNA sequencing identifies distinct mouse medial ganglionic eminence cell types. AB - Many subtypes of cortical interneurons (CINs) are found in adult mouse cortices, but the mechanism generating their diversity remains elusive. We performed single cell RNA sequencing on the mouse embryonic medial ganglionic eminence (MGE), the major birthplace for CINs, and on MGE-like cells differentiated from embryonic stem cells. Two distinct cell types were identified as proliferating neural progenitors and immature neurons, both of which comprised sub-populations. Although lineage development of MGE progenitors was reconstructed and immature neurons were characterized as GABAergic, cells that might correspond to precursors of different CINs were not identified. A few non-neuronal cell types were detected, including microglia. In vitro MGE-like cells resembled bona fide MGE cells but expressed lower levels of Foxg1 and Epha4. Together, our data provide detailed understanding of the embryonic MGE developmental program and suggest how CINs are specified. PMID- 28361920 TI - Sedentary lifestyle related exosomal release of Hotair from gluteal-femoral fat promotes intestinal cell proliferation. AB - Pioneering epidemiological work has established strong association of sedentary lifestyle and obesity with the risk of colorectal cancer, while the detailed underlying mechanism remains unknown. Here we show that Hotair (HOX transcript antisense RNA) is a pro-adipogenic long non-coding RNA highly expressed in gluteal-femoral fat over other fat depots. Hotair knockout in adipose tissue results in gluteal-femoral fat defect. Squeeze of the gluteal-femoral fat induces intestinal proliferation in wildtype mice, while not in Hotair knockout mice. Mechanistically, squeeze of the gluteal-femoral fat induces exosomal Hotair secretion mainly by transcriptional upregulation of Hotair via NFkappaB. And increased exosomal Hotair in turn circulates in the blood and is partially endocytosed by the intestine, finally promoting the stemness and proliferation of intestinal stem/progenitor cells via Wnt activation. Clinically, obese subjects with sedentary lifestyle have much higher exosomal HOTAIR expression in the serum. These findings establish that sedentary lifestyle promotes exosomal Hotair release from the gluteal-femoral fat, which in turn facilitates intestinal stem and/or progenitor proliferation, raising a possible link between sedentary lifestyle with colorectal tumorigenesis. PMID- 28361919 TI - Discovery of the first dual GSK3beta inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer's disease. AB - The formation of neurofibrillary tangles (NFTs), oxidative stress and neuroinflammation have emerged as key targets for the treatment of Alzheimer's disease (AD), the most prevalent neurodegenerative disorder. These pathological hallmarks are closely related to the over-activity of the enzyme GSK3beta and the downregulation of the defense pathway Nrf2-EpRE observed in AD patients. Herein, we report the synthesis and pharmacological evaluation of a new family of multitarget 2,4-dihydropyrano[2,3-c]pyrazoles as dual GSK3beta inhibitors and Nrf2 inducers. These compounds are able to inhibit GSK3beta and induce the Nrf2 phase II antioxidant and anti-inflammatory pathway at micromolar concentrations, showing interesting structure-activity relationships. The association of both activities has resulted in a remarkable anti-inflammatory ability with an interesting neuroprotective profile on in vitro models of neuronal death induced by oxidative stress and energy depletion and AD. Furthermore, none of the compounds exhibited in vitro neurotoxicity or hepatotoxicity and hence they had improved safety profiles compared to the known electrophilic Nrf2 inducers. In conclusion, the combination of both activities in this family of multitarget compounds confers them a notable interest for the development of lead compounds for the treatment of AD. PMID- 28361922 TI - Surface Acoustic Waves to Drive Plant Transpiration. AB - Emerging fields of research in electronic plants (e-plants) and agro nanotechnology seek to create more advanced control of plants and their products. Electronic/nanotechnology plant systems strive to seamlessly monitor, harvest, or deliver chemical signals to sense or regulate plant physiology in a controlled manner. Since the plant vascular system (xylem/phloem) is the primary pathway used to transport water, nutrients, and chemical signals-as well as the primary vehicle for current e-plant and phtyo-nanotechnology work-we seek to directly control fluid transport in plants using external energy. Surface acoustic waves generated from piezoelectric substrates were directly coupled into rose leaves, thereby causing water to rapidly evaporate in a highly localized manner only at the site in contact with the actuator. From fluorescent imaging, we find that the technique reliably delivers up to 6x more water/solute to the site actuated by acoustic energy as compared to normal plant transpiration rates and 2x more than heat-assisted evaporation. The technique of increasing natural plant transpiration through acoustic energy could be used to deliver biomolecules, agrochemicals, or future electronic materials at high spatiotemporal resolution to targeted areas in the plant; providing better interaction with plant physiology or to realize more sophisticated cyborg systems. PMID- 28361924 TI - Bioinspired fractal electrodes for solar energy storages. AB - Solar energy storage is an emerging technology which can promote the solar energy as the primary source of electricity. Recent development of laser scribed graphene electrodes exhibiting a high electrical conductivity have enabled a green technology platform for supercapacitor-based energy storage, resulting in cost-effective, environment-friendly features, and consequent readiness for on chip integration. Due to the limitation of the ion-accessible active porous surface area, the energy densities of these supercapacitors are restricted below ~3 * 10-3 Whcm-3. In this paper, we demonstrate a new design of biomimetic laser scribed graphene electrodes for solar energy storage, which embraces the structure of Fern leaves characterized by the geometric family of space filling curves of fractals. This new conceptual design removes the limit of the conventional planar supercapacitors by significantly increasing the ratio of active surface area to volume of the new electrodes and reducing the electrolyte ionic path. The attained energy density is thus significantly increased to ~10-1 Whcm-3- more than 30 times higher than that achievable by the planar electrodes with ~95% coulombic efficiency of the solar energy storage. The energy storages with these novel electrodes open the prospects of efficient self-powered and solar-powered wearable, flexible and portable applications. PMID- 28361921 TI - Prion-like characteristics of the bacterial protein Microcin E492. AB - Microcin E492 (Mcc) is a pore-forming bacteriotoxin. Mcc activity is inhibited at the stationary phase by formation of amyloid-like aggregates in the culture. Here we report that, in a similar manner as prions, Mcc naturally exists as two conformers: a beta-sheet-rich, protease-resistant, aggregated, inactive form (Mccia), and a soluble, protease-sensitive, active form (Mcca). The exogenous addition of culture medium containing Mccia or purified in vitro-generated Mccia into the culture induces the rapid and efficient conversion of Mcca into Mccia, which is maintained indefinitely after passaging, changing the bacterial phenotype. Mccia prion-like activity is conformation-dependent and could be reduced by immunodepleting Mccia. Interestingly, an internal region of Mcc shares sequence similarity with the central domain of the prion protein, which is key to the formation of mammalian prions. A synthetic peptide spanning this sequence forms amyloid-like fibrils in vitro and is capable of inducing the conversion of Mcca into Mccia in vivo, suggesting that this region corresponds to the prion domain of Mcc. Our findings suggest that Mcc is the first prokaryotic protein with prion properties which harnesses prion-like transmission to regulate protein function, suggesting that propagation of biological information using a prion based conformational switch is an evolutionary conserved mechanism. PMID- 28361926 TI - Dispersion/dilution enhances phytoplankton blooms in low-nutrient waters. AB - Spatial characteristics of phytoplankton blooms often reflect the horizontal transport properties of the oceanic turbulent flow in which they are embedded. Classically, bloom response to horizontal stirring is regarded in terms of generation of patchiness following large-scale bloom initiation. Here, using satellite observations from the North Pacific Subtropical Gyre and a simple ecosystem model, we show that the opposite scenario of turbulence dispersing and diluting fine-scale (~1-100 km) nutrient-enriched water patches has the critical effect of regulating the dynamics of nutrients-phytoplankton-zooplankton ecosystems and enhancing accumulation of photosynthetic biomass in low-nutrient oceanic environments. A key factor in determining ecological and biogeochemical consequences of turbulent stirring is the horizontal dilution rate, which depends on the effective eddy diffusivity and surface area of the enriched patches. Implementation of the notion of horizontal dilution rate explains quantitatively plankton response to turbulence and improves our ability to represent ecological and biogeochemical processes in oligotrophic oceans. PMID- 28361923 TI - Stable mucus-associated bacterial communities in bleached and healthy corals of Porites lobata from the Arabian Seas. AB - Coral reefs are subject to coral bleaching manifested by the loss of endosymbiotic algae from coral host tissue. Besides algae, corals associate with bacteria. In particular, bacteria residing in the surface mucus layer are thought to mediate coral health, but their role in coral bleaching is unknown. We collected mucus from bleached and healthy Porites lobata colonies in the Persian/Arabian Gulf (PAG) and the Red Sea (RS) to investigate bacterial microbiome composition using 16S rRNA gene amplicon sequencing. We found that bacterial community structure was notably similar in bleached and healthy corals, and the most abundant bacterial taxa were identical. However, fine-scale differences in bacterial community composition between the PAG and RS were present and aligned with predicted differences in sulfur- and nitrogen-cycling processes. Based on our data, we argue that bleached corals benefit from the stable composition of mucus bacteria that resemble their healthy coral counterparts and presumably provide a conserved suite of protective functions, but monitoring of post-bleaching survival is needed to further confirm this assumption. Conversely, fine-scale site-specific differences highlight flexibility of the bacterial microbiome that may underlie adjustment to local environmental conditions and contribute to the widespread success of Porites lobata. PMID- 28361925 TI - Follistatin-like 1 protects against hypoxia-induced pulmonary hypertension in mice. AB - Pulmonary hypertension (PH) remains a life-limiting disease characterized by pulmonary vascular remodelling due to aberrant proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), thus leading to raised pulmonary arterial pressure and right ventricular hypertrophy. Secreted glycoprotein follistatin-like 1 (FSTL1) has been reported to ameliorate tissue remodelling in cardiovascular injuries. However, the role of FSTL1 in deranged pulmonary arteries remains elusive. We found that there were higher serum levels of FSTL1 in patients with PH related to chronic obstructive pulmonary diseases (COPD) and in mice model of hypoxia-induced PH (HPH). Haploinsufficiency of Fstl1 in mice contributed to an exacerbated HPH, as demonstrated by increased right ventricular systolic pressure, pulmonary arterial muscularization and right ventricular hypertrophy index. Conversely, FSTL1 administration attenuated HPH. In cultured human PASMCs, hypoxia-promoted cellular viability, DNA synthesis and migration were suppressed by exogenous FSTL1 but enhanced by small interfering RNA targeting FSTL1. Additionally, FSTL1 inhibited the proliferation and migration of PASMCs via extracellular regulated kinase (ERK) signal pathway. All these findings indicate that FSTL1 imposed a protective modulation on pulmonary vascular remodelling, thereby suggesting its role in the regulation of HPH. PMID- 28361928 TI - Diabetes: Loss of beta-cell mass - an acute event before T1DM presentation? PMID- 28361927 TI - Molecular profiling of thyroid nodule fine-needle aspiration cytology. AB - The differential diagnosis and malignancy risk stratification of thyroid nodules requires multidisciplinary expertise and knowledge of both local ultrasonography practices and the local malignancy rates for a given fine-needle aspiration (FNA) result. Even in such a multidisciplinary setting, FNA cytology has the inherent limitation that indeterminate cytology results cannot distinguish between follicular adenomas, follicular thyroid carcinomas or follicular variant papillary thyroid carcinomas. Accumulating evidence suggests that this limitation can be overcome by using molecular diagnostic approaches. In this Review, we present the advantages and disadvantages of the different molecular diagnostic methodologies, which can be divided into two approaches: those that 'rule out' malignancy (to reduce the overtreatment of benign nodules) and those that 'rule in' malignancy (to optimize surgical planning). We identify microRNA classifiers as potential additional markers for use in a two-step diagnostic approach, consider the potential implications of the reclassification of noninvasive encapsulated follicular variant papillary thyroid carcinomas to noninvasive follicular thyroid neoplasms with papillary-like nuclear features and discuss the cost-effectiveness of molecular testing. Molecular FNA diagnostics is an important complementary addition to FNA cytology that could substantially reduce unnecessary surgery and better define the need for appropriate surgery in patients who have thyroid nodules with indeterminate FNA cytology. PMID- 28361930 TI - Diabetes: Metformin in breast cancer. PMID- 28361931 TI - Stroke: Extracellular RNAs associated with stroke. PMID- 28361929 TI - Metabolism: Liver and adipose tissue control uridine biosynthesis. PMID- 28361932 TI - Neuro-oncology: CD47 antibody helps phagocytes fight paediatric cancer. PMID- 28361933 TI - Modeling of coupled motion and growth interaction of equiaxed dendritic crystals in a binary alloy during solidification. AB - Motion of growing dendrites is a common phenomenon during solidification but often neglected in numerical simulations because of the complicate underlying multiphysics. Here a phase-field model incorporating dendrite-melt two-phase flow is proposed for simulating the dynamically interacted process. The proposed model circumvents complexity to resolve dendritic growth, natural convection and solid motion simultaneously. Simulations are performed for single and multiple dendritic growth of an Al-based alloy in a gravity environment. Computing results of an isolated dendrite settling down in the convective supersaturated melt shows that solid motion is able to overwhelm solutal convection and causes a rather different growth morphology from the stationary dendrite that considers natural convection alone. The simulated tip growth dynamics are correlated with a modified boundary layer model in the presence of melt flow, which well accounts for the variation of tip velocity with flow direction. Polycrystalline simulations reveal that the motion of dendrites accelerates the occurrence of growth impingement which causes the behaviors of multiple dendrites are distinct from that of single dendrite, including growth dynamics, morphology evolution and movement path. These polycrystalline simulations provide a primary understanding of the sedimentation of crystals and resulting chemical homogeneity in industrial ingots. PMID- 28361934 TI - Tumour blood vessel normalisation by prolyl hydroxylase inhibitor repaired sensitivity to chemotherapy in a tumour mouse model. AB - Blood vessels are important tissue structures that deliver oxygen and nutrition. In tumour tissue, abnormal blood vessels, which are hyperpermeable and immature, are often formed; these tissues also have irregular vascularisation and intravasation. This situation leads to hypoperfusion in tumour tissue along with low oxygen and nutrition depletion; this is also called the tumour microenvironment and is characterised by hypoxia, depleted nutrition, low pH and high interstitial pressure. This environment induces resistance to anticancer drugs, which causes an increase in anticancer drug doses, leading to increased side effects. We hypothesised that normalised tumour blood vessels would improve tumour tissue perfusion, resupply nutrition and re-oxygenate the tumour tissue. Chemotherapy would then be more effective and cause a decrease in anticancer drug doses. Here we report a neovascularisation-inducing drug that improved tumour vascular abnormalities, such as low blood flow, blood leakage and abnormal vessel structure. These results could lead to not only an increased chemo-sensitivity and tissue-drug distribution but also an up-regulated efficiency for cancer chemotherapy. This suggests that tumour blood vessel normalisation therapy accompanied by angiogenesis may be a novel strategy for cancer therapy. PMID- 28361936 TI - Magnetic control of Goos-Hanchen shifts in a yttrium-iron-garnet film. AB - We investigate the Goos-Hanchen (GH) shifts reflected and transmitted by a yttrium-iron-garnet (YIG) film for both normal and oblique incidence. It is found that the nonreciprocity effect of the MO material does not only result in a nonvanishing reflected shift at normal incidence, but also leads to a slab thickness-independent term which breaks the symmetry between the reflected and transmitted shifts at oblique incidence. The asymptotic behaviors of the normal incidence reflected shift are obtained in the vicinity of two characteristic frequencies corresponding to a minimum reflectivity and a total reflection, respectively. Moreover, the coexistence of two types of negative-reflected-shift (NRS) at oblique incidence is discussed. We show that the reversal of the shifts from positive to negative values can be realized by tuning the magnitude of applied magnetic field, the frequency of incident wave and the slab thickness as well as the incident angle. In addition, we further investigate two special cases for practical purposes: the reflected shift with a total reflection and the transmitted shift with a total transmission. Numerical simulations are also performed to verify our analytical results. PMID- 28361935 TI - Passive smoking and stroke in men and women: a national population-based case control study in China. AB - An association between passive smoking and stroke is unclear in China, particularly the association with hemorrhagic stroke. This study included 16205 deaths due to stroke aged >=30 years and 16205 non-stroke controls randomly selected and frequency-matched to cases on gender and age. Smoking of spouses, defined as >=1 cigarette per day for up to 1 year, was taken as a measure of exposure to passive smoking of subjects that was retrospectively ascertained by interviewing surviving spouses. After adjustment for variables, passive smoking increased the risk of death by 10% (odds ratio (OR), 1.10; 95% confidence interval (CI), 1.05-1.16) for all strokes, by 10% (OR, 1.10; 95% CI, 1.04-1.16) for hemorrhagic stroke, and by 12% (OR, 1.12; 95% CI, 1.03-1.23) for ischemic stroke, compared with non-exposure. This finding was highly consistent in men or women and in smokers or non-smokers, and was generally consistent among zones of China despite geographic diversity. The risk significantly increased with exposure-years and quantity of cigarettes smoked daily by spouses. This study indicated that passive smoking is associated with deaths from all-type strokes. It is highly advisable for the government to promote strong tobacco prevention and cessation programs and smoke-free environments. PMID- 28361938 TI - Hippo interferes with antiviral defences. AB - The Hippo pathway responds to environmental factors including nutrient availability, cell density and substrate stiffness to regulate organ size. This pathway is now shown to also regulate antiviral defence by modulating the TBK1 mediated control of interferon production. PMID- 28361939 TI - Demystifying blood stem cell fates. AB - Determining the differentiation potential of stem and progenitor cells is essential for understanding their function, yet our ability to do so is limited by the restrictions of experimental assays. Based on single-cell functional and molecular profiling experiments, a new computational approach shows how lineage commitment may occur in human haematopoiesis. PMID- 28361937 TI - Identification of two p53 isoforms from Litopenaeus vannamei and their interaction with NF-kappaB to induce distinct immune response. AB - p53 is a transcription factor with capability of regulating diverse NF-kappaB dependent biological progresses such as inflammation and host defense, but the actual mechanism remains unrevealed. Herein, we firstly identified two novel alternatively spliced isoforms of p53 from Litopenaeus vannamei (LvDeltaNp53 and the full-length of p53, LvFLp53). We then established that the two p53 isoforms exerted opposite effects on regulating NF-kappaB induced antimicrobial peptides (AMPs) and white spot syndrome virus (WSSV) immediate-early (IE) genes expression, suggesting there could be a crosstalk between p53 and NF-kappaB pathways. Of note, both of the two p53 isoforms could interact directly with LvDorsal, a shrimp homolog of NF-kappaB. In addition, the activation of NF-kappaB mediated by LvDorsal was provoked by LvDeltaNp53 but suppressed by LvFLp53, and the increased NF-kappaB activity conferred by LvDeltaNp53 can be attenuated by LvFLp53. Furthermore, silencing of LvFLp53 in shrimp caused higher mortalities and virus loads under WSSV infection, whereas LvDeltaNp53-knockdown shrimps exhibited an opposed RNAi phenotype. Taken together, these findings present here provided some novel insight into different roles of shrimp p53 isoforms in immune response, and some information for us to understand the regulatory crosstalk between p53 pathway and NF-kappaB pathway in invertebrates. PMID- 28361940 TI - On data availability, reproducibility and reuse. PMID- 28361941 TI - Erratum: Tissue-scale coordination of cellular behaviour promotes epidermal wound repair in live mice. PMID- 28361942 TI - PARL paves the way to apoptosis. AB - Although the mitochondrial inner membrane rhomboid peptidase PARL is known to participate in critical signalling cascades, its role in apoptosis has remained unclear. PARL is now shown to process the mitochondrial pro-apoptotic protein Smac (also known as DIABLO) for its subsequent release into the cytosol where it antagonizes XIAP-mediated caspase inhibition to promote apoptosis. PMID- 28361943 TI - Talin gets SHANKed in the fight for integrin activation. AB - Genetic mutations in the SHANK family of proteins are linked to multiple neuropsychiatric disorders including autism spectrum disorders. A study now elucidates critical roles for SHANK in regulating integrin-mediated cell extracellular matrix adhesion, by sequestering integrin activators. PMID- 28361945 TI - High-performance spinel-rich Li1.5MnTiO4+delta ultralong nanofibers as cathode materials for Li-ion batteries. AB - Recently, composite materials based on Li-Mn-Ti-O system were developed to target low cost and environmentally benign cathodes for Li-ion batteries. The spinel layered Li1.5MnTiO4+delta bulk particles showed excellent cycle stability but poor rate performance. To address this drawback, ultralong nanofibers of a Li1.5MnTiO4+delta spinel-layered heterostructure were synthesized by electrospinning. Uniform nanofibers with diameters of about 80 nm were formed of tiny octahedral particles wrapped together into 30 MUm long fibers. The Li1.5MnTiO4+delta nanofibers exhibited an improved rate capability compared to both Li1.5MnTiO4+delta nanoparticles and bulk particles. The uniform one dimensional nanostructure of the composite cathode exhibited enhanced capacities of 235 and 170 mAh g-1 at C/5 and 1 C rates, respectively. Its unique structure provided a large effective contact area for Li+ diffusion, and low charge transfer resistance. Moreover, the layered phase contributed to its capacity in over 3 V region, which increased specific energy (726 Wh kg-1) compared to the bulk particles (534 Wh kg-1). PMID- 28361944 TI - Association Study of Reported Significant Loci at 5q35.3, 7p14.3, 13q14.1 and 16p12.3 with Urolithiasis in Chinese Han Ethnicity. AB - In this study, we aimed to validate the association of 8 reported significant loci at 5q35.3, 7p14.3, 13q14.1 and 16p12.3 with urolithiasis in Chinese Han population. We performed case-control association analysis using 624 patients with nephrolithiasis and 1008 control subjects. We selected single-nucleotide polymorphism (SNPs) including rs12654812 and rs11746443 from 5q32.3; rs12669187 and rs1000597 from 7q14.3; rs7981733, rs4142110 and rs17646069 from 13q14.1 and rs4293393 from 16p12.3 which were previously reported to be associated with nephrolithiasis. We found none of these eight reported SNPs were significant associated with urolithiasis risk in Chinese Han population, which suggested that differences could exist in the mechanisms of calcium urolithiasis between Chinese and Japanese Ethnics. The A allele of rs12669187 was significantly correlated with increased level of serum magnesium. The C allele of rs1000597 was associated with higher levels of serum creatinine, uric acid, calcium and lower urine pH level. The T allele of rs4142110 was correlated with higher levels of serum magnesium, phosphorus, and lower AKP level. The G alleles of rs4293393 was associated with higher serum CO2 level. The risk alleles of these SNPs were proved to be associated with the electrolytes metabolism that may result in the formation of urolithiasis. PMID- 28361946 TI - Rediscovery and reclassification of the dipteran taxon Nothomicrodon Wheeler, an exclusive endoparasitoid of gyne ant larvae. AB - The myrmecophile larva of the dipteran taxon Nothomicrodon Wheeler is rediscovered, almost a century after its original description and unique report. The systematic position of this dipteran has remained enigmatic due to the absence of reared imagos to confirm indentity. We also failed to rear imagos, but we scrutinized entire nests of the Brazilian arboreal dolichoderine ant Azteca chartifex which, combined with morphological and molecular studies, enabled us to establish beyond doubt that Nothomicrodon belongs to the Phoridae (Insecta: Diptera), not the Syrphidae where it was first placed, and that the species we studied is an endoparasitoid of the larvae of A. chartifex, exclusively attacking sexual female (gyne) larvae. Northomicrodon parasitism can exert high fitness costs to a host colony. Our discovery adds one more case to the growing number of phorid taxa known to parasitize ant larvae and suggests that many others remain to be discovered. Our findings and literature review confirm that the Phoridae is the only taxon known that parasitizes both adults and the immature stages of different castes of ants, thus threatening ants on all fronts. PMID- 28361947 TI - Mapping ECoG channel contributions to trajectory and muscle activity prediction in human sensorimotor cortex. AB - Studies on brain-machine interface techniques have shown that electrocorticography (ECoG) is an effective modality for predicting limb trajectories and muscle activity in humans. Motor control studies have also identified distributions of "extrinsic-like" and "intrinsic-like" neurons in the premotor (PM) and primary motor (M1) cortices. Here, we investigated whether trajectories and muscle activity predicted from ECoG were obtained based on signals derived from extrinsic-like or intrinsic-like neurons. Three participants carried objects of three different masses along the same counterclockwise path on a table. Trajectories of the object and upper arm muscle activity were predicted using a sparse linear regression. Weight matrices for the predictors were then compared to determine if the ECoG channels contributed more information about trajectory or muscle activity. We found that channels over both PM and M1 contributed highly to trajectory prediction, while a channel over M1 was the highest contributor for muscle activity prediction. PMID- 28361949 TI - Quasi-stokeslet induced by thermoplasmonic Marangoni effect around a water vapor microbubble. AB - Rapid Marangoni flows around a water vapor microbubble (WVMB) is investigated using the thermoplasmonic effect of a gold nanoisland film (GNF). By focusing a laser onto the GNF, a stable WVMB with a diameter of ~10 MUm is generated in degassed water, while an air bubble generated in non-degassed water is larger than 40 MUm. Under continuous heating, the WVMB involves significantly rapid Marangoni flow. This flow is well-described by a stokeslet sat ~10 MUm above the surface of GNF, from which the maximum flow speed around the WVMB is estimated to exceed 1 m/s. This rapid flow generation is attributed to the small bubble size, over which the temperature is graded, and the superheat at the bubble surface in contact with the GNF. It is expected to be useful not only for microfluidic mixing but also for fundamental research on viscous flow induced by a single stokeslet. PMID- 28361950 TI - Implementation of a quantum controlled-SWAP gate with photonic circuits. AB - Quantum information science addresses how the processing and transmission of information are affected by uniquely quantum mechanical phenomena. Combination of two-qubit gates has been used to realize quantum circuits, however, scalability is becoming a critical problem. The use of three-qubit gates may simplify the structure of quantum circuits dramatically. Among them, the controlled-SWAP (Fredkin) gates are essential since they can be directly applied to important protocols, e.g., error correction, fingerprinting, and optimal cloning. Here we report a realization of the Fredkin gate for photonic qubits. We achieve a fidelity of 0.85 in the computational basis and an output state fidelity of 0.81 for a 3-photon Greenberger-Horne-Zeilinger state. The estimated process fidelity of 0.77 indicates that our Fredkin gate can be applied to various quantum tasks. PMID- 28361948 TI - Degradation of neural representations in higher visual cortex by sleep deprivation. AB - A night of total sleep deprivation (TSD) impairs selective attention and is accompanied by attenuated activation within ventral visual cortex (VVC). However, finer details of how TSD compromises selectivity of visual processing remain unclear. Drawing from prior work in cognitive aging, we predicted that TSD would result in dedifferentiation of neural responses for faces and houses within the VVC. Instead, we found preservation of category selectivity. This was observed both in voxels highly selective for each category, and also across multiple voxels evaluated using MVPA. Based on prior findings of impaired attentional modulation following TSD, we also predicted reduced biasing of neural representations towards the attended category when participants viewed ambiguous face/house images. When participants were well rested, attention to houses (or faces) caused activation patterns to more closely resemble those elicited by isolated house (face) images than face (house) images. During TSD, attention to faces enhanced neural similarity to both target (face) and distractor (house) representations, signifying reduced suppression of irrelevant information. Degraded sensory processing reflected in reduced VVC activation following TSD, thus appears to be a result of impaired top-down modulation of sensory representations instead of degraded selectivity of maximally category sensitive voxels, or the dedifferentiation of neural activation patterns. PMID- 28361951 TI - Qualitative and Quantitative Imaging Evaluation of Renal Cell Carcinoma Subtypes with Grating-based X-ray Phase-contrast CT. AB - Current clinical imaging methods face limitations in the detection and correct characterization of different subtypes of renal cell carcinoma (RCC), while these are important for therapy and prognosis. The present study evaluates the potential of grating-based X-ray phase-contrast computed tomography (gbPC-CT) for visualization and characterization of human RCC subtypes. The imaging results for 23 ex vivo formalin-fixed human kidney specimens obtained with phase-contrast CT were compared to the results of the absorption-based CT (gbCT), clinical CT and a 3T MRI and validated using histology. Regions of interest were placed on each specimen for quantitative evaluation. Qualitative and quantitative gbPC-CT imaging could significantly discriminate between normal kidney cortex (54 +/- 4 HUp) and clear cell (42 +/- 10), papillary (43 +/- 6) and chromophobe RCCs (39 +/ 7), p < 0.05 respectively. The sensitivity for detection of tumor areas was 100%, 50% and 40% for gbPC-CT, gbCT and clinical CT, respectively. RCC architecture like fibrous strands, pseudocapsules, necrosis or hyalinization was depicted clearly in gbPC-CT and was not equally well visualized in gbCT, clinical CT and MRI. The results show that gbPC-CT enables improved discrimination of normal kidney parenchyma and tumorous tissues as well as different soft-tissue components of RCCs without the use of contrast media. PMID- 28361952 TI - USP9X regulates centrosome duplication and promotes breast carcinogenesis. AB - Defective centrosome duplication is implicated in microcephaly and primordial dwarfism as well as various ciliopathies and cancers. Yet, how the centrosome biogenesis is regulated remains poorly understood. Here we report that the X linked deubiquitinase USP9X is physically associated with centriolar satellite protein CEP131, thereby stabilizing CEP131 through its deubiquitinase activity. We demonstrate that USP9X is an integral component of centrosome and is required for centrosome biogenesis. Loss-of-function of USP9X impairs centrosome duplication and gain-of-function of USP9X promotes centrosome amplification and chromosome instability. Significantly, USP9X is overexpressed in breast carcinomas, and its level of expression is correlated with that of CEP131 and higher histologic grades of breast cancer. Indeed, USP9X, through regulation of CEP131 abundance, promotes breast carcinogenesis. Our experiments identify USP9X as an important regulator of centrosome biogenesis and uncover a critical role for USP9X/CEP131 in breast carcinogenesis, supporting the pursuit of USP9X/CEP131 as potential targets for breast cancer intervention. PMID- 28361953 TI - Cell-to-cell transfer of SAA1 protein in a cell culture model of systemic AA amyloidosis. AB - Systemic AA amyloidosis arises from the misfolding of serum amyloid A1 (SAA1) protein and the deposition of AA amyloid fibrils at multiple sites within the body. Previous research already established that mononuclear phagocytes are crucial for the formation of the deposits in vivo and exposure of cultures of such cells to SAA1 protein induces the formation of amyloid deposits within the culture dish. In this study we show that both non-fibrillar and fibrillar SAA1 protein can be readily transferred between cultured J774A.1 cells, a widely used model of mononuclear phagocytes. We find that the exchange is generally faster with non-fibrillar SAA1 protein than with fibrils. Exchange is blocked if cells are separated by a membrane, while increasing the volume of cell culture medium had only small effects on the observed exchange efficiency. Taken together with scanning electron microscopy showing the presence of the respective types of physical interactions between the cultured cells, we conclude that the transfer of SAA1 protein depends on direct cell-to-cell contacts or tunneling nanotubes. PMID- 28361954 TI - Hidden Markov models reveal complexity in the diving behaviour of short-finned pilot whales. AB - Diving behaviour of short-finned pilot whales is often described by two states; deep foraging and shallow, non-foraging dives. However, this simple classification system ignores much of the variation that occurs during subsurface periods. We used multi-state hidden Markov models (HMM) to characterize states of diving behaviour and the transitions between states in short-finned pilot whales. We used three parameters (number of buzzes, maximum dive depth and duration) measured in 259 dives by digital acoustic recording tags (DTAGs) deployed on 20 individual whales off Cape Hatteras, North Carolina, USA. The HMM identified a four-state model as the best descriptor of diving behaviour. The state-dependent distributions for the diving parameters showed variation between states, indicative of different diving behaviours. Transition probabilities were considerably higher for state persistence than state switching, indicating that dive types occurred in bouts. Our results indicate that subsurface behaviour in short-finned pilot whales is more complex than a simple dichotomy of deep and shallow diving states, and labelling all subsurface behaviour as deep dives or shallow dives discounts a significant amount of important variation. We discuss potential drivers of these patterns, including variation in foraging success, prey availability and selection, bathymetry, physiological constraints and socially mediated behaviour. PMID- 28361956 TI - Role for formin-like 1-dependent acto-myosin assembly in lipid droplet dynamics and lipid storage. AB - Lipid droplets (LDs) are cellular organelles specialized in triacylglycerol (TG) storage undergoing homotypic clustering and fusion. In non-adipocytic cells with numerous LDs this is balanced by poorly understood droplet dissociation mechanisms. We identify non-muscle myosin IIa (NMIIa/MYH-9) and formin-like 1 (FMNL1) in the LD proteome. NMIIa and actin filaments concentrate around LDs, and form transient foci between dissociating LDs. NMIIa depletion results in decreased LD dissociations, enlarged LDs, decreased hydrolysis and increased storage of TGs. FMNL1 is required for actin assembly on LDs in vitro and for NMIIa recruitment to LDs in cells. We propose a novel acto-myosin structure regulating lipid storage: FMNL1-dependent assembly of myosin II-functionalized actin filaments on LDs facilitates their dissociation, thereby affecting LD surface-to-volume ratio and enzyme accessibility to TGs. In neutrophilic leucocytes from MYH9-related disease patients NMIIa inclusions are accompanied by increased lipid storage in droplets, suggesting that NMIIa dysfunction may contribute to lipid imbalance in man. PMID- 28361955 TI - Endoscopic nipple sparing mastectomy with immediate implant-based reconstruction versus breast conserving surgery: a long-term study. AB - To evaluate the differences between endoscopic nipple sparing mastectomy (ENSM) with immediate implant-based reconstruction and breast conserving surgery(BCS) applied to early-stage breast cancer in postoperative outcomes, function, and cosmesis. we made a prospective, non-randomized study reviewed a total of 346 cases of breast cancer from January 2007 to December 2011, including 189 cases of BCS and 157 cases of ENSM. All the patients were followed up to April 2016, with a median follow-up time of 74 months. The operative time, blood loss and drainage, postoperative complications, postoperative cosmesis, local recurrence rate, disease-free survival rate and overall survival rate of the two groups were compared. we found out that the operative time of ENSM was longer than that of BCS. There was no difference in blood loss and drainage, the postoperative complications, the disease-free survival rate and overall survival rate between the two groups. In regarding to cosmesis, patients in the ENSM group were more likely to get a satisfactory postoperative breast appearance. we reached a conclusion that ENSM is a safe and effective operative method retainingadvantages of TSSM to further improve the postoperative cosmetic effect, without increasing other risks. The surgery provides a new choice for patients with early-stage breast cancer. PMID- 28361957 TI - Comparative Subcellular Proteomics Analysis of Susceptible and Near-isogenic Resistant Bombyx mori (Lepidoptera) Larval Midgut Response to BmNPV infection. AB - The molecular mechanism of silkworm resistance to Bombyx mori nucleopolyhedrovirus (BmNPV) infection remains largely unclear. Accumulating evidence suggests that subcellular fractionation combined with proteomics is an ideal technique to analyse host antiviral mechanisms. To clarify the anti-BmNPV mechanism of the silkworm, the near-isogenic line BC9 (resistant strain) and the recurrent parent P50 (susceptible strain) were used in a comparative subcellular proteomics study. Two-dimensional gel electrophoresis (2-DE) combined with mass spectrometry (MS) was conducted on proteins extracted from the cytosol, mitochondria, and microsomes of BmNPV-infected and control larval midguts. A total of 87 proteins were successfully identified from the three subcellular fractions. These proteins were primarily involved in energy metabolism, protein metabolism, signalling pathways, disease, and transport. In particular, disease relevant proteins were especially changed in microsomes. After infection with BmNPV, differentially expressed proteins (DEPs) primarily appeared in the cytosolic and microsomal fractions, which indicated that these two fractions might play a more important role in the response to BmNPV infection. After removing genetic background and individual immune stress response proteins, 16 proteins were identified as potentially involved in repressing BmNPV infection. Of these proteins, the differential expression patterns of 8 proteins according to reverse transcription quantitative PCR (RT-qPCR) analyses were consistent with the 2-DE results. PMID- 28361958 TI - Graphene-like nanoribbons periodically embedded with four- and eight-membered rings. AB - Embedding non-hexagonal rings into sp2-hybridized carbon networks is considered a promising strategy to enrich the family of low-dimensional graphenic structures. However, non-hexagonal rings are energetically unstable compared to the hexagonal counterparts, making it challenging to embed non-hexagonal rings into carbon based nanostructures in a controllable manner. Here, we report an on-surface synthesis of graphene-like nanoribbons with periodically embedded four- and eight membered rings. The scanning tunnelling microscopy and atomic force microscopy study revealed that four- and eight-membered rings are formed between adjacent perylene backbones with a planar configuration. The non-hexagonal rings as a topological modification markedly change the electronic properties of the nanoribbons. The highest occupied and lowest unoccupied ribbon states are mainly distributed around the eight- and four-membered rings, respectively. The realization of graphene-like nanoribbons comprising non-hexagonal rings demonstrates a controllable route to fabricate non-hexagonal rings in nanoribbons and makes it possible to unveil their unique properties induced by non-hexagonal rings. PMID- 28361959 TI - Dinaciclib potently suppresses MCL-1 and selectively induces the cell death in human iPS cells without affecting the viability of cardiac tissue. AB - Induced pluripotent stem (iPS) cells hold great potential for being a major source of cells for regenerative medicine. One major issue that hinders their advancement to clinic is the persistence of undifferentiated iPS cells in iPS derived tissue. In this report, we show that the CDKs inhibitor, Dinaciclib, selectively eliminates iPS cells without affecting the viability of cardiac cells. We found that low nanomolar concentration of dinaciclib increased DNA damage and p53 protein levels in iPSCs. This was accompanied by negative regulation of the anti-apoptotic protein MCL-1. Gene knockdown experiments revealed that p53 downregulation only increased the threshold of dinaciclib induced apoptosis in iPS cells. Dinaciclib also inhibited the phosphorylation of Serine 2 of the C-terminal domain of RNA Polyemrase II through CDK9 inhibition. This resulted in the inhibition of transcription of MCL-1 and the pluripotency genes, NANOG and c-MYC. Even though dinaciclib caused a slight downregulation of MCL-1 in iPS-derived cardiac cells, the viability of the cells was not significantly affected, and beating iPS-derived cardiac cell sheet could still be fabricated. These findings suggest a difference in tolerance of MCL-1 downregulation between iPSCs and iPS-derived cardiac cells which could be exploited to eliminate remaining iPS cells in bioengineered cell sheet tissues. PMID- 28361960 TI - Sequence analysis of pooled bacterial samples enables identification of strain variation in group A streptococcus. AB - Knowledge of the genomic variation among different strains of a pathogenic microbial species can help in selecting optimal candidates for diagnostic assays and vaccine development. Pooled sequencing (Pool-seq) is a cost effective approach for population level genetic studies that require large numbers of samples such as various strains of a microbe. To test the use of Pool-seq in identifying variation, we pooled DNA of 100 Streptococcus pyogenes strains of different emm types in two pools, each containing 50 strains. We used four variant calling tools (Freebayes, UnifiedGenotyper, SNVer, and SAMtools) and one emm1 strain, SF370, as a reference genome. In total 63719 SNPs and 164 INDELs were identified in the two pools concordantly by at least two of the tools. Majority of the variants (93.4%) from six individually sequenced strains used in the pools could be identified from the two pools and 72.3% and 97.4% of the variants in the pools could be mined from the analysis of the 44 complete Str. pyogenes genomes and 3407 sequence runs deposited in the European Nucleotide Archive respectively. We conclude that DNA sequencing of pooled samples of large numbers of bacterial strains is a robust, rapid and cost-efficient way to discover sequence variation. PMID- 28361961 TI - Exposure to paternal tobacco smoking increased child hospitalization for lower respiratory infections but not for other diseases in Vietnam. AB - Exposure to environmental tobacco smoke (ETS) is an important modifiable risk factor for child hospitalization, although its contribution is not well documented in countries where ETS due to maternal tobacco smoking is negligible. We conducted a birth cohort study of 1999 neonates between May 2009 and May 2010 in Nha Trang, Vietnam, to evaluate paternal tobacco smoking as a risk factor for infectious and non-infectious diseases. Hospitalizations during a 24-month observation period were identified using hospital records. The effect of paternal exposure during pregnancy and infancy on infectious disease incidence was evaluated using Poisson regression models. In total, 35.6% of 1624 children who attended follow-up visits required at least one hospitalization by 2 years of age, and the most common reason for hospitalization was lower respiratory tract infection (LRTI). Paternal tobacco smoking independently increased the risk of LRTI 1.76-fold (95% CI: 1.24-2.51) after adjusting for possible confounders but was not associated with any other cause of hospitalization. The population attributable fraction indicated that effective interventions to prevent paternal smoking in the presence of children would reduce LRTI-related hospitalizations by 14.8% in this epidemiological setting. PMID- 28361962 TI - Fractal and multifractal analyses of bipartite networks. AB - Bipartite networks have attracted considerable interest in various fields. Fractality and multifractality of unipartite (classical) networks have been studied in recent years, but there is no work to study these properties of bipartite networks. In this paper, we try to unfold the self-similarity structure of bipartite networks by performing the fractal and multifractal analyses for a variety of real-world bipartite network data sets and models. First, we find the fractality in some bipartite networks, including the CiteULike, Netflix, MovieLens (ml-20m), Delicious data sets and (u, v)-flower model. Meanwhile, we observe the shifted power-law or exponential behavior in other several networks. We then focus on the multifractal properties of bipartite networks. Our results indicate that the multifractality exists in those bipartite networks possessing fractality. To capture the inherent attribute of bipartite network with two types different nodes, we give the different weights for the nodes of different classes, and show the existence of multifractality in these node-weighted bipartite networks. In addition, for the data sets with ratings, we modify the two existing algorithms for fractal and multifractal analyses of edge-weighted unipartite networks to study the self-similarity of the corresponding edge weighted bipartite networks. The results show that our modified algorithms are feasible and can effectively uncover the self-similarity structure of these edge weighted bipartite networks and their corresponding node-weighted versions. PMID- 28361963 TI - Maternal Smoking during Pregnancy and Necrotizing Enterocolitis-associated Infant Mortality in Preterm Babies. AB - Few studies have examined the possible pregnancy-related risk factors for necrotizing enterocolitis (NEC)-associated deaths during infancy. Infant death due to NEC in preterm babies was identified from the US Linked Livebirth and Infant Death records between 2000 and 2004. The average number of cigarettes per day reported by the mothers who were smoking during pregnancy was classified in three categories: non-smoking, light smoking (<10 cigarettes/day) and heavy smoking (>=10 cigarettes/day). Logistic regression analyses examined the association between prenatal smoking and NEC-associated infant mortality rates with adjustment for potential confounders. Compared with non-smoking mothers, light and heavy smoking mothers have a higher risk of NEC-associated infant mortality [light smoking: adjusted odds ratio (aOR) = 1.21, 95% confidence interval (CI), 1.03-1.43; heavy smoking: aOR = 1.30, 95% CI, 1.12-1.52], respectively. Moreover, the association was stronger among white race (light smoking: aOR = 1.69, 95% CI, 1.34-2.13; heavy smoking: aOR = 1.44, 95% CI, 1.18 1.75) and female babies (light smoking: aOR = 1.31, 95% CI, 1.02-1.69; heavy smoking: aOR = 1.62, 95% CI, 1.29-2.02). Maternal smoking during pregnancy is associated with increased risks of infant mortality due to NEC in preterm babies, especially in white race and female babies. PMID- 28361964 TI - Experimental and numerical evaluations on palm microwave heating for Red Palm Weevil pest control. AB - The invasive Red Palm Weevil is the major pest of palms. Several control methods have been applied, however concern is raised regarding the treatments that can cause significant environmental pollution. In this context the use of microwaves is particularly attractive. Microwave heating applications are increasingly proposed in the management of a wide range of agricultural and wood pests, exploiting the thermal death induced in the insects that have a thermal tolerance lower than that of the host matrices. This paper describes research aiming to combat the Red Palm pest using microwave heating systems. An electromagnetic thermal model was developed to better control the temperature profile inside the palm tissues. In this process both electromagnetic and thermal parameters are involved, the latter being particularly critical depending on plant physiology. Their evaluation was carried out by fitting experimental data and the thermal model with few free parameters. The results obtained by the simplified model well match with both that of a commercial software 3D model and measurements on treated Phoenix canariensis palms with a ring microwave applicator. This work confirms that microwave heating is a promising, eco-compatible solution to fight the spread of weevil. PMID- 28361966 TI - Ash aggregation enhanced by deposition and redistribution of salt on the surface of volcanic ash in eruption plumes. AB - Interactions with volcanic gases in eruption plumes produce soluble salt deposits on the surface of volcanic ash. While it has been postulated that saturation driven precipitation of salts following the dissolution of ash surfaces by condensed acidic liquids is a primary mechanism of salt formation during an eruption, it is only recently that this mechanism has been subjected to detailed study. Here we spray water and HCl droplets into a suspension of salt-doped synthetic glass or volcanic ash particles, and produce aggregates. Deposition of acidic liquid droplets on ash particles promotes dissolution of existing salts and leaches cations from the underlying material surface. The flow of liquid, due to capillary forces, will be directed to particle-particle contact points where subsequent precipitation of salts will cement the aggregate. Our data suggest that volcanically-relevant loads of surface salts can be produced by acid condensation in eruptive settings. Several minor and trace elements mobilised by surface dissolution are biologically relevant; geographic areas with aggregation mediated ash fallout could be "hotspots" for the post-deposition release of these elements. The role of liquids in re-distributing surface salts and cementing ash aggregates also offers further insight into the mechanisms which preserve well structured aggregates in some ash deposits. PMID- 28361965 TI - Transcriptomics and proteomic studies reveal acaricidal mechanism of octadecanoic acid-3, 4 - tetrahydrofuran diester against Sarcoptes scabiei var. cuniculi. AB - In our previous study, a new compound, octadecanoic acid-3, 4-tetrahydrofuran diester, possessing potent acaricidal activity was obtained from neem oil. This study performed RNA-seq transcriptomics and iTRAQ proteomics to uncover the acaricidal mechanism of the compound against Sarcoptes scabiei var. cuniculi. The results of transcriptomics indicated that after treatment with octadecanoic acid 3, 4-tetrahydrofuran diester, genes related to "Energy metabolism" were significantly up-/down-regulated, including citrate cycle, oxidative phosphorylation pathway and fatty acid metabolism. Proteomics analysis showed accordant changes of proteins related to oxidative phosphorylation pathway. The target proteins of the compound were NADH dehydrogenase, Ubiquinol-cytochrome c reductase, Cytochrome c oxidase, ATP synthase, enolase and superoxide dismutase. In transcriptomics-proteomics correlation analysis, the concordance rate between protein abundances and their corresponding mRNAs was 57%, while others (43%) were discordant changes, suggesting divergent regulating effects of octadecanoic acid 3, 4-tetrahydrofuran diester. These results suggested that the acaricidal mechanism of octadecanoic acid-3, 4-tetrahydrofuran diester attributed to interference with energy metabolism, especially oxidative phosphorylation pathway. PMID- 28361967 TI - Precise Photodynamic Therapy of Cancer via Subcellular Dynamic Tracing of Dual loaded Upconversion Nanophotosensitizers. AB - Recent advances in upconversion nanophotosensitizers (UCNPs-PS) excited by near infrared (NIR) light have led to substantial progress in improving photodynamic therapy (PDT) of cancer. For a successful PDT, subcellular organelles are promising therapeutic targets for reaching a satisfactory efficacy. It is of vital importance for these nanophotosensitizers to reach specifically the organelles and to perform PDT with precise time control. To do so, we have in this work traced the dynamic subcellular distribution, especially in organelles such as lysosomes and mitochondria, of the poly(allylamine)-modified and dual loaded nanophotosensitizers. The apoptosis of the cancer cells induced by PDT with the dependence of the distribution status of the nanophotosensitizers in organelles was obtained, which has provided an in-depth picture of intracellular trafficking of organelle-targeted nanophotosensitizers. Our results shall facilitate the improvement of nanotechnology assisted photodynamic therapy of cancers. PMID- 28361968 TI - Photodynamic dye adsorption and release performance of natural zeolite. AB - Clinoptilolite type of zeolite (CZ) is a promising material for biomedicine and pharmaceutics due to its non-toxicity, thermal stability, expanded surface area, and exceptional ability to adsorb various atoms and organic molecules into micropores. Using multiphoton microscopy, we demonstrated that individual CZ particles produce two-photon excited luminescence and second harmonic generation signal at femtosecond laser excitation, and adsorb photo-dynamically active dyes such as hypericin and methylene blue. Furthermore, the release of hypericin from CZ pores in the presence of biomolecules is shown, and CZ can be considered as an effective material for drug delivery and controlled release in biological systems. The results may open new perspectives in application of CZ in biomedical imaging, and introducing of the optical approaches into the clinical environment. PMID- 28361969 TI - HEG1 is a novel mucin-like membrane protein that serves as a diagnostic and therapeutic target for malignant mesothelioma. AB - The absence of highly specific markers for malignant mesothelioma (MM) has served an obstacle for its diagnosis and development of molecular-targeting therapy against MM. Here, we show that a novel mucin-like membrane protein, sialylated protein HEG homolog 1 (HEG1), is a highly specific marker for MM. A monoclonal antibody against sialylated HEG1, SKM9-2, can detect even sarcomatoid and desmoplastic MM. The specificity and sensitivity of SKM9-2 to MM reached 99% and 92%, respectively; this antibody did not react with normal tissues. This accurate discrimination by SKM9-2 was due to the recognition of a sialylated O-linked glycan with HEG1 peptide. We also found that gene silencing of HEG1 significantly suppressed the survival and proliferation of mesothelioma cells; this result suggests that HEG1 may be a worthwhile target for function-inhibition drugs. Taken together, our results indicate that sialylated HEG1 may be useful as a diagnostic and therapeutic target for MM. PMID- 28361970 TI - PCTK3/CDK18 regulates cell migration and adhesion by negatively modulating FAK activity. AB - PCTAIRE kinase 3 (PCTK3) is a member of the cyclin dependent kinase family, but its physiological function remains unknown. We previously reported that PCTK3 knockdown HEK293T cells showed actin accumulation at the leading edge, suggesting that PCTK3 is involved in the regulation of actin reorganization. In this study, we investigated the physiological function and downstream signal transduction molecules of PCTK3. PCTK3 knockdown in HEK293T cells increased cell motility and RhoA/Rho-associated kinase activity as compared with control cells. We also found that phosphorylation at residue Tyr-397 in focal adhesion kinase (FAK) was increased in PCTK3-knockdown cells. FAK phosphorylation at Tyr-397 was increased in response to fibronectin stimulation, whereas its phosphorylation was suppressed by PCTK3. In addition, excessive expression of PCTK3 led to the formation of filopodia during the early stages of cell adhesion in HeLa cells. These results indicate that PCTK3 controls actin cytoskeleton dynamics by negatively regulating the FAK/Rho signaling pathway. PMID- 28361973 TI - Diabetes: Sacubitril/valsartan improves glycaemic control. PMID- 28361974 TI - Dyslipidaemia: Promising results with siRNA against PCSK9. PMID- 28361971 TI - PG2 for patients with acute spontaneous intracerebral hemorrhage: a double-blind, randomized, placebo-controlled study. AB - PG2 is an infusible polysaccharide extracted from Astragalus membranaceus, which is a Chinese herb traditionally used for stroke treatment. We investigated the effect of PG2 on patients with spontaneous acute intracerebral hemorrhage (ICH). A total of 61 patients with acute spontaneous ICH were randomized to either the treatment group (TG, 30 patients), which received 3 doses of PG2 (500 mg, IV) per week for 2 weeks, or the control group (CG, 31 patients), which received PG2 placebo. At 84 days after PG2 administration, the percentage of patients with a good Glasgow outcome scale (GOS 4-5) score in the TG was similar to that in the CG (69.0% vs. 48.4%; p = 0.2). The percentage of good mRS scores (0-2) in the TG was similar to that in the CG (62.1% vs. 45.2%; p = 0.3). In addition, no significant differences were seen when comparing differences in the C-reactive protein, erythrocyte sedimentation rate, interleukin-6 (IL-6), IL-1beta, tumor necrosis factor-alpha, and S100B levels between baseline and days 4, 7, and 14 after PG2 administration (all p > 0.05). The results are preliminary, necessitating a more thorough assessment. PMID- 28361975 TI - Heart failure: No early benefits of adjunct therapy with tolvaptan for acute heart failure. PMID- 28361972 TI - PABPN1 gene therapy for oculopharyngeal muscular dystrophy. AB - Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, late-onset muscle disorder characterized by ptosis, swallowing difficulties, proximal limb weakness and nuclear aggregates in skeletal muscles. OPMD is caused by a trinucleotide repeat expansion in the PABPN1 gene that results in an N-terminal expanded polyalanine tract in polyA-binding protein nuclear 1 (PABPN1). Here we show that the treatment of a mouse model of OPMD with an adeno-associated virus based gene therapy combining complete knockdown of endogenous PABPN1 and its replacement by a wild-type PABPN1 substantially reduces the amount of insoluble aggregates, decreases muscle fibrosis, reverts muscle strength to the level of healthy muscles and normalizes the muscle transcriptome. The efficacy of the combined treatment is further confirmed in cells derived from OPMD patients. These results pave the way towards a gene replacement approach for OPMD treatment. PMID- 28361976 TI - Coronary artery disease: Urbanization is a risk factor for CAD. PMID- 28361978 TI - Venous thromboembolism: Risk of recurrence lower with rivaroxaban than aspirin. PMID- 28361979 TI - Stem cells: Cell therapy for cardiac repair: what is needed to move forward? PMID- 28361980 TI - Anticoagulation therapy: Uninterrupted dabigatran during ablation for AF. PMID- 28361977 TI - Myocardial stress and autophagy: mechanisms and potential therapies. AB - Autophagy is a ubiquitous cellular catabolic process responsive to energy stress. Research over the past decade has revealed that cardiomyocyte autophagy is a prominent homeostatic pathway, important in adaptation to altered myocardial metabolic demand. The cellular machinery of autophagy involves targeted direction of macromolecules and organelles for lysosomal degradation. Activation of autophagy has been identified as cardioprotective in some settings (that is, ischaemia and ischaemic preconditioning). In other situations, sustained autophagy has been linked with cardiopathology (for example, sustained pressure overload and heart failure). Perturbation of autophagy in diabetic cardiomyopathy has also been observed and is associated with both adaptive and maladaptive responses to stress. Emerging research findings indicate that various forms of selective autophagy operate in parallel to manage various types of catabolic cellular cargo including mitochondria, large proteins, glycogen, and stored lipids. In this Review, induction of autophagy associated with cardiac benefit or detriment is considered. The various static and dynamic approaches used to measure autophagy are critiqued, and current inconsistencies in the understanding of autophagy regulation in the heart are highlighted. The prospects for pharmacological intervention to achieve therapeutic manipulation of autophagic processes are also discussed. PMID- 28361981 TI - Patterns in the skin microbiota differ in children and teenagers between rural and urban environments. AB - The composition of human microbiota is affected by a multitude of factors. Understanding the dynamics of our microbial communities is important for promoting human health because microbiota has a crucial role in the development of inflammatory diseases, such as allergies. We have studied the skin microbiota of both arms in 275 Finnish children of few months old to teenagers living in contrasting environments. We show that while age is a major factor affecting skin microbial composition, the living environment also discriminates the skin microbiota of rural and urban children. The effect of environment is age specific; it is most prominent in toddlers but weaker for newborns and non existent for teenagers. Within-individual variation is also related to age and environment. Surprisingly, variation between arms is smaller in rural subjects in all age groups, except in teenagers. We also collected serum samples from children for characterization of allergic sensitization and found a weak, but significant association between allergic sensitization and microbial composition. We suggest that physiological and behavioral changes, related to age and the amount of contact with environmental microbiota, jointly influence the dynamics of the skin microbiota, and explain why the association between the living environment skin microbiota is lost in teenager. PMID- 28361982 TI - Nonlinear responses of soil respiration to precipitation changes in a semiarid temperate steppe. AB - Extreme precipitation events are predicted to occur more frequently and will have significant influences on terrestrial ecosystem carbon (C) cycling in the future. However, response patterns of soil respiration to precipitation changes remain uncertain in terrestrial ecosystems. A field experiment with seven precipitation treatments (i.e. from -60% to +60% of ambient precipitation to form a drought to wet precipitation gradient) was conducted over three growing seasons (2010-2012) in a semiarid temperate steppe of Northern China. Results showed a nonlinear response pattern of soil respiration along the experimental precipitation gradient, with soil respiration suppressed by decreased precipitation and enhanced by increased precipitation. Over the three growing seasons, soil respiration was reduced more under the three drought treatments (by 45.8, 32.8, and 15.9% under the -60, -40, and -20% treatments, respectively) than stimulated under the three wet treatments (by 8.9, 14.3, and 18.5% under the +20, +40, and +60% treatments, respectively). Our results indicate that soil respiration was more sensitive to decreased than increased precipitation treatments. The nonlinear and asymmetric responses of soil respiration to precipitation changes should be built into ecosystem models to project ecosystem C cycling associated with climate change. PMID- 28361983 TI - Inhibitory Potential of Constituents from Osmanthus fragrans and Structural Analogues Against Advanced Glycation End Products, alpha-Amylase, alpha Glucosidase, and Oxidative Stress. AB - Inhibition of alpha-amylase and alpha-glucosidase, advanced glycation end products (AGEs) formation, and oxidative stress by isolated active constituents of Osmanthus fragrans flowers (9,12-octadecadienoic acid and 4-(2,6,6-trimethyl-1 cyclohexenyl)-3-buten-2-one) and their structural analogues were evaluated. 9,12 Octadecadienoic acid was 10.02 and 22.21 times more active against alpha-amylase and alpha-glucosidase, respectively, than acarbose and ascorbic acid, followed by 9,12,15-octadecatrienoic acid, 9-octadecenoic acid, 4-(2,6,6-trimethyl-1 cyclohexenyl)-3-buten-2-one, 4-(2,6,6-trimethyl-2-cyclohexenyl)-3-buten-2-one, 1 heptadecanecarboxylic acid, and 1-pentadecanecarboxylic acid. Concerning the inhibition of AGEs formation, similar with data for 2,2'-diphenyl-1-picrylhydrazl radical scavenging activities, 9,12-octadecadienoic acid was 3.54 times more active than aminoguanidine, followed by 9,12,15-octadecatrienoic acid, and 9 octadecenoic acid. These results indicate that 4-(2,6,6-trimethyl-1-cyclohexenyl) 3-buten-2-one, 9,12-octadecadienoic acid and their analogues inhibit alpha amylase and alpha-glucosidase, AGEs formation, and oxidative stress have potential value in alleviating diabetic pathological conditions. PMID- 28361985 TI - Assessing the Dynamics of Organic Aerosols over the North Atlantic Ocean. AB - The influence of aerosols on climate is highly dependent on the particle size distribution, concentration, and composition. In particular, the latter influences their ability to act as cloud condensation nuclei, whereby they impact cloud coverage and precipitation. Here, we simultaneously measured the concentration of aerosols from sea spray over the North Atlantic on board the exhaust-free solar-powered vessel "PlanetSolar", and the sea surface physico chemical parameters. We identified organic-bearing particles based on individual particle fluorescence spectra. Organic-bearing aerosols display specific spatio temporal distributions as compared to total aerosols. We propose an empirical parameterization of the organic-bearing particle concentration, with a dependence on water salinity and sea-surface temperature only. We also show that a very rich mixture of organic aerosols is emitted from the sea surface. Such data will certainly contribute to providing further insight into the influence of aerosols on cloud formation, and be used as input for the improved modeling of aerosols and their role in global climate processes. PMID- 28361984 TI - Neuronal p38alpha mediates synaptic and cognitive dysfunction in an Alzheimer's mouse model by controlling beta-amyloid production. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a severe and progressive neuronal loss leading to cognitive dysfunctions. Previous reports, based on the use of chemical inhibitors, have connected the stress kinase p38alpha to neuroinflammation, neuronal death and synaptic dysfunction. To explore the specific role of neuronal p38alpha signalling in the appearance of pathological symptoms, we have generated mice that combine expression of the 5XFAD transgenes to induce AD symptoms with the downregulation of p38alpha only in neurons (5XFAD/p38alpha?-N). We found that the neuronal-specific deletion of p38alpha improves the memory loss and long-term potentiation impairment induced by 5XFAD transgenes. Furthermore, 5XFAD/p38alpha?-N mice display reduced amyloid beta accumulation, improved neurogenesis, and important changes in brain cytokine expression compared with 5XFAD mice. Our results implicate neuronal p38alpha signalling in the synaptic plasticity dysfunction and memory impairment observed in 5XFAD mice, by regulating both amyloid-beta deposition in the brain and the relay of this accumulation to mount an inflammatory response, which leads to the cognitive deficits. PMID- 28361986 TI - Individual Differences in Moral Disgust Do Not Predict Utilitarian Judgments, Sexual and Pathogen Disgust Do. AB - The role of emotional disgust and disgust sensitivity in moral judgment and decision-making has been debated intensively for over 20 years. Until very recently, there were two main evolutionary narratives for this rather puzzling association. One of the models suggest that it was developed through some form of group selection mechanism, where the internal norms of the groups were acting as pathogen safety mechanisms. Another model suggested that these mechanisms were developed through hygiene norms, which were piggybacking on pathogen disgust mechanisms. In this study we present another alternative, namely that this mechanism might have evolved through sexual disgust sensitivity. We note that though the role of disgust in moral judgment has been questioned recently, few studies have taken disgust sensitivity to account. We present data from a large sample (N = 1300) where we analyzed the associations between The Three Domain Disgust Scale and the most commonly used 12 moral dilemmas measuring utilitarian/deontological preferences with Structural Equation Modeling. Our results indicate that of the three domains of disgust, only sexual disgust is associated with more deontological moral preferences. We also found that pathogen disgust was associated with more utilitarian preferences. Implications of the findings are discussed. PMID- 28361987 TI - Effects of atmospheric-pressure non-thermal bio-compatible plasma and plasma activated nitric oxide water on cervical cancer cells. AB - Atmospheric-pressure non-thermal bio-compatible plasma is a partially ionized gas with electrically charged particles. Previous studies demonstrated that dielectric barrier discharge (DBD) plasma could induce apoptosis of various cancer cells, in particular demonstrating the selective cytotoxicity of cancer cells over normal cells. Therefore, DBD plasma can be considered as a potential cancer treatment method for clinical applications. We previously developed a microwave jet plasma system, producing nitric oxide called nitric oxide-plasma activated water (NO-PAW). In this study, we explored the effects of NO-PAW on a cervical cancer cell line, in comparison with DBD plasma. The cytotoxicity results showed that the treatment of HeLa cell with DBD for 4 minutes and 7 MUM concentration of NO-PAW could reach almost IC60. For the apoptosis assay, 4 minutes treatment of DBD could induce 7% apoptotic effect, whereas 7 MUM NO-PAW could induce 18% apoptotic effect. In addition, we assumed that both DBD plasma and NO-PAW could induce HeLa cell apoptosis by facilitating an accumulation of intracellular reactive oxygen and nitrogen species (RONS). Although further detail on the molecular signal pathway is still needed, DBD and NO-PAW could become promising applications for effective and safe clinical trials for cancer therapy. PMID- 28361988 TI - International incidence and mortality trends of liver cancer: a global profile. AB - We examined the global incidence and mortality rates of liver cancer, and evaluated the association between incidence/mortality and socioeconomic development (Human Development Index [HDI] and Gross Domestic Product [GDP]) using linear regression analysis. The average annual percent change (AAPC) of the trends was evaluated from join-point regression analysis. The global incidence of liver cancer varied widely by nine-fold, and was negatively correlated with HDI (men: r = -0.232, p = 0.003; women: r = -0.369, p < 0.001) and GDP per capita (men: r = -0.164, p = 0.036; women: r = -0.212, p = 0.007). Its mortality showed a similarly negative correlation with both indices. The greatest incidence rise in men was observed in Poland (AAPC = 17.5, 95% C.I. = 5.6, 30.9) and Brazil (AAPC = 13.2, 95% C.I. = 5.9, 21.0), whereas Germany (AAPC = 6.6, 95% C.I = 2.0, 11.5) and Norway (AAPC = 6.5, 95% C.I. = 3.2, 10.0) had the greatest increase in women. The mortality rates paralleled the incidence rates in most countries. For mortality, Malta (AAPC = 11.5, 95% C.I. = 3.9, 19.8), Australia (AAPC = 6.8, 95% C.I. = 2.2, 11.5) and Norway (APCC = 5.6, 95% C.I. = 2.8, 8.5) reported the biggest increase among men; whilst Australia (AAPC = 13.4, 95% C.I. = 7.8, 19.4) and Singapore (AAPC = 7.7, 95% C.I. = 4.1, 11.5) showed the most prominent rise among women. These epidemiological data identified countries with potentially increasing trends of liver cancer for preventive actions. PMID- 28361989 TI - Testis Transcriptome Modulation in Klinefelter Patients with Hypospermatogenesis. AB - The main genetic cause of male infertility is represented by the Klinefelter Syndrome (KS), a condition accounting for 3% of all cases of infertility and up to15% of cases of azoospermia. KS is generally characterized by azoospermia; approximately 10% of cases have severe oligozoospermia. Among these, the 30-40% of patients show hypospermatogenesis. The mechanisms leading to adult testis dysfunctions are not completely understood. A microarray transcriptome analysis was performed on testis biopsies obtained from three KS patients with hypospermatogenesis and three control subjects. KS testis showed a differential up- and down-regulation of 303 and 747 transcripts, respectively, as compared to controls. The majority of down-regulated transcripts were involved in spermiogenesis failure and testis morphological defects, whereas up-regulated genes were responsible for testis apoptotic processes. Functional analysis of the transcriptionally altered genes indicated a deregulation in cell death, germ cell function and morphology as well as blood-testis-barrier maintenance and Leydig cells activity. These data support a complex scenario in which spermatogenic impairment is the result of functional and morphological alterations in both germinal and somatic components of KS testis. These findings could represent the basis for evaluating new markers of KS spermatogenesis and potential targets of therapeutic intervention to preserve residual spermatogenesis. PMID- 28361991 TI - Y14 governs p53 expression and modulates DNA damage sensitivity. AB - Y14 is a core component of the exon junction complex (EJC), while it also exerts cellular functions independent of the EJC. Depletion of Y14 causes G2/M arrest, DNA damage and apoptosis. Here we show that knockdown of Y14 induces the expression of an alternative spliced isoform of p53, namely p53beta, in human cells. Y14, in the context of the EJC, inhibited aberrant exon inclusion during the splicing of p53 pre-mRNA, and thus prevent p53beta expression. The anti cancer agent camptothecin specifically suppressed p53beta induction. Intriguingly, both depletion and overexpression of Y14 increased overall p53 protein levels, suggesting that Y14 governs the quality and quantity control of p53. Moreover, Y14 depletion unexpectedly reduced p21 protein levels, which in conjunction with aberrant p53 expression accordingly increased cell sensitivity to genotoxic agents. This study establishes a direct link between Y14 and p53 expression and suggests a function for Y14 in DNA damage signaling. PMID- 28361990 TI - A retinoraphe projection regulates serotonergic activity and looming-evoked defensive behaviour. AB - Animals promote their survival by avoiding rapidly approaching objects that indicate threats. In mice, looming-evoked defensive responses are triggered by the superior colliculus (SC) which receives direct retinal inputs. However, the specific neural circuits that begin in the retina and mediate this important behaviour remain unclear. Here we identify a subset of retinal ganglion cells (RGCs) that controls mouse looming-evoked defensive responses through axonal collaterals to the dorsal raphe nucleus (DRN) and SC. Looming signals transmitted by DRN-projecting RGCs activate DRN GABAergic neurons that in turn inhibit serotoninergic neurons. Moreover, activation of DRN serotoninergic neurons reduces looming-evoked defensive behaviours. Thus, a dedicated population of RGCs signals rapidly approaching visual threats and their input to the DRN controls a serotonergic self-gating mechanism that regulates innate defensive responses. Our study provides new insights into how the DRN and SC work in concert to extract and translate visual threats into defensive behavioural responses. PMID- 28361993 TI - The combined effects of sampling parameters on the sorbent tube sampling of phthalates in air. AB - The adsorption properties of various sorbent materials were investigated to assess the factors affecting biases in the sorbent tube (ST) sampling of airborne phthalates. The recovery of phthalates was assessed critically in relation to four key sampling parameters: (1) three types of sorbent materials (quartz wool (QW), glass wool (GW), and quartz wool plus Tenax TA (QWTN)), (2) the concentration level of phthalate standards, (3) purge flow rate, and (4) purge volume for analysis based on a 'sorbent tube-thermal desorption-gas chromatography-mass spectrometry (ST-TD-GC-MS)' system. Among these parameters, the type of ST was the most influential in determining the recovery of phthalates. For a given ST type, the recovery of phthalates tends to improve with increases in the concentration level of standards. In case of QW and QWTN tubes, the breakthrough of phthalates was not observed up to the maximum purge volume (100 L) tested in this work; however, in case of GW, the recovery decreased drastically to 60% even at a purge volume of 1 L for low molecular weight phthalates. The results of our study demonstrate that accurate analysis of airborne phthalates can be achieved through proper control of key sampling parameters, particularly the choice of sorbent material. PMID- 28361992 TI - Microvascular vasodilator properties of the angiotensin II type 2 receptor in a mouse model of type 1 diabetes. AB - Diabetes Mellitus is associated with severe cardiovascular disorders involving the renin-angiotensin system, mainly through activation of the angiotensin II type 1 receptor (AT1R). Although the type 2 receptor (AT2R) opposes the effects of AT1R, with vasodilator and anti-trophic properties, its role in diabetes is debatable. Thus we investigated AT2R-mediated dilatation in a model of type 1 diabetes induced by streptozotocin in 5-month-old male mice lacking AT2R (AT2R /y). Glucose tolerance was reduced and markers of inflammation and oxidative stress (cyclooxygenase-2, gp91phox p22phox and p67phox) were increased in AT2R-/y mice compared to wild-type (WT) animals. Streptozotocin-induced hyperglycaemia was higher in AT2R-/y than in WT mice. Arterial gp91phox and MnSOD expression levels in addition to blood 8-isoprostane and creatinine were further increased in diabetic AT2R-/y mice compared to diabetic WT mice. AT2R-dependent dilatation in both isolated mesenteric resistance arteries and perfused kidneys was greater in diabetic mice than in non-diabetic animals. Thus, in type 1 diabetes, AT2R may reduce glycaemia and display anti-oxidant and/or anti-inflammatory properties in association with greater vasodilatation in mesenteric arteries and in the renal vasculature, a major target of diabetes. Therefore AT2R might represent a new therapeutic target in diabetes. PMID- 28361994 TI - Systemic inflammation and family history in relation to the prevalence of type 2 diabetes based on an alternating decision tree. AB - To investigate unknown patterns associated with type 2 diabetes in the Japanese population, we first used an alternating decision tree (ADTree) algorithm, a powerful classification algorithm from data mining, for the data from 1,102 subjects aged 35-69 years. On the basis of the investigated patterns, we then evaluated the associations of serum high-sensitivity C-reactive protein (hs-CRP) as a biomarker of systemic inflammation and family history of diabetes (negative, positive or unknown) with the prevalence of type 2 diabetes because their detailed associations have been scarcely reported. Elevated serum hs-CRP levels were proportionally associated with the increased prevalence of type 2 diabetes after adjusting for probable covariates, including body mass index and family history of diabetes (P for trend = 0.016). Stratified analyses revealed that elevated serum hs-CRP levels were proportionally associated with increased prevalence of diabetes in subjects without a family history of diabetes (P for trend = 0.020) but not in those with a family history or with an unknown family history of diabetes. Our study demonstrates that systemic inflammation was proportionally associated with increased prevalence of type 2 diabetes even after adjusting for body mass index, especially in subjects without a family history of diabetes. PMID- 28361995 TI - Comparative Transcriptomic Analysis of Vernalization- and Cytokinin-Induced Floral Transition in Dendrobium nobile. AB - Vernalization is required for floral initiation in Dendrobium. Interestingly, those beneficial effects can also be achieved by exogenous cytokinin application in greenhouses. Thus, an as yet unknown crosstalk/interaction may exist between vernalization and cytokinin signaling pathways. In this study, we showed, by de novo transcriptome assembly using RNA-seq data from both vegetative and reproductive tissue samples, that some floral transition-related genes-DnVRN1, FT, SOC1, LFY and AP1-were differentially expressed in low-temperature-challenged (LT) or thidiazuron (TDZ)-treated plants, compared to those mock-treated (CK). Both LT and TDZ upregulated SOC1, LFY and AP1, while the upregulation of DnVRN1 and FT was only LT-induced. We further found that LT promoted the upregulation of some key cytokinin signaling regulators, including several cytokinin biosynthesis related genes and type-B response regulator (RR)-encoding genes, and that both LT and TDZ triggered the significant upregulation of some marker genes in the gibberellin (GA) signaling pathway, indicating an important low temperature cytokinin-GA axis in flowering. Our data thus have revealed a cytokinin-GA signal network underlying vernalization, providing a novel insight into further investigation of the molecular mechanism of floral initiation in Dendrobium. PMID- 28361996 TI - Increased mitochondrial coupling and anaerobic capacity minimizes aerobic costs of trout in the sea. AB - Anadromy is a distinctive life-history strategy in fishes that has evolved independently many times. In an evolutionary context, the benefits of anadromy for a species or population must outweigh the costs and risks associated with the habitat switch. The migration of fish across the freshwater-ocean boundary coincides with potentially energetically costly osmoregulatory modifications occurring at numerous levels of biological organization. By integrating whole animal and sub-cellular metabolic measurements, this study presents significant findings demonstrating how an anadromous salmonid (i.e. rainbow trout, Oncorhynchus mykiss) is able to transform from a hyper- to hypo-osmoregulatory state without incurring significant increases in whole animal oxygen consumption rate. Instead, underlying metabolic mechanisms that fuel the osmoregulatory machinery at the organ level (i.e. intestine) are modulated, as mitochondrial coupling and anaerobic metabolism are increased to satisfy the elevated energetic demands. This may have positive implications for the relative fitness of the migrating individual, as aerobic capacity may be maintained for locomotion (i.e. foraging and predator avoidance) and growth. Furthermore, the ability to modulate mitochondrial metabolism in order to maintain osmotic balance suggests that mitochondria of anadromous fish may have been a key target for natural selection, driving species adaptations to different aquatic environments. PMID- 28361997 TI - Zinc treatment is efficient against Escherichia coli alpha-haemolysin-induced intestinal leakage in mice. AB - Zinc homoeostasis exerts protective effects in inflammatory intestinal diseases and zinc supplementation has been successfully used for treating infectious diarrhoea. This study aimed at a characterisation of zinc effects on focal leak induction by alpha-haemolysin (HlyA)-producing Escherichia coli (E. coli) as protective mechanism for colitis. We conducted in vivo experiments by oral challenge of gnotobiotic mice colonised with HlyA-expressing E. coli-536. Mice were either fed a defined normal or high zinc diet to analyse effects of zinc as a therapeutic regimen. HlyA-deficient E. coli-536 mutants were used as controls. Mice infected with HlyA-producing E. coli showed impaired barrier integrity when receiving normal zinc. High zinc supplementation in HlyA-producing E. coli infected mice reduced epithelial dysfunction as indicated by ameliorated macromolecule permeability. Reduced size of focal leaks with diminished bacterial translocation was observed as inherent mechanisms of this zinc action. In human colon cell monolayers application of zinc rescued the HlyA-dependent decline in transepithelial electrical resistance via reduction of the calcium entry into HlyA-exposed cells. Calcium-dependent cell exfoliation was identified as mechanism for focal leak induction. In conclusion, zinc supplementation protects from HlyA-induced barrier dysfunction in vivo and in vitro, providing an explanation for the protective efficacy of zinc in intestinal disorders. PMID- 28361999 TI - Synthesis of Sr2Si5N8:Ce3+ phosphors for white LEDs via an efficient chemical vapor deposition [corrected]. AB - Novel chemical vapor deposition (CVD) process was successfully developed for the growth of Sr2Si5N8:Ce3+ phosphors with elevated luminescent properties. Metallic strontium was used as a vapor source for producing Sr3N2 vapor to react with Si3N4 powder via a homogeneous gas-solid reaction. The phosphors prepared via the CVD process showed high crystallinity, homogeneous particle size ranging from 8 to 10 MUm, and high luminescence properties. In contrast, the phosphors prepared via the conventional solid-state reaction process exhibited relative low crystallinity, non-uniform particle size in the range of 0.5-5 MUm and relatively lower luminescent properties than the phosphors synthesized via the CVD process. Upon the blue light excitation, Sr2-xCexSi5N8 phosphors exhibited a broad yellow band. A red shift of the emission band from 535 to 556 nm was observed with the increment in the doping amount of Ce3+ ions from x = 0.02 to x = 0.10. The maximum emission was observed at x = 0.06, and the external and internal quantum efficiencies were calculated to be 51% and 71%, respectively. Furthermore, the CVD derived optimum Sr1.94Ce0.06Si5N8 phosphor exhibited sufficient thermal stability for blue-LEDs and the activation energy was calculated to be 0.33 eV. The results demonstrate a potential synthesis process for nitride phosphors suitable for light emitting diodes. PMID- 28362000 TI - Emergence and Evolution of Cooperation Under Resource Pressure. AB - We study the influence that resource availability has on cooperation in the context of hunter-gatherer societies. This paper proposes a model based on archaeological and ethnographic research on resource stress episodes, which exposes three different cooperative regimes according to the relationship between resource availability in the environment and population size. The most interesting regime represents moderate survival stress in which individuals coordinate in an evolutionary way to increase the probabilities of survival and reduce the risk of failing to meet the minimum needs for survival. Populations self-organise in an indirect reciprocity system in which the norm that emerges is to share the part of the resource that is not strictly necessary for survival, thereby collectively lowering the chances of starving. Our findings shed further light on the emergence and evolution of cooperation in hunter-gatherer societies. PMID- 28361998 TI - Exosome-associated AAV2 vector mediates robust gene delivery into the murine retina upon intravitreal injection. AB - Widespread gene transfer to the retina is challenging as it requires vector systems to overcome physical and biochemical barriers to enter and diffuse throughout retinal tissue. We investigated whether exosome-associated adeno associated virus, (exo-AAV) enabled broad retinal targeting following intravitreal (IVT) injection, as exosomes have been shown to traverse biological barriers and mediate widespread distribution upon systemic injection. We packaged an AAV genome encoding green fluorescent protein (GFP) into conventional AAV2 and exo-AAV2 vectors. Vectors were IVT injected into the eyes of adult mice. GFP expression was noninvasively monitored by fundus imaging and retinal expression was analyzed 4 weeks post-injection by qRT-PCR and histology. Exo-AAV2 outperformed conventional AAV2 in GFP expression based on fundus image analysis and qRT-PCR. Exo-AAV2 demonstrated deeper penetration in the retina, efficiently reaching the inner nuclear and outer plexiform, and to a lesser extent the outer nuclear layer. Cell targets were ganglion cells, bipolar cells, Muller cells, and photoreceptors. Exo-AAV2 serves as a robust gene delivery tool for murine retina, and the simplicity of production and isolation should make it widely applicable to basic research of the eye. PMID- 28362002 TI - Only functional localization is faithful localization. PMID- 28362001 TI - Cross-talk among metabolic parameters, esophageal microbiota, and host gene expression following chronic exposure to an obesogenic diet. AB - Unhealthy diets, and ensuing weight gain, predispose individuals to the development of esophageal adenocarcinoma. We examined the effect of chronic high fat diet (HFD) on the esophageal microbiota of Sprague Dawley rats using Illumina MiSeq amplicon sequencing (V4, 515 F/806 R) and on esophageal expression of IL18, PTGS2, PPARA, FFAR3, and CRAT. The relationships among metabolic parameters, esophageal microbiota, and host gene expression were determined. We observed a significant difference between the upper and lower esophageal microbiota in control fed rats, emphasized by enrichment of Lactobacillus species in the lower esophagus. Rats on HFD gained significantly more fat and had reduced insulin sensitivity. Diet type significantly affected the esophageal microbiota, with Clostridium sensu stricto being enriched in both upper and lower segments of HFD fed rats. Of interest, bacterial pathways related to carotenoid biosynthesis were significantly decreased in the lower esophagus of HFD fed rats. We observed strong correlations between metabolic parameters, the esophageal microbial profiles, and host esophageal gene expression. In particular, Fusobacterium, Rothia, and Granulicatella showed consistent correlations across a range of metabolic and gene markers. Our data indicates that unhealthy diets can significantly alter the esophageal microbiota, and enrich for bacterial species previously associated with chronic gastrointestinal diseases. PMID- 28362004 TI - Toxoplasma control of host apoptosis: the art of not biting too hard the hand that feeds you. PMID- 28362003 TI - Fancy a gene? A surprisingly complex evolutionary history of peroxiredoxins. AB - While the phylum Apicomplexa includes "only" several thousand described species of obligatory parasites of animals, it may in fact be the most specious group of parasitic protists with over a million species 1. The best known representatives are Plasmodium spp., Toxoplasma gondii and Cryptosporidium spp., which belong to the most important and widespread human parasites exacting an enormous disease burden. On the other hand, dinoflagellates and colpodellids, which are monophyletic with the apicomplexans, are ecologically highly significant, as they belong to the most abundant marine protists 2. As the common ancestor of these groups was most likely a free-living photosynthesizing protist, one wonders, which evolutionary forces contributed to the dramatic transition of some of its descendants into the arguably most successful intracellular parasites? Although a range of various processes and mechanisms contributed to this transition, most likely it also involved an acquisition of genes via horizontal gene transfer (HGT), which might have provided typical characteristics of a parasitic cell, such as immune escape, nutritional dependence and the capacity to invade other cells. PMID- 28362005 TI - Metabolic pathways further increase the complexity of cell size control in budding yeast. AB - How organisms regulate their size is a major question in biology. With a few notable exceptions (such as cell divisions in the early embryo), most cells need to reach a critical size in order to initiate a new cell cycle. How cells set a critical cell size, and how they know it has been reached, is not well understood. Using various types of experimental systems, decades ago two main models were proposed for cell size homeostasis: the deterministic model and the probabilistic model. PMID- 28362006 TI - What's the role of autophagy in trypanosomes? PMID- 28362007 TI - Yeast screening platform identifies FDA-approved drugs that reduce Abeta oligomerization. PMID- 28362008 TI - Non-genetic impact factors on chronological lifespan and stress resistance of baker's yeast. AB - Survival under nutrient limitation is an essential feature of microbial cells, and it is defined by the chronological lifespan. We summarize recent findings, illustrating how crucial the choice of the experimental setup is for the interpretation of data in this field. Especially the impact of oxygen supply differs depending on the culture type, highlighting the differences of alternatives like the retentostat to classical batch cultures. Finally the importance of culture conditions on cell aging and survival in biotechnological processes is highlighted. PMID- 28362009 TI - Gearing up for survival - HSP-containing granules accumulate in quiescent cells and promote survival. PMID- 28362010 TI - Entropy-driven homochiral self-sorting of a dynamic library. AB - A dynamic mixture of stereoisomeric macrocycles derived from glutamic acid displayed a homochiral self-selection when increasing the acetonitrile content of the aqueous mixed medium. The homochiral self-sorting required the anionic form of the side chains and increased at higher temperature, implying an entropic origin. Conformational analysis (NMR and MD simulations) allowed us to explain the observed behaviour. The results show that entropy can play a role in the homochiral self-sorting in adaptive bio-inspired chemical systems. PMID- 28362011 TI - Effects of microsolvation on a SN2 reaction: indirect atomistic dynamics and weakened suppression of reactivity. AB - Systematic studies of microsolvation in the gas phase have enriched our knowledge of solvent effects. Here, the dynamics of a prototype SN2 reaction of a hydrated fluoride ion with methyl iodide is uncovered employing direct dynamics simulations that show strikingly distinct features from those determined for an unsolvated system. An indirect scattering is found to prevail, which occurs dominantly by forming hydrated F-(H2O)-HCH2I and F-(H2O)-CH3I pre-reaction complexes at low energies, but proceeds through their water-free counterparts at higher energies. This finding is in strong contrast to a general evolution from indirect to direct dynamics with enhancing energy for the unsolvated substitution reactions, and this discrepancy is understood by the substantial steric hindrance introduced by a water molecule. As established in experiments, solvation suppresses the reactivity, whereas we find that this depression is remarkably frustrated upon raising the energy given that collision-induced dehydration essentially diminishes the water block for reactive collisions. The present study sheds light on how solute-solvent interactions affect the underlying dynamics at a deeper atomic level, thereby promoting our understanding of the fundamental solvent effects on chemical reactions in solution. PMID- 28362012 TI - Facile synthesis and characterization of a SnO2-modified LiNi0.5Mn1.5O4 high voltage cathode material with superior electrochemical performance for lithium ion batteries. AB - A thin-layer-SnO2 modified LiNi0.5Mn1.5O4@SnO2 material is synthesized via a facile synthetic approach. It is physically and electrochemically characterized as a high-voltage lithium ion battery cathode and compared to the pristine LiNi0.5Mn1.5O4 material prepared under similar conditions. The two materials are proved to be crystals of a well-defined disordered spinel phase with the morphology of aggregates of micron/submicron polyhedral particles. The Mn3+ ions and the inactive NixLiyO phase in the LiNi0.5Mn1.5O4@SnO2 is less than those in the LiNi0.5Mn1.5O4 due to incorporation of a very small amount of Sn2+ into the spinel structure upon high-temperature calcination of the precursor. Besides, the mean particle size of the LiNi0.5Mn1.5O4@SnO2 is obviously smaller than that of the LiNi0.5Mn1.5O4. The LiNi0.5Mn1.5O4@SnO2 demonstrates much superior electrochemical performance over the LiNi0.5Mn1.5O4 in terms of specific capacity, rate capability and cyclability. For example, the discharge capacities at current rates of 0.2C, 2C and 20C are 145.4, 139.9 and 112.2 mA h g-1, respectively. A capacity retention rate of ca. 75% is obtained after 500 cycles at 2C rate. The improved electrochemical performance is attributed to the positive effect of the surface protective SnO2 coating layer as well as the structural and morphological modifications of the spinel. PMID- 28362013 TI - Controlling the atomic distribution in PtPd nanoparticles: thermal stability and reactivity during NO abatement. AB - In situ X-ray absorption spectroscopy and mass spectrometry measurements were employed to simultaneously probe the atom specific short range order and reactivity of Pd and PtPd nanoparticles towards NO decomposition at 300 degrees C. The nanoparticles were synthesized by a well controlled, eco-friendly wet chemical reduction of metal salts and later supported on activated carbon. Particularly for the bimetallic PtPd samples, distinct atomic arrangements were achieved using a seeding growth method, which allowed producing a random nanoalloy, or nanoparticles with Pt- or Pd-rich core. X-ray photoelectron spectroscopy, transmission electron microscopy, and X-ray diffraction provided additional insights on their electronic, morphological and long range order structural properties. The results revealed that the higher the thermal induced atomic migration observed within the nanoparticles during thermal treatments, the least were their reactivity for NO abatement. PMID- 28362014 TI - Azobenzene-benzoylphenylureas as photoswitchable chitin synthesis inhibitors. AB - Benzoylphenylureas (BPUs) are used as synthetic insect growth regulators for inhibiting chitin synthesis. Merging insecticidal BPUs with photoswitchable azobenzene generated photoresponsive chitin synthesis inhibitors. A prepared azobenzene-benzoylphenylurea can be activated upon irradiation with UV light, and shows 6-fold and 2-fold activity difference to armyworm (Mythimna separata) and German cockroach (Blattella germanica) sulfonylurea receptors, respectively. This is the first example of a photoswitchable BPU insecticide. The generation of such a photoresponsive BPU insecticide allows for modulation of the insecticidal activity by light, and may facilitate the spatiotemporal control over the sulfonylurea receptor and the mechanistic study of this kind of insecticide. PMID- 28362015 TI - Square sugars: challenges and synthetic strategies. AB - Square sugars (4-membered ring carbohydrate mimetics) are at the intersection of several important topics concerning the recent emergence, in medicinal chemistry, of glycomimetic drugs and small ring systems. Monosaccharide mimetics containing oxetane, azetidine, thiethane or cyclobutane rings present a number of synthetic challenges that are a powerful driving force for innovation in organic synthesis. In addition to the inherent issues associated with 4-membered rings, the high density of functional groups and asymmetric centres found in glycomimetics further complicates the matter and requires efficient stereoselective methodologies. The purpose of this review is to present an overview of the elegant strategies that have been developed to synthesize the different types of square sugars. PMID- 28362016 TI - A study of diketopiperazines as electron-donor initiators in transition metal free haloarene-arene coupling. AB - Several diketopiperazines have been shown to promote carbon-carbon coupling between benzene and aryl halides in the presence of potassium tert-butoxide and without the assistance of a transition metal catalyst. The structure of the diketopiperazine has an influence on its reductive potential and can help to promote the coupling of the more challenging aryl bromides with benzene. PMID- 28362017 TI - Correction: Understanding MAOS through computational chemistry. AB - Correction for 'Understanding MAOS through computational chemistry' by P. Prieto et al., Chem. Soc. Rev., 2017, 46, 431-451. PMID- 28362019 TI - Non-genetic risk factors for early and late age at menarche in Eastern Ukrainian females. AB - ABSTRACT: BACKGROUND: Age at menarche is a reproductive trait, which is largely influenced by environmental factors. Each population has a set of lifestyle factors that may shift age at menarche in different direction. Populations of Eastern Slavs, particularly Ukrainians, are underrepresented in studies of reproductive health. The objective of the present research was to determine important non-genetic risk factors, which may contribute to menarcheal onset in Eastern Ukrainians. METHODS: In total 620 females aged 17-25 years participated in the cross-sectional survey. The questionnaire included lifestyle factors previously reported in other populations as those, which might affect age at menarche. The risk factors for early and late age at menarche were determined using logistic regression models. The models were validated by receiver operating curves. RESULTS: Body composition in the prepubertal stage as presented by responders seems to have the strongest association with age at menarche. Those who were shorter and thinner as compared to their peers at age six had significantly more chance to start menstruating later (OR = 1.66, 95% CI [1.01 2.73]) and reduced chance to have menarche before 12 years old (OR = 0.32, 95% CI [0.14-0.73]). Maternal smoking during pregnancy and low protein intake reported during childhood may decrease a probability of late age at menarche. CONCLUSIONS: Although overall body composition at age of six was a main trait, which was associated with menarcheal timing, more information on body measurements (e.g. waist-hip ratio) in prepubertal stage would help to establish a greater degree of accuracy on this matter. PMID- 28362020 TI - Variation of height and BMI within school classes in 14-year-old children. AB - ABSTRACT: The aim of the study was to analyze the variation of height and weight of 14-year-old children within classes of primary schools in Wroclaw. All children were attending the 7th grade of primary schools in Wroclaw, and underwent a medical examination as part of a project (the Health Card of the Child) of the city of Wroclaw. The data were collected between January and December of 1997. The present study included height and weight of 1810 children (917 boys and 893 girls). For analyses, individual height and BMI [kg m-2] were standardized based on mean and SD of the whole population separately for boys and girls. The SDs of height and BMI in each class were tested by Student-t test for one sample to check the difference in comparison to population with SD equal 1. Additionally, the nested analysis of variance was used, where height and BMI were dependent variables, and classes were nested into schools. SDs of height and BMI within classes are significantly lower than for the whole population in boys and girls, whereas the means did not differ significantly from the whole population. Nested analysis of variance showed a significant effect of class for girls (for height and BMI) but not for boys. Also variation of height significantly differed between schools in girls but not in boys. It is hypothesized that decrease of variation within classes might be caused by the community effect. PMID- 28362018 TI - IL-37 suppresses MyD88-mediated inflammatory responses in human aortic valve interstitial cells. AB - BACKGROUND: Calcific aortic valve disease (CAVD) is common among the elderly, and aortic valve interstitial cells (AVICs) exhibit unique inflammatory and osteogenic responses to pro-inflammatory stimulation which play an important role in valvular fibrosis and calcification. Thus, suppression of AVIC pro inflammatory response may have therapeutic utility for prevention of CAVD progression. Interleukin (IL)-37, an anti-inflammatory cytokine, reduces tissue inflammation. OBJECTIVE: This study was to test the hypothesis that IL-37 suppresses human AVIC inflammatory responses to Toll-like receptor (TLR) agonists. METHODS AND RESULTS: Human AVICs were exposed to Pam3CSK4, poly(I:C) and lipopolysaccharide, respectively, in the presence and absence of recombinant human IL-37. Stimulation of TLR4 increased the production of intercellular adhesion molecule-1, IL-6, IL-8 and monocyte chemoattractant protein-1. Knockdown of myeloid differentiation factor 88 (MyD88) or TIR-domain-containing adaptor inducing interferon-beta (TRIF) differentially affected inflammatory mediator production following TLR4 stimulation. IL-37 reduced the production of these inflammatory mediators induced by TLR4. Moreover, knockdown of IL-37 enhanced the induction of these mediators by TLR4. IL-37 also suppressed inflammatory mediator production induced by the MyD88-dependent TLR2, but had no effect on the inflammatory responses to the TRIF-dependent TLR3. Furthermore, IL-37 inhibited NF-kappaB activation induced by TLR2 or TLR4 through a mechanism dependent of IL 18 receptor alpha-chain. CONCLUSION: Activation of TLR2, TLR3 or TLR4 up regulates the production of inflammatory mediators in human AVICs. IL-37 suppresses MyD88-mediated responses to reduce inflammatory mediator production following stimulation of TLR2 and TLR4. This anti-inflammatory cytokine may be useful for suppression of aortic valve inflammation elicited by MyD88-dependent TLR signaling. PMID- 28362021 TI - Sexual dimorphism in base of skull. AB - ABSTRACT: Sex determination is an important task in forensic medicine and physical anthropology. The aims of this study were to assess the presence of sexual dimorphism in the base of the skull and to compare the accuracy of sex estimation by this method with that achieved in other metric studies of this region. The sample comprised 109 individuals (53 males and 56 females) of known sex, age, and cause of death from San Jose cemetery in Granada (Spain). Six dimensions were analyzed and discriminant function analysis was performed. The discriminant capacity of the selected variables was then evaluated by using a cross-validation procedure. All dimensions were significantly higher in males than in females. The percentage accuracy was 75.7% (77.8% for males and 73.7% for females). Highest dimorphic values were for occipital condyle length and foramen magnum width. Skull base measurements should only serve to corroborate findings. PMID- 28362022 TI - Growth status of Korean orphans raised in the affluent West: anthropometric trend, multivariate determinants, and descriptive comparison with their North and South Korean peers. AB - ABSTRACT: This paper investigates the trend in height among adult Korean orphans who were adopted in early life into affluent Western nations. Final heights of 148 females were analyzed based on a Korean government survey conducted in 2008. Height of the orphans was descriptively compared against final heights of South and North Koreans. Furthermore, statistical determinants of orphan height were investigated in multivariate regressions. Mean height of Korean orphans was 160.44 cm (SD 5.89), which was higher than that of South Koreans at 158.83 cm (SD 5.01). Both Korean orphans and South Koreans were taller than North Koreans at 155.30 cm (SD 4.94). However, height of Korean orphans stagnated at around 160 161 cm while those of North and South Koreans improved over time. In the regression analysis, the socioeconomic status of the adoptive family was statistically significant in all models, while dummies for the adoptive nations and age at adoption were insignificant. This study shows that the mean final height of women experiencing extreme environmental improvements in early-life is capped at 160-161 cm, tentatively suggesting that social stress factors in the host nation or early-life factors in the birth nation might have offset some of the environmental enrichment effects achieved through intercountry adoption. PMID- 28362023 TI - Kinematic study of standing long jump in preadolescents before the occurrence of maximum growth age. AB - ABSTRACT: The aims of this study were to identify the kinematics characteristics of the standing long jump (SLJ) performance in groups of Mexican girls and boys, with a chronological age such that theoretically, corresponds to the age before the occurrence of the maximum growth. The jump distance is largely dependent on the kinematic values at the time of takeoff. A calculation method was used from video recordings of the sagittal projection of jumps. The location of the body mass center at takeoff was the source for measuring the kinematic values. The Mann-Whitney U non-parametric Test (p < 0.05) and a Z-scores analysis were applied to assess differences between the groups. Almost the 60% of all the participants are within the range that is considered as average BMI and stature, according to the WHO growing standard values. In the sample, boys are bigger, probably stronger and jump longer than girls. Although the statistical tests show there are some similarities, mainly in the older groups, it is not possible to conclude that girls and boys in the sample have an equally performance in the Standing Long Jump. PMID- 28362024 TI - Modeling a secular trend by Monte Carlo simulation of height biased migration in a spatial network. AB - ABSTRACT: Background: In a recent Monte Carlo simulation, the clustering of body height of Swiss military conscripts within a spatial network with characteristic features of the natural Swiss geography was investigated. In this study I examined the effect of migration of tall individuals into network hubs on the dynamics of body height within the whole spatial network. The aim of this study was to simulate height trends. Material and methods: Three networks were used for modeling, a regular rectangular fishing net like network, a real world example based on the geographic map of Switzerland, and a random network. All networks contained between 144 and 148 districts and between 265-307 road connections. Around 100,000 agents were initially released with average height of 170 cm, and height standard deviation of 6.5 cm. The simulation was started with the a priori assumption that height variation within a district is limited and also depends on height of neighboring districts (community effect on height). In addition to a neighborhood influence factor, which simulates a community effect, body height dependent migration of conscripts between adjacent districts in each Monte Carlo simulation was used to re-calculate next generation body heights. In order to determine the direction of migration for taller individuals, various centrality measures for the evaluation of district importance within the spatial network were applied. Taller individuals were favored to migrate more into network hubs, backward migration using the same number of individuals was random, not biased towards body height. Network hubs were defined by the importance of a district within the spatial network. The importance of a district was evaluated by various centrality measures. In the null model there were no road connections, height information could not be delivered between the districts. Results: Due to the favored migration of tall individuals into network hubs, average body height of the hubs, and later, of the whole network increased by up to 0.1 cm per iteration depending on the network model. The general increase in height within the network depended on connectedness and on the amount of height information that was exchanged between neighboring districts. If higher amounts of neighborhood height information were exchanged, the general increase in height within the network was large (strong secular trend). The trend in the homogeneous fishnet like network was lowest, the trend in the random network was highest. Yet, some network properties, such as the heteroscedasticity and autocorrelations of the migration simulation models differed greatly from the natural features observed in Swiss military conscript networks. Autocorrelations of district heights for instance, were much higher in the migration models. Conclusion: This study confirmed that secular height trends can be modeled by preferred migration of tall individuals into network hubs. However, basic network properties of the migration simulation models differed greatly from the natural features observed in Swiss military conscripts. Similar network-based data from other countries should be explored to better investigate height trends with Monte Carlo migration approach. PMID- 28362025 TI - The effect of neighboring districts on body height of Polish conscripts. AB - ABSTRACT: The aim of the study was to investigate the correlation of heights of conscripts living in neighboring districts in Poland. The study used 10% of a nationally representative sample of 26,178 males 18.5-19.5 years old examined during the National survey of Polish conscripts conducted in 2001. The sample represented all regions and social strata of the country and included 354 different districts within 16 voivodships (provinces). Analyses were performed with the R statistical software. A small but significant correlation (0.24, p < 0.0001) was observed for height between 1st order neighboring districts. Correlations decreased with increased distances between neighboring districts, but remained significant for 7th node neighbors (0.18, p < 0.0001). Regarding voivodships (provinces), average height showed a geographical trend from the northwest (relatively tall) to the southeast (relatively short), and the correlation was stronger for first order neighboring provinces (0.796, p < 0.001). This study revealed clusters of tall people and short people, providing a support for hypothesis of the community effect in height. Small correlations between 1st order neighbors than in another country (Switzerland) may be associated with differences in geography, since in Poland there are no natural barriers (e.g., mountains) and road infrastructure is well-developed. PMID- 28362026 TI - Erratum: Macroscopic singlet oxygen modeling for dosimetry of Photofrin-mediated photodynamic therapy: an in-vivo study. PMID- 28362027 TI - Ludwik Bierkowski and the early days of general anaesthesia in the Polish soil in February 1847. AB - Ludwik Bierkowski belonged to the elite of surgeons of the first half of the 19th century. Educated in an excellent German university, Bierkowski had in-depth and comprehensive knowledge, a wide range of practical skills and was continuously eager to search for new solutions. He introduced cotton wool for wound dressings, experimentally determined the conditions of blood transfusions and published two outstanding anatomo-surgical atlases, which ranks him among the leading physicians of those days. Moreover, he was the first to use ether for effective general anaesthesia in the Polish lands, the procedure that changed the course of the history of medicine. Bierkowski performed ether anaesthesia in less than four months after the first world and in less than two months after the first European demonstration, which rates him among the most modern surgeons of those times. This year we celebrate the 170th anniversary of this event. PMID- 28362028 TI - Perioperative haemodynamic optimisation in patients undergoing non-cardiac surgery - a position statement from the Cardiac and Thoracic Anaesthesia Section of the Polish Society of Anaesthesiology and Intensive Therapy. Part 1. PMID- 28362029 TI - Perioperative haemodynamic optimisation in patients undergoing non-cardiac surgery - a position statement from the Cardiac and Thoracic Anaesthesia Section of the Polish Society of Anaesthesiology and Intensive Therapy. Part 2. PMID- 28362030 TI - Effect of universal chlorhexidine decolonisation on the infection rate in intensive care patients. AB - BACKGROUND: Healthcare-associated infections (HAIs), particularly intensive care unit-acquired infections (HAI-ICU), are an important cause of morbidity and mortality in hospitals. Most of these infections are caused by multidrugresistant organisms. The results of recent studies have suggested that daily bathing with chlorhexidine (CHX)-universal decolonisation can prevent ICU infections. The purpose of the study was to determine the influence of CHX bathing on the rate and type of HAI-ICU in critically ill patients. METHODS: This observational study, conducted in a mixed, 16-bed tertiary ICU, compared the following three 3 month periods: I) pre-intervention (traditional soap-water bathing), II) intervention (bathing with 2% CHX clothes), and III) post-intervention (soap water bathing). The type and rate of HAI-ICU were registered according to the European Centre for Disease Prevention and Control (ECDC) guidelines. RESULTS: A total of 272 patients were included in the study. During the intervention period, the total infection rate was significantly lower than in the pre-intervention period (12.7% vs 22.2%, respectively). Significant decreases in the rate and density of catheter-related infections (CRI) were observed during the intervention period. A decrease in the isolation rate of multidrug-resistant bacteria was also observed during the intervention and post-intervention periods. CONCLUSIONS: Daily bathing of ICU patients with chlorhexidine-impregnated clothes significantly decreased the rate of HAI-ICU and the acquisition of CRI. This simple hygienic approach can be an important adjunctive intervention with the capability of reducing the burden of healthcare-associated infections in ICUs. PMID- 28362031 TI - Comparison of anaesthetic gas consumption and stability of anaesthesia using automatic and manual control over the course of anaesthesia. AB - BACKGROUND: The automatic control module of end-tidal volatile agents (EtC) was designed to reduce the consumption of anaesthetic gases, increase the stability of general anaesthesia and reduce the need for adjustments in the settings of the anaesthesia machine. The aim of this study was to verify these hypotheses. METHODS: The course of general anaesthesia with the use of the EtC module was analysed for haemodynamic stability, depth of anaesthesia, end-expiratory concentration of anaesthetic, number of ventilator key presses, fentanyl supply, consumption of volatile agents and anaesthesia and operation times. These data were compared with the data obtained during general anaesthesia controlled manually and were processed with statistical tests. RESULTS: Seventy-four patients underwent general anaesthesia for scheduled operations. Group AUTO-ET (n = 35) was anaesthetized with EtC, and group MANUAL-ET (n = 39) was controlled manually. Both populations presented similar anaesthesia stability. No differences were noted in the time of anaesthesia, saturation up to MAC 1.0 or awakening. Data revealed no differences in mean EtAA or the fentanyl dose. The AUTO-ET group exhibited fewer key presses per minute, 0.0603 min-1, whereas the MANUAL-ET exhibited a value of 0.0842 min-1; P = 0.001. The automatic group consumed more anaesthetic and oxygen per minute (sevoflurane 0.1171 mL min-1; IQR: 0.0503; oxygen 1.8286 mL min-1, IQR: 1,3751) than MANUAL-ET (sevoflurane 0.0824 mL min-1, IQR: 0.0305; oxygen 1,288 mL min-1, IQR: 0,6517) (P = 0.0028 and P = 0.0171, respectively). CONCLUSION: Both methods are equally stable and safe for patients. The consumption of volatile agents was significantly increased in the AUTO-ET group. EtC considerably reduces the number of key presses. PMID- 28362033 TI - Methods of pain assessment in adult intensive care unit patients - Polish version of the CPOT (Critical Care Pain Observation Tool) and BPS (Behavioral Pain Scale). AB - Many patients treated in the intensive care unit (ICU) experience pain that is a source of suffering and leaves a longterm imprint (chronic pain, post-traumatic stress disorder). Nearly 30% of patients experience pain at rest, while the percentage increases to 50% during nursing procedures. Pain in ICU patients can be divided into four categories: continuous ICU treatment-related pain/discomfort, acute illness-related pain, intermittent procedural pain and pre existing chronic pain present before ICU admission. As daily nursing procedures and interventions performed in the ICU may be a potential source of pain, it is crucial to use simple pain monitoring tools. The assessment of pain intensity in ICU patients remains an everyday challenge for clinicians, especially in sedated, intubated and mechanically ventilated patients. Regular assessment of pain intensity leads to improved outcome and better quality of life of patients in the ICU and after discharge from ICU. The gold standard in pain evaluation is patient self-reporting, which is not always possible. Current research shows that the two tools best validated for patients unable to self-report pain are the Behavioral Pain Scale (BPS) and the Critical Care Pain Observation Tool (CPOT). Although international guidelines recommend the use of validated tools for pain evaluation, they underline the need for translation into a given language. The authors of this publication obtained an official agreement from the authors of the two behavioral scales - CPOT and BPS - for translation into Polish. Validation of these tools in the Polish population will aid their wider use in pain assessment in ICUs in Poland. PMID- 28362032 TI - Randomized, comparative study of the effectiveness of three different techniques of interscalene brachial plexus block using 0.5% ropivacaine for shoulder arthroscopy. AB - BACKGROUND: Interscalene brachial plexus block is an effective regional anesthesia technique for shoulder surgeries. The superiority of the popular ultrasound-guided blocks over peripheral nerve stimulator-confirmed blocks remains unclear. In this study the efficacy of these different block techniques was compared. METHODS: This prospective, randomized, clinical study included 109 patients (ASA grades I-III) who receive 20 mL 0.5% ropivacaine with ultrasound guided blocks (U group), peripheral nerve stimulator-confirmed blocks (N group), or ultrasound-guided and peripheral nerve stimulator-confirmed blocks (dual guidance; NU group) for elective shoulder arthroscopy. Block onset time, duration, and effectiveness on the Lovett rating scale were assessed. RESULTS: There was no statistically significant intergroup difference in duration of block performance, irrespective of the technique (P = 0.232). Onset time of complete warmth sensation loss (P < 0.001) and muscle strength abolition (P < 0.001) was significantly longer and mean Lovett rating scale score distribution was significantly higher in the N group than in the other groups (P < 0.001). These findings show a statistically significant correlation between the performance of the used block technique and the necessity of conversion to general anesthesia because of insufficient block in the N group (58.54%) than in the U (24.44%) and NU (19.57%) groups. CONCLUSIONS: Peripheral nerve stimulator-confirmed needle placement is not necessary to ensure effectiveness of ultrasound-guided blocks, which is expressed as a lack of necessity of conversion to general anesthesia. Nevertheless, the dual guidance technique is recommended to reduce the risk of complications and might be considered the regional anesthesia of choice for shoulder surgery. PMID- 28362035 TI - Commentary to the article "Neuromuscular blockade in the elderly". PMID- 28362034 TI - Silesian Registry of Intensive Care Units. PMID- 28362036 TI - Hypermobile laryngeal granulomas: a potential cause of false negative cuff leak test. PMID- 28362037 TI - Silicone stents save lives without surgery in postintubation subglottic stenosis. PMID- 28362038 TI - Anaphylaxis during cardiac surgery for hypertrophic cardiomyopathy: patholophysiologic and therapeutic considerations. PMID- 28362039 TI - In response to: Anaphylaxis during cardiac surgery for hypetrophic cardiomyopathy: pathophysiologic and therapeutic considerations. PMID- 28362040 TI - Alternating air-medium exposure in rotating bioreactors optimizes cell metabolism in 3D novel tubular scaffold polyurethane foams. AB - BACKGROUND: In vitro dynamic culture conditions play a pivotal role in developing engineered tissue grafts, where the supply of oxygen and nutrients, and waste removal must be permitted within construct thickness. For tubular scaffolds, mass transfer is enhanced by introducing a convective flow through rotating bioreactors with positive effects on cell proliferation, scaffold colonization and extracellular matrix deposition. We characterized a novel polyurethane-based tubular scaffold and investigated the impact of 3 different culture configurations over cell behavior: dynamic (i) single-phase (medium) rotation and (ii) double-phase exposure (medium-air) rotation; static (iii) single-phase static culture as control. METHODS: A new mixture of polyol was tested to create polyurethane foams (PUFs) as 3D scaffold for tissue engineering. The structure obtained was morphologically and mechanically analyzed tested. Murine fibroblasts were externally seeded on the novel porous PUF scaffold, and cultured under different dynamic conditions. Viability assay, DNA quantification, SEM and histological analyses were performed at different time points. RESULTS: The PUF scaffold presented interesting mechanical properties and morphology adequate to promote cell adhesion, highlighting its potential for tissue engineering purposes. Results showed that constructs under dynamic conditions contain enhanced viability and cell number, exponentially increased for double-phase rotation; under this last configuration, cells uniformly covered both the external surface and the lumen. CONCLUSIONS: The developed 3D structure combined with the alternated exposure to air and medium provided the optimal in vitro biochemical conditioning with adequate nutrient supply for cells. The results highlight a valuable combination of material and dynamic culture for tissue engineering applications. PMID- 28362041 TI - Chyluria: the state of the art. AB - Chyluria is the passage of chyle in the urine. The cause seems to be the rupture of retroperitoneal lymphatics into the pyelocaliceal system, giving urine a milky appearance. This communication is caused by the obstruction of lymphatic drainage proximal to intestinal lacteals, resulting in dilatation of distal lymphatics and the eventual rupture of lymphatic vessels into the urinary collecting system.This condition, if left untreated, leads to significant morbidity because of hematochyluria, recurrent renal colic, nutritional problems due to protein losses and immunosuppression resulting from lymphocyturia.In this review, we summarize the state of the art of this condition and the newest treatments available. PMID- 28362042 TI - Gadolinium contrast agents - are they really safe? AB - Gadolinium-based contrast agents (GBCA) are used worldwide for enhanced MRI examinations, including heart and vessels. Gadolinium is a highly toxic heavy metal. If used in GBCA it must be tightly bound to ligands. The configuration of ligands influences the stability of the GBCA and two types of chelates have been used. Macrocyclic chelates offer better protection and binding of gadolinium ion than linear chelates with a flexible open chain - gadolinium could be more easily released from the latter ones. GBCAs are excreted from the body mostly by the kidneys, which is of importance in chronic kidney disease.Two states are related to gadolinium: nephrogenic systemic fibrosis (NSF) and gadolinium body storage. NSF is a severe and debilitating disease, directly connected to gadolinium toxicity, proven after the use of linear chelates. Due to strict recommendations of radiology societies, NSF was practically eradicated. Gadolinium deposition was observed especially in bones and in some brain areas: in dentate nucleus and in globus pallidus, even years after the GBCA administration. The form of the storage (chelated or free), as well as their clinical impact, are not clear, but first observations of "gadolinium deposition disease" have been reported. PMID- 28362044 TI - Comparison of post-creation procedures and costs between surgical and an endovascular approach to arteriovenous fistula creation. AB - INTRODUCTION: Due to early and late failures that may occur with surgically created hemodialysis arteriovenous fistulas (SAVF), post-creation procedures are commonly required to facilitate AVF maturation and maintain patency. This study compared AVF post-creation procedures and their associated costs in patients with SAVF to patients with a new endovascularly created AVF (endoAVF). METHODS: A 5% random sample from Medicare Standard Analytical Files was abstracted to determine post-creation procedures and associated costs for SAVF created from 2011 to 2013. Medicare enrollment during the 6 months prior to and after the AVF creation was required. Patients' follow-up inpatient, outpatient, and physician claims were used to identify post-creation procedures and to estimate average procedure costs. Comparative procedural information on endoAVF was obtained from the Novel Endovascular Access Trial (NEAT). RESULTS: Of 3764 Medicare SAVF patients, 60 successfully matched to endoAVF patients using 1:1 propensity score matching of baseline demographic and clinical characteristics. The total post-creation procedural event rate within 1 year was lower for endoAVF patients (0.59 per patient-year) compared to the matched SAVF cohort (3.43 per patient-year; p<0.05). In the endoAVF cohort, event rates of angioplasty, thrombectomy, revision, catheter placement, subsequent arteriovenous graft (AVG), new SAVF, and vascular access-related infection were all significantly lower than in the SAVF cohort. The average first year cost per patient-year associated with post creation procedures was estimated at US$11,240 USD lower for endoAVF than for SAVF. CONCLUSIONS: Compared to patients with SAVF, patients with endoAVF required fewer post-creation procedures and had lower associated mean costs within the first year. PMID- 28362043 TI - Transformation of the peripheral intravenous catheter placement experience in pediatrics. AB - BACKGROUND: "Needle pokes" are the most frequent cause of pain encountered by pediatric patients in the hospital setting. Poor control of pain during needle pokes leads to short- and long-term adverse outcomes for both patients and hospitals. J-Tips are a needle-free injection system that use pressurized gas to inject lidocaine in a fine stream of fluid that penetrates the skin. This study undertook an evaluation of their effectiveness at decreasing the pain of the needle poke that takes place with IV insertion. METHODS: Participation was limited to patients between the ages of 3 and 16 who received an IV during a 3 week period at an academic pediatric hospital. Furthermore, patients requiring more than one attempt to place the IV were not included. Participants were recruited within 24 hours after having received their IV. The 10-point, Wong Baker Faces Pain Rating Scale was the tool used to collect pain scores. Patients were recruited to the study by convenience sampling. RESULTS: Pain scores were collected from 85 patients. There were 41 patients who received needle-free injected lidocaine prior to IV insertion. There were 44 patients who received an IV without previous lidocaine injection. Mean pain scores for the two groups were 2.45 for the patients who received the needle-free injected lidocaine and 5.8 for the patients who did not (p value <0.001). CONCLUSIONS: Results were consistent with the hypothesis that needle-free injection of lidocaine is an effective therapy for the management of pain in children between the ages of 3-16 years who receive an IV. PMID- 28362045 TI - Optimizing the fluidized bed bioreactor as an external bioartificial liver. AB - BACKGROUND: Our team previously designed and validated a new bioartificial liver (BAL) called Suppliver based on a PrismaflexTM device, including fluidized bed bioreactors hosting alginate-encapsulated hepatocytes. To ensure correct fluidization within the bioreactor, the beads need to become heavier with the addition of inert glass microspheres. METHODS: In this study, we assessed the impact of this additional component on the bead production process, bed fluidization, mass transfer and the mechanical properties of the beads, as well as cell viability and basic metabolic function. RESULTS: A concentration of 20 mg (1% v/v) of microspheres for 15-20 million cells per milliliter of alginate solution appears to be the best configuration. The filling ratio for the beads in the bioreactors can reach 60%. Four 250-mL bioreactors represent approximately 15% of the hepatocytes in a liver, which is a reasonable target for extracorporeal liver supply. CONCLUSIONS: Increasing bead density clearly maintained the performances of the fluidized bed with plasma of different compositions, without any risk of release out of the bioreactor. A 1% (v/v) concentration of microspheres in alginate solution did not result in any alteration of the mechanical or biological behavior. This concentration can thus be applied to the production of large-scale encapsulated biomass for further use of the Suppliver setup in human scale preclinical studies. PMID- 28362046 TI - Co-microencapsulation of BMSCs and mouse pancreatic beta cells for improving the efficacy of type I diabetes therapy. AB - INTRODUCTION: To overcome the shortcomings of pancreas transplantation and insulin injection treatment for type I diabetes, biocompatible materials were used to prepare alginate-chitosan-alginate microcapsules that co-encapsulated bone marrow mesenchymal stem cells and mouse pancreatic beta cells to treat diabetic mice. METHODS: Blank alginate-chitosan-alginate (ACA) microcapsules and co-microencapsulated cells were prepared using a high-voltage electrostatic method and then characterized using an inverted microscope. Cell viability was evaluated using AO/EB staining. ELISA kit was used to detect insulin secretion. Peri-orbital blood samples were obtained from the mice for blood glucose determination every week for one month. RESULTS: After 28 days of in vitro culture, the secretion of insulin following co-microencapsulation was higher than that observed for microencapsulated beta-TC-6 cells alone. On the 28th day after transplantation, the blood glucose level was 6.86 mmol/L in the microencapsulated beta-TC-6 group. On the 14th day, the blood glucose level was 6.80 mmol/L in the co-microencapsulated BMSC/beta-TC-6 group, which was close to the normal blood glucose level of healthy mice. These results indicated that the efficacy in reducing blood glucose was better in the co-microencapsulated BMSC/beta-TC-6 group. CONCLUSIONS: This primary study indicated that combining microencapsulation technology and co-culture of stem cells and somatic cells shows promise for the treatment of type I diabetes mellitus. PMID- 28362048 TI - Comparison of estimates of resting energy expenditure equations in haemodialysis patients. AB - PURPOSE: Waste products of metabolism accumulate in patients with chronic kidney disease, and require clearance by haemodialysis (HD). We wished to determine whether there was an association between resting energy expenditure (REE) and total energy expenditure (TEE) in HD patients and body composition. SUBJECTS/METHODS: We determined REE by recently validated equations (CKD equation) and compared REE with that estimated by standard equations for REE, and TEE calculated from patient reported physical activity, in HD patients with corresponding body composition measured by dual energy X-ray absorptiometry (DEXA) scanning. RESULTS: We studied 107 patients, 69 male (64.5%), mean age 62.7 +/- 15.1 years. The CKD equation REE was 72.5 +/- 13.3 watts (W) and TEE 83.2 +/- 9.7 W. There was a strong association between REE with body surface area (BSA) (r2 = 0.80), total soft lean and fat lean tissue mass (r2 = 0.69), body mass index (BMI) (r2 = 0.34), all p<0.001. REE estimated using the modified Harris Benedict, Mifflin St. Jeor, Katch McArdle, Bernstein and Robertson equations underestimated REE compared to the CKD equation. TEE was more strongly associated with BSA (r2 = 0.51), appendicular muscle mass (r2 = 0.42), than BMI (r2 = 0.15) all p<0.001.TEE was greater for those employed (104.9 +/- 10.7 vs. 83.1 +/- 12.3 W, p<0.001), and with no co-morbidity (88.7 +/- 14.8 vs. 82.7 +/- 12.3 W, p<0.05). CONCLUSIONS: Standard equations underestimate REE in HD patients compared to the CKD equation. TEE was greater in those with more skeletal muscle mass, in those who were employed and in those with the least co-morbidity. More metabolically active patients may well require greater dialytic clearances. PMID- 28362047 TI - The Vietnamese pig as a translational animal model to evaluate tissue engineered heart valves: promising early experience. AB - Several animal models are currently used for the surgical implantation of either biologic or biopolymeric scaffolds in order to provide in vivo assessment of tissue-engineered heart valves. The Vietnamese pig (VP) is herein proposed as a suitable recipient to test the function of novel bioengineered valve substitutes, in the reconstruction of the right ventricular outflow tract (RVOT). This review aims to provide a complete and exhaustive panel of physiological parameters and methodological information for preclinical studies of tissue-engineered heart valves in the VP animal model. PMID- 28362049 TI - Robotic-arm assisted total hip arthroplasty results in smaller acetabular cup size in relation to the femoral head size: a matched-pair controlled study. AB - PURPOSE: To compare the acetabular component size relative to the patient's native femoral head size between conventional THA (CTHA) approach and robotic-arm assisted THA (RTHA) to infer which of these techniques preserved more acetabular bone. METHODS: Patients were included if they had primary osteoarthritis (OA) and underwent total hip replacement between June 2008 and March 2014. Patients were excluded if they had missing or rotated postoperative anteroposterior radiographs. RTHA patients were matched to a control group of CTHA patients, in terms of preoperative native femoral head size, age, gender, body mass index (BMI) and approach. Acetabular cup size relative to femoral head size was used as a surrogate for amount of bone resected. We compared the groups according to 2 measures describing acetabular cup diameter (c) in relation to femoral head diameter (f): (i) c-f, the difference between cup diameter and femoral head diameter and (ii) (c-f)/f, the same difference as a fraction of femoral head diameter. RESULTS: 57 matched pairs were included in each group. There were no significant differences between groups for demographic measures, femoral head diameter, or acetabular cup diameter (p>0.05). However, measures (i) and (ii) did differ significantly between the groups, with lower values in the RTHA group (p<0.02). CONCLUSIONS: Using acetabular cup size relative to femoral head size as an approximate surrogate measure of acetabular bone resection may suggest greater preservation of bone stock using RTHA compared to CTHA. Further studies are needed to validate the relationship between acetabular cup size and bone loss in THA. PMID- 28362050 TI - Clinical and radiographic outcomes of the Birmingham Hip Resurfacing arthroplasty at a minimum follow-up of 10 years: results from an independent centre. AB - BACKGROUND: Metal-on-metal hip resurfacing (MoMHR) has been proposed as an effective surgical treatment for young and active patients with symptomatic hip disease. Recently, good clinical and radiographic outcomes have been reported by the designer surgeons at a 15.3 years follow-up; however, results at long follow up by non-designer surgeons are less satisfactory. The aim of the study was to investigate if MoMHR can produce satisfactory clinical and radiographic results and if survival rate can be high even if the procedure is performed by non designer surgeons. METHODS: All patients were assessed about implant survival. All patients completed an Oxford Hip Score (OHS), Harris Hip Score (HHS) and a University of California Los Angeles (UCLA) activity score preoperatively, at 1 year and at last available follow-up; at this time, a standard anteroposterior weight-bearing radiograph was performed. RESULTS: The survival rate with revision for any reason is 96%, similar to those obtained by designer surgeons. All the clinical scores improved over time: according to the OHS the survivors are asymptomatic and according to the UCLA maintain a high level of function. 6 remodellings of the femoral neck and 2 heterotopic bone formations were seen, but they were asymptomatic. CONCLUSIONS: As designer surgeons have already shown, MoMHR can provide in active patients a durable treatment for hip arthritis, with low risk of revision and good results at 10 years follow-up, even if the procedure is performed by non-designer surgeons. PMID- 28362051 TI - Deep Capillary Macular Perfusion Indices Obtained with OCT Angiography Correlate with Degree of Nonproliferative Diabetic Retinopathy. AB - PURPOSE: To evaluate the integrity of macular and temporomacular vasculature in nonproliferative diabetic retinopathy (NPDR) with noninvasive optical coherence tomography angiography (OCTA) and correlate perfusion indices with degree of NPDR. METHODS: In this prospective observational cross-sectional study, 102 eyes with newly diagnosed NPDR (mild NPDR, 36; moderate NPDR, 21; severe NPDR, 13; NPDR with diabetic macular edema [DME], 32) underwent OCTA. Sixty eyes of normal subjects served as control. Degree of NPDR (based on Early Treatment Diabetic Retinopathy Study criteria) was confirmed with fluorescein angiography. Automated OCTA/split-spectrum amplitude decorrelation angiography software generated perfusion indices (vessel density and flow index) from images of the retina. The perfusion index of superficial and deep retinal plexuses was obtained in both perifoveal (central 1-3 mm) and parafoveal (3-6 mm) areas. RESULTS: Deep plexus parafoveal vessel density was 25.23% (+/-6.1) in mild NPDR, 20.16% (+/-6.16) in moderate NPDR, 11.16% (+/-4.16) in severe NPDR, and 17.91% (+/-4.42) in NPDR + DME compared to normal subjects (36.93% [+/-8.1]; (p<0.01). Spearman correlation coefficient (rs) between vessel density and level of NPDR severity in the parafoveal region showed inverse correlation for both superficial (rs -0.87; p = 0.083) and deep (rs -0.96; p = 0.017) plexus. Similarly, when vessel density of the perifoveal region was compared with level of NPDR severity, inverse correlation was noted in both superficial (rs -0.85; p = 0.08) and deep (rs 0.98; p = 0.011) plexus. CONCLUSIONS: Optical coherence tomography angiography clearly delineated the retinal microcirculation and allowed quantification of vascular perfusion of each layer. As diabetic retinopathy progressed, a decrease in perfusion index is more pronounced in the deep retinal plexus and precedes changes in superficial plexus. PMID- 28362052 TI - Plasmapheresis, Intravenous Immunoglobulins, and Autologous Serum Eyedrops in the Acute Eye Complications of Toxic Epidermal Necrolysis. AB - PURPOSE: Toxic epidermal necrolysis (TEN) is a rare, life-threatening, drug induced, mucocutaneous disease, which can severely affect the ocular surface. The purpose of this study was to investigate the efficacy of plasmapheresis, human IV immunoglobulins (IVIg), and autologous serum (AS) eyedrops in the treatment of the severe acute ocular complications of TEN. METHODS: A retrospective chart review of all patients admitted to the Burn Unit, Azienda Ospedaliero Universitaria-Sassari, Sassari, Italy, from 2009 to 2015, identified 9 patients (2 men, 7 women; mean age 63.8 +/- 24.7 years) with TEN. Bilateral, acute ocular surface complications were observed in 7 (78%) patients; 3 showed catarrhal conjunctivitis, whereas 4 had severe pseudomembranous conjunctivitis and corneal ulcers. RESULTS: All patients with TEN were immediately treated with plasmapheresis and human IVIg, which produced a marked improvement in the patients' general condition. In the 3 with catarrhal conjunctivitis, preservative free artificial tears and topical antibiotics were beneficial. In the 4 with severe pseudomembranous conjunctivitis and corneal ulcers, treatment with AS eyedrops resulted in corneal and conjunctival epithelium healing over 3-6 weeks. After a minimum follow-up of at least 12 months, there were minimal/mild residual signs and symptoms of dry eye. CONCLUSIONS: Plasmapheresis and IVIg may be life saving and contribute to reduce ocular surface inflammation in TEN. Autologous serum eyedrops, prepared after plasmapheresis completion and IVIg infusion, may be helpful in the management of the severe acute ocular complications of TEN. PMID- 28362053 TI - To what extent may Botulinum toxin type A injections be an alternative choice to surgery in infantile esotropia? AB - INTRODUCTION: Evaluation of a single injection of botulinum toxin A in infantile esotropia as an alternative choice to surgery in a retrospective cases serie. METHODS: Patients (65 consecutive children aged 9 to 26 months with infantile strabismus) underwent botulinum toxin A injection in both medial recti Botulinum toxin A injection. Clinical datas including measurement of angle of deviation before and after injection. visual acuity, stereoscopy and side effects were observed in a 24 months period of follow-up. RESULTS: Stable satisfactory result (angle equal to or less than 8 dioptres) was obtained in 33 cases (50.7%). Excellent result (-2 to + 4 dioptres) were obtained in 17 children (26%). Additional surgery was required in 32 cases for a residual (albeit smaller angle than the initial deviation) or recurrent deviation and/or DVD (49,2%). CONCLUSIONS: Botulinum toxin A reduces the tonic spastic motor component of strabismus and, should additional surgery be required (49% in our series), allows the procedure to be carried out on a smaller angle. A reduction in the maximum angle of deviation is thus achieved sooner, and allows the development of anomalous binocularity in a stable microtropia. PMID- 28362054 TI - A randomized study of the efficacy and safety of 0.1% cyclosporine A cationic emulsion in treatment of moderate to severe dry eye. AB - PURPOSE: The SICCANOVE study aimed to compare the efficacy and safety of 0.1% cyclosporine A cationic emulsion (CsA CE) versus vehicle in patients with moderate to severe dry eye disease (DED). METHODS: In this multicenter, double masked, parallel-group, controlled study, patients were randomized (1:1) to receive CsA CE (Ikervis(r)) or vehicle for 6 months. The co-primary efficacy endpoints at month 6 were mean change from baseline in corneal fluorescein staining (CFS; modified Oxford scale) and in global ocular discomfort (visual analogue scale [VAS]). RESULTS: The mean change in CFS from baseline to month 6 (CsA CE: n = 241; vehicle: n = 248) was significantly greater with CsA CE than with vehicle (-1.05 +/- 0.98 and -0.82 +/- 0.94, respectively; p = 0.009). Ocular discomfort improved similarly in both groups; however, the percentage of patients with >=25% improvement in VAS was significantly higher with CsA CE (50.2%) than with vehicle (41.9%; p = 0.048). In a post hoc analysis of patients with severe ocular surface damage (CFS score 4) at baseline (CsA CE: n = 43; vehicle: n = 42), the percentage of patients with improvements of >=2 grades in CFS score and >=30% in Ocular Surface Disease Index score was significantly greater with CsA CE (p = 0.003). Treatment compliance and ocular tolerability were satisfactory and as expected for CsA use. CONCLUSION: Cyclosporine A CE was well-tolerated and effectively improved signs and symptoms in patients with moderate to severe DED over 6 months, especially in patients with severe disease, who are at risk of irreversible corneal damage. PMID- 28362055 TI - Author's reply to: Effectiveness of anti-VEGF treatment on ophthalmic radiation side effects. PMID- 28362056 TI - Effectiveness of anti-VEGF treatment on ophthalmic radiation side effects. PMID- 28362057 TI - Correlation between choroidal thickness and degree of myopia assessed with enhanced depth imaging optical coherence tomography. AB - PURPOSE: To assess the choroidal thickness in different degrees of myopia using enhanced depth imaging optical coherence tomography (EDI-OCT) compared with healthy subjects. METHODS: We included 240 patients with myopia and 60 emmetropes as controls. Participants underwent full ophthalmologic examination, axial length measurement, and EDI-OCT imaging of the choroid. Choroidal thickness (CT) was measured at 5 locations, including subfoveal (SFCT), 2 mm nasal, temporal, upper, and lower to fovea. RESULTS: Choroidal thickness was significantly lower in myopic eyes compared to controls. Regardless of the degree of myopia, nasal regions showed the lowest CT with decremental pattern with advance of myopia (low myopia 279.00 +/- 24.50 um, moderate myopia 269.58 +/- 20.69 um, high myopia 189.58 +/- 25.95 um, advanced myopia 96.75 +/- 24.83 um). Highest CT was variable according to the degree of myopia with decremental pattern with advance of myopia (low myopia in subfoveal region 354.40 +/- 35.14 um, moderate myopia in temporal region 337.87 +/- 35.75 um, high myopia in lower region 312.15 +/- 38.90 um, and advanced myopia in upper region 201.25 +/- 18.27 um). Axial length showed significant negative correlation with SFCT and CT in different studied regions. CONCLUSIONS: Different degrees of myopia showed thinner choroidal thickness than that of normal control eyes with decremental thinning with progress of myopia. This might be secondary to the longer axial length, which was the determining factor in some locations such as subfoveal, nasal, and upper CT. PMID- 28362058 TI - Correlation between Postoperative Area of High Autofluorescence in Macula and Visual Acuity after Macular Hole Closure. AB - PURPOSE: To determine the correlation between the preoperative basal diameter of macular hole, the postoperative area of high autofluorescence (AF) in macula, and visual acuity in full-thickness macular hole. METHODS: Forty-nine patients with full-thickness macular hole who underwent vitrectomy and C3F8 filling were reviewed. The preoperative diameter of macular hole, the 6 months postoperative area of high AF in macula if it existed, the length of inner segment/outer segment (IS/OS) defect, and visual acuity were obtained. The correlation between them was determined. RESULTS: At postoperative 6 months, the rate of high AF in macula was 63.3%. There were statistical differences between with and without high AF groups in postoperative best-corrected visual acuity (BCVA) (t = -2.751, p = 0.008), preoperative basal diameter of macular hole (t = -4.946, p = 0.00001), and postoperative length of IS/OS defect (t = -8.351, p<0.00001). Simple linear regression analysis showed high positive correlations between preoperative basal diameter of macular hole and area of high AF (p<0.00001, r = 0.893), postoperative length of IS/OS defect and area of high fundus AF (FAF) (p<0.00001, r = 0.779), and negative correlations between area of high AF and postoperative BCVA (p = 0.037, r = 0.375). There was low correlation between diameter of macular hole and postoperative BCVA (p = 0.112). CONCLUSIONS: The preoperative basal diameter of macular hole and postoperative length of IS/OS defect decides the postoperative area of high AF in macula to some degree, and the postoperative area of high AF in macula can be an evaluating indicator for poor macular function recovery. PMID- 28362059 TI - Diffusion-weighted imaging in evaluating the efficacy of concurrent chemoradiotherapy in the treatment of non-small cell lung cancer. AB - OBJECTIVE: To explore the predictive value of diffusion-weighted imaging (DWI) in evaluating the short-term efficacy of concurrent chemoradiotherapy (CCRT) in the treatment of patients with non-small cell lung cancer (NSCLC). METHODS: A total of 192 patients with NSCLC were selected and treated with CCRT. Dynamic contrast enhanced magnetic resonance imaging combined with DWI was performed on all patients before and after CCRT treatment. Correspondingly, apparent diffusion coefficient (ADC) values were recorded before treatment (ADCpre), during treatment (ADCmid), and after treatment (ADCpost). Tumor response was evaluated as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic power of quantitative DWI parameters in predicting the short-term efficacy of CCRT for patients with NSCLC. RESULTS: There were 21 patients with CR, 82 with PR, 77 with SD, and 12 with PD. The ADCpre was negatively correlated with tumor regression rate, whereas ADCmid, ADCpost, and their respective change rates ?ADCmid and ?ADCpost were positively related to tumor regression rate. The ROC curve analysis suggested ADCpre = 1.38 * 10-3 mm2/s, ?ADCmid = 14.14%, and ?ADCpost = 20.39% as thresholds to predict the short-term efficacy of CCRT, with corresponding areas under the curve of 0.637, 0.743, and 0.752, respectively. CONCLUSIONS: These findings indicate that DWI provides promising predictive value in evaluating the short-term efficacy of CCRT in the treatment of patients with NSCLC. PMID- 28362060 TI - Maintenance immunosuppression for adults undergoing liver transplantation: a network meta-analysis. AB - BACKGROUND: As part of liver transplantation, immunosuppression (suppressing the host immunity) is given to prevent graft rejections resulting from the immune response of the body against transplanted organ or tissues from a different person whose tissue antigens are not compatible with those of the recipient. The optimal maintenance immunosuppressive regimen after liver transplantation remains uncertain. OBJECTIVES: To assess the comparative benefits and harms of different maintenance immunosuppressive regimens in adults undergoing liver transplantation through a network meta-analysis and to generate rankings of the different immunosuppressive regimens according to their safety and efficacy. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until October 2016 to identify randomised clinical trials on immunosuppression for liver transplantation. SELECTION CRITERIA: We included only randomised clinical trials (irrespective of language, blinding, or publication status) in adult participants undergoing liver transplantation (or liver retransplantation) for any reason. We excluded trials in which participants had undergone multivisceral transplantation or participants with established graft rejections. We considered any of the various maintenance immunosuppressive regimens compared with each other. DATA COLLECTION AND ANALYSIS: We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio, rate ratio, and hazard ratio (HR) with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS: We included a total of 26 trials (3842 participants) in the review, and 23 trials (3693 participants) were included in one or more outcomes in the review. The vast majority of the participants underwent primary liver transplantation. All of the trials were at high risk of bias, and all of the evidence was of low or very low quality. In addition, because of sparse data involving trials at high risk of bias, it is not possible to entirely rely on the results of the network meta analysis. The trials included mainly participants undergoing primary liver transplantation of varied aetiologies. The follow-up in the trials ranged from 3 to 144 months. The most common maintenance immunosuppression used as a control was tacrolimus. There was no evidence of difference in mortality (21 trials; 3492 participants) or graft loss (15 trials; 2961 participants) at maximal follow-up between the different maintenance immunosuppressive regimens based on the network meta-analysis. In the direct comparison, based on a single trial including 222 participants, tacrolimus plus sirolimus had increased mortality (HR 2.76, 95% CrI 1.30 to 6.69) and graft loss (HR 2.34, 95% CrI 1.28 to 4.61) at maximal follow-up compared with tacrolimus. There was no evidence of differences in the proportion of people with serious adverse events (1 trial; 719 participants), proportion of people with any adverse events (2 trials; 940 participants), renal impairment (8 trials; 2233 participants), chronic kidney disease (1 trial; 100 participants), graft rejections (any) (16 trials; 2726 participants), and graft rejections requiring treatment (5 trials; 1025 participants) between the different immunosuppressive regimens. The network meta-analysis showed that the number of adverse events was lower with cyclosporine A than with many other immunosuppressive regimens (12 trials; 1748 participants), and the risk of retransplantation (13 trials; 1994 participants) was higher with cyclosporine A than with tacrolimus (HR 3.08, 95% CrI 1.13 to 9.90). None of the trials reported number of serious adverse events, health-related quality of life, or costs. FUNDING: 14 trials were funded by pharmaceutical companies who would benefit from the results of the trial; two trials were funded by parties who had no vested interest in the results of the trial; and 10 trials did not report the source of funding. AUTHORS' CONCLUSIONS: Based on low-quality evidence from a single small trial from direct comparison, tacrolimus plus sirolimus increases mortality and graft loss at maximal follow-up compared with tacrolimus. Based on very low quality evidence from network meta-analysis, we found no evidence of difference between different immunosuppressive regimens. We found very low-quality evidence from network meta-analysis and low-quality evidence from direct comparison that cyclosporine A causes more retransplantation compared with tacrolimus. Future randomised clinical trials should be adequately powered; performed in people who are generally seen in the clinic rather than in highly selected participants; employ blinding; avoid postrandomisation dropouts or planned cross-overs; and use clinically important outcomes such as mortality, graft loss, renal impairment, chronic kidney disease, and retransplantation. Such trials should use tacrolimus as one of the control groups. Moreover, such trials ought to be designed in such a way as to ensure low risk of bias and low risks of random errors. PMID- 28362061 TI - Chlorhexidine mouthrinse as an adjunctive treatment for gingival health. AB - BACKGROUND: Dental plaque associated gingivitis is a reversible inflammatory condition caused by accumulation and persistence of microbial biofilms (dental plaque) on the teeth. It is characterised by redness and swelling of the gingivae (gums) and a tendency for the gingivae to bleed easily. In susceptible individuals, gingivitis may lead to periodontitis and loss of the soft tissue and bony support for the tooth. It is thought that chlorhexidine mouthrinse may reduce the build-up of plaque thereby reducing gingivitis. OBJECTIVES: To assess the effectiveness of chlorhexidine mouthrinse used as an adjunct to mechanical oral hygiene procedures for the control of gingivitis and plaque compared to mechanical oral hygiene procedures alone or mechanical oral hygiene procedures plus placebo/control mouthrinse. Mechanical oral hygiene procedures were toothbrushing with/without the use of dental floss or interdental cleaning aids and could include professional tooth cleaning/periodontal treatment.To determine whether the effect of chlorhexidine mouthrinse is influenced by chlorhexidine concentration, or frequency of rinsing (once/day versus twice/day).To report and describe any adverse effects associated with chlorhexidine mouthrinse use from included trials. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 28 September 2016); the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8) in the Cochrane Library (searched 28 September 2016); MEDLINE Ovid (1946 to 28 September 2016); Embase Ovid (1980 to 28 September 2016); and CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1937 to 28 September 2016). We searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We included randomised controlled trials assessing the effects of chlorhexidine mouthrinse used as an adjunct to mechanical oral hygiene procedures for at least 4 weeks on gingivitis in children and adults. Mechanical oral hygiene procedures were toothbrushing with/without use of dental floss or interdental cleaning aids and could include professional tooth cleaning/periodontal treatment. We included trials where participants had gingivitis or periodontitis, where participants were healthy and where some or all participants had medical conditions or special care needs. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results extracted data and assessed the risk of bias of the included studies. We attempted to contact study authors for missing data or clarification where feasible. For continuous outcomes, we used means and standard deviations to obtain the mean difference (MD) and 95% confidence interval (CI). We combined MDs where studies used the same scale and standardised mean differences (SMDs) where studies used different scales. For dichotomous outcomes, we reported risk ratios (RR) and 95% CIs. Due to anticipated heterogeneity we used random-effects models for all meta-analyses. MAIN RESULTS: We included 51 studies that analysed a total of 5345 participants. One study was assessed as being at unclear risk of bias, with the remaining 50 being at high risk of bias, however, this did not affect the quality assessments for gingivitis and plaque as we believe that further research is very unlikely to change our confidence in the estimate of effect. Gingivitis After 4 to 6 weeks of use, chlorhexidine mouthrinse reduced gingivitis (Gingival Index (GI) 0 to 3 scale) by 0.21 (95% CI 0.11 to 0.31) compared to placebo, control or no mouthrinse (10 trials, 805 participants with mild gingival inflammation (mean score 1 on the GI scale) analysed, high-quality evidence). A similar effect size was found for reducing gingivitis at 6 months. There were insufficient data to determine the reduction in gingivitis associated with chlorhexidine mouthrinse use in individuals with mean GI scores of 1.1 to 3 (moderate or severe levels of gingival inflammation). Plaque Plaque was measured by different indices and the SMD at 4 to 6 weeks was 1.45 (95% CI 1.00 to 1.90) standard deviations lower in the chlorhexidine group (12 trials, 950 participants analysed, high-quality evidence), indicating a large reduction in plaque. A similar large reduction was found for chlorhexidine mouthrinse use at 6 months. Extrinsic tooth staining There was a large increase in extrinsic tooth staining in participants using chlorhexidine mouthrinse at 4 to 6 weeks. The SMD was 1.07 (95% CI 0.80 to 1.34) standard deviations higher (eight trials, 415 participants analysed, moderate-quality evidence) in the chlorhexidine mouthrinse group. There was also a large increase in extrinsic tooth staining in participants using chlorhexidine mouthrinse at 7 to 12 weeks and 6 months. Calculus Results for the effect of chlorhexidine mouthrinse on calculus formation were inconclusive. Effect of concentration and frequency of rinsing There were insufficient data to determine whether there was a difference in effect for either chlorhexidine concentration or frequency of rinsing. Other adverse effects The adverse effects most commonly reported in the included studies were taste disturbance/alteration (reported in 11 studies), effects on the oral mucosa including soreness, irritation, mild desquamation and mucosal ulceration/erosions (reported in 13 studies) and a general burning sensation or a burning tongue or both (reported in nine studies). AUTHORS' CONCLUSIONS: There is high-quality evidence from studies that reported the Loe and Silness Gingival Index of a reduction in gingivitis in individuals with mild gingival inflammation on average (mean score of 1 on the 0 to 3 GI scale) that was not considered to be clinically relevant. There is high quality evidence of a large reduction in dental plaque with chlorhexidine mouthrinse used as an adjunct to mechanical oral hygiene procedures for 4 to 6 weeks and 6 months. There is no evidence that one concentration of chlorhexidine rinse is more effective than another. There is insufficient evidence to determine the reduction in gingivitis associated with chlorhexidine mouthrinse use in individuals with mean GI scores of 1.1 to 3 indicating moderate or severe levels of gingival inflammation. Rinsing with chlorhexidine mouthrinse for 4 weeks or longer causes extrinsic tooth staining. In addition, other adverse effects such as calculus build up, transient taste disturbance and effects on the oral mucosa were reported in the included studies. PMID- 28362062 TI - A novel Online-to-Offline (O2O) model for pre-exposure prophylaxis and HIV testing scale up. AB - INTRODUCTION: PrEP awareness and uptake among men who have sex with men (MSM) and transgender women (TG) in Thailand remains low. Finding ways to increase HIV testing and PrEP uptake among high-risk groups is a critical priority. This study evaluates the effect of a novel Adam's Love Online-to-Offline (O2O) model on PrEP and HIV testing uptake among Thai MSM and TG and identifies factors associated with PrEP uptake. METHODS: The O2O model was piloted by Adam's Love (www.adamslove.org) HIV educational and counselling website. MSM and TG reached online by PrEP promotions and interested in free PrEP and/or HIV testing services contacted Adam's Love online staff, received real-time PrEP eCounseling, and completed online bookings for receiving services at one of the four sites in Bangkok based on their preference. Auto-generated site- and service-specific e tickets and Quick Response (QR) codes were sent to their mobile devices enabling monitoring and check-in by offline site staff. Service uptake and participant's socio-demographic and risk behaviour characteristics were analyzed. Factors associated with PrEP uptake were assessed using multiple logistic regression. RESULTS: Between January 10th and April 11th, 2016, Adam's Love reached 272,568 people online via the PrEP O2O promotions. 425 MSM and TG received eCounseling and e-tickets. There were 325 (76.5%) MSM and TG who checked-in at clinics and received HIV testing. Nine (2.8%) were diagnosed with HIV infection. Median (IQR) time between receiving the e-ticket and checking-in was 3 (0-7) days. Of 316 HIV negative MSM and TG, 168 (53.2%) started PrEP. In a multivariate model, higher education (OR 2.30, 95%CI 1.14-4.66; p = 0.02), seeking sex partners online (OR 2.05, 95%CI 1.19-3.54; p = 0.009), being aware of sexual partners' HIV status (OR 2.37, 95%CI 1.29-4.35; p = 0.008), ever previously using post-exposure prophylaxis (PEP) (OR 2.46, 95%CI 1.19-5.09; p = 0.01), and enrolment at Adam's Love clinic compared to the other three sites (OR 3.79, 95%CI 2.06-6.95; p < 0.001) were independently associated with PrEP uptake. CONCLUSION: Adam's Love O2O model is highly effective in linking online at-risk MSM and TG to PrEP and HIV testing services, and has high potential to be replicated and scaled up in other settings with high Internet penetration among key populations. PMID- 28362063 TI - Adherence to antiretroviral therapy for HIV in sub-Saharan Africa and Asia: a comparative analysis of two regional cohorts. AB - INTRODUCTION: Our understanding of how to achieve optimal long-term adherence to antiretroviral therapy (ART) in settings where the burden of HIV disease is highest remains limited. We compared levels and determinants of adherence over time between HIV-positive persons receiving ART who were enrolled in a bi regional cohort in sub-Saharan Africa and Asia. METHODS: This multicentre prospective study of adults starting first-line ART assessed patient-reported adherence at follow-up clinic visits using a 30-day visual analogue scale. Determinants of suboptimal adherence (<95%) were assessed for six-month intervals, using generalized estimating equations multivariable logistic regression with multiple imputations. Region of residence (Africa vs. Asia) was assessed as a potential effect modifier. RESULTS: Of 13,001 adherence assessments in 3934 participants during the first 24 months of ART, 6.4% (837) were suboptimal, with 7.3% (619/8484) in the African cohort versus 4.8% (218/4517) in the Asian cohort (p < 0.001). In the African cohort, determinants of suboptimal adherence were male sex (odds ratio (OR) 1.27, 95% confidence interval (CI) 1.06 1.53; p = 0.009), younger age (OR 0.8 per 10 year increase; 0.8-0.9; p = 0.003), use of concomitant medication (OR 1.8, 1.0-3.2; p = 0.044) and attending a public facility (OR 1.3, 95% CI 1.1-1.7; p = 0.004). In the Asian cohort, adherence was higher in men who have sex with men (OR for suboptimal adherence 0.6, 95% CI 0.4 0.9; p = 0.029) and lower in injecting drug users (OR for suboptimal adherence 1.6, 95% CI 0.9-2.6; p = 0.075), compared to heterosexuals. Risk of suboptimal adherence decreased with longer ART duration in both regions. Participants in low and lower-middle-income countries had a higher risk of suboptimal adherence (OR 1.6, 1.3-2.0; p < 0.001), compared to those in upper-middle or high-income countries. Suboptimal adherence was strongly associated with virological failure, in Africa (OR 5.8, 95% CI 4.3-7.7; p < 0.001) and Asia (OR 9.0, 95% CI 5.0-16.2; p < 0.001). Patient-reported adherence barriers among African participants included scheduling demands, drug stockouts, forgetfulness, sickness or adverse events, stigma or depression, regimen complexity and pill burden. CONCLUSION: Psychosocial factors and health system resources may explain regional differences. Adherence-enhancing interventions should address patient-reported barriers tailored to local settings, prioritizing the first years of ART. PMID- 28362064 TI - Leveraging social capital: multilevel stigma, associated HIV vulnerabilities, and social resilience strategies among transgender women in Lima, Peru. AB - INTRODUCTION: In Peru, transgender women (TW) experience unique vulnerabilities for HIV infection due to factors that limit access to, and quality of, HIV prevention, treatment and care services. Yet, despite recent advances in understanding factors associated with HIV vulnerability among TW globally, limited scholarship has examined how Peruvian TW cope with this reality and how existing community-level resilience strategies are enacted despite pervasive social and economic exclusion facing the community. Addressing this need, our study applies the understanding of social capital as a social determinant of health and examines its relationship to HIV vulnerabilities to TW in Peru. METHODS: Using qualitative methodology to provide an in-depth portrait, we assessed (1) intersections between social marginalization, social capital and HIV vulnerabilities; and (2) community-level resilience strategies employed by TW to buffer against social marginalization and to link to needed HIV-related services in Peru. Between January and February 2015, 48 TW participated (mean age = 29, range = 18-44) in this study that included focus group discussions and demographic surveys. Analyses were guided by an immersion crystallization approach and all coding was conducted using Dedoose Version 6.1.18. RESULTS: Themes associated with HIV vulnerability included experiences of multilevel stigma and limited occupational opportunities that placed TW at risk for, and limited their engagement with, existing HIV services. Emergent resiliency-based strategies included peer-to-peer and intergenerational knowledge sharing, supportive clinical services (e.g. group-based clinic attendance) and emotional support through social cohesion (i.e. feeling part of a community). CONCLUSION: This study highlights the importance of TW communities as support structures that create and deploy social resiliency-based strategies aimed at deterring and mitigating the impact of social vulnerabilities to discrimination, marginalization and HIV risk for individual TW in Peru. Public health strategies seeking to provide HIV prevention, treatment and care for this population will benefit from recognizing existing social capital within TW communities and incorporating its strengths within HIV prevention interventions. At the intersection of HIV vulnerabilities and collective agency, dimensions of bridging and bonding social capital emerged as resiliency strategies used by TW to access needed healthcare services in Peru. Fostering TW solidarity and peer support are key components to ensure acceptability and sustainability of HIV prevention and promotion efforts. PMID- 28362065 TI - Alcohol use, viral hepatitis and liver fibrosis among HIV-positive persons in West Africa: a cross-sectional study. AB - INTRODUCTION: Liver fibrosis is often the first stage of liver disease in people living with HIV (PLWHIV) in industrialized countries. However, little is known about liver fibrosis and its correlates among PLWHIV in sub-Saharan Africa. METHODS: The study was undertaken in three HIV referral clinics in Cote d'Ivoire, Senegal and Togo. Enrolled PLWHIV underwent a non-invasive assessment of liver fibrosis combining liver stiffness measure (LSM) with transient elastography and the aspartate aminotransferase-to-platelet ratio index (APRI). Significant liver fibrosis was defined as LSM >=7.1 kPa. Patients were screened for alcohol use (alcohol use disorder identification test (AUDIT)-C questionnaire), hepatitis B virus (HBV) antigen, hepatitis Delta virus (HDV) antibody and anti-hepatitis C (HCV) antibody. A logistic regression model was used to identify the factors associated with significant liver fibrosis. RESULTS: A total of 807 PLWHIV were screened at a median age of 43 years (interquartile range (IQR): 36-50). Their median CD4 count was 393 cells/mm3 (IQR: 234-563) and 682 (84.5%) were on antiretroviral therapy (ART). The prevalence of significant fibrosis was 5.3% (3.8-6.7). Infections with HBV and HCV were identified in 74 (9.2%) and nine (1.1%) participants. Main factors associated with liver fibrosis were alcohol use (AUDIT-C >6): (odds ratio (OR) = 4.0, confidence interval (CI): 1.2-14.0), (Ref. AUDIT-C <4) and HBV infection (OR = 2.9, CI: 1.2-7.2). Of the 74 patients positively screened for HBV, 50.0% were on a tenofovir-based ART regimen. Overall, 10% of HIV/HBV coinfected patients were detected with a positive HDV antibody with a higher prevalence in patients with a significant liver fibrosis (43.0%) compared to others (6.3%) (p = 0.01). CONCLUSION: Considering the WHO recommendations to screen for HBV infection and treat co-infected patients with tenofovir-based ART, screening of alcohol use and brief interventions to prevent alcohol abuse should be implemented in West Africa, especially in HBV/HIV co infected patients. PMID- 28362066 TI - Adverse event profile of a mature voluntary medical male circumcision programme performing PrePex and surgical procedures in Zimbabwe. AB - INTRODUCTION: The frequency of adverse events (AEs) is a widely used indicator of voluntary medical male circumcision (VMMC) programme quality. Though over 11.7 million male circumcisions (MCs) have been performed, little published data exists on the profile of AEs from mature, large-scale programmes. No published data exists on routine implementation of PrePex, a device-based MC method. METHODS: The ZAZIC Consortium began implementing VMMC in Zimbabwe in 2013, supporting services at 36 facilities. Aggregate data on VMMC outputs are collected monthly from each facility. Detailed forms are completed describing the profile of each moderate and severe AE. Bivariate and multivariable analyses were conducted using log-binomial regression models. RESULTS: From October 2014 through September 2015, 44,868 clients were circumcised with 156 clients experiencing a moderate or severe AE. 96.2% of clients had a follow-up visit within 14 days of their procedure. AEs were uncommon, with 0.3% (116/41,416) of surgical and 1.2% (40/3,452) of PrePex clients experiencing a moderate or severe AE. After adjusting for VMMC site, we found that PrePex was associated with a 3.29-fold (95% CI: 1.78-6.06) increased risk of experiencing an AE compared to surgical procedures. Device displacements, when the PrePex device is intentionally or accidentally dislodged during the 7-day placement period, accounted for 70% of PrePex AEs. The majority of device displacements were intentional self-removals. Overall, infection was the most common AE among VMMC clients. Compared to clients aged 20 and above, clients aged 10-14 were 3.07-fold (95% CI: 1.36-6.91) more likely to experience an infection and clients aged 15-19 were 1.80-fold (95% CI: 0.82-3.92) more likely to experience an infection, adjusted for site. CONCLUSION: This exploratory analysis found that clients receiving PrePex were more likely to experience an AE than surgical circumcision clients. This is largely attributable to the occurrence of device displacements, which require prompt access to corrective surgical MC procedures as part of their clinical management. Most device displacements were self-removals which are preventable if client behaviour could be modified through counselling interventions. We also found that infection after MC is more common among younger clients, who may benefit from additional counselling or increased parental involvement. PMID- 28362068 TI - Liver fibrosis regression and progression during controlled hepatitis B virus infection among HIV-HBV patients treated with tenofovir disoproxil fumarate in France: a prospective cohort study. AB - INTRODUCTION: Long-term tenofovir disoproxil fumarate (TDF) use has been associated with significant regression of liver fibrosis during hepatitis B virus (HBV) mono-infection, yet little is known during HIV-HBV coinfection. The aim of this study was to evaluate the evolution of liver fibrosis and its determinants in TDF-treated coinfected patients. METHODS: In this prospective cohort study, 167 HIV-HBV-infected patients initiating TDF-containing antiretroviral therapy were included. Fibrosis was assessed using the FibroTest(r) at baseline and every six to twelve months. Risk factors for fibrosis progression (F0-F1-F2 to F3-F4) and regression (F3-F4 to F0-F1-F2) were evaluated. RESULTS: At baseline, 134 (80.2%) patients had detectable HBV-DNA (median = 4.93 log10 IU/mL, IQR = 2.94 7.15) and 104 (62.3%) had hepatitis B "e" antigen-positive serology. Median follow-up was sixty months (IQR = 36-93). In the 47 (28.1%) patients with F3-F4 baseline fibrosis, 7/47 (14.9%) regressed to F0-F1-F2 at last follow-up visit. Fibrosis regression was significantly associated with higher CD4+ cell counts (P = 0.009) and lower fasting triglyceride levels (P = 0.007) at TDF-initiation. In the 120 (71.9%) patients with F0-F1-F2-baseline fibrosis, 20/120 (16.7%) progressed to F3-F4 at last follow-up visit. Fibrosis progression was associated with male gender (P = 0.01), older age (P = 0.001), from low/moderate HBV-endemic country (P = 0.007), lower nadir CD4+ cell count (P = 0.03), higher fasting glycaemia (P = 0.03) and anaemia (P = 0.004) at TDF-initiation. Control of HBV replication at end of follow-up was extensive (88.1%), while no HBV-related factors emerged as predictors of progression/regression. Incidence of severe liver-related events was low (n = 4, rate = 0.5/100 person-years). CONCLUSION: Liver fibrosis levels are stable for most coinfected patients undergoing TDF, despite control of HBV replication. Nevertheless, a concerning amount of liver fibrosis progression did occur, which could be partly explained by metabolic abnormalities and past severe immunosuppression and requires further evaluation. PMID- 28362070 TI - Awareness and perceived fairness of Option B+ in Malawi: A population-level perspective AB - INTRODUCTION: Policies for rationing antiretroviral therapy (ART) have been subject to on-going ethical debates. Introduced in Malawi in 2011, Option B+ prioritized HIV-positive pregnant women for lifelong ART regardless of the underlying state of their immune system, shifting the logic of allocation away from medical eligibility. Despite the rapid expansion of this policy, we know little about how it has been understood and interpreted by the people it affects. METHODS: We assessed awareness and perceived fairness of the prioritization system for ART among a population-based sample of young women (n = 1440) and their partners (n = 574) in southern Malawi. We use a card-sort technique to elicit understandings of who gets ART under Option B+ and who should be prioritized, and we compare perceptions to actual ART policy using sequence analysis and optimal matching. We then use ordered logistic regression to identify the factors associated with policy awareness. RESULTS: In 2015, only 30.7% of women and 21.1% of male partners understood how ART was being distributed. There was widespread confusion around whether otherwise healthy HIV positive pregnant women could access ART under Option B + . Nonetheless, more young adults thought that the fairest policy should prioritize such women than believed the actual policy did. Women who were older, more educated or had recently engaged with the health system through antenatal care or ART had more accurate understandings of Option B + . Among men, policy awareness was lower, and was patterned only by education. CONCLUSION: Although most respondents were unaware that Option B+ afforded ART access to healthy-pregnant women, Malawians support the prioritization of pregnant women. Countries adopting Option B+ or other new ART policies such as universal test-and-treat should communicate the policies and their rationales to the public - such transparency would be more consistent with a fair and ethical process and could additionally serve to clarify confusion and enhance retention.. PMID- 28362067 TI - Personal contact with HIV-positive persons is associated with reduced HIV-related stigma: cross-sectional analysis of general population surveys from 26 countries in sub-Saharan Africa. AB - INTRODUCTION: HIV-related stigma hampers treatment and prevention efforts worldwide. Effective interventions to counter HIV-related stigma are greatly needed. Although the "contact hypothesis" suggests that personal contact with persons living with HIV (PLHIV) may reduce stigmatizing attitudes in the general population, empirical evidence in support of this hypothesis is lacking. Our aim was to estimate the association between personal contact with PLHIV and HIV related stigma among the general population of sub-Saharan Africa. METHODS: Social distance and anticipated stigma were operationalized using standard HIV related stigma questions contained in the Demographic and Health Surveys and AIDS Indicator Surveys of 26 African countries between 2003 and 2008. We fitted multivariable logistic regression models with country-level fixed effects, specifying social distance as the dependent variable and personal contact with PLHIV as the primary explanatory variable of interest. RESULTS: We analyzed data from 206,717 women and 91,549 men living in 26 sub-Saharan African countries. We estimated a statistically significant negative association between personal contact with PLHIV and desires for social distance (adjusted odds ratio [AOR] = 0.80; p < 0.001; 95% Confidence Interval [CI], 0.73-0.88). In a sensitivity analysis, a similar finding was obtained with a model that used a community-level variable for personal contact with PLHIV (AOR = 0.92; p < 0.001; 95% CI, 0.89 0.95). CONCLUSION: Personal contact with PLHIV was associated with reduced desires for social distance among the general population of sub-Saharan Africa. More contact interventions should be developed and tested to reduce the stigma of HIV. PMID- 28362071 TI - Differential effects of antiretrovirals on microbial translocation and gut microbiota composition of HIV-infected patients. AB - INTRODUCTION: Increased bacterial translocation and alterations to gut microbiota composition have been described in HIV infection and contribute to immune activation and inflammation. These effects persist despite combined antiretroviral therapy (cART). However, the contribution of different cART combinations has not yet been investigated. The aim of this study was to analyse the long-term effects of different combinations of cART on bacterial translocation and gut microbiota composition in HIV-infected patients. METHODS: We carried out a cross-sectional study of 45 HIV-infected patients on cART, classified as nucleoside reverse transcriptase inhibitors (NRTIs)+ protease inhibitors (PIs) (n = 15), NRTIs+ non-nucleoside reverse transcriptase inhibitors (NNRTIs) (n = 22), and NRTIs+ integrase strand transfer inhibitors (INSTIs) (n = 8). Untreated HIV-infected patients (n = 5) and non-infected volunteers (n = 21) were also included. Soluble markers of bacterial translocation and inflammation were measured and gut microbiota composition was analysed using 16S rDNA pyrosequencing (Illumina MiSeq). RESULTS: The NRTIs+INSTIs regimen was associated with levels of systemic inflammation that were similar to uninfected controls. The reduction in faecal bacterial diversity induced by HIV infection was also restored by this regimen. HIV infection was more closely related to changes in lower taxonomic units and diversity rather than at the phylum level. The NRTIs+PIs regimen showed the highest reduction in bacterial species, whereas NRTIs+INSTIs induced a minor loss of bacterial species and a significant increase in others. CONCLUSION: Our study demonstrated that INSTI-based ART was associated with levels of systemic inflammation and microbial diversity similar to that of uninfected controls. The role of INSTIs other than raltegravir needs to be further investigated. Patients on the NRTIs+PIs regimen presented the highest reduction in bacterial species compared with other antiretrovirals and naive patients. Thus, different cART regimens are associated with diverse profiles in gut microbiota composition. Longitudinal and functional studies are needed to better understand these findings. PMID- 28362072 TI - Postnatal HIV transmission in breastfed infants of HIV-infected women on ART: a systematic review and meta-analysis. AB - INTRODUCTION: To systematically review the literature on mother-to-child transmission in breastfed infants whose mothers received antiretroviral therapy and support the process of updating the World Health Organization infant feeding guidelines in the context of HIV and ART. METHODS: We reviewed experimental and observational studies; exposure was maternal HIV antiretroviral therapy (and duration) and infant feeding modality; outcomes were overall and postnatal HIV transmission rates in the infant at 6, 9, 12 and 18 months. English literature from 2005 to 2015 was systematically searched in multiple electronic databases. Papers were analysed by narrative synthesis; data were pooled in random effects meta-analyses. Postnatal transmission was assessed from four to six weeks of life. Study quality was assessed using a modified Newcastle-Ottawa Scale (NOS) and GRADE. RESULTS: Eleven studies were identified, from 1439 citations and review of 72 abstracts. Heterogeneity in study methodology and pooled estimates was considerable. Overall pooled transmission rates at 6 months for breastfed infants with mothers on antiretroviral treatment (ART) was 3.54% (95% CI: 1.15 5.93%) and at 12 months 4.23% (95% CI: 2.97-5.49%). Postnatal transmission rates were 1.08 (95% CI: 0.32-1.85) at six and 2.93 (95% CI: 0.68-5.18) at 12 months. ART was mostly provided for PMTCT only and did not continue beyond six months postpartum. No study provided data on mixed feeding and transmission risk. CONCLUSION: There is evidence of substantially reduced postnatal HIV transmission risk under the cover of maternal ART. However, transmission risk increased once PMTCT ART stopped at six months, which supports the current World Health Organization recommendations of life-long ART for all. PMID- 28362074 TI - Validity and reliability of submaximal fitness tests based on perceptual variables. AB - BACKGROUND: Few studies examined the validity of fitness tests based on perception scales. The field-based fitness tests batteries are composed by maximal tests and currently, a battery of submaximal tests does not exist. METHODS: Seventeen physically active male participants (age 40.5+/-10.7 years) performed the Multistage Fitness Test, the Crunch Test, the Push-Up Test and a Trunk Flexion Test with a submaximal protocol based on perceptual variables that were defined as non-validated submaximal. The mentioned tests were repeated three times to assess their reliability. The participants also performed four validated maximal tests comprising a velocity dependent ramp test on the treadmill, the Crunch Test, the Push-Up Test, and Sit-and-Reach Test. The submaximal tests were correlated to the maximal ones to assess their criterion validity. RESULTS: All the submaximal tests showed an ICC superior to 0.8 apart from the submaximal Crunch Test. The correlation between Maximal Treadmill Test and submaximal Multistage Fitness Test was 0.77. The correlation between Sit-and-Reach Test and submaximal Trunk Flexion Test was 0.71. Correlations equal to 0.66 and 0.60 were found between the maximal and submaximal Crunch Test and Push-Up Test respectively. CONCLUSIONS: The use of submaximal tests based on a fixed value of perception can represent a suitable tool to assess cardiorespiratory fitness and flexibility because of their correlation with the corresponding maximal evaluation tests and because of their reliability. On the contrary, muscular endurance capacity seems not to be assessable in the same manner. PMID- 28362073 TI - Feasibility and acceptability of HIV self-testing among pre-exposure prophylaxis users in Kenya. AB - INTRODUCTION: HIV testing is key to the delivery of pre-exposure prophylaxis (PrEP): testing HIV-uninfected at-risk persons is the first step for PrEP initiation and ongoing HIV testing is an essential part of PrEP delivery. Thus, novel and cost-effective HIV-testing approaches to streamline delivery of PrEP are urgently needed. Within a demonstration project of PrEP for HIV prevention among high-risk HIV serodiscordant couples in Kenya (the Partners Demonstration Project), we conducted a pilot evaluation of HIV self-testing. METHODS: Clinic visits were scheduled quarterly and included in-clinic HIV testing using fingerstick rapid HIV tests and refills of PrEP prescriptions. HIV oral fluid self-test kits were provided for participants to use in the two-month interval between scheduled quarterly clinic visits. Acceptability of HIV self-testing was assessed using both quantitative and qualitative methods. RESULTS: We found that 222 of 226 (98%) HIV-uninfected persons who were offered accepted self-testing. Nearly all (96.8%) reported that using the self-testing kit was easy. More than half (54.5%) reportedly did not share the HIV results from self-testing with anyone and almost all (98.7%) the participants did not share the HIV self-testing kits with anyone. Many participants reported that HIV self-testing was empowering and reduced anxiety associated with waiting between clinic HIV tests. CONCLUSION: HIV self-testing was highly acceptable and may therefore be a feasible strategy to efficiently permit routine HIV testing between PrEP refills. PMID- 28362075 TI - Association between the number of daily steps and the cardiovascular risk factors in basic education teachers. AB - BACKGROUND: Regular physical activity is suggested as an important non pharmacological mechanism to prevent cardiovascular diseases. Thus, the objective the present study was to verify the association of the number of daily steps with cardiovascular risk factors in basic education teachers and analyze the suitability of the cutoff of 10,000 steps/day as a predictor for the main risk factors in this sample. METHODS: Two hundred teachers (43.2+/-10.2 years) of basic education were assessed in Vicosa, Brazil. It was analyzed the number of daily steps, Body Mass Index (BMI), waist circumference (WC), waist-hip ratio, body fat percentage (%BF), systolic and diastolic blood pressure, glucose, total cholesterol, high-density (HDL-C) and low-density lipoprotein cholesterol, non HDL cholesterol and triglycerides. RESULTS: The group which exceeded the 10,000 steps had lower BMI, BF% and triglycerides (P<0.05) compared to those who did not reach this value. A weak inverse correlation between the number of steps and BMI, WC and %BF was observed. Overweight and dyslipidemia were significantly associated with low number of steps (<10,000). The average number of daily steps was predictive of major cardiovascular risk factors, with the best cutoff near the 8000 steps for the presented results. CONCLUSIONS: Basic education teachers who exceed the 10,000 daily steps have a lower BMI, %BF and triglycerides. On the other hand, teachers who do not overcome show a greater chance of overweight and dyslipidemia. The cutoff point of 8000 steps/day in this sample had an appropriate value in the prediction of the risk factors analyzed. PMID- 28362076 TI - A systematic review of preclinical studies on therapeutic potential of stem cells or stem cells products in peritoneal fibrosis. AB - INTRODUCTION: Peritoneal fibrosis remains a serious complication of long-term peritoneal dialysis. Stem cell therapy is an innovative field of scientific investigation with potential for clinical application. Here, we systematically reviewed the studies to determine whether stem cell based therapy could improve the peritoneal fibrosis in experimental models of peritoneal fibrosis. EVIDENCE ACQUISITION: Our systematic search of PubMed, Scopus, Web of Science, and Cochrane Library yield 5219 article. After screening for eligibility, in vivo, experimental, interventional studies using stem cells in animal models of peritoneal fibrosis; 11 articles were included. The studies underwent comprehensive review, quality assessment, and data extraction. EVIDENCE SYNTHESIS: Mesenchymal stem cells were the most used type (90.9%) originated either from bone marrow (70%), adipose tissue (20%), or umbilical cord (10%). In 90.9% of studies, stem cells were injected after peritoneal insult and 63.6% of studies used the intraperitoneal injection route. Eight studies met the >=50% of criteria indicated by ARRIVE recommendation. Information regarding the nature of ethical review permissions, species, strain and gender, dose, route and duration of treatment, was stated by all studies; 81.8% of the studies reported the number of animals in each group. Adverse events were reported in one study. Improvement in histological parameters including attenuation of submesothelial thickness (100%), inflammation (62.5%), angiogenesis (60%), and fibrosis (85.7%) was reported after stem cell therapy. Peritoneal permeability function by assessing the ultrafiltration, glucose transport and solute permeability was improved in all studies. Stem cell treatment resulted in mesothelial recovery in 100% of studies. CONCLUSIONS: In preclinical studies, the use of stem cells is associated with improved peritoneal fibrosis. This may provide an important foundation to support future translational clinical research using stem cell therapy to repair the injured peritoneum and modulate immune responses in PD patients. PMID- 28362077 TI - Lactosylated Glycogen Nanoparticles for Targeting Prostate Cancer Cells. AB - Glyconanoparticles that exhibit multivalent binding to lectins are desirable for molecular recognition and therapeutic applications. Herein we explore the use of glycogen nanoparticles as a biosourced glycoscaffold for engineering multivalent glyconanoparticles. Glycogen nanoparticles, a naturally occurring highly branched polymer of glucose, was functionalized with lactose, achieved through copper(I) catalyzed alkyne-azide cycloaddition chemistry, for targeted interaction with lectins ex situ and on prostate cancer cells. The lactosylated glycogen, which contains terminal beta-galactoside moieties, is termed galacto-glycogen (GG), and is found to interact strongly with peanut agglutinin (PNA), a beta-galactoside specific lectin, as observed by optical waveguide lightmode spectroscopy, dynamic light scattering, and quartz crystal microbalance measurements. The GG nanoparticles exhibit multivalent binding to PNA with an affinity constant of 3.4 * 105 M-1, and the GG-PNA complex cannot be displaced by lactose, demonstrating the competitive binding of GG to the lectin. These GG nanoparticles were tested for association with prostate cancer cell membranes in vitro, where the particles exhibited a high affinity for the membrane, as observed from flow cytometry and confocal microscopy. This is inferred to result from specific extracellular galectin-1 targeting. Furthermore, the GG nanoparticles induce aggregation between prostate cancer cells. Our results highlight a strategy for engineering a biosourced polysaccharide with surface moieties that exhibit strong multivalent interactions with lectins, and targeted interaction with prostate cancer cells. PMID- 28362078 TI - The Anxiolytic Etifoxine Binds to TSPO Ro5-4864 Binding Site with Long Residence Time Showing a High Neurosteroidogenic Activity. AB - The low binding affinity of the approved anxiolytic drug etifoxine (Stresam) at the steroidogenic 18 kDa translocator protein (TSPO) has questioned the specific contribution of this protein in mediating the etifoxine neurosteroidogenic efficacy. Residence time (RT) at the binding site of the classical TSPO ligand PK11195 is emerging as a relevant neurosteroidogenic efficacy measure rather than the binding affinity. Here etifoxine was evaluated for (i) the in vitro neurosteroidogenic activity in comparison to poorly neurosteroidogenic reference TSPO ligands (PK11195 and Ro5-4864) and (ii) the affinity and RT at [3H]PK11195 and [3H]Ro5-4864 binding sites in rat kidney membranes. Etifoxine shows (i) high neurosteroidogenic efficacy and (ii) low affinity/short RT at the [3H]PK11195 site and low affinity/long RT at the [3H]Ro5-4864 site, at which etifoxine competitively bound. These findings suggest that the long RT of etifoxine at the Ro5-4864 binding site could account for its high neurosteroidogenic efficacy. PMID- 28362079 TI - Role of Defects and Surface States in the Carrier Transport and Nonlinearity of the Diode Characteristics in PbS/ZnO Quantum Dot Solar Cells. AB - The roles of bulk surface states and interfacial defects are probed experimentally using a combination of current-voltage, capacitance-voltage, and impedance measurements. The critical importance of the quality of both the film and interfaces is evident in current-voltage measurements where shunting and interface states result in large dark currents and the subsequent loss of Jsc. These properties are shown to be critically related to the nature and role of the PbS QD interface with the (nominally) ohmic gold contact. Specifically, the nonideality of this interface results in the formation of an electric field and therefore a Schottky barrier that opposes the transport of carriers across the conventional ZnO-PbS CQD system. Nonidealities in the structure and absorber layer are also reflected in nonmonotonic behavior and dispersion in C-V measurements with trapping processes on the CQD surfaces, and the ZnO/PbS and PbS/Au interfaces also affecting the carrier dynamics, which is reflected in the response time of these systems under different biases. PMID- 28362080 TI - Polymer Composite with Improved Thermal Conductivity by Constructing a Hierarchically Ordered Three-Dimensional Interconnected Network of BN. AB - In this work, we report a fabrication of epoxy resin/ordered three-dimensional boron nitride (3D-BN) network composites through combination of ice-templating self-assembly and infiltration methods. The polymer composites possess much higher thermal conductivity up to 4.42 W m-1 K-1 at relatively low loading 34 vol % than that of random distribution composites (1.81 W m-1 K-1 for epoxy/random 3D BN composites, 1.16 W m-1 K-1 for epoxy/random BN composites) and exhibit a high glass transition temperature (178.9-229.2 degrees C) and dimensional stability (22.7 ppm/K). We attribute the increased thermal conductivity to the unique oriented 3D-BN thermally conducive network, in which the much higher thermal conductivity along the in-plane direction of BN microplatelets is most useful. This study paves the way for thermally conductive polymer composites used as thermal interface materials for next-generation electronic packaging and 3D integration circuits. PMID- 28362082 TI - Pore-Scale Geochemical Reactivity Associated with CO2 Storage: New Frontiers at the Fluid-Solid Interface. AB - The reactivity of carbonate and silicate minerals is at the heart of porosity and pore geometry changes in rocks injected with CO2, which ultimately control the evolution of flow and transport properties of fluids in porous and/or fractured geological reservoirs. Modeling the dynamics of CO2-water-rock interactions is challenging because of the resulting large geochemical disequilibrium, the reservoir heterogeneities, and the large space and time scales involved in the processes. In particular, there is a lack of information about how the macroscopic properties of a reservoir, e.g., the permeability, will evolve as a result of geochemical reactions at the molecular scale. Addressing this point requires a fundamental understanding of how the microstructures influence the macroscopic properties of rocks. The pore scale, which ranges from a few nanometers to centimeters, has stood out as an essential scale of observation of geochemical processes in rocks. Transport or surface reactivity limitations due to the pore space architecture, for instance, are best described at the pore scale itself. It can be also considered as a mesoscale for aggregating and increasing the gain of fundamental understanding of microscopic interfacial processes. Here we focus on the potential application of a combination of physicochemical measurements coupled with nanoscale and microscale imaging techniques during laboratory experiments to improve our understanding of the physicochemical mechanisms that occur at the fluid-solid interface and the dynamics of the coupling between the geochemical reactions and flow and transport modifications at the pore scale. Imaging techniques such as atomic force microscopy, vertical scanning interferometry, focused ion beam transmission electron microscopy, and X-ray microtomography, are ideal for investigating the reactivity dynamics of these complex materials. Minerals and mineral assemblages, i.e., rocks, exhibit heterogeneous and anisotropic reactivity, which challenges the continuum description of porous media and assumptions required for reactive transport modeling at larger scales. The conventional approach, which consists of developing dissolution rate laws normalized to the surface area, should be revisited to account for both the anisotropic crystallographic structure of minerals and the transport of chemical species near the interface, which are responsible for the intrinsic evolution of the mineral dissolution rate as the reaction progresses. In addition, the crystal morphology and the mineral assemblage composition, texture, and structural heterogeneities are crucial in determining whether the permeability and transport properties of the reservoir will be altered drastically or maintain the sealing properties required to ensure the safe sequestration of CO2 for hundreds of years. Investigating the transport properties in nanometer- to micrometer-thick amorphous Si-rich surface layers (ASSLs), which develop at the fluid-mineral interface in silicates, provides future direction, as ASSLs may prevent contact between the dissolving solids and the pore fluid, potentially inhibiting the dissolution/carbonation process. Equally, at a larger scale, the growth of micrometer- to millimeter-thick alteration layers, which result from the difference in reactivity between silicates and carbonates, slows the transport in the vicinity of the fluid-solid interface in polymineralic rocks, thus limiting the global reactivity of the carbonate matrix. In contrast, in pure limestone, the global reactivity of the monomineralic rock decreases because the flow localization promotes the local reactivity within the forming channels, thus enhancing permeability changes compared with more homogeneous dissolution of the rock matrix. These results indicate that the transformation of the rock matrix should control the evolution of the transport properties in reservoirs injected with CO2 to the same extent as the intrinsic chemical reactivity of the minerals and the reservoir hydrodynamics. This process, which is currently not captured by large-scale modeling of reactive transport, should benefit from the increasing capabilities of noninvasive and nondestructive characterization tools for pore-scale processes, ultimately constraining reactive transport modeling and improving the reliability of predictions. PMID- 28362081 TI - Photosensitized H2 Production Using a Zinc Porphyrin-Substituted Protein, Platinum Nanoparticles, and Ascorbate with No Electron Relay: Participation of Good's Buffers. AB - Development of efficient light-driven splitting of water, 2H2O -> 2H2 + O2, often attempts to optimize photosensitization of the reductive and oxidative half reactions individually. Numerous homogeneous and heterogeneous systems have been developed for photochemical stimulation of the reductive half reaction, 2H+ + 2e- -> H2. These systems generally consist of various combinations of a H+ reduction catalyst, a photosensitizer (PS), and a "sacrificial" electron donor. Zinc(II) porphyrins (ZnPs) have frequently been used as PSs for H2 generation, but they are subject to various self-quenching processes in aqueous solutions. Colloidal platinum in nanoparticle form (Pt NP) is a classical H+ reduction catalyst using ZnP photosensitizers, but efficient photosensitized H2 generation requires an electron relay molecule between ZnP and Pt NP. The present report describes an aqueous system for visible (white) light-sensitized generation of H2 using a protein-embedded Zn(II)-protoporphyrin IX as PS and Pt NP as H+ reduction catalyst without an added electron relay. This system operated efficiently in piperazino- and morpholino-alkylsulfonic acid (Good's buffers), which served as sacrificial electron donors. The system also required ascorbate at relatively modest concentrations, which stabilized the Zn(II)-protoporphyrin IX against photodegradation. In the absence of an electron relay molecule, the photosensitized H2 generation must involve formation of at least a transient complex between a protein-embedded Zn(II)-protoporphyrin IX species and Pt NP. PMID- 28362084 TI - Fluorometric Biosniffer Camera "Sniff-Cam" for Direct Imaging of Gaseous Ethanol in Breath and Transdermal Vapor. AB - Various volatile organic compounds can be found in human transpiration, breath and body odor. In this paper, a novel two-dimensional fluorometric imaging system, known as a "sniffer-cam" for ethanol vapor released from human breath and palm skin was constructed and validated. This imaging system measures ethanol vapor concentrations as intensities of fluorescence through an enzymatic reaction induced by alcohol dehydrogenase (ADH). The imaging system consisted of multiple ultraviolet light emitting diode (UV-LED) excitation sheet, an ADH enzyme immobilized mesh substrate and a high-sensitive CCD camera. This imaging system uses ADH for recognition of ethanol vapor. It measures ethanol vapor by measuring fluorescence of nicotinamide adenine dinucleotide (NADH), which is produced by an enzymatic reaction on the mesh. This NADH fluorometric imaging system achieved the two-dimensional real-time imaging of ethanol vapor distribution (0.5-200 ppm). The system showed rapid and accurate responses and a visible measurement, which could lead to an analysis of metabolism function at real time in the near future. PMID- 28362083 TI - Ultrasensitive and Selective Sensing of Selenium Using Nitrogen-Rich Ligand Interfaced Carbon Quantum Dots. AB - This work reports a label-free, ultrasensitive, and selective optical chemosensory system for trace level detection of selenite (SeO32-), the most toxic form of selenium, in water. The probe, i.e., carbon quantum dots (CQDs), is designed from citric acid by means of pyrolysis and is interfaced with a newly synthesized nitrogen-rich ligand to create a selective sensor platform (functionalized CQDs, fCQDs) for selenite in a water matrix. Spectral (NMR, UV vis, photoluminescence, Raman, and Fourier transform infrared analyses) and structural (high-resolution transmission electron microscopy) characteristics of the designed new probe were investigated. The developed sensor exhibits high sensitivity (limit of detection = 0.1 ppb), a wide detection range (0.1-1000 ppb range, relative standard deviation: 3.2%), and high selectivity even in the presence of commonly interfering ions reported to date, including Cl-, NO3-, NO2 , Br-, F-, As(V), As(III), Cu2+, Pb2+, Cd2+, Zn2+, Sr2+, Rb2+, Na+, Ca2+, Cs+, K+, Mg2+, Li+, NH4+, Co2+, etc. The observed selectivity is due to designed ligand characteristics in terms of strong Se-N chemistry. Ultrafast spectroscopic analysis of the fCQDs in the absence and presence of selenite was studied to understand the sensing mechanism. The sensor was successfully exemplified for real water samples and exhibits comparative performance to conventional ion channel chromatography as well as flame atomic absorption spectroscopy for selenite analysis. The promising results pave ways for realization of a field deployable device based upon a developed probe for selenite quantification in water. PMID- 28362085 TI - Wetting Transition of Condensed Droplets on Nanostructured Superhydrophobic Surfaces: Coordination of Surface Properties and Condensing Conditions. AB - Nanostructured superhydrophobic surfaces have been actively explored to promote favorable droplet dynamics for a wide range of technological applications. However, the tendency of condensed droplets to form as pinned states greatly limits their applicability in enhancing condensation heat transfer efficiency. Despite recent progresses, the understanding of physical mechanisms governing the wetting transition of condensed droplets is still lacking. In this work, a nanostructured superhydrophobic surface with tapered nanogaps is fabricated to demonstrate the coordination of surface wetting property, topography, and the condensing condition on the wetting state and dynamic behavior of condensed droplets. Combining the environmental scanning electron microscopy and optical visualization methods, we systematically show the morphology of nucleated droplets in nanostructures and the droplet dynamic evolution throughout the growth stages, which provides the direct evidence of condensing condition-induced droplet wetting transition. When the surface subcooling is smaller than 0.3 K, the droplets formed as the Cassie-Baxter state, followed by coalescence-induced droplet jumping. With the increase of surface subcooling up to 0.6 K, however, droplet formation occurs randomly inside nanogaps, resulting in the loss of superhydrophobicity. These new observations along with the new insights about the coordination of surface properties and condensing conditions on droplet wetting transition are useful for guiding the development of novel surfaces for improving droplet removal and phase-change heat transfer. PMID- 28362087 TI - Elucidating the Structures of the Low- and High-pH Mo(V) Species in Respiratory Nitrate Reductase: A Combined EPR, 14,15N HYSCORE, and DFT Study. AB - Respiratory nitrate reductases (Nars), members of the prokaryotic Mo/W-bis Pyranopterin Guanosine dinucleotide (Mo/W-bisPGD) enzyme superfamily, are key players in nitrate respiration, a major bioenergetic pathway widely used by microorganisms to cope with the absence of dioxygen. The two-electron reduction of nitrate to nitrite takes place at their active site, where the molybdenum ion cycles between Mo(VI) and Mo(IV) states via a Mo(V) intermediate. The active site shows two distinct pH-dependent Mo(V) electron paramagnetic resonance (EPR) signals whose structure and catalytic relevance have long been debated. In this study, we use EPR and HYSCORE techniques to probe their nuclear environment in Escherichia coli Nar (EcNar). By using samples prepared at different pH and through different enrichment strategies in 98Mo and 15N nuclei, we demonstrate that each of the two Mo(V) species is coupled to a single nitrogen nucleus with similar quadrupole characteristics. Structure-based density functional theory calculations allow us to propose a molecular model of the low-pH Mo(V) species consistent with EPR spectroscopic data. Our results show that the metal ion is coordinated by a monodentate aspartate ligand and permit the assignment of the coupled nitrogen nuclei to the Ndelta of Asn52, a residue located ~3.9 A to the Mo atom in the crystal structures. This is confirmed by measurements on selectively 15N-Asn labeled EcNar. Further, we propose a Mo-O(H)...HN structure to account for the transfer of spin density onto the interacting nitrogen nucleus deduced from HYSCORE analysis. This work provides a foundation for monitoring the structure of the molybdenum active site in the presence of various substrates or inhibitors in Nars and other molybdenum enzymes. PMID- 28362088 TI - Potential Retinal Benefits of Dietary Polyphenols Based on Their Permeability across the Blood-Retinal Barrier. AB - Whether all dietary polyphenols nourish the eyes via oral supplementation is controversial. Given that passage of dietary polyphenols across the blood-retina barrier (BRB) is the precondition for polyphenols to exhibit ocular benefits, the BRB permeability of polyphenols was assessed in this study. Being common dietary polyphenols in fruits and vegetables, nonanthocyanin flavonoids, anthocyanins, and phenolic acids were investigated. BRB was simulated in vitro by using a differentiated retinal pigment epithelial cell monolayer cultivated on a Transwell culture system. Penetration rate was calculated by quantitatively analyzing the polyphenols in basolateral media. The BRB permeability of different polyphenols obviously (p < 0.05) differed, as follows: phenolic acids > nonanthocyanin flavonoids > anthocyanins. Glycosylation and methylation improved the BRB permeability of nonanthocyanin flavonoids and anthocyanins. However, instability and carbonylation at the C-4 position severely suppressed the BRB permeability of anthocyanins and nonanthocyanin flavonoids. Moreover, a new metabolite was discovered during penetration of anthocyanins into the BRB. However, hydrophilic phenolic acids exhibited better BRB permeability than hydrophobic ones. Data demonstrate that BRB permeability of polyphenols was determined based on structural characteristics, hydrophilicity, stability, and metabolic changes. PMID- 28362086 TI - Caging and Photoactivation in Single-Molecule Forster Resonance Energy Transfer Experiments. AB - Caged organic fluorophores are established tools for localization-based super resolution imaging. Their use relies on reversible deactivation of standard organic fluorophores by chemical reduction or commercially available caged dyes with ON switching of the fluorescent signal by ultraviolet (UV) light. Here, we establish caging of cyanine fluorophores and caged rhodamine dyes, i.e., chemical deactivation of fluorescence, for single-molecule Forster resonance energy transfer (smFRET) experiments with freely diffusing molecules. They allow temporal separation and sorting of multiple intramolecular donor-acceptor pairs during solution-based smFRET. We use this "caged FRET" methodology for the study of complex biochemical species such as multisubunit proteins or nucleic acids containing more than two fluorescent labels. Proof-of-principle experiments and a characterization of the uncaging process in the confocal volume are presented. These reveal that chemical caging and UV reactivation allow temporal uncoupling of convoluted fluorescence signals from, e.g., multiple spectrally similar donor or acceptor molecules on nucleic acids. We also use caging without UV reactivation to remove unwanted overlabeled species in experiments with the homotrimeric membrane transporter BetP. We finally outline further possible applications of the caged FRET methodology, such as the study of weak biochemical interactions, which are otherwise impossible with diffusion-based smFRET techniques because of the required low concentrations of fluorescently labeled biomolecules. PMID- 28362089 TI - New Phenol Benzoate Cyanine Picolinium Salt Photoacid Excited-State Proton Transfer. AB - Steady-state and time-resolved fluorescence techniques were employed to study the excited-state proton transfer (ESPT) to water and D2O of a new photoacid, phenol benzoate cyanine picolinium salt (BCyP). We found that the ground-state pKa is about 6.5, whereas the excited-state pKa* is about -4.5. The ESPT rate constant, kPT, to water is ~0.5 * 1012s-1 (tauPT ~ 2 ps) and in D2O the rate is 0.33 * 1012 s-1. We determined that the BCyP photoacid belongs to the third regime of photoacids, the solvent-controlled regime. PMID- 28362091 TI - Synthesis of Cyano-Containing Phenanthridine Derivatives via Catalyst-, Base-, and Oxidant-Free Direct Cyanoalkylarylation of Isocyanides. AB - An efficient catalyst-, base-, and oxidant-free direct cyanoalkylarylation of isocyanides with AIBN has been developed under mild conditions. This strategy provides an elusive and rapid access to a wide range of cyano-containing phenanthridine derivatives in good yields via a one-pot alkylation/cyclization radical-cascade process. The mild reaction conditions together with no need of any catalyst, base, or oxidant make this protocol environmentally benign and practical. PMID- 28362090 TI - Effects of alpha-Galactooligosaccharides from Chickpeas on High-Fat-Diet-Induced Metabolic Syndrome in Mice. AB - The gut microbiota has the ability to modulate host energy homeostasis, which may regulate metabolic disorders. Functional oligosaccharide may positively regulate the intestinal microbiota. Therefore, effects of alpha-galactooligosaccharides (alpha-GOS) from chickpea on high-fat-diet (HFD)-induced metabolic syndrome and gut bacterial dysbiosis were investigated. After 6 weeks of intervention, HFD led to significant increases in levels of blood glucose, total cholesterol, triglyceride, glycated serum protein, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol of mice compared to normal-chow-fed mice. Meanwhile, all of the alpha-GOS-treated groups significantly decreased above parameters compared to the HFD group. HFD could significantly decrease the content of all bacteria, especially Bacteroides (9.82 +/- 0.09 versus 10.3 +/- 0.10; p < 0.05) and Lactobacillus (6.67 +/- 0.18 versus 7.30 +/- 0.24; p < 0.05), and a decrease in the production of short-chain fatty acids was also observed. Treatment with alpha-GOS significantly increased the number of Bifidobacterium (6.07 +/- 0.23 of the low-dose treatment versus 5.65 +/- 0.20 of the HFD group) and Lactobacillus (7.22 +/- 0.16 of the low-dose treatment). It also significantly promoted the secretion of propionic and butyric acids. These results indicate that alpha-GOS from chickpeas may affect the metabolic disorders and gut bacterial ecosystem in a positive way. PMID- 28362092 TI - Spiro Metalla-aromatics of Pd, Pt, and Rh: Synthesis and Characterization. AB - Since the concept of aromaticity represents one of the most fundamental principles in chemistry, the search for unprecedented and exciting aromatic systems, therefore, continues to drive research in this area. Herein we report the synthesis and characterization of spiro metalla-aromatics, in which the transition metal (Pd, Pt, or Rh) is the spiro atom, that cross-conjugates two aromatic five-membered metallacycles. These spiro metalla-aromatics tend to take square planar geometries, with the dihedral angle being influenced by the steric repulsion between the alpha-positioned substituents. Rationalized and classified via both experimental measurements (X-ray structural analysis, NMR spectroscopy, XPS, etc.) and theoretical analysis (DFT calculation, ISE, AICD, NICS, and CMOs), all these fundamental observations extend the concept of aromaticity and organometallic chemistry. PMID- 28362094 TI - Extraction, Processing, and Storage Effects on Curcuminoids and Oleoresin Yields from Curcuma longa L. Grown in Jamaica. PMID- 28362093 TI - Selective and Robust Stabilization of Triplex DNA Structures Using Cationic Comb type Copolymers. AB - DNA sequences capable of forming triplexes induce DNA double-strand breaks that have attracted attention in genome editing technologies (e.g., CRISPR/Cas9 system, TALEN, and ZFN). Therefore, novel functional tools that stabilize triplex DNA structures must be further investigated to spark renewed interest. In this study, we investigated the unique character of cationic comb-type copolymers for the selective stabilization of triplex DNA. The melting temperature (Tm) of triplex DNA increased from 24.5 to 73.0 degrees C (DeltaTm = 48.5 degrees C) by the addition of poly(allylamine)-graft-dextran (PAA-g-Dex) under physiological conditions (at pH 7.0), while PAA-g-Dex did not stabilize but rather destabilized the DNA duplex. On the other hand, poly(l-lysine)-graft-dextran (PLL-g-Dex) stabilized both the duplex and triplex structures at pH 7.0. Thermodynamic parameters evaluated by isothermal titration calorimetry (ITC) revealed that the binding constant (Ka) for the intermolecular triplex formation in the presence of PAA-g-Dex was 1.1 * 109 M-1 at 25 degrees C which is more than 10 times larger than that in the presence of PLL-g-Dex (8.6 * 107 M-1). Stabilizing activity and selectivity of cationic copolymers toward DNA assemblies were successfully controlled by selecting appropriate backbone structures of the copolymer. Various functional molecules that stabilize DNA duplexes have been developed and used in biological research. However, there are few cationic polymers that stabilize triplex DNA selectively. This study indicates that PAA-g-Dex has great potential to regulate the biological activities of triplex DNA. PMID- 28362095 TI - Correction to "Transition-Metal-Free Alkynylation of 2-Oxindoles through Radical Radical Coupling". PMID- 28362096 TI - Ultrahigh-Capacity Lithium-Oxygen Batteries Enabled by Dry-Pressed Holey Graphene Air Cathodes. AB - Lithium-oxygen (Li-O2) batteries have the highest theoretical energy density of all the Li-based energy storage systems, but many challenges prevent them from practical use. A major obstacle is the sluggish performance of the air cathode, where both oxygen reduction (discharge) and oxygen evolution (charge) reactions occur. Recently, there have been significant advances in the development of graphene-based air cathode materials with a large surface area and catalytically active for both oxygen reduction and evolution reactions, especially with additional catalysts or dopants. However, most studies reported so far have examined air cathodes with a limited areal mass loading rarely exceeding 1 mg/cm2. Despite the high gravimetric capacity values achieved, the actual (areal) capacities of those batteries were far from sufficient for practical applications. Here, we present the fabrication, performance, and mechanistic investigations of high-mass-loading (up to 10 mg/cm2) graphene-based air electrodes for high-performance Li-O2 batteries. Such air electrodes could be easily prepared within minutes under solvent-free and binder-free conditions by compression-molding holey graphene materials because of their unique dry compressibility associated with in-plane holes on the graphene sheet. Li-O2 batteries with high air cathode mass loadings thus prepared exhibited excellent gravimetric capacity as well as ultrahigh areal capacity (as high as ~40 mAh/cm2). The batteries were also cycled at a high curtailing areal capacity (2 mAh/cm2) and showed a better cycling stability for ultrathick cathodes than their thinner counterparts. Detailed post-mortem analyses of the electrodes clearly revealed the battery failure mechanisms under both primary and secondary modes, arising from the oxygen diffusion blockage and the catalytic site deactivation, respectively. These results strongly suggest that the dry-pressed holey graphene electrodes are a highly viable architectural platform for high-capacity, high performance air cathodes in Li-O2 batteries of practical significance. PMID- 28362097 TI - Infiltration of Solution-Processable Solid Electrolytes into Conventional Li-Ion Battery Electrodes for All-Solid-State Li-Ion Batteries. AB - Bulk-type all-solid-state lithium-ion batteries (ASLBs) have the potential to be superior to conventional lithium-ion batteries (LIBs) in terms of safety and energy density. Sulfide SE materials are key to the development of bulk-type ASLBs because of their high ionic conductivity (max of ~10-2 S cm-1) and deformability. However, the severe reactivity of sulfide materials toward common polar solvents and the particulate nature of these electrolytes pose serious complications for the wet-slurry process used to fabricate ASLB electrodes, such as the availability of solvent and polymeric binders and the formation of ionic contacts and networks. In this work, we report a new scalable fabrication protocol for ASLB electrodes using conventional composite LIB electrodes and homogeneous SE solutions (Li6PS5Cl (LPSCl) in ethanol or 0.4LiI-0.6Li4SnS4 in methanol). The liquefied LPSCl is infiltrated into the tortuous porous structures of LIB electrodes and solidified, providing intimate ionic contacts and favorable ionic percolation. The LPSCl-infiltrated LiCoO2 and graphite electrodes show high reversible capacities (141 and 364 mA h g-1) at 0.14 mA cm-2 (0.1 C) and 30 degrees C, which are not only superior to those for conventional dry-mixed and slurry-mixed ASLB electrodes but also comparable to those for liquid electrolyte cells. Good electrochemical performance of ASLBs employing the LPSCl-infiltrated LiCoO2 and graphite electrodes at 100 degrees C is also presented, highlighting the excellent thermal stability and safety of ASLBs. PMID- 28362098 TI - Visible Light as a Sole Requirement for Intramolecular C(sp3)-H Imination. AB - A novel, simple, and practical visible-light-mediated intramolecular alpha-C(sp3) H imination of tertiary aliphatic amines containing beta-O-aryl oximes leading to N-heterocycles has been developed. The reaction was performed well at rt with tolerance of some functional groups. Importantly, the selective C-H functionalization did not require added catalyst, oxidant, additive, acid, and base; visible light was the sole requirement. PMID- 28362099 TI - Palladium-Catalyzed Cleavage of alpha-Allenylic Aryl Ether toward Pyrazolemethylene-Substituted Phosphinyl Allenes and Their Transformations via Alkenyl C-P(O) Cleavage. AB - A palladium-catalyzed two-component coupling of allenylphosphine oxides with conjugated N-tosylhydrazones is revealed. For the first time, the cleavage of alpha-allenylic aryl ether toward pyrazolemethylene-substituted phosphinyl allenes enabled facile synthesis of combined motifs with pyrazole and allene. Moreover, the obtained adducts could be easily transformed to potential bioactive multifunctionalized phosphinates via a novel alkenyl C-P(O) cleavage. PMID- 28362100 TI - N-Heterocyclic Carbene Catalyzed 1,6-Conjugate Addition of Me3Si-CN to para Quinone Methides and Fuchsones: Access to alpha-Arylated Nitriles. AB - An organocatalytic approach toward alpha-arylated nitriles using N-heterocyclic carbene (NHC) as a catalyst is described. This protocol comprises an NHC catalyzed activation of Me3Si-CN followed by 1,6-conjugate addition of cyanide to para-quinone methides (p-QMs) and fuchsones leading to alpha-diaryl- and alpha triaryl nitriles in good to excellent yields. PMID- 28362101 TI - Reactivity of Ketyl and Acetyl Radicals from Direct Solar Actinic Photolysis of Aqueous Pyruvic Acid. AB - The variable composition of secondary organic aerosols (SOA) contributes to the large uncertainty for predicting radiative forcing. A better understanding of the reaction mechanisms leading to aerosol formation such as for the photochemical reaction of aqueous pyruvic acid (PA) at lambda >= 305 nm can contribute to constrain these uncertainties. Herein, the photochemistry of aqueous PA (5-300 mM) continuously sparged with air is re-examined in the laboratory under comparable irradiance at 38 degrees N at noon on a summer day. Several analytical methods are employed to monitor the time series of the reaction, including (1) the derivatization of carbonyl (C?O) functional groups with 2,4 dinitrophenylhydrazine (DNPH), (2) the separation of photoproducts by ultrahigh pressure liquid chromatography (UHPLC) and ion chromatography (IC) coupled to mass spectrometry (MS), (3) high resolution MS, (4) the assignment of 1H NMR and 13C gCOSY spectroscopic features, and (5) quantitative 1H NMR. The primary photoproducts are 2,3-dimethyltartaric acid and unstable 2-(1-carboxy-1 hydroxyethoxy)-2-methyl-3-oxobutanoic acid, a polyfunctional beta-ketocarboxylic acid with eight carbons (C8) that quickly decarboxylates into 2-hydroxy-2-((3 oxobutan-2-yl)oxy)propanoic acid. Kinetic isotope effect studies performed for the first time for this system reveal the existence of tunneling during the initial loss of PA. Thus, the KIEs support a mechanism initiated by photoinduced proton coupled electron transfer (PCET). Measured reaction rates at variable initial [PA]0 were used to calculate the sum of the quantum yields for the products, which displays a hyperbolic dependence: ?Phiproduct = 1.99 [PA]0/(113.2 + [PA]0). The fast photochemical loss of aqueous PA with an estimated lifetime of 21.7 min is interpreted as a significant atmospheric sink for this species. The complexity of these aqueous phase pathways indicates that the solar photochemistry of an abundant alpha-ketocarboxylic acid can activate chemical processes for SOA formation. PMID- 28362103 TI - Thermal Conductance in Cross-linked Polymers: Effects of Non-Bonding Interactions. AB - Weak interchain interactions have been considered to be a bottleneck for heat transfer in polymers, while covalent bonds are believed to give a high thermal conductivity to polymer chains. For this reason, cross-linkers have been explored as a means to enhance polymer thermal conductivity; however, results have been inconsistent. Some studies show an enhancement in the thermal conductivity for polymers upon cross-linking, while others show the opposite trend. In this work we study the mechanisms of heat transfer in cross-linked polymers in order to understand the reasons for these discrepancies, in particular examining the relative contributions of covalent (referred to here as "bonding") and nonbonding (e.g., van der Waals and electrostatic) interactions. Our results indicate cross linkers enhance thermal conductivity primarily when they are short in length and thereby bring polymer chains closer to each other, leading to increased interchain heat transfer by enhanced nonbonding interactions between the chains (nonbonding interactions being highly dependent on interchain distance). This suggests that enhanced nonbonding interactions, rather than thermal pathways through cross-linker covalent bonds, are the primary transport mechanism by which thermal conductivity is increased. We further illustrate this by showing that energy from THz acoustic waves travels significantly faster in polymers when nonbonding interactions are included versus when only covalent interactions are present. These results help to explain prior studies that measure differing trends in thermal conductivity for polymers upon cross-linking with various species. PMID- 28362104 TI - Is Geometric Frustration-Induced Disorder a Recipe for High Ionic Conductivity? AB - Ionic conductivity is ubiquitous to many industrially important applications such as fuel cells, batteries, sensors, and catalysis. Tunable conductivity in these systems is therefore key to their commercial viability. Here, we show that geometric frustration can be exploited as a vehicle for conductivity tuning. In particular, we imposed geometric frustration upon a prototypical system, CaF2, by ball milling it with BaF2, to create nanostructured Ba1-xCaxF2 solid solutions and increased its ionic conductivity by over 5 orders of magnitude. By mirroring each experiment with MD simulation, including "simulating synthesis", we reveal that geometric frustration confers, on a system at ambient temperature, structural and dynamical attributes that are typically associated with heating a material above its superionic transition temperature. These include structural disorder, excess volume, pseudovacancy arrays, and collective transport mechanisms; we show that the excess volume correlates with ionic conductivity for the Ba1-xCaxF2 system. We also present evidence that geometric frustration induced conductivity is a general phenomenon, which may help explain the high ionic conductivity in doped fluorite-structured oxides such as ceria and zirconia, with application for solid oxide fuel cells. A review on geometric frustration [ Nature 2015 , 521 , 303 ] remarks that classical crystallography is inadequate to describe systems with correlated disorder, but that correlated disorder has clear crystallographic signatures. Here, we identify two possible crystallographic signatures of geometric frustration: excess volume and correlated "snake-like" ionic transport; the latter infers correlated disorder. In particular, as one ion in the chain moves, all the other (correlated) ions in the chain move simultaneously. Critically, our simulations reveal snake-like chains, over 40 A in length, which indicates long-range correlation in our disordered systems. Similarly, collective transport in glassy materials is well documented [for example, J. Chem. Phys. 2013 , 138 , 12A538 ]. Possible crystallographic nomenclatures, to be used to describe long-range order in disordered systems, may include, for example, the shape, length, and branching of the "snake" arrays. Such characterizations may ultimately provide insight and differences between long-range order in disordered, amorphous, or liquid states and processes such as ionic conductivity, melting, and crystallization. PMID- 28362105 TI - Discrimination of Four Marine Biofilm-Forming Bacteria by LC-MS Metabolomics and Influence of Culture Parameters. AB - Most marine bacteria can form biofilms, and they are the main components of biofilms observed on marine surfaces. Biofilms constitute a widespread life strategy, as growing in such structures offers many important biological benefits. The molecular compounds expressed in biofilms and, more generally, the metabolomes of marine bacteria remain poorly studied. In this context, a nontargeted LC-MS metabolomics approach of marine biofilm-forming bacterial strains was developed. Four marine bacteria, Persicivirga (Nonlabens) mediterranea TC4 and TC7, Pseudoalteromonas lipolytica TC8, and Shewanella sp. TC11, were used as model organisms. The main objective was to search for some strain-specific bacterial metabolites and to determine how culture parameters (culture medium, growth phase, and mode of culture) may affect the cellular metabolism of each strain and thus the global interstrain metabolic discrimination. LC-MS profiling and statistical partial least-squares discriminant analyses showed that the four strains could be differentiated at the species level whatever the medium, the growth phase, or the mode of culture (planktonic vs biofilm). A MS/MS molecular network was subsequently built and allowed the identification of putative bacterial biomarkers. TC8 was discriminated by a series of ornithine lipids, while the P. mediterranea strains produced hydroxylated ornithine and glycine lipids. Among the P. mediterranea strains, TC7 extracts were distinguished by the occurrence of diamine derivatives, such as putrescine amides. PMID- 28362106 TI - Synthesis of a NbO Type Homochiral Cu(II) Metal-Organic Framework: Ferroelectric Behavior and Heterogeneous Catalysis of Three-Component Coupling and Pechmann Reactions. AB - A chiral tetracarboxylic acid ligand, H4L, incorporating the (S)-(+)-2 methylpiperazine moiety in its middle, solvothermally forms a homochiral Cu(II) framework, {[Cu2(L)(H2O)2].(4DMF)(4H2O)}n (LCu). It forms a non-interpenetrated structure consisting of [Cu2(COO)4] paddle-wheel secondary bonding units (SBUs) with NbO topology. Interestingly, the framework LCu exhibits excellent ferroelectric properties. It shows a remnant polarization (Pr) of ~3.5 MUC cm-2 and a coercive field (Ec) of ~12 kV cm-1 with a distinct electric hysteresis loop. Dielectric studies of LCu reveal almost frequency-independent behavior with a dielectric constant (epsilonr) of ~42 and a low dielectric loss (tan delta) of ~0.04 up to 106 Hz, for potential use in high-frequency applications. In addition, activated framework LCu' having uncoordinated metal sites acts as an efficient heterogeneous catalyst in the three-component coupling of amines, aldehydes, and alkynes, as well as in Pechmann reactions of phenols with beta ketoesters. PMID- 28362107 TI - Interactions between cell wall polysaccharides and polyphenols. AB - In plant-based food systems such as fruits, vegetables, and cereals, cell wall polysaccharides and polyphenols co-exist and commonly interact during processing and digestion. The noncovalent interactions between cell wall polysaccharides and polyphenols may greatly influence the physicochemical and nutritional properties of foods. The affinity of cell wall polysaccharides with polyphenols depends on both endogenous and exogenous factors. The endogenous factors include the structures, compositions, and concentrations of both polysaccharides and polyphenols, and the exogenous factors are the environmental conditions such as pH, temperature, ionic strength, and the presence of other components (e.g., protein). Diverse methods used to directly characterize the interactions include NMR spectroscopy, size-exclusion chromatography, confocal microscopy, isothermal titration calorimetry, molecular dynamics simulation, and so on. The un-bound polyphenols are quantified by liquid chromatography or spectrophotometry after dialysis or centrifugation. The adsorption of polyphenols by polysaccharides is mostly driven by hydrophobic interactions and hydrogen bonding, and can be described by various isothermal models such as Langmuir and Freundlich equations. Quality attributes of various food and beverage products (e.g., wine) can be significantly affected by polysaccharide-polyphenol interactions. Nutritionally, the interactions play an important role in the digestive tract of humans for the metabolism of both polyphenols and polysaccharides. PMID- 28362109 TI - Fruit and vegetable by-products as novel ingredients to improve the nutritional quality of baked goods. AB - The industrial manufacturing of fruits and vegetables generates approximately 50% by-product waste, causing a negative environmental impact and significant expenses. Nevertheless, fruit and vegetable by-products (FVB) are rich nutrients and extranutritional compounds that contribute to bowel health, weight management, lower blood cholesterol levels and improved control of glycemic and insulin responses. Due to the positive influence of FVB fibers and bioactive compounds during the digestion of glycemic carbohydrates, such as starch, baked goods are ideal food systems to accommodate FVB, since most of them have a high glycemic index. Therefore, this is an area of recent interest with critical environmental, economic and health implications worldwide. However, the utilization of FVB in baked goods leads to the loss of acceptability, in many cases caused by a lack of understanding of the physical structure and composition of FVB and their effects on food quality. The objective of this review is to provide a mechanistic understanding of the impact of the physical structure and composition of FVB on common baked goods and their influence on the nutritional and physical quality of the resulting product. This review will support the use of FVB as ideal ingredients while improving the added value of waste streams. PMID- 28362102 TI - Systems Toxicology: Real World Applications and Opportunities. AB - Systems Toxicology aims to change the basis of how adverse biological effects of xenobiotics are characterized from empirical end points to describing modes of action as adverse outcome pathways and perturbed networks. Toward this aim, Systems Toxicology entails the integration of in vitro and in vivo toxicity data with computational modeling. This evolving approach depends critically on data reliability and relevance, which in turn depends on the quality of experimental models and bioanalysis techniques used to generate toxicological data. Systems Toxicology involves the use of large-scale data streams ("big data"), such as those derived from omics measurements that require computational means for obtaining informative results. Thus, integrative analysis of multiple molecular measurements, particularly acquired by omics strategies, is a key approach in Systems Toxicology. In recent years, there have been significant advances centered on in vitro test systems and bioanalytical strategies, yet a frontier challenge concerns linking observed network perturbations to phenotypes, which will require understanding pathways and networks that give rise to adverse responses. This summary perspective from a 2016 Systems Toxicology meeting, an international conference held in the Alps of Switzerland, describes the limitations and opportunities of selected emerging applications in this rapidly advancing field. Systems Toxicology aims to change the basis of how adverse biological effects of xenobiotics are characterized, from empirical end points to pathways of toxicity. This requires the integration of in vitro and in vivo data with computational modeling. Test systems and bioanalytical technologies have made significant advances, but ensuring data reliability and relevance is an ongoing concern. The major challenge facing the new pathway approach is determining how to link observed network perturbations to phenotypic toxicity. PMID- 28362110 TI - Diet effects in the asthma treatment: A systematic review. AB - INTRODUCTION: Obesity in asthmatic patients has important relationships with asthma control, pulmonary function, and quality of life. The objective of this study was to conduct a systematic review of the literature on the effect of diet on asthma management in adults. METHODS: We searched PubMed, Embase, and Scopus (January 1948-October 2014) for randomized clinical trials that evaluated the effects of diet in adults with asthma. RESULTS: Of 12,215 studies identified, 21 were included. A reduction in weight of at least 7.5% from baseline as a result of caloric restriction can be beneficial for improving disease control, quality of life, and pulmonary function in obese patients with asthma. A dietary pattern rich in foods with potential antioxidant effect had an impact in improving asthma control, but with little clinical significance. Studies involving antioxidant supplementation showed improvements in asthma control with magnesium supplementation and less decline in lung function with vitamin C supplementation. Studies of fatty acid supplementation demonstrated effects on weight loss and improvement of asthma control and lung function. Studies of supplementation with propolis and caffeine reported significant increases in FEV1. Conversely, studies of high dietary salt intake reported greater declines in lung function. CONCLUSIONS: The evidence shows that, for obese adults with asthma, the best dietary intervention seems to be caloric restriction, regardless of specific dietary components. PMID- 28362111 TI - Alternative yeasts for winemaking: Saccharomyces non-cerevisiae and its hybrids. AB - Wine fermentation has not significantly changed since ancient times and the most traditional aspects are seen by the market as elements that uplift wine nuances and quality. In recent years, new trends have emerged from the sector in line with consumer preferences, and due to the effects of global climate change on grape ripening. In the first cases, the consumers are looking for wines with less ethanol and fruitier aromas and in the second cases the wineries want to reduce the wine alcohol levels and/or astringency. New yeast starters of alternative Saccharomyces species and their hybrids can help to solve some problems that wineries face. In this article we review several physiological and genetic aspects of S. uvarum and S. kudriavzevii and the hybrids, which are especially relevant during the winemaking process, such as their good fermentative capabilities at low temperatures, resulting in wines with lower alcohol and higher glycerol amounts. PMID- 28362108 TI - Alpha-1 Antitrypsin-Deficient Macrophages Have Increased Matriptase-Mediated Proteolytic Activity. AB - Alpha-1 antitrypsin (AAT) deficiency-associated emphysema is largely attributed to insufficient inhibition of neutrophil elastase released from neutrophils. Correcting AAT levels using augmentation therapy only slows disease progression, and that suggests a more complex process of lung destruction. Because alveolar macrophages (Mphi) express AAT, we propose that the expression and intracellular accumulation of mutated Z-AAT (the most common mutation) compromises Mphi function and contributes to emphysema development. Extracellular matrix (ECM) degradation is a hallmark of emphysema pathology. In this study, Mphi from individuals with Z-AAT (Z-Mphi) have greater proteolytic activity on ECM than do normal Mphi. This abnormal Z-Mphi activity is not abrogated by supplementation with exogenous AAT and is likely the result of cellular dysfunction induced by intracellular accumulation of Z-AAT. Using pharmacologic inhibitors, we show that several classes of proteases are involved in matrix degradation by Z-Mphi. Importantly, compared with normal Mphi, the membrane-bound serine protease, matriptase, is present in Z-Mphi at higher levels and contributes to their proteolytic activity on ECM. In addition, we identified matrix metalloproteinase (MMP)-14, a membrane-anchored metalloproteinase, as a novel substrate for matriptase, and showed that matriptase regulates the levels of MMP-14 on the cell surface. Thus, high levels of matriptase may contribute to increased ECM degradation by Z-Mphi, both directly and through MMP-14 activation. In summary, the expression of Z-AAT in Mphi confers increased proteolytic activity on ECM. This proteolytic activity is not rescued by exogenous AAT supplementation and could thus contribute to augmentation resistance in AAT deficiency-associated emphysema. PMID- 28362112 TI - The role of nonfat ingredients on confectionery fat crystallization. AB - Confections such as chocolate and biscuit fillings are composed of a continuous fat phase that contains dispersed nonfat ingredients such as sugar and cocoa powder. Research on fat crystallization and rheology in confections often extrapolates crystallization and textural properties from bulk to mixed systems while overlooking the important role of composition or particle interactions. For example, in chocolate processing the fat phase aids dispersed phase lubrication and fluidity whereas the dispersed particles assist in fat crystallization by providing many nucleation sites. In confections with a high dispersed phase volume fraction, fat crystallization may be hindered due to reduced triacyglycerol mobility, confinement, and increased tortuosity. This is further complicated in systems with slow crystallizing fats such as palm oil whose crystallization is exceptionally sensitive to composition and processing. This review breaks down the physical chemistry of fat-based confections and discusses the impact of different nonfat ingredients towards fat crystallization and rheology. The behavior of palm oil is further highlighted as it is becoming increasingly popular as a confectionery ingredient. Lastly, ingredient-ingredient interactions and their role in fat crystallization are described along with force spectroscopy as a novel tool to characterize such phenomena. Force spectroscopy utilizes atomic force microscopy to measure intermolecular forces as a function of distance but remains largely unexplored in the area of food science. PMID- 28362113 TI - Staphylococcal enterotoxins and enterotoxin-like toxins with special reference to dairy products: An overview. AB - Staphylococcal Enterotoxins (SEs) have been raising health concerns for food safety due to their association with staphylococcal foodborne poisoning (SFP). As superantigens, they also cause the life threatening toxic shock syndrome (TSS), the transmission of which via food cannot be ruled out despite the lack of epidemiological evidence. To date, at least 23 of these exotoxins are known and separated into SEs and Staphylococcal Enterotoxin-like (SEl) depending on whether or not they invoke emesis. This work presents an up-to-date overview on the presently known SEs/SEls from the perspective of their classification, pathogenesis, and genetic organisation. The incidence of these toxins in dairy products, the risk this poses to the public health, and possible control means are also reviewed. PMID- 28362115 TI - Novel EGFR (T790M)-cMET dual inhibitors: putative therapeutic agents for non small-cell lung cancer. AB - AIM: Different resistance mechanisms, especially, T790M secondary acquired point mutation and in some cases amplification of cMET, have been a major setback for the lung cancer therapies. METHODOLOGY: The current in silico study explored the small molecules which can act as putative EGFR (T790M)-cMET dual inhibitors. Databases were first filtered and subsequently cross filtered, initially by thoroughly validated pharmacophore models for both targets. As per score and interactions obtained in docking, the molecules were subjected to molecular dynamics simulations, to study the stability and binding orientations of their complexes with target proteins. CONCLUSION: Molecular dynamics simulations predicted three hits to possess good binding affinities and stability for EGFR (T790M) and cMET, which can be claimed to be potential dual inhibitors. PMID- 28362114 TI - (Meth)Acrylate Occupational Contact Dermatitis in Nail Salon Workers: A Case Series. AB - BACKGROUND: Recently, many cases of acrylate-associated allergic contact dermatitis have appeared among nail salon workers. Common acrylate-containing products in nail salons include traditional nail polish, ultraviolet-cured shellac nail polish, ultraviolet-cured gel nails, and press-on acrylic nails. METHODS: Nail salon technicians seen in the occupational medicine clinic in 2015 and 2016 were identified, and their patch test results and clinical features were summarized. Patch testing was done with the Chemotechnique (Meth)Acrylate nail series, and either the North American Standard series or the North American Contact Dermatitis Group screening series. RESULTS: Six patients were identified, all women, ages 38 to 58. Common presentations included erythematous dermatitis of the dorsa of the hands, palms, and forearms and fissures on the fingertips. Less common sites of eruptions included the periorbital region, cheeks, posterior ears, neck, sacral area, lateral thighs, and dorsa of the feet. All patients reacted to hydroxyethyl methacrylate, and 5 patients reacted to ethyl acrylate. Each patient also reacted to (meth)acrylates that are not found on either standard series, including ethyleneglycol dimethacrylate, 2-hydroxypropyl methacrylate, and 2-hydroxyethyl acrylate. CONCLUSIONS: The authors report 6 cases of allergic contact dermatitis to acrylates in nail technicians seen over the past year, representing a new trend in their clinic. These cases are reflective of a growing trend of nail technicians with allergic contact dermatitis associated with occupational (meth)acrylate exposure. Efforts to improve prevention are needed. PMID- 28362116 TI - Variability of HOMA and QUICKI insulin sensitivity indices. AB - Assessment of insulin sensitivity based on a single measurement of insulin and glucose, is both easy to understand and simple to perform. The tests most often used are HOMA and QUICKI. The aim of this study was to assess the biological variability of estimates of insulin sensitivity using HOMA and QUICKI indices. After a 12-h fast, blood was sampled for insulin and glucose determination. Sampling lasted for 90 min with an intersample interval of 2 min. A total of 56 subjects were included in the study, and in nine subjects sampling was done before and after weight reduction, so total number of analyzed series was 65. To compute the reference value of the insulin sensitivity index, averages of all 46 insulin and glucose samples were used. We also computed point estimates (single value estimates) of the insulin sensitivity index based on the different number of insulin/glucose samples (1-45 consecutive samples). To compute the variability of point estimates a bootstrapping procedure was used using 1000 resamples for each series and for each number of samples used to average insulin and glucose. Using a single insulin/glucose sample HOMA variability was 26.18 +/- 4.31%, and QUICKI variability was 3.30 +/- 0.54%. For 10 samples variability was 11.99 +/- 2.22% and 1.62 +/- 0.31% respectively. Biological variability of insulin sensitivity indices is significant, and it can be reduced by increasing the number of samples. Oscillations of insulin concentration in plasma are the major cause of variability of insulin sensitivity indices. PMID- 28362117 TI - New benzothiophene derivatives as dual COX-1/2 and 5-LOX inhibitors: synthesis, biological evaluation and docking study. AB - AIM: Simultaneous inhibition of 5-LOX/COX may enhance anti-inflammatory effects and reduce side effects. Hence, synthesis of novel dual inhibitors of 5-LOX/COX is an important strategy for treatment of inflammation. Results/methodology: The target compounds were designed to hybridize benzothiophene scaffold or its bioisostere benzofuran with various anti-inflammatory pharmacophore hetercycles through different atoms spacers. Compounds 4a, 4c, 4d, 5b, 7a, showed significant in vitro LOX inhibitory activity higher than that of meclofenamate sodium. Compounds 4b, 4e, 4f, 5a exhibited significant in vitro COX-2 inhibition higher than celecoxib and in vitro LOX inhibitory activity twice that of reference. These compounds elicited significant in vivo anti-inflammatory activities higher than celecoxib in formalin-induced paw edema test. Compound 4e exhibited gastrointestinal safety profile as celecoxib. The results were also consistent with the docking studies. CONCLUSION: Compound 4e could be considered as structural lead for the development of a new class of anti-inflammatory agents with better safety profile. PMID- 28362118 TI - Dietary Antioxidants: Potential Anticancer Agents. AB - There are several extrinsic and intrinsic factors involving reactive oxygen species that play critical roles in tumor development and progression by inducing DNA mutations, genomic instability, and aberrant pro-tumorigenic signaling. There are various essential micronutrients including minerals and vitamins in the diet, which play pivotal roles in maintaining and reinforcing antioxidant performance, affecting the complex network of genes (nutrigenomic approach) and encoding proteins for carcinogenesis. A lot of these antioxidant agents are available as dietary supplements and are predominant worldwide. However, the best antioxidant micronutrient (or a combination of micronutrients) for reducing cancer risks is unknown. The purpose of this review is to survey the literature on modern biological theories of cancer and the roles of dietary antioxidants in cancer. The roles and functions of antioxidant micronutrients, such as vitamin C (ascorbate), vitamin E (alpha-tocopherol), selenium, and vitamin A, provided through diet for the prevention of cancer are discussed in the present work. PMID- 28362119 TI - Enhancement of antimicrobial activity by liposomal oleic acid-loaded antibiotics for the treatment of multidrug-resistant Pseudomonas aeruginosa. AB - In this study, we examined the efficacy of liposomal oleic acid-based antibiotic formulations on 32 strains of multidrug-resistant Pseudomonas aeruginosa (MDRPa). The average size of liposomes were 93.12 +/- 2.3 nm holding a negative zeta potential at -57.3 +/- 0.89. Liposomal antibiotic formulations were tested against 32 MDRPa strains isolated from burn wounds and urine samples, which exhibited an MIC of <=8 MUg/mL, whereas MIC of free antibiotics ranged from 32 to >1024 MUg/mL. The results clearly indicate that the liposomes composed of naturally occurring oleic acid, could be used therapeutically either alone or in combination with antibiotics to effectively treat P. aeruginosa infections. PMID- 28362120 TI - Traumatic brain injury rehabilitation in Riyadh, Saudi Arabia: Time to rehabilitation admission, length of stay and functional outcome. AB - OBJECTIVES: (1) Describe trends in time to rehabilitation admission and rehabilitation length of stay (LOS), (2) compare functional independence at discharge from rehabilitation between patients who arrived directly from acute care versus those from elsewhere and (3) identify independent predictors of functional outcomes following rehabilitation. SETTING: Traumatic brain injuries rehabilitation unit of King Fahad Medical City, Riyadh, Saudi Arabia. METHODS: We collected information on time from injury to rehabilitation admission, rehabilitation LOS, functional independence measure (FIM) score (admission and discharge) and demographic variables for 66 patients who arrived to rehabilitation from acute care and 142 patients who arrived from elsewhere. A mixed model analysis of variance measured change in FIM score between groups. Hierarchical regression was employed to investigate variables associated with FIM score at rehabilitation discharge. RESULTS: Patients arriving directly from acute care had a time from injury to rehabilitation admission 1/3 that of, and a higher discharge FIM score than, patients arriving from elsewhere. For the latter group, increasing time from injury to rehabilitation admission was associated with lower rehabilitation discharge FIM score. CONCLUSIONS: Reducing time from injury to rehabilitation admission and promoting enrolment to inpatient traumatic brain injury rehabilitation directly from acute care may improve functional outcome at discharge from rehabilitation. PMID- 28362125 TI - Progress in the medicinal chemistry of silicon: C/Si exchange and beyond. AB - Application of silyl functionalities is one of the most promising strategies among various 'elements chemistry' approaches for the development of novel and distinctive drug candidates. Replacement of one or more carbon atoms of various biologically active compounds with silicon (so-called sila-substitution) has been intensively studied for decades, and is often effective for alteration of activity profile and improvement of metabolic profile. In addition to simple C/Si exchange, several novel approaches for utilizing silicon in medicinal chemistry have been suggested in recent years, focusing on the intrinsic differences between silicon and carbon. Sila-substitution offers great potential for enlarging the chemical space of medicinal chemistry, and provides many options for structural development of drug candidates. PMID- 28362126 TI - Epigenetics: new possibilities for drug discovery. PMID- 28362124 TI - Redox sensitive PEG controlled octaarginine and targeting peptide co-modified nanostructured lipid carriers for enhanced tumour penetrating and targeting in vitro and in vivo. AB - To strengthen the anti-tumour efficacy and weaken the side effects, a nano targeted drug delivery system was constructed. The nanostructured lipid carriers (NLCs) were prepared by the melt-emulsification method. Modified with the octaarginine, thiolytic cleavable polyethylene glycol (PEG) and targeting peptide simultaneously on the surface, this multifunctional NLC could not only actively target to tumour tissues, but also control the cell penetration effect of the octaarginine easily by a safe reducing agent l-cysteine (l-Cys). In the present study, the pharmaceutical characteristics, the cytotoxicity and cellular uptake on NCI-H1299 cells in vitro, the biodistribution and targeting effect and anti tumour ability in vivo were employed to evaluate the formulations. As the results revealed, various NLCs had a mean particle size of about 40 nm and a positive zeta potential of about 10 mV. The optimum density of cleavable PEG was confirmed as 10% and the best concentration of l-cysteine was determined as 20 mM via the qualitative and quantitative cellular uptake study. Based on these outcomes, the multiply decorated NLC manifested a great cell growth inhibition with the increased concentration of paclitaxel (PTX). Moreover, it preferred to accumulate at tumours, but not normal organs in vivo. Compared with Taxol(r), this preparation demonstrated stronger anti-tumour efficacy and better security. Therefore, the multifunctional NLC can be considered as a promising drug delivery system targeting to tumours. PMID- 28362127 TI - Welcome to the 2017 Annual Review of Sex Research. PMID- 28362128 TI - A pilot study on the applicability of thromboelastometry in detecting brain tumour-induced hypercoagulation. AB - Patients with intracranial tumours have an increased risk of venous thromboembolism, particularly during the first month after neurosurgery. A proposed explanation for this increased risk, are procoagulant tumour-derived substances, such as tissue factor, usually measured in peripheral blood. The aim of the present study is to investigate whether a rotational thromboelastometry (ROTEM) can measure the procoagulative activity of tumour tissue. The study included 21 patients who were undergoing a craniotomy and complete tumour resection after written consent and ethical approval were obtained. Tumour tissue was biopsied during surgery and used for in vitro spiking of patients own citrated whole blood. Blood samples with or without spiking were analyzed with ROTEM using different activating reagents. ROTEM clotting time significantly decreased (p < .001), indicating a hypercoagulative response on clot initiation that was strongest for glioma tumours. However, ROTEM clot formation time was significantly prolonged (p < .001), which was an opposite response that indicated poor initial clot propagation. ROTEM maximum lysis was increased in the tumour tissue-spiked samples (p < .001), indicating a strong fibrinolytic activity in brain tumour tissue. Tissue extracts from intracranial tumours have both procoagulant and fibrinolytic effects that are detectable with ROTEM. Glioma tumours had the strongest hypercoagulative response in our in vitro model. Larger studies are necessary to test the clinical relevance and accuracy of tumour extract spiked viscoelastic tests to predict the individual patient risk for developing a thrombotic complication. PMID- 28362129 TI - Radiofrequency ablation for management of malignant biliary obstruction: a single center experience and review of the literature. AB - BACKGROUND: Radiofrequency ablation (RFA) causes coagulative necrosis of tissue and may be beneficial prior to biliary stenting. We report our experience using RFA for malignant biliary obstruction and review the literature. METHODS: Retrospective analysis of all patients undergoing RFA for malignant biliary obstruction over the last two years. Success, complications and re-intervention following RFA were assessed. Controls were age, sex and disease matched who had stenting alone. RESULTS: 31 patients were included and 15 patients underwent biliary RFA prior to stenting (median age 78 years, 8 females). 14 patients had pancreatic cancer, 13 cholangiocarcinoma (6 hilar lesions) and 4 malignant disease invading the bile duct. Adverse events included acute pancreatitis (n = 2) and bacteremia in (n = 1). Median duration of intervention free survival was 220 days in the RFA group compared to 106.5 days in controls (hazard ratio 2.4, 95% CI 1.1 - 5.3, p = 0.025). Multivariable Cox proportional hazard analysis showed survival was associated with RFA (hazard ratio 2.55, 95% CI 1.09-5.96, p = 0.026) but not age, site or type of malignancy. CONCLUSION: Biliary RFA is a technically feasible with a low adverse event rate and is associated with increased survival. Multi-centre randomized controlled trials are required. PMID- 28362130 TI - Estimation of kinetic and thermodynamic ligand-binding parameters using computational strategies. AB - Kinetic and thermodynamic ligand-protein binding parameters are gaining growing importance as key information to consider in drug discovery. The determination of the molecular structures, using particularly x-ray and NMR techniques, is crucial for understanding how a ligand recognizes its target in the final binding complex. However, for a better understanding of the recognition processes, experimental studies of ligand-protein interactions are needed. Even though several techniques can be used to investigate both thermodynamic and kinetic profiles for a ligand-protein complex, these procedures are very often laborious, time consuming and expensive. In the last 10 years, computational approaches have enormous potential in providing insights into each of the above effects and in parsing their contributions to the changes in both kinetic and thermodynamic binding parameters. The main purpose of this review is to summarize the state of the art of computational strategies for estimating the kinetic and thermodynamic parameters of a ligand-protein binding. PMID- 28362131 TI - Reframing undergraduate medical education in global health: Rationale and key principles from the Bellagio Global Health Education Initiative. AB - Global health education (GHE) continues to be a growing initiative in many medical schools across the world. This focus is no longer limited to participants from high-income countries and has expanded to institutions and students from low and middle-income settings. With this shift has come a need to develop meaningful curricula through engagement between educators and learners who represent the sending institutions and the diverse settings in which GHE takes place. The Bellagio Global Health Education Initiative (BGHEI) was founded to create a space for such debate and discussion and to generate guidelines towards a universal curriculum for global health. In this article, we describe the development and process of our work and outline six overarching principles that ought to be considered when adopting an inclusive approach to GHE curriculum development. PMID- 28362132 TI - Identifying Patients Eligible for a Short Hospital Stay After Stoma Closure. AB - INTRODUCTION: The implementation of enhanced recovery programmes after elective colorectal surgery has dramatically reduced the length of stay. The objective of this study was to assess the selection of good candidates for short post operative stay (GCSS) in the context of stoma closure. METHODS: Between January 2011 and December 2014, 222 patients were included in the present retrospective, single-center study. The primary endpoint was the proportion of GCSS. We also identified factors associated with GCSS status and built a predictive score. RESULTS: The study population was predominantly male (n = 122, 55%). 60% of the patients had undergone ileostomy and 85% had undergone hand-sewn anastomosis. The postoperative ileus rate was 5% and the readmission rate was 3.5%. 41% (n = 92) of the study population were considered to be GCSS. In a multivariate analysis, age under 50 (odds ratio (OR) [95% confidence interval (CI)] = 2.8 [1.2-5.6], p = 0.008), the absence of vascular comorbidities (OR [95%CI] = 3.2 [1.3-12.3]; p = 0.006) and stapled anastomosis (OR: 4.2, 95%CI: 1.1-17.3, p = 0.03) were associated with GCSS status. Predictive scores of 0, 1, 2, and 3 were associated with GCSS rates of 20%, 18%, 44%, and 62%, respectively (p < 0.001). CONCLUSION: In the context of stoma closure, 41% of patients were GCSS. PMID- 28362133 TI - Intestinal Epithelial Stem Cells: Distinct Behavior After Surgical Injury and Teduglutide Administration. AB - BACKGROUND: Previous studies suggest that intestinal epithelial stem cells (IESC), critical drivers of homeostasis and regeneration, include two subpopulations: crypt-based columnar and "position +4" stem cells, identified by Lgr5 and Bmi1 biomarkers, respectively. Teduglutide is an enterotrophic counterpart of glucagon-like peptide 2. This study aimed to investigate the response of putative IESC to surgical injury and teduglutide administration on an animal model of intestinal resection and anastomosis. METHODS: Wistar rats (n = 59) were distributed into four groups: "Ileal Resection" versus "Laparotomy", subsequently subdivided into "Postoperative Teduglutide Administration" versus "No Treatment"; and sacrificed at third or seventh days, with ileal sample harvesting. Flow cytometry was used to analyze epithelial stem cells with monoclonal antibodies against Lgr5, Bmi1 and also CD44, CD24, CD166, and Grp78 surface markers. RESULTS: Surgical trauma induced an increase of epithelial stem cells population at third day (9.0 +/- 0.3 versus 5.7 +/- 0.3%, p = 0.0001), which was more intense and involved all subpopulations after ileal resection. At seventh day, teduglutide was significantly associated with higher proportion of Lgr5+/Bmi1- cells (5.8 +/- 0.1 versus 2.9 +/- 0.3%, p = 0.005) and, on the contrary, lower percentage of Lgr5-/Bmi1+ cells (0.03 +/- 0.01 versus 1.9 +/- 0.1%, p = 0.049) after ileal resection; and higher proportion of Lgr5+/Bmi1+ cells (1.7 +/- 0.1 versus 1.1 +/- 0.2%, p = 0.028) after isolated laparotomy. After surgery, Lgr5+/Bmi1- and Lgr5-/Bmi1+ subpopulations demonstrated an inverse correlation and both correlated negatively with Grp78 labeling index. Lgr5-/Bmi1+ and CD44+/CD24low/CD166+/Grp78+ cells proportions exhibited a high grade positive correlation. CONCLUSION: Those observations support the existence of two epithelial stem cells subpopulations with distinct behavior after surgical injury and teduglutide treatment. PMID- 28362136 TI - Analogical reasoning in children with specific language impairment: Evidence from a scene analogy task. AB - Analogical reasoning is a human ability that maps systems of relations. It develops along with relational knowledge, working memory and executive functions such as inhibition. It also maintains a mutual influence on language development. Some authors have taken a greater interest in the analogical reasoning ability of children with language disorders, specifically those with specific language impairment (SLI). These children apparently have weaker analogical reasoning abilities than their aged-matched peers without language disorders. Following cognitive theories of language acquisition, this deficit could be one of the causes of language disorders in SLI, especially those concerning productivity. To confirm this deficit and its link to language disorders, we use a scene analogy task to evaluate the analogical performance of SLI children and compare them to controls of the same age and linguistic abilities. Results show that children with SLI perform worse than age-matched peers, but similar to language-matched peers. They are more influenced by increased task difficulty. The association between language disorders and analogical reasoning in SLI can be confirmed. The hypothesis of limited processing capacity in SLI is also being considered. PMID- 28362134 TI - Estrogen signaling, through estrogen receptor beta, regulates DNA methylation and its machinery in male germ line in adult rats. AB - Estrogen, through its receptors, regulates various aspects of spermatogenesis and male fertility. To understand the roles of estrogen receptors (ERalpha and ERbeta) in male fertility, we have developed in vivo selective ER agonist administration models. Treatment of adult male rats with ERalpha or ERbeta agonist for 60 d decreases fertility and litter size mainly due to increased pre- and post-implantation embryo loss. Since epigenetic mechanisms like DNA methylation play a crucial role in male fertility, we investigated the effects of the ER agonists on DNA methylation in spermatozoa. Treatment with ERbeta agonist causes a significant decrease in DNA methylation both at the global level and at the H19 differentially methylated region (DMR). This could be due to decrease in DNA methyltransferases in the testis upon ERbeta agonist treatment. The hypomethylation observed at the H19 DMR corroborates with aberrant expression of Igf2 and H19 imprinted genes in the resorbed embryos sired by ERbeta agonist treated males. Thus, our study demonstrates that ERbeta regulates DNA methylation and methylating enzymes during adult rat spermatogenesis. Activation of estrogen signaling through ERbeta could therefore cause DNA methylation defects leading to impaired male fertility. These results define a role for estrogen in epigenetic regulation of male germ line, suggesting that epigenetic insults by exposure to environmental estrogens could potentially affect male fertility. PMID- 28362135 TI - Immunogenicity and safety evaluation of bivalent types 1 and 3 oral poliovirus vaccine by comparing different poliomyelitis vaccination schedules in China: A randomized controlled non-inferiority clinical trial. AB - BACKGROUND: The type 2 component of the oral poliovirus vaccine is targeted for global withdrawal through a switch from the trivalent oral poliovirus vaccine (tOPV) to a bivalent oral poliovirus vaccine (bOPV). The switch is intended to prevent paralytic polio caused by circulating vaccine-derived poliovirus type 2. We aimed to assess the immunogenicity and safety profile of 6 vaccination schedules with different sequential doses of inactivated poliovirus vaccine (IPV), tOPV, or bOPV. METHODS: A randomized controlled trial was conducted in China in 2015. Healthy newborn babies randomly received one of the following 6 vaccination schedules: cIPV-bOPV-bOPV(I-B-B), cIPV-tOPV-tOPV(I-T-T), cIPV-cIPV bOPV(I-I-B), cIPV-cIPV-tOPV(I-I-T), cIPV-cIPV-cIPV(I-I-I), or tOPV-tOPV-tOPV(T-T T). Doses were administered sequentially at 4-6 week intervals after collecting baseline blood samples. Patients were proactively followed up for observation of adverse events after the first dose and 30 days after all doses. The primary study objective was to investigate the immunogenicity and safety profile of different vaccine schedules, evaluated by seroconversion, seroprotection and antibody titer against poliovirus types 1, 2, and 3 in the per-protocol population. RESULTS: Of 600 newborn babies enrolled, 504 (84.0%) were included in the per-protocol population. For type 1 poliovirus, the differences in the seroconversion were 1.17% (95% CI = -2.74%, 5.08%) between I-B-B and I-T-T and 0.00% (95% CI: -6.99%, 6.99%) between I-I-B and I-I-T; for type 3 poliovirus, differences in the seroconversion were 3.49% (95% CI: -1.50%, 8.48%) between I-B B and I-T-T and -2.32% (95% CI: -5.51%, 0.86%) between I-I-B and I-I-T. The non inferiority conclusion was achieved in both poliovirus type 1 and 3 with the margin of -10%. Of 24 serious adverse events reported, no one was vaccine related. CONCLUSIONS: The vaccination schedules with bOPV followed by one or 2 doses of IPV were recommended to substitute for vaccinations involving tOPV without compromising the immunogenicity and safety in the Chinese population. The findings will be essential for policy formulation by national and global authorities to facilitate polio elimination. PMID- 28362137 TI - Magnitude and Determinants of the Ratio between Prevalence of Low Vision and Blindness in Rapid Assessment of Avoidable Blindness Surveys. AB - PURPOSE: To determine the magnitude and determinants of the ratio between prevalence of low vision and prevalence of blindness in rapid assessment of avoidable blindness (RAAB) surveys globally. METHODS: Standard RAAB reports were downloaded from the repository or requested from principal investigators. Potential predictor variables included prevalence of uncorrected refractive error (URE) as well as gross domestic product (GDP) per capita, health expenditure per capita of the country across World Bank regions. Univariate and multivariate linear regression were used to investigate the correlation between potential predictor variables and the ratio. RESULTS: The results of 94 surveys from 43 countries showed that the ratio ranged from 1.35 in Mozambique to 11.03 in India with a median value of 3.90 (Interquartile range 3.06;5.38). Univariate regression analysis showed that prevalence of URE (p = 0.04), logarithm of GDP per capita (p = 0.01) and logarithm of health expenditure per capita (p = 0.03) were significantly associated with the higher ratio. However, only prevalence of URE was found to be significant in multivariate regression analysis (p = 0.03). CONCLUSION: There is a wide variation in the ratio of the prevalence of low vision to the prevalence of blindness. Eye care service utilization indicators such as the prevalence of URE may explain some of the variation across the regions. PMID- 28362140 TI - Occurrence of Giardia in Swedish Red Foxes ( Vulpes vulpes ). AB - Giardia duodenalis is an intestinal protozoan capable of causing gastrointestinal disease in a range of vertebrate hosts. It is transmitted via the fecal-oral route. Understanding the epidemiology of G. duodenalis in animals is important, both for public health and for the health of the animals it infects. We investigated the occurrence of G. duodenalis in wild Swedish red foxes ( Vulpes vulpes ), with the aim of providing preliminary information on how this abundant predator might be involved in the transmission and epidemiology of G. duodenalis . Fecal samples (n=104) were analysed for G. duodenalis using a commercially available direct immunofluorescent antibody test. Giardia duodenalis cysts were found in 44% (46/104) of samples, with foxes excreting 100 to 140,500 cysts per gram of feces (mean, 4,930; median, 600). Molecular analysis, using PCR with sequencing of PCR amplicons, was performed on 14 samples, all containing over 2,000 cysts per gram feces. Amplification only occurred in four samples at the tpi gene, sequencing of which revealed assemblage B in all four samples. This study provides baseline information on the role of red foxes in the transmission dynamics of G. duodenalis in Sweden. PMID- 28362138 TI - Intestinal parasitic infections in different groups of immunocompromised patients in Kashan and Qom cities, central Iran. AB - INTRODUCTION: Intestinal parasitic infections (IPIs) are important causes of morbidity and mortality in patients with immunocompromising conditions. OBJECTIVE: The aim of this study was to determine the prevalence of IPIs in different groups of immunocompromised patients, including hemodialysis patients (HD), renal transplant recipients (RTR), cancer and HIV/AIDS patients in comparison with healthy individuals in two central cities of Iran (Kashan and Qom). METHODS: In this case-control study, the stool samples of 135 HD, 50 RTR, 60 cancer patients, 20 HIV/AIDS patients and 120 healthy subjects were tested using direct-smear, formol-ether concentration, Ziehl-Neelsen staining and Agar plate method. RESULTS: The overall infection rate was 11.7% (31/265) in patient groups and 0% (0/120) in the control group. The frequency of parasites was 25% in HIV/AIDS patients, 11.9% (16/135) in HD, 12.0% (6/50) in RTR and 6.7% (4/60) in cancer patients. Blastocystis hominis (4.2%) and Giardia lamblia (3.0%) were the most prevalent parasites in patient groups. The infection rate was significantly higher in male (17.6%) than female (5.4%) patients (p = .002), but no statistically significant association was observed according to the age and educational levels. CONCLUSIONS: This study showed a high prevalence of IPIs in immunocompromised patients. The results of this study suggest that periodic stool examinations for screening of IPIs should be included as a part of routine medical care in these patients. PMID- 28362141 TI - Using Off-the-Shelf Technologies to Mass Manufacture Oral Vaccine Baits for Wildlife. AB - Technology and infrastructure costs can limit access to oral vaccination tools for wildlife disease control. We describe vaccine bait mass manufacturing employing off-the-shelf technologies. Our approach has helped advance scaling-up of plague vaccination campaigns, but components of this production system could be translated into other wildlife vaccination applications. PMID- 28362142 TI - Elucidating the association between the self-harm inventory and several borderline personality measures in an inpatient psychiatric sample. AB - OBJECTIVE: The current study evaluated the utility of the self-harm inventory (SHI) as a proxy for and screening measure of borderline personality disorder (BPD) using several diagnostic and statistical manual of mental disorders (DSM) based BPD measures as criteria. METHODS: We used a sample of 145 psychiatric inpatients, who completed the SHI and a series of well-validated, DSM-based self report measures of BPD. RESULTS: Using a series of latent trait and latent class analyses, we found that the SHI was substantially associated with a latent construct representing BPD, as well as differentiated latent classes of 'high' vs. 'low' BPD, with good accuracy. CONCLUSIONS: The SHI can serve as proxy for and a good screening measure for BPD, but future research needs to replicate these findings using structured interview-based measurement of BPD. PMID- 28362143 TI - Stance foot alignment and hand positioning alter star excursion balance test scores in those with chronic ankle instability: What are we really assessing? AB - OBJECTIVE: The literature has consistently shown that the Star Excursion Balance Test (SEBT) is a reliable and valid tool to anticipate the risk of lower extremity injury, assess dynamic postural control differences among groups, and assess the effectiveness of balance training programs in both healthy individuals and people with lower extremity injuries. However, there is no standard administration technique for the SEBT in research, clinical practice, or performance settings. Therefore, the purpose of this investigation was to compare six different combinations (3 different foot alignments * 2 hand positions) on the SEBT performance in those with chronic ankle instability (CAI). DESIGN: Repeated Measures Design. SETTING: University Research Laboratory. PARTICIPANTS: Twenty-five university students with CAI (12 males, 13 females; age: 20.3 +/- 2.4 years, height: 172.7 +/- 7.4 cm, weight: 77.5 +/- 15.3 kg. , BMI: 25.9 +/- 4.0 kg/m2) voluntarily participated in the study. METHODS: Six different SEBT positions were used to assess dynamic postural control. Three foot positions: 1) Foot centered; 2) Toe fixed; and 3) Toe-heel changing and two hand placements: 1) Hands free and 2) Hands on the hips were used in this study. After 6familiarization trials for each condition, three Star Excursion Balance Test scores were recorded. MAIN OUTCOME MEASURES: Normalized reach distance (% of leg length) in the anterior, posteromedial, and posterolateral directions as well as a composite reach score quantified dynamic postural control. RESULTS: Both foot alignment and hand position significantly altered normalized SEBT reach distance in the anterior (p < 0.003), posteromedial (p < 0.001), posterolateral (p < 0.001), and composite reach scores (p < 0.001). CONCLUSION: Different foot alignments and hand constraints significantly altered normalized reach distances and the composite score in individuals with CAI. These results do not suggest that any combination of foot alignments and/or hand constraints is superior. However, changing the toe/heel position, while maintaining hands on the hips, may provide the best standardization for clinicians and researchers. PMID- 28362145 TI - Phase II dose-response trials: A simulation study to compare analysis method performance under design considerations. AB - Phase II trials are intended to provide information about the dose-response relationship and to support the choice of doses for a pivotal phase III trial. Recently, new analysis methods have been proposed to address these objectives, and guidance is needed to select the most appropriate analysis method in specific situations. We set up a simulation study to evaluate multiple performance measures of one traditional and three more recent dose-finding approaches under four design options and illustrate the investigated analysis methods with an example from clinical practice. Our results reveal no general recommendation for a particular analysis method across all design options and performance measures. However, we also demonstrate that the new analysis methods are worth the effort compared to the traditional ANOVA-based approach. PMID- 28362144 TI - Long-term effectiveness of vedolizumab in inflammatory bowel disease: a national study based on the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG). AB - OBJECTIVES: Clinical trials have demonstrated the efficacy of vedolizumab in inflammatory bowel disease (IBD). However, these findings may not reflect the clinical practice. Therefore, we aimed to describe a vedolizumab-treated patient population and assess long-term effectiveness. MATERIALS AND METHODS: Patients initiating vedolizumab between 1 June 2014 and 30 May 2015 were identified through the Swedish National Quality Registry for IBD. Prospectively collected data on treatment and disease activity were extracted. Clinical remission was defined as Patient Harvey Bradshaw index <5 in Crohn's disease (CD) and Patient Simple Clinical Colitis Activity index <3 in ulcerative colitis (UC). RESULTS: Two-hundred forty-six patients (147 CD, 92 UC and 7 IBD-Unclassified) were included. On study entry, 86% had failed TNF-antagonist and 48% of the CD patients had undergone >=1 surgical resection. After a median follow-up of 17 (IQR: 14-20) months, 142 (58%) patients remained on vedolizumab. In total, 54% of the CD- and 64% of the UC patients were in clinical remission at the end of follow-up, with the clinical activity decreasing (p < .0001 in both groups). Faecal-calprotectin decreased in CD (p < .0001) and in UC (p = .001), whereas CRP decreased in CD (p = .002) but not in UC (p = .11). Previous anti-TNF exposure (adjusted HR: 4.03; 95% CI: 0.96-16.75) and elevated CRP at baseline (adjusted HR: 2.22; 95% CI: 1.10-4.35) seemed to be associated with discontinuation because of lack of response. Female sex was associated with termination because of intolerance (adjusted HR: 2.75; 95% CI: 1.16-6.48). CONCLUSION: Vedolizumab treated patients represent a treatment-refractory group. A long-term effect can be achieved, even beyond 1 year of treatment. PMID- 28362147 TI - Benchmarking of copper(II) LFMM parameters for studying amyloid-beta peptides. AB - Ligand field molecular mechanics (LFMM) parameters have been benchmarked for copper (II) bound to the amyloid-beta1-16 peptide fragment. Several density functional theory (DFT) optimised small test models, representative of different possible copper coordination modes, have been used to test the accuracy of the LFMM copper bond lengths and angles, resulting in errors typically less than 0.1 A and 5 degrees . Ligand field molecular dynamics (LFMD) simulations have been carried out on the copper bound amyloid-beta1-16 peptide and snapshots extracted from the subsequent trajectory. Snapshots have been optimised using DFT and the semi-empirical PM7 method resulting in good agreement against the LFMM calculated geometry. Analysis of substructures within snapshots shows that the larger contribution of geometrical difference, as measured by RMSD, lies within the peptide backbone, arising from differences in DFT and AMBER, and the copper coordination sphere is reproduced well by LFMM. PM7 performs excellently against LFMM with an average RMSD of 0.2 A over 21 tested snapshots. Further analysis of the LFMD trajectory shows that copper bond lengths and angles have only small deviations from average values, with the exception of a carbonyl moiety from the N-terminus, which can act as a weakly bound fifth ligand. PMID- 28362146 TI - A longitudinal analysis of stress among incoming college freshmen. AB - OBJECTIVES: The objectives of this study were to: (1) examine changes in stress during first semester among freshmen undergraduates and (2) identify predictors of stress (coping strategies, emotional states, and quality of sleep). PARTICIPANTS: One hundred ninety-seven freshmen students were recruited for a 10 week study during first quarter (October-December, 2015). METHODS: Students completed weekly self-report surveys on stress, coping strategies, emotions, and quality of sleep. A generalized linear mixed model was used for analyses. RESULTS: Stress was elevated during examinations periods. Women reported a greater stress level than men. Increased stress level was significantly associated with lower sleep quality and greater negative emotions (fear, anger). Exercise was an effective stress coping strategy, while other coping methods (Internet usage, meditation, and self-isolation) were associated with higher stress. Social media usage did not influence stress level. CONCLUSIONS: Future stress management programs for freshmen need to consider gender differences and may focus on sleep, exercise, and decreased general Internet usage. PMID- 28362148 TI - Failure of Alveolar Type 2 Cell Maintenance Links Neonatal Distress with Adult Lung Disease. PMID- 28362149 TI - Releasing Tensin. PMID- 28362150 TI - The Cornerstone of the Aberrant Pathophysiology of Obstructive Sleep Apnea: Tissue Responses to Chronic Sustained Versus Intermittent Hypoxia. PMID- 28362152 TI - Finally, Progress in Pulmonary Hypertension Associated with Heart Failure with Preserved Ejection Fraction. PMID- 28362151 TI - alpha6beta4 Integrin Directs Alveolar Epithelial Migration. PMID- 28362154 TI - Factors influencing college women's contraceptive behavior: An application of the integrative model of behavioral prediction. AB - OBJECTIVE: This study investigated variables within the Integrative Model of Behavioral Prediction (IMBP) as well as differences across socioeconomic status (SES) levels within the context of inconsistent contraceptive use among college women. PARTICIPANTS: A nonprobability sample of 515 female college students completed an Internet-based survey between November 2014 and February 2015. METHODS: Respondents were asked about their contraception use, knowledge and information sources, demographic information, and IMBP factors, including attitudes, norms, and perceived behavioral control (PBC). RESULTS: While overall attitudes, norms, PBC, and intentions for contraceptive use were high, only 46.8% of women used contraception consistently. Data also revealed only moderate levels of knowledge about contraception. While there were no differences across SES levels for attitudes, PBC, norms or knowledge, SES levels did differ in sources used to acquire contraceptive information. CONCLUSIONS: This study highlights the need to consider where college women acquire contraceptive information which is associated with SES. PMID- 28362155 TI - Pathologists' Perspectives on Disclosing Harmful Pathology Error. AB - CONTEXT: - Medical errors are unfortunately common. The US Institute of Medicine proposed guidelines for mitigating and disclosing errors. Implementing these recommendations in pathology will require a better understanding of how errors occur in pathology, the relationship between pathologists and treating clinicians in reducing error, and pathologists' experiences with and attitudes toward disclosure of medical error. OBJECTIVE: - To understand pathologists' attitudes toward disclosing pathology error to treating clinicians and patients. DESIGN: - We conducted 5 structured focus groups in Washington State and Missouri with 45 pathologists in academic and community practice. Participants were questioned about pathology errors, how clinicians respond to pathology errors, and what roles pathologists should play in error disclosure to patients. RESULTS: - These pathologists believe that neither treating physicians nor patients understand the subtleties and limitations of pathologic diagnoses, which complicates discussions about pathology errors. Pathologists' lack of confidence in communication skills and fear of being misrepresented or misunderstood are major barriers to their participation in disclosure discussions. Pathologists see potential for their future involvement in disclosing error to patients, but at present advocate reliance on treating clinicians to disclose pathology errors to patients. Most group members believed that going forward pathologists should offer to participate more actively in error disclosure to patients. CONCLUSIONS: - Pathologists lack confidence in error disclosure communication skills with both treating physicians and patients. Improved communication between pathologists and treating physicians could enhance transparency and promote disclosure of pathology errors. Consensus guidelines for best practices in pathology error disclosure may be useful. PMID- 28362156 TI - Development and Validation of Clinical Whole-Exome and Whole-Genome Sequencing for Detection of Germline Variants in Inherited Disease. AB - CONTEXT: - With the decrease in the cost of sequencing, the clinical testing paradigm has shifted from single gene to gene panel and now whole-exome and whole genome sequencing. Clinical laboratories are rapidly implementing next-generation sequencing-based whole-exome and whole-genome sequencing. Because a large number of targets are covered by whole-exome and whole-genome sequencing, it is critical that a laboratory perform appropriate validation studies, develop a quality assurance and quality control program, and participate in proficiency testing. OBJECTIVE: - To provide recommendations for whole-exome and whole-genome sequencing assay design, validation, and implementation for the detection of germline variants associated in inherited disorders. DATA SOURCES: - An example of trio sequencing, filtration and annotation of variants, and phenotypic consideration to arrive at clinical diagnosis is discussed. CONCLUSIONS: - It is critical that clinical laboratories planning to implement whole-exome and whole genome sequencing design and validate the assay to specifications and ensure adequate performance prior to implementation. Test design specifications, including variant filtering and annotation, phenotypic consideration, guidance on consenting options, and reporting of incidental findings, are provided. These are important steps a laboratory must take to validate and implement whole-exome and whole-genome sequencing in a clinical setting for germline variants in inherited disorders. PMID- 28362157 TI - The Significance of Lymphovascular Invasion of the Spermatic Cord in the Absence of Cord Soft Tissue Invasion. AB - CONTEXT: - Testicular germ cell tumors with lymphovascular invasion (LVI) are staged pT2, and those with spermatic cord involvement are staged pT3. OBJECTIVE: To study the clinical significance of LVI within the spermatic cord without direct involvement of the cord soft tissues. DESIGN: - A retrospective, multi institutional review was performed on testicular GCTs with spermatic cord LVI in the absence of cord soft tissue invasion. RESULTS: - Forty-four germ cell tumors had LVI in the spermatic cord without soft tissue invasion; 37 of 44 patients (84%) had nonseminomatous germ cell tumors (NSGCT), and 7 (16%) had pure seminomas. Patients with NSGCTs and spermatic cord LVI had worse clinical outcomes compared with patients with pure seminoma and spermatic cord LVI (P = .008). We then compared patients with NSGCTs and spermatic cord LVI (n = 37) to patients with NSGCTs and LVI limited to the testis (n = 32). A significantly greater percentage of patients with LVI in the spermatic cord presented with advanced clinical stage (76% versus 50%; P = .01). There was no statistically significant difference in disease recurrence/progression or death between patients with spermatic cord LVI and patients with LVI limited to the testis (P = .40; P = .50). There was no significant difference in the presence of embryonal dominant histology (P = .30) or rete testis invasion (P = .50) between the 2 groups. More hilar soft tissue invasion was seen in patients with LVI present in the spermatic cord (P = .004). CONCLUSIONS: - In patients with NSGCTs, LVI in the spermatic cord, without soft tissue invasion, is associated with worse clinical stage at presentation compared with patients with LVI confined to the testis. PMID- 28362158 TI - Interpretation of relative effects. PMID- 28362159 TI - Attitudinal and behavioral differences between cigarette users who do and do not identify as "smokers". AB - OBJECTIVE: The current research aimed to understand differences in smoking related identity among college students and to illustrate the distinct characteristics of nonidentified smokers (NIS). PARTICIPANTS: Students from 2 colleges in Massachusetts (N = 538; April 2016). METHODS: Respondents reported by online survey whether or not they had smoked a cigarette in the past 30 days and if they self-identified as smokers. Nonsmokers (NIS) and identified smokers (IS) were then compared on their smoking attitudes and behavior. RESULTS: NIS made up 12.5% of the sample and 64% of all tobacco users. NIS perceived themselves as less addicted and were more confident in their ability to quit smoking. They also were less likely to smoke alone, buy their own cigarettes, or have friends who smoked. CONCLUSIONS: College health officials can best motivate NIS to quit smoking by focusing on peer norms and the potential of long-term addiction. PMID- 28362160 TI - Epidemiology of Skin Infections in Men's Wrestling: Analysis of 2009-2010 Through 2013-2014 National Collegiate Athletic Association Surveillance Data. AB - CONTEXT: Our knowledge of the current epidemiology of skin infections among wrestlers is limited. OBJECTIVE: To analyze and report the epidemiology of skin infections among National Collegiate Athletic Association (NCAA) men's wrestling student-athletes during the 2009-2010 through 2013-2014 academic years. DESIGN: Descriptive epidemiology study. SETTING: Aggregate skin infection and exposure data collected by the NCAA Injury Surveillance Program. PATIENTS OR OTHER PARTICIPANTS: Collegiate men's wrestling student-athletes. MAIN OUTCOME MEASURE(S): All viral, bacterial, or fungal skin infections reported by athletic trainers at 17 NCAA programs were analyzed, providing 35 team-seasons of data. Skin infection rates per 10 000 athlete-exposures (AEs), rate ratios, skin infection proportions, and skin infection proportion ratios were calculated. RESULTS: The athletic trainers reported 112 skin infections contracted by 87 student-athletes across 78 720 AEs. The overall skin infection rate was 14.23/10 000 AEs (95% confidence interval [CI] = 11.59, 16.86). Of the skin infections identified, 22.3% (n = 25) were recurrent skin infections. Most skin infections (65.2%) were attributable to 5 team-seasons (range, 11-19 infections). Most skin infections occurred during the regular season (n = 76, 67.9%), were identified during practice (n = 100, 89.3%), and resulted in >=24 hours' time loss (n = 83, 74.1%). The rate for viral skin infections was 1.72 times the rate for bacterial skin infections (95% CI = 1.09, 2.72) and 2.08 times the rate for fungal skin infections (95% CI = 1.28, 3.39). Fungal skin infections more often resulted in time loss <24 hours compared with all other skin infections (75.0% versus 12.5%; infection proportion ratio = 6.00; 95% CI = 3.30, 10.92). CONCLUSIONS: Our findings highlight the contagiousness of skin infections and suggest that skin infection rates may be attributable to high incidences among particular teams. PMID- 28362161 TI - Test-Retest Reliability of the King-Devick Test in an Adolescent Population. AB - CONTEXT: The King-Devick (KD) test is a screening tool designed to assess cognitive visual impairments, namely saccadic rhythm, postconcussion. Test-retest reliability of the KD in a healthy adolescent population has not yet been established. OBJECTIVE: To investigate the overall test-retest reliability of the KD among a sample of healthy adolescents. Additionally, we sought to determine if sex and age influenced reliability. DESIGN: Cross-sectional study. SETTING: Secondary school. PATIENTS OR OTHER PARTICIPANTS: Sixty-eight healthy adolescents, 41 boys (age = 15.4 +/- 1.9 years) and 27 girls (age = 15.4 +/- 1.9 years). MAIN OUTCOME MEASURE(S): Participants completed the KD (version 1) at 3 testing sessions (days 1, 30, and 45) following standard instructions. We recorded total time to complete the reading of 3 cards for each participant during each testing session. Two-way random-effects intraclass correlation coefficients (ICCs) using single measurements repeated over time and repeatability coefficients were calculated. Linear mixed models were used to determine whether differences existed at each testing time and to examine whether changes that took place among visits were different by sex or age. RESULTS: Adolescents who completed the KD demonstrated acceptable reliability (ICC = 0.81; 95% confidence interval = 0.73, 0.87); however, the repeatability coefficient was large (+/-8.76 seconds). The sample demonstrated improvements between visits 1 and 2 (mean +/- standard error = 4.3 +/- 0.5 seconds, P < .001) and between visits 2 and 3 (2.4 +/- 0.5 seconds, P < .001) for a total improvement of 6.9 seconds over 3 tests. No significant visit-by-sex or visit-by-age interactions were observed. CONCLUSIONS: Despite the ICC being clinically acceptable, providers using the KD test for serial assessment of concussion in adolescents should be cautious in interpreting the results due to a large learning effect. Incorporating multiple measures can ensure accurate detection of sport concussion. PMID- 28362163 TI - Ties That Bond: Youth Sport as a Vehicle for Social Identity and Positive Youth Development. AB - : An emerging area of research has focused on understanding how the group dynamics of a sport team influence positive youth development (PYD). The identities that youth form through their membership in sport teams (i.e., social identities) have been found to influence teammate behavior and team performance. Yet, minimal work exists on social identity and PYD in youth sport. PURPOSE: The purpose of this study was to investigate the relationship between social identity and PYD in sport. METHOD: Youth engaged in recreational sport (N = 219; Mage = 11.61 years, SD = 1.39 years) completed measures of social identity and PYD in sport. The social identity measure assessed 3 dimensions including ingroup ties (IGT; perceptions of similarity, bonding, belongingness), cognitive centrality (importance of being a team member), and ingroup affect (IGA; feelings associated with group membership). A regression analysis was performed separately for 4 PYD outcomes (personal and social skills, goal setting, initiative, negative experiences) with the 3 dimensions of social identity entered as predictors. RESULTS: Regression analyses revealed that IGT and IGA were positively associated with personal and social skills (R2 Adj. = .29). Further, IGT predicted initiative (R2 Adj. = .16), whereas IGA was positively associated with goal setting (R2 Adj. = .17) and negatively associated with negative experiences (R2 Adj. = .08). CONCLUSION: The findings extend previous research highlighting the benefits of social identity on teammate behavior and team performance and demonstrate how social identity may contribute to PYD through sport. PMID- 28362164 TI - Determination of restriction enzyme activity when cutting DNA labeled with the TOTO dye family. AB - Optical mapping, a single DNA molecule genome analysis platform that can determine methylation profiles, uses fluorescently labeled DNA molecules that are elongated on the surface and digested with a restriction enzyme to produce a barcode of that molecule. Understanding how the cyanine fluorochromes affect enzyme activity can lead to other fluorochromes used in the optical mapping system. The effects of restriction digestion on fluorochrome labeled DNA (Ethidium Bromide, DAPI, H33258, EthD-1, TOTO-1) have been analyzed previously. However, TOTO-1 is a part of a family of cyanine fluorochromes (YOYO-1, TOTO-1, BOBO-1, POPO-1, YOYO-3, TOTO-3, BOBO-3, and POPO-3) and the rest of the fluorochromes have not been examined in terms of their effects on restriction digestion. In order to determine if the other dyes in the TOTO-1 family inhibit restriction enzymes in the same way as TOTO-1, lambda DNA was stained with a dye from the TOTO family and digested. The restriction enzyme activity in regards to each dye, as well as each restriction enzyme, was compared to determine the extent of digestion. YOYO-1, TOTO-1, and POPO-1 fluorochromes inhibited ScaI-HF, PmlI, and EcoRI restriction enzymes. Additionally, the mobility of labeled DNA fragments in an agarose gel changed depending on which dye was intercalated. PMID- 28362162 TI - Hypoxia and Hypoglycemia synergistically regulate mRNA stability. AB - Ischemic events, common in many diseases, result from decreased blood flow and impaired delivery of oxygen and glucose to tissues of the body. While much is known about the cellular transcriptional response to ischemia, much less is known about the posttranscriptional response to oxygen and glucose deprivation. The goal of this project was to investigate one such posttranscriptional response, the regulation of mRNA stability. To that end, we have identified several novel ischemia-related mRNAs that are synergistically stabilized by oxygen and glucose deprivation including VEGF, MYC, MDM2, and CYR61. This increase in mRNA half-life requires the synergistic effects of both low oxygen (1%) as well as low glucose (<= 1 g/L) conditions. Oxygen or glucose deprivation alone fails to initiate the response, as exposure to either high glucose (4 g/L) or normoxic conditions inhibits the response. Furthermore, in response to hypoxia/hypoglycemia, the identified mRNAs are released from the RNA binding protein KHSRP which likely contributes to their stabilization. PMID- 28362165 TI - Physiological protection of probiotic microcapsules by coatings. AB - Nowadays, food and nutrition have a greater impact in people's concerns, with the awareness that nutrition have a direct impact in health and wellbeing. Probiotics have an important role in this topic and consumers are starting to really understand their potential in health, leading to an increasing interest of the companies to their commercial use in foods. However, there are several limitations to the use of probiotics in foods and beverages, being one of them their efficiency (directly associated to their survival rate) upon ingestion. This work is focused in microencapsulation techniques that have been used to increase probiotics efficiency. More specifically, this work reviews the most recent and relevant research about the production and coating techniques of probiotic-loaded microcapsules, providing an insight in the effect of these coatings in probiotics survival during the gastrointestinal phase. This review shows that coatings with the better performances in probiotics protection, against the harsh conditions of digestion, are chitosan, alginate, poly-L-lysine, and whey protein. Chitosan presented an interesting performance in probiotics protection being able to maintain the initial concentration of viable probiotics during a digestive test. The analyses of different works also showed that the utilization of several coatings does not guarantee a better protection in comparison with monocoated microcapsules. PMID- 28362166 TI - Illness uncertainty and illness intrusiveness as predictors of depressive and anxious symptomology in college students with chronic illnesses. AB - OBJECTIVE: To examine predictors of psychological functioning in college students with chronic illnesses. PARTICIPANTS: Participants (N = 1413) included 364 students with self-reported diagnoses of asthma or allergies, 148 students with other chronic illnesses (eg, epilepsy, type 1 diabetes), and 901 healthy students. Data were collected between November 2013 and May 2015. METHODS: Participants completed online measures of psychosocial functioning, including illness uncertainty, illness intrusiveness, depression, and anxiety. RESULTS: Students with chronic illnesses other than asthma or allergies evidenced the greatest levels of anxious (p <. 05), but not depressive symptomology. Additionally, this group reported greater illness uncertainty and intrusiveness (p <. 05) compared to their peers. Uncertainty and intrusiveness independently predicted depressive and anxious symptoms for students in both illness groups. CONCLUSIONS: Compared to peers with asthma or allergies, college students with other chronic illnesses reported higher levels of anxious symptoms. Illness uncertainty and intrusiveness appear to be predictors of psychological distress, regardless of illness. PMID- 28362167 TI - Adipocyte Secretome Increases Radioresistance of Malignant Melanocytes by Improving Cell Survival and Decreasing Oxidative Status. AB - Radiotherapy is a treatment option for the majority of malignancies. However, because melanoma is known to be radioresistant, the use of ionizing radiation as an adjuvant therapy in cutaneous melanoma patients is ineffective. Obesity has now been recognized as a risk factor for melanoma. High adiposity is generally associated with a more pro-oxidative status. Oxidative stress is a major player in radiation therapy and also a common link between obesity and cancer. Several adipocyte-released proteins are known to have a role in controlling cellular growth and pro-survival signaling. For that reason, we investigated the influence of 3T3-L1 mature adipocyte secretome in B16-F10 malignant melanocyte radiosensitivity. We evaluated B16-F10 cell survival and redox homeostasis when exposed to four daily doses of ionizing radiation (2 Gy per day) up to a total of 8 Gy in a medical linear accelerator. B16-F10 melanocytes exhibited slight alterations in survival, catalase activity, nitrative stress and total oxidant concentration after the first 2 Gy irradiation. The motility of the melanocytes was also delayed by ionizing radiation. Subsequent irradiations of the malignant melanocytes led to more prominent reductions in overall survival. Remarkably, 3T3 L1 adipocyte-secreted molecules were able to increase the viability and migration of melanocytes, as well as lessen the pro-oxidant burden induced by both the single and cumulative X-ray doses. In vitro adipocyte-released factors protected B16-F10 malignant melanocytes from both oxidative stress and loss of viability triggered by radiation, enhancing the radioresistant phenotype of these cells with a concomitant activation of the AKT signaling pathway. These results both help to elucidate how obesity influences melanoma radioresistance and support the usage of conventional medical linear accelerators as a valid model for the in vitro radiobiological study of tumor cell lines. PMID- 28362168 TI - Impact of Abbreviated Filgrastim Schedule on Survival and Hematopoietic Recovery after Irradiation in Four Mouse Strains with Different Radiosensitivity. AB - Filgrastim (Neupogen(r), granulocyte-colony stimulating factor) is among the few countermeasures recommended for management of patients in the event of lethal total-body irradiation. Despite the plethora of studies using filgrastim as a radiation countermeasure, relatively little is known about the optimal dose schedule of filgrastim to mitigate radiation lethality. We evaluated the efficacy of filgrastim in improving 30-day survival of CD2F1 mice irradiated with a lethal dose (LD70/30) in the AFRRI cobalt-60 facility. We tested different schedules of 1, 3, 5, 10 or 16 once-daily injections of filgrastim initiated one day after irradiation. Time optimization studies with filgrastim treatment were also performed, beginning 6-48 h postirradiation. Maximum survival was observed with 3 daily doses of 0.17 mg/kg filgrastim. Survival efficacy of the 3-day treatment was compared against the conventional 16-day filgrastim treatment after irradiation in four mouse strains with varying radiation sensitivities: C3H/HeN, C57BL/6, B6C3F1 and CD2F1. Blood indices, bone marrow histopathology and colony forming unit assays were also evaluated. Filgrastim significantly increased 30 day survival (P < 0.001) with a 3-day treatment compared to 16-day treatment. Filgrastim did not prevent cytopenia nadirs, but facilitated faster recovery of white blood cells, neutrophils, red blood cells, platelets, lymphocytes and hematocrits in all four strains. Accelerated hematopoietic recovery was also reflected in faster bone marrow reconstitution and significant increase in hematopoietic progenitors (P < 0.001) in all four mouse strains. These data indicate that prompt and abbreviated filgrastim treatment has potential benefit for triage in the event of a radiological incident for treating acute hematopoietic syndrome. PMID- 28362169 TI - Preliminary validation of the Portuguese Edinburgh Handedness Inventory in an adult sample. AB - The Edinburgh Handedness Inventory (EHI) is persistently the most used inventory to evaluate handedness, being neuropsychological investigation and clinical practice. Despite this, there is no information on how this instrument functions in a Portuguese population. The objective of this study was therefore to examine the sociodemographic influences on handedness and establish psychometric properties of the EHI in a Portuguese sample. The sample consisted of 342 adults (157 men and 185 women), assessed with a battery of neuropsychological tests. The mean EHI Laterality Quotient was 63.52 (SD = 38.00). A much high percentage of ambiguous-handedness compared to left-handedness was detected. An inconsistency was found between the preference for formal education activities (writing-drawing using scissors) and the remaining EHI activities. From sociodemographic variables, only age, area, and regions of residence showed significant influence on EHI scores. The reliability and temporal reliability of EHI were adequate. Confirmatory factor analysis indicated a one-factor model (chi2/df = 2.141; TLI = 0.972; CFI = 0.979; RMSEA = 0.058). The inconsistency between formal education and nonformal activities could be an indicator of social pressure. The present data give support for the notion that handedness measured by EHI is potentially sensitive to sociodemographic and cultural influences. PMID- 28362170 TI - Accuracy and reproducibility of dental measurements on tomographic digital models: a systematic review and meta-analysis. AB - OBJECTIVES: The aim of this systematic review with meta-analysis was to assess the accuracy and reproducibility of dental measurements obtained from digital study models generated from CBCT compared with those acquired from plaster models. METHODS: The electronic databases Cochrane Library, Medline (via PubMed), Scopus, VHL, Web of Science, and System for Information on Grey Literature in Europe were screened to identify articles from 1998 until February 2016. The inclusion criteria were: prospective and retrospective clinical trials in humans; validation and/or comparison articles of dental study models obtained from CBCT and plaster models; and articles that used dental linear measurements as an assessment tool. The methodological quality of the studies was carried out by Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. A meta analysis was performed to validate all comparative measurements. RESULTS: The databases search identified a total of 3160 items and 554 duplicates were excluded. After reading titles and abstracts, 12 articles were selected. Five articles were included after reading in full. The methodological quality obtained through QUADAS-2 was poor to moderate. In the meta-analysis, there were statistical differences between the mesiodistal widths of mandibular incisors, maxillary canines and premolars, and overall Bolton analysis. Therefore, the measurements considered accurate were maxillary and mandibular crowding, intermolar width and mesiodistal width of maxillary incisors, mandibular canines and premolars, in both arches for molars. CONCLUSIONS: Digital models obtained from CBCT were not accurate for all measures assessed. The differences were clinically acceptable for all dental linear measurements, except for maxillary arch perimeter. Digital models are reproducible for all measurements when intraexaminer assessment is considered and need improvement in interexaminer evaluation. PMID- 28362171 TI - Effects of Dietary Resistant Starch on the Wnt Signaling Pathway and Preneoplastic Cells in the Colons of Azoxymethane-Treated Rats. AB - Dietary resistant starch (RS) has been suggested to reduce colonic neoplasia. To determine the effects of digestion-resistant cornstarch on colonic carcinogenesis and Wnt signaling in azoxymethane (AOM)-treated F344 rats, diets containing naturally occurring RS from corn lines derived partially from Guat209 (GUAT), AR16035 (AR), or a hybrid (ARxGUAT), containing 34.5 +/- 2.0, 0.2 +/- 0.1, and 1.9 +/- 0.1% RS, respectively, were fed at 55% of the diet. GUAT-fed rats had increased cecal content and tissue weight and decreased cecal pH compared with AR or ARxGUAT-fed rats. Numbers of aberrant crypt foci (ACF) were not different among diet groups. Increased numbers of crypts/focus were observed in AOM injected rats fed GUAT compared with rats fed other diets. beta-catenin mRNA expression of the crypts was significantly increased in GUAT-fed rats injected with AOM relative to those injected with saline. These findings suggest that selected dietary RSs may at some level further enhance colonocyte proliferation and differentiation in an AOM-treated colon. PMID- 28362172 TI - Vitamin D Signaling Pathways Confer the Susceptibility of Esophageal Squamous Cell Carcinoma in a Northern Chinese Population. AB - Experimental studies have determined the chemopreventive effects of vitamin D against the esophageal squamous cell carcinoma (ESCC); however, results from the epidemiological studies are not yet well established. The current study aimed to evaluate the associations between plasma vitamin D levels and variants on vitamin D metabolic-related genes with the risks for ESCC. A hospital-based case-control study was performed. Five hundred eighty-two ESCC patients and 569 controls were recruited in a Northern Chinese population. Common variants on vitamin D metabolism-related genes CYP24A1, DHCR7, GC, CYP27B1, and vitamin D receptor (VDR) and the plasma 25(OH)D level were determined. The unconditional logistic regression method was applied to determine the associations between the variants and vitamin D level and ESCC. Higher plasma 25(OH)D was associated with a reduced risk for ESCC, especially for rs2296241, rs11568820, and rs4646536. The variants rs2296241 on CYP24A1 and rs11568820 on VDR are significantly associated with ESCC cancer. Vitamin D signaling pathways may participate in the ESCC development. Further studies with larger sample size are warranted to confirm the results. Intervention studies are needed to determine whether vitamin D supplementation may reduce the ESCC risk in the Chinese population. PMID- 28362174 TI - Thermodynamics, transport phenomena, and electrochemistry of external field assisted nonthermal food technologies. AB - Interest in the development and adoption of nonthermal technologies is burgeoning within the food and bioprocess industry, the associated research community, and among the consumers. This is evident from not only the success of some innovative nonthermal technologies at industrial scale, but also from the increasing number of publications dealing with these topics, a growing demand for foods processed by nonthermal technologies and use of natural ingredients. A notable feature of the nonthermal technologies such as cold plasma, electrohydrodynamic processing, pulsed electric fields, and ultrasound is the involvement of external fields, either electric or sound. Therefore, it merits to study the fundamentals of these technologies and the associated phenomenon with a unified approach. In this review, we revisit the fundamental physical and chemical phenomena governing the selected technologies, highlight similarities, and contrasts, describe few successful applications, and finally, identify the gaps in research. PMID- 28362175 TI - Synergistic Impact of d-delta-Tocotrienol and Geranylgeraniol on the Growth and HMG CoA Reductase of Human DU145 Prostate Carcinoma Cells. AB - The growth-suppressive effect of d-delta-tocotrienol and geranylgeraniol is at least partially attributed to their impact on 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme in the mevalonate pathway that provides essential intermediates for the posttranslational modification of growth related proteins including RAS. We hypothesize that these agents synergistically impact cell growth based on their complementary mechanisms of action with HMG CoA reductase. d-delta-tocotrienol (0-40 umol/L; half maximal inhibitory concentration [IC50] = 15 umol/L) and geranylgeraniol (0-100 umol/L; IC50 = 60 umol/L) each induced concentration-dependent suppression of the growth of human DU145 prostate carcinoma cells. Blends of the two agents synergistically suppressed the growth of DU145 cells, with combination index values ranging 0.67 0.75. While 7.5 umol/L d-delta-tocotrienol and 30 umol/L geranylgeraniol individually had no impact on cell cycle distribution in DU145 cells, a blend of the agents induced cell cycle arrest at the G1 phase. The synergistic downregulation of the expression of HMG CoA reductase by 7.5 umol/L d-delta tocotrienol and 30 umol/L geranylgeraniol was accompanied by a reduction in membrane K-RAS protein. Our finding supports the cancer chemopreventive action of plant-based diets and their isoprenoid constituents. Properly formulated isoprenoids and derivatives may provide novel approaches in prostate cancer prevention and therapy. PMID- 28362179 TI - Serotonin-induced hypophagia is mediated via alpha2 and beta2 adrenergic receptors in neonatal layer-type chickens. AB - 1. Serotoninergic and adrenergic systems play crucial roles in feed intake regulation in avians but there is no report on possible interactions among them. So, in this study, 5 experiments were designed to evaluate the interaction of central serotonergic and adrenergic systems on food intake regulation in 3 h food deprived (FD3) neonatal layer-type chickens. 2. In Experiment 1, chickens received intracerebroventricular (ICV) injection of control solution, serotonin (56.74 nmol), prazosin (alpha1 receptor antagonist, 10 nmol) and co-injection of serotonin plus prazosin. In Experiment 2, control solution, serotonin (56.74 nmol), yohimbine (alpha2 receptor antagonist, 13 nmol) and co-injection of serotonin plus yohimbine were used. In Experiment 3, the birds received control solution, serotonin (56.74 nmol), metoprolol (beta1 receptor antagonist, 24 nmol) and co-injection of serotonin plus metoprolol. In Experiment 4, injections were control solution, serotonin (56.74 nmol), ICI 118.551 (beta2 receptor antagonist, 5 nmol) and serotonin plus ICI 118.551. In Experiment 5, control solution, serotonin (56.74 nmol), SR59230R (beta3 receptor antagonist, 20 nmol) and co administration of serotonin and SR59230R were injected. In all experiments the cumulative food intake was measured until 120 min post injection. 3. The results showed that ICV injection of serotonin alone decreased food intake in chickens. A combined injection of serotonin plus ICI 118.551 significantly attenuated serotonin-induced hypophagia. Also, co-administration of serotonin and yohimbine significantly amplified the hypophagic effect of serotonin. However, prazosin, metoprolol and SR59230R had no effect on serotonin-induced hypophagia in chickens. 4. These results suggest that serotonin-induced feeding behaviour is probably mediated via alpha2 and beta2 adrenergic receptors in neonatal layer type chicken. PMID- 28362177 TI - Advances in Retinal Prosthetic Research: A Systematic Review of Engineering and Clinical Characteristics of Current Prosthetic Initiatives. AB - PURPOSE: To date, reviews of retinal prostheses have focused primarily on devices undergoing human trials in the Western Hemisphere and fail to capture significant advances in materials and engineering research in countries such as Japan and Korea, as well as projects in early stages of development. To address these gaps, this systematic review examines worldwide advances in retinal prosthetic research, evaluates engineering characteristics and clinical progress of contemporary device initiatives, and identifies potential directions for future research in the field of retinal prosthetics. METHODS: A literature search using PubMed, Google Scholar, and IEEExplore was conducted following the PRISMA Guidelines for Systematic Review. Inclusion criteria were peer-reviewed papers demonstrating progress in human or animal trials and papers discussing the prosthetic engineering design. For each initiative, a description of the device, its engineering considerations, and recent clinical results were provided. RESULTS: Ten prosthetic initiatives met our inclusion criteria and were organized by stimulation location. Of these initiatives, four have recently completed human trials, three are undergoing multi- or single-center human trials, and three are undergoing preclinical animal testing. Only the Argus II (FDA 2013, CE 2011) has obtained FDA approval for use in the United States; the Alpha-IMS (CE 2013) has achieved the highest visual acuity using a Landolt-C test to date and is the only device presently undergoing a multicenter clinical trial. CONCLUSION: Several distinct approaches to retinal stimulation have been successful in eliciting visual precepts in animals and/or humans. However, many clinical needs are still not met and engineering challenges must be addressed before a retinal prosthesis with the capability to fully and safely restore functional vision can be realized. PMID- 28362176 TI - Co-delivery of insulin-like growth factor 1 receptor specific siRNA and doxorubicin using chitosan-based nanoparticles enhanced anticancer efficacy in A549 lung cancer cell line. AB - Here, we investigated the effects of dual delivery of IGF-1R siRNA and doxorubicin by chitosan nanoparticles on viability of A549 lung cancer cells line by utilization of MTT and qRT-PCR. Furthermore apoptosis and migration of treated cells were assessed by Annexin-PI and wound healing assays, respectively. The chitosan nanoparticles had about 176 nm size with zeta potential and polydispersive index about 11 mV and 0.3, respectively. The IGF-1R siRNA had synergistic effect on DOX-induced cytotoxicity and apoptosis in tumour cells. In addition, siRNA/DOX-loaded chitosan nanoparticles could significantly decrease migration and expressions of mmp9, VEGF and STAT3 in A549 cells. PMID- 28362180 TI - Not All Orgasms Were Created Equal: Differences in Frequency and Satisfaction of Orgasm Experiences by Sexual Activity in Same-Sex Versus Mixed-Sex Relationships. AB - Which sexual activities result in the most frequent and most satisfying orgasms for men and women in same- and mixed-sex relationships? The current study utilized a convenience sample of 806 participants who completed an online survey concerning the types of sexual activities through which they experience orgasms. Participants indicated how frequently they reached orgasm, how satisfied they were from orgasms resulting from 14 sexual activities, and whether they desired a frequency change for each sexual activity. We present the overall levels of satisfaction, frequency, and desired frequency change for the whole sample and also compare responses across four groups of participants: men and women in same sex relationships and men and women in mixed-sex relationships. While all participants reported engaging in a wide variety of activities that either could, or often did, lead to the experience of orgasm, there were differences in the levels of satisfaction derived from different types of orgasms for different types of participants, who also engaged in such activities with varying degrees of frequency. We discuss group differences within the context of sexual scripts for same- and mixed-sex couples and question the potential explanations for gender differences in the ability to experience orgasm during partnered sexual activity. PMID- 28362181 TI - Infantile scurvy revealed by spontaneous orbital hematoma. PMID- 28362182 TI - Pediatric spinal cord astrocytomas: a retrospective study of 348 patients from the SEER database. AB - OBJECTIVE Intramedullary spinal cord tumors comprise 1%-10% of all childhood central nervous system neoplasms, with astrocytomas representing the most common subtype. Due to their rarity and poor prognosis, large population-based studies are needed to assess the epidemiology and survival risk factors associated with these tumors in the hope of improving outcome. The authors undertook this retrospective study to explore factors that may influence survival in pediatric patients with spinal cord astrocytomas. METHODS Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, a prospective cancer registry, the authors retrospectively assessed survival in histologically confirmed, primary spinal cord astrocytomas in patients 21 years of age and younger. Survival was described with Kaplan-Meyer curves, and a multivariate regression analysis was used to assess the association of several variables with survival while controlling for confounding variables. RESULTS This analysis of 348 cases showed that age (hazard ratio [HR] 1.05, 95% CI 1.01-1.09, p = 0.017), nonwhite race (HR 1.74, 95% CI 1.11-2.74, p = 0.014), high-grade tumor status (HR 14.67, 95% CI 6.69-32.14, p < 0.001), distant or invasive extension of the tumor (HR 2.37, 95% CI 1.02-5.49, p = 0.046), and radiation therapy (HR 3.74, 95% CI 2.18-6.41, p < 0.001) were associated with decreased survival. Partial resection (HR 0.37, 95% CI 0.16-0.83, p = 0.017) and gross-total resection (HR 0.39, 95% CI 0.16-0.95, p = 0.039) were associated with improved survival. CONCLUSIONS Younger age appears to be protective, while high-grade tumors have a much worse prognosis. Early diagnosis and access to surgery appears necessary for improving outcomes, while radiation therapy has an unclear role. There is still much to learn about this disease in the hope of curing children with the misfortune of having one of these rare tumors. PMID- 28362183 TI - Editorial. Early unplanned reoperation: we need more data. PMID- 28362184 TI - Surveillance survey of family history in children with neural tube defects. AB - OBJECTIVE Although there are known risk factors for the development of neural tube defects (NTDs), little is known regarding the role of family history. The authors' goal in this study is to describe the family history in their population of patients with NTDs. METHODS Surveys were completed for 254 patients who were accompanied by their biological mother during their annual visit to the multidisciplinary Spina Bifida Clinic at Children's of Alabama. An NTD has been diagnosed in all patients who are seen in this clinic (myelomeningocele, lipomeningocele, split cord malformation, and congenital dermal sinus tract). Each mother answered questions regarding known NTD risk factors and their pregnancy, as well as the family history of NTDs, other CNS disorders, and birth defects. RESULTS The overall prevalence of family history of NTDs in children with an NTD was 16.9% (n = 43), of which 3.1% (n = 8) were in first-degree relatives. In patients with myelomeningocele, 17.7% (n = 37) had a positive family history for NTDs, with 3.8% in first-degree relatives. Family history in the paternal lineage for all NTDs was 8.7% versus 10.6% in the maternal lineage. Twenty-two patients (8.7%) had a family history of other congenital CNS disorders. Fifteen (5.9%) had a family history of Down syndrome, 12 (4.7%) had a family history of cerebral palsy, and 13 (5.1%) patients had a family history of clubfoot. Fourteen (5.5%) had a family history of cardiac defect, and 13 (5.1%) had a family history of cleft lip or palate. CONCLUSIONS The family history of NTDs was 16.9% in children with NTD without a difference between maternal and paternal lineage. This high rate of positive family history suggests that genetics and epigenetics may play a larger role in the pathogenesis of NTD in the modern era of widespread folate supplementation. PMID- 28362185 TI - Reoperations within 48 hours following 7942 pediatric neurosurgery procedures. AB - OBJECTIVE Various indicators are used to evaluate the quality of care delivered by surgical services, one of which is early reoperation rate. The indications and rate of reoperations within a 48-hour time period have not been previously reported for pediatric neurosurgery. METHODS Between May 1, 2009, and December 30, 2014, 7942 surgeries were performed by the pediatric neurosurgery service in the operating rooms at a single institution. Demographic, socioeconomic, and clinical characteristics associated with each of the operations were prospectively collected. The procedures were grouped into 31 categories based on the nature of the procedure and underlying diseases. Reoperations within 48 hours at the conclusion of the index surgery were reviewed to determine whether the reoperation was planned or unplanned. Multivariate logistic regression was employed to analyze risk factors associated with unplanned reoperations. RESULTS Cerebrospinal fluid shunt-and hydrocephalus-related surgeries accounted for 3245 (40.8%) of the 7942 procedures. Spinal procedures, craniotomy for tumor resections, craniotomy for traumatic injury, and craniofacial reconstructions accounted for an additional 8.7%, 6.8%, 4.5%, and 4.5% of surgical volume. There were 221 reoperations within 48 hours of the index surgery, yielding an overall incidence of 2.78%; 159 of the reoperation were unplanned. Of these 159 unplanned reoperations, 121 followed index operations involving shunt manipulations. Using unplanned reoperations as the dependent variable (n = 159), index operations with a starting time after 3 pm and admission through the emergency department (ED) were associated with a two- to threefold increase in the likelihood of reoperations (after-hour surgery, odds ratio [OR] 2.01 [95% CI 1.43-2.83, p < 0.001]; ED admission, OR 1.97 (95% CI 1.32-2.96, p < 0.05]). CONCLUSIONS Approximately 25% of the reoperations within 48 hours of a pediatric neurosurgical procedure were planned. When reoperations were unplanned, contributing factors could be both surgeon related and system related. Further study is required to determine the extent to which these reoperations are preventable. The utility of unplanned reoperation as a quality indicator is dependent on proper definition, analysis, and calculation. PMID- 28362186 TI - A proposal for a new classification of complications in craniosynostosis surgery. AB - OBJECTIVE Complications have been used extensively to facilitate evaluation of craniosynostosis practice. However, description of complications tends to be nonstandardized, making comparison difficult. The authors propose a new pragmatic classification of complications that relies on prospective data collection, is geared to capture significant morbidity as well as any "near misses" in a systematic fashion, and can be used as a quality improvement tool. METHODS Data on complications for all patients undergoing surgery for nonsyndromic craniosynostosis between 2010 and 2015 were collected from a prospective craniofacial audit database maintained at the authors' institution. Information on comorbidities, details of surgery, and follow-up was extracted from medical records, anesthetic and operation charts, and electronic databases. Complications were defined as any unexpected event that resulted or could have resulted in a temporary or permanent damage to the child. RESULTS A total of 108 operations for the treatment of nonsyndromic craniosynostosis were performed in 103 patients during the 5-year study period. Complications were divided into 6 types: 0) perioperative occurrences; 1) inpatient complications; 2) outpatient complications not requiring readmission; 3) complications requiring readmission; 4) unexpected long-term deficit; and 5) mortality. These types were further subdivided according to the length of stay and time after discharge. The overall complication rate was found to be 35.9%. CONCLUSIONS The proportion of children with some sort of complication using the proposed definition was much higher than commonly reported, predominantly due to the inclusion of problems often dismissed as minor. The authors believe that these complications should be included in determining complication rates, as they will cause distress to families and may point to potential areas for improving a surgical service. PMID- 28362188 TI - Spinal column shortening for tethered cord syndrome associated with myelomeningocele, lumbosacral lipoma, and lipomyelomeningocele in children and young adults. AB - OBJECTIVE Tethered cord syndrome is the clinical manifestation of an abnormal stretch on the spinal cord, presumably causing mechanical injury, a compromised blood supply, and altered spinal cord metabolism. Tethered cord release is the standard treatment for tethered cord syndrome. However, direct untethering of the spinal cord carries potential risks, such as new neurological deficits from spinal cord injury, a CSF leak from opening the dura, and retethering of the spinal cord from normal scar formation after surgery. To avoid these risks, the authors applied spinal column shortening to children and transitional adults with primary and secondary tethered cord syndrome and report treatment outcomes. The authors' aim with this study was to determine the safety and efficacy of spinal column shortening for tethered cord syndrome by analyzing their experience with this surgical technique. METHODS The authors retrospectively reviewed the demographic and procedural data of children and young adults who had undergone spinal column shortening for primary or secondary tethered cord syndrome. RESULTS Seven patients with tethered cord syndrome caused by myelomeningocele, lipomyelomeningocele, and transitional spinal lipoma were treated with spinal column shortening. One patient with less than 24 months of follow-up was excluded from further analysis. There were 3 males and 4 females; the average age at the time was surgery was 16 years (range 8-30 years). Clinical presentations for our patients included pain (in 5 patients), weakness (in 4 patients), and bowel/bladder dysfunction (in 4 patients). Spinal column osteotomy was most commonly performed at the L-1 level, with fusion between T-12 and L-2 using a pedicle screw-rod construct. Pedicle subtraction osteotomy was performed in 6 patients, and vertebral column resection was performed in 1 patient. The average follow-up period was 31 months (range 26-37 months). Computed tomography-based radiographic outcomes showed solid fusion and no instrumentation failure in all cases by the most recent follow-up. Five of 7 patients (71%) reported improvement in preoperative symptoms during the follow-up period. The mean differences in initial and most recent Scoliosis Research Society Outcomes Questionnaire and Oswestry Disability Index scores were 0.26 and -13%, respectively; minimum clinically important difference in SRS-22 and ODI were assumed to be 0.4% and 12.8%, respectively. CONCLUSIONS Spinal column shortening seems to represent a safe and efficacious alternative to traditional untethering of the spinal cord for tethered cord syndrome. PMID- 28362187 TI - Three-dimensional changes in head shape after extended sagittal strip craniectomy with wedge ostectomies and helmet therapy. AB - OBJECTIVE Outcome studies for sagittal strip craniectomy have largely relied on the 2D measure of the cephalic index (CI) as the primary indicator of head shape. The goal of this study was to measure the 2D and 3D changes in head shape that occur after sagittal strip craniectomy and postoperative helmet therapy. METHODS The authors performed a retrospective review of patients treated with sagittal strip craniectomy at their institution between January 2012 and October 2015. Inclusion criteria were as follows: 1) isolated sagittal synostosis; 2) age at surgery < 200 days; and 3) helmet management by a single orthotist. The CI was calculated from 3D images. Color maps and dot maps were generated from 3D images to demonstrate the regional differences in the magnitude of change in head shape over time. RESULTS Twenty-one patients met the study inclusion criteria. The mean CI was 71.9 (range 63.0-77.9) preoperatively and 81.1 (range 73.0-89.8) at the end of treatment. The mean time to stabilization of the CI after surgery was 57.2 +/- 32.7 days. The mean maximum distances between the surfaces of the preoperative and 1-week postoperative and between the surfaces of the preoperative and end-of-treatment 3D images were 13.0 +/- 4.1 mm and 24.71 +/- 6.83 mm, respectively. The zone of maximum change was distributed equally in the transverse and vertical dimensions of the posterior vault. CONCLUSIONS The CI normalizes rapidly after sagittal strip craniectomy (57.2 days), with equal distribution of the change in CI occurring before and during helmet therapy. Three-dimensional analysis revealed significant vertical and transverse expansion of the posterior cranial vault. Further studies are needed to assess the 3D changes that occur after other sagittal strip craniectomy techniques. PMID- 28362189 TI - Canakinumab for the treatment of familial Mediterranean fever. AB - INTRODUCTION: Familial Mediterranean fever (FMF) is the most frequent of all hereditary autoinflammatory syndromes. It is characterized by recurrent attacks of fever and serositis. If not treated it may be complicated with AA amyloidosis. It is caused by mutations in the MEFV gene that encodes pyrin which is involved in the regulation of IL-1beta. The mainstay of treatment is colchicine, however a subset of patients requires an alternative treatment either due to inadequate response or intolerance. The accumulating data indicates that anti IL-1 drugs are effective in treating colchicine resistant FMF cases and improving their quality of life. Areas covered: This review focuses on canakinumab, a fully human anti IL 1beta antibody, treatment in FMF. Expert commentary: Canakinumab became the first approved therapy by the Food and Drug Administration for FMF very recently, which highlights its importance as the alternative treatment in FMF. PMID- 28362190 TI - HPV epigenetic mechanisms related to Oropharyngeal and Cervix cancers. AB - Human Papilloma Virus infection is very frequent in humans and is mainly transmitted sexually. The majority of infections are transient and asymptomatic, however, if the infection persists, it can occur with a variety of injuries to skin and mucous membranes, depending on the type of HPV involved. Some types of HPV are classified as high oncogenic risk as associated with the onset of cancer. The tumors most commonly associated with HPV are cervical and oropharyngeal cancer, epigenetic mechanisms related to HPV infection include methylation changes to host and viral DNA and chromatin modification in host species. This review is focused about epigenethic mechanism, such as MiRNAs expression, related to cervix and oral cancer. Specifically it discuss about molecular markers associated to a more aggressive phenotype. In this way we will analyze genes involved in meiotic sinaptonemal complex, transcriptional factors, of orthokeratins, sinaptogirin, they are all expressed in cancer in a way not more dependent on cell differentiation but HPV-dependent. PMID- 28362191 TI - Increase in depression diagnoses and prescribed antidepressants among young girls. A national cohort study 2000-2013. AB - AIMS: To analyse trends in depression diagnoses and antidepressant use according to age and gender. METHODS: Nationwide cohort study including all women and men of 10-49 years living in Denmark during 2000-2013. The Psychiatric Registry and Prescription Registry provided data on depression diagnoses and antidepressant medication, respectively. Incidence rates as well as 1-year prevalence rates were calculated. RESULTS: The incidence and 1-year prevalence rates of depression diagnoses increased during 2000-2013. The women/men rates were 2.0 for both 1 year prevalence of depressions diagnoses and antidepressant use. For adolescent girls, the absolute increase was 3 per 1000 for depression diagnoses and 8 per 1000 for first use of antidepressants, compared to boys who had an increase of 1.1 and 3 per 1000, respectively. Before puberty, boys and girls had almost the same incidence rates of both depression diagnoses and antidepressant use throughout the period. After puberty, girls had significantly higher incidence rates than boys, and experienced during the study period a steeper increase than boys. According to age, the girls/boys incidence rate ratio of a depression diagnosis increased from 0.8 in the 10-11 year age group to 2.7 at age 12-19 years and hereafter decreased with increasing age to 1.5 at age 45-49. CONCLUSIONS: Depression diagnosed and first use of antidepressants increased more for girls of 12-19 years than for boys during 2000-2013, and the incidences were similar for girls and boys before puberty, but higher after puberty for girls. PMID- 28362193 TI - Relations between awareness of morphosyntactic structures in Chinese compound words and reading abilities: A short report. AB - This is a short report of the investigation of the relationship between awareness of morphosyntactic structures in Chinese compound words and reading abilities on 268 fourth graders studying in three mainstream schools in Shenzhen. All children were assessed using reading and cognitive tasks including rapid automatized naming, phonological, orthographic and morphological awareness. A compound production task using pseudo compound words with different morphosyntactic structures in the first and second levels as stimuli was also conducted. Results of ANOVA indicated that main effect of first level morphosyntactic structures, main effect of second level morphosyntactic structures and interaction effects between the two were significant. Children's awareness of different morphosyntactic structures were affected by frequency of usage of individual morphosyntactic structures in the language. Results of hierarchical regression analyses revealed that the awareness of morphosyntactic structures in Chinese compound words is strongly associated with Chinese reading abilities. Theoretical and clinical implications were discussed. PMID- 28362192 TI - Ovarian metastasis from lung adenocarcinoma with ALK-positive rearrangement detected by next generation sequencing: A case report and literatures review. AB - Ovarian metastasis is an exceptionally rare condition in lung adenocarcinoma patients and is often difficult to distinguish from primary ovarian carcinoma. ALK (anaplastic lymphoma kinase) tyrosine kinase inhibitors elicit a significant objective response rate and are well-tolerated in advanced ALK-positive lung cancer. Hence, we report a case of a 41-year-old woman with ovarian metastases from NSCLC. After receiving a 6 course first line chemotherapy and 8 course maintenance therapy, the patient suffered acute abdominal pain, so surgery was performed. ALK rearrangement was detected by next generation sequencing, with a 13% abundance of ALK fusion. Crizotinib was administered, and the disease remained stable after 10 months of crizotinib therapy. Further, we reviewed the literature related to characteristics of metastatic ovarian malignancies that form from lung tumors, the utility of ALK inhibition for treating ALK-positive NSCLC, the molecular diagnosis of ALK rearrangement and the role of next generation sequencing for ALK rearrangement detection. PMID- 28362195 TI - Unproven Stem Cell Treatments for Lung Disease-An Emerging Public Health Problem. PMID- 28362194 TI - Induced Pluripotent Stem Cells in Pulmonary Arterial Hypertension. PMID- 28362196 TI - Post Hoc: Two (or More) for the Price of One. PMID- 28362197 TI - Sepsis-3: Syndromes and Empiricism in the Age of Big Data. PMID- 28362198 TI - The Use of Plasmapheresis in Patients with Bronchiectasis with Pseudomonas aeruginosa Infection and Inhibitory Antibodies. PMID- 28362199 TI - Effects of Lumacaftor/Ivacaftor in a Pediatric Cohort Homozygous for F508del CFTR. PMID- 28362200 TI - Maladaptive Suppression of Bacterial Clearance in Early Sepsis. Setting the Scene for Failure. PMID- 28362201 TI - Prolonged Apnea Supported by High-Frequency Noninvasive Ventilation: A Pilot Study. PMID- 28362202 TI - Eucapnic Voluntary Hyperpnea Testing in Athletes. PMID- 28362203 TI - Noninvasive Ventilation with Helium/Oxygen in Chronic Obstructive Pulmonary Disease Exacerbations. When Physiologic Improvement Does Not Translate into Clinical Benefit. PMID- 28362204 TI - Reply: Exploring Endomicroscopy in the Field of Pulmonology. PMID- 28362205 TI - Endomicroscopy, Not "Optical Biopsy" (Yet). PMID- 28362206 TI - A Glimpse into the Future: Automated Quantitative Computed Tomography as a Biomarker in Idiopathic Pulmonary Fibrosis. PMID- 28362207 TI - Reply: Reevaluating the Diagnostic Threshold for Eucapnic Voluntary Hyperpnea Testing in Athletes. PMID- 28362209 TI - Secondary metabolism in Penicillium expansum: Emphasis on recent advances in patulin research. AB - The plant pathogenic fungus Penicillium expansum is a major concern of the global food industry due to its wide occurrence and ability to produce various mycotoxins, of which the most significant is patulin. Relatively less highlighted in the literature, in comparison with the other food-borne mycotoxins, patulin is one of the main factors in economic losses of vegetables and fruits. Otherwise, patulin is a health hazard which results in both short-term and long-term risks. This review includes knowledge on the biosynthetic mechanisms used for secondary metabolite production in P. expansum, with special emphasis on patulin biosynthesis. The abiotic factors triggering the production of patulin and the strategies developed to reduce or prevent the contamination by this mycotoxin are comprehensively discussed. The database presented in this review would be useful for the prioritization and development of future research. PMID- 28362208 TI - The early-onset febrile reaction following vaccination and associated factors: An exploratory sub-study based on the Ebola vaccine clinical trial. AB - A phase-1 clinical trial aimed to assess the safety and immunogenicity of the type-5 adenovirus vector based Ebola vaccine (Ad5-EBOV) was conducted in China. To provide more evidence for the safety evaluation and dose-selection, an exploratory sub-study using a wireless automatic temperature measuring platform was done based on the phase-1 clinical trial. The main aim of the sub-study was to obtain more information about the occurrence of fever and detect the potential associated factors, second was to assess the feasibility of the temperature measuring platform in vaccine clinical trials. Temperature data of 3 treatment groups all presented a rising tendency during the first 6 hours after vaccination, the incidence of elevated temperature and possible associated factors were analyzed. For the incidence of elevated temperature, no marked dose response relationship was found in 6 hours with wireless thermometers; the information from mercury thermometers showed that the grade-1 fever proportion peaked at 6 hours and there was no difference between groups, while grade-2 fever proportion peaked at 24 hours and was significantly higher in high-dose group than those in the other 2 groups. Significant differences were found between sex groups (males vs. female, incidence rate ratios (IRR) = 2.93 and 7.62 for any grade, grade-2 fever respectively, P<0.001); a decline in grade-2 fever incidence was found with the increasing age groups (IRR = 0.78, P = 0.003) and body mass index (BMI, IRR = 0.67, P<0.001) .Our findings show that the dose-dependent manner between fever and the dose of Ad5-EBOV in this study might emerge after 6 hours, and which is slight and transient. Wireless thermometers secured on the skin surface are not suitable for a long time (longer than 6 hours) measurement, new methods for temperature monitoring, like ear temperature measurement, should be tested in the further research. PMID- 28362211 TI - Laser interstitial thermal therapy for palliative ablation of a chordoma metastasis to the spine: case report. AB - The authors present the first report of laser interstitial thermal therapy (LITT) ablation of a recurrent chordoma metastasis to the cervical spine. This patient was a 75-year-old woman who was diagnosed and treated for a sacral chordoma, and then developed metastases to the lung and upper thoracic spine. Unfortunately she experienced symptomatic recurrence at the C-7 spinous process. She underwent an uncomplicated LITT to the lesion. The patient convalesced without incident and was discharged on postoperative Day 1. She received stereotactic spinal radiosurgery to the lesion at a dose of 24 Gy in 1 fraction. At the 3-month follow-up evaluation she had radiographic response and improvement in her symptoms. PMID- 28362210 TI - Solar radiation is inversely associated with inflammatory bowel disease admissions. AB - OBJECTIVE: To explore the associations between latitude and solar radiation with inflammatory bowel disease admission rates in Chile, the country with the largest variation in solar radiation in the world. PATIENTS AND METHODS: This is an ecological study, which included data on all hospital-admitted population for inflammatory bowel disease between 2001 and 2012, according to different latitudes and solar radiation exposures in Chile. The data were acquired from the national hospital discharge database from the Department of Health Statistics and Information of the Chilean Ministry of Health. RESULTS: Between 2001 and 2012 there were 12,869 admissions due to inflammatory bowel disease (69% ulcerative colitis, 31% Crohn's disease). Median age was 36 years (IQR: 25-51); 57% were female. The national inflammatory bowel disease admission rate was 6.52 (95% CI: 6.40-6.63) per 100,000 inhabitants with increasing rates over the 12-year period. In terms of latitude, the highest admission rates for pediatric ulcerative colitis and Crohn's disease, as well as adult ulcerative colitis, were observed in the southernmost region with lowest annual solar radiation. Linear regression analysis showed that regional solar radiation was inversely associated with inflammatory bowel disease admissions in Chile (beta: -.44, p = .03). CONCLUSIONS: Regional solar radiation was inversely associated with inflammatory bowel disease admission rates in Chile; inflammatory bowel disease admissions were highest in the southernmost region with lowest solar radiation. Our results support the potential role of vitamin D deficiency on inflammatory bowel disease flares. PMID- 28362212 TI - Does clinical improvement of symptomatic degenerative lumbar disease impact obesity? AB - OBJECTIVE Obesity and low-back pain associated with degenerative spondylosis or spondylolisthesis are common comorbid conditions. Many patients report that the pain and disability associated with degenerative lumbar disease are key factors in their inability to lose weight. The aim of this retrospective study was to determine if there is an association between improved functional status and weight loss following a successful transforaminal lumbar interbody fusion (TLIF) procedure. METHODS A retrospective cohort study of patients who underwent single level TLIF was performed. Inclusion criteria were preoperative body mass index (BMI) greater than 30 kg/m2, achievement of minimum clinically important difference in the Oswestry Disability Index (ODI, defined as improvement of 15 points), and minimum 1-year postoperative followup BMI. Preoperative and postoperative BMI, ODI, and visual analog scale (VAS) scores were compared. A subgroup analysis of patients who achieved substantial clinical benefit (SCB, defined as a net improvement of 18.8 points on the ODI) was also performed. RESULTS A total of 56 patients met the inclusion criteria. The mean age of the study population was 55.6 +/- 13.7 years. The mean preoperative BMI was 34.8 +/- 4.6 kg/m2, the mean preoperative ODI was 66.2 +/- 10.1, and the mean preoperative VAS score was 7.1 +/- 1.7. The mean change in ODI was -33.1 +/- 13.5 (p < 0.01) and the mean change in the VAS score was -4.1 +/- 2.1 (p < 0.01). The mean change in BMI was +0.15 +/- 2.1 kg/m2 (range -4.2 to +6.5 kg/m2; p = 0.6). SCB was achieved in 46 patients on the ODI. The mean preoperative BMI for patients with SCB was 34.8 +/- 4.8 kg/m2, and the mean postoperative BMI was 34.7 +/- 5.0 kg/m2. The mean change in BMI was -0.03 +/- 1.9 kg/m2 (p = 0.9). CONCLUSIONS Despite successful surgical intervention via TLIF with achievement of improved function and pain, obese patients did not have significant change in weight postoperatively. PMID- 28362213 TI - Digital subtraction myelography in the investigation of post-dural puncture headache in 27 patients: technical note. AB - OBJECTIVE Post-dural puncture headaches are common, and the treatment of such headaches can be complex when they become chronic. Among patients with spontaneous spinal CSF leaks, digital subtraction myelography (DSM) can localize the exact site of the leak when an extradural CSF collection is present, and it can also demonstrate CSF-venous fistulas in those without an extradural CSF collection. The authors now report on the use of DSM in the management of patients with chronic post-dural puncture headaches. METHODS The patient population consisted of a consecutive group of 27 patients with recalcitrant post dural puncture headache that had lasted from 2 to 150 months (mean 26 months). RESULTS The mean age of the 17 women and 10 men was 39.1 years (range 18-77 years). An extensive extradural CSF collection was present in 5 of the 27 patients, and DSM was able to localize the exact site of the dural defect in all 5 patients. Among the 22 patients who did not have an extradural CSF collection, DSM showed a CSF-venous fistula in 1 patient (5%). Three other patients had a small pseudomeningocele at the level of the dural puncture. Percutaneous glue injection or microsurgical repair resulted in resolution of symptoms in 8 of the 9 patients in whom an abnormality had been identified on imaging. CONCLUSIONS Digital subtraction myelography is able to precisely localize the dural puncture site in patients with a post-dural puncture headache and an extensive extradural CSF collection, and it may rarely detect a CSF-venous fistula in such patients without an extradural CSF collection. PMID- 28362215 TI - A Parental Health Education Model of Children's Food Consumption: Influence on Children's Attitudes, Intention, and Consumption of Healthy and Unhealthy Foods. AB - This study proposes that parental mediation of television advertising and parental guidance of food consumption differentially influence children's attitude, intention, and behavior toward the consumption of healthy and unhealthy foods. Structural equation modeling based on a survey of 1,119 children aged 9-12 supported our model, revealing that parental education strategies influence children's food consumption in a complex manner that is highly context-dependent. Parental guidance of food consumption enhanced children's healthy food attitude and intention to consume, while reducing the intention to consume unhealthy food. However, parental mediation of television advertising influenced unhealthy food attitude to a greater extent than healthy food attitude. Implications for health promotion and education, as well as parents and policy makers are discussed. PMID- 28362214 TI - A systematic multidisciplinary initiative for reducing the risk of complications in adult scoliosis surgery. AB - OBJECTIVE Systematic multidisciplinary approaches to improving quality and safety in complex surgical care have shown promise. Complication rates from complex spine surgery range from 10% to 90% for all surgeries, and the overall mortality rate is 1%-4%. These rates suggest the need for improved perioperative complex spine surgery processes designed to minimize risk and improve quality. METHODS The Group Health Research Institute and Virginia Mason Medical Center implemented a systematic multidisciplinary protocol, the Seattle Spine Team Protocol, in 2010. This protocol involves the following elements: 1) a comprehensive multidisciplinary conference including clinicians from neurosurgery, anesthesia, orthopedics, internal medicine, behavioral health, and nursing, collaboratively deciding on each patient's suitability for surgery; 2) a mandatory patient education course that reviews the risks of surgery, preparation for the surgery, and postoperative care; 3) a dual-attending-surgeon approach involving 1 neurosurgeon and 1 orthopedic spine surgeon; 4) a dedicated specialist complex spine anesthesia team; and 5) rigorous intraoperative monitoring of a patient's blood loss and coagulopathy. The authors identified 71 patients who underwent complex spine surgery involving fusion of 6 or more levels before implementation of the protocol (surgery between 2008 and 2010) and 69 patients who underwent complex spine surgery after the implementation of the protocol (2010 and 2012). All patient demographic variables, including age, sex, body mass index, smoking status, diagnosis of diabetes and/or osteoporosis, previous surgery, and the nature of the spinal deformity, were comprehensively assessed. Also comprehensively assessed were surgical variables, including operative time, number of levels fused, and length of stay. The authors assessed overall complication rates at 30 days and 1 year and detailed deaths, cardiovascular events, infections, instrumentation failures, and CSF leaks. Chi-square and Wilcoxon rank-sum tests were used to assess differences in patient characteristics for patients with a procedure in the preimplementation period from those in the postimplementation period under a Poisson distribution model. RESULTS Patients who underwent surgery after implementation of the Seattle Spine Team Protocol had a statistically significant reduction (relative risk 0.49 [95% CI 0.30-0.78]) in all measured complications, including cardiovascular events, wound infections, other perioperative infections, and implant failures within 30 days after surgery; the analysis was adjusted for age and Charlson comorbidity score. A trend toward fewer deaths in this group was also found. CONCLUSIONS This type of systematic quality improvement strategy can improve quality and patient safety and might be applicable to other complex surgical disciplines. Implementation of these strategies in the treatment of adult spinal deformity will likely lead to better patient outcomes. PMID- 28362217 TI - Can Graduated Compressive Stockings Reduce Muscle Activity During Running? AB - PURPOSE: Graduated compressive stockings (GCS) have been suggested to influence performance by reducing muscle oscillations and improving muscle function and efficiency. However, no study to date has analyzed the influence of GCS on muscle activity during running. The objective of the study was to analyze the influence of GCS on the perception of comfort and muscle activation of the main muscles of the lower leg during running. METHOD: Thirty-six participants ran on a treadmill with (GCS) or without (control) GCS. The running tests consisted of a 10-min warm up followed by a 20-min intense run at 75% of the athlete's maximal aerobic speed. Surface electromyography of the tibialis anterior, peroneus longus, gastrocnemius lateralis (GL), and gastrocnemius medialis (GM) were recorded every 5 min during the run and analyzed using a non-linearly scaled wavelet analysis. Perception of comfort of the GCS was measured before and after the run. RESULTS: The GCS were reported as comfortable garments and reduced GL activity at Minute 0 (p < .05, [Formula: see text]= .245) and Minute 5 (p < .05, [Formula: see text]= .326) and GM activity at Minute 0 (p < .05, [Formula: see text]= .233) compared with running without garments, but their effect was temporary and disappeared after 5 min of running. CONCLUSION: Even though GCS reduced gastrocnemius muscle activity during the initial minutes of running, it is hypothesized that the GCS could have lost their initial levels of compression after some minutes of exercise, thereby reducing their influence on muscle activation. However, this hypothesis needs to be further investigated. PMID- 28362218 TI - Implicit and Explicit Attitudes Toward Sex and Romance in Asexuals. AB - Despite the recent surge of interest in sexuality, asexuality has remained relatively underresearched. Distinct from abstinence or chastity, asexuality refers to a lack of sexual attraction toward others. Past research suggests asexuals have negative attitudes toward sex, though no research has examined implicit attitudes. While preliminary evidence suggests that many asexuals are interested in engaging in romantic relationships, these attitudes have yet to be examined thoroughly, implicitly, or compared with a control group. This study investigated explicit and implicit attitudes toward sex and romance in a group of asexuals (N = 18, age M = 21.11) and a group of controls (N = 27, age M = 21.81), using the Asexuality Identification Scale (AIS), the Triangular Love Scale (TLS), semantic differentials, an Implicit Association Task (IAT), and two Single Category IATs. It was found that asexuals exhibited more negative explicit and implicit attitudes toward sex, as well as more negative explicit attitudes toward romance, relative to controls. There was no significant difference between groups on implicit romantic attitudes. Moreover, aromantic asexuals demonstrated significantly more negative explicit attitudes toward romance than romantic asexuals, though there was no significant difference between groups on implicit measures. Explanations and implications of these findings are discussed. PMID- 28362219 TI - Validity of auditory perceptual assessment of velopharyngeal function and dysfunction - the VPC-Sum and the VPC-Rate. AB - Overall weighted or composite variables for perceptual auditory estimation of velopharyngeal closure or competence have been used in several studies for evaluation of velopharyngeal function during speech. The aim of the present study was to investigate the validity of a composite score (VPC-Sum) and of auditory perceptual ratings of velopharyngeal competence (VPC-Rate). Available VPC-Sum scores and judgments of associated variables (hypernasality, audible nasal air leakage, weak pressure consonants, and non-oral articulation) from 391 5-year olds with repaired cleft palate (the Scandcleft project) were used to investigate content validity, and 339 of these were compared with an overall judgment of velopharyngeal competence (VPC-Rate) on the same patients by the same listeners. Significant positive correlations were found between the VPC-Sum and each of the associated variables (Cronbachs alpha 0.55-0.87, P < 0.001), and a moderately significant positive correlation between VPC-Sum and VPC-Rate (Rho 0.698, P < 0.01). The latter classified cases well when VPC-Sum was dichotomized with 67% predicted velopharyngeal competence and 90% velopharyngeal incompetence. The validity of the VPC-Sum was good and the VPC-Rate a good predictor, suggesting possible use of both measures depending on the objective. PMID- 28362220 TI - Design, synthesis, and in vitro anti-hepatocellular carcinoma of novel thymine thioglycoside analogs as new antimetabolic agents. AB - A first reported direct method for preparation of thymine thioglycoside analogs utilizing novel pyrimidine-2(1H)-thiones and alpha-bromoglucose or alpha bromogalactose tetraacetate as starting components is described. The synthetic potential of the method is demonstrated. The evaluation of antiproliferative activity against HepG-2 cell lines (Liver carcinoma cell lines) shows that most of the compounds have high antitumor activities especially 6b, 6e, 11b, and 12b. Moreover, molecular modelings of these compounds reveal that they have high binding affinity through hydrogen bond interaction with the binding pocket of thymidylate synthase dihydrofolate reductase (TS-DHFR). PMID- 28362223 TI - Examining the Error of Mis-Specifying Nonlinear Confounding Effect With Application on Accelerometer-Measured Physical Activity. AB - PURPOSE: Some confounders are nonlinearly associated with dependent variables, but they are often adjusted using a linear term. The purpose of this study was to examine the error of mis-specifying the nonlinear confounding effect. METHODS: We carried out a simulation study to investigate the effect of adjusting for a nonlinear confounder in the estimation of a causal relationship between the exposure and outcome in 3 ways: using a linear term, binning into 5 equal-size categories, or using a restricted cubic spline of the confounder. Continuous, binary, and survival outcomes were simulated. We examined the confounder across varying measurement error. In addition, we performed a real data analysis examining the 3 strategies to handle the nonlinear effects of accelerometer measured physical activity in the National Health and Nutrition Examination Survey 2003-2006 data. RESULTS: The mis-specification of a nonlinear confounder had little impact on causal effect estimation for continuous outcomes. For binary and survival outcomes, this mis-specification introduced bias, which could be eliminated using spline adjustment only when there is small measurement error of the confounder. Real data analysis showed that the associations between high blood pressure, high cholesterol, and diabetes and mortality adjusted for physical activity with restricted cubic spline were about 3% to 11% larger than their counterparts adjusted with a linear term. CONCLUSION: For continuous outcomes, confounders with nonlinear effects can be adjusting with a linear term. Spline adjustment should be used for binary and survival outcomes on confounders with small measurement error. PMID- 28362222 TI - Motivation for and use of social networking sites: Comparisons among college students with and without histories of non-suicidal self-injury. AB - OBJECTIVE: This research examines potential differences in social network use and motivation for social network use by non-suicidal self-injury (NSSI) status. PARTICIPANTS: 367 (73% women; Mage = 20.60) college students were recruited in November-December 2011. METHODS: A random sample of 2,500 students was accessed through a university registrar to recruit students interested in an online survey assessing NSSI and various health-related behaviors. RESULTS: Social network use and motivations for social networks did not differ by NSSI status. CONCLUSIONS: Results suggest that it is not patterns of use or motivation to use social networks that could lead to concern about online behavior (i.e., behavior increasing risk of future NSSI) among those with NSSI history. Rather, future preventive and intervention efforts should address the NSSI-related content that is available online, since this is unregulated, often explicit, and commonly includes "pro-NSSI" content that may be problematic and increase risk among vulnerable individuals. PMID- 28362224 TI - Prediction of Periodontitis Occurrence: Influence of Classification and Sociodemographic and General Health Information. AB - BACKGROUND: Prediction of periodontitis development is challenging. Use of oral health-related data alone, especially in a young population, might underestimate disease risk. This study investigates accuracy of oral, systemic, and socioeconomic data on estimating periodontitis development in a population-based prospective cohort. METHODS: General health history and sociodemographic information were collected throughout the life-course of individuals. Oral examinations were performed at ages 24 and 31 years in the Pelotas 1982 birth cohort. Periodontitis at age 31 years according to six classifications was used as the gold standard to compute area under the receiver operating characteristic curve (AUC). Multivariable binomial regression models were used to evaluate the effects of oral health, general health, and socioeconomic characteristics on accuracy of periodontitis development prediction. RESULTS: Complete data for 471 participants were used. Periodontitis classifications with lower thresholds yielded superior predictive power. Calculus, pocket, or bleeding presence at age 24 years separately presented fair accuracy. Accuracy increased using multivariable models; for example, the Beck et al. classification AUC from 0.59 to 0.75 combining proportion of teeth with calculus, bleeding, or pocket with income; number of lost teeth; sex; education; people living in the house; prosthetic needs; or number of decayed, missing, or filled teeth (DMFT). Proportion of teeth with pocket, bleeding, or calculus; number of DMFT; toothbrushing frequency; blood pressure; sex; and income were most frequently associated. CONCLUSIONS: Choice of classification might have an impact on accuracy to predict periodontitis occurrence. Regardless of the classification, predictive value for development of periodontitis in young adults might be increased by combining periodontal information, sociodemographic information, and general health history. PMID- 28362216 TI - Strategies for combating bacterial biofilms: A focus on anti-biofilm agents and their mechanisms of action. AB - Biofilm refers to the complex, sessile communities of microbes found either attached to a surface or buried firmly in an extracellular matrix as aggregates. The biofilm matrix surrounding bacteria makes them tolerant to harsh conditions and resistant to antibacterial treatments. Moreover, the biofilms are responsible for causing a broad range of chronic diseases and due to the emergence of antibiotic resistance in bacteria it has really become difficult to treat them with efficacy. Furthermore, the antibiotics available till date are ineffective for treating these biofilm related infections due to their higher values of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC), which may result in in-vivo toxicity. Hence, it is critically important to design or screen anti-biofilm molecules that can effectively minimize and eradicate biofilm related infections. In the present article, we have highlighted the mechanism of biofilm formation with reference to different models and various methods used for biofilm detection. A major focus has been put on various anti biofilm molecules discovered or tested till date which may include herbal active compounds, chelating agents, peptide antibiotics, lantibiotics and synthetic chemical compounds along with their structures, mechanism of action and their respective MICs, MBCs, minimum biofilm inhibitory concentrations (MBICs) as well as the half maximal inhibitory concentration (IC50) values available in the literature so far. Different mode of action of anti biofilm molecules addressed here are inhibition via interference in the quorum sensing pathways, adhesion mechanism, disruption of extracellular DNA, protein, lipopolysaccharides, exopolysaccharides and secondary messengers involved in various signaling pathways. From this study, we conclude that the molecules considered here might be used to treat biofilm-associated infections after significant structural modifications, thereby investigating its effective delivery in the host. It should also be ensured that minimum effective concentration of these molecules must be capable of eradicating biofilm infections with maximum potency without posing any adverse side effects on the host. PMID- 28362225 TI - A Sialidase-Deficient Porphyromonas gingivalis Mutant Strain Induces Less Interleukin-1beta and Tumor Necrosis Factor-alpha in Epi4 Cells Than W83 Strain Through Regulation of c-Jun N-Terminal Kinase Pathway. AB - BACKGROUND: Porphyromonas gingivalis is one of the major periodontal pathogens. In a previous study, a mouse abscess model showed that sialidase deficiency of P. gingivalis weakened its virulence, but the mechanism behind this observation remains unknown. METHODS: A sialidase-deficient mutant strain (?PG0352) and a complemented strain (com?PG0352) were constructed. Epi4 cells were stimulated by wild-type strain P. gingivalis W83, ?PG0352, or com?PG0352. Real-time polymerase chain reaction was carried out to detect expression of virulent genes in P. gingivalis and interleukin (IL)-1beta, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha in epi4 cells. Activities of sialidase, gingipains, and lipopolysaccharide (LPS) were compared among the different P. gingivalis strains. Levels of IL-1beta and TNF-alpha in the epi4 cells supernatant were detected by enzyme-linked immunosorbent assay and levels of p38, extracellular signal regulated kinase, c-Jun N-terminal kinase (JNK), and phospho-c-Jun were detected by western blotting. RESULTS: Compared with P. gingivalis W83 and com?PG0352, activities of Kgp and Rgp gingipains and amount of LPS decreased in ?PG0352, whereas there were no differences in LPS activity among these three strains. Level of phospho-JNK was lower in epi4 cells stimulated by ?PG0352. ?pG0352 induced less IL-1beta and TNF-alpha and more IL-8 in epi4 cells; differences in IL-1beta and TNF-alpha could not be detected after JNK blocking. CONCLUSION: A sialidase-deficient P. gingivalis mutant strain induces less IL-1beta and TNF alpha in epi4 cells than W83 strain through regulation of JNK pathway. PMID- 28362221 TI - The non-conserved region of MRP is involved in the virulence of Streptococcus suis serotype 2. AB - Muramidase-released protein (MRP) of Streptococcus suis serotype 2 (SS2) is an important epidemic virulence marker with an unclear role in bacterial infection. To investigate the biologic functions of MRP, 3 mutants named Deltamrp, Deltamrp domain 1 (Deltamrp-d1), and Deltamrp domain 2 (Deltamrp-d2) were constructed to assess the phenotypic changes between the parental strain and the mutant strains. The results indicated that MRP domain 1 (MRP-D1, the non-conserved region of MRP from a virulent strain, a.a. 242-596) played a critical role in adherence of SS2 to host cells, compared with MRP domain 1* (MRP-D1*, the non-conserved region of MRP from a low virulent strain, a.a. 239-598) or MRP domain 2 (MRP-D2, the conserved region of MRP, a.a. 848-1222). We found that MRP-D1 but not MRP-D2, could bind specifically to fibronectin (FN), factor H (FH), fibrinogen (FG), and immunoglobulin G (IgG). Additionally, we confirmed that mrp-d1 mutation significantly inhibited bacteremia and brain invasion in a mouse infection model. The mrp-d1 mutation also attenuated the intracellular survival of SS2 in RAW246.7 macrophages, shortened the growth ability in pig blood and decreased the virulence of SS2 in BALB/c mice. Furthermore, antiserum against MRP-D1 was found to dramatically impede SS2 survival in pig blood. Finally, immunization with recombinant MRP-D1 efficiently enhanced murine viability after SS2 challenge, indicating its potential use in vaccination strategies. Collectively, these results indicated that MRP-D1 is involved in SS2 virulence and eloquently demonstrate the function of MRP in pathogenesis of infection. PMID- 28362226 TI - Camel as a transboundary vector for emerging exotic Salmonella serovars. AB - The current study was conducted to shed light on the role of imported camels as a transboundary vector for emerging exotic Salmonella serovars. Fecal samples were collected from 206 camels directly after slaughtering including 25 local camels and 181 imported ones as well as stool specimens were obtained from 50 slaughterhouse workers at the same abattoir. The obtained samples were cultured while Salmonella serovars were identified through Gram's stain films, biochemical tests and serotyping with antisera kit. Moreover, the obtained Salmonella serovars were examined by PCR for the presence of invA and stn genes. The overall prevalence of Salmonella serovars among the examined camels was 8.3%. Stn gene was detected in the vast majority of exotic strains (11/14) 78.6% including emerging serovars such as Salmonella Saintpaul, S. Chester, S. Typhimurium whereas only one isolate from local camels carried stn gene (1/3) 33.3%. On the other hand, none of the examined humans yielded positive result. Our findings highlight the potential role of imported camels as a transboundary vector for exotic emerging Salomenella serovars. PMID- 28362227 TI - Realisation of voicing by French-speaking CI children after long-term implant use: An acoustic study. AB - Studies of speech production in French-speaking cochlear-implanted (CI) children are very scarce. Yet, difficulties in speech production have been shown to impact the intelligibility of these children. The goal of this study is to understand the effect of long-term use of cochlear implant on speech production, and more precisely on the coordination of laryngeal-oral gestures in stop production. The participants were all monolingual French children: 13 6;6- to 10;7-year-old CI children and 20 age-matched normally hearing (NH) children. We compared /p/, /t/, /k/, /b/, /d/ and /g/ in word-initial consonant-vowel sequences, produced in isolation in two different tasks, and we studied the effects of CI use, vowel context, task and age factors (i.e. chronological age, age at implantation and duration of implant use). Statistical analyses show a difference in voicing production between groups for voiceless consonants (shorter Voice Onset Times for CI children), with significance reached only for /k/, but no difference for voiced consonants. Our study indicates that in the long run, use of CI seems to have limited effects on the acquisition of oro-laryngeal coordination needed to produce voicing, except for specific difficulties located on velars. In a follow up study, further acoustic analyses on vowel and fricative production by the same children reveal more difficulties, which suggest that cochlear implantation impacts frequency-based features (second formant of vowels and spectral moments of fricatives) more than durational cues (voicing). PMID- 28362228 TI - The Role of Philanthropic Funding in Building Research Evidence to Support an Aging Population: A Case Study from Ireland. AB - This case study examines the role of philanthropic funding in building capacity for aging research in Ireland, and how this investment has addressed the lack of evidence to support planning for an aging population. The funding has supported a range of initiatives including the national longitudinal study on aging (TILDA), the creation of three professorships/chairs, and the establishment of four new research centers. Important potential outcomes are emerging across other domains including research-informed policy development and the generation of health benefits. The efforts of academic researchers to ensure that their findings are readily accessible to end users and to forge robust working relationships with all stakeholders have helped to enhance the use of research findings. Overall, philanthropy has played a pivotal role in building capacity, infrastructure, and expertise in academic settings in Ireland. Moreover, this work provides an excellent example of how such efforts can begin to inform effective planning and service provision. PMID- 28362229 TI - Late chronotypes are associated with neoadjuvant chemotherapy-induced nausea and vomiting in women with breast cancer. AB - Neoadjuvant chemotherapy, that is, the administration of chemotherapy before surgery, has been commonly used for locally advanced breast cancer to improve the surgical outcomes and increase the opportunity for breast-conserving therapy. Women with breast cancer often receive an anthracycline-based regimen as the neoadjuvant chemotherapy, which is associated with a high risk of emesis. Despite the development of novel antiemetics, chemotherapy-induced nausea and vomiting (CINV) has been commonly reported as a major adverse effect, affecting the quality of life of the patients. However, the factors predicting CINV in women with breast cancer undergoing neoadjuvant chemotherapy remain unclear. In this single-institution, prospective, observational study conducted at an outpatient cancer centre in the Republic of Korea from November 2013 to March 2016, we analysed women with breast cancer who planned to be treated with neoadjuvant chemotherapy before surgery. Candidate factors associated with CINV were assessed before neoadjuvant chemotherapy using the Munich Chronotype Questionnaire, Pittsburgh Sleep Quality Index and Hospital Anxiety and Depression Scale. CINV was assessed after chemotherapy by using the Multinational Association of Supportive Care in Cancer Antiemesis Tool. Of a total of 143 participants, 7 patients were lost to follow-up and 2 patients were excluded due to changes in their treatment plan; thus, 134 patients were finally included in the analyses. Overall, 48.5% of the participants experienced CINV, with delayed CINV prevalence (42.5%) being more common than acute (39.6%). In the univariate analyses, overall CINV was significantly associated with late chronotypes (odds ratio [OR], 3.49; 95% confidence interval [CI], 1.37-8.87; p = 0.009), a history of nausea/vomiting (OR, 2.19; 95% CI, 1.10-4.37; p = 0.026) and anxiety (OR, 2.25; 95% CI, 1.05 4.81; p = 0.036). In the multivariate analyses, late chronotypes (OR, 3.53; 95% CI, 1.27-9.79; p = 0.015) and a history of nausea/vomiting (OR, 2.83; 95% CI, 1.31-6.13; p = 0.008) remained significantly associated with CINV. In conclusion, in women with breast cancer undergoing neoadjuvant chemotherapy before surgery, late chronotypes were found to have an increased risk of CINV; these data suggest that clinicians need to assess and consider the chronotype in the management of CINV. PMID- 28362230 TI - Destigmatization by Association: Improving Children's Reactions to an Obese Storybook Character. AB - Second- through fourth-grade students were read a storybook that described a typical boy who interacted with an obese boy for one of four reasons (sympathy, curiosity, teacher instructed, or no reason) to explore the manner in which a typical storybook character's reason for associating with an obese storybook character influences children's responses to both characters. Results revealed that the children responded more favorably to the obese storybook character after than before learning about the typical storybook character's association with him, especially when the typical storybook character's reason for association was presented as internally motivated (sympathy or curiosity). In contrast to "stigma by association" findings reported in prior research, the children also responded more favorably to the typical storybook character after than before his association with the obese storybook character. PMID- 28362231 TI - Cognitive Factors Affecting Freeze-like Behavior in Humans. AB - Contemporary research on survival-related defensive behaviors has identified physiological markers of freeze/flight/fight. Our research focused on cognitive factors associated with freeze-like behavior in humans. Study 1 tested if an explicit decision to freeze is associated with the psychophysiological state of freezing. Heart rate deceleration occurred when participants chose to freeze. Study 2 varied the efficacy of freezing relative to other defense options and found "freeze" was responsive to variations in the perceived effectiveness of alternative actions. Study 3 tested if individual differences in motivational orientation affect preference for a "freeze" option when the efficacy of options is held constant. A trend in the predicted direction suggested that naturally occurring cognitions led loss-avoiders to select "freeze" more often than reward seekers. In combination, our attention to the cognitive factors affecting freeze like behavior in humans represents a preliminary step in addressing an important but neglected research area. PMID- 28362233 TI - Resiliency in the Face of Adversity: A Short Longitudinal Test of the Trait Hypothesis. AB - Resilience represents coping with adversity and is in line with a more positive paradigm for viewing responses to adversity. Most research has focused on resilience as coping-a state-based response to adversity. However, a competing hypothesis views resilience or resiliency as a trait that exists across time and types of adversity. We tested undergraduates enrolled in social work classes at a large southern university at two time periods during a single semester using measures of adversity, positive and negative affect, and trait-based resiliency. Consistent with the trait-based resiliency, and in contrast to state-based resilience, resiliency scores were not strongly correlated with adversity at both testing points but were with positive affect, and resiliency scores remained the same over time despite adversity variations. There was no gender or ethnic group difference in resilience scores. Black/African Americans reported significantly less negative affect and more positive affect than White/Caucasians. PMID- 28362232 TI - An Investigation of Sound-Symbolism in the Context of Tactile Feeling. AB - Sound symbolism suggests a non-arbitrary relationship between speech sounds and the concepts to which those sounds refer (Hinton, Nichols, & Ohala, 2006 ). Supporting evidence comes primarily from studies investigating how speech sounds relate to semantically compatible visual concepts. The present study therefore attempted to examine sound symbolism in the context of tactile perception. Contrary to the propositions of sound symbolism, participants in Experiment 1 did not consistently assign names with plosive consonant to objects with curved frames. Experiment 2, however, found that names with fricative consonants were more likely to be applied to materials with rough surfaces. The results suggested the existence of a direct relationship between speech sounds and their referent concepts that could be crucial in revealing the phenomenon of sound symbolism. A future study was also proposed to study the contributions of mouth shape and airflow to associations between speech sounds and tactile feelings. (161 words). PMID- 28362234 TI - Dissociating Medial Temporal and Striatal Memory Systems With a Same/Different Matching Task: Evidence for Two Neural Systems in Human Recognition. AB - The medial temporal lobe and striatum have both been implicated as brain substrates of memory and learning. Here, we show dissociation between these two memory systems using a same/different matching task, in which subjects judged whether four-letter strings were the same or different. Different RT was determined by the left-to-right location of the first letter different between the study and test string, consistent with a left-to-right comparison of the study and test strings, terminating when a difference was found. This comparison process results in same responses being slower than different responses. Nevertheless, same responses were faster than different responses. Same responses were associated with hippocampus activation. Different responses were associated with both caudate and hippocampus activation. These findings are consistent with the dual-system hypothesis of mammalian memory and extend the model to human visual recognition. PMID- 28362236 TI - Nonenhancing peritumoral hyperintense lesion on diffusion-weighted imaging in glioblastoma: a novel diagnostic and specific prognostic indicator. AB - OBJECTIVE Glioblastoma differentials include intracranial tumors, like malignant lymphomas and metastatic brain tumors with indiscernible radiological characteristics. The purpose of this study was to identify a distinct radiological feature for the preoperative differentiation of glioblastoma from its differentials, which include malignant lymphomas and metastatic brain tumors. METHODS Preoperative MR images, including diffusion-weighted imaging (DWI) studies (b = 1000 and 4000 sec/mm2), obtained in patients with newly diagnosed malignant tumor, were analyzed retrospectively after receiving approval from the institutional review board. Sixty-four patients with histologically confirmed glioblastoma, 32 patients with malignant lymphoma, and 46 patients with brain metastases were included. The presence of a nonenhancing peritumoral DWI high lesion (NePDHL, i.e., hyperintense lesion in a nonenhancing peritumoral area on DWI) was confirmed in both DWI sequences. Gray matter lesions were excluded. Lesions were termed "definite" if present within 3 cm of the hyperintense tumor border with a signal intensity ratio >= 30% when compared with the contralateral normal white matter in both sequences. Discriminant analysis between the histological diagnosis and the presence of Definite-NePDHL was performed, as well as Kaplan-Meier survival analysis incorporating the existence of Definite-NePDHL. RESULTS In 25% of glioblastoma patients, Definite-NePDHL was present, while it was conspicuously absent in patients with malignant lymphoma and metastatic brain tumors. The specificity and positive predictive value were 100%. In the glioblastoma subset, a higher preoperative Karnofsky Performance Scale score (p = 0.0028), high recursive partitioning analysis class (p = 0.0006), and total surgical removal (p = 0.0012) were associated with better median overall survival. Patients with Definite-NePDHL had significantly early local (p = 0.0467) and distant/dissemination recurrence (p < 0.0001) and poor prognosis (p = 0.0007). CONCLUSIONS The presence of Definite-NePDHL is very specific for glioblastoma and indicates poor prognosis. Definite-NePDHL is a significant indicator of early local and distant/dissemination recurrence in patients with glioblastoma. Studying peritumoral DWI and high-b-value DWI is useful for tumor differentiation. PMID- 28362235 TI - A supplementary grading scale combining lesion-to-eloquence distance for predicting surgical outcomes of patients with brain arteriovenous malformations. AB - OBJECTIVE Case selection for the surgical treatment of brain arteriovenous malformations (BAVMs) remains challenging. This study aimed to construct a predictive grading system combining lesion-to-eloquence distance (LED) for selecting patients with BAVMs for surgery. METHODS Between September 2012 and September 2015, the authors retrospectively studied 201 consecutive patients with BAVMs. All patients had undergone preoperative functional MRI and diffusion tensor imaging (DTI), followed by resection. Both angioarchitectural factors and LED were analyzed with respect to the change between preoperative and final postoperative modified Rankin Scale (mRS) scores. LED refers to the distance between the lesion and the nearest eloquent area (eloquent cortex or eloquent fiber tracts) measured on preoperative fMRI and DTI. Based on logistic regression analysis, the authors constructed 3 new grading systems. The HDVL grading system includes the independent predictors of mRS change (hemorrhagic presentation, diffuseness, deep venous drainage, and LED). Full Score combines the variables in the Spetzler-Martin (S-M) grading system (nidus size, eloquence of adjacent brain, and venous drainage) and the HDVL. For the third grading system, the fS-M grading system, the authors added information regarding eloquent fiber tracts to the S-M grading system. The area under the receiver operating characteristic (ROC) curves was compared with those of the S-M grading system and the supplementary S-M grading system of Lawton et al. RESULTS LED was significantly correlated with a change in mRS score (p < 0.001). An LED of 4.95 mm was the cutoff point for the worsened mRS score. Hemorrhagic presentation, diffuseness, deep venous drainage, and LED were independent predictors of a change in mRS score. Predictive accuracy was highest for the HDVL grading system (area under the ROC curve 0.82), followed by the Full Score grading system (0.80), the fS-M grading system (0.79), the supplementary S-M grading system (0.76), and least for the S-M grading system (0.71). Predictive accuracy of the HDVL grading system was significantly better than that of the Spetzler-Martin grade (p = 0.040). CONCLUSIONS LED was a significant predictor for the preoperative risk evaluation for surgery. The HDVL system was a good predictor of neurological outcomes after BAVM surgery. Adding the consideration of the involvement of eloquent fiber tracts to preoperative evaluation can effectively improve its predictive accuracy. PMID- 28362238 TI - Supratentorial cavernous malformations adjacent to the corticospinal tract: surgical outcomes and predictive value of diffusion tensor imaging findings. AB - OBJECTIVE Diffusion tensor imaging (DTI) findings may facilitate clinical decision making in patients with supratentorial cavernous malformations adjacent to the corticospinal tract (CST-CMs). The objective of this study was to determine the predictive value of preoperative DTI findings for surgical outcomes in patients with CST-CMs. METHODS A prospectively maintained database of patients with CM referred to the authors' hospital between September 2012 and October 2015 was reviewed to identify all consecutive surgically treated patients with CST-CM. All patients had undergone sagittal T1-weighted anatomical imaging and DTI before surgery. Both DTI findings and clinical characteristics of the patients and lesions were analyzed with respect to surgery-related motor deficits. DTI findings included lesion-to-CST distance (LCD) and the alteration (i.e., deviation, interruption, or degeneration due to the CM) of CST on preoperative DTI images. Surgery-related motor deficits at 1 week and the last clinic visit (>= 3 months) after surgery were defined as short-term and long-term deficits, respectively. Preoperative and final modified Rankin Scale scores were also analyzed to identify the surgical outcomes in these patients. RESULTS A total of 56 patients with 56 CST-CMs were included in this study. The mean LCD was 3.9 +/- 3.2 mm, and alterations of the CST were detected in 20 (36.7%) patients. One week after surgery, 21 (37.5%) patients had short-term surgery-related motor deficits, but only 14 (25.0%) patients had long term deficits at the last clinical visit. The mean patient follow-up was 14.7 +/- 10.1 months. The difference between preoperative and final modified Rankin Scale scores was not statistically significant (p = 0.490). Multivariate analysis showed that both short-term (p < 0.001) and long-term (p = 0.002) surgery-related motor deficits were significantly associated with LCD. Receiver operating characteristic (ROC) curve results were as follows: for short-term surgery-related motor deficits, the area under the ROC curve (AUC) was 0.860, and the cutoff point was LCD = 2.55 mm; for long-term deficits, the AUC was 0.894, and the cutoff point was LCD = 2.30 mm. Both univariate (p = 0.012) and multivariate (p = 0.049) analyses revealed that CST alteration on preoperative DTI was significantly correlated with short-term surgery-related motor deficits. On univariate analysis, deep location of the CST CMs was significantly correlated with long-term motor deficits (p = 0.016). Deep location of the CST-CMs had a trend toward significance with long-term motor deficits on the multivariate analysis (p = 0.060). CONCLUSIONS To facilitate clinical practice, the authors propose that 3.00 mm (2.55 to ~3.00 mm) may be the safe LCD for surgery in patients with CST-CMs. A CST alteration on preoperative DTI and a deep location of the CST-CM may be risk factors for short- and long term surgery-related motor deficits, respectively. A randomized controlled trial is needed to demonstrate the predictive value of preoperative DTI findings on surgical outcomes in patients with CST-CMs in future studies. PMID- 28362240 TI - Microvascularization of Grade I meningiomas: effect on tumor volume, blood loss, and patient outcome. AB - OBJECTIVE Quantitative assessment of tumor microvascularity has the potential to improve prognostication, advance understanding of tumor biology, and help narrow potential molecular therapies. While the role of tumor microvascularity has been widely studied in meningiomas, this study examines both the role of automated measurements and the impact on surgical outcome. METHODS Two hundred seven patients with Grade I meningiomas underwent surgery between 1996 and 2011. Tissue samples from each patient were retrospectively evaluated for histopathological measures of microvascularity, including staining for von Willebrand factor (vWF), CD31, CD105, hypoxia-inducible factor 1 (HIF-1), vascular endothelial growth factor, glucose transporter 1, and carbonic anhydrase IX. Manual methods of assessing microvascularity were supplemented by a computational analysis of the microvascular patterns by means of fractal analysis. MIB-1 proliferation staining was also performed on the same tumors. These measures were compared with various patient characteristics, tumor volume, estimated blood loss (EBL) during surgery, progression-free survival (PFS), and overall survival (OS). RESULTS The mean patient age was 55.4 +/- 14.8 years, and 63 (30.4%) patients were male. Patients harboring tumors >= 3 cm were significantly older (56.9 +/- 15.2 years vs 53.1 +/ 13.6 years; p = 0.07), more frequently male (40.8% vs 14.6%; p = 0.0001), and had greater EBL (446.5 +/- 532.2 ml vs 185.4 +/- 197.2 ml; p = 0.0001), greater tumor volume (33.9 +/- 38.1 ml vs 29.4 +/- 23.5 ml; p = 0.0001), higher MIB-1 index values (3.0% +/- 5.4% vs 1.7% +/- 1.7%; p = 0.03), higher vWF levels (85.6% +/- 76.9% vs 54.1% +/- 52.4%; p = 0.001), lower HIF-1 expression (1.4 +/- 1.3 vs 2.2 +/- 1.4; p = 0.004), and worse OS (199.9 +/- 7.6 months vs 180.8 +/- 8.1 months; p = 0.05) than patients with tumors < 3 cm. In the multivariate logistic regression, MIB-1 (OR 1.14; p = 0.05), vWF (OR 1.01; p = 0.01), and HIF-1 (OR 1.54; p = 0.0001) significantly predicted tumor size. Although multiple factors were predictive of EBL in the univariate linear regression, only vWF remained significant in the multivariate analysis (beta = 0.39; p = 0.004). Lastly, MIB-1 was useful via Kaplan-Meier survival analysis for predicting patients with disease progression, whereby an MIB-1 cutoff value of >= 3% conferred a 36% sensitivity and 82.5% specificity in predicting disease progression; an MIB-1 value >= 3% showed significantly shorter mean PFS (140.1 +/- 11.7 months vs 179.5 +/- 7.0 months; log-rank test, p = 0.05). The Cox proportional hazards model showed a trend for MIB-1 in predicting disease progression in a hazards model (OR 1.08; 95% CI 0.99-1.19; p = 0.08). CONCLUSIONS These results support the importance of various microvascularity measures in predicting preoperative (e.g., tumor size), intraoperative (e.g., EBL), and postoperative (e.g., PFS and OS) outcomes in patients with Grade I meningiomas. An MIB-1 cutoff value of 3% showed good specificity for predicting tumor progression. The predictive ability of various measures to detect aberrant tumor microvasculature differed, possibly reflecting the heterogeneous underlying biology of meningiomas. It may be necessary to combine assays to understand angiogenesis in meningiomas. PMID- 28362237 TI - Ionizing radiation augments glioma tropism of mesenchymal stem cells. AB - OBJECTIVE Mesenchymal stem cells (MSCs) have been shown to localize to gliomas after intravascular delivery. Because these cells home to areas of tissue injury, the authors hypothesized that the administration of ionizing radiation (IR) to tumor would enhance the tropism of MSCs to gliomas. Additionally, they sought to identify which radiation-induced factors might attract MSCs. METHODS To assess the effect of IR on MSC migration in vitro, transwell assays using conditioned medium (CM) from an irradiated commercially available glioma cell line (U87) and from irradiated patient-derived glioma stem-like cells (GSCs; GSC7-2 and GSC11) were employed. For in vivo testing, green fluorescent protein (GFP)-labeled MSCs were injected into the carotid artery of nude mice harboring orthotopic U87, GSC7 2, or GSC17 xenografts that were treated with either 0 or 10 Gy of IR, and brain sections were quantitatively analyzed by immunofluorescence for GFP-positive cells. These GSCs were used because GSC7-2 is a weak attractor of MSCs at baseline, whereas GSC17 is a strong attractor. To determine the factors implicated in IR-induced tropism, CM from irradiated GSC7-2 and from GSC11 was assayed with a cytokine array and quantitative ELISA. RESULTS Transwell migration assays revealed statistically significant enhanced MSC migration to CM from irradiated U87, GSC7-2, and GSC11 compared with nonirradiated controls and in a dose-dependent manner. After their intravascular delivery into nude mice harboring orthotopic gliomas, MSCs engrafted more successfully in irradiated U87 (p = 0.036), compared with nonirradiated controls. IR also significantly increased the tropism of MSCs to GSC7-2 xenografts (p = 0.043), which are known to attract MSCs only poorly at baseline (weak-attractor GSCs). Ionizing radiation also increased the engraftment of MSCs in strong-attractor GSC17 xenografts, but these increases did not reach statistical significance. The chemokine CCL2 was released by GSC7-2 and GSC11 after irradiation in a dose-dependent manner and mediated in vitro transwell migration of MSCs. Immunohistochemistry revealed increased CCL2 in irradiated GSC7-2 gliomas near the site of MSC engraftment. CONCLUSIONS Administering IR to gliomas enhances MSC localization, particularly in GSCs that attract MSCs poorly at baseline. The chemokine CCL2 appears to play a crucial role in the IR-induced tropism of MSCs to gliomas. PMID- 28362239 TI - Associations between clinical outcome and navigated transcranial magnetic stimulation characteristics in patients with motor-eloquent brain lesions: a combined navigated transcranial magnetic stimulation-diffusion tensor imaging fiber tracking approach. AB - OBJECTIVE Navigated transcranial magnetic stimulation (nTMS) and diffusion tensor imaging fiber tracking (DTI FT) based on nTMS data are increasingly used for preoperative planning and resection guidance in patients suffering from motor eloquent brain tumors. The present study explores whether nTMS-based DTI FT can also be used for individual preoperative risk assessment regarding surgery related motor impairment. METHODS Data derived from preoperative nTMS motor mapping and subsequent nTMS-based tractography in 86 patients were analyzed. All patients suffered from high-grade glioma (HGG), low-grade glioma (LGG), or intracranial metastasis (MET). In this context, nTMS-based DTI FT of the corticospinal tract (CST) was performed at a range of fractional anisotropy (FA) levels based on an individualized FA threshold ([FAT]; tracking with 50%, 75%, and 100% FAT), which was defined as the highest FA value allowing for visualization of fibers (100% FAT). Minimum lesion-to-CST distances were measured, and fiber numbers of the reconstructed CST were assessed. These data were then correlated with the preoperative, postoperative, and follow-up status of motor function and the resting motor threshold (rMT). RESULTS At certain FA levels, a statistically significant difference in lesion-to-CST distances was observed between patients with HGG who had no impairment and those who developed surgery-related transient or permanent motor deficits (75% FAT: p = 0.0149; 100% FAT: p = 0.0233). In this context, no patient with a lesion-to-CST distance >= 12 mm suffered from any new surgery-related permanent paresis (50% FAT and 75% FAT). Furthermore, comparatively strong negative correlations were observed between the rMT and lesion-to-CST distances of patients with surgery-related transient paresis (Spearman correlation coefficient [rs]; 50% FAT: rs = -0.8660; 75% FAT: rs = -0.8660) or surgery-related permanent paresis (50% FAT: rs = -0.7656; 75% FAT: rs = -0.6763). CONCLUSIONS This is one of the first studies to show a direct correlation between imaging, clinical status, and neurophysiological markers for the integrity of the motor system in patients with brain tumors. The findings suggest that nTMS-based DTI FT might be suitable for individual risk assessment in patients with HGG, in addition to being a surgery-planning tool. Importantly, necessary data for risk assessment were obtained without significant additional efforts, making this approach potentially valuable for direct clinical use. PMID- 28362241 TI - Safety of a meningococcal group B vaccine used in response to two university outbreaks. AB - OBJECTIVE: To assess the safety of meningococcal group B (MenB)-4C vaccine. PARTICIPANTS: Undergraduates, dormitory residents, and persons with high-risk medical conditions received the MenB-4C vaccine two-dose series during mass vaccination clinics from 12/2013 through 11/2014. METHODS: Adverse events (AEs) were identified by 15 minutes of observation postvaccination, spontaneous reports, surveys, and hospital surveillance. Causality was assessed for serious adverse events (SAEs). RESULTS: 16,974 persons received 31,313 MenB-4C doses. The incidence of syncope during the 15-minutes post-dose 1 was 0.88/1000 persons. 2% of participants spontaneously reported an AE (most common were arm pain and fever). 3 SAEs were suspected of being caused by the vaccine, including one case of anaphylaxis. CONCLUSIONS: Most AEs reported were nonserious and consistent with previous clinical trial findings. Measures to prevent injury from syncope and to treat anaphylaxis should be available wherever vaccines are administered. Our safety evaluation supports the use of MenB-4C in response to outbreaks. PMID- 28362242 TI - Arf GAPs: A family of proteins with disparate functions that converge on a common structure, the integrin adhesion complex. AB - ADP-ribosylation factors (Arfs) are members of the Ras GTPase superfamily. The function of Arfs is dependent on GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs), which allow Arfs to cycle between the GDP bound and GTP-bound forms. Arf GAPs have been shown to be present in integrin adhesion complexes, which include focal adhesions. Integrin adhesion complexes are composed of integrins, scaffolding proteins and signaling proteins and regulate cell proliferation, survival, differentiation and migration. Understanding the role of Arf GAPs in the regulation of integrin adhesion complexes is relevant to understanding normal physiology and cancer. In this review, we will discuss the contribution of the Arf GAP family members to the regulation of integrin adhesion complexes, examining the diverse mechanisms by which they control integrin adhesion complex formation, maturation and dissolution. GIT1 and ARAP2 serve as GAPs for Arf6, regulating Rac1 and other effectors by mechanisms still being defined. In contrast, GIT2 regulates Rac1 independent of Arf6. AGAP2 binds to and regulates focal adhesion kinase (FAK). ARAP2 and ACAP1, both Arf6 GAPs, regulate membrane trafficking of integrins through different endocytic pathways, exerting opposite effects on focal adhesions. ASAP1 not only regulates actin cytoskeleton remodeling through its interaction with nonmuscle myosin 2A, but is also important in integrin recycling. These examples illustrate the diversity and versatility of Arf GAPs as regulators of integrin adhesion complex structure and function. PMID- 28362243 TI - Sexual health and sexual trauma in women with severe mental illness: An exploratory survey of Western Australian community mental health services. AB - Australian women attending community mental health services were surveyed to determine the relationship between sexual trauma, sexual activity, and sexual health seeking behaviors. Self-reported history of "forced sex" was 58.4% (n = 122 out of 220). Latent class analysis revealed a three-class model: "sexually active and health seeking," "low sexual activity and health seeking" and "low sexual activity and not health seeking." An association with general practitioner engagement and sexual health seeking behaviors was found. Rates of self-reported sexual trauma reinforce the need for screening and trauma informed care. Groupings may reflect different aspects of recovery associated with sexual health behaviors. PMID- 28362244 TI - HPV vaccines: Global perspectives. AB - The discovery of HPV as the etiological factor for HPV-associated malignancies and disease has opened up several opportunities for prevention and therapy. Current commercially available HPV vaccines (Gardasil, Gardasil 9, and Cervarix) are prophylactic in nature and derived from adjuvanted L1-based virus-like particles of HPV. Globally, through several clinical trials, they were found to be very safe and efficacious. Certain limitations such as cost-effectiveness, low coverage against all HPV types and a 3-dose schedule make these vaccines difficult to use worldwide. Approaches to address these issues involve alternate expression systems using L1 or alternate antigen (L2) as well as optimizing doses and broadening protection to provide cheap and cross-protective vaccines. Additionally, promising preclinical immunogenicity results from our own studies using alternative hosts such as Pichia and an antigen delivery system-based measles vector have potential for development as next generation HPV prophylactic vaccines. Several other therapeutic approaches are also ongoing. PMID- 28362245 TI - Accessing VA Healthcare During Large-Scale Natural Disasters. AB - Natural disasters can lead to the closure of medical facilities including the Veterans Affairs (VA), thus impacting access to healthcare for U.S. military veteran VA users. We examined the characteristics of VA patients who reported having difficulty accessing care if their usual source of VA care was closed because of natural disasters. A total of 2,264 veteran VA users living in the U.S. northeast region participated in a 2015 cross-sectional representative survey. The study used VA administrative data in a complex stratified survey design with a multimode approach. A total of 36% of veteran VA users reported having difficulty accessing care elsewhere, negatively impacting the functionally impaired and lower income VA patients. PMID- 28362246 TI - Using Quality Tools and Methodologies to Improve a Hospital's Quality Position. AB - The authors identify the quality tools and methodologies most frequently used by quality-positioned hospitals versus nonquality hospitals. Northeastern U.S. hospitals in both groups received a brief, 12-question survey. The authors found that 93.75% of the quality hospitals and 81.25% of the nonquality hospitals used some form of process improvement methodologies. However, there were significant differences between the groups regarding the impact of quality improvement initiatives on patients. The findings indicate that in quality hospitals the use of quality improvement initiatives had a significantly greater positive impact on patient satisfaction and patient outcomes when compared to nonquality hospitals. PMID- 28362248 TI - Hope and adjustment to college in the context of collective trauma. AB - OBJECTIVES: To understand predictors of first-year college adjustment in the context of collective trauma, including a school shooting. PARTICIPANTS: Two consecutive years of entering freshman (Year 1 (Y1) N = 169, Year 2 (Y2) N = 94) were surveyed over time: Y1 in October 2012 and March 2013, and Y2 in October 2013 and August 2014. During Y2, several collective traumas occurred, impacting the campus community and providing a stark comparison. METHODS: Online surveys measuring predictors at the start of each year and adjustment at the end of each year. RESULTS: Hope was the only significant predictor of adjustment when included in a regression model with depression symptoms in Y1, and with depression symptoms, baseline posttraumatic stress symptoms, and traumatic exposure in Y2. CONCLUSIONS: Fostering hope may promote college adjustment, regardless of collective traumas that might occur on campus. PMID- 28362250 TI - Controversial issues in visual cortex mapping: Extrastriate cortex between areas V2 and MT in human and nonhuman primates. PMID- 28362249 TI - The intersection of nonsuicidal self-injury and suicide-related behavior: Patterns of elevated risk and implications for college mental health. AB - OBJECTIVE: To analyze the overlap of nonsuicidal self-injury (NSSI) and suicide related behaviors (SRB) among college students with regard to demographics, mental health, and coping styles. PARTICIPANTS: Respondents were 572 undergraduate students at a southwestern public university. METHODS: Data were collected in 2015. Respondents completed a demographic survey and assessments of NSSI, SRB, internalizing symptoms (ie, anxiety, stress, and depression), aggression, and negative coping strategies. The survey was administered via a Web based procedure. RESULTS: Women reported more frequent cutting behaviors than men. Endorsement of NSSI was also associated with an increased likelihood of lifetime SRB. A subgroup of students endorsing both NSSI and SRB demonstrated poorer mental health, more negative coping, and self-reported female sex. CONCLUSIONS: College healthcare providers may benefit from competency-based training in techniques for the combination treatment of NSSI and SRB, as well as culturally based models of suicide. PMID- 28362252 TI - Maxillofacial Trauma: Managing Potentially Dangerous And Disfiguring Complex Injuries. AB - Patients with maxillofacial trauma require a careful evaluation due to the anatomical proximity of the maxillofacial region to the head and neck. Facial injuries can range from soft-tissue lacerations and nondisplaced nasal fractures to severe, complex fractures, eye injuries, and possible brain injury. Though the Advanced Trauma Life Support (ATLS) guidelines provide a framework for the management of trauma patients, they do not provide a detailed reference for many subtle or complex facial injuries. This issue adds a more comprehensive and systematic approach to the secondary survey of the maxillofacial area and emergency department management of injuries to the face. In addition to an overall review of maxillofacial trauma pathophysiology, associated injuries, and physical examination, this review will also discuss relevant imaging, treatment, and disposition plans. PMID- 28362247 TI - A Qualitative Study of Hospitalists' Perceptions of Patient Satisfaction Metrics on Pain Management. AB - Hospital initiatives to promote pain management may unintentionally contribute to excessive opioid prescribing. To better understand hospitalists' perceptions of satisfaction metrics on pain management, the authors conducted 25 interviews with hospitalists. Transcribed interviews were systematically analyzed to identify emergent themes. Hospitalists felt institutional pressure to earn high satisfaction scores for pain, which they perceived influenced practices toward opioid prescribing. They felt tying compensation to satisfaction scores commoditized pain. Hospitalists believed satisfaction would improve with increased time spent at the bedside. Focusing on methods to improve patient physician communication, while maintaining efficiency in clinical practice, may promote both patient-centered pain management and satisfaction. PMID- 28362251 TI - Syncope In Pediatric Patients: A Practical Approach To Differential Diagnosis And Management In The Emergency Department. AB - Syncope is a condition that is often seen in the emergency department. Most syncope is benign, but it can be a symptom of a life-threatening condition. While syncope often requires an extensive workup in adults, in the pediatric population, critical questioning and simple, noninvasive testing is usually sufficient to exclude significant or life-threatening causes. For low-risk patients, resource-intensive workups are rarely diagnostic, and add significant cost to medical care. This issue will highlight critical diseases that cause syncope, identify high-risk "red flags," and enable the emergency clinician to develop a cost-effective, minimally invasive algorithm for the diagnosis and treatment of pediatric syncope. PMID- 28362254 TI - Hip, hip, hooray! AB - X-rays are best known for showing where bones have fractured, but researchers can also use X-rays to investigate why bones break, which could lead to treatments that reduce the number of elderly people who suffer broken hips. PMID- 28362253 TI - Bad medicine. AB - In his new book Ben Goldacre argues that the pharmaceutical industry is in poor health and in urgent need of treatment. Richard Smith agrees. PMID- 28362255 TI - Ribonuclease L mediates the cell-lethal phenotype of double-stranded RNA editing enzyme ADAR1 deficiency in a human cell line. AB - ADAR1 isoforms are adenosine deaminases that edit and destabilize double-stranded RNA reducing its immunostimulatory activities. Mutation of ADAR1 leads to a severe neurodevelopmental and inflammatory disease of children, Aicardi-Goutieres syndrome. In mice, Adar1 mutations are embryonic lethal but are rescued by mutation of the Mda5 or Mavs genes, which function in IFN induction. However, the specific IFN regulated proteins responsible for the pathogenic effects of ADAR1 mutation are unknown. We show that the cell-lethal phenotype of ADAR1 deletion in human lung adenocarcinoma A549 cells is rescued by CRISPR/Cas9 mutagenesis of the RNASEL gene or by expression of the RNase L antagonist, murine coronavirus NS2 accessory protein. Our result demonstrate that ablation of RNase L activity promotes survival of ADAR1 deficient cells even in the presence of MDA5 and MAVS, suggesting that the RNase L system is the primary sensor pathway for endogenous dsRNA that leads to cell death. PMID- 28362256 TI - Frequent exchange of the DNA polymerase during bacterial chromosome replication. AB - The replisome is a multiprotein machine that carries out DNA replication. In Escherichia coli, a single pair of replisomes is responsible for duplicating the entire 4.6 Mbp circular chromosome. In vitro studies of reconstituted E. coli replisomes have attributed this remarkable processivity to the high stability of the replisome once assembled on DNA. By examining replisomes in live E. coli with fluorescence microscopy, we found that the Pol III* subassembly frequently disengages from the replisome during DNA synthesis and exchanges with free copies from solution. In contrast, the DnaB helicase associates stably with the replication fork, providing the molecular basis for how the E. coli replisome can maintain high processivity and yet possess the flexibility to bypass obstructions in template DNA. Our data challenges the widely-accepted semi-discontinuous model of chromosomal replication, instead supporting a fully discontinuous mechanism in which synthesis of both leading and lagging strands is frequently interrupted. PMID- 28362258 TI - A CDC25 family protein phosphatase gates cargo recognition by the Vps26 retromer subunit. AB - We describe a regulatory mechanism that controls the activity of retromer, an evolutionarily conserved sorting device that orchestrates cargo export from the endosome. A spontaneously arising mutation that activates the yeast (Saccharomyces cerevisiae) CDC25 family phosphatase, Mih1, results in accelerated turnover of a subset of endocytosed plasma membrane proteins due to deficient sorting into a retromer-mediated recycling pathway. Mih1 directly modulates the phosphorylation state of the Vps26 retromer subunit; mutations engineered to mimic these states modulate the binding affinities of Vps26 for a retromer cargo, resulting in corresponding changes in cargo sorting at the endosome. The results suggest that a phosphorylation-based gating mechanism controls cargo selection by yeast retromer, and they establish a functional precedent for CDC25 protein phosphatases that lies outside of their canonical role in regulating cell cycle progression. PMID- 28362257 TI - Role of D-aminoacyl-tRNA deacylase beyond chiral proofreading as a cellular defense against glycine mischarging by AlaRS. AB - Strict L-chiral rejection through Gly-cisPro motif during chiral proofreading underlies the inability of D-aminoacyl-tRNA deacylase (DTD) to discriminate between D-amino acids and achiral glycine. The consequent Gly-tRNAGly 'misediting paradox' is resolved by EF-Tu in the cell. Here, we show that DTD's active site architecture can efficiently edit mischarged Gly-tRNAAla species four orders of magnitude more efficiently than even AlaRS, the only ubiquitous cellular checkpoint known for clearing the error. Also, DTD knockout in AlaRS editing defective background causes pronounced toxicity in Escherichia coli even at low glycine levels which is alleviated by alanine supplementation. We further demonstrate that DTD positively selects the universally invariant tRNAAla specific G3*U70. Moreover, DTD's activity on non-cognate Gly-tRNAAla is conserved across all bacteria and eukaryotes, suggesting DTD's key cellular role as a glycine deacylator. Our study thus reveals a hitherto unknown function of DTD in cracking the universal mechanistic dilemma encountered by AlaRS, and its physiological importance. PMID- 28362259 TI - Non-coding cancer driver candidates identified with a sample- and position specific model of the somatic mutation rate. AB - Non-coding mutations may drive cancer development. Statistical detection of non coding driver regions is challenged by a varying mutation rate and uncertainty of functional impact. Here, we develop a statistically founded non-coding driver detection method, ncdDetect, which includes sample-specific mutational signatures, long-range mutation rate variation, and position-specific impact measures. Using ncdDetect, we screened non-coding regulatory regions of protein coding genes across a pan-cancer set of whole-genomes (n = 505), which top-ranked known drivers and identified new candidates. For individual candidates, presence of non-coding mutations associates with altered expression or decreased patient survival across an independent pan-cancer sample set (n = 5454). This includes an antigen-presenting gene (CD1A), where 5'UTR mutations correlate significantly with decreased survival in melanoma. Additionally, mutations in a base-excision repair gene (SMUG1) correlate with a C-to-T mutational-signature. Overall, we find that a rich model of mutational heterogeneity facilitates non-coding driver identification and integrative analysis points to candidates of potential clinical relevance. PMID- 28362261 TI - Regulation of plant immune receptor accumulation through translational repression by a glycine-tyrosine-phenylalanine (GYF) domain protein. AB - Plant immunity is tightly regulated to ensure proper defense against surrounding microbial pathogens without triggering autoimmunity, which negatively impacts plant growth and development. Immune receptor levels are intricately controlled by RNA processing and post-translational modification events, such as ubiquitination. It remains unknown whether, and if yes, how, plant immune receptor homeostasis is regulated at the translational level. From a mutant, snc1 enhancing (muse) forward genetic screen, we identified MUSE11/EXA1, which negatively regulates nucleotide-binding leucine-rich repeat (NLR) receptor mediated defence. EXA1 contains an evolutionarily conserved glycine-tyrosine phenylalanine (GYF) domain that binds proline-rich sequences. Genetic and biochemical analysis revealed that loss of EXA1 leads to heightened NLR accumulation and enhanced resistance against virulent pathogens. EXA1 also associates with eIF4E initiation factors and the ribosome complex, likely contributing to the proper translation of target proteins. In summary, our study reveals a previously unknown mechanism of regulating NLR homeostasis through translational repression by a GYF protein. PMID- 28362260 TI - Evolution of substrate specificity in a retained enzyme driven by gene loss. AB - The connection between gene loss and the functional adaptation of retained proteins is still poorly understood. We apply phylogenomics and metabolic modeling to detect bacterial species that are evolving by gene loss, with the finding that Actinomycetaceae genomes from human cavities are undergoing sizable reductions, including loss of L-histidine and L-tryptophan biosynthesis. We observe that the dual-substrate phosphoribosyl isomerase A or priA gene, at which these pathways converge, appears to coevolve with the occurrence of trp and his genes. Characterization of a dozen PriA homologs shows that these enzymes adapt from bifunctionality in the largest genomes, to a monofunctional, yet not necessarily specialized, inefficient form in genomes undergoing reduction. These functional changes are accomplished via mutations, which result from relaxation of purifying selection, in residues structurally mapped after sequence and X-ray structural analyses. Our results show how gene loss can drive the evolution of substrate specificity from retained enzymes. PMID- 28362262 TI - A type I IFN-dependent DNA damage response regulates the genetic program and inflammasome activation in macrophages. AB - Macrophages produce genotoxic agents, such as reactive oxygen and nitrogen species, that kill invading pathogens. Here we show that these agents activate the DNA damage response (DDR) kinases ATM and DNA-PKcs through the generation of double stranded breaks (DSBs) in murine macrophage genomic DNA. In contrast to other cell types, initiation of this DDR depends on signaling from the type I interferon receptor. Once activated, ATM and DNA-PKcs regulate a genetic program with diverse immune functions and promote inflammasome activation and the production of IL-1beta and IL-18. Indeed, following infection with Listeria monocytogenes, DNA-PKcs-deficient murine macrophages produce reduced levels of IL 18 and are unable to optimally stimulate IFN-gamma production by NK cells. Thus, genomic DNA DSBs act as signaling intermediates in murine macrophages, regulating innate immune responses through the initiation of a type I IFN-dependent DDR. PMID- 28362263 TI - Inhibitor of ppGalNAc-T3-mediated O-glycosylation blocks cancer cell invasiveness and lowers FGF23 levels. AB - Small molecule inhibitors of site-specific O-glycosylation by the polypeptide N acetylgalactosaminyltransferase (ppGalNAc-T) family are currently unavailable but hold promise as therapeutics, especially if selective against individual ppGalNAc T isozymes. To identify a compound targeting the ppGalNAc-T3 isozyme, we screened libraries to find compounds that act on a cell-based fluorescence sensor of ppGalNAc-T3 but not on a sensor of ppGalNAc-T2. This identified a hit that subsequent in vitro analysis showed directly binds and inhibits purified ppGalNAc T3 with no detectable activity against either ppGalNAc-T2 or ppGalNAc-T6. Remarkably, the inhibitor was active in two medically relevant contexts. In cell culture, it opposed increased cancer cell invasiveness driven by upregulated ppGalNAc-T3 suggesting the inhibitor might be anti-metastatic. In cells and mice, it blocked ppGalNAc-T3-mediated glycan-masking of FGF23 thereby increasing its cleavage, a possible treatment of chronic kidney disease. These findings establish a pharmacological approach for the ppGalNAc-transferase family and suggest that targeting specific ppGalNAc-transferases will yield new therapeutics. PMID- 28362265 TI - The GuLF STUDY: A Prospective Study of Persons Involved in the Deepwater Horizon Oil Spill Response and Clean-Up. AB - BACKGROUND: The 2010 Deepwater Horizon disaster led to the largest ever marine oil spill. Individuals who worked on the spill were exposed to toxicants and stressors that could lead to adverse effects. OBJECTIVES: The GuLF STUDY was designed to investigate relationships between oil spill exposures and multiple potential physical and mental health effects. METHODS: Participants were recruited by telephone from lists of individuals who worked on the oil spill response and clean-up or received safety training. Enrollment interviews between 2011 and 2013 collected information about spill-related activities, demographics, lifestyle, and health. Exposure measurements taken during the oil spill were used with questionnaire responses to characterize oil exposures of participants. Participants from Gulf states completed a home visit in which biological and environmental samples, anthropometric and clinical measurements, and additional health and lifestyle information were collected. Participants are being followed for changes in health status. RESULTS: Thirty-two thousand six hundred eight individuals enrolled in the cohort, and 11,193 completed a home visit. Most were young (56.2% <= 45 years of age), male (80.8%), lived in a Gulf state (82.3%), and worked at least 1 day on the oil spill (76.5%). Workers were involved in response (18.0%), support operations (17.5%), clean-up on water (17.4%) or land (14.6%), decontamination (14.3%), and administrative support (18.3%). Using an ordinal job exposure matrix, 45% had maximum daily total hydrocarbon exposure levels >= 1.0 ppm. CONCLUSIONS: The GuLF STUDY provides a unique opportunity to study potential adverse health effects from the Deepwater Horizon oil spill. PMID- 28362267 TI - Unintentionally retained vascular devices: improving recognition and removal. AB - The increased demand for minimally invasive placement of intravascular medical devices has led to increased procedure-related complications, including retention of all or part of the implanted device. A number of risk factors can predispose to unintentionally retained vascular devices (uRVD); most are technical in etiology. Despite best efforts to insert and remove vascular devices properly, uRVD still occur. Prevention or early identification of uRVD is ideal; however, procedural complications are not always recognized at the time of device insertion or removal. In these cases, early radiologic diagnosis is important to enable expeditious removal and reduction of morbidity, mortality, and medicolegal consequences. The diagnostic radiologist's role is to identify suspected uRVD and ensure proper communication of the findings to the referring clinician. The diagnostic radiologist can implement various strategies to increase detection of uRVD and advise the referring clinician regarding the use of minimally invasive percutaneous techniques for safe removal of uRVD. PMID- 28362266 TI - The Prevalence of Antibiotic-Resistant Staphylococcus aureus Nasal Carriage among Industrial Hog Operation Workers, Community Residents, and Children Living in Their Households: North Carolina, USA. AB - BACKGROUND: Antibiotic use in industrial hog operations (IHOs) can support the emergence of antibiotic-resistant (ABR) Staphylococcus aureus. The extent of ABR S. aureus exposure in IHO workers and children living in their households remains unclear. OBJECTIVE: We investigated ABR S. aureus nasal carriage prevalence among adults with versus without occupational exposure to IHOs and among children living in their households. METHODS: In total, 198 IHO worker-child household pairs and 202 community referent (CR) adult-child household pairs completed a questionnaire and provided a nasal swab which was analyzed for S. aureus, methicillin-resistant S. aureus (MRSA), multidrug-resistant S. aureus (MDRSA), absence of scn (putative marker of livestock association), and spa type. RESULTS: S. aureus nasal carriage prevalence was higher among IHO (53%) compared with CR (31%) adults [adjusted prevalence ratio (aPR): 1.40; 95% confidence interval (CI): 1.07, 1.83], but MRSA nasal carriage prevalence was uncommon (2-3%) in IHO and CR adults. MDRSA nasal carriage prevalence was similar among IHO workers and CR adults (12% vs. 8%; aPR: 1.14; 95% CI: 0.56, 2.29). Nasal carriage prevalence was higher among IHO compared with CR children for S. aureus (49% vs. 31%; aPR: 1.50; 95% CI: 1.13, 1.99), MRSA (14% vs. 6%; aPR: 2.37; 95% CI: 1.14, 4.92), and MDRSA (23% vs. 8%; aPR: 2.64; 95% CI: 1.47, 4.75). We also found suggestive evidence of a higher prevalence of S. aureus, MRSA, and MDRSA among children living with an IHO worker who did versus did not report taking personal protective equipment (PPE) home from the IHO. Livestock-associated S. aureus nasal carriage predominated among IHO workers. CONCLUSION: Our findings support the importance of further research on the prevalence and potential sources of exposure to ABR S. aureus among children living with IHO workers. PMID- 28362269 TI - Daclatasvir plasma concentration assessment in HIV-HCV-coinfected real-life patients. PMID- 28362268 TI - Progressive multifocal leukoencephalopathy due to John Cunningham (JC) virus following allogeneic haematopoietic cell transplantation. AB - Progressive multifocal leukoencephalopathy (PML) is an uncommon infectious complication post allogeneic stem cell transplant. We present a case report of a patient developing this complication with a review of the current literature. It also describes the first use of artesunate in a clinical case of PML with no beneficial effect. PMID- 28362270 TI - Signature of surface periodicity in the electronic structure of Si(1 1 1)-(7 * 7). AB - The surface electronic structure of Si(1 1 1)-[Formula: see text] has been studied by angle-resolved photo electron spectroscopy. Replicas of the S 1 surface state are found in correspondence with several [Formula: see text] unit cells in the reciprocal space. This observation resolves in a direct way the long standing dichotomy between the structural and electronic properties of the system previously discussed on the basis of the [Formula: see text] or [Formula: see text] R30 degrees surface models. PMID- 28362264 TI - Small-Magnitude Effect Sizes in Epigenetic End Points are Important in Children's Environmental Health Studies: The Children's Environmental Health and Disease Prevention Research Center's Epigenetics Working Group. AB - BACKGROUND: Characterization of the epigenome is a primary interest for children's environmental health researchers studying the environmental influences on human populations, particularly those studying the role of pregnancy and early life exposures on later-in-life health outcomes. OBJECTIVES: Our objective was to consider the state of the science in environmental epigenetics research and to focus on DNA methylation and the collective observations of many studies being conducted within the Children's Environmental Health and Disease Prevention Research Centers, as they relate to the Developmental Origins of Health and Disease (DOHaD) hypothesis. METHODS: We address the current laboratory and statistical tools available for epigenetic analyses, discuss methods for validation and interpretation of findings, particularly when magnitudes of effect are small, question the functional relevance of findings, and discuss the future for environmental epigenetics research. DISCUSSION: A common finding in environmental epigenetic studies is the small-magnitude epigenetic effect sizes that result from such exposures. Although it is reasonable and necessary that we question the relevance of such small effects, we present examples in which small effects persist and have been replicated across populations and across time. We encourage a critical discourse on the interpretation of such small changes and further research on their functional relevance for children's health. CONCLUSION: The dynamic nature of the epigenome will require an emphasis on future longitudinal studies in which the epigenome is profiled over time, over changing environmental exposures, and over generations to better understand the multiple ways in which the epigenome may respond to environmental stimuli. PMID- 28362271 TI - Radial dose distributions from carbon ions of therapeutic energies calculated with Geant4-DNA. AB - We report on radial dose distributions [Formula: see text] for carbon ions calculated with Geant4-DNA code. These distributions characterize ion tracks on a nanoscale and are important for understanding the biological effects of ion beams. We present data for carbon ion beams in the energy range from 20 to 400 MeV u-1. To approximate the Monte Carlo results, we developed a simple formula that combines the well-known inverse square distance dependence with a factor correcting [Formula: see text] for small [Formula: see text]. The proposed formula can be used to calculate [Formula: see text] for any energy within the above range and for distances [Formula: see text] from 1 nm to 2 MUm with a maximum error not exceeding 14%. This range of distances corresponds to a dose range of over seven orders of magnitude. Differences between our results and those of previously published analytical models are discussed. PMID- 28362272 TI - Spectroscopic signatures of different symmetries of the superconducting order parameter in metal-decorated graphene. AB - Motivated by the recent experiments indicating superconductivity in metal decorated graphene sheets, we investigate their quasi-particle structure within the framework of an effective tight-binding Hamiltonian augmented by appropriate BCS-like pairing terms for p-type order parameter. The normal state band structure of graphene is modified not only through interaction with adsorbed metal atoms, but also due to the folding of bands at Brillouin zone boundaries resulting from a [Formula: see text] reconstruction. Several different types of pairing symmetries are analyzed utilizing Nambu-Gorkov Green's function techniques to show that [Formula: see text]-symmetric nearest-neighbor pairing yields the most enhanced superconducting gap. The character of the order parameter depends on the nature of the atomic orbitals involved in the pairing process and exhibits interesting angular and radial asymmetries. Finally, we suggest a method to distinguish between singlet and triplet type superconductivity in the presence of magnetic substitutional impurities using scanning tunneling spectroscopy. PMID- 28362273 TI - Introduction to the special issue on halogen bonding. PMID- 28362274 TI - Directional O...F halogen bonds. PMID- 28362275 TI - Coordination chemistry of anions through halogen-bonding interactions. PMID- 28362276 TI - Characterization of fluorine-centred 'F...O' sigma-hole interactions in the solid state. AB - In the current study, the crystal structure of 1-(3-nitrophenyl)-2,2,2 trifluoroethanone (A1) and (E)-4-((4-fluorophenyl) diazenyl)phenol (A2) has been analyzed for the characterization of the presence of a 'unique' and 'rare' intermolecular C(sp3/sp2)-F...O contact, which has been observed to play a significant role in the crystal packing. Theoretical charge-density calculations have been performed to study the nature and strength associated with the existence of this intermolecular F...O contact, wherein the F atom is attached to an sp3-hybridized C atom in the case of A1 and to an sp2 hybridized carbon in the case of A2. The crystal packing of the former contains two 'electronically different' Csp3-F...O contacts which are present across and in between the layers of molecules. In the latter case, it is characterized by the presence of a very 'short' (2.708 A) and 'highly directional' (168 degrees at ?C4-F1...O1 and 174 degrees at ?C10-O1...F1) Csp2-F...O contact. According to the Cambridge Structural Database (CSD) study, it is a rare example in molecular crystals. Topological features of F...O contacts in the solid state were compared with the gas-phase models. The two-dimensional and three-dimensional static deformation density obtained from theoretical multipole modeling confirm the presence of a charge depleted region on the F atoms. Minimization of the electrostatic repulsion between like charges are observed through subtle arrangements in the electronic environment in two of the short intermolecular F...O contacts. These contacts were investigated using inputs from pair energy decomposition analysis, Bader's quantum theory of atoms in molecules (QTAIM), Hirshfeld surface analysis, delocalization index, reduced density gradient (RDG) plot, electrostatic potential surface and distributed atomic polarizability. The intermolecular energy decomposition (PIXEL) and RDG-NCI (non-covalent interaction) analysis of the F...O contacts establish the interaction to be dispersive in nature. The mutual polarization of an O atom by fluorine and vice versa provides real physical insights into the role of atomic polarizability in interacting atoms in molecules in crystals. PMID- 28362277 TI - 1,3,5-Tri(iodoethynyl)-2,4,6-trifluorobenzene: halogen-bonded frameworks and NMR spectroscopic analysis. AB - Halogen bonding is the non-covalent interaction between the region of positive electrostatic potential associated with a covalently bonded halogen atom, named the sigma-hole, and a Lewis base. Single-crystal X-ray diffraction structures are reported for a series of seven halogen-bonded cocrystals featuring 1,3,5 tris(iodoethynyl)-2,4,6-trifluorobenzene (1) as the halogen-bond donor, and bromide ions (as ammonium or phosphonium salts) as the halogen-bond acceptors: (1).MePh3PBr, (1).EtPh3PBr, (1).acetonyl-Ph3PBr, (1).Ph4PBr, (1).[bis(4 fluorophenyl)methyl]triphenylphosphonium bromide, and two new polymorphs of (1).Et3BuNBr. The cocrystals all feature moderately strong iodine-bromide halogen bonds. The crystal structure of pure [bis(4 fluorophenyl)methyl]triphenylphosphonium bromide is also reported. The results of a crystal engineering strategy of varying the size of the counter-cation are explored, and the features of the resulting framework materials are discussed. Given the potential utility of (1) in future crystal engineering applications, detailed NMR analyses (in solution and in the solid state) of this halogen-bond donor are also presented. In solution, complex 13C and 19F multiplets are explained by considering the delicate interplay between various J couplings and subtle isotope shifts. In the solid state, the formation of (1).Et3BuNBr is shown through significant 13C chemical shift changes relative to pure solid 1,3,5 tris(iodoethynyl)-2,4,6-trifluorobenzene. PMID- 28362278 TI - A new tecton with parallel halogen-bond donors: a path to supramolecular rectangles. AB - A new tecton, 1,8-diiodoethynylanthracene, with two halogen-bond donor sites was synthesized and characterized. This tecton is capable of forming two parallel halogen bonds at once, which makes it a useful building block for the construction of a variety of supramolecular squares and rectangles. PMID- 28362279 TI - Taking the halogen bonding-hydrogen bonding competition one step further: complexes of difluoroiodomethane with trimethylphosphine, dimethyl sulfide and chloromethane. AB - To rationalize the driving factors in the competition of halogen bonding and hydrogen bonding, the complexes of the combined halogen-/hydrogen-bond donor difluoroiodomethane with the Lewis bases trimethylphosphine, dimethyl sulfide and chloromethane are studied. For all Lewis bases, ab initio calculations lead to halogen- and hydrogen-bonded complexes. Fourier transform-IR experiments involving solutions of mixtures of difluoroiodomethane with trimethylphosphine( d9) or dimethyl sulfide(-d6) in liquid krypton confirm the coexistence of a halogen-bonded and hydrogen-bonded complex. Also for solutions containing chloromethane, evidence of the formation of binary associations is found, but no definitive assignment of the multiple complex bands could be made. Using van't Hoff plots, the experimental complexation enthalpies for the halogen- and hydrogen-bonded complex of difluoroiodomethane with trimethylphosphine are determined to be -15.4 (4) and -10.5 (3) kJ mol-1, respectively, while for the halogen- and hydrogen-bonded complexes with dimethyl sulfide, the values are 11.3 (5) and -7.7 (6) kJ mol-1, respectively. The experimental observation that for both trimethylphospine and dimethyl sulfide the halogen-bonded complex is more stable than the hydrogen-bonded complex supports the finding that softer Lewis bases tend to favor iodine halogen bonding over hydrogen bonding. PMID- 28362280 TI - Cyclic networks of halogen-bonding interactions in molecular self-assemblies: a theoretical N-X...N versus C-X...N investigation. AB - The geometries and energetics of molecular self-assembly structures that contain a sequential network of cyclic halogen-bonding interactions are investigated theoretically. The strength of the halogen-bonding interactions is assessed by examining binding energies, electron charge transfer (NBO analysis) and electron density at halogen-bond critical points (AIM theory). Specifically, structural motifs having intramolecular N-X...N (X = Cl, Br, or I) interactions and the ability to drive molecular self-assembly via the same type of interactions are used to construct larger self-assemblies of up to three unit motifs. N-X...N halogen-bond cooperativity as a function of the self-assembly size, and the nature of the halogen atom is also examined. The cyclic network of the halogen bonding interactions provides a suitable cavity rich in electron density (from the halogen atom lone pairs not involved in the halogen bonds) that can potentially bind an electron-deficient species such as a metal ion. This possibility is explored by examining the ability of the N-X...N network to bind Na+. Likewise, molecular self-assembly structures driven by the weaker C-X...N halogen-bonding interactions are investigated and the results compared with those of their N-X...N counterparts. PMID- 28362281 TI - The evaluation of QM/MM-driven molecular docking combined with MM/GBSA calculations as a halogen-bond scoring strategy. AB - The combination of quantum mechanics/molecular mechanics-driven (QM/MM) molecular docking with binding free-energy calculations was successfully used to reproduce the X-ray geometries of protein-ligand complexes with halogen bonding. The procedure involves quantum-polarized ligand docking (QPLD) to obtain the QM derived ligand atomic charges in the protein environment at the B3PW91/cc-pVTZ level and the MM/GBSA (generalized-Born/surface area) algorithm to calculate the binding free energies of resultant complexes. The performance was validated using a set of 106 X-ray complexes and compared with the Glide and AutoDock VinaXB scoring functions in terms of RMSD and the reconstruction of halogen-bond geometry (distance and sigma-hole angle). The results revealed that docking and scoring using the QPLD-GBSA procedure outperformed the remaining scoring functions in the majority of instances. Additionally, a comparison of the orientation of the top ranked binding poses calculated using the fixed atomic charges of ligands obtained from force-field parameterization and by QM calculations in the protein environment provides strong evidence that the use of QM-derived charges is significant. PMID- 28362282 TI - Theoretical insights into the pi-hole interactions in the complexes containing triphosphorus hydride (P3H3) and its derivatives. AB - The pi-hole of triphosphorus hydride (P3H3) and its derivatives Z3X3 (Z = P, As; X = H, F, Cl, Br) was discovered and analyzed. MP2/aug-cc-pVDZ calculations were performed on the pi-hole interactions in the HCN...Z3X3 complexes and the mutual influence between pi-hole interactions and the hydrogen bond in the HCN...HCN...Z3X3 and HCN...Z3X3...HCN complexes studied. The pi-hole interaction belongs to the typical closed-shell noncovalent interaction. The linear relationship was found between the most positive electrostatic potential of the pi-hole (VS,max) and the interaction energy. Moreover, the VS,max of the pi-hole was also found to be linearly correlated to the electrostatic energy term, indicating the important contribution of the electrostatic energy term to the pi hole interaction. There is positive cooperativity between the pi-hole interaction and the hydrogen bond in the termolecular complexes. The pi-hole interaction has a greater influence on the hydrogen bond than vice versa. The mutual enhancing effect between the pi-hole interaction and the hydrogen bond in the HCN...HCN...Z3X3 complexes is greater than that in the HCN...Z3X3...HCN complexes. PMID- 28362284 TI - Cocrystal assembled by 1,4-diiodotetrafluorobenzene and phenothiazine based on C I...pi/N/S halogen bond and other assisting interactions. AB - The halogen-bonded cocrystal of 1,4-diiodotetrafluorobenzene (1,4-DITFB) with the butterfly-shape non-planar heterocyclic compound phenothiazine (PHT) was successfully assembled by the conventional solution-based method. X-ray single crystal diffraction analysis reveals a 3:2 stoichiometric ratio for the cocrystal (1,4-DITFB/PHT), and the cocrystal structure is constructed via C-I...pi, C-I...N and C-I...S halogen bonds as well as other assisting interactions (e.g. C-H...F/S hydrogen bond, C-H...H-C and C-F...F-C bonds). The small shift of the 1,4-DITFB vibrational band to lower frequencies in FT-IR and Raman spectroscopies provide evidence to confirm the existence of the halogen bond. In addition, the non planarity of the PHT molecule in the cocrystal results in PHT emitting weak phosphorescence and relatively strong delayed fluorescence. Thus, a wide range of delayed fluorescence and weak phosphorescence could play a significant role in selecting a proper pi-conjugated system to engineer functional cocrystal and luminescent materials by halogen bonds. PMID- 28362285 TI - Testing the tools for revealing and characterizing the iodine-iodine halogen bond in crystals. AB - To understand what tools are really suitable to identify and classify the iodine iodine non-covalent interactions in solid organic polyiodides, we have examined the anisotropy of the electron density within the iodine atomic basin along and across the iodine-iodine halogen bond using the Laplacian of electron density, one-electron potential and electron localization function produced by Kohn-Sham calculations with periodic boundary conditions. The Laplacian of electron density exhibits the smallest anisotropy and yields a vague picture of the outermost electronic shells. The one-electron potential does not show such a deficiency and reveals that the valence electron shell for the halogen-bond acceptor iodine is always wider than that for the halogen-bond donor iodine along its sigma-hole direction. We have concluded that the one-electron potential is the most suitable for classification of the iodine-iodine bonds and interactions in complicated cases, while the electron localization function allows to distinguish the diiodine molecule bonded with the monoiodide anion from the typical triiodide anion. PMID- 28362283 TI - Experimental investigation of halogen-bond hard-soft acid-base complementarity. AB - The halogen bond (XB) is a topical noncovalent interaction of rapidly increasing importance. The XB employs a 'soft' donor atom in comparison to the 'hard' proton of the hydrogen bond (HB). This difference has led to the hypothesis that XBs can form more favorable interactions with 'soft' bases than HBs. While computational studies have supported this suggestion, solution and solid-state data are lacking. Here, XB soft-soft complementarity is investigated with a bidentate receptor that shows similar associations with neutral carbonyls and heavy chalcogen analogs. The solution speciation and XB soft-soft complementarity is supported by four crystal structures containing neutral and anionic soft Lewis bases. PMID- 28362287 TI - Utilizing bifurcated halogen-bonding interactions with the uranyl oxo group in the assembly of a UO2-3-bromo-5-iodobenzoic acid coordination polymer. AB - The synthesis and crystal structure of a new uranyl coordination polymer featuring 3-bromo-5-iodobenzoic acid is described and the luminescent and vibrational properties of the material have been explored. Compound (1), [UO2(C7H3BrIO2)2]n, features dimeric uranyl units chelated and then linked by 3 bromo-5-iodobenzoic acid ligands to form a one-dimensional coordination polymer that is subsequently assembled via bifurcated halogen-bonding interactions with uranyl oxo atoms to form a supramolecular three-dimensional network. The asymmetric, bifurcated halogen-bonding interaction in (1) is notable as it represents the first observation of this synthon in a uranyl hybrid material. Raman and IR spectroscopy showed that halogen-bonding interactions with the uranyl oxo atoms result in small shifts in upsilon1 and upsilon3 frequencies, whereas luminescence spectra collected at an excitation wavelength of 420 nm reveal partially resolved uranyl emission. PMID- 28362286 TI - Halogen bonding stabilizes a cis-azobenzene derivative in the solid state: a crystallographic study. AB - Crystals of trans- and cis-isomers of a fluorinated azobenzene derivative have been prepared and characterized by single-crystal X-ray diffraction. The presence of F atoms on the aromatic core of the azobenzene increases the lifetime of the metastable cis-isomer, allowing single crystals of the cis-azobenzene to be grown. Structural analysis on the cis-azobenzene, complemented with density functional theory calculations, highlights the active role of the halogen-bond contact (N...I synthon) in promoting the stabilization of the cis-isomer. The presence of a long aliphatic chain on the azobenzene unit induces a phase segregation that stabilizes the molecular arrangement for both the trans- and cis isomers. Due to the rarity of cis-azobenzene crystal structures in the literature, our paper makes a step towards understanding the role of non-covalent interactions in driving the packing of metastable azobenzene isomers. This is expected to be important in the future rational design of solid-state, photoresponsive materials based on halogen bonding. PMID- 28362288 TI - Crystallographic insights into the structural aspects of thioctic acid based halogen-bond donor for the functionalization of gold nanoparticles. AB - The synthesis and self-assembly capabilities of a new halogen-bond donor ligand, 2,3,5,6-tetrafluoro-4-iodophenyl 5-(1,2-dithiolan-3-yl)pentanoate (1), are reported. The crystal structure of ligand (1) and the formation of a cocrystal with 1,2-di(4-pyridyl)ethylene, (1).(2), both show halogen bonds involving the 4 iodotetrafluorobenzene moiety. Ligand (1), being a self-complementary unit, forms an infinite halogen-bonded chain driven by the S...I synthon, while the cocrystal (1).(2) self-assembles into a discrete trimeric entity driven by the N...I synthon. Ligand (1) was also successfully used to functionalize the surface of gold nanoparticles, AuNP-(1). Experiments on the dispersibility profile of AuNP (1) demonstrated the potential of halogen bonding in facilitating the dispersion of modified NPs with halogen-bond donors in pyridine. PMID- 28362289 TI - Color-tunable phosphorescence of 1,10-phenanthrolines by 4,7-methyl/-diphenyl/ dichloro substituents in cocrystals assembled via bifurcated C-I...N halogen bonds using 1,4-diiodotetrafluorobenzene as a bonding donor. AB - Single-crystal X-ray diffraction reveals a series of phosphorescent cocrystals which were assembled by 1,4-diiodotetrafluorobenzene (1,4-DITFB) and either 4,7 dimethyl-1,10-phenanthroline (DMPhe), 4,7-diphenyl-1,10-phenanthroline (DPPhe) or 4,7-dichloro-1,10-phenanthroline (DClPhe) via C-I...N halogen bonding. These cocrystals, labeled (1), (2) and (3), respectively, are phosphorescent and a distinct change in phosphorescent color can be observed from orange-yellow, green to yellow-green, with well defined vibrational band maxima at 587, 520 and 611 nm for (1), (2) and (3). Based on the dependence of halogen bonding in sites and strength, we discussed the impact of substituents with different electron withdrawing effects and steric hindrance on intermolecular noncovalent interactions and phosphorescence. The method of inducing and modulating phosphorescence by halogen bonding and other weak non-covalent interactions through changing the substituent groups of molecules should be significant in both theory and the application of optical function materials with predictable and modulated luminescent properties. PMID- 28362290 TI - Relationships between hydrogen bonds and halogen bonds in biological systems. AB - The recent recognition that halogen bonding (XB) plays important roles in the recognition and assembly of biological molecules has led to new approaches in medicinal chemistry and biomolecular engineering. When designing XBs into strategies for rational drug design or into a biomolecule to affect its structure and function, we must consider the relationship between this interaction and the more ubiquitous hydrogen bond (HB). In this review, we explore these relationships by asking whether and how XBs can replace, compete against or behave independently of HBs in various biological systems. The complex relationships between the two interactions inform us of the challenges we face in fully utilizing XBs to control the affinity and recognition of inhibitors against their therapeutic targets, and to control the structure and function of proteins, nucleic acids and other biomolecular scaffolds. PMID- 28362291 TI - Nature of E2X2 sigma(4c-6e) of the X---E-E---X type at naphthalene 1,8-positions and model, elucidated by X-ray crystallographic analysis and QC calculations with the QTAIM approach. AB - The nature of E2X2 sigma(4c-6e) of the X-*-E-*-E-*-X type is elucidated for 1-(8 XC10H6)E-E(C10H6X-8')-1' [(1) E, X = S, Cl; (2) S, Br; (3) Se, Cl; (4) Se, Br] after structural determination of (1), (3) and (4), together with model A [MeX-- E(H)-E(H)---XMe (E = S and Se; X = Cl and Br)]. The quantum theory of atoms-in molecules dual functional analysis (QTAIM-DFA) is applied. The total electron energy densities Hb(rc) are plotted versus Hb(rc) - Vb(rc)/2 for the interactions at the bond critical points (BCPs; *), where Vb(rc) show the potential energy densities at the BCPs. Data for the perturbed structures around the fully optimized structures are employed for the plots, in addition to those of the fully optimized structures. The plots were analysed using the polar coordinate (R, theta) representation of the data of the fully optimized structures. Data containing the perturbed structures were analysed by (thetap, kappap), where thetap corresponds to the tangent line of the plot and kappap is the curvature. Whereas (R, theta) shows the static nature, (thetap, kappap) represents the dynamic nature of interactions. E-*-E are all classified as shared shell (S) interactions for (1)-(4) and as weak covalent (Cov-w) in nature (S/Cov-w). The nature of pure CS (closed shell)/typical-HB (hydrogen bond) with no covalency is predicted for E-*-X in (1) and (3), regular CS/typical-HB nature with covalency is predicted for (4), and an intermediate nature is predicted for (2). The NBO energies evaluated for E-*-X in (1)-(4) are substantially larger than those in model A due the shortened length at the naphthalene 1,8-positions. The nature of E2X2 of sigma(4c-6e) is well elucidated via QTAIM-DFA. PMID- 28362292 TI - Incommensurately modulated twin structure of nyerereite Na1.64K0.36Ca(CO3)2. AB - The incommensurately modulated twin structure of nyerereite Na1.64K0.36Ca(CO3)2 has been first determined in the (3 + 1)-dimensional symmetry group Cmcm(alpha00)00s with modulation vector q = 0.383a*. Unit-cell values are a = 5.062 (1), b = 8.790 (1), c = 12.744 (1) A. Three orthorhombic components are related by threefold rotation about [001]. Discontinuous crenel functions are used to describe the occupation modulation of Ca and some CO3 groups. The strong displacive modulation of the O atoms in vertexes of such CO3 groups is described using x-harmonics in crenel intervals. The Na, K atoms occupy mixed sites whose occupation modulation is described in two ways using either complementary harmonic functions or crenels. The nyerereite structure has been compared both with the commensurately modulated structure of K-free Na2Ca(CO3)2 and with the widely known incommensurately modulated structure of gamma-Na2CO3. PMID- 28362293 TI - Temperature-induced first-order displacive phase transition of isonicotinamide-4 methoxybenzoic acid co-crystal. AB - Isonicotinamide-4-methoxybenzoic acid co-crystal (1), C6H6N2O.C8H8O3, is formed through slow evaporation from methanol solution and it undergoes a first-order isosymmetry (monoclinic I2/a <-> monoclinic I2/a) structural phase transition at Tc = 142.5 (5) K, which has been confirmed by an abrupt jump of crystallographic interaxial angle beta from variable-temperature single-crystal XRD and small heat hysteresis (6.25 K) in differential scanning calorimetry measurement. The three dimensional X-ray crystal structures of (1) at the low-temperature phase (LTP) (100, 140 and 142 K) and the high-temperature phase (HTP) (143, 150, 200, 250 and 300 K) were solved and refined as a simple non-disordered model with final R[F2 > 2sigma(F2)] ? 0.05. The asymmetric unit of (1) consists of crystallographically independent 4-methoxybenzoic acid (A) and isonicotinamide (B) molecules in both enantiotropic phases. Molecule A adopts a 'near-hydroxyl' conformation in which the hydroxyl and methoxy groups are positioned on the same side. Both 'near hydroxyl' and 'near-carbonyl' molecular conformations possess minimum conformational energies with an energy difference of < 0.15 kJ mol-1 from a potential energy surface scan. In the crystal, molecules are joined into linear ABBA arrays by intermolecular N-H...O and O-H...N hydrogen bonds which were preserved in both phases. However, these ABBA arrays are displaced from planarity upon LTP-to-HTP transition and the changes in inter-array interactions are observed in two-dimensional fingerprint plots of their Hirshfeld surfaces. The PIXEL energies of each molecular pair in both phases were calculated to investigate the difference in intermolecular interaction energies before and after the displacement of ABBA arrays from planarity, which directly leads to the single-crystal-to-single-crystal phase transition of (1). PMID- 28362294 TI - A potential Cu/V-organophosphonate platform for tailored void spaces via terpyridine mold casting. AB - The reaction of appropriate copper and vanadium salts with tetratopic methane tetra-p-phenylphosphonic acid (MTPPA) in the presence of 2,2':6':2''-terpyridine (terpy) yielded the three-dimensional bimetallic copper vanadium phosphonate framework [{Cu(terpy)}4Cu(VO2)4(MTPPA-H)2].4H2O (1). Terpy has no net contribution to the three-dimensional structure providing a potential platform for void space formation via mold-casting. The structure was characterized by single-crystal X-ray diffraction and thermogravimetric analysis (TGA). Magnetic measurements were performed using a SQUID magnetometer. The crystal structure of the methanol solvate of the free ligand, MTPPA.MeOH, was analysed using Hirshfeld surfaces and fingerprint plots. PMID- 28362295 TI - Variable-temperature structural studies on valence tautomerism in cobalt bis(dioxolene) molecular complexes. AB - A variable-temperature single-crystal structural study of five valence tautomeric cobalt molecular complexes, CoII(3,5-DBSQ)2(DBPy)2 (1), CoII(3,5 DBSQ)2(DBPy)2.1.33C7H8 (1S), CoII(3,5-DBSQ)2(DCPy)2.C7H8 (2S), CoII(3,5 DBSQ)2(TBPy)2 (3) and CoII(3,5-DBSQ)2(TCPy)2 (4) (S = toluene, 3,5-DBSQ = 3,5-di tert-butylsemiquinonate, DBPy = 3,5-dibromopyridine, DCPy = 3,5-dichloropyridine, TBPy = 3,4,5-tribromopyridine and TCPy = 3,4,5-trichloropyridine) is reported. The re-crystallization of (1S) in toluene at 277 K resulted in a concomitant formation of a solvent-free polymorph, CoII(3,5-DBSQ)2(DBPy)2 (1). Thermally induced valence tautomerism (VT) is observed only in (1S), (1) and (2S) [hs CoII(3,5-DBSQ)2L2 <-> ls-CoIII(3,5-DBSQ)(3,5-DBCat)L2 (hs = high spin, ls = low spin, 3,5-DBCat = 3,5-di-tert-butylcatecholate)], whereas (3) and (4) remain locked in the hs-CoII(3,5-DBSQ)2 state during cooling of the sample. Multi temperature single-crystal studies demonstrate the change in cobalt coordination environment during the VT conversion. The non-solvated compound (1) shows a sharp VT transition (T1/2 ~ 245 K with DeltaT ~ 10 K) from hs-CoII(3,5-DBSQ)2(DBPy)2 to ls-CoIII(3,5-DBSQ)(3,5-DBCat)(DBPy)2 oxidation state, whereas the other polymorph with lattice solvent (1S) results in a broad transition (T1/2 ~ 150 K with DeltaT ~ 100 K). This increase in the VT transition temperature for (1) relative to (1S) illustrates the effect of lattice solvent on the VT transition mechanism. Additionally, the influence of halogen substitutions on the pyridine ring is discussed with respect to observed VT behaviour in the studied compounds. PMID- 28362296 TI - Triclinic crystal structure distortion of multiferroic BiMn7O12. AB - The quadruple perovskite BiMn7O12 obtained via high-pressure synthesis was investigated by high-resolution synchrotron X-ray powder diffraction over a temperature range of 10 to 295 K. Careful Rietveld analysis reveals triclinic lattice distortion of BiMn7O12 at 295 K, which increases upon cooling to 10 K. Also hkl-dependent anisotropic Bragg reflection shape was introduced to give a precise description of the diffracted intensities. Importantly BiMn7O12 crystal structure was described in the non-centrosymmetric I1 triclinic space group. We also demonstrate the use of irreducible representations analysis (ISODISTORT program) for crystal structure distortion from Im to I1 space group. The irreducible representation which describes crystal structure distortion points towards possible ferroelectricity. Finally anisotropic thermal lattice expansion was observed. PMID- 28362299 TI - Towards a research agenda for water, sanitation and antimicrobial resistance. AB - Clinically relevant antimicrobial resistant bacteria, genetic resistance elements, and antibiotic residues (so-called AMR) from human and animal waste are abundantly present in environmental samples. This presence could lead to human exposure to AMR. In 2015, the World Health Organization (WHO) developed a Global Action Plan for Antimicrobial Resistance with one of its strategic objectives being to strengthen knowledge through surveillance and research. With respect to a strategic research agenda on water, sanitation and hygiene and AMR, WHO organized a workshop to solicit input by scientists and other stakeholders. The workshop resulted in three main conclusions. The first conclusion was that guidance is needed on how to reduce the spread of AMR to humans via the environment and to introduce effective intervention measures. Second, human exposure to AMR via water and its health impact should be investigated and quantified, in order to compare with other human exposure routes, such as direct transmission or via food consumption. Finally, a uniform and global surveillance strategy that complements existing strategies and includes analytical methods that can be used in low-income countries too, is needed to monitor the magnitude and dissemination of AMR. PMID- 28362300 TI - Evaluation of DBPs formation from SMPs exposed to chlorine, chloramine and ozone. AB - Soluble microbial products (SMPs) are an important group of components in wastewater effluents. In this study, the formation of disinfection by-products (DBPs), including trihalomethanes (THMs), haloacetic acids (HAAs), chlorinated solvents (CSs), haloketones (HKs), haloacetonitriles (HANs) and trichloronitromethane (TCNM) (chloropicrin), from SMPs during chlorination, chloramination and ozonation was investigated. More carbonaceous DBPs (C-DBPs: THMs, HAAs, CSs and HKs) and nitrogenous DBPs (N-DBPs: HANs and TCNM) were formed in chlorination than chloramination. More dichloroacetic and N-DBPs, and higher DBP formation potential were generated by SMPs than by natural organic matter. The results also show that disinfection factors, including temperature, pH, disinfectant dose, reaction time and bromide level significantly affected the formation of DBPs from SMPs. Additionally, the bromine incorporation factor indicates that chloramination may be a good alternative to chlorination in reducing the formation of Br-DBPs from SMPs. Bromide level and pH were the key factors affecting the formation of DBPs in both chlorination and chloramination. PMID- 28362301 TI - Assessing the population dynamics of Escherichia coli in a metropolitan river after an extreme flood event. AB - We investigated Escherichia coli populations in a metropolitan river after an extreme flood event. Between nine and 15 of the 23 selected sites along the river were sampled fortnightly over three rounds. In all, 307 E. coli were typed using the PhP typing method and were grouped into common (C) or single (S) biochemical phenotypes (BPTs). A representative from each of the 31 identified C-BPTs was tested for 58 virulence genes (VGs) associated with intestinal and extra intestinal E. coli, resistance to 22 antibiotics, production of biofilm and cytotoxicity to Vero cells. The number of E. coli in the first sampling round was significantly (P < 0.01) higher than subsequent rounds, whereas the number of VGs was significantly (P < 0.05) higher in isolates from the last sampling round when compared to previous rounds. Comparison of the C-BPTs with an existing database from wastewater treatment plants (WWTPs) in the same catchment showed that 40.6% of the river isolates were identical to the WWTP isolates. The relatively high number of VGs and antibiotic resistance among the C-BPTs suggests possessing and retaining these genes may provide niche advantages for those naturalised and/or persistent E. coli populations which may pose a health risk to the community. PMID- 28362303 TI - Effect of sodium hypochlorite on typical biofilms formed in drinking water distribution systems. AB - Human health and biological safety problems resulting from urban drinking water pipe network biofilms pollution have attracted wide concern. Despite the inclusion of residual chlorine in drinking water distribution systems supplies, the bacterium is a recalcitrant human pathogen capable of forming biofilms on pipe walls and causing health risks. Typical drinking water bacterial biofilms and their response to different concentrations of chlorination was monitored. The results showed that the four bacteria all formed single biofilms susceptible to sodium hypochlorite. After 30 min disinfection, biomass and cultivability decreased with increasing concentration of disinfectant but then increased in high disinfectant doses. PMA-qPCR results indicated that it resulted in little cellular damage. Flow cytometry analysis showed that with increasing doses of disinfectant, the numbers of clusters increased and the sizes of clusters decreased. Under high disinfectant treatment, EPS was depleted by disinfectant and about 0.5-1 mg/L of residual chlorine seemed to be appropriate for drinking water treatment. This research provides an insight into the EPS protection to biofilms. Resistance of biofilms against high levels of chlorine has implications for the delivery of drinking water. PMID- 28362302 TI - Identification of the faecal indicator Escherichia coli in wastewater through the beta-D-glucuronidase activity: comparison between two enumeration methods, membrane filtration with TBX agar, and Colilert(r)-18. AB - Escherichia coli (E. coli) is one of the most commonly adopted indicators for the determination of the microbiological quality in water and treated wastewater. Two main types of methods are used for the enumeration of this faecal indicator: membrane filtration (MF) and enzyme substrate tests. For both types, several substrates based on the beta-D-glucuronidase activity have been commercialized. The specificity of this enzyme for E. coli bacteria has generated considerable use of methods that identify the beta-D-glucuronidase activity as a definite indication of the presence of E. coli, without any further confirmation. This approach has been recently questioned for the application to wastewater. The present study compares two methods belonging to the above-mentioned types for the enumeration of E. coli in wastewater: MF with Tryptone Bile X-glucuronide agar and the Colilert(r)-18 test. Confirmation tests showed low average percentages of false positives and false negatives for both enumeration methods (between 4 and 11%). Moreover, the counting capabilities of these two methods were compared for a set of 70 samples of wastewater having different origins and degrees of treatment. Statistical analysis showed that the Colilert(r)-18 test allowed on average for a significantly higher recovery of E. coli. PMID- 28362304 TI - The influence of the microbial quality of wastewater, lettuce cultivars and enumeration technique when estimating the microbial contamination of wastewater irrigated lettuce. AB - This study investigated the volume of wastewater retained on the surface of three different varieties of lettuce, Iceberg, Cos, and Oak leaf, following submersion in wastewater of different microbial qualities (10, 102, 103, and 104 E. coli MPN/100 mL) as a surrogate method for estimation of contamination of spray irrigated lettuce. Uniquely, Escherichia coli was enumerated, after submersion, on both the outer and inner leaves and in a composite sample of lettuce. E. coli were enumerated using two techniques. Firstly, from samples of leaves - the direct method. Secondly, using an indirect method, where the E. coli concentrations were estimated from the volume of wastewater retained by the lettuce and the E. coli concentration of the wastewater. The results showed that different varieties of lettuce retained significantly different volumes of wastewater (p < 0.01). No statistical differences (p > 0.01) were detected between E. coli counts obtained from different parts of lettuce, nor between the direct and indirect enumeration methods. Statistically significant linear relationships were derived relating the E. coli concentration of the wastewater in which the lettuces were submerged to the subsequent E. coli count on each variety the lettuce. PMID- 28362305 TI - Rapid molecular identification of fecal origin-colonies growing on Enterococcus spp.-specific culture methods. AB - The mEI, Chromocult(r) enterococci, and m-Enterococcus culture-based methods used to assess water quality by the detection of Enterococcus spp. were first compared in terms of sensitivity using (1) 41 different type strains of Enterococcus spp. and (2) environmental colonies identified by 16S rRNA sequencing. Then, two specific-rtPCR assays targeting Enterococcus spp. and Enterococcus faecalis/faecium were tested for their ability to confirm the identity of putative enterococcal colonies. The mEI, Chromocult(r) enterococci, and m Enterococcus methods detected beta-glucosidase activity for 28 (68.3%), 32 (78.0%), and 12 (29.3%) of the 41 reference enterococcal strains tested, respectively. Analysis with environmental colonies showed that mEI and Chromocult(r) enterococci media had false positive rates of 4.3% and 5.0%, respectively. Finally, the two rtPCR assays showed a specificity of 100%. Only two (2/19) colonies of E. faecium isolated from mEI agar were not detected by the Enterococcus faecium rtPCR assay, for a sensitivity of 89.5%. Our results showed that Chromocult(r) enterococci medium recovered more E. faecalis/faecium cells than the two other methods. Thus, the use of Chromocult(r) enterococci combined with the Enterococcus faecalis/faecium rtPCR assay showed the best combination to decrease the high false-positive rate obtained when the entire Enterococcus genus is targeted. PMID- 28362306 TI - Assessment of swine-specific bacteriophages of Bacteroides fragilis in swine farms with different antibiotic practices. AB - We assessed the occurrence and specificity of bacteriophages of Bacteroides fragilis in swine farms for their potential application in microbial source tracking. A local B. fragilis host strain, SP25 (DSM29413), was isolated from a pooled swine feces sample taken from a non-antibiotic farm. This strain was highly specific to swine fecal materials because it did not detect bacteriophages in any samples from human sewage, sheep, goats, cattle, dogs, and cats. The reference B. fragilis strain, RYC2056, could detect phages in swine samples but also detected phages in most human sewage and polluted urban canal samples. Phages of SP25 exist in the proximity of certain swine farms, regardless of their antibiotic use (p > 0.05). B. fragilis strain SP25 exhibited relatively high resistance to most of the veterinary antimicrobial agents tested. Interestingly, most farms that were positive for SP25 phages were also positive for RYC2056 phages. In conclusion, the swine-specific SP25 strain has the potential to indicate swine fecal contamination in certain bodies of water. Bacterial isolates with larger distributions are being studied and validated. This study highlights the importance of assessing the abundance of phages in local swine populations before determining their potential applicability for source tracking in local surface waters. PMID- 28362307 TI - Impact of surface maintenance on BioSand filter performance and flow. AB - The BioSand filter (BSF) is a household scaled, intermittently operated, slow sand filter. The BSF requires maintenance to remove trapped sediments. This study evaluated the effects of maintenance on the filter's flow rate and performance. Four concrete BSFs received three styles of maintenance: surface agitation (SA), stirring method (SM), and sand removal (SR). Effluent water was collected from the filter between 0-2 L effluent (0-2 L effluent) and between 15-20 L effluent (15 L+ effluent). After maintenance, effluent at 15 L+ (no pause time) showed a significant decrease in thermotolerant coliform removal rates by 0.66-0.91 log (SA), 0.57-0.67 log (SM) and 0.32-0.83 log (RM) (<0.001). Effluent water at 0-2 L (with pause time) did not significantly decrease in thermotolerant coliform removal rates (>0.17) for any maintenance method. The recovery duration after maintenance for all methods at 0-2 L effluent had a median recovery of <1.2 days. The effluent at 15 L+ had a longer recovery period (at least 3.9, 3.0 and 12.75 days for the SA, SM, and SR method, respectively). The flow rate recovery for SA (76%) and SM (82%) was lower compared to SR (138%). PMID- 28362308 TI - Hydrochemical characteristics of natural water and selenium-rich water resources in the Northern Daba Mountains, China. AB - The Northern Daba Mountains (NDM) of Shaanxi Province, China, are a well-known selenium (Se)-rich area, and the area is also known for endemic fluorine (F) and arsenic (As) poisoning. In order to study the hydrochemical characteristics and trace element contents of the natural waters of this region, 62 water samples were collected from Lan'gao area in the NDM. The hydrochemical composition was principally characterized by Ca.Mg-HCO3.SO4. F and As concentrations ranged from 0.01 to 0.67 mg/L and from 0.33 to 6.29 MUg/L, respectively, lower than Chinese national standard and international guidelines for drinking water quality. One year of monitoring proved that F and As in natural water were not the sources of the local fluorosis and arseniasis in the NDM. The average Se concentration in fissure water was 5.20 MUg/L. The average Se content of river water was 2.82 MUg/L, 14 times that of the world's surface level (0.2 MUg/L). The Se content in eight samples reached the Chinese national standards for mineral drinking water quality (>10 MUg/L). Contrasting the water samples of May, July, and September in 2015 shows that the Se content is relatively stable and the increase of humidity might be beneficial to increase the content of selenium and strontium in water. PMID- 28362310 TI - Seawater desalination and serum magnesium concentrations in Israel. AB - With increasing shortage of fresh water globally, more countries are consuming desalinated seawater (DSW). In Israel >50% of drinking water is now derived from DSW. Desalination removes magnesium, and hypomagnesaemia has been associated with increased cardiac morbidity and mortality. Presently the impact of consuming DSW on body magnesium status has not been established. We quantified changes in serum magnesium in a large population based study (n = 66,764), before and after desalination in regions consuming DSW and in regions where DSW has not been used. In the communities that switched to DSW in 2013, the mean serum magnesium was 2.065 +/- 0.19 mg/dl before desalination and fell to 2.057 +/- 0.19 mg/dl thereafter (p < 0.0001). In these communities 1.62% of subjects exhibited serum magnesium concentrations <=1.6 mg/dl between 2010 and 2013. This proportion increased by 24% between 2010-2013 and 2015-2016 to 2.01% (p = 0.0019). In contrast, no such changes were recorded in the communities that did not consume DSW. Due to the emerging evidence of increased cardiac morbidity and mortality associated with hypomagnesaemia, it is vital to consider re-introduction of magnesium to DSW. PMID- 28362309 TI - Updating national standards for drinking-water: a Philippine experience. AB - The latest version of the Philippine National Standards for Drinking-Water (PNSDW) was issued in 2007 by the Department of Health (DOH). Due to several issues and concerns, the DOH decided to make an update which is relevant and necessary to meet the needs of the stakeholders. As an output, the water quality parameters are now categorized into mandatory, primary, and secondary. The ten mandatory parameters are core parameters which all water service providers nationwide are obligated to test. These include thermotolerant coliforms or Escherichia coli, arsenic, cadmium, lead, nitrate, color, turbidity, pH, total dissolved solids, and disinfectant residual. The 55 primary parameters are site specific and can be adopted as enforceable parameters when developing new water sources or when the existing source is at high risk of contamination. The 11 secondary parameters include operational parameters and those that affect the esthetic quality of drinking-water. In addition, the updated PNSDW include new sections: (1) reporting and interpretation of results and corrective actions; (2) emergency drinking-water parameters; (3) proposed Sustainable Development Goal parameters; and (4) standards for other drinking-water sources. The lessons learned and insights gained from the updating of standards are likewise incorporated in this paper. PMID- 28362311 TI - Quantitative analysis of glutathione and cysteine S-conjugates of microcystin-LR in the liver, kidney and muscle of common carp (Cyprinus carpio) in Lake Taihu. AB - Tissue distribution of microcystin (MC)-LR-GSH, MC-LR-Cys and MC-LR of omnivorous fish in Lake Taihu was investigated. MC-LR and MC-LR-Cys were detected in liver, kidney and muscle. The concentration of MC-LR in liver and kidney was 0.052 MUg g 1 DW and 0.067 MUg g-1 DW, respectively. MC-LR-Cys appeared to be an important metabolite with average contents of 1.104 MUg g-1 DW and 0.724 MUg g-1 DW in liver and kidney, and the MC-LR-Cys/MC-LR ratio in liver and kidney reaching as high as 21.4 and 10.8. High MC-LR-Cys/MC-LR ratio and a significant correlation between MC-LR-Cys and MC-LR concentration in liver, suggest that liver is more active in detoxification of MC-LR by formation of MC-LR-Cys for omnivorous fish. Furthermore, there might be a balance between the accumulation and depuration/metabolism of MC-LR-Cys in kidney. The MC-LR-Cys can be formed in kidney directly, or transported from liver or other tissues, while the MC-LR-Cys in kidney might be dissociated to MC-LR or excreted. Although MC-LR and its metabolites were scarcely detected in muscle, it is necessary to investigate the distribution of toxic metabolites in edible muscle. PMID- 28362312 TI - Fungal biodiversity and mycotoxigenic fungi in cooling-tower water systems in Istanbul, Turkey. AB - This is the first study to assess fungal diversity and mycotoxigenic fungi in open recirculating cooling-tower (CT) water systems (biofilm and water phase). The production capability of mycotoxin from fungal isolates was also examined. The mean fungal count in 21 different water and biofilm samples was determined as 234 CFU/100 mL and 4 CFU/cm2. A total of 32 species were identified by internal transcribed spacer (ITS) sequencing. The most common isolated fungi belonged to the genera Aspergillus and Penicillium, of which the most prevalent fungi were Aspergillus versicolor, Aspergillus niger, and Penicillium dipodomyicola. From 42% of the surveyed CTs, aflatoxigenic A. flavus isolates were identified. The detection of opportunistic pathogens and/or allergen species suggests that open recirculating CTs are a possible source of fungal infection for both the public and for occupational workers via the inhalation of aerosols and/or skin contact. PMID- 28362313 TI - Identification and Characterization of Spontaneous Auxotrophic Mutants in Fusarium langsethiae. AB - Analysis of 49 strains of Fusarium langsethiae originating from northern Europe (Russia, Finland, Sweden, UK, Norway, and Latvia) revealed the presence of spontaneous auxotrophic mutants that reflect natural intraspecific diversity. Our investigations detected that 49.0% of F. langsethiae strains were auxotrophic mutants for biotin, and 8.2% of the strains required thiamine as a growth factor. They failed to grow on vitamin-free media. For both prototrophic and auxotrophic strains, no growth defect was observed in rich organic media. Without essential vitamins, a significant reduction in the growth of the auxotrophic strains results in a decrease of the formation of T-2 toxin and diacetoxyscirpenol. In addition, all analysed F. langsethiae strains were distinguished into two subgroups based on PCR product sizes. According to our results, 26 and 23 strains of F. langsethiae belong to subgroups I and II respectively. We determined that the deletion in the intergenic spacer (IGS) region of the rDNA of F. langsethiae belonging to subgroup II is linked with temperature sensitivity and causes a decrease in strain growth at 30 degrees C. Four thiamine auxotrophic strains were found in subgroup I, while 21 biotin auxotrophic strains were detected in subgroups II. To the best of our knowledge, the spontaneous mutations in F. langsethiae observed in the present work have not been previously reported. PMID- 28362314 TI - Energy-Efficient Channel Coding Strategy for Underwater Acoustic Networks. AB - Underwater acoustic networks (UAN) allow for efficiently exploiting and monitoring the sub-aquatic environment. These networks are characterized by long propagation delays, error-prone channels and half-duplex communication. In this paper, we address the problem of energy-efficient communication through the use of optimized channel coding parameters. We consider a two-layer encoding scheme employing forward error correction (FEC) codes and fountain codes (FC) for UAN scenarios without feedback channels. We model and evaluate the energy consumption of different channel coding schemes for a K-distributed multipath channel. The parameters of the FEC encoding layer are optimized by selecting the optimal error correction capability and the code block size. The results show the best parameter choice as a function of the link distance and received signal-to-noise ratio. PMID- 28362315 TI - The Use of Phononic Crystals to Design Piezoelectric Power Transducers. AB - It was recently proposed that the lateral resonances around the working resonance band of ultrasonic piezoelectric sandwich transducers can be stopped by a periodic array of circular holes drilled along the main propagation direction (a phononic crystal). In this work, the performance of different transducer designs made with this procedure is tested using laser vibrometry, electric impedance tests and finite element models (FEM). It is shown that in terms of mechanical vibration amplitude and acoustic efficiency, the best design for physiotherapy applications is when both, the piezoceramic and an aluminum capsule are phononic structures. The procedure described here can be applied to the design of power ultrasonic devices, physiotherapy transducers and other external medical power ultrasound applications where piston-like vibration in a narrow band is required. PMID- 28362318 TI - Acousto-Optic-Based Wavelength-Comb-Swept Laser for Extended Displacement Measurements. AB - We demonstrate a novel wavelength-comb-swept laser based on two intra-cavity filters: an acousto-optic tunable filter (AOTF) and a Fabry-Perot etalon filter. The AOTF is used for the tunable selection of the output wavelength with time and the etalon filter for the narrowing of the spectral linewidth to extend the coherence length. Compared to the conventional wavelength-swept laser, the acousto-optic-based wavelength-comb-swept laser (WCSL) can extend the measureable range of displacement measurements by decreasing the sensitivity roll-off of the point spread function. Because the AOTF contains no mechanical moving parts to select the output wavelength acousto-optically, the WCSL source has a high wavenumber (k) linearity of R2 = 0.9999 to ensure equally spaced wavelength combs in the wavenumber domain. PMID- 28362317 TI - MicroRNA-17-92 Regulates the Transcription Factor E2F3b during Myogenesis In Vitro and In Vivo. AB - Myogenic differentiation, which occurs during muscle development, is a highly ordered process that can be regulated by E2F transcription factors. Available data show that E2F3b, but not E2F3a, is upregulated and required for myogenic differentiation. However, the regulation of E2F3b expression in myogenic differentiation is not well understood. To investigate whether E2Fb expression is controlled by miRNAs, we used bioinformatics to combine the database of microRNAs downregulated during myogenesis and those predicted to target E2F3. This identified miR-17 and miR-20a as miRNAs potentially involved in E2F3 regulation. We found that miR-17-92 controls the expression of E2F3b in C2C12 cells during myogenic differentiation. Moreover, we confirmed that miR-20a regulates the expression of E2F3b proteins in vivo using a muscle regeneration model. PMID- 28362319 TI - Investigation of a Combined Surveying and Scanning Device: The Trimble SX10 Scanning Total Station. AB - Surveying fields from geosciences to infrastructure monitoring make use of a wide range of instruments for accurate 3D geometry acquisition. In many cases, the Terrestrial Laser Scanner (TLS) tends to become an optimal alternative to total station measurements thanks to the high point acquisition rate it offers, but also to ever deeper data processing software functionalities. Nevertheless, traditional surveying techniques are valuable in some kinds of projects. Nowadays, a few modern total stations combine their conventional capabilities with those of a laser scanner in a unique device. The recent Trimble SX10 scanning total station is a survey instrument merging high-speed 3D scanning and the capabilities of an image-assisted total station. In this paper this new instrument is introduced and first compared to state-of-the-art image-assisted total stations. The paper also addresses the topic of various laser scanning projects and the delivered point clouds are compared with those of other TLS. Directly and indirectly georeferenced projects have been carried out and are investigated in this paper, and a polygonal traverse is performed through a building. Comparisons with the results delivered by well-established survey instruments show the reliability of the Trimble SX10 for geodetic work as well as for scanning projects. PMID- 28362316 TI - Cancer/Testis Antigens: "Smart" Biomarkers for Diagnosis and Prognosis of Prostate and Other Cancers. AB - A clinical dilemma in the management of prostate cancer (PCa) is to distinguish men with aggressive disease who need definitive treatment from men who may not require immediate intervention. Accurate prediction of disease behavior is critical because radical treatment is associated with high morbidity. Here, we highlight the cancer/testis antigens (CTAs) as potential PCa biomarkers. The CTAs are a group of proteins that are typically restricted to the testis in the normal adult but are aberrantly expressed in several types of cancers. Interestingly, >90% of CTAs are predicted to belong to the realm of intrinsically disordered proteins (IDPs), which do not have unique structures and exist as highly dynamic conformational ensembles, but are known to play important roles in several biological processes. Using prostate-associated gene 4 (PAGE4) as an example of a disordered CTA, we highlight how IDP conformational dynamics may regulate phenotypic heterogeneity in PCa cells, and how it may be exploited both as a potential biomarker as well as a promising therapeutic target in PCa. We also discuss how in addition to intrinsic disorder and post-translational modifications, structural and functional variability induced in the CTAs by alternate splicing represents an important feature that might have different roles in different cancers. Although it is clear that significant additional work needs to be done in the outlined direction, this novel concept emphasizing (multi)functionality as an important trait in selecting a biomarker underscoring the theranostic potential of CTAs that is latent in their structure (or, more appropriately, the lack thereof), and casts them as next generation or "smart" biomarker candidates. PMID- 28362322 TI - The In Vitro-In Vivo Safety Confirmation of PEG-40 Hydrogenated Castor Oil as a Surfactant for Oral Nanoemulsion Formulation. AB - Evaluation on the safety use of high concentration of polyoxyl 40 (PEG-40) hydrogenated castor oil as a surfactant for oral nanoemulsion was performed in Webster mice. As previously reported, nearly 20% of PEG-40 hydrogenated castor oil was used to emulsify the glyceryl monooleate (GMO) as an oil to the aqueous phase. Thermodynamically stable and spontaneous nanoemulsion was formed by the presence of co-surfactant polyethylene glycol 400 (PEG-400). Standard parameters were analyzed for nanoemulsion including particle size and particle size distribution, the surface charge of nanoemulsion, and morphology. To ensure the safety of this nanoemulsion, several cell lines were used for cytotoxicity study. In addition, 5000 mg/kg body weight (BW) of the blank nanoemulsion was given orally to Webster mice once a day for 14 days. Several parameters such as gross anatomy, body weight, and main organs histopathology were observed. In particular, by considering the in vivo data, it is suggested that nanoemulsion composed with a high amount of PEG-40 hydrogenated castor oil is acceptable for oral delivery of active compounds. PMID- 28362320 TI - Resilience and Vulnerability to Pain and Inflammation in the Hippocampus. AB - Increasing evidence demonstrates the importance of hippocampal neurogenesis, a fundamental mechanism of neuroplasticity associated with cognition and emotion, in correlation to neurodegenerative and psychiatric disorders. Neuropsychiatric disorders are often a result of chronic stress or pain followed by inflammation; all these conditions manifest cognitive deficits and impairments in neurogenesis. However, while some individuals are more susceptible to stress, others are able to adapt to new environments via mechanisms of resilience. In light of this emerging field and based on extensive research, the role of neurogenesis is summarized and presented as a potentially powerful therapeutic tool. PMID- 28362323 TI - Optimizing Sample Size to Assess the Genetic Diversity in Common Vetch (Vicia sativa L.) Populations Using Start Codon Targeted (SCoT) Markers. AB - Common vetch (Vicia sativa subsp. sativa L.) is a self-pollinating annual forage legume with worldwide importance. Here, we investigate the optimal number of individuals that may represent the genetic diversity of a single population, using Start Codon Targeted (SCoT) markers. Two cultivated varieties and two wild accessions were evaluated using five SCoT primers, also testing different sampling sizes: 1, 2, 3, 5, 8, 10, 20, 30, 40, 50, and 60 individuals. The results showed that the number of alleles and the Polymorphism Information Content (PIC) were different among the four accessions. Cluster analysis by Unweighted Pair Group Method with Arithmetic Mean (UPGMA) and STRUCTURE placed the 240 individuals into four distinct clusters. The Expected Heterozygosity (HE) and PIC increased along with an increase in sampling size from 1 to 10 plants but did not change significantly when the sample sizes exceeded 10 individuals. At least 90% of the genetic variation in the four germplasms was represented when the sample size was 10. Finally, we concluded that 10 individuals could effectively represent the genetic diversity of one vetch population based on the SCoT markers. This study provides theoretical support for genetic diversity, cultivar identification, evolution, and marker-assisted selection breeding in common vetch. PMID- 28362321 TI - Early Assessment of Colorectal Cancer by Quantifying Circulating Tumor Cells in Peripheral Blood: ECT2 in Diagnosis of Colorectal Cancer. AB - Circulating tumor cells (CTCs) in peripheral blood is an indication of poor prognosis for patients with different cancer types. However, most of the available technologies for detecting CTCs show low sensitivity and specificity. Therefore, we attempted to find an alternative marker for CTCs of colorectal cancer. We have directly extracted RNA from CTCs contained in 1.5 mL peripheral blood from 90 colorectal cancer patients and 151 healthy donors, and screened these samples for candidate marker genes by nested real-time quantitative polymerase chain reaction (PCR). From genes selected from a public database of microarray analyses, we successfully identified epithelial cell transforming sequence 2 oncogene (ECT2) as a gene that exhibits high differential expression ratios (p < 0.01). ECT2 displays good sensitivity and specificity, with an area under the curve (AUC) value of 0.821. This marker gene also has a high detection rate in patients with serum carcinoembryonic antigen (CEA) concentrations below the diagnostic threshold of 5 ng/mL. The expression of ECT2 can therefore serve as an alternative measurement that can compensate for the inadequacy of the current CEA test in the diagnosis and monitoring of colorectal cancer patients. PMID- 28362326 TI - Natural Pathogen Control Chemistry to Replace Toxic Treatment of Microbes and Biofilm in Cooling Towers. AB - Application of toxic antibacterial agents is considered necessary to control prevalent fresh water microorganisms that grow in evaporative cooling water systems, but can adversely affect the environment and human health. However, natural antibacterial water chemistry has been applied in industrial cooling water systems for over 10 years to inhibit microorganisms with excellent results. The water chemistry method concentrates natural minerals in highly-softened water to produce elevated pH and dissolved solids, while maintaining low calcium and magnesium content. The method provides further benefits in water conservation, and generates a small volume of non-toxic natural salt concentrate for cost efficient separation and disposal if required. This report describes the antimicrobial effects of these chemistry modifications in the cooling water environment and the resultant collective inhibition of microbes, biofilm, and pathogen growth. This article also presents a novel perspective of parasitic microbiome functional relationships, including "Trojan Protozoans" and biofilms, and the function of polyvalent metal ions in the formation and inhibition of biofilms. Reducing global dependence on toxic antibacterial agents discharged to the environment is an emerging concern due to their impact on the natural microbiome, plants, animals and humans. Concurrently, scientists have concluded that discharge of antibacterial agents plays a key role in development of pathogen resistance to antimicrobials as well as antibiotics. Use of natural antibacterial chemistry can play a key role in managing the cooling water environment in a more ecologically sustainable manner. PMID- 28362324 TI - NG2 Proteoglycan Enhances Brain Tumor Progression by Promoting Beta-1 Integrin Activation in both Cis and Trans Orientations. AB - By physically interacting with beta-1 integrins, the NG2 proteoglycan enhances activation of the integrin heterodimers. In glioma cells, co-localization of NG2 and ?3?1 integrin in individual cells (cis interaction) can be demonstrated by immunolabeling, and the NG2-integrin interaction can be confirmed by co immunoprecipitation. NG2-dependent integrin activation is detected via use of conformationally sensitive monoclonal antibodies that reveal the activated state of the beta-1 subunit in NG2-positive versus NG2-negative cells. NG2-dependent activation of beta-1 integrins triggers downstream activation of FAK and PI3K/Akt signaling, resulting in increased glioma cell proliferation, motility, and survival. Similar NG2-dependent cis activation of beta-1 integrins occurs in microvascular pericytes, leading to enhanced proliferation and motility of these vascular cells. Surprisingly, pericyte NG2 is also able to promote beta-1 integrin activation in closely apposed endothelial cells (trans interaction). Enhanced beta-1 signaling in endothelial cells promotes endothelial maturation by inducing the formation of endothelial junctions, resulting in increased barrier function of the endothelium and increased basal lamina assembly. NG2-dependent beta-1 integrin signaling is therefore important for tumor progression by virtue of its affects not only on the tumor cells themselves, but also on the maturation and function of tumor blood vessels. PMID- 28362325 TI - Possible Roles of CC- and CXC-Chemokines in Regulating Bovine Endometrial Function during Early Pregnancy. AB - The aim of the present study was to determine the possible roles of chemokines in regulating bovine endometrial function during early pregnancy. The expression of six chemokines, including CCL2, CCL8, CCL11, CCL14, CCL16, and CXCL10, was higher in the endometrium at 15 and 18 days of pregnancy than at the same days in non pregnant animals. Immunohistochemical staining showed that chemokine receptors (CCR1, CCR2, CCR3, and CXCR3) were expressed in the epithelial cells and glandular epithelial cells of the bovine endometrium as well as in the fetal trophoblast obtained from a cow on day 18 of pregnancy. The addition of interferon-tau (IFNT) to an endometrial tissue culture system increased CCL8 and CXCL10 expression in the tissues, but did not affect CCL2, CCL11, and CCL16 expression. CCL14 expression by these tissues was inhibited by IFNT. CCL16, but not other chemokines, clearly stimulated interferon-stimulated gene 15 (ISG15) and myxovirus-resistance gene 1 (MX1) expression in these tissues. Cyclooxygenase 2 (COX2) expression decreased after stimulation with CCL8 and CCL14, and oxytocin receptor (OTR) expression was decreased by CCL2, CCL8, CCL14, and CXCL10. Collectively, the expression of chemokine genes is increased in the endometrium during early pregnancy. These genes may contribute to the regulation of endometrial function by inhibiting COX2 and OTR expression, subsequently decreasing prostaglandin production and preventing luteolysis in cows. PMID- 28362328 TI - Patients' Data Management System Protected by Identity-Based Authentication and Key Exchange. AB - A secure and distributed framework for the management of patients' information in emergency and hospitalization services is proposed here in order to seek improvements in efficiency and security in this important area. In particular, confidentiality protection, mutual authentication, and automatic identification of patients are provided. The proposed system is based on two types of devices: Near Field Communication (NFC) wristbands assigned to patients, and mobile devices assigned to medical staff. Two other main elements of the system are an intermediate server to manage the involved data, and a second server with a private key generator to define the information required to protect communications. An identity-based authentication and key exchange scheme is essential to provide confidential communication and mutual authentication between the medical staff and the private key generator through an intermediate server. The identification of patients is carried out through a keyed-hash message authentication code. Thanks to the combination of the aforementioned tools, a secure alternative mobile health (mHealth) scheme for managing patients' data is defined for emergency and hospitalization services. Different parts of the proposed system have been implemented, including mobile application, intermediate server, private key generator and communication channels. Apart from that, several simulations have been performed, and, compared with the current system, significant improvements in efficiency have been observed. PMID- 28362327 TI - The Salutary Influence of Forest Bathing on Elderly Patients with Chronic Heart Failure. AB - The aim of the current study was to test the hypothesis that forest bathing would be beneficial for elderly patients with chronic heart failure (CHF) as an adjunctive therapy. Two groups of participants with CHF were simultaneously sent to the forest or an urban control area for a four-day trip, respectively. Subjects exposed to the forest site showed a significant reduction of brain natriuretic peptide (BNP) in comparison to that of the city group and their own baseline levels. The values for the cardiovascular disease related pathological factors, including endothelin-1 (ET-1), and constituents of the renin-angiotensin system (RAS), including renin, angiotensinogen (AGT), angiotensin II (ANGII), and ANGII receptor type 1 or 2 (AT1 or AT2) in subjects exposed to the forest environment were lower than those in the urban control group. Obviously, a decreased level of inflammatory cytokines and improved antioxidant function was observed in the forest group rather than in the city group. The assessment of the profile of mood states (POMS) indicated that the negative emotional mood state was alleviated after forest bathing. As anticipated, a better air quality in the forest site was observed according to the detection of PM2.5 (particulate matter <2.5 MUm) and negative ions. These results provided direct evidence that forest bathing has a beneficial effect on CHF patients, and thus may pave the way for potential development of forest bathing as an effective adjunctive therapy on cardiovascular disorders. PMID- 28362329 TI - Bench-Top Fabrication of an All-PDMS Microfluidic Electrochemical Cell Sensor Integrating Micro/Nanostructured Electrodes. AB - In recent years, efforts in the development of lab-on-a-chip (LoC) devices for point-of-care (PoC) applications have increased to bring affordable, portable, and sensitive diagnostics to the patients' bedside. To reach this goal, research has shifted from using traditional microfabrication methods to more versatile, rapid, and low-cost options. This work focuses on the benchtop fabrication of a highly sensitive, fully transparent, and flexible poly (dimethylsiloxane) (PDMS) microfluidic (MUF) electrochemical cell sensor. The MUF device encapsulates 3D structured gold and platinum electrodes, fabricated using a shape-memory polymer shrinking method, which are used to set up an on-chip electrochemical cell. The PDMS to PDMS-structured electrode bonding protocol to fabricate the MUF chip was optimized and found to have sufficient bond strength to withstand up to 100 mL/min flow rates. The sensing capabilities of the on-chip electrochemical cell were demonstrated by using cyclic voltammetry to monitor the adhesion of murine 3T3 fibroblasts in the presence of a redox reporter. The charge transfer across the working electrode was reduced upon cell adhesion, which was used as the detection mechanism, and allowed the detection of as few as 24 cells. The effective utilization of simple and low cost bench-top fabrication methods could accelerate the prototyping and development of LoC technologies and bring PoC diagnostics and personalized medicine to the patients' bedside. PMID- 28362330 TI - The Additional Secondary Phase Correction System for AIS Signals. AB - This paper looks at the development and implementation of the additional secondary phase factor (ASF) real-time correction system for the Automatic Identification System (AIS) signal. A large number of test data were collected using the developed ASF correction system and the propagation characteristics of the AIS signal that transmits at sea and the ASF real-time correction algorithm of the AIS signal were analyzed and verified. Accounting for the different hardware of the receivers in the land-based positioning system and the variation of the actual environmental factors, the ASF correction system corrects original measurements of positioning receivers in real time and provides corrected positioning accuracy within 10 m. PMID- 28362331 TI - Review on the Processing and Properties of Polymer Nanocomposites and Nanocoatings and Their Applications in the Packaging, Automotive and Solar Energy Fields. AB - For the last decades, nanocomposites materials have been widely studied in the scientific literature as they provide substantial properties enhancements, even at low nanoparticles content. Their performance depends on a number of parameters but the nanoparticles dispersion and distribution state remains the key challenge in order to obtain the full nanocomposites' potential in terms of, e.g., flame retardance, mechanical, barrier and thermal properties, etc., that would allow extending their use in the industry. While the amount of existing research and indeed review papers regarding the formulation of nanocomposites is already significant, after listing the most common applications, this review focuses more in-depth on the properties and materials of relevance in three target sectors: packaging, solar energy and automotive. In terms of advances in the processing of nanocomposites, this review discusses various enhancement technologies such as the use of ultrasounds for in-process nanoparticles dispersion. In the case of nanocoatings, it describes the different conventionally used processes as well as nanoparticles deposition by electro-hydrodynamic processing. All in all, this review gives the basics both in terms of composition and of processing aspects to reach optimal properties for using nanocomposites in the selected applications. As an outlook, up-to-date nanosafety issues are discussed. PMID- 28362333 TI - The Promise and the Challenge of Technology-Facilitated Methods for Assessing Behavioral and Cognitive Markers of Risk for Suicide among U.S. Army National Guard Personnel. AB - Suicide was the 10th leading cause of death for Americans in 2015 and rates have been steadily climbing over the last 25 years. Rates are particularly high amongst U.S. military personnel. Suicide prevention efforts in the military are significantly hampered by the lack of: (1) assessment tools for measuring baseline risk and (2) methods to detect periods of particularly heightened risk. Two specific barriers to assessing suicide risk in military personnel that call for innovation are: (1) the geographic dispersion of military personnel from healthcare settings, particularly amongst components like the Reserves; and (2) professional and social disincentives to acknowledging psychological distress. The primary aim of this paper is to describe recent technological developments that could contribute to risk assessment tools that are not subject to the limitations mentioned above. More specifically, Behavioral Signal Processing can be used to assess behaviors during interaction and conversation that likely indicate increased risk for suicide, and computer-administered, cognitive performance tasks can be used to assess activation of the suicidal mode. These novel methods can be used remotely and do not require direct disclosure or endorsement of psychological distress, solving two challenges to suicide risk assessment in military and other sensitive settings. We present an introduction to these technologies, describe how they can specifically be applied to assessing behavioral and cognitive risk for suicide, and close with recommendations for future research. PMID- 28362334 TI - Proximity to Industrial Food Animal Production and Asthma Exacerbations in Pennsylvania, 2005-2012. AB - The research on industrial food animal production (IFAP) and asthma exacerbations in the United States has relied on small sample sizes and/or self-reported outcomes. We assessed associations of proximity to large-scale and densely stocked swine and dairy/veal IFAP with three types of asthma exacerbations: hospitalizations, emergency encounters, and oral corticosteroid (OCS) medication orders from Geisinger Clinic in Pennsylvania. We used a diagnosis code (International Classification of Diseases, 9th Revision, Clinical Modification code 493.x) and medication orders from electronic health records to identify these exacerbations among asthma patients (n = 35,269) from 2005-2012. We compared residential proximity to swine or dairy/veal IFAP (dichotomized as <3 miles (4.8 km) or >=3 miles) among asthma patients with and without exacerbations and estimated odds ratios using multilevel logistic regression. In adjusted models, proximity to IFAP was associated (odds ratio (95% confidence interval)) with OCS orders (1.11 (1.04-1.19)) and hospitalizations (1.29 (1.15-1.46)), but not emergency encounters (1.12 (0.91-1.37)). This study contributes to growing evidence that IFAP may impact health, in this case clinically-documented asthma exacerbations. No prior study has evaluated the association of IFAP and clinically-documented asthma exacerbations in the United States. PMID- 28362332 TI - Sphingosine-1-Phosphate Metabolism and Its Role in the Development of Inflammatory Bowel Disease. AB - Beyond their role as structural molecules, sphingolipids are involved in many important cellular processes including cell proliferation, apoptosis, inflammation, and migration. Altered sphingolipid metabolism is observed in many pathological conditions including gastrointestinal diseases. Inflammatory bowel disease (IBD) represents a state of complex, unpredictable, and destructive inflammation of unknown origin within the gastrointestinal tract. The mechanisms explaining the pathophysiology of IBD involve signal transduction pathways regulating gastro-intestinal system's immunity. Progressive intestinal tissue destruction observed in chronic inflammation may be associated with an increased risk of colon cancer. Sphingosine-1-phosphate (S1P), a sphingolipid metabolite, functions as a cofactor in inflammatory signaling and becomes a target in the treatment of IBD, which might prevent its conversion to cancer. This paper summarizes new findings indicating the impact of (S1P) on IBD development and IBD associated carcinogenesis. PMID- 28362336 TI - Biodegradable Poly(Amino Ester) with Aromatic Backbone as Efficient Nonviral Gene Delivery Vectors. AB - The development of gene delivery vectors with high efficiency and biocompatibility is one of the critical points of gene therapy. Two biodegradable poly(amino ester)s were synthesized via ring-opening polymerization between low molecular weight (LMW) PEI and diepoxide. The molecular weights of poly(amino ester)s were measured by GPC. Agarose gel retardation assays showed that these materials have good DNA-binding ability and can retard the electrophoretic mobility of plasmid DNA (pDNA) at a weight ratio of 1. The formed polyplexes have proper sizes of around 200 nm and zeta-potential values of about 30-40 mV for cellular uptake. In vitro experiments revealed that polymer P2 gave higher transfection efficiency than PEI 25KDa and Lipofectamine 2000 with less toxicity, especially in 293 cells. Results demonstrate that such a type of degradable poly(amino ester) may serve as a promising non-viral gene vector. PMID- 28362338 TI - Tracking a Non-Cooperative Target Using Real-Time Stereovision-Based Control: An Experimental Study. AB - Tracking a non-cooperative target is a challenge, because in unfamiliar environments most targets are unknown and unspecified. Stereovision is suited to deal with this issue, because it allows to passively scan large areas and estimate the relative position, velocity and shape of objects. This research is an experimental effort aimed at developing, implementing and evaluating a real time non-cooperative target tracking methods using stereovision measurements only. A computer-vision feature detection and matching algorithm was developed in order to identify and locate the target in the captured images. Three different filters were designed for estimating the relative position and velocity, and their performance was compared. A line-of-sight control algorithm was used for the purpose of keeping the target within the field-of-view. Extensive analytical and numerical investigations were conducted on the multi-view stereo projection equations and their solutions, which were used to initialize the different filters. This research shows, using an experimental and numerical evaluation, the benefits of using the unscented Kalman filter and the total least squares technique in the stereovision-based tracking problem. These findings offer a general and more accurate method for solving the static and dynamic stereovision triangulation problems and the concomitant line-of-sight control. PMID- 28362339 TI - Distributed Humidity Sensing in PMMA Optical Fibers at 500 nm and 650 nm Wavelengths. AB - Distributed measurement of humidity is a sought-after capability for various fields of application, especially in the civil engineering and structural health monitoring sectors. This article presents a method for distributed humidity sensing along polymethyl methacrylate (PMMA) polymer optical fibers (POFs) by analyzing wavelength-dependent Rayleigh backscattering and attenuation characteristics at 500 nm and 650 nm wavelengths. Spatially resolved humidity sensing is obtained from backscatter traces of a dual-wavelength optical time domain reflectometer (OTDR). Backscatter dependence, attenuation dependence as well as the fiber length change are characterized as functions of relative humidity. Cross-sensitivity effects are discussed and quantified. The evaluation of the humidity-dependent backscatter effects at the two wavelength measurements allows for distributed and unambiguous measurement of relative humidity. The technique can be readily employed with low-cost standard polymer optical fibers and commercial OTDR devices. PMID- 28362335 TI - Chemical and Biological Properties of S-1-Propenyl-l-Cysteine in Aged Garlic Extract. AB - S-1-Propenyl-l-cysteine (S1PC) is a stereoisomer of S-1-Propenyl-l-cysteine (SAC), an important sulfur-containing amino acid that plays a role for the beneficial pharmacological effects of aged garlic extract (AGE). The existence of S1PC in garlic preparations has been known since the 1960's. However, there was no report regarding the biological and/or pharmacological activity of S1PC until 2016. Recently, we performed a series of studies to examine the chemical, biological, pharmacological and pharmacokinetic properties of S1PC, and obtained some interesting results. S1PC existed only in trace amounts in raw garlic, but its concentration increased almost up to the level similar of SAC through aging process of AGE. S1PC showed immunomodulatory effects in vitro and in vivo, and reduced blood pressure in a hypertensive animal model. A pharmacokinetic study revealed that S1PC was readily absorbed after oral administration in rats and dogs with bioavailability of 88-100%. Additionally, S1PC had little inhibitory influence on human cytochrome P450 activities, even at a concentration of 1 mM. Based on these findings, S1PC was suggested to be another important, pharmacologically active and safe component of AGE similar to SAC. In this review, we highlight some results from recent studies on S1PC and discuss the potential medicinal value of S1PC. PMID- 28362337 TI - Action of Thyroid Hormones, T3 and T2, on Hepatic Fatty Acids: Differences in Metabolic Effects and Molecular Mechanisms. AB - The thyroid hormones (THs) 3,3',5,5'-tetraiodo-l-thyronine (T4) and 3,5,3' triiodo-l-thyronine (T3) influence many metabolic pathways. The major physiological function of THs is to sustain basal energy expenditure, by acting primarily on carbohydrate and lipid catabolism. Beyond the mobilization and degradation of lipids, at the hepatic level THs stimulate the de novo fatty acid synthesis (de novo lipogenesis, DNL), through both the modulation of gene expression and the rapid activation of cell signalling pathways. 3,5-Diiodo-l thyronine (T2), previously considered only a T3 catabolite, has been shown to mimic some of T3 effects on lipid catabolism. However, T2 action is more rapid than that of T3, and seems to be independent of protein synthesis. An inhibitory effect on DNL has been documented for T2. Here, we give an overview of the mechanisms of THs action on liver fatty acid metabolism, focusing on the different effects exerted by T2 and T3 on the regulation of the DNL. The inhibitory action on DNL exerted by T2 makes this compound a potential and attractive drug for the treatment of some metabolic diseases and cancer. PMID- 28362340 TI - Knowledge, Attitudes, and Practices about the Prevention of Mosquito Bites and Zika Virus Disease in Pregnant Women in Greece. AB - A survey among 573 pregnant women in Greece was conducted through self-completion of a questionnaire in July 2016. Traveling abroad the last six months was declared by 10.5% and 13.0% of pregnant women and their male sex partners, respectively, while 77.4% (441/570) had heard about Zika virus disease (ZVD). A lack of knowledge about sexual transmission of ZVD was identified in 63.3% of pregnant women, and 24.1% of responders did not know the risks to the fetus and baby. Approximately 73% of responders believed that the mosquito bites can affect their fetus and baby and 18% did not take measures to prevent mosquito bites routinely. Multivariable logistic regression models showed that traveling abroad the last six months by pregnant women correlated with correctly answering the question about the transmission of ZVD through bites of infected mosquitoes (Odds Ratio, OR = 10.47, 95% CI = 1.11-98.41). Traveling abroad with a male sex partner over the last six months correlated (OR = 2.05, 95% CI = 0.99-4.23) with responding correctly to the four key questions about the transmission of ZVD through mosquito bites, the risk of microcephaly, and the risks of traveling to the affected countries. A score of >=5 for the nine responses given to questions of knowledge and attitudes was associated with a Bachelor of Science degree (OR = 1.54, 95% CI = 1.09-2.18), antenatal care at a public hospital (OR = 2.26, 95% CI = 1.28-3.98), being a civil servant as occupation (OR = 1.96, 95% CI = 1.10 3.48), and having gotten information about ZVD from the public health sector (OR = 2.04, 95% CI = 1.05-3.98). In conclusion, we found considerable knowledge gaps related to ZVD among Greek pregnant women. These study results are useful in targeting pregnant women for the prevention of potential Zika virus infections. PMID- 28362343 TI - Characterization of Retail Conventional, Organic, and Grass Full-Fat Butters by Their Fat Contents, Free Fatty Acid Contents, and Triglyceride and Fatty Acid Profiling. AB - In the Netherlands, butter is produced from milk originating from three different production systems: conventional, organic, and grass-fed cows. The aim of the current study was to characterize these types of butters, and pinpoint distinct compositional differences. Retail conventional (n = 28), organic (n = 14), and grass (n = 12) full-fat butters were collected during the winter and summer seasons. Samples were analyzed for their fat content, free fatty acid (FFA) content, and triglyceride (TG) and fatty acid (FA) profiles. The fat content was significantly lower in conventional butters than in organic butters and the FFA content was significantly lower in conventional butters compared with grass butters. Also, organic butters differed significantly from their conventional counterparts with regard to their TG and FA profiles. The TG profiles of the organic and grass butters did not differ significantly. The FA profiles of grass butters were less distinct, since only a few FAs differed significantly from conventional (six FAs) and organic (eight FAs) butters. PMID- 28362342 TI - Activity Learning as a Foundation for Security Monitoring in Smart Homes. AB - Smart environment technology has matured to the point where it is regularly used in everyday homes as well as research labs. With this maturation of the technology, we can consider using smart homes as a practical mechanism for improving home security. In this paper, we introduce an activity-aware approach to security monitoring and threat detection in smart homes. We describe our approach using the CASAS smart home framework and activity learning algorithms. By monitoring for activity-based anomalies we can detect possible threats and take appropriate action. We evaluate our proposed method using data collected in CASAS smart homes and demonstrate the partnership between activity-aware smart homes and biometric devices in the context of the CASAS on-campus smart apartment testbed. PMID- 28362341 TI - The Role of MicroRNAs in Myocardial Infarction: From Molecular Mechanism to Clinical Application. AB - MicroRNAs (miRNAs) are a class of small single-stranded and highly conserved non coding RNAs, which are closely linked to cardiac disorders such as myocardial infarction (MI), cardiomyocyte hypertrophy, and heart failure. A growing number of studies have demonstrated that miRNAs determine the fate of the heart by regulating cardiac cell death and regeneration after MI. A deep understanding of the pathophysiology of miRNA dependent regulatory pathways in these processes is required. The role of miRNAs as diagnostic, prognostic, and therapeutic targets also needs to be explored in order to utilize them in clinical settings. This review summarizes the role of miRNAs in myocardial infarction and focuses mainly on their influence on cardiomyocyte regeneration and cell death including apoptosis, necrosis, and autophagy. In addition, the targets of pro- and anti-MI miRNAs are comparatively described. In particular, the possibilities of miRNA based diagnostic and therapeutic strategies for myocardial infarction are discussed in this review. PMID- 28362345 TI - Object Tracking Using Local Multiple Features and a Posterior Probability Measure. AB - Object tracking has remained a challenging problem in recent years. Most of the trackers can not work well, especially when dealing with problems such as similarly colored backgrounds, object occlusions, low illumination, or sudden illumination changes in real scenes. A centroid iteration algorithm using multiple features and a posterior probability criterion is presented to solve these problems. The model representation of the object and the similarity measure are two key factors that greatly influence the performance of the tracker. Firstly, this paper propose using a local texture feature which is a generalization of the local binary pattern (LBP) descriptor, which we call the double center-symmetric local binary pattern (DCS-LBP). This feature shows great discrimination between similar regions and high robustness to noise. By analyzing DCS-LBP patterns, a simplified DCS-LBP is used to improve the object texture model called the SDCS-LBP. The SDCS-LBP is able to describe the primitive structural information of the local image such as edges and corners. Then, the SDCS-LBP and the color are combined to generate the multiple features as the target model. Secondly, a posterior probability measure is introduced to reduce the rate of matching mistakes. Three strategies of target model update are employed. Experimental results show that our proposed algorithm is effective in improving tracking performance in complicated real scenarios compared with some state-of-the-art methods. PMID- 28362346 TI - Monitoring and Discovery for Self-Organized Network Management in Virtualized and Software Defined Networks. AB - This paper presents the Monitoring and Discovery Framework of the Self-Organized Network Management in Virtualized and Software Defined Networks SELFNET project. This design takes into account the scalability and flexibility requirements needed by 5G infrastructures. In this context, the present framework focuses on gathering and storing the information (low-level metrics) related to physical and virtual devices, cloud environments, flow metrics, SDN traffic and sensors. Similarly, it provides the monitoring data as a generic information source in order to allow the correlation and aggregation tasks. Our design enables the collection and storing of information provided by all the underlying SELFNET sublayers, including the dynamically onboarded and instantiated SDN/NFV Apps, also known as SELFNET sensors. PMID- 28362344 TI - Proactive Approach for Safe Use of Antimicrobial Coatings in Healthcare Settings: Opinion of the COST Action Network AMiCI. AB - Infections and infectious diseases are considered a major challenge to human health in healthcare units worldwide. This opinion paper was initiated by EU COST Action network AMiCI (AntiMicrobial Coating Innovations) and focuses on scientific information essential for weighing the risks and benefits of antimicrobial surfaces in healthcare settings. Particular attention is drawn on nanomaterial-based antimicrobial surfaces in frequently-touched areas in healthcare settings and the potential of these nano-enabled coatings to induce (eco)toxicological hazard and antimicrobial resistance. Possibilities to minimize those risks e.g., at the level of safe-by-design are demonstrated. PMID- 28362347 TI - Strong Tracking Spherical Simplex-Radial Cubature Kalman Filter for Maneuvering Target Tracking. AB - Conventional spherical simplex-radial cubature Kalman filter (SSRCKF) for maneuvering target tracking may decline in accuracy and even diverge when a target makes abrupt state changes. To overcome this problem, a novel algorithm named strong tracking spherical simplex-radial cubature Kalman filter (STSSRCKF) is proposed in this paper. The proposed algorithm uses the spherical simplex radial (SSR) rule to obtain a higher accuracy than cubature Kalman filter (CKF) algorithm. Meanwhile, by introducing strong tracking filter (STF) into SSRCKF and modifying the predicted states' error covariance with a time-varying fading factor, the gain matrix is adjusted on line so that the robustness of the filter and the capability of dealing with uncertainty factors is improved. In this way, the proposed algorithm has the advantages of both STF's strong robustness and SSRCKF's high accuracy. Finally, a maneuvering target tracking problem with abrupt state changes is used to test the performance of the proposed filter. Simulation results show that the STSSRCKF algorithm can get better estimation accuracy and greater robustness for maneuvering target tracking. PMID- 28362349 TI - Real-Time and High-Resolution 3D Face Measurement via a Smart Active Optical Sensor. AB - The 3D measuring range and accuracy in traditional active optical sensing, such as Fourier transform profilometry, are influenced by the zero frequency of the captured patterns. The phase-shifting technique is commonly applied to remove the zero component. However, this phase-shifting method must capture several fringe patterns with phase difference, thereby influencing the real-time performance. This study introduces a smart active optical sensor, in which a composite pattern is utilized. The composite pattern efficiently combines several phase-shifting fringes and carrier frequencies. The method can remove zero frequency by using only one pattern. Model face reconstruction and human face measurement were employed to study the validity and feasibility of this method. Results show no distinct decrease in the precision of the novel method unlike the traditional phase-shifting method. The texture mapping technique was utilized to reconstruct a nature-appearance 3D digital face. PMID- 28362348 TI - Effect of Temperature on Tolbutamide Binding to Glycated Serum Albumin. AB - Glycation process occurs in protein and becomes more pronounced in diabetes when an increased amount of reducing sugar is present in bloodstream. Glycation of protein may cause conformational changes resulting in the alterations of its binding properties even though they occur at a distance from the binding sites. The changes in protein properties could be related to several pathological consequences such as diabetic and nondiabetic cardiovascular diseases, cataract, renal dysfunction and Alzheimer's disease. The experiment was designed to test the impact of glycation process on sulfonylurea drug tolbutamide-albumin binding under physiological (T = 309 K) and inflammatory (T = 311 K and T = 313 K) states using fluorescence and UV-VIS spectroscopies. It was found in fluorescence analysis experiments that the modification of serum albumin in tryptophanyl and tyrosyl residues environment may affect the tolbutamide (TB) binding to albumin in subdomain IIA and/or IIIA (Sudlow's site I and/or II), and also in subdomains IB and IIB. We estimated the binding of tolbutamide to albumin described by a mixed nature of interaction (specific and nonspecific). The association constants Ka (L?mol-1) for tolbutamide at its high affinity sites on non-glycated albumin were in the range of 1.98-7.88 * 104 L?mol-1 (lambdaex = 275 nm), 1.20-1.64 * 104 L?mol-1 (lambdaex = 295 nm) and decreased to 1.24-0.42 * 104 L?mol-1 at lambdaex = 275 nm (T = 309 K and T = 311 K) and increased to 2.79 * 104 L?mol-1 at lambdaex = 275 nm (T = 313 K) and to 4.43-6.61 * 104 L?mol-1 at lambdaex = 295 nm due to the glycation process. Temperature dependence suggests the important role of van der Waals forces and hydrogen bonding in hydrophobic interactions between tolbutamide and both glycated and non-glycated albumin. We concluded that the changes in the environment of TB binding of albumin in subdomain IIA and/or IIIA as well as in subdomains IB and IIB influence on therapeutic effect and therefore the studies of the binding of tolbutamide (in diabetes) to transporting protein under glycation that refers to the modification of a protein are of great importance in pharmacology and biochemistry. This information may lead to the development of more effective drug therapy in people with diabetes. PMID- 28362350 TI - Individual and Store Characteristics Associated with Brand Choices in Select Food Category Redemptions among WIC Participants in Virginia. AB - The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) often allows participants to redeem food benefits for various brands at different costs. To aid the program's food cost containment efforts, it is important to understand the individual and store characteristics associated with brand choices. This study used the WIC Electronic Benefit Transfer (EBT) data for 239,062 Virginia WIC participants' brand choices in infant fruits and vegetables (F&Vs) and whole grain bread in May 2014-February 2015, one of the first such data sets available in the U.S. for research purposes. Mixed effects logistic regression models were used to analyze the choice of higher-priced brands over lower-priced brands. Minority participants were significantly more likely to redeem higher-priced brands of infant F&Vs, but more likely to choose lower priced brands of bread. Participants shopping in urban stores or midsized stores (with 5-9 registers) were less likely to choose higher-priced brands compared to rural stores or large stores (with 9+ registers). Race/ethnicity and store characteristics may be significant factors in participants' brand choices. The results can help develop interventions that encourage targeted participants to redeem lower-priced but equivalently healthy brands. This may not only help contain WIC program costs, but help participants manage their own non-WIC food expenses as well. PMID- 28362351 TI - Barbatic Acid Offers a New Possibility for Control of Biomphalaria Glabrata and Schistosomiasis. AB - This study evaluated the biological activity of an ether extract and barbatic acid (BAR) from Cladia aggregata on embryos and adult mollusks of Biomphalaria glabrata, cercariae of Schistosoma mansoni and the microcrustacean Artemia salina. The ether extract and BAR were obtained by successive extractions with diethyl ether. The obtained extracts were analyzed using thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), proton nuclear magnetic resonance (1H-NMR) and infrared (IR) spectroscopy. The results demonstrated that the ether extract exerted embryotoxic effects at 50 and 100 ug/mL and molluscicidal effects at 20 and 25 ug/mL. BAR exhibited no embryotoxicity, and its molluscicidal concentration was equal to that of the ether extract. However, after 60 min of exposure, 1 ug/mL BAR presented cercaricidal activity against the parasite S. mansoni at the second larval stage. Neither substance induced toxicity against A. salina. These results indicate the potential molluscicidal activities of the ether extract and BAR against B. glabrata and S. mansoni cercariae. In addition to these effects, there was a lack of toxicity against the aquatic environment and no damage to the biota, indicating the potential of these products for large-scale control and/or eradication of schistosomiasis. PMID- 28362352 TI - Optimization of Bromelain-Aided Production of Angiotensin I-Converting Enzyme Inhibitory Hydrolysates from Stone Fish Using Response Surface Methodology. AB - The stone fish is an under-utilized sea cucumber with many nutritional and ethno medicinal values. This study aimed to establish the conditions for its optimum hydrolysis with bromelain to generate angiotensin I-converting enzyme (ACE) inhibitory hydrolysates. Response surface methodology (RSM) based on a central composite design was used to model and optimize the degree of hydrolysis (DH) and ACE-inhibitory activity. Process conditions including pH (4-7), temperature (40 70 degrees C), enzyme/substrate (E/S) ratio (0.5%-2%) and time (30-360 min) were used. A pH of 7.0, temperature of 40 degrees C, E/S ratio of 2% and time of 240 min were determined using a response surface model as the optimum levels to obtain the maximum ACE-inhibitory activity of 84.26% at 44.59% degree of hydrolysis. Hence, RSM can serve as an effective approach in the design of experiments to improve the antihypertensive effect of stone fish hydrolysates, which can thus be used as a value-added ingredient for various applications in the functional foods industries. PMID- 28362353 TI - Ergosteryl 2-naphthoate, An Ergosterol Derivative, Exhibits Antidepressant Effects Mediated by the Modification of GABAergic and Glutamatergic Systems. AB - Phytosterols are a kind of natural component including sitosterol, campesterol, avenasterol, ergosterol (Er) and others. Their main natural sources are vegetable oils and their processed products, followed by grains, by-products of cereals and nuts, and small amounts of fruits, vegetables and mushrooms. In this study, three new Er monoester derivatives were obtained from the reflux reaction with Er: organic acids (furoic acid, salicylic acid and 2-naphthoic acid), 1-Ethylethyl-3 (3-dimethyllaminopropyl) carbodiimide hydrochloride (EDCI) and 4 dimethylaminopyridine (DMAP) in dichloromethane. Their chemical structures were defined by IR and NMR. The present study was also undertaken to investigate the antidepressant-like effects of Er and its derivatives in male adult mice models of depression, and their probable involvement of GABAergic and glutamatergic systems by the forced swim test (FST). The results indicated that Er and its derivatives display antidepressant effects. Moreover, one derivative of Er, ergosteryl 2-naphthoate (ErN), exhibited stronger antidepressant activity in vivo compared to Er. Acute administration of ErN (5 mg/kg, i.p.) and a combination of ErN (0.5 mg/kg, i.p.), reboxetine (2.5 mg/kg, i.p.), and tianeptine (15 mg/kg, i.p.) reduced the immobility time in the FST. Pretreatment with bicuculline (a competitive gamma-aminobutyric acid (GABA) antagonist, 4 mg/kg, i.p.) and N methyl-d-aspartic acid (NMDA, an agonist at the glutamate site, 75 mg/kg, i.p.) effectively reversed the antidepressant-like effect of ErN (5 mg/kg, i.p.). However, prazosin (a alpha1-adrenoceptor antagonist, 1 mg/kg, i.p.) and haloperidol (a non-selective D2 receptor antagonist, 0.2 mg/kg, i.p.) did not eliminate the reduced immobility time. Altogether, these results indicated that ErN produced antidepressant-like activity, which might be mediated by GABAergic and glutamatergic systems. PMID- 28362354 TI - Socio-Economic Position and Suicidal Ideation in Men. AB - People in low socio-economic positions are over-represented in suicide statistics and are at heightened risk for non-fatal suicidal thoughts and behaviours. Few studies have tried to tease out the relationship between individual-level and area-level socio-economic position, however. We used data from Ten to Men (the Australian Longitudinal Study on Male Health) to investigate the relationship between individual-level and area-level socio-economic position and suicidal thinking in 12,090 men. We used a measure of unemployment/employment and occupational skill level as our individual-level indicator of socio-economic position. We used the Index of Relative Socio-Economic Disadvantage (a composite multidimensional construct created by the Australian Bureau of Statistics that combines information from a range of area-level variables, including the prevalence of unemployment and employment in low skilled occupations) as our area level indicator. We assessed suicidal thinking using the Patient Health Questionnaire (PHQ-9). We found that even after controlling for common predictors of suicidal thinking; low individual-level and area-level socio-economic position heightened risk. Individual-level socio-economic position appeared to exert the greater influence of the two; however. There is an onus on policy makers and planners from within and outside the mental health sector to take individual- and area-level socio-economic position into account when they are developing strategic initiatives. PMID- 28362356 TI - Severe Pneumonia Caused by Influenza A (H1N1) Virus Successfully Managed with Extracorporeal Life Support in a Comorbid Former Preterm Infant. AB - Influenza A (H1N1) virus infection is a global health burden, leading to significant pediatric morbidity and mortality. Prematurity, young age and comorbidities are important risk factors for unfavorable outcomes. Preventive strategies, such as healthcare workers and household contacts vaccination as well as the implementation of infection control practices during the epidemic season, are crucial to protect the most vulnerable populations. Early diagnosis, timely administration of antiviral drugs and supportive therapy are crucial to lead to a complete recovery. When conventional treatment fails, extracorporeal life support (ECLS) may be employed. In neonates and young infants, this high-tech support is burdened by specific technical complexity. Despite the potential risks related to this aggressive approach, ECLS is a life-saving procedure in 65% of pediatric viral pneumonia and in 73% of sepsis cases. Here, we report the successful outcome of a 51-day formerly preterm infant, suffering from a surgical necrotizing enterocolitis (NEC), complicated with hospital-acquired pneumonia due to influenza A (H1N1) virus. She developed a severe respiratory failure, unresponsive to conventional therapy, and successfully treated with ECLS. To our knowledge, this is the first report on the use of ECLS in a formerly preterm infant, suffering from NEC complicated by influenza A (H1N1) virus infection. PMID- 28362355 TI - Daily Intake of Grape Powder Prevents the Progression of Kidney Disease in Obese Type 2 Diabetic ZSF1 Rats. AB - Individuals living with metabolic syndrome (MetS) such as diabetes and obesity are at high risk for developing chronic kidney disease (CKD). This study investigated the beneficial effect of whole grape powder (WGP) diet on MetS associated CKD. Obese diabetic ZSF1 rats, a kidney disease model with MetS, were fed WGP (5%, w/w) diet for six months. Kidney disease was determined using blood and urine chemical analyses, and histology. When compared to Vehicle controls, WGP intake did not change the rat bodyweight, but lowered their kidney, liver and spleen weight, which were in parallel with the lower serum glucose and the higher albumin or albumin/globin ratio. More importantly, WGP intake improved the renal function as urination and proteinuria decreased, or it prevented kidney tissue damage in these diabetic rats. The renal protection of WGP diet was associated with up-regulation of antioxidants (Dhcr24, Gstk1, Prdx2, Sod2, Gpx1 and Gpx4) and downregulation of Txnip (for ROS production) in the kidneys. Furthermore, addition of grape extract reduced H2O2-induced cell death of cultured podocytes. In conclusion, daily intake of WGP reduces the progression of kidney disease in obese diabetic rats, suggesting a protective function of antioxidant-rich grape diet against CKD in the setting of MetS. PMID- 28362357 TI - Targeting MYC Dependence by Metabolic Inhibitors in Cancer. AB - Abstract:MYC is a critical growth regulatory gene that is commonly overexpressed in a wide range of cancers. Therapeutic targeting of MYC transcriptional activity has long been a goal, but it has been difficult to achieve with drugs that directly block its DNA-binding ability. Additional approaches that exploit oncogene addiction are promising strategies against MYC-driven cancers. Also, drugs that target metabolic regulatory pathways and enzymes have potential for indirectly reducing MYC levels. Glucose metabolism and oxidative phosphorylation, which can be targeted by multiple agents, promote cell growth and MYC expression. Likewise, modulation of the signaling pathways and protein synthesis regulated by adenosine monophosphate-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) can also be an effective route for suppressing MYC translation. Furthermore, recent data suggest that metabolism of nucleotides, fatty acids and glutamine are exploited to alter MYC levels. Combination therapies offer potential new approaches to overcome metabolic plasticity caused by single agents. Although potential toxicities must be carefully controlled, new inhibitors currently being tested in clinical trials offer significant promise. Therefore, as both a downstream target of metabolism and an upstream regulator, MYC is a prominent central regulator of cancer metabolism. Exploiting metabolic vulnerabilities of MYC-driven cancers is an emerging research area with translational potential. PMID- 28362358 TI - Distal Proton Shuttle Mechanism of Ribosome Catalysed Peptide Bond Formation-A Theoretical Study. AB - In this work, we have investigated a novel distal proton shuttle mechanism of ribosome catalyzed peptide bond formation reaction. The reaction was found to follow a two-step mechanism. A distal water molecule located about 6.1 A away from the attacking amine plays as a proton acceptor and results in a charge separated intermediate that is stabilized by the N terminus of L27 and the A-site A76 5'-phosphate. The ribose A2451 bridges the proton shuttle pathway, thus plays critical role in the reaction. The calculated 27.64 kcal*mol-1 free energy barrier of the distal proton shuttle mechanism is lower than that of eight membered ring transition state. The distal proton shuttle mechanism studied in this work can provide new insights into the important biological peptide synthesis process. PMID- 28362360 TI - A Risk Assessment Matrix for Public Health Principles: The Case for E-Cigarettes. AB - Besides nicotine replacement therapies, a realistic alternative for smoking cessation or for smoking substitution may come from electronic cigarettes (ECs), whose popularity has been steadily growing. As for any emerging behaviour associated with exposure to inhalational agents, there is legitimate cause for concern and many health organizations and policy makers have pushed for restrictive policy measures ranging from complete bans to tight regulations of these products. Nonetheless, it is important to reframe these concerns in context of the well-known harm caused by cigarette smoking. In this article, we discuss key public health principles that should be considered when regulating ECs. These include the concept of tobacco harm reduction, importance of relative risk and risk continuum, renormalization of smoking, availability of low-risk product, proportionate taxation, and reassessment of the role of non-tobacco flavours. These public health principles may be systematically scrutinized using a risk assessment matrix that allows: (1) to determine the measure of certainty that a risk will occur; and (2) to estimate the impact of such a risk on public health. Consequently, the ultimate goal of responsible ECs regulation should be that of maximizing the favourable impact of these reduced-risk products whilst minimizing further any potential risks. Consumer perspectives, sound EC research, continuous post-marketing surveillance and reasonable safety and quality product standards should be at the very heart of future regulatory schemes that will address concerns while minimizing unintended consequences of ill-informed regulation. PMID- 28362361 TI - Time Trend and Demographic and Geographic Disparities in Childhood Obesity Prevalence in China-Evidence from Twenty Years of Longitudinal Data. AB - Childhood overweight and obesity (ow/ob) has become a serious threat to many countries, including China. However, limited evidence was obtained from longitudinal data in China. This study examined the secular trends and geographic variation in the prevalence of ow/ob and obesity only, and age, gender, and urban rural disparities among school-aged children across China. Data from children aged 6-17 surveyed in China Health and Nutrition Survey (CHNS) from 1991 (n = 2712) to 2011 (n = 1054) were used. Overweight and obesity were defined based on the International Obesity Task Force (IOTF) recommended Asian age-sex-specific BMI cut-off-points. We found that: (1) childhood ow/ob and obesity prevalence increased from 11.7% to 25.2% and from 2.8% to 10.1% during 1991-2011, respectively; (2) children aged 6-12 experienced a 1.3 and 1.6 times increase in ow/ob and obesity prevalence than children aged 13-17, respectively; (3) the urban-rural gap in ow/ob prevalence widened; (4) ow/ob prevalence in boys was higher and increased faster than in girls, especially in an urban setting; and (5) geographic variation was observed with faster increases in more economically developed east, central and northeast regions than in the less developed west. The findings added more nuances to the picture of temporal changes in ow/ob prevalence among Chinese children. PMID- 28362359 TI - Self-Organized TiO2-MnO2 Nanotube Arrays for Efficient Photocatalytic Degradation of Toluene. AB - Vertically oriented, self-organized TiO2-MnO2 nanotube arrays were successfully obtained by one-step anodic oxidation of Ti-Mn alloys in an ethylene glycol-based electrolyte. The as-prepared samples were characterized by scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), UV-Vis absorption, photoluminescence spectroscopy, X-ray diffraction (XRD), and micro-Raman spectroscopy. The effect of the applied potential (30-50 V), manganese content in the alloy (5-15 wt. %) and water content in the electrolyte (2-10 vol. %) on the morphology and photocatalytic properties was investigated for the first time. The photoactivity was assessed in the toluene removal reaction under visible light, using low-powered LEDs as an irradiation source (lambdamax = 465 nm). Morphology analysis showed that samples consisted of auto-aligned nanotubes over the surface of the alloy, their dimensions were: diameter = 76-118 nm, length = 1.0-3.4 MUm and wall thickness = 8-11 nm. It was found that the increase in the applied potential led to increase the dimensions while the increase in the content of manganese in the alloy brought to shorter nanotubes. Notably, all samples were photoactive under the influence of visible light and the highest degradation achieved after 60 min of irradiation was 43%. The excitation mechanism of TiO2 MnO2 NTs under visible light was presented, pointing out the importance of MnO2 species for the generation of e- and h+. PMID- 28362363 TI - Determining the Chemical Composition of Corrosion Inhibitor/Metal Interfaces with XPS: Minimizing Post Immersion Oxidation. AB - An approach for acquiring more reliable X-ray photoelectron spectroscopy data from corrosion inhibitor/metal interfaces is described. More specifically, the focus is on metallic substrates immersed in acidic solutions containing organic corrosion inhibitors, as these systems can be particularly sensitive to oxidation following removal from solution. To minimize the likelihood of such degradation, samples are removed from solution within a glove box purged with inert gas, either N2 or Ar. The glove box is directly attached to the load-lock of the ultra high vacuum X-ray photoelectron spectroscopy instrument, avoiding any exposure to the ambient laboratory atmosphere, and thus reducing the possibility of post immersion substrate oxidation. On this basis, one can be more certain that the X ray photoelectron spectroscopy features observed are likely to be representative of the in situ submerged scenario, e.g. the oxidation state of the metal is not modified. PMID- 28362362 TI - Combined Intravital Microscopy and Contrast-enhanced Ultrasonography of the Mouse Hindlimb to Study Insulin-induced Vasodilation and Muscle Perfusion. AB - It has been demonstrated that insulin's vascular actions contribute to regulation of insulin sensitivity. Insulin's effects on muscle perfusion regulate postprandial delivery of nutrients and hormones to insulin-sensitive tissues. We here describe a technique for combining intravital microscopy (IVM) and contrast enhanced ultrasonography (CEUS) of the adductor compartment of the mouse hindlimb to simultaneously visualize muscle resistance arteries and perfusion of the microcirculation in vivo. Simultaneously assessing insulin's effect at multiple levels of the vascular tree is important to study relationships between insulin's multiple vasoactive effects and muscle perfusion. Experiments in this study were performed in mice. First, the tail vein cannula is inserted for the infusion of anesthesia, vasoactive compounds and ultrasound contrast agent (lipid encapsulated microbubbles). Second, a small incision is made in the groin area to expose the arterial tree of the adductor muscle compartment. The ultrasound probe is then positioned at the contralateral upper hindlimb to view the muscles in cross-section. To assess baseline parameters, the arterial diameter is assessed and microbubbles are subsequently infused at a constant rate to estimate muscle blood flow and microvascular blood volume (MBV). When applied before and during a hyperinsulinemic-euglycemic clamp, combined IVM and CEUS allow assessment of insulin-induced changes of arterial diameter, microvascular muscle perfusion and whole-body insulin sensitivity. Moreover, the temporal relationship between responses of the microcirculation and the resistance arteries to insulin can be quantified. It is also possible to follow-up the mice longitudinally in time, making it a valuable tool to study changes in vascular and whole-body insulin sensitivity. PMID- 28362364 TI - A Method for Evaluating Insecticide Efficacy against Bed Bug, Cimex lectularius, Eggs and First Instars. AB - Standard toxicity evaluations of insecticides against insect pests are primarily conducted on adult insects. Evaluations are based on a dose-response or concentration-response curve, where mortality increases as the dose or concentration of an insecticide is increased. Standard lethal concentration (LC50) and lethal dose (LD50) tests that result in 50% mortality of a test population can be challenging for evaluating toxicity of insecticides against non adult insect life stages, such as eggs and early instar or nymphal stages. However, this information is essential for understanding insecticide efficacy in all bed bug life stages, which affects control and treatment efforts. This protocol uses a standard dipping bioassay modified for bed bug eggs and a contact insecticidal assay for treating nymphal first instars. These assays produce a concentration-response curve to further quantify LC50 values for insecticide evaluations. PMID- 28362365 TI - A Mouse Model of Fatigue Induced by Peripheral Irradiation. AB - Cancer-related fatigue (CRF) is a distressing and costly condition that often affects patients receiving cancer treatments, including radiation therapy. Here we describe a method using targeted peripheral irradiation to induce fatigue-like behavior in mice. With appropriate shielding, the irradiation targets the lower abdominal/pelvic region of the mouse, sparing the brain, in an effort to model radiation treatment received by individuals with pelvic cancers. We deliver an irradiation dose that is sufficient to induce fatigue-like behavior in mice, measured by voluntary wheel-running activity (VWRA), without causing obvious morbidity. Since wheel running is a normal, voluntary behavior in mice, its use should have little confounding effect on other behavioral tests or biological measures. Hence, wheel running can be used as a feasible outcome measure in understanding the behavioral and biological correlates of fatigue. CRF is a complex condition with frequent comorbidities, and likely has causes related both to cancer and its various treatments. The methods described in this paper are useful for investigating radiation-induced changes that contribute to the development of CRF and, more generally, to explore the biological networks that can explain the development and persistence of a peripherally-triggered but centrally-driven behavior like fatigue. PMID- 28362366 TI - Flow Cytometric Analysis of Natural Killer Cell Lytic Activity in Human Whole Blood. AB - NK cell cytotoxicity is a widely used measure to determine the effect of outside intervention on NK cell function. However, the accuracy and reproducibility of this assay can be considered unstable, either because of user's errors or because of the sensitivity of NK cells to experimental manipulation. To eliminate these issues, a workflow that reduces them to a minimum was established and is presented here. To illustrate, we obtained blood samples, at various time points, from runners (n = 4) that were submitted to an intense bout of exercise. First, NK cells are simultaneously identified and isolated through CD56 tagging and magnetic-based sorting, directly from whole blood and from as little as one milliliter. The sorted NK cells are removed of any reagent or capping antibodies. They can be counted in order to establish an accurate NK cell count per milliliter of blood. Secondly, the sorted NK cells (effectors cells or E) can be mixed with 3,3'-Diotadecyloxacarbocyanine Perchlorate (DiO) tagged K562 cells (target cells or T) at an assay-optimal 1:5 T:E ratio, and analyzed using an imaging flow-cytometer that allows for the visualization of each event and the elimination of any false positive or false negatives (such as doublets or effector cells). This workflow can be completed in about 4 h, and allows for very stable results even when working with human samples. When available, research teams can test several experimental interventions in human subjects, and compare measurements across several time points without compromising the data's integrity. PMID- 28362367 TI - Sublimation of DAN Matrix for the Detection and Visualization of Gangliosides in Rat Brain Tissue for MALDI Imaging Mass Spectrometry. AB - Sample preparation is key for optimal detection and visualization of analytes in Matrix-assisted Laser Desorption/Ionization (MALDI) Imaging Mass Spectrometry (IMS) experiments. Determining the appropriate protocol to follow throughout the sample preparation process can be difficult as each step must be optimized to comply with the unique characteristics of the analytes of interest. This process involves not only finding a compatible matrix that can desorb and ionize the molecules of interest efficiently, but also selecting the appropriate matrix deposition technique. For example, a wet matrix deposition technique, which entails dissolving a matrix in solvent, is superior for desorption of most proteins and peptides, whereas dry matrix deposition techniques are particularly effective for ionization of lipids. Sublimation has been reported as a highly efficient method of dry matrix deposition for the detection of lipids in tissue by MALDI IMS due to the homogeneity of matrix crystal deposition and minimal analyte delocalization as compared to many wet deposition methods 1,2. Broadly, it involves placing a sample and powdered matrix in a vacuum-sealed chamber with the samples pressed against a cold surface. The apparatus is then lowered into a heated bath (sand or oil), resulting in sublimation of the powdered matrix onto the cooled tissue sample surface. Here we describe a sublimation protocol using 1,5-diaminonaphthalene (DAN) matrix for the detection and visualization of gangliosides in the rat brain using MALDI IMS. PMID- 28362368 TI - Peptide Scanning-assisted Identification of a Monoclonal Antibody-recognized Linear B-cell Epitope. AB - The identification of an antigenic epitope by the immune system allows for the understanding of the protective mechanism of neutralizing antibodies that may facilitate the development of vaccines and peptide drugs. Peptide scanning is a simple and efficient method that straightforwardly maps the linear epitope recognized by a monoclonal antibody (mAb). Here, the authors present an epitope determination methodology involving serially truncated recombinant proteins, synthetic peptide design, and dot-blot hybridization for the antigenic recognition of nervous necrosis virus coat protein using a neutralizing mAb. This technique relies on the dot-blot hybridization of synthetic peptides and mAbs on a polyvinylidene fluoride (PVDF) membrane. The minimum antigenic region of a viral coat protein recognized by the RG-M56 mAb can be narrowed down by step-by step trimmed peptide mapping onto a 6-mer peptide epitope. In addition, alanine scanning mutagenesis and residue substitution can be performed to characterize the binding significance of each amino acid residue making up the epitope. The residues flanking the epitope site were found to play critical roles in peptide conformation regulation. The identified epitope peptide may be used to form crystals of epitope peptide-antibody complexes for an x-ray diffraction study and functional competition, or for therapeutics. PMID- 28362369 TI - Monovalent Cation Doping of CH3NH3PbI3 for Efficient Perovskite Solar Cells. AB - Here, we demonstrate the incorporation of monovalent cation additives into CH3NH3PbI3 perovskite in order to adjust the optical, excitonic, and electrical properties. The possibility of doping was investigated by adding monovalent cation halides with similar ionic radii to Pb2+, including Cu+, Na+, and Ag+. A shift in the Fermi level and a remarkable decrease of sub-bandgap optical absorption, along with a lower energetic disorder in the perovskite, was achieved. An order-of-magnitude enhancement in the bulk hole mobility and a significant reduction of transport activation energy within an additive-based perovskite device was attained. The confluence of the aforementioned improved properties in the presence of these cations led to an enhancement in the photovoltaic parameters of the perovskite solar cell. An increase of 70 mV in open circuit voltage for AgI and a 2 mA/cm2 improvement in photocurrent density for NaI- and CuBr-based solar cells were achieved compared to the pristine device. Our work paves the way for further improvements in the optoelectronic quality of CH3NH3PbI3 perovskite and subsequent devices. It highlights a new avenue for investigations on the role of dopant impurities in crystallization and controls the electronic defect density in perovskite structures. PMID- 28362371 TI - A Device for Performing Cell Migration/Wound Healing in a 96-Well Plate. AB - The cell migration/wounding assay is a commonly used method to study cell migration and other biological processes, such as angiogenesis and tumor metastasis. In this assay, cells are grown to form a confluent monolayer and a mechanical wound is created by scratching with a device. Then the migration rate of the cells towards the denuded area can be monitored by imaging. Our 8-channel mechanical wounder is designed to tackle most of the problems associated with the cell migration assay. Firstly, our wounder can be easily sterilized by autoclaving or with common disinfectants. Secondly, the individual adjustable pins allow even contact with the cell culture plate so that sharp and reproducible wounds can be created. Thirdly, the guiding bars on both sides of the wounder ensure consistent wounding position in each well. The use of disposable plastic pipette tips for wounding can further provide better handling of the wounder as well as to minimize cross-contamination. In conclusion, our cell wounder can provide researchers with a user friendly and reproducible device for performing the cell migration assay using the standard 96-well culture plate. PMID- 28362370 TI - Transmission of Multiple Signals through an Optical Fiber Using Wavefront Shaping. AB - The transmission of multiple independent optical signals through a multimode fiber is accomplished using wavefront shaping in order to compensate for the light distortion during the propagation within the fiber. Our methodology is based on digital optical phase conjugation employing only a single spatial light modulator, where the optical wavefront is individually modulated at different regions of the modulator, one region per light signal. Digital optical phase conjugation approaches are considered to be faster than other wavefront shaping approaches, where (for example) a complete determination of the wave propagation behavior of the fiber is performed. In contrast, the presented approach is time efficient since it only requires one calibration per light signal. The proposed method is potentially appropriate for spatial division multiplexing in communications engineering. Further application fields are endoscopic light delivery in biophotonics, especially in optogenetics, where single cells in biological tissue have to be selectively illuminated with high spatial and temporal resolution. PMID- 28362373 TI - Proximal Cadaveric Femur Preparation for Fracture Strength Testing and Quantitative CT-based Finite Element Analysis. AB - Cadaveric fracture testing is routinely used to understand factors that affect proximal femur strength. Because ex vivo biological tissues are prone to lose their mechanical properties over time, specimen preparation for experimental testing must be performed carefully to obtain reliable results that represent in vivo conditions. For that reason, we designed a protocol and a set of fixtures to prepare the femoral specimens such that their mechanical properties experienced minimal changes. The femora were kept in a frozen state except during preparation steps and mechanical testing. The relevant clinical measures of total hip and femoral neck bone mineral density (BMD) were obtained with a clinical dual X-ray absorptiometry (DXA) bone densitometer, and the 3D geometry and distribution of bone mineral were obtained using CT with a calibration phantom for quantitative estimations based on the greyscale values. Any possible bone disease, fracture, or the presence of implants or artifacts affecting the bone structure, was ruled out with X-ray scans. For preparation, all bones were carefully cleaned of excess soft tissue, and were cut and potted at the internal rotation angle of interest. A cutting fixture allowed the distal end of the bone to be cut off leaving the proximal femur at a desired length. To allow positioning of the femoral neck at prescribed angles during later CT scanning and mechanical testing, the proximal femoral shafts were potted in polymethylmethacrylate (PMMA) using a fixture designed specifically for desired orientations. The data collected from our experiments were then used for validation of quantitative computed tomography (QCT)-based finite element analysis (FEA), as described in a different protocol. In this manuscript, we present the protocol for the precise bone preparation for mechanical testing and subsequent QCT/FEA modeling. The current protocol was successfully applied to prepare about 200 cadaveric femora over a 6-year time period. PMID- 28362372 TI - Using Synthetic Biology to Engineer Living Cells That Interface with Programmable Materials. AB - We have developed an abiotic-biotic interface that allows engineered cells to control the material properties of a functionalized surface. This system is made by creating two modules: a synthetically engineered strain of E. coli cells and a functionalized material interface. Within this paper, we detail a protocol for genetically engineering selected behaviors within a strain of E. coli using molecular cloning strategies. Once developed, this strain produces elevated levels of biotin when exposed to a chemical inducer. Additionally, we detail protocols for creating two different functionalized surfaces, each of which is able to respond to cell-synthesized biotin. Taken together, we present a methodology for creating a linked, abiotic-biotic system that allows engineered cells to control material composition and assembly on nonliving substrates. PMID- 28362375 TI - Protocols for Quantifying Transferable Pesticide Residues in Turfgrass Systems. AB - Plant canopies in established turfgrass systems can intercept an appreciable amount of sprayed pesticides, which can be transferred through various routes onto humans. For this reason, transferable pesticide residue experiments are required for registration and re-registration by the United States Environmental Protection Agency (USEPA). Although such experiments are required, limited specificity is required pertaining to experimental approach. Experimental approaches used to assess pesticide transfer to humans including hand wiping with cotton gloves, modified California roller (moving a roller of known mass over cotton cloth) and soccer ball roll (ball wrapped with sorbent strip) over three treated turfgrass species (creeping bentgrass, hybrid bermudagrass and tall fescue maintained at 0.4, 5 and 9 cm, respectively) are presented. The modified California roller is the most extensively utilized approach to date, and is best suited for use at low mowing heights due to its reproducibility and large sampling area. The soccer ball roll is a less aggressive transfer approach; however, it mimics a very common occurrence in the most popular international sport, and has many implications for nondietary pesticide exposure from hand-to mouth contact. Additionally, this approach may be adjusted for other athletic activities with limited modification. Hand wiping is the best approach to transfer pesticides at higher mowing heights, as roller-based approaches can lay blades over; however, it is more subjective due to more variable sampling pressure. Utility of these methods across turfgrass species is presented, and additional considerations to conduct transferable pesticide residue research in turfgrass systems are discussed. PMID- 28362374 TI - A G-quadruplex DNA-affinity Approach for Purification of Enzymatically Active G4 Resolvase1. AB - Higher-order nucleic acid structures called G-quadruplexes (G4s, G4 structures) can form in guanine-rich regions of both DNA and RNA and are highly thermally stable. There are >375,000 putative G4-forming sequences in the human genome, and they are enriched in promoter regions, untranslated regions (UTRs), and within the telomeric repeat. Due to the potential for these structures to affect cellular processes, such as replication and transcription, the cell has evolved enzymes to manage them. One such enzyme is G4 Resolvase 1 (G4R1), which was biochemically co-characterized by our laboratory and Nagamine et al. and found to bind extremely tightly to both G4-DNA and G4-RNA (Kd in the low-pM range). G4R1 is the source of the majority of G4-resolving activity in HeLa cell lysates and has since been implicated to play a role in telomere metabolism, lymph development, gene transcription, hematopoiesis, and immune surveillance. The ability to efficiently express and purify catalytically active G4R1 is of importance for laboratories interested in gaining further insight into the kinetic interaction of G4 structures and G4-resolving enzymes. Here, we describe a detailed method for the purification of recombinant G4R1 (rG4R1). The described procedure incorporates the traditional affinity-based purification of a C terminal histidine-tagged enzyme expressed in human codon-optimized bacteria with the utilization of the ability of rG4R1 to bind and unwind G4-DNA to purify highly active enzyme in an ATP-dependent elution step. The protocol also includes a quality-control step where the enzymatic activity of rG4R1 is measured by examining the ability of the purified enzyme to unwind G4-DNA. A method is also described that allows for the quantification of purified rG4R1. Alternative adaptations of this protocol are discussed. PMID- 28362376 TI - A Comparative Study of Drug Delivery Methods Targeted to the Mouse Inner Ear: Bullostomy Versus Transtympanic Injection. AB - We present two minimally invasive microsurgical techniques in rodents for specific drug delivery into the middle ear so that it may reach the inner ear. The first procedure consists of perforation of the tympanic bulla, termed bullostomy; the second one is a transtympanic injection. Both emulate human clinical intratympanic procedures. Chitosan-glycerophosphate (CGP) and Ringer's Lactate buffer (RL) were used as biocompatible vehicles for local drug delivery. CGP is a nontoxic biodegradable polymer widely used in pharmaceutical applications. It is a viscous liquid at RT but it congeals to a semi solid phase at body temperature. RL is an isotonic solution used for intravenous administrations in humans. A small volume of this vehicle is precisely placed on the Round Window (RW) niche by means of a bullostomy. A transtympanic injection fills the middle ear and allows less control but broader access to the inner ear. The safety profiles of both techniques were studied and compared by using functional and morphological tests. Hearing was evaluated by registering the Auditory Brainstem Response (ABR) before and several times after microsurgery. The cytoarchitecture and preservation level of cochlear structures were studied by conventional histological techniques in paraformaldehyde-fixed and decalcified cochlear samples. In parallel, unfixed cochlear samples were taken and immediately frozen to analyze gene expression profiles of inflammatory markers by quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR). Both procedures are suitable as drug delivery methods into the mouse middle ear, although transtympanic injection proved to be less invasive compared to bullostomy. PMID- 28362377 TI - A Fluorescence-based Lymphocyte Assay Suitable for High-throughput Screening of Small Molecules. AB - High-throughput screening (HTS) is currently the mainstay for the identification of chemical entities capable of modulating biochemical reactions or cellular processes. With the advancement of biotechnologies and the high translational potential of small molecules, a number of innovative approaches in drug discovery have evolved, which explains the resurgent interest in the use of HTS. The oncology field is currently the most active research area for drug screening, with no major breakthrough made for the identification of new immunomodulatory compounds targeting transplantation-related complications or autoimmune ailments. Here, we present a novel in vitro murine fluorescent-based lymphocyte assay easily adapted for the identification of new immunomodulatory compounds. This assay uses T or B cells derived from a transgenic mouse, in which the Nur77 promoter drives GFP expression upon T- or B-cell receptor stimulation. As the GFP intensity reflects the activation/transcriptional activity of the target cell, our assay defines a novel tool to study the effect of given compound(s) on cellular/biological responses. For instance, a primary screening was performed using 4,398 compounds in the absence of a "target hypothesis", which led to the identification of 160 potential hits displaying immunomodulatory activities. Thus, the use of this assay is suitable for drug discovery programs exploring large chemical libraries prior to further in vitro/in vivo validation studies. PMID- 28362378 TI - Combining Intravital Fluorescent Microscopy (IVFM) with Genetic Models to Study Engraftment Dynamics of Hematopoietic Cells to Bone Marrow Niches. AB - Increasing evidence indicates that normal hematopoiesis is regulated by distinct microenvironmental cues in the BM, which include specialized cellular niches modulating critical hematopoietic stem cell (HSC) functions1,2. Indeed, a more detailed picture of the hematopoietic microenvironment is now emerging, in which the endosteal and the endothelial niches form functional units for the regulation of normal HSC and their progeny3,4,5. New studies have revealed the importance of perivascular cells, adipocytes and neuronal cells in maintaining and regulating HSC function6,7,8. Furthermore, there is evidence that cells from different lineages, i.e. myeloid and lymphoid cells, home and reside in specific niches within the BM microenvironment. However, a complete mapping of the BM microenvironment and its occupants is still in progress. Transgenic mouse strains expressing lineage specific fluorescent markers or mice genetically engineered to lack selected molecules in specific cells of the BM niche are now available. Knock-out and lineage tracking models, in combination with transplantation approaches, provide the opportunity to refine the knowledge on the role of specific "niche" cells for defined hematopoietic populations, such as HSC, B cells, T-cells, myeloid cells and erythroid cells. This strategy can be further potentiated by merging the use of two-photon microscopy of the calvarium. By providing in vivo high resolution imaging and 3-D rendering of the BM calvarium, we can now determine precisely the location where specific hematopoietic subsets home in the BM and evaluate the kinetics of their expansion over time. Here, Lys GFP transgenic mice (marking myeloid cells)9 and RBPJ knock-out mice (lacking canonical Notch signaling)10 are used in combination with IVFM to determine the engraftment of myeloid cells to a Notch defective BM microenvironment. PMID- 28362379 TI - Microfluidic Platform with Multiplexed Electronic Detection for Spatial Tracking of Particles. AB - Microfluidic processing of biological samples typically involves differential manipulations of suspended particles under various force fields in order to spatially fractionate the sample based on a biological property of interest. For the resultant spatial distribution to be used as the assay readout, microfluidic devices are often subjected to microscopic analysis requiring complex instrumentation with higher cost and reduced portability. To address this limitation, we have developed an integrated electronic sensing technology for multiplexed detection of particles at different locations on a microfluidic chip. Our technology, called Microfluidic CODES, combines Resistive Pulse Sensing with Code Division Multiple Access to compress 2D spatial information into a 1D electrical signal. In this paper, we present a practical demonstration of the Microfluidic CODES technology to detect and size cultured cancer cells distributed over multiple microfluidic channels. As validated by the high-speed microscopy, our technology can accurately analyze dense cell populations all electronically without the need for an external instrument. As such, the Microfluidic CODES can potentially enable low-cost integrated lab-on-a-chip devices that are well suited for the point-of-care testing of biological samples. PMID- 28362380 TI - Production and Administration of Therapeutic Mesenchymal Stem/Stromal Cell (MSC) Spheroids Primed in 3-D Cultures Under Xeno-free Conditions. AB - Mesenchymal stem/stromal cells (MSCs) hold great promise in bioengineering and regenerative medicine. MSCs can be isolated from multiple adult tissues via their strong adherence to tissue culture plastic and then further expanded in vitro, most commonly using fetal bovine serum (FBS). Since FBS can cause MSCs to become immunogenic, its presence in MSC cultures limits both clinical and experimental applications of the cells. Therefore, studies employing chemically defined xeno free (XF) media for MSC cultures are extremely valuable. Many beneficial effects of MSCs have been attributed to their ability to regulate inflammation and immunity, mainly through secretion of immunomodulatory factors such as tumor necrosis factor-stimulated gene 6 (TSG6) and prostaglandin E2 (PGE2). However, MSCs require activation to produce these factors and since the effect of MSCs is often transient, great interest has emerged to discover ways of pre-activating the cells prior to their use, thus eliminating the lag time for activation in vivo. Here we present protocols to efficiently activate or prime MSCs in three dimensional (3D) cultures under chemically defined XF conditions and to administer these pre-activated MSCs in vivo. Specifically, we first describe methods to generate spherical MSC micro-tissues or 'spheroids' in hanging drops using XF medium and demonstrate how the spheres and conditioned medium (CM) can be harvested for various applications. Second, we describe gene expression screens and in vitro functional assays to rapidly assess the level of MSC activation in spheroids, emphasizing the anti-inflammatory and anti-cancer potential of the cells. Third, we describe a novel method to inject intact MSC spheroids into the mouse peritoneal cavity for in vivo efficacy testing. Overall, the protocols herein overcome major challenges of obtaining pre-activated MSCs under chemically defined XF conditions and provide a flexible system to administer MSC spheroids for therapies. PMID- 28362381 TI - Vasodilation of Isolated Vessels and the Isolation of the Extracellular Matrix of Tight-skin Mice. AB - The interferon regulatory factor 5 (IRF5) is crucial for cells to determine if they respond in a pro-inflammatory or anti-inflammatory fashion. IRF5's ability to switch cells from one pathway to another is highly attractive as a therapeutic target. We designed a decoy peptide IRF5D with a molecular modeling software for designing small molecules and peptides. IRF5D inhibited IRF5, reduced alterations in extracellular matrix, and improved endothelial vasodilation in the tight-skin mouse (Tsk/+). The Kd of IRF5D for recombinant IRF5 is 3.72 +/- 0.74 x 10-6 M as determined by binding experiments using biolayer interferometry experiments. Endothelial cells (EC) proliferation and apoptosis were unchanged using increasing concentrations of IRF5D (0 to 100 ug/mL, 24 h). Tsk/+ mice were treated with IRF5D (1 mg/kg/d subcutaneously, 21 d). IRF5 and ICAM expressions were decreased after IRF5D treatment. Endothelial function was improved as assessed by vasodilation of facialis arteries from Tsk/+ mice treated with IRF5D compared to Tsk/+ mice without IRF5D treatment. As a transcription factor, IRF5 traffics from the cytosol to the nucleus. Translocation was assessed by immunohistochemistry on cardiac myocytes cultured on the different cardiac extracellular matrices. IRF5D treatment of the Tsk/+ mouse resulted in a reduced number of IRF5 positive nuclei in comparison to the animals without IRF5D treatment (50 ug/mL, 24 h). These findings demonstrate the important role that IRF5 plays in inflammation and fibrosis in Tsk/+ mice. PMID- 28362383 TI - Methodology for the Study of Horizontal Gene Transfer in Staphylococcus aureus. AB - One important feature of the major opportunistic human pathogen Staphylococcus aureus is its extraordinary ability to rapidly acquire resistance to antibiotics. Genomic studies reveal that S. aureus carries many virulence and resistance genes located in mobile genetic elements, suggesting that horizontal gene transfer (HGT) plays a critical role in S. aureus evolution. However, a full and detailed description of the methodology used to study HGT in S. aureus is still lacking, especially regarding natural transformation, which has been recently reported in this bacterium. This work describes three protocols that are useful for the in vitro investigation of HGT in S. aureus: conjugation, phage transduction, and natural transformation. To this aim, the cfr gene (chloramphenicol/florfenicol resistance), which confers the Phenicols, Lincosamides, Oxazolidinones, Pleuromutilins, and Streptogramin A (PhLOPSA)-resistance phenotype, was used. Understanding the mechanisms through which S. aureus transfers genetic materials to other strains is essential to comprehending the rapid acquisition of resistance and helps to clarify the modes of dissemination reported in surveillance programs or to further predict the spreading mode in the future. PMID- 28362384 TI - A Simple and Scalable Fabrication Method for Organic Electronic Devices on Textiles. AB - Today, wearable electronics devices combine a large variety of functional, stretchable, and flexible technologies. However, in many cases, these devices cannot be worn under everyday conditions. Therefore, textiles are commonly considered the best substrate to accommodate electronic devices in wearable use. In this paper, we describe how to selectively pattern organic electroactive materials on textiles from a solution in an easy and scalable manner. This versatile deposition technique enables the fabrication of wearable organic electronic devices on clothes. PMID- 28362382 TI - Video Movement Analysis Using Smartphones (ViMAS): A Pilot Study. AB - The use of smartphones in clinical practice is steadily increasing with the availability of low cost/freely available "apps" that could be used to assess human gait. The primary aim of this manuscript is to test the concurrent validity of kinematic measures recorded by a smartphone application in comparison to a 3D motion capture system in the sagittal plane. The secondary aim was to develop a protocol for clinicians on the set up of the smartphone camera for video movement analysis. The sagittal plane knee angle was measured during heel strike and toe off events using the smart phone app and a 3D motion-capture system in 32 healthy subjects. Three trials were performed at near (2-m) and far (4-m) smartphone camera distances. The order of the distances was randomized. Regression analysis was performed to estimate the height of the camera based on either the subject's height or leg length. Absolute measurement errors were least during toe off (3.12 +/- 5.44 degrees) compared to heel strike (5.81 +/- 5.26 degrees). There were significant (p < 0.05) but moderate agreements between the application and 3D motion capture measures of knee angles. There were also no significant (p > 0.05) differences between the absolute measurement errors between the two camera positions. The measurement errors averaged between 3 - 5 degrees during toe off and heel strike events of the gait cycle. The use of smartphone apps can be a useful tool in the clinic for performing gait or human movement analysis. Further studies are needed to establish the accuracy in measuring movements of the upper extremity and trunk. PMID- 28362385 TI - Induction of an Inflammatory Response in Primary Hepatocyte Cultures from Mice. AB - The liver plays a decisive role in the regulation of systemic inflammation. In chronic kidney disease in particular, the liver reacts in response to the uremic milieu, oxidative stress, endotoxemia and the decreased clearance of circulating proinflammatory cytokines by producing a large number of acute-phase reactants. Experimental tools to study inflammation and the underlying role of hepatocytes are crucial to understand the regulation and contribution of hepatic cytokines to a systemic acute phase response and a prolonged pro-inflammatory scenario, especially in an intricate setting such as chronic kidney disease. Since studying complex mechanisms of inflammation in vivo remains challenging, resource intensive and usually requires the usage of transgenic animals, primary isolated hepatocytes provide a robust tool to gain mechanistic insights into the hepatic acute-phase response. Since this in vitro technique features moderate costs, high reproducibility and common technical knowledge, primary isolated hepatocytes can also be easily used as a screening approach. Here, we describe an enzymatic-based method to isolate primary murine hepatocytes, and we describe the assessment of an inflammatory response in these cells using ELISA and quantitative real-time PCR. PMID- 28362387 TI - Analysis of Termination of Transcription Using BrUTP-strand-specific Transcription Run-on (TRO) Approach. AB - This manuscript describes a protocol for detecting transcription termination defect in vivo. The strand-specific TRO protocol using BrUTP described here is a powerful experimental approach for analyzing the transcription termination defect under physiological conditions. Like the traditional TRO assay, it relies on the presence of a transcriptionally active polymerase beyond the 3' end of the gene as an indicator of a transcription termination defect1. It overcomes two major problems encountered with the traditional TRO assay. First, it can detect if the polymerase reading through the termination signal is the one that initiated transcription from the promoter-proximal region, or if it is simply representing a pervasively transcribing polymerase that initiated non-specifically from somewhere in the body or the 3' end of the gene. Secondly, it can distinguish if the transcriptionally active polymerase signal beyond the terminator region is truly the readthrough sense mRNA transcribing polymerase or a terminator initiated non-coding anti-sense RNA signal. Briefly, the protocol involves permeabilizing the exponentially growing yeast cells, allowing the transcripts that initiated in vivo to elongate in the presence of the BrUTP nucleotide, purifying BrUTP-labelled RNA by the affinity approach, reverse transcribing the purified nascent RNA and amplifying the cDNA using strand-specific primers flanking the promoter and the terminator regions of the gene2. PMID- 28362386 TI - In Vitro Differentiation of Human Pluripotent Stem Cells into Trophoblastic Cells. AB - The placenta is the first organ to develop during embryogenesis and is required for the survival of the developing embryo. The placenta is comprised of various trophoblastic cells that differentiate from the extra-embryonic trophectoderm cells of the preimplantation blastocyst. As such, our understanding of the early differentiation events of the human placenta is limited because of ethical and legal restrictions on the isolation and manipulation of human embryogenesis. Human pluripotent stem cells (hPSCs) are a robust model system for investigating human development and can also be differentiated in vitro into trophoblastic cells that express markers of the various trophoblast cell types. Here, we present a detailed protocol for differentiating hPSCs into trophoblastic cells using bone morphogenic protein 4 and inhibitors of the Activin/Nodal signaling pathways. This protocol generates various trophoblast cell types that can be transfected with siRNAs for investigating loss-of-function phenotypes or can be infected with pathogens. Additionally, hPSCs can be genetically modified and then differentiated into trophoblast progenitors for gain-of-function analyses. This in vitro differentiation method for generating human trophoblasts starting from hPSCs overcomes the ethical and legal restrictions of working with early human embryos, and this system can be used for a variety of applications, including drug discovery and stem cell research. PMID- 28362389 TI - Accessing Valuable Ligand Supports for Transition Metals: A Modified, Intermediate Scale Preparation of 1,2,3,4,5-Pentamethylcyclopentadiene. AB - A reliable, intermediate scale preparation of 1,2,3,4,5 pentamethylcyclopentadiene (Cp*H) is presented, based on modifications of existing protocols that derive from initial 2-bromo-2-butene lithiation followed by acid mediated dienol cyclization. The revised synthesis and purification of the ligand avoids the use of mechanical stirring while still permitting access to significant quantities (39 g) of Cp*H in good yield (58%). The procedure offers other additional benefits, including a more controlled quench of excess lithium during the production of the intermediate heptadienols and a simplified isolation of Cp*H of sufficient purity for metallation with transition metals. The ligand was subsequently used to synthesize [Cp*MCl2]2 complexes of both iridium and ruthenium to demonstrate the utility of the Cp*H prepared and purified by our method. The procedure outlined herein affords substantial quantities of a ubiquitous ancillary ligand support used in organometallic chemistry while minimizing the need for specialized laboratory equipment, thus providing a simpler and more accessible entry point into the chemistry of 1,2,3,4,5 pentamethylcyclopentadiene. PMID- 28362388 TI - Analyzing Dendritic Morphology in Columns and Layers. AB - In many regions of the central nervous systems, such as the fly optic lobes and the vertebrate cortex, synaptic circuits are organized in layers and columns to facilitate brain wiring during development and information processing in developed animals. Postsynaptic neurons elaborate dendrites in type-specific patterns in specific layers to synapse with appropriate presynaptic terminals. The fly medulla neuropil is composed of 10 layers and about 750 columns; each column is innervated by dendrites of over 38 types of medulla neurons, which match with the axonal terminals of some 7 types of afferents in a type-specific fashion. This report details the procedures to image and analyze dendrites of medulla neurons. The workflow includes three sections: (i) the dual-view imaging section combines two confocal image stacks collected at orthogonal orientations into a high-resolution 3D image of dendrites; (ii) the dendrite tracing and registration section traces dendritic arbors in 3D and registers dendritic traces to the reference column array; (iii) the dendritic analysis section analyzes dendritic patterns with respect to columns and layers, including layer-specific termination and planar projection direction of dendritic arbors, and derives estimates of dendritic branching and termination frequencies. The protocols utilize custom plugins built on the open-source MIPAV (Medical Imaging Processing, Analysis, and Visualization) platform and custom toolboxes in the matrix laboratory language. Together, these protocols provide a complete workflow to analyze the dendritic routing of Drosophila medulla neurons in layers and columns, to identify cell types, and to determine defects in mutants. PMID- 28362391 TI - Absolute Quantification of Abeta1-42 in CSF Using a Mass Spectrometric Reference Measurement Procedure. AB - Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly and accounts for 60-80% of all cases of dementia. Currently, the diagnosis of AD is based on cognitive tests and mental state exams, but the peptide amyloid-beta (Abeta) in cerebrospinal fluid (CSF) is increasingly used in clinical trials and settings. As for most protein and peptide biomarkers, quantification is performed using antibody-based techniques, such as enzyme linked immunosorbent assay (ELISA). However, intra- and inter-laboratory variability in these assays hamper its use as a diagnostic marker in clinical routine. An antibody-independent Reference Measurement Procedure (RMP) was developed based on solid-phase extraction (SPE) and liquid chromatography (LC) tandem mass spectrometry (MS/MS), where stable, isotope-labeled Abeta peptides were used as internal standards, enabling absolute quantification. A high resolution quadrupole-orbitrap hybrid instrument was used for the measurements. The method allows for the quantification of CSF Abeta1-42 between 150-4,000 pg/mL. PMID- 28362390 TI - Blue-hazard-free Candlelight OLED. AB - A candlelight-style organic light emitting diode (OLED) is a human-friendly type of lighting because it is blue-hazard-free and has a low correlated color temperature (CCT) illumination. The low CCT lighting is deprived of high-energy blue radiation, and it can be used for a longer duration before causing retinal damage. This work presents the comprehensive protocols for the fabrication of blue-hazard-free candlelight OLEDs. The emission spectrum of the OLED was characterized by the maximum exposure time limit of the retina and the melatonin suppression sensitivity. The devices can be fabricated using dry and wet processes. The dry-processed OLED resulted in a CCT of 1,940 K and exhibited a maximum retinal exposure limit of 1,287 s at a brightness of 500 lx. It showed 2.61% melatonin suppression sensitivity relative to 480 nm blue light. The wet processed OLED, where the spin coating is used to deposit hole injection, hole transport, and emissive layers, making fabrication fast and economical, produced a CCT of 1,922 K and showed a maximum retinal exposure limit of 7,092 at a brightness of 500 lx. The achieved relative melatonin suppression sensitivity of 1.05% is 86% and 96% less than that of the light emitting diode (LED) and compact fluorescent lamp (CFL), respectively. Wet-processed blue-hazard-free candlelight OLED exhibited a power efficiency of 30 lm/W, which is 2 times that of the incandescent bulb and 300 times that of the candle. PMID- 28362392 TI - Fabrication of Nanopillar-Based Split Ring Resonators for Displacement Current Mediated Resonances in Terahertz Metamaterials. AB - Terahertz (THz) split ring resonator (SRR) metamaterials (MMs) has been studied for gas, chemical, and biomolecular sensing applications because the SRR is not affected by environmental characteristics such as the temperature and pressure surrounding the resonator. Electromagnetic radiation in THz frequencies is biocompatible, which is a critical condition especially for the application of the biomolecular sensing. However, the quality factor (Q-factor) and frequency responses of traditional thin-film based split ring resonator (SRR) MMs are very low, which limits their sensitivities and selectivity as sensors. In this work, novel nanopillar-based SRR MMs, utilizing displacement current, are designed to enhance the Q-factor up to 450, which is around 45 times higher than that of traditional thin-film-based MMs. In addition to the enhanced Q-factor, the nanopillar-based MMs induce a larger frequency shifts (17 times compared to the shift obtained by the traditional thin-film based MMs). Because of the significantly enhanced Q-factors and frequency shifts as well as the property of biocompatible radiation, the THz nanopillar-based SRR are ideal MMs for the development of biomolecular sensors with high sensitivity and selectivity without inducing damage or distortion to biomaterials. A novel fabrication process has been demonstrated to build the nanopillar-based SRRs for displacement current mediated THz MMs. A two-step gold (Au) electroplating process and an atomic layer deposition (ALD) process are used to create sub-10 nm scale gaps between Au nanopillars. Since the ALD process is a conformal coating process, a uniform aluminum oxide (Al2O3) layer with nanometer-scale thickness can be achieved. By sequentially electroplating another Au thin film to fill the spaces between Al2O3 and Au, a close-packed Au-Al2O3-Au structure with nano-scale Al2O3 gaps can be fabricated. The size of the nano-gaps can be well defined by precisely controlling the deposition cycles of the ALD process, which has an accuracy of 0.1 nm. PMID- 28362394 TI - Techniques of Sleeve Gastrectomy and Modified Roux-en-Y Gastric Bypass in Mice. AB - Obesity is a major public health issue, with a prevalence of 4 to 28% for men and 6.2 to 36.5% for women in Europe (from 2003 to 2008). Morbid obesity is frequently associated with metabolic complications, such as type 2 diabetes, hypertension, and dyslipidemia, reducing life expectancy and quality. In the absence of any effective noninvasive treatments, bariatric surgery is a valuable therapeutic option for patients with morbid obesity (body mass index (BMI) >40 kg/m2), leading to long-term, sustained weight loss and improvements in metabolic complications. However, the underlying cellular and molecular mechanisms sustaining the beneficial effects of bariatric surgery are not yet fully understood. Due to the numerous genetically-modified strains available, the mouse model is the most convenient animal model to explore the molecular mechanisms behind the pleiotropic beneficial effects of bariatric surgeries. Here, we detailed the optimized healthcare methods and surgical protocols in mice for the two most widely-used bariatric surgeries: the sleeve gastrectomy and the modified Roux-en-Y gastric bypass. Deciphering the molecular mechanisms underlying the therapeutic effects of bariatric surgeries offers the promise of identifying new therapeutics targets. PMID- 28362393 TI - Two Techniques to Create Hypoparathyroid Mice: Parathyroidectomy Using GFP Glands and Diphtheria-Toxin-Mediated Parathyroid Ablation. AB - Hypoparathyroidism (HP) is a disorder characterized by low levels of PTH which lead to hypocalcemia, hyperphosphatemia, and low bone turnover. The most common cause of the disease is accidental removal of the parathyroid glands during thyroid surgery. Novel therapies for HP are needed, but testing them requires reliable animal models of acquired HP. Here, we demonstrate the generation of two mouse models of acquired HP. In the GFP-PTX model, mice with green fluorescent protein (GFP) expressed specifically in the parathyroids (PTHcre-mTmG) were created by crossing PTHcre+ mice with Rosa-mTmGfl/fl mice. Green fluorescing parathyroid glands are easily identified under a fluorescence dissecting microscope and parathyroidectomy is performed in less than 20 min. After fluorescence-guided surgery, mice are profoundly hypocalcemic. Contrary to the traditional thyro-parathyroidectomy, this precise surgical approach leaves thyroid glands and thyroid function intact. The second model, which does not require surgery, is based on a diphtheria-toxin approach. PTHcre-iDTR mice, which express the diphtheria toxin (DT) receptor specifically in the parathyroids, were generated by crossing the inducible DTR mouse with the PTHcre mouse. Parathyroid cells are thus rendered sensitive to diphtheria toxin (DT) and can be selectively destroyed by systemically injecting mice with DT. The resulting hypocalcemic phenotype is stable. PMID- 28362395 TI - A Novel Technique for Generating and Observing Chemiluminescence in a Biological Setting. AB - Intraoperative imaging techniques have the potential to make surgical interventions safer and more effective; for these reasons, such techniques are quickly moving into the operating room. Here, we present a new approach that utilizes a technique not yet explored for intraoperative imaging: chemiluminescent imaging. This method employs a ruthenium-based chemiluminescent reporter along with a custom-built nebulizing system to produce ex vivo or in vivo images with high signal-to-noise ratios. The ruthenium-based reporter produces light following exposure to an aqueous oxidizing solution and re reduction within the surrounding tissue. This method has allowed us to detect reporter concentrations as low as 6.9 pmol/cm2. In this work, we present a visual guide to our proof-of-concept in vivo studies involving subdermal and intravenous injections in mice. The results suggest that this technology is a promising candidate for further preclinical research and might ultimately become a useful tool in the operating room. PMID- 28362396 TI - Fabrication of Three-dimensional Paper-based Microfluidic Devices for Immunoassays. AB - Paper wicks fluids autonomously due to capillary action. By patterning paper with hydrophobic barriers, the transport of fluids can be controlled and directed within a layer of paper. Moreover, stacking multiple layers of patterned paper creates sophisticated three-dimensional microfluidic networks that can support the development of analytical and bioanalytical assays. Paper-based microfluidic devices are inexpensive, portable, easy to use, and require no external equipment to operate. As a result, they hold great promise as a platform for point-of-care diagnostics. In order to properly evaluate the utility and analytical performance of paper-based devices, suitable methods must be developed to ensure their manufacture is reproducible and at a scale that is appropriate for laboratory settings. In this manuscript, a method to fabricate a general device architecture that can be used for paper-based immunoassays is described. We use a form of additive manufacturing (multi-layer lamination) to prepare devices that comprise multiple layers of patterned paper and patterned adhesive. In addition to demonstrating the proper use of these three-dimensional paper-based microfluidic devices with an immunoassay for human chorionic gonadotropin (hCG), errors in the manufacturing process that may result in device failures are discussed. We expect this approach to manufacturing paper-based devices will find broad utility in the development of analytical applications designed specifically for limited-resource settings. PMID- 28362397 TI - Analyzing Cell Surface Adhesion Remodeling in Response to Mechanical Tension Using Magnetic Beads. AB - Mechanosensitive cell surface adhesion complexes allow cells to sense the mechanical properties of their surroundings. Recent studies have identified both force-sensing molecules at adhesion sites, and force-dependent transcription factors that regulate lineage-specific gene expression and drive phenotypic outputs. However, the signaling networks converting mechanical tension into biochemical pathways have remained elusive. To explore the signaling pathways engaged upon mechanical tension applied to cell surface receptor, superparamagnetic microbeads can be used. Here we present a protocol for using magnetic beads to apply forces to cell surface adhesion proteins. Using this approach, it is possible to investigate not only force-dependent cytoplasmic signaling pathways by various biochemical approaches, but also adhesion remodeling by magnetic isolation of adhesion complexes attached to the ligand coated beads. This protocol includes the preparation of ligand-coated superparamagnetic beads, and the application of define tensile forces followed by biochemical analyses. Additionally, we provide a representative sample of data demonstrating that tension applied to integrin-based adhesion triggers adhesion remodeling and alters protein tyrosine phosphorylation. PMID- 28362398 TI - Automatic Detection of Highly Organized Theta Oscillations in the Murine EEG. AB - Theta activity is generated in the septohippocampal system and can be recorded using deep intrahippocampal electrodes and implantable electroencephalography (EEG) radiotelemetry or tether system approaches. Pharmacologically, hippocampal theta is heterogeneous (see dualistic theory) and can be differentiated into type I and type II theta. These individual EEG subtypes are related to specific cognitive and behavioral states, such as arousal, exploration, learning and memory, higher integrative functions, etc. In neurodegenerative diseases such as Alzheimer's, structural and functional alterations of the septohippocampal system can result in impaired theta activity/oscillations. A standard quantitative analysis of the hippocampal EEG includes a Fast-Fourier-Transformation (FFT) based frequency analysis. However, this procedure does not provide details about theta activity in general and highly-organized theta oscillations in particular. In order to obtain detailed information on highly-organized theta oscillations in the hippocampus, we have developed a new analytical approach. This approach allows for time- and cost-effective quantification of the duration of highly organized theta oscillations and their frequency characteristics. PMID- 28362399 TI - Methods to Study Epithelial Transport Protein Function and Expression in Native Intestine and Caco-2 Cells Grown in 3D. AB - The intestinal epithelium has important transport and barrier functions that play key roles in normal physiological functions of the body while providing a barrier to foreign particles. Impaired epithelial transport (ion, nutrient, or drugs) has been associated with many diseases and can have consequences that extend beyond the normal physiological functions of the transporters, such as by influencing epithelial integrity and the gut microbiome. Understanding the function and regulation of transport proteins is critical for the development of improved therapeutic interventions. The biggest challenge in the study of epithelial transport is developing a suitable model system that recapitulates important features of the native intestinal epithelial cells. Several in vitro cell culture models, such as Caco-2, T-84, and HT-29-Cl.19A cells are typically used in epithelial transport research. These cell lines represent a reductionist approach to modeling the epithelium and have been used in many mechanistic studies, including their examination of epithelial-microbial interactions. However, cell monolayers do not accurately reflect cell-cell interactions and the in vivo microenvironment. Cells grown in 3D have shown to be promising models for drug permeability studies. We show that Caco-2 cells in 3D can be used to study epithelial transporters. It is also important that studies in Caco-2 cells are complemented with other models to rule out cell specific effects and to take into account the complexity of the native intestine. Several methods have been previously used to assess the functionality of transporters, such as everted sac and uptake in isolated epithelial cells or in isolated plasma membrane vesicles. Taking into consideration the challenges in the field with respect to models and the measurement of transport function, we demonstrate here a protocol to grow Caco-2 cells in 3D and describe the use of an Ussing chamber as an effective approach to measure serotonin transport, such as in intact polarized intestinal epithelia. PMID- 28362400 TI - Minimally Invasive Transverse Aortic Constriction in Mice. AB - Minimally invasive transverse aortic constriction (MTAC) is a more desirable method for the constriction of the transverse aorta in mice than standard open chest transverse aortic constriction (TAC). Although transverse aortic constriction is a highly functional method for the induction of high pressure in the left ventricle, it is a more difficult and lengthy procedure due to its use of artificial ventilation with tracheal intubation. TAC is oftentimes also less survivable, as the newer method, MTAC, neither requires the cutting of the ribs and intercostal muscles nor tracheal intubation with a ventilation setup. In MTAC, as opposed to a thoracotomy to access to the chest cavity, the aortic arch is reached through a midline incision in the anterior neck. The thyroid is pulled back to reveal the sternal notch. The sternum is subsequently cut down to the second rib level, and the aortic arch is reached simply by separating the connective tissues and thymus. From there, a suture can be wrapped around the arch and tied with a spacer, and then the sternal cut and skin can be closed. MTAC is a much faster and less invasive way to induce left ventricular hypertension and enables the possibility for high-throughput studies. The success of the constriction can be verified using high-frequency trans-thoracic echocardiography, particularly color Doppler and pulsed-wave Doppler, to determine the flow velocities of the aortic arch and left and right carotid arteries, the dimension of the blood vessels, and the left ventricular function and morphology. A successful constriction will also trigger significant histopathological changes, such as cardiac muscle cell hypertrophy with interstitial and perivascular fibrosis. Here, the procedure of MTAC is described, demonstrating how the resulting flow changes in the carotid arteries can be examined with echocardiography, gross morphology, and histopathological changes in the heart. PMID- 28362401 TI - Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis. AB - Establishing a system of procedures to qualitatively and quantitatively characterize in vivo and in vitro hepatic steatosis is important for metabolic study in the liver. Here, numerous assays are described to comprehensively measure the phenotype and parameters of hepatic steatosis in mouse and hepatocyte models. Combining the physiological, histological, and biochemical methods, this system can be used to assess the progress of hepatic steatosis. In vivo, the measurements of body weight and nuclear magnetic resonance (NMR) provide a general understanding of mice in a non-invasive manner. Hematoxylin and Eosin (H&E) and Oil Red O staining determine the histological morphology and lipid deposition of liver tissue under nutrient overload conditions, such as high-fat diet feeding. Next, the total lipid contents are isolated by chloroform/methanol extraction, which are followed by a biochemical analysis for triglyceride and cholesterol. Moreover, mouse primary hepatocytes are treated with high glucose plus insulin to stimulate lipid accumulation, an efficient in vitro model to mimic diet-induced hyperglycemia and hyperinsulinemia in vivo. Then, the lipid deposition is measured by Oil Red O staining and chloroform/methanol extraction. Oil Red O staining determines intuitive hepatic steatotic phenotypes, while the lipid extraction analysis determines the parameters that can be analyzed statistically. The present protocols are of interest to scientists in the fields of fatty liver diseases, insulin resistance, and type 2 diabetes. PMID- 28362402 TI - Evaporation-reducing Culture Condition Increases the Reproducibility of Multicellular Spheroid Formation in Microtiter Plates. AB - Tumor models that closely imitate in vivo conditions are becoming increasingly popular in drug discovery and development for the screening of potential anti cancer drugs. Multicellular tumor spheroids (MCTSes) effectively mimic the physiological conditions of solid tumors, making them excellent in vitro models for lead optimization and target validation. Out of the various techniques available for MCTS culture, the liquid-overlay method on agarose is one of the most inexpensive methods for MCTS generation. However, the reliable transfer of MCTS cultures using liquid-overlay for high-throughput screening may be compromised by a number of limitations, including the coating of microtiter plates (MPs) with agarose and the irreproducibility of uniform MCTS formation across wells. MPs are significantly prone to edge effects that result from excessive evaporation of medium from the exterior of the plate, preventing the use of the entire plate for drug tests. This manuscript provides detailed technical improvements to the liquid-overlay technique to increase the scalability and reproducibility of uniform MCTS formation. Additionally, details on a simple, semi-automatic, and universally applicable software tool for the evaluation of MCTS features after drug treatment is presented. PMID- 28362403 TI - 3D Printing of Biomolecular Models for Research and Pedagogy. AB - The construction of physical three-dimensional (3D) models of biomolecules can uniquely contribute to the study of the structure-function relationship. 3D structures are most often perceived using the two-dimensional and exclusively visual medium of the computer screen. Converting digital 3D molecular data into real objects enables information to be perceived through an expanded range of human senses, including direct stereoscopic vision, touch, and interaction. Such tangible models facilitate new insights, enable hypothesis testing, and serve as psychological or sensory anchors for conceptual information about the functions of biomolecules. Recent advances in consumer 3D printing technology enable, for the first time, the cost-effective fabrication of high-quality and scientifically accurate models of biomolecules in a variety of molecular representations. However, the optimization of the virtual model and its printing parameters is difficult and time consuming without detailed guidance. Here, we provide a guide on the digital design and physical fabrication of biomolecule models for research and pedagogy using open source or low-cost software and low-cost 3D printers that use fused filament fabrication technology. PMID- 28362404 TI - A Customizable Chamber for Measuring Cell Migration. AB - Cell migration is a vital part of immune responses, growth, and wound healing. Cell migration is a complex process that involves interactions between cells, the extracellular matrix, and soluble and non-soluble chemical factors (e.g., chemoattractants). Standard methods for measuring the migration of cells, such as the Boyden chamber assay, work by counting cells on either side of a divider. These techniques are easy to use; however, they offer little geometric modification for different applications. In contrast, microfluidic devices can be used to observe cell migration with customizable concentration gradients of soluble factors1,2. However, methods for making microfluidics based assays can be difficult to learn. Here, we describe an easy method for creating cell culture chambers to measure cell migration in response to chemical concentration gradients. Our cell migration chamber method can create different linear concentration gradients in order to study cell migration for a variety of applications. This method is relatively easy to use and is typically performed by undergraduate students. The microchannel chamber was created by placing an acrylic insert in the shape of the final microchannel chamber well into a Petri dish. After this, poly(dimethylsiloxane) (PDMS) was poured on top of the insert. The PDMS was allowed to harden and then the insert was removed. This allowed for the creation of wells in any desired shape or size. Cells may be subsequently added to the microchannel chamber, and soluble agents can be added to one of the wells by soaking an agarose block in the desired agent. The agarose block is added to one of the wells, and time-lapse images can be taken of the microchannel chamber in order to quantify cell migration. Variations to this method can be made for a given application, making this method highly customizable. PMID- 28362405 TI - Local Field Fluorescence Microscopy: Imaging Cellular Signals in Intact Hearts. AB - In the heart, molecular signaling studies are usually performed in isolated myocytes. However, many pathological situations such as ischemia and arrhythmias can only be fully understood at the whole organ level. Here, we present the spectroscopic technique of local field fluorescence microscopy (LFFM) that allows the measurement of cellular signals in the intact heart. The technique is based on a combination of a Langendorff perfused heart and optical fibers to record fluorescent signals. LFFM has various applications in the field of cardiovascular physiology to study the heart under normal and pathological conditions. Multiple cardiac variables can be monitored using different fluorescent indicators. These include cytosolic [Ca2+], intra-sarcoplasmic reticulum [Ca2+] and membrane potentials. The exogenous fluorescent probes are excited and the emitted fluorescence detected with three different arrangements of LFFM epifluorescence techniques presented in this paper. The central differences among these techniques are the type of light source used for excitation and on the way the excitation light is modulated. The pulsed LFFM (PLFFM) uses laser light pulses while continuous wave LFFM (CLFFM) uses continuous laser light for excitation. Finally, light-emitting diodes (LEDs) were used as a third light source. This non coherent arrangement is called pulsed LED fluorescence microscopy (PLEDFM). PMID- 28362407 TI - A High-throughput Compatible Assay to Evaluate Drug Efficacy against Macrophage Passaged Mycobacterium tuberculosis. AB - The early drug development process for anti-tuberculosis drugs is hindered by the inefficient translation of compounds with in vitro activity to effectiveness in the clinical setting. This is likely due to a lack of consideration for the physiologically relevant cellular penetration barriers that exist in the infected host. We recently established an alternative infection model that generates large macrophage aggregate structures containing densely packed M. tuberculosis (Mtb) at its core, which was suitable for drug susceptibility testing. This infection model is inexpensive, rapid, and most importantly BSL-2 compatible. Here, we describe the experimental procedures to generate Mtb/macrophage aggregate structures that would produce macrophage-passaged Mtb for drug susceptibility testing. In particular, we demonstrate how this infection system could be directly adapted to the 96-well plate format showing throughput capability for the screening of compound libraries against Mtb. Overall, this assay is a valuable addition to the currently available Mtb drug discovery toolbox due to its simplicity, cost effectiveness, and scalability. PMID- 28362406 TI - Efficient Differentiation of Pluripotent Stem Cells to NKX6-1+ Pancreatic Progenitors. AB - Pluripotent stem cells have the ability to self renew and differentiate to multiple lineages, making them an attractive source for the generation of pancreatic progenitor cells that can be used for the study of and future treatment of diabetes. This article outlines a four-stage differentiation protocol designed to generate pancreatic progenitor cells from human embryonic stem cells (hESCs). This protocol can be applied to a number of human pluripotent stem cell (hPSC) lines. The approach taken to generate pancreatic progenitor cells is to differentiate hESCs to accurately model key stages of pancreatic development. This begins with the induction of the definitive endoderm, which is achieved by culturing the cells in the presence of Activin A, basic Fibroblast Growth Factor (bFGF) and CHIR990210. Further differentiation and patterning with Fibroblast Growth Factor 10 (FGF10) and Dorsomorphin generates cells resembling the posterior foregut. The addition of Retinoic Acid, NOGGIN, SANT-1 and FGF10 differentiates posterior foregut cells into cells characteristic of pancreatic endoderm. Finally, the combination of Epidermal Growth Factor (EGF), Nicotinamide and NOGGIN leads to the efficient generation of PDX1+/NKX6-1+ cells. Flow cytometry is performed to confirm the expression of specific markers at key stages of pancreatic development. The PDX1+/NKX6-1+ pancreatic progenitors at the end of stage 4 are capable of generating mature beta cells upon transplantation into immunodeficient mice and can be further differentiated to generate insulin producing cells in vitro. Thus, the efficient generation of PDX1+/NKX6-1+ pancreatic progenitors, as demonstrated in this protocol, is of great importance as it provides a platform to study human pancreatic development in vitro and provides a source of cells with the potential of differentiating to beta cells that could eventually be used for the treatment of diabetes. PMID- 28362408 TI - In Vitro Imaging and Quantification of the Drug Targeting Efficiency of Fluorescently Labeled GnRH Analogues. AB - GnRH analogues are effective targeting moieties and able to deliver anticancer agents selectively into malignant tumor cells which highly express GnRH receptors. However, the quantitative analysis of GnRH analogues' cellular uptake and the investigated cell types in GnRH-based drug delivery systems are currently limited. Previously introduced, selectively labeled fluorescent GnRH I, -II and III derivatives provide great detectability, and they have suitable chemical properties for reproducible and robust experiments. We also found that the appropriate up-to-date methods with these labeled GnRH analogues could offer novel information about the GnRH-based drug delivery systems. This manuscript introduces some simple and fast experiments regarding the cellular uptake of [D Lys6(FITC)]-GnRH-I, [D-Lys6(FITC)]-GnRH-II and [Lys8(FITC)]-GnRH-III on the EBC-1 (lung), the BxPC-3 (pancreas) and on the Detroit-562- (pharynx) malignant tumor cells. In parallel with these GnRH-FITC conjugates, the cell surface level of GnRH-I receptors was also examined on these cell lines before and after the GnRH treatment by confocal laser scanning microscopy. The cellular uptake of GnRH-FITC conjugates was quantified by fluorescence-activated cell sorting. In these experiments minor differences among GnRH analogues and major differences among cell types was observed. The significant differences among cell lines are correlated with their distinct level of cell surface GnRH-I receptors. The introduced experiments contain practical methods to visualize, quantify and compare the uptake efficiency of GnRH-FITC conjugates in a time- and concentration-dependent manner on various adherent cell cultures. These results could predict the drug targeting efficiency of GnRH conjugates on the given cell culture, and offer a good basis for further experiments in the examination of GnRH-based drug delivery systems. PMID- 28362410 TI - Evaluation of Drug Sorption to PVC- and Non-PVC-based Tubes in Administration Sets Using a Pump. AB - Administration sets are delivery tools for the direct application of drugs into the body and are composed of a spike, a drip chamber, tubes, Luer adapters (connectors), a needle cover for protection, and other accessories. Drug sorption to tubes of administration sets is a critical issue in terms of safety and efficacy. Although drug sorption is an important factor in the quality of an administration set, there are no standard evaluation methods for the regulation of drug sorption to the tubes. Here, we describe an evaluation protocol for drug sorption to tubes of administration sets. Tubes made of polyvinyl chloride (PVC)- and non-PVC-based polymeric materials were cut to 1 m in length. Diazepam and tacrolimus were used as model drugs. In the kinetic sorption study, we selected the drug concentration and flow rate based on the clinical usage of these drugs. After the dilution of each drug in a glass bottle, the diluted drug solution was delivered through tubes of administration sets using a pump. Samples were collected in amber vials at appropriate time points and the drugs were analyzed using high-performance liquid chromatography. Drug concentrations and sorption levels to tubes of the administration sets were calculated. Acceptable criteria to ensure the quality of administration sets are recommended. PMID- 28362409 TI - Intraductal Delivery to the Rabbit Mammary Gland. AB - Localized intraductal treatments for breast cancer offer potential advantages, including efficient delivery to the tumor and reduced systemic toxicity and adverse effects1,2,3,4,5,6,7. However, several challenges remain before these treatments can be applied more widely. The development and validation of intraductal therapeutics in an appropriate animal model facilitate the development of intraductal therapeutic strategies for patients. While the mouse mammary gland has been widely used as a model system of mammary development and tumorigenesis, the anatomy is distinct from the human gland. A larger animal model, such as the rabbit, may serve as a better model for mammary gland structure and intraductal therapeutic development. In contrast to mice, in which ten ductal trees are spatially distributed along the body axis, each terminating in a separate teat, the rabbit mammary gland more closely resembles the human gland, with multiple overlapping ductal systems that exit through separate openings in one teat. Here, we present minimally invasive methods for the delivery of reagents directly into the rabbit mammary duct and for visualization of the delivery itself with high-resolution ultrasound imaging. PMID- 28362411 TI - Continuous Manual Exchange Transfusion for Patients with Sickle Cell Disease: An Efficient Method to Avoid Iron Overload. AB - Children with sickle cell anemia (SCA) may be at risk of cerebral vasculopathy and strokes, which can be prevented by chronic transfusion programs. Repeated transfusions of packed red blood cells (PRBCs) is currently the simplest and most used technique for chronic transfusion programs. However, iron overload is one of the major side effects of this therapy. More developed methods exist, notably the apheresis of RBC (erythrapheresis), which is currently the safest and most efficient method. However, it is costly, complicated, and cannot be implemented everywhere, nor is it suitable for all patients. Manual exchange transfusions combine one or more manual phlebotomies with a PRBC transfusion. At the Reference Center of Sickle Cell Disease, we set up a continuous method of manual exchange transfusion that is feasible for all hospital settings, demands no specific equipment, and is widely applicable. In terms of HbS decrease, stroke prevention, and iron overload prevention, this method showed comparable efficiency to erythrapheresis. In cases where erythrapheresis is not available, this method can be a good alternative for patients and care centers. PMID- 28362412 TI - Conditional Reprogramming of Pediatric Human Esophageal Epithelial Cells for Use in Tissue Engineering and Disease Investigation. AB - Identifying and expanding patient-specific cells in culture for use in tissue engineering and disease investigation can be very challenging. Utilizing various types of stem cells to derive cell types of interest is often costly, time consuming and highly inefficient. Furthermore, undesired cell types must be removed prior to using this cell source, which requires another step in the process. In order to obtain enough esophageal epithelial cells to engineer the lumen of an esophageal construct or to screen therapeutic approaches for treating esophageal disease, native esophageal epithelial cells must be expanded without altering their gene expression or phenotype. Conditional reprogramming of esophageal epithelial tissue offers a promising approach to expanding patient specific esophageal epithelial cells. Furthermore, these cells do not need to be sorted or purified and will return to a mature epithelial state after removing them from conditional reprogramming culture. This technique has been described in many cancer screening studies and allows for indefinite expansion of these cells over multiple passages. The ability to perform esophageal screening assays would help revolutionize the treatment of pediatric esophageal diseases like eosinophilic esophagitis by identifying the trigger mechanism causing the patient's symptoms. For those patients who suffer from congenital defect, disease or injury of the esophagus, this cell source could be used as a means to seed a synthetic construct for implantation to repair or replace the affected region. PMID- 28362413 TI - Assessing Cardiomyocyte Subtypes Following Transcription Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts. AB - Direct reprogramming of one cell type into another has recently emerged as a powerful paradigm for regenerative medicine, disease modeling, and lineage specification. In particular, the conversion of fibroblasts into induced cardiomyocyte-like myocytes (iCLMs) by Gata4, Hand2, Mef2c, and Tbx5 (GHMT) represents an important avenue for generating de novo cardiac myocytes in vitro and in vivo. Recent evidence suggests that GHMT generates a greater diversity of cardiac subtypes than previously appreciated, thus underscoring the need for a systematic approach to conducting additional studies. Before direct reprogramming can be used as a therapeutic strategy, however, the mechanistic underpinnings of lineage conversion must be understood in detail to generate specific cardiac subtypes. Here we present a detailed protocol for generating iCLMs by GHMT mediated reprogramming of mouse embryonic fibroblasts (MEFs). We outline methods for MEF isolation, retroviral production, and MEF infection to accomplish efficient reprogramming. To determine the subtype identity of reprogrammed cells, we detail a step-by-step approach for performing immunocytochemistry on iCLMs using a defined set of compatible antibodies. Methods for confocal microscopy, identification, and quantification of iCLMs and individual atrial (iAM), ventricular (iVM), and pacemaker (iPM) subtypes are also presented. Finally, we discuss representative results of prototypical direct reprogramming experiments and highlight important technical aspects of our protocol to ensure efficient lineage conversion. Taken together, our optimized protocol should provide a stepwise approach for investigators to conduct meaningful cardiac reprogramming experiments that require identification of individual CM subtypes. PMID- 28362414 TI - Preparation and Observation of Thick Biological Samples by Scanning Transmission Electron Tomography. AB - This report describes a protocol for preparing thick biological specimens for further observation using a scanning transmission electron microscope. It also describes an imaging method for studying the 3D structure of thick biological specimens by scanning transmission electron tomography. The sample preparation protocol is based on conventional methods in which the sample is fixed using chemical agents, treated with a heavy atom salt contrasting agent, dehydrated in a series of ethanol baths, and embedded in resin. The specific imaging conditions for observing thick samples by scanning transmission electron microscopy are then described. Sections of the sample are observed using a through-focus method involving the collection of several images at various focal planes. This enables the recovery of in-focus information at various heights throughout the sample. This particular collection pattern is performed at each tilt angle during tomography data collection. A single image is then generated, merging the in focus information from all the different focal planes. A classic tilt-series dataset is then generated. The advantage of the method is that the tilt-series alignment and reconstruction can be performed using standard tools. The collection of through-focal images allows the reconstruction of a 3D volume that contains all of the structural details of the sample in focus. PMID- 28362415 TI - Physiological Preparation of Hair Cells from the Sacculus of the American Bullfrog (Rana catesbeiana). AB - The study of hearing and balance rests upon insights drawn from biophysical studies of model systems. One such model, the sacculus of the American bullfrog, has become a mainstay of auditory and vestibular research. Studies of this organ have revealed how sensory cells hair can actively detect signals from the environment. Because of these studies, we now better understand the mechanical gating and localization of a hair cell's transduction channels, calcium's role in mechanical adaptation, and the identity of hair cell currents. This highly accessible organ continues to provide insight into the workings of hair cells. Here we describe the preparation of the bullfrog's sacculus for biophysical studies on its hair cells. We include the complete dissection procedure and provide specific protocols for the preparation of the sacculus in specific contexts. We additionally include representative results using this preparation, including the calculation of a hair bundle's instantaneous force-displacement relation and measurement of a bundle's spontaneous oscillation. PMID- 28362416 TI - A Straightforward Method for Glucosinolate Extraction and Analysis with High pressure Liquid Chromatography (HPLC). AB - Glucosinolates are a well-studied and highly diverse class of natural plant compounds. They play important roles in plant resistance, rapeseed oil quality, food flavoring, and human health. The biological activity of glucosinolates is released upon tissue damage, when they are mixed with the enzyme myrosinase. This results in the formation of pungent and toxic breakdown products, such as isothiocyanates and nitriles. Currently, more than 130 structurally different glucosinolates have been identified. The chemical structure of the glucosinolate is an important determinant of the product that is formed, which in turn determines its biological activity. The latter may range from detrimental (e.g., progoitrin) to beneficial (e.g., glucoraphanin). Each glucosinolate-containing plant species has its own specific glucosinolate profile. For this reason, it is important to correctly identify and reliably quantify the different glucosinolates present in brassicaceous leaf, seed, and root crops or, for ecological studies, in their wild relatives. Here, we present a well-validated, targeted, and robust method to analyze glucosinolate profiles in a wide range of plant species and plant organs. Intact glucosinolates are extracted from ground plant materials with a methanol-water mixture at high temperatures to disable myrosinase activity. Thereafter, the resulting extract is brought onto an ion exchange column for purification. After sulfatase treatment, the desulfoglucosinolates are eluted with water and the eluate is freeze-dried. The residue is taken up in an exact volume of water, which is analyzed by high pressure liquid chromatography (HPLC) with a photodiode array (PDA) or ultraviolet (UV) detector. Detection and quantification are achieved by conducting comparisons of the retention times and UV spectra of commercial reference standards. The concentrations are calculated based on a sinigrin reference curve and well-established response factors. The advantages and disadvantages of this straightforward method, when compared to faster and more technologically advanced methods, are discussed here. PMID- 28362418 TI - Utilizing pHluorin-tagged Receptors to Monitor Subcellular Localization and Trafficking. AB - Understanding membrane protein trafficking, assembly, and expression requires an approach that differentiates between those residing in intracellular organelles and those localized on the plasma membrane. Traditional fluorescence-based measurements lack the capability to distinguish membrane proteins residing in different organelles. Cutting edge methodologies transcend traditional methods by coupling pH-sensitive fluorophores with total internal reflection fluorescence microscopy (TIRFM). TIRF illumination excites the sample up to approximately 150 nm from the glass-sample interface, thus decreasing background, increasing the signal to noise ratio, and enhancing resolution. The excitation volume in TIRFM encompasses the plasma membrane and nearby organelles such as the peripheral ER. Superecliptic pHluorin (SEP) is a pH sensitive version of GFP. Genetically encoding SEP into the extracellular domain of a membrane protein of interest positions the fluorophore on the luminal side of the ER and in the extracellular region of the cell. SEP is fluorescent when the pH is greater than 6, but remains in an off state at lower pH values. Therefore, receptors tagged with SEP fluoresce when residing in the endoplasmic reticulum (ER) or upon insertion in the plasma membrane (PM) but not when confined to a trafficking vesicle or other organelles such as the Golgi. The extracellular pH can be adjusted to dictate the fluorescence of receptors on the plasma membrane. The difference in fluorescence between TIRF images at neutral and acidic extracellular pH for the same cell corresponds to a relative number of receptors on the plasma membrane. This allows a simultaneous measurement of intracellular and plasma membrane resident receptors. Single vesicle insertion events can also be measured when the extracellular pH is neutral, corresponding to a low pH trafficking vesicle fusing with the plasma membrane and transitioning into a fluorescent state. This versatile technique can be exploited to study localization, expression, and trafficking of membrane proteins. PMID- 28362417 TI - Application of Genetically Encoded Fluorescent Nitric Oxide (NO*) Probes, the geNOps, for Real-time Imaging of NO* Signals in Single Cells. AB - Nitric Oxide (NO*) is a small radical, which mediates multiple important cellular functions in mammals, bacteria and plants. Despite the existence of a large number of methods for detecting NO* in vivo and in vitro, the real-time monitoring of NO* at the single-cell level is very challenging. The physiological or pathological effects of NO* are determined by the actual concentration and dwell time of this radical. Accordingly, methods that allow the single-cell detection of NO* are highly desirable. Recently, we expanded the pallet of NO* indicators by introducing single fluorescent protein-based genetically encoded nitric oxide (NO*) probes (geNOps) that directly respond to cellular NO* fluctuations and, hence, addresses this need. Here we demonstrate the usage of geNOps to assess intracellular NO* signals in response to two different chemical NO*-liberating molecules. Our results also confirm that freshly prepared 3-(2 hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-propanamine (NOC-7) has a much higher potential to evoke change in intracellular NO* levels as compared with the inorganic NO* donor sodium nitroprusside (SNP). Furthermore, dual-color live-cell imaging using the green geNOps (G-geNOp) and the chemical Ca2+ indicator fura-2 was performed to visualize the tight regulation of Ca2+-dependent NO* formation in single endothelial cells. These representative experiments demonstrate that geNOps are suitable tools to investigate the real-time generation and degradation of single-cell NO* signals in diverse experimental setups. PMID- 28362420 TI - Isolation of Intact Mitochondria from Skeletal Muscle by Differential Centrifugation for High-resolution Respirometry Measurements. AB - Mitochondria are involved in cellular energy metabolism and use oxygen to produce energy in the form of adenosine triphosphate (ATP). Differential centrifugation at low- and high-speed is commonly used to isolate mitochondria from tissues and cultured cells. Crude mitochondrial fractions obtained by differential centrifugation are used for respirometry measurements. The differential centrifugation technique is based on the separation of organelles according to their size and sedimentation velocity. The isolation of mitochondria is performed immediately after tissue harvesting. The tissue is immersed in an ice-cold homogenization medium, minced using scissors and homogenized in a glass homogenizer with a loose-fitting pestle. The differential centrifugation technique is efficient, fast and inexpensive and the mitochondria obtained by differential centrifugation are pure enough for respirometry assays. Some of the limitations and disadvantages of isolated mitochondria, based on differential centrifugation, are that the mitochondria can be damaged during the homogenization and isolation procedure and that large amounts of the tissue biopsy or cultured cells are required for the mitochondrial isolation. PMID- 28362419 TI - The CApillary FEeder Assay Measures Food Intake in Drosophila melanogaster. AB - For most animals, feeding is an essential behavior for securing survival, and it influences development, locomotion, health and reproduction. Ingestion of the right type and quantity of food therefore has a major influence on quality of life. Research on feeding behavior focuses on the underlying processes that ensure actual feeding and unravels the role of factors regulating internal energy homeostasis and the neuronal bases of decision-making. The model organism Drosophila melanogaster, with its great variety of genetically traceable tools for labeling and manipulating single neurons, allows mapping of neuronal networks and identification of molecular signaling cascades involved in the regulation of food intake. This report demonstrates the CApillary FEeder assay (CAFE) and shows how to measure food intake in a group of flies for time spans ranging from hours to days. This easy-to-use assay consists of glass capillaries filled with liquid food that flies can freely access and feed on. Food consumption in the assay is accurately determined using simple measurement tools. Herein we describe step-by step the method from setup to successful execution of the CAFE assay, and provide practical examples to analyze the food intake of a group of flies under controlled conditions. The reader is guided through possible limitations of the assay, and advantages and disadvantages of the method compared to other feeding assays in D. melanogaster are evaluated. PMID- 28362421 TI - A Protocol for Rapid Post-mortem Cell Culture of Diffuse Intrinsic Pontine Glioma (DIPG). AB - Diffuse Intrinsic Pontine Glioma (DIPG) is a childhood brainstem tumor that carries a universally fatal prognosis. Because surgical resection is not a viable treatment strategy and biopsy is not routinely performed, the availability of patient samples for research is limited. Consequently, efforts to study this disease have been challenged by a paucity of faithful disease models. To address this need, we describe here a protocol for the rapid processing of post-mortem autopsy tissue samples in order to generate durable patient-derived cell culture models that can be used in in vitro assays or in vivo orthotopic xenograft experiments. These models can be used to screen for potential drug targets and to study fundamental pathobiological processes within DIPG. This protocol can further be extended to analyze and isolate tumor and microenvironmental cells using Fluorescence-activated Cell Sorting (FACS), which enables subsequent analysis of gene expression, protein expression, or epigenetic modifications of DNA at the bulk cell or single cell level. Finally, this protocol can also be adapted to generate patient-derived cultures for other central nervous system tumors. PMID- 28362422 TI - In Vivo Imaging of Transgenic Gene Expression in Individual Retinal Progenitors in Chimeric Zebrafish Embryos to Study Cell Nonautonomous Influences. AB - The genetic and technical strengths have made the zebrafish vertebrate a key model organism in which the consequences of gene manipulations can be traced in vivo throughout the rapid developmental period. Multiple processes can be studied including cell proliferation, gene expression, cell migration and morphogenesis. Importantly, the generation of chimeras through transplantations can be easily performed, allowing mosaic labeling and tracking of individual cells under the influence of the host environment. For example, by combining functional gene manipulations of the host embryo (e.g., through morpholino microinjection) and live imaging, the effects of extrinsic, cell nonautonomous signals (provided by the genetically modified environment) on individual transplanted donor cells can be assessed. Here we demonstrate how this approach is used to compare the onset of fluorescent transgene expression as a proxy for the timing of cell fate determination in different genetic host environments. In this article, we provide the protocol for microinjecting zebrafish embryos to mark donor cells and to cause gene knockdown in host embryos, a description of the transplantation technique used to generate chimeric embryos, and the protocol for preparing and running in vivo time-lapse confocal imaging of multiple embryos. In particular, performing multiposition imaging is crucial when comparing timing of events such as the onset of gene expression. This requires data collection from multiple control and experimental embryos processed simultaneously. Such an approach can easily be extended for studies of extrinsic influences in any organ or tissue of choice accessible to live imaging, provided that transplantations can be targeted easily according to established embryonic fate maps. PMID- 28362423 TI - Ice Generation and the Heat and Mass Transfer Phenomena of Introducing Water to a Cold Bath of Brine. AB - We demonstrate a method for the study of the heat and mass transfer and of the freezing phenomena in a subcooled brine environment. Our experiment showed that, under the proper conditions, ice can be produced when water is introduced to a bath of cold brine. To make ice form, in addition to having the brine and water mix, the rate of heat transfer must bypass that of mass transfer. When water is introduced in the form of tiny droplets to the brine surface, the mode of heat and mass transfer is by diffusion. The buoyancy stops water from mixing with the brine underneath, but as the ice grows thicker, it slows down the rate of heat transfer, making ice more difficult to grow as a result. When water is introduced inside the brine in the form of a flow, a number of factors are found to influence how much ice can form. Brine temperature and concentration, which are the driving forces of heat and mass transfer, respectively, can affect the water to-ice conversion ratio; lower bath temperatures and brine concentrations encourage more ice to form. The flow rheology, which can directly affect both the heat and mass transfer coefficients, is also a key factor. In addition, the flow rheology changes the area of contact of the flow with the bulk fluid. PMID- 28362424 TI - Dissection, MicroCT Scanning and Morphometric Analyses of the Baculum. AB - Modern morphometrics provides powerful methods to quantify size and shape variation. A basic requirement is a list of coordinates that define landmarks; however such coordinates must represent homologous structures across specimens. While many biological objects consist of easily identified landmarks to satisfy the assumption of homology, many lack such structures. One potential solution is to mathematically place semi-landmarks on an object that represent the same morphological region across specimens. Here, we illustrate a recently developed pipeline to mathematically define semi-landmarks from the mouse baculum (penis bone). Our methods should be applicable to a wide range of objects. PMID- 28362425 TI - Role of magnetic resonance imaging in heavy eye syndrome. AB - PurposeThe aim of this study is to assess the importance of magnetic resonance imaging (MRI) before surgery in highly myopic patients, evaluating the capability of imaging to identify muscles displacement and orbital pulley abnormalities and their role in the pathogenesis of heavy eye syndrome (HES).MethodsWe reviewed the medical records and high-resolution orbital MRIs of highly myopic adults with HES, who underwent surgery for strabismus at the Sant'Orsola-Malpighi University Hospital of Bologna from January 2007 to June 2016. The measure of the angle of dislocation between lateral rectus and superior rectus and lateral rectus superior rectus band (LR-SR band) were evaluated on coronal MRI imaging.ResultsA total of 54 patients with HES were evaluated by MRI. Mean axial length was 30.5+/ 3 mm. Mean distance esotropia was 49.2+/-14.4 prism diopters (PD) and the mean hypotropia was 4.3+/-4.4 PD. All subjects exhibited severe superotemporal globe prolapse that displaced the lateral rectus inferiorly and the superior rectus muscle medially with mean angle of dislocation of 167.5+/-12.9 degrees on MRI. The LR-SR band was thinned in 56 eyes, ruptured in 8 and not evaluable in 1 case.ConclusionsIn our study, we detected muscles displacement in all subjects and we discovered alteration of the LR-SR band in patients with HES, suggesting a possible role in the pathogenesis of this disease. The evaluation of preoperative orbital MRI imaging in patients with highly myopic strabismus is helpful to detect different anatomical etiology and eventually to drive the choice of appropriate surgery. PMID- 28362426 TI - Bispectral index monitoring in vitrectomy surgery under local anaesthetic block with sedation: a single surgeon, single anaesthetist review. PMID- 28362427 TI - Anti-apoptotic proteins BCL-2, MCL-1 and A1 summate collectively to maintain survival of immune cell populations both in vitro and in vivo. AB - Survival of various immune cell populations has been proposed to preferentially rely on a particular anti-apoptotic BCL-2 family member, for example, naive T cells require BCL-2, while regulatory T cells require MCL-1. Here we examined the survival requirements of multiple immune cell subsets in vitro and in vivo, using both genetic and pharmacological approaches. Our findings support a model in which survival is determined by quantitative participation of multiple anti apoptotic proteins rather than by a single anti-apoptotic protein. This model provides both an insight into how the sum of relative levels of anti-apoptotic proteins BCL-2, MCL-1 and A1 influence survival of T cells, B cells and dendritic cells, and a framework for ascertaining how these different immune cells can be optimally targeted in treatment of immunopathology, transplantation rejection or hematological cancers. PMID- 28362428 TI - Delta133p53 represses p53-inducible senescence genes and enhances the generation of human induced pluripotent stem cells. AB - p53 functions to induce cellular senescence, which is incompatible with self renewal of pluripotent stem cells such as induced pluripotent stem cells (iPSC) and embryonic stem cells (ESC). However, p53 also has essential roles in these cells through DNA damage repair for maintaining genomic integrity and high sensitivity to apoptosis for eliminating severely damaged cells. We hypothesized that Delta133p53, a physiological inhibitory p53 isoform, is involved in the balanced regulation of self-renewing capacity, DNA damage repair and apoptosis. We examined 12 lines of human iPSC and their original fibroblasts, as well as three ESC lines, for endogenous protein levels of Delta133p53 and full-length p53 (FL-p53), and mRNA levels of various p53 target genes. While FL-p53 levels in iPSC and ESC widely ranged from below to above those in the fibroblasts, all iPSC and ESC lines expressed elevated levels of Delta133p53. The p53-inducible genes that mediate cellular senescence (p21WAF1, miR-34a, PAI-1 and IGFBP7), but not those for apoptosis (BAX and PUMA) and DNA damage repair (p53R2), were downregulated in iPSC and ESC. Consistent with these endogenous expression profiles, overexpression of Delta133p53 in human fibroblasts preferentially repressed the p53-inducible senescence mediators and significantly enhanced their reprogramming to iPSC. The iPSC lines derived from Delta133p53-overexpressing fibroblasts formed well-differentiated, benign teratomas in immunodeficient mice and had fewer numbers of somatic mutations than an iPSC derived from p53-knocked down fibroblasts, suggesting that Delta133p53 overexpression is non- or less oncogenic and mutagenic than total inhibition of p53 activities. Overexpressed Delta133p53 prevented FL-p53 from binding to the regulatory regions of p21WAF1 and miR-34a promoters, providing a mechanistic basis for its dominant-negative inhibition of a subset of p53 target genes. This study supports the hypothesis that upregulation of Delta133p53 is an endogenous mechanism that facilitates human somatic cells to become self-renewing pluripotent stem cells with maintained apoptotic and DNA repair activities. PMID- 28362429 TI - PU.1 supports TRAIL-induced cell death by inhibiting NF-kappaB-mediated cell survival and inducing DR5 expression. AB - The hematopoietic Ets-domain transcription factor PU.1/SPI1 orchestrates myeloid, B- and T-cell development, and also supports hematopoietic stem cell maintenance. Although PU.1 is a renowned tumor suppressor in acute myeloid leukemia (AML), a disease characterized by an accumulation of immature blast cells, comprehensive studies analyzing the role of PU.1 during cell death responses in AML treatment are missing. Modulating PU.1 expression in AML cells, we found that PU.1 supports tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis via two mechanisms: (a) by repressing NF-kappaB activity via a novel direct PU.1-RelA/p65 protein-protein interaction, and (b) by directly inducing TRAIL receptor DR5 expression. Thus, expression of NF-kappaB-regulated antiapoptotic genes was sustained in PU.1-depleted AML cells upon TRAIL treatment and DR5 levels were decreased. Last, PU.1 deficiency significantly increased AML cell resistance to anthracycline treatment. Altogether, these results reveal a new facet of PU.1's tumor suppressor function during antileukemic therapies. PMID- 28362430 TI - CYLD, A20 and OTULIN deubiquitinases in NF-kappaB signaling and cell death: so similar, yet so different. AB - Polyubiquitination of proteins has a pivotal role in the regulation of numerous cellular functions such as protein degradation, DNA repair and cell signaling. As deregulation of these processes can result in pathological conditions such as inflammatory diseases, neurodegeneration or cancer, tight regulation of the ubiquitin system is of tremendous importance. Ubiquitination by E3 ubiquitin ligases can be counteracted by the activity of several deubiquitinating enzymes (DUBs). CYLD, A20 and OTULIN have been implicated as key DUBs in the negative regulation of NF-kappaB transcription factor-mediated gene expression upon stimulation of cytokine receptors, antigen receptors and pattern recognition receptors, by removing distinct types of polyubiquitin chains from specific NF kappaB signaling proteins. In addition, they control TNF-induced cell death signaling leading to apoptosis and necroptosis via similar mechanisms. In the case of A20, also catalytic-independent mechanisms of action have been demonstrated to have an important role. CYLD, A20 and OTULIN have largely overlapping substrates, suggesting at least partially redundant functions. However, mice deficient in one of the three DUBs show significant phenotypic differences, indicating also non-redundant functions. Here we discuss the activity and polyubiquitin chain-type specificity of CYLD, A20 and OTULIN, their specific role in NF-kappaB signaling and cell death, the molecular mechanisms that regulate their activity, their role in immune homeostasis and the association of defects in their activity with inflammation, autoimmunity and cancer. PMID- 28362434 TI - Nanopore sequencing meets epigenetics. PMID- 28362435 TI - A guide to light-sheet fluorescence microscopy for multiscale imaging. AB - The impact of light-sheet fluorescence microscopy (LSFM) is visible in fields as diverse as developmental and cell biology, anatomical science, biophysics and neuroscience. Although adoption among biologists has been steady, LSFM has not displaced more traditional imaging methods despite its often-superior performance. One reason for this is that the field has largely conformed to a do it-yourself ethic, although the challenges of big image data cannot be overstated. With the most powerful implementations of LSFM available to only a few groups worldwide, the scope of this technique is unnecessarily limited. Here we elucidate the key developments and define a simple set of underlying principles governing LSFM. In doing so, we aim to clarify the decisions to be made for those who wish to develop and use bespoke light-sheet systems and to assist in identifying the best approaches to apply this powerful technique to myriad biological questions. PMID- 28362433 TI - IL-2 prevents deletion of developing T-regulatory cells in the thymus. AB - In the thymus, strongly self-reactive T cells may undergo apoptotic deletion or differentiate into Foxp3+ T-regulatory (T-reg) cells. Mechanisms that partition T cells into these two fates are unclear. Here, we show that IL-2 signalling is required to prevent deletion of CD4+ CD8- CCR7+ Helios+ thymocytes poised to upregulate Foxp3. The deletion prevented by IL-2 signalling is Foxp3 independent and occurs later in thymocyte development than the deletion that is prevented by Card11 signalling. Our results distinguish two bottlenecks at which strongly self reactive thymocytes undergo deletion or progress to the next stage of T-reg differentiation; Card11 regulates the first bottleneck and IL-2 regulates the second. PMID- 28362431 TI - Killers creating new life: caspases drive apoptosis-induced proliferation in tissue repair and disease. AB - Apoptosis is a carefully orchestrated and tightly controlled form of cell death, conserved across metazoans. As the executioners of apoptotic cell death, cysteine dependent aspartate-directed proteases (caspases) are critical drivers of this cellular disassembly. Early studies of genetically programmed cell death demonstrated that the selective activation of caspases induces apoptosis and the precise elimination of excess cells, thereby sculpting structures and refining tissues. However, over the past decade there has been a fundamental shift in our understanding of the roles of caspases during cell death-a shift precipitated by the revelation that apoptotic cells actively engage with their surrounding environment throughout the death process, and caspases can trigger a myriad of signals, some of which drive concurrent cell proliferation regenerating damaged structures and building up lost tissues. This caspase-driven compensatory proliferation is referred to as apoptosis-induced proliferation (AiP). Diverse mechanisms of AiP have been found across species, ranging from planaria to mammals. In this review, we summarize the current knowledge of AiP and we highlight recent advances in the field including the involvement of reactive oxygen species and macrophage-like immune cells in one form of AiP, novel regulatory mechanisms affecting caspases during AiP, and emerging clinical data demonstrating the critical importance of AiP in cancer. PMID- 28362432 TI - Regulation of transcriptional activators by DNA-binding domain ubiquitination. AB - Ubiquitin is a key component of the regulatory network that maintains gene expression in eukaryotes, yet the molecular mechanism(s) by which non-degradative ubiquitination modulates transcriptional activator (TA) function is unknown. Here endogenous p53, a stress-activated transcription factor required to maintain health, is stably monoubiquitinated, following pathway activation by IR or Nutlin 3 and localized to the nucleus where it becomes tightly associated with chromatin. Comparative structure-function analysis and in silico modelling demonstrate a direct role for DNA-binding domain (DBD) monoubiquitination in TA activation. When attached to the DBD of either p53, or a second TA IRF-1, ubiquitin is orientated towards, and makes contact with, the DNA. The contact is made between a predominantly cationic surface on ubiquitin and the anionic DNA. Our data demonstrate an unexpected role for ubiquitin in the mechanism of TA activity enhancement and provides insight into a new level of transcriptional regulation. PMID- 28362437 TI - Automatic tracing of ultra-volumes of neuronal images. PMID- 28362438 TI - Adaptive optical fluorescence microscopy. AB - The past quarter century has witnessed rapid developments of fluorescence microscopy techniques that enable structural and functional imaging of biological specimens at unprecedented depth and resolution. The performance of these methods in multicellular organisms, however, is degraded by sample-induced optical aberrations. Here I review recent work on incorporating adaptive optics, a technology originally applied in astronomical telescopes to combat atmospheric aberrations, to improve image quality of fluorescence microscopy for biological imaging. PMID- 28362439 TI - Choosing CRISPR-based screens in cancer. PMID- 28362436 TI - In vivo imaging of neural activity. AB - Since the introduction of calcium imaging to monitor neuronal activity with single-cell resolution, optical imaging methods have revolutionized neuroscience by enabling systematic recordings of neuronal circuits in living animals. The plethora of methods for functional neural imaging can be daunting to the nonexpert to navigate. Here we review advanced microscopy techniques for in vivo functional imaging and offer guidelines for which technologies are best suited for particular applications. PMID- 28362440 TI - Prognostic relevance of lymphocytopenia, monocytopenia and lymphocyte-to-monocyte ratio in primary myelodysplastic syndromes: a single center experience in 889 patients. AB - Current prognostic models for myelodysplastic syndromes (MDS), including the Revised International Prognostic Scoring System (IPSS-R), do not account for host immunity. We retrospectively examined the prognostic relevance of monocytopenia, lymphocytopenia and lymphocyte-to-monocyte ratio (LMR) in a cohort of 889 patients with primary MDS. After a median follow-up of 27 months, 712 (80%) deaths and 116 (13%) leukemic transformation were documented. In univariate analysis, subnormal absolute lymphocyte count (ALC) <0.9 * 109/l; P=0.001), ALC<1.2 * 109/l (P=0.0002), subnormal absolute monocyte count (AMC) <0.3 * 109/l (P=0.0003), LMR (P?0.0001) and LMR?5 (P=0.03) were all associated with inferior overall survival. In multivariable analysis that included other risk factors, significance was retained for LMR (P=0.02) and became borderline for ALC <1.2 * 109/l (P=0.06). Analysis in the context of IPSS-R resulted in P-values of 0.06 for ALC<1.2 * 109/l, 0.7 for monocytopenia and 0.2 for LMR. Leukemia-free survival was not affected by ALC, AMC or LMR. The observations from the current study suggest a possible detrimental role for altered host immunity in primary MDS, which might partly explain the therapeutic benefit of immune-directed therapy, including the use of immune modulators; however, IPSS-R-independent prognostic value for either ALC or AMC was limited. PMID- 28362443 TI - Correction: Programmable RNA microstructures for coordinated delivery of siRNAs. AB - Correction for 'Programmable RNA microstructures for coordinated delivery of siRNAs' by Jaimie Marie Stewart et al., Nanoscale, 2016, 8, 17542-17550. PMID- 28362442 TI - Prevalence of hepatitis B and hepatitis C viral infections in various subtypes of B-cell non-Hodgkin lymphoma: confirmation of the association with splenic marginal zone lymphoma. PMID- 28362444 TI - A water-soluble pillar[5]arene as a new carrier for an old drug. AB - The remarkable affinity of deca-carboxylatopillar[5]arene WP5 towards the aminoglycoside antibiotic, amikacin, in aqueous media is reported; in vitro studies on Gram-positive bacteria (Staphylococcus aureus) show that drug entrapment inside WP5 also takes place in the presence of the microrganisms, thus pointing to WP5 as an appealing carrier for amikacin targeted delivery. PMID- 28362441 TI - Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control. AB - Myeloma is heterogeneous at the molecular level with subgroups of patients characterised by features of epigenetic dysregulation. Outcomes for myeloma patients have improved over the past few decades except for molecularly defined high-risk patients who continue to do badly. Novel therapeutic approaches are, therefore, required. A growing number of epigenetic inhibitors are now available including EZH2 inhibitors that are in early-stage clinical trials for treatment of haematological and other cancers with EZH2 mutations or in which overexpression has been correlated with poor outcomes. For the first time, we have identified and validated a robust and independent deleterious effect of high EZH2 expression on outcomes in myeloma patients. Using two chemically distinct small-molecule inhibitors, we demonstrate a reduction in myeloma cell proliferation with EZH2 inhibition, which leads to cell cycle arrest followed by apoptosis. This is mediated via upregulation of cyclin-dependent kinase inhibitors associated with removal of the inhibitory H3K27me3 mark at their gene loci. Our results suggest that EZH2 inhibition may be a potential therapeutic strategy for the treatment of myeloma and should be investigated in clinical studies. PMID- 28362445 TI - Semi-continuous multi-step synthesis of lamivudine. AB - We report the first continuous flow synthesis of lamivudine, an antiretroviral drug used in the treatment of HIV/AIDS and hepatitis B. The key intermediate (5 acetoxy oxathiolane) was prepared by an integrated two step continuous flow process from l-menthyl glyoxalate hydrate in a single solvent, in 95% overall conversion. For the crucial glycosidation reaction, using pyridinium triflate as the novel catalyst, an improved conversion of 95% was obtained. The overall isolated yield of the desired isomer of lamivudine (40%) was improved in the flow synthesis compared to the batch process. PMID- 28362446 TI - Novel chemoenzymatic oxidation of amines into oximes based on hydrolase-catalysed peracid formation. AB - The efficient transformation of benzylamines into the corresponding oximes has been described by means of a chemoenzymatic process. This strategy is based on a two-step sequence developed in one-pot at 30 degrees C and atmospheric pressure. First, the formation of a reactive peracid intermediate occurs by means of a lipase-catalysed perhydrolysis reaction, and then this peracid acts as a chemical oxidising agent of the amines. A total of nine ketoximes were isolated in high purity after a simple extraction protocol (90-98% isolated yield), while for the eleven synthesised aldoximes a further column chromatography purification was required (71-82% isolated yield). In all cases excellent selectivities were attained, offering a practical method for amine oxidation in short reaction times (1 hour). The environmental impact of the process was analysed and compared with a recently published alternative chemical synthesis, finding for this metric a good E-factor value. PMID- 28362447 TI - Nonadiabatic dynamics of injected holes in conjugated polymers. AB - The dynamics of injected holes in short transient times that precede polaron formation is numerically studied in the framework of a tight-binding electron phonon interacting approach aimed at describing organic one-dimensional lattices. In particular, the direct impact of internal and external factors on the conversion of injected holes into polarons is carefully investigated. The results show that a hole injected at levels lower than the highest occupied molecular orbital forms self-trapped bound structures that can merge spontaneously to form a polaron after, at least, one picosecond. On the other hand, the life-time of such structures substantially decreases (up to a few hundreds of femtoseconds) when the influence of external electric fields, temperature effects and impurities is considered. Importantly, the critical values of the aforementioned factors in promoting the quenching of the self-trapped structures are obtained. These findings may enlighten the understanding of the mechanism of charge carrier generation in Polymer Light Emitting Diodes when several kinds of excitations are present. PMID- 28362449 TI - Synthesis and magnetic properties of new tellurate compounds Na4MTeO6 (M = Co and Ni) with a ferromagnetic spin-chain structure. AB - New tellurate compounds Na4MTeO6 (M = Co and Ni) were synthesized by a conventional high-temperature solid-state reaction. The title compounds crystallize in the monoclinic system of a space group P2/c and the triclinic system of a space group P1[combining macron], respectively. Both compounds exhibit a zigzag spin-chain structure, in which Na4CoTeO6 shows uniform chains built by Co2+ ions and Na4NiTeO6 shows alternating chains built by Ni2+ ions. Magnetic measurements confirm that Na4CoTeO6 and Na4NiTeO6 possess an antiferromagnetic ordering at TN = ~3 K and ~6.5 K, respectively, while a metamagnetic transition can be observed in the magnetization curve with an increasing field at 2 K. PMID- 28362450 TI - Multivariate quantification of mebendazole polymorphs by terahertz time domain spectroscopy (THZ-TDS). AB - This work presents an analytical method based on terahertz-time domain spectroscopy (THz-TDS) and partial least squares (PLS) regression models to quantify mebendazole (MBZ) polymorphs (forms A, B and C) in pharmaceutical raw material. Mebendazole polymorphs A, B and C were quantified with RMSEP values of 1.5% w/w, 1.2% w/w and 1.8% w/w, respectively. The limits of detection (LOD) ranges obtained with the best PLS regression models were 2.7-4.3% w/w, 2.9-4.0% w/w and 2.4-3.1% w/w, for polymorphs A, B and C, respectively. This analytical performance is better than those for the methods described in the literature using near (NIR) and middle (MIR) infrared spectroscopies. The main advantage of THz spectroscopy is its ability to access directly information related to crystal lattices. According to the results, the developed method is a powerful technique for the quantification of MBZ polymorphs in raw material. This methodology can be implemented as a Process Analytical Technology (PAT) tool for quality control of pharmaceutical feedstock. PMID- 28362448 TI - Synthesis of coenzyme Q0 through divanadium-catalyzed oxidation of 3,4,5 trimethoxytoluene with hydrogen peroxide. AB - The selective oxidation of methoxy/methyl-substituted arenes to the corresponding benzoquinones has been first realized using aqueous hydrogen peroxide as a green oxidant, acid tetrabutylammonium salts of the gamma-Keggin divanadium-substituted phosphotungstate [gamma-PW10O38V2(MU-O)2]5- (I) as a catalyst, and MeCN as a solvent. The presence of the dioxovanadium core in the catalyst is crucial for the catalytic performance. The reaction requires an acid co-catalyst or, alternatively, a highly protonated form of I can be prepared and employed. The industrially relevant oxidation of 3,4,5-trimethoxytoluene gives 2,3-dimethoxy-5 methyl-1,4-benzoquinone (ubiquinone 0 or coenzyme Q0, the key intermediate for coenzyme Q10 and other essential biologically active compounds) with 73% selectivity at 76% arene conversion. The catalyst retains its structure under turnover conditions and can be easily recycled and reused without significant loss of activity and selectivity. PMID- 28362451 TI - Kinetic investigation into the chemoselective hydrogenation of alpha,beta unsaturated carbonyl compounds catalyzed by Ni(0) nanoparticles. AB - A series of Ni(0) nanocatalysts was prepared from a Ni(COD)2 complex in the presence of different stabilizers (hexadecylamine, polyvinylpyrrolidone (PVP), PVP/triphenylphosphine, octanoic acid and stearic acid) for their evaluation in the selective hydrogenation reaction of alpha,beta-unsaturated carbonyl compounds by H2 under mild reaction conditions, i.e., low H2 pressure, temperature and catalyst loading. All nanocatalysts were active in reducing only the C[double bond, length as m-dash]C bond and this chemoselectivity was attributed to the reduced nature of the Ni-NPs surface. Moreover, the hydrogenation reaction rate appeared to be sensitive to ligand type, with the carboxylic acid-stabilized systems showing the best performances. A full kinetic investigation into the t chalcone chemoselective reduction of the C[double bond, length as m-dash]C bond, with the best catalyst (Ni-octanoic acid) revealed that the rate-determining step is the hydrogenation of the adsorbed substrate on the NPs surface, following a Horiuti-Polanyi type of mechanism. Regarding sustainable chemistry concerns, the best catalyst could be reused up to 10 times without significant loss of activity. PMID- 28362452 TI - Cleavage of 1,3-dicarbonyls through oxidative amidation. AB - A mild and convenient protocol for the oxidative cleavage of 1,3-diketone compounds is described. Under metal-free conditions, the method converts the 1,3 dicarbonyls into amides when treated with (nBu4N)N3 and iodine in the presence of an amine at room temperature. Using this method, a range of 1,3-dicarbonyls with various structural motifs including sterically demanding substituents and ordinary functional groups were easily fragmented, and it is demonstrated that cyclic 1,3-dicarbonyls can be directly transformed into acyclic diamides through ring-opening. Initial mechanistic studies show that diazidation of the enol form is followed by nucleophilic substitution with the amine. PMID- 28362453 TI - The origin of the measured chemical shift of 129Xe in UiO-66 and UiO-67 revealed by DFT investigations. AB - The NMR chemical shift of the xenon isotope 129Xe inside the metal-organic frameworks (MOFs) UiO-66 and UiO-67 (UiO - University of Oslo) has been investigated both with density functional theory (DFT) and in situ high-pressure 129Xe NMR measurements. The experiments reveal a decrease of the total chemical shift comparing the larger isoreticular MOF (UiO-67) with the smaller one (UiO 66), even though one may expect an increase due to the higher amount of adsorbed Xe atoms. We are able to calculate contributions to the chemical shift individually. This allows us to evaluate the shift inside the different pores independently. To compare the theoretical results with the experimental ones, we performed molecular dynamics simulations of Xe in the MOFs. For this purpose, the pores were completely filled with Xe to gain insight into the distribution of Xe at high pressures. The resulting trend of the total shift agrees well between the theoretical predictions and the experiments. Moreover, we are able to describe specific contributions to the total shift per pore, explaining the experimental behavior at an atomistic level. PMID- 28362454 TI - BODIPY blocked anthroxyl radicals: the substituent effect on reactivity and fluorescence turn-on detection of a hydroxyl radical. AB - Two BODIPY-substituted anthroxyl radicals were investigated. The one with two ethyl substituents (2Et-BO-An-O) is sensitive to air and silica gel due to the lack of sufficient kinetic blocking, while another one with four methyl substituents (4Me-BO-An-O) shows high stability. The structure of the latter was fully characterized by X-ray crystallographic analysis and electron-spin resonance spectra. 4Me-BO-An-O was subjected to react with various reactive oxygen/nitrogen species (ROS/RNS) and selective fluorescence turn-on detection of a hydroxyl radical was achieved, validating the concept of "using stable radicals to detect ROS/RNS". PMID- 28362455 TI - Positron insight into evolution of pore volume and penetration of the polymer network by n-heptane molecules in mesoporous XAD4. AB - The adsorption and desorption of n-heptane on the mesoporous polymer resin Amberlite XAD4 were investigated in situ by positron annihilation lifetime spectroscopy (PALS). This technique allows the monitoring of porosity and subnanometer free volume changes as well as the amount of liquid adsorbate captured within an investigated sorbent, without causing any interference with the course of adsorption/desorption. In consequence, the conducted studies provide microscale insight into the sorption processes of n-heptane (which is a significant component of volatile organic compounds - VOCs) on the polymeric material. The total pore volume decreases parabolically with n-heptane pressure until it reaches zero just below the saturated vapor pressure. Simultaneously, the average pore size increases linearly until it has approximately doubled. However, much faster rates of change in both these parameters occur at relative pressures below 0.05. The PALS results can be properly explained only if the swelling of the polymer skeleton is taken into account during the alkane adsorption process. This is confirmed by long-term pumping, which was required to achieve stabilization of PAL spectra during the final phase of desorption. In addition, the evolution of subnanometer free volumes (located between polymer chains and formed in liquid n-heptane) support this interpretation of the results. PMID- 28362456 TI - The non-Gaussian tops and tails of diffusing boomerangs. AB - Experiments involving the two-dimensional passive diffusion of colloidal boomerangs tracked off their centre of mobility have shown striking non-Gaussian tails in their probability distribution function [Chakrabarty et al., Soft Matter, 2016, 12, 4318]. This in turn can lead to anomalous diffusion characteristics, including mean drift. In this paper, we develop a general theoretical explanation for these measurements. The idea relies on calculating the two-dimensional probability densities at the centre of mobility of the particle, where all distributions are Gaussian, and then transforming them to a different reference point. Our model clearly captures the experimental results, without any fitting parameters, and demonstrates that the one-dimensional probability distributions may also exhibit strongly non-Gaussian tops. These results indicate that the choice of tracking point can cause a considerable departure from Gaussian statistics, potentially causing some common modelling techniques to fail. PMID- 28362457 TI - Shift work and cognitive aging: a longitudinal study. AB - Objectives The few studies of shift work and late life cognitive functioning have yielded mixed findings. The aim of the present study is to estimate the association between shift-work experience and change in cognitive performance before and after retirement age among older adults who were gainfully employed. Methods Five hundred and ninety five participants with no dementia were followed up for a mean of 17.6 standard deviation (SD) 8.8 years from a Swedish population based sample. Participants had self-reported information on any type of shift work experience (ever/never) in 1984 and measures of cognitive performance (verbal, spatial, memory, processing speed, and general cognitive ability) from up to 9 waves of cognitive assessments during 1986-2012. Night work history (ever/never) from 1998-2002 was available from a subsample (N=320). Early adult cognitive test scores were available for 77 men. Results In latent growth curve modeling, there were no main effects of "any-type" or night shift work on the mean scores or rate of change in any of the cognitive domains. An interaction effect between any-type shift work and education on cognitive performance at retirement was noted. Lower-educated shift workers performed better on cognitive tests than lower-educated day workers at retirement. Sensitivity analyses, however, indicated that the interactions appeared to be driven by selection effects. Lower-educated day workers demonstrated poorer cognitive ability in early adulthood than lower-educated shift workers, who may have selected jobs entailing higher cognitive demand. Conclusion There was no difference in late life cognitive aging between individuals with a history of working shifts compared to those who had typical day work schedules during midlife. PMID- 28362458 TI - Registered Nurses in Primary Care: What Will They Do? PMID- 28362459 TI - Individual and Collective Competence. AB - Concepts of competence and competency management continue to challenge and stress nursing professional development practitioners. A shift from focusing on individual competence to building the competence of a team is one strategy to meet the increasing needs of the current health care environment. J Contin Educ Nurs. 2017;48(4):148-150. PMID- 28362460 TI - Improvisation for Leadership Development. AB - Leaders are required to demonstrate agility, creativity, and innovation. Professional development educators can help leaders to develop the skills to listen carefully, be present in the moment, and contribute to any conversation by using improvisation. J Contin Educ Nurs. 2017;48(4):151-153. PMID- 28362461 TI - Let's Cooperate! Integrating Cooperative Learning Into a Lesson on Ethics. AB - Cooperative learning is an effective teaching strategy that promotes active participation in learning and can be used in academic, clinical practice, and professional development settings. This article describes that strategy and provides an example of its use in a lesson about ethics. J Contin Nurs Educ. 2017;48(4):154-156. PMID- 28362462 TI - Impact of Accreditation Standards on the Quality of Continuing Nursing Education Activities as Perceived by the Learner. AB - BACKGROUND: Continuing nursing education (CNE) activities are increasingly becoming a requirement for RNs to maintain licensure or certification and to remain competent in practice in the fast-changing health care environment. Regardless of the health care profession, continuing education should be a quality educational experience to positively influence practice and patient outcomes. METHOD: A 15-item matrix based on the 2013 American Nurses Credentialing Center Primary Accreditation criteria was used to evaluate CNE activities. The matrix reflected the characteristics that a learner should be able to identify when participating in a Web-based CNE activity. RESULTS: A measurable learner-perceived difference was observed in the quality of the educational experience between educational activities developed by organizations using accreditation criteria, compared with those that did not. CONCLUSION: Learners can use accreditation criteria as one method to discriminate high quality educational activities that are designed to positively influence practice and patient outcomes. J Contin Educ Nurs. 2017;48(4):157-164. PMID- 28362464 TI - Experience of Novice Clinical Adjunct Faculty: A Qualitative Study. AB - BACKGROUND: Despite the adjunct instructor's central role in the clinical training of nursing students, little research exists on the perspective of the clinical experts assuming this role. This qualitative study aimed to better understand how novice clinical adjunct faculty described their lived experiences in their significant role transition. METHOD: The sample consisted of nine novice adjunct clinical nursing faculty who provided direct clinical supervision of prelicensure students in the United States (i.e., Texas). The interview narratives were collected using an in-depth semi-structured approach. Conventional content analysis was used. RESULTS: Four key themes emerged from the data: Unpreparedness; Facilitators and Barriers in the Transition; New Learning Needs and Processes; and Salient Recommendations to Pass On. CONCLUSION: Nursing programs that use adjunct faculty to sustain clinical education must support their vital contribution and fresh perspective. Targeted, organized, and consistent efforts will optimally integrate this group into the academe. J Contin Nurs Educ. 2017;48(4):167-174. PMID- 28362465 TI - Increasing RN Perceived Competency With Substance Use Disorder Patients. AB - BACKGROUND: Although behavioral health and substance use disorder patients visit hospitals in significant numbers, nurses are often ill-prepared to care for them. METHOD: The purpose of this quasi-experimental preclass-postclass design was to determine the effects of an educational intervention on the perceived competency of 57 nurses who care for patients with behavioral and substance abuse disorders. The nurses who chose to participate were asked to respond to a demographic questionnaire and a survey designed to measure perceived competency. Survey data were analyzed to determine whether any differences (alpha = .05) existed between participants' attitudes and knowledge preclass and postclass. RESULTS: Immediately following the educational intervention, a statistically significant increase was found in perceived competency related to self-confidence, attitudes, communication, and knowledge of resource availability among participating nurses. CONCLUSION: Nurses working in acute care hospitals, particularly those without addiction and psychiatric services, may benefit from continuing education on this important topic. J Contin Nurs Educ. 2017;48(4):175-183. PMID- 28362466 TI - Using Research Findings to Design an Evidence-Based Practice Curriculum. AB - Evidence from a system-wide research study highlighted strengths and weaknesses in evidence-based practice (EBP) implementation, beliefs, and organizational readiness. To address this evidence, a curriculum was developed within the context of the shared governance and EBP models for nursing practice. The curriculum, Evidence-Based Practice: Clinical Applications in Professional Nursing Practice, consists of five modules that provide the knowledge, skills, and abilities relative to each step of EBP. The learning approach incorporates classroom- and unit-based education, facilitated by EBP curriculum mentors. Each module is rolled out quarterly for a 15-month curriculum cycle. Outcome data include pre- and post-learning assessments, in addition to EBP projects. This seamless approach to nursing education, based on research findings and established shared governance and EBP models, can be undertaken by community hospital systems. J Contin Nurs Educ. 2017;48(4):184-189. PMID- 28362467 TI - Exploring Discrepancies in Perceived Nursing Competence Between Postgraduate-Year Nurses and Their Preceptors. AB - BACKGROUND: Postgraduate clinical training programs improve the core competence of nurses. How postgraduate-year (PGY) nurses perceive their clinical competence and their preceptors' perceptions may affect program effectiveness. This study compared the perspectives of clinical competencies of PGY nurses engaged in a residency program in Taiwan with their preceptors' perspectives. METHOD: A cross sectional study was conducted at a medical center in Taiwan. The Nursing Competence Questionnaire was used to obtain data from 99 pairs of PGY nurses and preceptors. RESULTS: PGY nurses' scores were higher than their preceptors' for communication, patient education, and management competencies (p <.05). Preceptors with more years of clinical experience exhibited greater assessment discrepancies for clinical care, communication, patient education, research awareness, and overall competence (p <.05). CONCLUSION: Preceptor development courses should be grounded in a strong pedagogical framework. An assessment tool with explicit behavioral indicators would be needed for objective evaluation from both perspectives. J Contin Educ Nurs. 2017;48(4):190-196. PMID- 28362468 TI - Galactomyces geotrichum - moulds from dairy products with high biotechnological potential. AB - The article reviews the properties of the Galactomyces geotrichum species, the mould that is most important for the dairy industry. G. geotrichum mould has been isolated from milk, cheeses and alcoholic beverage. Its presence in food products makes it possible to obtain a characteristic aroma and taste, which corresponds to the needs and preferences of consumers. G. geotrichum plays an important role in ecology, where the mould is employed for the degradation of various hazardous substances and wastewater treatment. It has also been found to have potential for biofuel production. In addition to this, G. geotrichum can be applicable in two further major areas: agriculture and health protection. PMID- 28362469 TI - Control of natural microorganisms in chamomile (Chamomilla recutita L.) by gamma ray and electron beam irradiation. AB - BACKGROUND: Microbial contamination levels and corresponding sensitivities to gamma rays (GR) and elec- tron beam (EB) irradiation were tested in chamomile (Chamomile recutta L.). METHODS: Chamomile powders were treated with 10 and 20 kGy by GR and EB, respectively. Microbiological and chemical analyses were performed on controls and treated samples immediately after irradiation, and after 12 months of storage. RESULTS: The control samples of chamomile exhibited rather high microbiological contamination, exceeding the levels of 4 log10 CFU g 1 (CFU - colony forming units) reported by national and international authorities as the maximum permissible total count level. Irradiation with GR and EB was found to cause a reduction in microbial contamination proportionate to the dose delivered. The sterilizing effect of EB on microorganisms was higher than the GR one. A dose of 10 kGy of GR and EB significantly (p < 0.05) reduced the total bacte- rial, total coliform and total fungal contamination. A dose of 20 kGy of GR significantly (p < 0.05) reduced the total bacterial and total fungal contamination, while a 20 kGy dose of EB reduced the initial bacterial, total coliform and total fungal contamination to below detection level when the analysis was carried out im- mediately after irradiation treatment or after 12 months of storage. CONCLUSIONS: The comparative study demonstrated that electron beam was more effective for decontamination of chamomile powder than gamma irradiation. PMID- 28362470 TI - Impact of green tea extract addition on oxidative changes in the lipid fraction of pastry products. AB - BACKGROUND: Alongside flour, fat is the key ingredient of sponge cakes, including those with long shelf lives. It is an unstable food component, whose quality and nutritional safety depend on the composition and pres- ence of oxidation products. Consumption of fat oxidation products adversely affects the human body and contributes to the incidence of a number of medical conditions. Qualitative changes in fats extracted from thermostat sponge cakes with and without antioxidant additions were determined in this study. METHODS: In the study, two types of antioxidant were used: natural - green tea extract in three doses (0.02%; 0.2% and 1.0%) and synthetic BHA (0.02%) and 100%, solid bakery shortening. Sponge-cakes were thermostatted at temperatures 63 degrees C after twenty-eight days. In this study, the quality of the lipid fraction was analyzed. The amount of primary (PV) and secondary (AnV) oxidation products was determined, and a Rancimat test was performed. RESULTS: Adding antioxidants to fats varied in the degree to which oxidation processes of lipids fractions were inhibited. The peroxide value after twenty-eight days of thermostatting ranged from 3.57 meq O/kg (BHA) and 11.14 O meq/kg (extract content - 1%) to 62.85 meq O/kg (control sample). In turn, the value of AnV after the storage period ranged from 4.84 (BHA) and 6.71 (extract content - 1%) to 16.83 (control sample). CONCLUSIONS: The best protective effects in the process of oxidation was achieved by BHA. The longest in- duction time and the lowest peroxide value and anisidine value were obtained for this antioxidant. It was achieved after twenty-eight days of fat thermostatting. Nonetheless, the results demonstrated it is possible to use the commercially available green tea extract to slow the adverse process of fat oxidation in sponge cake products. PMID- 28362471 TI - Identification of suspected hazardous chemical contaminants in recycled pastry packaging. AB - BACKGROUND: The safe use of recycled paper and cardboard material for food packaging applications is an important area of investigation. Therefore, the aim of this study was to determine which hazardous chemi- cal pollutants were found in paper and cardboard samples used for pastry packaging, and to measure the migration of pollutants over time into the pastries. METHODS: In this study, the presence of some organic pollutants in common confectionery packaging, and the effects of storage time and type of pastry on pollutant migration, were investigated. RESULTS: The results of the study indicate that harmful compounds such as benzophenone, pentachlorophenol, bis(2-ethylhexyl) phthalate and dibutyl phthalate are present at high concentrations in most recycled boxes used for pastry packaging. CONCLUSIONS: Since the migration of some of the hazardous compounds from the packaging materials into the pastries under normal conditions was indicated, it is recommended that the procedure for preparing pastry packaging materials should be reconsidered and improved. PMID- 28362472 TI - Nutritional value and chemical composition of Sudanese millet-based fermented foods as affected by fermentation and method of preparation. AB - BACKGROUND: Although kissra and hulu-mur are well known millet-based foods in Sudan, the effect of fer- mentation and methods of preparation on their chemical compositions has not been thoroughly investigated. The aim of this study was to investigate the method of preparation and the composition of kisra, and hulu-mur. METHODS: The effect of fermentation and method of preparation on the composition, and mi- crobiological load were examined in millet flour during the preparation of Sudanese fermented foods (kisra & hulu-mur). RESULTS: A significant (P < 0.05) difference in the composition of millet flour and millet-based fermented foods was observed. Protein was significantly increased as a result of fermentation, while oil and carbo- hydrates were decreased. Most minerals increased significantly after the addition of spices to the hulu-mur batter. The total amino acid in millet flour (97.98 g 100 g-1 protein) was influenced by fermentation and preparation method, as it decreased to 86.09 and 88.7 g 100 g-1 protein, in millet batter and kisra, respectively. CONCLUSIONS: Kisra, and hulu mur were found to have apparent dietary qualities, in spite of some compounds being lost during their production. PMID- 28362473 TI - The effect of antioxidants on quantitative changes of lysine and methionine in linoleic acid emulsions at different pH conditions. AB - BACKGROUND: Plants are an important source of phenolic compounds. The antioxidant capacities of green tea, thyme and rosemary extracts that contain these compounds have been reported earlier. However, there is a lack of accessible information about their activity against lipid oxidation in emulsions and inhibit the interaction of lipid oxidation products with amino acids. Therefore, the influence of green tea, thyme and rosemary extracts and BHT (butylated hydroxytoluene) on quantitative changes in lysine and methionine in linoleic acid emulsions at a pH of isoelectric point and a pH lower than the isoelectric point of amino acids was investigated. METHODS: Total phenolic contents in plant extracts were determined spectrophotometrically by using Folin-Ciocalteu's reagent, and individual phenols by using HPLC. The level of oxidation of emulsion was determined using the measurement of peroxides and TBARS (thiobarbituric acid reactive substances). Methionine and lysine in the system were reacted with sodium nitroprusside and trinitrobenzenesulphonic acid respectively, and the absorbance of the complexes was measured. RESULTS: Extract of green tea had the highest total polyphenol content. The system containing antioxidants and amino acid protected linoleic acid more efficiently than by the addition of antioxidants only. Lysine and methionine losses in samples without the addition of antioxidants were lower in their isoelectric points than below these points. Antioxidants decrease the loss of amino acids. The protective properties of antioxidants towards methionine were higher in a pH of isoelectric point whereas towards lysine in pH below this point. CONCLUSIONS: Green tea, thyme and rosemary extracts exhibit antioxidant activity in linoleic acid emulsions. Moreover, they can be utilized to inhibit quantitative changes in amino acids in lipid emulsions. However, the antioxidant efficiency of these extracts seems to depend on pH conditions. Further investigations should be carried out to clarify this issue. PMID- 28362474 TI - Cold-pressed and hot-pressed rapeseed oil: The effects of roasting and seed moisture on the antioxi- dant activity, canolol, and tocopherol level. AB - BACKGROUND: The paper looks at the levels of canolol, tocopherols and antioxidant activity in cold-pressed and hot-pressed rapeseed oils produced from seeds of various moisture levels (5%, 7.5%, and 10%). The paper also considers the effects of seed roasting on the levels of these compounds. METHODS: The material used for the tests was rapeseed cv. Adrianna. The quality of the oils obtained is determined using peroxide and acid values. The levels of canolol and tocopherols are analyzed using HPLC. The DPPH radical-scavenging activity method for oil samples and phenolic extract from oils was used. RESULTS: It has been demonstrated that the oils produced from rapeseeds with a 5% moisture content, and in particular from cold-pressed oils, were characterized by the lowest peroxide values. Cold-pressed oils produced from rapeseeds with a 5% moisture content were characterized by higher levels of tocopherols and plastochromanol-8. In the case of hot-pressed oils, the highest levels of tocopherols were found in oils pro- duced from seeds with a 7.5% moisture content, and the greatest amount of PC-8 (more than 4 mg/100 g) was found in oils produced from seeds with a 10% moisture content. Hot-pressed oils have been shown to have higher levels of these compounds than cold-pressed oils. Both roasting and hot pressing led to an increase in the amount of canolol in the oils investigated. When analysing the antioxidant activity of the oils and phenolic extracts it was shown that phenolic compounds are responsible for approx. 10% of total antioxidant activity. CONCLUSIONS: Various levels of biologically active compounds were shown to be present in the rapeseed oil obtained from raw materials of a varying moisture content. The type of pressing process (cold-pressing or hot-pressing) and whether the seeds have undergone roasting has also been shown to affect the resulting oil and the level of native antioxidants it contains. PMID- 28362477 TI - Conditions of honey consumption in selected regions of Poland. AB - BACKGROUND: The nutritional value of honey is a factor that encourages the increase of its consumption. The aim of the study was to identify consumers' behaviours and preferences towards honey and their determinants. METHODS: Quantitative (PAPI method) survey was carried out in 2015 on a sample of 690 respondents from Mazowieckie, Podkarpackie and Zachodniopomorskie voivodeships. The data analyzed were: the frequency of and reasons for honey consumption, preferred buying locations, preferred types of honey, factors considered during purchase and different uses of honey. RESULTS: The study showed that Poles consume honey several times per month. The main incentives for honey consumption were: health benefits, a wide range of culinary uses, flavour and habits. It was established that Polish consumers buy honey mainly in apiaries and open-air markets. Primary factors considered during purchase were the type of honey (preferred types being lime, polyfloral and acacia), price and colour. Honey was chiefly used for consumption, most commonly as a sandwich spread and sweetener. Less popular ap- plications included medical and cosmetic purposes. Some socio demographic characteristics (gender, age, place of residence, income), self assessment of nutritional knowledge and, to a lesser extent, education sig- nificantly differentiated consumer behaviours in the honey market. CONCLUSIONS: The study has shown that Poles consume honey relatively seldom. For the increase of honey consumption nutritional education is needed. Further studies will allow a more detailed diagnosis, which is required for the development of effective information and marketing strategies. PMID- 28362475 TI - The genetic basis of obesity complications. AB - Intensive research is currently being performed into the genetic background of excess body mass compli- cations such as diabetes, cardiovascular disorders, especially atherosclerosis and coronary heart disease. Chronic inflammation is an important process in the pathogenesis of obesity, wherein there is an aberrant ex pression of genes encoding adipokines. Visceral tissue is characterized by a higher expression and secretion of interleukin-8, interleukin-1beta and plasminogen activator inhibitor 1 in the subcutaneous tissue secretion of leptin prevails. An important complication of obesity is obstructive sleep apnea, often observed in Prader- Willi syndrome. The genetic background of sleep apnea may be a polymorphism of the SREBF1 gene. The consequence of excess body mass is metabolic syndrome, which may be related to the occurrence of the rs926198 variant of gene encoding caveolin-1. The genes of transcription factor TCF7L2 and PPAR-gamma2 take part in the pathogenesis of diabetes development. It has been demonstrated that oncogenes FOS, FOSB, and JUN may be co-responsible not only for obesity but also for osteoporosis and colorectal cancer. It has been shown that weight loss causes a modification in the expression of about 100 genes involvedt in the production of substances such as cytokines and other responsible for chronic inflammation in obesity. In future studies on the complications of obesity, such scientific disciplines as proteomics, peptidomics, metabolomics and transcriptomics should be used. The aim of this study is to present the current state of knowledge about the genetic basis of obesity complications. PMID- 28362478 TI - Amorphous and Crystalline Vanadium Oxides as High-Energy and High-Power Cathodes for Three-Dimensional Thin-Film Lithium Ion Batteries. AB - Flexible wearable electronics and on-chip energy storage for wireless sensors drive rechargeable batteries toward thin-film lithium ion batteries. To enable more charge storage on a given surface, higher energy density materials are required, while faster energy storage and release can be obtained by going to thinner films. Vanadium oxides have been examined as cathodes in classical and thin-film lithium ion batteries for decades, but amorphous vanadium oxide thin films have been mostly discarded. Here, we investigate the use of atomic layer deposition, which enables electrode deposition on complex three-dimensional (3D) battery architectures, to obtain both amorphous and crystalline VO2 and V2O5, and we evaluate their thin-film cathode performance. Very high volumetric capacities are found, alongside excellent kinetics and good cycling stability. Better kinetics and higher volumetric capacities were observed for the amorphous vanadium oxides compared to their crystalline counterparts. The conformal deposition of these vanadium oxides on silicon micropillar structures is demonstrated. This study shows the promising potential of these atomic layer deposited vanadium oxides as cathodes for 3D all-solid-state thin-film lithium ion batteries. PMID- 28362476 TI - Dietary intake of boiled breadfruit (Treculia africana) seeds did not improve hyperglycemia in streptozotocin induced diabetic rats: Effect on the oral glucose tolerance of normoglycemic rats. AB - BACKGROUND: Although African breadfruit (Treculia africana) is said to be useful in the dietary management of diabetes, the effect of cooking on its glycemic index has not been reported. Hence this study has investi- gated the effect of a dietary intake of boiled breadfruit on the serum glucose, glucose tolerance, body weights and relative organ weights of streptozotocin (STZ) induced diabetic rats. METHODS: Twenty albino rats were used and were divided into four groups of five rats. Groups 1 (normal control) and 2 (diabetic control) received standard rat pellets while groups 3 (diabetic-test group) and 4 (non-diabetic) rats received breadfruit. RESULTS: The blood glucose of the normoglycemic rats fed standard rat feeds peaked at 30 min (149.75 +/-11.12 mg/dl) following oral glucose loading (3 g/kg) but reduced to 85.25 +/-21.05 mg/dl after another 90 min, while the blood glucose of the normoglycemic rats fed breadfruit peaked at 30 min (146.25 +/ 15.22 mg/dl) follow- ing oral glucose loading, but elevated (130.75 +/-36.69 mg/dl) after another 90 min. There was significant elevation (P < 0.05) of the serum glucose, relative liver weight (RLW) and relative kidney weight (RKW) but a significant decrease in the body weights of the diabetic control compared with the normal control; no sig- nificant difference (P > 0.05) in the serum glucose, body weights, RLW and RKW of the test group compared with the diabetic control, and no significant differences (P > 0.05) in the serum glucose, body weights, RLW and RKW of the normal rats fed the breadfruit diet compared to the normal control. CONCLUSIONS: The study showed that the traditional method of cooking African breadfruit negatively affects its hypoglycemic property. PMID- 28362479 TI - Studies on the Activation and Hydrosilylation Catalysis of RhCl3(Bu2S)3. AB - RhCl3(Bu2S)3 is an industrial precatalyst utilized in the curing of some solventless silicone-release coatings formulations. The catalyst requires no additional inhibitor, in contrast to typical Pt formulations, and so questions arose about how fast the catalyst could trigger curing if it were used in a more activated form. Studies on the activation of RhCl3(Bu2S)3 revealed multiple intermediates, of which [RhCl(Bu2S)2]2 and [RhHCl(SiMe(OSiMe3)2) (Bu2S)2]2 were isolated. [RhHCl(SiMe(OSiMe3)2)(Bu2S)2]2 is the most activated form of the precatalyst, showing a brief induction period. Various experiments were performed to analyze the nature of the catalyst, including Hg poisoning, addition of poison ligands, and comparisons versus Rh nanoparticles. The data tend to be more consistent with a molecular catalyst than Rh nanoparticles. Data are also provided that support the active catalyst containing a RhxClx(Bu2S)2x fragment, although the exact identity of the active catalyst is not yet determined. PMID- 28362480 TI - Flexible Light Emission Diode Arrays Made of Transferred Si Microwires-ZnO Nanofilm with Piezo-Phototronic Effect Enhanced Lighting. AB - Due to the fragility and the poor optoelectronic performances of Si, it is challenging and exciting to fabricate the Si-based flexible light-emitting diode (LED) array devices. Here, a flexible LED array device made of Si microwires-ZnO nanofilm, with the advantages of flexibility, stability, lightweight, and energy savings, is fabricated and can be used as a strain sensor to demonstrate the two dimensional pressure distribution. Based on piezo-phototronic effect, the intensity of the flexible LED array can be increased more than 3 times (under 60 MPa compressive strains). Additionally, the device is stable and energy saving. The flexible device can still work well after 1000 bending cycles or 6 months placed in the atmosphere, and the power supplied to the flexible LED array is only 8% of the power of the surface-contact LED. The promising Si-based flexible device has wide range application and may revolutionize the technologies of flexible screens, touchpad technology, and smart skin. PMID- 28362481 TI - CN-Modified Host Materials for Improved Efficiency and Lifetime in Blue Phosphorescent and Thermally Activated Delayed Fluorescent Organic Light-Emitting Diodes. AB - CN-modified host materials, 9-(2-(9-phenyl-9H-carbazol-3-yl)phenyl)-9H-carbazole 3-carbonitrile (o-CzCN) and 9-(3-(9-phenyl-9H-carbazol-3-yl)phenyl)-9H-carbazole 3-carbonitrile (m-CzCN), which can improve the external quantum efficiency and lifetime of both blue phosphorescent and thermally activated delayed fluorescent (TADF) emitters were developed. A molecular design approach to stabilize the molecular structure and reduce the energy gap produced two high triplet energy host materials of o-CzCN and m-CzCN compatible with the phosphorescent and TADF emitters. The new host materials lowered operation voltage, increased quantum efficiency, and elongated lifetime of both phosphorescent and TADF devices. PMID- 28362482 TI - Synthesis, Characterization, and Device Application of Antimony-Substituted Violet Phosphorus: A Layered Material. AB - Two-dimensional (2D) nanoflakes have emerged as a class of materials that may impact electronic technologies in the near future. A challenging but rewarding work is to experimentally identify 2D materials and explore their properties. Here, we report the synthesis of a layered material, P20.56(1)Sb0.44(1), with a systematic study on characterizations and device applications. This material demonstrates a direct band gap of around 1.67 eV. Using a laser-cutting method, the thin flakes of this material can be separated into multiple segments. We have also fabricated field effect transistors based on few-layer P20.56(1)Sb0.44(1) flakes with a thickness down to a few nanometers. Interestingly, these field effect transistors show strong photoresponse within the wavelength range of visible light. At room temperature, we have achieved good mobility values (up to 58.96 cm2/V.s), a reasonably high on/off current ratio (~103), and intrinsic responsivity up to 10 MUA/W. Our results demonstrate the potential of P20.56(1)Sb0.44(1) thin flakes as a two-dimensional material for applications in visible light detectors. PMID- 28362484 TI - Reduction of Bromate by Cobalt-Impregnated Biochar Fabricated via Pyrolysis of Lignin Using CO2 as a Reaction Medium. AB - In this study, pyrolysis of lignin impregnated with cobalt (Co) was conducted to fabricate a Co-biochar (i.e., Co/lignin biochar) for use as a catalyst for bromate (BrO3-) reduction. Carbon dioxide (CO2) was employed as a reaction medium in the pyrolysis to induce desired effects associated with CO2; (1) the enhanced thermal cracking of volatile organic compounds (VOCs) evolved from the thermal degradation of biomass, and (2) the direct reaction between CO2 and VOCs, which resulted in the enhanced generation of syngas (i.e., H2 and CO). This study placed main emphases on three parts: (1) the role of impregnated Co in pyrolysis of lignin in the presence of CO2, (2) the characterization of Co/lignin biochar, and (3) evaluation of catalytic capability of Co-lignin biochar in BrO3- reduction. The findings from the pyrolysis experiments strongly evidenced that the desired CO2 effects were strengthened due to catalytic effect of impregnated Co in lignin. For example, the enhanced generation of syngas from pyrolysis of Coimpregnated lignin in CO2 was more significant than the case without Co impregnation. Moreover, pyrolysis of Coimpregnated lignin in CO2 led to production of biochar of which surface area (599 m2 g-1) is nearly 100 times greater than the biochar produced in N2 (6.6 m2 g-1). Co/lignin biochar produced in CO2 also showed a great performance in catalyzing BrO3- reduction as compared to the biochar produced in N2. PMID- 28362486 TI - Substituent Effects That Control Conjugated Oligomer Conformation through Non covalent Interactions. AB - Although understanding the conformations and arrangements of conjugated materials as solids is key to their prospective applications, predictive power over these structural factors remains elusive. In this work, substituent effects tune non covalent interactions between side-chain fluorinated benzyl esters and main-chain terminal arenes, in turn controlling the conformations and interchromophore aggregation of three-ring phenylene-ethynylenes (PEs). Cofacial fluoroarene-arene (ArF-ArH) interactions cause twisting in the PE backbone, interrupting intramolecular conjugation as well as blocking chromophore aggregation, both of which prevent the typically observed bathochromic shift observed upon transitioning PEs from solution to solid. This work highlights two structural factors that determine whether the ArF-ArH interactions, and the resulting twisted, unaggregated chromophores, occur in these solids: (i) the electron releasing characteristic of substituents on ArH, with more electron-releasing character favoring ArF-ArH interactions, and (ii) the fluorination pattern of the ArF ring, with 2,3,4,5,6-pentafluorophenyl favoring ArF-ArH interactions over 2,4,6-trifluorophenyl. These trends indicate that considerations of electrostatic complementarity, whether through a polar-pi or substituent-substituent mechanism, can serve as an effective design principle in controlling the interaction strengths, and therefore the optoelectronic properties, of these molecules as solids. PMID- 28362485 TI - Nitrogen-Doped Nanoporous Carbon Membranes with Co/CoP Janus-Type Nanocrystals as Hydrogen Evolution Electrode in Both Acidic and Alkaline Environments. AB - Self-supported electrocatalysts being generated and employed directly as electrodes for energy conversion has been intensively pursued in the fields of materials chemistry and energy. Herein, we report a synthetic strategy to prepare freestanding hierarchically structured, nitrogen-doped nanoporous graphitic carbon membranes functionalized with Janus-type Co/CoP nanocrystals (termed as HNDCM-Co/CoP), which were successfully applied as a highly efficient, binder-free electrode in the hydrogen evolution reaction (HER). Benefited from multiple structural merits, such as a high degree of graphitization, three-dimensionally interconnected micro/meso/macropores, uniform nitrogen doping, well-dispersed Co/CoP nanocrystals, as well as the confinement effect of the thin carbon layer on the nanocrystals, HNDCM-Co/CoP exhibited superior electrocatalytic activity and long-term operation stability for HER under both acidic and alkaline conditions. As a proof-of-concept of practical usage, a 5.6 cm * 4 cm * 60 MUm macroscopic piece of HNDCM-Co/CoP was prepared in our laboratory. Driven by a solar cell, electroreduction of water in alkaline conditions (pH 14) was performed, and H2 was produced at a rate of 16 mL/min, demonstrating its potential as real-life energy conversion systems. PMID- 28362483 TI - Exploring the Influence of Domain Architecture on the Catalytic Function of Diterpene Synthases. AB - Terpenoid synthases catalyze isoprenoid cyclization reactions underlying the generation of more than 80,000 natural products. Such dramatic chemodiversity belies the fact that these enzymes generally consist of only three domain folds designated as alpha, beta, and gamma. Catalysis by class I terpenoid synthases occurs exclusively in the alpha domain, which is found with alpha, alphaalpha, alphabeta, and alphabetagamma domain architectures. Here, we explore the influence of domain architecture on catalysis by taxadiene synthase from Taxus brevifolia (TbTS, alphabetagamma), fusicoccadiene synthase from Phomopsis amygdali (PaFS, (alphaalpha)6), and ophiobolin F synthase from Aspergillus clavatus (AcOS, alphaalpha). We show that the cyclization fidelity and catalytic efficiency of the alpha domain of TbTS are severely compromised by deletion of the betagamma domains; however, retention of the beta domain preserves significant cyclization fidelity. In PaFS, we previously demonstrated that one alpha domain similarly influences catalysis by the other alpha domain [ Chen , M. , Chou , W. K. W. , Toyomasu , T. , Cane , D. E. , and Christianson , D. W. ( 2016 ) ACS Chem. Biol. 11 , 889 - 899 ]. Here, we show that the hexameric quaternary structure of PaFS enables cluster channeling. We also show that the alpha domains of PaFS and AcOS can be swapped so as to make functional chimeric alphaalpha synthases. Notably, both cyclization fidelity and catalytic efficiency are altered in all chimeric synthases. Twelve newly formed and uncharacterized C20 diterpene products and three C25 sesterterpene products are generated by these chimeras. Thus, engineered alphabetagamma and alphaalpha terpenoid cyclases promise to generate chemodiversity in the greater family of terpenoid natural products. PMID- 28362487 TI - Mesoporous, Three-Dimensional Wood Membrane Decorated with Nanoparticles for Highly Efficient Water Treatment. AB - Wood, an earth-abundant material, is widely used in our everyday life. With its mesoporous structure, natural wood is comprised of numerous long, partially aligned channels (lumens) as well as nanochannels that stretch along its growth direction. This wood mesostructure is suitable for a range of emerging applications, especially as a membrane/separation material. Here, we report a mesoporous, three-dimensional (3D) wood membrane decorated with palladium nanoparticles (Pd NPs/wood membrane) for efficient wastewater treatment. The 3D Pd NPs/wood membrane possesses the following advantages: (1) the uniformly distributed lignin within the wood mesostructure can effectively reduce Pd(II) ions to Pd NPs; (2) cellulose, with its abundant hydroxyl groups, can immobilize Pd NPs; (3) the partially aligned mesoporous wood channels as well as their inner ingenious microstructures increase the likelihood of wastewater contacting Pd NPs decorating the wood surface; (4) the long, Pd NP-decorated channels facilitate bulk treatment as water flows through the entire mesoporous wood membrane. As a proof of concept, we demonstrated the use and efficiency of a Pd NPs/wood membrane to remove methylene blue (MB, C16H18N3ClS) from a flowing aqueous solution. The turnover frequency of the Pd NPs/wood membrane, ~2.02 molMB.molPd 1.min-1, is much higher than the values reported in the literature. The water treatment rate of the 3D Pd NPs/wood membrane can reach 1 * 105 L.m-2.h-1 with a high MB removal efficiency (>99.8%). The 3D mesoporous wood membrane with partially aligned channels exhibits promising results for wastewater treatment and is applicable for an even wider range of separation applications. PMID- 28362489 TI - Catalytic Enolate Arylation with 3-Bromoindoles Allows the Formation of beta Carbolines. AB - Synthesis of substituted beta-carbolines was accomplished by utilizing the catalytic enolate arylation reaction of ketones in conjunction with several 3 bromoindole derivatives. Quenching of the arylation reaction in situ with an electrophile allowed ready incorporation of functionality at the carboline C-4 position in an efficient one-pot protocol. PMID- 28362488 TI - Serotonin Transporter Associated Protein Complexes Are Enriched in Synaptic Vesicle Proteins and Proteins Involved in Energy Metabolism and Ion Homeostasis. AB - The serotonin transporter (SERT) mediates Na+-dependent high-affinity serotonin uptake and plays a key role in regulating extracellular serotonin concentration in the brain and periphery. To gain novel insight into SERT regulation, we conducted a comprehensive proteomics screen to identify components of SERT associated protein complexes in the brain by employing three independent approaches. In vivo SERT complexes were purified from rat brain using an immobilized high-affinity SERT ligand, amino-methyl citalopram. This approach was combined with GST pulldown and yeast two-hybrid screens using N- and C-terminal cytoplasmic transporter domains as bait. Potential SERT associated proteins detected by at least two of the interaction methods were subjected to gene ontology analysis resulting in the identification of functional protein clusters that are enriched in SERT complexes. Prominent clusters include synaptic vesicle proteins, as well as proteins involved in energy metabolism and ion homeostasis. Using subcellular fractionation and electron microscopy we provide further evidence that SERT is indeed associated with synaptic vesicle fractions, and colocalizes with small vesicular structures in axons and axon terminals. We also show that SERT is found in close proximity to mitochondrial membranes in both, hippocampal and neocortical regions. We propose a model of the SERT interactome, in which SERT is distributed between different subcellular compartments through dynamic interactions with site-specific protein complexes. Finally, our protein interaction data suggest novel hypotheses for the regulation of SERT activity and trafficking, which ultimately impact on serotonergic neurotransmission and serotonin dependent brain functions. PMID- 28362490 TI - Convergence of Computed Aqueous Absorption Spectra with Explicit Quantum Mechanical Solvent. AB - For reliable condensed phase simulations, an accurate model that includes both short- and long-range interactions is required. Short- and long-range interactions can be particularly strong in aqueous solution, where hydrogen bonding may play a large role at short range and polarization may play a large role at long range. Although short-range solute-solvent interactions such as charge transfer, hydrogen bonding, and solute-solvent polarization can be taken into account with a quantum mechanical (QM) treatment of the solvent, it is unclear how much QM solvent is necessary to accurately model interactions with different solutes. In this work, we investigate the effect of explicit QM solvent on absorption spectra computed for a series of solutes with decreasing polarity. By adjusting the boundary between QM and classical molecular mechanical solvent to include up to 400 QM water molecules, convergence of the calculated absorption spectra with respect to the size of the QM region is achieved. We find that the rate of convergence does not correlate with solute polarity when excitation energies are calculated using time-dependent density functional theory with a range-separated hybrid functional, but it does correlate with solute polarity when using configuration interaction singles. We also find that larger basis sets converge the computed spectrum with fewer QM solvent molecules. To optimize the computational cost with respect to convergence, we test a mixed basis set with more basis functions for atoms of the chromophore and the solvent molecules that are nearest to it and fewer basis functions for the atoms of the remaining solvent molecules in the QM region. Our results show that using a mixed basis set is a potentially effective way to significantly lower the computational cost while reproducing the results computed with larger basis sets. PMID- 28362491 TI - Efficient, "On-the-Fly", Born-Oppenheimer and Car-Parrinello-type Dynamics with Coupled Cluster Accuracy through Fragment Based Electronic Structure. AB - We recently developed two fragment based ab initio molecular dynamics methods, and in this publication we have demonstrated both approaches by constructing efficient classical trajectories in agreement with trajectories obtained from "on the-fly" CCSD. The dynamics trajectories are obtained using both Born-Oppenheimer and extended Lagrangian (Car-Parrinello-style) options, and hence, here, for the first time, we present Car-Parrinello-like AIMD trajectories that are accurate to the CCSD level of post-Hartree-Fock theory. The specific extended Lagrangian implementation used here is a generalization to atom-centered density matrix propagation (ADMP) that provides post-Hartree-Fock accuracy, and hence the new method is abbreviated as ADMP-pHF; whereas the Born-Oppenheimer version is called frag-BOMD. The fragmentation methodology is based on a set-theoretic, inclusion exclusion principle based generalization of the well-known ONIOM method. Thus, the fragmentation scheme contains multiple overlapping "model" systems, and overcounting is compensated through the inclusion-exclusion principle. The energy functional thus obtained is used to construct Born-Oppenheimer forces (frag-BOMD) and is also embedded within an extended Lagrangian (ADMP-pHF). The dynamics is tested by computing structural and vibrational properties for protonated water clusters. The frag-BOMD trajectories yield structural and vibrational properties in excellent agreement with full CCSD-based "on-the-fly" BOMD trajectories, at a small fraction of the cost. The asymptotic (large system) computational scaling of both frag-BOMD and ADMP-pHF is inferred as [Formula: see text], for on-the-fly CCSD accuracy. The extended Lagrangian implementation, ADMP-pHF, also provides structural features in excellent agreement with full "on-the-fly" CCSD calculations, but the dynamical frequencies are slightly red-shifted. Furthermore, we study the behavior of ADMP-pHF as a function of the electronic inertia tensor and find a monotonic improvement in the red-shift as we reduce the electronic inertia. In all cases a uniform spectral scaling factor, that in our preliminary studies appears to be independent of system and independent of level of theory (same scaling factor for both MP2 and CCSD implementations ADMP-pHF and for ADMP DFT), improves on agreement between ADMP-pHF and full CCSD calculations. Hence, we believe both frag-BOMD and ADMP-pHF will find significant utility in modeling complex systems. The computational power of frag-BOMD and ADMP-pHF is demonstrated through preliminary studies on a much larger protonated 21-water cluster, for which AIMD trajectories with "on-the-fly" CCSD are not feasible. PMID- 28362492 TI - Synthesis of Low Pt-Based Quaternary PtPdRuTe Nanotubes with Optimized Incorporation of Pd for Enhanced Electrocatalytic Activity. AB - Improving heteroatomic interactions via alloying or forming heterogeneous catalysts is of importance to the enhancement in terms of electrocatalytic activity and stability. In this work, a simple galvanic replacement reaction was utilized to synthesize low Pt-based quaternary nanotubes (NTs). It is easy to obtain PtPdRuTe NTs with different composition and controlled shape using ultrathin Te nanowires (NWs) as sacrificial templates for its high activity. The NT wall thickness and formed NPs on the surface are closely related with the composition, especially Pd content. The optimized incorporation of Pd atoms into ternary PtRuTe NTs formed a uniform protecting PtPd surface and modified the Pt electronic structure to improve the methanol oxidation reaction (MOR) performance. X-ray photoelectron spectroscopy (XPS) reveals a larger extent of electron transfer from neighboring atoms to Pt on PtPdRuTe, consequently leading to a weaker bonding of the intermediate on Pt. As a result, the quaternary PtPdRuTe NTs exhibit enhanced activity and stability toward efficient MOR. PMID- 28362493 TI - Effect of Major Royal Jelly Proteins on Spatial Memory in Aged Rats: Metabolomics Analysis in Urine. AB - Royal jelly (RJ) produced by worker honeybees is the sole food for the queen bee throughout her life as well as the larvae of worker bees for the first 3 days after hatching. Supplementation of RJ in the diet has been shown to increase spatial memory in rodents. However, the key constituents in RJ responsible for improvement of cognitive function are unknown. Our objective was to determine if the major royal jelly proteins (MRJPs) extracted from RJ can improve the spatial memory of aged rats. The spatial memory assay using the Morris water maze test was administered once to rats after a 14-week feeding. Metabolomics analysis based on quadrupole time-of-flight mass spectrometry was conducted to examine the differences in compounds from urine. Aged male rats fed MRJPs showed improved spatial memory up to 48.5% when compared to the control male aged rats fed distilled water. The metabolite pattern of the MRJPs-fed aged rats was regressed to that of the young rats. Compounds altered by MRJPs were mapped to nicotinate and nicotinamide metabolism, cysteine taurine metabolism, and energy metabolism pathways. In summary, MRJPs may improve spatial memory and possess the potential for prevention of cognitive impairment via the cysteine and taurine metabolism and energy metabolism pathways in aged rats. PMID- 28362494 TI - Constructive and Destructive Interference in Nonadiabatic Tunneling via Conical Intersections. AB - As a manifestation of the molecular Aharonov-Bohm effect, tunneling-facilitated dissociation under a conical intersection (CI) requires the inclusion of the geometric phase (GP) to ensure a single-valued adiabatic wave function encircling the CI. In this work, we demonstrate using a simple two-dimensional model that the GP induces destructive interference for vibrational states with even quanta in the coupling mode, but it leads to constructive interference for those with odd quanta. The interference patterns are manifested in tunneling wave functions and clearly affect the tunneling lifetime. It is further shown that the inclusion of the diagonal Born-Oppenheimer correction is necessary for agreement with exact results. PMID- 28362495 TI - Mechanistic Studies on a Cu-Catalyzed Asymmetric Allylic Alkylation with Cyclic Racemic Starting Materials. AB - Mechanistic studies on Cu-catalyzed asymmetric additions of alkylzirconocene nucleophiles to racemic allylic halide electrophiles were conducted using a combination of isotopic labeling, NMR spectroscopy, kinetic modeling, structure activity relationships, and new reaction development. Kinetic and dynamic NMR spectroscopic studies provided insight into the oligomeric Cu-ligand complexes, which evolve during the course of the reaction to become faster and more highly enantioselective. The Cu-counterions play a role in both selecting different pathways and in racemizing the starting material via formation of an allyl iodide intermediate. We quantify the rate of Cu-catalyzed allyl iodide isomerization and identify a series of conditions under which the formation and racemization of the allyl iodide occurs. We developed reaction conditions where racemic allylic phosphates are suitable substrates using new phosphoramidite ligand D. D also allows highly enantioselective addition to racemic seven-membered-ring allyl chlorides for the first time. 1H and 2H NMR spectroscopy experiments on reactions using allylic phosphates showed the importance of allyl chloride intermediates, which form either by the action of TMSCl or from an adventitious chloride source. Overall these studies support a mechanism where complex oligomeric catalysts both racemize the starting material and select one enantiomer for a highly enantioselective reaction. It is anticipated that this work will enable extension of copper-catalyzed asymmetric reactions and provide understanding on how to develop dynamic kinetic asymmetric transformations more broadly. PMID- 28362497 TI - Intramolecular Light-Driven Accumulation of Reduction Equivalents by Proton Coupled Electron Transfer. AB - The photochemistry of a molecular pentad composed of a central anthraquinone (AQ) acceptor flanked by two Ru(bpy)32+ photosensitizers and two peripheral triarylamine (TAA) donors was investigated by transient IR and UV-vis spectroscopies in the presence of 0.2 M p-toluenesulfonic acid (TsOH) in deaerated acetonitrile. In ~15% of all excited pentad molecules, AQ is converted to its hydroquinone form (AQH2) via reversible intramolecular electron transfer from the two TAA units (tau = 65 ps), followed by intermolecular proton transfer from TsOH (tau ~ 3 ns for the first step). Although the light-driven accumulation of reduction equivalents occurs through a sequence of electron and proton transfer steps, the resulting photoproduct decays via concerted PCET (tau = 4.7 MUs) with an H/D kinetic isotope effect of 1.4 +/- 0.2. Moreover, the reoxidation of AQH2 seems to take place via a double electron transfer step involving both TAA+ units rather than sequential single electron transfer events. Thus, the overall charge-recombination reaction seems to involve a concerted proton-coupled two-electron oxidation of AQH2. The comparison of experimental data obtained in neat acetonitrile with data from acidic solutions suggests that the inverted driving-force effect can play a crucial role for obtaining long-lived photoproducts resulting from multiphoton, multielectron processes. Our pentad provides the first example of light-driven accumulation of reduction equivalents stabilized by PCET in artificial molecular systems without sacrificial reagents. Our study provides fundamental insight into how light-driven multielectron redox chemistry, for example the reduction of CO2 or the oxidation of H2O, can potentially be performed without sacrificial reagents. PMID- 28362496 TI - Near-Infrared-Triggered Photodynamic Therapy with Multitasking Upconversion Nanoparticles in Combination with Checkpoint Blockade for Immunotherapy of Colorectal Cancer. AB - While immunotherapy has become a highly promising paradigm for cancer treatment in recent years, it has long been recognized that photodynamic therapy (PDT) has the ability to trigger antitumor immune responses. However, conventional PDT triggered by visible light has limited penetration depth, and its generated immune responses may not be robust enough to eliminate tumors. Herein, upconversion nanoparticles (UCNPs) are simultaneously loaded with chlorin e6 (Ce6), a photosensitizer, and imiquimod (R837), a Toll-like-receptor-7 agonist. The obtained multitasking UCNP-Ce6-R837 nanoparticles under near-infrared (NIR) irradiation with enhanced tissue penetration depth would enable effective photodynamic destruction of tumors to generate a pool of tumor-associated antigens, which in the presence of those R837-containing nanoparticles as the adjuvant are able to promote strong antitumor immune responses. More significantly, PDT with UCNP-Ce6-R837 in combination with the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) checkpoint blockade not only shows excellent efficacy in eliminating tumors exposed to the NIR laser but also results in strong antitumor immunities to inhibit the growth of distant tumors left behind after PDT treatment. Furthermore, such a cancer immunotherapy strategy has a long-term immune memory function to protect treated mice from tumor cell rechallenge. This work presents an immune-stimulating UCNP-based PDT strategy in combination with CTLA-4 checkpoint blockade to effectively destroy primary tumors under light exposure, inhibit distant tumors that can hardly be reached by light, and prevent tumor reoccurrence via the immune memory effect. PMID- 28362498 TI - Sterically Protected N2O-Type Benzopyrromethene Boron Complexes from Boronic Acids with Intense Red/Near-Infrared Fluorescence. AB - A series of N2O-type benzopyrromethene boron complexes have been synthesized from the condensation of pyrrole, formylisoindole, and various boronic acids. These dyes have red/near-infrared absorption, high solution- and solid-state fluorescence, as well as good solubility in a variety of solvents due to the presence of axial-substituted groups that provide steric protection and prevent their possible aggregations. Two water-soluble derivatives with pyridinium ions were developed as near-infrared excitable mitochondrially localizing fluorescent probes. PMID- 28362499 TI - Two-Step, One-Flask Synthesis of an N-Confused Porphyrin Bearing Pentafluorophenyl Substituents. AB - A two-step, one-flask reaction of pyrrole and pentafluorobenzaldehyde was investigated as a streamlined synthetic route to an N-confused porphyrin bearing pentafluorophenyl substituents previously prepared by a stepwise route. A survey of acid catalysts, acid catalyst concentration, DDQ quantity, and reaction time was performed with monitoring by HPLC. The targeted N-confused porphyrin was observed from many reaction conditions. The best condition afforded the N confused porphyrin in an isolated yield of 10-12% (245-281 mg), providing improved access to this interesting porphyrinoid. PMID- 28362500 TI - Antibacterial Compounds from Marine Bacteria, 2010-2015. AB - This review summarizes the reports on antibacterial compounds that have been obtained from marine-derived bacteria during the period 2010-2015. Over 50 active compounds were isolated during this period, most of which (69%) were obtained from Actinobacteria. Several compounds were already known, such as etamycin A (11) and nosiheptide (65), and new experiments with them showed some previously undetected antibacterial activities, highlighting the fact that known natural products may be an important source of new antibacterial leads. New broad spectrum antibacterial compounds were reported with activity against antibiotic resistant Gram-positive and Gram-negative bacteria. Anthracimycin (33), kocurin (66), gageotetrins A-C (72-74), and gageomacrolactins 1-3 (86-88) are examples of compounds that display promising properties and could be leads to new antibiotics. A number of microbes produced mixtures of metabolites sharing similar chemical scaffolds, and structure-activity relationships are discussed. PMID- 28362502 TI - Testing Exact Upper Bounds to Exact Exchange. AB - The exact exchange energy and its energy density are useful but computationally expensive ingredients in density functional approximations for Kohn-Sham density functional theory. We present detailed tests of some exact nonempirical upper bounds to exact exchange. These "Rung 3.5" upper bounds contract the Kohn-Sham one-particle density matrix with model density matrices used to construct semilocal model exchange holes and invoke the Cauchy-Schwarz inequality. The contraction automatically eliminates the computationally expensive long-range component of the exact exchange hole. Numerical tests show that the exchange upper bounds underestimate total exchange energies while predicting other properties with accuracy approaching standard hybrid approximations. PMID- 28362503 TI - Direct Catalytic Asymmetric Reductive Amination of Aliphatic Ketones Utilizing Diphenylmethanamine as Coupling Partner. AB - The highly efficient direct catalytic reductive amination of ketones with diphenylmethanamine catalyzed by iridium-phosphoramidite complexes is described. As an effective coupling partner, diphenylmethanamine is suitable for a wide range of ketones to provide chiral amines in high yields and enantioselectivity. The chiral monodentate phosphoramidite ligands are tunable and competent to accommodate substrates with different structures. PMID- 28362501 TI - Indole Alkaloids from Hunteria zeylanica. AB - Six new bisindole alkaloids, hunterizeylines A-F (1-6), three new monomers, hunterizeylines G-I (7-9), and 13 known alkaloids were isolated from an aqueous MeOH extract of the twigs and leaves of Hunteria zeylanica. Hunterizeyline H, geissoschizol, and dihydrocorynantheol displayed weak insecticidal activity against the aphid Rhodobium porosum, with IC50 values of 168.2, 360.5, and 290.6 MUM, respectively. PMID- 28362504 TI - Synthesis of Indolizines via Reaction of 2-Substitued Azaarenes with Enals by an Amine-NHC Relay Catalysis. AB - A metal-free catalytic strategy for the facile synthesis of biologically relevant molecular architectures indolizines and imidazopyridines has been developed. The process is promoted by amine and N-heterocyclic carbene (NHC) relay catalysis via Michael addition-[3 + 2] fusion of simple azaarenes and alpha,beta-unsaturated aldehydes. The preparative power is demonstrated in the synthesis of anxiolytic drug saripidem via two simple one-pot operations with overall 45% yield. PMID- 28362505 TI - Radiation and Internal Loss Engineering of High-Stress Silicon Nitride Nanobeams. AB - High-stress Si3N4 nanoresonators have become an attractive choice for electro- and optomechanical devices. Membrane resonators can achieve quality factor (Q) frequency (f) products exceeding 1013 Hz, enabling (in principle) quantum coherent operation at room temperature. String-like beam resonators possess smaller Q * f products; however, on account of their significantly lower mass and mode density, they remain a canonical choice for precision force, mass, and charge sensing, and have recently enabled Heisenberg-limited position measurements at cryogenic temperatures. Here we explore two techniques to enhance the Q of a nanomechanical beam. The techniques relate to two main loss mechanisms: internal loss, which dominates for high aspect ratios and f ? 100 MHz, and radiation loss, which dominates for low aspect ratios and f ? 100 MHz. First, we show that by embedding a nanobeam in a 1D phononic crystal (PnC), it is possible to localize its flexural motion and shield it against radiation loss. Using this method, we realize f > 100 MHz modes with Q ~ 104, consistent with internal loss and contrasting sharply with unshielded beams of similar dimensions. We then study the Q * f product of high-order modes of millimeter long nanobeams. Taking advantage of the mode-shape dependence of stress-induced "loss dilution", we realize a f ~ 4 MHz mode with Q * f ~ 9 * 1012 Hz. Our results complement recent work on PnC-based "soft-clamping" of nanomembranes, in which mode localization is used to enhance loss dilution. Combining these strategies should enable ultra-low-mass nanobeam oscillators that operate deep in the quantum coherent regime at room temperature. PMID- 28362506 TI - Bias in Association between FEV1/FVC% Predicted at 7 Years and Asthma-Chronic Obstructive Pulmonary Disease Overlap Syndrome. PMID- 28362507 TI - Diagnostic errors when interpreting abdominopelvic computed tomography: a pictorial review. AB - Diagnostic errors remain an inevitable occurrence during abdominopelvic CT (APCT) interpretation, despite advances in imaging technology. The main cause of error is failure to identify a lesion (i.e. perceptual error) and failure to recognize a finding's significance (i.e. interpretive or cognitive error). Awareness and understanding of the causes of errors can reduce their occurrence and may lead to a reduction in morbidity and mortality. This pictorial essay highlights various causes of error in interpreting APCT scans and briefly discusses possible solutions for minimizing these errors. PMID- 28362510 TI - Apoptosis in Primary Hyperparathyroidism. AB - Primary hyperparathyroidism (PHPT) is defined by inappropriate elevation of parathormone, caused by parathyroid hyperplasia, also known as multi-gland disease (MGD), parathyroid adenoma (PA), or parathyroid carcinoma (PC). Although several studies have already been conducted, there is a lack of a definite diagnostic marker, which could unambiguously distinguish MGD from PA or PC. The accurate and prompt diagnosis has the key meaning for effective treatment and follow-up. This review paper presents the role of apoptosis in PHPT. The comparison of the expression of Fas, TRAIL, BCL-2 family members, p53 in MGD, PA, and PC, among others, was described. The expression of described factors varies among proliferative lesions of parathyroid gland; therefore, these could serve as additional markers to assist in the diagnosis. PMID- 28362508 TI - CT angiography for acute gastrointestinal bleeding: what the radiologist needs to know. AB - Acute gastrointestinal (GI) bleeding is a common cause of both emergency department visits and hospitalizations in the USA and can have a high morbidity and mortality if not treated rapidly. Imaging is playing an increasing role in both the diagnosis and management of GI bleeding. In particular, CT angiography (CTA) is a promising initial test for acute GI bleeding as it is universally available, can be performed rapidly and may provide diagnostic information to guide management. The purpose of this review was to provide an overview of the uses of imaging in the diagnosis and management of acute GI bleeding, with a focus on CTA. PMID- 28362512 TI - Prognostic Role of Cardiopulmonary Exercise Testing in Clinical Practice. AB - Risk stratification is a mainstay in the care of cardiac and pulmonary disorders, as the identification of adverse outcomes helps provide measures to improve survival and quality of life. The cardiopulmonary exercise test is a useful prognostic tool in the clinical evaluation of several pathological conditions, such as heart diseases, respiratory disorders, and pulmonary hypertension. If not contraindicated, a cardiopulmonary exercise test should always be performed and integrated with clinical, laboratory, and hemodynamic parameters to better stratify patient risk. In heart failure, the cardiopulmonary exercise test is important in all the stages of patient management, from diagnosis to risk assessment. Different exercise variables have been advocated as prognostic indicators in this condition, including peak oxygen uptake, ventilatory efficiency, respiratory patterns, and identification of the anaerobic threshold. The prognostic role of the cardiopulmonary exercise test in heart failure is amplified when included in multiparametric risk stratification methodology, currently considered the best method to assess patient outcome. In respiratory disorders and in pulmonary hypertension, cardiopulmonary exercise test parameters, focusing on ventilatory performance during exercise, may help evaluate the risk of adverse events. Finally, the cardiopulmonary exercise test may help define the presence of coexisting cardiac and respiratory disorders, a combination that leads to increased rates of disability and mortality. PMID- 28362511 TI - Effect of accurate heart delineation on cardiac dose during the CONVERT trial. AB - OBJECTIVE: This study investigated the effect of deviation from protocol in heart delineation for the Concurrent Once-daily Versus twice-daily Radiotherapy (CONVERT) Trial ( ClinicalTrials.gov Identifier NCT00433563) quality assurance (QA) programme and the effect of that on mean cardiac dose and percentage of heart volume receiving >=5 Gy (V5%) and percentage of heart volume receiving >=30 Gy (V30%). METHODS: Patients with limited-stage small-cell lung cancer in the CONVERT trial were randomized to receive 45 Gy in 30# twice daily or 66 Gy in 33# once daily radiotherapy, with concurrent chemotherapy in both arms. Of the 100 trial patient cases reviewed by the QA team [for patient selection, disease/organs at risk (OARs) outlining and treatment planning], 50 patient cases were selected, and the heart was reoutlined according to the "gold standard" trial protocol. Dose-volume histogram (DVH) data were extracted. The impact of change in heart volume on cardiac DVH is presented. RESULTS: For gold standard cardiac outlines, an increase in V5% and V30% was seen in 77.3% and 81.8% of cases, respectively, in the control arm (45 Gy) and in 78.6% and 82.1% of cases, respectively, in the experimental arm (66 Gy). The median increase in V5% was 1.4% and in V30%, it was 3.4%. The average of the mean cardiac dose for the control arm increased by 2.1 Gy (from 15.2 Gy for the centres outline to 17.3 Gy for the gold standard outline) and for the experimental arm by 2.4 Gy (from 16.2 to 18.6 Gy). CONCLUSION: This study demonstrates the importance of having a robust QA programme in place to ensure accuracy of cardiac delineation to facilitate future studies investigating the impact of cardiac dose on toxicity. Advances in knowledge: This study highlights the importance of ensuring accurate delineation of OARs in clinical trials, where conclusions about normal tissue toxicity are to be drawn. PMID- 28362513 TI - Birth Weight and Lung Function in Adulthood: A Systematic Review and Meta analysis. AB - RATIONALE: There is evidence suggesting that birth weight may influence lung function in adulthood, but it is unclear whether it might differentially affect restrictive (FVC) and obstructive (FEV1/FVC) patterns. OBJECTIVES: To summarize evidence available on the association of birth weight, weight at 1 year, and weight gain in the first year of life with FVC and FEV1/FVC in adulthood. METHODS: We performed a systematic review of the literature by searching MEDLINE, EMBASE, and Web of Science through January 2015. Data were combined using inverse variance weighted meta-analysis with random effects models and between-study heterogeneity evaluated. We conducted a priori subgroup or sensitivity analyses by age, country wealth, ethnicity, sex, and smoking. We evaluated risk of bias using the Newcastle Ottawa Scale and reporting bias using funnel plots. RESULTS: Eighteen articles were included in the review and 13 in the meta-analyses. Most studies were from high-income countries, and all had a low risk of bias. We found strong evidence of an association of birth weight with adult FVC, a 59.4 ml higher FVC in adulthood per kilogram increase in birth weight (95% confidence interval, 43.3-75.5), with no evidence of heterogeneity. Evidence of an association of birth weight with FEV1/FVC was weaker and showed some inconsistency across studies. Only one study investigated weight at 1 year, and another one reported weight gain in the first year. CONCLUSIONS: Our meta analyses show strong and consistent evidence of an association of birth weight with adult FVC, a measure of restrictive impairment, with much weaker evidence for airflow obstruction. PMID- 28362514 TI - Preclinical to phase II amyloid beta (Abeta) peptide modulators under investigation for Alzheimer's disease. AB - INTRODUCTION: Alzheimer disease (AD) is the most common form of dementia and its incidence is increasing at an alarming rate all over the world. The pathophysiology of AD is characterized by chronic, progressive neurodegeneration which involves early synaptotoxicity. One of the most obvious pathological feature of AD is the accumulation of amyloid-beta (Abeta) in the brain. Since current treatment options only provide symptomatic help and Abeta is thought to underlie early synaptic pathology, Abeta reduction or modulation in the brain may be a promising therapeutic strategy in preventing and /or reversing AD-related dysfunction. Areas covered: This paper outlines and evaluates the current landscape of preclinical and clinical studies focusing on modulating Abeta pathophysiology. Data and analysis for this review were procured from PubMed, clinicaltrials.gov and Alzforum. Expert opinion: According to current knowledge, reducing Abeta production offers numerous treatment options. However, targeting the initial steps by pharmacological interference with secretases is challenging due to the emergence of various side effects. The most promising approach seems to be the prevention of early Abeta oligomerization. Combination approaches targeting both Abeta and tau would seem to be another promising strategy that could have beneficial effects through the course of the disease. PMID- 28362515 TI - FBP1 is highly expressed in human hypertrophic scars and increases fibroblast proliferation, apoptosis, and collagen expression. AB - PURPOSE: FBP1, one of the far-upstream element binding proteins(FBPs), is a distal upstream binding protein of c-myc, which is highly expressed in tumor tissues. This study aimed to investigate FBP1 expression in human hypertrophic scars and to determine the effects of FBP1 on fibroblasts. MATERIALS AND METHODS: Human normal skin and scar specimens were collected during clinical surgery. One portion of each tissue specimen was embedded in paraffin and sliced to observe differences in histological features and FBP1 expression by immunohistochemistry and western blotting. The other portion of each tissue specimen was cultured to obtain fibroblasts. Fibroblasts from the second to the sixth passage were used for the experiments, which were divided into the following two groups: an experimental group, whose cells were transfected with an siRNA targeting FBP1, and a control group, whose cells where not transfected. MTT and TUNEL assays were performed, respectively, to assess fibroblast proliferation and apoptosis, and western blotting was performed to assess protein expression. RESULTS: We obtained fibroblasts by primary tissue culture and found that FBP1 was highly expressed in hypertrophic scars. MTT assay showed that an siRNA targeting FBP1 significantly reduced fibroblast proliferation in siRNA-treated cells compared to control cells. TUNEL assay showed that there was no difference in apoptosis between the two groups; however, western blotting showed that collagen I, collagen III, c myc, caspase-3, and caspase-9 expression levels were all decreased in the experimental group. CONCLUSION: FBP1 is highly expressed in human hypertrophic scars and increases fibroblast proliferation, apoptosis and collagen expression. PMID- 28362516 TI - Reply: Bias in Association between FEV1/FVC% Predicted at 7 Years and Asthma Chronic Obstructive Pulmonary Disease Overlap Syndrome. PMID- 28362517 TI - Long-Term Functional Outcome after Internal Delorme's Procedure for Obstructed Defecation Syndrome, and the Role of Postoperative Rehabilitation. AB - PURPOSE: To evaluate long-term functional outcomes of Internal Delorme's Procedure (IDP) in patients refractory to conservative treatment for Obstructed Defecation Syndrome (ODS), and to compare those who received postoperative rehabilitation with those who did not. MATERIALS AND METHODS: All patients with ODS refractory to nonoperative therapy were identified across three regional pelvic floor referral hospitals, and IDP was performed. Postoperatively selected patients received biofeedback therapy. Functional outcomes were established using the Cleveland Clinic Constipation (CCC) score and obstructed defecation score (OD score) preoperatively at 12 months and at the last available follow-up. Patient satisfaction was assessed with a visual analogue score. RESULTS: From October 2006 to September 2013, IDP was performed in 170 patients: 77 received postoperative biofeedback and 93 did not. Mean follow-up was 6.3 years (range 1-8 years). CCC and OD scores improved significantly in both groups after 12 months and at the last follow-up (p > 0.05). When comparing two groups while there was no significant difference between CCC and OD scores at 12 months, score was significantly better in the group that received rehabilitation at the last follow up (p = 0.001). Patient satisfaction was higher in the rehabilitation group (67%) compared with those without rehabilitation (55%). Clinical recurrence was recorded in nine patients who did not have postoperative rehabilitation. CONCLUSIONS: It has been demonstrated that IDP is associated with good long-term functional outcomes. Patients receiving rehabilitation had a better long-term follow-up, a higher overall satisfaction, and lower recurrence rate when compared with the patients who did not receive postoperative rehabilitation. PMID- 28362518 TI - Role of Angiography in Systemic Lupus Erythematosus-Induced Choroiditis. AB - PURPOSE: To report a case of systemic lupus erythematosus-induced choroidal vasculitis. METHODS: A 34-year-old woman with a long-standing history of systemic lupus erythematosus had a sudden painless loss of vision in the right eye over 12 hours. Ocular examination revealed a visual acuity of counting fingers of 1 foot on the right eye and 20/20 on the left. There was a relative afferent pupillary defect on the right side with a pink, distinct optic disk margin. RESULTS: Optical coherence tomography of the macula and fundus fluorescein angiogram for the eyes were normal. The MRI brain and orbit with the cerebral MRA did not show signs of optic neuritis or occipital vasculitic changes. However, the indocyanine green angiography revealed patches of ill-defined areas of choroidal hypofluorescence in the early- to mid-phase in the macula region. CONCLUSION: ICGA becomes the crucial tool in unmasking the presence of choroidal vasculitis. PMID- 28362519 TI - Salvage of Combat Hindfoot Fractures in 2003-2014 UK Military. AB - BACKGROUND: Hindfoot fractures pose a considerable challenge to military orthopaedic surgeons, as combat injuries are typically the result of energy transfers not seen in civilian practice. This study aimed to characterize the pattern of hindfoot injuries sustained by UK military casualties in recent conflicts, define the early amputation and infection rate, and identify factors associated with poor early outcomes. METHODS: The UK Joint Theatre Trauma Registry was searched for British military casualties sustaining a hindfoot fracture from Iraq and Afghanistan between 2003 and 2014. Data on the injury pattern and management were obtained along with 18-month follow-up data. Statistical analysis was performed with the chi-square test and binomial logistic regression analysis. The threshold for significance was set at P < .05. One hundred fourteen patients sustained 134 hindfoot injuries. Eighteen-month follow up was available for 92 patients (81%) and 114 hindfeet (85%). RESULTS: The calcaneus was fractured in 116 cases (87%): 54 (47%) were managed conservatively, 32 (28%) underwent K-wire fixation, and 30 (26%) underwent internal fixation. Nineteen patients (17%) required transtibial amputation during this time. A deep infection requiring operative treatment occurred in 13 cases (11%) with Staphylococcus aureus, the most common infectious organism (46%). A deep infection was strongly associated with operative fracture management ( P = .0016). When controlling for multiple variables, the presence of a deep infection was significantly associated with a requirement for amputation at 18 months ( P = .023). There was no association between open fractures and a requirement for amputation at 18 months ( P = .640), nor was conservative management associated with a requirement for amputation ( P = .999). Thirty-six fractures (32%) required unplanned revision surgery within the first 18 months following salvage, of which 19 (53%) involved amputation. CONCLUSION: A deep infection was the sole variable significantly associated with a requirement for amputation by 18 months. These results suggest that attempts at salvaging these injuries are at the limits of orthopaedic technical feasibility. LEVEL OF EVIDENCE: Level III, comparative series. PMID- 28362520 TI - A Systematic Review on Oral Isotretinoin Therapy and Clinically Observable Wound Healing in Acne Patients. AB - The association between isotretinoin and atypical wound healing remains controversial. It is common practice to delay elective procedures for 6 to 24 months after oral isotretinoin therapy. The studies supporting common practices (SCP) recommend extending this period to include the 6 to 24 months preceding treatment. The opposing studies (challenging common practices; CCP) state that the rate of scarring in isotretinoin patients is low and that delaying elective procedures is unnecessary. These practices impact a large number of dermatology patients undergoing acne treatment. This systematic review compiled articles obtained from online databases and examined data from both SCP and CCP studies. The inconsistencies in the reported data and the methodological flaws in the literature preclude any firm conclusions that can resolve the controversy. As such, this review demonstrates that there is insufficient evidence to either corroborate or refute delaying elective procedures in isotretinoin acne patients. Although the recent literature trends toward removing the procedural delay, we advocate for clinicians to consider the research presented in this review in the context of their own clinical experience and each individual patient's situation. The possible negative procedural outcomes must be weighed against the severity of the patient's acne scarring and the psychosocial impact of this scarring on the patient. PMID- 28362523 TI - A Man with Sleep-associated Symptomatic Bradycardia. PMID- 28362525 TI - Did Video Kill the Direct Laryngoscopy Star? Not Yet! PMID- 28362521 TI - A nationwide study on parathyroid carcinoma. AB - BACKGROUND: Parathyroid carcinoma (PC) is rare and diagnostically challenging. Reported outcomes are rather poor and the incidence might be increasing. MATERIAL AND METHODS: We performed a nationwide study on all cases (n= 32) diagnosed in 2000-2011 in Finland, and compared clinical and histopathological characteristics and outcome to atypical parathyroid (APA; n= 28) and parathyroid adenomas (PA; n= 72). The incidence in years 1955-1999 was compared to that in 2000-2013. RESULTS: Preoperatively, calcium and parathyroid hormone concentrations were higher in PC compared to APA and PA (1.76, 1.56 and 1.44 mmol/l, p < .001; and 989, 355 and 160 MUmol/l, p < .001, respectively). Calcium was <=1.77 mmol/l for all PAs. Hospitalization (44% vs. 22% and 3%, respectively, p = .01), renal (50% vs. 48% vs. 22%, respectively, p = .01) and bone (47% vs. 15% vs. 38%, respectively p = .002) manifestations were more common. PC and APA tumors were larger than PA (p < .001). Histopathological characteristics of PC compared to PA are increased mitotic activity (p= .001), chief cells (p = .003), diffuse growth pattern (p < .001), higher Ki67 (p< .001) and negative parafibromin (p < .001). One PC (1/18) and one APA (1/16) patient had a CDC73 mutation. After 6.7 (2-13.9) years of follow-up, 9.4% of PC had residual, 21% recurrent disease and 12.5% died of disease. Overall mortality did not differ between subgroups (p = .094). Recurrent PC was characterized by vascular invasion, lymph node metastases, high mitotic activity, necrosis and negative parafibromin. Incidence increased from 1.42 (range 0.52-2.14) to 7.14 (range 3.42-10.38)/10.000.000/years; (p < .001). CONCLUSIONS: PC associates with severe primary hyperparathyroidism and must be suspected if calcium >=1.77 mmol/l. The prevalence of CDC73 germline mutations in PC and APA in Finland is 6%. PC has distinct histopathological characteristics and its incidence has increased over the past decades. PMID- 28362522 TI - Multiple sclerosis update: use of MRI for early diagnosis, disease monitoring and assessment of treatment related complications. AB - MRI has long been established as the most sensitive in vivo technique for detecting multiple sclerosis (MS) lesions. The 2010 revisions of the McDonald Criteria have simplified imaging criteria, such that a diagnosis of MS can be made on a single contrast-enhanced MRI scan in the appropriate clinical context. New disease-modifying therapies have proven effective in reducing relapse rate and severity. Several of these therapies, most particularly natalizumab, but also dimethyl fumarate and fingolimod, have been associated with progressive multifocal leukoencephalopathy (PML). PML-immune reconstitution inflammatory syndrome (IRIS) has been recognized in patients following cessation of natalizumab owing to PML, and discontinuation for other reasons can lead to the phenomenon of rebound MS. These complications often provide a diagnostic dilemma and have implications for imaging surveillance of patients. We demonstrate how the updated McDonald Criteria aid the diagnosis of MS and describe the imaging characteristics of conditions such as PML and PML-IRIS in the context of MS. Potential imaging surveillance protocols are considered for the diagnosis and assessment of complications. We will explain how changes in MS treatment are leading to new imaging demands in order to monitor patients for disease progression and treatment-related complications. PMID- 28362524 TI - Multicenter Validation of a Customizable Scoring Tool for Selection of Trainees for a Residency or Fellowship Program. The EAST-IST Study. AB - RATIONALE: Few data have been published regarding scoring tools for selection of postgraduate medical trainee candidates that have wide applicability. OBJECTIVES: The authors present a novel scoring tool developed to assist postgraduate programs in generating an institution-specific rank list derived from selected elements of the U.S. Electronic Residency Application System (ERAS) application. METHODS: The authors developed and validated an ERAS and interview day scoring tool at five pulmonary and critical care fellowship programs: the ERAS Application Scoring Tool-Interview Scoring Tool. This scoring tool was then tested for intrarater correlation versus subjective rankings of ERAS applications. The process for development of the tool was performed at four other institutions, and it was performed alongside and compared with the "traditional" ranking methods at the five programs and compared with the submitted National Residency Match Program rank list. RESULTS: The ERAS Application Scoring Tool correlated highly with subjective faculty rankings at the primary institution (average Spearman's r = 0.77). The ERAS Application Scoring Tool-Interview Scoring Tool method correlated well with traditional ranking methodology at all five institutions (Spearman's r = 0.54, 0.65, 0.72, 0.77, and 0.84). CONCLUSIONS: This study validates a process for selecting and weighting components of the ERAS application and interview day to create a customizable, institution-specific tool for ranking candidates to postgraduate medical education programs. This scoring system can be used in future studies to compare the outcomes of fellowship training. PMID- 28362526 TI - By Expanding the Color Palette, CO-Oximetry Overcomes Some, but Not All, of the Uncommon Limitations of Pulse Oximetry. PMID- 28362527 TI - Three Years of Medical Education at the American Thoracic Society. PMID- 28362528 TI - Interpreting "Do Not Resuscitate": A Cautionary Tale of Physician Influence. PMID- 28362529 TI - Unilateral Pulmonary Edema after Visiting High Altitude. PMID- 28362530 TI - Pulmonary Cryptococcosis Developed from a Nodule after Treatment with Infliximab for Arthritis Associated with Ulcerative Colitis. PMID- 28362532 TI - Acute Orthodeoxia: Evaluation Using Point-of-Care Ultrasound Imaging. PMID- 28362531 TI - Comparison between Simulation-based Training and Lecture-based Education in Teaching Situation Awareness. A Randomized Controlled Study. AB - RATIONALE: Situation awareness has been defined as the perception of the elements in the environment within volumes of time and space, the comprehension of their meaning, and the projection of their status in the near future. Intensivists often make time-sensitive critical decisions, and loss of situation awareness can lead to errors. It has been shown that simulation-based training is superior to lecture-based training for some critical scenarios. Because the methods of training to improve situation awareness have not been well studied in the medical field, we compared the impact of simulation vs. lecture training using the Situation Awareness Global Assessment Technique (SAGAT) score. OBJECTIVES: To identify an effective method for teaching situation awareness. METHODS: We randomly assigned 17 critical care fellows to simulation vs. lecture training. Training consisted of eight cases on airway management, including topics such as elevated intracranial pressure, difficult airway, arrhythmia, and shock. During the testing scenario, at random times between 4 and 6 minutes into the simulation, the scenario was frozen, and the screens were blanked. Respondents then completed the 28 questions on the SAGAT scale. Sample items were categorized as Perception, Projection, and Comprehension of the situation. Results were analyzed using SPSS Version 21. RESULTS: Eight fellows from the simulation group and nine from the lecture group underwent simulation testing. Sixty-four SAGAT scores were recorded for the simulation group and 48 scores were recorded for the lecture group. The mean simulation vs. lecture group SAGAT score was 64.3 +/- 10.1 (SD) vs. 59.7 +/- 10.8 (SD) (P = 0.02). There was also a difference in the median Perception ability between the simulation vs. lecture groups (61.1 vs. 55.5, P = 0.01). There was no difference in the median Projection and Comprehension scores between the two groups (50.0 vs. 50.0, P = 0.92, and 83.3 vs. 83.3, P = 0.27). CONCLUSIONS: We found a significant, albeit modest, difference between simulation training and lecture training on the total SAGAT score of situation awareness mainly because of the improvement in perception ability. Simulation may be a superior method of teaching situation awareness. PMID- 28362534 TI - Reply: Did Video Kill the Direct Laryngoscopy Star? Not Yet! PMID- 28362533 TI - Modified Potts Shunt in an Adult with Idiopathic Pulmonary Arterial Hypertension. PMID- 28362535 TI - Diffuse Large B-Cell Lymphoma Presenting as Diffuse Bilateral Ground-Glass Opacities and Diagnosed on Transbronchial Lung Biopsy. PMID- 28362536 TI - What Baseball and Capitalism Can Teach Us about Selecting Residents and Fellows. PMID- 28362537 TI - Good Teaching and Good Teachers: The Role of Medical Education Research. PMID- 28362538 TI - Implementation of a Coaching Program for Peer Feedback on Large-Group Teaching. PMID- 28362539 TI - Whither the Pulmonary Ward Attending? Preserving Subspecialty Exposure in United States Internal Medicine Residency Training. AB - Twenty years ago, the term "hospitalist" was coined at the University of California-San Francisco (San Francisco, CA), heralding a new specialty focused on the care of inpatients. There are now more than 50,000 hospitalists practicing in the United States. At many academic medical centers, hospitalists are largely replacing subspecialists as attendings on the inpatient medicine wards. At University of California-San Francisco, this has been accompanied by declining percentages of residency graduates who enter subspecialty training in internal medicine. The decline in subspecialty medicine interest can be attributed to many factors, including differences in compensation, decreased subspecialist exposure, and a changing research funding landscape. Although there has not been systematic documentation of this trend in pulmonary and critical care medicine, we have noted previously pulmonary and critical care-bound trainees switching to hospital medicine instead. With our broad, multiorgan system perspective, pulmonary and critical care faculty should embrace teaching general medicine. Residency programs have instituted creative solutions to encourage more internal medicine residents to pursue careers in subspecialty medicine. Some solutions include creating rotations that promote more contact with subspecialists and physician scientists, creating clinician-educator tracks within fellowship programs, and appointing subspecialists to internal medicine residency leadership positions. We need more rigorous research to track the trends and implications of the generalist-specialist balance of inpatient ward teams on resident career choices, and learn what interventions affect those choices. PMID- 28362540 TI - Treatment of Acute Dyspnea with Morphine to Avert Respiratory Failure. PMID- 28362541 TI - Can neurophysiologic measures serve as biomarkers for the efficacy of repetitive transcranial magnetic stimulation treatment of major depressive disorder? AB - Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for Major Depressive Disorder (MDD). There are clinical data that support the efficacy of many different approaches to rTMS treatment, and it remains unclear what combination of stimulation parameters is optimal to relieve depressive symptoms. Because of the costs and complexity of studies that would be necessary to explore and compare the large number of combinations of rTMS treatment parameters, it would be useful to establish reliable surrogate biomarkers of treatment efficacy that could be used to compare different approaches to treatment. This study reviews the evidence that neurophysiologic measures of cortical excitability could be used as biomarkers for screening different rTMS treatment paradigms. It examines evidence that: (1) changes in excitability are related to the mechanism of action of rTMS; (2) rTMS has consistent effects on measures of excitability that could constitute reliable biomarkers; and (3) changes in excitability are related to the outcomes of rTMS treatment of MDD. An increasing body of evidence indicates that these neurophysiologic measures have the potential to serve as reliable biomarkers for screening different approaches to rTMS treatment of MDD. PMID- 28362542 TI - Visualization of Photoreceptors in Birdshot Chorioretinopathy Using Adaptive Optics Scanning Laser Ophthalmoscopy: A Pilot Study. AB - PURPOSE: Adaptive optics scanning laser ophthalmoscopy (AOSLO) allows en face visualization of specific layers of the retina. This pilot study evaluated the ability of AOSLO to visualize photoreceptor integrity in patients with birdshot chorioretinopathy (BCR). METHOD: A total of 16 consecutive patients with HLA-A29+ BCR were imaged using the prototype Apaeros retinal imaging system. Images of high quality were aligned with infrared reflectance photos and correlated with spectral domain optical coherence tomography (SD-OCT). RESULTS: Images of four eyes of three patients were of sufficient quality to allow posterior pole montage and point-to-point correlation with SD-OCT. Areas of photoreceptor disruption on SD-OCT were seen as patchy areas of loss on AOSLO, whereas areas of intact interdigitation zone and inner segment/outer segment junction correlated with normal appearing photoreceptors on AOSLO. CONCLUSIONS: Using AOSLO, we found one instance of subclinical photoreceptor disruption not seen on SD-OCT. Ultimately, there are unique challenges associated with imaging BCR patients using AOSLO. PMID- 28362543 TI - A Botanical Composition Mitigates Cartilage Degradations and Pain Sensitivity in Osteoarthritis Disease Model. AB - Osteoarthritis (OA) is a degenerative joint disease characterized by a progressive articular cartilage degradation manifested with significant functional impairment in consort with signs and symptoms of inflammation, stiffness, and loss of mobility. Current OA management is inadequate due to the lack of nominal therapies proven to be effective in hampering disease progression where symptomatic therapy focused intervention masks the primary etiology leading to irreversible structural damage. In this study, we describe the effect of UP1306, a composition containing a proprietary blend of two standardized extracts from the heartwood of Acacia catechu and the root bark of Morus alba, in maintaining joint structural integrity and alleviating OA associated symptoms in monosodium-iodoacetate (MIA)-induced rat OA disease model. Data from pain sensitivity, histopathology, and glycosaminoglycan (GAG) level were analyzed. Diclofenac at 10 mg/kg was used as a reference compound. Ex vivo proteoglycan protection model demonstrated 31.5%, 50.0%, and 54.8% inhibitions of proteoglycan degradations from UP1306 at concentrations of 50, 100, and 200 MUg/mL, respectively. The merit of combining two bioflavonoid standardized extracts from A. catechu and M. alba was demonstrated in their Ex vivo synergistic proteoglycan protection activity. In the MIA in vivo OA model, administered orally at 500 mg/kg, UP1306 resulted in reductions of 17.5%, 29.0%, 34.4%, 33.5%, and 40.9% through week 1-5 in pain sensitivity, statistically significant improvements in articular cartilage matrix integrity, and minimal subchondral bone damage. Therefore, UP1306 could potentially be considered as an alternative remedy from natural sources for the management of OA and/or its associated symptoms. PMID- 28362545 TI - Remote orbital recurrence of olfactory neuroblastoma (esthesioneuroblastoma). AB - Olfactory neuroblastoma is a rare and often locally aggressive malignancy that invades the orbit via local destruction. It is known to recur in a delayed fashion, particularly to the neck lymph nodes. This is a case of a 65-year-old gentleman who presents with recurrence in the orbit and a neck lymph node 19 years after treatment for his initial disease. This report describes the longest known interval in orbital recurrence and should alert the monitoring physician that extreme delays in recurrence can occur. PMID- 28362544 TI - What arguments on vaccinations run through YouTube videos in Italy? A content analysis. AB - BACKGROUND: The suspension of compulsory scheduling of some pediatric vaccines has been discussed for a long time by health authorities in Italy but the current decrease of vaccination rates is a matter of concern. YouTube is the most popular video-based social media website. Considering the demonstrated impact of internet on vaccination decision-making and the increasing use of social media to share and disseminate health information, the aim of this study was to explore the message available on YouTube videos about vaccination. METHODS: An observational study was conducted searching for YouTube videos in September 2015 and updated in January 2016, by using the keyword "vaccinations." We included recently posted videos in Italian on child vaccination (2014-2015). Videos were classified according to the message tone. RESULTS: A total of 123 videos were selected. Pro vaccination videos were 62 (50%), anti-vaccination 28 (23%), neutral or without a clear position in favor or against vaccination 33 (27%). Focusing on the first 2 groups, pro-vaccination videos had a higher number of views compared with those unfavorable (1602 +/- 6544 vs 1482 +/- 2735) (p < 0.001). However, anti vaccination videos were liked more by viewers (17.8 +/- 31.3) than positive ones (13.2 +/- 44.7) (p < 0.001) in addition to being more shared (23 +/- 22.6 vs 3.8 +/- 5.5, p < 0.001). CONCLUSIONS: Most of the videos were positive in tone, but those that disapproved of immunization were the most liked and shared. Considering the growing number of viewers, it is important to monitor the web to understand audience characteristics and what influences public opinions to use communication strategies more effectively. PMID- 28362546 TI - The knowledge, attitudes and practices on influenza among medical college students in Northwest China. AB - Objective This study aimed to understand the knowledge, attitudes and practices (KAP) on seasonal influenza among medical college students in a low-income multiethnic society. Methods A cross-sectional questionnaire survey collected information of KAP related to influenza. A knowledge score was calculated according to the total number of correct points out of 9 questions. Logistic regression was used to identify factors associated with influenza vaccine uptake. Results 856 valid questionnaires were obtained. The average knowledge score was 14.8 +/- 3.1 out of 22 correct points. Han Chinese got higher score than minorities (p < 0.001). Knowledge score increased with grade (p < 0.001). Students majoring in pharmacy had lower score than others. Questions on mode of transmission, symptoms, precautions, high risk groups and vaccination schedule had a correct rate lower than 50%. Hand hygiene was practiced by less than 40% of students after touching objects in public areas or sneezing. The proportion of participants received influenza vaccine in the past 3 y was 4.1%, 9.2% and 6.1% respectively. Willingness to receive free vaccine (OR = 2.49, 95% CI 1.31~4.28), and awareness of the vaccine effectiveness (OR = 1.67, 95% CI 1.08~2.56) were significantly associated with vaccine uptake, while the general knowledge about influenza, perceived susceptibility and severity, and demographic factors were not. The top 3 reasons for not being vaccinated were poor knowledge of the vaccine (46%), no perceived need due to good health (45%) and worry about adverse reactions (33%). Conclusion Health education is needed to improve the awareness of basic facts about influenza and vaccine, and more attention should be paid to minority groups. The coverage of seasonal influenza vaccine is quite low. Besides individual level behavior change, social and structural factors should be considered to increase the uptake of influenza vaccine. PMID- 28362547 TI - Acute and chronic disease caused by enteroviruses. PMID- 28362548 TI - Immune infiltration of tumor microenvironment following immunotherapy for glioblastoma multiforme. AB - Autologous dentritic cell immunotherapy has been proven effective in treating tumors outside the central nervous system. Current evidence from phase I and II trials suggest a similar efficacy for central nervous system tumors as well and that an active immune response against these tumors can be generated. We aim to review the literature to identify the types of immune responses against gliomas found to be generated by dendritic cell vaccinations and the types of immune cells subsequently infiltrating the glioma microenvironment. A systematic review of the literature was performed by searching the online databases PubMEd, Google Scholar, and EMBASE with use of the keywords intratumoral, infiltration, lymphocytic, vaccination and gliomas. Seven studies reporting lymphocytic infiltration of gliomas microenvironment were identified. Three studies (42.8%) reported presence of tumor infiltrating lymphocytes in 50%, 50% and 28.6% of included patients respectively in the post-vaccination specimens that were not present in the pre-vaccination samples. The remaining 4 (57.2%) reported an up to 6-fold increase in the number of pre-existing lymphocytes following vaccination. Present data indicate that tumor infiltration by lymphocytes can be induced by dentritic cell immunotherapy and that this may positively affect clinical outcome. It still remains unclear which factors influence the above reaction and therefore prediction of response to treatment is still not possible. PMID- 28362549 TI - CD8+ T-cell mediated anti-malaria protection induced by malaria vaccines; assessment of hepatic CD8+ T cells by SCBC assay. AB - Malaria is a severe infectious disease with relatively high mortality, thus having been a scourge of humanity. There are a few candidate malaria vaccines that have shown a protective efficacy in humans against malaria. One of the candidate human malaria vaccines, which is based on human malaria sporozoites and called PfSPZ Vaccine, has been shown to protect a significant proportion of vaccine recipients from getting malaria. PfSPZ Vaccine elicits a potent response of hepatic CD8+ T cells that are specific for malaria antigens in non-human primates. To further characterize hepatic CD8+ T cells induced by the sporozoite based malaria vaccine in a mouse model, we have used a cutting-edge Single-cell Barcode (SCBC) assay, a recently emerged approach/method for investigating the nature of T-cells responses during infection or cancer. Using the SCBC technology, we have identified a population of hepatic CD8+ T cells that are polyfunctional at a single cell level only in a group of vaccinated mice upon malaria challenge. The cytokines/chemokines secreted by these polyfunctional CD8+ T-cell subsets include MIP-1alpha, RANTES, IFN-gamma, and/or IL-17A, which have shown to be associated with protective T-cell responses against certain pathogens. Therefore, a successful induction of such polyfunctional hepatic CD8+ T cells may be a key to the development of effective human malaria vaccine. In addition, the SCBC technology could provide a new level of diagnostic that will allow for a more accurate determination of vaccine efficacy. PMID- 28362552 TI - Vaccination campaign at a temporary camp for victims of the earthquake in Lorca (Spain). AB - Outbreaks in temporary camps are an important risk for the health of the displaced population. The town of Lorca (Murcia, Spain) suffered 2 earthquakes on May 2011 that required the re-housing of 1,424 victims in a temporary camp. Following 4 cases of chickenpox control measures were adopted among the displaced population. These measures included vaccination against chickenpox; due to the existence of cases of measles in adjacent regions, it was decided to offer measles, mumps and rubella (MMR) vaccination as well. The immunization campaign was performed during 2 d (3 to 4 d after the first case). The immunity status of 1,041 (73,1%) of the residents was reviewed. Being vaccinated 523 (67%) against chickenpox and MMR, 133 (17%) against only MMR and 124 (16%) against only chickenpox. We consider the action taken was a success, as only 4 additional cases of chickenpox were subsequently recorded in the campsite, being avoidable only one of them. There is a major risk of outbreaks in a disaster situation. Because of this, conducting preventive actions are indicated to avoid doing worse this critical. PMID- 28362550 TI - Are children's vitamin D levels and BMI associated with antibody titers produced in response to 2014-2015 influenza vaccine? AB - BACKGROUND: Vitamin D is an immunomodulating hormone, which has been associated with susceptibility to infectious diseases. METHODS: Serum vitamin D levels in 135 children ages 3-17 y were measured at baseline and hemagglutinin influenza antibody titers were measured pre- and 21 d post influenza vaccination with live attenuated influenza vaccine (LAIV) or inactivated influenza vaccine (IIV). Height and weight were derived from the electronic medical record and were used to calculate body mass index (BMI). RESULTS: Thirty-nine percent of children were ages 3-8 years; 75% were black, 34% were obese (BMI >= 95th percentile); vitamin D levels were >20 ng/ml in 55%. In linear regression analyses, post vaccination antibody titers for LAIV B lineages (B Brisbane and B Massachusetts) were significantly higher among those with lower vitamin D levels and among younger participants (P < 0.05). No associations between vitamin D levels and responses to LAIV A strains (A/H1N1 and A/H3N2) or to any IIV strains or lineages were found. CONCLUSION: Low vitamin D levels were associated with higher response to LAIV B lineages in the 2014-2015 LAIV, but not related to LAIV A or any IIV strains. PMID- 28362553 TI - Agronomic performance of insect-protected and herbicide-tolerant MON 89034 * TC1507 * NK603 * DAS-40278-9 corn is equivalent to that of conventional corn. AB - Agronomic characteristics of genetically modified (GM) MON 89034 * TC1507 * NK603 * DAS-40278-9 (PowerCoreTM EnlistTM), MON 89034 * TC1507 * NK603 (PowerCoreTM), and DAS-40278-9 (EnlistTM) corn, a non-GM near-isogenic hybrid, and 2 commercial non-GM hybrids were assessed in a field study to determine if the agronomic performance of the GM corn hybrids is equivalent to that of non-transgenic hybrid corn. The MON 89034 * TC1507 * NK603 * DAS-40278-9 hybrid corn was developed through stacking of 4 individual transgenic events, MON 89034, TC1507, NK603, and DAS-40278-9 by traditional breeding and contains the cry1A.105 and cry2Ab2 (MON 89034), cry1F and pat (TC1507), cp4 epsps (NK603) and aad-1 (DAS-40278-9) transgenes. These transgenes encode the proteins Cry1A.105, Cry2Ab2, and Cry1F, which confer insect resistance, PAT, CP4 EPSPS, and AAD-1, which confer herbicide tolerance. The following agronomic characteristics were assessed in the study: initial and final stand count, seedling vigor, time to silk, time to pollen shed, pollen viability, plant height, ear height, stalk lodging, root lodging, days to maturity, stay green, disease incidence, insect damage, herbicide injury, and yield. The agronomic assessment was conducted in 2 regions of Brazil (Indianopolis-MG; Cravinhos-SP). The agronomic attributes for all GM entries were statistically indistinguishable from the non-GM near-isogenic hybrid. In addition, most of the agronomic assessments fell within the range of the commercial varieties included in the study. Taken together, MON 89034 * TC1507 * NK603 * DAS-40278, MON 89034 * TC1507 * NK603, and DAS-40278-9 were found to be agronomically equivalent to non-GM corn. PMID- 28362551 TI - The double life of the ribosome: When its protein folding activity supports prion propagation. AB - It is no longer necessary to demonstrate that ribosome is the central machinery of protein synthesis. But it is less known that it is also key player of the protein folding process through another conserved function: the protein folding activity of the ribosome (PFAR). This ribozyme activity, discovered more than 2 decades ago, depends upon the domain V of the large rRNA within the large subunit of the ribosome. Surprisingly, we discovered that anti-prion compounds are also potent PFAR inhibitors, highlighting an unexpected link between PFAR and prion propagation. In this review, we discuss the ancestral origin of PFAR in the light of the ancient RNA world hypothesis. We also consider how this ribosomal activity fits into the landscape of cellular protein chaperones involved in the appearance and propagation of prions and other amyloids in mammals. Finally, we examine how drugs targeting the protein folding activity of the ribosome could be active against mammalian prion and other protein aggregation-based diseases, making PFAR a promising therapeutic target for various human protein misfolding diseases. PMID- 28362554 TI - Detection of a new 20-bp insertion/deletion (indel) within sheep PRND gene using mathematical expectation (ME) method. AB - Prion-related protein doppel gene (PRND), as an essential member of the mammalian prion gene family, is associated with the scrapie susceptibility as well as phenotype traits, so the genetic variation of the PRND has been highly concerned recently, including the single nucleiotide polymorphism (SNP) and insertion/deletion (indel). Therefore, the objective of present study was to examine the possible indel variants by mathematical expectation (ME) detection method as well as explore its associations with phenotype traits. A novel 20-bp indel was verified in 623 tested individuals representing 4 diversity sheep breeds. The results showed that 3 genotypes were detected and the minor allelic frequency were 0.008 (Lanzhou Fat-Tail sheep, LFTS), 0.084 (Small Tail Han sheep, STHS), 0.021(Tong sheep, TS) and 0.083 (Hu sheep, HS), respectively. Comparing with the traditional method of detecting samples one by one, the reaction times with ME method was decreased by 36.22% (STHS), 37.00% (HS), 68.67% (TS) and 83.33% (LFTS), respectively. Besides, this locus was significantly associated to cannon circumference index (P = 0.012) and trunk index (P = 0.037) in the Hu sheep breed. Notably, it was not concordance with the present result of DNA sequencing (GCTGTCCCTGCAGGGCTTCT) and dbSNPase of NCBI (NC_443194: g.46184887- 46184906delCTGCTGTCCCTGCAGGGCTT). Consequently, it was the first time to detect the new 20-bp indel of sheep PRND gene by ME strategy, which might provide a valuable theoretical basis for marker-assisted selection in sheep genetics and breeding. PMID- 28362555 TI - Invited Commentary on "Chemoembolization of Hepatocellular Carcinoma with Extrahepatic Collateral Blood Supply". PMID- 28362556 TI - Bronchiolitis: A Practical Approach for the General Radiologist. AB - Radiologists consciously or unconsciously encounter bronchiolitis on images frequently. The purpose of this article is to simplify the concept of bronchiolitis to facilitate the formulation of a succinct and accurate differential diagnosis and suggest potential causes for the imaging findings. Direct and indirect signs of bronchiolitis that are seen on computed tomographic images are detailed. The most common causes of bronchiolitis are covered, including several distinct entities to be considered in specific clinical scenarios. In order of prevalence, the top two causes of bronchiolitis are infection and aspiration. Less common entities include respiratory bronchiolitis and hypersensitivity pneumonitis, which tend to manifest with ground-glass centrilobular nodules. Some types of bronchiolitis affect specific ethnic groups or are associated with a characteristic clinical history. For example, diffuse panbronchiolitis typically affects Japanese subjects. Constrictive bronchiolitis should be considered in lung transplant recipients with ongoing rejection. Given the high frequency of bronchiolitis, radiologists should develop a systematic approach to both cellular and constrictive bronchiolitis. Recognition of specific clinical or imaging characteristics may be sufficient for providing a relevant differential diagnosis. (c)RSNA, 2017. PMID- 28362558 TI - Ramped Up. PMID- 28362557 TI - Chemoembolization of Hepatocellular Carcinoma with Extrahepatic Collateral Blood Supply: Anatomic and Technical Considerations. AB - Transarterial chemoembolization (TACE) is considered a standard local-regional treatment for intermediate-stage hepatocellular carcinoma (HCC) and the most common bridging therapy. This treatment is offered to more than 70% of patients who are on the waiting list for liver transplantation in the United States. HCC typically receives its blood supply from the hepatic artery; however, it can recruit a parasitic supply from extrahepatic collateral (EHC) arteries. The development of an EHC arterial blood supply can interfere with the therapeutic efficacy of TACE and result in treatment failure and poor outcome. Cross sectional imaging-specifically computed tomography and magnetic resonance imaging has some limitations in depicting the presence or absence of an EHC arterial supply during the pre-TACE evaluation. Catheterization and angiography of every possible EHC artery during a routine TACE procedure would be time consuming and technically challenging and would not always be feasible. Therefore, the prediction of a potential EHC arterial supply on the basis of tumor location before, during, and after TACE is fundamental to achieving optimal therapeutic efficacy. To perform TACE through EHC arteries, special considerations are necessary to avoid potentially serious complications. The authors review the factors influencing the development of an EHC arterial blood supply to HCC and describe a systematic approach to enhance the ability to predict the presence of EHC arteries. They also describe the proper technique for TACE of each EHC artery and how to avoid potential technique-related complications. (c)RSNA, 2017. PMID- 28362561 TI - Spring. PMID- 28362560 TI - Comparing outcomes of pediatric and adult external dacryocystorhinostomy in Nepal: Is age a prognostic factor? AB - We determine whether age is a prognostic factor for surgical outcomes of external dacryocystorhinostomy (Ex-DCR). This retrospective cohort study conducted at Tilganga Institute of Ophthalmology (Kathmandu, Nepal) compared pediatric Ex-DCR procedures (age <= 15 years) to adult Ex-DCR procedures (age > 15 years) and was performed between January 2013 and December 2013, with a minimum follow-up period of 6 months. Primary outcome measure was rate of success, defined as complete resolution of subjective symptom(s) of epiphora (subjective success), combined with patent lacrimal passage on syringing (anatomical success) at last follow-up visit. Other outcome measures included clinical presentation, diagnosis, intraoperative complications and post-operative complications. In total, 154 Ex DCR procedures were included, with an age range of 8 months to 81 years (mean age 36.4 +/- 21.0 years). In all, 38 pediatric Ex-DCR procedures were compared to 116 adult procedures. Success rates were 97% in the pediatric group and 95% in the adult group, with no clinically or statistically significant difference in success rate or complication rate between groups (p > 0.05). Our study yielded high success rates of Ex-DCR in both pediatric and adult age groups suggesting that Ex-DCR remains an optimal treatment choice for all age groups. With no difference in surgical outcomes between pediatric and adult patients, including complication rate, we conclude that age is not a prognostic factor for Ex-DCR failure. We do not recommend adjuvant therapy for pediatric patients. PMID- 28362562 TI - Ten-Year Progression-Free and Overall Survival in Patients With Unresectable or Metastatic GI Stromal Tumors: Long-Term Analysis of the European Organisation for Research and Treatment of Cancer, Italian Sarcoma Group, and Australasian Gastrointestinal Trials Group Intergroup Phase III Randomized Trial on Imatinib at Two Dose Levels. AB - Purpose To report on the long-term results of a randomized trial comparing a standard dose (400 mg/d) versus a higher dose (800 mg/d) of imatinib in patients with metastatic or locally advanced GI stromal tumors (GISTs). Patients and Methods Eligible patients with advanced CD117-positive GIST from 56 institutions in 13 countries were randomly assigned to receive either imatinib 400 mg or 800 mg daily. Patients on the 400-mg arm were allowed to cross over to 800 mg upon progression. Results Between February 2001 and February 2002, 946 patients were accrued. Median age was 60 years (range, 18 to 91 years). Median follow-up time was 10.9 years. Median progression-free survival times were 1.7 and 2.0 years in the 400- and 800-mg arms, respectively (hazard ratio, 0.91; P = .18), and median overall survival time was 3.9 years in both treatment arms. The estimated 10-year progression-free survival rates were 9.5% and 9.2% for the 400- and 800-mg arms, respectively, and the estimated 10-year overall survival rates were 19.4% and 21.5%, respectively. At multivariable analysis, age (< 60 years), performance status (0 v >= 1), size of the largest lesion (smaller), and KIT mutation (exon 11) were significant prognostic factors for the probability of surviving beyond 10 years. Conclusion This trial was carried out on a worldwide intergroup basis, at the beginning of the learning curve of the use of imatinib, in a large population of patients with advanced GIST. With a long follow-up, 6% of patients are long-term progression free and 13% are survivors. Among clinical prognostic factors, only performance status, KIT mutation, and size of largest lesion predicted long-term outcome, likely pointing to a lower burden of disease. Genomic and/or immune profiling could help understand long-term survivorship. Addressing secondary resistance remains a therapeutic challenge. PMID- 28362564 TI - Posttraumatic Stress in Mothers Related to Giving Birth Prematurely: A Mixed Research Synthesis. AB - BACKGROUND: Globally the preterm birth rate for 184 countries in 2010 was 11.1%. Preterm births can be a traumatic experience for mothers. OBJECTIVE: This article provides a mixed research synthesis of the quantitative and qualitative studies on posttraumatic stress in mothers who have given birth prematurely. DESIGN: Narrative synthesis was the mixed research synthesis approach used. RESULTS: Included in this narrative synthesis were quantitative prevalence studies ( n = 19), quantitative intervention studies ( n = 6), and qualitative studies ( n = 5). Prevalence rates ranged from 14% to 79%. Four of the intervention studies had significant results and two did not. Qualitative data synthesis revealed five themes: (a) shocked and horrified, (b) consuming guilt, (c) pervasive anxiety and hypervigilance, (d) intrusive thoughts, and (e) numbing and avoiding reminders. CONCLUSIONS: Women's traumatic experiences of preterm birth are clearly important issues for psychiatric nurses to address. PMID- 28362565 TI - Hunter-Prey Discourse: A Critical Discourse Analysis of the Online Posts of Men Who Buy Sex. AB - BACKGROUND: The Internet has emerged as a major expediter of the commercial sex (CS) industry. While use of web-based CS industry sites is brisk, the full extent of their impact remains unclear particularly how they influence users' views of the CS industry. OBJECTIVE: This research study sought to uncover the nuances of buyers' interactions on an online CS website. DESIGN: Six hundred sixty-six online posts from 363 unique members were collected and analyzed using critical discourse analysis. RESULTS: Via the use of language and dialogue, particular ways of thinking about and talking about buying sex are normalized and reinforced. Evident within these discursive patterns are mechanisms by which assumptions are forwarded, perceptions shaped, and authority established. CONCLUSIONS: Information about how CS industry websites establish beliefs, relationships, and practices among its users may increase understanding of how the CS industry seeks to gain acceptance in the American culture and normalize its activities. PMID- 28362563 TI - Immunogenicity and safety of a novel MMR vaccine (live, freeze-dried) containing the Edmonston-Zagreb measles strain, the Hoshino mumps strain, and the RA 27/3 rubella strain: Results of a randomized, comparative, active controlled phase III clinical trial. AB - This phase III clinical trial was conducted to evaluate the immunogenicity and safety of the single-dose and multi-dose formulations of a novel MMR vaccine (live, freeze-dried) developed by M/s Cadila Healthcare Limited, India (Cadila MMR vaccine), containing the Hoshino mumps strain, compared to that of an existing MMR vaccine (live, freeze-dried) developed by M/s Serum Institute of India Limited, India (Serum MMR vaccine). These two vaccines have similar measles and rubella strains, but different mumps strains (Hoshino in Cadila MMR vaccine, and L-Zagreb in Serum MMR vaccine). Three hundred and twenty-eight subjects of either sex, aged 15-18 months, were randomized in a 2:1 ratio to receive either the Cadila or Serum MMR vaccine. Immunogenicity assessments (IgG antibodies against measles, mumps, and rubella viruses) were done at baseline and 42 d after vaccination. Solicited (local and systemic) and unsolicited adverse events were recorded for up to 42 d following vaccination. The Cadila MMR vaccine was found to be non-inferior to the Serum MMR vaccine in terms of end-of-study proportion of subjects seropositive for anti-measles antibodies (100.0% in both groups), anti-mumps antibodies (94.5% vs. 94.0%), and anti-rubella antibodies (95.5% vs. 91.0%). Both vaccines were well tolerated by all study participants; the most common adverse event reported in both groups was fever, followed by rash. The results of this phase III clinical trial show that the novel Cadila MMR vaccine is non-inferior to the Serum MMR vaccine. PMID- 28362567 TI - Psychologically Informed Implementations of Sugary-Drink Portion Limits. AB - In 2012, the New York City Board of Health prohibited restaurants from selling sugary drinks in containers that would hold more than 16 oz. Although a state court ruled that the Board of Health did not have the authority to implement such a policy, it remains a legally viable option for governments and a voluntary option for restaurants. However, there is very limited empirical data on how such a policy might affect the purchasing and consumption of sugary drinks. We report four well-powered, incentive-compatible experiments in which we evaluated two possible ways that restaurants might comply with such a policy: bundling (i.e., dividing the contents of oversized cups into two regulation-size cups) and providing free refills (i.e., offering a regulation-size cup with unlimited refills). Bundling caused people to buy less soda. Free refills increased consumption, especially when a waiter served the refills. This perverse effect was reduced in self-service contexts that required walking just a few steps to get a refill. PMID- 28362566 TI - Impact of air temperature variation on the ixodid ticks habitat and tick-borne encephalitis incidence in the Russian Arctic: the case of the Komi Republic. AB - BACKGROUND: The causes of the recent rise of tick-borne encephalitis (TBE) incidence in Europe are discussed. Our objective was to estimate the impact of air temperature change on TBE incidence in the European part of the Russian Arctic. METHODS: We analysed the TBE incidence in the Komi Republic (RK) over a 42-year period in relation to changes in local annual average air temperature, air temperature during the season of tick activity, tick abundance, TBE prevalence in ticks, tick-bite incidence rate, and normalised difference vegetation index within the area under study. RESULTS: In 1998-2011 in RK a substantial growth of TBE virus (TBEV) prevalence both in questing and feeding ticks was observed. In 1992-2011 there was 23-fold growth of the tick-bite incidence rate in humans, a northward shift of the reported tick bites, and the season of tick bites increased from 4 to 6 months. In 1998-2011 there was more than 6-fold growth of average annual TBE incidence compared with 1970-1983 and 1984-1997 periods. This resulted both from the northward shift of TBE, and its growth in the south. In our view it was related to local climate change as both the average annual air temperature, and the air temperature during the tick activity season grew substantially. We revealed in RK a strong correlation between the change in the air temperature and that in TBE incidence. The satellite data showed NDVI growth within RK, i.e. alteration of the local ecosystem under the influence of climate change. CONCLUSIONS: The rise in TBE incidence in RK is related considerably to the expansion of the range of Ixodes persulcatus. The territory with reported TBE cases also expanded northward. Climate change is an important driver of TBE incidence rate growth. PMID- 28362569 TI - Calorie and Protein Content of Parenteral Amino Acid Solutions. PMID- 28362568 TI - Political Orientation Predicts Credulity Regarding Putative Hazards. AB - To benefit from information provided by other people, people must be somewhat credulous. However, credulity entails risks. The optimal level of credulity depends on the relative costs of believing misinformation and failing to attend to accurate information. When information concerns hazards, erroneous incredulity is often more costly than erroneous credulity, given that disregarding accurate warnings is more harmful than adopting unnecessary precautions. Because no equivalent asymmetry exists for information concerning benefits, people should generally be more credulous of hazard information than of benefit information. This adaptive negatively biased credulity is linked to negativity bias in general and is more prominent among people who believe the world to be more dangerous. Because both threat sensitivity and beliefs about the dangerousness of the world differ between conservatives and liberals, we predicted that conservatism would positively correlate with negatively biased credulity. Two online studies of Americans supported this prediction, potentially illuminating how politicians' alarmist claims affect different portions of the electorate. PMID- 28362570 TI - Editor's Note. PMID- 28362571 TI - Transpyloric Feeding Tube Placement Using Electromagnetic Placement Device in Children. AB - BACKGROUND: Transpyloric feeding tubes (TPT) are often recommended in critically ill children. Blind tube placement, however, can be difficult, be time-consuming, and incur multiple radiation exposures. An electromagnetic device (EMD) is available for confirmation of successful placement of TPTs. We conducted a retrospective cohort study to evaluate the efficacy of an EMD for TPT placement in children and determine its impact on placement success, radiation exposure, confirmation time, and cost for tube placement compared with traditional blind TPT placement. MATERIALS AND METHODS: Retrospective data were collected in patients receiving a TPT before (pre-EMD group) and after implementation of an EMD (EMD group). RESULTS: Need for radiographic exposure decreased significantly in the EMD group (n = 40) compared with the pre-EMD group (n = 38) (0.6 vs 1.6 x rays, P < .001). TPTs were placed and confirmed without abdominal x-ray in 21 of 40 patients in the EMD group. There were no serious adverse events such as misplacement into the lung or pneumothorax or perforation injury of the stomach. Successful tube confirmation took a significantly shorter time in the EMD group than in the pre-EMD group (1.45 vs 4.59 hours, P < .0001). There was an estimated cost savings of $245.10 per placement associated with decreased x-ray and fluoroscopy. CONCLUSION: The use of an EMD in children significantly decreased radiation exposure and confirmation time while maintaining TPT placement success. The use of an EMD can potentially offer large cost savings. Elimination of abdominal x-ray with EMD during TPT placement was achieved without any serious complications in approximately half of the children. PMID- 28362572 TI - Indicators for Enteral Nutrition Use and Prophylactic Percutaneous Endoscopic Gastrostomy Placement in Patients With Head and Neck Cancer Undergoing Chemoradiotherapy. AB - BACKGROUND: Chemoradiotherapy (CRT) is a major risk factor for malnutrition and dehydration in patients with head and neck cancer. Enteral support is often needed, and a percutaneous endoscopic gastrostomy (PEG) is frequently placed. Specific indicators for PEG placement remain unclear. This study retrospectively determined which factors contributed to enteral nutrition (EN) use and PEG placement in a large patient group to gain insight on potential indicators for PEG placement protocol creation. METHODS: A retrospective chart review of 240 patients with head and neck cancer who underwent CRT in 2012-2015 was conducted. Lifestyle, oncological, treatment, and nutrition outcome characteristics were examined and compared between patients who used EN and those who did not, as well as between patients who received a PEG and those who did not. RESULTS: In total, 195 patients used EN (via PEG or nasogastric tube). Multivariate analysis showed that nodal disease presence ( P = .01) and bilateral neck irradiation ( P = .01) were significantly related to EN use while increased age ( P = .01), nodal disease presence ( P = .02), reconstruction extent other than primary closure ( P = .02), bilateral neck irradiation ( P < .01), and an adapted intake consistency prior to treatment ( P = .03) were significantly related to PEG placement. CONCLUSION: Important factors for EN usage and PEG placement consideration include nodal disease and planned bilateral neck irradiation. Results from this study in combination with existing literature can be taken into consideration in the design of a PEG placement protocol. A better understanding of predictive indicators to PEG placement should be explored in further prospective studies. PMID- 28362573 TI - Ultrasound-Assessed Gastric Antral Area Correlates With Aspirated Tube Feed Volume in Enterally Fed Critically Ill Patients. AB - BACKGROUND: Enteral tube feed (ETF) intolerance occurs frequently in hospitalized patients and more so in critically ill patients. Most critical care nurses continue to assess gastric residual volume (GRV), especially among those with a history of ETF intolerance. We hypothesized that ultrasound assessment of GRV correlates directly with aspirated tube feed volume. METHODS: This was a prospective cohort study of a convenience sample of critically ill mechanically ventilated patients admitted to an intensive care unit receiving ETF. The gastric antrum was imaged using the aorta and inferior vena cava (IVC) as landmarks concurrently and simultaneously using a curvilinear probe in the midline. All ultrasound measurements were performed at 30 degrees head up, in the supine position, and prior to the assessment of GRV by nursing staff blinding the ultrasonographer to gastric volume aspirated. Gastric antral area was determined by assessing anteroposterior (AP) and craniocaudal (CC) diameters of the gastric antrum. RESULTS: Gastric cross-sectional area (CSA) using IVC as a landmark ( R2 = 0.92, P < .0001) and aorta as a landmark ( R2 = 0.86, P < .0001) correlated with aspirated volume. CC diameter of the stomach measured using the aorta as a landmark correlated with aspirated volume and increased linearly with increasing GRV ( R2 = 0.78, P < .0001). A CC diameter of <10 cm using the aorta as a landmark predicted a gastric volume of <500 mL. CONCLUSIONS: Ultrasound assessment provides accurate assessment of gastric volume in real-life settings, and the CC diameter of the gastric antrum provides a simple surrogate of GRV. PMID- 28362574 TI - Enteral Feeding Set Handling Techniques. AB - BACKGROUND: Enteral nutrition therapy is common practice in pediatric clinical settings. Often patients will receive a pump-assisted bolus feeding over 30 minutes several times per day using the same enteral feeding set (EFS). This study aims to determine the safest and most efficacious way to handle the EFS between feedings. METHODS: Three EFS handling techniques were compared through simulation for bacterial growth, nursing time, and supply costs: (1) rinsing the EFS with sterile water after each feeding, (2) refrigerating the EFS between feedings, and (3) using a ready-to-hang (RTH) product maintained at room temperature. Cultures were obtained at baseline, hour 12, and hour 21 of the 24 hour cycle. A time-in-motion analysis was conducted and reported in average number of seconds to complete each procedure. Supply costs were inventoried for 1 month comparing the actual usage to our estimated usage. RESULTS: Of 1080 cultures obtained, the overall bacterial growth rate was 8.7%. The rinse and refrigeration techniques displayed similar bacterial growth (11.4% vs 10.3%, P = .63). The RTH technique displayed the least bacterial growth of any method (4.4%, P = .002). The time analysis in minutes showed the rinse method was the most time consuming (44.8 +/- 2.7) vs refrigeration (35.8 +/- 2.6) and RTH (31.08 +/- 0.6) ( P < .0001). CONCLUSIONS: All 3 EFS handling techniques displayed low bacterial growth. RTH was superior in bacterial growth, nursing time, and supply costs. Since not all pediatric formulas are available in RTH, we conclude that refrigerating the EFS between uses is the next most efficacious method for handling the EFS between bolus feeds. PMID- 28362575 TI - Review of Copper Provision in the Parenteral Nutrition of Adults [Formula: see text]. AB - The essential trace element copper (Cu) is required for a range of physiologic processes, including wound healing and functioning of the immune system. The correct amount of Cu must be provided in parenteral nutrition (PN) if deficiency and toxicity are to be avoided. While provision in line with the standard recommendations should suffice for most patients, Cu requirements may be higher in patients with increased gastrointestinal losses and severe burns and lower in those with cholestasis. The tests of Cu status that are currently available for clinical use are unreliable. Serum Cu concentration is the most commonly ordered test but is insensitive to Cu deficiency and toxicity and is misleadingly increased during the acute phase response. These limitations make it difficult for prescribers to assess Cu status and to decide how much Cu to provide. There is a need for better tests of Cu status to be developed to decrease uncertainty and improve individualization of Cu dosing. More information is needed on Cu requirements in disease and Cu contamination of PN components and other intravenous fluids. New multi-trace element products should be developed that provide Cu doses in line with the 2012 American Society for Parenteral and Enteral Nutrition recommendations. This article discusses the evaluation and treatment of Cu deficiency and toxicity in patients treated with PN. PMID- 28362577 TI - Coming soon to a screen near you. AB - As eLife starts to publish the accepted versions of certain Research Articles, we explain what happens once a manuscript has been accepted for publication. PMID- 28362576 TI - Ambra1 spatially regulates Src activity and Src/FAK-mediated cancer cell invasion via trafficking networks. AB - Here, using mouse squamous cell carcinoma cells, we report a completely new function for the autophagy protein Ambra1 as the first described 'spatial rheostat' controlling the Src/FAK pathway. Ambra1 regulates the targeting of active phospho-Src away from focal adhesions into autophagic structures that cancer cells use to survive adhesion stress. Ambra1 binds to both FAK and Src in cancer cells. When FAK is present, Ambra1 is recruited to focal adhesions, promoting FAK-regulated cancer cell direction-sensing and invasion. However, when Ambra1 cannot bind to FAK, abnormally high levels of phospho-Src and phospho-FAK accumulate at focal adhesions, positively regulating adhesion and invasive migration. Spatial control of active Src requires the trafficking proteins Dynactin one and IFITM3, which we identified as Ambra1 binding partners by interaction proteomics. We conclude that Ambra1 is a core component of an intracellular trafficking network linked to tight spatial control of active Src and FAK levels, and so crucially regulates their cancer-associated biological outputs. PMID- 28362578 TI - Automated Catheter Navigation With Electromagnetic Image Guidance. AB - This paper describes a novel method of controlling an endoscopic catheter by using an automated catheter tensioning system with the objective of providing clinicians with improved manipulation capabilities within the patient. Catheters are used in many clinical procedures to provide access to the cardiopulmonary system. Control of such catheters is performed manually by the clinicians using a handle, typically actuating a single or opposing set of pull wires. Such catheters are generally actuated in a single plane, requiring the clinician to rotate the catheter handle to navigate the system. The automation system described here allows closed-loop control of a custom bronchial catheter in tandem with an electromagnetic tracking of the catheter tip and image guidance by using a 3D Slicer. An electromechanical drive train applies tension to four pull wires to steer the catheter tip, with the applied force constantly monitored through force sensing load cells. The applied tension is controlled through a PC connected joystick. An electromagnetic sensor embedded in the catheter tip enables constant real-time position tracking, whereas a working channel provides a route for endoscopic instruments. The system is demonstrated and tested in both a breathing lung model and a preclinical animal study. Navigation to predefined targets in the subject's airways by using the joystick while using virtual image guidance and electromagnetic tracking was demonstrated. Average targeting times were 29 and 10 s, respectively, for the breathing lung and live animal studies. This paper presents the first reported remote controlled bronchial working channel catheter utilizing electromagnetic tracking and has many implications for future development in endoscopic and catheter-based procedures. PMID- 28362579 TI - Structured Learning for 3-D Perivascular Space Segmentation Using Vascular Features. AB - OBJECTIVE: The goal of this paper is to automatically segment perivascular spaces (PVSs) in brain from high-resolution 7T magnetic resonance (MR) images. METHODS: We propose a structured-learning-based segmentation framework to extract the PVSs from high-resolution 7T MR images. Specifically, we integrate three types of vascular filter responses into a structured random forest for classifying voxels into two categories, i.e., PVS and background. In addition, we propose a novel entropy-based sampling strategy to extract informative samples in the background for training an explicit classification model. Since the vascular filters can extract various vascular features, even thin and low-contrast structures can be effectively extracted from noisy backgrounds. Moreover, continuous and smooth segmentation results can be obtained by utilizing patch-based structured labels. RESULTS: The performance of our proposed method is evaluated on 19 subjects with 7T MR images, with the Dice similarity coefficient reaching 66%. CONCLUSION: The joint use of entropy-based sampling strategy, vascular features, and structured learning can improve the segmentation accuracy. SIGNIFICANCE: Instead of manual annotation, our method provides an automatic way for PVS segmentation. Moreover, our method can be potentially used for other vascular structure segmentation because of its data-driven property. PMID- 28362581 TI - Non-invasive Fetal ECG Signal Quality Assessment for Multichannel Heart Rate Estimation. AB - OBJECTIVE: The noninvasive fetal ECG (NI-FECG) from abdominal recordings offers novel prospects for prenatal monitoring. However, NI-FECG signals are corrupted by various nonstationary noise sources, making the processing of abdominal recordings a challenging task. In this paper, we present an online approach that dynamically assess the quality of NI-FECG to improve fetal heart rate (FHR) estimation. METHODS: Using a naive Bayes classifier, state-of-the-art and novel signal quality indices (SQIs), and an existing adaptive Kalman filter, FHR estimation was improved. For the purpose of training and validating the proposed methods, a large annotated private clinical dataset was used. RESULTS: The suggested classification scheme demonstrated an accuracy of Krippendorff's alpha in determining the overall quality of NI-FECG signals. The proposed Kalman filter outperformed alternative methods for FHR estimation achieving accuracy. CONCLUSION: The proposed algorithm was able to reliably reflect changes of signal quality and can be used in improving FHR estimation. SIGNIFICANCE: NI-ECG signal quality estimation and multichannel information fusion are largely unexplored topics. Based on previous works, multichannel FHR estimation is a field that could strongly benefit from such methods. The developed SQI algorithms as well as resulting classifier were made available under a GNU GPL open-source license and contributed to the FECGSYN toolbox. PMID- 28362582 TI - Multiview Rectification of Folded Documents. AB - Digitally unwrapping images of paper sheets is crucial for accurate document scanning and text recognition. This paper presents a method for automatically rectifying curved or folded paper sheets from a few images captured from multiple viewpoints. Prior methods either need expensive 3D scanners or model deformable surfaces using over-simplified parametric representations. In contrast, our method uses regular images and is based on general developable surface models that can represent a wide variety of paper deformations. Our main contribution is a new robust rectification method based on ridge-aware 3D reconstruction of a paper sheet and unwrapping the reconstructed surface using properties of developable surfaces via conformal mapping. We present results on several examples including book pages, folded letters and shopping receipts. PMID- 28362580 TI - Numerical Model Study of In Vivo Magnetic Nanoparticle Tumor Heating. AB - : Iron oxide nanoparticles are currently under investigation as heating agents for hyperthermic treatment of tumors. Major determinants of effective heating include the biodistribution and minimum iron oxide loading required to achieve adequate heating at practically achievable magnetic field strengths. These inter related criteria ultimately determine the practicality of this approach to tumor treatment. Further, in our experience the currently used treatment assessment criterion for hyperthermia treatment-cumulative equivalent minutes at 43 degrees C, CEM43 -provides an inadequate description of the expected treatment effectiveness. OBJECTIVES: Couple numerical models to experimental measurements to study the relative heating effectiveness described by cell death predictions. METHODS: FEM numerical models were applied to increase the understanding of a carefully calibrated series of experiments in mouse mammary adenocarcinoma. RESULTS: The numerical model results indicate that minimum tumor loadings between approximately 1.3 to 1.8 mg of Fe per cm3 of tumor tissue are required to achieve the experimentally observed temperatures in magnetic field strengths of 32 kA/m (rms) at 162 kHz. CONCLUSION: We show that including multiple cell death processes operating in parallel within the numerical models provides valuable perspective on the likelihood of successful treatment. SIGNIFICANCE: We show and believe that these assessment methods are more accurate than a single assessment figure of merit based only on the comparison of thermal histories, such as the CEM method. PMID- 28362583 TI - Back-Projection Cortical Potential Imaging: Theory and Results. AB - Electroencephalography (EEG) is the single brain monitoring technique that is non invasive, portable, passive, exhibits high-temporal resolution, and gives a directmeasurement of the scalp electrical potential. Amajor disadvantage of the EEG is its low-spatial resolution, which is the result of the low-conductive skull that "smears" the currents coming from within the brain. Recording brain activity with both high temporal and spatial resolution is crucial for the localization of confined brain activations and the study of brainmechanismfunctionality, whichis then followed by diagnosis of brain-related diseases. In this paper, a new cortical potential imaging (CPI) method is presented. The new method gives an estimation of the electrical activity on the cortex surface and thus removes the "smearing effect" caused by the skull. The scalp potentials are back-projected CPI (BP-CPI) onto the cortex surface by building a well-posed problem to the Laplace equation that is solved by means of the finite elements method on a realistic head model. A unique solution to the CPI problem is obtained by introducing a cortical normal current estimation technique. The technique is based on the same mechanism used in the well-known surface Laplacian calculation, followed by a scalp-cortex back-projection routine. The BP-CPI passed four stages of validation, including validation on spherical and realistic head models, probabilistic analysis (Monte Carlo simulation), and noise sensitivity tests. In addition, the BP-CPI was compared with the minimum norm estimate CPI approach and found superior for multi-source cortical potential distributions with very good estimation results (CC >0.97) on a realistic head model in the regions of interest, for two representative cases. The BP-CPI can be easily incorporated in different monitoring tools and help researchers by maintaining an accurate estimation for the cortical potential of ongoing or event-related potentials in order to have better neurological inferences from the EEG. PMID- 28362584 TI - Automated Anatomy-Based Tracking of Systemic Arteries in Arbitrary Field-of-View CTA Scans. AB - We propose an automated pipeline for vessel centerline extraction in 3-D computed tomography angiography (CTA) scans with arbitrary fields of view. The principal steps of the pipeline are body part detection, candidate seed selection, segment tracking, which includes centerline extraction, and vessel tree growing. The final tree-growing step can be instantiated in either a semi- or fully automated fashion. The fully automated initialization is carried out using a vessel position regression algorithm. Both semi-and fully automated methods were evaluated on 30 CTA scans comprising neck, abdominal, and leg arteries in multiple fields of view. High detection rates and centerline accuracy values for 38 distinct vessels demonstrate the effectiveness of our approach. PMID- 28362585 TI - Affine Non-Local Means Image Denoising. AB - This paper presents an extension of the Non-Local Means denoising method, that effectively exploits the affine invariant self-similarities present in the images of real scenes. Our method provides a better image denoising result by grounding on the fact that in many occasions similar patches exist in the image but have undergone a transformation. The proposal uses an affine invariant patch similarity measure that performs an appropriate patch comparison by automatically and intrinsically adapting the size and shape of the patches. As a result, more similar patches are found and appropriately used. We show that this image denoising method achieves top-tier performance in terms of PSNR, outperforming consistently the results of the regular Non-Local Means, and that it provides state-of-the-art qualitative results. PMID- 28362586 TI - Toward a Reliable Collection of Eye-Tracking Data for Image Quality Research: Challenges, Solutions, and Applications. AB - Image quality assessment potentially benefits from the addition of visual attention. However, incorporating aspects of visual attention in image quality models by means of a perceptually optimized strategy is largely unexplored. Fundamental challenges, such as how visual attention is affected by the concurrence of visual signals and their distortions; whether visual attention affected by distortion or that driven by the original scene only should be included in an image quality model; and how to select visual attention models for the image quality application context, remain. To shed light on the above unsolved issues, designing and performing eye-tracking experiments are essential. Collecting eye-tracking data for the purpose of image quality study is so far confronted with a bias due to the involvement of stimulus repetition. In this paper, we propose a new experimental methodology to eliminate such inherent bias. This allows obtaining reliable eye-tracking data with a large degree of stimulus variability. In fact, we first conducted 5760 eye movement trials that included 160 human observers freely viewing 288 images of varying quality. We then made use of the resulting eye-tracking data to provide insights into the optimal use of visual attention in image quality research. The new eye-tracking data are made publicly available to the research community. PMID- 28362587 TI - Bayesian K-SVD Using Fast Variational Inference. AB - Recent work in signal processing in general and image processing in particular deals with sparse representation related problems. Two such problems are of paramount importance: an overriding need for designing a well-suited overcomplete dictionary containing a redundant set of atoms-i.e., basis signals-and how to find a sparse representation of a given signal with respect to the chosen dictionary. Dictionary learning techniques, among which we find the popular K singular value decomposition algorithm, tackle these problems by adapting a dictionary to a set of training data. A common drawback of such techniques is the need for parameter-tuning. In order to overcome this limitation, we propose a fully-automated Bayesian method that considers the uncertainty of the estimates and produces a sparse representation of the data without prior information on the number of non-zeros in each representation vector. We follow a Bayesian approach that uses a three-tiered hierarchical prior to enforce sparsity on the representations and develop an efficient variational inference framework that reduces computational complexity. Furthermore, we describe a greedy approach that speeds up the whole process. Finally, we present experimental results that show superior performance on two different applications with real images: denoising and inpainting. PMID- 28362588 TI - Evaluating Interactive Graphical Encodings for Data Visualization. AB - User interfaces for data visualization often consist of two main components: control panels for user interaction and visual representation. A recent trend in visualization is directly embedding user interaction into the visual representations. For example, instead of using control panels to adjust visualization parameters, users can directly adjust basic graphical encodings (e.g., changing distances between points in a scatterplot) to perform similar parameterizations. However, enabling embedded interactions for data visualization requires a strong understanding of how user interactions influence the ability to accurately control and perceive graphical encodings. In this paper, we study the effectiveness of these graphical encodings when serving as the method for interaction. Our user study includes 12 interactive graphical encodings. We discuss the results in terms of task performance and interaction effectiveness metrics. PMID- 28362589 TI - Observability of Automata Networks: Fixed and Switching Cases. AB - Automata networks are a class of fully discrete dynamical systems, which have received considerable interest in various different areas. This brief addresses the observability of automata networks and switched automata networks in a unified framework, and proposes simple necessary and sufficient conditions for observability. The results are achieved by employing methods from symbolic computation, and are suited for implementation using computer algebra systems. Several examples are presented to demonstrate the application of the results. PMID- 28362590 TI - Discriminative Sparse Neighbor Approximation for Imbalanced Learning. AB - Data imbalance is common in many vision tasks where one or more classes are rare. Without addressing this issue, conventional methods tend to be biased toward the majority class with poor predictive accuracy for the minority class. These methods further deteriorate on small, imbalanced data that have a large degree of class overlap. In this paper, we propose a novel discriminative sparse neighbor approximation (DSNA) method to ameliorate the effect of class-imbalance during prediction. Specifically, given a test sample, we first traverse it through a cost-sensitive decision forest to collect a good subset of training examples in its local neighborhood. Then, we generate from this subset several class discriminating but overlapping clusters and model each as an affine subspace. From these subspaces, the proposed DSNA iteratively seeks an optimal approximation of the test sample and outputs an unbiased prediction. We show that our method not only effectively mitigates the imbalance issue, but also allows the prediction to extrapolate to unseen data. The latter capability is crucial for achieving accurate prediction on small data set with limited samples. The proposed imbalanced learning method can be applied to both classification and regression tasks at a wide range of imbalance levels. It significantly outperforms the state-of-the-art methods that do not possess an imbalance handling mechanism, and is found to perform comparably or even better than recent deep learning methods by using hand-crafted features only. PMID- 28362591 TI - Preconditioned Stochastic Gradient Descent. AB - Stochastic gradient descent (SGD) still is the workhorse for many practical problems. However, it converges slow, and can be difficult to tune. It is possible to precondition SGD to accelerate its convergence remarkably. But many attempts in this direction either aim at solving specialized problems, or result in significantly more complicated methods than SGD. This paper proposes a new method to adaptively estimate a preconditioner, such that the amplitudes of perturbations of preconditioned stochastic gradient match that of the perturbations of parameters to be optimized in a way comparable to Newton method for deterministic optimization. Unlike the preconditioners based on secant equation fitting as done in deterministic quasi-Newton methods, which assume positive definite Hessian and approximate its inverse, the new preconditioner works equally well for both convex and nonconvex optimizations with exact or noisy gradients. When stochastic gradient is used, it can naturally damp the gradient noise to stabilize SGD. Efficient preconditioner estimation methods are developed, and with reasonable simplifications, they are applicable to large scale problems. Experimental results demonstrate that equipped with the new preconditioner, without any tuning effort, preconditioned SGD can efficiently solve many challenging problems like the training of a deep neural network or a recurrent neural network requiring extremely long-term memories. PMID- 28362592 TI - Global Pinning Synchronization of Complex Networks With Sampled-Data Communications. AB - This paper investigates the global pinning synchronization problem for a class of complex networks with aperiodic samplings. Combined with the Writinger-based integral inequality, a new less conservative criterion is presented to guarantee the global pinning synchronization of the complex network. Furthermore, a novel condition is proposed under which the complex network is globally pinning synchronized with a given performance index. It is shown that the performance index has a positive correlation with the upper bound of the sampling intervals. Finally, the validity and the advantage of the theoretic results obtained are verified by means of the applications in Chua's circuit and pendulum. PMID- 28362593 TI - Stability Analysis and Application for Delayed Neural Networks Driven by Fractional Brownian Noise. AB - This paper deals with two types of the stability problem for the delayed neural networks driven by fractional Brownian noise (FBN). The existence and the uniqueness of the solution to the main system with respect to FBN are proved via fixed point theory. Based on Hilbert-Schmidt operator theory and analytic semigroup principle, the mild solution of the stochastic neural networks is obtained. By applying the stochastic analytic technique and some well-known inequalities, the asymptotic stability criteria and the exponential stability condition are established. Both numerical example and practical application for synchronization control of multiagent system are provided to illustrate the effectiveness and potential of the proposed techniques. PMID- 28362594 TI - Robust Finite-Time Stabilization of Fractional-Order Neural Networks With Discontinuous and Continuous Activation Functions Under Uncertainty. AB - This paper is concerned with robust finite-time stabilization for a class of fractional-order neural networks (FNNs) with two types of activation functions (i.e., discontinuous and continuous activation function) under uncertainty. It is worth noting that there exist few results about FNNs with discontinuous activation functions, which is mainly because classical solutions and theories of differential equations cannot be applied in this case. Especially, there is no relevant finite-time stabilization research for such system, and this paper makes up for the gap. The existence of global solution under the framework of Filippov for such system is guaranteed by limiting discontinuous activation functions. According to set-valued analysis and Kakutani's fixed point theorem, we obtain the existence of equilibrium point. In particular, based on differential inclusion theory and fractional Lyapunov stability theory, several new sufficient conditions are given to ensure finite-time stabilization via a novel discontinuous controller, and the upper bound of the settling time for stabilization is estimated. In addition, we analyze the finite-time stabilization of FNNs with Lipschitz-continuous activation functions under uncertainty. The results of this paper improve corresponding ones of integer-order neural networks with discontinuous and continuous activation functions. Finally, three numerical examples are given to show the effectiveness of the theoretical results. PMID- 28362595 TI - Epileptic Seizure Classification of EEGs Using Time-Frequency Analysis Based Multiscale Radial Basis Functions. AB - The automatic detection of epileptic seizures from electroencephalography (EEG) signals is crucial for the localization and classification of epileptic seizure activity. However, seizure processes are typically dynamic and nonstationary, and thus, distinguishing rhythmic discharges from nonstationary processes is one of the challenging problems. In this paper, an adaptive and localized time-frequency representation in EEG signals is proposed by means of multiscale radial basis functions (MRBF) and a modified particle swarm optimization (MPSO) to improve both time and frequency resolution simultaneously, which is a novel MRBF-MPSO framework of the time-frequency feature extraction for epileptic EEG signals. The dimensionality of extracted features can be greatly reduced by the principle component analysis algorithm before the most discriminative features selected are fed into a support vector machine (SVM) classifier with the radial basis function (RBF) in order to separate epileptic seizure from seizure-free EEG signals. The classification performance of the proposed method has been evaluated by using several state-of-art feature extraction algorithms and other five different classifiers like linear discriminant analysis, and logistic regression. The experimental results indicate that the proposed MRBF-MPSO-SVM classification method outperforms competing techniques in terms of classification accuracy, and shows the effectiveness of the proposed method for classification of seizure epochs and seizure-free epochs. PMID- 28362596 TI - A Method of Signal Scrambling to Secure Data Storage for Healthcare Applications. AB - A body sensor network that consists of wearable and/or implantable biosensors has been an important front-end for collecting personal health records. It is expected that the full integration of outside-hospital personal health information and hospital electronic health records will further promote preventative health services as well as global health. However, the integration and sharing of health information is bound to bring with it security and privacy issues. With extensive development of healthcare applications, security and privacy issues are becoming increasingly important. This paper addresses the potential security risks of healthcare data in Internet-based applications and proposes a method of signal scrambling as an add-on security mechanism in the application layer for a variety of healthcare information, where a piece of tiny data is used to scramble healthcare records. The former is kept locally and the latter, along with security protection, is sent for cloud storage. The tiny data can be derived from a random number generator or even a piece of healthcare data, which makes the method more flexible. The computational complexity and security performance in terms of theoretical and experimental analysis has been investigated to demonstrate the efficiency and effectiveness of the proposed method. The proposed method is applicable to all kinds of data that require extra security protection within complex networks. PMID- 28362597 TI - Medical Device for Automated Prick Test Reading. AB - Allergy tests are routinely performed in most hospitals everyday. However, measuring the outcomes of these tests is still a very laborious manual task. Current methods and systems lack of precision and repeatability. This paper presents a novel mechatronic system that is able to scan a patient's entire arm and provide allergists with precise measures of wheals for diagnosis. The device is based on 3-D laser technology and specific algorithms have been developed to process the information gathered. This system aims to automate the reading of skin prick tests and make gains in speed, accuracy, and reliability. Several experiments have been performed to evaluate the performance of the system. PMID- 28362598 TI - An OAIS-Based Hospital Information System on the Cloud: Analysis of a NoSQL Column-Oriented Approach. AB - The Open Archive Information System (OAIS) is a reference model for organizing people and resources in a system, and it is already adopted in care centers and medical systems to efficiently manage clinical data, medical personnel, and patients. Archival storage systems are typically implemented using traditional relational database systems, but the relation-oriented technology strongly limits the efficiency in the management of huge amount of patients' clinical data, especially in emerging cloud-based, that are distributed. In this paper, we present an OAIS healthcare architecture useful to manage a huge amount of HL7 clinical documents in a scalable way. Specifically, it is based on a NoSQL column oriented Data Base Management System deployed in the cloud, thus to benefit from a big tables and wide rows available over a virtual distributed infrastructure. We developed a prototype of the proposed architecture at the IRCCS, and we evaluated its efficiency in a real case of study. PMID- 28362599 TI - Adaptive Neural Control of Uncertain Nonlinear Systems Using Disturbance Observer. AB - This paper studies the problem of prescribed performance adaptive neural control for a class of uncertain multi-input and multi-output (MIMO) nonlinear systems in the presence of external disturbances and input saturation based on a disturbance observer. The system uncertainties are tackled by neural network (NN) approximation. To handle unknown disturbances, a Nussbaum disturbance observer is presented. By incorporating the disturbance observer and NNs, an adaptive prescribed performance neural control scheme is further developed. Then, the expected asymptotically convergent tracking errors between system output signals and desired signals are achieved. Numerical simulation results demonstrate the effectiveness of the proposed control scheme. PMID- 28362600 TI - FUIQA: Fetal Ultrasound Image Quality Assessment With Deep Convolutional Networks. AB - The quality of ultrasound (US) images for the obstetric examination is crucial for accurate biometric measurement. However, manual quality control is a labor intensive process and often impractical in a clinical setting. To improve the efficiency of examination and alleviate the measurement error caused by improper US scanning operation and slice selection, a computerized fetal US image quality assessment (FUIQA) scheme is proposed to assist the implementation of US image quality control in the clinical obstetric examination. The proposed FUIQA is realized with two deep convolutional neural network models, which are denoted as L-CNN and C-CNN, respectively. The L-CNN aims to find the region of interest (ROI) of the fetal abdominal region in the US image. Based on the ROI found by the L-CNN, the C-CNN evaluates the image quality by assessing the goodness of depiction for the key structures of stomach bubble and umbilical vein. To further boost the performance of the L-CNN, we augment the input sources of the neural network with the local phase features along with the original US data. It will be shown that the heterogeneous input sources will help to improve the performance of the L-CNN. The performance of the proposed FUIQA is compared with the subjective image quality evaluation results from three medical doctors. With comprehensive experiments, it will be illustrated that the computerized assessment with our FUIQA scheme can be comparable to the subjective ratings from medical doctors. PMID- 28362601 TI - Constrained Superpixel Tracking. AB - In this paper, we propose a constrained graph labeling algorithm for visual tracking where nodes denote superpixels and edges encode the underlying spatial, temporal, and appearance fitness constraints. First, the spatial smoothness constraint, based on a transductive learning method, is enforced to leverage the latent manifold structure in feature space by investigating unlabeled superpixels in the current frame. Second, the appearance fitness constraint, which measures the probability of a superpixel being contained in the target region, is developed to incrementally induce a long-term appearance model. Third, the temporal smoothness constraint is proposed to construct a short-term appearance model of the target, which handles the drastic appearance change between consecutive frames. All these three constraints are incorporated in the proposed graph labeling algorithm such that induction and transduction, short- and long term appearance models are combined, respectively. The foreground regions inferred by the proposed graph labeling method are used to guide the tracking process. Tracking results, in turn, facilitate more accurate online update by filtering out potential contaminated training samples. Both quantitative and qualitative evaluations on challenging tracking data sets show that the proposed constrained tracking algorithm performs favorably against the state-of-the-art methods. PMID- 28362602 TI - Adaptive Differential Evolution With Sorting Crossover Rate for Continuous Optimization Problems. AB - Differential evolution (DE) is one of the best evolutionary algorithms (EAs). The effort of improving its performance has received great research attentions, such as adaptive DE (JADE). Based on the analysis on the aspects that may improve the performance of JADE, we introduce a modified JADE version with sorting crossover rate (CR). In JADE, CR values are generated based on mean value and Gaussian distribution. In the proposed algorithm, a smaller CR value is assigned to individual with better fitness value. Therefore, the components of the individuals, which have better fitness values, can appear in the offspring with higher possibility. In addition, the better offspring generated from last iteration are supposed to have better schemes, hence these schemes are preserved in next offspring generation procedure. This modified version is called as JADE algorithm with sorting CR (JADE_sort). The experiments results with several excellent algorithms show the effectiveness of JADE_sort. PMID- 28362603 TI - Scale-Limited Lagrange Stability and Finite-Time Synchronization for Memristive Recurrent Neural Networks on Time Scales. AB - The existed results of Lagrange stability and finite-time synchronization for memristive recurrent neural networks (MRNNs) are scale-free on time evolvement, and some restrictions appear naturally. In this paper, two novel scale-limited comparison principles are established by means of inequality techniques and induction principle on time scales. Then the results concerning Lagrange stability and global finite-time synchronization of MRNNs on time scales are obtained. Scaled-limited Lagrange stability criteria are derived, in detail, via nonsmooth analysis and theory of time scales. Moreover, novel criteria for achieving the global finite-time synchronization are acquired. In addition, the derived method can also be used to study global finite-time stabilization. The proposed results extend or improve the existed ones in the literatures. Two numerical examples are chosen to show the effectiveness of the obtained results. PMID- 28362605 TI - Low-Cost 3-D Flow Estimation of Blood With Clutter. AB - Volumetric flow rate estimation is an important ultrasound medical imaging modality that is used for diagnosing cardiovascular diseases. Flow rates are obtained by integrating velocity estimates over a cross-sectional plane. Speckle tracking is a promising approach that overcomes the angle dependency of traditional Doppler methods, but suffers from poor lateral resolution. Recent work improves lateral velocity estimation accuracy by reconstructing a synthetic lateral phase (SLP) signal. However, the estimation accuracy of such approaches is compromised by the presence of clutter. Eigen-based clutter filtering has been shown to be effective in removing the clutter signal; but it is computationally expensive, precluding its use at high volume rates. In this paper, we propose low complexity schemes for both velocity estimation and clutter filtering. We use a two-tiered motion estimation scheme to combine the low complexity sum-of-absolute difference and SLP methods to achieve subpixel lateral accuracy. We reduce the complexity of eigen-based clutter filtering by processing in subgroups and replacing singular value decomposition with less compute-intensive power iteration and subspace iteration methods. Finally, to improve flow rate estimation accuracy, we use kernel power weighting when integrating the velocity estimates. We evaluate our method for fast- and slow-moving clutter for beam-to flow angles of 90 degrees and 60 degrees using Field II simulations, demonstrating high estimation accuracy across scenarios. For instance, for a beam to-flow angle of 90 degrees and fast-moving clutter, our estimation method provides a bias of -8.8% and standard deviation of 3.1% relative to the actual flow rate. PMID- 28362606 TI - Semi-Supervised Sparse Representation Based Classification for Face Recognition With Insufficient Labeled Samples. AB - This paper addresses the problem of face recognition when there is only few, or even only a single, labeled examples of the face that we wish to recognize. Moreover, these examples are typically corrupted by nuisance variables, both linear (i.e., additive nuisance variables, such as bad lighting and wearing of glasses) and non-linear (i.e., non-additive pixel-wise nuisance variables, such as expression changes). The small number of labeled examples means that it is hard to remove these nuisance variables between the training and testing faces to obtain good recognition performance. To address the problem, we propose a method called semi-supervised sparse representation-based classification. This is based on recent work on sparsity, where faces are represented in terms of two dictionaries: a gallery dictionary consisting of one or more examples of each person, and a variation dictionary representing linear nuisance variables (e.g., different lighting conditions and different glasses). The main idea is that: 1) we use the variation dictionary to characterize the linear nuisance variables via the sparsity framework and 2) prototype face images are estimated as a gallery dictionary via a Gaussian mixture model, with mixed labeled and unlabeled samples in a semi-supervised manner, to deal with the non-linear nuisance variations between labeled and unlabeled samples. We have done experiments with insufficient labeled samples, even when there is only a single labeled sample per person. Our results on the AR, Multi-PIE, CAS-PEAL, and LFW databases demonstrate that the proposed method is able to deliver significantly improved performance over existing methods. PMID- 28362607 TI - Partial Hash Update via Hamming Subspace Learning. AB - Hashing technique has become an effective method for information retrieval due to the fast calculation of the Hamming distance. However, with the continuous growth of data coming from the Internet, the online update of hashing on the massive social data becomes very time-consuming. To alleviate this issue, in this paper, we propose a novel updating technique for hashing methods, namely Hamming Subspace Learning (HSL). The motivation of HSL is to generate a low-dimensional Hamming subspace from a high-dimensional Hamming space by selecting representative hash functions. Through HSL, we aim to improve the speed of updating binary codes for all samples. We present a method for Hamming subspace learning based on greedy selection strategy and the Distribution Preserving Hamming Subspace learning (DHSL) algorithm by designing a novel loss function. The experimental results demonstrate that the HSL is effective to improve the speed of online updating and the performance of hashing algorithm. PMID- 28362608 TI - TMAGIC: A Model-Free 3D Tracker. AB - Significant effort has been devoted within the visual tracking community to rapid learning of object properties on the fly. However, state-of-the-art approaches still often fail in cases such as rapid out-of-plane rotation, when the appearance changes suddenly. One of the major contributions of this paper is a radical rethinking of the traditional wisdom of modeling 3D motion as appearance changes during tracking. Instead, 3D motion is modeled as 3D motion. This intuitive but previously unexplored approach provides new possibilities in visual tracking research. First, 3D tracking is more general, as large out-of-plane motion is often fatal for 2D trackers, but helps 3D trackers to build better models. Second, the tracker's internal model of the object can be used in many different applications and it could even become the main motivation, with tracking supporting reconstruction rather than vice versa. This effectively bridges the gap between visual tracking and structure from motion. A new benchmark data set of sequences with extreme out-of-plane rotation is presented and an online leader-board offered to stimulate new research in the relatively underdeveloped area of 3D tracking. The proposed method, provided as a baseline, is capable of successfully tracking these sequences, all of which pose a considerable challenge to 2D trackers (error reduced by 46%). PMID- 28362609 TI - Object Category Understanding via Eye Fixations on Freehand Sketches. AB - The study of eye gaze fixations on photographic images is an active research area. In contrast, the image sub-category of freehand sketches has not received as much attention for such studies. In this paper, we analyze the results of a free-viewing gaze fixation study conducted on 3904 freehand sketches distributed across 160 object categories. Our analysis shows that fixation sequences exhibit marked consistency within a sketch, across sketches of a category and even across suitably grouped sets of categories. This multi-level consistency is remarkable given the variability in depiction and extreme image content sparsity that characterizes hand-drawn object sketches. In this paper, we show that the multi level consistency in the fixation data can be exploited to 1) predict a test sketch's category given only its fixation sequence and 2) build a computational model which predicts part-labels underlying fixations on objects. We hope that our findings motivate the community to deem sketch-like representations worthy of gaze-based studies vis-a-vis photographic images. PMID- 28362610 TI - A Qualitative and Quantitative Evaluation of 8 Clear Sky Models. AB - We provide a qualitative and quantitative evaluation of 8 clear sky models used in Computer Graphics. We compare the models with each other as well as with measurements and with a reference model from the physics community. After a short summary of the physics of the problem, we present the measurements and the reference model, and how we "invert" it to get the model parameters. We then give an overview of each CG model, and detail its scope, its algorithmic complexity, and its results using the same parameters as in the reference model. We also compare the models with a perceptual study. Our quantitative results confirm that the less simplifications and approximations are used to solve the physical equations, the more accurate are the results. We conclude with a discussion of the advantages and drawbacks of each model, and how to further improve their accuracy. PMID- 28362611 TI - Sequential Monte Carlo Instant Radiosity. AB - Instant Radiosity and its derivatives are interactive methods for efficiently estimating global (indirect) illumination. They represent the last indirect bounce of illumination before the camera as the composite radiance field emitted by a set of virtual point light sources (VPLs). In complex scenes, current algorithms suffer from a difficult combination of two issues: it remains a challenge to distribute VPLs in a manner that simultaneously gives a high-quality indirect illumination solution for each frame, and to do so in a temporally coherent manner. We address both issues by building, and maintaining over time, an adaptive and temporally coherent distribution of VPLs in locations where they bring indirect light to the image. We introduce a novel heuristic sampling method that strives to only move as few of the VPLs between frames as possible. The result is, to the best of our knowledge, the first interactive global illumination algorithm that works in complex, highly-occluded scenes, suffers little from temporal flickering, supports moving cameras and light sources, and is output-sensitive in the sense that it places VPLs in locations that matter most to the final result. PMID- 28362612 TI - Neural Probes with Integrated Temperature Sensors for Monitoring Retina and Brain Implantation and Stimulation. AB - Gold (Au) resistive temperature sensors were integrated on flexible polyimide based neural probes to monitor temperature changes during neural probe implantation and stimulation. Temperature changes were measured as neural probes were implanted to infer the positions of the neural probes, and as the retina or the deep brain region was stimulated electrically. The temperature sensor consisted of a serpentine Au resistor and surrounded by four Au electrodes with 200 and [Formula: see text] diameter (dia.). The Au temperature sensors had temperature coefficient of 0.32%, and they were biocompatible and small in size. In vivo measurements of temperature changes during implantation and stimulation were carried out in the retina and deep brain region in rats. The desired implantation position was reached when temperature measured by the sensor increased to the calibrated level and became stable. There was no temperature increase when low level stimulation current of 8 and [Formula: see text] each for the two 200- and 400- [Formula: see text]-dia. electrodes, respectively, were applied. When higher level stimulation current of 100 and [Formula: see text] each were applied to the two 200- and 400- [Formula: see text]-dia. electrodes, respectively, maximum temperature increases of 1.2 degrees C in retina and 1 degrees C in deep brain region were found. PMID- 28362613 TI - Oscillatory Behaviors in Genetic Regulatory Networks Mediated by MicroRNA With Time Delays and Reaction-Diffusion Terms. AB - In this paper, we investigate the oscillatory expression in Escherichia coli mediated by microRNA with time delays and reaction-diffusion terms. First of all, the integrated effects of delays and diffusions are first introduced into the genetic regulatory networks involving microRNAs, and a general model of genetic regulatory networks is then formulated. Second, two functional issues on gene regulatory networks, i.e. stability and oscillation of such model, are addressed in detail, and an explicit algorithm determining the properties of periodic oscillation is also presented. We demonstrate that the oscillatory expression of Escherichia coli is not only crucially dependent on the transcriptional and translational delays, but also heavily influenced by the diffusion coefficients. The conclusion is practically verified by a lot of biological experiments and observations. We also find that if the diffusion coefficients of miRNA, mRNA, and protein are suitably small, it can predict that inhomogeneous periodic oscillations can occur unless there only exhibits spatially homogeneous periodic oscillations. The obtained results indicate that the effects of transcriptional and translational delays are essential factors for designing or controlling genetic regulatory networks, in the meantime the functions of reaction-diffusion must beconsidered. Finally, numerical examples are presented to illustrate and visualize theoretical results. PMID- 28362615 TI - Simultaneous Bayesian Clustering and Feature Selection Through Student's ${t}$ Mixtures Model. AB - In this paper, we proposed a generative model for feature selection under the unsupervised learning context. The model assumes that data are independently and identically sampled from a finite mixture of Student's distributions, which can reduce the sensitiveness to outliers. Latent random variables that represent the features' salience are included in the model for the indication of the relevance of features. As a result, the model is expected to simultaneously realize clustering, feature selection, and outlier detection. Inference is carried out by a tree-structured variational Bayes algorithm. Full Bayesian treatment is adopted in the model to realize automatic model selection. Controlled experimental studies showed that the developed model is capable of modeling the data set with outliers accurately. Furthermore, experiment results showed that the developed algorithm compares favorably against existing unsupervised probability model based Bayesian feature selection algorithms on artificial and real data sets. Moreover, the application of the developed algorithm on real leukemia gene expression data indicated that it is able to identify the discriminating genes successfully. PMID- 28362614 TI - HTM Spatial Pooler With Memristor Crossbar Circuits for Sparse Biometric Recognition. AB - Hierarchical Temporal Memory (HTM) is an online machine learning algorithm that emulates the neo-cortex. The development of a scalable on-chip HTM architecture is an open research area. The two core substructures of HTM are spatial pooler and temporal memory. In this work, we propose a new Spatial Pooler circuit design with parallel memristive crossbar arrays for the 2D columns. The proposed design was validated on two different benchmark datasets, face recognition, and speech recognition. The circuits are simulated and analyzed using a practical memristor device model and 0.18 MUm IBM CMOS technology model. The databases AR, YALE, ORL, and UFI, are used to test the performance of the design in face recognition. TIMIT dataset is used for the speech recognition. PMID- 28362616 TI - Neural-Network-Based Robust Optimal Tracking Control for MIMO Discrete-Time Systems With Unknown Uncertainty Using Adaptive Critic Design. AB - This paper is concerned with the robust optimal tracking control strategy for a class of nonlinear multi-input multi-output discrete-time systems with unknown uncertainty via adaptive critic design (ACD) scheme. The main purpose is to establish an adaptive actor-critic control method, so that the cost function in the procedure of dealing with uncertainty is minimum and the closed-loop system is stable. Based on the neural network approximator, an action network is applied to generate the optimal control signal and a critic network is used to approximate the cost function, respectively. In contrast to the previous methods, the main features of this paper are: 1) the ACD scheme is integrated into the controllers to cope with the uncertainty and 2) a novel cost function, which is not in quadric form, is proposed so that the total cost in the design procedure is reduced. It is proved that the optimal control signals and the tracking errors are uniformly ultimately bounded even when the uncertainty exists. Finally, a numerical simulation is developed to show the effectiveness of the present approach. PMID- 28362617 TI - Discrete-Time Stable Generalized Self-Learning Optimal Control With Approximation Errors. AB - In this paper, a generalized policy iteration (GPI) algorithm with approximation errors is developed for solving infinite horizon optimal control problems for nonlinear systems. The developed stable GPI algorithm provides a general structure of discrete-time iterative adaptive dynamic programming algorithms, by which most of the discrete-time reinforcement learning algorithms can be described using the GPI structure. It is for the first time that approximation errors are explicitly considered in the GPI algorithm. The properties of the stable GPI algorithm with approximation errors are analyzed. The admissibility of the approximate iterative control law can be guaranteed if the approximation errors satisfy the admissibility criteria. The convergence of the developed algorithm is established, which shows that the iterative value function is convergent to a finite neighborhood of the optimal performance index function, if the approximate errors satisfy the convergence criterion. Finally, numerical examples and comparisons are presented. PMID- 28362618 TI - Adaptive Fuzzy Neural Network Control for a Constrained Robot Using Impedance Learning. AB - This paper investigates adaptive fuzzy neural network (NN) control using impedance learning for a constrained robot, subject to unknown system dynamics, the effect of state constraints, and the uncertain compliant environment with which the robot comes into contact. A fuzzy NN learning algorithm is developed to identify the uncertain plant model. The prominent feature of the fuzzy NN is that there is no need to get the prior knowledge about the uncertainty and a sufficient amount of observed data. Also, impedance learning is introduced to tackle the interaction between the robot and its environment, so that the robot follows a desired destination generated by impedance learning. A barrier Lyapunov function is used to address the effect of state constraints. With the proposed control, the stability of the closed-loop system is achieved via Lyapunov's stability theory, and the tracking performance is guaranteed under the condition of state constraints and uncertainty. Some simulation studies are carried out to illustrate the effectiveness of the proposed scheme. PMID- 28362619 TI - Classification With Truncated Distance Kernel. AB - This brief proposes a truncated distance (TL1) kernel, which results in a classifier that is nonlinear in the global region but is linear in each subregion. With this kernel, the subregion structure can be trained using all the training data and local linear classifiers can be established simultaneously. The TL1 kernel has good adaptiveness to nonlinearity and is suitable for problems which require different nonlinearities in different areas. Though the TL1 kernel is not positive semidefinite, some classical kernel learning methods are still applicable which means that the TL1 kernel can be directly used in standard toolboxes by replacing the kernel evaluation. In numerical experiments, the TL1 kernel with a pregiven parameter achieves similar or better performance than the radial basis function kernel with the parameter tuned by cross validation, implying the TL1 kernel a promising nonlinear kernel for classification tasks. PMID- 28362620 TI - Finite-Horizon $H_{?infty }$ Tracking Control for Unknown Nonlinear Systems With Saturating Actuators. AB - In this paper, a neural network (NN)-based online model-free integral reinforcement learning algorithm is developed to solve the finite-horizon optimal tracking control problem for completely unknown nonlinear continuous-time systems with disturbance and saturating actuators (constrained control input). An augmented system is constructed with the tracking error system and the command generator system. A time-varying Hamilton-Jacobi-Isaacs (HJI) equation is formulated for the augmented problem, which is extremely difficult or impossible to solve due to its time-dependent property and nonlinearity. Then, an actor critic-disturbance NN structure-based scheme is proposed to learn the time varying solution to the HJI equation in real time without using the knowledge of system dynamics. Since the solution to the HJI equation is time-dependent, the form of NNs representation with constant weights and time-dependent activation functions is considered. Furthermore, an extra error is incorporated in order to satisfy the terminal constraints in the weight update law. Convergence and stability proofs are given based on the Lyapunov theory for nonautonomous systems. Two simulation examples are provided to demonstrate the effectiveness of the designed algorithm. PMID- 28362621 TI - Optimizing Evaluation Metrics for Multitask Learning via the Alternating Direction Method of Multipliers. AB - Multitask learning (MTL) aims to improve the generalization performance of multiple tasks by exploiting the shared factors among them. Various metrics (e.g., -score, area under the ROC curve) are used to evaluate the performances of MTL methods. Most existing MTL methods try to minimize either the misclassified errors for classification or the mean squared errors for regression. In this paper, we propose a method to directly optimize the evaluation metrics for a large family of MTL problems. The formulation of MTL that directly optimizes evaluation metrics is the combination of two parts: 1) a regularizer defined on the weight matrix over all tasks, in order to capture the relatedness of these tasks and 2) a sum of multiple structured hinge losses, each corresponding to a surrogate of some evaluation metric on one task. This formulation is challenging in optimization because both of its parts are nonsmooth. To tackle this issue, we propose a novel optimization procedure based on the alternating direction scheme of multipliers, where we decompose the whole optimization problem into a subproblem corresponding to the regularizer and another subproblem corresponding to the structured hinge losses. For a large family of MTL problems, the first subproblem has closed-form solutions. To solve the second subproblem, we propose an efficient primal-dual algorithm via coordinate ascent. Extensive evaluation results demonstrate that, in a large family of MTL problems, the proposed MTL method of directly optimization evaluation metrics has superior performance gains against the corresponding baseline methods. PMID- 28362622 TI - Programming the Future: Epigenetics in the Context of DOHaD. PMID- 28362623 TI - Erratum: "Microcystis Rising: Why Phosphorus Reduction Isn't Enough to Stop CyanoHABs". PMID- 28362624 TI - Erratum: "Telomere Length, Long-Term Black Carbon Exposure, and Cognitive Function in a Cohort of Older Men: The VA Normative Aging Study". PMID- 28362625 TI - A Blend of Old and New: Biomonitoring Methods to Study the Exposome. PMID- 28362626 TI - The Forest and the Trees: How Population-Level Health Protections Sometimes Fail the Individual. PMID- 28362627 TI - Retraction: "A Case-Cohort Study of Cadmium Body Burden and Gestational Diabetes Mellitus in American Women". PMID- 28362628 TI - Way to Go: Identifying Routes for Walkers and Cyclists to Avoid Air Pollutants. PMID- 28362629 TI - A Satellite-Ground Hybrid Approach: Relative Risks for Exposures to PM2.5 Estimated from a Combination of Data Sources. PMID- 28362631 TI - The undulatory swimming gait of elongated swimmers revisited. AB - An undulatory swimming gait is characterized by short lateral displacement waves that propagate backwards along the body of the swimmer faster than it swims. Hydrodynamic theory of elongated bodies predicts that if the amplitude of the displacement waves does not increase toward the caudal end, the part of the swimmer posteriad of the dorso-ventrally widest point takes no part in propulsion. It also predicts that if the amplitude does increase, then the hydrodynamic propulsion efficiency suffers. Cusk eels have their widest point located in the anterior half of the body with the bulk of their locomotive muscles located posteriad of it; indeed, they swim so that the amplitude of the propulsion wave increases toward the caudal end. Anguillid eels have their widest point posteriad of the mid-body, and their locomotive muscles are distributed along their entire length-but they swim as cusk eels, using the posterior half only. Apparently, both use hydrodynamically inefficient gaits. The paper questions the definition of propulsion efficiency and shows that biomechanical considerations are more important than hydrodynamic, and that most probably fish adjust their gait to maximize the ratio between the energy made good (the product of thrust and distance) and the chemical energy consumed by the muscles. The role of body shape is discussed. PMID- 28362633 TI - Terahertz plasmonic excitations in Bi2Se3 topological insulator. AB - After the discovery of Dirac electrons in condensed matter physics, more specifically in graphene and its derivatives, their potentialities in the fields of plasmonics and photonics have been readily recognized, leading to a plethora of applications in active and tunable optical devices. Massless Dirac carriers have been further found in three-dimensional topological insulators. These exotic quantum systems have an insulating gap in the bulk and intrinsic Dirac metallic states at any surface, sustaining not only single-particle excitations but also plasmonic collective modes. In this paper we will review the plasmon excitations in different microstructures patterned on Bi2Se3 topological insulator thin films as measured by terahertz spectroscopy. We discuss the dependence of the plasmon absorption versus the microstructure shape, wavevector, and magnetic field. Finally we will discuss the topological protection of both the Dirac single particle and plasmon excitations. PMID- 28362634 TI - Site-selective conjugation of an anticoagulant aptamer to recombinant albumins and maintenance of neonatal Fc receptor binding. AB - Aptamers are an attractive molecular medicine that offers high target specificity. Nucleic acid-based aptamers, however, are prone to nuclease degradation and rapid renal excretion that require blood circulatory half-life extension enabling technologies. The long circulatory half-life, predominately facilitated by engagement with the cellular recycling neonatal Fc receptor (FcRn), and ligand transport properties of albumin promote it as an attractive candidate to improve the pharmacokinetic profile of aptamers. This study investigates the effect of Cys34 site-selective covalent attachment of a factor IXa anticoagulant aptamer on aptamer functionality and human FcRn (hFcRn) engagement using recombinant human albumin (rHA) of either a wild type (WT) or an engineered human FcRn high binding variant (HB). Albumin-aptamer conjugates, connected covalently through a heterobifunctional succinimidyl 4-(N maleimidomethyl)cyclohexane-1-carboxylate linker, were successfully prepared and purified by high performance liquid chromatography as confirmed by gel electrophoresis band-shift analysis and matrix-assisted laser desorption/ionization time of flight. Minimal reduction (~25%) in activity of WT linked aptamer to that of aptamer alone was found using an anticoagulant activity assay measuring temporal levels of activated partial thrombin. Covalent albumin aptamer conjugation, however, substantially compromized binding to hFcRn, to 10% affinity of that of non-conjugated WT, determined by biolayer interferometry. Binding could be rescued by aptamer conjugation to recombinant albumin engineered for higher FcRn affinity (HB) that exhibited an 8-fold affinity compared to WT alone. This work describes a novel albumin-based aptamer delivery system whose hFcRn binding can be increased using a HB engineered albumin. PMID- 28362635 TI - Carbon nanotube radio-frequency electronics. AB - Carbon nanotube (CNT) is considered a promising material for radio-frequency (RF) applications, owing to its high carrier mobility and saturated drift velocity, as well as ultra-small intrinsic gate capacitance. Here, we review progress on CNT based devices and integrated circuits for RF applications, including theoretical projection of RF performance of CNT-based devices, preparation of CNT materials, fabrication, optimization of RF field-effect transistors (FETs) structures, and ambipolar FET-based RF applications, and we outline challenges and prospects of CNT-based RF applications. PMID- 28362630 TI - Measurement invariance of the Depression Anxiety Stress Scales-21 across medical student genders. AB - Objectives: This study aimed to assess whether male and female Iranian medical students perceived the meaning of the items in the Depression Anxiety Stress Scales-21 consistently. Methods: A convenience sample of 783 preclinical medical students from the first to sixth semester was invited to this cross-sectional study. Of the 477 respondents, 238 were male and 239 were female. All participants completed the Persian version of the Depression Anxiety Stress Scales-21. The graded response model was used to assess measurement invariance of the instrument across the gender groups. Categorical confirmatory factor analysis was used to evaluate the construct validity of the measure. Moreover, internal consistency was assessed via Cronbach's Alpha. Results: Statistically significant differential item functioning was flagged for just item 6 in the depression subscales (c2=6.5, df=1, p=0.011). However, removing or retaining the item 6 in the stress subscale did not change our findings significantly, when we compared stress scores across two genders. The results of categorical confirmatory factor analysis supported the fit of the three-factor model of Depression Anxiety Stress Scales-21. Moreover, Cronbach's alpha was greater than 0.7 in depression, anxiety and stress subscales. Conclusions: This study revealed that Depression Anxiety Stress Scales-21 is an invariant measure across male and female medical students. Hence, this reliable and valid instrument can be used for meaningful comparison of distress scores between medical student genders. Gender comparisons of medical students' psychological profiles provide a better insight into gender influences on the outcome of medical education and medical practice. PMID- 28362636 TI - An aerodynamic model for insect flapping wings in forward flight. AB - This paper proposes a semi-empirical quasi-steady aerodynamic model of a flapping wing in forward flight. A total of 147 individual cases, which consisted of advance ratios J of 0 (hovering), 0.125, 0.25, 0.5, 0.75, 1 and infinity, and angles of attack alpha of -5 to 95 degrees at intervals of 5 degrees , were examined to extract the aerodynamic coefficients. The Polhamus leading-edge suction analogy and power functions were then employed to establish the aerodynamic model. In order to preserve the existing level of simplicity, K P and K V, the correction factors of the potential and vortex force models, were rebuilt as functions of J and alpha. The estimations were nearly identical to direct force/moment measurements which were obtained from both artificial and practical wingbeat motions of a hawkmoth. The model effectively compensated for the influences of J, particularly showing outstanding moment estimation capabilities. With this model, we found that using a lower value of alpha during the downstroke would be an effective strategy for generating adequate lift in forward flight. The rotational force and moment components had noticeable portions generating both thrust and counteract pitching moment during pronation. In the upstroke phase, the added mass component played a major role in generating thrust in forward flight. The proposed model would be useful for a better understanding of flight stability, control, and the dynamic characteristics of flapping wing flyers, and for designing flapping-wing micro air vehicles. PMID- 28362637 TI - Method for determining optimal supercell representation of interfaces. AB - The geometry and structure of an interface ultimately determines the behavior of devices at the nanoscale. We present a generic method to determine the possible lattice matches between two arbitrary surfaces and to calculate the strain of the corresponding matched interface. We apply this method to explore two relevant classes of interfaces for which accurate structural measurements of the interface are available: (i) the interface between pentacene crystals and the (1 1 1) surface of gold, and (ii) the interface between the semiconductor indium-arsenide and aluminum. For both systems, we demonstrate that the presented method predicts interface geometries in good agreement with those measured experimentally, which present nontrivial matching characteristics and would be difficult to guess without relying on automated structure-searching methods. PMID- 28362639 TI - Enhancing performances of a resistivity-type hydrogen sensor based on Pd/SnO2/RGO nanocomposites. AB - Palladium/tin oxide/reduced graphene oxide (Pd/SnO2/RGO) nanocomposites with Pd and SnO2 crystalline nanoparticles of high density and uniformity coated on RGO have been synthesized by a two-step reduction process. A novel hydrogen (H2) sensor based on Pd/SnO2/RGO nanocomposites was fabricated by placing Pd/SnO2/RGO nanocomposites onto a pair of gold electrodes. The Pd/SnO2/RGO nanocomposite based sensor exhibited higher responses than Pd/RGO to H2 because the introduction of SnO2 nanoparticles enhances H2 adsorption and forms a P-N junction with RGO. The sensor shows a high response of 55% to 10 000 ppm H2, and a low detection limit, fast response, good selectivity and repeatability due to a combination effect of the Pd and SnO2 nanoparticles. The studies provide a novel strategy for great potential applications of graphene-based gas sensors. PMID- 28362638 TI - Task-driven optimization of CT tube current modulation and regularization in model-based iterative reconstruction. AB - Tube current modulation (TCM) is routinely adopted on diagnostic CT scanners for dose reduction. Conventional TCM strategies are generally designed for filtered backprojection (FBP) reconstruction to satisfy simple image quality requirements based on noise. This work investigates TCM designs for model-based iterative reconstruction (MBIR) to achieve optimal imaging performance as determined by a task-based image quality metric. Additionally, regularization is an important aspect of MBIR that is jointly optimized with TCM, and includes both the regularization strength that controls overall smoothness as well as directional weights that permits control of the isotropy/anisotropy of the local noise and resolution properties. Initial investigations focus on a known imaging task at a single location in the image volume. The framework adopts Fourier and analytical approximations for fast estimation of the local noise power spectrum (NPS) and modulation transfer function (MTF)-each carrying dependencies on TCM and regularization. For the single location optimization, the local detectability index (d') of the specific task was directly adopted as the objective function. A covariance matrix adaptation evolution strategy (CMA-ES) algorithm was employed to identify the optimal combination of imaging parameters. Evaluations of both conventional and task-driven approaches were performed in an abdomen phantom for a mid-frequency discrimination task in the kidney. Among the conventional strategies, the TCM pattern optimal for FBP using a minimum variance criterion yielded a worse task-based performance compared to an unmodulated strategy when applied to MBIR. Moreover, task-driven TCM designs for MBIR were found to have the opposite behavior from conventional designs for FBP, with greater fluence assigned to the less attenuating views of the abdomen and less fluence to the more attenuating lateral views. Such TCM patterns exaggerate the intrinsic anisotropy of the MTF and NPS as a result of the data weighting in MBIR. Directional penalty design was found to reinforce the same trend. The task-driven approaches outperform conventional approaches, with the maximum improvement in d' of 13% given by the joint optimization of TCM and regularization. This work demonstrates that the TCM optimal for MBIR is distinct from conventional strategies proposed for FBP reconstruction and strategies optimal for FBP are suboptimal and may even reduce performance when applied to MBIR. The task-driven imaging framework offers a promising approach for optimizing acquisition and reconstruction for MBIR that can improve imaging performance and/or dose utilization beyond conventional imaging strategies. PMID- 28362640 TI - Multi-isotope SPECT imaging of the 225Ac decay chain: feasibility studies. AB - Effective use of the [Formula: see text] decay chain in targeted internal radioimmunotherapy requires the retention of both [Formula: see text] and progeny isotopes at the target site. Imaging-based pharmacokinetic tests of these pharmaceuticals must therefore separately yet simultaneously image multiple isotopes that may not be colocalized despite being part of the same decay chain. This work presents feasibility studies demonstrating the ability of a microSPECT/CT scanner equipped with a high energy collimator to simultaneously image two components of the [Formula: see text] decay chain: [Formula: see text] (218 keV) and [Formula: see text] (440 keV). Image quality phantoms were used to assess the performance of two collimators for simultaneous [Formula: see text] and [Formula: see text] imaging in terms of contrast and noise. A hotrod resolution phantom containing clusters of thin rods with diameters ranging between 0.85 and 1.70 mm was used to assess resolution. To demonstrate ability to simultaneously image dynamic [Formula: see text] and [Formula: see text] activity distributions, a phantom containing a [Formula: see text] generator from [Formula: see text] was imaged. These tests were performed with two collimators, a high-energy ultra-high resolution (HEUHR) collimator and an ultra-high sensitivity (UHS) collimator. Values consistent with activity concentrations determined independently via gamma spectroscopy were observed in high activity regions of the images. In hotrod phantom images, the HEUHR collimator resolved all rods for both [Formula: see text] and [Formula: see text] images. With the UHS collimator, no rods were resolvable in [Formula: see text] images and only rods ?1.3 mm were resolved in [Formula: see text] images. After eluting the [Formula: see text] generator, images accurately visualized the reestablishment of transient equilibrium of the [Formula: see text] decay chain. The feasibility of evaluating the pharmacokinetics of the [Formula: see text] decay chain in vivo has been demonstrated. This presented method requires the use of a high performance high-energy collimator. PMID- 28362641 TI - Mesoscopic quantum effects in a bad metal, hydrogen-doped vanadium dioxide. AB - The standard treatment of quantum corrections to semiclassical electronic conduction assumes that charge carriers propagate many wavelengths between scattering events, and succeeds in explaining multiple phenomena (weak localization magnetoresistance (WLMR), universal conductance fluctuations, Aharonov-Bohm oscillations) observed in polycrystalline metals and doped semiconductors in various dimensionalities. We report apparent WLMR and conductance fluctuations in H x VO2, a poor metal (in violation of the Mott-Ioffe Regel limit) stabilized by the suppression of the VO2 metal-insulator transition through atomic hydrogen doping. Epitaxial thin films, single-crystal nanobeams, and nanosheets show similar phenomenology, though the details of the apparent WLMR seem to depend on the combined effects of the strain environment and presumed doping level. Self-consistent quantitative analysis of the WLMR is challenging given this and the high resistivity of the material, since the quantitative expressions for WLMR are derived assuming good metallicity. These observations raise the issue of how to assess and analyze mesoscopic quantum effects in poor metals. PMID- 28362643 TI - Simulation of a Novel Schedule for Intensivist Staffing to Improve Continuity of Patient Care and Reduce Physician Burnout. AB - OBJECTIVE: Despite widespread adoption of in-house call for ICU attendings, there is a paucity of research on optimal scheduling of intensivists to provide continuous on-site coverage. Overnight call duties have traditionally been added onto 7 days of continuous daytime clinical service. We designed an alternative ICU staffing model to increase continuity of attending physician care for patients while also decreasing interruptions to attendings' nonclinical weeks. DESIGN: Computer-based simulation of a 1-year schedule. SETTING: A simulated ICU divided into two daytime teams each covered by a different attending and both covered by one overnight on-call attending. SUBJECTS: Simulated patients were randomly admitted on different service days to assess continuity of care. INTERVENTIONS: A "shared service schedule" was compared to a standard "7 days on schedule." For the 7 days on schedule, an attending covered a team for 7 consecutive days and off-service attendings cross-covered each night. For the shared schedule, four attendings shared the majority of daytime and nighttime service for two teams over 2 weeks, with recovery periods built into the scheduled service time. MEASUREMENTS AND MAIN RESULTS: Continuity of care as measured by the Continuity of Attending Physician Index increased by 9% with the shared schedule. Annually, the shared service schedule was predicted to increase free weekends by 3.4 full weekends and 1.3 weekends with either Saturday or Sunday off. Full weeks without clinical obligations increased by 4 weeks. Mean time between clinical obligations increased by 5.8 days. CONCLUSIONS: A shared service schedule is predicted to improve continuity of care while increasing free weekends and continuity of uninterrupted nonclinical weeks for attendings. Computer-based simulation allows assessment of benefits and tradeoffs of the alternative schedule without disturbing existing clinical systems. PMID- 28362645 TI - Validation of the A&D UM-201 device for office blood pressure measurement according to the European Society of Hypertension International Protocol Revision 2010. AB - The aim of this study was to determine the accuracy of the A&D UM-201 device coupled to several cuffs for different arm sizes for office blood pressure (BP) measurement according to the International Protocol of the European Society of Hypertension. Evaluation was carried out in 33 individuals. The mean age of the individuals was 59.3+/-13.2 years, systolic BP was 145.4+/-20.6 mmHg (range: 109 186 mmHg), diastolic BP was 87.3+/-18.0 mmHg (range: 50-124 mmHg), and arm circumference was 30.4+/-4.2 cm (range: 23-39 cm). The protocol requirements were followed precisely. The UM-201 monitor passed all requirements, fulfilling the standards of the protocol. On average, the device overestimated systolic BP by 3.0+/-2.1 mmHg and diastolic BP by 2.6+/-2.0 mmHg. These data show that the A&D UM-201 device coupled to several cuffs for different ranges of arm circumference fulfilled the requirements for validation by the International Protocol and can be recommended for clinical use in the adult population. PMID- 28362642 TI - Assessment of Virus Interference in a Test-negative Study of Influenza Vaccine Effectiveness. AB - BACKGROUND: The observational test-negative study design is used to estimate vaccine effectiveness against influenza virus infection. An important assumption of the test-negative design is that vaccination does not affect the risk of infection with another virus. If such virus interference occurred, detection of other respiratory viruses would be more common among influenza vaccine recipients and vaccine effectiveness estimates could differ. We evaluated the potential for virus interference using data from the Influenza Incidence Surveillance Project. METHODS: From 2010 to 2013, outpatients presenting to clinics in 13 US jurisdictions with acute respiratory infections were tested for influenza and other respiratory viruses. We investigated whether virus interference might affect vaccine effectiveness estimates by first evaluating the sensitivity of estimates using alternative control groups that include or exclude patients with other respiratory virus detections by age group and early/middle/late stage of influenza seasons. Second, we evaluated the association between influenza vaccination receipt and other respiratory virus detection among influenza test negative patients. RESULTS: Influenza was detected in 3,743/10,650 patients (35%), and overall vaccine effectiveness was 47% (95% CI: 42%, 52%). Estimates using each control group were consistent overall or when stratified by age groups, and there were no differences among early, middle, or late phase during influenza season. We found no associations between detection of other respiratory viruses and receipt of influenza vaccination. CONCLUSIONS: In this 3-year test negative design study in an outpatient setting in the United States, we found no evidence of virus interference or impact on influenza vaccine effectiveness estimation. PMID- 28362644 TI - Using Clinically Accessible Tools to Measure Sound Levels and Sleep Disruption in the ICU: A Prospective Multicenter Observational Study. AB - OBJECTIVES: To use clinically accessible tools to determine unit-level and individual patient factors associated with sound levels and sleep disruption in a range of representative ICUs. DESIGN: A cross-sectional, observational study. SETTING: Australian and New Zealand ICUs. PATIENTS: All patients 16 years or over occupying an ICU bed on one of two Point Prevalence study days in 2015. INTERVENTIONS: Ambient sound was measured for 1 minute using an application downloaded to a personal mobile device. Bedside nurses also recorded the total time and number of awakening for each patient overnight. MEASUREMENTS AND MAIN RESULTS: The study included 539 participants with sound level recorded using an application downloaded to a personal mobile device from 39 ICUs. Maximum and mean sound levels were 78 dB (SD, 9) and 62 dB (SD, 8), respectively. Maximum sound levels were higher in ICUs with a sleep policy or protocol compared with those without maximum sound levels 81 dB (95% CI, 79-83) versus 77 dB (95% CI, 77-78), mean difference 4 dB (95% CI, 0-2), p < 0.001. There was no significant difference in sound levels regardless of single room occupancy, mechanical ventilation status, or illness severity. Clinical nursing staff in all 39 ICUs were able to record sleep assessment in 15-minute intervals. The median time awake and number of prolonged disruptions were 3 hours (interquartile range, 1-4) and three (interquartile range, 2-5), respectively. CONCLUSIONS: Across a large number of ICUs, patients were exposed to high sound levels and substantial sleep disruption irrespective of factors including previous implementation of a sleep policy. Sound and sleep measurement using simple and accessible tools can facilitate future studies and could feasibly be implemented into clinical practice. PMID- 28362646 TI - The De Winter ECG pattern: morphology and accuracy for diagnosing acute coronary occlusion: systematic review. AB - The De Winter ECG pattern has been reported to indicate acute left anterior descending coronary artery occlusion and is often considered to be an 'ST elevation myocardial infarction (STEMI) equivalent'. We aimed to investigate the morphology of the 'De Winter ECG pattern' and evaluate the test characteristics of the De Winter pattern for the diagnosis of acute coronary occlusion. We identified papers through the Medline, EMBASE and COCHRANE databases and screened for bias using QUADAS-2. First, measurements were recorded from every ECG reported in the literature and aggregated. Second, diagnostic accuracy data from eligible cohort studies were extracted. The primary outcome was defined as at least 70% angiographic stenosis of a major epicardial vessel. Thirteen papers reported data relevant to question 1 and three papers reported data relevant to question 2. All ECGs showed maximal up-sloping ST depression in lead V3 with a median amplitude of 0.3 mV (interquartile range: 0.2-4 mV). T-wave height peaked in lead V3 with a median amplitude 0.9 mV (interquartile range: 0.8-1.1 mV). The De Winter pattern had positive predictive values of 95.2% (95% confidence interval: 76.2-99.9%), 100% (69.2-100.0%) and 100% (51.7-100%) in the three respective diagnostic studies. There is limited evidence that the De Winter ECG pattern is a 'STEMI equivalent'. The available data suggest that the pattern has high positive predictive value for acute occlusion. Further research is required to evaluate specificity and to determine whether rapid revascularization improves mortality. PMID- 28362647 TI - Validity of the Pediatric Canadian Triage Acuity Scale in a tertiary children's hospital in Israel. AB - OBJECTIVE: In 2015, the Israeli Ministry of Health issued national guidelines demanding the use of a five-level triage system in pediatric emergency departments (EDs). The present study aimed to evaluate the validity of the Pediatric Canadian Triage Acuity Scale (PedCTAS) in the ED of a tertiary children's hospital in Israel. METHODS: A retrospective cohort study of all patients admitted between January 2011 and December 2015 was carried out. The proportion of hospitalization was the primary outcome measure. The secondary outcomes were proportion of admissions to the ICU, proportions of patients who left without being seen (LWBS), and length of stay (LOS) in the ED. RESULTS: A total of 83 609 patients were included in our analysis. Triage levels 1-5 included 533 (0.6%), 4428 (5.3%), 46 461 (55.6%), 28 510 (34.1%), and 3677 (4.4%) patients, respectively. Hospitalization proportions were 70, 51, 28, 15, and 12% for triage levels 1, 2, 3, 4, and 5, respectively. Admission proportions to ICU were 24.2, 3.05, 0.24, 0.05, and 0.05% for PedCTAS levels 1, 2, 3, 4, and 5, respectively. The proportions of LWBS were 0.001, 0.002, and 0.005% for triage levels 3, 4, and 5, respectively. LOS was shorter as the triage level increased from 2 to 5. CONCLUSION: Triage level was predictive of hospitalization, admission to the ICU, and proportions of LWBS and LOS in the ED. The findings suggest validity of the PedCTAS in this cohort. This is the first report of the performance of a triage tool in an Israeli ED. PMID- 28362648 TI - Abnormal angiogenesis in blood outgrowth endothelial cells derived from von Willebrand disease patients. AB - : Bleeding associated with angiodysplasia is a common, often intractable complication in patients with von Willebrand disease (VWD). von Willebrand factor (VWF), the protein deficient or defective in VWD, is a negative regulator of angiogenesis, which may explain the pathologic blood vessel growth in VWD. This study explores the normal range of angiogenesis in blood outgrowth endothelial cells (BOECs) derived from healthy donors and compares this to angiogenesis in BOECs from VWD patients of all types and subtypes. BOECs were assessed for VWF and angiopoietin-2 (Ang-2) gene expression, secretion, and storage. To explore angiogenic potential, we characterized cellular proliferation, matrix protein adhesion, migration, and tubule formation. We found great angiogenic variability in VWD BOECs with respect to each of the angiogenesis parameters. However, type 1 and 3 VWD BOECs had higher Ang-2 secretion associated with impaired endothelial cell migration velocity and enhanced directionality. Type 2A and 2B BOECs were the most proliferative and multiple VWD BOECs had impaired tubule formation in Matrigel. This study highlights the angiogenic variability in BOECs derived from VWD patients. Abnormal cell proliferation, migration, and increased Ang-2 secretion are common features of VWD BOECs. Despite the many abnormalities of VWD BOECs, significant heterogeneity among individual VWD phenotypes precludes a simple description of relationship between VWD type and in vitro surrogates for angiodysplasia. PMID- 28362649 TI - Rapid and well tolerated action of idarucizumab for antagonizing dabigatran in a patient needing urgent thrombolysis: a case report. AB - : Dabigatran is a direct oral anticoagulant drug exhibiting clinical benefits over vitamin K antagonists. A procedure for reversing the anticoagulant effect of direct oral anticoagulants may be needed in emergency clinical settings, and is traditionally accomplished by using plasma products or hemostatic physical interventions. Idarucizumab, a specific antidote for dabigatran, has recently become available. This compound can be rapidly administered by intravenous injection and is effective in reversing anticoagulation in few minutes. We describe here the case of a 78-year-old woman taking dabigatran for atrial fibrillation, who was admitted to the emergency department with a diagnosis of acute cerebral ischemia. Dabigatran plasma levels on admission (74 ng/ml) were measured with diluted thrombin time. Idarucizumab was immediately administered and dabigatran plasma concentration suddenly decreased to less than 2 ng/ml. Successful systemic thrombolysis could hence be performed with full recovery. PMID- 28362651 TI - Breast cancer education for schoolgirls: an exploratory study. AB - Adolescent girls are an important target group for breast cancer education and promoting breast awareness. However, research has not established schoolgirls' perceived importance of breast cancer education or explored factors that may impact engagement. This study aimed to identify schoolgirls' concerns about breast cancer, desire to know more and perceived importance of breast cancer education, and explored associations with demographic factors. Of 2089 schoolgirls (11-18 years) surveyed, 1958 completed all relevant breast cancer questions and demographic factors (ethnicity, school type, breast size, physical activity level and age). chi-Tests assessed associations between demographics, desire to know more and perceived importance of breast cancer. Overall, 44% of schoolgirls reported concerns about breast cancer, 72% wanted to know more and 77% rated the topic as extremely important. Breast size was not associated with wanting to know more about breast cancer. Schoolgirls who wanted to know more about breast cancer were White, from single-sex schools with boys at sixth form, more physically active and older. However, among other ethnic groups, school types and physical activity levels, the proportion of girls who wanted to know more about breast cancer was still high (>=61%). This study provides evidence of the need for breast cancer education for schoolgirls across all school types, irrespective of breast size or physical activity levels. The results highlight the need to be inclusive and engage schoolgirls from all ethnic groups and to promote breast awareness at a young age to ensure effective breast cancer education. PMID- 28362650 TI - Placental transfer of antibody and its relationship to vaccination in pregnancy. AB - PURPOSE OF REVIEW: Vaccination in pregnancy boosts maternal vaccine-specific antibody concentration and therefore increases transplacental transfer of antibody to optimize protection of the infant. The purpose of this review is to describe what is known about placental transfer of antibody in the context of vaccination in pregnancy, focussing on the recent literature and areas of debate, particularly about the timing of vaccination. RECENT FINDINGS: There is a debate about the timing of pertussis vaccination in pregnancy with some studies reporting that vaccination in the third trimester results in higher pertussis antigen-specific IgG concentrations in cord blood and others finding that the concentration is higher following vaccination in the second trimester. The impact of timing of vaccination on antibody avidity in cord blood has also been investigated and one study suggests that avidity may be increased following vaccination at 27-30 gestational weeks compared with later vaccination. SUMMARY: Understanding placental transfer of antibody is vital in informing maternal vaccination strategy. There has been recent research about the timing of pertussis vaccination in pregnancy that has implications for the timing of both current and future vaccines to be used in pregnancy. PMID- 28362652 TI - The association between plasma C-peptide concentration and the risk of prostate cancer: a nested case-control study within a Japanese population-based prospective study. AB - The association between plasma C-peptide concentration and prostate cancer is unclear. Inconsistency of results from previous studies motivates this study. Using the Japan Public Health Center-based Prospective study, 201 prostate cancer cases and 402 controls were matched by age, public health center area, residence, date and time of blood collection, and fasting duration before blood collection. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated by conditional logistic regression models. Out of 201 cases, 144 were localized and 48 were advanced. The overall association between median plasma C-peptide concentration and prostate cancer was not significant (OR for the highest tertile=0.81, 95% CI: 0.43-1.56, P-trend=0.54). Although stratification of prostate cancer by stage indicated different effects of plasma C-peptide on localized and advanced cases, there was no association between plasma C-peptide concentration and advanced prostate cancer (OR=2.82, 95% CI: 0.30-26.36 for the highest category, P trend=0.37) and localized cases (OR=0.49, 95% CI: 0.23-1.04 for the highest category, P-trend=0.06) for patients fasting at the time of blood collection. The association between plasma C-peptide concentration and prostate cancer risk differed by cancer stage. Differentiation of localized and advanced prostate cancer cases is crucial when investigating the association between plasma C peptide concentration and the risk of prostate cancer. PMID- 28362653 TI - Population-based organized cervical cancer screening pilot program in France. AB - In France, cervical cancer screening is recommended every 3 years for women aged 25-65 years. With the exception of a few local organized programs, screening is mainly opportunistic. In view of setting up a nationwide population-based organized screening program, a pilot intervention was implemented in nine geographic areas using a common protocol. Women aged 25-65 years who had not undergone a cytological screening in the past 3 years were invited for screening during 2010-2012 and reminded up to 1 year after the initial invitation. Cytological results and follow-up data were collected up to the end of 2014 for all women screened irrespective of whether spontaneously or following invitation. Aggregate data were centralized nationally. Among the 2.4 million women from the total target population aged 25-65 years, 1.3 million were invited for screening. The overall screening coverage during 2010-2012 was 62.3%, with wide variations across geographic areas, ranging from 41.6 to 72.5%. Initial invitations and reminders enabled nearly 280 000 women to be screened, corresponding to an estimated increase in coverage of 12% points. Overall, 4.2% of the women screened had an abnormal smear. A total of 5180 high-grade cervical precancers and 323 invasive cervical cancers were reported, corresponding to detection rates of, respectively, 623 and 39 per 100 000 women screened 3-yearly. This study indicates that such organized screening may markedly improve the uptake of cervical cancer screening. On the basis of this pilot program, nationwide organized cervical cancer screening is currently being rolled out in France. PMID- 28362655 TI - Burn Care of the Elderly. AB - As part of the State of Science Meeting, care in elderly was one of the foci. This "white paper" deriving from this meeting indicates advances in the field of burn injuries in the elderly but more importantly areas that are in need of novel insights and investigations. The group created specific segments of a patient's course pre- and postinjury to selectively identify specifics we need to improve on. Tasks were created that were assigned to volunteers of the group and are given in detail in this article. The overarching aim is to initiate substantial momentum among the members of the American Burn Association to improve the outcomes in the elderly burn patients. PMID- 28362654 TI - Nursing and Focal Dyscognitive Seizures: A Clinical Update When Managing Risk Using Advanced Nursing Skills. AB - Focal seizures are divided into simple and dyscognitive, with the latter resulting in the alteration of consciousness. In the ictal and postictal stages, patients may present with confusion, delirium, and psychosis, presenting a risk of safety to themselves and others. This article presents 3 case studies where patients have been admitted for visual and electroencephalographic monitoring. Seizure activity is provoked for the diagnosis and development of a management plan. These cases illustrate the unique nursing implications when caring for patients experiencing focal dyscognitive seizures, highlighting the unique circumstances for the neuroscience nurse regarding risk management, safe administration of radioactive isotopes, detection of subtle seizure manifestation, and use of family as experts in patient-centered care. Through a deliberate onset of seizures, neuroscience nurses are placed in nontypical nursing situations, thus managing risk in unpredictable conditions and displaying advanced and distinctive nursing skills. PMID- 28362656 TI - North America Wound, Ostomy, and Continence and Enterostomal Therapy Nurses Current Ostomy Care Practice Related to Peristomal Skin Issues. AB - PURPOSE: The purpose of this study was to describe the practice of 796 ostomy nurses in North America in 2014 related to peristomal skin issues. DESIGN: Descriptive study. SUBJECTS AND SETTING: Participants were 796 wound, ostomy, and continence (WOC) and enterostomal therapy (ET) nurses currently practicing in the United States or Canada and caring for patients with ostomies. The collection of data occurred in conjunction with an educational program on peristomal skin complications and practice issues and solicited the participant's perception on the incidence and frequency of peristomal skin issues as well as on practice patterns. METHODS: Participants attended an educational program. They were also asked to anonymously respond to multiple-choice questions on ostomy care management via an audience response system followed by discussion of each item and their responses. This descriptive study reports on the answers to the questions as well as the pertinent discussion points. RESULTS: Participants estimated that approximately 77.70% of their patients developed peristomal skin issues. The most commonly encountered problem was irritant contact dermatitis (peristomal moisture-associated skin damage). Contributing factors were inappropriate use of a pouching system owing to lack of follow-up after hospital discharge. Reported interventions for the prevention and management of peristomal skin issues included preoperative stoma site marking, use of a convex pouching system, and barrier rings. However, subsequent discussion revealed that the frequency of use of these products varied considerably. Participants identified shortened hospital stays, absence of preoperative stoma marking, and limited outpatient follow-up as contributing to development of peristomal skin problems. CONCLUSION: WOC and ET nurses estimate that more than three-quarters of persons living with an ostomy develop peristomal skin problems. Multiple interventions for managing these problems were identified, but some variability in management approaches emerged. PMID- 28362657 TI - Epigenetics of CD4+ T cells in autoimmune diseases. AB - PURPOSE OF REVIEW: Autoimmune disorders are a group of overactive symptoms because of abnormal immune responses. Progress of novel mechanisms for autoimmune diseases has been restrained by incomplete understanding of immune disturbance. Recent advances in autoimmune diseases have been well documented by epigenetic alterations (DNA methylation, histone modification, and microRNAs), which alter the transcription activity of genes that are involved in autoimmune responses. RECENT FINDINGS: Multiple environmental factors (trichloroethylene, breast milk, and vitamin C) initiate aberrant epigenetic modifications in CD4 T cells, leading to a list of transcriptional deregulations in several genes (Ifng, Cd70, Tnf, Dnmt3a, and Foxp3) that determine T-cell identity. In addition, epigenetics target regulatory genes (Tim-3, cereblon, protein kinase C theta, octamer transcription factor 1, basic leucine zipper transcription factor ATF-like, p70 kinase, and lactate dehydrogenase A) to influence T-cell activation, differentiation, and metabolism. SUMMARY: In this review, we decipher findings that identify how epigenetic regulates CD4 T-cell functions and the advancement of novel epigenetic mechanisms in systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. Further researches could be conducted to explore new clinical application of epigenetic regulation based on T cells in autoimmune diseases. PMID- 28362658 TI - CALLING ALL READERS: OPPORTUNITIES FOR SERVICE. PMID- 28362660 TI - Role of Nutrition and Feeding for the Chronically Ill Pediatric Liver Patient Awaiting Liver Transplant. AB - This article reviews the essential role of nutrition in optimizing care for pediatric patients with liver disease awaiting liver transplant. A review of growth and overall principles of feeding for pediatric patients, from infancy through childhood and into adolescence, is provided including the role of macro- and micronutrients, nutrient distribution, and nutrition supplementation. The importance of a thorough nutrition assessment is reviewed, including focus areas the nurse can address with patients and families such as diet histories, growth, and dietary modifications. Suggestions for monitoring and implementing nutrition strategies are provided. PMID- 28362659 TI - Neuroleptic Malignant Syndrome Secondary to Metoclopramide Use in an Elderly Gastroenterologic Surgery Patient. AB - An 84-year-old African American woman was admitted to the hospital secondary to severe abdominal pain accompanied by septic shock. She underwent exploratory laparotomy, which revealed extensive small bowel necrosis likely due to small bowel torsion. A small bowel resection was performed with primary anastomoses and the patient was subsequently transferred to the intensive care unit (ICU). She recovered from shock but had a persistent gastroparesis interfering with enteral feeding, for which metoclopramide was prescribed. She was then transferred to a general medical-surgical unit in a stable condition where she received a total of four 10-mg oral doses of metoclopramide administered every 8 hours. Approximately 32 hours after receiving the first dose of metoclopramide, the patient was subsequently transferred back to the ICU because of fever and inability to maintain respirations. Neuroleptic malignant syndrome was suspected, and the patient was intubated and received supportive care. After a week in the ICU, she was discharged back to the medical-surgical unit in a stable condition and recovered completely. The patient was later discharged home. PMID- 28362661 TI - A Study Comparing Colorectal Cancer Screening Techniques. AB - Colorectal cancer is in the top 3 of both diagnosed cancers and deaths related to cancer in the United States. Despite this, Americans are continuing to forgo colorectal cancer screening as part of their preventive health maintenance. Screening helps identify precancerous and early cancerous lesions so they can be easily treated and cured. The purpose of this study was to compare the rates of detection of adenomatous (precursors to colorectal cancer) polyps and colorectal cancer in 2 groups of asymptomatic patients: one group undergoing standard colonoscopy and the other group undergoing standard colonoscopy in conjunction with fecal occult blood testing. A pilot study was performed using a total of 63 patients who were randomly allocated into 2 groups: those receiving standard colonoscopy as the control group and those receiving standard colonoscopy in conjunction with fecal occult blood testing as the intervention group. Research participants also completed demographic information as well as a survey evaluating their perceptions regarding colorectal cancer screening. This survey was adopted from a previous study that evaluates colorectal cancer disease awareness and patients' perceptions following a Health Belief Model. The results show that despite a detection rate of 41% of adenomatous polyps in the intervention group, there were no positive fecal occult blood testing specimens. The Health Belief Model survey revealed that most participants were appropriately aware of the seriousness and treatability of colorectal cancer. They also agreed that colorectal cancer screening guidelines were important and beneficial to follow. PMID- 28362662 TI - The Social Stigma Experience in Patients With Hepatitis B Infection: A Qualitative Study. AB - The social stigma in patients with hepatitis B virus infection has caused several complications for both the patients and the associated medical system. This study aimed at demonstrating the social stigma experienced by these patients in Iran. This is a qualitative study using a content analysis approach with references to primary and secondary sources. The data were collected through 15 unstructured and in-depth interviews conducted in 2014. By analyzing the data, two main themes were noted: extrinsic concepts of social stigma (causing reprehension, embarrassment, and discrimination) and intrinsic concepts of social stigma (sense of rejection, isolation, and frustration). The analysis of participants' experiences showed that social stigma is a simple lack of knowledge among the patients and society and it is more intense in the first days after the diagnosis. Stigma is prevalent among patients with hepatitis B virus, causes them to hide the disease, and provokes various complications for them as well as society. This study emphasizes the necessity of implementing health education programs about hepatitis B and its associated stigma, especially considering the potential impact of a mass media campaign. PMID- 28362664 TI - DISCUSSION OF COLONOSCOPY PREPARATION. PMID- 28362665 TI - Comparing mortality between fibrinolysis and primary percutaneous coronary intervention in patients with acute myocardial infarction: a systematic review and meta-analysis of 27 randomized-controlled trials including 11 429 patients. AB - OBJECTIVES: We aimed to improve the limitations encountered in previously published studies and then compare mortality in patients with acute myocardial infarction (AMI) who were treated with either fibrinolysis or a primary percutaneous coronary intervention (PPCI). METHODS: EMBASE, MEDLINE, and the Cochrane databases were searched for trials comparing fibrinolysis with PPCI in patients with AMI. The only endpoint that was assessed in this analysis was all cause mortality. Therefore, in-hospital, short-term, mid-term, and long-term mortality were analyzed, whereby odds ratios (OR) with 95% confidence intervals (CIs) were calculated using the RevMan 5.3. RESULTS: A total of 11 429 patients obtained from 37 studies (involving 27 trials) were included. The results of this analysis showed that fibrinolytic therapy was associated with significantly higher in-hospital and mid-term mortality (OR: 0.61; 95% CI: 0.46-0.82, P=0.001 and OR: 0.73; 95% CI: 0.54-0.99, P=0.04, respectively). Short-term and long-term mortality were also significantly higher in the fibrinolytic group (OR: 0.76; 95% CI: 0.65-0.90, P=0.001, and OR: 0.82; 95% CI: 0.71-0.96, P=0.01, respectively) compared with PPCI. CONCLUSION: This analysis of 11 429 patients showed a significantly higher mortality rate to be associated with fibrinolysis compared with PPCI in these patients with AMI. Hence, compared with fibrinolysis, PPCI is expected to be the preferred method of revascularization in patients with AMI, especially in PCI-capable centers. PMID- 28362663 TI - RECURRENT GASTRIC POLYPOSIS IN A PATIENT USING ANTIEPILEPTIC DRUGS FOR A LONG TIME. PMID- 28362666 TI - Dyslipidaemia in type 2 diabetes mellitus: bad for the heart. AB - PURPOSE OF REVIEW: Type 2 diabetes mellitus (T2DM) is associated with increased coronary heart disease (CHD) morbidity and mortality. These patients are also more prone to heart failure, arrhythmias and sudden cardiac death. Furthermore, coronary interventions performed in such high-risk patients have worse outcomes. In this narrative review, we discuss the role of diabetic dyslipidaemia on the risk of CHD in patients with T2DM. The effects of hypolipidaemic, antihypertensive and antidiabetic drugs on lipid and glucose metabolism in T2DM are also considered. RECENT FINDINGS: Among CHD risk factors, diabetic dyslipidaemia characterized by moderately elevated low-density lipoprotein (LDL) cholesterol, increased triglycerides and small, dense LDL particles as well as decreased high-density lipoprotein cholesterol levels may contribute to the increased CHD risk associated with T2DM. Hypolipidaemic, antihypertensive and antidiabetic drugs can affect lipid and glucose parameters thus potentially influencing CHD risk. Such drugs may improve not only the quantity, but also the quality of LDL as well as postprandial lipaemia. SUMMARY: Current data highlight the importance of treating diabetic dyslipidaemia in order to minimize CHD risk. Both fasting and postprandial lipids are influenced by drugs in patients with T2DM; physicians should take this into consideration in clinical decision making. PMID- 28362667 TI - Implementation strategies in pediatric neurocritical care. AB - PURPOSE OF REVIEW: Brain-directed critical care for children is a relatively new area of subspecialization in pediatric critical care. Pediatric neurocritical care teams combine the expertise of neurology, neurosurgery, and critical care medicine. The positive impact of delivering specialized care to pediatric patients with acute neurological illness is becoming more apparent, but the optimum way to implement and sustain the delivery of this is complicated and poorly understood. We aim to provide emerging evidence supporting that effective implementation of pediatric neurocritical care pathways can improve patient survival and outcomes. We also provide an overview of the most effective strategies across the field of implementation science that can facilitate deployment of neurocritical care pathways in the pediatric ICU. RECENT FINDINGS: Implementation strategies can broadly be grouped according to six categories: planning, educating, restructuring, financing, managing quality, and attending to the policy context. Using a combination of these strategies in the last decade, several institutions have improved patient morbidity and mortality. Although much work remains to be done, emerging evidence supports that implementation of evidence-based care pathways for critically ill children with two common neurological diagnoses - status epilepticus and traumatic brain injury - improves outcomes. SUMMARY: Pediatric and neonatal neurocritical care programs that support evidence-based care can be effectively structured using appropriately sequenced implementation strategies to improve outcomes across a variety of patient populations and in a variety of healthcare settings. PMID- 28362668 TI - New role of ventricular assist devices as bridge to transplantation: European perspective. AB - PURPOSE OF REVIEW: Progress of ventricular assist devices (VAD) technology led to improved survival and apparently low morbidity. However, from the European perspective, updated analysis of EUROMACS reveals a somewhat less impressive picture with respect to mortality and morbidity. RECENT FINDINGS: We describe the great demand of cardiac allografts versus the lack of donors, which is larger in Europe than in the United States. Technical progress of VADs made it possible to work out a modern algorithm of bridge-to-transplant, which is tailored to the need of the particular patient. We analyze the burden of patients undergoing bridge-to-transplant therapy. They are condemned to an intermediate step, coupled with additional major surgery and potential adverse events during heart transplantation. SUMMARY: Based on current registry data, we do have to question the increasingly popular opinion, that the concept of heart transplantation is futureless, which seems to be for someone who treats and compares both patients (VAD and heart transplantation) in daily practice, questionable. Up to now, left ventricular assist device therapy remains a bridge to a better future, which means a bridge to technical innovations or to overcome the dramatic lack of donors in Europe. PMID- 28362669 TI - Retrospective Assessment of Follicular Unit Density in Asian Men With Androgenetic Alopecia. AB - BACKGROUND: Hair density, together with hair diameter has a tremendous impact on the cosmetic outcome of hair transplantation surgery. OBJECTIVE: This retrospective study aims to assess the average number of follicular unit (FU) grafts in the donor area of Asian men with androgenetic alopecia. METHODS: Seventy patients (ages 24-65 years old) with virgin scalp who had their first hair transplantation were included. During the harvesting procedure, a 2- to 3-cm wide area of the donor site was shaved from ear to ear with 5 specific areas assigned as reference points for the study namely the central occipital area, left and right parietal and temporal areas. A video microscope was used to capture the field of each reference point. Follicular units in each area were counted and the number of 1-hair, 2-hair, and 3-hair follicular groupings was recorded. RESULTS: East and Southeast Asians had an average of 61.1 FU/cm (111.2 hairs/cm); West Asians had an average density of 63.6 FU/cm (126.8 hairs/cm); South Asians were noted to have an average density of 63.5 FU/cm (126.8 hairs/cm). CONCLUSION: Asian hair density has slight variations in the number of FU grafts in each donor area. PMID- 28362670 TI - The Effectiveness of Matrix Cauterization With Bichloracetic Acid in the Treatment of Ingrown Toenails. AB - BACKGROUND: Chemical matricectomy is performed mainly by 2 agents, phenol and sodium hydroxide. Chemical matricectomy with phenol has a low recurrence rate and good cosmetic results, but it produces extensive tissue destruction and can result in drainage and a delayed healing time. These adverse effects have brought forward the use of chemical agents such as sodium hydroxide and trichloroacetic acid for matricectomy. OBJECTIVE: This prospective study aimed mainly to evaluate the efficacy of partial nail avulsion and selective chemical cauterization of the matrix using 90% bichloracetic acid (BCA) in the treatment of the ingrown nails. MATERIALS AND METHODS: A total of 30 patients with 58 ingrown toenail edges were included in this study. All of the patients underwent chemical matricectomy with 90% BCA after partial nail avulsion. Adverse effects such as postoperative pain and drainage were minimal in most of the patients. RESULTS: One patient who underwent matricectomy had recurrence in a single nail edge (1.8%) at the 12th month of the follow-up. No recurrence was observed in 29 patients during mean follow-up period. This was considered to be statistically significant (p < .001). CONCLUSION: This is the first study to use BCA for the treatment of ingrown toenail. Partial nail avulsion followed by BCA matricectomy is a safe, simple, and effective method with low rates of postoperative morbidity and high rates of success. Therefore, partial nail avulsion and BCA matricectomy can be used as an alternative treatment method for the treatment of ingrown toenails. PMID- 28362671 TI - Effects of Cryolipolysis on Testosterone. PMID- 28362672 TI - Photography in Dermatologic Surgery: Selection of an Appropriate Camera Type for a Particular Clinical Application. AB - BACKGROUND: Photographs are an essential tool for the documentation and sharing of findings in dermatologic surgery, and various camera types are available. OBJECTIVE: To evaluate the currently available camera types in view of the special functional needs of procedural dermatologists. METHODS: Mobile phone, point and shoot, digital single-lens reflex (DSLR), digital medium format, and 3 dimensional cameras were compared in terms of their usefulness for dermatologic surgeons. For each camera type, the image quality, as well as the other practical benefits and limitations, were evaluated with reference to a set of ideal camera characteristics. Based on these assessments, recommendations were made regarding the specific clinical circumstances in which each camera type would likely be most useful. RESULTS: Mobile photography may be adequate when ease of use, availability, and accessibility are prioritized. Point and shoot cameras and DSLR cameras provide sufficient resolution for a range of clinical circumstances, while providing the added benefit of portability. Digital medium format cameras offer the highest image quality, with accurate color rendition and greater color depth. Three-dimensional imaging may be optimal for the definition of skin contour. CONCLUSION: The selection of an optimal camera depends on the context in which it will be used. PMID- 28362673 TI - Fixed-Level Frequency Threshold Testing for Ototoxicity Monitoring. AB - OBJECTIVES: Hearing loss from ototoxicity is often most pronounced at high frequencies. To improve patient monitoring and compliance, high-frequency testing methods should be short and easy to administer. We evaluated the repeatability and accuracy of a Bekesy-like, fixed-level frequency threshold (FLFT) technique. This test takes less than a minute and could provide a rapid and effective way to determine the highest audible frequency. We hypothesized the FLFT test would be repeatable in normal-hearing subjects, and accurate when compared with Bekesy fixed-frequency audiometry in the sensitive region for ototoxicity (SRO). DESIGN: Twenty-nine normal-hearing subjects (20 females, 9 males) performed 2 different automated audiometry tests at least 4 times over a period of no less than 3 weeks. Ages ranged from 23 to 35 years (average = 28 years). Subjects completed testing under Sennheiser HDA-200 headsets. Initial fixed-frequency audiometry thresholds were obtained at frequencies ranging from 0.5 to 20 kHz to identify each subject's highest audible frequency, which was used to determine the SRO. The SRO was defined as the seven frequencies at and below the highest audible frequency in 1/6-octave steps. These frequencies were monitored with fixed frequency audiometry. At each session, the FLFT test was administered at 80 dB SPL. Subjects used a Bekesy-style tracking method to determine the frequency threshold. All testing was completed in a sound booth (single wall, Industrial Acoustics Company) using a computerized, laptop-based, system. FLFT repeatability was calculated as the root mean square difference from the first test session. FLFT accuracy was calculated as the difference from the highest audible frequency determined from fixed-frequency audiometry interpolated to 80 dB SPL level. RESULTS: The FLFT average RMSD for intersession variability was 0.05 +/- 0.05 octaves. The test showed no learning effect [F(3,78) = 0.7; p = 0.6]. The overall intersession variability for SRO fixed-frequency audiometry thresholds at all frequencies was within clinically acceptable test-retest variability (10 dB) at 5.8 dB (range 2.7 to 9.9 dB). The SRO fixed-frequency audiometry therefore served as a repeatable basis of comparison for accuracy of the FLFT test. The mean absolute difference between the fixed-frequency audiometry and FLFT-determined highest audible frequency was 0.03 octaves. The FLFT and the highest audible frequency via fixed-frequency audiometry at 80 dB SPL were not different statistically (p = 0.12). The FLFT took approximately 30 seconds to complete, compared with approximately 4.5 min for fixed-frequency audiometry SRO and 20 to 25 min for a traditional ototoxic audiometric assessment. CONCLUSIONS: The Bekesy style FLFT was repeatable within 1/12 octave (1 step size in the testing procedure). The FLFT agreed well with the highest audible frequency determined via fixed-frequency audiometry at 80 dB SPL. The FLFT test is amenable to automatic and self-administration and may enable quick, accurate, noise-tolerant ototoxicity, and high-frequency hearing monitoring. PMID- 28362675 TI - Novel immunotherapy and treatment modality for severe food allergies. AB - PURPOSE OF REVIEW: In recent years, many studies on oral immunotherapy (OIT) have been conducted; however, few have focused on severe food allergies. The purpose of this review was to assess the efficacy and safety of oral immunotherapies for patients with severe food allergy. RECENT FINDINGS: We reviewed multiple immunotherapy reports published within a few years or reports focusing on severe food allergies. We also investigated recent studies on OIT and novel food allergy management. SUMMARY: Immunotherapies targeting low-dose antigen exposure and oral food challenges using low-dose target volumes may be safer than conventional OIT. It is necessary to consider which immunotherapy regimen is appropriate based on allergy severity of the patient. PMID- 28362674 TI - Human Frequency Following Responses to Vocoded Speech. AB - OBJECTIVES: Vocoders offer an effective platform to simulate the effects of cochlear implant speech processing strategies in normal-hearing listeners. Several behavioral studies have examined the effects of varying spectral and temporal cues on vocoded speech perception; however, little is known about the neural indices of vocoded speech perception. Here, the scalp-recorded frequency following response (FFR) was used to study the effects of varying spectral and temporal cues on brainstem neural representation of specific acoustic cues, the temporal envelope periodicity related to fundamental frequency (F0) and temporal fine structure (TFS) related to formant and formant-related frequencies, as reflected in the phase-locked neural activity in response to vocoded speech. DESIGN: In experiment 1, FFRs were measured in 12 normal-hearing, adult listeners in response to a steady state English back vowel /u/ presented in an unaltered, unprocessed condition and six sine-vocoder conditions with varying numbers of channels (1, 2, 4, 8, 16, and 32), while the temporal envelope cutoff frequency was fixed at 500 Hz. In experiment 2, FFRs were obtained from 14 normal-hearing, adult listeners in response to the same English vowel /u/, presented in an unprocessed condition and four vocoded conditions where both the temporal envelope cutoff frequency (50 versus 500 Hz) and carrier type (sine wave versus noise band) were varied separately with the number of channels fixed at 8. Fast Fourier Transform was applied to the time waveforms of FFR to analyze the strength of brainstem neural representation of temporal envelope periodicity (F0) and TFS-related peaks (formant structure). RESULTS: Brainstem neural representation of both temporal envelope and TFS cues improved when the number of channels increased from 1 to 4, followed by a plateau with 8 and 16 channels, and a reduction in phase-locking strength with 32 channels. For the sine vocoders, peaks in the FFRTFS spectra corresponded with the low-frequency sine-wave carriers and side band frequencies in the stimulus spectra. When the temporal envelope cutoff frequency increased from 50 to 500 Hz, an improvement was observed in brainstem F0 representation with no change in brainstem representation of spectral peaks proximal to the first formant frequency (F1). There was no significant effect of carrier type (sine- versus noise-vocoder) on brainstem neural representation of F0 cues when the temporal envelope cutoff frequency was 500 Hz. CONCLUSIONS: While the improvement in neural representation of temporal envelope and TFS cues with up to 4 vocoder channels is consistent with the behavioral literature, the reduced neural phase-locking strength noted with even more channels may be because of the narrow bandwidth of each channel as the number of channels increases. Stronger neural representation of temporal envelope cues with higher temporal envelope cutoff frequencies is likely a reflection of brainstem neural phase-locking to F0-related periodicity fluctuations preserved in the 500-Hz temporal envelopes, which are unavailable in the 50-Hz temporal envelopes. No effect of temporal envelope cutoff frequency was seen for neural representation of TFS cues, suggesting that spectral side band frequencies created by the 500-Hz temporal envelopes did not improve neural representation of F1 cues over the 50-Hz temporal envelopes. Finally, brainstem F0 representation was not significantly affected by carrier type with a temporal envelope cutoff frequency of 500 Hz, which is inconsistent with previous results of behavioral studies examining pitch perception of vocoded stimuli. PMID- 28362676 TI - Behavioral interventions to improve asthma outcomes: a systematic review of recent publications. AB - PURPOSE OF REVIEW: Asthma outcomes are influenced by factors at multiple ecological levels: the individual and his/her family, home, medical care, and community. This systematic review describes recently published single-level and multilevel behavioral interventions to improve asthma outcomes. RECENT FINDINGS: Of the 23 total title/abstracts reviewed in the original systematic search of PubMed, Ovid, Scopus, PsychINFO, and CIHAHL reference review databases, six met inclusion criteria. Five of the studies focused on low-income and/or minority populations. Promising interventions include culturally tailored online asthma self-management programs and family-centered asthma education delivered at the bedside during hospitalization for an acute asthma exacerbation. SUMMARY: Culturally, tailored online self-management programs offer difficult-to-reach populations asthma support that can be completed at the time and pace most convenient for the individual user. Family-focused asthma education, delivered at the bedside during an acute asthma hospitalization by highly motivated lay volunteers, is an efficacious and low-cost approach to improving pediatric asthma self-management. PMID- 28362677 TI - Medial approach open reduction with ligamentum teres partial excision and plication for the management of congenital hip dislocation. AB - : Because of the known tendency for early redislocation following open reduction, we developed surgical methods for shortening the ligamentum teres to improve immediate postoperative stability when performing medial approach open reduction (MAOR) for the management of developmental dysplasia of the hip. Between 2004 and 2014, 32 patients with dysplasia of the hip were managed by MAOR with partial excision and plication of ligamentum teres. The patients were followed up for an average of 6.9 years. At the final follow-up, clinical outcomes achieved were categorized as excellent and good in 39 (39/40; 97.5%) hips. At the latest follow up, 97.5% (39 hips) were classified as good or excellent on the basis of the Severin classification (Severin grade 1 or 2). In conclusion, this series of MAOR, in which ligamentum teres partial excision and plication was utilized, we found stable reduction in all hips. On the basis of these positive results, we recommend this method for children treated with MAOR. LEVEL OF EVIDENCE: Level IV: case series. PMID- 28362678 TI - The Behavior Pain Assessment Tool for critically ill adults: a validation study in 28 countries. AB - Many critically ill adults are unable to communicate their pain through self report. The study purpose was to validate the use of the 8-item Behavior Pain Assessment Tool (BPAT) in patients hospitalized in 192 intensive care units from 28 countries. A total of 4812 procedures in 3851 patients were included in data analysis. Patients were assessed with the BPAT before and during procedures by 2 different raters (mostly nurses and physicians). Those who were able to self report were asked to rate their pain intensity and pain distress on 0 to 10 numeric rating scales. Interrater reliability of behavioral observations was supported by moderate (0.43-0.60) to excellent (>0.60) kappa coefficients. Mixed effects multilevel logistic regression models showed that most behaviors were more likely to be present during the procedure than before and in less sedated patients, demonstrating discriminant validation of the tool use. Regarding criterion validation, moderate positive correlations were found during procedures between the mean BPAT scores and the mean pain intensity (r = 0.54) and pain distress (r = 0.49) scores (P < 0.001). Regression models showed that all behaviors were significant predictors of pain intensity and pain distress, accounting for 35% and 29% of their total variance, respectively. A BPAT cut point score >3.5 could classify patients with or without severe levels (>=8) of pain intensity and distress with sensitivity and specificity findings ranging from 61.8% to 75.1%. The BPAT was found to be reliable and valid. Its feasibility for use in practice and the effect of its clinical implementation on patient pain and intensive care unit outcomes need further research. PMID- 28362679 TI - Blood pressure and risk of breast cancer, overall and by subtypes: a prospective cohort study. AB - OBJECTIVE: Blood pressure (BP) and breast cancer may share a common pathophysiologic pathway involving chronic inflammation, hormone synthesis and metabolism. Previous studies investigating the association between BP and breast cancer measured BP at a single time point and did not examine associations by breast cancer molecular subtypes. METHODS: We used data from 22 833 female participants in the Melbourne Collaborative Cohort Study. BP was objectively measured at baseline (1990-1994) and a follow-up visit (2003-2007). Cox regression was used to estimate hazard ratios for baseline BP and temporal changes in BP in relation to risk of breast cancer, overall and by molecular subtypes. RESULTS: We did not observe any associations between BP measured at baseline and breast cancer risk overall (per 5 mmHg SBP, hazard ratio = 1.00, 95% confidence interval: 0.99-1.02), nor by subtype (per 5 mmHg SBP: estrogen receptor-negative: hazard ratio = 0.99, 0.96-1.03, progesterone-receptor negative: hazard ratio = 1.01, 0.99-1.04, human epidermal growth factor receptor 2 negative: hazard ratio = 1.00, 0.98-1.01). Temporal changes in BP were not associated with risk of breast cancer (per 5 mmHg change in SBP, hazard ratio = 1.00, 0.97-1.03). Increased DBP over time was associated with higher risk of triple-negative breast cancer (P = 0.04), based on a small number of cases (N = 41). CONCLUSION: Our study supports previous findings of no association between BP and breast cancer. Similar conclusions were reached when assessing BP over time and when examining specific tumor subtypes. PMID- 28362680 TI - Telemonitoring in IVF/ICSI. AB - PURPOSE OF REVIEW: Traditionally, ovarian stimulation for IVF/intracytoplasmic sperm injection is performed by healthcare professionals, requiring the patient to make frequent visits to these centres. We describe the rationale, research findings and early clinical experience with home-based sonography for IVF patients. RECENT FINDINGS: Published experience indicates that selected patients are able to procure video sequences themselves; they value the empowerment, discretion and decreased stress involved in these visits; partner involvement increases as well. SUMMARY: Experience is still limited but consistently indicate patients' willingness and competence to procure sonograms; home sonography is positive from the patients' perspective but may be disruptive form the healthcare provider's point of view. PMID- 28362681 TI - Dual ovarian stimulation and random start in assisted reproductive technologies: from ovarian biology to clinical application. AB - PURPOSE OF REVIEW: The opportunity to use gonadotropins to stimulate the growth of antral follicles coming from different follicular waves available in different moment of the menstrual cycle allowed the implementation of innovative protocols in assisted reproductive technologies. The purpose of this review is to explore the possible advantages related to these new controlled ovarian stimulation (COS) strategies. RECENT FINDINGS: Women exhibit major and minor wave patterns of ovarian follicular development during the menstrual cycle, as it is in animal species. These observations led to the introduction of two new strategies for COS: the random start and the double ovarian stimulation within a single menstrual cycle. SUMMARY: The use of gonadotropin-releasing hormone antagonist COS protocols, started randomly at any day of the menstrual cycle, is today a standard procedure in those cases where obtaining oocytes is an urgent task, such as in case of fertility preservation for malignant diseases or other medical indications.On the other hand, in poor prognosis patients, double ovarian stimulation has been suggested with the aim of maximizing the number of oocytes retrieved within a single menstrual cycle and, in turn increasing the chance to obtain a reproductively competent embryo. Randomized control trials are necessary to confirm these preliminary findings. PMID- 28362684 TI - Editors' Preface. PMID- 28362682 TI - Genetic Determinants of Circulating Lipoproteins in Nonalcoholic Fatty Liver Disease. AB - BACKGROUND: Recent genome-wide association studies have identified 2 genetic polymorphisms in association with nonalcoholic fatty liver disease (NAFLD): patatin-like phospholipase domain containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), both of which appear to influence the production of very low density lipoprotein (VLDL). The impact of these genetic variations on lipoprotein metabolism in the setting of nonalcoholic steatohepatitis and liver fibrosis are not fully characterized. MATERIALS AND METHODS: We measured comprehensive lipoprotein profiles by nuclear magnetic resonance among 170 serially recruited patients in an NAFLD registry, and determined their relationships with PNPLA3 and TM6SF2 genotypes. RESULTS: In this cohort, 72% patients had at least 1 allele of either PNPLA3 I148M or TM6SF2 E167K, and 30% carried 2 alleles. In multivariate models adjusting for histologic features of nonalcoholic steatohepatitis and liver fibrosis, PNPLA3 I148M is associated with a decrease in VLDL particle size. Both PNPLA3 I148M and TM6SF2 E167K genotypes were associated with increases in the size of low density lipoprotein (LDL) and high density lipoprotein particles, phenotypes considered atheroprotective. When adjusted for both genotypes, NAFLD activity score, in particular the degree of hepatic steatosis was strongly associated with increases in the size of VLDL particles, the concentration of LDL, especially small LDL particles, and a decrease in the size of high density lipoprotein particles, all of which are linked with a proatherogenic phenotype. CONCLUSIONS: PNPLA3 and TM6SF2 are common genetic variants among NAFLD patients and impact lipoprotein profiles in slightly different ways. The interactions between genotypes, hepatic steatosis, and lipoprotein metabolism shed lights on the pathophysiology of NAFLD, and provide opportunities for personalized treatment in the era of emerging NAFLD therapeutics. PMID- 28362683 TI - Thrombin generation profiles as predictors of symptomatic venous thromboembolism after trauma: A prospective cohort study. AB - BACKGROUND: Reliable biomarkers predictive of venous thromboembolism (VTE) after acute trauma are uncertain. The objective of the study was to identify risk factors for symptomatic VTE after trauma, including individual plasma coagulome characteristics as reflected by thrombin generation. METHODS: In a prospective, case-cohort study, trauma patients were enrolled over the 4.5-year period, 2011 to 2015. Blood was collected by venipuncture into 3.2% trisodium citrate at 0, 6, 12, 24, and 72 hours after injury and at hospital discharge. Platelet poor plasma was stored at -80 degrees C until analysis. Thrombin generation, as determined by the calibrated automated thrombogram (CAT) using 5 pM tissue factor (TF)/4 MUM phospholipid (PS), was reported as peak height (nM thrombin) and time to peak height (ttPeak [minutes]). Data are presented as median [IQR] or hazard ratio with 95% CI. RESULTS: Among 453 trauma patients (injury severity score = 13.0 [6.0, 22.0], hospital length of stay = 4.0 [2.0, 10.0] days, age = 49 [28, 64] years, 71% male, 96% with blunt mechanism, mortality 3.2%), 83 developed symptomatic VTE within 92 days after injury (35 [42%] after hospital discharge). In a weighted, multivariate Cox model that included clinical and CAT characteristics available within 24 hours of admission, increased patient age (1.35 [1.19,1.52] per 10 years, p < 0.0001), body mass index >=30 kg/m (4.45 [2.13,9.31], p < 0.0001), any surgery requiring general anesthesia (2.53 [1.53,4.19], p = 0.0003) and first available ttPeak (1.67 [1.29, 2.15], p < 0.00001) were independent predictors of incident symptomatic VTE within 92 days after trauma (C-statistic = 0.799). CONCLUSION: The individual's plasma coagulome (as reflected by thrombin generation) is an independent predictor of VTE after trauma. Clinical characteristics and ttPeak can be used to stratify acute trauma patients into high and low risk for VTE. LEVEL OF EVIDENCE: Prognostic, level III. PMID- 28362685 TI - An Innovative Approach to Experiential Education and Interprofessional Collaboration Between Nursing and Software Engineering. PMID- 28362686 TI - 2017 is Year of the Healthy Nurse. PMID- 28362687 TI - Crossing Boarders: An Online Interdisciplinary Course in Health Informatics for Students From Two Countries. PMID- 28362688 TI - Morse Taper Implants Immediately Loaded in Fresh Extraction Sockets: A Prospective Cohort Study. AB - PURPOSE: To evaluate survival rate and bone response around immediate loaded Morse taper implants installed in fresh sockets on the anterior area of the maxilla. MATERIAL AND METHODS: The sample comprised 16 patients in whom 16 single implants were installed. All the teeth were extracted in a flapless surgery. Radiographic and tomographic evaluations were performed immediately after surgery (T1) and after 12 months (T2). The variables studied were height of the buccal wall (HBW), buccal wall width (BW) at 3 levels, and proximal bone height at 2 different areas: the alveolar crest level (CLH) and at the point where bone tissue meets the implant surface (BIS). RESULTS: Statistically significant differences were observed. The buccal plate showed bone loss in height (HBW = 0.50 +/- 0.42 mm) and in width (BW-1 = -0.71 +/- 0.48 mm; BW-2 = -0.48 +/- 0.34 mm; BW-3 = -0.48 +/- 0.34 mm). In the proximal areas, there was also bone loss in height (CLH-M = -0.85 +/- 0.89 mm; BIS-M = -0.91 +/- 0.70 mm; CLH-D = -0.64 +/- 0.57 mm; and BIS-D = -0.68 +/- 0.62 mm). CONCLUSION: There was 100% survival rate after a 12-month period, but bone loss was observed in all evaluated areas. PMID- 28362689 TI - Collaboration Patterns and Processes Between Dentists and Dental Laboratories When Planning and Fabricating Implant-Supported Restorations. AB - INTRODUCTION: The success of implant-supported restorations is dependent on proper treatment planning, effective communication within the clinical team, and the use of appropriate methods and materials in the dental laboratory. The objective of this study was to determine collaboration trends between dentists and laboratories and to assess the common methods and materials involved in fabricating implant-supported restorations. METHODS: Questionnaires were distributed to dental laboratories and technicians. Seventy questionnaires were answered and were included in the data analyses. RESULTS: Most of the impressions (87%) were taken using an individual custom-made open tray. In 83% of impressions, screw-retained transfer units were used, and in 61% of cases, the units were splinted. Bite registration was recorded in 91% of the cases. In 80% of cases, articulator setup was done. When matching the shade of a restoration in the anterior, 57% of the technicians do so in collaboration with the dentist, and 39% match the shade independently. Type of restoration and abutment selection were done mainly by the technicians. Abutment selection was reported to be carried out by 72% of the technicians. CONCLUSIONS: Generally, dentists and technicians follow the standards recommended in the contemporary literature, especially, in major procedures such as impression taking, bite registration, and articulator setup. However, principal decisions, such as abutment and color shade are done mainly by technicians. PMID- 28362690 TI - Perianal Pediatric Crohn Disease Is Associated With a Distinct Phenotype and Greater Inflammatory Burden. AB - OBJECTIVES: Data on the outcomes of children with perianal Crohn disease (pCD) are limited, although its presence is often used for justifying early use of biologics. We aimed to assess whether pCD in children is associated with more severe outcomes as found in adults. METHODS: Data were extracted from the ImageKids database, a prospective, multicenter, longitudinal cohort study. The study enrolled 246 children at disease onset or thereafter. All patients underwent comprehensive clinical, endoscopic, and radiologic evaluation at enrollment; 98 children had repeat evaluation at 18 months. RESULTS: Of the 234 included patients (mean age 14.2 +/- 2.4 years; 131 [56%] boys), 57 (24%) had perianal findings, whereas only 21 (9%) had fistulizing perianal disease. Children with pCD had reduced weight and height z scores compared with non-pCD patients (-0.9 vs -0.35, P = 0.03 and -0.68 vs -0.23, respectively; P = 0.04), higher weighted pediatric CD activity index (32 [interquartile range 16-50] vs 20 [8-37]; P = 0.004), lower serum albumin (3.6 +/- 0.7 vs 4.5 +/- 0.8, P = 0.016), and higher magnetic resonance enterography global inflammatory score (P = 0.04). Children with pCD had more rectal (57% vs 38%, P = 0.04), and jejunal involvement (31% vs 11% P = 0.003) and a higher prevalence of granulomas (64% vs 23%, P = 0.0001). Magnetic resonance enterography-based damage scores did not differ between groups. Patients with skin tags/fissures only, had similar clinical, endoscopic, and radiologic characteristics as patients with no perianal findings. CONCLUSIONS: Pediatric patients with pCD with fistulizing disease have distinct phenotypic features and a predisposition to a greater inflammatory burden. PMID- 28362691 TI - Increase of Intra-abdominal Adipose Tissue in Pediatric Crohn Disease. AB - BACKGROUND AND OBJECTIVE: Recent evidence points toward an active immunological role of intra-abdominal adipose tissue in Crohn disease (CD). We quantified the abdominal adipose tissue compartments using magnetic resonance imaging (MRI) in 27 pediatric patients with CD compared with 14 controls undergoing MRI examination for other reasons. METHODS: Total (TAAT), subcutaneous (SCAT) and intra-abdominal (IAAT) adipose tissue areas were measured by semiautomatic segmentation on a transverse slice centered on the umbilicus (mean +/- standard deviation in square centimeter) using standard T1-weighted sequences. IAAT/TAAT and IAAT/height ratios were calculated and analyzed for associations with disease duration, phenotype, or therapy. RESULTS: Patients with CD (median age 15.0 years, range 7.7-17.9, 18/27 boys, median disease duration 29 months, range 0 136) compared to controls (median age 13.9 years, range 3.3-17.8, 4/14 boys) had higher IAAT area (42.3 +/- 21.0 vs 28.7 +/- 11.6, P = 0.0494) but similar SCAT and TAAT areas (104.6 +/- 72.8 vs 96.5 +/- 50.8, P = 0.8170 and 146.9 +/- 87.3 vs 125.3 +/- 61.5, P = 0.7417, respectively). IAAT/TAAT ratio was higher in patients with CD compared to controls (0.32 +/- 0.10 vs 0.24 +/- 0.04, P = 0.0081). Patients with disease duration >2 years (n = 14) had higher IAAT/TAAT ratio than those with shorter disease and controls (0.35 +/- 0.10 vs 0.28 +/- 0.08, P = 0.0288 and 0.24 +/- 0.04, P = 0.0009, respectively). In these patients, increased IAAT/height ratio was associated with complicated disease (P = 0.043, r = 0.573). No association was found between IAAT/TAAT ratio and actual disease activity or therapy. CONCLUSIONS: IAAT is increased in pediatric CD and correlates with disease duration. Assessment of IAAT accumulation may be considered in future MRI scores for inflammation and bowel damage in CD and during follow-up of different therapeutic interventions. PMID- 28362694 TI - The Challenge of Treating Children With Hepatitis C Virus Infection. AB - The development of oral hepatitis C virus (HCV) direct-acting antivirals (DAAs) has revolutionized the therapeutic field. Nowadays, multiple safe and highly effective antiviral regimens are commercially available to treat adults with hepatitis C infection. These new regimens for the first time genuinely raise the prospects of eradicating HCV. Many challenges, however, remain from identifying infected individuals to optimizing treatment and ensuring global access to antiviral therapy to all population groups, including children. Recently, in April 2017, the association of sofosbuvir with ribavirin and the fixed-dose combination sofosbuvir/ledipasvir have been approved by the Food and Drug Administration for treatment of children with chronic HCV infection 12 years of age and older. The only drugs currently approved for children younger than 12 years are pegylated interferon and ribavirin. There are 6 registered ongoing pediatric trials assessing safety and efficacy of DAAs, but their current completion timelines are years away. Herein, we summarize the state of the art of DAAs' development for adult and children and highlight the crucial importance of overcoming barriers to treating children with HCV. PMID- 28362695 TI - Anxiety Associated With High-resolution Anorectal Manometry in Pediatric Patients and Parents. AB - High-resolution anorectal manometry is an increasingly common procedure performed in pediatric patients to rule out Hirschsprung and assess anorectal function and sensation. The purpose of the present study was to evaluate anxiety of patients and their parents associated with high-resolution anorectal manometry. Preprocedural anxiety was assessed by standardized questionnaire in all parents and children older than 8 years and observed behavioral distress was recorded by the attending pediatric gastroenterologist. Thirty-five children (mean age = 7.2 years, +/-2.8) and their parents completed the study. Patient anxiety was found to be markedly elevated. Observed behavioral distress was elevated compared to more invasive procedures. Self-reported parental anxiety was comparable to adults undergoing endoscopic procedures themselves. Despite the low risk of this procedure, healthcare providers should be aware of the high levels of anxiety and distress that occur in patients and their parents associated with anorectal manometry. PMID- 28362696 TI - Why Write a Letter to the Editor? PMID- 28362699 TI - Implementation of Feeding Guidelines Hastens the Time to Initiation of Enteral Feeds and Improves Growth Velocity in Very Low Birth-Weight Infants. PMID- 28362698 TI - NANN Approaches Changing Political Landscape With Vision, Fortitude, and Conviction. PMID- 28362700 TI - Dermatofibrosarcoma Protuberans: An Immunomarker Study of 57 Cases That Included Putative Mesenchymal Stem Cell Markers. AB - Dermatofibrosarcoma protuberans (DFSP) is a low-grade fibroblastic sarcoma with a superficial location that has been suggested to potentially be a type of mesenchymal stem cell tumor. We studied the expression of various immunomarkers, including putative stem cell markers, in a series of 57 DFSPs including variants, and 12 dermatofibromas (DFs). CD105, a mesenchymal stem cell marker, was weakly expressed in 24 DFSPs, whereas other stem cell markers, including CD133, ALK-1, and Oct3/4, were completely negative in all samples. The expression rates of CD105 and CD34 were significantly higher in DFSP (42% and 93%) than in DF (0% and 17%), and CD10 and D2-40 were significantly lower in DFSP (40% and 3.5%) than in DF (100% and 33%), respectively. CD99, CD117, PDGFB, and PDGFRbeta expression was comparable between the groups. CD105 mesenchymal cells were not observed in non neoplastic dermis. In summary, we did not obtain sufficient immunohistochemical evidence to support the DFSP as a cutaneous mesenchymal stem cell tumor. CD34 alone was the most consistent marker of DFSP, irrespective of its variants. Because CD34 non-neoplastic mesenchymal cells were distributed in a location similar to that of DFSP, we suggest that DFSP might have originated from CD34 mesenchymal cells in the dermis. PMID- 28362701 TI - Acute Myeloid Leukemia (AML): Upregulation of BAALC/MN1/MLLT11/EVI1 Gene Cluster Relate With Poor Overall Survival and a Possible Linkage With Coexpression of MYC/BCL2 Proteins. AB - BACKGROUND: Molecular heterogeneity accounts for the variable and often poor prognosis in acute myeloid leukemia (AML). The current risk stratification strategy in clinical practice is limited to karyotyping and limited molecular studies screening for genetic mutations such as FLT-3 and NPM1. There is opportunity to identify further molecular prognostic markers, which may also lay the groundwork for the development of novel targeted therapies. Complex molecular technologies require transition into widely available laboratory platforms, for better integration into routine clinical practice. METHOD: In a defined subset (MYC/BCL2 or MYC/BCL2) of AML patients (n=20), we examined expression signature of several genes (n=12) of established prognostic value in AML. RNA expression and MYC/BCL2 protein pattern was correlated with 3 cytogenetic risk groups and overall survival. RESULTS: K-means++ unsupervised clustering defined 2 distinct groups with high and low transcript levels of BAALC/MN1/MLLT11/EVI1/SOCS2 genes (>2.5-fold difference; P<0.001). This mRNA signature trended with higher prevalence of MYC/BCL2 coexpression (P<0.057) and poor overall survival (P<0.036), but did not correlate with conventional cytogenetic risk groups (P<0.084). CONCLUSIONS: This pilot study provides useful data, which may help further refine the prognostic scheme of AML patients outside conventional cytogenetic risk groups. It also presents some biological rationale for future studies to explore the use of novel agents targeting MYC and/or BCL2 genes in combination with conventional chemotherapy protocols for AML. PMID- 28362702 TI - The Usefulness of Phospholipase A2 Receptor and IgG4 Detection in Differentiation Primary Membranous Nephropathy From Secondary Membranous Nephropathy in Renal Biopsy. AB - Membranous nephropathy (MGN) is the most common cause of the nephrotic syndrome in adults. Most cases of MGN are primary, but secondary MGN are frequently encountered. Determination of secondary MGN is crucial for initiation of appropriate treatment. The diagnostic performance of the phospholipase A2 receptor (PLA2R) and immunoglobulin G4 (IgG4) detection based on immunohistochemistry were evaluated using biopsy tissues of 59 primary and 56 secondary MGN cases for discrimination between primary MGN and secondary MGN. The PLA2R and IgG4 detection based on immunohistochemistry were dominantly positive in primary MGN cases. Sensitivity and specificity values for identification of primary MGN were 83% and 88% for PLA2R, and 76% and 86% for IgG4. Both PLA2R and IgG4 positivity showed a high specificity of 96.4% for identifying primary MGN. A meta-analysis was performed for analysis of the diagnostic accuracy of histologic PLA2R and IgG4 deposition for differentiation of primary from secondary MGN. The overall sensitivity, specificity, and area under curve of summary receiver operating characteristics were 76%, 86%, 0.93 for histologic PLA2R deposition, and 80%, 69%, 0.82 for histologic IgG4 deposition. PLA2R and IgG4 detection based on immunohistochemistry can be useful for differentiation of primary MGN from secondary MGN. PMID- 28362703 TI - An Epithelioid Gastrointestinal Stromal Tumor of the Stomach With Strong Expression of Keratin: Clinicopathologic Correlation and Follow-up Post-Imatinib Therapy. AB - Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of the digestive tract. They are relatively rare neoplasms compared with gastrointestinal carcinomas and usually can readily be differentiated from carcinomas based on the morphology of the neoplastic cells that are typically spindled (70%), pure epithelioid, or mixed type. GISTs in general lack expression of cytokeratin and exhibit immunoreactivity toward CD117, CD34, or DOG1. GISTs can demonstrate a pure epithelioid morphology that can appear similar histologically to a carcinoma. Very few epithelioid GISTs have been reported to express cytokeratin, which can lead to diagnostic challenges especially in cases with pure epithelioid morphology. Epithelioid GISTs should be considered in the differential diagnosis when evaluating gastrointestinal neoplasms with overlapping epithelioid and carcinoma-like morphology. An accurate diagnosis can be made using additional immunohistochemical studies directed against CD117, CD34, or DOG1. Advanced investigations such as mutation analysis of KIT using molecular pathology methods can further assist in confirming the diagnosis. PMID- 28362704 TI - Downregulation of ADAMTS18 May Serve as a Poor Prognostic Biomarker for Cervical Cancer Patients. AB - ADAMTS18 is a member of ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family proteins which have been found to play important roles in cancer progression and metastasis in different cancer types. The present study aims at evaluating the prognostic significance of ADAMTS18 in cervical cancer. The expression levels of ADAMTS18 was evaluated by real-time PCR in normal (N=28) and cervical cancer tissues from patients at different stages as well as in tumor tissues from 35 cervical cancer patients with primary cancer and 29 patients with metastasis. The correlation between serum ADAMTS18 expression levels and clinicopathologic features or overall survival of cervical cancer patients was analyzed. ADAMTS18 expression levels were significantly decreased in cervical cancer tissues compared with normal tissues and it decreased gradually from early stage to late stage. Low expression of ADAMTS18 was positively associated with high tumor stage (P=0.0239), positive lymph node metastasis (P=0.0388), and distant metastasis (P=0.0004). Tissue levels of ADAMTS18 in patients with primary cancer were significantly lower compared with those with metastasis. Moreover, patients with low ADAMTS18 expression levels had shorter overall survival (P=0.0119) or disease-free survival (P=0.0033). Multivariate analysis demonstrated that ADAMTS18 was an independent prognostic factor for cervical cancer. Our study suggests that ADAMTS18 is downregulated in cervical cancer and ADAMTS18 may serve as a potential prognostic biomarker for cervical cancer. PMID- 28362705 TI - Loss of BAP1 Expression Occurs Rarely to Never in Colorectal Adenocarcinoma. PMID- 28362706 TI - Prostate Ductal Adenocarcinoma. AB - Prostate ductal adenocarcinoma (PDA) is a rare subtype of prostate adenocarcinoma that shows more aggressive behavior than conventional prostatic acinar adenocarcinoma. PDA demonstrates similar clinical and paraclinical features such as prostatic acinar adenocarcinoma; therefore, clinical distinction of the 2 entities is very difficult (if not impossible) and histopathology plays an important role in the diagnosis of the disease. This review discusses all the necessary information needed for the diagnosis and prognosis of PDA including the morphologic features of PDA, an introduction about the known variants of PDA with helpful hints in grading of each variant, tips on differential diagnosis of PDA from the common morphologic mimickers, a detailed discussion on the value of immunohistochemistry in the diagnosis of PDA, and pathologic features that are helpful in determining the outcome. PMID- 28362707 TI - Differential Expression of Cytochrome C Oxidase Subunit I Along the Colorectal Adenoma: Carcinoma Progression. AB - Loss in apoptosis competence often results in augmented genomic instability contributing to carcinogenesis. Cytochrome c oxidase subunit I (CcOI) can help assess apoptosis resistance in paraffin-embedded biopsies. In total, 50 colorectal cases including 10 control cases of colectomy for non-neoplastic condition, 15 cases of adenomatous colorectal polyps, and 25 cases of colorectal carcinoma were investigated in this retrospective study for immunohistochemical expression of CcOI. The staining pattern of CcOI was assessed and indices of aberrant expression were calculated as crypt-restricted loss and overall decreased immunostaining (ODI). ODI calculated in the adenocarcinoma tumor tissue was designated as Tr ODI. The crypt-restricted loss and ODI indices of the aberrant CcOI expression are significantly higher in the adenomatous polyps group (2.5% and 47.54%) and in the non-neoplastic mucosa among adenocarcinoma group (2.78% and 49.1%) when they are compared with the control group (0.55% and 7.32%) (P<0.001). A highly significant correlation was noted between Tr ODI and the tumor grade, the nodal status, and the stage among adenocarcinomas. In conclusion, colonic tumors arise in a field of crypts with aberrations in CcOI expression. This aberration is linked to biologically aggressive tumors. CcOI immunostaining may be applied on mucosal samples from patients with colonic adenomatous polyps and patients with previous cancer colon resection to determine individuals who are in need for frequent colonoscopies and/or chemopreventive strategies. Future follow-up studies are warranted to determine the level of expression predictive of recurrence or progression. PMID- 28362708 TI - Napsin-A, a Possible Diagnostic Marker for Differentiating Clear Cell Ovarian Carcinoma From Other High-grade Ovarian Carcinomas. AB - Ovarian clear cell carcinoma (CCC) is divergent from other types of epithelial ovarian carcinoma in terms of clinicopathologic and molecular features. It should be separated from other high-grade carcinomas of the ovary for appropriate treatment. Napsin A is a reliable marker for adenocarcinoma of the lungs, but its role in ovarian epithelial carcinomas is vague. We investigated the expression of a panel of TTF-1, paired box 8, estrogen receptor, Wilms tumor 1, and Napsin A in 100 cases of high-grade ovarian carcinomas. All the examined cases were TTF-1 negative and paired box 8 positive. The 2 biomarkers estrogen receptor together with Wilms tumor 1 can separate CCC from endometriod carcinoma, yet this cannot be carried out in the case of serous and mucinous carcinomas of high grade. Napsin A can differentiate CCC with high sensitivity and specificity. It can be concluded that Napsin A is a sensitive and specific marker for CCC of the ovary. However, an entire marker panel may be useful for distinguishing ovarian CCC from other mimics. PMID- 28362709 TI - A Diagnostic Algorithm Combining Immunohistochemistry and Molecular Cytogenetics to Diagnose Challenging Melanocytic Tumors. AB - Some melanocytic tumors are diagnostic challenges and require ancillary tools in helping the pathologists to determine their potential of malignancy. We intend to propose a diagnostic algorithm in helping to classify challenging melanocytic tumors combining histology, immunohistochemistry, and cytogenetics. We report on 24 spitzoid and/or misdiagnosed melanocytic tumors studied with a triple p16, Ki 67, and HMB45 immunohistochemistry score, fluorescent in situ hybridization (FISH) with melanoma-dedicated and non-melanoma-dedicated probes and comparative genomic hybridization on DNA microarray (CGH array). Melanoma-dedicated FISH probe classified as favor malignant 8/8 melanomas, 1/2 atypical spitzoid tumor, and 4/14 nevi with polyploidy. Only 10 CGH array assays were contributive and concluded in complex chromosomal patterns as hallmarks of malignancy in 5 melanomas, single isolated imbalances in 3 nevi, and no chromosomal gain or loss in 2 nevi. The p16-Ki-67-HMB45 immunohistochemistry score was favor benign (ie, 0 to 3) in 13/14 nevi and in the favor benign atypical spitzoid tumor according to FISH analyses. The FISH-favor malignant atypical spitzoid tumor, 8/8 melanomas, and 1 tumor initially diagnosed as a Spitz nevus had favor malignant p16-Ki-67 HMB45 immunohistochemistry scores (ie, 4 to 9). Additional FISH analyses detected a 9p21/CDKN2A double deletion, frequently reported in melanomas but not in nevi, in the tumor initially diagnosed as a Spitz nevus with a favor malignant p16-Ki 67-HMB45 score. To conclude, in our opinion, histology and p16-Ki-67-HMB45 immunohistochemistry could consist in first-line tools to diagnose a difficult melanocytic tumor, followed by cytogenetics analyses in cases of discrepancies between histology and immunohistochemistry. PMID- 28362710 TI - Detection of Loss of Heterozygosity (LOH) Using Circulating Cell-free DNA (cfDNA) by Fluorescence-based Multiplex PCR for Identification of Patients With Prostate Cancer. AB - Several lines of evidence suggest that loss of heterozygosity (LOH) in specific chromosomal regions is a common mechanism for the inactivation of tumor suppressor genes that are implicated in the pathogenesis of prostate cancer (PCa). Short tandem repeat (STR) sequences are extremely reliable genetic markers for the detection of LOH associated with cancers. Hence, in the current study, we investigated the detection of LOH at 6 STR markers (D8S360, D9S1748, D9S171, D8S137, D6S1631, and THRB) using blood circulating cell-free DNA (cfDNA), which can be used to distinguish PCa from benign prostatic hyperplasia (BPH). A total of 136 individuals were included in the study, 76 male patients diagnosed with PCa (50 male patients with localized PCa and 26 male patients with metastatic PCa) as experimental subjects and 60 male patients with BPH as controls. Circulating cfDNA was extracted from plasma samples and amplified with fluorescence-labeled primers specific for known STR markers. We also evaluated the serum prostate-specific antigen in both groups. Our findings revealed that the frequency of LOH at D8S360, D9S1748, D9S171, D8S137, and D6S1631 was significantly higher in PCa subjects than in controls (P<0.05). Of the 6 STR markers, LOH at D8S360 could discriminate metastatic PCa from localized PCa. We found that 71.05% of patients with PCa and 1.66% of BPH subjects had LOH at least at 3 of the markers in cfDNA. Our findings provide additional evidence to support the hypothesis that analysis of LOH at D8S360, D9S1748, D9S171, D8S137, and D6S1631 STR markers using cfDNA can be applied as a noninvasive diagnostic approach for the detection of PCa. PMID- 28362711 TI - Ectopic Thyroid Tissue: Immunohistochemistry and Molecular Analysis. AB - Ectopic thyroid tissue is rare and controversial. Some experts consider it to always be metastatic thyroid carcinoma, whereas others consider it benign as long as it is restricted to few follicles without cytoarchitectural features of papillary thyroid carcinoma. Immunohistochemistry (IHC) and molecular studies have not yet been performed to further characterize this entity. We retrospectively searched our pathology files for all ectopic thyroid inclusions and reviewed clinicopathologic characteristics and concurrent thyroid pathologic findings. We identified 8 cases from 7 patients. Ectopic thyroid tissue was present in the following locations: neck soft tissue: 3, thymus: 2, neck lymph nodes: 2, perihilar soft tissue: 1. All patients had histologically benign thyroid specimens. BRAFV600E (VE1) IHC, HBME-1 IHC, galectin-3 IHC, BRAFV600E allele-specific polymerase chain reaction (PCR) and NRAS/KRAS pyrosequencing were performed. To assess the sensitivity and specificity of BRAFV600E IHC compared with PCR; we tested 13 cases of primary and metastatic papillary and follicular thyroid carcinomas. All the ectopic cases were HBME-1, galectin-3, BRAFV600E (IHC, PCR), and NRAS/KRAS mutation negative (specificity=100%). Compared with PCR, BRAF IHC had 89% sensitivity and 100% specificity. Lack of common carcinoma associated mutations supports benign nature of this entity. BRAF, HBME-1, and galectin-3 IHC are accurate and helpful when not enough tissue is available for molecular studies. IHC and molecular studies are more helpful than morphology alone in identifying benign thyroid rests. PMID- 28362712 TI - Vascular Endothelial Growth Inhibitor, a Cytokine of the Tumor Necrosis Factor Family, is Associated With Epithelial-Mesenchymal Transition in Renal Cell Carcinoma. AB - Previous studies have revealed that the activation of the epithelial-mesenchymal transition (EMT) endows metastatic properties upon cancer cells to promote invasion and migration. In this study, immunohistochemical analysis was performed in 50 cases of clear cell renal cell carcinoma (RCC) and paired normal kidney tissues. We detected the expression of vascular endothelial growth inhibitor (VEGI) and EMT markers (E-cadherin, fibronectin, and Slug) and recorded the clinical, pathologic, and follow-up (median follow-up: 79.0 mo) information. The expression of VEGI and E-cadherin was significantly lower in RCC tissues compared with normal kidney tissues (P<0.001). However, the expression of fibronectin and Slug was higher in RCC tissues (P<0.05). VEGI and EMT marker expression marginally differed in tumor size and stage. Significant differences were found in the pathologic grade (P<0.05). The Spearman correlation analysis suggested a positive correlation between VEGI and E-cadherin (r=0.451, P<0.01). A negative correlation was shown between VEGI and fibronectin (r=-0.465, P<0.01). There was also a negative correlation between VEGI and Slug (r=-0.758, P<0.01). During the 79.0 months (range, 7 to 119 mo) of follow-up, 6 patients died due to RCC, and the tumor-free survival rate was 88% (44/50). We did not find a significant correlation between VEGI/EMT markers (E-cadherin, fibronectin, and Slug) and overall survival (P>0.05). Our findings indicate that VEGI plays an important role in EMT in RCC. It suggests that VEGI may be investigated as a disease biomarker and therapeutic target in RCC. PMID- 28362713 TI - Relative Adrenal Insufficiency in Cardiogenic Shock: Is There a Need for Action? PMID- 28362714 TI - Iloprost, Prostaglandin E1, and Papaverine Relax Human Mesenteric Arteries With Similar Potency. AB - OBJECTIVE: Nonocclusive mesenteric ischemia (NOMI) is accompanied by mesenteric artery spasms that are at least in part due to endothelin system activation. Acute treatment includes intra-arterial infusion of vasodilators such as iloprost, prostaglandin E1 (PGE1), and papaverine. Their effectiveness is not well characterized in human mesenteric arteries. We directly compared their potency to relax isolated human mesenteric arteries. To explore the potential of Rock inhibition to treat mesenteric artery spasms, we tested if endothelin-1 (ET 1)-induced mesenteric artery constrictions depend on rho kinase (Rock). METHODS: Mesenteric artery segments were obtained from patients who underwent elective abdominal surgery. Vasodilator concentration-response curves were recorded from ET-1-preconstricted vessels by small vessel myography. Rock expression was investigated by Western blot and the potency of Rock inhibition to blunt ET-1 induced mesenteric artery constriction was tested. RESULTS: Iloprost, PGE1, and papaverine similarly reduced vascular tone to 20% to 30% of ET-1-induced wall tension. In human mesenteric arteries, logEC50 was significantly less for iloprost than for PGE1 or papaverine. Respective logEC50 values were -7.72 +/- 0.08 mol/L, -6.58 +/- 0.17 mol/L, and -6.73 +/- 0.19 mol/L in 150 MUm to 300 MUm lumen diameter arteries. These vessels were also more sensitive to iloprost than 500 MUm to 1,000 MUm lumen diameter arteries (logEC50 -7.29 +/- 0.07 mol/L). Rock1 and Rock2 were expressed in human mesenteric arteries but Rock inhibition did not significantly affect ET-1-induced vasoconstrictions. CONCLUSIONS: Iloprost, PGE1, and papaverine have a similar potency to relax mesenteric arteries. Our data suggest that iloprost but not Rock inhibition may be particularly useful to treat ET-1-induced spasms of distal mesenteric arteries. PMID- 28362715 TI - Phenotypic Changes and Impaired Function of Peripheral gammadelta T Cells in Patients With Sepsis. AB - INTRODUCTION: Recent studies demonstrated the significant loss of gamma delta T (gammadelta T) cells in patients with sepsis. Given the distinct functions of gammadelta T cells in human anti-infection immunity, we are interested in evaluating the phenotype and function of peripheral gammadelta T cells in septic patients and determining their prognostic implication. METHOD: This prospective study has been conducted in three intensive care units of a university hospital. During the period from October 2014 to June 2015, we enrolled 107 patients who were consecutively admitted and diagnosed with severe sepsis or septic shock (excluding previous immunosuppression) and 45 healthy controls. Using flow cytometry, we analyzed the in vivo percentage of gammadelta T cells in cluster of differentiation (CD)3 cells from peripheral blood mononuclear cells as well as their expression of surface markers (CD69, natural-killer group 2 member D [NKG2D], programmed death receptor 1 [PD-1]) and intracellular cytokines (interferon-gamma [IFN-gamma], interleukin [IL]-17, IL-10, transforming growth factor-beta [TGF-beta]). Then we further evaluated the different responses of gammadelta T cells after the antigen stimulation ex vivo by measuring CD69 and IFN-gamma expression. Lastly, we conducted the multiple logistic regressions to analyze the risk factor for prognosis. RESULTS: Compared with control group, gammadelta T cells in septic patients displayed a decrease in percentage, increase in CD69, decrease in NKG2D, and increase in cytokine expression (pro inflammatory IFN-gamma, IL-17, anti-inflammatory IL-10, TGF-beta) in vivo. After the antigen stimulation ex vivo, both CD69 and IFN-gamma expression in gammadelta T cells were significantly lower in septic patients than control group. Importantly, the decrease in CD69 and IFN-gamma expression was more pronounced in non-survivors than survivors. Multiple logistic regression analysis revealed that lower expression of IFN-gamma after stimulation is a dependent risk factor that associated with patient 28-day death in septic patients (OR: 0.908 [95% CI: 0.853 0.966]). CONCLUSION: Septic patients showed altered phenotype and function of gammadelta T cells. The impaired IFN-gamma expression by gammadelta T cells after the antigen stimulation is associated with mortality in septic patients. PMID- 28362717 TI - Low activity versus high activity: noninferior response to radioiodine therapy in differentiated patients with extrathyroid extension. AB - OBJECTIVES: Radioactive iodine (RAI) therapy is recommended for differentiated thyroid cancer (DTC) patients with microscopic extrathyroid extension (ETE). Patients with a low preablative stimulated thyroglobulin (ps-Tg) level have a more favorable prognosis. It remains uncertain whether low-activity RAI could have the same efficacy in patients with low ps-Tg. This study aimed to evaluate the effectiveness of low-activity RAI therapy in low-level ps-Tg DTC with ETE. PATIENTS AND METHODS: The inclusion criteria for this retrospective study were as follows: (a) age 18 years or older, (b) DTC after total or near-total thyroidectomy of DTC, (c) no distant metastasis after thyroidectomy and before RAI therapy, (d) American Joint Committee on Cancer pT3 stage (with microscopic ETE) with any American Joint Committee on Cancer N stage, (e) ps-Tg level of 5 ng/ml or less, and (f) after the first time of RAI therapy. The response of patients was assessed at 20-24 months after RAI therapy and considered an excellent response (ER) or non-ER. RESULTS: A total of 132 patients were included, 69 patients in low activity (1100 MBq) and 63 in high activity (>=3700 MBq). ER was observed in 86.9% of patients in the low-activity group (60/69), which did not differ from the high-activity group (P=0.165) at 20-24 months' assessment. For patients with different N statuses (N0, N1a, N1b), a noninferior response could also be achieved under low-activity RAI therapy compared with the high-activity group (P=1.000, 0.286, 0.722, respectively). CONCLUSION: Low activity RAI therapy is not inferior to high-activity therapy in achieving an ER in microscopic ETE DTC with ps-Tg less than 5 ng/ml irrespective of the lymph node metastases. PMID- 28362718 TI - Radioactive seed localization is the preferred technique in nonpalpable breast cancer compared with wire-guided localization and radioguided occult lesion localization. AB - OBJECTIVES: Three commonly used techniques for localization of nonpalpable breast cancer are radioactive seed localization (RSL), wire-guided localization (WGL) and radioguided occult lesion localization (ROLL). In this study, we analysed the surgical margins of these three techniques. METHODS: Women diagnosed with nonpalpable breast cancer undergoing breast-conserving surgery with one of the above-mentioned techniques were retrospectively included. The primary outcome parameter was tumour-free margin rate. Secondary outcomes were re-excision rate, recurrence of disease and volume of removed tissue. RESULTS: In total, 272 women were included in whom RSL (n=69), WGL (n=76) or ROLL (n=137) was performed. RSL showed a higher tumour-free margin rate [64 (92.8%)] compared with WGL [51 (67.1%)] and ROLL [113 (82.5%)] (P=0.001). In our multivariable analysis, RSL showed a higher tumour-free margin rate as well compared with WGL (P=0.036) and ROLL (P=0.049). Also, fewer re-excisions were encountered using RSL [5 (7.2%)] compared with WGL [13 (17.1%)] and ROLL [15 (10.9%)] (P=0.171). In 11 patients (WGL n=2, ROLL n=9), recurrence of disease occurred, despite a radical excision. The mean resection volumes were comparable within the three groups. CONCLUSION: RSL results in a higher tumour-free margin rate in nonpalpable breast tumours compared with WGL and ROLL. Therefore, we prefer using RSL in nonpalpable breast tumours. PMID- 28362716 TI - PharmGKB summary: sorafenib pathways. PMID- 28362719 TI - Imaging markers of multiple sclerosis prognosis. AB - PURPOSE OF REVIEW: Studies of large longitudinal cohorts of patients with multiple sclerosis (MS) have emphasized the prognostic value of conventional MRI markers, at least during early stages. Advanced imaging metrics derived from quantitative MRI and PET provide relevant information about microstructural damage within and outside visible lesions that may be more sensitive to predict long-term disability. Here, we summarize the most recent findings regarding the prognostic value of imaging markers throughout MS stages. RECENT FINDINGS: In clinically isolated syndrome, the presence of at least one brain or spinal cord T2 lesion strongly increases the risk of conversion to clinically definite MS (hazard ratio ranging from 5 to 11). Similarly, the occurrence of new white matter lesions is strongly predictive of subsequent relapse rate and response to current disease modifying therapies. Beyond white matter lesions, volumetric changes in the grey matter and normal-appearing tissue damage are more sensitive prognostic markers for physical and cognitive disability, especially in progressive MS. SUMMARY: Although white matter lesion number and volume still remains the imaging metric used in daily clinical practice, further development of advanced imaging predictors of long-term disability should allow a better stratification of patients in future clinical trials aimed at promoting repair or neuroprotection. PMID- 28362720 TI - Diagnostic Value of Semiquantitative Analysis of 99mTechnetium Methoxyisobutylisonitrile (99mTc-MIBI) Imaging in Predicting Early-Stage Cervical Lymph Node Metastasis of Thyroid Carcinoma. AB - BACKGROUND The aim of this study was to evaluate the value of semiquantitative analysis (SQA) of 99mTc-MIBI imaging in predicting early-stage cervical lymph node metastasis (CLNM) in thyroid carcinoma (TC). MATERIAL AND METHODS TC patients (n =106) undergoing surgical resection and histopathological examination were enrolled. All patients received 99mTc-MIBI imaging prior to surgery. P glycoprotein (P-gp) expression was detected by PT-PCR and immunohistochemistry. With pathological results as the criterion standard, the diagnostic efficiency of 99mTc-MIBI imaging in predicting early-stage CLNM was evaluated. The correlation of P-gp with 99mTc-MIBI imaging was investigated. Logistic regression analysis was applied for analyzing the factors affecting early-stage CLNM. RESULTS The detection rate and misdiagnosis rate of 99mTc-MIBI imaging for early-stage CLNM diagnosis were 87.3% and 12.7%, respectively. Receiver operating characteristic (ROC) curve analysis showed an accuracy of 99mTc-MIBI imaging of 85.85%. Preoperative 99mTc-MIBI scan showed statistical differences between metastasis and non-metastasis groups in early and delayed T/NT and washout rate (all P<0.05). The percentage of P-gp-expressing cells and the expression rate of P-gp gene both exhibited statistical differences between metastasis and no-metastasis groups (both P<0.05). Tumor diameter, lesion distribution, the percentage of P-gp expressing cells, and the expression rate of P-gp gene were risk factors for CLNM (all P<0.05). CONCLUSIONS 99mTc-MIBI imaging has value in qualitative diagnosis of early-stage CLNM in TC. Tumor diameter, lesion distribution, the percentage of P-gp-expressing cells, and the expression rate of P-gp gene were risk factors for CLNM. PMID- 28362721 TI - Hidden diversity revealed by genome-resolved metagenomics of iron-oxidizing microbial mats from Lo'ihi Seamount, Hawai'i. AB - The Zetaproteobacteria are ubiquitous in marine environments, yet this class of Proteobacteria is only represented by a few closely-related cultured isolates. In high-iron environments, such as diffuse hydrothermal vents, the Zetaproteobacteria are important members of the community driving its structure. Biogeography of Zetaproteobacteria has shown two ubiquitous operational taxonomic units (OTUs), yet much is unknown about their genomic diversity. Genome-resolved metagenomics allows for the specific binning of microbial genomes based on genomic signatures present in composite metagenome assemblies. This resulted in the recovery of 93 genome bins, of which 34 were classified as Zetaproteobacteria. Form II ribulose 1,5-bisphosphate carboxylase genes were recovered from nearly all the Zetaproteobacteria genome bins. In addition, the Zetaproteobacteria genome bins contain genes for uptake and utilization of bioavailable nitrogen, detoxification of arsenic, and a terminal electron acceptor adapted for low oxygen concentration. Our results also support the hypothesis of a Cyc2-like protein as the site for iron oxidation, now detected across a majority of the Zetaproteobacteria genome bins. Whole genome comparisons showed a high genomic diversity across the Zetaproteobacteria OTUs and genome bins that were previously unidentified by SSU rRNA gene analysis. A single lineage of cosmopolitan Zetaproteobacteria (zOTU 2) was found to be monophyletic, based on cluster analysis of average nucleotide identity and average amino acid identity comparisons. From these data, we can begin to pinpoint genomic adaptations of the more ecologically ubiquitous Zetaproteobacteria, and further understand their environmental constraints and metabolic potential. PMID- 28362722 TI - Prokaryote genome fluidity is dependent on effective population size. AB - Many prokaryote species are known to have fluid genomes, with different strains varying markedly in accessory gene content through the combined action of gene loss, gene gain via lateral transfer, as well as gene duplication. However, the evolutionary forces determining genome fluidity are not yet well understood. We here for the first time systematically analyse the degree to which this distinctive genomic feature differs between bacterial species. We find that genome fluidity is positively correlated with synonymous nucleotide diversity of the core genome, a measure of effective population size Ne. No effects of genome size, phylogeny or homologous recombination rate on genome fluidity were found. Our findings are consistent with a scenario where accessory gene content turnover is for a large part dictated by neutral evolution. PMID- 28362723 TI - Chirality in microbial biofilms is mediated by close interactions between the cell surface and the substratum. AB - From microbial biofilms to human migrations, spatial competition is central to the evolutionary history of many species. The boundary between expanding populations is the focal point of competition for space and resources and is of particular interest in ecology. For all Escherichia coli strains studied here, these boundaries move in a counterclockwise direction even when the competing strains have the same fitness. We find that chiral growth of bacterial colonies is strongly suppressed by the expression of extracellular features such as adhesive structures and pili. Experiments with other microbial species show that chiral growth is found in other bacteria and exclude cell wall biosynthesis and anisotropic shape as the primary causes of chirality. Instead, intimate contact with the substratum is necessary for chirality. Our results demonstrate that through a handful of surface molecules cells can fundamentally reorganize their migration patterns, which might affect intra- and interspecific competitions through colony morphology or other mechanisms. PMID- 28362725 TI - Lorenz Poellinger MD, PhD (1957-2016). PMID- 28362724 TI - Gene mobility promotes the spread of resistance in bacterial populations. AB - Theory predicts that horizontal gene transfer (HGT) expands the selective conditions under which genes spread in bacterial populations. Whereas vertically inherited genes can only spread by positively selected clonal expansion, mobile genetic elements can drive fixation of genes by infectious HGT. We tested this using populations of Pseudomonas fluorescens and the conjugative mercury resistance (HgR) plasmid pQBR57. HGT expanded the selective conditions allowing the spread of HgR: Chromosomal HgR only increased in frequency under positive selection, whereas plasmid-encoded HgR reached fixation with or without positive selection. Tracking plasmid dynamics over time revealed that the mode of HgR inheritance varied across mercury environments. Under mercury selection, the spread of HgR was driven primarily by clonal expansion while in the absence of mercury HgR dynamics were dominated by infectious transfer. Thus, HGT is most likely to drive the spread of resistance genes in environments where resistance is useless. PMID- 28362727 TI - High-power 1018 nm ytterbium-doped fiber laser with output of 805 W. AB - This Letter presents a high-power 1018 nm ytterbium-doped fiber laser (YDFL) with optimized parameters. A record output power reaching 805 W was achieved, along with a light-to-light efficiency of 64.9% and a beam quality factor of M2=1.80. Further, a higher efficiency of 82.8% of 1018 nm YDFL pumped by wavelength-stabilized laser diodes for the first time, to the best of our knowledge, was shown. At last some attempts were made in bidirectional pumping structure. In this Letter, all the measured spectra showed strong amplified spontaneous emission suppression, and the power curves indicated the potential for further power scaling. PMID- 28362728 TI - Dielectric metasurfaces solve differential and integro-differential equations. AB - Leveraging subwavelength resonant nanostructures, plasmonic metasurfaces have recently attracted much attention as a breakthrough concept for engineering optical waves both spatially and spectrally. However, inherent ohmic losses concomitant with low coupling efficiencies pose fundamental impediments over their practical applications. Not only can all-dielectric metasurfaces tackle such substantial drawbacks, but also their CMOS-compatible configurations support both Mie resonances that are invariant to the incident angle. Here, we report on a transmittive metasurface comprising arrayed silicon nanodisks embedded in a homogeneous dielectric medium to manipulate phase and amplitude of incident light locally and almost independently. By taking advantage of the interplay between the electric/magnetic resonances and employing general concepts of spatial Fourier transformation, a highly efficient metadevice is proposed to perform mathematical operations including solution of ordinary differential and integro differential equations with constant coefficients. Our findings further substantiate dielectric metasurfaces as promising candidates for miniaturized, two-dimensional, and planar optical analog computing systems that are much thinner than their conventional lens-based counterparts. PMID- 28362726 TI - 'Hints' in the killer protein gasdermin D: unveiling the secrets of gasdermins driving cell death. AB - Pyroptosis is a lytic form of cell death distinguished from apoptosis, ferroptosis, necrosis, necroptosis, NETosis, oncosis, pyronecrosis and autophagy. Proinflammatory caspases cleave a gasdermin D (GSDMD) protein to generate a 31 kDa N-terminal domain. The cleavage relieves the intramolecular inhibition on the gasdermin-N domain, which then moves to the plasma membrane to exhibit pore forming activity. Thus, GSDMD acts as the final and direct executor of pyroptotic cell death. Owing to the selective targeting of the inner leaflet of the plasma membrane with the pore-forming that determines pyroptotic cell death, GSDMD could be a potential target to control cell death or extracellular bacterial infections. Intriguingly, other gasdermin family members also share similar N terminal domains, but they present different cell death programs. Herein, we summarize features and functions of the novel player proteins in cell death, including GSDMD triggering pyroptosis, Gsdma3/GSDMA initiating autophagy/apoptosis and DFNA5 inducing apoptosis/secondary necrosis. The gasdermin N terminus appears to be a novel pore-forming protein. This provides novel insight into the underlying roles and mechanisms of lytic or nonlytic forms of programmed cell death, as well as their potential applications in inflammation associated diseases. PMID- 28362729 TI - Experimental observation of quantum correlations in four-wave mixing with a conical pump. AB - Generation of multimode quantum states has drawn much attention recently due to its importance for both fundamental science and the future development of quantum technologies. Here, by using a four-wave mixing process with a conical pump beam, we have experimentally observed about -3.8 dB of intensity-difference squeezing between a single-axial probe beam and a conical conjugate beam. The multi-spatial mode nature of the generated quantum-correlated beams has been shown by comparing the variation tendencies of the intensity-difference noise of the probe and conjugate beams under global attenuation and local cutting attenuation. Due to its compactness, phase-insensitive nature, and easy scalability, our scheme may find potential applications in quantum imaging, quantum information processing, and quantum metrology. PMID- 28362730 TI - Influenza virus immunosensor with an electro-active optical waveguide under potential modulation. AB - Here we report the development of a novel immunosensor-based strategy for label free detection of viral pathogens by incorporating a sandwich bioassay onto a single-mode, electro-active, integrated optical waveguide (EA-IOW). Our strategy begins with the functionalization of the electro-active waveguide surface with a capture antibody aimed at a specific virus antigen. Once the target antigen is bound to the photonic interface, it promotes the binding of a secondary antibody that has been labeled with a methylene blue (MB) dye. The MB is a redox-active probe whose optical absorption can be electrically modulated and interrogated with high sensitivity by a propagating waveguide mode. In this effort, we have targeted the hemagglutinin (HA) protein from the H5N1 avian influenza A virus to demonstrate the capabilities of the EA-IOW device for detection and quantification of an important antigen. Our initial results for the HA H5N1 influenza virus show a remarkable limit of detection in the pico-molar range. PMID- 28362731 TI - Microwave-assisted frequency domain measurement of fiber-loop ring-down system. AB - A new frequency domain measurement method for a fiber-loop ring-down system is proposed in this Letter. Compared to traditional time domain measurement, this method uses a microwave modulated continuous wave (CW) laser as a light source, making full use of the duty cycle to achieve enhanced measurement efficiency. By measuring the amplitude modulation over a frequency span, this technique can be used to determine the ring-down time in the frequency domain, which will then be used to calculate the loss in the ring. PMID- 28362732 TI - Direct measurement of the negative Goos-Hanchen shift of single reflection in a two-dimensional photonic crystal with negative refractive index. AB - The negative Goos-Hanchen shift (GHS) on a two-dimensional photonic crystal with an effective negative refractive index is investigated by simulation and experiment. The measured refractive index of the fabricated photonic crystal is nearly -0.44. The difference between the Goos-Hanchen shift of the transverse electric wave GTE and that of the transverse magnetic wave GTM (DGHS) in the height direction of a silicon rod is measured at three incident angles. The result shows that DGHS is always smaller than GTM, thus GTE<0; therefore, the negative GHS does occur on the surface of the photonic crystal with a negative refractive index. PMID- 28362733 TI - Phase noise characterization of sub-hertz linewidth lasers via digital cross correlation. AB - Phase noise or frequency noise is a key metric to evaluate the short-term stability of a laser. This property is of great interest for the applications but delicate to characterize, especially for narrow linewidth lasers. In this Letter, we demonstrate a digital cross-correlation scheme to characterize the absolute phase noise of sub-hertz linewidth lasers. Three 1542 nm ultra-stable lasers are used in this approach. For each measurement, two lasers act as references to characterize a third one. Phase noise power spectral density from 0.5 Hz to 0.8 MHz Fourier frequencies can be derived for each laser by a mere change in the configuration of the lasers. To the best of our knowledge, this is the first time showing the phase noise of sub-hertz linewidth lasers with no reference limitation. We also present an analysis of the laser phase noise performance. PMID- 28362734 TI - Dimensional variation tolerant mode converter/multiplexer fabricated in SOI technology for two-mode transmission at 1550 nm. AB - The use of an integrated asymmetrical directional coupler for two-mode transmission at 1550 nm is analyzed. The design is based on silicon-on-insulator (SOI) technology and permits mode conversion and mode multiplexing/demultiplexing. In the nominal design, mode conversion and mode (de)multiplexing are achieved with 97% efficiency and a 23.4 dB crosstalk level in the 1540-1560 nm band using a 0.1 MUm gap. The dimension tolerance of the SOI process has been taken into account in the selection of the optimum design, and the coupling efficiency would remain above 82.3% (corresponding to 0.8 dB excess loss) with 3sigma accuracy. A 90% efficiency has been experimentally obtained. PMID- 28362735 TI - Silicon-gold core-shell nanowire array for an optically and electrically characterized refractive index sensor based on plasmonic resonance and Schottky junction. AB - This work reports the plasmonically enhanced refractive index sensor consisting of silicon nanowire array (Si-NWA) coated by a conformal gold (Au) nanoshell. Compared to the pure Si or Au NWA system, the Si-Au core-shell setup leads to substantially enhanced optical in-coupling to excite strong surface plasmon resonance (SPR) for highly sensitive sensors. Results indicate that the SPR wavelength can be subtly tuned by manipulating the nanowire radius, and it shows a strong shift with very small variation of the refractive index of the analyte. Furthermore, we configure the system into the Schottky junction, which can separate the photogenerated hot electrons so that the electrical outputs under various incident wavelengths can be measured. The capabilities of optical and electrical measurements ensure a high flexibility of the sensing system. Through our optoelectronic evaluation, the optimally designed system shows a sensitivity up to 1008 nm per refractive index unit and a full width at half-maximum of 9.89 nm; moreover, the high sensing performance can be sustained in a relatively large range of the incident angle. PMID- 28362736 TI - Single-longitudinal-mode ring diamond Raman laser. AB - We demonstrate a single-longitudinal-mode ring diamond Raman laser, pumped by a tunable single-mode Ti:sapphire laser. Two methods to achieving unidirectional operation have been demonstrated: increasing gain for one direction using a reinjecting mirror and increasing loss for one direction using sum frequency mixing in BBO. Both methods result in a stable single-longitudinal-mode operation. PMID- 28362737 TI - Depth-encoded optical coherence elastography for simultaneous volumetric imaging of two tissue faces. AB - Depth-encoded optical coherence elastography (OCE) enables simultaneous acquisition of two three-dimensional (3D) elastograms from opposite sides of a sample. By the choice of suitable path-length differences in each of two interferometers, the detected carrier frequencies are separated, allowing depth ranging from each interferometer to be performed simultaneously using a single spectrometer. We demonstrate depth-encoded OCE on a silicone phantom and a freshly excised sample of mouse liver. This technique minimizes the required spectral detection hardware and halves the total scan time. Depth-encoded OCE may expedite clinical translation in time-sensitive applications requiring rapid 3D imaging of multiple tissue surfaces, such as tumor margin assessment in breast conserving surgery. PMID- 28362738 TI - Self-eclipsing: alignment-free vortex coronagraphy. AB - We report on a self-induced strategy to achieve high-contrast optical imaging, without the need for any man-made optical masks, which relies on the self-induced spin-to-orbital angular momentum conversion phenomenon. This is experimentally demonstrated by realizing a laboratory demonstration of self-eclipsing of a light source following the generation of a self-adapted vectorial optical vortex transmission mask. The proposed concept, namely the realization of an alignment free optical vortex coronagraph, may inspire the development of future generations of smart astronomical imaging instruments. PMID- 28362739 TI - Wide-field imaging combined with confocal microscopy using a miniature f/5 camera integrated within a high NA objective lens. AB - Wide-field (WF) imaging paired with reflectance confocal microscopy can noninvasively detect skin cancer with high accuracy. However, two separate devices are required to perform each imaging procedure. We describe a new concept that integrates the two into one device: a miniature WF color camera within the objective lens used for confocal microscopy, providing simultaneous sub-surface cellular imaging and WF surface morphologic imaging. The camera, inserted between a hyperhemisphere front lens and a back lens group of the objective, commands a field of view of 4.0 mm, with a resolution better than 30 MUm, while confocal optical sectioning is preserved at sharper than 2.5 MUm. PMID- 28362740 TI - Fully suspended slot waveguides for high refractive index sensitivity. AB - A fully suspended mid-infrared (FSMIR) slot waveguide is proposed and experimentally demonstrated on a silicon-on-insulator (SOI) platform for the first time. The slotted waveguide core is mechanically supported by lateral subwavelength grating claddings. The fabricated waveguides possess low propagation loss, which is measured to be 7.9 dB/cm at the wavelength of 2.25 MUm. With the underlying buried oxide (BOX) removed, the FSMIR slot waveguide has a broad spectral range of transparency that is limited only by the absorption of silicon. Numerical simulation shows that its sensitivity, defined as the ratio between the change of the effective index and the ambient refractive index, can reach 1.123, which is 9.7% higher than the maximal sensitivity of conventional SOI slot waveguides on BOX. PMID- 28362741 TI - Microresonator-stabilized extended-cavity diode laser for supercavity frequency stabilization. AB - We demonstrate a simple, compact, and cost-effective laser noise reduction method for stabilizing an extended-cavity diode laser to a 3*105 finesse mirror Fabry-Perot (F-P) cavity, corresponding to a resonance linewidth of 10 kHz, by using a crystalline MgF2 whispering gallery mode microresonator. The laser linewidth is reduced to sub-kilohertz such that a stable Pound-Drever-Hall error signal is built up. The wavelength of the pre stabilized laser is tunable within a large bandwidth covering the high-reflection mirror coating of an F-P supercavity. PMID- 28362742 TI - Single-wavelength excited photoacoustic-fluorescence microscopy for in vivo pH mapping. AB - The balance between radiative and non-radiative decay is affected by various factors at the excitation state. A simultaneous acquisition of the fluorescence and photoacoustic signals from an appropriate probe provides an efficient, high resolution means to monitor such a balance in a biological target, and thus may render its physiological information. Acidity plays an important role in tissue physiology. Here, we report an integrated photoacoustic-fluorescence microscopy (PA-FLM) for high-resolution (<3 MUm) image mapping of interstitial pH by detecting the shift in the signal balance of a pH-sensitive probe. The hypothesis and the technical feasibility are validated with an in vivo tumor model. The results show that the technique can effectively monitor pH changes within the range of biological acidity and are independent of the excitation source fluctuation and local probe concentration. We thus propose that, with further research and selection of proper probes, PA-FLM may provide a potential alternative for monitoring tissue physiology. PMID- 28362743 TI - Characterizing a 14 * 14 OAM mode transfer matrix of a ring-core fiber based on quadrature phase-shift interference. AB - The transfer matrix of light propagating in fibers can quantitatively elucidate the mechanisms of mode coupling, thus having important implications for the knowledge such as the mode division multiplexing communication link characteristics in fibers. However, most methods for measuring the transfer matrix require a prior knowledge of the launched modes at the input and a complex optical system for the characterization at the output of the fiber. In this Letter, we use an interferometric approach for decomposing orbital angular momentum (OAM) modes of the output beams from a ring-core fiber, thereby processing a 14*14 OAM mode transfer matrix of the fiber with merely a camera imaging the mode field at the output of the fiber. The suitability of such a method is validated by the beam reconstruction. Thus, this method is crucial for characterizing the fiber transfer matrix with promising features of fast response and simple operation. PMID- 28362744 TI - Dual field-of-view step-zoom metalens. AB - A conventional optical zoom system is bulky, expensive, and complicated for real time adjustment. Recent progress in metasurface research has provided a new solution to achieve innovative compact optical systems. In this Letter, we propose a highly integrated step-zoom lens with dual field of view (FOV) based on double-sided metasurfaces. With silicon nanobrick arrays of spatially varying orientations sitting on both sides of a transparent substrate, this ultrathin step-zoom metalens can be designed to focus an incident circular polarized beam with handedness-dependent FOVs without varying the focal plane, which is important for practical applications. The proposed dual FOV step-zoom metalens, with advantages such as ultracompactness, flexibility, and replicability, can find applications in fields that require ultracompact zoom imaging and beam focusing. PMID- 28362745 TI - Fabrication of long period fiber gratings of subnanometric bandwidth. AB - This Letter reports on the fabrication of long period fiber gratings having subnanometric bandwidths in the 1500 nm spectral region. Large gratings have been photo inscribed in a high NA fiber; the grating pitch and the order of the HE cladding mode are optimized to produce gratings with a large number of periods and prevent the coupling to TE, TM, or EH modes. Resonances with a FWHM of 0.83 and 0.68 nm have been achieved for gratings 15 and 20 cm long, respectively; the free spectral range between the transmission notches is 125 nm. The polarization effects and the sensitivity of the gratings to temperature and to strain variations are presented as well. PMID- 28362746 TI - CPT-symmetric coupler with intermodal dispersion. AB - A dual-core waveguide with balanced gain and loss in different arms and with intermodal coupling is considered. The system is not invariant under the conventional PT symmetry, but obeys CPT symmetry where an additional spatial inversion C corresponds to swapping the coupler arms. We show that second-order dispersion of coupling allows for unbroken CPT symmetry and supports propagation of stable vector solitons along the coupler. Small-amplitude solitons are found in explicit form. The combined effect of gain-and-loss and dispersive coupling results in several interesting features which include a separation between the components in different arms, nontrivial dependence of stability of a soliton on its velocity, and the existence of more complex stationary two-hump solutions. Unusual decay dynamics of unstable solitons are also discussed. PMID- 28362747 TI - Functional in vivo imaging using fluorescence lifetime light-sheet microscopy. AB - Light-sheet microscopy has become an indispensable tool for fast, low phototoxicity volumetric imaging of biological samples, predominantly providing structural or analyte concentration data in its standard format. Fluorescence lifetime imaging microscopy (FLIM) provides functional contrast, but often at limited acquisition speeds and with complex implementation. Therefore, we incorporate a dedicated frequency domain CMOS FLIM camera and intensity-modulated laser into a light-sheet setup to add fluorescence lifetime imaging functionality, allowing the rapid acquisition of volumetric data with concentration independent contrast. We then apply the system to image live transgenic zebrafish, demonstrating the capacity to rapidly collect volumetric FLIM data from an in vivo sample. PMID- 28362748 TI - Compact, thermal-noise-limited reference cavity for ultra-low-noise microwave generation. AB - We demonstrate an easy-to-manufacture 25-mm-long ultra-stable optical reference cavity for transportable photonic microwave generation systems. Employing a rigid holding geometry that is first-order insensitive to the squeezing force and a cavity geometry that improves the thermal noise limit at room temperature, we observe a laser phase noise that is nearly thermal noise limited for three frequency decades (1 Hz to 1 kHz offset) and supports 10 GHz generation with phase noise near -100 dBc/Hz at 1 Hz offset and <-173 dBc/Hz for all offsets >600 Hz. The fractional frequency stability reaches 2*10-15 at 0.1 s of averaging. PMID- 28362749 TI - Self-referenced temperature sensing with a lithium niobate microdisk resonator. AB - Self-referenced temperature sensing based on thermo-optic birefringence is demonstrated on a Z-cut lithium niobate microdisk resonator. Due to the significant difference between thermo-optic coefficients of ordinary and extraordinary light, quasi-transverse magnetic (quasi-TM) and quasi-transverse electric (quasi-TE) modes in the microdisk show relative cavity resonance shift upon temperature change, which acts as a robust self-reference for temperature sensing. A temperature sensitivity of 0.834 GHz/K and a measurement uncertainty of 0.8 mK are demonstrated with an optical input power of only 1.5 MUW. PMID- 28362750 TI - Low-loss single-mode negatively curved square-core hollow fibers. AB - We introduce a novel design of anti-resonant fibers with negative-curvature square cores to be employed in 1.55 and 2.94 MUm transmission bands. The fibers have low losses and single-mode operation via optimizing the negative curvature of the guiding walls. The first proposed fiber shows a broadband transmission window spanning 0.9-1.7 MUm, with losses of 0.025 and 0.056 dB/m at 1.064 and 1.55 MUm, respectively. The second proposed fiber has approximately a 0.023 dB/m guiding loss at 2.94 MUm with a small cross-sectional area, useful for laser micromachining applications. PMID- 28362751 TI - Second-order nonlinearity induced transparency. AB - In analogy to electromagnetically induced transparency, optomechanically induced transparency was proposed recently in [Science330, 1520 (2010)SCIEAS0036 807510.1126/science.1195596]. In this Letter, we demonstrate another form of induced transparency enabled by second-order nonlinearity. A practical application of the second-order nonlinearity induced transparency is to measure the second-order nonlinear coefficient. Our scheme might find applications in quantum optics and quantum information processing. PMID- 28362752 TI - Far-detuned cascaded intermodal four-wave mixing in a multimode fiber. AB - We demonstrate far-detuned parametric frequency conversion processes in a few mode graded-index optical fibers pumped by a Q-switched picosecond laser at 1064 nm. Through a detailed analytical and numerical analysis, we show that the multiple sidebands are generated through a complex cascaded process involving inter-modal four-wave mixing. The resulting parametric wavelength detuning spans in the visible down to 405 nm and in the near-infrared up to 1355 nm. PMID- 28362753 TI - Fluorescent color centers in laser ablated 4H-SiC nanoparticles. AB - Nanostructured and bulk silicon carbide (SiC) has recently emerged as a novel platform for quantum nanophotonics due to its harboring of paramagnetic color centers, having immediate applications as a single photon source and spin optical probes. Here, using ultra-short pulsed laser ablation, we fabricated from electron irradiated bulk 4H-SiC, 40-50 nm diameter SiC nanoparticles, fluorescent at 850-950 nm. This photoluminescence is attributed to the silicon vacancy color centers. We demonstrate that the original silicon vacancy color centers from the target sample were retained in the final nanoparticles solution, exhibiting excellent colloidal stability in water over several months. Our work is relevant for quantum nanophotonics, magnetic sensing, and biomedical imaging applications. PMID- 28362754 TI - Optically switchable directional invisibility. AB - It is shown that a scatterer can be designed to be directionally invisible for an incident field composed of a given sum of plane waves. These scatterers are invisible only when all plane waves are present with the given amplitudes and directions of incidence, which suggests a new type of "switchable" invisibility. Such objects could find application in optical devices such as couplers, switches, and optical position sensors. It is also demonstrated that the designed scatterers have balanced gain-loss profiles that are more general than most PT symmetric objects considered so far. PMID- 28362755 TI - High-speed optical sensor interrogator with a silicon-ring-resonator-based thermally tunable filter. AB - On-chip optical interrogators employing a silicon-ring-resonator-based thermally tunable filter (SRRTF) offer a promising solution for realizing portable, compact optical sensing systems. However, the slow interrogation speed of conventional SRRTF-based interrogators (less than a few Hz) hinders real-time sensing of dynamic parameters. In this Letter, we report a 100 kHz of high-speed optical interrogation system based on the SRRTF. The speed enhancement is achieved by using the nonlinear transient response of the SRRTF to a square-wave input voltage. The entire spectral range of the SRRTF is scanned twice during its thermal response cycle. The time-domain sensor output signal, which is obtained by scanning the SRRTF over the sensor spectrum, is converted into spectrum domain based on the experimentally characterized, time-dependent resonance wavelength shifts of the SRRTF. With this system, we demonstrate high-speed interrogation of a fiber Bragg grating sensor under dynamic temperature change (200 Hz). PMID- 28362756 TI - Single-mode unidirectional-emission circular-side hexagonal resonator microlasers. AB - Circular-side hexagonal resonator (CSHR) microlasers connecting an output waveguide are proposed and demonstrated for enhancing the mode Q factor and realizing single-mode operation. Three-dimensional simulation results indicate that the CSHRs with an optimized deformation can greatly enhance mode Q factors. The CSHR microlasers with output waveguides are fabricated using a planar technology process. For a CSHR microlaser with a side length of 7.5 MUm and an output waveguide width of 2 MUm, single-mode operation is realized with a side mode suppression ratio of 43 dB and a threshold current of 2.5 mA. Furthermore, flat small-signal modulation responses are obtained with a 3 dB bandwidth of 13 GHz. PMID- 28362758 TI - Electro-holographic display using a ZBLAN glass as the image space. AB - An Er3+-doped ZBLAN glass is used to display a 360 degrees viewable reconstructed image from a hologram on a DMD. The reconstructed image, when the hologram is illuminated by a 852 nm wavelength laser beam, is situated at the inside of the glass, and then a 1530 nm wavelength laser beam is crossed through the image to light it with an upconversion green light, which is viewable at all surrounding directions. This enables us to eliminate the limitation of the viewing zone angle imposed by the finite size of pixels in electro-holographic displays based on digital display chips/panels. The amount of the green light is much higher than that known previously. This is partly caused by the upconversion luminescence induced by 852 and 1530 nm laser beams. PMID- 28362757 TI - Chip-based Brillouin radio frequency photonic phase shifter and wideband time delay. AB - We report a chip-based true-time-delay unit based on stimulated Brillouin scattering that uses an on-off Brillouin gain of 52 dB to enable 4 ns delay over a bandwidth of 100 MHz and a phase shift of ~200 degrees . To verify these operations, we use a two-tap microwave filter configuration and observed changes in the free spectral range of the filter and shift in the spectrum of the filter. The realization of these functionalities on chip-scale devices is critical for phased-array antennas, multibeam satellites, delay lines, arbitrary waveform generation, and reconfigurable microwave photonic filters. PMID- 28362759 TI - Optically driven full-angle sample rotation for tomographic imaging in digital holographic microscopy. AB - This study presents a novel tomographic imaging technique for living biomedical samples using an optically driven full-angle rotation scheme based on digital holographic microscopy, in which the three-dimensional refractive index distribution inside the sample can be measured and analyzed. To accomplish the full-angle sample rotation, two optical traps are driven by highly focused spots on the top and bottom of the sample. The rim image of the sample outside the focal depth at the different rotation angles and propagation distances can be corrected and compensated, respectively, via numerical focusing; therefore, tomographic imaging of the sample can be conducted. The proposed approach shows that an entire symmetric spectrum can be acquired for tomographic reconstruction without the missing apple core problem as in traditional sample-rotation schemes. The three-dimensional refractive index of living yeast in a fluid medium is measured and verified. PMID- 28362760 TI - Direct mapping and characterization of dry etch damage-induced PN junction for long-wavelength HgCdTe infrared detector arrays. AB - Mercury cadmium telluride is the standard material to fabricate high-performance infrared focal plane array (FPA) detectors. However, etch-induced damage is a serious obstacle for realizing highly uniform and damage-free FPA detectors. In this Letter, the high signal-to-noise ratio and high spatial resolution scanning photocurrent microscopy (SPCM) is used to characterize the dry etch-induced inversion layer of vacancy-doped p-type Hg1-xCdxTe (x=0.22) material under different etching temperatures. It is found that the peak-to-peak magnitude of the SPCM profile decreases with a decrease in etching temperature, showing direct proof of controlling dry etch-induced type conversion. Our work paves the way toward seeking optimal etching processes in large-scale infrared FPAs. PMID- 28362761 TI - General analytic expression and numerical approach for the Kerr nonlinear coefficient of optical waveguides. AB - The Kerr nonlinear coefficient gamma is a key parameter that quantifies the nonlinear strength of an optical waveguide. For lossy waveguides such as plasmonic waveguides, the literature is confusing because various expressions derived by different groups have generally not been validated, and the conditions when they apply are not explicitly specified. Here we derive a rigorous and full vectorial model, leading to both a general analytic expression and a general numerical approach for finding gamma, as well as to their underlying relationship. Our results, exemplified by lossless and lossy waveguides, are consistent not only with each other, but also with the results in literature under appropriate limiting conditions. This work provides a benchmarked framework to understand and engineer nonlinear nanophotonic devices. PMID- 28362762 TI - Phase-noise analysis of swept-source optical coherence tomography systems. AB - We propose a new model to characterize the phase noise in swept-source optical coherence tomography (SS-OCT). The new model explicitly incorporates scanning variability, timing jitter, and sample location in addition to intensity noise (shot noise). The model was analyzed and validated by using both Monte Carlo methods and experiments. We suggest that the proposed model can be used as a guideline for future SS-OCT experimental designs. PMID- 28362763 TI - Observation of whispering gallery modes through electron beam-induced deposition. AB - Surprisingly intense spectra of whispering gallery modes were observed in polymer microbeads after illumination with electrons in a scanning electron microscope and subsequent laser illumination and spectral analysis. It will be proposed that whispering gallery mode resonances became visible after local deposition of hydrocarbon material through electron beam-induced deposition. The illumination of deposited material with a near infrared laser generates a broad light spectrum, acting as a local "white light" source that couples, for favorable wavelengths, with the WGM sustained by the sphere. This facilitates a spectroscopic analysis of the WGM and provides the Q-factor and free spectral range for all investigated particles. The analysis by an integrated SEM and Raman micro-spectrometer offers a direct approach to the analysis of WGM resonators as they are, for instance, used in sensing. PMID- 28362764 TI - Optomechanical characterization of silicon nitride membrane arrays. AB - We report on the optical and mechanical characterization of arrays of parallel micromechanical membranes. Pairs of high-tensile stress, 100 nm thick silicon nitride membranes are assembled parallel to each other with separations ranging from 8.5 to 200 MUm. Their optical properties are accurately determined using transmission measurements under broadband and monochromatic illuminations, and the lowest vibrational mode frequencies and mechanical quality factors are determined interferometrically. The results and techniques demonstrated are promising for investigations of collective phenomena in optomechanical arrays. PMID- 28362765 TI - Paired leaky mode spatial light modulators with a 28 degrees total deflection angle. AB - In this Letter, we present a paired set of waveguide spatial light modulators (SLMs) capable of a maximum light deflection nearing 28 degrees for red. This deflection, which is several times larger than the angular sweep of current, state-of-the-art modulators, is made possible by the unilateral, near-collinear waveguide nature of the leaky mode interaction. The ability to double angular output in this way, which is either not possible or not practical in other SLMs, is possible in leaky mode devices, thanks to the absence of zero-order light and the lack of high-order outputs. This combined structure has angular deflection high enough to enable color holographic video monitors that do not require angular magnification. Furthermore, the low cost and high angular deflection of these devices may make it possible to make large arrays for flat-screen video holography. PMID- 28362766 TI - Selective suppression of high-order harmonics within phase-matched spectral regions. AB - Phase matching in high-harmonic generation leads to enhancement of multiple harmonics. It is sometimes desired to control the spectral structure within the phase-matched spectral region. We propose a scheme for selective suppression of high-order harmonics within the phase-matched spectral region while weakly influencing the other harmonics. The method is based on addition of phase mismatched segments within a phase-matched medium. We demonstrate the method numerically in two examples. First, we show that one phase-mismatched segment can significantly suppress harmonic orders 9, 15, and 21. Second, we show that two phase-mismatched segments can efficiently suppress circularly polarized harmonics with one helicity over the other when driven by a bi-circular field. The new method may be useful for various applications, including the generation of highly helical bright attosecond pulses. PMID- 28362767 TI - Highly sensitive fiber random-grating-based random laser sensor for ultrasound detection. AB - A novel highly sensitive ultrasound sensor based on a random fiber laser is proposed and demonstrated for the first time, to the best of our knowledge. The random fiber laser is constructed with the erbium-doped fiber gain. A fiber random grating provides random-distributed feedback for the random laser and acts as an ultrasound sensing head. The random laser can operate in a single-mode lasing scenario, which offers linear and pure temporal responses to the broadband ultrasonic acoustic emission from 20 kHz to 0.8 MHz. The multiple-interfering reflection spectrum of the random grating provides a large number of steep peak areas over a broad spectral range, which significantly enhances the sensitivity of the random laser sensor and makes it an ideal sensor in harsh environments with large temperature or strain variations. The proposed laser sensor offers signal-to-noise ratio improvement up to 20 dB and higher sensitivity compared with conventional piezoelectric acoustic sensors. PMID- 28362768 TI - Adopting higher-order similarity relations for improved estimation of optical properties from subdiffusive reflectance. AB - Estimation of optical properties from subdiffusive reflectance acquired at short source-detector separations is challenging due to the sensitivity to the underlying scattering phase function. In recent studies, a second-order similarity parameter gamma has been increasingly used alongside the absorption and reduced scattering coefficients to account for some of the phase function variability. By using Monte Carlo simulations, we show that the influence of the scattering phase function on the subdiffusive reflectance for the biologically relevant variations can be captured sufficiently well by considering gamma and a third-order similarity parameter delta. Utilizing this knowledge, we construct an inverse model that estimates the absorption and reduced scattering coefficients, gamma and delta, from spatially resolved reflectance. Nearly an order of magnitude smaller errors of the estimated optical properties are obtained in comparison to the inverse model that only composes gamma. PMID- 28362770 TI - Pupil segmentation adaptive optics for invivo mouse retinal fluorescence imaging. AB - Adaptive Optics (AO) for scanning laser ophthalmoscopy enables high-resolution retinal imaging that can be used for preclinical research of diseases causing vision loss. Pupil Segmentation (PS) is an approach to wavefront-sensorless AO that acquires images within subregions across the imaging pupil to measure the wavefront slopes at the corresponding locations of the beam. We present PS-AO as an approach to correct ocular aberrations in ~7 s, implemented to minimize respiratory motion from an anesthetized mouse. We demonstrated an improvement in resolution and an image intensity increase of ~25% across all results using PS-AO for in vivo fluorescence retinal imaging in mice using a MEMS-based segmented deformable mirror. PMID- 28362769 TI - Ultracompact x-ray dosimeter based on scintillators coupled to a nano-optical antenna. AB - We show that nano-optical antennas are capable of controlling the luminescence induced by the absorption of x rays into matter. The x-ray-excited luminescence from a tiny scintillation cluster coupled to a horn nano-optical antenna is highly directed and determined by the antenna's geometrical parameters. Directionality is sufficiently high to efficiently outcouple the x-ray-excited luminescence to a narrow single-mode optical fiber, thus enabling ultracompact fiber-integrated x-ray sensors. Our nano-optically driven approach offers the possibility of x-ray profiling and dosimetry in ultra-confined environments, opening up new avenues in the fields of x-ray imaging, as well as medical and industrial endoscopy. With this study, to the best of our knowledge, nano-optical antennas make a first key contribution to the development of x-ray sensing protocols and architectures. PMID- 28362771 TI - Rapid localized heating of graphene coating on a silicon mold by induction for precision molding of polymer optics. AB - In compression molding of polymer optical components with micro/nanoscale surface features, rapid heating of the mold surface is critical for the implementation of this technology for large-scale applications. In this Letter, a novel method of a localized rapid heating process is reported. This process is based on induction heating of a thin conductive coating deposited on a silicon mold. Since the graphene coating is very thin (~45 nm), a high heating rate of 10~20 degrees C/s can be achieved by employing a 1200 W 30 kHz electrical power unit. Under this condition, the graphene-coated surface and the polymer substrate can be heated above the polymer's glass transition temperature within 30 s and subsequently cooled down to room temperature within several tens of seconds after molding, resulting in an overall thermal cycle of about 3 min or shorter. The feasibility of this process was validated by fabrication of optical gratings, micropillar matrices, and microlens arrays on polymethylmethacrylate (PMMA) substrates with very high precision. The uniformity and surface geometries of the replicated optical elements are evaluated using an optical profilometer, a diffraction test setup, and a Shack-Hartmann wavefront sensor built with a molded PMMA microlens array. Compared with the conventional bulk heating molding process, this novel rapid localized induction heating process could improve replication efficiency with better geometrical fidelity. PMID- 28362772 TI - Split in phase singularities of an optical vortex by off-axis diffraction through a simple circular aperture. AB - Diffraction patterns of an optical vortex through several shaped apertures reveal its topological charge. In this Letter, we theoretically and experimentally show that diffraction of a Laguerre Gaussian beam through a circular aperture at an off-axis position can be used to determine the magnitude and sign of the topological charge. To our knowledge, this is the first time that a simple circular aperture has been used to detect orbital angular momentum of an incident optical vortex. PMID- 28362773 TI - Dual-channel recording based on the null reconstruction effect of orthogonal linear polarization holography. AB - We report on dual-channel recording within polarization holography written by orthogonal linear polarization waves. The null reconstruction effect (NRE) of linear polarization holography was experimentally achieved at a large cross-angle of pi/2 inside the polarization-sensitive media. Based on the NRE, two polarization encoded holograms were recorded in a dual-channel recording system with negligible inter-channel crosstalk. The two polarization multiplexed holograms could then be sequentially or simultaneously readout by shifting the polarization state of reference wave with the best signal-to-noise of 18:1 obtained within the experiment. PMID- 28362774 TI - 1 kW, 200 mJ picosecond thin-disk laser system. AB - We report on a laser system based on thin-disk technology and chirped pulse amplification, providing output pulse energies of 200 mJ at a 5 kHz repetition rate. The amplifier contains a ring-type cavity and two thin Yb:YAG disks, each pumped by diode laser systems providing up to 3.5 kW power at a 969 nm wavelength. The average output power of more than 1 kW is delivered in an excellent output beam characterized by M2=1.1. The output pulses are compressed to 1.1 ps at full power with a pair of dielectric gratings. PMID- 28362775 TI - Quasi-needle-like focus synthesized by optical coherence tomography. AB - It is known that lateral resolution and depth of focus (DOF) in an optical imaging system are coupled, and a compromise between them has to be made. In this Letter, we propose to resolve the trade-off between lateral resolution and the DOF by a synthetic effective point spread function in optical path length (OPL) domain. A quasi-needle-like focus is synthesized by optical coherence tomography. We demonstrate that the synthesized quasi-needle-like focus provides a four-fold extension of a conventional DOF, while maintaining a high lateral resolution of 2.5 MUm over a depth range of approximately 240 MUm. The focal range can be further extended with more optical path length coded beams for synthesis involved. PMID- 28362776 TI - Borrmann effect in photonic crystals. AB - We present the experimental observation of the optical Borrmann effect in 1D porous silica-based photonic crystals (PhC) composed of several hundreds of dielectric layers with different porosity. Two mechanisms of the effect are demonstrated, which involve the optical losses associated with light scattering and absorption in nanoporous layers. Absorption is introduced by a small amount of silicon in partially annealed porous silicon PhC. We show that the PhC transmittance increases substantially under the Bragg diffraction condition, which is a manifestation of the Borrmann effect. The observed effects along with their polarization sensitivity are confirmed by numerical calculations. PMID- 28362777 TI - Optical concatenation of a large number of beads with a single-beam optical tweezer. AB - Optical tweezers consist of the spatial confinement of microscopic dielectric particles by the action of forces produced by the change in momentum of the photons of a highly focused laser beam that are deviated by the particle. In experiments that use a single laser beam, it is common to capture not only one but a few particles in the optical trap. However, to our knowledge, the formation of a long chain of beads optically confined with a single laser beam has never been reported. In this work, up to 73 silica spheres immersed in water are seen concatenated along the propagation direction of a 976-nm wavelength Gaussian laser of 300 mW of power. This long chain of beads is obtained when the laser is focused through an oil-immersion DIN microscope objective with 100* magnification and a numerical aperture of 1.25. When performing the same experiment using an infinity-corrected UplanFLN 100* objective with a numerical aperture of 1.3, the maximum number of concatenated beads is only 14. Our results suggest that the mechanisms responsible for the observed phenomena involve successive refocusing of the laser beam by each trapped sphere, optically induced dipole coupling (commonly referred to as optical binding), and aberrations generated by the DIN microscope objective. PMID- 28362778 TI - Ultra-wideband microwave photonic filter with a high Q-factor using a semiconductor optical amplifier. AB - An ultra-wideband microwave photonic filter (MPF) with a high quality (Q)-factor based on the birefringence effects in a semiconductor optical amplifier (SOA) is presented, and the theoretical fundamentals of the design are explained. The proposed MPF along orthogonal polarization in an active loop operates at up to a Ku-band and provides a tunable free spectral range from 15.44 to 19.44 GHz by controlling the SOA injection current. A prototype of the equivalent second-order infinite impulse response filter with a Q-factor over 6300 and a rejection ration exceeding 41 dB is experimentally demonstrated. PMID- 28362779 TI - Fluorescence intensity ratio thermometer methodology of eliminating the "decoupling" effect of a pair of thermally coupled energy levels of rare-earth ions. AB - By separating the thermal and nonradiative relaxation population, the fluorescence intensity ratio (FIR) of a pair of thermally coupled energy levels of rare-earth ion is reformulated. For a pair of thermally coupled levels, if the ratio of the thermal population in the upper level to the total population of the lower level abides by the Boltzmann distribution law, the general FIR would be modulated by the proportion of the total population to the thermal population in the upper level. By defining the reciprocal of the proportion as the thermal population degree (eta), the product etaFIR will follow the pure Boltzmann distribution law. Considering the fluorescent transient process, the eta values may be obtained from the weights of the fluorescent dynamic components of the upper level. A method to calculate this eta factor is presented. PMID- 28362780 TI - Femtosecond pulse generation from a Ti3+:sapphire laser near 800 nm with voltage reconfigurable graphene saturable absorbers. AB - We experimentally show that a voltage-controlled graphene-gold supercapacitor saturable absorber (VCG-gold-SA) can be operated as a fast saturable absorber with adjustable linear absorption at wavelengths as low as 795 nm. This was made possible by the use of a novel supercapacitor architecture, consisting of a high dielectric electrolyte sandwiched between a graphene and a gold electrode. The high-dielectric electrolyte allowed continuous, reversible adjustment of the Fermi level and, hence, the optical loss of the VCG-gold-SA up to the visible wavelengths at low bias voltages of the order of a few volts (0-2 V). The fast saturable absorber action of the VCG-gold-SA and the bias-dependent reduction of its loss were successfully demonstrated inside a femtosecond Ti3+:sapphire laser operating near 800 nm. Dispersion compensation was employed by using dispersion control mirrors and a prism pair. At a bias voltage of 1.2 V, the laser operated with improved power performance in comparison with that at zero bias, and the VCG-gold-SA initiated the generation of nearly transform-limited pulses as short as 48 fs at a pulse repetition rate of 131.7 MHz near 830 nm. To the best of our knowledge, this represents the shortest wavelength where a VCG-gold-SA has been employed as a mode locker with adjustable loss. PMID- 28362781 TI - F/Yb-codoped sol-gel silica glasses: toward tailoring the refractive index for the achievement of high-power fiber lasers. AB - Accurate control of both the doping distribution inside the fiber core and the low refractive index contrast between the fiber core and cladding materials is essential for the development of high-power fiber lasers based on the use of single-mode large-mode-area (LMA) optical fibers. Herein, sol-gel monolithic F/Yb3+-codoped silica glasses were prepared from porous large silica xerogels doped with ytterbium salt solution, which had been subjected to fluorination with hexafluoroethane gas, before subsequent sintering. The fluorine content inside the doped glass has been varied by adjusting the fluorination duration. The space homogeneity of fluorine and ytterbium concentrations in the cylindrical preforms has been checked by chemical analysis and Raman spectroscopy. Moreover, the glass with the lowest fluorine content has been successfully integrated as a core material in a microstructured optical fiber made using the stack-and-draw method. This fiber was tested in an all-fiber cavity laser architecture to evaluate potential lasing performances of the F/Yb3+-codoped silica glass. It presents a maximum efficiency of 70.4%, achieved at 1031 nm from a 1.16 m length fiber. These results confirm the potentialities of the obtained F/Yb3+-codoped glasses for the fabrication of LMA optical fiber lasers. PMID- 28362782 TI - Self-gauged fiber-optic micro-heater with an operation temperature above 1000 degrees C. AB - We report a fiber-optic micro-heater based on a miniature crystalline silicon Fabry-Perot interferometer (FPI) fusion spliced to the endface of a single-mode fiber. The silicon FPI, having a diameter of 100 MUm and a length of 10 or 200 MUm, is heated by a 980 nm laser diode guided through the lead-in fiber, leading to a localized hot spot with a temperature that can be conveniently tuned from the ambient temperature to >1000 degrees C in air. In the meantime, using a white light system operating in the 1550 nm wavelength window where the silicon is transparent, the silicon FPI itself also serves as a thermometer with high resolution and high speed for convenient monitoring and precise control of the heater temperature. Due to its small size, high temperature capability, and easy operation, the micro-heater is attractive for applications in a variety of fields, such as biology, microfluidics system, mechanical engineering, and high temperature optical sensing. As an example, the application of this micro-heater as a micro-boiler and micro-bubble generator has been demonstrated. PMID- 28362783 TI - Asymptotically stable compensation of the soliton self-frequency shift. AB - We report on the stable cancellation of the soliton self-frequency shift (SSFS) in nonlinear optical fibers. A soliton, which scatters a group velocity matched pump wave in a so-called optical event horizon regime, may experience a blueshift in frequency, which counteracts the SSFS induced by Raman scattering. The SSFS can easily be compensated by a suitably prepared pump wave, but usually the compensation is unstable and is destroyed after a certain propagation length. We study this kind of soliton-pump wave interaction by an adiabatic approach and quantify the parameter range in which the stable SSFS compensation is possible. The theory enjoys agreement with numerical simulations of soliton propagation. PMID- 28362784 TI - Pseudo actinometry for the measurement of reactive species density. AB - To compensate for the effect of plasma parameters in the signal of optical emission spectroscopy, we should normalize the emission intensity from the species against that of an inert gas (i.e., the actinometer). In many plasma processes in the semiconductor industry, plasma etching without using a neutral gas for the actinometer has become popular to achieve better critical dimension uniformity. We propose "pseudo actinometry" for normalization in the absence of an inert gas in the process plasma. Based on the theory of optical actinometry, we define a correction factor as the ratio of the emission intensity to the number density of the inert gas. As we reduced the density of the inert gas, we experimentally determined the correction factor by taking its convergence when the concentration of the inert gas was zero. As proof of concept, we applied pseudo actinometry to measure the density distribution of atomic chlorine in a photomask etching process without an inert gas. By comparing the distributions of chlorine radicals and the etch rate as measured by an ellipsometer, we calculated the correlation coefficient between the distributions. The correlation coefficient rapidly decreased to 0.60 when we used the correction factor determined at a flow rate for the inert gas of 20 standard cubic centimeters per minute at STP. By using pseudo actinometry, we successfully determined the distribution of chlorine radicals with a correlation coefficient of 0.98 in a plasma etching process without an inert gas. PMID- 28362785 TI - Step-scan differential Fourier transform infrared photoacoustic spectroscopy (DFTIR-PAS): a spectral deconvolution method for weak absorber detection in the presence of strongly overlapping background absorptions. AB - The determination of small absorption coefficients of trace gases in the atmosphere constitutes a challenge for analytical air contaminant measurements, especially in the presence of strongly absorbing backgrounds. A step-scan differential Fourier transform infrared photoacoustic spectroscopy (DFTIR-PAS) method was developed to suppress the coherent external noise and spurious photoacoustic (PA) signals caused by strongly absorbing backgrounds. The infrared absorption spectra of acetylene (C2H2) and local air were used to verify the performance of the step-scan DFTIR-PAS method. A linear amplitude response to C2H2 concentrations from 100 to 5000 ppmv was observed, leading to a theoretical detection limit of 5 ppmv. The differential mode was capable of eliminating the coherent noise and dominant background gas signals, thereby revealing the presence of the otherwise hidden C2H2 weak absorption. Thus, the step-scan DFTIR-PAS modality was demonstrated to be an effective approach for monitoring weakly absorbing gases with absorption bands overlapped by strongly absorbing background species. PMID- 28362786 TI - Dark-field Brillouin microscopy. AB - Brillouin microscopy is a non-contact and label-free technique for mapping fundamental micro-mechanical properties in the volume of biological systems. Specular reflections and elastic scattering easily overwhelm the weak Brillouin spectra due to the limited extinction of virtually imaged phased array spectrometers, thereby affecting the image acquisition. In this Letter, a dark field method was demonstrated to reject the elastic background light using an annular illumination and a confocal detection. To validate the method, images of polystyrene and liquid samples were obtained using both a confocal and the dark field system. An extinction ratio of 30 dB was readily achieved. PMID- 28362787 TI - Dynamics of an optically bound structure made of particles of unequal sizes. AB - This theoretical study based on the coupled dipoles model focuses on the dynamics of two optically bound dielectric spheres of unequal sizes confined in counter propagating incoherent Bessel beams. We analyzed the relative motion of the particles with respect to each other and defined conditions where they form a stable optically bound structure (OBS). We also investigated the motion of the center of mass of the OBS and found that its direction depends on the particle separation in the structure. Besides the optical interaction between objects, we also considered a hydrodynamic coupling in order to obtain more precise results for moving an OBS. PMID- 28362788 TI - Creation of a longitudinally polarized photonic nanojet via an engineered microsphere. AB - Dielectric microspheres exhibit the ability to focus an incident beam to a subwavelength spot with strong localized field intensity. In this Letter, a high beam quality of a longitudinally polarized electromagnetic component is created by decorating the surface of the microsphere with engineered structures. By changing the design of the engineered microspheres, the relative contribution of the longitudinal and radial components of a radially polarized incident beam to the photonic nanojet can be modified efficiently, leading to a sharp spot size which exceeds the optical diffraction limit. More importantly, a high conversion efficiency of 0.89 is achieved. At a wavelength of 633 nm, a focal spot of 266 nm (0.42lambda) is achieved numerically by illuminating the engineered microsphere with a focusing beam at a numerical aperture of 0.7. PMID- 28362789 TI - Digital micromirror device-based common-path quantitative phase imaging. AB - We propose a novel common-path quantitative phase imaging (QPI) method based on a digital micromirror device (DMD). The DMD is placed in a plane conjugate to the objective back-aperture plane for the purpose of generating two plane waves that illuminate the sample. A pinhole is used in the detection arm to filter one of the beams after sample to create a reference beam. Additionally, a transmission type liquid crystal device, placed at the objective back-aperture plane, eliminates the specular reflection noise arising from all the "off" state DMD micromirrors, which is common in all DMD-based illuminations. We have demonstrated high sensitivity QPI, which has a measured spatial and temporal noise of 4.92 nm and 2.16 nm, respectively. Experiments with calibrated polystyrene beads illustrate the desired phase measurement accuracy. In addition, we have measured the dynamic height maps of red blood cell membrane fluctuations, showing the efficacy of the proposed system for live cell imaging. Most importantly, the DMD grants the system convenience in varying the interference fringe period on the camera to easily satisfy the pixel sampling conditions. This feature also alleviates the pinhole alignment complexity. We envision that the proposed DMD-based common-path QPI system will allow for system miniaturization and automation for a broader adaption. PMID- 28362790 TI - 2 MHz multi-wavelength pulsed laser for functional photoacoustic microscopy. AB - Fast functional photoacoustic microscopy requires multi-wavelength pulsed laser sources with high pulse repetition rates, short wavelength switching time, and sufficient pulse energies. Here, we report the development of a stimulated-Raman scattering-based multi-wavelength pulsed laser source for fast functional photoacoustic imaging. The new laser source is pumped with a 532 nm 1 MHz pulsed laser. The 532 nm laser beam is split into two: one pumps a 5 m optical fiber to excite a 558 nm wavelength via stimulated Raman scattering; the other goes through a 50 m optical fiber to delay the 532 nm pulse by 220 ns. The two beams are combined and coupled into an optical fiber for photoacoustic excitation. As a result, the new laser source can generate 2 million pulses per second, switch wavelengths in 220 ns, and provide hundreds of nanojoules pulse energy for each wavelength. Using this laser source, we demonstrate optical-resolution photoacoustic imaging of microvascular structures and oxygen saturation in the mouse ear. The ultrashort wavelength switching time enables oxygen saturation imaging of flowing red blood cells, which is valuable for high-resolution functional imaging. PMID- 28362791 TI - In vivo photoacoustic imaging of vasculature with a low-cost miniature light emitting diode excitation. AB - In this Letter, we present a photoacoustic imaging (PAI) system based on a low cost high-power miniature light emitting diode (LED) that is capable of in vivo mapping vasculature networks in biological tissue. Overdriving with 200 ns pulses and operating at a repetition rate of 40 kHz, a 1.2 W 405 nm LED with a radiation area of 1000 MUm*1000 MUm and a size of 3.5 mm*3.5 mm was used to excite photoacoustic signals in tissue. Phantoms including black stripes, lead, and hair were used to validate the system in which a volumetric PAI image was obtained by scanning the transducer and the light beam in a two-dimensional x-y plane over the object. In vivo imaging of the vasculature of a mouse ear shows that LED based PAI could have great potential for label-free biomedical imaging applications where the use of bulky and expensive pulsed lasers is impractical. PMID- 28362793 TI - Tilted fiber Bragg gratings in multicore optical fibers for optical sensing. AB - We have inscribed a tilted fiber Bragg grating (TFBG) in selected cores of a multicore optical fiber. The presence of the TFBG permits to couple light from the incident-guided mode to the cladding modes and to the neighbor cores, and this interaction can be used for optical sensing. We measured different magnitudes: strain, curvature magnitude and direction, and external refractive index. The curvature results show a linear dependence of the maximum crosstalk with the curvature magnitude with a sensitivity of 2.5 dB/m-1 as the curvature magnitude increases and at the same time a wavelength shift of 70 pm/m-1. Changes in the external refractive index gradually vanish the cladding modes resonances and the crosstalk between the different cores, obtaining a reduction of the 90% of the optical spectra integral area for refractive indexes between 1.398 and 1.474. PMID- 28362792 TI - Demonstration of a compressive-sensing Fourier-transform on-chip spectrometer. AB - We demonstrate compressive-sensing (CS) spectroscopy in a planar-waveguide Fourier-transform spectrometer (FTS) device. The spectrometer is implemented as an array of Mach-Zehnder interferometers (MZIs) integrated on a photonic chip. The signal from a set of MZIs is composed of an undersampled discrete Fourier interferogram, which we invert using l1-norm minimization to retrieve a sparse input spectrum. To implement this technique, we use a subwavelength engineered spatial heterodyne FTS on a chip composed of 32 independent MZIs. We demonstrate the retrieval of three sparse input signals by collecting data from restricted sets (8 and 14) of MZIs and applying common CS reconstruction techniques to this data. We show that this retrieval maintains the full resolution and bandwidth of the original device, despite a sampling factor as low as one-fourth of a conventional (non-compressive) design. PMID- 28362794 TI - Study of extra wide coherent optical combs generated by a QW-based integrated passively mode-locked ring laser. AB - We present an investigation of an InP quantum-well-based integrated extended cavity passively mode-locked laser which shows extra broad frequency comb generation. The ring laser was characterized in frequency and time domains for a range of the current levels injected in the semiconductor optical amplifier. The study showed an increase of the bandwidth to over 40 nm at the -20 dB level. The coherence between the longitudinal modes in the wide comb is demonstrated by the characterization of a spectrally filtered signal in time and RF domains. The relative time delay across the optical comb was measured. PMID- 28362795 TI - Linearly chirped tapered fiber-Bragg-grating-based Fabry-Perot cavity and its application in simultaneous strain and temperature measurement. AB - A novel concept of a Fabry-Perot (F-P) cavity composed of two linearly chirped fiber Bragg gratings written in a thermally fused fiber taper is presented. Both chirped gratings are written in counter-directional chirp configuration, where chirps resulting from the optical fiber taper profile and linearly increasing grating periods cancel each other out, forming a high-quality F-P resonator. A new strain-sensing mechanism is proposed in the presented structure, which is based on strain-induced detuning of the F-P resonator. Due to the different strain and temperature responses of the cavity, the resonator can be used for the simultaneous measurement of these physical quantities, or it can be used as a temperature-independent strain sensor. PMID- 28362796 TI - Robustness of meta-analyses in finding gene * environment interactions. AB - Meta-analyses that synthesize statistical evidence across studies have become important analytical tools for genetic studies. Inspired by the success of genome wide association studies of the genetic main effect, researchers are searching for gene * environment interactions. Confounders are routinely included in the genome-wide gene * environment interaction analysis as covariates; however, this does not control for any confounding effects on the results if covariate * environment interactions are present. We carried out simulation studies to evaluate the robustness to the covariate * environment confounder for meta regression and joint meta-analysis, which are two commonly used meta-analysis methods for testing the gene * environment interaction or the genetic main effect and interaction jointly. Here we show that meta-regression is robust to the covariate * environment confounder while joint meta-analysis is subject to the confounding effect with inflated type I error rates. Given vast sample sizes employed in genome-wide gene * environment interaction studies, non-significant covariate * environment interactions at the study level could substantially elevate the type I error rate at the consortium level. When covariate * environment confounders are present, type I errors can be controlled in joint meta-analysis by including the covariate * environment terms in the analysis at the study level. Alternatively, meta-regression can be applied, which is robust to potential covariate * environment confounders. PMID- 28362797 TI - Characterizing the spatial distribution of brown marmorated stink bug, Halyomorpha halys Stal (Hemiptera: Pentatomidae), populations in peach orchards. AB - Geospatial analyses were used to investigate the spatial distribution of populations of Halyomorpha halys, an important invasive agricultural pest in mid Atlantic peach orchards. This spatial analysis will improve efficiency by allowing growers and farm managers to predict insect arrangement and target management strategies. Data on the presence of H. halys were collected from five peach orchards at four farms in New Jersey from 2012-2014 located in different land-use contexts. A point pattern analysis, using Ripley's K function, was used to describe clustering of H. halys. In addition, the clustering of damage indicative of H. halys feeding was described. With low populations early in the growing season, H. halys did not exhibit signs of clustering in the orchards at most distances. At sites with low populations throughout the season, clustering was not apparent. However, later in the season, high infestation levels led to more evident clustering of H. halys. Damage, although present throughout the entire orchard, was found at low levels. When looking at trees with greater than 10% fruit damage, damage was shown to cluster in orchards. The Moran's I statistic showed that spatial autocorrelation of H. halys was present within the orchards on the August sample dates, in relation to both populations density and levels of damage. Kriging the abundance of H. halys and the severity of damage to peaches revealed that the estimations of these are generally found in the same region of the orchards. This information on the clustering of H. halys populations will be useful to help predict presence of insects for use in management or scouting programs. PMID- 28362798 TI - Interrogating the topological robustness of gene regulatory circuits by randomization. AB - One of the most important roles of cells is performing their cellular tasks properly for survival. Cells usually achieve robust functionality, for example, cell-fate decision-making and signal transduction, through multiple layers of regulation involving many genes. Despite the combinatorial complexity of gene regulation, its quantitative behavior has been typically studied on the basis of experimentally verified core gene regulatory circuitry, composed of a small set of important elements. It is still unclear how such a core circuit operates in the presence of many other regulatory molecules and in a crowded and noisy cellular environment. Here we report a new computational method, named random circuit perturbation (RACIPE), for interrogating the robust dynamical behavior of a gene regulatory circuit even without accurate measurements of circuit kinetic parameters. RACIPE generates an ensemble of random kinetic models corresponding to a fixed circuit topology, and utilizes statistical tools to identify generic properties of the circuit. By applying RACIPE to simple toggle-switch-like motifs, we observed that the stable states of all models converge to experimentally observed gene state clusters even when the parameters are strongly perturbed. RACIPE was further applied to a proposed 22-gene network of the Epithelial-to-Mesenchymal Transition (EMT), from which we identified four experimentally observed gene states, including the states that are associated with two different types of hybrid Epithelial/Mesenchymal phenotypes. Our results suggest that dynamics of a gene circuit is mainly determined by its topology, not by detailed circuit parameters. Our work provides a theoretical foundation for circuit-based systems biology modeling. We anticipate RACIPE to be a powerful tool to predict and decode circuit design principles in an unbiased manner, and to quantitatively evaluate the robustness and heterogeneity of gene expression. PMID- 28362799 TI - Organic cation transporter 1 (OCT1) is involved in pentamidine transport at the human and mouse blood-brain barrier (BBB). AB - Pentamidine is an effective trypanocidal drug used against stage 1 Human African Trypanosomiasis (HAT). At the blood-brain barrier (BBB), it accumulates inside the endothelial cells but has limited entry into the brain. This study examined transporters involved in pentamidine transport at the human and mouse BBB using hCMEC/D3 and bEnd.3 cell lines, respectively. Results revealed that both cell lines expressed the organic cation transporters (OCT1, OCT2 and OCT3), however, P gp was only expressed in hCMEC/D3 cells. Polarised expression of OCT1 was also observed. Functional assays found that ATP depletion significantly increased [3H]pentamidine accumulation in hCMEC/D3 cells (***p<0.001) but not in bEnd.3 cells. Incubation with unlabelled pentamidine significantly decreased accumulation in hCMEC/D3 and bEnd.3 cells after 120 minutes (***p<0.001). Treating both cell lines with haloperidol and amantadine also decreased [3H]pentamidine accumulation significantly (***p<0.001 and **p<0.01 respectively). However, prazosin treatment decreased [3H]pentamidine accumulation only in hCMEC/D3 cells (*p<0.05), and not bEnd.3 cells. Furthermore, the presence of OCTN, MATE, PMAT, ENT or CNT inhibitors/substrates had no significant effect on the accumulation of [3H]pentamidine in both cell lines. From the data, we conclude that pentamidine interacts with multiple transporters, is taken into brain endothelial cells by OCT1 transporter and is extruded into the blood by ATP dependent mechanisms. These interactions along with the predominant presence of OCT1 in the luminal membrane of the BBB contribute to the limited entry of pentamidine into the brain. This information is of key importance to the development of pentamidine based combination therapies which could be used to treat CNS stage HAT by improving CNS delivery, efficacy against trypanosomes and safety profile of pentamidine. PMID- 28362800 TI - An in vitro model of intestinal infection reveals a developmentally regulated transcriptome of Toxoplasma sporozoites and a NF-kappaB-like signature in infected host cells. AB - Toxoplasmosis is a zoonotic infection affecting approximately 30% of the world's human population. After sexual reproduction in the definitive feline host, Toxoplasma oocysts, each containing 8 sporozoites, are shed into the environment where they can go on to infect humans and other warm-blooded intermediate hosts. Here, we use an in vitro model to assess host transcriptomic changes that occur in the earliest stages of such infections. We show that infection of rat intestinal epithelial cells with mature sporozoites primarily results in higher expression of genes associated with Tumor Necrosis Factor alpha (TNFalpha) signaling via NF-kappaB. Furthermore, we find that, consistent with their biology, these mature, invaded sporozoites display a transcriptome intermediate between the previously reported day 10 oocysts and that of their tachyzoite counterparts. Thus, this study uncovers novel host and pathogen factors that may be critical for the establishment of a successful intracellular niche following sporozoite-initiated infection. PMID- 28362801 TI - Exposure to secondhand smoke and asthma severity among children in Connecticut. AB - OBJECTIVE: To determine whether secondhand smoke (SHS) exposure is associated with greater asthma severity in children with physician-diagnosed asthma living in CT, and to examine whether area of residence, race/ethnicity or poverty moderate the association. METHODS: A large childhood asthma database in CT (Easy Breathing) was linked by participant zip code to census data to classify participants by area of residence. Multinomial logistic regression models, adjusted for enrollment date, sex, age, race/ethnicity, area of residence, insurance type, family history of asthma, eczema, and exposure to dogs, cats, gas stove, rodents and cockroaches were used to examine the association between self reported exposure to SHS and clinician-determined asthma severity (mild, moderate, and severe persistent vs. intermittent asthma). RESULTS: Of the 30,163 children with asthma enrolled in Easy Breathing, between 6 months and 18 years old, living in 161 different towns in CT, exposure to SHS was associated with greater asthma severity (adjusted relative risk ratio (aRRR): 1.07 [1.00, 1.15] and aRRR: 1.11 [1.02, 1.22] for mild and moderate persistent asthma, respectively). The odds of Black and Puerto Rican/Hispanic children with asthma being exposed to SHS were twice that of Caucasian children. Though the odds of SHS exposure for publicly insured children with asthma were three times greater than the odds for privately insured children (OR: 3.02 [2.84,3,21]), SHS exposure was associated with persistent asthma only among privately insured children (adjusted odds ratio (aOR): 1.23 [1.11,1.37]). CONCLUSION: This is the first large-scale pragmatic study to demonstrate that children exposed to SHS in Connecticut have greater asthma severity, clinically determined using a systematic approach, and varies by insurance status. PMID- 28362803 TI - PCR artifact in testing for homologous recombination in genomic editing in zebrafish. AB - We report a PCR-induced artifact in testing for homologous recombination in zebrafish. We attempted to replace the lnx2a gene with a donor cassette, mediated by a TALEN induced double stranded cut. The donor construct was flanked with homology arms of about 1 kb at the 5' and 3' ends. Injected embryos (G0) were raised and outcrossed to wild type fish. A fraction of the progeny appeared to have undergone the desired homologous recombination, as tested by PCR using primer pairs extending from genomic DNA outside the homology region to a site within the donor cassette. However, Southern blots revealed that no recombination had taken place. We conclude that recombination happened during PCR in vitro between the donor integrated elsewhere in the genome and the lnx2a locus. We conclude that PCR alone may be insufficient to verify homologous recombination in genome editing experiments in zebrafish. PMID- 28362804 TI - Fishing for adaptive epistasis using mitonuclear interactions. PMID- 28362802 TI - Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases. AB - The term "motor neuron disease" encompasses a spectrum of disorders in which motor neurons are the primary pathological target. However, in both patients and animal models of these diseases, not all motor neurons are equally vulnerable, in that while some motor neurons are lost very early in disease, others remain comparatively intact, even at late stages. This creates a valuable system to investigate the factors that regulate motor neuron vulnerability. In this study, we aim to use this experimental paradigm to identify potential transcriptional modifiers. We have compared the transcriptome of motor neurons from healthy wild type mice, which are differentially vulnerable in the childhood motor neuron disease Spinal Muscular Atrophy (SMA), and have identified 910 transcriptional changes. We have compared this data set with published microarray data sets on other differentially vulnerable motor neurons. These neurons were differentially vulnerable in the adult onset motor neuron disease Amyotrophic Lateral Sclerosis (ALS), but the screen was performed on the equivalent population of neurons from neurologically normal human, rat and mouse. This cross species comparison has generated a refined list of differentially expressed genes, including CELF5, Col5a2, PGEMN1, SNCA, Stmn1 and HOXa5, alongside a further enrichment for synaptic and axonal transcripts. As an in vivo validation, we demonstrate that the manipulation of a significant number of these transcripts can modify the neurodegenerative phenotype observed in a Drosophila line carrying an ALS causing mutation. Finally, we demonstrate that vector-mediated expression of alpha synuclein (SNCA), a transcript decreased in selectively vulnerable motor neurons in all four screens, can extend life span, increase weight and decrease neuromuscular junction pathology in a mouse model of SMA. In summary, we have combined multiple data sets to identify transcripts, which are strong candidates for being phenotypic modifiers, and demonstrated SNCA is a modifier of pathology in motor neuron disease. PMID- 28362805 TI - Effects of contact structure on the transient evolution of HIV virulence. AB - Early in an epidemic, high densities of susceptible hosts select for relatively high parasite virulence; later in the epidemic, lower susceptible densities select for lower virulence. Thus over the course of a typical epidemic the average virulence of parasite strains increases initially, peaks partway through the epidemic, then declines again. However, precise quantitative outcomes, such as the peak virulence reached and its timing, may depend sensitively on epidemiological details. Fraser et al. proposed a model for the eco-evolutionary dynamics of HIV that incorporates the tradeoffs between transmission and virulence (mediated by set-point viral load, SPVL) and their heritability between hosts. Their model used implicit equations to capture the effects of partnership dynamics that are at the core of epidemics of sexually transmitted diseases. Our models combine HIV virulence tradeoffs with a range of contact models, explicitly modeling partnership formation and dissolution and allowing for individuals to transmit disease outside of partnerships. We assess summary statistics such as the peak virulence (corresponding to the maximum value of population mean log10 SPVL achieved throughout the epidemic) across models for a range of parameters applicable to the HIV epidemic in sub-Saharan Africa. Although virulence trajectories are broadly similar across models, the timing and magnitude of the virulence peak vary considerably. Previously developed implicit models predicted lower virulence and slower progression at the peak (a maximum of 3.5 log10 SPVL) compared both to more realistic models and to simple random-mixing models with no partnership structure at all (both with a maximum of ~ 4.7 log10 SPVL). In this range of models, the simplest random-mixing structure best approximates the most realistic model; this surprising outcome occurs because the dominance of extra pair contact in the realistic model swamps the effects of partnership structure. PMID- 28362807 TI - Role of keratin 24 in human epidermal keratinocytes. AB - Keratin 24 (K24) is a new kind of keratin genes, which encodes a novel keratin protein, K24 that bears high similarity to the type I keratins and displays a unique expression profile. However, the role of K24 is incompletely understood. In our study, we investigated the localization of K24 within the epidermis and possible functions. Keratin 24 was found to be modestly overexpressed in senescent keratinocytes and was mainly restricted to the upper stratum spinosum of epidermis. The protein was required for terminal differentiation upon CaCl2 induced differentiation. In vitro results showed that increased K24 in keratinocytes dramatically changed the differentiation of primary keratinocytes. It also inhibited cell survival by G1/S phase cell cycle arrest and induced senescence, autophagy and apoptosis of keratinocytes. In addition, K24 activated PKCdelta signal pathway involving in cellular survival. In summary, K24 may be suggested as a potential differentiation marker and anti-proliferative factor in the epidermis. PMID- 28362808 TI - Comparison of laser in situ ketatomileusis and photorefractive keratectomy for myopia using a mixed-effects model. AB - PURPOSE: To compare the results of laser in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) for myopia using a mixed-effects model. METHODS: This comparative retrospective study was conducted in 1,127 eyes of 579 patients after LASIK and 270 eyes of 144 patients after PRK who had two or more postoperative follow-ups after 3 months. Uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), manifest refractive spherical equivalent (MRSE), percentage of eyes within +/- 0.5 diopters (D) and +/- 1.0 D of targeted refraction, and central corneal thickness were compared between PRK and LASIK groups using a mixed-effects model. RESULTS: Compared with the LASIK group, UCVA in the PRK group was significantly worse in the initial year but was significantly better after 4 years. The average BSCVA was not significantly different between the LASIK and PRK groups after 4 years. The average gain of BSCVA in the PRK group was significantly larger than that of the LASIK group after 2 years. MRSE in the LASIK and PRK groups showed a gradual myopic shift until 6 years after surgery. After 6 years, MRSE in the PRK group remained stable whereas MRSE in the LASIK group continued a myopic shift. The percentages of eyes within +/- 0.5 D or +/- 1.0 D in the LASIK group were significantly higher than those in the PRK group at 3 months but were significantly lower than those in the PRK group at 10 years. CONCLUSIONS: PRK for myopia shows better efficacy than LASIK for myopia after 4 years. PMID- 28362809 TI - Antigen capsid-display on human adenovirus 35 via pIX fusion is a potent vaccine platform. AB - Durable protection against complex pathogens is likely to require immunity that comprises both humoral and cellular responses. While heterologous prime-boost regimens based on recombinant, replication-incompetent Adenoviral vectors (AdV) and adjuvanted protein have been able to induce high levels of concomitant humoral and cellular responses, complex manufacturing and handling in the field may limit their success. To combine the benefits of genetic and protein-based vaccination within one vaccine construct and to facilitate their use, we generated Human Adenovirus 35 (HAdV35) vectors genetically encoding a model antigen based on the Plasmodium falciparum (P. falciparum) circumsporozoite (CS) protein and displaying a truncated version of the same antigen (CSshort) via protein IX on the capsid, with or without a flexible glycine-linker and/or a 45A spacer. The four tested pIX-antigen display variants were efficiently incorporated and presented on the HAdV35 capsid irrespective of whether a transgene was encoded or not. Transgene-expression and producibility of the display-/expression vectors were not impeded by the pIX-display. In mice, the pIX modified vectors induced strong humoral antigen-specific immunity that increased with the inclusion of the linker-/spacer molecules, exceeded the responses induced by the genetic, transgene-expressing HAdV35 vector, and surpassed recombinant protein in potency. In addition, the pIX- display/expression vectors elicited high antigen-specific cellular immune responses that matched those of the genetic HAdV35 vector expressing CS. pIX-modified display-/expression HAdV vectors may therefore be a valuable technology for the development of vaccines against complex pathogens, especially in resource-limited settings. PMID- 28362806 TI - Evolved genetic and phenotypic differences due to mitochondrial-nuclear interactions. AB - The oxidative phosphorylation (OxPhos) pathway is responsible for most aerobic ATP production and is the only pathway with both nuclear and mitochondrial encoded proteins. The importance of the interactions between these two genomes has recently received more attention because of their potential evolutionary effects and how they may affect human health and disease. In many different organisms, healthy nuclear and mitochondrial genome hybrids between species or among distant populations within a species affect fitness and OxPhos functions. However, what is less understood is whether these interactions impact individuals within a single natural population. The significance of this impact depends on the strength of selection for mito-nuclear interactions. We examined whether mito nuclear interactions alter allele frequencies for ~11,000 nuclear SNPs within a single, natural Fundulus heteroclitus population containing two divergent mitochondrial haplotypes (mt-haplotypes). Between the two mt-haplotypes, there are significant nuclear allele frequency differences for 349 SNPs with a p-value of 1% (236 with 10% FDR). Unlike the rest of the genome, these 349 outlier SNPs form two groups associated with each mt-haplotype, with a minority of individuals having mixed ancestry. We use this mixed ancestry in combination with mt haplotype as a polygenic factor to explain a significant fraction of the individual OxPhos variation. These data suggest that mito-nuclear interactions affect cardiac OxPhos function. The 349 outlier SNPs occur in genes involved in regulating metabolic processes but are not directly associated with the 79 nuclear OxPhos proteins. Therefore, we postulate that the evolution of mito nuclear interactions affects OxPhos function by acting upstream of OxPhos. PMID- 28362811 TI - Phylogenetic reassessment of tribe Anemoneae (Ranunculaceae): Non-monophyly of Anemone s.l. revealed by plastid datasets. AB - Morphological and molecular evidence strongly supported the monophyly of tribe Anemoneae DC.; however, phylogenetic relationships among genera of this tribe have still not been fully resolved. In this study, we sampled 120 specimens representing 82 taxa of tribe Anemoneae. One nuclear ribosomal internal transcribed spacer (nrITS) and six plastid markers (atpB-rbcL, matK, psbA-trnQ, rpoB-trnC, rbcL and rps16) were amplified and sequenced. Both Maximum likelihood and Bayesian inference methods were used to reconstruct phylogenies for this tribe. Individual datasets supported all traditional genera as monophyletic, except Anemone and Clematis that were polyphyletic and paraphyletic, respectively, and revealed that the seven single-gene datasets can be split into two groups, i.e. nrITS + atpB-rbcL and the remaining five plastid markers. The combined nrITS + atpB-rbcL dataset recovered monophyly of subtribes Anemoninae (i.e. Anemone s.l.) and Clematidinae (including Anemoclema), respectively. However, the concatenated plastid dataset showed that one group of subtribes Anemoninae (Hepatica and Anemone spp. from subgenus Anemonidium) close to the clade Clematis s.l. + Anemoclema. Our results strongly supported a close relationship between Anemoclema and Clematis s.l., which included Archiclematis and Naravelia. Non-monophyly of Anemone s.l. using the plastid dataset indicates to revise as two genera, new Anemone s.l. (including Pulsatilla, Barneoudia, Oreithales and Knowltonia), Hepatica (corresponding to Anemone subgenus Anemonidium). PMID- 28362810 TI - A comparison of sampling methods for examining the laryngeal microbiome. AB - Shifts in healthy human microbial communities have now been linked to disease in numerous body sites. Noninvasive swabbing remains the sampling technique of choice in most locations; however, it is not well known if this method samples the entire community, or only those members that are easily removed from the surface. We sought to compare the communities found via swabbing and biopsied tissue in true vocal folds, a location that is difficult to sample without causing potential damage and impairment to tissue function. A secondary aim of this study was to determine if swab sampling of the false vocal folds could be used as proxy for true vocal folds. True and false vocal fold mucosal samples (swabbed and biopsied) were collected from six pigs and used for 454 pyrosequencing of the V3-V5 region of the 16S rRNA gene. Most of the alpha and beta measures of diversity were found to be significantly similar between swabbed and biopsied tissue samples. Similarly, the communities found in true and false vocal folds did not differ considerably. These results suggest that samples taken via swabs are sufficient to assess the community, and that samples taken from the false vocal folds may be used as proxies for the true vocal folds. Assessment of these techniques opens an avenue to less traumatic means to explore the role microbes play in the development of diseases of the vocal folds, and perhaps the rest of the respiratory tract. PMID- 28362812 TI - Extensive telomere erosion is consistent with localised clonal expansions in Barrett's metaplasia. AB - Barrett's oesophagus is a premalignant metaplastic condition that predisposes patients to the development of oesophageal adenocarcinoma. However, only a minor fraction of Barrett's oesophagus patients progress to adenocarcinoma and it is thus essential to determine bio-molecular markers that can predict the progression of this condition. Telomere dysfunction is considered to drive clonal evolution in several tumour types and telomere length analysis provides clinically relevant prognostic and predictive information. The aim of this work was to use high-resolution telomere analysis to examine telomere dynamics in Barrett's oesophagus. Telomere length analysis of XpYp, 17p, 11q and 9p, chromosome arms that contain key cancer related genes that are known to be subjected to copy number changes in Barrett's metaplasia, revealed similar profiles at each chromosome end, indicating that no one specific telomere is likely to suffer preferential telomere erosion. Analysis of patient matched tissues (233 samples from 32 patients) sampled from normal squamous oesophagus, Z line, and 2 cm intervals within Barrett's metaplasia, plus oesophago-gastric junction, gastric body and antrum, revealed extensive telomere erosion in Barrett's metaplasia to within the length ranges at which telomere fusion is detected in other tumour types. Telomere erosion was not uniform, with distinct zones displaying more extensive erosion and more homogenous telomere length profiles. These data are consistent with an extensive proliferative history of cells within Barrett's metaplasia and are indicative of localised clonal growth. The extent of telomere erosion highlights the potential of telomere dysfunction to drive genome instability and clonal evolution in Barrett's metaplasia. PMID- 28362813 TI - A novel adjustable automated system for inducing chronic intermittent hypoxia in mice. AB - BACKGROUND: Sleep apnea is a chronic, widely underdiagnosed condition characterized by disruption of sleep architecture and intermittent hypoxia due to short cessations of breathing. It is a major independent risk factor for myocardial infarction, congestive heart failure and stroke as well as one of the rare modifiable risk factors for Alzheimer's Dementia. Reliable animal disease models are needed to understand the link between sleep apnea and the various clinically linked disorders. NEW METHOD: An automated system for inducing hypoxia was developed, in which the major improvement was the possibility to efficiently adjust the length and intensity of hypoxia in two different periods. The chamber used a small volume of gas allowing for fast exchanges of different oxygen levels. The mice were kept in their cages adapted with the system on the cage lid. As a proof of principle, they were exposed to a three week period of intermittent hypoxia for 8 hours a day, with 90 s intervals of 5, 7% and 21% oxygen to validate the model. Treated (n = 8) and control mice (no hypoxia, n = 7) were handled in the same manner and their hippocampal brain regions compared by histology. RESULTS: The chamber provided a fast, reliable and precise intermittent hypoxia, without inducing noticeable side effects to the animals. The validation experiment showed that apoptotic neurons in the hippocampus were more numerous in the mice exposed to intermittent hypoxia than in the control group, in all tested hippocampal regions (cornu ammonis 1 (CA1) P <0.001; cornu ammonis 3 (CA3) P <0.001; and dentate gyrus (DG) P = 0.023). In both, control and hypoxic conditions, there was a significantly higher number of apoptotic neurons in the DG compared to the CA1 and CA3 subfields (P <0.001). CONCLUSION: The new design of a hypoxic chamber provides a fast, adjustable and reliable model of obstructive sleep apnea, which was validated by apoptosis of hippocampal neurons. PMID- 28362814 TI - Atypical protein disulfide isomerases (PDI): Comparison of the molecular and catalytic properties of poplar PDI-A and PDI-M with PDI-L1A. AB - Protein disulfide isomerases are overwhelmingly multi-modular redox catalysts able to perform the formation, reduction or isomerisation of disulfide bonds. We present here the biochemical characterization of three different poplar PDI isoforms. PDI-A is characterized by a single catalytic Trx module, the so-called a domain, whereas PDI-L1a and PDI-M display an a-b-b'-a' and a degrees -a-b organisation respectively. Their activities have been tested in vitro using purified recombinant proteins and a series of model substrates as insulin, NADPH thioredoxin reductase, NADP malate dehydrogenase (NADP-MDH), peroxiredoxins or RNase A. We demonstrated that PDI-A exhibited none of the usually reported activities, although the cysteines of the WCKHC active site signature are able to form a disulfide with a redox midpoint potential of -170 mV at pH 7.0. The fact that it is able to bind a [Fe2S2] cluster upon Escherichia coli expression and anaerobic purification might indicate that it does not have a function in dithiol disulfide exchange reactions. The two other proteins were able to catalyze oxidation or reduction reactions, PDI-L1a being more efficient in most cases, except that it was unable to activate the non-physiological substrate NADP-MDH, in contrast to PDI-M. To further evaluate the contribution of the catalytic domains of PDI-M, the dicysteinic motifs have been independently mutated in each a domain. The results indicated that the two a domains seem interconnected and that the a degrees module preferentially catalyzed oxidation reactions whereas the a module catalyzed reduction reactions, in line with the respective redox potentials of -170 mV and -190 mV at pH 7.0. Overall, these in vitro results illustrate that the number and position of a and b domains influence the redox properties and substrate recognition (both electron donors and acceptors) of PDI which contributes to understand why this protein family expanded along evolution. PMID- 28362815 TI - Metabolic profiling of two maize (Zea mays L.) inbred lines inoculated with the nitrogen fixing plant-interacting bacteria Herbaspirillum seropedicae and Azospirillum brasilense. AB - Maize roots can be colonized by free-living atmospheric nitrogen (N2)-fixing bacteria (diazotrophs). However, the agronomic potential of non-symbiotic N2 fixation in such an economically important species as maize, has still not been fully exploited. A preliminary approach to improve our understanding of the mechanisms controlling the establishment of such N2-fixing associations has been developed, using two maize inbred lines exhibiting different physiological characteristics. The bacterial-plant interaction has been characterized by means of a metabolomic approach. Two established model strains of Nif+ diazotrophic bacteria, Herbaspirillum seropedicae and Azospirillum brasilense and their Nif- couterparts defficient in nitrogenase activity, were used to evaluate the impact of the bacterial inoculation and of N2 fixation on the root and leaf metabolic profiles. The two N2-fixing bacteria have been used to inoculate two genetically distant maize lines (FV252 and FV2), already characterized for their contrasting physiological properties. Using a well-controlled gnotobiotic experimental system that allows inoculation of maize plants with the two diazotrophs in a N-free medium, we demonstrated that both maize lines were efficiently colonized by the two bacterial species. We also showed that in the early stages of plant development, both bacterial strains were able to reduce acetylene, suggesting that they contain functional nitrogenase activity and are able to efficiently fix atmospheric N2 (Fix+). The metabolomic approach allowed the identification of metabolites in the two maize lines that were representative of the N2 fixing plant-bacterial interaction, these included mannitol and to a lesser extend trehalose and isocitrate. Whilst other metabolites such as asparagine, although only exhibiting a small increase in maize roots following bacterial infection, were specific for the two Fix+ bacterial strains, in comparison to their Fix- counterparts. Moreover, a number of metabolites exhibited a maize-genotype specific pattern of accumulation, suggesting that the highly diverse maize genetic resources could be further exploited in terms of beneficial plant bacterial interactions for optimizing maize growth, with reduced N fertilization inputs. PMID- 28362816 TI - Livestock-associated risk factors for pneumonia in an area of intensive animal farming in the Netherlands. AB - Previous research conducted in 2009 found a significant positive association between pneumonia in humans and living close to goat and poultry farms. However, as this result might have been affected by a large goat-related Q fever epidemic, the aim of the current study was to re-evaluate this association, now that the Q fever epidemic had ended. In 2014/15, 2,494 adults (aged 20-72 years) living in a livestock-dense area in the Netherlands participated in a medical examination and completed a questionnaire on respiratory health, lifestyle and other items. We retrieved additional information for 2,426/2,494 (97%) participants from electronic medical records (EMR) from general practitioners. The outcome was self reported, physician-diagnosed pneumonia or pneumonia recorded in the EMR in the previous three years. Livestock license data was used to determine exposure to livestock. We quantified associations between livestock exposures and pneumonia using odds ratios adjusted for participant characteristics and comorbidities (aOR). The three-year cumulative frequency of pneumonia was 186/2,426 (7.7%). Residents within 2,000m of a farm with at least 50 goats had an increased risk of pneumonia, which increased the closer they lived to the farm (2,000m aOR 1.9, 95% CI 1.4-2.6; 500m aOR 4.4, 95% CI 2.0-9.8). We found no significant associations between exposure to other farm animals and pneumonia. However, when conducting sensitivity analyses using pneumonia outcome based on EMR only, we found a weak but statistically significant association with presence of a poultry farm within 1,000m (aOR: 1.7, 95% CI 1.1-2.7). Living close to goat and poultry farms still constitute risk factors for pneumonia. Individuals with pneumonia were not more often seropositive for Coxiella burnetii, indicating that results are not explained by Q fever. We strongly recommend identification of pneumonia causes by the use of molecular diagnostics and investigating the role of non-infectious agents such as particulate matter or endotoxins. PMID- 28362817 TI - Cis-eQTL-based trans-ethnic meta-analysis reveals novel genes associated with breast cancer risk. AB - Breast cancer is the most common solid organ malignancy and the most frequent cause of cancer death among women worldwide. Previous research has yielded insights into its genetic etiology, but there remains a gap in the understanding of genetic factors that contribute to risk, and particularly in the biological mechanisms by which genetic variation modulates risk. The National Cancer Institute's "Up for a Challenge" (U4C) competition provided an opportunity to further elucidate the genetic basis of the disease. Our group leveraged the seven datasets made available by the U4C organizers and data from the publicly available UK Biobank cohort to examine associations between imputed gene expression and breast cancer risk. In particular, we used reference datasets describing the breast tissue and whole blood transcriptomes to impute expression levels in breast cancer cases and controls. In trans-ethnic meta-analyses of U4C and UK Biobank data, we found significant associations between breast cancer risk and the expression of RCCD1 (joint p-value: 3.6x10-06) and DHODH (p-value: 7.1x10 06) in breast tissue, as well as a suggestive association for ANKLE1 (p-value: 9.3x10-05). Expression of RCCD1 in whole blood was also suggestively associated with disease risk (p-value: 1.2x10-05), as were expression of ACAP1 (p-value: 1.9x10-05) and LRRC25 (p-value: 5.2x10-05). While genome-wide association studies (GWAS) have implicated RCCD1 and ANKLE1 in breast cancer risk, they have not identified the remaining three genes. Among the genetic variants that contributed to the predicted expression of the five genes, we found 23 nominally (p-value < 0.05) associated with breast cancer risk, among which 15 are not in high linkage disequilibrium with risk variants previously identified by GWAS. In summary, we used a transcriptome-based approach to investigate the genetic underpinnings of breast carcinogenesis. This approach provided an avenue for deciphering the functional relevance of genes and genetic variants involved in breast cancer. PMID- 28362819 TI - Hydrogen gas alleviates oxygen toxicity by reducing hydroxyl radical levels in PC12 cells. AB - Hyperbaric oxygen (HBO) therapy through breathing oxygen at the pressure of above 1 atmosphere absolute (ATA) is useful for varieties of clinical conditions, especially hypoxic-ischemic diseases. Because of generation of reactive oxygen species (ROS), breathing oxygen gas at high pressures can cause oxygen toxicity in the central nervous system, leading to multiple neurological dysfunction, which limits the use of HBO therapy. Studies have shown that Hydrogen gas (H2) can diminish oxidative stress and effectively reduce active ROS associated with diseases. However, the effect of H2 on ROS generated from HBO therapy remains unclear. In this study, we investigated the effect of H2 on ROS during HBO therapy using PC12 cells. PC12 cells cultured in medium were exposed to oxygen gas or mixed oxygen gas and H2 at 1 ATA or 5 ATA. Cells viability and oxidation products and ROS were determined. The data showed that H2 promoted the cell viability and inhibited the damage in the cell and mitochondria membrane, reduced the levels of lipid peroxidation and DNA oxidation, and selectively decreased the levels of *OH but not disturbing the levels of O2*-, H2O2, or NO* in PC12 cells during HBO therapy. These results indicated that H2 effectively reduced *OH, protected cells against oxygen toxicity resulting from HBO therapy, and had no effect on other ROS. Our data supported that H2 could be potentially used as an antioxidant during HBO therapy. PMID- 28362818 TI - VivaxGEN: An open access platform for comparative analysis of short tandem repeat genotyping data in Plasmodium vivax populations. AB - BACKGROUND: The control and elimination of Plasmodium vivax will require a better understanding of its transmission dynamics, through the application of genotyping and population genetics analyses. This paper describes VivaxGEN (http://vivaxgen.menzies.edu.au), a web-based platform that has been developed to support P. vivax short tandem repeat data sharing and comparative analyses. RESULTS: The VivaxGEN platform provides a repository for raw data generated by capillary electrophoresis (FSA files), with fragment analysis and standardized allele calling tools. The query system of the platform enables users to filter, select and differentiate samples and alleles based on their specified criteria. Key population genetic analyses are supported including measures of population differentiation (FST), expected heterozygosity (HE), linkage disequilibrium (IAS), neighbor-joining analysis and Principal Coordinate Analysis. Datasets can also be formatted and exported for application in commonly used population genetic software including GENEPOP, Arlequin and STRUCTURE. To date, data from 10 countries, including 5 publicly available data sets have been shared with VivaxGEN. CONCLUSIONS: VivaxGEN is well placed to facilitate regional overviews of P. vivax transmission dynamics in different endemic settings and capable to be adapted for similar genetic studies of P. falciparum and other organisms. PMID- 28362821 TI - Does gamification increase engagement with online programs? A systematic review. AB - BACKGROUND: Engagement in online programs is difficult to maintain. Gamification is the recent trend that offers to increase engagement through the inclusion of game-like features like points and badges, in non-game contexts. This review will answer the following question, 'Are gamification strategies effective in increasing engagement in online programs?' METHOD: Eight databases (Web of Science, PsycINFO, Medline, INSPEC, ERIC, Cochrane Library, Business Source Complete and ACM Digital Library) were searched from 2010 to the 28th of October 2015 using a comprehensive search strategy. Eligibility criteria was based on the PICOS format, where "population" included adults, "intervention" involved an online program or smart phone application that included at least one gamification feature. "Comparator" was a control group, "outcomes" included engagement and "downstream" outcomes which occurred as a result of engagement; and "study design" included experimental studies from peer-reviewed sources. Effect sizes (Cohens d and 95% confidence intervals) were also calculated. RESULTS: 1017 studies were identified from database searches following the removal of duplicates, of which 15 met the inclusion criteria. The studies involved a total of 10,499 participants, and were commonly undertaken in tertiary education contexts. Engagement metrics included time spent (n = 5), volume of contributions (n = 11) and occasions visited to the software (n = 4); as well as downstream behaviours such as performance (n = 4) and healthy behaviours (n = 1). Effect sizes typically ranged from medium to large in direct engagement and downstream behaviours, with 12 out of 15 studies finding positive significant effects in favour of gamification. CONCLUSION: Gamification is effective in increasing engagement in online programs. Key recommendations for future research into gamification are provided. In particular, rigorous study designs are required to fully examine gamification's effects and determine how to best achieve sustained engagement. PMID- 28362820 TI - A large-scale stochastic spatiotemporal model for Aedes albopictus-borne chikungunya epidemiology. AB - Chikungunya is a viral disease transmitted to humans primarily via the bites of infected Aedes mosquitoes. The virus caused a major epidemic in the Indian Ocean in 2004, affecting millions of inhabitants, while cases have also been observed in Europe since 2007. We developed a stochastic spatiotemporal model of Aedes albopictus-borne chikungunya transmission based on our recently developed environmentally-driven vector population dynamics model. We designed an integrated modelling framework incorporating large-scale gridded climate datasets to investigate disease outbreaks on Reunion Island and in Italy. We performed Bayesian parameter inference on the surveillance data, and investigated the validity and applicability of the underlying biological assumptions. The model successfully represents the outbreak and measures of containment in Italy, suggesting wider applicability in Europe. In its current configuration, the model implies two different viral strains, thus two different outbreaks, for the two stage Reunion Island epidemic. Characterisation of the posterior distributions indicates a possible relationship between the second larger outbreak on Reunion Island and the Italian outbreak. The model suggests that vector control measures, with different modes of operation, are most effective when applied in combination: adult vector intervention has a high impact but is short-lived, larval intervention has a low impact but is long-lasting, and quarantining infected territories, if applied strictly, is effective in preventing large epidemics. We present a novel approach in analysing chikungunya outbreaks globally using a single environmentally-driven mathematical model. Our study represents a significant step towards developing a globally applicable Ae. albopictus-borne chikungunya transmission model, and introduces a guideline for extending such models to other vector-borne diseases. PMID- 28362823 TI - News exposure predicts anti-Muslim prejudice. AB - News coverage of Islamic extremism is reigniting debates about the media's role in promoting prejudice toward Muslims. Psychological theories of media-induced prejudice date to the 1950's, and find support from controlled experiments. However, national-scale studies of media effects on Muslim prejudice are lacking. Orthogonal research investigating media-induced prejudice toward immigrants has failed to establish any link. Moreover, it has been found that people interpret the news in ways that confirm pre-existing attitudes, suggesting that media induced Muslim prejudice in liberal democracies is unlikely. Here, we test the association between news exposure and anti-Muslim prejudice in a diverse national sample from one of the world's most tolerant societies, where media effects are least likely to hold (N = 16,584, New Zealand). In support of media-induced Islamophobia, results show that greater news exposure is associated with both increased anger and reduced warmth toward Muslims. Additionally, the relationship between media exposure and anti-Muslim prejudice does not reliably vary with political ideology, supporting claims that it is widespread representations of Muslims in the news, rather than partisan media biases, that drives anti-Muslim prejudice. PMID- 28362822 TI - Fasciola hepatica reinfection potentiates a mixed Th1/Th2/Th17/Treg response and correlates with the clinical phenotypes of anemia. AB - BACKGROUND: Fascioliasis is a severe zoonotic disease of worldwide extension caused by liver flukes. In human fascioliasis hyperendemic areas, reinfection and chronicity are the norm and anemia is the main sign. Herein, the profile of the Th1/Th2/Th17/Treg expression levels is analyzed after reinfection, correlating them with their corresponding hematological biomarkers of morbidity. METHODOLOGY/PRINCIPAL FINDINGS: The experimental design reproduces the usual reinfection/chronicity conditions in human fascioliasis endemic areas and included Fasciola hepatica primo-infected Wistar rats (PI) and rats reinfected at 8 weeks (R8), and at 12 weeks (R12), and negative control rats. In a cross sectional study, the expression of the genes associated with Th1 (Ifng, Il12a, Il12b, Nos2), Th2 (Il4, Arg1), Treg (Foxp3, Il10, Tgfb, Ebi3), and Th17 (Il17) in the spleen and thymus was analyzed. After 20 weeks of primary infection, PI did not present significant changes in the expression of those genes when compared to non-infected rats (NI), but an increase of Il4, Arg1 and Ifng mRNA in the spleen was observed in R12, suggesting the existence of an active mixed Th1/Th2 systemic immune response in reinfection. Foxp3, Il10, Tgfb and Ebi3 levels increased in the spleen in R12 when compared to NI and PI, indicating that the Treg gene expression levels are potentiated in chronic phase reinfection. Il17 gene expression levels in R12 in the spleen increased when compared to NI, PI and R8. Gene expression levels of Il10 in the thymus increased when compared to NI and PI in R12. Ifng expression levels in the thymus increased in all reinfected rats, but not in PI. The clinical phenotype was determined by the fluke burden, the rat body weight and the hemogram. Multivariate mathematical models were built to describe the Th1/Th2/Th17/Treg expression levels and the clinical phenotype. In reinfection, two phenotypic patterns were detected: i) one which includes only increased splenic Ifng expression levels but no Treg expression, correlating with severe anemia; ii) another which includes increased splenic Ifng and Treg expression levels, correlating with a less severe anemia. CONCLUSIONS/SIGNIFICANCE: In animals with established F. hepatica infection a huge increase in the immune response occurs, being a mixed Th2/Treg associated gene expression together with an expression of Ifng. Interestingly, a Th17 associated gene expression is also observed. Reinfection in the chronic phase is able to activate a mixed immune response (Th1/Th2/Th17/Treg) against F. hepatica but T and B proliferation to mitogens is strongly suppressed in all infected rats vs control in the advanced chronic phase independently of reinfection The systemic immune response is different in each group, suggesting that suppression is mediated by different mechanisms in each case. Immune suppression could be due to the parasite in PI and R8 rats and the induction of suppressive cells such as Treg in R12. This is the first study to provide fundamental insight into the immune profile in fascioliasis reinfection and its relation with the clinical phenotypes of anemia. PMID- 28362824 TI - Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia. AB - Hereditary ataxia and spastic paraplegia are heterogeneous monogenic neurodegenerative disorders. To date, a large number of individuals with such disorders remain undiagnosed. Here, we have assessed molecular diagnosis by gene panel sequencing in 105 early and late-onset hereditary ataxia and spastic paraplegia probands, in whom extensive previous investigations had failed to identify the genetic cause of disease. Pathogenic and likely-pathogenic variants were identified in 20 probands (19%) and variants of uncertain significance in ten probands (10%). Together these accounted for 30 probands (29%) and involved 18 different genes. Among several interesting findings, dominantly inherited KIF1A variants, p.(Val8Met) and p.(Ile27Thr) segregated in two independent families, both presenting with a pure spastic paraplegia phenotype. Two homozygous missense variants, p.(Gly4230Ser) and p.(Leu4221Val) were found in SACS in one consanguineous family, presenting with spastic ataxia and isolated cerebellar atrophy. The average disease duration in probands with pathogenic and likely-pathogenic variants was 31 years, ranging from 4 to 51 years. In conclusion, this study confirmed and expanded the clinical phenotypes associated with known disease genes. The results demonstrate that gene panel sequencing and similar sequencing approaches can serve as efficient diagnostic tools for different heterogeneous disorders. Early use of such strategies may help to reduce both costs and time of the diagnostic process. PMID- 28362826 TI - Depression-related difficulties disengaging from negative faces are associated with sustained attention to negative feedback during social evaluation and predict stress recovery. AB - The present study aimed to clarify: 1) the presence of depression-related attention bias related to a social stressor, 2) its association with depression related attention biases as measured under standard conditions, and 3) their association with impaired stress recovery in depression. A sample of 39 participants reporting a broad range of depression levels completed a standard eye-tracking paradigm in which they had to engage/disengage their gaze with/from emotional faces. Participants then underwent a stress induction (i.e., giving a speech), in which their eye movements to false emotional feedback were measured, and stress reactivity and recovery were assessed. Depression level was associated with longer times to engage/disengage attention with/from negative faces under standard conditions and with sustained attention to negative feedback during the speech. These depression-related biases were associated and mediated the association between depression level and self-reported stress recovery, predicting lower recovery from stress after giving the speech. PMID- 28362828 TI - Geospatial analysis of emergency department visits for targeting community-based responses to the opioid epidemic. AB - The opioid epidemic in the United States carries significant morbidity and mortality and requires a coordinated response among emergency providers, outpatient providers, public health departments, and communities. Anecdotally, providers across the spectrum of care at Massachusetts General Hospital (MGH) in Boston, MA have noticed that Charlestown, a community in northeast Boston, has been particularly impacted by the opioid epidemic and needs both emergency and longer-term resources. We hypothesized that geospatial analysis of the home addresses of patients presenting to the MGH emergency department (ED) with opioid related emergencies might identify "hot spots" of opioid-related healthcare needs within Charlestown that could then be targeted for further investigation and resource deployment. Here, we present a geospatial analysis at the United States census tract level of the home addresses of all patients who presented to the MGH ED for opioid-related emergency visits between 7/1/2012 and 6/30/2015, including 191 visits from 100 addresses in Charlestown, MA. Among the six census tracts that comprise Charlestown, we find a 9.5-fold difference in opioid-related ED visits, with 45% of all opioid-related visits from Charlestown originating in tract 040401. The signal from this census tract remains strong after adjusting for population differences between census tracts, and while this tract is one of the higher utilizing census tracts in Charlestown of the MGH ED for all cause visits, it also has a 2.9-fold higher rate of opioid-related visits than the remainder of Charlestown. Identifying this hot spot of opioid-related emergency needs within Charlestown may help re-distribute existing resources efficiently, empower community and ED-based physicians to advocate for their patients, and serve as a catalyst for partnerships between MGH and local community groups. More broadly, this analysis demonstrates that EDs can use geospatial analysis to address the emergency and longer-term health needs of the communities they are designed to serve. PMID- 28362827 TI - Alzheimer's amyloid-beta A2T variant and its N-terminal peptides inhibit amyloid beta fibrillization and rescue the induced cytotoxicity. AB - Alzheimer's disease (AD) is the most common dementia affecting tens of million people worldwide. The primary neuropathological hallmark in AD is amyloid plaques composed of amyloid-beta peptide (Abeta). Several familial mutations found in Abeta sequence result in early onset of AD. Previous studies showed that the mutations located at N-terminus of Abeta, such as the English (H6R) and Tottori (D7N) mutations, promote fibril formation and increase cytotoxicity. However, A2T mutant located at the very N-terminus of Abeta shows low-prevalence incidence of AD, whereas, another mutant A2V causes early onset of AD. To understand the molecular mechanism of the distinct effect and develop new potential therapeutic strategy, here, we examined the effect of full-length and N-terminal A2V/T variants to wild type (WT) Abeta40 by fibrillization assays and NMR studies. We found that full-length and N-terminal A2V accelerated WT fibrillization and induced large chemical shifts on the N-terminus of WT Abeta, whereas, full-length and N-terminal A2T retarded the fibrillization. We further examined the inhibition effect of various N-terminal fragments (NTFs) of A2T to WT Abeta. The A2T NTFs ranging from residue 1 to residue 7 to 10, but not 1 to 6 or shorter, are capable to retard WT Abeta fibrillization and rescue cytotoxicity. The results suggest that in the presence of full-length or specific N-terminal A2T can retard Abeta aggregation and the A2T NTFs can mitigate its toxicity. Our results provide a novel targeting site for future therapeutic development of AD. PMID- 28362825 TI - The preferred nucleotide contexts of the AID/APOBEC cytidine deaminases have differential effects when mutating retrotransposon and virus sequences compared to host genes. AB - The AID / APOBEC genes are a family of cytidine deaminases that have evolved in vertebrates, and particularly mammals, to mutate RNA and DNA at distinct preferred nucleotide contexts (or "hotspots") on foreign genomes such as viruses and retrotransposons. These enzymes play a pivotal role in intrinsic immunity defense mechanisms, often deleteriously mutating invading retroviruses or retrotransposons and, in the case of AID, changing antibody sequences to drive affinity maturation. We investigate the strength of various hotspots on their known biological targets by evaluating the potential impact of mutations on the DNA coding sequences of these targets, and compare these results to hypothetical hotspots that did not evolve. We find that the existing AID / APOBEC hotspots have a large impact on retrotransposons and non-mammalian viruses while having a much smaller effect on vital mammalian genes, suggesting co-evolution with AID / APOBECs may have had an impact on the genomes of the viruses we analyzed. We determine that GC content appears to be a significant, but not sole, factor in resistance to deaminase activity. We discuss possible mechanisms AID and APOBEC viral targets have adopted to escape the impacts of deamination activity, including changing the GC content of the genome. PMID- 28362830 TI - Patterns of cetacean vaginal folds yield insights into functionality. AB - Complex foldings of the vaginal wall are unique to some cetaceans and artiodactyls and are of unknown function(s). The patterns of vaginal length and cumulative vaginal fold length were assessed in relation to body length and to each other in a phylogenetic context to derive insights into functionality. The reproductive tracts of 59 female cetaceans (20 species, 6 families) were dissected. Phylogenetically-controlled reduced major axis regressions were used to establish a scaling trend for the female genitalia of cetaceans. An unparalleled level of vaginal diversity within a mammalian order was found. Vaginal folds varied in number and size across species, and vaginal fold length was positively allometric with body length. Vaginal length was not a significant predictor of vaginal fold length. Functional hypotheses regarding the role of vaginal folds and the potential selection pressures that could lead to evolution of these structures are discussed. Vaginal folds may present physical barriers, which obscure the pathway of seawater and/or sperm travelling through the vagina. This study contributes broad insights to the evolution of reproductive morphology and aquatic adaptations and lays the foundation for future functional morphology analyses. PMID- 28362829 TI - OAZ1 knockdown enhances viability and inhibits ER and LHR transcriptions of granulosa cells in geese. AB - An increasing number of studies suggest that ornithine decarboxylase antizyme 1 (OAZ1), which is regarded as a tumor suppressor gene, regulates follicular development, ovulation, and steroidogenesis. The granulosa cells in the ovary play a critical role in these ovarian functions. However, the action of OAZ1 mediating physiological functions of granulosa cells is obscure. OAZ1 knockdown in granulosa cells of geese was carried out in the current study. The effect of OAZ1 knockdown on polyamine metabolism, cell proliferation, apoptosis, and hormone receptor transcription of primary granulosa cells in geese was measured. The viability of granulosa cells transfected with the shRNA OAZ1 at 48 h was significantly higher than the control (p<0.05). The level of putrescine and spermidine in granulosa cells down-regulating OAZ1 was 7.04- and 2.11- fold higher compared with the control, respectively (p<0.05). The CCND1, SMAD1, and BCL-2 mRNA expression levels in granulosa cells down-regulating OAZ1 were each significantly higher than the control, respectively (p<0.05), whereas the PCNA and CASPASE 3 expression levels were significantly lower than the control (p<0.05). The estradiol concentration, ER and LHR mRNA expression levels were significantly lower in granulosa cells down-regulating OAZ1 compared with the control (p<0.05). Taken together, our results indicated that OAZ1 knockdown elevated the putrescine and spermidine contents and enhanced granulosa cell viability and inhibited ER and LHR transcriptions of granulosa cells in geese. PMID- 28362832 TI - Effects of p53-knockout in vascular smooth muscle cells on atherosclerosis in mice. AB - In vitro and in vivo evidence has indicated that the tumor suppressor, p53, may play a significant role in the regulation of atherosclerotic plaque formation. In vivo studies using global knockout mice models, however, have generated inconclusive results that do not address the roles of p53 in various cell types involved in atherosclerosis. In this study, we have specifically ablated p53 in vascular smooth muscle cells (VSMC) in the ApoE-/- mouse model to investigate the roles of p53 in VSMC in atherosclerotic plaque formation and stability. We found that p53 deficiency in VSMC alone did not affect the overall size of atherosclerotic lesions. However, there was a significant increase in the number of p53-/- VSMC in the fibrous caps of atherosclerotic plaques in the early stages of plaque development. Loss of p53 results in migration of VSMC at a faster rate using wound healing assays and augments PDGF-induced formation of circular dorsal ruffles (CDR), known to be involved in cell migration and internalization of surface receptors. Furthermore, aortic VSMC from ApoE-/- /p53-/- mice produce significantly more podosomes and are more invasive. We conclude that p53-/- VSMC are enriched in the fibrous caps of lesions at early stages of plaque formation, which is caused in part by an increase in VSMC migration and invasion as shown by p53-/- VSMC in culture having significantly higher rates of migration and producing more CDRs and invasive podosomes. PMID- 28362833 TI - Are health sciences students who sit at the back of the lecture hall not motivated? AB - OBJECTIVES: Motivation is a crucial determinant in learning and performance. It would therefore be advantageous for teachers to use strategies intended to have a positive effect on their students' motivation. With this in mind, the first thing to do is to identify students with motivation problems, which can be a complex exercise when there are large groups. We wanted to explore whether the place chosen by health sciences students in a classroom or lecture hall showed any correlation with their motivation. METHODS: We carried out a multicentre, prospective, observational study of 596 health sciences students in 9 training institutes. The students filled in a self-administered questionnaire to measure the different components of their motivation to take part in a mandatory lesson. These components were correlated with the row in which they sat in a classroom or lecture hall, when they had a free choice of where to sit. RESULTS: Apart from extrinsic motivation, all the components of motivation for the health sciences students recruited were significantly correlated with the row. The further the students were from the first row, the less they were motivated. CONCLUSION: In accordance with teachers' views, the level of motivation of the students was less the further their position in a classroom or lecture hall was from the first row. A student's position in the classroom could provide a useful indicator for teachers looking to target their motivational strategies for students with potential motivation problems in the environment, where identifying student motivation levels is impossible. PMID- 28362831 TI - The genetic evolution of canine parvovirus - A new perspective. AB - To trace the evolution process of CPV-2, all of the VP2 gene sequences of CPV-2 and FPV (from 1978 to 2015) from GenBank were analyzed in this study. Then, several new ideas regarding CPV-2 evolution were presented. First, the VP2 amino acid 555 and 375 positions of CPV-2 were first ruled out as a universal mutation site in CPV-2a and amino acid 101 position of FPV feature I or T instead of only I in existing rule. Second, the recently confusing nomenclature of CPV-2 variants was substituted with a optional nomenclature that would serve future CPV-2 research. Third, After check the global distribution of variants, CPV-2a is the predominant variant in Asia and CPV-2c is the predominant variant in Europe and Latin America. Fourth, a series of CPV-2-like strains were identified and deduced to evolve from modified live vaccine strains. Finally, three single VP2 mutation (F267Y, Y324I, and T440A) strains were caught concern. Furthermore, these three new VP2 mutation strains may be responsible for vaccine failure, and the strains with VP2 440A may become the novel CPV sub-variant. In conclusion, a summary of all VP2 sequences provides a new perspective regarding CPV-2 evolution and the correlative biological studies needs to be further performed. PMID- 28362835 TI - Numerical analysis of the slipstream development around a high-speed train in a double-track tunnel. AB - Analysis of the slipstream development around the high-speed trains in tunnels would provide references for assessing the transient gust loads on trackside workers and trackside furniture in tunnels. This paper focuses on the computational analysis of the slipstream caused by high-speed trains passing through double-track tunnels with a cross-sectional area of 100 m2. Three dimensional unsteady compressible Reynolds-averaged Navier-Stokes equations and a realizable k-epsilon turbulence model were used to describe the airflow characteristics around a high-speed train in the tunnel. The moving boundary problem was treated using the sliding mesh technology. Three cases were simulated in this paper, including two tunnel lengths and two different configurations of the train. The train speed in these three cases was 250 km/h. The accuracy of the numerical method was validated by the experimental data from full-scale tests, and reasonable consistency was obtained. The results show that the flow field around the high-speed trains can be divided into three distinct regions: the region in front of the train nose, the annular region and the wake region. The slipstream development along the two sides of train is not in balance and offsets to the narrow side in the double-track tunnels. Due to the piston effect, the slipstream has a larger peak value in the tunnel than in open air. The tunnel length, train length and length ratio affect the slipstream velocities; in particular, the velocities increase with longer trains. Moreover, the propagation of pressure waves also induces the slipstream fluctuations: substantial velocity fluctuations mainly occur in front of the train, and weaken with the decrease in amplitude of the pressure wave. PMID- 28362834 TI - The impact of inspired oxygen levels on calibrated fMRI measurements of M, OEF and resting CMRO2 using combined hypercapnia and hyperoxia. AB - Recent calibrated fMRI techniques using combined hypercapnia and hyperoxia allow the mapping of resting cerebral metabolic rate of oxygen (CMRO2) in absolute units, oxygen extraction fraction (OEF) and calibration parameter M (maximum BOLD). The adoption of such technique necessitates knowledge about the precision and accuracy of the model-derived parameters. One of the factors that may impact the precision and accuracy is the level of oxygen provided during periods of hyperoxia (HO). A high level of oxygen may bring the BOLD responses closer to the maximum M value, and hence reduce the error associated with the M interpolation. However, an increased concentration of paramagnetic oxygen in the inhaled air may result in a larger susceptibility area around the frontal sinuses and nasal cavity. Additionally, a higher O2 level may generate a larger arterial blood T1 shortening, which require a bigger cerebral blood flow (CBF) T1 correction. To evaluate the impact of inspired oxygen levels on M, OEF and CMRO2 estimates, a cohort of six healthy adults underwent two different protocols: one where 60% of O2 was administered during HO (low HO or LHO) and one where 100% O2 was administered (high HO or HHO). The QUantitative O2 (QUO2) MRI approach was employed, where CBF and R2* are simultaneously acquired during periods of hypercapnia (HC) and hyperoxia, using a clinical 3 T scanner. Scan sessions were repeated to assess repeatability of results at the different O2 levels. Our T1 values during periods of hyperoxia were estimated based on an empirical ex-vivo relationship between T1 and the arterial partial pressure of O2. As expected, our T1 estimates revealed a larger T1 shortening in arterial blood when administering 100% O2 relative to 60% O2 (T1LHO = 1.56+/-0.01 sec vs. T1HHO = 1.47+/-0.01 sec, P < 4*10-13). In regard to the susceptibility artifacts, the patterns and number of affected voxels were comparable irrespective of the O2 concentration. Finally, the model-derived estimates were consistent regardless of the HO levels, indicating that the different effects are adequately accounted for within the model. PMID- 28362837 TI - Conversion coefficients for determination of dispersed photon dose during radiotherapy: NRUrad input code for MCNP. AB - Radiotherapy is a common cancer treatment module, where a certain amount of dose will be delivered to the targeted organ. This is achieved usually by photons generated by linear accelerator units. However, radiation scattering within the patient's body and the surrounding environment will lead to dose dispersion to healthy tissues which are not targets of the primary radiation. Determination of the dispersed dose would be important for assessing the risk and biological consequences in different organs or tissues. In the present work, the concept of conversion coefficient (F) of the dispersed dose was developed, in which F = (Dd/Dt), where Dd was the dispersed dose in a non-targeted tissue and Dt is the absorbed dose in the targeted tissue. To quantify Dd and Dt, a comprehensive model was developed using the Monte Carlo N-Particle (MCNP) package to simulate the linear accelerator head, the human phantom, the treatment couch and the radiotherapy treatment room. The present work also demonstrated the feasibility and power of parallel computing through the use of the Message Passing Interface (MPI) version of MCNP5. PMID- 28362836 TI - Numerical study on the hydrodynamics of thunniform bio-inspired swimming under self-propulsion. AB - Numerical simulations are employed to study the hydrodynamics of self-propelled thunniform swimming. The swimmer is modeled as a tuna-like flexible body undulating with kinematics of thunniform type. The wake evolution follows the vortex structures arranged nearly vertical to the forward direction, vortex dipole formation resulting in the propulsion motion, and finally a reverse Karman vortex street. We also carry out a systematic parametric study of various aspects of the fluid dynamics behind the freely swimming behavior, including the swimming speed, hydrodynamic forces, power requirement and wake vortices. The present results show that the fin thrust as well as swimming velocity is an increasing function of both tail undulating amplitude Ap and oscillating amplitude of the caudal fin thetam. Whereas change on the propulsive performance with Ap is associated with the strength of wake vortices and the area of suction region on the fin, the swimming performance improves with thetam due to the favorable tilting of the fin that make the pressure difference force more oriented toward the thrust direction. Moreover, the energy loss in the transverse direction and the power requirement increase with Ap but decrease with thetam, and this indicates that for achieving a desired swimming speed increasing thetam seems more efficiently than increasing Ap. Furthermore, we have compared the current simulations with the published experimental studies on undulatory swimming. Comparisons show that our work tackles the flow regime of natural thunniform swimmers and follows the principal scaling law of undulatory locomotion reported. Finally, this study enables a detailed quantitative analysis, which is difficult to obtain by experiments, of the force production of the thunniform mode as well as its connection to the self-propelled swimming kinematics and vortex wake structure. The current findings help provide insights into the swimming performance and mechanisms of self-propelled thunniform locomotion. PMID- 28362838 TI - Biosorption of silver cations onto Lactococcus lactis and Lactobacillus casei isolated from dairy products. AB - The current work deals with the phenomenon of silver cations uptake by two kinds of bacteria isolated from dairy products. The mechanism of sorption of silver cations by Lactococcus lactis and Lactobacillus casei bacteria was investigated. Inductively coupled plasma-mass spectrometry (ICP-MS) was used for determination of silver concentration sorbed by bacteria. Analysis of charge distribution was conducted by diffraction light scattering method. Changes in the ultrastructure of Lactococcus lactis and Lactobacillus casei cells after treatment with silver cations were investigated using transmission electron microscopy observation. Molecular spectroscopy methods, namely Fourier transform-infrared spectroscopy (FT-IR) and matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) were employed for description of the sorption mechanism. Moreover, an analysis of volatile organic compounds (VOCs) extracted from bacterial cells was performed. PMID- 28362839 TI - Histopathological and prognostic significance of the expression of sex hormone receptors in bladder cancer: A meta-analysis of immunohistochemical studies. AB - OBJECTIVE: Emerging preclinical evidence suggests the involvement of sex hormones and their receptor signals in the development and progression of bladder cancer. Meanwhile, previous studies have demonstrated conflicting results on the relationship between the status of sex hormone receptors in urothelial tumors and histopathological characteristics of the tumors or patient outcomes. We therefore conducted this meta-analysis to assess the clinicopathological impact of the expression of androgen receptor (AR) and estrogen receptors (ERs) in bladder cancer. METHODS: A comprehensive literature search in databases (i.e. PubMed, Web of Science, Cochrane) was performed for all immunohistochemical studies stained for AR, ERalpha, and/or ERbeta in surgically resected bladder cancer specimens and analyzed for patient outcomes. We selected eligible studies in accordance with the PRISMA guidelines and analyzed data using R software. RESULTS: A total of 2,049 patients from 13 retrospective studies were included in this meta analysis. The difference in ERalpha expression between non-tumors and tumors was significant [odds ratio (OR) = 0.412; P<0.001], while those of AR (OR = 3.256; P = 0.336) or ERbeta (OR = 0.580; P = 0.674) were not statistically significant. AR positivity in tumors was strongly correlated with gender (male vs. female: OR = 0.658; P = 0.027) or tumor grade (low-grade vs. high-grade: OR = 0.575; P<0.001). ERbeta positive rates were significantly higher in high-grade (OR = 2.169; P<0.001) and muscle-invasive (OR = 3.104; P<0.001) tumors than in low-grade and non-muscle-invasive tumors, respectively. Survival analysis in patients with non muscle-invasive bladder cancer revealed associations between AR expression and better recurrence-free survival [hazard ration (HR) = 0.593; P = 0.006) as well as between ERbeta expression and worse recurrence-free (HR = 1.573; P = 0.013) or progression-free (HR = 4.148; P = 0.089) survivals. CONCLUSIONS: These data suggest down-regulation of ERalpha expression in bladder tumors, compared with non-neoplastic urothelial tissues. AR or ERbeta expression was down- or up regulated, respectively, in high-grade and/or muscle-invasive bladder cancers. Moreover, immunohistochemistry of AR/ERbeta in surgical specimens may serve as prognosticators in patients with non-muscle-invasive bladder tumor. PMID- 28362840 TI - Aspirin-triggered resolvin D1 attenuates PDGF-induced vascular smooth muscle cell migration via the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway. AB - BACKGROUND AND OBJECTIVES: Resolvin D1 (RvD1) is a specialized pro-resolving lipid mediator that has been previously shown to attenuate vascular smooth muscle cell (VSMC) migration, a key process in the development of intimal hyperplasia. We sought to investigate the role of the cAMP/PKA pathway in mediating the effects of the aspirin-triggered epimer 17R-RvD1 (AT-RvD1) on VSMC migration. METHODS: VSMCs were harvested from human saphenous veins. VSMCs were analyzed for intracellular cAMP levels and PKA activity after exposure to AT-RvD1. Platelet derived growth factor (PDGF)-induced migration and cytoskeletal changes in VSMCs were observed through scratch, Transwell, and cell shape assays in the presence or absence of a PKA inhibitor (Rp-8-Br-cAMP). Further investigation of the pathways involved in AT-RvD1 signaling was performed by measuring Rac1 activity, vasodilator stimulated phosphoprotein (VASP) phosphorylation and paxillin translocation. Finally, we examined the role of RvD1 receptors (GPR32 and ALX/FPR2) in AT-RvD1 induced effects on VSMC migration and PKA activity. RESULTS: Treatment with AT-RvD1 induced a significant increase in cAMP levels and PKA activity in VSMCs at 5 minutes and 30 minutes, respectively. AT-RvD1 attenuated PDGF-induced VSMC migration and cytoskeletal rearrangements. These effects were attenuated by the PKA inhibitor Rp-8-Br-cAMP, suggesting cAMP/PKA involvement. Treatment of VSMC with AT-RvD1 inhibited PDGF-stimulated Rac1 activity, increased VASP phosphorylation, and attenuated paxillin localization to focal adhesions; these effects were negated by the addition of Rp-8-Br-cAMP. The effects of AT RvD1 on VSMC migration and PKA activity were attenuated by blocking ALX/FPR2, suggesting an important role of this G-protein coupled receptor. CONCLUSIONS: Our results suggest that AT-RvD1 attenuates PDGF-induced VSMC migration via ALX/FPR2 and cAMP/PKA. Interference with Rac1, VASP and paxillin function appear to mediate the downstream effects of AT-RvD1 on VSMC migration. PMID- 28362841 TI - Alteration of the alpha1beta2/alpha2beta1 subunit interface contributes to the increased hemoglobin-oxygen affinity of high-altitude deer mice. AB - BACKGROUND: Deer mice (Peromyscus maniculatus) that are native to high altitudes in the Rocky Mountains have evolved hemoglobins with an increased oxygen-binding affinity relative to those of lowland conspecifics. To elucidate the molecular mechanisms responsible for the evolved increase in hemoglobin-oxygen affinity, the crystal structure of the highland hemoglobin variant was solved and compared with the previously reported structure for the lowland variant. RESULTS: Highland hemoglobin yielded at least two crystal types, in which the longest axes were 507 and 230 A. Using the smaller unit cell crystal, the structure was solved at 2.2 A resolution. The asymmetric unit contained two tetrameric hemoglobin molecules. CONCLUSIONS: The analyses revealed that alphaPro50 in the highland hemoglobin variant promoted a stable interaction between alphaHis45 and heme that was not seen in the alphaHis50 lowland variant. The alphaPro50 mutation also altered the nature of atomic contacts at the alpha1beta2/alpha2beta1 intersubunit interfaces. These results demonstrate how affinity-altering changes in intersubunit interactions can be produced by mutations at structurally remote sites. PMID- 28362842 TI - Virioplankton dynamics are related to eutrophication levels in a tropical urbanized bay. AB - Virioplankton are an important and abundant biological component of marine and freshwater ecosystems. Often overlooked, aquatic viruses play an important role in biogeochemical cycles on a global scale, infecting both autotrophic and heterotrophic microbes. Viral diversity, abundance, and viral interactions at different trophic levels in aqueous environments are not well understood. Tropical ecosystems are less frequently studied than temperate ecosystems, but could provide new insights into how physical and chemical variability can shape or force microbial community changes. In this study, we found high viral abundance values in Guanabara Bay relative to other estuaries around the world. Viral abundance was positively correlated with bacterioplankton abundance and chlorophyll a concentrations. Moreover, prokaryotic and viral abundance were positively correlated with eutrophication, especially in surface waters. These results provide novel baseline data on the quantitative distribution of aquatic viruses in tropical estuaries. They also provide new information on a complex and dynamic relationship in which environmental factors influence the abundance of bacterial hosts and consequently their viruses. Guanabara Bay is characterized by spatial and seasonal variations, and the eutrophication process is the most important factor explaining the structuring of virioplankton abundance and distribution in this tropical urbanized bay. PMID- 28362843 TI - The (non-)replicability of regulatory resource depletion: A field report employing non-invasive brain stimulation. AB - Cognitive effort and self-control are exhausting. Although evidence is ambiguous, behavioural studies have repeatedly suggested that control-demanding tasks seem to deplete a limited cache of self-regulatory resources leading to performance degradations and fatigue. While resource depletion has indirectly been associated with a decline in right prefrontal cortex capacity, its precise neural underpinnings have not yet been revealed. This study consisted of two independent experiments, which set out to investigate the causal role of the right dorsolateral prefrontal cortex (DLPFC) in a classic dual phase depletion paradigm employing non-invasive brain stimulation. In Experiment 1 we demonstrated a general depletion effect, which was significantly eliminated by anodal transcranial Direct Current Stimulation to the right DLPFC. In Experiment 2, however, we failed to replicate the basic psychological depletion effect within a second independent sample. The dissimilar results are discussed in the context of the current 'replication crisis' and suggestions for future studies are offered. While our current results do not allow us to firmly argue for or against the existence of resource depletion, we outline why it is crucial to further clarify which specific external and internal circumstances lead to limited replicability of the described effect. We showcase and discuss the current inter-lab replication problem based on two independent samples tested within one research group (intra-lab). PMID- 28362844 TI - Division of overall duration of stay into operative stay and postoperative stay improves the overall estimate as a measure of quality of outcome in burn care. AB - PATIENTS AND METHODS: Surgically managed burn patients admitted between 2010-14 were included. Operative stay was defined as the time from admission until the last operation, postoperative stay as the time from the last operation until discharge. The difference in variation was analysed with F-test. A retrospective review of medical records was done to explore reasons for extended postoperative stay. Multivariable regression was used to assess factors associated with operative stay and postoperative stay. RESULTS: Operative stay/TBSA% showed less variation than total duration/TBSA% (F test = 2.38, p<0.01). The size of the burn, and the number of operations, were the independent factors that influenced operative stay (R2 0.65). Except for the size of the burn other factors were associated with duration of postoperative stay: wound related, psychological and other medical causes, advanced medical support, and accommodation arrangements before discharge, of which the two last were the most important with an increase of (mean) 12 and 17 days (p<0.001, R2 0.51). CONCLUSION: Adjusted operative stay showed less variation than total hospital stay and thus can be considered a more accurate outcome measure for surgically managed burns. The size of burn and number of operations are the factors affecting this outcome measure. PMID- 28362845 TI - Clinicopathologic implication of meticulous pathologic examination of regional lymph nodes in gastric cancer patients. AB - BACKGROUND: We aimed to investigate effect of increased number of examined lymph nodes (LNs) to pN category, and compare various N categories in gastric cancer: American Joint Committee on Cancer (AJCC) 7th edition, metastatic LN ratio (MLR), and log odds of positive LNs (LODDS). METHODS: Four cohorts with a total of 2,309 gastric cancer patients were enrolled. For cohort 1 and 2, prognostic significance of each method by disease-specific survival was analyzed using Akaike and Bayesian information criterion (AIC and BIC). RESULTS: The total LNs in four cohorts significantly differed [median (range), 28 (6-97) in cohort 1, 37 (8-120) in cohort 2, 48 (7-122) in cohort 3, and 54 (4-221) in cohort 4; p<0.001]. The numbers of negative LNs increased with increase of total LN (p<0.001), but the numbers of metastatic LNs did not increase from cohort 1 to 4. MLR and LODDS in four cohorts had decreasing tendency with increase of total LNs in each pT3 and pT4 category (p<0.001), while the numbers of metastatic LNs did not differ significantly in any pT category (p>0.05). The AIC and BIC varied according to different cut-off values for MLR; model by cut-offs of 0.2 and 0.5 being better for cohort 1, while cut-offs 0.1 and 0.25 was better for cohort 2. CONCLUSION: Our study showed that the number of metastatic LNs did not increase with maximal pathologic examination of regional LNs. AJCC 7th system is suggested as the simplest method with single cut-off value, but prognostic significance of MLR may be influenced by various cut-offs. PMID- 28362846 TI - Literature-based condition-specific miRNA-mRNA target prediction. AB - miRNAs are small non-coding RNAs that regulate gene expression by binding to the 3'-UTR of genes. Many recent studies have reported that miRNAs play important biological roles by regulating specific mRNAs or genes. Many sequence-based target prediction algorithms have been developed to predict miRNA targets. However, these methods are not designed for condition-specific target predictions and produce many false positives; thus, expression-based target prediction algorithms have been developed for condition-specific target predictions. A typical strategy to utilize expression data is to leverage the negative control roles of miRNAs on genes. To control false positives, a stringent cutoff value is typically set, but in this case, these methods tend to reject many true target relationships, i.e., false negatives. To overcome these limitations, additional information should be utilized. The literature is probably the best resource that we can utilize. Recent literature mining systems compile millions of articles with experiments designed for specific biological questions, and the systems provide a function to search for specific information. To utilize the literature information, we used a literature mining system, BEST, that automatically extracts information from the literature in PubMed and that allows the user to perform searches of the literature with any English words. By integrating omics data analysis methods and BEST, we developed Context-MMIA, a miRNA-mRNA target prediction method that combines expression data analysis results and the literature information extracted based on the user-specified context. In the pathway enrichment analysis using genes included in the top 200 miRNA-targets, Context-MMIA outperformed the four existing target prediction methods that we tested. In another test on whether prediction methods can re-produce experimentally validated target relationships, Context-MMIA outperformed the four existing target prediction methods. In summary, Context-MMIA allows the user to specify a context of the experimental data to predict miRNA targets, and we believe that Context-MMIA is very useful for predicting condition-specific miRNA targets. PMID- 28362847 TI - Sexual and individual foraging segregation in Gentoo penguins Pygoscelis papua from the Southern Ocean during an abnormal winter. AB - Knowledge about sexual segregation and gender-specific, or indeed individual specialization, in marine organisms has improved considerably in the past decade. In this context, we tested the "Intersexual Competition Hypothesis" for penguins by investigating the feeding ecology of Gentoo penguins during their austral winter non-breeding season. We considered this during unusual environmental conditions (i.e. the year 2009 had observations of high sea surface and air temperatures) in comparison with the long term average at Bird Island, South Georgia. Through conventional (i.e. stomach contents) and stable isotopic values from red blood cells, plasma and feathers of both male and female Gentoo penguins, we showed that there were significant differences between sexes, with males feeding mainly on fish (54% by mass) followed by crustaceans (38%) whereas females fed mainly on crustaceans (89% by mass) followed by fish (4%). Themisto gaudichaudii was the most important crustacean prey for males (64% by mass; 82% by number; 53% by frequency of occurrence) and females (63% by mass; 77% by number; 89% by frequency of occurrence), contrasting with all previous studies that found Antarctic krill Euphausia superba were generally the main prey. Stable isotopic data showed that, in terms of habitat use (based on delta 13C), there were significant differences in short-term carbon signatures between males and females (based on plasma and red blood cells), suggesting that both sexes explored different habitats, with females exploring more offshore pelagic waters and males feeding more in coastal benthic waters. Based on delta 15N, males fed on significantly higher trophic level than females (based on plasma and red blood cells), in agreement with our diet results., Thus, Gentoo penguins behave in a similar manner to other non-breeding penguins species (e.g. king, macaroni and rockhopper penguins), albeit at a smaller spatial scale (as they do not disperse as these other penguins do), in that they have a wider habitat and trophic niche during the Antarctic Winter (in comparison to Summer). We also detected individual specialization in feeding/trophic levels for each gender, with certain males feeding mainly on fish and certain females mainly on crustaceans, which may be driven the prevailing environmental conditions that lead individuals to search for alternative prey, and cause sexual diet segregation. Our results provide further information to help improve understanding about sexual segregation and individual specialization of marine organisms, while contributing valuable information on the winter diet for Antarctic monitoring programs and for modelling Antarctic marine food webs. PMID- 28362848 TI - Epidemiology of alcohol dependence in UK primary care: Results from a large observational study using the Clinical Practice Research Datalink. AB - This study aims to investigate the incidence and annual presentation rates of alcohol dependence in general practice in the UK, and examine age-, gender-, socioeconomic-, and region-specific variation. We conducted a retrospective 'open' cohort study using the Clinical Practice Research Datalink (CPRD), an anonymised primary care database. Prior to data extraction, a case definition for alcohol dependence in CPRD was established using 47 Read codes, which included primary alcohol dependence and consequences of alcohol dependence. Directly standardised rates for incidence and annual presentation were calculated for each year between 1990 and 2013. Rates were compared by gender, age, UK home nation, and practice-level Index of Multiple Deprivation. The directly standardised annual incidence rates were 8.3 and 3.7 per 10,000 male and female patients, respectively. The estimated annual rates of presentation per 10,000 were 17.1 for males and 7.6 for females. Female to male rate ratios were: 0.40 (95% CI: 0.39 0.41) for incident cases; and 0.37 (95% CI: 0.36-0.39) for annual presentation. Rates were highest in those aged 35-54 for both measures and across genders, and lowest in those aged over 75 years. With England as the reference nation, Northern Ireland and Scotland had significantly higher rates for both measures. Patients from the most deprived areas had the highest incidence and annual presentation rates. There is unequal distribution of patients with severe alcohol dependence across population subgroups in general practice. Given the health and economic burden associated with dependent drinking, these data will be useful in informing future public health initiatives. PMID- 28362849 TI - Incidence, risk, and associated factors of depression in adults with physical and sensory disabilities: A nationwide population-based study. AB - BACKGROUND: Physical disability has been associated with the risk of depression. We examined the incidence, risk, and associated factors of depression in Taiwanese adults with physical/sensory disabilities. METHODS: Two national databases were used to retrospectively analyze 749,491 >=20-year-old Taiwanese with physical/sensory disabilities in 2002-2008. The incidence of depression was analyzed by univariate Poisson regression. Risk factors of depression were followed up through 2014 and examined with a Cox proportional hazards model. RESULTS: Among the study subjects, the incidence of depression was 6.29 per 1000 person-years, with 1.83 per 1000 person-years corresponding to major depression. The subjects' depression risk was affected by disability type, disability severity, gender, age, education, marital status, aboriginal status, monthly salary, residence urbanization level, and Charlson comorbidity index (CCI). Subjects with rare diseases, mild disability, female gender, age 35-44 years, a high school education level, divorced/widowed status, non-aboriginal status, a NT$22,801-28,800 monthly salary, a highly urbanized residence area, or a CCI>=3 were at higher risk for depression. CONCLUSIONS AND IMPLICATIONS: Adults with physical/sensory disabilities have a 3.7-fold higher incidence of depression than the general population. Social services departments and family members should take extra measures toward preventing and treating depression in this subpopulation. PMID- 28362850 TI - Chemical property based sequence characterization of PpcA and its homolog proteins PpcB-E: A mathematical approach. AB - Periplasmic c7 type cytochrome A (PpcA) protein is determined in Geobacter sulfurreducens along with its other four homologs (PpcB-E). From the crystal structure viewpoint the observation emerges that PpcA protein can bind with Deoxycholate (DXCA), while its other homologs do not. But it is yet to be established with certainty the reason behind this from primary protein sequence information. This study is primarily based on primary protein sequence analysis through the chemical basis of embedded amino acids. Firstly, we look for the chemical group specific score of amino acids. Along with this, we have developed a new methodology for the phylogenetic analysis based on chemical group dissimilarities of amino acids. This new methodology is applied to the cytochrome c7 family members and pinpoint how a particular sequence is differing with others. Secondly, we build a graph theoretic model on using amino acid sequences which is also applied to the cytochrome c7 family members and some unique characteristics and their domains are highlighted. Thirdly, we search for unique patterns as subsequences which are common among the group or specific individual member. In all the cases, we are able to show some distinct features of PpcA that emerges PpcA as an outstanding protein compared to its other homologs, resulting towards its binding with deoxycholate. Similarly, some notable features for the structurally dissimilar protein PpcD compared to the other homologs are also brought out. Further, the five members of cytochrome family being homolog proteins, they must have some common significant features which are also enumerated in this study. PMID- 28362851 TI - Clinical role, optimal timing and frequency of serum infliximab and anti infliximab antibody level measurements in patients with inflammatory bowel disease. AB - BACKGROUND: Serum infliximab (IFX) and antibody-to-infliximab (ATI) levels are objective parameters, that may have a great role in the therapeutic decisions during maintenance biological therapy. RESEARCH DESIGN AND METHODS: 48 inflammatory bowel disease patients receiving maintenance IFX therapy were prospectively enrolled and divided into adequate (complete remission N = 20) and inadequate responder (partial response, loss of response, dose escalation; N = 28) groups. Blood samples were collected just before (trough level, TL) and two (W2aTL) and six weeks (W6aTL) after the administration of IFX. RESULTS: Single measurement of ATI titer was insufficient for predicting therapeutic response due to transient expression of ATI, however, using the three points' measurements, significant difference has been detected between the adequate and inadequate responder group (5.0% vs 35.7%; p = 0.016). The mean value of TL was significantly higher in the adequate responder group (3.11+/-1.64 vs.1.19+/-1.11; p<0.001) without further difference on the second and sixth week. Sensitivity and specificity for predicting the therapeutic response were 85.0% and 71.4% based on the cut-off value of TL 2.0 MUg/ml. CONCLUSION: Simultaneous measurement of serum IFX level prior to administration of regular IFX infusion and ATI titers significantly increase the diagnostic accuracy for the therapeutic decision in patients uncertainly responding to the therapy. The measurement of W2aTL and W6aTL levels did not result in further improvement in the prediction of therapeutic response. PMID- 28362852 TI - Novel phosphate-activated macrophages prevent ectopic calcification by increasing extracellular ATP and pyrophosphate. AB - PURPOSE: Phosphorus is an essential nutrient involved in many pathobiological processes. Less than 1% of phosphorus is found in extracellular fluids as inorganic phosphate ion (Pi) in solution. High serum Pi level promotes ectopic calcification in many tissues, including blood vessels. Here, we studied the effect of elevated Pi concentration on macrophage polarization and calcification. Macrophages, present in virtually all tissues, play key roles in health and disease and display remarkable plasticity, being able to change their physiology in response to environmental cues. METHODS AND RESULTS: High-throughput transcriptomic analysis and functional studies demonstrated that Pi induces unpolarized macrophages to adopt a phenotype closely resembling that of alternatively-activated M2 macrophages, as revealed by arginine hydrolysis and energetic and antioxidant profiles. Pi-induced macrophages showed an anti calcifying action mediated by increased availability of extracellular ATP and pyrophosphate. CONCLUSION: We conclude that the ability of Pi-activated macrophages to prevent calcium-phosphate deposition is a compensatory mechanism protecting tissues from hyperphosphatemia-induced pathologic calcification. PMID- 28362853 TI - Mouse blastomeres acquire ability to divide asymmetrically before compaction. AB - The mouse preimplantation embryo generates the precursors of trophectoderm (TE) and inner cell mass (ICM) during the 8- to 16-cell stage transition, when the apico-basal polarized blastomeres undergo divisions that give rise to cells with different fate. Asymmetric segregation of polar domain at 8-16 cell division generate two cell types, polar cells which adopt an outer position and develop in TE and apolar cells which are allocated to inner position as the precursors of ICM. It is still not know when the blastomeres of 8-cell stage start to be determined to undergo asymmetric division. Here, we analyze the frequency of symmetric and asymmetric divisions of blastomeres isolated from 8-cell stage embryo before and after compaction. Using p-Ezrin as the polarity marker we found that size of blastomeres in 2/16 pairs cannot be used as a criterion for distinguishing symmetric and asymmetric divisions. Our results showed that at early 8-cell stage, before any visible signs of cortical polarity, a subset of blastomeres had been already predestined to divide asymmetrically. We also showed that almost all of 8-cell stage blastomeres isolated from compacted embryo divide asymmetrically, whereas in intact embryos, the frequency of asymmetric divisions is significantly lower. Therefore we conclude that in intact embryo the frequency of symmetric and asymmetric division is regulated by cell-cell interactions. PMID- 28362854 TI - Molecular and cellular responses of the pathogenic fungus Lomentospora prolificans to the antifungal drug voriconazole. AB - The filamentous fungus Lomentospora (Scedosporium) prolificans is an emerging opportunistic pathogen associated with fatal infections in patients with disturbed immune function. Unfortunately, conventional therapies are hardly of any use against this fungus due to its intrinsic resistance. Therefore, we performed an integrated study of the L. prolificans responses to the first option to treat these mycoses, namely voriconazole, with the aim of unveiling mechanisms involved in the resistance to this compound. To do that, we used a wide range of techniques, including fluorescence and electron microscopy to study morphological alterations, ion chromatography to measure changes in cell-wall carbohydrate composition, and proteomics-based techniques to identify the proteins differentially expressed under the presence of the drug. Significantly, we showed drastic changes occurring in cell shape after voriconazole exposure, L. prolificans hyphae being shorter and wider than under control conditions. Interestingly, we proved that the architecture and carbohydrate composition of the cell wall had been modified in the presence of the drug. Specifically, L. prolificans constructed a more complex organelle with a higher presence of glucans and mannans. In addition to this, we identified several differentially expressed proteins, including Srp1 and heat shock protein 70 (Hsp70), as the most overexpressed under voriconazole-induced stress conditions. The mechanisms described in this study, which may be directly related to L. prolificans antifungal resistance or tolerance, could be used as targets to improve existing therapies or to develop new ones in order to successfully eliminate these mycoses. PMID- 28362855 TI - Inhibition of ANO1 by luteolin and its cytotoxicity in human prostate cancer PC-3 cells. AB - Anoctamin 1 (ANO1), a calcium-activated chloride channel, is highly amplified in prostate cancer, the most common form of cancer and leading causes of cancer death in men, and downregulation of ANO1 expression or its functional activity is known to inhibit cell proliferation, migration and invasion in prostate cancer cells. Here, we performed a cell-based screening for the identification of ANO1 inhibitors as potential anticancer therapeutic agents for prostate cancer. Screening of ~300 selected bioactive natural products revealed that luteolin is a novel potent inhibitor of ANO1. Electrophysiological studies indicated that luteolin potently inhibited ANO1 chloride channel activity in a dose-dependent manner with an IC50 value of 9.8 MUM and luteolin did not alter intracellular calcium signaling in PC-3 prostate cancer cells. Luteolin inhibited cell proliferation and migration of PC-3 cells expressing high levels of ANO1 more potently than that of ANO1-deficient PC-3 cells. Notably, luteolin not only inhibited ANO1 channel activity, but also strongly decreased protein expression levels of ANO1. Our results suggest that downregulation of ANO1 by luteolin is a potential mechanism for the anticancer effect of luteolin. PMID- 28362856 TI - GABAA receptor-expressing neurons promote consumption in Drosophila melanogaster. AB - Feeding decisions are highly plastic and bidirectionally regulated by neurons that either promote or inhibit feeding. In Drosophila melanogaster, recent studies have identified four GABAergic interneurons that act as critical brakes to prevent incessant feeding. These GABAergic neurons may inhibit target neurons that drive consumption. Here, we tested this hypothesis by examining GABA receptors and neurons that promote consumption. We find that Resistance to dieldrin (RDL), a GABAA type receptor, is required for proper control of ingestion. Knockdown of Rdl in a subset of neurons causes overconsumption of tastants. Acute activation of these neurons is sufficient to drive consumption of appetitive substances and non-appetitive substances and acute silencing of these neurons decreases consumption. Taken together, these studies identify GABAA receptor-expressing neurons that promote Drosophila ingestive behavior and provide insight into feeding regulation. PMID- 28362857 TI - A novel synaptic junction preparation for the identification and characterization of cleft proteins. AB - Identification of synaptic cleft components has been hampered by the lack of a suitable preparation enriched in synaptic junctions devoid of adjoining peripheral membranes. Prior strategies for the isolation of synaptic junctions, relying on detergents for the removal of peripheral membranes, resulted in substantial loss of membranes lining the cleft. Here, a novel, detergent-free method is described for the preparation of a synaptic junction (SJ) fraction, using phospholipase A2. Limited digestion of synaptic plasma membrane (SPM) fraction with phospholipase A2 followed by centrifugation over a sucrose cushion results in selective removal of membranes peripheral to the cleft while junctional membranes remain relatively intact as observed by electron microscopy. Enrichment in synaptic junctional structures and loss of membranes peripheral to the junctional area are further verified by demonstrating enrichment in PSD-95 and loss in mGluR5, respectively. The SJ fraction is enriched in neuroligins and neurexins, in agreement with immuno-electron microscopy data showing their selective localization to the junctional area. Among additional cell adhesion molecules tested, N-cadherin and specific isoforms of the SynCAM and SALM families also show marked enrichment in the SJ fraction, suggesting preferential localization at the synaptic cleft while others show little enrichment or decrease, suggesting that they are not restricted to or concentrated at the synaptic cleft. Treatment of the SJ fraction with glycosidases results in electrophoretic mobility shifts of all cell adhesion molecules tested, indicating glycosylation at the synaptic cleft. Biochemical and ultrastructural data presented indicate that the novel synaptic junction preparation can be used as a predictive tool for the identification and characterization of the components of the synaptic cleft. PMID- 28362859 TI - Impact of experimental hypercalcemia on routine haemostasis testing. AB - BACKGROUND: The blood to anticoagulant ratio is standardized according to the physiological calcium concentration in blood samples conventionally used for hemostasis testing. Specifically, one fixed volume of 0.109 mmol/L sodium citrate is added to 9 volumes of blood. Since little is known about the impact of hypercalcemia on the calcium-binding capacity of citrate, this study was planned to investigate the effect of experimental hypercalcemia on routine hemostasis testing. METHODS: Fifteen pooled citrated plasmas with matching lithium-heparin pooled plasma from patients with different values of prothrombin time (PT) were divided in three aliquots of 0.6mL each. The first paired aliquots of both citrate and lithium-heparin plasma were supplemented with 60MUL of saline, the second paired aliquots with 30MUL of saline and 30MUL of calcium chloride and the third paired aliquots with 60MUL of calcium chloride. Total and ionized calcium was measured in all aliquots of citrate and lithium-heparin plasma, whereas PT, activated partial thromboplastin time (APTT) and fibrinogen were measured in citrate plasma aliquots. RESULTS: Total calcium concentration gradually increased in both lithium-heparin and citrate plasma aliquots 2 and 3 compared to baseline aliquot 1. The concentration of ionized calcium also gradually increased in lithium-heparin plasma aliquots 2 and 3, whereas it remained immeasurable (i.e., <0.10 mmol/L) in all citrate plasma aliquots. No significant differences were observed for values of PT, APTT and fibrinogen in citrate plasma aliquots 2 and 3 compared to the baseline aliquot 1, with a mean bias was always comprised within the desirable quality specifications derived from biological variability data. CONCLUSION: Hypercalcemia, up to severe hypercalcemia does not generate significant bias in results of first-line coagulations tests, so that hypothetical consideration of adjusting citrate-blood ratio is unjustified in hypercalcemic patients. PMID- 28362858 TI - 3-bromopyruvate and buthionine sulfoximine effectively kill anoikis-resistant hepatocellular carcinoma cells. AB - BACKGROUND & AIMS: Acquisition of anoikis resistance is a prerequisite for metastasis in hepatocellular carcinoma (HCC). However, little is known about how energy metabolism and antioxidant systems are altered in anoikis-resistant (AR) HCC cells. We evaluated anti-tumor effects of a combination treatment of 3 bromopyruvate (3-BP) and buthionine sulfoximine (BSO) in AR HCC cells. METHODS: We compared glycolysis, reactive oxygen species (ROS) production, and chemoresistance among Huh-BAT, HepG2 HCC cells, and the corresponding AR cells. Expression of hexokinase II, gamma-glutamylcysteine synthetase (rGCS), and epithelial-mesenchymal transition (EMT) markers in AR cells was assessed. Anti tumor effects of a combination treatment of 3-BP and BSO were evaluated in AR cells and an HCC xenograft mouse model. RESULTS: AR HCC cells showed significantly higher chemoresistance, glycolysis and lower ROS production than attached cells. Expression of hexokinase II, rGCS, and EMT markers was higher in AR HCC cells than attached cells. A combination treatment of 3-BP/BSO effectively suppressed proliferation of AR HCC cells through apoptosis by blocking glycolysis and enhancing ROS levels. In xenograft mouse models, tumor growth derived from AR HCC cells was significantly suppressed in the group treated with 3-BP/BSO compared to the group treated with 3-BP or sorafenib. CONCLUSIONS: These results demonstrated that a combination treatment of 3-BP/BSO had a synergistic anti tumor effect in an AR HCC model. This strategy may be an effective adjuvant therapy for patients with sorafenib-resistant HCC. PMID- 28362860 TI - Hyperlipidemia and statins use for the risk of new-onset anxiety/depression in patients with head and neck cancer: A population-based study. AB - OBJECTIVE: Anxiety/depression is common among patients with head and neck cancer (HNC), and can negatively affect treatment compliance and outcome. The aim of this study was to assess the association between hyperlipidemia and the risk of new-onset anxiety/depression after the diagnosis of HNC and the influence of administering statins. METHODS: A matched longitudinal cohort study of 1632 subjects (408 HNC patients with preexisting hyperlipidemia and 1224 age- and sex matched HNC patients without hyperlipidemia) was included and analyzed by using data from Taiwan's National Health Insurance Research Database from January 1996 to December 2012. The incidence and hazard ratios (HRs) for the development of new-onset anxiety/depression were examined between the two groups. Cox proportional hazard regression was applied to estimate the relative risks of anxiety/depressive disorders adjusted for potential confounding factors. To estimate the risks of anxiety/depression in different sub-groups, a stratified analysis was also used. RESULTS: HNC patients with preexisting hyperlipidemia had a higher risk for comorbidities such as hypertension, diabetes mellitus, and cardiovascular disease (P <0.001). The incidence rate of anxiety/depression in the HNC patients with preexisting hyperlipidemia was also significantly higher than that among patients without hyperlipidemia (10.78% vs 7.27%, respectively; P = 0.03). A Cox regression model revealed that preexisting hyperlipidemia was an independent risk factor for anxiety/depression (aHR, 1.96; 95% CI, 1.30-2.94). Statins use was protective against anxiety/depression among HNC patients with hyperlipidemia (aHR, 0.85; 95% CI, 0.46-1.57), especially for individuals older than 65 years and for females. CONCLUSIONS: Preexisting hyperlipidemia was associated with increased risk of new-onset anxiety/depression in the HNC patients. Statins use for HNC patients with hyperlipidemia could decrease the risk of anxiety/depression, especially for those older than 65 years and for female patients. PMID- 28362861 TI - Depression, distress and self-efficacy: The impact on diabetes self-care practices. AB - The prevalence of type 2 diabetes is increasing in Malaysia, and people with diabetes have been reported to suffer from depression and diabetes distress which influences their self-efficacy in performing diabetes self-care practices. This interviewer administered, cross sectional study, conducted in the district of Hulu Selangor, Malaysia, involving 371 randomly selected patients with type 2 diabetes, recruited from 6 health clinics, aimed to examine a conceptual model regarding the association between depression, diabetes distress and self-efficacy with diabetes self-care practices using the partial least square approach of structural equation modeling. In this study, diabetes self-care practices were similar regardless of sex, age group, ethnicity, education level, diabetes complications or type of diabetes medication. This study found that self-efficacy had a direct effect on diabetes self-care practice (path coefficient = 0.438, p<0.001). Self-care was not directly affected by depression and diabetes distress, but indirectly by depression (path coefficient = -0.115, p<0.01) and diabetes distress (path coefficient = -0.122, p<0.001) via self-efficacy. In conclusion, to improve self-care practices, effort must be focused on enhancing self-efficacy levels, while not forgetting to deal with depression and diabetes distress, especially among those with poorer levels of self-efficacy. PMID- 28362862 TI - Intimate partner violence in the post-war context: Women's experiences and community leaders' perceptions in the Eastern Province of Sri Lanka. AB - BACKGROUND: Exposure to armed conflict and/or war have been linked to an increase in intimate partner violence (IPV) against women. A substantial body of work has focused on non-partner rape and sexual violence in war and post-war contexts, but research about IPV is limited, particularly in Asian settings. This paper presents the finding of a study conducted in the Eastern Province of Sri Lanka. The study explored women's experiences of and responses to IPV as well as how health and social service providers perceive the problem. It also explored the IPV-related services and supports available after the end of a 30-year civil war. METHOD: We conducted in-depth, qualitative interviews with 15 women who had experienced IPV and 15 service providers who were knowledgeable about IPV in the Eastern Province of Sri Lanka. Interviews were translated into English, coded and organized using NVivo8, and analyzed using inductive thematic analysis. RESULTS: Participants described IPV as a widespread but hidden problem. Women had experienced various forms of abusive and controlling behaviours, some of which reflect the reality of living in the post-war context. The psychological effects of IPV were common, but were often attributed to war-related trauma. Some men used violence to control women and to reinstate power when their gender roles were reversed or challenged due to war and post-war changes in livelihoods. While some service providers perceived an increase in awareness about IPV and more services to address it, this was discordant with women's fears, feelings of oppression, and perception of a lack of redress from IPV within a highly militarized and ethnically-polarized society. Most women did not consider leaving an abusive relationship to be an option, due to realistic fears about their vulnerability to community violence, the widespread social norms that would cast them as outsiders, and the limited availability of related services and supports. IMPLICATIONS: These findings revealed the need for more research about IPV in post-war contexts. Women's experiences in such contexts are influenced and may be masked by a complex set of factors that intersect to produce IPV and entrap women in violence. A more nuanced understanding of the context-specific issues that shape women's experiences of IPV- and community responses to it-is needed to develop more comprehensive solutions that are relevant to the local context. PMID- 28362863 TI - Bacteriophage preparation lytic for Shigella significantly reduces Shigella sonnei contamination in various foods. AB - ShigaShieldTM is a phage preparation composed of five lytic bacteriophages that specifically target pathogenic Shigella species found in contaminated waters and foods. In this study, we examined the efficacy of various doses (9x105-9x107 PFU/g) of ShigaShieldTM in removing experimentally added Shigella on deli meat, smoked salmon, pre-cooked chicken, lettuce, melon and yogurt. The highest dose (2x107 or 9x107 PFU/g) of ShigaShieldTM applied to each food type resulted in at least 1 log (90%) reduction of Shigella in all the food types. There was significant (P<0.01) reduction in the Shigella levels in all phage treated foods compared to controls, except for the lowest phage dose (9x105 PFU/g) on melon where reduction was only ca. 45% (0.25 log). The genomes of each component phage in the cocktail were fully sequenced and analyzed, and they were found not to contain any "undesirable genes" including those listed in the US Code for Federal Regulations (40 CFR Ch1). Our data suggest that ShigaShieldTM (and similar phage preparations with potent lytic activity against Shigella spp.) may offer a safe and effective approach for reducing the levels of Shigella in various foods that may be contaminated with the bacterium. PMID- 28362865 TI - Towards an efficient compression of 3D coordinates of macromolecular structures. AB - The size and complexity of 3D macromolecular structures available in the Protein Data Bank is constantly growing. Current tools and file formats have reached limits of scalability. New compression approaches are required to support the visualization of large molecular complexes and enable new and scalable means for data analysis. We evaluated a series of compression techniques for coordinates of 3D macromolecular structures and identified the best performing approaches. By balancing compression efficiency in terms of the decompression speed and compression ratio, and code complexity, our results provide the foundation for a novel standard to represent macromolecular coordinates in a compact and useful file format. PMID- 28362864 TI - Epidemiological study of relapsing fever borreliae detected in Haemaphysalis ticks and wild animals in the western part of Japan. AB - The genus Borrelia comprises arthropod-borne bacteria, which are infectious agents in vertebrates. They are mainly transmitted by ixodid or argasid ticks. In Hokkaido, Japan, Borrelia spp. were found in deer and Haemaphysalis ticks between 2011 and 2013; however, the study was limited to a particular area. Therefore, in the present study, we conducted large-scale surveillance of ticks and wild animals in the western part of the main island of Japan. We collected 6,407 host seeking ticks from two regions and 1,598 larvae obtained from 32 engorged female ticks and examined them to elucidate transovarial transmission. In addition, we examined whole blood samples from 190 wild boars and 276 sika deer, as well as sera from 120 wild raccoons. We detected Borrelia spp. in Haemaphysalis flava, Haemaphysalis megaspinosa, Haemaphysalis kitaokai, Haemaphysalis longicornis, and Haemaphysalis formosensis. In addition, we isolated a strain from H. megaspinosa using Barbour-Stoenner-Kelly medium. The minimum infection rate of ticks was less than 5%. Transovarial transmission was observed in H. kitaokai. Phylogenetic analysis of the isolated strain and DNA fragments amplified from ticks identified at least four bacterial genotypes, which corresponded to the tick species detected. Bacteria were detected in 8.4%, 15%, and 0.8% of wild boars, sika deer, and raccoons, respectively. In this study, we found seasonal differences in the prevalence of bacterial genotypes in sika deer during the winter and summer. The tick activity season corresponds to the season with a high prevalence of animals. The present study suggests that a particular bacterial genotype detected in this study are defined by a particular tick species in which they are present. PMID- 28362867 TI - Working memory test battery for young adults: Computerized working memory assessment. AB - This study developed a battery of computerized working memory (WM) tests and a scoring system suitable for young adult users. The tests comprised five classic tasks derived from Baddeley's model of WM, reflecting each of the five WM functions. We recruited 115 undergraduate and graduate students from various academic fields and constructed a preliminary WM scoring norm for young adults. The scoring norm was used as a basis for developing a computerized assessment system. The results of correlation analysis show that the fluid intelligence of young adults is related to the memory function of WM, but not to the central executive system. The proposed working memory test battery for young adults comprehensively reflects the WM capacity of adults. PMID- 28362866 TI - Thoraco-abdominal coordination and performance during uphill running at altitude. AB - INTRODUCTION: Running races on mountain trails at moderate-high altitude with large elevation changes throughout has become increasingly popular. During exercise at altitude, ventilatory demands increase due to the combined effects of exercise and hypoxia. AIM: To investigate the relationships between thoraco abdominal coordination, ventilatory pattern, oxygen saturation (SpO2), and endurance performance in runners during high-intensity uphill exercise. METHODS: Fifteen participants (13 males, mean age 42+/-9 yrs) ran a "Vertical Kilometer," i.e., an uphill run involving a climb of approximately 1000 m with a slope greater than 30%. The athletes were equipped with a portable respiratory inductive plethysmography system, a finger pulse oximeter and a global positioning unit (GPS). The ventilatory pattern (ventilation (VE), tidal volume (VT), respiratory rate (RR), and VE/VT ratio), thoraco-abdominal coordination, which is represented by the phase angle (PhA), and SpO2 were evaluated at rest and during the run. Before and after the run, we assessed respiratory function, respiratory muscle strength and the occurrence of interstitial pulmonary edema by thoracic ultrasound. RESULTS: Two subjects were excluded from the respiratory inductive plethysmography analysis due to motion artifacts. A quadratic relationship between the slope and the PhA was observed (r = 0.995, p = 0.036). When the slope increased above 30%, the PhA increased, indicating a reduction in thoraco-abdominal coordination. The reduced thoraco-abdominal coordination was significantly related to reduced breathing efficiency (i.e., an increased VE/VT ratio; r = 0.961, p = 0.038) and SpO2 (r = -0.697, p<0.001). Lower SpO2 values were associated with lower speeds at 20%>=slope<=40% (r = 0.335, p<0.001 for horizontal and r = 0.36, p<0.001 for vertical). The reduced thoraco-abdominal coordination and consequent reduction in SpO2 were associated with interstitial pulmonary edema. CONCLUSION: Reductions in thoraco-abdominal coordination are associated with a less efficient ventilatory pattern and lower SpO2 during uphill running. This fact could have a negative effect on performance. PMID- 28362868 TI - A socioeconomic related 'digital divide' exists in how, not if, young people use computers. AB - Government initiatives have tried to ensure uniform computer access for young people; however a divide related to socioeconomic status (SES) may still exist in the nature of information technology (IT) use. This study aimed to investigate this relationship in 1,351 Western Australian children between 6 and 17 years of age. All participants had computer access at school and 98.9% at home. Neighbourhood SES was related to computer use, IT activities, playing musical instruments, and participating in vigorous physical activity. Participants from higher SES neighbourhoods were more exposed to school computers, reading, playing musical instruments, and vigorous physical activity. Participants from lower SES neighbourhoods were more exposed to TV, electronic games, mobile phones, and non academic computer activities at home. These patterns may impact future economic, academic, and health outcomes. Better insight into neighbourhood SES influences will assist in understanding and managing the impact of computer use on young people's health and development. PMID- 28362869 TI - High prevalence of curable sexually transmitted infections among pregnant women in a rural county hospital in Kilifi, Kenya. AB - BACKGROUND: Women attending antenatal care (ANC) in resource-limited countries are frequently screened for syphilis and HIV, but rarely for other sexually transmitted infections (STIs). We assessed the prevalence of curable STIs, defined as infection with either Chlamydia trachomatis or Neisseria gonorrhoeae or Trichomonas vaginalis, from July to September 2015. METHODS: In a cross sectional study, women attending ANC at the Kilifi County Hospital, Kenya, had a urine sample tested for C. trachomatis/N. gonorrhoeae by GeneXpert(r) and a vaginal swab for T. vaginalis by culture. Bacterial vaginosis (BV) was defined as a Nugent score of 7-10 of the Gram stain of a vaginal smear in combination with self-reported vaginal discharge. Genital ulcers were observed during collection of vaginal swabs. All women responded to questions on socio-demographics and sexual health and clinical symptoms of STIs. Predictors for curable STIs were assessed in multivariable logistic regression. RESULTS: A total of 42/202 (20.8%, 95% confidence interval (CI):15.4-27.0) women had a curable STI. The prevalence was 14.9% for C. trachomatis (95% CI:10.2-20.5), 1.0% for N. gonorrhoeae (95% CI: 0.1-3.5), 7.4% for T. vaginalis (95% CI:4.2-12.0), 19.3% for BV (95% CI: 14.1 25.4) and 2.5% for genital ulcers (95% CI: 0.8-5.7). Predictors for infection with curable STIs included women with a genital ulcer (adjusted odds ratio (AOR) = 35.0, 95% CI: 2.7-461.6) compared to women without a genital ulcer, women who used water for cleaning after visiting the toilet compared to those who used toilet paper or other solid means (AOR = 4.1, 95% CI:1.5-11.3), women who reported having sexual debut <= 17 years compared to women having sexual debut >=18 years (AOR = 2.7, 95% CI:1.1-6.6), and BV-positive women (AOR = 2.7, 95% CI:1.1-6.6) compared to BV-negative women. CONCLUSION: One in five women attending ANC had a curable STI. These infections were associated with genital ulcers, hygiene practices, early sexual debut and bacterial vaginosis. PMID- 28362870 TI - Gender differences in first and secondhand smoke exposure, spirometric lung function and cardiometabolic health in the old order Amish: A novel population without female smoking. AB - Due to their relatively homogeneous lifestyle and living environment, the Amish offer a novel opportunity to study the health associations of tobacco smoke exposure, particularly secondhand smoke. We hypothesized that secondhand smoke exposure is associated with worse pulmonary and cardiometabolic health. We examined cross-sectional data on 3568 Amish study participants, including tobacco use and secondhand smoke exposure from family members included in the study. Thirty-four percent of Amish men reported ever smoking. Of this proportion, 64% used cigars, 46% cigarettes, and 21% pipes. Less than 1% of women reported ever smoking. Smoking was associated with lower spirometric lung function, higher body mass index, lower HDL cholesterol, higher heart rate, lower ankle-brachial index, and larger aortic diameter in men. A greater number of sources of secondhand smoke exposure (defined from the total of spouses, parents, and siblings who smoke) was associated with higher body mass index (p = 0.03) and with higher fasting glucose in men (p = 0.01), but not in women (p = 0.007 for sex*secondhand smoke interaction). Secondhand smoke exposure was also associated with reduced HDL cholesterol only in women (p = 0.002) and a lower heart rate only in men (p = 0.006). Smoking habits among the Old Order Amish are notable for the absence of female participation and a high proportion of cigar and pipe use. Smoking is associated with decreased spirometric indices of lung function and increased cardiovascular risk in this population and secondhand smoke exposure is associated with a greater burden of risk factors for cardiovascular disease. Sex differences in correlations could reflect differences in exposure patterns, mechanisms, or susceptibilities. PMID- 28362871 TI - Establishing a small animal model for evaluating protective immunity against mumps virus. AB - Although mumps vaccines have been used for several decades, protective immune correlates have not been defined. Recently, mumps outbreaks have occurred in vaccinated populations. To better understand the causes of the outbreaks and to develop means to control outbreaks in mumps vaccine immunized populations, defining protective immune correlates will be critical. Unfortunately, no small animal model for assessing mumps immunity exists. In this study, we evaluated use of type I interferon (IFN) alpha/beta receptor knockout mice (IFN-alpha/betaR-/-) for such a model. We found these mice to be susceptible to mumps virus administered intranasally and intracranially. Passive transfer of purified IgG from immunized mice protected naive mice from mumps virus infection, confirming the role of antibody in protection and demonstrating the potential for this model to evaluate mumps immunity. PMID- 28362872 TI - Evaluating methods for estimating home ranges using GPS collars: A comparison using proboscis monkeys (Nasalis larvatus). AB - The development of GPS tags for tracking wildlife has revolutionised the study of home ranges, habitat use and behaviour. Concomitantly, there have been rapid developments in methods for estimating habitat use from GPS data. In combination, these changes can cause challenges in choosing the best methods for estimating home ranges. In primatology, this issue has received little attention, as there have been few GPS collar-based studies to date. However, as advancing technology is making collaring studies more feasible, there is a need for the analysis to advance alongside the technology. Here, using a high quality GPS collaring data set from 10 proboscis monkeys (Nasalis larvatus), we aimed to: 1) compare home range estimates from the most commonly used method in primatology, the grid-cell method, with three recent methods designed for large and/or temporally correlated GPS data sets; 2) evaluate how well these methods identify known physical barriers (e.g. rivers); and 3) test the robustness of the different methods to data containing either less frequent or random losses of GPS fixes. Biased random bridges had the best overall performance, combining a high level of agreement between the raw data and estimated utilisation distribution with a relatively low sensitivity to reduced fixed frequency or loss of data. It estimated the home range of proboscis monkeys to be 24-165 ha (mean 80.89 ha). The grid-cell method and approaches based on local convex hulls had some advantages including simplicity and excellent barrier identification, respectively, but lower overall performance. With the most suitable model, or combination of models, it is possible to understand more fully the patterns, causes, and potential consequences that disturbances could have on an animal, and accordingly be used to assist in the management and restoration of degraded landscapes. PMID- 28362873 TI - Chitosan-propolis nanoparticle formulation demonstrates anti-bacterial activity against Enterococcus faecalis biofilms. AB - Propolis obtained from bee hives is a natural substance with antimicrobial properties. It is limited by its insolubility in aqueous solutions; hence ethanol and ethyl acetate extracts of Malaysian propolis were prepared. Both the extracts displayed antimicrobial and anti-biofilm properties against Enterococcus faecalis, a common bacterium associated with hospital-acquired infections. High performance liquid chromatography (HPLC) analysis of propolis revealed the presence of flavonoids like kaempferol and pinocembrin. This study investigated the role of propolis developed into nanoparticles with chitosan for its antimicrobial and anti-biofilm properties against E. faecalis. Bacteria that grow in a slimy layer of biofilm are resistant to penetration by antibacterial agents. The use of nanoparticles in medicine has received attention recently due to better bioavailability, enhanced penetrative capacity and improved efficacy. A chitosan-propolis nanoformulation was chosen based on ideal physicochemical properties such as particle size, zeta potential, polydispersity index, encapsulation efficiency and the rate of release of the active ingredients. This formulation inhibited E. faecalis biofilm formation and reduced the number of bacteria in the biofilm by ~90% at 200 MUg/ml concentration. When tested on pre formed biofilms, the formulation reduced bacterial number in the biofilm by ~40% and ~75% at 200 and 300 MUg/ml, respectively. The formulation not only reduced bacterial numbers, but also physically disrupted the biofilm structure as observed by scanning electron microscopy. Treatment of biofilms with chitosan propolis nanoparticles altered the expression of biofilm-associated genes in E. faecalis. The results of this study revealed that chitosan-propolis nanoformulation can be deemed as a potential anti-biofilm agent in resisting infections involving biofilm formation like chronic wounds and surgical site infections. PMID- 28362874 TI - Plasma complement and vascular complement deposition in patients with coronary artery disease with and without inflammatory rheumatic diseases. AB - PURPOSE: Inflammatory rheumatic diseases (IRD) are associated with accelerated coronary artery disease (CAD), which may result from both systemic and vascular wall inflammation. There are indications that complement may be involved in the pathogenesis of CAD in Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA). This study aimed to evaluate the associations between circulating complement and complement activation products with mononuclear cell infiltrates (MCI, surrogate marker of vascular inflammation) in the aortic media and adventitia in IRDCAD and non-IRDCAD patients undergoing coronary artery bypass grafting (CABG). Furthermore, we compared complement activation product deposition patterns in rare aorta adventitial and medial biopsies from SLE, RA and non-IRD patients. METHODS: We examined plasma C3 (p-C3) and terminal complement complexes (p-TCC) in 28 IRDCAD (SLE = 3; RA = 25), 52 non-IRDCAD patients, and 32 IRDNo CAD (RA = 32) from the Feiring Heart Biopsy Study. Aortic biopsies taken from the CAD only patients during CABG were previously evaluated for adventitial MCIs. The rare aortic biopsies from 3 SLE, 3 RA and 3 non-IRDCAD were assessed for the presence of C3 and C3d using immunohistochemistry. RESULTS: IRDCAD patients had higher p-TCC than non-IRDCAD or IRDNo CAD patients (p<0.0001), but a similar p-C3 level (p = 0.42). Circulating C3 was associated with IRD duration (rho, p-value: 0.46, 0.03). In multiple logistic regression analysis, IRD remained significantly related to the presence and size of MCI (p<0.05). C3 was present in all tissue samples. C3d was detected in the media of all patients and only in the adventitia of IRD patients (diffuse in all SLE and focal in one RA). CONCLUSION: The independent association of IRD status with MCI and the observed C3d deposition supports the unique relationship between rheumatic disease, and, in particular, SLE with the complement system. Exaggerated systemic and vascular complement activation may accelerate CVD, serve as a CVD biomarker, and represent a target for new therapies. PMID- 28362875 TI - Identification and validation of reference genes for quantitative real-time PCR studies in long yellow daylily, Hemerocallis citrina Borani. AB - Gene expression analysis using reverse transcription quantitative real-time PCR (RT-qPCR) requires the use of reference gene(s) in the target species. The long yellow daylily, Hemerocallis citrina Baroni. is rich in beneficial secondary metabolites and is considered as a functional vegetable. It is widely cultivated and consumed in East Asian countries. However, reference genes for use in RT-qPCR in H. citrina are not available. In the present study, six potential reference genes, actin (ACT), AP-4 complex subunit (AP4), tubulin (TUB), ubiquitin (UBQ), 18S and 60S ribosomal RNA, were selected and their expression stability in different developmental stages, organs and accessions was evaluated using four statistical software packages (geNorm, NormFinder, BestKeeper, and RefFinder). For commercial flower buds of different landraces, the combination of 60S, TUB, and AP4 was appropriate whereas ACT and 60S was suitable for normalization of different organs. In addition, AP4 exhibited the most stable expression in flower buds among different developmental stages. UBQ was less stable than the other reference genes under the experimental conditions except under different organs was 18S. The relative expression levels of two genes, primary-amine oxidase (HcAOC3) and tyrosine aminotransferase (HcTAT) which play important roles in alkaloid biosynthesis were also examined in different organs of the 'Datong' landrace, which further confirmed the results of selected reference genes. This is the first report to evaluate the stability of reference genes in the long yellow daylily that can serve as a foundation for RT-qPCR analysis of gene expression in this species. PMID- 28362876 TI - Supervised exercise training versus usual care in ambulatory patients with left ventricular assist devices: A systematic review. AB - Implantation of left ventricular assist devices (LVAD) has increased because of improved safety profile and limited availability of heart transplantation. Although supervised exercise training (ET) programs are known to improve exercise capacity and quality of life (QoL) in heart failure (HF) patients, similar data is inconclusive in LVAD patients. Thus, we performed a systematic review on studies that incorporated supervised ET and measured peak oxygen uptake in LVAD patients. A total of 150 patients in exercise and 55 patients in control groups were included from 8 studies selected from our predefined criteria. Our systematic review suggests supervised ET has an inconsistent effect on exercise capacity and QoL when compared to control groups undergoing usual care. A quantitative sub-analysis was performed with 4 studies that provided enough data to compare peak oxygen uptake and QoL at baseline and at follow-up. After at least 6 weeks of training, LVAD patients undergoing supervised ET demonstrated significant improvement in exercise capacity (standardized mean difference [SMD] = 0.735, 95% Confidence Interval-[CI], 0.31-1.15 units of the standard deviation, P = 0.001) and QoL scores (SMD = 1.58, 95% CI 0.97-2.20 units of the standard deviation, P <0.001) when compared to the usual care group, with no serious adverse events with exercise. These results suggest that supervised ET is safe and can improve patient outcomes in LVAD patients when compared to the usual care. PMID- 28362877 TI - ARACHNE: A neural-neuroglial network builder with remotely controlled parallel computing. AB - Creating and running realistic models of neural networks has hitherto been a task for computing professionals rather than experimental neuroscientists. This is mainly because such networks usually engage substantial computational resources, the handling of which requires specific programing skills. Here we put forward a newly developed simulation environment ARACHNE: it enables an investigator to build and explore cellular networks of arbitrary biophysical and architectural complexity using the logic of NEURON and a simple interface on a local computer or a mobile device. The interface can control, through the internet, an optimized computational kernel installed on a remote computer cluster. ARACHNE can combine neuronal (wired) and astroglial (extracellular volume-transmission driven) network types and adopt realistic cell models from the NEURON library. The program and documentation (current version) are available at GitHub repository https://github.com/LeonidSavtchenko/Arachne under the MIT License (MIT). PMID- 28362878 TI - Deep sequencing is an appropriate tool for the selection of unique Hepatitis C virus (HCV) variants after single genomic amplification. AB - Hepatitis C virus (HCV) evolves rapidly in a single host and circulates as a quasispecies wich is a complex mixture of genetically distinct virus's but closely related namely variants. To identify intra-individual diversity and investigate their functional properties in vitro, it is necessary to define their quasispecies composition and isolate the HCV variants. This is possible using single genome amplification (SGA). This technique, based on serially diluted cDNA to amplify a single cDNA molecule (clonal amplicon), has already been used to determine individual HCV diversity. In these studies, positive PCR reactions from SGA were directly sequenced using Sanger technology. The detection of non-clonal amplicons is necessary for excluding them to facilitate further functional analysis. Here, we compared Next Generation Sequencing (NGS) with De Novo assembly and Sanger sequencing for their ability to distinguish clonal and non clonal amplicons after SGA on one plasma specimen. All amplicons (n = 42) classified as clonal by NGS were also classified as clonal by Sanger sequencing. No double peaks were seen on electropherograms for non-clonal amplicons with position-specific nucleotide variation below 15% by NGS. Altogether, NGS circumvented many of the difficulties encountered when using Sanger sequencing after SGA and is an appropriate tool to reliability select clonal amplicons for further functional studies. PMID- 28362879 TI - Prediction of diuretic response to tolvaptan by a simple, readily available spot urine Na/K ratio. AB - BACKGROUND: Tolvaptan is vasopressin type 2 receptor antagonist that inhibits water reabsorption. It is used in combination with standard diuretics to treat ascites unresponsive to standard diuretic therapy or hyponatremia because of liver cirrhosis. This study evaluated the effectiveness and safety of tolvaptan in clinical practice and aimed to determine the factors related to its effectiveness. METHODS: Tolvaptan was administered to 88 consecutive cirrhotic patients with ascites unresponsive to standard diuretic therapy. An effective treatment response was a >=2% reduction in body weight on day 7. The association of patient pretreatment characteristics with therapeutic effects was analyzed. RESULTS: Mean weight reduction on day 7 of tolvaptan therapy was -2.9% +/- 3.2%, and treatment was effective in 52% of patients. Multivariate analysis revealed that spot urine Na/K ratio >=2.5 at baseline was the only factor independently related to therapeutic effect, with an odds ratio of 7.85 (95% confidence interval 2.64-23.40, p = 0.0002). Weight reduction percentage on day 7 was -4.0% +/- 2.8% in patients with spot urine Na/K >=2.5, which was significantly greater than the 0.7% +/- 2.7% loss in those with urine Na/K < 2.5 (p < 0.05). A spot urine Na/K ratio >=2.5 had a sensitivity of 85% and specificity of 60% for predicting effective treatment. No adverse events of treatment led to treatment discontinuation. CONCLUSIONS: Baseline spot urine Na/K was predictive of an effective response to tolvaptan therapy. It is simple to perform and readily available and might serve as an indicator of optimal timing of tolvaptan administration in patients with inadequate response to conventional Na diuretic therapy. PMID- 28362880 TI - Exploring drivers for safe male circumcision: Experiences with health education and understanding of partial HIV protection among newly circumcised men in Wakiso, Uganda. AB - INTRODUCTION: About 2.5 million men have voluntarily been circumcised since Uganda started implementing the WHO recommendation to scale up safe male circumcision to reduce HIV transmission. This study sought to understand what influences men's circumcision decisions, their experiences with health education at health facilities and their knowledge of partial HIV risk reduction in Wakiso district. METHODS: Data were collected in May and June 2015 at five public health facilities in Wakiso District. Twenty-five in-depth interviews were held with adult safe male circumcision clients. Data were analysed using thematic network analysis. FINDINGS: Safe male circumcision decisions were mainly influenced by sexual partners, a perceived need to reduce the risk of HIV/STIs, community pressure and other benefits like hygiene. Sexual partners directly requested men to circumcise or indirectly influenced them in varied ways. Health education at facilities mainly focused on the surgical procedure, circumcision benefits especially HIV risk reduction, wound care and time to resumption of sex, with less focus on post-circumcision sexual behaviour. Five men reported no health education. All men reported that circumcision only reduces and does not eliminate HIV risk, and could mention ways it protects, although some extended the benefit to direct protection for women and prevention of other STIs. Five men thought social marketing messages were 'misleading' and feared risk compensation within the community. CONCLUSIONS: Participants reported positive community perception about safe male circumcision campaigns, influencing men to seek services and enabling female partners to impact this decision-making process. However, there seemed to be gaps in safe male circumcision health education, although all participants correctly understood that circumcision offers only partial protection from HIV. Standard health education procedures, if followed at health facilities offering safe male circumcision, would ensure all clients are well informed, especially about post-circumcision sexual behaviour that is key to prevention of risk compensation. PMID- 28362881 TI - The period effect in the prevalence of proliferative diabetic retinopathy, gross proteinuria, and peripheral neuropathy in type 1 diabetes: A longitudinal cohort study. AB - AIMS: To investigate whether, for a specific duration of type 1 diabetes, there is a significant change in the prevalence of proliferative diabetic retinopathy, gross proteinuria and peripheral neuropathy in those more recently diagnosed with diabetes (a period effect), in the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Where present, to determine how common risk factors for diabetic complications might be associated with it, and what might be driving it. MATERIALS AND METHODS: Longitudinal cohort study with seven examination phases between 1980 and 2014. Multivariate logistic regression models and ordinal parameterization were used to test for and evaluate any period effect. RESULTS: There is a period effect in the prevalence of gross proteinuria and peripheral neuropathy (decreasing), as seen with proliferative diabetic retinopathy (p < 0.001). Adjusting for changing levels of common risk factors attenuates the period effect, particularly for proliferative diabetic retinopathy. For gross proteinuria and peripheral neuropathy, however there is a persistent period effect in spite of adjusting for the major risk factors. CONCLUSIONS: There are period effects in the prevalence of proliferative diabetic retinopathy, gross proteinuria and peripheral neuropathy that cannot be fully explained by changes in common risk factors for complications of type 1 diabetes in this cohort. The role of other potential confounders warrants further exploration. PMID- 28362882 TI - Sex Disparity in Survival of Patients With Uveal Melanoma: Better Survival Rates in Women Than in Men in South Korea. AB - Purpose: The purpose of this study was to determine the survival rate of patients with uveal melanoma and sex disparity in this rate in South Korea. Methods: We extracted incident uveal melanoma patients using the Korea Central Cancer Registry (KCCR) database, which covered the entire population from 1999 to 2012 in South Korea. We estimated all-cause survival probabilities and cancer-specific survival probabilities of patients with uveal melanoma and compared these probabilities between subgroups (sex, tumor site, age at diagnosis, etc.) using Kaplan-Meier methods and log-rank tests. We fitted the Cox-proportional hazards models for all-cause death and cancer death to determine sex disparities in survival. Results: A total of 344 uveal melanoma patients (175 women, 51%) were ascertained. They comprised 283 patients with choroidal melanoma (82%) and 61 patients with ciliary body/iris melanoma (18%). The observed 5-year survival probability from all-cause death was 75% (95% confidence interval [CI]: 69%-79%); women with uveal melanoma showed higher survival probability (83% [95% CI: 76% 89%]) compared with men (66% [95% CI: 58%-73%], P < 0.01). After adjusting for age, year of diagnosis, tumor sites, and diagnostic verification method, the hazards for all-cause death and cancer death in women with uveal melanoma were lower than those in men (hazards ratio for cancer death = 0.50 [95% CI: 0.30 0.81]; hazards ratio for all-cause death = 0.39 [95% CI: 0.25-0.61]). Conclusions: Women with uveal melanoma have better survival probabilities relative to men with uveal melanoma. Our findings show a comprehensive picture of survival probability in uveal melanoma cancer patients in Korea, which requires further investigation of mechanism of the sex disparity in uveal melanoma. PMID- 28362883 TI - Use of Aspirin and P2Y12 Response Assays in Detecting Reversal of Platelet Inhibition With Platelet Transfusion in Patients With Traumatic Brain Injury on Antiplatelet Therapy. AB - BACKGROUND: At present, guidelines are lacking on platelet transfusion in patients with a traumatic intracranial bleed and history of antiplatelet therapy. The aspirin and P2Y 12 response unit (ARU and PRU, respectively) assays detect the effect of aspirin and P2Y 12 inhibitors in the cardiac population. OBJECTIVE: To describe the reversal of platelet inhibition after platelet transfusion using the ARU and PRU assays in patients with traumatic brain injury. METHODS: Between 2010 and 2015, we conducted a prospective comparative cohort study of patients presenting with a positive head computed tomography and a history of antiplatelet therapy. ARU and PRU assays were performed on admission and 6 hours after transfusion, with a primary end point of detection of disinhibition after platelet transfusion. RESULTS: One hundred seven patients were available for analysis. Seven percent of patients taking aspirin and 27% of patients taking clopidogrel were not therapeutic on admission per the ARU and PRU, respectively. After platelet transfusion, 51% of patients on any aspirin and 67% of patients on any clopidogrel failed to be reversed. ARU increased by 71 +/- 76 per unit of apheresis platelets for patients taking any aspirin, and PRU increased by 48 +/- 46 per unit of apheresis platelets for patients taking any clopidogrel. CONCLUSION: A significant percentage of patients taking aspirin or clopidogrel were not therapeutic and thus would be unlikely to benefit from a platelet transfusion. In patients with measured platelet inhibition, a single platelet transfusion was not sufficient to reverse platelet inhibition in almost half. PMID- 28362884 TI - Utility of the Aspirin and P2Y12 Response Assays to Determine the Effect of Antiplatelet Agents on Platelet Reactivity in Traumatic Brain Injury. AB - BACKGROUND: Premorbid antithrombotic medication may worsen intracranial injury and outcome after traumatic brain injury (TBI). Routine laboratory tests are insufficient to evaluate platelet activity. OBJECTIVE: To profile the spectrum of platelet inhibition, as measured by aspirin and P2Y12 response unit assays, in a TBI population on antiplatelet therapy. METHODS: This single-center, prospective cohort study included patients presenting to our institution between November 2010 and January 2015 with a clinical history of TBI. Serum platelet reactivity levels were determined immediately on admission and analyzed using the aspirin and P2Y12 response unit assays; test results were reported as aspirin response units and P2Y12 response units. We report congruence between assay results and clinical history as well as differences in assay results between types of antiplatelet therapy. RESULTS: A sample of 317 patients was available for analysis, of which 87% had experienced mild TBI, 7% moderate, and 6% severe; the mean age was 71.5 years. The mean aspirin response units in patients with a history of any aspirin use was 456 +/- 67 (range, 350-659), with 88% demonstrating therapeutic platelet inhibition. For clopidogrel, the mean P2Y12 response unit was 191 +/- 70 (range, 51-351); 77% showed therapeutic response. CONCLUSION: Rapid measurement of antiplatelet function using the aspirin and P2Y12 response assays indicated as many as one fourth of patients on antiplatelet therapy do not have platelet dysfunction. Further research is required to develop guidelines for the use of these assays to guide platelet transfusion in the setting of TBI. PMID- 28362885 TI - Long-Term Clinical and Angiographic Outcomes Following Pipeline Embolization Device Treatment of Complex Internal Carotid Artery Aneurysms: Five-Year Results of the Pipeline for Uncoilable or Failed Aneurysms Trial. AB - BACKGROUND: Early and mid-term safety and efficacy of aneurysm treatment with the Pipeline Embolization Device (PED) has been well demonstrated in prior studies. OBJECTIVE: To present 5-yr follow-up for patients treated in the Pipeline for Uncoilable or Failed Aneurysms clinical trial. METHODS: In our prospective, multicenter trial, 109 complex internal carotid artery (ICA) aneurysms in 107 subjects were treated with the PED. Patients were followed per a standardized protocol at 180 d and 1, 3, and 5 yr. Aneurysm occlusion, in-stent stenosis, modified Rankin Scale scores, and complications were recorded. RESULTS: The primary endpoint of complete aneurysm occlusion at 180 d (73.6%) was previously reported. Aneurysm occlusion for those patients with angiographic follow-up progressively increased over time to 86.8% (79/91), 93.4% (71/76), and 95.2% (60/63) at 1, 3, and 5 yr, respectively. Six aneurysms (5.7%) were retreated. New serious device-related events at 1, 3, and 5 yr were noted in 1% (1/96), 3.5% (3/85), and 0% (0/81) of subjects. There were 4 (3.7%) reported deaths in our trial. Seventy-eight (96.3%) of 81 patients with 5-yr clinical follow-up had modified Rankin Scale scores <=2. No delayed neurological deaths or hemorrhagic or ischemic cerebrovascular events were reported beyond 6 mo. No recanalization of a previously occluded aneurysm was observed. CONCLUSION: Our 5-yr findings demonstrate that PED is a safe and effective treatment for large and giant wide necked aneurysms of the intracranial ICA, with high rates of complete occlusion and low rates of delayed adverse events. PMID- 28362887 TI - Commentary: Ten-Year Follow-up on Tumor Growth and Hearing in Patients Observed With an Intracanalicular Vestibular Schwannoma. PMID- 28362886 TI - Concomitant Primary CNS Lymphoma and FSH-Pituitary Adenoma Arising Within the Sella. Entirely Coincidental? AB - BACKGROUND AND IMPORTANCE: Collision tumors are the simultaneous occurrence of more than one type of neoplasm within an anatomic space. In the pituitary sella, collision tumors are exceedingly rare, and not much is known about their etiology and prognosis. CLINICAL PRESENTATION: A 74-year-old man presented with a concomitant primary pituitary lymphoma (diffuse large B-cell non-Hodgkin's lymphoma; DLBCL) and follicle-stimulating hormone (FSH)-adenoma diagnosed histologically after clinical features of apoplexy prompted urgent surgical decompression and resection. Strong immunoreactivity for FSH by the lymphoma was evident. Full-body workup demonstrated no other source for the lymphoma. He subsequently underwent 4 cycles of chemotherapy and has been in remission for over 32 months. His ophthalmoplegia at presentation persisted with no further deficits. CONCLUSIONS: Four cases of collision tumors of primary pituitary lymphoma and adenoma have previously been reported. This case represents the first combination of an FSH-adenoma and a DLBCL in the literature. Prompt involvement of the hematology-oncology team contributed to the good outcome seen in this case. The putative role played by pituitary hormones in tumorigenesis is reviewed in this case report. The association is either a chance occurrence or due to the induction of lymphoma cell proliferation by the binding of FSH produced by the adenoma to the FSH receptors on the lymphoma cells. PMID- 28362888 TI - Carotid Stenting Without Protection: When is it Worth the Risk? PMID- 28362889 TI - Carotid Artery Angioplasty and Stenting Without Distal Embolic Protection Devices. PMID- 28362890 TI - A History of the Council of State Neurosurgical Societies. AB - As neurological surgery evolved into its own subspecialty early in the 20th century, a need arose to create an environment for communication and education among those surgeons working in this burgeoning surgical discipline. As the socioeconomic climate in health care began to change in the United States, an unforeseen need arose that was outside the scope of the American Association of Neurological Surgeons, Congress of Neurological Surgeons, and Society of Neurological Surgeons. The capacity to understand and address the evolving socioeconomic landscape and to offer a platform for advocacy required a new entity. Grassroots efforts of neurosurgeons at the state level ultimately yielded a formal organization of state neurosurgical societies to fill this void by recognizing, understanding, and addressing socioeconomic factors affecting the practice of neurological surgery. This formal organization became the Council of State Neurosurgical Societies (CSNS). The CSNS provides a forum in which state societies can meet to identify, understand, and advocate for policies on behalf of organized neurosurgery. The purpose of this paper is to detail the history of the formation of the CSNS. By understanding this history and the need for the development of the CSNS, it is hoped that its evolving role as a voice for neurological surgeons in the modern era of health care will be made clear. PMID- 28362891 TI - The Response of Cystic Acoustic Neuromas to Radiosurgery. PMID- 28362892 TI - Sellar and Parasellar Imaging. AB - The skull base is a complex anatomical region that harbors many important neurovascular structures in a relatively confined space. The pathology that can develop at this site is varied, and many disease processes may present with similar clinical and neuroimaging findings. While computed tomography maintains a role in the evaluation of many entities and can, for instance, delineate osseous erosion with great detail and characterize calcified tumor matrices, magnetic resonance imaging (MRI) is the mainstay in the neuroimaging assessment of most pathology occurring at the skull base. Various MRI sequences have proven to be robust tools for tissue characterization and can provide information on the presence of lipids, paramagnetic and diamagnetic elements, and tumor cellularity, among others. In addition, currently available MRI techniques are able to generate high spatial resolution images that allow visualization of cranial nerves and their involvement by adjacent pathology. The information obtained from such examinations may aid in the distinction of these disease processes and in the accurate delineation of their extent prior to biopsy or treatment planning. PMID- 28362893 TI - Letter: Comparison of 10-kHz High-Frequency and Traditional Low-Frequency Spinal Cord Stimulation for the Treatment of Chronic Back and Leg Pain: 24-Month Results From a Multicenter Randomized Controlled Pivotal Trial. PMID- 28362894 TI - Occipitocervical Instability After Far-Lateral Transcondylar Surgery: A Biomechanical Analysis. AB - BACKGROUND: After a far-lateral transcondylar approach, patients may maintain neutral alignment in the immediate postoperative period, but severe occipitoatlantal subluxation may occur gradually with cranial settling and possible neurological injury. Previous research is based on assumptions regarding the extent of condylar resection and the change in biomechanics that produces instability. OBJECTIVE: To quantify the extent of bone removal during a far lateral transcondylar approach, determine the changes in range of motion (ROM) and stiffness that occur after condylar resection, and identify the threshold of condylar resection that predicts alterations in occipitocervical biomechanics. METHODS: Nine human cadaveric specimens were biomechanically tested before and after far-lateral transcondylar resection extending into the hypoglossal canal (HC). The extent of condylar resection was quantified using volumetric comparison between pre- and postresection computed tomography scans. ROM and stiffness testing were performed in intact and resected states. The extent of resection that produced alterations in occipitocervical biomechanics was assessed with sensitivity analysis. RESULTS: Bone removal during condylar resection into the HC was 15.4%-63.7% (mean 35.7%). Sensitivity analysis demonstrated that changes in biomechanics may occur when just 29% of the occipital condyle was resected (area under the curve 0.80-1.00). CONCLUSION: Changes in occipitocervical biomechanics may be observed if one-third of the occipital condyle is resected. During surgery, the HC may not be a reliable landmark to guide the extent of resection. Patients who undergo condylar resections extending into or beyond the HC require close surveillance for occipitocervical instability. PMID- 28362895 TI - From Russian Refugee to Iowa's First Neurosurgeon and Pioneer of Cranial Hemostasis: The Legacy of Anatole Kolodny (1892-1948). AB - After immigrating to the United States from Russia in the wake of the First World War, Anatole Kolodny became the first surgeon in Iowa to specialize in neurological surgery. Kolodny was vital to the initial practice of neurosurgery in the state of Iowa and to the specific development of academic neurosurgery at the University of Iowa. In an effort to improve his surgical outcomes, Kolodny invented a hemostat that bears his name and is still used for cranial hemostasis. He also provided early outcomes of myelomenigocele repair and wrote extensively on bone sarcoma. Kolodny's achievements brought favorable attention to the university and altered the course of neurosurgery at the University of Iowa. Of significant importance, Kolodny influenced and trained Iowa's second neurosurgeon, Olan Hyndman, and this action led the way to the eventual recruitment of the university's first division head of neurosurgery. The purpose of this manuscript is to shed light on Kolodny's important contributions to the development of neurosurgery not only at Iowa, but also in the profession as a whole. PMID- 28362896 TI - Editorial: See One, Do One, Teach One? Paradigm Shift with Three-Dimensional Printing. PMID- 28362897 TI - Distinct perceptual rhythms for feature and conjunction searches. AB - Feature and conjunction searches are widely used to study attentional deployment. However, the spatiotemporal behavior of attention integration in these tasks remains under debate. Are multiple search stimuli processed in parallel or sequentially? Does sampling of visual information and attentional deployment differ between these two types of search? If so, how? We used an innovative methodology to estimate the distribution of attention on a single-trial basis for feature and conjunction searches. Observers performed feature- and conjunction search tasks. They had to detect and discriminate a tilted low-spatial-frequency grating among three low-spatial-frequency vertical gratings (feature search) or low-spatial-frequency vertical gratings and high-spatial-frequency tilted gratings (conjunction search). After a variable delay, two probes were flashed at random locations. Performance in reporting the probes was used to infer attentional deployment to those locations. By solving a second-degree equation, we determined the probability of probe report at the most (P1) and least (P2) attended locations on a given trial. Were P1 and P2 equal, we would conclude that attention had been uniformly distributed across all four locations. Otherwise, we would conclude that visual information sampling and attentional deployment had been nonuniformly distributed. Our results show that processing was nonuniformly distributed across the four locations in both searches, and was modulated periodically over time at ~5 Hz for the conjunction search and ~12 Hz for the feature search. We argue that the former corresponds to the periodicity of attentional deployment during the search, whereas the latter corresponds to ongoing sampling of visual information. Because different locations were not simultaneously processed, this study rules out a strict parallel model for both search types. PMID- 28362899 TI - Davida Teller Award Lecture 2016: Prologue. PMID- 28362898 TI - Dynamic modulation of illusory and physical target size on separate and coordinated eye and hand movements. AB - In everyday behavior, two of the most common visually guided actions-eye and hand movements-can be performed independently, but are often synergistically coupled. In this study, we examine whether the same visual representation is used for different stages of saccades and pointing, namely movement preparation and execution, and whether this usage is consistent between independent and naturalistic coordinated eye and hand movements. To address these questions, we used the Ponzo illusion to dissociate the perceived and physical sizes of visual targets and measured the effects on movement preparation and execution for independent and coordinated saccades and pointing. During independent movements, we demonstrated that both physically and perceptually larger targets produced faster preparation for both effectors. Furthermore, participants who showed a greater influence of the illusion on saccade preparation also showed a greater influence on pointing preparation, suggesting that a shared mechanism involved in preparation across effectors is influenced by illusions. However, only physical but not perceptual target sizes influenced saccade and pointing execution. When pointing was coordinated with saccades, we observed different dynamics: pointing no longer showed modulation from illusory size, while saccades showed illusion modulation for both preparation and execution. Interestingly, in independent and coordinated movements, the illusion modulated saccade preparation more than pointing preparation, with this effect more pronounced during coordination. These results suggest a shared mechanism, dominated by the eyes, may underlie visually guided action preparation across effectors. Furthermore, the influence of illusions on action may operate within such a mechanism, leading to dynamic interactions between action modalities based on task demands. PMID- 28362901 TI - Separate banks of information channels encode size and aspect ratio. AB - Size and aspect ratio are ecologically important visual attributes. Relative size confers depth, and aspect ratio is a size-invariant cue to object identity. The mechanisms of their analyses by the visual system are uncertain. In a series of three psychophysical experiments we show that adaptation causes perceptual repulsion in these properties. Experiment 1 shows that adaptation to a square causes a subsequently viewed smaller (larger) test square to appear smaller (larger) still. Experiment 2 reveals that a test rectangle with an aspect ratio (height/width) of two appears more slender after adaptation to rectangles with aspect ratios less than two, while the same test stimulus appears more squat after adaptation to a rectangle with an aspect ratio greater than two. Significantly, aftereffect magnitudes peak and then decline as the sizes or aspect ratios of adaptor and test diverge. Experiment 3 uses the results of Experiments 1 and 2 to show that the changes in perceived aspect ratio are due to adaptation to aspect ratio rather than adaptation to the height and width of the stimuli. The results are consistent with the operation of distinct banks of information channels tuned for different values of each property. The necessary channels have log-Gaussian sensitivity profiles, have equal widths when expressed as ratios, are labeled with their preferred magnitudes, and are distributed at exponentially increasing intervals. If an adapting stimulus reduces each channel's sensitivity in proportion to its activation then the displacement of the centroid of activity due to a subsequently experienced test stimulus predicts the measured size or aspect ratio aftereffect. PMID- 28362902 TI - Variation of axial and oblique astigmatism with accommodation across the visual field. AB - In this study we investigated the impact of accommodation on axial and oblique astigmatism along 12 meridians of the central 30 degrees of visual field and explored the compensation of corneal first-surface astigmatism by the remainder of the eye's optical system. Our experimental evidence revealed no systematic effect of accommodation on either axial or oblique astigmatism for two adult populations (myopic and emmetropic eyes). Although a few subjects exhibited systematic changes in axial astigmatism during accommodation, the dioptric value of these changes was much smaller than the amount of accommodation. For most subjects, axial and oblique astigmatism of the whole eye are both less than for the cornea alone, which indicates a compensatory role for internal optics at all accommodative states in both central and peripheral vision. A new method for determining the eye's optical axis based on visual field maps of oblique astigmatism revealed that, on average, the optical axis is 4.8 degrees temporal and 0.39 degrees superior to the foveal line-of-sight in object space, which agrees with previous results obtained by different methodologies and implies that foveal astigmatism includes a small amount of oblique astigmatism (0.06 D on average). Customized optical models of each eye revealed that oblique astigmatism of the corneal first surface is negligible along the pupillary axis for emmetropic and myopic eyes. Individual variation in the eye's optical axis is due in part to misalignment of the corneal and internal components that is consistent with tilting of the crystalline lens relative to the pupillary axis. PMID- 28362904 TI - Erratum. PMID- 28362903 TI - Schistosomal MicroRNAs Isolated From Extracellular Vesicles in Sera of Infected Patients: A New Tool for Diagnosis and Follow-up of Human Schistosomiasis. AB - Background: Schistosomiasis traditionally has been diagnosed by detecting eggs in stool or urine. However, the sensitivity of these examinations is limited, especially in travelers with a low worm burden. Serologic tests have a greater sensitivity, but their results remain positive regardless of treatment and thus cannot be used for follow-up of patients. We hypothesized that detection of worm microRNAs (miRNAs) in serum can overcome the drawbacks of the existing diagnostic methods. Methods and Results: Twenty-six returning travelers with schistosomiasis (based on positive results of serologic tests or detection of ova) and 17 healthy controls were included in the study. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) amplification of miRNA extracted directly from 500 uL of serum had limited sensitivity and specificity. However, qRT-PCR analysis of RNA extracted from 200 MUL of serum extracellular vesicles detected 4 schistosomal miRNAs; the sensitivity and specificity of the 2 highest expressed miRNAs (bantam and miR-2c-3p) were 86% and 84%, respectively. In 7 patients with posttreatment serum available for analysis, we observed outcomes ranging from a reduction in the schistosomal miRNA level to full recovery from disease. Conclusions: qRT-PCR of pathogen miRNAs isolated from extracellular vesicles in sera from infected individuals may provide a new tool for diagnosing schistosomiasis in patients with a low parasite burden. This assay could also be used for evaluating the outcome of therapy, as well as disease-control programs. PMID- 28362900 TI - The Davida Teller Award Lecture, 2016: Visual Brain Development: A review of "Dorsal Stream Vulnerability"-motion, mathematics, amblyopia, actions, and attention. AB - Research in the Visual Development Unit on "dorsal stream vulnerability' (DSV) arose from research in two somewhat different areas. In the first, using cortical milestones for local and global processing from our neurobiological model, we identified cerebral visual impairment in infants in the first year of life. In the second, using photo/videorefraction in population refractive screening programs, we showed that infant spectacle wear could reduce the incidence of strabismus and amblyopia, but many preschool children, who had been significantly hyperopic earlier, showed visuo-motor and attentional deficits. This led us to compare developing dorsal and ventral streams, using sensitivity to global motion and form as signatures, finding deficits in motion sensitivity relative to form in children with Williams syndrome, or perinatal brain injury in hemiplegia or preterm birth. Later research showed that this "DSV" was common across many disorders, both genetic and acquired, from autism to amblyopia. Here, we extend DSV to be a cluster of problems, common to many disorders, including poor motion sensitivity, visuo-motor spatial integration for planning actions, attention, and number skills. In current research, we find that individual differences in motion coherence sensitivity in typically developing children are correlated with MRI measures of area variations in parietal lobe, fractional anisotropy (from TBSS) of the superior longitudinal fasciculus, and performance on tasks of mathematics and visuo-motor integration. These findings suggest that individual differences in motion sensitivity reflect decision making and attentional control rather than integration in MT/V5 or V3A. Its neural underpinnings may be related to Duncan's "multiple-demand" (MD) system. PMID- 28362905 TI - Nitazoxanide Is an Ineffective Treatment of Chronic Norovirus in Patients With X Linked Agammaglobulinemia and May Yield False-Negative Polymerase Chain Reaction Findings in Stool Specimens. PMID- 28362907 TI - Erratum. PMID- 28362906 TI - Reply to Kempf et al. PMID- 28362908 TI - Erratum. PMID- 28362909 TI - Erratum. PMID- 28362910 TI - Treatment of Chronic Asymptomatic Plasmodium falciparum Infection Does Not Increase the Risk of Clinical Malaria Upon Reinfection. AB - Background: Chronic asymptomatic Plasmodium falciparum infections are common in endemic areas and are thought to contribute to the maintenance of malaria immunity. Whether treatment of these infections increases the subsequent risk of clinical episodes of malaria is unclear. Methods: In a 3-year study in Mali, asymptomatic individuals with or without P. falciparum infection at the end of the 6-month dry season were identified by polymerase chain reaction (PCR), and clinical malaria risk was compared during the ensuing 6-month malaria transmission season. At the end of the second dry season, 3 groups of asymptomatic children were identified: (1) children infected with P. falciparum as detected by rapid diagnostic testing (RDT) who were treated with antimalarials (n = 104), (2) RDT-negative children whose untreated P. falciparum infections were detected retrospectively by PCR (n = 55), and (3) uninfected children (RDT/PCR negative) (n = 434). Clinical malaria risk during 2 subsequent malaria seasons was compared. Plasmodium falciparum-specific antibody kinetics during the dry season were compared in children who did or did not harbor asymptomatic P. falciparum infections. Results: Chronic asymptomatic P. falciparum infection predicted decreased clinical malaria risk during the subsequent malaria season(s); treatment of these infections did not alter this reduced risk. Plasmodium falciparum-specific antibodies declined similarly in children who did or did not harbor chronic asymptomatic P. falciparum infection during the dry season. Conclusions: These findings challenge the notion that chronic asymptomatic P. falciparum infection maintains malaria immunity and suggest that mass drug administration during the dry season should not increase the subsequent risk of clinical malaria. PMID- 28362911 TI - Socioeconomic Factors Explain Racial Disparities in Invasive Community-Associated Methicillin-Resistant Staphylococcus aureus Disease Rates. AB - Background: Invasive community-associated methicillin-resistant Staphylococcus aureus (MRSA) incidence in the United States is higher among black persons than white persons. We explored the extent to which socioeconomic factors might explain this racial disparity. Methods: A retrospective cohort was based on the Centers for Disease Control and Prevention's Emerging Infections Program surveillance data for invasive community-associated MRSA cases (isolated from a normally sterile site of an outpatient or on hospital admission day <=3 in a patient without specified major healthcare exposures) from 2009 to 2011 in 33 counties of 9 states. We used generalized estimating equations to determine census tract-level factors associated with differences in MRSA incidence and inverse odds ratio-weighted mediation analysis to determine the proportion of racial disparity mediated by socioeconomic factors. Results: Annual invasive community-associated MRSA incidence was 4.59 per 100000 among whites and 7.60 per 100000 among blacks (rate ratio [RR], 1.66; 95% confidence interval [CI], 1.52 1.80). In the mediation analysis, after accounting for census tract-level measures of federally designated medically underserved areas, education, income, housing value, and rural status, 91% of the original racial disparity was explained; no significant association of black race with community-associated MRSA remained (RR, 1.05; 95% CI, .92-1.20). Conclusions: The racial disparity in invasive community-associated MRSA rates was largely explained by socioeconomic factors. The specific factors that underlie the association between census tract level socioeconomic measures and MRSA incidence, which may include modifiable social (eg, poverty, crowding) and biological factors (not explored in this analysis), should be elucidated to define strategies for reducing racial disparities in community-associated MRSA rates. PMID- 28362912 TI - Trends in Thyroid Cancer Incidence and Mortality in the United States, 1974-2013. AB - Importance: Thyroid cancer incidence has increased substantially in the United States over the last 4 decades, driven largely by increases in papillary thyroid cancer. It is unclear whether the increasing incidence of papillary thyroid cancer has been related to thyroid cancer mortality trends. Objective: To compare trends in thyroid cancer incidence and mortality by tumor characteristics at diagnosis. Design, Setting, and Participants: Trends in thyroid cancer incidence and incidence-based mortality rates were evaluated using data from the Surveillance, Epidemiology, and End Results-9 (SEER-9) cancer registry program, and annual percent change in rates was calculated using log-linear regression. Exposure: Tumor characteristics. Main Outcomes and Measures: Annual percent changes in age-adjusted thyroid cancer incidence and incidence-based mortality rates by histologic type and SEER stage for cases diagnosed during 1974-2013. Results: Among 77 276 patients (mean [SD] age at diagnosis, 48 [16] years; 58 213 [75%] women) diagnosed with thyroid cancer from 1974-2013, papillary thyroid cancer was the most common histologic type (64 625 cases), and 2371 deaths from thyroid cancer occurred during 1994-2013. Thyroid cancer incidence increased, on average, 3.6% per year (95% CI, 3.2%-3.9%) during 1974-2013 (from 4.56 per 100 000 person-years in 1974-1977 to 14.42 per 100 000 person-years in 2010-2013), primarily related to increases in papillary thyroid cancer (annual percent change, 4.4% [95% CI, 4.0%-4.7%]). Papillary thyroid cancer incidence increased for all SEER stages at diagnosis (4.6% per year for localized, 4.3% per year for regional, 2.4% per year for distant, 1.8% per year for unknown). During 1994 2013, incidence-based mortality increased 1.1% per year (95% CI, 0.6%-1.6%) (from 0.40 per 100 000 person-years in 1994-1997 to 0.46 per 100 000 person-years in 2010-2013) overall and 2.9% per year (95% CI, 1.1%-4.7%) for SEER distant stage papillary thyroid cancer. Conclusions and Relevance: Among patients in the United States diagnosed with thyroid cancer from 1974-2013, the overall incidence of thyroid cancer increased 3% annually, with increases in the incidence rate and thyroid cancer mortality rate for advanced-stage papillary thyroid cancer. These findings are consistent with a true increase in the occurrence of thyroid cancer in the United States. PMID- 28362914 TI - Understanding Hospital Volume-Outcome Relationship in Severe Traumatic Brain Injury. AB - BACKGROUND: The hospital volume-outcome relationship in severe traumatic brain injury (TBI) population remains unclear. OBJECTIVE: To examine the relationship between volume of patients with severe TBI per hospital and in-hospital mortality, major complications, and mortality following a major complication (ie, failure to rescue). METHODS: In a multicenter cohort study, data on 9255 adults with severe TBI were derived from 111 hospitals participating in the American College of Surgeons Trauma Quality Improvement Program over 2009-2011. Hospitals were ranked into quartiles based on their volume of severe TBI during the study period. Random-intercept multilevel models were used to examine the association between hospital quartile of severe TBI volume and in-hospital mortality, major complications, and mortality following a major complication after adjusting for patient and hospital characteristics. In sensitivity analyses, we examined these associations after excluding transferred cases. RESULTS: Overall mortality was 37.2% (n = 3447). Two thousand ninety-eight patients (22.7%) suffered from 1 or more major complication. Among patients with major complications, 27.8% (n = 583) died. Higher-volume hospitals were associated with lower mortality; the adjusted odds ratio of death was 0.50 (95% confidence interval: 0.29-0.85) in the highest volume quartile compared to the lowest. There was no significant association between hospital-volume quartile and the odds of a major complication or the odds of death following a major complication. After excluding transferred cases, similar results were found. CONCLUSION: High-volume hospitals might be associated with lower in-hospital mortality following severe TBI. However, this mortality reduction was not associated with lower risk of major complications or death following a major complication. PMID- 28362913 TI - Intramedullary Lesion Length on Postoperative Magnetic Resonance Imaging is a Strong Predictor of ASIA Impairment Scale Grade Conversion Following Decompressive Surgery in Cervical Spinal Cord Injury. AB - BACKGROUND: Evidence indicates that, over time, patients with spinal cord injury (SCI) improve neurologically in various degrees. We sought to further investigate indicators of grade conversion in cervical SCI. OBJECTIVE: To detect predictors of ASIA impairment scale (AIS) grade conversion in SCI following surgical decompression. METHODS: In a retrospective study, demographics, clinical, imaging, and surgical data from 100 consecutive patients were assessed for predictors of AIS grade conversion. RESULTS: American Spinal Injury Association motor score was 17.1. AIS grade was A in 52%, B in 29%, and C in 19% of patients. Surgical decompression took place on an average of 17.6 h following trauma (<=12 h in 51 and >12 h in 49). Complete decompression was verified by magnetic resonance imaging (MRI) in 73 patients. Intramedullary lesion length (IMLL) on postoperative MRI measured 72.8 mm, and hemorrhage at the injury epicenter was noted in 71 patients. Grade conversion took place in 26.9% of AIS grade A patients, 65.5% of AIS grade B, and 78.9% of AIS grade C. AIS grade conversion had statistical relationship with injury severity score, admission AIS grade, extent of decompression, presence of intramedullary hemorrhage, American Spinal Injury Association motor score, and IMLL. A stepwise multiple logistic regression analysis indicated IMLL was the sole and strongest indicator of AIS grade conversion (odds ratio 0.950, 95% CI 0.931-0.969). For 1- and 10-mm increases in IMLL, the model indicates 4% and 40% decreases, respectively, in the odds of AIS grade conversion. CONCLUSION: Compared with other surrogates, IMLL remained as the only predictor of AIS grade conversion. PMID- 28362916 TI - Letter: Distraction, Compression, Extension, and Reduction Combined With Joint Remodeling and Extra-articular Distraction: Description of 2 New Modifications for Its Application in Basilar Invagination and Atlantoaxial Dislocation: Prospective Study in 79 Cases. PMID- 28362915 TI - The Influence of Perioperative Seizure Prophylaxis on Seizure Rate and Hospital Quality Metrics Following Glioma Resection. AB - BACKGROUND: Antiepileptic drugs (AEDs) are frequently administered prophylactically to mitigate seizures following craniotomy for brain tumor resection. However, conflicting evidence exists regarding the efficacy of AEDs, and their influence on surgery-related outcomes is limited. OBJECTIVE: To evaluate the influence of perioperative AEDs on postoperative seizure rate and hospital-reported quality metrics. METHODS: A retrospective cohort study was conducted, incorporating all adult patients who underwent craniotomy for glioma resection at our institution between 1999 and 2014. Patients in 2 cohorts-those receiving and those not receiving prophylactic AEDs-were compared on the incidence of postoperative seizures and several hospital quality metrics including length of stay, discharge status, and use of hospital resources. RESULTS: Among 342 patients with glioma undergoing cytoreductive surgery, 301 (88%) received AED prophylaxis and 41 (12%) did not. Seventeen patients (5.6%) in the prophylaxis group developed a seizure within 14 days of surgery, compared with 1 (2.4%) in the standard group (OR = 2.2, 95% CI [0.3-17.4]). Median hospital and intensive care unit lengths of stay were similar between the cohorts. There was also no difference in the rate at which patients presented within 90 days postoperatively to the emergency department or required hospital readmission. In addition, the rate of hospital resource consumption, including electroencephalogram and computed tomography scan acquisition, and neurology consultation, was similar between both groups. CONCLUSION: The administration of prophylactic AEDs following glioma surgery did not influence the rate of perioperative seizures, nor did it reduce healthcare resource consumption. The role of perioperative seizure prophylaxis should be closely reexamined, and reconsideration given to this commonplace practice. PMID- 28362917 TI - In Reply: ORACLE Stroke Study: Opinion Regarding Acceptable Outcome Following Decompressive Hemicraniectomy for Ischemic Stroke. PMID- 28362918 TI - Letter: The History of Kernohan's Notch Revisited. PMID- 28362919 TI - Activation of Nuclear Factor-kappa B in Endothelial Cells of Chronic Subdural Hematoma Outer Membranes. AB - BACKGROUND: Chronic subdural hematoma (CSDH) is considered an angiogenic and inflammatory disease. Nuclear factor-kappa B (NF-kappaB) induces the production of inflammatory cytokines and adhesion molecules, which play an essential role in angiogenesis and inflammation. Recently, the double-stranded RNA-activated protein kinase (PKR) was shown to directly interact with NF-kappaB subunits to influence its transcriptional activity. OBJECTIVE: To examine the expression of NF-kappaB signaling pathway components and PKR in CSDH outer membranes. METHODS: Eight patients whose outer membranes were successfully obtained during trepanation surgery were included in this study. The IkappaBalpha, IKKbeta, IKKgamma, NF-kappaB, phosphorylated ( p )-NF-kappaB, and PKR expression levels were examined using western blotting analysis. NF-kappaB expression was also examined using immunohistochemistry. We investigated whether CSDH fluid could activate NF-kappaB in cultured endothelial cells in Vitro. RESULTS: The IkappaBalpha, IKKbeta, IKKgamma, and NF-kappaB levels were approximately the same. Additionally, p -NF-kappaB and PKR were detected at similar levels. Immunostaining showed that NF-kappaB was expressed in the vascular endothelium. p -NF-kappaB expression in endothelial cells was significantly induced immediately after treatment with CSDH fluid. Furthermore, NF-kappaB activation was significantly inhibited by treatment with antibodies directed against vascular endothelial growth factor. CONCLUSION: PKR might activate NF-kappaB through vascular endothelial growth factor in endothelial cells, which might be associated with endothelial cell proliferation in the CSDH outer membrane. Thus, the NF-kappaB signaling pathway could play a critical role in CSDH growth. PMID- 28362920 TI - In Reply: The History of the Kernohan Notch Revisited. PMID- 28362921 TI - Readmission After Craniotomy for Tumor: A National Surgical Quality Improvement Program Analysis. AB - BACKGROUND: Although readmission has become a common quality indicator, few national studies have examined this metric in patients undergoing cranial surgery. OBJECTIVE: To utilize the prospective National Surgical Quality Improvement Program 2011-2013 registry to evaluate the predictors of unplanned 30 d readmission and postdischarge mortality after cranial tumor resection. METHODS: Multivariable logistic regression was applied to screen predictors, which included patient age, sex, tumor location and histology, American Society of Anesthesiologists class, functional status, comorbidities, and complications from the index hospitalization. RESULTS: Of the 9565 patients included, 10.7% (n = 1026) had an unplanned readmission. Independent predictors of unplanned readmission were male sex, infratentorial location, American Society of Anesthesiologists class 3 designation, dependent functional status, a bleeding disorder, and morbid obesity (all P <= .03). Readmission was not associated with operative time, length of hospitalization, discharge disposition, or complications from the index admission. The most common reasons for readmission were surgical site infections (17.0%), infectious complications (11.0%), venous thromboembolism (10.0%), and seizures (9.4%). The 30-d mortality rate was 3.2% (n = 367), of which the majority (69.7%, n = 223) occurred postdischarge. Independent predictors of postdischarge mortality were greater age, metastatic histology, dependent functional status, hypertension, discharge to institutional care, and postdischarge neurological or cardiopulmonary complications (all P < .05). CONCLUSION: Readmissions were common after cranial tumor resection and often attributable to new postdischarge complications rather than exacerbations of complications from the initial hospitalization. Moreover, the majority of 30-d deaths occurred after discharge from the index hospitalization. The preponderance of postdischarge mortality and complications requiring readmission highlights the importance of posthospitalization management. PMID- 28362922 TI - Factors Leading to a Poor Functional Outcome in Spinal Meningioma Surgery: Remarks on 173 Cases. AB - BACKGROUND: Spinal meningiomas are common spinal tumors, in most cases benign and with a good surgical prognosis. However, specific location, infiltration of spinal cord, vascular encasement, or spinal root involvement can bring a less favorable prognosis. OBJECTIVE: To correlate these data with clinical/functional outcome. METHODS: Two hundred twenty-four consecutive patients with spinal meningiomas treated from 1976 to 2013 in our institution were analyzed; among these, 51 were excluded for incomplete clinical data or follow-up. The remaining 173 cases were classified in regards to sex, age, symptoms, axial location, Simpson grade resection, and functional pre-/postoperative status. RESULTS: Most recurring onset symptoms were pain (32.9%) and motor deficit (31.8%); thoracic spine was the most severely affected (69.8%). Functional improvement on the follow-up was observed in 86.7% of cases; 6.4% of patients resulted stable and 6.9% worsened. A low functional grade before surgery was connected to a lesser improvement after. Anterolateral meningiomas were the most represented (42.2%); a gross total resection (Simpson grades I and II) was conducted in 98.8%, and a macroscopically complete removal without dural resection or coagulation (Simpson grade III) was performed in 1.2%. Of the meningiomas, 98.3% were classified as WHO grade I. Recurrence rate was 2.3%, and 7 cases presented complications (4 of 7 required surgical procedure). CONCLUSION: We can affirm that negative prognostic factors in our study were anterior or anterolateral axial location, prolonged presentation before diagnosis, WHO grade >I, Simpson grade resections II and III, sphincter involvement, and worse functional grade at onset. PMID- 28362923 TI - Volume-Staged Stereotactic Radiosurgery for Intracranial Arteriovenous Malformations: Outcomes Based on an 18-Year Experience. AB - BACKGROUND: Radiation-based treatment options of large intracranial arteriovenous malformations (AVM) must balance the likelihood of obliteration with the risk of adverse radiation effects (ARE). OBJECTIVE: To analyze the efficacy and risks of volume-staged stereotactic radiosurgery (VS-SRS) for AVM. METHODS: Retrospective study of 34 AVM patients having VS-SRS between 1997 and 2012. A median of 2 stages (range, 2-4) was used to treat a median AVM volume of 22.2 cm 3 (range, 7.4-56.7). The median AVM margin dose was 16 Gy (range, 14-18); the median radiosurgery-based AVM score was 2.81 (range, 1.54-6.45). The median follow-up after VS-SRS was 8.2 years (range, 3-13.3). RESULTS: Nidus obliteration was noted in 18 patients (53%) after VS-SRS. The rate of obliteration was 14% at 3 years, 54% at 5 years, and 75% at 7 years. Six patients (18%) had 11 bleeds after VS SRS. Two patients (6%) remained neurologically stable, 2 (6%) patients had significant deficits, and 2 patients (6%) died. The actuarial risk of a first bleed after VS-SRS was 6% at 1 year, 12% at 3 years, and 19% at 7 years. Six patients (18%) underwent repeat SRS; all achieved nidus obliteration for an overall cure rate of 71%. Two patients (6%) had a permanent ARE after VS-SRS or repeat SRS. CONCLUSION: VS-SRS permitted large volume intracranial AVM to be treated with a low rate of ARE. Further study is needed on dose escalation and decreasing the treatment volume per stage to determine if this will increase the rate of obliteration with this technique. PMID- 28362924 TI - In Reply: Distraction, Compression, Extension, and Reduction Combined With Joint Remodeling and Extra-articular Distraction: Description of 2 New Modifications for Its Application in Basilar Invagination and Atlantoaxial Dislocation: Prospective Study in 79 Cases. PMID- 28362925 TI - Spontaneous Bilateral Carotid-Cavernous Fistulas Secondary to Cavernous Sinus Thrombosis. AB - Bilateral carotid cavernous fistulas are rare entities that can cause debilitating symptoms and can lead to more severe consequences if left untreated. Therefore, the recognition and adequate treatment of these pathologies is very important. We present 2 cases of bilateral carotid cavernous fistulas that arose as a result of cavernous sinus thrombosis. We review the literature and discuss the pathophysiology, symptomatology, management, and treatment of bilateral carotid cavernous fistulas. Within our own cases, treatment of the patients was varied. The patient in case 1 was successfully treated with endovascular therapy after a failed trial of anticoagulation. The patient in case 2 demonstrated resolution of bilateral carotid cavernous fistulas after anticoagulation therapy. Case 2 highlights the fact that certain cases of bilateral carotid cavernous fistulas due to cavernous sinus thrombosis may benefit from extensive anticoagulation therapy. If anticoagulation therapy is unsuccessful, endovascular therapy may prove beneficial in resolving the fistulous shunt. PMID- 28362927 TI - Understanding the Pathophysiology of Intracranial Aneurysm: The ICAN Project. AB - BACKGROUND: Understanding the pathophysiologic mechanism of intracranial aneurysm (IA) formation is a prerequisite to assess the potential risk of rupture. Nowadays, there are neither reliable biomarkers nor diagnostic tools to predict the formation or the evolution of IA. Increasing evidence suggests a genetic component of IA but genetics studies have failed to identify genetic variation causally related to IA. OBJECTIVE: To develop diagnostic and predictive tools for the risk of IA formation and rupture. METHODS: The French ICAN project is a noninterventional nationwide and multicentric research program. Each typical IA of bifurcation will be included. For familial forms, further IA screening will be applied among first-degree relatives. By accurate phenotype description with high throughput genetic screening, we aim to identify new genes involved in IA. These potential genetic markers will be tested in large groups of patients. Any relevant pathway identified will be further explored in a large cohort of sporadic carriers of IA, which will be well documented with clinical, biological, and imaging data. EXPECTED OUTCOMES: Discovering genetic risk factors, better understanding the pathophysiology, and identifying molecular mechanisms responsible for IA formation will be essential bases for the development of biomarkers and identification of therapeutic targets. DISCUSSION: Our protocol has many assets. A nationwide recruitment allows for the inclusion of large pedigrees with familial forms of IA. It will combine accurate phenotyping and comprehensive imaging with high-throughput genetic screening. Last, it will enable exploiting metadata to explore new pathophysiological pathways of interest by crossing clinical, genetic, biological, and imaging information. PMID- 28362926 TI - Launching Effectiveness Research to Guide Practice in Neurosurgery: A National Institute Neurological Disorders and Stroke Workshop Report. AB - This workshop addressed challenges of clinical research in neurosurgery. Randomized controlled clinical trials (RCTs) have high internal validity, but often insufficiently generalize to real-world practice. Observational studies are inclusive but often lack sufficient rigor. The workshop considered possible solutions, such as (1) statistical methods for demonstrating causality using observational data; (2) characteristics required of a registry supporting effectiveness research; (3) trial designs combining advantages of observational studies and RCTs; and (4) equipoise, an identified challenge for RCTs. In the future, advances in information technology potentially could lead to creation of a massive database where clinical data from all neurosurgeons are integrated and analyzed, ending the separation of clinical research and practice and leading to a new "science of practice." PMID- 28362928 TI - In Reply: Effect of Early Surgery, Material, and Method of Flap Preservation on Cranioplasty Infections: A Systematic Review. PMID- 28362929 TI - Metastatic Liposarcoma of the Skull Base: A Case Report and Review of Literature. AB - BACKGROUND AND IMPORTANCE: Myxoid liposarcoma is not an uncommon form of sarcoma. However, it usually affects the lower extremity long bones. Scapular involvement is extremely rare, as is a metastasis to the parasellar region. We present a case of liposarcoma of the skull base originating in the scapular region and metastasizing to the sellar and parasellar regions and provide a review of the pertinent literature. CLINICAL PRESENTATION: A 43-year-old female patient diagnosed with left scapular myxoid liposarcoma was treated with surgical resection. She had clear resection margins and was treated pre- and postoperatively with radiotherapy to the region. She remained asymptomatic for 2 years following surgery, after which she abruptly developed diplopia with right lateral gaze. There were no symptoms of raised intracranial pressure or impaired vision. Her examination was normal apart from complete right sixth nerve palsy. Imaging studies of the brain showed a large mass in the clivus eroding into the floor of the sella, encircling the right internal carotid artery in the cavernous sinus. The mass also displaced the sellar contents superiorly. An endonasal, endoscopic skull base approach was undertaken, and a subtotal resection was performed in an effort to avoid multiple cranial nerve pareses. CONCLUSION: Our literature search revealed that this case report is the first to document liposarcoma metastasis to the skull base originating from the scapular region. Subtotal surgical resection resulted in minimal improvement of the patient's sixth nerve palsy. Postoperative radiation was undertaken. A multidisciplinary approach on an individual patient basis is recommended. PMID- 28362931 TI - Outcome of Finger Extension After Nerve Transfer to Repair C7-T1 Brachial Plexus Palsy in Rats: Comparative Study of the Supinator Motor Branch Transfer to the Posterior Interosseous Nerve and the Contralateral C7 Transfer to the Lower Trunk. AB - BACKGROUND: Functional recovery following supinator motor branch transfer requires further investigation. OBJECTIVE: To compare the outcome of finger extension after supinator motor branch transfer or contralateral C7 (cC7) transfer in C7-T1 brachial plexus palsies in rats. METHODS: In this study, 120 adult rats underwent C7-T1 nerve root avulsion and received different nerve transfer repairs: group A, cC7 nerve transfer to the lower trunk; group B, supinator motor branch nerve transfer to the posterior interosseous nerve (PIN); and group C, no repair. The ethology of the rats, latency and amplitude of the compound muscle action potential from the PIN, muscle mass and muscle fiber cross sectional area of the extensor digitorum communis and extensor carpi ulnaris, and number of myelinated nerve fibers in the PIN were examined postoperatively. RESULTS: There was no finger extension in group C. We observed finger extension in groups A and B 50.2 +/- 5.66 and 13.1 +/- 2.08 days postoperatively, respectively. Finger extension restoration in group B was greater than that in group A at 4, 8, and 12 weeks postoperatively ( P < .05). Sixteen weeks after surgery, the recovery rate of the myelinated nerve fibers in group A was marginally higher than that in group B, but the difference was not significant. Of the other measured values, group B showed a greater and significant improvement compared to group A ( P < .05). CONCLUSION: Supinator motor branch transfer allows for faster recovery and is a more effective procedure for restoring finger extension in C7-T1 brachial plexus palsies. PMID- 28362930 TI - Past, Present, and Future of Neurosurgery in Uganda. AB - Neurosurgery in Uganda was virtually non-existent up until late 1960s. This changed when Dr. Jovan Kiryabwire spearheaded development of a neurosurgical unit at Mulago Hospital in Kampala. His work ethic and vision set the stage for rapid expansion of neurosurgical care in Uganda.At the beginning of the 2000s, Uganda was a country of nearly 30 million people, but had only 4 neurosurgeons. Neurosurgery's progress was plagued by challenges faced by many developing countries, such as difficulty retaining specialists, lack of modern hospital resources, and scarce training facilities. To combat these challenges 2 distinct programs were launched: 1 by Dr. Benjamin Warf in collaboration with CURE International, and the other by Dr. Michael Haglund from Duke University. Dr. Warf's program focused on establishing a facility for pediatric neurosurgery. Dr. Haglund's program to increase neurosurgical capacity was founded on a "4 T's Paradigm": Technology, Twinning, Training, and Top-Down. Embedded within this paradigm was the notion that Uganda needed to train its own people to become neurosurgeons, and thus Duke helped establish the country's first neurosurgery residency training program.Efforts from overseas, including the tireless work of Dr. Benjamin Warf, have saved thousands of children's lives. The influx of the Duke Program caused a dynamic shift at Mulago Hospital with dramatic effects, as evidenced by the substantial increase in neurosurgical capacity. The future looks bright for neurosurgery in Uganda and it all traces back to a rural village where 1 man had a vision to help the people of his country. PMID- 28362932 TI - Commentary: Pipeline Embolization Device for Small Intracranial Aneurysms: Evaluation of Safety and Efficacy in a Multicenter Cohort. PMID- 28362933 TI - In Reply: Surfer's Myelopathy: A Rare Form of Spinal Cord Infarction in Novice Surfers: A Systematic Review. PMID- 28362934 TI - Three-Dimensional Printed Modeling of Diffuse Low-Grade Gliomas and Associated White Matter Tract Anatomy. AB - BACKGROUND: Diffuse low-grade gliomas (DLGGs) represent several pathological entities that infiltrate and invade cortical and subcortical structures in the brain. OBJECTIVE: To describe methods for rapid prototyping of DLGGs and surgically relevant anatomy. METHODS: Using high-definition imaging data and rapid prototyping technologies, we were able to generate 3 patient DLGGs to scale and represent the associated white matter tracts in 3 dimensions using advanced diffusion tensor imaging techniques. RESULTS: This report represents a novel application of 3-dimensional (3-D) printing in neurosurgery and a means to model individualized tumors in 3-D space with respect to subcortical white matter tract anatomy. Faculty and resident evaluations of this technology were favorable at our institution. CONCLUSION: Developing an understanding of the anatomic relationships existing within individuals is fundamental to successful neurosurgical therapy. Imaging-based rapid prototyping may improve on our ability to plan for and treat complex neuro-oncologic pathology. PMID- 28362935 TI - Evolution and Transmission of Carbapenem-Resistant Klebsiella pneumoniae Expressing the blaOXA-232 Gene During an Institutional Outbreak Associated With Endoscopic Retrograde Cholangiopancreatography. AB - Background: Whole-genome sequencing (WGS) is an emerging and powerful technique by which to perform epidemiological studies in outbreak situations. Methods: WGS was used to identify and evaluate an outbreak of OXA-232-expressing carbapenem resistant Klebsiella pneumoniae (CRKP) transmitted to 16 patients over the course of 40 weeks via endoscopic retrograde cholangiopancreatography procedures at a single institution. WGS was performed on 32 OXA-232 CRKP isolates (1-7 per patient) and single-nucleotide variants (SNVs) were analyzed, with reference to the index patient's isolate. Results: Interhost genetic diversity of isolates was between 0 and 15 SNVs during the outbreak; molecular clock calculations estimated 12.31 substitutions per genome per year (95% credibility interval, 7.81-17.05). Both intra- and interpatient diversification at the plasmid and transposon level was observed, significantly impacting the antibiogram of outbreak isolates. The majority of isolates evaluated (n = 27) harbored a blaCTX-M-15 gene, but some (n = 5) lacked the transposon carrying this gene, which resulted in susceptibility to aztreonam and third- and fourth-generation cephalosporins. Similarly, an isolate from a colonized patient lacked the transposon carrying rmtF and aac(6')lb genes, resulting in susceptibility to aminoglycosides. Conclusions: This study broadens the understanding of how bacteria diversify at the genomic level over the course of a defined outbreak and provides reference for future outbreak investigations. PMID- 28362936 TI - High Frequency of Blackwater Fever Among Children Presenting to Hospital With Severe Febrile Illnesses in Eastern Uganda. AB - Background: In the Fluid Expansion as a Supportive Treatment (FEAST) trial, an unexpectedly high proportion of participants from eastern Uganda presented with blackwater fever (BWF). Methods: We describe the prevalence and outcome of BWF among trial participants and compare the prevalence of 3 malaria-protective red blood cell polymorphisms in BWF cases vs both trial (non-BWF) and population controls. Results: Of 3170 trial participants, 394 (12.4%) had BWF. The majority (318 [81.0%]) presented in eastern Uganda and were the subjects of further analysis. BWF cases typically presented with both clinical jaundice (254/318 [80%]) and severe anemia (hemoglobin level <5 g/dL) (238/310 [77%]). Plasmodium falciparum parasitemia was less frequent than in non-BWF controls, but a higher proportion were positive for P. falciparum histidine rich protein 2 (192/246 [78.0%]) vs 811/1154 [70.3%]; P = .014), suggesting recent antimalarial treatment. Overall, 282 of 318 (88.7%) received transfusions, with 94 of 282 (33.3%) and 9 of 282 (3.4%) receiving 2 or 3 transfusions, respectively. By day 28, 39 of 318 (12.3%) BWF cases and 154 of 1554 (9.9%) non-BWF controls had died (P = .21), and 7 of 255 (3.0%) vs 13/1212 (1%), respectively, had severe anemia (P = .036). We found no association with G6PD deficiency. The prevalence of both the sickle cell trait (10/218 [4.6%]) and homozygous alpha+thalassemia (8/216 [3.7%]) were significantly lower among cases than among population controls (334/2123 [15.7%] and 141/2114 [6.6%], respectively), providing further support for the role of malaria. Conclusions: We report the emergence of BWF in eastern Uganda, a condition that, according to local investigators, was rare until the last 7 years. We speculate that this might relate to the introduction of artemisinin-based combination therapies. Further studies investigating this possibility are urgently required. PMID- 28362937 TI - Diagnostic Performance of Tuberculosis-Specific IgG Antibody Profiles in Patients with Presumptive Tuberculosis from Two Continents. AB - Background: Development of rapid diagnostic tests for tuberculosis is a global priority. A whole proteome screen identified Mycobacterium tuberculosis antigens associated with serological responses in tuberculosis patients. We used World Health Organization (WHO) target product profile (TPP) criteria for a detection test and triage test to evaluate these antigens. Methods: Consecutive patients presenting to microscopy centers and district hospitals in Peru and to outpatient clinics at a tuberculosis reference center in Vietnam were recruited. We tested blood samples from 755 HIV-uninfected adults with presumptive pulmonary tuberculosis to measure IgG antibody responses to 57 M. tuberculosis antigens using a field-based multiplexed serological assay and a 132-antigen bead-based reference assay. We evaluated single antigen performance and models of all possible 3-antigen combinations and multiantigen combinations. Results: Three antigen and multiantigen models performed similarly and were superior to single antigens. With specificity set at 90% for a detection test, the best sensitivity of a 3-antigen model was 35% (95% confidence interval [CI], 31-40). With sensitivity set at 85% for a triage test, the specificity of the best 3-antigen model was 34% (95% CI, 29-40). The reference assay also did not meet study targets. Antigen performance differed significantly between the study sites for 7/22 of the best-performing antigens. Conclusions: Although M. tuberculosis antigens were recognized by the IgG response during tuberculosis, no single antigen or multiantigen set performance approached WHO TPP criteria for clinical utility among HIV-uninfected adults with presumed tuberculosis in high-volume, urban settings in tuberculosis-endemic countries. PMID- 28362939 TI - Primary Prophylaxis for Cryptococcosis With Fluconazole in Human Immunodeficiency Virus-Infected Patients With CD4 T-Cell Counts <100 Cells/uL and Receiving Antiretroviral Therapy. AB - A prospective observational cohort study was conducted in 302 human immunodeficiency virus-infected patients who had a CD4 T-cell count <100 cells/uL and negative serum cryptococcal antigen initiating antiretroviral therapy in a resource-limited setting. During 2-year follow-up, there were no differences of survival rates and occurrences of newly diagnosed cryptococcosis between patients with and without fluconazole for primary prophylaxis of cryptococcosis. PMID- 28362940 TI - Different Epidemiology of Hospital-Acquired Bloodstream Infections Between Small Community Hospitals and Large Community Hospitals. PMID- 28362941 TI - Reply to Buetti et al. PMID- 28362938 TI - The Use of Noncarbapenem beta-Lactams for the Treatment of Extended-Spectrum beta Lactamase Infections. AB - The continued rise in infections caused by extended-spectrum beta-lactamase (ESBL)-producing pathogens is recognized globally as one of the most pressing concerns facing the healthcare community. Carbapenems are widely regarded as the antibiotics of choice for the treatment of ESBL-producing infections, even when in vitro activity to other beta-lactams has been demonstrated. However, indiscriminant carbapenem use is not without consequence, and carbapenem overuse has contributed to the emergence of carbapenem-resistant Enterobacteriaceae. The use of non-carbapenem beta-lactams for the treatment of ESBL infections has yielded conflicting results. In this review, we discuss the available data for the use of cephamycins, cefepime, piperacillin-tazobactam, ceftolozane tazobactam, and ceftazidime-avibactam for the treatment of ESBL infections. PMID- 28362942 TI - Old Antibiotics for Tuberculosis. PMID- 28362943 TI - Reply to Raoult. PMID- 28362944 TI - Zika Virus Infects Human Fetal Brain Microglia and Induces Inflammation. AB - Background: The unprecedented reemergence of Zika virus (ZIKV) has startled the world with reports of increased microcephaly in Brazil. ZIKV can infect human neural progenitors and impair brain growth. However, direct evidence of ZIKV infection in human fetal brain tissues remains elusive. Methods: Investigations were performed with brain cell preparations obtained from 9 donors. Virus infectivity was assessed by detection of virus antigen by flow cytometry together with various hematopoietic cell surface markers. Virus replication was determined by viral RNA quantification. Cytokine levels in supernatant obtained from virus infected fetal brain cells were measured simultaneously in microbead-based immunoassays. Results: We also show that ZIKV infection was particularly evident in hematopoietic cells with microglia, the brain-resident macrophage population being one of the main targets. Infection induces high levels of proinflammatory immune mediators such as interleukin 6 (IL-6), tumor necrosis factor alpha (TNF alpha), interleukin 1beta (IL-1beta), and monocyte chemotactic protein 1 (MCP-1). Conclusions: Our results highlight an important role for microglia and neuroinflammation during congenital ZIKV pathogenesis. PMID- 28362946 TI - Invasive Candidiasis in Very Premature Neonates: Tiny Tots With Big Problems. PMID- 28362945 TI - Complex Routes of Nosocomial Vancomycin-Resistant Enterococcus faecium Transmission Revealed by Genome Sequencing. AB - Background: Vancomycin-resistant Enterococcus faecium (VREfm) is a leading cause of nosocomial infection. Here, we describe the utility of whole-genome sequencing in defining nosocomial VREfm transmission. Methods: A retrospective study at a single hospital in the United Kingdom identified 342 patients with E. faecium bloodstream infection over 7 years. Of these, 293 patients had a stored isolate and formed the basis for the study. The first stored isolate from each case was sequenced (200 VREfm [197 vanA, 2 vanB, and 1 isolate containing both vanA and vanB], 93 vancomycin-susceptible E. faecium) and epidemiological data were collected. Genomes were also available for E. faecium associated with bloodstream infections in 15 patients in neighboring hospitals, and 456 patients across the United Kingdom and Ireland. Results: The majority of infections in the 293 patients were hospital-acquired (n = 249) or healthcare-associated (n = 42). Phylogenetic analysis showed that 291 of 293 isolates resided in a hospital associated clade that contained numerous discrete clusters of closely related isolates, indicative of multiple introductions into the hospital followed by clonal expansion associated with transmission. Fine-scale analysis of 6 exemplar phylogenetic clusters containing isolates from 93 patients (32%) identified complex transmission routes that spanned numerous wards and years, extending beyond the detection of conventional infection control. These contained both vancomycin-resistant and -susceptible isolates. We also identified closely related isolates from patients at Cambridge University Hospitals NHS Foundation Trust and regional and national hospitals, suggesting interhospital transmission. Conclusions: These findings provide important insights for infection control practice and signpost areas for interventions. We conclude that sequencing represents a powerful tool for the enhanced surveillance and control of nosocomial E. faecium transmission and infection. PMID- 28362948 TI - Spatial Analysis of the Human Immunodeficiency Virus Epidemic among Men Who Have Sex with Men in China, 2006-2015. AB - Background: Studies have shown a recent upsurge in human immunodeficiency virus (HIV) burden among men who have sex with men (MSM) in China, especially in urban areas. For intervention planning and resource allocation, spatial analyses of HIV/AIDS case-clusters were required to identify epidemic foci and trends among MSM in China. Methods: Information regarding MSM recorded as HIV/AIDS cases during 2006-2015 were extracted from the National Case Reporting System. Demographic trends were determined through Cochran-Armitage trend tests. Distribution of case-clusters was examined using spatial autocorrelation. Spatial temporal scan was used to detect disease clustering. Spatial correlations between cases and socioenvironmental factors were determined by spatial regression. Results: Between 2006 and 2015, in China, 120 371 HIV/AIDS cases were identified among MSM. Newly identified HIV/AIDS cases among self-reported MSM increased from 487 cases in 2006 to >30 000 cases in 2015. Among those HIV/AIDS cases recorded during 2006-2015, 47.0% were 20-29 years old and 24.9% were aged 30-39 years. Based on clusters of HIV/AIDS cases identified through spatial analysis, the epidemic was concentrated among MSM in large cities. Spatial-temporal clusters contained municipalities, provincial capitals, and main cities such as Beijing, Shanghai, Chongqing, Chengdu, and Guangzhou. Spatial regression analysis showed that sociodemographic indicators such as population density, per capita gross domestic product, and number of county-level medical institutions had statistically significant positive correlations with HIV/AIDS among MSM. Conclusions: Assorted spatial analyses revealed an increasingly concentrated HIV epidemic among young MSM in Chinese cities, calling for targeted health education and intensive interventions at an early age. PMID- 28362947 TI - Geographic Differences in Temporal Incidence Trends of Hepatitis C Virus Infection Among People Who Inject Drugs: The InC3 Collaboration. AB - Background: We determined temporal trends (1985-2011) in hepatitis C virus (HCV) incidence and associated behavioral exposures for people who inject drugs (PWID) from the United States (Boston, Baltimore, and San Francisco), Canada (Montreal), the Netherlands (Amsterdam), and Australia (Sydney and Melbourne). Methods: Using population-based cohort data from HCV-negative PWID, we calculated overall and within-city HCV incidence trends, HCV rates by study enrollment period (1985 2011), and temporal trends in exposure behaviors. Poisson regression models estimated trends in HCV incidence over calendar-time. Survival models identified risk factors for HCV incidence across cities and estimated independent effects of city and calendar period on HCV infection risk. Results: Among 1391 initially HCV negative participants followed prospectively (1644.5 person-years of observation [PYO]), 371 HCV incident infections resulted in an overall incidence of 22.6 per 100 PYO (95% confidence interval [CI], 20.4-25.0). Incidence was highest and remained elevated in Baltimore (32.6/100 PYO), San Francisco (24.7/100 PYO), and Montreal (23.5/100 PYO), lowest in Melbourne and Amsterdam (7.5/100 PYO and 13.1/100 PYO, respectively), and moderate (21.4/100 PYO) in Sydney. Higher rates of syringe and equipment sharing and lower prevalence of opioid agonist therapy were associated with HCV incidence in cities with the highest incidence. Risk for infection dropped by 18% for every 3-year increase in calendar-time (adjusted hazard ratio, 0.8 [95% CI, .8-.9]) in the multivariable model. Conclusions: Differences in prevention strategies and injecting contexts may explain the ongoing high HCV incidence in these North American cities and emphasize the need for scale-up of opioid agonist therapy and increased coverage of needle and syringe programs in North America. PMID- 28362951 TI - Treatment of Early Syphilis in HIV: What Do We Really Know? PMID- 28362949 TI - Two Doses of Inactivated Influenza Vaccine Improve Immune Response in Solid Organ Transplant Recipients: Results of TRANSGRIPE 1-2, a Randomized Controlled Clinical Trial. AB - Background: Influenza vaccine effectiveness is not optimal in solid organ transplant recipients (SOTR). We hypothesized that a booster dose might increase it. Methods: TRANSGRIPE 1-2 is a phase 3, randomized, controlled, multicenter, open-label clinical trial. Patients were randomly assigned (1:1 stratified by study site, type of organ, and time since transplantation) to receive 1 dose (control group) or 2 doses (booster group) of the influenza vaccine 5 weeks apart. Results: A total of 499 SOTR were enrolled. Although seroconversion at 10 weeks did not meet significance in the modified intention-to-treat population, seroconversion rates were significantly higher in the booster arm for the per protocol population (53.8% vs 37.6% for influenza A(H1N1)pdm; 48.1% vs 32.3% for influenza A(H3N2); and 90.7% vs 75% for influenza B; P < .05). Furthermore, seroprotection at 10 weeks was higher in the booster group: 54% vs 43.2% for A(H1N1)pdm; 56.9% vs 45.5% for A(H3N2); and 83.4% vs 71.8% for influenza B (P < .05). The number needed to treat to seroprotect 1 patient was <10. The clinical efficacy (99.2% vs 98.8%) and serious adverse events (6.4% vs 7.5%) were similar for both groups. Conclusions: In SOTR, a booster strategy 5 weeks after standard influenza vaccination is safe and effective and induces an increased antibody response compared with standard influenza vaccination consisting of a single dose. Clinical Trials Registration: EudraCT (2011-003243-21). PMID- 28362952 TI - Timing of Prenatal Tdap Immunization and Protection Against Pertussis. PMID- 28362950 TI - Crisis in Infectious Diseases: 2 Decades Later. PMID- 28362953 TI - Reply to Abu Raya and Giles. PMID- 28362956 TI - Herpes Zoster Vaccine and the Medicare Population. PMID- 28362955 TI - Effectiveness and Duration of Protection Provided by the Live-attenuated Herpes Zoster Vaccine in the Medicare Population Ages 65 Years and Older. AB - Background: Tens of millions of seniors are at risk of herpes zoster (HZ) and its complications. Live attenuated herpes zoster vaccine (HZV) reduces that risk, although questions regarding effectiveness and durability of protection in routine clinical practice remain. We used Medicare data to investigate HZV effectiveness (VE) and its durability. Methods: This retrospective cohort study included beneficiaries ages >=65 years during January 2007 through July 2014. Multiple adjustments to account for potential bias were made. HZV-vaccinated beneficiaries were matched to unvaccinated beneficiaries (primary analysis) and to HZV-unvaccinated beneficiaries who had received pneumococcal vaccination (secondary analysis). HZ outcomes in community and hospital settings were analyzed, including ophthalmic zoster (OZ) and postherpetic neuralgia (PHN). Results: Among eligible beneficiaries (average age 77 years), the primary analysis found VE for community HZ of 33% (95% CI: 32%-35%) and 19% (95% CI: 17% 22%), for the first 3, and subsequent 4+ years postvaccination, respectively. In the secondary analysis, VE was, respectively, 37% (95% CI: 36%-39%) and 22% (95% CI: 20%-25%). In the primary analysis, VE for PHN was 57% (95% CI: 52%-61%) and 45% (95% CI: 36%-53%) in the first 3 and subsequent 4+ years, respectively; VE for hospitalized HZ was, respectively, 74% (95% CI: 67%-79%) and 55% (95% CI: 39% 67%). Differences in VE by age group were not significant. Conclusions: In both the primary and secondary analyses, HZV provided protection against HZ across all ages, but effectiveness declined over time. VE was higher and better preserved over time for PHN and HZ-associated hospitalizations than for community HZ. PMID- 28362954 TI - Chronic Granulomatous Disease in Patients Reaching Adulthood: A Nationwide Study in France. AB - Background: Although prognosis of Chronic Granulomatous Disease (CGD) has greatly improved, few studies have focused on its long-term outcome. We studied the clinical course and sequelae of CGD patients diagnosed before age 16, at various adult time points. Method: Cross-sectional French nationwide retrospective study of patients screened through the National Reference Center for Primary Immunodeficiencies (CEREDIH) registry. Results: Eighty CGD patients (71 males [88.7%], 59 X-linked [73.7%], median age 23.9 years [minimum, 16.6; maximum, 59.9]) were included, Median ages at diagnosis and last follow-up were 2.52 and 23.9 years, respectively. Seven patients underwent hematopoietic stem cell transplantation. A total of 553 infections requiring hospitalization occurred in 2017 patient-years. The most common site of infection was pulmonary (31%). Aspergillus spp. (17%) and Staphylococcus aureus (10.7%) were the commonest pathogens. A total of 224 inflammatory episodes occurred in 71 patients, mainly digestive (50%). Their characteristics as well as their annual frequency did not vary before and after age 16. Main sequelae were a small adult height and weight and mild chronic restrictive respiratory failure. At age 16, only 53% of patients were in high school. After age 30 years, 9/13 patients were working. Ten patients died during adulthood. Conclusions: Adult CGD patients displayed similar characteristics and rates of severe infections and inflammatory episodes that those of childhood. The high rate of handicap has become a matter of medical and social consideration. Careful follow-up in centers of expertise is strongly recommended and an extended indication of curative treatment by HSCT should be considered. PMID- 28362957 TI - Low-pressure Hydrocephalus in Children: A Case Series and Review of the Literature. AB - Background: Low-pressure hydrocephalus (LPH) is a rare phenomenon characterized by a clinical picture consistent with elevated intracranial pressure (ICP) and ventricular enlargement, but also a well-functioning shunt and low or negative ICP. Objective: To report our experience in evaluating this challenging problem. Methods: Patients with LPH were identified from several sources, including institutional procedural databases and personal case logs. Electronic medical records were reviewed to collect demographic, clinical, surgical, and radiographic data to determine the presence of LPH. Each patient's clinical course, including presentation, management, and outcome, is reported. Results: Thirty instances of LPH were identified in 29 patients. Eleven cases (37.9%) of LPH were after lumbar puncture (LP), and 19 cases (62.1%) occurred without any preceding spinal procedure. Among the post-LP patients, conservative measures alone were successful in 3 cases (27%); lumbar blood patch was successful in 2 cases (18%); and 6 cases (55%) required external cerebrospinal fluid (CSF) drainage. Of the spontaneous cases, 5 patients did not receive the full spectrum of treatment because of terminal prognosis. Of the remaining 14 patients, 11 (78.6%) required external CSF drainage. Post-LP patients required fewer days of external CSF drainage (median, 4 [range, 0-12] vs median, 11 [range, 0-90]) and had a shorter hospital stay (median, 2 [range, 2-16] vs median, 8 [range, 0-26]). Conclusion: This study represents the largest series of LPH. Although its pathophysiology remains a mystery, there are a variety of management options. Multiple procedures and a protracted hospital stay are often required to successfully treat LPH. PMID- 28362958 TI - Outcomes of Transferring a Healthy Motor Fascicle From the Radial Nerve to a Branch for the Triceps to Recover Elbow Extension in Partial Brachial Plexus Palsy. AB - Background: Triceps reinnervation is an important objective to pursue when repairing the brachial plexus for cases with upper roots injuries, and a number of different techniques have been developed in order to restore elbow extension in such cases. Objective: To demonstrate the surgical outcomes associated with the technique of transferring a single healthy motor fascicle from the radial nerve of the affected arm to a branch innervating 1 of the 3 heads of the triceps. Methods: A retrospective study of 13 adult patients sustaining an upper trunk syndrome associated with total elbow extension palsy who underwent the proposed technique as part of the surgical planning for reconstruction of the brachial plexus. Results: Outcomes scored as M4 for elbow extension were noted in 9 cases (70%), M3 in 3 (23%), and M1 in 1 subject (7%). No patient considered the postoperative strength for carpal or finger extension as impaired. There were no differences in outcomes by using a fascicle activating carpal or finger extension as donor, as well as regarding the use of the branch to the medial or lateral head of the triceps as the recipient. Conclusion: The technique of transferring a healthy motor fascicle from the radial nerve of the affected side to one of its nonfunctional motor branches to the triceps is an effective and safe procedure for recovering elbow extension function in patients sustaining partial injuries of the brachial plexus. PMID- 28362959 TI - Cubital Tunnel Syndrome: Incidence and Demographics in a National Administrative Database. AB - Background: Compressive neuropathy of the ulnar nerve at the elbow, or cubital tunnel syndrome (CuTS), is the second most common entrapment neuropathy of the upper extremity after carpal tunnel syndrome. While several studies have reported risk factors and outcomes for select populations (mostly surgical), it is difficult to interpret these data without an accurate measure of CuTS disease burden in the general population. Objective: To estimate the incidence of CuTS among US health plan enrollees, using a large administrative health care claims database comprised of individuals from all 50 states. Methods: An administrative database of commercial insurance beneficiaries was queried for diagnosis and treatment of CuTS over a 6-yr period. We examined subsequent claims to determine frequency of subsequent surgical treatment. Descriptive statistics were used to determine the association of incident cases and surgical treatment with age and gender. Results: The estimated adjusted incidence rate of CuTS is 30.0 per 100 000 person-years. Of the 53 401 identified new cases within this cohort from 2006 to 2012, 41.3% were treated surgically. Incident cases were identified more frequently in men than in women (31.2 vs 28.8 cases per 100 000 person-years), though we observed more cases in women than in men below 50 yr of age (20.9 vs 19.5 cases per 100 000 person-years). Overall, incident cases increase with age in both men and women. In addition to incident cases being more common with increasing age, the percentage of cases treated surgically also increases with age (surgery in 34.4% of cases in the 18-30 yr group vs 48.8% of cases in the 60 65 yr group). Conclusion: The purpose of this study was to estimate the incidence of CuTS among US health plan enrollees. This is the largest published study on the incidence of CuTS, and the first to look at a US population. The overall adjusted incidence of CuTS was 30.0 per 100 000 person-years. Of patients who developed CuTS, 41.3% were treated surgically during the study period. Our results corroborate previously reported literature suggesting incidence increases significantly with age, with a slightly higher incidence in males. A high percentage of people who were diagnosed with CuTS and ended up receiving surgical intervention (41.3%) were older males. These results may aid practitioners in providing some basic prognostic information to patients who develop CuTS. PMID- 28362960 TI - Ipsilateral Motor Innervation Discovered Incidentally on Intraoperative Monitoring: A Case Report. AB - Background and importance: Lesions in the corticospinal tract above the decussation at the medullary pyramids almost universally produce contralateral deficits. Rare cases of supratentorial lesions causing ipsilateral motor deficits have been reported previously, but only ever found secondary to stroke or congenital pyramidal tract malformations. Clinical presentation: Herein, we report a case of ipsilateral corticospinal tract innervation discovered incidentally with intraoperative monitoring during a microsurgical resection of a vestibular schwannoma. Intraoperative monitoring with electrical transcranial stimulation of the frontal scalp triggered motor-evoked potentials in the ipsilateral arms. The uncrossed pathways were later confirmed with MRI tractography using diffusion tensor imaging. Conclusion: To the best of our knowledge, this is the first case of isolated ipsilateral motor innervation of the corticospinal tract discovered incidentally during a neurosurgical procedure. Given the increasing use of intraoperative monitoring, this case underscores the importance of cautious interpretation of seemingly discordant neurophysiological findings. Once technical issues have been ruled out, ipsilateral motor innervation may be considered as a possible explanation and neurosurgeons should be aware of the existence of this rare anatomic variant. PMID- 28362961 TI - Audiovestibular Handicap and Quality of Life in Patients With Vestibular Schwannoma and "Excellent" Hearing. AB - BACKGROUND: Studies examining patient-reported outcomes in subjects with vestibular schwannoma (VS) and "excellent" hearing are lacking. OBJECTIVE: To assess patient-reported audiovestibular handicap and overall quality of life (QoL) in VS patients with class A hearing in both ears. METHODS: Among 539 VS patients treated during 1998 to 2008, we identified 296 patients with either bilateral class A (AA) hearing or 1 good ear and 1 deaf ear (AD) according to the American Academy of Otolaryngology-Head and Neck Surgery classification. Patients responded to validated hearing, tinnitus, and dizziness handicap inventories and 2 QoL questionnaires, and the 2 groups were compared. A reference group of 103 adults filled out the same questionnaires. RESULTS: Forty-nine patients (16.6%) had class AA and 247 patients (83.4%) had class AD hearing. AA patients scored poorer than control subjects without tumor on all handicap questionnaires ( P < .001) and a VS-specific QoL instrument ( P = .006). Con-versely, AA patients scored significantly better than patients with AD on the hearing inventory and the disease-specific QoL instrument ( P < .001), but no difference was found between these groups with regard to tinnitus and dizziness. The hearing disability score was approximately 3 times poorer for AA patients compared with control subjects without tumor; a third of AA patients reported a hearing handicap. CONCLUSION: Patients with VS and bilateral class A hearing report significantly poorer hearing handicap than control subjects without tumor but better hearing than those with unilateral deafness. When patients with bilateral class A hearing are counseled, it should be noted that one-third of patients experience self-perceived hearing handicap. PMID- 28362962 TI - Correlation of Subjective Hospital Compare Metrics With Objective Outcomes of Cranial Neurosurgical Procedures in New York State. AB - Background: Public reporting is at the forefront of health care reform. Objective: To investigate whether patient satisfaction as expressed in a public reporting platform correlates with objective outcomes for cranial neurosurgery patients. Methods: We performed a cohort study involving patients undergoing cranial neurosurgery from 2009 to 2013 who were registered in the Statewide Planning and Research Cooperative System database. This cohort was merged with the corresponding data from the Centers for Medicare and Medicaid Services Hospital Compare website. The association of patient satisfaction metrics with outcomes was examined with the use of a propensity-adjusted regression model. Results: Overall, 19 591 patients underwent cranial neurosurgery during the study. Using a propensity-adjusted multivariable regression analysis, we demonstrated that hospitals with a greater percentage of patient-assigned "high" scores had decreased mortality (OR, 0.60; 95% CI, 0.53-0.67), rate of discharge to rehabilitation (OR, 0.93; 95% CI, 0.88-0.98), length of stay (adjusted difference, -1.29; 95% CI, -1.46 to -1.13), and hospitalization charges (adjusted difference, -23%; 95% CI, -36% to -9%) after cranial neurosurgery. Similar associations were identified for hospitals with a higher percentage of patients, who would recommend these institutions to others. Conclusion: In a Centers for Medicare and Medicaid Services Hospital Compare-Statewide Planning and Research Cooperative System merged dataset, we observed an association of higher performance in patient satisfaction measures with decreased mortality, rate of discharge to rehabilitation, hospitalization charges, and length of stay. PMID- 28362964 TI - Commentary: An Introduction to Leadership Self-Assessment at the Society of Neurological Surgeons Post-Graduate Year 1 Boot Camp: Observations and Commentary. AB - Recent trends in graduate medical education have emphasized the mastery of nontechnical skills, especially leadership, for neurosurgical trainees. Accordingly, we introduced leadership development and self-awareness training to interns attending the Society of Neurological Surgeons Post-Graduate Year 1 Boot Camp in the Northeast (New England/New York/New Jersey) region in 2015. Feedback about the session was collected from interns. While neurosurgical interns conveyed a desire to receive more information on improving their leadership skills, most indicated that guidance seemed to be lacking in this critical area. We discuss some of the professional development needs uncovered during this process. PMID- 28362963 TI - Lumbar Spinal Stenosis Associated With Degenerative Lumbar Spondylolisthesis: A Systematic Review and Meta-analysis of Secondary Fusion Rates Following Open vs Minimally Invasive Decompression. AB - Background: Decompression without fusion is a treatment option in patients with lumbar spinal stenosis (LSS) associated with stable low-grade degenerative spondylolisthesis (DS). A minimally invasive unilateral laminotomy (MIL) for "over the top" decompression might be a less destabilizing alternative to traditional open laminectomy (OL). Objective: To review secondary fusion rates after open vs minimally invasive decompression surgery. Methods: We performed a literature search in Pubmed/MEDLINE using the keywords "lumbar spondylolisthesis" and "decompression surgery." All studies that separately reported the outcome of patients with LSS+DS that were treated by OL or MIL (transmuscular or subperiosteal route) were included in our systematic review and meta-analysis. The primary end point was secondary fusion rate. Secondary end points were total reoperation rate, postoperative progression of listhetic slip, and patient satisfaction. Results: We identified 37 studies (19 with OL, 18 with MIL), with a total of 1156 patients, that were published between 1983 and 2015. The studies' evidence was mostly level 3 or 4. Secondary fusion rates were 12.8% after OL and 3.3% after MIL; the total reoperation rates were 16.3% after OL and 5.8% after MIL. In the OL cohort, 72% of the studies reported a slip progression compared to 0% in the MIL cohort, respectively. After OL, satisfactory outcome was 62.7% compared to 76% after MIL. Conclusion: In patients with LSS and DS, minimally invasive decompression is associated with lower reoperation and fusion rates, less slip progression, and greater patient satisfaction than open surgery. PMID- 28362965 TI - Transsylvian Selective Amygdalohippocampectomy for Mesiotemporal Epilepsy: Experience with 162 Procedures. AB - Background: Mesial temporal lobe epilepsy (MTLE) is one of the most common forms of epilepsy refractory to medical therapy. Among different surgical approaches, selective amygdalohippocampectomy has gained increasing interest for its rationale of isolated removal of the epileptogenic mesiotemporal area. Objective: To summarize our experience with surgical treatment of MTLE in 162 patients using the transsylvian approach and to analyze possible effects of length of hippocampal resection and postoperative gliosis on seizure and cognitive outcome. Methods: Clinical, radiological, histopathological and neuropsychological findings of 162 patients with MTLE who were operated by the senior author between 1993 and 2012 were retrospectively evaluated. Postoperative follow-up mounted up to 240 months (59 +/- 56 months). Seizure outcome was available in 156 patients with minimum follow-up of 3 months. Extent of hippocampal resection was evaluated in 70 and postoperative gliosis in 62 of the 92 patients. Results were then correlated with seizure and cognitive outcome. Results: Of 134 patients with a follow-up of at least 1 year, 85 (63.4%) remained completely seizure free (Engel Ia) and 118 (88.0%) had a worthwhile improvement after surgery (Engel I+II). There was no perioperative death. Permanent morbidity was encountered in 4 patients (2.5%). Neither the extent of hippocampal resection nor postoperative gliosis correlated with seizure outcome or postoperative memory performance. Conclusion: Transsylvian selective amygdalohippocampectomy can be recommended as an adequate procedure for the surgical treatment of mesiotemporal epilepsy with favorable epileptological results and acceptable morbidity. PMID- 28362966 TI - Does MIS Surgery Allow for Shorter Constructs in the Surgical Treatment of Adult Spinal Deformity? AB - Background: The length of construct can potentially influence perioperative risks in adult spinal deformity (ASD) surgery. A head-to-head comparison between open and minimally invasive surgery (MIS) techniques for treatment of ASD has yet to be performed. Objective: To examine the impact of MIS approaches on construct length and clinical outcomes in comparison to traditional open approaches when treating similar ASD profiles. Methods: Two multicenter databases for ASD, 1 involving MIS procedures and the other open procedures, were propensity matched for clinical and radiographic parameters in this observational study. Inclusion criteria were ASD and minimum 2-year follow-up. Independent t -test and chi square test were used to evaluate and compare outcomes. Results: A total of 1215 patients were identified, with 84 patients matched in each group. Statistical significance was found for mean levels fused (4.8 for circumferential MIS [cMIS] and 10.1 for open), mean interbody fusion levels (3.6 cMIS and 2.4 open), blood loss (estimated blood loss 488 mL cMIS and 1762 mL open), and hospital length of stay (6.7 days cMIS and 9.7 days open). There was no significant difference in preoperative radiographic parameters or postoperative clinical outcomes (Owestry Disability Index and visual analog scale) between groups. There was a significant difference in postoperative lumbar lordosis (43.3 degrees cMIS and 49.8 degrees open) and pelvic incidence-lumbar lordosis correction (10.6 degrees cMIS and 5.2 degrees open) in the open group. There was no significant difference in reoperation rate between the 2 groups. Conclusion: MIS techniques for ASD may reduce construct length, reoperation rates, blood loss, and length of stay without affecting clinical and radiographic outcomes when compared to a similar group of patients treated with open techniques. PMID- 28362967 TI - Anticoagulation vs Antiplatelet Treatment in Patients with Carotid and Vertebral Artery Dissection: A Study of 370 Patients and Literature Review. AB - Background: Dissection of the carotid and vertebral arteries is an important cause of stroke in young patients. Objective: The objective of this study is to compare antithrombotic treatments in patients with carotid and vertebral dissections. Methods: Three hundred seventy patients with carotid and vertebral artery dissections were included. Univariate and multivariate analyses were conducted to analyze the association between treatment and new or recurrent events and clinical outcome. Results: Mean follow-up was 24.3 months. In patients with spontaneous dissection, 55% received antiplatelets, 29.4% anticoagulation, and 12.6% combined treatment. New or recurrent ischemic and hemorrhagic events occurred in 9.6% of patients on antiplatelets, 10.4% on anticoagulation, and 13.3% on combined treatment. For traumatic dissection, 58.3% received antiplatelets, 26.9% anticoagulation, and 10.2% combined treatment. New or recurrent ischemic and hemorrhagic events occurred in 6.9% on antiplatelets, 11.1% on anticoagulation, and 20% on combined treatment. In patients with intracranial dissection, 63.1% were started on antiplatelets, 19.7% on anticoagulation, and 14.5% on combined treatment. Ischemic and hemorrhagic events occurred in 8.5% on antiplatelet treatment, 15.4% on anticoagulation, and 18.2% on combined treatment. In patients with extracranial dissection, 54.4% were on antiplatelets, 28.9% on anticoagulation, and 11.2% on combined treatment. Ischemic and hemorrhagic events occurred in 10.1% on antiplatelet treatment, 9.3% on anticoagulation, and 13.8% on combined treatment. The association between antithrombotic treatment and ischemic/hemorrhagic events and clinical outcome was not significant for all subtypes of dissection. Conclusion: The rate of new or recurrent events is similar with antiplatelet and anticoagulation treatment in treating intracranial and extracranial carotid and vertebral artery dissection. PMID- 28362968 TI - Letter: ORACLE Stroke Study: Opinion Regarding Acceptable Outcome Following Decompressive Hemicraniectomy for Ischemic Stroke. PMID- 28362969 TI - Letter: Effect of Early Surgery, Material, and Method of Flap Preservation on Cranioplasty Infections: A Systematic Review. PMID- 28362970 TI - Commentary: Appropriate Use Criteria for Lumbar Degenerative Scoliosis: Developing Evidence-based Guidance for Complex Treatment Decisions. AB - Lumbar degenerative scoliosis is a relatively common problem, and is being treated more frequently due to the confluence of an aging population and an increased capacity and willingness to manage difficult problems in older patients. Lumbar degenerative scoliosis is a complex pathology as it often involves the intersection of degenerative spinal stenosis and spinal deformity. While previous studies provide an indication that these patients may benefit from surgical treatment, the substantial variability in treatment underscores the opportunity for improvement. Optimizing treatment for lumbar degenerative scoliosis is critical as surgical intervention, while potentially providing substantial clinical benefit also entails measurable risk and significant expense. In light of these issues, evidence-based guidance generated through Appropriate Use Criteria (AUC) development offers the potential to improve both the quality and cost effectiveness of care.The lumbar degenerative scoliosis AUC represents a significant step toward evidence-based treatment in spinal surgery. This is the first time that spine societies and industry partners have collaborated to support evidence development. The willingness of all involved to support a completely independent process underlines a commitment to trust the evidence. Subsequent studies may validate and/or refine the AUC recommendations, but the most important result is that the standard for evidence quality has been raised. PMID- 28362971 TI - Stabilization, Rolling, and Addition of Other Extracellular Matrix Proteins to Collagen Hydrogels Improve Regeneration in Chitosan Guides for Long Peripheral Nerve Gaps in Rats. AB - Background: Autograft is still the gold standard technique for the repair of long peripheral nerve injuries. The addition of biologically active scaffolds into the lumen of conduits to mimic the endoneurium of peripheral nerves may increase the final outcome of artificial nerve devices. Furthermore, the control of the orientation of the collagen fibers may provide some longitudinal guidance architecture providing a higher level of mesoscale tissue structure. Objective: To evaluate the regenerative capabilities of chitosan conduits enriched with extracellular matrix-based scaffolds to bridge a critical gap of 15 mm in the rat sciatic nerve. Methods: The right sciatic nerve of female Wistar Hannover rats was repaired with chitosan tubes functionalized with extracellular matrix-based scaffolds fully hydrated or stabilized and rolled to bridge a 15 mm nerve gap. Recovery was evaluated by means of electrophysiology and algesimetry tests and histological analysis 4 months after injury. Results: Stabilized constructs enhanced the success of regeneration compared with fully hydrated scaffolds. Moreover, fibronectin-enriched scaffolds increased muscle reinnervation and number of myelinated fibers compared with laminin-enriched constructs. Conclusion: A mixed combination of collagen and fibronectin may be a promising internal filler for neural conduits for the repair of peripheral nerve injuries, and their stabilization may increase the quality of regeneration over long gaps. PMID- 28362972 TI - Prevention of Axonal Degeneration by Perineurium Injection of Mitochondria in a Sciatic Nerve Crush Injury Model. AB - Background: Axon degeneration leads to cytoskeletal disassembly, metabolism imbalance, and mitochondrial dysfunction during neurodegeneration or nerve injury. Objective: In this study, we assess the possibility of mitigating axon degeneration by local injection of mitochondria in a crushed sciatic nerve. Methods: Sciatic nerve explants cocultured with mitochondria were assessed for the optimal dosage in local injection and nerve regeneration potential. The left sciatic nerve was crushed in Sprague-Dawley rats and then local injection of mitochondria into the distal end of the injured nerve was conducted for further assessment. Results: Mitochondrial coculture attenuated cytoskeletal loss and oxidative stress in isolated nerve explants. In Vivo analyses also showed that mitochondrial transplantation improved animal neurobehaviors, electrophysiology of nerve conduction, and muscle activities. Mitochondria injection significantly attenuated the oxidative stress and increased the expression of neurotrophic factors both in injured nerves and denervated muscles, as well as restored muscular integrity, and increased the pool of muscular progenitor cells and total muscle weight. Conclusion: Mitochondria injection can protect injured nerves from axonal degeneration both in Vitro and in Vivo. This improvement was accompanied with the expression of neurotrophic factors as well as the reduction of oxidative stress, which may account for the functional recovery of both injured nerves and denervated muscles. PMID- 28362973 TI - Letter: Surfer's Myelopathy: A Rare Form of Spinal Cord Infarction in Novice Surfers: A Systematic Review. PMID- 28362974 TI - Effect of Whole Brain Radiation Therapy on Cognitive Function PMID- 28362975 TI - GSTM1 polymorphism in patients with clinical manifestations of atherosclerosis. AB - Atherosclerosis is characterized by lesions, called atheroma or atheromatous plaques, in the inner layer of blood vessels, which block the vascular lumen and weaken the underlying tunica media. Several modifiable and non-modifiable risk factors for the development of atherosclerosis exist. The modifiable risk factors include hypertension, smoking, obesity, high LDL and low HDL cholesterol levels, sedentary lifestyle, and stress; the non-modifiable factors include diabetes mellitus, family history of hypertension and heart disease, thrombophilia, sex, age, and genetic factors. The association of polymorphisms in GST with coronary artery disease has been studied since the polymorphisms can affect enzyme activity and contribute to the onset of atherosclerosis. We analyzed polymorphisms in GSTM1 in individuals diagnosed with atherosclerosis as well as in healthy individuals (control group). The frequency of the GSTM1 present genotype in the atherosclerosis group was 1.2 times higher than that observed in the control group. We found no sex- or alcohol-consumption-dependent differences between the occurrences of the present and null genotypes. However, the GSTM1 present genotype occurred in 52.6% individuals with atherosclerosis who reported smoking 20 or more cigarettes per day and in 60% individuals who smoked 10 to 20 cigarettes per day (P = 0.0035). In addition, the GSTM1 present genotype was more frequent in individuals who reported being former smokers - 45.5% in individuals with atherosclerosis who smoked for more than 20 years and 50% each for individuals in the control group who smoked for less than 10 years or for 10 to 20 years, respectively (P = 0.0240). PMID- 28362976 TI - Paracrine effect of bone marrow mesenchymal stem cells on proliferation, apoptosis, and alpha-actin-2 expression in hepatic stellate cells. AB - We investigated the paracrine effects of bone marrow mesenchymal stem cells (BMSCs) on the proliferation, apoptosis, and alpha-actin-2 (ACTA2) expression of hepatic stellate cells (HSCs), and explored the possible mechanisms of hepatocyte growth factor (HGF). We established a co-culture system by culturing BMSCs on the upper layer and HSCs on the lower layer of a 6-well Transwell plate. Normal HSCs were cultured alone as a control. Cell apoptosis was determined by flow cytometry. We detected the expression of ACTA2 mRNA and ACTA2 protein in HSC using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting, respectively. ACTA2 in HSCs was detected by fluorescent staining, and HGF in the co-culture supernatant was detected by enzyme-linked immunosorbent assay (ELISA). The apoptotic rate of HSCs in the experiment group was 2.6 times that in the control group (P < 0.05). The expression levels of ACTA2 mRNA and ACTA2 protein were significantly inhibited in HSCs compared with the control group (P < 0.05). HGF concentration in the co-culture supernatant was 0.43 +/- 0.47 mM in the experimental group, which was significantly higher than in the control group (0.16 +/- 0.43 mM) (P < 0.05). The paracrine effect of BMSCs, which was caused by the suppression of ACTA2 and HGF expression, induced HSC apoptosis. PMID- 28362977 TI - Anti-inflammatory effects of essential oils from Mangifera indica. AB - Mangifera indica is widely found in Brazil, and its leaves are used as an anti inflammatory agent in folk medicine. The aim of this study is to perform composition analysis of essential oils from the M. indica varieties, espada (EOMIL1) and coracao de boi (EOMIL2), and confirm their anti-inflammatory properties. Twenty-three volatile compounds were identified via gas chromatography-mass spectrometry (GC-MS) in two essential oils from the leaves. Paw edema and myeloperoxidase (MPO) activity were evaluated using the carrageenan induced paw model, while leukocyte migration was analyzed using the pleurisy model. At oral doses of 100 and 300 mg/kg, the essential oils significantly reduced edema formation and the increase in MPO activity induced by carrageenan in rat paws. For a dose of 300 mg/kg EOMIL1, 62 +/- 8% inhibition of edema was observed, while EOMIL2 led to 51 +/- 7% inhibition of edema. At a dose of 100 mg/kg, the inhibition was 54 +/- 9% for EOMIL1 and 37 +/- 7% for EOMIL2. EOMIL1 and EOMIL2 significantly reduced MPO activity at doses of 100 mg/kg (47 +/- 5 and 23 +/- 8%, respectively) and 300 mg/kg (50 +/- 9 and 31 +/- 7%, respectively). In the pleurisy model, inhibitions were also observed for EOMIL1 and EOMIL2 in the leukocyte migration test. The results of the present study show that essential oils from M. indica differ in chemical composition and anti-inflammatory activity in rats. PMID- 28362978 TI - Dynamic relationship between SIPA1 gene and protein expression and the development of gastric cancer. AB - Association of signal-induced proliferation-associated 1 (SIPA) gene and protein expression with gastric cancer development was examined. SIPA1 mRNA and protein levels were determined by real-time quantitative polymerase chain reaction and western blot, respectively, in 40 gastric tumor and tumor-adjacent normal tissues. SIPA1, VEGF-A, and FVIII levels in 60 gastric tumor and 40 tumor adjacent normal tissues were examined by immunohistochemical staining. Correlations between SIPA1, VEGF-A, and microvessel density (MVD) were analyzed. SIPA1 mRNA levels were significantly lower in tumor tissues than in tumor adjacent normal tissues (P < 0.05). Similarly, protein levels were significantly lower in tumor tissues (0.3043 +/- 0.1062) than in tumor-adjacent normal tissues (0.5423 +/- 0.0682, P < 0.05). Positive staining rates of SIPA1 (48.3%) and VEGF A (36.7%) were lower and higher, respectively, in tumor tissues than in tumor adjacent normal tissues (65.0 and 2.5%, P < 0.05). Positive protein staining rates in tumor tissues correlated with the degree of differentiation, lymph node metastases, and clinical grading (P < 0.05) and not with sex, age, or tumor size (P > 0.05). Significantly higher MVD (57.4 +/- 9.3) was observed in tumor tissues displaying positive SIPA1 staining than in tumor-adjacent normal tissues (41.2 +/ 5.7, P < 0.05). SIPA1 and VEGF-A expression in tumor tissues were negatively correlated (r = -0.736, P < 0.05). SIPA1 and its protein may play important roles in gastric cancer invasion, metastasis, and biological behavior. Low SIPA1 levels in gastric cancer may accelerate tumor development and progression by promoting VEGF-A expression to increase vascular density. PMID- 28362979 TI - Nramp1 gene expression in different tissues of Meishan piglets from newborn to weaning. AB - Natural resistance-associated macrophage protein gene 1 (Nramp1) plays an important role in the innate immune response of swine, and is believed to influence disease resistance. In this study, a real-time quantitative polymerase chain reaction technique was used to investigate Nramp1 expression in 12 different tissues in newborn and 7-, 14-, 21-, 28-, and 35-day-old Meishan piglets. Results indicated that Nramp1 was expressed to varying degrees in all sample tissues, although expression differed among growth stages. For example, Nramp1 was highly expressed in the spleen, but minimally expressed in heart, liver, and muscle tissues among the various piglet age classes. Overall, Nramp1 expression increased with age, reaching significant levels in 21- and 28-day-old animals. Nramp1 was expressed in all 12 tissues tested; however, expression in spleen, lung, kidney, and thymus tissues was highest among newborns, which is consistent with this gene's role in innate immunity improvement. Before and after weaning, Nramp1 was highly expressed in digestive (stomach) and intestinal (duodenum, jejunum, and ileum) tissues, further indicating a genetic role in both immune regulation to compensate for weaning stress and enhanced development of intestinal immunity. PMID- 28362980 TI - Role of Th1/Th2 cytokines in the diagnosis and prognostic evaluation of ankylosing spondylitis. AB - Ankylosing spondylitis (AS), a progressive disease of the spine, manifests as peripheral arthritis with tendon and ligament inflammation that restricts activity. AS is a rheumatoid autoimmune disease although the rheumatoid factor is absent in patients with AS. It is characterized by inflammatory changes such as elevated levels of serum inflammatory factors. The roles of Th1 and Th2 cytokines in autoimmune diseases are well known. However, the roles of these cytokines in the diagnosis and prognosis of AS is poorly understood. The aim of this study was to investigate the roles of Th1/Th2 cytokines in the diagnosis and prognosis of AS. The BASDAI activity, BASFI functional index, BASMI measurement score, and the levels of CRP and ESR were measured during the treatment of patients with active AS. The levels of IFN-gamma and TNF-alpha (Th1 cytokines) and IL-4 and IL-10 (Th2 cytokines) were quantified. The levels of IL-4 and IL-10 were significantly low in the serum of patients with active AS, who also had high IFN-gamma and TNF alpha levels compared to those in the control individuals (P < 0.05). After treatment, the levels of IL-4 and IL-10 increased while those of IFN-gamma and TNF-alpha decreased compared to those in individuals with active AS (P < 0.05). The disease activity index correlated positively with levels of IFN-gamma and TNF alpha and negatively with levels of IL-4 and IL-10, but not with that of CRP or ESR. Changes in the levels of Th1/2 cytokines in patients with AS may reflect disease activity and prognosis. PMID- 28362981 TI - Effect of propolis ethanol extract on myostatin gene expression and muscle morphometry of Nile tilapia in net cages. AB - Propolis can be used as growth enhancer due to its antimicrobial, antioxidant, and immune-stimulant properties, but its effects on morphometry and muscle gene expression are largely unknown. The present study evaluates the influence of propolis on muscle morphometry and myostatin gene expression in Nile tilapia (Oreochromis niloticus) bred in net cages. Reversed males (GIFT strain) with an initial weight of 170 +/- 25 g were distributed in a (2 x 4) factorial scheme, with two diets (DPRO, commercial diet with 4% propolis ethanol extract and DCON, commercial diet without propolis, control) and four assessment periods (0, 35, 70, and 105 experimental days). Muscles were evaluated at each assessment period. Histomorphometric analysis classified the fiber diameters into four groups: <20 MUm; 20-30 MUm; 30-50 MUm; and > 50 MUm. RT-qPCR was performed to assess myostatin gene expression. Fibers < 20 um diameter were more frequent in DPRO than in DCON at all times. Fiber percentages >30 um (30-50 and > 50 um) at 70 days were 25.39% and 40.07% for DPRO and DCON, respectively. There was greater myostatin gene expression at 105 days, averaging 1.93 and 1.89 for DCON and DPRO, respectively, with no significant difference in any of the analyzed periods. Propolis ethanol extract did not affect the diameter of muscle fibers or the gene expression of myostatin. Future studies should describe the mechanisms of natural products' effects on muscle growth and development since these factors are highly relevant for fish production performance. PMID- 28362982 TI - Morphology and muscle gene expression in GIFT and Supreme Nile tilapia varieties reared in two cultivation systems. AB - Tissue growth in most fishes occurs by muscular hyperplasia and hypertrophy, which are influenced by different regulatory factors, such as myostatin. The current study evaluated the influence of cultivation in hapas and earthen ponds on the diameter of white muscle fibers and on the myostatin (MSTN-1) gene in GIFT and Supreme varieties of tilapia. Fish of both varieties were reared for 204 days and then divided into four developmental stages. White muscle samples, corresponding to 100 fibers per slide, were collected from the middle region of fish of each variety and cultivation system, and were measured and divided into two classes representing hyperplasia and hypertrophy. Samples were subjected to real-time PCR to analyze gene expression. Hyperplasia decreased during the developing stages, coupled with increased hypertrophy. There was a higher rate of hypertrophy in fish raised in earthen ponds when compared to those raised in hapas, during juvenile and developing phases, and greater hypertrophic growth was observed in GIFT specimens when compared to Supreme specimens in earthen ponds. Since increased MSTN-1 gene expression was observed in GIFT specimens during the developing phase in pond cultivations, and in Supreme tilapia in hapas, MSTN-1 expression is related to greater hypertrophy. These results demonstrate the capacity for increased muscle growth in earthen pond cultivation in which the GIFT variety developed best. How the environment affects the growth of different tilapia varieties may be employed to optimize culture management and genetic improvement programs. Further investigations should aim to describe mechanisms affecting muscle growth and development. PMID- 28362983 TI - Association between C807T(C/T) polymorphism of platelet glycoprotein gene and sensitivity to ischemic stroke: a meta-analysis. AB - Ischemic stroke can lead to loss of neurologic functions. It occurs due to obstruction in blood supply to the brain. It has been proposed that C807T(C/T) polymorphism within the platelet glycoprotein gene may be associated with density and function of glycoprotein Ia/IIa receptors and contributes to the pathogenesis of thrombotic disease. We assessed the association between C807T(C/T) and risk of ischemic stroke. Databases such as PubMed, Medline, Springer, Elsevier Science Direct, Cochrane Library, Google scholar, Wanfang Data (Chinese), and Chinese National Knowledge Infrastructure (CNKI, Chinese) were used to search for relevant studies. We found 16 eligible studies, which totaled to 4897 (case group 2340; control group 2557) participants. Overall, our results showed significant associations between C807T(C/T) polymorphism and risk of ischemic stroke based on T-allele comparisons (T vs C, pooled OR = 0.78, 95%CI = 0.68-0.90, P < 0.01), TT vs CC comparisons (pooled OR = 0.58, 95%CI = 0.42-0.81, P < 0.01), recessive models (TT vs TC + CC, pooled OR = 0.72, 95%CI = 0.59-0.87, P < 0.01) and dominant models (TT + TC vs CC, pooled OR = 0.70, 95%CI = 0.54-0.92, P < 0.05). There was no association in TC vs CC comparisons (pooled OR = 0.81, 95%CI = 0.63 1.04, P > 0.05). Subgroup analyses stratified according to Hardy-Weinberg equilibrium, sample size, and ethnicity also demonstrated significant associations between the two variables. Therefore, C807T(C/T) polymorphism in the platelet glycoprotein gene may be associated with susceptibility to ischemic stroke, and the T allele at this locus may decrease risk to ischemic stroke. PMID- 28362984 TI - Multivariate statistics applied to the reaction of common bean plants to parasitism by Meloidogyne javanica. AB - The availability of common bean cultivars tolerant to Meloidogyne javanica is limited in Brazil. Thus, the present study aimed to evaluate the reactions of 33 common bean genotypes (23 landrace, 8 commercial, 1 susceptible standard and 1 resistant standard) to M. javanica, employing multivariate statistics to discriminate the reaction of the genotypes. The experiment was conducted in a greenhouse using a completely randomized design with seven replicates. The seeds were sown in 1-L pots containing autoclaved soil and sand in a 1:1 ratio (v:v). On day 19, after emergence of the seedlings, the plants were treated with inoculum containing 4000 eggs + second-stage juveniles (J2). At 60 days after inoculation, the seedlings were evaluated based on biometric and parasitism related traits, such as number of galls, final nematode population per root system, reproduction factor, and percent reduction in the reproduction factor of the nematode (%RRF). The data were subjected to analysis of variance using the F test. The Mahalanobis generalized distance was used to obtain the dissimilarity matrix, and the average linkage between groups was used for clustering. The use of multivariate statistics allowed groups to be separated according to the resistance levels of genotypes, as observed in the %RRF. The landrace genotypes FORT-09, FORT-17, FORT-31, FORT-32, FORT-34 and FORT-36 presented resistance to M. javanica; thus, these genotypes can be considered potential sources of resistance. PMID- 28362985 TI - Relationship between Psidium species (Myrtaceae) by resistance gene analog markers: focus on nematode resistance. AB - Guava (Psidium guajava L.) crop is severely affected by the nematode Meloidogyne enterolobii. Native Psidium species have been reported as sources of resistance against this nematode. Knowledge on the molecular relationship between Psidium species based on plant resistance gene analogs (RGA) can be useful in the genetic breeding of guava for resistance to M. enterolobii. In this study, RGA markers from conserved domains, and structural features of plant R genes, were employed to characterize Psidium species and establish genetic proximity, with a focus on nematode resistance. SSR markers were also applied owing to their neutral nature, thus differing from RGA markers. For this, species reported as sources of resistance to M. enterolobii, such as P. cattleianum and P. friedrichsthalianum, as well as species occurring in the Atlantic Rainforest and susceptible genotypes, were investigated. In 10 evaluated Psidium species, high interspecific genetic variability was verified through RGA and SSR markers, with intraspecific variation in P. guajava higher with SSR, as was expected. Resistant species were clustered by RGA markers, and differential amplicons among genotypes resistant and susceptible to M. enterolobii were identified. Knowledge on the molecular relationships between Psidium species constitutes useful information for breeding of the guava tree, providing direction for hybridization and material for rootstocks. Additionally, the genetic relationship between native species, which have been little studied, and P. guajava were estimated by RGAs, which were confirmed as important markers for genetic diversity related to pathogen resistance. PMID- 28362986 TI - Genetic diversity of mitochondrial control region (D-Loop) polymorphisms in Coilia ectenes taihuensis inhabiting Taihu Lake, China. AB - Coilia ectenes is a commercially important fishery species in China. C. ectenes taihuensis is an endemic and dominant species found in Taihu Lake of China. When compared with C. ectenes, C. ectenes taihuensis lacks anadromous behavior, and can independently grow and reproduce in Taihu Lake. In this study, the mitochondrial DNA control region (D-loop) sequences were employed to investigate the genetic diversity and population structure of C. ectenes taihuensis. Sixty eight individuals collected from 4 localities in Taihu Lake were examined. Results indicated that in the 887-bp D-loop region, seventy-seven (8.68%) sites were variant, contributing to 53 distinct haplotypes. Although the population haplotype diversity (Hd = 0.971 to 1.000) was generally high, the nucleotide diversity (pi = 0.616 to 0.731%) was relatively low among the 4 populations. Additionally, the genetic distances ranged from 0.62 to 0.74% within the populations and from 0.67 to 0.74% between the populations. The neighbor-joining tree indicated that a distinct distribution of phylogenetic structure existed among haplotypes. Analysis of molecular variance and FST statistics suggested that a divergence existed among populations in 4 localities, indicating that gene communication might have occurred among those populations. Furthermore, neutral tests and analysis of mismatch distribution reflected that C. ectenes taihuensis might have undergone a population expansion during the evolution process. Our study showed the population genetic diversity and structure of C. ectenes taihuensis. Results from this study might be helpful in the development and protection of fishery resource within the localities in Taihu Lake in future. PMID- 28362987 TI - Effects of alendronate on osteoporosis treatment and levels of related cytokines. AB - Alendronate regulates the activity of osteoclasts and healing of osteoporosis. This study investigated the effect of alendronate on bone healing and changes in the levels of cytokines. Bilateral ovaries of 10 adult female rabbits were removed surgically in aseptic condition to establish the animal model of osteoporosis. Five rabbits in group A were treated with alendronate (1.15 mg.kg 1.week-1) once a week by a stomach tube, whereas the remaining 5 in group B were treated with physiological saline. The success of the animal model establishment and the efficacy of alendronate treatment were evaluated by the sports ability score and the Basso, Beattie, and Bresnahan (BBB) score; the healing degree of osteoporosis was determined by X-ray analysis and measurement of biomechanical properties; the changes in the levels of related cytokines were measured by enzyme-linked immunosorbent assay (ELISA) and immunohistochemical staining. Treatment improved dyskinesia of the animals in group A than that in group B, with significant improvement occurring in the 4th week of treatment. The BBB score of the group A animals revealed movements similar to normal, but that of the group B animals exhibited significant motor disturbance (P < 0.01). X-ray examination showed that with time, the X-ray ratings increased. Measurement of the biomechanical properties further showed that alendronate had a positive effect on osteoporosis healing. The results of ELISA and immunohistochemistry showed that the levels of ALP, BMP-2, bFGF, and IGF-1 were upregulated in group A. In conclusion, alendronate accelerated osteoporosis healing probably via certain cytokine-related mechanism. PMID- 28362988 TI - Expression of metallothionein type 2 and 3 genes in Prosopis glandulosa leaves treated with copper. AB - For a better understanding of the strategies that are used by Prosopis glandulosa in heavy metal tolerance, the present study evaluated the gene expression of three metallothioneins (MTs; PgMt2-1, PgMt2, and PgMt3) in plants exposed to sub lethal concentrations of copper. The PgMt2-1, PgMt2, and PgMt3 sequences were homologous to the MT type 2 (isoform 1), Mt2, and Mt3 sequences of other plant species found in GenBank. A reverse transcriptase-polymerase chain reaction showed that treatment with 100 mM Cu2+ induced a significant increase in PgMt2 and PgMt3 expression during the first 4 h of exposure compared to that of PgMt2 1. However, after 8 h of exposure, the expression levels of PgMt2 and PgMt3 were significantly lower than those of PgMt2-1. PgMt transcript levels only increased significantly during the first hour after exposure to copper, suggesting that PgMts could play a key role in the plant's detoxification mechanism. However, additional studies are required to confirm MTs as a mechanism of heavy metal tolerance and accumulation in this species. PMID- 28362989 TI - Effects of Moquiniastrum polymorphum ssp floccosum ethnolic extract on colorectal carcinogenesis induced by 1,2-dimethylhydrazine. AB - The objective of this study was to evaluate the effect of Moquiniastrum polymorphum ssp floccosum ethanolic extract (MPEE) on 1,2 dimethylhydrazine (DMH) induced colorectal carcinogenesis in mice. Forty-two male Swiss mice (Mus musculus) were subdivided into six groups (N = 7/group): negative control, DMH, MPEE, pre-treatment, simultaneous, and post-treatment. Results showed that MPEE has antigenotoxic potential on the tested protocols pre- and silmultaneous treatment, and the percent damage reductions (%DRs) were 81.88 and 93.12%, respectively. The micronucleus test demonstrated that MPEE has great antimutagenic activity, with %DRs higher than 77.09 in the associated groups. The aberrant crypt focus assay demonstrated anticarcinogenic potential of MPEE as the associated groups showed %DRs that ranged from 62.13 to 95.14%. The study shows that MPEE is nontoxic and has chemopreventive and anticarcinogenic activity, thus it may prove to be a promising medicinal plant in view of its demonstrated properties. PMID- 28362990 TI - Path analysis of the energy density of wood in eucalyptus clones. AB - Path analysis has been used for establishing selection criteria in genetic breeding programs for several crops. However, it has not been used in eucalyptus breeding programs yet. In the present study, we aimed to identify the wood technology traits that could be used as the criteria for direct and indirect selection of eucalyptus genotypes with high energy density of wood. Twenty-four eucalyptus clones were evaluated in a completely randomized design with five replications. The following traits were assessed: basic wood density, total extractives, lignin content, ash content, nitrogen content, carbon content, hydrogen content, sulfur content, oxygen content, higher calorific power, holocellulose, and energy density. After verifying the variability of all evaluated traits among the clones, a two-dimensional correlation network was used to determine the phenotypic patterns among them. The obtained coefficient of determination (0.94) presented a higher magnitude in relation to the effect of the residual variable, and it served as an excellent model for explaining the genetic effects related to the variations observed in the energy density of wood in all eucalyptus clones. However, for future studies, we recommend evaluating other traits, especially the morphological traits, because of the greater ease in their measurement. Selecting clones with high basic density is the most promising strategy for eucalyptus breeding programs that aim to increase the energy density of wood because of its high heritability and magnitude of the cause-and-effect relationship with this trait. PMID- 28362991 TI - Antifungal activity, yield, and composition of Ocimum gratissimum essential oil. AB - Ocimum gratissimum L. or clove basil, belongs to the Lamiaceae family, has various desirable uses and applications. Beyond its aromatic, seasoning, and medicinal applications, this plant also has antimicrobial activity. This study was aimed at assessing the antifungal activity, yield, and composition of the essential oil (EO) of O. gratissimum. The species was cultivated in garden beds with dystrophic red latosol soil type containing high organic-matter content. The EO was obtained by hydrodistillation of dried leaves in a modified Clevenger apparatus, followed by determination of its content. Chemical characterization was carried out by gas chromatography-mass spectrometry (GC-MS). Microbial activity was assessed using the broth microdilution method, by determining the minimum inhibitory concentration (MIC), in order to compare the antimicrobial effect of EO in 10 isolates-Fusarium oxysporum f. sp tracheiphilum (CMM-0033), F. oxysporum f. sp. cubense (CMM-0813 and CMM-2819), F. oxysporum f. sp lycopersici (CMM-1104), F. solani (CMM-3828), Rhizoctonia solani (CMM-3274), and Macrophomina phaseolina (CMM-2715, CMM-3875, CMM-3615, and CMM-3650). The EO was a highly effective inhibitor of the studied phytopathogenic fungi, with MICs varying from 31.25 to 125 ug/mL. F. oxysporum f. sp lycopersici and R. solani were the most sensitive; both were inhibited at an MIC of 31.25 ug/mL. The EO content in the plant extract was 0.18%. Thirty chemical compounds were detected via GC-MS, with linalool (32.9%) being the major compound followed by 1,8-cineole (21.9%), both oxygenated monoterpenes. It can be concluded that clove basil EO is a highly effective antifungal agent, and therefore, a potential alternative for the control of plant pathogenic diseases. PMID- 28362992 TI - Comparative transcriptome analysis of self-incompatible flower stigmas and self compatible bud stigmas following self-pollination in broccoli. AB - DH07 is a DH line of Class I S-haplotype in broccoli (Brassica oleracea var. italica), in which stigmas of flowers show self-incompatibility (SI) and stigmas of buds show self-compatibility (SC). The molecular mechanisms that lead to stigmas at different developmental stages having different responses to self pollination are yet unknown. In the present study, comparative transcriptome profiling of the stigmas of flowers and buds before and after self-pollination was performed by RNA-sequencing using an Illumina HiSeqTM 2000. A total of 80,102,897 reads were generated for further analysis in four libraries. Comparisons of the transcriptome profiles before and after self-pollination revealed 579 differentially expressed genes (DEGs) in the stigmas of buds (SBs); of these, 431 DEGs showed increased and 148 DEGs showed decreased transcript abundance after self-pollination in SBs. There were a total of 686 DEGs between unpollinated stigmas of flowers (SFs) and pollinated SFs, among which, 517 DEGs were up regulated and 169 DEGs were down regulated. Following the self pollination, 379 identified DEGs were common in both SBs and SFs. It was found that ARR7-like and oxysterol-binding family protein related DEGs could play key roles in SI or SC signal transduction. The results obtained in this study would form the foundation for further studies on investigating the molecular mechanisms of SI and SC in Brassica. PMID- 28362993 TI - Association between interleukin-17 gene polymorphisms and the risk of laryngeal cancer in a Chinese population. AB - IL-17 is associated with the occurrence and development of laryngeal cancer. However, no study has reported the association between IL-17 polymorphisms and laryngeal cancer susceptibility. Therefore, we analyzed the association of three polymorphism loci (rs2275913, 197 G/A; rs3748067, 383 A/G; and rs763780, 7488 T/C) of IL-17A and IL-17F with laryngeal cancer in the Chinese population. A case control study was performed with 325 patients and 325 controls. Polymorphisms were detected by polymerase chain reaction and sequencing methods. SPSS17.0 software was used for statistical analysis. Allele and genotype frequencies of IL 17A rs2275913 were significantly different between patients and controls (P < 0.05). Frequencies of rs2275913 (197 G/A) AA and GA+AA genotypes compared to the GG genotype were significantly higher in patients than in controls, indicating the association of these genes with laryngeal cancer susceptibility; adjusted OR values were 2.54 (1.50-4.23) and 1.62 (1.19-2.17), respectively. Furthermore, individuals with the GA+AA genotype, compared to the GG genotype, aged <=60 years, with smoking and alcohol consumption habits, and without a family history of cancer showed a higher cancer risk (OR = 2.74, 95%CI = 1.41-5.23; OR = 2.11, 95%CI = 1.21-3.55; OR = 1.91, 95%CI = 1.02-3.70; OR = 1.99, 95%CI = 1.08-3.39, respectively). In conclusion, the rs2275913 IL-17A (197 G/A) is associated with the incidence and development of laryngeal cancer in the Chinese population, and the AA and GA+AA genotypes harbor a high laryngeal cancer risk. PMID- 28362994 TI - Identification of genes related to floral organ development in pak choi by expression profiling. AB - Pak choi is a highly nutritious vegetable that is widely grown in China, Southeast Asia, and other parts of the world. Because it reproduces by seed, it is very important to understand the mechanism of floral organ development. Therefore, using the Chinese cabbage genome as a reference, this study analyzed the expression profiles of shoot apex genes at flower bud differentiation stages 1 and 5, in order to identify genes related to floral organ development. The results showed that the proportion of mapped genes was high, with 84.25 and 83.80% of clean reads from the two sample saligned to the reference genome, respectively. A total of 525 differentially expressed genes (DEGs) were identified, 224 of which were upregulated and 301 were downregulated. The expression levels of genes homologous to Chinese cabbage flowering genes were also analyzed at stages 1 and 5; the expression levels of Bra012997 (ap1), Bra000393 (SOC1), and Bra004928 (SOC1) were significantly upregulated at stage 5, suggesting that these three genes positively regulate floral development in pak choi. DEGs involved in floral organ development were analyzed with homologous genes from Arabidopsis thaliana; the homologous genes Bra029281 (AGL42), Bra026577 (ARPN), Bra022954 (SPL3), Bra029293 (ARF2), Bra007978 (AtRLP12), Bra033221 (SPL8), Bra008037 (LOX4), Bra001598 (IAA19), Bra003892 (PATL1), Bra038778 (AT4G21323), Bra025315 (KLCR2), and Bra013906 (DTX35) are directly related to floral organ development in Arabidopsis, suggesting that these genes have corresponding functions during flower organ development in pak choi, and could be candidates for further genetic research. These results provide a foundation for research on the molecular mechanism of flower organ development in pak choi and other Brassica rapa vegetables. PMID- 28362995 TI - Targeting effect of microRNA on CD133 and its impact analysis on proliferation and invasion of glioma cells. AB - MiR-200b, a member of the microRNA-200 family, has been identified to be capable of suppressing glioma cell growth through targeting CREB1 or CD133. However, whether miR-200b affects the biological behavior (proliferation, invasion, and migration) of glioma cells is poorly understood. The aim of this study was to evaluate the effect of miR-200b on the biological behavior of glioma cells in vitro. MiRNA-200b mimics, miRNA-200b inhibitor, and mimic control were transfected into conventionally cultured glioma U251 cells, followed by measuring the expression of miR-200b and CD133 in transfected cells by RT-PCR; effect of miR-200b on CD133 mRNA 3'-UTR luciferase activity by luciferase reporter assay; proliferation activity of transfected U251 cells by MTT method; and changes in U251 cell invasion and migration by Transwell method after transfection. Compared to that in the miRNA-200b inhibitor, mimic control, and blank control groups, miRNA-200b expression was significantly increased and CD133 mRNA expression was significantly decreased in the mimic miRNA-200b group in a time-dependent manner (P < 0.05). Meanwhile, dual luciferase reporter assay showed that miR-200b could inhibit CD133 activity through binding to the 3'-UTR of CD133 mRNA (P < 0.05). Furthermore, the proliferation activity and invasion and migration abilities of U251 cells transfected with miRNA-200b mimic were significantly decreased (P < 0.05). In conclusion, overexpression of miR-200b inhibited the proliferation, invasion, and migration of glioma cells possibly through targeting CD133. PMID- 28362997 TI - Transforming growth factor beta-1 expression in macrophages of human chronic periapical diseases. AB - The objective of this study was to observe the distribution of macrophages (MPs) expressing transforming growth factor beta-1 (TGF-beta1) in tissue samples from patients with different human chronic periapical diseases. In this study, samples were collected from 75 volunteers, who were divided into three groups according to classified standards, namely, healthy control (N = 25), periapical granuloma (N = 25), and periapical cyst (N = 25). The samples were fixed in 10% buffered formalin for more than 48 h, dehydrated, embedded, and stained with hematoxylin and eosin for histopathology. Double immunofluorescence was conducted to analyze the expression of TGF-beta-CD14 double-positive MPs in periapical tissues. The number of double-positive cells (cells/mm2) were significantly higher in the chronic periapical disease tissues (P < 0.01) compared to that in the control tissue; in addition, the density of TGF-beta1-CD14 double positive cells was significantly higher in the periapical cyst group than in the periapical granuloma group (P < 0.01). The number of TGF-beta1 expressing macrophages varied with human chronic periapical diseases. The TGF-beta1-CD14 double-positive cells might play an important role in the pathology of human chronic periapical diseases. PMID- 28362996 TI - Effect of overexpression of citrus 9-cis-epoxycarotenoid dioxygenase 3 (CsNCED3) on the physiological response to drought stress in transgenic tobacco. AB - 9-cis-epoxycarotenoid dioxygenase (NCED) encodes a key enzyme in abscisic acid (ABA) biosynthesis. Little is known regarding the regulation of stress response by NCEDs at physiological levels. In the present study, we generated transgenic tobacco overexpressing an NCED3 ortholog from citrus (CsNCED3) and investigated its relevance in the regulation of drought stress tolerance. Wild-type (WT) and transgenic plants were grown under greenhouse conditions and subjected to drought stress for 10 days. Leaf predawn water potential (Psiwleaf), stomatal conductance (gs), net photosynthetic rate (A), transpiration rate (E), instantaneous (A/E) and intrinsic (A/gs) water use efficiency (WUE), and in situ hydrogen peroxide (H2O2) and abscisic acid (ABA) production were determined in leaves of irrigated and drought-stressed plants. The Psiwleaf decreased throughout the drought stress period in both WT and transgenic plants, but was restored after re-watering. No significant differences were observed in gs between WT and transgenic plants under normal conditions. However, the transgenic plants showed a decreased (P <= 0.01) gs on the 4th day of drought stress, which remained lower (P <= 0.001) than the WT until the end of the drought stress. The A and E levels in the transgenic plants were similar to those in WT; therefore, they exhibited increased A/gs under drought conditions. No significant differences in A, E, and gs values were observed between the WT and transgenic plants after re-watering. The transgenic plants had lower H2O2 and higher ABA than the WT under drought conditions. Our results support the involvement of CsNCED3 in drought avoidance. PMID- 28362998 TI - Characterization of maize genotypes for genetic diversity on the basis of inter simple sequence repeats. AB - Genetic diversity in crops is essential to make improvements related to superior germplasms. Implementation of molecular markers to identify suitable genotypes speeds up the breeding progress by enhancing selection efficiency. This study was carried out to probe genetic diversity among 21 maize genotypes using 20 inter simple sequence repeat (ISSR) markers. We identified a total of 190 polymorphic bands with an average of 9.5 alleles per primer. The highest number of polymorphic bands (17) was found using ISSR marker UBC-10, whereas the lowest number of polymorphic bands (4) was found using UBC-809. The coefficient of genetic similarity ranged from 0.888 to 0.118%. The highest similarity was found between accessions 12 (015224) and 9 (015114), whereas the lowest similarity was found between genotypes 20 (EV-5098) and 14 (015030). The polymorphism information content ranged from 0.17 to 0.47. A dendrogram was generated based on Jaccard's distance matrix. The genotypes were found to group into two major clusters that could be further partitioned into two sub-clusters. Genotypes located within the same cluster are genetically more closely related to each other. The present study efficiently identified diverse genotypes that may be used for creating new varieties with distinct characteristics. The identified genotypes could be used as parents for future development of diverse populations. PMID- 28363000 TI - Association between single nucleotide polymorphisms in AKT1 and the risk of prostate cancer in the Chinese Han population. AB - AKT1, also known as v-akt murine thymoma viral oncogene homolog 1, is involved in the regulation of cell-survival and anti-apoptotic activities, which may affect the pathogenesis of various cancers. However, the association between genetic variants of AKT1 and the risk of developing prostate cancer has not been investigated before. This study investigated the associations between three polymorphisms (rs1130214, rs3730358, and rs2494732) in AKT1 and the risk of development of prostate cancer in the Chinese Han population. Sequenom MassARRAY & iPLEX technology were used to genotype these polymorphisms in 493 Chinese Han patients with prostate cancer and 309 age-matched healthy individuals. Compared to the CC genotype of the rs3730358 polymorphism, the CT genotype of the same polymorphism was strongly associated with a decreased risk of prostate cancer (OR = 0.617, 95%CI = 0.390-0.976, P = 0.037). However, there was no significant difference between the allele frequency of the rs3730358 polymorphism and those of the other two polymorphisms (P > 0.05). Moreover, no significant difference was found in the haplotype analysis (P > 0.05). Our study found that the variant genotype CT of rs3730358 of AKT1 was associated with a decreased risk of prostate cancer, which suggested that this polymorphism could play an important role in the development of the disease. PMID- 28363001 TI - Effect of everolimus on the expression of Ki-67 and caspase-3 in patients with neuroendocrine tumors. AB - Tumors, especially neuroendocrine tumors (NETs), can cause adverse effects on human health. The expression and significance of Ki-67 and caspase-3 in NET remain to be further explored. Everolimus is an important drug used for the treatment of NETs. In this study, we aimed to investigate whether everolimus exerts anti-tumor effects by suppressing the expression of Ki-67 and caspase-3 in NET. Tumor (different developmental stages) and adjacent tissues were collected from patients with NET. The expression of Ki-67 and caspase-3 were detected in 244 paraffin sections of NET using immunohistochemistry. RT-PCR and western blot were used to detect the expression of Ki-67 and caspase-3 at mRNA and protein levels, respectively. The patients (N = 244) were randomly divided into everolimus-intervention and control groups. RT-PCR and western blot were used to measure the expression changes of Ki-67 and caspase-3 before and after everolimus treatment. The rates of Ki-67 expression in NET grades 1-6 were 14.2, 22.1, 37.5, 59.9, 69.9, and 77.8%, respectively. The difference between the groups was significant. The rates of caspase-3 expression in NET grades 1-6 were 28.6, 33.3, 31.3, 60.0, 80.0, and 88.9%, respectively, and the difference between groups was significant. Moreover, the expression of Ki-67 and caspase-3 showed a significant negative correlation. The expression of Ki-67 decreased while that of caspase-3 increased after everolimus treatment. In conclusion, the decrease in Ki-67 expression and increase in caspase-3 expression after everolimus treatment indicated that everolimus exerted its anti-cancer effect by regulating the expression of Ki-67 and caspase-3. PMID- 28362999 TI - Effects of ginsenoside Rg1 on glucose metabolism and liver injury in streptozotocin-induced type 2 diabetic rats. AB - Type 2 diabetes mellitus (T2-DM) is a chronic metabolic disorder characterized by high blood glucose levels. T2-DM patients suffer from many complications, such as diabetic fatty liver and diabetic nephropathy. The liver, the pivotal organ involved in both glucose and lipid metabolism, is primarily damaged in T2-DM patients, especially in those with high levels of blood lipid. In this study, the hepatoprotective activity of ginsenoside Rg1 was investigated in a T2-DM rat model. The results revealed a potent hepatoprotective effect of ginsenoside Rg1. This effect was primarily mediated by the antiapoptotic effect, inhibition of JNK activity, and suppression of inflammation after ginsenoside Rg1 treatment. Ginsenoside Rg1 also lowered the blood glucose level and insulin resistance index in T2-DM rats. Moreover, the blood lipid profile (total cholesterol, triglycerides, and low-density lipoprotein cholesterol levels) and liver function (aspartate transaminase and alanine transaminase levels) improved after ginsenoside Rg1 treatment. The aforementioned hepatoprotective effects of ginsenoside Rg1 in the T2-DM rat model suggests its clinical potential as an adjuvant drug for T2-DM therapy, especially for T2-DM patients with fatty liver disease. PMID- 28363002 TI - Leptin (rs7799039) and solute carrier family 30 zinc transporter (rs13266634) polymorphisms in Euro-Brazilian pregnant women with gestational diabetes. AB - Leptin (LEP), a protein that plays a fundamental role in the metabolism of energy reserves, and the solute carrier family 30 A8 zinc transporter (SLC30A8) have been consistently associated with diabetes. Women with gestational diabetes are at moderate risk of developing diabetes type 1 and 2 after pregnancy, in addition to complications to the fetus. We investigated the association of the polymorphisms rs7799039 (LEP) and rs13266634 (SLC30A8) in a case-control study in Euro-Brazilians with gestational diabetes (GDM, N = 134) and healthy pregnant women (control, N = 180). Real-time PCR with fluorescent probes (TaqMan system) was applied to genotyping. All polymorphisms were in Hardy-Weinberg equilibrium. The minor allele frequencies, for healthy and GDM, respectively, for the A-allele (LEP gene rs7799039) were 40.3% (95%CI = 35-45%) vs 36.6% (95%CI = 31-42%), P = 0.345; and for the T-allele (SLC30A8 gene rs13266634) were 27.8% (95%CI = 23-32%) vs 23.5% (95%CI = 18-29%), P = 0.227. Genotype comparisons for both polymorphisms showed no significant difference (P > 0.05). The polymorphisms rs7799039 and rs13266634 were not associated with GDM in the population studied (P > 0.05). The minor allele frequencies for both polymorphisms were similar to those of other Caucasian populations. PMID- 28363003 TI - Genetic progress in homogeneous regions of wheat cultivation in Rio Grande do Sul State, Brazil. AB - The State of Rio Grande do Sul (RS) stands out as the largest wheat producer in Brazil. Wheat is the most emphasized winter cereal in RS, attracting public and private investments directed to wheat genetic breeding. The study of genetic progress should be performed routinely at breeding programs to study the behavior of cultivars developed for homogeneous regions of cultivation. The objectives of this study were: 1) to evaluate the genetic progress of wheat grain yield in RS; 2) to evaluate the influence of cultivar competition trial stratification in homogeneous regions of cultivation on the study of genetic progress. Grain yield data of 122 wheat cultivars evaluated in 137 trials arranged in randomized block design with three or four replications were used. Field trials were carried out in 23 locations in RS divided into two homogeneous regions during the period from 2002 to 2013. Genetic progress for RS and homogeneous regions was studied utilizing the method proposed by Vencovsky. Annual genetic progress for wheat grain yield during the period of 12 years in the State of RS was 2.86%, oscillating between homogeneous regions of cultivation. The difference of annual genetic progress in region 1 (1.82%) in relation to region 2 (4.38%) justifies the study of genetic progress by homogeneous regions of cultivation. PMID- 28363004 TI - Direct effects on scenarios and types of path analyses in corn hybrids. AB - The objective of this study was to estimate the direct effects of explanatory variables on the grain yield of corn in the combinations formed by three types of hybrids x two harvests x nine scenarios of explanatory variables x two types of path analyses. Eleven explanatory variables were measured in 361, 373, and 416 single-, triple-, and double-cross hybrid plants from the 2008/2009 harvest, respectively, and in 1777, 1693, and 1720 single-, triple-, and double-cross hybrid plants from the 2009/2010 harvest, respectively: plant height at harvest (PH), ear insertion height (EIH), ear weight (EW), number of grain rows per ear (NR), ear length (EL), ear diameter (ED), cob weight (CW), cob diameter (CD), 100 grain mass (HGM), number of grains per ear (NGE), grain length (GL) and, the main variable, grain yield (YIELD). Before conducting the traditional and ridge path analyses, 0, 1, 2, 3, 4, 5, 6, 7, and 8 explanatory variables were excluded from scenarios 1, 2, 3, 4, 5, 6, 7, 8, and 9, respectively. Next, the direct effects of explanatory variables on YIELD were estimated for each hybrid, harvest, scenario, and type of path analysis. The variables EW, NGE, and HGM had stronger direct effects on YIELD in the first three scenarios and the variables EL and ED had stronger direct effects on YIELD in the other scenarios regardless of hybrid or harvest. The use of the ninth scenario of path analysis is recommended regardless of hybrid and harvest given the ease of explanatory variable measurement (EIH, EL, and ED), the low degree of multicollinearity and the good prediction of the path analysis (R2 >= 0.78). PMID- 28363005 TI - Multicollinearity in canonical correlation analysis in maize. AB - The objective of this study was to evaluate the effects of multicollinearity under two methods of canonical correlation analysis (with and without elimination of variables) in maize (Zea mays L.) crop. Seventy-six maize genotypes were evaluated in three experiments, conducted in a randomized block design with three replications, during the 2009/2010 crop season. Eleven agronomic variables (number of days from sowing until female flowering, number of days from sowing until male flowering, plant height, ear insertion height, ear placement, number of plants, number of ears, ear index, ear weight, grain yield, and one thousand grain weight), 12 protein-nutritional variables (crude protein, lysine, methionine, cysteine, threonine, tryptophan, valine, isoleucine, leucine, phenylalanine, histidine, and arginine), and 6 energetic-nutritional variables (apparent metabolizable energy, apparent metabolizable energy corrected for nitrogen, ether extract, crude fiber, starch, and amylose) were measured. A phenotypic correlation matrix was first generated among the 29 variables for each of the experiments. A multicollinearity diagnosis was later performed within each group of variables using methodologies such as variance inflation factor and condition number. Canonical correlation analysis was then performed, with and without the elimination of variables, among groups of agronomic and protein nutritional, and agronomic and energetic-nutritional variables. The canonical correlation analysis in the presence of multicollinearity (without elimination of variables) overestimates the variability of canonical coefficients. The elimination of variables is an efficient method to circumvent multicollinearity in canonical correlation analysis. PMID- 28363006 TI - Genetic diversity and relatedness between Caninde and British Alpine goat breeds in Northeastern Brazil accessed by microsatellite markers. AB - The aim of this study was to access the genetic diversity and relatedness between Caninde and British Alpine goat breeds in the States of Piaui and Ceara using microsatellite markers. Genomic DNA was isolated from hair samples of 99 goats belonging to six different flocks. A panel of polymorphic heterologous microsatellite loci was used to genotype individuals. The microsatellite markers resulted in a total number of 145 alleles, with an average of 8.5 alleles per locus. The observed and expected heterozygosities were >=0.687 and >=0.627, respectively, for all loci. The polymorphic information content showed that all loci were highly informative with an overall mean of 0.757. Overall FST across all populations and loci was 18%, which was consistent with the coefficient of gene differentiation (GST = 0.104). AMOVA revealed that 12.8% of the variation was captured between breeds. The Bayesian STRUCTURE clustering detected the maximum likelihood for a model of two genetically distinct groups, in agreement with the number of predefined studied breeds and the two-dimensional plot from the PCoA analysis. The exotic British Alpine breed and the naturalized Brazilian Caninde breed were clearly differentiated by the microsatellite markers, indicating that these two breeds have distant genetic identities, despite the phenotypic similarity. PMID- 28363007 TI - Genetic divergence in the common bean (Phaseolus vulgaris L.) in the Cerrado Pantanal ecotone. AB - Evaluating genetic diversity among genotypes is important for providing parameters for the identification of superior genotypes, because the choice of parents that form segregating populations is crucial. Our objectives were to i) evaluate agronomic performance; ii) compare clustering methods; iii) ascertain the relative contributions of the variables evaluated; and iv) identify the most promising hybrids to produce superior segregating populations. The trial was conducted in 2015 at the State University of Mato Grosso do Sul, Brazil. We used a randomized block design with three replications, and recorded the days to emergence, days to flowering, days to maturity, plant height, number of branches, number of pods, number of seeds per pod, weight of 100 grains, and productivity. The genetic diversity of the genotypes was determined by cluster analysis using two dissimilarity measures: the Euclidean distance and the standardized mean Mahalanobis distance using the Ward hierarchical method. The genotypes 'CNFC 10762', 'IAC Dawn', and 'BRS Style' had the highest grain yields, and clusters that were based on the Euclidean distance differed from those based on the Mahalanobis distance, the second being more precise. The yield grain character has greater relevance to the dispute. Hybrids with a high heterotic effect can be obtained by crossing 'IAC Alvorada' with 'CNFC 10762', 'IAC Alvorada' with 'CNFC 10764', and 'BRS Style' with 'IAC Alvorada'. PMID- 28363008 TI - Analysis of the 19 Y-STR and 16 X-STR loci system in the Han population of Shandong province, China. AB - The sex-linked short tandem repeats (STR), Y-STR and X-STR, are important for autosomal STRs in forensic paternity testing. We evaluated the forensic parameters of 19 Y-STRs and 16 X-STRs in the Han population of Shandong province, China. A Goldeneye 20Y kit (DYS391, DYS389I, DYS390, DYS389II, DYS348, DYS456, Y GATA-H4, DYS447, DYS19, DYS392, DYS393, DYS388, DYS439, DYS635, DYS448, DYS460, DYS458, DYS437, DYS385 a/b) was used to analyze the forensic parameters of 534 unrelated males. A Goldeneye17X system (DXS6795, DXS9902, DXS8378, HPRTB, GATA165B12, DXS7132, DXS7424, DXS6807, DXS6803, GATA172D05, DXS6800, DXS10134, GATA31E08, DXS10159, DXS6789, DXS6810, amelogenin) was used to analyze 97 unrelated males and 214 females. In addition, we used the kits to examine 5 cases with abnormal amelogenin test results, as well as a male child with agenosomia typed by autosomal STR. We found 203 Y-STR haplotypes with allele frequencies ranging from 0.0019 to 0.7959, and GD ranging from 0.3429 to 0.9667. Expect in DXS6803, the allele frequencies of the other 15 X-STR loci showed no differences between females and males. PDF ranged from 0.5504 to 0.9638, while PDM ranged from 0.3176 to 0.8377. With the exception of DXS6803 and DXS6810, the allele frequencies of other X-STR loci were in accordance with Hardy-Weinberg equilibrium in females. One amelogenin negative case was characterized as a deletion of Y-DYS458. This paper provided data regarding the genetic polymorphism of Y-STRs and X-STRs in the Han population, and demonstrated the importance of Y STR and X-STR in forensic autosomal STR analysis. PMID- 28363009 TI - TNFR1 -383 A?C polymorphism and ankylosing spondylitis in a Russian Caucasian population: a preliminary study. AB - The aim of this study was to assess the association between the TNFR1 rs2234649 polymorphism and ankylosing spondylitis susceptibility in a Russian Caucasian population. A total of 41 ankylosing spondylitis patients and 43 healthy controls, matched according to age and sex, were enrolled, and polymerase chain reaction-restriction fragment length polymorphism analysis was used to genotype the rs2234649 variant. We evaluated genotype distributions in the patient and control groups with the chi-square test, and assessed the relationship between genotypes and ankylosing spondylitis using the odds ratio. Our analysis showed that the rs2234649 polymorphism does not increase ankylosing spondylitis risk. In conclusion, the TNFR1 gene polymorphism tested does not appear to be useful for assessing predisposition to this disease or for its diagnosis or prognosis. PMID- 28363010 TI - Genetic and molecular characterization of multiflorous spikelet in oat. AB - Multiflorous spikelets are found in several grass species of agricultural and economic interest. In oat, this morphological characteristic is associated with the production of naked grains. Although many genetic studies have been performed over the past century, the inheritance of the multiflorous spikelet trait is not fully understood in oat. The objectives of this study were to evaluate environmental effects on the multiflorous spikelet trait, to estimate the number of genes controlling the trait, and to clone and characterize sequences of the AP2 gene in oat. Two genetic populations of recombinant inbreed lines were screened for the multiflorous spikelet trait from different years and sowing dates under field experiments. Normal, multiflorous, and mosaic spikelets were analyzed in the whole panicle for both years and sowing dates. Specific primer pairs for the AP2 gene was utilized to amplify and clone oat sequences. The results demonstrate that under higher temperature and day-length conditions, the variable expressivity of the multiflorous spikelet trait was less pronounced in both populations. Genetic analyses indicated the action of one major gene and two or three modifying genes controlling the expression of the multiflorous spikelet trait in oat, depending on the genetic background. Sequences with similarity to the AP2 gene were isolated from the oat lines UFRGS 017004-2 and URS Taura, and genetic polymorphisms were identified, which are valuable to confirm the action of AP2 on the multiflorous spikelet trait. Our results provide information to assist in the development of future studies of the multiflorous spikelet trait in oat. PMID- 28363011 TI - SHORT-COMMUNICATION Evaluation of perfused bovine udder for gene expression studies in dairy cows. AB - Intramammary infections are one of the main causes of productivity loss in dairy cows. To better understand the immune system response and to avoid the use of live animals, we validated the use of isolated bovine udder as an ex situ model. Six mammary glands were collected from cows ready for culling. Three udders were perfused with Tyrode's solution and three were not-perfused. During six hours, we collected perfusate samples for biochemical analysis. We also collected alveolar and teat canal tissue to evaluate gene expression. The biochemical parameters indicated that the perfused udders remained viable for the entire period of the experiment. A real-time polymerase chain reaction showed an increase in 18S rRNA gene expression in the alveolar tissue at 3 and 4 h after perfusion. There was also an increase in the Ubiquitin gene in the teat canal from not-perfused udders at 1, 3, and 4 h after slaughter. In general, gene expression was stable during the experiment. Our results indicated that the isolated perfused bovine udder model is appropriate for genetic studies, opening a new perspective in animal experimentation methods. PMID- 28363012 TI - Fluorescence Image Analyzer - FLIMA: software for quantitative analysis of fluorescence in situ hybridization. AB - The Fluorescence Image Analyzer (FLIMA) software was developed for the quantitative analysis of images generated by fluorescence in situ hybridization (FISH). Currently, the images of FISH are examined without a coefficient that enables a comparison between them. Through GD Graphics Library, the FLIMA software calculates the amount of pixels on image and recognizes each present color. The coefficient generated by the algorithm shows the percentage of marks (probes) hybridized on the chromosomes. This software can be used for any type of image generated by a fluorescence microscope and is able to quantify digoxigenin probes exhibiting a red color, biotin probes exhibiting a green color, and double FISH probes (digoxigenin and biotin used together), where the white color is displayed. PMID- 28363013 TI - Probing Evolution of Twist-Angle-Dependent Interlayer Excitons in MoSe2/WSe2 van der Waals Heterostructures. AB - Interlayer excitons were observed at the heterojunctions in van der Waals heterostructures (vdW HSs). However, it is not known how the excitonic phenomena are affected by the stacking order. Here, we report twist-angle-dependent interlayer excitons in MoSe2/WSe2 vdW HSs based on photoluminescence (PL) and vdW corrected density functional theory calculations. The PL intensity of the interlayer excitons depends primarily on the twist angle: It is enhanced at coherently stacked angles of 0 degrees and 60 degrees (owing to strong interlayer coupling) but disappears at incoherent intermediate angles. The calculations confirm twist-angle-dependent interlayer coupling: The states at the edges of the valence band exhibit a long tail that stretches over the other layer for coherently stacked angles; however, the states are largely confined in the respective layers for intermediate angles. This interlayer hybridization of the band edge states also correlates with the interlayer separation between MoSe2 and WSe2 layers. Furthermore, the interlayer coupling becomes insignificant, irrespective of twist angles, by the incorporation of a hexagonal boron nitride monolayer between MoSe2 and WSe2. PMID- 28363014 TI - Chromosomal Aberrations in Large Japanese Field Mice (Apodemus speciosus) Captured near Fukushima Dai-ichi Nuclear Power Plant. AB - Since the Fukushima Dai-ichi Nuclear Power Plant accident, radiation effects on nonhuman biota in the contaminated areas have been a major concern. Here, we analyzed the frequencies of chromosomal aberrations (translocations and dicentrics) in the splenic lymphocytes of large Japanese field mice (Apodemus speciosus) inhabiting Fukushima Prefecture. A. speciosus chromosomes 1, 2, and 5 were flow-sorted in order to develop A. speciosus chromosome-specific painting probes, and FISH (fluorescence in situ hybridization) was performed using these painting probes to detect the translocations and dicentrics. The average frequency of the translocations and dicentrics per cell in the heavily contaminated area was significantly higher than the frequencies in the case of the noncontaminated control area and the slightly and moderately contaminated areas, and this aberration frequency in individual mice tended to roughly increase with the estimated dose rates and accumulated doses. In all four sampling areas, the proportion of aberrations occurring in chromosome 2 was approximately >3 times higher than that in chromosomes 1 and 5, which suggests that A. speciosus chromosome 2 harbors a fragile site that is highly sensitive to chromosome breaks induced by cellular stress such as DNA replication. The elevated frequency of chromosomal aberrations in A. speciosus potentially resulting from the presence of a fragile site in chromosome 2 might make it challenging to observe the mild effect of chronic low-dose-rate irradiation on the induction of chromosomal aberrations in A. speciosus inhabiting the contaminated areas of Fukushima. PMID- 28363015 TI - Solution-Assembled Blends of Regioregularity-Controlled Polythiophenes for Coexistence of Mechanical Resilience and Electronic Performance. AB - Considering all the potential applications of organic electronics in portable, wearable, and implantable devices, it is of great importance to develop electroactive materials that possess mechanical reliability along with excellent electronic performance. The coexistence of these two attributes, however, is very difficult to achieve because there is an inverse relationship between the electrical properties and the mechanical flexibility, both of which are associated with the conjugation length and intermolecular ordering of the polymers. Herein, we demonstrate a simple and robust approach based on solution assembly of two different poly(3-hexylthiophene)s (P3HTs) with regioregularity (RR) contents of 97% and 66% to impart both electrical and mechanical properties to films for organic electronic applications. The 97% RR P3HT exhibits high electronic performance but poor mechanical resilience, and vice versa for the 66% RR P3HT. Selective crystallization of high RR P3HT induced by solution assembly allows the use of a one-step process to construct percolated networks of high RR P3HT nanowires (NWs) in a low RR P3HT matrix. Only 5 wt % of high RR P3HT NWs in a 95 wt % low RR P3HT matrix was required to produce hole mobilities comparable to that of pure high RR P3HT, and this blend film exhibited improvements by factors of 20 and 60 in elongation at break and toughness, respectively. Selective self-assembly of RR-controlled polymers allowed us to overcome the fragile nature of highly crystalline conjugated polymer films without sacrificing their electronic properties. PMID- 28363016 TI - Photochemical Reaction of OCSe with ClF in Argon Matrix: A Light-Driven Formation of XC(O)SeY (X, Y = F or Cl) Species. AB - The photochemistry of OCSe with ClF trapped together in argon matrices at cryogenic temperatures has been explored and the first interhalogen representatives of the elusive XC(O)SeY family, namely syn-ClC(O)SeF, anti ClC(O)SeF, syn-FC(O)SeCl, and anti-FC(O)SeCl, as well as the hitherto triatomic species ClSeF complexed by a CO molecule, were obtained. Both ClC(O)SeF conformers appear to be produced independently by photolysis of the respective precursors; while formation of both FC(O)SeCl structures is ruled by the presence of an angular molecular complex OCSe...Cl-F formed prior to photolysis. This latter photochemical pathway seems to favor the formation of the less stable anti FC(O)SeCl structure instead of the more stable syn- one. With the aid of quantum chemical calculations, using ab initio, DFT, TDDFT, and CASSCF methods, the mechanism for this photochemical reaction is rationalized both in terms of radical processes as well as a photoinduced electron transfer occurring into the OCSe...Cl-F complex. Also a singlet-triplet conical intersection between anti and syn rotamers of the FC(O)SeCl molecule is theoretically explored. PMID- 28363017 TI - Cell and Protein Fouling Properties of Polymeric Mixtures Containing Supramolecular Poly(ethylene glycol) Additives. AB - Fouling properties of new biomaterials are important for the performance of a material in a biological environment. Here, a set of three supramolecular polymeric additives consisting of ureidopyrimidinone (UPy)-functionalized poly(ethylene glycol) (UPyPEG) were formulated with UPy-modified polycaprolactone into thin supramolecular material films. The antifouling properties of these material films were determined by investigation of the relation of cell adhesion and protein adsorption on these materials films. The presence of the UPyPEG additives at the surface of the films was evident by an increased hydrophilicity. Adhesion of human epithelial and endothelial cells was strongly reduced for two of the UPyPEG-containing films. Analysis of adsorption of the first three proteins from the Vroman series, albumin, gamma-globulin, and fibrinogen, using quartz crystal microbalance with dissipation in combination with viscoelastic modeling, revealed that the surfaces containing the UPyPEG additives had a limited effect on adsorption of these proteins. Despite a limited reduction of protein adsorption, UPyPEG-containing mixtures were non-cell-adhesive, which shows that non-cell-adhesive properties of supramolecular polymer surfaces are not always directly correlated to protein adsorption. PMID- 28363018 TI - Single-Cell Mass Spectrometry of Metabolites Extracted from Live Cells by Fluidic Force Microscopy. AB - Single-cell metabolite analysis provides valuable information on cellular function and response to external stimuli. While recent advances in mass spectrometry reached the sensitivity required to investigate metabolites in single cells, current methods commonly isolate and sacrifice cells, inflicting a perturbed state and preventing complementary analyses. Here, we propose a two step approach that combines nondestructive and quantitative withdrawal of intracellular fluid with subpicoliter resolution using fluidic force microscopy, followed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The developed method enabled the detection and identification of 20 metabolites recovered from the cytoplasm of individual HeLa cells. The approach was further validated in 13C-glucose feeding experiments, which showed incorporation of labeled carbon atoms into different metabolites. Metabolite sampling, followed by mass spectrometry measurements, enabled the preservation of the physiological context and the viability of the analyzed cell, providing opportunities for complementary analyses of the cell before, during, and after metabolite analysis. PMID- 28363019 TI - Low-Temperature Synchrotron Photoionization Study of 2-Methyl-3-buten-2-ol (MBO) Oxidation Initiated by O(3P) Atoms in the 298-650 K Range. AB - This work studies the oxidation of 2-methyl-3-buten-2-ol initiated by O(3P) atoms. The oxidation was investigated at room temperature, 550, and 650 K. Using the synchrotron radiation from the Advanced Light Source (ALS) of the Lawrence Berkley National Laboratory, reaction intermediates and products were studied by multiplexed photoionization mass spectrometry. Mass-to-charge ratios, kinetic time traces, photoionization spectra, and adiabatic ionization energies for each primary reaction species were obtained and used to characterize their identity. Using electronic structure calculations, potential energy surface scans of the different species produced throughout the oxidation were examined and presented in this paper to further validate the primary chemistry occurring. Branching fractions of primary products at all three temperatures were also provided. At room temperature only three primary products formed: ethenol (26.6%), acetaldehyde (4.2%), and acetone (53.4%). At 550 and 650 K the same primary products were observed in addition to propene (5.1%, 11.2%), ethenol (18.1%, 2.8%), acetaldehyde (8.9%, 5.7%), cyclobutene (1.6%, 10.8%), 1-butene (2.0%, 10.9%), trans-2-butene (3.2%, 23.1%), acetone (50.4%, 16.8%), 3-penten-2-one (1.0%, 11.5%), and 3-methyl-2-butenal (0.9%, 2.5%), where the first branching fraction value in parentheses corresponds to the 550 K data. At the highest temperature, a small amount of propyne (1.0%) was also observed. PMID- 28363020 TI - Highly efficient Blue-Emitting CdSe-derived Core/Shell Gradient Alloy Quantum Dots with Improved Photoluminescent Quantum Yield and Enhanced Photostability. AB - Highly efficient blue-emitting CdSe-derived core/shell gradient alloy quantum dots (CSGA QDs) with photoluminescence quantum yield (PL QY) of ca. 90% have been synthesized through a facile "one-pot" approach. CdSe nuclei are initially formed as core and gradient alloy shells such as CdSexS1-x/ZnSeyS1-y simultaneously encapsulate the preformed CdSe core in an energy-gradient fashion eventually followed by coating with ZnS shells due to the faster precursor reaction kinetics of Cd and Se compared to analog of Zn and S. During the formation of core/shell structure, red-shifting of absorption/emission peaks followed by blue-shifting of analogues were observed due to the intradiffusion of sulfur anion to CdSe luminescent center. In this gradient architecture, interfacial lattice strain can be effectively alleviated, and thus high PL QY (ca. 90%) and enhanced photochemical stability can be achieved. The synthesized blue-emitting gradient alloy QDs with superior optical properties tunable in the range of 450-490 nm can be used for highly efficient blue-emitters and potentially applicable for the fabrication of white-light LEDs. PMID- 28363021 TI - A Spinning Umbrella: Carbon Monoxide and Dinitrogen Bound MB12- Clusters (M = Co, Rh, Ir). AB - Strong binding of carbon monoxide (CO) and dinitrogen (N2) by MB12- (M = Co, Rh, Ir) clusters results in a spinning umbrella-like structure. For OCMB12- and NNMB12- complexes, the bond dissociation energy values range within 50.3-67.7 kcal/mol and 25.9-35.7 kcal/mol, respectively, with the maximum value obtained in Ir followed by that in Co and Rh analogues. COMB12- complex is significantly less stable than the corresponding C-side bonded isomer. The associated dissociation processes for OCMB12- and NNMB12- into CO or N2 and MB12- are highly endergonic in nature at 298 K, implying their high thermochemical stability with respect to dissociation. In OCMB12- and NNMB12- complexes, the C-O and N-N bonds are found to be elongated by 0.022-0.035 A along with a large red-shift in the corresponding stretching frequencies, highlighting the occurrence of bond activation therein toward further reactivity due to complexation. The obtained red-shift is explained by the dominance of L<-M pi-back-donation (L = CO, OC, NN) over L->M sigma-donation. The binding of L enhances the energy barrier for the rotation of the inner B3 unit within the outer B9 ring by 0.4-1.8 kcal/mol, which can be explained by a reduction in the distance of the longest bond between inner B3 and outer B9 rings upon complexation. A good correlation is found between the change in rotational barrier relative to that in MB12- and the energy associated with the L->M sigma-donation. Born-Oppenheimer molecular dynamics simulations further support that the M-L bonds in the studied systems are kinetically stable enough to retain the original forms during the internal rotation of inner B3 unit. PMID- 28363022 TI - Molecular Dynamics Simulation of a RNA Aptasensor. AB - Single-stranded RNA aptamers have emerged as novel biosensor tools. However, the immobilization procedure of the aptamer onto a surface generally induces a loss of affinity. To understand this molecular process, we conducted a complete simulation study for the Flavin mononucleotide aptamer for which experimental data are available. Several molecular dynamics simulations (MD) of the Flavin in complex with its RNA aptamer were conducted in solution, linked with six thymidines (T6) and, finally, immobilized on an hexanol-thiol-functionalized gold surface. First, we demonstrated that our MD computations were able to reproduce the experimental solution structure and to provide a meaningful estimation of the Flavin free energy of binding. We also demonstrated that the T6 linkage, by itself, does not generate a perturbation of the Flavin recognition process. From the simulation of the complete biosensor system, we observed that the aptamer stays oriented parallel to the surface at a distance around 36 A avoiding, this way, interaction with the surface. We evidenced a structural reorganization of the Flavin aptamer binding mode related to the loss of affinity and induced by an anisotropic distribution of sodium cationic densities. This means that ionic diffusion is different between the surface and the aptamer than above this last one. We suggest that these findings might be extrapolated to other nucleic acids systems for the future design of biosensors with higher efficiency and selectivity. PMID- 28363023 TI - Reconstructing Early Industrial Contributions to Legacy Trace Metal Contamination in Southwestern Pennsylvania. AB - Early industrial trace metal loadings are poorly characterized but potentially substantial sources of trace metals to the landscape. The magnitude of legacy contamination in southwestern Pennsylvania, the cradle of North American fossil fuel industrialization, is reconstructed from trace metal concentrations in a sediment core with proxies including major and trace metal chemistry, bulk density, and magnetic susceptibility. Trace metal chemistry in this sediment record reflects 19th and 20th century land use and industry. In particular, early 19th century arsenic loadings to the lake are elevated from pesticides used by early European settlers at a lakeside tannery. Later, sediment barium concentrations rise, likely reflecting the onset of acidic mine drainage from coal operations. Twentieth century zinc, cadmium, and lead concentrations are dominated by emissions from the nearby, infamous Donora Zinc Works yet record both the opening of a nearby coal-fired power plant and amendments to the Clean Air Act. The impact of early industry is substantial and rivals more recent metal fluxes, resulting in a significant potential source of contaminated sediments. Thus, modern assessments of trace metal contamination cannot ignore early industrial inputs, as the potential remobilization of legacy contamination would impact ecosystem and human health. PMID- 28363024 TI - Phase Diagram of Fatty Acid Langmuir Monolayers from Rheological Measurements. AB - Langmuir monolayers of fatty acids and alcohols are two-dimensional systems with a rich equilibrium phase diagram. We have explored the temperature and surface pressure-dependent shear response of monolayers formed by fatty acids of different chain lengths and a fatty alcohol. This has been accomplished with an interfacial shear rheometer utilizing magnetic tweezers and equipped with a refined temperature control and acquisition system. Our rheological results have allowed us to draw a phase diagram from the viscoelastic properties of these 2-D systems and show new phenomena that strongly depend on temperature: the existence of a maximum in viscosity at the L2' phase, the behavior of the elastic modulus to the storage modulus ratio at the L2 phase, and the increase or decrease in viscosity at the L2-LS phase transition. In addition, we unambiguously show that the LS phase displays a counterintuitive behavior in which the loss modulus increases with temperature. We demonstrate, through isothermal surface pressure sweeps and isobaric temperature sweeps, that the exponential dependence of the loss modulus on temperature at the LS phase appears for all hydrophobic tail lengths studied and for both acid and alcohol head groups. PMID- 28363025 TI - Channeling through Two Stacked Guanine Quartets of One and Two Alkali Cations in the Li+, Na+, K+, and Rb+ Series. Assessment of the Accuracy of the SIBFA Anisotropic Polarizable Molecular Mechanics Potential. AB - Stacking of guanine quartets (GQs) can trigger the formation of DNA or RNA quadruple helices, which play numerous biochemical roles. The GQs are stabilized by alkali cations, mainly K+ and Na+, which can reside in, or channel through, the central axis of the GQ stems. Further, ion conduction through GQ wires can be leveraged for nanochemistry applications. G-quadruplex systems have been extensively studied by classical molecular dynamics (MD) simulations using pair additive force fields or by quantum-chemical (QC) calculations. However, the non polarizable force fields are very approximate, while QC calculations lack the necessary sampling. Thus, ultimate description of GQ systems would require long enough simulations using advanced polarizable molecular mechanics (MM). However, to perform such calculations, it is first mandatory to evaluate the method's accuracy using benchmark QC. We report such an evaluation for SIBFA polarizable MM, bearing on the channeling (movement) of an alkali cation (Li+, Na+, K+, or Rb+) along the axis of two stacked G quartets interacting with either one or two ions. The QC energy profiles display markedly different features depending upon the cation but can be retrieved in the majority of cases by the SIBFA profiles. An appropriate balance of first-order (electrostatic and short-range repulsion) and second-order (polarization, charge-transfer, and dispersion) contributions within DeltaE is mandatory. With two cations in the channel, the relative weights of the second-order contributions increase steadily upon increasing the ion size. In the G8 complexes with two K+ or two Rb+ cations, the sum of polarization and charge-transfer exceeds the first order terms for all ion positions. PMID- 28363026 TI - Hydroxypyridinone and 5-Aminolaevulinic Acid Conjugates for Photodynamic Therapy. AB - Photodynamic therapy (PDT) is a promising treatment strategy for malignant and nonmalignant lesions. 5-Aminolaevulinic acid (ALA) is used as a precursor of the photosensitizer, protoporphyrin IX (PpIX), in dermatology and urology. However, the effectiveness of ALA-PDT is limited by the relatively poor bioavailability of ALA and rapid conversion of PpIX to haem. The main goal of this study was to prepare and investigate a library of single conjugates designed to coadminister the bioactive agents ALA and hydroxypyridinone (HPO) iron chelators. A significant increase in intracellular PpIX levels was observed in all cell lines tested when compared to the administration of ALA alone. The higher PpIX levels observed using the conjugates correlated well with the observed phototoxicity following exposure of cells to light. Passive diffusion appears to be the main mechanism for the majority of ALA-HPOs investigated. This study demonstrates that ALA-HPOs significantly enhance phototherapeutic metabolite formation and phototoxicity. PMID- 28363027 TI - Exchange Phenomena in the Electron Paramagnetic Resonance Spectra of the Nitroxyl and Trityl Radicals: Multifunctional Spectroscopy and Imaging of Local Chemical Microenvironment. AB - This Feature overviews the basic principles of using stable organic radicals involved in reversible exchange processes as functional paramagnetic probes. We demonstrate that these probes in combination with electron paramagnetic resonance (EPR)-based spectroscopy and imaging techniques provide analytical tools for quantitative mapping of critical parameters of local chemical microenvironment. The Feature is written to be understandable to people who are laymen to the EPR field in anticipation of future progress and broad application of these tools in biological systems, especially in vivo, over the next years. PMID- 28363028 TI - Spectroscopic Investigation of the Formation and Disruption of Hydrogen Bonds in Pharmaceutical Semicrystalline Dispersions. AB - We recently found that indomethacin (IMC) can effectively act as a powerful crystallization inhibitor for polyethylene glycol 6000 (PEG) despite the fact that the absence of interactions between the drug and the carrier in the solid state was reported in the literature. However, in the present study, we investigate the possibility of drug-carrier interactions in the liquid state to explain the polymer crystallization inhibition effect of IMC. We also aim to discover other potential PEG crystallization inhibitors. Drug-carrier interactions in both liquid and solid state are characterized by variable temperature Fourier transform infrared spectroscopy (FTIR) and cross-polarization magic angle spinning 13C nuclear magnetic resonance spectroscopy (CP/MAS NMR). In the liquid state, FTIR data show evidence of the breaking of hydrogen bonding between IMC molecules to form interactions of the IMC monomer with PEG. The drug carrier interactions are disrupted upon storage and polymer crystallization, resulting in segregation of IMC from PEG crystals that can be observed under polarized light microscopy. This process is further confirmed by 13C NMR since in the liquid state, when the IMC/PEG monomer units ratio is below 2:1, IMC signals are undetectable because of the loss of cross-polarization efficiency in the mobile IMC molecules upon attachment to PEG chains via hydrogen bonding. This suggests that each ether oxygen of the PEG unit can form hydrogen bonds with two IMC molecules. The NMR spectrum of IMC shows no change in solid dispersions with PEG upon storage, indicating the absence of interactions in the solid state, hence confirming previous studies. The drug-carrier interactions in the liquid state elucidate the crystallization inhibition effect of IMC on PEG as well as other semicrystalline polymers such as poloxamer and Gelucire. However, hydrogen bonding is a necessary but apparently not a sufficient condition for the polymer crystallization inhibition. Screening of crystallization inhibitors of semicrystalline polymers discovers numerous candidates that exhibit the same behavior as IMC, demonstrating a general pattern of polymer crystallization inhibition rather than a particular case. Furthermore, the crystallization inhibition effect of drugs on PEG is independent of the carrier molecular weight. These mechanistic findings on the formation and disruption of hydrogen bonds in semicrystalline dispersions can be extended to amorphous dispersions and are of significant importance for preparation of solid dispersions with consistent and reproducible physicochemical properties. PMID- 28363031 TI - Recurring Giant Mediastinal Cystic Lymphangioma. PMID- 28363032 TI - Poor Response to Periodontal Treatment May Predict Future Cardiovascular Disease. AB - Periodontal disease has been associated with cardiovascular disease (CVD), but whether the response to the treatment of periodontal disease affects this association has not been investigated in any large prospective study. Periodontal data obtained at baseline and 1 y after treatment were available in 5,297 individuals with remaining teeth who were treated at a specialized clinic for periodontal disease. Poor response to treatment was defined as having >10% sites with probing pocket depth >4 mm deep and bleeding on probing at >=20% of the sites 1 y after active treatment. Fatal/nonfatal incidence rate of CVD (composite end point of myocardial infarction, stroke, and heart failure) was obtained from the Swedish cause-of-death and hospital discharge registers. Poisson regression analysis was performed to analyze future risk of CVD. During a median follow-up of 16.8 y (89,719 person-years at risk), those individuals who did not respond well to treatment (13.8% of the sample) had an increased incidence of CVD ( n = 870) when compared with responders (23.6 vs. 15.3%, P < 0.001). When adjusting for calendar time, age, sex, educational level, smoking, and baseline values for bleeding on probing, probing pocket depth >4 mm, and number of teeth, the incidence rate ratio for CVD among poor responders was 1.28 (95% CI, 1.07 to 1.53; P = 0.007) as opposed to good responders. The incidence rate ratio among poor responders increased to 1.39 (95% CI, 1.13 to 1.73; P = 0.002) for those with the most remaining teeth. Individuals who did not respond well to periodontal treatment had an increased risk for future CVD, indicating that successful periodontal treatment might influence progression of subclinical CVD. PMID- 28363030 TI - Integrated Stress Response Mediates Epithelial Injury in Mechanical Ventilation. AB - Ventilator-induced lung injury (VILI) is a severe complication of mechanical ventilation that can lead to acute respiratory distress syndrome. VILI is characterized by damage to the epithelial barrier with subsequent pulmonary edema and profound hypoxia. Available lung-protective ventilator strategies offer only a modest benefit in preventing VILI because they cannot impede alveolar overdistension and concomitant epithelial barrier dysfunction in the inflamed lung regions. There are currently no effective biochemical therapies to mitigate injury to the alveolar epithelium. We hypothesize that alveolar stretch activates the integrated stress response (ISR) pathway and that the chemical inhibition of this pathway mitigates alveolar barrier disruption during stretch and mechanical ventilation. Using our established rat primary type I-like alveolar epithelial cell monolayer stretch model and in vivo rat mechanical ventilation that mimics the alveolar overdistension seen in acute respiratory distress syndrome, we studied epithelial responses to mechanical stress. Our studies revealed that the ISR signaling pathway is a key modulator of epithelial permeability. We show that prolonged epithelial stretch and injurious mechanical ventilation activate the ISR, leading to increased alveolar permeability, cell death, and proinflammatory signaling. Chemical inhibition of protein kinase RNA-like endoplasmic reticulum kinase, an upstream regulator of the pathway, resulted in decreased injury signaling and improved barrier function after prolonged cyclic stretch and injurious mechanical ventilation. Our results provide new evidence that therapeutic targeting of the ISR can mitigate VILI. PMID- 28363033 TI - Using an Internet-Based Breast Cancer Risk Assessment Tool to Improve Social Cognitive Precursors of Physical Activity. AB - BACKGROUND: Internet-based cancer risk assessment tools might serve as a strategy for translating epidemiological risk prediction research into public health practice. Understanding how such tools affect key social-cognitive precursors of behavior change is crucial for leveraging their potential into effective interventions. PURPOSE: To test the effects of a publicly available, Internet based, breast cancer risk assessment tool on social-cognitive precursors of physical activity. METHODS: Women (N = 132) aged 40-78 with no personal cancer history indicated their perceived risk of breast cancer and were randomly assigned to receive personalized ( www.yourdiseaserisk.wustl.edu ) or nonpersonalized breast cancer risk information. Immediately thereafter, breast cancer risk perceptions and physical activity-related behavioral intentions, self efficacy, and response efficacy were assessed. RESULTS: Personalized information elicited higher intentions, self-efficacy, and response efficacy than nonpersonalized information, P values < 0.05. Self-efficacy and response efficacy mediated the effect of personalizing information on intentions. Women who received personalized information corrected their inaccurate risk perceptions to some extent, P values < 0.05, but few fully accepted the information. CONCLUSION: Internet-based risk assessment tools can produce beneficial effects on important social-cognitive precursors of behavior change, but lingering skepticism, possibly due to defensive processing, needs to be addressed before the effects can be maximized. PMID- 28363035 TI - The Benefits and Risks of CrossFit: A Systematic Review. AB - With the increase in popularity of the CrossFit exercise program, occupational health nurses may be asked questions about the appropriateness of CrossFit training for workers. This systematic literature review was conducted to analyze the current research on CrossFit, and assess the benefits and risks of this exercise strategy. Thirteen studies ( N = 2,326 participants) examined the use of CrossFit training among adults; CrossFit is comparable to other exercise programs with similar injury rates and health outcomes. Occupational health nurses should assess previous injuries prior to recommending this form of exercise. Ideal candidates for CrossFit are adults who seek high-intensity exercise with a wide variety of exercise components. PMID- 28363034 TI - Machine-Learning Algorithms to Code Public Health Spending Accounts. AB - OBJECTIVES: Government public health expenditure data sets require time- and labor-intensive manipulation to summarize results that public health policy makers can use. Our objective was to compare the performances of machine-learning algorithms with manual classification of public health expenditures to determine if machines could provide a faster, cheaper alternative to manual classification. METHODS: We used machine-learning algorithms to replicate the process of manually classifying state public health expenditures, using the standardized public health spending categories from the Foundational Public Health Services model and a large data set from the US Census Bureau. We obtained a data set of 1.9 million individual expenditure items from 2000 to 2013. We collapsed these data into 147 280 summary expenditure records, and we followed a standardized method of manually classifying each expenditure record as public health, maybe public health, or not public health. We then trained 9 machine-learning algorithms to replicate the manual process. We calculated recall, precision, and coverage rates to measure the performance of individual and ensembled algorithms. RESULTS: Compared with manual classification, the machine-learning random forests algorithm produced 84% recall and 91% precision. With algorithm ensembling, we achieved our target criterion of 90% recall by using a consensus ensemble of >=6 algorithms while still retaining 93% coverage, leaving only 7% of the summary expenditure records unclassified. CONCLUSIONS: Machine learning can be a time- and cost-saving tool for estimating public health spending in the United States. It can be used with standardized public health spending categories based on the Foundational Public Health Services model to help parse public health expenditure information from other types of health-related spending, provide data that are more comparable across public health organizations, and evaluate the impact of evidence-based public health resource allocation. PMID- 28363036 TI - Shrimp oil extracted from the shrimp processing waste reduces the development of insulin resistance and metabolic phenotypes in diet-induced obese rats. AB - Diet-induced obesity, insulin resistance, impaired glucose tolerance, chronic inflammation, and oxidative stress represent the main features of type 2 diabetes mellitus. The present study was conducted to examine the efficacy and mechanisms of shrimp oil on glucose homeostasis in obese rats. Male CD rats fed a high-fat diet (52 kcal% fat) and 20% fructose drinking water were divided into 4 groups and treated with the dietary replacement of 0%, 10%, 15%, or 20% of lard with shrimp oil for 10 weeks. Age-matched rats fed a low-fat diet (10 kcal% fat) were used as the normal control. Rats on the high-fat diet showed impaired (p < 0.05) glucose tolerance and insulin resistance compared with rats fed the low-fat diet. Shrimp oil improved (p < 0.05) oral glucose tolerance, insulin response, and homeostatic model assessment-estimated insulin resistance index; decreased serum insulin, leptin, hemoglobin A1c, and free fatty acids; and increased adiponectin. Shrimp oil also increased (p < 0.05) antioxidant capacity and reduced oxidative stress and chronic inflammation. The results demonstrated that shrimp oil dose dependently improved glycemic control in obese rats through multiple mechanisms. PMID- 28363037 TI - THE PASSAGE AND DURATION OF ANTIBODIES TO WEST NILE VIRUS IN HUMBOLDT PENGUINS (SPHENISCUS HUMBOLDTI). AB - West Nile virus (genus Flavivirus) outbreaks and mortality events have been documented in both wild and captive avian species, including penguins. Serologic response to vaccination in avian species has varied and appears to be largely species dependent; however, Humboldt penguins ( Spheniscus humboldti ) previously showed excellent rates of seroconversion. The goal of this study was to determine virus neutralization titers of 17 Humboldt penguin hens and their subsequent eggs, chicks, or both following vaccination with a killed West Nile vaccine. Chicks were also vaccinated at 56, 70, and 84 days old. Titers were measured from 10-346 days prior to lay as well as serially in seven chicks. Data collected showed positive rank correlation between maternal titers and yolk titers (rho = 0.90, P < 0.0001, n = 14) but no association between booster vaccination and yolk titers. All seven chicks had detectable antibody on days 14 and 28, and antibody levels had increased (relative to day 56) in 3 of 6 chicks (50%; 95% confidence interval 14-86%) by day 112. Further information is provided on a suggested vaccination schedule for Humboldt penguin chicks based on a time-dependent decline in maternal antibody titers. Cell-mediated immunity and experimental challenge following vaccination have not yet been investigated in this species. PMID- 28363038 TI - BAYLISASCARIS PROCYONIS LARVA MIGRANS IN TWO CAPTIVE NORTH AMERICAN BEAVERS (CASTOR CANADENSIS). AB - Baylisascaris procyonis larva migrans was diagnosed in two North American beavers ( Castor canadensis ) belonging to a zoological park in Clarke County, Georgia. Both beavers presented with neurological signs. One beaver died naturally and despite attempted treatment, the other beaver was euthanatized because of severe clinical signs and poor prognosis. Histologic evaluation of the beavers revealed evidence of parasitic migration characterized by several lesions, including eosinophilic granulomas in various organs, as well as necrotizing eosinophilic and lymphoplasmacytic to granulomatous polioencephalitis, leukoencephalitis and cervical leukomyelitis. This represents the first confirmed case of B. procyonis larva migrans in beaver and the first non-raccoon ( Procyon lotor ) host in the southeastern United States. This report highlights the need for clinicians and diagnosticians to consider baylisascariasis in animals with compatible clinical signs. Preventative measures should be considered for captive animals, because early diagnosis of B. procyonis is challenging, and treatment is often unrewarding. PMID- 28363039 TI - GRANULOMATOUS FILARIAL ENCEPHALOMYELITIS CAUSED BY CHANDLERELLA QUISCALI IN A NORTHERN CRESTED CARACARA (CARACARA CHERIWAY). AB - A northern crested caracara (Caracara cheriway) was presented after being found nonambulatory in a field. On physical examination, the bird had severe hind-limb paresis. The bird did not improve after 10 days of hospitalization and was euthanized. Histologic examination of the cerebrum and spinal cord revealed multiple adult filarial nematodes surrounded by granulomatous inflammation with several multinucleated giant cells. These parasites were confirmed to be Chandlerella quiscali with polymerase chain reaction. This is the first report of C. quiscali in a bird of prey. PMID- 28363040 TI - TREATMENT OF PULMONICOLA COCHLEOTREMA INFECTION WITH IVERMECTIN-PRAZIQUANTEL COMBINATION IN AN ANTILLEAN MANATEE (TRICHECHUS MANATUS MANATUS). AB - The aim of this study was to report the use of an oral combination of ivermectin plus praziquantel in the treatment of a Pulmonicola cochleotrema in an Antillean manatee ( Trichechus manatus manatus). A female manatee was found exhibiting respiratory changes and the presence of parasites in the nares. Based on clinical manifestations presented by the manatee, a symptomatic therapeutic protocol was employed, which included an anthelmintic treatment using a combination of ivermectin plus praziquantel. The parasites retrieved were identified as P. cochleotrema. The fourth day after the onset of the therapeutic protocol, the clinical signs declined and on the seventh day posttreatment no clinical signs were observed. This is the first time a therapeutic protocol of ivermectin plus praziquantel has been used in the treatment of P. cochleotrema in manatees. PMID- 28363041 TI - DECLINE OF GAME BIRDS (PHASIANUS COLCHICUS AND PERDIX PERDIX) IN BAVARIA: A SURVEY ON PATHOGENIC BACTERIA, PARASITES, PESTICIDE RESIDUES, AND INFLUENCE OF SET-ASIDE LAND AND MAIZE CULTIVATION. AB - Due to a Europe-wide decline of grey partridge ( Perdix perdix ) and pheasant ( Phasianus colchicus ) populations, this study was conducted focusing on the county of Bavaria, south Germany. The aim was to assess the health status of game birds and identify possible causes of decline. For this purpose 203 pheasants and 11 partridges were examined during the 2011 hunting season. Pathologic examinations were conducted including examinations for parasites and bacteria. Due to public health significance, a screening for Salmonella sp., as well as real-time polymerase chain reaction examinations for Campylobacter sp. and Mycobacterium avium ssp. avium, were done. Because pesticides and land-usage can possibly influence bird numbers, the birds were screened for environmental toxin residues, including neonicotinoid insecticides, and land-usage data were correlated with the hunting bags. The result was a very-strong positive correlation of set-aside areas and a less-strong negative correlation of maize cultivation acreage. More than 90% of the birds had a good health status; only individuals showed pathologic alterations. For example, avian tuberculosis was found in two pheasants and a severe capillariosis in two partridges. A possible role of female reproductive disorders has to be confirmed in further investigations. In conclusion, results suggest the decrease of set-aside areas could be a possible reason for decline. PMID- 28363044 TI - AAZV PUBLICATIONS AVAILABLE. PMID- 28363042 TI - CLINICAL MANAGEMENT OF THIRD PHALANX FRACTURES IN LESSER (TRAGELAPHUS IMBERBIS) AND GREATER KUDU (TRAGELAPHUS STREPSICEROS). AB - Two greater kudu ( Tragelaphus strepsiceros ) and one lesser kudu ( T. imberbis ) from two zoological institutions presented with overgrown front hooves, and were diagnosed with fractures of the third phalanges in the affected digits. Both greater kudu had milder lamenesses at diagnosis, and were managed conservatively with hoof trims, stall rest, and nonsteroidal anti-inflammatory medications. Ongoing management through regular hoof trims led to improvement and eventual resolution of lameness. The more severely lame lesser kudu received hoof blocks on the front claws not associated with fractured phalanges. This therapy was well tolerated and resulted in resolution of lameness immediately after application. Radiographic evidence of healing was present 8 wk posttherapy. Diagnosis of these fractures was greatly aided by radiographic views obtained at a 45 degrees oblique angle with the claws distracted. PMID- 28363045 TI - ASSESSMENT OF SERUM 25-HYDROXYVITAMIN D CONCENTRATIONS IN TWO COLLECTIONS OF CAPTIVE GORILLAS (GORILLA GORILLA GORILLA). AB - Serum 25-hydroxyvitamin D concentrations were assessed in subadult to adult captive lowland gorillas ( Gorilla gorilla gorilla) (n = 26) at two institutions with different husbandry and management practices. Serum 25-hydroxyvitamin D (25[OH]D) concentrations for gorillas managed predominantly indoors was low (14.2 +/- 5.9 ng/ml), despite consuming commercial biscuits fortified with vitamin D3. Concentrations of 25(OH)D in gorillas with near daily outdoor access were significantly higher than gorillas managed indoors, although many individuals still had serum values below concentrations recommended for adult humans. Consideration should be given to assessing 25(OH)D concentrations in all captive gorillas and providing specific supplementation, particularly to juveniles without access to direct sunlight. PMID- 28363046 TI - STRESS INFLUENCE ON PLASMA PROTEIN ELECTROPHORESIS IN THE RED-BREASTED GOOSE (BRANTA RUFICOLLIS) AND HAWAIIAN GOOSE (BRANTA SANDVICENSIS). AB - The objective of this study was to evaluate the effects of stress (as measured by total heterophil + eosinophil counts [THECs] and plasma corticosterone [PC] levels) on plasma protein electrophoresis (PPE) in two Anseriform species. Ten red-breasted geese ( Branta ruficollis ) and eight Hawaiian geese (Branta sandvicensis) were received into quarantine at Beauval Zoo and housed together with other Anseriformes. Two days later, all were examined as part of routine quarantine procedures, and blood was collected. THECs were performed using a Malassez hemocytometer after a 1 : 200 dilution with an eosinophil dilution liquid containing phloxine B. PPE, as well as total protein and PC assays, was performed on lithium heparin plasma. Twenty days after arrival, all birds were similarly restrained, examined, and sampled. Pododermatitis lesions were identified on four geese that were excluded from statistical analysis. For each goose, THECs and PC values were sorted by value (lower or higher) independently from the day of sampling. A Wilcoxon signed rank test showed no significant differences between lower and higher values of THECs for any of the PPE fractions. Higher values of corticosterone were associated with higher values of prealbumin, but none of the other fractions were significantly different. A Spearman rank correlation coefficient showed that THECs and PC were not correlated; this suggested differences in kinetics between these stress markers. Results did not show significant alterations of electrophoresis patterns associated with stress as measured with THECs and PC. The results also highlight the complexity of precisely assessing acute and chronic stress in avian species. PMID- 28363048 TI - CLINICAL CHALLENGE. PMID- 28363047 TI - PHARMACOKINETICS OF A SINGLE DOSE OF ORAL AND SUBCUTANEOUS ENROFLOXACIN IN CARIBBEAN FLAMINGOS (PHOENICOPTERUS RUBER RUBER). AB - Enrofloxacin is a fluoroquinolone antimicrobial that is widely used in veterinary medicine because of its bactericidal activity and safety in a broad range of species. Caribbean flamingos, a member of the order Phoenicopteriformes, are popular in zoological collections and suffer from a variety of conditions that can result from or lead to bacterial infection. In this study, two groups of 7 adult captive Caribbean flamingos received a single dose of 15 mg/kg enrofloxacin, administered either orally or subcutaneously. Plasma concentrations of enrofloxacin and its metabolite, ciprofloxacin, were measured using liquid chromatography and mass spectrometry. Pharmacokinetic analysis was performed using noncompartmental methods. The pharmacokinetic parameters for both routes of administration were similar, with a mean peak plasma concentration (Cmax) of 5.25 and 5.77 MUg/ml, a mean time to peak plasma concentration (Tmax) of 1.49 and 1.1 hr, a mean area under the curve (AUC) of 49.9 and 47.3 hr.MUg/ml, and a mean terminal half-life (t1/2) of 5.83 and 6.46 hr for oral and subcutaneous dosing, respectively. Conversion to ciprofloxacin was minimal, with the AUC of ciprofloxacin representing <3% of the enrofloxacin AUC for both routes of administration. Based on the results of the present study, a dose of 15 mg/kg enrofloxacin delivered either orally or subcutaneously in the Caribbean flamingo every 24 hr is recommended for susceptible bacterial pathogens with a minimal inhibitory concentration <= 0.25 MUg/ml. PMID- 28363049 TI - THE USE OF THE LIGASURETM DEVICE FOR SCROTAL ABLATION IN MARSUPIALS. AB - Five sugar gliders ( Petaurus breviceps ), ranging in age from 3 mo to 3.5 yr of age, and one opossum ( Didelphis virginianus ), age 4.5 mo, presented for elective orchiectomy and scrotal ablation. The LigaSureTM device was safely used for orchiectomy and scrotal ablation in both species. Surgical time with the LigaSure was approximately 4 sec. No grooming of the incision site or self mutilation was seen in the first 72 hr postoperatively. One sugar glider required postoperative wound care approximately 10 days postoperatively following incision site grooming by a conspecific. The LigaSure provides a rapid, technologically simple and safe surgical technique for scrotal ablation and orchiectomy in the marsupial patient that minimizes surgical, anesthetic, and recovery times. PMID- 28363050 TI - INTRAVENOUS REGIONAL ANTIBIOTIC PERFUSION THERAPY AS AN ADJUNCTIVE TREATMENT FOR DIGITAL LESIONS IN SEABIRDS. AB - Foot infections are a common problem among seabirds in wildlife rehabilitation. Pododermatitis and digital infections are often challenging to treat because of the presence of suboptimal substrates, abnormal weight-bearing due to injuries, and suboptimal nutritional or health status. Seabirds represent the majority of animals requiring rehabilitation after oil spills, and foot problems are a common reason for euthanasia among these birds. Antibiotic intravenous regional perfusion therapy is frequently used in humans and other species to treat infections of the distal extremities, but it has not been evaluated in seabirds. During the 2015 Refugio oil spill response, four birds with foot lesions (pododermatitis, osteomyelitis, or both) were treated with ampicillin/sulbactam administered intravenously to the affected limb(s) in addition to systemic antibiotics and anti-inflammatories. Three of the birds, all brown pelicans ( Pelecanus occidentalis ) recovered rapidly and were released. Two of these birds had acute pododermatitis and were treated once with intravenous regional perfusion. They were released approximately 3 wk after the perfusion therapy. The third pelican had osteomyelitis of a digit. It was treated twice with intravenous regional perfusion and was released about 1 mo after the initial perfusion therapy. The fourth bird, a Pacific loon ( Gavia pacifica ), was treated once with perfusion therapy but did not respond to treatment and was euthanatized. No serious adverse effects were observed. This technique should be explored further in avian species. PMID- 28363051 TI - EFFECTS OF PLANT PROTEIN DIETS ON THE HEALTH OF FARMED AMERICAN ALLIGATORS (ALLIGATOR MISSISSIPPIENSIS). AB - The objective of this prospective, blinded study was to compare plasma biochemical values and gross and histologic evaluation of kidney and liver from American alligators ( Alligator mississippiensis ) fed extruded diets with protein derived from animal or plant sources. Alligators in two treatment groups were fed an extruded diet with protein derived primarily from plant products for 7 (n = 20) or 10 (n = 20) mo prior to harvest. A control group (n = 20) was fed a commercial diet with protein derived from animal products for the duration of the study. Plasma biochemistry panels were obtained and gross and histologic examination of kidney and liver tissues was conducted for each animal. No differences were found between alligators fed diets with animal or plant protein in terms of either biochemistry profiles or gross or histologic examination of kidney and liver. Plant-based diets, fed for up to 10 mo, do not appear to have any ill effects on the kidney or liver of American alligators. PMID- 28363052 TI - TERATOMA OF THE OVARY IN A FREE-RANGING JAPANESE RACCOON DOG (NYCTEREUTES PROCYONOIDES VIVERRINUS). AB - A young adult, female, free-ranging Japanese raccoon dog ( Nyctereutes procyonoides viverrinus) with scabies infection was found dead as a result of traumatic injuries presumed to reflect vehicular trauma. Necropsy showed a large solid mass located on the left ovarian region, occupying a third of the abdominal cavity. Histologically, the mass contained complex tissues derived from three germinal layers, with areas of cuboidal or columnar epithelium, keratinized squamous epithelium, bone, cartilage, and adipose tissue. This paper presents the first morphologic description of ovarian teratoma in a raccoon dog. PMID- 28363053 TI - ATYPICAL PRESENTATION OF CRYPTOCOCCUS NEOFORMANS IN A KOALA (PHASCOLARCTOS CINEREUS): A MAGNETIC RESONANCE IMAGING AND COMPUTED TOMOGRAPHY STUDY. AB - Cryptococcosis is a worldwide and potentially fatal mycosis documented in wild and captive koalas ( Phascolarctos cinereus ) caused by Cryptococcus neoformans . Though mainly a subclinical disease, when the nasal cavity is affected, epistaxis, mucopurulent nasal discharge, dyspnea, and facial distortion may occur. This report describes a case of cryptococcosis in a koala where unilateral exophthalmos was the only evident clinical sign and magnetic resonance imaging and computed tomography findings are described. Both advanced imaging techniques should be considered as standard and complementary techniques for nasal cavity evaluation in koalas. PMID- 28363054 TI - ANESTHETIC MANAGEMENT OF AN INDO-PACIFIC BOTTLENOSE DOLPHIN (TURSIOPS ADUNCUS) REQUIRING SURGICAL DEBRIDEMENT OF A TAIL ABSCESS. AB - This report describes the anesthetic management of a 14-yr-old, 160-kg, female Indo-Pacific bottlenose dolphin ( Tursiops aduncus ) that underwent surgical debridement for a refractory subcutaneous abscess twice within a 6-mo interval. The animal was otherwise in good physical condition at each anesthetic procedure. Following premedication with intramuscular midazolam and butorphanol, anesthesia was induced with propofol and maintained with sevoflurane by intubation. During surgery ventilation was controlled. Blood pressure was indirectly estimated using either oscillometric or pulse oximetry. Presumed hypotension was managed by adjusting the sevoflurane concentration and infusion of dopamine. During recovery, the dolphin regained adequate spontaneous respiration following intravenous administration of flumazenil and doxapram. The dolphin was extubated at 85 min and 53 min after the first and second surgeries, respectively. Successful weaning from the ventilator and initiation of spontaneous respiration was the most important complication encountered. Establishment of a reliable blood pressure measurement technique is critical to success for anesthesia in this species. PMID- 28363055 TI - CARDIORESPIRATORY EFFECTS OF DEXMEDETOMIDINE-BUTORPHANOL-MIDAZOLAM (DBM): A FULLY REVERSIBLE ANESTHETIC PROTOCOL IN CAPTIVE AND SEMI-FREE-RANGING CHEETAHS (ACINONYX JUBATUS). AB - Multiple anesthesia protocols have been used in the cheetah ( Acinonyx jubatus ). Twenty healthy, captive cheetahs were immobilized with dexmedetomidine (15.8 +/- 1.9 MUg/kg), butorphanol (0.22 +/- 0.03 mg/kg), and midazolam (0.18 +/- 0.03 mg/kg) by intramuscular injection. Induction, recumbency, and recovery times were recorded, and physiologic parameters were monitored. Anesthesia was antagonized with atipamezole (0.125 +/- 0.02 mg/kg) and naltrexone (0.1 +/- 0.014 mg/kg) intramuscularly. All cheetahs were safely anesthetized with this protocol. Cheetahs were laterally recumbent by 8 +/- 3.5 min. Cardiorespiratory values were stable throughout the length of anesthesia. Moderate hypertension, with systolic blood pressure ranging from 178 +/- 19.8 mm Hg, was initially observed but decreased over time. There was a statistical decreasing trend in temperature; SpO2; and systolic, mean, and diastolic blood pressure, but not in heart rate and end-tidal CO2. Recoveries were rapid, with cheetahs standing by 11.3 +/- 5.7 min postreversal administration. This is the first report of a dexmedetomidine butorphanol-midazolam anesthetic combination in cheetahs. Overall, this anesthetic protocol proved to be safe and effective. PMID- 28363056 TI - NOVEL RADIOGRAPHIC TECHNIQUE FOR PREGNANCY DETECTION IN THE MANED WOLF (CHRYSOCYON BRACHYURUS) WITHOUT ANESTHESIA. AB - Maned wolves ( Chrysocyon brachyurus ) maintained in ex situ populations challenge veterinarians and managers with high neonatal mortality and parental incompetence. These challenges led to the development of a novel diagnostic approach for pregnancy detection using radiographic imaging without anesthesia or sedation. To do this, a specialized crate was constructed to easily contain a single maned wolf, allowing the capture of lateral projection radiographic images of the abdomen prior to and throughout a 66-day pregnancy (days 20, 34, 48, and 55 of 66). Radiographs taken at days 48 and 55 postbreeding showed evidence of neonatal skeleton mineralization, confirming pregnancy with two pups. The dam gave birth at day 66 to two pups. This technical report describes a novel approach without anesthesia for successful radiographic pregnancy detection and determination of litter size in the maned wolf, a midsize carnivore, using a specially constructed crate. PMID- 28363057 TI - A PRELIMINARY ASSESSMENT OF THE EFFECTS OF REPRODUCTIVE SEASONALITY ON SEMINAL PLASMA CHARACTERISTICS IN NORTH AMERICAN BISON (BISON BISON). AB - The two subspecies of the North American bison, plains ( Bison bison bison) and wood ( Bison bison athabascae) bison, are seasonal breeders. The objective of this study was to conduct a preliminary investigation into the effects of season on semen. To test the hypothesis that there are seasonal effects on seminal plasma, protein profiles of seminal plasma from plains and wood bison (n = 2 of each subspecies) were compared between breeding and nonbreeding seasons. Using two-dimensional gel electrophoresis of seminal plasma proteins, 54 of 170 spots (plains bison) and 19 of 153 spots (wood bison) had differential expression (>=2 fold; P < 0.01) between seasons. Based on immunoblotting, BSP5 and TIMP-2 (two fertility-associated proteins in cattle) were higher during the breeding vs. nonbreeding season. Furthermore, epididymal sperm incubated with seminal plasma from the nonbreeding season had lower postthaw progressive motility (17.33 +/- 7.47 vs. 22.09 +/- 6.67%; mean +/- SD) and an increased ability to undergo a lysophosphatidylcholine-induced acrosome reaction (77.83 +/- 8.47 vs. 52.67 +/- 7.76%; mean +/- SD) as compared to epididymal sperm incubated with seminal plasma from the breeding season. In a heterologous in vitro fertilization system (using bovine oocytes), cleavage rate was higher for sperm exposed to seminal plasma from the breeding vs. the nonbreeding season (75.35 +/- 16.55 vs. 33.63 +/- 12.44%; mean +/- SD). This study suggested that differential expression of seminal plasma characteristics modulating sperm function is one of the mechanisms by which reproductive seasonality affects sperm function in the North American bison. PMID- 28363058 TI - INVESTIGATION OF THE PRESENCE OF ATOXOPLASMA SPP. IN BLUE-CROWNED LAUGHINGTHRUSH (DRYONASTES COURTOISI) ADULTS AND NEONATES. AB - Between 1996 and 2013, 71 blue-crowned laughingthrush (Dryonastes courtoisi) chicks, a small passerine bird endemic to China, were born at Mulhouse Zoo in northeast France. None of them survived past 1 yr, and 82% died between 0 and 6 days old of an unidentified cause and despite an attempt to establish an artificial breeding protocol. Atoxoplasma spp., causing a disease known as systemic isosporosis, is a coccidian parasite that can infect several species of birds. Mulhouse's adult birds were suspected to be infected with Atoxoplasma spp. and to transmit this parasite to their offspring. A treatment with toltrazuril (Baycox(r) 2.5%) was implemented in the four adult birds. Coprologic examinations were performed before, during, and after the treatment to quantify the parasite load in feces. Polymerase chain reaction (PCR) assays were used to test blood samples from the adult and liver, lung, gizzard, and kidney samples from 10 chicks to detect Atoxoplasma spp. Five of the 10 chicks had some tissue samples positive for Atoxoplasma spp. in at least one of the three repeats of the atoxoplasmosis PCR. An average of 181 Isospora spp. oocysts per gram of feces were found in the group of adults before treatment. This number was reduced to zero 1 wk after the beginning of the toltrazuril treatment. The PCR results suggest a transovarian transmission of Atoxoplasma spp., but further investigation is needed for confirmation. The treatment with toltrazuril appears to allow a significant reduction of the parasite excretion. PMID- 28363059 TI - EVALUATION OF FEEDING BEHAVIOR AS AN INDICATOR OF PAIN IN SNAKES. AB - The necessity to prevent and manage pain in reptiles is becoming increasingly important, as their use in scientific research and popularity as exotic pets continues to rise. It was hypothesized that feeding behavior would provide an adequate indicator of pain perception in the ball python (Python regius). Normal feeding was defined the previous week, where a dead rodent was struck within 12 sec (n = 10). Eighteen pythons were randomly assigned to one of three treatments: anesthesia only (AO), chemical noxious stimulus (CS; capsaicin injection), or surgical noxious stimulus (SS; surgical incision). The time to strike was recorded 4 hr after the procedure and weekly during the subsequent 3 wk. Delayed feeding was observed in animals in the CS and SS groups, and normal feeding resumed after 1 and 3 wk, respectively. Spontaneous feeding remained uninterrupted for the AO group. These findings demonstrate feeding behavior as a potential model to assess pain in snakes. PMID- 28363060 TI - LAPAROSCOPIC OVARIECTOMY IN THE ASIATIC BLACK BEAR (URSUS THIBETANUS) WITH THE USE OF THE SONICISIONTM DEVICE. AB - Laparoscopic ovariectomy was performed in two Asiatic black bears ( Ursus thibetanus ). Bears were placed in a 20 degrees Trendelenburg position on a surgical table. A three-portal technique was used. A camera port was established 10 cm caudal to the umbilicus with a 5-mm cannula. Two instrument ports were made 1 cm caudal to the umbilicus with a 5-mm cannula and 8 cm caudal to the camera port with a 12-mm cannula, respectively. The suspensory ligament, ovarian vasculature, and uterine horn tip were progressively dissected following coagulation with the SonicisionTM cordless ultrasonic dissection device. The resected ovary was exteriorized through the 12-mm instrument portal site but enlarged to a 2-cm incision length. The abdominal musculature, subcutaneous tissue, and skin of the portal sites were closed separately. Total surgical time was 113 min (Bear A) and 49 min (Bear B), and no postoperative complications were encountered. This is the first report of laparoscopic ovariectomy in the Asiatic black bear. PMID- 28363062 TI - INTRAMUSCULAR EPINEPHRINE RESULTS IN REDUCED ANESTHETIC RECOVERY TIME IN AMERICAN ALLIGATORS (ALLIGATOR MISSISSIPPIENSIS) UNDERGOING ISOFLURANE ANESTHESIA. AB - Inhalants are commonly used to anesthetize reptiles, but volatile anesthetics have been associated with prolonged recovery times. The objective of this study was to determine the effects of intramuscular (IM) epinephrine on anesthetic recovery times following isoflurane anesthesia in a population of subadult American alligators ( Alligator mississippiensis ). In this prospective randomized crossover study, five clinically healthy alligators were anesthetized for 90 min with the use of isoflurane. Alligators were randomly assigned into one of two treatment groups: Group E received IM epinephrine (0.1 mg/kg), and Group S received an equal volume of 0.9% saline administered after isoflurane was discontinued. Time from the end of inhalant administration to return of spontaneous ventilation, return of the palpebral reflex, movement in response to a standardized toe pinch, and spontaneous movement was recorded. The time of extubation was noted and occurred following the return of spontaneous ventilation and movement. Pulse rate, surface body temperature, and airway gases including expiratory and inspiratory isoflurane concentrations and end-tidal carbon dioxide were measured every 5 min throughout the study. The time from the end of anesthesia to extubation was significantly faster in Group E (51.2 +/- 16.7 min) compared to Group S (107.4 +/- 43.7 min). Pulse rate was significantly higher within the first 15 min following epinephrine injection compared to the saline group at these time points. Therefore, IM epinephrine administered at the end of general anesthesia can significantly hasten anesthetic recovery from isoflurane in alligators. PMID- 28363061 TI - COMPROMISED FERTILITY IN FREE FEEDING OF WILD-CAUGHT NORWAY RATS (RATTUS NORVEGICUS) WITH A LIQUID BAIT CONTAINING 4-VINYLCYCLOHEXENE DIEPOXIDE AND TRIPTOLIDE. AB - Wild rat pests in the environment cause crop and property damage and carry disease. Traditional methods of reducing populations of these pests involve poisons that can cause accidental exposures in other animals and humans. Fertility management with nonlethal chemicals would be an improved method of rat pest population control. Two chemicals known to target ovarian function in female rats are 4-vinylcyclohexene diepoxide (VCD) and triptolide. Additionally, triptolide impairs spermatogenesis in males. A liquid bait containing no active ingredients (control), or containing triptolide (0.001%) and VCD (0.109%; active) was prepared to investigate the potential use of these agents for wild rat pest population control. Liquid bait was made available to male (n = 8 control; n = 8 active) and female (n = 8 control; n = 8 active) Sprague Dawley rats ( Rattus norvegicus ) for oral consumption prior to breeding. Whereas, control bait treated females produced normal-sized litters (10.0 +/- 1.7 pups/litter), treated females delivered no pups. Wild Norway male (n = 20) and female (n = 20) rats ( Rattus norvegicus ) were trapped, individually housed, and one group given free access to control bait, one group to active bait. Following three cycles of treatment-matched mating pairs, females consuming control bait (control) produced normal litter sizes (9.73 +/- 0.73 pups/litter). Females who had consumed active bait (treated) produced no litters on breeding cycles one and two; however, 2 of 10 females produced small litters on the third mating cycle. In a fourth breeding cycle, control females were crossmated with treated males, and treated females were crossmated with control males. In both groups, some dams produced litters, while others did not. The differences in response reflect a heterogeneity in return to cyclicity between females. These results suggest a potential approach to integrated pest management by compromising fertility, and could provide a novel alternative to traditional poisons for reducing populations of wild rat pests. PMID- 28363063 TI - FATAL ACINETOBACTER BAUMANNII INFECTION IN THE CRITICALLY ENDANGERED EUROPEAN MINK (MUSTELA LUTREOLA). AB - The present study reports the first case of fatal Acinetobacter baumannii infection in the critically endangered European mink ( Mustela lutreola ). Gross examination revealed a severe, diffuse hemorrhagic pneumonia and generalized congestion as main features. Microscopically, the main lesions were an acute, severe fibrinous-hemorrhagic pneumonia associated with proliferation of coccobacilli and generalized acute-subacute congestion. Cultures yielded A. baumannii ; the species was confirmed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and the strain presented a multidrug-resistant pattern. The results are not only of conservation concern but also of public health concern given A. baumannii is one of the most important pathogens implicated in nosocomial infections in humans. PMID- 28363064 TI - CONJUNCTIVAL BACTERIAL FLORA, ANTIBIOGRAM, AND LACRIMAL PRODUCTION TESTS OF COLLARED ANTEATER (TAMANDUA TETRADACTYLA). AB - The collared anteater ( Tamandua tetradactyla ) is adapted to a variety of habitats. It is a solitary species for which no reference values for ophthalmic tests have been established. Eight animals ranging from 1 to 4 yr of age, two males and six females, were manually restrained for assessment. Ophthalmic tests included evaluation of tear production by Schirmer tear test 1 (STT1), endodontic absorbent paper point tear test (EAPPTT), palpebral fissure length (PFL), culture of the conjunctival bacterial flora, and antimicrobial susceptibility test. Median +/- semi-interquartile range (S-IQR) STT1, EAPPTT, and PFL were 8.50 +/- 4.13 mm/min, 14.13 +/- 3.24 mm/min, and 15.91 +/- 2.51 mm, respectively. Bacterial growth was present in 100% of the samples, with predominance of Gram positive bacteria (70.27%). Staphylococcus spp. was the most frequently isolated genus. Antimicrobial susceptibility test showed sensitivity of Staphylococcus epidermidis and Staphylococcus spp. to neomycin, tobramycin, and gentamicin. The results in this study can benefit the determination of reference values for different diagnostic techniques, and may be used as a guide for diagnosis and treatment of ocular diseases in collared anteaters. PMID- 28363066 TI - CONGESTIVE HEART FAILURE ASSOCIATED WITH PREGNANCY IN OKAPI (OKAPIA JOHNSTONI). AB - Acute signs associated with cardiovascular disease occurred in three pregnant okapi ( Okapia johnstoni ) during early to midgestation and progressed to congestive heart failure. Congestive heart failure was diagnosed antemortem using echocardiography and plasma cardiac troponin levels. Clinical signs included decreased activity, hyporexia, tachypnea, dyspnea, flared nostrils, and productive coughing with copious amounts of foamy nasal discharge. Parenteral and oral treatment with furosemide, enalapril, and spironolactone controlled clinical signs in the three okapi allowing each to carry out one pregnancy to term. Two okapi carried the first pregnancy to term after showing signs, while one okapi aborted the first calf and gave birth to a healthy calf in a subsequent pregnancy. Subsequent pregnancy in one okapi ended with abortion and associated dystocia and endometritis. Following parturition, clinical signs associated with heart failure resolved in all three individuals; serial echocardiography in two individuals showed improvement in fractional shortening and left atrial size and all three okapi showed markedly decreased pleural effusion and resolution of pulmonary edema. However, subsequent pregnancies in all three okapi induced respiratory distress and recurrence of congestive heart failure; one okapi died from congestive heart failure associated with subsequent pregnancy. This case series describes the clinical presentation and pathologic findings of congestive heart failure during pregnancy in adult okapi. PMID- 28363065 TI - ULCERATIVE AND NECROTIZING GASTRITIS IN A CAPTIVE SLOTH (BRADYPUS VARIEGATUS, XENARTHRA, BRADYPODIDAE) DUE TO SEVERE PARASITISM WITH PARALEIURIS LOCCHII (NEMATODA, SPIROCERCIDAE). AB - This is the first reported case of lethal gastric parasitism by the nematode Paraleiuris locchii in a captive sloth ( Bradypus variegatus ). There were more than 600 parasites in the stomach of the sloth, associated with extensive areas of ulceration and necrosis. The animal developed emaciation, dehydration, and anemia that progressed to death. PMID- 28363067 TI - UTERINE RUPTURE AND CESAREAN SURGERY IN THREE RIO CAUCA CAECILIANS (TYPHLONECTES NATANS). AB - A uterine rupture of unknown etiology during gestation causing the death in a Rio Cauca caecilian ( Typhlonectes natans ) and successful anesthesia using tricaine methanesulfonate and cesarean section in three occasions in two other specimens because of suspected dystocia are described. One of the surgeries was performed at an early stage of embryo development, thereby preventing the survival of the neonates. PMID- 28363068 TI - ISOLATION OF STREPTOCOCCI FROM A FATAL CASE OF MYOCARDITIS IN A CAPTIVE BROWN BEAR (URSUS ARCTOS). AB - A 10-yr-old, male brown bear ( Ursus arctos ) from Bursa Zoo in Turkey died without any apparent signs. Severe purulent pericarditis and myocarditis with mild ascites, lung edema, and moderate liver congestion were observed during necropsy. Microscopically, there were severe neutrophilic infiltrations in the myocardium and thoracic lymph nodes. A member of the Streptococcus bovis - Streptococcus equinus complex (SBSEC) was isolated and identified phenotypically. PMID- 28363069 TI - MAMMARY GLAND ADENOCARCINOMA IN A MALE BORNEAN ORANGUTAN (PONGO PYGMAEUS). AB - An adult male Bornean orangutan ( Pongo pygmaeus ) was diagnosed with invasive, poorly differentiated grade 9/9 mammary gland adenocarcinoma from a subcutaneous mass that was surgically removed during a routine preventative health examination. The tumor was tested for estrogen and progesterone receptors, human epidermal growth factor receptor 2 (HER2), and HER2 fluorescence in situ hybridization (HER2 FISH). Whole blood was tested for breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) genes. The orangutan was treated orally with two common human breast cancer drugs; tamoxifen and anastrozole. The orangutan lived for 4.5 yr postdetection, dying from an unrelated cause. This is the first reported case of mammary gland adenocarcinoma in a male great ape. PMID- 28363070 TI - MULTIHORMONAL ISLET CELL CARCINOMAS IN THREE KOMODO DRAGONS (VARANUS KOMODOENSIS). AB - Multihormonal pancreatic islet cell carcinomas were found in one female and two male captive geriatric Komodo dragons (Varanus komodoensis). Gross changes in the pancreas were visible in two of the cases. Clinical signs noted in the Komodo dragons were lethargy, weakness, and anorexia. Histologically, the tumors were comprised of nests and cords of well-differentiated neoplastic islet cells with scant amounts of eosinophilic cytoplasm and round, euchromatic nuclei, with rare mitoses. Infiltration by the islet cell tumor into the surrounding acinar tissue was observed in all cases, but no metastatic foci were seen. Multihormone expression was observed in all tumors, which labeled strongly positive for glucagon and somatostatin and focally positive for polypeptide. Pancreatic islet cell neoplasms should be considered in the differential diagnosis for geriatric Komodo dragons presenting with weakness, lethargy, and poor appetite. PMID- 28363071 TI - CALVARIAL OSTEOSARCOMA WITH CEREBRAL COMPRESSION IN A FREE-RANGING POWERFUL OWL (NINOX STRENUA). AB - A free-ranging powerful owl (Ninox strenua) presented in a dull state with extensive bruising of the skin overlying the skull, due to suspected trauma. Supportive care was provided, which resulted in the return to a normal state, although intermittent subtle neurologic abnormalities remained. One month from original presentation, intermittent episodes of head turning and a possible seizure were noted, but behavior and appetite were otherwise normal. The owl was referred to Taronga Wildlife Hospital for evaluation. On presentation, the owl exhibited severe neurologic abnormalities, prompting euthanasia. At necropsy the dorsum of the skull exhibited marked osseous proliferation, extending ventrally and compressing the cerebrum. The skull was radiographed and submitted for histopathology. A diagnosis of osteoblastic osteosarcoma was made. This is the first report of a calvarial osteosarcoma in a powerful owl. PMID- 28363072 TI - RADIOGRAPHY IN THE FIELD: ASSESSING A LIGHTWEIGHT, HANDHELD, BATTERY-POWERED DENTISTRY UNIT FOR FIELD DIAGNOSTIC APPLICATIONS. AB - Radiography units are not used commonly in wildlife medicine field settings, primarily because of their weight and requirement for a power supply. In this study, a portable, battery-powered, and lightweight radiography unit, originally developed for dentistry, was assessed for its potential field applications. Radiographs of various animal species (ranging in weight from 14 g to 1,000 kg) were imaged using varying source image distance (SID) and exposure time. The quality of these images was evaluated for their resolution, image noise, and motion blur. When required, image resolutions were further enhanced using computed radiography postprocessing. Other parameters evaluated were the freehand use of the device, its battery durability, the maximum obtainable image size, and multiple use of a single computed radiography cassette. Using an SID of 60 cm, radiographs delivered adequate image quality. The quality, however, was found deteriorated in images of larger animals (>50 kg) or thicker tissues (>15 cm). The use of a tripod proved unnecessary in most cases, and its exclusion greatly facilitated equipment handling. Under field conditions, the battery was depleted after a total running time of 1.6 hr or 36 radiographs. The maximum size of a radiographic image reached a diameter of 40 cm, and radiation shielding allowed the multiple use of a single computed radiography cassette. Taken together, the radiography unit evaluated in this study presented a balanced compromise between portability and radiograph quality for field use. However, the unit image resolution cannot replace those of the fixed standard radiography units commonly used in veterinary medicine. PMID- 28363073 TI - THE MANAGEMENT OF AN ORAL ANAPLASTIC SARCOMA IN A PYGMY HIPPOPOTAMUS (CHOEROPSIS LIBERIENSIS) USING INTRALESIONAL CHEMOTHERAPY. AB - An adult female captive pygmy hippopotamus (Choeropsis liberiensis) was diagnosed with an oral anaplastic sarcoma. The tumor was surgically debulked and intralesional chemotherapy with mitomycin C (0.4 mg/cm3 of tumor) and cisplatin (1 mg/cm3 of tumor) was administered. Chemotherapeutic treatment proved difficult due to the risks of repeated anesthetics and unknown drug efficacies. Marked proliferation of the mass was observed during estrus, and chemotherapy was repeated as an experimental treatment to slow tumor progression in order for the animal to remain in the species breeding program. Tumor proliferation was detected during the first trimester of pregnancy; however, in the lactation period, the mass became quiescent. No adverse reactions to chemotherapeutic drugs were observed and the animal continues to be monitored for tumor progression. This is the first report of an anaplastic sarcoma and of chemotherapy use in a pygmy hippopotamus and it highlights logistical considerations for treating neoplasia in this species. PMID- 28363074 TI - PROPOFOL AS AN IMMERSION ANESTHETIC AND IN A MINIMUM ANESTHETIC CONCENTRATION (MAC) REDUCTION MODEL IN GOLDFISH (CARASSIUS AURATUS). AB - Propofol is a novel immersion anesthetic in goldfish ( Carassius auratus ). Objectives were to characterize propofol as an anesthetic and assess its suitability in a minimum anesthetic concentration (MAC) reduction model. Using a crossover design, eight goldfish were submerged in 1, 5, or 10 mg/L propofol. Data included induction time, recovery time, heart rate, opercular rate, and response to supramaximal stimulation. Baseline MAC (Dixon's up-and-down method) was determined, and 15 fish were anesthetized with propofol on 4 consecutive days with MAC determination on the fifth day, weekly, for 1 mo. Using a crossover design, MAC of propofol (n = 15) was determined 1 hr following administration of i.m. butorphanol 0.05, 0.5, and 1 mg/kg, dexmedetomidine 0.01, 0.02, and 0.04 mg/kg, ketoprofen 0.5, 1, and 2 mg/kg, morphine 5, 10, and 15 mg/kg, or saline 1 ml/kg. Comparisons were performed with Wilcoxon signed-rank tests (P < 0.05) and Tango's score confidence interval. Propofol at 1 mg/L did not produce anesthesia. Induction time with 10 mg/L (112, 84-166 s) was faster than 5 mg/L (233, 150-289 s; P = 0.0078). Heart and opercular rates for 5 and 10 mg/L were 36 (24-72) beats/min, 58 (44-68) operculations/min and 39 (20-48) beats/min, 57 (48-80) operculations/min, respectively. Recovery time was 249 (143-396) s and 299 (117 886) s with 5 and 10 mg/L, respectively. Response to supramaximal stimulation was not significantly different with 5 mg/L (1/8) compared with 10 mg/L (0/8). Baseline and weekly MAC following daily exposure was 8.4 and 9.0, 8.1, 8.1, and 8.7 mg/L, respectively. MAC reduction was no more than 8% following any drug or dosage. Propofol at 5 and 10 mg/L produced anesthesia, and anesthetic needs were similar following repeated exposure. Propofol was not suitable to test MAC reduction in goldfish in this study. PMID- 28363075 TI - MASTICATORY MUSCLE MYOSITIS IN A GRAY WOLF (CANIS LUPUS). AB - A 10-yr-old male, neutered gray wolf ( Canis lupus ) was presented for atrophy of the temporalis and masseter muscles. Clinical signs and magnetic resonance imaging were consistent with a myopathy. Positive serology for antibody titers directed against Type 2M myofibers, and the observation of a mixed mononuclear inflammatory cell infiltrate along with eosinophils and neutrophils within the temporalis muscle, were diagnostic for masticatory muscle myositis. Importantly, protozoal myositis was excluded based on other clinicopathologic data. The case highlights the potential for immune-mediated polymyositis in canids other than the domesticated dog ( Canis lupus familaris). Additionally, awareness of a diet in which raw meat is used should prompt a thorough investigation for an underlying infectious myositis in the gray wolf. PMID- 28363078 TI - PLASMA THYROXINE (T4) CONCENTRATION IN ZOO-KEPT BLACK-TAILED PRAIRIE DOGS (CYNOMYS LUDOVICIANUS). AB - This study was conducted to determine plasma thyroxine (T4) concentrations in zoo kept black-tailed prairie dogs ( Cynomys ludovicianus ). Thirty-one healthy prairie dogs of both sexes were studied as part of their annual clinical health evaluation, performed under general isoflurane anesthesia. Each animal underwent a complete physical examination, complete blood count, plasma biochemistry, and venous blood gas analysis. Heparinized venous blood samples were collected individually and processed for plasma T4 analysis using a veterinary biochemistry analyzer. The median plasma T4 concentration for the prairie dogs in this study was 4.1 MUg/dl (minimum = 0.6 MUg/dl; maximum = 8.0 MUg/dl). The mean +/- standard deviation plasma T4 concentration was 4.49 +/- 2.39 MUg/dl. No significant differences were found for varying ages, sexes, weights, or housing systems. The data presented in this report can promote better physiologic understanding and improve clinical management of this rodent species. PMID- 28363076 TI - CONTINUOUS INTRAVENOUS INFUSION ANESTHESIA WITH MEDETOMIDINE, KETAMINE, AND MIDAZOLAM AFTER INDUCTION WITH A COMBINATION OF ETORPHINE, MEDETOMIDINE, AND MIDAZOLAM OR WITH MEDETOMIDINE, KETAMINE, AND BUTORPHANOL IN IMPALA (AEPYCEROS MELAMPUS). AB - In order to develop a long-term anesthesia for flighty antelope species in field situations, two different protocols for induction and maintenance with an intravenous infusion were evaluated in wild-caught impala ( Aepyceros melampus ). Ten adult female impala were induced with two induction protocols: one consisted of 0.2 mg/kg medetomidine, 4 mg/kg ketamine, and 0.15 mg/kg butorphanol (MKB) and one consisted of 0.375 mg/kg etorphine, 0.2 mg/kg medetomidine, and 0.2 mg/kg midazolam (EMM). In both treatments, anesthesia was maintained with a continuous intravenous infusion (CII) at an initial dose rate of 1.2 MUg/kg per hr medetomidine, 2.4 mg/kg per hr ketaminen and 36 MUg/kg per hr midazolam. Partial reversal was achieved with naltrexone (2 : 1 mg butorphanol; 20 : 1 mg etorphine) and atipamezole (5 : 1 mg medetomidine). Evaluation of anesthesia included respiratory rate, heart rate, rectal temperature, arterial blood pressure, oxygen saturation, end tidal carbon dioxide tension, and tidal volume at 5-min intervals, palpebral reflex and response to painful stimuli at 15-min intervals, and arterial blood gases at 30-min intervals. Plasma cortisol concentration was determined after induction and before reversal. Duration and quality of induction and recovery were evaluated. EMM caused a faster induction of 9.5 +/- 2.9 min compared to 11.0 +/- 6.4 min in MKB. Recovery was also quicker in EMM (EMM: 6.3 +/- 5.4 min; MKB: 9.8 +/- 6.0 min). However, EMM also produced more cardiopulmonary side effects, including hypoxemia and hypercapnia, and calculated oxygenation indices (PaCO2-PETCO2) were worse than in MKB. One animal died after induction with EMM. The CII provided surgical anesthesia in 7 of 10 animals in MKB and in 9 of 9 animals in EMM for 120 min. In conclusion, the MKB induction protocol had advantages for prolonged anesthesia in impala with significantly less cardiopulmonary depression compared to EMM. The comparably decreased anesthetic depth could easily be adjusted by an increase of the CII. PMID- 28363077 TI - EXAMINING THE PREFERENCE FOR SHADE STRUCTURES IN FARMED GREEN SEA TURTLES (CHELONIA MYDAS) AND SHADE'S EFFECT ON GROWTH AND TEMPERATURES. AB - The Cayman Turtle Farm raises thousands of green sea turtles ( Chelonia mydas ) annually under aquaculture conditions. Historically, the turtles have been raised in tanks without routine access to a shade structure. The purpose of this study was to determine the effects of adding a shade structure on curved carapace length (CCL) and weight gain of green sea turtles. In addition, water and cloacal temperatures were compared across treatment groups and shade cover preferences observed. Ninety turtles were split equally into three treatment groups for this 8-wk study. In the first group turtles were kept in tanks in full sun, the second group in half-shaded tanks, and the third group in tanks completely covered with shade cloth. Time-lapse cameras mounted above half-shaded tanks were used to determine turtle shade structure preferences throughout the day. There were no differences in CCL among treatment groups. Significant increases in weights were noted in turtles kept in full sun and half-shaded tanks versus the fully shaded tanks. Significantly higher water and cloacal turtle temperatures were noted in the full-sun tank compared with the half-shaded or completely shaded tanks. A significantly lower number of turtles was observed in the sun in the half-shaded tanks, indicating a possible preference by turtles for a shade structure. Results suggest that providing shade structures for sea turtles results in a significant decrease in both overall water temperature as well as a reduction in maximum high daily temperatures. Results also suggest that turtles exhibit a preference for shade structures when it is provided as an option. From these results, we recommend that a shade structure be provided when housing green sea turtles in outdoor enclosures. PMID- 28363079 TI - IDENTIFICATION OF BACTERIA IN BLOOD CULTURES FROM CLINICALLY ILL CAPTIVE ANTILLEAN MANATEES (TRICHECHUS MANATUS MANATUS). AB - Between September 2001 and March 2013, 62 bacterial cultures (37 aerobic and 25 anaerobic) were performed on 37 blood samples from 23 Antillean manatees ( Trichechus manatus manatus) that were kept in captivity at the Brazilian National Center for Research and Conservation of Aquatic Mammals (CMA) in Pernambuco (CMA PE) and Alagoas (CMA-AL), Brazil. All of the animals sampled exhibited clinical signs at the time of sampling including abscesses (n = 8), debilitation and anorexia (n = 22), and profound lethargy-moribundity (n = 7). The 4 animals with profound lethargy-moribundity died shortly after sampling of unknown causes. Bacteria were isolated from 15/37 (40.5%) and aerobic blood cultures from 13/23 animals (56.5%). None of the anaerobic cultures were positive. Aeromonas caviae , Aeromonas hydrophila , Aeromonas sp., Escherichia coli , Leclercia adecarboxylata , Pantoea agglomerans , Pseudomonas aeruginosa , Pseudomonas stutzeri , Pseudomonas sp., Sphingomonas paucimobilis , coagulase-negative Staphylococcus, and Staphylococcus epidermidis were each found in only one animal; Staphylococcus spp. was found in two; and Vibrio fluvialis in four. Thirteen samples had only one bacteria isolated, one sample had two bacteria, and one sample had three bacteria isolated. Regarding sex, age group, and origin among the manatees examined, 54.5% (6/11) of the females, 58.3% (7/12) of the males, 40% (2/5) of the calves, 66.7% (8/12) of the juveniles, 50% (3/6) of the adults, 55.5% (10/18) at CMA-PE, and 60% (3/5) at CMA-AL were found to be positive for bacterial growth during at least one sampling time. All Antillean manatees were clinically ill. Regarding clinical signs, bacteria were found in 50% (11/22) of blood samples of the animals showing debilitation and anorexia, 1 of 8 (12.5%) of blood samples of the animals showing abscesses, and 3 of 7 (42.9%) of blood samples of the animals showing profound lethargy-moribundity. PMID- 28363080 TI - HEMATOLOGY AND PLASMA CHEMISTRY OF THE PLOUGHSHARE TORTOISE (ASTROCHELYS YNIPHORA) IN A CAPTIVE BREEDING PROGRAM. AB - Blood samples from 172 captive and 40 wild, healthy, juvenile and adult, ploughshare tortoises ( Astrochelys yniphora ) were analyzed to determine hematological and biochemical reference intervals. Hematological analytes included packed cell volume (PCV), white blood cell count (WBC), and WBC differential estimates. Biochemical analysis included total protein measured by photometry (TP) and by refractometry (TPr), albumin (ALB), creatine kinase (CK), aspartate aminotransferase (AST), glutamate dehydrogenase (GLDH), bile acids (BA), calcium (Ca), phosphorus (P), urea (UREA), and uric acid (UA). The jugular vein was identified as the preferred venipuncture site as subcarapacial vein venipuncture resulted in regular hemodilution. In due consideration of small sample sizes in some of the groups studied, adult tortoises had significantly higher plasma GLDH activity and TPr, TP, ALB, BA, and UREA concentrations and significantly lower AST activity and P concentration than juveniles. Captivity had a significant influence in some reference intervals, with captive adults presenting significantly higher WBC, and estimated counts of all white cell types as well as UREA and TPr than wild counterparts. Captive juveniles also showed significantly higher estimated monocyte and lower estimated eosinophil and basophil counts. Although these differences most likely reflect local environmental or dietary differences, without representing pathology or a deviation from the normal, they question the applicability of reference values from captive animals to wild animals and vice versa. Significant sex differences were only observed for PCV and UA. The reported reference intervals may serve as benchmarks for clinical assessment and conservation of this critically endangered species. PMID- 28363081 TI - PROPOSAL AND APPLICATION OF A NOVEL DISSEMINATED INTRAVASCULAR COAGULATION SCORING SYSTEM IN THE FLORIDA MANATEE (TRICHECHUS MANATUS LATIROSTRIS). AB - Disseminated intravascular coagulopathy (DIC) is an acquired disorder of hemostasis resulting in activation of the coagulation and fibrinolytic pathways. It is reported secondarily to multiple disease processes and can be associated with increased mortality. Previous research at Tampa's Lowry Park Zoo (LPZ) demonstrated that Florida manatees ( Trichechus manatus latirostris) with cold stress syndrome (CSS) demonstrated thromboembolic disease. The object of this retrospective study was to establish the presence and clinical relevance of DIC in Florida manatees admitted to LPZ for rehabilitation from 07 March 2010 to 15 August 2015. A coagulation panel, including prothrombin time, partial thromboplastin time, platelet count, fibrinogen level, and D-dimer level was used to diagnose DIC. There were 100 cases identified in the study period: 35 trauma, 43 CSS, 17 secondary to harmful algae blooms (HAB), and five miscellaneous. Manatees with CSS had the highest incidence of DIC with 24 of 43 cases (56%) affected, followed by trauma with 18 of 35 cases (52%) affected. None of the manatees with HAB were found to have DIC. Manatees that developed DIC during rehabilitation or when DIC progressed did not survive. Due to the clinical implications of DIC, identifying its presence and recognizing its severity could improve clinical outcomes by enabling more intensive treatment protocols. PMID- 28363082 TI - Corrigendum to "Variants of estrogen receptor alpha and beta genes modify the severity of sporadic breast cancer" [Gene 608C (2017) 73-78]. PMID- 28363083 TI - Nanomaterial scaffolds to regenerate musculoskeletal tissue: signals from within for neovessel formation. AB - Current treatments for musculoskeletal disease and injury are restricted with the usage of autografts and allografts. Tissue engineering that applies the principles of biology and engineering to develop functional substitutes has potential promise of therapeutic regeneration for musculoskeletal tissues. However, engineering sizable tissues needs a vascular network to supply cells with nutrients, oxygen and signals after implantation. For this purpose, recent developments on therapeutic nanomaterials have been explored in delivering different vessel-inductive growth factors, small biomolecules and ions for scalable engineering into vascularizable scaffolds. Here, we provide an overview on the current efforts, and propose future perspectives for precise regulation on vascularization processes and musculoskeletal tissue functionality. PMID- 28363085 TI - Population-based stroke and dementia incidence trends: Age and sex variations. AB - INTRODUCTION: We discovered a concomitant decline in stroke and dementia incidence rates at a whole population level in Ontario, Canada. This study explores these trends within demographic subgroups. METHODS: We analyzed administrative data sources using validated algorithms to calculate stroke and dementia incidence rates from 2002 to 2013. RESULTS: For more than 12 years, stroke incidence remained unchanged among those aged 20 to 49 years and decreased for those aged 50 to 64, 65 to 79, and 80+ years by 22.7%, 36.9%, and 37.9%, respectively. Dementia incidence increased by 17.3% and 23.5% in those aged 20 to 49 and 50 to 64 years, respectively, remained unchanged in those aged 65 to 79 years, and decreased by 15.4% in those aged 80+ years. DISCUSSION: The concomitant decline in stroke and dementia incidence rates may depict how successful stroke prevention has targeted shared risk factors of both conditions, especially at advanced ages where such risk factors are highly prevalent. We lend support for the development of an integrated system of stroke and dementia prevention. PMID- 28363084 TI - The metabolic syndrome induces early changes in the swine renal medullary mitochondria. AB - The metabolic syndrome (MetS) is associated with nutrient surplus and kidney hyperfiltration, accelerating chronic renal failure. Mitochondria can be overwhelmed by substrate excess, leading to inefficient energy production and thereby tissue hypoxia. Mitochondrial dysfunction is emerging as an important determinant of renal damage, but whether it contributes to MetS-induced renal injury remains unknown. We hypothesized that early MetS induces kidney mitochondrial abnormalities and dysfunction, which would be notable in the vulnerable renal medulla. Pigs were studied after 16 weeks of diet-induced MetS, MetS treated for the last 4 weeks with the mitochondria-targeted peptide elamipretide (0.1 mg/kg SC q.d), and Lean controls (n = 7 each). Single-kidney renal blood flow, glomerular filtration rate, and oxygenation were measured in vivo, whereas cortical and medullary mitochondrial structure and function and renal injurious pathways were studied ex-vivo. Blood pressure was slightly elevated in MetS pigs, and their renal blood flow and glomerular filtration rate were elevated. Blood oxygen level-dependent magnetic resonance imaging demonstrated that this was associated with medullary hypoxia, whereas cortical oxygenation remained intact. MetS decreased renal content of the inner mitochondrial membrane cardiolipin, particularly the tetra-linoleoyl (C18:2) cardiolipin species, and altered mitochondrial morphology and function, particularly in the medullary thick ascending limb. MetS also increased renal cytochrome-c-induced apoptosis, oxidative stress, and tubular injury. Chronic mitoprotection restored mitochondrial structure, ATP synthesis, and antioxidant defenses and decreased mitochondrial oxidative stress, medullary hypoxia, and renal injury. These findings implicate medullary mitochondrial damage in renal injury in experimental MetS, and position the mitochondria as a therapeutic target. PMID- 28363086 TI - Phenomenology of hoarding in children with comorbid attention deficit/hyperactivity disorder (ADHD): The perceptions of parents. AB - Individuals with ADHD and comorbid hoarding disorder are vulnerable to severe consequences from hoarding symptoms. Despite this, and the early onset of hoarding disorder, the nature of hoarding symptoms in children with comorbid ADHD is unknown. We therefore explored the phenomenology of hoarding symptoms among ten 8-12year olds with ADHD and clinically significant hoarding symptoms through parental perceptions. Parents completed in-depth semi-structured interviews. The data was analyzed using Interpretative Phenomenological Analysis. Six superordinate themes were identified: emotional distress; parental avoidance and accommodating behaviors; family impacts of hoarding; excessive acquisition and saving; executive functioning; parental insight and intervention. In contrast to previous suggestions that emotional distress was not associated with hoarding in ADHD, these findings highlight that emotional distress appeared to be core to the hoarding disorder profile of the present sample of children with ADHD. This has important implications for health practitioners who may consider conceptualizing, assessing, and treating hoarding symptoms in children with comorbid ADHD using a cognitive behavioral model of hoarding disorder. PMID- 28363087 TI - Geolocalization of HIV-1 subtypes and resistance mutations of patients failing antiretroviral therapy in Salvador - Brazil. AB - BACKGROUND: Geographical distribution of HIV variants is an important way to understand the circulation and spread of such viral strains. OBJECTIVES: To evaluate the spatial distribution of HIV-1 variants in patients failing antiretroviral therapy, in Salvador, Brazil. METHODS: We performed a cross sectional evaluation of HIV resistance test reports of patients who underwent genotyping tests in a referral center in Salvador, Brazil, for the years 2008 2014. The laboratory database contains around 2500 resistance reports of patients failing antiretroviral therapy. Genotypic tests were performed by sequencing of HIV-1 POL region (TrueGene, Siemens). We assessed HIV-1 resistance mutations and subtype, as well as residential address, age, and gender of patients. RESULTS: We evaluated 1300 reports, 772 (59.4%) of them from male patients. As expected, subtype B predominated (79%) followed by subtypes F1 (6.7%) and BF (6.5%). The most frequent mutations in HIV-1 reverse transcriptase were 184V (79.1%), 41L (33.5%), 67N (30.4%), 103N (42.4%), and 108I (11.1%). Most frequent mutations in HIV-1 protease were 63P (52.4%), 36I (47.9%), 15 V (33.0%), 62 V (28.1%) and 13 V (25.8%). Some mutations (41L, 215Y, 210W) were significantly more frequent among men. We detected a significantly higher accumulation of 103N mutation in specific areas of Salvador. We identified a more restricted circulation pattern for subtype FB (more frequent in some regions), and F1 (almost absent in a specific region). CONCLUSION: Our results suggest that specific subtypes/resistance mutations present a distinct frequency rate in specific areas of Salvador, probably due to a restricted circulation pattern. This trend to clustering was observed in regions covered by AIDS referral centers, suggesting that pattern of care for such patients can interfere in virological outcomes. PMID- 28363089 TI - Comparison of metal-binding strength between methionine and cysteine residues: Implications for the design of metal-binding motifs in proteins. AB - Metals play vital role in various physiological processes and are bound to biomolecules. Although cysteine sulfur is more frequently found as metal-binding ligand, methionine prefers to occur in copper-binding motifs of some proteins. To address methionine's lower preference in copper-binding sites in comparison to cysteine, we have considered copper-binding motifs (His-Cys-His-Met) from seven different high-resolution protein structures. We performed quantum chemical calculations to find out the strength of interactions between sulfur and metal ion in both Met and Cys residues. In the case of Cys, both neutral (CysH) and the deprotonated form (Cys-) were considered. We used two different levels of theory (B3LYP and M06-2X) and the model compounds methyl propyl sulfide, ethanethiol and ethanethiolate were used to represent Met, CysH and Cys- respectively. To compare the metal-binding strength, we mutated Met in silico to CysH/Cys- and performed the calculations. We also carried out calculations with wild-type Cys present in the same metal-binding motif. On average, interactions of Met with copper ion are stronger by 13-35kcal/mol compared to CysH. However, Cys- interactions with copper is stronger than that of Met by ~250kcal/mol. We then considered the entire metal-binding motif with four residues and calculated the interaction energies with the copper ion. We also considered Met->Cys- mutation in the motif and repeated the calculations. Interaction of the wild-type motif with the copper ion is ~160kcal/mol weaker than that of mutated motif. Our studies suggest the factors that could explain why Met is not as frequently observed as Cys in the metal-binding motifs. Results of these studies will help in designing metal binding motifs in proteins with varying interaction strengths. PMID- 28363088 TI - Permeability and microstructure of model stratum corneum lipid membranes containing ceramides with long (C16) and very long (C24) acyl chains. AB - The Stratum corneum (SC) prevents water loss from the body and absorption of chemicals. SC intercellular spaces contain ceramides (Cer), free fatty acids (FFA), cholesterol (Chol) and cholesteryl sulfate (CholS). Cer with "very long" acyl chains (for example, N-lignoceroyl-sphingosine, CerNS24) are important for skin barrier function, whereas increased levels of "long" acyl Cer (for example, N-palmitoyl-sphingosine, CerNS16) occur in patients suffering from atopic eczema or psoriasis. We studied the impact of the replacement of CerNS24 by CerNS16 on the barrier properties and microstructure of model SC lipid membranes composed of Cer/FFA/Chol/CholS. Membranes containing the long CerNS16 were significantly more permeable to water (by 38-53%), theophylline (by 50-55%) and indomethacin (by 83 120%) than those containing the very long CerNS24 (either with lignoceric acid or a mixture of long to very long chain FFA). Langmuir monolayers with CerNS24 were more condensed than with CerNS16 and atomic force microscopy showed differences in domain formation. X-ray powder diffraction revealed that CerNS24-based membranes formed one lamellar phase and separated Chol, whereas the CerNS16-based membranes formed up to three phases and Chol. These results suggest that replacement of CerNS24 by CerNS16 has a direct negative impact on membrane structure and permeability. PMID- 28363090 TI - A case of urinary retention in the early stages of herpes simplex virus type-1 encephalitis. AB - A 70-year-old man developed urinary retention in the early stages of herpes simplex virus (HSV) type-1 encephalitis. A nerve conduction study suggested latent myeloradiculitis. This is the first report of human herpes simplex virus-1 encephalitis followed by urinary retention at early stage from the onset like the Elsberg syndrome. Although relatively few similar cases have been reported, we consider that urinary retention is common in HSV-1 encephalitis, in which disturbances of consciousness usually require bladder catheterization from the onset. We further emphasize that urinary retention may occasionally occur in early stages of HSV-1 encephalitis, with a significant possibility of recovery. PMID- 28363091 TI - Corrigendum to 'AFM nanoindentation detection of the elastic modulus of tongue squamous carcinoma cells with different metastatic potentials' [Nanomedicine 9 (2013) 864-874]. PMID- 28363092 TI - Vehicles as outdoor BFR sources: Evidence from an investigation of BFR occurrence in road dust. AB - The distribution of brominated flame retardants (BFRs) including ?8PBDEs, DBDPE, BTBPE, EH-TBB, BEH-TEBP and PBEB in road dust (RD) collected in Xinxiang, China was characterized. Analysis of RD samples indicated that the BFR abundance declined as traffic density decreased, with total mean levels of 292, 184, 163, 104 and 70 ng g-1 dust at sites from traffic intersections, main roads, collector streets, bypasses and parks, respectively. A possible explanation for this phenomenon is that the majority of BFRs may be emitted from the interior of vehicles via their ventilation systems. Of the 13 analyzed substances, BDE-209 and BEH-TEBP were the most abundant components in RD from Xinxiang. Similar amounts of ?BDEs excluding BDE-209 were found at different types of sampling sites, and thus, atmospheric deposition is also a probable source of BFRs in RD which can be subject to air transportation. The main PBDE sources were traced to commercial products including DE-71, Bromkal 79-8DE, Saytex 201E and Bromkal 82 DE mixtures. Our results confirm that the use of deca-BDE commercial mixture is a major source of PBDE contamination in RD. Risk assessment indicated the concentrations of BFRs in RD in this study do not constitute a non-cancer or cancer risk to humans through ingestion. Annual emission fluxes of the commonly detected BFRs via RD in China were estimated to be up to 4980 kg year-1. PMID- 28363093 TI - Accumulation of toxic metals and organic micro-pollutants in sediments from tropical urban rivers, Kinshasa, Democratic Republic of the Congo. AB - The increasing contamination of fresh water resource by toxic metals and Persistence Organic Pollutants (POPs) is a major environmental concern globally. In the present investigation, surface sediments collected from three main rivers named, Makelele, Kalamu and Nsanga, draining through the city of Kinshasa, Democratic Republic of the Congo, were characterized for grain size, organic matter, toxic metals, POPs (including organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs)), and polycyclic aromatic hydrocarbons (PAHs). Furthermore, enrichment factor (EF) and geoaccumulation index (Igeo) were performed to determine metal source and pollution status. The results highlighted high concentration of toxic metals in all sediment samples, reaching the values (mg kg-1) of 325 (Cu), 549 (Zn), 165 (Pb) and 1.5 (Cd). High values of PCBs and OCPs were detected in sediment samples, e.g. in Makelele river, PCB values ranged from 0.9 to 10.9 with total PCBs (?7 PCBs * 4.3): 169.3 MUg kg-1; OCPs from 21.6 to 146.8 with ?OCPs: 270.6 MUg kg-1. The PBDEs concentrations were higher in investigated rivers comparatively with values detected in many rivers from Sub-Saharan Africa. The SigmaPAHs value ranged from 22.6 to 1011.9 MUg kg-1. River contamination may be explained by local intense domestic activities, urban and agricultural runoff, industrial and hospital wastewaters discharge into the rivers without prior treatment. This research provides not only a first baseline information on the extent of contamination in this tropical ecosystem but also represents useful tools incorporated to evaluate sediment quality in the river receiving systems which can be applied to similar aquatic environments. PMID- 28363094 TI - Quantitative structure-activity relationships for green algae growth inhibition by polymer particles. AB - After use and disposal of chemical products, many types of polymer particles end up in the aquatic environment with potential toxic effects to primary producers like green algae. In this study, we have developed Quantitative Structure Activity Relationships (QSARs) for a set of highly structural diverse polymers which are capable to estimate green algae growth inhibition (EC50). The model (N = 43, R2 = 0.73, RMSE = 0.28) is a regression-based decision tree using one structural descriptor for each of three polymer classes separated based on charge. The QSAR is applicable to linear homo polymers as well as copolymers and does not require information on the size of the polymer particle or underlying core material. Highly branched polymers, non-nitrogen cationic polymers and polymeric surfactants are not included in the model and thus cannot be evaluated. The model works best for cationic and non-ionic polymers for which cellular adsorption, disruption of the cell wall and photosynthesis inhibition were the mechanisms of action. For anionic polymers, specific properties of the polymer and test characteristics need to be known for detailed assessment. The data and QSAR results for anionic polymers, when combined with molecular dynamics simulations indicated that nutrient depletion is likely the dominant mode of toxicity. Nutrient depletion in turn, is determined by the non-linear interplay between polymer charge density and backbone flexibility. PMID- 28363095 TI - Microwave-assisted solvothermal synthesis of hierarchical TiO2 microspheres for efficient electro-field-assisted-photocatalytic removal of tributyltin in tannery wastewater. AB - Organotin compounds have been widely used in recent decades, however, the residential tributyltin (TBT) in environment has potential harmful effects on human health due to the disruption of endocrine system even at trace level. Herein, this work reports on an effective electro-field-assisted-photocatalytic technique for removal of TBT by applying an electric field to photocatalysis of as-prepared hierarchical TiO2 microspheres. The synthesis of catalytic materials is based on a self-assembly process induced by microwave-assisted solvothermal reaction. Hierarchical TiO2 microspheres consisting of nanowires can be obtained in short time with this facile method and possess high surface area and superior optical properties. As the catalyst, it was found that the reaction rate constant of electro-field-assisted-photocatalytic removal (0.0488 min-1) of TBT exhibited almost a 9 fold improvement as compared to that of photocatalysis (0.0052 min-1). The proposed mechanism of electro-field-assisted-photocatalytic removal of TBT was verified by using 117Sn-enriched TBT spike solution as an isotopic tracer. In addition, varying impacts from some key reaction conditions, such as voltage of potential, pH value and the presence of Cr and formaldehyde were also discussed. The overall satisfactory TBT removal performance of the proposed electro-field assisted-photocatalysis procedure with hierarchical TiO2 microspheres, which was validated using actual tannery wastewater samples from three different kinds of tanning procedures. These attributes suggest that this electro-field-assisted photocatalysis may have broad applications for the treatment of tannery wastewater. PMID- 28363096 TI - Associations of long-term exposure to air pollution and road traffic noise with cognitive function-An analysis of effect measure modification. AB - BACKGROUND: Adverse effects of traffic-related air pollution (AP) and noise on cognitive functions have been proposed, but little is known about their interactions and the combined effect of co-exposure. METHODS: Cognitive assessment was completed by 4086 participants of the population-based Heinz Nixdorf Recall cohort study using five neuropsychological subtests and an additively calculated global cognitive score (GCS). We assessed long-term residential concentrations for size-fractioned particulate matter (PM) and nitrogen oxides with land use regression. Road traffic noise (weighted 24-h (LDEN) and night-time (LNIGHT) means) was assessed according to the EU directive 2002/49/EC. Linear regression models adjusted for individual-level characteristics were calculated to estimate effect modification of associations between AP and noise with cognitive function. We used multiplicative interaction terms and categories of single or double high exposure, dichotomizing the potential effect modifier at the median (AP) or at an a priori defined threshold (road traffic noise). RESULTS: In fully adjusted models, high noise exposure increased the association of AP with cognitive function. For example, for an interquartile range increase of PM2.5 (IQR 1.43), association s with GCS were: estimate (beta)=-0.16 [95% confidence interval: -0.33; 0.01] and beta=-0.48 [ 0.72; -0.23] for low and high LDEN, respectively. The association of noise with GCS was restricted to highly AP-exposed participants. We observed stronger negative associations in those participants with double exposure compared to the addition of effect estimates of each single exposure. CONCLUSIONS: Our study suggests that AP and road traffic noise might act synergistically on cognitive function in adults. PMID- 28363097 TI - Gastrointestinal emergencies in critically ill cancer patients. AB - PURPOSE: To describe gastrointestinal emergencies in cancer patients. METHODS: All cancer patients admitted to the medical ICU of Saint-Louis Hospital for an acute abdominal syndrome during the study period (1997-2011) were included. RESULTS: A total of 164 patients were included. The most common diagnoses were: neutropenic enterocolitis (NE) (n=54, 33%), infectious colitis and peritonitis (n=51, 31%), bowel infiltration by malignancy (n=14, 9%), and mucosal toxicity of chemotherapy (n=12, 7%). Microbiologically documented infections were reported in 82 patients (50%), including 12 fungal infections. Twenty-seven patients (16%) underwent urgent surgery. The hospital mortality rate was 35%. Five factors were independently associated with hospital mortality: the Simplified Acute Physiology Score II (SAPS II) score on day 1 (OR 1.03/SAPS II point, 95% CI 1.01 to 1.05), microbiological documentation (OR 0.27, 95% CI 0.11 to 0.64), neutropenia (OR 0.42, 95% CI 0.19 to 0.95), allogenic hematopoietic stem-cell transplantation (HSCT) (OR 5.13, 95% CI 1.71 to 15.4), and mechanical ventilation (OR 3.42, 95% CI 1.37 to 8.51). CONCLUSIONS: Gastrointestinal emergencies in cancer patients are associated with significant mortality. Mortality correlated both with the severity of organ failure upon ICU admission and the underlying diagnosis. Interestingly, patients admitted to the ICU with neutropenia had better survival. PMID- 28363099 TI - Effect of aquifer storage and recovery (ASR) on recovered stormwater quality variability. AB - Aquifer Storage and Recovery (ASR) is increasingly being considered as a means of reusing urban stormwater to supplement available urban water resources. Storage of stormwater in an aquifer has been shown to affect water quality but it has also been claimed that storage will also decrease the stormwater quality variability making for improved predictability and management. This study is the first to document the changes in stormwater quality variability as a result of subsurface storage at four full scale ASR sites using advanced statistical techniques. New methods to examine water quality are required as data is often highly left censored and so traditional measures of variability such as the coefficient of variation are inappropriate. It was observed that for some water quality parameters (most notably E. coli) there was a marked improvement of water quality and a significant decrease in variability at all sites. This means that aquifer storage prior to engineered treatment systems may be advantageous in terms of system design to avoid over engineering. For other parameters such as metal(loids)s and nutrients the trend was less clear due to the numerous processes occurring during storage leading to an increase in variability, especially for geogenic metals and metalloids such as iron and arsenic. Depending upon the specific water quality parameters and end use, use of ASR may not have a dampening effect on stormwater quality variability. PMID- 28363100 TI - Strategies for liquid-liquid extraction of oxide particles for applications in supercapacitor electrodes and thin films. AB - Bottom-up and top-down liquid-liquid extraction methods have been developed for the transfer of colloidal metal oxide particles, synthesized in an aqueous phase, to organic phases. In such methods the agglomeration of the particles during the drying stage was avoided. Hexadecylamine was used as an extractor for MnO2 particles in the bottom-up extraction to the 1-butanol phase and top-down extraction to the dichloromethane phase. The reduction of particle agglomeration facilitated the fabrication of MnO2-carbon nanotube composite electrodes for electrochemical supercapacitors with enhanced mixing of the individual components and active mass as high as 35mgcm-2. Electrochemical testing results showed superior performance of the composite MnO2-carbon nanotube electrodes, prepared by the bottom-up strategy. The new strategies allowed the fabrication of advanced electrodes, which showed a capacitance of 5.48Fcm-2 at a scan rate of 2mVs-1, good capacitance retention at high scan rates and low resistance. In another conceptually new bottom-up strategy colloidal titania particles were modified during synthesis with 2,3,4-trihydroxybenzaldehyde, which allowed strong catecholate-type bonding to the Ti atoms on the particle surface. The Schiff base reaction with hexadecylamine at the liquid-liquid interface allowed for particle extraction. The extraction strategies developed in this investigation pave the way for agglomerate-free processing of advanced films, coatings and devices by colloidal methods. PMID- 28363098 TI - Brand-to-generic levetiracetam switch in patients with epilepsy in a routine clinical setting. AB - PURPOSE: The therapeutic equivalence of generic and brand antiepileptic drugs, based on studies performed on healthy volunteers, has been questioned. We compare, in a routine clinical setting, brand versus generic levetiracetam (LEV) bioequivalence in patients with epilepsy and also the clinical efficacy and tolerability of the substitution. METHODS: A prospective, open-label, non randomized, steady-state, multiple-dose, bioequivalence study was conducted in 12 patients with epilepsy (5 females), with a mean age of 38.4+/-16.2 years. Patients treated with the brand LEV (Keppra; UCB Pharma) were closely followed for a four-week period and subsequently switched to a generic LEV (Pharmaten) and followed for another four-week period. Blood samples were collected at the end of each 4-week period, during a dose interval for each formulation, for LEV concentration measurements by liquid chromatography mass spectrometry. Steady state area under the curve (AUC) and peak plasma concentration (Cmax) data were subjected to conventional average bioequivalence analysis. Secondary clinical outcomes, including seizure frequency and adverse events, were recorded. RESULTS: Patients had epilepsy for a mean period of 14.1+/-10.6years and the mean daily LEV dose was 2583.3+/-763.7mg. The mean AUC+/-SD and Cmax+/-SD was 288.4+/ 86.3(mg/L)h and 37.8+/-10.4mg/L respectively for brand LEV and 319.2+/ 104.7(mg/L)h and 41.6+/-12.3mg/L respectively for the generic LEV. Statistic analysis showed no statistical significant difference in bioequivalence. Also, no change in seizures frequency and/or adverse events was recorded. CONCLUSIONS: In our clinical setting, generic LEV was determined to be bioequivalent to brand LEV. Furthermore, seizures frequency or/and adverse events were not affected upon switching from brand to generic LEV. PMID- 28363101 TI - Two-dimensional layered compound based anode materials for lithium-ion batteries and sodium-ion batteries. AB - Rechargeable batteries, such as lithium-ion and sodium-ion batteries, have been considered as promising energy conversion and storage devices with applications ranging from small portable electronics, medium-sized power sources for electromobility, to large-scale grid energy storage systems. Wide implementations of these rechargeable batteries require the development of electrode materials that can provide higher storage capacities than current commercial battery systems. Within this greater context, this review will present recent progresses in the development of the 2D material as anode materials for battery applications represented by studies conducted on graphene, molybdenum disulfide, and MXenes. This review will also discuss remaining challenges and future perspectives of 2D materials in regards to a full utilization of their unique properties and interactions with other battery components. PMID- 28363103 TI - Customized tuning of aggregation-induced emission of a napthalimide dye by surfactants and cyclodextrin. AB - The aggregation-induced emission behaviour of an environment sensitive 2,3 substituted napthalimide dye has been investigated at neutral pH in presence of three different surfactants i.e., cationic, anionic, and neutral. The changes observed in the excitation spectrum of the dye compared to its absorption spectra in water in presence of the surfactants above their micellar concentration reveals the transformation of the H-aggregates of the dye to the monomeric form. The alteration of the dye aggregates to its monomeric form and its consequence on emission properties has been utilized to estimate the surfactant concentration parameter for pre-micellar to micellar transformation. The aggregation of the dye molecules has been made reversible by removal of the surfactant molecules from the system upon host-guest complexation with alpha-cyclodextrin. This switchable aggregation-deaggregation phenomenon of DMN-Bu by employing surfactants and alpha cyclodextrin at neutral pH in water is utilized for determining their critical micellar concentration. PMID- 28363102 TI - Green synthesized nano silver: Synthesis, physicochemical profiling, antibacterial, anticancer activities and biological in vivo toxicity. AB - Green synthesis of nanoparticles using plants is gaining much interest in recent years. Anyway, intricate details on the role of phytochemicals involved in capping and stabilization of nanoparticles in diminishing toxicity and enhancing therapeutic potential are required. In this study, Ficus religiosa silver nanoparticles (FRAgNPs) were synthesized using Ficus religiosa leaf extract (FRLE) and characterized. The FRAgNPs showed good antibacterial activity and also cytotoxic effect in different cancer cell lines. Induction of apoptotic cell death was confirmed by various staining techniques, increased expression of cleaved caspases-8, 9, 3, lamin, PARP and oxidative stress markers in A549 and Hep2 cells. The in vivo studies performed in rats revealed significant increase in serum levels of AST, ALT, and LDH, TNF-alpha and IL-6 on day 29 following oral administration of FRAgNPs. However, these levels reverted back to normal at the end of wash out period on day 89. ICP-OES analysis revealed accumulation of silver in liver, brain and lungs on day 29 with respective concentration of 4.77, 3.94 and 3.043MUg/g tissue. However, complete elimination of silver was observed on day 89. Histological analysis performed in vital organs indicated pathological changes only in liver which was also normalized after 89days. PMID- 28363104 TI - Preparation of concave magnetoplasmonic core-shell supraparticles of gold-coated iron oxide via ion-reducible layer-by-layer method for surface enhanced Raman scattering. AB - Preparation of suprastructure assemblies with unique colloidal and optical properties remains challenging. Non-uniform covering of magnetic nanoparticles (NPs) with an external inert Au shell has been attempted to protect the magnetic core against oxidation as well as to produce multifunctional supraparticles (SPs) possessing respective optical and magnetic properties. In this study, a concave Au NP coating was deposited on magnetic nanoparticles (MNPs) with precise control of the shell thickness and roughness through a layer-by-layer (LbL) assisted ionic reduction method termed ion-reducible LbL (IR-LbL) method. Surface enhanced Raman spectra were obtained using graphene quantum dots (GQDs) on the magnetically aligned structure of the prepared core-shell SPs. It is probable that this synthesis method and the generated SPs are essential for characterizing the merge of electronics and magnetism in the nano-regime and may be applicable for further electronics, magnetic storage, and biomedical applications. PMID- 28363105 TI - Liquid phase high shear exfoliated graphene nanoplatelets as counter electrode material for dye-sensitized solar cells. AB - Graphene nanoplatelets (GNPs) are prepared from natural graphite by a simple and low-cost liquid phase high shear exfoliation method. The as-prepared GNPs are used as a counter electrode (CE) material for dye-sensitized solar cells (DSSCs). To confirm the Exfoliated GNPs, structural and morphological studies are carried out using X-ray diffraction (XRD), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM) and selected area electron diffraction (SAED) studies. The electrochemical behaviour of GNPs as a counter electrode material is evaluated and compared with standard Platinum (Pt) electrode using cyclic-voltammetry (CV) and electrochemical impedance spectroscopy (EIS). These studies indicated that electrocatalytic activity towards I-/I3- redox mediator exhibited by the GNPs based electrode is comparable to standard Pt counter electrodes. DSSCs are fabricated using the counter electrodes made of GNPs and the photo-conversion efficiency is found to be 6.23% under standard test conditions, which is comparable to Pt based DSSCs proving them as potential alternative materials for counter electrodes. PMID- 28363106 TI - Individual differences in the Simon effect are underpinned by differences in the competitive dynamics in the basal ganglia: An experimental verification and a computational model. AB - Cognitive control is thought to be made possible by the activity of the prefrontal cortex, which selectively uses task-specific representations to bias the selection of task-appropriate responses over more automated, but inappropriate, ones. Recent models have suggested, however, that prefrontal representations are in turn controlled by the basal ganglia. In particular, neurophysiological considerations suggest that the basal ganglia's indirect pathway plays a pivotal role in preventing irrelevant information from being incorporated into a task, thus reducing response interference due to the processing of inappropriate stimuli dimensions. Here, we test this hypothesis by showing that individual differences in a non-verbal cognitive control task (the Simon task) are correlated with performance on a decision-making task (the Probabilistic Stimulus Selection task) that tracks the contribution of the indirect pathway. Specifically, the higher the effect of the indirect pathway, the smaller was the behavioral costs associated with suppressing interference in incongruent trials. Additionally, it was found that this correlation was driven by individual differences in incongruent trials only (with little effect on congruent ones) and specific to the indirect pathway (with almost no correlation with the effect of the direct pathways). Finally, it is shown that this pattern of results is precisely what is predicted when competitive dynamics of the basal ganglia are added to the selective attention component of a simple model of the Simon task, thus showing that our experimental results can be fully explained by our initial hypothesis. PMID- 28363107 TI - Do online reviews diminish physician authority? The case of cosmetic surgery in the U.S. AB - This article analyzes the substance and perception of online physician reviews, which are qualitative and quantitative assessments of physicians written and shared by patients, in the case of U.S. cosmetic surgery. Like other cash-pay medical specialties, cosmetic surgery is elective and paid for largely out of pocket, with patients having latitude in their choice of surgeon. Drawing on qualitative data from interviews, observations of an American Society of Aesthetic Plastic Surgery professional meeting, and online reviews from the platforms RealSelf and Yelp, I identify two interdependent contributors to physician authority: reputation and expertise. I argue that surgeons see reviews overwhelmingly as a threat to their reputation, even as actual review content often positively reinforces physician expertise and enhances physician reputation. I show that most online reviews linked to interview participants are positive, according considerable deference to surgeons. Reviews add patients' embodied and consumer expertise as a circumscribed supplement to surgeons' technical expertise. Moreover, reviews change the doctor-patient relationship by putting it on display for a larger audience of prospective patients, enabling patients and review platforms to affect physician reputation. Surgeons report changing how they practice to establish and maintain their reputations. This research demonstrates how physician authority in medical consumerist contexts is a product of reputation as well as expertise. Consumerism changes the doctor patient relationship and makes surgeons feel diminished authority by dint of their reputational vulnerability to online reviews. PMID- 28363108 TI - A novel small molecule compound possesses immunomodulatory properties on bone marrow-derived dendritic cells via TLR7 signaling pathway and alleviates the development of SLE. AB - Dendritic cells (DCs) play an important role in the development and maintenance of immune tolerance. Activation of TLR7, which is expressed in DCs, is thought to contribute to the complex pathophysiology of systemic lupus erythematosus (SLE). In this study, we analyzed the in vitro and in vivo function of a novel small molecule compound, FC-99, which was previously reported to have immunomodulatory functions. We found that FC-99 inhibited the expression of CD40 and inflammatory mediators (IL-6, IL-12, and CXCL-10), as well as R848-induced phosphorylation of IkappaB-alpha. We also present evidence that FC-99 is remarkably efficacious in the treatment of murine lupus. Interestingly, FC-99 affected the maturation and percentage of DCs in lupus-prone mice. Therefore, FC-99 may serve as a potential drug candidate for treatment of SLE. PMID- 28363109 TI - Platycodin D protects against cigarette smoke-induced lung inflammation in mice. AB - Cigarette smoke is the one of the major factors that leads to chronic obstructive pulmonary disease (COPD). Inflammation and oxidant stress have been known to play critical roles in the development of COPD. Platycodin D (PLD) has been reported to have anti-inflammatory and anti-oxidant effects. In this study, we aimed to investigate the protective effects of PLD on cigarette smoke (CS)-induced lung inflammation in mice. PLD was adminstrated i.p. to mice 2h before CS exposure daily for five consecutive days. The production of inflammatory cytokines TNF alpha and IL-1beta were measured by ELISA. The levels of malonaldehyde (MDA) and nitric oxide (NO) were also detected in this study. The expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NF-kappaB, and IkappaBalpha were detected by western blot analysis. The results showed that PLD significantly attenuated CS-induced lung pathological changes, inflammatory cells infiltration, as well as TNF-alpha and IL-1beta production. CS-induced MDA and NO production were also inhibited by treatment of PLD. Western blot analysis showed that PLD significantly suppressed CS-induced NF-kappaB activation. In addition, PLD was found to increase the expression of Nrf2 and HO-1. Taken together, these results indicated that PLD protected against CS-induced lung inflammation by inhibiting inflammatory and oxidative response through activating Nrf2 signaling pathway. PLD might be an effective treatment for CS-induced lung inflammation. PMID- 28363110 TI - 'I was told not to do it but...': Infant feeding practices amongst HIV-positive women in southern Thailand. AB - BACKGROUND AND OBJECTIVES: mothers living with HIV are encouraged not to breastfeed as it can transmit HIV to their infants. However, there is little known about how Thai women with HIV perceive and experience their infant feeding practices. This paper explores the breastfeeding experiences among Thai women living with HIV in southern Thailand. METHODS: semi-structured interviews and drawing methods were used with 30 HIV-positive women in rural communities of southern Thailand. Thematic analysis was used for data analysis. FINDINGS: HIV positive mothers had ambivalent feelings about not being able to breastfeed their infants. They perceived themselves as a 'contaminated mother'. Healthcare centres and hospitals supply free infant formula for HIV-positive mothers up to one and a half years. Despite this, many mothers had to deal with some difficulties. Some infants developed an allergy to the infant formula. The free infant formula was not sufficient for some infants and the mothers had to find alternative means for the well-being of their infants: many mothers relied on condensed milk whereas some fed mashed banana. The women made every effort to fulfill their ideology of being a good and responsible mother. CONCLUSION: this paper contributes a conceptual understanding about the lived experiences of breastfeeding among women living with HIV in southern Thailand. The findings have implications for midwifery care and health policy. The provision of different options of feeding should be made available to infants along with accessible resources and professional support and guidance. PMID- 28363112 TI - Ribosome profiling and dynamic regulation of translation in mammals. AB - Protein synthesis is an energy-demanding cellular process. Consequently, a well timed, fine-tuned and plastic regulation of translation is needed to adjust and maintain cell states under dynamically changing environments. Genome-wide monitoring of translation was recently facilitated by ribosome profiling, which uncovered key features of translation regulation. In this review, we summarize recent ribosome profiling studies in mammals providing novel insight in dynamic translation regulation, notably related to circadian rhythms, diurnal feeding/fasting cycles, cell cycle progression, stress responses, and tRNA landscapes. In particular, recent results show that regulating translation initiation and elongation represent important mechanisms used in mammalian cells to rapidly modulate protein expression in dynamically changing environments. PMID- 28363113 TI - The attractor recurrent neural network based on fuzzy functions: An effective model for the classification of lung abnormalities. AB - The respiratory system dynamic is of high significance when it comes to the detection of lung abnormalities, which highlights the importance of presenting a reliable model for it. In this paper, we introduce a novel dynamic modelling method for the characterization of the lung sounds (LS), based on the attractor recurrent neural network (ARNN). The ARNN structure allows the development of an effective LS model. Additionally, it has the capability to reproduce the distinctive features of the lung sounds using its formed attractors. Furthermore, a novel ARNN topology based on fuzzy functions (FFs-ARNN) is developed. Given the utility of the recurrent quantification analysis (RQA) as a tool to assess the nature of complex systems, it was used to evaluate the performance of both the ARNN and the FFs-ARNN models. The experimental results demonstrate the effectiveness of the proposed approaches for multichannel LS analysis. In particular, a classification accuracy of 91% was achieved using FFs-ARNN with sequences of RQA features. PMID- 28363111 TI - 3T hippocampal glutamate-glutamine complex reflects verbal memory decline in aging. AB - The hippocampus is a critical site for alterations that are responsible for age related changes in memory. Here, we present a relatively novel approach of examining the relationship between memory performance and glutamate-glutamine levels using short echo time magnetic resonance spectroscopy. Specifically, we investigated the relationship between Glx (a composite of glutamate and glutamine) levels in the hippocampus, performance on a word-recall task, and resting-state functional connectivity. While there was no overall difference in Glx intensity between young and aging adults, we identified a positive correlation between delayed word-list recall and Glx, bilaterally in older adults, but not in young adults. Collapsed across age, we also discovered a negative relationship between Glx intensity and resting-state functional connectivity between the anterior hippocampus and regions in the subcallosal gyrus. These findings demonstrate the possible utility of Glx in identifying age related changes in the brain and behavior and provide encouragement that magnetic resonance spectroscopy can be useful in predicting age-related decline before any physical abnormalities are present. PMID- 28363114 TI - Mechanical mandible competence in rats with nutritional growth retardation. AB - OBJECTIVE: In order to provide a better understanding of the sympathetic nervous system as a negative regulator of bone status, the aim of the study was to establish the biomechanical mandible response to different doses of a beta adrenergic antagonist such as propranolol (P) in a stress-induced food restriction model of growth retardation. METHODS: Rats were assigned to eight groups: Control (C), C+P3.5 (CP3.5), C+P7 (CP7), C+P14 (CP14), NGR, NGR+P3.5 (NGRP3.5), NGR+P7 (NGRP7) and NGR+P14 (NGRP14). C, CP3.5, CP7 and CP14 rats were freely fed with the standard diet. NGR, NGRP3.5, NGRP7 and NGRP14 rats received, for 4 weeks (W4), 80% of the amount of controls food consumed. Propranolol 3.5, 7 and 14mg/kg/day was injected ip 5days per week in CP3.5 and NGRP3.5, CP7 and NGRP7, CP14 and NGRP14, respectively. At W4, zoometry, mandible morphometry, static histomorphometric and biomechanical competence were performed. RESULTS: A dose of Propranolol 7mg/kg/day induced interradicular bone volume accretion reaching a mandible stiffness according to chronological age. CONCLUSION: These findings evidenced that sympathetic nervous system activity is a negative regulator of mandible mechanical competence in the nutritional growth retardation model. Propranolol 7mg/kg/day, under the regimen usage, seems to be appropriate to blockade SNS activity on mandible mechanical performance in NGR rats, probably associated to an effect on bone mechanostat system ability to detect disuse mode as an error. PMID- 28363115 TI - The effect of childrens' eating behaviors and parental feeding style on childhood obesity. AB - In is important to determine the factors that affect obesity in childhood, in order to raise generations of healthy children. This study aims to determine the effect of primary school students' eating behaviors and parental feeding styles on obesity in childhood. This descriptive cross-sectional study was conducted with 1201 children and their parents between September 2014 and March 2015. The data were collected using the socio-demographic data collection form for children and parents, the Children's Eating Behavior Questionnaire and the Parental Feeding Style Questionnaire. The data were analyzed using percentage calculators, mean, Spearman's correlation analysis, Pearson's correlation analysis and multiple regression analysis. Of the children, 16.9% were found to be obese. Three models were created considering the relationships between the variables in this study and the occurrence of obesity. In the first model, the factors that affect childhood obesity were found to be enjoyment of food, emotional overeating, food responsiveness, satiety responsiveness and food fussiness. In the second model, the factors were prompting/encouragement and control over eating. Enjoyment of food, emotional overeating, food responsiveness, satiety responsiveness, emotional feeding and food fussiness were also found to be the factors in the third model (p<0.05). This study showed that children's eating behaviors and parental feeding style affect the occurrence of obesity in childhood. PMID- 28363116 TI - Clinical significance of anti-domain 1 beta2-glycoprotein I antibodies in antiphospholipid syndrome. AB - BACKGROUND: Antiphospholipid syndrome (APS) is characterized by the presence of circulating antiphospholipid antibodies (aPL) in patients with thrombosis and/or pregnancy morbidity. In APS patients anti-domain 1 beta2-glycoprotein I (anti-D1 beta2GPI) IgG antibodies correlate strongly with thrombosis and to the lesser extent, with pregnancy complications. The aim of this study was to assess clinical utility of the anti-D1 beta2GPI antibodies in the diagnosis and risk stratification of antiphospholipid syndrome. PATIENTS/METHODS: In this retrospective study 202 autoimmune patients were studied (primary APS - 58, secondary - 45 SLE - 99). Anticardiolipin (aCL) and anti-beta2GPI (abeta2GPI antibodies) (IgG and IgM class) together with anti-D1 IgG were tested with QUANTA Flash chemiluminescent immunoassay and lupus anticoagulant (LA) with coagulometric methods. RESULTS: The highest anti-D1 values were observed in triple positive patients as compared to patients with other antiphospholipid antibody profiles. A strong correlation was found between levels of anti-D1 IgG and a beta2GPI IgG antibodies for all patients analyzed (Spearman's rho=0.87; p<0.0001). Anti-D1 IgG antibodies increase specificity resulting from classic aPL positivity but at the expense of sensitivity. Anti-D1 test does not add accuracy in predicting APS thrombotic complications on the top of accuracy offered by classic aPL tests and their profiles. CONCLUSIONS: Anti-D1 IgG antibodies did not add diagnostic power to the standard laboratory aPL tests as assessed by this retrospective study. A true clinical significance of anti-D1 antibodies in thrombotic risk stratification of aPL positive patients will require a properly designed clinical prospective trials. PMID- 28363117 TI - Evaluation of tissue factor bearing microparticles in the cord blood of preterm and term newborns. PMID- 28363118 TI - Gender differences in automatic thoughts and cortisol and alpha-amylase responses to acute psychosocial stress in patients with obsessive-compulsive personality disorder. AB - INTRODUCTION: Obsessive-compulsive personality disorder (OCPD) has a pervasive pattern of preoccupation with orderliness, perfection, and mental and interpersonal control at the expense of flexibility, openness, and efficiency. The aims of the present study were to explore the relationship between OCPD and psychological stress and psychological tests. METHODS: We evaluated 63 OCPD patients and 107 healthy controls (HCs). We collected saliva samples from patients and controls before and after a social stress procedure, the Trier Social Stress Test (TSST), to measure the concentrations of salivary alpha amylase (sAA) and salivary cortisol. The Childhood Trauma Questionnaire (CTQ), Profile of Mood State (POMS), State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI), Social Adaptation Self-Evaluation Scale (SASS), and Depression and Anxiety Cognition Scale (DACS) were administered to patients and HCs. RESULTS: Following TSST exposure, the salivary amylase and cortisol levels were significantly decreased in male patients compared with controls. Additionally, OCPD patients had higher CTQ, POMS, STAI, and BDI scores than HCs and exhibited significantly higher anxiety and depressive states. OCPD patients scored higher on future denial and threat prediction as per the DACS tool. According to a stepwise regression analysis, STAI, POMS, and salivary cortisol responses were independent predictors of OCPD. CONCLUSIONS: Our results suggested that attenuated sympathetic and parasympathetic reactivity in male OCPD patients occurs along with attenuated salivary amylase and cortisol responses to the TSST. In addition, there was a significant difference between OCPD patients and HCs in child trauma, mood, anxiety, and cognition. The finding support the modeling role of cortisol (20min) on the relationships between STAI trait and depression among OCPD. PMID- 28363119 TI - Diagnosis of Grave's disease with pulmonary hypertension on chest CT. AB - OBJECTIVE: To evaluate the diagnostic accuracy of chest CT findings to diagnose Grave's disease in pulmonary hypertension. METHODS: We retrospectively evaluated chest CT and the medical records of 13 patients with Grave's disease with (n=6) or without pulmonary hypertension (n=7) and in 17 control patients. RESULTS: Presence of iso-attenuation of diffusely enlarged thyroid glands compared with adjacent neck muscle on non-enhanced CT as a diagnostic clue of Grave's disease, and assessment of pulmonary hypertension on CT has high diagnostic accuracy. CONCLUSION: Chest CT has the potential to diagnose Grave's disease with pulmonary hypertension in the absence of other information. PMID- 28363121 TI - Excitation of hypersonic acoustic waves in diamond-based piezoelectric layered structure on the microwave frequencies up to 20GHz. AB - First ultrahigh frequency (UHF) investigation of quality factor Q for the piezoelectric layered structure "Al/(001)AlN/Mo/(100) diamond" has been executed in a broad frequency band from 1 up to 20GHz. The record-breaking Q.f quality parameter up to 2.7.1014Hz has been obtained close to 20GHz. Frequency dependence of the form factor m correlated with quality factor has been analyzed by means of computer simulation, and non-monotonic frequency dependence can be explained by proper features of thin-film piezoelectric transducer (TFPT). Excluding the minimal Q magnitudes measured at the frequency points associated with minimal TFPT effectiveness, one can prove a rule of Qf~f observed for diamond on the frequencies above 1GHz and defined by Landau-Rumer's acoustic attenuation mechanism. Synthetic IIa-type diamond single crystal as a substrate material for High-overtone Bulk Acoustic Resonator (HBAR) possesses some excellent acoustic properties in a wide microwave band and can be successfully applied for design of acoustoelectronic devices, especially the ones operating at a far UHF band. PMID- 28363120 TI - Awareness and understanding of HIV non-disclosure case law among people living with HIV who use illicit drugs in a Canadian setting. AB - BACKGROUND: In 2012, the Supreme Court of Canada (SCC) ruled that people living with HIV (PLWH) could face criminal charges if they did not disclose their serostatus before sex posing a "realistic possibility" of HIV transmission. Condom-protected vaginal sex with a low (i.e., <1500copies/mL) HIV viral load (VL) incurs no duty to disclose. Awareness and understanding of this ruling remain uncharacterized, particularly among marginalized PLWH. METHODS: We used data from ACCESS, a community-recruited cohort of PLWH who use illicit drugs in Vancouver. The primary outcome was self-reported awareness of the 2012 SCC ruling, drawn from cross-sectional survey data. Participants aware of the ruling were asked how similar their understanding was to a provided definition. Sources of information from which participants learned about the ruling were determined. Multivariable logistic regression identified factors independently associated with ruling awareness. RESULTS: Among 249 participants (39% female), median age was 50 (IQR: 44-55) and 80% had a suppressed HIV VL (<50copies/mL). A minority (112, 45%) of participants reported ruling awareness, and 44 (18%) had a complete understanding of the legal obligation to disclose. Among those aware (n=112), newspapers/media (46%) was the most frequent source from which participants learned about the ruling, with 51% of participants reporting that no healthcare providers had talked to them about the ruling. Ruling awareness was negatively associated with VL suppression (AOR:0.51, 95% CI:0.27,0.97) and positively associated with recent condomless sex vs. no sex (AOR:2.00, 95% CI:1.03,3.92). CONCLUSION: Most participants were not aware of the 2012 SCC ruling, which may place them at risk of prosecution. Discussions about disclosure and the law were lacking in healthcare settings. Advancing education about HIV disclosure and the law is a key priority. The role of healthcare providers in delivering information and support to PLWH in this legal climate should be further explored. PMID- 28363122 TI - Trace DNA evidence dynamics: An investigation into the deposition and persistence of directly- and indirectly-transferred DNA on regularly-used knives. AB - Empirical data on the transfer and persistence of trace DNA are crucial to the evaluation of forensic DNA evidence. This evaluation can be complicated by the occurrence of indirect DNA transfer; the possibility of which is well established, but research into such transfer is often focussed on unrealistic situations, e.g. handling of DNA-free items after participants have shaken hands for 1-2min. To simulate more realistic scenarios, this study investigated the deposition and persistence of both directly- and indirectly-transferred DNA on knives that had been artificially set up as 'regularly-used'. Each knife was handled in a prescribed manner by a specific participant over two consecutive days to simulate regular use. Each participant then shook hands for 10s with a fellow volunteer and immediately stabbed one of their knives into a foam block repeatedly for 60s. DNA was recovered by mini-taping from triplicate sets of knife handles from four pairings of volunteers after regular use, and at one hour, one day and one week after the handshaking and stabbing events. Total amounts of DNA recovered from the knives, regularly used by a single person, varied among individuals; one volunteer consistently deposited significantly greater amounts than the others, whilst another volunteer did not always leave complete profiles. DNA attributed to the regular user persisted for at least a week, declining with increasing time between DNA deposition and recovery. Non donor DNA was co-deposited at <5% of the profiles recovered, except for one volunteer, who consistently left DNA from their romantic partner on their knives at ~25% and ~11% of the profiles before and after the handshaking and stabbing events, respectively. In three pairings of volunteers, after the handshaking and stabbing events, alleles that could be attributed to the respective handshakers' profiles were detected as partial minor profiles, equating to ~10% of the profiles recovered. For the fourth pairing of volunteers, only complete single source DNA profiles matching the regular user's profile were recovered. However, it is important to note that, when indirectly-transferred handshaker DNA was detected, it declined with increasing time between DNA deposition and recovery. These data provide an initial insight into the detection and persistence of directly- and indirectly-transferred DNA that extend the data already available on forensic DNA transfer. The results herein suggest that the sooner an item is sampled after an offence has occurred, the greater the chance of recovering indirectly-transferred DNA, which has implications for forensic reconstructions. PMID- 28363123 TI - The implications of shedder status and background DNA on direct and secondary transfer in an attack scenario. AB - In court questions are often raised related to how trace DNA was deposited, directly during the crime or innocently for instance by secondary transfer. It is therefore of interest to have knowledge of the probability of transfer or secondary transfer in different situations. Factors that could influence transfer probabilities are background DNA and the shedder status of the involved persons. In this study, we have classified participants as high or low DNA shedders. We observed DNA transfer in a simulated attack scenario, and demonstrated that shedder status has a significant influence of transfer rates. We have examined the background DNA in samples from T-shirts worn in an area with frequent human traffic and detected multiple contributors. We further demonstrated that DNA from co-workers of a T-shirt wearer can be secondarily transferred from the environment and detected in samples, and that the composition of background DNA is correlated with the shedder status of the wearer. Finally, we have illustrated the inference with the results of transfer probabilities and a fictive case with the use of a Bayesian network. PMID- 28363124 TI - Structural principles controlling HIV envelope glycosylation. AB - The heavily glycosylated, trimeric HIV-1 envelope (Env) protein is the sole viral protein exposed on the HIV-1 virion surface and is thus a main focus of antibody mediated vaccine development. Dense glycosylation at the outer domain of Env constrains normal enzymatic processing, stalling the glycans at immature oligomannose-type structures. Furthermore, native trimerization imposes additional steric constraints, which generate an extensive 'trimer-induced mannose patch'. Importantly, the immature glycans present a highly conserved feature of the virus that is targeted by broadly neutralizing antibodies. Quantitative mass spectrometry of glycopeptides together with structures of the trimeric viral-spike define the steric principles controlling processing and provide a detailed map of the glycan shield. PMID- 28363126 TI - Interaction between the zebrafish (Danio rerio) organic cation transporter 1 (Oct1) and endo- and xenobiotics. AB - Organic cation transporters (OCTs) serve as uptake transporters of numerous endo- and xenobiotics. They have been in the focus of medical toxicological research for more than a decade due to their key role in absorption, distribution, metabolism and excretion due to their expression on basolateral membranes of various barrier tissues. OCTs belong to the SLC22A family within the SLC (Solute carrier) protein superfamily, with three co-orthologs identified in humans (OCT1, 2 and 3), and two Oct orthologs in zebrafish (Oct1 and Oct2). The structural and functional properties of zebrafish Octs, along with their toxicological relevance, have still not been explored. In this study, we performed a functional characterization of zebrafish Oct1 using transient and stable heterologous expression systems and model fluorescent substrates as the basis for interaction studies with a wide range of endo- and xenobiotics. We also conducted a basic topology analysis and homology modeling to determine the structure and membrane localization of Oct1. Finally, we performed an MTT assay to evaluate the toxic effects of the seven interactors identified - oxaliplatin, cisplatin, berberine, MPP+, prazosin, paraquat and mitoxantrone - in human embryonic kidney cells (HEK293T) stably expressing zebrafish Oct1 (HEK293T-drOct1 cells). Our results show that the zebrafish Oct1 structure consists of 12 transmembrane alpha helices, which form the active region with more than one active site. Five new fluorescent substrates of Oct1 were identified: ASP+ (Km=26MUM), rhodamine 123 (Km=103.7nM), berberine (Km=3.96MUM), DAPI (Km=780nM), and ethidium bromide (Km=97nM). Interaction studies revealed numerous interactors that inhibited the Oct1-dependent uptake of fluorescent substrates. The identified interactors ranged from physiological compounds (mainly steroid hormones) to different classes of xenobiotics, with IC50 values in nanomolar (e.g., pyrimethamine and prazosin) to millimolar range (e.g., cimetidine). Cytotoxicity experiments with HEK293T-drOct1 cells enabled us to identify berberine, oxaliplatin and MPP+ as substrates of Oct1. The data presented in this study provide the first insights into the functional properties of zebrafish Oct1 and offer an important basis for more detailed molecular and ecotoxicological characterizations of this transporter. PMID- 28363125 TI - Pause & go: from the discovery of RNA polymerase pausing to its functional implications. AB - The synthesis of nascent RNA is a discontinuous process in which phases of productive elongation by RNA polymerase are interrupted by frequent pauses. Transcriptional pausing was first observed decades ago, but was long considered to be a special feature of transcription at certain genes. This view was challenged when studies using genome-wide approaches revealed that RNA polymerase II pauses at promoter-proximal regions in large sets of genes in Drosophila and mammalian cells. High-resolution genomic methods uncovered that pausing is not restricted to promoters, but occurs globally throughout gene-body regions, implying the existence of key-rate limiting steps in nascent RNA synthesis downstream of transcription initiation. Here, we outline the experimental breakthroughs that led to the discovery of pervasive transcriptional pausing, discuss its emerging roles and regulation, and highlight the importance of pausing in human development and disease. PMID- 28363128 TI - Toxic effect of cadmium adsorbed by different sizes of nano-hydroxyapatite on the growth of rice seedlings. AB - Information regarding the toxic effects of cadmium (Cd) adsorbed by nano hydroxyapatite (NHAP-Cd) on the growth of crop plants remain limited. We investigated the mechanism of NHAP-Cd (diameters, 20 and 40nm; NHAP20-Cd and NHAP40-Cd, respectively) phytotoxicity. Rice seedlings treated with Cd and NHAP20 Cd showed more severe growth retardation compared to those treated with NHAP40 Cd, for the same Cd concentration. Transmission electron microscopy revealed NHAP in the seedlings. The nanoparticles entered the rice seedlings with no Cd2+ signals in the NHAP treatments compared to -0.47pmolcm-2s-1 of Cd2+ fluxes in the Cd treatment. The higher Cd2+ content in the leaves and mesocotyl of NHAP20-Cd treated rice seedlings suggested that smaller NHAP-Cd can translocate easily to the aboveground parts. Further, NHAP-Cd increased oxidative stress, which was determined as catalase activity changes in this study. Thus, NHAP-Cd particles in the growth medium can be transported to rice seedlings and cause toxicity. PMID- 28363127 TI - Tissue uptake, distribution and excretion of brevetoxin-3 after oral and intratracheal exposure in the freshwater turtle Trachemys scripta and the diamondback terrapin Malaclemys terrapin. AB - Harmful algal blooms (HABs) occur nearly annually off the west coast of Florida and can impact both humans and wildlife, resulting in morbidity and increased mortality of marine animals including sea turtles. The key organism in Florida red tides is the dinoflagellate Karenia brevis that produces a suite of potent neurotoxins referred to as the brevetoxins (PbTx). Despite recent mortality events and rehabilitation efforts, still little is known about how the toxin directly impacts sea turtles, as they are not amenable to experimentation and what is known about toxin levels and distribution comes primarily from post mortem data. In this study, we utilized the freshwater turtle Trachemys scripta and the diamondback terrapin, Malaclemys terrapin as model organisms to determine the distribution, clearance, and routes of excretion of the most common form of the toxin, brevetoxin-3, in turtles. Turtles were administered toxin via esophageal tube to mimic ingestion (33.48MUg/kg PbTx-3, 3*/week for two weeks for a total of 7 doses) or by intratracheal instillation (10.53MUg/kg, 3*/week for four weeks for a total of 12 doses) to mimic inhalation. Both oral and intratracheal administration of the toxin produced a suite of behavioral responses symptomatic of brevetoxicosis. The toxin distributed to all organ systems within 1h of administration but was rapidly cleared out over 24-48h, corresponding to a decline in clinical symptoms. Excretion appears to be primarily through conjugation to bile salts. Histopathological study revealed that the frequency of lesions varied within experimental groups with some turtles having no significant lesions at all, while similar lesions were found in a low number of control turtles suggesting another common factor(s) could be responsible. The overall goal of this research is better understand the impacts of brevetoxin on turtles in order to develop better treatment protocols for sea turtles exposed to HABs. PMID- 28363129 TI - Severe camphor poisoning, a seven-year observational study. AB - In a retrospective case series from 2007 to 2014, we searched for any accidental/intentional, and recreational cases of pure camphor poisoning through hospital records. Epidemiological data, as well as factors correlated with seizure, were evaluated. Thirty cases including 29 males were recruited with a median age of 18 years (range; 0.2-87). Patient's reported ingestion rate of camphor was 1.5-15 grams. Almost all of the patients (96.7%) were conscious on arrival time and the ingestion to the presentation time ratio was 7+/-5h. It was observed that in a majority of the cases (53.4%), decreasing libido was the main intent of Camphor ingestion. Nausea and vomiting occurred in 22 (73.3%) cases and tonic-clonic seizure was seen in 12 (40%) patients. Mean presentation time was significantly longer in patients who experienced seizure (9.1+/-6.1h vs. 5.2+/ 2.8h, p=0.05). No correlation was found between the amount of ingested camphor (grams or mg/kg) and vital signs along with the bio-chemistry results. Not only did all of our cases survive but also they exclusively received supportive care. PMID- 28363130 TI - Comparison of pseudorabies virus China reference strain with emerging variants reveals independent virus evolution within specific geographic regions. AB - Pseudorabies virus (PRV) China reference strain Ea is genetically closely related to newly emerged variants; however, there is limited information about PRV Ea. Here, we compared PRV Ea with new variant strains by growth kinetics, genome sequencing, and protein expression analysis. Growth analysis showed that strain Ea forms smaller plaques than strain HNX. The full-length genome sequence of Ea revealed that it is clustered in the same subgroup as HNX. Ea and HNX strains exhibited similar extracellular virion protein polymorphisms, whereas strain Bartha expressed less VP26 and more GAPDH. In infected cells, strain Ea expressed high levels of IE180 protein, and Ea and HNX produced higher levels of UL21 protein than strain Bartha. These findings provide evidence that PRV China reference strain Ea is genetically closely related to the newly emerged variant strains, indicating that strain PRV China may have evolved independently leading to the emergence of a variant strain. PMID- 28363132 TI - Separate and unequal: Structural racism and infant mortality in the US. AB - We examined associations between state-level measures of structural racism and infant mortality among black and white populations across the US. Overall and race-specific infant mortality rates in each state were calculated from national linked birth and infant death records from 2010 to 2013. Structural racism in each state was characterized by racial inequity (ratio of black to white population estimates) in educational attainment, median household income, employment, imprisonment, and juvenile custody. Poisson regression with robust standard errors estimated infant mortality rate ratios (RR) and 95% confidence intervals (CI) associated with an IQR increase in indicators of structural racism overall and separately within black and white populations. Across all states, increasing racial inequity in unemployment was associated with a 5% increase in black infant mortality (RR=1.05, 95% CI=1.01, 1.10). Decreasing racial inequity in education was associated with an almost 10% reduction in the black infant mortality rate (RR=0.92, 95% CI=0.85, 0.99). None of the structural racism measures were significantly associated with infant mortality among whites. Structural racism may contribute to the persisting racial inequity in infant mortality. PMID- 28363131 TI - Preoperative cervical carotid artery contrast-enhanced ultrasound findings are associated with development of microembolic signals on transcranial Doppler during carotid exposure in endarterectomy. AB - BACKGROUND AND AIMS: Emboli from the surgical site during exposure of the carotid arteries cause new cerebral ischemic lesions or neurological deficits after carotid endarterectomy (CEA). The purpose of the present study was to determine whether preoperative contrast-enhanced ultrasound findings of the cervical carotid arteries are associated with the development of microembolic signals (MES) on transcranial Doppler, during exposure of the arteries in CEA, and to compare the predictive accuracy of contrast-enhanced ultrasound findings with that of gray-scale median (GSM). METHODS: Seventy patients with internal carotid artery stenosis (>=70%) underwent preoperative cervical carotid artery ultrasound and CEA under transcranial Doppler monitoring of MES in the ipsilateral middle cerebral artery. Maximally enhanced intensities on the intraplaque and lumen time intensity curves, respectively, were obtained from contrast-enhanced ultrasonography data, and the ratio of the maximal intensity (EIp) of the intraplaque curve to that (EIl) of the lumen curve was calculated. The GSM value of the plaque was also measured. RESULTS: The area under the receiver operating characteristic curve to discriminate between the presence and absence of MES during exposure of the carotid arteries was significantly greater for EIp/EIl than for GSM (p = 0.0108). Multivariate statistical analysis demonstrated that only EIp/EIl was significantly associated with the development of MES during exposure of the carotid arteries (p = 0.0002). CONCLUSIONS: Preoperative contrast enhanced ultrasound findings of the cervical carotid arteries are associated with development of MES on transcranial Doppler during exposure of the arteries in CEA, and the predictive accuracy of contrast-enhanced ultrasound is greater than that of GSM. PMID- 28363133 TI - The use of step aerobics and the stability ball to improve balance and quality of life in community-dwelling older adults - a randomized exploratory study. AB - OBJECTIVE: To explore the use of step aerobics (SA) and the stability ball (SB) as tools for balance improvement in community-dwelling older adults. METHOD: Forty-two women (age: 72.2+/-5.8 years) who attended a community day center volunteered to participate in the study. Following the first assessment session, 28 women were assigned randomly to one of two experimental groups (the use of either SA or SB). The other 14 participants, who were engaged in a ceramic class, served as the control group. The study design was based on four assessment sessions and eight weeks of intervention. Assessment included four balance tests: Timed Up and Go (TUG), One-Leg Stand, Functional Reach, and the Performance Oriented Assessment of Mobility (POMA). Quality of life was assessed by the use of the Short Form-36 Health Survey questionnaire. RESULTS: The TUG and POMA intervention improved significantly (d=.83 and d=.95, respectively) following the SA. In addition, general health perception following both the SA and SB interventions improved significantly relative to the control condition (d=.62 and d=.22, respectively). DISCUSSION: The findings of this study may imply that trainers should consider the inclusion of SA and SB as components of physical activity programs for seniors, aimed at improving balance ability and quality of life. PMID- 28363134 TI - Dissociable effects of age and testosterone on adolescent impatience. AB - The onset of adolescence is associated with an increase in transgressive behaviours-from juvenile delinquency to substance use and unprotected sex-that are often attributed to increased impulsiveness. In the past, this increase was ascribed to "raging hormones"; more recently, to an imbalance in the maturation of different brain regions. However, it remains unclear how these large-scale biological changes impact specific processes that result in impulsive decisions, namely, sensitivity to immediate rewards and general discounting of future options. To gain further insight into these questions, we used an intertemporal choice task to investigate the role of testosterone in impatient decision-making in boys at the developmental transition to adolescence (N=72, ages 11-14). Our results suggest that increased testosterone (but not age) is related to increased sensitivity to immediate rewards, whereas increased age (but not testosterone) is related to a reduction in general impatience. These results are discussed in the context of recent neurobiological models of adolescent development. PMID- 28363135 TI - Mesoporous silica nanoparticles incorporated hybrid monolithic stationary phase immobilized with pepsin for enantioseparation by capillary electrochromatography. AB - In this study, a novel mesoporous silica nanoparticles incorporated chiral hybrid monolithic stationary phase was developed. The stationary phase was firstly prepared by an in situ copolymerization of amino-modified mesoporous silica nanoparticles (NH2-MSN), glycidyl methacrylate (GMA), and ethylene dimethacrylate (EDMA) and then functionalized with pepsin as chiral selector. The incorporated mesoporous silica nanoparticles provided additional interactions sites, and in turn yielded different enantioselectivity thus enhancing the overall separation. The column was successfully employed for enantioseparation of fifteen basic chiral drugs in capillary electrochromatography. Effects of nanoparticles percentage, pepsin concentration, the pH of running buffer and the applied voltage were investigated. All the analytes could be eluted in less than ten minutes and nine of them could achieve baseline separation. Satisfactory repeatabilities with relative standard deviations less than 4.2% were achieved through intraday, interday, column-to-column and batch-to-batch investigations. These results indicated that the simultaneous utilization of the unique properties of mesoporous silica nanoparticles and versatile features of monoliths could be a promising strategy for enantioseparation. PMID- 28363137 TI - Structures related to attachment and motility in the marine eugregarine Cephaloidophora cf. communis (Apicomplexa). AB - Gregarines represent a highly diversified group of ancestral apicomplexans, with various modes of locomotion and host-parasite interactions. The eugregarine parasite of the barnacle Balanus balanus, Cephaloidophora cf. communis, exhibits interesting organisation of its attachment apparatus along with unique motility modes. The pellicle covered gregarine is arranged into longitudinal epicytic folds. The epimerite is separated from the protomerite by a septum consisting of tubulin-rich filamentous structures and both are packed with microneme-like structures suggestive of their function in the production of adhesives important for attachment and secreted through the abundant epimerite pores. Detached trophozoites and gamonts are capable of gliding motility, enriched by jumping and rotational movements with rapid changes in gliding direction and cell flexions. Actin in its polymerised form (F-actin) is distributed throughout the entire gregarine, while myosin, detected in the cortical region of the cell, follows the pattern of the epicytic folds. Various motility modes exhibited by individuals of C. cf. communis, together with significant changes in their cell shape during locomotion, are not concordant with the gliding mechanisms generally described in apicomplexan zoites and indicate that additional structures must be involved (e.g. two 12-nm filaments; the specific dentate appearance of internal lamina inside the epicytic folds). PMID- 28363136 TI - Urinary metabonomics study of the hepatoprotective effects of total alkaloids from Corydalis saxicola Bunting on carbon tetrachloride-induced chronic hepatotoxicity in rats using 1H NMR analysis. AB - Chronic liver injury has been shown to cause liver fibrosis due to the sustained pathophysiological wound healing response of the liver, and eventually progresses to cirrhosis. The total alkaloids of Corydalis saxicola Bunting (TACS), a collection of important bioactive ingredients derived from the traditional Chinese folk medicine Corydalis saxicola Bunting (CS), have been reported to have protective effects on the liver. However, the underlying molecular mechanisms need further elucidation. In this study, the urinary metabonomics and the biochemical changes in rats with carbon tetrachloride (CCl4)-induced chronic liver injury due to treatment TACS or administration of the positive control drug bifendate were studied via proton nuclear magnetic resonance (1H NMR) analysis. Partial least squares-discriminate analysis (PLS-DA) suggested that metabolic perturbation caused by CCl4 damage was recovered with TACS and bifendate treatment. A total of seven metabolites including 2-oxoglutarate, citrate, dimethylamine, taurine, phenylacetylglycine, creatinine and hippurate were considered as potential biomarkers involved in the development of CCl4-induced chronic liver injury. According to pathway analysis using identified metabolites and correlation network construction, the tricarboxylic acid (TCA) cycle, gut microbiota metabolism and taurine and hypotaurine metabolism were recognized as the most affected metabolic pathways associated with CCl4 chronic hepatotoxicity. Notably, the changes in 2-oxoglutarate, citrate, taurine and hippurate during the process of CCl4-induced chronic liver injury were significantly restored by TACS treatment, which suggested that TACS synergistically mediated the regulation of multiple metabolic pathways including the TCA cycle, gut microbiota metabolism and taurine and hypotaurine metabolism. This study could bring valuable insight to evaluating the efficacy of TACS intervention therapy, help deepen the understanding of the hepatoprotective mechanisms of TACS and enable optimal diagnosis of chronic liver injury. PMID- 28363138 TI - Origin and diversity of testate amoebae shell composition: Example of Bullinularia indica living in Sphagnum capillifolium. AB - Testate amoebae are free-living shelled protists that build a wide range of shells with various sizes, shapes, and compositions. Recent studies showed that xenosomic testate amoebae shells could be indicators of atmospheric particulate matter (PM) deposition. However, no study has yet been conducted to assess the intra-specific mineral, organic, and biologic grain diversity of a single xenosomic species in a natural undisturbed environment. This study aims at providing new information about grain selection to develop the potential use of xenosomic testate amoebae shells as bioindicators of the multiple-origin mineral/organic diversity of their proximal environment. To fulfil these objectives, we analysed the shell content of 38 Bullinularia indica individuals, a single xenosomic testate amoeba species living in Sphagnum capillifolium, by scanning electron microscope (SEM) coupled with X-ray spectroscopy. The shells exhibited high diversities of mineral, organic, and biomineral grains, which confirms their capability to recycle xenosomes. Mineral grain diversity and size of B. indica matched those of the atmospheric natural mineral PM deposited in the peatbog. Calculation of grain size sorting revealed a discrete selection of grains agglutinated by B. indica. These results are a first step towards understanding the mechanisms of particle selection by xenosomic testate amoebae in natural conditions. PMID- 28363139 TI - Ophryocystis anatoliensis sp. nov., a new neogregarine pathogen of the chrysomelid beetle Chrysomela populi. AB - Chrysomela populi (Coleoptera: Chrysomelidae) is the most abundant and most important pest species that causes damage to poplar trees. Members of the family Chrysomelidae are frequently infected by protist pathogens but no neogregarine has been reported to date at the species level. In the present study we identify a new neogregarine pathogen from the chrysomelid C. populi. The infection was observed in the Malpighian tubules of adult beetles. A reddening of the Malpighian tubules was the most distinctive symptom of the infection. Single fusiform oocysts (9.8*4.7MUm) were formed within a gamontocyst. The polar plugs were very thin, varying from 380 to 525nm in thickness. The oocyst wall was smooth and also quite thin (90-120nm). Morphological and ultrastructural characteristics of the pathogen indicate that the described neogregarine in C. populi is clearly different from known Ophryocystis species which infect coleopterans. Therefore, the neogregarine pathogen was determined to be a newly discovered species and named Ophryocystis anatoliensis sp. nov. PMID- 28363140 TI - Knowledge training and the change of fertilizer use intensity: Evidence from wheat farmers in China. AB - High fertilizer use intensity is a serious issue throughout China, with adverse environmental and economic impacts. The lack of knowledge of Chinese farmers has been found to be the primary constraint. Using a propensity score matching (PSM) method to create a credible counterfactual analysis, this study examines the causal effects of two kinds of knowledge training approaches, traditional one time training and in-field guidance, on the change of fertilizer use intensity of wheat farmers in China. The estimated results provide evidence that the traditional one-time training approach has a small effect on fertilizer use intensity reduction (only a 4% average), while the in-field guidance has a larger effect on fertilizer use intensity reduction (a 17% average). Moreover, we also found knowledge training has heterogeneous treatment effects. The reduction in fertilizer use intensity is larger for the farmers who are male and middle aged, have acquired a middle level of education, receive a lower share of off-farm income, collect a lower income, and operate a larger farm. PMID- 28363142 TI - Local co-administration of gene-silencing RNA and drugs in cancer therapy: State of-the art and therapeutic potential. AB - Gene-silencing miRNA and siRNA are emerging as attractive therapeutics with potential to suppress any genes, which could be especially useful in combination cancer therapy to overcome multidrug resistant (MDR) cancer. Nanomedicine aims to advance cancer treatment through functional nanocarriers that delivers one or more therapeutics to cancer tissue and cells with minimal off-target effects and suitable release kinetics and dosages. Although much effort has gone into developing circulating nanocarriers with targeting functionality for systemic administration, another alternative and straightforward approach is to utilize formulations to be administered directly to the site of action, such as pulmonary and intratumoral delivery. The combination of gene-silencing RNA with drugs in nanocarriers for localized delivery is emerging with promising results. In this review, the current progress and strategies for local co-administration of RNA and drug for synergistic effects and future potential in cancer treatment are presented and discussed. Key advances in RNA-drug anticancer synergy and localized delivery systems were combined with a review of the available literature on local co-administration of RNA and drug for cancer treatment. It is concluded that advanced delivery systems for local administration of gene silencing RNA and drug hold potential in treatment of cancer, depending on indication. In particular, there are promising developments using pulmonary delivery and intratumoral delivery in murine models, but further research should be conducted on other local administration strategies, designs that achieve effective intracellular delivery and maximize synergy and feasibility for clinical use. PMID- 28363141 TI - Antimony and sleep-related disorders: NHANES 2005-2008. AB - BACKGROUND: Antimony is used as a flame-retardant in textiles and plastics, in semiconductors, pewter, and as pigments in paints, lacquers, glass and pottery. Subacute or chronic antimony poisoning has been reported to cause sleeplessness. The prevalence of short sleep duration (<7h/night) has been reported to be 37.1% in the general US population, and obstructive sleep apnea (OSA) affects 12-28 million US adults. Insufficient sleep and OSA have been linked to the development of several chronic conditions including diabetes, cardiovascular disease, obesity and depression, conditions that pose serious public health threats. OBJECTIVE: To investigate whether there is an association between antimony exposure and sleep related disorders in the US adult population using the National Health and Nutrition Examination Survey (NHANES) 2005-2008. METHODS: We performed multivariate logistic regression to analyze the association of urinary antimony with several sleep disorders, including insufficient sleep and OSA, in adult (ages 20 years and older) participants of NHANES 2005-2008 (n=2654). RESULT: We found that participants with higher urinary antimony levels had higher odds to experience insufficient sleep (<=6h/night) (OR 1.73; 95%CI; 1.04, 2.91) as well as higher odds to have increased sleep onset latency (>30min/night). Furthermore, we found that higher urinary antimony levels in participants were associated with OSA (OR 1.57; 95%CI; 1.05, 2.34), sleep problems, and day-time sleepiness. CONCLUSION: In this study, we found that urinary antimony was associated with higher odds to have insufficient sleep and OSA. Because of the public health implications of sleep disorders, further studies, especially a prospective cohort study, are warranted to evaluate the association between antimony exposure and sleep-related disorders. PMID- 28363144 TI - Influence of the electronic structures on the heterogeneous photoelectrocatalytic performance of Ti/RuxSn1-xO2 electrodes. AB - DSA-type Ti/RuxSn1-xO2 electrodes were prepared by thermal decomposition method as photoelectrocatalysts (PECs) and extensively characterized by various sophisticated techniques. First-principles calculations was employed to study the effects of Ru content on the electronic structures of the RuxSn1-xO2 coatings. The photoelectric-synergistic catalytic activity of the Ti/RuxSn1-xO2 electrodes was evaluated for the degradation of methyl orange (MO) in aqueous solution. The results show that the RuO2-SnO2 solid solution could be formed. The band gaps of the RuxSn1-xO2 coatings gradually decreased and eventually turned into metallic conductivity with the increase of ruthenium content. As a PEC electrode, reducing band gap is helpful to improve electronic conductivity and the electrocatalytic activity, but not always advantageous to increase the photocatalytic activity. Because too narrow band gap will sacrifice the photogenerated charge carriers and thus reduce photocatalytic activity of the electrode. In our experiments, the rate constant of Ti/Ru0.05Sn0.95O2 electrode increased with increasing Ru content and exhibited the maximum rate for 5% Ru loading. The stability test showed the photoelectrocatalytic activity of the Ti/Ru0.05Sn0.95O2 electrode almost had no attenuation after 100h photoelectrolysis, revealing that this electrode has good long-term stability. PMID- 28363143 TI - Nanotoxicity of graphene oxide: Assessing the influence of oxidation debris in the presence of humic acid. AB - This study sought to evaluate the toxicological effects of graphene oxide (GO) through tests with Danio rerio (zebrafish) embryos, considering the influence of the base washing treatment and the interaction with natural organic matter (i.e., humic acid, HA). A commercial sample of GO was refluxed with NaOH to remove oxidation debris (OD) byproducts, which resulted in a base washed GO sample (bw GO). This process decreased the total oxygenated groups in bw-GO and its stability in water compared to GO. When tested in the presence of HA, both GO and bw-GO stabilities were enhanced in water. Although the embryo exposure showed no acute toxicity or malformation, the larvae exposed to GO showed a reduction in their overall length and acetylcholinesterase activity. In the presence of HA, GO also inhibited acid phosphatase activity. Our findings indicate a mitigation of material toxicity after OD removal. The difference in the biological effects may be related to the materials' bioavailability and biophysicochemical interactions. This study reports for the first time the critical influence of OD on the GO material biological reactivity and HA interaction, providing new data for nanomaterial environmental risk assessment and sustainable nanotechnology. PMID- 28363145 TI - Removal of sulfamethoxazole by electrochemically activated sulfate: Implications of chloride addition. AB - Electrochemical oxidation is considered to be an attractive alternative to chemical oxidation for the treatment of polluted water. Given the of ability of boron-doped diamond (BDD) electrodes to generate hydroxyl radicals (OH), they are often selected for the degradation of persistent organic contaminants. Recently, BDD anodes have been demonstrated to form strong oxidants, sulfate radicals (SO4 ), directly from sulfate ions. In this study, electrochemical activation of sulfate to SO4- at BDD anodes enhanced the removal of an antibiotic sulfamethoxazole (SMX). The rate of SMX oxidation was 6 times higher in sulfate anolyte compared to inert nitrate anolyte. Addition of chloride accelerated the disappearance of SMX in both anolytes due to electrochlorination. Yet, mineralization efficiency was decreased, particularly in Na2SO4 anolyte due to the scavenging of SO4- by Cl-. Electrogenerated SO4- yielded nitroso- and nitro derivatives, which were not observed in the absence of sulfate. The peak intensities of chlorinated TPs were three orders of magnitude lower in Na2SO4 than in NaNO3 anolyte, suggesting that addition of sulfate may lower the formation of chlorinated organics. However, attention should be paid to the formation of inorganic byproducts, as the formation rates of toxic chlorate and in particular perchlorate were higher in Na2SO4 anolyte. PMID- 28363146 TI - A simple post-synthesis conversion approach to Zn(OH)F and the effects of fluorine and hydroxyl on the photodegradation properties of dye wastewater. AB - In this work, Zn(OH)F is prepared by an initiative, simple post-synthesis method, in which the molar ratio of F/Zn (RF) was varied to investigate the effect of the NH4F amounts added on the samples. Further, we have mainly investigated their energy bands and photochemical properties. Under UV light irradiation (lambdaL420nm), the samples (RF=0,1,2) show the high degradation activities of methylene blue (MB) dye, namely, 80% of MB can be degraded after 8min. It is found that the hydroxyl and fluorine have greatly down shifted the conduction band (CB, 0.99eV) and valence band (VB, 4.17eV) of Zn(OH)F, compared with ZnO (CB=-0.31eV, VB=2.89eV), but with the nearly same band gap. For the degradation of MB dye, the main oxidative species are holes and hydroxyl radicals for ZnO and Zn(OH)F, respectively. This study suggests that this simple post-synthesis fluorination approach could be extended to develop the other photocatalysts; moreover, we can facilely tune the band structure and photocatalytic activity by introducing or removing hydroxyl and fluorine, which could benefit to develop new photocatalysts. PMID- 28363147 TI - Renewable energy production by photoelectrochemical oxidation of organic wastes using WO3 photoanodes. AB - The present work has studied renewable hydrogen production by photoelectrocatalytic degradation of model organic substances representing biomass derived organic wastes. Its purpose was to show that renewable energy can be produced by consuming wastes. The study has been carried out by employing nanoparticulate WO3 photoanodes in the presence of ethanol, glycerol or sorbitol, i.e. three substances which are among typical biomass products. In these substances, the molecular weight and the number of hydroxyl groups increases from ethanol to sorbitol. The photocurrent produced by the cell was the highest in the presence of ethanol, smaller in the case of glycerol and further decreased in the presence of sorbitol. The photocurrent was roughly the double of that produced in the absence of an organic additive thus demonstrating current doubling phenomena. Hydrogen was produced only under illumination and was monitored at two forward bias, 0.8 and 1.6V vs Ag/AgCl. Hydrogen production rates followed the same order as the photocurrent thus indicating that hydrogen production by reduction of protons mainly depends on the current flowing through the external circuit connecting photoanode with cathode. The maximum solar-to-hydrogen efficiency reached by the present system was 2.35%. PMID- 28363148 TI - Beyond the tendon: Experiences and perceptions of people with persistent Achilles tendinopathy. AB - BACKGROUND: Achilles tendinopathy (AT) is associated with persistent pain leading to a significant physical and psychological burden. Psychosocial factors are considered to be important mediators following exercise interventions. Despite the recognition of the importance of psychosocial variables in persistent MSK disorders, there is a distinct lack of qualitative research investigating psychosocial factors in AT. PURPOSE: To qualitatively explore the perceptions and experiences of people with AT prior to an intervention study. METHODOLOGY: A qualitative, interpretive description design was performed using semi-structured telephone interviews. The questioning route covered history of AT, perceived cause of AT, effect of AT pain, experience in managing AT, and perspective on prognosis of AT pain. Interviews were transcribed verbatim. The study has been reported in accordance with the consolidated criteria for reporting qualitative research (COREQ) checklist. To facilitate the rigor of methodology and the transparency of the research process an audit trail was created. RESULTS: Eight participant's (Five male and three female). Four main themes were identified in the data: (i) pain as a feature of everyday life; (ii) experience with the management process; (iii) identifying with and self-managing AT, and (iv) looking to the future. CONCLUSIONS: This study suggests that persistent AT is associated with a significant psychosocial impact, particularly in terms of participation in daily life and valued activities. Better understanding the experiences and personal impacts of AT may enhance management of this persistent disorder, and facilitate individuals with AT complying with evidence-based approaches including exercise and pain reconceptualization. PMID- 28363149 TI - Chemical principles additive model aligns low consensus DNA targets of p53 tumor suppressor protein. AB - Computational prediction of the interaction between protein transcription factors and their cognate DNA binding sites in genomic promoters constitutes a formidable challenge in two situations: when the number of discriminatory interactions is small compared to the length of the binding site, and when DNA binding sites possess a poorly conserved consensus binding motif. The transcription factor p53 tumor suppressor protein and its target DNA exhibit both of these issues. From crystal structure analysis, only three discriminatory amino acid side chains contact the DNA for a binding site spanning ten base pairs. Furthermore, our analysis of a dataset of genome wide fragments binding to p53 revealed many sequences lacking the expected consensus. The low information content leads to an overestimation of binding sites, and the lack of conservation equates to a computational alignment problem. Within a fragment of DNA known to bind to p53, computationally locating the position of the site equates to aligning the DNA with the binding interface. From a molecular perspective, that alignment implies a specification of which DNA bases are interacting with which amino acid side chains, and aligning many sequences to the same protein interface concomitantly produces a multiple sequence alignment. From this vantage, we propose to cast prediction of p53 binding sites as an alignment to the protein binding surface with the novel approach of optimizing the alignment of DNA fragments to the p53 binding interface based on chemical principles. A scoring scheme based on this premise was successfully implemented to score a dataset of biological DNA fragments known to contain p53 binding sites. The results illuminate the mechanism of recognition for the protein-DNA system at the forefront of cancer research. These findings implicate that p53 may recognize its target binding sites via several different mechanisms which may include indirect readout. PMID- 28363150 TI - Osteophyte induced lung fibrosis prevalence and osteophyte qualities predicting disease. AB - OBJECTIVE: To determine the prevalence of osteophyte induced lung fibrosis (OIF) and its relationship to osteophyte size, location, and surrounding fat. METHODS: 94 CT scans of the chest were reviewed, size of the largest osteophyte and the presence of fibrosis were recorded. RESULTS: Presence of fibrosis was higher among patient with large (>10 mm) osteophytes compared to those with small (1 10mm) osteophytes. Age and presence of periosteophyte fat were significantly associated with presence of fibrosis. CONCLUSIONS: As the size of an osteophyte increases, there is a greater likelihood of lung fibrosis. Subpleural fat protects the lung from OIF. PMID- 28363151 TI - Irritability in ADHD: Associations with depression liability. AB - BACKGROUND: Irritability and the new DSM-5 diagnostic category of Disruptive Mood Dysregulation Disorder (DMDD) have been conceptualised as related to mood disorder. Irritability is common in Attention Deficit Hyperactivity Disorder (ADHD) but little is known about its association with depression risk in this group. This study aims to establish levels of irritability and prevalence of DMDD in a clinical sample of children with ADHD, and examine their association with anxiety, depression and family history of depression. METHODS: The sample consisted of 696 children (mean age 10.9 years) with a diagnosis of ADHD, recruited from UK child psychiatry and paediatric clinics. Parents completed the Child and Adolescent Psychiatric Assessment, a semi-structured diagnostic interview, about their child. This was used to establish prevalence of DMDD, anxiety disorder and depressive disorder, as well as obtain symptom scores for irritability, anxiety and depression. Questionnaires assessed current parental depression, and family history of depression. RESULT: Irritability was common, with 91% endorsing at least one irritable symptom. 3-month DMDD prevalence was 31%. Children with higher levels of irritability or DMDD were more likely to have comorbid symptoms of anxiety, depression and a family history of depression. LIMITATIONS: Results are based on a clinical sample, so may not be generalizable to children with ADHD in the general population. CONCLUSIONS: Irritability and DMDD were common, and were associated with markers of depression liability. Longitudinal studies are needed to examine the association between irritability and depression in youth with ADHD as they get older. PMID- 28363152 TI - Placebo and nocebo reactions in randomized trials of pharmacological treatments for persistent depressive disorder. A meta-regression analysis. AB - BACKGROUND: We aimed to investigate placebo and nocebo reactions in randomized controlled trials (RCT) of pharmacological treatments for persistent depressive disorder (PDD). METHODS: We conducted a systematic electronic search and included RCTs investigating antidepressants for the treatment of PDD. Outcomes were the number of patients experiencing response and remission in placebo arms (=placebo reaction). Additional outcomes were the incidence of patients experiencing adverse events and related discontinuations in placebo arms (=nocebo reaction). A priori defined effect modifiers were analyzed using a series of meta-regression analyses. RESULTS: Twenty-three trials were included in the analyses. We found a pooled placebo response rate of 31% and a placebo remission rate of 22%. The pooled adverse event rate and related discontinuations were 57% and 4%, respectively. All placebo arm outcomes were positively associated with the corresponding medication arm outcomes. Placebo response rate was associated with a greater proportion of patients with early onset depression, a smaller chance to receive placebo and a larger sample size. The adverse event rate in placebo arms was associated with a greater proportion of patients with early onset depression, a smaller proportion of females and a more recent publication. CONCLUSIONS: Pooled placebo and nocebo reaction rates in PDD were comparable to those in episodic depression. The identified effect modifiers should be considered to assess unbiased effects in RCTs, to influence placebo and nocebo reactions in practice. LIMITATIONS: Limitations result from the methodology applied, the fact that we conducted only univariate analyses, and the number and quality of included trials. PMID- 28363153 TI - Structure activity study of carbonic anhydrase IX: Selective inhibition with ureido-substituted benzenesulfonamides. AB - Ureido-substituted benzenesulfonamides (USBs) show great promise as selective and potent inhibitors for human carbonic anhydrase hCA IX and XII, with one such compound (SLC-0111/U-F) currently in clinical trials (clinical trials.gov, NCT02215850). In this study, the crystal structures of both hCA II (off-target) and an hCA IX-mimic (target) in complex with selected USBs (U-CH3, U-F, and U NO2), at resolutions of 1.9 A or better, are presented, and demonstrate differences in the binding modes within the two isoforms. The presence of residue Phe 131 in hCA II causes steric hindrance (U-CH3, 1765 nM; U-F, 960 nM; U-NO2, 15 nM) whereas in hCA IX (U-CH3, 7 nM; U-F, 45 nM; U-NO2, 1 nM) and hCA XII (U-CH3, 6 nM; U-F, 4 nM; U-NO2, 6 nM), 131 is a Val and Ala, respectively, allows for more favorable binding. Our results provide insight into the mechanism of USB selective inhibition and useful information for structural design and drug development, including synthesis of hybrid USB compounds with improved physiochemical properties. PMID- 28363154 TI - Synthesis, stability and mechanistic studies of potent anticryptococcal hexapeptides. AB - The growing incidents of cryptococcosis in immuno-compromised patients have created a need for novel drug therapies capable of eradicating the disease. The peptide-based drug therapy offers many advantages over the traditional therapeutic agents, which has been exploited in the present study by synthesizing a series of hexapeptides that exhibits promising activity against a panel of Gram negative and Gram-positive bacteria and various pathogenic fungal strains; the most exemplary activity was observed against Cryptococcus neoformans. The peptides 3, 24, 32 and 36 displayed potent anticryptococcal activity (IC50 = 0.4 0.46 MUg/mL, MIC = 0.63-1.25 MUg/mL, MFC = 0.63-1.25 MUg/mL), and stability under proteolytic conditions. Besides this, several other peptides displayed promising inhibition of pathogenic bacteria. The prominent ones include peptides 18-20, and 26 that exhibited IC50 values ranged between 2.1 and 3.6 MUg/mL, MICs of 5-20 MUg/mL and MBCs of 10-20 MUg/mL against Staphylococcus aureus and methicillin resistant S. aureus. The detailed mechanistic study on selected peptides demonstrated absolute selectivity towards the bacterial membranes and fungal cells by causing perturbations in the cell membranes, confirmed by the scanning electron microscopy and transmission electron microscopy studies. PMID- 28363155 TI - Novel aryl piperazines for alleviation of 'andropause' associated prostatic disorders and depression. AB - A series of seventeen piperazine derivatives have been synthesized and biologically evaluated for the management of andropause-associated prostatic disorders and depression. Five compounds 16, 19, 20, 21 and 22 significantly inhibited proliferation of androgen-sensitive LNCaP prostatic cell line with EC50 values of 12.4 MUM, 15.6 MUM, 11.8 MUM, 10.4 MUM, 12.2 MUM respectively and decreased Ca2+ entry through adrenergic-receptor alpha1A blocking activity. Anti androgenic behaviour of compound 19 and 22 was evident by decreased luciferase activity. The high EC50 value in AR-negative cells PC3 and DU145 suggested that the cytotoxicity of compounds was due to AR down regulation. Compound 19 reduced the prostate weight of rats by 53.8%. Further, forced-swimming and tail suspension tests revealed antidepressant-like activity of compound 19, lacking effects on neuromuscular co-ordination. In silico ADMET predictions revealed that the compound 19 had good oral absorption, aqueous solubility, non-hepatotoxic and good affinity for plasma protein binding. Pharmacokinetic and tissue uptake of 19 at 10 mg/kg demonstrated an oral bioavailability of 35.4%. In silico docking studies predicted similar binding pattern of compound 19 on androgen receptor as hydroxyflutamide. Compound 19 appears to be a unique scaffold with promising activities against androgen associated prostatic disorders in males like prostate cancer and BPH and associated depression. PMID- 28363156 TI - F-actin reorganization upon de- and rehydration in the aeroterrestrial green alga Klebsormidium crenulatum. AB - Filamentous actin (F-actin) is a dynamic network involved in many cellular processes like cell division and cytoplasmic streaming. While many studies have addressed the involvement of F-actin in different cellular processes in cultured cells, little is known on the reactions to environmental stress scenarios, where this system might have essential regulatory functions. We investigated here the de- and rehydration kinetics of breakdown and reassembly of F-actin in the streptophyte green alga Klebsormidium crenulatum. Measurements of the chlorophyll fluorescence (effective quantum yield of photosystem II [DeltaF/Fm']) via pulse amplitude modulation were performed as a measure for dehydration induced shut down of physiological activity, which ceased after 141+/-15min at ~84% RH. We hypothesized that there is a link between this physiological parameter and the status of the F-actin system. Indeed, 20min of dehydration (DeltaF/Fm'=0) leads to a breakdown of the fine cortical F-actin network as visualized by Atto 488 phalloidin staining, and dot-like structures remained. Already 10min after rehydration a beginning reassembly of F-actin is observed, after 25min the F actin network appeared similar to untreated controls, indicating a full recovery. These results demonstrate the fast kinetics of F-actin dis- and reassembly likely contributing to cellular reorganization upon rehydration. PMID- 28363157 TI - Memory B cells: total recall. AB - Immunological memory is a cornerstone of adaptive immune responses in higher vertebrates. The remarkable ability to generate memory cells following Ag exposure, in the context of natural infection or immunization, provides long lived protection against infectious diseases, often for the hosts' lifetime. Indeed, the generation of memory B cells and long-lived plasma cells underpins the success of most vaccines. The concept of immunological memory is not new-it was first proposed nearly 2500 years ago. While our understanding of the complexities of humoral and cell-mediated memory continues to evolve, important aspects of this process remain unresolved. Here, we will provide an overview of recent advances in B-cell memory in mice and humans, and in health and disease. PMID- 28363158 TI - Evaluation of the separation and purification of 227Th from its decay progeny by anion exchange and extraction chromatography. AB - Thorium-227 is currently undergoing evaluation as a potential radionuclide for targeted cancer therapy, and as such a high chemical purity of the material is required. To establish a reliable procedure for radiochemical isolation of 227Th from the parent 227Ac and decay progeny, which includes the radiotherapeutic 223Ra, the performance of three different separation schemes based on ion exchange and extraction chromatography have been evaluated. The results suggest that both ion exchange and extraction chromatographic techniques can be successfully used for the separation of 227Th from its decay progeny, however extraction chromatographic resins demonstrate favourable performance in terms of Th recovery and purification from radionuclide impurities. PMID- 28363159 TI - Toolmarks made by lathe chuck jaws. AB - This paper presents a forensic method to evidentially tie a workpiece with a specific lathe. Examining using this method can prove or exclude a connection between the two. The importance of this method is mostly due to the growing trend among lawbreakers of manufacturing improvised firearm parts using machining processes. This method is based on comparing jaw impressions made by the chuck on a workpiece. PMID- 28363160 TI - Ion channelopathies associated genetic variants as the culprit for sudden unexplained death. AB - Forensic identification of sudden unexplained death (SUD) has always been a ticklish issue because it used to be defined as sudden death without a conclusive diagnosis after autopsy. However, benefiting from the developments in genome research, a growing body of evidence points to the importance of ion channelopathies associated genetic variants in the pathogenesis of SUD. Genetic diagnosis of the deceased is also a new trend in epidemiological studies, for it enables the undertaking for preventive approach in individuals with high risks. In this review, we briefly discuss the molecular structure of ion channels and the role of genetic variants in regulating their functions as well as the diverse mechanisms underlying the ion channelopathies at gene level. PMID- 28363161 TI - Family history of cancer and the risk of bladder cancer: A case-control study from Italy. AB - BACKGROUND: A family history of bladder cancer has been associated with the risk of bladder cancer, but quantification of the excess risk in different populations is still a relevant issue. Further, the role of a family history of other cancers on the risk of bladder cancer remains unclear. METHODS: We analyzed data from an Italian case-control study, including 690 bladder cancer cases and 665 hospital controls. Odds ratios (ORs) were estimated through unconditional logistic regression models, adjusted for sex, age, study center, year of interview and further for education, smoking and sibling's number. RESULTS: The OR for family history of bladder cancer was 2.13 (95% confidence intervals (95%CIs) 1.02-4.49) from the model with partial adjustment, and 1.99 (95%CI 0.91-4.32) after additional adjustment for smoking and siblings' number, based on 23 cases (3.3%) and 11 controls (1.7%) with a family history of bladder cancer. The fully adjusted OR was 3.77 when the relative was diagnosed at age below 65years. Smokers with a family history of bladder cancer had a four-fold increased risk compared to non-smokers without a family history. Bladder cancer risk was significantly increased among subjects with a family history of hemolymphopoietic cancers (OR=2.97, 95%CI 1.35-6.55). Family history of cancer at other sites showed no significant association with bladder cancer risk. CONCLUSION: This study confirms an approximately two-fold increased risk of bladder cancer for family history of bladder cancer, and indicates a possible familial clustering of bladder cancer with cancers of the hemolymphopoietic system. PMID- 28363162 TI - Non-invasive characterization of colorants by portable diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy and chemometrics. AB - During the last years the need for non-invasive and non-destructive analytical methods brought to the development and application of new instrumentation and analytical methods for the in-situ analysis of cultural heritage objects. In this work we present the application of a portable diffuse reflectance infrared Fourier transform (DRIFT) method for the non-invasive characterization of colorants prepared according to ancient recipes and using egg white and Gum Arabic as binders. Approximately 50 colorants were analyzed with the DRIFT spectroscopy: we were able to identify and discriminate the most used yellow (i.e. yellow ochres, Lead-tin Yellow, Orpiment, etc.), red (i.e. red ochres, Hematite) and blue (i.e. Lapis Lazuli, Azurite, indigo) colorants, creating a complete DRIFT spectral library. The Principal Component Analysis-Discriminant Analysis (PCA-DA) was then employed for the colorants classification according to the chemical/mineralogical composition. The DRIFT analysis was also performed on a gouache painting of the artist Sutherland" and the colorants used by the painter were identified directly in-situ and in a non-invasive manner. PMID- 28363163 TI - Catalase as a regulator of reactive sulfur metabolism; a new interpretation beyond hydrogen peroxide?. PMID- 28363164 TI - Effect of naturally acquired type-specific serum antibodies against human papillomavirus type 16 infection. AB - BACKGROUND: While vaccine-induced antibodies are known to confer protection against incident human papillomavirus (HPV) infection, there is inconsistent data regarding the protective effect of naturally acquired anti-HPV antibodies. OBJECTIVES: To estimate the protective effect of naturally acquired anti-HPV16 serum antibodies against incident anogenital infection with HPV16 in females aged 20-64 years and to assess whether antibodies influence the persistence/clearance of anogenital HPV16 infection. STUDY DESIGN: 4432 women attending the organized national cervical cancer screening program in Slovenia were initially enrolled. 2199 and 1848 women had valid HPV DNA results obtained using PCR-based assays and HPV antibody serotyping results obtained using pseudovirion-based serological assay, at baseline and at three-year follow-up, respectively. RESULTS: Baseline HPV16 seroprevalence was 2.4-fold higher among HPV16 DNA-positive women (55.7% vs. 23.2%; p<0.01). Baseline HPV16 DNA-positive/seronegative women frequently acquired anti-HPV16 antibodies during follow-up (OR=8.2; 95% CI: 3.8-17.8). Baseline anti-HPV16 antibodies persisted at follow-up, irrespective of baseline HPV16 DNA status (OR=40.6; 95% CI: 30.3-54.5). Baseline HPV16 DNA negative/seropositive women were less likely to acquire HPV16 infection at follow up (unadjusted OR=0.2; 0.1-0.9). However, the age-adjusted association was non significant (adjusted OR=0.3; 0.1-1.2). The tendency for protective effect was stronger among women older than 25 years (OR=0.2; 0.03-1.8). Baseline anti-HPV16 antibodies were not associated with persistence/clearance of HPV16 infection at follow-up (OR=0.8; 0.3-1.9). CONCLUSIONS: Naturally acquired anti-HPV16 serum antibodies appeared to protect against anogenital HPV16 infection, but this association was at least partially confounded by age. Baseline anti-HPV16 serum antibodies did not influence persistence/clearance of HPV16 infection at follow up. PMID- 28363165 TI - Hepatoprotective activity of Rhus oxyacantha root cortex extract against DDT induced liver injury in rats. AB - The present investigation aimed to study the antioxidant activity and hepatoprotective effects of ethyl acetate extract of R. oxyacantha root cortex (RE) against DDT-induced liver injury in male rats. The RE exhibited high total phenolic, flavonoid and condensed tannins contents. The antioxidant activity in vitro systems showed a significant potent free radical scavenging activity of the extract. The HPLC finger print of R. oxyacantha active extract showed the presence of five phenolic compounds with higher amounts of catechol and gallic acid. The in vivo results showed that a single intraperitoneal administration of DDT enhanced levels of hepatic markers (ALT, AST and LDH) in serum of experimental animals. It also increased the oxidative stress markers resulting in increased levels of the lipid peroxidation with a significant induction of SOD and GPx, metallothioneins (MTs) and a concomitant decrease of non protein thiols (NPSH) in liver. However, pretreatment of rats with RE at a dose of 150 and 300mg/kg body weight significantly lowered serum transaminases and LDH in treated rats. A significant reduction in hepatic thiobarbituric reactive substances and a decrease in antioxidant enzymes activities and hepatic MTs levels by treatment with plant extract against DDT, were observed. These biochemical changes were consistent with histopathological observations, suggesting marked hepatoprotective effect of RE with the two doses used. These results strongly suggest that treatment with ethyl acetate extract normalizes various biochemical parameters and protects the liver against DDT-induced oxidative damage in rats and thus help in evaluation of traditional claim on this plant. PMID- 28363166 TI - Insight into anti-diabetic effect of low dose of stevioside. AB - Diabetes mellitus is a chronic disease characterized by abnormal carbohydrate, lipid and protein metabolism due to a lack of insulin or reduced target cell sensitivity to insulin. Stevia rebaudiana is an important source of biochemically active substances with proven anti-diabetic effect. The aim of this study was to determine anti-diabetic effects of the low dose of stevioside in NMRI Haan mice. Aqueous stevioside solution (20mg/kg body weight) was administered by oral route of administration. Anti-diabetic effect of stevioside was estimated by oral glucose tolerance test, adrenaline test after a 10day stevioside treatment, and alloxan induced hyperglycaemia in mice (two experimental groups, 10day stevioside treatment before and after alloxan administration). Aqueous stevioside solution prevented significant increase in glycaemia in oral glucose tolerance test (9.22+/-1.13 to 9.85+/-1.32mmol/l, P<0.05), and not in adrenaline test. Significant difference in glycaemia was detected in mice pre-treated with saline and stevioside in alloxan induced hyperglycaemia (saline 23.32+/-2.14, stevioside 14.70+/-4.95mmol/l, P<0.05). In mice pre-treated with stevioside, smallest beta cells loss was found compared to other alloxan treated groups. Preserved normal cytoarchitectonic arrangement in islets was detected. Based on the given results we presume there exist a potential therapeutic use of low dose stevioside in diabetes. PMID- 28363168 TI - Gut microbiota and renal transplant outcome. AB - Gaining long-term graft function and patient survival remain a critical challenge following kidney transplantation. Genetic and environmental factors do not completely account for the individual's graft outcome. Recently, it is reported that gut microbial community (microbiota) is associated with complications in kidney allograft recipients, as well. Commensal microbiota plays a significant role in the immunomodulation of transplant recipient responses. Different factors can disrupt the reciprocal interaction between microbiota and the host immune responses and lead to infection and rejection complications in the organ recipient. In this review, we address the relation between microbiota and immune system along with their possible roles in renal graft outcome. We next highlight the beneficial effects of probiotics on the management of kidney diseases and solid organ transplantation. Finally, we reflect on the potential impacts of probiotics on host physiology. Hopefully, a deeper understanding of the function and composition of microbiota can help clinics develop strategies to restore the normal microbiota and facilitate the clinical management of grafts in the forthcoming future. PMID- 28363167 TI - Emodin targets mitochondrial cyclophilin D to induce apoptosis in HepG2 cells. AB - Emodin has demonstrated potent anticancer activity in human hepatocarcinoma cells and animal models, however, the cellular targets of emodin have not been fully defined. Here we report that emodin induces the dysfunction of mitochondria and the apoptosis in HepG2 cells through an enrichment in mitochondria. Specifically, A mitochondrial matrix protein (cyclophilin D, CyPD) is involved in emodin induced apoptosis, and the inhibitor of CyPD (cyclosporin A) could almost completely suppressing the apoptosis; Moreover, as the expression of CyPD could be effectively inhibited by antioxidant N-acetyl-l-cysteine and epidermal growth factor (the activator of ERK), reactive oxygen species and ERK might be involved in the relevant role of CyPD. A further molecule-docking discloses the existence of three hydrogen-bonds in CyPD-emodin complex. Thus, target localization and CyPD in mitochondria provides an insight into the action of emodin in the treatment of liver cancer. PMID- 28363169 TI - Glucocorticoid-induced leucine zipper may play an important role in icariin by suppressing osteogenesis inhibition induced by glucocorticoids in osteoblasts. AB - BACKGROUND AND PURPOSE: Icariin is a potent stimulator of osteogenic differentiation; however, the mechanism underlying its osteogenic effect remains unclear. The osteogenic effect of icariin is related to the upstream glucocorticoid-induced leucine zipper (GILZ) signaling pathway, and antagonism with dexamethasone-induced osteoblast inhibition was noted. METHODS: MC3T3-E1 cells were cultured in induced medium treated with icariin with or without dexamethasone. After short interfering RNA (siRNA) were used to silence GILZ expression, the degree of mineralization, proliferation, and GILZ expression as well as the levels of osteogenic (OPG, RANKL, ALP, OC and RUNX2) markers were tested. RESULTS: Dexamethasone inhibited, while icariin increased, osteogenic activity, as indicated by ALP activity and calcium nodules. Meanwhile, dexamethasone dose-dependently (10-6M-10-4M) increased GILZ and RANKL expression and reduced ALP, OPG and OC, but the pattern of mRNA expression was reversed when icariin was added. Furthermore, GILZ (dexamethasone-induced) inhibition caused by icariin or moderately silenced by GILZ siRNA abolished the osteogenesis inhibition effect of dexamethasone, as indicated by the changes in the GILZ, ALP, OPG and RANKL expression levels; ALP activity; and calcium nodule. CONCLUSIONS: These results indicate that the GILZ-mediated osteogenic signal pathway is involved in the osteogenic effect induced by icariin. PMID- 28363170 TI - Anti-coagulative and gastrointestinal motility regulative activities of Fructus Aurantii Immaturus and its effective fractions. AB - OBJECTIVE: Fructus Aurantii Immaturus (FAI) has been used in the treatment of gastrointestinal disorders (GIDs) in traditional Chinese medicine (TCM) for thousands of years, which also has been found to have effects on cardiovascular diseases (CVDs) in recent years. The current study aimed at investigating the anti-coagulative and gastrointestinal motility regulative activities of different fractions isolated from FAI, which may have both effects on gastrointestinal and cardiovascular systems, in the manners of network pharmacology analysis and experiments in vivo and in vitro. METHODS: We obtained water decoction, volatile oils, alkaloids and flavonoids from FAI, which were identified by gas chromatography-mass spectrometry (GC-MS) and high performance liquid chromatography (HPLC). Network pharmacological analysis was used to explore the relationship between the various types of chemical constituents, gene target and biological pathways of FAI. Then, the effective fractions in terms of anti coagulative and gastrointestinal motility regulative activities were investigated by the experiment of rabbit intestinal smooth muscles contraction, mice small intestine propulsion rate and blood-clotting time, and verified by the blood stasis model. RESULTS: From the Network pharmacological analysis, the flavonoids were predicted to be the main active ingredients on gastrointestinal and cardiovascular systems. Experimental results also showed that flavonoids could significantly increase the small intestine propulsion rate and extend the blood clotting time of mice. The Flavonoids could alleviate the increased fractional shortening (FS), left ventricular outflow, hematocrit and fibrinogen, and ameliorate the pathological changes of myocardial tissues caused by blood stasis. CONCLUSION: These findings indicated that flavonoids in FAI might be the main effective fractions on gastrointestinal motility and anti-coagulation. PMID- 28363171 TI - Severe soft tissue injuries of the upper extremity in motor vehicle crashes involving partial ejection: the protective role of side curtain airbags. AB - INTRODUCTION: Partial ejection (PE) of the upper extremity (UE) can occur in a motor vehicle crash (MVC) resulting in complex and severe soft tissue injuries (SSTI). This study evaluated the relationship between partial ejection and UE injuries, notably SSTIs, in MVCs focusing on crash types and characteristics, and further examined the role of side curtain airbags (SCABs) in the prevention of partial ejection and reducing SSTI of the UE. METHODS: Weighted data was analyzed from the National Automotive Sampling System Crashworthiness Data System (NASS CDS) from 1993 to 2012. Logistic regression models were used to assess the relationship of PE with SSTI of the UE and the effect of SCABs in both nearside impacts and rollover collisions. Crash Injury Research and Engineering Network (CIREN) case studies illustrated PE involving SSTI of the UE, and long term treatment. RESULTS: Rollover and nearside impact collisions had the highest percentages of partial ejection, with over half occurring in rollover collisions. Annually over 800 SSTIs of the UE occurred in all MVCs. For nearside lateral force impacts, a multivariable analysis adjusting for belt use and delta V showed a 15 times (OR 15.35, 95% CI 4.30, 54.79) greater odds of PE for occupants without SCABs compared to those with a SCAB deployment. No occupants (0 of 51,000) sustained a SSTI of the UE when a SCAB deployed in nearside impacts, compared to 0.01% (114 of 430,000) when SCABs were unavailable or did not deploy. In rollover collisions, a multivariable analysis adjusted for number of quarter turns and belt use showed 3 times the odds (OR 3.02, 95% CI 1.22, 7.47) of PE for occupants without SCABs compared to those with a SCAB deployment. Just 0.17% (32 of 19,000) of the occupants sustained a SSTI of the UE in rollovers with a SCAB deployment, compared to 0.53% (2294 of 431,000) of the occupants when SCABs were unavailable or did not deploy. CIREN case studies illustrated the injury causation of SSTI of the UE due to partial ejection, and the long term treatment and medical costs associated with a SSTI to the UE. CONCLUSIONS: The majority of severe soft tissue injuries (SSTI) of the upper extremity (UE) involved partial ejection out the nearside window of outboard seated occupants in nearside impacts and rollover collisions. Real world case studies showed that SSTIs of the upper extremity require extensive treatment, extended hospitalization and are costly. Occupants without a side curtain airbag (SCAB) deployment had an increase in the odds of partial ejection. SCAB deployments provided protection against partial ejection and prevented SSTIs of the UE, with none occurring in nearside impacts, and a small percentage and reduction occurring in rollover collisions compared to those where SCABs were unavailable or did not deploy. PMID- 28363172 TI - Response of phenolic metabolism to cadmium and phenanthrene and its influence on pollutant translocations in the mangrove plant Aegiceras corniculatum (L.) Blanco (Ac). AB - Polyphenolic compounds are abundant in mangrove plants, playing a pivotal role in the detoxification of pollutants extruded from surrounding environments into plant tissues. The present study aimed to examine the variations of phenolic compounds, namely total polyphenolics, soluble tannins, condensed tannins and lignin, in the mangrove plant Aegiceras corniculatum (L.) due to the presence of exogenous cadmium and phenanthrene and to explore the influence of phenolic metabolism on biological translocation of these pollutants from roots to leaves. After a 6-week exposure to cadmium and phenanthrene, significant accumulations of both pollutants were observed. All determined phenolic compounds in both leaves and roots at high dosage levels were enhanced compared to the uncontaminated plant. Elevations of polyphenols in both treatments are possibly a result of stimulation in the activity of phenylalanine ammonia-lyase (PAL) and the enrichment of soluble sugar. Additionally, a significantly positive dosage relationship between polyphenolic metabolism intensity and phenanthrene contamination levels was found, while the trend observed in cadmium treatment was weak since cadmium at high levels inhibited phenolic production. The enrichment of polyphenols led to a decline in the biological translocation of these pollutants from roots to leaves. The immobilization of pollutants in the plant roots is possibly linked to the adsorption potential of polyphenols. These results will improve the understanding of the tolerance of mangrove plants to exogenous pollutants and will guide the selection of plants in phytoremediation because of the variability of polyphenol concentrations among species. PMID- 28363173 TI - Soil Cd, Cr, Cu, Ni, Pb and Zn sorption and retention models using SVM: Variable selection and competitive model. AB - The aim of this study was to model the sorption and retention of Cd, Cu, Ni, Pb and Zn in soils. To that extent, the sorption and retention of these metals were studied and the soil characterization was performed separately. Multiple stepwise regression was used to produce multivariate models with linear techniques and with support vector machines, all of which included 15 explanatory variables characterizing soils. When the R-squared values are represented, two different groups are noticed. Cr, Cu and Pb sorption and retention show a higher R-squared; the most explanatory variables being humified organic matter, Al oxides and, in some cases, cation-exchange capacity (CEC). The other group of metals (Cd, Ni and Zn) shows a lower R-squared, and clays are the most explanatory variables, including a percentage of vermiculite and slime. In some cases, quartz, plagioclase or hematite percentages also show some explanatory capacity. Support Vector Machine (SVM) regression shows that the different models are not as regular as in multiple regression in terms of number of variables, the regression for nickel adsorption being the one with the highest number of variables in its optimal model. On the other hand, there are cases where the most explanatory variables are the same for two metals, as it happens with Cd and Cr adsorption. A similar adsorption mechanism is thus postulated. These patterns of the introduction of variables in the model allow us to create explainability sequences. Those which are the most similar to the selectivity sequences obtained by Covelo (2005) are Mn oxides in multiple regression and change capacity in SVM. Among all the variables, the only one that is explanatory for all the metals after applying the maximum parsimony principle is the percentage of sand in the retention process. In the competitive model arising from the aforementioned sequences, the most intense competitiveness for the adsorption and retention of different metals appears between Cr and Cd, Cu and Zn in multiple regression; and between Cr and Cd in SVM regression. PMID- 28363174 TI - Distinction, quantification and mapping of potential and realized supply-demand of flow-dependent ecosystem services. AB - This study addresses and conceptualizes the possible dependence of ecosystem services on prevailing air and/or water flow processes and conditions, and particularly on the trajectories and associated spatial reach of these flows in carrying services from supply to demand areas in the landscape. The present conceptualization considers and accounts for such flow-dependence in terms of potential and actually realized service supply and demand, which may generally differ and must therefore be distinguished due to and accounting for the prevailing conditions of service carrier flows. We here concretize and quantify such flow-dependence for a specific landscape case (the Stockholm region, Sweden) and for two examples of regulating ecosystem services: local climate regulation and storm water regulation. For these service and landscape examples, we identify, quantify and map key areas of potential and realized service supply and demand, based for the former (potential) on prevailing relatively static types of landscape conditions (such as land-cover/use, soil type and demographics), and for the latter (realized) on relevant carrier air and water flows. These first order quantification examples constitute first steps towards further development of generally needed such flow-dependence assessments for various types of ecosystem services in different landscapes over the world. PMID- 28363175 TI - Energy demand analysis via small scale hydroponic systems in suburban areas - An integrated energy-food nexus solution. AB - The study is a qualitative approach and looks into new ways for the effective energy management of a wind farm (WF) operation in a suburban or near-urban environment in order the generated electricity to be utilised for hydroponic farming purposes as well. Since soilless hydroponic indoor systems gain more and more attention one basic goal, among others, is to take advantage of this not typical electricity demand and by managing it, offering to the grid a less fluctuating electricity generation signal. In this paper, a hybrid business model is presented where the Distributed Energy Resources (DER) producer is participating in the electricity markets under competitive processes (spot market, real-time markets etc.) and at the same time acts as a retailer offering based on the demand - to the hydroponic units for their mass deployment in an area, putting forward an integrated energy-food nexus approach. PMID- 28363176 TI - An approach of habitat degradation assessment for characterization on coastal habitat conservation tendency. AB - Coastal zones are population and economy highly intensity regions all over the world, and coastal habitat supports the sustainable development of human society. The accurate assessment of coastal habitat degradation is the essential prerequisite for coastal zone protection. In this study, an integrated framework of coastal habitat degradation assessment including landuse classification, habitat classifying and zoning, evaluation criterion of coastal habitat degradation and coastal habitat degradation index has been established for better regional coastal habitat assessment. Through establishment of detailed three class landuse classification, the fine landscape change is revealed, the evaluation criterion of coastal habitat degradation through internal comparison based on the results of habitat classifying and zoning could indicate the levels of habitat degradation and distinguish the intensity of human disturbances in different habitat subareas under the same habitat classification. Finally, the results of coastal habitat degradation assessment could be achieved through coastal habitat degradation index (CHI). A case study of the framework is carried out in the Circum-Bohai-Sea-Coast, China, and the main results show the following: (1) The accuracy of all land use classes are above 90%, which indicates a satisfactory accuracy for the classification map. (2) The Circum Bohai-Sea-Coast is divided into 3 kinds of habitats and 5 subareas. (3) In the five subareas of the Circum-Bohai-Sea-Coast, the levels of coastal habitat degradation own significant difference. The whole Circum-Bohai-Sea-Coast generally is in a worse state according to area weighting of each habitat subarea. This assessment framework of coastal habitat degradation would characterize the landuse change trend, realize better coastal habitat degradation assessment, reveal the habitat conservation tendency and distinguish intensity of human disturbances. Furthermore, it would support for accurate coastal zone protection measures for the specific coastal area. PMID- 28363177 TI - Petroleum oil and mercury pollution from shipwrecks in Norwegian coastal waters. AB - Worldwide there are tens of thousands of sunken shipwrecks lying on the coastal seabed. These potentially polluting wrecks (PPW) are estimated to hold 3 25milliont of oil. Other hazardous cargo in PPW includes ordnance, chemicals and radioactive waste. Here, we present and discuss studies on mercury (Hg) and oil pollution in coastal marine sediment caused by two of the >2100 documented PPW in Norwegian marine waters. The German World War II (WWII) submarine (U-864) lies at about 150m below the sea surface, near the Norwegian North Sea island of Fedje. The submarine is estimated to have been carrying 67t of elemental Hg, some of which has leaked on to surrounding sediment. The total Hg concentration in bottom surface sediment within a 200m radius of the wreckage decreases from 100g/kgd.w. at the wreckage hotspot to about 1mg/kgd.w. at 100m from the hotspot. The second wreck is a German WWII cargo ship (Nordvard), that lies at a depth of ca. 30m near the Norwegian harbor of Moss. Oil leakage from Nordvard has contaminated the bottom coastal sediment with polycyclic aromatic hydrocarbons (PAH). The findings from this study provide useful insight to coastal administration authorities involved in assessing and remediating wreck-borne pollution from any of the tens of thousands of sunken shipwrecks. PMID- 28363178 TI - Characterization of non-methane hydrocarbons and their sources in an industrialized coastal city, Yangtze River Delta, China. AB - Ningbo is a highly industrialized city in the coastal area of the Yangtze River Delta (YRD), China. Large emissions and transport of non-methane hydrocarbons (NMHCs) may contribute to regional ozone (O3) and particulate matter (PM) pollution; however, the concentrations and sources of ambient NMHCs have not yet been investigated in Ningbo. In this study, ambient NMHCs were measured at two residential (SZ and CX) and two industrial (ZH and BL) sites and one suburban (XS) site over ten consecutive days in each season (10-20 December 2012 in winter, 14-23 April 2013 in spring, 15-24 July 2013 in summer, 22-31 October 2013, in autumn). A positive matrix factorization (PMF) model using multiple site data was deployed to explore the source contributions and their spatial and seasonal characteristics. The measurement results showed obvious seasonal variations in ambient NMHC concentrations (ranging from 17.89-28.48ppbv); chemical compositions were similar among the five sampling sites. PMF analysis showed that the petrochemical industry was the largest contributor (an average of 35.64%) to ambient NMHCs, while contributions of smaller sources (i.e., chemical and paint industries [14.34%], fuel and tank evaporation [16.02%], and residential solvent usage [7.24%]) showed spatial variations. Liquefied petroleum gas and fuel and tank evaporation contributed more in summer and autumn, while the contribution of the chemical and paint industries was greater in spring and winter. An evaluation of the ozone formation potential and secondary organic aerosol potential suggested that petrochemical and solvent-related sources were key parameters in mitigation of secondary pollutant formation. Seasonal variations in source contributions should be considered when formulating an effective NMHC abatement strategy. PMID- 28363179 TI - Integrated socio-hydrogeological approach to tackle nitrate contamination in groundwater resources. The case of Grombalia Basin (Tunisia). AB - Nitrate contamination still remains one of the main groundwater quality issues in several aquifers worldwide, despite the perduring efforts of the international scientific community to effectively tackle this problem. The classical hydrogeological and isotopic investigations are obviously of paramount importance for the characterization of contaminant sources, but are clearly not sufficient for the correct and long-term protection of groundwater resources. This paper aims at demonstrating the effectiveness of the socio-hydrogeological approach as the best tool to tackle groundwater quality issues, while contributing bridging the gap between science and society. An integrated survey, including land use, hydrochemical (physicochemical parameters and major ions) and isotopic (delta15NNO3 and delta18ONO3) analyses, coupled to capacity building and participatory activities was carried out to correctly attribute the nitrate origin in groundwater from the Grombalia Basin (North Tunisia), a region where only synthetic fertilizers have been generally identified as the main source of such pollution. Results demonstrates that the basin is characterized by high nitrate concentrations, often exceeding the statutory limits for drinking water, in both the shallow and deep aquifers, whereas sources are associated to both agricultural and urban activities. The public participation of local actors proved to be a fundamental element for the development of the hydrogeological investigation, as it permitted to obtain relevant information to support data interpretation, and eventually guaranteed the correct assessment of contaminant sources in the studied area. In addition, such activity, if adequately transferred to regulators, will ensure the effective adoption of management practices based on the research outcomes and tailored on the real needs of the local population, proving the added value to include it in any integrated investigation. PMID- 28363180 TI - Influence of seasonality, air mass origin and particulate matter chemical composition on airborne bacterial community structure in the Po Valley, Italy. AB - The integration of chemical and biological data in aerosol studies represents a new challenge in atmospheric science. In this perspective it will be possible to gain a clearer and deeper comprehension of biogeochemical cycles in the atmosphere. In this view, this study aimed to investigate the relationships occurring between bacterial populations and PM chemical composition in one of the most polluted and urbanized areas in Europe: the Po Valley (Italy). Moreover, seasonality, long- and short-range transports were also evaluated to investigate the influence on airborne bacterial communities. PM samples were collected in two cities of the Po Valley (Milan and Venice) characterized by different meteorological conditions and atmospheric pollutant sources. Samples were analysed for water-soluble inorganic ions (WSIIs) and bacterial community structure. Chemical and biological data were jointly processed by using redundancy discriminate analysis (RDA), while the influence of atmospheric circulation was evaluated by using wind ground data and back-trajectories analysis. Results showed strong seasonal shifts of bacterial community structure in both cities, while a different behaviour was observed for air mass circulation at Milan ad Venice sites: long-range transport significantly affected bacterial populations in Milan whereas local ground wind had more influence in the Venice area. Moreover, difference in taxonomic composition can be mostly addressed to the characteristics of sampling sites. This evidence could suggest that, while PM composition is influenced by long-range transport, bacterial populations are affected, besides transport, by other factors (i.e., season and sampling site location). This perspective allow to better understand and explain airborne bacterial community behaviour. PMID- 28363181 TI - The effective migration of Massilia sp. WF1 by Phanerochaete chrysosporium and its phenanthrene biodegradation in soil. AB - Pollutant-degrading bacteria migrated by fungi may enhance the contacts between microorganisms and pollutants and improve the bioremediation efficiency of persistent organic pollutants in soil. Here, the migration of phenanthrene (PHE) degrading bacteria Massilia sp. WF1 and Mycobacterium sp. WY10 by the hydrophobic fungi Phanerochaete chrysosporium (P. chrysosporium) and its effects on the PHE biodegradation in soil were investigated. Migration of the hydrophilic bacterium WF1 was better than that of the hydrophobic bacterium WY10 by P. chrysosporium mycelia since strain WF1 possesses flagellum and the type III secretion system. The interaction energy change of P. chrysosporium-WF1 was lower, but the interaction forces (van der Waals attractions, capillary forces, and cross linking effects) were stronger than those of P. chrysosporium-WY10. Thus, the adhesive attraction between strain WF1 and P. chrysosporium was stronger, and consequently, strain WF1 was migrated by P. chrysosporium to a greater extent than WY10. The corresponding migration mechanism was inferred to be a bacterial 'passive' method: bacteria adhered to mycelia before they migrated with the growing mycelia. Moreover, migrated strain WF1 via P. chrysosporium showed effective PHE biodegradation in soil. Fungus-mediated migration of pollutant degrading bacteria may play an important role in the bioremediation of pollutants in soil. PMID- 28363182 TI - Sulfate radical-based oxidation of antibiotics sulfamethazine, sulfapyridine, sulfadiazine, sulfadimethoxine, and sulfachloropyridazine: Formation of SO2 extrusion products and effects of natural organic matter. AB - The widespread occurrence of sulfonamide antibiotics in the environment has raised great concerns about their potential to proliferate antibacterial resistance. Sulfate radical (SO4*-) based advanced oxidation processes (SR-AOPs) are promising in-situ chemical oxidation (ISCO) technologies for remediation of soil and groundwater contaminated by antibiotics. The present study reported that thermally activated persulfate oxidation of sulfonamides (SAs) bearing six membered heterocyclic rings, e.g., sulfamethazine (SMZ), sulfapyridine (SPD), sulfadiazine (SDZ), sulfadimethoxine (SDM), and sulfachloropyridazine (SCP), all produced SO2 extrusion products (SEPs), a phenomenon that is of potential importance, but not systematically studied. As an electrophilic oxidant, SO4*- tends to attack the aniline moiety, the reactive site of SAs, via electro transfer mechanism. The resulting anilinyl radical cations are subjected to further intermolecular Smiles-type rearrangement to produce SEPs. Formation of SEPs is expected to occur in other SR-AOPs as well. The temperature-dependent evolution pattern of SEP of SMZ, 4-(2-imino-4,6-dimethylpyrimidin-1(2H) yl)aniline, can be well fitted by kinetic modeling concerning sequential formation and transformation of intermediate product. The presence of natural organic matter (NOM) influenced the evolution patterns of 4-(2-imino-4,6 dimethylpyrimidin-1(2H)-yl)aniline significantly. Toxicological effects of SEPs on ecosystem and human health remain largely unknown, thus, further monitoring studies are highly desirable. PMID- 28363183 TI - Progrip self-gripping mesh in Rives-Stoppa repair: Are there any differences in outcomes versus a retromuscular polypropylene mesh fixed with sutures? A "case series" study. AB - BACKGROUND: Rives-Stoppa repair is widely accepted technique in large midline IH, and appears to be advantageous compared to other surgical techniques concerning complications and recurrence rates. The aim of this case series study was to analyze 1-year outcomes in patients with IH treated with Progrip self-gripping mesh compared to polypropylene (PPL) mesh fixed with sutures during the Rives Stoppa technique. METHODS: Between June 2014 and June 2015, we performed a prospective comparative non-randomized (case series) analysis between 25 patients with IH using retromuscular Progrip self-gripping mesh and 25 patients with retromuscular PPL mesh fixed with sutures, under Rives-Stoppa repair. All intraoperative and perioperative morbidities were reported with particular attention to wound infection, seroma or hematoma formation, duration of hospital stay, presence of abdominal wall pain (VAS) and recurrence during long-term follow-up. RESULTS: Mean operative time in Progrip group was shorter than Non Progrip group (101+/-29.5 versus 121+/-39.8min). In Progrip group, the only postoperative complication was seroma in two patients; however, in Non-Progrip group, we reported seroma in three patients, and hematoma in 4 patients (p=0.03). The median hospital stay was shorter in Progrip group (5.8+/-2.2days versus 6.6+/ 2.9days). Mean VAS score in the first 48h was higher in Non-Progrip group than Progrip group (4.9+/-2.1 versus 8.1+/-2)(p=0.01). The median follow-up was 13 months (range 12-20 months) and none of the 50 patients had a hernia recurrence. CONCLUSIONS: In Rives-Stoppa repair, retromuscular Progrip mesh causes less postoperative pain in the first 48h and lower rate of hematoma than PPL mesh fixed with sutures in the short term follow-up. PMID- 28363184 TI - Treatment with platelet-derived growth factor (PDGF) and rock inhibitors is related to declined nerve growth factor (NGF) signaling in an experimental model of rat pulmonary hypertension. AB - BACKGROUND: Recent studies reveal that nerve growth factor (NGF) plays a critical role in the pathobiology of pulmonary hypertension (PH). The aim of the present study is to clarify the relationship between NGF signaling and treatment with PDGF or ROCK inhibitors in an animal model of PH. METHODS: Lung tissues were obtained from animals with monocrotaline (MCT)-challenged PH which had been administered long term imatinib, fasudil or statin. Reversal of disease was indicated by decreases in right ventricle pressure (RVP) and hypertrophy. NGF expression was examined at the mRNA and protein levels using quantitative real time PCR reaction and ELISA. RESULTS: MCT significantly increased NGF mRNA and protein content in lung tissue. ROCK inhibitor (fasudil) and PDGF inhibitor (imatinib) caused significant decreases in NGF mRNA and protein content when administered alone, with no further effects noted when used in combination. CONCLUSION: The beneficial reversal of MCT-mediated effects in PH caused by PDGF or ROCK inhibition may be also partially mediated by decreased NGF signaling. PMID- 28363186 TI - A model to evaluate the costs and clinical effectiveness of human papilloma virus screening compared with annual papanicolaou cytology in Germany. AB - OBJECTIVES: We modelled human papilloma virus (HPV) primary screening scenarios compared with Pap cytology to evaluate clinical effectiveness and projected annual costs in Germany. STUDY DESIGN: A Markov cohort model was built to compare the budget impact of annual Pap cytology with different 5-yearly HPV screening scenarios: (1) a positive HPV test followed by Pap cytology; (2) a positive HPV test followed by p16/Ki-67 dual-stained cytology; (3) a positive HPV test followed by colposcopy if HPV-16/18-positive or p16/Ki-67 dual-stained cytology if positive for other subtypes; (4) co-testing with HPV and Pap. Screening scenarios were based on a 10-year horizon. RESULTS: All HPV screening scenarios in the model were associated with fewer deaths from missed diagnosis of cervical cancer compared with Pap screening; 10-year totals n=172-344 (1.5-3 per 100,000) versus n=477 (4.1 per 100,000), respectively. Total annual costs were lower with HPV screening than Pap cytology. The projected average annual cost for HPV screening ranged from ?117 million to ?136 million compared with ?177 million for Pap screening, representing annual savings of ?41-60 million. The greatest clinical impact was achieved with primary HPV screening (with genotyping) followed by colposcopy for HPV 16/18-positive women or p16/Ki-67 dual-stained cytology for women positive for other HPV subtypes. CONCLUSION: Screening strategies including primary HPV testing for high-risk subtypes (HPV-16/18) in conjunction with p16/Ki-67 dual-stained cytology can improve the detection of cervical cancer at a lower total annual cost than conventional Pap cytology screening. PMID- 28363185 TI - Associations of C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR) gene with male infertility risk: A meta-analysis. AB - PURPOSE: Methylenetetrahydrofolate reductase is one of the key enzymes in folate metabolism. But the association between polymorphism and the risk of male infertility is still controversial. Therefore, this study used a meta-analysis on the collection of data to analyze MTHFR gene C677T polymorphism (known as c.665 C>T, rs1801133, p.Ala222Val). METHODS: PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), and Wan fang. Data were searched to identify eligible studies. We sifted the data collection by Hardy-Weinberg equilibrium calculator and used odds ratios (ORs) and 95% confidence intervals (95% CIs) to conduct data through RevMan5.0 and StataSE12.0 software. RESULTS: A total of 15 studies have 3853 patients with infertility and 3613 healthy controls in this meta-analysis. Our results showed that T variant of MTHFR C677T gene polymorphism was significantly associated with an increased risk of male infertility (forT vs. C: OR=1.38, 95% CI=1.18-1.63; for TT vs. CC: OR=1.86, 95% CI=1.36-2.54; for CT vs. CC: OR=1.34, 95% CI=1.03-1.74; for TT vs. CT: OR=1.52, 95% CI=1.26-1.84; for TT vs. CT+CC: OR=1.42, 95% CI=1.19-1.70; for TT+CT versus CC: OR=1.46, 95%CI=1.05 2.04). In addition, the results indicated that T allele had the positive association which was driven by East-asian populations (random: OR=1.44, 95% CI=1.2-1.74; fixed: OR=1.39, 95% CI=1.20-1.61), Middle-eastern populations (random: OR=1.30, 95% CI=1.05-1.63; fixed: OR=1.30, 95% CI=1.05-1.63) and Mixed race (random: OR=1.96, 95% CI=1.35-2.85; fixed: OR=1.31, 95% CI=1.20-1.43). CONCLUSION: This meta-analysis suggests that MTHFR C677T polymorphism is associated with male infertility. PMID- 28363187 TI - The impact of anal sphincter injury on perceived body image. AB - OBJECTIVE: Obstetric anal sphincter injury is common but the effect on body image is unreported. The aim of this study was to explore patient perceived changes in body image and other psychological aspects in women attending a perineal follow up clinic. STUDY DESIGN: This retrospective study analysed women's responses to a self-reported questionnaire. Consecutive women with anal sphincter injury who attended a United Kingdom Maternity Hospital perineal follow-up clinic between January 1999 and January 2012 were identified and the records obtained and reviewed. Multivariate regression analyses were performed to examine variables influencing self-reported change in body image. RESULTS: Questionnaires and operation notes were analysed from 422 women who attended at a median of four months after delivery. 222 (53%) reported a change in body image with 80 (19%) reporting lower self-esteem and 75 (18%) a change in their personality due to the change in body image. 248 (59%) perceived an anatomical change due to the delivery. Factors associated with increased likelihood of reporting a change in body image were reporting a perceived change in anatomy due to the delivery, adjusted OR 6.11 (3.56-10.49), anal incontinence, OR 1.97 (1.16-3.36), and delivery by forceps, OR 2.59 (1.23-5.43). CONCLUSIONS: This is the first study to quantify body image changes in women after anal sphincter injury sustained in childbirth. These were found to be very common, affecting up to 50% of women. The study has several limitations but it does highlight the significant psychosocial problems of negative self-esteem and personality changes associated with a perceived change in body image that has not previously been reported. It also outlines the further research questions that need to be addressed. PMID- 28363188 TI - Delivery mode and intraventricular hemorrhage risk in very-low-birth-weight infants: Observational data of the German Neonatal Network. AB - BACKGROUND: Very-low-birth-weight infants (VLBWI) are frequently delivered by cesarean section (CS). However, it is unclear at what gestational age the benefits of spontaneous delivery outweigh the perinatal risks, i.e. intraventricular hemorrhage (IVH) or death. OBJECTIVES: To assess the short-term outcome of VLBWI on IVH according to mode of delivery in a population-based cohort of the German Neonatal Network (GNN). STUDY DESIGN: A total cohort of 2203 singleton VLBWI with a birth weight <1500g and gestational age between 22 0/7 and 36 6/7 weeks born and discharged between 1st of January 2009 and 31st of December 2015 was available for analysis. VLBWI were stratified into three categories according to mode of delivery: (1) planned cesarean section (n=1381), (2) vaginal delivery (n=632) and (3) emergency cesarean section (n=190). Outcome was assessed in univariate and logistic regression analyses. RESULTS: Prevalence of IVH was significantly higher in the vaginal delivery (VD) (26.6%) and emergency CS group (31.1%) as compared to planned CS (17.2%), respectively. In a logistic regression analysis including known risk factors for IVH, vaginal delivery (OR 1.725 [1.325 2.202], p<=0.001) and emergency cesarean section (OR 1.916 [1.338-2.746], p<=0.001) were independently associated with IVH risk. In the subgroup of infants >30 weeks of gestation prevalence for IVH was not significantly different in VD and planned CS (5.3% vs. 4.4%). CONCLUSIONS: Our observational data demonstrate that elective cesarean section is associated with a reduced risk of IVH in preterm infants <30 weeks gestational age when presenting with preterm labor. PMID- 28363189 TI - Identification and expression analysis of photoreceptor genes in kiwifruit leaves under natural daylength conditions and their relationship with other genes that regulate photoperiodic flowering. AB - Kiwifruit (Actinidia chinensis var. deliciosa (A. Chev) A. Chev.) is a dioecious vine highly dependent on pollination, which is limited by a lack of synchrony of flowering time between male and female plants. In many plant species, the regulation of the timing of flowering depends largely on seasonal cues such as photoperiod, which is detected by photoreceptors. In this report, we determined the full sequences of the PHYB (AcPHYB) and PHYA (AcPHYA) genes and a partial sequence of the CRY2 (AcCRY2) gene in kiwifruit. Next, we monitored the expression patterns of these photoreceptor genes (AcPHYA, AcPHYB and AcCRY2) as well as other genes involved in flowering regulation (AcCO-like and AcFT) in the leaves of kiwifruit plants grown under natural photoperiods in the field. The annual expression patterns of AcPHYB, AcPHYA and AcCRY2 genes showed that they were significantly highly expressed from late flower development until full bloom and fitting with floral evocation, closely matching the peaks of expression detected for the AcFT and AcCO-like genes. In addition, the daily expression patterns of AcPHYB, AcPHYA and AcCRY2 were analyzed in leaves collected under different daylength conditions. Under long-day (LD) conditions, maximum expression levels were detected in the middle of the day in April (before full bloom), while their expression lost their daily rhythmic patterns in June (after full bloom) and were consistently expressed at low levels. Under short-day (SD) conditions, AcPHYB, AcPHYA and AcCRY2 gene expression patterns were the opposite of those observed in April. With respect to AcFT, no expression was detected in SD conditions. In contrast, the AcCO-like gene oscillated for all daylength conditions with the same daily rhythm. Our results seem to indicate the involvement of photoreceptor genes in kiwifruit flowering regulation. The different daily expression patterns detected for AcPHYA, AcPHYB, AcCRY2 and AcFT under different daylength conditions suggest that photoperiod regulates their expression, while the uniform expression of the AcCO-like gene is in agreement with its reported regulation by the circadian clock. PMID- 28363190 TI - Nose to brain delivery in rats: Effect of surface charge of rhodamine B labeled nanocarriers on brain subregion localization. AB - Nose to brain delivery and nanotechnology are the combination of innovative strategies for molecules to reach the brain and to bypass blood brain barriers. In this work we investigated the fate of two rhodamine B labeled polymeric nanoparticles (Z-ave <250nm) of opposite surface charge in different areas of the brain after intranasal administration in rats. A preliminary screening was carried out to select the suitable positive (chitosan/poly-l-lactide-co glycolide) nanocarrier through photon correlation spectroscopy and turbiscan. Physico-chemical and technological characterizations of poly-l-lactide-co glycolide (negative) and chitosan/poly-l-lactide-co-glycolide (positive) fluorescent labeled nanoparticles were performed. The animals were allocated to three groups receiving negative and positive polymeric nanoparticles via single intranasal administration or no treatment. The localization of both nanocarriers in different brain areas was detected using fluorescent microscopy. Our data revealed that both nanocarriers reach the brain and are able to persist in the brain up to 48h after intranasal administration. Surface charge influenced the involved pathways in their translocation from the nasal cavity to the central nervous system. The positive charge of nanoparticles slows down brain reaching and the trigeminal pathway is involved, while the olfactory pathway may be responsible for the transport of negatively charged nanoparticles, and systemic pathways are not excluded. PMID- 28363192 TI - Rifampicin loaded chitosan nanoparticle dry powder presents an improved therapeutic approach for alveolar tuberculosis. AB - Current treatment therapeutic approach for tuberculosis is the administration of first line drugs in the form of tablets and capsules for 4-6 months. However, this approach leads to severe adverse effects. Therefore, present study was designed to achieving local and sustained targeting of anti-tubercular drugs in order to reduce dose and frequency. The nanoparticle based dry powder formulation of rifampicin was developed and analyzed with respect to its direct targeting potential of lungs. Rifampicin loaded nanoparticles were formulated by ionic gelation probe sonication method, and characterized with respect to particle size, zeta potential, entrapment and drug loading efficiency. The range of size and entrapment efficiency of prepared nanoparticles was estimated from 124.1+/ 0.2 to 402.3+/-2.8nm and 72.00+/-0.1%, respectively. The freeze-dried powder of nanoparticle formulation was used to carry out in vitro lung deposition studies through Andersen cascade impactor. The cumulative in vitro drug release studies with developed nanoparticle formulation showed sustained release up to 24h. Our in vitro sustained drug release results were corroborated by the extended residence and slow clearance of rifampicin from the lungs. Furthermore, our results suggest the minimum lung distribution of drug in treated rats which confirms the negligible toxicity rendered by nanoparticle dry powder formulation. Moreover, pharmacokinetic and toxicity studies carried out with prepared NPs dry powder inhalation (DPI) formulations and compared with conventional DPI. PMID- 28363191 TI - Ruthenium bipyridine sensitized MoO3 multifunctional nanostructures: Study of opto-electrochemical properties, biocompatibility and bioimaging. AB - Simple and versatile methodology to synthesize hybrid nanostructures with multi functionality for device application is advantageous. Herein, we report the synthesis of MoO3 nanostructures integrated with [Ru(bpy)3]2+ and PEGylation to obtain hybrid MoO3-[Ru(bpy)3]2+ nanostructures. Chemically interacted [Ru(bpy)3]2+ provides optical and electrochemical properties to the hybrid structures. PEG3k enhances the aqueous solubility of the hybrid system. Morphology, chemical structure, optical and electrochemical properties of hybrid nanostructures were studied from electron microscopic, spectroscopic and voltammetric techniques. The synthesized hybrid nanostructures exhibited a metal to-ligand charge transfer absorbance and emission bands in the range of 450nm and 605nm, respectively. Electrode modified with MoO3-[Ru(bpy)3]2+ and MoO3 [Ru(bpy)3]2+/PEG3k exhibit improved voltammetric properties than pristine MoO3. Confocal cellular imaging supported that these hybrid particles were easily uptaken by endothelial cells with minimal cytotoxic effects. The hybrid nanocomplex displayed unique opto-electrochemical, cellular biocompatibility and imaging features that may be an ideal platform for electrochemical biosensor devices with simultaneous bioimaging function. PMID- 28363193 TI - Dual-mode electrochemical analysis of microRNA-21 using gold nanoparticle decorated MoS2 nanosheet. AB - The detection of microRNA plays an important role in early cancer diagnosis. Herein, a dual-mode electronic biosensor was developed for microRNA-21 (miRNA-21) detection based on gold nanoparticle-decorated MoS2 nanosheet (AuNPs@MoS2). A classical DNA "sandwich" structure was employed to construct MoS2-based electrochemical sensor, including capture DNA, target miRNA-21 and DNA-modified nanoprobe. [Fe(CN)6]3-/4- and [Ru(NH3)6]3+ were selected as electrochemical indicators to monitor the preparation process and evaluate the performance of MoS2-based electrochemical biosensor by electrochemical impedance spectroscopy (EIS) and differential pulse voltammetry (DPV), respectively. Such MoS2-based biosensor exhibited excellent performance for miRNA-21 detection in the range from 10 fM to 1nM with detection limit of 0.78fM and 0.45fM for DPV and EIS technique, respectively. Furthermore, the proposed MoS2-based biosensor displayed high selectivity and stability, which could be used to determine miRNA-21 in human serum samples with satisfactory results. All data suggested that such MoS2 based nanocomposite may be a potential candidate for biosensing ranging from nucleic acid to protein detection. PMID- 28363195 TI - Promoting Breast Milk Nutrition in Infants With Cleft Lip and/or Palate. PMID- 28363196 TI - Parent Support Programs and Coping Mechanisms in NICU Parents. AB - BACKGROUND: Many neonatal intensive care unit (NICU) parents experience emotional distress leading to adverse infant outcomes. Parents may not cope positively in stressful situations, and support programs often are underutilized. PURPOSE: To determine coping mechanisms utilized by NICU parents, and types of support programs parents are likely to attend. To determine whether sociodemographic and length-of-stay differences impact coping mechanisms utilized, and types of support programs preferred. METHODS: A correlational cross-sectional survey design was used. The 28-item Brief COPE tool, questions about demographics and preferred support program styles, was distributed to a convenience sample of NICU parents in a level IV NICU in the southeastern United States. RESULTS: One hundred one NICU parents used coping mechanisms, with acceptance emotional support, active coping, positive reframing, religion, planning, and instrumental support being the most common. Preferred support classes were infant development and talking with other NICU parents. Caucasians more commonly coped using active coping, planning, emotional support, acceptance, instrumental support, and venting compared with other races. Women utilized self-blame coping mechanisms more often compared with men. Younger parents were more likely to use venting and denial coping mechanisms. Parents with a shorter stay utilized self-distraction coping and preferred the class of talking with other parents. IMPLICATIONS FOR PRACTICE: Support program preference, type of coping mechanism utilized, and sociodemographic factors may be used to guide the creation of NICU support programs. IMPLICATIONS FOR RESEARCH: Additional studies are needed to determine whether support program offering according to preferences and sociodemographic characteristics increases attendance and decreases emotional distress. PMID- 28363194 TI - Small molecule modulation of voltage gated sodium channels. AB - Voltage gated sodium channels are fundamental players in animals physiology. By triggering the depolarization of the lipid membrane they enable generation and propagation of the action potential. The involvement of these channels in numerous pathological conditions makes them relevant target for pharmaceutical intervention. Therefore, modulation of sodium conductance via small molecule binding constitutes a promising strategy to treat a large variety of diseases. However, this approach entails significant challenges: voltage gated sodium channels are complex nanomachines and the details of their workings have only recently started to become clear. Here we review - with emphasis on the computational studies - some of the major milestones in the long-standing search of a quantitative microscopic description of the molecular mechanism and modulation of voltage-gated sodium channels. PMID- 28363197 TI - The Effects of Postdischarge Telephone Counseling and Short Message Service on the Knee Function, Activities of Daily Living, and Life Satisfaction of Patients Undergoing Total Knee Replacement. AB - BACKGROUND: No study comparing short message service (SMS) texts and telephone counseling for patients undergoing total knee replacement (TKR) has been reported. PURPOSE: The purpose of the study was to provide postdischarge telephone counseling and SMS texts to TKR patients and to analyze the effects of these services on their knee function (KF), activities of daily living (ADL), and life satisfaction (LS). METHODS: This study used a randomized clinical trial design. This study was conducted with 40 patients (counseling group: 21; SMS group: 19). In the telephone counseling group and the SMS group, KF, ADL, and LS were assessed before surgery and 1 and 3 months after TKR. RESULTS: Telephone counseling and SMS texts have the same effects on KF, ADL, and LS of TKR patients. CONCLUSION: Future research is needed to determine optimal frequency and duration of post-TKR SMS to support patients who have undergone TKR. PMID- 28363198 TI - Hemostatic Changes Associated With Increased Mortality Rates in Hospitalized Patients With HIV-Associated Tuberculosis: A Prospective Cohort Study. AB - Background: Mortality rates remain high for human immunodeficiency virus (HIV) associated tuberculosis, and our knowledge of contributing mechanisms is limited. We aimed to determine whether hemostatic changes in HIV-tuberculosis were associated with mortality or decreased survival time and the contribution of mycobacteremia to these effects. Methods: We conducted a prospective study in Khayelitsha, South Africa, in hospitalized HIV-infected patients with CD4 cell counts <350/uL and microbiologically proved tuberculosis. HIV-infected outpatients without tuberculosis served as controls. Plasma biomarkers reflecting activation of procoagulation and anticoagulation, fibrinolysis, endothelial cell activation, matricellular protein release, and tissue damage were measured at admission. Cox proportional hazard models were used to assess variables associated with 12-week mortality rates. Results: Of 59 patients with HIV tuberculosis, 16 (27%) died after a median of 12 days (interquartile range, 0-24 days); 29 (64%) of the 45 not receiving anticoagulants fulfilled criteria for disseminated intravascular coagulation. Decreased survival time was associated with higher concentrations of markers of fibrinolysis, endothelial activation, matricellular protein release, and tissue damage and with decreased concentrations for markers of anticoagulation. In patients who died, coagulation factors involved in the common pathway were depleted (factor II, V, X), which corresponded to increased plasma clotting times. Mycobacteremia modestly influenced hemostatic changes without affecting mortality. Conclusions: Patients with severe HIV-tuberculosis display a hypercoagulable state and activation of the endothelium, which is associated with mortality. PMID- 28363199 TI - Longitudinal changes in adolescents with TOF: implications for care. AB - Background: We sought to identify predictors of change in right ventricular function and exercise capacity in adolescents following repair for tetralogy of Fallot. Methods and results: We performed a longitudinal study with serial cardiac magnetic resonance imaging and/or exercise stress tests. Patients with interim intervention on the pulmonary valve were excluded. Paired t-test was used to detect longitudinal changes and multivariable regression models were built to identify predictors of change. Initial and follow up magnetic resonance and exercise stress test studies were available for 65 and 63 subjects, respectively. Age at initial testing was 11.7 +/- 2.7 years. Average follow up time was 4.5 +/- 1.8 (magnetic resonance) and 4.0 +/- 1.6 (exercise test) years. There was a significant increase in right ventricular end diastolic and systolic volume (119 +/- 34 to 128 +/- 35 ml/m2, P = 0.006; 49 +/- 20 to 56 +/- 23 ml/m2, P = 0.001, respectively), and a decrease in right ventricular ejection fraction (60 +/- 7 to 56 +/- 8%, P = 0.001), with no significant change in pulmonary regurgitant fraction or right ventricular cardiac index. Predictors of right ventricular dilation over time included: time elapsed from surgical repair, severity of pulmonary insufficiency and right ventricular dilation at the initial magnetic resonance imaging. Of those, time elapsed from surgical repair had the most significant effect. There was no change in exercise capacity. Discussion: In the adolescent with tetralogy of Fallot, longer time from surgery, more pulmonary insufficiency and greater right ventricular dilation at initial magnetic resonance imaging are associated with progressive right ventricular dilation. These results suggest early monitoring with magnetic resonance imaging might identify those at highest risk for progressive disease. PMID- 28363200 TI - Evolution of right ventricular size over time after tetralogy of Fallot repair: a longitudinal cardiac magnetic resonance study. AB - Aims: It is commonly believed that pulmonary regurgitation (PR) after surgical repair of tetralogy of Fallot (TOF) leads to progressive right ventricular (RV) enlargement. However, progressive RV dilatation has never clearly been documented in this patient population. Therefore, we studied the size of the RV over time in patients after surgical TOF repair. Methods and results: Fifty-one consecutive patients after surgical TOF repair underwent at least two cardiovascular magnetic resonance (CMR) exams using a single CMR scanner. Patients with RV outflow tract obstruction, interventions other than the initial repair and CMR exams with use of sedation were excluded. Three subgroups with different repair techniques were studied: transannular patch repair [n = 22, age 17 +/- 10 years], subvalvular patch repair [n = 15, age 22 +/- 8 years], or non-patch repair/infundibulectomy (n = 14, age 28 +/- 11 years). Right ventricular end-diastolic volume index (RVEDVI) and PR fraction did not change during the 37 +/- 21 months follow-up between first and last CMR in the whole group (RVEDVI: 118 +/- 23 mL/m2 vs. 119 +/- 23 mL/m2, P = 0.720; PR fraction: 33% (23-40%) vs. 32% (24-39%), P = 0.268). RVEDVI remained stable in all subgroups (transannular patch: 120 +/- 21 mL/m2 vs. 122 +/- 22 mL/m2, subvalvular patch: 112 +/- 23 mL/m2 vs. 111 +/- 23 mL/m2, non patch: 123 +/- 28 mL/m2 vs. 123 +/- 23 mL/m2, P = 0.827). RVEDVI at last CMR did not differ between groups (P = 0.301). Conclusions: This study shows no progression of RV dilatation in patients after surgical repair of TOF with moderately dilated RVs and significant PR during a 3-year follow-up. RV dilatation in our patient group seems to be independent from surgical repair techniques. PMID- 28363201 TI - Bilateral coronary ostial stenosis after a Bentall procedure. PMID- 28363202 TI - Right ventricular remodelling after tetralogy of Fallot repair: new insights from longitudinal follow-up data. PMID- 28363204 TI - Recommendations on the echocardiographic assessment of aortic valve stenosis: a focused update from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. AB - Echocardiography is the key tool for the diagnosis and evaluation of aortic stenosis. Because clinical decision-making is based on the echocardiographic assessment of its severity, it is essential that standards are adopted to maintain accuracy and consistency across echocardiographic laboratories. Detailed recommendations for the echocardiographic assessment of valve stenosis were published by the European Association of Echocardiography and the American Society of Echocardiography in 2009. In the meantime, numerous new studies on aortic stenosis have been published with particular new insights into the difficult subgroup of low gradient aortic stenosis making an update of recommendations necessary. The document focuses in particular on the optimization of left ventricular outflow tract assessment, low flow, low gradient aortic stenosis with preserved ejection fraction, a new classification of aortic stenosis by gradient, flow and ejection fraction, and a grading algorithm for an integrated and stepwise approach of artic stenosis assessment in clinical practice. PMID- 28363205 TI - Visit-to-visit blood pressure variability: an epiphenomenon or a risk for the progression of carotid artery remodelling: reply. PMID- 28363203 TI - Improved 5-year prediction of all-cause mortality by coronary CT angiography applying the CONFIRM score. AB - Aims: To investigate the long-term performance of the CONFIRM score for prediction of all-cause mortality in a large patient cohort undergoing coronary computed tomography angiography (CCTA). Methods and results: Patients with a 5 year follow-up from the international multicentre CONFIRM registry were included. The primary endpoint was all-cause mortality. The predictive value of the CONFIRM score over clinical risk scores (Morise, Framingham, and NCEP ATP III score) was studied in the entire patient population as well as in subgroups. Improvement in risk prediction and patient reclassification were assessed using categorical net reclassification index (NRI) and integrated discrimination improvement (IDI). During a median follow-up period of 5.3 years, 982 (6.5%) of 15 219 patients died. The CONFIRM score outperformed the prognostic value of the studied three clinical risk scores (c-indices: CONFIRM score 0.696, NCEP ATP III score 0.675, Framingham score 0.610, Morise score 0.606; c-index for improvement CONFIRM score vs. NCEP ATP III score 0.650, P < 0.0001). Application of the CONFIRM score allowed reclassification of 34% of patients when compared with the NCEP ATP III score, which was the best clinical risk score. Reclassification was significant as revealed by categorical NRI (0.06 with 95% CI 0.02 and 0.10, P = 0.005) and IDI (0.013 with 95% CI 0.01 and 0.015, P < 0.001). Subgroup analysis revealed a comparable performance in a variety of patient subgroups. Conclusions: The CONFIRM score permits a significantly improved prediction of mortality over clinical risk scores for >5 years after CCTA. These findings are consistent in a large variety of patient subgroups. PMID- 28363206 TI - Recent developments in the science of proarrhythmic cardiac safety of new drugs. AB - Following marketing withdrawals of several drugs due to proarrhythmic safety concerns, the ICH Guidelines S7B and E14 were released in 2005 and have guided pre-approval cardiac safety assessments in multiple regulatory jurisdictions. While this S7B-E14 paradigm has successfully prevented drugs with unanticipated potential for inducing Torsades de Pointes entering the market, it has unintentionally resulted in the termination of development programs for potentially important compounds that could have exhibited a favourable benefit risk balance. The Comprehensive In vitro Proarrhythmia Assay paradigm is currently attracting considerable attention as a solution to this problem. While much evaluative work in this new paradigm will be conducted in the non-clinical domain, human electrocardiographic assessments will remain an important component of the overall investigational strategy, possibly being conducted in Phase I trials employing exposure-response modelling. This article reviews recent developments in proarrhythmic cardiac safety assessments of new drugs, their rationales, and current limitations. PMID- 28363207 TI - A commentary on the new ESC guidelines on dyslipidaemias. PMID- 28363208 TI - Coronary artery disease and arrhythmias. PMID- 28363209 TI - Successful transvenous cardiac resynchronisation therapy in a case of coronary sinus ostial atresia. PMID- 28363210 TI - Neutrophil contributions to ischaemic heart disease. PMID- 28363211 TI - Coronary artery disease in diabetes. PMID- 28363212 TI - The e-health revolution. PMID- 28363213 TI - Social media: a powerful tool for physicians and patients. PMID- 28363214 TI - Big data: big promise. PMID- 28363216 TI - Dr Calum MacRae and research team receive $75M investment award. PMID- 28363218 TI - Multiple bacterial aneurysms caused by stent infections. PMID- 28363217 TI - ACC/AHA guidelines superior to ESC/EAS guidelines for primary prevention with statins in non-diabetic Europeans: the Copenhagen General Population Study. AB - Aim: We compared the 2013 American College of Cardiology/American Heart Association (ACC/AHA) and the 2016 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines on prevention of atherosclerotic cardiovascular disease (ASCVD) using different risk prediction models [US Pooled Cohort Equations (US-PCE for any ASCVD) and European Systematic COronary Risk Evaluation system (European-SCORE for fatal ASCVD)] and different statin eligibility criteria. Methods and results: We examined 44 889 individuals aged 40 75 recruited in 2003-09 in the Copenhagen General Population Study, all free of ASCVD, diabetes, and statin use at baseline. We detected 2217 any ASCVD events and 199 fatal ASCVD events through 2014. The predicted-to-observed event ratio was 1.2 using US-PCE for any ASCVD and 5.0 using European-SCORE for fatal ASCVD. The US-PCE, but not the European-SCORE, was well-calibrated around decision thresholds for statin therapy. For a Class I recommendation, 42% of individuals qualified for statins using the ACC/AHA guidelines vs. 6% with the ESC/EAS guidelines. Using ACC/AHA- vs. ESC/EAS-defined statin eligibility led to a substantial gain in sensitivity (+62% for any ASCVD and +76% for fatal ASCVD) with a smaller loss in specificity (-35% for any ASCVD and -36% for fatal ASCVD). Similar differences between the ACC/AHA and ESC/EAS guidelines were found for men and women separately, and for Class IIa recommendations. The sensitivity and specificity of a US-PCE risk of 5% were similar to those of a European-SCORE risk of 1.4%, whereas a US-PCE risk of 7.5% was similar to a European-SCORE risk of 2.4%. Conclusions: The ACC/AHA guidelines were superior to the ESC/EAS guidelines for primary prevention of ASCVD, that is, for accurately assigning statin therapy to those who would benefit. PMID- 28363220 TI - Time to change the SCORE? PMID- 28363219 TI - Associations between single and multiple cardiometabolic diseases and cognitive abilities in 474 129 UK Biobank participants. AB - Aims: Cardiometabolic diseases (hypertension, coronary artery disease [CAD] and diabetes are known to associate with poorer cognitive ability but there are limited data on whether having more than one of these conditions is associated with additive effects. We aimed to quantify the magnitude of their associations with non-demented cognitive abilities and determine the extent to which these associations were additive. Methods and results: We examined cognitive test scores in domains of reasoning, information processing speed and memory, included as part of the baseline UK Biobank cohort assessment (N = 474 129 with relevant data), adjusting for a range of potentially confounding variables. The presence of hypertension, CAD and diabetes generally associated with poorer cognitive scores on all tests, compared with a control group that reported none of these diseases. There was evidence of an additive deleterious dose effect of an increasing number of cardiometabolic diseases, for reasoning scores (unstandardized additive dose beta per disease = -0.052 score points out of 13, 95% CI [confidence intervals] -0.063 to - 0.041, P < 0.001), log reaction time scores (exponentiated beta = 1.005, i.e. 0.5% slower, 95% CI 1.004-1.005, P < 0.001) and log memory errors (exponentiated beta = 1.005 i.e. 0.5% more errors; 95% CI 1.003-1.008). Conclusion: Cardiometabolic diseases are associated with worse cognitive abilities, and the potential effect of an increasing number of cardiometabolic conditions appears additive. These results reinforce the notion that preventing or delaying cardiovascular disease or diabetes may delay cognitive decline and possible dementia. PMID- 28363221 TI - The challenge of risk estimation in cardiovascular prevention. PMID- 28363223 TI - First, do no (irreparable) harm: infarction, bleeding, and subsequent risk of death. The dangers of false equivalency. PMID- 28363224 TI - Improving outcome in acute coronary syndromes: ischaemic conditioning, antithrombosis and bleeding, and inflammasome antagonism. PMID- 28363225 TI - Percutaneous transvenous direct annuloplasty of a human tricuspid valve using the Valtech Cardioband. PMID- 28363226 TI - Frontiers of valvular heart disease: from aortic stenosis to the tricuspid valve and congenital anomalies. PMID- 28363222 TI - Trade-off of myocardial infarction vs. bleeding types on mortality after acute coronary syndrome: lessons from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) randomized trial. AB - Aims: Dual antiplatelet therapy reduces non-fatal ischaemic events after acute coronary syndrome (ACS) but increases bleeding to a similar extent. We sought to determine the prognostic impact of myocardial infarction (MI) vs. bleeding during an extended follow-up period to gain insight into the trade-off between efficacy and safety among patients after ACS. Methods and results: In 12 944 patients with non-ST-segment elevation ACS from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial, we investigated the relative impact of MI and bleeding occurring >30 days post-ACS and subsequent all cause mortality. Bleeding was graded according to Bleeding Academic Research Consortium (BARC) criteria. MI was associated with a five-fold increase in mortality. BARC type 2 and 3, but not type 1, bleeding had a significant impact on mortality. MI was associated with a greater risk of mortality compared with BARC 2 [relative risk (RR) 3.5; 95% confidence interval (CI) 2.08-4.77; P < 0.001] and BARC 3a bleeding (RR 2.23; 95% CI 1.36-3.64; P = 0.001), and a risk similar to BARC 3b bleeding (RR 1.37; 95% CI 0.81-2.30; P = 0.242). Risk of death after MI was significantly lower than after BARC 3c bleeding (RR 0.22; 95% CI 0.13-0.36; P < 0.001). MI and bleeding had similar time-associations with mortality, which remained significant for several months, still being higher early after the event. Conclusion: In patients treated with antiplatelet therapy after ACS, both MI and bleeding significantly impacted mortality with similar time-dependency. Although BARC 2 and 3a bleeding were less prognostic for death than MI, the risk of mortality was equivalent between BARC 3b bleeding and MI, and was higher following BARC 3c bleeding. PMID- 28363228 TI - Super-Thin and Suprafascial Anterolateral Thigh Perforator Flaps for Extremity Reconstruction. AB - Background The anterolateral thigh (ALT) flap remains a workhorse for soft tissue reconstruction. However, the traditional ALT flap is often too bulky for resurfacing shallow, distal extremity defects, prohibiting adequate function, or well-fitted orthotics. This study evaluates extremity reconstruction using ALT flaps elevated in the suprafascial or super-thin plane. Methods Retrospective review of ALT free flap reconstruction from October 2014 to July 2016 was performed. Suprafascial and super-thin flaps were those elevated just above the crural fascia and within the superficial scarpal plane, respectively. Adjunct operative procedures, demographics, and complications were recorded. Results A total of 25 patients underwent suprafascial (n = 14) or super-thin (n = 11) ALT flap reconstruction for primarily lower extremity wounds (n = 19), with an average age and body mass index of 53.8 years and 26.3 kg/m2, respectively. Follow-up was 6.3 months. Comorbidities included smoking (n = 7), diabetes (n = 8), peripheral vascular disease (n = 6), and hypertension (n = 8). The presence of hardware (n = 9), trauma (n = 10), and chronic infection (n = 12) were common risk factors. Average flap size was 8.2 * 21.5 cm, with 64% (n = 16) taken on one perforator. Forty-eight percent (n = 12) were end-to-side anastomoses and 62% (n = 13) utilized one venous anastomosis. Mean hospital stay was 7.8 days with a 24% (n = 6) complication rate. There were no partial or complete flap losses. Conclusion The ALT flap, elevated in a suprafascial or super-thin plane, is a safe, effective option for extremity soft tissue reconstruction. The decreased flap volume and bulk provides the improved contour and pliability necessary for appropriate distal extremity function. The potential versatility of super-thin flaps reinforces the importance of continued innovation by reconstructive microsurgeons. PMID- 28363229 TI - [A Projection of the Need for Rehabilitation in Germany Till 2040 Based on Demographic Factors]. AB - The demographic changes in Germany leads to a significant shift in the composition of the population and the workforce, this affecting the future need for medical rehabilitation. This paper estimates the future change in rehabilitation demand based on a forecast for demographic changes till 2040. First, the sensitivity of the rehabilitation demand with respect to demographic factors is estimated. Second, the demographic factors are projected by stochastic methods, resulting in forecasts for the future need for medical rehabilitation. The projections show that the short-term demand is likely to rise. Theoretically, yearly wage increases of about 2.2% are needed for covering the increasing medical rehabilitation costs from 2010 till 2017. For the mid-term demand, the model predicts a slight decline in rehabilitation cases. Considering all these facts, the budget for rehabilitation will probably not cover the future costs for rehabilitation. However, the long-term forecast is subject to considerable uncertainty. PMID- 28363230 TI - Ovarian Manson's Schistosomiasis: Rare Diagnosis or Underestimated Prevalence? AB - The occurrence of Manson's schistosomiasis in organs of the female reproductive tract is an uncommon event, given that the etiological agent for this disease is a blood parasite that inhabits the mesenteric veins. In this case report, a 45 year-old female patient reported that her first symptoms had been strong pain in the left iliac region around two years earlier. An endovaginal pelvic ultrasonography showed that the left ovary was enlarged, and the report suggested that this finding might be correlated with clinical data and tumor markers. After being examined at several healthcare services, the patient was referred to an oncology service due to suspected neoplasia, where she underwent a left ovariectomy. The result from the histopathological examination showed the presence of granulomatous inflammatory processes surrounding both viable and calcified eggs of Schistosoma mansoni. There was no evidence of any neoplastic tissue. The patient was medicated and followed-up as an outpatient. PMID- 28363231 TI - [Management of adverse effects of opioid therapy]. AB - More than 6 million people in Germany suffer from chronic pain which greatly impairs their wellbeing. Often the only therapeutic option is to use class 2 or 3 analgesic opioids in the WHO classification, as class 1 analgesics may be toxic or of limited efficacy. However, the high incidence of opioid side effects leads to high discontinuation rates. Thus, the success of opioid treatment is also highly dependent on the management of the safety and tolerability of the treatment. Most opioid side effects, such as nausea and sedation, predominantly occur in the initial phase of therapy. In contrast, opioid-induced constipation can last throughout opioid therapy. First-line treatment with laxatives does not solve the problem in all patients. Possible second-line therapies include opioid receptor antagonists, such as Naloxone, oral-administered Naloxegol, or subcutaneously given Methylnaltrexone. The discussion also covers the management of other common side effects of opioids, such as nausea, vomiting, sedation, pruritus, micturition disorder, and further symptoms. PMID- 28363233 TI - ? PMID- 28363234 TI - ["Die Plazenta ist die Lunge des Feten"]. PMID- 28363236 TI - X-ray Study of Structural Formation and Thermomechanical Properties of Silver Containing Polymer Nanocomposites. AB - The structural organization and thermomechanical properties of nanocomposites prepared from interpolyelectrolyte-metal complex (IMC) involving anionic polyelectrolyte, pectin and AgNO3, and cationic polyelectrolyte, poly(4 vinylpyridine), have been investigated using the methods of wide- and small-angle X-ray scattering and thermomechanical analysis. It is established that chemical reduction of Ag+ ions in the IMC by sodium borohydride results in formation of the nanocomposite based on the "pectin-poly(4-vinylpyridine)" interpolyelectrolyte complex (IPEC) and Ag0 nanoparticles as well. At the same time, the level of nanocomposites' structural heterogeneity is substantially enhancing, while effective size of the heterogeneity regions decreases. The nanocomposites IPEC-Ag0 prepared are shown much bigger T g value and enhanced ability for deformation than those for IMC. PMID- 28363235 TI - The Synthesis of Size-Adjustable Superparamagnetism Fe3O4 Hollow Microspheres. AB - One hundred fifty to 300-nm-sized monodisperse iron oxide (Fe3O4) hollow microspheres were synthesized by the one-pot hydrothermal method. The morphology and crystal structure of the as-prepared hollow microspheres was characterized by scanning electron microscopy, X-ray diffraction, transmission electron microscopy, and high-resolution transmission electron microscopy, while the magnetic property was investigated by vibrating sample magnetometer. We found that the particle size of the hollow microspheres was related to the amount of sodium citrate, polyacrylamide (PAM), and urea. The hollow structure of Fe3O4 microspheres has high magnetization saturation values ranging in 49.10-75.41 emu/g. PMID- 28363237 TI - Quantum Entanglement in Double Quantum Systems and Jaynes-Cummings Model. AB - In the paper, we proposed a new approach to producing the qubits in electron transport in low-dimensional structures such as double quantum wells or double quantum wires (DQW). The qubit could arise as a result of quantum entanglement of two specific states of electrons in DQW structure. These two specific states are the symmetric and antisymmetric (with respect to inversion symmetry) states arising due to tunneling across the structure, while entanglement could be produced and controlled by means of the source of nonclassical light. We examined the possibility to produce quantum entanglement in the framework of Jaynes Cummings model and have shown that at least in principle, the entanglement can be achieved due to series of "revivals" and "collapses" in the population inversion due to the interaction of a quantized single-mode EM field with a two-level system. PMID- 28363238 TI - Preparation and Properties of Nanocellulose from Organosolv Straw Pulp. AB - The object of this work is to present a study of nanocellulose preparation from organosolv straw pulp (OSP) and its properties. OSP was obtained through thermal treatment in the system of isobutyl alcohol-H2O-KOH-hydrazine followed by processing in the mixture of acetic acid and hydrogen peroxide for bleaching and removal of residual non-cellulosic components. We have obtained nanocellulose from OSP through acid hydrolysis with lower consumption of sulfuric acid and followed by ultrasound treatment. The structural change and crystallinity degree of OSP and nanocellulose were studied by means of SEM and XRD techniques. It has been established that nanocellulose has a density up to 1.3 g/cm3, transparency up to 70%, crystallinity degree 72.5%. The TEM and AFM methods shown that nanocellulose have diameter of particles in the range from 10 to 40 nm. Thermogravimetric analysis confirmed that nanocellulose films have more dense structure and smaller mass loss in the temperature range 220-260 degrees C compared with OSP. The obtained nanocellulose films had high Young's modulus up to 11.45 GPa and tensile strength up to 42.3 MPa. The properties of obtained nanocellulose from OSP exhibit great potential in its application for the preparation of new nanocomposite materials. PMID- 28363239 TI - Influence of Fabrication Processes and Annealing Treatment on the Minority Carrier Lifetime of Silicon Nanowire Films. AB - Surface passivation and bulk carrier lifetime of silicon nanowires (SiNWs) are essential for their application in solar cell devices. The effective minority carrier lifetime of a semiconductor material is influenced by both its surface passivation and bulk carrier lifetime. We found that the effective carrier lifetime of SiNWs passivated with aluminum oxide (Al2O3) was significantly influenced by the fabrication process of SiNWs. We could not measure the effective lifetime of SiNWs fabricated by thermal annealing of amorphous silicon nanowires. Nevertheless, the SiNWs fabricated by metal-assisted chemical etching of polycrystalline silicon displayed an effective lifetime of 2.86 MUs. Thermal annealing of SiNWs at 400 degrees C in a forming gas improved the effective carrier lifetime from 2.86 to 15.9 MUs because of the improvement in surface passivation at the interface between the SiNWs and Al2O3 layers. PMID- 28363240 TI - Sol-gel Synthesis, Photo- and Electrocatalytic Properties of Mesoporous TiO2 Modified with Transition Metal Ions. AB - Mesoporous nanosized titania films modified with Co2+, Ni2+, Mn3+, and Cu2+ ions have been produced by templated sol-gel method and characterized by optical spectroscopy, X-ray diffraction (XRD), and Brunauer, Emmett, and Teller (BET) surface area measurement. Band gap energy and the position of flat band potentials were estimated by photoelectrochemical measurements. The films doped with transition metals possessed higher photocurrent quantum yield, as well as photo- and electrochemical activity compared to undoped samples. Mn+/TiO2 (M-Co, Ni, Mn, Cu) electrodes with low dopant content demonstrate high efficiency in electrocatalytic reduction of dissolved oxygen. Polarization curves of TiO2, TiO2/Ni2+, TiO2/Co2+/3+, and TiO2/Mn3+ electrodes contain only one current wave (oxygen reduction current). It means that reaction proceeds without the formation of an intermediate product H2O2. PMID- 28363241 TI - Composition, Microstructure, and Electrical Properties Control of the Powders Synthesized by Sol-Gel Auto-Combustion Method Using Citric Acid as the Fuel. AB - Nanocrystalline lithium ferrite Li 0.5 Fe 1.7 Mg 0.8 O 4 powders were synthesized by the sol-gel auto-combustion method from the corresponding metal nitrates using citric acid as fuel.The results from XRD, SEM, and AC electrical conductivity studies are summarized as follows: The results of XRD analysis showed that all the samples were formed in single-phase cubic spinel structure at different annealing temperatures from 300 to 700 degrees C for 2 h. The lattice parameter was found to decrease on increasing the temperature. The microstructure of lithium ferrite powders was temperature dependent. The particle size was increased with the annealing temperature. AC electrical properties were investigated using the super-linear power law and activation energies were calculated for all compositions. The electron mobility in Li 0.5 Fe 1.7 Mg 0.8 O 4 samples ranged from 0.05 to 0.29 eV, which clearly indicated that the present lithium ferrites have semiconductor-like behavior. The frequency exponent "s" of lithium ferrite lies in the range 0.5 < s < 1, which confirms the electron hopping between Fe 2 + and Fe 3 + ions. PMID- 28363242 TI - Enhanced Performance of Planar Perovskite Solar Cells Using Low-Temperature Solution-Processed Al-Doped SnO2 as Electron Transport Layers. AB - Lead halide perovskite solar cells (PSCs) appear to be the ideal future candidate for photovoltaic applications owing to the rapid development in recent years. The electron transport layers (ETLs) prepared by low-temperature process are essential for widespread implementation and large-scale commercialization of PSCs. Here, we report an effective approach for producing planar PSCs with Al3+ doped SnO2 ETLs prepared by using a low-temperature solution-processed method. The Al dopant in SnO2 enhanced the charge transport behavior of planar PSCs and increased the current density of the devices, compared with the undoped SnO2 ETLs. Moreover, the enhanced electrical property also improved the fill factors (FF) and power conversion efficiency (PCE) of the solar cells. This study has indicated that the low-temperature solution-processed Al-SnO2 is a promising ETL for commercialization of planar PSCs. PMID- 28363243 TI - Pd Nanoparticles and MOFs Synergistically Hybridized Halloysite Nanotubes for Hydrogen Storage. AB - Natural halloysite nanotubes (HNTs) were hybridized with metal-organic frameworks (MOFs) to prepare novel composites. MOFs were transformed into carbon by carbonization calcination, and palladium (Pd) nanoparticles were introduced to build an emerging ternary compound system for hydrogen adsorption. The hydrogen adsorption capacities of HNT-MOF composites were 0.23 and 0.24 wt%, while those of carbonized products were 0.24 and 0.27 wt% at 25 degrees C and 2.65 MPa, respectively. Al-based samples showed higher hydrogen adsorption capacities than Zn-based samples on account of different selectivity between metal and hydrogen and approximate porous characteristics. More pore structures are generated by the carbonization reaction from metal-organic frameworks into carbon; high specific surface area, uniform pore size, and large pore volume benefited the hydrogen adsorption ability of composites. Moreover, it was also possible to promote hydrogen adsorption capacity by incorporating Pd. The hydrogen adsorption capacity of ternary compound, Pd-C-H3-MOFs(Al), reached 0.32 wt% at 25 degrees C and 2.65 MPa. Dissociation was assumed to take place on the Pd particles, then atomic and molecule hydrogen spilled over to the structure of carboxylated HNTs, MOFs, and the carbon products for enhancing the hydrogen adsorption capacity. PMID- 28363244 TI - Optical Constants and Band Gap Evolution with Phase Transition in Sub-20-nm-Thick TiO2 Films Prepared by ALD. AB - Titanium dioxide (TiO2) ultrathin films with different thicknesses below 20 nm were grown by atomic layer deposition (ALD) on silicon substrates at 300 degrees C. Spectroscopic ellipsometry (SE) measurements were operated to investigate the effect of thickness on the optical properties of ultrathin films in the spectra range from 200 to 1000 nm with Forouhi-Bloomer (F-B) dispersion relation. It has been found that the refractive index and extinction coefficient of the investigated TiO2 ultrathin film increase while the band gap of TiO2 ultrathin film decreases monotonically with an increase in film thickness. Furthermore, with the purpose of studying the temperature dependence of optical properties of TiO2 ultrathin film, the samples were annealed at temperature from 400 to 900 degrees C in N2 atmosphere. The crystalline structure of deposited and annealed films was deduced by SE and supported by X-ray diffraction (XRD). It was revealed that the anatase TiO2 film started to transform into rutile phase when the annealing temperature was up to 800 degrees C. In this paper, a constructive and effective method of monitoring the phase transition in ultrathin films by SE has been proposed when the phase transition is not so obvious analyzed by XRD. PMID- 28363245 TI - An Experimental Study of the Kinetics of OH/OD(v = 1,2,3) + SO2: The Limiting High-Pressure Rate Coefficients as a Function of Temperature. AB - The kinetics of the reaction OH/OD(v = 1,2,3) + SO2 were studied using a photolysis/laser-induced fluorescence technique. The rate coefficients OH/OD(v = 1,2,3) + SO2, k1, over the temperature range of 295-810 K were used to determine the limiting high-pressure limit k1infinity. This method is usually applicable if the reaction samples the potential well of the adduct HOSO2 and if intramolecular vibrational relaxation is fast. In the present case, however, the rate coefficients showed an additional fast removal contribution as evidenced by the increase in k1 with vibrational level; this behavior together with its temperature dependence is consistent with the existence of a weakly bound complex on the potential energy surface prior to adduct formation. The data were analyzed using a composite mechanism that incoporates energy-transfer mechanisms via both the adduct and the complex, and yielded a value of k1infinity(295 K) equal to (7.2 +/- 3.3) * 10-13 cm3 molecule-1 s-1 (errors at 1sigma), a factor of between 2 and 3 smaller than the current recommended IUPAC and JPL values of (2.0 1.0+2.0) and (1.6 +/- 0.4) * 10-12 cm3 molecule-1 s-1 at 298 K, respectively, although the error bars do overlap. k1infinity was observed to only depend weakly on temperature. Further evidence for a smaller k1infinity is presented in the companion paper. PMID- 28363246 TI - Results From a Tailored SMS and Behavior-Tracking Pilot Study on Sun-Safe Behaviors in Young Women. AB - BACKGROUND: The elevated rates of ultraviolet radiation (UVR) exposure and low rates of sun protection in young adult women indicate a need for age- and gender appropriate interventions that address these behaviors. AIMS: To examine the effects of daily behavior tracking and individually tailored text messages on sun protection and UVR exposure behaviors in young adult women at moderate to high risk of developing skin cancer. METHOD: One hundred and four young adult women at risk of skin cancer were randomized to receive the behavior-tracking intervention only, tailored text messages only, both interventions, or neither. Outcomes were self-reported UVR exposure and sun protection behaviors. RESULTS: Those who received the behavior-tracking intervention reported significantly fewer UVR exposure behaviors at 4-week follow-up, relative to those who did not receive behavior tracking. At 4-week follow-up, those who received daily tailored text messages reported significantly greater UVR exposure behaviors but were more likely to report wearing a hat as a form of sun protection, relative to those who did not receive tailored messages. DISCUSSION: Daily behavior tracking may be repetitive, but repetition may facilitate cognitive processing and the development of healthy habits. Health messages that are less interactive, on the other hand, need to be adequately tailored and delivered with the most advantageous timing to be impactful. CONCLUSION: Future research should continue to examine how these interventions differentially affect behavior and how they can be adapted to apply to other health behaviors. PMID- 28363249 TI - Applying proteomics to detect early signs of chronic kidney disease: where has the magic gone? PMID- 28363247 TI - Gene Delivery of Calreticulin Anti-Angiogenic Domain Attenuates the Development of Choroidal Neovascularization in Rats. AB - Choroidal neovascularization (CNV) is a common pathological feature in neovascular age-related macular degeneration, which is the leading cause of vision loss among elderly populations in developed countries. This study evaluated the effect of a novel endogenous inhibitor of angiogenesis, calreticulin anti-angiogenic domain (CAD), subconjunctivally delivered by an adenoviral vector (Ad-CAD) in a rat model of laser-induced CNV. CAD was expressed in Ad-CAD-infected cells and inhibited the angiogenic activity in human umbilical vein endothelial cells in vitro. CAD expression was also found in various ocular tissues after in vivo subconjunctival Ad-CAD injection. Via bioluminescence imaging it is shown that a single subconjunctival injection of Ad-luciferase induced the expression of the transgene in the injected eyes within 24 h, which lasted for at least 112 days. Forty-two days after subconjunctival injection of Ad-CAD, retinal structure and function were unaffected, as measured using optical coherence tomography and electroretinography, respectively. After laser injury, subconjunctival Ad-CAD gene delivery significantly inhibited CNV lesions as measured via choroid flat-mounts (51% reduction at 21 days; p < 0.001), as well as by fundus fluorescein angiography (19.3%, 28.2%, 31%, and 27.5% reductions at days 21, 28, 35, and 42, respectively; p < 0.05) in rats. The data suggest that subconjunctival Ad-CAD gene therapy could effectively inhibit laser-induced CNV and might be an attractive therapeutic approach for the management of choroidal neovascularization. PMID- 28363250 TI - Prevalence of ADHD in Publicly Insured Adults. AB - OBJECTIVE: To estimate the prevalence of adult ADHD diagnosis and treatment in U.S. Medicaid beneficiaries. METHOD: Using outpatient, inpatient, and pharmacy billing records for patients eligible for Medicaid fee-for-service benefits within 29 states from 1999 to 2010, we estimated the annual prevalence of ADHD diagnosis and treatment. RESULTS: The prevalence of ADHD diagnosis increased from 2.20 per 1,000 patients in 1999 to 10.57 in 2010. Likewise, prevalence of ADHD treatment increased from 1.95 per 1,000 patients in 1999 to 13.16 in 2010. Between 40% and 65%, patients had ADHD drug prescription fills 6 months after ADHD diagnosis, whereas 45% to 55% of the beneficiaries with an ADHD drug prescription fill had ADHD diagnoses within 6 months before the prescription. CONCLUSION: In publicly insured adults, the prevalence of ADHD diagnosis and treatment increased dramatically over the years. Approximately half of the diagnosed patients are not treated, whereas half of the treated adults are not diagnosed. PMID- 28363248 TI - The Resting-State Functional Magnetic Resonance Imaging Regional Homogeneity Metrics-Kendall's Coefficient of Concordance-Regional Homogeneity and Coherence Regional Homogeneity-Are Valid Indicators of Tumor-Related Neurovascular Uncoupling. AB - The aim of this study is to determine whether regional homogeneity (ReHo) of resting-state blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (rsfMRI) data based on Kendall's coefficient of concordance (KCC-ReHo) and coherence (Cohe-ReHo) metrics may allow detection of brain tumor induced neurovascular uncoupling (NVU) in the sensorimotor network similar to findings in standard motor task-based BOLD fMRI (tbfMRI) activation. Twelve de novo brain tumor patients undergoing clinical fMRI exams (tbfMRI and rsfMRI) were included in this Institutional Review Board (IRB)-approved study. Each patient displayed decreased/absent tbfMRI activation in the primary ipsilesional sensorimotor cortex in the absence of corresponding motor deficit or suboptimal task performance, consistent with NVU. Z-score maps for motor tasks were obtained from the general linear model (GLM) analysis (reflecting motor activation vs. rest). KCC-ReHo and Cohe-ReHo maps were calculated from rsfMRI data. Precentral and postcentral gyri in contralesional (CL) and ipsilesional (IL) hemispheres were parcellated using an automated anatomical labeling (AAL) template for each patient. Similar region of interest (ROI) analysis was performed on tbfMRI, KCC ReHo, and Cohe-ReHo maps to allow direct comparison of results. Voxel values in CL and IL ROIs of each map were divided by the corresponding global mean of KCC ReHo and Cohe-ReHo in bihemispheric cortical brain tissue. Group analysis revealed significantly decreased IL mean KCC-ReHo (p = 0.02) and Cohe-ReHo (p = 0.04) metrics compared with respective values in the CL ROIs, consistent with similar findings of significantly decreased ipsilesional BOLD signal for tbfMRI (p = 0.0005). Ipsilesional abnormalities in ReHo derived from rsfMRI may serve as potential indicators of NVU in patients with brain tumors and other resectable brain lesions; as such, ReHo findings may complement findings on tbfMRI used for presurgical planning. PMID- 28363251 TI - Assessment of air sampling methods and size distribution of virus-laden aerosols in outbreaks in swine and poultry farms. AB - Swine and poultry viruses, such as porcine reproductive and respiratory syndrome virus (PRRSV), porcine epidemic diarrhea virus (PEDV), and highly pathogenic avian influenza virus (HPAIV), are economically important pathogens that can spread via aerosols. The reliability of methods for quantifying particle associated viruses as well as the size distribution of aerosolized particles bearing these viruses under field conditions are not well documented. We compared the performance of 2 size-differentiating air samplers in disease outbreaks that occurred in swine and poultry facilities. Both air samplers allowed quantification of particles by size, and measured concentrations of PRRSV, PEDV, and HPAIV stratified by particle size both within and outside swine and poultry facilities. All 3 viruses were detectable in association with aerosolized particles. Proportions of positive sampling events were 69% for PEDV, 61% for HPAIV, and 8% for PRRSV. The highest virus concentrations were found with PEDV, followed by HPAIV and PRRSV. Both air collectors performed equally for the detection of total virus concentration. For all 3 viruses, higher numbers of RNA copies were associated with larger particles; however, a bimodal distribution of particles was observed in the case of PEDV and HPAIV. PMID- 28363252 TI - First Published Study with Embryonated Hen Egg Infected with Zika Virus Is Dated from 1952. PMID- 28363253 TI - The Traumatic Brain Injury Endpoints Development (TED) Initiative: Progress on a Public-Private Regulatory Collaboration to Accelerate Diagnosis and Treatment of Traumatic Brain Injury. AB - The Traumatic Brain Injury Endpoints Development (TED) Initiative is a 5-year, Department of Defense (DoD) funded project that is working toward the ultimate goal of developing better designed clinical trials, leading to more precise diagnosis, and effective treatments for traumatic brain injury (TBI). TED is comprised of leading academic clinician-scientists, along with innovative industry leaders in biotechnology and imaging technology, patient advocacy organizations, and philanthropists, working collaboratively with regulatory authorities, specifically the US Food and Drug Administration (FDA). The goals of the TED Initiative are to gain consensus and validation of TBI clinical outcome assessment measures and biomarkers for endorsement by global regulatory agencies for use in drug and device development processes. This manuscript summarizes the Initiative's Stage 1 progress over the first 18 months, including intensive engagement with a number of FDA divisions responsible for review and validation of biomarkers and clinical outcome assessments, progression into the prequalification phase of FDA's Medical Device Development Tool program for a candidate set of neuroimaging biomarkers, and receipt of FDA's Recognition of Research Importance Letter regarding TBI. Other signal achievements relate to the creation of the TED Metadataset, harmonizing study measures across eight major TBI studies, and the leadership role played by TED investigators in the conversion of the NINDS TBI Common Data Elements (CDEs) to Clinical Data Interchange Standards Consortium (CDISC) standards. This paper frames both the near-term expectations and the Initiative's long-term vision to accelerate approval of treatments for patients affected by TBI in urgent need of effective therapies. PMID- 28363254 TI - Pancreatic neuroendocrine carcinoma with exocrine differentiation in a young cat. AB - A 35-mo-old spayed female mixed-breed cat with continuous vomiting, emaciation, and abdominal distention for 2 wk was presented to a private veterinary clinic for evaluation. At 71 d after the initial visit, the cat died with anemia, jaundice, and hypoalbuminemia, and was subjected to autopsy. Grossly, numerous firm masses, 0.5-2.5 cm diameter, were randomly located in the left lobe of the pancreas. Histologic examination revealed that the pancreatic mass consisted of 2 tumor cell types: mostly small round cells with a minority of epithelial cells. The small cells were arranged in nests of various sizes, which were separated by thin fibrous stroma, and had small, round, hyperchromatic nuclei, scant cytoplasm containing argyrophilic granules, and often formed rosettes. The epithelial cells formed luminal structures. Metastases were observed in the liver, greater omentum, and pancreatic, gastric, pulmonary, and mediastinal lymph nodes. Immunohistochemical examination revealed that the small cells were positive for vimentin, neuron-specific enolase, chromogranin A, cytokeratin (CK) AE1/AE3, and trypsin, whereas the epithelial cells were positive for AE1/AE3, trypsin, CK19, and nestin. Ultrastructurally, the small cells contained abundant electron-dense granules, ~200 nm diameter, whereas the epithelial cells had apical microvilli and numerous zymogen granules, ~300 nm diameter. These findings indicated that the tumor was a pancreatic neuroendocrine carcinoma with exocrine differentiation and systemic metastases. PMID- 28363256 TI - Transplantation of Amniotic Scaffold-Seeded Mesenchymal Stem Cells and/or Endothelial Progenitor Cells From Bone Marrow to Efficiently Repair 3-cm Circumferential Urethral Defect in Model Dogs. AB - The treatment options for patients with a urethral defect are limited by the availability of autologous tissues. We hypothesized that transplantation of decellularized human amniotic scaffolds (dHAS) seeded with allogeneic bone marrow mesenchymal cells (BMSCs) and/or endothelial progenitor cells (EPCs) may serve as a promising repair strategy for long segment of circumferential urethral defect. To verify the hypothesis, with urinary catheterization, a 3-cm segment of whole urethra in 25 male mongrel dogs was excised and replaced by dHAS seeded with allogeneic BMSCs and/or EPCs. Postoperative observation and ascending urethrogram found that dHAS+BMSCs+EPCs and dHAS+EPCs groups demonstrated unhindered urination and capacious urethral caliber, which were similar to the normal group, while urethrostenosis was revealed in dHAS+BMSCs, dHAS, and sham-operated groups, with the shortest narrow section in dHAS+BMSCs group and the longest in sham-operated group. Urethral anatomy check and histological analyses showed that new urethral mucosa composed of stratified columnar epithelium completely covered on the inner surface of the graft site in dHAS+BMSCs+EPCs and dHAS+EPCs groups, but the middle epithelium was thin in dHAS+EPCs group, while incompletely covered in dHAS+BMSCs, dHAS, and sham-operated groups, and there were monolayer epithelial cells at the urethrostenosis in dHAS+BMSCs and dHAS groups. In addition, abundant new vessel and blood sinus showed at submucosa in dHAS+BMSCs+EPCs and dHAS+EPCs groups, instead of the scar tissue of collagen deposition and structural distortion at the urethrostenosis in dHAS+BMSCs, dHAS, and sham-operated groups. This study demonstrates that dHAS seeded with BMSCs+EPCs or EPCs can successfully repair a 3 cm circumferential urethral defect in model dogs, but the former works best. This technology may provide some references for human clinical trials on long segment of circumferential urethral defect repair. PMID- 28363255 TI - Glycyrrhizin, a Direct HMGB1 Antagonist, Ameliorates Inflammatory Infiltration in a Model of Autoimmune Thyroiditis via Inhibition of TLR2-HMGB1 Signaling. AB - BACKGROUND: High mobility group box-1 (HMGB1), a non-histone protein, plays an important role in autoimmune diseases. However, the significance of HMGB1 in the pathogenesis of autoimmune thyroiditis has not been reported. The purpose of this study was to explore whether HMGB1 participates in the pathogenesis of autoimmune thyroiditis, and whether glycyrrhizin (GL), a direct inhibitor of HMGB1, attenuates the severity of thyroid inflammatory infiltration in a murine model of autoimmune thyroiditis. METHODS: A total of 80 male NOD.H-2h4 mice were randomly divided into a control or iodine supplement (NaI) group at four weeks of age, and the control group was fed with regular water, whereas the NaI group was supplied with 0.005% sodium iodine water. Another 24 male NOD.H-2h4 mice were also randomized into three groups (eight mice per group) as follows: control, NaI, and GL treatment after iodine supplementation (NaI + GL). The NOD.H-2h4 mice were fed with 0.005% sodium iodide water for eight weeks to enhance autoimmune thyroiditis. After iodine treatment, the mice received intraperitoneal injections of GL for four weeks. The severity of lymphocytic infiltration in the thyroid gland was measured by histopathological studies. The serum levels of HMGB1, tumor necrosis factor alpha, interleukin (IL)-6, IL-1beta, and thyroglobulin antibody titers were measured using an enzyme-linked immunosorbent assay. HMGB1 expression was measured by immunohistochemical staining and real-time polymerase chain reaction. TLR2, HMGB1, MyD88, and nuclear transcription factor kappaB were measured by Western blot. RESULTS: The mRNA expression of HMGB1 was significantly higher at 8 and 16 weeks in the NaI group than it was in the control group. Serum levels of thyroglobulin antibodies, HMGB1, tumor necrosis factor alpha, IL-6, and IL-1beta were significantly increased in the NaI group, but they were dramatically attenuated with GL injection. The prevalence of thyroiditis and the infiltration of lymphocytes were significantly decreased in the NaI + GL group. GL administration also significantly reduced the protein expression of TLR2, MyD88, HMGB1 and nuclear transcription factor kappaB in the thyroid gland and attenuated the severity of thyroiditis. CONCLUSION: HMGB1 may play a crucial role in autoimmune thyroiditis by causing inflammatory infiltration, thus increasing the severity of autoimmune thyroiditis. GL effectively attenuated thyroiditis in the iodine-induced NOD.H-2h4 mice via a molecular mechanism related to the inhibition of TLR2-HMGB1 signaling. PMID- 28363257 TI - Brain lesions associated with acute toxic hepatopathy in cattle. AB - Samples of the liver, telencephalon, brainstem, and cerebellum were obtained from 22 bovids suffering from spontaneous or experimental acute toxic liver disease. Perreyia flavipes larvae, and leaves of Cestrum corymbosum, Cestrum intermedium, Dodonaea viscosa, Trema micrantha, and Xanthium cavanillesii were the causal agents in the disorders studied. Hematoxylin and eosin and periodic acid-Schiff staining, as well as anti-S100 protein (anti-S100), anti-glial fibrillary acidic protein (anti-GFAP), and anti-vimentin immunostaining were used to evaluate the brain sections. Astrocytic changes were observed in all samples and were characterized by swollen vesicular nuclei in gray (Alzheimer type II astrocytes) and white matter; and by abundant eosinophilic or vacuolated cytoplasm with pyknotic nuclei in the white matter. These changes were evidenced by anti-S100 and anti-GFAP immunostaining. Our study demonstrates major changes in astrocytes of cattle that died with neurologic clinical signs as the result of acute toxic liver disease. PMID- 28363259 TI - Suicide Prevention Involves All of Us, Together. PMID- 28363258 TI - Peripheral Hypoarousal but Not Preparation-Vigilance Impairment Endures in ADHD Remission. AB - OBJECTIVE: This study investigates whether impairments associated with persistent ADHD-impaired attention allocation (P3 amplitude), peripheral hypoarousal (skin conductance level [SCL]), and adjustment in preparatory state (contingent negative variation [CNV])-reflect enduring deficits unrelated to ADHD outcome or are markers of ADHD remission. METHOD: Young people with childhood ADHD (73 persisters and 18 remitters) and 144 controls were compared on neurophysiological measures during two conditions (baseline and fast-incentive) of a four-choice reaction time task. RESULTS: ADHD remitters differed from persisters, and were indistinguishable from controls, on baseline P3 amplitude and fast-incentive CNV amplitude ( p <= .05). ADHD remitters differed from controls ( p <= .01), and were indistinguishable from persisters ( p > .05), on baseline SCL. CONCLUSION: Preparation-vigilance measures were markers of ADHD remission, confirming previous findings with other measures. Yet, SCL-measured peripheral hypoarousal emerges as an enduring deficit unrelated to ADHD improvement. Future studies should explore potential compensatory mechanisms that enable efficient preparation-vigilance processes in ADHD remitters. PMID- 28363260 TI - Suicide Prevention. PMID- 28363261 TI - Age of Onset of Mental Disorders. PMID- 28363262 TI - Psychometric Evaluation of the Mental Health Continuum-Short Form in French Canadian Young Adults. AB - OBJECTIVE: To examine the factor structure, internal consistency, reliability, sex invariance, and discriminant validity of the French Canadian version of the Mental Health Continuum-Short Form (MHC-SF). METHOD: A total of 1485 French speaking postsecondary students in Quebec, Canada (58% female; mean age = 18.4, SD = 2.4), completed the MHC-SF. Confirmatory factor analysis (CFA) was used to assess the factorial structure of the MHC-SF. Internal consistency was assessed with Cronbach's alpha, and reliability was assessed with the rho reliability coefficient. Invariance testing across sex was conducted using multigroup CFA comparing 4 increasingly restrictive models, and discriminant validity was examined against the Hospital Anxiety and Depression Scale (HADS) using Pearson correlation coefficients and CFA. RESULTS: CFA supported the correlated 3-factor structure of the MHC-SF, with emotional, social, and psychological well-being subscales. The scale and each subscale items had internal consistency coefficients (Cronbach's alphas) above .70 and reliability coefficients (Joreskog's rho) ranging from .79 to .90. Based on the multigroup CFA, configural, metric, scalar, and error variance invariance of the MHC-SF was observed across sex. Finally, the 2-continua model, suggesting that mental health and mental illness are distinct but related dimensions, was supported by both moderate inverse correlations between MHC-SF and HADS subscale scores and the 2 factor structure in CFA. CONCLUSIONS: These data support the multidimensional structure of the MHC-SF and provide evidence of internal consistency, reliability, and invariance across sex. The MHC-SF is a valid and reliable measure of mental health that is distinct from mental illness among French Canadian young adults. PMID- 28363263 TI - Child and Youth Mental Health. PMID- 28363264 TI - Evaluating Community-Academic Partnerships of the South Carolina Healthy Brain Research Network. AB - Community-academic partnerships have a long history of support from public health researchers and practitioners as an effective way to advance research and solutions to issues that are of concern to communities and their citizens. Data on the development and evaluation of partnerships focused on healthy aging and cognitive health were limited. The purpose of this article is to examine how community partners view the benefits and barriers of a community-academic partner group established to support activities of the South Carolina Healthy Brain Research Network (SC-HBRN). The SC-HBRN is part of the national Healthy Brain Research Network, a thematic research network funded by the Centers for Disease Control and Prevention (CDC). It is focused on improving the scientific and research translation agenda on cognitive health and healthy aging. Semistructured interviews, conducted at end of Year 2 of the 5-year partnership, were used to collect data from partners of the SC-HBRN. Reported benefits of the partnership were information sharing and networking, reaching a broader audience, and humanizing research. When asked to describe what they perceived as barriers to the collaborative, partners described some lack of clarity regarding goals of the network and opportunities to contribute to the partnership. Study results can guide and strengthen other public health-focused partnerships. PMID- 28363265 TI - Two-Stage Biomarker Protocols for Improving the Precision of Early Detection of Prostate Cancer. AB - BACKGROUND: New cancer biomarkers are being discovered at a rapid pace; however, these tests vary in their predictive performance characteristics, and it is unclear how best to use them. METHODS: We investigated 2-stage biomarker-based screening strategies in the context of prostate cancer using a partially observable Markov model to simulate patients' progression through prostate cancer states to mortality from prostate cancer or other causes. Patients were screened every 2 years from ages 55 to 69. If the patient's serum prostate-specific antigen (PSA) was over a specified threshold in the first stage, a second stage biomarker test was administered. We evaluated design characteristics for these 2 stage strategies using 7 newly discovered biomarkers as examples. Monte Carlo simulation was used to estimate the number of screening biopsies, prostate cancer deaths, and quality-adjusted life-years (QALYs) per 1000 men. RESULTS: The all cancer biomarkers significantly underperformed the high-grade cancer biomarkers in terms of QALYs. The screening strategy that used a PSA threshold of 2 ng/mL and a second biomarker test with high-grade sensitivity and specificity of 0.86 and 0.62, respectively, maximized QALYs. This strategy resulted in a prostate cancer death rate within 1% of using PSA alone with a threshold of 2 ng/mL, while reducing the number of biopsies by 20%. Sensitivity analysis suggests that the results are robust with respect to variation in model parameters. CONCLUSIONS: Two-stage biomarker screening strategies using new biomarkers with risk thresholds optimized for high-grade cancer detection may increase quality adjusted survival and reduce unnecessary biopsies. PMID- 28363266 TI - A Qualitative assessment of the impact of handedness among left-handed surgeons in Saudi Arabia. AB - Among Muslims, the use of the left hand in daily activities is discouraged; many people believe that left-handed physicians lack the competency for surgery. The study aim was to document the experience of left-handed surgeons in Saudi Arabia and the impact of handedness on their training, job performance, collegial relationships, and career progression. This qualitative study included 9 left handed physicians in various surgical specialties from 4 major hospitals in Al Qassim, Saudi Arabia. Face-to-face interviews using a semi-structured questionnaire were conducted. Interview transcripts were analysed with Qualitative Content Analysis Method. Of the participants, 78% were male and the mean age was 40 years. Twenty-two per cent were consultants, 67% were specialists, and 11% were resident physicians. Participants reported the following: (a) a lack of training programmes specific to handedness in undergraduate and postgraduate medical training, (b) inconvenience while being assisted by a right-handed colleague, (c) stress, fatigue, and physical pain due to the use of right-handed instruments, and (d) training of the right hand being the most common adaptation technique for a left-handed surgeon. It was concluded that left-handed surgeons experience difficulty with right-handed instruments and right-handed colleagues during surgery. It is recommended that clinical curriculum incorporate hand-specific training in surgery. PMID- 28363267 TI - Identification and prevalence of swine pasivirus 1 in eastern Romanian pig farms. AB - Swine pasivirus 1 (SPaV-1) was first detected in the feces of healthy pigs in France as a new species in family Picornaviridae. We investigated the presence, distribution, and genetic variability of this virus in 7 geographic areas with intensive pig breeding farms in eastern Romania. A total of 564 porcine specimens, including 82 fecal specimens and 482 pools of organs, were collected from healthy pigs in different stages of production from pathogen-free swine farming units. The virus was found in 6 of 7 areas investigated. Of the 564 samples analyzed, 218 were positive for SPaV-1, with the highest prevalence of the virus in organ homogenates (39% positive) followed by feces (37% positive). The highest susceptibility to infection was found in nurseries (50% positive in both the first and second months of feeding). Sequencing analysis of VP0 revealed 3 different Romanian sequences. The phylogenetic investigations suggest that the Romanian sequences cluster with other Pasivirus strains selected from the GenBank database, forming a separate clade from other Picornaviridae genera and defining the described Pasivirus. PMID- 28363270 TI - Hip Pain: Dry Needling Versus Cortisone Injections. AB - Greater trochanteric pain syndrome (GTPS) is chronic, intermittent pain and tenderness on the outside of the hip. The medical community once thought that a swollen hip bursa was the source of such pain, which led to the use of corticosteroid injections to the bursa to help decrease swelling and pain. However, researchers now believe that injuries to the muscles and tendons around the hip are the actual cause of this pain, and that inflammation is often not involved. A study published in the April 2017 issue of JOSPT explores dry needling as an alternative to cortisone injections to reduce pain and improve function in patients with GTPS. J Orthop Sports Phys Ther 2017;47(4):240. doi:10.2519/jospt.2017.0504. PMID- 28363268 TI - MicroRNA-183-5p Increases with Age in Bone-Derived Extracellular Vesicles, Suppresses Bone Marrow Stromal (Stem) Cell Proliferation, and Induces Stem Cell Senescence. AB - Microvesicle- and exosome-mediated transport of microRNAs (miRNAs) represents a novel cellular and molecular pathway for cell-cell communication. In this study, we tested the hypothesis that these extracellular vesicles (EVs) and their miRNAs might change with age, contributing to age-related stem cell dysfunction. EVs were isolated from the bone marrow interstitial fluid (supernatant) of young (3-4 months) and aged (24-28 months) mice to determine whether the size, concentration, and miRNA profile of EVs were altered with age in vivo. Results show that EVs isolated from bone marrow are CD63 and CD9 positive, and the concentration and size distribution of bone marrow EVs are similar between the young and aged mice. Bioanalyzer data indicate that EVs from both young and aged mice are highly enriched in miRNAs, and the miRNA profile of bone marrow EVs differs significantly between the young and aged mice. Specifically, the miR-183 cluster (miR-96/-182/-183) is highly expressed in aged EVs. In vitro assays demonstrate that aged EVs are endocytosed by primary bone marrow stromal cells (BMSCs), and these aged EVs inhibit the osteogenic differentiation of young BMSCs. Transfection of BMSCs with miR-183-5p mimic reduces cell proliferation and osteogenic differentiation, increases senescence, and decreases protein levels of the miR-183-5p target heme oxygenase-1 (Hmox1). In vitro assays utilizing H2O2 induced oxidative stress show that H2O2 treatment of BMSCs increases the abundance of miR-183-5p in BMSC-derived EVs, and Amplex Red assays demonstrate that H2O2 is elevated in the bone marrow microenvironment with age. Together, these data indicate that aging and oxidative stress can significantly alter the miRNA cargo of EVs in the bone marrow microenvironment, which may in turn play a role in stem cell senescence and osteogenic differentiation by reducing Hmox1 activity. PMID- 28363269 TI - Establishing a Large-Animal Model for In Vivo Reprogramming of Bile Duct Cells into Insulin-Secreting Cells to Treat Diabetes. AB - Type 1 diabetes manifests as autoimmune destruction of beta cells requiring metabolic management with an exogenous replacement of insulin, either by repeated injection of recombinant insulin or by transplantation of allogeneic islets from cadaveric donors. Both of these approaches have severe limitations. Repeated insulin injection requires intensive blood glucose monitoring, is expensive, and is associated with decreased quality-of-life measures. Islet transplantation, while highly effective, is severely limited by shortage of donor organs. Clinical translation of beta cells derived from pluripotent stem cells is also not yet a reality, and alternative approaches to solving the replacement of lost beta cell function are required. In vivo direct reprogramming offers an attractive approach to generating new endogenous insulin-secreting cells by permanently altering the phenotype of somatic cells after transient expression of transcription factors. Previously, we have successfully restored control of blood glucose in diabetic mice by reprogramming liver cells into glucose-sensitive insulin-secreting cells after the transient, simultaneous delivery of three transcription factors (Pdx1, Ngn3, and MafA) to the liver of diabetic mice, using an adenoviral vector (Ad PNM). Establishing a clinically relevant, large-animal model is a critical next step in translating this approach beyond the proof-of-principle stage in rodents and allowing investigation of vector design, dose and delivery, host response to vector infusion, and establishment of suitable criteria for measuring safety and efficacy. In this feasibility study we infused Ad-PNM into the liver of three diabetic cynomolgus macaques via portal vein catheter. Vector presence and cargo gene and protein expression were detected in liver tissue after infusion with no adverse effects. Refinement of immune suppression significantly extended the period of exogenous PNM expression. This pilot study establishes the suitability of this large-animal model to examine the translation of this approach for treating diabetes. PMID- 28363271 TI - Prediction of Future Injury in Sport: Primary and Secondary Anterior Cruciate Ligament Injury Risk and Return to Sport as a Model. AB - Can we predict future events? Biostatisticians might answer with an unequivocal yes and state that logistic regression models do exactly that: they predict the relative risk of an outcome on the basis of logistic regression of multiple independent variables. If this is the case, then which approaches improve predictive capability? We are not attempting to predict individual events in individual athletes. However, certain approaches can improve predictive power. J Orthop Sports Phys Ther 2017;47(4):228-231. doi:10.2519/jospt.2017.0603. PMID- 28363272 TI - Left Knee Synovial Osteochondromatosis. AB - A 28-year-old male military service member reported to a physical therapist with progressively worsening left knee pain during impact activity and with work duties. Following examination, he physical therapist ordered radiographs of the knee, which revealed severe osteochondromatosis and tricompartmental arthritis. J Orthop Sports Phys Ther 2017;47(4):294. doi:10.2519/jospt.2017.7016. PMID- 28363273 TI - Intra-articular Focal Nodular Synovitis of the Knee. AB - A 32-year-old woman was referred to physical therapy by her primary care provider (PCP) for complaints of limited right knee extension and pain. Radiographs of her right knee ordered by her PCP prior to physical therapy evaluation were noncontributory. To rule out intra-articular pathology, the physical therapist ordered magnetic resonance imaging, which revealed an intra-articular mass. The radiologist recommended contrast imaging to further characterize the mass, which was found to be consistent with focal nodular synovitis. J Orthop Sports Phys Ther 2017;47(4):293. doi:10.2519/jospt.2017.7221. PMID- 28363275 TI - 2016 JOSPT Awards: Additive Effects and Biological Mechanisms of Interventions Offer Important Insights. AB - During the American Physical Therapy Association's Combined Sections Meeting in San Antonio, TX in February 2017, JOSPT recognized the authors of the most outstanding research and clinical practice manuscripts published in JOSPT during 2016. The 2016 JOSPT Excellence in Research Award was presented to Carol A. Courtney, Alana D. Steffen, Cesar Fernandez-de-las-Penas, John Kim, and Samuel J. Chmell, MD, for their March 2016 article "Joint Mobilization Enhances Mechanisms of Conditioned Pain Modulation in Individuals With Osteoarthritis of the Knee." The 2016 George J. Davies-James A. Gould Excellence in Clinical Inquiry Award was presented to Seyda Toprak Celenay, Turkan Akbayrak, and Derya Ozer Kaya for their February 2016 article "A Comparison of the Effects of Stabilization Exercises Plus Manual Therapy to Those of Stabilization Exercises Alone in Patients With Nonspecific Mechanical Neck Pain: A Randomized Clinical Trial." J Orthop Sports Phys Ther 2017;47(4):225-227. doi:10.2519/jospt.2017.0104. PMID- 28363274 TI - April 2017 Letter to the Editor-in-Chief. AB - Letter to the Editor-in-Chief of JOSPT as follows: "Subgrouping Patients With Low Back Pain" with Authors' Response J Orthop Sports Phys Ther 2017;47(4):295. doi:10.2519/jospt.2017.0203. PMID- 28363277 TI - Erratum to: Pharmaceutical cost management in an ambulatory setting using a risk adjustment tool. PMID- 28363276 TI - Relationship between serum bilirubin concentrations and diabetic nephropathy in Shanghai Han's patients with type 1 diabetes mellitus. AB - BACKGROUND: Recent studies highlight a negative association between total bilirubin concentrations and albuminuria in patients with type 2 diabetes mellitus. Our study evaluated the relationship between bilirubin concentrations and the prevalence of diabetic nephropathy (DN) in Chinese patients with type 1 diabetes mellitus (T1DM). METHODS: A total of 258 patients with T1DM were recruited and bilirubin concentrations were compared between patients with or without diabetic nephropathy. Multiple stepwise regression analysis was used to examine the relationship between bilirubin concentrations and 24 h urinary microalbumin. Binary logistic regression analysis was performed to assess independent risk factors for diabetic nephropathy. Participants were divided into four groups according to the quartile of total bilirubin concentrations (Q1, 0.20 0.60; Q2, 0.60-0.80; Q3, 0.80-1.00; Q4, 1.00-1.90 mg/dL) and the chi-square test was used to compare the prevalence of DN in patients with T1DM. RESULTS: The median bilirubin level was 0.56 (interquartile: 0.43-0.68 mg/dL) in the DN group, significantly lower than in the non-DN group (0.70 [interquartile: 0.58-0.89 mg/dL], P < 0.001). Spearman's correlational analysis showed bilirubin concentrations were inversely correlated with 24 h urinary microalbumin (r = 0.13, P < 0.05) and multiple stepwise regression analysis showed bilirubin concentrations were independently associated with 24 h urinary microalbumin. In logistic regression analysis, bilirubin concentrations were significantly inversely associated with nephropathy. In addition, in stratified analysis, from the first to the fourth quartile group, increased bilirubin concentrations were associated with decreased prevalence of DN from 21.90% to 2.00%. CONCLUSION: High bilirubin concentrations are independently and negatively associated with albuminuria and the prevalence of DN in patients with T1DM. PMID- 28363278 TI - Erratum to: A mixed methods feasibility study of nicotine-assisted smoking reduction programmes delivered by community pharmacists - The RedPharm study. PMID- 28363280 TI - Erratum to: Is pre-operative haemoglobin A1c level a successful predictor of adverse outcome after cardiac surgery? PMID- 28363279 TI - Blood markers of fibrinolysis and endothelial activation in canine babesiosis. AB - BACKGROUND: Canine babesiosis is a tick-borne disease caused by hemoprotozoan parasites of the genus Babesia. The disease can be clinically classified into uncomplicated and complicated forms. The aim of this study was to assess the level of endothelial activation and alterations in the fibrinolytic pathway during canine babesiosis. RESULTS: Blood samples were collected on the day of admission and on the 6th day after treatment with imidocarb propionate, from 30 dogs of various breeds and of both sexes with naturally occurring babesiosis caused by B. canis. In this prospective study, plasminogen activity was assessed using a chromogenic assay, and concentrations of high mobility group box-1 protein (HMGB-1), intercellular adhesive molecule-1 (ICAM-1), vascular adhesive molecule-1 (VCAM-1), soluble urokinase receptor of plasminogen activator (suPAR), thrombin activatable fibrinolysis inhibitor (TAFI), soluble thrombomodulin (TM) and plasminogen activator inhibitor-1 (PAI-1) were determined using a canine specific ELISA. Concentrations of TM, HMGB-1, VCAM-1 and suPAR were increased in dogs with babesiosis at admission compared to healthy dogs. After treatment, concentrations of TM were lower in infected dogs compared to healthy dogs. Dogs with babesiosis also had increased concentrations of TM, ICAM-1 and HMGB-1 and decreased plasminogen and PAI-1 at presentation compared to day 6 after treatment. Dogs with complicated babesiosis had higher concentrations of TM, HMGB1 and TAFI at admission compared to the 6th day. CONCLUSIONS: Biomarkers of endothelial activation and fibrinolysis were altered in dogs with babesiosis. Further studies into their usefulness as biomarkers of disease severity or prognosis is warranted. PMID- 28363281 TI - Thoracic spondylolisthesis and spinal cord compression in diffuse idiopathic skeletal hyperostosis: a case report. AB - BACKGROUND: Diffuse idiopathic skeletal hyperostosis has long been regarded as a benign asymptomatic clinical entity with an innocuous clinical course. Neurological complications are rare in diffuse idiopathic skeletal hyperostosis. However, if they do occur, the consequences are often significant enough to warrant major neurosurgical intervention. Neurological complications occur when the pathological process of ossification in diffuse idiopathic skeletal hyperostosis extends to other vertebral ligaments, causing ossification of the posterior longitudinal ligaments and/or ossification of the ligamentum flavum. Thoracic spondylolisthesis with spinal cord compression in diffuse idiopathic skeletal hyperostosis has not previously been reported in the literature. CASE PRESENTATION: A 78-year-old Japanese man presented with a 6-month history of gait disturbance. A magnetic resonance imaging scan of his cervical and thoracic spine revealed anterior spondylolisthesis and severe cord compression at T3 to T4 and T10 to T11, as well as high signal intensity in a T2-weighted image at T10/11. Computed tomography revealed diffuse idiopathic skeletal hyperostosis at T4 to T10. He underwent partial laminectomy of T10 and posterior fusion of T9 to T12. The postoperative magnetic resonance imaging revealed resolution of the spinal cord compression and an improvement in the high signal intensity on the T2 weighted image. CONCLUSIONS: We report the first case of thoracic spondylolisthesis and spinal cord compression in diffuse idiopathic skeletal hyperostosis. Neurosurgical intervention resulted in a significant improvement of our patient's neurological symptoms. PMID- 28363282 TI - Inhaled nitric oxide and acute kidney injury: new insights from observational data. PMID- 28363283 TI - The future of percutaneous renal ablation. PMID- 28363284 TI - Protein coding gene CRNKL1 as a potential prognostic biomarker in esophageal adenocarcinoma. AB - BACKGROUND: Esophageal adenocarcinoma (EAC) is one of the most aggressive gastroesophageal cancers. PTGS2, EGFR, ERBB2 and TP53 are the traditional EAC prognostic biomarkers, but they are still limited in their ability to effectively predict the overall survival. OBJECTIVES: To identify an improved biomarker for predicting the prognosis of EAC by using the expression profile. MATERIALS AND METHODS: Differential co-expression analysis and differential expression analysis were performed to identify the related genes of EAC. The 5-fold cross-validation was used to select a prognostic biomarker from the 532 EAC related genes. RESULTS: CRNKL1 was identified as a prognostic biomarker to predict the survival of EAC patients. It could significantly stratify EAC patients into high-risk and low-risk groups and was much better than the traditional biomarkers. Furthermore, ROC curve also verified that CRNKL1 with the highest area under the curve (AUC), reaching a sensitivity of 83.33% and a specificity of 78.57%. CONCLUSIONS: Our research proposed that CRNKL1 might be a novel prognostic biomarker with better predictive ability by comparing with the traditional biomarkers, which provided a preferable opportunity in the clinical applications of EAC. PMID- 28363286 TI - Analysis of cancer-related lncRNAs using gene ontology and KEGG pathways. AB - BACKGROUND: Cancer is a disease that involves abnormal cell growth and can invade or metastasize to other tissues. It is known that several factors are related to its initiation, proliferation, and invasiveness. Recently, it has been reported that long non-coding RNAs (lncRNAs) can participate in specific functional pathways and further regulate the biological function of cancer cells. Studies on lncRNAs are therefore helpful for uncovering the underlying mechanisms of cancer biological processes. METHODS: We investigated cancer-related lncRNAs using gene ontology (GO) terms and KEGG pathway enrichment scores of neighboring genes that are co-expressed with the lncRNAs by extracting important GO terms and KEGG pathways that can help us identify cancer-related lncRNAs. The enrichment theory of GO terms and KEGG pathways was adopted to encode each lncRNA. Then, feature selection methods were employed to analyze these features and obtain the key GO terms and KEGG pathways. RESULTS: The analysis indicated that the extracted GO terms and KEGG pathways are closely related to several cancer associated processes, such as hormone associated pathways, energy associated pathways, and ribosome associated pathways. And they can accurately predict cancer-related lncRNAs. CONCLUSIONS: This study provided novel insight of how lncRNAs may affect tumorigenesis and which pathways may play important roles during it. These results could help understanding the biological mechanisms of lncRNAs and treating cancer. PMID- 28363285 TI - DisTeam: A decision support tool for surgical team selection. AB - OBJECTIVE: Surgical service providers play a crucial role in the healthcare system. Amongst all the influencing factors, surgical team selection might affect the patients' outcome significantly. The performance of a surgical team not only can depend on the individual members, but it can also depend on the synergy among team members, and could possibly influence patient outcome such as surgical complications. In this paper, we propose a tool for facilitating decision making in surgical team selection based on considering history of the surgical team, as well as the specific characteristics of each patient. METHODS: DisTeam (a decision support tool for surgical team selection) is a metaheuristic framework for objective evaluation of surgical teams and finding the optimal team for a given patient, in terms of number of complications. It identifies a ranked list of surgical teams personalized for each patient, based on prior performance of the surgical teams. DisTeam takes into account the surgical complications associated with teams and their members, their teamwork history, as well as patient's specific characteristics such as age, body mass index (BMI) and Charlson comorbidity index score. RESULTS: We tested DisTeam using intra operative data from 6065 unique orthopedic surgery cases. Our results suggest high effectiveness of the proposed system in a health-care setting. The proposed framework converges quickly to the optimal solution and provides two sets of answers: a) The best surgical team over all the generations, and b) The best population which consists of different teams that can be used as an alternative solution. This increases the flexibility of the system as a complementary decision support tool. CONCLUSION: DisTeam is a decision support tool for assisting in surgical team selection. It can facilitate the job of scheduling personnel in the hospital which involves an overwhelming number of factors pertaining to patients, individual team members, and team dynamics and can be used to compose patient-personalized surgical teams with minimum (potential) surgical complications. PMID- 28363287 TI - Editorial from the new Editor-in-Chief: Artificial Intelligence in Medicine and the forthcoming challenges. PMID- 28363288 TI - Temporal detection and analysis of guideline interactions. AB - BACKGROUND: Clinical practice guidelines (CPGs) are assuming a major role in the medical area, to grant the quality of medical assistance, supporting physicians with evidence-based information of interventions in the treatment of single pathologies. The treatment of patients affected by multiple diseases (comorbid patients) is one of the main challenges for the modern healthcare. It requires the development of new methodologies, supporting physicians in the treatment of interactions between CPGs. Several approaches have started to face such a challenging problem. However, they suffer from a substantial limitation: they do not take into account the temporal dimension. Indeed, practically speaking, interactions occur in time. For instance, the effects of two actions taken from different guidelines may potentially conflict, but practical conflicts happen only if the times of execution of such actions are such that their effects overlap in time. OBJECTIVES: We aim at devising a methodology to detect and analyse interactions between CPGs that considers the temporal dimension. METHODS: In this paper, we first extend our previous ontological model to deal with the fact that actions, goals, effects and interactions occur in time, and to model both qualitative and quantitative temporal constraints between them. Then, we identify different application scenarios, and, for each of them, we propose different types of facilities for user physicians, useful to support the temporal detection of interactions. RESULTS: We provide a modular approach in which different Artificial Intelligence temporal reasoning techniques, based on temporal constraint propagation, are widely exploited to provide users with such facilities. We applied our methodology to two cases of comorbidities, using simplified versions of CPGs. CONCLUSION: We propose an innovative approach to the detection and analysis of interactions between CPGs considering different sources of temporal information (CPGs, ontological knowledge and execution logs), which is the first one in the literature that takes into account the temporal issues, and accounts for different application scenarios. PMID- 28363289 TI - Identification of adverse drug-drug interactions through causal association rule discovery from spontaneous adverse event reports. AB - OBJECTIVE: Drug-drug interaction (DDI) is of serious concern, causing over 30% of all adverse drug reactions and resulting in significant morbidity and mortality. Early discovery of adverse DDI is critical to prevent patient harm. Spontaneous reporting systems have been a major resource for drug safety surveillance that routinely collects adverse event reports from patients and healthcare professionals. In this study, we present a novel approach to discover DDIs from the Food and Drug Administration's adverse event reporting system. METHODS: Data driven discovery of DDI is an extremely challenging task because higher-order associations require analysis of all combinations of drugs and adverse events and accurate estimate of the relationships between drug combinations and adverse event require cause-and-effect inference. To efficiently identify causal relationships, we introduce the causal concept into association rule mining by developing a method called Causal Association Rule Discovery (CARD). The properties of V-structures in Bayesian Networks are utilized in the search for causal associations. To demonstrate feasibility, CARD is compared to the traditional association rule mining (AR) method in DDI identification. RESULTS: Based on physician evaluation of 100 randomly selected higher-order associations generated by CARD and AR, CARD is demonstrated to be more accurate in identifying known drug interactions compared to AR, 20% vs. 10% respectively. Moreover, CARD yielded a lower number of drug combinations that are unknown to interact, i.e., 50% for CARD and 79% for AR. CONCLUSION: Evaluation analysis demonstrated that CARD is more likely to identify true causal drug variables and associations to adverse event. PMID- 28363290 TI - Acute Management of Hand Burns. AB - The hand is extremely susceptible to burn injuries, and hand burns can occur in up to 90% of all major burns. A thorough neurovascular examination of the hand should be performed in the acute setting. Escharotomies are required in patients with full-thickness or circumferential burns, when perfusion of the upper extremity is compromised. The decision for excision and grafting is based on whether the wound will heal in the first 2 to 3 weeks after the burn injury. Acute care and resuscitation are always importance in this patient population; subsequent care leads to optimal hand functionality and cosmetic long-term outcomes. PMID- 28363292 TI - A 3-Phase Approach for the Management of Upper Extremity Electrical Injuries. AB - Upper extremity electrical injuries present with unique pathophysiologic considerations due to the differing mechanisms of injury produced by the electromagnetic field. The initial phase of treatment consists of recognition of other life-threatening injuries, stabilization of patients, and multisystem resuscitation. The second phase of treatment consists of excising devitalized tissue, appropriate wound care to prevent delayed infection, providing temporary and definitive coverage over vital structures, and preventing contracture and joint stiffness via aggressive therapy. The final phase of treatment consists of sensorimotor functional reconstruction via nerve grafting and tendon transfers available based on patients' deficits and available redundant sources. PMID- 28363291 TI - Management of Acute Pediatric Hand Burns. AB - Worldwide, approximately 500,000 children are admitted to the hospital with burn injuries every year. Referral to an accredited burn center is required for burns that involve the hand regardless of age. As with most burn injuries, a multidisciplinary approach is important; however, in the younger pediatric patient, extra resources such as child life services, pediatric psychotherapy, and music therapy all play major roles alongside the nurse, physical therapists, and psychiatrists so that together with the appropriate support for the family involved, a successful outcome can be achieved. PMID- 28363293 TI - Cold Injuries. AB - New treatments of frostbite have led to unprecedented salvage of extremities including fingers and toes. Success is predicated on prompt institution of time sensitive protocols initiated soon after rewarming, particularly the use of thombolytics. Unfortunately, in the urban setting, most patients are not candidates for these treatment modalities. Triple-phase bone scans have allowed for early determination of devitalized parts that need amputation. Reconstructive surgical techniques are typically used to salvage limb length in these devastating injuries. PMID- 28363294 TI - The Use of Dermal Skin Substitutes for the Treatment of the Burned Hand. AB - The hand is commonly affected in burn injuries. Joints and extensor tendons are vulnerable given their superficial location. Durable coverage that permits relative frictionless tendon gliding and minimizes scar contracture is required to optimize functional outcomes. When soft tissue donor sites are limited, the use of dermal skin substitutes provides stable coverage with minimal scarring, good mobility, and acceptable appearance. A comprehensive review of dermal skin substitutes and their use with burn reconstruction of the hand is provided. PMID- 28363295 TI - Biological Principles of Scar and Contracture. AB - Hypertrophic scar and contracture in burn patients is a complex process. Contributing factors include critical injury depth and activation of key cell subpopulations, including deep dermal fibroblasts, myofibroblasts, fibrocytes, and T-helper cells, which cause scarring rather than regeneration. These cells influence each other via cellular profibrotic and antifibrotic signals, which help to determine the outcome. These cells also both modify and interact with extracellular matrix of the wound, ultimately forming hypertrophic scar. Current treatments reduce hypertrophic scar formation or improve remodeling by targeting these pathways and signals. PMID- 28363296 TI - Postburn Upper Extremity Occupational Therapy. AB - Upper extremity burns can result in lifelong complications. A comprehensive occupational therapy program is imperative for restoration of arm function. Edema management, splinting, exercise, scar management, and activities of daily living are key treatment elements to achieve optimal postburn outcomes. Proper patient and family education are essential for therapeutic success. Burn recovery requires a commitment to therapeutic techniques that can progress a patient to their maximal independence. PMID- 28363298 TI - Postburn Contractures of the Hand. AB - Postburn contractures are a common occurrence after severe burn injuries. It is important to understand the pathologic condition and anatomy of specific postburn deformities in order to provide comprehensive surgical care. Postburn contractures can result in a flexion contracture, boutonniere deformity, burn syndactyly, metacarpophalangeal extension contracture, wrist contracture, or claw hand. A patient evaluation is performed before proceeding to the operating room. Surgery sequences require proper incision design, release of the skin, and deeper contracted structures and coverage with an appropriate flap or graft. Postoperative splinting, scar care, and therapy are equally important for a successful outcome. PMID- 28363297 TI - Scar Management of the Burned Hand. AB - Burn injury can result in hypertrophic scar formation that can lead to debilitating functional deficits and poor aesthetic outcomes. Although nonoperative modalities in the early phase of scar maturation are critical to minimize hypertrophic scar formation, surgical management is often indicated to restore hand function. The essential tenant of operative scar management is release of tension, which can often be achieved through local tissue rearrangement. Laser therapy has emerged as a central pillar of subsequent scar rehabilitation. These treatment tools provide an effective resource for the reconstructive surgeon to treat hypertrophic hand scars. PMID- 28363299 TI - Reconstruction of the Adult and Pediatric Burned Hand. AB - Thermal injuries of the hand can have a great impact on function. Initial treatment should focus on the prevention of contracture through the use of tissue sparing techniques and optimized occupational therapy. Surgical intervention should follow the standard reconstructive ladder and can involve several techniques from simple to complex including minimally invasive techniques, such as laser and steroid injection, contracture release and skin grafting, and local tissue rearrangement and regional flaps as well as distant pedicled and free flaps. Reconstructive surgery of the hand, when performed well, can lead to meaningful functional improvement in severe burns. PMID- 28363300 TI - Microsurgical Reconstruction of the Burned Hand and Upper Extremity. AB - Improvements in critical care and burn victim resuscitation have led to increased survival of burned patients. Initial resuscitation, early excision of burned tissues, prevention of burn wound sepsis, and wound coverage remain mainstays of care. Many burn wounds require complex reconstruction. This is particularly important in the hand. Coverage of tendons, ligaments, joints, vessels, nerves, and bones of the hand requires healthy vascularized tissue to maintain viability and function. Local flaps or regional flaps may be within the burn zone of injury. Refined microvascular free tissue transfer techniques offer free tissue transfer as a procedure that can be safely performed. PMID- 28363302 TI - Postburn Contractures of the Elbow and Heterotopic Ossification. AB - Postburn contractures of the elbow are uncommon debilitating sequelae of severe burn injuries, which result from thermal injury to both deep and superficial tissues. When periarticular heterotopic bone forms in association with burn injuries, severe and rigid contractures may develop that prohibit basic functions of daily living and are often refractory to nonoperative intervention. Surgical intervention is aimed at releasing or excising all pathologic anatomy limiting elbow motion. In patients with proper indications, surgical intervention can result in substantial improvement in elbow motion, allowing patients to return to activities of daily living, employment, and recreational activities. PMID- 28363301 TI - Heterotopic Ossification Following Upper Extremity Injury. AB - Heterotopic ossification (HO) presents a substantial barrier to rehabilitation for patients with severe burns or trauma. Although surgical excision is a mainstay of management for this condition, this is unable to address the chronic sequelae of HO, including chronic pain, joint contractures, nerve dysfunction, and open wounds. Current therapeutic modalities are aimed at excision and the prevention of recurrence using nonsteroidal antiinflammatory drugs (NSAIDs) or radiation therapy. Research is now focused on identifying alternative strategies to prevent the initial occurrence of HO through NSAIDs and novel inhibitors of the bone morphogenetic protein signaling pathway. PMID- 28363304 TI - International Disease Burden of Hand Burns: Perspective from the Global Health Arena. AB - Measuring the extent and impact of a health problem is key to being able to address it appropriately. This review uses available information within the framework of the Global Burden of Disease studies to estimate the disease burden due to burn injuries of the hands. The GBD indicates that since 1990 there has been an approximately 30% decrease in the disease burden related to burn injuries. The GBD methods have not been applied specifically to hand burns, but from available data, it is estimated that about 18 million people in the world suffer from sequelae of burns to the hands. PMID- 28363305 TI - Optimizing the Treatment of Burn Injuries of the Upper Extremity. PMID- 28363303 TI - Outcomes Assessment After Hand Burns. AB - Accurately assessing function and disability after hand burns is imperative to improving the management of patients. The biological, social, and psychological impact of these injuries should be considered. The International Classification of Functioning Disability (ICF) and Health Core Sets for Hand Conditions provides a guide to what should be measured and reported. Although many outcomes measures instruments are available to assess patients with hand or burn injuries, few are validated in the subpopulation of hand burns. Further efforts are required to investigate the ability of current assessment instruments to evaluate hand burn outcomes within the ICF framework. PMID- 28363306 TI - High-pressure NMR techniques for the study of protein dynamics, folding and aggregation. AB - High-pressure is a well-known perturbation method used to destabilize globular proteins and dissociate protein complexes or aggregates. The heterogeneity of the response to pressure offers a unique opportunity to dissect the thermodynamic contributions to protein stability. In addition, pressure perturbation is generally reversible, which is essential for a proper thermodynamic characterization of a protein equilibrium. When combined with NMR spectroscopy, hydrostatic pressure offers the possibility of monitoring at an atomic resolution the structural transitions occurring upon unfolding and determining the kinetic properties of the process. The recent development of commercially available high pressure sample cells greatly increased the potential applications for high pressure NMR experiments that can now be routinely performed. This review summarizes the recent applications and future directions of high-pressure NMR techniques for the characterization of protein conformational fluctuations, protein folding and the stability of protein complexes and aggregates. PMID- 28363307 TI - Being a professional in a tumultuous environment. PMID- 28363308 TI - Shaping policy in an antipolicy environment. PMID- 28363309 TI - Improving maternal and infant outcomes by promoting normal physiologic birth on hospital birthing units. PMID- 28363310 TI - Position statement: Political interference in sexual and reproductive health research and health professional education. PMID- 28363311 TI - Council happenings. PMID- 28363313 TI - Honorary note to celebrate the 80th birthday of professor Sandor Barany. PMID- 28363312 TI - High-dose acyclovir combined with foscavir (foscarnet) in the management of severe herpes simplex virus meningoencephalitis. PMID- 28363314 TI - Prescription opioids: New perspectives and research on their role in chronic pain management and addiction. PMID- 28363317 TI - Validation of prescriber risk indicators obtained from prescription drug monitoring program data. AB - BACKGROUND: Prescription opioids are commonly overprescribed. However, validated measures of inappropriate controlled substance prescribing are lacking. This study examined associations between prescriber risk indicators developed as part of a public health surveillance project and medical board disciplinary actions against prescribers. METHODS: We compiled 12 prescriber risk indicators using data from the Maine prescription drug monitoring program (PDMP) for 2010. We used logistic regression models to assess the relative likelihood of the top 1%, 2%, 5%, and 10% of prescribers on each risk indicator having been subject to medical board disciplinary actions, those citing inappropriate prescribing, or those involving license suspension or revocation, during 2010-2014, controlling for prescriber medical specialty and gender. RESULTS: The top 1% of prescribers for number of patients, opioid prescriptions per day, and opioid dosage prescribed per day had a greater likelihood of medical board disciplinary actions citing inappropriate prescribing, relative to a matched sample of other (non-top 1%) prescribers. Of the 56 prescribers in the top 1% for opioid prescriptions per day, nine (16.1%) were sanctioned for inappropriate prescribing, compared with 11 of 224 (0.5%) in the comparison group. The top 2% of prescribers for opioid dosage per day, and average distance patients travel to prescriber, had a greater likelihood of actions involving license suspension, revocation, or denial for renewal. CONCLUSIONS: Measures derived from PDMP data may be useful in assessing levels of inappropriate prescribing of controlled substances in a population of prescribers, and in evaluating changes associated with efforts to influence prescriber behavior. PMID- 28363315 TI - Providing chronic pain management in the "Fifth Vital Sign" Era: Historical and treatment perspectives on a modern-day medical dilemma. AB - BACKGROUND: Over 100 million Americans are living with chronic pain, and pain is the most common reason that patients seek medical attention. Despite the prevalence of pain, the practice of pain management and the scientific discipline of pain research are relatively new fields compared to the rest of medicine - contributing to a twenty-first century dilemma for health care providers asked to relieve suffering in the "Fifth Vital Sign" era. METHODS: This manuscript provides a narrative review of the basic mechanisms of chronic pain and history of chronic pain management in the United States - including the various regulatory, health system and provider factors that contributed to the decline of multidisciplinary pain treatment in favor of the predominant opioid treatment strategy seen today. Multiple non-opioid pain treatment strategies are then outlined. The manuscript concludes with three key questions to help guide future research at the intersection of pain and addiction. CONCLUSIONS: The assessment and treatment of chronic pain will continue to be one of the most common functions of a health care provider. To move beyond an over reliance on opioid medications, the addiction and pain research communities must unite with chronic pain patients to increase the evidence base supporting non-opioid analgesic strategies. PMID- 28363316 TI - Targeting practitioners: A review of guidelines, training, and policy in pain management. AB - This paper reviews the current literature on clinical guidelines, practitioner training, and government/payer policies that have come forth in response to the national rise in prescription opioid overdoses. A review of clinical opioid prescribing guidelines highlights the need for more research on safe and effective treatment options for chronic pain, improved guidance for the best management of post-operative pain, and evaluation of the implementation and impact of guideline recommendations on patient risk and outcomes. Although there is increasing attention to training in pain management in medical schools and medical residency programs, educational opportunities remain highly variable, and the need for additional clinician training in the recognition and treatment of pain as well as opioid use disorder has been recognized. Mandated use of private, federal and state educational and clinical initiatives such as Risk Evaluation and Mitigation Strategies (REMS) and Prescription Drug Monitoring Programs (PDMPs) generally increase utilization of these initiatives, but more research is needed to determine the impact of these initiatives on provider behaviors, treatment access, and patient outcomes. Finally, there is an acute need for more research on safe and effective treatments for chronic pain as well as an increased multi-level focus on improving training and access to evidence-based treatment for opioid use disorder as well as non-pharmacologic and non interventional chronic pain treatments, so that these guideline-recommended interventions can become mainstream, accessible, first-line interventions for chronic pain and/or opioid use disorders. PMID- 28363319 TI - Understanding the demand side of the prescription opioid epidemic: Does the initial source of opioids matter? AB - BACKGROUND: These studies were carried out to examine whether the onset and progression of an opioid substance use disorder (SUD) differed in those who first used opioids to get "high" compared to those who received a prescription from a doctor to relieve pain (Non-Rx vs. Rx groups, respectively). METHODS: A subset of patients (N=214) from an ongoing larger study of patients entering one of 125 drug treatment programs for opioid use disorder across the country agreed to give up their anonymity and participate in structured and open-ended online interviews examining drug abuse patterns. RESULTS: With the exception that the Non-Rx group began their opioid abuse at a younger age than the Rx group and more quickly evolved from initial exposure to regular opioid abuse, there were relatively few differences in the characteristics, patterns and trajectories of opioid abuse. The vast majority of patients in both groups, most of whom had serious, antecedent psychiatric disorders, indicated that they used opioids to self medicate psychological problems (67-73%) and/or stated that opioids provided a means to "escape" from the stresses of everyday life (79-85%). As the SUD progressed, for many individuals any "positive" attributes of opioids waned and avoidance of withdrawal became the overriding concern, often serving as the impetus for treatment. CONCLUSIONS: Our results suggest that self-treatment of co morbid psychiatric disturbances is a powerful motivating force to initiate and sustain abuse of opioids and that the initial source of drugs-a prescription or experimentation-is largely irrelevant in the progression to a SUD. PMID- 28363318 TI - Randomized controlled trial of a computerized opioid overdose education intervention. AB - BACKGROUND: Opioid overdose (OD) has become a significant public health problem in need of effective interventions. The majority of existing educational interventions target provision of naloxone and are conducted in-person; these elements present logistical barriers that may limit wide-spread implementation. This study developed and evaluated an easily disseminated opioid OD educational intervention and compared computerized versus pamphlet delivery METHODS: Participants (N=76) undergoing opioid detoxification were randomly assigned to receive OD education via a Pamphlet (N=25), Computer (N=24), or Computer+Mastery (N=27) with identical content for all delivery modalities. Primary outcomes were changes from pre- to post-intervention in knowledge of opioid effects, opioid OD symptoms, and recommended opioid OD responses, as well as intervention acceptability. Also assessed at 1 and 3-month follow-ups were retention of knowledge and change in reported OD risk behaviors. RESULTS: Knowledge increased following all three intervention-delivery modalities with few between-group differences observed in knowledge gain or acceptability ratings. Largest gains were in the domain of opioid OD response (from 41.8% to 73.8% mean correct responses; p<0.001). Knowledge was well sustained at the 1 and 3-month follow-ups among completers, where a significant reduction was seen in the critical behavioral risk factor of using opioids while alone. CONCLUSION: Opioid overdose education delivered by computer or written pamphlet produced sustained increases in knowledge and reduction in a key behavioral risk factor. RESULTS: Results support further evaluation of this educational intervention that can be used alone or to complement naloxone-training programs. PMID- 28363320 TI - The Prescription Opioid Addiction Treatment Study: What have we learned. AB - BACKGROUND: The multi-site Prescription Opioid Addiction Treatment Study (POATS), conducted by the National Drug Abuse Treatment Clinical Trials Network, was the largest clinical trial yet conducted with patients dependent upon prescription opioids (N=653). In addition to main trial results, the study yielded numerous secondary analyses, and included a 3.5-year follow-up study, the first of its kind with this population. This paper reviews key findings from POATS and its follow-up study. METHODS: The paper summarizes the POATS design, main outcomes, predictors of outcome, subgroup analyses, the predictive power of early treatment response, and the long-term follow-up study. RESULTS: POATS examined combinations of buprenorphine-naloxone of varying duration and counseling of varying intensity. The primary outcome analysis showed no overall benefit to adding drug counseling to buprenorphine-naloxone and weekly medical management. Only 7% of patients achieved a successful outcome (abstinence or near-abstinence from opioids) during a 4-week taper and 8-week follow-up; by comparison, 49% of patients achieved success while subsequently stabilized on buprenorphine naloxone. Long-term follow-up results were more encouraging, with higher abstinence rates than in the main trial. Patients receiving opioid agonist treatment at the time of follow-up were more likely to have better outcomes, though a sizeable number of patients succeeded without agonist treatment. Some patients initiated risky use patterns, including heroin use and drug injection. A limitation of the long-term follow-up study was the low follow-up rate. CONCLUSIONS: POATS was the first large-scale study of the treatment of prescription opioid dependence; its findings can influence both treatment guidelines and future studies. PMID- 28363321 TI - Buprenorphine physician supply: Relationship with state-level prescription opioid mortality. AB - BACKGROUND: Buprenorphine is an effective treatment for opioid use disorder but the supply of buprenorphine physicians is currently inadequate to address the nation's prescription opioid crisis. Perception of need due to rising opioid overdose rates is one possible reason for physicians to adopt buprenorphine. This study examined associations between rates of growth in buprenorphine physicians and prescription opioid overdose mortality rates in US states. METHODS: The total buprenorphine physician supply and number of physicians approved to treat 100 patients (per 100,000 population) were measured from June 2013 to January 2016. States were divided into two groups: those with rates of prescription opioid overdose mortality in 2013 at or above the median (>5.5 deaths per 100,000 population) and those with rates below the median. State-level growth curves were estimated using mixed-effects regression to compare rates of growth between high and low overdose states. RESULTS: The total supply and the supply of 100-patient buprenorphine physicians grew significantly (total supply from 7.7 to 9.9 per 100,000 population, p<0.001; 100-patient supply from 2.2 to 3.4 per 100,000 population, p<0.001). Rates of growth were significantly greater in high overdose states when compared to low overdose states (total supply b=0.033, p<0.01; 100 patient b=0.022, p<0.01). CONCLUSIONS: The magnitude of the US prescription opioid crisis, as measured by the rate of prescription opioid overdose mortality, is associated with growth in the number of buprenorphine physicians. Because this observational design cannot establish causality, further research is needed to elucidate the factors influencing physicians' decisions to begin prescribing buprenorphine. PMID- 28363323 TI - Prescription opioid addiction and chronic pain: More than a feeling. AB - A patient, long before becoming the subject of medical scrutiny is, at first simply a storyteller, a narrator of suffering-a traveler who has visited the kingdom of the ill. "To relieve an illness one must begin, then, by understanding the story." The Emperor of All Maladies; Siddhartha Mukherjee. PMID- 28363322 TI - Pain, hedonic regulation, and opioid misuse: Modulation of momentary experience by Mindfulness-Oriented Recovery Enhancement in opioid-treated chronic pain patients. AB - BACKGROUND: Given the risk of opioid misuse among chronic pain patients being treated with long-term opioid pharmacotherapy, non-pharmacological treatments are needed. Further, in light of hedonic deficits in this population, therapies that enhance positive affect may be useful. The purpose of this study was to examine effects of a Mindfulness-Oriented Recovery Enhancement (MORE) intervention on ecological momentary assessments (EMA) of pain and positive affective experience, and to determine if changes in pain, affect, and their interaction were associated with opioid misuse at post-treatment. METHODS: This study examined unpublished EMA data from a subset of participants (N=55) in a previously published RCT (NCT01505101) of MORE versus a support group (SG) control. Across 8 weeks of treatment, patients completed up to 224 EMA measures of pain and affect. Multilevel models and generalized estimating equations examined effects of treatment on momentary pain and positive affect, and generalized linear models examined associations between pain and affect and changes in opioid misuse by post-treatment. RESULTS: Patients in MORE reported significantly greater improvements in momentary pain (p=0.01) and positive affect (p=0.004) than patients in the SG. Further, over the entire course of treatment, patients in MORE were significantly more likely to exhibit positive affect regulation (OR=2.75) than patients in the SG. Finally, improvements in positive affect (but not pain) over the course of intervention were associated with reduced risk of misusing opioids by post-treatment (p=0.02). CONCLUSION: MORE may be a useful non pharmacological treatment for pain and hedonic deficits among chronic pain patients at risk for opioid misuse. PMID- 28363325 TI - Highlighting Abstracts from the 2016 American Society of Pain Management Nursing Conference: Taking the Next Steps. PMID- 28363324 TI - Sociodemographic predictors of variation in coverage of the national shingles vaccination programme in England, 2014/15. AB - INTRODUCTION: In September 2013, England introduced a shingles vaccination programme to reduce incidence and severity of shingles in the elderly. This study aims to assess variation in vaccine coverage with regards to selected sociodemographic factors to inform activities for improving equity of the programme. METHODS: Eligible 70year-olds were identified from a national vaccine coverage dataset in 2014/15 that includes 95% of GPs in England. NHS England Local Team (LT) and index of multiple deprivation (IMD) scores were assigned to patients based on GP-postcode. Vaccine coverage (%) with 95% confidence intervals (CIs), were calculated overall and by LT, ethnicity and IMD, using binomial regression. RESULTS: Of 502,058 eligible adults, 178,808 (35.6%) had ethnicity recorded. Crude vaccine coverage was 59.5% (95%CI: 59.3-59.7). Coverage was lowest in London (49.6% coverage, 95%CI: 49.0-50.2), and compared to this coverage was significantly higher in all other LTs (+6.3 to +10.4, p<0.001) after adjusting for ethnicity and IMD. Coverage decreased with increasing deprivation and was 8.2% lower in the most deprived (95%CI: 7.3-9.1) compared with the least deprived IMD quintile (64.1% coverage, 95%CI: 63.6-64.6), after adjustment for ethnicity and LT. Compared with White-British (60.7% coverage, 95%CI: 60.5-61.0), other ethnic groups had between 4.0% (Indian) and 21.8% (Mixed: White and Black African) lower coverage. After adjusting for IMD and LT, significantly lower coverage by ethnicity persisted in all groups, except in Mixed: Other, Indian and Bangladeshi compared with White-British. CONCLUSIONS: After taking geography and deprivation into account, shingles vaccine coverage varied by ethnicity. White British, Indian and Bangladeshi groups had highest coverage; Mixed: White and Black African, and Black-other ethnicities had the lowest. Patients' ethnicity and IMD are predictors of coverage which contribute to, but do not wholly account for, geographical variation coverage. Interventions to address service-related, sociodemographic and ethnic inequalities in shingles vaccine coverage are required. PMID- 28363326 TI - Can A Complex Online Intervention Improve Cancer Nurses' Pain Screening and Assessment Practices? Results from a Multicenter, Pre-post Test Pilot Study. AB - Unrelieved cancer pain has an adverse impact on quality of life. While routine screening and assessment forms the basis of effective cancer pain management, it is often poorly done, thus contributing to the burden of unrelieved cancer pain. The aim of this study was to test the impact of an online, complex, evidence based educational intervention on cancer nurses' pain assessment capabilities and adherence to cancer pain screening and assessment guidelines. Specialist inpatient cancer nurses in five Australian acute care settings participated in an intervention combining an online spaced learning cancer pain assessment module with audit and feedback of pain assessment practices. Participants' self perceived pain assessment competencies were measured at three time points. Prospective, consecutive chart audits were undertaken to appraise nurses' adherence with pain screening and assessment guidelines. The differences in documented pre-post pain assessment practices were benchmarked and fed back to all sites post intervention. Data were analyzed using inferential statistics. Participants who completed the intervention (n = 44) increased their pain assessment knowledge, assessment tool knowledge, and confidence undertaking a pain assessment (p < .001). The positive changes in nurses' pain assessment capabilities translated into a significant increasing linear trend in the proportion of documented pain assessments in patients' charts at the three time points (chi2 trend = 18.28, df = 1, p < .001). There is evidence that learning content delivered using a spaced learning format, augmented with pain assessment audit and feedback data, improves inpatient cancer nurses' self-perceived pain screening and assessment capabilities and strengthens cancer pain guideline adherence. PMID- 28363327 TI - Prevalence and characterization of postoperative pain in the Postanaesthesia Care Unit. AB - INTRODUCTION: Immediate postoperative pain occurs initially after surgery, while the patient is in the Post-Anaesthesia Recovery Unit. Very few studies assess this pain in this most immediate phase. OBJECTIVE: Cross-sectional study of the prevalence and characteristics of immediate postoperative pain in patients after surgery. MATERIAL AND METHODS: Between August 2014 and February 2015, a sample of 503 patients from the Post-Anaesthesia Recovery Unit was followed. Immediate postoperative pain was assessed (by the patient and the researcher) using the visual analogue scale (VAS; range 0-10) on 5 occasions after surgery. The impact of numerous factors (age, gender, type of surgery, type of anaesthesia and analgesic) on the pain, as well as variation in vital signs and the presence of side effects, were analysed. RESULTS: Assessment of the pain showed overall VAS values of 2.2+/-2.8 on all occasions. Pain was reported to be of greatest intensity 20min after the patients' arrival in the Post-Anaesthesia Recovery Unit (P<.001). The VAS values reported by the researcher (1.4+/-2.0) were lower than those reported by the patients. Although there was a very strong correlation (R2=0.82; P<.001) and they followed a parallel distribution, there was moderate concordance (kappa=0.4). Plastic surgery and neurosurgery were the specialties with the highest percentages of VAS values in the strong intensity range (8-10). Patients with regional block techniques (with or without general anaesthesia) had lower VAS values than other general anaesthesia groups. Male patients and older patients displayed less pain than female and young patients, respectively (P<.001). CONCLUSIONS: Studying the characteristics of postoperative pain at such an early stage allows for improved management. It helps to predict, according to the type of surgery and the anaesthesia used, those patients in which higher VAS values may be seen and to better adapt analgesic therapy. PMID- 28363328 TI - Cerebrospinal fluid cutaneous fistula following obstetric epidural analgaesia. Case report. AB - Cutaneous fistula of cerebrospinal fluid is a rare complication of neuroaxial blockade. We report the case of a parturient in whom an epidural catheter was placed for labour analgesia and 12h after the catheter was removed, presented an abundant asymptomatic fluid leak from the puncture site, compatible in the cyto chemical analysis with cerebrospinal fluid. She was treated with acetazolamide, compression of skin orifice of the fluid leakage, antibiotic prophylaxis, hydration and rest, and progressed satisfactorily without requiring blood patch. PMID- 28363329 TI - Rupture of aneurysm of sinus of Vasalva. PMID- 28363330 TI - Reply. PMID- 28363331 TI - Sensitizing pathogens to antibiotics using the CRISPR-Cas system. AB - The extensive use of antibiotics over the last century has resulted in a significant artificial selection pressure for antibiotic-resistant pathogens to evolve. Various strategies to fight these pathogens have been introduced including new antibiotics, naturally-derived enzymes/peptides that specifically target pathogens and bacteriophages that lyse these pathogens. A new tool has recently been introduced in the fight against drug-resistant pathogens-the prokaryotic defense mechanism-clustered regularly interspaced short palindromic repeats-CRISPR associated (CRISPR-Cas) system. The CRISPR-Cas system acts as a nuclease that can be guided to cleave any target DNA, allowing sophisticated, yet feasible, manipulations of pathogens. Here, we review pioneering studies that use the CRISPR-Cas system to specifically edit bacterial populations, eliminate their resistance genes and combine these two strategies in order to produce an artificial selection pressure for antibiotic-sensitive pathogens. We suggest that intelligent design of this system, along with efficient delivery tools into pathogens, may significantly reduce the threat of antibiotic-resistant pathogens. PMID- 28363332 TI - The importance of breast cancer resistance protein to the kidneys excretory function and chemotherapeutic resistance. AB - The relevance of membrane transporters gained momentum in recent years and it is now widely recognized that transporters are key players in drug disposition and chemoresistance. As such, the kidneys harbor a variety of drug transporters and are one of the main routes for xenobiotic excretion. The breast cancer resistance protein (BCRP/ABCG2) is widely accepted as a key mediator of anticancer drug resistance and is a prominent renal drug transporter. Here, we review the role of BCRP in both processes and present a multitude of variables that can influence its activity. An increasing number of renally cleared chemotherapeutics, including tyrosine kinase inhibitors, described as BCRP substrates can modulate its activity via transcription factors and cellular signaling pathways, such as the phosphoinositide 3-kinase (PI3K) pathway. In addition to pharmacological actions, genetic variations, as well as differences between species and gender can affect BCRP function, which are also discussed. Furthermore, the role of BCRP in light of cancer treatments and the implications for novel therapeutic interventions that take into account renal function are discussed. PMID- 28363333 TI - Inverse correlation between the metastasis suppressor RKIP and the metastasis inducer YY1: Contrasting roles in the regulation of chemo/immuno-resistance in cancer. AB - Several gene products have been postulated to mediate inherent and/or acquired anticancer drug resistance and tumor metastasis. Among these, the metastasis suppressor and chemo-immuno-sensitizing gene product, Raf Kinase Inhibitor Protein (RKIP), is poorly expressed in many cancers. In contrast, the metastasis inducer and chemo-immuno-resistant factor Yin Yang 1 (YY1) is overexpressed in many cancers. This inverse relationship between RKIP and YY1 expression suggests that these two gene products may be regulated via cross-talks of molecular signaling pathways, culminating in the expression of different phenotypes based on their targets. Analyses of the molecular regulation of the expression patterns of RKIP and YY1 as well as epigenetic, post-transcriptional, and post translational regulation revealed the existence of several effector mechanisms and crosstalk pathways, of which five pathways of relevance have been identified and analyzed. The five examined cross-talk pathways include the following loops: RKIP/NF-kappaB/Snail/YY1, p38/MAPK/RKIP/GSK3beta/Snail/YY1, RKIP/Smurf2/YY1/Snail, RKIP/MAPK/Myc/Let-7/HMGA2/Snail/YY1, as well as RKIP/GPCR/STAT3/miR-34/YY1. Each loop is comprised of multiple interactions and cascades that provide evidence for YY1's negative regulation of RKIP expression and vice versa. These loops elucidate potential prognostic motifs and targets for therapeutic intervention. Chiefly, these findings suggest that targeted inhibition of YY1 by specific small molecule inhibitors and/or the specific induction of RKIP expression and activity are potential therapeutic strategies to block tumor growth and metastasis in many cancers, as well as to overcome anticancer drug resistance. These strategies present potential alternatives for their synergistic uses in combination with low doses of conventional chemo immunotherapeutics and hence, increasing survival, reducing toxicity, and improving quality of life. PMID- 28363334 TI - Novel immune check point inhibiting antibodies in cancer therapy-Opportunities and challenges. AB - Drug resistance of tumor cells to chemotherapy is limiting the therapeutic efficacy of most anticancer drugs and represents a major obstacle in medical oncology. However, treatment of various human malignancies with biologics, mostly monoclonal antibodies (mAbs), is not limited by such chemoresistance mechanisms. However, other resistance or evasion mechanisms limit the efficacy to anticancer therapeutic mAbs that engage tumor-associated antigens on the surface of the malignant cells. Immune checkpoint blocking monoclonal antibodies are heralded as a promising therapeutic approach in clinical oncology. These mAbs do not directly attack the malignant cells as most anticancer mAbs; rather, they enhance the anti tumor response of the immune system by targeting immune regulatory pathways. Three mAbs targeting immune checkpoint molecules are currently used in the clinic and new mAbs that target other potential inhibitory targets are being actively investigated. This therapeutic approach, while proving as highly beneficial for many patients, is prone to toxicities and side effects of an autoimmune nature. Defining suitable management algorithms and biomarkers that predict therapeutic effects and adverse toxicity are required to provide survival benefit for larger numbers of cancer patients. Overcoming these challenges, along with opportunities for new agents and combinatorial strategies are the main focus of immune checkpoint blockade research today. PMID- 28363335 TI - Drug-biomarker co-development in oncology - 20 years and counting. AB - Predictive biomarkers for oncology are necessary to accurately identify patients who will benefit from anticancer treatment. Recently approved oncology drugs target discrete molecular aberrations or pathways in tumor cells and consequently are active on a subset of patient population, yet clinical studies have shown that not all biomarker-positive patients respond. The advancement of predictive biomarkers needs to detect novel and evolving drug resistance mechanisms, not only to guide the selection of patient subsets for specific treatments, but to identify new therapeutic targets. Going beyond the "one marker, one drug" model to incorporate genomics, transcriptomics, and receptor status assessments during biomarker-drug co-development can aid in the successful application of molecular marker-based cancer therapy. This review provides the latest update of biomarker based cancer therapeutics approved by the US Food and Drug Administration. We provide case studies of therapeutics selectively targeting HER2, EGFR, or PD-1/PD L1 signaling pathways. We also discuss the challenges and promising future directions in the co-development of targeted cancer therapeutics and paired predictive biomarkers. PMID- 28363336 TI - Active efflux in dormant bacterial cells - New insights into antibiotic persistence. AB - Bacterial persisters are phenotypic variants of an isogenic cell population that can survive antibiotic treatment and resume growth after the antibiotics have been removed. Cell dormancy has long been considered the principle mechanism underlying persister formation. However, dormancy alone is insufficient to explain the full range of bacterial persistence. Our recent work revealed that in addition to 'passive defense' via dormancy, persister cells employ 'active defense' via enhanced efflux activity to expel drugs. This finding suggests that persisters combine two seemingly contradictory mechanisms to tolerate antibiotic attack. Here, we review the passive and active aspects of persister formation, discuss new insights into the process, and propose new techniques that can facilitate the study of bacterial persistence. PMID- 28363337 TI - [Gardner-Diamond syndrome in a young man: A case report and literature review]. AB - INTRODUCTION: Gardner-Diamond syndrome is a rare condition secondary to a sensitization to self-erythrocytes. It is predominantly seen in women and presents as a painful ecchymotic disorder. An underlying psychiatric disease or a triggering psychological stress is of important diagnostic value. CASE REPORT: We report a 24-year-old patient who presented with intermittent spontaneous painful ecchymosis since 5 years. Complementary investigations failed to identify an organic disorder. Gardner-Diamond syndrome was retained because of the clinical presentation, the negativity of diagnostic work-up and the identification of a psychological trauma. Patient management (pain, psychological support) is difficult, justifying a multidisciplinary approach. CONCLUSION: Gardner-Diamond syndrome is a rare and unrecognized disorder, which should be discussed in the presence of ecchymotic or purpuric lesions that do not have a diagnostic orientation. Early recognition of this disorder enables initiation of an appropriate management, but also limits unnecessary additional explorations. PMID- 28363338 TI - Phase 1 clinical trials and toxicity. PMID- 28363339 TI - Anticoagulant therapy for symptomatic calf deep vein thrombosis. PMID- 28363340 TI - Anticoagulant therapy for symptomatic calf deep vein thrombosis - Authors' reply. PMID- 28363341 TI - Risk of secondary cancers: Bridging epidemiology and modeling. AB - Epidemiological studies of long term radiotherapy survivors provide useful insights into dose-response relationships for secondary cancer induction risk at high doses. There are uncertainties involved in estimating the dose to the location of the second malignancy, because the dose distributions in radiotherapy patients can be spatially highly heterogeneous and the size of the diagnosed tumor is on the order of a few cm. Therefor it is nearly impossible to obtain the exact dose corresponding to the exact tumor induction location and so organ specific dose-response relationships have large errors not only in the reported risk, but also in the estimated dose. In this work two alternative methods are proposed for future applications involving investigations into dose response relationships for second cancer induction risk, the method of organ sub-division and the method of risk equivalent dose. The method of organ sub-division takes the inevitable inhomogeneous dose distribution into account by applying epidemiological methods to organ sub-divisions which have a nearly homogenous dose. The method of risk equivalent dose combines risk modeling and epidemiological data analysis. Risk models can be optimized by using an iterative procedure assuming a variation of organ specific dose-responses. The advantage of the alternative methods is that the inhomogeneity of the dose in the organs at risk is taken into account. The second method has the additional advantage that the dose to the location of the tumor site must not be known and that epidemiologically obtained risks that were not stratified by organ specific risk can be used. PMID- 28363342 TI - Chance-constrained multi-objective optimization of groundwater remediation design at DNAPLs-contaminated sites using a multi-algorithm genetically adaptive method. AB - In this paper, a multi-algorithm genetically adaptive multi-objective (AMALGAM) method is proposed as a multi-objective optimization solver. It was implemented in the multi-objective optimization of a groundwater remediation design at sites contaminated by dense non-aqueous phase liquids. In this study, there were two objectives: minimization of the total remediation cost, and minimization of the remediation time. A non-dominated sorting genetic algorithm II (NSGA-II) was adopted to compare with the proposed method. For efficiency, the time-consuming surfactant-enhanced aquifer remediation simulation model was replaced by a surrogate model constructed by a multi-gene genetic programming (MGGP) technique. Similarly, two other surrogate modeling methods-support vector regression (SVR) and Kriging (KRG)-were employed to make comparisons with MGGP. In addition, the surrogate-modeling uncertainty was incorporated in the optimization model by chance-constrained programming (CCP). The results showed that, for the problem considered in this study, (1) the solutions obtained by AMALGAM incurred less remediation cost and required less time than those of NSGA-II, indicating that AMALGAM outperformed NSGA-II. It was additionally shown that (2) the MGGP surrogate model was more accurate than SVR and KRG; and (3) the remediation cost and time increased with the confidence level, which can enable decision makers to make a suitable choice by considering the given budget, remediation time, and reliability. PMID- 28363343 TI - Early analysis of laparoscopic common bile duct exploration simulation. AB - BACKGROUND: We developed a laparoscopic common bile duct exploration (LCBDE) simulation course for resident surgeons (RS) and practicing surgeons (PS). We hypothesized that course completion would provide LCBDE procedural skills and increase procedure utilization. METHODS: RS and PS were prospectively enrolled. Pre- and post-course ability were assessed with written examinations and LCBDE simulations. PS completed pre-course, post-course, and 1-year follow-up surveys (5-point Likert-type scale). RESULTS: 17 RS and 8 PS were enrolled. Median written test scores improved (70.0%-80.0%, p < 0.001) and median LCBDE simulation times (seconds) improved (585-314, p = 0.001) among all participants. Comparing RS and PS, median written assessment scores pre-course (70% vs 72.5%, p = 0.953) and post-course (77.5% vs 80.0%, p = 0.198) were not significantly different. Simulation completion times (seconds) improved similarly from pre-course (608.0 vs 521.5, p = 0.885) to post-course (314.0 vs 373.0, p = 0.287) between groups. PS comfort with LCBDE improved (2-4, p = 0.03). All PS reported LCBDE utilization 1 year post-course. CONCLUSIONS: The LCBDE course is appropriate for RS and PS. PS also reported increased comfort with LCBDE and procedure utilization. PMID- 28363344 TI - Development of a multimedia tutorial to educate how to assess the critical view of safety in laparoscopic cholecystectomy using expert review and crowd-sourcing. AB - We sought to determine the feasibility of developing a multimedia educational tutorial to teach learners to assess the critical view of safety using input from expert surgeons, non-surgeons and crowd-sourcing. We intended to develop a tutorial that would teach learners how to identify the basic anatomy and physiology of the gallbladder, identify the components of the critical view of safety criteria, and understand its significance for performing a safe gallbladder removal. Using rounds of assessment with experts, laypersons and crowd-workers we developed an educational video with improving comprehension after each round of revision. We demonstrate that the development of a multimedia educational tool to educate learners of various backgrounds is feasible using an iterative review process that incorporates the input of experts and crowd sourcing. When planning the development of an educational tutorial, a step-wise approach as described herein should be considered. PMID- 28363345 TI - Advanced laparoscopic bariatric surgery Is safe in general surgery training. AB - BACKGROUND: Bariatric surgery makes up an increasing percentage of general surgery training. The safety of resident involvement in these complex cases has been questioned. We evaluated patient outcomes in resident performed laparoscopic bariatric procedures. METHODS: Retrospective review of patients undergoing a laparoscopic bariatric procedure over seven years at a tertiary care single center. Procedures were primarily performed by a general surgery resident and proctored by an attending surgeon. Primary outcomes included operative volume, operative time and leak rate with perioperative outcomes evaluated as secondary outcomes. RESULTS: A total of 1649 bariatric procedures were evaluated. Operations included laparoscopic bypass (690) and laparoscopic sleeve gastrectomy (959). Average operating time was 136 min. Eighteen leaks (0.67%) were identified. Graduating residents performed an average of 89 laparoscopic bariatric cases during their training. There were no significant differences between resident levels with concern to operative time or leak rate (p 0.97 and p = 0.54). CONCLUSIONS: General surgery residents can safely perform laparoscopic bariatric surgery. When proctored by a staff surgeon, a resident's level of training does not significantly impact leak rate. PMID- 28363346 TI - Formal thought disorder and neurocognition in schizophrenia: The question of individual mechanisms. PMID- 28363348 TI - Primary anetoderma: A cutaneous predictor of autoimmunity. PMID- 28363347 TI - Increased serum levels of cysteine in patients with schizophrenia: A potential marker of cognitive function preservation. AB - BACKGROUND: Oxidative stress has been implicated in the psychopathology of schizophrenia. Cysteine, a semi-essential amino acid, is the precursor of the antioxidant glutathione. The aim of this study was to investigate the differences in serum levels of cysteine between patients with schizophrenia and healthy controls. The relationships between levels of cysteine, psychopathology and cognitive function were also explored. METHODS: We recruited 65 patients with schizophrenia and 65 age- and gender-matched healthy controls. Blood samples were collected to determine the serum levels of cysteine and plasma levels of metabolic parameters. The cognitive function of participants was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS). The psychopathology of schizophrenic patients was evaluated using the Positive and Negative Syndrome Scale. RESULTS: Serum cysteine levels were significantly higher in schizophrenic patients than in controls (P<0.001). In patients with schizophrenia, serum levels of cysteine were positively correlated with cognitive function in terms of verbal memory (P=0.013), working memory (P=0.004), verbal fluency (P=0.027), attention and processing speed (P=0.025), executive function (P=0.024) and the composite score on the BACS (P=0.013). In healthy controls, no significant correlation was observed between cysteine level and cognitive function. CONCLUSIONS: These findings suggest that oxidative stress may be involved in the pathogenesis of schizophrenia, and compensatory elevated levels of cysteine may serve as an indicator of cognition preservation. Further prospective studies are warranted to investigate the dynamic alterations in cysteine and the underlying pathophysiology of schizophrenia. PMID- 28363349 TI - Intestinal Burkitt lymphoma in a patient with coeliac disease. PMID- 28363350 TI - Should Environmental Filtering be Abandoned? AB - Environmental filtering, where the environment selects against certain species, is thought to be a major mechanism structuring communities. However, recent criticisms cast doubt on our ability to accurately infer filtering because competition can give rise to patterns identical to those caused by environmental filtering. While experiments can distinguish mechanisms, observational patterns are especially problematic. The environment determines community composition not only directly via survival, but also by influencing competition. If species population growth rates covary with environmental gradients, then outcomes of competitive exclusion will also vary with the environment. Here, we argue that observational studies remain valuable, but inferences about the importance of the environment cannot rely on compositional data alone, and that species abundances, population growth, or traits must be correlated with the environment. PMID- 28363351 TI - Comparison of Ventricular Septal Measurements in Hypertrophic Cardiomyopathy Patients Who Underwent Surgical Myectomy Using Multimodality Imaging and Implications for Diagnosis and Management. AB - Accurate and reproducible quantification of ventricular septal (VS) thickness in hypertrophic cardiomyopathy (HC) is essential for diagnosis, surgical planning, and risk stratification. We sought to compare VS thickness measurements using transthoracic echocardiography (TTE), transesophageal echocardiography (TEE), and cardiac magnetic resonance (CMR) in patients with HC. Prospectively reported measurements of VS thickness were compared using analysis of variance and Bland Altman plots in 90 consecutive patients with HC who underwent a TTE, TEE, and CMR within 3 months. A subset was re-measured on 2 separate occasions by 2 readers to assess inter- and intraobserver variability. There was modest correlation between modalities, with CMR and TTE measurements of VS thickness showing the greatest correlation (CMR vs TTE, r = 0.70; CMR vs TEE, r = 0.60; TTE vs TEE, r = 0.56). Smaller measurements were seen using CMR versus either echocardiographic technique (13% smaller vs TEE, 8% smaller vs TTE, p <0.001 for both). The variability of measurement between modalities was not correlated with the degree of VS thickness. There was significantly lower intraobserver variability with CMR versus echocardiography (p = 0.01 for both), but no difference in interobserver variability. CMR delineated a different area of maximal VS thickness other than the basal anteroseptum more frequently than echocardiography (44% of cases vs 24% for TTE and 11% for TEE). In conclusion, CMR assessment of VS thickness differs significantly from echocardiography in patients with HC, with a systemic bias toward lower measurements seen with CMR. PMID- 28363352 TI - Impact of Left Ventricular Diastolic Property on Left Atrial Function from Simultaneous Left Atrial and Ventricular Three-Dimensional Echocardiographic Volume Measurement. AB - Simultaneous left atrial (LA) and left ventricular (LV) 3-dimensional (3D) echocardiographic volume measurements enable the quantifying of precise LA function, by virtue of their independence on any geometric assumption and capability of measurement for net LA conduit volume. We sought to elucidate the impact of conventional Doppler LV diastolic property on LA volume and function derived from this method. Our study subjects consisted of 381 patients who underwent 3D echocardiography. From LA time-volume curve, maximum and minimum volume index (VI) and VI before atrial contraction (LAVIpre-c) were determined; subsequently, active emptying volume was calculated as LAVIpre-c - minimum LAVI. From LA and LV volume measurement, conduit volume was calculated as LV stroke VI (maximum LAVI - minimum LAVI). LA volume increased depending on the severity of diastolic dysfunction. Compared with patients with normal diastolic function, LA booster pump function, as the contribution of active emptying volume to LV filling, was higher in those with mild diastolic dysfunction. Additionally, it gradually decreased as diastolic dysfunction was advanced from mild to moderate and moderate to severe degree (23.2 +/- 15.5%, 29.5 +/- 15.1%, 25.1 +/- 16.2%, 14.9 +/- 14.1%, respectively; p <0.001). Contrarily, conduit contribution was significantly higher in patients with severe diastolic dysfunction than in those with mild diastolic dysfunction; furthermore, conduit function tended to increase, reciprocally to booster pump function, as diastolic dysfunction grade was advanced (39.1 +/- 28.8%, 36.8 +/- 26.2%, 42.7 +/- 25.6%, 52.9 +/- 26.2%, respectively; p = 0.034). In conclusion, simultaneous LA and LV volumetric analyses through 3D echocardiography clearly demonstrate the characteristic LA functional alterations following LA dilation caused by LV diastolic dysfunction. PMID- 28363353 TI - Propranolol Versus Digoxin in the Neonate for Supraventricular Tachycardia (from the Pediatric Health Information System). AB - Conflicting data exist for the appropriate management of a neonate with supraventricular tachycardia (SVT). We sought to assess postnatal prescribing trends for neonates with SVT and to evaluate if there were therapy-specific mortality and resource utilization benefits. Nationally distributed data from 44 pediatric hospitals in the 2004 to 2015 Pediatric Health Information System database were used to identify patients admitted at <=2 days of age with structurally normal hearts and treated with an antiarrhythmic medication. Outcome variables were mortality, cost, and length of stay (LOS). Multivariable models and propensity score matching were used. There were 2,657 neonates identified with a median gestational age of 37 weeks (interquartile range 34 to 39). Digoxin and propranolol were most commonly prescribed; digoxin use steadily decreased to 23% of antiarrhythmic medication administrations over the study period, whereas propranolol increased to 77%. Multivariable comparisons revealed that the odds of mortality for neonates on propranolol were 0.32 times those on digoxin (95% confidence interval 0.17 to 0.59; p <0.001); hospital costs were $16,549 lower for propranolol versus digoxin (95% confidence interval $5,502 to $27,596, p = 0.003). No difference was found for LOS. Propensity score matching and subset analyses of patients with only arrhythmia diagnostic codes confirmed mortality benefits for propranolol, although longer LOS was observed. In conclusion, propranolol use for the neonate with SVT is associated with lower in-hospital mortality and hospital costs compared with digoxin. PMID- 28363354 TI - Management of Major Bleeding in Patients With Atrial Fibrillation Treated With Non-Vitamin K Antagonist Oral Anticoagulants Compared With Warfarin in Clinical Practice (from Phase II of the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation [ORBIT-AF II]). AB - Non-vitamin K antagonist oral anticoagulants (NOACs) are effective at preventing stroke in patients with atrial fibrillation (AF). However, little is known about the management of bleeding in contemporary, clinical use of NOACs. We aimed to assess the frequency, management, and outcomes of major bleeding in the setting of community use of NOACs. Using the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II registry, we analyzed rates of International Society on Thrombosis and Haemostasis major bleeding and subsequent outcomes in patients treated with NOACs versus warfarin. Outcomes of interest included acute and chronic bleeding management, recurrent bleeding, thromboembolic events, and death. In total, 344 patients with atrial fibrillation experienced major bleeding events over a median follow-up of 360 days follow-up: n = 273 on NOAC (3.3 per 100 patient-years) and n = 71 on warfarin (3.5 per 100 patient-years). Intracranial bleeding was uncommon but similar (0.34 per 100 patient-years for NOAC vs 0.44 for warfarin, p = 0.5), as was gastrointestinal bleeding (1.8 for NOAC vs 1.3 for warfarin, p = 0.1). Blood products and correction agents were less commonly used in NOAC patients with major bleeds compared with warfarin treated patients (53% vs 76%, p = 0.0004 for blood products; 0% vs 1.5% for recombinant factor; p = 0.0499); no patients received pharmacologic hemostatic agents (aminocaproic acid, tranexamic acid, desmopressin, aprotinin). Within 30 days, 23 NOAC-treated patients (8.4%) died versus 5 (7.0%) on warfarin (p = 0.7). At follow-up, 126 NOAC-treated (46%) and 29 warfarin-treated patients (41%) were not receiving any anticoagulation. In conclusion, rates of major bleeding are similar in warfarin and NOAC-treated patients in clinical practice. However, NOAC related bleeds require less blood product administration and rarely require factor replacement. PMID- 28363355 TI - Association of Obesity With In-Hospital Mortality of Cardiogenic Shock Complicating Acute Myocardial Infarction. AB - Several previous studies have shown obesity to be counterintuitively associated with more favorable mortality in patients with acute myocardial infarction (AMI); however, the association of obesity with in-hospital mortality of cardiogenic shock complicating AMI has not been previously examined. We queried the 2004 to 2013 National Inpatient Sample databases to identify all patients >=18 years hospitalized with the principal diagnosis of AMI. Multivariable regression models adjusting for demographics, hospital characteristics, and co-morbidities were used to examine differences in incidence and in-hospital mortality of cardiogenic shock complicating AMI between obese and nonobese patients. Of 6,097,817 patients with AMI, 290,894 (4.8%) had cardiogenic shock. There was no difference in risk adjusted incidence of cardiogenic shock between obese and nonobese patients (adjusted odds ratio 1.00, 95% CI 0.98 to 1.01; p = 0.46). Of the patients with cardiogenic shock complicating AMI, 8.9% had a documented diagnosis of obesity. Obese patients were on average 6 years younger and had higher prevalence of most cardiovascular co-morbidities. Obese patients were more likely to receive revascularization (73.0% vs 63.4%, p <0.001) and had lower risk-adjusted in hospital mortality compared with nonobese patients (28.2% vs 36.5%; adjusted odds ratio 0.89, 95% CI 0.86 to 0.92; p <0.001). Similar findings were seen in subgroups of patients with cardiogenic shock complicating ST elevation or non-ST elevation MI. In conclusion, this large retrospective analysis of a nationwide cohort of patients with cardiogenic shock complicating AMI demonstrated that obese patients were younger, more likely to receive revascularization, and had modestly lower risk-adjusted in-hospital mortality compared with nonobese patients. PMID- 28363356 TI - Diversity dynamics: The experience of male Robert Wood Johnson Foundation nurse faculty scholars. AB - BACKGROUND: Managing diversity dynamics in academic or clinical settings for men in nursing has unique challenges resulting from their minority status within the profession. PURPOSE: The purpose of this study was to share challenges and lessons learned identified by male scholars in the Robert Wood Johnson Foundation Nurse Faculty Scholars program and suggest strategies for creating positive organizations promoting inclusive excellence. METHODS: Multiple strategies including informal mentored discussions and peer-to-peer dialogue throughout the program, formal online surveys of scholars and National Advisory Committee members, and review of scholar progress reports were analyzed as part of the comprehensive evaluation plan of the program. DISCUSSION: Diversity dynamic issues include concerns with negative stereotyping, microaggression, gender intelligence, and differences in communication and leadership styles. CONCLUSION: Male nurse faculty scholars report experiencing both opportunities and challenges residing in a predominately female profession. This article attempts to raise awareness and suggest strategies to manage diversity dynamics in service of promoting the development of a culture of health that values diversity and inclusive excellence for both men and women in academic, research, and practice contexts. PMID- 28363358 TI - An educational video program to increase aging services technology awareness among older adults. AB - OBJECTIVE: Aging services technologies (ASTs), health technology that meets the needs of seniors, are being underutilized due to a lack of awareness. This study evaluated a video-based educational program to increase AST awareness. METHODS: Two hundred and thirty-one older adults completed AST measures pre- and post program. RESULTS: Participants endorsed significantly improved AST knowledge and attitude and a lower level of perceived stigma post-program. Hierarchical regression analyses showed that a greater reduction in stigma post-program and a higher number of physical/cognitive needs supported by ASTs at baseline were significant predictors of a greater increase in expressed intention to use ASTs following the video program. Furthermore, individuals living in their own homes, with a lower level of education, fewer physical and/or cognitive needs supported by ASTs at baseline, and greater functional limitations were found to be more likely to report a significant reduction in perceived stigma post-program. Four week follow-up data from 75 individuals showed stable program gains. Program feedback was positive. CONCLUSION: The current findings provide support for the utility of the AST videos. PRACTICAL IMPLICATIONS: The educational materials used in this study can be used clinically or for public health education to increase awareness and adoption of ASTs. PMID- 28363357 TI - Variation in Placebo Effect Sizes in Clinical Trials of Oral Interventions for Management of the Behavioral and Psychological Symptoms of Dementia (BPSD): A Systematic Review and Meta-Analysis. AB - Increasing placebo effect sizes over time have been reported in randomized controlled trials (RCTs) for outcomes related to psychiatric symptoms. The Neuropsychiatric Inventory (NPI) is a key outcome measure in clinical trials of the behavioral and psychological symptoms of dementia (BPSD). Accurate placebo effect size estimates for NPI are needed for sample size calculations in order to adequately power future studies. This study investigated variation in placebo effect sizes for NPI in RCTs testing oral interventions for BPSD. A search of PubMed was conducted in April 2016 for two-armed, double-blinded, placebo controlled RCTs testing any oral intervention for management of BPSD using the NPI. Meta-analysis was conducted of baseline versus end of treatment placebo group data of included studies. Twenty-five RCTs published from 2000 to 2015 were included. Substantial variation in placebo effect sizes was detected. Participants in placebo groups showed greater improvements in recent studies compared with earlier studies. Subgroup analyses indicated robustness of this finding. From 2000 to 2008 there was no significant change in total NPI scores within placebo groups (12 studies; 1,056 participants), whereas from 2009 to 2015 there was significant improvement (mean difference: -2.68; 95% confidence interval: -4.38, -0.99; z = 3.10; p = 0.002, random effects; I2 = 76%; 13 studies; 1,170 participants). This increase in NPI effect sizes in placebo groups has important implications for power calculations for future clinical trials of BPSD. Effect size estimates for NPI need to be based on more recent studies. PMID- 28363359 TI - The most important needs and preferences of patients for support from health care professionals: A reflective practice on (transitional) care for young adults with Juvenile Idiopathic Arthritis. AB - In this manuscript, presented as a Reflective Practice, the learning experiences and reflections of a healthcare team on redeveloping the transitional care for young adults with a juvenile rheumatic disease are described. In this process of redeveloping care, the healthcare team experienced that small step, driven by patient stories and involvement of patients in all phases from development to evaluation, led to meaningful results. The eHealth interventions, developed to support the transition and to increase self-management were found to be feasible and evaluated positively by the young adult group. But the healthcare team also experienced that the focus on the patient alone, is not enough to implement self management interventions and sustain patient centered care in daily practice. How healthcare professionals personally think and feel about patient centered care is essential and needs to be discussed in daily care.It determines the way of being present with attention and commitment in daily health care. It affects the hands, head and heart. A daily reflection on shared answers of the patient and the health care professional to the question 'what is the most important to you?'may help to implement patient centered care in health practice. PMID- 28363360 TI - [A prospective study to assess the burden of influenza-related hospitalizations and emergency department visits among children in Bilbao, Spain (2010-2011)]. AB - INTRODUCTION: This study was undertaken to estimate the burden of morbidity associated with laboratory-confirmed influenza in children below 15 years of age. PATIENTS AND METHODS: Children presenting with acute respiratory infection and/or isolated fever at the Basurto University Hospital, Bilbao, Spain between November 2010 and May 2011 were included in this study (NCT01592799). Two nasopharyngeal secretion samples were taken from each; one for a rapid influenza diagnostic test in the emergency department, and the second for laboratory analysis using real time polymerase chain reaction and viral culture. RESULTS: A total of 501 children were recruited, of whom 91 were hospitalized. Influenza diagnosis was confirmed in 131 children (26.1%); 120 of 410 (29.3%) treated as outpatients and 11 of 91 (12.1%) hospitalized children. A total of 370 of 501 children (73.9%) had no laboratory test positive for influenza. The proportion of subjects with other respiratory viruses was 145/501 (28.9%) cases and co-infection with the influenza virus plus another respiratory virus was detected in 7/501 (1.4%) cases. Influenza virus types were: A (H1N1 and H3N2) 53.2% (67/126); B (Victoria and Yamagata) 46.0% (58/126); A+B 0.8% (1/126). The median direct medical costs associated with each case of laboratory-confirmed influenza was ?177.00 (N=131). No significant differences were observed between the medical costs associated with influenza A and B. CONCLUSION: Almost half of the cases were influenza virus B type. The administration of a vaccine containing influenza A and B types to children below 15 years of age might reduce the overall burden of the illness. PMID- 28363361 TI - Parent Participation in Pediatric Intensive Care Unit Rounds via Telemedicine: Feasibility and Impact. AB - OBJECTIVES: To evaluate feasibility and impact of telemedicine for remote parent participation in pediatric intensive care unit (PICU) rounds when parents are unable to be present at their child's bedside. STUDY DESIGN: Parents of patients admitted to a 14-bed PICU were approached, and those unable to attend rounds were eligible subjects. Nurse and physician caregivers were also surveyed. Parents received an iPad (Apple Inc, Cupertino, California) with an application enabling audio-video connectivity with the care team. At a predetermined time for bedside rounds with the PICU team, parents entered a virtual meeting room to participate. Following each telemedicine encounter, participants (parent, physician, nurse) completed a brief survey rating satisfaction (0?=?not satisfied, 10?=?completely satisfied) and disruption (0?=?no disruption at all, 10?=?very disruptive). RESULTS: A total of 153 surveys were completed following 51 telemedicine encounters involving 13 patients. Parents of enrolled patients cited work demands (62%), care for other dependents (46%), and transportation difficulties (31%) as reasons for study participation. The median levels of satisfaction and disruption were 10 (range 5-10) and 0 (range 0-5), respectively. All parents reported that telemedicine encounters had a positive effect on their level of reassurance regarding their child's care and improved communication with the care team. CONCLUSIONS: This proof-of-concept study indicates that remote parent participation in PICU rounds is feasible, enhances parent-provider communication, and offers parents reassurance. Providers reported a high level of satisfaction with minimal disruption. Technological advancements to streamline teleconferencing workflow are needed to ensure program sustainability. PMID- 28363362 TI - Congenital Chylothorax as the Initial Presentation of PTPN11-Associated Noonan Syndrome. PMID- 28363364 TI - Maintenance of Certification Part 4: From Trial to Tribute. PMID- 28363365 TI - Chest Wall Trauma. AB - Chest wall trauma is common, and contributes significantly to morbidity and mortality of trauma patients. Early identification of major chest wall and concomitant intrathoracic injuries is critical. Generalized management of multiple rib fractures and flail chest consists of adequate pain control (including locoregional modalities); management of pulmonary dysfunction by invasive and noninvasive means; and, in some cases, surgical fixation. Multiple studies have shown that patients with flail chest have substantial benefit (decreased ventilator and intensive care unit days, improved pulmonary function, and improved long-term functional outcome) when they undergo surgery compared with nonoperative management. PMID- 28363366 TI - Minimal Invasive Repair of Pectus Excavatum and Carinatum. AB - Minimal invasive surgery has become the gold standard for surgical repair of pectus excavatum. The procedure can be performed as fast-track surgery and cosmetic results are excellent. In addition, cardiac performance improves after correction. With increased awareness on the Internet, the number of patients who seek help continues to rise, primarily for cosmetic reasons. Pectus carinatum is much less frequent than pectus excavatum. Over the past decade surgery has largely been replaced by compression techniques that use a brace, and cosmetic results are good. Rare combinations of pectus excavatum and carinatum may be treated by newer surgical methods. PMID- 28363367 TI - Straight Back Syndrome. AB - Straight back syndrome is a rare condition usually associated with mitral valve prolapse and "pseudo-heart disease" caused by a very narrow anterior-posterior chest due to the loss of the normal dorsal curvature of the thoracic spine. More rarely, the narrowed upper chest may compress the trachea causing extrinsic tracheal obstruction. If severe enough, this requires operative repair by effectively opening up the upper chest by a variety of techniques to allow the trachea enough room to avoid compression. PMID- 28363363 TI - Dexamethasone for Parapneumonic Pleural Effusion: A Randomized, Double-Blind, Clinical Trial. AB - OBJECTIVE: To assess whether dexamethasone (DXM) decreases the time to recovery in patients with parapneumonic pleural effusion. STUDY DESIGN: This was a multicenter, randomized, double blind, parallel-group, placebo-controlled clinical trial of 60 children, ranging in age from 1 month to 14 years, with community-acquired pneumonia (CAP) and pleural effusion. Patients received either intravenous DXM (0.25?mg/kg/dose) or placebo every 6 hours over a period of 48 hours, along with antibiotics. The primary endpoint was the time to recovery in hours, defined objectively. We also evaluated complications and adverse events. RESULTS: Among the 60 randomized patients (mean age, 4.7 years; 58% female), 57 (95%) completed the study. Compared with placebo recipients, the patients receiving DXM had a shorter time to recovery, after adjustment by severity group and stratification by center (hazard ratio, 1.95; 95% CI, 1.10-3.45; P?=?.021). The median time to recovery for patients receiving DXM was 68 hours (2.8 days) shorter than patients receiving placebo (109 hours vs 177 hours; P?=?.037). In exploratory subgroup analysis, the median time to recovery for patients with simple effusion receiving DXM was 76 hours (3.1 days) shorter than for patients with simple effusion receiving placebo (P?=?.017). The median time to recovery for patients with complicated effusion receiving DXM was 14 hours (0.5 days) shorter than for patients with complicated effusion receiving placebo (P?=?.66). The difference in the effect of DXM in the 2 severity groups was not statistically significant (P?=?.138 for interaction). There were no significant differences in complications or adverse events attributable to the study drugs, except for hyperglycemia. CONCLUSION: In this trial, DXM seemed to be a safe and effective adjunctive therapy for parapneumonic pleural effusion. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01261546. PMID- 28363368 TI - Management of Primary Soft Tissue Tumors of the Chest Wall. AB - Primary chest wall tumors are rare and represent a challenging clinical entity. Preoperative work-up includes a thorough history, radiographic imaging, and a biopsy approach that does not make a future definitive resection more difficult. Treatment decisions are based on tumor histology, stage, local aggressiveness, and responsiveness to chemotherapy and radiation. Wide excision is the foundation of treatment of most malignant primary chest wall tumors. The role of radiation therapy in the neoadjuvant or adjuvant setting is to reduce local recurrence. The use of adjuvant chemotherapy is more controversial. For most primary chest wall malignancies, margin-negative resection remains the best chance of cure. PMID- 28363369 TI - Management of Lung Cancer Invading the Superior Sulcus. AB - Superior sulcus tumors have posed a formidable therapeutic challenge since their original description by Pancoast and Tobias in the early twentieth century. Initial therapeutic efforts with radiotherapy were associated with high rates of relapse and mortality. Bimodality therapy with complete surgical resection in the 1960s paved the way for trimodality therapy as the current standard of care in the treatment of superior sulcus tumors. The evolution of treatment approaches over time has provided outcomes that come increasingly closer to rivaling those of similarly staged nonapical lung cancer. PMID- 28363370 TI - Management of Breast Cancer Invading Chest Wall. AB - Surgical treatment of locally advanced or recurrent breast cancer involving the chest wall continues to play a role in the therapeutic armamentarium as part of the multidisciplinary treatment regimen. Significant progress has been made in chest wall resections and reconstructions, thanks to the availability of novel materials and tissue transfer methods. The understanding of cancer biology and behavior, and novel drugs further improved the field. Patient selection and superb knowledge of the most recent and effective treatment options are necessary to maximize the survival benefit and quality of life for patients affected with breast cancer involving the chest wall. PMID- 28363371 TI - Chest Wall Reconstruction Without Prosthetic Material. AB - The surgical resection of primary and secondary tumors involving the chest wall often requires reconstruction with prosthetic and soft tissues, such as muscle flaps. There are situations when a soft tissue reconstruction of the chest wall is preferable. Prosthetic material can become infected and require reoperation for removal of the infected material. Rigid prosthetic materials can result in chest wall pain and deformity. Muscle is the soft tissue of choice for coverage of full-thickness chest wall defects with or without prosthetic material. Muscle flaps can be transferred to chest wall defects with either pedicle muscle transposition or free muscle transfer. PMID- 28363373 TI - Primary Tumors of the Osseous Chest Wall and Their Management. AB - Primary osseous tumors of the chest wall are uncommon neoplasms. They occur in a wide variety of pathologic forms, most of which can be distinguished by unique radiologic appearance. Management of these tumors depends on the diagnosis and stage. Adequate surgical resection is critical in achieving the best outcomes for most of these tumors. Chemotherapy and radiation may have an adjuvant role. Surgeons considering resection of any chest wall tumor should have a sound knowledge of the principles of resection and reconstruction. PMID- 28363374 TI - Surgical Management of Lung Cancer Involving the Chest Wall. AB - The prevalence of chest wall invasion by non-small cell lung cancer is < 10% in published surgical series. The role of radiation or chemotherapy around the complete resection of lung cancer invading the chest wall, excluding the superior sulcus of the chest, is poorly defined. Survival of patients with lung cancer invading the chest wall is dependent on lymph node involvement and completeness of en-bloc resection. In some patients harboring T3N0 disease, 5-year survival in excess of 50% can be achieved. Offering en-bloc resection of lung cancer invading chest wall to patients with T3N1 or T3N2 disease is controversial. PMID- 28363372 TI - Surgical Management of the Radiated Chest Wall and Its Complications. AB - Radiation to the chest wall is common before resection of tumors. Osteoradionecrosis can occur after radiation treatment. Radical resection and reconstruction can be lifesaving. Soft tissue coverage using myocutaneous or omental flaps is determined by the quality of soft tissue available and the status of the vascular pedicle supplying available myocutaneous flaps. Radiation induced sarcomas of the chest wall occur most commonly after radiation therapy for breast cancer. Although angiosarcomas are the most common radiation-induced sarcomas, osteosarcoma, myosarcomas, rhabdomyosarcoma, and undifferentiated sarcomas also occur. The most effective treatment is surgical resection. Inoperable tumors are treated with chemotherapy, with low response rates. PMID- 28363375 TI - Prosthetic Reconstruction of the Chest Wall. AB - Large chest wall resections can result in skeletal instability, altered respiratory mechanics, and significant cosmetic defects. Here the authors review a variety of prostheses that can be used to reconstruct these defects, the indications for their use, the technique for implantation, and the available data regarding their clinical outcomes. PMID- 28363376 TI - Acute Chest Wall Infections: Surgical Site Infections, Necrotizing Soft Tissue Infections, and Sternoclavicular Joint Infection. AB - Acute chest wall infections are uncommon and share similar risk factors for infection at other surgical sites. Smoking cessation has been shown to decrease the risk of surgical site infection. Depending on the depth of infection and/or involvement of the organ space, adequate therapy involves antibiotics and drainage. Early diagnosis and debridement of necrotizing soft tissue infections is essential to reduce mortality. Sternoclavicular joint infections require surgical debridement, en bloc resection, and antibiotic therapy. A standard approach to wound closure after resection has yet to be established. Vacuum assisted closure is a valuable adjunct to standard therapy. PMID- 28363377 TI - Chronic Infections of the Chest Wall. AB - Chronic chest wall infections may occur in soft tissue, cartilage, and bone. They may present as localized chest wall pain, a discrete mass initially mistaken for neoplasm, a superficial infection, or a draining sinus. Chronic chest wall infections are typically non-necrotizing and associated with lower morbidity than their more acute and necrotizing counterparts. Effective management of chest wall infections ranges from antimicrobial administration to wide surgical resection and subsequent reconstruction. PMID- 28363379 TI - Preface. PMID- 28363378 TI - Thoracoplasty for Tuberculosis in the Twenty-first Century. AB - A new modification of osteoplastic collapse thoracoplasty performed with a minimally invasive approach has been proposed. This operation is a variant of extrapleural thoracoplasty used in the treatment of destructive tuberculosis. The benefits of the proposed method, the surgical techniques, and the results of the authors' research are described. Compared with the conventional variant of osteoplastic thoracoplasty, the rates of bacteriologic conversion (odds ratio [OR], 1.84; 95% confidence interval [CI], 1.72-1.97) and of the closure of cavities (OR, 2.13; 95% CI, 1.98-2.28) have been proved to be higher when the operation is performed with a minimally invasive approach. PMID- 28363380 TI - Malnutrition in the elderly and Wernicke encephalopathy. PMID- 28363381 TI - Professional identity development: Learning and journeying together. AB - BACKGROUND: Pharmacy students start to develop their professional values through engagement with the course, practice exposure, staff and fellow students. Group working is an element of pedagogy which draws on the social aspects of learning to facilitate knowledge and skills development, but its potential role in facilitating professional identity formation has as yet been under researched. OBJECTIVES: This study aimed to explore the potential of mutual learning through group work to contribute not only to academic knowledge and understanding, but also to the development of students' professional values and selves. METHODS: Semi-structured interviews were conducted with 17 home and international first year undergraduate pharmacy students in a UK School of Pharmacy, to explore their experiences of interacting for learning with other students on the course. FINDINGS: Thematic analysis of the interview data highlighted four main benefits of mutual learning, which are that it: promotes friendly interactions; aids learning about the subject and the profession; opens the mind through different opinions and ways of thinking; and enables learning about other people. Through working together students developed their communication skills and confidence; reflectively considered their own stance in the light of others' experiences and healthcare perspectives; and started to gain a wider worldview, potentially informing their future interactions with patients and colleagues. Some difficulties arose when group interactions functioned less well. CONCLUSIONS: Opportunity for collaboration and exchange can positively influence development of students' professional outlook and values. However, careful management of group working is required, in order to create a mutually supportive environment wherein students feel able to interact, share and develop together. PMID- 28363382 TI - The biomechanical consequences of longirostry in crocodilians and odontocetes. AB - Unrelated clades of aquatic tetrapod have evolved a similar range of skull shapes, varying from longirostrine (elongate and narrow rostrum) to brevirostrine (short rostrum). However, it is unclear which aspects of organismal performance are associated with this convergence in the range of skull shapes. Furthermore, it is not known how fundamental anatomical differences between groups influence these relationships. Here we address this by examining the load bearing capabilities of the skulls of two of the most diverse groups of living aquatic tetrapod: crocodilians and odontocetes. We use finite element analysis to examine the abilities of different cranial morphologies to resist a range of biologically relevant feeding loads including biting, shaking and twisting. The results allow for form/function relationships to be compared and contrasted between the two groups. We find that cranial shape has similar influences on performance during biting, shaking or twisting load cases at the anterior tooth positions, e.g. brevirostrine species experienced less strain than longirostrine species. The pattern of this form/function relationship is similar for both crocodilians and odontocetes, despite their fundamentally different anatomies. However, when loading teeth at the posterior end or middle of the tooth row the results do not follow the same pattern. Behavioural differences in bite location plays a key role in determining functional abilities in aquatic tetrapod taxa. PMID- 28363383 TI - Becoming Inclusive: A Code of Conduct for Inclusion and Diversity. AB - There are increasing concerns about exclusionary behaviors and lack of diversity in the nursing profession. Exclusionary behaviors, which may include incivility, bullying, and workplace violence, discriminate and isolate individuals and groups who are different, whereas inclusive behaviors encourage diversity. To address inclusion and diversity in nursing, this article offers a code of conduct. This code of conduct builds on existing nursing codes of ethics and applies to nursing students and nurses in both educational and practice settings. Inclusive behaviors that are demonstrated in nurses' relationships with patients, colleagues, the profession, and society are described. This code of conduct provides a basis for measureable change, empowerment, and unification of the profession. Recommendations, implications, and a pledge to action are discussed. PMID- 28363384 TI - Dedicated Educational Nursing Unit: Clinical Instructors Role Perceptions and Learning Needs. AB - Over the past decade, health care leaders have called for a radical transformation in health care and nursing education. Patient care has become complex, demanding succinct interprofessional communication and collaboration to optimize the care of the patient, and the nurse at the bedside is the optimal leader at the point of care. Assistance with the clinical reasoning and critical thinking with nursing students is pivotal for successful patient outcomes. The expert clinical nurse at the bedside is the premier faculty to guide the young practitioner in the care of the patient. A dedicated educational unit (DEU) is an example of an academic-practice partnership designed to provide students with a positive clinical learning environment. The purpose of this qualitative research study was to identify the role perceptions of staff nurse's participating as clinical instructors on a DEU and the perceived educational learning needs of the experienced staff nurses. After Veterans Affairs Boston Healthcare System Institutional Review Board approval, a total of 8 nurses serving in the role of clinical instructor on a DEU participated in the study. Content analyses were used to code and synthesize common theses from the interviews. The themes that emerged related to role perception were mentoring, ensuring competency with basic skills and tasks, and development of critical thinking in nursing clinical education. The themes related to perceived learning needs of staff nurses related to the role of clinical instructor were the need for clear objectives from the academic affiliate, more coordination and acknowledgement by the academic affiliate, and addition education in dealing with students with diverse learning needs and accommodations. PMID- 28363385 TI - Lateral Violence in Nursing: Implications and Strategies for Nurse Educators. AB - Lateral violence among nurses persists as a prevalent problem, contributing to psychological distress, staff turnover, and attrition. Newly graduated nurses are at particular risk for being targets of lateral violence and experiencing its negative sequelae. Preparing student nurses to respond to lateral violence prior to entering the nursing may alter this scenario. A review of the literature was conducted to determine the potential for nursing faculty to change the cycle of lateral violence. Based on this review, we recommend 3 main strategies, specifically for nursing faculty, aimed at reducing incidences of lateral violence and preparing students to manage this phenomenon. First, curricular content can address integrating lateral violence content into simulation experiences and facilitating this knowledge into clinical experiences. Second, codes of conduct should guide behaviors for both students and faculty. Finally, as role models, faculty should be aware of their own behaviors, role model respectful communication, facilitate a courteous academic environment, and develop nurses capable of identifying and appropriately responding to lateral violence. PMID- 28363386 TI - Using Objective Structured Clinical Examination (OSCE) as Education in Advanced Practice Registered Nursing Education. AB - Approximately 3 million nurses make up the U.S. health care workforce. The Robert Wood Johnson Foundation and the Institute of Medicine (2011) supported the call to strengthen the nursing profession by establishing global standards of educational criteria and outcomes. Throughout the world, health education is affected by fundamental inadequacies related to static, fragmented, and content oriented curricula. There are inadequacies in our curricula, and nursing faculties are facing challenges with clinical placements (both the number and quality of these placements); therefore, alternative methods of providing practice to students need to be considered. A transformative agenda comprising changes in the way students are taught fully harnessing the potential of information and communications technology (i.e., simulation) is necessary. Simulated patient encounters and Objective Structured Clinical Examinations are 2 means to achieve needed practice in a safe environment. The purpose of this article is to show, by using simulation, how students can practice and be evaluated within their clinical practice role in a safe, controlled environment. In addition, this practice can (a) enable students to increase the complexity of their understanding and their autonomy and (b) educate students about social accountability, health and gender equity, social justice, and human rights. PMID- 28363387 TI - Promoting the Future of Nursing by Increasing Zest for Research in Undergraduate Nursing Students. AB - Nurses are expected to deliver cost-effective, high-quality care. In order to provide this care, nurse researchers are needed to evaluate and research effective health care models and interventions. By including research concepts within a baccalaureate nursing program, interest in nursing research can be increased. The purpose of this article is to present a case study of strategies used in an undergraduate liberal arts nursing program to promote zest in research and increase the pursuit of graduate studies among baccalaureate nursing students. Using the Bronfenbrenner ecological framework, the promotion of research is categorized into microsystems (individual), mesosystems (multiple setting), exosystems (program), and macrosystem (institutional culture) levels. The microsystem level includes engagement in the classroom, engagement in one-on one meetings, and faculty members as role models. The mesosystem involves engagement outside the classroom and encouragement from faculty members. The exosystem level describes specific learning activities and programs the nursing department utilizes such as community assessments, preconception reproductive knowledge promotion, and women supporting women. Finally, the macrosystem includes a supportive and encouraging environment. By working together, each system contributes to the students' zest for nursing research and interest in graduate studies in nursing to pursue the role of a nurse researcher. PMID- 28363388 TI - An Integrative Review of Flipped Classroom Teaching Models in Nursing Education. AB - Nursing care is changing dramatically given the need for students to address complex and multiple patient comorbidities. Students experience difficulties applying knowledge gained from didactic instruction to make important clinical decisions for optimal patient care. To optimize nursing education pedagogy, innovative teaching strategies are required to prepare future nurses for practice. This integrative review synthesized the state of the science on flipped classroom models from 13 empirical studies published through May 2016. The purpose of the review was to evaluate studies conducted on flipped classroom models among nursing students using a validated framework by Whittemore and Knafl. Multiple academic databases were searched, ranging in scope including PubMed, Embase (Elsevier), CINAHL (Ebsco), Scopus, Web of Science, and Google Scholar, resulting in 95 unique records. After screening and full-text reviews, 82 papers were removed. Thirteen empirical studies were included in the final analysis and results provided (a) design and process information on flipped classroom models in nursing education, (b) a summary of the state of the evidence to inform the implementation of flipped classrooms, and (c) a foundation to build future research in this area of nursing education. To develop sound evidence based teaching strategies, rigorous scientific methods are needed to inform the implementation of flipped classroom approaches. PMID- 28363389 TI - Joining Forces: The Status of Military and Veteran Health Care in Nursing Curricula. AB - According to the Department of Veterans Affairs, there are approximately 23 million veterans living in the United States. In 2012, the Joining Forces initiative highlighted the need to enhance nursing education for the military and veteran population. With the drawdown of 2 long, large-scale conflicts, a young cohort of veterans presented new challenges in health care. Although not necessarily a traditional vulnerable population, given their emergent health care needs, they are vulnerable. Purnell's Model for Cultural Competence provided a framework for this exploratory descriptive study. A national on-line survey of 123 nursing programs that pledged to support Joining Forces responded as to how they addressed the initiatives, curricular content, and facilitators and barriers to the process. The findings suggest that some schools/colleges of nursing have exceeded the initiative goals, some who have implemented little, whereas most are in the process. Respondents shared approaches used to enhance courses and curricula. Faculty who were veterans were a strength to program enhancement. The majority felt that incorporating this content was important, although lack of time and a content-laden curriculum were common barriers. Nurse educators have an ethical obligation to teach culturally sensitive care. Making the pledge was only the first step. PMID- 28363391 TI - Male Nurses in Israel: Barriers, Motivation, and How They Are Perceived by Nursing Students. AB - The current worldwide nursing shortage remains a challenge for the nursing profession. Encouraging men to become nurses and, thereby, increasing the number of practitioners are crucial factors in facing this challenge. The historiography of nursing presents nursing as "women's work," based on the assumption that it is inherently appropriate for women only. Although men were employed as nurses even before nursing was recognized as a profession, male nurses were always a minority in the field. Over the years, the proportion of male nurses has increased, but they still comprise only 5 to 10% of the nursing workforce in the western world. This study examined men's motives for a career choice of nursing, how male nurses are perceived, and the barriers that they face. The study was conducted among 336 nursing students studying in a co-educational program in various academic tracks at a public, nonsectarian university in the south of Israel. Participants completed the following questionnaires in one study session: sociodemographic questionnaire; Attitudes Towards Men in Nursing Scale; motives for career choice questionnaire; and the questionnaire of the perceptions of the professional status of nursing. Study findings revealed that men tended to choose nursing because of financial constraints significantly more frequently than women (P=.001). Among the participants, there was no significant between-sex difference in the perception nursing as women's work (P=.002) or in perception of male nurses as homosexuals. Results of the study showed that the status of the nursing profession is considered low, and the low status deters men from choosing nursing as a career. The motivation for men's career choice must be understood, and men must be empowered to improve their work conditions and financial remuneration in order to recruit men to the field and to improve the perception of the profession and its public status. PMID- 28363392 TI - Have You Ever Considered Being a Journal Manuscript Reviewer? PMID- 28363390 TI - Factors Associated With Nursing Students' Resilience: Communication Skills Course, Use of Social Media and Satisfaction With Clinical Placement. AB - The purpose of this study was to explore the (a) associations between students' personal and group resilience to their utilization of social networking platforms and formally taught communication skills, (b) students' personal and clinical characteristics that are related to personal and group resilience and the perceived helpfulness of communication course, and (c) factors that contribute to students' satisfaction with their clinical placement. Data were collected from 149 second year nursing students learning in a major university in the country of Israel with the use of a self-administered structured questionnaire. Students' satisfaction from their clinical placement was measured using 1 open-ended question, analyzed through qualitative methods. Results demonstrated positive correlations between students' use of social networking to their personal and group resilience (P<.05). Moreover, social media use, religion, and clinical placement characteristics were related to resilience and to the perceived helpfulness of the communication course (P<.01). Students' satisfaction with their clinical placement was based primarily on the clinical instructors' personal and professional skills. In conclusion, social networking can and should be used as a learning tool to promote resilience among nursing students. Faculty and nurse managers should be aware of the central role of the clinical instructor and initiate collaborative and supporting initiatives. PMID- 28363393 TI - An Academic-Practice Partnership to Advance DNP Education and Practice. AB - During the past decade, the growth of doctor of nursing practice (DNP) programs in the United States has been phenomenal, with most focusing on the preparation of advanced practice registered nurses. Simultaneously, academic-practice partnerships have been a frequent subject of discussion for nursing's leading academic, administrative, and practice organizations. Numerous reports about academic-practice partnerships concerning aspects of baccalaureate nursing education exist, but partnership accounts for DNP programs are essentially nonexistent. The purpose of this article is to describe the initial phase of an academic-practice partnership between a multisystem health care organization and a college of nursing in a public land-grant university in the southeastern United States. The 7-year partnership agreement between Norton Healthcare and the University of Kentucky College of Nursing was designed to prepare 5 cohorts of 20 to 30 baccalaureate-prepared staff nurses as DNP graduates for advanced practice registered nurse eligibility. The description of partnering institution characteristics frames an emphasis on elements of the partnership proposal, contractual agreement, and partner responsibilities along with the logic model evaluation plan. Lessons learned include the importance of proposals and contracts to sustain the partnership, frequent communication to build trust, and strategic analysis for rapid response to challenging situations. PMID- 28363394 TI - Imagine Something Different: How a Group Approach to Scholarly Faculty Development Can Turn Joy-Stealing Competition Into Scholarly Productivity. AB - As academic institutions across the country raise the scholarly bar for retention, promotion, and tenure, academic leaders are being asked to scholar ready nursing faculty. With the retirement of senior scholars and too few scholar mentors to go around, leaders often find themselves squeezed between scholarly expectations on the rise and faculty groups less than ready to meet those expectations. Today's nursing faculty present a formidable scholarly development challenge. A diverse mix of master's-prepared clinicians and recent graduates from doctor of philosophy and doctor of nursing practice programs, they come with a broad range of scholarly learning needs. These inequities not only leave many faculty feeling like scholar-impostors but also they can breed competitions that erode collegial bonds and sow the seeds of incivilities that steal scholarly joy, slow scholarly progress, and stress academic workplaces. What if leaders began imagining something different for themselves and with faculty groups? This is what can happen when leaders expand their perspective on scholarly faculty development from individual challenge to collective responsibility. More essay than research paper, this article describes how scholarly joy-stealing patterns can infiltrate faculty groups, shares thought leaders' visions for supportive scholarly communities, and offers strategies leaders can use to invite faculty groups to co-create cultures of scholarly caring. PMID- 28363395 TI - Is denitrifying anaerobic methane oxidation-centered technologies a solution for the sustainable operation of wastewater treatment Plants? AB - With the world's increasing energy crisis, society is growingly considered that the operation of wastewater treatment plants (WWTPs) should be shifted in sustainable paradigms with low energy input, or energy-neutral, or even energy output. There is a lack of critical thinking on whether and how new paradigms can be implemented in WWTPs based on the conventional process. The denitrifying anaerobic methane oxidation (DAMO) process, which uses methane and nitrate (or nitrite) as electron donor and acceptor, respectively, has recently been discovered. Based on critical analyses of this process, DAMO-centered technologies can be considered as a solution for sustainable operation of WWTPs. In this review, a possible strategy with DAMO-centered technologies was outlined and illustrated how this applies for the existing WWTPs energy-saving and newly designed WWTPs energy-neutral (or even energy-producing) towards sustainable operations. PMID- 28363396 TI - The requirement of integrins for breast epithelial proliferation. AB - Epithelial cells forming mammary gland ducts and alveoli require adhesion to the extracellular matrix for their function. Mammary epithelial cells need beta1 integrins for normal cell cycle regulation. However, the role of beta1-integrins in tumorigenesis has not been fully resolved. beta1-integrin is necessary for tumour formation in transgenic mice expressing the Polyomavirus Middle T antigen, but it is dispensable in those overexpressing ErbB2. This suggests that some oncogenes can manage without beta1-integrin to proliferate and form tumours, while others still require it. Here we have developed a model to test whether expression of an oncogene can surpass the need for beta1-integrin to drive proliferation. We co-expressed the ErbB2 or Akt oncogenes with shRNA to target beta1-integrin in mammary epithelial cells, and found that they show a differential dependence on beta1-integrin for cell division. Moreover, we identified a key proliferative role of the Rac1-Pak axis downstream of beta1 integrin signalling. Our data suggest that, in mammary epithelial cells, oncogenes with the ability to signal to Pak surpass the requirement of integrins for malignant transformation. This highlights the importance of using the correct combination therapy for breast cancer, depending on the oncogenes expressed in the tumour. PMID- 28363397 TI - Can an Out-of-Hospital Medication History Save Lives for Injured Older Adults? PMID- 28363398 TI - Corrigendum to ''Modelling cross-reactivity and memory in the cellular adaptive immune response to influenza infection in the host'' [J.Theor. Biol. 413 (2017) 34-49]. PMID- 28363399 TI - Identification of the larval serum proteins as major fruit fly (Drosophila melanogaster) occupational allergens. PMID- 28363400 TI - Eosinophilic Esophagitis: A Primary Disease of the Esophageal Mucosa. PMID- 28363402 TI - Effect of Roux-en-Y gastric bypass on carotid intima-media thickness in Chinese obese patients with type 2 diabetes. AB - BACKGROUND: The effect of Roux-en-Y gastric bypass (RYGB) on carotid intima-media thickness (C-IMT) in obese patients with type 2 diabetes (T2D) has not been well studied. OBJECTIVE: To investigate the effect of RYGB on C-IMT and the relationship between C-IMT and some cardiovascular risk factors 12 months after surgery on Chinese obese patients with T2D. SETTING: University hospital, China. METHODS: Thirty-three consecutive obese patients with T2D and 18 healthy volunteers matched in age and sex were enrolled in this retrospective study. The anthropometric data, metabolism variables, and C-IMT were recorded before and 12 months after RYGB. RESULTS: The patient group had significantly higher C-IMT than the control group before surgery (589.5+/-96.9 MUm versus 457.9+/-48.6 MUm, respectively; P<.01). C-IMT had significant positive relationships with age, body mass index, systolic blood pressure, visceral fat area (VFA), and serum leptin (r = .56, .44, .38, .42, and .38, respectively; P<.01). Twelve months after RYGB, the anthropometric data, metabolism variables, and C-IMT had improved significantly. The change in C-IMT was positively correlated with changes in VFA and leptin level (r = .39 and .36, respectively; P<.01). CONCLUSION: RYGB surgery seems to be effective on C-IMT for obese patients with T2D in China. VFA and leptin level are related to improvement of C-IMT. PMID- 28363401 TI - Neutrophilic Steroid-Refractory Recurrent Wheeze and Eosinophilic Steroid Refractory Asthma in Children. AB - BACKGROUND: Little is known about inflammatory pathways of severe recurrent wheeze in preschool children and severe asthma in children. OBJECTIVES: The aim of the Severe Asthma Molecular Phenotype cohort was to characterize phenotypes of severe recurrent wheeze and severe asthma during childhood in terms of triggers (allergic or not), involved cells (eosinophil or neutrophil), and corticoid responsiveness. METHODS: Children with moderate-to-severe asthma and preschool children with moderate-to-severe recurrent wheeze were enrolled prospectively. They underwent standardized clinical and blood workup, and bronchoalveolar lavage (BAL) evaluation. Cluster analysis was applied to 350 children with 34 variables. RESULTS: Three clusters were identified: cluster 1, Neutrophilic steroid refractory recurrent wheeze phenotype, with 138 children uncontrolled despite high-dose inhaled corticosteroids (ICS) (92%, P < .001), with more history of pneumonia (31%, P < .001), more gastroesophageal reflux disease (37%, P < .001), and the highest blood neutrophil count (mean 4.524 cells/mm3, P = .05); cluster 2, Severe recurrent wheeze with sensitization to a single aeroallergen (12%, P = .002), with 104 children controlled with high-dose ICS (63%, P < .001); cluster 3, Eosinophilic steroid-refractory asthma phenotype, with 108 children uncontrolled despite high-dose ICS (76%, P < .001) with more allergic rhinitis, atopic dermatitis, and food allergies (82%, 40%, 31%, P < .001, respectively). They also had a higher blood eosinophil count and a higher percentage of BAL eosinophil (506/mm3, 2.6%, P < .001 respectively). CONCLUSIONS: Inflammation pathway of asthma and recurrent wheeze are related to eosinophil cells in older children and neutrophil cells in younger children. These results could improve personalized treatments. PMID- 28363403 TI - Metabolic signatures in an adolescent with Silver-Russell syndrome and outcomes after bariatric surgery. PMID- 28363405 TI - How can we treat postbariatric hypoglycemia by medical nutrition therapy? PMID- 28363404 TI - Acute antibody mediated rejection following sleeve gastrectomy in a kidney transplant recipient treated with a belatacept-Mycophenolate mofetil based therapy. PMID- 28363406 TI - Are Next-Generation Sequencing Tools Ready for the Cloud? AB - Cloud-based next-generation sequencing (NGS) tools are currently at an early stage. In this Forum article, we provide a clear picture of the current cloud based NGS solutions and highlight what is still missing, along with future challenges for the achievement of an ecosystem of biotechnology clouds. PMID- 28363407 TI - Endolichenic Fungi: A Hidden Reservoir of Next Generation Biopharmaceuticals. AB - Endolichenic fungi (ELF) offer an opportunity to discover emerging natural drugs. ELF are promising bioresources given their ability to produce bioactive metabolites that represent unique and diverse structural classes. Here, we assess the potential of recent technologies to provide insight into the chemical diversity of ELF for biopharmaceutical development. PMID- 28363408 TI - Bioproduction of Antibody-Drug Conjugate Payload Precursors by Engineered Cell Factories. AB - Antibody-drug conjugates (ADCs), which combine the exquisite specificity of antibodies with the cell-killing ability of cytotoxic drug payloads, have emerged as an attractive means for treating cancers. All (pre)clinical ADCs employ biosynthesized cytotoxins as their ADC payload precursors (APPs). The cost effective bioproduction of APPs is receiving great interest from both academia and industry. Given the lack of systematic overviews of the topic, we provide the current status of APPs and focus on their state-of-the-art bioproduction strategies, illustrated with typical examples and critical analyses. Challenges in further enhancing the bioproduction efficiency of APPs and other cytotoxins are also discussed. This research has implications for bioprocess and metabolic engineering, systems and synthetic biology, and biopharmaceutical drug discovery, development, and industrialization. PMID- 28363409 TI - An Ounce of Prevention: Deaths Averted From Primary Prevention Interventions. AB - INTRODUCTION: The U.S. lags in the nationwide implementation of primary prevention interventions that have been shown to be efficacious. However, the potential population health benefit of widespread implementation of these primary prevention interventions remains unclear. METHODS: The meta-analytic literature from October 2013 to March 2014 of primary prevention interventions published between January 2000 and March 2014 was reviewed. The authors then estimated the number of deaths that could have been averted in the U.S. in 2010 if all rigorously studied, efficacious primary prevention interventions for which population attributable risk proportions could be estimated were implemented nationwide. RESULTS: A total of 372,054 (15.1%) of all U.S. deaths in 2010 would have been averted if all rigorously studied, efficacious primary prevention interventions were implemented. Two in three averted deaths would have been from cardiovascular disease or malignancy. CONCLUSIONS: A substantial proportion of deaths in the U.S. in 2010 could have been averted if efficacious primary prevention interventions were implemented nationwide. Further investment in the implementation of efficacious interventions is warranted to maximize population health in the U.S. PMID- 28363410 TI - Factors Related to Pre-exposure Prophylaxis Prescription by U.S. Primary Care Physicians. AB - INTRODUCTION: Although pre-exposure prophylaxis (PrEP) greatly reduces risk of HIV infection in HIV-negative individuals, use is not widespread enough to impact HIV incidence. Involvement of primary care physicians (PCPs) in PrEP prescription is essential, but previous research has shown low rates of prescription among PCPs. To identify targets for interventions, the information-motivation behavioral skills model for PrEP discussion and prescription was tested in a ten city sample of PCPs. METHODS: PCPs from ZIP codes with high HIV incidence in ten U.S. cities (N=280, 52% male, 56% white) completed a survey online between July 2014 and May 2015. Information items assessed knowledge, motivation items evaluated attitudes, and behavioral skills items measured comfort with behaviors involved in prescribing PrEP. Providers indicated whether they had discussed PrEP with or prescribed PrEP to patients. Data were analyzed in 2015 and 2016. RESULTS: One third of PCPs had discussed and 17% had prescribed PrEP. A structural equation model with good fit supported the information-motivation behavioral skills model. Information and motivation predicted behavioral skills (b=0.35, 95% CI=0.13, 0.57; and b=0.31, 95% CI=0.14, 0.47, respectively). Behavioral skills predicted prescription (b=0.27, 95% CI=0.12, 0.42). Furthermore, behavioral skills mediated effects of information and motivation on prescription (b=0.10, 95% CI=0.03, 0.19; and b=0.08, 95% CI=0.03, 0.16, respectively). CONCLUSIONS: The information-motivation-behavioral skills model can be applied to PCPs' PrEP discussion and prescription. Its constructs represent potential targets for PCP-directed interventions to increase PrEP use in high-risk populations. PMID- 28363411 TI - Recommendations on surveillance and management of biallelic mismatch repair deficiency (BMMRD) syndrome: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer. PMID- 28363412 TI - FTY720-derivatives do not induce FTY720-like lymphopenia. AB - FTY720 is an immunosuppressive multiple sclerosis (MS) drug that stimulates the expression of neuroprotective brain-derived-neurotrophic-factor (BDNF). In vivo preclinical data suggest that FTY720 could be beneficial for treating Parkinson's patients, though its immunosuppressive effects might limit its efficacy. Two novel FTY720-derivatives, FTY720-C2 and FTY720-Mitoxy, also stimulate BDNF expression and enter brain like FTY720 but are not phosphorylated, suggesting they will not produce FTY720-like immunosuppression. Using FTY720 as a positive control, we measured low and high dose FTY720-derivatives, which did not stimulate FTY720-like lymphopenia or immunosuppressive signaling. These findings support the further preclinical assessment of the derivatives as potential novel Parkinson's therapies. PMID- 28363413 TI - Action of Bacopa monnieri to antagonize cisplatin-induced emesis in Suncus murinus (house musk shrew). AB - Bacopa monnieri (BM, family Scrophulariaceae) is used in several traditional systems of medicine for the management of epilepsy, depression, neuropathic pain, sleep disorders and memory deficits. The present study investigated the potential of BM methanol (BM-MetFr) and BM n-butanol fractions (BM-ButFr) to reduce chemotherapy-induced emesis in Suncus murinus (house musk shrew). Cisplatin (30 mg/kg, i.p.) reliably induced retching and/or vomiting over a 2 day period. BM MetFr (10-40 mg/kg, s.c.) and BM-ButFr (5-20 mg/kg, s.c.) antagonized the retching and/or vomiting response by ~59.4% (p < 0.05) and 78.9% (p < 0.05), respectively, while the 5-HT3 receptor antagonist, palonosetron (0.5 mg/kg, s.c.), reduced the response by ~71% (p < 0.05). The free radical scavenger/antioxidant, N-(2-mercaptopropionyl)-glycine (30-300 mg/kg, s.c.) reduced the retching and/or vomiting response occurring on day one non significantly by 44% (p > 0.05). In conclusion, the n-butanol fractions of BM have anti-emetic activity comparable with palonosetron and MPG. BM may be useful alone or in combination with other anti-emetic drugs for the treatment of chemotherapy-induced emesis in man. PMID- 28363414 TI - A multidimensional liquid chromatography-tandem mass spectrometry platform to improve protein identification in high-throughput shotgun proteomics. AB - A new on-line multidimensional system for sequential trapping and individual elution and separation of peptides based on their molecular weight is described. By sequentially using two chemically different trapping columns, a polymethacrylate monolith and a packed C18 one, peptides from complex samples can be on-line trapped and divided into two fractions, containing respectively mainly medium-large peptides and smaller peptides. Then, by means of two switching valves working in parallel, the two fractions were individually separated by reversed phase chromatography. The whole gradient consisted of two subgradients, with the first one dedicated to the separation of smaller peptides and the second one to the separation of larger peptides. Such configuration allowed to identify up to 1476 proteins in a standard E. coli tryptic digest, with improved performance, increased average sequence coverage and reduced single unique peptide identifications compared to a conventional shotgun proteomics configuration comprising only the C18 trapping column and the analytical column. PMID- 28363415 TI - Graphitic carbon nitride nanofibers in seaweed-like architecture for gas chromatographic separations. AB - Seaweed-like graphitic carbon nitride (g-C3N4) has a unique porous architecture composed of interlocking g-C3N4 nanofibers (NF-C3N4) with much higher surface area than bulk g-C3N4 and shows good potential in separation science. This work investigated the separation performance of NF-C3N4 as stationary phase for capillary gas chromatographic (GC) separations. The NF-C3N4 column exhibits weak polarity and high column efficiency of 4728 plates/m for n-dodecane. Importantly, it displays good separation performance for a wide range of analytes and shows different retention behaviors from the bulk g-C3N4 column and commercial HP-5MS column with 5% phenylpolysiloxane. Particularly, it shows high resolving capability for both aliphatic and aromatic isomers. In addition, NF-C3N4 column has high thermal stability up to 280 degrees C and good separation repeatability with relative standard deviation (RSD) values in the range of 0.29-0.61% for intra-day, 0.56-1.1% for inter-day and 2.0-4.9% for between-column, respectively. Moreover, it was applied for the determination of isomer impurities in real samples, showing good potential in GC applications. PMID- 28363416 TI - Trapping multiple dual mode centrifugal partition chromatography for the separation of intermediately-eluting components: Operating parameter selection. AB - The preparative separation of intermediately-eluting components in liquid-liquid chromatography is commonly performed with isocratic batch injections, a technique which often leads to low yield and/or purity as a result of peak overlap. Two column trapping multiple dual mode centrifugal partition chromatography, an alternative discontinuous method for the separation of a mixture into three product fractions (early-, intermediately-, and late-eluting components) at full recovery, is presented in this work. A mathematical shortcut method based on equilibrium theory assumptions is derived for the determination of the key operating parameters (i.e., step durations and number of steps). The feasibility of the technique and the accompanying short-cut method is demonstrated by proof of-concept experiments for the separation of two paraben model mixtures. PMID- 28363417 TI - Multiresidue determination of estrogens in different dairy products by ultra-high performance liquid chromatography triple quadrupole mass spectrometry. AB - In this work, a simple and fast methodology has been validated and applied for the analysis of a group of 22 estrogenic compounds including eight phytoestrogens (i.e. daidzein, enterodiol, glycitein, enterolactone, genistein, formononetin, prunetin, biochanin A), six mycotoxins (beta-zearalanol, beta-zearalenol, alpha zearalanol, alpha-zearalenol, zearalanone, zearalenone) as well as four synthetic (i.e. ethynylestradiol, diethylstilbestrol, dienestrol, hexestrol) and four natural estrogens (i.e. estriol, 17beta-estradiol, 17alpha-estradiol, estrone) in different dairy products. Extraction was carried out using the QuEChERS method while separation, determination and quantification of the target analytes were achieved by ultra-high-performance liquid chromatography coupled to triple quadrupole mass spectrometry with an electrospray ionization interface. The methodology was validated for four dairy product samples with relevant interest for the population including skimmed and whole cheese and goat and cow kefir, using 17beta-estradiol-2,4,16,16,17-d5 as internal standard for natural and synthetic estrogens and beta-zeralanol-10,10,11,12,12-d5 as internal standard for mycotoxins and phytoestrogens. Recovery ranged from 70 to 119% for the four types of matrices with RSD values lower than 14% and the limits of quantification of the method achieved were in the range 0.025-2.50MUg/kg for all samples. Finally, the analysis of commercially available products was carried out finding the presence of daidzein, glycitein enterolactone and genistein in some of the studied samples. PMID- 28363418 TI - The use of Oscik's equation to describe the retention in reversed phase liquid chromatography. AB - The Oscik's equation based on the theory of conformal solutions was used to describe the chromatographic process in RP-HPLC. Theoretically calculated values of the logarithms of retention factors (logk) were compared with experimental values for a group of aromatic substances, i.e. alkylbenzenes, PAHs, and polar benzene derivatives. Studies were conducted using two columns: RP-18 and RP-4, as well as water-methanol and water-acetonitrile mixtures as mobile phases. The applicability of Everett's equation to describe the composition of surface phase was also verified. For this purpose, the excess methanol adsorption isotherm on LiChrospher RP-18e, was experimentally determined. PMID- 28363419 TI - The importance of ion-pairing in peptide purification by reversed-phase liquid chromatography. AB - The adsorption mechanism for three peptides was studied under overloaded conditions through adsorption isotherm measurements in the presence of an ion pairing reagent, trifluoroacetic acid (TFA), on an end-capped C18-bonded stationary phase. The overall aim of the study was to obtain a better understanding of how the acetonitrile and the TFA fractions in the eluent affected the overloaded elution profiles and the selectivity between peptides using mechanistic modelling and multivariate design of experiments. When studying the effect of TFA, direct evidence for ion pair formation between a peptide and TFA in acetonitrile-water solutions was provided by fluorine-proton nuclear Overhauser NMR enhancement experiments and the adsorption of TFA on the stationary phase was measured by frontal analysis. The adsorption isotherms for each peptide were then determined by the inverse method at eight TFA concentrations ranging from 2.6mM to 37.3mM (0.02-0.29vol-%) in isocratic elution. The equilibrium between the peptide ion and the peptide-TFA complex was modelled by coupling the mass-balance to reaction kinetics and determining separate adsorption isotherms for the two species. We found that a Langmuir isotherm described the elution profile of peptide-TFA complex well while the peptide ion was described by a bi-Langmuir adsorption isotherm since it exhibited strong secondary interactions. The elution profiles had an unfavorable shape at low TFA concentrations consisting of a spike in their front and a long tailing rear due to the secondary interactions for the peptide ion having very low saturation capacity. The acetonitrile dependence on the adsorption isotherms was studied by determination of adsorption isotherms directly from elution profiles obtained in gradient elution which enabled a broad acetonitrile interval to be studied. Here, it was found that the column saturation capacity was quickly reached at very low acetonitrile fractions and that there were significant variations in adsorption with the molecular weight. Finally, practical implications for method development are discussed based on an experimental design where gradient slope and TFA concentrations are used as factors. PMID- 28363420 TI - Patient Understanding, Expectations, Outcomes, and Satisfaction Regarding Anterior Cruciate Ligament Injuries and Surgical Management. AB - Patient satisfaction has become an increasingly important outcome metric in orthopaedics and medicine in general as many initiatives at both the state and national levels aim to improve the efficiency and quality of health care. Anterior cruciate ligament injuries are among the most common injuries in orthopaedics, with anterior cruciate ligament reconstruction (ACLR) surgery consistently reported as one of the most frequently performed procedures by orthopaedic surgeons. Patient-reported outcomes are frequently used to evaluate outcomes from the patient's perspective, and many physicians also ask patients about their satisfaction with treatment. A growing volume of literature has investigated the relation between preoperative patient expectations and postoperative patient satisfaction. The quality of online resources, patient expectations for ACLR, and factors associated with and/or predictive of either poor or good to excellent outcomes after surgery are described. This article critically reviews the orthopaedic literature on this important topic and identifies variables that influence patient expectations and satisfaction to help treating physicians better counsel and evaluate patients and ultimately improve outcomes of and satisfaction with ACLR surgery. PMID- 28363421 TI - The Effect of Femoral Nerve Block on Quadriceps Strength in Anterior Cruciate Ligament Reconstruction: A Systematic Review. AB - PURPOSE: To assess the isokinetic, functional, and patient-reported outcomes of femoral nerve block (FNB) compared with traditional multimodal anesthesia for FNB in anterior cruciate ligament (ACL) reconstruction. METHODS: A systematic search of PubMed, Scopus, Cumulative Index to Nursing and Allied Health Literature, Cochrane Reviews, and Google Scholar was conducted according to the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Effects of FNB on quadriceps function were evaluated by isokinetic testing, functional scoring systems, range of motion, and patient self-report questionnaires. Heterogeneous reporting of outcomes precluded a formal meta analysis. The methodologic merit of all studies included was evaluated by the Coleman Methodology Score. RESULTS: Six studies were identified with outcome measures reported between 7 days and 6 months postoperatively. At 6 months, 2 of 4 studies that reported isokinetic testing found significantly greater deficits among patients who received a nerve block; one of the remaining studies showed a deficit at 6 weeks but not 6 months. Limited data showed no significant differences in functional or patient-reported outcomes at 6 months after reconstruction, and data regarding the impact of FNB on return to sport were inconclusive. The mean Coleman Methodology Score for the included studies was 53, indicating poor overall methodologic quality of the available literature. CONCLUSIONS: The limited data available suggest that FNB causes a measurable deficit in quadriceps isokinetic strength during the early postoperative period but has no effect on functional outcomes or return to sport at 6 months after ACL reconstruction. However, current clinical evidence is not sufficient to draw any valid or definitive conclusions regarding the effect of FNB on postoperative outcomes after ACL reconstruction. LEVEL OF EVIDENCE: Level IV, systemic review of Level I through IV studies. PMID- 28363422 TI - The triangle inequality constraint in similarity judgments. AB - Since Tversky's (1977) seminal investigation, the triangle inequality, along with symmetry and minimality, have had a central role in investigations of the fundamental constraints on human similarity judgments. The meaning of minimality and symmetry in similarity judgments has been straightforward, but this is not the case for the triangle inequality. Expressed in terms of dissimilarities, and assuming a simple, linear function between dissimilarities and distances, the triangle inequality constraint implies that human behaviour should be consistent with Dissimilarity (A,B) + Dissimilarity (B,C) >= Dissimilarity (A,C), where A, B, and C are any three stimuli. We show how we can translate this constraint into one for similarities, using Shepard's (1987) generalization law, and so derive the multiplicative triangle inequality for similarities, Sim(A,C)>=Sim(A,B)?Sim(B,C) where 0<=Sim(x,y)<=1. Can humans violate the multiplicative triangle inequality? An empirical demonstration shows that they can. PMID- 28363423 TI - New technique for nephron-sparing surgery in polar tumours. A modification of the Kim technique. AB - INTRODUCTION AND OBJECTIVES: Nephron-sparing surgery (NSS) is the indication, provided it is feasible and meets the international treatment guidelines. One of the objectives of performing NSS is to reduce the ischemia time as much as possible. We propose a surgical technique for treating polar renal tumours and those larger than 4cm based on the principle of the technique described by Kim in 1964. METHOD: The technique performs a continuous circular suture on the base of the tumour, achieving compression of the renal pole without vascular clamping, facilitating haemostasis and avoiding the blind transfixion performed in Kim's original technique. We selected 28 patients for the implementation of the technique. RESULTS: The patients' mean age was 56 years (30-69). The R.E.N.A.L. scores were as follows: 12 of low complexity, 12 of moderate complexity and 4 of high complexity. The mean surgical time was 109minutes (75-140), and the mean estimated blood loss was 120mL (50-300mL). No positive margins were identified, and no patients required blood transfusions. The mean stay was 3.7 days (2-6). There were no Clavien grade 2 or higher complications. There were 3 Clavien 1 complications (fever). The difference in glomerular filtration rate was 0.71mL/min/m2. The pathology was malignant in 26 cases, 19 of them clear-cell carcinomas. Two cases were reported as oncocytomas. CONCLUSION: The proposed technique showed acceptable results, with a low rate of complications in the patient group. PMID- 28363424 TI - Higher PKD3 expression in hepatocellular carcinoma (HCC) tissues predicts poorer prognosis for HCC patients. AB - AIM: Protein kinase D (PKD) acts as a key mediator in several cancer development signaling pathways. The aim of this study was to investigate the clinical significance and prognostic value of PKD3 expression in hepatocellular carcinoma (HCC) patients after hepatectomy. METHODS: PKD3 mRNA and protein expression levels in tumor and matched non-tumoral (NT) tissues, HCC cell lines were evaluated by quantitative PCR (qRT-PCR), western blotting and immunohistochemical staining (IHC). Additionally, PKD3 mRNA expression in HCC tissues correlated with clinicopathological characteristics and survival. RESULTS: PKD3 mRNA and protein expression was elevated in HCC tissues and HCC cell lines. Our data also showed that in HCC patients after resection, a high-expression of PKD3 mRNA and protein significantly correlated with multiple tumor nodules (P=0.009, P=0.020, respectively), poor tumor differentiation (P=0.001, P=0.004, respectively), high serum AFP level (P=0.005, P=0.002, respectively), vascular invasion (P=0.006, P=0.009, respectively) and advanced AJCC stage (P=0.001, P=0.022, respectively). A Kaplan-Meier analysis indicated that an elevated PKD3 mRNA expression correlated with shorter overall survival (OS) (P<0.001) and disease-free survival (DFS) (P=0.008). Moreover, multivariate analysis showed that a high-expression of PKD3 was an independent prognostic factor for three-year overall survival rate. CONCLUSIONS: Our findings suggest that abnormal PKD3 expression might contribute to HCC progression. Furthermore, high PKD3 expression predicts a poor prognosis in HCC patients after hepatectomy. PMID- 28363425 TI - The prevalence of hypertension in relation with the normal albuminuria range in type 2 diabetes mellitus within the South Korean population: The Korean National Health and Nutrition Examination Survey, 2011-2012. AB - AIMS: The coexistence of hypertension (HTN) and diabetes mellitus (DM) increases the risk of cardiovascular disease. In some studies, normal albuminuria has also been associated with cardiovascular disease and HTN. Therefore, we examined the relationships between albuminuria and the prevalence of HTN and its control rate in type 2 DM patients. RESULTS: We analyzed data from the 2011-2012 Korea National Health and Nutrition Examination Survey, and 1188 subjects with type 2 DM were included in the study. We divided albuminuria into 3 albuminuria tertiles (T): T1: <4.82mg/g; T2: 4.82-17.56mg/g; and T3: >=17.56mg/g. The systolic and diastolic blood pressure were positively correlated with the albumin to creatinine ratio (ACR) after adjusting for all covariates (P<0.001). Type 2 DM subjects with hypertension had more ACR T3 (odds ratio=2.018, 95% confidence interval=1.445-2.818) than subjects without HTN. Subjects with controlled HTN had less ACR T3 than subjects without controlled HTN (odds ratio=0.566, 95% confidence interval=0.384-0.836). When, we redivided albuminuria by <10, 10-30 (high normal albuminuria), 30-300mg/g (microalbuminuria), and 300mg/g<=(macroalbuminuria), the odds ratio for high normal albuminuria and microalbuminuria was 1.52 and 2.24, respectively in the presence of HTN, however, high normal albuminuria was not associated with HTN control. CONCLUSIONS: In conclusion, albuminuria within the high normal range was associated with the prevalence of HTN in South Korean patients with type 2 DM. PMID- 28363426 TI - Molecular pathology of skeletal growth anomalies in the brain coral Platygyra carnosa: A meta-transcriptomic analysis. AB - Coral skeletal growth anomaly (GA) is a common coral disease. Although extensive ecological characterizations of coral GA have been performed, the molecular pathology of this disease remains largely unknown. We compared the meta transcriptome of normal and GA-affected polyps of Platygyra carnosa using RNA Seq. Approximately 50 million sequences were generated from four pairs of normal and GA-affected tissue samples. There were 109 differentially expressed genes (DEGs) in P. carnosa and 31 DEGs in the coral symbiont Symbiodinium sp. These differentially expressed host genes were enriched in GO terms related to osteogenesis and oncogenesis. There were several differentially expressed immune genes, indicating the presence of both bacteria and viruses in GA-affected tissues. The differentially expressed Symbiodinium genes were enriched in reproduction, nitrogen metabolism and pigment formation, indicating that GA affects the physiology of the symbiont. Our results have provided new insights into the molecular pathology of coral GA. PMID- 28363427 TI - Coastal and inland water monitoring using a portable hyperspectral laser fluorometer. AB - The potential for a ship-mounted laser fluorometer to provide rapid, non intrusively measurements in both coastal and lake conditions are investigated. The instrument consists of a high pulse repetition frequency (10-kHz) microchip laser for fluorescence excitation, a broadband hyperspectral micro spectrometer for spectral detection, and a confocal reflective fluorescent probe for signal collection; it weighs only about 1.7kg. Chlorophyll a (chl-a) and colored dissolved organic matter (CDOM) measured by the new instrument were observed to agree well with those measured by traditional time-consuming laboratory methods in Hangzhou Bay seawater and Qiandao Lake inland water. Subsequently, laser fluorescence distribution and characteristics of chl-a and CDOM in these regions were analyzed, which will improve our understanding of biogeochemical processes in these optically complex aquatic systems. The portable system is promising for water environment monitoring, especially in coastal and inland water. PMID- 28363428 TI - Triclosan alterations of estuarine phytoplankton community structure. AB - Antimicrobial additives in pharmaceutical and personal care products are a major environmental concern due to their potential ecological impacts on aquatic ecosystems. Triclosan (TCS) has been used as an antiseptic, disinfectant, and preservative in various media. The sublethal and lethal effects of TCS on estuarine phytoplankton community composition were investigated using bioassays of natural phytoplankton communities to measure phytoplankton responses to different concentrations of TCS ranging from 1 to 200MUgl-1. The EC50 (the concentration of an inhibitor where the growth is reduced by half) for phytoplankton groups (diatoms, chlorophytes, cryptophytes) examined in this ranged from 10.7 to 113.8MUg TCS l-1. Exposures resulted in major shifts in phytoplankton community composition at concentrations as low as 1.0MUg TCS l-1. This study demonstrates estuarine ecosystem sensitivity to TCS exposure and highlights potential alterations in phytoplankton community composition at what are typically environmental concentrations of TCS in urbanized estuaries. PMID- 28363429 TI - Silver nanoparticles uptake by salt marsh plants - Implications for phytoremediation processes and effects in microbial community dynamics. AB - : This study investigated the uptake of silver nanoparticles (AgNPs) by a salt marsh plant, Phragmites australis, as well as AgNPs effects on rhizospheric microbial community, evaluating the implications for phytoremediation processes. Experiments were carried out with elutriate solution doped with Ag, either in ionic form or in NP form. Metal uptake was evaluated in plant tissues, elutriate solutions and sediments (by AAS) and microbial community was characterized in terms of bacterial community structure (evaluated by ARISA). Results showed Ag accumulation but only in plant belowground tissues and only in the absence of rhizosediment, the presence of sediment reducing Ag availability. But in plant roots Ag accumulation was higher when Ag was in NP form. Multivariate analysis of ARISA profiles showed significant effect of the absence/presence of Ag either in ionic or NP form on microbial community structure, although without significant differences among bacterial richness and diversity. Overall, P. australis can be useful for phytoremediation of medium contaminated with Ag, including with AgNPs. However, the presence of Ag in either forms affected the microbial community structure, which may cause disturbances in ecosystems function and compromise phytoremediation processes. Such considerations need to be address regarding environmental management strategies applied to the very important estuarine areas. CAPSULE: The form in which the metal was added affected metal uptake by Phragmites australis and rhizosediment microbial community structure, which can affect phytoremediation. PMID- 28363430 TI - Benthic habitat health assessment using macrofauna communities of a sub-tropical semi-enclosed bay under excess nutrients. AB - This research was conducted to assess the ecosystem health of Daya Bay benthic habitat, investigate the effects of anthropogenic nutrients, and evaluate the application of ecological indicators for benthic health assessment. Environmental indicators and macrobenthic communities, were investigated during summer and winter 2015. Results indicated a strong seasonality in biotope of intertidal and subtidal zones. Lower macrobenthic diversity were calculated from subtidal inner bay, reflecting the effects of anthropogenic nutrients. However, intertidal sites in that part were indicated to be in a relatively healthier ecological status. Seasonal effects of excess nutrients on benthic habitat were reflected in ecological indicators. It is concluded that the excess nutrients at spatiotemporal scales, influences on the health of benthic habitat. Eventually, it is recommended by this research that, with considering the natural/anthropogenic circumstances, the taxonomic and phylogenetic ecological indicators would be helpful tools to evaluate the benthic health of a typical sub tropical semi-enclosed bay. PMID- 28363431 TI - Restenosis after Carotid Interventions and Its Relationship with Recurrent Ipsilateral Stroke: A Systematic Review and Meta-analysis. AB - OBJECTIVE: Do asymptomatic restenoses > 70% after carotid endarterectomy (CEA) and carotid stenting (CAS) increase the risk of late ipsilateral stroke? METHODS: Systematic review identified 11 randomised controlled trials (RCTs) reporting rates of restenosis > 70% (and/or occlusion) in patients who had undergone CEA/CAS for the treatment of primary atherosclerotic disease, and nine RCTs reported late ipsilateral stroke rates. Proportional meta-analyses and odds ratios (OR) at end of follow-up were performed. RESULTS: The weighted incidence of restenosis > 70% was 5.8% after "any" CEA, median 47 months (11 RCTs; 4249 patients); 4.1% after patched CEA, median 32 months (5 RCTs; 1078 patients), and 10% after CAS, median 62 months (5 RCTs; 2716 patients). In four RCTs (1964 patients), one of 125 (0.8%) with restenosis > 70% (or occlusion) after CAS suffered late ipsilateral stroke over a median 50 months, compared with 37 of 1839 (2.0%) in CAS patients with no significant restenosis (OR 0.87; 95% CI 0.24 3.21; p = .8339). In seven RCTs (2810 patients), 13 out of 141 (9.2%) with restenosis > 70% (or occlusion) after CEA suffered late ipsilateral stroke over a median 37 months, compared with 33 out of 2669 (1.2%) in patients with no significant restenoses (OR 9.02; 95% CI 4.70-17.28; p < .0001). Following data correction to exclude patients whose surveillance scan showed no evidence of restenosis > 70% before stroke onset, the prevalence of stroke ipsilateral to an untreated asymptomatic > 70% restenosis was seven out of 135 (5.2%) versus 40 out of 2704 (1.5%) in CEA patients with no significant restenosis (OR 4.77; 95% CI 2.29-9.92). CONCLUSIONS: CAS patients with untreated asymptomatic > 70% restenosis had an extremely low rate of late ipsilateral stroke (0.8% over 50 months). CEA patients with untreated, asymptomatic > 70% restenosis had a significantly higher risk of late ipsilateral stroke (compared with patients with no restenosis), but this was only 5% at 37 months. Overall, 97% of all late ipsilateral strokes after CAS and 85% after CEA occurred in patients without evidence of significant restenosis or occlusion. PMID- 28363432 TI - [Syndrome of irreversible lithium-effectuated neurotoxicity or SILENT: A case report]. PMID- 28363434 TI - Switching biologics in the treatment of psoriatic arthritis. AB - OBJECTIVE: Psoriatic arthritis (PsA) is a heterogeneous inflammatory disorder that requires targeted treatment based on clinical manifestations, symptom severity, comorbidities, and other factors. Moderate or severe peripheral arthritis symptoms are typically treated with disease-modifying antirheumatic drugs (DMARDs) or biologic DMARDs (bDMARDs), and early and aggressive treatment is recommended in order to prevent permanent damage. Although rheumatologists are now able to choose between several bDMARDs for PsA that have different chemical structures, pharmacokinetic properties, dosing regimens, immunogenicity, safety profiles, and mechanisms of action, there is a lack of typical patient profiles or detailed treatment algorithms that can be followed when patients require alterations in their therapeutic regimens. METHODS: PsA treatment recommendations were evaluated to identify consensus guidelines on switching between bDMARD therapies. PubMed literature searches were then conducted using the terms psoriatic arthritis, switch/switching, biologic, and TNF/tumor necrosis factor. Articles were deemed relevant if they presented data on switching between different bDMARDs in patients with PsA. RESULTS: Data from the clinical literature on switching bDMARD therapies in PsA are limited. Evidence suggests that response to adalimumab, etanercept, and ustekinumab is lower after previous tumor necrosis factor inhibitor (TNFi) therapy and the efficacy of infliximab is independent of previous bDMARD treatment. Trials of ustekinumab and secukinumab showed efficacy responses were greater compared with placebo in patients who failed to respond to >=1 TNFi. CONCLUSION: Switching bDMARD therapies is a recommended strategy for patients who experience treatment failure. Many factors must be considered for determining which agent to switch to including PsA disease characteristics, comorbidities, cardiometabolic risk factors, treatment history, and patient preference. Switching between TNFis can be effective for many patients, but bDMARDs with different mechanisms of action may be superior alternatives. PMID- 28363433 TI - Improved skeletal muscle mass and strength after heavy strength training in very old individuals. AB - Age-related loss of muscle mass and function represents personal and socioeconomic challenges. The purpose of this study was to determine the adaptation of skeletal musculature in very old individuals (83+ years) performing 12weeks of heavy resistance training (3*/week) (HRT) compared to a non-training control group (CON). Both groups received similar protein supplementations. We studied 26 participants (86.9+/-3.2 (SD) (83-94, range) years old) per-protocol. Quadriceps cross-sectional area (CSA) differed between groups at post-test (P<0.05) and increased 1.5+/-0.7cm2 (3.4%) (P<0.05) in HRT only. The increase in CSA is correlated inversely with the baseline level of CSA (R2=0.43, P<0.02). Thigh muscle isometric strength, isokinetic peak torque and power increased significantly only in HRT by 10-15%, whereas knee extension one-repetition maximum (1 RM) improved by 91%. Physical functional tests, muscle fiber type distribution and size did not differ significantly between groups. We conclude that in protein supplemented very old individuals, heavy resistance training can increase muscle mass and strength, and that the relative improvement in mass is more pronounced when initial muscle mass is low. PMID- 28363435 TI - Caffeic acid phenethyl ester protects against glucocorticoid-induced osteoporosis in vivo: Impact on oxidative stress and RANKL/OPG signals. AB - Glucocorticoid-induced osteoporosis (GIO) is one of the most common causes of secondary osteoporosis. Given that glucocorticoids are considered as a main component of the treatment protocols for a variety of inflammation and immune mediated diseases besides its use as adjuvant to several chemotherapeutic agents, it is crucial to find ways to overcome this critical adverse effect. Caffeic acid phenethyl ester (CAPE), which is a natural compound derived from honeybee propolis displayed promising antiosteoporotic effects against mechanical bone injury in various studies. The current work aimed at investigating the potential protective effect of CAPE against GIO in vivo with emphasis on the modulation of oxidative status and receptor activator of NF-kB ligand (RANKL)/osteoprotegrin (OPG) signaling. The results showed that CAPE opposed dexamethasone (DEX) mediated alterations in bone histology and tartarate-resistant acid phosphatase (TRAP) activity. In addition, CAPE restored oxidative balance, Runt-related transcription factor 2 (RunX2) expression and reduced caspase-3 activity in femur tissues. Co-administration of CAPE with DEX normalized RANKL/OPG ratio and Akt activation indicating a reduction in DEX-osteoclastogenesis. In conclusion, concurrent treatment of CAPE with DEX exhibited promising effects in the protection against DEX-induced osteoporosis through opposing osteoclastogenesis and protecting osteoblasts. The potent antioxidant activity of CAPE is, at least in part, involved in its anti-apoptotic effects and modulation of RunX2 and RANKL/OPG signals. The use of CAPE-enriched propolis formulas is strongly recommended for patients on chronic glucocorticoid therapy to help in the attenuation of GIO. PMID- 28363436 TI - Brain activity associated with selective attention, divided attention and distraction. AB - Top-down controlled selective or divided attention to sounds and visual objects, as well as bottom-up triggered attention to auditory and visual distractors, has been widely investigated. However, no study has systematically compared brain activations related to all these types of attention. To this end, we used functional magnetic resonance imaging (fMRI) to measure brain activity in participants performing a tone pitch or a foveal grating orientation discrimination task, or both, distracted by novel sounds not sharing frequencies with the tones or by extrafoveal visual textures. To force focusing of attention to tones or gratings, or both, task difficulty was kept constantly high with an adaptive staircase method. A whole brain analysis of variance (ANOVA) revealed fronto-parietal attention networks for both selective auditory and visual attention. A subsequent conjunction analysis indicated partial overlaps of these networks. However, like some previous studies, the present results also suggest segregation of prefrontal areas involved in the control of auditory and visual attention. The ANOVA also suggested, and another conjunction analysis confirmed, an additional activity enhancement in the left middle frontal gyrus related to divided attention supporting the role of this area in top-down integration of dual task performance. Distractors expectedly disrupted task performance. However, contrary to our expectations, activations specifically related to the distractors were found only in the auditory and visual cortices. This suggests gating of the distractors from further processing perhaps due to strictly focused attention in the current demanding discrimination tasks. PMID- 28363437 TI - Effect of Systemic Inflammation on Survival in Patients With Metastatic Renal Cell Carcinoma Receiving Second-line Molecular-targeted Therapy. AB - BACKGROUND: The role of systemic inflammatory markers, including C-reactive protein (CRP), the neutrophil/lymphocyte ratio (NLR), and the platelet/lymphocyte ratio (PLR), in predicting survival for patients with metastatic renal cell carcinoma receiving second-line molecular-targeted therapy (mTT) after first-line tyrosine kinase inhibitor failure remains unclear. Thus, we investigated the relationship between systemic inflammation and survival in such patients. PATIENTS AND METHODS: Sixty-three patients were evaluated. Progression-free survival (PFS) and overall survival (OS) after second-line mTT initiation were evaluated according to the inflammatory marker levels. In addition, the prognostic factors for survival were examined. RESULTS: The receiver operating characteristic curves for CRP, NLR, and PLR had areas under the curve of 0.779, 0.619, and 0.655, respectively; no significant differences were noted. The corresponding cutoff values were 0.48, 2.53, and 183. Patients with higher CRP (n = 40), NLR (n = 32), and PLR (n = 22) levels had significantly lower PFS and OS than those with lower CRP, NLR, and PLR levels. Multivariate analyses showed that CRP was the sole independent predictor for PFS and OS. CONCLUSION: Systemic inflammation is associated with survival after second-line mTT. In particular, CRP was a strong independent predictive biomarker of prognosis. PMID- 28363439 TI - Patient satisfaction and informed consent for surgery. AB - BACKGROUND: Informed consent is a process that necessitates time and effort. Underlying this investment is the belief that informing patients about the surgery promotes patient satisfaction with the decision for surgery and potentially satisfaction more broadly. OBJECTIVE: The objective of the study was to investigate the extent to which preoperative satisfaction with a decision to pursue surgery is associated with understanding after an informed consent discussion. STUDY DESIGN: We performed an observational study of adult women seeking surgical treatment for pelvic floor disorders. Study participants were recruited after routine preoperative counseling by board-certified or board eligible urogynecologists. In our practice, the preoperative informed consent process typically includes a discussion of the indications, risks, benefits, alternatives, and chance of success of the procedures. Participants completed a 35 question survey preoperatively at one setting. The primary outcome, satisfaction with decision, was measured with a validated 6 item Satisfaction with Decision Scale-Pelvic Floor Disorder. Participants were classified as highly satisfied if they indicated the highest level of satisfaction for all items. The primary exposure was patient knowledge of the planned surgery, measured using a newly adapted 20 item Informed Consent Questionnaire including 15 yes/no questions and 5 free-text questions. Additionally, the survey included a validated 3 item tool for health literacy, a single-item anxiety measure, and demographic data. Analyses were performed with a chi2 test, a Student t test, and a multivariable logistic regression using the binary outcome variable, highly satisfied or not highly satisfied. RESULTS: A total of 150 participants were enrolled, with a mean age of 57.5 years. The majority were non-Hispanic (97.3%) or white (87.3%), with at least some college education (51.0%). The median number of days between the informed consent discussion and the survey was 35. The mean total Satisfaction with Decision score was 27.9 (SD, 2.6; range, 19-30), indicating overall high satisfaction with the decision. A patient's preoperative satisfaction with her decision was strongly associated with increased knowledge of the planned surgery, as measured on the Informed Consent Questionnaire (P = .003). The mean score for the highly satisfied group was 17.8 (n = 70; SD, 3.6; range, 6-20) and for the not highly satisfied group was 16.1 (n = 77; SD, 2.8; range, 9-20). There were no significant differences between the highly satisfied and not highly satisfied groups with respect to age, race, education level, anxiety score, or health literacy. The odds of being highly satisfied increased for every 1 point increase in the Informed Consent Questionnaire score (odds ratio, 1.28; 95% confidence interval, 1.06-1.32; P = .003). The association between decisional satisfaction and knowledge persisted after controlling for demographic and clinical variables including education level, health literacy, race/ethnicity, age, surgeon years since completing fellowship, diagnosis, surgery category, number of visits in the past 6 months, and number of days between informed consent discussion and survey. CONCLUSION: This study found that patient knowledge and understanding of surgery are important components of a patient's satisfaction with her decision to proceed with pelvic floor surgery. By measuring patient understanding after informed consent discussions, clinicians may be able to better manage preoperative expectations, increase patient satisfaction, and improve the informed consent process. PMID- 28363438 TI - Reducing surgical site infections after hysterectomy: metronidazole plus cefazolin compared with cephalosporin alone. AB - BACKGROUND: Organisms that are isolated from vaginal cuff infections and pelvic abscesses after hysterectomy frequently include anaerobic vaginal flora. Metronidazole has outstanding coverage against nearly all anaerobic species, which is superior to both cefazolin and second-generation cephalosporins. Cefazolin plus metronidazole has been demonstrated to reduce infectious morbidity compared with either cefazolin or second-generation cephalosporins in other clean contaminated procedures, which include both as colorectal surgery and cesarean delivery. OBJECTIVE: The purpose of this study was to evaluate whether the combination of cefazolin plus metronidazole before hysterectomy was more effective in the prevention of surgical site infection than existing recommendations of cefazolin or second-generation cephalosporin. STUDY DESIGN: This was a retrospective cohort study of patients in the Michigan Surgical Quality Collaborative from July 2012 through February 2015. The primary outcome was surgical site infection. Patients who were >18 years old and who underwent abdominal, vaginal, laparoscopic, or robotic hysterectomy for benign or malignant indications were included if they received 1 of the following prophylactic antibiotic regimens: cefazolin, second-generation cephalosporin, or cefazolin plus metronidazole. Multivariate logistic regression modeling was performed to evaluate the independent effect of an antibiotic regimen, and propensity score matching was used to validate the findings. RESULTS: The study included 18,255 hysterectomies. The overall rate of surgical site infection was 1.8% (n=329). The unadjusted rate of surgical site infection was 1.8% (n=267) for cefazolin, 2.1% (n=49) for second-generation cephalosporin, and 1.4% (n=13) for cefazolin plus metronidazole. After adjustment for differences in patient and operative factors among the antibiotic cohorts, compared with cefazolin plus metronidazole, we found the risk of surgical site infection was significantly higher for patients who received cefazolin (odds ratio, 2.30; 95% confidence interval, 1.06-4.99) or second-generation cephalosporin (odds ratio, 2.31; 95% confidence interval, 1.21 4.41). CONCLUSION: In this large cohort, the use of prophylactic cefazolin plus metronidazole resulted in lower surgical site infection rates after hysterectomy compared with cefazolin or second-generation cephalosporin. PMID- 28363440 TI - SucStruct: Prediction of succinylated lysine residues by using structural properties of amino acids. AB - Post-Translational Modification (PTM) is a biological reaction which contributes to diversify the proteome. Despite many modifications with important roles in cellular activity, lysine succinylation has recently emerged as an important PTM mark. It alters the chemical structure of lysines, leading to remarkable changes in the structure and function of proteins. In contrast to the huge amount of proteins being sequenced in the post-genome era, the experimental detection of succinylated residues remains expensive, inefficient and time-consuming. Therefore, the development of computational tools for accurately predicting succinylated lysines is an urgent necessity. To date, several approaches have been proposed but their sensitivity has been reportedly poor. In this paper, we propose an approach that utilizes structural features of amino acids to improve lysine succinylation prediction. Succinylated and non-succinylated lysines were first retrieved from 670 proteins and characteristics such as accessible surface area, backbone torsion angles and local structure conformations were incorporated. We used the k-nearest neighbors cleaning treatment for dealing with class imbalance and designed a pruned decision tree for classification. Our predictor, referred to as SucStruct (Succinylation using Structural features), proved to significantly improve performance when compared to previous predictors, with sensitivity, accuracy and Mathew's correlation coefficient equal to 0.7334 0.7946, 0.7444-0.7608 and 0.4884-0.5240, respectively. PMID- 28363441 TI - Has the primary care oral surgery service reduced the activity in secondary care oral and maxillofacial units? AB - To find out if the devolution of some dentoalveolar services into primary care in 2007 was having an effect on the workload of oral and maxillofacial units, I reviewed the workload of two units in 2011-13. PMID- 28363442 TI - Transatlantic flight: Not only jet lag. PMID- 28363443 TI - Atrophy of Swallowing Muscles Is Associated With Severity of Dysphagia and Age in Patients With Acute Stroke. AB - IMPORTANCE: Sarcopenia has been identified as an independent risk factor for dysphagia. Dysphagia is one of the most important and prognostically relevant complications of acute stroke. The role of muscle atrophy as a contributing factor for the occurrence of poststroke dysphagia is yet unclear. OBJECTIVE: To assess whether there is a correlation between age and muscle volume and whether muscle volume is related to dysphagia in acute stroke patients. DESIGN, SETTING, AND PARTICIPANTS: This retrospective, single-center study included 73 patients with acute ischemic or hemorrhagic stroke who underwent computed tomography angiography on admission and an objective dysphagia assessment by Fiberoptic Endoscopic Evaluation of Swallowing within 72 hours from admission. With the help of semiautomated muscle segmentation and 3-dimensional reconstruction volumetry of the digastric, temporal, and geniohyoid muscles was performed. For further analysis, participants were first divided into 4 groups according to their age (<61 years, n = 12; 61-75 years, n = 16; 76-85 years, n = 28; >=86 years, n = 17), secondly into 3 different groups according to their dysphagia severity using the Fiberoptic Endoscopic Dysphagia Severity Scale (FEDSS) (FEDSS 1 and 2, n = 25; FEDSS 3 and 4, n = 32; FEDSS 5 and 6, n = 16). MAIN OUTCOME AND MEASURE: Correlation of muscle volumes with age and dysphagia severity. RESULTS: Muscle volumes of single muscles (except for geniohyoid and the right digastric muscles) as well as the sum muscle volume were significantly and inversely related to dysphagia severity. We found a significant decline of muscle volume with advancing age for most muscle groups and, in particular, for the total muscle volume. CONCLUSIONS: Apart from features being determined by the acute stroke itself (eg, site and size of stroke), also premorbid conditions, in particular age-related muscle atrophy, have an impact on the complex pathophysiology of swallowing disorders poststroke. PMID- 28363444 TI - Discovery of a series of 1,3,4-oxadiazole-2(3H)-thione derivatives containing piperazine skeleton as potential FAK inhibitors. AB - Focal adhesion kinase (FAK) is an important drug target that plays a fundamental role in mediating signal transduction system. We report herein the discovery of a novel class of 1,3,4-oxadiazole-2(3H)-thione derivatives containing piperazine skeleton with improved potency toward FAK. All of the 17 new synthesized compounds were assayed for the anticancer activities against four cancer cells, HepG2, Hela, SW116 and BGC823. Because of the combination of 1,4-benzodioxan, 1,3,4-oxadiazole and piperazine ring, most of them exhibited remarkable antitumor activities. Notably, compound 5m showed the most potent biological activities (IC50=5.78MUM for HepG2, and IC50=47.15MUM for SW1116), and its anti-FAK inhibitory activity (IC50=0.78MUM) was also the best. Computational docking studies also showed that compound 5m has interaction with FAK key residues in the active site. PMID- 28363445 TI - Erratum to "Synthesis, biological evaluation, and physicochemical property assessment of 4-substituted 2-phenylaminoquinazolines as Mer tyrosine kinase inhibitors" [Bioorg. Med. Chem. 24 (2016) 3083-3092]. PMID- 28363446 TI - Spatial distribution and source identification of heavy metals in surface soils in a typical coal mine city, Lianyuan, China. AB - In this study, we investigated the pollution degree and spatial distribution of heavy metals and determined their sources in topsoil in a typical coal mine city, Lianyuan, Hunan Province, China. We collected 6078 soil surface samples in different land use types. And the concentrations of Zn, Cd, Cu, Hg, Pb, Sb, As, Mo, V, Mn, Fe and Cr were measured. The average contents of all heavy metals were lower than their corresponding Grade II values of Chinese Soil Quality Standard with the exception of Hg. However, average contents of twelve heavy metals, except for Mn, exceeded their background level in soils in Hunan Province. Based on one-way analysis of variance (ANOVA), the contents of Cu, Zn, Cd, Pb, Hg, Mo and V were related to the anthropogenic source and there were statistically significant differences in their concentrations among different land use patterns. The spatial variation of heavy metal was visualized by GIS. The PMF model was used to ascertain contamination sources of twelve heavy metals and apportion their source contributions in Lianyuan soils. The results showed that the source contributions of the natural source, atmospheric deposition, industrial activities and agricultural activities accounted for 33.6%, 26.05%, 23.44% and 16.91%, respectively. PMID- 28363447 TI - Calculation of controllability and observability matrices for special case of continuous-time multi-order fractional systems. AB - In this paper, controllability and observability matrices for pseudo upper or lower triangular multi-order fractional systems are derived. It is demonstrated that these systems are controllable and observable if and only if their controllability and observability matrices are full rank. In other words, the rank of these matrices should be equal to the inner dimension of their corresponding state space realizations. To reduce the computational complexities, these matrices are converted to simplified matrices with smaller dimensions. Numerical examples are provided to show the usefulness of the mentioned matrices for controllability and observability analysis of this case of multi-order fractional systems. These examples clarify that the duality concept is not necessarily true for these special systems. PMID- 28363448 TI - Trauma associated sleep disorder: A parasomnia induced by trauma. AB - Nightmares and disruptive nocturnal behaviors that develop after traumatic experiences have long been recognized as having different clinical characteristics that overlap with other established parasomnia diagnoses. The inciting experience is typically in the setting of extreme traumatic stress coupled with periods of sleep disruption and/or deprivation. The limited number of laboratory documented cases and symptomatic overlap with rapid eye movement sleep behavior disorder (RBD) and posttraumatic stress disorder (PTSD) have contributed to difficulties in identifying what is a unique parasomnia. Trauma associated sleep disorder (TSD) incorporates the inciting traumatic experience and clinical features of trauma related nightmares and disruptive nocturnal behaviors as a novel parasomnia. The aims of this theoretical review are to 1) summarize the known cases and clinical findings supporting TSD, 2) differentiate TSD from clinical disorders with which it has overlapping features, 3) propose criteria for the diagnosis of TSD, and 4) present a hypothetical neurobiological model for the pathophysiology of TSD. Hyperarousal, as opposed to neurodegenerative changes in RBD, is a component of TSD that likely contributes to overriding atonia during REM sleep and the comorbid diagnosis of insomnia. Lastly, a way forward to further establish TSD as an accepted sleep disorder is proposed. PMID- 28363449 TI - Medication induced sleepwalking: A systematic review. AB - Medications that trigger sleepwalking may inadvertently put the patient at risk of injury to themselves and/or others, and contribute to poor treatment adherence. The aim of this study was to systematically review the literature to identify drugs that may increase the risk of sleepwalking. A search of CINAHL, EMBASE, PsycINFO, PubMed, and ScienceDirect was conducted with the keywords 'sleepwalking' OR 'somnambulism'. Of the original 83 sourced papers, 62 met the inclusion criteria and were subsequently included for review. Twenty-nine drugs, primarily in four classes-benzodiazepine receptor agonists and other gamma aminobutyric acid (GABA) modulators, antidepressants and other serotonergic agents, antipsychotics, and beta-blockers-were identified as possible triggers for sleepwalking. The strongest evidence for medication-induced sleepwalking was for zolpidem and sodium oxybate. All other associations were based on case reports. This research highlights the importance of considering sleepwalking in risk profiles in clinical trials, particularly for drugs that enhance GABA activity at the GABAA receptor, enhance serotonergic activity, or block the activity of noradrenaline at beta receptors. The results also have implications for prescribers to consider sleepwalking as a potential adverse effect and ensure that: 1) the patient is educated about a safe sleep environment; 2) they are encouraged to report the onset or exacerbation of sleepwalking, and 3) alternative treatments are considered if sleepwalking occurs. PMID- 28363450 TI - A new method for independent component analysis with priori information based on multi-objective optimization. AB - BACKGROUND: Currently the problem of incorporating priori information into an independent component analysis (ICA) model is often solved under the framework of constrained ICA, which utilizes the priori information as a reference signal to form a constraint condition and then introduce it into classical ICA. However, it is difficult to pre-determine a suitable threshold parameter to constrain the closeness between the output signal and the reference signal in the constraint condition. NEW METHOD: In this paper, a new model of ICA with priori information as a reference signal is established on the framework of multi-objective optimization, where an adaptive weighted summation method is introduced to solve this multi-objective optimization problem with a new fixed-point learning algorithm. RESULTS: The experimental results of fMRI hybrid data and task-related data on the single-subject level have demonstrated that the proposed method has a better overall performance on the recover abilities of both spatial source and time course. COMPARISON WITH EXISTING METHODS: At the same time, compared with traditional ICA with reference methods and classical ICA method, the experimental results of resting-state fMRI data on the group-level have showed that the group independent component calculated by the proposed method has a higher correlation with the corresponding independent component of each subject through T-test. CONCLUSIONS: The proposed method does not need us to select a threshold parameter to constrain the closeness between the output signal and the reference signal. In addition, the performance of functional connectivity detection has a great improvement in comparison with traditional methods. PMID- 28363451 TI - Characterization of three commercial ELISA kits for detection of BOHV-1 gE specific antibodies in serum and milk samples and applicability of bulk milk for determination of herd status. AB - Vaccination of animals with gE-deleted vaccine strains (gE- marker vaccines) and differential detection of vaccinated vs infected animals with antibody ELISA targeting the gE or the gB proteins have been proved to be useful tools in programs for control and eradication of the bovine herpesvirus 1 (BoHV-1) responsible for infectious bovine rhinotracheitis (IBR), a major pathogen of cattle. The diagnostic sensitivity (DSe) and specificity (DSp) of three commercial gE ELISA kits from IDEXX, IDVet and CIV-HIPRA were compared for serum and milk matrices. Limiting the analysis to 198 individual with concordant ELISA results in serum (91 naive, 37 vaccinated and 70 infected) the DSe of gE kits was estimated to 0,97 for IDEXX, 0,93 for CIV-HIPRA and 0,53 for IDVet using milk samples and the DSp to 0,95 for IDEXX, 1,00 for IDVet and CIV-HIPRA. The applicability of gE ELISA for individual or bulk milk testing as an additional tool in control programs dedicated to the certification and control of vaccinated herds was evaluated. Two of the three evaluated gE ELISA kits presented substantial to good agreement individual milk and serum samples. The bulk-tank milk also proved to be suitable for the detection of BoHV-1 in vaccinated herds provided that gE prevalence is superior to 10% as false negative results are often observed at lower gE herd prevalence. This limitation could be reduced to 8% of prevalence when a prior concentration step was applied to bulk milk samples. PMID- 28363452 TI - An algorithm for direct causal learning of influences on patient outcomes. AB - OBJECTIVE: This study aims at developing and introducing a new algorithm, called direct causal learner (DCL), for learning the direct causal influences of a single target. We applied it to both simulated and real clinical and genome wide association study (GWAS) datasets and compared its performance to classic causal learning algorithms. METHOD: The DCL algorithm learns the causes of a single target from passive data using Bayesian-scoring, instead of using independence checks, and a novel deletion algorithm. We generate 14,400 simulated datasets and measure the number of datasets for which DCL correctly and partially predicts the direct causes. We then compare its performance with the constraint-based path consistency (PC) and conservative PC (CPC) algorithms, the Bayesian-score based fast greedy search (FGS) algorithm, and the partial ancestral graphs algorithm fast causal inference (FCI). In addition, we extend our comparison of all five algorithms to both a real GWAS dataset and real breast cancer datasets over various time-points in order to observe how effective they are at predicting the causal influences of Alzheimer's disease and breast cancer survival. RESULTS: DCL consistently outperforms FGS, PC, CPC, and FCI in discovering the parents of the target for the datasets simulated using a simple network. Overall, DCL predicts significantly more datasets correctly (McNemar's test significance: p<<0.0001) than any of the other algorithms for these network types. For example, when assessing overall performance (simple and complex network results combined), DCL correctly predicts approximately 1400 more datasets than the top FGS method, 1600 more datasets than the top CPC method, 4500 more datasets than the top PC method, and 5600 more datasets than the top FCI method. Although FGS did correctly predict more datasets than DCL for the complex networks, and DCL correctly predicted only a few more datasets than CPC for these networks, there is no significant difference in performance between these three algorithms for this network type. However, when we use a more continuous measure of accuracy, we find that all the DCL methods are able to better partially predict more direct causes than FGS and CPC for the complex networks. In addition, DCL consistently had faster runtimes than the other algorithms. In the application to the real datasets, DCL identified rs6784615, located on the NISCH gene, and rs10824310, located on the PRKG1 gene, as direct causes of late onset Alzheimer's disease (LOAD) development. In addition, DCL identified ER category as a direct predictor of breast cancer mortality within 5 years, and HER2 status as a direct predictor of 10-year breast cancer mortality. These predictors have been identified in previous studies to have a direct causal relationship with their respective phenotypes, supporting the predictive power of DCL. When the other algorithms discovered predictors from the real datasets, these predictors were either also found by DCL or could not be supported by previous studies. CONCLUSION: Our results show that DCL outperforms FGS, PC, CPC, and FCI in almost every case, demonstrating its potential to advance causal learning. Furthermore, our DCL algorithm effectively identifies direct causes in the LOAD and Metabric GWAS datasets, which indicates its potential for clinical applications. PMID- 28363453 TI - A high-order representation and classification method for transcription factor binding sites recognition in Escherichia coli. AB - BACKGROUND: Identifying transcription factors binding sites (TFBSs) plays an important role in understanding gene regulatory processes. The underlying mechanism of the specific binding for transcription factors (TFs) is still poorly understood. Previous machine learning-based approaches to identifying TFBSs commonly map a known TFBS to a one-dimensional vector using its physicochemical properties. However, when the dimension-sample rate is large (i.e., number of dimensions/number of samples), concatenating different physicochemical properties to a one-dimensional vector not only is likely to lose some structural information, but also poses significant challenges to recognition methods. MATERIALS AND METHOD: In this paper, we introduce a purely geometric representation method, tensor (also called multidimensional array), to represent TFs using their physicochemical properties. Accompanying the multidimensional array representation, we also develop a tensor-based recognition method, tensor partial least squares classifier (abbreviated as TPLSC). Intuitively, multidimensional arrays enable borrowing more information than one-dimensional arrays. The performance of each method is evaluated by average F-measure on 51 Escherichia coli TFs from RegulonDB database. RESULTS: In our first experiment, the results show that multiple nucleotide properties can obtain more power than dinucleotide properties. In the second experiment, the results demonstrate that our method can gain increased prediction power, roughly 33% improvements more than the best result from existing methods. CONCLUSION: The representation method for TFs is an important step in TFBSs recognition. We illustrate the benefits of this representation on real data application via a series of experiments. This method can gain further insights into the mechanism of TF binding and be of great use for metabolic engineering applications. PMID- 28363454 TI - Piecewise-linear criterion functions in oblique survival tree induction. AB - OBJECTIVE: Recursive partitioning is a common, assumption-free method of survival data analysis. It focuses mainly on univariate trees, which use splits based on a single variable in each internal node. In this paper, I provide an extension of an oblique survival tree induction technique, in which axis-parallel splits are replaced by hyperplanes, dividing the feature space into areas with a homogeneous survival experience. METHOD AND MATERIALS: The proposed tree induction algorithm consists of two steps. The first covers the induction of a large tree with internal nodes represented by hyperplanes, whose positions are calculated by the minimization of a piecewise-linear criterion function, the dipolar criterion. The other phase uses a split-complexity algorithm to prune unnecessary tree branches and a 10-fold cross-validation technique to choose the best tree. The terminal nodes of the final tree are characterised by Kaplan-Meier survival functions. A synthetic data set was used to test the performance, while seven real data sets were exploited to validate the proposed method. RESULTS: The evaluation of the method was focused on two features: predictive ability and tree size. These were compared with two univariate tree models: the conditional inference tree and recursive partitioning for survival trees, respectively. The comparison of the predictive ability, expressed as an integrated Brier score, showed no statistically significant differences (p=0.486) among the three methods. Similar results were obtained for the tree size (p=0.11), which was calculated as a median value over 20 runs of a 10-fold cross-validation. CONCLUSIONS: The predictive ability of trees generated using piecewise-linear criterion functions is comparable to that of univariate tree-based models. Although a similar conclusion may be drawn from the analysis of the tree size, in the majority of the studied cases, the number of nodes of the dipolar tree is one of the smallest among all the methods. PMID- 28363455 TI - The evaluation of trustworthiness to identify health insurance fraud in dentistry. AB - OBJECTIVE: According to the investigations of the U.S. Government Accountability Office (GAO), health insurance fraud has caused an enormous pecuniary loss in the U.S. In Taiwan, in dentistry the problem is getting worse if dentists (authorized entities) file fraudulent claims. Several methods have been developed to solve health insurance fraud; however, these methods are like a rule-based mechanism. Without exploring the behavior patterns, these methods are time-consuming and ineffective; in addition, they are inadequate for managing the fraudulent dentists. METHODS: Based on social network theory, we develop an evaluation approach to solve the problem of cross-dentist fraud. The trustworthiness score of a dentist is calculated based upon the amount and type of dental operations performed on the same patient and the same tooth by that dentist and other dentists. RESULTS: The simulation provides the following evidence. (1) This specific type of fraud can be identified effectively using our evaluation approach. (2) A retrospective study for the claims is also performed. (3) The proposed method is effective in identifying the fraudulent dentists. CONCLUSIONS: We provide a new direction for investigating the genuineness of claims data. If the insurer can detect fraudulent dentists using the traditional method and the proposed method simultaneously, the detection will be more transparent and ultimately reduce the losses caused by fraudulent claims. PMID- 28363456 TI - Handling limited datasets with neural networks in medical applications: A small data approach. AB - MOTIVATION: Single-centre studies in medical domain are often characterised by limited samples due to the complexity and high costs of patient data collection. Machine learning methods for regression modelling of small datasets (less than 10 observations per predictor variable) remain scarce. Our work bridges this gap by developing a novel framework for application of artificial neural networks (NNs) for regression tasks involving small medical datasets. METHODS: In order to address the sporadic fluctuations and validation issues that appear in regression NNs trained on small datasets, the method of multiple runs and surrogate data analysis were proposed in this work. The approach was compared to the state-of the-art ensemble NNs; the effect of dataset size on NN performance was also investigated. RESULTS: The proposed framework was applied for the prediction of compressive strength (CS) of femoral trabecular bone in patients suffering from severe osteoarthritis. The NN model was able to estimate the CS of osteoarthritic trabecular bone from its structural and biological properties with a standard error of 0.85MPa. When evaluated on independent test samples, the NN achieved accuracy of 98.3%, outperforming an ensemble NN model by 11%. We reproduce this result on CS data of another porous solid (concrete) and demonstrate that the proposed framework allows for an NN modelled with as few as 56 samples to generalise on 300 independent test samples with 86.5% accuracy, which is comparable to the performance of an NN developed with 18 times larger dataset (1030 samples). CONCLUSION: The significance of this work is two-fold: the practical application allows for non-destructive prediction of bone fracture risk, while the novel methodology extends beyond the task considered in this study and provides a general framework for application of regression NNs to medical problems characterised by limited dataset sizes. PMID- 28363457 TI - Social cognitive correlates of physical activity among persons with multiple sclerosis: Influence of depressive symptoms. AB - BACKGROUND: Physical inactivity and elevated depressive symptoms are both highly prevalent and correlated among persons with multiple sclerosis (MS). Variables from Social Cognitive Theory (SCT) might be differentially correlated with physical activity in persons with MS who have elevated depressive symptoms. PURPOSE: This study investigated the influence of elevated depressive symptoms on correlates of physical activity based on SCT in persons with MS. METHODS: Participants (mean age = 50.3 years, 87% female, 69% Caucasian) completed questionnaires on physical activity, depressive symptoms, self-efficacy, social support, outcome expectations, functional limitations, and goal setting. The questionnaires were delivered and returned through the U.S. Postal Service. The sample (N = 551) was divided into 2 subgroups (i.e., elevated vs non-elevated levels of depressive symptoms) for statistical analyses. Bivariate correlations and stepwise multiple regressions were conducted using SPSS. RESULTS: Self efficacy (r = 0.16), functional limitations (r = 0.22) and goal-setting (r = 0.42) were significantly (p < 0.05) associated with physical activity among the elevated depressive sample. The regression analysis indicated that self-efficacy predicted physical activity in Step 1 (beta = 0.16, p < 0.05), but was no longer significant when goal-setting (beta = 0.06, p > 0.05) entered the model. All social cognitive variables were significantly associated with physical activity levels (r = 0.16-0.40, p < 0.001) among the non-elevated depressive sample. Self efficacy predicted physical activity in Step 1 (beta = 0.24, p < 0.001), but it was no longer significant once goal-setting, functional limitations, and self evaluative outcome expectations entered the model. CONCLUSION: Based on SCT, self efficacy and goal-setting represent possible targets of behavior interventions for increasing physical activity among persons with MS who have elevated depressive symptoms. There is a larger set of targets among those with MS who do not have elevated symptoms. PMID- 28363458 TI - Ardipithecus ramidus and the evolution of language and singing: An early origin for hominin vocal capability. AB - In this paper we analyse the possibility that the early hominin Ardipithecus ramidus had vocal capabilities far exceeding those of any extant non-human primate. We argue that erect posture combined with changes in craniofacial morphology, such as reduced facial and jaw length, not only provide evidence for increased levels of pro-sociality, but also increased vocal ability. Reduced length of the face and jaw, combined with a flexed cranial base, suggests the larynx in this species was situated deeper in the neck than in chimpanzees, a trait which may have facilitated increased vocal ability. We also provide evidence that Ar. ramidus, by virtue of its erect posture, possessed a degree of cervical lordosis significantly greater than chimpanzees. This is indicative of increased mobility of the larynx within the neck and hence increased capacity to modulate vocalisations. In the paleoanthropological literature, these changes in early hominin skull morphology have to date been analysed in terms of a shift in mating and social behaviour, with little consideration given to vocally mediated sociality. Similarly, in the literature on language evolution there is a distinct lacuna regarding links between craniofacial correlates of social and mating systems and vocal ability. These are surprising oversights given that pro sociality and vocal capability require identical alterations to the common ancestral skull and skeletal configuration. We therefore propose a model which integrates data on whole organism morphogenesis with evidence for a potential early emergence of hominin socio-vocal adaptations. Consequently, we suggest vocal capability may have evolved much earlier than has been traditionally proposed. Instead of emerging in the Homo genus, we suggest the palaeoecological context of late Miocene and early Pliocene forests and woodlands facilitated the evolution of hominin socio-vocal capability. We also propose that paedomorphic morphogenesis of the skull via the process of self-domestication enabled increased levels of pro-social behaviour, as well as increased capacity for socially synchronous vocalisation to evolve at the base of the hominin clade. PMID- 28363459 TI - Primary gastric small cell carcinoma. PMID- 28363460 TI - A bone of contention. PMID- 28363461 TI - HSV1 latent transcription and non-coding RNA: A critical retrospective. AB - Virologists have invested great effort into understanding how the herpes simplex viruses and their relatives are maintained dormant over the lifespan of their host while maintaining the poise to remobilize on sporadic occasions. Piece by piece, our field has defined the tissues in play (the sensory ganglia), the transcriptional units (the latency-associated transcripts), and the responsive genomic region (the long repeats of the viral genomes). With time, the observed complexity of these features has compounded, and the totality of viral factors regulating latency are less obvious. In this review, we compose a comprehensive picture of the viral genetic elements suspected to be relevant to herpes simplex virus 1 (HSV1) latent transcription by conducting a critical analysis of about three decades of research. We describe these studies, which largely involved mutational analysis of the notable latency-associated transcripts (LATs), and more recently a series of viral miRNAs. We also intend to draw attention to the many other less characterized non-coding RNAs, and perhaps coding RNAs, that may be important for consideration when trying to disentangle the multitude of phenotypes of the many genetic modifications introduced into recombinant HSV1 strains. PMID- 28363462 TI - Neurodevelopmental and cardiometabolic outcome in 4-year-old twins and singletons born after IVF. AB - This prospective cohort study evaluated whether the cognitive development, neurological condition, anthropometrics and blood pressure of 4-year-old IVF twins differed from those of 4-year-old IVF singletons; 103 IVF singletons and 48 IVF twins born after conventional IVF treatment were included. Primary outcome was total intelligence quotient (IQ). Secondary outcomes were minor neurological dysfunction, anthropometrics and blood pressure. Unadjusted analyses found that the total IQ score of twins was lower than that of singletons, with a mean difference of -5.4 (-9.7 to -1.0). Weight (singletons: 18.6 [18.1 to 19.1] kg; twins: 16.9 [16.0 to 17.9] kg) and height (singletons: 108.8 [107.9 to 109.8] cm; twins: 105.9 [104.0 to 107.7] cm) of twins were lower than those of singletons (mean values [95% CI]). All differences disappeared after adjusting for mediators and confounders. Neurological outcome, systolic and diastolic blood pressure of twins and singletons were similar. Four-year-old IVF twins had a lower total IQ ( 5.4 points), lowerbodyweight (-1.7 kg) and were shorter (-2.9 cm) than 4-year-old IVF singletons. After adjustment, the adverse twin effect disappeared, implying that increased risk for impaired health and development in twins also holds true for IVF twins, and is not altered by IVF. PMID- 28363464 TI - Circulating Cell-free DNA Utility for the Surveillance of Patients with Treated Diffuse Large B-cell Lymphoma. PMID- 28363463 TI - Dietary patterns and the phenotype of polycystic ovary syndrome: the chance of ongoing pregnancy. AB - Polycystic ovary syndrome (PCOS) is generally considered a complex disorder caused by interactions between genetic and environmental factors. In a sub-cohort of women with PCOS visiting the preconception outpatient clinic of a tertiary hospital with follow-up in a periconception cohort, we identified specific dietary patterns and adherence in patients with PCOS with and without hyperandrogenism and the chance of ongoing pregnancy. Food frequency questionnaires were available from 55 patients diagnosed with PCOS during follow up in routine clinical practice, including 25 with hyperandrogenism and 30 without hyperandrogenism. Strong adherence to the healthy dietary pattern was inversely associated with the hyperandrogenic PCOS phenotype (Adjusted OR 0.27; 95% CI 0.07 to 0.99). In women with PCOS overall, a strong adherence to the healthy dietary pattern showed a three-fold higher chance of ongoing pregnancy (adjusted OR 3.38; 95% CI 1.01 to 11.36) and an association with anti-Mullerian hormone concentration (beta -0.569 ug/L; 95% CI -0.97 to -0.17). The effect of this dietary pattern on the chance of ongoing pregnancy and AMH suggests causality, which needs further investigation in prospective studies in the general population. PMID- 28363465 TI - Targeting Stem Cells in Radiation Oncology. PMID- 28363466 TI - Primary prophylaxis in haemophilia care: Guideline update 2016. AB - This paper reviews the current status on recommendations or guidelines for primary prophylaxis based on recent published papers from organizations or group of experts as well as some original key papers. A rather uniform view exists that prophylaxis should be initiated at an early age before or after no more than a single joint bleed and, if possible, preferably be continued for life. The dose and dose frequency of prophylaxis is dependent on the goal of treatment, bleeding phenotype, compliance, venous access and economic resources in the health care system and should be tailored individually based on clinical outcome and pharmacokinetics. For children, the effectiveness of prophylaxis is more dependent on maintaining minimum trough levels than in adults. Novel extended half-life products are being introduced, which should not affect the decision on when to start prophylaxis nor the initial dose, but which may be helpful for patients with difficult venous access and which may enable higher trough levels of factor VIII. PMID- 28363468 TI - Donor mesenchymal stem cells home to maternal wounds after transamniotic stem cell therapy (TRASCET) in a rodent model. AB - PURPOSE: Transamniotic stem cell therapy (TRASCET) with amniotic fluid-derived MSCs (afMSCs) has emerged experimentally as a practical treatment strategy for congenital anomalies. In this study, we sought to determine whether afMSCs migrate to the mother following TRASCET. METHODS: Pregnant rat dams were divided into three groups. Two groups received volume-matched injections into all amniotic cavities of either a suspension of afMSCs labeled with a luciferase reporter gene or the luciferase protein alone. In a third group, a suspension of labeled cells was aliquoted onto the serosal surface of the uterus. Maternal samples from the laparotomy scar (fascia and skin separately), bone marrow, and peripheral blood were procured, along with placenta and umbilical cord. Specimens were screened for luminescence via microplate luminometry. RESULTS: Luminescence was detected in 60% (9/15) of the fascial scars from the group receiving intraamniotic injection of afMSCs, but in none of the other groups (P<0.001). There was a direct correlation between the presence of donor cells in the placenta and their presence in maternal fascia (Wald test=10.2; P=0.001). CONCLUSIONS: Amniotic mesenchymal stem cells migrate to maternal sites of injury after intraamniotic injection. Maternal homing of donor cells must be considered in the setting of transamniotic stem cell therapy. LEVEL OF EVIDENCE: N/A (animal and laboratory study). PMID- 28363467 TI - Investigation of the electrostatic and hydration properties of DNA minor groove binding by a heterocyclic diamidine by osmotic pressure. AB - Previous investigations of sequence-specific DNA binding by model minor groove binding compounds showed that the ligand/DNA complex was destabilized in the presence of compatible co-solutes. Inhibition was interpreted in terms of osmotic stress theory as the uptake of significant numbers of excess water molecules from bulk solvent upon complex formation. Here, we interrogated the AT-specific DNA complex formed with the symmetric heterocyclic diamidine DB1976 as a model for minor groove DNA recognition using both ionic (NaCl) and non-ionic cosolutes (ethylene glycol, glycine betaine, maltose, nicotinamide, urea). While the non ionic cosolutes all destabilized the ligand/DNA complex, their quantitative effects were heterogeneous in a cosolute- and salt-dependent manner. Perturbation with NaCl in the absence of non-ionic cosolute showed that preferential hydration water was released upon formation of the DB1976/DNA complex. As salt probes counter-ion release from charged groups such as the DNA backbone, we propose that the preferential hydration uptake in DB1976/DNA binding observed in the presence of osmolytes reflects the exchange of preferentially bound cosolute with hydration water in the environs of the bound DNA, rather than a net uptake of hydration waters by the complex. PMID- 28363469 TI - Down-regulation of N-deacetylase-N-sulfotransferase-1 signaling in the developing diaphragmatic vasculature of nitrofen-induced congenital diaphragmatic hernia. AB - BACKGROUND: Congenital diaphragmatic hernia (CDH) has been attributed to various developmental abnormalities of the underlying tissue components. N-deacetylase-N sulfotransferase-1 (Ndst1) is a strongly expressed biosynthetic enzyme in endothelial cells, which has recently been identified as an important factor during diaphragmatic vascularization. Loss of endothelial Ndst1 has been demonstrated to cause angiogenic defects in the developing diaphragm and disrupt normal diaphragmatic development. Furthermore, deficiency of Ndst1 diminishes the expression of slit homolog 3 (Slit3), a known CDH-related gene that has been associated with reduced vascular density and muscle defects in the diaphragm of Slit3-/- mice. We hypothesized that expression of Ndst1 and Slit3 is decreased in the diaphragmatic vasculature of fetal rats with nitrofen-induced CDH. METHODS: Time-mated rats received either nitrofen or vehicle on gestational day 9 (D9). Fetal diaphragms were microdissected on D13, D15 and D18, and divided into control and nitrofen-exposed specimens. Gene expression levels of Ndst1 and Slit3 were assessed using qRT-PCR. Immunofluorescence-double-staining for Ndst1 and Slit3 was performed to evaluate protein expression and localization. RESULTS: Relative mRNA expression of Ndst1 and Slit3 was significantly decreased in pleuroperitoneal folds (D13), developing diaphragms (D15) and fully muscularized diaphragms (D18) of nitrofen-exposed fetuses compared to controls. Confocal-laser scanning-microscopy revealed markedly diminished Ndst1 and Slit3 expression in endothelial cells within the diaphragmatic vasculature on D13, D15 and D18 compared to controls. CONCLUSIONS: Down-regulation of Ndst1 signaling in the developing diaphragm may impair endothelial cell migration and angiogenesis, thus leading to defective diaphragmatic vascular development and CDH. LEVEL OF EVIDENCE: Ib. PMID- 28363470 TI - Time-driven activity-based costing: A dynamic value assessment model in pediatric appendicitis. AB - OBJECTIVES: Healthcare reform policies are emphasizing value-based healthcare delivery. We hypothesize that time-driven activity-based costing (TDABC) can be used to appraise healthcare interventions in pediatric appendicitis. METHODS: Triage-based standing delegation orders, surgical advanced practice providers, and a same-day discharge protocol were implemented to target deficiencies identified in our initial TDABC model. Post-intervention process maps for a hospital episode were created using electronic time stamp data for simple appendicitis cases during February to March 2016. Total personnel and consumable costs were determined using TDABC methodology. RESULTS: The post-intervention TDABC model featured 6 phases of care, 33 processes, and 19 personnel types. Our interventions reduced duration and costs in the emergency department (-41min, $23) and pre-operative floor (-57min, -$18). While post-anesthesia care unit duration and costs increased (+224min, +$41), the same-day discharge protocol eliminated post-operative floor costs (-$306). Our model incorporating all three interventions reduced total direct costs by 11% ($2753.39 to $2447.68) and duration of hospitalization by 51% (1984min to 966min). CONCLUSION: Time-driven activity-based costing can dynamically model changes in our healthcare delivery as a result of process improvement interventions. It is an effective tool to continuously assess the impact of these interventions on the value of appendicitis care. LEVEL OF EVIDENCE: II, Type of study: Economic Analysis. PMID- 28363471 TI - Hypotension and the need for transfusion in pediatric blunt spleen and liver injury: An ATOMAC+ prospective study. AB - PURPOSE: Children with blunt liver or spleen injury (BLSI) requiring early transfusion may present without hypotension despite significant hypovolemia. This study sought to determine the relationship between early transfusion in pediatric BLSI and hypotension. METHODS: Secondary analysis of a 10-institution prospective observational study was performed of patients 18years and younger presenting with BLSI. Patients with central nervous system (CNS) injury were excluded. Children receiving blood transfusion within 4h of injury were evaluated. Time to first transfusion, vital signs, and physical exams were analyzed. Patients with hypotension were compared to those without hypotension. RESULTS: Of 1008 patients with BLSI, 47 patients met inclusion criteria. 22 (47%) had documented hypotension. There was no statistical difference in median time to first transfusion for those with or without hypotension (2h vs. 2.5h, p=0.107). The hypotensive group was older (median 15.0 versus 9.5years; p=0.007). Median transfusion volume in the first 24h was 18.2mL/kg (IQR: 9.6, 25.7) for those with hypotension and 13.9mL/kg (IQR: 8.3, 21.0) for those without (p=0.220). Mortality was 14% (3/22) in children with hypotension and 0% (0/25) in children without hypotension. CONCLUSION: Hypotension occurred in less than half of patients requiring early transfusion following pediatric BLSI suggesting that hypotension does not consistently predict the need for early transfusion. TYPE OF STUDY: Secondary analysis of a prospective observational study. LEVEL OF EVIDENCE: Level IV cohort study. PMID- 28363472 TI - Surgical management and surveillance of pediatric appendiceal carcinoid tumor. AB - PURPOSE: Appendiceal carcinoid tumors are rare neuroendocrine neoplasms. The aim of this study was to determine if postoperative oncologic follow-up was necessary for this tumor. METHODS: A retrospective review was performed of patients with appendiceal carcinoid 2000-2015. RESULTS: 8382 patients underwent appendectomy 2000-2015. 30 (0.3%) had appendiceal carcinoid. 70% were female (n=21) with an average age of 13.5+/-2.8 years (range 8-18). Most presented with abdominal pain (n=29, 97%). 20% (n=6) had appendiceal perforation. Mean tumor size was 5.4+/-4mm (range microscopic - 15mm) with most at the appendiceal tip (n=18, 60%). No node infiltration was found, although 10% (n=3) had perineural and 3% (n=1) had lymphovascular invasion. Five were transmural (17%). Most patients were referred to oncology (n=19, 63%) for staging and surveillance including ultrasonography (n=11, 65%), MRI (n=7, 41%), and CT (n=6, 35%). The majority (79%, n=15) underwent serial 5-HIAA testing. All surveillance was found to be normal, and no patients required further treatment. Mean follow-up was 36+/-34 months, with 58% (n=11) continuing surveillance. Medical charges ranged $8500-$44,000. No recurrences have been identified. CONCLUSION: Appendectomy is an adequate treatment for pediatric appendiceal carcinoid <16 mm despite presence of histological risk factors. More aggressive surgery and extensive oncologic follow up are of limited value. LEVEL OF EVIDENCE: III. TYPE OF STUDY: Retrospective comparative study. PMID- 28363474 TI - Disparity between pre-existing management of penile cancer and NCCN guidelines. AB - OBJECTIVE: To determine the locoregional management of penile cancer before the introduction of NCCN guidelines and how much shift in practice patterns is required to meet the guidelines. METHODS: The National Cancer Data Base was queried to identify 6,396 patients with squamous cell carcinoma of the penis diagnosed between 2004 and 2013. The cohort was divided into management groups based on the NCCN guidelines: cTa and cTis (cTa/is), pT1 low grade (T1LG), pT1 high grade (T1HG), and pT2 or greater (T234). These groups were analyzed to determine if management of locoregional disease complies with the 2016 NCCN guidelines and logistic regression analyses were performed to determine factors associated with adherence. RESULTS: Nationwide management of the primary tumor closely follows the NCCN guidelines, with 96.9% adherence for cTa/is, 91.4% for T1LG, and 94.2% for T234. Management of regional lymph nodes (LNs) was inadequate with only 62.9% of patients with clinical N1 or N2 disease undergoing regional LN dissection (LND). The percentage of patients with known LN metastases who received regional LND increased over time (46.2% in 2004 to 69.4% in 2013, P = 0.034). Patients treated at community cancer programs (odds ratio [OR] = 0.26, 95% CI: 0.19-0.35), comprehensive community cancer programs (OR = 0.34, 95% CI: 0.29-0.41), and integrated network cancer programs (OR = 0.36, 95% CI: 0.25-0.52) were significantly less likely to receive LND compared with patients treated at academic comprehensive cancer programs. CONCLUSIONS: Before the introduction of NCCN guidelines, national practice patterns for the management of the primary tumor were consistent with the recommendations. However, the management of regional LNs deviated from the guidelines, reflecting an area for improvement. PMID- 28363475 TI - Clin Cancer Res. 2004 Sep 15; 10(18 Pt 2):6371S-6376S. AB - Current standard treatments for patients with metastatic (stage IV) renal cell carcinoma involve both surgical removal of tumors and treatment with biological agents such as interleukin 2 or IFN-alpha. Unfortunately, such approaches are inadequate for most patients with stage IV disease; the result is a median time to progression of 2 to 4 months and an overall survival of 6 to 17 months. Standard chemotherapy has been uniformly disappointing in this disorder. It is clear that new therapies are needed to approach these patients. Recently, a greater understanding of cancer genetics has led to the successful development of novel therapeutics directed against targets linked to specific types of cancer. During the past decade, researchers have identified the von Hippel-Lindau (VHL) gene as an important tumor suppressor in clear cell carcinoma of the kidney. Elucidation of the VHL gene product (pVHL) and its regulation of hypoxia inducible factor signaling have created a potential genetic basis for growth factor-targeted strategies in this disease. This review will focus on the potential growth factor targets in clear cell carcinoma, their relation to VHL and hypoxia-inducible factor, and the clinical challenges that face their development. PMID- 28363473 TI - End-stage renal disease secondary to renal malignancy: Epidemiologic trends and survival outcomes. AB - OBJECTIVES: Loss of renal parenchyma after surgery may contribute to chronic kidney disease; however, the long-term consequences of chronic kidney disease may differ by cause. We analyzed the outcomes of patients with end-stage renal disease (ESRD) based on various medical and surgical causes. MATERIALS AND METHODS: In the United States Renal Data System from the period 1983 to 2007, patients with renal tumors, traumatic surgical loss, diabetes, or other known causes were identified. The annual incidence, prevalence, and influence of age, race, sex, and primary cause on survival were evaluated. RESULTS: Of 1.3 million patients, 6,812 (0.49%) had renal malignancy-related ESRD (RM-ESRD). An increased over time was noted in the standardized incidence rates of patients with RM-ESRD (R2 = 0.973, P<0.0001). Patients with RM-ESRD had a worse median survival (1.9 vs. 3.4 y, P<0.0001), whereas those with ESRD related to nonmalignant surgical loss had improved survival (3.8 y) compared to diabetic ESRD (P<0.0001). The 5 year cancer-specific mortality was higher for RM-ESRD (30.9% vs. 5.5%, P<0.0001) compared to ESRD from other known causes; however, the non-cancer-specific mortality was improved compared to patients with ESRD with diabetic causes (P<0.0001). Limitations include retrospective analysis and lack of specific clinical data, such as cancer grade. CONCLUSIONS: The incidence of RM-ESRD is increasing, possibly owing to the increased rate of renal cell carcinoma treatment. Although overall survival for RM-ESRD was worse than either that of nonmalignant surgical loss or other known causes, non-cancer-specific mortality was decreased compared to diabetic causes, likely due to systemic effects by cause of ESRD. PMID- 28363476 TI - Frozen section during partial nephrectomy: Does it predict positive margins? Gordetsky J, Gorin MA, Canner J, Ball MW, Pierorazio PM, Allaf ME, Epstein JI. BJU Int. 2015 Dec; 116(6):868-72. [Epub 2015 Mar 23]. doi: 10.1111/bju.13011. AB - OBJECTIVE: To investigate the clinical utility of frozen section (FS) analysis performed during partial nephrectomy (PN) and its influence on intra-operative management. PATIENTS AND METHODS: We performed a retrospective analysis of consecutive PN cases from 2010 to 2013. We evaluated the concordance between the intra-operative FS diagnosis and the FS control diagnosis, a postoperative quality assurance measure performed on all FS diagnoses after formalin fixation of the tissue. We also evaluated the concordance between the intra-operative FS diagnosis and the final specimen margin. Operating reports were reviewed for change in intra-operative management for cases with a positive or atypia FS diagnosis, or if the mass was sent for FS. RESULTS: A total of 576 intra operative FSs were performed in 351 cases to assess the PN tumor bed margin, 19 (5.4%) of which also had a mass sent for FS to assess the tumor type. The concordance rate between the FS diagnosis and the FS control diagnosis was 98.3%. There were 30 (8.5%) final positive specimen margins, of which four (13.3%) were classified as atypia, 17 (56.7%) as negative and nine (30%) as positive on FS diagnosis. Intra-operative management was influenced in six of nine cases with a positive FS diagnosis and in one of nine cases with an FS diagnosis of atypia. CONCLUSIONS: The relatively high false-negative rate, controversy over the prognosis of a positive margin, and inconsistency in influencing intra-operative management are arguments against the routine use of FS in PN cases. PMID- 28363477 TI - The Significance of Memory in Sensory Cortex. AB - Early sensory cortex is typically investigated in response to sensory stimulation, masking the contribution of internal signals. Recently, van Kerkoerle and colleagues reported that attention and memory signals segregate from sensory signals within specific layers of primary visual cortex, providing insight into the role of internal signals in sensory processing. PMID- 28363478 TI - Influence of gender on the QT interval variability and duration in different wake sleep stages in non-sleep apneic individuals: Analysis of polysomnographic recordings. AB - INTRODUCTION: The aim of the study was to determine the influence of gender and sleep stages, especially rapid eye movement sleep (REM), on QT interval variability and duration in normal subjects. METHODS: Polysomnographic recordings of 24 male and 24 female patients without obstructive sleep apnea were analyzed. In each patient, the QT interval variability index (QTVI) and the corrected QT interval (QTc) values were calculated as means of 2 awake, 4 non-rapid eye movement sleep (NREM) and 3 REM episodes, 300s each. For the QTc calculation, five different correction formulas were used. RESULTS: Gender-related differences in the QT interval variability and duration were detected between all sleep stages (P<0.05). In males, mean values of QTVI while awake, in NREM and REM sleep were -1.1+/-0.2, -1.1+/-0.3, -1.3+/-0.2. In females, mean values of QTVI were 0.9+/-0.4, -0.9+/-0.4, and -1.1+/-0.3, respectively. No difference between sleep stages was detected in the mean values of QTVI and QTc in both groups (P>0.05). CONCLUSION: The results of our study demonstrate no significant overall impact of sleep stages on ventricular repolarization variability and duration during physiological sleep in both genders. We found gender differences in the mean values of QTVI and QTc during different sleep stages, which confirm that gender is a modulating factor of ventricular repolarization. PMID- 28363479 TI - Seven scientists win the 2017 Gairdner Awards. PMID- 28363481 TI - Reaching again: a glimpse of the future with neuroprosthetics. PMID- 28363482 TI - Are we ready for targeted therapy for IgA nephropathy? PMID- 28363480 TI - Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial. AB - BACKGROUND: IgA nephropathy is thought to be associated with mucosal immune system dysfunction, which manifests as renal IgA deposition that leads to impairment and end-stage renal disease in 20-40% of patients within 10-20 years. In this trial (NEFIGAN) we aimed to assess safety and efficacy of a novel targeted-release formulation of budesonide (TRF-budesonide), designed to deliver the drug to the distal ileum in patients with IgA nephropathy. METHODS: We did a randomised, double-blind, placebo-controlled phase 2b trial, comprised of 6-month run-in, 9-month treatment, and 3-month follow-up phases at 62 nephrology clinics across ten European countries. We recruited patients aged at least 18 years with biopsy-confirmed primary IgA nephropathy and persistent proteinuria despite optimised renin-angiotensin system (RAS) blockade. We randomly allocated patients with a computer algorithm, with a fixed block size of three, in a 1:1:1 ratio to 16 mg/day TRF-budesonide, 8 mg/day TRF-budesonide, or placebo, stratified by baseline urine protein creatinine ratio (UPCR). Patients self-administered masked capsules, once daily, 1 h before breakfast during the treatment phase. All patients continued optimised RAS blockade treatment throughout the trial. Our primary outcome was mean change from baseline in UPCR for the 9-month treatment phase, which was assessed in the full analysis set, defined as all randomised patients who took at least one dose of trial medication and had at least one post dose efficacy measurement. Safety was assessed in all patients who received the intervention. This trial is registered with ClinicalTrials.gov, number NCT01738035. FINDINGS: Between Dec 11, 2012, and June 25, 2015, 150 randomised patients were treated (safety set) and 149 patients were eligible for the full analysis set. Overall, at 9 months TRF-budesonide (16 mg/day plus 8 mg/day) was associated with a 24.4% (SEM 7.7%) decrease from baseline in mean UPCR (change in UPCR vs placebo 0.74; 95% CI 0.59-0.94; p=0.0066). At 9 months, mean UPCR had decreased by 27.3% in 48 patients who received 16 mg/day (0.71; 0.53-0.94; p=0.0092) and 21.5% in the 51 patients who received 8 mg/day (0.76; 0.58-1.01; p=0.0290); 50 patients who received placebo had an increase in mean UPCR of 2.7%. The effect was sustained throughout followup. Incidence of adverse events was similar in all groups (43 [88%] of 49 in the TRF-budesonide 16 mg/day group, 48 [94%] of 51 in the TRF-budesonide 8 mg/day, and 42 [84%] of 50 controls). Two of 13 serious adverse events were possibly associated with TRF-budesonide-deep vein thrombosis (16 mg/day) and unexplained deterioration in renal function in follow up (patients were tapered from 16 mg/day to 8 mg/day over 2 weeks and follow-up was assessed 4 weeks later). INTERPRETATION: TRF-budesonide 16 mg/day, added to optimised RAS blockade, reduced proteinuria in patients with IgA nephropathy. This effect is indicative of a reduced risk of future progression to end-stage renal disease. TRF-budesonide could become the first specific treatment for IgA nephropathy targeting intestinal mucosal immunity upstream of disease manifestation. FUNDING: Pharmalink AB. PMID- 28363484 TI - Radiobiological parameters of liver and lung metastases derived from tumor control data of 3719 metastases. AB - BACKGROUND AND PURPOSE: The radiobiological parameters for liver and lung metastases treated with stereotactic body radiation therapy (SBRT) are poorly defined. This project aimed at estimating these parameters from published tumor control probability (TCP) data, and separately for metastases with colorectal cancer (CRC) and non-CRC histology. MATERIALS AND METHODS: A total of 62 studies with 89 different treatment prescriptions for a total of 3719 metastases were analyzed in a Bayesian framework using four different radiobiological models: The LQ, mLQ, LQ-L and the regrowth model which accounts for tumor regrowth after SBRT. RESULTS: Depending on the particular model, alpha/beta ratios in the range 13-23Gy for pulmonary metastases and 16-28Gy for hepatic metastases were estimated. For CRC metastases the estimated alpha/beta ratio was 43.1+/-4.7Gy compared to 21.6+/-7.8Gy for non-CRC metastases. Typical isocenter dose prescriptions of 3*12Gy, 3*14.5Gy and 3*17Gy applied within 5days were predicted sufficient to control 90% of lung, liver and CRC metastases after 1yr, respectively. CONCLUSIONS: alpha/beta ratios for liver and lung metastases are higher than the usually assumed 10Gy. Differences between CRC and non-CRC histology were found. Future studies confirming these findings in individual patient data are needed. PMID- 28363485 TI - Re: Ipsilateral axillary recurrence after breast conservative surgery: The protective effect of whole breast radiotherapy. PMID- 28363486 TI - Magnitude and variability of respiratory-induced diaphragm motion in children during image-guided radiotherapy. AB - BACKGROUND AND PURPOSE: To analyse the variability of respiratory motion during image-guided radiotherapy in paediatric cancer patients and to investigate possible relationships thereof with patient-specific factors. MATERIAL AND METHODS: Respiratory-induced diaphragm motion was retrospectively analysed on 480 cone beam CTs acquired during the treatment course of 45 children (<18years). The cranial-caudal positions of the top of the right diaphragm in exhale and inhale phases were manually selected in the projection images. The difference in position between both phases defines the amplitude. The cycle time equalled inspiratory plus expiratory time. We analysed the variability of the intra- and interfractional respiratory motion and studied possible correlations between respiratory-induced diaphragm motion and age, height, and weight. RESULTS: Over all patients, mean amplitude and cycle time were 10.7mm (range 4.1-17.4mm) and 2.9s (range 2.1-3.9s). Intrafractional variability was larger than interfractional variability (2.4mmvs. 1.4mm and 0.5svs. 0.4s for amplitude and cycle time, respectively). Correlations between mean amplitude and patient specific factors were significant but weak (p<0.05, rho<=0.45). CONCLUSIONS: Large ranges of amplitude and cycle time and weak correlations confirm that respiratory motion is patient-specific and requires an individualized approach to account for. Since interfractional variability was small, we suggest that a pre treatment 4DCT in children could be sufficiently predictive to quantify the respiratory motion. PMID- 28363483 TI - Restoration of reaching and grasping movements through brain-controlled muscle stimulation in a person with tetraplegia: a proof-of-concept demonstration. AB - BACKGROUND: People with chronic tetraplegia, due to high-cervical spinal cord injury, can regain limb movements through coordinated electrical stimulation of peripheral muscles and nerves, known as functional electrical stimulation (FES). Users typically command FES systems through other preserved, but unrelated and limited in number, volitional movements (eg, facial muscle activity, head movements, shoulder shrugs). We report the findings of an individual with traumatic high-cervical spinal cord injury who coordinated reaching and grasping movements using his own paralysed arm and hand, reanimated through implanted FES, and commanded using his own cortical signals through an intracortical brain computer interface (iBCI). METHODS: We recruited a participant into the BrainGate2 clinical trial, an ongoing study that obtains safety information regarding an intracortical neural interface device, and investigates the feasibility of people with tetraplegia controlling assistive devices using their cortical signals. Surgical procedures were performed at University Hospitals Cleveland Medical Center (Cleveland, OH, USA). Study procedures and data analyses were performed at Case Western Reserve University (Cleveland, OH, USA) and the US Department of Veterans Affairs, Louis Stokes Cleveland Veterans Affairs Medical Center (Cleveland, OH, USA). The study participant was a 53-year-old man with a spinal cord injury (cervical level 4, American Spinal Injury Association Impairment Scale category A). He received two intracortical microelectrode arrays in the hand area of his motor cortex, and 4 months and 9 months later received a total of 36 implanted percutaneous electrodes in his right upper and lower arm to electrically stimulate his hand, elbow, and shoulder muscles. The participant used a motorised mobile arm support for gravitational assistance and to provide humeral abduction and adduction under cortical control. We assessed the participant's ability to cortically command his paralysed arm to perform simple single-joint arm and hand movements and functionally meaningful multi-joint movements. We compared iBCI control of his paralysed arm with that of a virtual three-dimensional arm. This study is registered with ClinicalTrials.gov, number NCT00912041. FINDINGS: The intracortical implant occurred on Dec 1, 2014, and we are continuing to study the participant. The last session included in this report was Nov 7, 2016. The point-to-point target acquisition sessions began on Oct 8, 2015 (311 days after implant). The participant successfully cortically commanded single-joint and coordinated multi-joint arm movements for point-to-point target acquisitions (80-100% accuracy), using first a virtual arm and second his own arm animated by FES. Using his paralysed arm, the participant volitionally performed self-paced reaches to drink a mug of coffee (successfully completing 11 of 12 attempts within a single session 463 days after implant) and feed himself (717 days after implant). INTERPRETATION: To our knowledge, this is the first report of a combined implanted FES+iBCI neuroprosthesis for restoring both reaching and grasping movements to people with chronic tetraplegia due to spinal cord injury, and represents a major advance, with a clear translational path, for clinically viable neuroprostheses for restoration of reaching and grasping after paralysis. FUNDING: National Institutes of Health, Department of Veterans Affairs. PMID- 28363487 TI - Treatment options for patients with brain metastases from EGFR/ALK-driven lung cancer. AB - INTRODUCTION: Brain metastases in EGFR/ALK-driven NSCLC frequently pose treatment dilemmas. Tyrosine kinase inhibitors (TKIs) can control extracranial disease, but radiotherapy is often required for intracranial control. We aimed to evaluate the impact of first-line whole brain radiotherapy (WBRT), stereotactic radiotherapy (SRS) or TKI alone on outcomes of patients with brain metastases from EGFR/ALK driven NSCLC. METHODS: This single center retrospective review included 184 patients with brain metastases from EGFR/ALK-driven NSCLC, and analyzed effect of treatment choice on time to intracranial progression (TTIP) and overall survival (OS). RESULTS: First-line treatment for brain metastases consisted of WBRT in 120 patients, SRS in 37 and TKI alone in 27. WBRT-treated patients had more brain metastases, and more baseline symptoms. Median TTIP was longer in the WBRT group at 50.5months than SRS or TKI groups at 12 and 15months (p=0.0038). No significant difference was seen in median OS: 21.6months in the WBRT group, 23.9months in the SRS group and 22.6months in the TKI group (p=0.67). In multivariable analysis, age>65years (HR 2.2, p=0.0014), greater number of brain metastases (HR 2.48, p=0.0002) and greater number of extracranial metastatic sites (2 vs 0-1 HR=2.05, p=0.014 and 3+ vs 0-1 HR=2.95, p=0.0001 were associated with shorter OS. No independent effect was seen from first-line CNS treatment choice. CONCLUSIONS: First-line WBRT for brain metastases from EGFR/ALK-driven NSCLC was associated with longer TTIP than SRS or TKI alone, with no difference in OS. These results could support deferral of WBRT until intracranial progression in selected patients who are closely monitored. PMID- 28363488 TI - [Kerion of the vulva: A common pathology in an unusual location]. PMID- 28363489 TI - Recommendations on Surveillance and Management of Biallelic Mismatch Repair Deficiency (BMMRD) Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. AB - The US Multi-Society Task Force on Colorectal Cancer, with invited experts, developed a consensus statement and recommendations to assist health care providers with appropriate management of patients with biallelic mismatch repair deficiency (BMMRD) syndrome, also called constitutional mismatch repair deficiency syndrome. This position paper outlines what is known about BMMRD, the unique genetic and clinical aspects of the disease, and reviews the current management approaches to this disorder. This article represents a starting point from which diagnostic and management decisions can undergo rigorous testing for efficacy. There is a lack of strong evidence and a requirement for further research. Nevertheless, providers need direction on how to recognize and care for BMMRD patients today. In addition to identifying areas of research, this article provides guidance for surveillance and management. The major challenge is that BMMRD is rare, limiting the ability to accumulate unbiased data and develop controlled prospective trials. The formation of effective international consortia that collaborate and share data is proposed to accelerate our understanding of this disease. PMID- 28363490 TI - Geniposide improves insulin production and reduces apoptosis in high glucose induced glucotoxic insulinoma cells. AB - Our previous work revealed that in the pancreatic beta cell line, geniposide modulated ATP production and glucose-stimulated insulin secretion (GSIS) induced by the acute stimulation of high glucose concentration. However, the effects of geniposide on functional impairment and the mass of beta-cells exposed to elevated levels of glucose remains unknown. In the present study, impaired GSIS and restrained proliferation were observed in the prolonged culture of insulinoma INS-1 cells with 33mM of glucose (high glucose). Our results indicate that the glucose-induced impairment of insulin release was significantly reverted by the inclusion of 1 or 10MUM of geniposide. Moreover, induction of the phosphorylation of AMP-activated protein kinase (AMPK) was observed, which promoted the utilization of nutrient stores for energy production. AMPK phosphorylation was enhanced by an increased number of INS-1 cells, and the increased expression of AMPK downstream target heme oxygenase 1 (HO-1), under high glucose concentration. Furthermore, geniposide protected rat insulinoma cells from apoptosis in high glucose concentrations. We have shown that these effects were associated with an increased apoptosis-related Bcl-2/BAX protein ratio. In conclusion, geniposide dose dependently improves beta-cell function and increases the proliferation of beta-cells exposed to prolonged hyperglycemia. PMID- 28363491 TI - Dendrimer pre-treatment enhances the skin permeation of chlorhexidine digluconate: Characterisation by in vitro percutaneous absorption studies and Time-of-Flight Secondary Ion Mass Spectrometry. AB - Skin penetration and localisation of chlorhexidine digluconate (CHG) within the skin have been investigated in order to better understand and optimise the delivery using a nano polymeric delivery system of this topically-applied antimicrobial drug. Franz-type diffusion cell studies using in vitro porcine skin and tape stripping procedures were coupled with Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) to visualise the skin during various treatments with CHG and polyamidoamine dendrimers (PAMAM). Pre-treatment of the skin with PAMAM dendrimers significantly increased the amount and depth of permeation of CHG into the skin in vitro. The effect observed was not concentration dependant in the range 0.5-10mM PAMAM. This could be important in terms of the efficiency of treatment of bacterial infection in the skin. It appears that the mechanism of enhancement is due to the PAMAM dendrimer disrupting skin barrier lipid conformation or by occluding the skin surface. Franz-type diffusion cell experiments are complimented by the detailed visualisation offered by the semi quantitative ToF-SIMS method which provides excellent benefits in terms of sensitivity and fragment ion specificity. This allows a more accurate depth profile of chlorhexidine permeation within the skin to be obtained and potentially affords the opportunity to map the co-localisation of permeants with skin structures, thus providing a greater ability to characterise skin absorption and to understand the mechanism of permeation, providing opportunities for new and more effective therapies. PMID- 28363492 TI - Commentary on "Accelerated partial breast irradiation consensus statement: Update of an ASTRO Evidence-Based Consensus Statement". PMID- 28363493 TI - [Adequacy of the referrals from primary care to pneumology]. PMID- 28363494 TI - Clinical and endoscopic features in patients with hospital-acquired diarrhea associated with Clostridium difficile infection. AB - INTRODUCTION AND AIMS: Clostridium difficile infection is the main cause of hospital-acquired diarrhea, and the clinical and endoscopic findings in those patients have been studied very little in Mexico. The aim of the present study was to describe those findings. MATERIALS AND METHODS: A prospective cohort study was conducted that included patients with hospital-acquired diarrhea associated with Clostridium difficile diagnosed through polymerase chain reaction. The hypervirulent NAP027 strain was also determined. The clinical and endoscopic findings in the study patients, as well as the variables associated with severity, were analyzed. RESULTS: Of the 127 patients with hospital-acquired diarrhea, 97 were excluded from the study due to lack of colonoscopy. The remaining 39 study patients had a mean age of 48 years, and their most common signs/symptoms were abdominal pain (49%), mucus in stools (41%), and blood in stools (10%). The most common alterations in the laboratory results were leukocytosis in 49%, fecal leukocytes (61%), and hypoalbuminemia (67%). The main risk factor was antibiotic use in 62%, and ceftriaxone was the most widely used. The hypervirulent strain was present in 54% of the cases. Endoscopic abnormalities were found in 87% of the patients. Thirty-eight percent presented with pseudomembranous colitis, with lesions in the left colon in 53%, and in the right colon in 13%. No association was found between proton-pump inhibitor use and Clostridium difficile-associated diarrhea. There was a significant association between hypoalbuminemia (< 3.3g/dL) and a greater risk for severe colitis, with a RR of 8.2 (p=0.008). CONCLUSIONS: Pseudomembranous colitis lesions associated with the hypervirulent Clostridium difficile strain were predominant in the left colon. Hypoalbuminemia was a significant severity predictor. PMID- 28363496 TI - Therapeutic progenitor cell application for tissue regeneration: Analyzing the impact of toll-like receptor signaling on c-kit+ cell migration following ischemia-reperfusion injury in vivo. AB - OBJECTIVES: Toll-like-receptor (TLR) mediated immune response has been shown to regulate myocardial damage following cardiac ischemia-reperfusion (IR). It has not been described conclusively so far whether migration of therapeutically applied progenitor cells following an IR event depends on TLR-signaling. METHODS: In vivo migratory capacity murine c-kit+ cells following IR injury was quantified by intravital fluorescence microscopy, utilizing the mouse cremaster muscle model and analyzing early (rolling) and late (adhesion) c-kit+ cell interaction with the local endothelium. The role of TLR-2 and TLR-4, as well as MyD88 and TRIF was analyzed by applying specific knock-out models. RESULTS: A sequence of 15min ischemia followed by 15min of reperfusion induced firm endothelial c-kit+ cell adhesion (5.6+/-1.3cells/mm2 in Control vs. 30.2+/-10.1cells/mm2 in IR, p<0.05). Knock-out of TLR-2 and TLR-4 diminished both IR induced early c-kit+ cell endothelial cell interactions (67.6+/-2.3% c-kit+ cell rolling in IR vs. 46.3+/ 4.8% c-kit+ cell rolling in IR-TLR-2-ko vs. 45.3+/-4.8% c-kit+ cell rolling in IR TLR-4-ko, p<0.05) as well as firm endothelial c-kit+ cell adhesion (30.2+/ 10.1cells/mm2 in IR vs. 16.3+/-3.9cells/mm2 in IR-TLR-2-ko vs. 14.5+/ 4.4cells/mm2 in IR-TLR-4-ko, p<0.05). Adaptor protein knock-out resulted in a significantly decreased firm endothelial c-kit+ cell adhesion only in MyD88 knock out but not in TRIF knock-out (9.2+/-2.2cells/mm2 in IR-MyD88-ko vs. 30.1+/ 9.9cells/mm2 in IR-WT, p<0.05). CONCLUSION: Artificially applied c-kit+ cells interact with the target organ endothelium following IR injury. This interaction seems to depend on TLR-MyD88 signaling. Therapeutic blockade of TLR signaling for anti-inflammatory purposes might interfere with regenerative cell-based therapy protocols. PMID- 28363497 TI - The effects of social exclusion on response inhibition in borderline personality disorder and major depression. AB - It is a prevalent notion that borderline personality disorder (BPD) is characterized by deficits in executive functions (EF) like inhibition. Yet experimental studies yield inconsistent results. However, despite emotional dysregulation being a core feature of BPD, most paradigms did not control for emotional state or comorbid mental disorders. In the present study, subjects with BPD and comorbid MDD (BPD+MDD), with major depression (MDD) and healthy controls (HC) partook in a social exclusion paradigm combined with an inhibition task. We expected inhibition to be more strongly impaired in BPD+MDD than in depression and HC when experiencing negative emotions. Respecting inhibition, depressed patients performed best while (BPD+MDD) patients performed worst. Surprisingly, MDD & HC participants' performance improved during social exclusion, but this was not the case for BPD+MDD. Inhibition deficits were correlated with childhood trauma. These results challenge the hypothesis that an induction of negative emotion results in inferior inhibition in (BPD+MDD). Instead, patients with (BPD+MDD) seem to suffer from a more general inhibitory dysfunction. Importantly, (BPD+MDD) patients were not able to improve their performance during social exclusion like HC and MDD patients did. These findings need to be investigated further, particularly regarding the efficiency of neural networks regulating inhibition and effects of trauma. PMID- 28363495 TI - Nitric oxide release by deoxymyoglobin nitrite reduction during cardiac ischemia: A mathematical model. AB - Interactions between cardiac myoglobin (Mb), nitrite, and nitric oxide (NO) are vital in regulating O2 storage, transport, and NO homeostasis. Production of NO through the reduction of endogenous myocardial nitrite by deoxygenated myoglobin has been shown to significantly reduce myocardial infarction damage and ischemic injury. We developed a mathematical model for a cardiac arteriole and surrounding myocardium to examine the hypothesis that myoglobin switches functions from being a strong NO scavenger to an NO producer via the deoxymyoglobin nitrite reductase pathway. Our results predict that under ischemic conditions of flow, blood oxygen level, and tissue pH, deoxyMb nitrite reduction significantly elevates tissue and smooth muscle cell NO. The size of the effect is consistent at different flow rates, increases with decreasing blood oxygen and tissue pH and, in extreme pathophysiological conditions, NO can even be elevated above the normoxic levels. Our simulations suggest that cardiac deoxyMb nitrite reduction is a plausible mechanism for preserving or enhancing NO levels using endogenous nitrite despite the rate-limiting O2 levels for endothelial NO production. This NO could then be responsible for mitigating deleterious effects under ischemic conditions. PMID- 28363498 TI - T cell metabolism in metabolic disease-associated autoimmunity. AB - This review discusses the relevant metabolic pathways and their regulators which show potential for T cell metabolism-based immunotherapy in diseases hallmarked by both metabolic disease and autoimmunity. Multiple therapeutic approaches using existing pharmaceuticals are possible from a rationale in which T cell metabolism forms the hub in dampening the T cell component of autoimmunity in metabolic diseases. Future research into the effects of a metabolically aberrant micro environment on T cell metabolism and its potential as a therapeutic target for immunomodulation could lead to novel treatment strategies for metabolic disease associated autoimmunity. PMID- 28363499 TI - Expression and secretory profile of buffalo fetal fibroblasts and Wharton's jelly feeder layers. AB - The present study examined the comparative expression and secretory profile of vital signaling molecules in buffalo fetal fibroblasts (BFF) and Wharton's jelly (BWJ) feeder layers at different passages. Both feeder layers were expanded up to 8th passage. Signaling molecules viz. bone morphogenetic protein 4 (BMP4), fibroblast growth factor 2 (FGF2), leukemia inhibitory factor (LIF) and transforming growth factor beta 1 (TGFB1) and pluripotency-associated transcriptional factors (POU5F1, SOX2, NANOG, KLF4, MYC and FOXD3) were immunolocalized in the both feeder types. A clear variation in the expression pattern of key signaling molecules with passaging was registered in both feeders compared to primary culture (0 passage). The conditioned media (CM) was collected from different passages (2, 4, 6, 8) of both the feeder layers and was quantified using enzyme-linked immunosorbent assay (ELISA). Concomitant to expression profile, protein quantification also revealed differences in the concentration of signaling molecules at different time points. Conjointly, expression and secretory profile revealed that 2nd passage of BFF and 6th passage of BWJ exhibit optimal levels of key signaling molecules thus may be selected as best passages for embryonic stem cells (ESCs) propagation. Further, the effect of mitomycin-C (MMC) treatment on the expression profile of signaling molecules in the selected passages of BFF and BWJ revealed that MMC modulates the expression profile of these molecules. In conclusion, the results indicate that feeder layers vary in expression and secretory pattern of vital signaling molecules with passaging. Based on these findings, the appropriate feeder passages may be selected for the quality propagation of buffalo ESCs. PMID- 28363500 TI - Corrigendum to "Metformin affects macrophages' phenotype and improves the activity of glutathione peroxidase, superoxide dismutase, catalase and decreases malondialdehyde concentration in a partially AMPK-independent manner in LPS stimulated human monocytes/macrophages" [Pharmacol. Rep. 66 (2014) 418-429]. PMID- 28363501 TI - Corrigendum to "Partial depletion of natural gut flora by antibiotic aggravates collagen induced arthritis (CIA) in mice" [Pharmacol. Rep. 66 (2014) 250-255]. PMID- 28363502 TI - Bovine sperm separation by Swim-up and density gradients (Percoll and BoviPure): Effect on sperm quality, function and gene expression. AB - This study assesses the effect of bovine sperm (obtained from three bulls) separation using density gradients (Percoll and BoviPure) and Swim-up on sperm function and gene expression. Sperm evaluations included the plasma membrane integrity (SYBR14/PI), acrosomal integrity (PNA-FITC/PI), oxidative stress (ROS; CH2FDDA), DNA fragmentation (TUNEL assay) and mitochondrial membrane potential (DeltaYm; TMRM) using flow cytometry. Sperm motility was evaluated by computer assisted sperm analysis (CASA) and gene expression using RT-qPCR. The results showed that separation by Percoll achieves a higher proportion of sperm with intact plasma and acrosomal membranes (89.8 and 87.5%, respectively) than the unseparated control (70.3 and 62.4%, respectively), as well as by Swim-up (74.9 and 63.3%, respectively) and BoviPure (83.3 and 80.4%, respectively). No differences were observed in the proportion of spermatozoa with high DeltaPsim between Percoll and BoviPure (84.3% and 83.5%, respectively), which were higher than Swim-up and the unseparated control (72.8% and 43.8%, respectively). The ROS levels were higher in the spermatozoa separated by Percoll and no differences were observed in the sperm DNA integrity between all groups. The motility analysis showed that the separation methods improve (p<0.05) total and progressive motility compared to the control, with Percoll proving the most efficient in this regard. Finally, the gene expression analysis of leptin (LEP), aromatase cytochrome P450 (CYP19) and protamine I (PRM1), after validation of 6 reference genes, showed no differences between groups. In conclusion, bovine sperm separation using density gradient improves the parameters of motility and sperm function without affecting the gene expression. PMID- 28363503 TI - The impact of the fabrication method on the three-dimensional accuracy of an implant surgery template. AB - PURPOSE: The use of a surgical template is a well-established method in advanced implantology. In addition to conventional fabrication, computer-aided design and computer-aided manufacturing (CAD/CAM) work-flow provides an opportunity to engineer implant drilling templates via a three-dimensional printer. In order to transfer the virtual planning to the oral situation, a highly accurate surgical guide is needed. The aim of this study was to evaluate the impact of the fabrication method on the three-dimensional accuracy. MATERIALS AND METHODS: The same virtual planning based on a scanned plaster model was used to fabricate a conventional thermo-formed and a three-dimensional printed surgical guide for each of 13 patients (single tooth implants). Both templates were acquired individually on the respective plaster model using an optical industrial white light scanner (ATOS II, GOM mbh, Braunschweig, Germany), and the virtual datasets were superimposed. Using the three-dimensional geometry of the implant sleeve, the deviation between both surgical guides was evaluated. RESULTS: The mean discrepancy of the angle was 3.479 degrees (standard deviation, 1.904 degrees ) based on data from 13 patients. Concerning the three-dimensional position of the implant sleeve, the highest deviation was in the Z-axis at 0.594 mm. The mean deviation of the Euclidian distance, dxyz, was 0.864 mm. CONCLUSION: Although the two different fabrication methods delivered statistically significantly different templates, the deviations ranged within a decimillimeter span. Both methods are appropriate for clinical use. PMID- 28363504 TI - Perioral soft tissue change after isolated mandibular surgery for asymmetry patients. AB - INTRODUCTION: This study was intended to determine whether isolated mandibular surgery for the correction of asymmetry could also change perioral soft tissue asymmetry. PATIENTS AND METHODS: Skeletal class III patients who had undergone mandibular set-back surgery were included. The subjects were composed of two groups with (n = 20) or without (n = 30) menton (Me) deviation over 4 mm. The perioral lip landmarks were analyzed on three-dimensional image from cone-beam computed tomography taken before and 6 months after the operation. The bilateral and inter-group differences and pre- and post-operative changes were statistically analyzed. RESULTS: The corner of mouth on the deviated side was 1.9 mm shorter vertically than that on the contralateral side in patients with asymmetry. After mandibular surgery, the deviated Me moved 5.5 mm to the contralateral side and the lip canting was corrected by 2.4 degrees in the asymmetry group. The degree of Me deviation was significantly correlated with the degree of midline asymmetry in perioral soft tissue landmarks including subnasale, upper and lower lip midline. The predictor variable that affected the changes in lip cant was the surgical correction of Me deviation. DISCUSSION: The correction of chin deviation by isolated mandibular surgery could significantly improve the subnasal and lip asymmetry. PMID- 28363505 TI - A different scintigraphic approach to evaluate the glomerular filtration rate. AB - OBJECTIVE: Multiple nuclear medicine techniques for measuring renal glomerular filtration rate (GFR) are available but some of them are not practical in daily routine use and others have some accuracy issues. Hence the aim of the study was to design a new camera-based approach to measure the GFR and to compare our results with other measured GFR (mGFR) and estimated GFRs (eGFRs) derived from available measurements and equations used in daily clinical practice. MATERIAL AND METHODS: 34 patients were included in the study. ~74MBq (2mCi) Technetium 99m diethylene-triamine-pentaacetic acid (99mTc-DTPA) was administered to the patients during 5min. A simple formula based on a dilution principle was used to measure GFR (ScinGFR). RESULTS: Our formula provided similar mGFR results in narrower range as creatinine clearance did and our results correlated well with results derived from other equations. When ScinGFR values were compared to others, there was a significant difference among them (p=0.031) due to difference between the ScinGFR and Cockroft-Gault. When the results of the ScinGFR compared to others without Cockroft-Gault, the difference among them was not significant (p=0.164). CONCLUSION: A simple formula considering the extracellular fluid volume was used to predict the split and global kidney functions and despite some discrepancies, good correlation among our results and those derived from available formulas was detected. PMID- 28363506 TI - Three novel indole alkaloids from Kopsia officinalis. AB - Three new indole alkaloids, named kopsioffines A-C (1-3), possessing relatively novel ten-membered lactam ring, and one known compound (11,12-demethoxy-16 deoxypauciflorine, 4) were isolated from the leaves and stems of Kopsia officinalis. Their structures were elucidated by means of spectroscopic methods. The absolute configuration of 1 was determined by calculated electronic circular dichroism data. The hypothetical biosynthetic pathway of 1 was postulated. All these isolates were evaluated for their inhibitory effects on alpha-glucosidase. None of them showed activity with IC50 far beyond 50MUM. PMID- 28363508 TI - Risk factors associated with the onset and progression of Alzheimer's disease: A systematic review of the evidence. AB - A systematic review was conducted to identify risk factors associated with the onset and progression of Alzheimer's disease (AD). Moderate and high quality systematic reviews were eligible for inclusion. Primary studies reporting on non genetic risk factors associated with neuropathologically or clinically confirmed AD were considered. Eighty one systematic reviews reporting on AD onset and 12 reporting on progression satisfied the eligibility criteria. Four hundred and thirty-two relevant primary studies reporting on onset were identified; however, only those published between 2010 and 2012 (n=65) were included in the qualitative synthesis. Several factors including statins, light-to-moderate alcohol consumption, compliance with a Mediterranean diet, higher educational attainment, physically and cognitively stimulating activities, and APOE epsilon2 appeared to be associated with a decreased risk of AD onset. The evidence was suggestive of an increased risk of AD associated with head injury in males, age, diabetes mellitus, conjugated equine estrogen use with medroxyprogesterone acetate, current smoking, and lower social engagement. With respect to genetic factors, APOE epsilon4 remained the strongest predictor of AD. Physical and cognitive activities were associated with a beneficial effect on cognitive function and other indicators of dementia progression while higher educational attainment was associated with faster cognitive decline. Although suggestive of an association, the current evidence for a majority of the identified putative factors for AD onset and progression was weak, at best due to conflicting findings across studies or inadequate evidence. Further research is required to confirm the etiological or protective role of a number of risk factors. PMID- 28363509 TI - Response to: "Teleophthalmology for the screening of diabetic retinopathy: Value of continuing education". PMID- 28363507 TI - A new cineol derivative, polyphenols and norterpenoids from Saharan myrtle tea (Myrtus nivellei): Isolation, structure determination, quantitative determination and antioxidant activity. AB - The phytochemical profile of decoction and infusion, obtained from the dried leaves of M. nivellei, consumed as tea in Saharan region, was characterized by UHPLC-PDA-HRMS. Fourteen compounds were characterized and, to confirm the proposed structures a preparative procedure followed by NMR spectroscopy was applied. Compound 3 (2-hydroxy-1,8-cineole disaccharide) was a never reported whereas a bicyclic monoterpenoid glucoside (2), two ionol glucosides (1 and 12), a tri-galloylquinic acid (4), two flavonol glycosides (5 and 9), and a tetra galloylglucose (7), were reported in Myrtus spp. for the first time. Five flavonol O-glycosides (6, 8, 10-11, and 14) togheter a flavonol (13) were also identified. Quantitative determination of phenolic constituents from decoction and infusion has been performed by HPLC-UV-PDA. The phenolic content was found to be 150.5 and 102.6mg/g in decoction and infusion corresponding to 73.8 and 23.6mg/100mL of a single tea cup, respectively. Myricetin 3-O-beta-d-(6" galloyl)glucopyranoside (5), isomyricitrin (6) and myricitrin (8) were the compounds present in the highest concentration. The free-radical scavenging activities of teas and isolated compounds was measured by the DPPH assay and compared with the values of other commonly used herbal teas (green and black teas). Decoction displayed higher potency in scavenging free-radicals than the infusion and green and black teas. PMID- 28363510 TI - X-Linked Cobalamin Disorder (HCFC1) Mimicking Nonketotic Hyperglycinemia With Increased Both Cerebrospinal Fluid Glycine and Methylmalonic Acid. AB - BACKGROUND: Autosomal recessive or X-linked inborn errors of intracellular cobalamin metabolism can lead to methylmalonic aciduria and homocystinuria. In neonates, both increased cerebrospinal fluid glycine and cerebrospinal fluid/plasma glycine ratio are biochemical features of nonketotic hyperglycinemia. METHODS: We describe a boy presenting in the neonatal period with hypotonia, tonic, clonic, and later myoclonic seizures, subsequently evolving into refractory epilepsy and severe neurocognitive impairment. RESULTS: Increased cerebrospinal fluid glycine and cerebrospinal fluid to plasma glycine ratio were indicative of nonketotic hyperglycinemia. Early magnetic resonance imaging showed restricted diffusion and decreased apparent diffusion coefficient values in posterior limb of internal capsules and later in entire internal capsules and posterior white matter. Sequencing did not show a mutation in AMT, GLDC, or GCSH. Biochemical analysis identified persistently increased cerebrospinal fluid levels of glycine and methylmalonic acid and increased urinary methylmalonic acid and plasma homocysteine levels, which improved on higher parenteral hydroxocobalamin dose. Exome sequencing identified a known pathogenic sequence variant in X-linked cobalamin (HCFC1), c.344C>T, p. Ala115Val. In addition, a hemizygous mutation was found in the ATRX (c. 2728A>G, p. Lys910Glu). Retrospective review of two other patients with X-linked cobalamin deficiency also identified increased cerebrospinal fluid glycine levels. CONCLUSIONS: This boy had X-linked cobalamin deficiency (HCFC1) with increased cerebrospinal fluid glycine and methylmalonic acid and increased cerebrospinal fluid to plasma glycine ratio suggesting a brain hyperglycinemia. Putative binding sites for HCFC1 and its binding partner THAP11 were identified near genes of the glycine cleavage enzyme, providing a potential mechanistic link between HCFC1 mutations and increased glycine. PMID- 28363511 TI - Risk Factors for Malnutrition Among Children With Cerebral Palsy in Botswana. AB - BACKGROUND: Children with cerebral palsy in low-resource settings are at high risk of malnutrition, which further increases their risk of poor health outcomes. However, there are few available data on specific risk factors for malnutrition among children with cerebral palsy in the developing world. METHODS: We performed a case-control study among children with cerebral palsy receiving care at a tertiary care hospital in Gaborone, Botswana. Children with cerebral palsy and malnutrition were identified according to World Health Organization growth curves and compared with subjects with cerebral palsy without malnutrition. Risk factors for malnutrition were identified using multivariable logistic regression models. These risk factors were then used to generate a Malnutrition Risk Score, and Receiver Operating Characteristic curves were used to identify optimal cutoffs to identify subjects at high risk of malnutrition. RESULTS: We identified 61 children with cerebral palsy, 26 of whom (43%) met criteria for malnutrition. Nonambulatory status (odds ratio 13.8, 95% confidence interval [CI] 3.8-50.1, P < 0.001) and a composite measure of socioeconomic status (odds ratio 1.6, 95% CI 1.0-2.5, P = 0.03) were the strongest risk factors for malnutrition. A Malnutrition Risk Score was constructed based on these risk factors, and receiver operating characteristic curve analysis demonstrated excellent performance characteristics of this score (area under the curve 0.92, 95% CI 0.89-0.94). CONCLUSIONS: Malnutrition is common among children with cerebral palsy in Botswana, and a simple risk score may help identify children with the highest risk. Further studies are needed to validate this screening tool and to determine optimal nutritional interventions in this population. PMID- 28363512 TI - Diffusion-weighted magnetic resonance imaging in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. AB - PURPOSE: To analyze diffusion-weighted magnetic resonance imaging (DW-MRI) for treatment response assessment in locally advanced rectal cancer (LARC). PATIENTS AND METHODS: Patients with histologically proven rectal adenocarcinoma, stage II III disease, were enrolled and underwent surgery following neoadjuvant chemoradiotherapy (nCRT). All patients were referred for a DW-MRI protocol on a 3 Tesla MR-system, consisting of axial T2-weighted and DWI sequences prior (I), during (II) and after (III) nCRT. Corresponding apparent diffusion coefficient (ADC) values were calculated. RESULTS: Between February 2011 and June 2015, 37 patients participated in the study. All patients completed programmed treatment. Overall, 11 patients (29.7%) had pathologic complete response (pCR). No correlation between the mean pre- (ADC-I), during (ADC-II), post- (ADC-III) ADC and the reduction in tumor size after nCRT was recorded. No substantial difference in the ADC distribution was found between pCR and no-pCR patients. The ADC-II level significantly increased in the pCR cases (T = 1.675; p < 0.05). CONCLUSION: ADC value could be useful for discriminating between the pCR patients and the no-pCR patients. Further studies are necessary to identify the optimal MRI parameters combination to predict tumor response to nCRT. It is hoped that these data will provide the basis for a more solid scientific evidence. PMID- 28363513 TI - Measuring Iran's success in achieving Millennium Development Goal 4: a systematic analysis of under-5 mortality at national and subnational levels from 1990 to 2015. AB - BACKGROUND: Child mortality as one of the key Millennium Development Goals (MDG 4 to reduce child mortality by two-thirds from 1990 to 2015), is included in the Sustainable Development Goals (SDG 3, target 2-to reduce child mortality to fewer than 25 deaths per 1000 livebirths for all countries by 2030), and is a key indicator of the health system in every country. In this study, we aimed to estimate the level and trend of child mortality from 1990 to 2015 in Iran, to assess the progress of the country and its provinces toward these goals. METHODS: We used three different data sources: three censuses, a Demographic and Health Survey (DHS), and 5-year data from the death registration system. We used the summary birth history data from four data sources (the three censuses and DHS) and used maternal age cohort and maternal age period methods to estimate the trends in child mortality rates, combining the estimates of these two indirect methods using Loess regression. We also used the complete birth history method to estimate child mortality rate directly from DHS data. Finally, to synthesise different trends into a single trend and calculate uncertainty intervals (UI), we used Gaussian process regression. FINDINGS: Under-5 mortality rates (deaths per 1000 livebirths) at the national level in Iran in 1990, 2000, 2010, and 2015 were 63.6 (95% UI 63.1-64.0), 38.8 (38.5-39.2), 24.9 (24.3-25.4), and 19.4 (18.6 20.2), respectively. Between 1990 and 2015, the median annual reduction and total overall reduction in these rates were 4.9% and 70%, respectively. At the provincial level, the difference between the highest and lowest child mortality rates in 1990, 2000, and 2015 were 65.6, 40.4, and 38.1 per 1000 livebirths, respectively. Based on the MDG 4 goal, five provinces had not decreased child mortality by two-thirds by 2015. Furthermore, six provinces had not reached SDG 3 (target 2). INTERPRETATION: Iran and most of its provinces achieved MDG 4 and SDG 3 (target 2) goals by 2015. However, at the subnational level in some provinces, there is substantial inequity. Local policy makers should use effective strategies to accelerate the reduction of child mortality for these provinces by 2030. Possible recommendations for such strategies include enhancing the level of education and health literacy among women, tackling sex discrimination, and improving incomes for families. FUNDING: Iran Ministry of Health and Education. PMID- 28363514 TI - Voxel-Based Lesion Mapping of Cryptogenic Stroke in Patients with Advanced Cancer: A Detailed Magnetic Resonance Imaging Analysis of Distribution Pattern. AB - BACKGROUND: Ischemic stroke is one form of cancer-associated thrombosis that can greatly worsen a patient's performance status. The present investigation aimed to elucidate the characteristic distribution pattern(s) of cryptogenic stroke lesions using a voxel-based lesion-mapping technique and examine the differences in clinical manifestations between cryptogenic and conventional strokes in patients with advanced cancer. METHODS: Data from 43 patients with advanced cancer who developed acute ischemic stroke were retrospectively collected. Stroke etiology was grouped into either cryptogenic or conventional stroke etiology according to the ASCO stroke score. Clinical data were reviewed, and voxel-based lesion mapping using diffusion-weighted imaging (DWI) was performed to visualize the cross-patient spatial distribution of the lesions. RESULTS: Of the 43 patients, 25 were classified as having cryptogenic stroke etiology and 18 were classified as having conventional stroke etiology. Median survival time of patients from stroke onset was 96 days for cryptogenic stroke etiology and 570 days for conventional stroke etiology (P = .01). D-dimer of patients was significantly higher in cryptogenic stoke etiology than in conventional stroke etiology (P = .006). Voxel-based lesion mapping showed that DWI hyperintense lesions accumulated at cortical and internal watershed areas of the cerebrum and at the vascular border zone of the superior cerebellar and posterior inferior cerebellar arteries at the cerebellum. CONCLUSIONS: Voxel-based lesion mapping for cryptogenic stroke in patients with advanced cancer showed that lesions accumulated at vascular border zones within the brain both at the cerebrum and at the cerebellum, but not at perforating arterial territories. PMID- 28363515 TI - Mosquitoes of the Caatinga: 2. Species from periodic sampling of bromeliads and tree holes in a dry Brazilian forest. AB - The Caatinga is a dry tropical forest, located in the Brazilian semiarid region and rich in phytotelmata. This study investigated the culicid fauna of phytotelmata of the caatinga by sampling for 19 consecutive months aquatic immatures from tree holes and bromeliads. A total of 127L of water was taken from the plants, containing 6764 immature culicids of 16 species, of which 11 (69%) are undescribed and respond to 90% of the total abundance of the specimens collected. Epiphytic bromeliads harbor a large number of immature Culicidae, although terrestrial bromeliads are the most abundant and widely distributed in the region. The richness of culicid species was similar between terrestrial and epiphytic bromeliads and lower in habitats represented by tree hole phytotelmata. There was no similarity in the composition of culicid species that developed in bromeliads or tree holes. Temperature and humidity were the environmental parameters most strongly associated with the proportion of positive plants. The Caatinga has a great number of endemic species that remain unknown to science and many additional culicid species may await discovery from there. PMID- 28363518 TI - Laying in silico pipelines for drug repositioning: a paradigm in ensemble analysis for neurodegenerative diseases. AB - When faced with time- and money-consuming problems, new practices in pharmaceutical R&D arose when trying to alleviate them. Drug repositioning has great promise and when combined with today's computational power and intelligence it becomes more precise and potent. This work showcases current approaches of creating a computational pipeline for drug repositioning, along with an extensive example of how researchers can influence therapeutic approaches and further understanding, through either single or multiple disease studies. This paradigm is based on three neurodegenerative diseases with pathophysiological similarities. It is our goal to provide the readers with all the information needed to enrich their research and note expectations along the way. PMID- 28363517 TI - Assessment of mechanism, type and severity of injury in multiple trauma patients: A cross sectional study of a trauma center in Iran. AB - PURPOSE: To accurately assess the mechanism, type and severity of injury in Iranian multiple trauma patients of a trauma center. METHODS: Patients with multiple traumas referring to the emergency department of Hasheminejad University Hospital in Mashhad, Iran, entered this cross sectional study from March 2013 to December 2013. All the patients with injury severity score (ISS) > 9 were included in this study. Data analysis was performed by SPSS software (Version 11.5) and P values less than 0.05 were considered as significant differences. RESULTS: Among the 6306 hospitalized trauma patients during this period, 148 had ISS>9. The male female ratio was 80%. The mean age of the patients was (33.5 +/- 19.3) years. And 71% of the patients were younger than 44 years old. There were 19 (13%) deaths from which 68.5% were older than 44 years old. The mean transfer time from the injury scene to hospital was (55 +/- 26) minutes. The most frequent mechanisms of injury were motorcycle crashes and falling from height, which together included 66.2% of all the injuries. A total of 84% of hospital deaths occurred after the first 24 h of hospitalization. Head and neck were the most common body injured areas with a prevalence of 111 cases (75%). CONCLUSION: Motorcycle crashes have high frequency in Iran. Since most victims are young males, injury prevention strategies should be considered to reduce the burden of injuries. PMID- 28363519 TI - Pretargeting with bispecific fusion proteins facilitates delivery of nanoparticles to tumor cells with distinct surface antigens. AB - Tumor heterogeneity, which describes the genetically and phenotypically distinct subpopulations of tumor cells present within the same tumor or patient, presents a major challenge to targeted delivery of diagnostic and/or therapeutic agents. An ideal targeting strategy should deliver a given nanocarrier to the full diversity of cancer cells, which is difficult to achieve with conventional ligand conjugated nanoparticles. We evaluated pretargeting (i.e., multistep targeting) as a strategy to facilitate nanoparticle delivery to multiple target cells by measuring the uptake of biotinylated nanoparticles by lymphoma cells with distinct surface antigens pretreated with different bispecific streptavidin-scFv fusion proteins. Fusion proteins targeting CD20 or tumor-associated glycoprotein 72 (TAG-72) mediated the specific in vitro uptake of 100nm biotin-functionalized nanoparticles by Raji and Jurkat lymphoma cells (CD20-positive and TAG-72 positive cells, respectively). Greater uptake was observed for pretargeted nanoparticles with increasing amounts of surface biotin, with 6- to 18-fold higher uptake vs. non-biotinylated nanoparticle and fusion protein controls. Fully biotin-modified particles remained resistant to cultured macrophage cell uptake, although they were still quickly cleared from systemic circulation in vivo (t1/2<1h). For single Raji tumor-bearing mice, pretargeting with CD20 specific FP significantly increased nanoparticle tumor targeting. In mice bearing both Raji and Jurkat tumors, pretargeting with both fusion proteins markedly increased nanoparticle targeting to both tumor types, compared to animals dosed with nanoparticles alone. These in vitro and in vivo observations support further evaluations of pretargeting fusion protein cocktails as a strategy to enhance nanoparticle delivery to a diverse array of molecularly distinct target cells. PMID- 28363516 TI - Vascular disease in cocaine addiction. AB - Cocaine, a powerful vasoconstrictor, induces immune responses including cytokine elevations. Chronic cocaine use is associated with functional brain impairments potentially mediated by vascular pathology. Although the Crack-Cocaine epidemic has declined, its vascular consequences are increasingly becoming evident among individuals with cocaine use disorder of that period, now aging. Paradoxically, during the period when prevention efforts could make a difference, this population receives psychosocial treatment at best. We review major postmortem and in vitro studies documenting cocaine-induced vascular toxicity. PubMed and Academic Search Complete were used with relevant terms. Findings consist of the major mechanisms of cocaine-induced vasoconstriction, endothelial dysfunction, and accelerated atherosclerosis, emphasizing acute, chronic, and secondary effects of cocaine. The etiology underlying cocaine's acute and chronic vascular effects is multifactorial, spanning hypertension, impaired homeostasis and platelet function, thrombosis, thromboembolism, and alterations in blood flow. Early detection of vascular disease in cocaine addiction by multimodality imaging is discussed. Treatment may be similar to indications in patients with traditional risk-factors, with few exceptions such as enhanced supportive care and use of benzodiazepines and phentolamine for sedation, and avoiding beta blockers. Given the vascular toxicity cocaine induces, further compounded by smoking and alcohol comorbidity, and interacting with aging of the crack generation, there is a public health imperative to identify pre-symptomatic markers of vascular impairments in cocaine addiction and employ preventive treatment to reduce silent disease progression. PMID- 28363520 TI - Sequence segregation improves non-covalent protein delivery. AB - The impermeability of the plasma membrane towards large, hydrophilic biomolecules is a major obstacle in their use and development against intracellular targets. To overcome such limitations, protein transduction domains (PTDs) have been used as protein carriers, however they often require covalent fusion to the protein for efficient delivery. In an effort to develop more efficient and versatile biological vehicles, a series of PTD-inspired polyoxanorbornene-based synthetic mimics with identical chemical compositions but different hydrophobic/hydrophilic segregation were used to investigate the role of sequence segregation on protein binding and uptake into Jurkat T cells and HEK293Ts. This series was composed of a strongly segregated block copolymer, an intermediately segregated gradient copolymer, and a non-segregated homopolymer. Among the series, the block copolymer maximized both protein binding and translocation efficiencies, closely followed by the gradient copolymer, resulting in two protein transporter molecules more efficacious than currently commercially available agents. These two polymers were also used to deliver the biologically active Cre recombinase into a loxP-reporter T cell line. Since exogenous Cre must reach the nucleus and retain its activity to induce gene recombination, this in vitro experiment better exemplifies the broad applicability of this synthetic system. This study shows that increasing segregation between hydrophobic and cationic moieties in these polymeric mimics improves non-covalent protein delivery, providing crucial design parameters for the creation of more potent biological delivery agents for research and biomedical applications. PMID- 28363521 TI - Effectiveness of tissue engineered chitosan-gelatin composite scaffold loaded with human platelet gel in regeneration of critical sized radial bone defect in rat. AB - Although many strategies have been utilized to accelerate bone regeneration, an appropriate treatment strategy to regenerate a new bone with optimum morphology and mechanical properties has not been invented as yet. This study investigated the healing potential of a composite scaffold consisting of chitosan (CS), gelatin (Gel) and platelet gel (PG), named CS-Gel-PG, on a bilateral critical sized radial bone defect in rat. Eighty radial bone defects were bilaterally created in 40 Sprague-Dawley rats and were randomly divided into eight groups including untreated, autograft, CS, Gel, CS-PG, Gel-PG, CS-Gel, and CS-Gel-PG treated defects. The bone defects were evaluated clinically and radiologically during the study and their bone samples were assessed by gross and histopathology, histomorphometry, CT-scan, scanning electron microscopy, and biomechanical testing after 8weeks of bone injury. The autograft and CS-Gel-PG groups showed significantly higher new bone formation, density of osseous and cartilaginous tissues, bone volume, and mechanical performance than the defect, CS and Gel-PG groups (P?0.05). In addition, bone volume, density of osseous and cartilaginous tissues, and numbers of osteons in the CS-Gel-PG group were significantly superior to the CS-PG, CS-Gel and Gel groups (P?0.05). Increased mRNA levels of alkaline phosphatase, runt-related transcription factor 2, osteocalcin, collagen type 1 and CD31, vascular endothelial growth factor as osteogenic and angiogenic differentiation markers were found with the CS-Gel-PG scaffold by quantitative real-time PCR in vitro after 30days of culturing on bone marrow-derived mesenchymal stem cells. In conclusion, the healing potential of CS Gel scaffold embedded with PG was comparable to autografting and therefore, it can be offered as an appropriate scaffold in bone tissue engineering and regenerative applications. PMID- 28363523 TI - Cordycepin-enriched WIB-801C from Cordyceps militaris improves functional recovery by attenuating blood-spinal cord barrier disruption after spinal cord injury. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cordyceps militaris is an ingredient of traditional Chinese medicine and have been widely used for inflammatory diseases and cancer. Cordycepin is one of the major bioactive components of Cordyceps militaris, and has been known to have anti-inflammatory and anti-oxidant effects. AIM OF THIS STUDY: In the present study, we examined whether WIB-801C, a standardized and cordycepin-enriched extract of caterpillar fungus (Cordyceps militaris), would attenuate blood-spinal cord barrier (BSCB) disruption by inhibiting matrix metalloprotease (MMP)-9 activity, leading to improvement of functional outcomes after spinal cord injury (SCI). MATERIALS AND METHODS: Male Sprague-Dawley rats were subjected to contusive SCI using a New York University (NYU) impactor, and WIB-801C (50mg/kg) was administered at 2h and 8h after injury orally and further treated once a day for indicated time points. BSCB disruption, MMP-9 activity, blood infiltration, inflammation, neuronal apoptosis, axonal loss, demyelination, and neurological deficit were evaluated. RESULTS: We found that WIB-801C significantly attenuated BSCB disruption by inhibiting MMP-9 expression and activation after injury. The infiltration of neutrophils at 1 d and macrophage at 5 d after SCI was also ameliorated by WIB-801C as compared with vehicle control. In addition, the expression of inflammatory cytokines and mediators such as Tnf-alpha, IL-1beta, IL-6, Cox-2, and inos as well as chemokines such as Gro-alpha and Mip-2alpha was significantly inhibited by WIB 801C. Furthermore, WIB-801C inhibits p38MAPK activation and proNGF production in microglia after injury. These events eventually led to the inhibition of apoptotic cell death of neurons and oligodendrocytes, improved functional recovery and attenuated demyelination and axon loss after SCI. CONCLUSION: Our results suggest that WIB-801C can be used as a therapeutic agent after SCI by attenuating BSCB disruption followed inflammation. PMID- 28363522 TI - Reversal of multidrug resistance by Marsdenia tenacissima and its main active ingredients polyoxypregnanes. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Multidrug resistance (MDR) of cancer is often associated with the overexpression of ATP-binding cassette (ABC) transporters, such as P-glycoprotein (P-gp), multidrug resistance-associated protein-1 (MRP-1) and breast cancer resistance protein (BCRP or ABCG2), in cancer cells, which facilitates the active efflux of a wide variety of chemotherapeutic drugs out of the cells. Marsdenia tenacissima is a traditional Chinese medicinal herb that has long been clinically used for treatment of cancers, particularly in combinational use with anticancer drugs. Polyoxypregnanes (POPs) are identified as main constituents of this herb, and three of them have been reported to exhibit P-gp modulatory effect and thus reverse MDR. Therefore, it is of great necessity to investigate more POPs that have potential to reverse transporters-mediated MDR. AIM OF THE STUDY: We aimed to identify POPs as the chemical basis responsible for circumventing ABC transporters-mediated MDR by M. tenacissima. MATERIALS AND METHODS: The MDR reversal effects of M. tenacissima crude extract together with a series of isolated POPs were evaluated on several MDR cancer cell lines that overexpress P-gp, MRP1 or ABCG2. The activities of P-gp, MRP1 and ABCG2 were determined by the flow cytometry-based substrate efflux assay. Molecular docking of POPs to a three-dimensional human P-gp homology structure was also performed. RESULTS: The crude extract of M. tenacissima was firstly found to circumvent P-gp mediated MDR. Then, 11 polyoxypregnane compounds (POPs) isolated from this herb were found to overcome P-gp-, MRP1- and/or ABCG2-mediated MDR. Further mechanistic study delineated that the reversal of MDR by these POPs was due to significant increase in the intracellular concentrations of the substrate anticancer drugs via their inhibition of different ABC transporter-mediated efflux activities. Furthermore, molecular docking revealed that POPs with P-gp modulatory effect bound to P-gp and fitted well into the cavity between the alpha and beta subunit of P-gp via forming hydrogen bonds. In addition, several key structural determinants for inhibition of P-gp, MRP1 or ABCG2 by POPs were illustrated. CONCLUSIONS: Our findings advocated the rational use of M. tenacissima to enhance efficacies of conventional anticancer drugs in tumors with ABC drug transporters-mediated MDR. Furthermore, 11 POPs were found to contribute to MDR reversal effect of M. tenacissima via inhibition of different ABC efflux transporters. PMID- 28363524 TI - An overview on Leucosidea sericea Eckl. & Zeyh.: A multi-purpose tree with potential as a phytomedicine. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Leucosidea sericea (the sole species in this genus) is a tree species found in southern Africa and possesses several therapeutical effects against infectious diseases in humans and livestock. This review aims to document and summarize the botany, phytochemical and biological properties of Leucosidea sericea. MATERIALS AND METHODS: Using the term 'Leucosidea sericea', we systematically searched literature including library catalogues, academic dissertations and databases such as PubMed, SciFinder, Web of Science, Google Scholar and Wanfang. Taxonomy of the species was validated using 'The Plant List' (www.theplantlist.org). RESULTS: Leucosidea sericea remains a widely used species among the different ethnic groups in southern Africa. The species is a rich source of approximately 50 essential oils and different classes of phytochemicals (phenolics, phloroglucinols, cholestane triterpenoids, alkaloids and saponins) which may account for their diverse biological properties. Documented biological activities which were mainly observed under in vitro systems included antimicrobial, anti-parasitic, antioxidant, acetylcholinesterase (AChE) inhibition and anti-inflammatory properties. Preliminary safety tests on Leucosidea sericea extracts suggest moderate cytotoxic effects based on a few cell lines that were investigated. CONCLUSIONS: Leucosidea sericea possesses diverse medicinal potential with the antimicrobial, anti-parasitic, antioxidant and anti-inflammatory activities being the most prominent. The relative abundance and tendency of Leucosidea sericea to evade in nature suggest an abundant reservoir of raw materials for potential commercialization (upon validation of its pharmacological potential). However, more stringent investigations on the extracts (and isolated bioactive compounds) focusing on the mode of actions, which will inevitably unravel their pharmacokinetics, pharmacodynamics and clinical relevance remain pertinent. PMID- 28363525 TI - Protective effect of a phenolic extract containing indoline amides from Portulaca oleracea against cognitive impairment in senescent mice induced by large dose of D-galactose /NaNO2. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Portulaca oleracea L. is a potherb and also a widely used traditional Chinese medicine. In accordance with its nickname "longevity vegetable", pharmacological study demonstrated that this plant possessed antioxidant, anti-aging, and cognition-improvement function. Active principles pertaining to these functions of P. oleracea need to be elucidated. AIM OF THE STUDY: The present study evaluated the effect of a phenolic extract (PAAs) from P. oleracea which contained specific antioxidant indoline amides on cognitive impairment in senescent mice. MATERIALS AND METHODS: PAAs was prepared through AB-8 macroporous resin column chromatography. Total phenol content was determined using colorimetric method, and contents of indoline amides were determined using HPLC-UV method. Senescent Kunming mice with cognitive dysfunction were established by intraperitoneal injection of D-galactose (D-gal, 1250mg/kg/day) and NaNO2 (90mg/kg/day) for 8 weeks, L-PAAs (360mg/kg/day), H-PAAs (720mg/kg/day), and nootropic drug piracetam (PA, 400mg/kg/day) as the positive control were orally administered. Spatial learning and memory abilities were evaluated by Morris water maze experiment. Activities of AChE, SOD, CAT, and levels of GSH and MDA in the brain or plasma were measured. Hippocampal morphology was observed by HE staining. RESULTS: Chronic treatment of large dose of D-gal/NaNO2 significantly reduced lifespan, elevated AChE activity, decreased CAT activity, compensatorily up-regulated SOD activity and GSH level, increased MDA level, induced neuronal damage in hippocampal CA1, CA3 and CA4 regions, and impaired cognitive function. Similar to PA, PAAs prolonged the lifespan and improved spatial memory ability. Moreover, PAAs improved learning ability. H-PAAs significantly reversed compensatory increase in SOD activity to the normal level, elevated serum CAT activity, and reduced MDA levels in brain and plasma, more potent than L-PAAs. Besides these, PAAs evidently inhibited hippocampal neuronal damage. However, it had no effect on brain AChE activity. CONCLUSION: PAAs as the bioactive principles of P. oleracea attenuated oxidative stress, improved survival rate, and enhanced cognitive function in D-gal/NaNO2-induced senile mice, similar to piracetam. This phenolic extract provides a promising candidate for prevention of aging and aging-related cognitive dysfunction in clinic. PMID- 28363527 TI - Elevated levels of soluble humanleukocyte antigen-G in the airways are a marker for a low-inflammatory endotype of asthma. PMID- 28363526 TI - A randomised, double-blind, phase 3 study comparing the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem for complicated intra abdominal infections in hospitalised adults in Asia. AB - Ceftazidime/avibactam comprises the broad-spectrum cephalosporin ceftazidime and the non-beta-lactam beta-lactamase inhibitor avibactam. This phase 3, randomised, double-blind study (NCT01726023) assessed the efficacy and safety of ceftazidime/avibactam plus metronidazole compared with meropenem in patients with complicated intra-abdominal infection (cIAI) in Asian countries. Subjects aged 18 90 years and hospitalised with cIAI requiring surgical intervention were randomised 1:1 to receive every 8 h either: ceftazidime/avibactam (2000/500 mg, 2 h infusion) followed by metronidazole (500 mg, 60-min infusion); or meropenem (1000 mg, 30-min infusion). Non-inferiority of ceftazidime/avibactam plus metronidazole to meropenem was concluded if the lower limit of the 95% confidence interval (CI) for the between-group difference in clinical cure rate was greater than -12.5% at the test-of-cure (TOC) visit (28-35 days after randomisation) in the clinically evaluable (CE) population. Safety was also evaluated. Of 441 subjects randomised, 432 received at least one dose of study medication (ceftazidime/avibactam plus metronidazole, n = 215; meropenem, n = 217). In the CE population at the TOC visit, non-inferiority of ceftazidime/avibactam plus metronidazole to meropenem was demonstrated, with clinical cure reported for 93.8% (166/177) and 94.0% (173/184) of subjects, respectively (between-group difference, -0.2, 95% CI -5.53 to 4.97). The clinical cure rate with ceftazidime/avibactam plus metronidazole was comparable in subjects with ceftazidime-non-susceptible and ceftazidime-susceptible isolates (95.7% vs. 92.1%, respectively). Adverse events were similar between the study groups. Ceftazidime/avibactam plus metronidazole was non-inferior to meropenem in the treatment of cIAIs in Asian populations and was effective against ceftazidime-non susceptible pathogens. No new safety concerns were identified. PMID- 28363528 TI - Determination of carrageenan by means of photometric titration with Methylene Blue and Toluidine Blue dyes. AB - A new approach to carrageenan quantitation was described. The method consists in titration of carrageenan solution by Methylene Blue dye or Toluidine Blue dye solution until a certain absorbance value. The optimal wavelengths are 660nm and 640nm when titrating with Methylene Blue dye and Toluidine Blue dye, respectively. Rectilinear calibration plots (R2>0.996) provide carrageenan determination in the concentration range from 2 to 60mg/L with relative standard deviation from 1 to 5%. The proposed method is simple and feasible in use due to optical dip probe providing in situ absorbance measurements. The proposed way of end-point recognition as pre-set voltage is applicable with any automatic titrator. The method was tested on model jelly dessert sachet. No interference was registered from typical ingredients of jellies such as sucrose, citric acid, sodium citrate, malic acid, potassium sorbate as well as blue colorant. The neutral polysaccharides such as guar gum and locust bean gum have insignificant interference when their content is fivefold as compared to that of carrageenan. PMID- 28363529 TI - Potential of glucans as vaccine adjuvants: A review of the alpha-glucans case. AB - alpha-Glucans are present in virtually all domains of life, and these glucose chains linked by alpha-1,4- and alpha-1,6-linked branches form the most important storage carbohydrates in cells. It is likely for this reason that alpha-glucans are not generally considered as bioactive molecules as beta-glucans are. Nevertheless, it is known that depending on their source, many alpha-glucans play important roles as modulators of immune response. Recent efforts have attempted to elucidate the mechanisms through which alpha-glucans exert their immunostimulant effects; however, the main challenge is the accurate identification of the receptors of immune cells involved in their recognition. Here, we review the adjuvant properties reported for some polysaccharides and ultimately focus on alpha-glucans and how their structural characteristics, such as molecular weight, solubility and derivatization, influence their immunostimulatory properties. As a final point, we discuss the potential and associated challenges of using these polysaccharides as adjuvants, particularly in mucosal vaccination. PMID- 28363530 TI - Chitin nanowhisker (ChNW)-functionalized electrospun PVDF membrane for enhanced removal of Indigo carmine. AB - In this study, an active functional adsorbent membrane developed by combining both hydrophilic bio polymer filler such as chitin nanowhiskers (ChNW) which contains two functional groups and a hydrophobic polymer matrix such as polyvinylidene fluoride (PVDF) using electrospinning technique. Here ChNW were successfully extracted by excluding proteins and mineral and well characterized using FTIR, XRD, SEM and TEM. The optimized combination of PVDF/ChNW (15%:1%) membrane was fabricated and well characterized using SEM, water contact angle and FTIR spectroscopy. There was a remarkable difference in contact angle observed for PVDF/ChNW (22.72 degrees ) compared to neat PVDF (93.1 degrees ) membrane. Ultimately the membrane used for indigo carmine (IC) adsorption and an enhanced removal efficiency (88.9%) and adsorption capacity (72.6mgg-1) were observed compared to neat PVDF. In the future, the overall idea can make leads to various applications such as proteins, virus and hormones adsorption from the contaminated sources. PMID- 28363531 TI - Solid polymer electrolyte production from 2-hydroxyethyl cellulose: Effect of ammonium nitrate composition on its structural properties. AB - Addition of doping materials can possibly enhance the ionic conduction of solid polymer electrolyte (SPE). In this work, a new SPE using 2-hydroxyethyl cellulose (2-HEC) incorporated with different ammonium nitrate (NH4NO3) composition was prepared via solution casting method. Studies of structural properties were conducted to correlate the ionic conductivity of 2-HECNH4NO3 SPE using X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy. Encouraging result was obtained as the ionic conductivity increased about two orders of magnitude upon addition of 12wt% of NH4NO3. XRD analysis shows the most amorphous SPE was obtained at 12-NH4NO3. From FTIR spectra, the interactions between 2-HEC and NH4NO3 were observed by the shifts of COH peak from 1355cm-1 to 1330cm-1 and the presence of new NH peak in the OH region. The spectrum has been validated theoretically using Gaussian software. The results obtained from this study corroborate that the complexes of 2-HEC and NH4NO3 responsible to promote the ionic conductivity to the higher value. PMID- 28363532 TI - Stabilizing alkenyl succinic anhydride (ASA) emulsions with starch nanocrystals and fluorescent carbon dots. AB - Stabilizing alkenyl succinic anhydride (ASA) emulsions using fine particles instead of cationic starch have attracted much attention in recent years. Herein, starch nanocrystals (SNCs) made from maize starch by H2SO4 hydrolysis were used to co-stabilize ASA emulsions with fluorescent carbon dots (CDs) made hydrothermally from gelatin. The introduction of CDs can significantly enhance the stability and reduce the droplet size of SNC-stabilized ASA-in-water emulsions. Consequently, the sizing performance of the SNC-stabilized ASA emulsion is significantly improved by increasing the CD-to-SNC mass ratio. SNC and CD co-stabilized ASA emulsions show much better sizing performance than starch and CD co-stabilized ASA emulsions, achieving their best sizing performance at a CD-to-SNC mass ratio of 80%. Meanwhile, the morphology of SNC/starch and CD co-stabilized ASA emulsions can be traced under UV excitation. PMID- 28363534 TI - Effects of amadumbe starch nanocrystals on the physicochemical properties of starch biocomposite films. AB - The influence of amadumbe starch nanocrystals (SNCs) at varying concentrations (2.5, 5 and 10%) on the physicochemical properties of biocomposite films prepared using two starch matrices, amadumbe and potato starches were investigated. Amadumbe SNCs exhibited square-like platelets morphology, typical of SNC derived from A-type starches. In general, the inclusion of SNCs significantly decreased water vapour permeability (WVP) of composite films whilst thermal stability and opacity were increased. Amadumbe starch films showed substantially high tensile strength (TS) compared to potato starch in the presence of SNCs. At 2.5% SNCs, TS of composite amadumbe film (8MPa) was about four times that of composite potato films. However, SNCs>=5% generally decreased TS of both potato and amadumbe films. Amadumbe SNCs can potentially be used as fillers to improve the properties of biodegradable starch films. Amadumbe starch has better film forming properties compared to potato starch. PMID- 28363533 TI - Multi-layer mucilage of Plantago ovata seeds: Rheological differences arise from variations in arabinoxylan side chains. AB - Mucilages are hydrocolloid solutions produced by plants for a variety of functions, including the creation of a water-holding barrier around seeds. Here we report our discovery of the formation of three distinct mucilage layers around Plantago ovata seeds upon their hydration. Each layer is dominated by different arabinoxylans (AXs). These AXs are unusual because they are highly branched and contain beta-1,3-linked xylose in their side chains. We show that these AXs have similar monosaccharide and linkage composition, but vary in their polymer conformation. They also exhibit distinct rheological properties in aqueous solution, despite analytical techniques including NMR showing little difference between them. Using enzymatic hydrolysis and chaotropic solvents, we reveal that hydrogen bonding and side chain distribution are key factors underpinning the distinct rheological properties of these complex AXs. PMID- 28363535 TI - Sulfated chitosan/PVA absorbent membrane for removal of copper and nickel ions from aqueous solutions-Fabrication and sorption studies. AB - Novel absorbents for the removal of Cu2+ and Ni2+ ions from aqueous solutions were prepared from solution cast sulfated chitosan/polyvinyl alcohol membranes (SCS/PVA) and their properties were investigated. FTIR, SEM, XRD and TGA analyses were used to determine membrane structure. The effect of environmental parameters on absorption was studied, including pH, contact time, temperature and the initial concentration of Ni2+ and Cu2+ ions. Freundlich and Langmuir absorption isotherms were fitted to experimental data and a pseudo-second order rate equation was employed to model the kinetics of uptake for several copper and nickel ion concentrations. The results indicate that the affinity of an SCS/PVA membrane for Cu2+ ions was higher than that for Ni2+ ions. The study demonstrated that the SCS/PVA system can be utilized as highly efficient sorbents, to extract Ni2+ and Cu2+ from aqueous feed solutions. PMID- 28363536 TI - Synthesis and characterization of polyvinyl alcohol- carboxymethyl tamarind gum based composite films. AB - The present study delineates the synthesis of novel composite films using polyvinyl alcohol and carboxymethyl tamarind gum. The microscopic study results confirmed the formation of composite matrices. FTIR spectroscopy suggested the occurrence of hydrogen-bonding amongst the components of the films. The extent of hydrogen bonding was composition-dependent which reached a critical higher limit at a particular composition. At the critical composition, the instantaneous and the intermediate polymer relaxation time were longer. All the films were found to be viscoelastic in nature. The melting endotherm was also highest for the composition described above. Ciprofloxacin loaded films showed excellent antimicrobial property against E. coli, suggesting that the drug was released in its active form. Cell proliferation study using human keratinocytes suggested better cell proliferation in the CMT containing films as compared to the control (PVA only) film. In gist, the developed films can be explored for skin tissue engineering and drug delivery applications. PMID- 28363537 TI - Surface and nutraceutical properties of edible films made from starchy sources with and without added blackberry pulp. AB - The surface and nutraceutical properties have been poorly studied on edible films. The aim of this study was to investigate the surface properties and potential health effects in terms of in vitro digestibility and anti-inflammatory activity. The materials were developed from native plantain starch and pre gelatinized plantain flour with and without added blackberry pulp using casting methodology. Thermogravimetric analysis, contact angle, scanning electron microscopy, atomic force microscopy, resistant starch, in vitro digestibility, cell viability, reactive oxygen species, anti-inflammatory activity and sensory evaluation were the tests carried out in this study. Films containing blackberry pulp had more compact and smooth morphologies, which were related to the lower in vitro digestibility rate and the higher resistant starch content. In addition, these materials had higher anti-inflammatory activity, higher cell viability, and better acceptance by the panelists, thus suggesting potential health effects of consumers with special feeding regimes such as obese, diabetics and celiacs. PMID- 28363538 TI - Biophysical features of cereal endosperm that decrease starch digestibility. AB - The influence of the physical structure of cereal endosperm on the natural structural integrity (intact cells) and starch bioaccessibility of the resultant flours was studied using maize as example. Endosperm hardness, defined by its intracellular (protein matrix) and extracellular (cell walls) constituents, affected the granular and molecular damage of the starch of the resultant flours leading to higher digestibility of raw hard than soft endosperm flours, but comparatively lower digestibility after cooking. After milling, hard endosperm possessed more damaged starch (radial splitting of amylopectin clusters) in the periphery of the resultant particles that increased in vitro starch digestibility of raw flours. Conversely, the hard endosperm plant tissue matrix significantly limited water availability and heat transfer on starch gelatinisation, thereby decreasing the digestion rate after hydrothermal processing (in particle size flours >80MUm). This study provides a unique mechanistic understanding to obtain cereal flours with slow digestion property for commercial utilisation. PMID- 28363539 TI - In vitro and in vivo immunomodulatory activity of sulfated polysaccharide from Porphyra haitanensis. AB - The immunoregulatory activity of sulfated polysaccharide from Porphyra haitanensis (PHPS) was investigated in a RAW264.7 macrophages cell model and a BALB/c murine model. The subpopulation of dendritic cells (DCs) and regulatory T cells (Tregs) from PHPS-treated mice splenocytes were also measured by flow cytometry. Consistent with previous reports, we showed that PHPS increased the phagocytosis of RAW264.7 macrophages, and enhanced the secretion of interleukin (IL)-6, IL-10 and tumor necrosis factor-alpha (TNF-alpha). Meanwhile, PHPS induced the production of nitric oxide via the Jun N-terminal kinase (JNK) and the Janus kinase (JAK2) signaling pathways in RAW264.7 macrophages. Furthermore, PHPS promoted the proliferation of mice lymphocytes, inducing the generation of TNF-alpha and IL-10 in vivo, as well as the subpopulation of CD4+ splenic T lymphocytes, DCs, and Tregs. These results indicated that PHPS plays key roles in immunoregulation and may be apply to develop new health foods. PMID- 28363540 TI - The characteristic and dispersion stability of nanocellulose produced by mixed acid hydrolysis and ultrasonic assistance. AB - Axiolitic shape nanocellulose particles were prepared using a combined mixed acid hydrolysis and ultrasonic treatment. The crystallinity, morphology and stability properties of cellulose were characterized to investigate the mechanism of nanocellulose formation and stability. It was found the hydrodynamic radius decreased from 205nm to 89nm, and the crystallinity index of the nanocellulose increased from 62.90% to 72.31% with an increase in hydrolysis time from 2 to 10h. Sulfate esters and sulfonate group were present in the nanocellulose, and released more COH groups after hydrolysis. The zeta-potential of cellulose decreased from -11.5 to -43.8mV after 10h of hydrolysis. These results illustrated the amorphous characteristic of cellulose was removed after acid hydrolysis and ultrasonic treatment. The higher zeta-potential and relatively small cellulose particles caused a more stable suspension, suggesting that electrostatic interactions played an important role in maintaining the stability and dispersibility of the nanocellulose particles. PMID- 28363541 TI - Estimation of uronic acids using diverse approaches and monosaccharide composition of alkali soluble polysaccharide from Vitex negundo Linn. AB - Vitex negundo L. is one of the most important species in traditional system of medicine to cure various ailments. Alkali soluble polysaccharide (ASP) from V. negundo stems was isolated and purified in 0.61% yield. Complete hydrolysis of ASP followed by paper chromatography and GLC analysis indicated the presence of l rhamnose, l-arabinose, d-xylose, d-galactose and d-glucose in mole percent of 1.28, 2.25, 73.49, 8.08, 8.11 along with 2.48 d-galacturonic acid and 4.27 d glucuronic acid. Uronic acids were also estimated by spectrophotometric methods using carbazole, m-hydroxydiphenyl and 3, 5-dimethyl phenol (DMP) as colorimetric reagents. Estimation of uronic acids using DMP corroborated the results of GLC analysis. The study evaluated the utility of colorimetric methods for uronic acid estimation in polysaccharide having interferences from neutral sugars especially xylose, glucose and galactose. The analysis also resulted in composition of constituent monosaccharides of ASP and co-relation analysis of uronic acids content. The results may divulge the structural moiety of the polysaccharide responsible for its bio-efficacy. PMID- 28363542 TI - Alkalization of dissolving cellulose pulp with highly concentrated caustic at low NaOH stoichiometric excess. AB - We present a quantitative study, using Raman spectroscopy combined with multivariate data analysis, to determine the degree of activation of softwood sulphite dissolving cellulose pulp by aqueous sodium hydroxide. We have chosen industrially relevant conditions, including low stoichiometric ratio of NaOH/Anhydroglucose Unit (AGU)<2 and highly concentrated caustic (>=45% w/w [NaOH]). A design of experiments is used to investigate the effects of simultaneous variation of a set of key parameters on the degree of activation (i.e. transformation to alkali cellulose, denoted as DoA): (a) the NaOH/AGU stoichiometric ratio, denoted (r); (b) the concentration of NaOH, denoted [NaOH]; (c) temperature, denoted (T); and (d) reaction time, denoted (t). Solid-state 13C CP/MAS NMR spectroscopy was applied to investigate the reproducibility of the experiments and to select the range for (t). According to the model, (r) is found to have a statistically significant effect on DoA (increasing from DoA=6-30% at the lowest (r)=0.8, to DoA=48-87% at the highest (r)=1.8), together with [NaOH]. The influence of [NaOH] depends strongly on (r). The other studied variables are found to be insignificant in the model and has a complicated influence on the activation. In particular, (T) is found to be unimportant in the studied range (30-60 degrees C), but increasing (t) from 5 to 25min shows a positive influence on DoA, depending on both (r) and [NaOH]. A mercerisation mechanism that is controlled by diffusion is proposed to explain these phenomena. PMID- 28363543 TI - Submicrometric hypromellose acetate succinate particles as carrier for soy isoflavones extract with improved skin penetration performance. AB - In this study, hypromellose acetate succinate (HPMCAS) stable submicronic particles loaded with a soy isoflavones extract have been obtained by nano spray drying technology. HPMCAS has been used as excipient able to increase both stability and supersaturation levels of the active ingredients hence able to enhance skin penetration performance of genistein and daidzein. The influence of polymer/extract ratio as other process variables, on particle size, morphology and permeation performance, have been investigated. Particles in submicronic range (mean size around 550nm) and narrow size distribution with high encapsulation efficiency (up to 86%) were obtained. HPMCAS was able to improve amorphization of genistein during the atomization process and avoid recrystallization during storage, even in harsh environmental condition. Moreover, the enhanced affinity of the optimized formulations with aqueous media, strongly increased isoflavones penetration through membrane with diffusive properties well-correlated to human skin, up to 10-fold higher than pure soy isoflavones extract raw material. PMID- 28363544 TI - Compositional and structural characteristics of sulfated polysaccharide from Enteromorpha prolifera. AB - Polysaccharide from Enteromorpha prolifera (PE) has been reported to have biological activities such as anticancer, antioxidant and immunomodulatory activities, but the structural characteristics of PE remain unclear. In this study, the composition of PE was characterized using chemical methods, IR spectroscopy and HPLC. PE was identified as a sulfated polysaccharide mainly composed of rhamnose (Rha), glucuronic (GlcUA), xylose (Xyl) at a molar ratio of 3.2: 1.1: 1, and the average molecular weight was 620.3kDa. An enzymatic hydrolysis method was used to obtain three carbohydrate products. The MS and NMR results of these residues revealed that the backbone of PE consisted of D-GlcUAp alpha-(1->4)-3-sulfate-l-Rha p-beta-(1->4)-d-Xyl p-beta-(1->4)-3-sulfate-l-Rha p units. In this study, specific carbohydrate residues rich in sulfated rhamnose were prepared from E. prolifera. The structural determination of these sulfated carbohydrates may contribute to future studies on the relationship between structure and bioactivities. PMID- 28363545 TI - Development of an infusion method for encapsulating ascorbyl palmitate in V-type granular cold-water swelling starch. AB - Certain lipophilic components can be inserted very efficiently as guest molecule in the existing single helical amylose cavities in VH-type crystalline granular cold-water swelling starch (GCWSS). In the present study, ascorbyl palmitate (AscP) was used as a model guest compound. The impacts of temperature (20 and 60 degrees C) and ethanol [48 and 68% (v/v)] and AscP [1.0, 2.5, 5.0, 10.0% (w/w)] concentrations on encapsulation performance were investigated. First, native maize and potato starches were converted into VH-type GCWSS by aqueous ethanol [48% (v/v)] treatment at 95 degrees C. Exposing GCWSS to AscP induced the formation of inclusion complexes when a particular solvent (and temperature) environment was met. In 48% (v/v) ethanol, raising the treatment temperature to 60 degrees C did not significantly impact on the encapsulation performance. Maximum degrees of AscP encapsulation were 2.9 and 1.5% (w/w) for maize and potato starch, respectively, as determined by proton nuclear magnetic resonance measurements. As maize GCWSS contained more 'parent' VH-type crystals, it was capable of entrapping more AscP than potato GCWSS. PMID- 28363546 TI - Optimized pH-responsive film based on a eutectic mixture-plasticized chitosan. AB - Chitosan (CS, 2g/100mL)/curcumin 1g/100mL in acetic acid aqueous solution were used to prepare films to be used as food indicator. Microcrystalline cellulose (MCC) and a eutectic mixture (DES) were incorporated as reinforcing and plasticizing agents, respectively. The MCC content (133 mas%) and DES composition (7.93 mass%), based on CS dry mass, were optimized. The properties of the DES plasticized film were compared to those for the unplasticized and glycerol (G) plasticized CS films. The DES-plasticized film presented initial temperature of thermal decomposition at 267.7 degrees C, dynamic glass transition at 149.3 degrees C, water vapor permeability of 7.21*10-10gs-1m-1Pa-1, water solubility of 3.07% and stress at break of 20.1MPa. The incorporation of MCC contributed to increase the crystallinity of the composite films. Colorimetric tests, carried out in aqueous environments for the DES-plasticized film, revealed accentuated color changes, mainly at pHs higher than pH 8. PMID- 28363547 TI - Fabrication of phosphate microcrystalline rice husk based cellulose particles and their electrorheological response. AB - As a dry-based electrorheological (ER) material, phosphate microcrystalline cellulose (MCC), which exhibits ER properties under anhydrous conditions, was fabricated by the phosphorylation of MCC particles. The MCC particles were initially synthesized by the three step preparation of an alkali treatment, bleaching, and hydrolysis of cellulose particles from rice husk. The phosphate MCC was then synthesized via the phosphoric ester reaction of urea with phosphoric acid and MCC, and its chemical characteristics were examined by energy dispersive X-ray spectroscopy and Fourier transform infrared spectroscopy. The phosphate MCC particles were dispersed in silicone oil to produce an ER fluid (10vol%), and its chain structure was observed directly by optical microscopy. The rheological behavior of the ER fluid was tested using a rotational rheometer under a range of electric fields, showing a polarization mechanism with a slope of 2.0 for the yield stress as a function of the applied electric field strengths. PMID- 28363548 TI - In-situ deposition of Cu2O micro-needles for biologically active textiles and their release properties. AB - Metal/metal oxide containing fibres are gradually increasing in textile industrialization recently, owing to their high potential for application as antimicrobial textiles. In this study, the reducing properties of cellulose were applied to synthesize cuprous oxide in-situ. The direct formation of Cu2O on viscose fabrics was achieved via quite simple technique in two subsequent steps: alkalization and sorption. Cu contents in fabrics before and after rinsing ranged between 45.2-86.4mmol/kg and 18.1-67.7mmol/kg, respectively. Uniform micro needles of Cu2O were obtained with regular size and dimensions of 1.60+/-0.20MUm in length and 0.13+/-0.03MUm in width. Release of Cu1+/2+ ions from selected samples was studied in water, physiological fluid and artificial sweat. Copper containing fabrics exhibited a percent of 96.8-97.8% and 85.5-89.0% for reduction in microbial viability, which was tested for S. aureus (as gram positive bacteria), E. coli (as gram-negative bacteria) and C. albicans and A. niger (as fungal species), respectively after 24h contact time. PMID- 28363550 TI - Energy efficient facile extraction process of cellulose nanofibres and their dimensional characterization using light scattering techniques. AB - A chemi-mechanical approach was used to extract cellulose nanofibres (CNFs) from waste mango wood scraps using a mild chemical treatment ensuring no acid hydrolysis. The dimensional analysis for CNFs has been done by taking into account both the microscopic and light scattering techniques. The FESEM (field emission scanning electron microscopy) analysis revealed the diameter of obtained CNFs in the range of 5-40nm with an average diameter of approximately 12nm. The AFM (atomic force microscopy) analysis gave a more precise average diameter value of 5nm for the obtained CNFs. The aspect ratio as determined by applying mathematical calculations on the data revealed through dynamic and static light scattering techniques (DLS, SLS) was approximately 200. The characteristic shape determined by fractal dimension investigation from SLS measurement revealed the rod/thread like shape of CNFs at lower concentrations. PMID- 28363549 TI - Exploration of zwitterionic cellulose acetate antifouling ultrafiltration membrane for bovine serum albumin (BSA) separation. AB - This study focused on the preparation of a new kind of membrane material, zwitterionic cellulose acetate (ZCA), via a three-step procedure consist of oxidization, Schiff base and quaternary amination reaction, and the fabrication of antifouling ZCA ultrafiltration membrane by the non-solvent-induced phase separation method (NIPS). The morphologies, surface chemical structures and compositions of the obtained CA and ZCA membranes were thoroughly characterized by field emission scanning electron microscopy (FE-SEM) with energy dispersive X ray (EDX) spectroscopy, Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS), respectively. Meanwhile, the thermal stability, porosity and average pore size of two investigated membranes were also studied. As a result, the ZCA membrane displayed significantly improved hydrophilicity and water permeability compared with those of the reference CA membrane, despite a slight decrease in the protein rejection ratio. According to the cycle ultrafiltration performance of bovine serum albumin (BSA) solution and protein adsorption experiment, ZCA membrane exhibited better flux recovery property and fouling resistant ability, especially irreversible fouling resistant ability, suggesting superior antifouling performance. This new approach gives polymer based membrane a long time life and excellent ultrafiltration performance, and seems promising for potential applications in the protein separation. PMID- 28363551 TI - Sustainable hydroxypropyl methylcellulose/xyloglucan/gentamicin films with antimicrobial properties. AB - Hydroxypropyl methylcellulose (HPMC) and xyloglucan (XG) crosslinked with citric acid over a range of HPMC/XG weight ratios formed sustainable blend films characterized by Fourier transform infrared spectroscopy, thermogravimetric analysis, scanning electron microscopy, tensile tests, circular dichroism and determination of inhibitory activity against Staphylococcus aureus and Escherichia coli. Both in solution and in the crosslinked films, HPMC chains lost the original ordered conformation upon interacting with XG, giving rise to an entropic gain. The highest values of tensile strength (25MPa) and Young's modulus (689MPa) occurred for the 50:50 HPMC/XG blend films. In vitro loading of gentamicin sulfate (GS) in the films amounted to 0.18+/-0.05 -0.37+/-0.05g of GS per g polymer. At pH 7.4 and 37 degrees C, the GS release kinetics from the films fitted with the Korsmeyer-Peppas model revealed a non-Fickian release mechanism with diffusional coefficient n~0.7. The cross-linked films of HPMC, XG and their blends loaded with GS showed outstanding antibacterial activity against Staphylococcus aureus and Escherichia coli, disclosing their potential for novel biomedical applications. PMID- 28363552 TI - Acacia gum polysaccharide based hydrogel wound dressings: Synthesis, characterization, drug delivery and biomedical properties. AB - Keeping in view the importance of polysaccharide gums for wound care, in the present article, an attempt has been made to explore antioxidant nature of gum acacia in designing hydrogel wound dressing to improve its wound healing potential. These polymers were prepared by using acacia gum polyvinylpyrollidone/carbopol and were characterized by 13C NMR, FTIR, SEM, AFM, cryo-SEM, XRD, TGA, DSC and elemental analysis techniques. Some important biomaterial properties of wound dressings such as wound fluid absorption, haemo compatibility, bioactive assessment, gaseous/water/microbial permeability, mechanical properties, bio-adhesion, drug release, and histology of wound healing were also determined. Hydrogel wound dressings were found non-haemolytic, antioxidant and mucoadhesive in nature. Release of drug occurred through non Fickian diffusion mechanism and release profile best fitted in Higuchi model. PMID- 28363553 TI - Reinforced collagen with oxidized microcrystalline cellulose shows improved hemostatic effects. AB - Sponges composed of different levels of composite collagen/oxidized microcrystalline cellulose (collagen/OMCC), denoted M1-M4, were studied to improve the hemostatic effect of single-collagen sponges. Surface morphological observations showed that structural combinations and intermolecular interactions occurred between collagen and OMCC in the composites. M2 presented the best physical properties and platelet activation and was thus selected for the investigations of the in vitro coagulation time and hemostatic and biological effects on animals. The results illustrated that M2 could reduce the length of the activated partial thromboplastin time (APTT) and thrombin time (TT) and presented rapid hemostatic efficiency in the two injury models (P<0.05). These findings were used to evaluate the hemostatic mechanism of M2, which can promote blood absorption and platelet activation and could be directly involved in the intrinsic coagulation pathway to accelerate hemostasis. Furthermore, M2 was not cytotoxic and was completely biodegraded in subcutaneous tissue within 28days. PMID- 28363554 TI - Electrospun alginate nanofibres impregnated with silver nanoparticles: Preparation, morphology and antibacterial properties. AB - Silver nanoparticles are amongst the most valuable nanoparticles with interesting properties, such as a non-toxic nature and high antibacterial efficiency, making them applicable for tissue scaffold, protective clothing and wound dressing. In this study, silver nanoparticles (AgNPs) have been synthesized using chitosan as reducing and stabilizing agent. The formation of silver nanoparticles was confirmed by UV-vis, and the TEM showed that different shapes were obtained depending on the heating duration. The chitosan/AgNPs was coated onto an electrospun alginate membrane to produce stable polyelectrolyte complex (PEC) nanofibre composites with high antibacterial efficiency. These composites were characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD). AgNPs were successfully impregnated into the PEC nanofibre composite, while there was complexation between the electrospun alginate and the chitosan/AgNPs composite. PEC demonstrated a good antibacterial activity against both gram negative and gram positive bacteria with acceptable water vapour transmission within the range required for the treatment of injuries or wounds. PMID- 28363555 TI - Synthesis and antimicrobial properties of Zn-mineralized alginate nanocomposites. AB - New bioactive and antimicrobial biomaterials were produced by alginate-mediated biomineralization with Zn-mineral phase. The synthesis procedure is simple, cost effective and resulted in two different Zn-mineralized alginate nanocomposites, Zn-carbonate/Zn-alginate and Zn-phosphate/Zn-alginate. The presence of Zn-mineral phase and its type, have significantly affected nanocomposite morphology, stability, total metallic loading and potential to release Zn(II) in physiological environment. Antimicrobial experiments showed that both types of Zn mineralized nanocomposites exhibit strong antimicrobial effect against Escherichia coli, Staphylococcus aureus and Candida albicans. These results suggest that alginate biomineralization, where minerals are salts of essential metallic ions like Zn(II), represents a good strategy for designing multifunctional biomaterials for potential biomedical applications. PMID- 28363556 TI - Preparation and characterization of metformin surface modified cellulose nanofiber gel and evaluation of its anti-metastatic potentials. AB - Metastasis is the main problem in successful treatment of many types of cancer such as melanoma. The extracellular matrix degradation has a crucial role in the cancer metastasis. Nanofibers can mimic the structure of extracellular matrix and limit the cancer cells migration if they are implanted in and around the tumors. Moreover, local delivery of anti-metastatic drugs such as metformin to tumor can be useful. In this study, Metformin surface modified cellulose nanofibers (Met Cel-NFs) were successfully prepared by attachment of metformin on the surface of cellulose nanofibers through electrostatic interaction. FTIR spectroscopy and zeta potential of Met-Cel-NFs proved the occurrence of this attachment. SEM images showed the nanofibrous structure of Met-Cel-NFs. Met-Cel-NFs significantly suppressed the migration of melanoma cells. Additionally the sufficient adhesion of the melanoma cells on the Met-Cel-NFs can decrease melanoma cells invasion. Therefore, Met-Cel-NFs present a promising approach to the prevention of melanoma metastasis. PMID- 28363557 TI - Effect of O-chitosan nanoparticles on the development and membrane permeability of Verticillium dahliae. AB - Verticillium dahliae, which causes wilting in over 300 woody and herbaceous plant species, is a representative of fungal plant diseases for which effective controls are still needed. In this study, the antifungal action of oleoyl chitosan nanoparticles was investigated against V. dahliae. Media containing oleoyl-chitosan nanoparticles dramatically decreased the mycelium growth. The highest antifungal indexes were observed on media amended with 2mg/mL nanoparticles. Optical microscopy showed that spore germination and hyphae morphology were affected. Scanning electron microscopy and transmission electron microscopy demonstrated degenerative alterations including crumpled hyphae and spores, thickened cell walls, disappeared membranous organelles, massive vacuolation of the cytoplasm, and cell wall-plasmalemma separation. Fluorescence microscopy showed that nanoparticles were internalized by fungal cells. The sharp increase in the release of intracellular components and decrease of total cellular protein concentration demonstrated damaged cell membranes. Overall, the results indicate that oleoyl-chitosan nanoparticles have the potential to control phytopathogens in agriculture. PMID- 28363558 TI - Effect of selenylation modification on antitumor activity of peptidoglycan from Lactobacillus acidophilus. AB - Selenium is an essential trace element for human with the antitumor properties. In the present study, the peptidoglycan (PG) derived from Lactobacillus acidophilus was modified by selenylation with the HNO3-Na2SeO3 method. Reaction temperature, reaction duration and the selenide content were optimized according to orthogonal design of three-factors. In addition, the molecular structure of selenizing peptidoglycan (Se-PG) was determined by infrared spectroscopy analysis. Furthermore, the antitumor activity of Se-PG was also investigated in HT-29 cells. The results showed that Se-PG exerted a greater antitumor activity than non-modified PG in a dose-dependent manner. These findings indicated that selenylation modification can enhance the antitumor activity of PG, and Se-PG could achieve its potential in antitumor activity. PMID- 28363559 TI - Lipopolysaccharide of Pantoea agglomerans 7969: Chemical identification, function and biological activity. AB - Lipopolysaccharide (LPS) of Pantoea agglomerans 7969 isolated from apple tree was purified and characterized chemically by sugar and fatty acid analysis. Lipid A was analysed by negative-ion mode ESI MS and found to consist mainly of hexa- and tetra-acyl species typical of E. coli lipid A. The O-specific polysaccharide of the LPS was studied by sugar analysis, Smith degradation, and one- and two dimensional 1H and 13C NMR spectroscopy. The polysaccharide is built up of linear tetrasaccharide repeating units, and about ~25% repeats contain glycerol 1 phosphate on the GlcNAc residue: ->3)-alpha-l-Rha p-(1->6)-alpha-d-Man p-(1->3) alpha-d-Fuc p-(1->3)-beta-d-Glc pNAc-(1->~25% Gro-1-P-(O->6)? The LPS showed low levels of toxic and pyrogenic activities and reduced the average adhesion and the index of adhesiveness. PMID- 28363560 TI - Nanocellulose crystals derivative-silica hybrid sol open tubular capillary column for enantioseparation. AB - Broad spectrum separation of chiral compounds is a challenge task for analysts. It is significant for preparation of chiral stationary phase and selection of separation technology in the field. Here, we present a novel nanocellulose crystals (NCCs) which were derivation with 3,5-dimethylphenyl isocynate (DMPC) and silane with 3-triethoxysilylpropylisocyanate form sol in tetraethylorthosilicate (TEOS) and layer-by-layer self-assembly in the inner of capillary to fabricate the organic-inorganic hybrid open tubular capillary column (DMPC/NCCs-OTC) for enantiomers separation by capillary electrochromatography technology (CEC). The experimental results verified that this coating column has the broad spectrum separation ability and high resolution efficiency for thirteen different enantiomers at the optimal CEC conditions. The mechanizations of DMPC/NCCs-OTC modified layer numbers and structure effect on chiral separation performance have been investigated and compared. Although the limitation and difficulty in fabrication of open tubular coating column, this work provided the preparation method of stability, controlled, long column life, adequate repeatability and satisfied enantioseparation performance. PMID- 28363561 TI - A kinetic model of the gelation of konjac glucomannan induced by deacetylation. AB - The gelation of konjac glucomannan (KGM) often involves an induction period featured by an initial drop in modulus. The gelation kinetics recorded as a time dependent modulus change is composed of an initial drop followed by a steady increase in modulus until an equilibrium stage is reached. In this work, the time dependent modulus curve is described by a kinetic model which incorporates the cascade theory with the kinetic equations consisting of sequential reactions of deacetylation and cross-link formation. The proposed model is capable of predicting the presence of the induction period and the kinetic parameters can be extracted from the concentration dependence of the initial drop. A rheological experiment of KGM gelation using sodium carbonate as deacetylation agent was conducted to illustrate the feasibility of the proposed fitting approach, which yields kinetic curves agreeing satisfactorily with the experimental results. PMID- 28363562 TI - Preparation and properties of a novel macro porous Ni2+-imprinted chitosan foam adsorbents for adsorption of nickel ions from aqueous solution. AB - In this study, novel macro porous Ni2+-imprinted chitosan foam adsorbents (F-IIP) were prepared using sodium bicarbonate and glycerine to obtain a porogen for adsorbing nickel ions from aqueous solutions. The use of the ion-imprinting technique for adsorbents preparation improved the nickel ion selectivity and adsorption capacity. We characterised the imprinted porous foam adsorbents in terms of the effects of the initial pH value, initial metal ion concentration, and contact time on the adsorption of nickel ions. The adsorption process was described best by Langmuir monolayer adsorption models, and the maximum adsorption capacity calculated from the Langmuir equation was 69.93mgg-1. The kinetic data could be fitted to a pseudo-second-order equation. Our analysis of selective adsorption demonstrated the excellent preference of the F-IIP foams for nickel ions compared with other coexisting metal ions. Furthermore, tests over five cycle runs suggested that the F-IIP foam adsorbents had good durability and efficiency. PMID- 28363563 TI - Tethering antimicrobial peptides onto chitosan: Optimization of azide-alkyne "click" reaction conditions. AB - Antimicrobial peptides (AMP) are promising alternatives to classical antibiotics, due to their high specificity and potency at low concentrations, and low propensity to elicit pathogen resistance. Immobilization of AMP onto biomaterials is an emergent field of research, towards creation of novel antimicrobial materials able to avoid formation of biofilms on the surfaces of medical devices. Herein, we report the chemical route towards one such material, where chitosan was used as biocompatible carrier for the covalent grafting of Dhvar-5, a well known potent AMP, via the chemoselective ("click") Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The material's structure, as well as peptide loading, were confirmed by Fourier-transformed infra-red (FT-IR) and X-ray photoelectron (XPS) spectroscopies, and by Amino Acid Analysis (AAA), respectively. Results herein reported demonstrate that, with proper optimization, the "click" CuAAC is an attractive approach for the tethering of AMP onto chitosan, in order to create novel antimicrobial materials potentially valuable for biomedical applications. PMID- 28363564 TI - Salicyl-imine-chitosan hydrogels: Supramolecular architecturing as a crosslinking method toward multifunctional hydrogels. AB - Hydrogels based on chitosan and salicyladehyde were obtained by dynamic covalent chemistry. The unusual chitosan gelling in the presence of the monoaldehyde has been deciphered following and correlating data of NMR, FTIR, single crystal and wide angle XRD, POM and optical measurements. Of significant importance in understanding the crosslinking features was the synthesis of a model compound and the successfully growth as single crystal allowing the study of its supramolecular peculiarities. The hydrogels exhibited in SEM a porous or fibrous morphology, in good correlation with the crosslinking degree. They swelled very fast, similar to the superporous hydrogels of third generation and exhibited self healing properties. Rheological investigation demonstrated good mechanical properties, thermosensitivity and thixotropy. The paper revealed a hydrogel with suitable properties for use in bio-medical applications, and moreover, revealed a new concept of obtaining chitosan hydrogels using monoaldehydes - which are widespread in nature, cheap and beneficial to the human body. PMID- 28363565 TI - Zinc complexed chitosan/TPP nanoparticles: A promising micronutrient nanocarrier suited for foliar application. AB - Cultivation of cereals in zinc deficient soils leads to declined nutritional quality of grain. Zinc deficiency in humans is a consequence of consumption of micronutrient deficient cereals as staple food. To achieve an increase in zinc density in grain, we evaluated zinc complexed chitosan nanoparticles (Zn-CNP) as a potential 'nanocarrier' suited for foliar fertilization. Zn-CNP were synthesized using tri-polyphosphate as a cross-linker. Spherical Zn-CNP (diameter 250-300nm) were positively charged (zeta potential, +42.34mV) and contained ~20mg Zn/g (w/w). Plant growth in zinc deficient sand media, followed by foliar application of Zn-CNP (twice-a-week, for 5 weeks) after anthesis resulted in 27 and 42% increase in grain zinc content of MACS 3125 and UC1114 (durum wheat cultivars) respectively. Translocation of zinc ions from foliar applied Zn-CNP into the leaf and seed tissue was demonstrated using zinquin and dithizone stains, respectively. The study indicates the suitability of chitosan-based nanocarriers in agronomic biofortification. PMID- 28363566 TI - Encapsulation of the antioxidant ascorbyl palmitate in V-type granular cold-water swelling starch affects the properties of both. AB - This study reports on the functionality of V-type crystalline granular cold-water swelling starch (GCWSS) in complex with lipid (functionalized) molecules. Maize and potato GCWSS contain (empty) single helical amylose (AM) crystals which can serve as lipid complexing matrices. Different concentrations of ascorbyl palmitate (AscP) were inserted in the hydrophobic cavities of the GCWSS AM helices by a low temperature infusion method. Volumetric particle size distributions of the ensuing products in water were determined using laser light scattering. Upon contact with water, the parent maize GCWSS formed lumps more than did the parent potato GCWSS. It is hypothesized that variations in the spatial distribution of cold-water soluble V-type crystals are at the origin of this difference. In contrast, GCWSS-AscP inclusion complexes formed homogenous dispersions in water. Furthermore, the impact of inclusion complex formation on cold-water swelling properties was investigated. The close packing concentration increased and the swelling power and carbohydrate leaching decreased when the level of encapsulated AscP increased. Finally, in a Trolox equivalent antioxidant capacity test, encapsulated AscP still had up to 70% of the antioxidant capacity of free AscP. PMID- 28363567 TI - Development of a new type of multifunctional fucoidan-based nanoparticles for anticancer drug delivery. AB - Fucoidan, a sulfated marine polysaccharide, has many potential biological functions, including anticancer activity. Recently, fucoidan has been reported to target P-selectin expressed on metastatic cancer cells. Increasing research attention has been devoted to the developments of fucoidan-based nanomedicine. However, the application of traditional chitosan/fucoidan nanoparticles in anticancer drug delivery may be limited due to the deprotonation of chitosan at a pH greater than 6.5. In this study, a mutli-stimuli-responsive nanoparticle self assembled by fucoidan and a cationic polypeptide (protamine) was developed, and their pH-/enzyme-responsive properties were characterized by circular dichroism (CD) spectroscopy, dynamic light scattering (DLS), and zeta potential analysis. Enzymatic digestion and acidic intracellular microenvironment (pH 4.5-5.5) in cancer cells triggered the release of an anticancer drug (doxorubicin) from the nanoparticles. The protamine/fucoidan complex nanoparticles with P-selectin mediated endocytosis, charge conversion and stimuli-tunable release properties showed an improved inhibitory effect against a metastatic breast cancer cell line (MDA-MB-231). PMID- 28363568 TI - Enhancement the thermo-regulating property of cellulosic fabric using encapsulated paraffins in modified pectin. AB - Synthesis of smart hosting materials from solvent free modified pectin with fatty acid (have different molecular weight) have been occurred and characterised. Modified pectin with phase change material (PCM) have been prepared and applied to textile material. Smart composite matrix based on modified pectin was produce thermo-regulating characteristics which play the main role to control body temperature for various daily wear. The microcapsules (pectin/PCM) and treated fabric were characterized using SEM, DSC and FT-IR. The results confirmed the synthesis of modified pectin using solvent free method, and also confirmed its reaction with cotton surface. DSC result confirmed that, the treated fabrics have a thermo-regulating property. PMID- 28363569 TI - Surface lignin removal on coir fibers by plasma treatment for improved adhesion in thermoplastic starch composites. AB - The high lignin to cellulose ratio of coir fibers results in low compatibility between these fibers and natural polymers like starch, leading to poor mechanical properties in the composites. Plasma treatment using either air or oxygen proved to be an effective in removing the lignin rich amorphous layer on coir fibers, as it was clearly observed by SEM. The ratio of the FTIR signal related to lignin (1508cm-1) and cellulose (1317cm-1) decreases 10 times for air plasma treated fibers and 20 times for oxygen plasma treated samples. Composites of plasma treated short coir fibers and thermoplastic starch presented considerable increase in mechanical properties in comparison to composites made with untreated fibers. Tensile strength increased by up to 300% and elastic modulus improved by a factor of nearly 20 times, which was associated with enhanced fiber-matrix adhesion after plasma treatment with oxygen for 7.2min at 80W power. PMID- 28363570 TI - Transparent nanostructured cellulose acetate films based on the self assembly of PEO-b-PPO-b-PEO block copolymer. AB - In this study fabrication and characterization of transparent nanostructured composite films based on cellulose triacetate (CTA) and poly(ethylene oxide)-b poly(propylene oxide)-b-poly(ethylene oxide) (EPE) triblock copolymer were presented. The effect of the addition of EPE triblock copolymer on the thermal stability, morphology, and mechanical properties of cellulose triacetate films was investigated. The triblock EPE was chosen since PEO blocks interact favorably with CTA, whereas, PPO blocks remain immiscible which provokes a microphase separation. This allows to obtain EPE/CTA composite films with ordered microphase separated structures where PPO spherical microdomains are well-dispersed in PEO/CTA matrix by simple solvent-evaporation process. During this process, PEO block chains selectively interact with CTA by strong interpolymer hydrogen bonding while PPO block microseparated. The addition even 40wt% of EPE leads to nanostructured EPE/CTA composite. The cytotoxicity assay of CTA and EPE/CTA composite films confirm non-toxic character of designed transparent nanostructured composites based on sustainable matrices. PMID- 28363571 TI - Preparation, characterization and in vitro biological evaluation of (1:2) phenoxodiol-beta-cyclodextrin complex. AB - Phenoxodiol is an isoflavone analogue that possesses potent anticancer properties. However, the poor water solubility of phenoxodiol limits its overall efficacy as an anticancer agent. To overcome this, beta-cyclodextrin was used to encapsulate phenoxodiol. The phenoxodiol-beta-cyclodextrin complex was prepared via a modified co-evaporation method and characterized by 1H NMR and X-ray crystallography, revealing a 1:2 stoichiometry. The 2D ROESY NMR spectroscopy suggested the limited motion of phenoxodiol within the cavity of beta cyclodextrin while the X-ray crystal data displays by far the best 'ship-in-a bottle' case of 1:2 inclusion complex. The aqueous solubility of the phenoxodiol in beta-cyclodextrin had improved and the in vitro biological evaluation revealed enhanced anti-proliferative activity against three cancer cell lines. Additionally, the toxicity of the complex against normal human cell line was 2.5 times lower. These data indicates that the encapsulation of phenoxodiol into beta cyclodextrin leads to an improvement in its overall water solubility and biological activity. PMID- 28363573 TI - Effects of fucoidans and heparin on reactions of neutrophils induced by IL-8 and C5a. AB - Fucose-containing sulfated polysaccharides (fucoidans) from brown algae exhibit anti-inflammatory activity in vivo, however, there is only limited knowledge about their mode of action. Potential targets may be the chemokine interleukin 8 (IL-8) and the anaphylatoxin C5a, as they are closely linked to inflammatory processes. In this study, two fucoidans from Saccharina latissima and Fucus vesiculosus, and unfractionated heparin (UFH) were examined for their binding properties to IL-8 and C5a and their effects on IL-8- and C5a-induced reactions of polymorphonuclear neutrophils (PMN). As proved by a competitive sulfated polysaccharide-coating-ELISA, both fucoidans bind to IL-8 and C5a, whereby they showed higher affinity to IL-8. Whereas UFH displayed only moderate effects, the fucoidans concentration-dependently reduced the IL-8- and C5a-induced intracellular calcium release, Erk1/2 phosphorylation and chemotaxis of PMN. Their inhibitory potency is dependent on the target protein, but also other aspects than the binding turned out to play a role. PMID- 28363572 TI - Facile fabrication of moldable antibacterial carboxymethyl chitosan supramolecular hydrogels cross-linked by metal ions complexation. AB - Herein, carboxymethyl chitosan (CMCh) supramolecular hydrogels cross-linked by metal ions (Ag+, Cu2+ and Zn2+) are reported. The hydrogels were formed within a few seconds by simple mixing of CMCh solution with metallic salt solutions at an appropriate pH. The prepared hydrogels were characterized by using FT-IR, XRD, SEM and rotational rheometery. FT-IR measurements suggested that the facile complexation of metal ions with carboxylic, amino and hydroxyl groups of CMCh chains promoted the rapid hydrogelation. SEM images revealed a cross-linked structure of hydrogels, while microstructural openings were observed by cross sectional studies of the freeze-dried hydrogels. Moreover, the hydrogels showed a remarkable moldability to form free standing objects. The antibacterial activities of the hydrogels were also studied against Escherichia coli and Staphylococcus aureus by agar well diffusion method. The results demonstrated an excellent antibacterial activity of the supramolecular hydrogels. Therefore, the developed CMCh supramolecular hydrogels might be used effectively in biomedical field. PMID- 28363574 TI - Corrigendum to "Antimicrobial and antioxidant activities of Flammulina velutipes polysacchrides and polysacchride-iron(III) complex" [Carbohydrate Polymers 161 (2017) 26-32]. PMID- 28363575 TI - Processing and characterization of nanocomposite based on poly(butylene/triethylene succinate) copolymers and cellulose nanocrystals. AB - A new class of biodegradable materials developed by a combination of random eco friendly copolyesters containing butylene succinate (BS) and triethylene succinate (TES) sequences with cellulose nanocrystals (CNC), is proposed and studied. Polymers and nanocomposite films were prepared by an optimized extrusion process to improve the processability and mechanical response for flexible film manufacturing. Poly(butylene succinate) (PBS) homopolymer and two random copolyesters containing different amounts of TES co-units, P(BS85TES15) and P(BS70TES30), were synthesized by melt polycondensation. The effect of TES and CNC presence and content on the microstructure, tensile properties, thermal characteristics and disintegration under composting conditions, as well as on the toughening mechanism of the blends was investigated. Material properties were modulated by varying the chemical composition. CNC were used as reinforcement additive and their effect is modulated by the interaction with the three polymeric matrices. The extruded films displayed tunable degradation rates, mechanical properties and wettability, and showed promising results for different industrial applications. PMID- 28363576 TI - Novel levan and pNIPA temperature sensitive hydrogels for 5-ASA controlled release. AB - Levan based cross-linker was successfully synthesized and used to prepare a series of more biocompatible and temperature responsive levan/N-isopropyl acrylamide (levan/pNIPA) hydrogels by redox polymerization at room temperature. Volume phase transition temperature (VPTT) of the hydrogels were precisely determined by derivative differential scanning calorimetry (DDSC). Incorporation of levan into the pNIPA hydrogel increased the VPTT from 32.8 degrees C to 35.09 degrees C, approaching to body temperature. Swelling behavior and 5 aminosalicylic acid (5-ASA) release of the hydrogels were found to vary significantly with temperature and composition. Moreover, a remarkable increase in thermal stability of levan within hydrogel with increase of pNIPA content was recorded. The biocompatibility of the hydrogels were tested against mouse fibroblast L929 cell line in phosphate buffer saline (PBS, pH 7.4). The hydrogels showed increasing biocompatibility with increasing levan ratio, indicating levan enhanced the hydrogel surface during swelling. PMID- 28363577 TI - The structure of a fucosylated chondroitin sulfate from the sea cucumber Cucumaria frondosa. AB - A fucosylated chondroitin sulfate (FCS) CF was isolated from the sea cucumber Cucumaria frondosa and purified by anion-exchange chromatography. Chemical and NMR spectroscopic methods were applied for the structural characterization of this biopolymer. The backbone of CF was found to consist of chondroitin sulfate A and E fragments together with rather uncommon disaccharide repeating units ->3) beta-d-GalNAc4S6S-(1->4)-beta-d-GlcA3S-(1-> and ->3)-beta-d-GalNAc4S-(1->4)-beta d-GlcA3S-(1->. Three types of branches were found in molecules of CF. Two of them were identified as alpha-l-Fuc p3S4S and alpha-l-Fuc p2S4S attached to O-3 of Glc pA residues, while the third one was per-O-sulfated alpha-l-Fuc p linked to O-6 of Gal pNAc residue. The ratio of these branches was 5:2:1. According to these data, CF has more complicated structure than the corresponding FCS, isolated from the same holothurian species and described previously (Liu et al., 2016). The presence of new structural features both in the backbone and in branches of CF gives an additional example of structural variability within holothurian FCS. PMID- 28363578 TI - TEMPO-mediated oxidation of polysaccharides: An ongoing story. AB - The oxidation of natural polysaccharides by TEMPO has become by now an "old chemical reaction" which led to numerous studies mainly conducted on cellulose. This regioselective oxidation of primary alcohol groups of neutral polysaccharides has generated a new class of polyuronides not identified before in nature, even if the discovery of enzymes promoting an analogous oxidation has been more recently reported. Around the same time, the scientific community discovered the surprising biological and techno-functional properties of these anionic macromolecules with a high potential of application in numerous industrial fields. The objective of this review is to establish the state of the art of TEMPO chemistry applied to polysaccharide oxidation, its history, the resulting products, their applications and the associated modifying enzymes. PMID- 28363579 TI - Smart nanopaper based on cellulose nanofibers with hybrid PEDOT:PSS/polypyrrole for energy storage devices. AB - In the current work, flexible, lightweight, and strong conductive nanopapers based on cellulose nanofibers (CNFs) with poly(3,4 ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) and/or polypyrrole (PPy) were prepared by following a mixing and in situ chemical polymerization method. A successful homogeneous coating of PEDOT:PSS on cellulose nanofibers occurred by means hydrogen-bonding interactions between the hydroxyl functionalized CNF and the electronically charged PEDOT:PSS, as shown by FTIR spectra. The electrical conductivity and the specific capacitance of CNF PEDOT:PSS nanopapers were 2.58Scm-1 and 6.21Fg-1, respectively. Further coating of PPy produced a substantial improvement on the electrical conductivity (10.55Scm-1) and the specific capacitance (315.5Fg-1) of the resulting CNF PEDOT:PSS-PPy nanopaper. A synergistic phenomenon between both conductive polymers supported the high electrical conductivity and specific capacitance of the ternary formulation. Moreover, CNF-PEDOT:PSS-PPy nanopaper showed higher mechanical properties and it was more flexible than the nanopaper containing only polypyrrole conducting polymer (CNF-PPy). It is concluded that the good mechanical, electrical and electrochemical properties of the ternary formulation can apply for smart nanopaper in flexible electronics and energy storage devices. PMID- 28363581 TI - The Effect of Triglyceride Concentration on Attainment of Lipid Targets in Patients with Diabetes. AB - OBJECTIVES: To evaluate the effects of triglyceride (TG) and glycated hemoglobin (A1C) concentrations in the percentage of patients with diabetes who are within target (WT) for low-density lipoprotein-cholesterol (LDL-C), non-high-density lipoprotein-cholesterol (non-HDL-C) and apolipoprotein B (ApoB), as defined by the Canadian Lipid Guidelines, in a cohort of outpatients presenting at a 350-bed community hospital. METHODS: Laboratory samples from 1919 patients, 18 years or older, who had A1C levels of 6.5% or above were used. Fasting lipid profiles were retrieved, and ApoB was measured. RESULTS: We found no significant difference in the percentage of those WT for LDL-C as TG increased from normal to intermediate and high levels. For non-HDL-C, we saw a substantial decrease in the percentage of patients WT as TG levels increased from normal (61%) to intermediate (30.4%) and high levels (14.0%). ApoB showed a similar pattern to non-HDL-C: decreasing from normal (68.8%) to intermediate (40.7%) and high levels (21.0%). No significant difference was seen in the percentage of patients WT for the 3 lipid parameters studied with the increase in A1C levels. CONCLUSIONS: As TG increases, we saw discordance in the percentage of patients WT for LDL-C in relation to non HDL-C and ApoB. Alternative targets to LDL-C should preferentially be used when the TG concentration is elevated. PMID- 28363580 TI - Rhein functionalized magnetic chitosan as a selective solid phase extraction for determination isoflavones in soymilk. AB - A new solid-phase extraction mode was developed for separation some flavones from the complex interference system. In the experiment, rhein anchored on magnetic chitosan microparticles, prepared facilely without removal of the template molecule, was used as sorbents for the extraction of target analytes; after completion of the extraction process, Fe3O4 particles acted as carrier to retrieve rhein functionalized magnetic chitosan microparticles (RMCMPs) from the sample solution. RMCMPs showed excellent selective adsorption capacity of isoflavones. The result suggested that the method was useful for fast determination and quantification of isoflavones in soymilk. The RMCMPs were characterized by scanning electron microscope (SEM), X-ray diffraction (XRD) and Fourier transforms infrared spectrometer (FTIR). PMID- 28363582 TI - Depressive Symptoms, Diabetes Distress and Serum Hemoglobin A1C in South Asians With Type 2 Diabetes Mellitus Living in Canada. PMID- 28363583 TI - Foreword. PMID- 28363584 TI - Upper Gastrointestinal Toxicity Associated With Long-Term Aspirin Therapy: Consequences and Prevention. AB - Antiplatelet therapy represents a fundamental part of preventive management for patients who are at risk of a secondary cardiovascular disease (CVD) event. In most cases, the antiplatelet regimen is based on low-dose aspirin, a drug that is highly effective in reducing the incidence of CVD events, but is associated with a substantial risk of gastrointestinal (GI) toxicity. The dyspeptic symptoms, which can result from aspirin administration, and which may occur with or without associated ulceration and bleeding, may lead patients to discontinue therapy, thus increasing their CVD risk. For patients in whom aspirin is indicated and who are deemed to be at increased risk of upper GI events, concomitant therapy with a proton pump inhibitor (PPI) is currently recommended. These agents are highly effective in reducing the upper GI lesions associated with aspirin therapy and have been associated with increased aspirin adherence. However, widespread under prescribing of PPIs and potential noncompliance with their use means that substantial numbers of patients are at unnecessary risk of upper GI toxicity and if aspirin therapy is discontinued-CVD events. Provision of aspirin and an immediate-release PPI as a coordinated-delivery combination tablet has been shown to both reduce the risk of gastric ulcer formation and improve patient compliance. This strategy, which may ultimately reduce the incidence of CVD outcomes because of the associated reduction in GI symptoms and the potential for greater patient adherence to aspirin, warrants further investigation under both randomized controlled conditions (explanatory trials), and in real-life settings (pragmatic trials). PMID- 28363585 TI - Comparison of anal HPV natural history among men by country of residence: Brazil, Mexico, and the United States. AB - OBJECTIVES: Globally, anal cancer incidence is rare, but is increasing in some world regions. Our objective was to assess differences in anal HPV natural history in three countries. METHODS: Men aged 18-70 years were recruited from the US (n = 634), Mexico (n = 665), and Brazil (n = 731). Anal specimens were collected every six-months. HPV genotyping was assessed by Linear Array. Anal HPV prevalence was compared using the Fisher's exact test. HPV infection incidence rates (IR) and 95% confidence intervals (CI) were calculated. RESULTS: Any anal HPV prevalence was highest among men from Brazil (24%) compared to Mexico (15%) and the US (15%). When stratified by sexual history, the prevalence of any HPV among MSM/MSMW was 43%, 37%, and 45% and 9%, 12%, and 10% for MSW from Brazil, Mexico, and US, respectively. Any HPV incidence was significantly higher among men from Brazil compared to US men (IRR = 2.4, 95% CI = 1.7-3.4) and comparable between men from Mexico and the US (IRR = 1.2, 95% CI = 0.8-1.8). CONCLUSION: Men in Brazil and Mexico often have similar, if not higher incidence of anal HPV compared to men from the U.S., and may benefit from gender neutral HPV vaccine policies. PMID- 28363586 TI - Increase in tear film lipid layer thickness after instillation of 3% diquafosol ophthalmic solution in healthy human eyes. AB - PURPOSE: To evaluate the effect of 3% diquafosol ophthalmic solution on tear film lipid layer thickness (LLT) in normal human eyes by tear interferometry. METHODS: Forty-seven healthy men (mean age of 42.4 years) randomly received one drop of artificial tears in one eye and one drop of 3% diquafosol ophthalmic solution in the other. LLT of each eye was quantified by tear interferometry before and 15, 30, and 60 min after instillation. Ocular symptoms were assessed before and 30 min after instillation. Baseline LLT, tear film breakup time (TBUT), meibomian gland area (meiboscore) of the upper and lower eyelids, and Schirmer test value were evaluated on a different day before treatment. RESULTS: LLT before and 15, 30, and 60 min after diquafosol instillation was 62.3 +/- 31.1, 77.0 +/- 39.5, 79.3 +/- 40.5, and 77.7 +/- 43.6 nm, respectively, with the diquafosol-induced increase in LLT being significant at each time point. Artificial tears did not result in a significant increase in LLT. TBUT (rho = 0.32, P = 0.026), meiboscore of the lower eyelid (rho = -0.33, P = 0.022), and the maximum difference in LLT between before and after diquafosol instillation (DeltaLLTmax) (rho = 0.35, P = 0.016) were significantly correlated with baseline LLT in the diquafosol group. Age was not significantly related to baseline LLT or DeltaLLTmax. Symptoms did not differ significantly between the two groups. CONCLUSIONS: Topical instillation of 3% diquafosol ophthalmic solution increased LLT for up to 60 min in normal human eyes regardless of age. PMID- 28363587 TI - A PP2C-1 Allele Underlying a Quantitative Trait Locus Enhances Soybean 100-Seed Weight. AB - Cultivated soybeans may lose some useful genetic loci during domestication. Introgression of genes from wild soybeans could broaden the genetic background and improve soybean agronomic traits. In this study, through whole-genome sequencing of a recombinant inbred line population derived from a cross between a wild soybean ZYD7 and a cultivated soybean HN44, and mapping of quantitative trait loci for seed weight, we discovered that a phosphatase 2C-1 (PP2C-1) allele from wild soybean ZYD7 contributes to the increase in seed weight/size. PP2C-1 may achieve this function by enhancing cell size of integument and activating a subset of seed trait-related genes. We found that PP2C-1 is associated with GmBZR1, a soybean ortholog of Arabidopsis BZR1, one of key transcription factors in brassinosteroid (BR) signaling, and facilitate accumulation of dephosphorylated GmBZR1. In contrast, the PP2C-2 allele with variations of a few amino acids at the N-terminus did not exhibit this function. Moreover, we showed that GmBZR1 could promote seed weight/size in transgenic plants. Through analysis of cultivated soybean accessions, we found that 40% of the examined accessions do not have the PP2C-1 allele, suggesting that these accessions can be improved by introduction of this allele. Taken together, our study identifies an elite allele PP2C-1, which can enhance seed weight and/or size in soybean, and pinpoints that manipulation of this allele by molecular-assisted breeding may increase production in soybean and other legumes/crops. PMID- 28363588 TI - Effects of synbiotics on immunity and disease resistance of narrow-clawed crayfish, Astacus leptodactylus leptodactylus (Eschscholtz, 1823). AB - The aim of this study was to evaluate the effects of prebiotics (mannanoligosaccharide and xylooligosaccharide), probiotics (Enterococcus faecalis and Pediococcus acidilactici) and synbiotics for 126 days on the immune responses, hemolymph indices, antioxidant enzymes, and biological responses after a 48-hour Aeromonas hydrophila exposure of sub-adult crayfish (11.45 +/- 1.87 g). Most antibacterial activities were observed in the shell mucus of crayfish fed a diet containing xylooligosaccharide + E. faecalis and mannanoligosaccharide + Pediococcus acidilactici against Nocardia brasilience and Vibrio harveyi (p < 0.05). Feeding crayfish a xylooligosaccharide + E. faecalis diet increased protein levels and the activities of alkaline phosphatase and lysozyme in the shell mucus after the feeding trial and 48 h after the A. hydrophila-injection challenge (p < 0.05). The highest ratio of the lactobacillus count to the total viable count was observed in synbiotic diets (p < 0.05). Feeding crayfish a xylooligosaccharide + E. faecalis diet increased the growth rate and the resistance to the A. hydrophila-injection challenge (p < 0.05). These results revealed that feeding crayfish with synbiotic diets was more effective than a single administration with prebiotics and probiotics. PMID- 28363590 TI - Evolving concepts of the RBC storage lesion using Omics and other novel diagnostic tools. PMID- 28363591 TI - Extracellular vesicle characteristics in stored red blood cell concentrates are influenced by the method of detection. AB - Extracellular vesicles (EVs), including microvesicles and exosomes, are small phospholipid vesicles (<=1MUm in diameter) that are present in blood products, accumulate during storage, and have a potential transfusion-related immunomodulatory role. Knowledge of EVs in stored blood products is limited due to the challenges and difficulties in detecting these heterogeneous submicron sized vesicles. The aim of this study was to assess the impact of different approaches to characterize EVs in stored RBC products. Quantification and size profiling of EVs in leukoreduced red cell concentrates (RCCs) were examined on day 3, 7, 21, and 42 of storage using tunable resistive plus sensing (TRPS), flow cytometer (FC), and dynamic light scatting (DLS) methods. Using the TRPS method, the concentration of EVs<200nm significantly increased throughout storage (p<0.05). This change in exosome concentration was not detectable with FC or DLS due to limitations in their ability to resolve particles <200nm and/or accurately determine EV concentration. Both the TRPS and FC demonstrate that the concentration of EVs>=200nm significantly increases in RCCs by day 42/43 compared to EVs present on day 3 (p<0.001). As the DLS measures the average size of particles in suspension, only an increase in the zeta-average size was observed during storage. EV size and concentration in RBC products is significantly influenced by the length of storage. Overall, this study shows that combining technologies may be important to improve the characterization and study of EVs in stored RCCs. PMID- 28363589 TI - The Extended-Synaptotagmins. AB - The extended-synaptotagmins (tricalbins in yeast) derive their name from their partial domain structure similarity to the synaptotagmins, which are characterized by an N-terminal membrane anchor and cytosolically exposed C2 domains. However, they differ from the synaptotagmins in localization and function. The synaptotagmins tether secretory vesicles, including synaptic vesicles, to the plasma membrane (PM) via their C2 domains and regulate their Ca2+ triggered exocytosis. In contrast, the extended-synaptotagmins are resident proteins of the endoplasmic reticulum (ER), which tether this organelle to the plasma membrane via their C2 domains, but not as a premise to fusion of the two membranes. They transport glycerolipids between the two bilayers via their lipid harboring SMP domains and Ca2+ regulates their membrane tethering and lipid transport function. Additionally, the extended-synaptotagmins are more widely expressed in different organisms, as they are present not only in animal cells, but also in fungi and plants, which do not express the synaptotagmins. Thus, they have a more general function than the synaptotagmins, whose appearance in animal species correlated with the occurrence of Ca2+ triggered exocytosis. This article is part of a Special Issue entitled: Membrane Contact Sites edited by Christian Ungermann and Benoit Kornmann. PMID- 28363592 TI - A survey of critical care nurses' practices and perceptions surrounding early intravenous antibiotic initiation during septic shock. AB - BACKGROUND: Delays in antibiotic administration after severe sepsis recognition increases mortality. While physician and pharmacy-related barriers to early antibiotic initiation have been well evaluated, those factors that affect the speed by which critical care nurses working in either the emergency department or the intensive care unit setting initiate antibiotic therapy remains poorly characterized. AIM: To evaluate the knowledge, practices and perceptions of critical care nurses regarding antibiotic initiation in patients with newly recognised septic shock. METHODS: A validated survey was distributed to 122 critical care nurses at one 320-bed academic institution with a sepsis protocol advocating intravenous(IV) antibiotic initiation within 1hour of shock recognition. RESULTS: Among 100 (82%) critical care nurses responding, nearly all (98%) knew of the existence of the sepsis protocol. However, many critical care nurses stated they would optimise blood pressure [with either fluid (38%) or both fluid and a vasopressor (23%)] before antibiotic initiation. Communicated barriers to rapid antibiotic initiation included: excessive patient workload (74%), lack of awareness IV antibiotic(s) ordered (57%) or delivered (69%), need for administration of multiple non-antibiotic IV medications (54%) and no IV access (51%). CONCLUSIONS: Multiple nurse-related factors influence IV antibiotic(s) initiation speed and should be incorporated into sepsis quality improvement efforts. PMID- 28363593 TI - Seeing beyond monitors-Critical care nurses' multiple skills in patient observation: Descriptive qualitative study. AB - OBJECTIVES: The aim of this study was to provide a comprehensive description of multiple skills in patient observation in critical care nursing. RESEARCH METHODOLOGY: Data from semi-structured interviews were analysed using thematic analysis. SETTING: Experienced critical care nurses (n=20) from three intensive care units in two university hospitals in Finland. FINDINGS: Patient observation skills consist of: information gaining skills, information processing skills, decision-making skills and co-operation skills. The first three skills are integrated in the patient observation process, in which gaining information is a prerequisite for processing information that precedes making decisions. Co operation has a special role as it occurs throughout the process. CONCLUSION: This study provided a comprehensive description of patient observation skills related to the three-phased patient observation process. The findings contribute to clarifying this part of the competence. The description of patient observation skills may be applied in both clinical practice and education as it may serve as a framework for orientation, ensuring clinical skills and designing learning environments. Based on this study, patient observation skills can be recommended to be included in critical care nursing education, orientation and as a part of critical care nurses' competence evaluation. PMID- 28363594 TI - Thematic Analysis: How do patient diaries affect survivors' psychological recovery? AB - AIM: This review aims to use thematic analysis to explore and synthesise evidence of the actual or potential reported effects of diaries on the psychological rehabilitation and recovery of discharged critical care patients. BACKGROUND: Evidence suggests that whilst admission to critical care may save patient lives, the psychological aftermath can damage a patient's recovery and these needs must be met. Patient diaries are one potential intervention to aid patients understand their critical illness and fill memory gaps caused by sedation, thus reducing psychological distress post-discharge. Prospective patient diaries are increasing in popularity amongst critical care units in the United Kingdom, however there is little evidence base to support their use or understand their effects. METHOD: A literature review using systematic methods was undertaken of studies relating to the effects of diaries on discharged patients. Thematic analysis enabled the generation and synthesis of themes. RESULTS: Three themes arose from the generated codes: 1) Reclaiming ownership of lost time. 2) Emphasising personhood. 3) Fear and frustration. The diary intervention was shown to have a largely positive impact on survivors' psychological rehabilitation. However, caution should be exercised as recipients could find the contents painful and emotional. Diaries should be embedded within a robust critical care follow-up plan. CONCLUSION: This review suggests that diaries have the potential to form one aspect of rehabilitation and make a positive impact on patients' recovery. More research is indicated to fully evaluate the effects of diaries on their recipients. PMID- 28363595 TI - Gastric incarceration in a peristomal hernia. PMID- 28363596 TI - "Iliac hernia", an original form of ventral hernia that is probably not so uncommon. PMID- 28363597 TI - The cytotoxic effects of VE-3N, a novel 1,4-dihydropyridine derivative, involve the mitochondrial bioenergetic disruption via uncoupling mechanisms. AB - Several 1,4-dihydropyridine derivatives overcome the multidrug resistance in tumors, but their intrinsic cytotoxic mechanisms remain unclear. Here we addressed if mitochondria are involved in the cytotoxicity of the novel 1,4 dihydropyridine derivative VE-3N [ethyl 6-chloro-5-formyl-2-methyl-4-(3 nitrophenyl)-1,4-dihydropyridine-3-carboxylate] towards cancer cells by employing hepatic carcinoma (HepG2) cells and isolated rat liver mitochondria. In HepG2 cells, VE-3N induced mitochondrial membrane potential dissipation, ATP depletion, annexin V/propidium iodide double labeling, and Hoechst staining; events indicating apoptosis induction. In isolated rat liver mitochondria, VE-3N promoted mitochondrial uncoupling by exerting protonophoric actions and by increasing membrane fluidity. Mitochondrial uncoupling was evidenced by an increase in resting respiration, dissipation of mitochondrial membrane potential, inhibition of Ca2+ uptake, stimulation of Ca2+ release, decrease in ATP synthesis, and swelling of valinomycin-treated organelles in hyposmotic potassium acetate media. Furthermore, uncoupling concentrations of VE-3N in the presence of Ca2+ plus ruthenium red induced the mitochondrial permeability transition process. These results indicate that mitochondrial uncoupling is potentially involved in the VE-3N cytotoxic actions towards HepG2 cells. Considering that hepatocellular carcinoma is the most common form of liver cancer, our findings may open a new avenue for the development of VE-3N-based cancer therapies, and help to unravel the cytotoxic mechanisms of 1,4-dihydropyridines towards cancer cells. PMID- 28363598 TI - p,p'-Methoxyl-diphenyl diselenide-loaded polymeric nanocapsules are chemically stable and do not induce toxicity in mice. AB - Organoselenium compounds have been targeted to new therapeutic tools development due to their pharmacological actions. However, some toxicity issues and physicochemical limitations delay the clinical application of these compounds. The incorporation of organoselenium molecules into nanostructured systems arises as a promising alternative to overcome such restrictions. The current study proposed the characterization of the polymeric nanocapsules of p,p'-methoxyl diphenyl diselenide [(OMePhSe)2] as well as the evaluation of the in vivo toxicity and biodistribution profile. The nanocapsules, which were composed by medium-chain triglycerides as the oil core and poly(epsilon-caprolactone) as the polymeric wall, showed nanometric size (236+/-4), low polydispersity (<0.2), negative zeta potential (-5.4+/-0.06), neutral pH values (7.2+/-0.08) and a high encapsulation efficiency (98%). Besides, the nanoencapsulation process increased the (OMePhSe)2 stability. The repeated intragastric administration of (OMePhSe)2 nanoencapsulated (25mg/kg/day during 7days) did not cause any alteration in the oxidative status, hematological parameters, and plasma biochemical markers of cellular damage. Moreover, the (OMePhSe)2 incorporation into nanocapsules increased the selenium concentrations in the tissues (kidneys, liver and plasma) suggesting an improvement in its oral bioavailability. PMID- 28363599 TI - Fluorescent carbon dot-gated multifunctional mesoporous silica nanocarriers for redox/enzyme dual-responsive targeted and controlled drug delivery and real-time bioimaging. AB - A distinctive and personalized nanocarrier is described here for controlled and targeted antitumor drug delivery and real-time bioimaging by combining a redox/enzyme dual-responsive disulfide-conjugated carbon dot with mesoporous silica nanoparticles (MSN-SS-CDHA). The carbon dot with controlling and targeting abilities was prepared through a polymerizing reaction by applying citric acid and HA as starting materials (named CDHA). The as-prepared MSN-SS-CDHA exhibited not only superior photostability and excellent biocompatibility, but also the ability to target A549 cells with overexpression of CD44 receptors. Upon loading the antitumor drug, doxorubicin (DOX), into the mesoporous channels of MSN nanoparticles, CDHA with a diameter size of 3nm completely blocked the pore entrance of DOX-encapsulated MSN nanoparticles with a pore size of about 3nm, thus preventing the premature leakage of DOX and increasing the antitumor activity until being triggered by specific stimuli in the tumor environment. The results of the cell imaging and cytotoxicity studies demonstrated that the redox/enzyme dual-responsive DOX-encapsulated MSN-SS-CDHA nanoparticles can selectively deliver and control the release of DOX into tumor cells. Ex vivo fluorescence images showed a much stronger fluorescence of MSN-SS-CDHA-DOX in the tumor site than in normal tissues, greatly facilitating the accumulation of DOX in the target tissue. However, its counterpart, MSN-SH-DOX exhibited no or much lower tumor cytotoxicity and drug accumulation in tumor tissue. In addition, MSN SS-CD was also used as a control to investigate the ability of MSN-SS-CDHA to target A549 cells. The results obtained indicated that MSN-SS-CDHA possessed a higher cellular uptake through the CD44 receptor-mediated endocytosis compared with MSN-SS-CD in the A549 cells. Such specific redox/enzyme dual-responsive targeted nanocarriers are a useful strategy achieving selective controlled and targeted delivery of therapeutic reagents with real-time bioimaging, and may also facilitate the development of drug delivery systems for a number of clinical applications. PMID- 28363600 TI - Heme modulates Trypanosoma cruzi bioenergetics inducing mitochondrial ROS production. AB - Trypanosoma cruzi is the causative agent of Chagas disease and has a single mitochondrion, an organelle responsible for ATP production and the main site for the formation of reactive oxygen species (ROS). T. cruzi is an obligate intracellular parasite with a complex life cycle that alternates between vertebrate and invertebrate hosts, therefore the development of survival strategies and morphogenetic adaptations to deal with the various environments is mandatory. Over the years our group has been studying the vector-parasite interactions using heme as a physiological oxidant molecule that triggered epimastigote proliferation however, the source of ROS induced by heme remained unknown. In the present study we demonstrate the involvement of heme in the parasite mitochondrial metabolism, decreasing oxygen consumption leading to increased mitochondrial ROS and membrane potential. First, we incubated epimastigotes with carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP), an uncoupler of oxidative phosphorylation, which led to decreased ROS formation and parasite proliferation, even in the presence of heme, correlating mitochondrial ROS and T. cruzi survival. This hypothesis was confirmed after the mitochondria-targeted antioxidant ((2-(2,2,6,6 Tetramethylpiperidin-1-oxyl-4 ylamino)-2-oxoethyl) triphenylphosphonium chloride (MitoTEMPO) decreased both heme-induced ROS and epimastigote proliferation. Furthermore, heme increased the percentage of tetramethylrhodamine methyl ester (TMRM) positive parasites tremendously-indicating the hyperpolarization and increase of potential of the mitochondrial membrane (DeltaPsim). Assessing the mitochondrial functional metabolism, we observed that in comparison to untreated parasites, heme-treated epimastigotes decreased their oxygen consumption, and increased the complex II III activity. These changes allowed the electron flow into the electron transport system, even though the complex IV (cytochrome c oxidase) activity decreased significantly, showing that heme-induced mitochondrial ROS appears to be a consequence of the enhanced mitochondrial physiological modulation. Finally, the parasites that were submitted to high concentrations of heme presented no alterations in the ultrastructure. Consequently, our results suggest that heme released by the insect vector after the blood meal, modify epimastigote mitochondrial physiology to increase ROS as a metabolic mechanism to maintain epimastigote survival and proliferation. PMID- 28363602 TI - Zinc regulates Nox1 expression through a NF-kappaB and mitochondrial ROS dependent mechanism to induce senescence of vascular smooth muscle cells. AB - AIMS: The role of oxidative stress and inflammation in the development and progression of cardiovascular diseases (CVD) is well established. Increases in oxidative stress can further exacerbate the inflammatory response and lead to cellular senescence. We previously reported that angiotensin II (Ang II) and zinc increase reactive oxygen species (ROS) and cause senescence of vascular smooth muscle cells (VSMCs) and that senescence induced by Ang II is a zinc-dependent process. Zinc stimulated NADPH oxidase (Nox) activity; however, the role of Nox isoforms in zinc effects was not determined. RESULTS: Here, we show that downregulation of Nox1, but not Nox4, by siRNA prevented both Ang II- and zinc induced senescence in VSMCs. On the other hand, overexpression of Nox1 induced senescence, which was associated with reduced proliferation, reduced expression of telomerase and increased DNA damage. Zinc increased Nox1 protein expression, which was inhibited by chelation of zinc with TPEN and by overexpression of the zinc exporters ZnT3 and ZnT10. These transporters work to reduce cytosolic zinc, suggesting that increased cytosolic zinc mediates Nox1 upregulation. Other metals including copper, iron, cobalt and manganese failed to upregulate Nox1, suggesting that this pathway is zinc specific. Nox1 upregulation was inhibited by actinomycin D (ACD), an inhibitor of transcription, by inhibition of NF-kappaB, a known Nox1 transcriptional regulator and by N-acetyl cysteine (NAC) and MitoTEMPO, suggesting that NF-kappaB and mitochondrial ROS mediate zinc effects. Supporting this idea, we found that zinc increased NF-kappaB activation in the cytosol, stimulated the translocation of the p65 subunit to the nucleus, and that zinc accumulated in mitochondria increasing mitochondrial ROS, measured using MitoSox. Further, zinc-induced senescence was reduced by inhibition of NF-kappaB or reduction of mitochondrial ROS with MitoTEMPO. NF-kappaB activity was also reduced by MitoTEMPO, suggesting that mitochondrial ROS is upstream of NF-kappaB. INNOVATION AND CONCLUSION: Our data demonstrate that altered zinc distribution leading to accumulation of zinc in the mitochondria increases mitochondrial ROS production causing NF-kappaB activation which in turn upregulates Nox1 expression inducing senescence of VSMCs. PMID- 28363601 TI - Methylglyoxal-induced AMPK activation leads to autophagic degradation of thioredoxin 1 and glyoxalase 2 in HT22 nerve cells. AB - Methylglyoxal (MGO) is a major glycating agent that reacts with basic residues of proteins and promotes the formation of advanced glycation end products which are believed to play key roles in a number of pathologies, such as diabetes, Alzheimer's disease, and inflammation. We previously showed that MGO treatment targets the thioredoxin and the glyoxalase systems, leading to a decrease in Trx1 and Glo2 proteins in immortalized mouse hippocampal HT22 nerve cells. Here, we propose that autophagy is the underlying mechanism leading to Glo2 and Trx1 loss induced by MGO. The autophagic markers p62, and the lipidated and active form of LC3, were increased by MGO (0.5mM). Autophagy inhibition with bafilomycin or chloroquine prevented the decrease in Trx1 and Glo2 at 6 and 18h after MGO treatment. Proteasome inhibition by MG132 exacerbated the effect of MGO on Trx1 and Glo2 degradation (18h), further suggesting a role for autophagy. ATG5 small interfering RNA protected Trx1 and Glo2 from MGO-induced degradation, confirming Trx1 and Glo2 loss is mediated by autophagy. In the search for the signals that control autophagy, we found that AMPK activation, a known autophagy inducer, was markedly increased by MGO treatment. AMPK activation was confirmed by increased acetyl coenzyme A carboxylase phosphorylation, a direct AMPK substrate and by decreased mTOR phosphorylation, an indirect marker of AMPK activation. To confirm that MGO-mediated Trx1 and Glo2 degradation was AMPK-dependent, AMPK-deficient mouse embryonic fibroblasts (MEFs) were treated with MGO. Wildtype MEFs presented the expected decrease in Trx1 and Glo2, while MGO was ineffective in decreasing these proteins in AMPK-deficient cells. Overall, the data indicate that MGO activates autophagy in an AMPK-dependent manner, and that autophagy was responsible for Trx1 and Glo2 degradation, confirming that Trx1 and Glo2 are molecular targets of MGO. PMID- 28363604 TI - The endoplasmic reticulum: A hub of protein quality control in health and disease. AB - One third of the eukaryotic proteome is synthesized at the endoplasmic reticulum (ER), whose unique properties provide a folding environment substantially different from the cytosol. A healthy, balanced proteome in the ER is maintained by a network of factors referred to as the ER quality control (ERQC) machinery. This network consists of various protein folding chaperones and modifying enzymes, and is regulated by stress response pathways that prevent the build-up as well as the secretion of potentially toxic and aggregation-prone misfolded protein species. Here, we describe the components of the ERQC machinery, investigate their response to different forms of stress, and discuss the consequences of ERQC break-down. PMID- 28363606 TI - Observational Study of Neonatal Safety for Outpatient Labour Induction Priming with Dinoprostone Vaginal Insert. AB - OBJECTIVES: To evaluate the safety of outpatient induction with dinoprostone insert in low-risk labour inductions for premature rupture of membranes or postdates gestation. METHODS: This retrospective cohort study compared outpatient labour induction priming with inpatient induction in terms of neonatal safety, mode of delivery, and obstetrical parameters. The sample included all inductions for premature rupture of membranes or postdate gestation. The analysis used logistic regression. The statistical power of the sample was 80% to detect a difference of 5.6% for the composite neonatal safety outcome (5-minute Apgar score <7 and NICU admission for >12 hours or transfer to a level III nursery). RESULTS: Compared with the inpatient cohort (n = 568), the outpatient cohort (n = 611) included more postdate gestations (93% vs. 67%) with less cervical dilatation (0.5 cm vs. 1.0 cm) and larger infants (3705 g vs. 3551 g). There were no differences in measures of neonatal safety or mode of delivery. The outpatient cohort required more dinoprostone inserts (1.59 vs. 1.23) and were less likely to deliver within 24 hours (OR 0.24, 95% CI 0.17 to 0.34) but were also less likely to deliver by CS (OR 0.71, 95% CI 0.54 to 0.95), after adjusting for obstetrical parameters. CONCLUSION: An outpatient model of labour induction using dinoprostone inserts is feasible and safe. PMID- 28363605 TI - Genetic or pharmacological depletion of cannabinoid CB1 receptor protects against dopaminergic neurotoxicity induced by methamphetamine in mice. AB - Accumulating evidence suggests that cannabinoid ligands play delicate roles in cell survival and apoptosis decisions, and that cannabinoid CB1 receptors (CB1R) modulate dopaminergic function. However, the role of CB1R in methamphetamine (MA) induced dopaminergic neurotoxicity in vivo remains elusive. Multiple high doses of MA increased phospho-ERK and CB1R mRNA expressions in the striatum of CB1R (+/+) mice. These increases were attenuated by CB1R antagonists (i.e., AM251 and rimonabant), an ERK inhibitor (U0126), or dopamine D2R antagonist (sulpiride). In addition, treatment with MA resulted in dopaminergic impairments, which were attenuated by CB1R knockout or CB1R antagonists (i.e., AM251 and rimonabant). Consistently, MA-induced oxidative stresses (i.e., protein oxidation, lipid peroxidation and reactive oxygen species) and pro-apoptotic changes (i.e., increases in Bax, cleaved PKCdelta- and cleaved caspase 3-expression and decrease in Bcl-2 expression) were observed in the striatum of CB1R (+/+) mice. These toxic effects were attenuated by CB1R knockout or CB1R antagonists. Consistently, treatment with four high doses of CB1R agonists (i.e., WIN 55,212-2 36mg/kg and ACEA 16mg/kg) also resulted in significant oxidative stresses, pro-apoptotic changes, and dopaminergic impairments. Since CB1R co-immunoprecipitates PKCdelta in the presence of MA or CB1R agonists, we applied PKCdelta knockout mice to clarify the role of PKCdelta in the neurotoxicity elicited by CB1Rs. CB1R agonist induced toxic effects were significantly attenuated by CB1R knockout, CB1R antagonists or PKCdelta knockout. Therefore, our results suggest that interaction between D2R, ERK and CB1R is critical for MA-induced dopaminergic neurotoxicity and that PKCdelta mediates dopaminergic damage induced by high-doses of CB1R agonist. PMID- 28363603 TI - Oxidative DNA damage & repair: An introduction. AB - This introductory article should be viewed as a prologue to the Free Radical Biology & Medicine Special Issue devoted to the important topic of Oxidatively Damaged DNA and its Repair. This special issue is dedicated to Professor Tomas Lindahl, co-winner of the 2015 Nobel Prize in Chemistry for his seminal discoveries in the area repair of oxidatively damaged DNA. In the past several years it has become abundantly clear that DNA oxidation is a major consequence of life in an oxygen-rich environment. Concomitantly, survival in the presence of oxygen, with the constant threat of deleterious DNA mutations and deletions, has largely been made possible through the evolution of a vast array of DNA repair enzymes. The articles in this Oxidatively Damaged DNA & Repair special issue detail the reactions by which intracellular DNA is oxidatively damaged, and the enzymatic reactions and pathways by which living organisms survive such assaults by repair processes. PMID- 28363607 TI - End-of-Rotation Examinations in Canadian Obstetrics and Gynaecology Residency Programs: The Perspectives of Faculty Members and Residents. AB - The Royal College Competence by Design curriculum in obstetrics and gynaecology will launch in 2019, and it will depend heavily on multiple tools for accurate resident assessment. Several Canadian obstetrics and gynaecology residency programs use rotation-specific examinations at the end of various rotations for formative feedback. The obstetrics and gynaecology residency program at the University of Toronto adopted end-of-rotation examinations (EOREs) in 2014. We conducted a national survey to assess the current use of EOREs across Canada and to examine the attitudes and beliefs of residents and program directors regarding their use. We discuss faculty and resident experiences with EOREs and their perceptions of them. We also consider the role and benefit of these examinations in the context of the educational literature, and how they may integrate with future competency-based medical education frameworks. PMID- 28363608 TI - Interpregnancy Interval and Adverse Perinatal Outcomes: A Record-Linkage Study Using the Manitoba Population Research Data Repository. AB - OBJECTIVE: To examine the association between the interpregnancy interval (IPI) and preterm birth, low birth weight, and SGA birth in a developed country with universal health coverage. METHODS: We conducted a secondary analysis of data housed at the Manitoba Centre for Health Policy. All live births in Manitoba hospitals over a 29-year period were identified and consecutive births to the same mother were grouped into sibling pairs to calculate the IPI for the younger siblings. Logistic regression models were fit to examine the association between the IPI and adverse perinatal outcomes, adjusted for potentially confounding sociodemographic and clinical factors. RESULTS: In a cohort of more than 171 000 births and relative to IPIs of 18 to 23 months, IPIs shorter than 12 and longer than 23 months were associated with significantly increased odds of preterm birth overall and both medically indicated and spontaneous preterm births, low birth weight, and SGA birth. The strongest association observed was for intervals shorter than 6 months and spontaneous preterm birth (adjusted OR 1.83, 95% CI 1.65-2.03). When the outcome was modelled as GA categories, the strongest association observed was for intervals shorter than 6 months and early preterm birth (<34 weeks' GA; adjusted OR 2.47, 95% CI 2.07-2.94). CONCLUSION: If the associations observed between the IPI and adverse perinatal outcomes in this large, population-based cohort are causal, birth spacing could form an important target of public health messaging in Canada. PMID- 28363609 TI - Maternal-Fetal Monitoring of Opioid-Exposed Pregnancies: Analysis of a Pilot Community-Based Protocol and Review of the Literature. AB - OBJECTIVES: To describe/analyse a novel, community-based prenatal monitoring protocol for opioid-exposed pregnancies developed by our centre in 2014 to optimize prenatal care for this population. A literature review of published monitoring protocols for this population is also presented. METHODS: Retrospective comparison of pre-protocol (n = 215) and post-protocol (n = 251) cohorts. Medline and Embase were searched between 2000-2016 using MeSH terms: [fetal monitoring OR prenatal care] AND [opioid-related disorders OR substance related disorders] in Medline and [fetal monitoring OR prenatal care] AND [opiate addiction OR substance abuse] in Embase, producing 518 results. Thirteen studies included protocols for monitoring opioid-exposed pregnancies. No comprehensive monitoring protocols with high-quality supporting evidence were found. RESULTS: We evaluated 466 opioid-exposed pregnancies, 215 before and 251 after introduction of the protocol. Since implementation, there was a significant increase in the number of opioid-exposed patients who have underwent urine drug screening (72.6% to 89.2%, P < 0.0001); a significant reduction in the number of urine drug screenings positive for illicit opioids (50.2% to 29.1%, P < 0.0001); and a significant increase in the number of patients who discontinued illicit opioid use by the time of delivery (24.7% to 39.4%, P < 0.01). There was no difference in the CS rate (27.4% vs. 26.3%, P > 0.05). There were no observed differences in the rate of preterm birth, birth weight <2500 g, or Apgar score <7 (P > 0.05). CONCLUSIONS: Care of women with increased opioid use during pregnancy is an important but under-studied health issue. A novel protocol for focused antenatal care provision for women with opioid-exposed pregnancies improves standard of care and maternal/fetal outcomes. PMID- 28363610 TI - Unnecessary overuse. Study of "inadvisable practices" for patients with atrial fibrillation. AB - OBJECTIVE: To identify overuse (diagnostic, therapeutic and self-care practices that represent risks that outweigh the potential benefits) in patients with atrial fibrillation. METHOD: The study was based on qualitative research techniques. Using the "Metaplan" technique, we identified and ordered potentially inappropriate, ineffective and inefficient practices. By means of a consensus conference, we then established a number of "inadvisable practice" measures (relatively common practices that should be eliminated based on the scientific evidence or clinical experience). Professionals from the specialties of cardiology, haematology, neurology, internal medicine, family medicine and nursing participated in the consensus. RESULTS: We developed a catalogue of 19 "inadvisable practices" related to the diagnosis, treatment and care of anticoagulated patients that were inappropriate, had questionable effectiveness or were ineffective, as well as 13 beliefs or behaviours for anticoagulated patients that could result in injury or were useless or inefficient. CONCLUSION: The "inadvisable practices" approach helps identify practices that represent greater risks than benefits for patients. It seems appropriate to include algorithms in the clinical decision-making support systems that consider this information for the diagnosis, treatment and for home care. For this last case, recommendations have also been prepared that define specific contents for the healthcare education of these patients. PMID- 28363611 TI - New Insight in a New Entity: NIFTPS and Valuable Role of Ancillary Techniques. The Role of PD-L1. PMID- 28363612 TI - Programmed Death - Ligand 1 Expression Distinguishes Invasive Encapsulated Follicular Variant of Papillary Thyroid Carcinoma from Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features. AB - BACKGROUND: The noninvasive Encapsulated follicular variant of papillary thyroid cancer (EFVPTC) has been reclassified as Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) without a significant risk for malignant behavior. However the evaluation remains a challenge for clinicians. We sought to determine whether programmed death-ligand 1 (PD-L1) expression may serve as a biomarker to predict invasiveness of EFVPTC and assist to distinguish these neoplasms from NIFTP. METHODS: Immunohistochemical staining of PD-L1 expression was performed in sections of 174 Formalin-fixed paraffin-embedded (FFPE) tissue blocks from surgery removed thyroid nodules. RESULTS: Cytoplasmic PD-L1 expression was significantly increased in invasive EFVPTC (4.76+/-1.49) as compared to NIFTP (3.06+/-2.16, p<0.001). Increased cytoplasmic PD-L1 expression was associated with invasiveness in EFVPTC (p<0.001); PD-L1 positive EFVPTC cases were at 3.16 folds higher risk in developing invasion than the PD-L1 negative cases. No significant difference in cytoplasmic PD-L1 expression was observed between NIFTP and benign nodules. CONCLUSION: PD-L1 expression may serve as a useful biomarker in predicting invasiveness of EFVPTC and distinguishing NIFTP from invasive EFVPTC. To our knowledge this is the first report suggesting the application of a protein biomarker to confirm NIFTP as benign indolent neoplasms. PMID- 28363613 TI - "Determining fluid responsiveness in sepsis: The quest continues". PMID- 28363615 TI - Retrospective comparison of the Low Risk Ankle Rules and the Ottawa Ankle Rules in a pediatric population. AB - BACKGROUND: A recent multicenter prospective Canadian study presented prospective evidence supporting the Low Risk Ankle Rules (LRAR) as a means of reducing the number of ankle radiographs ordered for children presenting with an ankle injury while maintaining nearly 100% sensitivity. This is in contrast to a previous prospective study which showed that this rule yielded only 87% sensitivity. OBJECTIVE: It is important to further investigate the LRAR and compare them with the already validated Ottawa Ankle Rules (OAR) to potentially curb healthcare costs and decrease unnecessary radiation exposure without compromising diagnostic accuracy. METHODS: We conducted a retrospective chart review of 980 qualifying patients ages 12months to 18years presenting with ankle injury to a commonly staffed 310 bed children's hospital and auxiliary site pediatric emergency department. RESULTS: There were 28 high-risk fractures identified. The Ottawa Ankle Rules had a sensitivity of 100% (95% CI 87.7-100), specificity of 33.1% (95% CI 30.1-36.2), and would have reduced the number of ankle radiographs ordered by 32.1%. The Low Risk Ankle Rules had a sensitivity of 85.7% (95% CI 85.7-96), specificity of 64.9% (95% CI 61.8-68), and would have reduced the number of ankle radiographs ordered by 63.1%. The latter rule missed 4 high-risk fractures. CONCLUSION: The Low Risk Ankle Rules may not be sensitive enough for use in Pediatric Emergency Departments, while the Ottawa Ankle Rules again demonstrated 100% sensitivity. Further research on ways to implement the Ottawa Ankle Rules and maximize its ability to decrease wait times, healthcare costs, and improve patient satisfaction are needed. PMID- 28363614 TI - Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism. AB - BACKGROUND: Ipilimumab (a monoclonal antibody against CTLA-4) and nivolumab (a humanized antibody against PD-1) target these immune checkpoint pathways and are used for treatment of melanoma and an increasing number of other cancers. However, they may cause immune-related adverse effects (IRAEs). Although many endocrinopathies are known to be IRAEs, primary hypoparathyroidism with severe hypocalcemia has never been reported. This is the first case of hypoparathyroidism as an IRAE presenting to an Emergency Department with acute hypocalcemia. CASE DESCRIPTION: A 73-year-old man with metastatic melanoma presented to the Emergency Department for the chief complaints of imbalance, general muscle weakness, abdominal pain and tingling in extremities. He had wide spread metastasis, and begun immunotherapy with concurrent ipilimumab and nivolumab 1.5months ago. At presentation, he had ataxia, paresthesia in the hands and feet, and abdominal cramping. Magnetic resonance imaging of the brain was unremarkable. He was found to be hypocalcemic with undetectable plasma parathyroid hormone. He was admitted for treatment of symptomatic hypocalcemia and was diagnosed with primary hypoparathyroidism. Shortly afterwards, he had thyrotoxicosis manifesting as tachycardia and anxiety, followed by development of primary hypothyroidism. At 4months after the Emergency Department visit, his parathyroid function and thyroid function had not recovered, and required continued thyroid hormone replacement and calcium and vitamin D treatment for hypocalcemia. CONCLUSIONS: Primary hypoparathyroidism caused by ipilimumab and nivolumab may acute manifest with severe symptomatic hypocalcemia. Emergency care providers should be aware of hypoparathyroidism as a new IRAE in this new era of immuno-oncology. PMID- 28363616 TI - An end-user's guide to the HEART score and pathway. AB - BACKGROUND: Chest pain accounts for a significant percentage of emergency department (ED) presentations. The HEART score and pathway have demonstrated an ability to appropriately risk stratify and discharge from the ED a significant proportion of patients. OBJECTIVE: This review evaluates vital components of the HEART score and pathway, while discussing important considerations for current and future use. DISCUSSION: Chest pain is a common ED presentation, and several conditions associated with chest pain result in patient morbidity and mortality. One major disease is acute coronary syndrome (ACS). Despite the fear associated with this disease, it accounts for a minority of patients with chest pain in the ED. Emergency physicians rarely miss myocardial infarction (MI) or ACS, with miss rates<1%. Many have sought a score and pathway that allow physicians to safely and reliably risk stratify patients. The HEART score and pathway have revolutionized chest pain evaluation, as they can risk stratify a significant number of patients accurately into separate categories based on history, electrocardiogram (ECG), troponin, age, and risk factors while displaying high sensitivity for MACE. Several intricacies must be considered in the use of this score including risk factors, ECG, troponin, age, history, gestalt, follow up, borderline score, and shared decision making. The HEART pathway can supplement clinician decision making. CONCLUSIONS: Appropriate use of the HEART pathway reliably risk stratifies patients. Physicians must consider several key components when utilizing the HEART pathway, and future directions may incorporate other patient factors. PMID- 28363617 TI - Exploring the best predictors of fluid responsiveness in patients with septic shock. AB - OBJECTIVE: To evaluate respiratory variations in carotid and brachial peak velocity and other hemodynamic parameters to predict responsiveness to fluid challenge. METHODS: A prospective observational study was performed on mechanically ventilated patients with septic shock. Outcomes included the measurements of central venous pressure, intrathoracic blood volume index, stroke volume variation (SVV), pleth variability index(PVI), and ultrasound assessments of respiratory variations in inferior vena cava diameter (DeltaIVC), carotid Doppler peak velocity (DeltaCDPV), and brachial artery peak velocity (DeltaVpeak brach). RESULTS: All patients received 200 mL normal saline challenge. There were 27 responders and 22 non-responders. Responders had higher SVV, PVI, DeltaIVC, DeltaCDPV, and DeltaVpeak brach measurements. In addition, all these measurements had statistically significant linear correlations with changes in cardiac index (CI).When responders were defined by DeltaCI>=10%, receiver operating characteristics (ROC) curve analysis showed that fluid responsiveness could be predicted:11.5% optimal cut-off 1evels of SVV with sensitivity of 75% and specificity of 85%, 15.5% optimal cut-off 1evels of PVI with sensitivity of 65% and specificity of 80%, 20.5% optimal cut-off 1evels of DeltaIVC with sensitivity of 67% and specificity of 77%, 13% optimal cut-off 1evels of DeltaCDPV with sensitivity of 78%% and specificity of 90%, 11.7% optimal cut-off 1evels of DeltaVpeak brach with sensitivity of 70% and specificity of 80%. CONCLUSION: Ultrasound assessment of DeltaIVC and DeltaVpeak brach, especially DeltaCDPV, could predict fluid responsiveness and might be recommended as a continuous and noninvasive method to monitor functional hemodynamic parameter in mechanically ventilated patients with septic shock. PMID- 28363618 TI - Extracorporeal CPR and intra-aortic balloon pumping in tachycardia-induced cardiomyopathy complicating cardiac arrest. AB - Although tachycardia-induced cardiomyopathy (TIC) due to atrial fibrillation occurs frequently, it is under-recognized in clinical settings. TIC has a wide range of clinical manifestations, from asymptomatic tachycardia to cardiomyopathy leading to end stage heart failure. We present a case of a 48year-old-woman who presented as cardiogenic shock, and rapidly progressed to cardiac arrest from recently diagnosed but undertreated atrial fibrillation, resulting TIC in the emergency department (ED). She was rescued by extracorporeal cardiopulmonary resuscitation (E-CPR) for refractory cardiac arrest in the ED, and received concomitant intra-aortic balloon counterpulsation (IABP) support for severe left ventricular failure. Cardiogenic shock can present as an initial manifestation of TIC, and E-CPR and subsequent IABP support can be a valuable rescue therapy for severe TIC. PMID- 28363619 TI - Body mass index and outcome of out-of-hospital cardiac arrest patients not treated by targeted temperature management. AB - BACKGROUND: Obesity has been demonstrated to increase the risk of out-of-hospital cardiac arrest (OHCA) and may influence the quality and effectiveness of cardiopulmonary resuscitation. Our aim was to investigate the association between body mass index (BMI) and the outcome of OHCA victims not treated by targeted temperature management. METHODS: This was a prospective observational study of OHCA patients. The patients were categorized according to BMI into two groups: the normal BMI group (nBMI) and the elevated BMI group (eBMI). The primary endpoint was return of spontaneous circulation (ROSC), while secondary outcomes were survival to intensive care unit (ICU) admission and survival to ICU discharge. RESULTS: Of the initial 99 patients who were transported to the Emergency Department, 84 (85%) were included in the study. Mean BMI was 29.8kg/m2. Thirteen (15.5%) patients achieved ROSC and were admitted to the ICU, with the mean duration of ICU length of stay being 6.7+/-4.9days. Survival to ICU admission and ICU discharge were higher in the eBMI group (17.6% vs. 6.25%, p=0.010 and 10.3% vs. 6.25%, p=0.021, respectively). Survival to ICU discharge was higher in ventricular fibrillation patients compared to patients with non shockable rhythms, irrespectively of their BMI (p=0.002). All patients that survived to ICU discharge did so with a cerebral performance category score of 2. CONCLUSIONS: Survival to ICU admission and ICU discharge were higher in the eBMI group. PMID- 28363621 TI - The utility of Tdap in the Emergency Department. PMID- 28363620 TI - Usefulness of glycated hemoglobin A1c-based adjusted glycemic variables in diabetic patients presenting with acute ischemic stroke. AB - Acute hyperglycemia is a common condition among patients with diabetes who are admitted to the emergency department (ED) for acute ischemic stroke (AIS). Previous findings regarding the association between hyperglycemia at admission and adverse outcomes among patients with diabetes and AIS have been inconsistent. When investigating this association, it is necessary to consider premorbid blood glucose control. The objective of the current study was to assess whether HbA1c based adjusted glycemic variables were associated with unfavorable outcomes among patients admitted to the hospital for AIS. We retrospectively analyzed data from 309 patients who were hospitalized for AIS at a single medical center in Taiwan between January 1, 2013, and October 31, 2015. We found that 1) HbA1c-based adjusted glycemic variables, including the glycemic gap and stress hyperglycemia ratio, were associated with both AIS severity and neurological status at discharge; additionally, 2) HbA1c-based adjusted glycemic variables showed superior discriminative power compared with acute hyperglycemia regarding the development of severe AIS. We conclude that both the glycemic gap and stress hyperglycemia ratio might be useful in assessing the disease severity and prognosis of patients presenting with AIS. Further prospective long-term follow up studies should be performed to validate these findings. PMID- 28363622 TI - Response to: Students' participation in collaborative research should be recognised. PMID- 28363623 TI - External hernia of the supravesical fossa: Rare or simply misidentified? AB - BACKGROUND: External hernias of the supravesical fossa are considered rare, perhaps wrongly. Highlighting clinical and anatomical features could be useful for correct, preoperative diagnosis, thus avoiding the risk of complications such as incarceration. The study aims to demonstrate that the incidence of external protrusions of the supravesical fossa is higher that supposed. Probably, being mistaken for direct hernias, these hernia types are misidentified and not included in current classifications. This issue deserves attention due to the elevated risk of incarceration related to its distinctive structure. MATERIAL AND METHODS: 249 consecutive open anterior inguinal hernia procedures were analyzed. Hernias were categorized according to the Nyhus classification. A subgroup of direct hernias involved true hernias of the supravesical fossa. Multiple ipsilateral, as well as combined hernias having a multi-component structure, were also considered. RESULTS: 13 true hernias of the supravesical fossa and 19 multiple ipsilateral or combined hernias composed of direct and/or indirect hernia, together with one hernia of the supravesical fossa were identified. 4 true hernias of the supravesical fossa presented signs of incarceration. In three other combined protrusions, the herniated component of the supravesical fossa also showed incarceration of the visceral content. CONCLUSIONS: Hernias of the supravesical fossa would appear to be more frequent than imagined. These protrusions show a diverticular shape and the base is often tightened by the stiffer medial umbilical fold. This explains the apparently higher tendency to incarceration that distinguishes this hernia type. Preoperative signs of inguinal pain and irreducibility are pathognomonic for correct diagnosis. In these cases, surgical treatment in the short term is recommended. PMID- 28363624 TI - Surgical management of hydatid Bilio-bronchial fistula by exclusive thoracotomy. AB - In the industrialized countries, most of Bilio-bronchial fistula are secondary to hepatobiliary trauma, hepatic resection surgery or in the case of congenital malformation of the biliary tract, Bilio-bronchial fistula is recognized as the complication of a number of infectious pathologies such as hydatidosis and hepatic amoebiasis. Among the causes, the Bilio-bronchial fistula of hydatic origin is by far the most frequent especially in the zones of hydatid endemic as Morocco. It is a serious complication of liver hydatid cysts. The surgical management has long been believed to be difficult, and often associated with a very pejorative prognosis due to the simultaneous attack of the thoracic and abdominal stage through the diaphragm. This tripartite involvement reflects the difficulty of choosing the first approach between the thoracic, abdominal or a combination of both approaches. However, progress, especially in the possibility of carrying out adequate preoperative preparation with the increasing introduction of retrograde endoscopic cholangiography with sphincterotomy, has made possible this exclusive thoracotomy surgery with acceptable outcomes. PMID- 28363625 TI - Quantifying neuromuscular ultrasound in amyotrophic lateral sclerosis. PMID- 28363626 TI - Validating Signs and Symptoms From An Actual Mass Casualty Incident to Characterize An Irritant Gas Syndrome Agent (IGSA) Exposure: A First Step in The Development of a Novel IGSA Triage Algorithm. AB - CONTRIBUTION TO EMERGENCY NURSING PRACTICE: * Chemical exposures daily pose a significant threat to life. Rapid assessment by first responders/emergency nurses is required to reduce death and disability. Currently, no informatics tools for Irritant Gas Syndrome Agents (IGSA) exposures exist to process victims efficiently, continuously monitor for latent signs/symptoms, or make triage recommendations. * This study uses actual patient data from a chemical incident to characterize and validate signs/symptoms of an IGSA Syndrome. Validating signs/symptoms is the first step in developing new emergency department informatics tools with the potential to revolutionize the process by which emergency nurses manage triage victims of chemical incidents. ABSTRACTINTRODUCTION: Chemical exposures can pose a significant threat to life. Rapid assessment by first responders/emergency nurses is required to reduce death and disability. Currently, no informatics tools for irritant gas syndrome agents (IGSA) exposures exist to process victims efficiently, continuously monitor for latent signs/symptoms, or make triage recommendations. This study describes the first step in developing ED informatics tools for chemical incidents: validation of signs/symptoms that characterize an IGSA syndrome. METHODS: Data abstracted from 146 patients treated for chlorine exposure in one emergency department during a 2005 train derailment and 152 patients not exposed to chlorine (a comparison group) were mapped to 93 possible signs/symptoms within 2 tools (WISER and CHEMM-IST) designed to assist emergency responders/emergency nurses with managing hazardous material exposures. Inferential statistics (chi2/Fisher's exact test) and diagnostics tests were used to examine mapped signs/symptoms of persons who were and were not exposed to chlorine. RESULTS: Three clusters of signs/symptoms are statistically associated with an IGSA syndrome (P < .01): respiratory (shortness of breath, wheezing, coughing, and choking); chest discomfort (tightness, pain, and burning), and eye, nose and/or throat (pain, irritation, and burning). The syndrome requires the presence of signs/symptoms from at least 2 of these clusters. The latency period must also be considered for exposed/potentially exposed persons. DISCUSSION: This study uses actual patient data from a chemical incident to characterize and validate signs/symptoms of an IGSA syndrome. Validating signs/symptoms is the first step in developing new ED informatics tools with the potential to revolutionize the process by which emergency nurses manage triage victims of chemical incidents. PMID- 28363627 TI - Evaluation of a Nurse-Initiated Acute Gastroenteritis Pathway in the Pediatric Emergency Department. AB - PROBLEM: Acute gastroenteritis (AGE) is a common illness treated in the emergency department. Delays in initiating rehydration for children with mild or moderate dehydration from AGE can lead to prolonged ED visits and increased resource utilization that do not provide prognostic value or support family-centered care. The purpose of this quality improvement project was to promote early oral rehydration therapy (ORT) for persons with AGE in an attempt to reduce unnecessary resource utilization and length of stay (LOS). METHODS: This prospective quality improvement project used a nurse-initiated waiting room ORT pathway for patients 6 months to 21 years of age who presented to the emergency department with diarrhea with or without vomiting. Outcomes related to nurse initiated ORT, intravenous fluid use, laboratory studies or diagnostic imaging, and LOS were measured before and after implementation. RESULTS: Of 643 patients for whom the pathway was initiated, 392 received nurse-initiated care. The proportion of intravenous fluid use was 10.2% lower (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.27-0.68) and laboratory test ordering was 7.4% lower (OR, 0.64; 95% CI, 0.43-0.94) in patients receiving nurse-initiated care. Time to discharge after provider examination was 46 minutes faster in the nurse-initiated care group (P < .001), resulting in an overall LOS reduction by 40 minutes (P < .001). IMPLICATIONS FOR PRACTICE: Nurse autonomy in using an AGE pathway facilitates evidence-based practice, improves ED efficiency, and decreases resource utilization and LOS. Future research should focus on family satisfaction and ED revisits within 72 hours of discharge. PMID- 28363628 TI - Semiquantitative Assessment of Tumor Spread through Air Spaces (STAS) in Early Stage Lung Adenocarcinomas. AB - INTRODUCTION: Tumor spread through air spaces (STAS) has recently been reported as a form of tumor invasion having an unfavorable prognosis, but the significance of a small amount of STAS is not known. The aim of this study was to perform a semiquantitative assessment of STAS. METHODS: Small (<=2 cm) stage I lung adenocarcinomas surgically resected at our institution between 2003 and 2009 were assessed semiquantitatively in the most prominent area as no STAS, low STAS (1-4 single cells or clusters of STAS), or high STAS (>=5 single cells or clusters of STAS) by using a 20* objective and a 10* ocular lens. A statistical analysis was performed to determine the impact of clinicopathologic parameters on STAS and to clarify the relationship between STAS and patient survival. RESULTS: STAS was assessed as no STAS in 109 of 208 cases (52.4%), as low STAS in 38 cases (18.3%), and as high STAS in 61 cases (29.3%). There were statistically significant associations between higher STAS and solid predominant invasive adenocarcinoma (p < 0.001), pleural invasion (p < 0.001), lymphatic invasion (p < 0.001), vascular invasion (p < 0.001), and tumor size of 10 mm or more (p = 0.037). There was a significant association between increasing STAS and shorter recurrence-free survival (RFS) in univariate analysis (no STAS, 154.2 months; low STAS, 147.6 months; and high STAS, 115.6 months). In a multivariate Cox proportional hazards model, only STAS (p = 0.015) remained a significant predictor of RFS. CONCLUSIONS: We found that one-third of resected small adenocarcinomas had high STAS. Higher STAS was predictive of worse RFS. PMID- 28363631 TI - Erratum to (421) a novel, non-opioid, conesnail peptide-based analgesic as a therapeutic alternative for the treatment of chronic pain. J Pain 17:S79-S80, 2016. PMID- 28363630 TI - Erratum to Archer KR, Devin CJ, Vanston SW, Koyama T, Phillips SE, Mathis SL, George SZ, McGirt MJ, Spengler DM, Aaronson OS, Cheng JS, Wegener ST: Cognitive Behavioral-Based Physical Therapy for Patients With Chronic Pain Undergoing Lumbar Spine Surgery: A Randomized Controlled Trial. J Pain 17:76-89, 2016. PMID- 28363629 TI - Juvenile hemochromatosis and hepatocellular carcinoma in a patient with a novel mutation in the HJV gene. AB - Juvenile hemochromatosis is a rare but the most severe form of hereditary hemochromatosis which develops due to mutations in the HJV or HAMP genes. It presents in the early adulthood mainly as cardiomyopathy, hypogonadism and liver fibrosis. Unlike hereditary hemochromatosis due to HFE mutation, hepatocellular carcinoma is not known to be associated with juvenile hemochromatosis. Here, we report a patient of Arab ancestry who presented with severe cardiomyopathy. Sequence analysis of the HJV gene followed by homozygosity mapping, identified a previously undescribed homozygous missense variation in exon 3 (c.497A > G; p.H166R) in both the proband and his clinically asymptomatic brother. The former, later developed hepatocellular carcinoma. To the best of our knowledge, neither the mutation identified in our patient, nor a case of juvenile hemochromatosis with hepatocellular carcinoma has been reported before. PMID- 28363632 TI - Regional localization of activin-betaA, activin-betaC, follistatin, proliferation, and apoptosis in adult and developing mouse prostate ducts. AB - Activins and inhibins, members of the TGF-beta superfamily, are growth and differentiation factors involved in the regulation of several biological processes, including reproduction, development, and fertility. Previous studies have shown that the activin-betaA subunit plays a pivotal role in prostate development. Activin-A inhibits branching morphogenesis in the developing prostate, and its expression is associated with increased apoptosis in the adult prostate. Follistatin, a structurally unrelated protein to activins, is an antagonist of activin-A. A balance between endogenous activin-A and follistatin is required to maintain prostatic branching morphogenesis. Deregulation of this balance leads to branching inhibition or excessive branching and increased maturation of the stroma surrounding the differentiating epithelial ducts. Recent work identified another member of the TGF-beta superfamily, the activin-betaC subunit, as a novel antagonist of activin-A. Over-expression of activin-C (betaC betaC) alters prostate homeostasis, by interfering with the activin-A signaling. The current study characterized the spatiotemporal localization of activin-A, activin-C and follistatin in the adult and developing mouse prostate using immunohistochemical analysis. Results showed activin-C and follistatin are differentially expressed during prostate development and suggested that the antagonistic property of follistatin is secondary to the action of activin-C. In conclusion, the present study provides evidence to support a role of activin-C in prostate development and provides new insights in the spatiotemporal localization of activins and their antagonists during mouse prostate development. PMID- 28363633 TI - High resolution methylation analysis of the HoxA5 regulatory region in different somatic tissues of laboratory mouse during development. AB - Homeobox genes encode a group of DNA binding regulatory proteins whose key function occurs in the spatial-temporal organization of genome during embryonic development and differentiation. The role of these Hox genes during ontogenesis makes it an important model for research. HoxA5 is a member of Hox gene family playing a central role during axial body patterning and morphogenesis. DNA modification studies have shown that the function of Hox genes is partly governed by the methylation-mediated gene expression regulation. Therefore the study aimed to investigate the role of epigenetic events in regulation of tissue-specific expression pattern of HoxA5 gene during mammalian development. The methodology adopted were sodium bisulfite genomic DNA sequencing, quantitative real-time PCR and chromatin-immunoprecipitation (ChIP). Methylation profiling of HoxA5 gene promoter shows higher methylation in adult as compared to fetus in various somatic tissues of mouse being highest in adult spleen. However q-PCR results show higher expression during fetal stages being highest in fetal intestine followed by brain, liver and spleen. These results clearly indicate a strict correlation between DNA methylation and tissue-specific gene expression. The findings of chromatin-immunoprecipitation (ChIP) have also reinforced that epigenetic event like DNA methylation plays important role in the regulation of tissue specific expression of HoxA5. PMID- 28363634 TI - Diffuse Abdominal Pain and Fever in an Elderly Man. PMID- 28363635 TI - Glycogen synthase kinase-3 (GSK3) regulates TNF production and haemocyte phagocytosis in the immune response of Chinese mitten crab Eriocheir sinensis. AB - Glycogen synthase kinase-3 (GSK3) is a serine/threonine protein kinase firstly identified as a regulator of glycogen synthesis. Recently, it has been proved to be a key regulator of the immune reaction. In the present study, a GSK3 homolog gene (designated as EsGSK3) was cloned from Chinese mitten crab, Eriocheir sinensis. The open reading frame (ORF) was 1824 bp, which encoded a predicted polypeptide of 607 amino acids. There was a conserved Serine/Threonine Kinase domain and a DNA binding domain found in EsGSK3. Phylogenetic analysis showed that EsGSK3 was firstly clustered with GSK3-beta from oriental river prawn Macrobrachium nipponense in the invertebrate branch, while GSK3s from vertebrates formed the other distinct branch. EsGSK3 mRNA transcripts could be detected in all tested tissues of the crab including haepatopancreas, eyestalk, muscle, gonad, haemocytes and haematopoietic tissue with the highest expression level in haepatopancreas. And EsGSK3 protein was mostly detected in the cytoplasm of haemocyte by immunofluorescence analysis. The expression levels of EsGSK3 mRNA increased significantly at 6 h after Aeromonas hydrophila challenge (p < 0.05) in comparison with control group, and then gradually decreased to the initial level at 48 h (p > 0.05). The mRNA expression of lipopolysaccharide-induced tumor necrosis factor (TNF)-alpha factor (EsLITAF) was also induced by A. hydrophila challenge. However, the mRNA expression of EsLITAF and TNF-alpha production was significantly suppressed after EsGSK3 was blocked in vivo with specific inhibitor lithium, while the phagocytosis of crab haemocytes was significantly promoted. These results collectively demonstrated that EsGSK3 could regulate the innate immune responses of E. sinensis by promoting TNF-alpha production and inhibiting haemocyte phagocytosis. PMID- 28363636 TI - Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised study. AB - BACKGROUND: DSM265 is a novel antimalarial that inhibits plasmodial dihydroorotate dehydrogenase, an enzyme essential for pyrimidine biosynthesis. We investigated the safety, tolerability, and pharmacokinetics of DSM265, and tested its antimalarial activity. METHODS: Healthy participants aged 18-55 years were enrolled in a two-part study: part 1, a single ascending dose (25-1200 mg), double-blind, randomised, placebo-controlled study, and part 2, an open-label, randomised, active-comparator controlled study, in which participants were inoculated with Plasmodium falciparum induced blood-stage malaria (IBSM) and treated with DSM265 (150 mg) or mefloquine (10 mg/kg). Primary endpoints were DSM265 safety, tolerability, and pharmacokinetics. Randomisation lists were created using a validated, automated system. Both parts were registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12613000522718 (part 1) and number ACTRN12613000527763 (part 2). FINDINGS: In part 1, 73 participants were enrolled between April 12, 2013, and July 14, 2015 (DSM265, n=55; placebo, n=18). In part 2, nine participants were enrolled between Sept 30 and Nov 25, 2013 (150 mg DSM265, n=7; 10 mg/kg mefloquine, n=2). In part 1, 117 adverse events were reported; no drug-related serious or severe events were reported. The most common drug-related adverse event was headache. The mean DSM265 peak plasma concentration (Cmax) ranged between 1310 ng/mL and 34 800 ng/mL and was reached in a median time (tmax) between 1.5 h and 4 h, with a mean elimination half-life between 86 h and 118 h. In part 2, the log10 parasite reduction ratio at 48 h in the DSM265 (150 mg) group was 1.55 (95% CI 1.42-1.67) and in the mefloquine (10 mg/kg) group was 2.34 (2.17-2.52), corresponding to a parasite clearance half life of 9.4 h (8.7-10.2) and 6.2 h (5.7-6.7), respectively. The median minimum inhibitory concentration of DSM265 in blood was estimated as 1040 ng/mL (range 552-1500), resulting in a predicted single efficacious dose of 340 mg. Parasite clearance was significantly faster in participants who received mefloquine than in participants who received DSM265 (p<0.0001). INTERPRETATION: The good safety profile, long elimination half-life, and antimalarial effect of DSM265 supports its development as a partner drug in a single-dose antimalarial combination treatment. FUNDING: Wellcome Trust, UK Department for International Development, Global Health Innovative Technology Fund, Bill & Melinda Gates Foundation. PMID- 28363638 TI - Investment in antimalarial drug development is bearing fruit. PMID- 28363637 TI - DSM265 for Plasmodium falciparum chemoprophylaxis: a randomised, double blinded, phase 1 trial with controlled human malaria infection. AB - BACKGROUND: A drug for causal (ie, pre-erythrocytic) prophylaxis of Plasmodium falciparum malaria with prolonged activity would substantially advance malaria control. DSM265 is an experimental antimalarial that selectively inhibits the parasite dihydroorotate dehydrogenase. DSM265 shows in vitro activity against liver and blood stages of P falciparum. We assessed the prophylactic activity of DSM265 against controlled human malaria infection (CHMI). METHODS: At the Institute of Tropical Medicine, Eberhard Karls University (Tubingen, Germany), healthy, malaria-naive adults were allocated to receive 400 mg DSM265 or placebo either 1 day (cohort 1A) or 7 days (cohort 2) before CHMI by direct venous inoculation (DVI) of 3200 aseptic, purified, cryopreserved P falciparum sporozoites (PfSPZ Challenge; Sanaria Inc, Rockville, MD, USA). An additional group received daily atovaquone-proguanil (250-100 mg) for 9 days, starting 1 day before CHMI (cohort 1B). Allocation to DSM265, atovaquone-proguanil, or placebo was randomised by an interactive web response system. Allocation to cohort 1A and 1B was open-label, within cohorts 1A and 2, allocation to DSM265 and placebo was double-blinded. All treatments were given orally. Volunteers were treated with an antimalarial on day 28, or when parasitaemic, as detected by thick blood smear (TBS) microscopy. The primary efficacy endpoint was time-to-parasitaemia, assessed by TBS. All participants receiving at least one dose of chemoprophylaxis or placebo were considered for safety, those receiving PfSPZ Challenge for efficacy analyses. Log-rank test was used to compare time-to-parasitemia between interventions. The trial was registered with ClinicalTrials.gov, number NCT02450578. FINDINGS: 22 participants were enrolled between Oct 23, 2015, and Jan 18, 2016. Five participants received 400 mg DSM265 and two participants received placebo 1 day before CHMI (cohort 1A), six participants received daily atovaquone-proguanil 1 day before CHMI (cohort 1B), and six participants received 400 mg DSM265 and two participants received placebo 7 days before CHMI (cohort 2). Five of five participants receiving DSM265 1 day before CHMI and six of six in the atovaquone-proguanil cohort were protected, whereas placebo recipients (two of two) developed malaria on days 11 and 14. When given 7 days before CHMI, three of six volunteers receiving DSM265 became TBS positive on days 11, 13, and 24. The remaining three DSM265-treated, TBS-negative participants of cohort 2 developed transient submicroscopic parasitaemia. Both participants receiving placebo 7 days before CHMI became TBS positive on day 11. The only possible DSM265-related adverse event was a moderate transient elevation in serum bilirubin in one participant. INTERPRETATION: A single dose of 400 mg DSM265 was well tolerated and had causal prophylactic activity when given 1 day before CHMI. Future trials are needed to investigate further the use of DSM265 for the prophylaxis of malaria. FUNDING: Global Health Innovative Technology Fund, Wellcome Trust, Bill & Melinda Gates Foundation through Medicines for Malaria Venture, and the German Center for Infection Research. PMID- 28363641 TI - Our New President- Sheila E. Crowe, MD. PMID- 28363642 TI - Hepatocellular Carcinoma After Sustained Virologic Response: Leave No One Behind. PMID- 28363639 TI - Increased Expression of Cytotoxic T-Lymphocyte-Associated Protein 4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure. AB - BACKGROUND & AIMS: Patients with acute liver failure (ALF) have defects in innate immune responses to microbes (immune paresis) and are susceptible to sepsis. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4), which interacts with the membrane receptor B7 (also called CD80 and CD86), is a negative regulator of T cell activation. We collected T cells from patients with ALF and investigated whether inhibitory signals down-regulate adaptive immune responses in patients with ALF. METHODS: We collected peripheral blood mononuclear cells from patients with ALF and controls from September 2013 through September 2015 (45 patients with ALF, 20 patients with acute-on-chronic liver failure, 15 patients with cirrhosis with no evidence of acute decompensation, 20 patients with septic shock but no cirrhosis or liver disease, and 20 healthy individuals). Circulating CD4+ T cells were isolated and analyzed by flow cytometry. CD4+ T cells were incubated with antigen, or agonist to CD3 and dendritic cells, with or without antibody against CTLA4; T-cell proliferation and protein expression were quantified. We measured levels of soluble B7 molecules in supernatants of isolated primary hepatocytes, hepatic sinusoidal endothelial cells, and biliary epithelial cells from healthy or diseased liver tissues. We also measured levels of soluble B7 serum samples from patients and controls, and mice with acetaminophen-induced liver injury using enzyme-linked immunosorbent assays. RESULTS: Peripheral blood samples from patients with ALF had a higher proportion of CD4+ CTLA4+ T cells than controls; patients with infections had the highest proportions. CD4+ T cells from patients with ALF had a reduced proliferative response to antigen or CD3 stimulation compared to cells from controls; incubation of CD4+ T cells from patients with ALF with an antibody against CTLA4 increased their proliferative response to antigen and to CD3 stimulation, to the same levels as cells from controls. CD4+ T cells from controls up-regulated expression of CTLA4 after 24-48 hours culture with sera from patients with ALF; these sera were found to have increased concentrations of soluble B7 compared to sera from controls. Necrotic human primary hepatocytes exposed to acetaminophen, but not hepatic sinusoidal endothelial cells and biliary epithelial cells from patients with ALF, secreted high levels of soluble B7. Sera from mice with acetaminophen-induced liver injury contained high levels of soluble B7 compared to sera from mice without liver injury. Plasma exchange reduced circulating levels of soluble B7 in patients with ALF and expression of CTLA4 on T cells. CONCLUSIONS: Peripheral CD4+ T cells from patients with ALF have increased expression of CTLA4 compared to individuals without ALF; these cells have a reduced response to antigen and CD3 stimulation. We found sera of patients with ALF and from mice with liver injury to have high concentrations of soluble B7, which up-regulates CTLA4 expression by T cells and reduces their response to antigen. Plasma exchange reduces levels of B7 in sera from patients with ALF and might be used to restore antimicrobial responses to patients. PMID- 28363640 TI - Sphingosine-1-Phosphate Prevents Egress of Hematopoietic Stem Cells From Liver to Reduce Fibrosis. AB - BACKGROUND & AIMS: There is growing interest in the use of bone marrow cells to treat liver fibrosis, however, little is known about their antifibrotic efficacy or the identity of their effector cell(s). Sphingosine-1-phosphate (S1P) mediates egress of immune cells from the lymphoid organs into the lymphatic vessels; we investigated its role in the response of hematopoietic stem cells (HSCs) to liver fibrosis in mice. METHODS: Purified (c-kit+/sca1+/lin-) HSCs were infused repeatedly into mice undergoing fibrotic liver injury. Chronic liver injury was induced in BoyJ mice by injection of carbon tetrachloride (CCl4) or placement on a methionine-choline-deficient diet. Some mice were irradiated and given transplants of bone marrow cells from C57BL6 mice, with or without the S1P antagonist FTY720; we then studied HSC mobilization and localization. Migration of HSC lines was quantified in Transwell assays. Levels of S1P in liver, bone marrow, and lymph fluid were measured using an enzyme-linked immunosorbent assay. Liver tissues were collected and analyzed by immunohistochemical quantitative polymerase chain reaction and sphingosine kinase activity assays. We performed quantitative polymerase chain reaction analyses of the expression of sphingosine kinase 1 and 2, sphingosine-1-phosphate lyase 1, and sphingosine-1-phosphate phosphatase 1 in normal human liver and cirrhotic liver from patients with alcohol-related liver disease (n = 6). RESULTS: Infusions of HSCs into mice with liver injury reduced liver scarring based on picrosirius red staining (49.7% reduction in mice given HSCs vs control mice; P < .001), and hepatic hydroxyproline content (328 mg/g in mice given HSCs vs 428 mg/g in control mice; P < .01). HSC infusion also reduced hepatic expression of alpha-smooth muscle actin (0.19 +/- 0.007-fold compared with controls; P < .0001) and collagen type I alpha 1 chain (0.29 +/- 0.17-fold compared with controls; P < .0001). These antifibrotic effects were maintained with infusion of lymphoid progenitors that lack myeloid potential and were associated with increased numbers of recipient neutrophils and macrophages in liver. In studies of HSC cell lines, we found HSCs to recruit monocytes, and this process to require C-C motif chemokine receptor 2. In fibrotic liver tissue from mice and patients, hepatic S1P levels increased owing to increased hepatic sphingosine kinase-1 expression, which contributed to a reduced liver:lymph S1P gradient and limited HSC egress from the liver. Mice given the S1P antagonist (FTY720) with HSCs had increased hepatic retention of HSCs (1697 +/- 247 cells in mice given FTY720 vs 982 +/- 110 cells in controls; P < .05), and further reductions in fibrosis. CONCLUSIONS: In studies of mice with chronic liver injury, we showed the antifibrotic effects of repeated infusions of purified HSCs. We found that HSCs promote recruitment of endogenous macrophages and neutrophils. Strategies to reduce SIP signaling and increase retention of HSCs in the liver could increase their antifibrotic activities and be developed for treatment of patients with liver fibrosis. PMID- 28363644 TI - Juan Rodes-In Memoriam. PMID- 28363643 TI - Genetic Features of Aflatoxin-Associated Hepatocellular Carcinoma. AB - BACKGROUND & AIMS: Dietary exposure to aflatoxin is an important risk factor for hepatocellular carcinoma (HCC). However, little is known about the genomic features and mutations of aflatoxin-associated HCCs compared with HCCs not associated with aflatoxin exposure. We investigated the genetic features of aflatoxin-associated HCC that can be used to differentiate them from HCCs not associated with this carcinogen. METHODS: We obtained HCC tumor tissues and matched non-tumor liver tissues from 49 patients, collected from 1990 through 2016, at the Qidong Liver Cancer Hospital Institute in China-a high-risk region for aflatoxin exposure (38.2% of food samples test positive for aflatoxin contamination). Somatic variants were identified using GATK Best Practices Pipeline. We validated part of the mutations from whole-genome sequencing and whole-exome sequencing by Sanger sequencing. We also analyzed genomes of 1072 HCCs, obtained from 5 datasets from China, the United States, France, and Japan. Mutations in 49 aflatoxin-associated HCCs and 1072 HCCs from other regions were analyzed using the Wellcome Trust Sanger Institute mutational signatures framework with non-negative matrix factorization. The mutation landscape and mutational signatures from the aflatoxin-associated HCC and HCC samples from general population were compared. We identified genetic features of aflatoxin associated HCC, and used these to identify aflatoxin-associated HCCs in datasets from other regions. Tumor samples were analyzed by immunohistochemistry to determine microvessel density and levels of CD34 and CD274 (PD-L1). RESULTS: Aflatoxin-associated HCCs frequently contained C>A transversions, the sequence motif GCN, and strand bias. In addition to previously reported mutations in TP53, we found frequent mutations in the adhesion G protein-coupled receptor B1 gene (ADGRB1), which were associated with increased capillary density of tumor tissue. Aflatoxin-associated HCC tissues contained high-level potential mutation associated neoantigens, and many infiltrating lymphocytes and tumors cells that expressed PD-L1, compared to HCCs not associated with aflatoxin. Of the HCCs from China, 9.8% contained the aflatoxin-associated genetic features, whereas 0.4% 3.5% of HCCs from other regions contained these genetic features. CONCLUSIONS: We identified specific genetic and mutation features of HCCs associated with aflatoxin exposure, including mutations in ADGRB1, compared to HCCs from general populations. We associated these mutations with increased vascularization and expression of PD-L1 in HCC tissues. These findings might be used to identify patients with HCC due to aflatoxin exposure, and select therapies. PMID- 28363646 TI - Characterisation of acid-soluble and pepsin-solubilised collagen from frog (Rana nigromaculata) skin. AB - As the first vertebrates connecting water and land, frogs must have evolved certain specialisations. To find the difference among the collagens from amphibian, fish and mammal animals, acid-soluble collagen (ASC) and pepsin solubilised collagen (PSC) from frog skin were isolated and characterised. The yield of PSC (19.59%, dry weight) was higher than that of ASC (1.83%, dry weight). The hydroxyproline-to-protein ratio of frog skin was 8.37%, which was higher than that of carp skin ASC (7.83%) but significantly lower than that of calf skin collagen (10.16%), which was in accordance with the living environment of frog. The denaturation temperature of frog skin collagens was approximately 31.5 degrees C. The SDS-PAGE electrophoresis revealed that ASC and PSC were type I collagens. Fourier transform infrared spectroscopy proved that the ASC and PSC retained their helical structures. The results indicated the properties of frog skin collagen were close to those of skin collagen from freshwater fish. The frog skin collagens can potentially be used in biomaterial and other fields. PMID- 28363645 TI - Kinetics and mechanics of photo-polymerized triazole-containing thermosetting composites via the copper(I)-catalyzed azide-alkyne cycloaddition. AB - OBJECTIVE: Several features necessary for polymer composite materials in practical applications such as dental restorative materials were investigated in photo-curable CuAAC (copper(I)-catalyzed azide-alkyne cycloaddition) thermosetting resin-based composites with varying filler loadings and compared to a conventional BisGMA/TEGDMA based composite. METHODS: Tri-functional alkyne and di-functional azide monomers were synthesized for CuAAC resins and incorporated with alkyne-functionalized glass microfillers for CuAAC composites. Polymerization kinetics, in situ temperature change, and shrinkage stress were monitored simultaneously with a tensometer coupled with FTIR spectroscopy and a data-logging thermocouple. The glass transition temperature was analyzed by dynamic mechanical analysis. Flexural modulus/strength and flexural toughness were characterized in three-point bending on a universal testing machine. RESULTS: The photo-CuAAC polymerization of composites containing between 0 and 60wt% microfiller achieved ~99% conversion with a dramatic reduction in the maximum heat of reaction (~20 degrees C decrease) for the 60wt% filled CuAAC composites as compared with the unfilled CuAAC resin. CuAAC composites with 60wt% microfiller generated more than twice lower shrinkage stress of 0.43+/-0.01MPa, equivalent flexural modulus of 6.1+/-0.7GPa, equivalent flexural strength of 107+/-9MPa, and more than 10 times higher energy absorption of 10+/-1MJm-3 when strained to 11% relative to BisGMA-based composites at equivalent filler loadings. SIGNIFICANCE: Mechanically robust and highly tough, photo-polymerized CuAAC composites with reduced shrinkage stress and a modest reaction exotherm were generated and resulted in essentially complete conversion. PMID- 28363647 TI - Chitosan/gelatin/platelet gel enriched by a combination of hydroxyapatite and beta-tricalcium phosphate in healing of a radial bone defect model in rat. AB - This study compared the regeneration potentials of the hydroxyapatite (HA) and beta-tricalcium phosphate (beta-TCP) alone or in combination with a HA:TCP ratio of 30:70 in the critical-sized radial bone defects of rats. Bilateral 60 radial bone defects created were randomly divided into six equal groups (n=10 defects/group) including autograft, untreated or defect, chitosan-gelatin platelet gel (CGP), CGP-HA, CGP-TCP and CGP-HA/TCP. The defects were evaluated by radiography, morphology, histopathology, histomorphometry, CT scan, scanning electron microscopy and biomechanical testing after eight weeks. Compared with the untreated and CGP-HA groups, the CGP and CGP-HA/TCP groups showed significantly higher new bone formation, bone volume, and mechanical properties. The CGP-HA and CGP-TCP scaffolds showed low biodegradability, whereas the CGP scaffolds were completely degraded. Osteoconductivity and osteoinductivity of the CGP and CGP-HA/TCP scaffolds were superior to the CGP-HA ones. The untreated and CGP-HA groups repaired mostly through fibrosis, while there were evidence of higher bone formation in the autograft, CGP and CGP-HA/TCP groups. In conclusion, addition of HA or beta-TCP alone into the CGP scaffolds impaired bone regeneration, while bone regeneration with the CGP and CGP-HA/TCP scaffolds was comparable with the autograft. Therefore, the CGP-HA/TCP scaffold can be a possible option to substitute the autologous bone grafting. PMID- 28363648 TI - Studies on electrochemical glucose sensing, antimicrobial activity and cytotoxicity of fabricated copper nanoparticle immobilized chitin nanostructure. AB - In this study, copper nanoparticle immobilized chitin nanocomposite (CNP/CuNP) was synthesized and used for the development of non-enzymatic electrochemical sensor. The CNP/CuNP was characterized by X-ray diffraction (XRD), fourier transform infra red (FTIR) spectroscopy and high resolution transmission electron microscopy (HRTEM) analysis. The glucose sensing property of CNP/CuNP was investigated by cyclic voltammetry (CV) and chronoamperometry (CA). As a result of the synergistic effect of CNP and CuNP, the modified electrode displayed effective electro-oxidation of glucose in 0.1M NaOH solution. At 0.45V potential the modified electrode showed response towards glucose in the linear range of 1 1000MUM with a lowest detection limit of 0.776MUM with better selectivity and stability. In addition, the antimicrobial activity of CNP/CuNP was evaluated against bacterial and fungal strains. CNP/CuNP displayed enhanced antimicrobial activity when compared to CNP and CuNP alone. Similarly, cytotoxicity of CNP/CuNP was tested against Artemia salina, which showed no toxic effect in the tested concentration. PMID- 28363649 TI - Immobilization of Euphorbia tirucalli peroxidase onto chitosan-cobalt oxide magnetic nanoparticles and optimization using response surface methodology. AB - Euphorbia tirucalli peroxidase (ETP) was immobilized on chitosan beads having magnetic properties for the ease of separation and increasing the reusability of ETP for cost effective assay conditions. The present work reports immobilization of ETP on polymeric support chitosan-cobalt oxide beads subsequently activated with 0.05% cynuric chloride. The magnetic immobilized enzyme was characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) analysis and scanning electron microscopy (SEM). The immobilized ETP can be reused up to 10 cycles with retention of more than 60% activity. The optimum pH was shifted from 6.0 to 5.5 for soluble ETP to immobilized ETP and optimum temperature from 50 degrees C and 55 degrees C for the immobilized ETP. Based on response surface methodology, the optimal immobilization conditions obtained were: enzyme concentration, 2mg/286mg beads; optimal pH, 4.93; temperature, 28.88; cynuric chloride concentration, 0.17%; reaction time, 14.4h, which resulted 74.51% maximum immobilization. The enzyme magnetic nanoparticles could be separated magnetically for easy reuse. Immobilization of ETP onto the magnetic nanoparticles could be useful for biotechnological applications and bioassay due to its reusability and improved stability. PMID- 28363650 TI - Role of phosphorylation of phosvitin in the phase transformation of mineralization. AB - Phosvitin is a unique highly phosphorylated protein that plays a role in the regulation of mineralization. This study investigated the role of phosphorylation of phosvitin in the phase transformation of calcium phosphate in the mineralization solution. Partially dephosphorylated phosvitins (T1, T2, T3 and T4) were prepared with 2.98, 19.46, 43.39 and 71.07% of phosphate released from native phosvitin, respectively. And their effect on regulating the phase transformation was investigated, the characterization and composition analysis was performed by circular dichroism, Fourier transform infrared spectroscopy, X ray diffraction and scanning electron microscopy. Results showed that phosvitin in the acceleration effect of phase transformation was dose-concentration effect by pH-stat titration. With lower dephosphorylation degree of phosvitin (<20%), the acceleration effect was weaker than native phosvitin, since phosphorylation and random structure of phosvitin were reduced. However, with higher dephosphorylation degree of phosvitin (>40%), the acceleration effect was enhanced compared to native phosvitin, in which the beta-sheet structure was increased and phosvitin was partially hydrolyzed to phosphopeptides. The acceleration effect of phase transformation was as follows: T4>T3>phosvitin>T1>T2> Control. This study clearly demonstrated that phosphorylation of phosvitin played an important role in the regulation of mineralization. PMID- 28363651 TI - Effects of extraction methods on molecular characteristics, antioxidant properties and immunomodulation of alginates from Sargassum angustifolium. AB - The relationship between molecular structure and bioactivity was evaluated for alginates obtained under different extraction methods (water, acid, alcalase and cellulase) from Sargassum angustifolium. The use of enzymes considerably reduced protein (from 14.58% to <0.4%) and polyphenol (from 16.0% to <1.7mg GA/g sample) contaminations of alginates compared to those of water and acid. The FT-IR spectrum revealed that extraction method did not affect the structure of the recovered alginates. The highest molecular weight (Mw) (557.1*103g/mol) was found in acid treated alginate while the Mw of cellulase assistant alginate (356.2*103g/mol) was the minimum. The SVg values varied from 2.79-5.17cm3/g revealing the loosed conformational structures of alcalase and cellulase assistant alginates. Alcalase assistant alginate stimulated RAW264.7 cells to release nitric oxide and inflammatory cytokines TNF-alpha, IL-1, IL-6, IL-10 and IL-12. Enzyme treated alginates showed maximum DPPH radical scavenging activity and reducing power. Therefore, the present results showed the determinant effect of pretreatment during the extraction process of alginate and the beneficial influence of enzymatic process when biological functions of alginates are of high interest in the industry. PMID- 28363652 TI - FTIR, XRD and DSC studies of nanochitosan, cellulose acetate and polyethylene glycol blend ultrafiltration membranes. AB - In the present work, a series of novel nanochitosan/cellulose acetate/polyethylene glycol (NCS/CA/PEG) blend flat sheet membranes were fabricated in different ratios (1:1:1, 1:1:2, 2:1:1, 2:1:2, 1:2:1, 2:2:1) in a polar solvent of N,N'-dimethylformamide (DMF) using the most popular phase inversion method. Nanochitosan was prepared by the ionotropic gelation method and its average particle size has been analyzed using Dynamic Light Scattering (DLS) method. The effect of blending of the three polymers was investigated using FTIR and XRD studies. FTIR results confirmed the formation of well-blended membranes and the XRD analysis revealed enhanced amorphous nature of the membrane ratio 2:1:2. DSC study was conducted to find out the thermal behavior of the blend membranes and the results clearly indicated good thermal stability and single glass transition temperature (Tg) of all the prepared membranes. Asymmetric nature and rough surface morphology was confirmed using SEM analysis. From the results it was evident that the blending of the polymers with higher concentration of nanochitosan can alter the nature of the resulting membranes to a greater extent and thus amorphous membranes were obtained with good miscibility and compatibility. PMID- 28363653 TI - Dithiocarbamate to modify magnetic graphene oxide nanocomposite (Fe3O4-GO): A new strategy for covalent enzyme (lipase) immobilization to fabrication a new nanobiocatalyst for enzymatic hydrolysis of PNPD. AB - Immobilization of lipase was successfully achieved on the surface of magnetically separable Fe3O4/graphene oxide (GO) via a post-modification. This post modification was achieved in alternation to glutaraldehyde post-modification. The activity of immobilized lipase had not a significant loss in the activity while on the other hand, it is simply extractable (by keeping its major activity) from reaction crude by a magnet. Each step of immobilization was carefully monitored by characterization and all were successfully proved. SEM, TEM, XRD, EDX, and FTIR were used to characterize the support and immobilization process. PMID- 28363654 TI - Production of exopolysaccharides by selected Bacillus strains: Optimization of media composition to maximize the yield and structural characterization. AB - Selected Bacillus strains were investigated for the production of exopolysaccharides (EPS) by fermentation in three different culture media: (i) mineral base-medium with added yeast extract (M1), (ii) succinate-containing mineral base-medium with added yeast extract (M2) and (iii) tryptone and yeast extract-containing base-medium (M3). Modest EPS yield of 6.7g/L was recorded for Bacillus amyloliquefaciens 23350 grown on M1, where the EPS produced was characterized by a low MW (<5kDa) and of being mainly glucans. The most significant yield (48.57g/L) was obtained with Bacillus licheniformis 14580 in M2; the EPS produced was 5-30kDa in size and characterized by an exceptionally heterogeneous monosaccharide profile with galactose, fructose and glucose as the predominating monomers. The use of M1 medium for the growth of B. licheniformis 14580 resulted in low yield; however, the obtained heteropolymers EPS were characterized by a higher MW 30-100kDa. The effect of the concentrations of yeast extract, sodium succinate and sucrose on the EPS production by B. licheniformis 14580 were studied using response surface methodology analysis. Greater EPS yields were achieved with increased concentrations of sodium succinate and sucrose and with decreased concentrations of yeast extract in the mineral media. PMID- 28363655 TI - Structural effect of quaternary ammonium chitin derivatives on their bactericidal activity and specificity. AB - The effect of the quaternary ammonium chitin structure on the bactericidal activity and specificity against Escherichia coli and Staphylococcus aureus was investigated. Quaternary ammonium chitins were synthesized by the separate acylation of chitin (CT) with carboxymethyl trimethylammonium chloride (CMA), 3 carboxypropyl trimethylammonium chloride (CPA) and N-dodecyl-N,N (dimethylammonio)butyrate (DDMAB). The successful acylation was confirmed by newly formed ester linkage. All three derivatives had a higher surface charge than chitin due to the additional positively charged quaternary ammonium groups. The N-short alkyl substituent (methyl) of CTCMA and CTCPA increased the hydrophilicity whilst the N-long alkyl substituent (dodecyl) of CTDDMAB increased the hydrophobicity compared to chitin. Chitin did not exhibit any bactericidal activity, while CTCMA and CTCPA completely killed E. coli and S. aureus in 30 and 60min, respectively, and CTDDMAB completely killed S. aureus in 10min but did not kill E. coli after a 2-h exposure. Therefore, the N-short alkyl substituent was more effective for killing E. coli and the N-long alkyl substituent conferred specific bactericidal activity against S. aureus. PMID- 28363656 TI - Structural variations of lignin macromolecule from different growth years of Triploid of Populus tomentosa Carr. AB - To better understand the variations of structural characteristics of lignin macromolecules during different growth years of Triploid of Populus tomentosa Carr, a novel lignin isolation procedure based on double ball-milling and enzymatic hydrolysis (DEL) was proposed in this study. The morphological distributions of lignin in the plant cell wall of these poplar wood samples were monitored by Confocal Raman Microscopy (CRM). The ultrahigh yields (105.1% 111.2%) of DELs were significantly higher than those (24.4-31.8%) of corresponding cellulolytic enzyme lignins (CELs). DELs and CELs were elaborately characterized by HPAEC, GPC, 2D-HSQC NMR and 31P NMR techniques, and NMR results showed that DEL samples possess similar structural features as compared to CEL counterparts except for the decreased S/G ratio and p-hydroxybenzoate (PB) as well as increased p-hydroxyphenyl units (H). There are no obvious differences in the structural characteristics except for high contents of PB and H units in DEL 1, as well as high S/G ratio and beta-O-4' linkages in DEL-5. It is believed that the DEL proposed in the present study can be used for characterizing the entire structural features of lignin macromolecules in the plant cell wall of different kinds of lignocellulosic biomass. PMID- 28363657 TI - Sulfated modification, characterization, and antioxidant and moisture absorption/retention activities of a soluble neutral polysaccharide from Enteromorpha prolifera. AB - A purified polysaccharide from Enteromorpha prolifera (PEP) with a molecular mass of 147.8kDa, was prepared by hot-water extraction method and purified by anion exchange chromatography and gel filtration chromatography. Low Mw polysaccharide of E. prolifera (LEP, 44.8kDa) was obtained by enzymatic degradation. Sulfated derivatives of the two different Mw polysaccharides were synthesized by chlorosulfonic acid/pyridine method, and the degrees of substitution of SPEP and SLEP were 0.57 and 0.81, respectively. Physicochemical properties and FT-IR spectra showed that enzymatic degradation and sulfated modification of polysaccharides were successful. 13C NMR analysis showed that the sulfate groups mainly attached to C-6 of rhamnose. Moreover, the study revealed that enzymatic degradation and sulfated modification of polysaccharides improved significantly superoxide, hydroxyl and DPPH radicals scavenging activities in vitro, and enhanced obviously moisture absorption/retention capacities. Therefore, these results demonstrated that molecular weight and sulfate groups had obvious effects on antioxidant activities and moisture absorption/retention abilities of the polysaccharides from E. prolifera. PMID- 28363658 TI - Polysaccharides from the peels of Citrus aurantifolia induce apoptosis in transplanted H22 cells in mice. AB - In this study, an acidic polysaccharide (CAs) was extracted and purified from the peels of Citrus aurantifolia by Sephadex G-150. HPGPC showed the molecular weight of CAs was about 7.94*106Da. Ion chromatography (IC) analysis showed CAs was mainly composed of rhamnose (Rha), arabinose (Ara), galactose (Gal), glucose (Glu), mannose (Man) and galacturonic acid (GalA), with the molar ratio of 0.67: 7.67: 10.83: 3.83: 4.00: 1.00. 1H and 13C NMR spectra of CAs also identified the presence of five kinds of monosaccharides and galacturonic acid. Moreover, the antitumor activity of CAs was evaluated in mice transplanted H22 hepatoma cells. It was shown that CAs dose-dependently suppressed tumor cells growth with few toxic effects on host. Further investigations revealed that CAs increased the levels of tumor infiltrating CD8+ T lymphocytes, blocked tumor cell cycle in S phase, down-regulated anti-apoptotic protein Bcl-xL and Mcl-1 expression, and led to the activation of caspase 3. These results suggested that CAs had capacity of inducing tumor cells apoptosis in vivo, and it supported considering CAs as an adjuvant reagent in hepatocellular carcinoma treatment. PMID- 28363660 TI - Expanding role of percutaneous ablative and consolidative treatments for musculoskeletal tumours. AB - Interventional approaches to musculoskeletal tumours have significantly changed over the last several years, and new treatments continue to be developed. All ablative modalities are currently applied to the treatment of bone tumours, including radiofrequency, cryo-, microwave, and laser ablation devices. Indications for ablation of bone and soft-tissue tumours have expanded beyond palliation of painful bone metastases and eradication of osteoid osteomas to the local control of oligometastatic disease from a number of primary tumours and ablation of desmoid tumours. In addition, tools for consolidation of bone tumours at risk of pathological fracture have also expanded. With these developments, ablation has become the primary treatment for osteoid osteomas and, at some institutions, desmoid tumours. It may be the primary or secondary treatment for palliation of painful bone tumours, frequently used in patients with pain refractory to or recurrent after radiation therapy. It is used as a treatment for limited metastatic disease or for metastases that grow disproportionately in patients with multifocal metastases, either in combination with systemic therapy or to reserve systemic therapy and its toxicity for more widespread disease progression. Moreover, percutaneous methods to consolidate bone at risk of fracture have become more commonplace, aided by techniques using materials beyond typical bone cement. PMID- 28363659 TI - Accuracy of contemporary oesophageal cancer lymph node staging with radiological pathological correlation. AB - AIM: To evaluate the accuracy of contemporary N-staging and provide radiological pathological correlation in patients with lymph node metastases (LNMs) that were radiologically staged N0. MATERIALS AND METHODS: One hundred and twelve patients were included who underwent surgery alone (n=41) or neoadjuvant therapy (n=71) between October 2010 and December 2015. Contrast-enhanced computed tomography (CECT), endoscopic ultrasound (EUS), and combined positron-emission tomography (PET) and CT N-stage were compared to pathological N-stage [node-negative (N0) versus node-positive (N+) groups]. Fifty LNMs from 15 patients preoperatively staged as N0 were measured and the maximum size recorded. RESULTS: Accuracy, sensitivity, and specificity of N0 versus N+ disease with CECT, EUS, and PET/CT was 54.5%, 39.7% and 77.3%, 55.4%, 42.6% and 75%, and 57.1% 35.3%, and 90.9%, respectively. All techniques were more likely to under-stage nodal disease; CECT (X2 32.890, df=1, p<0.001), EUS (X2 28.471, df=1, p<0.001), and PET/CT (X2 50.790, df=1, p<0.001). PET/CT was more likely to under-stage nodal disease than EUS (p=0.031). Median LNM size was 3 mm, with 41 (82%) of LNMs measuring <6 mm and 22 (44%) classified as micro-metastases (<=2 mm). CONCLUSION: This study has demonstrated poor N-staging accuracy in the modern era of radiological staging. Eighty-two percent of LNMs measured <6 mm, making direct identification extremely challenging on medical imaging. Future research should focus on investigating and developing alternative surrogate markers to predict the likelihood of LNMs. PMID- 28363661 TI - Breast fat volume measurement using wide-bore 3 T MRI: comparison of traditional mammographic density evaluation with MRI density measurements using automatic segmentation. AB - AIM: To compare magnetic resonance imaging (MRI)-derived breast density measurements using automatic segmentation algorithms with radiologist estimations using the Breast Imaging Reporting and Data Systems (BI-RADS) density classification. MATERIALS AND METHODS: Forty women undergoing mammography and dynamic breast MRI as part of their clinical management were recruited. Fat-water separated MRI images derived from a two-point Dixon technique, phase-sensitive reconstruction, and atlas-based segmentation were obtained before and after intravenous contrast medium administration. Breast density was assessed using software from Advanced MR Analytics (AMRA), Linkoping, Sweden, with results compared to the widely used four-quartile quantitative BI-RADS scale. RESULTS: The proportion of glandular tissue in the breast on MRI was derived from the AMRA sequence. The mean unenhanced breast density was 0.31+/-0.22 (mean+/-SD; left) and 0.29+/-0.21 (right). Mean breast density on post-contrast images was 0.32+/ 0.19 (left) and 0.32+/-0.2 (right). There was "almost perfect" correlation between pre- and post-contrast breast density quantification: Spearman's correlation rho=0.98 (95% confidence intervals [CI]: 0.97-0.99; left) and rho=0.99 (95% CI: 0.98-0.99; right). The 95% limits of agreement were -0.11-0.08 (left) and -0.08-0.03 (right). Interobserver reliability for BI-RADS was "substantial": weighted Kappa k=0.8 (95% CI: 0.74-0.87). The Spearman correlation coefficient between BI-RADS and MRI breast density was rho=0.73 (95% CI: 0.60 0.82; left) and rho=0.75 (95% CI: 0.63-0.83; right) which was also "substantial". CONCLUSION: The AMRA sequence provides a fully automated, reproducible, objective assessment of fibroglandular breast tissue proportion that correlates well with mammographic assessment of breast density with the added advantage of avoidance of ionising radiation. PMID- 28363662 TI - Response to Letter to the Editor: "Blood transfusions in severe burn patients: Epidemiology and predictive factors; Methodological issues". PMID- 28363663 TI - Enzymatic debridement of deeply burned faces: Healing and early scarring based on tissue preservation compared to traditional surgical debridement. AB - INTRODUCTION: Facial burns occur frequently and depending on the injured skin layers often heal with scars which may cause permanent functional and cosmetic sequelae. Preservation of the sensitive facial skin layers, especially of the dermis is essential for scarless epithelialisation. Enzymatic debridement of deep thermal burns has already been shown to assist with preserving viable dermis. However, up to date, there are no published reports on wound healing and in the long term aesthetic outcome after enzymatic debridement of facial burns. METHODS: Therefore we performed a-single centre clinical trial that included 26 subjects aged 18-78 years with facial burns clinically evaluated as deep dermal or deeper. Burns were treated either with enzymatic debridement or excisional surgical debridement. Then we compared both groups regarding debridement selectivity, wound closure and scar quality after more than 12 months. RESULTS: Enzymatic debridement significantly reduced time to complete wound closure after admission (19.85 days versus 42.23 days, p=0.002), and after enzymatic eschar removal (18.92 days versus 35.62 days, p=0.042). The number of procedures to complete debridement were significantly lower in the enzymatic debridement group (1.00 versus 1.77, p=0.003). 77% of facial burns that had been debrided enzymatically were found to be more superficially burned than initially estimated. Wounds undergoing autografting of any size were significantly reduced by enzymatic debridement (15% versus 77%, p=0.002). Scar quality after enzymatic debridement was superior compared to surgical debridement after 12 months regarding pigmentation (p=0.016), thickness (p=0.16), relief (p=0.10), pliability (p=0.01), surface area (p=0.004), stiffness (p=0.023), thickness (0.011) and scar irregularity (p=0.011). Regarding erythema and melanin, viscoelasticity and pliability, trans-epidermal water loss or laser tissue oxygen saturation, haemoglobin level and microcirculation we found no significant differences for treated and untreated skin in the EDNX group. CONCLUSION: In our current study we found Bromelain based enzymatic debridement better in some aspects of tissue preservation in deep dermal facial burn. PMID- 28363664 TI - Evaluating accuracy and reliability of active stereophotogrammetry using MAVIS III Wound Camera for three-dimensional assessment of hypertrophic scars. AB - OBJECTIVE: Current strategies for estimating positive scar volume following burns is limited to employing subjective scar scales. This study assesses the accuracy and reliability of Measurement of Area and Volume Instrument System (MAVIS) III, a portable 3D active stereophotogrammetric imaging system, for non-invasive assessment of hypertrophic scar volume and elucidates factors that leads to inaccurate volume determination. METHODS: To determine accuracy, hypertrophic scars arising in various skin and wound types were modeled using moldable putty substance. Volumetric measurements calculated by the camera's software were compared to measurements determined by fluid displacement. To assess inter-rater reliability, 25 images of patients with hypertrophic scars on various anatomical regions (hand, arm, leg, and flank area) were assessed by three blind evaluators. RESULTS: Volumetric measurements obtained from MAVIS III ranged from adequate to excellent accuracy (Pearson's correlation coefficient of 0.54-0.90) compared to measurements determined by fluid displacement. The reliability of volume determination of human hypertrophic scars was rated excellent (overall Intraclass correlation coefficient of 0.95). CONCLUSIONS: This study finds that MAVIS III is accurate in its volumetric measurements and is reliable between users; making it a potential candidate for non-invasive assessment of hypertrophic scars. Further considerations for refining active stereo-photogrammetry and the user interface of the software are also highlighted to allow superior evaluation of scar volume. PMID- 28363665 TI - [Extension of the thoracodorsal artery perforator flap's pedicle: Anatomical study]. AB - PURPOSE: In recent years, the indications of latissimus dorsi myocutaneous flap decreased in favor of its version preserving muscle: the thoracodorsal artery perforator flap (TDAP). The intramuscular dissection reduce donor site morbidity but also allows an extension of the pedicle compared to conventional latissimus dorsi flap pedicle. The purpose of this study was to quantify objectively elongation of the pedicle when the perforator is dissected through the muscle. METHOD: Sixteen TDAP flap were dissected in 9 cadavers. The pedicle was divided into 4 distinct parts: (1) hypodermis, (2) subcutaneous fat, (3) intramuscular, (4) conventional pedicle. RESULTS: The length of the pedicle is significantly increased when the pedicle is dissected through the muscle. This extends the theoretical length from 5.25cm up to 9.19cm if the dissection is extended to the deep fat. Indeed, this results in a potentially exploitable TDAP pedicle length of 20.66cm. CONCLUSION: The dissection of the perforator allows an extension of the pedicle of about 5 or 9cm if we continue the dissection in the subcutaneous fat. A long pedicle may be interesting in lower limb reconstructive surgery and facial reconstruction where microsurgery is not feasible. PMID- 28363666 TI - Risk factors for mortality after surgery of osteoporotic hip fracture in patients over 65 years of age. AB - OBJECTIVE: To evaluate, from a clinical perspective, and with easily identifiable variables, those factors that influence the survival of patients admitted to a care unit designed for the comprehensive treatment of patients with hip fracture after being surgically treated. MATERIAL AND METHODS: A prospective study was conducted on a cohort of patients (n=202) aged 65 years or older with a low impact hip fracture, who were surgically intervened in a tertiary hospital. An analysis was performed to determine mortality at 90 days, and at one and 2years after surgery using demographic, clinical, analytical, and functional variables. RESULTS: The independent risk factors of mortality in the 3periods analysed were age (P=.047, P=.016, and P=.000 at 90 days, 1, and 2 years, respectively) and a low Barthel index (P=.014, P=.005, and P=.004 to 90 days, 1, and 2 years, respectively). Male sex (P=.004) and a high risk for anaesthesia (P=.011) were only independent risk factors of mortality at 2years after surgery. DISCUSSION AND CONCLUSION: Age and dependency were the major determining factors of mortality at 30 days, 1, and 2 years after surgery for hip fracture. Both are easily measurable to identify patients susceptible to poor outcomes, and could benefit from a more thorough care plan. PMID- 28363667 TI - Stop or Go? Endosome Positioning in the Establishment of Compartment Architecture, Dynamics, and Function. AB - The endosomal system constitutes a key negotiator between the environment of a cell and its internal affairs. Comprised of a complex membranous network, wherein each vesicle can in principle move autonomously throughout the cell, the endosomal system operates as a coherent unit to optimally face external challenges and maintain homeostasis. Our appreciation of how individual endosomes are controlled in time and space to best serve their collective purpose has evolved dramatically in recent years. In light of these efforts, the endoplasmic reticulum (ER) - with its expanse of membranes permeating the cytoplasmic space - has emerged as a potent spatiotemporal organizer of endosome biology. We review the latest advances in our understanding of the mechanisms underpinning endosomal transport and positioning, with emphasis on the contributions from the ER, and offer a perspective on how the interplay between these aspects shapes the architecture and dynamics of the endosomal system and drives its myriad cellular functions. PMID- 28363669 TI - Characteristics, Trends, and Quality of Systematic Review and Meta-Analysis in General Radiology between 2007 and 2015. AB - RATIONALE AND OBJECTIVES: To evaluate the trends, characteristics, and quality of systematic review and meta-analysis in general radiology journals. MATERIALS AND METHODS: We performed a PubMed search to identify systematic reviews and meta analyses that had been carried out in the field of radiology between 2007 and 2015. The following data were extracted: journal, impact factor, type of research, year of publication, radiological subspecialty, imaging modalities used, number of authors, affiliated department of the first and corresponding authors, presence of a radiologist and a statistician among the authors, discordance between the first and corresponding authors, funding, country of first author, methodological quality, methods used for quality assessment, and statistics. RESULTS: Ultimately, we included 210 articles from nine general radiology journals. The European Journal of Radiology was the most common journal represented (47 of 210; 22.4%). Meta-analyses (n = 177; 84.3%) were published about five times more than systematic reviews without meta-analysis (n = 33; 15.7%). Radiology of the gastrointestinal tract was the most commonly represented subspecialty (n = 49, 23.3%). The first authors were most frequently located in China (n = 64; 30.3%). In terms of modality, magnetic resonance imaging was used most often (n = 59; 28.1%). The number of authors tended to progressively increase over time, and the ratio of discordance between the first and corresponding authors also increased significantly, as did the proportion of research that has received funding from an external source. The mean AMSTAR assessment score improved over time (5.87/11 in 2007-2009, 7.11/11 in 2010-2012, and 7.49/11 in 2013-2015). In this regard, the journal Radiology had the highest score (7.59/11). CONCLUSIONS: The quantity and quality of radiological meta analyses have significantly increased over the past 9 years; however, specific weak areas remain, providing the opportunity for quality improvement. PMID- 28363671 TI - Role of Health Services Research in Radiology. PMID- 28363670 TI - Using the Analytic Hierarchy Process for Prioritizing Imaging Tests in Diagnosis of Suspected Appendicitis. AB - RATIONALE AND OBJECTIVES: In clinical guideline or criteria development processes, such as those used in developing American College of Radiology Appropriateness Criteria (ACR AC), experts subjectively evaluate benefits and risks associated with imaging tests and make complex decisions about imaging recommendations. The analytic hierarchy process (AHP) decomposes complex decisions into structured smaller decisions, incorporates quantitative evidence and qualitative expert opinion, and promotes structured consensus building. AHP may supplement and/or improve the transparency of expert opinion contributions to developing guidelines or criteria. MATERIALS AND METHODS: To conduct an empirical test using health services research tools, we convened a mock ACR AC panel of emergency department radiology and nonradiology physicians to evaluate by multicriteria decision analysis, the relative appropriateness of imaging tests for diagnosing suspected appendicitis. Panel members selected benefit-risk criteria via an online survey and assessed contrast-enhanced computed tomography, magnetic resonance imaging, and ultrasound using an AHP-based software. Participants were asked whether the process was manageable, transparent, and improved shared understanding. Priority scores were converted to rankings and compared to the rank order of ACR AC ratings. RESULTS: When compared to magnetic resonance and ultrasound imaging, participants agreed with the ACR AC that contrast-enhanced computed tomography is the most appropriate test. Contrary to the ACR AC ratings, study results suggest that magnetic resonance is preferable to ultrasound. When compared to nonradiologists, radiologists' priority scores reflect a stronger preference for computed tomography. CONCLUSIONS: Study participants addressed decision-making challenges using a relatively efficient data collection mechanism, suggesting that AHP may benefit the ACR AC guideline development process in identifying the relative appropriateness of imaging tests. With additional development, AHP may improve transparency when expert opinion is used in clinical guideline or appropriateness criteria development. PMID- 28363668 TI - Methylphenidate alleviates manganese-induced impulsivity but not distractibility. AB - Recent studies from our lab have demonstrated that postnatal manganese (Mn) exposure in a rodent model can cause lasting impairments in fine motor control and attention, and that oral methylphenidate (MPH) treatment can effectively treat the dysfunction in fine motor control. However, it is unknown whether MPH treatment can alleviate the impairments in attention produced by Mn exposure. Here we used a rodent model of postnatal Mn exposure to determine whether (1) oral MPH alleviates attention and impulse control deficits caused by postnatal Mn exposure, using attention tasks that are variants of the 5-choice serial reaction time task, and (2) whether these treatments affected neuronal dendritic spine density in the medial prefrontal cortex (mPFC) and dorsal striatum. Male Long Evans rats were exposed orally to 0 or 50Mn/kg/d throughout life starting on PND 1, and tested as young adults (PND 107-115) on an attention task that specifically tapped selective attention and impulse control. Animals were treated with oral MPH (2.5mg/kg/d) throughout testing on the attention task. Our findings show that lifelong postnatal Mn exposure impaired impulse control and selective attention in young adulthood, and that a therapeutically relevant oral MPH regimen alleviated the Mn-induced dysfunction in impulse control, but not selective attention, and actually impaired focused attention in the Mn group. In addition, the effect of MPH was qualitatively different for the Mn-exposed versus control animals across a range of behavioral measures of inhibitory control and attention, as well as dendritic spine density in the mPFC, suggesting that postnatal Mn exposure alters catecholaminergic systems modulating these behaviors. Collectively these findings suggest that MPH may hold promise for treating the behavioral dysfunction caused by developmental Mn exposure, although further research is needed with multiple MPH doses to determine whether a dose can be identified that ameliorates the dysfunction in both impulse control and selective attention, without impairing focused attention. PMID- 28363672 TI - Sentinel lymph node mapping reduces practice pattern variations in surgical staging for endometrial adenocarcinoma: A before and after study. AB - OBJECTIVE: To examine the effects of universal sentinel lymph node mapping on the use of nodal staging in endometrial adenocarcinoma. METHODS: Two approaches to laparoscopic staging for endometrial adenocarcinoma were compared using a before and after study design. The before cohort underwent selective lymphadenectomy from January 1, 2014-October 1, 2015 while the after cohort underwent universal sentinel lymph node (SLN) mapping from October 2, 2015-September 29, 2016. RESULTS: The before cohort comprised 215 patients and the after cohort 166 patients. In women undergoing SLN mapping, a sentinel node was identified at least unilaterally in 146/153 cases (95.4%), and bilaterally in 114/153 (74.5%) of cases. Pelvic nodes were removed in 35.8% of the before cohort versus 92.2% of the after cohort (p<0.0001) with more nodal evaluation among both low risk (9.6% vs. 91%, p<0.0001) and high risk cases (66% vs. 94%, p<0.0001). While the proportion of low risk cases diagnosed with nodal involvement did not significantly change (0.9% to 3.1%, p=0.32), there was a trend toward more diagnoses of nodal involvement in high risk cases (5% to 13.2%, p=0.06). Mean number of pelvic lymph nodes removed (15 vs. 4, p<0.0001), mean operative time (181min vs. 137min, p<0.0001), estimated blood loss (80ml vs. 56ml, p=0.004), and rate of post-operative complications (13% vs. 5.2%, p=0.04) all decreased after the adoption of SLN dissection. CONCLUSIONS: Universal sentinel lymph node dissection for laparoscopic endometrial cancer staging reduces heterogeneity in surgeon staging practice, increases nodal detection, and lowers post-operative complications. PMID- 28363673 TI - Lipids Can Make Them Stick Together. AB - To be active, membrane proteins often need to assemble into multimers either transiently or permanently. Using high-end mass spectrometry (MS), Robinson and colleagues show that the formation of transient multimers may require lipids at the interface while stable oligomers appear not to require such help. PMID- 28363674 TI - Assessment of Female Medical Students' Interest in Careers in Cardiothoracic Surgery. AB - OBJECTIVE: Although over half of medical students are females, women comprise only 21% of cardiothoracic (CT) surgery residency applicants and 5% of the CT workforce. We sought to gain insight into female medical students' perceptions of CT surgery and identify targets to increase interest. DESIGN: A 33-question survey queried career selection factors, perceptions of CT surgery, and ways to increase interest in the field. Responses were stratified by sex and preclinical versus clinical years. SETTING: Women at 13 US medical schools were compared to men at a Midwest medical school. PARTICIPANTS: Surveys were distributed to approximately 4400 women and were completed by 372 (8.5%) women. Comparison surveys were distributed to approximately 170 preclinical men and were completed by 98 (57.6%) men. RESULTS: Preclinical woman had broad interests, whereas clinical women were more interested in primary care (p = 0.0124). Intellectual interest and lifestyle were important in specialty selection for men and women (91% versus 90%; 78% versus 86%). Although preclinical men valued perceived prestige and salary significantly more than preclinical women (39% versus 20%, p = 0.0014; 64% versus 48%, p = 0.0173), preclinical women valued caring for specific ethnicities and addressing health disparities significantly more than preclinical men (26% versus 15%, p = 0.0173; 53% versus 33%, p = 0.0019). Making family plans was cited by 83% of women as difficult if they choose to become a CT surgeon. Women thought that attaining their career interests and life goals (76%) or access to female CT surgery mentors (63%) would make the field more appealing. Over 70% of preclinical women were interested in shadowing a CT surgeon. Of these women, 12% attempted to shadow. CONCLUSIONS: Although baseline interest in CT surgery is low among women, there are many targets for increasing interest especially during preclinical years. Residency programs have the opportunity to entice women to the field by addressing their priorities of lifestyle, family planning, and addressing health disparities. PMID- 28363675 TI - Effect of Ongoing Assessment of Resident Operative Autonomy on the Operating Room Environment. AB - OBJECTIVE: We have previously demonstrated the feasibility and validity of a smartphone-based system called Procedural Autonomy and Supervision System (PASS), which uses the Zwisch autonomy scale to facilitate assessment of the operative performances of surgical residents and promote progressive autonomy. To determine whether the use of PASS in a general surgery residency program is associated with any negative consequences, we tested the null hypothesis that PASS implementation at our institution would not negatively affect resident or faculty satisfaction in the operating room (OR) nor increase mean OR times for cases performed together by residents and faculty. METHODS: Mean OR times were obtained from the electronic medical record at Northwestern Memorial Hospital for the 20 procedures most commonly performed by faculty members with residents before and after PASS implementation. OR times were compared via two-sample t-test. The OR Educational Environment Measure tool was used to assess OR satisfaction with all clinically active general surgery residents (n = 31) and full-time general surgery faculty members (n = 27) before and after PASS implementation. Results were compared using the Mann-Whitney rank sum test. RESULTS: A significant prolongation in mean OR time between control and study period was found for only 1 of the 20 operative procedures performed at least 20 times by participating faculty members with residents. Based on the overall survey score, no significant differences were found between resident and faculty responses to the OR Educational Environment Measure survey before and after PASS implementation. When individual survey items were compared, while no differences were found with resident responses, differences were noted with faculty responses for 7 of the 35 items addressed although after Bonferroni correction none of these differences remained significant. CONCLUSIONS: Our data suggest that PASS does not increase mean OR times for the most commonly performed procedures. Resident OR satisfaction did not significantly change during PASS implementation, whereas some changes in faculty satisfaction were noted suggesting that PASS implementation may have had some negative effect with them. Although the effect on faculty satisfaction clearly requires further investigation, our findings support that use of an autonomy-based OR performance assessment system such as PASS does not appear to have a major negative influence on OR times nor OR satisfaction. PMID- 28363676 TI - Variable Operative Experience in Hand Surgery for Plastic Surgery Residents. AB - BACKGROUND: Efforts to standardize hand surgery training during plastic surgery residency remain challenging. We analyze the variability of operative hand experience at U.S. plastic surgery residency programs. METHODS: Operative case logs of chief residents in accredited U.S. plastic surgery residency programs were analyzed (2011-2015). Trends in fold differences of hand surgery case volume between the 10th and 90th percentiles of residents were assessed graphically. Percentile data were used to calculate the number of residents achieving case minimums in hand surgery for 2015. RESULTS: Case logs from 818 plastic surgery residents were analyzed of which a minority were from integrated (35.7%) versus independent/combined (64.3%) residents. Trend analysis of fold differences in case volume demonstrated decreasing variability among procedure categories over time. By 2015, fold differences for hand reconstruction, tendon cases, nerve cases, arthroplasty/arthrodesis, amputation, arterial repair, Dupuytren release, and neoplasm cases were below 10-fold. Congenital deformity cases among independent/combined residents was the sole category that exceeded 10-fold by 2015. Percentile data suggested that approximately 10% of independent/combined residents did not meet case minimums for arterial repair and congenital deformity in 2015. CONCLUSIONS: Variable operative experience during plastic surgery residency may limit adequate exposure to hand surgery for certain residents. Future studies should establish empiric case minimums for plastic surgery residents to ensure hand surgery competency upon graduation. PMID- 28363677 TI - Large Rotation of the N-terminal Domain of Hsp90 Is Important for Interaction with Some but Not All Client Proteins. AB - The 90-kDa heat shock protein (Hsp90) chaperones the late folding steps of many protein kinases, transcription factors, and a diverse set of other protein clients not related in sequence and structure. Hsp90's interaction with clients appears to be coupled to a series of conformational changes. How these conformational changes contribute to its chaperone activity is currently unclear. Using crosslinking, hydrogen exchange mass spectrometry, and fluorescence experiments, we demonstrate here that the N-terminal domain of Hsp90 rotates by approximately 180 degrees as compared to the crystal structure of yeast Hsp90 in complex with Sba1 and AMPPNP. Surprisingly, Aha1 but not Sba1 suppresses this rotation in the presence of AMPPNP but not in its absence. A minimum length of the largely unstructured linker between N-terminal and middle domain is necessary for this rotation, and interfering with the rotation strongly affects the interaction with Aha1 and the intrinsic and Aha1-stimulated ATPase activity. Surprisingly, suppression of the rotation only affects the activity of some clients and does not compromise yeast viability. PMID- 28363678 TI - Transcription-Coupled DNA Double-Strand Break Repair: Active Genes Need Special Care. AB - For decades, it has been speculated that specific loci on eukaryotic chromosomes are inherently susceptible to breakage. The advent of high-throughput genomic technologies has now paved the way to their identification. A wealth of data suggests that transcriptionally active loci are particularly fragile and that a specific DNA damage response is activated and dedicated to their repair. Here, we review current understanding of the crosstalk between transcription and double strand break repair, from the reasons underlying the intrinsic fragility of genes to the mechanisms that restore the integrity of damaged transcription units. PMID- 28363679 TI - Tumor infiltrating lymphocytes in early breast cancer. AB - Immunoediting represents a complex and dynamic process involving cancer and immune system cells, composed by three intertwined phases: elimination, equilibrium and escape. A large number of immune cell subtypes are involved, each playing a peculiar role in interacting with cancer cells: cytotoxic CD8+ T cells play a main role in cancer killing by inducing tumor cell death, while FOXP3+ T regulatory cells represent an immune-inhibitory cell subtype. The evaluation of tumor infiltrating lymphocytes (TILs) in H&E routine samples has been shown to represent a reliable surrogate of the immune anti-tumor activity and a robust independent prognostic biomarker in breast cancer (BC) patients, especially in the Tripe Negative and HER2+ subtypes. The present review addresses the mechanisms of breast cancer immunoediting, its cell complexity and prognostic/predictive relevance, providing evidence that TILs represent one the most promising biomarkers for BC patients. PMID- 28363680 TI - Exercising Control Over Memory Consolidation. AB - Exercise can improve human cognition. A mechanistic connection between exercise and cognition has been revealed in several recent studies. Exercise increases cortical excitability and this in turn leads to enhanced memory consolidation. Together these studies dovetail with our growing understanding of memory consolidation and how it is regulated through changes in motor cortical excitability. PMID- 28363681 TI - A Network Model of the Emotional Brain. AB - Emotion is often understood in terms of a circumscribed set of cortical and subcortical brain regions. I propose, instead, that emotion should be understood in terms of large-scale network interactions spanning the entire neuroaxis. I describe multiple anatomical and functional principles of brain organization that lead to the concept of 'functionally integrated systems', cortical-subcortical systems that anchor the organization of emotion in the brain. The proposal is illustrated by describing the cortex-amygdala integrated system and how it intersects with systems involving the ventral striatum/accumbens, septum, hippocampus, hypothalamus, and brainstem. The important role of the thalamus is also highlighted. Overall, the model clarifies why the impact of emotion is wide ranging, and how emotion is interlocked with perception, cognition, motivation, and action. PMID- 28363683 TI - Validity of thoracic respiratory inductive plethysmography in high body mass index subjects. AB - We aim to evaluate thoracic respiratory inductive plethysmography (RIP) in high body mass index (BMI) subjects with a pneumotachometer (PT) as a reference. We simultaneously evaluated spontaneous breathing by RIP and PT in 10 low and 10 high BMI subjects at rest and in moderate exercise. We then recorded RIP amplitude with different excursions mimicking respiratory thoracic deformation, with different sizes of RIP belts surrounding cylinders of different perimeters with or without deformable foam simulating adipose tissue. RIP responses correlated with PT values in low and high BMI groups for inspiratory time (r=0.86 and r=0.91, respectively), expiratory time (r=0.96 and r=0.91, respectively) and amplitude (r=0.82 for both) but with a bias (-0.23+/-0.25L) for high BMI subjects. ANOVA revealed the effects of perimeter and simulated adiposity (p<0.001 for both). We concluded that thoracic perimeter and deformity of adipose tissue are responsible for biases in RIP response in high BMI subjects. PMID- 28363684 TI - Effect of spironolactone on the risks of mortality and hospitalization for heart failure in pre-dialysis advanced chronic kidney disease: A nationwide population based study. AB - BACKGROUND: Spironolactone has been shown to reduce cardiovascular death in patients with mild-to-moderate chronic kidney disease (CKD), but its risks and benefits in advanced CKD remain unsettled. We aimed to assess whether spironolactone reduces cardiovascular mortality and morbidity in pre-dialysis stage 5 CKD patients. METHODS: Using Taiwan's National Health Insurance Research Database from January 2000 to June 2009, we enrolled 27,213 pre-dialysis stage 5 CKD adult patients, in whom 1363 patients were treated with spironolactone (user) and 25,850 were not (nonuser). Outcomes were all-cause mortality, hospitalization for heart failure (HHF) and major adverse cardiac event (MACE, the composite of acute myocardial infarction and ischemic stroke). Patients were followed up till December 31, 2009. RESULTS: Over 85,758 person-years of follow-up, spironolactone users had higher incidence for all-cause mortality (24.7/100 person-years vs. 10.6/100 person-years), infection-related death (4.4/100 person-years vs. 1.7/100 person-years) and HHF (4.0/100 person-years vs. 1.4/100 person-years). Multivariable Cox hazards model showed that spironolactone users were associated with higher risks of all-cause mortality (adjusted hazard ratio [aHR] 1.35, 95% confidence interval [CI] 1.24-1.46), infection-related death (aHR 1.42, CI 1.16 1.73) and HHF (aHR 1.35, CI 1.08-1.67) as compared to nonusers. The risks for cardiovascular mortality, MACE and hyperkalemia-associated hospitalization were similar between two groups. After matching users and nonusers (1:3 ratio) by propensity scores, the results were consistent in matched cohort and across subgroups. CONCLUSIONS: Spironolactone may be associated with higher risks for all-cause and infection-related mortality and HHF in pre-dialysis stage 5 CKD patients. Spironolactone should be used with caution in advanced CKD patients. PMID- 28363682 TI - Twelve-month outcome of patients with an established indication for oral anticoagulation undergoing coronary artery stenting and stratified by the baseline risk of bleeding: Insights from the Warfarin and Coronary Stenting (War Stent) Registry. AB - PURPOSE: To evaluate the outcome of patients with an established indication for oral anticoagulation (OAC) undergoing coronary stent implantation (PCI-S) and stratified by the baseline risk of bleeding. MATERIAL AND METHODS: The database of the prospective, multicentre, observational WAR-STENT registry (ClinicalTrials.gov identifier NCT00722319) was analyzed and patients with atrial fibrillation and CHA2DS2-VASc score >=2, mechanical heart valve, prior cardiac embolism, intra-cardiac thrombus and recent venous thromboembolism who were treated with either triple (warfarin, aspirin and clopidogrel) or dual (warfarin and clopidogrel) or dual antiplatelet (aspirin and clopidogrel) therapy, identified. Patients were then sorted into two groups at non-low and low risk of bleeding, as defined by an ATRIA score >3 and <=3 respectively, and compared regarding major adverse cardiac and vascular events (MACVE) and bleeding. RESULTS: At 12-month follow up, MACVE were comparable in the two groups, whereas total, major and minor bleeding, as well as combined MACVE and total bleeding, were significantly more frequent in the non-low bleeding risk group. Upon Cox univariate and multivariable analysis, non-low bleeding risk category confirmed as an independent predictor of major bleeding. The choice of antithrombotic therapy however, appeared not to be influenced by the bleeding risk category at baseline. CONCLUSIONS: In patients with an established indication for OAC undergoing PCI-S, non-low bleeding risk category is the most potent independent predictor of major bleeding. Stratification of the bleeding risk at baseline should therefore be regarded as an indispensable process to be carried out before selection of the antithrombotic therapy. PMID- 28363685 TI - Direct oral anticoagulants for the prevention of thromboembolic complications of atrial fibrillation: The more you pay, the less you spend? PMID- 28363686 TI - Treatment and outcomes of acute coronary syndromes in women: An analysis of a multicenter quality improvement Chinese study. AB - BACKGROUND: Variations in care and outcomes by sex in patients with acute coronary syndrome (ACS) have been reported worldwide. The aims of this study are to describe ACS management according to sex in China and the effects of a quality improvement program in Chinese male and female ACS patients. METHODS AND RESULTS: Clinical Pathways for Acute Coronary Syndromes - Phase 2 (CPACS-2) was a cluster randomized trial to test whether a clinical pathways-based intervention would improve ACS management in China. The study enrolled 15,141 hospitalized patients [4631 (30.6%) were women] from 75 hospitals throughout China between October 2007 and August 2010. The intervention included clinical pathway implementation and performance measurement using standardized indicators with 6 monthly audit feedback cycles. Eight key performance indicators reflecting in hospital management of ACS were measured. After adjustment for differences in patient characteristics and comorbidities at presentation, women were significantly less likely to undergo coronary angiography when indicated (RR 0.88 [0.85 to 0.92], P<0.001), less likely to receive guideline recommended medical therapies at discharge (RR 0.94 [0.91 to 0.98], P=0.003) and more likely to be hospitalized for shorter (mean difference -0.42 [-0.73 to -0.12] days, P=0.007). However, in hospital clinical outcomes did not differ by sex. There was no evidence of heterogeneity in the relative effects of the quality improvement initiative by sex. CONCLUSIONS: Sex disparities were apparent in some key quality of care indicators for patients with suspected with ACS presenting to hospitals in China. The beneficial effect of the quality improvement program was consistent in women and men. CLINICAL TRIAL REGISTRATION: http://www.anzctr.org.au/default.aspx. Unique identifier: ACTRN12609000491268. PMID- 28363687 TI - Conservative versus aggressive treatment strategy with angiographic guidance alone in patients with intermediate coronary lesions: The SMART-CASE randomized, non-inferiority trial. AB - BACKGROUND: Although coronary angiography is still the technique most widely used to guide percutaneous coronary intervention (PCI), the appropriate angiographic indication of revascularization for intermediate coronary lesions remains controversial. The aim of this study was to compare conservative versus aggressive strategies with angiographic guidance alone in patients with intermediate coronary lesions. METHODS AND RESULTS: A total of 899 patients with intermediate coronary lesions between 50% and 70% diameter stenosis by quantitative coronary analysis were randomly assigned to the conservative group (n=449) or the aggressive group (n=450). For intermediate lesions, PCI was performed using everolimus-eluting stents in the aggressive group, but was deferred in the conservative group. The primary end point was a composite of all cause death, myocardial infarction, or any revascularization at 1year. The number of treated lesions per patient was 0.8+/-0.9 in the conservative group and 1.7+/ 0.9 in the aggressive group (p<0.001). The cumulative rate of the primary endpoint was 7.3% in the conservative group and 6.8% in the aggressive group (the upper limit of the one-sided 95% confidence interval [CI], 3.4%; p=0.006 for non inferiority with a predefined non-inferiority margin of 5.0%). The risk of death or myocardial infarction (hazard ratio [HR] 0.50; 95% CI, 0.19-1.33; p=0.17) and revascularization (HR 1.42; 95% CI, 0.80-2.52; p=0.23) was not significantly different between the 2 groups. CONCLUSIONS: Conservative revascularization was non-inferior to aggressive revascularization for intermediate coronary lesions. Revascularization of intermediate lesions can be safely deferred in patients undergoing PCI with angiographic guidance alone. CLINICAL TRIAL REGISTRATION: URL: http://ClinicalTrials.gov. Unique identifier: NCT00743899. PMID- 28363688 TI - Pharmacological treatment changes of chronic heart failure during cardiac resynchronization therapy: A 1-year follow-up study. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) is associated with improved morbidity and mortality in patients with chronic heart failure (HF) on optimal medical therapy. We aimed to evaluate changes of medical therapy during CRT and its influence on the CRT response. METHODS: We evaluated 85 HF patients' pharmacological treatment changes during 1-year follow-up of CRT. Statistical analysis was performed using IBM SPSS statistical software (SPSS v.21.0 for Mac OS X). RESULTS: Beta-blockers (BAB) were used in 81.2% of patients before CRT, and consumption increased after CRT implantation (96.5% at 1-year follow-up visit) (p<0.002). Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) consumption and dose didn't significantly change statistically during the study. 55.3% of patients were taking spironolactone before CRT, and this number increased at discharge till 76.5% (p<0.001) and till 70.6% (p=0.01) at 1-year follow-up visit. The average dose of spironolactone during the study significantly decreased statistically. The use of diuretics was higher after CRT device implantation, compared with the period before CRT 80% to 84.7% (p<0.001), but torasemide dose hadn't significantly changed statistically and remained almost the same. Cardiovascular medication consumption was significantly lower before CRT, compared with discharge (p<0.001) and follow-up (p<0.001) periods. However, no statistically significant relation between pharmacological treatment and echocardiographic response was found. CONCLUSIONS: The present study confirmed that pharmacological treatment has changed during the period before and after CRT. But no statistically significant relation between pharmacological treatment and echocardiographic response was found. PMID- 28363689 TI - Medication and Supplement Use in Disability Football World Championships. AB - BACKGROUND: Individuals with an impairment comprise more than 15% of the world's population, many of whom can benefit greatly from participation in sport. The provision of medical services in disability sport is a challenging area with a lack of scientific evidence. Given the positive impact that sport can have on the people with an impairment, it is vital that measures are taken to better understand the medical issues posed by disability sport. It is well established that medications and supplements are overused in sport, particularly within professional football, but there is no current evidence on medication or supplement use in elite disability football. OBJECTIVE: To examine and describe the use of medication and supplements in disability football, before and during international tournaments, and to identify the profile of substances used by category. DESIGN: Prospective, descriptive, cohort study. SETTING: International Blind Sport Association Football World Cup 2015 and the International Federation of Cerebral Palsy Football World Cup 2015. PARTICIPANTS: Two hundred forty-two elite-level disability footballers, classified with B1 visual impairment or cerebral palsy. METHODS: Team clinicians were asked to document all medication and supplements taken in the 48 hours before each match. RESULTS: This study recorded the use of 1648 substances in 242 players, with more than one half (53.1%) classified as supplements. There was an overall rate of 1.26 substances used per player per match and a medication use rate of 0.59 medications per player per match. Seventy percent (170/242) of players reported using at least one substance per tournament, with 57.9% (140/242) using at least one prescribed medication (63.6% of players at International Blind Sports Association World Games and 57.7% of players at International Federation of Cerebral Palsy World Cup). The most commonly prescribed category of medications was nonsteroidal anti inflammatory drugs, representing 39.3% of all reported medications. CONCLUSION: This study highlights the potential overuse of medication and supplements in disability football, particularly in the use of nonsteroidal anti-inflammatory drugs. These trends are comparable to previous research in Federation Internationale de Football Association World Cup competitions. LEVEL OF EVIDENCE: Not applicable. PMID- 28363690 TI - An Update of the American Urological Association White Paper on the Prevention and Treatment of the More Common Complications Related to Prostate Biopsy. AB - PURPOSE: In this white paper update we identify and discuss the prevalence and prevention of common complications of prostate needle biopsy. MATERIALS AND METHODS: A literature review was performed on prostate biopsy complications via queries of PubMed and EMBASE(r) databases for prostate biopsy complications from January 1, 2010 until June 1, 2015. We focused on infection, bleeding, urinary retention, needle tract seeding and erectile dysfunction. A total of 346 articles were identified for full text review and 119 are included in the final data synthesis. RESULTS: Infection is the most common complication of prostate biopsy with fluoroquinolone resistant Escherichia coli having a prominent role. Reported rates of infectious complications range from 0.1% to 7.0%, and sepsis rates range from 0.3% to 3.1% depending on antibiotic prophylaxis regimens. Mild, self limiting and transient bleeding is also a common complication. Other complications are extremely rare. CONCLUSIONS: This white paper provides a concise reference document for the more common prostate biopsy complications and prevention strategies. Risk assessment should be performed for all patients to identify known risk factors for harboring fluoroquinolone resistance. If infection incidence increases check the local antibiogram, current equipment and cleaning practices, and consider alternate approaches to antibiotic prevention such as needle cleaning, risk basked augmentation, rectal culture with targeted prophylaxis and transperineal biopsy. If infection occurs, actively re-situate the patient and start empiric intravenous treatment with carbapenems, amikacin or second and third generation cephalosporins. PMID- 28363691 TI - MYC and HIF in shaping immune response and immune metabolism. AB - Upon antigen stimulation, quiescent naive T cells undergo a phase of cell mass accumulation followed by cell cycle entry, clonal expansion, differentiation into functional subsets and back again to a quiescent state as they develop into memory cells. The transitions between these distinct cellular states place unique metabolic demands on energy, redox and biosynthesis. To fulfill these demands, T cells switch back and forth between their primary catabolic pathways. While quiescent naive and memory T cells largely rely on the oxidation of fatty acids and glucose, active T cells rely on glycolysis and glutaminolysis to sustain cell growth, proliferation and differentiation. Beyond several key signaling kinase cascades, the hypoxia inducible factor 1 (HIF-1) and the proto-oncogene MYC, act alone or in concert, to coordinate T cell metabolic reprogramming, cell proliferation, functional differentiation and apoptosis, enabling a robust T cell mediated adaptive immune response. PMID- 28363692 TI - IL-6 signaling in diabetic nephropathy: From pathophysiology to therapeutic perspectives. AB - Diabetic nephropathy (DN) is a leading cause of chronic kidney disease (CKD). Interleukin-6 (IL-6) signaling participates in inflammation responses central to the progression of DN. Current evidence suggests that these IL-6 responses are mediated via gp130-STAT3 dependent mechanisms which, on one hand, trigger globally the transition from innate to adaptive immune response, and on the other hand act locally for tissue remodeling and immune cell infiltration. In diabetic conditions the role of IL-6 is not well elucidated. Both IL-6 classical signaling pathway via receptor IL-6R (IL-6R) and IL-6 trans-signaling pathway via soluble IL-6R (sIL-6R) were shown to participate in the pathogenesis and progression of DN, and IL-6 appears to influence renal cells also in an autocrine manner. To date, evidence is limited. The goal of this review is to provide an overview of our current understanding on the role of IL-6 signaling in DN and to delineate challenges for future research. Putative sequential events related to IL-6 secretion by different cell populations in diabetic conditions are outlined. Further, we discuss potential applications of anti-IL-6 therapy in the context of DN. PMID- 28363693 TI - Structural optimization of an aptamer generated from Ligand-Guided Selection (LIGS) resulted in high affinity variant toward mIgM expressed on Burkitt's lymphoma cell lines. AB - Aptamers are synthetic, short nucleic acid molecules capable of specific target recognition. Aptamers are selected using a screening method termed Systematic Evolution of Ligands by Exponential enrichment (SELEX). We recently have introduced a variant of SELEX called "Ligand-Guided-Selection" (LIGS) that allows the identification of specific aptamers against known cell-surface proteins. Utilizing LIGS, we introduced three specific aptamers against membrane-bound IgM (mIgM), which is the hallmark of B cells. Out of the three aptamers selected against mIgM, an aptamer termed R1, in particular, was found to be interesting due to its ability to recognize mIgM on target cells and then block anti-IgM antibodies binding their antigen. We systematically truncated parent aptamer R1 to design shorter variants with enhanced affinity. Importantly, herein we show that the specificity of the most optimized variant of R1 aptamer is similar to that of anti-IgM antibody, indicating that the specificity of the ligand utilized in selective elution of the aptamer determines the specificity of the LIGS generated aptamer. Furthermore, we report that truncated variants of R1 are able to recognize mIgM-positive human B lymphoma BJAB cells at physiological temperature, demonstrating that LIGS-generated aptamers could be re-optimized into higher affinity variants. Collectively, these findings show the significance of LIGS in generating highly specific aptamers with potential applications in biomedicine. PMID- 28363694 TI - Cost-effectiveness of EOB-MRI for Hepatocellular Carcinoma in Japan. AB - PURPOSE: The objective of the study was to evaluate the cost-effectiveness of gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) in the diagnosis and treatment of hepatocellular carcinoma (HCC) in Japan compared with extracellular contrast media-enhanced MRI (ECCM-MRI) and contrast media-enhanced computed tomography (CE-CT) scanning. METHODS: A 6-stage Markov model was developed to estimate lifetime direct costs and clinical outcomes associated with EOB-MRI. Diagnostic sensitivity and specificity, along with clinical data on HCC survival, recurrence, treatment patterns, costs, and health state utility values, were derived from predominantly Japanese publications. Parameters unavailable from publications were estimated in a Delphi panel of Japanese clinical experts who also confirmed the structure and overall approach of the model. Sensitivity analyses, including one-way, probabilistic, and scenario analyses, were conducted to account for uncertainty in the results. FINDINGS: Over a lifetime horizon, EOB MRI was associated with lower direct costs (Y2,174,869) and generated a greater number of quality-adjusted life years (QALYs) (9.502) than either ECCM-MRI (Y2,365,421, 9.303 QALYs) or CE-CT (Y2,482,608, 9.215 QALYs). EOB-MRI was superior to the other diagnostic strategies considered, and this finding was robust over sensitivity and scenario analyses. A majority of the direct costs associated with HCC in Japan were found to be costs of treatment. The model results revealed the superior cost-effectiveness of the EOB-MRI diagnostic strategy compared with ECCM-MRI and CE-CT. IMPLICATIONS: EOB-MRI could be the first-choice imaging modality for medical care of HCC among patients with hepatitis or liver cirrhosis in Japan. Widespread implementation of EOB-MRI could reduce health care expenditures, particularly downstream treatment costs, associated with HCC. PMID- 28363695 TI - In Vitro Anaerobic Pharmacokinetic/Pharmacodynamic Model to Simulate the Bactericidal Activity of Levornidazole Against Bacteroides fragilis. AB - PURPOSE: This study was designed to correlate the pharmacokinetic/pharmacodynamic (PK/PD) parameters with PD indices of levornidazole against Bacteroides fragilis and to calculate the PK/PD target value for levornidazole to attain its expected maximal bactericidal effect using an in vitro anaerobic dynamic PK/PD model. METHODS: An anaerobic dynamic PK/PD model was developed in vitro. The scheme for PK modeling was designed according to the PK parameters of levornidazole in the human body. The device of 2-compartment PK/PD model was constructed by using digital control of flow rate to simulate 4 regimens of single-dose intravenous infusion of levornidazole to determine the bactericidal activity of levornidazole against the 3 strains of B fragilis within 72 hours. PD parameters such as reduction of colony count within 24 hours (?Log24h), area under bactericidal curve (AUBC), and 2-hour initial killing rate (IKR) were calculated and correlated with PK/PD parameters. Sigmoid Emax model of levornidazole was established to calculate PK/PD target values to attain corresponding PD effect. FINDINGS: PK and PD validation proved the stability of the model in simulating levornidazole against B fragilis and the precision and accuracy in the results of PK modeling. Cmax and AUC0-24h found only -1.46% and -6.72% differences from the values in vivo. Our study found that ?Log24h, AUBC, and IKR were more correlated with AUC0-24h/MIC and Cmax/MIC than with %T>MIC. According to ?Log24h, the PK/PD target values of AUC0-24h/MIC, Cmax/MIC, and %T>MIC of levornidazole against B fragilis were 157.6%, 14.1%, and 56.4%, respectively. IMPLICATIONS: Our findings are useful for optimizing the clinical dosing regimen of levornidazole sodium chloride injection to attain maximal bactericidal effect. PMID- 28363696 TI - Clinical Outcomes Associated with Switching or Discontinuation from Anti-TNF Inhibitors for Nonmedical Reasons. AB - PURPOSE: This study evaluated clinical outcomes and health care resource utilization associated with nonmedical switching from or discontinuation of anti tumor necrosis factor (TNF) therapies in US clinical practice. METHODS: Responding physicians extracted data from the medical charts of patients with Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, or psoriatic arthritis who achieved response on an anti TNF therapy. Physicians selected 2 cohorts of patients that were matched on diagnosis: patients who were switched/discontinued, for nonmedical reasons, from the anti-TNF therapy on which they achieved response (switchers/discontinuers), and patients who continued on their anti-TNF (continuers). Switchers/discontinuers were followed up for 12 months from the date of discontinuation (index date); continuers were followed up for 12 months from the date of an office visit within 2 months of the matched switcher/discontinuer's index date. Multivariate regression was used to compare disease flares, disease control, and health care resource utilization between cohorts, with adjustment for baseline characteristics. Subgroup analyses compared data from the continuer cohort to those from (1) patients who were switched to another biologic therapy and (2) patients who were switched to conventional therapy or discontinued from all therapy. FINDINGS: A total of 377 matched pairs of continuers and switchers/discontinuers were analyzed (N = 754), with the latter cohort comprising 284 patients (73.3%) who were and 93 (24.7%) who did not switch to another treatment (biologic or conventional treatment) immediately after discontinuation. Switchers/discontinuers had more frequent flares than did continuers, across severity levels (adjusted incidence rate ratios = 1.67, 2.36, and 3.48 for mild, moderate, and severe flares, respectively; all, P < 0.05). Switchers/discontinuers had a lower rate of well-controlled disease symptoms (46.9% vs 88.1%; adjusted odds ratio = 0.11; P < 0.001). Switchers/discontinuers also had more frequent inpatient hospitalizations, emergency department visits, and outpatient visits (adjusted incidence rate ratios = 3.58, 5.73, and 1.12, respectively; all, P < 0.001). Findings from the subgroup analyses of data from the 183 patients who switched to a biologic therapy and 194 who switched to conventional therapy or discontinued from all therapy were largely consistent with the overall analysis. IMPLICATIONS: In this study, switching/discontinuation from an anti-TNF therapy for nonmedical reasons was associated with significantly worse clinical outcomes and increased health care resource utilization-factors that should be considered when developing treatment algorithms. PMID- 28363698 TI - Dihydromyricetin prevents obesity-induced slow-twitch-fiber reduction partially via FLCN/FNIP1/AMPK pathway. AB - Obesity is often accompanied by decreases in the proportion of skeletal muscle slow-twitch fibers and insulin sensitivity. Increased plasma non-esterified fatty acids (NEFA) levels are responsible for obesity-associated insulin resistance. Palmitate, one of the most elevated plasma NEFA in obesity, has been recognized as the principle inducer of insulin resistance. The present study showed that increased plasma NEFA levels were negatively linked to slow-twitch fiber proportion and insulin sensitivity, while slow-twitch fiber proportion was positively correlated to insulin sensitivity in high fat diet (HFD)-fed and ob/ob mice. Dihydromyricetin (DHM) intervention increased slow-twitch fiber proportion and improved insulin resistance. In cultured C2C12 myotubes, palmitate treatment resulted in decrease of slow-twitch fiber specific Myh7 expression and insulin resistance, concomitant with folliculin (FLCN) and folliculin-interacting protein 1 (FNIP1) expression increase, AMP-activated protein kinase (AMPK) inactivation and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC 1alpha) expression decrease. Those palmitate-induced effects could be blocked by knock-down of FLCN expression or DHM intervention. Meanwhile, the protective effects of DHM were alleviated by over-expression of FLCN. In addition, the changes in AMPK activity and expression of FLCN and FNIP1 in vivo were consistent with those occurring in vitro. These findings suggest that DHM treatment prevents palmitate-induced slow-twitch fibers decrease partially via FLCN-FNIP1-AMPK pathway thereby improving insulin resistance in obesity. PMID- 28363697 TI - Polymorphisms and mutations in the melanocortin-3 receptor and their relation to human obesity. AB - Inactivating mutations in the melanocortin 3 receptor (Mc3r) have been described as causing obesity in mice, but the physiologic effects of MC3R mutations in humans have been less clear. Here we review the MC3R polymorphisms and mutations identified in humans, and the in vitro, murine, and human cohort studies examining their putative effects. Some, but not all, studies suggest that the common human MC3R variant T6K+V81I, as well as several other rare, function altering mutations, are associated with greater adiposity and hyperleptinemia with altered energy partitioning. In vitro, the T6K+V81I variant appears to decrease MC3R expression and therefore cAMP generation in response to ligand binding. Knockin mouse studies confirm that the T6K+V81I variant increases feeding efficiency and the avidity with which adipocytes derived from bone or adipose tissue stem cells store triglycerides. Other MC3R mutations occur too infrequently in the human population to make definitive conclusions regarding their clinical effects. This article is part of a Special Issue entitled: Melanocortin Receptors - edited by Ya-Xiong Tao. PMID- 28363700 TI - Caregivers: Do They Make a Difference to Patient Recovery in Subacute Stroke? AB - OBJECTIVE: To evaluate the relationship between caregiver nature and availability, and rehabilitation outcomes in subacute stroke. DESIGN: Retrospective cohort study. SETTING: Four community rehabilitation hospitals. PARTICIPANTS: Patients with subacute, first-time stroke (N=4042; 48.5% men; mean age +/- SD, 70.12+/-10.4y; 51.5% women; mean age +/- SD, 72.54 +/-10.0y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Rehabilitation effectiveness, defined as the percentage of potential improvement eventually achieved with rehabilitation; and rehabilitation efficiency, defined as the rate of functional improvement during rehabilitation. RESULTS: In our cohort, 96.7% had available caregiver(s), of which 42.0% were primarily supported by foreign domestic workers (FDWs), 25.9% by spouses, 19.3% by first-degree relatives, 7.8% by other relatives, and 5.1% by other caregivers. Using quantile regression, we found that having a caregiver was independently associated with rehabilitation efficiency (beta=-3.83; 95% confidence interval [CI], -6.99 to -0.66; P=.018). The relationship between caregiver availability and rehabilitation effectiveness was modified by patient sex in that the negative association was significantly greater in men (beta=-22.81; 95% CI, -32.70 to -12.94; P<.001) than women (beta= 5.64; 95% CI, -14.72 to 3.44; P=.223). Having a FDW as a caregiver compared with a spousal caregiver was negatively associated with rehabilitation effectiveness (beta=-3.95; 95% CI, -6.94 to -0.95; P=.01) and rehabilitation efficiency (beta= 1.83; 95% CI, -3.14 to -0.53; P=.006). The number of potential caregivers was only significantly associated with rehabilitation effectiveness at the bivariate level (P=.006). CONCLUSIONS: Caregiver identity, and possibly availability, appears to negatively affect rehabilitation outcomes in subacute stroke. A better understanding of these relationships has potential implications on clinical practice and policy directions. PMID- 28363701 TI - Measuring Inpatient Rehabilitation Facility Quality of Care: Discharge Self-Care Functional Status Quality Measure. AB - OBJECTIVE: To describe the calculation and psychometric properties of the discharge self-care functional status quality measure implemented in the Centers for Medicare & Medicaid Services' (CMS) Inpatient Rehabilitation Facility (IRF) Quality Reporting Program on October 1, 2016. DESIGN: Medicare fee-for-service (FFS) patients from 38 IRFs that participated in the CMS Post-Acute Care Payment Reform Demonstration were included in this cohort study. Data came from the Continuity Assessment Record and Evaluation Item Set, IRF-Patient Assessment Instrument, and Medicare claims. For each patient, we calculated an expected discharge self-care score, risk-adjusted for demographic and baseline clinical characteristics. The performance score of each IRF equaled the percentage of patient stays where the observed discharge self-care score met or exceeded the expected score. We assessed the measure's discriminatory ability across IRFs and reliability. SETTING: IRFs. PARTICIPANTS: Medicare FFS patients aged >=21 years (N=4769). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Facility-level discharge self-care quality measure performance score. RESULTS: A total of 4769 patient stays were included; 57% of stays were in women, and 12.1% were in patients aged <65 years. Stroke was the most common diagnosis (21.8%). The mean+/ SD performance score was 55.1%+/-16.6% (range, 25.8%-100%). About 54% of IRFs had scores significantly different from the percentage of stays that met or exceeded the expected discharge self-care score in the overall demonstration sample. The quality measure showed strong reliability, with intraclass correlation coefficients of .91. CONCLUSIONS: The discharge self-care quality measure showed strong discriminatory ability and reliability, representing an important initial step in evaluation of IRF self-care outcomes. A wide range in performance scores suggested a gap in quality of care across IRFs. Future work should include testing the measure with nationwide data from all IRFs. PMID- 28363702 TI - Communication Skills Training for Practitioners to Increase Patient Adherence to Home-Based Rehabilitation for Chronic Low Back Pain: Results of a Cluster Randomized Controlled Trial. AB - OBJECTIVE: To assess the effect of an intervention designed to enhance physiotherapists' communication skills on patients' adherence to recommendations regarding home-based rehabilitation for chronic low back pain. DESIGN: Cluster randomized controlled trial. SETTING: Publicly funded physiotherapy clinics. PARTICIPANTS: A sample (N=308) of physiotherapists (n=53) and patients with chronic low back pain (n=255; 54% female patients; mean age, 45.3y). INTERVENTIONS: Patients received publicly funded individual physiotherapy care. In the control arm, care was delivered by a physiotherapist who had completed a 1 hour workshop on evidence-based chronic low back pain management. Patients in the experimental arm received care from physiotherapists who had also completed 8 hours of communication skills training. MAIN OUTCOME MEASURES: (1) Patient reported adherence to their physiotherapists' recommendations regarding home based rehabilitation measured at 1, 4, 12, and 24 weeks after the initial treatment session. (2) Pain and pain-related function measured at baseline and at 4, 12, and 24 weeks. RESULTS: A linear mixed model analysis revealed that the experimental arm patients' ratings of adherence were higher than those of controls (overall mean difference, .41; 95% confidence interval, .10-.72; d=.28; P=.01). Moderation analyses revealed that men, regardless of the intervention, showed improvements in pain-related function over time. Only women in the experimental arm showed functional improvements; female controls showed little change in function over time. The Communication Style and Exercise Compliance in Physiotherapy intervention did not influence patients' pain, regardless of their sex. CONCLUSIONS: Communication skills training for physiotherapists had short term positive effects on patient adherence. This training may provide a motivational basis for behavior change and could be a useful component in complex interventions to promote adherence. Communication skills training may also improve some clinical outcomes for women, but not for men. PMID- 28363703 TI - Carers' Experiences, Needs, and Preferences During Inpatient Stroke Rehabilitation: A Systematic Review of Qualitative Studies. AB - OBJECTIVE: To report and synthesize the experiences, needs, and preferences of carers of stroke survivors undergoing inpatient rehabilitation. DATA SOURCES: MEDLINE, CINAHL, Embase, PsycINFO, and Web of Science were searched to March 2016. Reference lists of relevant publications were searched. No language restrictions were applied. STUDY SELECTION: Eligible qualitative studies reported the experiences of carers of stroke survivors who underwent inpatient rehabilitation. The search yielded 3532 records; 93 full-text publications were assessed for eligibility, and 34 documents (33 studies) were included. Comprehensiveness of reporting was assessed using the Consolidated Criteria for Reporting Qualitative Health Research framework. DATA EXTRACTION: Data on the characteristics of included studies were independently extracted by 2 authors. Differences in data extraction between authors were resolved through discussion or by a third author. All text in studies' results and discussion sections were extracted for analysis. DATA SYNTHESIS: Extracted texts were analyzed inductively using thematic synthesis. Seven analytical themes were developed that related to the carers' experiences, needs, and preferences: (1) overwhelmed with emotions; (2) recognition as a stakeholder in recovery; (3) desire to be heard and informed; (4) persisting for action and outcomes; (5) being legitimate clients; (6) navigating an alien culture and environment; and (7) managing the transition home. CONCLUSIONS: This systematic review provides new insights into the experiences, needs, and preferences of carers of stroke survivors undergoing inpatient rehabilitation. Carers experienced distress as they navigated a foreign culture and environment without adequate communication and processes in place for their inclusion. We recommend deliberate efforts to provide a more inclusive environment that better supports and prepares carers for their new role. PMID- 28363704 TI - Measuring Participation of Rehabilitation Patients: Test-Retest Reliability and Mode of Administration Concordance of the Participation Measure-3 Domains, 4 Dimensions (PM-3D4D). AB - OBJECTIVE: To evaluate the test-retest reliability and the concordance between the interviewer-administered version and the self-administered version of a newly developed participation measure, Participation Measure-3 Domains, 4 Dimensions (PM-3D4D). DESIGN: Multicenter observational study. SETTING: Outpatient rehabilitation programs. PARTICIPANTS: Rehabilitation outpatients (N=262) participated in the study, including those (n=202) who participated in the test retest study and those (n=60) who participated in the 2 modes of the administration study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The PM-3D4D includes 19 items measuring participation in productivity, social, and community domains across 4 dimensions: diversity of participation, frequency of participation, desire for change, and difficulty in participation. RESULTS: The test-retest reliability was good across domains and dimensions (intraclass correlation coefficients, .76-.96) as well as in neurological and nonneurological groups. The test-retest reliability was also mostly good at the item level. A high concordance was found between the 2 administration modes (intraclass correlation coefficients, 0.96-1.00). CONCLUSIONS: The study results lend support to the use of the PM-3D4D to reliably assess participation of rehabilitation patients. The high concordance between the 2 administration modes suggests the potential use of the instrument in population-based research. PMID- 28363705 TI - Relationship between plasma adropin levels and body composition and lipid characteristics amongst young adolescents in Taiwan. AB - Adropin is a 76 amino acid peptide hormone with a molecular weight of 4999.9Da that may be associated with energy homeostasis, insulin resistance and lipid metabolism in mice and human. There is only a few studies that examine plasma adropin levels and body composition in children. This study is to evaluate the relationship between plasma adropin levels, body composition and lipid variables amongst young adolescents in Taiwan. We examined 492 adolescents (269 females and 223 males) ranging from 12 to 15 years old, with a mean age of 13.6 years. Body composition was measured using impedance method by Tanita-BC418. Plasma lipid variables were measured using standard methods and plasma adropin levels were measured using the ELISA method. There was no significant difference in plasma adropin levels between males and females (3.52 vs. 3.58ng/ml). Plasma adropin levels were negatively correlated with fat free mass (r=-0.12, p<0.01). More interestingly, children with higher plasma adropin levels had lower waist-to-hip ratios (WHR) and lower body fat percentage by mass. Furthermore, there is no difference in lipid profiles in high vs. low adropin subjects. Plasma adropin levels are not consistency associated with body composition and no association with lipid variables amongst Taiwanese adolescents. The role of adropin in the development of obesity is still not clear, and further studies are need especially for children. PMID- 28363706 TI - Do All Patients With Heart Failure Benefit From a Program for Early Follow-up After Hospital Discharge? PMID- 28363699 TI - Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016. AB - The discovery of the endogenous melanocortin agonists in the 1950s have resulted in sixty years of melanocortin ligand research. Early efforts involved truncations or select modifications of the naturally occurring agonists leading to the development of many potent and selective ligands. With the identification and cloning of the five known melanocortin receptors, many ligands were improved upon through bench-top in vitro assays. Optimization of select properties resulted in ligands adopted as clinical candidates. A summary of every melanocortin ligand is outside the scope of this review. Instead, this review will focus on the following topics: classic melanocortin ligands, selective ligands, small molecule (non-peptide) ligands, ligands with sex-specific effects, bivalent and multivalent ligands, and ligands advanced to clinical trials. Each topic area will be summarized with current references to update the melanocortin field on recent progress. This article is part of a Special Issue entitled: Melanocortin Receptors - edited by Ya-Xiong Tao. PMID- 28363707 TI - Effects of Ivabradine on Heart Rate and Hemodynamic Parameters in a Swine Model of Cardiogenic Shock. PMID- 28363709 TI - Radiation Exposure to the Pregnant Interventional Cardiologist. Is It Really Necessary? PMID- 28363708 TI - Trends and Characteristics of Hospitalization for Heart Failure in a Population Setting From 2003 to 2013. AB - INTRODUCTION AND OBJECTIVES: Population-based studies in other countries have reported a reduction of standardized rates of hospitalization for heart failure (HF) but data from a well-defined population are lacking in Spain. METHODS: All hospitalizations with a principal diagnosis of HF between 2003 and 2013 were obtained from the Minimum Basic Data Set, which includes all hospitals in the Region of Murcia. Health care episodes were identified by the individual health card (27 158 episodes). For each year, we studied the following parameters: crude, age-standardized and sex-standardized hospitalization rates for HF, length of stay, mortality, clinical variables, and the Elixhauser index. Time trends were analyzed using joinpoint regression. RESULTS: Hospitalization rates increased by 76.7%, from 1.280/00 to 2.260/00 (crude) and 1.060/00 to 1.770/00 (standardized); the mean annual percentage of change (APC) was 8.2% until 2007 and was subsequently 1.9% (P < .05). Rates doubled in persons >= 75 years, reaching 19.90/00 in those aged 75 to 84 years (APC, 5.4%) and 32.50/00 in those aged >= 85 years (APC, 11.7%) but were unchanged in persons aged < 75 years. The hospitalization rate was 36% higher in women than in men but was equal after age standardization and showed no temporal change. The Elixhauser comorbidity index increased by almost 1 point during the study period and episodes > 6 points increased by 2-fold. Length of stay and mortality were unchanged during the study period. CONCLUSIONS: Between 2003 and 2013, there was a sustained increase in standardized rates of hospitalization for HF, which affected persons >= 75 years and was associated with a rise in comorbidity. There is a need for strategies focused on this population. PMID- 28363710 TI - Heart Failure Programs / Units. A Multidisciplinary Approach. PMID- 28363711 TI - Prevalence of Electrocardiographic Patterns Associated With Sudden Cardiac Death in the Spanish Population Aged 40 Years or Older. Results of the OFRECE Study. AB - INTRODUCTION AND OBJECTIVES: Some electrocardiographic patterns are associated with an increased risk of sudden cardiac death due to ventricular arrhythmias. There is no information on the prevalence of these patterns in the general population in Spain. The objective of this study was to analyze the prevalence of these patterns and associated clinical and epidemiological factors. METHODS: This subanalysis of the OFRECE study selected a representative sample of the Spanish population aged >= 40 years. We studied the presence or absence of electrocardiographic patterns of Brugada syndrome and QT interval abnormalities. Clinical data and electrocardiograms were available in all participants. Electrocardiograms were evaluated by 2 cardiologists and a third cardiologist was consulted if there was disagreement in the diagnosis. We calculated the weighted prevalence and clinical factors associated with the presence of Brugada-type patterns or QT segment abnormalities. RESULTS: Overall, 8343 individuals were evaluated (59.2 years, 52.4% female). There were 12 Brugada cases (type 1, 2 cases; type 2, 10 cases; weighted prevalence, 0.13%). For corrected QT (QTc) analysis, we excluded participants with left bundle branch block or without sinus rhythm. Weighted prevalences were as follows: short QTc (< 340ms) 0.18%, borderline QTc (441-469ms) 8.33%, long QTc (>= 470ms criterion) 1.01% and long QTc (>= 480 criterion) 0.42%. CONCLUSIONS: A total of 0.6% to 1.1% of the Spanish population aged >= 40 years has an electrocardiographic pattern associated with a higher risk of sudden death (Brugada syndrome, long QT, or short QT). PMID- 28363712 TI - Partial cricotracheal resection for severe upper tracheal stenosis: Potential impacts on the outcome. AB - OBJECTIVE: The aim of this study was to investigate the potential impact of multiple preoperative and intraoperative variables on the outcome of partial cricotracheal resection and tracheal resection anastomosis (PCTR/TRA). METHODS: The study was conducted on 35 consecutive patients of grade III and IV upper tracheal stenosis with or without subglottic involvement. The indication of PCTR/TRA was post intubation stenosis in all patients. Overall complications (major and minor) occurred in 18 patients. Perioperative mortality occurred in 1 patient. Anastomotic complications do not always mean failure of surgery. They may indicate one or more interventions; such as removal of granulation tissue or dilatation of restenosis, with good results in most cases. RESULTS: At the end of treatment, 30 (85.7%) patients were decannulated successfully with effortless breathing and with good phonation and swallowing. Several perioperative factors were found to have a significant impact on the outcome of PCTR/TRA. Of these factors, comorbidities had the most significant negative impact, and indeed all the three patients who had comorbidities, were not successfully decannulated. Duration of intubation, length of resected segment and previous open airway interventions was reported to have a significant negative impact on the outcome of surgery. CONCLUSION: PCTR/TRA for treatment of post traumatic subglottic or upper tracheal stenosis has a high success rate, especially in healthy patients without comorbidities, and without previous open airway interventions. PMID- 28363713 TI - The indication for endoscopic butterfly cartilage myringoplasty in children. PMID- 28363714 TI - The Effects of Requiring Parental Consent for Research on Adolescents' Risk Behaviors: A Meta-analysis. AB - PURPOSE: Requiring parental consent may result in sampling biases that confound scientific conclusions and stifle the representation of children most at risk for adverse outcomes. This study aims to investigate whether active parental consent, compared with passive parental consent, creates a bias in response rate, demographic makeup, and adverse outcomes in adolescent samples. METHODS: A meta analysis was performed on peer-reviewed articles and unpublished dissertations from 1975 to 2016 in five computerized databases ERIC, PsycINFO, MEDLINE, PubMed and ProQuest. Quantitative studies were retained if they included the following keywords: active consent (or informed consent or parental consent), passive consent (or waiver of consent), risk behavior, adolescen*. RESULTS: Fifteen studies were identified with a total number of 104,074 children. Results showed (1) response rates were significantly lower for studies using active consent procedure than those using passive consent procedure (Z = 3.05, p = .002); (2) more females, younger participants, and less African-Americans were included in studies using active consent procedures than studies using passive procedures (Z = -2.73, p = .006; Z = -12.06, p < .00001; Z = 2.19, p = .03, respectively); (3) studies with passive consent procedures showed higher rates of self-reported substance use than studies using active consent procedures (Z = 3.07, p = .002). CONCLUSIONS: Requiring active parental consent can lead to a systematic bias in the sample where the population under study is misrepresented. Institutional review board committees should collaborate with researchers to find solutions that protect minors without silencing the voice of high-risk youth in the literature. PMID- 28363715 TI - Why Are Orphaned Adolescents More Likely to Be HIV Positive? Distinguishing Between Maternal and Sexual HIV Transmission Using 17 Nationally Representative Data Sets in Africa. AB - PURPOSE: Why do orphans have higher rates of HIV infection than nonorphaned peers? Research consistently assumes that orphans acquire HIV primarily through sexual behavior, but infections may instead be due to maternal transmission. Although these two pathways have very different implications for HIV programs and policies, their relative contribution has not been previously examined. In this research, we compare the contribution of maternal and sexual transmission to HIV infection among orphans in Africa. METHODS: We use Demographic and Health Survey data for 21,463 women and 18,359 men from 17 countries. We propose a conceptual framework linking orphanhood to HIV, and use mediation analysis and structural equation modeling to compare the potential contribution of maternal transmission (measured through direct pathways from orphanhood to HIV) and sexual transmission (measured through reports of risky sexual behavior) to orphan HIV infection. RESULTS: Our results suggest that maternal transmission is the predominant pathway of HIV infection among orphaned adolescents: there is strong evidence for a direct pathway from maternal (odds ratio [OR]: 2.45; 95% confidence interval [CI]: 1.72-3.51 for females and OR: 2.45; 95% CI: 1.53-3.90 for males) and double orphanhood (OR: 2.69; 95% CI: 1.97-3.66 and OR: 2.53; 95% CI: 1.68-3.82, respectively) to HIV; greater excess HIV risk in maternal versus paternal orphans. The contribution of sexual behavior is largely not significant. We do not observe correspondingly high orphan disparities in other sexually transmitted diseases. CONCLUSIONS: Maternal transmission is a more likely explanation than sexual transmission for heightened HIV infection among orphans. These results suggest that programs designed to address HIV infection among adolescents should focus on reducing maternal transmission and on identifying and testing undiagnosed HIV among orphans. PMID- 28363716 TI - Fertility Preservation for Transgender Adolescents. AB - PURPOSE: To describe fertility preservation (FP) utilization by transgender adolescents within a pediatric gender clinic between July 2013 and July 2016. METHODS: A retrospective chart review was conducted to abstract demographic and clinical information among adolescents initiating gender-affirming hormones, including patient age at initial FP consultation, birth-assigned sex, race/ethnicity, and outcome of FP consultation. RESULTS: In our sample of 105 transgender adolescents, a total of 13 (seven transgender men and six transgender women) between the age of 14.2 and 20.6 years were seen in formal consultation for FP before initiating hormones. Of these adolescents, four completed sperm cryopreservation and one completed oocyte cryopreservation. CONCLUSIONS: Rates of FP utilization among transgender youth were low, which is consistent with a recently published report of FP utilization among transgender youth at another pediatric institution. Identified barriers to FP in our sample included cost, invasiveness of procedures, and desire not to delay medical transition. PMID- 28363717 TI - Prevalence of Metabolically Healthy but Overweight/Obese Phenotype and Its Association With Sedentary Time, Physical Activity, and Fitness. AB - PURPOSE: Childhood obesity is one of the major concerns in the last years due to the association with future health problems and all-cause mortality. However, there is a subset of adolescents with overweight/obesity who present a metabolic healthy profile. Therefore, the aim of this study was to examine the prevalence of metabolically healthy but overweight/obese adolescents and whether sedentary time, physical activity, and fitness differ between metabolically healthy and nonmetabolically healthy phenotypes. METHODS: A subsample of 237 European adolescents from the HEalthy Lifestyle in Europe by Nutrition in Adolescence study (n = 3,528, participation rate: 61.3%) with overweight/obesity were included. The study sample was not fully representative for the European adolescent population. Based on sex- and age-specific metabolic syndrome cutoff points for triglycerides, glucose, blood pressure, and high-density cholesterol participants were classified as metabolically healthy or nonmetabolically healthy. Sedentary time, physical activity, and fitness were assessed by accelerometry and the Alpha battery, respectively. RESULTS: The prevalence of metabolically healthy status in adolescents with overweight and obesity was higher in girls (87%) than in boys (74%, p = .019), being similar when only obesity was considered. Sedentary time was lower in metabolically healthy overweight/obese than in nonmetabolically healthy participants (mean difference = 48.0 minutes, p = .012). Moderate and moderate-to-vigorous physical activity were higher (p's < .05) in metabolically healthy than in nonmetabolically healthy adolescents with overweight/obesity (mean difference = 7.9 min/day and 10.9 min/day, respectively). No significant differences were found in fitness. Overall, these results persisted when only adolescents with obesity were included in the analyses. CONCLUSIONS: Metabolically healthy adolescents with overweight/obesity are less sedentary and more active than their nonmetabolically healthy peers with overweight/obesity, yet consistent differences in fitness were not observed. PMID- 28363718 TI - Adolescent Tobacco Use in Urban Versus Rural Areas of the United States: The Influence of Tobacco Control Policy Environments. AB - PURPOSE: Adults and adolescents who reside in rural areas of the United States are traditionally more likely to be tobacco users. This urban-rural disparity remains largely unexplained and, more recently, it is unclear what impact the emergence of electronic cigarettes (e-cigarettes) has had on adolescent tobacco use in urban and rural areas. Our objective is to evaluate the influence of sociodemographics and tobacco control policy environments on adolescent tobacco use in urban versus rural areas, as well as to identify the effect of e cigarettes on traditional patterns of urban-rural tobacco use. METHODS: This study analyzes repeated cross-sectional data from the National Youth Tobacco Survey for the years 2011-2014. We estimate the associations between rural residence, cigarette taxes, tobacco advertisement exposure, and ease of access to tobacco with six tobacco use outcomes: current (past 30-day) use of cigarettes, e cigarettes, cigars, smokeless tobacco, multiple tobacco products, and any tobacco. RESULTS: E-cigarette use among urban youths aged 11-17 years in the United States increased from .82% in 2011 to 8.62% in 2014 (p < .001). Tobacco advertisement exposure was significantly positively associated with all current tobacco use outcomes (p < .001) except for e-cigarettes. Our predictors account for approximately 40% of the difference in urban-rural cigarette use. CONCLUSIONS: Sociodemographics, cigarette taxes, and tobacco advertisement exposure are significant predictors of adolescent tobacco use in the United States but do not entirely explain urban-rural disparities. In addition, e cigarettes appear to be rapidly changing traditional patterns of tobacco use, particularly in urban areas. PMID- 28363719 TI - Teen Dating Violence Victimization, Trauma Symptoms, and Revictimization in Early Adulthood. AB - PURPOSE: This research examined whether experiencing physical teen dating violence (TDV) relates to trauma symptoms, which in turn, predict future physical dating violence victimization in early adulthood. METHODS: Adolescents (N = 843) recruited from high schools reported on their experiences of physical TDV victimization and trauma symptoms. The sample was followed over a 5-year period to assess for revictimization in early adulthood. RESULTS: Trauma symptoms functioned as a mediator between experiences of physical TDV victimization during adolescence and later revictimization in early adulthood, even in a conservative test of mediation that controlled for baseline trauma symptoms. Multigroup analyses testing for gender differences suggest that this mediation model is significant for females but not for males. CONCLUSIONS: The present findings suggest that the mental health consequences of experiencing physical TDV are an important factor contributing to future victimization in early adulthood. This holds potentially important implications for school-based efforts for reducing physical TDV. Specifically, school-based efforts to reduce victimization may be enhanced by supplementing existing efforts with empirically supported programs for addressing trauma symptoms. PMID- 28363722 TI - Skunkworks project for Big Pharma. PMID- 28363721 TI - Prevalence of Adolescent Gender Experiences and Gender Expression in Germany. AB - PURPOSE: Adolescence marks a transition period in the development of gender experience and expression. Although there is growing awareness about various gender identities in health research, only limited data on the prevalence of adolescent gender variance in the general population exist. METHODS: German female and male adolescents (n = 940) aged 10-16 years participating in the nationally representative "Health Behaviour in School-aged Children" Hamburg survey were asked to report their current gender experience (identification as both feminine and masculine) and gender expression (gender role as a girl or boy). Two overall categories and five subcategories on gender experience and expression were established based on previous research. RESULTS: In total, 4.1% of the adolescents' responses were rated as variant in gender experience and 3.0% as nonconforming in expression. Both variant experiences and nonconforming expression together were present in only .9% of adolescents. Gender variance was more strongly present in girls and in younger age groups. In detail, 1.6% reported an incongruent, 1.1% an ambivalent, and 1.5% no gender identification. Another 8.0% of the responses could be rated as only somewhat congruent. CONCLUSIONS: Fluidity between clearly congruent or incongruent pathways is present in adolescence, including variant as well as possibly still developing (only somewhat clear) gender experiences, whereas clearly incongruent identification and nonconforming expression were less frequent. Understanding adolescent gender development as multidimensional is important to identify the needs of those who do not fit into the current understanding of either female or male. PMID- 28363720 TI - Engagement With Online Tobacco Marketing and Associations With Tobacco Product Use Among U.S. Youth. AB - PURPOSE: Youth who engage with online tobacco marketing may be more susceptible to tobacco use than unengaged youth. This study examines online engagement with tobacco marketing and its association with tobacco use patterns. METHODS: Cross sectional analysis of youths aged 12-17 years who participated in wave 1 of the Population Assessment of Tobacco and Health Study (N = 13,651). Engagement with tobacco marketing was based on 10 survey items including signing up for email alerts about tobacco products in the past 6 months. Logistic regression was used to examine the association of online engagement with tobacco marketing and susceptibility to use any tobacco product among never-tobacco users, ever having tried tobacco, and past 30-day tobacco use. RESULTS: An estimated 2.94 million U.S. youth (12%) engaged with >= one forms of online tobacco marketing. Compared with no engagement, the odds of susceptibility to the use of any tobacco product among never-tobacco users was independently associated with the level of online engagement: adjusted odds ratio (AOR) = 1.48 (95% confidence interval [CI], 1.24 1.76) for one form of engagement and AOR = 2.37 (95% CI, 1.53-3.68) for >= two forms of engagement. The odds of ever having tried tobacco were also independently associated with the level of online engagement: AOR = 1.33 (95% CI: 1.11-1.60) for one form of engagement and AOR = 1.54 (95% CI, 1.16-2.03) for >= two forms of engagement. The level of online engagement was not independently associated with past 30-day tobacco use. CONCLUSIONS: Online engagement with tobacco marketing may represent an important risk factor for the onset of tobacco use in youth. PMID- 28363723 TI - Regulation of PCSK9 by nutraceuticals. AB - PCSK9 (proprotein convertase subtilisin kexin type 9) is a liver secretory enzyme that regulates plasma low-density lipoprotein (LDL) cholesterol (LDL-C) levels through modulation of LDL receptor (LDLR) density on the surface of hepatocytes. Inhibition of PCSK9 using monoclonal antibodies can efficiently lower plasma LDL C, non-high-density lipoprotein cholesterol and lipoprotein (a). PCSK9 inhibition is also an effective adjunct to statin therapy; however, the cost-effectiveness of currently available PCSK9 inhibitors is under question. Nutraceuticals offer a safe and cost-effective option for PCSK9 inhibition. Several nutraceuticals have been reported to modulate PCSK9 levels and exert LDL-lowering activity. Mechanistically, those nutraceuticals that inhibit PCSK9 through a SREBP (sterol responsive element binding protein)-independent pathway can be more effective in lowering plasma LDL-C levels compared with those inhibiting PCSK9 through the SREBP pathway. The present review aims to collect available data on the nutraceuticals with PCSK9-inhibitory effect and the underlying mechanisms. PMID- 28363724 TI - Hidden targets of ubiquitin proteasome system: To prevent diabetic nephropathy. AB - Diabetic nephropathy (DN) is the major cause of end stage renal failure. Although, several therapeutic targets have emerged to prevent the progression of DN, the number of people with DN still continues to rise worldwide, suggesting an urgent need of novel targets to prevent DN completely. Currently, the role of ubiquitin proteasome system (UPS) has been highlighted in the pathogenesis and progression of various diseases like obesity, insulin resistance, atherosclerosis, cancers, neurodegerative disorders and including secondary complications of diabetes. UPS mainly involves in protein homeostatis through ubiquitination (post translational modification) and proteasomal degradation of various proteins. Ubiquitination, not only involves in proteasomal degradation, but also directs the substrate proteins to participate in multitude of cell signalling pathways. However, very little is known about ubiquitination and UPS in the progression of DN. This review mainly focuses on UPS and its components including E2 conjugating enzymes, E3 ligases and deubiquitinases (DUBs) in the development of DN and thus may help us to find novel therapeutic targets with in UPS to prevent DN completely in future. PMID- 28363726 TI - Time for a paradigm shift in paediatric anaesthesia in Europe. PMID- 28363727 TI - Re: Clinicopathological Features and Prognostic Value of Incidental Prostatic Adenocarcinoma in Radical Cystoprostatectomy Specimens: A Systematic Review and Meta-analysis of 13 140 Patients. PMID- 28363728 TI - Pelvic radiotherapy in the setting of rheumatoid arthritis: Refining the paradigm. AB - PURPOSE: Conflicting results concerning the toxicity of radiotherapy in the setting of rheumatoid arthritis were reported in literature. This work describes the toxicity profiles of patients with rheumatoid arthritis undergoing pelvic radiotherapy for gynecologic malignancies at our institution. PATIENTS AND METHODS: Charts of patients with rheumatoid arthritis who underwent pelvic radiotherapy for cervical or endometrial cancer in a curative intent at the Gustave-Roussy Cancer Campus between 1990 and 2015 were reviewed for treatment related toxicities. Acute and late effects were graded as per the Common Terminology Criteria for Adverse Events version 4.0 scoring system. RESULTS: Eight patients with cervical cancer and three with endometrial cancer were identified. Median follow-up was 56 months. Median external beam radiotherapy dose was 45Gy. All patients received a brachytherapy boost using either pulse- or low-dose rate technique. Concomitant chemotherapy was used in seven cases. Median time from rheumatoid arthritis diagnosis to external beam radiation therapy was 5 years. No severe acute gastrointestinal or genitourinary toxicity was reported. One patient had grade 3 dermatitis. Any late toxicity occurred in 7 /11 patients, and one patient experienced severe late toxicities. One patient with overt systemic rheumatoid arthritis symptoms at the time of external beam radiation therapy experienced late grade 3 ureteral stenosis, enterocolitis and lumbar myelitis. CONCLUSION: Pelvic radiotherapy, in the setting of rheumatoid arthritis, appears to be feasible, with potentially slight increase in low grade late events compared to other anatomic sites. Patients with overt systemic rheumatoid arthritis manifestation at the time of radiotherapy might be at risk of potential severe toxicities. PMID- 28363729 TI - Independent correlates of chronic kidney disease awareness among adults with type 2 diabetes. AB - BACKGROUND: Chronic Kidney Disease (CKD) is usually silent until advanced stages. Awareness of CKD is important to mitigate poorer outcomes. This study aims to understand the relationship(s) between CKD self-awareness and diagnosed CKD. METHODS: The study included 345 adults with type 2 diabetes from two primary care settings. Participants completed surveys assessing demographic information, self care behaviors and co-morbidities. Biological data were taken from medical records. CKD was diagnosed as eGFR=<59ml/min. CKD awareness was defined by a positive response to "has a doctor, nurse or other health professional ever told you that you have a kidney disease?" and/or "have you ever had kidney failure that required dialysis or a kidney transplant?" Logistic regression models were used to examine the association between CKD awareness and clinical/socio demographic variables. RESULTS: 31% of study patients had CKD based on eGFR (of which only 63% were aware). Stepwise regression showed that non-Hispanic blacks (OR=3.49, p=0.04), those with college education (OR=8.02, p=0.01), history of myocardial infarction (OR=10.12, p=0.002) or hypertension (OR=23.25, p=0.02), and those with Medicare, VA insurance, or other insurance (OR=8.08, 8.72, 101.47, respectively, p<0.01) were significantly more likely to be aware of CKD. Those with a history of stroke or depression (OR=0.21, 0.28, respectively, p=0.03, p=0.04) were significantly less likely to be aware of CKD. CONCLUSION: CKD awareness was found to be lower than diagnosed CKD rates. Factors associated with awareness include race, educational status and cardiovascular disease. Targeted strategies to increase CKD awareness may lead to improved health outcomes. PMID- 28363730 TI - What factors influence uptake of retinal screening among young adults with type 2 diabetes? A qualitative study informed by the theoretical domains framework. AB - AIMS: Young adults with type 2 diabetes (T2D, 18-39years) face increased risk of vision loss from diabetic retinopathy (DR). Retinal screening is essential to detect DR, yet screening rates for this group are low and little is known about the underlying factors influencing this important behavior. Using the theoretical domains framework (TDF) to guide data collection and analysis, we explored screening barriers and facilitator, contrasting them with a comparator group of older adults with T2D (40+ years). METHODS: Thirty semi-structured telephone interviews (10 younger, 20 older adults) were conducted. Data were coded into TDF domains with salience identified by "frequency" of reference. Screening facilitators and barriers were systematically compared between groups. RESULTS: Although many screening facilitators and barriers were shared by younger and older adults, additional factors highly relevant to the former included: social comparison with others ('social influences'); concern for the impact on the family unit, unrealistic optimism and perceived invulnerability ('beliefs about consequences'); lack of time and financial resources ('environmental context and resources'), and DR misconceptions ('knowledge'). CONCLUSIONS: This study demonstrated that young adult retinal screening behavior was influenced by additional social cognitive factors compared to older adults, providing a first step evidence base for clinicians and other health professionals, and potential targets for future eye health and retinal screening interventions. PMID- 28363731 TI - Kidney Injury and Repair Biomarkers in Marathon Runners. AB - BACKGROUND: Investigation into strenuous activity and kidney function has gained interest given increasing marathon participation. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: Runners participating in the 2015 Hartford Marathon. PREDICTOR: Completing a marathon. OUTCOMES: Acute kidney injury (AKI) as defined by AKI Network (AKIN) criteria. Stage 1 AKI was defined as 1.5- to 2-fold or 0.3-mg/dL increase in serum creatinine level within 48 hours of day 0 and stage 2 was defined as a more than 2- to 3-fold increase in creatinine level. Microscopy score was defined by the number of granular casts and renal tubular epithelial cells. MEASUREMENTS: Samples were collected 24 hours premarathon (day 0), immediately postmarathon (day 1), and 24 hours postmarathon (day 2). Measurements of serum creatinine, creatine kinase, and urine albumin were completed, as well as urine microscopy analysis. 6 injury urine biomarkers (IL-6, IL-8, IL-18, kidney injury molecule 1, neutrophil gelatinase-associated lipocalin, and tumor necrosis factor alpha) and 2 repair urine biomarkers (YKL-40 and monocyte chemoattractant protein 1) were measured. RESULTS: 22 marathon runners were included. Mean age was 44 years and 41% were men. 82% of runners developed an increase in creatinine level equivalent to AKIN-defined AKI stages 1 and 2. 73% had microscopy diagnoses of tubular injury. Serum creatinine, urine albumin, and injury and repair biomarker levels peaked on day 1 and were significantly elevated compared to day 0 and day 2. Serum creatine kinase levels continued to significantly increase from day 0 to day 2. LIMITATIONS: Small sample size and limited clinical data available at all time points. CONCLUSIONS: Marathon runners developed AKI and urine sediment diagnostic of tubular injury. An increase in injury and repair biomarker levels suggests structural damage to renal tubules occurring after marathon. The results of our study should be validated in larger cohorts with longer follow-up of kidney function. PMID- 28363733 TI - Quasi-experimental study designs series-paper 12: strengthening global capacity for evidence synthesis of quasi-experimental health systems research. AB - Evidence from quasi-experimental studies is often excluded from systematic reviews of health systems research despite the fact that such studies can provide strong causal evidence when well conducted. This article discusses global coordination of efforts to institutionalize the inclusion of causal evidence from quasi-experiments in systematic reviews of health systems research. In particular, we are concerned with identifying opportunities for strengthening capacity at the global and local level for implementing protocols necessary to ensure that reviews that include quasi-experiments are consistently of the highest quality. We first describe the current state of the global infrastructure that facilitates the production of systematic reviews of health systems research. We identify five important types of actors operating within this infrastructure: review authors; synthesis collaborations that facilitate the review process; synthesis interest groups that supplement the work of the larger collaborations; review funders; and end users, including policymakers. Then, we examine opportunities for intervening to build the capacity of each type of actors to support the inclusion of quasi-experiments in reviews. Finally, we suggest practical next steps for proceeding with capacity building efforts. Because of the complexity and relative nascence of the field, we recommend a carefully planned and executed approach to strengthening global capacity for the inclusion of quasi-experimental studies in systematic reviews. PMID- 28363732 TI - Race, Serum Potassium, and Associations With ESRD and Mortality. AB - BACKGROUND: Recent studies suggest that potassium levels may differ by race. The basis for these differences and whether associations between potassium levels and adverse outcomes differ by race are unknown. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: Associations between race and potassium level and the interaction of race and potassium level with outcomes were investigated in the Racial and Cardiovascular Risk Anomalies in Chronic Kidney Disease (RCAV) Study, a cohort of US veterans (N=2,662,462). Associations between African ancestry and potassium level were investigated in African Americans in the Atherosclerosis Risk in Communities (ARIC) Study (N=3,450). PREDICTORS: Race (African American vs non-African American and percent African ancestry) for cross-sectional analysis; serum potassium level for longitudinal analysis. OUTCOMES: Potassium level for cross-sectional analysis; mortality and end-stage renal disease for longitudinal analysis. RESULTS: The RCAV cohort was 18% African American (N=470,985). Potassium levels on average were 0.162mmol/L lower in African Americans compared with non-African Americans, with differences persisting after adjustment for demographics, comorbid conditions, and potassium-altering medication use. In the ARIC Study, higher African ancestry was related to lower potassium levels ( 0.027mmol/L per each 10% African ancestry). In both race groups, higher and lower potassium levels were associated with mortality. Compared to potassium level of 4.2mmol/L, mortality risk associated with lower potassium levels was lower in African Americans versus non-African Americans, whereas mortality risk associated with higher levels was slightly greater. Risk relationships between potassium and end-stage renal disease were weaker, with no difference by race. LIMITATIONS: No data for potassium intake. CONCLUSIONS: African Americans had slightly lower serum potassium levels than non-African Americans. Consistent associations between potassium levels and percent African ancestry may suggest a genetic component to these differences. Higher and lower serum potassium levels were associated with mortality in both racial groups. PMID- 28363734 TI - The Dutch-Flemish PROMIS Physical Function item bank exhibited strong psychometric properties in patients with chronic pain. AB - OBJECTIVE: The objective of this study was to assess the psychometric properties of the Dutch-Flemish Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function item bank in Dutch patients with chronic pain. STUDY DESIGN AND SETTING: A bank of 121 items was administered to 1,247 Dutch patients with chronic pain. Unidimensionality was assessed by fitting a one-factor confirmatory factor analysis and evaluating resulting fit statistics. Items were calibrated with the graded response model and its fit was evaluated. Cross cultural validity was assessed by testing items for differential item functioning (DIF) based on language (Dutch vs. English). Construct validity was evaluated by calculation correlations between scores on the Dutch-Flemish PROMIS Physical Function measure and scores on generic and disease-specific measures. RESULTS: Results supported the Dutch-Flemish PROMIS Physical Function item bank's unidimensionality (Comparative Fit Index = 0.976, Tucker Lewis Index = 0.976) and model fit. Item thresholds targeted a wide range of physical function construct (threshold-parameters range: -4.2 to 5.6). Cross-cultural validity was good as four items only showed DIF for language and their impact on item scores was minimal. Physical Function scores were strongly associated with scores on all other measures (all correlations <= -0.60 as expected). CONCLUSION: The Dutch Flemish PROMIS Physical Function item bank exhibited good psychometric properties. Development of a computer adaptive test based on the large bank is warranted. PMID- 28363735 TI - Evolution of tenofovir-resistant HIV-1 isolates exposed to tenofovir alafenamide dose escalation. AB - Resistance selection experiments using HIV-1 isolates harboring pre-existing tenofovir (TFV)-resistance (K65R, 3TAMs, and Q151M complex) were carried out with the novel tenofovir prodrug tenofovir alafenamide (TAF) as well as with tenofovir (TFV), to investigate the potential for additional resistance development in the presence of TAF or TFV. Extended resistance selection of these TFV resistance associated mutations (RAMs)-containing viruses with TAF or TFV did not lead to the accumulation of additional known RAMs, or significant additional phenotypic resistance, after 6 months in culture. Two new mutations were found during the selections (L429I, T69I) that were further characterized, and found to have very limited or no role in resistance to TAF or TFV. Notably, viral survival in the presence of drug increases could not be sustained and led to viral cure in cell culture, suggesting a lack of alternative resistance pathways for the mutant viruses. PMID- 28363738 TI - Ex vivo lung perfusion: The makings of a game changer. PMID- 28363737 TI - Coordinated development of the limb musculoskeletal system: Tendon and muscle patterning and integration with the skeleton. AB - Functional movement and stability of the limb depends on an organized and fully integrated musculoskeletal system composed of skeleton, muscle, and tendon. Much of our current understanding of musculoskeletal development is based on studies that focused on the development and differentiation of individual tissues. Likewise, research on patterning events have been largely limited to the primary skeletal elements and the mechanisms that regulate soft tissue patterning, the development of the connections between tissues, and their interdependent development are only beginning to be elucidated. This review will therefore highlight recent exciting discoveries in this field, with an emphasis on tendon and muscle patterning and their integrated development with the skeleton and skeletal attachments. PMID- 28363740 TI - The First Filmed Prostatectomy, 1917: 100 Years of Movies in Urological Education. PMID- 28363736 TI - Systems biology of facial development: contributions of ectoderm and mesenchyme. AB - The rapid increase in gene-centric biological knowledge coupled with analytic approaches for genomewide data integration provides an opportunity to develop systems-level understanding of facial development. Experimental analyses have demonstrated the importance of signaling between the surface ectoderm and the underlying mesenchyme are coordinating facial patterning. However, current transcriptome data from the developing vertebrate face is dominated by the mesenchymal component, and the contributions of the ectoderm are not easily identified. We have generated transcriptome datasets from critical periods of mouse face formation that enable gene expression to be analyzed with respect to time, prominence, and tissue layer. Notably, by separating the ectoderm and mesenchyme we considerably improved the sensitivity compared to data obtained from whole prominences, with more genes detected over a wider dynamic range. From these data we generated a detailed description of ectoderm-specific developmental programs, including pan-ectodermal programs, prominence- specific programs and their temporal dynamics. The genes and pathways represented in these programs provide mechanistic insights into several aspects of ectodermal development. We also used these data to identify co-expression modules specific to facial development. We then used 14 co-expression modules enriched for genes involved in orofacial clefts to make specific mechanistic predictions about genes involved in tongue specification, in nasal process patterning and in jaw development. Our multidimensional gene expression dataset is a unique resource for systems analysis of the developing face; our co-expression modules are a resource for predicting functions of poorly annotated genes, or for predicting roles for genes that have yet to be studied in the context of facial development; and our analytic approaches provide a paradigm for analysis of other complex developmental programs. PMID- 28363739 TI - Functional status of United States children supported with a left ventricular assist device at heart transplantation. AB - BACKGROUND: As survival with pediatric left ventricular assist devices (LVADs) has improved, decisions regarding the optimal support strategy may depend more on quality of life and functional status (FS) rather than mortality alone. Limited data are available regarding the FS of children supported with LVADs. We sought to compare the FS of children supported with LVADs vs vasoactive infusions to inform decision making around support strategies. METHODS: Organ Procurement and Transplant Network data were used to identify all United States children aged between 1 and 21 years at heart transplant (HT) between 2006 and 2015 for dilated cardiomyopathy and supported with an LVAD or vasoactive infusions alone at HT. FS was measured using the 10-point Karnofsky and Lansky scale. RESULTS: Of 701 children who met the inclusion criteria, 430 (61%) were supported with vasoactive infusions, and 271 (39%) were supported with an LVAD at HT. Children in the LVAD group had higher median FS scores at HT than children in the vasoactive infusion group (6 vs 5, p < 0.001) but lower FS scores at listing (4 vs 6, p < 0.001). The effect persisted regardless of patient location at HT (home, hospital, intensive care) or device type. Discharge by HT occurred in 46% of children in the LVAD group compared with 26% of children in the vasoactive infusion cohort (p = 0.001). Stroke was reported at HT in 3% of children in the LVAD cohort and in 1% in the vasoactive infusion cohort (p = 0.04). CONCLUSIONS: Among children with dilated cardiomyopathy undergoing HT, children supported with LVADs at HT have higher FS than children supported with vasoactive infusions at HT, regardless of device type or hospitalization status. Children supported with LVADs at HT were more likely to be discharged from the hospital but had a higher prevalence of stroke at HT. PMID- 28363741 TI - Intraductal Carcinoma of the Prostate: A Risk for Rapid Recurrence. AB - Intraductal carcinoma of the prostate (IDC-P), recently defined by the World Health Organization in 2016, is a distinct histologic entity associated with an aggressive clinical course, including increased risk of biochemical recurrence, metastasis, and mortality. Differential diagnosis includes intraductal spread of urothelial carcinoma, prostatic ductal carcinoma, and high-grade prostatic intraepithelial neoplasia. BRCA mutations are associated with an increased risk of IDC-P. The presence of IDC-P on initial biopsy or radical prostatectomy should trigger aggressive treatment and should be considered a contraindication to active surveillance, regardless of tumor volume. PMID- 28363742 TI - Liraglutide relieves myocardial damage by promoting autophagy via AMPK-mTOR signaling pathway in zucker diabetic fatty rat. AB - Liraglutide, a glucose-lowering agent used to treat type 2 diabetic mellitus is reported to exert cardioprotective effects in clinical trials and animal experiments. However, the cardioprotective mechanism of liraglutide on diabetic cardiomyopathy has not been fully illustrated. The present study was performed to investigate whether liraglutide alleviates diabetic myocardium injury by promoting autophagy and its underlying mechanisms. Our results show that liraglutide significantly reduced the levels of creatine kinase (CK) and lactate dehydrogenase (LDH), improved left ventricular functional status and alleviated myocardial fibrosis in the Zucker diabetic fatty (ZDF) rat model. Liraglutide also mitigated high glucose-induced injury in NRCs. However these effects were partly reversed by the autophagic inhibitor chloroquine (CQ). Liraglutide promoted myocardial autophagy in the vivo and in the vitro models. Furthermore, liraglutide-induced enhancement of autophagy was related to increased AMPK phosphorylation and decreased mTOR phosphorylation, which was partially abolished by the AMPK inhibitor compound C (Comp C). Collectively, our data provide evidence that liraglutide mediated diabetic myocardium injury by promoting AMPK dependent autophagy. PMID- 28363743 TI - Xenopus metamorphosis as a model to study thyroid hormone receptor function during vertebrate developmental transitions. AB - A hormone-dependent developmental transition from aquatic to terrestrial existence occurs in all tetrapod vertebrates, such as birth, hatching, and metamorphosis. Thyroid hormones (TH) and their receptors (TRs) are key players in the tissue transformations comprising vertebrate developmental transitions. The African clawed frog, Xenopus, is a premier model for the role of TRs in developmental transitions because of the numerous and dramatic TH-dependent tissue transformations during metamorphosis and because of the endocrine, molecular, and genomic resources available. TRs are nuclear receptors that repress TH-response genes when plasma TH is minimal and that activate those same genes to induce tissue-specific gene regulation cascades when TH plasma levels increase. Tissue-specific TR expression levels help determine tissue sensitivity and responsivity to TH thereby regulating the initiation and rate of developmental change in TH-sensitive tissues which govern the tissue developmental asynchrony observed during metamorphosis. This review highlighting Xenopus presents the key experimental findings underpinning the roles TRs play in control of vertebrate developmental transitions. PMID- 28363744 TI - DREF plays multiple roles during Drosophila development. AB - DREF was originally identified as a transcription factor that coordinately regulates the expression of DNA replication- and proliferation-related genes in Drosophila. Subsequent studies demonstrated that DREF is involved in tumor suppressor pathways including p53 and Hippo signaling. DREF also regulates the expression of genes encoding components of the JNK and EGFR pathways during Drosophila development. DREF itself is under the control of the TOR pathway during cell and tissue growth responding to nutrition. Recent studies revealed that DREF plays a role in chromatin organization including insulator function, chromatin remodeling, and telomere maintenance. DREF is also involved in the regulation of genes related to mitochondrial biogenesis, linking it to cellular proliferation. Thus, DREF is now emerging as not only a transcription factor, but also a multi-functional protein. In this review, we summarize current advances in studies on the novel functions of Drosophila DREF. PMID- 28363745 TI - NKT cells in cardiovascular diseases. AB - Despite life-style advice and the prescription of cholesterol-lowering and anti thrombotic drugs, cardiovascular diseases are still the leading cause of death worldwide. Therefore, there is an urgent need for new therapeutic strategies focussing on atherosclerosis, the major underlying pathology of cardiovascular diseases characterized by an accumulation of lipids in an inflamed arterial/vessel wall. CD1d-restricted lipid-sensing natural killer T (NKT) cells, bridging the innate and adaptive immunity, and CD1d-expressing antigen-presenting cells are detected in atherosclerotic lesions of mice and humans. In this review we will summarize studies that point to a critical role for NKT cells in the pathogenesis of atherosclerosis and other cardiovascular diseases by the secretion of pro-atherogenic cytokines and cytotoxins. These pro-atherogenic NKT cells are potential targets for new therapeutic strategies in the prevention and treatment of cardiovascular diseases. Additionally, proteins transferring lipids during atherosclerosis, which are also important in the loading of lipids onto CD1d and possible endogenous ligands responsible for the activation of NKT cells during atherosclerosis will be discussed. PMID- 28363746 TI - A novel urotensin II receptor antagonist, KR-36676, prevents ABCA1 repression via ERK/IL-1beta pathway. AB - Urotensin II (U-II), the most potent vasoconstrictor peptide known to date, is expressed at a high level in vascular smooth muscle cells (VSMC) and endothelial cells, whereas its receptor, urotensin (UT) receptor, is abundant in monocytes and macrophages of atherosclerotic lesions. U-II is highly present in the coronary arteries of the atherosclerotic patients compared to normal subjects. Recently, U-II was shown to down-regulate ATP binding cassette transporter-A1 (ABCA1) expression, which is responsible for reverse cholesterol transport in macrophages of atherosclerotic lesions. However, the mechanism of this observation was not clearly elucidated. Previous studies also revealed that the proinflammatory cytokine interleukin-1beta (IL-1beta) repressed ABCA1 expression. To clarify the signaling pathway involved with respect to U-II-induced ABCA1 down regulation, we investigated whether IL-1beta was involved. Our results provided that U-II repressed ABCA1 through an ERK/ IL-1beta pathway. We further demonstrated that U-II receptor antagonist KR-36676 decreased IL-1beta production and significantly led to a recovery of ABCA1 expression at both mRNA and protein levels. In previous investigations, U-II receptor antagonists have been shown to protect atherosclerosis in cell and animal models. Our results imply that U-II receptor antagonist KR-36676 might be a potent candidate for treating atherosclerosis, and leading to a recovery of ABCA1 expression, affected by the ERK/IL-1beta pathway. PMID- 28363747 TI - Corrigendum to "The 2',4'-dihydroxychalcone could be explored to develop new inhibitors against the glycerol-3-phosphate dehydrogenase from Leishmania species" [Bioorg. Med. Chem. Lett. 25 (2015) 3564-3568]. PMID- 28363749 TI - Antimycobacterial N-alkoxyphenylhydroxynaphthalenecarboxamides affecting photosystem II. AB - N-(Alkoxyphenyl)-2-hydroxynaphthalene-1-carboxamides (series A) and N (alkoxyphenyl)-1-hydroxynaphthalene-2-carboxamides (series B) affecting photosystem (PS) II inhibited photosynthetic electron transport (PET) in spinach chloroplasts. Their inhibitory activity depended on the compound lipophilicity as well as on the position of the alkoxy substituent. The most potent PET inhibitors were 2-hydroxy-N-phenylnaphthalene-1-carboxamide and N-[3-(but-2-yloxy)phenyl]-2 hydroxynaphthalene-1-carboxamide within series A (IC50=28.9 and 42.5uM, respectively) and 1-hydroxy-N-(3-propoxyphenyl)naphthalene-2-carboxamide and 1 hydroxy-N-(3-ethoxyphenyl)-naphthalene-2-carboxamide (IC50=2.0 and 3.1uM, respectively) within series B. The inhibitory activity of C'(3) or C'(4) alkoxy substituted compounds of series B was considerably higher than that of C'(2) ones within series A. The PET-inhibiting activities of both series were compared with the PET inhibition of isomeric N-alkoxyphenyl-3-hydroxynaphthalene-2-carboxamides (series C) reported recently. Interactions of the studied compounds with chlorophyll a and aromatic amino acids present in pigment-protein complexes mainly in PS II were documented by fluorescence spectroscopy. The section between P680 and plastoquinone QB in the PET chain occurring on the acceptor side of PSII can be suggested as the site of action of the compounds. PMID- 28363748 TI - Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs). Part II: Optimization of 4-(pyrrolidin-1-yl)benzonitrile derivatives. AB - We recently reported a class of novel tissue-selective androgen receptor modulators (SARMs), represented by a naphthalene derivative A. However, their pharmacokinetic (PK) profiles were poor due to low metabolic stability. To improve the PK profiles, we modified the hydroxypyrrolidine and benzonitrile substituents of 4-(pyrrolidin-1-yl)benzonitrile derivative B, which had a comparable potency as that of compound A. This optimization led us to further modifications, which improved metabolic stability while maintaining potent androgen agonistic activity. Among the synthesized compounds, (2S,3S)-2,3 dimethyl-3-hydroxylpyrrolidine derivative 1c exhibited a suitable PK profile and improved metabolic stability. Compound 1c demonstrated significant efficacy in levator ani muscle without increasing the weight of the prostate in an in vivo study. In addition, compound 1c showed agonistic activity in the CNS, which was detected using sexual behavior induction assay. PMID- 28363751 TI - Laboratory medicine - A hidden treasure in healthcare. PMID- 28363750 TI - Synthesis of PET probe O6-[(3-[11C]methyl)benzyl]guanine by Pd0-mediated rapid C [11C]methylation toward imaging DNA repair protein O6-methylguanine-DNA methyltransferase in glioblastoma. AB - O6-Benzylguanine (O6-BG) is a substrate of O6-methylguanine-DNA methyltransferase (MGMT), which is involved in drug resistance of chemotherapy in the majority of glioblastoma multiform. For clinical diagnosis, it is hoped that the MGMT expression level could be determined by a noninvasive method to understand the detailed biological properties of MGMT-specific tumors. We synthesized 11C labeled O6-[(3-methyl)benzyl]guanine ([11C]mMeBG) as a positron emission tomography probe. Thus, a mixed amine-protected stannyl precursor, N9-(tert butoxycarbonyl)-O6-[3-(tributylstannyl)benzyl]-N2-(trifluoroacetyl)guanine, was subjected to rapid C-[11C]methylation under [11C]CH3I/[Pd2(dba)3]/P(o CH3C6H4)3/CuCl/K2CO3 in NMP, followed by quick deprotection with LiOH/H2O, giving [11C]mMeBG with total radioactivity of 1.34GBq and >=99% radiochemical and chemical purities. PMID- 28363752 TI - Are prehospital deaths from trauma and accidental injury preventable? A direct historical comparison to assess what has changed in two decades. AB - BACKGROUND & OBJECTIVES: In 1994, Hussain and Redmond revealed that up to 39% of prehospital deaths from accidental injury might have been preventable had basic first aid care been given. Since then there have been significant advances in trauma systems and care. The exclusion of prehospital deaths from the analysis of trauma registries, giv en the high rate of those, is a major limitation in prehospital research on preventable death. We have repeated the 1994 study to identify any changes over the years and potential developments to improve patient outcomes. METHODS: We examined the full Coroner's inquest files for prehospital deaths from trauma and accidental injury over a three-year period in Cheshire. Injuries were scored using the Abbreviated-Injury-Scale (AIS-1990) and Injury Severity Score (ISS), and probability of survival estimated using Bull's probits to match the original protocol. RESULTS: One hundred and thirty-four deaths met our inclusion criteria; 79% were male, average age at death was 53.6 years. Sixty two were found dead (FD), fifty-eight died at scene (DAS) and fourteen were dead on arrival at hospital (DOA). The predominant mechanism of injury was fall (39%). The median ISS was 29 with 58 deaths (43%) having probability of survival of >50%. Post-mortem evidence of head injury was present in 102 (76%) deaths. A bystander was on scene or present immediately after injury in 45% of cases and prior to the Emergency Medical Services (EMS) in 96%. In 93% of cases a bystander made the call for assistance, in those DAS or DOA, bystander intervention of any kind was 43%. CONCLUSIONS: The number of potentially preventable prehospital deaths remains high and unchanged. First aid intervention of any kind is infrequent. There is a potentially missed window of opportunity for bystander intervention prior to the arrival of the ambulance service, with simple first-aid manoeuvres to open the airway, preventing hypoxic brain injury and cardiac arrest. PMID- 28363753 TI - The use of external fixators in the definitive stabilisation of the pelvis in polytrauma patients: Safety, efficacy and clinical outcomes. AB - OBJECTIVES: To analyse the complications and outcomes (functional/radiographic) of Pelvic External Fixators applied as part of the definitive fixation in polytrauma patients. DESIGN: A single center retrospective chart review. SETTING: A level-1 trauma center. PATIENTS AND METHODS: We reviewed all the polytrauma patients (ISS>16) between 2007 and 2012 that had a PEF applied more than 30days. Complications including infection, aseptic loosening, neurological injury, loss of reduction, non-union and mal-union were recorded. Pelvic asymmetry and Deformity Index (DI) were measured at the immediate postoperative radiographs and final follow-up. The functional outcome at final follow up was estimated using a scale previously reported by Chiou et al. RESULTS: 59 patients with mean age of 38.4 (16 - 81) years and mean ISS score 28 (16- 66) were included. The PEFs were applied for mean duration of 56 (30-104) days. The average follow-up was 403days. 22 injuries were type B and 37 type C (AO/OTA). The most common symptomatic complications were pin site infection in 11 (18.6%) and loosening in 5 (8.5%) cases. 44 (74.5%) patients had satisfactory functional outcome. The immediate post-operative and final asymmetry and DI were compared between the two pelvic injury groups (type B and C fractures). The difference in displacement progression was more for type C injuries (p=0.034) but no correlation to the functional outcome was evident. CONCLUSION: PEF can be used as definitive alternative stabilization method in specific situations at polytrauma setting. Radiological displacement occurred in both type B and C injuries but the clinical outcome was not correlated to this displacement. Complications related to PEF do not affect the final clinical outcome. LEVEL OF EVIDENCE: Therapeutic Level III. PMID- 28363754 TI - Intrathecal insulin-like growth factor 1 but not insulin enhances myelin repair in young and aged rats. AB - One main pathological hallmark of multiple sclerosis (MS) is demyelination. Novel therapies which enhance myelin repair are urgently needed. Insulin and insulin like growth factor 1 (IGF-1) have strong functional relationships. Here, we addressed the potential capacity of IGF-1 and insulin to enhance remyelination in an animal demyelination model in vivo. We found that chronic intrathecal infusion of IGF-1 enhanced remyelination after lysolecithin-induced demyelination in the spinal cord of young and aged rats. Aged rats showed a weaker innate remyelination capacity and are therefore a good model for progressive MS which is defined by chronic demyelination. In contrast to IGF-1, Insulin had no effect on remyelination in either age group. Our findings highlight the potential use of IGF-1 as remyelinating therapy for MS, particularly the progressive stage in which chronic demyelination is the hallmark. PMID- 28363755 TI - An investigation of gene expression in single cells derived from Nestin expressing cells in the adult mouse midbrain in vivo. AB - Generation of new dopamine (DA) neurons in the adult midbrain is a controversial issue in development of better treatments for Parkinson's disease (PD). Previous research suggests Nestin-expressing neural precursor cells (NPCs) have a propensity to differentiate into neurons here, including DA neurons. In the present study we sought confirmation of this by studying gene expression in single Nestin-expressing cells and their progeny/ontogeny within the adult mouse midbrain. Cells were identified by administering a pulse of Tamoxifen to adult Nestin-CreERT2*R26eYFP transgenic mice. Samples of cytoplasm were harvested 4 days to 8 months later from individual eYFP+ cells in acutely prepared midbrain slices and analysed by RT-qPCR for gene expression. Remarkably, most eYFP+ cells co-expressed genes associated with mature (including DA) neurons (i.e. NeuN, Gad1, Gad2, vGlut2, TH and/or D2R) and neurogenesis (i.e. Ki67, Dcx, Ncam, Pax6, Ngn2 and/or Msx1), and this was true at all time-points following Tamoxifen. Indeed, cell proliferation genes (Nestin, Ki67) were exclusively expressed by eYFP+ cells with mature neuronal morphology and gene expression, and only at early time-points after Tamoxifen. Expression of proneuronal genes (Pax6, Msx1, Ngn2) was, however, higher in eYFP+ cells with immature morphology compared with mature morphology. Gene expression bore no relationship to cell location indicating that, in contrast to development, Nestin-expressing cells arise throughout the midbrain parenchyma and do not migrate long distances. On the other hand, gene expression did change with time after Tamoxifen, although not in a way consistent with neurogenesis. Overall, our results suggest that Nestin expression in the adult midbrain occurs in mature neurons, casting doubt on the premise of neurogenesis from Nestin+ NPCs here. PMID- 28363756 TI - HER2 as an Emerging Oncotarget for Colorectal Cancer Treatment After Failure of Anti-Epidermal Growth Factor Receptor Therapy. AB - Amplification of the HER2 gene is an indicator of poor prognosis for several kinds of malignancies such as breast and gastric cancer, and anti-HER2 targeting therapies provide clinical benefits in these patients. In 2011, HER2 was identified as a resistance molecule for de novo and secondary anti-epidermal growth factor receptor (EGFR) antibody therapy. HER2 activation provides a bypass signaling pathway after anti-EGFR antibody treatment of colorectal cancer. Cell line-based screening revealed that HER2 genomic amplification induces resistance to the anti-EGFR antibody cetuximab in colorectal cancer. Recently, HER2 itself has been recognized as a target for oncotherapy in colorectal cancer. The first part of this review provides an update on the present state of knowledge about the role of HER2 in colorectal cancer, including its prognostic relevance and role in resistance to anti-EGFR antibody treatment. In the second part of the review, we discuss the results of preclinical and clinical studies that examined the potential utility of anti-HER2 targeted therapy in colorectal cancer. Although it acts as a barrier for other molecular targeting agents such as cetuximab, HER2 itself is a promising target for oncotherapy. Current research indicates that anti-HER2 drugs will be developed further and introduced into clinical practice for the treatment of patients with HER2-positive colorectal cancer. PMID- 28363757 TI - Bactericidal effect of the photocatalystic reaction of titanium dioxide using visible wavelengths on Streptococcus mutans biofilm. AB - BACKGROUND: The aim of this study was to determine the effect of titanium dioxide (TiO2) photocatalysis induced by the application of clinically acceptable visible light at 405nm on the growth of Streptococcus mutans biofilms. METHODS: S. mutans biofilms were grown on a hydroxyapatite (HA) disk and deposited in a rutile-type TiO2 solution at a concentration of 0.1mg/mL. TiO2 photocatalysis was measured for exposure to visible light (405nm) and ultraviolet (UV) light (254nm) produced by light-emitting diodes for 10, 20, 30, and 40min. After two treatments, the number of colonies formed in the final S. mutans biofilm on the HA disk were measured to confirm their viability, and the morphological changes of S. mutans were evaluated using scanning electronic microscopy. RESULTS: The bactericidal effects of 254- and 405-nm light resulted in > 5-log and 4-log reductions, respectively (p<0.05), after 20min of treatment and a>7-log reduction after 40min of treatment in both treatment groups relative to the control group. CONCLUSION: It was confirmed that the antibacterial effect could be shown by causing the photocatalytic reaction of TiO2 in S. mutans biofilm even at the wavelength of visible light (405nm) as at the wavelength of ultraviolet light (254nm). PMID- 28363758 TI - Fluorescence spectroscopy as a tool to in vivo discrimination of distinctive skin disorders. AB - BACKGROUND: Fast and non-invasive analytical methods, as in fluorescence spectroscopy, have potential applications to detect modifications of biochemical and morphologic properties of malignant tissues. In this study, we propose to analyze the fluorescence spectra using k-Nearest Neighbours algorithm (k-NN) and ratio of the fluorescence intensity (FI) to differentiate skin disorders of distinctive etiologies and morphologies. MATERIALS AND METHODS: Laser-induced autofluorescence spectra upon excitation at 408nm were collected from basal cell carcinoma (BCC) subtypes (n=45/212 spectra), psoriasis (PS) (n=37/193 spectra) and Bowen's disease (BD) (n=04/19 spectra) lesions and respective normal skin at sun-exposed (EXP) and non-exposed (NEXP) sites of the same patient. RESULTS: The mean ratios of FI values at selected wavelengths of emission (FI600nm/FI500nm) were significantly lower in BCC and PS lesions compared to EXP [P=0.0001; P=0.0002, respectively]; but there were no significant differences between abnormal conditions. The analysis of fluorescence spectra using k-NN can discriminate normal or abnormal skin conditions (EXP, BCC, BD, PS) of distinctive etiology, neoplastic or inflammatory (BCC, BD and PS) and morphologies (nodular and superficial BCC, BD and PS) as high as 88% and 93% sensitivity and specificity means, respectively; also, similar erythematous-squamous features (superficial BCC, BD and PS) with 98% and 97% sensitivity and specificity means, respectively. The k-NN computational analysis appears to be a promising approach to distinguish skin disorders. PMID- 28363759 TI - Moving From One to Many. PMID- 28363761 TI - T1rho mapping improvement using stretched-type adiabatic locking pulses for assessment of human liver function at 3T. AB - PURPOSE: The purpose of this study is to investigate the performance of stretched type adiabatic spin lock pulses for homogeneous spin locking with a flexible spin lock time (TSL) setting. METHODS: T1rho values were obtained from 61 patients and five normal volunteers who were categorized using the Child-Pugh classification and scanned using each spin lock pulse type. The pulses used were the block and two kinds of hyperbolic secant (HS); HS8_10, and HS8_5. Visual scoring was categorized using a four point scale (1:Severe, 2:Moderate, 3:Mild and 4:None) to evaluate the homogeneity of the T1rho map and the source images obtained by each spin lock pulse. Mean T1rho values among the patient groups with different Child Pugh classification were compared. RESULTS: The visual assessment scores were 1.98 +/- 1.05 for block pulse locking, 3.87 +/- 0.39 for HS8_10 pulse locking, and 3.83 +/- 0.45 for HS8_5 pulse locking, respectively. The scores between block pulse and HS8_10 were significantly different (p < 0.001), as were those between block pulse and HS8_5 (p < 0.001). The median T1rho values of normal liver function, Child-Pugh A, and Child-Pugh B or C were 37.00 ms, 40.77 ms, and 42.20 ms for block pulse, 46.75 ms, 50.78 ms, and 55.60 ms for HS8_10, and 48.80 ms, 55.42 ms, and 57.80 ms for HS8_5, respectively. CONCLUSION: The spin locking sequence using stretched-type adiabatic pulses provides homogeneous liver T1rho maps with reduced artifact and is necessary for a robust evaluation of liver function using T1rho. PMID- 28363725 TI - Incidence of severe critical events in paediatric anaesthesia (APRICOT): a prospective multicentre observational study in 261 hospitals in Europe. AB - BACKGROUND: Little is known about the incidence of severe critical events in children undergoing general anaesthesia in Europe. We aimed to identify the incidence, nature, and outcome of severe critical events in children undergoing anaesthesia, and the associated potential risk factors. METHODS: The APRICOT study was a prospective observational multicentre cohort study of children from birth to 15 years of age undergoing elective or urgent anaesthesia for diagnostic or surgical procedures. Children were eligible for inclusion during a 2-week period determined prospectively by each centre. There were 261 participating centres across 33 European countries. The primary endpoint was the occurence of perioperative severe critical events requiring immediate intervention. A severe critical event was defined as the occurrence of respiratory, cardiac, allergic, or neurological complications requiring immediate intervention and that led (or could have led) to major disability or death. This study is registered with ClinicalTrials.gov, number NCT01878760. FINDINGS: Between April 1, 2014, and Jan 31, 2015, 31 127 anaesthetic procedures in 30 874 children with a mean age of 6.35 years (SD 4.50) were included. The incidence of perioperative severe critical events was 5.2% (95% CI 5.0-5.5) with an incidence of respiratory critical events of 3.1% (2.9-3.3). Cardiovascular instability occurred in 1.9% (1.7-2.1), with an immediate poor outcome in 5.4% (3.7-7.5) of these cases. The all-cause 30-day in-hospital mortality rate was 10 in 10 000. This was independent of type of anaesthesia. Age (relative risk 0.88, 95% CI 0.86-0.90; p<0.0001), medical history, and physical condition (1.60, 1.40-1.82; p<0.0001) were the major risk factors for a serious critical event. Multivariate analysis revealed evidence for the beneficial effect of years of experience of the most senior anaesthesia team member (0.99, 0.981-0.997; p<0.0048 for respiratory critical events, and 0.98, 0.97-0.99; p=0.0039 for cardiovascular critical events), rather than the type of health institution or providers. INTERPRETATION: This study highlights a relatively high rate of severe critical events during the anaesthesia management of children for surgical or diagnostic procedures in Europe, and a large variability in the practice of paediatric anaesthesia. These findings are substantial enough to warrant attention from national, regional, and specialist societies to target education of anaesthesiologists and their teams and implement strategies for quality improvement in paediatric anaesthesia. FUNDING: European Society of Anaesthesiology. PMID- 28363762 TI - An integrated network analysis reveals that nitric oxide reductase prevents metabolic cycling of nitric oxide by Pseudomonas aeruginosa. AB - Nitric oxide (NO) is a chemical weapon within the arsenal of immune cells, but is also generated endogenously by different bacteria. Pseudomonas aeruginosa are pathogens that contain an NO-generating nitrite (NO2-) reductase (NirS), and NO has been shown to influence their virulence. Interestingly, P. aeruginosa also contain NO dioxygenase (Fhp) and nitrate (NO3-) reductases, which together with NirS provide the potential for NO to be metabolically cycled (NO->NO3-->NO2- >NO). Deeper understanding of NO metabolism in P. aeruginosa will increase knowledge of its pathogenesis, and computational models have proven to be useful tools for the quantitative dissection of NO biochemical networks. Here we developed such a model for P. aeruginosa and confirmed its predictive accuracy with measurements of NO, O2, NO2-, and NO3- in mutant cultures devoid of Fhp or NorCB (NO reductase) activity. Using the model, we assessed whether NO was metabolically cycled in aerobic P. aeruginosa cultures. Calculated fluxes indicated a bottleneck at NO3-, which was relieved upon O2 depletion. As cell growth depleted dissolved O2 levels, NO3- was converted to NO2- at near stoichiometric levels, whereas NO2- consumption did not coincide with NO or NO3- accumulation. Assimilatory NO2- reductase (NirBD) or NorCB activity could have prevented NO cycling, and experiments with DeltanirB, DeltanirS, and DeltanorC showed that NorCB was responsible for loss of flux from the cycle. Collectively, this work provides a computational tool to analyze NO metabolism in P. aeruginosa, and establishes that P. aeruginosa use NorCB to prevent metabolic cycling of NO. PMID- 28363763 TI - Systematic Review of the Effectiveness of Physical Therapy Modalities in Women With Provoked Vestibulodynia. AB - INTRODUCTION: Pelvic floor muscle physical therapy is recommended in clinical guidelines for women with provoked vestibulodynia (PVD). Including isolated or combined treatment modalities, physical therapy is viewed as an effective first line intervention, yet no systematic review concerning the effectiveness of physical therapy has been conducted. AIM: To systematically appraise the current literature on the effectiveness of physical therapy modalities for decreasing pain during intercourse and improving sexual function in women with PVD. METHODS: A systematic literature search using PubMed, Scopus, CINHAL, and PEDro was conducted until October 2016. Moreover, a manual search from reference lists of included articles was performed. Ongoing trials also were reviewed using clinicaltrial.gov and ISRCTNregistry. Randomized controlled trials, prospective and retrospective cohorts, and case reports evaluating the effect of isolated or combined physical therapy modalities in women with PVD were included in the review. MAIN OUTCOME MEASURES: Main outcome measures were pain during intercourse, sexual function, and patient's perceived improvement. RESULTS: The literature search resulted in 43 eligible studies including 7 randomized controlled trials, 20 prospective studies, 5 retrospective studies, 6 case reports, and 6 study protocols. Most studies had a high risk of bias mainly associated with the lack of a comparison group. Another common bias was related to insufficient sample size, non-validated outcomes, non-standardized intervention, and use of other ongoing treatment. The vast majority of studies showed that physical therapy modalities such as biofeedback, dilators, electrical stimulation, education, multimodal physical therapy, and multidisciplinary approaches were effective for decreasing pain during intercourse and improving sexual function. CONCLUSION: The positive findings for the effectiveness of physical therapy modalities in women with PVD should be investigated further in robust and well-designed randomized controlled trials. Morin M, Carroll M-S, Bergeron S. Systematic Review of the Effectiveness of Physical Therapy Modalities in Women With Provoked Vestibulodynia. Sex Med Rev 2017;5:295-322. PMID- 28363760 TI - Interstitial lung disease in newborns. AB - The term 'interstitial lung disease' (ILD) refers to a group of disorders involving both the airspaces and tissue compartments of the lung, and these disorders are more accurately termed diffuse lung diseases. Although rare, they are associated with significant morbidity and mortality, with the prognosis depending upon the specific diagnosis. The major categories of ILD in children that present in the neonatal period include developmental disorders, growth disorders, surfactant dysfunction disorders, and specific conditions of unknown etiology unique to infancy. Whereas lung histopathology has been the gold standard for the diagnosis of ILD, as many of the disorders have a genetic basis, non-invasive diagnosis is feasible, and characteristic clinical and imaging features may allow for specific diagnosis in some circumstances. The underlying mechanisms, clinical, imaging, and lung pathology features and outcomes of ILD presenting in newborns are reviewed with an emphasis on genetic mechanisms and diagnosis. PMID- 28363766 TI - The brain's spontaneous activity and its psychopathological symptoms - "Spatiotemporal binding and integration". AB - Neuroimaging provided much insight into the neural activity of the brain and its alterations in psychiatric disorders. However, despite extensive research, the exact neuronal mechanisms leading to the various psychopathological symptoms remain unclear, yet. In addition to task-evoked activity during affective, cognitive, or other challenges, the brain's spontaneous or resting state activity has come increasingly into the focus. Basically all psychiatric disorders show abnormal resting state activity with the relation to psychopathological symptoms remaining unclear though. I here suggest to conceive the brain's spontaneous activity in spatiotemporal terms that is, by various mechanisms that are based on its spatial, i.e., functional connectivity, and temporal, i.e., fluctuations in different frequencies, features. I here point out two such spatiotemporal mechanisms, i.e., "spatiotemporal binding and integration". Alterations in the resting state's spatial and temporal features lead to abnormal "spatiotemporal binding and integration" which results in abnormal contents in cognition as in the various psychopathological symptoms. This, together with concrete empirical evidence, is demonstrated in depression and schizophrenia. I therefore conclude that we need to develop a spatiotemporal approach to psychopathology, "spatiotemporal psychopathology:" as I call it. PMID- 28363764 TI - Ferroptosis Inhibition: Mechanisms and Opportunities. AB - The past decade has yielded tremendous insights into how cells die. This has come with our understanding that several distinct forms of cell death are encompassed under the umbrella term necrosis. Among these distinct forms of regulated necrotic cell death, ferroptosis has attracted considerable attention owing to its putative involvement in diverse pathophysiological processes. A key feature of the ferroptosis process is the requirement of phospholipid peroxidation, a process that has been linked with several human pathologies. Now with the establishment of a connection between lipid peroxidation and a distinctive cell death pathway, the search for new small molecules able to suppress lipid peroxidation has gained momentum and may yield novel cytoprotective strategies. We review here advances in our understanding of the ferroptotic process and summarize the development of lipid peroxidation inhibitors with the ultimate goal of suppressing ferroptosis-relevant cell death and related pathologies. PMID- 28363767 TI - Time-scaling based sliding mode control for Neuromuscular Electrical Stimulation under uncertain relative degrees. AB - This paper addresses the application of the sliding mode approach to control the arm movements by artificial recruitment of muscles using Neuromuscular Electrical Stimulation (NMES). Such a technique allows the activation of motor nerves using surface electrodes. The goal of the proposed control system is to move the upper limbs of subjects through electrical stimulation to achieve a desired elbow angular displacement. Since the human neuro-motor system has individual characteristics, being time-varying, nonlinear and subject to uncertainties, the use of advanced robust control schemes may represent a better solution than classical Proportional-Integral (PI) controllers and model-based approaches, being simpler than more sophisticated strategies using fuzzy logic or neural networks usually applied in this control problem. The objective is the introduction of a new time-scaling base sliding mode control (SMC) strategy for NMES and its experimental evaluation. The main qualitative advantages of the proposed controller via time-scaling procedure are its independence of the knowledge of the plant relative degree and the design/tuning simplicity. The developed sliding mode strategy allows for chattering alleviation due to the impact of the integrator in smoothing the control signal. In addition, no differentiator is applied to construct the sliding surface. The stability analysis of the closed-loop system is also carried out by using singular perturbation methods. Experimental results are conducted with healthy volunteers as well as stroke patients. Quantitative results show a reduction of 45% in terms of root mean square (RMS) error (from 5.9 degrees to [Formula: see text] ) in comparison with PI control scheme, which is similar to that obtained in the literature. PMID- 28363765 TI - Investigating the link between drug-naive first episode psychoses (FEPs), weight gain abnormalities and brain structural damages: Relevance and implications for therapy. AB - Evidence suggests that obesity and overweight may be associated with severe brain structural abnormalities and poor cognitive and functional outcomes in the general population. Despite these observations and the high prevalence of weight gain abnormalities in patients with psychosis spectrum disorders (PSDs), no studies have investigated the impact that these metabolic disturbances may have on brain structures and development in the earliest stages of PSDs. In the present review we shed light on the association between weight gain and brain structural abnormalities that may affect the course of illness in drug-naive FEPs. Given the lack of studies directly investigating this issue, we firstly identified and critically evaluated the literature assessing weight gain abnormalities and gray or white matter (GM, WM) volumes (either globally or in specific regions of interest) in otherwise healthy obese/overweight adolescents and young adults. We then compared the results of this systematic review with those of two recent meta-analysis investigating GM and WM abnormalities in drug naive FEPs. Weight gain in otherwise healthy subjects was consistently associated with frontal and temporal GM atrophy and with reduced integrity of WM in the corpus callosum. Of relevance, all these brain regions are affected in drug-naive FEPs, and their integrity is associated with clinical, cognitive and functional outcomes. The underlying mechanisms that may explain the association between weight gain, adiposity, and brain damage in both healthy subjects and drug-naive FEPs are widely discussed. On the basis of this knowledge, we tried: a) to deduce an integrative model for the development of obesity in psychosis spectrum disorders; b) to identify the key vulnerability factors underlying the association between weight gain and psychosis; c) to provide information on new potential targets of intervention. PMID- 28363768 TI - Serum Galectin-3 and ST2 as predictors of unfavorable outcome in stable dilated cardiomyopathy patients. AB - Dilated cardiomyopathy (DCM) is the third cause of heart failure and the most frequent cause of heart transplantation (HT). The value of biomarkers in prognostic stratification may be important to identification the patients for more advanced treatment. Assessment of serum Galectin-3 (Gal-3) and ST2 as biomarkers of unfavorable outcome (death and combined endpoint: HT or death or left ventricular assist device implantation) in stable DCM patients. 107 DCM patients age 39-56 years were included into the study and followed-up for mean 4.8 years. Gal-3 and ST2 concentrations were measured ELISA tests. Clinical data, treatment, laboratory parameters, NT-proBNP, Gal-3 and ST2 measured at time of inclusion were assessed as risk factors for reaching the study endpoints using log rank test and Cox proportional-hazards model. During follow-up 27 patients died, 40 achieved combined endpoint. ROC curves indicated cut-off value of ST2 17.53 ng/ml, AUC-0.65 (0.53-0.76) and of NT-proBNP-669 pg/ml, AUC 0.61 (0.50 0.73) for prediction of death. In multivariate analysis ST2 was predictor of death (HR per unit increase in log ST2 2.705, 95 % CI 1.324-5.528, P=0.006) and combined endpoint (HR per unit increase in log ST2 2.753, 95 % CI 1.542-4.914, P<0.001). NT-proBNP was predictive variable only for death in multivariate analysis. Gal-3 concentration was not associated with adverse outcome. ST2 but not Gal-3 may be useful for predicting adverse outcome in stable dilated cardiomyopathy patients. PMID- 28363769 TI - Pancreatico-gastric fistula complicating an intraductal papillary mucinous neoplasm. AB - Fistula as a complication of pancreatic intraductal papillary mucinous neoplasms (IPMN) is rare and may involve different adjacent organs, sometimes, several organs at the same time. Our patient had a pancreatico-gastric fistula, discovered at work-up for IPMN, which required extensive surgery. PMID- 28363770 TI - Lectin-functionalized mesoporous silica nanoparticles for endoscopic detection of premalignant colonic lesions. AB - Colorectal cancer (CRC) is one of the leading causes of cancer-deaths worldwide. Methods for the early in situ detection of colorectal adenomatous polyps and their precursors - prior to their malignancy transformation into CRC - are urgently needed. Unfortunately at present, the primary diagnostic method, colonoscopy, can only detect polyps and carcinomas by shape/morphology; with sessile polyps more likely to go unnoticed than polypoid lesions. Here we describe our development of polyp-targeting, fluorescently-labeled mesoporous silica nanoparticles (MSNs) that serve as targeted endoscopic contrast agents for the early detection of colorectal polyps and cancer. In vitro cell studies, ex vivo histopathological analysis, and in vivo colonoscopy and endoscopy of murine colorectal cancer models, demonstrate significant binding specificity of our nanoconstructs to pathological lesions via targeting aberrant alpha-L-fucose expression. Our findings strongly suggest that lectin-functionalized fluorescent MSNs could serve as a promising endoscopic contrast agent for in situ diagnostic imaging of premalignant colonic lesions. PMID- 28363771 TI - Gold nanoshell-based betulinic acid liposomes for synergistic chemo-photothermal therapy. AB - A novel synthesis approach is first developed to fabricate a multifunctional smart nanodrug delivery system: gold nanoshell-coated betulinic acid liposomes (AuNS-BA-Lips) mediated by a glutathione. The AuNS-BA-Lips exhibited good size distribution (149.4+/-2.4nm), preferable photothermal conversion ability and synergistic chemo-photothermal therapy. Additionally, the absorption wavelength of AuNS-BA-Lips showed a significantly red-shifted to near infrared (NIR) region, which can strongly absorbed NIR laser and efficiently convert it into localized heat, thus providing controlled drug release and antitumor thermotherapy. Moreover, the nanocarriers excited by NIR light significantly promoted cell uptake compared to those without irradiation, resulting in an enhanced intracellular drug accumulation. Upon NIR irradiation, the AuNS-BA-Lips showed highly efficient antitumor effects on tumor-bearing mice with an inhibition rate of 83.02%, thus demonstrating a remarkable synergistic therapeutic effect of chemotherapy and thermotherapy. Therefore, this work provides new insight into developing a multifunctional antitumor drug. PMID- 28363772 TI - Characterization of signal bias at the GLP-1 receptor induced by backbone modification of GLP-1. AB - The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor that is a major therapeutic target for the treatment of type 2 diabetes. Activation of this receptor promotes insulin secretion and blood glucose regulation. The GLP-1R can initiate signaling through several intracellular pathways upon activation by GLP-1. GLP-1R ligands that preferentially stimulate subsets among the natural signaling pathways ("biased agonists") could be useful as tools for elucidating the consequences of specific pathways and might engender therapeutic agents with tailored effects. Using HEK-293 cells recombinantly expressing human GLP-1R, we have previously reported that backbone modification of GLP-1, via replacement of selected alpha-amino acid residues with beta-amino acid residues, generates GLP-1 analogues with distinctive preferences for promoting G protein activation versus beta-arrestin recruitment. Here, we have explored the influence of cell background across these two parameters and expanded our analysis to include affinity and other key signaling pathways (intracellular calcium mobilization and ERK phosphorylation) using recombinant human GLP-1R expressed in a CHO cell background, which has been used extensively to demonstrate biased agonism of GLP-1R ligands. The new data indicate that alpha/beta-peptide analogues of GLP-1 exhibit a range of distinct bias profiles relative to GLP-1 and that broad assessment of signaling endpoints is required to reveal the spectrum of behavior of modified peptides. These results support the view that backbone modification via alpha->beta amino acid replacement can enable rapid discovery of peptide hormone analogues that display substantial signal bias at a cognate GPCR. PMID- 28363774 TI - Patients' experience of trauma care in the emergency department of a major trauma centre in the UK. PMID- 28363773 TI - Amylin receptor ligands reduce the pathological cascade of Alzheimer's disease. AB - Amylin is an important gut-brain axis hormone. Since amylin and amyloid-beta peptide (Abeta) share similar beta sheet secondary structure despite not having the same primary sequences, we hypothesized that the accumulation of Abeta in the brains of subjects with Alzheimer's disease (AD) might compete with amylin for binding to the amylin receptor (AmR). If true, adding exogenous amylin type peptides would compete with Abeta and reduce the AD pathological cascade, improving cognition. Here we report that a 10-week course of peripheral treatment with human amylin significantly reduced multiple different markers associated with AD pathology, including reducing levels of phospho-tau, insoluble tau, two inflammatory markers (Iba1 and CD68), as well as cerebral Abeta. Amylin treatment also led to improvements in learning and memory in two AD mouse models. Mechanistic studies showed that an amylin receptor antagonist successfully antagonized some protective effects of amylin in vivo, suggesting that the protective effects of amylin require interaction with its cognate receptor. Comparison of signaling cascades emanating from AmR suggest that amylin electively suppresses activation of the CDK5 pathway by Abeta. Treatment with amylin significantly reduced CDK5 signaling in a receptor dependent manner, dramatically decreasing the levels of p25, the active form of CDK5 with a corresponding reduction in tau phosphorylation. This is the first report documenting the ability of amylin treatment to reduce tauopathy and inflammation in animal models of AD. The data suggest that the clinical analog of amylin, pramlintide, might exhibit utility as a therapeutic agent for AD and other neurodegenerative diseases. PMID- 28363775 TI - The human meibomian gland epithelial cell line as a model to study meibomian gland dysfunction. AB - The meibomian gland dysfunction (MGD) is the leading cause of dry eye disease (DED) throughout the world. The investigation of MGD lacks suitable in vivo and in vitro models. In 2010 a human meibomian gland epithelial cell line (HMGEC) was established, so far the only available meibomian gland cell line. The characterization of HMGEC is of major importance to clarify its suitability for studying the meibomian gland (patho)physiology in vitro. The current culture protocol and new concepts of HMGEC culture will be compared. Hormones are believed to be a key factor in meibomian gland dysfunction thus HMGEC responsiveness to hormone stimulation is crucial to elucidate the hormonal influence on the meibomian gland. This review will summarize current findings about HMGEC and discuss its role in the meibomian gland dysfunction research. PMID- 28363776 TI - Facilitating trypanosome imaging. AB - Research on trypanosomes as a model organism has provided a substantial contribution to a detailed understanding of basic cellular processes within the last few years. At the same time, major advances in super-resolution microscopy have been achieved, facilitating the resolution of biological structures in living cells at a scale of a few nm. However, the motility of trypanosomes has prevented access to high resolution microscopy of live cells. Here, we present a hydrogel based on poly(ethylene glycol) functionalized with either norbornene or thiol moieties for UV induced thiol-ene crosslinking for the embedding and imaging of live trypanosomes. The resulting gel exhibits low autofluorescence properties, immobilizes the cells efficiently on the nanometer scale and is compatible with cell viability for up to one hour at 24 degrees C. We applied super-resolution imaging to the inner plasma membrane leaflet using lipid anchored eYFP as a probe. We find specific domains within the membrane where the fluorescence either accumulates or appears diluted rather than being homogenously distributed. Based on a Ripley's analysis, the size of the domains was determined to be raccumulated=170+/-5 nm and rdilute>115+/-15 nm. We hypothesize that this structuring of the membrane is associated with the underlying cytoskeleton. PMID- 28363778 TI - Aminopeptidase N is not required for porcine epidemic diarrhea virus cell entry. AB - Porcine epidemic diarrhea virus (PEDV) is an emerging pathogenic coronavirus that causes a significant economic burden to the swine industry. The virus infects the intestinal epithelium and causes villous atrophy, resulting in diarrhea and dehydration. Interaction of the viral spike (S) surface glycoprotein - through its S1 subunit - with the host cell receptor is the first step in infection and the main determinant for virus tropism. As for several other alphacoronaviruses including the porcine transmissible gastroenteritis virus (TGEV) and the human coronavirus 229E (HCoV-229E), the aminopeptidase N (APN) protein was reported to be a functional receptor for PEDV. In this study we examined the role of APN as a receptor. We show that overexpression of porcine APN renders MDCK cells susceptible to TGEV, but not to PEDV. Consistently, unlike TGEV-S1, PEDV-S1 exhibited no binding to cell-surface expressed APN or to a soluble version of APN. Moreover, preincubation of these viruses with soluble APN or pretreatment of APN expressing ST cells with soluble TGEV-S1 blocked TGEV infection, but had no effect on infection by PEDV. The combined observations indicated that APN is not required for PEDV infection. To definitively prove this conclusion, we applied CRISPR/Cas9 genome engineering to knock out APN expression in PEDV-susceptible porcine (ST) and human cell lines (Huh7 and HeLa). As a consequence these cells no longer bound TGEV-S1 and HCoV-229E-S1 at their surface and were resistant to infection by the corresponding viruses. However, genetic ablation of APN expression had no effect on their infectability by PEDV, demonstrating that APN is not essential for PEDV cell entry. PMID- 28363777 TI - Dual genetic absence of STAT6 and IL-10 does not abrogate anti-hyperglycemic effects of Schistosoma mansoni in streptozotocin-treated diabetic mice. AB - Schistosoma mansoni (Sm) is known to exert protective effects against various allergic and autoimmune disorders. It has been reported that this parasite protects NOD mice from spontaneous type 1 diabetes (T1D) and ameliorates streptozotocin (STZ)-induced T1D in wild-type mice. Here, we tried to clarify the anti-diabetic mechanisms of Sm in the latter model. Sm infection partially prevented the degradation of pancreatic islets and hyperglycemia in multiple low dose (MLD) STZ-treated mice. Neither Treg cell depletion nor genetic absences of IL-10 and/or STAT6 abrogated the anti-hyperglycemic effects of Sm. Among M2 macrophage markers, Arg-1 and Ym1, but not Retnla, remained up-regulated in the pancreatic lymph nodes and in the spleens of STAT6/IL-10 double deficient (DKO) mice. Collectively, it is suggested that Sm exerts anti-diabetic effects on this experimental T1D model via Treg/IL-4/IL-13/IL-10-independent mechanisms. Augmented expressions of Arg-1 and Ym1 in the lymphoid organs adjacent to pancreas may be relevant to the anti-diabetic effects of Sm. PMID- 28363779 TI - Genome-wide analysis and expression profiling of the GRF gene family in oilseed rape (Brassica napus L.). AB - Growth regulating-factors (GRFs) are plant-specific transcription factors that help regulate plant growth and development. Genome-wide identification and evolutionary analyses of GRF gene families have been performed in Arabidopsis thaliana, Zea mays, Oryza sativa, and Brassica rapa, but a comprehensive analysis of the GRF gene family in oilseed rape (Brassica napus) has not yet been reported. In the current study, we identified 35 members of the BnGRF family in B. napus. We analyzed the chromosomal distribution, phylogenetic relationships (Bayesian Inference and Neighbor Joining method), gene structures, and motifs of the BnGRF family members, as well as the cis-acting regulatory elements in their promoters. We also analyzed the expression patterns of 15 randomly selected BnGRF genes in various tissues and in plant varieties with different harvest indices and gibberellic acid (GA) responses. The expression levels of BnGRFs under GA treatment suggested the presence of possible negative feedback regulation. The evolutionary patterns and expression profiles of BnGRFs uncovered in this study increase our understanding of the important roles played by these genes in oilseed rape. PMID- 28363780 TI - miR-199a-5p and miR-495 target GRP78 within UPR pathway of lung cancer. AB - INTRODUCTION: Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer. One of the signal transduction pathways related to NSCLC is Unfolded Protein Response (UPR), which is mainly regulated by GRP78 (HSPA5, Gene ID: 3309). The aim of this study was to employ bioinformatics tools to predict microRNAs (miRNAs) affecting GRP78 expression, experimentally validate interaction of these miRNAs with GRP78 and also evaluating the expression correlation of GRP78 and its predicted miRNAs in clinical samples. MATERIALS AND METHODS: Various software were used to predict miRNAs that simultaneously target all upstream and downstream components of GRP78 in the UPR, as well as the main components of PI3K/AKT, MAPK, ErbB and calcium pathways. For experimental analysis, 36 pairs of Formalin-Fixed Paraffin-Embedded (FFPE) lung tumor and non tumor tissue samples were obtained. Additionally, A549 and QU-DB lung cancer cell lines were used for expression determination of GRP78 and its predicted targeting miRNAs. We also employed a luciferase assay to evaluate interactions between candidate miRNAs with the 3'-UTR of GRP78. RESULTS: hsa-miR-495 and hsa-miR-199 5p were chosen based on several criteria including thermodynamic binding features of miRNAs to the target transcripts, number of recognition sites, and conservation of binding sites within the 3'-UTR of GRP78. RT-qPCR data revealed a significant up-regulation of GRP78 (3.87 times, P=0.002) and down-regulation of miR-199a-5p (0.13 times, P=0.0001) and miR-495 (0.085 times, P=0.0001) in tumor samples. Luciferase assay confirmed an interaction of hsa-miR-199a-5p and hsa-miR 495 with the 3'-UTR of GRP78 transcript. In addition, over-expression and competitive inhibition of the aforementioned miRNAs, significantly altered the expression of GRP78 and spliced XBP1 level. CONCLUSION: Our data revealed a significant up-regulation of GRP78 and a concomitant down-regulation of miR-495 and miR-199a-5p in NSCLC. Accordingly, our data suggest a causative role for miR 199-5p and miR-495 in tumorgenesis of lung and probably other cancer types. PMID- 28363781 TI - Hyperpolarization-activated current Ih in mouse trigeminal sensory neurons in a transgenic mouse model of familial hemiplegic migraine type-1. AB - Transgenic knock-in (KI) mice that express CaV2.1 channels containing an R192Q gain-of-function mutation in the alpha1A subunit known to cause familial hemiplegic migraine type-1 in patients, exhibit key disease characteristics and provide a useful tool to investigate pathophysiological mechanisms of pain transduction. Previously, KI trigeminal sensory neurons were shown to exhibit constitutive hyperexcitability due to up-regulation of ATP-gated P2X3 receptors that trigger spike activity at a more negative threshold. This implies that intrinsic neuronal conductances may shape action potential generation in response to ATP, which could act as a mediator of migraine headache. Here we investigated whether the hyperpolarization-activated conductance Ih, mediated by hyperpolarization activated cyclic nucleotide-gated channels (HCN), contributes to sub-threshold behavior and firing in wild-type (WT) and KI trigeminal ganglia (TG) neurons. Whereas most WT and KI trigeminal neurons expressed Ih current, blocked by the specific inhibitor ZD7288, it was smaller in KI neurons despite similar activation and deactivation kinetics. HCN1 and HCN2 were the most abundantly expressed subunits in TG, both in situ and in culture. In KI TG neurons, HCN2 subunits were predominantly present in the cytoplasm, not at the plasma membrane, likely accounting for the smaller Ih of such cells. ZD7288 hyperpolarized the membrane potential, thereby raising the firing threshold, and prolonging the spike trajectory to generate fewer spikes due to P2X3 receptor activation. The low amplitude of Ih in KI TG neurons suggests that down regulation of Ih current in sub-threshold behavior acts as a compensatory mechanism to limit sensory hyperexcitability, manifested under certain stressful stimuli. PMID- 28363783 TI - Depletion of rostral ventrolateral medullary catecholaminergic neurons impairs the hypoxic ventilatory response in conscious rats. AB - The stimuli that commonly activate the catecholaminergic C1 neurons (nociception, hypotension, and hypoxia) also increase breathing. Pharmacogenetic evidence suggests that catecholaminergic neurons regulate breathing. Therefore, we evaluated whether the loss of C1 cells affects cardiorespiratory control during resting, hypoxic (8% O2) and hypercapnic (7% CO2) conditions. A bilateral injection of the immunotoxin anti-dopamine beta-hydroxylase-saporin (anti-DbetaH SAP; 2.4ng/100nl) or saline was performed in adult male Wistar rats (270-300g, N=5-8/group). Histology revealed a 60-75% loss of C1 neurons in anti-DbetaH-SAP treated rats, but no significant changes or C1 cell loss was observed in sham treated rats or those with off-target injection sites. Bilateral depletion of C1 neurons did not alter cardiorespiratory variables during rest and hypercapnia (7% CO2), but it did affect the response to hypoxia. Specifically, the increase in ventilation, the number of sighs, and the tachycardia were reduced, but unexpectedly, the mean arterial pressure increased during hypoxia (8% O2). The present study indicates that C1 neurons contribute to cardiorespiratory control during hypoxia rather than at rest or during hypercapnia. PMID- 28363782 TI - Fyn regulates multipolar-bipolar transition and neurite morphogenesis of migrating neurons in the developing neocortex. AB - Fyn is a non-receptor protein tyrosine kinase that belongs to Src family kinases. Fyn plays a critical role in neuronal migration, but the mechanism remains unclear. Here, we reported that suppression of Fyn expression in mouse cerebral cortex led to migration defects of both early-born and late-born neurons. Morphological analysis showed that loss of Fyn function impaired multipolar bipolar transition of newly generated neurons and neurite formation in the early phase of migration. Moreover, Fyn inhibition increased the length of leading process and decreased the branching number of the migrating cortical neurons. Together, these results indicate that Fyn controls neuronal migration by regulating the cytoskeletal dynamics and multipolar-bipolar transition of newly generated neurons during cortical development. PMID- 28363784 TI - The effect of cannabinoid receptor 1 blockade on hepatic free fatty acid profile in mice with nonalcoholic fatty liver disease. AB - We used rimonabant to investigate the role of CB1 receptor on hepatic FFAs profile during NAFLD. Male mice C57BL/6 were divided into: control group fed with control diet 20 weeks (C; n=6); group fed with HFD 20 weeks (HF; n=6); group fed with control diet and treated with rimonabant after 18 weeks (R; n=9); group fed with HFD and treated with rimonabant after 18 weeks (HFR; n=10). Rimonabant (10mg/kg) was administered daily to HFR and R group by oral gavage. Rimonabant decreased liver palmitic acid proportion in HFR group compared to HF group (p<0.05). Liver stearic and oleic acid proportions were decreased in R group compared to control (p<0.01 respectively). Rimonabant increased liver linoleic and arachidonic acid proportions in HFR group compared to HF group (p<0.01 respectively). CB1 blockade may be useful in the treatment of HFD-induced NAFLD due to modulation of plasma lipid and hepatic FFA profile. PMID- 28363785 TI - Targeted delivery of hyaluronic acid to the ocular surface by a polymer-peptide conjugate system for dry eye disease. AB - : Hyaluronic acid (HA) solutions effectively lubricate the ocular surface and are used for the relief of dry eye related symptoms. However, HA undergoes rapid clearance due to limited adhesion, which necessitates frequent instillation. Conversely, highly viscous artificial tear formulations with HA blur vision and interfere with blinking. Here, we developed an HA-eye drop formulation that selectively binds and retains HA for extended periods of time on the ocular surface. We synthesized a heterobifunctional polymer-peptide system with one end binding HA while the other end binding either sialic acid-containing glycosylated transmembrane molecules on the ocular surface epithelium, or type I collagen molecule within the tissue matrix. HA solution was mixed with the polymer-peptide system and tested on both ex vivo and in vivo models to determine its ability to prolong HA retention. Furthermore, rabbit ocular surface tissues treated with binding peptides and HA solutions demonstrated superior lubrication with reduced kinetic friction coefficients compared to tissues treated with conventional HA solution. The results suggest that binding peptide-based solution can keep the ocular surface enriched with HA for prolonged times as well as keep it lubricated. Therefore, this system can be further developed into a more effective treatment for dry eye patients than a standard HA eye drop. STATEMENT OF SIGNIFICANCE: Eye drop formulations containing HA are widely used to lubricate the ocular surface and relieve dry eye related symptoms, however its low residence time remains a challenge. We designed a polymer-peptide system for the targeted delivery of HA to the ocular surface using sialic acid or type I collagen as anchors for HA immobilization. The addition of the polymer-peptide system to HA eye drop exhibited a reduced friction coefficient, and it can keep the ocular surface enriched with HA for prolonged time. This system can be further developed into a more effective treatment for dry eye than a standard HA eye drop. PMID- 28363786 TI - Non-invasive monitoring of in vivo degradation of a radiopaque thermoreversible hydrogel and its efficacy in preventing post-operative adhesions. AB - : In vivo behavior of hydrogel-based biomaterials is very important for rational design of hydrogels for various biomedical applications. Herein, we developed a facile method for in situ fabrication of radiopaque hydrogel. An iodinated functional diblock copolymer of poly(ethylene glycol) and aliphatic polyester was first synthesized by coupling the hydroxyl end of the diblock copolymer with 2,3,5-triiodobenzoic acid (TIB) and then a radiopaque thermoreversible hydrogel was obtained by mixing it with the virgin diblock copolymer. A concentrated aqueous solution of the copolymer blend was injectable at room temperature and spontaneously turned into an in situ hydrogel at body temperature after injection. The introduction of TIB moieties affords the capacity of X-ray opacity, enabling in vivo visualization of the hydrogel using Micro-CT. A rat model with cecum and abdominal defects was utilized to evaluate the efficacy of the radiopaque hydrogel in the prevention of post-operative adhesions, and a significant reduction of the post-operative adhesion formation was confirmed. Meanwhile, the maintenance of the radiopaque hydrogel in the abdomen after administration was non-destructively detected via Micro-CT scanning. The reconstructed three-dimensional images showed that the radiopaque hydrogel with an irregular morphology was located on the injured abdominal wall. The time dependent profile of the volume of the radiopaque hydrogel determined by Micro-CT imaging was well consistent with the trend obtained from the dissection observation. Therefore, the radiopaque thermoreversible hydrogel can serve as a potential visualized biomedical implant and this practical mixing approach is also useful for further extension into the in vivo monitoring of other biomaterials. STATEMENT OF SIGNIFICANCE: While a variety of biomaterials have been extensively studied, it is rare to monitor in vivo degradation and medical efficacy of a material after being implanted deeply into the body. Herein, the radiopaque thermoreversible hydrogel developed by us not only holds desirable performance on the prevention of post-operative abdominal adhesions, but also allows non-invasive monitoring of its in vivo degradation with CT imaging in a real-time, quantitative and three-dimensional manner. The methodology based on CT imaging provides important insights into the in vivo fate of the hydrogel after being deeply implanted into mammals for different biomedical applications and significantly reduces the amount of animals sacrificed. PMID- 28363787 TI - Comparative analysis of biological effect of corannulene and graphene on developmental and sleep/wake profile of zebrafish larvae. AB - : Little is known about the biological effect of non-planar polycyclic aromatic hydrocarbons (PAH) such as corannulene on organisms. In this study, we compared the effect of corannulene (non-planar PAH) and graphene (planar PAH) on embryonic development and sleep/wake behaviors of larval zebrafish. First, the toxicity of graded doses of corannulene (1, 10, and 50MUg/mL) was tested in developing zebrafish embryos. Corannulene showed minimal developmental toxicity only induced an epiboly delay. Further, a significant decrease in locomotion/increase in sleep was observed in larvae treated with the highest dose (50MUg/mL) of corannulene while no significant locomotion alterations were induced by graphene. Finally, the effect of corannulene or graphene on the hypocretin (hcrt) system and sleep/wake regulators such as hcrt, hcrt G-protein coupled receptor (hcrtr), and arylalkylamine N-acetyltransferase-2 (aanat2) was evaluated. Corannulene increased sleep and reduced locomotor activity and the expression of hcrt and hcrtr mRNA while graphene did not obviously disturb the sleep behavior and gene expression patterns. These results suggest that the corannulene has the potential to cause hypnosis-like behavior in larvae and provides a fundamental comparative understanding of the effects of corannulene and graphene on biology systems. STATEMENT OF SIGNIFICANCE: Little is known about the biological effect of non planar polycyclic aromatic hydrocarbons (PAH) such as corannulene on organisms. Here, we compare the effect of corannulene (no-planar PAH) and graphene (planar PAH) on embryonic development and sleep/wake behaviors of larval zebrafish. And we aim to investigate the effect of curvature on biological system. First, toxicity of corannulene over the range of doses (1MUg/mL, 10MUg/mL and 50MUg/mL) was tested in developing zebrafish embryos. Corannulene has minimal developmental toxicity, only incurred epiboly delay. Subsequently, a significant decrease in locomotion/increase in sleep at the highest dose (50MUg/mL) was detected in corannulene treated larvae while no significant locomotion alterations was induced by graphene. Finally, the impact of corannulene or graphene on hypocretin system and sleep/wake regulator such as hcrt, hcrtr and aanat2 was evaluated. Corannulene increased sleep, reduced locomotor activity and the expression of hcrt and hcrtr mRNA while graphene did not obviously disturb the sleep behaviors and gene expression patterns. This result may indicate the potential effect of corannulene to cause hypnosia-like behavior in larvae and provide the fundamental understanding for the biological effect of curvature on biology system. PMID- 28363788 TI - Mesenchymal stem cell fate following non-viral gene transfection strongly depends on the choice of delivery vector. AB - : Controlling the phenotype of mesenchymal stem cells (MSCs) through the delivery of regulatory genes is a promising strategy in tissue engineering (TE). Essential to effective gene delivery is the choice of gene carrier. Non-viral delivery vectors have been extensively used in TE, however their intrinsic effects on MSC differentiation remain poorly understood. The objective of this study was to investigate the influence of three different classes of non-viral gene delivery vectors: (1) cationic polymers (polyethylenimine, PEI), (2) inorganic nanoparticles (nanohydroxyapatite, nHA) and (3) amphipathic peptides (RALA peptide) on modulating stem cell fate after reporter and therapeutic gene delivery. Despite facilitating similar reporter gene transfection efficiencies, these nanoparticle-based vectors had dramatically different effects on MSC viability, cytoskeletal morphology and differentiation. After reporter gene delivery (pGFP or pLUC), the nHA and RALA vectors supported an elongated MSC morphology, actin stress fibre formation and the development of mature focal adhesions, while cells appeared rounded and less tense following PEI transfection. These changes in MSC morphology correlated with enhanced osteogenesis following nHA and RALA transfection and adipogenesis following PEI transfection. When therapeutic genes encoding for transforming growth factor beta 3 (TGF-beta3) and/or bone morphogenic protein 2 (BMP2) were delivered to MSCs, nHA promoted osteogenesis in 2D culture and the development of an endochondral phenotype in 3D culture, while RALA was less osteogenic and appeared to promote a more stable hyaline cartilage-like phenotype. In contrast, PEI failed to induce robust osteogenesis or chondrogenesis of MSCs, despite effective therapeutic protein production. Taken together, these results demonstrate that the differentiation of MSCs through the application of non-viral gene delivery strategies depends not only on the gene delivered, but also on the gene carrier itself. STATEMENT OF SIGNIFICANCE: Nanoparticle-based non-viral gene delivery vectors have been extensively used in regenerative medicine, however their intrinsic effects on mesenchymal stem cell (MSC) differentiation remain poorly understood. This paper demonstrates that different classes of commonly used non viral vectors are not inert and they have a strong effect on cell morphology, stress fiber formation and gene transcription in MSCs, which in turn modulates their capacity to differentiate towards osteogenic, adipogenic and chondrogenic lineages. These results also point to the need for careful and tissue-specific selection of nanoparticle-based delivery vectors to prevent undesired phenotypic changes and off-target effects when delivering therapeutic genes to damaged or diseased tissues. PMID- 28363789 TI - pH-responsive pHLIP (pH low insertion peptide) nanoclusters of superparamagnetic iron oxide nanoparticles as a tumor-selective MRI contrast agent. AB - : Superparamagnetic iron oxide nanoparticles (SPION) are contrast agents used for noninvasive tumor magnetic resonance imaging (MRI). SPION with active targeting by tumor-specific ligands can effectively enhance the MRI sensitivity and specificity of tumors. However, the challenge remains when the tumor specific markers are yet to be determined, especially in the case of early tumor detection. In this study, the effectiveness of pH-responsive SPION via a pH low insertion peptide (pHLIP) to target tumor acidic microenvironments was investigated. Polylysine polymers were first successfully modified with pHLIP to have the pH-responsive capability. SPION pHLIP nanoclusters of 64, 82, 103, and 121nm size were then assembled by the pH-responsive polymers in a size-controlled manner. The pH-responsive SPION nanoclusters of the 64nm size exhibited the most effective pH-responsive retention in cells and tumor selective imaging in MRI. More importantly, the unique contrast enhancement of tumor inner core by the pH responsive SPION in three different tumor models demonstrated the clinical potential to target tumor acidic microenvironment through pHLIP for tumor early detection and diagnosis by MRI. STATEMENT OF SIGNIFICANCE: Detection and diagnosis of tumors at early stage are critical for the improvement of the survival rate of cancer patients. However, the challenge remains when the tumor specific markers are yet to be determined, especially in early tumor detection. pH low insertion peptide (pHLIP) has been used as a specific ligand to target the tumor acidic microenvironment for tumors at early and metastatic stages. Superparamagnetic iron nanoparticles (SPION) are contrast enhancing agents used in the noninvasive magnetic resonance imaging for tumors. This research has demonstrated that pH-responsive pHLIP nanoclusters of SPION were able to target different tumors and facilitate the noninvasive diagnosis of tumors by MRI. PMID- 28363791 TI - Inhibition of long noncoding RNA BDNF-AS rescues cell death and apoptosis in hypoxia/reoxygenation damaged murine cardiomyocyte. AB - BACKGROUND: Hypoxia/reoxygenation (H/R)-induced cardiomyocyte damage in vitro bears many similarities to myocardial infraction in vivo. In this study, we investigated whether long noncoding RNA (lncRNA) BDNF-AS has functional role in rescuing H/R-induced damage in cardiomyocyte in vitro. METHOD: Murine neonatal cardiomyocytes were cultured in vitro, and treated with either long (Hypoxia (L)) or short (Hypoxia (S)) H/R conditions. Viability and TUNEL assays were conducted to assess cardiomyocyte death or apoptosis. QRT-PCR was used to examine BDNF-AS mRNA expression. Endogenous BDNF-AS was downregulated by siRNA in cardiomyocyte. Its effect on H/R-induced cardiomyocyte damage was then examined. In addition, survival-associated proteins, including BDNF, VEGF and Akt were examined by western blot in siRNA-transfected cardiomyocytes. RESULTS: Hypoxia (S) induced apoptosis whereas Hypoxia (L) induced cell death in murine neonatal cardiomyocyte in vitro. Under both conditions, endogenous cardiomyocyte BDNF-AS was significantly upregulated. SiRNA-mediated BDNF-AS downregulation rescued cardiomyocyte death under Hypoxia (L) condition, and reduced cardiomyocyte apoptosis under Hypoxia (L) condition. Moreover, BDNF-AS downregulation activated BDNF and VEGF through upregulation, and activated Akt through phosphorylation in H/R-damaged cardiomyocyte. CONCLUSION: Inhibition of lncRNA BDNF-AS may be an efficient way to rescue cardiomyocyte from H/R-induced apoptosis or cell death. PMID- 28363790 TI - A fungal catalase reacts selectively with the 13S fatty acid hydroperoxide products of the adjacent lipoxygenase gene and exhibits 13S-hydroperoxide dependent peroxidase activity. AB - The genome of the fungal plant pathogen Fusarium graminearum harbors six catalases, one of which has the sequence characteristics of a fatty acid peroxide metabolizing catalase. We cloned and expressed this hemoprotein (designated as Fg cat) along with its immediate neighbor, a 13S-lipoxygenase (cf. Brodhun et al., PloS One, e64919, 2013) that we considered might supply a fatty acid hydroperoxide substrate. Indeed, Fg-cat reacts abruptly with the 13S hydroperoxide of linoleic acid (13S-HPODE) with an initial rate of 700-1300s-1. By comparison there was no reaction with 9R- or 9S-HPODEs and extremely weak reaction with 13R-HPODE (~0.5% of the rate with 13S-HPODE). Although we considered Fg-cat as a candidate for the allene oxide synthase of the jasmonate pathway in fungi, the main product formed from 13S-HPODE was identified by UV, MS, and NMR as 9-oxo-10E-12,13-cis-epoxy-octadecenoic acid (with no traces of AOS activity). The corresponding analog is formed from the 13S-hydroperoxide of alpha linolenic acid along with novel diepoxy-ketones and two C13 aldehyde derivatives, the reaction mechanisms of which are proposed. In a peroxidase assay monitoring the oxidation of ABTS, Fg-cat exhibited robust activity (kcat 550s-1) using the 13S-hydroperoxy-C18 fatty acids as the oxidizing co-substrate. There was no detectable peroxidase activity using the corresponding 9S-hydroperoxides, nor with t-butyl hydroperoxide, and very weak activity with H2O2 or cumene hydroperoxide at micromolar concentrations of Fg-cat. Fg-cat and the associated lipoxygenase gene are present together in fungal genera Fusarium, Metarhizium and Fonsecaea and appear to constitute a partnership for oxidations in fungal metabolism or defense. PMID- 28363792 TI - Analysing the outcome of CRISPR-aided genome editing in embryos: Screening, genotyping and quality control. AB - The application of CRISPR/Cas9 technology has revolutionised genetics by greatly enhancing the efficacy of genome editing in the early embryo. Furthermore, the system has enabled the generation of allele types previously incompatible with in vivo mutagenesis. Despite its versatility and ease of implementation, CRISPR/Cas9 editing outcome is unpredictable and can generate mosaic founders. Therefore, careful genotyping and characterisation of new mutants is proving essential. The literature presents a wide range of protocols for molecular characterisation, each representing different levels of investment. We present strategies and protocols for designing, producing and screening CRISPR/Cas9 edited founders and genotyping their offspring according to desired allele type (indel, point mutation and deletion). PMID- 28363793 TI - Adiponectin: Serum-saliva associations and relations with oral and systemic markers of inflammation. AB - This study addresses gaps in our understanding about the validity and utility of using salivary adiponectin to index serum adiponectin levels. Matched blood and saliva samples were collected on a single occasion from healthy adults (n=99; age 18-36 years, 53% male). Serum and saliva was assayed for adiponectin and inflammatory cytokines (IL-1beta, IL-6, IL-8, TNFalpha), and saliva was also assayed for markers of blood contamination (transferrin), total protein (salivary flow rate) and matrix metalloproteinase-8 (MMP-8). We examined the extent to which salivary adiponectin was associated with serum adiponectin, and the influence of potential confounders on the serum-saliva correlation, including age, sex, body mass index, and markers of inflammation, oral health, salivary blood contamination, and flow rate. Findings revealed a modest serum-saliva association for adiponectin, and strong positive associations between salivary adiponectin and salivary levels of inflammatory cytokines, MMP-8, transferrin, and total protein. By contrast, salivary adiponectin was not related to serum levels of inflammatory activity. The magnitude of the serum-saliva association was strengthened when controlling for total protein in saliva, blood leakage into oral fluid, salivary inflammatory cytokines, and MMP-8. The pattern of findings extends our understanding of salivary adiponectin and its potential use as an index of circulating adiponectin levels. PMID- 28363794 TI - Adaptive evolution of insect selective excitatory beta-type sodium channel neurotoxins from scorpion venom. AB - Insect selective excitatory beta-type sodium channel neurotoxins from scorpion venom (beta-NaScTxs) are composed of about 70-76 amino acid residues and share a common scaffold stabilized by four unique disulfide bonds. The phylogenetic analysis of these toxins was hindered by limited sequence data. In our recent study, two new insect selective excitatory beta-NaScTxs, LmIT and ImIT, were isolated from Lychas mucronatus and Isometrus maculatus, respectively. With the sequences previously reported, we examined the adaptive molecular evolution of insect selective excitatory beta-NaScTxs by estimating the nonsynonymous-to synonymous rate ratio (omega=dN/dS). The results revealed 12 positively selected sites in the genes of insect selective excitatory beta-NaScTxs. Moreover, these positively selected sites match well with the sites important for interacting with sodium channels, as demonstrated in previous mutagenesis study. These results reveal that adaptive evolution after gene duplication is one of the most important genetic mechanisms of scorpion neurotoxin diversification. PMID- 28363795 TI - Glucagon-like petide-2 acts on colon cancer myofibroblasts to stimulate proliferation, migration and invasion of both myofibroblasts and cancer cells via the IGF pathway. AB - Glucagon-like peptide (GLP)-2 stimulates intestinal epithelial proliferation by acting, in part, via IGF release from sub-epithelial myofibroblasts. The response of myofibroblasts to GLP-2 remains incompletely understood. We studied the action of GLP-2 on myofibroblasts from colon cancer and adjacent tissue, and the effects of conditioned medium from these cells on epithelial cell proliferation, migration and invasion. GLP-2 stimulated proliferation, migration and invasion of myofibroblasts and the proliferative and invasive responses of cancer-associated myofibroblasts were greater than those of myofibroblasts from adjacent tissue. The responses were inhibited by an IGF receptor inhibitor, AG1024. Conditioned medium from GLP-2 treated myofibroblasts increased proliferation, migration and invasion of SW480, HT29, LoVo epithelial cells and these responses were inhibited by AG1024; GLP-2 alone had no effect on these cells. In addition, when myofibroblasts and epithelial cells were co-cultured in Ibidi chambers there was mutual stimulation of migration in response to GLP-2. The latter increased both IGF-1 and IGF-2 transcript abundance in myofibroblasts. Moreover, a number of IGF binding proteins (IGFBP-4, -5, -7) were identified in myofibroblast medium; in the presence of GLP-2 there was increased abundance of the cleavage products of IGBBP-4 and IGFBP-5 suggesting activation of a degradation mechanism that might increase IGF bioavailability. The data suggest that GLP-2 stimulates cancer myofibroblast proliferation, migration and invasion; GLP-2 acts indirectly on epithelial cells partly via increased IGF expression in myofibroblasts and partly, perhaps, by increased bioavailability through degradation of IGFBPs. PMID- 28363796 TI - Structure-constrained endomorphin analogs display differential antinociceptive mechanisms in mice after spinal administration. AB - We previously reported a series of novel endomorphin analogs with unnatural amino acid modifications. These analogs display good binding affinity and functional activity toward the MU opioid receptor (MOP). In the present study, we further investigated the spinal antinociceptive activity of these compounds. The analogs were potent in several nociceptive models. Opioid antagonists and antibodies against several endogenous opioid peptides were used to determine the mechanisms of action of these peptides. Intrathecal pretreatment with naloxone and beta funaltrexamine (beta-FNA) effectively inhibited analog-induced analgesia, demonstrating that activity of the analogs is regulated primarily through MOP. Antinociception induced by analog 2 through 4 was not reversed by delta opioid receptor (DOP) or kappa opioid receptor (KOP) antagonist; antibodies against dynorphin-A (1-17), dynorphin-B (1-13), and Leu5/Met5-enkephalin had no impact on the antinociceptive effects of these analogs. In contrast, antinociceptive effects induced by a spinal injection of the fluorine substituted analog 1 were significantly reversed by KOP antagonism. Furthermore, intrathecal pretreatment with antibodies against dynorphin-B (1-13) attenuated the antinociceptive effect of analog 1. These results indicate that the antinociceptive activity exerted by intrathecally-administered analog 1 is mediated, in part, through KOP with increased release of dynorphin-B (1-13). The chemical modifications used in the present study may serve as a useful tool to gain insight into the mechanisms of endomorphins activity. PMID- 28363797 TI - Scavenger receptor class B member 1 (SCARB1) variants modulate hepatitis C virus replication cycle and viral load. AB - BACKGROUND & AIMS: There are numerous coding and non-coding variants in the SCARB1 gene that encodes scavenger receptor class B member 1 (SR-BI), a key receptor for both high density lipoproteins and hepatitis C virus (HCV). Many have been linked to clinical phenotypes, yet their impact on the HCV replication cycle is incompletely understood. The aim of this study was to analyze the impact of these variants on the molecular biology and clinical course of HCV. METHODS: We analyzed key coding non-synonymous as well as non-coding SCARB1 variants using virological in vitro and human genetics approaches. RESULTS: Non-synonymous variants: S112F and T175A have greatly reduced HCV receptor function. When present on the cell surface, these variants are impaired in their ability to interact with HCV E2. Non-coding variants: The G allele in rs3782287 is associated with decreased viral load. Haplotype analysis confirmed these findings and identified haplotype rs3782287 A/rs5888 C as a risk allele associated with increased viral load. We also detected a trend towards lower hepatic SR-BI expression in individuals with the rs3782287 GG genotype associated with low viral load suggesting a potential underlying mechanism. CONCLUSION: Coding and non-coding genetic SCARB1 variants modulate the HCV replication cycle and possibly clinical features of hepatitis C. These findings underscore the relevance of SR-BI as an HCV receptor and contribute to our understanding of inter-individual variation in HCV infection. LAY SUMMARY: The cell surface receptor SR-BI (scavenger receptor class B member 1), is essential for hepatitis C virus (HCV) entry into hepatocytes. Variations in the gene coding this receptor influence infectivity and viral load. We analyzed these variations to gain a better understanding of inter-individual differences over the course of HCV infection. PMID- 28363798 TI - How to unveil chronic respiratory diseases in clinical practice? A model of alliance between general practitioners and pulmonologists. AB - INTRODUCTION: Asthma and COPD are under-diagnosed and undertreated in adult populations, mainly due to the discrepancy between guideline recommendations and clinicians' practices. One of the reasons of this discrepancy is the difficulty encountered in real life in sharing the management of chronic respiratory diseases between general practitioners (GPs) and respiratory physicians. METHODS: An explorative, population-based investigation was performed to test whether, and to what extent, an active collaboration between GPs and pulmonologists increases the diagnosis and proper treatment of chronic obstructive airway diseases. The "COPD action" involved an in-house intervention by pulmonologists who trained GPs on how to diagnose the disease and interpret the spirometry, yielding a final agreed diagnosis. RESULTS: A total of 210 subjects (M/F: 156/54; age: 62.5 +/- 13.8, mean +/- SD) were consecutively invited by 20 GPs and classified in a) healthy, b) symptomatic with no airway obstruction, and 3) affected by chronic respiratory diseases. 11% of previously defined "healthy" subjects were diagnosed with COPD, and symptomatic subjects were diagnosed with asthma (20%) or COPD (23%). In addition, in those who already carried a diagnosis of chronic respiratory diseases as judged by GPs, the diagnosis of COPD decreased significantly after respiratory specialist intervention (p = 0.001), in favor of asthma and chronic bronchitis. Furthermore, following the clinical and lung function assessments performed by the respiratory physicians, changes in inhaled treatments were statistically significant for each therapeutic category (test retest reliability: r = 0.42; p < 0.001). CONCLUSION: In conclusion, the collaboration between GPs and pulmonologists based on a pro-active approach to the individuals attending the primary care offices followed by an in-house intervention by specialists may largely improve the diagnosis and management of chronic respiratory diseases. PMID- 28363800 TI - How the shapes of seeds can influence pathology. AB - It is widely accepted that the loss of function of different cellular proteins following their aggregation into highly stable aggregates or the gain of pathologic function of the resulting macromolecular assemblies or both processes are tightly associated to distinct debilitating neurodegenerative diseases such as Alzheimer's, Parkinson's, Creutzfeldt-Jacob, Amyotrophic Lateral Sclerosis and Huntington's diseases. How the aggregation of one given protein leads to distinct diseases is unclear. Here, a structural-molecular explanation based on the ability of proteins such as alpha-synuclein or tau to form assemblies that differ by their intrinsic architecture, stability, seeding capacity, and surfaces is proposed to account for distinct synucleinopathies and tauopathies. The shape and surfaces of the seeds is proposed to define at the same time their seeding capacity, interactome and tropism for defined neuronal cells within the central nervous system. PMID- 28363799 TI - Neuroserpin polymers cause oxidative stress in a neuronal model of the dementia FENIB. AB - The serpinopathies are human pathologies caused by mutations that promote polymerisation and intracellular deposition of proteins of the serpin superfamily, leading to a poorly understood cell toxicity. The dementia FENIB is caused by polymerisation of the neuronal serpin neuroserpin (NS) within the endoplasmic reticulum (ER) of neurons. With the aim of understanding the toxicity due to intracellular accumulation of neuroserpin polymers, we have generated transgenic neural progenitor cell (NPC) cultures from mouse foetal cerebral cortex, stably expressing the control protein GFP (green fluorescent protein), or human wild type, G392E or delta NS. We have characterised these cell lines in the proliferative state and after differentiation to neurons. Our results show that G392E NS formed polymers that were mostly retained within the ER, while wild type NS was correctly secreted as a monomeric protein into the culture medium. Delta NS was absent at steady state due to its rapid degradation, but it was easily detected upon proteasomal block. Looking at their intracellular distribution, wild type NS was found in partial co-localisation with ER and Golgi markers, while G392E NS was localised within the ER only. Furthermore, polymers of NS were detected by ELISA and immunofluorescence in neurons expressing the mutant but not the wild type protein. We used control GFP and G392E NPCs differentiated to neurons to investigate which cellular pathways were modulated by intracellular polymers by performing RNA sequencing. We identified 747 genes with a significant upregulation (623) or downregulation (124) in G392E NS-expressing cells, and we focused our attention on several genes involved in the defence against oxidative stress that were up-regulated in cells expressing G392E NS (Aldh1b1, Apoe, Gpx1, Gstm1, Prdx6, Scara3, Sod2). Inhibition of intracellular anti-oxidants by specific pharmacological reagents uncovered the damaging effects of NS polymers. Our results support a role for oxidative stress in the cellular toxicity underlying the neurodegenerative dementia FENIB. PMID- 28363801 TI - Continuous cerebroventricular administration of dopamine: A new treatment for severe dyskinesia in Parkinson's disease? AB - In Parkinson's disease (PD) depletion of dopamine in the nigro-striatal pathway is a main pathological hallmark that requires continuous and focal restoration. Current predominant treatment with intermittent oral administration of its precursor, Levodopa (l-dopa), remains the gold standard but pharmacological drawbacks trigger motor fluctuations and dyskinesia. Continuous intracerebroventricular (i.c.v.) administration of dopamine previously failed as a therapy because of an inability to resolve the accelerated dopamine oxidation and tachyphylaxia. We aim to overcome prior challenges by demonstrating treatment feasibility and efficacy of continuous i.c.v. of dopamine close to the striatum. Dopamine prepared either anaerobically (A-dopamine) or aerobically (O-dopamine) in the presence or absence of a conservator (sodium metabisulfite, SMBS) was assessed upon acute MPTP and chronic 6-OHDA lesioning and compared to peripheral l-dopa treatment. A-dopamine restored motor function and induced a dose dependent increase of nigro-striatal tyrosine hydroxylase positive neurons in mice after 7days of MPTP insult that was not evident with either O-dopamine or l-dopa. In the 6-OHDA rat model, continuous circadian i.c.v. injection of A-dopamine over 30days also improved motor activity without occurrence of tachyphylaxia. This safety profile was highly favorable as A-dopamine did not induce dyskinesia or behavioral sensitization as observed with peripheral l-dopa treatment. Indicative of a new therapeutic strategy for patients suffering from l-dopa related complications with dyskinesia, continuous i.c.v. of A-dopamine has greater efficacy in mediating motor impairment over a large therapeutic index without inducing dyskinesia and tachyphylaxia. PMID- 28363802 TI - Sociocultural Factors Influencing Eating Practices Among Office Workers in Urban South Korea. AB - OBJECTIVE: To understand the sociocultural factors affecting the eating behaviors of South Korean employees. DESIGN: In-depth individual interviews. SETTING: Two metropolitan areas of South Korea. PARTICIPANTS: Thirteen male and 9 female office workers. PHENOMENON OF INTEREST: The effects of sociocultural factors on office workers' eating behaviors. ANALYSIS: The researchers transcribed and analyzed audio-recorded interviews using thematic analysis. RESULTS: Among social and economic factors, participants with a family described a connection between female employment and lower frequency of home-cooked family meals. Working parents felt guilty about their need to depend on eating outside the home and eating processed foods because of their schedules. In addition, competitive and stressful working environments negatively affected workers' nutritional choices. Regarding cultural factors, given the powerful influences of collectivism and Confucianism on daily life, hierarchy and group harmony clearly had an important role in workers' everyday food choices. These included choosing menus that were most suitable for group meals and having to miss dinnertime while waiting until higher-position workers to leave work in the evening. CONCLUSIONS AND IMPLICATIONS: In this sociocultural setting, targeting office workers and changing social norms for healthy eating may be more effective than providing individualized interventions. These findings may be transferable to other, similar Asian countries. PMID- 28363803 TI - Testing a Beverage and Fruit/Vegetable Education Intervention in a University Dining Hall. AB - OBJECTIVE: To test the effect of a nutrition intervention that included education and 2 labeling components on students' food choices. DESIGN: Repeat cross sectional study taking place on 6 dinner occasions before and 6 afterward. SETTING: The study was conducted during dinner meals in a buffet-style dining hall in a university campus residence, where students paid a set price and consumed all they cared to eat. PARTICIPANTS: University students (n = 368 to 510) visited the cafeteria on each of the data collection dates. INTERVENTION: Fruit and vegetable consumption were encouraged; sugar-sweetened beverage consumption was discouraged using physical activity calorie equivalent labeling. MAIN OUTCOME MEASURES: Beverage choices and vegetable/fruit bar visits. ANALYSIS: Logistic regression was used to compare the proportion of student who selected each beverage, fruit, or vegetable before and after the intervention, while controlling for menu and gender as covariates. RESULTS: There was a significant decrease in the proportion of students selecting a sugar-sweetened beverage before vs after the intervention (49% vs 41%, respectively; P = .004) and an increase in students choosing water (43% vs 54%, respectively; P < .001). There was a significant increase in students who took fruit after the intervention (36%; P < .001) vs before (30%). The number of students visiting the vegetable bar significantly increased from 60% to 72% (P < .001). CONCLUSIONS: This intervention may be a way to encourage healthy dietary choices in campus dining halls. PMID- 28363804 TI - Clusters of Healthy and Unhealthy Eating Behaviors Are Associated With Body Mass Index Among Adults. AB - OBJECTIVE: To identify eating styles from 6 eating behaviors and test their association with body mass index (BMI) among adults. DESIGN: Cross-sectional analysis of self-report survey data. SETTING: Twelve primary care and specialty clinics in 5 states. PARTICIPANTS: Of 11,776 adult patients who consented to participate, 9,977 completed survey questions. VARIABLES MEASURED: Frequency of eating healthy food, frequency of eating unhealthy food, breakfast frequency, frequency of snacking, overall diet quality, and problem eating behaviors. The primary dependent variable was BMI, calculated from self-reported height and weight data. ANALYSIS: k-Means cluster analysis of eating behaviors was used to determine eating styles. A categorical variable representing each eating style cluster was entered in a multivariate linear regression predicting BMI, controlling for covariates. RESULTS: Four eating styles were identified and defined by healthy vs unhealthy diet patterns and engagement in problem eating behaviors. Each group had significantly higher average BMI than the healthy eating style: healthy with problem eating behaviors (beta = 1.9; P < .001), unhealthy (beta = 2.5; P < .001), and unhealthy with problem eating behaviors (beta = 5.1; P < .001). CONCLUSIONS AND IMPLICATIONS: Future attempts to improve eating styles should address not only the consumption of healthy foods but also snacking behaviors and the emotional component of eating. PMID- 28363805 TI - Evidence of Cognitive Bias in Decision Making Around Implantable-Cardioverter Defibrillators: A Qualitative Framework Analysis. AB - BACKGROUND: Studies have demonstrated that patients with primary prevention implantable cardioverter-defibrillators (ICDs) often misunderstand the ICD. Advances in behavioral economics demonstrate that some misunderstandings may be due to cognitive biases. We aimed to explore the influence of cognitive bias on ICD decision making. METHODS AND RESULTS: We used a qualitative framework analysis including 9 cognitive biases: affect heuristic, affective forecasting, anchoring, availability, default effects, halo effects, optimism bias, framing effects, and state dependence. We interviewed 48 patients from 4 settings in Denver. The majority were male (n = 32). Overall median age was 61 years. We found frequent evidence for framing, default, and halo effects; some evidence of optimism bias, affect heuristic, state dependence, anchoring and availability bias; and little or no evidence of affective forecasting. Framing effects were apparent in overestimation of benefits and downplaying or omitting potential harms. CONCLUSIONS: We found evidence of cognitive bias in decision making for ICD implantation. The majority of these biases appeared to encourage ICD treatment. PMID- 28363807 TI - Repetitive transcranial magnetic stimulation reduces anxiety symptoms, drug cravings, and elevates 1H-MRS brain metabolites: A case report. PMID- 28363806 TI - Novel role of insulin in the regulation of glucose excretion by mourning doves (Zenaida macroura). AB - In mammals, insulin primarily lowers plasma glucose (PGlu) by increasing its uptake into tissues. Studies have also shown that insulin lowers PGlu in mammals by modulating glomerular filtration rate (GFR). Birds have naturally high PGlu and, although insulin administration significantly decreases glucose concentrations, birds are resistant to insulin-mediated glucose uptake into tissues. Since prior work has not examined the effects of insulin on GFR in birds, the purpose of the present study was to assess whether insulin can augment renal glucose excretion and thereby lower PGlu. Therefore, the hypothesis of the present study was that insulin lowers PGlu in birds by augmenting GFR, as estimated by inulin clearance (CIn). Adult mourning doves (Zenaida macroura) were used as experimental animals. Doves were anesthetized and the brachial vein was cannulated for administration of [14C]-inulin and insulin and the brachial artery was cannulated for blood collections. Ureteral urine was collected via a catheter inserted into the cloaca. Ten minutes following administration of exogenous insulin (400MUg/kg body mass, i.v.) plasma glucose was significantly decreased (p=0.0003). Twenty minutes following insulin administration, increases in GFR (p=0.016) were observed along with decreases in urine glucose concentrations (p=0.008), glucose excretion (p=0.028), and the fractional excretion of glucose (p=0.003). Urine flow rate (p=0.051) also tended to increase after administration of insulin. These data demonstrate a significant role for insulin in modulating GFR in mourning doves, which may in part explain the lower PGlu measured following insulin administration. PMID- 28363809 TI - Vaginismus Treatment: Clinical Trials Follow Up 241 Patients. AB - INTRODUCTION: Vaginismus is mostly unknown among clinicians and women. Vaginismus causes women to have fear, anxiety, and pain with penetration attempts. AIM: To present a large cohort of patients based on prior published studies approved by an institutional review board and the Food and Drug Administration using a comprehensive multimodal vaginismus treatment program to treat the physical and psychologic manifestations of women with vaginismus and to record successes, failures, and untoward effects of this treatment approach. METHODS: Assessment of vaginismus included a comprehensive pretreatment questionnaire, the Female Sexual Function Index (FSFI), and consultation. All patients signed a detailed informed consent. Treatment consisted of a multimodal approach including intravaginal injections of onabotulinumtoxinA (Botox) and bupivacaine, progressive dilation under conscious sedation, indwelling dilator, follow-up and support with office visits, phone calls, e-mails, dilation logs, and FSFI reports. MAIN OUTCOME MEASURES: Logs noting dilation progression, pain and anxiety scores, time to achieve intercourse, setbacks, and untoward effects. Post-treatment FSFI scores were compared with preprocedure scores. RESULTS: One hundred seventy-one patients (71%) reported having pain-free intercourse at a mean of 5.1 weeks (median = 2.5). Six patients (2.5%) were unable to achieve intercourse within a 1-year period after treatment and 64 patients (26.6%) were lost to follow-up. The change in the overall FSFI score measured at baseline, 3 months, 6 months, and 1 year was statistically significant at the 0.05 level. Three patients developed mild temporary stress incontinence, two patients developed a short period of temporary blurred vision, and one patient developed temporary excessive vaginal dryness. All adverse events resolved by approximately 4 months. One patient required retreatment followed by successful coitus. CONCLUSION: A multimodal program that treated the physical and psychologic aspects of vaginismus enabled women to achieve pain-free intercourse as noted by patient communications and serial female sexual function studies. Further studies are indicated to better understand the individual components of this multimodal treatment program. Pacik PT, Geletta S. Vaginismus Treatment: Clinical Trials Follow Up 241 Patients. Sex Med 2017;5:e114-e123. PMID- 28363808 TI - Validation of cortical bone mineral density distribution using micro-computed tomography. AB - Changes in the bone mineral density distribution (BMDD), due to disease or drugs, can alter whole bone mechanical properties such as strength, stiffness and toughness. The methods currently available for assessing BMDD are destructive and two-dimensional. Micro-computed tomography (MUCT) has been used extensively to quantify the three-dimensional geometry of bone and to measure the mean degree of mineralization, commonly called the tissue mineral density (TMD). The TMD measurement has been validated to ash density; however parameters describing the frequency distribution of TMD have not yet been validated. In the current study we tested the ability of MUCT to estimate six BMDD parameters: mean, heterogeneity (assessed by the full-width-at-half-maximum (FWHM) and the coefficient of variation (CoV)), the upper and lower 5% cutoffs of the frequency distribution, and peak mineralization) in rat sized femoral cortical bone samples. We used backscatter scanning electron microscopy (bSEM) as the standard. Aluminum and hydroxyapatite phantoms were used to identify optimal scanner settings (70kVp, and 57MUA, with a 1500ms integration time). When using hydroxyapatite samples that spanned a broad range of mineralization levels, high correlations were found between MUCT and bSEM for all BMDD parameters (R2>=0.92, p<0.010). When using cortical bone samples from rats and various species machined to mimic rat cortical bone geometry, significant correlations between MUCT and bSEM were found for mean mineralization (R2=0.65, p<0.001), peak mineralization (R2=0.61, p<0.001) the lower 5% cutoff (R2=0.62, p<0.001) and the upper 5% cutoff (R2=0.33, p=0.021), but not for heterogeneity, measured by FWHM (R2=0.05, p=0.412) and CoV (R2=0.04, p=0.469). Thus, while mean mineralization and most parameters used to characterize the BMDD can be assessed with MUCT in rat sized cortical bone samples, caution should be used when reporting the heterogeneity. PMID- 28363811 TI - Australian consumers' insights into potatoes - Nutritional knowledge, perceptions and beliefs. AB - BACKGROUND: There has been a decline in the consumption of potatoes in developed countries worldwide due to many factors including the introduction of new foods and meal trends. In turn, this shift in eating patterns has dramatically affected the Australian potato industry which represents the largest horticulture contributor to gross food revenue. Many factors may influence consumers' food preferences, including the individual's nutrition knowledge, lifestyle factors, personal preferences, attitudes and beliefs. The present study aimed to capture an understanding of the consumer's level of nutritional knowledge and what currently drives consumer decision making. METHODS: Participants aged between 25 and 54 years responded to an online survey which included 52 questions specifically looking at potatoes, nutritional knowledge, views, eating habits and lifestyle factors, preferences and beliefs. Questions in the survey included multiple choice, rank and scale responses and free answers. RESULTS: A total of 1208 males and females (males n = 598, females n = 610) were included in the final analysis. The results show that the majority (88.5%) of the participants consume potatoes (not including hot chips/french fries) 4 times per week or less (41.6% <= 1 week; 46.9% 2-4 times/week). Overall, 33% of the participants stated that their potato consumption over the last five years had decreased. The main reasons stated for this decrease were that potatoes were high in carbohydrates (30%) and that starchy vegetables were not a healthy option (23%). CONCLUSIONS: Results showed that consumers believe that potatoes are good for all ages, are versatile, convenient, good value for money and delicious. However, the results indicate the majority of people have limited knowledge regarding the nutrient composition of potatoes and associate them negatively with carbohydrates. PMID- 28363812 TI - Changes in sucrose and quinine taste reactivity patterns in infant rat pups after exposure to the other tastant. AB - The taste reactivity test is considered as an objective measure to assess the hedonic impact of tastes. Both the appetitive and aversive pattern of responses are plastic and can change based on previous experience. The present study assessed the repertoire of taste responses elicited by sucrose and quinine in preweanling rats, and described changes in these taste reactivity patterns after exposure to the other tastant. We exposed infant rats (17 days old at the start of training) to sweet (2% sucrose) or bitter (0.01% quinine) tastants during 4, 10-min trials in two different random sequences. The subjects were weighed before and after each trial to provide a measure of percent body weight gained. The following taste reactivity responses were registered: duration of mouthing and paw lick, frequency of chin rub, head shake and flailing of the forelimbs, frequency and duration of face washing, wall climbing and paw tread. The consummatory and affective taste responses changed depending on the order in which the solutions were administered. The order of exposure to the tastants did not affect the levels of sucrose intake. Conversely, rat pups showed more ingestive, and fewer aversive, responses to the sweet tastant when access to the solution followed the intraoral infusion of quinine. Likewise, intraoral delivery of quinine elicited a more aversive taste reactivity pattern when delivered after the access to sucrose than when presented to sucrose-naive pups. This research contributes to the analysis of taste reactivity responses during the early ontogeny of the rat and highlights the importance of previous experiences on the subsequent assessment of rewards. PMID- 28363810 TI - A Meta-Analysis Detailing Overall Sexual Function and Orgasmic Function in Women Undergoing Midurethral Sling Surgery for Stress Incontinence. AB - INTRODUCTION: More than 200,000 midurethral slings are placed yearly for stress urinary incontinence. Approximately 14% to 20% of women experience worsening sexual function overall after these procedures. We postulated that sling placement injures neural pathways regulating "female prostate" tissue within the anterior vaginal wall. AIM: To perform a meta-analysis for overall sexual function and orgasm using validated questionnaires for transvaginal tape, transobturator tape, and their variants. METHODS: Effect sizes of preoperative and postoperative questionnaire scores for overall sexual function and orgasm were calculated. Random-effects models were selected for meta-analyses. Statistical analysis involved determination of the ratio of total heterogeneity to total variability. MAIN OUTCOME MEASURES: Differences of overall sexual and orgasm functions were calculated by subtracting postoperative sling scores from preoperative sling scores. Forest plots of effect sizes were performed. RESULTS: Sixty-seven percent of midurethral sling procedures analyzed showed no change or improvement in overall sexual function postoperatively, whereas 33% of studies analyzed for orgasm function showed improvement after the procedure. For transvaginal tape, mean total sexual function and orgasm postoperative scores were significantly higher than preoperative scores. For transobturator tape, mean total postoperative score was significantly higher than the preoperative score; however, the mean orgasm postoperative score was not significantly higher than the preoperative score, possibly because of variability in transobturator tape data. CONCLUSION: There is a discrepancy between postoperative sexual satisfaction and orgasmic function after midurethral sling surgery. Although overall sexual function remained the same or improved for most women, orgasmic function in only one third of cases improved overall, with most women experiencing no change or deterioration in orgasmic function. Dissection for, and placement of, the midurethral sling can compromise the neural integrity of the anterior vaginal wall, thereby detrimentally affecting the periurethral prostate tissue that is essential to the orgasmic response. We propose that this surgical procedure can compromise orgasmic function in some women. Szell N, Komisaruk B, Goldstein SW, et al. A Meta-Analysis Detailing Overall Sexual Function and Orgasmic Function in Women Undergoing Midurethral Sling Surgery for Stress Incontinence. Sex Med 2017;5:e84-e93. PMID- 28363813 TI - The social image of food: Associations between popularity and eating behavior. AB - One factor that determines what we eat and why we eat is our social environment. In the present research, two online studies examined the relationship between food intake and social images. Specifically, the present research assessed the relationship between the food intake university students ascribed to peers who varied in popularity and own self-reported food intake, and whether this relationship was moderated by identification with the peer group. Participants (N = 97 in Study 1; N = 402 in Study 2) were randomly presented with one of four (Study 1) or two of eight (Study 2) vignettes describing a popular or unpopular student (male or female) from their university without receiving any information about the peer's eating behavior. Subsequently, healthy and unhealthy eating ascribed to the peers and own self-reported eating behavior were assessed. Results indicated that popular peers were perceived to eat more healthily than unpopular peers. Moreover, eating behavior ascribed to popular peers were associated with own healthy and unhealthy eating. Importantly, the relationship between healthy eating behavior ascribed to popular peers and own healthy eating behavior was moderated by identification with the student group - the more participants identified with their peers, the more their own eating was aligned with the healthy eating ascribed to a popular peer. Hence, the popularity of others seems to shape perceptions of the food they eat and may facilitate healthy eating via social influence. PMID- 28363814 TI - The impact of video technology on learning: A cooking skills experiment. AB - This study examines the role of video technology in the development of cooking skills. The study explored the views of 141 female participants on whether video technology can promote confidence in learning new cooking skills to assist in meal preparation. Prior to each focus group participants took part in a cooking experiment to assess the most effective method of learning for low-skilled cooks across four experimental conditions (recipe card only; recipe card plus video demonstration; recipe card plus video demonstration conducted in segmented stages; and recipe card plus video demonstration whereby participants freely accessed video demonstrations as and when needed). Focus group findings revealed that video technology was perceived to assist learning in the cooking process in the following ways: (1) improved comprehension of the cooking process; (2) real time reassurance in the cooking process; (3) assisting the acquisition of new cooking skills; and (4) enhancing the enjoyment of the cooking process. These findings display the potential for video technology to promote motivation and confidence as well as enhancing cooking skills among low-skilled individuals wishing to cook from scratch using fresh ingredients. PMID- 28363815 TI - Proteomic profiling of isogenic primary and metastatic medulloblastoma cell lines reveals differential expression of key metastatic factors. AB - : Medulloblastoma is the most common malignant brain tumor in children. Around 30% of medulloblastoma patients are diagnosed with metastasis, which often results in a poor prognosis. Unfortunately, molecular mechanisms of medulloblastoma metastasis remain largely unknown. In this study, we employed the recently developed deep proteome analysis approach to quantitatively profile the expression of >10,000 proteins from CHLA-01-MED and CHLA-01R-MED isogenic cell lines derived from the primary and metastatic tumor of the same patient diagnosed with a group IV medulloblastoma. Using statistical analysis, we identified ~1400 significantly altered proteins between the primary and metastatic cell lines including known factors such as placental growth factor (PLGF), LIM homeobox 1 (LHX1) and prominim 1 (PROM1), as well as the negative regulator secreted protein acidic and cysteine rich (SPARC). Additional transwell experiments and immunohistochemical analysis of clinical medulloblastoma samples implicated yes associated protein 1 (YAP1) as a potential key factor contributing to metastasis. Taken together, our data broadly defines the metastasis-relevant regulated proteome and provides a precious resource for further investigating potential mechanisms of medulloblastoma metastasis. SIGNIFICANCE: This study represented the first deep proteome analysis of metastatic medulloblastomas and provided a valuable candidate list of altered proteins in metastatic medulloblastomas. The primary data suggested YAP1 as a potential driver for the metastasis of medulloblastoma. These results open up numerous avenues for further investigating the underlying mechanisms of medulloblastoma metastasis and improving the prognosis of medulloblastoma patients. PMID- 28363816 TI - Paecilomyces variotii peritonitis in a patient on continuous ambulatory peritoneal dialysis. AB - Paecilomyces variotii (P. variotii) is an extremely rare cause of continuous ambulatory peritoneal dialysis (CAPD) peritonitis. When diagnosed, it usually portends poor prognosis. Patient's survival depends on early laboratory diagnosis and proper treatment. We herein report a P. variotii peritonitis in a patient on CAPD which is a quite rare clinical entity. Laboratory diagnosis was confirmed via both morphological analysis and DNA sequencing. Antifungal susceptibility tests were performed and interpreted according to the Clinical Laboratory Standards Institute M38-A2 guidelines. After laboratory diagnosis, the patient was treated succesfully with liposomal amphotericin B and itraconazole combination and the peritoneal catheter was removed. This case is worthy of reporting since P. variotii is an uncommon cause of peritonitis and leads to dilemmas in both laboratory diagnosis and treatment strategies. PMID- 28363817 TI - Regression analysis and categorical agreement of fluconazole disk zone diameters and minimum inhibitory concentration by broth microdilution of clinical isolates of Candida. AB - AIM AND OBJECTIVES: Rampant use of fluconazole in Candida infections has led to predominance of less susceptible non-albicans Candida over Candida albicans. The aim of the study was to determine if zone diameters around fluconazole disk can be used to estimate the minimum inhibitory concentration (MIC) for clinical isolates of Candida species and vice versa. Categorical agreement between the Clinical & Laboratory Standards Institute (CLSI) recommended disk diffusion and CLSI broth microdilution method was sought for. MATERIAL AND METHODS: Antifungal susceptibility testing by disk diffusion and Broth microdilution was done as per CLSI document M44-S3 and CLSI document M27-S4 for Candida isolates respectively. Regression analysis correlating zone diameters to MIC value was done. Pearson's correlation coefficient was calculated to determine correlation between disk zone diameters and MICs. RESULTS: Candida albicans (33.3%) was clearly outnumbered by other non-albicans species predominantly Candida tropicalis (42.5%) and Candida glabrata (18.4%). Ten percent of the strains were resistant to fluconazole by disk diffusion and 13% by broth microdilution. MIC range for Candida albicans and Candida tropicalis ranged from<=0.25-64MUg/ml while that of Candida glabrata ranged from<=0.25-128MUg/ml. Categorical agreement between disk diffusion and broth microdilution was 86.8%. Pearson's coefficient of correlation was -0.5975 indicating moderate negative correlation between the two variables. CONCLUSION: Zone sizes can be used to estimate the MIC values, although with limited accuracy. There should be a constant effort to upgrade the guidelines in view of new clinical data, and laboratories should make an active effort to incorporate them. PMID- 28363818 TI - Ancient DNA analysis of the extinct North American flat-headed peccary (Platygonus compressus). AB - The geographical range of extant peccaries extends from the southwestern United States through Central America and into northern Argentina. However, from the Miocene until the Pleistocene now-extinct peccary species inhabited the entirety of North America. Relationships among the living and extinct species have long been contentious. Similarly, how and when peccaries moved from North to South America is unclear. The North American flat-headed peccary (Platygonus compressus) became extinct at the end of the Pleistocene and is one of the most abundant subfossil taxa found in North America, yet despite this extensive fossil record its phylogenetic position has not been resolved. This study is the first to present DNA data from the flat-headed peccary and full mitochondrial genome sequences of all the extant peccary species. We performed a molecular phylogenetic analysis to determine the relationships among ancient and extant peccary species. Our results suggested that the flat-headed peccary is sister taxon to a clade comprising the extant peccary species. Divergence date estimates from our molecular dating analyses suggest that if extant peccary diversification occurred in South America then their common ancestor must have dispersed from North America to South America well before the establishment of the Isthmus of Panama. We also investigated the genetic diversity of the flat-headed peccary by performing a preliminary population study on specimens from Sheriden Cave, Ohio. Flat-headed peccaries from Sheriden Cave appear to be genetically diverse and show no signature of population decline prior to extinction. Including additional extinct Pleistocene peccary species in future phylogenetic analyses will further clarify peccary evolution. PMID- 28363819 TI - Association between bystander cardiopulmonary resuscitation and redeemed prescriptions for antidepressants and anxiolytics in out-of-hospital cardiac arrest survivors. AB - AIM: This study aimed to examine rates of redeemed prescriptions of antidepressants and anxiolytics, used as markers for cerebral dysfunction in out of-hospital cardiac arrest (OHCA) survivors, and examine the association between bystander CPR and these psychoactive drugs. METHODS: We included all 30-day survivors of OHCA in Denmark between 2001 and 2011, who had not redeemed prescriptions for antidepressants or anxiolytics in the last six months prior to OHCA. Main outcome measures were redeemed prescriptions of antidepressants and anxiolytics within one year after OHCA. RESULTS: Among 2,001 30-day survivors, 174 (8.6% died and 12.0% redeemed a first prescription for an antidepressant and 8.2% for an anxiolytic drug within one year after arrest. The corresponding frequencies for redeemed prescribed drugs among age- and sex-matched population controls were 7.5% and 5.2%, respectively. Among survivors who received bystander CPR, prescriptions for antidepressants and anxiolytics were redeemed in 11.1% [95% CI 9.2-13.3%] and 6.3% [95% CI 4.9-8.0%] of the cases, respectively, versus 17.2% [95% CI 13.9-21.1%] and 13.4% [95% CI 10.5-17.0%], respectively, among patients who had not received bystander CPR. Adjusted for age, sex, year of arrest, comorbidity, witnessed status and socioeconomic status, bystander CPR was associated with significant reductions in redeemed prescriptions for antidepressants, Hazard Ratio (HR) 0.71 [95% CI 0.52-0.98], P=0.031; and anxiolytics, HR 0.55 [95% CI 0.38-0.81], P=0.002. CONCLUSION: Relative to no bystander CPR, redeemed prescriptions for antidepressants and anxiolytics were significantly lower among 30-day survivors of OHCA who received bystander CPR, suggesting a cerebral dysfunction-lowering potential of bystander CPR. PMID- 28363820 TI - Ventricular fibrillation waveform characteristics of the surface ECG: Impact of the left ventricular diameter and mass. AB - BACKGROUND: Despite a promising association between VF waveform characteristics and prognosis after resuscitation, studies with VF-guided treatment have so far not improved outcomes. While driven by the idea that the VF waveform reflects arrest duration, increasing evidence suggests that pre-existent disease-related changes of the myocardium affect ECG-characteristics of VF as well. In this context, we studied the impact of the left ventricular (LV) diameter and mass. METHODS: Cohort of 193 ICD-patients with defibrillation testing at the Radboudumc (2010-2014). Surface ECG-recordings (leads I,II,aVF,V1,V3,V6) were analysed to study amplitude and frequency characteristics of the induced VF. Both for LV diameter and mass, patients were categorised in two groups, using echocardiographic data (ASE-guidelines). RESULTS: In all ECG-leads, dominant and median frequencies were significantly lower in patients with (n=40) than in patients without (n=151) an increased LV diameter. The mean amplitude and amplitude spectrum area (AMSA) did not differ. In contrast, we observed no differences in frequency characteristics in relation to the LV mass, whereas mean amplitude (I,aVF,V3) and AMSA (I,V3) were significantly higher in patients with (n=57) than in patients without (n=120) an increased LV mass. CONCLUSIONS: Frequency characteristics of VF were consistently lower in case of an increased LV diameter. Whereas LV mass does not affect the frequency of the VF waveform, amplitudes seem higher with increasing mass. These findings add to the current knowledge of factors that modulate VF characteristics of the surface ECG and provide insight into factors which may be accounted for in future studies on VF guided resuscitative interventions. PMID- 28363821 TI - Accurate Neuroprognostication in Cardiac Arrest Survivors: Details Matter! PMID- 28363822 TI - Lewis-Sumner syndrome in a patient with rheumatoid arthritis: Link between rheumatoid arthritis and demyelinating polyradiculoneuropathies. AB - Chronic inflammatory demyelinating polyradiculoneuropathies are a group of autoimmune neuropathies with a chronic course. Lewis-Sumner syndrome is a variant of this disease, characterized by an asymmetrical distal and mostly motor involvement, predominating at upper limb. We report the case of a patient who developed almost currently rheumatoid arthritis and Lewis-Sumner syndrome, which raised the problem of therapeutic intensification for his rheumatism when methotrexate proved to be ineffective. Finally, rituximab had been introduced by common consent with neurologists, and the patient noticed an improvement fifteen days after the first infusion. Even if it is striking that both dysimmune diseases had declared within a few months, the association between chronic inflammatory demyelinating polyradiculoneuropathies and rheumatoid arthritis is exceptional, since the only cases reported in the literature are secondary to TNF alpha inhibitors. Given the potential demyelinating impact of some biologics, rituximab and perhaps abatacept seem to be the best therapeutic options when DMARDs had proven insufficient to control the rheumatism activity. PMID- 28363823 TI - Sustained tocilizumab-induced hypofibrinogenemia and thrombocytopenia. Comment on: "Tocilizumab-induced hypofibrinogenemia: A report of 7 cases" by Martis et al., Joint Bone Spine 2016, doi: 10.1016/j.jbspin.2016.04.008. PMID- 28363824 TI - Muscular calcified cysticercosis. PMID- 28363825 TI - Monitoring of Epstein-Barr virus (EBV)/cytomegalovirus (CMV)/varicella-zoster virus (VZV) load in patients receiving tocilizumab for rheumatoid arthritis. PMID- 28363826 TI - Precision and sources of variability in the assessment of rheumatoid arthritis erosions by HRpQCT. AB - OBJECTIVES: To assess the precision and the sources of variation due to repositioning of the manual measurement of erosions located on the metacarpophalangeal joints (MCP) with High-Resolution peripheral Quantitative Computed Tomography (HRpQCT) in rheumatoid arthritis (RA). METHODS: RA patients with at least one erosion on the 2nd, 3rd or 4th MCP on conventional radiographs were included. Two scans were performed the same day with repositioning. The main outcome was to calculate the short-term precision of the width, depth, and volume of erosions. Secondary outcomes were intra-operator and inter-operator precision, the least significant change, and the sources of variability of the measurement. RESULTS: Twenty-nine patients were included, allowing analysis of 406 erosions from 0.9 to 3mm of diameter. Intraclass correlation coefficients (ICC) for the precision of the measurement of the axial width, axial depth, and volume after repositioning were 0.80, 0.96, and 0.99, respectively. RMS CV and RMS SD were 16%, 0.26mm; 17.5%, 0.32mm; and 19.7%, 0.93mm3, respectively. For intra-operator precision, ICCs were 0.92, 0.97, and 0.99 with RMS CV of 16%, 16.4%, and 18.7%, respectively. Inter-operator precision of the volume was 0.99 with RMS CV of 14%. Least significant change of width, depth, and volume were 0.3mm, 0.2mm, and 0.3mm3. There was no significant correlation with bone microarchitecture parameters. CONCLUSION: HRpQCT analysis is a reproducible method to characterize and measure erosions, without effect of the repositioning. However, we showed weak precision in manual measurement due to intra-operator variability. PMID- 28363827 TI - A multi-parameter response prediction model for rituximab in rheumatoid arthritis. AB - OBJECTIVES: To validate the IFN response gene (IRG) set for the prediction of non response to rituximab in rheumatoid arthritis (RA) and assess the predictive performance upon combination of this gene set with clinical parameters. METHODS: In two independent cohorts of 93 (cohort I) and 133 (cohort II) rituximab starting RA patients, baseline peripheral blood expression of eight IRGs was determined, and averaged into an IFN score. Predictive performance of IFN score and clinical parameters was assessed by logistic regression. A multivariate prediction model was developed using a forward stepwise selection procedure. Patients with a decrease in disease activity score (DeltaDAS28)>=1.8 after 6 months of therapy were considered responders. RESULTS: The mean IFN score was higher in non-responders compared to responders in both cohorts, but this difference was most pronounced in patients who did not use prednisone, as described before. Univariate analysis in cohort I showed that baseline DAS28, IFN score, DMARD use and negativity for IgM-RF and/or ACPA were associated with rituximab non-response. The multivariate model consisted of DAS28, IFN score and DMARD use, which showed an area under the curve (AUC) of 0.82. In cohort II, this model revealed a comparable AUC in PREDN-negative patients (0.78), but AUC in PREDN-positive patients was significantly lower (0.63), which seemed due to effect modification of the IFN score by prednisone. CONCLUSIONS: Combination of predictive parameters provided a promising model for the prediction of non response to rituximab, with possibilities for optimization via definition of the exact interfering effect of prednisone on IFN score. TRIAL REGISTRATION (COHORT II, SMART TRIAL): NCT01126541, registered 18 May 2010. PMID- 28363830 TI - Hedgehog signaling contributes to basic fibroblast growth factor-regulated fibroblast migration. AB - Fibroblast migration is a central process in skin wound healing, which requires the coordination of several types of growth factors. bFGF, a well-known fibroblast growth factor (FGF), is able to accelerate fibroblast migration; however, the underlying mechanism of bFGF regulation fibroblast migration remains unclear. Through the RNA-seq analysis, we had identified that the hedgehog (Hh) canonical pathway genes including Smoothened (Smo) and Gli1, were regulated by bFGF. Further analysis revealed that activation of the Hh pathway via up regulation of Smo promoted fibroblast migration, invasion, and skin wound healing, but which significantly reduced by GANT61, a selective antagonist of Gli1/Gli2. Western blot analyses and siRNA transfection assays demonstrated that Smo acted upstream of phosphoinositide 3-kinase (PI3K)-c-Jun N-terminal kinase (JNK)-beta-catenin to promote cell migration. Moreover, RNA-seq and qRT-PCR analyses revealed that Hh pathway genes including Smo and Gli1 were under control of beta-catenin, suggesting that beta-catenin turn feedback activates Hh signaling. Taken together, our analyses identified a new bFGF-regulating mechanism by which Hh signaling regulates human fibroblast migration, and the data presented here opens a new avenue for the wound healing therapy. PMID- 28363829 TI - Integrin signaling potentiates transforming growth factor-beta 1 (TGF-beta1) dependent down-regulation of E-Cadherin expression - Important implications for epithelial to mesenchymal transition (EMT) in renal cell carcinoma. AB - Signal transduction through the transforming growth factor-beta 1 (TGF-beta1) pathway affects epithelial to mesenchymal transition (EMT), partly by modulation of E-Cadherin expression. The concurrent impact of extracellular matrix driven regulation of integrin signaling on EMT has not been well characterized. We assessed the cumulative effect and molecular mechanisms of TGF-beta1 and integrin signal transduction on E-Cadherin in a renal cell cancer (RCC) model. Stimulation of RCC cells with TGF-beta1 demonstrated a three-fold increased expression of integrin alphav. A ligand of integrin alphav-beta3, (cyclopentapeptide containing Arginyl-Glycyl-Aspartic acid motif, RGD), was used to mimic integrin signaling. Treatment of cells with RGD and TGF-beta1 demonstrated significantly greater E cadherin depletion than either ligand alone. This cooperative action on E Cadherin expression is regulated by transcription factor Snai1 and is followed on a cellular level by increased cellular mobility as evidenced in a wound healing assay. Subsequent silencing of potential downstream mediators of the cumulative action of RGD and TGF-beta1 was carried out by small interfering RNA transfection and confirmed by Western blotting and/or RT-PCR. SiRNA mediated silencing of FAK and PINCH1 independently abrogated the cumulative effect of RGD and TGF-beta1 on E-Cadherin expression. We have identified a novel mechanism through which extracellular matrix event transduction by integrins further augments TGF-beta1 related effects on EMT. Molecular machinery involved in the integrin alphav-TGF beta1 interplay may represent a therapeutic target in RCC. PMID- 28363828 TI - Rho GTPases and actomyosin: Partners in regulating epithelial cell-cell junction structure and function. AB - Epithelial tissues are defined by polarized epithelial cells that are integrated into tissues and exhibit barrier function in order to regulate what is allowed to pass between cells. Cell-cell junctions must be stable enough to promote barrier function and tissue integrity, yet plastic enough to remodel when necessary. This remarkable ability to dynamically sense and respond to changes in cell shape and tissue tension allows cell-cell junctions to remain functional during events that disrupt epithelial homeostasis including morphogenesis, wound healing, and cell division. In order to achieve this plasticity, both tight junctions and adherens junctions are coupled to the underlying actomyosin cytoskeleton. Here, we discuss the importance of the junctional linkage to actomyosin and how a localized zone of active RhoA along with other Rho GTPases work together to orchestrate junctional actomyosin dynamics. We focus on how scaffold proteins help coordinate Rho GTPases, their upstream regulators, and their downstream effectors for efficient, localized Rho GTPase signaling output. Additionally, we highlight important roles junctional actin-binding proteins play in addition to their traditional roles in organizing actin. Together, Rho GTPases, their regulators, and effectors form compartmentalized signaling modules that regulate actomyosin structure and contractility to achieve proper cell-cell adhesion and tissue barriers. PMID- 28363831 TI - Constant-Current Deep Brain Stimulation of the Globus Pallidus Internus in the Treatment of Primary Dystonia by a Novel 8-Contact (Octrode) Lead. AB - OBJECTIVE: To evaluate bilateral constant-current globus pallidus internus (GPi) deep brain stimulation using an 8-contact lead. METHODS: This prospective, open label, single-center pilot study of 10 patients assessed the feasibility of delivering bilaterally constant-current GPi deep brain stimulation with a novel 8 channel lead to treat primary dystonia using standard scales as outcome measures. RESULTS: Patients included 4 men and 6 women with a mean age of 35.8 years +/- 9.2 (range, 27-49 years). Mean age of onset was 18.5 years +/- 9.1 (range, 8-35 years), and mean disease duration was 17.3 years (range, 7-27 years). All had primary dystonia (8 generalized dystonia, 1 segmental dystonia, 1 focal dystonia). The primary variable was determined as 50% reduction in dystonia symptoms from baseline to the 6-month follow-up, as defined by the Burke-Fahn Marsden Dystonia Rating Scale. Six patients (60.0%) achieved >50% reduction in Burke-Fahn-Marsden Dystonia Rating Scale score and were classified as responders at the 6-month follow-up. Five of these 6 responders (83.3%) sustained that response through the assessment at the end of the first year. Constant-current stimulation was associated with significant improvement in pain and quality of life in all patients. Nearly 84% of the overall improvement occurred by the end of first month after stimulation onset, documenting an early response to treatment. Axial symptoms responded the best. CONCLUSIONS: Constant-current GPi deep brain stimulation proved safe and efficacious for treatment of primary dystonia. Motor scores improved by 54%, mostly within the first month. No phenotype-specific stimulation could be achieved, despite the capability of the new lead to stimulate specific loci within the GPi. PMID- 28363832 TI - Primary Central Nervous System Lymphomas of the Brain: A Retrospective Analysis in a Single Institution. AB - BACKGROUND: Primary central nervous system lymphomas (PCNSLs) are relatively rare brain tumors. Accurate diagnosis is usually made by surgical biopsy. In addition to surgical biopsy and decompression, treatment options include high-dose methotrexate and chemotherapy, radiation therapy, and stem cell therapy. Because of the rarity of this disease, guidelines for PCNSL diagnosis and treatment usually are formed from a large series of experiences. METHODS: We retrospectively reviewed 79 patients in our tertiary referral center during a 13 year period. All patients with PCNSL underwent surgical or bone marrow biopsy procedures, and diagnoses were confirmed by hematologists or neuropathologists. At the time of diagnosis, 44 patients presented with a single lesion. Human immunodeficiency virus was confirmed positive in 1 patient. The standard therapy protocol included high-dose methotrexate (intravenous and intrathecal) and chemotherapy with cytosine arabinoside, followed by external irradiation of the brain. RESULTS: Significant prognostic factors in these patients were low serum lactate dehydrogenase levels and radiation therapy. Multiplicity of lesions at time of diagnosis did not imply a worse outcome, and surgical resection and debulking did not show a significant survival benefit. CONCLUSIONS: PCNSL has a poor prognosis. Further clinical trials and diagnostic tools are needed to reveal the complexity of this disease. PMID- 28363833 TI - Postoperative Neurosurgical Infection Rates After Shared-Resource Intraoperative Magnetic Resonance Imaging: A Single-Center Experience with 195 Cases. AB - OBJECTIVES: To determine the rate of surgical-site infections (SSI) in neurosurgical procedures involving a shared-resource intraoperative magnetic resonance imaging (ioMRI) scanner at a single institution derived from a prospective clinical quality management database. METHODS: All consecutive neurosurgical procedures that were performed with a high-field, 2-room ioMRI between April 2013 and June 2016 were included (N = 195; 109 craniotomies and 86 endoscopic transsphenoidal procedures). The incidence of SSIs within 3 months after surgery was assessed for both operative groups (craniotomies vs. transsphenoidal approach). RESULTS: Of the 109 craniotomies, 6 patients developed an SSI (5.5%, 95% confidence interval [CI] 1.2-9.8%), including 1 superficial SSI, 2 cases of bone flap osteitis, 1 intracranial abscess, and 2 cases of meningitis/ventriculitis. Wound revision surgery due to infection was necessary in 4 patients (4%). Of the 86 transsphenoidal skull base surgeries, 6 patients (7.0%, 95% CI 1.5-12.4%) developed an infection, including 2 non-central nervous system intranasal SSIs (3%) and 4 cases of meningitis (5%). Logistic regression analysis revealed that the likelihood of infection significantly decreased with the number of operations in the new operational setting (odds ratio 0.982, 95% CI 0.969-0.995, P = 0.008). CONCLUSIONS: The use of a shared-resource ioMRI in neurosurgery did not demonstrate increased rates of infection compared with the current available literature. The likelihood of infection decreased with the accumulating number of operations, underlining the importance of surgical staff training after the introduction of a shared-resource ioMRI. PMID- 28363834 TI - Endovascular Stenting for Symptomatic Carotid Dissection with Hemodynamic Insufficiency. AB - OBJECTIVE: To date, no controlled studies on the treatment of carotid artery dissection (CAD) have been reported. The purpose of this study was to demonstrate the technical feasibility and clinical efficacy of stent-supported angioplasty (SSA) as primary treatment for acute stroke due to CAD. METHODS: A review of medical records identified 21 patients who underwent SSA as primary treatment for acute stroke related to CAD between 2008 and 2014. The inclusion criteria were recent transient ischemic attack (n = 7, 33.3%) or acute infarct (n = 14, 66.7%) due to CAD (>=70% narrowing) with hemodynamic impairment. Technical success rates, complications, and angiographic and clinical outcomes were analyzed retrospectively. RESULTS: SSA was technically successful in all patients. Of 21 patients, 8 (38.1%) showed an additional intracranial occlusion. Intracranial recanalization to a thrombolysis in cerebral infarction >=2b flow was achieved in 50% of the cases. Procedure-related mortality was 4.8%, and morbidity was 9.5%. Five (35.7%) of 14 patients presenting with an acute infarct showed significant improvement (decrease in National Institutes of Health Stroke Scale score of >=4 points compared with admission score) at 7 days after SSA. During the observation period (mean, 20.5 months), stroke recurrence occurred in only 1 patient (5%), resulting in an annual stroke risk of 2.9%. A favorable outcome (modified Rankin Scale score <=2) was achieved in all 7 patients with a transient ischemic attack (100%) and in 7 of 14 patients with an acute infarct (50%) at the 90-day follow up. CONCLUSION: Our results provide evidence that SSA is a feasible and effective strategy as primary treatment for steno-occlusive CAD patients with significant hypoperfusion or a large penumbra. PMID- 28363837 TI - When math operations have visuospatial meanings versus purely symbolic definitions: Which solving stages and brain regions are affected? AB - How does processing differ during purely symbolic problem solving versus when mathematical operations can be mentally associated with meaningful (here, visuospatial) referents? Learners were trained on novel math operations (?, ?), that were defined strictly symbolically or in terms of a visuospatial interpretation (operands mapped to dimensions of shaded areas, answer = total area). During testing (scanner session), no visuospatial representations were displayed. However, we expected visuospatially-trained learners to form mental visuospatial representations for problems, and exhibit distinct activations. Since some solution intervals were long (~10s) and visuospatial representations might only be instantiated in some stages during solving, group differences were difficult to detect when treating the solving interval as a whole. However, an HSMM-MVPA process (Anderson and Fincham, 2014a) to parse fMRI data identified four distinct problem-solving stages in each group, dubbed: 1) encode; 2) plan; 3) compute; and 4) respond. We assessed stage-specific differences across groups. During encoding, several regions implicated in general semantic processing and/or mental imagery were more active in visuospatially-trained learners, including: bilateral supramarginal, precuneus, cuneus, parahippocampus, and left middle temporal regions. Four of these regions again emerged in the computation stage: precuneus, right supramarginal/angular, left supramarginal/inferior parietal, and left parahippocampal gyrus. Thus, mental visuospatial representations may not just inform initial problem interpretation (followed by symbolic computation), but may scaffold on-going computation. In the second stage, higher activations were found among symbolically-trained solvers in frontal regions (R. medial and inferior and L. superior) and the right angular and middle temporal gyrus. Activations in contrasting regions may shed light on solvers' degree of use of symbolic versus mental visuospatial strategies, even in absence of behavioral differences. PMID- 28363836 TI - Multi-echo fMRI: A review of applications in fMRI denoising and analysis of BOLD signals. AB - In recent years the field of fMRI research has enjoyed expanded technical abilities related to resolution, as well as use across many fields of brain research. At the same time, the field has also dealt with uncertainty related to many known and unknown effects of artifact in fMRI data. In this review we discuss an emerging fMRI technology, called multi-echo (ME)-fMRI, which focuses on improving the fidelity and interpretability of fMRI. Where the essential problem of standard single-echo fMRI is the indeterminacy of sources of signals, whether BOLD or artifact, this is not the case for ME-fMRI. By acquiring multiple echo images per slice, the ME approach allows T2* decay to be modeled at every voxel at every time point. Since BOLD signals arise by changes in T2* over time, an fMRI experiment sampling the T2* signal decay can be analyzed to distinguish BOLD from artifact signal constituents. While the ME approach has a long history of use in theoretical and validation studies, modern MRI systems enable whole brain multi-echo fMRI at high resolution. This review covers recent multi-echo fMRI acquisition methods, and the analysis steps for this data to make fMRI at once more principled, straightforward, and powerful. After a brief overview of history and theory, T2* modeling and applications will be discussed. These applications include T2* mapping and combining echoes from ME data to increase BOLD contrast and mitigate dropout artifacts. Next, the modeling of fMRI signal changes to detect signal origins in BOLD-related T2* versus artifact-related S0 changes will be reviewed. A focus is on the use of ME-fMRI data to extract and classify components from spatial ICA, called multi-echo ICA (ME-ICA). After describing how ME-fMRI and ME-ICA lead to a general model for analysis of fMRI signals, applications in animal and human imaging will be discussed. Applications include removing motion artifacts in resting state data at subject and group level. New imaging methods such as multi-band multi-echo fMRI and imaging at 7T are demonstrated throughout the review, and a practical analysis pipeline is described. The review culminates with evidence from recent studies of major boosts in statistical power from using multi-echo fMRI for detecting activation and connectivity in healthy individuals and patients with neuropsychiatric disease. In conclusion, the review shows evidence that the multi-echo approach expands the range of experiments that is practicable using fMRI. These findings suggest a compelling future role of the multi-echo approach in subject-level and clinical fMRI. PMID- 28363835 TI - Functional dynamics of hippocampal glutamate during associative learning assessed with in vivo 1H functional magnetic resonance spectroscopy. AB - fMRI has provided vibrant characterization of regional and network responses associated with associative learning and memory; however, their relationship to functional neurochemistry is unclear. Here, we introduce a novel application of in vivo proton functional magnetic resonance spectroscopy (1H fMRS) to investigate the dynamics of hippocampal glutamate during paired-associated learning and memory in healthy young adults. We show that the temporal dynamics of glutamate differed significantly during processes of memory consolidation and retrieval. Moreover, learning proficiency was predictive of the temporal dynamics of glutamate such that fast learners were characterized by a significant increase in glutamate levels early in learning, whereas this increase was only observed later in slow learners. The observed functional dynamics of glutamate provides a novel in vivo marker of brain function. Previously demonstrated N-methyl-D aspartate (NMDA) receptor mediated synaptic plasticity during associative memory formation may be expressed in glutamate dynamics, which the novel application of 1H MRS is sensitive to. The novel application of 1H fMRS can provide highly innovative vistas for characterizing brain function in vivo, with significant implications for studying glutamatergic neurotransmission in health and disorders such as schizophrenia. PMID- 28363839 TI - Selection for high aerobic capacity has no protective effect against obesity in laboratory mice. AB - Aerobic capacity (VO2max measured during intensive physical exercise) both trained and intrinsic (i.e. genetically determined) has recently been deemed a good predictor of cardiometabolic risks. However, the underlying mechanisms linking VO2max and health risk factors are not entirely clear, as it seems that not VO2max per se, but rather some correlated traits, like spontaneous physical activity (SPA) are responsible for sustaining the lean phenotype. Here we investigated the link between genetically determined aerobic capacity, SPA and resistance to diet-induced health risks using replicated lines of mice selected for high aerobic capacity during swimming in mid-cold water (25 degrees C) and Randomly Bred control mice. After four months of consumption of the western type HFat and HCarb diets and no forced nor voluntary training, we found no evidence of protective effects of intrinsic high VO2max. The Selected mice displayed similar levels of blood glucose, cholesterol, triglycerides and body fat as the Random Bred control animals. Most notably we found no correlation between VO2max and SPA levels. Our results therefore call into question the ubiquity of VO2max as a predictor of metabolic health and leanness, at least in animal models. PMID- 28363838 TI - Orexin activation counteracts decreases in nonexercise activity thermogenesis (NEAT) caused by high-fat diet. AB - Overweight and obesity result from an imbalance between caloric intake and energy expenditure, including expenditure from spontaneous physical activity (SPA). Changes in SPA and resulting changes in non-exercise activity thermogenesis (NEAT) likely interact with diet to influence risk for obesity. However, previous research on the relationship between diet, physical activity, and energy expenditure has been mixed. The neuropeptide orexin is a driver of SPA, and orexin neuron activity can be manipulated using DREADDs (Designer Receptors Exclusively Activated by Designer Drugs). We hypothesized that HFD decreases SPA and NEAT, and that DREADD-mediated activation of orexin neuron signaling would abolish this decrease and produce an increase in NEAT instead. To test these ideas, we characterized behaviors to determine the extent to which access to a high-fat diet (HFD) influences the proportion and probability of engaging in food intake and activity. We then measured NEAT following access to HFD and following a DREADD intervention targeting orexin neurons. Two cohorts of orexin-cre male mice were injected with an excitatory DREADD virus into the caudal hypothalamus, where orexin neurons are concentrated. Mice were then housed in continuous metabolic phenotyping cages (Sable Promethion). Food intake, indirect calorimetry, and SPA were automatically measured every second. For cohort 1 (n=8), animals were given access to chow, then switched to HFD. For cohort 2 (n=4/group), half of the animals were given access to HFD, the other access to chow. Then, among animals on HFD, orexin neurons were activated following injections of clozapine n-oxide (CNO). Mice on HFD spent significantly less time eating (p<0.01) and more time inactive compared to mice on chow (p<0.01). Following a meal, mice on HFD were significantly more likely to engage in periods of inactivity compared to those on chow (p<0.05). NEAT was decreased in animals on HFD, and was increased to the NEAT level of control animals following activation of orexin neurons with DREADDs. Food intake (kilocalories) was not significantly different between mice on chow and HFD, yet mice on chow expended more energy per unit of SPA, relative to that in mice consuming HFD. These results suggest that HFD consumption reduces SPA and NEAT, and increases inactivity following a meal. Together, the data suggest a change in the efficiency of energy expenditure based upon diet, such that SPA during HFD burns fewer calories compared to SPA on a standard chow diet. PMID- 28363842 TI - Potential of angiotensin II receptor blockers in the treatment of diabetic retinopathy. AB - Impairments in renin-angiotensin-aldosterone system during diabetes mellitus, leading to its dysfunction, have been known since a decade. Hyperglycemia induces several pathological alterations which upregulate this system, accounting for overexpression of its downstream signaling molecules, amongst which angiotensin II (Ang II) and aldosterone hold prime pathological notoriety. Although it is well known that elevated plasma levels of Ang II play a crucial role in the pathophysiology of type-II diabetic mellitus, by inducing and aggravating insulin resistance, it is not quite much known that it equally elevates the possibility/risk of development of diabetic complications. Also, amongst the various diabetic complications, the effects of Ang II upregulation are more widely acknowledged in studies concerning the pathophysiology of diabetic nephropathy; however, its role in exacerbating diabetic retinopathy has not received much attention. Ang II, indeed, plays a detrimental role in the progression of diabetic retinopathy by augmenting the principal events involved in its pathogenesis, namely oxidative stress, angiogenesis and inflammation. The utility of angiotensin receptor blockers has shown positive results in research studies and hence, might potentially provide a novel adjuvant therapy for treating this complication and preventing the associated vision-loss in diabetic patients. PMID- 28363841 TI - ACA, an inhibitor phospholipases A2 and transient receptor potential melastatin-2 channels, attenuates okadaic acid induced neurodegeneration in rats. AB - AIM: In recent studies, it has been shown that the Transient Receptor Potential Melastatin-2 Channels (TRPM2) and Phospholipases A2 (PLA2) inhibitors may have a protective effect on neurons. This study was aimed to investigate the protective effect of TRPM2 and PLA2 inhibitor N-(p-amylcinnamoyl) Anthranilic Acid (ACA) in a neurodegenerative model induced by Okadaic Acid (OKA). MAIN METHODS: OKA (200ng/10MUl) was administered bilateral intracerebroventricularly as a single injection. KEY FINDINGS: OKA-treated rats showed significant impairments of spatial memory in Morris Water Maze Test. OKA-induced memory-impaired rats showed increased numbers of degenerated neurons and Caspase-3, tau phosphorylated ser396, beta-amyloid positive cells in the hippocampus and cerebral cortex. Furthermore, OKA-treated rats exhibited significantly increased MDA, TNF-alpha levels, and decreased SOD, GSH-PX enzyme activates and GSH levels of the tissues. ACA administration ameliorated OKA-induced memory impairment in rats. The ACA treatment also increased SOD and GSH-PX enzyme activation and GSH levels, and conversely decreased the levels of MDA, TNF-alpha. It was found that the numbers of the degenerated neurons and Caspase-3 positive cells of cortex and hippocampus regions were significantly reduced. SIGNIFICANCE: ACA administration attenuates the oxidative stress and neuroinflammation of OKA-induced neurodegeneration; and ameliorates the cognitive decline and neurodegeneration. PMID- 28363843 TI - Toll-like receptor 9 mediates paraquat-induced acute lung injury: an in vitro and in vivo study. AB - AIMS: This study aimed to investigate the role of Toll-like receptor 9 in paraquat-induced acute lung injury (ALI). MAIN METHODS: For in vivo study,C57BL mice were randomly assigned into the vehicle control group, paraquat group, paraquat + TLR9 antagonist (ODN2088) group, and TLR9 antagonist (ODN2088) group (n=36 per group). After paraquat 30mg/kg ip for 2, 24 and 48h, serum samples and lung tissues were collected to evaluate ALI and TLR9 signaling by lung injury score, protein levels of TLR9, MyD88, p-IRAK4, p-p65, and serum TNF-alpha and IL 1beta levels. As for in vitro research A549 cells were randomly divided into the control group, paraquat group, paraquat + TLR9 siRNA group, and TLR9 siRNA group. After paraquat treatment for 24h, the cells and supernatant were collected to measureTLR9, TNF-alpha, IL-1 mRNA expression, and detect activation of NF-kappaB, caspase-3. KEY FINDINGS: In vivo, the lung injury score, the TLR9, MyD88, p-IRAK4 and p-p65 protein levels, and cytokines TNF-alpha and IL-1beta levels in paraquat group were significantly higher than that in the control group;TLR9 blocker ODN2088 pretreatment attenuated lung injury, inhibited MyD88 and NF-kappaB activation, and reduced TNF-alpha and IL-1beta in serum. In vitro result shows that the gene silencing of TLR9 reduced the mRNA expression of TLR9, TNF-alpha and IL-1, inhibited NF-kappaB and caspase-3 activation, attenuated cell apoptosis. SIGNIFICANCE: TLR9 mediates paraquat-induced ALI, antagonizing TLR9 or silencing TLR9gene may attenuate paraquat-induced ALI. PMID- 28363845 TI - The expression of the clock gene cycle has rhythmic pattern and is affected by photoperiod in the moth Sesamia nonagrioides. AB - To obtain clues to the link between the molecular mechanism of circadian and photoperiod clocks, we have cloned the circadian clock gene cycle (Sncyc) in the corn stalk borer, Sesamia nonagrioides, which undergoes facultative diapause controlled by photoperiod. Sequence analysis revealed a high degree of conservation among insects for this gene. SnCYC consists of 667 amino acids and structural analysis showed that it contains a BCTR domain in its C-terminal in addition to the common domains found in Drosophila CYC, i.e. bHLH, PAS-A, PAS-B domains. The results revealed that the sequence of Sncyc showed a similarity to that of its mammalian orthologue, Bmal1. We also investigated the expression patterns of Sncyc in the brain of larvae growing under long-day 16L: 8D (LD), constant darkness (DD) and short-day 10L: 14D (SD) conditions using qRT-PCR assays. The mRNAs of Sncyc expression was rhythmic in LD, DD and SD cycles. Also, it is remarkable that the photoperiodic conditions affect the expression patterns and/or amplitudes of circadian clock gene Sncyc. This gene is associated with diapause in S. nonagrioides, because under SD (diapause conditions) the photoperiodic signal altered mRNA accumulation. Sequence and expression analysis of cyc in S. nonagrioides shows interesting differences compared to Drosophila where this gene does not oscillate or change in expression patterns in response to photoperiod, suggesting that this species is an interesting new model to study the molecular control of insect circadian and photoperiodic clocks. PMID- 28363840 TI - Behind binge eating: A review of food-specific adaptations of neurocognitive and neuroimaging tasks. AB - Recurrent binge eating, or overeating accompanied by a sense of loss of control, is a major public health concern. Identifying similarities and differences among individuals with binge eating and those with other psychiatric symptoms and characterizing the deficits that uniquely predispose individuals to eating problems are essential to improving treatment. Research suggests that altered reward and control-related processes may contribute to dysregulated eating and other impulsive behaviors in binge-eating populations, but the best methods for reliably assessing the contributions of these processes to binge eating are unclear. In this review, we summarize standard neurocognitive and neuroimaging tasks that assess reward and control-related processes, describe adaptations of these tasks used to study eating and food-specific responsivity and deficits, and consider the advantages and limitations of these tasks. Future studies integrating both general and food-specific tasks with neuroimaging will improve understanding of the neurocognitive processes and neural circuits that contribute to binge eating and could inform novel interventions that more directly target or prevent this transdiagnostic behavior. PMID- 28363844 TI - Identification and functional analysis of chitinase 7 gene in white-backed planthopper, Sogatella furcifera. AB - Chitinase is used to degrade chitin in insect cuticles and the peritrophic matrix. In this study, the full-length cDNA sequence of a Cht gene (SfCht7) was identified and characterized from the white-black planthopper, Sogatella furcifera. The SfCht7 cDNA was 3148bp, contained an open reading frame of 2877bp and encoded 958 amino acids with a predicted molecular weight of 107.9kDa. Homology analysis indicated that SfCht7 has typical chitinase features include a chitin-binding domain, two catalytic domains and a signal peptide region. Phylogenetic analysis suggested that SfCht7 belonged to the group III chitinases. Quantitative real-time PCR analyses showed that SfCht7 was highly expressed before molting. After injecting SfCht7 double-stranded RNA in the nymph stage, insects exhibited phenotypes of difficulty in molting and wing development. A lethal phenotype was that nymph bodies exuviated from the head but the old cuticle did not detach completely from the body. Another lethal phenotype was that elongated distal wing pads of fifth-instar nymphs with junctions between the thorax and abdomen in the treatment group that were thinner than in the control group, giving a "wasp-waisted" appearance. In another phenotype that was not lethal, nymphs exuviated and old cuticles detached completely from the body, but the wings of adults did not stretch normally. PMID- 28363847 TI - Ridge augmentation with titanium mesh: A case report. AB - : Insufficient bone volume for dental implant placement in the maxillary anterior segment is a constant challenge in oral surgery. Several techniques have been suggested to reconstruct deficient alveolar ridges and to facilitate dental implant placement. These techniques include bone splitting osteotomy, distraction osteogenesis, inlay and onlay bone grafting. Guided bone regeneration (GBR) is also a promising alternative that increases the bone volume by the use of a subperiosteal barrier. AIM: The aim of this case was to demonstrate that the use of rigid titanium occlusive barrier is a reliable alternative to perform a lateral alveolar bone augmentation and treat localized ridge deformities before reaching an ideal implant placement. OBSERVATION: A 25-year-old healthy male was referred for implant placement in the maxillary central incisor. The alveolar bone width at the implant site 21 was less than 5mm. Hard tissue augmentation was accomplished using guided bone regeneration. A rigid titanium occlusive barrier was customized to desired shape of future alveolar ridge then secured with tent and fixing screws. Autogenous bone graft harvested with an auto-chip-maker adjacent to the surgical site were mixed with a xenograft and putted under the barrier. The wound was closed using a vestibular mucoperiosteal flap. At 4 months, the rigid barrier was removed, and a 7mm crestal width transversal bone was observed. At the same time, a fixture (4*10mm) was placed. A definitive ceramometal crown was completed after full osseointegration with periodical clinical maintenance. The exposure of the titanium mesh occurred in this case and was visible with a circular flap dehiscence at 1-month follow-up visit. This exposure did not affect the successful regenerative outcomes. After removal of the titanium mesh from the grafted defects, the space beneath the membrane enclosure was seen to be almost completely filled with new hard tissue covered by a thin layer of soft tissue. The postoperative follow-ups revealed that the implant was stable with excellent osseointegration and the buccal depression of the surgical area was reconstructed. CONCLUSION: The use of rigid titanium occlusive screwed barrier with autogenous and bovine bone graft might be a reliable technique for alveolar ridge reconstruction. This approach achieve excellent final esthetic outcome of the implant-supported restoration. PMID- 28363848 TI - Perioperative use of gabapentinoids in France. Mismatch between clinical practice and scientific evidence. AB - BACKGROUND: Gabapentinoids have governmental health agency approval for "chronic neuropathic pain." Over the last decade, however, the perioperative prescription of gabapentinoids has become more popular among anaesthesiologists due to their anxiolytic and antihyperalgesic proprieties, despite weak scientific evidence supporting the risk/benefit ratio for this indication. METHODS: Our aim was to extensively describe the use of perioperative gabapentinoids by French anaesthesiologists. An online questionnaire was sent to the French Society of Anaesthesiology members. The questionnaire, focusing on gabapentinoid prescriptions, included questions on demographic data, patient conditions and types of surgeries, mode of prescription, motives and presumed side effects (dizziness, confusion, desaturation and visual disorders). RESULTS: Five hundred and eight questionnaires were analysed, among which 70% reported gabapentinoid use. Twenty-five percent of prescribers stated using gabapentinoids in all types of surgeries, 30% in outpatient surgeries and 46% in combination with regional anaesthesia. In 66% of the cases, preoperative and postoperative prescriptions were combined. Sedation, dizziness and visual disturbance were expected side effects according to 68%, 45% and 20% of anaesthesiologists, respectively. Reported reasons in favor of gabapentinoid prescription were prevention of chronic pain (93%), expected high postoperative acute pain, i.e. painful surgeries (91%), a history of chronic pain (72%) and patient opioid dependence (72%). DISCUSSION: French anaesthesiologists have recently included gabapentinoids in the multimodal management of postoperative pain but they are unaware of certain frequent side effects. Moreover, their expectations about the prevention of chronic pain are not validated. Our survey is a call to moderate the systematic prescription of these drugs in the perioperative period. PMID- 28363849 TI - Unravelling the genetics of inherited retinal dystrophies: Past, present and future. AB - The identification of the genes underlying monogenic diseases has been of interest to clinicians and scientists for many years. Using inherited retinal dystrophies as an example of monogenic disease we describe the history of molecular genetic techniques that have been pivotal in the discovery of disease causing genes. The methods that were developed in the 1970's and 80's are still in use today but have been refined and improved. These techniques enabled the concept of the Human Genome Project to be envisaged and ultimately realised. When the successful conclusion of the project was announced in 2003 many new tools and, as importantly, many collaborations had been developed that facilitated a rapid identification of disease genes. In the post-human genome project era advances in computing power and the clever use of the properties of DNA replication has allowed the development of next-generation sequencing technologies. These methods have revolutionised the identification of disease genes because for the first time there is no need to define the position of the gene in the genome. The use of next generation sequencing in a diagnostic setting has allowed many more patients with an inherited retinal dystrophy to obtain a molecular diagnosis for their disease. The identification of novel genes that have a role in the development or maintenance of retinal function is opening up avenues of research which will lead to the development of new pharmacological and gene therapy approaches. Neither of which can be used unless the defective gene and protein is known. The continued development of sequencing technologies also holds great promise for the advent of truly personalised medicine. PMID- 28363846 TI - Enteric glia regulate gut motility in health and disease. AB - The enteric nervous system, often referred to as the second brain, is the largest assembly of neurons and glia outside the central nervous system. The enteric nervous system resides within the wall of the digestive tract and regulates local gut reflexes involved in gastrointestinal motility and fluid transport; these functions can be accomplished in the absence of the extrinsic innervation from the central nervous system. It is neurons and their circuitry within the enteric nervous system that govern the gut reflexes. However, it is becoming clear that enteric glial cells are also actively involved in this process through the bidirectional signaling with neurons and other cells in the gut wall. We synthesize the recently discovered modulatory roles of enteric gliotransmission in gut motility and provide our perspective for future lines of research. PMID- 28363850 TI - Di-n-butyl phthalate exposure negatively influences structural and functional neuroplasticity via Rho-GTPase signaling pathways. AB - Di-n-butyl phthalate (DBP) has been reported to cause disruptions in hippocampal plasticity, but its specific mechanism has not yet been ascertained. In this research, a mouse model of chronic DBP exposure was generated by intragastric administration of DBP (10, 50, or 250 degrees mg/kg/d) for 5 weeks. Chronic exposure to high concentrations of DBP (250 degrees mg/kg/d) induced a spatial learning deficit in the Morris water maze in male mice. By determining the activity of Rho-GTPase signaling pathways in the hippocampal tissues, we found that DBP exposure inhibited the activity of Rac1/PAK1/LIMK1 but activated RhoA/ROCK/LIMK2 signaling and eventually suppressed cofilin activity by phosphorylation. Consistent with this, the differential activation was also observed in the acute exposure model of neuronal cells generated by incubation with DBP (100 degrees ng/ml, 1, 10, or 100 degrees MUg/ml) for 72 hours. Moreover, acute exposure to high concentrations of DBP (100 degrees MUg/ml) altered cell morphology by inhibiting neurite outgrowth. A ROCK inhibitor, but not inhibitors of Rac1 or PAK1, reversed the inhibition of DBP to the activity of cofilin and neurite outgrowth in cells. These findings provide the first evidence that DBP exposure results in impairment of neuroplasticity by differential regulation of Rho-GTPase signaling pathways. PMID- 28363851 TI - An overview of anticancer activity of Garcinia and Hypericum. AB - Cancer is one of the leading causes of death worldwide (approximately 8.2 million cases/year) and, over the next two decades, a 70% increase in new cancer cases is expected. Through analysis of the available drugs between the years of 1930 and 2014, it was found that 48% were either natural products or their derivatives. This proportion increased to 66% when semi-synthetic products were included. The family Clusiaceae Juss. (Malpighiales) includes approximately 1000 species distributed throughout all tropical and temperate regions. The phytochemical profile of this family includes many chemicals with interesting pharmacological activities, including anticancer activities. This study includes an overview of the in vitro and in vivo anticancer activity of secondary metabolites from Garcinia and Hypericum and the mechanisms involved in this activity. Hypericum no longer belong to Clusiaceae family, but was considered in the past by taxonomists, due to similarities with this family. Research in the area has shown that several compounds belonging to different chemical classes exhibit activity in several tumor cell lines in different experimental models. This review shows the significant antineoplasic activity of these compounds, in particular of these two genera and validates the importance of natural products in the search for anticancer drugs. PMID- 28363852 TI - Understanding the role of 3-O-Acetyl-11-keto-beta-boswellic acid in conditions of oxidative-stress mediated hepatic dysfunction during benzo(a)pyrene induced toxicity. AB - The present study was planned to see whether 3-O-Acetyl-11- keto-beta-boswellic acid has any protective effects against benzo(a)pyrene (BaP) induced toxicity or not. In vitro studies show concentration dependent linear association of radical scavenging activity of AK which is comparable to ascorbic acid taken as reference compound. For in vivo studies, the animals were divided randomly into five groups which included a) normal control, b) vehicle treated (olive oil), c) BaP treated, d) AK treated and e) AK + BaP (combined treated). BaP was administered at a dose of 50mg/kg in olive oil twice a week orally for 4 weeks and AK (50mg/kg) was given in olive oil thrice a week for 4 weeks before and after BaP exposure. BaP treated animals showed a significant increase (p < 0.001) in lipid peroxidation (LPO) and protein carbonyl contents (PCC) in hepatic tissue. Further, a significant increase (p < 0.001) in the liver marker enzymes as well as citrulline and nitric oxide levels in the hepatic tissue was also observed. Interestingly, AK when supplemented to BaP treated animals ameliorated the above said biochemical indices appreciately. The histopathological observations also showed appreciable improvement when BaP treated animals were supplemented with AK, thus emphasing the protective potential of AK. PMID- 28363853 TI - Cytotoxic triterpenoids isolated from sweet chestnut heartwood (Castanea sativa) and their health benefits implication. AB - For centuries wood containers have been used in aging of wines and spirits, due to the pleasant flavors they give to the beverages. Together with oak, sweet chestnut wood (Castanea sativa) have been often used for such purpose. The maturation process involves the transfer of secondary metabolites, mainly phenolics, from the wood to the liquid. At the same time, other metabolites, such as triterpenoids and their glycosides, can also be released. Searching for the extractable triterpenoids from sweet chestnut heartwood (C. sativa), two new ursane-type triterpenoid saponins named chestnoside A (1) and chestnoside B (2), together with two known oleanen-type analogs (3 and 4) were isolated and characterized. The cytotoxicity of isolated compounds was tested against two cancer cell lines (PC3 and MCF-7), and normal lymphocytes. Breast cancer cells (MCF-7) were more affected by tested compounds than prostate cancer cells (PC3). Chestnoside B (2) exhibited the strongest cytotoxicity with an IC50 of 12.3 MUM against MCF-7 cells, lower than those of positive controls, while it was moderately active against normal lymphocytes (IC50 = 67.2 MUM). These results highlight the occurrence of triterpenoid saponins in sweet chestnut heartwood and their potential for the chemoprevention of breast cancer. PMID- 28363854 TI - Effects of individual and combined toxicity of bisphenol A, dibutyl phthalate and cadmium on oxidative stress and genotoxicity in HepG 2 cells. AB - Bisphenol A, dibutyl phthalate and cadmium can be found in environment simultaneously. Several studies suggested that they had genotoxic effect. In this study, mono-exposure and co-exposure treatments, designed by 3 * 3 full factorial, were established to determine the individual toxicity and binary mixtures' combined effects on the oxidative stress and genotoxicity in HepG 2 cells. The highest oxidative damage was observed in the Cd treatments groups. Compared with control groups, the maximum level of reactive oxygen species and malondialdehyde were ~1.4 fold and ~2.22 fold respectively. And a minimum level of superoxide dismutase activity was found with the decrease of 43%. The mechanism that excessive oxidative stress led to the DNA damage was inferred. However, cells treated with BPA showed the worst DNA damage rather than Cd, which may because Cd mainly damages DNA repairing mechanism. For the joint effect, different interactions can be found in different biological endpoints for different combinations since different mechanisms have been clarified in mixture toxicity studies. It is sure that the co-exposure groups enhanced cytotoxicity, oxidative stress and genotoxicity compared to the mono-exposures. Synergistic and additive interactions were considered, which means greater threat to organisms when exposed to multiple estrogenic endocrine disruptors. PMID- 28363855 TI - Planetary ball milling and supercritical fluid technology as a way to enhance dissolution of bicalutamide. AB - Dissolution of bicalutamide processed with polyvinylpyrrolidone by either supercritical carbon dioxide or ball milling has been investigated. Various compositions as well as process parameters were used to obtain binary systems of the drug with the carrier. Thermal analysis and powder X-ray diffractometry confirmed amorphization of bicalutamide mechanically activated by ball milling and the decrease in crystallinity of the supercritical carbon dioxide-treated drug. Both methods led to reduction of particles size what was confirmed by scanning electron microscopy and laser diffraction measurements. Moreover, the effect of micronisation was found to depend on the parameters of applied process. Fourier transform infrared spectroscopy revealed the appearance of intermolecular interactions between drug and carrier molecules that play an important role in the stabilization of amorphous form of the active compound. Changes in crystal structure combined with reduced size of particles of bicalutamide dispersed within polymer matrix were found to improve dissolution of bicalutamide by 4 to 10-fold in comparison to untreated drug. It is of particular importance as poor dissolution profiles are considered to be the major limitation in bioavailability of the drug. PMID- 28363856 TI - Bitterness prediction in-silico: A step towards better drugs. AB - Bitter taste is innately aversive and thought to protect against consuming poisons. Bitter taste receptors (Tas2Rs) are G-protein coupled receptors, expressed both orally and extra-orally and proposed as novel targets for several indications, including asthma. Many clinical drugs elicit bitter taste, suggesting the possibility of drugs re-purposing. On the other hand, the bitter taste of medicine presents a major compliance problem for pediatric drugs. Thus, efficient tools for predicting, measuring and masking bitterness of active pharmaceutical ingredients (APIs) are required by the pharmaceutical industry. Here we highlight the BitterDB database of bitter compounds and survey the main computational approaches to prediction of bitter taste based on compound's chemical structure. Current in silico bitterness prediction methods provide encouraging results, can be constantly improved using growing experimental data, and present a reliable and efficient addition to the APIs development toolbox. PMID- 28363857 TI - Oil-in-water microemulsions stabilized by 3-(N,N- dimethylalkylammonio)propanesulfonate surfactants of varying alkyl chain length: Solubilisation of testos-terone propionate. AB - Solubilisation of the poorly-water soluble drug, testosterone propionate, in co surfactant-free, dilutable, oil-in-water microemulsions stabilized by zwitterionic surfactants of varying alkyl chain length, namely 3-(N,N dimethyloctylammonio)propanesulfonate and 3-(N,N dimethyldodecylammonio)propanesulfonate and containing one of four ethyl ester oils, has been investigated. Both 3-(N,N-dimethyloctylammonio)propanesulfonate and 3-(N,N-dimethyldodecylammonio)propanesulfonate-stabilized microemulsions containing two short chain length oils, ethyl butyrate and ethyl caprylate, while only 3-(N,N-dimethyldodecylammonio)propanesulfonate formed microemulsions incorporating the longer chain length oils, ethyl palmitate and ethyl oleate, albeit to a very much reduced extent. Significantly the microemulsions containing the short chain length oils, ethyl butyrate and ethyl caprylate solubilised more testosterone propionate than the corresponding micelles. However, an inverse correlation existed between testosterone propionate solubility in the bulk oil and solubilisation in the microemulsions, in that ethyl caprylate containing microemulsions solubilised more testosterone propionate than those containing an equivalent amount of ethyl butyrate, despite the drug being more soluble in ethyl butyrate. These results suggest that drug solubility in bulk oil is a poor indicator of drug solubility in microemulsions containing that oil, and whether or not the addition of oil improves drug solubility is dependent upon on how it is incorporated within the microemulsion. The longer the chain length of the oil, the more likely the oil is to form a core in the microemulsion droplet, resulting in an additional locus of drug solubilisation and the possibility of an enhanced solubilisation capacity. PMID- 28363858 TI - Influence of controlled ice nucleation on the freeze-drying of pharmaceutical products: the secondary drying step. AB - Vacuum Induced Nucleation is often discussed in the context of primary drying performances and its tunability, with the potential to tailor the nucleation temperature to the desired porous structure. Instead, here we investigate its influence on secondary drying dynamics and, in particular, on rate of desorption and vial-to-vial inhomogeneity. So as to track the evolution of residual moisture during secondary drying, vials were regularly collected through a vacuum-tight sampling device; the residual moisture and the morphology of the porous cake was then determined by Karl Fischer titration and Scanning Electron Microscopy, respectively. The control of freezing promotes the formation of larger ice crystals and, as a result, accelerates the sublimation of ice and slows down the desorption process. Overall, we found that it reduces the total (primary and secondary) drying time and produces much more uniform batches than those obtained by the conventional freezing, and this positive effect was observed since the end of primary drying. In conclusion, the control of freezing was beneficial to the total drying time reduction, vial-to-vial homogeneity and allowed a better control of product inhomogeneity. PMID- 28363859 TI - Assessment of decision-making capacity for research participation: When, how and why to do it. PMID- 28363860 TI - Person centered-care and recovery: Could it be used for obtaining a humanized health care? PMID- 28363862 TI - Limited mobility of target pests crucially lowers controllability when sterile insect releases are spatiotemporally biased. AB - The sterile insect technique (SIT) is a genetic pest control method wherein mass reared sterile insects are periodically released into the wild, thereby impeding the successful reproduction of fertile pests. In Okinawa Prefecture, Japan, the SIT has been implemented to eradicate the West Indian sweet potato weevil Euscepes postfasciatus (Fairmaire), which is a flightless agricultural pest of sweet potatoes. It is known that E. postfasciatus is much less mobile than other insects to which the SIT has been applied. However, previous theoretical studies have rarely examined effects of low mobility of target pests and variation in the spatiotemporal evenness of sterile insect releases. To theoretically examine the effects of spatiotemporal evenness on the regional eradication of less mobile pests, we constructed a simple two-patch population model comprised of a pest and sterile insect moving between two habitats, and numerically simulated different release strategies (varying the number of released sterile insects and release intervals). We found that spatially biased releases allowed the pest to spatially escape from the sterile insect, and thus intensively lowered its controllability. However, we showed that the temporally counterbalancing spatially biased releases by swapping the number of released insects in the two habitats at every release (called temporal balancing) could greatly mitigate this negative effect and promote the controllability. We also showed that the negative effect of spatiotemporally biased releases was a result of the limited mobility of the target insect. Although directed dispersal of the insects in response to habitats of differing quality could lower the controllability in the more productive habitat, the temporal balancing could promote and eventually maximize the controllability as released insects increased. PMID- 28363861 TI - Prevalence and Predictors of Chronic Postsurgical Pain in Children: A Systematic Review and Meta-Analysis. AB - : Emerging research suggests that pain may persist longer-term for many children after major surgery, with significant effects on their health outcomes. This systematic review identified the prevalence of chronic postsurgical pain (CPSP) in children after surgery, and determined presurgical biomedical and psychosocial risk factors associated with CPSP prevalence or severity. Prospective studies assessing CPSP 3 to 12 months after surgery in children 6 to 18 years of age published in English in MedLine, EMBASE, PsycINFO, and Cochrane Database of Systematic Reviews since 1996 were eligible for inclusion. Of 16,084 abstracts yielded by the search, 123 full articles were assessed for eligibility, and 12 studies were included in the review. Overall quality of included studies assessed using the Quality in Prognostic Studies tool was low. On the basis of 4 studies with a total of 628 participants across all surgery types, median prevalence of CPSP across studies was 20% (25th percentile = 14.5%, 75th percentile = 38%) at 12 months after surgery. Presurgical pain intensity, child anxiety, child pain coping efficacy, and parental pain catastrophizing were the only presurgical factors identified as predictive of CPSP. Biological and medical factors assessed were not associated with CPSP in any study. Well designed studies examining prevalence and predictors of CPSP are critically needed in children. PERSPECTIVE: In this systematic review, the median prevalence of CPSP in children was 20% across studies. Presurgical pain intensity, and child and parent psychosocial factors predicted CPSP. Additional resources and interventions are needed for youth who report persistent pain after surgery. PMID- 28363863 TI - Evolution of stinginess and generosity in finite populations. AB - In iterated continuous games, the cooperative investment in a given round is determined by the initial investment and the reciprocation rate, which describe the investment in the first round and the dependence of current investment on the partner's last move, respectively. These two traits usually intertwine during evolution. However, their coevolution is not fully explored. In this paper, we thereby study their coevolution in the iterated continuous public goods games. We find that the reciprocation rate plays a dominant role during the coevolution in both finite and infinite populations. If it exceeds a threshold, a stingy population where individuals invest no more than their partner's last investment evolves to full cooperation, and a generous population where individuals invest more than their partner's last investment decreases to a moderate cooperative state, investing a portion in the first round and then escalating investment in the following rounds. Otherwise, the stingy population evolves to full defection, and the generous one rises to another moderate cooperative state. PMID- 28363865 TI - High affinity binding of amyloid beta-peptide to calmodulin: Structural and functional implications. AB - Amyloid beta-peptides (Abeta) are a major hallmark of Alzheimer's disease (AD) and their neurotoxicity develop with cytosolic calcium dysregulation. On the other hand, calmodulin (CaM), a protein which plays a major multifunctional role in neuronal calcium signaling, has been shown to be involved in the regulation of non-amyloidogenic processing of amyloid beta precursor protein (APP). Using fluorescent 6-bromoacetyl-2-dimethylaminonaphthalene derivatives of CaM, Badan CaM, and human amyloid beta(1-42) HiLyteTM-Fluor555, we show in this work that Abeta binds with high affinity to CaM through the neurotoxic Abeta25-35 domain. In addition, the affinity of Abeta for calcium-saturated CaM conformation is approximately 20-fold higher than for CaM conformation in the absence of calcium (apo-CaM). Moreover, the value of Kd of 0.98 +/- 0.11 nM obtained for Abeta1-42 dissociation from CaM saturated by calcium points out that CaM is one of the cellular targets with highest affinity for neurotoxic Abeta peptides. A major functional consequence of Abeta-CaM interaction is that it slowdowns Abeta fibrillation. The novel and high affinity interaction between calmodulin and Abeta shown in this work opens a yet-unexplored gateway to further understand the neurotoxic effect of Abeta in different neural cells and also to address the potential of calmodulin and calmodulin-derived peptides as therapeutic agents in AD. PMID- 28363864 TI - Alveolar septal patterning during compensatory lung growth: Part II the effect of parenchymal pressure gradients. AB - In most mammals, compensatory lung growth occurs after the removal of one lung (pneumonectomy). Although the mechanism of alveolar growth is unknown, the patterning of complex alveolar geometry over organ-sized length scales is a central question in regenerative lung biology. Because shear forces appear capable of signaling the differentiation of important cells involved in neoalveolarization (fibroblasts and myofibroblasts), interstitial fluid mechanics provide a potential mechanism for the patterning of alveolar growth. The movement of interstitial fluid is created by two basic mechanisms: 1) the non-uniform motion of the boundary walls, and 2) parenchymal pressure gradients external to the interstitial fluid. In a previous study (Haber et al., Journal of Theoretical Biology 400: 118-128, 2016), we investigated the effects of non-uniform stretching of the primary septum (associated with its heterogeneous mechanical properties) during breathing on generating non-uniform Stokes flow in the interstitial space. In the present study, we analyzed the effect of parenchymal pressure gradients on interstitial flow. Dependent upon lung microarchitecture and physiologic conditions, parenchymal pressure gradients had a significant effect on the shear stress distribution in the interstitial space of primary septa. A dimensionless parameter delta described the ratio between the effects of a pressure gradient and the influence of non-uniform primary septal wall motion. Assuming that secondary septa are formed where shear stresses were the largest, it is shown that the geometry of the newly generated secondary septa was governed by the value of delta. For delta smaller than 0.26, the alveolus size was halved while for higher values its original size was unaltered. We conclude that the movement of interstitial fluid, governed by parenchymal pressure gradients and non-uniform primary septa wall motion, provides a plausible mechanism for the patterning of alveolar growth. PMID- 28363866 TI - Interferon induces interleukin 8 and bone marrow stromal cell antigen 2 expression, inhibiting the production of hepatitis B virus surface antigen from human hepatocytes. AB - Hepatitis B virus (HBV) surface antigen (HBsAg) loss is one of the treatment goals of chronic HBV infection. Bone marrow stromal cell antigen 2 (BST2) is one of the interferon (IFN)-stimulated genes (ISGs) and inhibits the release of various enveloped viruses. Here we examined the effects of antiviral treatment on HBsAg levels and its intracellular mechanism in HBsAg-producing hepatocytes. In PLC/PRF/5 and Huh1, IFNalpha-2a treatment decreased HBsAg levels in their conditioned media. Upregulation of interleukin 8 (IL8), toll-like receptor 2 (TLR2) and interferon gamma-induced protein 10 (IP10) mRNAs was associated with the reduction of HBsAg in both PLC/PRF/5 and Huh1. The HBsAg level was upregulated by knockdown of IL8, TLR2 or IP10. Exogenous addition of IL8 enhanced BST2 promoter activity and BST2 mRNA expression. Additionally, knockdown of IL8 could lead to the downregulation of BST2 mRNA. Transfection of poly(I-C) enhanced IL8 and BST2 mRNA expression and inhibited HBsAg secretion from PLC/PRF/5 cells. In conclusion, IL8 might play an important role in the enhancement of BST2 and be involved in HBsAg eradication. PMID- 28363867 TI - Developmentally regulated GTP-binding protein 2 depletion leads to mitochondrial dysfunction through downregulation of dynamin-related protein 1. AB - Mitochondrial dynamics, including constant fusion and fission, play critical roles in maintaining mitochondrial morphology and function. Here, we report that developmentally regulated GTP-binding protein 2 (DRG2) regulates mitochondrial morphology by modulating the expression of the mitochondrial fission gene dynamin related protein 1 (Drp1). shRNA-mediated silencing of DRG2 induced mitochondrial swelling, whereas expression of an shRNA-resistant version of DRG2 decreased mitochondrial swelling in DRG2-depleted cells. Analysis of the expression levels of genes involved in mitochondrial fusion and fission revealed that DRG2 depletion significantly decreased the level of Drp1. Overexpression of Drp1 rescued the defect in mitochondrial morphology induced by DRG2 depletion. DRG2 depletion reduced the mitochondrial membrane potential, oxygen consumption rate (OCR), and amount of mitochondrial DNA (mtDNA), whereas it increased reactive oxygen species (ROS) production and apoptosis. Taken together, our data demonstrate that DRG2 acts as a regulator of mitochondrial fission by controlling the expression of Drp1. PMID- 28363868 TI - Neoagarooligosaccharides prevent septic shock by modulating A20-and cyclooxygenase-2-mediated interleukin-10 secretion in a septic-shock mouse model. AB - Analysis of the signaling mechanism triggered by endotoxin-mediated toll-like receptor-4 activation using immune cell systems or rodent models may help identify potential agents for the prevention of Gram-negative bacteria infection. beta-agarase cleaves the beta-1,4-linkages of agar to produce neoagarooligosaccharides (NAOs), which have various physiological functions. The aim of this study was to investigate the efficacy of NAOs in preventing experimental sepsis caused by the administration of endotoxin or Gram-negative bacteria. Organ damage and neutrophil infiltration in an endotoxemia and septic shock mouse model were suppressed by NAOs. Pro-inflammatory cytokine level was decreased, but IL-10 level was increased by NAO-treatment. Further induction by NAOs in the presence of endotoxin was associated with a significant induction of A20 and cyclooxygenase (COX)-2 expressions. Our data suggest that NAOs have a beneficial preventive effect in septic shock correlated with the enhancement of IL-10 via the induction of A20 and COX-2. PMID- 28363870 TI - Transformation of crustacean pathogenic bacterium Spiroplasma eriocheiris and expression of yellow fluorescent protein. AB - Spiroplasma eriocheiris, the cause of crab trembling disease, is a wall-less bacterium, related to Mycoplasmas, measuring 2.0-10.0 MUm long. It features a helical cell shape and a unique swimming mechanism that does not use flagella; instead, it moves by switching the cell helicity at a kink traveling from the front to the tail. S. eriocheiris seems to use a novel chemotactic system that is based on the frequency of reversal swimming behaviors rather than the conventional two-component system, which is generally essential for bacterial chemotaxis. To identify the genes involved in these novel mechanisms, we developed a transformation system by using oriC plasmid harboring the tetracycline resistant gene, tetM, which is under the control of a strong promoter for an abundant protein, elongation factor-Tu. The transformation efficiency achieved was 1.6 * 10-5 colony forming unit (CFU) for 1 MUg DNA, enabling the expression of the enhanced yellow fluorescent protein (EYFP). PMID- 28363869 TI - A simple comparison of the extrinsic noise in gene expression between native and foreign regulations in Escherichia coli. AB - Living cells reorganize their gene expression through regulatory machineries in response to external perturbations. The contribution of the regulation to the noise in gene expression is of great interest. In this study, we evaluate the contribution of both native and foreign regulations to the extrinsic noise in gene expression. We analyzed the gene expression data of a mini-library containing 70 genetic constructs of 136 clones into which the gfp gene had been chromosomally incorporated under the control of either native or foreign regulation. We found that the substitution of native by foreign regulation, i.e., the insertion of the Ptet promoter, triggered a decrease in the extrinsic noise, which was independent of the protein abundance. The reanalyses of varied genomic data sets verified that the noisy gene expression mediated by native regulations is a common feature, regardless of the diversity in the genetic approaches used. Disturbing native regulations by a synthetic promoter reduced the extrinsic noise in gene expression in Escherichia coli. It indicated that the extrinsic noise in gene expression caused by the native regulation could be further repressed. These results suggest a tendency of released regulation leading to reduced noise and a linkage between noise and plasticity in the regulation of gene expression. PMID- 28363871 TI - Impact of antibody subclass and disulfide isoform differences on the biological activity of CD200R and betaklotho agonist antibodies. AB - Agonism of cell surface receptors by monoclonal antibodies is dependent not only on its ability to bind the target, but also to deliver a biological signal through receptors to the cell. Immunoglobulin G2 antibodies (IgG2s) are made up of a mixture of distinct isoforms (IgG2-A, -B and A/B), which differ by the disulfide connectivity at the hinge region. When evaluating panels of agonistic antibodies against CD200 receptor (CD200R) or betaklotho receptor (betaklotho), we noticed striking activity differences of IgG1 or IgG2 antibodies with the same variable domains. For the CD200R antibody, the IgG2 antibody demonstrated higher activity than the IgG1 or IgG4 antibody. More significantly, for betaklotho, agonist antibodies with higher biological activity as either IgG2 or IgG1 were identified. In both cases, ion exchange chromatography was able to isolate the bioactivity to the IgG2-B isoform from the IgG2 parental mixture. The subclass related increase in agonist activity was not correlated with antibody aggregation or binding affinity, but was driven by enhanced avidity for the CD200R antibody. These results add to the growing body of evidence that show that conformational differences in the antibody hinge region can have a dramatic impact on the antibody activity and must be considered when screening and engineering therapeutic antibody candidates. The results also demonstrate that the IgG1 (IgG2 A like) or the IgG2-B form may provide the most active form of agonist antibodies for different antibodies and targets. PMID- 28363872 TI - Novel therapeutic strategies to target leukemic cells that hijack compartmentalized continuous hematopoietic stem cell niches. AB - Acute myeloid leukemia and acute lymphoblastic leukemia cells hijack hematopoietic stem cell (HSC) niches in the bone marrow and become leukemic stem cells (LSCs) at the expense of normal HSCs. LSCs are quiescent and resistant to chemotherapy and can cause relapse of the disease. HSCs in niches are needed to generate blood cell precursors that are committed to unilineage differentiation and eventually production of mature blood cells, including red blood cells, megakaryocytes, myeloid cells and lymphocytes. Thus far, three types of HSC niches are recognized: endosteal, reticular and perivascular niches. However, we argue here that there is only one type of HSC niche, which consists of a periarteriolar compartment and a perisinusoidal compartment. In the periarteriolar compartment, hypoxia and low levels of reactive oxygen species preserve the HSC pool. In the perisinusoidal compartment, hypoxia in combination with higher levels of reactive oxygen species enables proliferation of progenitor cells and their mobilization into the circulation. Because HSC niches offer protection to LSCs against chemotherapy, we review novel therapeutic strategies to inhibit homing of LSCs in niches for the prevention of dedifferentiation of leukemic cells into LSCs and to stimulate migration of leukemic cells out of niches. These strategies enhance differentiation and proliferation and thus sensitize leukemic cells to chemotherapy. Finally, we list clinical trials of therapies that tackle LSCs in HSC niches to circumvent their protection against chemotherapy. PMID- 28363873 TI - Production of recombinant human acid alpha-glucosidase with high-mannose glycans in gnt1 rice for the treatment of Pompe disease. AB - Lysosomal storage diseases are a group of inherited metabolic disorders. Patients are treated with enzyme replacement therapy (ERT), in which the replacement enzymes are required to carry terminal mannose or mannose 6-phosphate residues to allow efficient uptake into target cells and tissues. N acetylglucosaminyltransferase-I (GnTI) mediates N-glycosylation in the cis cisternae of the Golgi apparatus by adding N-acetylglucosamine to the exposed terminal mannose residue of core N-glycan structures for further processing. Mutant rice lacking GnTI produces only high mannosylated glycoproteins. In this study, we introduced a gene encoding recombinant human acid alpha-glucosidase (rhGAA), which is used in ERT for Pompe disease, into gnt1 rice callus by particle bombardment. Integration of the target gene into the genome of the gnt1 rice line and its mRNA expression were confirmed by PCR and Northern blot, respectively. Western blot analysis was performed to confirm secretion of the target proteins into the culture media. Using an indirect enzyme linked immunosorbent assay, we determined the maximum expression of rhGAA to be approximately 45mg/L, 13days after induction. To assay the enzymatic activity and determine the N-glycan profile of rhGAA, we purified the protein using a 6*histidine tag. The in vitro alpha-glucosidase activity of rhGAA from gnt1 rice callus (gnt1-GAA) was 3.092U/mg, similar to the activity of the Chinese hamster ovary cell-derived GAA (3.154U/mg). N-glycan analysis revealed the presence of high-mannose N-glycans on gnt1-GAA. In addition, the production of high-mannose GAA using gnt1 rice calli as an expression host was characterized, which may aid the future development of therapeutic enzymes for the treatment of Pompe disease. PMID- 28363874 TI - Label-free protein quantification of sodium butyrate treated CHO cells by ESI-UHR TOF-MS. AB - Effects of butyrate on CHO producer cells are contradictory, promoting productivity and at the same time repressing proliferation. Though in previous omics studies the background of butyrate impact on producer cells has been investigated, the knowledge about the mechanism is still very limited. As previous proteomic results on this field are mainly based on 2DE-gels, we conducted a label-free MS quantification, based on fast high resolution ESI-MS and a straight forward software solution, to gain insight in shifted cellular processes of CHO cells 25h after butyrate treatment. 118 proteins or subunits with significantly altered abundances were identified suggesting changes in carbohydrate, protein metabolic and cell cycle processes. Effects of butyrate on the nucleosome assembly as a known direct epigenetic influence on HDAC activity turned out to be unexpectedly fast and persistent, as confirmed by Western blots of histone-H4 acetylation. Contradictory to increased cell specific productivity, most elements of protein metabolism exhibited decreased levels after butyrate treatment. In comparison to published results some overlap of our label free MS data could be observed but also apparently diverging findings, showing the need for complementary omics techniques for a holistic view on cellular processes such as response to butyrate. PMID- 28363875 TI - Improvement of a continuous ethanol fermentation from sweet sorghum stem juice using a cell recycling system. AB - The process variables (aeration rate and recycle ratio) of a continuous ethanol fermentation with a cell recycling system (CRS) by Saccharomyces cerevisiae NP 01 from sweet sorghum stem juice were optimized using response surface methodology (RSM). The relationship between intracellular composition and fermentation efficiency was also investigated. RSM results revealed that the optimum aeration rate and recycle ratio were 0.25vvm and 0.625, respectively. The validation experiment under the optimum conditions indicated high precision and reliability of the experiment, achieving an actual ethanol concentration (PE) of 99.28g/l, which was very close to the predicted value (98.01g/l), and a very high ethanol productivity (QP) of 7.94g/lh. The intracellular composition of the yeast cells (i.e., unsaturated fatty acids (UFAs), total fatty acids (TFAs), ergosterol and trehalose) was positively related to the fermentation efficiency and yeast adaptive response under ethanol stress. A higher ratio of UFAs/TFAs and ergosterol strongly promoted yeast viability and ethanol fermentation. Additionally, high trehalose content was observed when the yeast was subjected to stress conditions. PMID- 28363876 TI - Neuronal polarization: From spatiotemporal signaling to cytoskeletal dynamics. AB - Neuronal polarization establishes distinct molecular structures to generate a single axon and multiple dendrites. Studies over the past years indicate that this efficient separation is brought about by a network of feedback loops. Axonal growth seems to play a major role in fueling those feedback loops and thereby stabilizing neuronal polarity. Indeed, various effectors involved in feedback loops are pivotal for axonal growth by ultimately acting on the actin and microtubule cytoskeleton. These effectors have key roles in interconnecting actin and microtubule dynamics - a mechanism crucial to commanding the growth of axons. We propose a model connecting signaling with cytoskeletal dynamics and neurite growth to better describe the underlying processes involved in neuronal polarization. We will discuss the current views on feedback loops and highlight the current limits of our understanding. PMID- 28363878 TI - Interest of the "compress test" in diagnosis of nerve injury in hand wounds. AB - INTRODUCTION: Hand wounds are a common cause of emergency department admission. Digital nerve lesions are found in 5% of palm wounds. Early diagnosis reduces the risk of morbidity, sequelae and litigation. Screening for digital nerve injury by the usual tests is difficult in an emergency context. We assessed the diagnostic value of the simple "compress test" to screen for pulp sensibility disorder and the factors that may influence the value of this examination, with a view to validating routine use. MATERIAL AND METHOD: A retrospective study included 821 palm wounds treated between January 2014 and May 2016. There were 605 male and 216 patients; mean age, 42.8 years (range: 18-90 years). The dominant hand was involved in 307 cases (37.4%). Sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios of the compress test were calculated. Diagnostic value was also calculated according to age, gender, affected digit, dominant side and examiner's experience. RESULTS: Clinical deficit was found in 412 cases (50.2%). A digital nerve lesion was found intraoperatively in 277 cases (33.6%). Test sensitivity was 87.3%, specificity 68.6%, positive predictive value 58.5%, negative predictive value 91.4%, positive likelihood ratio 2.78 and negative likelihood ratio 0.18. The test was more effective for thumb wounds and for examination by a junior surgeon. There were no differences according to injured side, innervation territory or gender. CONCLUSION: This clinical test is reliable, with very good negative predictive value and good sensitivity, allowing its use in routine clinical practice. Nevertheless, surgical exploration of deep palm injuries should remain the rule. PMID- 28363877 TI - Subacromial temperature profile during bipolar radiofrequency use in shoulder arthroscopy. Comparison of Coblation(r) vs. VAPR(r). AB - BACKGROUND: The use of bipolar electrodes for arthroscopic procedures carries a theoretical ex vivo risk of inducing burn injuries. Few studies have measured the in vivo temperatures produced by bipolar electrodes during arthroscopy, and their results are conflicting. The objective of this study was to evaluate the temperature profile within the subacromial space during shoulder arthroscopy with two different electrode systems. HYPOTHESIS: The primary hypothesis was that the two electrode systems produced similar temperature variations and peak temperatures. The secondary hypothesis was that neither electrode system produced irrigation-fluid temperatures above the tissue-damage threshold. MATERIAL AND METHODS: A comparative, prospective, single-centre, single-surgeon, single-blind study was conducted to compare the Coblation(r) system (Smith&Nephew, Andover, MA, USA) and the VAPR(r) system (DePuy Synthes Mitek Sports Medicine, Raynham, MA, USA) in 13 patients undergoing shoulder arthroscopy. A temperature probe inserted into the subacromial space was used to record temperatures at 10-second intervals for 60seconds during continuous radiofrequency application. RESULTS: Mean baseline temperature was 21.4+/-0.7 degrees C with VAPR(r) and 23.0+/-2.2 degrees C with Coblation(r). No significant between-group differences were found during the first 40seconds. The mean peak temperature reached after 60seconds was 25.0+/-1.9 degrees C with VAPR(r) and 27.9+/-2.8 degrees C with Coblation(r) (P<0.05). DISCUSSION: Few studies have compared the in vivo temperatures produced during arthroscopy by different electrode systems. In vivo studies have established that temperature increases can cause tissue damage, particularly to chondrocytes, and that the irrigation flow rate plays a key role in lowering the in vivo temperatures. Our study showed a significant difference between the two electrode systems after 50seconds of use, with lower temperatures with the VAPR(r). Nevertheless, neither system increased the irrigation-fluid temperatures above the tissue-damage threshold. Both systems can be used safely, provided the manufacturer instructions are followed and the irrigation system is effective. LEVEL OF EVIDENCE: II (prospective randomized trial). PMID- 28363879 TI - Get+Connected: Development and Pilot Testing of an Intervention to Improve Computer and Internet Attitudes and Internet Use Among Women Living With HIV. AB - BACKGROUND: For persons living with chronic medical conditions, the Internet can be a powerful tool for health promotion, and allow for immediate access to medical information and social support. However, women living with human immunodeficiency virus (HIV) in the United States face numerous barriers to computer and Internet use. Health behavior change models suggest that the first step towards adopting a new health behavior is to improve attitudes towards that behavior. OBJECTIVE: To develop and pilot test Get+Connected, an intervention to improve computer and Internet attitudes and Internet use among women living with HIV. METHODS: To develop Get+Connected, we reviewed the extant literature, adapted an existing curriculum, and conducted a focus group with HIV-positive women (n=20) at a community-based organization in the Bronx, New York. Get+Connected was comprised of five weekly sessions covering the following topics: basic computer knowledge and skills, identifying reliable health-related websites, setting up and using email and Facebook accounts, and a final review session. We recruited 12 women to participate in pilot testing. At baseline, we collected data about participants' sociodemographic information, clinical characteristics, and technology device ownership and use. At baseline, intervention completion, and three months postintervention, we collected data regarding attitudes towards computers and the Internet (Attitudes Towards Computers and the Internet Questionnaire [ATCIQ]; possible scores range from 5 50) as well as frequency of Internet use (composite measure). To examine changes in ATCIQ scores and Internet use over time, we used generalized estimating equations. We also collected qualitative data during intervention delivery. RESULTS: Among women in our sample, the median age was 56 years (interquartile range=52-63). All participants were black/African American and/or Latina. Seven participants (7/12, 58%) had a high school diploma (or equivalent) or higher degree. Ten participants (10/12, 83%) reported owning a mobile phone, while only one (1/12, 8%) reported owning a computer or tablet. Only one participant (1/12, 8%) reported having ever used the Internet or email. Internet nonusers cited lack of computer/Internet knowledge (6/11, 54%) and lack of access to a computer or similar device (4/11, 36%) as the main barriers to use. Over time, we observed an improvement in attitudes towards computers and the Internet (ATCIQ scores: 33.5 at baseline, 35 at intervention completion, and 36 at three months postintervention; P=.008). No significant increase in Internet use was observed (P=.61). Qualitative findings indicated excitement and enthusiasm for the intervention. CONCLUSIONS: In our sample of urban, technology-inexperienced HIV positive women, participation in Get+Connected was associated with an improvement in attitudes towards computers and the Internet, but not Internet use. Changing attitudes is the first step in many health behavior change models, indicating that with improved access to computer and Internet resources, frequency of Internet use may also have increased. Future studies should consider addressing issues of access to technology in conjunction with Get+Connected. PMID- 28363880 TI - Effectiveness of a Web-Based Health Education Program to Promote Oral Hygiene Care Among Stroke Survivors: Randomized Controlled Trial. AB - BACKGROUND: Oral hygiene care is of key importance among stroke patients to prevent complications that may compromise rehabilitation or potentially give rise to life-threatening infections such as aspiration pneumonia. OBJECTIVE: The aim of this study was to evaluate the effectiveness of a Web-based continuing professional development (CPD) program on "general intention" of the health carers to perform daily mouth cleaning for stroke patients using the theory of planned behavior (TPB). METHODS: A double-blind cluster randomized controlled trial was conducted among 547 stroke care providers across 10 hospitals in Malaysia. The centers were block randomized to receive either (1) test intervention (a Web-based CPD program on providing oral hygiene care to stroke patients using TPB) or (2) control intervention (a Web-based CPD program not specific to oral hygiene). Domains of TPB: "attitude," "subjective norm" (SN), "perceived behavior control" (PBC), "general intention" (GI), and "knowledge" related to providing oral hygiene care were assessed preintervention and at 1 month and 6 months postintervention. RESULTS: The overall response rate was 68.2% (373/547). At 1 month, between the test and control groups, there was a significant difference in changes in scores of attitude (P=.004) and subjective norm (P=.01), but not in other TPB domains (GI, P=.11; PBC, P=.51; or knowledge, P=.08). At 6 months, there were significant differences in changes in scores of GI (P=.003), attitude (P=.009), SN (P<.001) and knowledge (P=.001) between the test and control groups. Regression analyses identified that the key factors associated with a change in GI at 6 months were changes in SN (beta=.36, P<.001) and changes in PBC (beta=.23, P<.001). CONCLUSIONS: The Web-based CPD program based on TPB increased general intention, attitudes, subjective norms, and knowledge to provide oral hygiene care among stroke carers for their patients. Changing subjective norms and perceived behavioral control are key factors associated with changes in general intention to provide oral hygiene care. TRIAL REGISTRATION: National Medical Research Register, Malaysia NMRR-13-1540-18833 (IIR); https://www.nmrr.gov.my/ fwbLoginPage.jsp. PMID- 28363881 TI - Trajectories of Depressive Symptoms Among Web-Based Health Risk Assessment Participants. AB - BACKGROUND: Health risk assessments (HRAs), which often screen for depressive symptoms, are administered to millions of employees and health plan members each year. HRA data provide an opportunity to examine longitudinal trends in depressive symptomatology, as researchers have done previously with other populations. OBJECTIVE: The primary research questions were: (1) Can we observe longitudinal trajectories in HRA populations like those observed in other study samples? (2) Do HRA variables, which primarily reflect modifiable health risks, help us to identify predictors associated with these trajectories? (3) Can we make meaningful recommendations for population health management, applicable to HRA participants, based on predictors we identify? METHODS: This study used growth mixture modeling (GMM) to examine longitudinal trends in depressive symptomatology among 22,963 participants in a Web-based HRA used by US employers and health plans. The HRA assessed modifiable health risks and variables such as stress, sleep, and quality of life. RESULTS: Five classes were identified: A "minimal depression" class (63.91%, 14,676/22,963) whose scores were consistently low across time, a "low risk" class (19.89%, 4568/22,963) whose condition remained subthreshold, a "deteriorating" class (3.15%, 705/22,963) who began at subthreshold but approached severe depression by the end of the study, a "chronic" class (4.71%, 1081/22,963) who remained highly depressed over time, and a "remitting" class (8.42%, 1933/22,963) who had moderate depression to start, but crossed into minimal depression by the end. Among those with subthreshold symptoms, individuals who were male (P<.001) and older (P=.01) were less likely to show symptom deterioration, whereas current depression treatment (P<.001) and surprisingly, higher sleep quality (P<.001) were associated with increased probability of membership in the "deteriorating" class as compared with "low risk." Among participants with greater symptomatology to start, those in the "severe" class tended to be younger than the "remitting" class (P<.001). Lower baseline sleep quality (P<.001), quality of life (P<.001), stress level (P<.001), and current treatment involvement (P<.001) were all predictive of membership in the "severe" class. CONCLUSIONS: The trajectories identified were consistent with trends in previous research. The results identified some key predictors: we discuss those that mirror prior studies and offer some hypotheses as to why others did not. The finding that 1 in 5 HRA participants with subthreshold symptoms deteriorated to the point of clinical distress during succeeding years underscores the need to learn more about such individuals. We offer additional recommendations for follow-up research, which should be designed to reflect changes in health plan demographics and HRA delivery platforms. In addition to utilizing additional variables such as cognitive style to refine predictive models, future research could also begin to test the impact of more aggressive outreach strategies aimed at participants who are likely to deteriorate or remain significantly depressed over time. PMID- 28363885 TI - Canada announces plans to legalise recreational marijuana. PMID- 28363882 TI - Designing Health Apps to Support Dietetic Professional Practice and Their Patients: Qualitative Results From an International Survey. AB - BACKGROUND: Dietitians are engaging with mobile health (mHealth) technologies, particularly with diet and nutrition apps in their patient care. Despite the plethora of apps available, the majority are not designed with a dietitian's input. OBJECTIVE: The aim of this study was to identify the user preferences of dietitians in relation to tools, resources, and design features for smartphone health apps that would support their dietetic professional practice and their patients. METHODS: As part of a larger international Web-based survey of health app use among dietitians, three open-ended responses were included for specific exploration of app design features and additional resources or tools that could guide the development of apps for use in dietetic practice and patient care. Inductive thematic analysis of responses was conducted using the qualitative data analysis program, NVivo version 11 (QSR International Pty Ltd), to understand the design preferences and features valued by dietitians. RESULTS: The responses from 381 dietitian respondents were analyzed. Five key themes were identified. Dietitians wanted access to credible apps, suggesting that dietetic associations should have greater involvement in reviewing and endorsing evidence-based apps for use in dietary counseling. Improvements to the usability of apps, relating to their ease of use and design, were also raised, as self-monitoring of dietary behaviors using existing nutrition apps was deemed to be burdensome. Furthermore, apps providing dietitian-oriented support were favored, for example, those with the ability to streamline the dietary assessment process, so that dietitians could spend more time on dietary counseling and negotiating patient goals for dietary and lifestyle behavior change. Provision of patient-oriented support, such as functionality to tailor apps to patient-specific needs, was also considered important. Finally, respondents valued apps that could integrate into their work systems to enhance the quality of the dietitian-patient relationship. CONCLUSIONS: App developers should draw upon the features and characteristics valued by dietitians to guide their development of apps that support dietetic practice and enhance patient care. Moreover, to achieve better dietitian and patient-centered app design, it is imperative that app developers take a collaborative approach with dietitians, their professional associations, and their patients. PMID- 28363883 TI - Methods for Coding Tobacco-Related Twitter Data: A Systematic Review. AB - BACKGROUND: As Twitter has grown in popularity to 313 million monthly active users, researchers have increasingly been using it as a data source for tobacco related research. OBJECTIVE: The objective of this systematic review was to assess the methodological approaches of categorically coded tobacco Twitter data and make recommendations for future studies. METHODS: Data sources included PsycINFO, Web of Science, PubMed, ABI/INFORM, Communication Source, and Tobacco Regulatory Science. Searches were limited to peer-reviewed journals and conference proceedings in English from January 2006 to July 2016. The initial search identified 274 articles using a Twitter keyword and a tobacco keyword. One coder reviewed all abstracts and identified 27 articles that met the following inclusion criteria: (1) original research, (2) focused on tobacco or a tobacco product, (3) analyzed Twitter data, and (4) coded Twitter data categorically. One coder extracted data collection and coding methods. RESULTS: E-cigarettes were the most common type of Twitter data analyzed, followed by specific tobacco campaigns. The most prevalent data sources were Gnip and Twitter's Streaming application programming interface (API). The primary methods of coding were hand coding and machine learning. The studies predominantly coded for relevance, sentiment, theme, user or account, and location of user. CONCLUSIONS: Standards for data collection and coding should be developed to be able to more easily compare and replicate tobacco-related Twitter results. Additional recommendations include the following: sample Twitter's databases multiple times, make a distinction between message attitude and emotional tone for sentiment, code images and URLs, and analyze user profiles. Being relatively novel and widely used among adolescents and black and Hispanic individuals, Twitter could provide a rich source of tobacco surveillance data among vulnerable populations. PMID- 28363887 TI - Hip surgery - state of the art: Totally Hip 2017: Gothenburg. PMID- 28363888 TI - Prevention of periprosthetic joint infection: new guidelines. AB - The World Health Organization (WHO) and the Centre for Disease Control and Prevention (CDC) recently published guidelines for the prevention of surgical site infection. The WHO guidelines, if implemented worldwide, could have an immense impact on our practices and those of the CDC have implications for healthcare policy in the United States. Our aim was to review the strategies for prevention of periprosthetic joint infection in light of these and other recent guidelines. Cite this article: Bone Joint J 2017;99-B(4 Supple B):3-10. PMID- 28363889 TI - Hip revision arthroplasty for failed osteosynthesis in periprosthetic Vancouver type B1 fractures using a cementless, modular, tapered revision stem. AB - AIMS: To evaluate the hypothesis that failed osteosynthesis of periprosthetic Vancouver type B1 fractures can be treated successfully with stem revision using a transfemoral approach and a cementless, modular, tapered revision stem with reproducible rates of fracture healing, stability of the revision stem, and clinically good results. PATIENTS AND METHODS: A total of 14 patients (11 women, three men) with a mean age of 72.4 years (65 to 90) undergoing revision hip arthroplasty after failed osteosynthesis of periprosthetic fractures of Vancouver type B1 were treated using a transfemoral approach to remove the well-fixed stem before insertion of a modular, fluted titanium stem which obtained distal fixation. These patients were clinically and radiologically followed up for a mean 52.2 months (24 to 144). RESULTS: After a mean of 15.5 weeks (standard deviation (sd) 5.7) all fractures had healed. No stems subsided and bony-ingrowth fixation had occurred according to the classification of Engh et al. The mean Harris Hip Score increased from a pre-operative score of 22.2 points (sd 9.7) to 81.5 points (sd 16.8) 24 months post-operatively. All hips had obtained an excellent result according to the classification of Beals and Tower. CONCLUSIONS: The technique described here for stem revision provides reproducibly good results in the treatment of failed osteosynthesis for Vancouver types B1 periprosthetic fractures of the hip. Cite this article: Bone Joint J 2017;99-B(4 Supple B):11 16. PMID- 28363890 TI - A systematic review of Vancouver B2 and B3 periprosthetic femoral fractures. AB - AIMS: The aim of this study was to investigate the outcomes of Vancouver type B2 and B3 fractures by performing a systematic review of the methods of surgical treatment which have been reported. MATERIALS AND METHODS: A systematic search was performed in Ovid MEDLINE, Embase and the Cochrane Central Register of Controlled Trials. For inclusion, studies required a minimum of ten patients with a Vancouver type B2 and/or ten patients with a Vancouver type B3 fracture, a minimum mean follow-up of two years and outcomes which were matched to the type of fracture. Studies were also required to report the rate of re-operation as an outcome measure. The protocol was registered in the PROSPERO database. RESULTS: A total of 22 studies were included based on the eligibility criteria, including 343 B2 fractures and 167 B3 fractures. The mean follow-up ranged from 32 months to 74 months. Of 343 Vancouver B2 fractures, the treatment in 298 (86.8%) involved revision arthroplasty and 45 (12.6%) were treated with internal fixation alone. A total of 37 patients (12.4%) treated with revision arthroplasty and six (13.3%) treated by internal fixation only underwent further re-operation. Of 167 Vancouver B3 fractures, the treatment in 160 (95.8%) involved revision arthroplasty and eight (4.8%) were treated with internal fixation without revision. A total of 23 patients (14.4%) treated with revision arthroplasty and two (28.6%) treated only with internal fixation required re-operation. CONCLUSION: A significant proportion, particularly of B2 fractures, were treated without revision of the stem. These were associated with a higher rate of re operation. The treatment of B3 fractures without revision of the stem resulted in a high rate of re-operation. This demonstrates the importance of careful evaluation and accurate characterisation of the fracture at the time of presentation to ensure the correct management. There is a need for improvement in the reporting of data in case series recording the outcome of the surgical treatment of periprosthetic fractures. We have suggested a minimum dataset to improve the quality of data in studies dealing with these fractures. Cite this article: Bone Joint J 2017;99-B(4 Supple B):17-25. PMID- 28363891 TI - Cement-in-cement revision of the femoral stem: analysis of 1179 first-time revisions in the Swedish Hip Arthroplasty Register. AB - AIMS: Compared with primary total hip arthroplasty (THA), revision surgery can be challenging. The cement-in-cement femoral revision technique involves removing a femoral component from a well-fixed femoral cement mantle and cementing a new stem into the original mantle. This technique is widely used and when carried out for the correct indications, is fast, relatively inexpensive and carries a reduced short-term risk for the patient compared with the alternative of removing well-fixed cement. We report the outcomes of this procedure when two commonly used femoral stems are used. PATIENTS AND METHODS: We identified 1179 cement-in cement stem revisions involving an Exeter or a Lubinus stem reported to the Swedish Hip Arthroplasty Register (SHAR) between January 1999 and December 2015. Kaplan-Meier survival analysis was performed. RESULTS: Survivorship is reported up to six years and was better in the Exeter group (91% standard deviation (sd) 2.8% versus 85% sd 5.0%) (p = 0.02). There was, however, no significant difference in the survival of the stem and risk of re-revision for any reason (p = 0.58) and for aseptic loosening (p = 0.97), between revisions in which the Exeter stem (94% sd 2.2%; 98% sd 1.6%) was used compared with those in which the Lubinus stem (95% sd 3.2%; 98% sd 2.2%) was used. The database did not allow identification of whether a further revision was indicated for loosening of the acetabular or femoral component or both. CONCLUSION: The cement-in-cement technique for revision of the femoral component gave promising results using both designs of stem, six years post-operatively. Cite this article: Bone Joint J 2017;99-B(4 Supple B):27-32. PMID- 28363892 TI - Mid-term changes in blood metal ion levels after Articular Surface Replacement arthroplasty of the hip. AB - AIMS: Our first aim was to determine whether there are significant changes in the level of metal ions in the blood at mid-term follow-up, in patients with an Articular Surface Replacement (ASR) arthroplasty. Secondly, we sought to identify risk factors for any increases. PATIENTS AND METHODS: The study involved 435 patients who underwent unilateral, metal-on-metal (MoM) hip resurfacing (HRA) or total hip arthroplasty (THA). These patients all had one measurement of the level of metal ions in the blood before seven years had passed post-operatively (early evaluation) and one after seven years had passed post-operatively (mid-term evaluation). Changes in ion levels were tested using a Wilcoxon signed-rank test. We identified subgroups at the highest risk of increase using a multivariable linear logistic regression model. RESULTS: There were significant increases in the levels of metal ions for patients who underwent both MoM HRA (Chromium (Cr): 0.5 parts per billion (ppb); Cobalt (Co): 1.1 ppb) and MoM THA (Cr: 0.5 ppb; Co: 0.7 ppb). In a multivariable model considering MoM HRAs, the change in the levels of metal ions was influenced by female gender (Co: Odds Ratio (OR) 1.42; p = 0.002 and Cr: OR 1.08; p = 0.006). The change was found to be irrespective of the initial level for the MoM HRAs, whereas there was a negative relationship between the initial level and the change in the level for those with a MoM THA (Co: OR 0.43; p < 0.001 and Cr: OR -0.14; p = 0.033). CONCLUSION: The levels of metal ions in the blood increase significantly over the period until mid-term follow-up in patients with both a MoM HRA and those with a MoM THA. We recommend that the levels of metal ions be measured most frequently for women with a MoM HRA. While those with a MoM THA appear to stabilise at a certain level, the accuracy of this trend is not yet clear. Vigilant follow-up is still recommended. Cite this article: Bone Joint J 2017;99-B(4 Supple B):33-40. PMID- 28363893 TI - Osseous impingement occurs early in flexion in cam-type femoroacetabular impingement: a 4D CT model. AB - AIMS: The aim of this study was to examine the real time in vivo kinematics of the hip in patients with cam-type femoroacetabular impingement (FAI). PATIENTS AND METHODS: A total of 50 patients (83 hips) underwent 4D dynamic CT scanning of the hip, producing real time osseous models of the pelvis and femur being moved through flexion, adduction, and internal rotation. The location and size of the cam deformity and its relationship to the angle of flexion of the hip and pelvic tilt, and the position of impingement were recorded. RESULTS: In these patients with cam-type FAI, there was significant correlation between the alpha angle and flexion to the point of impingement (mean 41.36 degrees ; 14.32 degrees to 57.95 degrees ) (R = -0.5815 and p = < 0.001). Patients with a large cam deformity (alpha angle > 78 degrees ) had significantly less flexion to the point of impingement (mean 36.30 degrees ; 14.32 degrees to 55.18 degrees ) than patients with a small cam deformity (alpha angle 60 degrees to 78 degrees ) (mean 45.34 degrees ; 27.25 degrees to 57.95 degrees ) (p = < 0.001). CONCLUSION: This study has shown that cam-type impingement can occur early in flexion (40 degrees ), particularly in patients with large anterior deformities. These patients risk chondrolabral damage during routine activities such as walking, and going up stairs. These findings offer important insights into the cause of the symptoms, the mechanisms of screening and the forms of treatment available for these patients. Cite this article: Bone Joint J 2017;99-B(4 Supple B):41-8. PMID- 28363894 TI - Early performance-based and patient-reported outcomes of a contemporary taper fit bone-conserving short stem femoral component in total hip arthroplasty. AB - AIMS: The aim of this study was to compare early functional and health related quality of life outcomes (HRQoL) in patients who have undergone total hip arthroplasty (THA) using a bone conserving short stem femoral component and those in whom a conventional length uncemented component was used. Outcome was assessed using a validated performance based outcome instrument as well as patient reported outcome measures (PROMs). PATIENTS AND METHODS: We prospectively analysed 33 patients whose THA involved a contemporary proximally porous coated tapered short stem femoral component and 53 patients with a standard conventional femoral component, at a minimum follow-up of two years. The mean follow-up was 31.4 months (24 to 39). Patients with poor proximal femoral bone quality were excluded. The mean age of the patients was 66.6 years (59 to 77) and the mean body mass index was 30.2 kg/m2 (24.1 to 41.0). Outcome was assessed using the Oxford Hip Score (OHS) and the University College Hospital (UCH) hip score which is a validated performance based instrument. HRQoL was assessed using the EuroQol 5D (EQ-5D). RESULTS: There were no major peri-operative complications. There was no difference in the mean post-operative OHS, EQ-5D or function subscale of the UCH hip scores between the two groups. The mean pre-operative OHS and EQ-5D scores improved significantly (all p < 0.001). The mean functional component of the UCH hip score at final follow-up was 42.5 and 40.6 in the short stem and conventional stem groups, respectively. There was no statistically significant difference between the groups (p = 0.42). A total of seven patients (21.2%) in the short stem group and nine (16.98%) in the conventional group achieved a ceiling effect using the OHS; none did using the function subscale of the UCH hip score. CONCLUSION: The proximally porous coated tapered short stem femoral component achieves comparable short-term functional outcomes when compared with a conventional longer stem uncemented femoral component when THA is undertaken in patients with good bone quality. Cite this article: Bone Joint J 2017;99-B(4 Supple B):49-55. PMID- 28363895 TI - Clarification of RCOG advice on obese women in pregnancy. PMID- 28363896 TI - Author's reply. PMID- 28363897 TI - Differentiation of germinal center B cells into plasma cells is initiated by high affinity antigen and completed by Tfh cells. AB - Plasma cells (PCs) derived from germinal centers (GCs) secrete the high-affinity antibodies required for long-term serological immunity. Nevertheless, the process whereby GC B cells differentiate into PCs is uncharacterized, and the mechanism underlying the selective PC differentiation of only high-affinity GC B cells remains unknown. In this study, we show that differentiation into PCs is induced among a discrete subset of high-affinity B cells residing within the light zone of the GC. Initiation of differentiation required signals delivered upon engagement with intact antigen. Signals delivered by T follicular helper cells were not required to initiate differentiation but were essential to complete the differentiation process and drive migration of maturing PCs through the dark zone and out of the GC. This bipartite or two-signal mechanism has likely evolved to both sustain protective immunity and avoid autoantibody production. PMID- 28363899 TI - Spontaneous coronary artery dissection. PMID- 28363898 TI - There is still a role for cytology in the 'liquid biopsy' era. A lesson from a TKI-treated patient showing adenocarcinoma to squamous cell carcinoma transition during disease progression. AB - Non-small cell lung carcinoma harbouring epidermal growth factor receptor (EGFR) mutation, usually progress after an initial response to tyrosine-kinase inhibitors (TKI). Liquid biopsy enables with a simple blood draw the accurate detection of EGFR p.T790M mutation, the most common resistance mechanism, avoiding the more invasive tissue re-biopsy. However, in a subset of cases, resistance mechanisms are more complex featuring both genetic and morphological changes. Here we report the case of a 67 years-old woman, affected by an EGFR mutated lung adenocarcinoma and treated by TKI. At disease progression, the patient developed a morphological transition to squamous cell carcinoma in association to the arising of a PIK3CA p.E542K mutant subclone. This case illustrates that, even in the "liquid biopsy" era, cytology can have still a role by providing an overall assessment of both morphology and genetic TKI resistance mechanisms. PMID- 28363901 TI - Time to ReSPECT personal resuscitation plans for adults? PMID- 28363900 TI - Computational analysis of nascent peptides that induce ribosome stalling and their proteomic distribution in Saccharomyces cerevisiae. AB - Interactions between the ribosomal exit tunnel and the nascent peptide can affect translation elongation rates. While previous studies have already demonstrated the feasibility of such interactions, little is known about the nature of the stalling peptide sequences and their distribution in the proteome. Here we ask which peptide sequences tend to occupy the tunnel of stalled ribosomes and how they are distributed in the proteome. Using computational analysis of ribosome profiling data from S. cerevisiae, we identified for the first time dozens of short stalling peptide sequences and studied their statistical properties. We found that short peptide sequences associated with ribosome stalling tend significantly to be either over- or underrepresented in the proteome. We then showed that the stalling interactions may occur at different positions along the length of the tunnel, prominently close to the P-site. Our findings throw light on the determinants of nascent peptide-mediated ribosome stalling during translation elongation and support the novel conjecture that mRNA translation affects the proteomic distribution of short peptide sequences. PMID- 28363902 TI - Ontogeny of bite force in a validated biomechanical model of the American alligator. AB - Three-dimensional computational modeling offers tools with which to investigate forces experienced by the skull during feeding and other behaviors. American alligators (Alligator mississippiensis) generate some of the highest measured bite forces among extant tetrapods. A concomitant increase in bite force accompanies ontogenetic increases in body mass, which has been linked with dietary changes as animals increase in size. Because the flattened skull of crocodylians has substantial mediolaterally oriented muscles, crocodylians are an excellent model taxon in which to explore the role of mediolateral force components experienced by the feeding apparatus. Many previous modeling studies of archosaur cranial function focused on planar analysis, ignoring the mediolateral aspects of cranial forces. Here, we used three-dimensionally accurate anatomical data to resolve 3D muscle forces. Using dissection, imaging and computational techniques, we developed lever and finite element models of an ontogenetic series of alligators to test the effects of size and shape on cranial loading and compared estimated bite forces with those previously measured in vivo in A. mississippiensis We found that modeled forces matched in vivo data well for intermediately sized individuals, and somewhat overestimated force in smaller specimens and underestimated force in larger specimens, suggesting that ontogenetically static muscular parameters and bony attachment sites alone cannot account for all the variation in bite force. Adding aponeurotic muscle attachments would likely improve force predictions, but such data are challenging to model and integrate into analyses of extant taxa and are generally unpreserved in fossils. We conclude that anatomically accurate modeling of muscles can be coupled with finite element and lever analyses to produce reliable, reasonably accurate estimate bite forces and thus both skeletal and joint loading, with known sources of error, which can be applied to extinct taxa. PMID- 28363903 TI - IFN Regulatory Factor 3 Potentiates Emphysematous Aggravation by Lipopolysaccharide. AB - Acute exacerbation of chronic obstructive pulmonary disease (COPD) is often induced by infection and often has a poor prognosis. Bacterial LPS activates innate immune receptor TLR4 followed by activation of a transcriptional factor IFN regulatory factor-3 (IRF3) as well as NF-kappaB, resulting in upregulation of various inflammatory mediators. To clarify the role of IRF3 in the pathogenesis of LPS-triggered COPD exacerbation, porcine pancreatic elastase (PPE) followed by LPS was administered intranasally to wild-type (WT) or IRF3-/- male mice. Sequential quantitative changes in emphysema were evaluated by microcomputed tomography, and lung histology was evaluated at the sixth week. WT mice treated with PPE and LPS exhibited enlarged alveolar spaces, whereas this feature was attenuated in similarly treated IRF3-/- mice. Moreover, LPS-induced emphysema aggravation was detected only in WT mice. Analysis of acute inflammation induced by PPE plus LPS revealed that the lungs of treated IRF3-/- mice had decreased mRNA transcripts for MCP-1, MIP-1alpha, TNF-alpha, and IFN-gamma-inducible protein-10 but had increased neutrophils. IRF3 was involved in the production of mediators from macrophages, alveolar epithelial cells, and neutrophils. Furthermore, compared with isolated WT neutrophils from inflamed lung, those of IRF3-/- neutrophils exhibited impaired autophagic activation, phagocytosis, and apoptosis. These results suggest that IRF3 accelerated emphysema formation based on distinct profiles of mediators involved in LPS-induced COPD exacerbation. Regulation of the IRF3 pathway can affect multiple cell types and contribute to ameliorate pathogenesis of infection-triggered exacerbation of COPD. PMID- 28363904 TI - Hydrogen Peroxide Triggers a Dual Signaling Axis To Selectively Suppress Activated Human T Lymphocyte Migration. AB - H2O2 is an early danger cue required for innate immune cell recruitment to wounds. To date, little is known about whether H2O2 is required for the migration of human adaptive immune cells to sites of inflammation. However, oxidative stress is known to impair T cell activity, induce actin stiffness, and inhibit cell polarization. In this study, we show that low oxidative concentrations of H2O2 also impede chemokinesis and chemotaxis of previously activated human T cells to CXCL11, but not CXCL10 or CXCL12. We show that this deficiency in migration is due to a reduction in inflammatory chemokine receptor CXCR3 surface expression and cellular activation of lipid phosphatase SHIP-1. We demonstrate that H2O2 acts through an Src kinase to activate a negative regulator of PI3K signaling, SHIP-1 via phosphorylation, providing a molecular mechanism for H2O2 induced chemotaxis deficiency. We hypothesize that although H2O2 serves as an early recruitment trigger for innate immune cells, it appears to operate as an inhibitor of T lymphocyte immune adaptive responses that are not required until later in the repair process. PMID- 28363905 TI - CD137 Plays Both Pathogenic and Protective Roles in Type 1 Diabetes Development in NOD Mice. AB - We previously reported that CD137 (encoded by Tnfrsf9) deficiency suppressed type 1 diabetes (T1D) progression in NOD mice. We also demonstrated that soluble CD137 produced by regulatory T cells contributed to their autoimmune-suppressive function in this model. These results suggest that CD137 can either promote or suppress T1D development in NOD mice depending on where it is expressed. In this study, we show that NOD.Tnfrsf9-/- CD8 T cells had significantly reduced diabetogenic capacity, whereas absence of CD137 in non-T and non-B cells had a limited impact on T1D progression. In contrast, NOD.Tnfrsf9-/- CD4 T cells highly promoted T1D development. We further demonstrated that CD137 was important for the accumulation of beta cell-autoreactive CD8 T cells but was dispensable for their activation in pancreatic lymph nodes. The frequency of islet-infiltrating CD8 T cells was reduced in NOD.Tnfrsf9-/- mice in part because of their decreased proliferation. Furthermore, CD137 deficiency did not suppress T1D development in NOD mice expressing the transgenic NY8.3 CD8 TCR. This suggests that increased precursor frequency of beta cell-autoreactive CD8 T cells in NY8.3 mice obviated a role for CD137 in diabetogenesis. Finally, blocking CD137-CD137 ligand interaction significantly delayed T1D onset in NOD mice. Collectively, our results indicate that one important diabetogenic function of CD137 is to promote the expansion and accumulation of beta cell-autoreactive CD8 T cells, and in the absence of CD137 or its interaction with CD137 ligand, T1D progression is suppressed. PMID- 28363908 TI - Nonspecific DNA Binding of cGAS N Terminus Promotes cGAS Activation. AB - The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) mediates innate immune responses against invading pathogens, or against self-dsDNA, which causes autoimmune disorders. Upon nonspecific binding of cytosolic B-form DNA, cGAS synthesizes the second messenger 2'3'-cGAMP and triggers STING-dependent signaling to produce type I IFNs. The cGAS comprises less-conserved N-terminal residues and highly conserved nucleotidyltransferase/Mab21 domains. The function and structure of the well-conserved domains have been extensively studied, whereas the physiological function of the N-terminal domain of cGAS is largely uncharacterized. In this study we used a single-molecule technique combined with traditional biochemical and cellular assays to demonstrate that binding of nonspecific dsDNA by the N-terminal domain of cGAS promotes its activation. We have observed that the N terminus of human cGAS (hcGAS-N160) undergoes secondary structural change upon dsDNA binding in solution. Furthermore, we showed that the hcGAS-N160 helps full length hcGAS to expand the binding range on lambdaDNA and facilitates its binding efficiency to dsDNA compared with hcGAS without the 160 N terminal residues (hcGAS-d160). More importantly, hcGAS-N160 endows full length hcGAS relatively higher enzyme activity and stronger activation of STING/IRF3 mediated cytosolic DNA signaling. These findings strongly indicate that the N terminal domain of cGAS plays an important role in enhancing its function. PMID- 28363910 TI - Pembrolizumab Approved for Hodgkin Lymphoma. AB - The FDA has approved pembrolizumab for adults and children with classical Hodgkin lymphoma whose disease is refractory to or has relapsed after at least three prior therapies. The approval marks the first time that a PD-1 inhibitor has been indicated for blood cancers-and for children. PMID- 28363906 TI - Varied Role of Ubiquitylation in Generating MHC Class I Peptide Ligands. AB - CD8+ T cell immunosurveillance is based on recognizing oligopeptides presented by MHC class I molecules. Despite decades of study, the importance of protein ubiquitylation to peptide generation remains uncertain. In this study, we examined the ability of MLN7243, a recently described ubiquitin-activating enzyme E1 inhibitor, to block overall cytosolic peptide generation and generation of specific peptides from vaccinia- and influenza A virus-encoded proteins. We show that MLN7243 rapidly inhibits ubiquitylation in a variety of cell lines and can profoundly reduce the generation of cytosolic peptides. Kinetic analysis of specific peptide generation reveals that ubiquitylation of defective ribosomal products is rate limiting in generating class I peptide complexes. More generally, our findings demonstrate that the requirement for ubiquitylation in MHC class I-restricted Ag processing varies with class I allomorph, cell type, source protein, and peptide context. Thus, ubiquitin-dependent and -independent pathways robustly contribute to MHC class I-based immunosurveillance. PMID- 28363907 TI - Retinoic Acid Regulates Immune Responses by Promoting IL-22 and Modulating S100 Proteins in Viral Hepatitis. AB - Although large amounts of vitamin A and its metabolite all-trans retinoic acid (RA) are stored in the liver, how RA regulates liver immune responses during viral infection remains unclear. In this study, we demonstrated that IL-22, mainly produced by hepatic gammadelta T cells, attenuated liver injury in adenovirus-infected mice. RA can promote gammadelta T cells to produce mTORC1 dependent IL-22 in the liver, but inhibits IFN-gamma and IL-17. RA also affected the aptitude of T cell responses by modulating dendritic cell (DC) migration and costimulatory molecule expression. These results suggested that RA plays an immunomodulatory role in viral infection. Proteomics data revealed that RA downregulated S100 family protein expression in DCs, as well as NF-kappaB/ERK pathway activation in these cells. Furthermore, adoptive transfer of S100A4 repressed, virus-pulsed DCs into the hind foot of naive mice failed to prime T cell responses in draining lymph nodes. Our study has demonstrated a crucial role for RA in promoting IL-22 production and tempering DC function through downregulating S100 family proteins during viral hepatitis. PMID- 28363916 TI - Analysis of CTG repeat length variation in the DMPK gene in the general population and the molecular diagnosis of myotonic dystrophy type 1 in Malaysia. AB - OBJECTIVE: The lack of epidemiological data and molecular diagnostic services in Malaysia has hampered the setting-up of a comprehensive management plan for patients with myotonic dystrophy type 1 (DM1), leading to delayed diagnosis, treatment and support for patients and families. The aim of this study was to estimate the prevalence of DM1 in the 3 major ethnic groups in Malaysia and evaluate the feasibility of a single tube triplet-primed PCR (TP-PCR) method for diagnosis of DM1 in Malaysia. DESIGN, SETTING AND PARTICIPANTS: We used PCR to determine the size of CTG repeats in 377 individuals not known to be affected by DM and 11 DM1 suspected patients, recruited from a tertiary hospital in Kuala Lumpur. TP-PCR was performed on selected samples, followed by Southern blot hybridisation of PCR amplified fragments to confirm and estimate the size of CTG expansion. OUTCOME MEASURES: The number of individuals not known to be affected by DM with (CTG)>18 was determined according to ethnic group and as a whole population. The chi2 test was performed to compare the distribution of (CTG)>18 with 12 other populations. Additionally, the accuracy of TP-PCR in detecting CTG expansion in 11 patients with DM1 was determined by comparing the results with that from Southern blot hybridisation. RESULTS: Of the 754 chromosomes studied, (CTG)>18 frequency of 3.60%, 1.57% and 4.00% in the Malay, Chinese and Indian subpopulations, respectively, was detected, showing similarities to data from Thai, Taiwanese and Kuwaiti populations. We also successfully detected CTG expansions in 9 patients using the TP-PCR method followed by the estimation of CTG expansion size via Southern blot hybridisation. CONCLUSIONS: The results show a low DM1 prevalence in Malaysia with the possibility of underdiagnosis and demonstrates the feasibility of using a clinical and TP-PCR-based approach for rapid and cost-effective DM1 diagnosis in developing countries. PMID- 28363909 TI - A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic BRAF-Mutant Colorectal Cancer. AB - Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in BRAFV600E colorectal cancer models. Patients with refractory BRAFV600-mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab), with (n = 28) or without (n = 26) a PI3Kalpha inhibitor (alpelisib). The primary objective was to determine the maximum tolerated dose (MTD) or a recommended phase II dose. Dose-limiting toxicities were reported in 3 patients receiving dual treatment and 2 patients receiving triple treatment. The MTD was not reached for either group and the phase II doses were selected as 200 mg encorafenib (both groups) and 300 mg alpelisib. Combinations of cetuximab and encorafenib showed promising clinical activity and tolerability in patients with BRAF-mutant mCRC; confirmed overall response rates of 19% and 18% were observed and median progression-free survival was 3.7 and 4.2 months for the dual- and triple-therapy groups, respectively.Significance: Herein, we demonstrate that dual- (encorafenib plus cetuximab) and triple- (encorafenib plus cetuximab and alpelisib) combination treatments are tolerable and provide promising clinical activity in the difficult to-treat patient population with BRAF-mutant mCRC. Cancer Discov; 7(6); 610-9. (c)2017 AACR.See related commentary by Sundar et al., p. 558This article is highlighted in the In This Issue feature, p. 539. PMID- 28363917 TI - Funnel plots and choropleth maps in cancer risk communication: a comparison of tools for disseminating population-based incidence data to stakeholders. AB - BACKGROUND: Population-based cancer registries provide epidemiological cancer information, but the indicators are often too complex to be interpreted by local authorities and communities, due to numeracy and literacy limitations. The aim of this paper is to compare the commonly used visual formats to funnel plots to enable local public health authorities and communities to access valid and understandable cancer incidence data obtained at the municipal level. METHODS: A funnel plot representation of standardised incidence ratio (SIR) was generated for the 82 municipalities of the Palermo Province with the 2003-2011 data from the Palermo Province Cancer Registry (Sicily, Italy). The properties of the funnel plot and choropleth map methodologies were compared within the context of disseminating epidemiological data to stakeholders. RESULTS: The SIRs of all the municipalities remained within the control limits, except for Palermo city area (SIR=1.12), which was sited outside the upper control limit line of 99.8%. The Palermo Province SIRs funnel plot representation was congruent with the choropleth map generated from the same data, but the former resulted more informative as shown by the comparisons of the weaknesses and strengths of the 2 visual formats. CONCLUSIONS: Funnel plot should be used as a complementary valuable tool to communicate epidemiological data of cancer registries to communities and local authorities, visually conveying an efficient and simple way to interpret cancer incidence data. PMID- 28363918 TI - Accuracy of a step counter during treadmill and daily life walking by healthy adults and patients with cardiac disease. AB - BACKGROUND: Step counters have been used to observe activity and support physical activity, but there is limited evidence on their accuracy. OBJECTIVE: The purpose was to investigate the step accuracy of the Fitbit Zip (Zip) in healthy adults during treadmill walking and in patients with cardiac disease while hospitalised at home. METHODS: Twenty healthy adults aged 39+/-13.79 (mean +/-SD) wore four Zips while walking on a treadmill at different speeds (1.7-6.1 km/hour), and 24 patients with cardiac disease (age 67+/-10.03) wore a Zip for 24 hours during hospitalisation and for 4 weeks thereafter at home. A Shimmer3 device was used as a criterion standard. RESULTS: At a treadmill speed of 3.6 km/hour, the relative error (+/-SD) for the Zips on the upper body was -0.02+/-0.67 on the right side and -0.09 (0.67) on the left side. For the Zips on the waist, this was 0.08+/ 0.71 for the right side and -0.08 (0.47) on the left side. At a treadmill speed of 3.6 km/hour and higher, the average per cent of relative error was <3%. The 24 hour test for the hospitalised patients showed a relative error of -47.15+/-24.11 (interclass correlation coefficient (ICC): 0.60), and for the 24-hour test at home, the relative error was -27.51+/-28.78 (ICC: 0.87). Thus, none of the 24 hour tests had less than the expected 20% error. In time periods of evident walking during the 24 h test, the Zip had an average per cent relative error of <3% at 3.6 km/hour and higher speeds. CONCLUSIONS: A speed of 3.6 km/hour or higher is required to expect acceptable accuracy in step measurement using a Zip, on a treadmill and in real life. Inaccuracies are directly related to slow speeds, which might be a problem for patients with cardiac disease who walk at a slow pace. PMID- 28363919 TI - Impact of changes in pill appearance in the adherence to angiotensin receptor blockers and in the blood pressure levels: a retrospective cohort study. AB - OBJECTIVE: To assess the level of adherence to angiotensin receptor blockers (ARBs) in patients regularly attending a community pharmacy and the influence of a change in patients' adherence to pharmacological treatment. DESIGN: Retrospective cohort study of a random sample of consecutive patients collecting their medication. SETTING: 40 community pharmacies in Alicante (Southeast Spain). PARTICIPANTS: 602 consecutive >=18 years old patients following treatment with ARBs at least 3 previous refills were included. MAIN OUTCOME MEASURES: Prevalence of uncontrolled blood pressure (BP) and adherence to prescribed pharmacological treatment (measured through both the Batalla and the Morisky-Green tests). A multivariate Poisson regression model was used to estimate the adjusted risk ratio (RRa) for non-adherence to pharmacological treatment by the presence of a change in patient's adherence and other significant variables. RESULTS: 161/602 (13.7%) patients presented uncontrolled BP. According to the Morisky test, 410/602 (68.2%) patients were considered adherent to pharmacological treatment and 231/602 (38.4%) patients according to the Batalla test. According to the Morisky-Green test, in the multivariable analysis, patients with a previous change in pill appearance were less likely to be adherent than those patients with no change in their pharmacological treatment (RRa 0.45; CI 95% 0.22 to 0.90; p=0.024). Systolic BP was higher in patients with a change in pill appearance in the previous 3 refills (median BP 142 mm Hg; IQR 136-148) than in those who did not have a change (median BP 127 mm Hg; IQR 118-135; p<0.001). CONCLUSIONS: There was a low percentage of adherence and nearly 15% of uncontrolled BP in patients who regularly collected their medication. Switching between pills of different appearances was associated with lower patient adherence to pharmacological treatment and a higher uncontrolled BP than no change in pharmacological treatment or change only in package but not in pill appearance. PMID- 28363922 TI - Awareness and attitudes of the Lebanese population with regard to physician pharmaceutical company interaction: a survey study. AB - OBJECTIVE: To assess the awareness and attitudes of the general public in Lebanon regarding the interactions between physicians and pharmaceutical companies. SETTING: Primary healthcare clinics and shopping malls in the Greater Beirut Area. PARTICIPANTS: 263 participants completed the questionnaire, of whom 62% were female and 38% were male. Eligible participants were Arabic-speaking or English-speaking adults (age>=18 years) residing in Lebanon for at least 5 years. PRIMARY AND SECONDARY OUTCOME MEASURES: Awareness, attitudes and beliefs of the general public. RESULTS: 263 out of 295 invited individuals (89% completion rate) completed the questionnaire. While the majority of participants were aware of pharmaceutical company presence (or absence) in physicians' offices (range of 71 76% across questions), smaller percentages were aware of gift-related practices of physicians (range of 26-69% across questions). 40% thought that the acceptance of small gifts or meals by physicians is wrong/unethical. The percentage of participants reporting lower trust in physicians due to their participation in various pharmaceutical company-related activities ranged from 12% to 45% (the highest percentage being for large gifts). Participants who reported receiving free medication samples were significantly more likely to consider physicians' acceptance of small gifts as 'not a problem' than 'unethical' (OR=1.53; p=0.044). CONCLUSIONS: Participants in our survey were generally more aware of pharmaceutical company presence (or absence) in physicians' offices than of gift related practices of physicians. While the level of trust was not affected for the majority of participants for various types of interactions, it was affected the most for accepting large gifts. PMID- 28363920 TI - Design and rationale of a matched cohort study to assess the effectiveness of a combined household-level piped water and sanitation intervention in rural Odisha, India. AB - INTRODUCTION: Government efforts to address massive shortfalls in rural water and sanitation in India have centred on construction of community water sources and toilets for selected households. However, deficiencies with water quality and quantity at the household level and community coverage and actual use of toilets have led Gram Vikas, a local non-governmental organization in Odisha, India, to develop an approach that provides household-level piped water connections contingent on full community-level toilet coverage. METHODS: This matched cohort study was designed to assess the effectiveness of a combined piped water and sanitation intervention. Households with children <5 years in 45 randomly selected intervention villages and 45 matched control villages will be followed over 17 months. The primary outcome is prevalence of diarrhoeal diseases; secondary health outcomes include soil-transmitted helminth infection, nutritional status, seroconversion to enteric pathogens, urogenital infections and environmental enteric dysfunction. In addition, intervention effects on sanitation and water coverage, access and use, environmental fecal contamination, women's empowerment, as well as collective efficacy, and intervention cost and cost-effectiveness will be assessed. ETHICS AND DISSEMINATION: The study protocol has been reviewed and approved by the ethics boards of the London School of Hygiene and Tropical Medicine, UK and KIIT University, Bhubaneswar, India. Findings will be disseminated via peer-reviewed literature and presentation to stakeholders, government officials, implementers and researchers. TRIAL REGISTRATION NUMBER: NCT02441699. PMID- 28363921 TI - Evidence of potential bias in a comparison of beta blockers and calcium channel blockers in patients with chronic obstructive pulmonary disease and acute coronary syndrome: results of a multinational study. AB - OBJECTIVES: A number of observational studies have reported that, in patients with chronic obstructive pulmonary disease (COPD), beta blockers (BBs) decrease risk of mortality and COPD exacerbations. To address important methodological concerns of these studies, we compared the effectiveness and safety of cardioselective BBs versus non-dihydropyridine calcium channel blockers (non-DHP CCBs) in patients with COPD and acute coronary syndromes (ACS) using a propensity score (PS)-matched, active comparator, new user design. We also assessed for potential unmeasured confounding by examining a short-term COPD hospitalisation outcome. SETTING AND PARTICIPANTS: We identified 22 985 patients with COPD and ACS starting cardioselective BBs or non-DHP CCBs across 5 claims databases from the USA, Italy and Taiwan. PRIMARY AND SECONDARY OUTCOME MEASURES: Stratified Cox regression models were used to estimate HRs for mortality, cardiovascular (CV) hospitalisations and COPD hospitalisations in each database after variable-ratio PS matching. Results were combined with random-effects meta-analyses. RESULTS: Cardioselective BBs were not associated with reduced risk of mortality (HR, 0.90; 95% CI 0.78 to 1.02) or CV hospitalisations (HR, 1.06; 95% CI 0.91 to 1.23), although statistical heterogeneity was observed across databases. In contrast, a consistent, inverse association for COPD hospitalisations was identified across databases (HR, 0.54; 95% CI 0.47 to 0.61), which persisted even within the first 30 days of follow-up (HR, 0.55; 95% CI 0.37 to 0.82). Results were similar across a variety of sensitivity analyses, including PS trimming, high dimensional-PS matching and restricting to high-risk patients. CONCLUSIONS: This multinational study found a large inverse association between cardioselective BBs and short term COPD hospitalisations. The persistence of this bias despite state-of-the-art pharmacoepidemiologic methods calls into question the ability of claims data to address confounding in studies of BBs in patients with COPD. PMID- 28363923 TI - Interactive web-based pulmonary rehabilitation programme: a randomised controlled feasibility trial. AB - OBJECTIVES: The aim of this study was to determine if an interactive web-based pulmonary rehabilitation (PR) programme is a feasible alternative to conventional PR. DESIGN: Randomised controlled feasibility trial. SETTING: Participants with a diagnosis of chronic obstructive pulmonary disease were recruited from PR assessments, primary care and community rehabilitation programmes. Patients randomised to conventional rehabilitation started the programme according to the standard care at their referred site on the next available date. PARTICIPANTS: 103 patients were recruited to the study and randomised: 52 to conventional rehabilitation (mean (+/-SD) age 66 (+/-8) years, Medical Research Council (MRC) 3 (IQR2-4)); 51 to the web arm (mean (+/-SD) age 66 (+/-10) years, MRC 3 (IQR2 4)). Participants had to be willing to participate in either arm of the trial, have internet access and be web literate. INTERVENTIONS: Patients randomised to the web-based programme worked through the website, exercising and recording their progress as well as reading educational material. Conventional PR consisted of twice weekly, 2 hourly sessions (an hour for exercise training and an hour for education). OUTCOME MEASURES: Recruitment rates, eligibility, patient preference and dropout and completion rates for both programmes were collected. Standard outcomes for a PR assessment including measures of exercise capacity and quality of life questionnaires were also evaluated. RESULTS: A statistically significant improvement (p<=0.01) was observed within each group in the endurance shuttle walk test (WEB: mean change 189+/-211.1; PR classes: mean change 184.5+/-247.4 s) and Chronic Respiratory disease Questionnaire-Dyspnoea (CRQ-D; WEB: mean change 0.7+/-1.2; PR classes: mean change 0.8+/-1.0). However, there were no significant differences between the groups in any outcome. Dropout rates were higher in the web-based programme (57% vs 23%). CONCLUSIONS: An interactive web-based PR programme is feasible and acceptable when compared with conventional PR. Future trials maybe around choice-based PR programmes for select patients enabling stratification of patient care. TRIAL REGISTRATION NUMBER: ISRCTN03142263; Results. PMID- 28363924 TI - Tobacco control environment: cross-sectional survey of policy implementation, social unacceptability, knowledge of tobacco health harms and relationship to quit ratio in 17 low-income, middle-income and high-income countries. AB - OBJECTIVES: This study examines in a cross-sectional study 'the tobacco control environment' including tobacco policy implementation and its association with quit ratio. SETTING: 545 communities from 17 high-income, upper-middle, low middle and low-income countries (HIC, UMIC, LMIC, LIC) involved in the Environmental Profile of a Community's Health (EPOCH) study from 2009 to 2014. PARTICIPANTS: Community audits and surveys of adults (35-70 years, n=12 953). PRIMARY AND SECONDARY OUTCOME MEASURES: Summary scores of tobacco policy implementation (cost and availability of cigarettes, tobacco advertising, antismoking signage), social unacceptability and knowledge were associated with quit ratios (former vs ever smokers) using multilevel logistic regression models. RESULTS: Average tobacco control policy score was greater in communities from HIC. Overall 56.1% (306/545) of communities had >2 outlets selling cigarettes and in 28.6% (154/539) there was access to cheap cigarettes (<5cents/cigarette) (3.2% (3/93) in HIC, 0% UMIC, 52.6% (90/171) LMIC and 40.4% (61/151) in LIC). Effective bans (no tobacco advertisements) were in 63.0% (341/541) of communities (81.7% HIC, 52.8% UMIC, 65.1% LMIC and 57.6% LIC). In 70.4% (379/538) of communities, >80% of participants disapproved youth smoking (95.7% HIC, 57.6% UMIC, 76.3% LMIC and 58.9% LIC). The average knowledge score was >80% in 48.4% of communities (94.6% HIC, 53.6% UMIC, 31.8% LMIC and 35.1% LIC). Summary scores of policy implementation, social unacceptability and knowledge were positively and significantly associated with quit ratio and the associations varied by gender, for example, communities in the highest quintile of the combined scores had 5.0 times the quit ratio in men (Odds ratio (OR) 5.0, 95% CI 3.4 to 7.4) and 4.1 times the quit ratio in women (OR 4.1, 95% CI 2.4 to 7.1). CONCLUSIONS: This study suggests that more focus is needed on ensuring the tobacco control policy is actually implemented, particularly in LMICs. The gender-related differences in associations of policy, social unacceptability and knowledge suggest that different strategies to promoting quitting may need to be implemented in men compared to women. PMID- 28363925 TI - Methods to decrease variability in histological scoring in placentas from a cohort of preterm infants. AB - OBJECTIVE: Reliable semiquantitative assessment of histological placental acute inflammation is problematic, even among experts. Tissue samples in histology slides often show variability in the extent and location of neutrophil infiltrates. We sought to determine whether the variability in pathologists' scoring of neutrophil infiltrates in the placenta could be reduced by the use of 'regions of interest' (ROIs) that break the sample into smaller components. DESIGN: ROIs were identified within stained H&E slides from a cohort of 56 women. ROIs were scored using a semiquantitative scale (0-4) for the average number of neutrophils by at least two independent raters. SETTING: Preterm singleton births at Yale New Haven Hospital. PARTICIPANTS: This study used stained H&E placental slides from a cohort of 56 women with singleton pregnancies who had a clinically indicated amniocentesis within 24 hours of delivery. PRIMARY AND SECONDARY OUTCOME MEASURES: Interrater agreement was assessed with the intraclass correlation coefficient (ICC) and log-linear regression. Predictive validity was assessed using amniotic fluid protein profile scores (neutrophil defensin-2, neutrophil defensin-1, calgranulin C and calgranulin A). RESULTS: Excellent agreement by the ICC was found for the average neutrophil scores within a region of interest. Log-linear analyses suggest that even where there is disagreement, responses are positively associated along the diagonal. There was also strong evidence of predictive validity comparing pathologists' scores with amniotic fluid protein profile scores. CONCLUSIONS: Agreement among observers of semiquantitative neutrophil scoring through the use of digitised ROIs was demonstrated to be feasible with high reliability and validity. PMID- 28363926 TI - Measles outbreaks in the UK, is it when and where, rather than if? A database cohort study of childhood population susceptibility in Liverpool, UK. AB - OBJECTIVES: There was a large outbreak of measles in Liverpool, UK, in 2012-2013, despite measles, mumps and rubella (MMR) immunisation uptake rates that were higher than the national average. We estimated measles susceptibility of a cohort of children born in Liverpool between 1995 and 2012 to understand whether there was a change in susceptibility before and after the outbreak and to inform vaccination strategy. DESIGN: Retrospective cohort study. SETTING: The city of Liverpool, North West UK. PARTICIPANTS: All children born in Liverpool (72 101) between 1995 and 2012 inclusive who were identified using the Child Health Information System (CHIS) and were still resident within Liverpool in 2014. PRIMARY AND SECONDARY OUTCOME MEASURES: We estimated cohort age-disaggregated and neighbourhood-disaggregated measles susceptibility according to WHO thresholds before and after the outbreak for children aged 1-17 years. RESULTS: Susceptibility to measles was above WHO elimination thresholds before and after the measles outbreak in the 10+ age group. The proportion of children susceptible before and after outbreak, respectively: age 1-4 years 15.0% before and 14.9% after; age 5-9 years 9.9% before and 7.7% after; age 10+ years 8.6% before and 8.5% after. Despite an intensive MMR immunisation catch-up campaign after the 2012-2013 measles outbreak, the overall proportion of children with no MMR remains high at 6.1% (4390/72 351). Across all age groups and before and after the outbreak, measles susceptibility was clustered by neighbourhood, with deprived areas having the greatest proportion of susceptible children. CONCLUSIONS: The risk of sustained measles outbreaks remains, especially as large pools of susceptible older children will start leaving secondary education and continue to aggregate in higher education, employment and other community settings and institutions resulting in the potential for a propagated measles outbreak. PMID- 28363927 TI - Ongoing university studies and the risk of suicide: a register-based nationwide cohort study of 5 million young and middle-aged individuals in Sweden, 1993-2011. AB - OBJECTIVES: To investigate the risk of suicide, unnatural death and all-cause death in university students compared with non-students, taking previous educational attainment into account. DESIGN: Open cohort study of all residents aged 18-39 and living in Sweden at any time between 1 January 1993 and 31 December 2011. SETTING: We linked data from national registers and calculated person-years during university studies for three time periods (1993-1999, 2000 2005 and 2006-2011). Time as non-student was calculated and categorised according to attained educational level. Incidence rate ratios (IRR) with 95% CIs were calculated with Poisson regression models, controlling for age and period. PARTICIPANTS: The cohort consisted of 5 039 419 individuals, 51% men and 49% women. MAIN OUTCOME MEASURES: Incidence of suicide (International Classification of Diseases (ICD)-9: E950-E959, ICD-10: X60-X84) or death with undetermined intent (ICD-9: E980-E989, ICD-10: Y10-Y34), unnatural death (ICD-9: E800-E999 and ICD-10: V01-Y99) and all-cause death. RESULTS: A total of 7316 deaths due to suicide were identified, of which 541 were registered among university students. The risk of suicide was twofold during ongoing university studies compared with when having attained university education, IRR 2.37 (95% CI 2.07 to 2.72) in men and IRR 2.15 (95% CI 1.77 to 2.61) in women. CONCLUSIONS: Having ongoing university studies was associated with a higher risk of suicide compared with having attained university-level education. This finding highlights the importance of achieving a deeper understanding of suicidal behaviour during years at university. Further studies should assess risk factors for suicide and suicidal behaviour in university students. PMID- 28363928 TI - Atraumatic versus traumatic lumbar puncture needles: a systematic review and meta analysis protocol. AB - INTRODUCTION: Lumbar puncture is one of the oldest and most commonly performed procedures in medicine, used to diagnose and treat disease. Headache following lumbar puncture remains a frequent complication, causing significant patient discomfort and often requiring narcotic analgesia or invasive therapy. Needle tip design has been proposed to affect the incidence of headache postlumbar puncture, with pencil-point 'atraumatic' needles thought to reduce its incidence in comparison to bevelled 'traumatic' needles. Despite this, the use of atraumatic needles and knowledge of their existence remains significantly limited among clinicians. This study will systematically review the evidence on atraumatic lumbar puncture needles and compare them with traumatic needles across a variety of clinical outcomes. METHODS AND ANALYSES: We will include published randomised controlled trials (RCTs), observational studies and abstracts, with no publication type or language restrictions. Search strategies will be designed to peruse the MEDLINE, EMBASE, Web of Science, ClinicalTrials.gov, CINAHL, WHO Clinical Trials Database and Cochrane Library databases. We will also implement strategies to search the grey literature. 3 reviewers will thoroughly and independently examine the search results, complete data abstraction and conduct quality assessment. Included RCTs will be assessed using the Cochrane risk of bias assessment tool and eligible observational studies will be examined using the Newcastle-Ottawa Scale. We will examine the outcomes of: headache and its type, intensity, duration and treatment; backache; success rate; hearing disturbance and nerve root irritation. The primary outcome will be the incidence of postdural puncture headache. We will calculate pooled estimates, relative risks for dichotomous outcomes and weighted mean differences for continuous outcomes, with corresponding 95% CIs. Statistical heterogeneity will be measured using Cochran's Q test and quantified using the I2 statistic. We will also conduct prespecified subgroup and sensitivity analyses to examine if covariates exist and to explore potential heterogeneity. ETHICS AND DISSEMINATION: Research ethics board approval is not required for this study as it draws from published data and raises no concerns related to patient privacy. This review will provide a comprehensive assessment of the evidence on atraumatic needles for lumbar puncture and is directed to a wide audience. Results from the review will be disseminated extensively through conferences and submitted to a peer-reviewed journal for publication. TRIAL REGISTRATION NUMBER: CRD42016047546. PMID- 28363929 TI - Tobacco and alcohol use among drug users receiving methadone maintenance treatment: a cross-sectional study in a rural prefecture of Yunnan Province, Southwest China. AB - OBJECTIVE: To estimate the prevalence of ever, current and heavy tobacco and alcohol use and their correlates among patients undergoing methadone maintenance treatment (MMT). DESIGN: Cross-sectional study. SETTING: The study was conducted in all of the 5 MMT clinics in Dehong Prefecture, China. PARTICIPANTS: 2121 (81.6%) eligible MMT participants were included in the study population. ANALYSIS: Ordinal logistic regression was used to estimate the ORs and their 95% CIs. RESULTS: The overall prevalence of ever, current and heavy smoking was 98.6%, 97.8% and 66.3%, respectively; while that of ever, current and hazardous alcohol drinking was 86.6%, 58.6% and 16.6%, respectively. Among HIV-infected participants, the proportions of those experiencing harmful effects of tobacco and alcohol on AIDS were 53.6% and 72.5%, respectively, and 16.9% and 49.3% had ever tried to quit after diagnosis with HIV. After adjusting for potential confounders, heavier smokers and more hazardous drinkers were more likely to be men, older and less educated. Ethnic minorities were less likely to heavily smoke, but more likely to engage in hazardous drinking. In addition, hazardous drinking was negatively associated with longer years of MMT and HIV infection. Moreover, heavier smoking (OR>=2=2.08, 95% CI 1.16 to 3.73) and more hazardous drinking (OR>=2=2.46, 95% CI 1.53 to 3.97) were positively associated with having multiple sexual partners, and both were positively associated with each other. CONCLUSIONS: The prevalence of tobacco and alcohol consumption was extraordinarily high among MMT participants in China, suggesting the urgent need of enhancing MMT patients' awareness of the harmful effects of tobacco and alcohol consumption and implementing comprehensive education and effective intervention programmes. PMID- 28363931 TI - Adult children's socioeconomic resources and mothers' survival after a breast cancer diagnosis: a Swedish population-based cohort study. AB - OBJECTIVES: Socioeconomic inequalities in survival after breast cancer persist worldwide. We aim to determine whether adult offspring's socioeconomic resources contribute to inequalities in mothers' survival after breast cancer. METHODS: 14 231 women, aged 65-79 years, with a child aged >=30 years and a first primary diagnosis of breast cancer in the National Cancer Register between 2001 and 2010 were followed until death, 10 years after diagnosis, or end of study (December 2015). Relative survival proportions and excess mortality within 10 years of diagnosis by strata of offspring's education level and disposable income were estimated using flexible parametric models accounting for measures of mothers' socioeconomic position and expected mortality in the general population. RESULTS: 4292 women died during 102 236 person-years of follow-up. Crude 10-year relative survival proportions for mothers of children with >14, 12-14 and <12 years of education were 0.89 (0.87 to 0.91), 0.87 (0.85 to 0.89) and 0.79 (0.76 to 0.81), respectively. Compared with mothers of children with >14 years of education, mothers of children with <12 or 12-14 years of education had substantially higher excess mortality (excess HR 1.69 (1.38 to 2.07) and 1.22 (1.00 to 1.48), respectively). Higher mortality did not differ between tertiles of offspring's disposable income. CONCLUSIONS: Adult offspring's education level may contribute to inequalities in mothers' survival after breast cancer. Clinicians should be aware of the educational context beyond the individual and women with less educated offsprings may require extra support. This should be considered in future research, policy frameworks and interventions aimed at reducing survival inequalities. PMID- 28363930 TI - What are the physical and psychological health effects of suicide bereavement on family members? Protocol for an observational and interview mixed-methods study in Ireland. AB - INTRODUCTION: Research indicates that experiencing the suicide of a relative can have a significant impact on family members' emotional health. However, research incorporating the impact of suicide bereavement on family members' physical health is sparse. This paper details the protocol for a mixed-methods study of suicide-bereaved family members. The study will primarily examine the physical and mental health needs of those bereaved by suicide. A secondary objective of the study is to describe the support service needs of family members bereaved by suicide. METHODS AND ANALYSIS: A mixed-methods approach, using semistructured interviews and self-report questionnaires, will be used. Interviews will be conducted with a group of 15-20 relatives who experienced suicide bereavement. This protocol will follow the COREQ checklist criteria for the reporting of qualitative research interviews. Thematic analysis will be used to examine experiences and impact of bereavement on psychological and physical health. Self report quantitative data on well-being will be analysed using descriptive statistics. ETHICS AND DISSEMINATION: Ethical approval to conduct this study has been granted from the Clinical Research Ethics Committee of the Cork Teaching Hospitals. Pseudonyms will be given to participants to protect anonymity. It will be explained to participants that participation in the study is voluntary and they have to right to withdraw at any time. The findings of this research will be disseminated to regional, national and international audiences through publication in peer-reviewed international journals and presentations at scientific conferences. This research also forms part of a PhD thesis. PMID- 28363932 TI - Patient-reported outcome measures for monitoring primary care patients with depression: PROMDEP feasibility randomised trial. AB - OBJECTIVES: To determine the feasibility of a trial of patient-reported outcome measures (PROMs) for monitoring primary care patients with depression. DESIGN: Partly individually randomised, partly cluster-randomised controlled trial. SETTING: Nine general practices in Southern England. PARTICIPANTS: 47 adults with new episodes of depression: 22 intervention, 25 control. RANDOMISATION: Remote computerised sequence generation and allocation. INTERVENTIONS: Patient Health Questionnaire, Distress Thermometer Analogue Scale and PSYCHLOPS problem profile for monitoring depression, following diagnosis and at 10-35 days later. Feedback of scores to patients was determined by practitioners. BLINDING: Non-blinded, using self-completed measures. PRIMARY OUTCOME: Beck Depression Inventory (BDI II). SECONDARY OUTCOME MEASURES: Work and Social Adjustment Scale (WSAS), EuroQol Five-item, Five-level (EQ-5D-5L) Scale for quality of life, modified Client Service Receipt Inventory for costs, Medical Informant Satisfaction Scale (MISS), qualitative interviews with 14 patients and 13 practice staff about feasibility and acceptability of trial design. RESULTS: Three practices failed to recruit the target of six patients in 12 months. Follow-up rates were intervention patients: 18 (82%) at 12 weeks and 15 (68%) at 26 weeks; controls: 18 (72%) and 15 (60%), respectively. At 12 weeks, mean BDI-II score was lower among intervention group patients than controls by 5.8 points (95% CI -11.1 to -0.5), adjusted for baseline differences and clustering. WSAS scores were not significantly different. At 26 weeks, there were no significant differences in symptoms, social functioning, quality of life or costs, but mean satisfaction score was higher among controls by 22.0 points (95% CI -40.7 to -3.29). Intervention patients liked completing PROMs, but were disappointed when practitioners did not use the results to inform management. CONCLUSIONS: PROMs may improve depression outcome in the short term, even if PROM scores do not inform practitioners' management. Challenges in recruiting and following up patients need addressing for a definitive trial of relatively brief measures which can potentially inform management. https://www.isrctn.com/search?q=97492541 TRIAL REGISTRATION NUMBER: ISRCTN 97492541; Pre-results. PMID- 28363934 TI - Positive and negative roles of p85alpha and p85beta regulatory subunits of phosphoinositide 3-kinase in insulin signaling. PMID- 28363935 TI - POZ-, AT-hook-, and zinc finger-containing protein (PATZ) interacts with the human oncogene B cell lymphoma 6 (BCL6) and is required for its negative autoregulation. PMID- 28363933 TI - Feasibility of melatonin for prevention of delirium in critically ill patients: a protocol for a multicentre, randomised, placebo-controlled study. AB - INTRODUCTION: Delirium is highly prevalent in the intensive care unit (ICU) and is associated with adverse clinical outcomes. At this time, there is no drug that effectively prevents delirium in critically ill patients. Alterations in melatonin secretion and metabolism may contribute to the development of delirium. Administration of exogenous melatonin has been shown to prevent delirium in non critically ill surgical and medical patients. This trial will demonstrate the feasibility of a planned multicentre, randomised controlled trial to test the hypothesis that melatonin can prevent delirium in critically ill patients compared with placebo. METHODS AND ANALYSIS: This feasibility trial is a randomised, 3-arm, placebo-controlled study of melatonin (2 vs 0.5 mg vs placebo, administered for a maximum of 14 days) for the prevention of delirium in critically ill patients. A total of 69 patients aged 18 years and older with an expected ICU length of stay >48 hours will be recruited from 3 Canadian ICUs. The primary outcome is protocol adherence (ie, overall proportion of study drug doses administered in the prescribed administration window). Secondary outcomes include pharmacokinetic parameters, incidence, time to onset, duration of delirium, number of delirium-free days, adverse events, self-reported sleep quality, rest activity cycles measured by wrist actigraphy, duration of mechanical ventilation, ICU length of stay and mortality. Data will be analysed using an intention-to treat approach. ETHICS AND DISSEMINATION: The study has been approved by Health Canada and the research ethics board of each study site. Trial results will be presented at international conferences and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT02615340: Pre-results. PMID- 28363936 TI - omega- versus (omega-1)-hydroxylation: Cytochrome P450 4B1 sterics make the call. AB - Many family 4 cytochrome P450s play key roles in fatty acid hydroxylation at the terminal, or omega, carbon, but the mechanistic basis for this energetically disfavored regiostereochemistry has been less clear. A co-crystal structure of the rabbit family 4 enzyme CYP4B1 with its substrate octane reveals that the propensity for omega-hydroxylation is orchestrated by active-site sterics, partially mediated by an unusual heme-polypeptide ester bond. PMID- 28363937 TI - Elective surgery targets scrapped in favour of better cancer and A&E services. PMID- 28363940 TI - Government "must get tough" on food companies that miss sugar reduction targets. PMID- 28363938 TI - Somatic mosaicism containing double mutations in PTCH1 revealed by generation of induced pluripotent stem cells from nevoid basal cell carcinoma syndrome. AB - BACKGROUND: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterised by developmental defects and tumorigenesis, such as medulloblastomas and basal cell carcinomas, caused by mutations of the patched-1 (PTCH1) gene. In this article, we seek to demonstrate a mosaicism containing double mutations in PTCH1 in an individual with NBCCS. METHODS AND RESULTS: A de novo germline mutation of PTCH1 (c.272delG) was detected in a 31-year-old woman with NBCCS. Gene analysis of two out of four induced pluripotent stem cell (iPSC) clones established from the patient unexpectedly revealed an additional mutation, c.274delT. Deep sequencing confirmed a low-prevalence somatic mutation (5.5% 15.6% depending on the tissue) identical to the one found in iPSC clones. CONCLUSIONS: This is the first case of mosaicism unequivocally demonstrated in NBCCS. Furthermore, the mosaicism is unique in that the patient carries one normal and two mutant alleles. Because these mutations are located in close proximity, reversion error is likely to be involved in this event rather than a spontaneous mutation. In addition, this study indicates that gene analysis of iPSC clones can contribute to the detection of mosaicism containing a minor population carrying a second mutation. PMID- 28363939 TI - Nasopharyngeal microbiome in premature infants and stability during rhinovirus infection. AB - RATIONALE: The nasopharyngeal (NP) microbiota of newborns and infants plays a key role in modulating airway inflammation and respiratory symptoms during viral infections. Premature (PM) birth modifies the early NP environment and is a major risk factor for severe viral respiratory infections. However, it is currently unknown if the NP microbiota of PM infants is altered relative to full-term (FT) individuals. OBJECTIVES: To characterize the NP microbiota differences in preterm and FT infants during rhinovirus (RV) infection. METHODS: We determined the NP microbiota of infants 6 months to <=2 years of age born FT (n=6) or severely PM<32 weeks gestation (n=7). We compared microbiota composition in healthy NP samples and performed a longitudinal analysis during naturally occurring RV infections to contrast the microbiota dynamics in PM versus FT infants. RESULTS: We observed significant differences in the NP bacterial community of PM versus FT. NP from PM infants had higher within-group dissimilarity (heterogeneity) relative to FT infants. Bacterial composition of NP samples from PM infants showed increased Proteobacteria and decreased in Firmicutes. There were also differences in the major taxonomic groups identified, including Streptococcus, Moraxella, and Haemophilus. Longitudinal data showed that these prematurity related microbiota features persisted during RV infection. CONCLUSIONS: PM is associated with NP microbiota changes beyond the neonatal stage. PM infants have an NP microbiota with high heterogeneity relative to FT infants. These prematurity-related microbiota features persisted during RV infection, suggesting that the NP microbiota of PM may play an important role in modulating airway inflammatory and immune responses in this vulnerable group. PMID- 28363944 TI - Patient safety test will be part of NHS staff appraisals from 2018. PMID- 28363943 TI - Rae1/YacP, a new endoribonuclease involved in ribosome-dependent mRNA decay in Bacillus subtilis. AB - The PIN domain plays a central role in cellular RNA biology and is involved in processes as diverse as rRNA maturation, mRNA decay and telomerase function. Here, we solve the crystal structure of the Rae1 (YacP) protein of Bacillus subtilis, a founding member of the NYN (Nedd4-BP1/YacP nuclease) subfamily of PIN domain proteins, and identify potential substrates in vivo Unexpectedly, degradation of a characterised target mRNA was completely dependent on both its translation and reading frame. We provide evidence that Rae1 associates with the B. subtilis ribosome and cleaves between specific codons of this mRNA in vivo Critically, we also demonstrate translation-dependent Rae1 cleavage of this substrate in a purified translation assay in vitro Multiple lines of evidence converge to suggest that Rae1 is an A-site endoribonuclease. We present a docking model of Rae1 bound to the B. subtilis ribosomal A-site that is consistent with this hypothesis and show that Rae1 cleaves optimally immediately upstream of a lysine codon (AAA or AAG) in vivo. PMID- 28363946 TI - Emergence of new-onset psychotic disorder following recovery from LGI1 antibody associated limbic encephalitis. AB - Neuronal autoantibodies targeting cell surface antigens have been described in association with autoimmune encephalitides which frequently feature psychosis and other psychiatric disturbances alongside neurological signs and symptoms. Little has been written however about the long-term psychiatric status of individuals following recovery from the acute phase of autoimmune encephalitis, despite case series and anecdotal evidence suggesting this may be a cause of considerable disability. Here, we describe a man aged 58 years with no psychiatric history who developed a severe and acute psychotic disorder following resolution of a protracted course of limbic encephalitis associated with antibodies to leucine rich glioma inactivated 1 protein. No indications of a gross ongoing inflammatory or encephalopathic process were present at presentation of his psychosis. Possible aetiologies of his acute psychosis are discussed. This case highlights the importance of ongoing psychiatric follow-up of patients following an episode of autoimmune encephalitis. PMID- 28363945 TI - Successful treatment of multidrug-resistant Pseudomonas aeruginosa pubic symphysis osteomyelitis with ceftolozane/tazobactam. AB - New antibiotic options are needed for the treatment of multidrug-resistant (MDR) Pseudomonas infections. We present a case of a man aged 64 years with a bladder fistula due to radiation, ultimately causing osteomyelitis of the pubic symphysis. Repeated antibiotic courses, without correcting the fistula, resulted in infection with MDR Pseudomonas aeruginosa. He was successfully treated for his osteomyelitis through cystectomy, aggressive debridement and a prolonged course of antimicrobials directed at the MDR Pseudomonas isolate. PMID- 28363947 TI - Antimitochondrial antibodies-positive myositis accompanied by cardiac involvement. AB - We report a 55-year-old man who experienced proximal muscle weakness accompanied by the atrial flutter (AFL) with 1:1 conduction. Detailed examination revealed elevated antimitochondrial antibodies (AMA) and creatine kinase (CK). AFL was converted to sinus rhythm by cardioversion. He was diagnosed as AMA-positive myositis-associated AFL and was treated by prednisolone. Although his muscle weakness and CK level improved, AFL with 1:1 conduction reappeared. Therefore, radiofrequency catheter ablation (RFCA) was needed to treat the AFL, resulting in maintenance of sinus rhythm. This case report describes cardiac involvement in a patient with AMA-positive myositis. PMID- 28363942 TI - USP49 negatively regulates tumorigenesis and chemoresistance through FKBP51-AKT signaling. AB - The AKT pathway is a fundamental signaling pathway that mediates multiple cellular processes, such as cell proliferation and survival, angiogenesis, and glucose metabolism. We recently reported that the immunophilin FKBP51 is a scaffolding protein that can enhance PHLPP-AKT interaction and facilitate PHLPP mediated dephosphorylation of AKT at Ser473, negatively regulating AKT activation. However, the regulation of FKBP51-PHLPP-AKT pathway remains unclear. Here we report that a deubiquitinase, USP49, is a new regulator of the AKT pathway. Mechanistically, USP49 deubiquitinates and stabilizes FKBP51, which in turn enhances PHLPP's capability to dephosphorylate AKT Furthermore, USP49 inhibited pancreatic cancer cell proliferation and enhanced cellular response to gemcitabine in a FKBP51-AKT-dependent manner. Clinically, decreased expression of USP49 in patients with pancreatic cancer was associated with decreased FKBP51 expression and increased AKT phosphorylation. Overall, our findings establish USP49 as a novel regulator of AKT pathway with a critical role in tumorigenesis and chemo-response in pancreatic cancer. PMID- 28363948 TI - False-negative contrast-enhanced spectral mammography: use of more than one imaging modality and application of the triple test avoids misdiagnosis. AB - A 50-year-old woman presented with chest tenderness. On examination, both breasts were lumpy. Bilateral mammography showed heterogeneously dense parenchyma, with possible stromal distortion laterally on the right at the 0900 position. On ultrasound (US), a corresponding 13*9*10 mm irregular hypoechoic mass with internal vascularity was noted and both breasts had a complex heterogeneous fibroglandular background pattern. US-guided core biopsy with marker clip insertion was performed with the diagnosis of a grade 2 invasive ductal carcinoma (IDC). In view of the parenchymal pattern on mammography and US, contrast enhanced spectral mammography (CESM) was performed for local staging. Mild background enhancement was noted, but there was no enhancement at the lesion site. The patient elected to have bilateral mastectomies and sentinel node biopsies. Final histopathology showed a node negative 11 mm grade 2 oestrogen and progesterone receptor positive, IDC. PMID- 28363949 TI - Incidental finding of anomalous circumflex coronary artery from right coronary sinus prior to aortic valve surgery. AB - Anomalous origin of the left circumflex (Cx) artery is a common and mostly benign coronary artery anomaly. We report the case of a man aged 52 years who presented to his local hospital with progressive breathlessness on exertion and syncopal episodes. His admission transthoracic echocardiography (TTE) showed bicuspid aortic valve, severe aortic stenosis with a valve area of 0.5 cm2 and his left ventricular ejection fraction (LVEF) was 27%. His coronary angiogram showed normal coronary arteries but anomalous origin of the Cx artery from the right coronary. He underwent elective bioprosthetic aortic valve replacement. His postoperative recovery was uneventful and he was discharged on day 5 postoperatively. His TTE postoperatively showed well-seated aortic valve, improved LVEF to 51%. We here report a case of incidental finding of anomalous Cx artery arising from the right coronary while the patient is being worked up for aortic valve replacement for congenital bicuspid aortic valve. PMID- 28363952 TI - CD73-derived adenosine and tenascin-C control cytokine production by epicardium derived cells formed after myocardial infarction. AB - Epicardium-derived cells (EPDCs) play a fundamental role in embryonic cardiac development and are reactivated in the adult heart in response to myocardial infarction (MI). In this study, EPDCs from post-MI rat hearts highly expressed the ectoenzyme CD73 and secreted the profibrotic matricellular protein tenascin-C (TNC). CD73 on EPDCs extensively generated adenosine from both extracellular ATP and NAD. This in turn stimulated the release of additional nucleotides from a Brefeldin A-sensitive intracellular pool via adenosine-A2BR signaling, forming a positive-feedback loop. A2BR activation, in addition, strongly promoted the release of major regulatory cytokines, such as IL-6, IL-11, and VEGF. TNC was found to stimulate EPDC migration and, together with ATP-P2X7R signaling, to activate inflammasomes in EPDCs via TLR4. Our results demonstrate that EPDCs are an important source of various proinflammatory factors in the post-MI heart controlled by purinergic and TNC signaling.-Hesse, J., Leberling, S., Boden, E., Friebe, D., Schmidt, T., Ding, Z., Dieterich, P., Deussen, A., Roderigo, C., Rose, C. R., Floss, D. M., Scheller, J., Schrader, J. CD73-derived adenosine and tenascin-C control cytokine production by epicardium-derived cells formed after myocardial infarction. PMID- 28363953 TI - Avathrin: a novel thrombin inhibitor derived from a multicopy precursor in the salivary glands of the ixodid tick, Amblyomma variegatum. AB - Tick saliva is a rich source of antihemostatic compounds. We amplified a cDNA from the salivary glands of the tropical bont tick (Amblyomma variegatum) using primers based on the variegin sequence, which we previously identified as a novel thrombin inhibitor from the same tick species. The transcript encodes a precursor protein comprising a signal peptide and 5 repeats of variegin-like sequences that could be processed into multiple short peptides. These peptides share 31 to 34% identity with variegin. Here, we structurally and functionally characterized one of these peptides named "avathrin." Avathrin is a fast, tight binding competitive inhibitor with an affinity of 545 pM for thrombin and is 4 orders of magnitude more selective towards thrombin than to the other serine proteases of the coagulation cascade. The crystal structure of thrombin-avathrin complex at 2.09 A revealed that avathrin interacts with the thrombin active site and exosite-I. Although avathrin is cleaved by thrombin, the C-terminal cleavage product continues to exert prolonged inhibition. Avathrin is more potent than hirulog-1 in a murine carotid artery thrombosis model. Such precursor proteins that could be processed into multiple thrombin inhibiting peptides appear to be widespread among Amblyomminae, providing an enormous library of molecules for development as potent antithrombotics.-Iyer, J. K., Koh, C. Y., Kazimirova, M., Roller, L., Jobichen, C., Swaminathan, K., Mizuguchi, J., Iwanaga, S., Nuttall, P. A., Chan, M. Y., Kini, R. M. Avathrin: a novel thrombin inhibitor derived from a multicopy precursor in the salivary glands of the ixodid tick, Amblyomma variegatum. PMID- 28363954 TI - Estrogen deficiency attenuates fluid flow-induced [Ca2+]i oscillations and mechanoresponsiveness of MLO-Y4 osteocytes. AB - It has been proposed that estrogen regulates the mechanosensitivity of osteocytes; however, the effects of estrogen deficiency that arises during postmenopausal osteoporosis on mechanical stimulation-induced calcium signaling in osteocytes remain elusive. Here, we pretreated MLO-Y4 osteocytes with 10 nM E2 for 2, 3 and 5 d, then simulated postmenopausal conditions either by estrogen withdrawal (EW) from culture medium, or by inhibiting the estrogen receptor by using fulvestrant and estrogen (FE; ICI 182,780) in vitro We investigated [Ca2+]i oscillations and mechanobiologic responses of osteocytes (EW and FE) that were exposed to oscillatory fluid flow (OFF; 1 Pa, 0.5 Hz). We demonstrated that estrogen treatment enhanced OFF-induced [Ca2+]i oscillations and that this effect was abrogated both by FE and EW. Moreover, osteocytes in both estrogen-depleted groups (EW and FE) had reduced levels of NO and prostaglandin E2 release, down regulated dentin matrix protein-1, sclerostin, osteopontin, osteocalcin, and alkaline phosphatase mRNA expression, and reduced F-actin fiber formation after OFF stimulation compared with estrogen-treated cells. We propose a link between estrogen deficiency and alterations in [Ca2+]i-mediated mechanosensitivity of osteocytes, which ultimately alter osteocyte function and differentiation. Deepak, V., Kayastha, P., McNamara, L. M. Estrogen deficiency attenuates fluid flow-induced [Ca2+]i oscillations and mechanoresponsiveness of MLO-Y4 osteocytes. PMID- 28363956 TI - Facial palsy in a baby with acute otitis media. PMID- 28363955 TI - Dendritic cells, engineered to overexpress 25-hydroxyvitamin D 1alpha-hydroxylase and pulsed with a myelin antigen, provide myelin-specific suppression of ongoing experimental allergic encephalomyelitis. AB - Multiple sclerosis (MS) is caused by immune-mediated damage of myelin sheath. Current therapies aim to block such immune responses. However, this blocking is not sufficiently specific and hence compromises immunity, leading to severe side effects. In addition, blocking medications usually provide transient effects and require frequent administration, which further increases the chance to compromise immunity. In this regard, myelin-specific therapy may provide the desired specificity and a long-lasting therapeutic effect by inducing myelin-specific regulatory T (Treg) cells. Tolerogenic dendritic cells (TolDCs) are one such therapy. However, ex vivo generated TolDCs may be converted into immunogenic DCs in a proinflammatory environment. In this study, we identified a potential novel myelin-specific therapy that works with immunogenic DCs, hence without the in vivo conversion concern. We showed that immunization with DCs, engineered to overexpress 25-hydroxyvitamin D 1alpha-hydroxylase for de novo synthesis of a focally high 1,25-dihydroxyvitamin D concentration in the peripheral lymphoid tissues, induced Treg cells. In addition, such engineered DCs, when pulsed with a myelin antigen, led to myelin-specific suppression of ongoing experimental allergic encephalomyelitis (an MS animal model), and the disease suppression depended on forkhead-box-protein-P3(foxp3)+ Treg cells. Our data support a novel concept that immunogenic DCs can be engineered for myelin-specific therapy for MS.-Li, C.-H., Zhang, J., Baylink, D. J., Wang, X., Goparaju, N. B., Xu, Y., Wasnik, S., Cheng, Y., Berumen, E. C., Qin, X., Lau, K.-H. W., Tang, X. Dendritic cells, engineered to overexpress 25-hydroxyvitamin D 1alpha-hydroxylase and pulsed with a myelin antigen, provide myelin-specific suppression of ongoing experimental allergic encephalomyelitis. PMID- 28363957 TI - Structure-Based Engineering of an Artificially Generated NADP+-Dependent d-Amino Acid Dehydrogenase. AB - A stable NADP+-dependent d-amino acid dehydrogenase (DAADH) was recently created from Ureibacillus thermosphaericusmeso-diaminopimelate dehydrogenase through site directed mutagenesis. To produce a novel DAADH mutant with different substrate specificity, the crystal structure of apo-DAADH was determined at a resolution of 1.78 A, and the amino acid residues responsible for the substrate specificity were evaluated using additional site-directed mutagenesis. By introducing a single D94A mutation, the enzyme's substrate specificity was dramatically altered; the mutant utilized d-phenylalanine as the most preferable substrate for oxidative deamination and had a specific activity of 5.33 MUmol/min/mg at 50 degrees C, which was 54-fold higher than that of the parent DAADH. In addition, the specific activities of the mutant toward d-leucine, d-norleucine, d methionine, d-isoleucine, and d-tryptophan were much higher (6 to 25 times) than those of the parent enzyme. For reductive amination, the D94A mutant exhibited extremely high specific activity with phenylpyruvate (16.1 MUmol/min/mg at 50 degrees C). The structures of the D94A-Y224F double mutant in complex with NADP+ and in complex with both NADPH and 2-keto-6-aminocapronic acid (lysine oxo analogue) were then determined at resolutions of 1.59 A and 1.74 A, respectively. The phenylpyruvate-binding model suggests that the D94A mutation prevents the substrate phenyl group from sterically clashing with the side chain of Asp94. A structural comparison suggests that both the enlarged substrate-binding pocket and enhanced hydrophobicity of the pocket are mainly responsible for the high reactivity of the D94A mutant toward the hydrophobic d-amino acids with bulky side chains.IMPORTANCE In recent years, the potential uses for d-amino acids as source materials for the industrial production of medicines, seasonings, and agrochemicals have been growing. To date, several methods have been used for the production of d-amino acids, but all include tedious steps. The use of NAD(P)+ dependent d-amino acid dehydrogenase (DAADH) makes single-step production of d amino acids from oxo-acid analogs and ammonia possible. We recently succeeded in creating a stable DAADH and demonstrated that it is applicable for one-step synthesis of d-amino acids, such as d-leucine and d-isoleucine. As the next step, the creation of an enzyme exhibiting different substrate specificity and higher catalytic efficiency is a key to the further development of d-amino acid production. In this study, we succeeded in creating a novel mutant exhibiting extremely high catalytic activity for phenylpyruvate amination. Structural insight into the mutant will be useful for further improvement of DAADHs. PMID- 28363958 TI - Toxicity and Binding Studies of Bacillus thuringiensis Cry1Ac, Cry1F, Cry1C, and Cry2A Proteins in the Soybean Pests Anticarsia gemmatalis and Chrysodeixis (Pseudoplusia) includens. AB - Anticarsia gemmatalis (velvetbean caterpillar) and Chrysodeixis includens (soybean looper, formerly named Pseudoplusia includens) are two important defoliating insects of soybeans. Both lepidopteran pests are controlled mainly with synthetic insecticides. Alternative control strategies, such as biopesticides based on the Bacillus thuringiensis (Bt) toxins or transgenic plants expressing Bt toxins, can be used and are increasingly being adopted. Studies on the insect susceptibilities and modes of action of the different Bt toxins are crucial to determine management strategies to control the pests and to delay outbreaks of insect resistance. In the present study, the susceptibilities of both soybean pests to the Bt toxins Cry1Ac, Cry1Fa, Cry1Ca, and Cry2Aa have been investigated. Bioassays performed in first-instar larvae showed that both insects are susceptible to all these toxins. Competition-binding studies carried out with Cry1Ac and Cry1Fa 125-iodine labeled proteins demonstrated the presence of specific binding sites for both of them on the midgut brush border membrane vesicles (BBMVs) of both A. gemmatalis and C. includens Competition-binding experiments and specific-binding inhibition studies performed with selected sugars and lectins indicated that Cry1Ac and Cry1Fa share some, but not all, binding sites in the midguts of both insects. Also, the Cry1Ac- or Cry1Fa-binding sites were not shared with Cry1Ca or Cry2Aa in either soybean pest. This study contributes to the knowledge of Bt toxicity and midgut toxin binding sites in A. gemmatalis and C. includens and sheds light on the cross-resistance potential of Cry1Ac, Cry1Fa, Cry1Ca, and Cry2Aa Bt proteins as candidate proteins for Bt pyramided crops.IMPORTANCE In the present study, the toxicity and the mode of action of the Bacillus thuringiensis (Bt) toxins Cry1Ac, Cry1Fa, Cry1Ca, and Cry2Aa in Anticarsia gemmatalis and Chrysodeixis includens (important defoliating pests of soybeans) have been investigated. These studies are crucial for determining management strategies for pest control. Bioassays showed that both insects were susceptible to the toxins. Competition-binding studies demonstrated the presence of Cry1Fa- and Cry1Ac-specific binding sites in the midguts of both pests. These results, together with the results from binding inhibition studies performed with sugars and lectins, indicated that Cry1Ac and Cry1Fa share some, but not all, binding sites, and that they were not shared with Cry1Ca or Cry2Aa in either soybean pest. This study contributes to the knowledge of Bt toxicity in A. gemmatalis and C. includens and sheds light on the cross-resistance potential of Cry1Ac, Cry1Fa, Cry1Ca, and Cry2Aa Bt proteins as candidate proteins for Bt pyramided crops. PMID- 28363959 TI - Microbiota Analysis of an Environmental Slurry and Its Potential Role as a Reservoir of Bovine Digital Dermatitis Pathogens. AB - At present, very little information exists regarding what role the environmental slurry may play as an infection reservoir and/or route of transmission for bovine digital dermatitis (DD), a disease which is a global problem in dairy herds. To investigate whether DD-related bacteria belong to the indigenous microbiota of the dairy herd environment, we used deep amplicon sequencing of the 16S rRNA gene in 135 slurry samples collected from different sites in 22 dairy farms, with and without DD-infected cows. Both the general bacterial populations and digital dermatitis-associated Treponema were targeted in this study. The results revealed significant differences in the bacterial communities between the herds, with only 12 bacterial taxa shared across at least 80% of all the individual samples. These differences in the herd microbiota appeared to reflect mainly between-herd variation. Not surprisingly, the slurry was dominated by ubiquitous gastrointestinal bacteria, such as Ruminococcaceae and Lachnospiraceae Despite the low relative abundance of spirochetes, which ranged from 0 to 0.6%, we were able to detect small amounts of bacterial DNA from DD-associated treponemes in the slurry. However, the DD-associated Treponema spp. were detected only in samples from herds with reported DD problems. These data indicate that treponemes involved in the pathogenesis of DD are not part of the normal environmental microflora in dairy herds without clinical DD and, consequently, that slurry is not a primary reservoir of infection.IMPORTANCE Bovine digital dermatitis (DD), a dermal disease which causes lameness in dairy cattle, is a serious problem worldwide. To control this disease, the infection reservoirs and transmission routes of DD pathogens need to be clarified. The dairy herd slurry may be a pathogen reservoir of DD-associated bacteria. The rationale for the present study was, therefore, to examine whether DD-associated bacteria are always present in slurry or if they are found only in DD-afflicted herds. The results strongly indicated that DD Treponema spp. are not part of the indigenous slurry and, therefore, do not comprise an infection reservoir in healthy herds. This study applied next-generation sequencing technology to decipher the microbial compositions of environmental slurry of dairy herds with and without digital dermatitis. PMID- 28363960 TI - Genetic (In)stability of 2,6-Dichlorobenzamide Catabolism in Aminobacter sp. Strain MSH1 Biofilms under Carbon Starvation Conditions. AB - Aminobacter sp. strain MSH1 grows on and mineralizes the groundwater micropollutant 2,6-dichlorobenzamide (BAM) and is of interest for BAM removal in drinking water treatment plants (DWTPs). The BAM-catabolic genes in MSH1 are located on plasmid pBAM1, carrying bbdA, which encodes the conversion of BAM to 2,6-dichlorobenzoic acid (2,6-DCBA) (BbdA+ phenotype), and plasmid pBAM2, carrying gene clusters encoding the conversion of 2,6-DCBA to tricarboxylic acid (TCA) cycle intermediates (Dcba+ phenotype). There are indications that MSH1 easily loses its BAM-catabolic phenotype. We obtained evidence that MSH1 rapidly develops a population that lacks the ability to mineralize BAM when grown on nonselective (R2B medium) and semiselective (R2B medium with BAM) media. Lack of mineralization was explained by loss of the Dcba+ phenotype and corresponding genes. The ecological significance of this instability for the use of MSH1 for BAM removal in the oligotrophic environment of DWTPs was explored in lab and pilot systems. A higher incidence of BbdA+ Dcba- MSH1 cells was also observed when MSH1 was grown as a biofilm in flow chambers under C and N starvation conditions due to growth on nonselective residual assimilable organic carbon. Similar observations were made in experiments with a pilot sand filter reactor bioaugmented with MSH1. BAM conversion to 2,6-DCBA was not affected by loss of the DCBA-catabolic genes. Our results show that MSH1 is prone to BAM-catabolic instability under the conditions occurring in a DWTP. While conversion of BAM to 2,6-DCBA remains unaffected, BAM mineralization activity is at risk, and monitoring of metabolites is warranted.IMPORTANCE Bioaugmentation of dedicated biofiltration units with bacterial strains that grow on and mineralize micropollutants was suggested as an alternative for treating micropollutant contaminated water in drinking water treatment plants (DWTPs). Organic-pollutant catabolic genes in bacteria are often easily lost, especially under nonselective conditions, which affects the bioaugmentation success. In this study, we provide evidence that Aminobacter sp. strain MSH1, which uses the common groundwater micropollutant 2,6-dichlorobenzamide (BAM) as a C source, shows a high frequency of loss of its BAM-mineralizing phenotype due to the loss of genes that convert 2,6-DCBA to Krebs cycle intermediates when nonselective conditions occur. Moreover, we show that catabolic-gene loss also occurs in the oligotrophic environment of DWTPs, where growth of MSH1 depends mainly on the high fluxes of low concentrations of assimilable organic carbon, and hence show the ecological relevance of catabolic instability for using strain MSH1 for BAM removal in DWTPs. PMID- 28363961 TI - The Tale of a Neglected Energy Source: Elevated Hydrogen Exposure Affects both Microbial Diversity and Function in Soil. AB - The enrichment of H2-oxidizing bacteria (HOB) by H2 generated by nitrogen-fixing nodules has been shown to have a fertilization effect on several different crops. The benefit of HOB is attributed to their production of plant growth-promoting factors, yet their interactions with other members of soil microbial communities have received little attention. Here we report that the energy potential of H2, when supplied to soil, alters ecological niche partitioning of bacteria and fungi, with multifaceted consequences for both generalist and specialist microbial functions. We used dynamic microcosms to expose soil to the typical atmospheric H2 mixing ratio (0.5 ppmv) permeating soils, as well as mixing ratios comparable to those found at the soil-nodule interface (10,000 ppmv). Elevated H2 exposure exerted direct effects on two HOB subpopulations distinguished by their affinity for H2 while enhancing community level carbon substrate utilization potential and lowering CH4 uptake activity in soil. We found that H2 triggered changes in the abundance of microorganisms that were reproducible yet inconsistent across soils at the taxonomic level and even among HOB. Overall, H2 exposure altered microbial process rates at an intensity that depends upon soil abiotic and biotic features. We argue that further examination of direct and indirect effects of H2 on soil microbial communities will lead to a better understanding of the H2 fertilization effect and soil biogeochemical processes.IMPORTANCE An innovative dynamic microcosm chamber system was used to demonstrate that H2 diffusing in soil triggers changes in the distribution of HOB and non-HOB. Although the response was uneven at the taxonomic level, an unexpected coordinated response of microbial functions was observed, including abatement of CH4 oxidation activity and stimulation of carbon turnover. Our work suggests that elevated H2 rewires soil biogeochemical structure through a combination of direct effects on the growth and persistence of HOB and indirect effects on a variety of microbial processes involving HOB and non-HOB. PMID- 28363951 TI - Heterotrimeric G proteins in the control of parathyroid hormone actions. AB - Parathyroid hormone (PTH) is a key regulator of skeletal physiology and calcium and phosphate homeostasis. It acts on bone and kidney to stimulate bone turnover, increase the circulating levels of 1,25 dihydroxyvitamin D and calcium and inhibit the reabsorption of phosphate from the glomerular filtrate. Dysregulated PTH actions contribute to or are the cause of several endocrine disorders. This calciotropic hormone exerts its actions via binding to the PTH/PTH-related peptide receptor (PTH1R), which couples to multiple heterotrimeric G proteins, including Gs and Gq/11 Genetic mutations affecting the activity or expression of the alpha-subunit of Gs, encoded by the GNAS complex locus, are responsible for several human diseases for which the clinical findings result, at least partly, from aberrant PTH signaling. Here, we review the bone and renal actions of PTH with respect to the different signaling pathways downstream of these G proteins, as well as the disorders caused by GNAS mutations. PMID- 28363962 TI - Mechanisms for Pseudoalteromonas piscicida-Induced Killing of Vibrios and Other Bacterial Pathogens. AB - Pseudoalteromonas piscicida is a Gram-negative gammaproteobacterium found in the marine environment. Three strains of pigmented P. piscicida were isolated from seawater and partially characterized by inhibition studies, electron microscopy, and analysis for proteolytic enzymes. Growth inhibition and death occurred around colonies of P. piscicida on lawns of the naturally occurring marine pathogens Vibrio vulnificus, Vibrio parahaemolyticus, Vibrio cholerae, Photobacterium damselae, and Shewanella algae Inhibition also occurred on lawns of Staphylococcus aureus but not on Escherichia coli O157:H7 or Salmonella enterica serovar Typhimurium. Inhibition was not pH associated, but it may have been related to the secretion of a cysteine protease with strong activity, as detected with a synthetic fluorogenic substrate. This diffusible enzyme was secreted from all three P. piscicida strains. Direct overlay of the Pseudoalteromonas colonies with synthetic fluorogenic substrates demonstrated the activity of two aminopeptidase Bs, a trypsin-like serine protease, and enzymes reactive against substrates for cathepsin G-like and caspase 1-like proteases. In seawater cultures, scanning electron microscopy revealed numerous vesicles tethered to the outer surface of P. piscicida and a novel mechanism of direct transfer of these vesicles to V. parahaemolyticus Vesicles digested holes in V. parahaemolyticus cells, while the P. piscicida congregated around the vibrios in a predatory fashion. This transfer of vesicles and vesicle-associated digestion of holes were not observed in other bacteria, suggesting that vesicle binding may be mediated by host-specific receptors. In conclusion, we show two mechanisms by which P. piscicida inhibits and/or kills competing bacteria, involving the secretion of antimicrobial substances and the direct transfer of digestive vesicles to competing bacteria.IMPORTANCEPseudoalteromonas species are widespread in nature and reduce competing microflora by the production of antimicrobial compounds. We isolated three strains of P. piscicida and characterized secreted and cell associated proteolytic enzymes, which may have antimicrobial properties. We identified a second method by which P. piscicida kills V. parahaemolyticus It involves the direct transfer of apparently lytic vesicles from the surface of the Pseudoalteromonas strains to the surface of Vibrio cells, with subsequent digestion of holes in the Vibrio cell walls. Enzymes associated with these vesicles are likely responsible for the digestion of holes in the cell walls. Pseudoalteromonas piscicida has potential applications in aquaculture and food safety, in control of the formation of biofilms in the environment, and in food processing. These findings may facilitate the probiotic use of P. piscicida to inactivate pathogens and may lead to the isolation of enzymes and other antimicrobial compounds of pharmacological value. PMID- 28363963 TI - Improved Xylose Metabolism by a CYC8 Mutant of Saccharomyces cerevisiae. AB - Engineering Saccharomyces cerevisiae for the utilization of pentose sugars is an important goal for the production of second-generation bioethanol and biochemicals. However, S. cerevisiae lacks specific pentose transporters, and in the presence of glucose, pentoses enter the cell inefficiently via endogenous hexose transporters (HXTs). By means of in vivo engineering, we have developed a quadruple hexokinase deletion mutant of S. cerevisiae that evolved into a strain that efficiently utilizes d-xylose in the presence of high d-glucose concentrations. A genome sequence analysis revealed a mutation (Y353C) in the general corepressor CYC8, or SSN6, which was found to be responsible for the phenotype when introduced individually in the nonevolved strain. A transcriptome analysis revealed altered expression of 95 genes in total, including genes involved in (i) hexose transport, (ii) maltose metabolism, (iii) cell wall function (mannoprotein family), and (iv) unknown functions (seripauperin multigene family). Of the 18 known HXTs, genes for 9 were upregulated, especially the low or nonexpressed HXT10, HXT13, HXT15, and HXT16 Mutant cells showed increased uptake rates of d-xylose in the presence of d-glucose, as well as elevated maximum rates of metabolism (Vmax) for both d-glucose and d-xylose transport. The data suggest that the increased expression of multiple hexose transporters renders d-xylose metabolism less sensitive to d-glucose inhibition due to an elevated transport rate of d-xylose into the cell.IMPORTANCE The yeast Saccharomyces cerevisiae is used for second-generation bioethanol formation. However, growth on xylose is limited by pentose transport through the endogenous hexose transporters (HXTs), as uptake is outcompeted by the preferred substrate, glucose. Mutant strains were obtained with improved growth characteristics on xylose in the presence of glucose, and the mutations mapped to the regulator Cyc8. The inactivation of Cyc8 caused increased expression of HXTs, thereby providing more capacity for the transport of xylose, presenting a further step toward a more robust process of industrial fermentation of lignocellulosic biomass using yeast. PMID- 28363964 TI - Enhanced Antimicrobial Activity Based on a Synergistic Combination of Sublethal Levels of Stresses Induced by UV-A Light and Organic Acids. AB - The reduction of microbial load in food and water systems is critical for their safety and shelf life. Conventionally, physical processes such as heat or light are used for the rapid inactivation of microbes, while natural compounds such as lactic acid may be used as preservatives after the initial physical process. This study demonstrates the enhanced and rapid inactivation of bacteria based on a synergistic combination of sublethal levels of stresses induced by UV-A light and two food-grade organic acids. A reduction of 4.7 +/- 0.5 log CFU/ml in Escherichia coli O157:H7 was observed using a synergistic combination of UV-A light, gallic acid (GA), and lactic acid (LA), while the individual treatments and the combination of individual organic acids with UV-A light resulted in a reduction of less than 1 log CFU/ml. Enhanced inactivation of bacteria on the surfaces of lettuce and spinach leaves was also observed based on the synergistic combination. Mechanistic investigations suggested that the treatment with a synergistic combination of GA plus LA plus UV-A (GA+LA+UV-A) resulted in significant increases in membrane permeability and intracellular thiol oxidation and affected the metabolic machinery of E. coli In addition, the antimicrobial activity of the synergistic combination of GA+LA+UV-A was effective only against metabolically active E. coli O157:H7. In summary, this study illustrates the potential of simultaneously using a combination of sublethal concentrations of natural antimicrobials and a low level of physical stress in the form of UV-A light to inactivate bacteria in water and food systems.IMPORTANCE There is a critical unmet need to improve the microbial safety of the food supply, while retaining optimal nutritional and sensory properties of food. Furthermore, there is a need to develop novel technologies that can reduce the impact of food processing operations on energy and water resources. Conventionally, physical processes such as heat and light are used for inactivating microbes in food products, but these processes often significantly reduce the sensory and nutritional properties of food and are highly energy intensive. This study demonstrates that the combination of two natural food-grade antimicrobial agents with a sublethal level of physical stress in the form of UV-A light can greatly increase microbial load inactivation. In addition, this report elucidates the potential mechanisms for this synergistic interaction among physical and chemical stresses. Overall, these results provide a novel approach to develop antimicrobial solutions for food and water systems. PMID- 28363965 TI - Contamination of Fresh Produce by Microbial Indicators on Farms and in Packing Facilities: Elucidation of Environmental Routes. AB - To improve food safety on farms, it is critical to quantify the impact of environmental microbial contamination sources on fresh produce. However, studies are hampered by difficulties achieving study designs with powered sample sizes to elucidate relationships between environmental and produce contamination. Our goal was to quantify, in the agricultural production environment, the relationship between microbial contamination on hands, soil, and water and contamination on fresh produce. In 11 farms and packing facilities in northern Mexico, we applied a matched study design: composite samples (n = 636, equivalent to 11,046 units) of produce rinses were matched to water, soil, and worker hand rinses during two growing seasons. Microbial indicators (coliforms, Escherichia coli, Enterococcus spp., and somatic coliphage) were quantified from composite samples. Statistical measures of association and correlations were calculated through Spearman's correlation, linear regression, and logistic regression models. The concentrations of all microbial indicators were positively correlated between produce and hands (rho range, 0.41 to 0.75; P < 0.01). When E. coli was present on hands, the handled produce was nine times more likely to contain E. coli (P < 0.05). Similarly, when coliphage was present on hands, the handled produce was eight times more likely to contain coliphage (P < 0.05). There were relatively low concentrations of indicators in soil and water samples, and a few sporadic significant associations were observed between contamination of soil and water and contamination of produce. This methodology provides a foundation for future field studies, and results highlight the need for interventions surrounding farmworker hygiene and sanitation to reduce microbial contamination of farmworkers' hands.IMPORTANCE This study of the relationships between microbes on produce and in the farm environment can be used to support the design of targeted interventions to prevent or reduce microbial contamination of fresh produce with associated reductions in foodborne illness. PMID- 28363966 TI - Evolution of a Biomass-Fermenting Bacterium To Resist Lignin Phenolics. AB - Increasing the resistance of plant-fermenting bacteria to lignocellulosic inhibitors is useful to understand microbial adaptation and to develop candidate strains for consolidated bioprocessing. Here, we study and improve inhibitor resistance in Clostridium phytofermentans (also called Lachnoclostridium phytofermentans), a model anaerobe that ferments lignocellulosic biomass. We survey the resistance of this bacterium to a panel of biomass inhibitors and then evolve strains that grow in increasing concentrations of the lignin phenolic, ferulic acid, by automated, long-term growth selection in an anaerobic GM3 automat. Ultimately, strains resist multiple inhibitors and grow robustly at the solubility limit of ferulate while retaining the ability to ferment cellulose. We analyze genome-wide transcription patterns during ferulate stress and genomic variants that arose along the ferulate growth selection, revealing how cells adapt to inhibitors through changes in gene dosage and regulation, membrane fatty acid structure, and the surface layer. Collectively, this study demonstrates an automated framework for in vivo directed evolution of anaerobes and gives insight into the genetic mechanisms by which bacteria survive exposure to chemical inhibitors.IMPORTANCE Fermentation of plant biomass is a key part of carbon cycling in diverse ecosystems. Further, industrial biomass fermentation may provide a renewable alternative to fossil fuels. Plants are primarily composed of lignocellulose, a matrix of polysaccharides and polyphenolic lignin. Thus, when microorganisms degrade lignocellulose to access sugars, they also release phenolic and acidic inhibitors. Here, we study how the plant-fermenting bacterium Clostridium phytofermentans resists plant inhibitors using the lignin phenolic, ferulic acid. We examine how the cell responds to abrupt ferulate stress by measuring changes in gene expression. We evolve increasingly resistant strains by automated, long-term cultivation at progressively higher ferulate concentrations and sequence their genomes to identify mutations associated with acquired ferulate resistance. Our study develops an inhibitor-resistant bacterium that ferments cellulose and provides insights into genomic evolution to resist chemical inhibitors. PMID- 28363967 TI - Reexamination of the Physiological Role of PykA in Escherichia coli Revealed that It Negatively Regulates the Intracellular ATP Levels under Anaerobic Conditions. AB - Pyruvate kinase is one of the three rate-limiting glycolytic enzymes that catalyze the last step of glycolysis, conversion of phosphoenolpyruvate (PEP) into pyruvate, which is associated with ATP generation. Two isozymes of pyruvate kinase, PykF and PykA, are identified in Escherichia coli PykF is considered important, whereas PykA has a less-defined role. Prior studies inactivated the pykA gene to increase the level of its substrate, PEP, and thereby increased the yield of end products derived from PEP. We were surprised when we found a pykA::Tn5 mutant in a screen for increased yield of an end product derived from pyruvate (n-butanol), suggesting that the role of PykA needs to be reexamined. We show that the pykA mutant exhibited elevated intracellular ATP levels, biomass concentrations, glucose consumption, and n-butanol production. We also discovered that the pykA mutant expresses higher levels of a presumed pyruvate transporter, YhjX, permitting the mutant to recapture and metabolize excreted pyruvate. Furthermore, we demonstrated that the nucleotide diphosphate kinase activity of PykA leads to negative regulation of the intracellular ATP levels. Taking the data together, we propose that inactivation of pykA can be considered a general strategy to enhance the production of pyruvate-derived metabolites under anaerobic conditions.IMPORTANCE This study showed that knocking out pykA significantly increased the intracellular ATP level and thus significantly increased the levels of glucose consumption, biomass formation, and pyruvate derived product formation under anaerobic conditions. pykA was considered to be encoding a dispensable pyruvate kinase; here we show that pykA negatively regulates the anaerobic glycolysis rate through regulating the energy distribution. Thus, knocking out pykA can be used as a general strategy to increase the level of pyruvate-derived fermentative products. PMID- 28363968 TI - Benign Rabbit Calicivirus in New Zealand. AB - The Czech v351 strain of rabbit hemorrhagic disease virus (RHDV1) is used in Australia and New Zealand as a biological control agent for rabbits, which are important and damaging introduced vertebrate pests in these countries. However, nonpathogenic rabbit caliciviruses (RCVs) can provide partial immunological cross protection against lethal RHDV infection and thus interfere with effective rabbit biocontrol. Antibodies that cross-reacted against RHDV antigens were found in wild rabbits before the release of RHDV1 in New Zealand in 1997, suggesting that nonpathogenic RCVs were already present in New Zealand. The aim of this study was to confirm the presence of nonpathogenic RCV in New Zealand and describe its geographical distribution. RCV and RHDV antibody assays were used to screen serum samples from 350 wild rabbits from 14 locations in New Zealand. The serological survey indicated that both RCV and RHDV are widespread in New Zealand wild rabbits, with antibodies detected in 10 out of 14 and 12 out of 14 populations, respectively. Two closely related RCV strains were identified in the duodenal tissue from a New Zealand wild rabbit (RCV Gore-425A and RCV Gore-425B). Both variants are most closely related to Australian RCV strains, but with 88% nucleotide identity, they are genetically distinct. Phylogenetic analysis revealed that the New Zealand RCV strains fall within the genetic diversity of the Australian RCV isolates, indicating a relatively recent movement of RCVs between Australia and New Zealand.IMPORTANCE Wild rabbits are important and damaging introduced vertebrate pests in Australia and New Zealand. Although RHDV1 is used as a biological control agent, some nonpathogenic RCVs can provide partial immunological cross-protection against lethal RHDV infection and thus interfere with its effectiveness for rabbit control. The presence of nonpathogenic RCVs in New Zealand wild rabbits has been long hypothesized, but earlier attempts to isolate a New Zealand RCV strain have been unsuccessful. Therefore, it is important to determine if such nonpathogenic viruses exist in New Zealand rabbits, especially considering the proposed introduction of new RHDV strains into New Zealand as biocontrols. PMID- 28363969 TI - Simulated rRNA/DNA Ratios Show Potential To Misclassify Active Populations as Dormant. AB - The use of rRNA/DNA ratios derived from surveys of rRNA sequences in RNA and DNA extracts is an appealing but poorly validated approach to infer the activity status of environmental microbes. To improve the interpretation of rRNA/DNA ratios, we performed simulations to investigate the effects of community structure, rRNA amplification, and sampling depth on the accuracy of rRNA/DNA ratios in classifying bacterial populations as "active" or "dormant." Community structure was an insignificant factor. In contrast, the extent of rRNA amplification that occurs as cells transition from dormant to growing had a significant effect (P < 0.0001) on classification accuracy, with misclassification errors ranging from 16 to 28%, depending on the rRNA amplification model. The error rate increased to 47% when communities included a mixture of rRNA amplification models, but most of the inflated error was false negatives (i.e., active populations misclassified as dormant). Sampling depth also affected error rates (P < 0.001). Inadequate sampling depth produced various artifacts that are characteristic of rRNA/DNA ratios generated from real communities. These data show important constraints on the use of rRNA/DNA ratios to infer activity status. Whereas classification of populations as active based on rRNA/DNA ratios appears generally valid, classification of populations as dormant is potentially far less accurate.IMPORTANCE The rRNA/DNA ratio approach is appealing because it extracts an extra layer of information from high throughput DNA sequencing data, offering a means to determine not only the seedbank of taxa present in communities but also the subset of taxa that are metabolically active. This study provides crucial insights into the use of rRNA/DNA ratios to infer the activity status of microbial taxa in complex communities. Our study shows that the approach may not be as robust as previously supposed, particularly in complex communities composed of populations employing different growth strategies, and identifies factors that inflate the erroneous classification of active populations as dormant. PMID- 28363971 TI - The bacterial virulence factors VopL and VopF nucleate actin from the pointed end. AB - VopL and VopF (VopL/F) are tandem WH2-domain actin assembly factors used by infectious Vibrio species to induce actin assembly in host cells. There is disagreement about the filament assembly mechanism of VopL/F, including whether they associate with the filament barbed or pointed end. Here, we used multicolor total internal reflection fluorescence microscopy to directly observe actin assembly with fluorescently labeled VopL/F. In actin monomer assembly reactions, VopL/F exclusively nucleate actin filament assemblies, remaining only briefly associated with the pointed end. VopL/F do not associate with the ends of preassembled filaments. In assembly reactions with saturating profilin, ~85% of VopL/F molecules also promote nucleation from the pointed end, whereas a smaller fraction (<15%) associate for ~25 s with the barbed end of preassembled filaments, inhibiting their elongation. We conclude that VopL/F function primarily as actin nucleation factors that remain briefly (~100 s) associated with the pointed end. PMID- 28363974 TI - A model for predicting the growth of unruptured intracranial aneurysms: Beyond fortune telling. PMID- 28363970 TI - Hedgehog signaling establishes precursors for germline stem cell niches by regulating cell adhesion. AB - Stem cells require different types of supporting cells, or niches, to control stem cell maintenance and differentiation. However, little is known about how those niches are formed. We report that in the development of the Drosophila melanogaster ovary, the Hedgehog (Hh) gradient sets differential cell affinity for somatic gonadal precursors to specify stromal intermingled cells, which contributes to both germline stem cell maintenance and differentiation niches in the adult. We also report that Traffic Jam (an orthologue of a large Maf transcription factor in mammals) is a novel transcriptional target of Hh signaling to control cell-cell adhesion by negative regulation of E-cadherin expression. Our results demonstrate the role of Hh signaling in niche establishment by segregating somatic cell lineages for differentiation. PMID- 28363973 TI - Electrical and structural adaptations of the paediatric athlete's heart: a systematic review with meta-analysis. AB - AIM: To describe the electrocardiographic (ECG) and echocardiographic manifestations of the paediatric athlete's heart, and examine the impact of age, race and sex on cardiac remodelling responses to competitive sport. DESIGN: Systematic review with meta-analysis. DATA SOURCES: Six electronic databases were searched to May 2016: MEDLINE, PubMed, EMBASE, Web of Science, CINAHL and SPORTDiscus. INCLUSION CRITERIA: (1) Male and/or female competitive athletes, (2) participants aged 6-18 years, (3) original research article published in English language. RESULTS: Data from 14 278 athletes and 1668 non-athletes were included for qualitative (43 articles) and quantitative synthesis (40 articles). Paediatric athletes demonstrated a greater prevalence of training-related and training-unrelated ECG changes than non-athletes. Athletes >=14 years were 15.8 times more likely to have inferolateral T-wave inversion than athletes <14 years. Paediatric black athletes had significantly more training-related and training unrelated ECG changes than Caucasian athletes. Age was a positive predictor of left ventricular (LV) internal diameter during diastole, interventricular septum thickness during diastole, relative wall thickness and LV mass. When age was accounted for, these parameters remained significantly larger in athletes than non-athletes. Paediatric black athletes presented larger posterior wall thickness during diastole (PWTd) than Caucasian athletes. Paediatric male athletes also presented larger PWTd than females. CONCLUSIONS: The paediatric athlete's heart undergoes significant remodelling both before and during 'maturational years'. Paediatric athletes have a greater prevalence of training related and training unrelated ECG changes than non-athletes, with age, race and sex mediating factors on cardiac electrical and LV structural remodelling. PMID- 28363972 TI - Myosin II promotes the anisotropic loss of the apical domain during Drosophila neuroblast ingression. AB - Epithelial-mesenchymal transitions play key roles in development and cancer and entail the loss of epithelial polarity and cell adhesion. In this study, we use quantitative live imaging of ingressing neuroblasts (NBs) in Drosophila melanogaster embryos to assess apical domain loss and junctional disassembly. Ingression is independent of the Snail family of transcriptional repressors and down-regulation of Drosophila E-cadherin (DEcad) transcription. Instead, the posttranscriptionally regulated decrease in DEcad coincides with the reduction of cell contact length and depends on tension anisotropy between NBs and their neighbors. A major driver of apical constriction and junctional disassembly are periodic pulses of junctional and medial myosin II that result in progressively stronger cortical contractions during ingression. Effective contractions require the molecular coupling between myosin and junctions and apical relaxation of neighboring cells. Moreover, planar polarization of myosin leads to the loss of anterior-posterior junctions before the loss of dorsal-ventral junctions. We conclude that planar-polarized dynamic actomyosin networks drive apical constriction and the anisotropic loss of cell contacts during NB ingression. PMID- 28363975 TI - Fine particulate matter exposure and incidence of stroke: A cohort study in Hong Kong. AB - OBJECTIVE: We aimed to assess the association of long-term residential exposure to fine particulate matter (PM) with aerodynamic diameter less than 2.5 MUm (PM2.5) with the incidence of stroke and its major subtypes. METHODS: We ascertained the first occurrence of emergency hospital admission for stroke in a Hong Kong Chinese cohort of 66,820 older people (65+ years) who enrolled during 1998-2001 (baseline) and were followed up to December 31, 2010. High-resolution (1 * 1 km) yearly mean concentrations of PM2.5 were predicted from local monitoring data and US National Aeronautics and Space Administration satellite data using linear regression. Baseline residential PM2.5 exposure was used as a proxy for long-term exposure. We used Cox proportional hazards to evaluate the risk of incident stroke associated with PM2.5 exposure adjusted for potential confounders, including individual and neighborhood factors. RESULTS: Over a mean follow-up of 9.4 years, we ascertained 6,733 cases of incident stroke, of which 3,526 (52.4%) were ischemic and 1,175 (17.5%) were hemorrhagic. The hazard ratio for every 10 MUg/m3 higher PM2.5 concentration was statistically significant at 1.21 (95% confidence interval [CI] 1.04-1.41) for ischemic and non-statistically significant at 0.90 (95% CI 0.70-1.17) for hemorrhagic stroke in fully adjusted model 3. The estimates for ischemic stroke were higher in older participants (>70 years), less educated participants, and in men for current smokers. CONCLUSION: Long-term PM2.5 exposure was associated with higher risk of incident ischemic stroke, but the association with incident hemorrhagic stroke was less clear. PMID- 28363976 TI - ELAPSS score for prediction of risk of growth of unruptured intracranial aneurysms. AB - OBJECTIVE: To develop a risk score that estimates 3-year and 5-year absolute risks for aneurysm growth. METHODS: From 10 cohorts of patients with unruptured intracranial aneurysms and follow-up imaging, we pooled individual data on sex, population, age, hypertension, history of subarachnoid hemorrhage, and aneurysm location, size, aspect ratio, and shape but not on smoking during follow-up and family history of intracranial aneurysms in 1,507 patients with 1,909 unruptured intracranial aneurysms and used aneurysm growth as outcome. With aneurysm-based multivariable Cox regression analysis, we determined predictors for aneurysm growth, which were presented as a risk score to calculate 3-year and 5-year risks for aneurysm growth by risk factor status. RESULTS: Aneurysm growth occurred in 257 patients (17%) and 267 aneurysms (14%) during 5,782 patient-years of follow up. Predictors for aneurysm growth were earlier subarachnoid hemorrhage, location of the aneurysm, age >60 years, population, size of the aneurysm, and shape of the aneurysm (ELAPSS). The 3-year growth risk ranged from <5% to >42% and the 5 year growth risk from <9% to >60%, depending on the risk factor status. CONCLUSIONS: The ELAPSS score consists of 6 easily retrievable predictors and can help physicians in decision making on the need for and timing of follow-up imaging in patients with unruptured intracranial aneurysms. PMID- 28363978 TI - Genetic Architecture of Phenomic-Enabled Canopy Coverage in Glycine max. AB - Digital imagery can help to quantify seasonal changes in desirable crop phenotypes that can be treated as quantitative traits. Because limitations in precise and functional phenotyping restrain genetic improvement in the postgenomic era, imagery-based phenomics could become the next breakthrough to accelerate genetic gains in field crops. Whereas many phenomic studies focus on exploratory analysis of spectral data without obvious interpretative value, we used field images to directly measure soybean canopy development from phenological stage V2 to R5. Over 3 years, we collected imagery using ground and aerial platforms of a large and diverse nested association panel comprising 5555 lines. Genome-wide association analysis of canopy coverage across sampling dates detected a large quantitative trait locus (QTL) on soybean (Glycine max, L. Merr.) chromosome 19. This QTL provided an increase in yield of 47.3 kg ha-1 Variance component analysis indicated that a parameter, described as average canopy coverage, is a highly heritable trait (h2 = 0.77) with a promising genetic correlation with grain yield (0.87), enabling indirect selection of yield via canopy development parameters. Our findings indicate that fast canopy coverage is an early season trait that is inexpensive to measure and has great potential for application in breeding programs focused on yield improvement. We recommend using the average canopy coverage in multiple trait schemes, especially for the early stages of the breeding pipeline (including progeny rows and preliminary yield trials), in which the large number of field plots makes collection of grain yield data challenging. PMID- 28363977 TI - Facilitating Neuron-Specific Genetic Manipulations in Drosophila melanogaster Using a Split GAL4 Repressor. AB - Efforts to map neural circuits have been galvanized by the development of genetic technologies that permit the manipulation of targeted sets of neurons in the brains of freely behaving animals. The success of these efforts relies on the experimenter's ability to target arbitrarily small subsets of neurons for manipulation, but such specificity of targeting cannot routinely be achieved using existing methods. In Drosophila melanogaster, a widely-used technique for refined cell type-specific manipulation is the Split GAL4 system, which augments the targeting specificity of the binary GAL4-UAS (Upstream Activating Sequence) system by making GAL4 transcriptional activity contingent upon two enhancers, rather than one. To permit more refined targeting, we introduce here the "Killer Zipper" (KZip+), a suppressor that makes Split GAL4 targeting contingent upon a third enhancer. KZip+ acts by disrupting both the formation and activity of Split GAL4 heterodimers, and we show how this added layer of control can be used to selectively remove unwanted cells from a Split GAL4 expression pattern or to subtract neurons of interest from a pattern to determine their requirement in generating a given phenotype. To facilitate application of the KZip+ technology, we have developed a versatile set of LexAop-KZip+ fly lines that can be used directly with the large number of LexA driver lines with known expression patterns. KZip+ significantly sharpens the precision of neuronal genetic control available in Drosophila and may be extended to other organisms where Split GAL4 like systems are used. PMID- 28363979 TI - Densin-180 Controls the Trafficking and Signaling of L-Type Voltage-Gated Cav1.2 Ca2+ Channels at Excitatory Synapses. AB - Voltage-gated Cav1.2 and Cav1.3 (L-type) Ca2+ channels regulate neuronal excitability, synaptic plasticity, and learning and memory. Densin-180 (densin) is an excitatory synaptic protein that promotes Ca2+-dependent facilitation of voltage-gated Cav1.3 Ca2+ channels in transfected cells. Mice lacking densin (densin KO) exhibit defects in synaptic plasticity, spatial memory, and increased anxiety-related behaviors-phenotypes that more closely match those in mice lacking Cav1.2 than Cav1.3. Therefore, we investigated the functional impact of densin on Cav1.2. We report that densin is an essential regulator of Cav1.2 in neurons, but has distinct modulatory effects compared with its regulation of Cav1.3. Densin binds to the N-terminal domain of Cav1.2, but not that of Cav1.3, and increases Cav1.2 currents in transfected cells and in neurons. In transfected cells, densin accelerates the forward trafficking of Cav1.2 channels without affecting their endocytosis. Consistent with a role for densin in increasing the number of postsynaptic Cav1.2 channels, overexpression of densin increases the clustering of Cav1.2 in dendrites of hippocampal neurons in culture. Compared with wild-type mice, the cell surface levels of Cav1.2 in the brain, as well as Cav1.2 current density and signaling to the nucleus, are reduced in neurons from densin KO mice. We conclude that densin is an essential regulator of neuronal Cav1 channels and ensures efficient Cav1.2 Ca2+ signaling at excitatory synapses.SIGNIFICANCE STATEMENT The number and localization of voltage-gated Cav Ca2+ channels are crucial determinants of neuronal excitability and synaptic transmission. We report that the protein densin-180 is highly enriched at excitatory synapses in the brain and enhances the cell surface trafficking and postsynaptic localization of Cav1.2 L-type Ca2+ channels in neurons. This interaction promotes coupling of Cav1.2 channels to activity-dependent gene transcription. Our results reveal a mechanism that may contribute to the roles of Cav1.2 in regulating cognition and mood. PMID- 28363982 TI - Deficiency in Neuronal TGF-beta Signaling Leads to Nigrostriatal Degeneration and Activation of TGF-beta Signaling Protects against MPTP Neurotoxicity in Mice. AB - Transforming growth factor-beta (TGF-beta) plays an important role in the development and maintenance of embryonic dopaminergic (DA) neurons in the midbrain. To study the function of TGF-beta signaling in the adult nigrostriatal system, we generated transgenic mice with reduced TGF-beta signaling in mature neurons. These mice display age-related motor deficits and degeneration of the nigrostriatal system. Increasing TGF-beta signaling in the substantia nigra through adeno-associated virus expressing a constitutively active type I receptor significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration and motor deficits. These results suggest that TGF beta signaling is critical for adult DA neuron survival and that modulating this signaling pathway has therapeutic potential in Parkinson disease.SIGNIFICANCE STATEMENT We show that reducing Transforming growth factor-beta (TGF-beta) signaling promotes Parkinson disease-related pathologies and motor deficits, and increasing TGF-beta signaling reduces neurotoxicity of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine, a parkinsonism-inducing agent. Our results provide a rationale to pursue a means of increasing TGF-beta signaling as a potential therapy for Parkinson's disease. PMID- 28363981 TI - Alcohol Dependence Disrupts Amygdalar L-Type Voltage-Gated Calcium Channel Mechanisms. AB - L-type voltage-gated calcium channels (LTCCs) are implicated in several psychiatric disorders that are comorbid with alcoholism and involve amygdala dysfunction. Within the amygdala, the central nucleus (CeA) is critical in acute alcohol's reinforcing actions, and its dysregulation in human alcoholics drives their negative emotional state and motivation to drink. Here we investigated the specific role of CeA LTCCs in the effects of acute alcohol at the molecular, cellular physiology, and behavioral levels, and their potential neuroadaptation in alcohol-dependent rats. Alcohol increases CeA activity (neuronal firing rates and GABA release) in naive rats by engaging LTCCs, and intra-CeA LTCC blockade reduces alcohol intake in nondependent rats. Alcohol dependence reduces CeA LTCC membrane abundance and disrupts this LTCC-based mechanism; instead, corticotropin releasing factor type 1 receptors (CRF1s) mediate alcohol's effects on CeA activity and drive the escalated alcohol intake of alcohol-dependent rats. Collectively, our data indicate that alcohol dependence functionally alters the molecular mechanisms underlying the CeA's response to alcohol (from LTCC- to CRF1 driven). This mechanistic switch contributes to and reflects the prominent role of the CeA in the negative emotional state that drives excessive drinking.SIGNIFICANCE STATEMENT The central amygdala (CeA) plays a critical role in the development of alcohol dependence. As a result, much preclinical alcohol research aims to identify relevant CeA neuroadaptions that promote the transition to dependence. Here we report that acute alcohol increases CeA neuronal activity in naive rats by engaging L-type calcium channels (LTCCs) and that intra-CeA LTCC blockade reduces alcohol intake in nondependent rats. Alcohol dependence disrupts this LTCC-based mechanism; instead, corticotropin-releasing factor type 1 receptors (CRF1s) mediate alcohol's effects on CeA activity and drive the escalated alcohol intake of alcohol-dependent rats. This switch reflects the important role of the CeA in the pathophysiology of alcohol dependence and represents a new potential avenue for therapeutic intervention during the transition period. PMID- 28363980 TI - A Presynaptic Group III mGluR Recruits Gbetagamma/SNARE Interactions to Inhibit Synaptic Transmission by Cone Photoreceptors in the Vertebrate Retina. AB - G-protein betagamma subunits (Gbetagamma) interact with presynaptic proteins and regulate neurotransmitter release downstream of Ca2+ influx. To accomplish their roles in sensory signaling, photoreceptor synapses use specialized presynaptic proteins that support neurotransmission at active zone structures known as ribbons. While several G-protein coupled receptors (GPCRs) influence synaptic transmission at ribbon synapses of cones and other retinal neurons, it is unknown whether Gbetagamma contributes to these effects. We tested whether activation of one particular GPCR, a metabotropic glutamate receptor (mGluR), can reduce cone synaptic transmission via Gbetagamma in tiger salamander retinas. In recordings from horizontal cells, we found that an mGluR agonist (L-AP4) reduced cone-driven light responses and mEPSC frequency. In paired recordings of cones and horizontal cells, L-AP4 slightly reduced cone ICa (~10%) and caused a larger reduction in cone-driven EPSCs (~30%). Proximity ligation assay revealed direct interactions between SNAP-25 and Gbetagamma subunits in retinal synaptic layers. Pretreatment with the SNAP-25 cleaving protease BoNT/A inhibited L-AP4 effects on synaptic transmission, as did introduction of a peptide derived from the SNAP-25 C terminus. Introducing Gbetagamma subunits directly into cones reduced EPSC amplitude. This effect was inhibited by BoNT/A, supporting a role for Gbetagamma/SNAP-25 interactions. However, the mGluR-dependent reduction in ICa was not mimicked by Gbetagamma, indicating that this effect was independent of Gbetagamma. The finding that synaptic transmission at cone ribbon synapses is regulated by Gbetagamma/SNAP-25 interactions indicates that these mechanisms are shared by conventional and ribbon-type synapses. Gbetagamma liberated from other photoreceptor GPCRs is also likely to regulate synaptic transmission.SIGNIFICANCE STATEMENT Dynamic regulation of synaptic transmission by presynaptic G-protein coupled receptors shapes information flow through neural circuits. At the first synapse in the visual system, presynaptic metabotropic glutamate receptors (mGluRs) regulate cone photoreceptor synaptic transmission, although the mechanisms and functional impact of this are unclear. We show that mGluRs regulate light response encoding across the cone synapse, accomplished in part by triggering G-protein betagamma subunits (Gbetagamma) interactions with SNAP-25, a core component of the synaptic vesicle fusion machinery. In addition to revealing a role in visual processing, this provides the first demonstration that Gbetagamma/SNAP-25 interactions regulate synaptic function at a ribbon-type synapse, contributing to an emerging picture of the ubiquity of Gbetagamma/SNARE interactions in regulating synaptic transmission throughout the nervous system. PMID- 28363983 TI - Synaptotagmin2 (Syt2) Drives Fast Release Redundantly with Syt1 at the Output Synapses of Parvalbumin-Expressing Inhibitory Neurons. AB - Parvalbumin-expressing inhibitory neurons in the mammalian CNS are specialized for fast transmitter release at their output synapses. However, the Ca2+ sensor(s) used by identified inhibitory synapses, including the output synapses of parvalbumin-expressing inhibitory neurons, have only recently started to be addressed. Here, we investigated the roles of Syt1 and Syt2 at two types of fast releasing inhibitory connections in the mammalian CNS: the medial nucleus of the trapezoid body to lateral superior olive glycinergic synapse, and the basket/stellate cell-Purkinje GABAergic synapse in the cerebellum. We used conditional and conventional knock-out (KO) mouse lines, with viral expression of Cre-recombinase and a light-activated ion channel for optical stimulation of the transduced fibers, to produce Syt1-Syt2 double KO synapses in vivo Surprisingly, we found that KO of Syt2 alone had only minor effects on evoked transmitter release, despite the clear presence of the protein in inhibitory nerve terminals revealed by immunohistochemistry. We show that Syt1 is weakly coexpressed at these inhibitory synapses and must be genetically inactivated together with Syt2 to achieve a significant reduction and desynchronization of fast release. Thus, our work identifies the functionally relevant Ca2+ sensor(s) at fast-releasing inhibitory synapses and shows that two major Syt isoforms can cooperate to mediate release at a given synaptic connection.SIGNIFICANCE STATEMENT During synaptic transmission, the influx of Ca2+ into the presynaptic nerve terminal activates a Ca2+ sensor for vesicle fusion, a crucial step in the activity dependent release of neurotransmitter. Synaptotagmin (Syt) proteins, and especially Syt1 and Syt2, have been identified as the Ca2+ sensor at excitatory synapses, but the Ca2+ sensor(s) at inhibitory synapses in native brain tissue are not well known. We found that both Syt1 and Syt2 need to be genetically inactivated to cause a significant reduction of activity-evoked release at two types of fast inhibitory synapses in mouse brain. Thus, we identify Syt2 as a functionally important Ca2+ sensor at fast-releasing inhibitory synapses, and show that Syt1 and Syt2 can redundantly control transmitter release at specific brain synapses. PMID- 28363984 TI - Blood Pressure Regulation by the Rostral Ventrolateral Medulla in Conscious Rats: Effects of Hypoxia, Hypercapnia, Baroreceptor Denervation, and Anesthesia. AB - Current understanding of the contribution of C1 neurons to blood pressure (BP) regulation derives predominantly from experiments performed in anesthetized animals or reduced ex vivo preparations. Here, we use ArchaerhodopsinT3.0 (ArchT) loss-of-function optogenetics to explore BP regulation by C1 neurons in intact, unanesthetized rats. Using a lentivirus that expresses ArchT under the Phox2b activated promoter PRSx8 (PRSx8-ArchT), ~65% of transduced neurons were C1 (balance retrotrapezoid nucleus, RTN). Other rats received CaMKII-ArchT3.0 AAV2 (CaMKII-ArchT), which transduced C1 neurons and larger numbers of unidentified glutamatergic and GABAergic cells. Under anesthesia, ArchT photoactivation reduced sympathetic nerve activity and BP and silenced/strongly inhibited most (7/12) putative C1 neurons. In unanesthetized PRSx8-ArchT-treated rats breathing room air, bilateral ArchT photoactivation caused a very small BP reduction that was only slightly larger under hypercapnia (6% FiCO2), but was greatly enhanced during hypoxia (10 and 12% FiO2), after sino-aortic denervation, or during isoflurane anesthesia. The degree of hypotension correlated with percentage of ArchT-transduced C1 neurons. ArchT photoactivation produced similar BP changes in CaMKII-ArchT-treated rats. Photoactivation in PRSX8-ArchT rats reduced breathing frequency (FR), whereas FR increased in CaMKII-ArchT rats. We conclude that the BP drop elicited by ArchT activation resulted from C1 neuron inhibition and was unrelated to breathing changes. C1 neurons have low activity under normoxia, but their activation is important to BP stability during hypoxia or anesthesia and contributes greatly to the hypertension caused by baroreceptor deafferentation. Finally, C1 neurons are marginally activated by hypercapnia and the large breathing stimulation caused by this stimulus has very little impact on resting BP.SIGNIFICANCE STATEMENT C1 neurons are glutamatergic/peptidergic/catecholaminergic neurons located in the medulla oblongata, which may operate as a switchboard for differential, behavior appropriate activation of selected sympathetic efferents. Based largely on experimentation in anesthetized or reduced preparations, a rostrally located subset of C1 neurons may contribute to both BP stabilization and dysregulation (hypertension). Here, we used Archaerhodopsin-based loss-of-function optogenetics to explore the contribution of these neurons to BP in conscious rats. The results suggest that C1 neurons contribute little to resting BP under normoxia or hypercapnia, C1 neuron discharge is restrained continuously by arterial baroreceptors, and C1 neuron activation is critical to stabilize BP under hypoxia or anesthesia. This optogenetic approach could also be useful to explore the role of C1 neurons during specific behaviors or in hypertensive models. PMID- 28363985 TI - Structure and Dynamics of the Liver Receptor Homolog 1-PGC1alpha Complex. AB - Peroxisome proliferator-activated gamma coactivator 1-alpha (PGC1alpha) regulates energy metabolism by directly interacting with transcription factors to modulate gene expression. Among the PGC1alpha binding partners is liver receptor homolog 1 (LRH-1; NR5A2), an orphan nuclear hormone receptor that controls lipid and glucose homeostasis. Although PGC1alpha is known to bind and activate LRH-1, mechanisms through which PGC1alpha changes LRH-1 conformation to drive transcription are unknown. Here, we used biochemical and structural methods to interrogate the LRH-1-PGC1alpha complex. Purified, full-length LRH-1, as well as isolated ligand binding domain, bound to PGC1alpha with higher affinity than to the coactivator, nuclear receptor coactivator-2 (Tif2), in coregulator peptide recruitment assays. We present the first crystal structure of the LRH-1-PGC1alpha complex, which depicts several hydrophobic contacts and a strong charge clamp at the interface between these partners. In molecular dynamics simulations, PGC1alpha induced correlated atomic motion throughout the entire LRH-1 activation function surface, which was dependent on charge-clamp formation. In contrast, Tif2 induced weaker signaling at the activation function surface than PGC1alpha but promoted allosteric signaling from the helix 6/beta-sheet region of LRH-1 to the activation function surface. These studies are the first to probe mechanisms underlying the LRH-1-PGC1alpha interaction and may illuminate strategies for selective therapeutic targeting of PGC1alpha-dependent LRH-1 signaling pathways. PMID- 28363986 TI - Gender and international clinician educators. AB - OBJECTIVES: To describe gender differences of international clinician educators (CEs) and leaders, and CEs' perceptions by gender of preparation, roles, rewards and factors affecting job satisfaction and retention in emerging international competency-based residency programmes. METHODS: Cross-sectional surveys of CEs and leadership were conductedJune 2013-June 2014 at institutions that had adopted competency-based graduate medical education and were accredited by the Accreditation Council for Graduate Medical Education-International. RESULTS: 274 (76.3%) of 359 eligible participants responded; 69 (25.2%) were female. Two (18%) of 11 chief executive officers and 1 (9%) of 11 chief medical officers were women. Female CEs were younger, more likely to be single and childless. They were less likely to hold academic appointments, despite no gender differences in length of time at current institution or in current position. A greater proportion of female CEs felt they were 'never' rewarded by academic promotion. Satisfaction rates were similar between the genders. Single female CEs were five times as likely to report being 'extremely likely' to stay in the country. Female CEs with children <21 were less likely to report high likelihood of staying in academia. Marital status and children were not associated with outcomes for male CEs. CONCLUSIONS: In the international academic medicine programmes studied, there were fewer female CEs in the pipeline and they perceived a gender gap in appointment and advancement. Stakeholders at international programmes need to develop contextualised strategies to expand entry and decrease attrition of women into CE tracks, and promote gender equity. PMID- 28363988 TI - Implementing tools to support evidence-based practice: a survey and brief intervention study of the National Elf Service across Oxford Health NHS Foundation Trust. AB - BACKGROUND: Technology and the internet has enabled rapid access to research but most mental health professionals do not have time to keep up with the vast and growing scientific literature. Secondary information sources, such as the National Elf Service (NES), aim to summarise the most important and up-to-date research to improve mental health professionals' access to information to support evidence-based medicine (EBM). OBJECTIVE: To explore mental health professionals' attitudes towards evidence-based practice and methods used to keep up-to-date with research. To promote use of a digital evidence-based platform (the National Elf Service), assess its use and explore its potential to impact clinical practice. METHODS: Baseline and follow-up surveys were distributed among staff of 5 adult mental health community teams and 2 early intervention services (n=331) in Oxford Health Foundation Trust (OHFT) prior to and following an intervention raising awareness of the National Elf Service. FINDINGS: Of 133 baseline survey responders, the majority of staff reported their clinical practice was informed by evidence, mostly using existing clinical guidelines and online resources. Few had used the National Elf Service. 122 staff members completed the follow-up survey. Postintervention, 42 staff members indicated they had used the National Elf Service (compared with 13 preintervention) and that it had improved access to research. Lack of time was most often the barrier restricting evidence-based practice. CONCLUSIONS: Mental health professionals are engaged with EBM and those that used the National Elf Service felt it did, or could have the potential to impact on their clinical practice. CLINICAL IMPLICATIONS: Barriers and challenges to implement EBM more widely suggest targeted efforts should be made to embed evidence-based practice into the working culture. PMID- 28363989 TI - Reporting guidance considerations from a statistical perspective: overview of tools to enhance the rigour of reporting of randomised trials and systematic reviews. AB - OBJECTIVE: Research waste has received considerable attention from the biomedical community. One noteworthy contributor is incomplete reporting in research publications. When detailing statistical methods and results, ensuring analytic methods and findings are completely documented improves transparency. For publications describing randomised trials and systematic reviews, guidelines have been developed to facilitate complete reporting. This overview summarises aspects of statistical reporting in trials and systematic reviews of health interventions. METHODS: A narrative approach to summarise features regarding statistical methods and findings from reporting guidelines for trials and reviews was taken. We aim to enhance familiarity of statistical details that should be reported in biomedical research among statisticians and their collaborators. RESULTS: We summarise statistical reporting considerations for trials and systematic reviews from guidance documents including the Consolidated Standards of Reporting Trials (CONSORT) Statement for reporting of trials, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Statement for trial protocols, the Statistical Analyses and Methods in the Published Literature (SAMPL) Guidelines for statistical reporting principles, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement for systematic reviews and PRISMA for Protocols (PRISMA-P). Considerations regarding sharing of study data and statistical code are also addressed. CONCLUSIONS: Reporting guidelines provide researchers with minimum criteria for reporting. If followed, they can enhance research transparency and contribute improve quality of biomedical publications. Authors should employ these tools for planning and reporting of their research. PMID- 28363987 TI - Progesterone induces neuroprotection following reperfusion-promoted mitochondrial dysfunction after focal cerebral ischemia in rats. AB - Organelle damage and increases in mitochondrial permeabilization are key events in the development of cerebral ischemic tissue injury because they cause both modifications in ATP turnover and cellular apoptosis/necrosis. Early restoration of blood flow and improvement of mitochondrial function might reverse the situation and help in recovery following an onset of stroke. Mitochondria and related bioenergetic processes can be effectively used as pharmacological targets. Progesterone (P4), one of the promising neurosteroids, has been found to be neuroprotective in various models of neurological diseases, through a number of mechanisms. This influenced us to investigate the possible role of P4 in the mitochondria-mediated neuroprotective mechanism in an ischemic stroke model of rat. In this study, we have shown the positive effect of P4 administration on behavioral deficits and mitochondrial health in an ischemic stroke injury model of transient middle cerebral artery occlusion (tMCAO). After induction of tMCAO, the rats received an initial intraperitoneal injection of P4 (8 mg/kg body weight) or vehicle at 1 h post-occlusion followed by subcutaneous injections at 6, 12 and 18 h. Behavioral assessment for functional deficits included grip strength, motor coordination and gait analysis. Findings revealed a significant improvement with P4 treatment in tMCAO animals. Staining of isolated brain slices from P4-treated rats with 2,3,5-triphenyltetrazolium chloride (TTC) showed a reduction in the infarct area in comparison to the vehicle group, indicating the presence of an increased number of viable mitochondria. P4 treatment was also able to attenuate mitochondrial reactive oxygen species (ROS) production, as well as block the mitochondrial permeability transition pore (mPTP), in the tMCAO injury model. In addition, it was also able to ameliorate the altered mitochondrial membrane potential and respiration ratio in the ischemic animals, thereby suggesting that P4 has a positive effect on mitochondrial bioenergetics. In conclusion, these results demonstrate that P4 treatment is beneficial in preserving the mitochondrial functions that are altered in cerebral ischemic injury and thus can help in defining better therapies. PMID- 28363990 TI - A dirty little secret: stigma, shame and hepatitis C in the health setting. AB - While recent medical innovation shows great promise in treating hepatitis C (HCV), it remains a condition associated with profound stigma. HCV is a bloodborne virus (BBV) most commonly transmitted in high-income countries by injecting drug use, and it is the stigmatising association between the two which is deeply problematic for those with HCV. A qualitative study undertaken in 2002 found that disclosure in health settings places those with HCV in positions of pronounced vulnerability. Disclosure is a primal scene, an interface, where the stigma of HCV, replete with connotations of disease and deviance, potentially transforms those affected into shamed subjects. Standard precautions protect health workers and minimise the transmission of contagion, measures which, in theory, also mitigate the requirement of those with BBVs to unnecessarily disclose their blood status. However, questions on pre-employment health checks, concerns that health treatments might adversely affect the liver and an ethical need to pre-emptively inform healthcare professionals undertaking exposure prone procedures are occasions when those with HCV confront the decision to disclose their blood status. This paper employs Goffman's model of actual and virtual social identities, along with Douglas' notion of dirt and pollution, to examine the dilemmas around disclosure those with HCV negotiate within the health setting. Discriminatory responses by healthcare professionals elucidate the stigmatising potential HCV carries. The subsequent reticence by those with HCV to disclose their blood status risks less than optimum healthcare. Recent studies indicate that stigma occurring in health settings remains a perennial concern for those with HCV. PMID- 28363991 TI - Regulatory Phosphorylation of Bacterial-Type PEP Carboxylase by the Ca2+ Dependent Protein Kinase RcCDPK1 in Developing Castor Oil Seeds. AB - Phosphoenolpyruvate carboxylase (PEPC) is a tightly controlled cytosolic enzyme situated at a crucial branch point of central plant metabolism. In developing castor oil seeds (Ricinus communis) a novel, allosterically desensitized 910-kD Class-2 PEPC hetero-octameric complex, arises from a tight interaction between 107-kD plant-type PEPC and 118-kD bacterial-type (BTPC) subunits. The native Ca2+ dependent protein kinase (CDPK) responsible for in vivo inhibitory phosphorylation of Class-2 PEPC's BTPC subunit's at Ser-451 was highly purified from COS and identified as RcCDPK1 (XP_002526815) by mass spectrometry. Heterologously expressed RcCDPK1 catalyzed Ca2+-dependent, inhibitory phosphorylation of BTPC at Ser-451 while exhibiting: (i) a pair of Ca2+ binding sites with identical dissociation constants of 5.03 MUM, (ii) a Ca2+-dependent electrophoretic mobility shift, and (iii) a marked Ca2+-independent hydrophobicity. Pull-down experiments established the Ca2+-dependent interaction of N-terminal GST-tagged RcCDPK1 with BTPC. RcCDPK1-Cherry localized to the cytosol and nucleus of tobacco bright yellow-2 cells, but colocalized with mitochondrial-surface associated BTPC-enhanced yellow fluorescent protein when both fusion proteins were coexpressed. Deletion analyses demonstrated that although its N-terminal variable domain plays an essential role in optimizing Ca2+-dependent RcCDPK1 autophosphorylation and BTPC transphosphorylation activity, it is not critical for in vitro or in vivo target recognition. Arabidopsis (Arabidopsis thaliana) CPK4 and soybean (Glycine max) CDPKbeta are RcCDPK1 orthologs that effectively phosphorylated castor BTPC at Ser-451. Overall, the results highlight a potential link between cytosolic Ca2+ signaling and the posttranslational control of respiratory CO2 refixation and anaplerotic photosynthate partitioning in support of storage oil and protein biosynthesis in developing COS. PMID- 28363994 TI - Validating the Manchester Acute Coronary Syndromes (MACS) and Troponin-only Manchester Acute Coronary Syndromes (T-MACS) rules for the prediction of acute myocardial infarction in patients presenting to the emergency department with chest pain. AB - BACKGROUND: The Manchester Acute Coronary Syndromes (MACS) rule and the Troponin only MACS (T-MACS) rule risk stratify patients with suspected acute coronary syndrome (ACS). This observational study sought to validate and compare the MACS and T-MACS rules for assessment of acute myocardial infarction (AMI). METHODS: Prospectively collected data from twoEDs in Australia and New Zealand were analysed. Patients were assigned a probability of ACS based on the MACS and T MACS rules, incorporating high-sensitivity troponin T, heart-type fatty acid binding protein, ECG results and clinical symptoms. Patients were then deemed very low risk, low risk, intermediate or high risk if their MACS probability was less than 2%, between 2% and 5%, between 5% and 95% and greater than 95%, respectively. The primary endpoint was 30-day diagnosis of AMI. The secondary endpoint was 30-day major adverse cardiac event (MACE) including AMI, revascularisation or coronary stenosis (>70%). Sensitivity, specificity and predictive values were calculated to assess the accuracy of the MACS and T-MACS rules. RESULTS: Of the 1244 patients, 114 (9.2%) were diagnosed with AMI and 163 (13.1%) with MACE. The MACS and T-MACS rules categorised 133 (10.7%) and 246 (19.8%) patients, respectively, as very low risk and potentially suitable for early discharge from the ED. There was one false negative case for both rules making sensitivity 99.1% (95.2%-100%). CONCLUSIONS: MACS and T-MACS accurately risk stratify very low risk patients. The T-MACS rule would allow for more patients to be discharged early. The potential for missed MACE events means that further outpatient testing for coronary artery disease may be required for patients identified as very low risk. PMID- 28363992 TI - MtLAX2, a Functional Homologue of the Arabidopsis Auxin Influx Transporter AUX1, Is Required for Nodule Organogenesis. AB - Most legume plants can form nodules, specialized lateral organs that form on roots, and house nitrogen-fixing bacteria collectively called rhizobia. The uptake of the phytohormone auxin into cells is known to be crucial for development of lateral roots. To test the role of auxin influx in nodulation we used the auxin influx inhibitors 1-naphthoxyacetic acid (1-NOA) and 2-NOA, which we found reduced nodulation of Medicago truncatula. This suggested the possible involvement of the AUX/LAX family of auxin influx transporters in nodulation. Gene expression studies identified MtLAX2, a paralogue of Arabidopsis (Arabidopsis thaliana) AUX1, as being induced at early stages of nodule development. MtLAX2 is expressed in nodule primordia, the vasculature of developing nodules, and at the apex of mature nodules. The MtLAX2 promoter contains several auxin response elements, and treatment with indole-acetic acid strongly induces MtLAX2 expression in roots. mtlax2 mutants displayed root phenotypes similar to Arabidopsis aux1 mutants, including altered root gravitropism, fewer lateral roots, shorter root hairs, and auxin resistance. In addition, the activity of the synthetic DR5-GUS auxin reporter was strongly reduced in mtlax2 roots. Following inoculation with rhizobia, mtlax2 roots developed fewer nodules, had decreased DR5-GUS activity associated with infection sites, and had decreased expression of the early auxin responsive gene ARF16a Our data indicate that MtLAX2 is a functional analog of Arabidopsis AUX1 and is required for the accumulation of auxin during nodule formation in tissues underlying sites of rhizobial infection. PMID- 28363996 TI - miR-34a and miR-34b/c Suppress Intestinal Tumorigenesis. AB - The p53-inducible miR-34a and miR-34b/c genes are frequently silenced in colorectal cancer. To address the in vivo relevance of miR-34a/b/c function for suppression of intestinal tumor formation, we generated ApcMin/+ mice with deletions of the miR-34a and/or miR-34b/c genes separately or in combination. Combined deletion of miR-34a/b/c increased the number of intestinal stem cells as well as Paneth and Goblet cells, resulting in enlarged intestinal crypts. miR 34a/b/c-deficient ApcMin/+ mice displayed an increased tumor burden and grade and decreased survival. miR-34a/b/c-deficient adenomas showed elevated proliferation and decreased apoptosis and displayed pronounced bacterial infiltration, which may be due to an observed decrease in infiltrating immune cells and downregulation of barrier proteins. mRNA induction in miR-34a/b/c-deficient tumors was enriched for miR-34a/b/c seed-matching sites and for mRNAs encoding proteins related to epithelial-mesenchymal transition, stemness, and Wnt signaling. Accordingly, cells explanted from miR-34a/b/c-deficient adenomas formed tumor organoids at an increased rate. Several upregulated miR-34 targets displayed elevated expression in primary human colorectal cancers that was associated with lymph-node metastases (INHBB, AXL, FGFR1, and PDFGRB) and upregulation of INHBB and AXL in primary colorectal cancer was associated with poor patient survival. In conclusion, our results show that miR-34a/b/c suppress tumor formation caused by loss of Apc and control intestinal stem cell and secretory cell homeostasis by downregulation of multiple target mRNAs. Cancer Res; 77(10); 2746-58. (c)2017 AACR. PMID- 28363993 TI - Temporal Dynamics of Stomatal Behavior: Modeling and Implications for Photosynthesis and Water Use. PMID- 28363995 TI - Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors. AB - Insertion mutations in EGFR and HER2 both occur at analogous positions in exon 20. Non-small cell lung cancer (NSCLC) patients with tumors harboring these mutations seldom achieve clinical responses to dacomitinib and afatinib, two covalent quinazoline-based inhibitors of EGFR or HER2, respectively. In this study, we investigated the effects of specific EGFR and HER2 exon 20 insertion mutations from NSCLC patients that had clinically achieved a partial response after dacomitinib treatment. We identified Gly770 as a common feature among the drug-sensitive mutations. Structural modeling suggested that this mutation may facilitate inhibitor binding to EGFR. Introduction of Gly770 into two dacomitinib resistant EGFR exon 20 insertion mutants restored sensitivity to dacomitinib. Based on these findings, we used afatinib to treat an NSCLC patient whose tumor harbored the HER2 V777_G778insGSP mutation and achieved a durable partial response. We further identified secondary mutations in EGFR (T790M or C797S) and HER2 (C805S) that mediated acquired drug resistance in drug-sensitive EGFR or HER2 exon 20 insertion models. Overall, our findings identified a subset of EGFR and HER2 exon 20 insertion mutations that are sensitive to existing covalent quinazoline-based EGFR/HER2 inhibitors, with implications for current clinical treatment and next-generation small-molecule inhibitors. Cancer Res; 77(10); 2712 21. (c)2017 AACR. PMID- 28363997 TI - Development of a T-cell Receptor Mimic Antibody against Wild-Type p53 for Cancer Immunotherapy. AB - The tumor suppressor p53 is widely dysregulated in cancer and represents an attractive target for immunotherapy. Because of its intracellular localization, p53 is inaccessible to classical therapeutic monoclonal antibodies, an increasingly successful class of anticancer drugs. However, peptides derived from intracellular antigens are presented on the cell surface in the context of MHC I and can be bound by T-cell receptors (TCR). Here, we report the development of a novel antibody, T1-116C, that acts as a TCR mimic to recognize an HLA-A*0201 presented wild-type p53 T-cell epitope, p5365-73(RMPEAAPPV). The antibody recognizes a wide range of cancers, does not bind normal peripheral blood mononuclear cells, and can activate immune effector functions to kill cancer cells in vitroIn vivo, the antibody targets p5365-73 peptide-expressing breast cancer xenografts, significantly inhibiting tumor growth. This represents a promising new agent for future cancer immunotherapy. Cancer Res; 77(10); 2699 711. (c)2017 AACR. PMID- 28363998 TI - E3 Ligase cIAP2 Mediates Downregulation of MRE11 and Radiosensitization in Response to HDAC Inhibition in Bladder Cancer. AB - The MRE11/RAD50/NBS1 (MRN) complex mediates DNA repair pathways, including double strand breaks induced by radiotherapy. Meiotic recombination 11 homolog (MRE11) is downregulated by histone deacetylase inhibition (HDACi), resulting in reduced levels of DNA repair in bladder cancer cells and radiosensitization. In this study, we show that the mechanism of this downregulation is posttranslational and identify a C-terminally truncated MRE11, which is formed after HDAC inhibition as full-length MRE11 is downregulated. Truncated MRE11 was stabilized by proteasome inhibition, exhibited a decreased half-life after treatment with panobinostat, and therefore represents a newly identified intermediate induced and degraded in response to HDAC inhibition. The E3 ligase cellular inhibitor of apoptosis protein 2 (cIAP2) was upregulated in response to HDAC inhibition and was validated as a new MRE11 binding partner whose upregulation had similar effects to HDAC inhibition. cIAP2 overexpression resulted in downregulation and altered ubiquitination patterns of MRE11 and mediated radiosensitization in response to HDAC inhibition. These results highlight cIAP2 as a player in the DNA damage response as a posttranscriptional regulator of MRE11 and identify cIAP2 as a potential target for biomarker discovery or chemoradiation strategies in bladder cancer. Cancer Res; 77(11); 3027-39. (c)2017 AACR. PMID- 28363999 TI - ATM Deficiency Is Associated with Sensitivity to PARP1- and ATR Inhibitors in Lung Adenocarcinoma. AB - Defects in maintaining genome integrity are a hallmark of cancer. The DNA damage response kinase ATM is frequently mutated in human cancer, but the significance of these events to chemotherapeutic efficacy has not been examined deeply in whole organism models. Here we demonstrate that bi-allelic Atm deletion in mouse models of Kras-mutant lung adenocarcinoma does not affect cisplatin responses. In marked contrast, Atm-deficient tumors displayed an enhanced response to the topoisomerase-II poison etoposide. Moreover, Atm-deficient cells and tumors were sensitive to the PARP inhibitor olaparib. This actionable molecular addiction to functional PARP1 signaling was preserved in models that were proficient or deficient in p53, resembling standard or high-risk genetic constellations, respectively. Atm deficiency also markedly enhanced sensitivity to the ATR inhibitor VE-822. Taken together, our results provide a functional rationale to profile human tumors for disabling ATM mutations, particularly given their impact on PARP1 and ATR inhibitors. Cancer Res; 77(11); 3040-56. (c)2017 AACR. PMID- 28364001 TI - Morphoproteomic Characterization of Lung Squamous Cell Carcinoma Fragmentation, a Histological Marker of Increased Tumor Invasiveness. AB - Accurate stratification of tumors is imperative for adequate cancer management. In addition to staging, morphologic subtyping allows stratification of patients into additional prognostic groups. In this study, we used an image-based computational method on pan-cytokeratin IHC stainings to quantify tumor fragmentation (TF), a measure of tumor invasiveness of lung squamous cell carcinoma (LSCC). In two independent clinical cohorts from tissue microarrays (TMA: n = 208 patients) and whole sections (WS: n = 99 patients), TF was associated with poor prognosis and increased risk of blood vessel infiltration. A third cohort from The Cancer Genome Atlas (TCGA: n = 335 patients) confirmed the poor prognostic value of TF using a similar human-based score on hematoxylin eosin staining. Integration of RNA-seq data from TCGA and LC-MS/MS proteomics from WS revealed an upregulation of extracellular matrix remodeling and focal adhesion processes in tumors with high TF, supporting their increased invasive potential. This proposed histologic parameter is an independent and unfavorable prognostic marker that could be established as a new grading parameter for LSCC. Cancer Res; 77(10); 2585-93. (c)2017 AACR. PMID- 28364000 TI - Anti-PD-L1 Efficacy Can Be Enhanced by Inhibition of Myeloid-Derived Suppressor Cells with a Selective Inhibitor of PI3Kdelta/gamma. AB - Checkpoint inhibitors are relatively inefficacious in head and neck cancers, despite an abundance of genetic alterations and a T-cell-inflamed phenotype. One significant barrier to efficacy may be the recruitment of myeloid-derived suppressor cells (MDSC) into the tumor microenvironment. Here we demonstrate functional inhibition of MDSC with IPI-145, an inhibitor of PI3Kdelta and PI3Kgamma isoforms, which enhances responses to PD-L1 blockade. Combination therapy induced CD8+ T lymphocyte-dependent primary tumor growth delay and prolonged survival only in T-cell-inflamed tumor models of head and neck cancers. However, higher doses of IPI-145 reversed the observed enhancement of anti-PD-L1 efficacy due to off-target suppression of the activity of tumor-infiltrating T lymphocytes. Together, our results offer a preclinical proof of concept for the low-dose use of isoform-specific PI3Kdelta/gamma inhibitors to suppress MDSC to enhance responses to immune checkpoint blockade. Cancer Res; 77(10); 2607-19. (c)2017 AACR. PMID- 28364002 TI - Tissue-Specific Signaling Networks Rewired by Major Somatic Mutations in Human Cancer Revealed by Proteome-Wide Discovery. AB - Massive somatic mutations discovered by large cancer genome sequencing projects provide unprecedented opportunities in the development of precision oncology. However, deep understanding of functional consequences of somatic mutations and identifying actionable mutations and the related drug responses currently remain formidable challenges. Dysfunction of protein posttranslational modification plays critical roles in tumorigenesis and drug responses. In this study, we proposed a novel computational oncoproteomics approach, named kinome-wide network module for cancer pharmacogenomics (KNMPx), for identifying actionable mutations that rewired signaling networks and further characterized tumorigenesis and anticancer drug responses. Specifically, we integrated 746,631 missense mutations in 4,997 tumor samples across 16 major cancer types/subtypes from The Cancer Genome Atlas into over 170,000 carefully curated nonredundant phosphorylation sites covering 18,610 proteins. We found 47 mutated proteins (e.g., ERBB2, TP53, and CTNNB1) that had enriched missense mutations at their phosphorylation sites in pan-cancer analysis. In addition, tissue-specific kinase-substrate interaction modules altered by somatic mutations identified by KNMPx were significantly associated with patient survival. We further reported a kinome-wide landscape of pharmacogenomic interactions by incorporating somatic mutation-rewired signaling networks in 1,001 cancer cell lines via KNMPx. Interestingly, we found that cell lines could highly reproduce oncogenic phosphorylation site mutations identified in primary tumors, supporting the confidence in their associations with sensitivity/resistance of inhibitors targeting EGF, MAPK, PI3K, mTOR, and Wnt signaling pathways. In summary, our KNMPx approach is powerful for identifying oncogenic alterations via rewiring phosphorylation-related signaling networks and drug sensitivity/resistance in the era of precision oncology. Cancer Res; 77(11); 2810-21. (c)2017 AACR. PMID- 28364004 TI - Acute Cytotoxic and Vasogenic Edema after Subarachnoid Hemorrhage: A Quantitative MRI Study. AB - BACKGROUND AND PURPOSE: The mechanism of early brain injury following subarachnoid hemorrhage is not well understood. We aimed to evaluate if cytotoxic and vasogenic edema are contributing factors. MATERIALS AND METHODS: A retrospective analysis was conducted in patients with SAH undergoing diffusion weighted MR imaging within 72 hours of onset. Apparent diffusion coefficient values derived from DWI were evaluated by using whole-brain histograms and 19 prespecified ROIs in patients with SAH and controls with normal findings on MRI. Cytotoxic edema observed outside the ROIs was assessed in patients with SAH. The average median ADC values were compared between patients with SAH and controls and patients with SAH with mild (Hunt and Hess 1-3) versus severe early brain injury (Hunt and Hess 4-5). RESULTS: We enrolled 33 patients with SAH and 66 controls. The overall average median whole-brain ADC was greater for patients with SAH (808 * 10-6 mm2/s) compared with controls (788 * 10-6 mm2/s, P < .001) and was higher in patients with SAH across ROIs after adjusting for age: cerebral gray matter (826 versus 803 * 10-6 mm2/s, P = .059), cerebral white matter (793 versus 758 * 10-6 mm2/s, P = .023), white matter tracts (797 versus 739 * 10-6 mm2/s, P < .001), and deep gray matter (754 versus 713 * 10-6 mm2/s, P = .016). ADC values trended higher in patients with Hunt and Hess 4-5 versus those with Hunt and Hess 1-3. Early cytotoxic edema was observed in 13 (39%) patients with SAH and was more prevalent in those with severe early brain injury (87.5% of patients with Hunt and Hess 4-5 versus 24.0% of those with Hunt and Hess 1-3, P = .001). CONCLUSIONS: Age-adjusted ADC values were globally increased in patients with SAH compared with controls, even in normal-appearing brain regions, suggesting diffuse vasogenic edema. Cytotoxic edema was also present in patients with SAH and correlated with more severe early brain injury. PMID- 28364003 TI - Multidrug Analyses in Patients Distinguish Efficacious Cancer Agents Based on Both Tumor Cell Killing and Immunomodulation. AB - The vision of a precision medicine-guided approach to novel cancer drug development is challenged by high intratumor heterogeneity and interpatient diversity. This complexity is rarely modeled accurately during preclinical drug development, hampering predictions of clinical drug efficacy. To address this issue, we developed Comparative In Vivo Oncology (CIVO) arrayed microinjection technology to test tumor responsiveness to simultaneous microdoses of multiple drugs directly in a patient's tumor. Here, in a study of 18 canine patients with soft tissue sarcoma (STS), CIVO captured complex, patient-specific tumor responses encompassing both cancer cells and multiple immune infiltrates following localized exposure to different chemotherapy agents. CIVO also classified patient-specific tumor resistance to the most effective agent, doxorubicin, and further enabled assessment of a preclinical autophagy inhibitor, PS-1001, to reverse doxorubicin resistance. In a CIVO-identified subset of doxorubicin-resistant tumors, PS-1001 resulted in enhanced antitumor activity, increased infiltration of macrophages, and skewed this infiltrate toward M1 polarization. The ability to evaluate and cross-compare multiple drugs and drug combinations simultaneously in living tumors and across a diverse immunocompetent patient population may provide a foundation from which to make informed drug development decisions. This method also represents a viable functional approach to complement current precision oncology strategies. Cancer Res; 77(11); 2869-80. (c)2017 AACR. PMID- 28364005 TI - Presurgical Brain Mapping of the Ventral Somatomotor Network in Patients with Brain Tumors Using Resting-State fMRI. AB - BACKGROUND AND PURPOSE: Resting-state fMRI readily identifies the dorsal but less consistently the ventral somatomotor network. Our aim was to assess the relative utility of resting-state fMRI in the identification of the ventral somatomotor network via comparison with task-based fMRI in patients with brain tumor. MATERIALS AND METHODS: We identified 26 surgically naive patients referred for presurgical fMRI brain mapping who had undergone both satisfactory ventral motor activation tasks and resting-state fMRI. Following standard preprocessing for task-based fMRI and resting-state fMRI, general linear model analysis of the ventral motor tasks and independent component analysis of resting-state fMRI were performed with the number of components set to 20, 30, 40, and 50. Visual overlap of task-based fMRI and resting-state fMRI at different component levels was assessed and categorized as full match, partial match, or no match. Rest-versus task-fMRI concordance was calculated with Dice coefficients across varying fMRI thresholds before and after noise removal. Multithresholded Dice coefficient volume under the surface was calculated. RESULTS: The ventral somatomotor network was identified in 81% of patients. At the subject level, better matches between resting-state fMRI and task-based fMRI were seen with an increasing order of components (53% of cases for 20 components versus 73% for 50 components). Noise removed group-mean volume under the surface improved as component numbers increased from 20 to 50, though ANOVA demonstrated no statistically significant difference among the 4 groups. CONCLUSIONS: In most patients, the ventral somatomotor network can be identified with an increase in the probability of a better match at a higher component number. There is variable concordance of the ventral somatomotor network at the single-subject level between resting-state and task-based fMRI. PMID- 28364006 TI - Detection of Focal Longitudinal Changes in the Brain by Subtraction of MR Images. AB - BACKGROUND AND PURPOSE: The detection of new subtle brain pathology on MR imaging is a time-consuming and error-prone task for the radiologist. This article introduces and evaluates an image-registration and subtraction method for highlighting small changes in the brain with a view to minimizing the risk of missed pathology and reducing fatigue. MATERIALS AND METHODS: We present a fully automated algorithm for highlighting subtle changes between multiple serially acquired brain MR images with a novel approach to registration and MR imaging bias field correction. The method was evaluated for the detection of new lesions in 77 patients undergoing cardiac surgery, by using pairs of fluid-attenuated inversion recovery MR images acquired 1-2 weeks before the operation and 6-8 weeks postoperatively. Three radiologists reviewed the images. RESULTS: On the basis of qualitative comparison of pre- and postsurgery FLAIR images, radiologists identified 37 new ischemic lesions in 22 patients. When these images were accompanied by a subtraction image, 46 new ischemic lesions were identified in 26 patients. After we accounted for interpatient and interradiologist variability using a multilevel statistical model, the likelihood of detecting a lesion was 2.59 (95% CI, 1.18-5.67) times greater when aided by the subtraction algorithm (P = .017). Radiologists also reviewed the images significantly faster (P < .001) by using the subtraction image (mean, 42 seconds; 95% CI, 29-60 seconds) than through qualitative assessment alone (mean, 66 seconds; 95% CI, 46 96 seconds). CONCLUSIONS: Use of this new subtraction algorithm would result in considerable savings in the time required to review images and in improved sensitivity to subtle focal pathology. PMID- 28364008 TI - Striving for the Best: How Far Should We Go? Regarding "Impact of Modified TICI 3 versus Modified TICI 2b Reperfusion Score to Predict Good Outcome following Endovascular Therapy". PMID- 28364007 TI - Combined Diffusion Tensor Imaging and Apparent Transverse Relaxation Rate Differentiate Parkinson Disease and Atypical Parkinsonism. AB - BACKGROUND AND PURPOSE: Both diffusion tensor imaging and the apparent transverse relaxation rate have shown promise in differentiating Parkinson disease from atypical parkinsonism (particularly multiple system atrophy and progressive supranuclear palsy). The objective of the study was to assess the ability of DTI, the apparent transverse relaxation rate, and their combination for differentiating Parkinson disease, multiple system atrophy, progressive supranuclear palsy, and controls. MATERIALS AND METHODS: A total of 106 subjects (36 controls, 35 patients with Parkinson disease, 16 with multiple system atrophy, and 19 with progressive supranuclear palsy) were included. DTI and the apparent transverse relaxation rate measures from the striatal, midbrain, limbic, and cerebellar regions were obtained and compared among groups. The discrimination performance of DTI and the apparent transverse relaxation rate among groups was assessed by using Elastic-Net machine learning and receiver operating characteristic curve analysis. RESULTS: Compared with controls, patients with Parkinson disease showed significant apparent transverse relaxation rate differences in the red nucleus. Compared to those with Parkinson disease, patients with both multiple system atrophy and progressive supranuclear palsy showed more widespread changes, extending from the midbrain to striatal and cerebellar structures. The pattern of changes, however, was different between the 2 groups. For instance, patients with multiple system atrophy showed decreased fractional anisotropy and an increased apparent transverse relaxation rate in the subthalamic nucleus, whereas patients with progressive supranuclear palsy showed an increased mean diffusivity in the hippocampus. Combined, DTI and the apparent transverse relaxation rate were significantly better than DTI or the apparent transverse relaxation rate alone in separating controls from those with Parkinson disease/multiple system atrophy/progressive supranuclear palsy; controls from those with Parkinson disease; those with Parkinson disease from those with multiple system atrophy/progressive supranuclear palsy; and those with Parkinson disease from those with multiple system atrophy; but not those with Parkinson disease from those with progressive supranuclear palsy, or those with multiple system atrophy from those with progressive supranuclear palsy. CONCLUSIONS: DTI and the apparent transverse relaxation rate provide different but complementary information for different parkinsonisms. Combined DTI and apparent transverse relaxation rate may be a superior marker for the differential diagnosis of parkinsonisms. PMID- 28364009 TI - Imaging Findings in Patients with Zoster-Associated Plexopathy. AB - Herpes zoster is a reactivation of the latent varicella zoster virus. Among the complications of herpes zoster is zoster-associated limb paresis. The clinical and imaging features of patients with zoster-associated limb paresis due to plexopathies (zoster-associated plexopathy) have had limited description in the literature. The Mayo Clinic patient data base was searched by diagnostic code for patients diagnosed with herpes zoster between January 1, 1996, and September 30, 2012. Patients who met the inclusion criteria for zoster-associated limb paresis or herpes zoster with MRIs obtained were reviewed. Ten patients with zoster associated plexopathy were identified. Imaging abnormalities were found in 70% of patients. Secondary denervation changes in shoulder girdle muscles and nerve T2 signal hyperintensity were the most frequent abnormalities (50%), followed by nerve enlargement (20%). Enhancement was not evident in any cases despite early imaging in 80% of the cohort. These results demonstrate the clinical utility of MR imaging in confirming the diagnosis of zoster-associated plexopathy. PMID- 28364010 TI - Initial Performance of NI-RADS to Predict Residual or Recurrent Head and Neck Squamous Cell Carcinoma. AB - BACKGROUND AND PURPOSE: The Head and Neck Imaging Reporting and Data System (NI RADS) surveillance template for head and neck cancer includes a numeric assessment of suspicion for recurrence (1-4) for the primary site and neck. Category 1 indicates no evidence of recurrence; category 2, low suspicion of recurrence; category 3, high suspicion of recurrence; and category 4, known recurrence. Our purpose was to evaluate the performance of the NI-RADS scoring system to predict local and regional disease recurrence or persistence. MATERIALS AND METHODS: This study was classified as a quality-improvement project by the institutional review board. A retrospective database search yielded 500 consecutive cases interpreted using the NI-RADS template. Cases without a numeric score, non-squamous cell carcinoma primary tumors, and primary squamous cell carcinoma outside the head and neck were excluded. The electronic medical record was reviewed to determine the subsequent management, pathology results, and outcome of clinical and radiologic follow-up. RESULTS: A total of 318 scans and 618 targets (314 primary targets and 304 nodal targets) met the inclusion criteria. Among the 618 targets, 85.4% were scored NI-RADS 1; 9.4% were scored NI RADS 2; and 5.2% were scored NI-RADS 3. The rates of positive disease were 3.79%, 17.2%, and 59.4% for each NI-RADS category, respectively. Univariate association analysis demonstrated a strong association between the NI-RADS score and ultimate disease recurrence, with P < .001 for primary and regional sites. CONCLUSIONS: The baseline performance of NI-RADS was good, demonstrating significant discrimination among the categories 1-3 for predicting disease. PMID- 28364012 TI - Reply. PMID- 28364011 TI - Spectrum of Spinal Cord, Spinal Root, and Brain MRI Abnormalities in Congenital Zika Syndrome with and without Arthrogryposis. AB - BACKGROUND AND PURPOSE: Arthrogryposis is among the malformations of congenital Zika syndrome. Similar to the brain, there might exist a spectrum of spinal cord abnormalities. The purpose of this study was to explore and describe in detail the MR imaging features found in the spinal cords, nerve roots, and brains of children with congenital Zika syndrome with and without arthrogryposis. MATERIALS AND METHODS: Twelve infants with congenital Zika syndrome (4 with arthrogryposis and 8 without) who had undergone brain and spinal cord MR imaging were retrospectively selected. Qualitative and quantitative analyses were performed and compared between groups. RESULTS: At visual inspection, both groups showed reduced thoracic spinal cord thickness: 75% (6/8) of the group without arthrogryposis and 100% (4/4) of the arthrogryposis group. However, the latter had the entire spinal cord reduced and more severely reduced conus medullaris anterior roots (respectively, P = .002 and .007). Quantitative differences were found for conus medullaris base and cervical and lumbar intumescences diameters (respectively, P = .008, .048, .008), with more prominent reduction in arthrogryposis. Periventricular calcifications were more frequent in infants with arthrogryposis (P = .018). CONCLUSIONS: Most infants had some degree of spinal cord thickness reduction, predominant in the thoracic segment (without arthrogryposis) or in the entire spinal cord (with arthrogryposis). The conus medullaris anterior roots were reduced in both groups (thinner in arthrogryposis). A prominent anterior median fissure of the spinal cord was absent in infants without arthrogryposis. Brain stem hypoplasia was present in all infants with arthrogryposis, periventricular calcifications, in the majority, and polymicrogyria was absent. PMID- 28364013 TI - 3D Ultrasound for Imaging and Quantifying Carotid Ulcers. PMID- 28364015 TI - Clinically Relevant Concentrations of Anticancer Drugs: A Guide for Nonclinical Studies. AB - Approved and marketed drugs are frequently studied in nonclinical models to evaluate the potential application to additional disease indications or to gain insight about molecular mechanisms of action. A survey of the literature reveals that nonclinical experimental designs (in vitro or in vivo) often include evaluation of drug concentrations or doses that are much higher than what can be achieved in patients (i.e., above the maximally tolerated dose or much higher than the clinically relevant exposures). The results obtained with these high concentrations may be particularly helpful in elucidating off-target effects and toxicities, but it is critical to have a dose-response curve that includes the minimally effective or clinically effective concentration for comparison. We have reviewed the clinical literature and drug product labels for all small molecules and biological agents approved by the FDA for use in oncology to identify and compile the available pharmacokinetic parameters. The data summarized here can serve as a guide for selection of in vitro concentrations and in vivo plasma exposures for evaluation of drug effects in nonclinical studies. Inclusion of drug concentrations or exposures that are relevant to those observed in clinical practice can improve translation of nonclinical mechanism of action findings into potentially relevant clinical effects. Clin Cancer Res; 23(14); 3489-98. (c)2017 AACR. PMID- 28364014 TI - Radium-223 Inhibits Osseous Prostate Cancer Growth by Dual Targeting of Cancer Cells and Bone Microenvironment in Mouse Models. AB - Purpose: Radium-223 dichloride (radium-223, Xofigo), a targeted alpha therapy, is currently used for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone metastases. This study examines the mode-of-action and antitumor efficacy of radium-223 in two prostate cancer xenograft models.Experimental Design: Mice bearing intratibial LNCaP or LuCaP 58 tumors were randomized into groups (n = 12-17) based on lesion grade and/or serum PSA level and administered radium-223 (300 kBq/kg) or vehicle, twice at 4-week intervals. X-rays and serum samples were obtained biweekly. Soft tissue tumors were observed macroscopically at sacrifice. Tibiae were analyzed by gamma counter, micro-CT, autoradiography and histology.Results: Radium-223 inhibited tumor-induced osteoblastic bone growth and protected normal bone architecture, leading to reduced bone volume in LNCaP and abiraterone-resistant LuCaP 58 models. Furthermore, radium-223 resulted in lower PSA values and reduced total tissue and tumor areas, indicating that treatment constrains prostate cancer growth in bone. In addition, radium-223 suppressed abnormal bone metabolic activity as evidenced by decreased number of osteoblasts and osteoclasts and reduced level of the bone formation marker PINP. Mode-of-action studies revealed that radium-223 was deposited in the intratumoral bone matrix. DNA double-strand breaks were induced in cancer cells within 24 hours after radium-223 treatment, and PSA levels were significantly lower 72 hours after treatment, providing further evidence of the antitumor effects.Conclusions: Taken together, radium-223 therapy exhibits a dual targeting mode-of-action that induces tumor cell death and suppresses tumor-induced pathologic bone formation in tumor microenvironment of osseous CRPC growth in mice. Clin Cancer Res; 23(15); 4335-46. (c)2017 AACR. PMID- 28364016 TI - Reduced membrane cholesterol limits pulmonary endothelial Ca2+ entry after chronic hypoxia. AB - Chronic hypoxia (CH)-induced pulmonary hypertension is associated with diminished production of endothelium-derived Ca2+-dependent vasodilators such as nitric oxide. Interestingly, ATP-induced endothelial Ca2+ entry as well as membrane cholesterol (Chol) are decreased in pulmonary arteries from CH rats (4 wk, barometric pressure = 380 Torr) compared with normoxic controls. Store-operated Ca2+ entry (SOCE) and depolarization-induced Ca2+ entry are major components of the response to ATP and are similarly decreased after CH. We hypothesized that membrane Chol facilitates both SOCE and depolarization-induced pulmonary endothelial Ca2+ entry and that CH attenuates these responses by decreasing membrane Chol. To test these hypotheses, we administered Chol or epicholesterol (Epichol) to acutely isolated pulmonary arterial endothelial cells (PAECs) from control and CH rats to either supplement or replace native Chol, respectively. The efficacy of membrane Chol manipulation was confirmed by filipin staining. Epichol greatly reduced ATP-induced Ca2+ influx in PAECs from control rats. Whereas Epichol similarly blunted endothelial SOCE in PAECs from both groups, Chol supplementation restored diminished SOCE in PAECs from CH rats while having no effect in controls. Similar effects of Chol manipulation on PAEC Ca2+ influx were observed in response to a depolarizing stimulus of KCl. Furthermore, KCl induced Ca2+ entry was inhibited by the T-type Ca2+ channel antagonist mibefradil but not the L-type Ca2+ channel inhibitor diltiazem. We conclude that PAEC membrane Chol is required for ATP-induced Ca2+ entry and its two components, SOCE and depolarization-induced Ca2+ entry, and that reduced Ca2+ entry after CH may be due to loss of this key regulator.NEW & NOTEWORTHY This research is the first to examine the direct role of membrane cholesterol in regulating pulmonary endothelial agonist-induced Ca2+ entry and its components. The results provide a potential mechanism by which chronic hypoxia impairs pulmonary endothelial Ca2+ influx, which may contribute to pulmonary hypertension. PMID- 28364019 TI - Arterial viscoelasticity: role in the dependency of pulse wave velocity on heart rate in conduit arteries. AB - Experimental investigations have established that the stiffness of large arteries has a dependency on acute heart rate (HR) changes. However, the possible underlying mechanisms inherent in this HR dependency have not been well established. This study aimed to explore a plausible viscoelastic mechanism by which HR exerts an influence on arterial stiffness. A multisegment transmission line model of the human arterial tree incorporating fractional viscoelastic components in each segment was used to investigate the effect of varying fractional order parameter (alpha) of viscoelasticity on the dependence of aortic arch to femoral artery pulse wave velocity (afPWV) on HR. HR was varied from 60 to 100 beats/min at a fixed mean flow of 100 ml/s. PWV was calculated by intersecting tangent method (afPWVTan) and by phase velocity from the transfer function (afPWVTF) in the time and frequency domain, respectively. PWV was significantly and positively associated with HR for alpha >= 0.6; for alpha = 0.6, 0.8, and 1, HR-dependent changes in afPWVTan were 0.01 +/- 0.02, 0.07 +/- 0.04, and 0.22 +/- 0.09 m/s per 5 beats/min; HR-dependent changes in afPWVTF were 0.02 +/- 0.01, 0.12 +/- 0.00, and 0.34 +/- 0.01 m/s per 5 beats/min, respectively. This crosses the range of previous physiological studies where the dependence of PWV on HR was found to be between 0.08 and 0.10 m/s per 5 beats/min. Therefore, viscoelasticity of the arterial wall could contribute to mechanisms through which large artery stiffness changes with changing HR. Physiological studies are required to confirm this mechanism.NEW & NOTEWORTHY This study used a transmission line model to elucidate the role of arterial viscoelasticity in the dependency of pulse wave velocity on heart rate. The model uses fractional viscoelasticity concepts, which provided novel insights into arterial hemodynamics. This study also provides a means of assessing the clinical manifestation of the association of pulse wave velocity and heart rate. PMID- 28364018 TI - Ultrasound detection of altered placental vascular morphology based on hemodynamic pulse wave reflection. AB - Abnormally pulsatile umbilical artery (UA) Doppler ultrasound velocity waveforms are a hallmark of severe or early onset placental-mediated intrauterine growth restriction (IUGR), whereas milder late onset IUGR pregnancies typically have normal UA pulsatility. The diagnostic utility of these waveforms to detect placental pathology is thus limited and hampered by factors outside of the placental circulation, including fetal cardiac output. In view of these limitations, we hypothesized that these Doppler waveforms could be more clearly understood as a reflection phenomenon and that a reflected pulse pressure wave is present in the UA that originates from the placenta and propagates backward along the UA. To investigate this, we developed a new ultrasound approach to isolate that portion of the UA Doppler waveform that arises from a pulse pressure wave propagating backward along the UA. Ultrasound measurements of UA lumen diameter and flow waveforms were used to decompose the observed flow waveform into its forward and reflected components. Evaluation of CD1 and C57BL/6 mice at embryonic day (E)15.5 and E17.5 demonstrated that the reflected waveforms diverged between the strains at E17.5, mirroring known changes in the fractal geometry of fetoplacental arteries at these ages. These experiments demonstrate the feasibility of noninvasively measuring wave reflections that originate from the fetoplacental circulation. The observed reflections were consistent with theoretical predictions based on the area ratio of parent to daughters at bifurcations in fetoplacental arteries suggesting that this approach could be used in the diagnosis of fetoplacental vascular pathology that is prevalent in human IUGR. Given that the proposed measurements represent a subset of those currently used in human fetal surveillance, the adaptation of this technology could extend the diagnostic utility of Doppler ultrasound in the detection of placental vascular pathologies that cause IUGR.NEW & NOTEWORTHY Here, we describe a novel approach to noninvasively detect microvascular changes in the fetoplacental circulation using ultrasound. The technique is based on detecting reflection pulse pressure waves that travel along the umbilical artery. Using a proof-of-principle study, we demonstrate the feasibility of the technique in two strains of experimental mice. PMID- 28364017 TI - Recording sympathetic nerve activity in conscious humans and other mammals: guidelines and the road to standardization. AB - Over the past several decades, studies of the sympathetic nervous system in humans, sheep, rabbits, rats, and mice have substantially increased mechanistic understanding of cardiovascular function and dysfunction. Recently, interest in sympathetic neural mechanisms contributing to blood pressure control has grown, in part because of the development of devices or surgical procedures that treat hypertension by manipulating sympathetic outflow. Studies in animal models have provided important insights into physiological and pathophysiological mechanisms that are not accessible in human studies. Across species and among laboratories, various approaches have been developed to record, quantify, analyze, and interpret sympathetic nerve activity (SNA). In general, SNA demonstrates "bursting" behavior, where groups of action potentials are synchronized and linked to the cardiac cycle via the arterial baroreflex. In humans, it is common to quantify SNA as bursts per minute or bursts per 100 heart beats. This type of quantification can be done in other species but is only commonly reported in sheep, which have heart rates similar to humans. In rabbits, rats, and mice, SNA is often recorded relative to a maximal level elicited in the laboratory to control for differences in electrode position among animals or on different study days. SNA in humans can also be presented as total activity, where normalization to the largest burst is a common approach. The goal of the present paper is to put together a summary of "best practices" in several of the most common experimental models and to discuss opportunities and challenges relative to the optimal measurement of SNA across species.Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/guidelines-for-measuring-sympathetic nerve-activity/. PMID- 28364020 TI - Facilitated dissociation of transcription factors from single DNA binding sites. AB - The binding of transcription factors (TFs) to DNA controls most aspects of cellular function, making the understanding of their binding kinetics imperative. The standard description of bimolecular interactions posits that TF off rates are independent of TF concentration in solution. However, recent observations have revealed that proteins in solution can accelerate the dissociation of DNA-bound proteins. To study the molecular basis of facilitated dissociation (FD), we have used single-molecule imaging to measure dissociation kinetics of Fis, a key Escherichia coli TF and major bacterial nucleoid protein, from single dsDNA binding sites. We observe a strong FD effect characterized by an exchange rate [Formula: see text], establishing that FD of Fis occurs at the single-binding site level, and we find that the off rate saturates at large Fis concentrations in solution. Although spontaneous (i.e., competitor-free) dissociation shows a strong salt dependence, we find that FD depends only weakly on salt. These results are quantitatively explained by a model in which partially dissociated bound proteins are susceptible to invasion by competitor proteins in solution. We also report FD of NHP6A, a yeast TF with structure that differs significantly from Fis. We further perform molecular dynamics simulations, which indicate that FD can occur for molecules that interact far more weakly than those that we have studied. Taken together, our results indicate that FD is a general mechanism assisting in the local removal of TFs from their binding sites and does not necessarily require cooperativity, clustering, or binding site overlap. PMID- 28364021 TI - Lateral Segregation of Photosystem I in Cyanobacterial Thylakoids. AB - Photosystem I (PSI) is the dominant photosystem in cyanobacteria and it plays a pivotal role in cyanobacterial metabolism. Despite its biological importance, the native organization of PSI in cyanobacterial thylakoid membranes is poorly understood. Here, we use atomic force microscopy (AFM) to show that ordered, extensive macromolecular arrays of PSI complexes are present in thylakoids from Thermosynechococcus elongatus, Synechococcus sp PCC 7002, and Synechocystis sp PCC 6803. Hyperspectral confocal fluorescence microscopy and three-dimensional structured illumination microscopy of Synechocystis sp PCC 6803 cells visualize PSI domains within the context of the complete thylakoid system. Crystallographic and AFM data were used to build a structural model of a membrane landscape comprising 96 PSI trimers and 27,648 chlorophyll a molecules. Rather than facilitating intertrimer energy transfer, the close associations between PSI primarily maximize packing efficiency; short-range interactions with Complex I and cytochrome b6f are excluded from these regions of the membrane, so PSI turnover is sustained by long-distance diffusion of the electron donors at the membrane surface. Elsewhere, PSI-photosystem II contact zones provide sites for docking phycobilisomes and the formation of megacomplexes. PSI-enriched domains in cyanobacteria might foreshadow the partitioning of PSI into stromal lamellae in plants, similarly sustained by long-distance diffusion of electron carriers. PMID- 28364022 TI - The phosphorylation status of T522 modulates tissue-specific functions of SIRT1 in energy metabolism in mice. AB - SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase, is an important metabolic regulator. However, the mechanisms by which SIRT1 is regulated in vivo remain unclear. Here, we report that phosphorylation modification of T522 on SIRT1 is crucial for tissue-specific regulation of SIRT1 activity in mice. Dephosphorylation of T522 is critical for repression of its activity during adipogenesis. The phospho-T522 level is reduced during adipogenesis. Knocking-in a constitutive T522 phosphorylation mimic activates the beta-catenin/GATA3 pathway, repressing PPARgamma signaling, impairing differentiation of white adipocytes, and ameliorating high-fat diet-induced dyslipidemia in mice. In contrast, phosphorylation of T522 is crucial for activation of hepatic SIRT1 in response to over-nutrition. Hepatic SIRT1 is hyperphosphorylated at T522 upon high-fat diet feeding. Knocking-in a SIRT1 mutant defective in T522 phosphorylation disrupts hepatic fatty acid oxidation, resulting in hepatic steatosis after high-fat diet feeding. In addition, the T522 dephosphorylation mimic impairs systemic energy metabolism. Our findings unveil an important link between environmental cues, SIRT1 phosphorylation, and energy homeostasis and demonstrate that the phosphorylation of T522 is a critical element in tissue-specific regulation of SIRT1 activity in vivo. PMID- 28364024 TI - Angiotensin II Peptide Vaccine Protects Ischemic Brain Through Reducing Oxidative Stress. AB - BACKGROUND AND PURPOSE: Medication nonadherence is one of major risk factors for the poor outcome in ischemic stroke. Vaccination is expected to solve such a problem because of its long-lasting effects, but its effect on ischemic brain damage is still unknown. Here, we focused on vaccination for renin-angiotensin system and examined the effects of angiotensin II (Ang II) peptide vaccine in permanent middle cerebral artery occlusion model in rats. METHODS: Male Wistar rats were exposed to permanent middle cerebral artery occlusion after 3* injections of Ang II peptide vaccine, and the serum or brain level of anti-Ang II antibody was examined. The effects of the vaccine were evaluated by differences in infarction volume, brain renin-angiotensin system components, and markers for neurodegeneration and oxidative stress. RESULTS: Ang II vaccination successfully produced anti-Ang II antibodies in serum without concomitant change in blood pressure. Sufficient production of serum anti-Ang II antibody led to reduction of infarct volume and induced the penetration of anti-Ang II antibody in ischemic hemisphere, with suppressed expression of Ang II type 1 receptor mRNA. Vaccinated rats with sufficient antibody production showed the reduction of Fluoro-Jade B positive cells, spectrin fragmentation, 4-hydroxynonenal-positive cells, and Nox 2 mRNA expression. CONCLUSIONS: Our findings indicate that Ang II vaccination exerts neuroprotective and antioxidative effects in cerebral ischemia, with renin angiotensin system blockade by penetration of anti-Ang II antibodies into ischemic brain lesion. Ang II peptide vaccination could be a promising approach to treat ischemic stroke. PMID- 28364023 TI - RNA activation-independent DNA targeting of the Type III CRISPR-Cas system by a Csm complex. AB - The CRISPR-Cas system is an adaptive and heritable immune response that destroys invading foreign nucleic acids. The effector complex of the Type III CRISPR-Cas system targets RNA and DNA in a transcription-coupled manner, but the exact mechanism of DNA targeting by this complex remains elusive. In this study, an effector Csm holocomplex derived from Thermococcus onnurineus is reconstituted with a minimalistic combination of Csm1121334151, and shows RNA targeting and RNA activated single-stranded DNA (ssDNA) targeting activities. Unexpectedly, in the absence of an RNA transcript, it cleaves ssDNA containing a sequence complementary to the bound crRNA guide region in a manner dependent on the HD domain of the Csm1 subunit. This nuclease activity is blocked by a repeat tag found in the host CRISPR loci. The specific cleavage of ssDNA without a target RNA suggests a novel ssDNA targeting mechanism of the Type III system, which could facilitate the efficient and complete degradation of foreign nucleic acids. PMID- 28364025 TI - Cortical Superficial Siderosis in Different Types of Cerebral Small Vessel Disease. AB - BACKGROUND AND PURPOSE: Cortical superficial siderosis (cSS) has emerged as a clinically relevant imaging feature of cerebral amyloid angiopathy (CAA). However, it remains unknown whether cSS is also present in nonamyloid-associated small vessel disease and whether patients with cSS differ in terms of other small vessel disease imaging features. METHODS: Three hundred sixty-four CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) patients, 372 population-based controls, and 100 CAA patients with cSS (fulfilling the modified Boston criteria for possible/probable CAA) were included. cSS and cerebral microbleeds were visually rated on T2* weighted magnetic resonance imaging. White matter hyperintensities were segmented on fluid-attenauted inversion recovery images, and their spatial distribution was compared between groups using colocalization analysis. Cerebral microbleeds location was determined in an observer-independent way using an atlas in standard space. RESULTS: cSS was absent in CADASIL and present in only 2 population-based controls (0.5%). Cerebral microbleeds were present in 64% of CAA patients with cSS, 34% of patients with CADASIL, and 12% of population-based controls. Among patients with cerebral microbleeds, lobar location was found in 95% of CAA patients with cSS, 48% of CADASIL patients, and 69% of population-based controls. The spatial distribution of white matter hyperintensities was comparable between CAA with cSS and CADASIL as indicated by high colocalization coefficients. CONCLUSIONS: cSS was absent in CADASIL, whereas other small vessel disease imaging features were similar to CAA patients with cSS. Our findings suggest that cSS in combination with other small vessel disease imaging markers is highly indicative of CAA. PMID- 28364027 TI - Skeletal muscle myopenia in mice model of bile duct ligation and carbon tetrachloride-induced liver cirrhosis. AB - Skeletal muscle myopathy is universal in cirrhotic patients, however, little is known about the main mechanisms involved. The study aims to investigate skeletal muscle morphological, histological, and functional modifications in experimental models of cirrhosis and the principal molecular pathways responsible for skeletal muscle myopathy. Cirrhosis was induced by bile duct ligation (BDL) and carbon tetrachloride (CCl4) administration in mice. Control animals (CTR) underwent bile duct exposure or vehicle administration only. At sacrifice, peripheral muscles were dissected and weighed. Contractile properties of extensor digitorum longus (EDL) were studied in vitro. Muscle samples were used for histological and molecular analysis. Quadriceps muscle histology revealed a significant reduction in cross-sectional area of muscle and muscle fibers in cirrhotic mice with respect to CTR. Kinetic properties of EDL in both BDL and CCl4 were reduced with respect to CTR; BDL mice also showed a reduction in muscle force and a decrease in the resistance to fatigue. Increase in myostatin expression associated with a decrease in AKT-mTOR expressions was observed in BDL mice, together with an increase in LC3 protein levels. Upregulation of the proinflammatory citochines TNF-a and IL6 and an increased expression of NF-kB and MuRF-1 were observed in CCl4 mice. In conclusion, skeletal muscle myopenia was present in experimental models of BDL and CCl4-induced cirrhosis. Moreover, reduction in protein synthesis and activation of protein degradation were the main mechanisms responsible for myopenia in BDL mice, while activation of ubiquitin-pathway through inflammatory cytokines seems to be the main potential mechanism involved in CCl4 mice. PMID- 28364029 TI - Intact blood pressure, but not sympathetic, responsiveness to sympathoexcitatory stimuli in a patient with unilateral carotid body resection. AB - Despite rapidly growing interest in the therapeutic resection of the carotid body (CB) chemoreceptors, few physiologic studies exist on the consequences of unilateral CB resection. We present a case of an otherwise healthy postmenopausal female who underwent unilateral CB resection for a paraganglioma. Approximately 4 years postoperatively, she underwent analysis of her sympathetic and hemodynamic responses to hypoxia, lower body negative pressure, cold pressor test (CPT), and ischemic hand grip exercise and postexercise ischemia (IHE/PEI). Hypoxic ventilatory response and baroreflex sensitivity were relatively normal. Hemodynamic responses to IHE/PEI and CPT showed characteristic increases in cardiac output (from 3.9 L/min to 5.2 L/min [IHE/PEI] and 4.9 L/min [CPT]) and blood pressure (from 126/72 mmHg to 161/87 mmHg [IHE/PEI] and 171/93 mmHg [CPT]). However, muscle sympathetic nerve activity (microneurography of the peroneal nerve) decreased from baseline during IHE/PEI and CPT (burst incidence nadir of 45% and 40% of baseline, respectively) and there was no observable change in total peripheral resistance (from 24 mmHg*min/L to 22 mmHg*min/L [IHE/PEI] and 25 mmHg*min/L [CPT]). These findings illustrate intact blood pressure responsiveness despite attenuated sympathoexcitation, possibly due to an increase in cardiac output and/or adaptive inhibitory effect of the baroreflex on peripheral sympathetic activity. PMID- 28364028 TI - Methanosphaera stadtmanae induces a type IV hypersensitivity response in a mouse model of airway inflammation. AB - Despite improved awareness of work-related diseases and preventive measures, many workers are still at high risk of developing occupational hypersensitivity airway diseases. This stems from a lack of knowledge of bioaerosol composition and their potential effects on human health. Recently, archaea species were identified in bioaerosols, raising the possibility that they play a major role in exposure related pathology. Specifically, Methanosphaera stadtmanae (MSS) and Methanobrevibacter smithii (MBS) are found in high concentrations in agricultural environments and respiratory exposure to crude extract demonstrates immunomodulatory activity in mice. Nevertheless, our knowledge of the specific impact of methanogens exposure on airway immunity and their potential to induce airway hypersensitivity responses in workers remains scant. Analysis of the lung mucosal response to methanogen crude extracts in mice demonstrated that MSS and MBS predominantly induced TH17 airway inflammation, typical of a type IV hypersensitivity response. Furthermore, the response to MSS was associated with antigen-specific IgG1 and IgG2a production. However, despite the presence of eosinophils after MSS exposure, only a weak TH2 response and no airway hyperresponsiveness were observed. Finally, using eosinophil and mast cell deficient mice, we confirmed that these cells are dispensable for the TH17 response to MSS, although eosinophils likely contribute to the exacerbation of inflammatory processes induced by MSS crude extract exposure. We conclude that, as MSS induces a clear type IV hypersensitivity lung response, it has the potential to be harmful to workers frequently exposed to this methanogen, and that preventive measures should be taken to avoid chronic hypersensitivity disease development in workers. PMID- 28364030 TI - Exercise performance and physiological responses: the potential role of redox imbalance. AB - Increases in oxidative stress or decreases in antioxidant capacity, or redox imbalance, are known to alter physiological function and has been suggested to influence performance. To date, no study has sought to manipulate this balance in the same participants and observe the impact on physiological function and performance. Using a single-blind, placebo-controlled, and counterbalanced design, this study examined the effects of increasing free radicals, via hyperoxic exposure (FiO2 = 1.0), and/or increasing antioxidant capacity, through consuming an antioxidant cocktail (AOC; vitamin-C, vitamin-E, alpha-lipoic acid), on 5-kilometer (km) cycling time-trial performance, and the physiological and fatigue responses in healthy college-aged males. Hyperoxic exposure prior to the 5 km TT had no effect on performance, fatigue, or the physiological responses to exercise. The AOC significantly reduced average power output (222 +/- 11 vs. 214 +/- 12 W), increased 5 km time (516 +/- 17 vs. 533 +/- 18 sec), suppressed ventilation (VE; 116 +/- 5 vs. 109 +/- 13 L/min), despite similar oxygen consumption (VO2; 43.1 +/- 0.8 vs. 44.9 +/- 0.2 mL/kg per min), decreased VE/VO2 (35.9 +/- 2.0 vs. 32.3 +/- 1.5 L/min), reduced economy (VO2/W; 0.20 +/- 0.01 vs. 0.22 +/- 0.01), increased blood lactate (10 +/- 0.7 vs. 11 +/- 0.7 mmol), and perception of fatigue (RPE; 7.39 +/- 0.4 vs. 7.60 +/- 0.3) at the end of the TT, as compared to placebo (main effect, placebo vs. AOC, respectively). Our data demonstrate that prior to exercise, ingesting an AOC, but not exposure to hyperoxia, likely disrupts the delicate balance between pro- and antioxidant forces, which negatively impacts ventilation, blood lactate, economy, perception of fatigue, and performance (power output and 5 km time) in young healthy males. Thus, caution is warranted in athletes taking excess exogenous antioxidants. PMID- 28364031 TI - The effect of acute maximal exercise on postexercise hemodynamics and central arterial stiffness in obese and normal-weight individuals. AB - Central arterial stiffness is associated with incident hypertension and negative cardiovascular outcomes. Obese individuals have higher central blood pressure (BP) and central arterial stiffness than their normal-weight counterparts, but it is unclear whether obesity also affects hemodynamics and central arterial stiffness after maximal exercise. We evaluated central hemodynamics and arterial stiffness during recovery from acute maximal aerobic exercise in obese and normal weight individuals. Forty-six normal-weight and twenty-one obese individuals underwent measurements of central BP and central arterial stiffness at rest and 15 and 30 min following acute maximal exercise. Central BP and normalized augmentation index (AIx@75) were derived from radial artery applanation tonometry, and central arterial stiffness was obtained via carotid-femoral pulse wave velocity (cPWV) and corrected for central mean arterial pressure (cPWV/cMAP). Central arterial stiffness increased in obese individuals but decreased in normal-weight individuals following acute maximal exercise, after adjusting for fitness. Obese individuals also exhibited an overall higher central BP (P < 0.05), with no exercise effect. The increase in heart rate was greater in obese versus normal-weight individuals following exercise (P < 0.05), but there was no group differences or exercise effect for AIx@75 In conclusion, obese (but not normal-weight) individuals increased central arterial stiffness following acute maximal exercise. An assessment of arterial stiffness response to acute exercise may serve as a useful detection tool for subclinical vascular dysfunction. PMID- 28364032 TI - Sodium glucose transporter-2 inhibition has no renoprotective effects on non diabetic chronic kidney disease. AB - Sodium glucose transporter (SGLT)-2 inhibition has renoprotective effects in diabetic kidney disease. Whether similar effects can be achieved also in non diabetic kidney disease is speculative. Chronic kidney disease was induced in C57BL/6N mice by feeding an oxalate-rich diet for 14 days, known to induce nephrocalcinosis-related tubular atrophy and interstitial fibrosis without directly affecting the glomerular compartment. Empagliflozin treatment started from day 0 of oxalate feeding had no effect on the decline of glomerular filtration rate, crystal deposition, blood urea nitrogen or serum creatinine levels on day 7 and 14. Tissue morphometry of tubular injury and kidney mRNA levels of kidney injury molecule-1 or tissue inhibitor of metalloproteinase-2 were comparable between empagliflozin- and vehicle-treated mice with oxalate nephropathy on day 7 and 14. Similarly, empagliflozin did not affect markers of interstitial fibrosis, including silver, alpha smooth muscle actin (alphaSMA) and collagen 1 staining, and mRNA levels of fibronectin-1, collagen 1alpha1, fibroblast-specific protein-1, and transforming growth factor (TGF)-beta2 on day 7 and 14. Thus, the specific renoprotective mechanisms-of-action of SGLT2 inhibition in diabetic kidney disease do not apply to chronic oxalosis, a non diabetic form of chronic kidney disease. PMID- 28364033 TI - Case report: acute facial swelling in a recreational technical diver. AB - A recreational scuba diver wore a second scuba regulator against his face during a scuba dive, attached by an elastic rubber cord necklace. After surfacing, the diver's left face became swollen. Through a process of elimination all other items of scuba equipment were excluded as potential causes. A dive with the same equipment minus the necklace confirmed the involvement of the necklace in the pathogenesis of the hypersensitive reaction. In vitro ImmunoCap IgE assay was positive to latex (1.30 kUa/L), subsequent patch testing for contact dermatitis provoked a reaction for benzophenone-4, (a UV stabalizer) and Fourier Transform Infra Red spectroscopy identified the elastic as ethylene propylene rubber, containing additional unidentified compounds. Allergy to natural rubber latex occurs in as many as 6% of Americans and Australians. Around three million American residents are thought to scuba dive each year. Recreational divers are, therefore, advised to check such necklaces, which are typically worn around the throat, for frayed ends and exposed rubber filaments. PMID- 28364035 TI - Distinct Patterns of Gene Gain and Loss: Diverse Evolutionary Modes of NBS Encoding Genes in Three Solanaceae Crop Species. AB - Plant resistance conferred by nucleotide binding site (NBS)-encoding resistance genes plays a key role in the defense against various pathogens throughout the entire plant life cycle. However, comparative analyses for the systematic evaluation and determination of the evolutionary modes of NBS-encoding genes among Solanaceae species are rare. In this study, 447, 255, and 306 NBS-encoding genes were identified from the genomes of potato, tomato, and pepper, respectively. These genes usually clustered as tandem arrays on chromosomes; few existed as singletons. Phylogenetic analysis indicated that three subclasses [TNLs (TIR-NBS-LRR), CNLs (CC-NBS-LRR), and RNLs (RPW8-NBS-LRR)] each formed a monophyletic clade and were distinguished by unique exon/intron structures and amino acid motif sequences. By comparing phylogenetic and systematic relationships, we inferred that the NBS-encoding genes in the present genomes of potato, tomato, and pepper were derived from 150 CNL, 22 TNL, and 4 RNL ancestral genes, and underwent independent gene loss and duplication events after speciation. The NBS-encoding genes therefore exhibit diverse and dynamic evolutionary patterns in the three Solanaceae species, giving rise to the discrepant gene numbers observed today. Potato shows a "consistent expansion" pattern, tomato exhibits a pattern of "first expansion and then contraction," and pepper presents a "shrinking" pattern. The earlier expansion of CNLs in the common ancestor led to the dominance of this subclass in gene numbers. However, RNLs remained at low copy numbers due to their specific functions. Along the evolutionary process of NBS-encoding genes in Solanaceae, species-specific tandem duplications contributed the most to gene expansions. PMID- 28364037 TI - A Bayesian Poisson-lognormal Model for Count Data for Multiple-Trait Multiple Environment Genomic-Enabled Prediction. AB - When a plant scientist wishes to make genomic-enabled predictions of multiple traits measured in multiple individuals in multiple environments, the most common strategy for performing the analysis is to use a single trait at a time taking into account genotype * environment interaction (G * E), because there is a lack of comprehensive models that simultaneously take into account the correlated counting traits and G * E. For this reason, in this study we propose a multiple trait and multiple-environment model for count data. The proposed model was developed under the Bayesian paradigm for which we developed a Markov Chain Monte Carlo (MCMC) with noninformative priors. This allows obtaining all required full conditional distributions of the parameters leading to an exact Gibbs sampler for the posterior distribution. Our model was tested with simulated data and a real data set. Results show that the proposed multi-trait, multi-environment model is an attractive alternative for modeling multiple count traits measured in multiple environments. PMID- 28364036 TI - Genotyping-by-Sequencing Facilitates a High-Density Consensus Linkage Map for Aegilops umbellulata, a Wild Relative of Cultivated Wheat. AB - High-density genetic maps are useful to precisely localize QTL or genes that might be used to improve traits of nutritional and/or economical importance in crops. However, high-density genetic maps are lacking for most wild relatives of crop species, including wheat. Aegilops umbellulata is a wild relative of wheat known for its potential as a source of biotic and abiotic stress resistance genes. In this work, we have developed a framework consensus genetic map using two biparental populations derived from accessions PI 298905, PI 542369, PI 5422375, and PI 554395. The framework map comprised 3009 genotype-by-sequence SNPs with a total map size of 948.72 cM. On average, there were three SNPs per centimorgan for each chromosome. Chromosome 1U was the shortest (66.5 cM), with only 81 SNPs, whereas the remaining chromosomes had between 391 and 591 SNP markers. A total of 2395 unmapped SNPs were added to the linkage maps through a recombination frequency approach, and increased the number of SNPs placed on the consensus map to a total of 5404 markers. Segregation distortion was disproportionally high for chromosome 1U for both populations used to construct component linkage maps, and thus segregation distortion could be one of the probable reasons for the exceptionally reduced linkage size for chromosome 1U. From comparative analysis, Aeumbellulata chromosomes except 4U showed moderate to strong collinearity with corresponding homeologous chromosomes of hexaploid wheat and barley. The present consensus map may serve as a reference map in QTL mapping and validation projects, and also in genome assembly to develop a reference genome sequence for Ae. umbellulata. PMID- 28364038 TI - How Changes in Anti-SD Sequences Would Affect SD Sequences in Escherichia coli and Bacillus subtilis. AB - The 3' end of the small ribosomal RNAs (ssu rRNA) in bacteria is directly involved in the selection and binding of mRNA transcripts during translation initiation via well-documented interactions between a Shine-Dalgarno (SD) sequence located upstream of the initiation codon and an anti-SD (aSD) sequence at the 3' end of the ssu rRNA. Consequently, the 3' end of ssu rRNA (3'TAIL) is strongly conserved among bacterial species because a change in the region may impact the translation of many protein-coding genes. Escherichia coli and Bacillus subtilis differ in their 3' ends of ssu rRNA, being GAUCACCUCCUUA3' in E. coli and GAUCACCUCCUUUCU3' or GAUCACCUCCUUUCUA3' in B. subtilis Such differences in 3'TAIL lead to species-specific SDs (designated SDEc for E. coli and SDBs for B. subtilis) that can form strong and well-positioned SD/aSD pairing in one species but not in the other. Selection mediated by the species-specific 3'TAIL is expected to favor SDBs against SDEc in B. subtilis, but favor SDEc against SDBs in E. coli Among well-positioned SDs, SDEc is used more in E. coli than in B. subtilis, and SDBs more in B. subtilis than in E. coli Highly expressed genes and genes of high translation efficiency tend to have longer SDs than lowly expressed genes and genes with low translation efficiency in both species, but more so in B. subtilis than in E. coli Both species overuse SDs matching the bolded part of the 3'TAIL shown above. The 3'TAIL difference contributes to the host specificity of phages. PMID- 28364039 TI - Identification of QTLs for 14 Agronomically Important Traits in Setaria italica Based on SNPs Generated from High-Throughput Sequencing. AB - Foxtail millet (Setaria italica) is an important crop possessing C4 photosynthesis capability. The S. italica genome was de novo sequenced in 2012, but the sequence lacked high-density genetic maps with agronomic and yield trait linkages. In the present study, we resequenced a foxtail millet population of 439 recombinant inbred lines (RILs) and developed high-resolution bin map and high density SNP markers, which could provide an effective approach for gene identification. A total of 59 QTL for 14 agronomic traits in plants grown under long- and short-day photoperiods were identified. The phenotypic variation explained ranged from 4.9 to 43.94%. In addition, we suggested that there may be segregation distortion on chromosome 6 that is significantly distorted toward Zhang gu. The newly identified QTL will provide a platform for sequence-based research on the S. italica genome, and for molecular marker-assisted breeding. PMID- 28364040 TI - Hypoxia reduces HNF4alpha/MODY1 protein expression in pancreatic beta-cells by activating AMP-activated protein kinase. AB - Hypoxia plays a role in the deterioration of beta-cell function. Hepatocyte nuclear factor 4alpha (HNF4alpha) has an important role in pancreatic beta-cells, and mutations of the human HNF4A gene cause a type of maturity-onset diabetes of the young (MODY1). However, it remains unclear whether hypoxia affects the expression of HNF4alpha in beta-cells. Here, we report that hypoxia reduces HNF4alpha protein expression in beta-cells. Hypoxia-inducible factor was not involved in the down-regulation of HNF4alpha under hypoxic conditions. The down regulation of HNF4alpha was dependent on the activation of AMP-activated protein kinase (AMPK), and the reduction of HNF4alpha protein expression by metformin, an AMPK activator, and hypoxia was inhibited by the overexpression of a kinase-dead (KD) form of AMPKalpha2. In addition, hypoxia decreased the stability of the HNF4alpha protein, and the down-regulation of HNF4alpha was sensitive to proteasome inhibitors. Adenovirus-mediated overexpression of KD-AMPKalpha2 improved insulin secretion in metformin-treated islets, hypoxic islets, and ob/ob mouse islets. These results suggest that down-regulation of HNF4alpha could be of importance in beta-cell dysfunction by hypoxia. PMID- 28364041 TI - Galectin-3 interacts with the cell-surface glycoprotein CD146 (MCAM, MUC18) and induces secretion of metastasis-promoting cytokines from vascular endothelial cells. AB - The galactoside-binding protein galectin-3 is increasingly recognized as an important player in cancer development, progression, and metastasis via its interactions with various galactoside-terminated glycans. We have shown previously that circulating galectin-3, which is increased up to 30-fold in cancer patients, promotes blood-borne metastasis in an animal cancer model. This effect is partly attributable to the interaction of galectin-3 with unknown receptor(s) on vascular endothelial cells and causes endothelial secretion of several metastasis-promoting cytokines. Here we sought to identify the galectin-3 binding molecule(s) on the endothelial cell surface responsible for the galectin 3-mediated cytokine secretion. Using two different galectin-3 affinity purification processes, we extracted four cell membrane glycoproteins, CD146/melanoma cell adhesion molecule (MCAM)/MUC18, CD31/platelet endothelial cell adhesion molecule-1 (PECAM-1), CD144/VE-cadherin, and CD106/Endoglin, from vascular endothelial cells. CD146 was the major galectin-3-binding ligand and strongly co-localized with galectin-3 on endothelial cell surfaces treated with exogenous galectin-3. Moreover, galectin-3 bound to N-linked glycans on CD146 and induced CD146 dimerization and subsequent activation of AKT signaling. siRNA mediated suppression of CD146 expression completely abolished the galectin-3 induced secretion of IL-6 and G-CSF cytokines from the endothelial cells. Thus, CD146/MCAM is the functional galectin-3-binding ligand on endothelial cell surfaces responsible for galectin-3-induced secretion of metastasis-promoting cytokines. We conclude that CD146/MCAM interactions with circulating galectin-3 may have an important influence on cancer progression and metastasis. PMID- 28364042 TI - Kinetic-based trapping by intervening sequence variants of the active sites of protein-disulfide isomerase identifies platelet protein substrates. AB - Thiol isomerases such as protein-disulfide isomerase (PDI) direct disulfide rearrangements required for proper folding of nascent proteins synthesized in the endoplasmic reticulum. Identifying PDI substrates is challenging because PDI catalyzes conformational changes that cannot be easily monitored (e.g. compared with proteolytic cleavage or amino acid phosphorylation); PDI has multiple substrates; and it can catalyze either oxidation, reduction, or isomerization of substrates. Kinetic-based substrate trapping wherein the active site motif CGHC is modified to CGHA to stabilize a PDI-substrate intermediate is effective in identifying some substrates. A limitation of this approach, however, is that it captures only substrates that are reduced by PDI, whereas many substrates are oxidized by PDI. By manipulating the highly conserved -GH- residues in the CGHC active site of PDI, we created PDI variants with a slowed reaction rate toward substrates. The prolonged intermediate state allowed us to identify protein substrates that have biased affinities for either oxidation or reduction by PDI. Because extracellular PDI is critical for thrombus formation but its extracellular substrates are not known, we evaluated the ability of these bidirectional trapping PDI variants to trap proteins released from platelets and on the platelet surface. Trapped proteins were identified by mass spectroscopy. Of the trapped substrate proteins identified by mass spectroscopy, five proteins, cathepsin G, glutaredoxin-1, thioredoxin, GP1b, and fibrinogen, showed a bias for oxidation, whereas annexin V, heparanase, ERp57, kallekrein-14, serpin B6, tetranectin, and collagen VI showed a bias for reduction. These bidirectional trapping variants will enable more comprehensive identification of thiol isomerase substrates and better elucidation of their cellular functions. PMID- 28364044 TI - High serum thrombospondin-1 concentration is associated with slower abdominal aortic aneurysm growth and deficiency of thrombospondin-1 promotes angiotensin II induced aortic aneurysm in mice. AB - Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Thrombospondin-1 (TSP-1; gene Thbs1) is a member of the matricellular protein family important in the control of extracellular matrix (ECM) remodelling. In the present study, the association of serum TSP-1 concentration with AAA progression was assessed in 276 men that underwent repeated ultrasound for a median 5.5 years. AAA growth was negatively correlated with serum TSP-1 concentration (Spearman's rho -0.129, P=0.033). Men with TSP-1 in the highest quartile had a reduced likelihood of AAA growth greater than median during follow-up (OR: 0.40; 95% confidence interval (CI): 0.19-0.84, P=0.016, adjusted for other risk factors). Immunohistochemical staining for TSP-1 was reduced in AAA body tissues compared with the relatively normal AAA neck. To further assess the role of TSP-1 in AAA initiation and progression, combined TSP-1 and apolipoprotein deficient (Thbs1-/-ApoE-/-, n=20) and control mice (ApoE-/-, n=20) were infused subcutaneously with angiotensin II (AngII) for 28 days. Following AngII infusion, Thbs1-/- ApoE-/- mice had larger AAAs by ultrasound (P=0.024) and ex vivo morphometry measurement (P=0.006). The Thbs1-/-ApoE-/- mice also showed increased elastin filament degradation along with elevated systemic levels and aortic expression of matrix metalloproteinase (MMP)-9. Suprarenal aortic segments and vascular smooth muscle cells (VSMCs) isolated from Thbs1-/-ApoE-/- mice showed reduced collagen 3A1 gene expression. Furthermore, Thbs1-/-ApoE-/- mice had reduced aortic expression of low-density lipoprotein (LDL) receptor-related protein 1. Collectively, findings from the present study suggest that TSP-1 deficiency promotes maladaptive remodelling of the ECM leading to accelerated AAA progression. PMID- 28364043 TI - Unraveling the structural basis for the unusually rich association of human leukocyte antigen DQ2.5 with class-II-associated invariant chain peptides. AB - Human leukocyte antigen (HLA)-DQ2.5 (DQA1*05/DQB1*02) is a class-II major histocompatibility complex protein associated with both type 1 diabetes and celiac disease. One unusual feature of DQ2.5 is its high class-II-associated invariant chain peptide (CLIP) content. Moreover, HLA-DQ2.5 preferentially binds the non-canonical CLIP2 over the canonical CLIP1. To better understand the structural basis of HLA-DQ2.5's unusual CLIP association characteristics, better insight into the HLA-DQ2.5.CLIP complex structures is required. To this end, we determined the X-ray crystal structure of the HLA-DQ2.5. CLIP1 and HLA DQ2.5.CLIP2 complexes at 2.73 and 2.20 A, respectively. We found that HLA-DQ2.5 has an unusually large P4 pocket and a positively charged peptide-binding groove that together promote preferential binding of CLIP2 over CLIP1. An alpha9-alpha22 alpha24-alpha31-beta86-beta90 hydrogen bond network located at the bottom of the peptide-binding groove, spanning from the P1 to P4 pockets, renders the residues in this region relatively immobile. This hydrogen bond network, along with a deletion mutation at alpha53, may lead to HLA-DM insensitivity in HLA-DQ2.5. A molecular dynamics simulation experiment reported here and recent biochemical studies by others support this hypothesis. The diminished HLA-DM sensitivity is the likely reason for the CLIP-rich phenotype of HLA-DQ2.5. PMID- 28364046 TI - Neonatal Hypoglycemia. AB - Lower blood glucose values are common in the healthy neonate immediately after birth as compared to older infants, children, and adults. These transiently lower glucose values improve and reach normal ranges within hours after birth. Such transitional hypoglycemia is common in the healthy newborn. A minority of neonates experience a more prolonged and severe hypoglycemia, usually associated with specific risk factors and possibly a congenital hypoglycemia syndrome. Despite the lack of a specific blood glucose value that defines hypoglycemia, concern for substantial neurologic morbidity in the neonatal population has led to the generation of guidelines by both the American Academy of Pediatrics (AAP) and the Pediatric Endocrine Society (PES). Similarities between the 2 guidelines include recognition that the transitional form of neonatal hypoglycemia likely resolves within 48 hours after birth and that hypoglycemia that persists beyond that duration may be pathologic. One major difference between the 2 sets of guidelines is the goal blood glucose value in the neonate. This article reviews transitional and pathologic hypoglycemia in the neonate and presents a framework for understanding the nuances of the AAP and PES guidelines for neonatal hypoglycemia. PMID- 28364045 TI - Diagnostic Accuracy of 3.0-T Magnetic Resonance T1 and T2 Mapping and T2-Weighted Dark-Blood Imaging for the Infarct-Related Coronary Artery in Non-ST-Segment Elevation Myocardial Infarction. AB - BACKGROUND: Patients with recent non-ST-segment elevation myocardial infarction commonly have heterogeneous characteristics that may be challenging to assess clinically. METHODS AND RESULTS: We prospectively studied the diagnostic accuracy of 2 novel (T1, T2 mapping) and 1 established (T2-weighted short tau inversion recovery [T2W-STIR]) magnetic resonance imaging methods for imaging the ischemic area at risk and myocardial salvage in 73 patients with non-ST-segment elevation myocardial infarction (mean age 57+/-10 years, 78% male) at 3.0-T magnetic resonance imaging within 6.5+/-3.5 days of invasive management. The infarct related territory was identified independently using a combination of angiographic, ECG, and clinical findings. The presence and extent of infarction was assessed with late gadolinium enhancement imaging (gadobutrol, 0.1 mmol/kg). The extent of acutely injured myocardium was independently assessed with native T1, T2, and T2W-STIR methods. The mean infarct size was 5.9+/-8.0% of left ventricular mass. The infarct zone T1 and T2 times were 1323+/-68 and 57+/-5 ms, respectively. The diagnostic accuracies of T1 and T2 mapping for identification of the infarct-related artery were similar (P=0.125), and both were superior to T2W-STIR (P<0.001). The extent of myocardial injury (percentage of left ventricular volume) estimated with T1 (15.8+/-10.6%) and T2 maps (16.0+/-11.8%) was similar (P=0.838) and moderately well correlated (r=0.82, P<0.001). Mean extent of acute injury estimated with T2W-STIR (7.8+/-11.6%) was lower than that estimated with T1 (P<0.001) or T2 maps (P<0.001). CONCLUSIONS: In patients with non-ST-segment elevation myocardial infarction, T1 and T2 magnetic resonance imaging mapping have higher diagnostic performance than T2W-STIR for identifying the infarct-related artery. Compared with conventional STIR, T1 and T2 maps have superior value to inform diagnosis and revascularization planning in non-ST segment elevation myocardial infarction. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02073422. PMID- 28364048 TI - Pleural Effusions and Pneumothoraces. PMID- 28364047 TI - Meningococcal Disease. PMID- 28364050 TI - Case 2: Bacteremia with an Inconsistently Abnormal Newborn Screen. PMID- 28364049 TI - Case 1: Vertigo and Episodes of Slurred Speech in a 5-year-old Girl. PMID- 28364051 TI - Case 3: Hypotonia, Respiratory Distress, and Cardiomegaly in a 3-month-old Boy. PMID- 28364052 TI - Case 4: Frontal Headache, Photophobia, Fever and Vomiting in a 10-year-old Girl. PMID- 28364053 TI - Case 5: Right Upper Quadrant Abdominal Pain in an Otherwise Healthy 8-year-old Girl. PMID- 28364054 TI - Case 6: Failure to Thrive with Congenital Glaucoma in a 2-month-old Girl. PMID- 28364055 TI - Hemangiomas. PMID- 28364056 TI - Visual Diagnosis: 9-month-old Boy with Coarse Facial Features and Hepatosplenomegaly. PMID- 28364058 TI - From polyformacy to formacology. PMID- 28364057 TI - Acute lymphoblastic leukemia of the central nervous system: on the role of PBX1. PMID- 28364064 TI - Campaigning to amend air gun licensing laws. PMID- 28364061 TI - Pig industry fears withdrawal of zinc oxide from this summer. PMID- 28364071 TI - UK to get a centralised national database for horses this summer. PMID- 28364072 TI - Do cats serve as good sentinels for Bartonella species infection risk in people and animals? PMID- 28364073 TI - Canine synovial fluid biomarkers for early detection and monitoring of osteoarthritis. PMID- 28364080 TI - Improving pedigree dog health. PMID- 28364081 TI - Improving pedigree dog health. PMID- 28364082 TI - Reclassification of monepantel. PMID- 28364083 TI - Dogs needed for soft tissue sarcoma trial. PMID- 28364084 TI - New BVA Working Groups get under way. AB - BVA's new working groups are looking at a range of issues, including surveillance, farm assurance and antimicrobial resistance. The role of the new groups - which were developed following a review by the BVA Policy Committee - will be to have a proactive approach to policymaking. PMID- 28364085 TI - Northern Ireland's young vets host impressive YVN event. AB - Laura Carleton, BVA member services and policy support officer, reports on a recent CPD event held in Northern Ireland for young graduates in the region. PMID- 28364087 TI - BVA at the London Vet Show. AB - BVA marketing manager Zoe Davies describes what BVA has in store for members at the London Vet Show. PMID- 28364088 TI - Nominate an outstanding vet for a BVA award. AB - One of the highlights of the BVA year is the presentation of our awards at Members' Day. Public affairs manager Helena Cotton invites members to nominate outstanding vets to be considered for a BVA award. PMID- 28364089 TI - Feeling a part of the veterinary family. AB - Becky Richardson, Young Vet Network representative on BVA Council, jointly hosted a meeting attended by BVA President Gudrun Ravetz. PMID- 28364090 TI - My career - from a youth training scheme to practice manager. AB - Renay Rickard is practice manager of Kernow Veterinary Group in Cornwall. Her entry to the veterinary profession was as a veterinary nurse, but her role evolved into a management one as the practice grew into a group. She is president of the Veterinary Practice Management Association. PMID- 28364092 TI - Use of beta-Blockers in Pulmonary Hypertension. AB - Contrasting with the major attention that left heart failure has received, right heart failure remains understudied both at the preclinical and clinical levels. However, right ventricle failure is a major predictor of outcomes in patients with precapillary pulmonary hypertension because of pulmonary arterial hypertension, and in patients with postcapillary pulmonary hypertension because of left heart disease. In pulmonary hypertension, the status of the right ventricle is one of the most important predictors of both morbidity and mortality. Paradoxically, there are currently no approved therapies targeting the right ventricle in pulmonary hypertension. By analogy with the key role of beta blockers in the management of left heart failure, some authors have proposed to use these agents to support the right ventricle function in pulmonary hypertension. In this review, we summarize the current knowledge on the use of beta-blockers in pulmonary hypertension. PMID- 28364091 TI - Effect of Intensive Blood Pressure Treatment on Heart Failure Events in the Systolic Blood Pressure Reduction Intervention Trial. AB - BACKGROUND: Acute decompensated heart failure (ADHF) was a frequent common outcome in SPRINT (Systolic Blood Pressure Intervention Trial). We examined whether there was differential reduction in ADHF events from intensive blood pressure [BP] treatment among the 6 key, prespecified subgroups in SPRINT: age >=75 years, prior cardiovascular disease, chronic kidney disease, women, black race, and 3 levels of baseline systolic BP (<=132 versus >132 to <145 versus >=145 mm Hg). METHODS AND RESULTS: ADHF was defined as hospitalization for ADHF, confirmed and formally adjudicated by a blinded events committee using standardized protocols. At 3.29 years follow-up, there were 103 ADHF events (2.2%) among 4683 standard arm participants and 65 ADHF events (1.4%) among 4678 intensive arm participants (Cox proportional hazards ratio, 0.63; 95% confidence interval, 0.46-0.85; P value =0.003). In multivariable analyses, including treatment arm, baseline covariates that were significant predictors for ADHF included chronic kidney disease, cardiovascular disease, age>=75 years, body mass index, and higher systolic BP. The beneficial effect of the intervention on incident ADHF was consistent across all prespecified subgroups. Participants who had incident ADHF had markedly increased risk of subsequent cardiovascular events, including a 27-fold increase (P<0.001) in cardiovascular death. CONCLUSIONS: Targeting a systolic BP<120 mm Hg, compared with <140 mm Hg, significantly reduced ADHF events, and the benefit was similar across all key, prespecified subgroups. Participants who developed ADHF had markedly increased risk for subsequent cardiovascular events and death, highlighting the importance of strategies aimed at prevention of ADHF, especially intensive BP reduction. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01206062. PMID- 28364094 TI - [Effect of nucleolin on cardiac cell apoptosis in Type 2 diabetic cardiomyopathy mice]. AB - OBJECTIVE: To investigate the effect of nucleolin on cardiac cell apoptosis in Type 2 diabetic cardiomyopathy mice.? Methods: Mice were fed with high-fat and high-sugar food for 20 weeks (mice were injected intraperitoneally with 60 mg/kg streptozotocin in the 5th and 6th weeks) to establish a mouse model of Type 2 diabetes. The mice were divided into 4 groups: a wild type (WT) control group, a nucleolin transgenic (TG) control group, a WT diabetic group, a TG diabetic group. Diabetes-related indicators were detected at the end of the 8th week. At the end of the 20th week, HE staining was used to observe myocardial morphological changes; TUNEL staining and caspase-3 activity were used to detect the extent of apoptosis of cardiac myocytes.? Results: The level of fasting blood glucose was significantly increased in the diabetic group than that in the control group. In WT diabetic group, myocardial disarrangement, fragmentation and dissolution were observed (determined by HE staining); cellular apoptosis (determined by TUNEL staining and caspase-3 activity) also increased markedly in the WT diabetic group. Compared with the wild mice in the diabetic group, myocardial morphological changes and cardiac myocytes apoptosis were alleviated significantly. ? Conclusion: Nucleolin overexpression affectes the occurrence and development of diabetic cardiomyopathy through inhibition of cardiac myocyte apoptosis. PMID- 28364093 TI - Spatial distribution and molecular dynamics of dystrophin glycoprotein components at the neuromuscular junction in vivo. AB - A bimolecular fluorescence complementation (BiFC) approach was used to study the molecular interactions between different components of the postsynaptic protein complex at the neuromuscular junction of living mice. We show that rapsyn forms complex with both alpha-dystrobrevin and alpha-syntrophin at the crests of junctional folds. The linkage of rapsyn to alpha-syntrophin and/or alpha dystrobrevin is mediated by utrophin, a protein localized at acetylcholine receptor (AChR)-rich domains. In mice deficient in alpha-syntrophin, in which utrophin is no longer present at the synapse, rapsyn interaction with alpha dystrobrevin was completely abolished. This interaction was completely restored when either utrophin or alpha-syntrophin was introduced into muscles deficient in alpha-syntrophin. However, in neuromuscular junctions deficient in alpha dystrobrevin, in which utrophin is retained, complex formation between rapsyn and alpha-syntrophin was unaffected. Using fluorescence recovery after photobleaching, we found that alpha-syntrophin turnover is 5-7 times faster than that of AChRs, and loss of alpha-dystrobrevin has no effect on rapsyn and alpha syntrophin half-life, whereas the half-life of AChR was significantly altered. Altogether, these results provide new insights into the spatial distribution of dystrophin glycoprotein components and their dynamics in living mice. PMID- 28364095 TI - [Association of Toll-like receptor 2 and 4 gene polymorphisms with risk of coronary atherosclerotic artery disease in Hunan Han population]. AB - OBJECTIVE: To explore Toll-like receptor 2 (TLR2) and TLR4 polymorphism in Han people from Hunan region and its association with coronary atherosclerotic heart disease.? Methods: Sanger sequence and statistical analysis were performed to identify the polymorphism of TLR2 and TLR4 genes in 347 unrelated Hunan Han subjects, including 180 healthy people (control group) and 167 patients with coronary atherosclerotic heart disease (coronary atherosclerotic heart disease group).? Results: There was no significant difference in the genotype frequency and allelic frequency for TLR2 SNP2258G>A and TLR4 SNP896A>G between the 2 groups (P>0.05), while there was significant difference in the TLR4 SNP1196C>T between the 2 groups (P<0.05).? Conclusion: TLR4 SNP1196C>T polymorphism is associated with coronary atherosclerotic heart disease in Chinese Han populationin in Hunan region. PMID- 28364096 TI - [Effects of dexamethasone on MRL/lpr mice with systemic lupus erythematosus complicated with cognitive dysfunction]. AB - OBJECTIVE: To evaluate the effects of dexamethasone on systemic lupus erythematosus complicated with cognitive dysfunction.? Methods: Ten wild type mice and 20 MRL/lpr mice were applied for the research. MRL/lpr mice were randomly assigned to a MRL/lpr group and a MRL/lpr + dexamethasone (1.5 mg/kg) group. Interleukin-6 (IL-6), IL-1beta, and tumor necrosis factor alpha (TNF alpha) in serum and hippocampus were detected. The protein phosphorylation levels of phosphoinositide 3-kinase (P-PI3K), protein kinase B (P-Akt), NF-kappa-B inhibitor alpha (P-IkappaBa) and nuclear transcription factor ?kappa-B p65 (P-NF kappaB p65) were detected by Western blot, the level of P-NF-kappaB p65 also was detected by immunohistochemistry. ? Results: Treatment with dexamethasone (1.5 mg/kg) alleviated the cognitive dysfunction and decreased the levels of IL-6, IL 1beta and TNF-alpha in serum and hippocampus, and reduced the levels of P-PI3K, P Akt, P-IkappaBa and P-NF-kappaB p65 in hippocampus in MRL/lpr mice.? Conclusion: Dexamethasone may play a protective role in the cognitive function by decreasing the levels of TNF-alpha and IL-1beta in the hippocampus of MRL/lpr lupus mice. PMID- 28364097 TI - [Effect of lamivudine and silymarin on liver fibrosis-relevant factors in HBV transgenic mice with alcohol drinking]. AB - OBJECTIVE: To observe the role of lamividine and silymarin preventing and curing liver fibrosis-relevant factors induced by alcohol drinking in hepatitis B virus (HBV) transgenic mice (Tg mice).? Methods: Forty HBV-Tg BALB/C mice with 1.3 copy were randomly divided into 4 groups: a control group, a model group, a lamivudine group and a silymarin group. Tg mice in control group were treated with normal saline via intragastric administration; Tg-mice in the model group were treated with 50% alcohol (5 mL/kg) once a day via intragastric administration; while Tg mice in lamivudine group and silymarin group were treated with alcohol (5 mL/kg) plus laminvudine (100 mg/kg) and silymarin (200 mg/kg) once a day via intragastric administration respectively. All groups were raised for 10 weeks. The levels of HBV-DNA copy number, ALT, AST in serum, the degree of inflammation, the degree of fibrosis, the mRNA expression levels of TGF-beta1, Smad3, Smad7 and connective tissue growth factor (CTGF), and the protein expression levels of TGF beta1, CTGF and alpha-SMA in liver tissue were detected. All the images were scanned with electronic computer and the data were analyzed with SPSS13.0 software.? Results: Compared with the control group, liver injury were significantly aggravated, while HBV-DNA copies, mRNA levels of TGF-beta1, Smad3, Smad7 and CTGF as well as the protein levels of TGF-beta1, CTGF and alpha-SMA were significantly increased (P<0.05). Compared with the model group, liver injury were significantly attenuated in silymarine group and lamivudine group, while mRNA levels of TGF-beta1, Smad3 and CTGF as well as the protein levels of TGF-beta1, CTGF and alpha-SMA were significantly decreased; mRNA level of Smad7 was further increased (P<0.05); the levels of ALT and AST in serum were decreased in the silymarine group (P<0.05).? Conclusion: Lamivudine and silymarin relieve the histological damage in the liver of alcohol-fed Tg mice. The mechanisms for the beneficial effects of lamivudine or silymarin might be related to inhibiting the expression of TGF-beta1, Smad3 and CTGF, modulating the expression of Smads and suppressing the activation of HSC. PMID- 28364098 TI - [Delphinidin induces autophagy in HER-2+ breast cancer cells via inhibition of AKT/mTOR pathway]. AB - OBJECTIVE: To explore the effect of delphinidin on breast cancer and the underlying mechanisms.? Methods: Human epidermal growth factor receptor-2 (HER-2) positive breast cancer cells MDA-MB-453 were treated by delphinidin. Proliferation of MDA-MB-453 cells was detected by CCK-8 after 48 h. TdT-mediated dUTP nick end labeling (TUNEL) assay and Western blot were used to explore apoptotic status for MDA-MB-453 cells. Fluorescence dot assay, immunofluorescence, and Western blot were used to identify autophagy in breast cancer cells.? Results: Delphinidin suppressed proliferation of MDA-MB-453 cells. Delphinidin increased the number of TUNEL positive cells. Delphinidin downregulated the expression of caspase-3 and caspase-9, while upregulated the expression of cleaved caspase-3 and cleaved caspase-9 in a dose-dependent manner. Delphinidin enhanced the number of GFP-LC3 punctate dots, LC3 immunofluorescence dots and the expression of LC3-II and ATG5. Delphinidin inhibited the expression of proteins in mTOR signaling pathway, including AKT, mTOR, eIF4E and p70s6k.? Conclusion: Delphinidin induced apoptosis and autophagy by inhibition of AKT/mTOR pathway in HER positive breast cancer cells. PMID- 28364100 TI - [Expression of matrix Gla protein and bone morphogenetic protein 2 in renal papillary tissues in patients with calcium oxalate kidney stones]. AB - OBJECTIVE: To compare expression levels of matrix Gla protein (MGP) and bone morphogenetic protein 2 (BMP-2) in Randall's plaque of renal papillary tissues in patients with calcium oxalate kidney stones and the underlying mechanism for stone formation.? Methods: A total of 30 samples of Randall's plaque in renal papillary tissues from patients with calcium oxalate kidney stones were collected from the Department of Urology of Xiangya Hospital of Central South University from April, 2015 to December, 2015 and served as an experimental group. Ten samples of renal papillary tissues in patients undergone renal tumor nephrectomy were collected from the same hospital and served as a control group. The expressions of MGP and BMP-2 mRNA and protein were detected by quantitative real time PCR and Western blot.Meanwhile, immunohistochemical technique was used to observe the expressions of MGP and BMP-2 in different parts of renal papillary tissues in the 2 groups.? Results: 1) The mRNA expression levels of MGP in the experimental group and the control group were 0.760+/-0.804 and 1.365+/-0.348, respectively, with significant difference between them (P<0.05). Them RNA levels of BMP-2 in the experimental group and the control group were 2.500+/-0.725 and 1.485+/-0.870, respectively, with significant difference between them (P<0.05). The expression levels of MGP protein in the experimental group and the control group were 0.130+/-0.424 and 0.202+/-0.704, respectively, with no significant difference between them (P>0.05). The expression levels of BMP-2 protein in the experimental group and the control group were 0.885+/-0.220 and 0.682+/-0.272, respectively, with significant difference between them (P<0.05). The immunohistochemistry showed that the protein expression of MGP in the experimental group was lower than that in the control group, while the protein expression of BMP-2 in the experimental group was higher than that in the control group (both P<0.05).? Conclusion: The BMP-2 expression is increased while MGP expression is decreased in renal papillary tissues in patients with calcium oxalate kidney stones, and the formation of calcium oxalate kidney stone might be a kind of osteogenetic reaction or ectopic calcification. PMID- 28364099 TI - [Dexmedetomidine improves function of lung oxygenation in patients with moderate chronic obstructive pulmonary disease underwent lung cancer surgery]. AB - OBJECTIVE: To determine whether dexmedetomidine (Dex) improves oxygenation and lung mechanics in patients with moderate chronic obstructive pulmonary disease (COPD) during lung cancer surgery.? Methods: Fifty-six patients with moderate COPD were randomly allocated to a control group and a Dex group (n=28 each). In the Dex group, dexmedetomidine was given as an initial loading dose at 1.0 MUg/kg lasting for 10 min followed by a maintenance dose at 0.5 MUg/(kg.h) during OLV while the control group was administered an equal volume of 0.9% saline accordingly.? Results: Patients in the Dex group had a significantly higher oxygenation index (P<0.05) and higher dynamic lung compliance at Dex-30 and Dex 60 (P<0.05) compared with those in the control group. In the Dex group, oxygenation index in the postoperative period was significantly higher (P= 0.025) and postoperative complications were lower than those in the control group.? Conclusion: Dex administration may provide clinically relevant benefits by improving o xygenation index and lung mechanics, and reducing postoperative pulmonary complications in patients with moderate COPD underwent lung cancer surgery. PMID- 28364101 TI - [Expression levels of ubiquitin C-terminal hydrolase-L1 and serum glial fibrillary acidic protein and its clinical significance in patients with acute cerebral infarction]. AB - OBJECTIVE: To determine expression levels of ubiquitin C-terminal hydrolase-L1 (UCH-L1) and serum glial fibrillary acidic protein (GFAP) in patients with acute cerebral infarction and their clinical significance.? Methods: A total of 80 patients with acute cerebral infarction in Chongqing Cancer Hospital from January 2014 to February 2016 were enrolled as an observation group. Another 80 healthy people served as a control group. The expression levels of UCH-L1 and GFAP in the 2 groups were detected.? Results: Sensibility and specificity for UCH-L1 and GFAP were 75.0%, 87.5% and 81.3%, 90.0%, respectively. Receiver operating characteristic curve areas of UCH-L1 and GFAP were 0.670 and 0.757, respectively. There were no significant significance in age, gender, drinking, smoke, diabetes, and hyperlipidemia in the 2 groups (P>0.05). High blood pressure rate in the observation group was higher than that in the control group (P<0.05). Spearson/Pearson analysis showed that serum UCH-L1 and GFAP levels were positively correlated with hypertension, but they were negatively correlated with sex, age, diabetes, hyperlipidemia, alcohol consumption, smoking, and other factors. General data at different time in the observation group was not statistically different (P>0.05). The expression levels of UCH-L1 and GFAP in the observation group was higher than that in the control group (P<0.05). UCH-L1 and GFAP levels at different time in the 2 groups were not statistically different (P>0.05). UCH-L1 and GFAP levels in the light, medium, and heavy groups were higher than those in the control group (P<0.05), while UCH-L1 and GFAP levels in the medium and heavy groups were higher than those in the light group (P<0.05). There was significant difference between levels of UCH-L1 or GFAP and infarction size at different time in the observation group (P<0.05). The results of Pearson correlation analysis showed that the levels of serum UCH-L1 and GFAP were positively correlated (r=0.634, P=0.001).? Conclusion: The levels of serum UCH-L1 and GFAP are significantly increased at the early stage of acute cerebral infarction, and they have a certain correlation with the severity of cerebral infarction, which can provide a basis for early clinical diagnosis and treatment. PMID- 28364103 TI - [Association between loneliness and risks of depressive episode among rural older people]. AB - OBJECTIVE: To investigate association between loneliness and depressive episode among rural older people.? Methods: A total of 839 rural adults (aged over 60 years) from Liuyang in Hunan were enrolled by using multi-stage cluster sampling method. The Short-form of the UCLA Loneliness Scale, the Social Support Rating Scale, the Life Events Scale for the Elderly, Quality of Life Scale, and the Activity of Daily Living Scale were used to assess loneliness, the social support condition, the stimulating quantity of negative life events, the quality of life, and the abilities of daily life activities, respectively. The Structured Clinical Interview for DSM-IV-TR Axis I Disorders questionnaire survey was performed by a face-to-face interview.? Results: The prevalence rate of depressive episode among the rural older people was 6.8%. Multivariable analysis showed that the elderly who were with stronger loneliness were the risk factor of depression (OR=1.126, 95%CI 1.038 to 1.221).? Conclusion: Loneliness is positively associated with an increased risk of depressive episode. PMID- 28364102 TI - [Value of 1H-MRS on SCA3/MJD diagnosis and clinical course]. AB - OBJECTIVE: To investigate the value of proton magnetic resonance spectroscopy (1H MRS) on the diagnosis of SCA3/MJD, and to calculate the correlation between 1H MRS ratio and the clinical score.? Methods: Sixteen patients with SCA3/MJD and 19 healthy volunteers were scanned with 1H-MRS. The data of N-acetyl aspartate, creatine, choline-containing compounds, myoinositol, NAA/Cr, Cho/Cr, and mI/Cr ratio were collected, which were grouped for comparative study. The onset patients with SCA3/MJD were evaluated with the International Cooperative Ataxia Rating Scale and Scale for the Assessment and Rating of Ataxia, the correlation between NAA/Cr, Cho/Cr or mI/Cr ratio and the clinical score was calculated.? Results: The NAA/Cr in the pons and cerebellar dentate nucleus from the onset patients with SCA3/MJD was significantly reduced compared to that in the normal control group. The NAA/Cr in the cerebellar dentate nucleus of onset patients with SCA3/MJD was obviously correlated with ICARS.? Conclusion: SCA3/MJD lesions are mainly located in the cerebellum and brainstem, where gray and white mater are also involved. The cerebellar dentate nucleus may be the earliest involved area. There is a correlation between the ICARS and the cerebellar lesion degree. The ICARS reflects the severity of clinical manifestations. 1H-MRS is useful in the diagnosis of SCA3/MJD. PMID- 28364104 TI - [Space-time analysis of over-limit of sodium nitrite in cooked meat products from Hunan Province in 2010-2014]. AB - OBJECTIVE: To determine over-limit status of sodium nitrite in cooked meat products in Hunan Province, and to provide scientific evidence for making health supervision.? Methods: In accordance with the national standards for sampling and testing, data were analyzed by classical and spatial statistic methods.? Results: The total over-limit rate of sodium nitrite was 5.5% in 731 samples. The relative higher sodium nitrite over-limit rates were Xiangxi Tujia and Miao autonomous prefecture and Zhangjiajie. October and February were the main months in nitrite over-limit. Five regions with over-limit of sodium nitrite in cooked meat products were detected in Hunan.? Conclusion: With obvious space-time clustering, over-limit of sodium nitrite in cooked meat products is a common problem particularly in northwest Hunan and Zhuzhou City. Supervision in October should be further strengthened in above-mentioned areas to guarantee the consumers health. PMID- 28364105 TI - [Effect of telephone follow-up on compliance and Helicobacter pylori eradication in patients with Helicobacter pylori infection]. AB - OBJECTIVE: To evaluate effect of telephone follow-up combined with written instruction on compliance and Helicobacter pylori (H. pylori) eradication in patients with H. pylori infection.? Methods: A total of 160 H. pylori positive patients were randomly divided into an experimental group and a control group (n=80 in each group). All the patients got the guide instruction named "the guidance of clinical medication for H. pylori infection patients" before the treatment. The patients in the experimental group were added individualized follow-up with telephone. The compliance, eradication of H. pylori, adverse events, and satisfaction were compared between the 2 groups.? Results: The eradication rate of H. pylori in the perprotocol analysis for the experimental group and control group were 64.4% (47/73) and 56.5%(35/62), respectively (P=0.380), while in the intention-to-treat analysis, the rates were 58.8% (47/80) and 43.8% (35/80, P=0.082), respectively. The compliance rate in the experimental group was significantly higher than that in the control group (91.3% vs 77.5%, P<0.05). There was significant difference in patients' satisfaction in good ones (75.3% vs 51.6%) and poor ones (5.5% vs 21.0%) between the 2 groups (P<0.05). There were 11 patients in the experimental group and 36 patients in the control group, who appeared adverse reactions such as nausea, bad breath, abdominal distention, poor appetite, and defecation habit change during the process of eradicating H. pylori, but the occurrence rate in the experimental group was obviously lower than that in the control group (15.1% vs 58.1%, P<0.05).? Conclusion: The telephone follow-up cannot increase the H. pylori eradication rate, but it can improve compliance and satisfaction for the patients and relieve adverse effects. PMID- 28364106 TI - Efficacy of temporary ligation of infrarenal abdominal aorta during cesarean section in pernicious placenta previa. AB - OBJECTIVE: To evaluate the efficacy and safety of temporary loop ligation of the infrarenal abdominal aorta for control of intraoperative blood loss in patients with pernicious placenta previa.? Methods: We retrospectively analyzed the clinical data of 14 patients with pernicious placenta previa, who underwent temporary loop ligation of the infrarenal abdominal aorta for control of blood loss during cesarean section between July 2013 and December 2014.? Results: Eight patients received conservative management to preserve the uterus and 6 patients underwent cesarean hysterectomy. The occlusion time of the abdominal aorta was (31.42+/-12.67) min. The average estimated intraoperative blood loss was (1 117.85+/-745.13) mL. The volume of packed red blood cell transfusion was (3.91+/ 3.24) units, and the volume of fresh frozen plasma transfusion was (192.85+/ 156.71) mL. Post-operative histologic diagnosis revealed 6 cases of placenta percreta, 4 of increta, 3 of accreta and 1 non-creta. All patients experienced an uneventful postoperative recovery.? Conclusion: In patients with pernicious placenta previa, temporary ligation of the infrarenal abdominal aorta provide a safe and effective means for controlling intraoperative hemorrhage during cesarean section. Additionally, the procedure may provide an opportunity to preserve fertility by avoiding a cesarean hysterectomy. PMID- 28364108 TI - [Bactericidal effects and smear layer removal of Er:YAG-laser radiation against Enterococcus faecalis in root canals]. AB - OBJECTIVE: To evaluate the cleaning ability of Er:YAG laser against Enterococcus faecalis in root canals.? Methods: The single-rooted human teeth were sterilized and inoculated with Enterococcus faecalis and were randomly assigned into 2 groups. A group of teeth was irrigated with saline during root canal preparation while another group with NaClO. After mechanical preparation, the two groups were randomly divided into 3 subgroups according to the different treatments: Samples, laser radiation, and calcium hydroxide intracanal medication for 7 days. Bactericical effects were compared among groups. Root canal walls and dental tubules were observed under scanning electron microscope.? Results: Er:YAG laser was the most efficient way for anti-bacteria among the groups (P<0.05), but there was no significant difference between the 2 laser groups (P>0.05). Meanwhile the smear laser was efficiently removed by laser compared with other treatments, and the laser could open the dentinal tubules.? Conclusion: Er:YAG laser can be effectively used for root canal disinfection without NaClO and Ca(OH)2. PMID- 28364107 TI - [Advantage of extralevator abdominoperineal excision comparing to the conventional abdominoperineal excision for low rectal cancer: a Meta-analysis]. AB - OBJECTIVE: Whether extralevator abdominoperineal excision (ELAPE) improves survival and safety remains controversial. Systematic review of all comparative studies to define the superiority of ELAPE to conventional abdominoperineal excision (APE).? Methods: Corresponding data, with case-control studies or cohorts regarding intraoperative perforation rate, the local recurrence rate and postoperative complications in the ELAPE group and the APE group, were retrieved from PubMed, Embase, the Cochrane Library, Chinese Biomedical Literature (CMB), VIP, China National Knowledge Infrastructure (CNKI), and Wanfang Database. Meta analysis was performed by using RenMan 5.2.? Results: A total of 10 articles were included. Intraperative perforation rate (MD=0.54, 95% CI 0.31 to 1.39, P=0.03), local recurrence rate (MD=0.30, 95% CI 0.21 to 0.42, P<0.001) in the ELAPE group was significantly lower than that in the APE group. The difference in positive margin rate between the 2 groups was not statistically significant (P=0.07).? Conclusion: Through gap repair of episiotomy and individualized therapy can improve ELAPE postoperative quality of life. ELAPE shows certain advantages in treating lower rectal cancer comparing to APE, but it should pay attention to individualized treatment. More studies through large sample multi-center, medium and long term randomized design are necessary to determine the effect of surgery on tumor. PMID- 28364109 TI - [Role of substance P and calcitonin gene-related peptide in bone metabolism]. AB - Substance P (SP) and calcitonin gene-related peptide (CGRP) are the neuropeptides released from the sensory nerve endings. Neuropeptides play a role in bone and the relevant organs. It exerts functions in regulation of the bone metabolism, fracture healing and pain by a certain way. The biological properties and distributions of SP and CGRP are closely related to the pathogenesis and development of bone metabolism, fracture healing and pain. PMID- 28364110 TI - [Role of cannabinoid receptor 1-mediated synaptic plasticity in neuropathic pain and associated depression]. AB - Neuropathic pain is a class of pain caused by an injury or diseases of the somatosensory system and characterized by spontaneous pain, allodynia, and hyperalgesia. It is well established that central sensitization is one of the key mechanisms underlying the development and maintenance of neuropathic pain. Cannabinoid receptor 1 (CB1R) of endocannabinoid system modulates synaptic transmission, regulates synaptic plasticity, inhibits central sensitization, and thus attenuates neuropathic pain. Recent studies have shown that activation of CB1R also involves in the relief of neuropathic pain-induced depression. PMID- 28364112 TI - [Research progress in endoscopic incision in treating gastrointestinal benign stricture]. AB - Gastrointestinal benign stricture is a common disease with symptoms of dysphagia, abdominal pain and difficult defecation, which severely impair the quality of life for patients. Endoscopic intervention is the first-line treatment, and the available methods include balloon dilation, local drug injection and stent insertion, etc. Endoscopic incision was first used for the treatment of Schatzki's rings, and later it was used for the treatment of other gastrointestinal benign strictures, and the promising results were achieved. PMID- 28364111 TI - [Inhibitory effects of melatonin on breast cancer]. AB - Melatonin has a significant inhibitory effect on various cancers, especially on breast cancer. In estrogen receptor (ER)-positive human breast cancer, anti cancer effects of melatonin on breast cancer cells and transplanted tumors mainly achieve by suppressing ER mRNA expression and ER transcriptional activity via the MT1 receptor. In addition, melatonin regulates the transactivation of other members of the nuclear receptor super-family, estrogen metabolizing enzymes, and the expression of related genes. Furthermore, melatonin also suppresses tumor aerobic metabolism, critical cell-signaling pathways relevant to cell proliferation, survival, metastasis, and drug resistance. Melatonin demonstrates both cytostatic and cytotoxic activity in breast cancer cells that appears to be cell-type specific. Studies on animal and human models indicate that disruption of the circadian nocturnal melatonin signal promotes the growth, metabolism, and signaling of human breast cancer, resulting in invalid hormone therapy and chemotherapeutic resistance in breast tumors. PMID- 28364113 TI - [Research progress in vasculogenic mimicry in ?multiple tumors]. AB - Vasculogenic mimicry (VM) is a brand-new tumor vascular pattern with the ability to form vessel-like networks without participation of endothelial cells and independent on angiogenesis. It can provide adequate blood supply for tumor growth. The formation of VM involves multiple molecule mechanisms and signal pathways, including cancer stem cell and epithelial-mesenchymal transition. As a unique blood-supply pattern, VM is associated with cancer invasion, metastasis and poor prognosis. Because of its important role in cancer progression, VM will become a new target for therapy of cancers. PMID- 28364115 TI - An Eye Popping Case of Orbital Necrotizing Fasciitis Treated with Antibiotics, Surgery, and Hyperbaric Oxygen Therapy. AB - BACKGROUND Necrotizing fasciitis (NF) of the orbit is a rare and deadly condition that requires prompt surgical and medical management to decrease morbidity and mortality. CASE REPORT Here we present an interesting case of an individual who developed fulminant NF of the left orbit requiring emergent surgical intervention, antibiotics, and subsequent hyperbaric oxygen therapy in an attempt to save the eye. CONCLUSIONS With an early and aggressive multifaceted approach using antibiotics, surgery, and hyperbaric oxygen it may be possible to preserve eye structure and function. Without treatment NF is a rapidly progressive condition and can result in significant morbidity. PMID- 28364116 TI - Chasing the thermodynamical noise limit in whispering-gallery-mode resonators for ultrastable laser frequency stabilization. AB - Ultrastable high-spectral-purity lasers have served as the cornerstone behind optical atomic clocks, quantum measurements, precision optical microwave generation, high-resolution optical spectroscopy, and sensing. Hertz-level lasers stabilized to high-finesse Fabry-Perot cavities are typically used for these studies, which are large and fragile and remain laboratory instruments. There is a clear demand for rugged miniaturized lasers with stabilities comparable to those of bulk lasers. Over the past decade, ultrahigh-Q optical whispering gallery-mode resonators have served as a platform for low-noise microlasers but have not yet reached the stabilities defined by their fundamental noise. Here, we show the noise characteristics of whispering-gallery-mode resonators and demonstrate a resonator-stabilized laser at this limit by compensating the intrinsic thermal expansion, allowing a sub-25 Hz linewidth and a 32 Hz Allan deviation. We also reveal the environmental sensitivities of the resonator at the thermodynamical noise limit and long-term frequency drifts governed by random walk-noise statistics.High-quality optical resonators have the potential to provide a miniaturized frequency reference for metrology and sensing but they often lack stability. Here, Lim et al. experimentally characterize the stability of whispering-gallery resonators at their fundamental noise limits. PMID- 28364114 TI - Cross-Cultural Adaptation and Psychometric Properties Testing of the Arabic Anterior Knee Pain Scale. AB - BACKGROUND PFPS is one of the most frequently occurring overuse injuries affecting the lower limbs. A variety of functional and self-reported outcome measures have been used to assess clinical outcomes of patients with PFPS, however, only the Anterior Knee Pain Scale (AKPS) has been designed for PFPS patients. MATERIAL AND METHODS We followed international recommendations to perform a cross-cultural adaptation of the AKPS. The Arabic AKPS and the Arabic RAND 36-item Health Survey were administered to 40 patients who were diagnosed with PFPS. Participants were assessed at baseline and after 2 to 3 days assessed with the Arabic AKPS only. The measurements tested were reliability, validity, and feasibility. RESULTS The Arabic AKPS showed high reliability for both temporal stability, internal consistency (Cronbach's alpha was 0.81 for the first assessment and 0.75 for the second), excellent test-retest reliability (Intraclass Correlation Coefficients ICC=0.96; 95% confidence interval (CI): 0.93, 0.98) and good agreement (standard error of measurement SEM=1.8%). The Arabic AKPS was significantly correlated with physical components of the RAND 36 Item Health Survey (Spearman's rho=0.69: p<0.001). No ceiling or floor effects were observed. CONCLUSIONS The Arabic AKPS is a valid and reliable tool and is comparable to the original English version and other translated versions. PMID- 28364117 TI - Positive affect, surprise, and fatigue are correlates of network flexibility. AB - Advances in neuroimaging have made it possible to reconstruct functional networks from the activity patterns of brain regions distributed across the cerebral cortex. Recent work has shown that flexible reconfiguration of human brain networks over short timescales supports cognitive flexibility and learning. However, modulating network flexibility to enhance learning requires an understanding of an as-yet unknown relationship between flexibility and brain state. Here, we investigate the relationship between network flexibility and affect, leveraging an unprecedented longitudinal data set. We demonstrate that indices associated with positive mood and surprise are both associated with network flexibility - positive mood portends a more flexible brain while increased levels of surprise portend a less flexible brain. In both cases, these relationships are driven predominantly by a subset of brain regions comprising the somatomotor system. Our results simultaneously suggest a network-level mechanism underlying learning deficits in mood disorders as well as a potential target - altering an individual's mood or task novelty - to improve learning. PMID- 28364119 TI - Transition from Anomalous Hall Effect to Topological Hall Effect in Hexagonal Non Collinear Magnet Mn3Ga. AB - We report experimental observation of large anomalous Hall effect exhibited in non-collinear triangular antiferromagnet D019-type Mn3Ga with coplanar spin structure at temperatures higher than 100 K. The value of anomalous Hall resistivity increases with increasing temperature, which reaches 1.25 MUOmega . cm at a low field of ~300 Oe at room temperature. The corresponding room temperature anomalous Hall conductivity is about 17 (Omega . cm)-1. Most interestingly, as temperature falls below 100 K, a temperature-independent topological-like Hall effect was observed. The maximum peak value of topological Hall resistivity is about 0.255 MUOmega . cm. The appearance of the topological Hall effect is attributed to the change of spin texture as a result of weak structural distortion from hexagonal to orthorhombic symmetry in Mn3Ga. Present study suggests that Mn3Ga shows promising possibility to be antiferromagnetic spintronics or topological Hall effect-based data storage devices. PMID- 28364118 TI - Enablers and determinants of the provision of written action plans to patients with asthma: a stratified survey of Canadian physicians. AB - : Despite national recommendations, most patients with asthma are not given a written action plan . The objectives were to ascertain physicians' endorsement of potential enablers to providing a written action plan, and the determinants and proportion, of physician-reported use of a written action plan. We surveyed 838 family physicians, paediatricians, and emergency physicians in Quebec. The mailed questionnaire comprised 102 questions on asthma management, 11 of which pertained to written action plan and promising enablers. Physicians also selected a case vignette that best corresponded to their practice and reported their management. The survey was completed by 421 (56%) physicians (250 family physicians, 115 paediatricians and 56 emergency physicians); 43 (5.2%) reported providing a written action plan to >=70% of their asthmatic patients and 126 (30%) would have used a written action plan in the selected vignette. Most (>60%) physicians highly endorsed the following enablers: patients requesting a written action plan, adding a blank written action plan to the chart, receiving a copy of the written action plan completed by a consultant, receiving a monetary compensation for its completion, and having another healthcare professional explain the completed written action plan to patients. Four determinants were significantly associated with providing a written action plan: being a paediatrician (RR:2.1), treating a child (RR:2.0), aiming for long-term asthma control (RR:2.5), and being aware of national recommendations to provide a written action plan to asthmatic patients (RR:2.9). A small minority of Quebec physicians reported providing a written action plan to most of their patients, revealing a huge care gap. Several enablers to improve uptake, highly endorsed by physicians, should be prioritised in future implementation efforts. ASTHMA: ENCOURAGING DOCTORS TO PROVIDE WRITTEN ACTION PLANS: Changes to practice organization and doctors' perceptions should encourage the provision of written action plans for all asthma patients. International guidelines state that effective long-term treatment of asthma requires educated self-management, regular reviews and provision of a written action plan (WAP). However, many patients have poor asthma control and as few as 30 per cent have a WAP. Fabienne Djandji at the Saint-Justine University Central Hospital in Montreal, Canada, and co-workers conducted a survey of 421 doctors to determine their attitudes and provision of WAPs. Only 5.2 per cent of respondents provided WAPs to patients; those treating children or aiming for long term asthma control were more likely to do so. The doctors said that incentives to provide WAPs would include requests from patients themselves, being paid to complete WAPs and having extra support from specialists or other health care professionals such as pharmacists. PMID- 28364120 TI - Lateral Antimicrobial Resistance Genetic Transfer is active in the open environment. AB - Historically, the environment has been viewed as a passive deposit of antimicrobial resistance mechanisms, where bacteria show biological cost for maintenance of these genes. Thus, in the absence of antimicrobial pressure, it is expected that they disappear from environmental bacterial communities. To test this scenario, we studied native IntI1 functionality of 11 class 1 integron positive environmental strains of distant genera collected in cold and subtropical forests of Argentina. We found natural competence and successful site specific insertion with no significant fitness cost of both aadB and bla VIM-2 antimicrobial resistance gene cassettes, in a model system without antibiotic pressure. A bidirectional flow of antimicrobial resistance gene cassettes between natural and nosocomial habitats is proposed, which implies an active role of the open environment as a reservoir, recipient and source of antimicrobial resistance mechanisms, outlining an environmental threat where novel concepts of rational use of antibiotics are extremely urgent and mandatory. PMID- 28364121 TI - Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis. AB - The myocardin-related transcription factor/serum response factor (MRTF/SRF) pathway represents a promising therapeutic target to prevent fibrosis. We have tested the effects of new pharmacological inhibitors of MRTF/SRF signalling in a preclinical model of fibrosis. CCG-222740, a novel MRTF/SRF inhibitor, markedly decreased SRF reporter gene activity and showed a greater inhibitory effect on MRTF/SRF target genes than the previously described MRTF-A inhibitor CCG-203971. CCG-222740 was also five times more potent, with an IC50 of 5 MUM, in a fibroblast-mediated collagen contraction assay, was less cytotoxic, and a more potent inhibitor of alpha-smooth muscle actin protein expression than CCG-203971. Local delivery of CCG-222740 and CCG-203971 in a validated and clinically relevant rabbit model of scar tissue formation after glaucoma filtration surgery increased the long-term success of the surgery by 67% (P < 0.0005) and 33% (P < 0.01), respectively, and significantly decreased fibrosis and scarring histologically. Unlike mitomycin-C, neither CCG-222740 nor CCG-203971 caused any detectable epithelial toxicity or systemic side effects with very low drug levels measured in the aqueous, vitreous, and serum. We conclude that inhibitors of MRTF/SRF-regulated gene transcription such as CCG-222740, potentially represent a new therapeutic strategy to prevent scar tissue formation in the eye and other tissues. PMID- 28364122 TI - A Convenient Cas9-based Conditional Knockout Strategy for Simultaneously Targeting Multiple Genes in Mouse. AB - The most powerful way to probe protein function is to characterize the consequence of its deletion. Compared to conventional gene knockout (KO), conditional knockout (cKO) provides an advanced gene targeting strategy with which gene deletion can be performed in a spatially and temporally restricted manner. However, for most species that are amphiploid, the widely used Cre-flox conditional KO (cKO) system would need targeting loci in both alleles to be loxP flanked, which in practice, requires time and labor consuming breeding. This is considerably significant when one is dealing with multiple genes. CRISPR/Cas9 genome modulation system is advantaged in its capability in targeting multiple sites simultaneously. Here we propose a strategy that could achieve conditional KO of multiple genes in mouse with Cre recombinase dependent Cas9 expression. By transgenic construction of loxP-stop-loxP (LSL) controlled Cas9 (LSL-Cas9) together with sgRNAs targeting EGFP, we showed that the fluorescence molecule could be eliminated in a Cre-dependent manner. We further verified the efficacy of this novel strategy to target multiple sites by deleting c-Maf and MafB simultaneously in macrophages specifically. Compared to the traditional Cre-flox cKO strategy, this sgRNAs-LSL-Cas9 cKO system is simpler and faster, and would make conditional manipulation of multiple genes feasible. PMID- 28364123 TI - Anomalous evolution of broadband optical absorption reveals dynamic solid state reorganization during eumelanin build-up in thin films. AB - The origin of eumelanin optical properties remains a formidable conundrum preventing a detailed understanding of the complex photo-protective role of these widespread natural pigments and the rational design of innovative bioinspired materials for optoelectronic applications. Here we report the unusual kinetic and thickness-dependent evolution of the optical properties of black eumelanin polymers generated by spontaneous aerial polymerization of 5,6-dihydroxyindole (DHI) thin films (0.1-1 MUm), consistent with peculiar solid state reorganization mechanisms governing broadband absorption. The complete reversal of eumelanin UV visible transmittance spectrum curvature on passing from 0.2 to 0.5 MUm thick films, the marked increase in visible extinction coefficients with increasing film thickness and the higher UV extinction coefficients in slowly vs. rapidly generated polymers concur to support distinct dynamic regimes of solid-state molecular reorganization at the nanoscale level and to do affect the development of broadband visible absorption. Solid state control of molecular reorganization disclosed herein may delineate new rational strategies for tuning optical properties in eumelanin thin films for optoelectronic applications. PMID- 28364124 TI - A Circulating MicroRNA Signature Capable of Assessing the Risk of Hepatocellular Carcinoma in Cirrhotic Patients. AB - With the availability of potent antiviral therapies, complete suppression of hepatitis B virus (HBV) replication and total eradication of hepatitis C virus (HCV) can now be achieved. Despite these advances, hepatocellular carcinoma (HCC) still develops in a substantial proportion of cirrhotic patients, suggesting that host factors remain critical. Dysregulation of miRNAs is noted in many cancers, and circulating miRNAs can be readily assayed. In this study, we aimed to develop a circulating miRNA signature to assess the risk of HCC in cirrhotic patients. We first discovered that HBV- and HCV-related cirrhotic patients had distinguishable circulating miRNA profiles. A cohort of 330 cirrhotic patients was then compared against a cohort of 42 early HCC patients with complete remission. A score comprising 5 miRNAs and a binary etiology variable was established that was capable of differentiating between these two groups (AUC = 72.5%, P < 0.001). The 330 cirrhotic patients were further stratified into high- and low-risk groups, and all patients were longitudinally followed for 752 (11-891) days. Of them, 19 patients developed HCC. The high-risk group had significantly higher cumulative HCC incidence (P = 0.038). In summary, a circulating miRNA-based score was developed that is capable of assessing HCC risks in cirrhotic patients. PMID- 28364125 TI - Molecular Characteristics and Serodiagnostic Potential of Dihydrofolate Reductase from Echinococcus granulosus. AB - The larval stage of Echinococcus granulosus causes cystic echinococcosis (CE), a neglected tropical disease that leads to morbidity and mortality in humans and livestock worldwide. Here, we identified and characterized dihydrofolate reductase (Eg-DHFR) from E. granulosus, and evaluated its potential as a diagnostic antigen for sheep CE. Comparison between mammalian (host) DHFR and Eg DHFR indicates that 45.7% of the 35 active site residues are different. Immunolocalisation analysis showed that native Eg-DHFR was widely distributed in all life-cycle stages of E. granulosus. Recombinant Eg-DHFR (rEg-DHFR) showed typical DHFR enzymatic parameters towards substrate, and was very sensitive to inhibition by methotrexate (IC50 = 27.75 +/- 1.03 nM) and aminopterin (IC50 = 63.67 +/- 6.76 nM). However, inhibition of DHFR exhibited little protoscolicidal effect in vitro. As there is no reliable method to monitor sheep CE, the immunogenicity of rEg-DHFR was detected, and we developed an indirect ELISA (iELISA) for CE serodiagnosis. The iELISA exhibited diagnostic specificity of 89.58%, diagnostic sensitivity of 95.83%, and the diagnostic accuracy was 91.67% compared with necropsy. Cross-reactivity assay showed analytical specificity of 85.7%. These suggest that rEg-DHFR is an effective antigen for the diagnosis of sheep CE. PMID- 28364126 TI - Carbon Dots' Antiviral Functions Against Noroviruses. AB - This study reported the first assessment of carbon dots' (CDots) antiviral activity to human norovirus virus-like-particles (VLPs), GI.1 and GII.4 VLPs. CDots with different surface passivation molecules, 2,2' (ethylenedioxy)bis(ethylamine) (EDA)-CDots and 3-ethoxypropylamine (EPA)-CDots, were synthesized and evaluated. The results indicated both EDA- and EPA- CDots were highly effective to inhibit both strains of VLPs' bindings to histo-blood group antigens (HBGA) receptors on human cells at CDots concentration of 5 ug/mL, with EDA-CDots achieving 100% inhibition and EPA CDots achieving 85-99% inhibition. At low CDots concentration (2 ug/mL), positively charged EDA-CDots exhibited higher inhibitory effect (~82%) than non-charged EPA-CDots (~60%), suggesting the surface charge status of CDots played a role in the interactions between CDots and the negatively charged VLPs. Both types of CDots also exhibited inhibitory effect on VLP's binding to their respective antibodies, but much less effective than those to HBGA binding. After CDots treatments, VLPs remained intact, and no degradation was observed on VLPs' capsid proteins. Taken together, the observed antiviral effects of CDots on noroviruses were mainly through the effective inhibition of VLPs' binding to HBGA receptors and moderate inhibition of VLPs' binding to their antibodies, without affecting the integrity of viral capsid protein and the viral particle. PMID- 28364127 TI - 'Two-level' measurements of processing speed as cognitive markers in the differential diagnosis of DSM-5 mild neurocognitive disorders (NCD). AB - Processing speed is an updated diagnostic factor for neurocognitive disorders (NCD) in DSM-5. This study investigated the characteristics of processing speed and their diagnostic values in NCD patients. A flanker test was conducted in 31 adults with NCD due to vascular disease (NCD-vascular), 36 patients with NCD due to Alzheimer's disease (NCD-AD), and 137 healthy controls. The processing speed was evaluated using two measurements: mean reaction time (RT) and intra individual variability of RT. Mean RT represents the global processing speed. Intra-individual variability of RT is the short-term fluctuation of RT and consists of two indices, which are intra-individual coefficient of variation of reaction time (ICV-RT) and intra-individual standard deviations (iSD). We observed elevated ICV-RT and iSD in NCD-AD and NCD-vascular patients. Additionally, there was a slowed RT in NCD-AD patients. The intra-individual variability of RT had a moderate power to differentiate NCD subgroups. The mean RT was able to discriminate the NCD-AD from NCD-vascular patients. Our findings highlight the clinical utility of the combined 'two-level' measurements of processing speed to distinguish between individuals with different cognitive status. Furthermore, the 'two-level' features of processing speed embedded in the psychometric property may also reflect the diverse aetiology underlying certain 'disease-specific' neurocognitive disorders. PMID- 28364128 TI - SNPs in bone-related miRNAs are associated with the osteoporotic phenotype. AB - Biogenesis and function of microRNAs can be influenced by genetic variants in the pri-miRNA sequences leading to phenotypic variability. This study aims to identify single nucleotide polymorphisms (SNPs) affecting the expression levels of bone-related mature microRNAs and thus, triggering an osteoporotic phenotype. An association analysis of SNPs located in pri-miRNA sequences with bone mineral density (BMD) was performed in the OSTEOMED2 cohort (n = 2183). Functional studies were performed for assessing the role of BMD-associated miRNAs in bone cells. Two SNPs, rs6430498 in the miR-3679 and rs12512664 in the miR-4274, were significantly associated with femoral neck BMD. Further, we measured these BMD associated microRNAs in trabecular bone from osteoporotic hip fractures comparing to non-osteoporotic bone by qPCR. Both microRNAs were found overexpressed in fractured bone. Increased matrix mineralization was observed after miR-3679-3p inhibition in human osteoblastic cells. Finally, genotypes of rs6430498 and rs12512664 were correlated with expression levels of miR-3679 and miR-4274, respectively, in osteoblasts. In both cases, the allele that generated higher microRNA expression levels was associated with lower BMD values. In conclusion, two osteoblast-expressed microRNAs, miR-3679 and miR-4274, were associated with BMD; their overexpression could contribute to the osteoporotic phenotype. These findings open new areas for the study of bone disorders. PMID- 28364129 TI - The scavenging capacity of DMBT1 is impaired by germline deletions. AB - The Scavenger Receptor Cysteine-Rich (SRCR) proteins are an archaic group of proteins characterized by the presence of multiple SRCR domains. They are membrane-bound or secreted proteins, which are generally related to host defense systems in animals. Deleted in Malignant Brain Tumors 1 (DMBT1) is a SRCR protein which is secreted in mucosal fluids and involved in host defense by pathogen binding by its SRCR domains. Genetic polymorphism within DMBT1 leads to DMBT1 alleles giving rise to polypeptides with interindividually different numbers of SRCR domains, ranging from 8 SRCR domains (encoded by 6 kb DMBT1 variant) to 13 SRCR domains (encoded by the 8 kb DMBT1 variant). In the present study, we have investigated whether reduction from 13 to 8 amino-terminal SRCR domains leads to reduction of bacterial binding. The 6 kb variant bound ~20-45% less bacteria compared to the 8 kb variant. These results support the hypothesis that genetic variation in DMBT1 may influence microbial defense. PMID- 28364131 TI - Comparative analysis of overall cost and rate of healthcare utilization among apical prolapse procedures. AB - INTRODUCTION AND HYPOTHESIS: The annual cost of prolapse surgeries is expected to grow at twice the rate of population growth. Understanding the economic impact of apical prolapse procedures, including sacrospinous fixation (SSF), abdominal sacrocolpopexy (ASC), and laparoscopic sacrocolpopexy (LSC), is crucial. We aimed to compare overall cost of SSF versus ASC and LSC, as well as health resource utilization, up to 90-day follow-up. METHODS: Truven Marketscan Commercial Claims and Encounter databases 2008-2012 were used to calculate index and 90-day follow up costs for SSF, ASC, and LSC with/without hysterectomy. Rates of inpatient readmissions, outpatient visits, and emergency room (ER) visits were also calculated during the follow-up period. Statistical analyses were performed using SAS 9.3. RESULTS: There were 17,549 SSF, 6126 ASC, and 10,708 LSC procedures. Mean index cost was lower for SSF (US$10,993) than ASC ($12,763, p < 0.0001) and LSC ($13,647, p < 0.0001). Concurrent hysterectomy impacted costs. Follow-up costs were likewise lower for SSF ($13,916) than ASC ($15,716, p < 0.0001) and LSC ($16,838, p < 0.0001). Lower rates of readmission were reported in SSF (4.22%) than ASC (5.40%, p = 0.0001) and LSC (4.64%, p = 0.0411). The rate of at least one ER visit was also lower for SSF (10.9%) than for ASC (12.0%, p = 0.0170) and comparable with LSC (10.6%, p = 0.0302). CONCLUSIONS: Overall mean costs are significantly lower for SSF than ASC/LSC, as are those for health resource utilization. Besides lower morbidity rates being associated with vaginal procedures, our results demonstrate another reason to consider the increased use of SSF over sacrocolpopexies in apical prolapse surgery. PMID- 28364130 TI - Bacterial Signatures of "Red-Operculum" Disease in the Gut of Crucian Carp (Carassius auratus). AB - Fish gut microbiota play important roles in fish immunity, nutrition, and the adaptation to environmental changes. To date, few studies have focused on the interactions among environmental factors, fish diseases, and gut microbiota compositions. We compared the gut bacterial communities of healthy crucian carps (Carassius auratus) with those of individuals affected by "red-operculum" disease and corresponding water and sediment microbiota in four fish farm ponds. Distinct gut bacterial communities were observed in healthy and diseased fish. The bacterial communities of diseased fish were less diverse and stable than those of healthy individuals. The differences in bacterial community compositions between diseased and healthy fish were explained by the changes in the relative abundances of some specific bacterial OTUs, which belonged to the genera such as Vibrio, Aeromonas, and Shewanella, and they were prevalent in diseased fish, but rare or even absent in environmental samples. Water temperature and ammonia concentration were the two most important environmental factors that impacted gut microbiota in diseased fish. These results highlighted the surge of some potential pathogens as bacterial signatures that were associated with "red operculum" disease in crucian carps. PMID- 28364134 TI - Evaluating the Dimensionality of Pornography. AB - Pornography may be a construct with a single trait or one with many traits. Research in the past was inconsistent in this regard with most researchers assuming that pornography was unidimensional (with one single trait of pornography). However, the considerable amounts of residual variation found in these studies beyond that explained by the single trait hints at what might be a multidimensional construct (with multiple traits such as sensitization and differentiation). Consequently, in this study, we intended to address the question of whether pornography consisted of a single trait or if it was multidimensional. Using MTurk, 2173 participants from the United States and the Commonwealth of Nations (in which pornography is not strictly illegal) were recruited and asked to rate how pornographic they thought a list of different depictions were. The data were analyzed utilizing the cross-validation procedure in which two subsamples were created from the main sample and one was used to establish the model building and the other to validate the model. Various models, including first-order and higher-order exploratory and confirmatory factor models, were tested. Results indicated that a bi-factor (multidimensional) model generated the best model fit, and that it was most appropriate to consider pornography multidimensional. The final model contained two dimensions ("Sensitization" and "Differentiation"). While sensitization revealed the participants' general tendency to rate all items to be more or less pornographic, differentiation revealed the participants' tendency to differentiate highly pornographic items from less pornographic items. Based on the findings of this study, we suggest that future research on the usage and effects of pornography be conducted while taking into consideration the multidimensional nature of pornography. PMID- 28364132 TI - Challenges in establishing genotype-phenotype correlations in ARPKD: case report on a toddler with two severe PKHD1 mutations. AB - BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) constitutes an important cause of pediatric end stage renal disease and is characterized by a broad phenotypic variability. The disease is caused by mutations in a single gene, Polycystic Kidney and Hepatic Disease 1 (PKHD1), which encodes a large transmembrane protein of poorly understood function called fibrocystin. Based on current knowledge of genotype-phenotype correlations in ARPKD, two truncating mutations are considered to result in a severe phenotype with peri- or neonatal mortality. Infants surviving the neonatal period are expected to carry at least one missense mutation. CASE-DIAGNOSIS/TREATMENT: We report on a female patient with two truncating PKHD1 mutations who survived the first 30 months of life without renal replacement therapy. Our patient carries not only a known stop mutation, c.8011C>T (p.Arg2671*), but also the previously reported c.51A>G PKHD1 sequence variant of unknown significance in exon 2. Using functional in vitro studies we have confirmed the pathogenic nature of c.51A>G, demonstrating activation of a new donor splice site in intron 2 that results in a frameshift mutation and generation of a premature stop codon. CONCLUSIONS: This case illustrates the importance of functional mutation analyses and also raises questions regarding the current belief that the presence of at least one missense mutation is necessary for perinatal survival in ARPKD. PMID- 28364133 TI - In Brachypodium a complex signaling is actuated to protect cells from proteotoxic stress and facilitate seed filling. AB - MAIN CONCLUSION: A conserved UPR machinery is required for Brachypodium ER stress resistance and grain filling. Human and livestock diets depend on the accumulation of cereal storage proteins and carbohydrates, including mixed linkage glucan (MLG), in the endosperm during seed development. Storage proteins and proteins responsible for the production of carbohydrates are synthesized in the endoplasmic reticulum (ER). Unfavorable conditions during growth that hamper the ER biosynthetic capacity, such as heat, can cause a potentially lethal condition known as ER stress, which activates the unfolded protein response (UPR), a signaling response designed to mitigate ER stress. The UPR relies primarily on a conserved ER-associated kinase and ribonuclease, IRE1, which splices the mRNA of a transcription factor (TF), such as bZIP60 in plants, to produce an active TF that controls the expression of ER resident chaperones. Here, we investigated activation of the UPR in Brachypodium, as a model to study the UPR in seeds of a monocotyledon species, as well as the consequences of heat stress on MLG deposition in seeds. We identified a Brachypodium bZIP60 orthologue and determined a positive correlation between bZIP60 splicing and ER stress induced by chemicals and heat. Each stress condition led to transcriptional modulation of several BiP genes, supporting the existence of condition-specific BiP regulation. Finally, we found that the UPR is elevated at the early stage of seed development and that MLG production is negatively affected by heat stress via modulation of MLG synthase accumulation. We propose that successful accomplishment of seed filling is strongly correlated with the ability of the plant to sustain ER stress via the UPR. PMID- 28364135 TI - Sexual Closeness Discrepancies: What They Are and Why They Matter for Sexual Well Being in Romantic Relationships. AB - This study examined the impact of sexual closeness on sexual well-being. We developed a nuanced and multifaceted conceptualization of sexual closeness in the form of a constellation of ideal sexual closeness with a partner, actual sexual closeness, and the discrepancy between the two. Data were obtained from a diverse sample of N = 619 participants who took part in the Lives and Relationships Study: A longitudinal survey of men and women in relationships living in the U.S. and Canada. Increases in sexual closeness discrepancies over a period of 1 year predicted concomitant decreases in two indicators of sexual well-being: sexual satisfaction and orgasm frequency evaluations. Decreases in sexual closeness discrepancies resulted in improvement in sexual well-being. Individuals who reported no sexual closeness discrepancies and experienced no changes in sexual closeness discrepancies tended to have the highest levels of sexual well-being. Importantly, sexual closeness discrepancies were robust predictors of sexual well being, above and beyond individuals' actual sexual closeness, general relationship closeness, and other demographic and relationship characteristics known to be associated with sexual well-being. The present findings demonstrate that how close people feel sexually to their relationship partners is part of a general constellation of factors related to relationship closeness that, only when considered together, sufficiently explain the ways in which experiences of closeness impact sexual well-being in romantic relationships. PMID- 28364137 TI - Hypoattenuation on CTA images with large vessel occlusion: timing affects conspicuity. AB - PURPOSE: Parenchymal hypoattenuation distal to occlusions on CTA source images (CTASI) is perceived because of the differences in tissue contrast compared to normally perfused tissue. This difference in conspicuity can be measured objectively. We evaluated the effect of contrast timing on the conspicuity of ischemic areas. METHODS: We collected consecutive patients, retrospectively, between 2012 and 2014 with large vessel occlusions that had dynamic multiphase CT angiography (CTA) and CT perfusion (CTP). We identified areas of low cerebral blood volume on CTP maps and drew the region of interest (ROI) on the corresponding CTASI. A second ROI was placed in an area of normally perfused tissue. We evaluated conspicuity by comparing the absolute and relative change in attenuation between ischemic and normally perfused tissue over seven time points. RESULTS: The median absolute and relative conspicuity was greatest at the peak arterial (8.6 HU (IQR 5.1-13.9); 1.15 (1.09-1.26)), notch (9.4 HU (5.8-14.9); 1.17 (1.10-1.27)), and peak venous phases (7.0 HU (3.1-12.7); 1.13 (1.05-1.23)) compared to other portions of the time-attenuation curve (TAC). There was a significant effect of phase on the TAC for the conspicuity of ischemic vs normally perfused areas (P < 0.00001). CONCLUSION: The conspicuity of ischemic areas distal to a large artery occlusion in acute stroke is dependent on the phase of contrast arrival with dynamic CTASI and is objectively greatest in the mid-phase of the TAC. PMID- 28364138 TI - Erratum to: Oculo-auriculo-vertebral spectrum: going beyond the first and second pharyngeal arch involvement. PMID- 28364136 TI - Relapsing polychondritis: a chameleon among orphan diseases. AB - Relapsing polychondritis (RPC) is a rare disease with recurrent episodes of inflammation of cartilage tissue leading to fibrosis and organ damage. Despite unknown etiology, there is some evidence of a genetic predisposition. The clinical presentation is heterogeneous and an association with other autoimmune disorders such as rheumatoid arthritis or different forms of vasculitis has been described. All organ systems containing cartilage can be affected, such as ear, nose, joints, trachea, aorta, and coronary arteries. Given the broad spectrum of potential manifestations, a variety of medical specialists may be involved in the management of RPC patients. As establishing the diagnosis of RPC may be difficult, an interdisciplinary approach may be preferable. Treatment options include glucocorticoids, dapsone, disease-modifying antirheumatic drugs, and biologics. Prognosis is as heterogeneous as the clinical picture, depending on the severity of organ damage. In this paper we give an overview of the current knowledge with regard to pathogenesis, clinical picture, diagnosis, and therapy of RPC. PMID- 28364139 TI - Exercise affects biological characteristics of mesenchymal stromal cells derived from bone marrow and adipose tissue. AB - Both bone marrow mesenchymal stromal cells (BMSCs) and adipose-derived mesenchymal stromal cells (ADSCs) are good sources for tissue engineering. To maximize therapeutic efficacy of MSCs, an appropriate source of MSCs should be selected according to their own inherent characteristics for future clinical application. Hence, this study was conducted to compare proliferative, differential and antiapoptosis abilities of both MSCs derived from exercised and sedentary rats under normal and hypoxia/serum deprivation conditions (H/SD). Our results showed that exercise may enhance proliferative ability and decrease adipogenic ability of BMSCs and ADSCs. However, positive effect of exercise on osteogenesis was only observed for BMSCs in either environment. Little effect was observed on the antiapoptotic ability of both MSC types. It was also suggested that biological characteristics of both types were partly changed. It is therefore believed that BMSCs derived from exercised rat on early passage may be a good cell source for bone tissue engineering. PMID- 28364141 TI - Long-Term Neuropsychological Outcomes of Childhood Onset Acute Disseminated Encephalomyelitis (ADEM): a Meta-Analysis. AB - The long-term neurocognitive prognosis of childhood onset acute disseminated encephalomyelitis (ADEM) is unclear. This review and quantitative synthesis of the available literature examined whether there are long-term impacts of childhood ADEM on neurocognitive functioning. A search of online databases (MEDLINE, EMBASE, EBSCO CINAHL, PsycINFO and the Cochrane Database of Systematic Reviews) from their inception to October 2015 and reference lists identified 13 papers eligible for inclusion in the systematic review; seven of these were eligible for inclusion in meta-analyses. The systematic review indicated that, at a group level there is a positive long-term neuropsychological outcome from childhood onset ADEM. However, despite the apparent absence of long-term negative impacts of ADEM at a group level, at an individual level impairments in the areas of IQ, attention, executive functioning, processing speed, learning and memory, visuospatial skills and internalising symptoms were found in up to 43% of patients when aggregated across the studies. No significant negative effect of ADEM for any of the neuropsychological domains examined was found in meta analyses. However, the effects for Processing Speed (r mean = -0.296 (CI 95% = 0.605-0.013)) and Internalising symptoms (r mean = 0.242 (CI 95% = -0.014-0.564)) approached significance (p = 0.06), suggesting a trend towards ADEM leading to long-term reduced processing speed and elevated internalising symptoms. Together, our findings suggest that despite a generally positive neurocognitive outcome post childhood ADEM there are a subset of individuals who can suffer from ongoing specific cognitive impairments. Clinical implications and research priorities are discussed. PMID- 28364142 TI - Pioneering particle-based strategy for isolating viable bacteria from multipart soil samples compatible with Raman spectroscopy. AB - The study of edaphic bacteria is of great interest, particularly for evaluating soil remediation and recultivation methods. Therefore, a fast and simple strategy to isolate various bacteria from complex soil samples using poly(ethyleneimine) (PEI)-modified polyethylene particles is introduced. The research focuses on the binding behavior under different conditions, such as the composition, pH value, and ionic strength, of the binding buffer, and is supported by the characterization of the surface properties of particles and bacteria. The results demonstrate that electrostatic forces and hydrophobicity are responsible for the adhesion of target bacteria to the particles. Distinct advantages of the particle based isolation strategy include simple handling, enrichment efficiency, and the preservation of viable bacteria. The presented isolation method allows a subsequent identification of the bacteria using Raman microspectroscopy in combination with chemometrical methods. This is demonstrated with a dataset of five different bacteria (Escherichia coli, Bacillus subtilis, Pseudomonas fluorescens, Streptomyces tendae, and Streptomyces acidiscabies) which were isolated from spiked soil samples. In total 92% of the Raman spectra could be identified correctly. PMID- 28364140 TI - Insights into Jumonji C-domain containing protein 6 (JMJD6): a multifactorial role in foot-and-mouth disease virus replication in cells. AB - The Jumonji C-domain containing protein 6 (JMJD6) has had a convoluted history, and recent reports indicating a multifactorial role in foot-and-mouth disease virus (FMDV) infection have further complicated the functionality of this protein. It was first identified as the phosphatidylserine receptor on the cell surface responsible for recognizing phosphatidylserine on the surface of apoptotic cells resulting in their engulfment by phagocytic cells. Subsequent study revealed a nuclear subcellular localization, where JMJD6 participated in lysine hydroxylation and arginine demethylation of histone proteins and other non histone proteins. Interestingly, to date, JMDJ6 remains the only known arginine demethylase with a growing list of known substrate molecules. These conflicting associations rendered the subcellular localization of JMJD6 to be quite nebulous. Further muddying this area, two different groups illustrated that JMJD6 could be induced to redistribute from the cell surface to the nucleus of a cell. More recently, JMJD6 was demonstrated to be a host factor contributing to the FMDV life cycle, where it was not only exploited for its arginine demethylase activity, but also served as an alternative virus receptor. This review attempts to coalesce these divergent roles for a single protein into one cohesive account. Given the diverse functionalities already characterized for JMJD6, it is likely to continue to be a confounding protein resulting in much contention going into the near future. PMID- 28364143 TI - Clump formation in mouse pituitary-derived non-endocrine cell line Tpit/F1 promotes differentiation into growth-hormone-producing cells. AB - The adenohypophysis comprises six types of endocrine cells, including PIT1 lineage cells such as growth hormone (GH)-producing cells and heterogeneous non endocrine cells, such as pituitary stem/progenitor cells as a source of endocrine cells. We determine the expression of characteristic stem cell marker genes, including sex-determining region Y-box 2 (Sox2), in mouse pituitary-derived non endocrine cell lines Tpit/E, Tpit/F1 and TtT/GF. We observed high expression of fibroblast growth factor (FGF) receptors in Tpit/F1 cells, which we characterised by cultivation in medium containing a basic FGF and B27 supplement as used for neural stem-cell differentiation. A 4-day cultivation of Tpit/F1 produced floating embryonic stem-cell-like clumps accompanied by a three-fold increase in Sox2 expression. Passages in these clumps maintained the proliferative activity and Sox2 expression levels. After 10 days of cultivation, Tpit/F1 cell clumps were immuno-positive for SOX2 and Ki67 (proliferation marker) and loosely attached to the well bottom. An additional 10 days of cultivation induced the emergence of GH-positive/pituitary-specific transcription factor (PIT1)-negative cells showing migration from the clumps. Pit1 overexpression in attached cells could not induce GH production. Finally, we confirmed the presence of PIT1 negative GH-producing cells (3.2-7.7 % of all GH-positive cells) in rat pituitary. Thus, we demonstrate that Tpit/F1 has the plasticity to differentiate into one type of hormone-producing cell. PMID- 28364145 TI - Deep anesthesia: too much of a good thing? PMID- 28364146 TI - Bundled payments in total joint arthroplasty and spine surgery. AB - PURPOSE OF REVIEW: The goal of this manuscript is to provide an overview and analysis of bundled payment models for joint replacement and select spine procedures. Advantages and disadvantages of bundled payment models will be discussed. RECENT FINDINGS: In select populations, bundled payment models have been shown to reduce costs while maintaining satisfactory outcomes. These models have not been tested with complex patient cohorts, such as older adults with fragility hip fractures, and limited data exist with bundled payment analysis in spine procedures. The reduction of healthcare costs, satisfactory patient outcomes, and favorable payments to healthcare systems can be achieved through bundled payments. Modifications of existing bundled payment models should be critically tested prior to implementation across higher risk populations. Bundled payment models will also require healthcare systems to define what services are necessary for an episode of care regarding a specific condition or disease. PMID- 28364144 TI - Current advances in the development of natural meniscus scaffolds: innovative approaches to decellularization and recellularization. AB - The increasing rate of injuries to the meniscus indicates the urgent need to develop effective repair strategies. Irreparably damaged menisci can be replaced and meniscus allografts represent the treatment of choice; however, they have several limitations, including availability and compatibility. Another approach is the use of artificial implants but their chondroprotective activities are still not proved clinically. In this situation, tissue engineering offers alternative natural decellularized extracellular matrix (ECM) scaffolds, which have shown biomechanical properties comparable to those of native menisci and are characterized by low immunogenicity and promising regenerative potential. In this article, we present an overview of meniscus decellularization methods and discuss their relative merits. In addition, we comparatively evaluate cell types used to repopulate decellularized scaffolds and analyze the biocompatibility of the existing experimental models. At present, acellular ECM hydrogels, as well as slices and powders, have been explored, which seems to be promising for partial meniscus regeneration. However, their inferior biomechanical properties (compressive and tensile stiffness) compared to natural menisci should be improved. Although an optimal decellularized meniscus scaffold still needs to be developed and thoroughly validated for its regenerative potential in vivo, we believe that decellularized ECM scaffolds are the future biomaterials for successful structural and functional replacement of menisci. PMID- 28364147 TI - SAGES clinical spotlight review: intraoperative cholangiography. PMID- 28364148 TI - Robotic valvuloplastic esophagogastrostomy using double flap technique following proximal gastrectomy: technical aspects and short-term outcomes. AB - BACKGROUND: Valvuloplastic esophagogastrostomy by double flap technique (VEG-DFT) is a promising procedure to prevent reflux after proximal gastrectomy (PG), and is achieved by the burial of the abdominal esophagus into the gastric submucosa; however, laparoscopic VEG-DFT is technically demanding due to complicated suturing and ligation maneuvers. The present study was designed to determine the feasibility and safety of robotic VEG-DFT. METHODS: After robotic PG, seromuscular flaps were extracorporeally created at the anterior wall of the remnant stomach through a small umbilical incision. Then, using a robot, the posterior wall of the esophagus was fixed to the cranial end of the mucosal window, and layer-to-layer sutures were placed between the anterior aspects of esophagus and the remnant stomach. Finally, the anastomosis was covered by seromuscular flaps. Short-term outcomes of 12 consecutive patients who underwent VEG-DFT between January 2014 and December 2015 were assessed. RESULTS: Operations were successfully completed using robotic assistance in all patients. Median operative, surgeon console, and anastomosis times were 406 (324-613 min), 267 (214-483), and 104 (76-186) min, respectively, and median estimated blood loss was 31 (5-130) ml. The first six cases were required to reach a learning plateau. Both mortality and morbidity rates within 30 days after surgery were 0%. Postoperative hospital stay was 10 (9-30) days. No postoperative reflux esophagitis was observed, whereas anastomotic stenosis, which required endoscopic balloon dilation, developed in three patients (25%) in postoperative month 2. There was a significant association between the total number of stitches used for VEG-DFT and anastomotic stenosis (p < 0.001). CONCLUSIONS: Robotic assistance may be useful for VEG-DFT with a short learning curve. Attention is required to prevent postoperative anastomotic stenosis possibly caused by an excessive number of stitches for esophagogastrostomy. PMID- 28364149 TI - The use of expanding ports in laparo-endoscopic single-site surgery may cause more pain: a meta-analysis of randomized clinical trials. AB - BACKGROUND: Previous meta-analyses on the clinical outcome after laparo endoscopic single-site surgery (LESS) versus conventional laparoscopic surgery (CLS) have not revealed any major differences in postoperative pain between the two procedures. This meta-analysis aims to evaluate the difference in postoperative pain between the two procedures, focusing on whether LESS was conducted with a non-expanding port (LESSnonex) or a port expanding (LESSex) within the incision. METHOD: EMBASE, Medline, PubMed, Science Citation Index Expanded, and Cochrane Central Register of Controlled Trials were searched for randomized clinical trials (RCTs) on LESS versus CLS for general abdominal procedures. Weighted mean difference (WMD) and Odds ratios (OR) were calculated with 95% confidence intervals (CI). RESULTS: A total of 29 RCTs with 2999 procedures were included. Pain (VAS 0-10) 6 h after surgery was significantly lower in the group where LESS was conducted with LESSnonex compared to CLS, WMD= 0.72 (- 1.10 to - 0.33). Pain 18-24 h was significantly higher in the group where LESS was conducted with LESSex compared to CLS, WMD = 0.38 (0.01-0.75). Wound related complications were significantly more frequent in LESSex procedures compared to CLS, OR = 1.94 (1.03-3.63). CONCLUSION: The present meta-analysis indirectly indicates that the type of access device that is used for an abdominal LESS procedure may contribute to the development of early postoperative pain as the use of a non-expanding model was associated with a more advantageous outcome. Direct randomized comparison of LESSnonex and LESSex is warranted to confirm if the use of expanding access devices generates more pain and wound complications. PMID- 28364150 TI - Repair of symptomatic paraesophageal hernias in elderly (>70 years) patients results in sustained quality of life at 5 years and beyond. AB - BACKGROUND: Paraesophageal hernias (PEHs) involve herniation of stomach and/or other viscera into the mediastinum. These commonly occur in the elderly and can severely limit quality of life. Short term outcomes of repaired PEH demonstrated low morbidity and significant improvement in quality of life, but long-term data for all patients, especially the elderly, are lacking. METHODS: Retrospective chart review of a prospectively collected database of patients aged 70 or greater with a symptomatic PEH repaired 5+ years ago. Quality of life data were assessed preoperatively, at 12-24 months, and at 5+ years using QOLRAD, GERD-HRQL, and DSS. RESULTS: We identified 137 patients who met the age criteria, with 69 patients undergoing surgery 5+ years ago. With ten patients were lost to follow up, 59 patients were analyzed, including 24 males and 35 females. Median age at repair was 77 years. There were two 90-day mortalities, with one occurring within 30 days of surgery. Patients alive at evaluation had a median age of 74 years and were followed a median 7.4 years. From baseline, QOLRAD improved from 4 to 6.5, GERD-HRQL improved from 11 to 5, and swallowing improved from 11 to 38. During follow-up, 21 patients died. Deceased patients lived a median of 4 years after repair, with a median age at repair of 80 years. At a median time follow-up of 2 years, this group's QOLRAD improved from 5.1 to 7, GERD-HRQL improved from 16 to 4, and swallowing improved from 14.5 to 35. CONCLUSIONS: In elderly patients with symptomatic PEH undergoing surgical repair more than 5 years ago, there was sustained improvement in quality of life. This justifies surgical repair of symptomatic PEH in elderly patients. PMID- 28364152 TI - Sleeve gastrectomy revision by endoluminal sleeve plication gastroplasty: a small pilot case series. AB - BACKGROUND: The necessity for reoperation due to insufficient weight loss after bariatric surgery has led to a novel endoluminal plication of the gastric sleeve using a endoscopic suturing device. Advances in endoluminal endoscopy and other minimally invasive bariatric surgeries have inspired innovative techniques and have produced reliable suturing tools for gastric volume reduction. METHODS: Retrospective pilot case series of 5 patients with an enlarged gastric sleeve. RESULTS: The data show a sustained weight loss for all patients ranging from 19 to 36 lbs at 1 year, with the greatest average weight loss (27 lbs) observed at 6 months. At 1 year post-op, the mean body mass index was 33 kg/m2. Four of the patients were considered successful, with a excess weight loss (EWL) sustained at 1 year post-procedure, ranging from 21 to 61% with a mean of 38%. One patient experienced a EWL of only 13%, which was attributed to failed lifestyle modification. The mean EWL of the series is 33%. The percent total weight loss (%WL) ranged from 6.7 to 17.2%. CONCLUSIONS: The endoluminal approach with an endoscopic suturing device for sleeve revision by plication is showing early promising results and expands the management of weight gain following laparoscopic sleeve gastrectomy. This simple approach may offer a significant option for these patients as an interventional strategy in the early phases of weight regain, and prior to reaching a BMI of 40 kg/m2, such as the traditional surgical approach. PMID- 28364151 TI - Evolution of a laparoscopic liver resection program: an analysis of 203 cases. AB - BACKGROUND: Techniques for laparoscopic liver resection (LLR) have been developed over the past two decades. The aim of this study is to analyze the outcomes and trends of LLR. METHODS: 203 patients underwent LLR between 2006 and 2015. Trends in techniques and outcomes were assessed dividing the experience into 2 periods (before and after 2011). RESULTS: Tumor type was malignant in 62%, and R0 resection was achieved in 87.7%. Procedures included segmentectomy/wedge resection in 64.5%. Techniques included a purely laparoscopic approach in 59.1% and robotic 12.3%. Conversion to open surgery was necessary in 6.4% cases. Mean hospital stay was 3.7 +/- 0.2 days. 90-day mortality was 0% and morbidity 20.2%. Pre-coagulation and the robot were used less often, while the performance of resections for posteriorly located tumors increased in the second versus the first period. CONCLUSION: This study confirms the safety and efficacy of LLR, while describing the evolution of a program regarding patient and technical selection. With building experience, the number of resections performed for posteriorly located tumors have increased, with less reliance on pre-coagulation and the robot. PMID- 28364153 TI - Comparative study of safety and efficacy of synthetic surgical glue for mesh fixation in ventral rectopexy. AB - BACKGROUND: Ventral mesh rectopexy (VMR) is a surgical option to treat rectal prolapse with pelvic floor dysfunction (PFD). Using synthetic surgical glue to fix the mesh to the anterior rectal wall after ventral dissection could be advantageous in comparison with sutured or stapled fixation. This study aimed to evaluate the safety and efficacy of synthetic surgical glue for mesh fixation compared with suture mesh fixation in VMR. METHODS: This observational cohort study is a retrospective analysis conducted in a University Hospital Pelvic Surgery Center. All consecutive female patients (n = 176) who underwent laparoscopic or laparotomic VMR between January 2009 and December 2014 were included. Two groups were defined based on mesh fixation technique of the rectal wall: VMR with synthetic glue (n = 66) and VMR with suture (n = 110). The recurrence-free survival after VMR was determined by Kaplan-Meier method and multivariate analysis by Cox regression. Short-term postoperative complications, postoperative symptom improvement, the need for complementary treatment postoperatively, and procedure length were evaluated. RESULTS: A total of 176 females patients (mean age, 58.6 +/- 13.7 years) underwent VMR with synthetic mesh. Mean recurrence-free survivals after VMR were 17.16 (CI 95% 16.54-17.80) and 17.33 (CI 95% 16.89-17.77) months in the glue group and the suture group, respectively (p > 0.05). Cox regression identified an independent effect on the recurrence risk of the external rectal prolapse, alone, or in combination with other anatomical abnormalities (HR = 0.37; CI 95% 0.14-0.93; p = 0.03). There was no significant difference of short-term postoperative morbidity, procedure length, postoperative symptom improvement, or need for complementary treatment postoperatively between suture versus glue groups (all p > 0.05). CONCLUSIONS: Use of glue to fix the mesh in VMR was safe and had no impact on outcomes. External prolapse was the unique significant predictive factor for recurrence. PMID- 28364154 TI - Impact of intraoperative blood loss on the short-term outcomes of laparoscopic liver resection. AB - BACKGROUND: Intraoperative blood loss is one of the predictors of outcome of open hepatectomy. But the impact of blood loss in laparoscopic hepatectomy (LH) on postoperative outcomes is poorly understood. The aim of this study is to analyze the association between blood loss and postoperative outcomes after LH. METHODS: A retrospective analysis of prospectively maintained database of patients undergoing LH from 1995 to 2016 was performed. The data were divided into two groups based on the extent of blood loss: Group 1 (<250 ml) and Group 2 (>=250 ml). The basic characteristics and postoperative outcomes were compared between these groups. RESULTS: A total of 504 patients underwent 611 LH (Group 1: 414 and Group 2: 197). The mean age was 62.4 years. The most common indication was liver secondaries (71.7%). Major hepatectomy was performed in 37% cases. Mean operative time was 225 +/- 110.5 min and estimated blood loss was 239 +/- 399.4 ml (range 0 4500 ml). Group 2 had significantly higher number of patients with malignant lesions undergoing major hepatectomy, anatomical resection with higher requirement for blood transfusion, and longer hospital stay. The incidence of conversion rate, overall complications including liver failure, renal failure, and postoperative mortality, was significantly higher in Group 2. However, the bile leak rate was similar in the two groups. CONCLUSION: Intraoperative blood loss is most frequent in patients undergoing major LH. Blood loss >=250 ml during LH may adversely affect the postoperative outcomes. PMID- 28364155 TI - Impact of minimally invasive surgery on healthcare utilization, cost, and workplace absenteeism in patients with Incisional/Ventral Hernia (IVH). AB - BACKGROUND: Incisional hernia repair is one of the most common general surgery operations being performed today. With the advancement of laparoscopy since the 1990s, we have seen vast improvements in faster return to normal activity, shorter hospital stays and less post-operative narcotic use, to name a few. OBJECTIVE: The key aims of this review were to measure the impact of minimally invasive surgery versus open surgery on health care utilization, cost, and work place absenteeism in the patients undergoing inpatient incisional/ventral hernia (IVH) repair. METHODS: We analyzed data from the Truven Health Analytics MarketScan(r) Commercial Claims and Encounters Database. Total of 2557 patients were included in the analysis. RESULTS: Of the patient that underwent IVH surgery, 24.5% (n = 626) were done utilizing minimally invasive surgical (MIS) techniques and 75.5% (n = 1931) were done open. Ninety-day post-surgery outcomes were significantly lower in the MIS group compared to the open group for total payment ($19,288.97 vs. $21,708.12), inpatient length of stay (3.12 vs. 4.24 days), number of outpatient visit (5.48 vs. 7.35), and estimated days off (11.3 vs. 14.64), respectively. At 365 days post-surgery, the total payment ($27,497.96 vs. $30,157.29), inpatient length of stay (3.70 vs. 5.04 days), outpatient visits (19.75 vs. 23.42), and estimated days off (35.71 vs. 41.58) were significantly lower for MIS group versus the open group, respectively. CONCLUSION: When surgical repair of IVH is performed, there is a clear advantage in the MIS approach versus the open approach in regard to cost, length of stay, number of outpatient visits, and estimated days off. PMID- 28364157 TI - Increased identification of parathyroid glands using near infrared light during thyroid and parathyroid surgery. AB - BACKGROUND: Parathyroid gland (PG) identification during thyroid and parathyroid surgery is challenging. Accidental parathyroidectomy increases the rate of postoperative hypocalcaemia. Recently, autofluorescence with near infrared light (NIRL) has been described for PG visualization. The aim of this study is to analyze the increased rate of visualization of PGs with the use of NIRL compared to white light (WL). MATERIALS AND METHODS: All patients undergoing thyroid and parathyroid surgery were included in this study. PGs were identified with both NIRL and WL by experienced head and neck surgeons. The number of PGs identified with NIRL and WL were compared. The identification of PGs was correlated to age, sex, and histopathological diagnosis. RESULTS: Seventy-four patients were included in the study. The mean age was 48.4 (SD +/-13.5) years old. Mean PG fluorescence intensity (47.60) was significantly higher compared to the thyroid gland (22.32) and background (9.27) (p < 0.0001). The mean number of PGs identified with NIRL and WL were 3.7 and 2.5 PG, respectively (p < 0.001). The difference in the number of PGs identified with NIRL and WL and fluorescence intensity was not related to age, sex, or histopathological diagnosis, with the exception of the diagnosis of thyroiditis, in which there was a significant increase in the number of PGs visualized with NIRL (p = 0.026). CONCLUSION: The use of NIRL for PG visualization significantly increased the number of PGs identified during thyroid and parathyroid surgery, and the differences in fluorescent intensity among PGs, thyroid glands, and background were not affected by age, sex, and histopathological diagnosis. PMID- 28364158 TI - Angiogenesis Review Commentary. PMID- 28364156 TI - Predicting postoperative complications after bariatric surgery: the Bariatric Surgery Index for Complications, BASIC. AB - BACKGROUND: Around 20% of bariatric surgery patients develop a short- or long term complication. OBJECTIVE: Aim of this study was to develop a risk model predicting complications: the Bariatric Surgery Index for Complications (BASIC). SETTING: The Obesity Center Amsterdam, located in a large teaching hospital, in Amsterdam, The Netherlands. METHODS: A prospective consecutive database including patients operated between November 2007 and February 2015 was used. For the BASIC, analysis according to the TRIPOD statement was performed to identify risk factors for complications. Class I included patients with zero to one risk factor, class II patients with two risk factors, and class III patients with three or more risk factors. RESULTS: Of 1709 analyzed patients, mean age was 45 years (+/-SD 10.7), 1393 (81.5%) were female; mean body mass index was 44.5 kg/m2 (6.8). Overall, 271 (15.9%) patients developed a complication of which 197 (72.5%) occurred within 30 days. Predictors in multivariable analysis were use of anticoagulants (odd's ratio (OR) 1.5); chronic obstructive pulmonary disease (OR 2.3); dyslipidemia (OR 1.4); gender (OR 1.4); psychiatric history (OR 1.3); and revisional surgery (OR 1.5). In class I, 13.5% (181 out of 1338) experienced complications, in class II 58 (21.6%) of the 269 patients and in class III 32 (31.4%) of the 102 patients, respectively. There was a significant difference (p < 0.001) in both overall and 30 day complications. CONCLUSION: The BASIC uses six preoperative variables to classify patients in a low-, intermediate-, or high risk group for postoperative complications after bariatric surgery. PMID- 28364159 TI - Modulation of aberrant splicing in human RNA diseases by chemical compounds. AB - Pre-mRNA splicing is an essential step for gene expression in higher eukaryotes. Alternative splicing contributes to diversity of the expressed proteins from the limited number of genes. Disruption of splicing regulation often results in hereditary and sporadic diseases called as 'RNA diseases'. Modulation of splicing by small chemical compounds and nucleic acids has been tried to target aberrant splicing in those diseases. Several RNA diseases and splicing-target therapeutic approaches will be briefly introduced in this review. Accumulating knowledge about molecular mechanism of aberrant splicing and their correction by chemical compounds is important not only for RNA biologists, but also for clinicians who desire therapies for those diseases. PMID- 28364161 TI - Comparison of CT and PET/CT for biopsy guidance in oncological patients. AB - PURPOSE: To compare FDG PET/CT and CT for the guidance of percutaneous biopsies with histological confirmation of lesions. METHODS: We prospectively evaluated 323 patients of whom 181 underwent FDG PET/CT-guided biopsy (total 188 biopsies) and 142 underwent CT-guided biopsy (total 146 biopsies). Biopsies were performed using the same PET/CT scanner with a fluoroscopic imaging system. Technical feasibility, clinical success and complication rates in the two groups were evaluated. RESULTS: Of the 188 biopsies with PET/CT guidance, 182 (96.8%) were successful with conclusive tissue samples obtained and of the 146 biopsies with CT guidance, 137 (93.8%) were successful. Therefore, 6 of 188 biopsies (3.1%) with PET/CT guidance and 9 of 146 (6.1%) with CT guidance were inconclusive (p = 0.19). Due to inconclusive histological results, 4 of the 188 lesions (2.1%) were rebiopsied with PET/CT guidance and 3 of 146 lesions (2.0%) were rebiopsied with CT guidance. Histology demonstrated that 142 of 188 lesions (75.5%) were malignant, and 40 (21.2%) were benign in the PET/CT-guided group, while 89 of 146 lesions (60.9%) were malignant and 48 (32.8%) were benign in the CT-guided group (p = 0.004 and 0.01, respectively). Patients with a histological diagnosis of benign lesion had no recurrence of disease with a minimum of 6 months follow-up. Of the 188 PET/CT-guided biopsies, 6 (3.1%) were repeat biopsies due to a previous nondiagnostic CT-guided biopsy performed in a different diagnostic centre. The interval between the two biopsies was less than a month in all cases. Histology revealed five malignant lesions and one benign lesion among these. The complication rate in the PET/CT-guided biopsy group was 12.7% (24 of 188), while in the CT-guided group, was 9.5% (14 of 146, p = 0.26). Therefore, there was no significant difference in complication rates between PET/CT and CT guidance. CONCLUSION: PET/CT-guided biopsy is already known to be a feasible and accurate method in the diagnostic work-up of suspected malignant lesions. This prospective analysis of a large number of patients demonstrated the feasibility and advantages of using PET/CT as the imaging method of choice for biopsy guidance, especially where FDG-avid foci do not show corresponding lesions on the CT scan. There were no significant differences in the ability to obtain a diagnostic specimen or in the complication rates between PET/CT and CT guidance. PMID- 28364162 TI - 18F-FDG PET/CT in Erdheim-Chester disease. PMID- 28364160 TI - The clinical application of angiostatic therapy in combination with radiotherapy: past, present, future. AB - Although monotherapy with angiostatic drugs is still far from effective, there is abundant evidence that angiostatic therapy can improve the efficacy of conventional treatments like radiotherapy. This has instigated numerous efforts to optimize and clinically implement the combination of angiostatic drugs with radiation treatment. The results from past and present clinical trials that explored this combination therapy indeed show encouraging results. However, current findings also show that the combination has variable efficacy and is associated with increased toxicity. This indicates that combining radiotherapy with angiostatic drugs not only holds opportunities but also provides several challenges. In the current review, we provide an update of the most recent insights from clinical trials that evaluated the combination of angiostatic drugs with radiation treatment. In addition, we discuss the outstanding questions for future studies in order to improve the clinical benefit of combining angiostatic therapy with radiation therapy. PMID- 28364163 TI - Envisaging an alpha therapy programme in the atomic energy establishments: the priorities and the nuances. PMID- 28364164 TI - Individual Placement and Support (IPS): Possible Avenues to Maximize its Potential Benefits. PMID- 28364167 TI - New Austrian medical training regulations : Will they encourage young Austrian medical graduates to stay at home? PMID- 28364166 TI - An ignored and potential source of taste and odor (T&O) issues-biofilms in drinking water distribution system (DWDS). AB - It is important for water utilities to provide esthetically acceptable drinking water to the public, because our consumers always initially judge the quality of the tap water by its color, taste, and odor (T&O). Microorganisms in drinking water contribute largely to T&O production and drinking water distribution systems (DWDS) are known to harbor biofilms and microorganisms in bulk water, even in the presence of a disinfectant. These microbes include T&O-causing bacteria, fungi, and algae, which may lead to unwanted effects on the organoleptic quality of distributed water. Importantly, the understanding of types of these microbes and their T&O compound-producing mechanisms is needed to prevent T&O formation during drinking water distribution. Additionally, new disinfection strategies and operation methods of DWDS are also needed for better control of T&O problems in drinking water. This review covers: (1) the microbial species which can produce T&O compounds in DWDS; (2) typical T&O compounds in DWDS and their formation mechanisms by microorganisms; (3) several common factors in DWDS which can influence the growth and T&O generation of microbes; and (4) several strategies to control biofilm and T&O compound formation in DWDS. At the end of this review, recommendations were given based on the conclusion of this review. PMID- 28364168 TI - Expression of caveolin-1 in breast cancer stroma as a potential prognostic biomarker of survival and progression: a meta-analysis. AB - BACKGROUND: It has been shown that caveolin-1 plays a potential role as a diagnostic and prognostic biomarker in various cancer types. The aim of the present study was to clarify whether caveolin-1 expressed in the breast cancer stroma could be a prognostic factor for breast cancer patients. METHODS: We searched the PubMed, ScienceDirect and Web of Science databases for published literature investigating associations between stromal caveolin-1 expression and survival outcome in breast cancer patients. With respect to survival outcomes, the pooled hazard ratios (HRs) of caveolin-1 and the 95% confidence intervals (CI) were calculated. RESULTS: Our meta-analysis identified a total of 10 studies involving 2072 cases. Further investigation demonstrated that a lack of caveolin 1 expression in the breast cancer stroma is a hazard for overall survival (OS) (HR = 2.33, 95% CI: 1.57-3.46) and disease-free/progression-free survival (DFS/PFS) (HR = 3.05, 95% CI: 2.26-4.12) in breast cancer patients. Moreover, lack of caveolin-1 expression in the cancer-associated fibroblasts was a significant predictor of DFS/PFS (HR = 2.79, 95% CI: 1.75-4.46). CONCLUSION: Our results indicated that lack of expression of caveolin-1 in the breast cancer stroma is associated with a poor prognosis. PMID- 28364165 TI - Post-mastectomy cancer recurrence with and without a continuous paravertebral block in the immediate postoperative period: a prospective multi-year follow-up pilot study of a randomized, triple-masked, placebo-controlled investigation. AB - PURPOSE: Retrospective studies have associated perioperative regional anesthesia/analgesia during mastectomy for breast cancer with a decreased incidence of cancer recurrence. However, to date, no prospective data from a randomized controlled trial have been reported. In a previous study we found that extending a single-injection paravertebral block with a multiple-day perineural local anesthetic infusion improves analgesia. This follow-up study investigates the rates of cancer recurrence for the single-injection and multiple-day infusion treatments. METHODS: Patients undergoing unilateral (n = 24) or bilateral mastectomy (n = 36) were included in the study. All patients had been diagnosed with breast cancer or tumor in situ, except for six patients who were receiving prophylactic bilateral mastectomy and were excluded from analyses. Patients received unilateral or bilateral single-injection thoracic paravertebral block(s) corresponding to their surgical site(s) with ropivacaine and perineural catheter(s). Subsequently, patients were randomized to receive either ropivacaine 0.4% (n = 30) or normal saline (n = 30) via their catheter(s) until catheter removal on postoperative day 3. Cancer recurrence from the date of surgery until at least 2 years post surgery was investigated via chart review. RESULTS: Five of the 54 (9.2%) patients experienced a cancer recurrence following mastectomy-3 of 26 (11.5%) of the patients with perineural ropivacaine and 2 of 28 (7.1%) of the patients with perineural saline. CONCLUSIONS: This pilot study found no evidence that extending a single-injection paravertebral block with a multi-day perineural local anesthetic infusion decreases the risk of post-mastectomy cancer recurrence. However, due to the small sample size of this investigation, further research is needed to draw definitive conclusions. PMID- 28364169 TI - Changes in brain microstructure during infancy and childhood using clinical feasible ADC-maps. AB - PURPOSE: The purpose of this study was to examine age-related changes in apparent diffusion coefficient (ADC) during infancy and childhood using routine MRI data. METHODS: A total of 112 investigations of patients aged 0 to 17.2 years showing a normal degree of myelination and no signal abnormalities on conventional MRI were retrospectively selected from our pool of pediatric MRI examinations at 1.5T. ADC maps based on our routinely included axial diffusion weighted sequence were created from the scanner. ADC values were measured in 35 different brain regions investigating normal age-related changes during the maturation of the human brain in infancy and childhood using clinical feasible sequences at 1.5T. RESULTS: The relationship between ADC values and age in infancy and childhood can be described as an exponential function. With increasing age, the ADC values decrease significantly in all brain regions, especially during the first 2 years of life. Except in the peritrigonal white matter, no significant differences were found between both hemispheres. Between 0 and 2 years of life, no significant gender differences were detected. CONCLUSIONS: Using ADC maps based on a routinely performed axial diffusion weighted sequence, it was possible first to describe the relationship between ADC values and age in infancy and childhood as exponential function in the whole brain and second to determine normative age related ADC values in multiple brain regions. PMID- 28364170 TI - Factors contributing to spinal cord infarction occurring in surgery performed in the prone position. PMID- 28364171 TI - [Relaxation techniques and behavioural therapy for the treatment of migraine : Guidelines from the German Migraine and Headache Society]. AB - Besides pharmacological and interventional possibilities nonpharmacological options, deriving from behavioural approaches may be helpful in the treatment of migraine. Already consulting a patient reduces frequency of attacks. Relaxation (especially progressive muscle relaxation), endurance sports, and biofeedback as well as cognitive behavioural therapy are effective in treatment of migraine. The combination of these treatment options also with pharmacological treatment increase the positive effects. PMID- 28364172 TI - Mapping French people and health professionals' positions regarding the circumstances of morphine use to relieve cancer pain. AB - BACKGROUND: Cancer patients suffer in part because some health professionals prescribe or administer amounts of analgesics, namely opioids, which are too small or too widely spaced to be fully effective. Patients' reluctance to use opioids for pain treatment is often mentioned as a reason not to apply the official guidelines, but very few studies have been conducted on people's attitudes about opioid use to relieve cancer pain. METHODS: One hundred twenty lay participants and 30 health professionals (7 physicians and 23 nurses) were presented with a set of vignettes describing a terminally ill woman with cancer who is in pain. The vignettes were composed according to a four within-subject factor design: (a) level of pain reported by the patient, (b) patient's explicit request for additional administration of analgesics, (c) the physicians' final decision (e.g., to use a stronger analgesic combining paracetamol and codeine), and (d) the way the decision was made (collectively or not). Participants were asked to assess the extent to which the physician's decision was, in their view, acceptable. RESULTS: Seven qualitatively different positions were found among participants. They were called as follows: tend to disagree with any decision (9%), increase the strength of the painkiller in any case (16%), give morphine preferentially (9%), partly depends on pain level (23%), fully depends on pain level (6%), depends on decision process and on pain level (22%), and tend not to disagree with any collective decision (25%). CONCLUSIONS: Overall, 91% of participants agreed with the use of morphine in terminally ill cancer patients when the pain level was high (score of 7) and the decision to increase the strength of the painkiller was taken collectively. This percentage dropped to 69% when the team was not involved in the decision and to 40% when the pain level was lower (score of 4). If opposition to the use of morphine exists, it is not opposition to morphine itself but opposition to the circumstances of its use. PMID- 28364174 TI - Primate beta oscillations and rhythmic behaviors. AB - The study of non-human primates in complex behaviors such as rhythm perception and entrainment is critical to understand the neurophysiological basis of human cognition. Next to reviewing the role of beta oscillations in human beat perception, here we discuss the role of primate putaminal oscillatory activity in the control of rhythmic movements that are guided by a sensory metronome or internally gated. The analysis of the local field potentials of the behaving macaques showed that gamma-oscillations reflect local computations associated with stimulus processing of the metronome, whereas beta-activity involves the entrainment of large putaminal circuits, probably in conjunction with other elements of cortico-basal ganglia-thalamo-cortical circuit, during internally driven rhythmic tapping. Thus, this review emphasizes the need of parametric neurophysiological observations in non-human primates that display a well controlled behavior during high-level cognitive processes. PMID- 28364173 TI - A systematic review of methodologies, endpoints, and outcome measures in randomized trials of radiation therapy-induced nausea and vomiting. AB - PURPOSE: Clinical trials in radiation therapy-induced nausea and vomiting (RINV) appear to have varied methodologies, endpoints, and outcome measures. This complicates trial comparisons, weakens practice guideline recommendations, and contributes to variability in supportive care patterns of practice. We systematically reviewed RINV trials to describe and compare their pertinent design features. MATERIALS AND METHODS: Ovid versions of the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, EMBASE, and MEDLINE to January/February 2017 were searched for adult phase III trials of RINV management strategies. Key abstracted data included trial interventions and eligibility criteria, standard radiation therapy (RT) metrics, symptom assessment procedures, symptom definitions and grading systems, pre specified and reported endpoints, and other outcome measures. RESULTS: From 1166 references identified in the initial database search, we selected 34 trials for analysis that collectively randomized 4529 patients (median 61, range 11-1492). Twenty-eight trials (82%) were published prior to the year 2000. Twenty-seven trials (79%) involved multiple fraction RT and 7 (21%) single fraction RT. Twenty four trials (71%) evaluated prophylactic interventions, 9 (26%) rescue interventions, and 1 trial did not specify. Thirty-three trials (97%) evaluated pharmacologic interventions. Twenty trials (59%) had patient report symptoms, 5 (15%) healthcare professionals or researchers, and 10 (29%) did not specify. Nausea was not defined in any trial but was reported as a stand-alone symptom in 26 trials (76%) and was graded in 20 (59%), with categorical qualitative scales being the most common method. Vomiting was defined in 3 trials (9%), was reported as a stand-alone symptom in 17 (47%), and was graded in 7 (21%), with continuous numerical scales being the most common method. Retching was defined in 3 trials, was not reported as a stand-alone symptom in any trial, and was graded in 1 (3%). Twenty-one trials (62%) created compound symptom measures that combined individual symptoms. Fifteen trials (44%) reported "emetic episode/event" measures but only 9 defined them. Seventeen trials (50%) reported complicated endpoints (e.g., "response," "control," "success") that combined multiple symptom or compound symptom measures, but 7 did not define them comprehensively. Ten trials (29%) defined a primary endpoint a priori. CONCLUSIONS: Methodologies, endpoints, and outcome measures varied considerably among 34 randomized trials in RINV. PMID- 28364175 TI - Evaluation of radiological risk during coronary angioplasty procedures: comparison of transradial and transfemoral approaches. AB - Increasing operator experience and newer available interventional cardiology devices require reassessment of radiological risk related to percutaneous coronary interventions (PCI). We aimed at comparison of radiological risk and procedural data of PCIs performed by radial (RA) and femoral (FA) approach in real life patients. Detailed retrospective analysis of 1500 consecutive PCIs with the use of radial or femoral access was performed. Comparison between RA and FA groups included procedural time (PT), fluoroscopy time (FT), radiation dose and contrast volume usage. There was no significant differences between RA and FA procedures in FT (12.6 +/- 13.5 vs. 11.7 +/- 9.5 min), X-ray dose generated during PCI (805.9 +/- 615.9 vs. 792.2 +/- 633.9 mGy) and use of contrast medium (145.2 +/- 62.2 vs. 152.5 +/- 64.2 ml). Mean total PT was shorter in RA (43.7 +/- 24.5 min) than in FA group (47.2 +/- 30.13 min, p < 0.02). Patients' age positively correlated with FT (r = 0.14, p < 0.05) and PT (r = 0.07, p < 0.05) in RA but not in FA group (r = 0.05; r = -0.06, respectively). Despite younger age, PCIs in males needed higher usage of contrast medium (151.7 +/- 69.2 vs. 139.1 +/ 49.3 ml; p < 0.001), and higher X-ray dose (887.0 +/- 660.4 vs. 657.8 +/- 515.2 mGy; p < 0.001). Age significantly correlated with PT only in female (r = 0.093, p < 0.05) but not in male patients (r = 0.015). We conclude that fluoroscopy times, X-ray dose and use of contrast medium were similar in RA and FA, but mean total procedural time was significantly shorter in RA than in FA group. However, older patients in RA group needed longer fluoroscopy and procedural times to complete PCI and this was not seen in FA. PMID- 28364176 TI - Reproducibility of echocardiographic assessment of 2D-derived longitudinal strain parameters in a population-based study (the STANISLAS Cohort study). AB - Global peak systolic longitudinal strain (PLS) derived from speckle tracking echocardiography (STE) is a widely used left ventricular deformation parameter. Modern ultrasound systems with improved temporal resolution and new software now allow automated multilayer analysis; however, there is limited evidence regarding its reproducibility. We performed intra- and inter-observer analyses within a population-based cohort study using conventional quantitative strain analysis (GE Healthcare). Fifty patients (49 +/- 14 years) were randomly selected among the fourth visit of the STANISLAS Cohort. Multilayer PLS (transmural, subendocardial, and subepicardial), and strain rate (peak systolic, early and late diastolic) were evaluated. Peak systolic shortening (PSS) and early positive systolic strain (EPS) were calculated, as well as post-systolic index (PSI) and pre-stretch index (PST), two additional strain-derived parameters. Intra-observer intraclass correlation coefficients (ICC) were >0.75 for all analyzed parameters. The mean relative intra-observer differences were <5% for all considered parameters, and their 1.96 SDs were <15% for multilayer PLS, strain rate and PSS, but not for EPS, PSI and PST. Inter-observer ICCs were >0.70 (the majority being >0.80). The mean relative inter-observer differences were <7.5% for all considered parameters, with 1.96 SDs of relative differences being <21% for multilayer PLS, strain rate and PSS, but not for EPS, PSI and PST. In this population-based study, in subjects without or with a limited number of cardiovascular risk factors and no previous cardiovascular events, deformation parameters were found to be highly reproducible, except for EPS, PSI and PST, which showed moderately higher variability. Quantitative strain analysis appears to be an effective clinical and research tool, providing insights regarding longitudinal deformation using a simple three-step post-processing procedure. PMID- 28364178 TI - Optimizing left anterior oblique (LAO) caudal imaging in coronary angiography using the Taguchi method: A phantom study with clinical verification. AB - The aim of this work tried to optimize the spider view of the coronary angiograph for the clinical diagnosis of cardiac artery disease by cardiologists. A qualified spider view in coronary angiography must be exactly a "quasi-spider" image, which can help to diagnose a lesion in left main coronary artery and related regions. Coronary artery phantom was placed in a 75 mm-thick acrylic box to model a 70 kg human thorax. Eighteen groups of various combinations of operating factors of the X-ray facility were organized based on a Taguchi analysis. The six factors that govern the imaging quality of X-ray were (A) whether the X-rays emitted through a filter, (B, C) the Left Anterior Oblique (LAO) and Caudal Angulation (CAU) projection angles, (D) X-ray peak voltage (kVp), (E) X-ray pulse duration and current (mAs) and (F) distance between X-ray source and intensifying plate (SID). The obtained X-ray spider view images of each group were graded to determine the optimal settings; X-ray emitted without filter, 70 degrees LAO, 30 degrees CAU, 110 kVp, 1.5 mAs and 108 cm of SID. X ray imaging quality optimal result was confirmed based on a clinical diagnosis of 43 patients, to prove the effectiveness of this study. PMID- 28364179 TI - Applications and theory of electrokinetic enrichment in micro-nanofluidic chips. AB - This review reports the progress on the recent development of electrokinetic enrichment in micro-nanofluidic chips. The governing equations of electrokinetic enrichment in micro-nanofluidic chips are given. Various enrichment applications including protein analysis, DNA analysis, bacteria analysis, viruses analysis and cell analysis are illustrated and discussed. The advantages and difficulties of each enrichment method are expatiated. This paper will provide a particularly convenient and valuable reference to those who intend to research the electrokinetic enrichment based on micro-nanofluidic chips. PMID- 28364180 TI - Combined small cell lung carcinoma and giant cell carcinoma: a case report. AB - BACKGROUND: Combined small cell lung carcinoma (SCLC) is defined as SCLC combined with elements of non-small cell lung carcinoma (NSCLC), accounting for approximately 30% of cases of SCLC. However, combined SCLC and giant cell carcinoma (GC) is very rare. CASE PRESENTATION: A 50-year-old woman with a 45 pack-year smoking history was referred to our hospital for further investigation of an abnormal left hilar shadow. Chest computed tomography (CT) revealed a 28-mm solid pulmonary nodule in the left lower lobe and an enlarged left hilar lymph node adjacent to the left main pulmonary artery. CT-guided biopsy of the pulmonary nodule led to the diagnosis of high-grade neuroendocrine carcinoma. The preoperative clinical stage was defined as cT1bN1M0. Thus, the patient underwent left lower lobectomy with ND2a-2 lymph node dissection via thoracotomy. Pathological investigation revealed a 22-mm tumor and dense sheet-like growth of small tumor cells with scant cytoplasm and finely granular nuclear chromatin. Moreover, there was a sheet-like growth of bizarre, highly pleomorphic mono- or occasionally multinucleated giant cells, accounting for approximately 40% of the tumor. Both the small and giant cell components were thyroid transcription factor 1-positive and p40-negative and exhibited neuroendocrine differentiation, as indicated by positivity for synaptophysin and CD56 and negativity for chromogranin A. While the small cell component was E-cadherin-positive and vimentin-negative, the giant cell component was E-cadherin-negative and vimentin positive, indicating an epithelial-to-mesenchymal transition. Only the small cell component was found within the mediastinal and hilar lymph nodes. The final pathological diagnosis was combined SCLC and GC, pT1bN2M0, and pStage IIIA. The patient received adjuvant chemotherapy with 4 cycles of cisplatin and irinotecan. No sign of recurrence has been noted for 1 year after the surgery. CONCLUSIONS: This is the first detailed report of a unique case with combined SCLC and GC. The coexistence of SCLC and GC in the presented case might indicate several possibilities: (1) GC may arise from SCLC via epithelial-to-mesenchymal transition, (2) SCLC may arise from GC through phenotypic conversion, and (3) SCLC and GC may have derived from a common neuroendocrine origin. Further investigation is necessary to reveal the underlying pathological process. PMID- 28364181 TI - Commentary on Anatomy and Aesthetics of the Labia Minora: The Ideal Vulva? PMID- 28364177 TI - Magnetic resonance imaging for characterizing myocardial diseases. AB - The National Institute of Health defined cardiomyopathy as diseases of the heart muscle. These myocardial diseases have different etiology, structure and treatment. This review highlights the key imaging features of different myocardial diseases. It provides information on myocardial structure/orientation, perfusion, function and viability in diseases related to cardiomyopathy. The standard cardiac magnetic resonance imaging (MRI) sequences can reveal insight on left ventricular (LV) mass, volumes and regional contractile function in all types of cardiomyopathy diseases. Contrast enhanced MRI sequences allow visualization of different infarct patterns and sizes. Enhancement of myocardial inflammation and infarct (location, transmurality and pattern) on contrast enhanced MRI have been used to highlight the key differences in myocardial diseases, predict recovery of function and healing. The common feature in many forms of cardiomyopathy is the presence of diffuse-fibrosis. Currently, imaging sequences generating the most interest in cardiomyopathy include myocardial strain analysis, tissue mapping (T1, T2, T2*) and extracellular volume (ECV) estimation techniques. MRI sequences have the potential to decode the etiology by showing various patterns of infarct and diffuse fibrosis in myocarditis, amyloidosis, sarcoidosis, hypertrophic cardiomyopathy due to aortic stenosis, restrictive cardiomyopathy, arrythmogenic right ventricular dysplasia and hypertension. Integrated PET/MRI system may add in the future more information for the diagnosis and progression of cardiomyopathy diseases. With the promise of high spatial/temporal resolution and 3D coverage, MRI will be an indispensible tool in diagnosis and monitoring the benefits of new therapies designed to treat myocardial diseases. PMID- 28364182 TI - Occlusion-Fit V-Line Guide and Gooseneck Saw for Safe and Accurate Mandibuloplasty in Asians. AB - BACKGROUND: A slender or slim face with narrow facial features is considered esthetically appealing in Asian people. Plastic surgery to obtain an oval face, called a 'V-line,' is popular among young people. MATERIALS AND METHODS: A total of 20 Korean patients were included in this study. The patients underwent mandibular anguloplasty with three-dimensional computer-aided design and manufacturing surgical guides that were accurately fitted to the upper and lower teeth, allowing for precise replication of a virtual surgery during a real surgical procedure. RESULTS: There were no significant complications, including severe bleeding, facial nerve injury, or airway obstruction. All patients were satisfied with the esthetic and functional results, except for one who was neutral toward the result. The mean satisfaction score was 4.75, which was between 'satisfied' and 'very satisfied.' CONCLUSION: The V-line guide and gooseneck saw allowed for safe and fast resection of bone in the mandibular angle area. This technique provides consistent results during surgery as well as minimizing surgical complications. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266 . PMID- 28364183 TI - Comparative performance of the EQ-5D-5L and SF-6D index scores in adults with type 2 diabetes. AB - PURPOSE: To explore the comparative performance including discriminative and longitudinal validity of EQ-5D-5L and SF-6D index scores in adults with type 2 diabetes. METHODS: Data from an on-going cohort study of adults with type 2 diabetes in Alberta, Canada, were used. Known-groups approach was used to examine discriminative validity. Correlation and agreement indices and scatter and Bland Altman plots were used to examine the relationship between the two measures. Longitudinal validity was explored using Wilcoxon signed-rank test, effect size, and standardized response mean. RESULTS: In 1832 participants at baseline (age 64.3, standard deviation 10.6 years; 45% female), median EQ-5D-5L score was 0.85 [interquartile range (IQR) 0.17], and floor and ceiling effects of 0.1 and 16.1%, respectively; median SF-6D score was 0.72 (IQR 0.24), and floor and ceiling effects of 0.1 and 3.2%, respectively. EQ-5D-5L and SF-6D index scores were significantly correlated with an overall Spearman correlation coefficient of 0.73, and an ICC of 0.62 (95% CI 0.42-0.74). Both EQ-5D-5L and SF-6D scores demonstrated statistically significant differences in self-reported chronic conditions, depressive symptoms, and diabetes-related distress, and were able to detect changes in depressive symptoms and diabetes distress across all change groups. CONCLUSIONS: Both EQ-5D-5L and SF-6D index scores provide valid measurement in this patient population. Considerable overlap between the measures means it is not necessary to include both in surveys, however, the advantages and disadvantages of each should be considered. PMID- 28364184 TI - Etiology and clinical relevance of elevated platelet count in ICU patients : A retrospective analysis. AB - BACKGROUND: Thrombocytosis is a common phenomenon in critically ill patients. Although thrombocytosis is an independent risk factor for complications, it does not seem to influence mortality in intensive care (ICU) patients. OBJECTIVES: Our investigation aimed to evaluate the etiological and clinical relevance of a platelet count greater than 450 * 109/l in ICU patients. MATERIALS AND METHODS: Patients admitted for a minimum of 4 days to an interdisciplinary ICU during a 45 month period were enrolled in this retrospective observational study. Thrombocytopenic patients (platelet count <150 * 109/l in at least one measurement) were excluded. The study patients were divided into two groups: thrombocytosis group (thrombocytes >450 * 109/l in at least one measurement) and control group (thrombocytes = 150 - 450 * 109/l during ICU stay). Univariate and multiple regression analysis were used to determine the influence of severe co morbidities on the development of thrombocytosis and the association of elevated platelet count with thrombotic embolism, length of stay (LOS) in ICU, and mortality. RESULTS: A total of 307 patients were analyzed, of whom thrombocytosis was observed in 119 cases. Independent risk factors for the development of thrombocytosis included SIRS, mechanical ventilation, and acute bleeding. Increasing age reduced the risk of thrombocytosis. Thromboembolism occurred in 16 patients (13.4%) with an elevated platelet count and only in nine patients (4.7%) with physiological platelet values (OR: 3.1; 95% CI: 1.3-7.2; p = 0.009). Mean duration of LOS was significantly longer in patients with thrombocytosis (25.2 vs.11.7 days, p < 0.0001). Elevated platelet count showed a negative correlation with ICU mortality (OR: 0.32; 95%-CI: 0.12-0.83; p = 0.019). CONCLUSION: In our retrospective analysis the occurrence of thrombocytosis in a cohort of interdisciplinary ICU patients was associated with a higher rate of complications and longer LOS in the ICU. Despite these findings, thrombocytosis seems to reduce mortality in critical ill patients. PMID- 28364186 TI - Effect of Nerve Growth Factor on Neural Differentiation of Mouse Embryonic Stem Cells. AB - The cholinergic, GABAergic, and catecholaminergic neurons derived from mouse embryonic stem cells in a culture medium supplemented with recombinant NGF were phenotyped and scored. NGF stimulated generation of neurons, but not neuronal progenitors from embryonic stem cells and affected the proportion of specific types of neurons in cultures of differentiating embryonic stem cells. These findings open vista to employ NGF for generation of specific neuron types from embryonic stem cells for fundamental and toxicological studies. PMID- 28364185 TI - Cerebellar Pathology in Familial vs. Sporadic Essential Tremor. AB - Familial and sporadic essential tremor (ET) cases differ in several respects. Whether they differ with respect to cerebellar pathologic changes has yet to be studied. We quantified a broad range of postmortem features (Purkinje cell (PC) counts, PC axonal torpedoes, a host of associated axonal changes, heterotopic PCs, and hairy basket ratings) in 60 ET cases and 30 controls. Familial ET was defined using both liberal criteria (n = 27) and conservative criteria (n = 20). When compared with controls, ET cases had lower PC counts, more torpedoes, more heterotopic PCs, a higher hairy basket rating, an increase in PC axonal collaterals, an increase in PC thickened axonal profiles, and an increase in PC axonal branching. Familial and sporadic ET had similar postmortem changes, with few exceptions, regardless of the definition criteria. The PC counts were marginally lower in familial than sporadic ET (respective p values = 0.059 [using liberal criteria] and 0.047 [using conservative criteria]). The PC thickened axonal profile count was marginally lower in familial ET than sporadic ET (respective p values = 0.037 [using liberal criteria] and 0.17 [using conservative criteria]), and the PC axonal branching count was marginally lower in familial than sporadic ET (respective p values = 0.045 [using liberal criteria] and 0.079 [using conservative criteria]). After correction for multiple comparisons, however, there were no significant differences. Overall, familial and sporadic ET cases share very similar cerebellar postmortem features. These data indicate that pathological changes in the cerebellum are a part of the pathophysiological cascade of events in both forms of ET. PMID- 28364188 TI - What is This Image? 2017: Image 6 Result : The Cobra Head Sign: A useful sign in discrimination between anterior wall myocardial ischemia and soft tissue attenuation artifact. PMID- 28364189 TI - Lesion contrast recovery for partial-volume averaging: Quantitative correction or qualitative enhancement? PMID- 28364187 TI - Chrysin Attenuates IL-1beta-Induced Expression of Inflammatory Mediators by Suppressing NF-kappaB in Human Osteoarthritis Chondrocytes. AB - Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation and inflammation. Chrysin, a natural flavonoid extracted from honey and propolis, has been reported to have anti-inflammatory effects. However, the anti-inflammatory effects of chrysin on OA have not been reported. This study aimed to assess the effects of chrysin on human OA chondrocytes. Human OA chondrocytes were pretreated with chrysin (1, 5, 10 MUM) for 2 h and subsequently stimulated with IL-1beta for 24 h. Production of NO, PGE2, MMP-1, MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5 was evaluated by the Griess reaction and ELISAs. The messenger RNA (mRNA) expression of COX-2, iNOS, MMP-1, MMP-3, MMP-13, ADAMTS-4, ADAMTS-5, aggrecan, and collagen-II was measured by real-time PCR. The protein expression of COX-2, iNOS, p65, p-p65, IkappaB-alpha, and p-IkappaB-alpha was detected by Western blot. The protein expression of collagen-II and p65 nuclear translocation was evaluated by immunofluorescence. We found that chrysin significantly inhibited the IL-1beta-induced production of NO and PGE2; expression of COX-2, iNOS, MMP-1, MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5; and degradation of aggrecan and collagen-II. Furthermore, chrysin dramatically blocked IL-1beta-stimulated IkappaB-alpha degradation and NF-kappaB activation. Taken together, these results suggest that chrysin may be a potential agent in the treatment of OA. PMID- 28364191 TI - Extreme Selection Unifies Evolutionary Game Dynamics in Finite and Infinite Populations. AB - We show that when selection is extreme-the fittest strategy always reproduces or is imitated-the unequivalence between the possible evolutionary game scenarios in finite and infinite populations resolves, in the sense that the three generic outcomes-dominance, coexistence, and mutual exclusion-emerge in well-mixed populations of any size. We consider the simplest setting of a 2-player-2 strategy symmetric game and the two most common microscopic definitions of strategy spreading-the frequency-dependent Moran process and the imitation process by pairwise comparison-both in the case allowing any intensity of selection. We show that of the seven different invasion and fixation scenarios that are generically possible in finite populations-fixation being more or less likely to occur and rapid compared to the neutral game-the three that are possible in large populations are the same three that occur for sufficiently strong selection: (1) invasion and fast fixation of one strategy; (2) mutual invasion and slow fixation of one strategy; (3) no invasion and no fixation. Moreover (and interestingly), in the limit of extreme selection 2 becomes mutual invasion and no fixation, a case not possible for finite intensity of selection that better corresponds to the deterministic case of coexistence. In the extreme selection limit, we also derive the large population deterministic limit of the two considered stochastic processes. PMID- 28364190 TI - Pu'erh tea extract-mediated protection against hepatosteatosis and insulin resistance in mice with diet-induced obesity is associated with the induction of de novo lipogenesis in visceral adipose tissue. AB - BACKGROUND: White adipose tissue (WAT) is important for the maintenance of metabolic homeostasis, and metabolic syndrome is sometimes associated with WAT dysfunction in humans and animals. WAT reportedly plays a key, beneficial role in the maintenance of glucose and lipid homeostasis during de novo lipogenesis (DNL). Pu'erh tea extract (PTE) can inhibit harmful, ectopic DNL in the liver, thus protecting against hepatosteatosis, in mice with diet-induced obesity. We examined whether PTE could induce DNL in WAT and consequently protect against hepatosteatosis. METHODS: C57BL/6 male mice were fed a high-fat diet (HFD) with/without PTE for 16 weeks. Systemic insulin sensitivity was determined using HOMA-IR, insulin- and glucose-tolerance tests, and WAT adipogenesis was evaluated by histological analysis. Adipogenesis-, inflammation-, and DNL-related gene expression in visceral AT (VAT) and subcutaneous AT (SAT) was measured using quantitative reverse transcription-PCR. Regression analysis was used to investigate the association between DNL in WAT and systemic insulin resistance or hepatosteatosis. RESULTS: Pu'erh tea extract significantly reduced the gain of body weight and SAT, but not VAT adiposity, in mice fed the high-fat diet and induced adipogenesis in VAT. The expression of DNL-related genes, including Glut4, encoding an important insulin-regulated glucose transporter (GLUT4), were highly elevated in VAT. Moreover, PTE inhibited VAT inflammation by simultaneously downregulating inflammatory molecules and inducing expression of Gpr120 that encodes an anti-inflammatory and pro-adipogenesis receptor (GPR-120) that recognizes unsaturated long-chain fatty acids, including DNL products. The expression of DNL-related genes in VAT was inversely correlated with hepatosteatosis and systemic insulin resistance. CONCLUSIONS: Activation of DNL in VAT may explain PTE-mediated alleviation of hepatosteatosis symptoms and systemic insulin resistance. PMID- 28364194 TI - Carbon Treatment as a Method to Remove Imidacloprid from Agriculture Runoff. AB - Use of neonicotinoid pesticides is increasing worldwide and there is growing evidence of surface water contamination from this class of insecticide. Due to their high solubility, traditional mitigation practices may be less effective at reducing neonicotinoid concentrations in agricultural runoff. In the current study, laboratory experiments were conducted to determine if granulated activated carbon (GAC) reduces concentrations of the neonicotinoid imidacloprid in water under simulated flow conditions. Imidacloprid was pumped through columns packed with GAC using flow rates scaled to mimic previously reported field studies. Treatments were tested at two different flow rates and samples were collected after 200 and 2500 mL of treated water were pumped through the column. Chemical analysis of the post-column effluent showed the GAC removed all detectable imidacloprid from solution at both flow rates and at both sample times. These results demonstrate the efficacy of GAC for treating neonicotinoids and the results are discussed in the context of incorporating this treatment into integrated vegetated treatment systems for mitigating pesticides in agricultural runoff. Future studies are being designed to evaluate this technology in full scale field trials. PMID- 28364193 TI - Radiofrequency Ablation of the Atherosclerotic Plaque: a Proof of Concept Study in an Atherosclerotic Model. AB - Increased plaque vascularization is causatively associated with the progression of unstable atherosclerotic vessel disease. We investigated the safety and efficacy of heat-generating radiofrequency ablation (RFA) in reducing the number of vessels in the plaque and adventitia and its effect on plaque size and composition. To this end, New Zealand White rabbits were fed a cholesterol enriched diet and subjected to balloon denudation of the infrarenal aorta to induce atherosclerotic plaque formation. After 13 weeks, the proximal or distal half of the infrarenal aorta was exposed to transluminal RFA. The untreated half served as an intra-individual control. Optical coherence tomography (OCT) was performed directly after RFA. We found that RFA on the rabbit atherosclerotic plaque is safe and leads to decreased intraplaque vessel density and smooth muscle cell content but does not affect other components of plaque composition or size. PMID- 28364192 TI - Protein arginine methylation: a prominent modification and its demethylation. AB - Arginine methylation of histones is one mechanism of epigenetic regulation in eukaryotic cells. Methylarginines can also be found in non-histone proteins involved in various different processes in a cell. An enzyme family of nine protein arginine methyltransferases catalyses the addition of methyl groups on arginines of histone and non-histone proteins, resulting in either mono- or dimethylated-arginine residues. The reversibility of histone modifications is an essential feature of epigenetic regulation to respond to changes in environmental factors, signalling events, or metabolic alterations. Prominent histone modifications like lysine acetylation and lysine methylation are reversible. Enzyme family pairs have been identified, with each pair of lysine acetyltransferases/deacetylases and lysine methyltransferases/demethylases operating complementarily to generate or erase lysine modifications. Several analyses also indicate a reversible nature of arginine methylation, but the enzymes facilitating direct removal of methyl moieties from arginine residues in proteins have been discussed controversially. Differing reports have been seen for initially characterized putative candidates, like peptidyl arginine deiminase 4 or Jumonji-domain containing protein 6. Here, we review the most recent cellular, biochemical, and mass spectrometry work on arginine methylation and its reversible nature with a special focus on putative arginine demethylases, including the enzyme superfamily of Fe(II) and 2-oxoglutarate-dependent oxygenases. PMID- 28364195 TI - Historical Characteristics of Contamination and Risk of Heavy Metals in Weishan Lake, China. AB - Combined with the dating analysis of 210Pb and 137Cs, the historical concentration and risk of As, Cd, Cr, Cu, Hg, Ni, Pb and Zn in the core sediment of Weishan Lake were determined. Pollution concentrations, enrichment factor, geo accumulation index, and ecological risk index of these metals and C/N ratio indicate that the natural inputs prevailed till early 1900s. From late 1970s onwards, the risk posed by these metals was significantly increased. Cu and Hg might cause adverse biological effects. The increase of soil erosion and wastewater discharge in the watershed promoted input and accumulation of these metals in the lake. The coal and petroleum industry in the catchment led the more accumulation of Hg, Cd and Cu in the lake. PMID- 28364196 TI - Citizenship, length of stay, and screening for breast, cervical, and colorectal cancer in women, 2000-2010. AB - BACKGROUND: Two factors jointly account for significant gaps in access to health care among immigrants who are present in the U.S.-legal status, and length of residence. The objective of this study is to examine the association between citizenship and length of residence in the U.S. and cancer screening (breast, cervical, and colorectal) among women. METHODS: We analyzed 11 years (2000-2010) of consolidated data from the Medical Expenditure Panel Survey linked with the National Health Interview Survey. Multivariate analyses compared cancer screening among U.S.-born citizens (n = 58,484), immigrant citizens (n = 8,404), and immigrant non-citizens (n = 6,564). RESULTS: Immigrant non-citizens living in the U.S. for less than 5 years were less likely to receive guideline-concordant breast (OR = 0.68 [0.53-0.88]), cervical (OR = 0.65 [0.54-0.78]), and colorectal (OR = 0.31 [0.19-0.50]) cancer screening compared to U.S.-born citizens. Immigrant citizens and non-citizens living in the U.S. for 5 years or more had higher odds of being screened for breast and cervical cancer compared to U.S. born citizens; (OR = 1.26 [1.13-1.41] and OR = 1.17 [1.06-1.29]) for immigrant citizens, (OR = 1.28 [1.13-1.45] and OR = 1.23 [1.09-1.38]) for non-citizens. Immigrant non-citizens living in the U.S. for 5 years or more had lower odds of being screened for colorectal cancer compared to U.S.-born citizens (OR = 0.76 [0.65-0.90]). CONCLUSIONS: Based on these findings, duration mandates in immigration policy may indirectly influence future pathways to preventive health care and cancer disparities disproportionately affecting immigrant women. We suggest that limits of duration mandates be reevaluated, as they may offer pathways to preventive health care for this vulnerable population, and prevent future cancer disparities. PMID- 28364197 TI - The role of particle size of glyburide crystals in improving its oral absorption. AB - Currently, nanosizing is becoming increasingly prevalent as an efficient way for the improvement of oral drug absorption. This study mainly focuses on two points, namely the crystal properties, and the in vitro and in vivo characterizations of drug crystals during the nanosizing process. We used glyburide, an oral type 2 diabetes (T2D) medication, as our model drug. We sought to reduce the crystalline size of this drug and evaluate its absorption properties by comparing it with the original coarse drug because of previous reports about its gastrointestinal absorption insufficiency. Glyburide crystals, ranging from 237.6 to 4473 nm were prepared successfully by jet milling and media milling. The particle sizes and the crystal morphology were analyzed by characterization of the solid states, equilibrium solubility, and dissolution behavior. Additionally, pharmacokinetic study was performed in SD rats. The solid state results indicated a loss in crystallinity, amide-imidic acid interconversion, and partial amorphization during nanosizing. Further, in in vitro tests, nanocrystal formulations remarkably increased the solubility and dissolution of the drug (compared to microcrystals). In the in vivo test, reducing the particle size from 601.3 to 312.5 nm showed no improvement on the C max and AUC (0-36 h) values, while a profound slowing of the drug elimination occurred with reduction of particle size. Further reduction from 312.5 to 237.6 nm lead to a significant increase (p < 0.001) of the AUC (0-36 h) from 6857.8 +/- 369.3 ng mL-1 h to 12,928.3 +/- 1591.4 ng mL-1 h, respectively, in rats. Our present study confirmed that nanosizing has a tremendous impact on promoting the oral absorption of glyburide. PMID- 28364199 TI - Flow dynamics and energy efficiency of flow in the left ventricle during myocardial infarction. AB - Cardiovascular disease is a leading cause of death worldwide, where myocardial infarction (MI) is a major category. After infarction, the heart has difficulty providing sufficient energy for circulation, and thus, understanding the heart's energy efficiency is important. We induced MI in a porcine animal model via circumflex ligation and acquired multiple-slice cine magnetic resonance (MR) images in a longitudinal manner-before infarction, and 1 week (acute) and 4 weeks (chronic) after infarction. Computational fluid dynamic simulations were performed based on MR images to obtain detailed fluid dynamics and energy dynamics of the left ventricles. Results showed that energy efficiency flow through the heart decreased at the acute time point. Since the heart was observed to experience changes in heart rate, stroke volume and chamber size over the two post-infarction time points, simulations were performed to test the effect of each of the three parameters. Increasing heart rate and stroke volume were found to significantly decrease flow energy efficiency, but the effect of chamber size was inconsistent. Strong complex interplay was observed between the three parameters, necessitating the use of non-dimensional parameterization to characterize flow energy efficiency. The ratio of Reynolds to Strouhal number, which is a form of Womersley number, was found to be the most effective non dimensional parameter to represent energy efficiency of flow in the heart. We believe that this non-dimensional number can be computed for clinical cases via ultrasound and hypothesize that it can serve as a biomarker for clinical evaluations. PMID- 28364198 TI - Drug-induced sleep endoscopy with target-controlled infusion using propofol and monitored depth of sedation to determine treatment strategies in obstructive sleep apnea. AB - BACKGROUND: Drug-induced sleep endoscopy (DISE) has become an important diagnostic examination tool in the treatment decision process for surgical therapies in the treatment of obstructive sleep apnea (OSA). Currently, there is a variety of regimes for the performance of DISE, which renders comparison and assessment across results difficult. It remains unclear how the different regimes influence the findings of the examination and the resulting conclusions and treatment recommendations. This study aimed to investigate the correlation between increasing levels of sedation (i.e., light, medium, and deep) induced by propofol using a target-controlled infusion (TCI) pump, with the obstruction patterns at the levels of the velum, oropharynx, tongue base, and epiglottis (i.e., VOTE classification). A second goal was the establishment of a sufficient sedation level to enable a reliable decision regarding treatment recommendations. MATERIAL AND METHODS: Forty-three patients with OSA underwent a DISE procedure using propofol TCI. Three levels of sedation were defined, depending on entropy levels and assessment of sedation: light sedation, medium sedation, and deep sedation. The evaluation of the upper airway at each level, with increasing sedation, was documented using the VOTE classification. The elapsed time at which each assessment was performed was recorded. RESULTS: Upper airway changes occurred and were measured throughout the DISE procedure. Clinically useful determinations of airway closure occurred at medium sedation; this level of sedation was most probably achieved with a blood propofol concentration of 3.2 MUg/ml. In all 43 patients, definite treatment decisions could be made at medium sedation level. Increasing sedation did not result in changes in the treatment decision. CONCLUSIONS: Changes in upper airway collapse during DISE with propofol TCI occur at levels of medium sedation. Decisions regarding surgical treatment could be made at this level of sedation. CLINICAL TRIAL NAME: Upper Airway Collapse in Patients with Obstructive Sleep Apnea Syndrome by Drug Induced Sleep Endoscopy (URL: https://clinicaltrials.gov/ct2/results?term=NCT02588300&Search=Search ) REGISTRATION NUMBER: NCT02588300. PMID- 28364201 TI - Effectiveness of carbon dioxide against different developmental stages of Cadra cautella and Tribolium castaneum. AB - Methyl bromide is an excellent fumigant but has been banned because it has high potential for depleting the ozone layer which leads to many environmental and human health hazard issues. In this connection, effectiveness of carbon dioxide (CO2, 99.9%) was studied as an alternative to methyl bromide under various exposure timings, 25 +/- 1 degrees C, against different developmental stages of the almond moth, Cadra cautella, and red flour beetle, Tribolium castaneum. In case of C. cautella, the LT99 against adult, pupa, and larval stages was achieved after 37.5, 78.1, and 99.9 h of CO2 application, respectively. While for T. castaneum, the LT99 values were obtained after exposure timings of 29.3, 153.9, and 78.4 h against adult, pupa, and larval stages, respectively. Adults were very susceptible; in contrast, pupae and larvae were more tolerant. The susceptibility order was observed as follows: T. castaneum adult > C. cautella adult > C. cautella pupae > T. castaneum larvae > C. cautella larvae > T. castaneum pupae. This study could be useful in developing the management strategies to prevent stored dates from C. cautella and T. castaneum infestation. PMID- 28364200 TI - Sphingosine-1-phosphate is involved in inflammatory reactions in patients with Graves' orbitopathy. AB - OBJECTIVE: Graves' orbitopathy (GO) is initiated by excessive amount of various inflammatory mediators produced by orbital fibroblasts. This study aimed to assess the crucial role of sphingosine-1-phosphate (S1P) in the inflammatory process of GO. METHODS: Orbital adipose/connective tissue samples were obtained from 10 GO patients and 10 normal control individuals during surgery. Primary orbital fibroblast culture was done. After the expression of S1P receptors and sphingosine kinase (SphK) was assessed with the treatment of interleukin (IL) 1beta, we evaluated the expression of pro-inflammatory factors [intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2) and IL-6] after treating S1P. S1P receptor antagonists and SphK 1 inhibitor were pretreated and the expression of the pro-inflammatory factors was assessed. RESULTS: IL-1beta exacerbated the inflammatory process by enhancing the expression of S1P receptors and SphK in GO orbital fibroblasts. IL-1beta also induced the expressions of ICAM 1, COX-2, and IL-6 in GO orbital fibroblasts, and these expressions were effectively inhibited by S1P receptor antagonists and SphK1 inhibitor. CONCLUSION: S1P has an important role in the pathological inflammatory process of GO, which is mediated through the SphK1-S1P- S1P receptor pathway. SphK1 inhibitors and S1P receptors or antagonists could be potential approaches for controlling the inflammatory process of GO. PMID- 28364202 TI - Microbial profiles of a drinking water resource based on different 16S rRNA V regions during a heavy cyanobacterial bloom in Lake Taihu, China. AB - Understanding of the bacterial community structure in drinking water resources helps to enhance the security of municipal water supplies. In this study, bacterial communities were surveyed in water and sediment during a heavy cyanobacterial bloom in a drinking water resource of Lake Taihu, China. A total of 325,317 high-quality sequences were obtained from different 16S ribosomal RNA (rRNA) regions (V3, V4, and V6) using the Miseq sequencing platform. A notable difference was shown between the water and sediment samples, as predominated by Cyanobacteria, Proteobacteria, and Actinobacteria in the water and Proteobacteria, Chloroflexi, and Verrucomicrobia in the sediment, respectively. The LD12 family dominated the water surface and was tightly associated with related indicators of cyanobacterial propagation, indicating involvement in the massive proliferation of cyanobacterial blooms. Alternatively, the genus Nitrospira dominated the sediment samples, which indicates that nitrite oxidation was very active in the sediment. Although pathogenic bacteria were not detected in a large amount, some genera such as Mycobacterium, Acinetobacter, and Legionella were still identified but in very low abundance. In addition, the effects of different V regions on bacterial diversity survey were evaluated. Overall, V4 and V3 were proven to be more promising V regions for bacterial diversity survey in water and sediment samples during heavy water blooms in Lake Taihu, respectively. As longer, cheaper, and faster DNA sequencing technologies become more accessible, we expect that bacterial community structures based on 16S rRNA amplicons as an indicator could be used alongside with physical and chemical indicators, to conduct comprehensive assessments for drinking water resource management. PMID- 28364203 TI - Subsurface cadmium loss from a stony soil-effect of cow urine application. AB - Cadmium (Cd) losses in subsurface flow from stony soils that have received cow urine are potentially important, but poorly understood. This study investigated Cd loss from a soil under a winter dairy-grazed forage crop that was grazed either conventionally (24 h) or with restricted grazing (6 h). This provided an opportunity to test the hypothesis that urine inputs could increase Cd concentrations in drainage. It was thought this would be a result of cow urine either (i) enhancing dissolved organic carbon (DOC) concentrations via an increase in soil pH, resulting in the formation of soluble Cd-organic carbon complexes and, or (ii) greater inputs of chloride (Cl) via cow urine, promoting the formation of soluble Cd-Cl complexes. Cadmium concentrations in subsurface flow were generally low, with a spike above the water quality guidelines for a month after the 24-h grazing. Cadmium fluxes were on average 0.30 g Cd ha-1 year 1 (0.27-0.32 g Cd ha-1 year-1), in line with previous estimates for agricultural soils. The mean Cd concentration in drainage from the 24-h grazed plots was significantly higher (P < 0.05) than 6-h plots. No increase in DOC concentrations between the treatments was found. However, Cl concentrations in drainage were significantly higher (P < 0.001) from the 24-h than the 6-h grazed treatment plots, and positively correlated with Cd concentrations, and therefore, a possible mechanism increasing Cd mobility in soil. Further study is warranted to confirm the mechanisms involved and quantities of Cd lost from other systems. PMID- 28364204 TI - Characteristics and mechanisms of nickel adsorption on biochars produced from wheat straw pellets and rice husk. AB - The adsorption characteristics and mechanisms of Ni2+ on four-standard biochars produced from wheat straw pellets (WSP550, WSP700) and rice husk (RH550, RH700) at 550 and 700 degrees C, respectively, were investigated. The kinetic results show that the adsorption of Ni2+ on the biochars reached an equilibrium within 5 min. The increase of the solid to liquid ratio resulted in an increase of Ni2+ removal percentage but a decrease of the adsorbed amount of Ni2+ per weight unit of biochar. The Ni2+ removal percentage increased with the increasing of initial solution pH values at the range of 2-4, was relatively constant at the pH range of 4-8, and significantly increased to >=98% at pH 9 and stayed constantly at the pH range of 9-10. The calculated maximum adsorption capacities of Ni2+ for the biochars follow the order of WSP700 > WSP550 > RH700 > RH550. Both cation exchange capacity and pH of biochar can be a good indicator of the maximum adsorption capacity for Ni2+ showing a positively linear and exponential relationship, respectively. This study also suggests that a carefully controlled standardised production procedure can make it reliable to compare the adsorption capacities between different biochars and investigate the mechanisms involved. PMID- 28364206 TI - The problem of dephosphorization using waste recycling. AB - The article considers optimizing methods for wastewater treatment systems. Nutrients (nitrogen and phosphorus) are discharged from the river basin of the northwest Russia. Disruption of ecological safety and healthy state of water basins takes place when excess amount of nitrogen and phosphorus is discharged from wastewater. This results in eutrophication that is increased growth of seaweeds and, therefore, in ecological system disruption. The cities of the northwest region are short of funds for renovation of water treatment systems. However, the new solution lies in improvement of biological water treatment system by means of chemical injection. The main research task is implementation of methods for enhanced biological phosphorus removal from domestic sewage. The problem of recycling and ecological safety of rivers within the northwest of Russia and the Baltic Sea is not solved completely. That is why for wastewater dephosphorization, the authors suggest using sulfuric acid production waste at chemical plant "Ammophos," Cherepovets (ferrous sulfate FeSO4.7H2O and phosphogypsum SaSO4.R2O5), as reagents. The advantage of these reagents is their low cost. The authors show the efficiency of the new optimal reagent's combination. Filtering the wastewater through sand filters after secondary settlers increases the total phosphorus removal efficiency up to 90%. The high effect of all types of phosphorus and total nitrogen removal from wastewater can be resulted from the features of micelle creation during coagulation. PMID- 28364205 TI - Spatial distribution of atmospheric PAHs and their genotoxicity in petrochemical industrialized Lanzhou valley, northwest China. AB - The present study investigated the spatial and seasonal variations and sources of 16 priority polycyclic aromatic hydrocarbons (PAHs) in Lanzhou, a petrochemical industrialized and the capital city of Gansu province, northwest China. The human health risks to these PAHs were assessed using an in vitro genotoxic bioassay technique. Associations among direct genotoxic potency, atmospheric PAH concentrations, and potential carcinogen risks were examined. Due to high PAH emissions from fossil fuel combustion and petrochemical industries, considerable higher PAH levels in the atmosphere were observed in Xigu district, a suburb featured by heavy petrochemical industry, compared with those collected at downtown and rural sampling sites. Ambient PAH levels at all sampling sites during the wintertime were higher than that in the summertime due to the winter domestic heating. BaP equivalent (BaPeq) concentrations in winter (41 ng/m3) and summer (28 ng/m3) exceeded the China's new national daily BaPeq standard. The average excess inhalation cancer risks (ECR) due to human exposure to PAHs during winter and summer sampling periods were 45-3540 cancer cases and 31-2451 cases per million people, respectively. The average ECR in the industrial area of Lanzhou valley was 1.97 (winter) and 1.88 times (summer) higher than that in other sampling areas. The higher ECR in the industrial area was resulted primarily by industrial activities and insufficient emission control measures. Extracts from passive air samples in genotoxicity SOS/umu test demonstrated that the genotoxic effect of atmospheric PAHs in Lanzhou was seasonal dependent. PAH air samples collected in winter showed more statistically significant genotoxicity, as manifested by a strong correlation between in vitro genotoxicity and atmospheric PAH concentrations. This indicates that the local residents were under higher potential cancer risk through the inhalation of ambient PAH air concentrations in Lanzhou valley during the wintertime. PMID- 28364207 TI - Effects of applying biosolids to soils on the adsorption and bioavailability of 17alpha-ethinylestradiol and triclosan in wheat plants. AB - Biosolids contain inorganic and organic contaminants, including pharmaceutical and personal care products (PPCPs) that have accounted for a series of emerging contaminants, such as triclosan (TCS) and the hormone 17alpha-ethinylestradiol (EE2). The general aim of this study was to evaluate the effects of biosolid application on EE2 and TCS adsorption and bioavailability in soils through testing with wheat plants. For the bioavailability study, sand and two soils, Lampa and Lo Prado, were used. The sand and soils were treated using two biosolid application rates (0 and 90 mg ha-1), and the EE2 and TCS concentrations in the biosolids were determined as 0.54 +/- 0.06 and 8.31 +/- 0.19 mg kg-1, respectively. The concentration observed in wheat plants indicated that EE2 and TCS are mainly concentrated in the roots rather than in the shoots. Furthermore, the bioavailability of the compounds in plants depends on the properties of the contaminants and the soil. Adsorption studies showed that increasing the soil organic matter content increases the adsorption of TCS and EE2 on these substrates and that both compounds follow the Freundlich adsorption model. The desorption procedure indicated that availability for both TCS and EE2 depended on the soil type because TCS and EE2 were small in the Lampa soil with and without biosolid application and TCS increased by nearly 50% in the Lo Prado soil. The Lo Prado soil had an acidic pH (5.9) and the Lampa soil had a neutral pH of 7.3, and the organic carbon content was smaller. PMID- 28364208 TI - Polycyclic aromatic hydrocarbons and polychlorinated biphenyls in soils of Mayabeque, Cuba. AB - Cuba is a country in transition with a considerable potential for economic growth. Soils are recipients and integrators of chemical pollution, a frequent negative side effect of increasing industrial activities. Therefore, we established a soil monitoring network to monitor polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) in soils of Mayabeque, a Cuban province southeast of Havana. Concentrations of the sum of the 16 US EPA PAHs and of the seven IRMM PCBs in soils from 39 locations ranged from 20 to 106 MUg kg-1 and from 1.1 to 7.6 MUg kg-1, respectively. While such concentrations can be considered as low overall, they were in several cases correlated with the distance of sampling sites to presumed major emission sources, with some of the concomitantly investigated source diagnostic PAH ratios, and with black carbon content. The presented data adds to the limited information on soil pollution in the Caribbean region and serves as a reference time point before the onset of a possible further industrial development in Cuba. It also forms the basis to set up and adapt national environmental standards. PMID- 28364209 TI - Characteristic comparison of heavy metal contamination between road-deposited and roof-deposited sediments in suburban area. AB - Surface-deposited sediment in urban area is an essential environmental medium for assessing heavy metal contamination. A total of 10 sampling trips were conducted to collect road-deposited and roof-deposited sediments for the comparison of nickel (Ni), copper (Cu), cadmium (Cd), lead (Pb), zinc (Zn), and chromium (Cr) contamination characteristics. Results indicated that roof sediment appeared to have a finer size distribution than road sediments. Roof sediment indicated higher metal concentration and lower surface loading than road sediment. The impact of particle size on heavy metal contamination was quantified by using the developed pioneering term of finer particle effect factor; it differed according to surface types and grain size fraction. Particles in individual grain size fraction showed different contribution to the surface loading for bulk sediments. No consistent trend was found for the grain size fraction loading along with grain size for the studied heavy metals for road sediments. In contrast, an asymmetric "W" trend was observed for the roof sediments, and it had the following results: Fraction of <63 and 250-500 MUm showed higher loading, while fraction of 90-125 and >850 MUm indicated the smaller loading. Findings above facilitated the appropriate management practice selection for the treatment of surface-deposited sediments. PMID- 28364210 TI - Being Poorer Than the Rest of the Neighborhood: Relative Deprivation and Problem Behavior of Youth. AB - According to the neighborhood effects hypothesis, there is a negative relation between neighborhood wealth and youth's problem behavior. It is often assumed that there are more problems in deprived neighborhoods, but there are also reports of higher rates of behavioral problems in more affluent neighborhoods. Much of this literature does not take into account relative wealth. Our central question was whether the economic position of adolescents' families, relative to the neighborhood in which they lived, was related to adolescents' internalizing and externalizing problem behavior. We used longitudinal data for youth between 12-16 and 16-20 years of age, combined with population register data (N = 926; 55% females). We employ between-within models to account for time-invariant confounders, including parental background characteristics. Our findings show that, for adolescents, moving to a more affluent neighborhood was related to increased levels of depression, social phobia, aggression, and conflict with fathers and mothers. This could be indirect evidence for the relative deprivation mechanism, but we could not confirm this, and we did not find any gender differences. The results do suggest that future research should further investigate the role of individuals' relative position in their neighborhood in order not to overgeneralize neighborhood effects and to find out for whom neighborhoods matter. PMID- 28364211 TI - Colorectal surgery and surgical site infection: is a change of attitude necessary? AB - INTRODUCTION: Surgical site infection (SSI) can be as high as 30% in patients undergoing colorectal surgery and is associated with an increase in morbidity and mortality. The aim of this study is to evaluate the impact of a set of simple preventive measures that have resulted in a reduction in surgical site infection in colorectal surgery. APPLIED METHOD: Prospective study with two groups of patients treated in the colorectal unit of the "Clinico Universitario Lozano Blesa" hospital in Zaragoza. One group was subject to our measures from February to May 2015. The control group was given conventional treatment within a time period of 3 months before the set of measures were implemented. RESULTS: One hundred forty-nine patients underwent a major colorectal surgical procedure. Seventy (47%) belonged to the control group and were compared to the remaining 79 patients (53% of the total), who were subject to our treatment bundle in the period tested. Comparing the two groups revealed that our set of measures led to a general reduction in SSI (31.4 vs. 13.6%, p = 0.010) and in superficial site infection (17.1 vs. 2.5%, p = 0.002). As a consequence, the postoperative hospital stay was shortened (10.0 vs. 8.0 days, p = 0.048). However, it did not, the number of readmissions nor the re-operation rate. SSI was clearly related to open surgery. CONCLUSIONS: The preventive set of measures applied in colorectal surgery led to a significant reduction of the SSI and of the length of hospital stay. PMID- 28364213 TI - Sources of practice knowledge among Australian fitness trainers. AB - Few studies have examined the sources of practice knowledge fitness trainers use to inform their training methods and update knowledge. This study aims to describe sources of practice knowledge among Australian fitness trainers. In July 2014, 9100 Australian fitness trainers were invited to complete an online survey. Respondents reported the frequency of use of eight sources of practice knowledge (e.g. fitness magazines, academic texts). In a separate survey, exercise science experts (n = 27) ranked each source as either (1) 'high-quality' or (2) 'low quality'. Proportions of users of 'high-quality' sources were calculated across demographic (age, sex) and fitness industry-related characteristics (qualification, setting, role). A multivariate logistic regression analysis assessed the odds of being classified as a user of high-quality sources, adjusting for demographic and fitness industry-related factors. Out of 1185 fitness trainers (response rate = 13.0%), aged 17-72 years, 47.6% (95% CI, 44.7 50.4%) were classified as frequent users of high-quality sources of practice knowledge. In the adjusted analysis, compared to trainers aged 17-26 years, those aged >=61 years (OR, 2.15; 95% CI, 1.05-4.38) and 40-50 years (OR, 1.54; 95% CI, 1.02-2.31) were more likely to be classified as a user of high-quality sources. When compared to trainers working in large centres, those working in outdoor settings (OR, 1.81; 95% CI, 1.23-2.65) and medium centres (OR, 1.59; 95% CI, 1.12 2.29) were more likely to be classified as users of high-quality sources. Our findings suggest that efforts should be made to improve the quality of knowledge acquisition among Australian fitness trainers. PMID- 28364212 TI - Parenchymal-Sparing Versus Anatomic Liver Resection for Colorectal Liver Metastases: a Systematic Review. AB - INTRODUCTION: Colorectal liver metastases develop in 50% of patients diagnosed with colorectal cancer. Surgical resection for colorectal liver metastasis typically involves either anatomical resection (AR) or parenchymal-sparing hepatectomy (PSH). The objective of the current study was to analyze data on parenchymal versus non-parenchymal-sparing hepatic resections for CLM. METHODS: A systematic review of the literature regarding parenchymal-sparing hepatectomy was performed. MEDLINE/PubMed, Cochrane, and EMBASE databases were searched for publications containing the following medical subject headings (MeSH): "Colorectal Neoplasms," "Neoplasm Metastasis," "Liver Neoplasms" and "Hepatectomy". Besides, the following keywords were used to complete the literature search: "Hepatectomy," "liver resection," "hepatic resection," "anatomic/anatomical," "nonanatomic/ nonanatomical," "major," "minor," "limited," "wedge," "CRLM/CLM," and "colorectal liver metastasis." Data was reviewed, aggregated, and analyzed. RESULTS: Two thousand five hundred five patients included in 12 studies who underwent either PSH (n = 1087 patients) or AR (n = 1418 patients) were identified. Most patients had a primary tumor that originated in the colon (PSH 52.2-74.4% vs. AR 53.9-74.3%) (P = 0.289). The majority of studies included a large subset of patients with only a solitary tumor with a reported median tumor number of 1-2 regardless of whether the patient underwent PSH or AR. Median EBL was no different among patients undergoing PSH (100-896 mL) versus AR (200-1489 mL) for CLM (P = 0.248). There was no difference in median length-of-stay following PSH (6-17 days) versus AR (7-15 days) (P = 0.747). While there was considerable inter-study variability regarding margin status, there was no difference in the incidence of R0 resection among patients undergoing PSH (66.7-100%) versus AR (71.6-98.6%) (P = 0.58). When assessing overall survival, there was no difference whether resection of CLM was performed with PSH (5 years OS: mean 44.7%, range 29-62%) or AR (5 years OS: mean 44.6%, range 27-64%) (P = 0.97). CONCLUSION: PSH had a comparable safety and efficacy profile compared with AR and did not compromise oncologic outcomes. PSH should be considered an appropriate surgical approach to treatment for patients with CLM that facilitates preservation of hepatic parenchyma. PMID- 28364215 TI - DNA methylation age is elevated in breast tissue of healthy women. AB - BACKGROUND: Limited evidence suggests that female breast tissue ages faster than other parts of the body according to an epigenetic biomarker of aging known as the "epigenetic clock." However, it is unknown whether breast tissue samples from healthy women show a similar accelerated aging effect relative to other tissues, and what could drive this acceleration. The goal of this study is to validate our initial finding of advanced DNA methylation (DNAm) age in breast tissue, by directly comparing it to that of peripheral blood tissue from the same individuals, and to do a preliminary assessment of hormonal factors that could explain the difference. METHODS: We utilized n = 80 breast and 80 matching blood tissue samples collected from 40 healthy female participants of the Susan G. Komen Tissue Bank at the Indiana University Simon Cancer Center who donated these samples at two time points spaced at least a year apart. DNA methylation levels (Illumina 450K platform) were used to estimate the DNAm age. RESULTS: DNAm age was highly correlated with chronological age in both peripheral blood (r = 0.94, p < 0.0001) and breast tissues (r = 0.86, p < 0.0001). A measure of epigenetic age acceleration (age-adjusted DNAm Age) was substantially increased in breast relative to peripheral blood tissue (p = 1.6 * 10-11). The difference between DNAm age of breast and blood decreased with advancing chronologic age (r = -0.53, p = 4.4 * 10-4). CONCLUSIONS: Our data clearly demonstrate that female breast tissue has a higher epigenetic age than blood collected from the same subject. We also observe that the degree of elevation in breast diminishes with advancing age. Future larger studies will be needed to examine associations between epigenetic age acceleration and cumulative hormone exposure. PMID- 28364214 TI - Frailty and long-term mortality of older breast cancer patients: CALGB 369901 (Alliance). AB - PURPOSE: Breast cancer patients aged 65+ ("older") vary in frailty status. We tested whether a deficits accumulation frailty index predicted long-term mortality. METHODS: Older patients (n = 1280) with non-metastatic, invasive breast cancer were recruited from 78 Alliance sites from 2004 to 2011, with follow-up to 2015. Frailty categories (robust, pre-frail, and frail) were based on 35 baseline illness and function items. Cox proportional hazards and competing risk models were used to calculate all-cause and breast cancer-specific mortality for up to 7 years, respectively. Potential covariates included demographic, psychosocial, and clinical factors, diagnosis year, and care setting. RESULTS: Patients were 65-91 years old. Most (76.6%) were robust; 18.3% were pre-frail, and 5.1% frail. Robust patients tended to receive more chemotherapy +/- hormonal therapy (vs. hormonal) than pre-frail or frail patients (45% vs. 37 and 36%, p = 0.06), and had the highest adherence to hormonal therapy. The adjusted hazard ratios for all-cause mortality (n = 209 deaths) were 1.7 (95% CI 1.2-2.4) and 2.4 (95% CI 1.5-4.0) for pre-frail and frail versus robust women, respectively, with an absolute mortality difference of 23.5%. The adjusted hazard of breast cancer death (n-99) was 3.1 (95% CI 1.6-5.8) times higher for frail versus robust patients (absolute difference of 14%). Treatment differences did not account for the relationships between frailty and mortality. CONCLUSIONS: Most older breast cancer patients are robust and could consider chemotherapy where otherwise indicated. Patients who are frail or pre-frail have elevated long-term all-cause and breast cancer mortality. Frailty indices could be useful for treatment decision-making and care planning with older patients. PMID- 28364216 TI - Prolactin/androgen-inducible carboxypeptidase-D increases with nitrotyrosine and Ki67 for breast cancer progression in vivo, and upregulates progression markers VEGF-C and Runx2 in vitro. AB - PURPOSE: Carboxypeptidase-D (CPD) cleaves C-terminal arginine (Arg) to produce nitric oxide (NO). Upregulation of CPD and NO by 17beta-estradiol, prolactin (PRL), and androgen increases survival of human breast cancer (BCa) cells in vitro. To demonstrate similar events in vivo, CPD, nitrotyrosine (NT, hallmark of NO action), androgen receptor (AR), prolactin receptor (PRLR), and phospho-Stat5a (for activated PRLR) levels were evaluated in benign and malignant human breast tissues, and correlated with cell proliferation (Ki67) and BCa progression (Cullin-3) biomarkers. METHODS: Paraffin-embedded breast tissues were analyzed by immunohistochemistry (IHC). BCa progression markers in human MCF-7 and T47D BCa cell lines treated with NO donor SIN-1 or PRL, +/-CPD inhibitors were analyzed by RT-qPCR and immunoblotting. RESULTS: IHC showed progressive increases in CPD, NT, Ki67, and Cullin-3 from low levels in benign tissues to high levels in ductal carcinoma in situ, low-grade, high-grade, and triple-negative BCa. CPD and NT staining were closely associated, implicating CPD in NO production. Phospho Stat5a increased significantly from benign to high-grade BCa and was mostly nuclear. AR and PRLR were abundant in benign breast and BCa, including triple negative tumors. SIN-1 and PRL increased VEGF-C and Runx2, but not Cullin-3, in BCa cell lines. PRL induction of VEGF-C and Runx2 was inhibited partly by CPD inhibitors, implicating NO, produced by PRL-regulated CPD, in BCa progression. CONCLUSIONS: The CPD-Arg-NO pathway contributes to BCa progression in vitro and in vivo. PRL/androgen activation of the pathway support combined AR and PRLR blockade as an additional therapy for BCa. PMID- 28364217 TI - The efficacy of mycophenolate mofetil in treating Takayasu arteritis: a systematic review and meta-analysis. AB - The purpose of this study is to assess the effectiveness of mycophenolate mofetil (MMF) in treating Takayasu arteritis (TA) patients. Embase, Cochrane Library, Pubmed, Clinicaltrials. Gov and three Chinese literature databases (VIP, CNKI, WanFang) were searched; randomized-controlled trials and observational studies that compared the efficacy before and after treatment with MMF were included. The efficacy outcomes were disease activity, the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) values and steroid dosage. The results were expressed as mean differences with 95% confidence intervals. Compared with the baseline, there were significant reductions in the ESR (-14.92 [25.35, -4.48]), CRP values (-12.99 [-23.29, -2.68]) and the steroid dosage (-17.64 [-24.89, 10.4]) after the addition of MMF, and the disease tended to stabilize. Therefore, MMF might be an alternative immunosuppressive drug for TA for the control of disease activity and to taper the steroid dosage. PMID- 28364218 TI - [Memorandum of the German Society for Rheumatology on the quality of treatment in rheumatology - Update 2016]. AB - On behalf of the Steering Committee of the German Society for Rheumatology, in 2016 the Interdisciplinary Commission on Healthcare Quality updated the 2008 memorandum on rheumatological healthcare in Germany. The update considers changes in therapeutic strategies, treatment targets as well as current structures in healthcare and the political framework. It concentrates on examination of the need for rheumatologists with a background in internal medicine and determines the gap between needs and supply. The internist rheumatologist is responsible for the care of patients with inflammatory rheumatic diseases and contributes to the care of patients with severe forms of other musculoskeletal diseases. At least 2 internist rheumatologists are needed for the outpatient care of 100,000 adult inhabitants, equivalent to 1350 rheumatologists in Germany. With currently 776 rheumatologists, we have little more than half of what we need. The German Society for Rheumatology calls for specific requirements planning for rheumatologists in outpatient care in order to decrease the deficit. In acute inpatient care we need specialized hospitals and wards that ensure a high quality of treatment for patients with complex diseases. We need up to 50 beds per 1 million inhabitants. At least 2 full-time internist rheumatologists and 3 further physicians are needed per 30 beds. In inpatient and outpatient rehabilitation we need 40 beds or outpatient places per 1 million inhabitants with at least 1 full time rheumatologist and 1 further physician. In order to reduce the existing deficits and to cover the increasing future need for rheumatologists, more emphasis has to be laid on primary and secondary education. Chairs for internal rheumatology are needed at each medical university and more positions for postgraduate training in rheumatology should be provided. In all segments of healthcare the treatment aims should be jointly defined between patients and physicians. The patients should be treated in an interdisciplinary network, comprising other medical specialties, health professionals as well as patient organizations. PMID- 28364224 TI - Jonathan W. Amy, March 3, 1923-December 4, 2016. PMID- 28364223 TI - Remarkable reactivity of alkoxide/acetato-bridged binuclear copper(II) complex as artificial carboxylesterase. AB - Bromo-containing binuclear Schiff base copper(II) complex, Cu2L(OAc), with an alkoxo/acetato-bridged moiety was employed as a model of carboxylesterases to promote the hydrolytic cleavage of p-nitrophenyl picolinate (PNPP). Furthermore, the reactivity of a mononuclear complex (CuHL) was evaluated for comparing it with that of binuclear one. The results reveal that the as-prepared binuclear Cu2L(OAc) efficiently accelerated the hydrolysis of PNPP, giving rise to excess four orders of magnitude rate enhancement in contrast to the un-catalyzed reaction. Cu2L(OAc) represented an enzyme-like bell-shaped pH-responsive kinetic behavior. Moreover, the binuclear one is more reactive than its mononuclear analogue (CuHL) by two orders of magnitude. The total efficiency of Cu2L(OAc) is about 61-fold than that of its mononuclear analogue, CuHL. In addition, a contrast experiment reveals that binuclear Cu2L(OAc) displayed good activity in the hydrolysis of PNPP as well another active ester, i.e., S-2-benzothiazolyl 2 amino-alpha-(methoxyimino)-4-thiazolethiolacetate (AE-active ester). Noteworthyly, it was found that mononuclear one inspired more obvious rate enhancement in the hydrolysis of AE-active ester relative to PNPP hydrolysis. The estimated pK a1 of bound water on the binuclear Cu2L(OAc) using second derivative method (SDM) is relatively smaller than that for CuHL by a gap of about 0.8 pK unit, which facilitates the hydrolysis of PNPP. Four orders of magnitude rate enhancement was observed for the catalytic hydrolysis of p-nitrophenyl picolinate (PNPP) by one MU-alkoxide/acetato-bridged binuclear copper(II) complex under physiological conditions. Substrate specificity of the resulting binuclear complexes was observed for the hydrolysis of PNPP and AE-active ester. PMID- 28364222 TI - Siderophores and mussel foot proteins: the role of catechol, cations, and metal coordination in surface adhesion. AB - Metal coordination, hydrogen bonding, redox reactions, and covalent crosslinking are seemingly disparate chemical and physicochemical processes that are all accomplished in natural materials by the catechol functional group. This review focuses on the reactivity of catechols in tris-2,3-dihydroxybenzoyl-containing microbial siderophores and synthetic analogs, as well as Dopa-(3,4 dihydroxyphenylalanine)-containing mussel foot proteins that adhere to surfaces in aqueous conditions. Mussel foot proteins with a high content of Dopa and cationic amino acids, Lys and Arg, adhere strongly to mica, an aluminosilicate mineral, in aqueous conditions. The siderophore cyclic trichrysobactin, tris-(2,3 dihydroxybenzoyl-D-Lys-L-Ser) and related synthetic analogs in which the tri-Ser macrolactone is replaced by Tren, tris-(2-aminoethyl)amine, also adheres strongly to mica. Variation in the nature of the catechol and cationic groups in synthetic analogs reveals a synergism between the cationic amino acid and the catechol, required for strong aqueous adhesion. Autoxidation and iron(III)-catalyzed oxidation of 2,3-dihydroxy and 3,4-dihydroxy catechols are also considered. These siderophore analogs provide a platform to understand catechol interactions and reactivity on surfaces, which may ultimately improve the design of synthetic materials that address diverse challenges in medicine, materials science, as well as other disciplines, in which surface adhesion in aqueous conditions is important. PMID- 28364225 TI - Comparison of Ambient and Atmospheric Pressure Ion Sources for Cystic Fibrosis Exhaled Breath Condensate Ion Mobility-Mass Spectrometry Metabolomics. AB - Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The vast majority of the mortality is due to progressive lung disease. Targeted and untargeted CF breath metabolomics investigations via exhaled breath condensate (EBC) analyses have the potential to expose metabolic alterations associated with CF pathology and aid in assessing the effectiveness of CF therapies. Here, transmission-mode direct analysis in real time traveling wave ion mobility spectrometry time-of-flight mass spectrometry (TM-DART-TWIMS TOF MS) was tested as a high-throughput alternative to conventional direct infusion (DI) electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) methods, and a critical comparison of the three ionization methods was conducted. EBC was chosen as the noninvasive surrogate for airway sampling over expectorated sputum as EBC can be collected in all CF subjects regardless of age and lung disease severity. When using pooled EBC collected from a healthy control, ESI detected the most metabolites, APCI a log order less, and TM-DART the least. TM-DART-TWIMS-TOF MS was used to profile metabolites in EBC samples from five healthy controls and four CF patients, finding that a panel of three discriminant EBC metabolites, some of which had been previously detected by other methods, differentiated these two classes with excellent cross-validated accuracy. Graphical Abstract ?. PMID- 28364226 TI - Habitat degradation increases stress-hormone levels during the breeding season, and decreases survival and reproduction in adult common lizards. AB - The allostatic load model describes how individuals maintain homeostasis in challenging environment and posits that costs induced by a chronic perturbation (i.e., allostatic load) are correlated to the secretion of glucocorticoids, such as corticosterone. Habitat perturbations from anthropogenic activities are multiple and functional responses to those are still unclear. Here, we manipulated the habitat quality in 24 semi-natural populations of the common lizard during 1 year. We tested the predictions of the allostatic load model that habitat degradation should increase baseline corticosterone levels, and should induce concomitant physiological changes, such as lipid mobilization and lower immunocompetence, and demographic changes, such as lower body growth, survival and/or reproductive performances. Our results highlight stage-dependent effects of habitat degradation on physiological traits during the breeding season: adult lizards had higher baseline corticosterone levels and yearling lizards had a lower inflammatory response than adults, whereas juveniles had higher circulating lipid levels than yearlings and adults without concomitant change in corticosterone levels. In addition, habitat degradation reduced the performances of adults but not of juveniles: in low habitat quality populations, adult males had a lower survival and females had a smaller fecundity. These results are in accordance with the allostatic load model given that allostatic load was detected only during the season and in life stages of maximal energy expenditure. This underlines the importance to account for individual energy requirements to better understand demographic responses to habitat perturbation. PMID- 28364227 TI - An anti-mycobacterial bisfunctionalized sphingolipid and new bromopyrrole alkaloid from the Indonesian marine sponge Agelas sp. AB - In the course of our studies on anti-mycobacterial substances from marine organisms, the known dimeric sphingolipid, leucettamol A (1), was isolated as an active component, together with the new bromopyrrole alkaloid, 5-bromophakelline (2), and twelve known congeners from the Indonesian marine sponge Agelas sp. The structure of 2 was elucidated based on its spectroscopic data. Compound 1 and its bis TFA salt showed inhibition zones of 12 and 7 mm against Mycobacterium smegmatis at 50 MUg/disk, respectively, while the N,N'-diacetyl derivative (1a) was not active at 50 MUg/disk. Therefore, free amino groups are important for anti-mycobacterial activity. This is the first study to show the anti mycobacterial activity of a bisfunctionalized sphingolipid. Compound 13 exhibited weak PTP1B inhibitory activity (29% inhibition at 35 MUM). PMID- 28364229 TI - Invention and Early History of Morpholinos: From Pipe Dream to Practical Products. AB - Beginning with my concept in 1969 to treat disease at the nucleic acid level using antisense nucleic acids, antisense has evolved to the current Morpholino oligos. Morpholinos have been the dominant gene knockdown system in developmental biology. Lack of delivery technologies has limited their use in adult animals (including humans), though alteration in muscles in Duchenne muscular dystrophy (DMD) allows delivery into adult muscle. Morpholinos are currently in Phase 3 clinical trials for DMD and a Morpholino oligo for skipping dystrophin exon 51 has been approved by the US FDA. With improved delivery techniques, such as those in development at Gene Tools, therapeutic Morpholinos for many difficult-to-treat diseases will be possible. Initial applications are expected to be custom cocktails of delivery-enabled Morpholinos for treating cancers. PMID- 28364228 TI - A monoclonal antibody-based immunoassay for the determination of oxyresveratrol from Artocarpus lacucha Buch.-Ham. AB - Oxyresveratrol is a major active compound in the heartwood of Artocarpus lacucha. It plays an important role in anti-tyrosinase, antioxidant, anti-inflammatory, antiviral and neuroprotective properties. There are many A. lacucha commercial products available on the market for skin whitening and anti-aging effects. To evaluate the quality of raw material from the plant, a monoclonal antibody (MAb) against oxyresveratrol was generated in this study. The immunogen was prepared by the Mannich reaction for the conjugation of oxyresveratrol and cationized bovine serum albumin (cBSA). The conjugation of oxyresveratrol-cBSA at a ratio of 1:50 was used for the immunization. The novel MAb (E4) was specific to oxyresveratrol and resveratrol. An indirect competitive enzyme-linked immunosorbent assay (ELISA) using the MAb (E4) was developed for the determination of oxyresveratrol. The linear range for the measurement of oxyresveratrol was 63-500 ng/mL and the precision (% relative standard deviation) was found to be <10% with the percentages of recovery from 95.93-103.55%. According to the validation analysis, the established ELISA can be applied for the determination of oxyresvertrol in the heartwood of A. lacucha and samples of the traditional drug Puag-Haad. With reliability and high sensitivity, this assay can provide an alternative approach for the quantitative analysis of oxyresveratrol in A. lacucha samples. PMID- 28364231 TI - Aggregation and Disaggregation of Morpholino Oligomers in Solution. AB - Morpholino oligomers are effective antisense molecules to regulate gene expression and the US FDA has approved a Morpholino drug for the treatment of Duchenne muscular dystrophy. However, it has been observed that the antisense activities of aqueous solutions of some Morpholinos decrease over time. We hypothesize that the decreased activity is caused by the formation of soluble aggregates of the Morpholinos. Here, we analyzed three Morpholino sequences by size exclusion chromatography and found two of them have over time formed soluble aggregates in water. The degree of aggregation is sequence-, temperature-, and time-dependent. We describe a simple procedure for detecting and breaking down the aggregates to return the Morpholinos to their monomeric forms. PMID- 28364230 TI - Making a Morpholino Experiment Work: Controls, Favoring Specificity, Improving Efficacy, Storage, and Dose. AB - A good Morpholino experiment starts with oligos that have been carefully designed to minimize off-target RNA binding. Performing a successful, reproducible, and well-controlled Morpholino experiment requires oligos that are single stranded and in solution at a known concentration. The outcome of treatment with the oligo needs to be checked for specificity, that is, that the observed outcome is due to interaction with the intended RNA and not an interaction with an unexpected RNA. In this chapter, I will discuss Morpholino use mostly in the context of embryonic microinjection experiments, though many techniques and warnings will be applicable to cell culture or adult animal experiments as well. Controls are critical to a good experiment, but good techniques in designing, preparing, storing, and using the oligos can improve the strength and specificity of the knockdown. Finally, it is important to know the solution concentration of the oligo to ensure that the results are reproducible. PMID- 28364232 TI - End-Modifications on Morpholino Oligos. AB - Modifications at either end, both ends, or in-between the ends of a Morpholino oligo provide functional groups for further conjugation. Amino groups are the most useful and efficient reactive entities for chemical bonding with other molecules. The combination of modifications at both ends, especially with double functionalization at the 3'-end, yields myriad opportunities for diverse applications. An orthogonally protected diamine for advanced 3'-end double modification on the solid phase synthesis support allows the convenient assembly of a vast variety of custom-designed molecules. A particular application is the assembly of a class of Vis-Vivo-Morpholino where at the 3'-end an optically visible fluorophore is installed at one side for fluorescent detection and an in vivo delivery moiety is attached at the other side for intracellular activity studies. PMID- 28364233 TI - Inducible Inhibition of Gene Function with Photomorpholinos. AB - Photoactivatable morpholinos (MO) allow specific temporal and spatial inhibition of gene function, which is not possible with conventional morpholino or genetic global gene knock-out approaches. Here, we describe an application of commercially available photoactivatable MO technology for specific gene inhibition in a zebrafish embryonic model and discuss the required controls related to the specificity and efficacy of this method. A similar approach should be also applicable to other model organisms. PMID- 28364234 TI - Blocking Zebrafish MicroRNAs with Morpholinos. AB - Antisense morpholino oligonucleotides have been commonly used in zebrafish to inhibit mRNA function, either by inhibiting pre-mRNA splicing or by blocking translation initiation. Even with the advent of genome editing by CRISP/Cas9 technology, morpholinos provide a useful and rapid tool to knockdown gene expression. This is especially true when dealing with multiple alleles and large gene families where genetic redundancy can complicate knockout of all family members. miRNAs are small noncoding RNAs that are often encoded in gene families and can display extensive genetic redundancy. This redundancy, plus their small size which can limit targeting by CRISPR/Cas9, makes morpholino-based strategies particularly attractive for inhibition of miRNA function. We provide the rationale, background, and methods to inhibit miRNA function with antisense morpholinos during early development and in the adult retina in zebrafish. PMID- 28364235 TI - Using Morpholinos to Examine Gene Function During Fin Regeneration. AB - In the zebrafish regenerating fin, specific gene-targeting morpholinos have been widely utilized to assess gene function. Unlike in embryos, injection of standard morpholinos in the adult regenerating fin is not sufficient for cellular uptake. Rather, morpholinos are first injected extracellularly into the blastemal compartment, followed by electroporation for cellular uptake. Knockdown phenotypes are evaluated 1-4 days post electroporation. This chapter provides a description of the reagents, equipment, and procedure for successful injection and electroporation of morpholinos into the regenerating fin. PMID- 28364236 TI - Using Morpholinos to Probe Gene Networks in Sea Urchin. AB - The control processes that underlie the progression of development can be summarized in maps of gene regulatory networks (GRNs). A critical step in their assembly is the systematic perturbation of network candidates. In sea urchins the most important method for interfering with expression in a gene-specific way is application of morpholino antisense oligonucleotides (MOs). MOs act by binding to their sequence complement in transcripts resulting in a block in translation or a change in splicing and thus result in a loss of function. Despite the tremendous success of this technology, recent comparisons to mutants generated by genome editing have led to renewed criticism and challenged its reliability. As with all methods based on sequence recognition, MOs are prone to off-target binding that may result in phenotypes that are erroneously ascribed to the loss of the intended target. However, the slow progression of development in sea urchins has enabled extremely detailed studies of gene activity in the embryo. This wealth of knowledge paired with the simplicity of the sea urchin embryo enables careful analysis of MO phenotypes through a variety of methods that do not rely on terminal phenotypes. This article summarizes the use of MOs in probing GRNs and the steps that should be taken to assure their specificity. PMID- 28364237 TI - Manipulating Gene Expression in the Chick Embryo. AB - The chick embryo is a well-established representative of amniote embryos, which has been used to make many discoveries, including many major concepts, which have moved our knowledge of developmental biology in hugely important ways. The chick has a relatively compact genome and is easily amenable to embryological manipulations and in vivo imaging. Morpholino gene manipulations have been used in a variety of contexts, and constitute a quick and versatile molecular tool. Here we describe methods to deliver morpholinos to chick embryos, allowing targeting of specific cell populations at defined developmental stages, using two stages as examples: the epiblast of the embryo in the first day of incubation, when the primary germ layers of the embryo are specified, and in ovo electroporation of the neural tube as an example of a later stage. With slight modifications, these general methods can be used to target other embryonic tissues. PMID- 28364238 TI - Inhibition of Bacterial Growth by Peptide-Conjugated Morpholino Oligomers. AB - Morpholino oligomers (MOs) are antisense molecules designed for sequence-specific binding of target mRNA. In bacteria, inhibition is hypothesized to occur by preventing translation initiation. Cell-penetrating peptides may be conjugated to the 5'- or 3'-termini of an MO to enhance cellular entry and therefore inhibition. Here we describe the three standard microbiological assays to assess in vitro antibacterial MO efficacy. PMID- 28364239 TI - Use of Translation Blocking Morpholinos for Gene Knockdown in Giardia lamblia. AB - Giardia lamblia, a major parasite, is an emerging model organism due to its compact genomic arrangement and composition. The most popular reverse genetic technique, RNAi, is ineffective in Giardia. In contrast, protein depletion by translation blocking morpholinos is suitable for most gene targets and provides up to 80% depletion of the target protein. The method is fast, reliable, and specific. After antisense morpholino oligomer delivery into Giardia trophozoites by electroporation, the cells can be used for many subsequent analyses 8-48 h after treatment. In this chapter, suitable gene tags, plasmids, and techniques necessary for proper morpholino targeting are described. PMID- 28364240 TI - Regulation of Isoform Expression by Blocking Polyadenylation Signal Sequences with Morpholinos. AB - Alternative polyadenylation is increasingly being recognized as an important layer of gene regulation. Antisense-mediated modulation of alternative polyadenylation represents an attractive strategy for the regulation of gene expression as well as potential therapeutic applications. In this chapter, we describe methods to upregulate the functional Kv11.1 isoform expression by blocking intronic polyadenylation signal sequences with antisense morpholinos. PMID- 28364241 TI - Targeting Functional Noncoding RNAs. AB - Noncoding RNAs have essential biochemical functions in different areas of cellular metabolism, including protein synthesis, RNA splicing, protein secretion, and DNA replication. We have successfully used Morpholino antisense oligonucleotides for the functional inactivation of small noncoding RNAs required for DNA replication (Y RNAs in vertebrates and stem-bulge RNAs in nematodes). Here we discuss specific issues of targeting functional noncoding RNAs for inactivation by Morpholino antisense oligonucleotides. We present protocols for the design, preparation, and efficacy controls of Morpholino antisense oligonucleotides, as well as brief descriptions for their delivery into vertebrate and nematode embryos. PMID- 28364242 TI - Use of Morpholino Oligomers for Pretargeting. AB - Differing from the conventional direct-targeting strategy in which a probe or payload is directly loaded onto a targeting molecule that binds to the native target, pretargeting is an improved targeting strategy. It converts the native target to an artificial target specific for a secondary targeting molecule loaded with the probe or payload (effector). The effector is small and does not accumulate in normal tissues, which accelerates the targeting process and generates high target to nontarget ratios. DNA/cDNA analogs can serve as the recognition pair, i.e., the artificial target and the secondary targeting effector. Morpholino oligomers are so far the most investigated and the most successful DNA/cDNA analog recognition pairs for pretargeting. Herein, we describe the pretargeting principles, the pretargeting strategy using Morpholino oligomers, and the preclinical success so far achieved. PMID- 28364243 TI - Diagnostic Applications of Morpholinos and Label-Free Electrochemical Detection of Nucleic Acids. AB - Diagnostic applications of morpholinos take advantage of their unique properties including backbone charge neutrality, a weak impact of ionic strength on their hybridization behavior, and their resistance to enzymatic degradation. This chapter overviews how these properties have advanced transduction and other capabilities useful for the analysis of nucleic acids. In many cases, the benefits stem from electrostatic mechanisms; for example, use of low ionic strengths improves sensitivity of detection while decreasing background signals because only the nucleic acid analyte is charged. While most literature reports focus on in vitro assays in buffer, morpholinos have been also used for biodistribution measurements of species such as fungal rRNA and miRNA. After reviewing the diagnostic applications of morpholinos, the chapter describes preparation of morpholino monolayers on metal supports for electrochemical diagnostics and the procedure for performing label-free detection of DNA from changes in surface capacitance. PMID- 28364244 TI - Intranasal Delivery of Peptide-Morpholinos to Knockdown Influenza Host Factors in Mice. AB - Influenza viruses replicate primarily in the lung tissue of different host species. For efficient replication the virus utilizes host factors that are expressed in target cells. Cell-penetrating peptide-conjugated Morpholino oligomers (PPMOs) designed to target viral proteins have shown promising results as potential antiviral drugs in tissue culture and animal models. However, since viruses tend to have high rates of mutations, targeting viral proteins may result in viral escape mutants. An alternative approach to inhibit virus replication with PPMOs is to target host factors that are required for virus replication. Delivery of PPMO through the intranasal route has been shown to be effective in knockdown of host factors or microbial genes leading to protection against respiratory pathogens and reduced microbial burden. In addition, protective host innate antiviral immune responses in the lung can be studied by knockdown of immune signaling factors using PPMOs. Here we describe a successful approach using PPMOs to knockdown either proviral or antiviral host factors leading to changes in influenza virus replication in the lungs of mice, providing a tool to investigate immune responses and host-virus interactions in vivo. PMID- 28364245 TI - Systemic Delivery of Morpholinos to Skip Multiple Exons in a Dog Model of Duchenne Muscular Dystrophy. AB - Exon-skipping therapy is an emerging approach that uses synthetic DNA-like molecules called antisense oligonucleotides (AONs) to splice out frame-disrupting parts of mRNA, restore the reading frame, and produce truncated yet functional proteins. Multiple exon skipping utilizing a cocktail of AONs can theoretically treat 80-90% of patients with Duchenne muscular dystrophy (DMD). The success of multiple exon skipping by the systemic delivery of a cocktail of AONs called phosphorodiamidate morpholino oligomers (PMOs) in a DMD dog model has made a significant impact on the development of therapeutics for DMD, leading to clinical trials of PMO-based drugs. Here, we describe the systemic delivery of a cocktail of PMOs to skip multiple exons in dystrophic dogs and the evaluation of the efficacies and toxicity in vivo. PMID- 28364246 TI - In Vivo and Explant Electroporation of Morpholinos in the Developing Mouse Retina. AB - Neonatal in vivo electroporations and retinal explant electroporations have been widely employed in understanding the effects of loss or gain of function of protein-coding genes in retinal development. Here, we describe a rapid and efficient delivery of morpholinos to add another tool to perturb gene expression during mouse retinal development. PMID- 28364247 TI - Intracerebroventricular Delivery in Mice for Motor Neuron Diseases. AB - The use of antisense oligonucleotides to target specific mRNA sequences represents a promising therapeutic strategy for neurological disorders. Recent advances in antisense technology enclose the development of phosphorodiamidate morpholino oligomers (MO), which is one of the best candidates for molecular therapies due to MO's excellent pharmacological profile.Nevertheless, the route of administration of antisense compounds represents a critical issue in the neurological field. Particularly, as regards motor neuron diseases, intracerebroventricular (ICV) injection is undoubtedly the most efficient procedure to directly deliver therapeutic molecules in the central nervous system (CNS). Indeed, we recently demonstrated the outstanding efficacy of the MO antisense approach by its direct administration to CNS of the transgenic mouse models of Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS).Here, we describe methods to perform the ICV delivery of MO in neonatal SMA mice and in adult ALS mice. PMID- 28364249 TI - Surface Plasmon Resonance-Based Concentration Determination Assay: Label-Free and Antibody-Free Quantification of Morpholinos. AB - Surface plasmon resonance (SPR) is a physical process that allows label-free and real-time detection of biomolecular interactions. SPR provides a rapid and quantitative method for studying interactions of macromolecules such as proteins and nucleic acids. Antisense Morpholino oligomers are widely used to regulate gene expression and the US FDA has approved a Morpholino drug for treatment of Duchenne muscular dystrophy. Here, we describe an antibody-free, label-free, high throughput, and walk-away SPR method for quantification of Morpholino compounds extracted from biological specimens. This provides a valuable way for determining pharmacokinetics and pharmacodynamics of Morpholino oligomers in biological matrices for research and therapeutic applications. PMID- 28364248 TI - Delivery of Morpholino Antisense Oligonucleotides to a Developing Ovine Conceptus via Luminal Injection into a Ligated Uterine Horn. AB - In vivo delivery of morpholino antisense oligonucleotides (MAO) directly into the uterine lumen of a peri-implantation period pregnant sheep is an effective technique for evaluation of gene products for conceptus development. The highly phagocytic conceptus is undergoing rapid morphological change, thereby the available MAO are readily consumed and delivered to developing cells. Here, we describe the method for preparation and surgical delivery of MAO-Endo-Porter complex to developing ovine conceptus on day 8 postmating. Also outlined are methods for posttreatment sample recovery on day 16 postmating. PMID- 28364250 TI - Ultrasensitive Hybridization-Based ELISA Method for the Determination of Phosphorodiamidate Morpholino Oligonucleotides in Biological samples. AB - Determining the concentration of oligonucleotide in biological samples such as tissue lysate and serum is essential for determining the biodistribution and pharmacokinetic profile, respectively. ELISA-based assays have shown far greater sensitivities compared to other methods such as HPLC and LC/MS. Here, we describe a novel ultrasensitive hybridization-based ELISA method for quantitating morpholino oligonucleotides in mouse tissue lysate and serum samples. The assay has a linear detection range of 5-250 pM (R2 > 0.99). PMID- 28364252 TI - The lipopolysaccharide lipid A structure from the marine sponge-associated bacterium Pseudoalteromonas sp. 2A. AB - Suberites domuncula is a marine demosponge harbouring a large bacterioflora, including commensal, opportunistic and pathogenic bacteria, among which, species of the Gram-negative genus Pseudoalteromonas were identified. The sponge-bacteria interaction mechanisms are still not fully understood. As the main component of the Gram-negative bacterial outer membrane, the lipopolysaccharide (LPS) may play a role in such a crucial relationship. Moreover, the LPS is known to be the most versatile bioactive macromolecule of Gram-negative bacteria and its lipid A structure is responsible for the immunological activity of the whole LPS on eukaryotic host cells. Here it is reported the structural characterisation of the LPS lipid A moiety isolated from the S. domuncula-associated commensal bacterium, Pseudoalteromonas sp. 2A. Chemical and MALDI mass spectrometry analyses, performed on both the LPS and the isolated lipid A as well as on the intact bacterial cells, highlighted a complex family of penta-acylated lipid A species carrying two phosphate units on the disaccharide backbone. PMID- 28364251 TI - Allosteric modulation model of the mu opioid receptor by herkinorin, a potent not alkaloidal agonist. AB - Modulation of opioid receptors is the primary choice for pain management and structural information studies have gained new horizons with the recently available X-ray crystal structures. Herkinorin is one of the most remarkable salvinorin A derivative with high affinity for the mu opioid receptor, moderate selectivity and lack of nitrogen atoms on its structure. Surprisingly, binding models for herkinorin are lacking. In this work, we explore binding models of herkinorin using automated docking, molecular dynamics simulations, free energy calculations and available experimental information. Our herkinorin D-ICM-1 binding model predicted a binding free energy of -11.52 +/- 1.14 kcal mol-1 by alchemical free energy estimations, which is close to the experimental values 10.91 +/- 0.2 and -10.80 +/- 0.05 kcal mol-1 and is in agreement with experimental structural information. Specifically, D-ICM-1 molecular dynamics simulations showed a water-mediated interaction between D-ICM-1 and the amino acid H2976.52, this interaction coincides with the co-crystallized ligands. Another relevant interaction, with N1272.63, allowed to rationalize herkinorin's selectivity to mu over delta opioid receptors. Our suggested binding model for herkinorin is in agreement with this and additional experimental data. The most remarkable observation derived from our D-ICM-1 model is that herkinorin reaches an allosteric sodium ion binding site near N1503.35. Key interactions in that region appear relevant for the lack of beta-arrestin recruitment by herkinorin. This interaction is key for downstream signaling pathways involved in the development of side effects, such as tolerance. Future SAR studies and medicinal chemistry efforts will benefit from the structural information presented in this work. PMID- 28364253 TI - Women with prior gestational diabetes mellitus and prediabetes are characterised by a decreased incretin effect. AB - AIMS/HYPOTHESIS: We investigated whether a reduced incretin effect, as observed in patients with type 2 diabetes, can be detected in high-risk individuals, such as women with prior gestational diabetes mellitus (pGDM). METHODS: In this cross sectional study, 102 women without diabetes with pGDM and 15 control participants without pGDM and with normal glucose tolerance (NGT) underwent a 4 h 75 g OGTT and an isoglycaemic i.v. glucose infusion (IIGI). Women with pGDM were classified as having NGT or prediabetes (impaired fasting glucose and/or impaired glucose tolerance). Insulin sensitivity was assessed using the Matsuda index and HOMA2-IR and the incretin effect was calculated from insulin responses during the study (100% * [AUCinsulin,OGTT - AUCinsulin,IIGI]/AUCinsulin,OGTT). RESULTS: Sixty three of the 102 women with pGDM (62%) had prediabetes (median [interquartile range]: age, 38.3 [6.5] years; BMI, 32.1 [5.8] kg/m2) and 39 women (38%) had NGT (age, 39.5 [5.6] years; BMI, 31.0 [6.7] kg/m2). Control participants (n = 15) were not significantly different from the pGDM group with regards to age (39.2 [7.4] years) and BMI (28.8 [9.2] kg/m2). Compared with women with NGT and control participants, women with prediabetes had lower insulin sensitivity, as measured by the Matsuda index (3.0 [2.4] vs 5.0 [2.6] vs 1.5 [1.8], respectively; p < 0.001). The incretin effect was 55.3% [27.8], 73.8% [19.0] and 76.7% [24.6] in women with prediabetes, women with normal glucose tolerance and control participants, respectively (p < 0.01). CONCLUSION/INTERPRETATION: Prediabetes was highly prevalent in women with pGDM, and alterations in the incretin effect were detected in this group before the development of type 2 diabetes. TRIAL REGISTRATION: clinicaltrialsregister.eu 2012-001371-37-DK. PMID- 28364254 TI - Characterisation of rapid progressors to type 1 diabetes among children with HLA conferred disease susceptibility. AB - AIMS/HYPOTHESIS: In this study, we aimed to characterise rapid progressors to type 1 diabetes among children recruited from the general population, on the basis of HLA-conferred disease susceptibility. METHODS: We monitored 7410 HLA predisposed children participating in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study for the development of beta cell autoimmunity and type 1 diabetes from birth over a median follow-up time of 16.2 years (range 0.9-21.1 years). Islet cell antibodies (ICA) and autoantibodies to insulin (IAA), GAD (GADA) and islet antigen 2 (IA-2A) were assessed as markers of beta cell autoimmunity. Rapid progression was defined as progression to clinical type 1 diabetes within 1.5 years of autoantibody seroconversion. We analysed the association between rapid progression and demographic and autoantibody characteristics as well as genetic markers, including 25 non-HLA SNPs predisposing to type 1 diabetes. RESULTS: Altogether, 1550 children (21%) tested positive for at least one diabetes-associated autoantibody in at least two samples, and 248 (16%) of seroconverters progressed to type 1 diabetes by the end of 2015. The median time from seroconversion to diagnosis was 0.51 years in rapid progressors (n = 42, 17%) and 5.4 years in slower progressors. Rapid progression was observed both among young (<5 years) and early pubertal children (>7 years), resulting in a double-peak distribution of seroconversion age. Compared with slower progressors, rapid progressors had a higher frequency of positivity for multiple (>=2) autoantibodies and had higher titres of ICA, IAA and IA-2A at seroconversion, and there was a higher prevalence of the secretor genotype in the FUT2 gene among those carrying the high-risk HLA genotype. Compared with autoantibody-positive non-progressors, rapid progressors were younger, were more likely to carry the high-risk HLA genotype and a predisposing SNP in the PTPN22 gene, had higher frequency of ICA, IAA, GADA and IA-2A positivity and multipositivity, and had higher titres of all four autoantibodies at seroconversion. CONCLUSIONS/INTERPRETATION: At seroconversion, individuals with rapid progression to type 1 diabetes were characterised by a younger age, higher autoantibody titres, positivity for multiple autoantibodies and higher prevalence of a FUT2 SNP. The double-peak profile for seroconversion age among the rapid progressors demonstrates for the first time that rapid progression may take place not only in young children but also in children in early puberty. Rapid progressors might benefit from careful clinical follow-up and early preventive measures. PMID- 28364256 TI - Inter-rater and intra-rater reliability of an adapted Wolf motor function test for older patients with shoulder injuries. AB - BACKGROUND AND OBJECTIVE: The Wolf motor function test (WMFT) evaluates the upper extremity performance of patients with neurological disorders and traumatic brain injuries by assessing time and functional capacity. It was later modified to also measure the quality of the performed movements. This study aimed to adapt the WMFT for patients with shoulder injuries and to evaluate the inter-rater and intra-rater reliability of this adapted version. SUBJECTS AND METHODS: A total of 20 individuals with a median age of 80.5 years were assessed using a test-retest design after surgical or conservative treatment of shoulder injuries. Two raters rated performance to determine inter-rater reliability. One rater rated the performance again to determine intra-rater reliability. Both inter-rater and intra-rater agreement were determined by weighted Cohen's kappa statistics with corresponding confidence intervals. Cronbach's alpha was calculated to determine internal consistency. RESULTS: The inter-rater Cohen's kappa values ranged from 0.84-1.00 for functional capacity and from 0.79-1.00 for quality of movement. For intra-rater reliability the Cohen's kappa ranged from 0.71-1.00. Cronbach's alpha was >0.94 for functional capacity and >0.96 for quality of movement. CONCLUSION: The adapted version of the WMFT shows high intra-rater and inter-rater reliability for patients with shoulder injuries. PMID- 28364255 TI - MicroRNA-184 is a downstream effector of albuminuria driving renal fibrosis in rats with diabetic nephropathy. AB - AIMS/HYPOTHESIS: Renal fibrosis is a common complication of diabetic nephropathy and is a major cause of end-stage renal disease. Despite the suggested link between renal fibrosis and microRNA (miRNA) dysregulation in diabetic nephropathy, the identification of the specific miRNAs involved is still incomplete. The aim of this study was to investigate miRNA profiles in the diabetic kidney and to identify potential downstream targets implicated in renal fibrosis. METHODS: miRNA expression profiling was investigated in the kidneys of 8-month-old Zucker diabetic fatty (ZDF) rats during overt nephropathy. Localisation of the most upregulated miRNA was established by in situ hybridisation. The candidate miRNA target was identified by in silico analysis and its expression documented in the diabetic kidney associated with fibrotic markers. Cultured tubule cells served to assess which of the profibrogenic stimuli acted as a trigger for the overexpressed miRNA, and to investigate underlying epigenetic mechanisms. RESULTS: In ZDF rats, miR-184 showed the strongest differential upregulation compared with lean rats (18-fold). Tubular localisation of miR-184 was associated with reduced expression of lipid phosphate phosphatase 3 (LPP3) and collagen accumulation. Transfection of NRK-52E cells with miR-184 mimic reduced LPP3, promoting a profibrotic phenotype. Albumin was a major trigger of miR-184 expression. Anti-miR-184 counteracted albumin-induced LPP3 downregulation and overexpression of plasminogen activator inhibitor-1. In ZDF rats, ACE-inhibitor treatment limited albuminuria and reduced miR-184, with tubular LPP3 preservation and tubulointerstitial fibrosis amelioration. Albumin induced miR-184 expression in tubule cells was epigenetically regulated through DNA demethylation and histone lysine acetylation and was accompanied by binding of NF-kappaB p65 subunit to miR-184 promoter. CONCLUSIONS/INTERPRETATION: These results suggest that miR-184 may act as a downstream effector of albuminuria through LPP3 to promote tubulointerstitial fibrosis, and offer the rationale to investigate whether targeting miR-184 in association with albuminuria-lowering drugs may be a new strategy to achieve fully anti-fibrotic effects in diabetic nephropathy. PMID- 28364257 TI - [Geriatric assessment of patients with hematological neoplasms]. AB - Hematological malignancies are typical diseases of the elderly. The aging of the population in the Western World results in a significant increase in the number of elderly patients with hematological malignant diseases. This has important consequences for medicine. One consequence of this development is that the need for tools for the evaluation of both functional and global status of the elderly increases. The use of these tools enables the hematologist to better stratify the patients, to individualize therapy better, to possibly modify therapy in order to improve implementation of supportive measures and interventions, to minimize toxicity and side effects and ultimately to tailor the treatment to the individual patient. Several tools are available for geriatric assessment (GA) and there is strong evidence that an effective GA can detect previously unknown problems. The targeted intervention improves the prognosis and compliance of therapy in elderly patients with hematological malignant diseases. PMID- 28364258 TI - Dementia care management in primary care : Current collaborative care models and the case for interprofessional education. AB - BACKGROUND: Dementia is one of the most prevalent diseases in the older population. Various dementia care models have been developed to address patient's healthcare needs. They can be described as "collaborative care" or "person centered care". Referring to the needs of the workforce working with persons with dementia, a key element is the use of interprofessional education (IPE). OBJECTIVE: The purpose of this article is to describe different international collaborative care models to define a minimum standard of healthcare professions for collaborative dementia care in primary care. This helps to identify requirements for IPE to optimize care of people with dementia and to support informal caregivers in the future. MATERIAL AND METHODS: In this article six dementia care models from 4 different countries (Germany, USA, UK and Netherlands) are described and compared regarding aims, interventions and healthcare professionals involved. RESULTS: Care teams are minimally comprised of general practitioners or primary care providers, nurses, and social workers. Additional healthcare disciplines may be involved for specific interventions. Mostly, care team members received specific training but such training did not necessarily incorporate the IPE approach. To ensure successful collaboration of professions, IPE training programs should at least consist of the following core topics: (1) early diagnosis, (2) postdiagnostic support, (3) advanced care planning for patients and caregivers and (4) effective collaborative care. CONCLUSION: The IPE programs for dementia should be expanded and must be widely implemented in order to assess the impact on collaborative practice. This study will provide the knowledge base for structuring IPE trainings developing educational agendas and adapting existing guidelines to improve collaborative dementia care in the future. PMID- 28364259 TI - The effects of sclerostin antibody plus parathyroid hormone (1-34) on bone formation in ovariectomized rats. AB - Previous studies have demonstrated the effects of sclerostin antibody (Scl-Ab) and parathyroid hormone (1-34, PTH) on healing in osteoporosis; however, reports about the combined effects of Scl-Ab plus PTH on osteoporosis are limited. This study was designed to investigate the impact of combined treatment with Scl-Ab and PTH on osteoporosis healing in ovariectomized (OVX) rats. After bilateral ovariectomy, 12 weeks were allowed to pass for the establishment of standard conditions for osteoporosis in animal models. The rats then randomly received a vehicle (control), Scl-Ab (25 mg/kg body weight, twice weekly), PTH (60 MUg/kg, three times per week) or PTH plus Scl-Ab until death at 12 weeks. The blood and distal femurs of the rats were harvested for evaluation. The results of treatment for osteoporosis were evaluated by serum analysis, histology, microcomputed tomography (micro-CT) and biomechanical tests. Results from this study indicated that PTH + Scl-Ab had stronger effects on the prevention and treatment of osteoporosis than either of the monotherapies in OVX rats. The PTH + Scl-Ab produced the strongest effects on bone volume fraction (BV/TV), bone trabecular thickness (Tb.Th), trabecular number (Tb.N) and trabecular spacing (Tb.Sp), bone mineral density (BMD) and strength of distal femurs and increased the levels of procollagen type I N-terminal propeptide (PINP) and osteocalcin. In contrast, monotherapy with PTH or Scl-Ab showed no differences between treated groups in the assessment of the metaphysis of contralateral femurs by histology, serum, biomechanical tests and micro-CT. These results seem to indicate that Scl-Ab plus PTH has an additive effect on osteoporosis in OVX rats. PMID- 28364260 TI - Optimising care for patients with cognitive impairment and dementia following hip fracture. AB - The global shift in demographics towards aging populations is leading to a commensurate increase in age-related disease and frailty. It is essential to optimise health services to meet current needs and prepare for anticipated future demands. This paper explores issues impacting on people living with cognitive impairment and/or dementia who experience a hip fracture and are cared for in acute settings. This is important given the high mortality and morbidity associated with this population. Given the current insufficiency of clear evidence on optimum rehabilitation of this patient group, this paper explored three key themes namely: recognition of cognitive impairment, response by way of training and education of staff to optimise care for this patient group and review of the importance of outcomes measures. Whilst there is currently insufficient evidence to draw conclusions about the optimal ways of caring for patients living with dementia following hip fracture, this paper concludes that future research should improve understanding of healthcare staff education to improve the outcomes for this important group of patients. PMID- 28364262 TI - Mitigation of inbreeding while preserving genetic gain in genomic breeding programs for outbred plants. AB - KEY MESSAGE: Heuristic genomic inbreeding controls reduce inbreeding in genomic breeding schemes without reducing genetic gain. Genomic selection is increasingly being implemented in plant breeding programs to accelerate genetic gain of economically important traits. However, it may cause significant loss of genetic diversity when compared with traditional schemes using phenotypic selection. We propose heuristic strategies to control the rate of inbreeding in outbred plants, which can be categorised into three types: controls during mate allocation, during selection, and simultaneous selection and mate allocation. The proposed mate allocation measure GminF allocates two or more parents for mating in mating groups that minimise coancestry using a genomic relationship matrix. Two types of relationship-adjusted genomic breeding values for parent selection candidates ([Formula: see text]) and potential offspring ([Formula: see text]) are devised to control inbreeding during selection and even enabling simultaneous selection and mate allocation. These strategies were tested in a case study using a simulated perennial ryegrass breeding scheme. As compared to the genomic selection scheme without controls, all proposed strategies could significantly decrease inbreeding while achieving comparable genetic gain. In particular, the scenario using [Formula: see text] in simultaneous selection and mate allocation reduced inbreeding to one-third of the original genomic selection scheme. The proposed strategies are readily applicable in any outbred plant breeding program. PMID- 28364261 TI - Regulation of Cell Surface CB2 Receptor during Human B Cell Activation and Differentiation. AB - Cannabinoid receptor type 2 (CB2) is the primary receptor pathway mediating the immunologic consequences of cannabinoids. We recently reported that human peripheral blood B cells express CB2 on both the extracellular membrane and at intracellular sites, where-as monocytes and T cells only express intracellular CB2. To better understand the pattern of CB2 expression by human B cells, we examined CD20+ B cells from three tissue sources. Both surface and intracellular expression were present and uniform in cord blood B cells, where all cells exhibited a naive mature phenotype (IgD+/CD38Dim). While naive mature and quiescent memory B cells (IgD-/CD38-) from tonsils and peripheral blood exhibited a similar pattern, tonsillar activated B cells (IgD-/CD38+) expressed little to no surface CB2. We hypothesized that regulation of the surface CB2 receptor may occur during B cell activation. Consistent with this, a B cell lymphoma cell line known to exhibit an activated phenotype (SUDHL-4) was found to lack cell surface CB2 but express intracellular CB2. Furthermore, in vitro activation of human cord blood resulted in a down-regulation of surface CB2 on those B cells acquiring the activated phenotype but not on those retaining IgD expression. Using a CB2 expressing cell line (293 T/CB2-GFP), confocal microscopy confirmed the presence of both cell surface expression and multifocal intracellular expression, the latter of which co-localized with endoplasmic reticulum but not with mitochondria, lysosomes, or nucleus. Our findings suggest a dynamic multi compartment expression pattern for CB2 in B cells that is specifically modulated during the course of B cell activation. PMID- 28364265 TI - Molecular characterization and SNP identification in HSPB6 gene in Karan Fries (Bos taurus x Bos indicus) cattle. AB - Heat shock proteins (HSPs) act as molecular chaperones which are preferentially transcribed in response to severe perturbations of the cellular homeostasis such as heat stress. The present study was undertaken for molecular characterization and detection of genetic polymorphisms of HSPB6 gene in 100 Karan Fries Cattle. HSPB6 gene was mapped on Bos taurus autosome 18 (BTA 18), comprising three exons and two introns. Four sets of primers for HSPB6 gene were designed using Primer3 software (version 0.4.0). For detecting single nucleotide polymorphisms (SNPs), sequence data was analyzed using BioEdit software (version 7.2). Comparative sequence analysis of HSPB6 gene showed five nucleotide polymorphisms, which included three transitions viz. g.161A > G, g.436G > A and g.2152A > G and two transversions viz. g.1743C > G and g.2417A > T compared to B. taurus (NCBI GenBank: AC_000175.1). HSPB6 gene of Karan Fries cattle exhibited a high percentage of nucleotide identity (47.0-100.0%) with the corresponding mammalian homologue. The present study indicated a high degree of genetic variability in the HSPB6 gene in the Karan Fries cattle populations. PMID- 28364263 TI - Development of a text messaging system to improve receipt of survivorship care in adolescent and young adult survivors of childhood cancer. AB - PURPOSE: This study aimed to develop and examine the acceptability, feasibility, and usability of a text messaging, or Short Message Service (SMS), system for improving the receipt of survivorship care for adolescent and young adult (AYA) survivors of childhood cancer. METHODS: Researchers developed and refined the text messaging system based on qualitative data from AYA survivors in an iterative three-stage process. In stage 1, a focus group (n = 4) addressed acceptability; in stage 2, key informant interviews (n = 10) following a 6-week trial addressed feasibility; and in stage 3, key informant interviews (n = 23) following a 6-week trial addressed usability. Qualitative data were analyzed using a constant comparative analytic approach exploring in-depth themes. RESULTS: The final system includes programmed reminders to schedule and attend late effect screening appointments, tailored suggestions for community resources for cancer survivors, and messages prompting participant feedback regarding the appointments and resources. Participants found the text messaging system an acceptable form of communication, the screening reminders and feedback prompts feasible for improving the receipt of survivorship care, and the tailored suggestions for community resources usable for connecting survivors to relevant services. Participants suggested supplementing survivorship care visits and forming AYA survivor social networks as future implementations for the text messaging system. CONCLUSIONS: The text messaging system may assist AYA survivors by coordinating late effect screening appointments, facilitating a partnership with the survivorship care team, and connecting survivors with relevant community resources. IMPLICATIONS FOR CANCER SURVIVORS: The text messaging system has the potential to improve the receipt of survivorship care. PMID- 28364264 TI - Seagrass metabolism and carbon dynamics in a tropical coastal embayment. AB - Net ecosystem metabolism and subsequent changes in environmental variables were studied seasonally in the seagrass-dominated Palk Bay, located along the southeast coast of India. The results showed that although the water column was typically net heterotrophic, the ecosystem as a whole displayed autotrophic characteristics. The mean net community production from the seagrass meadows was 99.31 +/- 45.13 mM C m-2 d-1, while the P/R ratio varied between 1.49 and 1.56. Oxygen produced through in situ photosynthesis, exhibited higher dependence over dissolved CO2 and available light. Apportionment of carbon stores in biomass indicated that nearly three-fourths were available belowground compared to aboveground. However, the sediment horizon accumulated nearly 40 times more carbon than live biomass. The carbon storage capacities of the sediments and seagrass biomass were comparable with the global mean for seagrass meadows. The results of this study highlight the major role of seagrass meadows in modification of seawater chemistry. Though the seagrass meadows of Palk Bay are increasingly subject to human impacts, with coupled regulatory and management efforts focused on improved water quality and habitat conservation, these key coastal ecosystems will continue to be valuable for climate change mitigation, considering their vital role in C dynamics and interactions with the overlying water column. PMID- 28364266 TI - A study on some reproductive disorders in dromedary camel herds in Saudi Arabia with special references to uterine infections and abortion. AB - Dromedary camels complaining from conception failure or abortion were investigated and their herders interviewed in Al Ahsa province, Kingdom of Saudi Arabia (KSA) during 2013 and 2015. The most important reproductive disorder according to the responders is uterine infection (60.2%) followed by obesity (22.3%) then physiological conditions (hormonal disturbances; 7.8%), adhesions (3.9%) and repeat breeders (2.9%). Of the camel herders, 78.6% reported previous occurrence of abortion in their herds and 46% reported abortion cases in the last season (2015/2016), while 21.4% reported no history of abortion. Most of the responders (97.1%) do not call a veterinarian for cases of abortion in their herds and 53.4% do not discard aborted materials. The majority of the herders (76.7%) deny that handling aborted materials or touching vaginal fluids can result in human infection, or replied they do not know. Uterine swab samples were collected and tested by PCR for seven potential pathogens and sera tested for antibodies against bovine viral diarrhea virus (BVDV) and Brucella. Five pathogens were identified in infected uterine samples, namely Coxiella burnetii (36%), Campylobacter spp. (27%), Brucella spp. (17%), Salmonella spp. (13%), and Chlamydia spp. (7%). Sero-prevalence of Brucella and BVDV was 8.2 and 29.1% in overall sera, respectively, and varies with regard to the region. The findings of the present study demonstrate that reproductive disorders dominated by uterine infections and abortions are widespread in dromedary camels in KSA. PMID- 28364267 TI - Utility of 12-lead and signal-averaged Holter electrocardiograms after pilsicainide provocation for risk stratification in Brugada syndrome. AB - Non-invasive risk stratification for ventricular fibrillation (VF) in Brugada syndrome (BrS) has not been fully evaluated. The aim of this study was to assess the utility of signal-averaged Holter electrocardiogram (Holter SAECG) and 12 lead Holter electrocardiogram (Holter ECG) after a pilsicainide provocation test for non-invasive risk stratification in BrS. We enrolled 30 consecutive patients with BrS [divided into 2 groups: the VF group, those with a previous history of VF (n = 10); and the non-VF group, those without a history of VF (n = 20)] and 10 control subjects without type 1 ECG. We evaluated late potentials [LP: filtered QRS (f-QRS), RMS40, and LAS40] on the Holter SAECG for 4 h after the pilsicainide provocation and in the same patients on another day without performing the pilsicainide provocation. Furthermore, we measured QRS duration and QTc interval in leads V2 and V5, and J amplitude in lead V2 on the Holter ECG after the pilsicainide provocation. On the Holter SAECG, the f-QRS at 1 h and LAS40 at 3 h after the pilsicainide provocation were significantly larger in the VF group than in the non-VF group (f-QRS at 1 h: 113.9 +/- 8.9 vs. 104.9 +/- 8 ms; p = 0.01, LAS40 at 3 h: 45.4 +/- 5.9 vs. 35.5 +/- 7.4 ms; p < 0.001). The receiver operating characteristic curve analysis for a single parameter of VF occurrence was determined [f-QRS at 1 h: area under the curve (AUC) 0.8, with sensitivity 80% and specificity 80%; and LAS40 at 3 h: AUC 0.87, with sensitivity 90% and specificity 75%]. On the Holter ECG, there were no significant differences in these parameters between the VF and non-VF groups. In conclusion, the LP after the pilsicainide provocation using Holter SAECG may be useful for risk stratification of VF episodes in patients with BrS. PMID- 28364269 TI - Systemic therapies and cognitive impairment for breast cancer: an overview of the current literature. AB - Both endocrine and chemotherapy can be utilized for breast cancer patients' management, in multiple setting (i.e., primary systemic therapy, adjuvant, metastatic treatment). Health-related quality of life in breast cancer survivors can be significantly influenced by cognitive impairment, which has been related in several previously reported experiences to systemic therapies administration. However, although the growing body of literature, the impact of both chemo- and endocrine therapy on cognitive function is currently unclear, due to many confounding factors (i.e., multiple therapies, duration of therapy, comorbidity, age). The aim of the present review is to present an overview of the current literature concerning the possible influence of endocrine and systemic therapy on breast cancer patients' cognitive impairment. PMID- 28364268 TI - The dopamine D2 receptor mediates approach-avoidance tendencies in smokers. AB - Dopamine D2 receptors (DRD2) have been strongly implicated in reward processing of natural stimuli and drugs. Using the approach-avoidance task (AAT), we recently demonstrated that smokers show an increased approach-bias toward smoking related cues but not toward naturally rewarding stimuli. Here, we examined the contribution of the DRD2 Taq1B polymorphism to smokers' and non-smokers' responsivity toward smoking versus naturally rewarding stimuli in the AAT. Smokers carrying the minor B1 allele of the DRD2 Taq1B polymorphism showed reduced approach behavior for food-related pictures compared to non-smokers with the same allele. In the group of smokers, a higher approach-bias toward smoking related compared to food-related pictures was found in carriers of the B1 allele. This pattern was not evident in smokers homozygous for the B2 allele. In addition, smokers with the B1 allele reported fewer attempts to quit smoking relative to smokers homozygous for the B2 allele. This is the first study demonstrating that behavioral shifts in response to smoking relative to natural rewards in smokers are mediated by the DRD2 Taq1B polymorphism. Our results indicate a reduced natural-reward brain reactivity in smokers with a genetically determined decrease in dopaminergic activity (i.e., reduction of DRD2 availability). It remains to be determined whether this pattern might be related to a different outcome after psychological cessation interventions, i.e., AAT modification paradigms, in smokers. PMID- 28364270 TI - SAFE trial: an ongoing randomized clinical study to assess the role of cardiotoxicity prevention in breast cancer patients treated with anthracyclines with or without trastuzumab. AB - Over the years, thanks to the addition of new generation systemic agents, as well as the use of more advanced and precise radiotherapy techniques, it was able to obtain a high curability rate for breast cancer. Anthracyclines play a key role in the treatment of breast disease, with a well-known benefit on disease-free survival of patients with positive nodal status. Trastuzumab have shown a significant outcome advantage after 1-year administration in case of HER2 positive disease. Unfortunately, significant increase in cardiotoxicity has been observed after anthracyclines and trastuzumab therapies. Even though the cardiology and oncology community strongly recommend a cardiotoxicity prevention strategy for this subset of patients, there is still no consensus on the optimal patient's approach. We aimed to review the published and ongoing researches on cardioprevention strategies and to present the SAFE trial (CT registry ID: NCT2236806; EudraCT number: 2015-000914-23). It is a randomized phase 3, four arm, single-blind, placebo-controlled study that aims to evaluate the effect of bisoprolol, ramipril or both drugs, compared to placebo, on subclinical heart damage evaluated by speckle tracking cardiac ultrasound in non-metastatic breast cancer patients. PMID- 28364272 TI - Vegetation Changes in a Native Forest Produced by Atta vollenweideri Forel 1893 (Hymenoptera: Formicidae) Nests. AB - Herbivory is an important factor to generate spatial mosaics with variations in a plant community composition and organization. The objective of this work was to determine the impact of Atta vollenweideri Forel 1893 nests on herbaceous and shrub vegetation in a degraded native forest of the Espinal ecoregion. The study was carried out in the Protected Area and Multiple Use Nature Reserve called Estancia "El Caraya" (Entre Rios, Argentina). Ten A. vollenweideri nests were selected by simple random sampling through internal roads, and two transects were drawn from the center of the nest (0 m) up to 60 m away in opposite directions. The line intercept method was used to quantify the percentage of vegetation cover of herbaceous and shrub species, while the floristic composition was estimated by the Canfield method. Afterwards, a nonparametric test between positions and a conglomerate analysis to evaluated distance were applied. Grass species, legumes, and sedges fell in the adjacent areas to nests, highlighting the bare soil at the crest and base of the nests. Fifteen plant species were identified, and two families correspond to monocotyledonous and dicotyledonous species. In conclusion, the nests of A. vollenweideri affect the community of herbaceous and shrub vegetation of the studied degraded native forest of the Espinal ecoregion since these ants perform a high selection of herbaceous species considered as pioneers of plant successions. PMID- 28364273 TI - Stereotactic MR-guided focused ultrasound deep brain lesioning: the resurrection of posteroventral pallidotomy and thalamotomy for Parkinson's disease? PMID- 28364271 TI - ALK rearrangement in specific subtypes of lung adenocarcinoma: immunophenotypic and morphological features. AB - Lung adenocarcinomas are characterized by a variety of genetic and epigenetic changes that lead to activation of specific signaling pathways. This allowed the classification of lung adenocarcinomas according to genetic alterations and the clinical development of novel anticancer agents that affect the activity of specific oncoproteins. In such a context, chromosomal rearrangements that cause constitutive activation of ALK gene define a category of lung adenocarcinomas that is amenable to targeted therapy with ALK inhibitors. Thus, a major issue of current research is to define the morphological and immunophenotypic features of lung ALK-rearranged adenocarcinomas to improve the selection of tumors suitable for molecular genotyping. ALK status was determined, by immunohistochemistry and fluorescence in situ hybridization, in 94 surgically resected lung adenocarcinomas and correlated with histomorphological parameters. Indeed, ALK rearrangement was observed in 10/94 (11%) lung adenocarcinomas and enriched in tumors with a predominant mucinous (46%; p < 0.05) and solid (29%; p < 0.05) pattern. By contrast, it was lacking or sporadically observed in lung adenocarcinomas with predominant acinar, papillary or lepidic pattern. Moreover, the presence of signet-ring cells was predominantly observed in ALK-rearranged tumors (47%; p < 0.05). These data suggest that ALK rearrangement is associated with specific and distinct clinical-pathological characters compared to other genotypes. Thus, the knowledge of these characteristics can improve the diagnostic accuracy and lead to a better understanding of the behavior of ALK rearranged NSCLC. PMID- 28364274 TI - Quorum quenching properties of Actinobacteria isolated from Malaysian tropical soils. AB - In this study, a total of 147 soil actinobacterial strains were screened for their ability to inhibit response of Chromobacterium violaceum CV026 to short chain N-acyl homoserine lactone (AHL) which is a quorum sensing molecule. Of these, three actinobacterial strains showed positive for violacein inhibition. We further tested these strains for the inhibition of Pseudomonas aeruginosa PAO1 quorum sensing-regulated phenotypes, namely, swarming and pyocyanin production. The three strains were found to inhibit at least one of the quorum sensing regulated phenotypes of PAO1. Phylogenetic analysis of the 16S rRNA gene sequences indicated that these strains belong to the genera Micromonospora, Rhodococcus and Streptomyces. This is the first report presenting quorum quenching activity by a species of the genus Micromonospora. Our data suggest that Actinobacteria may be a rich source of active compounds that can act against bacterial quorum sensing system. PMID- 28364275 TI - Magnetic resonance imaging in diffuse idiopathic skeletal hyperostosis: similarities to axial spondyloarthritis. AB - Diffuse idiopathic skeletal hyperostosis (DISH) is a non-inflammatory condition that involves calcification and ossification of the spinal ligaments and entheses. While, characteristic magnetic resonance imaging (MRI) lesions of the spine in patients with axial spondyloarthritis, another enthesitis-related disease, have been described and defined, there is a paucity of information regarding the MRI findings in DISH. The aim of this study was to describe the MRI findings of patients with DISH. We collected computed tomography studies with findings characteristic of DISH and that also had corresponding and concurrent MRI studies of the spine. For each patient, sagittal T1-weighted and STIR MRI sequences were evaluated for anterior/posterior vertebral corners of bone marrow edema (BME) and fat deposition. In total, we assessed 156 vertebral units in 10 patients that had both radiographic evidence of DISH and available MRI studies of the spine. Lesions consistent with BME corners were detected in five patients, and in three of them, three separate sites were involved, a finding that is suggestive of axial spondyloarthritis (SpA) according to the ASAS/OMERACT consensus statement. Fat deposition corners were detected in eight patients and in seven of them, several sites were involved. Spinal MRI lesions that are characteristic of axial SpA were commonly observed in a cohort of patients with DISH. This bears relevance to cases with diagnostic uncertainty and may imply overlapping pathogenetic mechanisms for new bone formation in both SpA and DISH. Further study is indicated to better characterize the similarities and differences between the MRI lesions of DISH and SpA. PMID- 28364276 TI - [Computer-assisted diagnosis of rare diseases]. AB - To establish a comprehensive diagnosis is by far the most challenging task in a physician's daily routine. Especially rare diseases place high demands on differential diagnosis, caused by the high number of around 8000 diseases and their clinical variability. No clinician can be aware of all the different entities and memorizing them all is impossible and inefficient. Specific diagnostic decision-supported systems provide better results than standard search engines in this context. The systems FindZebra, Phenomizer, Orphanet, and Isabel are presented here concisely with their advantages and limitations. An outlook is given to social media usage and big data technologies. Due to the high number of initial misdiagnoses and long periods of time until a confirmatory diagnosis is reached, these tools might be promising in practice to improve the diagnosis of rare diseases. PMID- 28364277 TI - Pediatric choledochal cysts: diagnosis and current management. AB - Choledochal cysts are rare congenital disorders first described by Vater and Ezler in 1723. Their exact etiology remains incompletely understood; however, an anomalous pancreaticobiliary union (APBDU) and subsequent reflux of biliary contents into the biliary tree are thought to play a role. Accordingly, APBDU associated choledochal cyst patients are significantly more likely to have evidence of hepatitis, cholangitis or pancreatitis and pathologically confirmed inflammation. In 1977, Todani and colleagues modified the original Alonso-Lej classification to include five types of CC. Type I and IV are the most common and most likely to be associated with malignancy. The majority of choledochal cysts are diagnosed in childhood. Clinical presentation varies and most often consists of nonspecific abdominal pain. Diagnosis is typically accomplished using multimodality imaging techniques including computed tomography, magnetic resonance imaging, ultrasound and MRCP. The use of diagnostic PTC and ERCP in CC has been largely replaced by MRCP. Appropriate management consists of prompt, complete cyst excision followed by restoration of biliary enteric continuity when necessary. Minimally invasive CC resection in the pediatric population has demonstrated acceptable outcomes. Prognosis is generally excellent; however, malignancy risk remains higher than the general population even after complete surgical excision. PMID- 28364278 TI - The development and function of dendritic cell populations and their regulation by miRNAs. AB - Dendritic cells (DCs) are important immune cells linking innate and adaptive immune responses. DCs encounter various self and non-self antigens present in the environment and induce different types of antigen specific adaptive immune responses. DCs can be classified into lymphoid tissue-resident DCs, migratory DCs, non-lymphoid resident DCs, and monocyte derived DCs (moDCs). Recent work has also established that DCs consist of developmentally and functionally distinct subsets that differentially regulate T lymphocyte function. The development of different DC subsets has been found to be regulated by a network of different cytokines and transcriptional factors. Moreover, the response of DC is tightly regulated to maintain the homeostasis of immune system. MicroRNAs (miRNAs) are an important class of cellular regulators that modulate gene expression and thereby influence cell fate and function. In the immune system, miRNAs act at checkpoints during hematopoietic development and cell subset differentiation, they modulate effector cell function, and are implicated in the maintenance of homeostasis. DCs are also regulated by miRNAs. In the past decade, much progress has been made to understand the role of miRNAs in regulating the development and function of DCs. In this review, we summarize the origin and distribution of different mouse DC subsets in both lymphoid and non-lymphoid tissues. The DC subsets identified in human are also described. Recent progress on the function of miRNAs in the development and activation of DCs and their functional relevance to autoimmune diseases are discussed. PMID- 28364281 TI - Dictionaries and distributions: Combining expert knowledge and large scale textual data content analysis : Distributed dictionary representation. AB - Theory-driven text analysis has made extensive use of psychological concept dictionaries, leading to a wide range of important results. These dictionaries have generally been applied through word count methods which have proven to be both simple and effective. In this paper, we introduce Distributed Dictionary Representations (DDR), a method that applies psychological dictionaries using semantic similarity rather than word counts. This allows for the measurement of the similarity between dictionaries and spans of text ranging from complete documents to individual words. We show how DDR enables dictionary authors to place greater emphasis on construct validity without sacrificing linguistic coverage. We further demonstrate the benefits of DDR on two real-world tasks and finally conduct an extensive study of the interaction between dictionary size and task performance. These studies allow us to examine how DDR and word count methods complement one another as tools for applying concept dictionaries and where each is best applied. Finally, we provide references to tools and resources to make this method both available and accessible to a broad psychological audience. PMID- 28364280 TI - Oncogenic miR-19a and miR-19b co-regulate tumor suppressor MTUS1 to promote cell proliferation and migration in lung cancer. AB - MTUS1 (microtubule-associated tumor suppressor 1) has been identified that can function as a tumor suppressor gene in many malignant tumors. However, the function and mechanisms underlying the regulation of MTUS1 are unclear. In the present study, we reported that miR-19a and miR-19b (miR-19a/b) promote proliferation and migration of lung cancer cells by targeting MTUS1. First, MTUS1 was proved to function as a tumor suppressor in lung cancer and was linked to cell proliferation and migration promotion. Second, an inverse correlation between miR-19a/b expression and MTUS1 mRNA/protein expression was noted in human lung cancer tissues. Third, MTUS1 was appraised as a direct target of miR-19a/b by bioinformatics analysis. Fourth, direct MTUS1 regulation by miR-19a/b in lung cancer cells was experimentally affirmed by cell transfection assay and luciferase reporter assay. Finally, miR-19a/b were shown to cooperatively repress MTUS1 expression and synergistically regulate MTUS1 expression to promote lung cancer cell proliferation and migration. In conclusion, our findings have provided the first clues regarding the roles of miR-19a/b, which appear to function as oncomirs in lung cancer by downregulating MTUS1. PMID- 28364282 TI - Manipulating perceptual parameters in a continuous performance task. AB - Sustained attention (SA) is among the most studied faculties of human cognition, and thought to be crucial for many aspects of behavior. Measuring SA often relies on performance on a continuous, low-demanding task. Such continuous performance tasks (CPTs) have many variations, and sustained attention is typically estimated based on variability in reaction times. While relying on reaction times may be useful in some cases, it can pose a challenge when working with clinical populations. To increase interpersonal variability in task parameters that do not rely on speed, researchers have increased demands for memory and response inhibition. These approaches, however, may be confounded when used to assess populations that suffer from multiple cognitive deficits. In the current study, we propose a new approach for increasing task variability by increasing the attentional demands. In order to do so, we created a new variation of a CPT - a masked version, where inattention is more likely to cause misidentifying a target. After establishing that masking indeed decreases target detection, we further investigated which task parameter may influence response biases. To do so, we contrasted two versions of the CPT with different target/distractor ratio. We then established how perceptual parameters can be controlled independently in a CPT. Following the experimental manipulations, we tested the MCCPT with aging controls and chronic stroke patients to assure the task can be used with target populations. The results confirm the MCCPT as a task providing high sensitivity without relying on reaction speed, and feasible for patients. PMID- 28364283 TI - Lisbon Emoji and Emoticon Database (LEED): Norms for emoji and emoticons in seven evaluative dimensions. AB - The use of emoticons and emoji is increasingly popular across a variety of new platforms of online communication. They have also become popular as stimulus materials in scientific research. However, the assumption that emoji/emoticon users' interpretations always correspond to the developers'/researchers' intended meanings might be misleading. This article presents subjective norms of emoji and emoticons provided by everyday users. The Lisbon Emoji and Emoticon Database (LEED) comprises 238 stimuli: 85 emoticons and 153 emoji (collected from iOS, Android, Facebook, and Emojipedia). The sample included 505 Portuguese participants recruited online. Each participant evaluated a random subset of 20 stimuli for seven dimensions: aesthetic appeal, familiarity, visual complexity, concreteness, valence, arousal, and meaningfulness. Participants were additionally asked to attribute a meaning to each stimulus. The norms obtained include quantitative descriptive results (means, standard deviations, and confidence intervals) and a meaning analysis for each stimulus. We also examined the correlations between the dimensions and tested for differences between emoticons and emoji, as well as between the two major operating systems-Android and iOS. The LEED constitutes a readily available normative database (available at www.osf.io/nua4x ) with potential applications to different research domains. PMID- 28364284 TI - Not every credible interval is credible: Evaluating robustness in the presence of contamination in Bayesian data analysis. AB - As Bayesian methods become more popular among behavioral scientists, they will inevitably be applied in situations that violate the assumptions underpinning typical models used to guide statistical inference. With this in mind, it is important to know something about how robust Bayesian methods are to the violation of those assumptions. In this paper, we focus on the problem of contaminated data (such as data with outliers or conflicts present), with specific application to the problem of estimating a credible interval for the population mean. We evaluate five Bayesian methods for constructing a credible interval, using toy examples to illustrate the qualitative behavior of different approaches in the presence of contaminants, and an extensive simulation study to quantify the robustness of each method. We find that the "default" normal model used in most Bayesian data analyses is not robust, and that approaches based on the Bayesian bootstrap are only robust in limited circumstances. A simple parametric model based on Tukey's "contaminated normal model" and a model based on the t-distribution were markedly more robust. However, the contaminated normal model had the added benefit of estimating which data points were discounted as outliers and which were not. PMID- 28364285 TI - Modeling when people quit: Bayesian censored geometric models with hierarchical and latent-mixture extensions. AB - People often interact with environments that can provide only a finite number of items as resources. Eventually a book contains no more chapters, there are no more albums available from a band, and every Pokemon has been caught. When interacting with these sorts of environments, people either actively choose to quit collecting new items, or they are forced to quit when the items are exhausted. Modeling the distribution of how many items people collect before they quit involves untangling these two possibilities, We propose that censored geometric models are a useful basic technique for modeling the quitting distribution, and, show how, by implementing these models in a hierarchical and latent-mixture framework through Bayesian methods, they can be extended to capture the additional features of specific situations. We demonstrate this approach by developing and testing a series of models in two case studies involving real-world data. One case study deals with people choosing jokes from a recommender system, and the other deals with people completing items in a personality survey. PMID- 28364279 TI - TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation: pro inflammatory response induced by their activation and their sensitization. AB - Cutaneous neurogenic inflammation (CNI) is inflammation that is induced (or enhanced) in the skin by the release of neuropeptides from sensory nerve endings. Clinical manifestations are mainly sensory and vascular disorders such as pruritus and erythema. Transient receptor potential vanilloid 1 and ankyrin 1 (TRPV1 and TRPA1, respectively) are non-selective cation channels known to specifically participate in pain and CNI. Both TRPV1 and TRPA1 are co-expressed in a large subset of sensory nerves, where they integrate numerous noxious stimuli. It is now clear that the expression of both channels also extends far beyond the sensory nerves in the skin, occuring also in keratinocytes, mast cells, dendritic cells, and endothelial cells. In these non-neuronal cells, TRPV1 and TRPA1 also act as nociceptive sensors and potentiate the inflammatory process. This review discusses the role of TRPV1 and TRPA1 in the modulation of inflammatory genes that leads to or maintains CNI in sensory neurons and non neuronal skin cells. In addition, this review provides a summary of current research on the intracellular sensitization pathways of both TRP channels by other endogenous inflammatory mediators that promote the self-maintenance of CNI. PMID- 28364286 TI - Adult height after spontaneous pubertal growth or GnRH analog treatment in girls with early puberty: a meta-analysis. AB - : Early puberty (EP) has been defined as the onset of puberty in the low-normal range; it may be a cause for concern regarding a possible impairment of adult height (AH). This paper meta-analysed data on AH after spontaneous growth or after gonadotropin-releasing hormone (GnRH) analog treatment in girls with EP. A computerized literature search was conducted from 1980 to June 30, 2016. Only published studies in English were considered. Eight papers were selected (483 cases). In untreated girls (n = 300), predicted adult height (PAH) at start of follow-up (-0.559 SDS (95%CI -1.110 to 0.001); P = 0.050) was close to mid parental height (MPH) (-0.557 SDS (95%CI -0.736 to -0.419); P < 0.0001) and AH ( 0.663 SDS (95%CI -0.803 to -0.524); P < 0.0001). In GnRH analog treated girls (n = 183), PAH before the start of treatment was slightly reduced (-0.939 SDS (95%CI -1.401 to -0.477; P < 0.0001) vs MPH (-0.678 SDS (95%CI -0.942 to -0.414); P < 0.0000), but AH (-0.604 SDS (95%CI -0.877 to -0.338); P < 0.0000) was close to MPH. CONCLUSION: Present meta-analysis indicates that girls with EP spontaneously reach their MPH and that GnRH analog treatment does not widely change growth outcome. Differences among the selected studies for definition of EP, inclusion criteria, treatment duration, age at discontinuation of therapy, definition of AH may affect results. What is Known: * Early puberty represents a main cause of consultation in paediatric endocrinology offices due to concerns of both practitioners and parents. * Treatment with GnRH analogs is sometimes attempted with the aim to improve adult height. What is New: * Untreated and GnRH analog treated girls with early puberty reached similar adult height. * Adult height was consistent with mid-parental height in both untreated and GnRH analog treated girls with early puberty. PMID- 28364290 TI - Axillary Lymphadenectomy in Sentinel Lymph Node-Positive Breast Cancer. PMID- 28364288 TI - Co-administration of proton pump inhibitors ameliorates nephrotoxicity in patients receiving chemotherapy with cisplatin and fluorouracil: a retrospective cohort study. AB - PURPOSE: The nephrotoxicity of cisplatin (CDDP) is its dose-limiting side effect, and is caused by renal accumulation of CDDP mainly via organic cation transporter 2 (OCT2). Because proton pump inhibitors (PPIs) are known to inhibit OCT2 activity, PPI might ameliorate CDDP-induced nephrotoxicity. In the present study, we retrospectively investigated the effect of co-administration of PPI on CDDP induced nephrotoxicity. METHODS: We analyzed the impact of PPI on the development of nephrotoxicity in 133 patients who received CDDP and fluorouracil (5-FU) therapy for the treatment of esophageal cancer or head and neck cancer. Nephrotoxicity that developed within 14 days following CDDP administration was evaluated in accordance with Common Terminology Criteria for Adverse Events ver. 4.0 for acute kidney injury. RESULTS: The rate of nephrotoxicity in patients with PPI (12%, n = 33) was significantly lower than that in patients without PPI (30%, n = 100). Severe nephrotoxicity greater than Grade 2 was not observed in patients with PPI, whereas the rate of hematological toxicity was comparable between patients with and without PPI. Kaplan-Meier analysis showed that the time to nephrotoxicity following CDDP administration was significantly prolonged in patients with PPI. Multivariate analysis revealed that co-administration of PPI with CDDP and 5-FU was an independent factor significantly contributing to the amelioration of nephrotoxicity (odds ratio 0.239, p = 0.033). CONCLUSIONS: These findings indicate that co-administration of clinical doses of PPI could ameliorate nephrotoxicity without exacerbation of hematological toxicity in patients receiving CDDP and 5-FU therapy. PMID- 28364291 TI - Invited comment to: Open retromuscular large mesh reconstruction of lumbar incisional hernias including the atrophic muscular area. Y. Renard, L. de Mestier, A. Cagniet et al. PMID- 28364287 TI - How phenotype guides management of non-conventional squamous cell carcinomas of the larynx? AB - Although the majority of laryngeal malignancies are the conventional squamous cell carcinomas (SCC), a wide variety of malignant epithelial tumors can affect the larynx. Current treatment guidelines are designed to guide clinicians in management of conventional laryngeal SCC. Less is known about the biological behavior and responsiveness to therapy and overall outcomes of other malignant epithelial lesions. Because a spectrum of disease biology is represented by these rare phenotypes, an understanding of the basic biology can help direct management to optimize clinical outcome in this group of patients. This review provides a critical analysis of literature relating to the diagnosis, management, and outcome of patients with non-conventional squamous malignant epithelial neoplasms of the larynx. Particular attention is paid to features which are at variance with the conventional SCC and how these impact on management of these rare tumors. PMID- 28364292 TI - Continuous subcutaneous apomorphine infusion in advanced Parkinson's disease: 10 year experience with 230 patients. AB - Continuous apomorphine infusion (APO) is one of the treatments available for advanced Parkinson disease (PD). Over 10 years, we have treated 230 patients with APO. Mean age was 66.8 and average evolution time at APO onset was 13.0 years. Mean duration of the treatment was 26.3 months. As of June 2016, 93 remained on the medication (active group), while 137 had stopped. This active group had mean age 67.3 at recruitment and mean evolution 14.2 years. The main indication for APO was lack of deep brain stimulation criteria (DBS). Twelve patients were on waiting list for DBS. Average time since APO onset was 40.0 months. In the active group, APO decreased off-state in 4 h and allowed reducing levodopa and dopamine agonists. Dyskinesia and balance did not worsen. Cognitive decline did not change within the first 15 months. Hallucinations were the same within the first 39 months. The presence of subcutaneous nodules was the most frequent adverse event in this group. The main reason for discontinuation was side effects, being psychosis the most common. Within the first year, 82 patients stopped APO. Eighteen of these patients eventually got DBS. APO is a good option for advanced PD, since it permits a significant reduction in off-time and other antiparkinsonian drugs. This effect is sustained over time. We have treated 132 patients for over a year. Dyskinesia seems not to worsen. Combining APO with DBS simultaneously or alternatively provides good results. PMID- 28364293 TI - Parkinsonism in a patient with valosin-containing protein gene mutation showing: a case report. PMID- 28364295 TI - Objective assessment of visual pursuit in patients with disorders of consciousness: an exploratory study. AB - Visual pursuit is a key marker of residual consciousness in patients with disorders of consciousness (DOC). Currently, its assessment relies on subjective clinical decisions. In this study, we explore the variability of such clinical assessments, and present an easy-to-use device composed of cameras and video processing algorithms that could help the clinician to improve the detection of visual pursuit in a clinical context. Visual pursuit was assessed by an experienced research neuropsychologist on 31 patients with DOC and on 23 healthy subjects, while the device was used to simultaneously record videos of both one eye and the mirror. These videos were then scored by three researchers: the experienced research neuropsychologist who did the clinical assessment, another experienced research neuropsychologist, and a neurologist. For each video, a consensus was decided between the three persons, and used as the gold standard of the presence or absence of visual pursuit. Almost 10% of the patients were misclassified at the bedside according to their consensus. An automatic classifier analyzed eye and mirror trajectories, and was able to identify patients and healthy subjects with visual pursuit, in total agreement with the consensus on video. In conclusion, our device can be used easily in patients with DOC while respecting the current guidelines of visual pursuit assessment. Our results suggest that our material and our classification method can identify patients with visual pursuit, as well as the three researchers based on video recordings can. PMID- 28364298 TI - Prevalence of Parkinson symptoms in patients with different peripheral vestibular disorders. PMID- 28364297 TI - Varicella zoster virus encephalitis in a patient with a solid carcinoma: a case report. PMID- 28364296 TI - Juvenile-onset myasthenia gravis: autoantibody status, clinical characteristics and genetic polymorphisms. AB - Myasthenia gravis (MG) is an autoimmune disorder mediated by antibodies against proteins at the neuromuscular junction. Juvenile-onset MG (JMG) has been reported to have special characteristics. It is still unclear whether there are any pathogenic and genetic differences between juvenile and adult MG. In this study, we evaluated the clinical characteristics, autoantibody status (antibodies against AChR, MuSK, LRP4, titin and RyR) and genetic susceptibility (CHRNA1, CTLA4 and AIRE) in 114 Chinese JMG patients, and compared with 207 young adult MG patients (onset age 18-40 years). JMG patients were classified into two subgroups: the very early onset group (<8 years) and puberty onset group (8-18 years). The very early onset MG patients had a higher proportion of ocular MG and thymus hyperplasia, compared with puberty onset MG and young adult MG (P < 0.05). AChR antibodies were found in majority of JMG patients and were associated with more severe disease (P < 0.05), while other antibodies were rare in JMG. Moreover, the very early onset MG had a more prominent genetic predisposition than puberty and adult MG, affecting the susceptible genes CHRNA1 and CTLA4. JMG has the same pathogenic background as adult MG, but has typical clinical features and a prominent genetic predisposition in very early onset patients (<8 years). Specific therapeutic considerations are needed. PMID- 28364299 TI - Life Satisfaction and Psychological Status of Mothers with Disabled Children: A Descriptive Study. AB - The purpose of this study is to determine the life satisfaction, general health conditions, and depression levels of mothers with disabled children and the problems they experienced. This descriptive study was conducted between 1 and 30 December 2014 in a rehabilitation center that renders services for totally 254 physically and mentally-disabled children in Turkey. 184 mothers participated in the study. The data were collected by using an information form, the life satisfaction scale, the general health questionnaire, and the Beck depression inventory. General Health Questionnaire scores of the mothers who had another disabled child and Beck Depression Inventory scores of the working mothers were significantly high. In addition, a significant difference was found between the scores of Life Satisfaction Scale, General Health Questionnaire, and Beck Depression Inventory by mothers who had difficulties regarding care of their children, were worried for their children, and experienced uncertainty with regard to the future. PMID- 28364294 TI - Intermediate Charcot-Marie-Tooth disease: an electrophysiological reappraisal and systematic review. AB - Charcot-Marie-Tooth disease (CMT) is the most frequent form of inherited neuropathy with great variety of phenotypes, inheritance patterns, and causative genes. According to median motor nerve conduction velocity (MNCV), CMT is divided into demyelinating (CMT1) with MNCV below 38 m/s, axonal (CMT2) with MNCV above 38 m/s, and intermediate CMT with MNCV between 25 and 45 m/s. In each category, transmission may be autosomal dominant, autosomal recessive, or X-linked. The nosology of intermediate CMT is controversial because of concerns about electrophysiological delimitation. A systematic computer-based literature search was conducted on PubMed, using the following MeSH: (1) intermediate Charcot-Marie Tooth; (2) X-linked intermediate Charcot-Marie-Tooth; and (3) X-linked Charcot Marie-Tooth and electrophysiology. We retrieved 225 articles reporting X-linked CMT or intermediate CMT with electrophysiological information. After eligibility, 156 papers were used for this review. In assessing median MNCV, compound muscle action potential (CMAP) amplitudes were taken into account. In cases with attenuated CMAP and wherever possible, proximal median MNCV was used for accurate definition of conduction slowing in the intermediate range. In the vast majority of males with X-linked CMT associated with GJB1 mutation (CMTX1), median MNCV was intermediate. CMT associated with DRP2 mutation is another well-documented X linked intermediate disorder. Autosomal dominant intermediate CMT (DI-CMT) encompasses 11 different types; six of them with assigned phenotype MIM number and the remaining five being unnumbered. Based on available electrophysiological information, we wonder if DI-CMTA should be reclassified within CMT2. Autosomal recessive intermediate CMT (RI-CMT) covers four numbered MIM phenotypes though, in accordance with reported electrophysiology, two of them (RI-CMTB and RI-CMTD) should probably be reclassified within AR-CMT2. We conclude that intermediate CMT is a complex inherited syndrome, whose characterization requires a specific electrophysiological protocol comprising evaluation of upper limb proximal nerve trunks when distal CMAP amplitudes are reduced, and that an updated version of MIM phenotype numbering is needed. PMID- 28364301 TI - Relying on objective data: the glass half empty of high-flow nasal cannula in bronchiolitis. PMID- 28364300 TI - Providers' Behaviors and Beliefs on Prescribing Antipsychotic Medication to Children: A Qualitative Study. AB - Fragmentation in behavioral and mental health care to children has resulted in suboptimal care and high rates of psychotropic medication use, especially antipsychotic medications (APM). A qualitative study, based on the Theory of Planned Behavior (TPB), aimed to better understand prescribing practices, barriers to optimal treatment, and potential interventions to safeguard the use of APM for children in Kentucky. The most common barrier to optimal care was access to mental health specialists. Social norms and pressure from families contribute to increased medication use. We identify promising interventions to safeguard the use of APM through the lens of the TPB. PMID- 28364302 TI - Beware the siren's song of novel endotracheal tube designs. PMID- 28364305 TI - [International guidelines from the Surviving Sepsis Campaign : 2016 update]. AB - An update to the international guidelines for sepsis therapy was published by the Surviving Sepsis Campaign (SSC) in March 2017. The guidelines have been completely restructured and comprehensively deal with new evidence. The guidelines discuss sepsis-specific therapeutic measures and provide detailed recommendations on general intensive care measures for sepsis. This article summarizes the most important amendments and suggests delving deeper into the guidelines. PMID- 28364303 TI - Acute kidney injury in sepsis. AB - Acute kidney injury (AKI) and sepsis carry consensus definitions. The simultaneous presence of both identifies septic AKI. Septic AKI is the most common AKI syndrome in ICU and accounts for approximately half of all such AKI. Its pathophysiology remains poorly understood, but animal models and lack of histological changes suggest that, at least initially, septic AKI may be a functional phenomenon with combined microvascular shunting and tubular cell stress. The diagnosis remains based on clinical assessment and measurement of urinary output and serum creatinine. However, multiple biomarkers and especially cell cycle arrest biomarkers are gaining acceptance. Prevention of septic AKI remains based on the treatment of sepsis and on early resuscitation. Such resuscitation relies on the judicious use of both fluids and vasoactive drugs. In particular, there is strong evidence that starch-containing fluids are nephrotoxic and decrease renal function and suggestive evidence that chloride rich fluid may also adversely affect renal function. Vasoactive drugs have variable effects on renal function in septic AKI. At this time, norepinephrine is the dominant agent, but vasopressin may also have a role. Despite supportive therapies, renal function may be temporarily or completely lost. In such patients, renal replacement therapy (RRT) becomes necessary. The optimal intensity of this therapy has been established, while the timing of when to commence RRT is now a focus of investigation. If sepsis resolves, the majority of patients recover renal function. Yet, even a single episode of septic AKI is associated with increased subsequent risk of chronic kidney disease. PMID- 28364304 TI - Inter-Subject Variability in OCT1 Activity in 27 Batches of Cryopreserved Human Hepatocytes and Association with OCT1 mRNA Expression and Genotype. AB - PURPOSE: OCT1/3 (Organic Cation Transporter-1 and -3; SLC22A1/3) are transmembrane proteins localized at the basolateral membrane of hepatocytes. They mediate the uptake of cationic endogenous compounds and/or xenobiotics. The present study was set up to verify whether the previously observed variability in OCT activity in hepatocytes may be explained by inter-individual differences in OCT1/3 mRNA levels or OCT1 genotype. METHODS: Twenty-seven batches of cryopreserved human hepatocytes (male and female, age 24-88 y) were characterized for OCT activity, normalized OCT1/3 mRNA expression, and OCT1 genetic mutation. ASP+ (4-[4-(dimethylamino)styryl]-N-methylpyridinium iodide) was used as probe substrate. RESULTS: ASP+ uptake ranged between 75 +/- 61 and 2531 +/- 202 pmol/(min * million cells). The relative OCT1 and OCT3 mRNA expression ranged between 0.007-0.46 and 0.0002-0.005, respectively. The presence of one or two nonfunctional SLC22A1 alleles was observed in 13 batches and these exhibited significant (p = 0.04) association with OCT1 and OCT3 mRNA expression. However, direct association between genotype and OCT activity could not be established. CONCLUSION: mRNA levels and genotype of OCT only partially explain inter individual variability in OCT-mediated transport. Our findings illustrate the necessity of in vitro transporter activity profiling for better understanding of inter-individual drug disposition behavior. PMID- 28364307 TI - A density functional theory study on the interactions between dibenzothiophene and tetrafluoroborate-based ionic liquids. AB - The interactions between dibenzothiophene (DBT) and N-butyl-N-methylimidazolium tetrafluoroborate ([BMIM][BF4]), N-butyl-N-methylmorpholinium tetrafluoroborate ([Bmmorpholinium][BF4]), N-butyl-N-methylpiperdinium tetrafluoroborate ([BMPiper][BF4]), N-butyl-N-methylpyrrolidinium tetrafluoroborate ([BMPyrro][BF4]), and N-butylpyridinium tetrafluoroborate ([BPY][BF4]) were investigated using density functional theory approach. Geometric, electron, and topological properties were analyzed using natural bond orbital, atoms in molecules theory, and noncovalent interaction methods in order to understand intermolecular interactions between DBT and ionic liquids. The result shows that hydrogen bond and van der Waals interactions are widespread in all the ionic liquids-DBT systems. Ion-pi interactions between DBT and cation or anion are also observed, while pi+-pi interactions are only found in the [BMIM][BF4]-DBT and [BPY][BF4]-DBT systems. The order of interaction energy is [BPY][BF4]-DBT > [BMIM][BF4]-DBT >> [BMPiper][BF4]-DBT > [BMPyrro][BF4]-DBT > [BMmorpholinum][BF4] DBT. The energies between DBT and the two ionic liquids containing aromatic cations are significantly higher. PMID- 28364306 TI - [Antipyretics in intensive care patients]. AB - BACKGROUND: Antipyretics are among the most widely prescribed drugs in German hospitals. Despite this widespread use, their role for treatment of critically ill patients still remains unclear. In particular, the questionable positive effects of reducing fever are discussed. OBJECTIVES: In this review we aimed to summarize and discuss current study results covering the use of antipyretics in critically ill patients. Suspected effects with regard to fever reduction and lethality should be considered. MATERIALS AND METHODS: A selective literature search was carried out in the PubMed database. We reviewed the bibliographies of all work considered relevant. RESULTS: There are only a few studies on the use of antipyretics in intensive care patients, which are difficult to compare systematically due to different designs, protocols and endpoints. All in all, the decrease in temperature was very low (0.3 degrees C) and showed even adverse effects on 28-days mortality in sepsis. In patients with sepsis and ASS medication, a decreased mortality has been shown in retrospective analysis. CONCLUSIONS: The benefit of fever control using antipyretics in intensive care patients with regard to endpoints like lethality remains unclear. Randomized controlled trials with suitable protocols and endpoints are needed to provide a solid base for development of guidelines. PMID- 28364308 TI - DFT study of isomers of the ruthenium dihydride complex RuH2(CO)2(AsMe2Ph)2. AB - A density functional theory (DFT) study of cct-As, ccc, and cct-CO isomers of the ruthenium dihydride complex RuH2(CO)2(AsMe2Ph)2 is reported (see Scheme for the labeling isomer 34 structures of RuH2(CO)2(AsMe2Ph)2). Complex geometries and relative energies of different isomers have been calculated with both B3LYP and M06-2X functionals. The results show that the B3LYP calculated Boltzmann populations of cct-As, ccc, and cct-CO isomers are 65.5, 34.2, and 0.3%, respectively. These are in better agreement with the experimental data than those calculated at the M06-2X level. However, the calculations of 1H NMR chemical shifts were found to be better described with M06-2X than with B3LYP or with HF level of theories. In addition, a transition state between the two most stable isomers was determined through DFT/(B3LYP or M06-2X) calculations. Graphical Abstract Scheme: Labeling structure of RuH2(CO)2(AsMe2Ph)2. PMID- 28364309 TI - Modeling zigzag CNT: dependence of structural and electronic properties on length, and application to encapsulation of HCN and C2H2. AB - Density functional theory (B3LYP, B3LYP-D2 and wB97XD functionals) was used in finite models of zigzag carbon nanotubes (CNT), (n,0)*k with n = 6-9 and k = 2-4, to systematically investigate the effects of size on their structural and electronic properties. We found that the ratio between the length (L t) and the diameter (d t) of the pristine CNT has to be larger than 2, i.e., L t/d t > 2, in order to provide the observed experimental trends of C=C bond distances, as well as to maintain the atomic charges nearly constant and zero around the center of the tube. Therefore, the concepts of useful length and volume were developed and tested for the encapsulation process of HCN and C2H2 into CNTs. The energies involved in these processes, as well as the changes in molecular structure and electronic properties of the dopants and the CNTs are discussed and rationalized by the amount of charge transferred between dopant and CNT. Graphical Abstract Illustration of zigzag CNT length and diameter ratio in order to represent C=C bond experimental trend. PMID- 28364310 TI - Rate constant calculations of the C2 + HCN -> CCCN+H addition via the Master Equation. AB - The addition of C2 to HCN is of relevant interest in astrochemistry. We studied the pathways of this addition to produce CCCN and estimated its reaction rate using the Master Equation in the circumstellar environment. From the results of this study, it was possible to show that a different pathway in the Surface Potential Energy-PES can also be investigated. In a circumstellar envelop environment, with temperatures varying between 1000 K and 2000 K, the abundances of these species are favorable to this kind of addition, and our branching ratio for the rate constant showed that the new pathway is more favorable in comparison with other possibilities for this range of temperatures in this environment, and must be taken into account in any computation of the rate constant. Graphical Abstract Branching ratios of pathways involved in the C2 + HCN -> CCCN+H addition, at a temperature range of 1000-2000 K. PMID- 28364311 TI - Erratum to: Sarcopenia and sarcopenic obesity in comparison: prevalence, metabolic profile, and key differences. A cross-sectional study in Italian hospitalized elderly. PMID- 28364312 TI - Physical and social characteristics and support needs of adult female childhood cancer survivors who underwent hormone replacement therapy. AB - BACKGROUND: Female childhood cancer survivors who develop gonadal dysfunction require female hormone replacement therapy (HRT) from puberty until menopause. However, the support provided in such cases has not been studied. We investigated the physical and social characteristics and support needs of adult female childhood cancer survivors who underwent HRT. METHODS: Forty-nine adult female childhood cancer survivors completed self-administered questionnaires. We compared the clinical characteristics, health status, and social conditions between a group that underwent HRT and a group that did not, and we surveyed support needs of the group that underwent HRT. RESULTS: The median age of the subjects was 25.0 years (range 20-41). Twenty subjects (40.8%) underwent HRT. A significantly high number of those who underwent HRT also underwent radiation therapy (p < 0.01) and hematopoietic stem cell transplantation (p < 0.001), and none of them had a history of pregnancy or childbirth (p < 0.05). There were no significant differences in physical symptoms and social characteristics between the groups. Those who experienced anxiety regarding fertility required information about HRT, a platform to share their concerns, and psychological support and cooperation among healthcare providers. CONCLUSIONS: Although the subjects of this survey exhibited good social adjustment regardless of whether or not they underwent HRT, they were anxious about fertility. It is important to understand the concerns and anxieties unique to female childhood cancer survivors and to enhance psychological support in addition to providing educational support so that HRT can be administered. PMID- 28364313 TI - Dominant lymph drainage patterns in the occipital and parietal regions: evaluation of lymph nodes in patients with skin cancer of the head. AB - BACKGROUND: The purpose of this study was to evaluate the superficial lymph drainage patterns of primary skin cancers of the head arising from the occipital or parietal region. METHODS: The dominant patterns of lymph drainage were retrospectively reviewed in eight patients aged 36-85 years with skin cancers in the occipital or parietal region in whom sentinel lymph node biopsy or lymph node dissection had been performed at Hokkaido University Hospital between January 1981 and December 2015. RESULTS: Lymph drainage was mainly to the occipital (6/8, 75%), level II (5/8, 63%), and level V lymph nodes (5/8, 63%). Of the six patients with drainage to the occipital lymph nodes, four (67%) also had drainage to level V nodes. CONCLUSION: The dominant lymph drainage pattern in patients with skin cancer arising from the occipital or parietal region was to the occipital, level II, and level V lymph nodes. Further, lymph tended to drain directly from the occipital region to the level V lymph nodes. PMID- 28364315 TI - Mucosal healing of Crohn's disease in a patient with concurrent systemic lupus erythematosus using infliximab. AB - We describe a patient with Crohn's disease (CD) concurrent with systemic lupus erythematosus (SLE). Continuous prednisolone and cyclosporine treatment resulted in no recurrent symptoms. However, diarrhea, vomiting, and fever occurred for approximately 3 months. A colonoscopy was then performed, which showed a discontinuous cobblestone appearance and longitudinal ulcers extending from the sigmoid colon to the descending colon and distal ileum. A biopsy revealed a noncaseating granulomatous lesion in the colonic mucosa. These findings led to a diagnosis of CD concurrent with SLE. We first attempted treatment with a full elemental diet, mesalazine, and azathioprine, in that order. However, as there was no improvement in inflammation, we started infliximab, a tumor necrosis factor-alpha inhibitor. Transanal double-balloon enteroscopy performed 4 months after starting infliximab showed mucosal healing, suggesting that infliximab was effective. There are few reports of treating patients with CD concurrent with SLE using a tumor necrosis factor-alpha inhibitor. We report our experience with a patient who had mucosal healing with infliximab and review the literature. PMID- 28364314 TI - Endoscopic tissue shielding for esophageal perforation caused by endoscopic resection. AB - In Japan, endoscopic resection (ER), including endoscopic mucosal resection and endoscopic submucosal dissection, is widely performed for superficial esophageal neoplasms and accepted as a minimally invasive treatment. Perforation is a major complication of ER, with an incidence rate of 1-5%. While conservative treatment has become a more common choice, surgical treatment of perforations is sometimes required, especially for large perforations. Of 1408 cases of esophageal ER that have been performed, 17 cases of perforation occurred at the Cancer Institute Hospital between 2005 and 2016. Most cases were treated with endoscopic clipping and managed conservatively; however, 2 cases were not eligible for endoscopic closure. We report two cases of large perforations of 15 and 20 mm, respectively. Both cases were treated conservatively with endoscopic tissue shielding, in which the perforations were covered with a large polyglycolic acid (PGA) sheet that was affixed with fibrin glue. Neither of the cases required open surgery. In both cases, feeding started three weeks after the procedure (19 and 21 days), and both were discharged within a month (29 and 30 days). In conclusion, tissue shielding with PGA sheets in large perforations after esophageal ER is a good choice to safely proceed with conservative treatment. On the other hand, endoscopic clipping is effective and reasonable for small perforations. PMID- 28364317 TI - Herbal Use and Medical Pluralism Among Latinos in Southern California. AB - Complementary and alternative medicine (CAM) is often used alongside conventional medical care, yet few patients disclose CAM use to medical doctors. Our objectives were to (1) assess Latino herbal use, (2) explore the most commonly used herbs for common ailments, and (3) examine patients' disclosure of herb use to their physicians. Self-administered questionnaires were collected from 318 Latino patients seeking treatment at community health centers. Descriptive statistical analysis was conducted to determine the frequency of stated objectives among the participants. Fisher's exact test was used to compare differences among CAM users and non-users. Most respondents (90%) reported using herbs. Less than a third (31%) of those herb users felt comfortable speaking English to their physician. A majority (74.8%) of the respondents utilizing herbs reported never disclosing their herbal use to their healthcare providers, and of those that did, majority (63%) were under the age of 36 years. Of those that disclosed their herbal use, only 31% perceived receiving a positive reaction about herbal use from their providers. Chamomile, cinnamon, Aloe vera, spearmint, and key lime were the top used herbs in this population. Herbal use disclosure reflects a greater sense of trust and communication between patient and provider. Therefore, a need exists to increase provider competency for patients using herbs in order to improve consistency of care and facilitate healthy patients and communities, especially among Spanish-speaking Latinos in Southern California. PMID- 28364316 TI - A case of annular pancreas with Wirsung's duct encircling the duodenum: embryological hypothesis based on cholangiopancreatographic and immunohistochemical findings. AB - We present a resected case of annular pancreas in which Wirsung's duct encircled the duodenum and continued directly to the main pancreatic duct in the body and tail. Furthermore, Wirsung's duct coursed along the right side of the lower bile duct near the major duodenal papilla. Histologically, the islets of Langerhans in the annular pancreas were irregular in shape and were characterized by a striking abundance of pancreatic polypeptide (PP)-positive cells. The PP-rich area that encircled the duodenum was fused with the PP-poor area in the head of the pancreas. The following embryological hypothesis is proposed. The tip of the ventral pancreatic anlage adhered to the duodenal wall and stretched to form a ring during clockwise rotation. The rotation was incomplete, and the pancreatic duct did not cross over the lower bile duct. Since there was adequate ventral anlage in the lower part of the head of the pancreas, fusion between the ducts of the ventral and dorsal anlagen did not occur. The tip of the ventral anlage overgrew and adhered to the dorsal anlage, and the annular duct fused with the main duct of the dorsal anlage. PMID- 28364318 TI - Reassessing the Ecology of Medical Care in Japan. AB - Studies on ecology of medical care can provide valuable information on how people seek healthcare in a specific geographic area. The objective of this study was to update a 2003 report on the ecology of medical care in Japan, identifying relevant changes in healthcare patterns. We collected information based on a prospective health diary recorded for a month in 2013 (n = 4548; 3787 adults and 797 children) using a population-weighted random sample from a nationally representative panel. We compared our overall and stratified findings with a similar study conducted in 2003. During a one-month period, per 1000 adults and children living in Japan, we estimated that 794 report at least one symptom, 447 use an over-the-counter (OTC) drug, 265 visit a physician's office, 117 seek help from a professional provider of complementary or alternative medicine (CAM), 70 visit a hospital outpatient clinic (60 community-based and 10 university-based), 6 are hospitalized, and 4 visit a hospital emergency department. After adjusting for demographic variables, we found that healthcare seeking behaviors were influenced by age, gender and area of living. Compared with the 2003 study, participants in this study had fewer symptoms, fewer physician and emergency room visits, and less OTC use, but reported higher frequency of CAM use (p < .01 for all). Compared with 2003, reported symptoms, physician visits and OTC use has decreased, while CAM use has increased. Our findings may be useful to policymakers in Japan in a context where healthcare expenditure and a rapidly aging population are two challenging issues. PMID- 28364319 TI - Purchases Made with a Fruit and Vegetable Voucher in a Rural Mexican-Heritage Community. AB - Recent recommendations for US food assistance programs are intended to ensure foods provided through these programs help households consume a varied, healthful diet. From a policy viewpoint, it is important to examine the impact of economic incentives to purchase healthy foods across subpopulations, particularly low income Latinos, who comprise 40% of the WIC program nationwide. Our aim was to determine how rural, Mexican-heritage households (N = 227) residing in California's Central Valley distributed fruit and vegetable (F/V) voucher spending among F/V subgroups and specific items over a 1-year period. Households contained at least one child who was between 3 and 8 years old at baseline and had a parent of Mexican-heritage. F/V voucher purchase data were collected via grocery store scanners. Expenditure and frequency shares of subgroups and individual items were analyzed to determine purchasing habits. Fruits were the most commonly purchased subgroup, representing 55% of spending and 45% of frequency. Households allocated low percentages of their voucher to dark green and red/orange vegetables-7 and 9% respectively. Approximately 20% of purchases were good potassium sources and 30% of purchases were good fiber sources. Many of the most frequently purchased items were of cultural significance (tomatillo, chayote, chili/jalapeno pepper, and Mexican squash). This study suggests that economic incentives can contribute important nutrients to participants' diets and targeted vouchers provided by food assistance programs should continue to include culturally important foods and be aware of the cultural values of their participants. PMID- 28364320 TI - Repetitive atrial activation during ongoing atrial fibrillation-comparison using different mapping algorithms: preliminary findings. AB - PURPOSE: Targeting repetitive sources identified during atrial fibrillation (focal impulse and rotor modulation, FIRM) has been used as an ablation strategy using specific mapping tools. Aim of this study was to evaluate FIRM mapped rotors with a new multipolar mapping algorithm. METHODS: Patients with persistent atrial fibrillation undergoing FIRM ablation were included. Mapping of left atrial rotors was performed with a 64-pole basket catheter in conjunction with a specialized phase mapping algorithm. Subsequently, raw signals were analyzed by a novel mapping system (CARTOFINDERTM). Comparison of FIRM identified sources with areas of repetitive activation analyzed by CARTOFINDERTM was performed. RESULTS: Nine patients were included (5 redo procedures; male n = 6; 66.5 +/- 8.6 years) and 28 left atrial rotors were compared with the findings of the novel mapping system. CARTOFINDERTM identified repetitive activation patterns in 6 mapping sequences at remote sites (2 rotational patterns, 4 linear activation patterns). CONCLUSIONS: In this comparative preliminary study, two different mapping technologies to detect repetitive atrial activation during ongoing AF were used. Whereas rotational activation was documented using FIRM mapping no corresponding repetitive activation patterns near sites of FIRM-mapped rotor cores were identified using the novel mapping technology even though using the same electrogram characteristics and mapping basket position. PMID- 28364321 TI - Satisfactory outcomes following combined unicompartmental knee replacement and anterior cruciate ligament reconstruction. AB - PURPOSE: There exist limited options for treatment of patients with combined medial compartment arthritis and anterior cruciate ligament (ACL) deficiency. Ideal treatment is one that offers lasting relief of symptoms not compromising any future surgery. Unicompartmental knee replacement has shown consistently good results in the relatively young and active population, but there is a high reported incidence of failure up to 20%, if performed in ACL-deficient knees. One of the recognized treatment modality is combined ACL reconstruction and unicompartmental arthroplasty. A systematic review was conducted looking at the demographics, techniques, complications and outcome of combined ACL reconstruction with unicompartmental knee arthroplasty. METHODS: A systematic literature search within the online Medline, PubMed Database, EMBASE, Web of Science, Cochrane and Google Scholar was carried out until October 2016 to identify relevant articles. A study was defined eligible if it met the following inclusion criteria: the surgical procedure combined unicompartmental knee arthroplasty and anterior cruciate ligament reconstruction; patient's clinical and/or functional outcomes were reported; any complications intra-operatively and post-operatively were reported; and the full-text articles, written in English, German, Italian, Dutch or Spanish, were available. Quality and risk of bias assessments were done using standardized criteria set. RESULTS: A total of 8 studies met the inclusion criteria encompassing 186 patients who were treated with simultaneous ACL reconstruction and unicompartmental knee arthroplasty. The mean age was 50.5 years (range from 44 to 56) with a mean follow-up of 37.6 months (range from 24 to 60). There was an improvement in mean Oxford Score from 27.5 to 36.8. Complications reported included tibial inlay dislocation (n = 3), conversion to a total knee arthroplasty (n = 1), infection requiring two-stage revision (n = 2), deep-vein thrombosis (n = 1), stiffness requiring manipulation under anaesthesia (n = 1), retropatellar pain requiring arthroscopic adhesiolysis (n = 1). CONCLUSION: Unicompartmental knee arthroplasty combined with ACL reconstruction can be a valid treatment option for selected patients, with combined medial unicompartmental knee osteoarthritis and ACL deficiency. LEVEL OF EVIDENCE: Systematic Review of Level IV Studies, Level IV. PMID- 28364322 TI - Arthroscopic management of lesser tuberosity osteochondroma causing impingement and subscapularis tear of the shoulder. AB - Although the proximal humerus is a common site of osteochondroma, osteochondroma arising from the lesser tuberosity of the proximal humerus is rare. Because of the anatomy of the shoulder, mechanical impingement can occur via direct contact of the protruding lesser tuberosity against the glenoid rim or coracoid. In younger patients, this may cause isolated tearing of the subscapularis. In this study, is presented a rare case of osteochondroma on the lesser tuberosity that caused a subscapularis tear after shoulder impingement in a 34-year-old male. This case was managed using an arthroscopic approach. One year after the surgery, the patient had recovered a normal range of motion, with the resolution of impingement symptoms and the tearing of the subscapularis. Level of evidence IV. PMID- 28364323 TI - Circulating and renal expression of HLA-G prevented chronic renal allograft dysfunction in Japanese recipients. AB - BACKGROUND: Although the risk of acute rejection has been studied in renal transplanted patients, there is little data about the long-term renal survival effects of non-classical human leukocyte antigen class I (HLA-G) in Japanese patients. METHOD: We investigated the changes in the estimated glomerular filtration rate (eGFR) for Japanese, and factors affecting the eGFR in 141 adult Japanese subjects whose allografts had survived for at least 1 year. Clinical background data, gender, HLA matching status, the total ischemic time, ABO incompatibility, immunosuppressive therapy, and the serum soluble(s) HLA-G5 level were examined. In addition, renal biopsy specimens from 32 cases, which were obtained before, or 2-4 weeks or one year after the transplant were also evaluated for HLA-G1/5 expression using monoclonal anti-HLA-G antibodies (clone 87G or 4H84). RESULTS: The rates of change per year in the median eGFR (DeltaeGFR) and sHLA-G5 were -1.5 ml/min/1.73 m2/year and 11.8 ng/ml, respectively. A positive correlation was detected between the DeltaeGFR and sHLA G5 (r = 0.188, p = 0.025). In multivariate regression analysis, sHLA-G5 and HLA matching were significant predictors of an improvement in eGFR (beta for sHLA-G: 0.374, p = 0.009; beta for mismatching: -1.135, p = 0.045). The renal tubular epithelial cells (TEC) in 11 cases showed a perinuclear HLA-G1/5 expression after renal transplantation. The renal HLA-G1/5-positive patients displayed much better DeltaeGFR (p < 0.05). In conclusion, the sHLA-G5 level and HLA matching status are independent predictors of renal allograft function, as determined by the DeltaeGFR, in Japanese patients. HLA-G1/5 was also detected on TEC in the patients with favorable renal function. PMID- 28364324 TI - Primary hyperparathyroidism: insights from the Indian PHPT registry. AB - The presentation of primary hyperparathyroidism (PHPT) is variable throughout the world. The present study explored retrospective data submitted to the Indian PHPT registry ( http://www.indianphptregistry.com ) between July 2005 and June 2015 from 5 centres covering four different geographical regions. The clinical, biochemical, radiological and histopathological characteristics of PHPT patients across India were analysed for similarity and variability across the centres. A total of 464 subjects (137 men and 327 women) with histopathologically proven PHPT were analysed. The mean age was 41 +/- 14 years with a female:male ratio of 2.4:1. The majority (95%) of patients were symptomatic. Common clinical manifestations among all the centres were weakness and fatigability (58.7%), bone pain (56%), renal stone disease (31%), pancreatitis (12.3%) and gallstone disease (11%). Mean serum calcium, parathyroid hormone and inorganic phosphorus levels were 11.9 +/- 1.6 mg/dL, 752.4 +/- 735.2 pg/mL and 2.8 +/- 0.9 mg/dL, respectively. Sestamibi scanning had better sensitivity than ultrasonography in the localisation of parathyroid adenoma; however, when these two modalities were combined, 93% of the cases were correctly localised. Mean parathyroid adenoma weight was 5.6 +/- 6.5 g (0.1-54 g). It was concluded that the majority of PHPT patients within India are still mainly symptomatic with >50% of patients presenting with bone disease and one-third with renal impairment. Compared to Western countries, Indian patients with PHPT are younger, biochemical abnormalities are more severe, and adenoma weight is higher. As our observation is largely derived from a tertiary care hospital (no routine screening of serum calcium level), the results do not reflect racial differences in susceptibility to PHPT. PMID- 28364325 TI - Vitamin D status and abdominal aortic calcification in postmenopausal women. AB - Vitamin D has an important role in bone metabolism and may be involved in the process of vascular calcification. The objective of this study was to evaluate the effect of vitamin D status on the presence of abdominal aortic calcification (AAC). We enrolled, in a cross-sectional study, 429 postmenopausal women [mean age, weight, and BMI of 59.5 +/- 8.3 (50-83) years, 75.8 +/- 13.3 (35-165) kg, and 29.9 +/- 5.2 (14.6-50.8) kg/m2, respectively]. Lateral vertebral fracture assessment (VFA) images and scans of the lumbar spine and proximal femur were obtained using a Lunar Prodigy densitometer. Vertebral fractures (VFs) were defined using the Genant semiquantitative (SQ) approach. We used the Kauppila score to assess AAC extension. Clinical risk factors of osteoporosis were collected, and 25-hydroxy vitamin D was measured using electrochemiluminescence (Roche). Prevalence of osteoporosis and hypovitaminosis D (<20 ng/ml) was 21.0% and 78.1%, respectively. VFs grade 2/3 were identified in 76 patients (17.7%). Two thirds of the evaluable participants did not have any detectable AAC. The prevalence of significant atherosclerotic burden, defined as a radiographic 24 point AAC score of 5 or higher, was 7.9%. The group of women with extended AAC were older and had a statistically significant higher menopause duration and more prevalent grade 2/3 VFs. Compared to women with normal values of vitamin D, women with vitamin D insufficiency (<20 ng/ml) and deficiency (<10 ng/ml) had a lower BMD and more prevalent VFs. No difference was noted with regard to AAC among the three groups. Multiple stepwise conditional logistic regression analysis showed that the presence of AAC was associated significantly with age and the presence of VFs. Extended aortic calcifications are independently associated with prevalent VFA-identified VFs but not with serum vitamin D levels in postmenopausal women. VFA imaging using DXA may detect at the same time prevalent VFs and AAC, an important cardiovascular disease risk factor. PMID- 28364327 TI - Assessment of chlorine tolerance profile of Citrobacter species recovered from wastewater treatment plants in Eastern Cape, South Africa. AB - This present study assessed the chlorine tolerance of some Citrobacter species recovered from secondary effluents from the clarifiers of two wastewater treatment plants in the Eastern Cape, South Africa. The bacterial survival, chlorine lethal dose and inactivation kinetics at lethal doses were examined. Inactivation of the test bacteria (n = 20) at the recommended dose of 0.5 mg/l for 30 min exposure showed a progressive reduction in bacterial population from 4 to 5 log reduction and residuals ranged between 0.12 and 0.46 mg/l. The bactericidal activity of chlorine increased at higher dosages with a substantial reduction in viability of the bacteria and complete inactivation of the bacterial population at a lethal dose of 0.75 and 1.0 mg/l in 30 min. For the inactivation kinetics, bactericidal activity of chlorine increased with time showing a 3.67 5.4 log reduction in 10 min, 4.0-5.6 log reduction in 20 min and above 6.3 log reductions to complete sterilization of bacterial population over 30 min for all the entire test Citrobacter isolates used in this study. Furthermore, there was a strong correlation (R 2 > 0.84) between bacteria inactivation and increase in contact time. This study appears to have provided support for laboratory evidence of bacterial tolerance to chlorine disinfection at current recommended dose (0.5 mg/l for 30 min), and chlorine concentration between 0.75 and 1.0 mg/l was found to have a better disinfecting capacity to check tolerance of Citrobacter species. PMID- 28364328 TI - Use of three monitoring approaches to manage a major Chrysosporum ovalisporum bloom in the Murray River, Australia, 2016. AB - An unusual bloom of Chrysosporum ovalisporum (basionym Aphanizomenon ovalisporum) occurred for the first time in the Murray River and distributary rivers in New South Wales, Australia, from mid-February to early June 2016. At its greatest extent, it contaminated a combined river length of ca. 2360 km. Chrysosporum ovalisporum usually comprised >99% of the total bloom biovolume at most locations sampled, which at times exceeded 40 mm3 l-1. The origins of the bloom were most likely reservoirs on the upper Murray River, with cyanobacterial-infested water released from them contaminating the river systems downstream. An integrated approach using three analytical methods: (1) identification and enumeration by microscopy, (2) multiplex quantitative polymerase chain reaction (qPCR), and (3) toxin analysis, was used to obtain data for the assessment of risk to water users and management of the bloom. qPCR indicated some cyrA and stxA genes responsible for cylindrospermopsin and saxitoxin biosynthesis respectively were present, but mostly below the level of quantification. No mcyE genes for microcystin biosynthesis were detected. Toxin analysis also revealed that cylindrospermopsin, saxitoxin and microcystin were all below detection. Lack of measurable toxicity in a species usually considered a cylindrospermopsin producer elsewhere meant the possibility of relaxing management guidelines; however, high (Red) alerts needed to be maintained due to risk to water users from other biohazards potentially produced by the cyanobacteria such as contact irritants. A three-tiered monitoring strategy is suggested for monitoring cyanobacterial blooms to provide enhanced data for bloom management. PMID- 28364326 TI - Of Cytometry, Stem Cells and Fountain of Youth. AB - Outlined are advances of cytometry applications to identify and sort stem cells, of laser scanning cytometry and ImageStream imaging instrumentation to further analyze morphometry of these cells, and of mass cytometry to classify a multitude of cellular markers in large cell populations. Reviewed are different types of stem cells, including potential candidates for cancer stem cells, with respect to their "stemness", and other characteristics. Appraised is further progress in identification and isolation of the "very small embryonic-like stem cells" (VSELs) and their autogenous transplantation for tissue repair and geroprotection. Also assessed is a function of hyaluronic acid, the major stem cells niche component, as a guardian and controller of stem cells. Briefly appraised are recent advances and challenges in the application of stem cells in regenerative medicine and oncology and their future role in different disciplines of medicine, including geriatrics. PMID- 28364329 TI - Comparing the natural variation of oribatid mite communities with their changes associated with anthropogenic disturbance. AB - Several organism communities serve as ecological and environmental indicators to detect changes in human-impacted habitats. However, the composition of indicator communities may vary because of natural variation in addition to the changes associated with human disturbances. This meta-analysis compared the natural variation of oribatid mite assemblages, a good indicator model group in soil ecosystems, with their deviations associated with disturbance using diversity and dissimilarity indices and three human disturbance types. Literature data were collected about oribatid mite assemblages from natural and disturbed habitats. Human disturbances consisted of agriculture, heavy metal pollution and forest management. Biodiversity indices (Shannon and Berger-Parker) and dissimilarity indices (Jaccard and Bray-Curtis) were calculated among natural habitats and between disturbed and control habitats at the species and genus level. We considered oribatid mite assemblages as effective community-level indicators when the methods separated the differences of assemblages between disturbed and control habitats from their varieties among natural habitats. In addition, the study analysed the correlation between these indices and environmental variables of the study sites. Oribatid mite assemblages performed high indication strength with Bray-Curtis index for agricultural disturbances since dissimilarity values between disturbed and control habitats were as high as between different natural habitats and higher than among the same types of natural habitats. Genus-level values showed similar results to the species level. This approach may be useful to test the effectiveness of other indicator groups and methods. PMID- 28364330 TI - ERP Evidence for the Activation of Syntactic Structure During Comprehension of Lexical Idiom. AB - The present study used event-related potentials to investigate whether the syntactic structure was activated in the comprehension of lexical idioms, and if so, whether it varied as a function of familiarity and semantic transparency. Participants were asked to passively read the "1+2" structural Chinese lexical idioms with each being presented following 3-5 contextual "1+2" (congruent structure condition) or "2+1" structural Chinese phrases (incongruent-structure condition). The N400 ERP responses showed more positivity in congruent-structure condition relative to incongruent-structure condition in idioms with high familiarity and high semantic transparency, but less positivity in congruent structure condition in idioms with high familiarity but low semantic transparency, idioms with low familiarity but high semantic transparency, and idioms with low familiarity and low semantic transparency. Our results suggest that syntactic structure, as the unnecessarity of lexical idiomatic words, was nevertheless activated, independent of familiarity and semantic transparency. PMID- 28364332 TI - Repetitive nerve stimulation as a diagnostic aid for distinguishing cervical spondylotic amyotrophy from amyotrophic lateral sclerosis. AB - PURPOSE: To identify and compare the features of compound muscle action potential (CMAP) decrements in repetitive nerve stimulation (RNS) in patients with cervical spondylotic amyotrophy (CSA) and in patients with amyotrophic lateral sclerosis (ALS). METHODS: The cohort consisted of 43 CSA (distal-type to proximal-type ratio: 27-16) and 35 ALS patients. Five muscles, including abductor pollicis brevis (APB), abductor digiti minimi (ADM), biceps brachii (BB), middle deltoid (Del), and upper trapezius (Trap), were tested by 3-Hz RNS. Decrements greater than cutoff values (APB > 5.8%; ADM > 4.8%; BB > 5.2%; Del > 6%; Trap > 5.1%) determined using receiver operating characteristic (ROC) curves were defined as abnormal, and the conventional criterion (>=10%) was also considered. RESULTS: A significant CMAP decrement (>cutoff values) was recorded from at least one tested muscle in 91.4% of ALS patients, and was most common in the proximal muscle, a finding that differed significantly from CSA patients (32.6%, P < 0.05). The application of cutoff values greatly improved the sensitivity of RNS over the conventional criterion (>=10%) for the detection of ALS (P < 0.05). The specificity of this technique remained higher when performing RNS in the proximal muscles, especially in the upper trapezius (AUC = 0.864, sensitivity = 0.643, and specificity = 1.000). The decrement percentages were significantly greater in the proximal muscles of ALS patients than in those of the CSA patients (P < 0.05). In addition, illness duration was not correlated with decrement percentage in either patient group, and no difference in the frequency of decrement among different ALS diagnostic categories was observed (P > 0.05). CONCLUSIONS: The application of RNS, especially in proximal muscles, may provide a simple accurate and noninvasive supplementary test for distinguishing CSA from ALS, even in the early stage of these diseases. A combination of RNS, needle EMG, clinical features and cervical magnetic resonance imaging may yield sufficient diagnostic information to differentiate CSA and ALS. PMID- 28364333 TI - The effect from different numbers of segmental arteries ligation to the spinal cord in the clinical practice of posterior vertebral column resection correction. AB - PURPOSE: In using posterior vertebral column resection (PVCR) to treat severe kyphoscoliosis, it is unavoidable to ligate and cut off several segmental arteries (SAs) of the spinal cord for exposure and hemostasis, but which would raise the neurological risks. The aim of this study is to explore the changes of intraoperative spinal cord monitoring (IOM) following ligating different numbers of SAs in PVCR. METHODS: Twenty-one consecutive patients with severe kyphoscoliosis were included and treated by PVCR correction. In operation, according to ligate different numbers of SAs, the IOM changes were recorded, respectively. Examinations of the covariance between different numbers of SAs ligations and IOM changes were performed to reveal the effect to the spinal cord by SAs ligations. RESULTS: In all the 21 cases, averaging 1.9 pairs of SAs were ligated. With the increased numbers of ligations, SSEP amplitudes and latencies were changed more obviously: from 1 to 3 pairs ligations, the mean decreased percentages of amplitudes were from 53.20 to 78.15%, the mean increased percentages of latency were from 1.23 to 1.40%, and the mean durations of decreased SSEP amplitudes were from 3.23 to 5.2 min; but without abnormal MEP changes. None occurred postoperative or delayed neurological deficit. Correlation analysis identified significant correlations between the number of SAs ligation and decreased percentage of SSEP amplitude (r = 0.945, P < 0.0001), and between the number of SAs being ligated and the duration of SSEP change (r = 0.945, P = 0.0002). CONCLUSIONS: Following the increased number of SAs ligation, the amplitude of SSEP is decreased more obviously with a much longer duration of recovery and the risk to spinal cord will be increased greatly. In the PVCR correction on the basis of spinal shortening, the numbers of SAs ligations should be as less as possible for neurological safety. PMID- 28364331 TI - Senicapoc: Repurposing a Drug to Target Microglia KCa3.1 in Stroke. AB - Stroke is the leading cause of serious long-term disability and the fifth leading cause of death in the United States. Treatment options for stroke are few in number and limited in efficacy. Neuroinflammation mediated by microglia and infiltrating peripheral immune cells is a major component of stroke pathophysiology. Interfering with the inflammation cascade after stroke holds the promise to modulate stroke outcome. The calcium activated potassium channel KCa3.1 is expressed selectively in the injured CNS by microglia. KCa3.1 function has been implicated in pro-inflammatory activation of microglia and there is recent literature suggesting that this channel is important in the pathophysiology of ischemia/reperfusion (stroke) related brain injury. Here we describe the potential of repurposing Senicapoc, a KCa3.1 inhibitor, to intervene in the inflammation cascade that follows ischemia/reperfusion. PMID- 28364335 TI - Neurological complications of thoracic posterior vertebral column resection for severe congenital spinal deformities. AB - PURPOSE: The risk of neurological injury during vertebral column resection is high. In this study, we investigated the incidence and risk factors for neurological complications when treating spinal deformities by thoracic posterior vertebral column resection (PVCR). METHODS: Between 2008 and 2013, there were 62 consecutive patients (34 female patients and 28 male; the mean age: 16.3 years, range 6-46 years) treated with thoracic PVCR. We retrospectively reviewed the clinical records to obtain demographic and radiographic data, operative time, estimated blood loss (EBL, the ratio between circulating and lost blood), bleeding volume (the lost blood), number of vertebrae fused, number of vertebrae resected, usage of titanium mesh cage, and intraoperative neuromonitoring data. Multi-factor logistic regression was used to find the major risk factors for neurological complications. RESULTS: The average follow-up period was 46 months (range 24-88 months); no patients were lost to follow up. The average operative time was 524.8 +/- 156.8 min (range 165.0-880.0 min), the average bleeding volume was 2585 +/- 2210 ml (100-9600 ml), and the average estimated blood loss was 75.8% (9-278%). Ten patients (16.1%) developed post-operative neurological complications (nine transient and one permanent). Multi-factor logistic regression revealed that the risk factors for neurological complications were age >=18 years, pulmonary dysfunction, and EBL >50%. CONCLUSIONS: Thoracic PVCR can lead to satisfactory outcomes in the treatment of severe spinal deformities. Risk factors for neurological complications include the age over 18 years, presence of pulmonary dysfunction, and EBL greater than 50%. The pulmonary dysfunction can be regarded as the most valuable indicator to measure the severity of the spine deformity. PMID- 28364334 TI - Diagnosis of painful cemented vertebrae from failed vertebroplasty: modified dynamic radiographs play an important role. AB - PURPOSE: The diagnosis of painful cemented vertebrae resulting from failed PV is not clearly defined in literature. This report evaluates the effectiveness of modified dynamic radiographs in diagnosing painful cemented vertebrae resulting from failed PV. METHODS: From January 2011 to June 2015, 345 patients with a total of 399 VCFs underwent PV at our institution. Among the 345 patients, 27 patients underwent repeated PV at the cemented vertebrae because of persisting or recurrent pain after vertebroplasty. The prevertebroplasty examinations included routine radiographs, modified dynamic radiographs, and MRI. Kyphotic angles and the anterior vertebral body height (AVBH) were measured. The image findings in routine radiographs, modified dynamic radiographs, and MRI were compared. Finally, a visual analog scale was used to measure the outcome. RESULTS: The patients ranged in age from 67 to 90 years. MRI revealed a moderate amount of fluid (definite diagnosis of refracture) in the cemented vertebrae in seven patients, bone edema without fluid in nine patients, and bone edema with minimal fluid in ten patients. The rate of diagnosis of painful cemented vertebrae according to MRI was 27% (7/26). The difference in the kyphotic angle between sitting and supine cross-table lateral radiographs was -9.36 degrees +/- 5.20 degrees (P < 0.001). The difference in AVBH was 8.08 +/- 3.21 mm (P < 0.001). All 27 patients were confirmed to have dynamic mobility according to the modified dynamic radiographs. CONCLUSIONS: When the diagnosis of painful cemented vertebrae is questionable, modified dynamic radiographs can help diagnose painful cemented vertebrae resulting from failed PV. PMID- 28364337 TI - Expert's comment concerning Grand Rounds case entitled "Atypical presentation of a cervical synovial cyst" by Daniela Linhares et al. (2017) Eur Spine J: doi:10.1007/s00586-017-4947-4. PMID- 28364336 TI - Reduced instantaneous center of rotation movement in patients with low back pain. AB - PURPOSE: The instantaneous center of rotation (ICR) can be used to investigate movement coordination and control in patients with low back pain (LBP). Tracking of the ICR in LBP patients has not been systematically investigated. This study aimed to (1) determine the within-session measurement error of ICR parameters, and (2) characterize the change in ICR among three groups of participants (no history of LBP = HC; history of LBP = HLBP; and current LBP = LBP). METHODS: Ninety-three participants (HC = 31; HLBP = 33; and LBP = 29) were recruited. Participants performed two sets of three repetitions of an active forward bend, while their lumbar and pelvic movements were recorded with an electromagnetic tracking system. Total ICR displacement and the radius of the bounding sphere containing the ICR were derived during the forward bending and the return to upright phases. Intra-class correlation coefficients (ICC3,3) and minimal detectable difference (MDD) were used to determine measurement error and interpret findings of the group analysis. One-way ANOVAs and post hoc Bonferroni comparisons were used to determine differences among groups. RESULTS: ICC3,3 demonstrated excellent within-session test-retest reliability of the ICR parameters (ICC3,3 = 0.86-0.97). The MDD values were 0.20-3.40 mm. Comparisons between the HC and LBP groups and between the HLBP and LBP groups showed significant differences (p < 0.05) for all ICR parameters, with medium effect sizes (0.51-0.66), except for total displacement during forward bending between the HC and LBP groups. CONCLUSION: Less ICR displacement and variability in patients with LBP may indicate coping strategies to stiffen the lumbar spine. This could result from patients with LBP adopting a strategy of increased muscle activation to provide spinal stability during functional tasks. PMID- 28364338 TI - Assessment of choroidal osteoma complicating choroidal neovascularization by optical coherence tomography angiography. AB - PURPOSE: Choroidal osteoma (CO) frequently leads to progressive visual loss due to complications of secondary choroidal neovascularization (CNV).We report herein the function of optical coherence tomography angiography (OCTA) in observation of CO complicating CNV. METHODS: A 25-year-old female presented to our hospital with chief complaint of sudden unilateral visual acuity decrease for one week, with metamorphopsia in the left eye. Her best corrected visual acuity was 0.12 in the left eye. Then complete ophthalmological examinations including fundus photography, B-scan ultrasound, fundus fluorescent angiography, and spectral domain optical coherence tomography (SD-OCT) were performed. She was diagnosed as CO on the basis of these results. But the diagnosis could not explain the sudden visual loss and submacular hyperreflective lesion by SD-OCT. Furthermore, she underwent OCTA and indocyanine green angiography. RESULTS: A diagnosis of classic juxtafoveal CNV secondary to CO was made eventually. Then she was treated with an intravitreous injection of ranibizumab twice. The visual acuity got better and better during the treatment, and the efficacy was stable, giving rise to both subjective and anatomic improvement. CONCLUSIONS: Optical coherence tomography angiography has the advantage of varying the segmentation and scrolling through the different retinal layers, and layer-specific observation of blood flow in each layer. In addition, OCTA can measure the vessel area change of CNV and provide a better appreciation of CNV, observing the efficacy more elaboratively and quantizedly. OCTA makes promising noninvasive identification of the CO related CNV. PMID- 28364339 TI - Characteristics of orbital lymphoma: a clinicopathological study of 26 cases. AB - OBJECTIVE: Evaluation of the medical data of patients with orbital and adnexal lymphoma. DESIGN: Cohort study of all cases diagnosed with orbital or adnexal lymphoma at Meir Medical Center between 1993 and 2007. PARTICIPANTS: Twenty-six patients, with intraorbital or subconjunctival masses with orbital involvement, were examined and followed up between 1 and 8 years. MATERIALS AND METHODS: Examined data included: clinical presentation, age, gender, imaging, tumor location, surgical management, and pathological diagnosis. RESULTS: Presenting signs and symptoms included proptosis, eyelid lesions, tearing, chemosis, decreased visual acuity, ptosis, pain, squint, and optic nerve compression. In five cases, lymphoma was misdiagnosed on neuroimaging. Bone changes were seen in four patients. All cases were B cell lymphomas; with the majority (22 cases) of small B cell type; consisting of primary extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue and two cases of small cell lymphoma. One small cell lymphomas was of follicular type on a background of CLL, and the other was CLL/SLL type. Fourteen cases were primary orbital disease, and 12 cases were systemic disease. Macroscopic appearance of lymphoma at open biopsy was characteristic in most cases. Flow cytometry phenotyping gave rapid reliable diagnosis of the disease. CONCLUSIONS: Epiphora or chemosis in the presence of an orbital mass should alert the ophthalmologist to suspect lymphoma. Lymphoma may be easily misinterpreted on neuroimaging for other diseases. Bone changes seen on CT are more common than is generally perceived. Macroscopic appearance at open biopsy was characteristic. PMID- 28364341 TI - The role of stimulus predictability in the allocation of attentional resources: an eye-tracking study. AB - By allocating less attention to predictable events we are able to focus on novel, unpredictable and unexpected events that require more extensive processing. This strategy should result in improved performance by optimizing the use of brain's limited resources. Participants' task was to look at two types of stimuli presented simultaneously at the opposite sides of a computer screen: "static" stimuli, i.e. emotionally neutral photographs; and "dynamic" stimuli, i.e. video clips presenting a moving dot. The dot moved along a predictable, semi predictable or random trajectory. This was followed by a memory test of the static stimuli. Participants spent more time looking at the dynamic stimuli when its trajectory was less predictable. Additionally, participants who readily adjusted their dwell time allocation to the dot trajectory performed better in the memory test, as demonstrated by a positive correlation between memory test sensitivity and the rate of eye movement patterns adjustment to stimulus predictability. This suggests that people adjust gaze duration to stimulus predictability and that doing so optimizes attentional resource allocation and improves performance. However, study design did not allow to distinguish between spatial and temporal predictability, so it is impossible to estimate the impact of each type of predictability specifically. PMID- 28364342 TI - In vitro proliferation and osteogenic differentiation of endometrial stem cells and dental pulp stem cells. AB - Stem-cell-based therapies were introduced aiming to overcome the limitations of the existing procedures for regeneration of mineralized tissues. Stem cells isolated from the endometrial tissue and dental pulp have the capacity to differentiate into various functional cells including osteoblasts. However, studies comparing their ability to regenerate mineralized tissue are lacking. The purpose of this study was to compare the proliferation and osteogenic differentiation potential of endometrial stem cells (EnSCs) and dental pulp stem cells (DPSCs) using in vitro cell culture technique. The DPSCs and EnSCs were isolated from human dental pulp and endometrium, respectively. Their proliferation and osteogenic potential were compared in the same osteogenic medium (OM) after 3, 5, 7 and 10 days using the methyl thiazol tetrazolium assay, alizarin red staining, and real-time quantitative reverse transcription polymerase chain reaction (Real-Time qRT-PCR). The EnSCs showed higher proliferation rate compared to DPSCs. Regarding osteogenesis, alizarin red positive colonies appeared earlier and in greater amounts in DPSCs group. The real-time qRT-PCR demonstrated significantly greater osteogenic potential of DPSCs compared to EnSCs. Our findings revealed significant differences in stem cell properties based on the tissue source. The EnSCs had greater proliferation rate than DPSCs, while DPSCs showed greater osteogenic potential compared to EnSCs in the same OM. PMID- 28364340 TI - Orbitofrontal and caudate volumes in cannabis users: a multi-site mega-analysis comparing dependent versus non-dependent users. AB - RATIONALE: Cannabis (CB) use and dependence are associated with regionally specific alterations to brain circuitry and substantial psychosocial impairment. OBJECTIVES: The objective of this study was to investigate the association between CB use and dependence, and the volumes of brain regions critically involved in goal-directed learning and behaviour-the orbitofrontal cortex (OFC) and caudate. METHODS: In the largest multi-site structural imaging study of CB users vs healthy controls (HC), 140 CB users and 121 HC were recruited from four research sites. Group differences in OFC and caudate volumes were investigated between HC and CB users and between 70 dependent (CB-dep) and 50 non-dependent (CB-nondep) users. The relationship between quantity of CB use and age of onset of use and caudate and OFC volumes was explored. RESULTS: CB users (consisting of CB-dep and CB-nondep) did not significantly differ from HC in OFC or caudate volume. CB-dep compared to CB-nondep users exhibited significantly smaller volume in the medial and the lateral OFC. Lateral OFC volume was particularly smaller in CB-dep females, and reduced volume in the CB-dep group was associated with higher monthly cannabis dosage. CONCLUSIONS: Smaller medial OFC volume may be driven by CB dependence-related mechanisms, while smaller lateral OFC volume may be due to ongoing exposure to cannabinoid compounds. The results highlight a distinction between cannabis use and dependence and warrant examination of gender-specific effects in studies of CB dependence. PMID- 28364344 TI - Giant-cell tumour of proximal radius in a 50-year-old female with wrist drop: a rare case report. AB - Giant-cell tumour is a locally aggressive tumour of long bones of epiphyseal region commonly occurring in adults aged 20-40 years. Most common location is distal femur, proximal tibia, and distal radius. Different treatment options being used are curettage with bone graft or bone cement, resection with arthrodesis, reconstruction, radiation, and chemotherapy. We are reporting a case of giant-cell tumour of right proximal radius in a 50-year-old female with posterior interosseous nerve palsy. It is very rare, and only four cases have been reported in the literature. It was treated by wide margin resection with fibular grafting, titanium elastic nail system along with cancellous bone graft reconstruction. PMID- 28364343 TI - Management of Pediatric Malignant Germ Cell Tumors: ICMR Consensus Document. AB - With the introduction of cisplatin, the outcome of children with malignant germ cell tumors (MGCT) has improved to nearly 90% 5 year survival. Over the years, through the results of various multinational co-operative trials, the chemotherapy and surgical guidelines for both the gonadal and extra-gonadal MGCTs have been refined to decrease the early and late morbidities and at the same time improve survival. Introduction of risk categorization has further added to this effort. There has been no recommendation on how the children with malignant germ cell tumors should be treated in India. The current manuscript is written with the objective of developing a consensus guideline for practitioners at a National level. Based on extensively reviewed literature and personal experience of the major pediatric oncology centres in India, the ICMR Expert group has made recommendations for management of children with MGCT India. PMID- 28364345 TI - What is the time course of working memory attentional refreshing? AB - One way of maintaining information in working memory is through attentional refreshing, a process that was recently shown to be independent from verbal rehearsal. In the classical working memory complex span task, the usual assumption is that memoranda are refreshed in a cumulative fashion, starting from the first item, going in a forward order until the latest one, and cycling until there is no time to continue the process. However, there is no evidence that refreshing operates in that way. The present study proposes a computational modelling study, which constitutes a powerful method to investigate alternative hypotheses. Different refreshing schedules are investigated within computational implementation of the time-based resource sharing model. Their ability to fit three sets of behavioral data and to reproduce the major time-based resource sharing predictions were evaluated using standard model selection criteria. Besides an already published schedule in which the attentional focus is expanded, it appeared that one schedule, the least-activated-first, outperforms the classical cumulative one. The memory trace refreshed at a given time is the one that is the least activated in working memory at that time. These findings characterized the time course of attentional refreshing in working memory and specified the contribution of refreshing to primacy and recency effects. Moreover, in the light of various fields of cognitive psychology, we propose that such refreshing schedules can operate without a homunculus within a general framework including cognitive control and strategic considerations. PMID- 28364347 TI - CYP1A1 based on metabolism of xenobiotics by cytochrome P450 regulates chicken male germ cell differentiation. AB - This study aimed to explore the regulatory mechanism of metabolism of xenobiotics by cytochrome P450 during the differentiation process of chicken embryonic stem cells (ESCs) into spermatogonial stem cells (SSCs) and consummate the induction differentiation system of chicken embryonic stem cells (cESCs) into SSCs in vitro. We performed RNA-Seq in highly purified male ESCs, male primordial germ cells (PGCs), and SSCs that are associated with the male germ cell differentiation. Thereinto, the metabolism of xenobiotics by cytochrome P450 was selected and analyzed with Venny among male ESC vs male PGC, male PGC vs SSC, and male ESC vs SSC groups and several candidates differentially expressed genes (DEGs) were excavated. Finally, quantitative real-time PCR (qRT-PCR) detected related DEGs under the condition of retinoic acid (RA) induction in vitro, and the expressions were compared with RNA-Seq. By knocking down CYP1A1, we detected the effect of CYP1A1-mediated metabolism of xenobiotics by cytochrome P450 on male germ cell differentiation by qRT-PCR and immunocytochemistry. Results showed that 17,742 DEGs were found during differentiation of ESCs into SSCs and enriched in 72 differently significant pathways. Thereinto, the metabolism of xenobiotics by cytochrome P450 was involved in the whole differentiation process of ESCs into SSCs and several candidate DEGs: CYP1A1, CYP3A4, CYP2D6, ALDH3B1, and ALDH1A3 were expressed with the same trend with RNA-Seq. Knockdown of CYP1A1 caused male germ cell differentiation under restrictions. Our findings showed that the metabolism of xenobiotics by cytochrome P450 was significantly different during the process of male germ cell differentiation and was persistently activated when we induced cESCs to differentiate into SSCs with RA in vitro, which illustrated that the metabolism of xenobiotics by cytochrome P450 played a crucial role in the differentiation process of ESCs into SSCs. PMID- 28364348 TI - Analysis of soluble factors in conditioned media derived from primary cultures of cirrhotic liver of biliary atresia. AB - Biliary atresia (BA) is a rare and serious liver disease in newborn infants. Previously, we reported that non-parenchymal cell (NPC) fractions from cirrhotic liver of BA may contain hepatic stem/progenitor cells in primary culture of NPC fractions. In this study, NPC fractions were subjected to primary or passage culture and found that clusters of hepatocyte-like cells appear even without adding hepatocyte growth factor (HGF) to the culture medium, but not in their passage culture used as a control. Based on these findings, conditioned media (CMs) were collected and soluble factors in the CMs were analyzed in order to elucidate the mechanism of the appearance of hepatocyte-like cells or their clusters. A large amount of active HGF consisting of alpha and beta chains was detected in CMs derived from primary culture, but not in CMs from passage culture, as determined by western blot analysis, bone morphogenetic protein (BMP) 4, oncostatin M (OSM), and transforming growth factor (TGF)-beta1 were not detected in any of the CMs. The number of hepatocyte-like cells in primary culture tended to decrease following treatment with the HGF receptor c-Met inhibitor, SU11274 in a dose-dependent manner. Furthermore, the clusters of hepatocyte-like cells tended to increase in size and number when freshly isolated NPC fractions were cultured in the presence of 10% of CMs collected after 3-4 wk of primary culture. In conclusion, these findings indicate that CMs derived from primary culture of NPC fractions of BA liver contain a large amount of active HGF, which may activate hepatic stem/progenitor cells and promote the appearance of hepatocyte-like cells or their clusters through HGF/c-Met signaling. The present study would lead to cell therapy using the patient's own cells for the treatment of BA. PMID- 28364350 TI - [Conservative treatment of hallux valgus : What can be achieved with splints and insoles?] AB - In hallux valgus syndrome conservative measures can only be applied to relieve the symptoms. Insoles, orthoses, and toe alignment splints cannot improve forefoot deformity. However, symptoms due to increased local pressure can be alleviated with orthotic devices. After surgically realigning the hallux, splints are helpful to retain joint congruency and assure proper toe position during soft tissue healing. PMID- 28364349 TI - Effect of blood biochemical factors on nontraumatic necrosis of the femoral head : Logistic regression analysis. AB - OBJECTIVE: This case-control study aimed to identify the risk factors of nontraumatic necrosis of the femoral head (NONFH). METHODS: In all, 242 patients with NONFH treated at the hip disease research center of our hospital between March 2012 and October 2015 were included. After excluding 19 patients with tumor or tuberculosis, 223 patients were enrolled. Controls comprised 223 healthy persons selected from our hospital database. Single-factor variance analysis and t test were performed to select the index of statistical significance. The 95% confidence interval (95% CI) and normal range of the selected indicators were compared, and abnormal related indexes were selected from the femoral head necrosis group. The selected indicators were based on the increase or decrease to locate the risk indicators and render their corresponding assignment. Logistic regression analysis of the risk factors was performed after the assignment. RESULTS: The necrotic group of patients with decreased carbon dioxide combining power (CO2CP), increased total cholesterol, increased low-density lipoprotein, and decreased high-density lipoprotein levels had statistically significant partial regression coefficient values and the odds ratios were 73.5 (95% CI 24.59 219.74), 7.15 (3.51-14.85), 633.07 (121.7-3304.78), and 20.11 (9.36-43.8), respectively, indicating that these are strong risk factors for NONFH. CONCLUSIONS: Abnormal lipid metabolism is a strong risk factor of NONFH. Lipid examination can be used as a screening tool for NONFH in high-risk populations, for alcoholism, and many hormone applications. The decreased CO2CP was associated with NONFH, and bone microcirculation was considered to possibly lead various conditions such as ischemia and hypoxia-related bone metabolic acidosis. However, further study is needed. PMID- 28364346 TI - The growing world of small heat shock proteins: from structure to functions. AB - Small heat shock proteins (sHSPs) are present in all kingdoms of life and play fundamental roles in cell biology. sHSPs are key components of the cellular protein quality control system, acting as the first line of defense against conditions that affect protein homeostasis and proteome stability, from bacteria to plants to humans. sHSPs have the ability to bind to a large subset of substrates and to maintain them in a state competent for refolding or clearance with the assistance of the HSP70 machinery. sHSPs participate in a number of biological processes, from the cell cycle, to cell differentiation, from adaptation to stressful conditions, to apoptosis, and, even, to the transformation of a cell into a malignant state. As a consequence, sHSP malfunction has been implicated in abnormal placental development and preterm deliveries, in the prognosis of several types of cancer, and in the development of neurological diseases. Moreover, mutations in the genes encoding several mammalian sHSPs result in neurological, muscular, or cardiac age-related diseases in humans. Loss of protein homeostasis due to protein aggregation is typical of many age-related neurodegenerative and neuromuscular diseases. In light of the role of sHSPs in the clearance of un/misfolded aggregation-prone substrates, pharmacological modulation of sHSP expression or function and rescue of defective sHSPs represent possible routes to alleviate or cure protein conformation diseases. Here, we report the latest news and views on sHSPs discussed by many of the world's experts in the sHSP field during a dedicated workshop organized in Italy (Bertinoro, CEUB, October 12-15, 2016). PMID- 28364351 TI - [Prevention of lateral cortex fractures in open wedge high tibial osteotomies : The anteroposterior drill hole approach]. AB - BACKGROUND: In osteotomies with larger correction angles, the capacity for elastic deformation is frequently exceeded, resulting in plastic deformation and fracture of the opposite cortex, which may lead to subsequent loss of correction. An anteroposterior drill hole at the apex of the horizontal osteotomy (= hinge) is supposed to increase the capacity of the bony hinge for elastic deformation and ideally to prevent fractures of the opposite cortex. MATERIALS AND METHODS: A high tibial osteotomy (HTO) using standard surgical technique was performed in 20 each of Synbones, Sawbones, and human cadaver tibial specimens. In 10 specimens per group, an additional anteroposterior hinge drilling was performed at the apex of the horizontal osteotomy. All fractures of the opposite cortex were photographically and radiographically documented. All fractures were classified according to fracture types 1-3 of the Takeuchi classification. RESULTS: Regardless of the study group, all tibial bones with an additional hinge drilling achieved larger correction angles during the spreading of the wedge until a fracture of the opposite cortex occurred. The average correction angle of all specimens without the drill hole was 2.7 degrees , which increased to 4.8 degrees with the hinge drill (increase by 77.8%). In correction angles exceeding 5 degrees , all specimen showed a hinge fracture regardless of the presence or absence of a hinge drill. CONCLUSIONS: The hinge-protecting effect is restricted to small correction angles, i. e., to unload cartilage repair regions in the absence of severe malalignment. For the treatment of varus gonarthrosis, there is no fracture-protecting effect from a hinge drill. PMID- 28364352 TI - Effects of bufalin on up-regulating methylation of Wilm's tumor 1 gene in human erythroid leukemic cells. AB - OBJECTIVE: To explore the effects of bufalin on inhibiting proliferation, up regulating methylation of Wilm' tumor 1 gene (WT1) as well as its possible mechanisms in human erythroid leukemic (HEL) cells. METHODS: The HEL cells were treated with bufalin at various concentrations to observe cellular morphology, proliferation assay and cell cycle. The mRNA and protein expression levels of WT1 were detected by reverse transcription polymerase chain reaction (RT-PCR), Western blot and immunocytochemistry, DNA methylation of WT1 and protein expression levels of DNA methyltransferase 3a (DNMT3a) and DNMT3b were analyzed by methylation-specific PCR, and Western blot respectively. RESULTS: The bufalin was effective to inhibit proliferation of HEL cells in a dose-dependent manner, their suppression rates were from 23.4%+/-2.1% to 87.2%+/-5.4% with an half maximal inhibit concentration (IC50) of 0.046 MUmol/L. Typical apoptosis morphology was observed in bufalin-treated HEL cells. The proliferation index of cell cycle decreased from 76.4%+/-1.9% to 49.7%+/-1.3%. The expression levels of WT1 mRNA and its protein reduced gradually with increasing doses of bufalin, meanwhile, the methylation status of WT1 gene changed from unmethylated into partially or totally methylated. While, the expression levels of DNMT3a and DNMT3b protein gradually increased by bufalin treatment in a dose-dependent manner. CONCLUSIONS: Bufalin can not only significantly inhibit the proliferation of HEL cells and arrest cell cycle at G0/G1 phase, but also induce cellular apoptosis and down-regulate the expression level of WT1. Our results provide the evidence of bufalin for anti-leukemia, its mechanism may involve in increasing WT1 methylation status which is related to the up-regulation of DNMT3a and DNMT3b proteins in erythroid leukemic HEL cells. PMID- 28364353 TI - Mitochondrial Cx43 hemichannels contribute to mitochondrial calcium entry and cell death in the heart. AB - Mitochondrial connexin 43 (Cx43) plays a key role in cardiac cytoprotection caused by repeated exposure to short periods of non-lethal ischemia/reperfusion, a condition known as ischemic preconditioning. Cx43 also forms calcium (Ca2+) permeable hemichannels that may potentially lead to mitochondrial Ca2+ overload and cell death. Here, we studied the role of Cx43 in facilitating mitochondrial Ca2+ entry and investigated its downstream consequences. To that purpose, we used various connexin-targeting peptides interacting with extracellular (Gap26) and intracellular (Gap19, RRNYRRNY) Cx43 domains, and tested their effect on mitochondrial dye- and Ca2+-uptake, electrophysiological properties of plasmalemmal and mitochondrial Cx43 channels, and cell injury/cell death. Our results in isolated mice cardiac subsarcolemmal mitochondria indicate that Cx43 forms hemichannels that contribute to Ca2+ entry and may trigger permeability transition and cell injury/death. RRNYRRNY displayed the strongest effects in all assays and inhibited plasma membrane as well as mitochondrial Cx43 hemichannels. RRNYRRNY also strongly reduced the infarct size in ex vivo cardiac ischemia reperfusion studies. These results indicate that Cx43 contributes to mitochondrial Ca2+ homeostasis and is involved in triggering cell injury/death pathways that can be inhibited by RRNYRRNY peptide. PMID- 28364354 TI - Precision Medicine Approaches to Diabetic Kidney Disease: Tissue as an Issue. AB - PURPOSE OF REVIEW: Precision medicine approaches, that tailor medications to specific individuals has made paradigm-shifting improvements for patients with certain cancer types. RECENT FINDINGS: Such approaches, however, have not been implemented for patients with diabetic kidney disease. Precision medicine could offer new avenues for novel diagnostic, prognostic and targeted therapeutics development. Genetic studies associated with multiscalar omics datasets from tissue and cell types of interest of well-characterized cohorts are needed to change the current paradigm. In this review, we will discuss precision medicine approaches that the nephrology community can take to analyze tissue samples to develop new therapeutics for patients with diabetic kidney disease. PMID- 28364355 TI - Population Health Management for Diabetes: Health Care System-Level Approaches for Improving Quality and Addressing Disparities. AB - PURPOSE OF REVIEW: Population care approaches for diabetes have the potential to improve the quality of care and decrease diabetes-related mortality and morbidity. Population care strategies are particularly relevant as accountable care organizations (ACOs), patient-centered medical homes (PCMH), and integrated delivery systems are increasingly focused on managing chronic disease care at the health system level. This review outlines the key elements of population care approaches for diabetes in the current health care environment. RECENT FINDINGS: Population care approaches proactively identify diabetes patients through disease registries and electronic health record data and utilize multidisciplinary care teams, personalized provider feedback, and decision support tools to target and care for patients at risk for poor outcomes. Existing evidence suggests that these strategies can improve care outcomes and potentially ameliorate existing race/ethnic disparities in health care. However, such strategies may be less effective for patients who are disengaged from the health care system. As population care for diabetes continues to evolve, future initiatives should consider ways to tailor population care to meet individual patient needs, while leveraging improvements in clinical information systems and care integration to optimally manage and prevent diabetes in the future. PMID- 28364357 TI - Treatment of Diabetic Ketoacidosis (DKA)/Hyperglycemic Hyperosmolar State (HHS): Novel Advances in the Management of Hyperglycemic Crises (UK Versus USA). AB - PURPOSE OF REVIEW: Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are diabetic emergencies that cause high morbidity and mortality. Their treatment differs in the UK and USA. This review delineates the differences in diagnosis and treatment between the two countries. RECENT FINDINGS: Large scale studies to determine optimal management of DKA and HHS are lacking. The diagnosis of DKA is based on disease severity in the USA, which differs from the UK. The diagnosis of HHS in the USA is based on total rather than effective osmolality. Unlike the USA, the UK has separate guidelines for DKA and HHS. Treatment of DKA and HHS also differs with respect to timing of fluid and insulin initiation. There is considerable overlap but important differences between the UK and USA guidelines for the management of DKA and HHS. Further research needs to be done to delineate a unifying diagnostic and treatment protocol. PMID- 28364356 TI - Diabetes in Cushing Disease. AB - PURPOSE OF REVIEW: This review focuses on the pathophysiological and clinical aspects of diabetes mellitus occurring in patients with Cushing disease (CD). RECENT FINDINGS: Insulin resistance and impairment in insulin secretion are both involved in the pathogenesis of glucocorticoid-induced diabetes. Correction of glucocorticoid excess does not always resolve abnormalities of glucose homeostasis, and correction of hyperglycaemia is specifically required. In fact, insulin resistance may persist even after correction of glucocorticoid excess and diabetes needs to be treated for long term. On the other hand, emerging drugs used in the treatment of CD, such as the novel somatostatin analog pasireotide, may have direct effects on glucose homeostasis regardless of control of cortisol excess. Diabetes mellitus is a frequent and early complication of CD with important diagnostic, prognostic and therapeutic implications. Specifically, diagnosis of CD in patients with diabetes may be difficult due to potential misinterpretation of markers of cortisol hypersecretion. Moreover, diabetes mellitus is often difficult to be controlled in CD requiring a careful and dedicated therapeutic approach. Finally, the coexistence of diabetes may influence the therapeutic decision making in CD, since drugs used in this setting may variably influence glucose homeostasis regardless of control of hypercortisolism. PMID- 28364358 TI - A Mutual Authentication Framework for Wireless Medical Sensor Networks. AB - Wireless medical sensor networks (WMSN) comprise of distributed sensors, which can sense human physiological signs and monitor the health condition of the patient. It is observed that providing privacy to the patient's data is an important issue and can be challenging. The information passing is done via the public channel in WMSN. Thus, the patient, sensitive information can be obtained by eavesdropping or by unauthorized use of handheld devices which the health professionals use in monitoring the patient. Therefore, there is an essential need of restricting the unauthorized access to the patient's medical information. Hence, the efficient authentication scheme for the healthcare applications is needed to preserve the privacy of the patients' vital signs. To ensure secure and authorized communication in WMSN, we design a symmetric key based authentication protocol for WMSN environment. The proposed protocol uses only computationally efficient operations to achieve lightweight attribute. We analyze the security of the proposed protocol. We use a formal security proof algorithm to show the scheme security against known attacks. We also use the Automated Validation of Internet Security Protocols and Applications (AVISPA) simulator to show protocol secure against man-in-the-middle attack and replay attack. Additionally, we adopt an informal analysis to discuss the key attributes of the proposed scheme. From the formal proof of security, we can see that an attacker has a negligible probability of breaking the protocol security. AVISPA simulator also demonstrates the proposed scheme security against active attacks, namely, man-in-the-middle attack and replay attack. Additionally, through the comparison of computational efficiency and security attributes with several recent results, proposed scheme seems to be battered. PMID- 28364359 TI - mHealth App for iOS to Help in Diagnostic Decision in Ophthalmology to Primary Care Physicians. AB - Decision support systems (DSS) are increasingly demanded due that diagnosis is one of the main activities that physicians accomplish every day. This fact seems critical when primary care physicians deal with uncommon problems belonging to specialized areas. The main objective of this paper is the development and user evaluation of a mobile DSS for iOS named OphthalDSS. This app has as purpose helping in anterior segment ocular diseases' diagnosis, besides offering educative content about ophthalmic diseases to users. For the deployment of this work, firstly it has been used the Apple IDE, Xcode, to develop the OphthalDSS mobile application using Objective-C as programming language. The core of the decision support system implemented by OphthalDSS is a decision tree developed by expert ophthalmologists. In order to evaluate the Quality of Experience (QoE) of primary care physicians after having tried the OphthalDSS app, a written inquiry based on the Likert scale was used. A total of 50 physicians answered to it, after trying the app during 1 month in their medical consultation. OphthalDSS is capable of helping to make diagnoses of diseases related to the anterior segment of the eye. Other features of OphthalDSS are a guide of each disease and an educational section. A 70% of the physicians answered in the survey that OphthalDSS performs in the way that they expected, and a 95% assures their trust in the reliability of the clinical information. Moreover, a 75% of them think that the decision system has a proper performance. Most of the primary care physicians agree with that OphthalDSS does the function that they expected, it is a user-friendly and the contents and structure are adequate. We can conclude that OphthalDSS is a practical tool but physicians require extra content that makes it a really useful one. PMID- 28364360 TI - Impact of age on efficacy and toxicity of nilotinib in patients with chronic myeloid leukemia in chronic phase: ENEST1st subanalysis. AB - PURPOSE: Achievement of deep molecular response with a tyrosine kinase inhibitor in patients with chronic myeloid leukemia (CML) is required to attempt discontinuation of therapy in these patients. The current subanalysis from the Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) study evaluated whether age has an impact on the achievement of deeper molecular responses or safety with frontline nilotinib in patients with CML. METHODS: ENEST1st is an open-label, multicenter, single-arm, prospective study of nilotinib 300 mg twice daily in patients with newly diagnosed CML in chronic phase. The patients were stratified into the following 4 groups based on age: young (18-39 years), middle age (40-59 years), elderly (60-74 years), and old (>=75 years). The primary end point was the rate of molecular response 4 ([MR4] BCR-ABL1 <=0.01% on the international scale) at 18 months from the initiation of nilotinib. RESULTS: Of the 1091 patients enrolled, 1089 were considered in the analysis, of whom, 23% (n = 243), 45% (n = 494), 27% (n = 300), and 5% (n = 52) were categorized as young, middle age, elderly, and old, respectively. At 18 months, the rates of MR4 were 33.9% (95% confidence interval [CI], 27.8-40.0%) in the young, 39.6% (95% CI, 35.3-44.0%) in the middle-aged, 40.5% (95% CI, 34.8-46.1%) in the elderly, and 35.4% (95% CI, 21.9-48.9%) in the old patients. Although the incidence of adverse events was slightly different, no new specific safety signals were observed across the 4 age groups. CONCLUSIONS: This subanalysis of the ENEST1st study showed that age did not have a relevant impact on the deep molecular response rates associated with nilotinib therapy in newly diagnosed patients with CML and eventually on the eligibility of the patients to attempt treatment discontinuation. PMID- 28364363 TI - Preface - Emerging Viruses: From Early Detection to Intervention. AB - In the last decades, several viruses emerged, as the consequence of cross-species passage from animal reservoirs to human being. Emerging infections always represent a significant challenge for public health system as knowledge about specific pathogens are generally little while and no/few effective interventions are available. In this volume we explored special aspects of emerging infectious diseases including: the application of the theory of focality of diseases to infective syndrome; the human-animal inter-face focusing on influenza; the role of bats as main reservoir of emerging and novel human pathogens; Middle East Respiratory Syndrome Coronavirus (MERS-CoV) epidemiology and clinical presentation; immediate impact on human health of the last Zika virus outbreak occurred in Pacific Ocean and the Americas; the role and potential application of animal models for the study of emerging infections, to improve disease knowledge and for developing therapeutic drugs during ongoing outbreak. PMID- 28364361 TI - A novel method to generate single-cell-derived cancer-associated fibroblast clones. AB - BACKGROUND: Cancer-associated fibroblasts (CAFs) communicate with cancer cells to play important roles in tumor progression. However, CAFs have heterogeneous phenotypes and functions. To understand how much of this heterogeneity relates to different biological responses, a more efficient method of generating single-cell derived CAF clones is required. METHOD: We transduced two primary CAF cultures (CAFs-608 and CAFs-621) from lung adenocarcinoma with human telomerase reverse transcriptase (hTERT), mutant forms of cyclin dependent kinase 4 (CDK4R24C) independently and in combination (hTERT/CDK4R24C). After live imaging of each sorted-single cell, we evaluated the numbers of successfully established clones from CAFs-hTERT, CAFs-CDK4R24C, and CAFs-hTERT/CDK4R24C. Furthermore, we examined the expression levels of genes associated with tumor promoting pathways in established clones by qRT-PCR. RESULTS: Overexpression of hTERT and CDK4R24C efficiently extended the lifespan of both CAFs-608 and CAFs-621. The number of established CAF clones was highest for CAFs-hTERT/CDK4R24C, with 57 and 62 clones established from CAFs-608 and CAFs-621, respectively. Conversely, 16 and 11 CAFs hTERT clones were derived from CAFs-608 and CAFs-621, respectively and 10 and 8 CAFs-CDK4R24C clones were from CAFs-608 and CAFs-621, respectively. TGF-b, ATCA2, and HSF1 mRNA levels differed in individual clones established from CAFs hTERT/CDK4R24C. The expression levels of ATCA2 and HSF1 were much higher in one clone than in the other established clones and the parental CAFs. CONCLUSION: Our results show that combined exogenous expression of hTERT and mutant CDK4 is an effective method to generate single-cell-derived CAF clones. This provides an innovative and suitable approach to investigate the heterogeneous function and phenotype of CAFs. PMID- 28364362 TI - Advantages of genome sequencing by long-read sequencer using SMRT technology in medical area. AB - PacBio RS II is the first commercialized third-generation DNA sequencer able to sequence a single molecule DNA in real-time without amplification. PacBio RS II's sequencing technology is novel and unique, enabling the direct observation of DNA synthesis by DNA polymerase. PacBio RS II confers four major advantages compared to other sequencing technologies: long read lengths, high consensus accuracy, a low degree of bias, and simultaneous capability of epigenetic characterization. These advantages surmount the obstacle of sequencing genomic regions such as high/low G+C, tandem repeat, and interspersed repeat regions. Moreover, PacBio RS II is ideal for whole genome sequencing, targeted sequencing, complex population analysis, RNA sequencing, and epigenetics characterization. With PacBio RS II, we have sequenced and analyzed the genomes of many species, from viruses to humans. Herein, we summarize and review some of our key genome sequencing projects, including full-length viral sequencing, complete bacterial genome and almost complete plant genome assemblies, and long amplicon sequencing of a disease associated gene region. We believe that PacBio RS II is not only an effective tool for use in the basic biological sciences but also in the medical/clinical setting. PMID- 28364364 TI - Possible Reversal of PTSD-Related DNA Methylation by Sympathetic Blockade. AB - Studies have shown that brain-derived neurotrophic factor (BDNF) level increase is associated with post-traumatic stress disorder (PTSD) risk. BDNF may be a "missing-link" that mediates the interaction between genetics, environment, and the sympathetic system. Trauma has been shown to induce DNA methylation that in turn can increase BDNF concentration due to increased gene expression. Therapies that focus on the reduction of beta-NGF (BNGF) levels may impact PTSD symptoms. The focus of this paper is to discuss possible effect of stellate ganglion block (SGB) on epigenetic changes noted with PTSD mediated by BDNF and NGF. Stellate ganglion block has recently shown significant therapeutic efficacy for treatment of PTSD symptoms. Previously reported theoretical mechanisms of SGB impact on PTSD have focused on likely reduction of NGF, leading to eventual loss of extraneous sympathetic nerve growth, eventually leading to reduction of secondary norepinephrine level, which in turn is hypothesized to reduce PTSD symptoms. We used PUBMED to obtain available data following a search for the following: DNA, neurotrophic factors, post-traumatic stress disorder, and demethylation following local anesthetic application. A number of articles meeting criteria were found and reviewed. Based on the evidence summarized, trauma can lead to DNA methylation, as well as BNGF/NGF level increase, which in turn starts a cascade of sympathetic sprouting, leading to increased brain norepinephrine, and finally symptomatic PTSD. Cascade reversal may occur in part by demethylation of DNA caused by application of local anesthetic to the stellate ganglion. PMID- 28364366 TI - A new tool-using bird to crow about. AB - The Hawaiian crow has been revealed as a skilled tool user, confirmed by testing the last members of this endangered species that survive in captivity. The finding suggests its behavior is tantalizingly similar to that of the famous tool using New Caledonian crow and has implications for the evolution of tool use and intelligence in birds. PMID- 28364365 TI - Release from proactive interference in rat spatial working memory. AB - A three-phase procedure was used to produce proactive interference (PI) in one trial on an eight-arm radial maze. Rats were forced to enter four arms for reward on an initial interference phase, to then enter the four remaining arms on a target phase, and to then choose among all eight arms on a retention test, with only the arms not visited in the target phase containing reward. Control trials involved only the target phase and the retention test. Lower accuracy was found on PI trials than on control trials, but performance on PI trials significantly exceeded chance, showing some retention of target memories. Changes in temporal and reward variables between the interference, target, and retention test phases showed release from PI, but changes in context and pattern of arm entry did not. It is suggested that the release from PI paradigm can be used to understand spatial memory encoding in rats and other species. PMID- 28364367 TI - Effects of task-irrelevant grouping on visual selection in partial report. AB - Perceptual grouping modulates performance in attention tasks such as partial report and change detection. Specifically, grouping of search items according to a task-relevant feature improves the efficiency of visual selection. However, the role of task-irrelevant feature grouping is not clearly understood. In the present study, we investigated whether grouping of targets by a task-irrelevant feature influences performance in a partial-report task. In this task, participants must report as many target letters as possible from a briefly presented circular display. The crucial manipulation concerned the color of the elements in these trials. In the sorted-color condition, the color of the display elements was arranged according to the selection criterion, and in the unsorted color condition, colors were randomly assigned. The distractor cost was inferred by subtracting performance in partial-report trials from performance in a control condition that had no distractors in the display. Across five experiments, we manipulated trial order, selection criterion, and exposure duration, and found that attentional selectivity was improved in sorted-color trials when the exposure duration was 200 ms and the selection criterion was luminance. This effect was accompanied by impaired selectivity in unsorted-color trials. Overall, the results suggest that the benefit of task-irrelevant color grouping of targets is contingent on the processing locus of the selection criterion. PMID- 28364368 TI - User Fees in General Practice: Willingness to Pay and Potential Substitution Patterns-Results from a Danish GP Patient Survey. AB - BACKGROUND: Increases in public expenditures to general practitioner (GP) services and specialist care have spurred debate over whether to implement user fees for healthcare services such as GP consultations in Denmark. OBJECTIVE: The objective of this study was to examine Danish patients' attitudes towards user fees and their willingness to pay (WTP) for a consultation, and to investigate how user charges may impact patients' behaviour. METHODS: A questionnaire survey was conducted in a GP clinic. RESULTS: A total of 343 individual persons answered the questionnaire. One hundred and seventy (50%) persons were not willing to pay for a consultation. Among patients reporting positive WTP values, the mean WTP was 137 (standard deviation 140) Danish kroner (DKK). Patients who were 65 years old or older were more likely to be willing to pay for a GP consultation than patients under the age of 65 years. Furthermore, patients with a personal annual income of more than 200,000 DKK were more likely to be willing to pay for a consultation than other income groups. With respect to patients with a positive WTP value, their own assessment of the seriousness of the consultation and their self-assessed health influenced the amount they would be willing to pay. Finally, we observed a stated willingness to substitute GP consultations with alternatives that are free of charge. CONCLUSION: About half of the patients with an appointment for a GP consultation are willing to pay for the consultation. User charges may potentially influence the patients' behaviour. ClinicalTrials.gov NCT01784731. PMID- 28364369 TI - Predicting Productivity Losses from Health-Related Quality of Life Using Patient Data. AB - OBJECTIVE: This paper estimates productivity loss using the health of the patient in order to allow indirect estimation of these costs for inclusion in economic evaluation. METHODS: Data from two surveys of inpatients [Health outcomes data repository (HODaR) sample (n = 42,442) and health improvement and patient outcomes (HIPO) sample (n = 6046)] were used. The number of days off paid employment or normal activities (excluding paid employment) was modelled using the health of the patients measured by the EQ-5D, international classification of diseases (ICD) chapters, and other health and sociodemographic data. Two-part models (TPMs) and zero-inflated negative binomial (ZINB) models were identified as the most appropriate specifications, given large spikes at the minimum and maximum days for the dependent variable. Analysis was undertaken separately for the two datasets to account for differences in recall period and identification of those who were employed. RESULTS: Models were able to reflect the large spike at the minimum (zero days) but not the maximum, with TPMs doing slightly better than the ZINB model. The EQ-5D was negatively associated with days off employment and normal activities in both datasets, but ICD chapters only had statistically significant coefficients for some chapters in the HODaR. CONCLUSIONS: TPMs can be used to predict productivity loss associated with the health of the patient to inform economic evaluation. Limitations include recall and response bias and identification of who is employed in the HODaR, while the HIPO suffers from a small sample size. Both samples exclude some patient groups. PMID- 28364370 TI - Recommendations for Managing Drug-Drug Interactions with Statins and HIV Medications. AB - The discovery of antiretroviral therapy (ART) for the treatment of human immunodeficiency virus (HIV) has enabled individuals to live longer. As a result, HIV is now often considered a chronic condition. However, as a result of the increase in longevity or the HIV treatment modalities themselves, individuals with HIV are at high risk for the development of atherosclerotic cardiovascular disease. Therefore, these patients should be optimized with pharmacologic therapy to lower their cardiovascular risk through the addition of statin therapy to their regimen. Unfortunately, many medications utilized to treat HIV interact with this class of agents, making prescribing of statin therapy in these patients challenging. While several classes of ARTs do not pose an increased risk of drug drug interactions with statins, HIV treatment often requires several combinations of medications, enhancing the complexity and drug-drug interaction risk. Clinicians should be aware of interactions with statins and ART and carefully review the degree and clinical significance of each particular medication. With this understanding, the appropriate statin as well as statin dose can be selected in order to optimize the treatment of this patient population, while minimizing the potential risk of adverse effects. PMID- 28364371 TI - Overcoming Challenges in Recruitment of South Asians for Health Disparities Research in the USA. AB - South Asians-individuals with origins in the countries of Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan, Sri Lanka, and other regions of the subcontinent-are an understudied and at-risk racial/ethnic minority population for disproportionate burden of preventable diseases in the USA. Notwithstanding lack of research disaggregating Asian American subgroups, a key factor in this paucity of data is the lack of participation and engagement of community members in studies which examine distribution and determinants of adverse health outcomes. The purpose of this case study series is to elucidate distinct barriers in recruitment of South Asians in health disparities research within four diverse study designs. These illustrations are followed by a discussion of effective strategies and promising practices to increase and enhance the participation of community members in health-related studies in order to ultimately understand and address disparities among this rapidly growing cultural group in the US systematic collection of data which not only is representative of this understudied population but also elucidates contextual influences on community health and well-being and is pivotal to the reduction and elimination of preventable disparities among South Asians in the USA. PMID- 28364372 TI - The Latino Physician Shortage: How the Affordable Care Act Increases the Value of Latino Spanish-Speaking Physicians and What Efforts Can Increase Their Supply. AB - The United States Latino population is growing at a rapid pace and is set to reach nearly 30% by 2050. The demand for culturally and linguistically competent health care is increasing in lockstep with this growth; however, the supply of doctors with skills and experience suited for this care is lagging. In particular, there is a major shortage of Latino Spanish-speaking physicians, and the gap between demand and supply is widening. The implementation of the Affordable Care Act (ACA) has increased the capacity of the US healthcare system to care for the growing Latino Spanish-speaking population, through health insurance exchanges, increased funding for safety net institutions, and efforts to improve efficiency and coordination of care, particularly with Accountable Care Organizations and the Hospital Readmissions Reduction Program. With these policies in mind, the authors discuss how the value of Latino Spanish-speaking physicians to the healthcare system has increased under the environment of the ACA. In addition, the authors highlight key efforts to increase the supply of this physician population, including the implementation of the Deferred Action for Childhood Arrivals Act, premedical pipeline programs, and academic medicine and medical school education initiatives to increase Latino representation among physicians. PMID- 28364373 TI - Longitudinal Changes and High-Risk Subgroups for Obesity and Overweight/Obesity Among Refugees in Buffalo, NY, 2004-2014. AB - INTRODUCTION: Very few studies have been conducted on non-communicable diseases among resettled refugees. The purpose of the study was to examine longitudinal changes in obesity and overweight/obesity rates among resettled refugees and identify high-risk subgroups. METHODS: Longitudinal health assessment data of 818 children (2-18 years) and 1055 adults (>=19 years) were used from a refugee clinic in Buffalo, NY, during 2004-2014. Univariate and bivariate analyses were performed. Risk factors of obesity and overweight/obesity were assessed using multivariate regression models. RESULTS: Obesity (8.7 to 12.7%) and overweight/obesity (16.9 to 26.7%) rates increased among children over 4.5 years (p < 0.01). Over 3.9 years, overweight/obesity rates increased in men (39.6 to 58.6%, p < 0.01) and women (55.1 to 73.5%, p < 0.01), exceeding the prevalence of overweight/obesity of 65.8% in US-born women. Interestingly, longitudinal overweight/obesity rates decreased among Middle Eastern (81.4 vs 78.0%, p < 0.01) and East European (75.0 vs 70.8%, p < 0.01) women. African children had 2.31 folds (odds ratio [OR] = 2.31; 95% confidence interval [CI] = 1.46-3.67) greater overweight/obesity risk than Asians. African girls who were not overweight or obese at baseline had the highest risk of becoming obese at follow-up visits (OR = 0.21; 95%CI = 0.09-0.52). For each additional year refugees lived in the USA, overweight/obesity risk among men (OR = 1.23; 95%CI = 1.09-1.39) and women (OR = 1.18; 95%CI = 1.04-1.35) increased. CONCLUSION: Obesity and overweight/obesity rates increased among refugees, but significant variations existed. Overweight/obesity rate among refugee women surpassed the US average. African origin, baseline weight, and longer duration of stay in the USA were risk factors. Culturally tailored programs are needed to prevent obesity and reduce health disparities among refugees. PMID- 28364374 TI - Improving Urban Minority Girls' Health Via Community Summer Programming. AB - Summertime has emerged as a high-risk period for weight gain among low-income minority youth who often experience a lack of resources when not attending school. Structured programming may be an effective means of reducing risk for obesity by improving obesogenic behaviors among these youth. The current multi method study examined sedentary time, physical activity, and dietary intake among low-income urban minority girls in two contexts: an unstructured summertime setting and in the context of a structured 4-week community-based summer day camp program promoting physical activity. Data were analyzed using paired-sample t tests and repeated-measure analyses of variance with significance at the p < .05 level. Results evidenced no significant differences in total calories and fat consumed between the unstructured and structured settings. Participants exhibited significant increases in fruit consumption and physical activity and significant decreases in sedentary time of over 2 h/day and dairy consumption when engaged in structured summer programming. All improvements were independent of weight status and age, and African-American participants evidenced greater changes in physical activity during programming. The study concludes that structured, community-based summertime programming may be associated with fewer obesogenic behaviors in low income urban youth and may be a powerful tool to address disparities in weight gain and obesity among high-risk samples. PMID- 28364375 TI - Longitudinal Motion Assessment of the Carotid Artery Using Speckle Tracking and Scale-Invariant Feature Transform. AB - The purpose of this work is to present and validate a novel approach for ultra sound-based speckle tracking to measure the carotid artery longitudinal displacement, and to assess the apparent sliding between of Intima-Media Complex (IMC) and Adventitia (Ad) layers. This method utilizes feature detectors and descriptors to localize and track keypoints for local motion quantification. The procedure was tested and validated on an in silico dataset and on 18 heathy volunteers and 16 patients. Accuracy measured on in silico data gave a mean +/- standard deviation of 23 +/- 15 and 19 +/- 18 MUm for IMC and Ad respectively, and thus smaller than the pixel size (0.0925 mm). Robustness analysis was performed on in vivo images, obtaining a maximum variation coefficient, over 5 repeated measures, of 9.5 and 13.8% for IMC and Ad, respectively. The novel method capability for detecting the relative motion of IMC vs. Ad was compared with visual assessment performed by 2 physicians, leading to a correlation coefficient R of 0.7 in the worst case. (Healthy group scored by rater #1.) In conclusion, our results provide evidence that the novel method is able to accurately and reliably track carotid artery layer motion and that it overcomes limitations currently present in the literature, therefore providing an automatic tool for clinical evaluation of IMC vs. Ad relative displacement. PMID- 28364376 TI - Incidental spade-shaped FDG uptake in the left ventricular apex suggests apical hypertrophic cardiomyopathy. AB - PURPOSE: Apical wall thickening with an "ace-of-spades" configuration is a unique sign of apical hypertrophic cardiomyopathy (AHCM). We investigated spade-shaped FDG uptake around the left ventricular apex (SSUA) incidentally found in routine oncological FDG PET. METHODS: Cases showing SSUA were selected based on retrospective review. The pattern or intensity of SSUA was compared with the results of electrocardiogram (ECG), echocardiography, and stress myocardial perfusion SPECT. The diagnosis of ACHM was based on the presence of giant negative T wave in ECG, thickness of spade-shaped hypertrophy in the apex in echocardiography, and increased tracer uptake in the apex in rest SPECT. RESULTS: Among the 34 patients in 36 PET scans showing SSUA, SSUA was weak in 17 and intense in 17. There were isolated SSUA (n = 29) and SSUA with diffuse or other focal left ventricular uptake (n = 5). Three patients with the latter uptake pattern turned out to have coexistence of AHCM and asymmetric septal hypertrophy. Of the 16 SSUA-positive patients who underwent echocardiography, 13 (81%) were diagnosed as AHCM and the remaining 3 were regarded as borderline AHCM (apical wall thickness, 14-15 mm). There were 16 patients with SSUA who also underwent PET scans after the study period among which 11 (69%) had persistent SSUA in the follow-up PET. In the remaining 5, follow-up PET scans showed diffuse left ventricular uptake and SSUA was barely visible. The intensity of SSUA was significantly or marginally associated with giant negative T wave (p < 0.01), apical asynergy (p = 0.08), and impaired coronary flow reserve (p < 0.05). There were no other factors correlated with the pattern or intensity of SSUA. CONCLUSION: SSUA incidentally found in oncological FDG PET appeared to be associated with AHCM, especially in ischemic conditions. The moderate repeatability of SSUA was probably due to obscurity by physiological uptake. PMID- 28364378 TI - Stoichiometry in aboveground and fine roots of Seriphidium korovinii in desert grassland in response to artificial nitrogen addition. AB - Nitrogen (N) input by atmospheric deposition and human activity enhances the availability of N in various ecosystems, which may further affect N and phosphorus (P) cycling and use by plants. However, the internal use of N, P, and N:P stoichiometry by plants in response to N supply, particularly for grass species in a desert steppe ecosystem, remains unclear. In this work, a field experiment was conducted at an infertile area in a desert steppe to investigate the effects of N fertilizer addition rates on the stoichiometry of N and P in a dominant grass species, Seriphidium korovinii. Results showed that for both aboveground and fine roots of S. korovinii, N inputs exponentially increased the N concentration and N:P ratios while P concentrations decreased. Meanwhile, the relationships between N and P concentrations for both aboveground and fine roots were significantly negative. Furthermore, while the N concentrations in the plants were relatively low, P concentrations were higher than the global means, resulting in a relatively low N:P ratio. These results suggest that the stoichiometric characteristics of N were different from that of P for this desert plant species. Results also show that the intraspecific variations in the main element traits (N, P, and N:P ratios) were consistent at the whole-plant level. Our results also suggest that N should be part of any short-term fertilization plan that is part of a management strategy designed to restore degraded desert grassland. These findings highlight that nutrient addition by atmospheric N deposition and human activity can have significant effects on the internal use of N and P by plants. Therefore, establishing a nutrient-conservation strategy for desert grasslands is important. PMID- 28364377 TI - Autophagy, programmed cell death and reactive oxygen species in sexual reproduction in plants. AB - Autophagy is one of the major cellular processes of recycling of proteins, metabolites and intracellular organelles, and plays crucial roles in the regulation of innate immunity, stress responses and programmed cell death (PCD) in many eukaryotes. It is also essential in development and sexual reproduction in many animals. In plants, although autophagy-deficient mutants of Arabidopsis thaliana show phenotypes in abiotic and biotic stress responses, their life cycle seems normal and thus little had been known until recently about the roles of autophagy in development and reproduction. Rice mutants defective in autophagy show sporophytic male sterility and immature pollens, indicating crucial roles of autophagy during pollen maturation. Enzymatic production of reactive oxygen species (ROS) by respiratory burst oxidase homologues (Rbohs) play multiple roles in regulating anther development, pollen tube elongation and fertilization. Significance of autophagy and ROS in the regulation of PCD of transient cells during plant sexual reproduction is discussed in comparison with animals. PMID- 28364379 TI - MicroR-545 mediates colorectal cancer cells proliferation through up-regulating epidermal growth factor receptor expression in HOTAIR long non-coding RNA dependent. AB - The functional impact of recently discovered miRNAs in human cancer remains to be clarified. One miRNA in colorectal cancer which has attracted attention is miR 545. In this study, we examined the function of miR-545 in proliferation of colorectal cancer cells. Expressions of HOTAIR, miRNA-545, and epidermal growth factor receptor (EGFR) mRNA were measured in 100 paired cancerous and non cancerous tissues as well as in SW480 and LOVO colorectal cancer cell (CRC) lines by quantitative RT-PCR. The relative protein level of EGFR was measured using western blotting. Effects of miRNA-545 and HOTAIR on gastric cancer cells were studied by overexpression and RNA interference approaches. Insight of mechanism of promotion cancer by miR-545 was gained from luciferase reporter assay and gene expression analysis. CRC proliferation was evaluated using clone formation and MTT assay. Differential expressions of HOTAIR, miR-545, and EGFR were observed in cancerous tissues in comparison to non-cancerous tissues. By expressional management of miR-545, we observed that miR-545 negatively regulated cell proliferation. Also luciferase reporter assay revealed that miR-545 inhibited regulated EGFR expression by affecting its 3'-UTR activity. In addition, miR-545 expression was suppressed by HOTAIR overexpression whereas enhanced by HOTAIR silence. Suppression of EGFR expression by miR-545 mimic was abrogated by HOTAIR overexpression. Monitoring of tumor growth in mice showed that miR-545 overexpression suppressed LOVO tumor growth. Our data suggested that HOTAIR long non-coding RNA mediates microR-545 regulating colorectal cancer cells proliferation. PMID- 28364381 TI - Adalimumab with Methotrexate in Treatment-Naive Japanese Patients with Rheumatoid Arthritis at Risk of Progressive Structural Joint Damage: A Postmarketing Observational Study. AB - INTRODUCTION: The objective of this study was to evaluate the real-world safety and effectiveness of adalimumab with methotrexate (MTX) in disease-modifying antirheumatic drug (DMARD)- and biologic-naive Japanese patients with rheumatoid arthritis (RA) at risk of progressive structural joint damage. METHODS: This multicenter, prospective, observational, postmarketing surveillance study was conducted between February 2013 and April 2015 at 84 centers in Japan. Patients with RA at risk of progressive structural joint damage were enrolled and initiated treatment with adalimumab and MTX. Adverse events were recorded up to week 28. Effectiveness/disease activity was assessed using the Disease Activity Score based on a 28-joint count with erythrocyte sedimentation rate and C reactive protein (DAS28-4ESR and DAS28-4CRP), Clinical Disease Activity Index, and Simplified Disease Activity Index at 0, 4, 12, and 24 weeks. DAS28-4CRP response was evaluated in the low-dose (<8 mg/week) and high-dose (>=8 mg to <=16 mg/week) MTX groups at week 24. RESULTS: One hundred fifty-seven of 163 patients comprised the safety cohort: mean (SD) age, 56.5 (13.9) years; females, 65.6%; rheumatoid factor positive, 73.2%; anti-cyclic citrullinated peptide antibody positive, 66.9%; bone erosions, 51.6%; mean disease duration, 9.5 months. The majority of patients (>=80%) had moderate or high disease activity at baseline, and >=50% with available data achieved remission or low disease activity at week 24 (DAS28-4CRP <3.2). Five serious adverse drug reactions occurred in four patients, including pyelonephritis, Pneumocystis jiroveci pneumonia, interstitial lung disease, pleurisy, and pericarditis; the outcomes were either recovered or recovering. Significant improvements/reductions in disease activity over 24 weeks were noted in all effectiveness measures (P < 0.0001). Most of the population achieved DAS28-4CRP remission (<2.6) at week 24 regardless of the MTX dose. CONCLUSION: Adalimumab in combination with MTX could be a beneficial treatment option for DMARD- and biologic-naive Japanese patients with RA at risk of progressive structural joint damage. FUNDING: AbbVie GK and Eisai. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01783730. PMID- 28364380 TI - Ubiquitin-specific protease 14 regulates LPS-induced inflammation by increasing ERK1/2 phosphorylation and NF-kappaB activation. AB - Persistent activation of nuclear factor B (NF-kappaB) is very important in the modulation of macrophages cellular response to microbial infections. The deubiquitinase USP14, which is critical for ubiquitin-mediated proteasomal degradation of proteins, is known to be involved in cancer, neurological diseases, and aging. However, the mechanism by which USP14 regulates inflammation remains unclear. Here, we demonstrated that decreasing the deubiquitinase activity of USP14 resulted in reduced lipopolysaccharides (LPS)-mediated tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 release in THP-1 and RAW264.7 cells. Meanwhile, USP14 knockdown by siRNA showed the same effects, with no cytotoxicity in THP-1 cells. Moreover, inhibiting the deubiquitinase activity of USP14 or USP14 knockdown resulted in decreased ERK1/2 and IkappaBalpha phosphorylation, increased amounts of the NF-kappaB inhibitor IkappaBalpha, and reduced NF-kappaB p65 transport from the cytoplasm into nucleus. These findings suggested that USP14 induces NF-kappaB activity and ERK1/2 phosphorylation triggered by microbial infection. PMID- 28364382 TI - Hypersensitivity to Orthopedic Implants: A Review of the Literature. AB - Awareness of rare etiologies for implant failure is becoming increasingly important. In addition to the overall increase in joint arthroplasties, revision surgeries are projected to increase dramatically in the coming years, with volume increasing up to seven-fold between 2005 and 2030. The literature regarding the relationship between metal allergy and implant failure is controversial. It has proven difficult to determine whether sensitization is a cause or a consequence of implant failure. Testing patients with functional implants is not a clinically useful approach, as the rate of hypersensitivity is higher in implant recipients than in the general population, regardless of the status of the implant. As a result of the ineffectiveness of preoperative patch testing for predicting adverse outcomes, as well as the high cost of implementing such patch testing as standard procedure, most orthopedists and dermatologists agree that an alternative prosthesis should only be considered for patients with a history of allergy to a metal in the standard implant. In patients with a failed implant requiring revision surgery, hypersensitivity to an implant component should be considered in the differential diagnosis. Because a metal allergy to implant components is currently not commonly considered in the differential for joint failure in the orthopedic literature, there should be improved communication and collaboration between orthopedists and dermatologists when evaluating joint replacement patients with a presentation suggestive of allergy. PMID- 28364383 TI - Acridine yellow. A novel use to estimate and measure the plasma membrane potential in Saccharomyces cerevisiae. AB - Translocation of ions and other molecules across the plasma membrane of yeast requires the electric potential generated by a H+-ATPase. We measured under different conditions fluorescence changes and accumulation of acridine yellow, looking for qualitative and quantitative estimations of the PMP in Saccharomyces cerevisiae in various conditions. Fluorescence changes indicated an accumulation of the dye requiring a substrate, and accumulation and quenching by mitochondria that could be released by an uncoupler. K+ produced a decrease of the fluorescence that was much lower upon the addition of Na+. These changes were confirmed by images of the cells under the microscope. The dye accumulation under different conditions showed changes consistent with the physiological situation of the cells. Since it accumulates due to the PMP, but a large part of it binds to the internal components, we permeabilized the cells with chitosan to subtract this factor and correct the accumulation data. Both raw and corrected values of PMP are different to those obtained before by other authors and our group, showing acridine yellow as a promising indicator to follow changes of the PMP by the fluorescence changes, but also by its accumulation. Under conditions described, the dye is a low cost monitor to define and follow qualitative and quantitative changes of PMP in yeast. Acridine yellow can also be used to follow changes of the mitochondrial membrane potential. PMID- 28364384 TI - Speaking Up: How Patient and Physician Voices Shaped a Trial to Improve Goals-of Care Discussions. AB - BACKGROUND: Patients with advanced cancer benefit from early goals-of-care (GoC) conversations, but few facilitators are known. OBJECTIVE: We describe the process and outcomes of involving patient and physician stakeholders in the design and development of a trial, funded by the Patient-Centered Outcomes Research Institute (PCORI), to enhance oncologists' communication skills and their propensity to facilitate productive, meaningful GoC discussions with patients with advanced cancer. METHODS: We recruited oncologists, palliative care physicians, and patient stakeholders to participate in proposal development, intervention design and modification, identification of outcome measures, and refinement of study tools. Formats for exchange included 1:1 structured interviews, workshops, and stakeholder meetings. RESULTS: Patient and physician voices helped craft and implement a study of an intervention to enhance oncologists' ability to facilitate GoC discussions with patients with advanced cancer. Physician inputs guided the creation of an oncologist and palliative care physician "joint visit" intervention at a turning point in disease management. Patient inputs impacted on the language used, outcome measures assessed, and approaches used to introduce patients to the intervention visit. CONCLUSIONS: Stakeholder input informed the development of a novel intervention that physicians seemed to find both valuable and in sync with their needs and their practice schedules. Where communication about difficult subjects and shared decision making are involved, including multiple stakeholder groups in study design, implementation, and outcomes measurement may have far-reaching effects. PMID- 28364385 TI - Patient Preferences for Pain Management in Advanced Cancer: Results from a Discrete Choice Experiment. AB - BACKGROUND: Pain from advanced cancer remains prevalent, severe and often under treated. AIM: The aim of this study was to conduct a discrete choice experiment with patients to understand their preferences for pain management services and inform service development. METHODS: Focus groups were used to develop the attributes and levels of the discrete choice experiment. The attributes were: waiting time, type of healthcare professional, out-of-pocket costs, side-effect control, quality of communication, quality of information and pain control. Patients completed the discrete choice experiment along with clinical and health related quality of life questions. Conditional and mixed logit models were used to analyse the data. RESULTS: Patients with cancer pain (n = 221) and within palliative care services completed the survey (45% were female, mean age 64.6 years; age range 21-92 years). The most important aspects of pain management were: good pain control, zero out-of-pocket costs and good side-effect control. Poor or moderate pain control and L30 costs drew the highest negative preferences. Respondents preferred control of side effects and provision of better information and communication, over access to certain healthcare professionals. Those with lower health-related quality of life were less willing to wait for treatment and willing to incur higher costs. The presence of a carer influenced preferences. CONCLUSIONS: Outcome attributes were more important than process attributes but the latter were still valued. Thus, supporting self management, for example by providing better information on pain may be a worthwhile endeavour. However, service provision may need to account for individual characteristics given the heterogeneity in preferences. PMID- 28364386 TI - Revolutionizing Informed Consent: Empowering Patients with Certified Decision Aids. PMID- 28364387 TI - Patients' Preferences for Outcome, Process and Cost Attributes in Cancer Treatment: A Systematic Review of Discrete Choice Experiments. AB - INTRODUCTION: As several studies have been conducted to elicit patients' preferences for cancer treatment, it is important to provide an overview and synthesis of these studies. This study aimed to systematically review discrete choice experiments (DCEs) about patients' preferences for cancer treatment and assessed the relative importance of outcome, process and cost attributes. METHODS: A systematic literature review was conducted using PubMed and EMBASE to identify all DCEs investigating patients' preferences for cancer treatment between January 2010 and April 2016. Data were extracted using a predefined extraction sheet, and a reporting quality assessment was applied to all studies. Attributes were classified into outcome, process and cost attributes, and their relative importance was assessed. RESULTS: A total of 28 DCEs were identified. More than half of the studies (56%) received an aggregate score lower than 4 on the PREFS (Purpose, Respondents, Explanation, Findings, Significance) 5-point scale. Most attributes were related to outcome (70%), followed by process (25%) and cost (5%). Outcome attributes were most often significant (81%), followed by process (73%) and cost (67%). The relative importance of outcome attributes was ranked highest in 82% of the cases where it was included, followed by cost (43%) and process (12%). CONCLUSION: This systematic review suggests that attributes related to cancer treatment outcomes are the most important for patients. Process and cost attributes were less often included in studies but were still (but less) important to patients in most studies. Clinicians and decision makers should be aware that attribute importance might be influenced by level selection for that attribute. PMID- 28364388 TI - Erratum to: Online information seeking by patients with bipolar disorder: results from an international multisite survey. PMID- 28364389 TI - Boron-bridged RG-II and calcium are required to maintain the pectin network of the Arabidopsis seed mucilage ultrastructure. AB - The structure of a pectin network requires both calcium (Ca2+) and boron (B). Ca2+ is involved in crosslinking pectic polysaccharides and arbitrarily induces the formation of an "egg-box" structure among pectin molecules, while B crosslinks rhamnogalacturonan II (RG-II) side chain A apiosyl residues in primary cell walls to generate a borate-dimeric-rhamnogalacturonan II (dRG-II-B) complex through a boron-bridge bond, leading to the formation of a pectin network. Based on recent studies of dRG-II-B structures, a hypothesis has been proposed suggesting that Ca2+is a common component of the dRG-II-B complex. However, no in vivo evidence has addressed whether B affects the stability of Ca2+ crosslinks. Here, we investigated the L-fucose-deficient dwarf mutant mur1, which was previously shown to require exogenous B treatment for phenotypic reversion. Imbibed Arabidopsis thaliana seeds release hydrated polysaccharides to form a halo of seed mucilage covering the seed surface, which consists of a water soluble outer layer and an adherent inner layer. Our study of mur1 seed mucilage has revealed that the pectin in the outer layer of mucilage was relocated to the inner layer. Nevertheless, the mur1 inner mucilage was more vulnerable to rough shaking or ethylene diamine tetraacetic acid (EDTA) extraction than that of the wild type. Immunolabeling analysis suggested that dRG-II-B was severely decreased in mur1 inner mucilage. Moreover, non-methylesterified homogalacturonan (HG) exhibited obvious reassembly in the mur1 inner layer compared with the wild type, which may imply a possible connection between dRG-II-B deficiency and pectin network transformation in the seed mucilage. As expected, the concentration of B in the mur1 inner mucilage was reduced, whereas the distribution and concentration of Ca2+in the inner mucilage increased significantly, which could be the reason why pectin relocates from the outer mucilage to the inner mucilage. Consequently, the disruption of B bridges appears to result in the extreme sensitivity of the mur1 mucilage pectin complex to EDTA extraction, despite the reinforcement of the pectin network by excessive Ca2+. Therefore, we propose a hypothesis that B, in the form of dRG-II-B, works together with Ca2+to maintain pectin network crosslinks and ultimately the mucilage ultrastructure in seed mucilage. This work may serve to complement our current understanding of mucilage configuration. PMID- 28364390 TI - In silico analysis of the sequence features responsible for alternatively spliced introns in the model green alga Chlamydomonas reinhardtii. AB - Alternatively spliced introns are the ones that are usually spliced but can be occasionally retained in a transcript isoform. They are the most frequently used alternative splice form in plants (~50% of alternative splicing events). Chlamydomonas reinhardtii, a unicellular alga, is a good model to understand alternative splicing (AS) in plants from an evolutionary perspective as it diverged from land plants a billion years ago. Using over 7 million cDNA sequences from both pyrosequencing and Sanger sequencing, we found that a much higher percentage of genes (~20% of multi-exon genes) undergo AS than previously reported (3-5%). We found a full component of SR and SR-like proteins possibly involved in AS. The most prevalent type of AS event (40%) was retention of introns, most of which were supported by multiple cDNA evidence (72%) while only 20% of them have coding capacity. By comparing retained and constitutive introns, we identified sequence features potentially responsible for the retention of introns, in the framework of an "intron definition" model for splicing. We find that retained introns tend to have a weaker 5' splice site, more Gs in their poly pyrimidine tract and a lesser conservation of nucleotide 'C' at position -3 of the 3' splice site. In addition, the sequence motifs found in the potential branch-point region differed between retained and constitutive introns. Furthermore, the enrichment of G-triplets and C-triplets among the first and last 50 nt of the introns significantly differ between constitutive and retained introns. These could serve as intronic splicing enhancers. All the alternative splice forms can be accessed at http://bioinfolab.miamioh.edu/cgi bin/PASA_r20140417/cgi-bin/status_report.cgi?db=Chre_AS . PMID- 28364391 TI - Histone Deacetylase 2 Inhibition Attenuates Downregulation of Hippocampal Plasticity Gene Expression during Aging. AB - The brain undergoes several anatomical, biochemical, and molecular changes during aging, which subsequently result in downregulation of synaptic plasticity genes and decline of memory. However, the regulation of these genes during aging is not clearly understood. Previously, we reported that the expression of histone deacetylase (HDAC)2 was upregulated in the hippocampus of old mice and negatively correlated with the decline in recognition memory. As HDAC2 regulates key synaptic plasticity neuronal immediate early genes (IEGs), we have examined their expression and epigenetic regulation. We noted that the expression of neuronal IEGs decreased both at mRNA and protein level in the hippocampus of old mice. To explore the underlying regulation, we analyzed the binding of HDAC2 and level of histone acetylation at the promoter of neuronal IEGs. While the binding of HDAC2 was higher, H3K9 and H3K14 acetylation level was lower at the promoter of these genes in old as compared to young and adult mice. Further, we inhibited HDAC2 non specifically by sodium butyrate and specifically by antisense oligonucleotide to recover epigenetic modification, expression of neuronal IEGs, and memory in old mice. Inhibition of HDAC2 increased histone H3K9 and H3K14 acetylation level at the promoter of neuronal IEGs, their expression, and recognition memory in old mice as compared to control. Thus, inhibition of HDAC2 can be used as a therapeutic target to recover decline in memory due to aging and associated neurological disorders. PMID- 28364392 TI - Burkholderia cepacia complex in cystic fibrosis in the post-epidemic period: multilocus sequence typing-based approach. AB - Cystic fibrosis (CF) patients in the Czech Republic suffered in the late 1990s from an epidemic with ST32 strain of Burkholderia cepacia complex (Bcc). Cohort segregation of Bcc and of ST32 positive patients was introduced in 1999 and 2002, respectively. We performed a study to evaluate the molecular epidemiology of Bcc infection after implementation of these infection control measures. Patients attending the Prague CF adult Centre from 2000 to 2015 were included in the present study. Demographic data and microbial statuses were collected from patient records. All Bcc isolates were analyzed using multilocus sequence typing (MLST). The prevalences of epidemic strain ST32 and of other Bcc strains were calculated. Ninety out of 227 CF patients were infected with Bcc during the study period. The prevalence of ST32 cases significantly decreased from 46.5% in 2000 2001 to 10.4% in 2014-2015 (P < 0.001) due to occurrence of only one new case in 2003, as well as to the death of 72% of ST32-infected patients. Conversely, there was a significant increase in prevalence of other Bcc strains, which rose from 0 to 14.9% (P = 0.015) and of transient infections. A micro-epidemic of infection with ST630 strain was observed in 2014 in lung transplant patients hospitalized in intensive care unit. The prevalence of epidemic strain ST32 decreased, whereas that of non-clonal strains of Bcc increased. Routine use of MLST allowed early detection of new and potentially epidemic strains. PMID- 28364393 TI - Lipid emulsion enhances cardiac performance after ischemia-reperfusion in isolated hearts from summer-active arctic ground squirrels. AB - Hibernating mammals, like the arctic ground squirrel (AGS), exhibit robust resistance to myocardial ischemia/reperfusion (IR) injury. Regulated preference for lipid over glucose to fuel metabolism may play an important role. We tested whether providing lipid in an emulsion protects hearts from summer-active AGS better than hearts from Brown Norway (BN) rats against normothermic IR injury. Langendorff-prepared AGS and BN rat hearts were perfused with Krebs solution containing 7.5 mM glucose with or without 1% IntralipidTM. After stabilization and cardioplegia, hearts underwent 45-min global ischemia and 60-min reperfusion. Coronary flow, isovolumetric left ventricular pressure, and mitochondrial redox state were measured continuously; infarct size was measured at the end of the experiment. Glucose-only AGS hearts functioned significantly better on reperfusion than BN rat hearts. IntralipidTM administration resulted in additional functional improvement in AGS compared to glucose-only and BN rat hearts. Infarct size was not different among groups. Even under non-hibernating conditions, AGS hearts performed better after IR than the best-protected rat strain. This, however, appears to strongly depend on metabolic fuel: IntralipidTM led to a significant improvement in return of function in AGS, but not in BN rat hearts, suggesting that year-round endogenous mechanisms are involved in myocardial lipid utilization that contributes to improved cardiac performance, independent of the metabolic rate decrease during hibernation. Comparative lipid analysis revealed four candidates as possible cardioprotective lipid groups. The improved function in IntralipidTM-perfused AGS hearts also challenges the current paradigm that increased glucose and decreased lipid metabolism are favorable during myocardial IR. PMID- 28364394 TI - Transcatheter Mitral Valve Interventions: Current Therapies and Future Directions. AB - OPINION STATEMENT: Transcatheter interventions for the treatment of aortic valve stenosis have become commonplace since the advent of transcatheter aortic valve implantation. However, transcatheter mitral valve therapies have lagged in development due to the complexity of mitral valve anatomy. Transcatheter edge-to edge leaflet repair using the MitraClip device provides an option for the treatment of severe primary mitral valve regurgitation in high or prohibitive surgical risk patients, and multiple novel approaches are evolving to replace or repair the mitral valve. Devices for the treatment of calcific mitral stenosis, primary mitral regurgitation, and functional mitral regurgitation have been developed and are currently either being evaluated in clinical trials or are in earlier stages of preclinical development. We are optimistic that our armamentarium will soon expand to include a myriad of transcatheter interventions for mitral valve disease. PMID- 28364396 TI - Interleukin-5 Inhibitors for Severe Asthma: Rationale and Future Outlook. AB - In this review, we outline the pathophysiology of severe asthma and discuss the role of anti-interleukin (IL)-5 inhibitors for the treatment of asthma. Anti-IL-5 treatments have shown efficacy in reducing the rate of severe asthma attacks in eosinophilic asthma. We review the history of the development of these agents, lessons learnt about severe asthma along the way and key clinical trials supporting efficacy of the three anti-IL-5 treatments that are clinically available or undergoing clinical trials in asthma. PMID- 28364395 TI - Severe and Asymptomatic Aortic Stenosis Management Challenge: Knowing That We Do Not Really Know. AB - OPINION STATEMENT: The clinical management of asymptomatic patients with severe aortic valve stenosis (AS) may be challenging. Indeed, there is substantial controversy over the optimal timing of intervention for these patients, as some advocate early intervention while others urge for a conservative management until symptom onset. In the meantime of randomized clinical trials aiming to compare both strategies of management, an integrative approach including several imaging modalities as well as biomarkers of the myocardial damage may help to improve the risk stratification of patients with asymptomatic severe AS and individualize strategy of treatment. The extent of aortic valve calcification, semi quantitatively assessed by echocardiography but better fully quantitatively measured by computed tomography (CT), provides incremental value to predict rapid disease progression and adverse event and thus could be a potential trigger for early referral to intervention or guide the timing of clinical follow-up. In addition, the assessment of disease activity using positron emission tomography, combined with CT calcium scoring, may also help to better predict the disease progression. The comprehensive assessment of left ventricular (LV) function using speckle-tracking echocardiography and/or cardiac magnetic resonance may provide useful information regarding the actual repercussion of AS on the myocardium. Besides imaging modalities, the measurement of several circulating biomarkers associated with the extent of the myocardial damage may also improve the risk stratification of asymptomatic patients with severe AS and help guiding management. Finally, it should be emphasized that a personalized medicine, including this comprehensive integrative approach in heart valve clinics, should be advocated for the management of these challenging patients. PMID- 28364397 TI - Superior mesenteric artery syndrome after lung transplantation: a rare early gastrointestinal complication of lung transplantation. AB - Gastrointestinal complications sometimes occur after lung transplantation and remain a cause of postoperative morbidity. Superior mesenteric artery syndrome is caused by the compression of the duodenum by the superior mesenteric artery, but few reports have described superior mesenteric artery syndrome after lung transplantation. We herein report two cases of superior mesenteric artery syndrome as an early complication after lung transplantation. Both patients were emaciated and had lost weight before transplantation. They also lost an additional 2-4 kg early after transplantation. They were medically treated with enteral nutrition and recovered without recurrence of the syndrome. Since critically ill patients with pulmonary disease usually lose weight both before and early after lung transplantation, superior mesenteric artery syndrome is important to consider in the differential diagnosis of gastrointestinal complications after transplantation. PMID- 28364398 TI - Risk factors for complications after diverting ileostomy closure in patients who have undergone rectal cancer surgery. AB - PURPOSE: To clarify the risk factors for complications after diverting ileostomy closure in patients who have undergone rectal cancer surgery. METHODS: The study group comprised 240 patients who underwent a diverting ileostomy at the time of lower anterior resection or internal anal sphincter resection, in our department, between 2004 and 2015. Univariate and multivariate analyses of 18 variables were performed to establish which of these are risk factors for postoperative complications. RESULTS: The most common complications were intestinal obstruction and wound infection. Univariate analysis showed that an age of 72 years or older (p = 0.0028), an interval between surgery and closure of 6 months or longer (p = 0.0049), and an operation time of 145 min or longer (p = 0.0293) were significant risk factors for postoperative complications. Multivariate analysis showed that age (odds ratio, 3.4236; p = 0.0025), the interval between surgery and closure (odds ratio, 3.4780; p = 0.0039), and operation time (odds 2.5179; p = 0.0260) were independent risk factors. CONCLUSIONS: Age, interval between surgery and closure, and operation time were independent risk factors for postoperative complications after diverting ileostomy closure. Thus, temporary ileostomy closure should be performed within 6 months after surgery for rectal cancer. PMID- 28364399 TI - Sphingosine-1-phosphate/sphingosine kinase 1-dependent lymph node metastasis in esophageal squamous cell carcinoma. AB - PURPOSE: To establish whether Sphingosine-1-phosphate (S1P) and sphingosine kinase 1 (SphK1) contribute to lymph node metastasis in esophageal squamous cell carcinoma. METHODS: Immunohistochemical analysis of SphK1 expression was performed using a tissue microarray containing 177 thoracic squamous cell esophageal cancer specimens resected at surgery, to investigate the association between intratumoral SphK1 expression and lymph node metastasis. Serum S1P levels and intratumoral SphK1 mRNA and protein expression were also evaluated in mice with vs. mice without lymph node metastasis in a murine lymph node metastasis model. RESULTS: Among 177 esophageal cancer patients, 127 (72%) were defined as being SphK1-positive. In univariate and multivariate analyses, SphK1 expression status was a significant factor contributing to lymph node metastasis and poorer 5-year overall survival. In the murine lymph node metastasis model, there was no difference in tumor volume or weight between the lymph node metastasis-negative and lymph node metastasis-positive groups. However, levels of SphK1 mRNA and protein and serum S1P levels were all much higher in the metastasis-positive group. CONCLUSIONS: S1P/SphK1 may be novel targets for inhibiting lymph node metastasis in esophageal squamous cell carcinoma, and may provide the basis for a therapeutic strategy to suppress lymph node metastasis. PMID- 28364400 TI - Impact of raking and bioturbation-mediated ecological manipulation on sediment water phosphorus diagenesis: a mesocosm study supported with radioactive signature. AB - The study examined the impact of raking and fish bioturbation on modulating phosphorus (P) concentrations in the water and sediment under different trophic conditions. An outdoor experiment was set to monitor physicochemical and microbiological parameters of water and sediment influencing P diagenesis. A pilot study with radioactive 32P was also performed under the agency of raking and bacteria (Bacillus sp.). Raking was more effective in release of P under unfertilized conditions by significantly enhancing orthophosphate (35%) and soluble reactive phosphate (31.8%) over respective controls. Bioturbation increased total and available P in sediments significantly as compared to control. The rates of increase were higher in the unfertilized conditions (17.6 28.4% for total P and 12.2 to 23.2% for available P) than the fertilized ones (6.5-12.4% for total P and 9.1 to 15% for available P). The combined effects of raking and bioturbation on orthophosphate and soluble reactive phosphate were also stronger under unfertilized state (54.5 and 81.8%) than fertilized ones (50 and 70%). The tracer signature showed that coupled action of introduced bacteria and repeated raking resulted in 59.2, 23 and 16% higher counts of radioactive P than the treatments receiving raking once, repeated raking and bacteria inoculation, respectively. Raking alone or in sync with bioturbation exerted pronounced impact on P diagenesis through induction of coupled mineralization and nutrient release. It has significant implication for performing regular raking of fish-farm sediments and manipulation of bottom-grazing fish to regulate mineralization of organic matter and release of obnoxious gases from the system. Further, they synergistically can enhance the buffering capacity against organic overload and help to maintain aquatic ecosystem health. PMID- 28364401 TI - Impaired engagement of the ventral attention system in neurofibromatosis type 1. AB - Individuals with neurofibromatosis type 1 (NF1) exhibit significant impairments in attention across multiple domains. Very little is known about the contributing neural networks. We used task-based functional magnetic resonance imaging (fMRI) to examine dorsal and ventral attention networks during auditory oddball processing in children and adolescents with NF1 and typically developing controls. Significant differences in neural activation patterns were identified within brain regions supporting the ventral attention system. Children with NF1 demonstrated hypoactivation in the temporoparietal junction and the anterior cingulate cortex compared to typically developing children. Hypoactivation in the anterior cingulate cortex was associated with poorer selective attention and attentional control in children with NF1. Results indicate an abnormality in bottom-up attention networks in NF1 that may lead to inefficient and faulty suppression of stimulus-driven information outside the current attentional set that play a significant role in the NF1 behavioral phenotype. PMID- 28364403 TI - Before You Send Out that Survey: The Nuts and Bolts of Implementing a Medical Student Survey Study. PMID- 28364402 TI - A Qualitative Exploration of the Help-Seeking Behaviors of Students Who Experience Psychological Distress Around Assessment at Medical School. AB - OBJECTIVE: Medical students are at high risk of experiencing psychological distress at medical school and developing mental ill-health during professional practice. Despite efforts by faculty to raise awareness about this risk, many students choose to suffer in silence in the face of psychological distress. The aim of this study was to explore drivers that prompted help-seeking behavior and barriers that prevented individuals prioritizing their well-being around the time of high-stakes assessment at medical school. METHODS: Semi-structured interviews were conducted with fifty-seven students who failed high-stakes assessment at two UK medical schools, exploring their experience of academic difficulty and perceptions about causes. A thematic analysis of twenty transcripts that met inclusion criteria was completed to identify key factors that influenced participants' decisions around seeking help for their psychological distress, and in some cases, mental health problems. Twenty participants who specifically described a deterioration in their mental health around the time of assessment were included in this study. RESULTS: Barriers to seeking help in these instances included: normalization of symptoms or situation; failure to recognize a problem existed; fear of stigmatisation; overt symptoms of mental distress; and misconceptions about the true nature of the medical school, for example beliefs about a punitive response from the school if they failed. Drivers for seeking help appropriately included: building trust with someone in order to confide in them later on, and self-awareness about the need to maintain good mental health. CONCLUSION: There are various drivers and barriers for students' help seeking behaviors when experiencing psychological distress around the time of assessment, particularly self-awareness about the problem and prioritisation of well-being. Students who fail to recognize their own deteriorating mental health are at risk of academic failure and medical schools need to develop strategies to tackle this problem in order to protect these students from harm. PMID- 28364404 TI - DSM-5 Post-Traumatic Stress Disorder Criteria in "Precious" (2009): Media Content Analysis for Educational Purposes. PMID- 28364406 TI - Component-resolved diagnostics in Thai children with cow's milk and egg allergy. AB - BACKGROUND AND OBJECTIVE: Component-resolved diagnostics (CRD) have garnered a lot of attention in recent years in the diagnosis of food allergies. We aimed to investigate sensitization against cow's milk and egg white components, and to study the clinical usefulness of serum food-specific immunoglobulin E (sIgE) to cow's milk and egg white components in Thai children with cow's milk and egg allergies. METHOD: Children with IgE-mediated cow's milk and/or egg allergy were enrolled. Clinical reactions were determined. Specific IgE against cow's milk, egg white, alpha-lactalbumin (ALA), beta-lactoglobulin (BLG), casein, ovomucoid, ovalbumin and conalbumin were measured. RESULTS: Thirteen cow's milk allergic subjects and 32 egg allergic subjects were identified. The sensitization rate to BLG and casein was 91.7%, followed by ALA (66.7%) for cow's milk, and the sensitization rate to ovalbumin was 93.8%, followed by ovomucoid (81.3%) and conalbumin (37.5%) for egg. Patients in the urticaria group had a higher level of casein sIgE than the atopic dermatitis (AD) group but this difference was not significant (9.8 kUA/L vs. 0.9 kUA/L, p = 0.11). The level of ovomucoid sIgE was significantly higher in the non-AD group than in the AD group (3.8 kUA/L vs. 1.3 kUA/L, p = 0.048). CONCLUSIONS: BLG and casein for cow's milk and ovomucoid and ovalbumin for egg were the common components causing sensitization in cow's milk and egg allergic patients. Among the patients with cow's milk allergy, the level of casein sIgE in the urticaria group tended to be higher than the AD group, and in egg allergic patients, the non-AD group had a significantly higher ovomucoid sIgE level compared with the AD group. PMID- 28364405 TI - Evidence accumulation in the integrated and primed Stroop tasks. AB - We report distributional analyses of response times (RT) in two variants of the color-word Stroop task using manual keypress responses. In the classic Stroop task, in which the color and word dimensions are integrated into a single stimulus, the Stroop congruence effect increased across the quantiles. In contrast, in the primed Stroop task, in which the distractor word is presented ahead of colored symbols, the Stroop congruence effect was manifested solely as a distributional shift, remaining constant across the quantiles. The distributional shift pattern mirrors the semantic-priming effect that has been reported in semantic categorization tasks. The results are interpreted within the framework of evidence accumulation, and implications for the roles of task conflict and informational conflict are discussed. PMID- 28364407 TI - Mosquito allergy in children: Clinical features and limitation of commercially available diagnostic tests. AB - OBJECTIVE: To determine the clinical features of mosquito allergy in children and the ability of commercially available mosquito allergy tests to detect children with mosquito allergy in Thailand. METHODS: Patients with mosquito allergy aged 1 month to 18 years were recruited. Demographic data, history of mosquito allergy (onset of the reaction, reaction type) and clinical features were recorded. A skin prick test using a commercially available whole body allergen extract from Culex pipiens was performed, and serum was tested for specific IgE antibodies to Aedes communis whole body extract. RESULTS: A total of 50 patients with mosquito allergy were enrolled. The median age of enrolled children was 6.2 years with an average age of onset of 2 years [interquartile range (IQR) 1-6]. Half of the children were female. The most common skin lesion from mosquito allergy was erythematous papules (n = 45, 76.3%). The majority of children (58%) were in stage 3 (immediate and delayed type of reactions). One child (2%) was in the desensitization stage after 4.6 years of symptoms. The causative mosquito species could be identified only in 26 (52%) children: 16 (32%) children were positive for Aedes communis, 17 (34%) children were positive for Culex pipiens and 7 (14%) children were positive for both Aedes communis and Culex pipiens. Having positive IgE antibodies against Aedes communis was significantly more common in boys (n = 13, 48.1%) than girls (n = 3, 13%) (p < 0.01). CONCLUSIONS: Immediate and delayed skin reaction is the most common manifestation in mosquito allergy children. Commercially available tests for mosquito allergy can detect only 30-50% of children with mosquito allergy. PMID- 28364408 TI - Comparison of the efficacy and safety of pollen allergen extracts using skin prick testing and serum specific IgE as references. AB - BACKGROUND: Allergen extracts may be different due to the difference in dissemination of allergen-containing species in various geographical areas. Therefore, we wish to develop our own extracts to ensure the precision and quality of diagnosis. OBJECTIVES: To compare the efficacy and safety of our locally prepared pollen allergen extracts to imported ones, using skin prick testing (SPT) and serum specific IgE (sIgE) as references. METHODS: This prospective, randomized, double-blinded, self-controlled study was performed in respiratory allergic adult volunteers who are sensitized to at least one kind of pollen. Each subject was pricked with our Bermuda grass, Johnson grass and careless weed pollen allergen extracts, and also with the imported ones. sIgE levels were measured by using ImmunoCAP?. RESULTS: In 68 volunteers, our Bermuda, Johnson and careless weed extracts showed 91.2%, 45.6% and 54.4% positive SPTs, respectively, while for the imported ones 73.5%, 45.6% and 54.4% SPTs were positive, respectively. No adverse reaction was found in all procedures. The concentration of 10,000 BAU/mL of Bermuda grass, 1 : 20 w/v or 10,000 PNU/mL of Johnson grass and 1 : 40 w/v or 10,000 PNU/mL of careless weed yielded the most positive SPT results. There was no significant difference in mean wheal diameter (MWD) yielded from using local and imported extracts. Significant correlation was found between MWDs of imported pollen extracts and serum sIgE levels (p < 0.01). CONCLUSIONS: No significant difference between SPT results of local and imported pollen allergen extracts was found. Significant correlation was found between MWDs of imported pollen extract SPT and serum sIgE levels. PMID- 28364409 TI - Metabolomics analysis of anaphylactoid reaction reveals its mechanism in a rat model. AB - BACKGROUND: Anaphylactoid reactions, accounting for more than 77% of all immune mediated immediate hypersensitivity reactions, have become a serious threat to public health, but their effect mechanism is not clear and diagnostic tests are limited. Comprehensive metabolite analysis may reveal the anaphylactoid effect mechanism systematically and provide reference for future diagnostic purposes. METHODS: Plasma from Brown Norway rats given intravenous injection of saline, compound 48/80 (2.5 mL/kg) or ovalbumin (20 mL/kg) in 20 s for the first time was used to study the effect mechanism of anaphylactoid reactions through metabolomics (UPLC-qTOF-MS/MS). Metabolomics integrated with proteomics data were used to analyze the anaphylactoid pathways by MetaboAnalyst followed by integrated pathway analysis. RESULTS: Thirty metabolites were identified through the METLIN database by MS/MS and 18 of them were confirmed by authentic standards. The results showed that adenosine, histamine, N-acetylhistamine, N(alpha)-gamma-glutamylhistamine, malate and xanthine are important indices for anaphylactoid reactions. It could be concluded that the effect mechanism is mainly composed of histidine metabolism, arachidonic acid metabolism, energy metabolism, purine metabolism and other small molecules through 30 metabolites. Multiple linear regression analysis indicated that not only histamine but also N(alpha)-gamma-glutamylhistamine and arachidonic acid could be used to evaluate anaphylactoid symptoms of animals. Furthermore, the citrate cycle, histidine metabolism and arachidonic acid metabolism could be the main pathways of anaphylactoid reactions as determined by MetaboAnalyst. CONCLUSION: The results may provide a reference to improve diagnostic accuracy and predict and monitor treatment efficacy in anaphylactoid reactions in the clinical setting. PMID- 28364410 TI - Association analyses identify two susceptibility loci 5q31 and 5q22.1 for atopic dermatitis in Chinese Han population. AB - BACKGROUND: Atopic dermatitis (AD) and other atopic diseases often share some common genetic and pathogenic bases. Recent genome-wide association studies (GWAS) have identified several loci associated with atopic diseases, allergic sensitization and asthma in different populations. The aim of this study was to investigate whether these susceptibility loci were related to AD in Chinese Han population. METHODS: Eight single nucleotide polymorphisms (SNPs) from recent atopic diseases and allergic sensitization GWAS were genotyped in 3,013 AD patients and 5,483 healthy controls in Chinese Han population using Sequenom MassArray system. Data was analyzed with PLINK 1.07 software. RESULTS: We identified that the susceptibility loci at 5q31 (RAD50/IL13, rs2158177, P = 1.08*10-3, OR = 1.15) and 5q22.1 (TSLP, rs1837253, P = 2.66*10-3, OR = 0.91) were significantly associated with AD. Genotype-based association testing revealed that the dominant model provided the best fit for both rs2158177 (P = 3.75*10-3) and rs1837253 (P = 5.30*10-3). Pathway analysis conformed that both loci were associated with the JAK-STAT signaling pathway. CONCLUSIONS: We identified two susceptibility loci 5q31 and 5q22.1 for AD that might bear candidate genes conferring susceptibility to AD. PMID- 28364411 TI - Urinary cysteinyl leukotriene E4 level and therapeutic response to montelukast in children with mild obstructive sleep apnea. AB - BACKGROUND: Antileukotriene has been used for alleviating disease severity in children with adenotonsillar hypertrophy (ATH) and mild obstructive sleep apnea (OSA). Previous study showed the relationship between urinary cysteinyl leukotriene E4 (uLTE4) level and therapeutic response to montelukast in asthmatic adults. However, this relationship has never been investigated in pediatric OSA. OBJECTIVES: To determine the relationship between uLTE4 level and therapeutic response to montelukast in children with ATH and mild OSA. METHODS: Children aged 3-15 yrs who had ATH and mild OSA were enrolled. All had quality of life (assessed by Thai version OSA-18 QoL questionnaire) and uLTE4 levels measured prior to start a 6-week course of montelukast treatment. Overnight polysomnography (PSG) and QoL reassessment were performed after completing the treatment. Those who demonstrated a large improvement of mean total QoL score or >= 50% decrease of obstructive apnea-hypopnea index (OAHI) after the treatment were defined as responders. RESULTS: Twenty-six children were enrolled (mean age 7.5 +/- 2.9 yrs, 38.5% male). After 6-week course of montelukast, nine (34.6%) children showed significant improvement. The mean uLTE4 level from the responders was higher comparing to the non-responders (2,952.56 +/- 966.9 vs. 978.6 +/- 460.8 pg/mg creatinine; p < 0.001). uLTE4 level of >= 1,457 pg/mg creatinine had 100% sensitivity and 88.2% specificity in identifying the responders. CONCLUSIONS: We found the association between ULTE4 and therapeutic response to monteleukast. The uLTE4 level of >= 1,457 pg/mg creatinine could predict the therapeutic response to montelukast in children who had ATH and mild OSA. PMID- 28364412 TI - The validation and evaluation of anti-HIV testing algorithm used in mobile clinic setting for men who have sex with men in metropolitan Bangkok, Thailand. AB - BACKGROUND: Same-day anti-HIV testing algorithm is recommended by Thai National Guidelines. We compared performance characteristics of algorithms used in a mobile clinic and a facility-based clinic for men who have sex with men (MSM) in Bangkok. METHODS: Mobile clinic samples collected from 4 saunas and 2 spa venues were tested by Alere DetermineTM HIV 1/2, followed by DoubleCheck GoldTM Ultra HIV 1/2 and SD Bioline HIV 1/2 3.0. All samples were re-tested at the Thai Red Cross Anonymous Clinic (TRCAC) by Architect HIV Ag/Ab or Elecsys HIV combi PT, followed by Alere DetermineTM HIV 1/2 and Serodia HIV 1/2. Non-reactive samples were tested by Aptima nucleic acid amplification test (NAAT) and reactive/inconclusive samples were tested by less-sensitive immunoassays (IA) and HIV-1 RNA to detect acute HIV infection (positive NAAT or non-reactive IA/positive HIV-1 RNA). RESULTS: Of 233 MSM, 36 (15.5%) had HIV infection diagnosed using mobile clinic algorithm. Two additional acute HIV cases (1 positive NAAT and 1 reactive Architect with detectable HIV-1 RNA) were diagnosed using TRCAC algorithm. The mobile clinic algorithm had a sensitivity of 94.9% (95% CI: 82.7, 99.4) and a specificity of 100% (95% CI: 98.1, 100). CONCLUSION: Use of whole blood on rapid test kits demonstrated satisfactory performance and allowed same-day HIV test result through a mobile clinic model. For populations with high HIV incidence, careful history taking to define the window period is crucial and repeat testing must be encouraged if the testing algorithm does not include 4th generation anti-HIV assay or NAAT. PMID- 28364413 TI - Family Income and Material Deprivation: Do They Matter for Sleep Quality and Quantity in Early Life? Evidence From a Longitudinal Study. AB - Introduction: The aim of this article is to investigate the determinants of sleeping patterns in children up to age 9 on a large and geographically homogeneous sample of British children and parents, focusing in particular on the role of economic and social factors, specifically on income. Aims and Methods: The data of this study come from the Avon Longitudinal Study of Parents and Children, a long-term health research project that recruited over 14000 pregnant women who were due to give birth between April 1991 and December 1992 in Bristol and its surrounding areas, including some of Somerset and Gloucestershire. Logistic regression models for the sleep problem dummies and log-linear models for the sleep quantity. Results: One additional item in the material deprivation index is associated to an increase of around 10-20% in the odds of having at least 1 sleep problem. Similarly, children from the richest families are less likely to have any sleep problem up to 115 months (around 20% reduction in the odds). Mother's characteristics (i.e., education and mental health in the pregnancy period) are also significant predictors. Sleep quantity does not vary much and is not sensitive to socioeconomic factors. Conclusion: Exposure to income-related inequalities affects child sleep. Further research is needed to understand if sleep in early life influences future health and economic trajectories. PMID- 28364414 TI - Orexin and Epilepsy: Potential Role of REM Sleep. AB - Interest in orexin receptor antagonism as a novel mechanism of action against seizures and epilepsy has increased in recent years. Loss of orexinergic activity is associated with rapid eye movement (REM) sleep onset, and REM sleep is generally protective against seizures. This paper discusses the dynamic modulation of seizure threshold by orexin through a postulated "orexi-cortical" axis in which the specific type of orexinergic activity exquisitely regulates sleep-wake states to modify ascending subcortical influences on cortical synchronization with profound subsequent consequences on seizure threshold. This paper also explores the current state of research into experimental orexinergic modulation of seizure threshold and suggests possible future research directions to fully understand the promise and peril of orexinergic manipulation in seizures and epilepsy. PMID- 28364416 TI - Periodic Limb Movements During Sleep Mimicking REM Sleep Behavior Disorder: A New Form of Periodic Limb Movement Disorder. AB - Study Objectives: To describe a group of patients referred because of abnormal sleep behaviors that were suggestive of rapid eye movement (REM) sleep behavior disorder (RBD) in whom video-polysomnography ruled out RBD and showed the reported behaviors associated with vigorous periodic limb movements during sleep (PLMS). Aims and Methods: Clinical history and video-polysomnography review of patients identified during routine visits in a sleep center. Results: Patients were 15 men and 2 women with a median age of 66 (range: 48-77) years. Reported sleep behaviors were kicking (n = 17), punching (n = 16), gesticulating (n = 8), falling out of bed (n = 5), assaulting the bed partner (n = 2), talking (n = 15), and shouting (n = 10). Behaviors resulted in injuries in 3 bed partners and 1 patient. Twelve (70.6%) patients were not aware of displaying abnormal sleep behaviors that were only noticed by their bed partners. Ten (58.8%) patients recalled unpleasant dreams such as being attacked or chased. Video polysomnography showed (1) frequent and vigorous stereotyped PLMS involving the lower limbs, upper limbs, and trunk (median PLMS index 61.2; median PLMS index in NREM sleep 61.9; during REM sleep only 8 patients had PLMS and their median PLMS index in REM sleep was 39.5); (2) abnormal behaviors (e.g., punching, groaning) during some of the arousals that immediately followed PLMS in NREM sleep; and (3) ruled out RBD and other sleep disorders such as obstructive sleep apnea. Dopaminergic agents were prescribed in 14 out of the 17 patients and resulted in improvement of abnormal sleep behaviors and unpleasant dreams in all of them. After dopaminergic treatment, follow-up video-polysomnography in 7 patients showed a decrease in the median PLMS index from baseline (108.9 vs. 19.2, p = .002) and absence of abnormal behaviors during the arousals. Conclusions: Abnormal sleep behaviors and unpleasant dreams simulating RBD symptomatology may occur in patients with severe PLMS. In these cases, video-polysomnography ruled out RBD and identified prominent PLMS followed by arousals containing abnormal behaviors. Our cases represent an objectively documented subtype of periodic limb movement disorder causing abnormal sleep behaviors. PMID- 28364415 TI - Using Oscillating Sounds to Manipulate Sleep Spindles. AB - Introduction: EEG oscillations known as sleep spindles have been linked with various aspects of cognition, but the specific functions they signal remain controversial. Two types of EEG sleep spindles have been distinguished: slow spindles at 11-13.5 Hz and fast spindles at 13.5-16 Hz. Slow spindles exhibit a frontal scalp topography, whereas fast spindles exhibit a posterior scalp topography and have been preferentially linked with memory consolidation during sleep. To advance understanding beyond that provided from correlative studies of spindles, we aimed to develop a new method to systematically manipulate spindles. Aims and Methods: We presented repeating bursts of oscillating white noise to people during a 90-min afternoon nap. During stage 2 and slow-wave sleep, oscillations were embedded within contiguous 10-s stimulation intervals, each comprising 2 s of white noise amplitude modulated at 12 Hz (targeting slow spindles), 15 Hz (targeting fast spindles), or 50 Hz followed by 8 s of constant white noise. Results: During oscillating stimulation compared to constant stimulation, parietal EEG recordings showed more slow spindles in the 12-Hz condition, more fast spindles in the 15-Hz condition, and no change in the 50-Hz control condition. These effects were topographically selective, and were absent in frontopolar EEG recordings, where slow spindle density was highest. Spindles during stimulation were similar to spontaneous spindles in standard physiological features, including duration and scalp distribution. Conclusions: These results define a new method to selectively and noninvasively manipulate spindles through acoustic resonance, while also providing new evidence for functional distinctions between the 2 types of EEG spindles. PMID- 28364418 TI - The Benefit of Directed Forgetting Persists After a Daytime Nap: The Role of Spindles and Rapid Eye Movement Sleep in the Consolidation of Relevant Memories. AB - Study Objectives: We aimed to investigate the effect of directed forgetting instruction on memory retention after a 2-hour delay involving a daytime nap or an equivalent amount of time spent awake. We examined the associations between sleep-specific oscillations and the retention of relevant and irrelevant study materials. Methods: We applied a list-method directed forgetting paradigm manipulating the perceived relevance of previously encoded lists of words. Participants were randomly assigned to either a nap or an awake group, and to a remember or a forget subgroup. The remember and the forget subgroups were both instructed to study two consecutive lists of words, although, the forget subgroup was manipulated to forget the first list and memorize only the second one. Participants were 112 healthy individuals (44 men; Mage = 21.4 years, SD = 2.4). Results: A significant directed forgetting effect emerged after a 2-hour delay both in the awake and sleep conditions; however, the effect was more pronounced within the sleep group. The benefit of directed forgetting, that is, relatively enhanced recall of relevant words in the forget group, was evidenced only in those participants that reached rapid eye movement (REM) phase. Non-rapid eye movement (NREM) sigma power was correlated with memory performance for the relevant (second) list, and sleep spindle amplitude was associated with the retention of both lists. These associations, however, were detected only within the forget subgroup. REM duration correlated with recall performance for the relevant (second) list within the forget subgroup, and with recall performance for the first list within the remember subgroup. Conclusions: A directed forgetting effect persists after a 2-hour delay spent awake or asleep. Spindle related activity and subsequent REM sleep might selectively facilitate the processing of memories that are considered to be relevant for the future. PMID- 28364417 TI - An Aggregate Measure of Sleep Health Is Associated With Prevalent and Incident Clinically Significant Depression Symptoms Among Community-Dwelling Older Women. AB - Objectives: Sleep can be characterized along multiple dimensions. We investigated whether an aggregate measure of sleep health was associated with prevalent and incident clinically significant depression symptoms in a cohort of older women. Methods: Participants were older women (mean age 80.1 years) who completed baseline (n = 6485) and follow-up (n = 3806) visits, approximately 6 years apart, in the Study of Osteoporotic Fractures (SOF). Self-reported sleep over the past 12 months was categorized as "good" or "poor" across 5 dimensions: satisfaction with sleep duration, daytime sleepiness, mid-sleep time, sleep onset latency, and sleep duration. An aggregate measure of sleep health was calculated by summing the number of "poor" dimensions. Clinically significant depression symptoms were defined as a score >=6 on the Geriatric Depression Scale. Relationships between sleep health and depression symptoms were evaluated with multivariate logistic regression, adjusting for health measures and medications. Results: Individual sleep health dimensions of sleep satisfaction, daytime sleepiness, mid-sleep time, and sleep onset latency were significantly associated with prevalent depression symptoms (odds ratios [OR] = 1.26-2.69). Sleep satisfaction, daytime sleepiness, and sleep onset latency were significantly associated with incident depression symptoms (OR = 1.32-1.79). The number of "poor" sleep health dimensions was associated in a gradient fashion with greater odds of prevalent (OR = 1.62-5.41) and incident (OR = 1.47-3.15) depression symptoms. Conclusion: An aggregate, multidimensional measure of sleep health was associated with both prevalent and incident clinically-significant depression symptoms in a gradient fashion. Future studies are warranted to extend these findings in different populations and with different health outcomes. PMID- 28364419 TI - Sleep Perception and Misperception in Chronic Cocaine Users During Abstinence. AB - Study Objectives: During abstinence, chronic cocaine users experience an objective worsening of sleep that is perceived as qualitatively improving. This phenomenon has been termed "occult insomnia." The objective of this study was to determine whether chronic cocaine users experience positive sleep state misperception during abstinence. Methods: Forty-three cocaine-dependent persons were admitted to an inpatient research facility for 12 days and 11 nights to participate in a treatment study of modafinil. Polysomnographic sleep recordings were performed on study nights 3, 4, 10, and 11, when participants were on average 1 and 2 weeks abstinent from cocaine. Participants also completed sleep diary questionnaires every evening before bed and every morning upon awakening. Polysomnographic and sleep diary measurements of total sleep time, sleep latency, time awake after sleep onset, and time in bed after final awakening were compared. Results: Chronic cocaine users accurately reported total sleep time after 1 week of abstinence but overreported total sleep time by an average of 40 min after 2 weeks of abstinence. Underestimating sleep latency and time spent awake after sleep onset were responsible for this difference. Conclusions: Positive sleep state misperception is revealed in chronic cocaine users after 2 weeks of abstinence and is consistent with the previously identified "occult insomnia" in this population. PMID- 28364422 TI - Mediterranean Diet and Changes in Sleep Duration and Indicators of Sleep Quality in Older Adults. AB - Study Objective: To examine the association between adherence to a Mediterranean diet (MD) and changes in sleep duration and sleep quality in older adults. Methods: We used data from 1596 participants in the Seniors-ENRICA cohort aged >= 60 years. MD was evaluated in 2012 with the Mediterranean Diet Adherence Screener (MEDAS) score. Sleep duration (h) and indicators of poor sleep quality were assessed both in 2012 and 2015. Analyses were adjusted for sociodemographic, lifestyle and morbidity variables, and for sleep duration and the number of poor sleep indicators at baseline. Results: Over a median follow-up of 2.8 years, 12.2% of individuals increased and 8.8% decreased their sleep duration by >=2 h/night. Compared with those in the lowest tertile of adherence to the MD in 2012, those in the highest tertile showed both a lower risk of a >=2 h/night increase in sleep duration (odds ratio [OR]: 0.54, 95% confidence interval [CI] 0.34-0.85, p-trend = .01) and of a >=2 h/night decrease (OR: 0.58, 95% CI 0.35 0.95, p-trend = 0.02) from 2012 to 2015. Being in the highest tertile of MD in 2012 was also associated with lower risk of poor sleep quality at follow-up, the OR (95% CI) for having 2-3 indicators of poor sleep was 0.70 (0.51-0.97) and for >=4 indicators was 0.68 (0.47-0.99, p-trend = .04). High adherence to the MD was also associated with 56% lower odds of having large changes in sleep duration and >=2 indicators of poor sleep quality simultaneously (OR: 0.44, 95% CI 0.29-0.68, p trend < .001). Conclusions: Adherence to a MD pattern was associated with lower risk of changes in sleep duration and with better sleep quality in older adults. PMID- 28364420 TI - CD4+ T-Cell Reactivity to Orexin/Hypocretin in Patients With Narcolepsy Type 1. AB - Introduction: Narcolepsy type 1 is accompanied by a selective loss of orexin/hypocretin (hcrt) neurons in the lateral hypothalamus caused by yet unknown mechanisms. Epidemiologic and genetic associations strongly suggest an immune-mediated pathogenesis of the disease. Methods: We compared specific T-cell reactivity to orexin/hcrt peptides in peripheral blood mononuclear cells of narcolepsy type 1 patients to healthy controls by a carboxyfluorescein succinimidyl ester proliferation assay. Orexin/hcrt-specific T-cell reactivity was also determined by cytokine (interferon gamma and granulocyte-macrophage colony-stimulating factor) analysis. Individuals were considered as responders if the cell division index of CD3+CD4+ T cells and both stimulation indices of cytokine secretion exceeded the cutoff 3. Additionally, T-cell reactivity to orexin/hcrt had to be confirmed by showing reactivity to single peptides present in different peptide pools. Results: Using these criteria, 3/15 patients (20%) and 0/13 controls (0%) showed orexin/hcrt-specific CD4+ T-cell proliferation (p = .2262). The heterogeneous reactivity pattern did not allow the identification of a preferential target epitope. Conclusions: A significant role of orexin/hcrt specific T cells in narcolepsy type 1 patients could not be confirmed in this study. Further studies are needed to assess the exact role of CD4+ T cells and possible target antigens in narcolepsy type 1 patients. PMID- 28364421 TI - Development of Circadian Sleep Regulation in the Rat: A Longitudinal Study Under Constant Conditions. AB - Study Objectives: To better understand the development of sleep, we characterized the development of circadian rhythms in sleep and wakefulness in the artificially reared, isolated rat pup using an experimental design that minimized the effects of maternal separation. Methods: Neonatal rats were reared in constant conditions (dim red light) while electroencephalographic and electromyographic signals were continuously recorded for up to 3 weeks. This time period spanned the preweaned and weaned ages. The distribution of sleep-wake states was analyzed to estimate the emergence of circadian rhythms. Results: Overt ~24-hour rhythms in time spent awake and asleep appear by postnatal day (P)17. A marked bi-modal sleep-wake pattern was also observed, evidenced by the appearance of a pronounced ~12-hour component in the periodogram over the subsequent 3 days (P17-P21). This suggested the presence of two ~24-hour components consistent with the dual-oscillator concept. During this 3-day time window, waking bouts became longer resulting in a repartition of the duration of intervals without non-rapid-eye movement (NREM) sleep into short (<30 minutes) and longer inter-NREM sleep episodes. These longer waking bouts did not immediately result in an increase in NREM sleep delta (0.5 4.0 Hz) power, which is an index of sleep homeostasis in adult mammals. The sleep homeostatic response did not fully mature until P25. Conclusions: These results demonstrate that the maturation of circadian organization of sleep-wake behavior precedes the expression of mature sleep homeostasis. PMID- 28364423 TI - Changes in Sleep Duration, Quality, and Medication Use Are Prospectively Associated With Health and Well-being: Analysis of the UK Household Longitudinal Study. AB - Introduction: Sleep is a plausible target for public health promotion. We examined the association of changes in sleep with subsequent health and well being in the general population. Aims and Methods: We analyzed data from the UK Household Longitudinal Survey, involving 30594 people (aged > 16) who provided data on sleep and health and well-being at both Wave 1 (2009-2011) and Wave 4 (2012-2014) assessments. Predicting variables were changes in sleep quantity, sleep quality, and sleep medication use over the 4-year period. Outcome variables were the General Health Questionnaire (GHQ-12) and the 12-Item Short-Form Health Survey (SF-12) mental (MCS) and physical (PCS) component scores at Wave 4. Linear regression on each outcome was fully adjusted for potential confounders and baseline values of the relevant predicting and outcome variables. Results: Better outcomes were associated with an increase in sleep duration (GHQ: beta = 1.031 [95% confidence interval {CI}: -1.328, -0.734]; MCS: 1.531 [1.006, 2.055]; PCS: 0.071 [-0.419, 0.56]), sleep quality (GHQ: beta = -2.031 [95% CI: -2.218, 1.844]; MCS: 3.027 [2.692, 3.361]; PCS: 0.924 [0.604, 1.245]), and a reduction in sleep medication use (GHQ: beta = -1.929 [95% CI: -2.400, -1.459]; MCS: 3.106 [2.279, 3.933]; PCS: 2.633 [1.860, 3.406]). Poorer outcomes were on the other hand associated with a reduction in sleep duration, a decrease in sleep quality, and an increase in sleep medication use. Changes in sleep quality yielded the largest effects on the health and well-being outcomes. Conclusions: Changes in sleep were temporally associated with subsequent health and well-being. Initiatives that aim to protect a critical amount of sleep, promote sleep quality, and reduce sleep medication use may have public health values. PMID- 28364425 TI - Sleep Disturbance May Alter White Matter and Resting State Functional Connectivities in Parkinson's Disease. AB - Study Objectives: To clarify whether sleep disturbance would alter the patterns of structural and functional networks underlying cognitive dysfunction in patients with Parkinson's disease (PD). Methods: Among the 180 patients with nondemented PD in our cohort, 45 patients were classified as the group with sleep disturbance according to the 5-item scales for outcomes in Parkinson's disease nighttime scale. Based on propensity scores, another 45 PD patients without sleep disturbance were matched to this group. We performed a comparative analysis of cortical thickness, diffusion tensor imaging-based white matter integrity, resting-state functional connectivity, and cognitive performance between PD patients with and without sleep disturbance. Results: PD patients with sleep disturbance showed poorer performance in attention and working memory and a tendency toward a lower score in frontal executive function relative to those without sleep disturbance. The PD with sleep disturbance group exhibited widespread white matter disintegration compared to the PD without sleep disturbance group, although there were no significant differences in cortical thickness between the PD subgroups. On functional network analysis, PD patients with sleep disturbance exhibited less severely decreased cortical functional connectivity within the default mode network, central executive network, and dorsal attention network when compared to those without sleep disturbance. Conclusions: The present study suggests that sleep disturbance in PD patients could be associated with white matter and functional network alterations in conjunction with cognitive impairment. PMID- 28364424 TI - Symptomless Multi-Variable Apnea Prediction Index Assesses Obstructive Sleep Apnea Risk and Adverse Outcomes in Elective Surgery. AB - Study Objective: To validate that the symptomless Multi-Variable Apnea Prediction index (sMVAP) is associated with Obstructive Sleep Apnea (OSA) diagnosis and assess the relationship between sMVAP and adverse outcomes in patients having elective surgery. We also compare associations between Bariatric surgery, where preoperative screening for OSA risk is mandatory, and non-Bariatric surgery groups who are not screened routinely for OSA. Methods: Using data from 40 432 elective inpatient surgeries, we used logistic regression to determine the relationship between sMVAP and previous OSA, current hypertension, and postoperative complications: extended length of stay (ELOS), intensive-care-unit stay (ICU-stay), and respiratory complications (pulmonary embolism, acute respiratory distress syndrome, and/or aspiration pneumonia). Results: Higher sMVAP was associated with increased likelihood of previous OSA, hypertension and all postoperative complications (p < .0001). The top sMVAP quintile had increased odds of postoperative complications compared to the bottom quintile. For ELOS, ICU-stay, and respiratory complications, respective odds ratios (95% CI) were: 1.83 (1.62, 2.07), 1.44 (1.32, 1.58), and 1.85 (1.37, 2.49). Compared against age , gender- and BMI-matched patients having Bariatric surgery, sMVAP was more strongly associated with postoperative complications in non-Bariatric surgical groups, including: (1) ELOS (Orthopedics [p < .0001], Gastrointestinal [p = .024], Neurosurgery [p = .016], Spine [p = .016]); (2) ICU-stay (Orthopedics [p = .0004], Gastrointestinal [p < .0001], and Otorhinolaryngology [p = .0102]); and (3) respiratory complications (Orthopedics [p =.037] and Otorhinolaryngology [p =.011]). Conclusions: OSA risk measured by sMVAP correlates with higher risk for select postoperative complications. Associations are stronger for non-Bariatric surgeries, where preoperative screening for OSA is not routinely performed. Thus, preoperative screening may reduce OSA-related risk for adverse postoperative outcomes. PMID- 28364426 TI - Long-Term Maintenance of Therapeutic Gains Associated With Cognitive-Behavioral Therapy for Insomnia Delivered Alone or Combined With Zolpidem. AB - Study objectives: To document the long-term sleep outcomes at 12 and 24 months after patients with chronic insomnia were treated with cognitive-behavioral therapy (CBT), either singly or combined with zolpidem medication. Methods: Participants were 160 adults with chronic insomnia. They were first randomized for a six-week acute treatment phase involving CBT alone or CBT combined with nightly zolpidem, and randomized for a six-month extended treatment phase involving CBT, no additional treatment, CBT combined with zolpidem as needed, or CBT with zolpidem tapered. This paper reports results of the 12- and 24-month follow-ups on the main outcome measures derived from the Insomnia Severity Index and sleep diaries. Results: Clinical improvements achieved 6 months following the end of treatment were well-maintained in all four conditions, with insomnia remission rates ranging from 48% to 74% at the 12-month follow-up, and from 44% to 63% at the 24-month follow-up. Participants receiving CBT with zolpidem taper in the extended treatment phase had significantly better results than those receiving CBT with continued zolpidem as needed. The magnitude of improvements on sleep diary parameters was similar between conditions, with a slight advantage for the CBT with zolpidem taper condition. The addition of extended CBT did not alter the long-term outcome over improvements obtained during the initial 6-week CBT. Conclusions: The results suggest that CBT for insomnia, when delivered alone or in combination with medication, produce durable sleep improvements up to two years after completion of treatment. These long-term results indicate that even if a combined CBT plus medication approach provide an added benefit immediately after treatment, extending CBT while tapering medication produce better sustained improvements compared to continued use of medication as needed. PMID- 28364427 TI - Tourette Syndrome as an Independent Risk Factor for Subsequent Sleep Disorders in Children: A Nationwide Population-Based Case-Control Study. AB - Study objectives: Tourette syndrome (TS) is associated with a variety of neuropsychiatric comorbidities. However, the relationship between TS and sleep disorders in children is less investigated. This nationwide population-based case control study aimed to determine the correlation of TS and sleep disorders in children. Methods: Patients aged less than 18 years with newly diagnosed TS from 2001 to 2007 were collected (n = 1124) using data from Taiwan's National Health Insurance Research Database and were compared with a comparison cohort (n = 3372). The adjusted hazard ratio (aHR) for developing sleep disorders was calculated by multivariate Cox proportional hazards model. Results: TS was more prevalent in boys, with a male to female ratio of 3.16:1. TS group also had significantly higher urbanization level of residence than controls (p < .001). The overall incidence rate of sleep disorders was 7.240/00 in children with TS, compared to 3.530/00 in controls. The TS group was associated with a significantly higher rate of sleep disorders, with a crude HR of 2.05 (95% confidence inerval [CI] = 1.43-2.95, p < .001). Among the comorbidities of TS, anxiety disorder was associated with the highest risk for sleep disorders (crude HR = 3.26, 95% CI = 1.52-7.00, p < .001). The aHR for TS cohort to develop sleep disorders was 1.72 (95% CI = 1.16-2.53, p = .007). Conclusions: The increased risk of sleep disorders in children with TS cannot be fully attributed to its comorbidities, and TS is an independent risk factor for sleep disorders in children. PMID- 28364428 TI - Enhanced Memory Consolidation Via Automatic Sound Stimulation During Non-REM Sleep. AB - Introduction: Slow-wave sleep (SWS) slow waves and sleep spindle activity have been shown to be crucial for memory consolidation. Recently, memory consolidation has been causally facilitated in human participants via auditory stimuli phase locked to SWS slow waves. Aims: Here, we aimed to develop a new acoustic stimulus protocol to facilitate learning and to validate it using different memory tasks. Most importantly, the stimulation setup was automated to be applicable for ambulatory home use. Methods: Fifteen healthy participants slept 3 nights in the laboratory. Learning was tested with 4 memory tasks (word pairs, serial finger tapping, picture recognition, and face-name association). Additional questionnaires addressed subjective sleep quality and overnight changes in mood. During the stimulus night, auditory stimuli were adjusted and targeted by an unsupervised algorithm to be phase-locked to the negative peak of slow waves in SWS. During the control night no sounds were presented. Results: Results showed that the sound stimulation increased both slow wave (p = .002) and sleep spindle activity (p < .001). When overnight improvement of memory performance was compared between stimulus and control nights, we found a significant effect in word pair task but not in other memory tasks. The stimulation did not affect sleep structure or subjective sleep quality. Conclusions: We showed that the memory effect of the SWS-targeted individually triggered single-sound stimulation is specific to verbal associative memory. Moreover, the ambulatory and automated sound stimulus setup was promising and allows for a broad range of potential follow-up studies in the future. PMID- 28364429 TI - Patient-Reported Usability of Positive Airway Pressure Equipment Is Associated With Adherence in Older Adults. AB - Study objectives: To examine the usability of positive airway pressure (PAP) devices and its association with PAP adherence among older adults with sleep disordered breathing. Methods: We mailed questionnaires to patients aged >=65 years prescribed PAP therapy during the prior 36 months from two large healthcare systems. Survey participants completed the Usability of Sleep Apnea Equipment Positive Airway Pressure (USE-PAP) questionnaire, which assessed the usability of their PAP device. Other questionnaire items included demographics and self-rated health. We also abstracted adherence data (mean nightly hours of PAP use available from one site) and interface type from the electronic health record. Results: Five hundred sixty-four patients completed the survey (response rate = 33%). The mean USE-PAP score (0 = best to 100 = worst) was 20 (SD +/- 20). Mean duration of PAP use (available in 189 respondents) was 5.2 hours per night (SD +/ 2.0). In a nested regression model predicting nightly hours of PAP use, a 10 point (0.5 SD) increase in USE-PAP score corresponded to a 0.37 hour/night reduction in PAP use. The model including the USE-PAP score explained a significant proportion (R2 = 15%) of the variation in nightly hours of PAP use above and beyond demographics, self-reported health, and interface type (?R2 = 12%). Conclusions: Our results demonstrate that PAP usability varies among older patients and is associated with PAP adherence, above and beyond other predictors of adherence. These results support measuring and improving PAP usability to further improve PAP adherence for older patients. PMID- 28364430 TI - Signal-to-Noise Ratio in PVT Performance as a Cognitive Measure of the Effect of Sleep Deprivation on the Fidelity of Information Processing. AB - Study Objectives: There is a long-standing debate about the best way to characterize performance deficits on the psychomotor vigilance test (PVT), a widely used assay of cognitive impairment in human sleep deprivation studies. Here, we address this issue through the theoretical framework of the diffusion model and propose to express PVT performance in terms of signal-to-noise ratio (SNR). Methods: From the equations of the diffusion model for one-choice, reaction-time tasks, we derived an expression for a novel SNR metric for PVT performance. We also showed that LSNR-a commonly used log-transformation of SNR can be reasonably well approximated by a linear function of the mean response speed, LSNRapx. We computed SNR, LSNR, LSNRapx, and number of lapses for 1284 PVT sessions collected from 99 healthy young adults who participated in laboratory studies with 38 hr of total sleep deprivation. Results: All four PVT metrics captured the effects of time awake and time of day on cognitive performance during sleep deprivation. The LSNR had the best psychometric properties, including high sensitivity, high stability, high degree of normality, absence of floor and ceiling effects, and no bias in the meaning of change scores related to absolute baseline performance. Conclusions: The theoretical motivation of SNR and LSNR permits quantitative interpretation of PVT performance as an assay of the fidelity of information processing in cognition. Furthermore, with a conceptual and statistical meaning grounded in information theory and generalizable across scientific fields, LSNR in particular is a useful tool for systems-integrated fatigue risk management. PMID- 28364431 TI - Validation of the Sonomat Against PSG and Quantitative Measurement of Partial Upper Airway Obstruction in Children With Sleep-Disordered Breathing. AB - Study Objectives: To validate the Sonomat against polysomnography (PSG) metrics in children and to objectively measure snoring and stertor to produce a quantitative indicator of partial upper airway obstruction that accurately reflects the pathology of pediatric sleep-disordered breathing (SDB). Methods: Simultaneous PSG and Sonomat recordings were performed in 76 children (46 male, age 5.8 +/- 2.8, BMI = 18.5 +/- 3.8 kg/m2). Sleep time, individual respiratory events and the apnea/hypopnea index (AHI) were compared. Obstructed breathing sounds were measured from the unobtrusive non-contact experimental device. Results: There was no significant difference in total sleep time (TST), respiratory events or AHI values, the latter over-estimated by 0.3 events hr-1 by the Sonomat. Poor signal quality was minimal and gender, BMI, and body position did not adversely influence event detection. Obstructive and central events were classified correctly. The number of runs and duration of snoring (13 399 events, 20% TST) and stertor (5748 events, 24% TST) were an order of magnitude greater than respiratory events (1367 events, 1% TST). Many children defined as normal by PSG had just as many or more runs of snoring and stertor as those with mild, moderate and severe obstructive sleep apnea (OSA). Conclusions: The Sonomat accurately diagnoses SDB in children using current metrics. In addition, it permits quantification of partial airway obstruction that can be used to better describe pediatric SDB. Its non-contact design makes it ideal for use in children. PMID- 28364432 TI - Sleep Duration, Snoring Prevalence, Obesity, and Behavioral Problems in a Large Cohort of Primary School Students in Japan. AB - Study Objectives: Poor or short sleep and the presence of snoring indicative of sleep-disordered breathing (SDB) have been associated with behavioral problems in school-aged children. We examined the relationship between SDB, sleep duration, obesity risk, and behavioral characteristics in Japanese elementary school students using a large-scale survey. Methods: We conducted a cross-sectional study of children enrolled in all 46 public primary schools in Matsuyama city, Japan. The children's parents or guardians completed a questionnaire that covered sleep habits, presence of SDB risk, and behavioral characteristics. Results: In total, 24 296 responses were received (90% response rate). After excluding incomplete responses, we analyzed complete datasets for 17 769 children. Mean sleep duration decreased with age, as did the prevalence of pediatric SDB. We found an increased risk for the presence of SDB and short sleep among overweight/obese children. With SDB or short sleep, we observed significantly increased odds of restless behaviors, fidgety behaviors, and poor concentration in school. Conclusions: Shorter sleep duration was associated with increased risk of obesity, and in turn, obesity increased SDB risk. Both short sleep duration and SDB risk were significantly associated with behavioral problems in school. PMID- 28364433 TI - The Relationship Between Estrogen and the Decline in Delta Power During Adolescence. AB - Study Objectives: During adolescence, there is a precipitous decrease in slow wave sleep (SWS) and its spectral correlate, delta power, which may reflect cortical reorganization. The temporal association between the decrease in delta power and puberty suggests that sex steroids may initiate these changes. This association has not been previously investigated. Methods: To determine whether estrogen triggers the adolescent decline in delta power, we compared delta power in 14 girls with central precocious puberty (CPP) and 6 age-matched, prepubertal controls. Five CPP participants were re-studied 7-14 months after pubertal suppression to determine if the changes in delta power are reversible after restoring a prepubertal hormonal milieu. The change in delta power was also compared between CPP participants and five historic controls from a longitudinal polysomnographic study. Results: CPP participants (6.7-10.5 years) spent 30% of the night in SWS. Delta power (3.7 * 106 +/- 2.7 * 105 uV2) predominated in the first 2 non-rapid eye movement episodes and decayed exponentially (tau 0.006 minutes). Age-matched controls demonstrated similar sleep staging (24% SWS) and delta dynamics (3.3 * 106 +/- 5.1 * 105 uV2, tau 0.004 minutes). Four out of 5 CPP participants had a significant decrease (26%) in delta power after hormone suppression (p < .05), similar to historic controls. Conclusion: Using an innovative model of girls with CPP studied before and after estrogen suppression, the effects of puberty on the decline in delta power were dissociated from those of chronologic age. The current studies suggest that increased estrogen does not cause the adolescent decline in delta power and indicate that neurodevelopmental changes per se or other factors associated with puberty drive these sleep changes. PMID- 28364435 TI - Uniportal middle lobectomy after a previous right upper lobectomy. AB - Video-assisted thoracoscopic surgery (VATS) using a 3.5 cm single incision (uniportal) may not only result in better pain control, earlier mobilization and shorter hospital stays, but can also provide safer and clear visualization to perform thoracoscopic dissection during complex surgeries. This is a case of a 55 year-old woman who underwent redo-thoracoscopy through uniportal approach for a middle-lobe lobectomy, after a previous right-upper lobectomy. PMID- 28364436 TI - Treatment solution by Rivas-Oural et al. PMID- 28364437 TI - eComment: Expanding aortic arch pseudoaneurysm in a high-risk patient with previous coronary surgery: a treatment strategy. PMID- 28364434 TI - The Prevalence of Sleep Apnea in Type B Aortic Dissection: Implications for False Lumen Thrombosis. AB - Introduction: Obstructive sleep apnea (OSA) has been implicated in aortic dissection. Thrombosis of the false lumen is associated with a prognosis of type B aortic dissection (AoD), and partial thrombosis has been reported to be an independent predictor of mortality. This study sought to explore whether the severity of OSA is associated with false lumen thrombosis. Aims and Methods: In this observational study, 151 type B AoD patients were recruited consecutively from 2013 to 2015. The status of the false lumen was classified as patent, partially thrombosed, or completely thrombosed based on a computer tomography angiography image. Patients were divided into non-OSA group (apnea-hypopnea index [AHI] < 5), and mild (5 <= AHI <= 15), moderate (15 < AHI <= 30), and severe OSA groups (AHI > 30) using the AHI. Results: The prevalence of OSA in type B dissection was 66.2%. Among 151 cases, 51 patients (33.8%) were in the non-OSA group, 56 (37.1%) were in the mild group, 21 (13.9%) were in the moderate group, and 23 (15.2%) were in the severe group. Additionally, a partially thrombosed false lumen was observed in 88 patients (58.3%). Multivariable analysis revealed that OSA severity was positively associated with partial thrombosis (odds ratio, 1.784, 95% confidence interval: 1.182-2.691, P = .006) after adjusting for other confounding factors. Conclusions: OSA was present in two-thirds of patients with type B AoD. The severity of OSA was significantly associated with an increased risk of partial false lumen thrombosis. OSA may therefore be implicated in both the etiology and prognosis of AoD. PMID- 28364438 TI - Preoperative vascular screening: a novel breakthrough in minimally invasive mitral valve surgery. PMID- 28364439 TI - Immersing lungs in hydrogen-rich saline attenuates lung ischaemia-reperfusion injury. AB - Objectives: Anti-oxidant effects of hydrogen have been reported in studies examining ischaemia-reperfusion injury (IRI). In this study, we evaluated the therapeutic efficacy of immersing lungs in hydrogen-rich saline on lung IRI. Methods: Lewis rats were divided into three groups: (i) sham, (ii) normal saline and (iii) hydrogen-rich saline. In the first experiment, the left thoracic cavity was filled with either normal saline or hydrogen-rich saline for 1 h. Then, we measured the hydrogen concentration in the left lung using a sensor gas chromatograph ( N = 3 per group). In the second experiment, lung IRI was induced by occlusion of the left pulmonary hilum for 1 h, followed by reperfusion for 3 h. During the ischaemic period, the left thoracic cavity was filled with either normal saline or hydrogen-rich saline. After reperfusion, we assessed lung function, histological changes and cytokine production ( N = 5-7 per group). Results: Immersing lungs in hydrogen-rich saline resulted in an elevated hydrogen concentration in the lung (6.9 +/- 2.9 MUmol/1 g lung). After IRI, pulmonary function (pulmonary compliance and oxygenation levels) was significantly higher in the hydrogen-rich saline group than in the normal saline group ( P < 0.05). Similarly, pro-inflammatory cytokine levels (interleukin-1beta and interleukin-6) in the left lung were significantly lower in the hydrogen-rich saline group than in the normal saline group ( P < 0.05). Conclusions: Immersing lungs in hydrogen rich saline delivered hydrogen into the lung and consequently attenuated lung IRI. Hydrogen-rich solution appears to be a promising approach to managing lung IRI. PMID- 28364440 TI - Incidence and predictors of vasoplegia after heart failure surgery. AB - Objectives: Vasoplegia has been described as a complication after cardiac surgery, particularly in patients with a poor left ventricular ejection fraction. The aim of this study was to assess the incidence, survival and predictors of vasoplegia in patients undergoing heart failure surgery and to propose a risk model. Methods: A retrospective study including heart failure patients who underwent surgical left ventricular restoration, CorCap implantation or left ventricular assist device implantation between 2006 and 2015. Patients were classified by the presence or absence of vasoplegia. Results: Two hundred and twenty-five patients were included. The incidence of vasoplegia was 29%. The 90 day survival rate in vasoplegic patients was lower compared with non-vasoplegic patients (71% vs 91%, P < 0.001). After adjusting for age, sex and surgical procedure, anaemia (OR 2.195; 95% CI 1.146, 4.204; P = 0.018) and a higher thyroxine level (OR 1.140; 95% CI 1.033, 1.259; P = 0.009) increased the risk of vasoplegia; a higher creatinine clearance (OR 0.980; 95% CI 0.965, 0.994; P = 0.006) and beta-blocker use (OR 0.257; 95% CI 0.112, 0.589; P = 0.001) decreased the risk. The risk model consisted of the same variables and could adequately identify patients at risk for vasoplegia. Conclusions: Vasoplegia after heart failure surgery is common and results in a lower survival rate. Anaemia and a higher thyroxine level are associated with an increased risk on vasoplegia. In contrast, a higher creatinine clearance and beta-blocker use decrease the risk on vasoplegia. These factors are used in the risk model that may guide treatment strategy. PMID- 28364441 TI - Survival after lung transplantation for cystic fibrosis in Sweden. AB - Objectives: In Sweden, lung transplantation has been performed in patients with end-stage lung disease since 1990. We assessed survival after lung transplantation for cystic fibrosis (CF) with focus on early mortality and outcome for patients infected with certain multiresistant bacteria, considered a relative contraindication for lung transplantation. Methods: Review of CF and transplant databases and patient charts. The Kaplan-Meier method and log-rank test were used for survival analysis and group comparison. Results: From November 1991 to December 2014, 115 transplantations were performed in 106 CF patients (9 retransplantations): 3 heart-lung, 106 double lung-, 1 double lobar- and 5 single lung transplantations, constituting 13% (115/909) of all lung-transplant procedures performed in Sweden. The mean age at surgery was 31 (SD 10, range 10 61) years and there were 48% females. Overall 1-year survival after lung transplantation for CF was 86.4%, 5-year survival was 73.7% and 10-year survival was 62.4%. The mean and median survival after transplantation were 13.1 (95% confidence interval (CI): 11-15.3) and 14.6 (95% CI: 9.3-19.8) years, respectively, and there was no significant difference for gender or transplant centre. Extracorporeal membrane oxygenation was used as a bridge to transplantation in 11 cases and five patients received reconditioned lungs. Vascular and infectious complications contributed to eight deaths within the first three postoperative months. The mean survival for 14 patients infected pretransplant with Mycobacterium abscessus or Burkholderia cepacia complex was 8.8 (95% CI: 6.1-11.6) years compared to 13.2 (95% CI: 10.9-15.8) years for patients negative for these bacteria. Nineteen patients (14% of all listed), of whom three were listed for retransplantation, died while waiting a median time of 94 days (range 4 days-2.5 years) after listing. Conclusions: Survival after lung transplantation in Sweden is good, also for patients with pretransplant infection with M. abscessus or B. cepacia complex, and comparable to international data. PMID- 28364442 TI - Coronary bypass versus percutaneous intervention: sex matters. The impact of gender on long-term outcomes of coronary revascularization. AB - Objectives: Women have a higher mortality than men following coronary artery bypass grafting (CABG). The influence of patient sex on outcomes of percutaneous coronary interventions (PCI) is controversial. Since patient selection for randomized clinical trials may not reflect clinical practice, we investigated the impact of sex on outcomes of CABG versus PCI in a comprehensive registry of coronary revascularization (CR). Methods: All patients undergoing CR in a network of eight community hospitals were enrolled. Follow-up was obtained after 5 years (median, 79.7 months). ST-elevation myocardial infarction (MI) patients were excluded. Propensity-score matching accounted for differences between groups. Results: There were 2162 men (673 CABG, 1489 PCI) and 991 women (294 CABG, 697 PCI). Survival free from major adverse cardiac events (MACE)-all cause mortality, nonfatal MI, re-intervention at 5 years for PCI versus CABG was 77.1 +/- 1.1 vs. 83.1 +/- 1.5, hazard ratio (HR) 0.588 (95% confidence interval [CI]: 0.491-0.704; P < 0.001) for men, but 75.0 +/- 1.6 vs. 74.5 +/- 2.5, HR 0.869 (95% CI: 0.687 1.100; P = 0.24) for women. After matching, MACE-free survival for men remained significantly different, 69.5 +/- 2.2 vs. 79.5 +/- 2.0, HR 0.548 (95% CI: 0.424 0.682; P < 0.001) but not for women, 68.1 +/- 3.4 vs. 69.4 +/- 3.4, HR 0.752 (95% CI: 0.540-1.049; P = 0.093). Conclusions: In a 'real world' unselected cohort of CR patients, men enjoy improved survival and reduced MACE with CABG versus PCI. Outcomes for women are worse than for men and are equivalent with either procedure, emphasizing importance of accounting for sex in assessing outcomes of comparative CR procedures. PMID- 28364443 TI - A large aortic valve vegetation: an unusual case of non-bacterial thrombotic (marantic) endocarditis. PMID- 28364444 TI - Acute type A dissection in octogenarians: does emergency surgery impact in hospital outcome or long-term survival? AB - Objectives: Surgical therapy for acute aortic dissection type A (AADA) in octogenarians carries high morbidity and mortality. The role of isolated medical treatment in this setting is controversial. The aim of this study is to determine whether risk of surgery for AADA outweighs risk of death from medical treatment only. Methods: From 2002 to 2015, 90 consecutive octogenarians (mean age, 83.5 +/ 3 years) were treated for AADA at three institutions: 67 patients underwent surgery, 23 patients received medical treatment. Analysis of early and late outcome was performed. Results: Patients in the medical treatment group were significantly older than in the surgical group (84.9 +/- 3.7 vs 83 +/- 2.5 years, P = 0.008) and in a more critical state. In patients undergoing surgical repair, perioperative mortality was 14.9% ( n = 10). Rate of prolonged ventilation (63.2% vs 5.9%; P < 0.001) and renal failure (35.1% vs 5.9%, P = 0.029) was significantly higher in the surgical group. Thirty-day survival was impaired in the medical treatment group (34.8% vs 61.2% in the surgical group; P = 0.032). Coronary artery disease (OR 3.95, 95% CI 1.16-13.49; P = 0.029) and complicated dissections (OR 5.28, 95% CI 1.48-18.88; P = 0.010)-composite variable of preoperative resuscitation, neurological injury and malperfusion-emerged as independent risk factors for 30-day mortality in the surgical group. There was no difference in long-term survival. Conclusions: Emergency surgery for AADA in octogenarians is associated with relatively high intraoperative mortality and may reasonably be avoided in patient with complicated presentation. Despite better immediate survival after surgery, long-term survival does not differ between medical and surgical patients, reflecting the extremely advanced point in life cycle octogenarians. PMID- 28364445 TI - Surgery for pulmonary metastases: quo vadis? PMID- 28364447 TI - Association Between Short Sleep Duration and Risk Behavior Factors in Middle School Students. AB - Study Objectives: To examine the association between self-reported sleep duration (SD) and peer/individual factors predictive of risky behaviors (risk behavior factors) in a large socioeconomically diverse school-based sample of early adolescents. Design, Setting, and Participants: Survey data collected from 10718 and 11240 eighth-grade students in 2010 and 2012, respectively, were analyzed. Intervention: N/A. Measurements and Results: Self-reported school night SD was grouped as <=4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, and >=10 hours. Scores on 10 peer/individual risk behavior factor scales were dichotomized according to national eigth-grade cut points. The percentage of students reporting an "optimal" SD of 9 hours was 14.8% and 15.6% in 2010 and 2012, respectively; 45.6% and 46.1% reported <7 hours. Adjusted for covariates of gender, race, and SES, multilevel logistic regression results showed that odds ratios (ORs) for 9 of 10 risk factor scales increased with SD <7 hours, with a dose-response effect for each hour less sleep compared to an SD of 9 hours. For example, ORs for students sleeping <7 hours ranged from 1.3 (early initiation of antisocial behavior) to 1.8 (early initiation of drug use). The risk factor scale ORs for <5 hours SD ranged from 3.0 (sensation seeking) to 6.4 (gang involvement). Conclusions: Middle school students are at high risk of insufficient sleep; in particular, an SD <7 hours is associated with increased risk behavior factors. PMID- 28364446 TI - Randomized, Prospective Study of the Impact of a Sleep Health Program on Firefighter Injury and Disability. AB - Study Objectives: Firefighters' schedules include extended shifts and long work weeks which cause sleep deficiency and circadian rhythm disruption. Many firefighters also suffer from undiagnosed sleep disorders, exacerbating fatigue. We tested the hypothesis that a workplace-based Sleep Health Program (SHP) incorporating sleep health education and sleep disorders screening would improve firefighter health and safety compared to standard practice. Design: Prospective station-level randomized, field-based intervention. Setting: US fire department. Participants: 1189 firefighters. Interventions: Sleep health education, questionnaire-based sleep disorders screening, and sleep clinic referrals for respondents who screened positive for a sleep disorder. Measurements and Results: Firefighters were randomized by station. Using departmental records, in an intention-to-treat analysis, firefighters assigned to intervention stations which participated in education sessions and had the opportunity to complete sleep disorders screening reported 46% fewer disability days than those assigned to control stations (1.4 +/- 5.9 vs. 2.6 +/- 8.5 days/firefighter, respectively; p = .003). There were no significant differences in departmental injury or motor vehicle crash rates between the groups. In post hoc analysis accounting for intervention exposure, firefighters who attended education sessions were 24% less likely to file at least one injury report during the study than those who did not attend, regardless of randomization (OR [95% CI] 0.76 [0.60, 0.98]; chi2 = 4.56; p = .033). There were no significant changes pre- versus post-study in self reported sleep or sleepiness in those who participated in the intervention. Conclusions: A firefighter workplace-based SHP providing sleep health education and sleep disorders screening opportunity can reduce injuries and work loss due to disability in firefighters. PMID- 28364448 TI - Cerebrospinal Fluid Biomarkers of Neurodegeneration Are Decreased or Normal in Narcolepsy. AB - Objectives: To investigate whether cerebrospinal fluid (CSF) biomarkers of neurodegeneration are altered in narcolepsy in order to evaluate whether the hypocretin deficiency and abnormal sleep-wake pattern in narcolepsy leads to neurodegeneration. Methods: Twenty-one patients with central hypersomnia (10 type 1 narcolepsy, 5 type 2 narcolepsy, and 6 idiopathic hypersomnia cases), aged 33 years on average and with a disease duration of 2-29 years, and 12 healthy controls underwent CSF analyses of the levels of beta-amyloid, total tau protein (T-tau), phosphorylated tau protein (P-tau181), alpha-synuclein, neurofilament light chain (NF-L), and chitinase 3-like protein-1 (CHI3L1). Results: Levels of beta-amyloid were lower in patients with type 1 narcolepsy (375.4 +/- 143.5 pg/mL) and type 2 narcolepsy (455.9 +/- 65.0 pg/mL) compared to controls (697.9 +/- 167.3 pg/mL, p < .05). Furthermore, in patients with type 1 narcolepsy, levels of T-tau (79.0 +/- 27.5 pg/mL) and P-tau181 (19.1 +/- 4.3 pg/mL) were lower than in controls (162.2 +/- 49.9 pg/mL and 33.8 +/- 9.2 pg/mL, p < .05). Levels of alpha-synuclein, NF-L, and CHI3L1 in CSF from narcolepsy patients were similar to those of healthy individuals. Conclusion: Six CSF biomarkers of neurodegeneration were decreased or normal in narcolepsy indicating that taupathy, synucleinopathy, and immunopathy are not prevalent in narcolepsy patients with a disease duration of 2-29 years. Lower CSF levels of beta-amyloid, T-tau protein, and P-tau181 in narcolepsy may indicate that hypocretin deficiency and an abnormal sleep-wake pattern alter the turnover of these proteins in the central nervous system. PMID- 28364449 TI - Modeling Neurocognitive Decline and Recovery During Repeated Cycles of Extended Sleep and Chronic Sleep Deficiency. AB - Study Objectives: Intraindividual night-to-night sleep duration is often insufficient and variable. Here we report the effects of such chronic variable sleep deficiency on neurobehavioral performance and the ability of state-of-the art models to predict these changes. Methods: Eight healthy males (mean age +/- SD: 23.9 +/- 2.4 years) studied at our inpatient intensive physiologic monitoring unit completed an 11-day protocol with a baseline 10-hour sleep opportunity and three cycles of two 3-hour time-in-bed (TIB) and one 10-hour TIB sleep opportunities. Participants received one of three polychromatic white light interventions (200 lux 4100K, 200 or 400 lux 17000K) for 3.5 hours on the morning following the second 3-hour TIB opportunity each cycle. Neurocognitive performance was assessed using the psychomotor vigilance test (PVT) administered every 1-2 hours. PVT data were compared to predictions of five group-average mathematical models that incorporate chronic sleep loss functions. Results: While PVT performance deteriorated cumulatively following each cycle of two 3-hour sleep opportunities, and improved following each 10-hour sleep opportunity, performance declined cumulatively throughout the protocol at a more accelerated rate than predicted by state-of-the-art group-average mathematical models. Subjective sleepiness did not reflect performance. The light interventions had minimal effect. Conclusions: Despite apparent recovery following each extended sleep opportunity, residual performance impairment remained and deteriorated rapidly when rechallenged with subsequent sleep loss. None of the group-average models were capable of predicting both the build-up in impairment and recovery profile of performance observed at the group or individual level, raising concerns regarding their use in real-world settings to predict performance and improve safety. PMID- 28364450 TI - Detecting the Cognitive Prodrome of Dementia with Lewy Bodies: A Prospective Study of REM Sleep Behavior Disorder. AB - Study Objectives: Long-term studies in REM sleep behavior disorder (RBD) have shown a high rate of conversion into synucleinopathies. We aimed to prospectively follow-up a large cohort of RBD patients to identify cognitive markers for early detection of prodromal dementia. Methods: Seventy-six idiopathic RBD patients underwent polysomnography and a complete neuropsychological and neurological assessment and were then followed for a mean of 3.6 years. Cognitive characteristics at baseline were compared between patients who remained disease free and those who developed a synucleinopathy, and between those who developed dementia first and those who developed parkinsonism first. Receiver operating characteristic curves were calculated to assess the diagnostic value of cognitive tests for detecting prodromal dementia. Results: At follow-up, 34 patients developed a neurodegenerative disease: 19 parkinsonism-first and 15 dementia first. RBD patients who first developed dementia were impaired at baseline in all cognitive domains (attention/executive functions, learning/memory, and visuospatial) compared to patients who developed parkinsonism. Moreover, 93% of patients who first developed dementia had mild cognitive impairment at baseline compared to 42% of patients who developed parkinsonism. RBD patients who developed parkinsonism first were similar at baseline to disease-free RBD patients on cognition. In dementia-first patients, two cognitive tests assessing attention and executive functions (Stroop Color Word Test and Trail Making Test) reliably predicted dementia (area under the curve >=0.85) compared to parkinsonism-first patients or controls. Conclusions: This study shows that cognitive tests assessing attention and executive functions strongly predict conversion to dementia in RBD patients, and may be useful endpoints to determine the effectiveness of interventions to prevent cognitive deterioration in RBD patients. PMID- 28364451 TI - Objective Measurements of Energy Balance Are Associated With Sleep Architecture in Healthy Adults. AB - Study Objectives: We objectively measured body composition, energy expenditure, caloric intake, and sleep in a large, diverse sample of healthy men and women and determined how energy balance and diet associated with sleep physiology. Methods: Healthy adults (n = 50; 21-50 years) participated in an in-laboratory study involving two baseline sleep nights (BL1-2, 10 hours time-in-bed/night, 2200-0800 hours). Polysomnography was recorded on BL2. Demographic information, body composition, and energy expenditure measurements were collected at study admittance and on BL1. Daily food/drink intake was recorded both before (on BL1) and after (on BL2) the sleep measurement. Partial Pearson's correlations assessed the relationship between energy balance and sleep physiology variables. Results: At baseline, greater fat-free mass associated with lower total sleep time (r = 0.52, p = .030), lower sleep efficiency (r = -0.53, p = .004), and greater wake after sleep onset (r = 0.55, p = .002). Higher body fat percentage (r = 0.39, p = .038) and being overweight (Body Mass Index [BMI] 25-30; p = .026) associated with more rapid eye movement (REM) sleep. Higher protein intake (r's = 0.46-0.52; p's < .001-.002) and lower carbohydrate intake (r's = -0.31 to -0.34; p's = .027 .046) on BL1 and BL2 associated with more REM sleep. Greater fiber consumption on BL1 and BL2 associated with more slow-wave sleep (SWS; r's = 0.33-0.35; p's = .02 .03). More SWS related to increased carbohydrate intake the following day (BL2, r = 0.32, p = .037). Conclusions: Body composition and diet were related to baseline sleep characteristics, including SWS and REM sleep duration and sleep maintenance. Future studies should further evaluate the influence of energy balance measures on sleep physiology, since dietary interventions may be useful in treating insufficient sleep, poor sleep quality, excessive sleepiness or other sleep disorders. PMID- 28364452 TI - Insomnia Patients With Objective Short Sleep Duration Have a Blunted Response to Cognitive Behavioral Therapy for Insomnia. AB - Study Objectives: This study examined whether individuals with insomnia and objective short sleep duration <6 h, a subgroup with greater risks of adverse health outcomes, differ in their response to cognitive-behavioral therapy for insomnia (CBT-I) when compared to individuals with insomnia and normal sleep duration >=6 h. Methods: Secondary analyses of a randomized, clinical trial with 60 adult participants (n = 31 women) from a single academic medical center. Outpatient treatment lasted 8 weeks, with a final follow-up conducted at 6 months. Mixed-effects models controlling for age, sex, CBT-I treatment group assignment, and treatment provider examined sleep parameters gathered via actigraphy, sleep diaries, and an Insomnia Symptom Questionnaire (ISQ) across the treatment and follow-up period. Results: Six months post-CBT-I treatment, individuals with insomnia and normal sleep duration >=6 h fared significantly better on clinical improvement milestones than did those with insomnia and short sleep duration <6 h. Specifically, individuals with insomnia and normal sleep duration had significantly higher insomnia remission (ISQ < 36.5; chi2[1, N = 60] = 44.72, p < .0001), more normative sleep efficiency (SE) on actigraphy (SE > 80%; chi2[1, N = 60] = 21, p < .0001), normal levels of middle of the night wake after sleep onset (MWASO) <31 minutes (chi2[1, N = 60] = 37.85, p < .0001), and a >50% decline in MWASO (chi2[1, N = 60] = 60, p < .0001) compared to individuals with insomnia and short sleep duration. Additionally, those with insomnia and normal sleep duration had more success decreasing their total wake time (TWT) at the 6-month follow-up compared to those with insomnia and short sleep duration (chi2[2, N = 60] = 44.1, p < .0001). Receiver-operating characteristic curve analysis found that using a 6-h cutoff with actigraphy provided a 95.7% sensitivity and 91.9% specificity for determining insomnia remission, with the area under the curve = 0.986. Conclusions: Findings suggest that individuals with insomnia and objective short sleep duration <6 h are significantly less responsive to CBT-I than those with insomnia and normal sleep duration >=6 h. Using an actigraphy TST cutoff of 6 hours to classify sleep duration groups was highly accurate and provided good discriminant value for determining insomnia remission. PMID- 28364453 TI - Characteristics and Consequences of Non-apneic Respiratory Events During Sleep. AB - Rationale: Current scoring criteria of non-apneic events (ie, hypopnea) require the presence of oxyhemoglobin desaturation and/or arousal. However, other sleep study parameters may help to identify abnormal respiratory events (REs) and assist in making more accurate diagnosis. Objectives: To investigate whether non apneic REs without desaturation or cortical arousal are associated with respiratory and cardiac consequences. Methods: Thirteen participants with sleep disturbances (snoring and/or excessive day time sleepiness), were screened using attended in laboratory polysomnography (PSG) while monitoring pressure and airflow via a nasal mask with an attached pneumotach. To separate the contribution of the upper airway resistance (RUA) and total pulmonary resistance (RL), supraglottic and esophageal pressures were measured using Millar pressure catheters. RL and RUA were calculated during baseline and hypopneas. RL was defined as the resistive pressure divided by the maximal flow during inspiration and expiration. Hypopnea was defined 30% decrease in flow with 3% desaturation and/or cortical arousal. REs was defined as 30% decrease in the flow without desaturation and/or cortical arousal. In eight subjects continuous positive airway pressure (CPAP) was titrated to optimal pressure. R-R interval (RRI) was defined as consecutive beat-to-beat intervals on single lead electrocardiograph (ECG) during baseline, RE/hypopnea and on optimal CPAP. Results: REs associated with increased expiratory RUA (14.6 +/- 11.3 vs. 7.5 +/- 4.5 cmH2O L-1 s-1; p < .05), and increased expiratory RL relative to baseline (29.2 +/- 14.6 vs. 20.9 +/ 11.0 and 23.7 +/- 12.1 vs. 14.3 +/- 5.6 cmH2O L-1 s-1 during inspiration and expiration, respectively; p < .05). RRI decreased significantly following RE and hypopnea relative to baseline (804.8 +/- 33.1 vs. 806.4 +/- 36.3 vs. 934.3 +/- 45.8 ms; p < .05). Optimal CPAP decreased expiratory RUA (4.0 +/- 2.5 vs. 7.5 +/- 4.5 cmH2O L-1 s-1; p < .05), decreased inspiratory RL (12.6 +/- 14.1 vs. 7.5 +/- 4.5 cmH2O L-1 s-1; p < .05), and allowed RRI to return to baseline (p < .05). RRI dips index was an independent predictor of sleep-disordered breathing (SDB) when non-apneic REs were accounted for in symptomatic patients (p < .05). Conclusions: Non-apneic REs without cortical arousal or desaturation are associated with significant respiratory and heart rate changes. Optimal CPAP and the reduction of resistive load are associated with the normalization of heart rate indicating potential clinical benefit. PMID- 28364455 TI - Cntnap2 Knockout Rats and Mice Exhibit Epileptiform Activity and Abnormal Sleep Wake Physiology. AB - Study Objectives: Although recent innovations have enabled modification of the rat genome, it is unclear whether enhanced utility of rodents as human disease models will result. We compared electroencephalogram (EEG) and behavioral phenotypes of rats and mice with homozygous deletion of Cntnap2, a gene associated with cortical dysplasia-focal epilepsy (CDFE) and autism spectrum disorders (ASD). Methods: Male contactin-associated protein-like 2 (Cntnap2) knockout (KO) and wild-type (WT) rats and male Cntnap2 KO and WT mice were implanted with telemeters to record EEG, electromyogram, body temperature, and locomotor activity. Animals were subjected to a test battery for ASD-related behaviors, followed by 24-hr EEG recordings that were analyzed for sleep-wake parameters and subjected to spectral analysis. Results: Cntnap2 KO rats exhibited severe motor seizures, hyperactivity, and increased consolidation of wakefulness and REM sleep. By contrast, Cntnap2 KO mice demonstrated absence seizure-like events, hypoactivity, and wake fragmentation. Although seizures observed in Cntnap2 KO rats were more similar to those in CDFE patients than in KO mice, neither model fully recapitulated the full spectrum of disease symptoms. However, KOs in both species had reduced spectral power in the alpha (9-12 Hz) range during wake, suggesting a conserved EEG biomarker. Conclusions: Deletion of Cntnap2 impacts similar behaviors and EEG measures in rats and mice, but with profound differences in nature and phenotypic severity. These observations highlight the importance of cross-species comparisons to understand conserved gene functions and the limitations of single- species models to provide translational insights relevant to human diseases. PMID- 28364456 TI - Insomnia, Sleep Duration, Depressive Symptoms, and the Onset of Chronic Multisite Musculoskeletal Pain. AB - Study objective: The temporal relationships among sleep, depressive symptoms, and pain are unclear. This longitudinal study examines whether insomnia and sleep duration predict the onset of chronic multisite musculoskeletal pain over 6 years and whether this association is mediated by depressive symptoms. Methods: 1860 subjects of the Netherlands Study of Depression and Anxiety, free from chronic multisite musculoskeletal pain at baseline, were followed up for the onset of chronic multisite musculoskeletal pain over 6 years (Chronic Pain Grade Questionnaire). We determined baseline insomnia (Women's Health Initiative Insomnia Rating Scale >=9) and sleep duration (short: <=6 hr, normal: 7-9 hr, long: >=10 hr). Depressive symptoms were assessed at baseline and as a change score over time (Inventory of Depressive Symptomatology). Results: Insomnia (hazard ratio [HR] [95% confidence interval, 95%CI] = 1.60 [1.30-1.96], p < .001) and short sleep duration (HR [95%CI] = 1.52 [1.22-1.90], p < .001) were associated with chronic pain onset. Adding baseline depressive symptoms as a mediator attenuated the associations for insomnia and short sleep with chronic pain onset (?B = 40% and 26%, respectively). Adding the change score of depressive symptoms further weakened the association for insomnia (?B = 16%) but not for short sleep. All direct effects for sleep measures with chronic pain onset remained statistically significant (p < .05). Conclusions: This longitudinal study shows that insomnia and short sleep duration are risk factors for developing chronic pain. Depressive symptoms partially mediate the effect for insomnia and short sleep with developing chronic pain. PMID- 28364454 TI - Neighborhood Factors as Predictors of Poor Sleep in the Sueno Ancillary Study of the Hispanic Community Health Study/Study of Latinos. AB - Study Objectives: To evaluate whether an adverse neighborhood environment has higher prevalence of poor sleep in a US Hispanic/Latino population. Methods: A cross-sectional analysis was performed in 2156 US Hispanic/Latino participants aged 18-64 years from the Sueno ancillary study of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Participants completed surveys of neighborhood environment including perceived safety, violence and noise, the Insomnia Severity Index (ISI), and 7 days of wrist actigraphy. Results: In age and sex-adjusted analyses, short sleep, low sleep efficiency, and late sleep midpoint were all more prevalent among those living in an unsafe neighborhood. After adjustment for background, site, nativity, income, employment, depressive symptoms, and sleep apnea, the absolute risk of sleeping <6 hours was 7.7 (95% CI [0.9, 14.6]) percentage points greater in those living in an unsafe compared to a safe neighborhood. There were no differences in the prevalence of insomnia by level of safety or violence. Insomnia was more prevalent among those living in a noisy neighborhood. In adjusted analysis, the absolute risk of insomnia was 4.4 (95% CI [0.4, 8.4]) percentage points greater in those living in noisy compared to non noisy neighborhoods. Conclusion: Using validated measures of sleep duration and insomnia, we have demonstrated the existence of a higher prevalence of short sleep and insomnia by adverse neighborhood factors. An adverse neighborhood environment is an established risk factor for a variety of poor health outcomes. Our findings suggest negative effects on sleep may represent one pathway by which neighborhood environment influences health. PMID- 28364458 TI - Sleep, Cognitive impairment, and Alzheimer's disease: A Systematic Review and Meta-Analysis. AB - Study Objectives: Mounting evidence implicates disturbed sleep or lack of sleep as one of the risk factors for Alzheimer's disease (AD), but the extent of the risk is uncertain. We conducted a broad systematic review and meta-analysis to quantify the effect of sleep problems/disorders on cognitive impairment and AD. Methods: Original published literature assessing any association of sleep problems or disorders with cognitive impairment or AD was identified by searching PubMed, Embase, Web of Science, and the Cochrane library. Effect estimates of individual studies were pooled and relative risks (RR) and 95% confidence intervals (CI) were calculated using random effects models. We also estimated the population attributable risk. Results: Twenty-seven observational studies (n = 69216 participants) that provided 52 RR estimates were included in the meta analysis. Individuals with sleep problems had a 1.55 (95% CI: 1.25-1.93), 1.65 (95% CI: 1.45-1.86), and 3.78 (95% CI: 2.27-6.30) times higher risk of AD, cognitive impairment, and preclinical AD than individuals without sleep problems, respectively. The overall meta-analysis revealed that individuals with sleep problems had a 1.68 (95% CI: 1.51-1.87) times higher risk for the combined outcome of cognitive impairment and/or AD. Approximately 15% of AD in the population may be attributed to sleep problems. Conclusion: This meta-analysis confirmed the association between sleep and cognitive impairment or AD and, for the first time, consolidated the evidence to provide an "average" magnitude of effect. As sleep problems are of a growing concern in the population, these findings are of interest for potential prevention of AD. PMID- 28364457 TI - Sleep-Wake Concordance in Couples Is Inversely Associated With Cardiovascular Disease Risk Markers. AB - Aim: To determine whether interdependence in couples' sleep (sleep-wake concordance i.e., whether couples are awake or asleep at the same time throughout the night) is associated with two markers of cardiovascular disease (CVD) risk, ambulatory blood pressure (BP) and systemic inflammation. Methods: This community based study is a cross-sectional analysis of 46 adult couples, aged 18-45 years, without known sleep disorders. Percent sleep-wake concordance, the independent variable, was calculated for each individual using actigraphy. Ambulatory BP monitors measured BP across 48 h. Dependent variables included mean sleep systolic BP (SBP) and diastolic BP (DBP), mean wake SBP and DBP, sleep-wake SBP and DBP ratios, and C-reactive protein (CRP). Mixed models were used and were adjusted for age, sex, education, race, and body mass index. Results: Higher sleep-wake concordance was associated with lower sleep SBP (b = -.35, SE = .01) and DBP (b = -.22, SE = .10) and lower wake SBP (b = -.26, SE = .12; all p values < .05). Results were moderated by sex; for women, high concordance was associated with lower BP. Men and women with higher sleep-wake concordance also had lower CRP values (b = -.15, SE = .03, p < .05). Sleep-wake concordance was not associated with wake DBP or sleep/wake BP ratios. Significant findings remained after controlling for individual sleep quality, duration, and wake after sleep onset. Conclusions: Sleep-wake concordance was associated with sleep BP, and this association was stronger for women. Higher sleep-wake concordance was associated with lower systemic inflammation for men and women. Sleep-wake concordance may be a novel mechanism by which marital relationships are associated with long-term CVD outcomes. PMID- 28364459 TI - Anti-Tribbles Pseudokinase 2 (TRIB2)-Immunization Modulates Hypocretin/Orexin Neuronal Functions. AB - Study Objectives: Recent findings showed that 16%-26% of narcolepsy patients were positive for anti-tribbles pseudokinase 2 (TRIB2) antibody, and the intracerebroventricular administration of immunoglobulin-G purified from anti TRIB2 positive narcolepsy patients caused hypocretin/orexin neuron loss. We investigated the pathophysiological role of TRIB2 antibody using TRIB2-immunized rats and hypocretin/ataxin-3 transgenic (ataxin-3) mice. Methods: Plasma, cerebrospinal fluid (CSF), and hypothalamic tissues from TRIB2-immunized rats were collected. Anti-TRIB2 titers, hypocretin contents, mRNA expressions, the cell count of hypocretin neurons, and immunoreactivity of anti-TRIB2 antibodies on hypocretin neurons were investigated. The plasma from ataxin-3 mice was also used to determine the anti-TRIB2 antibody titer changes following the loss of hypocretin neurons. Results: TRIB2 antibody titers increased in the plasma and CSF of TRIB2-immunized rats. The hypothalamic tissue immunostained with the sera from TRIB2-immunized rats revealed positive signals in the cytoplasm of hypcretin neurons. While no changes were found regarding hypothalamic hypocretin contents or cell counts, but there were significant decreases of the hypocretin mRNA level and release into the CSF. The plasma from over 26-week-old ataxin-3 mice, at the advanced stage of hypocretin cell destruction, showed positive reactions against TRIB2 antigen, and positive plasma also reacted with murine hypothalamic hypocretin neurons. Conclusions: Our results suggest that the general activation of the immune system modulates the functions of hypocretin neurons. The absence of a change in hypocretin cell populations suggested that factors other than anti TRIB2 antibody play a part in the loss of hypocretin neurons in narcolepsy. The increased anti-TRIB2 antibody after the destruction of hypocretin neurons suggest that anti-TRIB2 antibody in narcolepsy patients is the consequence rather than the inciting cause of hypocretin cell destruction. PMID- 28364461 TI - Double-Blind, Placebo-Controlled, Crossover Study of Armodafinil Treatment of Daytime Sleepiness Associated With Treated Nocturia. AB - Study Objectives: Nocturia, voids which disturb sleep, is the most common cause of awakenings and is associated with daytime sleepiness. Because the standard treatments for the most common causes of nocturia are relatively ineffective, many treated patients with nocturia are left with residual sleepiness. We carried out this pilot study to evaluate the potential of armodafinil to be an effective means of addressing the sleepiness that persists in many nocturia patients, despite their receiving standard therapy. Methods: This was a double-blind, placebo-controlled, crossover study carried out in 28 patients with nocturia who were receiving standard clinical therapy for their nocturia and who had an Epworth Sleepiness Scale (ESS) score of at least 10. Subjects received 4 weeks of both armodafinil (150-250 mg) and placebo with order randomized. Results: Armodafinil led to statistically significant improvement in sleepiness compared to placebo as indicated by the ESS (the primary outcome; p < .002) as well as the Clinical Global Impression of Improvement in Sleepiness scale (key secondary outcome; p = .01). Armodafinil did not increase nocturic events or significantly increase adverse effects versus placebo. Conclusions: This pilot study, the first double-blind, placebo-controlled trial assessing whether a wake-promoting therapy can improve residual daytime sleepiness in patients with treated nocturia, indicates the promise of armodafinil for addressing this residual sleepiness and provides impetus to carry out a large-scale study to definitively evaluate whether armodafinil is an effective therapy for the many patients with nocturia who experience daytime sleepiness that persists, despite their receiving standard therapy for this condition. PMID- 28364460 TI - Estimation of Pharyngeal Collapsibility During Sleep by Peak Inspiratory Airflow. AB - Objectives: Pharyngeal critical closing pressure (Pcrit) or collapsibility is a major determinant of obstructive sleep apnea (OSA) and may be used to predict the success/failure of non-continuous positive airway pressure (CPAP) therapies. Since its assessment involves overnight manipulation of CPAP, we sought to validate the peak inspiratory flow during natural sleep (without CPAP) as a simple surrogate measurement of collapsibility. Methods: Fourteen patients with OSA attended overnight polysomnography with pneumotachograph airflow. The middle third of the night (non-rapid eye movement sleep [NREM]) was dedicated to assessing Pcrit in passive and active states via abrupt and gradual CPAP pressure drops, respectively. Pcrit is the extrapolated CPAP pressure at which flow is zero. Peak and mid-inspiratory flow off CPAP was obtained from all breaths during sleep (excluding arousal) and compared with Pcrit. Results: Active Pcrit, measured during NREM sleep, was strongly correlated with both peak and mid inspiratory flow during NREM sleep (r = -0.71, p < .005 and r = -0.64, p < .05, respectively), indicating that active pharyngeal collapsibility can be reliably estimated from simple airflow measurements during polysomnography. However, there was no significant relationship between passive Pcrit, measured during NREM sleep, and peak or mid-inspiratory flow obtained from NREM sleep. Flow measurements during REM sleep were not significantly associated with active or passive Pcrit. Conclusions: Our study demonstrates the feasibility of estimating active Pcrit using flow measurements in patients with OSA. This method may enable clinicians to estimate pharyngeal collapsibility without sophisticated equipment and potentially aid in the selection of patients for non- positive airway pressure therapies. PMID- 28364462 TI - The Developmental Course of Sleep Disturbances Across Childhood Relates to Brain Morphology at Age 7: The Generation R Study. AB - Objectives: Little is known about the impact of sleep disturbances on the structural properties of the developing brain. This study explored associations between childhood sleep disturbances and brain morphology at 7 years. Methods: Mothers from the Generation R cohort reported sleep disturbances in 720 children at ages 2 months, 1.5, 2, 3, and 6 years. T1-weighted Magnetic Resonance Imaging (MRI) images were used to assess brain structure at 7 years. Associations of sleep disturbances at each age and of sleep disturbance trajectories with brain volumes (total brain volume, cortical and subcortical grey matter, white matter) were tested with linear regressions. To assess regional differences, sleep disturbance trajectories were tested as determinants for cortical thickness in whole-brain analyses. Results: Sleep disturbances followed a declining trend from toddlerhood onwards. Infant sleep was not associated with brain morphology at age 7. Per SD sleep disturbances (one frequent symptom or two less frequent symptoms) at 2 and 3 years of age, children had -6.3 (-11.7 to -0.8) cm3 and -6.4 (-11.7 to -1.7) cm3 smaller grey matter volumes, respectively. Sleep disturbances at age 6 years were associated with global brain morphology (grey matter: -7.3 (-12.1 to 2.6), p value = .01). Consistently, trajectory analyses showed that more adverse developmental course of childhood sleep disturbances are associated with smaller grey matter volumes and thinner dorsolateral prefrontal cortex. Conclusion: Sleep disturbances from age 2 years onwards are associated with smaller grey matter volumes. Thinner prefrontal cortex in children with adverse sleep disturbance trajectories may reflect effects of sleep disturbances on brain maturation. PMID- 28364463 TI - Change in Job Strain as a Predictor of Change in Insomnia Symptoms: Analyzing Observational Data as a Non-randomized Pseudo-Trial. AB - Study objectives: To examine whether change in job strain leads to change in insomnia symptoms. Methods: Among 24873 adults (82% women, mean age 44 years) who participated in a minimum of three consecutive study waves (2000-2012), job strain was assessed at the first and second wave and insomnia symptoms at all three waves. We analyzed observational data as a "pseudo-trial" including participants with no job strain in the first wave and no insomnia symptoms in the first and second wave (n = 7354) to examine whether the onset of job strain between the first and second waves predicted the onset of insomnia symptoms in the third wave. We used a corresponding approach, including those with job strain in the first wave and insomnia symptoms in the first and second wave (n = 2332), to examine whether the disappearance of job strain between the first two waves predicted remission of insomnia symptoms in the third wave. Results: The onset of job strain predicted the onset of subsequent insomnia symptoms after adjustment for sex, age, marital status, education, smoking, physical activity, alcohol consumption, body mass index, and comorbidities (odds ratio compared to no onset of job strain 1.32, 95% CI 1.16-1.51). The disappearance of job strain was associated with lower odds of repeated insomnia symptoms (odds ratio compared to no disappearance of job strain 0.78, 95% CI 0.65-0.94). Further adjustment for shift work or sleep apnea did not change these associations. Conclusions: These results suggest that job strain is a modifiable risk factor for insomnia symptoms. PMID- 28364464 TI - Relationships Between Smoking and Sleep Problems in Black and White Adolescents. AB - Study Objectives: The relationship between sleeping and smoking during adolescence remains unclear and is likely complex. We aim to evaluate the longitudinal reciprocal associations between sleep problems, sleep duration, and smoking among non-Hispanic white (NHW) and non-Hispanic black (NHB) youth. Design: Prospective cohort study. Setting: NEXT Generation Health Study. Participants: A national sample (N = 1394) of NHB and NHW 10th graders were surveyed annually between 2009 (Wave 1) and 2012 (Wave 3). Interventions: N/A. Measurements and Results: Past 30-day smoking, chronic difficulty falling asleep, recent difficulty falling asleep, difficulty staying asleep, and weekday and weekend sleep duration were measured at each wave. Using structural equation models, we observed significant autocorrelations over time for sleep problems and sleep duration. We found significant reciprocal, prospective relationships between smoking and sleep problems. The strengths of the relationships differed by race, with a stronger association between sleep problems and subsequent smoking for NHB than NHW youth. Conversely, a stronger association between smoking and subsequent sleep problems for NHW than NHB youth was observed. These association were independent of demographics, snoring or sleep apnea, body mass index, depressive symptoms, alcohol use, and soda consumption. Conclusions: Reciprocal and prospective relationships exist for youth smoking and sleep problems and duration in both NHW and NHB youth. Further research is needed to unravel the complex relationship between the direct effects of nicotine, lifestyle choices that may link smoking and sleep problems, and racial differences. PMID- 28364466 TI - Chronic Kidney Disease and Sleep Apnea Association of Kidney Disease With Obstructive Sleep Apnea in a Population Study of Men. AB - Study Objectives: To determine the relationship between obstructive sleep apnea (OSA) and chronic kidney disease (CKD). Previous population studies of the association are sparse, conflicting and confined largely to studies of administrative data. Methods: Cross-sectional analysis in unselected participants of the Men Androgens Inflammation Lifestyle Environment and Stress (MAILES) study, aged >40 years. Renal data were available for 812 men without a prior OSA diagnosis who underwent full in-home polysomnography (Embletta X100) in 2010 2011. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 or eGFR>=60 and albuminuria (albumin-creatinine ratio >=3.0 mg/mmol). Results: CKD (10.5%, n = 85 [Stage 1-3, 9.7%; Stage 4-5, 0.7%]) of predominantly mild severity showed significant associations with OSA (apnea hypoapnea index [AHI] >= 10): odds ratio (OR) = 1.9, 95% confidence interval (CI): 1.02-3.5; severe OSA (AHI >= 30/h): OR = 2.6, 95% CI: 1.1-6.2; and respiratory-related arousal index: >=7.6/h, OR = 2.3, 95%CI: 1.1-4.7; but not measures of hypoxemia after adjustment for age, hypertension, diabetes, smoking, obesity, and NSAID use. There was no association of CKD with daytime sleepiness. In men with CKD, those with OSA were not significantly more likely to report symptoms (sleepiness, snoring, and apneas) or be identified with the STOP OSA screening questionnaire, compared to men without OSA. Conclusions: Predominantly mild CKD is associated with severe OSA and arousals. Further population studies examining the longitudinal relationship between CKD and OSA are warranted. Better methods are needed to identify OSA in CKD which may have few symptoms. PMID- 28364465 TI - Coordination of Slow Waves With Sleep Spindles Predicts Sleep-Dependent Memory Consolidation in Schizophrenia. AB - Study Objectives: Schizophrenia patients have correlated deficits in sleep spindle density and sleep-dependent memory consolidation. In addition to spindle density, memory consolidation is thought to rely on the precise temporal coordination of spindles with slow waves (SWs). We investigated whether this coordination is intact in schizophrenia and its relation to motor procedural memory consolidation. Methods: Twenty-one chronic medicated schizophrenia patients and 17 demographically matched healthy controls underwent two nights of polysomnography, with training on the finger tapping motor sequence task (MST) on the second night and testing the following morning. We detected SWs (0.5-4 Hz) and spindles during non-rapid eye movement (NREM) sleep. We measured SW-spindle phase-amplitude coupling and its relation with overnight improvement in MST performance. Results: Patients did not differ from controls in the timing of SW spindle coupling. In both the groups, spindles peaked during the SW upstate. For patients alone, the later in the SW upstate that spindles peaked and the more reliable this phase relationship, the greater the overnight MST improvement. Regression models that included both spindle density and SW-spindle coordination predicted overnight improvement significantly better than either parameter alone, suggesting that both contribute to memory consolidation. Conclusion: Schizophrenia patients show intact spindle-SW temporal coordination, and these timing relationships, together with spindle density, predict sleep-dependent memory consolidation. These relations were seen only in patients suggesting that their memory is more dependent on optimal spindle-SW timing, possibly due to reduced spindle density. Interventions to improve memory may need to increase spindle density while preserving or enhancing the coordination of NREM oscillations. PMID- 28364468 TI - Intervening Leg Movements Disrupt PLMS Sequences. AB - Study Objectives: Periodic leg movements during sleep (PLMS) occur within a subject as a series with a remarkably stable period defined by the intermovement interval (IMI). Sometimes a non-PLMS movement occurs intervening between two PLMS. PLMS scoring rules totally ignore these intervening leg movements (iLM). This implicitly assumes an iLM results from a process sufficiently independent from the periodic process producing PLMS that it does not affect the periodicity of the surrounding PLMS. This study for the first time tests this basic assumption and explores characteristics of iLM as a potentially significant class of leg movements during sleep. Methods: Leg movements were analyzed from two nights of polysomnography recordings from 27 RLS patients and 22 controls using the validated MATPLM1.1 program. All periods (IMI) between PLMS containing an iLM were compared to the local PLMS period defined as the immediately preceding PLMS IMI using pairwise two-sided Wilcoxon sign-rank tests. Similarly, iLM were tested to see if they started a new PLMS series by having the same period as the subsequent PLMS. Results: The periods (IMIs) containing iLM were longer than the previous periods in RLS subjects, but not controls (p < .05). The periods beginning with the iLM were shorter than the subsequent periods in both RLS and controls (p < .05). Conclusions: iLM as a separate type of LM distort PLMS periodicity and do not restart PLMS series. iLM end PLMS series. PMID- 28364467 TI - Partial Sleep Deprivation Attenuates the Positive Affective System: Effects Across Multiple Measurement Modalities. AB - Objective: Ample behavioral and neurobiological evidence links sleep and affective functioning. Recent self-report evidence suggests that the affective problems associated with sleep loss may be stronger for positive versus negative affective state and that those effects may be mediated by changes in electroencepholographically measured slow wave sleep (SWS). In the present study, we extend those preliminary findings using multiple measures of affective functioning. Design: In a within-subject randomized crossover experiment, we tested the effects of one night of sleep continuity disruption via forced awakenings (FA) compared to one night of uninterrupted sleep (US) on three measures of positive and negative affective functioning: self-reported affective state, affective pain modulation, and affect-biased attention. Setting: The study was set in an inpatient clinical research suite. Participants: Healthy, good sleeping adults (N = 45) were included. Measurement and Results: Results indicated that a single night of sleep continuity disruption attenuated positive affective state via FA-induced reductions in SWS. Additionally, sleep continuity disruption attenuated the inhibition of pain by positive affect as well as attention bias to positive affective stimuli. Negative affective state, negative affective pain facilitation, nor negative attention bias were altered by sleep continuity disruption. Conclusions: The present findings, observed across multiple measures of affective function, suggest that sleep continuity disruption has a stronger influence on the positive affective system relative to the negative affective affective system. PMID- 28364469 TI - Chronic Rhinosinusitis Impairs Sleep Quality: Results of the GA2LEN Study. AB - Study objectives: To analyze the prevalence of sleep problems in subjects with Chronic rhinosinusitis (CRS) and to determine whether the disease severity of CRS affects sleep quality. Methods: Questionnaires were sent to a random sample of 45 000 adults in four Swedish cities. Questions on CRS, asthma, allergic rhinitis, co-morbidities, tobacco use, educational level, and physical activity were included. CRS was defined according to the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) epidemiological criteria. The disease severity of CRS was defined by the number of reported CRS symptoms. Sleep quality was assessed using the Basic Nordic Sleep Questionnaire. Results: Of the 26 647 subjects, 2249 (8.4%) had CRS. Reported sleep problems were 50%-90% more common among subjects with CRS compared with those without or the total population. The prevalence of reported sleep problems increased in conjunction with the severity of CRS. After adjusting for gender, BMI, age, tobacco use, asthma, somatic diseases, physical activity level, and educational level, participants with four symptoms of CRS (compared with subjects without CRS symptoms) displayed a higher risk of snoring (adj. OR [95% CI]: 3.13 [2.22-4.41]), difficulties inducing sleep (3.98 [2.94-5.40]), difficulties maintaining sleep (3.44 [2.55-4.64]), early morning awakening (4.71 [3.47-6.38]) and excessive daytime sleepiness (4.56 [3.36 6.18]). The addition of persistent allergic rhinitis to CRS further increased the risk of sleep problems. Conclusions: Sleep problems are highly prevalent among subjects with CRS. The disease severity of CRS negatively affects sleep quality. PMID- 28364471 TI - Intermittent Short Sleep May Contribute to Orexinergic Signaling Dysregulation in Alzheimer's Disease. PMID- 28364470 TI - Objective Sleep Duration Is Prospectively Associated With Endothelial Health. AB - Study Objectives: The mechanisms linking short sleep duration to cardiovascular disease (CVD) are poorly understood. Emerging evidence suggests that endothelial dysregulation may lie along the causal pathway linking sleep duration to cardiovascular risk, although current evidence in humans is based on cross sectional studies. Our objective was to evaluate the prospective association between objectively assessed sleep duration and clinical indices of endothelial health. Methods: A total of 141 medically healthy adults underwent an overnight laboratory sleep study when they were between the ages of 21 and 60 years. Total sleep time was objectively assessed by polysomnography at study entry. Endothelial health, including brachial artery diameter (BAD) and flow-mediated dilation (FMD), was measured 18.9 +/- 4.6 years later. Medical health and psychiatric status were assessed at both time points. Approximately half of the sample had a lifetime history of major depressive disorder. Results: In univariate analyses, shorter sleep duration was associated with increased BAD (beta = -0.24, p = .004) and decreased FMD (beta = 0.17, p = .042). BAD, but not FMD, remained significantly associated with sleep duration after adjusting for sex, age, body mass index (BMI), smoking, diabetes, hypertension, and lifetime history of major depressive disorder (MDD) at T2. The association between sleep duration and BAD was stronger than the association between BAD and an aggregate measure of CVD risk including three or more of the following risk factors: male sex, age >= 65 years, smoker, BMI >= 30, diabetes, hypertension, and MDD. Conclusions: Objectively assessed short sleep duration was prospectively associated with increased BAD over a 12- to 30-year period. PMID- 28364472 TI - Transcriptional Signatures of Sleep Duration Discordance in Monozygotic Twins. AB - Introduction: Habitual short sleep duration is associated with adverse metabolic, cardiovascular, and inflammatory effects. Co-twin study methodologies account for familial (eg, genetics and shared environmental) confounding, allowing assessment of subtle environmental effects, such as the effect of habitual short sleep duration on gene expression. Therefore, we investigated gene expression in monozygotic twins discordant for actigraphically phenotyped habitual sleep duration. Methods: Eleven healthy monozygotic twin pairs (82% female; mean age 42.7 years; SD = 18.1), selected based on subjective sleep duration discordance, were objectively phenotyped for habitual sleep duration with 2 weeks of wrist actigraphy. Peripheral blood leukocyte (PBL) RNA from fasting blood samples was obtained on the final day of actigraphic measurement and hybridized to Illumina humanHT-12 microarrays. Differential gene expression was determined between paired samples and mapped to functional categories using Gene Ontology. Finally, a more comprehensive gene set enrichment analysis was performed based on the entire PBL transcriptome. Results: The mean 24-hour sleep duration of the total sample was 439.2 minutes (SD = 46.8 minutes; range 325.4-521.6 minutes). Mean within-pair sleep duration difference per 24 hours was 64.4 minutes (SD = 21.2; range 45.9-114.6 minutes). The twin cohort displayed distinctive pathway enrichment based on sleep duration differences. Habitual short sleep was associated with up-regulation of genes involved in transcription, ribosome, translation, and oxidative phosphorylation. Unexpectedly, genes down-regulated in short sleep twins were highly enriched in immuno-inflammatory pathways such as interleukin signaling and leukocyte activation, as well as developmental programs, coagulation cascade, and cell adhesion. Conclusions: Objectively assessed habitual sleep duration in monozygotic twin pairs appears to be associated with distinct patterns of differential gene expression and pathway enrichment. By accounting for familial confounding and measuring real life sleep duration, our study shows the transcriptomic effects of habitual short sleep on dysregulated immune response and provides a potential link between sleep deprivation and adverse metabolic, cardiovascular, and inflammatory outcomes. PMID- 28364473 TI - Prevalence of Circadian Misalignment and Its Association With Depressive Symptoms in Delayed Sleep Phase Disorder. AB - Study Objective: To examine the prevalence of circadian misalignment in clinically diagnosed delayed sleep phase disorder (DSPD) and to compare mood and daytime functioning in those with and without a circadian basis for the disorder. Methods: One hundred and eighty-two DSPD patients aged 16-64 years, engaged in regular employment or school, underwent sleep-wake monitoring in the home, followed by a sleep laboratory visit for assessment of salivary dim light melatonin onset (DLMO). Based on the DLMO assessments, patients were classified into two groups: circadian DSPD, defined as DLMO occurring at or after desired bedtime (DBT), or non-circadian DSPD, defined as DLMO occurring before DBT. Results: One hundred and three patients (57%) were classified as circadian DSPD and 79 (43%) as non-circadian DSPD. DLMO occurred 1.66 hours later in circadian DSPD compared to non-circadian DSPD (p < .001). Moderate-severe depressive symptoms (Beck Depression Inventory-II) were more prevalent in circadian DSPD (14.0%) than in non-circadian DSPD (3.8%; p < .05). Relative to non-circadian DSPD patients, circadian DSPD patients had 4.31 times increased odds of at least mild depressive symptoms (95% CI 1.75 to 10.64; p < .01). No group differences were found for daytime sleepiness or function, but DSPD symptoms were rated by clinicians to be more severe in those with circadian DSPD. Conclusions: Almost half of patients clinically diagnosed with DSPD did not show misalignment between the circadian pacemaker and the DBT, suggesting that the reported difficulties initiating sleep at the DBT are unlikely to be explained by the (mis)timing of the circadian rhythm of sleep propensity. Circadian misalignment in DSPD is associated with increased depressive symptoms and DSPD symptom severity. PMID- 28364474 TI - The Neighborhood Social Environment and Objective Measures of Sleep in the Multi Ethnic Study of Atherosclerosis. AB - Study objectives: To investigate cross-sectional associations of neighborhood social environment (social cohesion, safety) with objective measures of sleep duration, timing, and disturbances. Methods: A racially/ethnically diverse population of men and women (N = 1949) aged 54 to 93 years participating in the Multi-Ethnic Study of Atherosclerosis Sleep and Neighborhood Ancillary studies. Participants underwent 1-week actigraphy between 2010 and 2013. Measures of sleep duration, timing, and disruption were averaged over all days. Neighborhood characteristics were assessed via questionnaires administered to participants and an independent sample within the same neighborhood and aggregated at the neighborhood (census tract, N = 783) level using empirical Bayes estimation. Multilevel linear regression models were used to assess the association between the neighborhood social environment and each sleep outcome. Results: Neighborhood social environment characterized by higher levels of social cohesion and safety were associated with longer sleep duration and earlier sleep midpoint. Each 1 standard deviation higher neighborhood social environment score was associated with 6.1 minutes longer [95% confidence interval (CI): 2.0, 10.2] sleep duration and 6.4 minutes earlier (CI: 2.2, 10.6) sleep midpoint after adjustment for age, sex, race, socioeconomic status, and marital status. These associations persisted after adjustment for other risk factors. Neighborhood social factors were not associated with sleep efficiency or sleep fragmentation index. Conclusions: A more favorable neighborhood social environment is associated with longer objectively measured sleep duration and earlier sleep timing. Intervening on the neighborhood environment may improve sleep and subsequent health outcomes. PMID- 28364475 TI - Tailored Behavioral Intervention Among Blacks With Metabolic Syndrome and Sleep Apnea: Results of the MetSO Trial. AB - Study Objectives: To assess effectiveness of a culturally and linguistically tailored telephone-delivered intervention to increase adherence to physician recommended evaluation and treatment of obstructive sleep apnea (OSA) among blacks. Methods: In a two-arm randomized controlled trial, we evaluated effectiveness of the tailored intervention among blacks with metabolic syndrome, relative to those in an attention control arm (n = 380; mean age = 58 +/- 13; female = 71%). The intervention was designed to enhance adherence using culturally and linguistically tailored OSA health messages delivered by a trained health educator based on patients' readiness to change and unique barriers preventing desired behavior changes. Results: Analysis showed 69.4% of the patients in the intervention arm attended initial consultation with a sleep specialist, compared to 36.7% in the control arm; 74.7% of those in the intervention arm and 66.7% in the control arm completed diagnostic evaluation; and 86.4% in the intervention arm and 88.9% in the control arm adhered to PAP treatment based on subjective report. Logistic regression analyses adjusting for sociodemographic factors indicated patients in the intervention arm were 3.17 times more likely to attend initial consultation, compared to those in the control arm. Adjusted models revealed no significant differences between the two arms regarding adherence to OSA evaluation or treatment. Conclusion: The intervention was successful in promoting importance of sleep consultation and evaluation of OSA among blacks, while there was no significant group difference in laboratory-based evaluation and treatment adherence rates. It seems that the fundamental barrier to OSA care in that population may be the importance of seeking OSA care. PMID- 28364476 TI - Sleep and Cognitive Performance From Teens To Old Age: More Is Not Better. AB - Objectives: To determine the interaction of age and habitual sleep duration in predicting cognitive performance in a large sample of participants aged 15 to 89 years. Methods: This study is a cross-sectional analysis of performance data gathered between January 2012 and September 2013. First-time players (N = 512823) of three internet cognitive training games measuring processing speed, working memory, visuospatial memory, and arithmetic participated in the study. Results: Performance was based on a measure of speed and accuracy for each game. The relationship between performance and self-reported habitual sleep duration was examined in the sample as a whole and across 10-year age groups starting at age 15 and ending at 75 and older. Performance peaked at 7 h of sleep duration for all three games in the sample as a whole, and the decrements in performance for sleep durations greater than 7 h were either comparable or greater in the youngest as compared to the oldest age groups. Conclusions: These findings challenge the hypothesis that deteriorating cognitive performance with long sleep duration is driven by medical comorbidities associated with aging. Further, these data are consistent with an optimal dose model of sleep and suggest that the model for the homeostatic recovery of cognitive function as a function of sleep duration should incorporate a curvilinear decline with longer duration sleep, indicating that there may be a cost to increased sleep. Replication and further research is essential for clarifying the sleep duration-cognition relationship in youth and adults of all ages. PMID- 28364477 TI - Temporal Changes in the Cerebrospinal Fluid Level of Hypocretin-1 and Histamine in Narcolepsy. AB - Study Objectives: To follow the temporal changes of cerebrospinal fluid (CSF) biomarker levels in narcoleptic patients with unexpected hypocretin level at referral. Methods: From 2007 to 2015, 170 human leukocyte antigen (HLA) DQB1*06:02-positive patients with primary narcolepsy and definite (n = 155, 95 males, 60 females, 36 children) or atypical cataplexy (n = 15, 4 males, 3 children) were referred to our center. Cerebrospinal hypocretin deficiency was found in 95.5% and 20% of patients with definitive and atypical cataplexy, respectively. CSF hypocretin-1 (n = 6) and histamine/tele-methylhistamine (n = 5) levels were assessed twice (median interval: 14.4 months) in four patients with definite and in two with atypical cataplexy and hypocretin level greater than 100 pg/mL at baseline. Results: CSF hypocretin levels decreased from normal/intermediate to undetectable levels in three of the four patients with definite cataplexy and remained stable in the other (>250 pg/mL). Hypocretin level decreased from 106 to 27 pg/mL in one patient with atypical cataplexy, and remained stable in the other (101 and 106 pg/mL). CSF histamine and tele methylhistamine levels remained stable, but for one patient showing increased frequency of cataplexy and a strong decrease (-72.5%) of tele-methylhistamine levels several years after disease onset. No significant association was found between relative or absolute change in hypocretin level and demographic/clinical features. Conclusions: These findings show that in few patients with narcolepsy with cataplexy, symptoms and CSF marker levels can change over time. In these rare patients with cataplexy without baseline hypocretin deficiency, CSF markers should be monitored over time with potential for immune therapies in early stages to try limiting hypocretin neuron loss. PMID- 28364480 TI - Treatment solution: treatment of choice in a case of haemodynamic instability after endovascular repair of a complicated acute type-B aortic dissection. PMID- 28364478 TI - Common Genetic Variation Near Melatonin Receptor 1A Gene Linked to Job-Related Exhaustion in Shift Workers. AB - Study Objectives: Tolerance to shift work varies; only some shift workers suffer from disturbed sleep, fatigue, and job-related exhaustion. Our aim was to explore molecular genetic risk factors for intolerance to shift work. Methods: We assessed intolerance to shift work with job-related exhaustion symptoms in shift workers using the emotional exhaustion subscale of the Maslach Burnout Inventory General Survey, and carried out a genome-wide association study (GWAS) using Illumina's Human610-Quad BeadChip (n = 176). The most significant findings were further studied in three groups of Finnish shift workers (n = 577). We assessed methylation in blood cells with the Illumina HumanMethylation450K BeadChip, and examined gene expression levels in the publicly available eGWAS Mayo data. Results: The second strongest signal identified in the GWAS (p = 2.3 * 10E-6) was replicated in two of the replication studies with p < .05 (p = 2.0 * 10E-4 when combining the replication studies) and indicated an association of job-related exhaustion in shift workers with rs12506228, located downstream of the melatonin receptor 1A gene (MTNR1A). The risk allele was also associated with reduced in silico gene expression levels of MTNR1A in brain tissue and suggestively associated with changes in DNA methylation in the 5' regulatory region of MTNR1A. Conclusions: These findings suggest that a variant near MTNR1A may be associated with job-related exhaustion in shift workers. The risk variant may exert its effect via epigenetic mechanisms, potentially leading to reduced melatonin signaling in the brain. These results could indicate a link between melatonin signaling, a key circadian regulatory mechanism, and tolerance to shift work. PMID- 28364479 TI - Detection of intraoperative myocardial dysfunction by accelerometer during aortic valve replacement. AB - OBJECTIVES: Myocardial dysfunction may occur during weaning from cardiopulmonary bypass (CPB). Epicardial accelerometers have been shown to be useful in continuous monitoring of myocardial ischaemia during beating-heart surgery. We aimed to investigate whether an accelerometer can detect myocardial dysfunction during weaning from CPB. METHODS: In 23 patients undergoing isolated aortic valve replacement (AVR), a three-axis accelerometer was attached to the left ventricle and 3D velocity was calculated from the signals. Peak early systolic velocity (Vsys) and velocity at aortic valve closure (Vavc) were measured. Measurements were undertaken during normothermia with 50% bypass flow and atrial pacing (90 beats/min) before aortic cross-clamping and after cross-clamp removal. Myocardial dysfunction was defined as Vsys < Vavc, and patients were classified as having normal function or dysfunction. Left ventricular (LV) stroke work via pulmonary artery catheter and systolic velocity by echocardiography were compared between groups and used as reference methods. RESULTS: The accelerometer identified a substantial proportion of patients with myocardial dysfunction during weaning from CPB, 56% of patients compared with 11% before aortic cross-clamping. Patients classified with normal myocardial function during weaning significantly improved their LV stroke work and systolic velocity by echocardiography in response to AVR, whereas those classified with dysfunction did not. Accelerometer classification of normal function predicted an increase in echocardiographic systolic velocity [r = 0.63, regression coefficient 1.98, 95% CI (0.57, 3.40) (P < 0.01)]. CONCLUSIONS: The accelerometer detected myocardial dysfunction during weaning from CPB in accordance with measures obtained by echocardiography and pulmonary artery catheter. Clinical Trials identifier: NCT01926067. https://clinicaltrials.gov/. PMID- 28364482 TI - Treatment solution by Residual dissected brachiocephalic artery aneurysm after the repair of acute type A aortic dissection. PMID- 28364481 TI - Postoperative interventricular septal haematoma following tetralogy of Fallot repair and perimembranous ventricular septal defect repair. AB - Interventricular septal haematoma is a rare postoperative complication in congenital heart surgery. We present one case of a 6-month-old after tetralogy of Fallot repair and 1 case of a 10-month-old after ventricular septal defect repair. Both were noted to have interventricular septal haematoma on intraoperative transoesophageal and postoperative echocardiogram. Although multiple previous reports, mainly in adults, have suggested aggressive intervention, both these cases were managed conservatively, highlighting the management and evolution of a rare postoperative complication in the paediatric population. PMID- 28364483 TI - eComment. The Nuss technique: A track full of hazards. PMID- 28364484 TI - eComment: "Repair of an acute type A aortic dissection: how to deal with a residual dissected branchiocephalic artery aneurysm ". PMID- 28364485 TI - Objective, but Not Subjective, Sleepiness is Associated With Inflammation in Sleep Apnea. AB - Study objectives: Objective and subjective measures of excessive daytime sleepiness (EDS) are only weakly associated. No study, however, has examined whether these two measures of EDS differ in terms of underlying mechanisms and prognostic value. Pro-inflammatory cytokines, that is, interleukin-6 (IL-6) appear to promote sleepiness/fatigue, while the stress hormone cortisol promotes vigilance. We hypothesized that objective sleepiness is associated with increased levels of IL-6 and decreased levels of cortisol. Methods: We studied 58 obstructive sleep apnea (OSA) patients with clinical EDS and/or cardiovascular comorbidities who underwent 8-hour in-lab polysomnography for four consecutive nights. Objective and subjective daytime sleepiness were measured by Multiple Sleep Latency Test (MSLT), Epworth Sleepiness Scale (ESS), and Stanford Sleepiness Scale (SSS), respectively. Twenty-four-hour profiles of IL-6 and cortisol levels were assessed on the fourth day. Results: The agreement between objective and subjective EDS in OSA patients was fair (kappa = 0.22). Objective EDS (lower MSLT) in OSA patients was associated with significantly elevated 24 hour (beta = -0.34, p = .01), daytime (beta = -0.30, p = .02) and nighttime (beta = -0.38, p < .01) IL-6 levels, and significantly decreased daytime (beta = 0.35, p = .01) cortisol levels. In contrast, subjective EDS (higher ESS/SSS) was not associated with either elevated IL-6 levels or decreased cortisol levels. Conclusions: Our findings suggest that OSA with objective EDS is the more severe phenotype of the disorder associated with low-grade inflammation, a link to cardiometabolic morbidity and mortality. Compared to subjective EDS, objective EDS is a stronger predictor of OSA severity and may be useful in the clinical management of the disorder. PMID- 28364487 TI - A Population-Based Study on Nighttime Road Traffic Noise and Insomnia. AB - Study Objectives: The aims of the present study were to investigate how nighttime road traffic noise relates to self-reported symptoms of insomnia and sleep medication use. Methods: We used questionnaire data from the population-based study Health and Environment in Oslo (HELMILO) (2009-2010; n = 13019). The insomnia symptoms difficulties falling asleep, awakenings during the night, and waking up too early in the morning as well as self-reported sleep medication use were included as outcomes. Modeled noise levels (Lnight) were assigned to each participant's home address. For selecting covariates to the statistical model, we used a directed acyclic graph. The associations between noise and sleep were analyzed using logistic regression models. Results: After adjustment for potential confounders, we found an odds ratio (OR) of 1.05 (95% confidence interval [CI]: 1.01-1.09) for the association between traffic noise and difficulties falling asleep, in the total study population. For the association between traffic noise and awakenings during the night, the OR was 1.04 (95% CI: 1.00-1.08) and for waking up too early, the OR was 1.06 (95% CI: 1.02-1.11). The effect estimates are given per 5-dB increase in traffic noise level (Lnight). Self-reported sleep medication use was not statistically significantly associated with traffic noise exposure. Conclusions: In an adult population from Oslo, traffic noise was associated with difficulties falling asleep and waking up too early. These findings indicate that sleep quantity may be compromised for individuals living in areas highly exposed to nighttime traffic noise. PMID- 28364486 TI - Genetic Basis of Chronotype in Humans: Insights From Three Landmark GWAS. AB - Study Objectives: Chronotype, or diurnal preference, refers to behavioral manifestations of the endogenous circadian system that governs preferred timing of sleep and wake. As variations in circadian timing and system perturbations are linked to disease development, the fundamental biology of chronotype has received attention for its role in the regulation and dysregulation of sleep and related illnesses. Family studies indicate that chronotype is a heritable trait, thus directing attention toward its genetic basis. Although discoveries from molecular studies of candidate genes have shed light onto its genetic architecture, the contribution of genetic variation to chronotype has remained unclear with few related variants identified. In the advent of large-scale genome-wide association studies (GWAS), scientists now have the ability to discover novel common genetic variants associated with complex phenotypes. Three recent large-scale GWASs of chronotype were conducted on subjects of European ancestry from the 23andMe cohort and the UK Biobank. This review discusses the findings of these landmark GWASs in the context of prior research. Methods: We systematically reviewed and compared methodological and analytical approaches and results across the three GWASs of chronotype. Results: A good deal of consistency was observed across studies with 9 genes identified in 2 of the 3 GWASs. Several genes previously unknown to influence chronotype were identified. Conclusions: GWAS is an important tool in identifying common variants associated with the complex chronotype phenotype, the findings of which can supplement and guide molecular science. Future directions in model systems and discovery of rare variants are discussed. PMID- 28364488 TI - Short Sleep Duration Is Associated With Eating More Carbohydrates and Less Dietary Fat in Mexican American Children. AB - Study Objective: Short sleep duration is a risk factor for childhood obesity. Mechanisms are unclear, but may involve selection of high carbohydrate foods. This study examined the association between estimated sleep duration and macronutrient intake as percentages of total energy among Mexican American (MA) 9 11 year olds. Methods: This cross-sectional study measured diet using two 24-hour recalls and estimated sleep duration using hip-worn accelerometry in MA children (n = 247) who were part of a cohort study. Child and maternal anthropometry were obtained; mothers reported on demographic information. Using linear regression, we examined the relationship of sleep duration with energy intake, sugar intake, and the percentage of energy intake from carbohydrates, fat, and protein. Results: Children were 47% male; mean age was 10 (SD = 0.9) years. Mean sleep duration was 9.6 (SD = 0.8) hours; 53% were overweight/obese, with a mean energy intake of 1759 (SD = 514) calories. Longer sleep duration was independently associated with a lower percentage of energy intake from carbohydrates (beta = 0.22, p < .01) and a higher percentage of energy from fat (beta = 0.19, p < .01), driven by the percentage of energy from polyunsaturated fatty acids (PUFA; beta = 0.17, p < .05). No association was found with the intake of energy or total sugars, or the percent of calories from protein. Conclusions: MA children who slept longer consumed diets with a lower percentage of calories from carbohydrates and a higher percentage from fat, especially from PUFA. Short sleep duration may be a risk factor for food cravings that are high in carbohydrate content and may displace heart-healthy dietary fat, and thereby increase obesity risk among children. PMID- 28364489 TI - Sleep Quality and Nocturnal Sleep Duration in Pregnancy and Risk of Gestational Diabetes Mellitus. AB - Study Objectives: To examine the influence of maternal sleep quality and nocturnal sleep duration on risk of gestational diabetes mellitus (GDM) in a multiethnic Asian population. Methods: A cohort of 686 women (376 Chinese, 186 Malay, and 124 Indian) with a singleton pregnancy attended a clinic visit at 26 28 weeks of gestation as part of the Growing Up in Singapore Towards healthy Outcomes mother-offspring cohort study. Self-reported sleep quality and sleep duration were assessed using the Pittsburgh Sleep Quality Index (PSQI). GDM was diagnosed based on a 75-g oral glucose tolerance test administered after an overnight fast (1999 WHO criteria). Multiple logistic regression was used to model separately the associations of poor sleep quality (PSQI score > 5) and short nocturnal sleep duration (<6 h) with GDM, adjusting for age, ethnicity, maternal education, body mass index, previous history of GDM, and anxiety (State Trait Anxiety Inventory score). Results: In the cohort 296 women (43.1%) had poor sleep quality and 77 women (11.2%) were categorized as short sleepers; 131 women (19.1%) were diagnosed with GDM. Poor sleep quality and short nocturnal sleep duration were independently associated with increased risk of GDM (poor sleep, adjusted odds ratio [OR] = 1.75, 95% confidence interval [CI] 1.11 to 2.76; short sleep, adjusted OR = 1.96, 95% CI 1.05 to 3.66). Conclusions: During pregnancy, Asian women with poor sleep quality or short nocturnal sleep duration exhibited abnormal glucose regulation. Treating sleep problems and improving sleep behavior in pregnancy could potentially reduce the risk and burden of GDM. PMID- 28364490 TI - Sleep Disturbances in Individuals With Phelan-McDermid Syndrome: Correlation With Caregivers' Sleep Quality and Daytime Functioning. AB - Study Objectives: The aims of this study were to document sleep disturbances in individuals with Phelan-McDermid syndrome (PMS), to assess whether these individuals had been evaluated for sleep disorders, and to examine relationships between the sleep behavior of these individuals and the sleep behavior and daytime functioning of their caregivers. Methods: Participants were 193 caregivers of individuals with PMS recruited by the Phelan-McDermid Syndrome Foundation. Data were collected through a survey comprising 2 questionnaires: the Children's Sleep Habits Questionnaire (CSHQ) and the Parents' Sleep Habits Questionnaire. Data were analyzed using multiple linear regression analyses, Pearson correlation analyses, and independent-samples t-tests. Results: Ninety percent of individuals with PMS showed evidence of marked sleep disturbance based on caregiver responses to the CSHQ. However, only 22% of individuals had undergone a formal sleep assessment. Reported increased sleep disturbance in individuals with PMS was a statistically significant predictor of reported increased sleep disturbance and daytime sleepiness in their caregivers. Conclusions: Sleep disturbance may be present in a substantial proportion of individuals with PMS and is negatively associated with caregivers' well-being. However, most individuals with PMS have not been evaluated for sleep disorders. When properly diagnosed, many sleep disorders can be alleviated with intervention. Thus, routine screening for and evaluation of sleep disturbances in individuals with PMS may have long-term positive impacts on the well-being of these individuals and their caregivers. PMID- 28364491 TI - Too Long, Too Short, or Too Variable? Sleep Intraindividual Variability and Its Associations With Perceived Sleep Quality and Mood in Adolescents During Naturalistically Unconstrained Sleep. AB - Introduction: Research has extensively examined the relationship between adolescents' mental health and average sleep duration/quality. Using rigorous methodology, this study characterized adolescents' objective sleep intraindividual variability (IIV) and examined its role on mood beyond the effects of their respective individual mean (IIM) values. Aims and Methods: One hundred forty-six community-dwelling adolescents (47.3% male) aged 16.2 +/- 1.0 (M +/- SD) years wore an actigraph that assessed bedtime, risetime, time-in-bed (TIB), and sleep onset latency (SOL) throughout a 15-day vacation with relatively unconstrained sleep opportunity. Self-report sleep quality (SSQ), negative mood (MOOD), and other covariates were assessed using questionnaires. For each sleep variable, individuals' mean values (IIM) and IIV were used to simultaneously predict MOOD with SSQ as a mediator. Models were estimated in a Bayesian IIV framework; both linear and quadratic effects of the IIM and IIV were examined. Results: Longer and more variable TIB, as well as more variable SOL (but not mean SOL), were associated with poorer SSQ (ps < .01), which in turn, was associated with more negative MOOD (ps < .05). The indirect effect of SOL IIV was curvilinear, such that as SOL became more variable, the deteriorating effect of high SOL IIV accelerated. Neither bedtime nor risetime IIV was significantly associated with SSQ or MOOD. Conclusions: During relatively unconstrained sleep opportunity, more variable TIB and SOL were associated with more negative mood, mediated by poorer perceived sleep quality. Significant effects of IIV were over and above that of mean values, suggesting that unique aspects of sleep IIV are relevant to how adolescents perceive sleep quality and their mood. PMID- 28364492 TI - Neuropsychological Function in Patients With Acute Tetraplegia and Sleep Disordered Breathing. AB - Study objectives: To investigate the relationship between apnea severity and neuropsychological function in patients with acute-onset tetraplegia and sleep disordered breathing. Methods: Polysomnography and neuropsychological testing were performed on 104 participants (age M = 45.60, SD = 16.38; 10 female) across 11 international sites, 2 months postinjury (M = 60.70 days, SD = 39.48). Neuropsychological tests assessed attention, information processing, executive function, memory, learning, mood, and quality of life. Results: More severe sleep apnea was associated with poorer attention, information processing, and immediate recall. Deficits did not extend to memory. Higher preinjury intelligence and being younger reduced the associations with sleep disordered breathing; however, these protective factors were insufficient to counter the damage to attention, immediate recall, and information processing associated with sleep disordered breathing. Conclusions: These data suggest that new spinal cord injury may function as a model of "acute sleep apnea" and that more widespread sleep apnea related deficits, including memory, may only be seen with longer exposure to apnea. These findings have important implications for functioning and skill acquisition during rehabilitation and, as such, highlight the importance of sleep health following tetraplegia. PMID- 28364493 TI - Effects of Melatonin and Bright Light Treatment in Childhood Chronic Sleep Onset Insomnia With Late Melatonin Onset: A Randomized Controlled Study. AB - Study Objectives: Chronic sleep onset insomnia with late melatonin onset is prevalent in childhood, and has negative daytime consequences. Melatonin treatment is known to be effective in treating these sleep problems. Bright light therapy might be an alternative treatment, with potential advantages over melatonin treatment. In this study, we compare the effects of melatonin and bright light treatment with a placebo condition in children with chronic sleep onset insomnia and late melatonin onset. Methods: Eighty-four children (mean age 10.0 years, 61% boys) first entered a baseline week, after which they received melatonin (N = 26), light (N = 30), or placebo pills (N = 28) for 3 to 4 weeks. Sleep was measured daily with sleep diaries and actigraphy. Before and after treatment children completed a questionnaire on chronic sleep reduction, and Dim Light Melatonin Onset (DLMO) was measured. Results were analyzed with linear mixed model analyses. Results: Melatonin treatment and light therapy decreased sleep latency (sleep diary) and advanced sleep onset (sleep diary and actigraphy), although for sleep onset the effects of melatonin were stronger. In addition, melatonin treatment advanced DLMO and had positive effects on sleep latency and sleep efficiency (actigraphy data), and sleep time (sleep diary and actigraphy data). However, wake after sleep onset (actigraphy) increased with melatonin treatment. No effects on chronic sleep reduction were found. Conclusions: We found positive effects of both melatonin and light treatment on various sleep outcomes, but more and stronger effects were found for melatonin treatment. PMID- 28364494 TI - Eating Decisions Based on Alertness Levels After a Single Night of Sleep Manipulation: A Randomized Clinical Trial. AB - Study Objectives: To determine the relationship between an ecologically-relevant change in sleep behavior and its subsequent effects on daytime alertness and feeding behavior. Methods: Fifty healthy, young participants (10 male, 40 female) completed two 3-hour study sessions that were at least five days apart. The first session was a baseline evaluation. On the night prior to Session 2, the amount of time in bed was manipulated to be 60%-130% of the individual's habitual sleep time. Within both sessions, subjective (Stanford Sleepiness Scale) and objective (Psychomotor Vigilance Test) alertness were measured. During the middle of each session, a 40-minute ad libitum meal opportunity allowed participants to eat from eight different food items. Food healthfulness, caloric density, distribution, and number of calories were measured and compared to alertness levels. Results: The induced variation in time in bed resulted in induced variation in both subjective and objective (p < .05) measures of alertness. Decreased subjective alertness was associated with increased total caloric consumption (p < .05), and a greater number of calories consumed from less healthy food (p < .05), as rated by both the investigators and by the participant. Decreased objective alertness was associated with less healthy food choices (p < .05), and the consumption of more food from the calorically-dense items (p < .05). Conclusions: Ecologically relevant impairments in subjective and objective alertness are associated with increased caloric intake and dysfunctional eating decisions. People experiencing reduced alertness after modest sleep loss may be more willing to eat food they recognize as less healthful, and appear to prefer more calorically-dense foods. PMID- 28364495 TI - Sexsomnia: A Specialized Non-REM Parasomnia? AB - Introduction: To describe patients with sexsomnia and to contrast their clinical and sleep measures with those of healthy controls and sleepwalkers. Aims and Methods: Subjects referred for sexsomnia and for sleepwalking/night terror were interviewed, completed the Paris Arousal Disorder Severity Scale (PADSS), and were monitored 1-2 nights with video-polysomnography. Results: Seventeen patients (70.6% male, aged 17-76 years) had sexsomnia, with amnestic fondling of the bed partner (n = 11), complete sexual intercourse (n = 8), masturbation (n = 8), and spontaneous orgasm (n = 1). The sexual behaviors were more direct during sleep than during wakefulness (n = 12), leading to 6 sexual assaults, including intra conjugal rape (n = 3), assault of a family member (n = 2), rape of a friend (n = 1), and forensic consequences (n = 2). In 47% of sexsomnia patients, there was a history or current occurrences of sleepwalking/night terrors. Patients with sexsomnia had more N3 awakenings than healthy matched controls and the same amount as regular sleepwalkers. Half of them presented evidence of cortico cortical dissociation, including concomitant slow (mostly frontal) and rapid (mostly temporal and occipital) electroencephalography (EEG) rhythms, with concomitant N3 penile erection in 1 case. Of 89 sleepwalkers, 10% had previous episodes of amnestic sexual behaviors, with a higher PADSS-A score and a trend of a higher total PADSS score than the 80 sleepwalkers without sexsomnia. Conclusion: In this single-center series, we confirmed the male predominance of sexsomnias and its potential for severe clinical and forensic consequences. The results suggest a continuum of regular sleepwalking, sleepwalking with occasional sexsomnia, and quasi-exclusive sexsomnia. PMID- 28364496 TI - Pareidolias in REM Sleep Behavior Disorder: A Possible Predictive Marker of Lewy Body Diseases? AB - Study Objectives: To investigate conditions and clinical significance of pareidolias in patients with idiopathic rapid eyemovent (REM) sleep behavior disorder (iRBD). Methods: This cross-sectional study examined 202 patients with iRBD (66.8 +/- 8.0 yr, 58 female) and 46 healthy control subjects (64.7 +/- 5.8 years, 14 females). They underwent the Pareidolia test, a newly developed instrument for evoking pareidolias, video polysomnography, olfactory tests, and Addenbrooke's cognitive examination-revised. Results: Results show that 53.5% of iRBD patients exhibited one or more pareidolic responses: The rate was higher than control subjects showed (21.7%). The pictures evoking pareidolic responses were more numerous for iRBD patients than for control subjects (1.2 +/- 1.8 vs. 0.4 +/- 0.8, p < .001). Subgroup analyses revealed that iRBD patients with pareidolic responses had higher amounts of REM sleep without atonia (RWA), with lower sleep efficiency, lower cognitive function, and older age than subjects without pareidolic responses. Results of multivariate analyses show the number of pareidolic responses as a factor associated with decreased cognitive function in iRBD patients with better predictive accuracy. Morbidity length and severity of iRBD, olfactory function, and the amount of RWA were not factors associated with better predictive accuracy. Conclusions: Half or more of the iRBD patients showed pareidolic responses. The responses were proven to be associated more intimately with their cognitive decline than clinical or physiological variables related to RBD. Pareidolias in iRBD are useful as a predictive marker of future development of Lewy body diseases. PMID- 28364497 TI - Impact of Multi-Night Experimentally Induced Short Sleep on Adolescent Performance in a Simulated Classroom. AB - Study Objectives: Investigate whether a realistic "dose" of shortened sleep, relative to a well-rested state, causes a decline in adolescents' learning and an increase in inattentive and sleepy behaviors in a simulated classroom setting. Methods: Eighty-seven healthy 14.0- to 16.9-year olds underwent a 3-week sleep manipulation protocol, including two 5-night sleep manipulation conditions presented in a randomly counterbalanced within-subjects cross-over design. Wake time was held constant. Bedtimes were set to induce Short Sleep (SS; 6.5 hours in bed) versus Healthy Sleep (HS; 10 hours in bed). During the morning at the end of each condition, participants underwent a simulated classroom procedure in which they viewed lecture-based educational videotapes and completed relevant quizzes. Their behaviors in the simulated classroom were later coded by condition-blind raters for evidence of inattention and sleepiness. Results: Adolescents had a longer average sleep period during HS (9.1 hours) than SS (6.5 hours). Compared to scores during HS, adolescents scored significantly lower on the quiz, showed more behaviors suggestive of inattention and sleepiness in the simulated classroom, and were reported by adolescents themselves and by their parents to be more inattentive and sleepy during SS. However, the impact of the manipulation on quiz scores was not mediated by changes in attention or sleepiness. Conclusions: Although effect sizes were modest, these findings suggest that previously reported correlations between sleep duration and academic performance reflect true cause-effect relationships. Findings add to the growing evidence that the chronically shortened sleep experienced by many adolescents on school nights adversely impacts their functioning and health. PMID- 28364498 TI - Sleep Characteristics and Carotid Atherosclerosis Among Midlife Women. AB - Introduction: Midlife, which encompasses the menopause transition in women, can be a time of disrupted sleep and accelerated atherosclerosis accumulation. Short or poor sleep quality has been associated with cardiovascular disease (CVD) risk; few studies have investigated relations among midlife women. We tested whether shorter actigraphy sleep time or poorer subjective sleep quality was associated with carotid atherosclerosis among midlife women. Aims and Methods: Two hundred fifty-six peri- and postmenopausal women aged 40-60 years completed 3 days of wrist actigraphy, hot flash monitoring, questionnaires (Pittsburgh Sleep Quality Index [PSQI], Berlin), a blood draw, and carotid ultrasound [intima media thickness (IMT), plaque]. Associations of objective (actigraphy) and subjective (PSQI) sleep with IMT/plaque were tested in regression models (covariates: age, race, education, body mass index, blood pressure, lipids, insulin resistance, medications, snoring, depressive symptoms, sleep hot flashes, and estradiol). Results: Shorter objective sleep time was associated with higher odds of carotid plaque (for each hour shorter sleep, plaque score >= 2, odds ratio (OR) [95% confidence interval, CI] = 1.58 [1.11-2.27], p = .01; plaque score = 1, OR [95% CI] = 0.95 [0.68-1.32], p = .75, vs. no plaque, multivariable). Poorer subjective sleep quality was associated with higher mean IMT [beta, b (standard error, SE) = 0.004 (0.002), p = .03], maximal IMT [b (SE) = 0.009 (0.003), p = .005], and plaque [plaque score >= 2, OR (95% CI) = 1.23 (1.09-1.40), p = .001; score = 1, OR (95% CI) = 1.06 (0.93-1.21), p = .37, vs. no plaque] in multivariable models. Findings persisted additionally adjusting for sleep hot flashes and estradiol. Conclusions: Shorter actigraphy-assessed sleep time and poorer subjective sleep quality were associated with increased carotid atherosclerosis among midlife women. Associations persisted adjusting for CVD risk factors, hot flashes, and estradiol. PMID- 28364499 TI - Familial Aggregation of Insomnia. AB - Study Objectives: There is little information about familial aggregation of insomnia; however, this type of information is important to (1) improve our understanding of insomnia risk factors and (2) to design more effective treatment and prevention programs. This study aimed to investigate evidence of familial aggregation of insomnia among first-degree relatives of probands with and without insomnia. Methods: Cases (n = 134) and controls (n = 145) enrolled in a larger epidemiological study were solicited to invite their first-degree relatives and spouses to complete a standardized sleep/insomnia survey. In total, 371 first degree relatives (Mage = 51.9 years, SD = 18.0; 34.3% male) and 138 spouses (Mage = 55.5 years, SD = 12.2; 68.1% male) completed the survey assessing the nature, severity, and frequency of sleep disturbances. The dependent variable was insomnia in first-degree relatives and spouses. Familial aggregation was claimed if the risk of insomnia was significantly higher in the exposed (relatives of cases) compared to the unexposed cohort (relatives of controls). The risk of insomnia was also compared between spouses in the exposed (spouses of cases) and unexposed cohort (spouses of controls). Results: The risk of insomnia in exposed and unexposed biological relatives was 18.6% and 10.4%, respectively, yielding a relative risk (RR) of 1.80 (p = .04) after controlling for age and sex. The risk of insomnia in exposed and unexposed spouses was 9.1% and 4.2%, respectively; however, corresponding RR of 2.13 (p = .28) did not differ significantly. Conclusions: Results demonstrate evidence of strong familial aggregation of insomnia. Additional research is warranted to further clarify and disentangle the relative contribution of genetic and environmental factors in insomnia. PMID- 28364500 TI - Antibodies Against Hypocretin Receptor 2 Are Rare in Narcolepsy. AB - Study Objectives: Recently, antibodies to the hypocretin receptor 2 (HCRTR2-Abs) were reported in a high proportion of narcolepsy patients who developed the disease following Pandemrix(r) vaccination. We tested a group of narcolepsy patients for the HCRTR2-Abs using a newly established cell-based assay. Methods: Sera from 50 narcolepsy type 1 (NT1) and 11 narcolepsy type 2 (NT2) patients, 22 patients with other sleep disorders, 15 healthy controls, and 93 disease controls were studied. Cerebrospinal fluid (CSFs) from three narcoleptic patients were subsequently included. Human embryonic kidney cells were transiently transfected with human HCRTR2, incubated with patients' sera for 1 hr at 1:20 dilution and then fixed. Binding of antibodies was detected by fluorescently labeled secondary antibodies to human immunoglobulin G (IgG) and the different IgG subclasses. A nonlinear visual scoring system was used from 0 to 4; samples scoring >=1 were considered positive. Results: Only 3 (5%) of 61 patients showed a score >=1, one with IgG1- and two with IgG3-antibodies, but titers were low (1:40-1:100). CSFs from these patients were negative. The three positive patients included one NT1 case with associated psychotic features, one NT2 patient, and an NT1 patient with normal hypocretin CSF levels. Conclusions: Low levels of IgG1 or IgG3 antibodies against HCRTR2 were found in 3 of 61 patients with narcolepsy, although only 1 presented with full-blown NT1. HCRTR2-Abs are not common in narcolepsy unrelated to vaccination. PMID- 28364501 TI - Comparison Between Automatic and Visual Scorings of REM Sleep Without Atonia for the Diagnosis of REM Sleep Behavior Disorder in Parkinson Disease. AB - Study Objectives: To compare three different methods, two visual and one automatic, for the quantification of rapid eye movement (REM) sleep without atonia (RSWA) in the diagnosis of REM sleep behavior disorder (RBD) in Parkinson's disease (PD) patients. Methods: Sixty-two consecutive patients with idiopathic PD underwent video-polysomnographic recording and showed more than 5 minutes of REM sleep. The electromyogram during REM sleep was analyzed by means of two visual methods (Montreal and SINBAR) and one automatic analysis (REM Atonia Index or RAI). RBD was diagnosed according to standard criteria and a series of diagnostic accuracy measures were calculated for each method, as well as the agreement between them. Results: RBD was diagnosed in 59.7% of patients. The accuracy (85.5%), receiver operating characteristic (ROC) area (0.833) and Cohen's K coefficient (0.688) obtained with RAI were similar to those of the visual parameters. Visual tonic parameters, alone or in combination with phasic activity, showed high values of accuracy (93.5-95.2%), ROC area (0.92-0.94), and Cohen's K (0.862-0.933). Similarly, the agreement between the two visual methods was very high, and the agreement between each visual methods and RAI was substantial. Visual phasic measures alone performed worse than all the other measures. Conclusion: The diagnostic accuracy of RSWA obtained with both visual and automatic methods was high and there was a general agreement between methods. RAI may be used as the first line method to detect RSWA in the diagnosis of RBD in PD, together with the visual inspection of video-recorded behaviors, while the visual analysis of RSWA might be used in doubtful cases. PMID- 28364502 TI - Altered CD8+ T-Cell Lymphocyte Function and TC1 Cell Stemness Contribute to Enhanced Malignant Tumor Properties in Murine Models of Sleep Apnea. AB - Study Objective: The presence of obstructive sleep apnea (OSA) in patients with cancer appears to be accompanied by poorer outcomes. However, the mechanisms underlying such association are unknown. Tumor infiltrating lymphocytes (TILs), including CD8+ T cells, function as cytotoxic T lymphocytes (CTLs) and mount immune responses to cancer by the release of cytolytic enzymes, including granzyme B (GzmB), perforin (Prf), and cytokines such as interferon (IFN)-gamma. Methods: Using established in vivo mouse models, we investigated CD8+ T cells and cancer stem cells (CSCs) in intermittent hypoxia (IH) and sleep fragmentation (SF) in the context of tumor environment. Results: Both IH and SF promoted increased tumor growth and invasion toward adjacent tissues compared to controls. The number and frequency of GzmB-producing CD8+ T cells per milligram of tumor tissue was significantly reduced in IH-exposed mice with impaired cytolytic function in both the groups and correlated with tumor weight. We also found that Oct4+ and CD44+CD133+ expressing CSCs were considerably increased in IH and SF tumors, respectively. Conclusions: Reductions in GzmB in intratumoral CD8+ T cells in combination with the changes in tumor microenvironment that maintain the ability of CSCs to self-renew and even confer this capability to the nonstem population are compatible with reduced immunosurveillance and adverse tumor outcomes in animal models of OSA. PMID- 28364503 TI - Glutamate Is a Wake-Active Neurotransmitter in Drosophila melanogaster. AB - Introduction: In mammals, there is evidence that glutamate has a role as a wake active neurotransmitter. So using video-based analysis of Drosophila behavior, we undertook a study to examine if glutamate, which has been previously shown to have an excitatory role in neuromuscular junctions in Drosophila, may have a conserved wake-active role in the adult brain. Aims and Methods: Using 6- to 9 day-old female flies, we examined the effect of perturbations of the glutamatergic signaling on total wakefulness and wake bout architecture. We increased and decreased neuronal activity of glutamatergic neurons in the brains of adult flies using Upstream Activating Sequence (UAS) NaChBac and UAS EKO, respectively. We blocked neurotransmission from glutamatergic neurons in adult flies using the UAS-driven temperature-sensitive dynamin mutation shibirets. We examined the behavior of flies with loss of function mutations of individual subunits of brain-specific ionotropic glutamate receptors. Results: Increasing the activity of glutamatergic neurons in the adult brain led to a significant increase in wakefulness compared to the control groups both in the daytime and nighttime and decreasing the activity of these same neurons reduced wakefulness in the nighttime. Blocking neurotransmitter release in glutamatergic neurons significantly reduced wake in the nighttime. The ionotropic receptor mutants had significantly less wake in the nighttime than their respective genetic background controls. Conclusion: The results show the following: glutamate is indeed a wake active neurotransmitter in Drosophila; there is a major time of day effect associated with loss of glutamatergic neurotransmission; and it is a major wake active neurotransmitter in the nighttime. PMID- 28364505 TI - Association of Restless Legs Syndrome With Incident Parkinson's Disease. AB - Study Objectives: The association between restless legs syndrome (RLS) and Parkinson's disease (PD) has been extensively studied with inconclusive results; therefore, we prospectively examined the associations of the presence of RLS with development of incident PD. Methods: From a nationally representative prospective cohort of almost 3.5 million US veterans (age: 60 +/- 14 years, 93% male, median follow-up time of 7.8 years [interquartile range: 6.4-8.4 years]), we created a propensity-matched cohort of 100882 PD-free patients and examined the association between prevalent RLS and incident PD. This association was also assessed in the entire cohort. Associations were examined using Cox models. Results: There were 68 incident PD events (0.13%, incidence rate 1.87 [1.48-2.37]/10000 patient years) in the RLS-negative group, and 185 incident PD events (0.37%, incidence rate 4.72 [4.09-5.45]/10000 patient-years) in the RLS-positive group in the propensity-matched cohort. Prevalent RLS was associated with more than twofold higher risk of incident PD (hazard ratio [HR]: 2.57, 95% confidence interval [CI]: 1.95-3.39) compared to RLS-negative patients. Qualitatively similar results were found when we examined the entire 3.5 million cohort: Prevalent RLS was associated with more than twofold higher risk of incident PD (multivariable adjusted HR: 2.81, 95%CI: 2.41-3.27). Conclusion: RLS and PD share common risk factors. In this large cohort of US veterans, we found that prevalent RLS is associated with higher risk of incident PD during 8 years of follow-up, suggesting that RLS could be an early clinical feature of incident PD. PMID- 28364504 TI - Effects of Tiagabine on Slow Wave Sleep and Arousal Threshold in Patients With Obstructive Sleep Apnea. AB - Introduction: Obstructive sleep apnea (OSA) severity is markedly reduced during slow-wave sleep (SWS) even in patients with a severe disease. The reason for this improvement is uncertain but likely relates to non-anatomical factors (i.e. reduced arousability, chemosensitivity, and increased dilator muscle activity). The anticonvulsant tiagabine produces a dose-dependent increase in SWS in subjects without OSA. This study aimed to test the hypothesis that tiagabine would reduce OSA severity by raising the overall arousal threshold during sleep. Aims and Methods: After a baseline physiology night to assess patients' OSA phenotypic traits, a placebo-controlled, double-blind, crossover trial of tiagabine 12 mg administered before sleep was performed in 14 OSA patients. Under each condition, we assessed the effects on sleep and OSA severity using standard clinical polysomnography. Results: Tiagabine increased slow-wave activity (SWA) of the electroencephalogram (1-4 Hz) compared to placebo (1.8 [0.4] vs. 2.0 [0.5] LogMUV2, p = .04) but did not reduce OSA severity (apnea-hypopnea index [AHI] 41.5 [20.3] vs. 39.1 [16.5], p > .5). SWS duration (25 [20] vs. 26 [43] mins, p > .5) and arousal threshold (-26.5 [5.0] vs. -27.6 [5.1] cmH2O, p = .26) were also unchanged between nights. Conclusions: Tiagabine modified sleep microstructure (increase in SWA) but did not change the duration of SWS, OSA severity, or arousal threshold in this group of OSA patients. Based on these findings, tiagabine should not be considered as a therapeutic option for OSA treatment. PMID- 28364506 TI - Sleep Consolidates Motor Learning of Complex Movement Sequences in Mice. AB - Introduction: Sleep-dependent consolidation of motor learning has been extensively studied in humans, but it remains unclear why some, but not all, learned skills benefit from sleep. Aims and Methods: Here, we compared 2 different motor tasks, both requiring the mice to run on an accelerating device. In the rotarod task, mice learn to maintain balance while running on a small rod, while in the complex wheel task, mice run on an accelerating wheel with an irregular rung pattern. Results: In the rotarod task, performance improved to the same extent after sleep or after sleep deprivation (SD). Overall, using 7 different experimental protocols (41 sleep deprived mice, 26 sleeping controls), we found large interindividual differences in the learning and consolidation of the rotarod task, but sleep before/after training did not account for this variability. By contrast, using the complex wheel, we found that sleep after training, relative to SD, led to better performance from the beginning of the retest session, and longer sleep was correlated with greater subsequent performance. As in humans, the effects of sleep showed large interindividual variability and varied between fast and slow learners, with sleep favoring the preservation of learned skills in fast learners and leading to a net offline gain in the performance in slow learners. Using Fos expression as a proxy for neuronal activation, we also found that complex wheel training engaged motor cortex and hippocampus more than the rotarod training. Conclusions: Sleep specifically consolidates a motor skill that requires complex movement sequences and strongly engages both motor cortex and hippocampus. PMID- 28364507 TI - Neurobehavioral Impact of Successive Cycles of Sleep Restriction With and Without Naps in Adolescents. AB - Study Objectives: To characterize adolescents' neurobehavioral changes during two cycles of restricted and recovery sleep and to examine the effectiveness of afternoon naps in ameliorating neurobehavioral deficits associated with multiple nights of sleep restriction. Methods: Fifty-seven healthy adolescents (aged 15-19 years; 31 males) participated in a parallel group study. They underwent two cycles of sleep restriction (5-hr time in bed [TIB] for five and three nights in the first and the second cycles, respectively; 01:00-06:00) and recovery (9-hr TIB for two nights per cycle; 23:00-08:00) intended to simulate the weekday sleep loss and weekend attempt to "catch up" on sleep. Half of the participants received a 1-hr nap opportunity at 14:00 following each sleep-restricted night, while the other half stayed awake. Sustained attention, sleepiness, speed of processing, executive function, and mood were assessed 3 times each day. Results: Participants who were not allowed to nap showed progressive decline in sustained attention that did not return to baseline after two nights of recovery sleep. Exposure to the second period of sleep restriction increased the rate of vigilance deterioration. Similar patterns were found for other neurobehavioral measures. Napping attenuated but did not eliminate performance decline. These findings contrasted with the stable performance of adolescents, given 9-hr TIB each night in our recent study. Conclusions: Adolescents' neurobehavioral functions may not adapt to successive cycles of sleep curtailment and recovery. In sleep-restricted adolescents, weekend "catch-up sleep," even when combined with napping during weekdays, is inferior to receiving a 9-hr sleep opportunity each night. PMID- 28364508 TI - Financial Analysis of an Intensive Pediatric Continuous Positive Airway Pressure Program. AB - Study Objectives: Continuous positive airway pressure (CPAP) is effective in treating obstructive sleep apnea in children, but adherence to therapy is low. Our center created an intensive program that aimed to improve adherence. Our objective was to estimate the program's efficacy, cost, revenue and break-even point in a generalizable manner relative to a standard approach. Methods: The intensive program included device consignment, behavioral psychology counseling, and follow-up telephone calls. Economic modeling considered the costs, revenue and break-even point. Costs were derived from national salary reports and the Pediatric Health Information System. The 2015 Medicare reimbursement schedule provided revenue estimates. Results: Prior to the intensive CPAP program, only 67.6% of 244 patients initially prescribed CPAP appeared for follow-up visits and only 38.1% had titration polysomnograms. In contrast, 81.4% of 275 patients in the intensive program appeared for follow-up visits (p < .001) and 83.6% had titration polysomnograms (p < .001). Medicare reimbursement levels would be insufficient to cover the estimated costs of the intensive program; break-even points would need to be 1.29-2.08 times higher to cover the costs. Conclusions: An intensive CPAP program leads to substantially higher follow-up and CPAP titration rates, but costs are higher. While affordable at our institution due to the local payer mix and revenue, Medicare reimbursement levels would not cover estimated costs. This study highlights the need for enhanced funding for pediatric CPAP programs, due to the special needs of this population and the long term health risks of suboptimally treated obstructive sleep apnea. PMID- 28364509 TI - Dual Orexin Receptor Antagonist, Almorexant, in Elderly Patients With Primary Insomnia: A Randomized, Controlled Study. AB - Objective: Sleep laboratory study to determine the dose-related efficacy and safety of almorexant in elderly patients with primary chronic insomnia. Methods: Patients aged >=65 years with primary insomnia were enrolled into a prospective, randomized, double-blind, placebo-controlled, multicenter dose-finding study with a five-period, five-way Latin square cross-over design. Patients were randomized to one of 10 unique sequences of two-night treatment with oral almorexant 25, 50, 100, or 200 mg capsules, or matching placebo. The primary efficacy endpoint was polysomnography (PSG)-determined mean wake time after sleep onset (WASO). Secondary and exploratory efficacy endpoints were also assessed. Results: 112 patients were randomized (mean [SD] age 72.1 [5.0] years; 69.9% female). Significant, dose-related improvements (reductions) in mean WASO were observed with almorexant. Least-squares mean (95% CI) treatment effects in the almorexant 200, 100, 50, and 25 mg dose groups versus placebo were -46.5 minutes (-53.0, 39.9; p < .0001), -31.4 minutes (-38.0, -24.9; p < .0001), -19.2 minutes (-25.7, 12.6; p < .0001), and -10.4 minutes (-17.0, -3.9; p = .0018), respectively. Mean total sleep time was significantly increased with each almorexant dose (mean increases versus placebo ranged 55.1-14.3 minutes; p < .0001 for each dose). Latency to persistent sleep was statistically significantly reduced only with almorexant 200 mg versus placebo (mean [95% CI] treatment effect -10.2 minutes, [ 15.4, -5.0]; p = .0001). No unexpected safety concerns were identified. Adverse events were similar between all almorexant dose groups and placebo. Conclusions: Two-night oral administration of almorexant was effective and well tolerated in treating primary insomnia in elderly patients. PMID- 28364510 TI - Effectiveness of Benzodiazepine Receptor Agonists in the Treatment of Insomnia: An Examination of Response and Remission Rates. AB - Study objectives: To examine the real-world effectiveness of benzodiazepine receptor agonists (BzRAs) by quantifying response and remission rates in a clinical sample receiving chronic BzRA treatment for insomnia. Methods: Participants were outpatients (N = 193; 72% female; 55.2 +/- 11.1 year) who had an insomnia diagnosis per medical records, and who were taking a therapeutic dose of BzRA for their insomnia. Endpoints were nocturnal sleep disturbance and Insomnia Severity Index (ISI) scores. A reduction meeting the criterion for the minimally important difference in ISI scores (change >= 6) constituted "response"; "remission" was inferred when symptoms fell below the clinical cutoff (ISI < 11). Results: Most participants (71%) used BzRAs at least 5 nights per week. Mean ISI scores were significantly lower (t = 22.31; p < .01) while on BzRAs than when untreated, but remained in the clinical range (mean = 11.0; standard deviation = 5.7). Although 76.7% responded to treatment, only 47.7% remitted. The majority (68.9%) of participants had a sleep-onset latency > 30 minutes and/or wake-time after sleep onset > 60 minutes while on BzRAs. After controlling for gender and insomnia severity when untreated, odds of insomnia persistence despite BzRA use were 2 times higher in patients with comorbid medical [odds ratio (OR) = 2.39; 95% confidence interval (CI) = 1.20% to 4.77%; p < .05] and psychiatric disorders (OR = 2.24; 95% CI = 1.21% to 4.13%; p < .05). Conclusions: This is the first study to distinguish between response and remission in insomnia patients taking BzRAs. Findings suggest that while many insomnia patients respond to chronic BzRA treatment, most do not remit. Remission rates are particularly low for comorbid insomnia, the most prevalent phenotype of the disorder. PMID- 28364511 TI - Mid-Treatment Sleep Duration Predicts Clinically Significant Knee Osteoarthritis Pain reduction at 6 months: Effects From a Behavioral Sleep Medicine Clinical Trial. AB - Study Objectives: To determine the relative influence of sleep continuity (sleep efficiency, sleep onset latency, total sleep time [TST], and wake after sleep onset) on clinical pain outcomes within a trial of cognitive behavioral therapy for insomnia (CBT-I) for patients with comorbid knee osteoarthritis and insomnia. Methods: Secondary analyses were performed on data from 74 patients with comorbid insomnia and knee osteoarthritis who completed a randomized clinical trial of 8 session multicomponent CBT-I versus an active behavioral desensitization control condition (BD), including a 6-month follow-up assessment. Data used herein include daily diaries of sleep parameters, actigraphy data, and self-report questionnaires administered at specific time points. Results: Patients who reported at least 30% improvement in self-reported pain from baseline to 6-month follow-up were considered responders (N = 31). Pain responders and nonresponders did not differ significantly at baseline across any sleep continuity measures. At mid-treatment, only TST predicted pain response via t tests and logistic regression, whereas other measures of sleep continuity were nonsignificant. Recursive partitioning analyses identified a minimum cut-point of 382 min of TST achieved at mid-treatment in order to best predict pain improvements 6-month posttreatment. Actigraphy results followed the same pattern as daily diary-based results. Conclusions: Clinically significant pain reductions in response to both CBT-I and BD were optimally predicted by achieving approximately 6.5 hr sleep duration by mid-treatment. Thus, tailoring interventions to increase TST early in treatment may be an effective strategy to promote long-term pain reductions. More comprehensive research on components of behavioral sleep medicine treatments that contribute to pain response is warranted. PMID- 28364512 TI - Nocturnal Dynamics of Sleep-Wake Transitions in Patients With Narcolepsy. AB - Introduction: We investigate how characteristics of sleep-wake dynamics in humans are modified by narcolepsy, a clinical condition that is supposed to destabilize sleep-wake regulation. Subjects with and without cataplexy are considered separately. Differences in sleep scoring habits as a possible confounder have been examined. Aims and Methods: Four groups of subjects are considered: narcolepsy patients from China with (n = 88) and without (n = 15) cataplexy, healthy controls from China (n = 110) and from Europe (n = 187, 2 nights each). After sleep-stage scoring and calculation of sleep characteristic parameters, the distributions of wake-episode durations and sleep-episode durations are determined for each group and fitted by power laws (exponent alpha) and by exponentials (decay time tau). Results: We find that wake duration distributions are consistent with power laws for healthy subjects (China: alpha = 0.88, Europe: alpha = 1.02). Wake durations in all groups of narcolepsy patients, however, follow the exponential law (tau = 6.2-8.1 min). All sleep duration distributions are best fitted by exponentials on long time scales (tau = 34-82 min). Conclusions: We conclude that narcolepsy mainly alters the control of wake episode durations but not sleep-episode durations, irrespective of cataplexy. Observed distributions of shortest wake and sleep durations suggest that differences in scoring habits regarding the scoring of short-term sleep stages may notably influence the fitting parameters but do not affect the main conclusion. PMID- 28364515 TI - Prevalence of Sleep-Related Hypermotor Epilepsy-Formerly Named Nocturnal Frontal Lobe Epilepsy-in the Adult Population of the Emilia-Romagna Region, Italy. PMID- 28364513 TI - Sleep Duration and Adiposity in Early Childhood: Evidence for Bidirectional Associations from the Born in Bradford Study. AB - Study Objectives: To examine independent associations of sleep duration with total and abdominal adiposity, and the bidirectionality of these associations, in a young biethnic sample of children from a disadvantaged location. Methods: Child sleep duration (h/day) was parent-reported by questionnaire and indices of total (body weight, body mass index, percent body fat (%BF), sum of skinfolds) and abdominal adiposity (waist circumference) were measured using standard anthropometric procedures at approximately 12, 18, 24, and 36 months of age in 1,338 children (58% South Asian; 42% White). Mixed effects models were used to quantify independent associations (expressed as standardised beta-coefficients (95% confidence interval (CI)) of sleep duration with adiposity indices using data from all four time-points. Factors considered for adjustment in models included basic demographics, pregnancy and birth characteristics, and lifestyle behaviours. Results: With the exception of the sum of skinfolds, sleep duration was inversely and independently associated with indices of total and abdominal adiposity in South Asian children. For example, one standard deviation (SD) higher sleep duration was associated with reduced %BF by -0.029 (95% CI: -0.053, 0.0043) SDs. Higher adiposity was also independently associated with shorter sleep duration in South Asian children (for example, %BF: beta = -0.10 (-0.16, 0.028) SDs). There were no significant associations in White children. Conclusions: Associations between sleep duration and adiposity are bidirectional and independent among South Asian children from a disadvantaged location. The results highlight the importance of considering adiposity as both a determinant of decreased sleep and a potential consequence. PMID- 28364514 TI - Actigraphic Sleep Patterns of U.S. Hispanics: The Hispanic Community Health Study/Study of Latinos. AB - Study objective: To assess the extent to which objective sleep patterns vary among U.S. Hispanics/Latinos. Methods: We assessed objective sleep patterns in 2087 participants of the Hispanic Community Health Study/Study of Latinos from 6 Hispanic/Latino subgroups aged 18-64 years who underwent 7 days of wrist actigraphy. Results: The age- and sex-standardized mean (SE) sleep duration was 6.82 (0.05), 6.72 (0.07), 6.61 (0.07), 6.59 (0.06), 6.57 (0.10), and 6.44 (0.09) hr among individuals of Mexican, Cuban, Dominican, Central American, Puerto Rican, and South American heritage, respectively. Sleep maintenance efficiency ranged from 89.2 (0.2)% in Mexicans to 86.5 (0.4)% in Puerto Ricans, while the sleep fragmentation index ranged from 19.7 (0.3)% in Mexicans to 24.2 (0.7)% in Puerto Ricans. In multivariable models adjusted for age, sex, season, socioeconomic status, lifestyle habits, and comorbidities, these differences persisted. Conclusions: There are important differences in actigraphically measured sleep across U.S. Hispanic/Latino heritages. Individuals of Mexican heritage have longer and more consolidated sleep, while those of Puerto Rican heritage have shorter and more fragmented sleep. These differences may have clinically important effects on health outcomes. PMID- 28364517 TI - An Integrative Review on Standardized Exams as a Predictive Admission Criterion for RN Programs. AB - Nursing programs reject qualified applicants due to limited clinical placements and faculty. By admitting the strongest candidates, schools of nursing will reduce attrition rates, increase NCLEX-RN pass rates, and speed the entry into practice of well-prepared nurses to help stem the nursing shortage. This integrative review identified the standardized admission exams most predictive of student success. Included were articles published between 2005 and 2016 that focused on admission criteria, RN programs, specific exams (e. g., HESI-A2, TEAS, SAT, CAAP, or ACT), NCLEX-RN performance, or program success. Standardized exams are effective predictors of success in programs of nursing and first-attempt NCLEX-RN. While predictive accuracy differs between exams, findings suggest that the HESI-A2 is currently the best predictor of success. By optimizing the use of standardized exams as admission criteria, nursing programs can reduce attrition rates and improve NCLEX-RN pass rates. This will maximize program capacity and contribute to a greater number of practicing nurses. PMID- 28364516 TI - Asleep at the Wheel-The Road to Addressing Drowsy Driving. AB - Drowsy driving is a dangerous behavior that leads to thousands of deaths and injuries each year. It is also a controllable factor for drivers. Drivers are capable of modifying this behavior if given sufficient information and motivation. Our goal is to establish a comprehensive and strategic effort to end drowsy driving crashes and deaths. This article highlights some of the conclusions of a unique recent meeting of sleep experts and highway safety professionals and describes the first steps the community has taken and plans to take in the future to address this issue. PMID- 28364520 TI - Successful Aging 2.0: Resilience and Beyond. PMID- 28364518 TI - Interaction Between Ezrin and Cortactin in Promoting Epithelial to Mesenchymal Transition in Breast Cancer Cells. AB - BACKGROUND Epithelial to mesenchymal transition (EMT) contributes to metastases in various types of tumors, and is also the key step in the breast cancer metastatic cascade. In our previous study, a mouse model containing human-derived normal breast tissue was established and allowed EMT/MET process of human breast cancer cells to be mimicked in a humanized mammary microenvironment. MATERIAL AND METHODS Two-dimensional electrophoresis (2-DE) and mass spectrometry were used to detect different proteins between parental MDA-MB-231 and its variant sub-line obtained from tumors grown in transplanted normal human breast tissue (MDA-MB 231br). We knocked down the ezrin in 2 cell lines (MDA-MB-231 and SUM1315). The migration and invasion ability was assessed. EMT markers were examined by real time reverse transcription PCR analysis and Western blot analysis. The relationship of ezrin with cortactin was tested by tissue microarray and co immunoprecipitation. RESULTS Proteomic analysis revealed 81 differentially expressed proteins between parental MDA-MB-231 and MDA-MB-231br. Among these proteins, the expression of ezrin and cortactin and the phosphorylation of ezrin were significantly correlated, accompanied with a group of classic EMT makers. Knockdown of ezrin reversed the expression of EMT markers and downregulated cortactin and EMT transcription factors. Ezrin silencing inhibited tumor cell migration and invasion. Breast cancer tissue microarray and immunohistochemistry showed a significant positive association between ezrin and cortactin. CONCLUSIONS These findings indicate that ezrin is correlated with cortactin in facilitating EMT in breast cancer. The interaction between ezrin and cortactin is a novel mechanism contributing to the EMT process in cancer metastases. PMID- 28364519 TI - Adapting to Aging: Older People Talk About Their Use of Selection, Optimization, and Compensation to Maximize Well-being in the Context of Physical Decline. AB - Objectives: Selection, Optimization, and Compensation (SOC) may contribute to successful aging by helping older people maximize well-being in the context of physical decline. To explore this hypothesis, and to investigate the potential for narrative analysis to improve understanding of SOC, we analyze interviews conducted with 15 members of the 6-Day Sample, a cohort of Scots born in 1936. Method: Interviewees were chosen based on their physical function and well-being scores. Interviews were analyzed to investigate "SOC talk," that is, older people's talk about SOC behaviors in everyday life. Types and amounts of SOC talk were quantified, and talk was narratively analyzed. We hypothesized that older people who engaged in more SOC talk would have higher well-being. Results: Older people who engaged in high levels of SOC talk had high well-being despite low physical function. Those who engaged in little SOC talk had low well-being despite higher physical function. Discussion: The concept of successful aging is valuable in part because of its narrative quality: One must strive to keep one's life story developing despite physical decline and other losses. We provide evidence, from the perspectives of older people themselves, of the ways in which SOC may play a role in that process. PMID- 28364521 TI - RNA immunoprecipitation identifies novel targets of DAZL in human foetal ovary. AB - Study question: Can novel meiotic RNA targets of DAZL (deleted in azoospermia like) be identified in the human foetal ovary? Summary answer: SYCP1 (synaptonemal complex protein-1), TEX11 (testis expressed 11) and SMC1B (structural maintenance of chromosomes 1B) are novel DAZL targets in the human foetal ovary, thus DAZL may have previously unrecognised roles in the translational regulation of RNAs involved in chromosome cohesion and DNA recombination in the oocyte from the time of initiation of meiosis. What is known already: The phenotype of Dazl deficiency in mouse is infertility in both sexes and DAZL has also been linked to infertility in humans. Few studies have explored targets of this RNA-binding protein. The majority of these investigations have been carried out in mouse, and have focussed on the male thus the basis for its central function in regulating female fertility is largely unknown. Study design size, duration: We carried out RNA sequencing after immunoprecipitation of endogenous DAZL from human foetal ovarian tissue (17 weeks of gestation, obtained after elective termination of pregnancy) to identify novel DAZL targets involved in meiosis (n = 3 biological replicates). Participants/materials, setting, methods: Using quantitative RT-PCR, we examined the expression of selected RNAs identified by our immunoprecipitation across gestation, and visualised the expression of potential target SMC1B in relation to DAZL, with a combination of in situ hybridisation and immunohistochemistry. 3' untranslated region (3'UTR) luciferase reporter assays and polysome profile analysis were used to investigate the regulation of three RNA targets by DAZL, representing key functionalities: SYCP1, TEX11 and SMC1B. Main results and the role of chance: We identified 764 potential RNA targets of DAZL in the human foetal ovary (false discovery rate 0.05 and log-fold change >= 2), with functions in synaptonemal complex formation (SYCP1, SYCP3), cohesin formation (SMC1B, RAD21), spindle assembly checkpoint (MAD2L1, TRIP13) and recombination and DNA repair (HORMAD1, TRIP13, TEX11, RAD18, RAD51). We demonstrated that the translation of novel targets SYCP1 (P = 0.004), TEX11 (P = 0.004) and SMC1B (P = 0.002) is stimulated by the presence of DAZL but not by a mutant DAZL with impaired RNA-binding activity. Large scale data: The raw data are available at GEO using the study ID: GSE81524. Limitations, reasons for caution: This analysis is based on identification of DAZL targets at the time when meiosis starts in the ovary: it may have other targets at other stages of oocyte development, and in the testis. Representative targets were validated, but detailed analysis was not performed on the majority of putative targets. Wider implications of the findings: These data indicate roles for DAZL in the regulation of several key functions in human oocytes. Through the translational regulation of novel RNA targets SMC1B and TEX11, DAZL may have a key role in regulating chromosome cohesion and DNA recombination; two processes fundamental in determining oocyte quality and whose establishment in foetal life may support lifelong fertility. Study funding and competing interest(s): This study was supported by the UK Medical Research Council (grant no G1100357 to R.A.A. and an intramural MRC programme grant to I.R.A.). The authors declare no competing interests. PMID- 28364524 TI - Extended Submuscular Implant-Based Breast Reconstruction with Pectoralis-Serratus Sling and Acellular Dermal Matrix. PMID- 28364522 TI - Spindlin 1 is essential for metaphase II stage maintenance and chromosomal stability in porcine oocytes. AB - Study question: What is the function of Spindlin 1 (Spin1) in metaphase II stage oocytes in pigs? Summary answer: Depletion of Spin1 induces spontaneous oocyte activation and overexpression of Spin1 causes multinuclear formation through induction of DNA damage in porcine oocytes. What is known already: Little is known about the function of Spin1 in oocytes and embryos. In mouse oocytes, Spin1 is specifically expressed during gametogenesis and is essential for meiotic resumption. In somatic cells, Spin1 promotes cancer cell proliferation and activates WNT/T-cell factor signaling. Study design size, duration: After knockdown (KD) or overexpression of Spin1 in porcine MII-stage oocytes, MII maintenance was checked following additional culture for 24 h. Investigated parthenotes were cultured up to the four cell (72 h) or blastocyst (7 days) stages. Participants/materials, setting, methods: Spin1 was knocked down in porcine oocytes and embryos via microinjection of pig Spin1-targeting siRNA. For Spin1 overexpression, porcine Spin1-eGFP cRNA was generated. Additionally, for rescue experiments, cRNA encoding siRNA-resistant mouse Spin1 was added to the pig Spin1-targeting siRNA. For the overexpression and rescue experiments, microinjection and culture were performed using the same methods as the KD experiments. Main results and the role of chance: KD of Spin1 in MII-stage porcine oocytes reduced metaphase-promoting factor and mitogen-activated protein kinase activities, resulting in spontaneous pronuclear formation without calcium activation. However, the DNA damage response was triggered by Spin1 overexpression, generating the checkpoint protein gammaH2A.X. Furthermore, Spin1 overexpression blocked metaphase-anaphase transition and led to multinucleation in oocytes and embryos. Large scale data: None. Limitations, reasons for caution: This study is based on in vitro investigations with abnormal expression levels of Spin1. This may or may not accurately reflect the situation in vivo. Wider implications of the findings: Spin1 is essential to maintain MII arrest, but a high level of Spin1 induces DNA damage in oocytes and embryos. Thus, a system to accurately regulate Spin1 expression operates in porcine MII-stage oocytes and embryos. Study funding and competing interest(s): This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (No. 2015R1D1A1A01057629). The authors declare no competing financial interests. PMID- 28364523 TI - Adipose Stem Cell Function Maintained with Age: An Intra-Subject Study of Long Term Cryopreserved Cells. AB - Background: The progressive decline in tissue mechanical strength that occurs with aging is hypothesized to be due to a loss of resident stem cell number and function. As such, there is concern regarding use of autologous adult stem cell therapy in older patients. To abrogate this, many patients elect to cryopreserve the adipose stromal-vascular fraction (SVF) of lipoaspirate, which contains resident adipose stem cells (ASC). However, it is not clear yet if there is any clinical benefit from banking cells at a younger age. Objectives: We performed a comparative analysis of SVF composition and ASC function from cells obtained under GMP conditions from the same three patients with time gap of 7 to 12 years. Methods: SVF, cryobanked under good manufacturing practice (GMP) conditions, was thawed and cell yield, viability, and cellular composition were assessed. In parallel, ASC proliferation and efficiency of tri-lineage differentiation were evaluated. Results: The results showed no significant differences existed in cell yield and SVF subpopulation composition within the same patient between harvest procedures 7 to 12 years apart. Further, no change in proliferation rates of cultured ASCs was found, and expanded cells from all patients were capable of tri lineage differentiation. Conclusions: By harvesting fat from the same patient at two time points, we have shown that despite the natural human aging process, the prevalence and functional activity of ASCs in an adult mesenchymal stem cell, is highly preserved. Level of Evidence: 5. PMID- 28364525 TI - Complications After Cosmetic Surgery Tourism. AB - Background: Cosmetic surgery tourism characterizes a phenomenon of people traveling abroad for aesthetic surgery treatment. Problems arise when patients return with complications or need of follow-up care. Objectives: To investigate the complications of cosmetic surgery tourism treated at our hospital as well as to analyze arising costs for the health system. Methods: Between 2010 and 2014, we retrospectively included all patients presenting with complications arising from cosmetic surgery abroad. We reviewed medical records for patients' characteristics including performed operations, complications, and treatment. Associated cost expenditure and Diagnose Related Groups (DRG)-related reimbursement were analyzed. Results: In total 109 patients were identified. All patients were female with a mean age of 38.5 +/- 11.3 years. Most procedures were performed in South America (43%) and Southeast (29.4%) or central Europe (24.8%), respectively. Favored procedures were breast augmentation (39.4%), abdominoplasty (11%), and breast reduction (7.3%). Median time between the initial procedure abroad and presentation was 15 days (interquartile range [IQR], 9) for early, 81.5 days (IQR, 69.5) for midterm, and 4.9 years (IQR, 9.4) for late complications. Main complications were infections (25.7%), wound breakdown (19.3%), and pain/discomfort (14.7%). The majority of patients (63.3%) were treated conservatively; 34.8% became inpatients with a mean hospital stay of 5.2 +/- 3.8 days. Overall DRG-related reimbursement premiums approximately covered the total costs. Conclusions: Despite warnings regarding associated risks, cosmetic surgery tourism has become increasingly popular. Efficient patients' referral to secondary/tertiary care centers with standardized evaluation and treatment can limit arising costs without imposing a too large burden on the social healthcare system. Level of Evidence: 4. PMID- 28364526 TI - Expanding Role of Orbital Decompression in Aesthetic Surgery. AB - Background: Eye prominence is a source of cosmetic "deformity" for many patients not afflicted by Graves. Objectives: To report our experience in using customized orbital decompression for purely aesthetic reason to reduce eye prominence in non thyroid patients. Methods: Retrospective analysis of patients undergoing cosmetic orbital decompression by one surgeon. Surgical technique included customized graded orbital bony-wall decompression (lateral-wall, basin, medial-wall, posterior-strut) and intraconal fat removal using eyelid crease and/or caruncle incisions. Inclusion criteria included any patient with relative prominent eye due to non-thyroid etiology. Preoperative and postoperative photographs at longest follow-up were used for analysis. Outcome measures included patient satisfaction (via a written questionnaire) and complication rates. Results: Etiologies of prominent eyes included congenital shallow orbits (14), congenital hypoplasia of malar-eminence (5), enlarged globe from high myopia (5), buphthalmos (1), and relative proptosis from contralateral enophthalmos (1). Concurrent procedures included lower eyelid-retractors lysis (5), periocular fat injection (3), tear-trough implant (3), canthoplasty (3), and periocular filler injection (3). Mean patient age was 33.8 years (range, 19-60 years). The average follow-up was 9 months (range, 6 months-4 years). All 26 patients (11 males, 15 females) had reduction in globe prominence. The mean reduction in axial globe position was 3.1 mm (range, 1.5-6.2 mm). Twenty-four of 26 patients were satisfied with the surgical outcome, with 2 patients complaining of sunken eyes. No case of permanent diplopia occurred. Conclusions: Orbital decompression may be done for cosmetic purpose, effectively and safely, to reduce eye prominence in non-thyroid patients by an experienced orbital surgeon. Level of Evidence: 4. PMID- 28364527 TI - The "Maintenance" Facelift: A Misnomer? PMID- 28364528 TI - Commentary on: Role of Macrotextured Shaped Extra Full Projection Cohesive Gel Implants in Primary Aesthetic Breast Augmentation. PMID- 28364529 TI - Contradictions in Piezosurgery. PMID- 28364530 TI - Response to "Comparing a Propofol Infusion with General Endotracheal Anesthesia in Plastic Surgery Patients". PMID- 28364531 TI - Comparing a Propofol Infusion With General Endotracheal Anesthesia in Plastic Surgery Patients. PMID- 28364532 TI - Response to "Contradictions in Piezosurgery". PMID- 28364533 TI - Drainless Abdominoplasty Using Barbed Progressive Tension Sutures. AB - We describe our current technique of drainless abdominoplasty using barbed progressive tension sutures. The perioperative management and detailed steps of procedure are outlined, including indications for concomitantly performing liposuction and repair of diastasis of the rectus abdominis muscles. This approach reliably improves abdominal contour, minimizes complications, and is straightforward to learn and perform. PMID- 28364534 TI - Three-Dimensional (3D) Columellar Strut Graft in Rhinoplasty. AB - Background: Nasal tip surgery is the most important and most difficult step of an aesthetic rhinoplasty operation. Various suture and grafting techniques have been described for adequate tip rotation and projection in nasal tip surgery. Objectives: The author describes his technique of "three-dimensional (3D) columellar strut graft" in nasal tip surgery. Methods: Each patient is treated using the open technique rhinoplasty. The author's technique uses a 3D dorsal columellar strut with a special anatomy in the shape of a Y- on a horizontal plane. When the dorsal columellar strut is placed in a way to maintain the interdomal angle, this technique perfectly stabilizes the lower lateral cruses (LLCs) that have been shaped with cephalic dome suture (CDS). Results: A retrospective analysis of 78 patients, who underwent 3D columellar strut graft technique, were included in the study. The mean follow-up period was 15 months. All of the patients were satisfied with their tip shapes. Conclusions: The 3D dorsal columellar strut graft technique is an easily administered technique with reliable outcomes. The purpose of this graft is to support the reshaped LLCs with a perfect anatomic alignment. It does not require any additional cartilaginous graft in patients undergoing a reduction of the dorsum. Level of Evidence: 4. PMID- 28364535 TI - Commentary on: Three-Dimensional (3D) Columellar Strut Graft in Rhinoplasty. PMID- 28364536 TI - Comments on "Simplified Muscle-Suspension Lower Blepharoplasty by Orbicularis Hitch". PMID- 28364537 TI - Response to "Comments on 'Simplified Muscle-Suspension Lower Blepharoplasty by Orbicularis Hitch'". PMID- 28364538 TI - Commentary on: The Impact of a Plastic Surgeon's Gender on Patient Choice. PMID- 28364539 TI - Commentary on: Expanding Role of Orbital Decompression in Aesthetic Surgery. PMID- 28364540 TI - Mitochondrial Mutation Rate, Spectrum and Heteroplasmy in Caenorhabditis elegans Spontaneous Mutation Accumulation Lines of Differing Population Size. PMID- 28364541 TI - Science, Societies, and Society. PMID- 28364542 TI - Defining Aging Phenotypes and Related Outcomes: Clues to Recognize Frailty in Hospitalized Older Patients. AB - Background: Because frailty is a complex phenomenon associated with poor outcomes, the identification of patient profiles with different care needs might be of greater practical help than to look for a unifying definition. This study aimed at identifying aging phenotypes and their related outcomes in order to recognize frailty in hospitalized older patients. Methods: Patients aged 65 or older enrolled in internal medicine and geriatric wards participating in the REPOSI registry. Relationships among variables associated to sociodemographic, physical, cognitive, functional, and medical status were explored using a multiple correspondence analysis. The hierarchical cluster analysis was then performed to identify possible patient profiles. Multivariable logistic regression was used to verify the association between clusters and outcomes (in hospital mortality and 3-month postdischarge mortality and rehospitalization). Results: 2,841 patients were included in the statistical analyses. Four clusters were identified: the healthiest (I); those with multimorbidity (II); the functionally independent women with osteoporosis and arthritis (III); and the functionally dependent oldest old patients with cognitive impairment (IV). There was a significantly higher in-hospital mortality in Cluster II (odds ratio [OR] = 2.27, 95% confidence interval [CI] = 1.15-4.46) and Cluster IV (OR = 5.15, 95% CI = 2.58-10.26) and a higher 3-month mortality in Cluster II (OR = 1.66, 95% CI = 1.13-2.44) and Cluster IV (OR = 1.86, 95% CI = 1.15-3.00) than in Cluster I. Conclusions: Using alternative analytical techniques among hospitalized older patients, we could distinguish different frailty phenotypes, differently associated with adverse events. The identification of different patient profiles can help defining the best care strategy according to specific patient needs. PMID- 28364544 TI - Fear of Life Extension. PMID- 28364543 TI - Clinical Trials Targeting Aging and Age-Related Multimorbidity. AB - Background: There is growing interest in identifying interventions that may increase health span by targeting biological processes underlying aging. The design of efficient and rigorous clinical trials to assess these interventions requires careful consideration of eligibility criteria, outcomes, sample size, and monitoring plans. Methods: Experienced geriatrics researchers and clinical trialists collaborated to provide advice on clinical trial design. Results: Outcomes based on the accumulation and incidence of age-related chronic diseases are attractive for clinical trials targeting aging. Accumulation and incidence rates of multimorbidity outcomes were developed by selecting at-risk subsets of individuals from three large cohort studies of older individuals. These provide representative benchmark data for decisions on eligibility, duration, and assessment protocols. Monitoring rules should be sensitive to targeting aging related, rather than disease-specific, outcomes. Conclusions: Clinical trials targeting aging are feasible, but require careful design consideration and monitoring rules. PMID- 28364545 TI - Transcranial magnetic stimulation as a biomarker for epilepsy. PMID- 28364546 TI - Reply: Transcranial magnetic stimulation as a biomarker for epilepsy. PMID- 28364547 TI - Stable functional networks exhibit consistent timing in the human brain. AB - Despite many advances in the study of large-scale human functional networks, the question of timing, stability, and direction of communication between cortical regions has not been fully addressed. At the cellular level, neuronal communication occurs through axons and dendrites, and the time required for such communication is well defined and preserved. At larger spatial scales, however, the relationship between timing, direction, and communication between brain regions is less clear. Here, we use a measure of effective connectivity to identify connections between brain regions that exhibit communication with consistent timing. We hypothesized that if two brain regions are communicating, then knowledge of the activity in one region should allow an external observer to better predict activity in the other region, and that such communication involves a consistent time delay. We examine this question using intracranial electroencephalography captured from nine human participants with medically refractory epilepsy. We use a coupling measure based on time-lagged mutual information to identify effective connections between brain regions that exhibit a statistically significant increase in average mutual information at a consistent time delay. These identified connections result in sparse, directed functional networks that are stable over minutes, hours, and days. Notably, the time delays associated with these connections are also highly preserved over multiple time scales. We characterize the anatomic locations of these connections, and find that the propagation of activity exhibits a preferred posterior to anterior temporal lobe direction, consistent across participants. Moreover, networks constructed from connections that reliably exhibit consistent timing between anatomic regions demonstrate features of a small-world architecture, with many reliable connections between anatomically neighbouring regions and few long range connections. Together, our results demonstrate that cortical regions exhibit functional relationships with well-defined and consistent timing, and the stability of these relationships over multiple time scales suggests that these stable pathways may be reliably and repeatedly used for large-scale cortical communication. PMID- 28364548 TI - Distinct brain imaging characteristics of autoantibody-mediated CNS conditions and multiple sclerosis. AB - Brain imaging characteristics of MOG antibody disease are largely unknown and it is unclear whether they differ from those of multiple sclerosis and AQP4 antibody disease. The aim of this study was to identify brain imaging discriminators between those three inflammatory central nervous system diseases in adults and children to support diagnostic decisions, drive antibody testing and generate disease mechanism hypotheses. Clinical brain scans of 83 patients with brain lesions (67 in the training and 16 in the validation cohort, 65 adults and 18 children) with MOG antibody (n = 26), AQP4 antibody disease (n = 26) and multiple sclerosis (n = 31) recruited from Oxford neuromyelitis optica and multiple sclerosis clinical services were retrospectively and anonymously scored on a set of 29 predefined magnetic resonance imaging features by two independent raters. Principal component analysis was used to perform an overview of patients without a priori knowledge of the diagnosis. Orthogonal partial least squares discriminant analysis was used to build models separating diagnostic groups and identify best classifiers, which were then tested on an independent cohort set. Adults and children with MOG antibody disease frequently had fluffy brainstem lesions, often located in pons and/or adjacent to fourth ventricle. Children across all conditions showed more frequent bilateral, large, brainstem and deep grey matter lesions. MOG antibody disease spontaneously separated from multiple sclerosis but overlapped with AQP4 antibody disease. Multiple sclerosis was discriminated from MOG antibody disease and from AQP4 antibody disease with high predictive values, while MOG antibody disease could not be accurately discriminated from AQP4 antibody disease. Best classifiers between MOG antibody disease and multiple sclerosis were similar in adults and children, and included ovoid lesions adjacent to the body of lateral ventricles, Dawson's fingers, T1 hypointense lesions (multiple sclerosis), fluffy lesions and three lesions or less (MOG antibody). In the validation cohort patients with antibody-mediated conditions were differentiated from multiple sclerosis with high accuracy. Both antibody-mediated conditions can be clearly separated from multiple sclerosis on conventional brain imaging, both in adults and children. The overlap between MOG antibody oligodendrocytopathy and AQP4 antibody astrocytopathy suggests that the primary immune target is not the main substrate for brain lesion characteristics. This is also supported by the clear distinction between multiple sclerosis and MOG antibody disease both considered primary demyelinating conditions. We identify discriminatory features, which may be useful in classifying atypical multiple sclerosis, seronegative neuromyelitis optica spectrum disorders and relapsing acute disseminated encephalomyelitis, and characterizing cohorts for antibody discovery. PMID- 28364551 TI - Refining Alzheimer's disease diagnosis with MRI. PMID- 28364552 TI - Corrigendum. PMID- 28364550 TI - Individual brain structure and modelling predict seizure propagation. AB - See Lytton (doi:10.1093/awx018) for a scientific commentary on this article.Neural network oscillations are a fundamental mechanism for cognition, perception and consciousness. Consequently, perturbations of network activity play an important role in the pathophysiology of brain disorders. When structural information from non-invasive brain imaging is merged with mathematical modelling, then generative brain network models constitute personalized in silico platforms for the exploration of causal mechanisms of brain function and clinical hypothesis testing. We here demonstrate with the example of drug-resistant epilepsy that patient-specific virtual brain models derived from diffusion magnetic resonance imaging have sufficient predictive power to improve diagnosis and surgery outcome. In partial epilepsy, seizures originate in a local network, the so-called epileptogenic zone, before recruiting other close or distant brain regions. We create personalized large-scale brain networks for 15 patients and simulate the individual seizure propagation patterns. Model validation is performed against the presurgical stereotactic electroencephalography data and the standard-of-care clinical evaluation. We demonstrate that the individual brain models account for the patient seizure propagation patterns, explain the variability in postsurgical success, but do not reliably augment with the use of patient-specific connectivity. Our results show that connectome-based brain network models have the capacity to explain changes in the organization of brain activity as observed in some brain disorders, thus opening up avenues towards discovery of novel clinical interventions. PMID- 28364549 TI - Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy. AB - Cellular distribution and dynamics of mitochondria are regulated by several motor proteins and a microtubule network. In neurons, mitochondrial trafficking is crucial because of high energy needs and calcium ion buffering along axons to synapses during neurotransmission. The trafficking kinesin proteins (TRAKs) are well characterized for their role in lysosomal and mitochondrial trafficking in cells, especially neurons. Using whole exome sequencing, we identified homozygous truncating variants in TRAK1 (NM_001042646:c.287-2A > C), in six lethal encephalopathic patients from three unrelated families. The pathogenic variant results in aberrant splicing and significantly reduced gene expression at the RNA and protein levels. In comparison with normal cells, TRAK1-deficient fibroblasts showed irregular mitochondrial distribution, altered mitochondrial motility, reduced mitochondrial membrane potential, and diminished mitochondrial respiration. This study confirms the role of TRAK1 in mitochondrial dynamics and constitutes the first report of this gene in association with a severe neurodevelopmental disorder. PMID- 28364553 TI - Towards a multi-function mapping of the cerebellar cortex. PMID- 28364554 TI - Computers, causality and cure in epilepsy. PMID- 28364555 TI - Penumbral salvage and thrombolysis outcome: a drop of brain, a week of life. PMID- 28364556 TI - Editorial. PMID- 28364557 TI - An essay on the shaking palsy. PMID- 28364558 TI - Changing epidemiology of candidaemia in Australia. AB - Objectives: Knowledge of contemporary epidemiology of candidaemia is essential. We aimed to identify changes since 2004 in incidence, species epidemiology and antifungal susceptibilities of Candida spp. causing candidaemia in Australia. Methods: These data were collected from nationwide active laboratory-based surveillance for candidaemia over 1 year (within 2014-2015). Isolate identification was by MALDI-TOF MS supplemented by DNA sequencing. Antifungal susceptibility testing was performed using Sensititre YeastOneTM. Results: A total of 527 candidaemia episodes (yielding 548 isolates) were evaluable. The mean annual incidence was 2.41/105 population. The median patient age was 63 years (56% of cases occurred in males). Of 498 isolates with confirmed species identity, Candida albicans was the most common (44.4%) followed by Candida glabrata complex (26.7%) and Candida parapsilosis complex (16.5%). Uncommon Candida species comprised 25 (5%) isolates. Overall, C. albicans (>99%) and C. parapsilosis (98.8%) were fluconazole susceptible. However, 16.7% (4 of 24) of Candida tropicalis were fluconazole- and voriconazole-resistant and were non-WT to posaconazole. Of C. glabrata isolates, 6.8% were resistant/non-WT to azoles; only one isolate was classed as resistant to caspofungin (MIC of 0.5 mg/L) by CLSI criteria, but was micafungin and anidulafungin susceptible. There was no azole/echinocandin co-resistance. Conclusions: We report an almost 1.7-fold proportional increase in C. glabrata candidaemia (26.7% versus 16% in 2004) in Australia. Antifungal resistance was generally uncommon, but azole resistance (16.7% of isolates) amongst C. tropicalis may be emerging. PMID- 28364560 TI - Towards more accurate HIV testing in sub-Saharan Africa: a multi-site evaluation of HIV RDTs and risk factors for false positives. AB - INTRODUCTION: Although individual HIV rapid diagnostic tests (RDTs) show good performance in evaluations conducted by WHO, reports from several African countries highlight potentially significant performance issues. Despite widespread use of RDTs for HIV diagnosis in resource-constrained settings, there has been no systematic, head-to-head evaluation of their accuracy with specimens from diverse settings across sub-Saharan Africa. We conducted a standardized, centralized evaluation of eight HIV RDTs and two simple confirmatory assays at a WHO collaborating centre for evaluation of HIV diagnostics using specimens from six sites in five sub-Saharan African countries. METHODS: Specimens were transported to the Institute of Tropical Medicine (ITM), Antwerp, Belgium for testing. The tests were evaluated by comparing their results to a state-of-the art reference algorithm to estimate sensitivity, specificity and predictive values. RESULTS: 2785 samples collected from August 2011 to January 2015 were tested at ITM. All RDTs showed very high sensitivity, from 98.8% for First Response HIV Card Test 1-2.0 to 100% for Determine HIV 1/2, Genie Fast, SD Bioline HIV 1/2 3.0 and INSTI HIV-1/HIV-2 Antibody Test kit. Specificity ranged from 90.4% for First Response to 99.7% for HIV 1/2 STAT-PAK with wide variation based on the geographical origin of specimens. Multivariate analysis showed several factors were associated with false-positive results, including gender, provider-initiated testing and the geographical origin of specimens. For simple confirmatory assays, the total sensitivity and specificity was 100% and 98.8% for ImmunoComb II HIV 12 CombFirm (ImmunoComb) and 99.7% and 98.4% for Geenius HIV 1/2 with indeterminate rates of 8.9% and 9.4%. CONCLUSION: In this first systematic head-to-head evaluation of the most widely used RDTs, individual RDTs performed more poorly than in the WHO evaluations: only one test met the recommended thresholds for RDTs of >=99% sensitivity and >=98% specificity. By performing all tests in a centralized setting, we show that these differences in performance cannot be attributed to study procedure, end-user variation, storage conditions, or other methodological factors. These results highlight the existence of geographical and population differences in individual HIV RDT performance and underscore the challenges of designing locally validated algorithms that meet the latest WHO-recommended thresholds. PMID- 28364561 TI - Comprehensiveness of HIV care provided at global HIV treatment sites in the IeDEA consortium: 2009 and 2014. AB - INTRODUCTION: An important determinant of the effectiveness of HIV treatment programs is the capacity of sites to implement recommended services and identify systematic changes needed to ensure that invested resources translate into improved patient outcomes. We conducted a survey in 2014 of HIV care and treatment sites in the seven regions of the International epidemiologic Database to Evaluate AIDS (IeDEA) Consortium to evaluate facility characteristics, HIV prevention, care and treatment services provided, laboratory capacity, and trends in the comprehensiveness of care compared to data obtained in the 2009 baseline survey. METHODS: Clinical staff from 262 treatment sites in 45 countries in IeDEA completed a site survey from September 2014 to January 2015, including Asia Pacific with Australia (n = 50), Latin America and the Caribbean (n = 11), North America (n = 45), Central Africa (n = 17), East Africa (n = 36), Southern Africa (n = 87), and West Africa (n = 16). For the 55 sites with complete data from both the 2009 and 2014 survey, we evaluated change in comprehensiveness of care. RESULTS: The majority of the 262 sites (61%) offered seven essential services (ART adherence, nutritional support, PMTCT, CD4+ cell count testing, tuberculosis screening, HIV prevention, and outreach). Sites that were publicly funded (64%), cared for adults and children (68%), low or middle Human Development Index (HDI) rank (68%, 68%), and received PEPFAR support (71%) were most often fully comprehensive. CD4+ cell count testing was universally available (98%) but only 62% of clinics offered it onsite. Approximately two-thirds (69%) of sites reported routine viral load testing (44-100%), with 39% having it onsite. Laboratory capacity to monitor antiretroviral-related toxicity and diagnose opportunistic infections varied widely by testing modality and region. In the subgroup of 55 sites with two surveys, comprehensiveness of services provided significantly increased across all regions from 2009 to 2014 (5.7 to 6.5, p < 0.001). CONCLUSION: The availability of viral load monitoring remains suboptimal and should be a focus for site capacity, particularly in East and Southern Africa, where the majority of those initiating on ART reside. However, the comprehensiveness of care provided increased over the past 5 years and was related to type of funding received (publicly funded and PEPFAR supported). PMID- 28364562 TI - Latent class analysis of acceptability and willingness to pay for self-HIV testing in a United States urban neighbourhood with high rates of HIV infection. AB - INTRODUCTION: Acceptability and willingness to both take and pay for HIV self tests (HIVSTs) in US neighbourhoods with high rates of HIV infection are not well understood. METHODS: We surveyed 1,535 individuals about acceptability and willingness to take and pay for an HIVST in a predominately African American neighbourhood with 3% HIV seroprevalence. We recruited individuals presenting for HIV screening services in a community-based programme. Latent class analysis (LCA) grouped individuals with similar patterns of HIV-risk behaviours and determined which groups would be most willing to use and buy HIVSTs. RESULTS: Nearly 90% of respondents were willing to use an HIVST; 55% were willing to buy HIVSTs, but only 23% were willing to pay the market price of US $40. Four distinct groups emerged and were characterized by risk behaviours: (1) low risk (N = 324); (2) concurrent partnerships (N = 346); (3) incarceration and substance use (N = 293); and (4) condomless sex/multiple partners (N = 538). Individuals in the low-risk class were less willing to self-test compared to concurrent sexual partners (OR = 0.39, p = .003) and incarceration and substance use (OR = 0.46, p = .011) classes. There were no significant differences across classes in the amount individuals were willing to pay for an HIVST. CONCLUSION: HIVSTs were overwhelmingly acceptable but cost prohibitive; most participants were unwilling to pay the market rate of US $40. Subsidizing and implementing HIVST programmes in communities with high rates of infection present a public health opportunity, particularly among individuals reporting condomless sex with multiple partners, concurrent sexual partnerships and those with incarceration and substance use histories. PMID- 28364563 TI - Changes in second-line regimen durability and continuity of care in relation to national ART guideline changes in South Africa. AB - INTRODUCTION: Little is known about the impact of antiretroviral therapy (ART) guideline changes on the durability of second-line ART and continuity of care. This study examines predictors of early drug substitutions and treatment interruptions using a cohort analysis of HIV positive adults switched to second line ART between January 2004 and September 2013 in Johannesburg, South Africa. METHODS: The main outcomes were having a drug substitution or treatment interruption in the first 24 months on second-line ART. Kaplan Meiers analyses and Cox proportional hazards regression were used to identify predictors of drug substitutions and treatment interruptions. RESULTS: Of 3028 patients on second line ART, 353 (11.7%) had a drug substitution (8.6 per 100PY, 95% CI: 7.8-9.6) and 260 (8.6%) had a treatment interruption (6.3 per 100PY, 95% CI: 5.6-7.1). While treatment interruptions decreased from 32.5 per 100PY for the 2004 cohort to 2.3 per 100PY for the 2013 cohort, the rates of drug substitutions steadily increased, peaking at an incidence of 26.7 per 100PY for the 2009 cohort and then decreased to 4.2 per 100PY in the 2011 cohort. Compared to the 2004 to 2008 cohorts, the hazard of early drug substitutions was highest among patients switched to AZT + ddI + LPVr in 2009 to 2010 (aHR 5.1, 95% CI: 3.4-7.1) but remained low over time among patients switched to TDF + 3TC/FTC + LPVr or AZT/ABC + 3TC + LPVr. The main common predictor of both treatment interruption and drug substitution was drug toxicity. CONCLUSION: Our results show a rapid transition between 2004 and 2010 ART guidelines and concurrent improvements in continuity of care among second-line ART patients. Drug toxicity reporting and monitoring systems need improvements to inform timely regimen changes and ensure that patients remain in care. However, reasons for drug substitutions should be closely monitored to ensure that patients do not run out of treatment options in the future. PMID- 28364564 TI - Age-disparate sex and HIV risk for young women from 2002 to 2012 in South Africa. AB - INTRODUCTION: Age-disparate sex has long been considered a factor that increases HIV risk for young women in South Africa. However, recent studies from specific regions in South Africa have found conflicting evidence. Few studies have assessed the association between age-disparate partnerships (those involving an age gap of 5 years or more) and HIV risk at the national level. This study investigates the relationship between age-disparate sex and HIV status among young women aged 15-24 in South Africa. METHODS: Nationally representative weighted data from the 2002, 2005, 2008, and 2012 South African National HIV Surveys were analysed for young women aged 15-24 years using bivariate analyses and multiple logistic regressions. RESULTS: After conducting multiple logistic regression analyses and controlling for confounders, young women with age disparate partners had greater odds of being HIV positive in every survey year: 2002 (aOR = 1.74, 95%CI: 0.81-3.76, p = 0.16); 2005 (aOR = 2.11, 95%CI: 1.22 3.66, p < 0.01); 2008 (aOR = 2.02, 95%CI: 1.24-3.29, p < 0.01); 2012 (aOR = 1.53, 95%CI: 0.92-2.54, p < 0.1). The odds of being HIV positive increased for each year increase in their male partner's age in 2002 (aOR = 1.10, 95%CI: 0.98-1.22, p = 0.11), 2005 (aOR = 1.10, 95%CI: 1.03-1.17, p < 0.01), 2008 (aOR = 1.08, 95%CI: 1.01-1.15, p < 0.05), and 2012 (aOR = 1.08, 95%CI: 1.01-1.16, p < 0.05). Findings were statistically significant (p < 0.1) for the years 2005, 2008, and 2012. CONCLUSION: Our findings suggest that age-disparate sex continues to be a risk factor for young women aged 15-24 in South Africa at a national level. These results may reflect variation in HIV risk at the national level compared to the differing results from recent studies in a demographic surveillance system and trial contexts. In light of recent contradictory study results, further research is required on the relationship between age-disparate sex and HIV for a more nuanced understanding of young women's HIV risk. PMID- 28364567 TI - Punitive laws, key population size estimates, and Global AIDS Response Progress Reports: An ecological study of 154 countries AB - INTRODUCTION: UN global plans on HIV/AIDS have committed to reducing the number of countries with punitive laws criminalizing key populations. This study explores whether punitive laws are associated with countries' performance on targets set in the global plans. METHODS: The study used chi-square tests of independence to explore associations between legal status, key population size estimates, and HIV service coverage for 193 countries from 2007 to 2014. We used data reported by countries on United Nations Global AIDS Progress Report (GARPR) indicators, and legal data from UNAIDS, UNDP, and civil society organizations. Due to lack of sufficiently reliable legal data, only men who have sex with men (MSM) could be studied. The study utilized public data aggregated at the national level. Correspondence with individual experts in a subset of countries stated the purpose of the study, and all responses were anonymized. RESULTS AND DISCUSSION: A significantly larger proportion of countries that criminalize same-sex sexual behaviour reported implausibly low size estimates or no size estimates for MSM. This is consistent with findings in qualitative research that MSMs are marginalized and reluctant to be studied in countries where same-sex sexuality is criminalized. Size estimates are often used as the denominators for national HIV service coverage reports. Initially, countries that criminalized same-sex sexuality appeared to have higher HIV testing coverage among MSM than did countries where it is not criminalized. However, investigation of a subset of countries that have reported 90-100% HIV testing coverage among MSM found that most were based on implausibly low or absent size estimates. CONCLUSION: Criminalization of same-sex sexuality is associated with implausibly low or absent MSM size estimates. Low size estimates may contribute to official denial of the existence of MSM; to failure to adequately address their needs; and to inflated HIV service coverage reports that paint a false picture of success. To enable and measure progress in the HIV response, UN agencies should lead a collaborative process to systematically, independently and rigorously gather data on laws and their enforcement. PMID- 28364566 TI - Identifying gaps in HIV service delivery across the diagnosis-to-treatment cascade: findings from health facility surveys in six sub-Saharan countries. AB - INTRODUCTION: Despite the rollout of antiretroviral therapy (ART), challenges remain in ensuring timely access to care and treatment for people living with HIV. As part of a multi-country study to investigate HIV mortality, we conducted health facility surveys within 10 health and demographic surveillance system sites across six countries in Eastern and Southern Africa to investigate clinic level factors influencing (i) use of HIV testing services, (ii) use of HIV care and treatment and (iii) patient retention on ART. METHODS: Health facilities (n = 156) were sampled within 10 surveillance sites: Nairobi and Kisumu (Kenya), Karonga (Malawi), Agincourt and uMkhanyakude (South Africa), Ifakara and Kisesa (Tanzania), Kyamulibwa and Rakai (Uganda) and Manicaland (Zimbabwe). Structured questionnaires were administered to in-charge staff members of HIV testing, prevention of mother-to-child transmission (PMTCT) and ART units within the facilities. Forty-one indicators influencing uptake and patient retention along the continuum of HIV care were compared across sites using descriptive statistics. RESULTS: The number of facilities surveyed ranged from six in Malawi to 36 in Zimbabwe. Eighty percent were government-run; 73% were lower-level facilities and 17% were district/referral hospitals. Client load varied widely, from less than one up to 65 HIV testing clients per provider per week. Most facilities (>80%) delivered services or interventions that would support patient retention in care such as delivering free services, offering PMTCT within antenatal care, pre-ART monitoring and adherence counselling. Many facilities under-delivered in several areas, however, such as targeted testing for high-risk groups (21%) and mobile testing (36%). There were also intra-site and inter-site differences, including in the delivery of Option B+ (ranging from 6% in Kisumu to 93% in Kyamulibwa), and nurse-led ART initiation (ranging from 50% in Kisesa to 100% in Karonga and Agincourt). Only facilities in Malawi did not require additional lab tests for ART initiation. Stock-outs of HIV test kits and antiretroviral drugs were particularly common in Tanzania. CONCLUSION: We identified a high standard of health facility performance in delivering strategies that may support progression through the continuum of HIV care. HIV testing policy and practice was particularly weak. Inter- and intra-country differences in quality and coverage represent opportunities to improve the delivery of comprehensive services to people living with HIV. PMID- 28364565 TI - How common and frequent is heterosexual anal intercourse among South Africans? A systematic review and meta-analysis. AB - BACKGROUND: HIV is transmitted more effectively during anal intercourse (AI) than vaginal intercourse (VI). However, patterns of heterosexual AI practice and its contribution to South Africa's generalized epidemic remain unclear. We aimed to determine how common and frequent heterosexual AI is in South Africa. METHODS: We searched for studies reporting the proportion practising heterosexual AI (prevalence) and/or the number of AI and unprotected AI (UAI) acts (frequency) in South Africa from 1990 to 2015. Stratified random-effects meta-analysis by sub groups was used to produce pooled estimates and assess the influence of participant and study characteristics on AI prevalence. We also estimated the fraction of all sex acts which were AI or UAI and compared condom use during VI and AI. RESULTS: Of 41 included studies, 31 reported on AI prevalence and 14 on frequency, over various recall periods. AI prevalence was high across different recall periods for sexually active general-risk populations (e.g. lifetime = 18.4% [95%CI:9.4-27.5%], three-month = 20.3% [6.1-34.7%]), but tended to be even higher in higher-risk populations such as STI patients and female sex workers (e.g. lifetime = 23.2% [0.0-47.4%], recall period not stated = 40.1% [36.2 44.0%]). Prevalence was higher in studies using more confidential interview methods. Among general and higher-risk populations, 1.2-40.0% and 0.7-21.0% of all unprotected sex acts were UAI, respectively. AI acts were as likely to be condom protected as vaginal acts. CONCLUSION: Reported heterosexual AI is common but variable among South Africans. Nationally and regionally representative sexual behaviour studies that use standardized recall periods and confidential interview methods, to aid comparison across studies and minimize reporting bias, are needed. Such data could be used to estimate the extent to which AI contributes to South Africa's HIV epidemic. PMID- 28364570 TI - Excessive Fragmentary Myoclonus: What Do We Know? AB - Excessive fragmentary myoclonus (EFM) is a polysomnographic finding registered by the surface electromyography (EMG) and characterized as a result of the muscle activity consisting of sudden, isolated, arrhythmic, asynchronous and asymmetric brief twitches. The EMG potentials are defined by the exact criteria in The International Classification of the Sleep Disorders, 3rd edition and they appear with high intensity in all sleep stages. Clinical significance of EFM is unclear. It was observed in combination with other diseases and features such as obstructive and central sleep apnea, narcolepsy, periodic limb movements, insomnia, neurodegenerative disorders and peripheral nerve dysfunction. Relation to such wide range of diseases supports the opinion that EFM is nor a specific sleep disorder nor a specific polysomnographic sign. The option that EFM is a normal variant has also not been ruled out so far. PMID- 28364571 TI - 3D Multislice and Cone-beam Computed Tomography Systems for Dental Identification. AB - 3D Multislice and Cone-beam computed tomography (CBCT) in forensic odontology has been shown to be useful not only in terms of one or a few of dead bodies but also in multiple fatality incidents. 3D Multislice and Cone-beam computed tomography and digital radiography were demonstrated in a forensic examination form. 3D images of the skull and teeth were analysed and validated for long ante mortem/post mortem intervals. The image acquisition was instantaneous; the images were able to be optically enlarged, measured, superimposed and compared prima vista or using special software and exported as a file. Digital radiology and computer tomography has been shown to be important both in common criminalistics practices and in multiple fatality incidents. Our study demonstrated that CBCT imaging offers less image artifacts, low image reconstruction times, mobility of the unit and considerably lower equipment cost. PMID- 28364568 TI - Spatial patterns of HIV prevalence and service use in East Zimbabwe: implications for future targeting of interventions. AB - INTRODUCTION: Focusing resources for HIV control on geographic areas of greatest need in countries with generalized epidemics has been recommended to increase cost-effectiveness. However, socioeconomic inequalities between areas of high and low prevalence could raise equity concerns and have been largely overlooked. We describe spatial patterns in HIV prevalence in east Zimbabwe and test for inequalities in accessibility and uptake of HIV services prior to the introduction of spatially-targeted programmes. METHODS: 8092 participants in an open-cohort study were geo-located to 110 locations. HIV prevalence and HIV testing and counselling (HTC) uptake were mapped with ordinary kriging. Clusters of high or low HIV prevalence were detected with Kulldorff statistics, and the socioeconomic characteristics and sexual risk behaviours of their populations, and levels of local HIV service availability (measured in travel distance) and uptake were compared. Kulldorff statistics were also determined for HTC, antiretroviral therapy (ART), and voluntary medical male circumcision (VMMC) uptake. RESULTS: One large and one small high HIV prevalence cluster (relative risk [RR] = 1.78, 95% confidence interval [CI] = 1.53-2.07; RR = 2.50, 95% CI = 2.08-3.01) and one low-prevalence cluster (RR = 0.70, 95% CI = 0.60-0.82) were detected. The larger high-prevalence cluster was urban with a wealthier population and more high-risk sexual behaviour than outside the cluster. Despite better access to HIV services, there was lower HTC uptake in the high-prevalence cluster (odds ratio [OR] of HTC in past three years: OR = 0.80, 95% CI = 0.66 0.97). The low-prevalence cluster was predominantly rural with a poorer population and longer travel distances to HIV services; however, uptake of HIV services was not reduced. CONCLUSION: High-prevalence clusters can be identified to which HIV control resources could be targeted. To date, poorer access to HIV services in the poorer low-prevalence areas has not resulted in lower service uptake, whilst there is significantly lower uptake of HTC in the high-prevalence cluster where health service access is better. Given the high levels of risky sexual behaviour and lower uptake of HTC services, targeting high-prevalence clusters may be cost-effective in this setting. If spatial targeting is introduced, inequalities in HIV service uptake may be avoided through mobile service provision for lower prevalence areas. PMID- 28364572 TI - Comparison of Cold Technique Tonsillectomy and Thermal Welding Tonsillectomy at Different Age Groups. AB - The aim of this study is to compare objectively advantages and disadvantages of cold technique tonsillectomy and thermal welding tonsillectomy at the same case. A total of 100 patients, 53 patients younger than 12 years of age and 47 patients elder than 12 years of age, were included in this study. Tonsillectomy was performed by using cold technique on the right side of the palatine tonsils and thermal welding on the left side. Right and left sides were compared regarding perioperative bleeding, surgical dissection time, postoperative pain scale at the 1st and 7th day and postoperative bleeding parameters. Perioperative bleeding was found to be higher in cold technique side in patients younger than 12 years of age (p<0.001). Postoperative pain score on the day 1 was significantly higher in cold technique side, whereas it was found to be higher in thermal welding side at postoperative day 7 (p<0.001). Perioperative bleeding was found to be significantly higher in cold technique side (p<0.001) and surgical dissection time of thermal welding was found to be longer (p<0.001) in patients elder than 12 years of age. Postoperative pain score at the day 1 and day 7 was found to be higher in thermal welding side (p<0.001). Postoperative pain score at the day 1 and day 7 were statistically significantly higher in patients elder than 12 years of age. As a result, both techniques have its unique superior aspects and both can be applied as a routine tonsillectomy technique. PMID- 28364573 TI - Quantitative Parameters of Interdental Gingiva in Chronic Periodontitis Patients with IFN-gamma Gene Polymorphism. AB - Chronic periodontitis (CP), an infectious disease resulting in inflammation within the periodontal tissue, is the main cause of adult tooth loss. CP is a multi-factorial disorder and the interaction between multiple genetic and environmental factors results in the manifestation of this disease. Recent researches in periodontitis has focused on cytokine gene polymorphisms that play important role in periodontal inflammation, but few studies investigated histological change that occur during CP in the supporting tissue of teeth. The aims of this study were to investigate the association of IFN-gamma +874 A/T polymorphisms and quantitative parameters of interdental gingiva in CP patients. The study samples were interdental gingiva biopsies from 60 individuals including 38 patients and 22 healthy subjects. After determination of IFN-gamma +874 A/T gene polymorphism by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR), patients were divided in three subgroups: 10 AA, 18 AT and 10 TT. After slides preparation, quantitative parameters were estimated by Cavalieri's point-counting method. Statistical analyses were performed using Mann Whitney and Kruskal-Wallis test to compare differences between groups. The volume density (Vv) of epithelium, connective tissue and its components were significantly different between the control and CP groups (P<0.05). Statistically significant differences in the Vv of collagenous and non-collagenous matrix of interdental gingiva between AA, AT and TT groups were found (P<0.05). Result of present study shows that IFN-gamma +874 A/T is strongly associated with some quantitative parameters of connective tissue constituents of interdental papilla in CP patients. PMID- 28364575 TI - Morphological awareness and reading comprehension: Examining mediating factors. AB - The relation between morphological awareness-defined as the awareness of and ability to manipulate the smallest units of meaning in language-and reading comprehension remains in need of specification. In this study, we evaluated four potential intervening variables through which morphological awareness may contribute indirectly to reading comprehension. We assessed word reading and vocabulary as well as children's ability to read and analyze the meaning of morphologically complex words (morphological decoding and morphological analysis, respectively). Controls of phonological awareness and nonverbal ability were included in the model. Participants were 221 English-speaking children in Grade 3. Multivariate path analyses revealed evidence of two indirect relations and one direct relation between morphological awareness and reading comprehension. In the first indirect path, morphological awareness contributed to morphological decoding, which then influenced word reading and finally reading comprehension. In a second indirect path, morphological awareness contributed to morphological analysis, which contributed to reading comprehension. Finally, in a direct path, morphological awareness contributed to reading comprehension beyond all other variables. These findings inform as to the potential mechanisms underlying the relation between morphological awareness and reading comprehension in children. PMID- 28364574 TI - Can Platelet and Leukocyte Indicators Give Us an Idea about Distant Metastasis in Nasopharyngeal Cancer? AB - This study aimes to evaluate platelet and leucocyte indicators, such as the mean platelet volume, platelet distribution width, plateletcrit, white blood cell count, neutrophil to lymphocyte ratio in nasopharyngeal cancer patients and also to evaluate the relationship between these indicators and nasopharyngeal cancer with distant metastasis. The medical records of 118 patients diagnosed with nasopharyngeal cancer in our hospital between January 2006 and August 2015 were reviewed. The nasopharyngeal cancer group was further sub grouped according to the presence or absence of distant metastasis and TNM (tumour - T, node - N, metastasis - M) classification. A control group consisted of 120 healthy patients. The platelet and leucocyte values at the time of the initial diagnosis were recorded. Neutrophil to lymphocyte ratio and platelet distribution width values were significantly higher in the nasopharyngeal cancer group. But only platelet distribution width values were significantly higher in the nasopharyngeal cancer group with distant metastasis compared to the nasopharyngeal cancer group without distant metastasis. Neutrophil to lymphocyte ratio and platelet distribution width values may increase in nasopharyngeal cancer. But only the platelet distribution width values may give us an idea about the distant metastasis in nasopharyngeal cancer. PMID- 28364576 TI - Different methods used to form oxygen reducing biocathodes lead to different biomass quantities, bacterial communities, and electrochemical kinetics. AB - Six biocathodes catalyzing oxygen reduction were designed from the same environmental inoculum but using three different methods. Two were formed freely at open circuit potential, two using conventional aerobic polarization at 0.2V/SCE and two by reversion of already established acetate-fed bioanodes. Observation of the biofilms by SEM and epifluorescence microscopy revealed that reversible bioelectrodes had the densest biofilms. Electrochemical characterization revealed two different redox systems for oxygen reduction, at 0.30 and +0.23V/SCE. The biocathodes formed under aerobic polarization gave higher electrocalatytic performance for O2 reduction, due to production of the redox systems at +0.23V/SCE. Analyses of the bacterial communities on the biocathodes by 16S-rRNA pyrosequencing showed different selection (or enrichment) of microorganisms depending on the method used. This study highlights how the method chosen for designing oxygen biocathodes can affect the cathode coverage, the selection of bacterial populations and the electrochemical performance. PMID- 28364577 TI - The role of city income inequality, sex ratio and youth mortality rates in the effect of violent victimization on health-risk behaviors in Brazilian adolescents. AB - This study integrates insights from evolutionary psychology and social epidemiology to present a novel approach to contextual effects on health-risk behaviors (unprotected sex, drunkenness episodes, drugs and tobacco experimentation) among adolescents. Using data from the 2012 Brazilian National Survey of Adolescent Health (PeNSE), we first analyzed the effects of self reported violent victimization on health-risk behaviors of 47,371 adolescents aged 10-19 nested in the 26 Brazilian state capitals and the Federal District. We then explored whether the magnitude of these associations was correlated with cues of environmental harshness and unpredictability (youth external mortality and income inequality) and mating competition (sex ratio) from the city level. Results indicated that self-reported violent victimization is associated with an increased chance of engagement in health-risk behaviors in all Brazilian state capitals, for both males and females, but the magnitude of these associations varies in relation to broader environmental factors, such as the cities' age specific mortality rates, and specifically for females, income inequality and sex ratio. In addition to introducing a novel theoretical and empirical approach to contextual effects on adolescent health-risk behaviors, our findings reinforce the need to consider synergies between people's life experiences and the conditions where they live, when studying health-risk behaviors in adolescence. PMID- 28364578 TI - Physician associates in primary health care in England: A challenge to professional boundaries? AB - Like other health care systems, the National Health Service (NHS) in England has looked to new staffing configurations faced with medical staff shortages and rising costs. One solution has been to employ physician associates (PAs). PAs are trained in the medical model to assess, diagnose and commence treatment under the supervision of a physician. This paper explores the perceived effects on professional boundaries and relationships of introducing this completely new professional group. It draws on data from a study, completed in 2014, which examined the contribution of PAs working in general practice. Data were gathered at macro, meso and micro levels of the health care system. At the macro and meso level data were from policy documents, interviews with civil servants, senior members of national medical and nursing organisations, as well as regional level NHS managers (n = 25). At the micro level data came from interviews with General Practitioners, nurse practitioners and practice staff (n = 30) as well as observation of clinical and professional meetings. Analysis was both inductive and also framed by the existing theories of a dynamic system of professions. It is argued that professional boundaries become malleable and subject to negotiation at the micro level of service delivery. Stratification within professional groups created differing responses between those working at macro, meso and micro levels of the system; from acceptance to hostility in the face of a new and potentially competing, occupational group. Overarching this state agency was the requirement to underpin legislatively the shifts in jurisdictional boundaries, such as prescribing required for vertical substitution for some of the work of doctors. PMID- 28364579 TI - Frequency of prescription opioid misuse and suicidal ideation, planning, and attempts. AB - The goal of this study was to examine the relationship between past-year frequency of prescription opioid misuse and past-year suicidal ideation, suicide planning, and suicide attempts. Secondary data analyses were conducted using data from 41,053 participants of the 2014 National Survey of Drug Use and Health. Past year frequency of prescription opioid misuse was grouped into 4 categories: none, less than monthly (1-11 times), monthly to weekly (12-51 times), and weekly or more (52 times or more). Binomial logistic regression analyses adjusted for demographics, overall health rating, depression, anxiety, and substance use disorders to test the associations between frequency of prescription opioid misuse and suicide-related variables. Compared to those who did not endorse prescription opioid misuse in the past year, prescription opioid misuse was significantly associated with suicidal ideation, suicide planning, and suicide attempts for each frequency of use category in unadjusted models (p < 0.05). In adjusted models, frequency of prescription opioid misuse remained significantly associated with suicidal ideation (p < 0.05 for each frequency category); however, only the group reporting weekly or more use on average was associated with suicide planning and attempts (p < 0.05). The findings provide novel specificity regarding prescription opioid use in relation to suicide-related outcomes further supporting enhanced access to suicide prevention and nonpharmacological approaches to pain management across various settings. PMID- 28364580 TI - End-organ radiographic manifestations of cranial neuropathies: A concise review. AB - BACKGROUND: Cranial neuropathies are a spectrum of disorders associated with dysfunction of one or more of the twelve cranial nerves and the subsequent anatomic structures they innervate. OBJECTIVE: The purpose of this article is to review radiographic imaging findings of end-organ aberrations secondary to cranial neuropathies. METHOD: All articles related to cranial neuropathies were retrieved through the PubMed MEDLINE NCBI database from January 1, 1991 to August 31, 2014. These manuscripts were analyzed for their relation to cranial nerve end organ disease pathogenesis and radiographic imaging. RESULTS: The present review reveals detectable end-organ changes on CT and/or MRI for the following cranial nerves: olfactory nerve, optic nerve, oculomotor nerve, trochlear nerve, trigeminal nerve, abducens nerve, facial nerve, vestibulocochlear nerve, glossopharyngeal nerve, vagus nerve, accessory nerve, and hypoglossal nerve. CONCLUSION: Radiographic imaging can assist in the detailed evaluation of end organ involvement, often revealing a corresponding cranial nerve injury with high sensitivity and diagnostic accuracy. A thorough understanding of the distal manifestations of cranial nerve disease can optimize early pathologic detection as well as dictate further clinical management. PMID- 28364581 TI - Self-reported confidence in patient safety knowledge among Australian undergraduate nursing students: A multi-site cross-sectional survey study. AB - BACKGROUND: Patient safety is critical to the provision of quality health care and thus is an essential component of nurse education. OBJECTIVE: To describe first, second and third year Australian undergraduate nursing students' confidence in patient safety knowledge acquired in the classroom and clinical settings across the three years of the undergraduate nursing program. DESIGN: A cross-sectional online survey conducted in 2015. SETTING: Seven Australian universities with campuses across three states (Queensland, New South Wales, South Australia). PARTICIPANTS: A total of 1319 Australian undergraduate nursing students. METHODS: Participants were surveyed using the 31-item Health Professional Education in Patient Safety Survey (H-PEPSS). Descriptive statistics summarised the sample and survey responses. Paired t-tests, ANOVA and generalized estimating-equations models were used to compare responses across learning settings (classroom and clinical), and year of nursing course. RESULTS: Participants were most confident in their learning of clinical safety skills and least confident in learning about the sociocultural dimensions of working in teams with other health professionals, managing safety risks and understanding human and environmental factors. Only 59% of students felt confident they could approach someone engaging in unsafe practice, 75% of students agreed it was difficult to question the decisions or actions of those with more authority, and 78% were concerned they would face disciplinary action if they made a serious error. One patient safety subscale, Recognising and responding to remove immediate safety risks, was rated significantly higher by third year nursing students than by first and second year students. Two broader aspects of patient safety scales, Consistency in how patient safety issues are dealt with by different preceptors, and System aspects of patient safety are well covered in our program, were rated significantly higher by first year nursing students than by second and third year students. One scale, Understanding that reporting adverse events and close calls can lead to change and can reduce recurrence of events, was rated significantly higher by third year students than first and second year students. CONCLUSIONS: In order are to achieve meaningful improvements in patient safety, and create harm free environments for patients, it is crucial that nursing students develop confidence communicating with others to improve patient safety, particularly in the areas of challenging poor practice, and recognising, responding to and disclosing adverse events, including errors and near misses. PMID- 28364582 TI - Clinical relevance of TP53 polymorphic genetic variations in chronic lymphocytic leukemia. AB - OBJECTIVES: To analyze the distribution of single nucleotide polymorphisms (SNPs) in the TP53 gene in chronic lymphocytic leukemia (CLL) patients and to evaluate their associations with clinical behavior of the disease. METHODS: SNPs in exons and parts of adjacent introns of the TP53 gene were analyzed in 235 CLL patients observed during 2005-2012 years. Data on individuals of European descent from the 1000 Genomes Project data set were used as a reference. RESULTS: In the recessive model of inheritance, we found borderline associations between CLL risk and C/C genotype of rs1642785 (p=0.048); G/G genotype of rs2909430 (in men only; p=0.036) and Pro72Pro genotype of rs1042522 (in men only; p=0.045). Risk of CLL was increased also in carriers of rare haplotypes (p=0.0049). Besides, genotypes Pro72Pro of rs1042522, C/C of rs1642785, and G/G of rs2909430 were associated with an increased incidence of TP53 mutations. Median of overall survival in rs1800372 carriers was comparable to that of patients with TP53 mutations. Other evaluated SNPs were not associated with survival. CONCLUSION: Our data suggest that some TP53 variants may affect the risk of CLL. rs1800372 polymorphism might be the marker of unfavorable prognosis of the disease. PMID- 28364583 TI - Creatine kinase in human erythrocytes: A genetic anomaly reveals presence of soluble brain-type isoform. AB - For maintaining energy homeostasis, creatine kinase (CK) is present at elevated levels in tissues with high and/or fluctuating energy requirements such as muscle, brain, and epithelia, while there is very few CK, if any, in peripheral blood cells. However, an ectopic expression of brain-type creatine kinase (BCK) has been reported for platelets and leukocytes in an autosomal dominant inherited anomaly named CKBE. Here we investigated CK in erythrocytes of CKBE individuals from eight unrelated families. The data revealed a varying but significant increase of CK activity in CKBE individuals as compared to controls, reaching an almost 800-fold increase in two CKBE individuals which also had increased erythrocyte creatine. Immunoblotting with highly specific antibodies confirmed that the expressed CK isoform is BCK. Cell fractionation evidenced soluble BCK, suggesting cytosolic and not membrane localization of erythrocyte CK as reported earlier. These results are discussed in the context of putative CK energy buffering and transfer functions in red blood cells. PMID- 28364584 TI - Follistatin during pregnancy and its potential role as an ovarian suppressing agent. AB - OBJECTIVE: Ovarian quiescence is a common condition during pregnancy. In vitro, follistatin, an antagonist of follicle-stimulating hormone, blocks follicular development at early stages, and its serum levels increase during pregnancy. A possible surrogate biomarker of ovarian arrest during pregnancy is a decrease in anti-mullerian hormone (AMH) levels followed by an increase in these levels on the second day after labor. The purpose of this study was to determine whether follistatin could act as an ovarian-suppressing agent during pregnancy. Follistatin levels and AMH levels were determined at various stages of pregnancy and postpartum. STUDY DESIGN: The follistatin and AMH levels of 69 patients were retrospectively determined with the AMH Gen II ELISA and with the Human Follistatin Quantikine ELISA Kit. For 49 patients, samples were available from various trimesters for cross-sectional analysis; for the other 20, samples were available longitudinally from day one before labor and then daily on days 1 through 4 after labor. Statistical significance was determined with linear regression, the Friedman rank sum test and the Wilcoxon-Nemenyi-McDonald-Thompson post hoc test. RESULTS: The behavior of follistatin levels was exactly opposite that of AMH levels: Follistatin levels increased significantly during pregnancy and on the first day after parturition but declined afterwards, whereas AMH levels decreased significantly during pregnancy and increased after labor. CONCLUSION: Follistatin can induce ovarian arrest during pregnancy. PMID- 28364585 TI - Network analysis and in silico prediction of protein-protein interactions with applications in drug discovery. AB - Protein-protein interactions (PPIs) are vital to maintaining cellular homeostasis. Several PPI dysregulations have been implicated in the etiology of various diseases and hence PPIs have emerged as promising targets for drug discovery. Surface residues and hotspot residues at the interface of PPIs form the core regions, which play a key role in modulating cellular processes such as signal transduction and are used as starting points for drug design. In this review, we briefly discuss how PPI networks (PPINs) inferred from experimentally characterized PPI data have been utilized for knowledge discovery and how in silico approaches to PPI characterization can contribute to PPIN-based biological research. Next, we describe the principles of in silico PPI prediction and survey the existing PPI and PPI site prediction servers that are useful for drug discovery. Finally, we discuss the potential of in silico PPI prediction in drug discovery. PMID- 28364586 TI - Imperfect information on physical activity and caloric intake. AB - Using the National Health and Nutrition Examination Survey Data, I find that individuals who overestimate their activity level by one standard deviation consume 40-60 extra calories per day, or enough to gain five pounds per year. These extra calories are composed mainly of sugar and carbohydrate, and are concentrated among individuals in the 75th and 90th percentiles of caloric intake. The link between overeating and inaccurate estimation of physical activity is strongest among less educated individuals and individuals with high variance in their physical activity, suggesting that imperfect recall or information gaps explain at least part of the relationship of interest. These results imply the existence of a necessary condition for physical activity-based information treatments to be effective in changing health behaviors and obesity rates. PMID- 28364587 TI - Obsessive-compulsive disorder and family accommodation: A 3-year follow-up. AB - The present study assessed 3-year maintenance of family accommodation (FA) reduction in a sample from a randomized clinical trial that assessed the impact of 12 sessions of cognitive-behavioral group therapy (CBGT) for obsessive compulsive disorder (OCD), with the involvement of family members in two sessions. Of the 46 original pairs of patients/family members, 35 were assessed at 3 years. Demographic and clinical characteristics remained similar. Post-CBGT improvement of OCD symptoms remained significant; FA reduced 39% after the therapy and 51% at follow-up. FA reduction remained over time, underscoring the importance of permanently assessing FA and involving family members when treating OCD. PMID- 28364588 TI - A latent profile analysis of schizotypal dimensions: Associations with psychopathology and personality. AB - The main goal of the present study was to explore the latent structure of schizotypal traits in non-clinical young adults, and compare the latent profiles in clinical and personality characteristics: mental distress, psychosis proneness, hypomanic experiences, and anticipatory and consummatory pleasure. A large sample of college students (N =1002; mean age =21.11 years; SD =3.92) were administered the Schizotypal Personality Questionnaire-Brief Revised, the Mood Disorder Questionnaire, the short version of the Oxford-Liverpool Inventory of Feelings and Experiences, the General Health Questionnaire-12, and the Temporal Experience of Pleasure Scale. Using latent profile analysis, four latent classes (LC) were identified: "low schizotypy" (62.4%), "average schizotypy" (17.6%), "interpersonal schizotypy" (17.1%), and "high schizotypy" (2.9%). The "high schizotypy" class scored higher on most psychometric indicators of psychopathology and personality (i.e., mental distress, schizotypy, hypomanic experiences, and anticipatory and consummatory pleasure) relative to other three latent classes. The other three schizotypal latent profiles also varied in terms of these psychopathology and personality factors. The identification of homogeneous subgroups of individuals potentially at-risk for psychosis based on schizotypal latent profiles may improve early identification and prevention efforts aimed at reducing the burden associated with psychotic-spectrum disorders and mental health problems. PMID- 28364590 TI - Hyperarousal during sleep in untreated primary insomnia sufferers: A polysomnographic study. AB - Because some evidence favors the hyperarousal model of insomnia, we sought to learn more about the dynamics of this phenomenon during sleep. Polysomnographic data from 30 normative subjects and 86 untreated primary insomnia sufferers recruited from the database of the sleep laboratory were studied for whole nights and in terms of thirds of the night. Untreated primary insomnia sufferers had an increased sleep latency and excess of WASO, together with a deficit in REM and NREM sleep during the entire night. In terms of thirds of the night, they presented a major excess of WASO during the first and last thirds of the night but an excess of lesser importance during the middle third. A deficit in SWS was found during the first third of the night, but for REM, the deficit was present during both the first and last thirds. Primary insomnia sufferers had no SWS or REM deficit during the second third of the night. We found that the hyperarousal phenomenon occurs mainly during the sleep-onset period of the first and last thirds of the night and is less important during the middle third. These results open new avenues for understanding the pathophysiology of primary insomnia. PMID- 28364591 TI - Seasonal affective disorder and alcohol abuse disorder in a population-based study. AB - Seasonal affective disorder (SAD) is a recurrent major depressive disorder with a seasonal pattern, which is characterized by sad mood, low energy, longer sleep duration and carbohydrate craving. Furthermore, seasonal changes in mood and behavior may be closely related to alcohol use disorder (AUD). Nevertheless, there is scarce research on the study of cognitive impairments in SAD and AUD. We aimed to examine the relationship between the prevalence between SAD and AUD patients, and how cognitive functioning might be related to these variables. To do this, a sample of 8135 Finnish subjects was invited to take part in the population-based Health 2011 Survey, of whom 5903 did participate and 4554 were interviewed for mental health status with the Munich version of Composite International Diagnostic Interview. They also completed the modified Seasonal Pattern Assessment Questionnaire, the Mini-Mental State Examination, the category (animals) verbal fluency test, and the Rey Auditory Verbal Learning Test. Our results reveal the existence of a strong link between SAD and AUD in a large sample of Finnish population, as well as association between SAD and short-term memory problems. PMID- 28364589 TI - Investigating insomnia as a cross-sectional and longitudinal predictor of loneliness: Findings from six samples. AB - Loneliness has been repeatedly associated with sleep problems; however, there is a dearth of research examining the prospective relationship between insomnia and loneliness, as well as this association controlling for other psychiatric symptoms. This study evaluated the cross-sectional and prospective relationship between insomnia and loneliness using six samples: 666 undergraduates; 2785 Army recruiters; 208 adults with a history of suicidality and/or depression; 343 adult psychiatric outpatients; 326 young adults at elevated suicide risk; and 183 undergraduates. A meta-analysis also was conducted to examine the magnitude of the relationship between insomnia and loneliness across the six studies. More severe insomnia symptoms were significantly associated with greater feelings of loneliness while accounting for some (e.g., anxiety, nightmares) but not all (i.e., depression) psychiatric covariates. Findings underscore the strength of the association between insomnia and loneliness and suggest that depression may account for this relationship. Additional studies are needed to further establish the temporal relationship between these variables, delineate the role of depression in the association between insomnia and loneliness, and test whether insomnia may confer unique risk for subsequent loneliness. PMID- 28364592 TI - Social cognitive impairment in 22q11 deletion syndrome: A review. AB - Individuals with 22q11.2 deletion syndrome (22q11DS) exhibit a broad array of physical and psychiatric features, of which impaired social cognition and poor social functioning are common. This review seeks to (1) characterize the current understanding of impairment across social cognitive domains in the context of 22q11DS, and (2) synthesize the relevant literature on social cognition and psychosis, given that the prevalence of psychosis in 22q11DS is especially high compared to the general population. A total of 16 papers examining social cognition in 22q11DS were identified through a comprehensive literature search conducted using electronic databases such as PubMed and PSYCInfo. Results suggest that individuals with 22q11DS exhibit impaired emotion processing and complex theory of mind relative to their typically developing peers, though some findings were accounted for by neurocognitive and intellectual abilities. Further, no studies have examined the domains of attribution bias or social perception in 22q11DS, highlighting a critical gap in the extant literature. More research is needed to better elucidate the trajectory of how and why social cognitive impairment develops in 22q11DS, and to explore possible relationships to psychiatric comorbidities like psychosis. Treatment implications and future steps are considered. PMID- 28364593 TI - Household adoption of energy and water-efficient appliances: An analysis of attitudes, labelling and complementary green behaviours in selected OECD countries. AB - Using a household-based data set of more than 12,000 households from 11 OECD countries, we analyse the factors underlying the decision by households to adopt energy-efficient and water-efficient equipment. We evaluate the roles of both attitudes and labelling schemes on the adoption of energy and water-efficient equipment, and also the interaction and complementarity between energy and water conservation behaviours. Our findings show: one, 'green' social norms and favourable attitudes towards the environment are associated with an increased likelihood of households' adoption of energy and water-efficient appliances; two, households' purchase decisions are positively affected by their awareness, understanding, and trust of labelling schemes; and three, there is evidence of complementarity between energy conservation and water conservation behaviours. PMID- 28364594 TI - Heteroatoms doped porous carbon derived from hydrothermally treated sewage sludge: Structural characterization and environmental application. AB - The heteroatoms (N and S) doped porous carbons (HAPCs) were prepared from sewage sludge by hydrothermal carbonization and chemical activation for the first time. The porous structures and surface properties of HAPCs were characterized by multiple techniques including SEM-EDS, TEM, BET, XRD, Raman spectroscopy and Boehm's titration. The resultant materials were showed to be naturally N and S dual-doped porous carbons (HAPCs), especially for HAPCHCl+HF obtained by HCl-HF washing, which was typical 3D hierarchically porous structure with abundant mesopores as well as big pore diameter. Then the performance of HAPCHCl+HF on AO7 removal was determined through Response surface methodology. The results showed the adsorption behavior obeyed Langmuir isotherm model and the maximum adsorption capacity was up to 440.53 mg g-1 at 25 degrees C. Kinetics study revealed that the adsorption followed pseudo second-order kinetic and intra-particle diffusion was the main control step. The high removal rate of AO7 was ascribed to the unique properties of HAPCHCl+HF. The great Vmes and big pore diameter facilitated the diffusion of AO7 into the intra surface of particle. Meanwhile, the basic groups and doping of N and S made HAPCHCl+HF surface had positive charges, then strong pi-pi stacking interaction and electrostatic attraction contributed to the highly effective adsorption. This study indicated hydrothermal carbonization coupled with chemical activation was a cost-effective approach to prepare efficient heteroatoms doped porous carbon from sewage sludge towards azo dye contaminated wastewater treatment. PMID- 28364595 TI - Hippocampal development in youth with a history of childhood maltreatment. AB - Childhood maltreatment (CM) is associated with enhanced risk of psychiatric illness and reduced subcortical grey matter in adulthood. The hippocampus and amygdala, due to their involvement in stress and emotion circuitries, have been subject to extensive investigations regarding the effect of CM. However, the complex relationship between CM, subcortical grey matter and mental illness remains poorly understood partially due to a lack of longitudinal studies. Here we used segmentation and linear mixed effect modelling to examine the impact of CM on hippocampal and amygdala development in young people with emerging mental illness. A total of 215 structural magnetic resonance imaging (MRI) scans were acquired from 123 individuals (age: 14-28 years, 79 female), 52 of whom were scanned twice or more. Hippocampal and amygdala volumes increased linearly with age, and their developmental trajectories were not moderated by symptom severity. However, exposure to CM was associated with significantly stunted right hippocampal growth. This finding bridges the gap between child and adult research in the field and provides novel evidence that CM is associated with disrupted hippocampal development in youth. Although CM was associated with worse symptom severity, we did not find evidence that CM-induced structural abnormalities directly underpin psychopathology. This study has important implications for the psychiatric treatment of individuals with CM since they are clinically and neurobiologically distinct from their peers who were not maltreated. PMID- 28364596 TI - Cardioprotective effects of calcitonin gene-related peptide in isolated rat heart and in H9c2 cells via redox signaling. AB - The calcitonin-gene-related-peptide (CGRP) release is coupled to the signaling of Angeli's salt in determining vasodilator effects. However, it is unknown whether CGRP is involved in Angeli's salt cardioprotective effects and which are the mechanisms of protection. We aimed to determine whether CGRP is involved in myocardial protection induced by Angeli's salt. We also analyzed the intracellular signaling pathway activated by CGRP. Isolated rat hearts were pre treated with Angeli's salt or Angeli's salt plus CGRP8-37, a specific CGRP receptor antagonist, and subjected to ischemia (30-min) and reperfusion (120 min). Moreover, we studied CGRP-induced protection during oxidative stress (H2O2) and hypoxia/reoxygenation protocols in H9c2 cardiomyocytes. Cell vitality and mitochondrial membrane potential (DeltaYm, MMP) were measured using MTT and JC-1 dyes. Angeli's salt reduced infarct size and ameliorated post-ischemic cardiac function via a CGRP-receptor-dependent mechanism. Pre-treatment with CGRP increased H9c2 survival upon challenging with either H2O2 (redox stress) or hypoxia/reoxygenation (H/R stress). Under these stress conditions, reduction in MMP and cell death were partly prevented by CGRP. These CGRP beneficial effects were blocked by CGRP8-37. During H/R stress, pre-treatment with either CGRP receptor, protein kinase C (PKC) or mitochondrial KATP channel antagonists, and pre-treatment with an antioxidant (2-mercaptopropionylglycine) blocked the protection mediated by CGRP. In conclusion, CGRP is involved in the cardioprotective effects of Angeli's salt. In H9c2 cardiomyocytes, CGRP elicits PKC-dependent and mitochondrial-KATP-redox-dependent mechanisms. Hence, CGRP is an important factor in the redox-sensible cardioprotective effects of Angeli's salt. PMID- 28364597 TI - A new acridine derivative induces cell cycle arrest and antiangiogenic effect on Ehrlich ascites carcinoma model. AB - BACKGROUND: Acridine derivatives, including amsacrine, have antitumor activity. However, side effects, development of resistance and their low bioavailability, have limited their use. Herein, we described the synthesis, and evaluated the toxicity and antitumor activity of a new amsacrine analogous, the N'-(2-chloro-6 methoxy-acridin-9-yl)-2-cyano-3-(4-dimethylaminophenyl)-acrilohidrazida (ACS AZ10). METHODS: The compound was obtained in a linear pathway where the ASC-Az intermediate was obtained by coupling of 6,9-dichloro-3-methoxy-acridine and 2 ciany-acethohidrazide followed by condensation with the corresponding aldehyde. The toxicity of ACS-AZ10 was evaluated in mice using acute toxicity and micronucleus assays. Ehrlich ascites carcinoma model was used to investigate the antitumor activity and toxicity of ACS-AZ10 (7.5, 15 or 30mg/kg, i.p.), after nine days of treatment. Cell cycle and angiogenesis were also evaluated. RESULTS: The ASC-AZ10 was obtained with satisfactory yields and its structure was confirmed by spectroscopic and spectrometric techniques. On acute toxicity study, ACS-AZ10 (2000mg/kg, i.p.) induced transient depressant effects on central nervous system. The LD50 was approximately 2500mg/kg. ACS-AZ10 (15 or 30mg/kg) displayed significant antitumor activity considering the tumor weight and volume, cell viability, and total Ehrlich cell count. ACS-AZ10 (7.5mg/kg) induced an increase in sub-G1 peak, suggesting apoptosis. At 15mg/kg ACS-AZ10 induced cell cycle arrest in G2/M phase and a reduction in the percentage of cells in G0/G1 and S phases, suggesting a pre-mitotic blockade. ACS-AZ10 reduced the microvessel density, indicating an antiangiogenic effect. Weak hematological, biochemical and histopathological toxicity were observed. The compound doesn't show genotoxicity in micronucleus assay. CONCLUSIONS: ACS-AZ10 has potent antitumor activity in vivo along with low toxicity. PMID- 28364598 TI - An in vitro evaluation of anti-aging effect of guluronic acid (G2013) based on enzymatic oxidative stress gene expression using healthy individuals PBMCs. AB - BACKGROUND: Aging is usually associated with increased levels of oxidants, and may result in damages caused by oxidative stress. There is a direct relationship between aging and increased incidence of inflammatory diseases. The present research intended to study the anti-aging and anti-inflammatory effects of the drug G2013 (guluronic acid) at low and high doses on the genes expression of a number of enzymes involved in oxidative stress (including SOD2, GPX1, CAT, GST, iNOS, and MPO) in peripheral blood mononuclear cells (PBMCs) of healthy individuals under in vitro conditions. METHODS: Venous blood samples were taken from 20 healthy individuals, the PBMCs were isolated and their RNAs extracted and their cDNAs were synthesized, and the genes expression levels were measured using the qRT-PCR technique. RESULTS: Our results indicated that this drug could, at both low and high doses, significantly reduce the expression of the genes for SOD2, GPX1, CAT, and GST compared to the LPS group (p<0.0001). Moreover, it was noticed that the drug is able to significantly reduce gene expression levels at the high dose and at both doses (low and high), for iNOS and MPO compared to the LPS group (p<0.0001), respectively. CONCLUSIONS: The present research showed that G2013, as a novel NSAID drug with immunomodulatory properties, could modulate the expression levels of the genes for SOD2, GPX1, CAT, GST, iNOS, and MPO, to the level of healthy gene expression, and possibly it might reduce the pathological process of aging and age-related inflammatory diseases. PMID- 28364599 TI - Flavonoids from Enicostema littorale blume enhances glucose uptake of cells in insulin resistant human liver cancer (HepG2) cell line via IRS-1/PI3K/Akt pathway. AB - Diabetes mellitus has spread over the world with 347 million people affected. Insulin resistance is a main pathogenic event in Type 2 Diabetes Mellitus (T2DM) leading to a reduction in glucose uptake by peripheral tissue and increased hepatic glucose output. In this study, we have isolated four flavonoid rich fractions fraction A (FA), fraction B (FB), fraction C (FC) and fraction D (FD) from Enicostema littorale. All the fractions were preliminary screened for TLC fingerprinting, total flavonoid content. Total eight flavonoids were identified by LC/MS. Insulin resistant HepG2 (IR/HepG2) model was established by inducing insulin resistance in HepG2 cells to investigate the effect of these fractions on IR/HepG2 cell line for their glucose uptake. The results showed the significant dose dependant increase in glucose uptake of cells treated with FD. It showed significant activity at a concentration of 10MUg/ml. The LC/MS results of FD demonstrated the presence of C-glycoside Swertisin which could be responsible for the effect. Further, to investigate the mechanism of action, gene expression for insulin receptor substrate 1 (IRS-1), protein kinase B (Akt-2) and glucose transporter 4 (GLUT-4) genes were evaluated by real time PCR. A significant upregulation of these genes was observed in FD treated samples, thereby indicating the enhancement of glucose uptake rate of cells via IRS-1/PI3K/Akt pathway. PMID- 28364600 TI - MiR-370 functions as oncogene in melanoma by direct targeting pyruvate dehydrogenase B. AB - BACKGROUND: Accumulating evidence has shown that miR-370 play an important role in the development and progression of tumor. However, the role of miR-370 in melanoma remains largely unknown. The present study is designed to investigate the function of miR-370 in melanoma and to explore the molecular mechanism underlying its function. MATERIALS AND METHODS: The expression level of miR-370 was detected in melanoma tissues and cell lines by real-time quantitative polymerase chain reaction (qRT-PCR). The effect of overexpression of miR-370 on in vitro cell proliferation, apoptosis, invasion as well as glyclolysis was examined. Western blotting analysis was used to detect the influence of miR-370 on the expression of target genes, and Pearson analysis was used to calculate the correlation between the expression of targets gene and miR-370 in melanoma tissues. RESULTS: Our study showed that miR-370 was upregulated in melanoma tissues compared with non-cancerous tissues (P<0.01). In addition, the expression of miR-370 in melanoma cell lines was also significantly higher (P<0.01). Enforced expression of miR-370 promotes melanoma cell proliferation, inhibits apoptosis and enhances invasion and glycolysis and led to downregulation of the PDHB protein. Moreover, the expression level of miR-370 in melanoma tissues showed inverse relationship with the expression level of PDHB protein. CONCLUSIONS: In conclusion, our findings suggested that miR-370 represents a potential oncogenic miRNA and plays an important role in melanoma progression by directly targeting PDHB. PMID- 28364601 TI - Pro-apoptotic activity of nano-escheriosome based oleic acid conjugate against 7,12-dimethylbenz(a)anthracene (DMBA) induced cutaneous carcinogenesis. AB - AIM: 2,6-Diisopropylphenol-oleic acid (2,6P-OLA) is an ester conjugate of oleic acid that has displayed a strong anticancer activity on different types of cancer cell lines (Khan et al., 2012). The present study is focused on the development of a nano-liposome-based approach for the delivery of 2,6P-OLA on 7,12 dimethylbenz(a)anthracene (DMBA) induced cutaneous papilloma in experimental mice. For effective and specific delivery of the conjugate to the tumor site, it was incorporated into escheriosome (EC); an Escherichia coli lipid nanoparticle. MATERIALS AND METHODS: I determined the size, zeta-potential, entrapment and release efficacy of 2,6P-OLA-EC nano-formulation. The consequence of 2,6P-OLA-EC treatment was initially analyzed by regression in tumor volume, inhibition of cutaneous papilloma and survival of treated mice. Its anticancer activity was further examined by histopathology, fluorescence microscopy, flow cytometry and electroblot-immuno assay of apoptotic factors. RESULTS: Distinct disperse circular shaped EC nanoparticles showed slow and sustained release of therapeutic concentration of 2,6P-OLA in the surrounding milieu. 2,6P-OLA-EC significantly reduced tumor volume and inhibited onset of new papilloma. Treatment with nano formulation revealed induced caspase-9 activity and noteworthy apoptotic response as visualized by fluorescence microscopy and TUNEL assay. Electroblot-immuno analysis revealed significant modulation of p53wt and p53mut expression levels. CONCLUSION: The results suggest the therapeutic potential of 2,6P-OLA entrapped in nano-escheriosomes against cutaneous papilloma and can become a promising system against various forms of cancer as well. PMID- 28364602 TI - MicroRNA-485-5p represses melanoma cell invasion and proliferation by suppressing Frizzled7. AB - MicroRNAs (miRNAs) have emerged as critical regulators for malignant melanoma development. miR-485-5p has been suggested as a tumor-suppressive miRNA in many types of human malignancies. However, the role of miR-485-5p in melanoma remains unknown. In this study, we aimed to explore the potential role and underlying mechanism of miR-485-5p in the regulation of melanoma development. Here, we showed that miR-485-5p was significantly decreased in melanoma tissues and cell lines compared with their corresponding controls. Transwell invasion assay showed that miR-485-5p overexpression markedly inhibited melanoma cell invasion. WST-1 and cell cycle assays exhibited that miR-485-5p overexpression significantly suppressed melanoma cell proliferation. By contrast, miR-485-5p suppression promoted the invasion and proliferation of melanoma cells. Using bioinformatics analysis, we observed that miR-485-5p potentially targets the 3'-untranslated region (3'-UTR) of Frizzled7 (FZD7). Dual-luciferase assay confirmed the direct binding between miR-485-5p and FZD7 3'-UTR. Meanwhile, real-time quantitative polymerase chain reaction and Western blot analysis showed that miR-485-5p overexpression suppressed FZD7 expression, whereas miR-485-5p suppression resulted in the opposite effect. Moreover, miR-485-5p expression was observed to be inversely correlated with FZD7 mRNA expression in melanoma tissues. Further experiments showed that miR-485-5p regulated Wnt signaling. The restoration of FZD7 expression markedly reversed the antitumor effects induced by miR-485-5p overexpression in melanoma cells. Taken together, our study suggests that miR-485 5p represses melanoma cell invasion and proliferation by suppressing FZD7, indicating a new tumor-suppressive role for miR-485-5p in melanoma. The miR-485 5p/FZD7 axis may provide novel insights into understanding the molecular pathogenesis of melanoma and may be a promising therapeutic target for melanoma. PMID- 28364603 TI - Ampelopsin attenuates the atrophy of skeletal muscle from d-gal-induced aging rats through activating AMPK/SIRT1/PGC-1alpha signaling cascade. AB - The atrophy of skeletal muscle is highly correlated with oxidative damage, excessive apoptosis and dysfunctional autophagy. Ampelopsin, a natural flavonoid, has multiple biological functions including anti-inflammatory, anti-oxidative, and hepatoprotective functions. Sprague-Dawley (SD) rats subjected to intraperitoneal injection of d-galactose (d-gal) at the dose of 150mg/kg.d revealed an obvious atrophy of skeletal muscle with significantly reduced muscle mass/body mass ratio, cross-sectional area and fiber diameter of skeletal muscle in d-gal-induced aging rats when compared to normal control rats without d-gal administration for 6 consecutive weeks. In contrast, the combinatorial administration of d-gal at the identical dose and DHM at the dose of 100 or 200mg/kg.d could alleviate the reduction of these hallmarks associated with the atrophy of skeletal muscle. In addition, d-gal administration could result in obvious apoptosis and impaired autophagy in skeletal muscle, which could be mitigated upon DHM treatment due to its role in decreasing ubiquitin and Atrogin 1/MAFbx and up-regulating AMPK and SIRT1 signal pathways. Therefore, DHM may be a potential candidate for the prevention and treatment of skeletal muscle atrophy associated aging process. PMID- 28364604 TI - Elucidating environmental dimensions of neurological disorders and disease: Understanding new tools from federal chemical testing programs. AB - BACKGROUND: Federal agencies are making significant investments to advance predictive approaches to evaluate chemical hazards and risks. Environmental Defense Fund (EDF) believes that engagement with the broader scientific community is critical to building and maintaining a strong biological foundation for these approaches. OBJECTIVES: On June 18-19, 2015, EDF organized a meeting to 1) foster a conversation between federal scientists advancing predictive approaches and environmental health researchers investigating environmental exposures and neurological outcomes, and 2) explore opportunities and challenges for the use of federal chemical high-throughput in vitro screening (HTS) data in hypothesis driven research toward, ultimately, improved data for public health decision making. DISCUSSION: The meeting achieved its objectives. Government scientists showcased their chemical testing programs and vision for how emerging data may be used to meet agency missions. Environmental health researchers shared their experiences using federal HTS data, offered recommendations for strengthening federal HTS platforms, and expressed great interest in continued engagement with evolving federal chemical testing initiatives. CONCLUSIONS: The meeting provided an invaluable exchange between two scientific communities with a shared interest in protecting public health from harmful environmental exposures, but who have not sufficiently engaged with each other. Discussions identified opportunities and work ahead for the use of HTS data in hypothesis-driven research. Though the meeting focused on neurological outcomes, the purpose, objectives and experience of the meeting are broadly applicable. EDF strongly encourages more discourse and collaboration between federal and non-government scientists working to understand environmental influences on health outcomes. PMID- 28364605 TI - Changes in soil characteristics and C dynamics after mangrove clearing (Vietnam). AB - Of the blue carbon sinks, mangroves have one of the highest organic matter (OM) storage capacities in their soil due to low mineralization processes resulting from waterlogging. However, mangroves are disappearing worldwide because of demographic increases. In addition to the loss of CO2 fixation, mangrove clearing can strongly affect soil characteristics and C storage. The objectives of the present study were to quantify the evolution of soil quality, carbon stocks and carbon fluxes after mangrove clearing. Sediment cores to assess physico-chemical properties were collected and in situ CO2 fluxes were measured at the soil-air interface in a mangrove of Northern Vietnam. We compared a Kandelia candel mangrove forest with a nearby zone that had been cleared two years before the study. Significant decrease of clay content and an increase in bulk density for the upper 35cm in the cleared zone were observed. Soil organic carbon (OC) content in the upper 35cm decreased by >65% two years after clearing. The quantity and the quality of the carbon changed, with lower carbon to nitrogen ratios, indicating a more decomposed OM, a higher content of dissolved organic carbon, and a higher content of inorganic carbon (three times higher). This highlights the efficiency of mineralization processes following clearing. Due to the rapid decrease in the soil carbon content, CO2 fluxes at sediment interface were >50% lower in the cleared zone. Taking into account carbonate precipitation after OC mineralization, the mangrove soil lost ~10MgOCha-1yr-1 mostly as CO2 to the atmosphere and possibly as dissolved forms towards adjacent ecosystems. The impacts on the carbon cycle of mangrove clearing as shown by the switch from a C sink to a C source highlight the importance of maintaining these ecosystems, particularly in a context of climate change. PMID- 28364606 TI - Atmospheric removal of PM2.5 by man-made Three Northern Regions Shelter Forest in Northern China estimated using satellite retrieved PM2.5 concentration. AB - Atmospheric removal of PM2.5 by the Three Northern Regions Shelter Forest (TNRSF) - the so called Green Great Wall (GGW) in northern China through dry deposition process was estimated using a bulk big-leaf model and a vegetation collection model. Decadal trend of PM2.5 dry deposition flux from 1999 to 2010 was calculated from modeled dry deposition velocity and air concentration retrieved from the satellite remote sensing. Dry deposition velocities of PM2.5 calculated using the two deposition models increased in many places of the TNRSF over the last decade due to increasing vegetation coverage of the TNRSF. Both increasing deposition velocity due to forest expansion and PM2.5 atmospheric level contributed to the increasing deposition flux of PM2.5. The highest atmospheric deposition flux of PM2.5 was found in the Central-north region covering Beijing Tianjin-Hebei area, followed by the Northwestern and the Northeastern regions of the TNRSF. While greater collection of PM2.5 by vegetation was identified in the Northeastern region of the TNRSF due to higher forest coverage over this region, the most significant incline of the PM2.5 atmospheric removal due to vegetation collection was discerned in the Central-north region because of the most rapid increase in the vegetation coverage in this region. A total mass of 2.85*107t PM2.5 was estimated to be removed from the atmosphere through dry deposition process over the TNRSF from 1999 to 2010. The two deposition models simulated similar magnitude and spatial patterns of PM2.5 dry deposition fluxes. Our results suggest that the TNRSF plays a moderate role in PM2.5 uptake, but enhances PM2.5 atmospheric removal by 30% in 2010 than in 1980. PMID- 28364607 TI - Passive sampling as a tool for identifying micro-organic compounds in groundwater. AB - The paper presents the use of a simple and cost efficient passive sampling device with integrated active carbon with which to test the possibility of determining the presence of micro-organic compounds (MOs) in groundwater and identifying the potential source of pollution as well as the seasonal variability of contamination. Advantage of the passive sampler is to cover a long sampling period by integrating the pollutant concentration over time, and the consequently analytical costs over the monitoring period can be reduced substantially. Passive samplers were installed in 15 boreholes in the Maribor City area in Slovenia, with two sampling campaigns covered a period about one year. At all sampling sites in the first series a total of 103 compounds were detected, and 144 in the second series. Of all detected compounds the 53 most frequently detected were selected for further analysis. These were classified into eight groups based on the type of their source: Pesticides, Halogenated solvents, Non-halogenated solvents, Domestic and personal, Plasticizers and additives, Other industrial, Sterols and Natural compounds. The most frequently detected MO compounds in groundwater were tetrachloroethene and trichloroethene from the Halogenated solvents group. The most frequently detected among the compound's groups were pesticides. Analysis of frequency also showed significant differences between the two sampling series, with less frequent detections in the summer series. For the analysis to determine the origin of contamination three groups of compounds were determined according to type of use: agriculture, urban and industry. Frequency of detection indicates mixed land use in the recharge areas of sampling sites, which makes it difficult to specify the dominant origin of the compound. Passive sampling has proved to be useful tool with which to identify MOs in groundwater and for assessing groundwater quality. PMID- 28364608 TI - Cerium negatively impacts the nutritional status in rapeseed. AB - Cerium (Ce) has been reported to be both beneficial and harmful to plants. This contradiction deserves explanation in the light of increased anthropogenic release of Ce in the environment. Ce tolerance and accumulation were evaluated in hydroponically cultivated Brassica napus L. (rapeseed). Ce and other nutrient concentrations were measured with increasing Ce concentration in the nutrient solution. Moreover, Ce and calcium (Ca) accumulation were evaluated at different Ca and Ce concentrations in nutrient solution and a Michaelis-Menten type inhibition model considering Ce and Ca competition was tested. Plants were also sprayed with Ce solution in Ca-deficient media. Ce decreased the growth and root function, which affected shoot nutritional status. Calcium was the most severely inhibited nutrient in both roots and shoots. High Ca concentrations in the nutrient solution inhibited Ce accumulation in a non-competitive way. Moreover, phosphorus (P) precipitated Ce inside root cells. Ce spraying did not alleviate Ca deficiency symptoms and the results were critically compared to the available literature. PMID- 28364609 TI - Anthropogenic 236U and 129I in the Mediterranean Sea: First comprehensive distribution and constrain of their sources. AB - The first basin-wide distribution of 236U/238U atom ratios and 129I concentrations is presented for the Mediterranean Sea. During the GEOTRACES GA04S MedSeA expedition in 2013 seawater was collected from 10 vertical profiles covering the principal sub-basins of the Mediterranean Sea. The main objective was to understand the distributions of 236U and 129I in relation to the water masses, and to constrain their sources in this region. The 236U/238U atom ratios and the 129I concentrations ranged from (710+/-40)*10-12 to (2220+/-60)*10-12 and from (4.0+/-0.1)*107 to (13.8+/-0.3)*107at.kg-1, respectively. The results show that radionuclide-poor Atlantic Water is entering at the surface through the Strait of Gibraltar whereas comparably radionuclide-enriched Levantine Intermediate Water is sinking in the Eastern Basin and flowing westward at intermediate depths. Low radionuclide levels were found in the oldest water masses at about 1000-2000m depth in the Eastern Basin. At greater depths, waters were relatively enriched in 236U and 129I due to dense water formation occurring in both, the Eastern and Western Basins. The inventories of 236U and 129I cannot be explained only by global fallout from atmospheric nuclear bomb testings carried out in the 1950s and 1960s. We estimate that the liquid input of 236U from the nuclear reprocessing facility of Marcoule (France), via the Rhone river, was of the same order of magnitude than the contribution from global fallout, whereas liquid and gaseous releases of 129I from Marcoule were up to two orders of magnitude higher than global fallout. For both radionuclides, the contribution from the Chernobyl accident is found to be minor. PMID- 28364610 TI - Groundwater discharge in high-mountain watersheds: A valuable resource for downstream semi-arid zones. The case of the Berchules River in Sierra Nevada (Southern Spain). AB - Aquifers in permeable formations developed in high-mountain watersheds slow down the transfer of snowmelt to rivers, modifying rivers' flow pattern. To gain insight into the processes that control the hydrologic response of such systems the role played by groundwater in an alpine basin located at the southeastern part of the Iberian Peninsula is investigated. As data in these environments is generally scarce and its variability is high, simple lumped parameter hydrological models that consider the groundwater component and snow accumulation and melting are needed. Instead of using existing models that use many parameters, the Temez lumped hydrological model of common use in Spain and Ibero American countries is selected and modified to consider snow to get a simplified tool to separate hydrograph components. The result is the TDD model (Temez-Degree Day) which is applied in a high mountain watershed with seasonal snow cover in Southern Spain to help in quantifying groundwater recharge and determining the groundwater contribution to the outflow. Average groundwater recharge is about 23% of the precipitation, and groundwater contribution to total outflow ranges between 70 and 97%. Direct surface runoff is 1% of precipitation. These values depend on the existence of snow. Results are consistent with those obtained with chloride atmospheric deposition mass balances by other authors. They highlight the important role of groundwater in high mountain areas, which is enhanced by seasonal snow cover. Results compare well with other areas. This effect is often neglected in water planning, but can be easily taken into account just by extending the water balance tool in use, or any other, following the procedure that has being developed. PMID- 28364611 TI - The association between human perceived heat and early-stage syphilis and its variance: Results from a case-report system. AB - BACKGROUND: The relationship between temperature and syphilis is poorly understood despite clues and suggestions from previous studies. We examined the association between human perceived temperature (humidex) and the relative risk of early-stage syphilis in the most affected area of China, as well as its variance across social-economic status and age groups. METHODS: Information regarding early-stage (primary and secondary) syphilis cases reported to the China Case Report System between 2005-2013 from Guangdong province was analyzed in this study. Weather data were obtained from the National Meteorological Information Center. Distributed lag nonlinear models were applied to assess the relationship between humidex and the relative risk of early-stage syphilis. Results were further stratified by social-economic status and age groups. RESULTS: The relative risks of early-stage syphilis mainly increased with increased humidex, and were elevated when the humidex was around 30 or greater than 38. The humidex-RR association for the 15-40 age group was similar to the scenario pooled across the age groups, particularly in the Pearl-River Delta Region. The relative risk of syphilis in the elderly for the non-Pearl-River Delta Region did not show a clear change with humidex, whereas that in the Pearl River Delta Region substantially increased, particularly when humidex was above 25. CONCLUSIONS: Human perceived temperature was positively related to the relative risk of early-stage syphilis. People in the Pearl-River Delta Region tended to be more sensitive, with relative risk elevated at potential comfortable times or under excessively hot conditions. The vulnerability of the elderly in the Pearl-River Delta Region is concerning. PMID- 28364612 TI - Human exposure to HBCD and TBBPA via indoor dust in Korea: Estimation of external exposure and body burden. AB - Human exposure to brominated flame retardants (BFRs) such as hexabromocyclododecane (HBCD) and tetrabromobisphenol A (TBBPA) mainly occurs through diet and dust ingestion. In this study, the BFR concentrations in 124 vacuum dust samples of six categories of indoor environments (homes, offices, kindergartens, cars, schools, and public indoor environments) and 32 surface dust samples were investigated. The median SigmaHBCD concentrations ranged from 106.30ngg-1 in home dust to 496.13ngg-1 in office dust. The TBBPA concentrations in indoor dust (from 78.87 to 463.81ngg-1) were among the highest compared to other countries because of the high market demand for this flame retardant in Korea. The TBBPA concentrations in surface dust of living rooms were significantly higher (p<0.05) than sleeping rooms, due to the presence of more electrical equipment in living rooms. The estimated daily intakes (EDI) of SigmaHBCD and TBBPA (dust+diet) for toddlers were 6.18ngkg-1bwd-1 and 2.54ngkg 1bwd-1, respectively. In general, the SigmaHBCD estimated body burden of Korean adults showed good agreement with the reported SigmaHBCD median concentrations in their sera. Since the developmental health effect of exposure to HBCD was categorized as "high hazard" by the US Environmental Protection Agency, the estimated high body burden of SigmaHBCD in Korean toddlers (7.91ngg-1 lw) warns us of possible adverse effects on the development of essential systems in their bodies. PMID- 28364613 TI - Behaviour of glyphosate in a reservoir and the surrounding agricultural soils. AB - Glyphosate (GPS) is an herbicide currently used on olive crops in Spain, and can be transported to the nearby reservoirs currently used for human consumption. The purpose of this work was to study the behaviour and environmental fate of GPS in water and sediments of the Vibora Reservoir, its tributary river, and the surrounding agricultural soils to assess the risk of water pollution of this reservoir. The adsorption of GPS by different matrices was as follows: heading of the reservoir sediment (Cabecera)>tail sediment (Cola)>soils>Vibora sediment. The highest amount of oxides (especially Fe oxides) was observed in sediments from Cabecera and Cola whereas the lowest values were recorded on Vibora sediment. Results indicate that the highest GPS adsorption is due to the amorphous oxides and the edge sites of the clay minerals. Glyphosate adsorption increased with decreasing pH from 8 to 7. The desorption percentage of GPS from the four soils studied ranged only from 0.40 to 1.22%. Desorption was almost irreversible for Cabecera and Cola sediments, with values between 0 and 1.1%. Conversely, Vibora sediment presented about 20% desorption, probably due to its coarse texture and lower levels of amorphous oxides. Hockey-stick first-order kinetics was the best descriptor for water glyphosate dissipation at the Cabecera and Cola locations, and simple first-order kinetic for the water from the tributary Vibora River. The half-lives (DT50) were between 6.3 and 11.0days. The rapid degradation of GPS in surface waters and its practically irreversible sorption on these soils and sediments implies that GPS use in similar agricultural areas is of very low environmental risk. This manuscript also outlines the importance of the presence of photo-sensitizers in waters in the degradation routes of GPS in reservoirs. PMID- 28364614 TI - Life history and point prevalence of low back pain in pre-professional and professional dancers. AB - OBJECTIVES: To investigate lifetime history and point prevalence of low back pain (LBP) in pre-professional and professional dancers and to identify any demographic or physical factors associated with LBP in dancers. DESIGN: Cross sectional study. SETTING: One pre-professional ballet school, two pre professional university dance programs, and a professional nationally touring ballet company. PARTICIPANTS: Male and female classical ballet and contemporary dancers aged 12 years old and above. MAIN OUTCOME MEASURES: Lifetime history and point prevalence of LBP. RESULTS: A total of 110 (n = 19 male) dancers (mean (SD) 17.8 (2.9) years old) participated in the study, which represented 50% of the population invited to participate. A 74% lifetime prevalence of LBP was reported by dancers. Point and 12 month prevalence were 24 and 64%, respectively. No significant association was observed between LBP and any demographic or physical variables. CONCLUSION: Pre-professional and professional dancers have an increased vulnerability to LBP. The development of LBP within this population is complex and may not be associated with individual factors measured in this study. PMID- 28364615 TI - Strength and endurance training reduces the loss of eccentric hamstring torque observed after soccer specific fatigue. AB - OBJECTIVES: To investigate the effect of two hamstring training protocols on eccentric peak torque before and after soccer specific fatigue. PARTICIPANTS: Twenty-two university male soccer players. DESIGN: Isokinetic strength tests were performed at 60 degrees /s pre and post fatigue, before and after 2 different training interventions. A 45-min soccer specific fatigue modified BEAST protocol (M-BEAST) was used to induce fatigue. Players were randomly assigned to a 4 week hamstrings conditioning intervention with either a maximum strength (STR) or a muscle endurance (END) emphasis. MAIN OUTCOME MEASURES: The following parameters were evaluated: Eccentric peak torque (EccPT), angle of peak torque (APT), and angle specific torques at knee joint angles of 10 degrees , 20 degrees , 30 degrees , 40 degrees , 50 degrees , 60 degrees , 70 degrees , 80 degrees and 90 degrees . RESULTS: There was a significant effect of the M-BEAST on the Eccentric torque angle profile before training as well as significant improvements in post fatigue torque angle profile following the effects of both strength and muscle endurance interventions. CONCLUSIONS: Forty-five minutes of simulated soccer activity leads to reduced eccentric hamstring torque at longer muscle lengths. Short-term conditioning programs (4-weeks) with either a maximum strength or a muscular endurance emphasis can equally reduce fatigue induced loss of strength over this time period. PMID- 28364616 TI - New tris(dopamine) derivative as an iron chelator. Synthesis, solution thermodynamic stability, and antioxidant research. AB - A new tris(dopamine) derivative, containing three dopamine chelate moieties which were attached to a trimesic acid molecular scaffold, has been prepared and fully characterized by NMR, FTIR and HRMS. The solution thermodynamic stability of the chelator with Fe(III), Mg(II), Zn(II) and Fe(II) ions was investigated. Results demonstrated that the chelator exhibited effective binding ability and improved selectivity to Fe(III) ion. The chelator possessed affinity similar to that of diethylenetriaminepentaacetic acid chelator for Fe(III) ion. The high affinity could be attributed to the favorable geometric arrangement between the chelator and Fe(III) ion coordination preference. The chelator also exhibited high antioxidant activity and nontoxicity to neuron-like rat pheochromocytoma cells. Hence, the chelator could be used as chelating agent for iron overload situations without depleting essential metal ions, such as Mg(II) and Zn(II) ions. PMID- 28364617 TI - Synthesis, crystal structure and hydrolysis activity of a novel heterobinuclear cobalt(III) sodium(I) Schiff base complex. AB - A novel heterobinuclear complex [CoNa(C15H10NO4F)2(CH3OH)]2 with Schiff base (C15H10NO4F: 2-amino-4-fluorobenzoic acid-3-methoxysalicylaldehyde) was synthesized and characterized by IR and 1H NMR spectroscopy, elemental analysis and single crystal X-ray diffraction. X-ray crystallography reveals that the cobalt atom is six-coordinated by two nitrogen atoms from -CN-, two carboxylate oxygen atoms and two hydroxyl oxygen atoms in different ligands, while the sodium atom is seven-coordinated by two methoxy oxygen atoms, two hydroxyl oxygen atoms in different ligands, two oxygen atoms in the same carboxylate and one oxygen atom of solvent methanol. The reaction results of the complex with the p nitrophenylphosphate (pNPP) and the adenosine monophosphate (AMP) reveal that the complex can hydrolyze phosphoester bonds. Then the DNA-hydrolysis activity is studied experimentally and theoretically, indicating that the complex can effectively hydrolyze the pBR322 supercoiled plasmid DNA. The molecular docking technology predicts the best binding site and binding affinity between the complex and DNA, and then the catalytic mechanism of hydrolysis is supposed. The study results suggest that the Schiff base metal complex, as a potent artificial enzyme, may find its applications in catalytic hydrolysis and biotechnological areas. PMID- 28364618 TI - Effect of the protein ligand in DMSO reductase studied by computational methods. AB - The DMSO reductase family is the largest and most diverse family of mononuclear molybdenum oxygen-atom-transfer proteins. Their active sites contain a Mo ion coordinated to two molybdopterin ligands, one oxo group in the oxidised state, and one additional, often protein-derived ligand. We have used density-functional theory to evaluate how the fourth ligand (serine, cysteine, selenocysteine, OH-, O2-, SH-, or S2-) affects the geometries, reaction mechanism, reaction energies, and reduction potentials of intermediates in the DMSO reductase reaction. Our results show that there are only small changes in the geometries of the reactant and product states, except from the elongation of the MoX bond as the ionic radius of XO, S, Se increases. The five ligands with a single negative charge gave an identical two-step reaction mechanism, in which DMSO first binds to the reduced active site, after which the SO bond is cleaved, concomitantly with the transfer of two electrons from Mo in a rate-determining second transition state. The five models gave similar activation energies of 69-85kJ/mol, with SH- giving the lowest barrier. In contrast, the O2- and S2- ligands gave much higher activation energies (212 and 168kJ/mol) and differing mechanisms (a more symmetric intermediate for O2- and a one-step reaction without any intermediate for S2-). The high activation energies are caused by a less exothermic reaction energy, 13-25kJ/mol, and by a more stable reactant state owing to the strong MoO2 or MoS2- bonds. PMID- 28364619 TI - Reducing the rehospitalization risk after a manic episode: A population based cohort study of lithium, valproate, olanzapine, quetiapine and aripiprazole in monotherapy and combinations. AB - BACKGROUND: Data on real-world rehospitalization risks in patients using different drugs and combination therapies for relapse prevention after a manic episode is limited. METHODS: We conducted a nationwide population based cohort study using data from Swedish national registers. Swedish residents aged 18-75 years who were hospitalized for a manic episode between July 1, 2006 and December 2, 2014 were included. Prescription fills of lithium, valproate, olanzapine, quetiapine and aripiprazole were recorded throughout the first four weeks after hospital discharge, after which the patients were followed for up to one year. General and treatment specific rehospitalization risks were determined and results were adjusted for clinical and sociodemographic factors. RESULTS: The study included follow-up data from 6 502 hospitalizations for mania. Pharmacologic relapse prevention was used after 78% of these hospitalizations. Monotherapies and combination therapies were equally common. The average one-year rehospitalization risk for patients who did versus did not initiate prophylactic treatment was 39% and 46%, respectively. The lowest rehospitalization risks were seen in patients on combination therapy with olanzapine and valproate or olanzapine and lithium, experiencing one year rehospitalization risks of 32% and 34% (adjusted hazard ratios 0.76 (95% confidence interval [CI] 0.62-0.93) and 0.83 (95% CI 0.70-0.98), compared to lithium monotherapy). LIMITATIONS: Register data does not provide information on all clinical parameters affecting treatment choices. CONCLUSIONS: One-year rehospitalization rates after a manic episode are considerable also for patients who initiate prophylactic treatment. Combination therapies including olanzapine and a classic mood-stabilizer may be beneficial for reducing rehospitalization risks after a manic episode. PMID- 28364620 TI - A personality-based latent class typology of outpatients with major depressive disorder: association with symptomatology, prescription pattern and social function. AB - BACKGROUND: While major depressive disorder (MDD) is considered to be a heterogeneous disorder, the nature of the heterogeneity remains unclear. Studies have attempted to classify patients with MDD using latent variable techniques, yet the empirical approaches to symptom-based subtyping of MDD have not provided conclusive evidence. Here we aimed to identify homogeneous classes of MDD based on personality traits, using a latent profile analysis. METHODS: We studied 238 outpatients with DSM-IV MDD recruited from our specialized depression outpatient clinic and assessed their dimensional personality traits with the Temperament and Character Inventory. Latent profile analysis was conducted with 7 dimensions of the Temperament and Character Inventory as indicators. Relationships of the identified classes with symptomatology, prescription pattern, and social function were then examined. RESULTS: The latent profile analysis indicated that a 3-class solution best fit the data. Of the sample, 46.2% was classified into a "neurotic" group characterized by high harm avoidance and low self-directedness; 30.3% into an "adaptive" group characterized by high self-directedness and cooperativeness; and 23.5% into a "socially-detached" group characterized by low reward dependence and cooperativeness and high self-transcendence. The 2 maladaptive groups, namely neurotic and socially-detached groups, demonstrated unique patterns of symptom expression, different classes of psychotropic medication use, and lower social functioning. LIMITATIONS: Generalizability of the findings was limited since our patients were recruited from the specialized depression outpatient clinic. CONCLUSIONS: Our personality-based latent profile analysis identified clinically meaningful 3 MDD groups that were markedly different in their personality profiles associated with distinct symptomatology and functioning. PMID- 28364621 TI - "Working towards being ready": A grounded theory study of how practising midwives maintain their ongoing competence to practise their profession. AB - OBJECTIVE: to present a grounded theory research study explaining how New Zealand midwives maintain their ongoing competence to practise their profession. DESIGN: grounded theory, an interpretive emergent research methodology was used to examine the process of maintaining competence in midwifery practice. SETTING: New Zealand urban and rural practice settings. PARTICIPANTS: twenty-six midwives from across New Zealand were interviewed and asked about maintaining their competence to practise. Five midwives were interviewed twice, to explore the emerging findings and as one method of member checking. FINDINGS: the grounded theory of 'working towards being ready' describes a continuous process in which midwives engage as they work to maintain practice competence. The component parts comprise professional positioning, identifying needs, strategizing solutions and reflecting on practice. The process is contextual, diverse and is influenced by the practice setting where the salient conditions of resourcing, availability and opportunity for engagement in activities are significant. KEY CONCLUSIONS: across the midwifery profession, midwives in New Zealand are currently working under the generic umbrella of midwifery practice. Midwives work across a range of practice arenas in diverse ways focussed on providing safe care and require a range of professional development activities germane to their area of practice. When the midwife has access to professional development pertinent to their practice, women and the profession benefit. As there is diversity of practice, then mandated processes for ongoing competence need to have flexibility to reflect that diversity. IMPLICATIONS FOR PRACTICE: midwives engage in development that allows them to remain current in practice and that enables them to provide appropriate care to women and their babies. As a consequence they can develop expertise in certain aspects of midwifery. Mandated processes that require engagement in activities aimed at demonstration of competence should be evaluated and tailored to ensure they meet the needs of the developing profession. PMID- 28364622 TI - Identification and characterization of lactic acid bacteria and yeasts of PDO Tuscan bread sourdough by culture dependent and independent methods. AB - Sourdough fermentation has been increasingly used worldwide, in accordance with the demand of consumers for tasty, natural and healthy food. The high diversity of lactic acid bacteria (LAB) and yeast species, detected in sourdoughs all over the world, may affect nutritional, organoleptic and technological traits of leavened baked goods. A wide regional variety of traditional sourdough breads, over 200 types, has been recorded in Italy, including special types selected as worthy of either Protected Geographical Indication (PGI) or Protected Designation of Origin (PDO), whose sourdough microbiota has been functionally and molecularly characterized. As, due to the very recent designation, the microbiota of Tuscan bread sourdough has not been investigated so far, the aim of the present work was to isolate and characterize the species composition of LAB and yeasts of PDO Tuscan bread sourdough by culture-independent and dependent methods. A total of 130 yeasts from WLN medium and 193 LAB from both mMRS and SDB media were isolated and maintained to constitute the germplasm bank of PDO Tuscan bread. Ninety six LAB from mMRS medium and 68 yeasts from WLN medium were randomly selected and molecularly identified by ARDRA (Amplified Ribosomal DNA Restriction Analysis) and PCR-RFLP analysis of the ITS region, respectively, and sequencing. The yeast identity was confirmed by 26S D1/D2 sequencing. All bacterial isolates showed 99% identity with Lactobacillus sanfranciscensis, 65 yeast isolates were identified as Candida milleri, and 3 as Saccharomyces cerevisiae. Molecular characterization of PDO Tuscan bread sourdough by PCR-DGGE confirmed such data. The distinctive tripartite species association, detected as the microbiota characterizing the sourdough used to produce PDO Tuscan bread, encompassed a large number of L. sanfranciscensis and C. milleri strains, along with a few of S. cerevisiae. The relative composition and specific physiological characteristics of such microbiota could potentially affect the nutritional features of PDO Tuscan bread, as suggested by the qualitative functional characterization of the isolates. Investigations on the differential functional traits of such LAB and yeast isolates could lead to the selection of the most effective single strains and of the best performing strain combinations to be used as starters for the production of baked goods. PMID- 28364623 TI - African fermented dairy products - Overview of predominant technologically important microorganisms focusing on African Streptococcus infantarius variants and potential future applications for enhanced food safety and security. AB - Milk is a major source of nutrients, but can also be a vehicle for zoonotic foodborne diseases, especially when raw milk is consumed. In Africa, poor processing and storage conditions contribute to contamination, outgrowth and transmission of pathogens, which lead to spoilage, reduced food safety and security. Fermentation helps mitigate the impact of poor handling and storage conditions by enhancing shelf life and food safety. Traditionally-fermented sour milk products are culturally accepted and widely distributed in Africa, and rely on product-specific microbiota responsible for aroma, flavor and texture. Knowledge of microbiota and predominant, technologically important microorganisms is critical in developing products with enhanced quality and safety, as well as sustainable interventions for these products, including Africa-specific starter culture development. This narrative review summarizes current knowledge of technologically-important microorganisms of African fermented dairy products (FDP) and raw milk, taking into consideration novel findings and taxonomy when re analyzing data of 29 publications covering 25 products from 17 African countries. Technologically-important lactic acid bacteria such as Lactococcus lactis and Streptococcus infantarius subsp. infantarius (Sii), Lactobacillus spp. and yeasts predominated in raw milk and FDP across Africa. Re-analysis of data also suggests a much wider distribution of Sii and thus a potentially longer history of use than previously expected. Therefore, evaluating the role and safety of African Sii lineages is important when developing interventions and starter cultures for FDP in Africa to enhance food safety and food security. In-depth functional genomics, epidemiologic investigations and latest identification approaches coupled with stakeholder involvement will be required to evaluate the possibility of African Sii lineages as novel food-grade Streptococcus lineage. PMID- 28364624 TI - Biocontrol of the internalization of Salmonella enterica and Enterohaemorrhagic Escherichia coli in mung bean sprouts with an endophytic Bacillus subtilis. AB - Internalization of Salmonella enterica and enterohaemorrhagic Escherichia coli (EHEC) in seed sprouts poses a health risk to consumers, and the conventional sanitization methods are not always effective to reduce this risk. This study initiated a biocontrol approach to limit the internalization using endophytic Bacillus subtilis strains, which were isolated from the inner tissue of mung bean seeds or lettuce stems. By using the deferred agar method, 12 strains of B. subtilis out of 94 putative Bacillus isolates displayed inhibitory activity against at least one of the pathogenic indicators, S. enterica Typhimurium ATCC 14028 and E. coli O157:H7 505B. Two B. subtilis isolates (LCA1 and M24) showed a broad inhibitory spectrum against multiple strains of S. enterica and EHEC, Staphylococcus aureus sp., Klebsiella pneumoniae ATCC 700603, and Listeria monocytogenes Scott A, while the laboratory B. subtilis strain 168 was only moderately inhibitory against L. monocytogenes. To facilitate the tracking of the three B. subtilis strains (LCA1, M24, and 168) in the mung bean sprouts, the three strains were genetically engineered to carry the chloramphenicol acetyltransferase (cat), generating the strains LCA1-cat, M24-cat, and 168-cat, respectively. Data of the study using the cat-tagged strains demonstrated that both the two vegetable-associated and the laboratory B. subtilis strains could internalize in mung bean sprouts during the sprouting, but the latter displayed about 1.2 lg CFU/g of seeds lower in internalization. Overall, the presence of the three B. subtilis strains could significantly reduce the internalization of S. enterica or EHEC cocktail in mung bean sprouts during the sprouting. Among them, LCA1 showed the greatest inhibition against the EHEC cocktails with a reduction of about 2.0lg CFU/g of seeds by the end of sprouting (day 5), while 168 had the smallest reduction at about 0.6lg CFU/g of seeds. In addition, the three strains demonstrated a similar inhibition against the S. enterica cocktails by a reduction of about 1.1-1.4lg CFU/g of seeds by day 5. Results of this study suggest that the source (native vs. alien) of B. subtilis isolates may not affect the efficacy of the inhibition, but it might be affected by the production of antimicrobial substance and/or nutrition/space competition. The results also indicate that strain LCA1 may be useful as a biocontrol agent to reduce Salmonella and EHEC contamination in seed sprouts. PMID- 28364625 TI - Study of temperature effects on the electrical behavior of polypropylene-clay nanocomposites submitted to electron beam irradiation in a SEM. AB - Charge transport and electron emission properties in polypropylene and its nanocomposites filled with nanoclay particles submitted to an electron irradiation, in a Scanning Electron Microscope (SEM), are investigated using induced displacement and leakage currents. The measurements have been performed at various temperatures ranging from 20 degrees C to 75 degrees C at a primary beam energy of 20keV and a primary beam current of 1nA with the aim to highlight the effect of temperature and nanoclay content on these properties. The results show, at a given temperature, that the incorporation of clay in polypropylene (PP) matrix paradoxically leads to a concomitant increase in the electrical conductivity and the charge accumulated. In contrast, if the clay content is fixed, there is an increase in conductivity and a reduction of the charge accumulated when the temperature increases. The mobility of charge carriers and the corresponding activation energy are deduced from the measured leakage current during discharging step. The mobility was found to be an order of magnitude higher for the nanocomposites. The study of the influence of the temperature and nanoclay concentration on electron emission yield is also addressed. PMID- 28364626 TI - Schisantherin A protects against liver ischemia-reperfusion injury via inhibition of mitogen-activated protein kinase pathway. AB - Schisantherin A (SchA) is a dibenzocyclooctadiene lignan isolated from the fruit of Schisandra sphenanthera. The role of SchA in liver injury induced by ischemia and reperfusion (I/R) has not yet been elucidated. The present study hypothesized the protective effects of SchA in hepatic I/R model. Either sham laparotomy or hepatic I/R was induced in C57BL/6 male mice after SchA or vehicle administration. Liver function, histological damage, oxidative/nitrosative stress, inflammatory infiltration, cytokine production, cell apoptosis, cell autophagy, and I/R-associated intracellular signaling pathway were assessed to evaluate the impact of SchA pretreatment on I/R-induced liver injury. After liver I/R injury, the mice pretreated with appropriate SchA displayed significantly preserved liver function, less histological damage, ameliorated oxidative/nitrosative stress, attenuated inflammatory state, and reduced cell apoptosis. However, no differences in the autophagic response were detected after SchA pretreatment. The underlying protective mechanism putatively involves the inhibition of mitogen-activated protein kinase (MAPK) signaling pathway. Based on the beneficial effects, SchA pretreatment may serve as a potential prophylactic measure to prevent liver I/R injury related to various clinical conditions. PMID- 28364627 TI - Protective role of rhapontin in experimental pulmonary fibrosis in vitro and in vivo. AB - BACKGROUND: Pulmonary fibrosis is a scaring process related to chronic lung injury of all causes. The treatment options for pulmonary fibrosis are very limited. Rhapontin has anti-inflammatory effect and anti-proliferative activity which is widely distributed in the medicinal plants of Rheum genus in China. However, the anti-fibrotic activities of rhapontin have not been previously investigated. METHODS: The effect of rhapontin on TGF-beta1-mediated extracellular matrix (ECM) deposition in primary lung fibroblast (PLF) cells, on TGF-beta1 secretion in LPS-stimulated human THP-1 derived macrophages in vitro, and on bleomycin (BLM)-induced pulmonary fibrosis was investigated in vivo. Fibrotic mice were induced by intratracheal instillation of bleomycin, and then treated with rhapontin (25, 50, or 100mg/kg/day) or prednisone (6.5mg/kg/day, positive drug) for 2weeks. RESULTS: In TGF-beta1 stimulated PLFs, treatment with rhapontin resulted in a reduction of ECM with a decrease in Lox2 and p-Smad2/3. In LPS activated macrophages, treatment with rhapontin reduced TGF-beta1 production. However, in vitro the attenuated ECM deposition and inflammatory response by rhapontin were closely associated with AMPK activation, and these suppression of rhapontin were significantly abolished by the AMPK inhibitor. Treatment with rhapontin for 2weeks resulted in an amelioration of the BLM induced pulmonary fibrosis in rats with a lower Lox2, whereas a higher AMPK expression, with reductions of the pathological score, collagen deposition, TGF beta1, alpha-SMA, Lox2, and HIF-1alpha expressions in lung tissues at fibrotic stage at 100mg/kg. CONCLUSION: In summary, rhapontin reversed ECM, as well as Lox2 proliferation in vitro and prevented pulmonary fibrosis in vivo by modulating AMPK activation and suppressing the TGF-beta/Smad pathway. PMID- 28364628 TI - Human adipose tissue-derived mesenchymal stem cells in rheumatoid arthritis: Regulatory effects on peripheral blood mononuclear cells activation. AB - BACKGROUND AND OBJECTIVES: Mesenchymal stem cells (MSCs) are multipotent adult stem cells with immunomodulatory properties. The mechanisms by which MSCs inhibit the proliferation of pro-inflammatory T cells have not been fully elucidated yet. It is assumed that pro-inflammatory T-cells play an important role in the development of autoimmune diseases. We investigated the potential therapeutic effects of human adipose tissue derived (Ad)-MSCs on the peripheral blood mononuclear cells (PBMCs) of rheumatoid arthritis (RA) patients and healthy individuals, with a particular focus on Th17-associated cytokines. MATERIALS AND METHODS: PBMCs from RA patients and healthy donors were co-cultured with Ad-MSCs and HeLa with or without Phytohemagglutinin (PHA). Finally, IL-6, IL-17, IL-21, IL-23 and TGF-beta levels were determined by ELISA and quantitative real-time RT PCR on co-culture supernatants and PBMCs, respectively. RESULTS: In co-culture interaction, Ad-MSCs inhibited IL-17 secretion by PBMCs compared to unstimulated PBMCs cultured alone. In addition, IL-21 expressions in PBMCs of the patient group, and IL-17 and IL-21 in healthy group were inhibited by Ad-MSCs compared to PBMCs cultured alone. TGF-beta expression in healthy individuals remarkably increased in both MSC-treated groups with and without PHA in comparison to PHA stimulated and -unstimulated PBMCs. CONCLUSIONS: This study demonstrates that human Ad-MSCs act as key regulators of immune tolerance by inhibiting the inflammation. Therefore, they can be attractive candidates for immunomodulatory cell-based therapy in RA. PMID- 28364629 TI - Relations between mental health diagnoses, mental health treatment, and substance use in homeless youth. AB - BACKGROUND: Youth experiencing homelessness have elevated rates of mental illness and substance use compared to the general population. However, the extent to which underlying mental health issues may contribute to substance use as a way to manage symptoms and whether mental health treatment may reduce risk for substance use is unclear. This paper investigated these relations in a community sample of homeless youth. METHODS: Youth ages 13-24 (N=416) were interviewed as part of a community count and survey of homeless youth in Houston, Texas. A path analysis examined relations among lifetime diagnoses of ADHD, bipolar disorder, and depression; past-month marijuana, alcohol, and synthetic marijuana use, and hypothesized mediators of past-year mental health treatment and perceived unmet need for treatment. RESULTS: Rates of prior mental disorder diagnoses were high, with extensive comorbidity across the three diagnoses (n=114, 27.3% had all three diagnoses). Relations varied by diagnoses and substances. ADHD was positively related to current marijuana use (beta=0.55 (0.16), p<0.001), a relation that mental health treatment did not mediate. Depression was positively related to synthetic marijuana use through unmet need (beta=0.25 (0.09), p=0.004) and to alcohol use through unmet need (beta=0.20 (0.10), p=0.04) CONCLUSIONS: This study provides new information about relations between prior mental health diagnoses and substance use in homeless youth. Findings support the need to consider prior mental disorder diagnoses in relation to current substance use and to assess for whether youth perceive they have unmet needs for mental health treatment. PMID- 28364630 TI - Charge convertibility and near infrared photon co-enhanced cisplatin chemotherapy based on upconversion nanoplatform. AB - Optimal nano-sized drug carrier requires long blood circulation, selective extravasation, and efficient cell uptake. Here we develop a charge-convertible nanoplatform based on Pt(IV) prodrug loaded NaYF4:Yb,Tm upconversion nanoparticles (UCNs), followed by coating a layer of PEG-PAH-DMMA polymer (UCNs Pt(IV)@PEG-PAH-DMMA). The polymer endows the platform with high biocompatibility, initial nano-size for prolonged blood circulation and selective extravasation. Especially, the anionic polymer can response to the mild acidic stimulus (pH ~6.5) of tumor extracellular microenvironment and experience charge-shifting to a cationic polymer, resulting in electrostatic repulsion and releases of positive UCNs-Pt(IV). The positive UCNs-Pt(IV) nanoparticles have high affinity to negative cell membrane, leading to efficacious cell internalization. Simultaneously, the ultraviolet (UV) light emitted from UCNs upon near-infrared (NIR) light irradiation, together with the reductive glutathione (GSH) in cancer cells efficiently activate the Pt(IV) prodrug to highly cytotoxic Pt(II), realizing NIR photon improved chemotherapy. The experimental results reveal the charge convertibility, low adverse effect and markedly enhanced tumor ablation efficacy upon NIR laser irradiation of this smart nanoplatform. Moreover, combining the inherent upconversion luminescence (UCL) and computed tomography (CT) imaging capabilities, an alliance of cancer diagnosis and therapy has been achieved. PMID- 28364631 TI - Synthetic vaccine nanoparticles target to lymph node triggering enhanced innate and adaptive antitumor immunity. AB - In this study, synthetic vaccine nanoparticles (SVNPs) that efficiently targeted lymph nodes, where immune responses against foreign antigens are primed, were developed to enhance antitumor immunity. The size (20-70 nm) and surface character (amination) of poly(gamma-glutamic acid)-based SVNPs were selected for effective loading and delivery (i.e., migration and retention) of model tumor antigen (OVA) and toll-like receptor 3 agonist (poly (I:C)) to immune cells in lymph nodes. Antigen-presenting cells treated with SVNP-OVA and SVNP-IC showed higher uptake of OVA and poly (I:C) and higher secretion of inflammatory cytokines (TNF-alpha, IL-6) and type I interferon (IFN-alpha, IFN-beta) than those treated with OVA and poly (I:C) alone. In vivo analysis revealed higher levels of activation markers, inflammatory cytokines, and type I IFNs in the lymph nodes of mice immunized with SVNP-IC compared to those of mice in other groups. SVNP-IC-treated mice showed significantly greater in vivo natural killer cell expansion/activation (NK1.1+ cells) and CD8+ T cell response (CD8+ INF gamma+ cells) in innate and adaptive immunity, respectively. Both preventive and therapeutic vaccination of EG7-OVA tumor-bearing mice using the simultaneous injection of both SVNP-OVA and SVNP-IC induced higher antitumor immunity and inhibited tumor growth. PMID- 28364632 TI - Testicular organoid generation by a novel in vitro three-layer gradient system. AB - A system that models the testicular microenvironment and spermatogonial stem-cell (SSC) niche in vitro has not been produced yet. Here, we developed and characterized a novel three-dimensional multilayer model, the Three-Layer Gradient System (3-LGS), which permits the generation of rat testicular organoids with a functional blood-testis barrier (BTB) and germ cell establishment and proliferation. The model is unique as regards the formation of cellular organizations that more closely represent the in vivo germ-to-somatic cell associations in vitro. Moreover, we also verified the roles of retinoic acid (RA), IL-1alpha, TNFalpha and RA inhibitors in germ cell maintenance and BTB organization in vitro. Treatment with RA was beneficial for germ cell maintenance, while IL-1alpha and TNFalpha were observed to impair the formation of testicular organoids and germ cell maintenance. Taking in account our characterization and validation results, we propose the 3-LGS as a new platform to investigate the SSC niche in vitro and to search for novel unknown factors involved in germ cell proliferation and differentiation. Moreover, we suggest that this model can be used in other scientific fields to study organogenesis and development by the generation of organoids. PMID- 28364633 TI - Improved xylitol production by expressing a novel d-arabitol dehydrogenase from isolated Gluconobacter sp. JX-05 and co-biotransformation of whole cells. AB - In the present study, a novel ardh gene encoding d-arabitol dehydrogenase (ArDH) was cloned and expressed in Escherichia coli from a new isolated strain of Gluconobacter sp. JX-05. Sequence analysis revealed that ArDH containing a NAD(P) binding motif and a classical active site motif belongs to the short-chain dehydrogenase family. Subsequently, the optimal pH and temperature, specific activities and kinetic parameter of ArDH were determined. In the co biotransformation by the whole cells of BL21-ardh and BL21-xdh, 26.1g/L xylitol was produced from 30g/L d-arabitol in 22h with a yield of 0.87g/g. The xylitol production was increased by more than two times as compared with that of Gluconobacter sp. alone, and was improved 10.1% than that of Gluconobacter sp. mixed with BL21-xdh. PMID- 28364634 TI - Isolation of a bacterial strain, Acinetobacter sp. from centrate wastewater and study of its cooperation with algae in nutrients removal. AB - Algae were able to grow healthy on bacteria-containing centrate wastewater in a pilot-scale bioreactor. The batch experiment indicated that the co-cultivation of algae and wastewater-borne bacteria improved the removal efficiencies of chemical oxygen demand and total phosphorus in centrate wastewater to 93.01% and 98.78%, respectively. A strain of beneficial aerobic bacteria, Acinetobacter sp., was isolated and its biochemical characteristics were explored. Synergistic cooperation was observed in the growth of algae and Acinetobacter sp. Removal efficiencies of some nutrients were improved significantly by the co-cultivation of algae and Acinetobacter sp. After treatment, residual nutrients in centrate wastewater reached the permissible discharge limit. The cooperation between algae and Acinetobacter sp. was in part attributed to the exchange of carbon dioxide and oxygen between the algae and bacteria. This synergetic relationship between algae and Acinetobacter sp. provided a promising way to treat the wastewater by improving the nutrients removal and biomass production. PMID- 28364635 TI - Hydrothermal treatment followed by enzymatic hydrolysis and hydrothermal carbonization as means to valorise agro- and forest-based biomass residues. AB - The suitability of several abundant but underutilized agro and forest based biomass residues for hydrothermal treatment followed by enzymatic hydrolysis as well as for hydrothermal carbonization was studied. The selected approaches represent simple biotechnical and thermochemical treatment routes suitable for wet biomass. Based on the results, the hydrothermal pre-treatment followed by enzymatic hydrolysis seemed to be most suitable for processing of carbohydrate rich corn leaves, corn stover, wheat straw and willow. High content of thermally stable components (i.e. lignin) and low content of ash in the biomass were advantageous for hydrothermal carbonization of grape pomace, coffee cake, Scots pine bark and willow. PMID- 28364636 TI - Associations of maternal obesity and excessive weight gain during pregnancy with subcutaneous fat mass in infancy. AB - BACKGROUND: Not much is known about the associations of maternal obesity and excessive gestational weight gain with body fat in infancy. OBJECTIVE: To examine the associations of maternal pre-pregnancy body mass index and gestational weight gain with infant subcutaneous fat. METHODS: In a population-based prospective cohort study among 845 mothers and their infants, we obtained maternal pre pregnancy body mass index and measured maternal weight during pregnancy. At 1.5, 6 and 24months, we estimated infant total subcutaneous fat (sum of biceps, triceps, suprailiacal and subscapular skinfold thicknesses) and central-to-total subcutaneous fat ratio (sum of suprailiacal and subscapular skinfold thicknesses/total subcutaneous fat). RESULTS: Maternal body mass index was positively associated with higher infant body mass index from 6months onwards. Maternal body mass index was not associated with infant subcutaneous fat measures at 1.5 or 6months. A 1-standard deviation scores (SDS) higher maternal body mass index was associated with a 0.09 (95% Confidence Interval 0.01, 0.17) SDS higher infant total subcutaneous fat at 24months, but not with central-to-total subcutaneous fat ratio. No associations were present for maternal total or period specific gestational weight gain with infant fat. CONCLUSION: Maternal body mass index was positively associated with infant body mass index and total subcutaneous fat in late infancy. Maternal total and period-specific gestational weight gain were not associated with infant body fat mass measures. PMID- 28364637 TI - Industrial release of fluoroquinolones (FQs) in the waste water bodies with their associated ecological risk in Pakistan. AB - The unchecked production and use of fluoroquinolones (FQs) for the treatment of infections in human and livestock has increased in Pakistan, which resulted in large amount of antibiotics in water bodies. In the current study, the prevalence and associated ecological risk of three FQs were investigated in waste-water bodies and sludge samples of Kahuta and Hattar industrial zones. The average concentrations of ciprofloxacin (CIP), enrofloxacin (ENR) and levofloxacin (LEV) in the waste-water samples were slightly higher in Kahuta (i.e. 58, 32.9, and 36.7MUgL-1 respectively), than those in Hattar sites (i.e. 42.1, 41.2, and 48.9MUgL-1 respectively). However, the concentrations of CIP, ENR and LEV in the sludge samples were significantly higher (i.e. 159; 153 and 164MUgkg-1 respectively) in Hattar sites, compared to those in Kahuta sites (i.e. 129, 58 and 91MUgkg-1 respectively). The uses of FQs in the health sector resulted in water pollution and poses the ecological risk to aquatic organisms. The individual risk associated with CIP was highest in Kahuta industrial sites for green algae ranging (2900-9100) followed by M. aeruginosa (5800-18200), cyanobacteria (580-18204) and invertebrates (24.2-75.8). These values suggested that the prevalence of antibiotics in the waste-disposal sites could be potential risk for the aquatic ecosystem, and harmful to biodiversity. PMID- 28364638 TI - Nrf2 is crucial for the down-regulation of Cyp7a1 induced by arachidonic acid in Hepg2 cells. AB - In former research, cyp7a1 expression was decreased but Nrf2 transcription and hepatic arachidonic acid (AA) concentration were increased in high-fat diet fed mice. This study aims to investigate the influence of AA in CYP7A1 expression and the role of Nrf2 in regulating CYP7A1 in the process. HepG2 cells were administered with different concentrations of AA. Nrf2 and CYP7A1 expressions were analyzed by real-time PCR and western blot. Nrf2 silenced and over-expressed cell models were constructed by Nrf2 siRNA and eukaryotic expression vector transient transfections and were used to investigate the role of Nrf2 in regulating CYP7A1 following AA administration. The results showed that Nrf2 was increased dose-dependently but CYP7A1 was decreased dose-dependently in cells treated with increasing concentrations of AA. The expression of CYP7A1 was increased by Nrf2 silence and was decreased by Nrf2 over-expression in HepG2 cells treated with different concentrations of AA. In conclusion, Nrf2 plays a significant role in the down-regulation of CYP7A1 induced by AA in HepG2 cells. PMID- 28364639 TI - The impacts of emergent pollutants on Ruditapes philippinarum: biochemical responses to carbon nanoparticles exposure. AB - Multi-walled carbon nanotubes (MWCNTs) are one of the most important carbon Nanoparticles (NPs). The production and use of these NPs are increasing rapidly and, therefore, the need to assess their presence in the environment and associated risks has become of prime importance. Recent studies demonstrated the impacts of different NPs on bivalves, a taxonomic group where species tolerance to anthropogenic stressors, such as pollutants, is widely variable. The Manila clam Ruditapes philippinarum is one of the most commonly used bivalve species in environmental monitoring studies and ecotoxicology tests, however, to our knowledge, no information is available on biochemical alterations on this species due to MWCNTs exposure. Thus, the present study aimed to assess the toxic effects of different MWCNT concentrations (0.01; 0.10 and 1.00mg/L) in R. philippinarum biochemical (energy reserves, metabolic capacity, oxidative status and neurotoxicity) performance, after 28days of exposure. The results obtained revealed that exposure to MWCNTs altered energy-related responses, with higher metabolic capacity and lower glycogen and protein concentrations in clams exposed to these carbon NPs. Moreover, R. philippinarum exposed to MWCNTs showed oxidative stress expressed in higher lipid peroxidation and lower ratio between reduced and oxidized glutathione, despite the activation of defence mechanisms in exposed clams. Additionally, neurotoxicity was observed by inhibition of cholinesterases activity in organisms exposed to MWCNTs. The present study provides valuable information regarding how these emerging pollutans could become a potential risk for the environment and living organisms. PMID- 28364640 TI - Blue light differentially represses mesophyll conductance in high vs low latitude genotypes of Populus trichocarpa Torr. & Gray. AB - To explore what role chloroplast positioning might have in relation to latitudinal variation in mesophyll conductance (gm) of Populus trichocarpa Torr. & Gray (black cottonwood), we examined photosynthetic response to different blue light treatments in six representative genotypes (three northern and three southern). The proportion of blue (B) to red light was varied from 0:100, 10:90, 20:80, 40:60, and 60:40 while keeping the total photosynthetic photon flux density constant. Mesophyll conductance was estimated by monitoring chlorophyll fluorescence in combination with gas exchange. Compared to the control (10% B), gm was significantly lower with increasing blue light. Consistent with a change in chloroplast positioning, there was a simultaneous but reversible decrease in chlorophyll content index (CCI), as measured by foliar greenness, while the extracted, actual chlorophyll content (ACC) remained unchanged. Blue-light induced decreases in gm and CCI were greater in northern genotypes than in southern genotypes, both absolutely and proportionally, consistent with their inherently higher photosynthetic rate. Treatment of leaves with cytochalasin D, an inhibitor of actin-based chloroplast motility, reduced both CCI and ACC but had no effect on the CCI/ACC ratio and fully blocked any effect of blue light on CCI. Cytochalasin D reduced gm by ~56% under 10% B, but did not block the effect of 60% B on gm, which was reduced a further 20%. These results suggest that the effect of high blue light on gm is at least partially independent of chloroplast repositioning. High blue light reduced carbonic anhydrase activity by 20% (P<0.05), consistent with a possible reduction in protein-mediated facilitation of CO2 diffusion. PMID- 28364642 TI - In custody deaths of men related to mental illness and substance use: A cross sectional analysis of administrative records in Ontario, Canada. AB - Highly publicized incidents of in-custody deaths have drawn attention to the well being of individuals who are held in custodial settings and have contributed to questions surrounding the role played by mental illness and substance use. The data for this descriptive study consist of administrative records from the Office of the Chief Coroner of Ontario. Section 10(4) jury verdicts filed from January 1, 1996 through December 31, 2010 were drawn for analysis. The final sample includes 478 males who died while in custody. Logistic and multinomial regressions were conducted to assess how a history of mental illness and substance use is related to deaths in custody and how those deaths vary across custodial jurisdictions. Approximately half of all deaths in custody occurred among those with a history of mental illness or substance use and those deaths disproportionately occurred in local police or provincial custody, compared to those held in federal custody. Further, the joint effects of a co-occurring history of mental illness and substance use were found to be statistically significant with the strongest effects observed in local police custody. The results from this study underscore concerns surrounding the well-being of individuals with a history of mental illness or substance use and who come into contact with the criminal justice system. With more offenders presenting with complex mental-health and substance-use problems, the implications for local police become apparent in the context of developing policies and practices directed towards preventing deaths. PMID- 28364641 TI - Tracking reorganization of large-scale effective connectivity in aphasia following right hemisphere stroke. AB - In this paper we demonstrate the application of new effective connectivity analyses to characterize changing patterns of task-related directed interaction in large (25-55 node) cortical networks following the onset of aphasia. The subject was a left-handed woman who became aphasic following a right-hemisphere stroke. She was tested on an auditory word-picture verification task administered one and seven months after the onset of aphasia. MEG/EEG and anatomical MRI data were used to create high spatiotemporal resolution estimates of task-related cortical activity. Effective connectivity analyses of those data showed a reduction of bilateral network influences on preserved right-hemisphere structures, and an increase in intra-hemispheric left-hemisphere influences. She developed a connectivity pattern that was more left lateralized than that of right-handed control subjects. Her emergent left hemisphere network showed a combination of increased functional subdivision of perisylvian language areas and recruitment of medial structures. PMID- 28364644 TI - Effects of cellular electromechanical coupling on functional heterogeneity in a one-dimensional tissue model of the myocardium. AB - Based on the experimental evidence, we developed a one-dimensional (1D) model of heterogeneous myocardial tissue consisting of in-series connected cardiomyocytes from distant transmural regions using mathematical models of subendocardial and subepicardial cells. The regional deformation patterns produced by our 1D model are consistent with the transmural regional strain patterns obtained experimentally in the normal heart in vivo. The modelling results suggest that the mechanical load may essentially affect the transmural gradients in the electrical and mechanical properties of interacting myocytes within a tissue, thereby regulating global myocardial output. PMID- 28364643 TI - A multi-resolution approach for spinal metastasis detection using deep Siamese neural networks. AB - Spinal metastasis, a metastatic cancer of the spine, is the most common malignant disease in the spine. In this study, we investigate the feasibility of automated spinal metastasis detection in magnetic resonance imaging (MRI) by using deep learning methods. To accommodate the large variability in metastatic lesion sizes, we develop a Siamese deep neural network approach comprising three identical subnetworks for multi-resolution analysis and detection of spinal metastasis. At each location of interest, three image patches at three different resolutions are extracted and used as the input to the networks. To further reduce the false positives (FPs), we leverage the similarity between neighboring MRI slices, and adopt a weighted averaging strategy to aggregate the results obtained by the Siamese neural networks. The detection performance is evaluated on a set of 26 cases using a free-response receiver operating characteristic (FROC) analysis. The results show that the proposed approach correctly detects all the spinal metastatic lesions while producing only 0.40 FPs per case. At a true positive (TP) rate of 90%, the use of the aggregation reduces the FPs from 0.375 FPs per case to 0.207 FPs per case, a nearly 44.8% reduction. The results indicate that the proposed Siamese neural network method, combined with the aggregation strategy, provide a viable strategy for the automated detection of spinal metastasis in MRI images. PMID- 28364645 TI - Laboratory investigation of PCB bake-out from tertiary contaminated concrete for remediation of buildings. AB - Polychlorinated biphenyls (PCBs) have been used in flexible construction products from the 1950s to the 1970s. Despite a relatively low vapour pressure, PCBs have over the years emitted to the indoor air and adsorbed to other surfaces, creating tertiary sources. While necessary to protect the environment and health of building occupants, remediation of the contaminated buildings is an expensive and difficult process. The aim of this study was to investigate the effect of bake out as a method for removing PCB from contaminated indoor surfaces. Four painted and four sandblasted samples of concrete wall were kept at 50 or 65 degrees C for 10 or 20 days in small scale chambers, which were ventilated with clean air at area specific rates comparable to full scale rooms. The air concentrations were measured several times during the bake-out. Concentrations of PCB in paint, plaster and concrete were measured before and after the experiment. For the painted samples, PCB28 and PCB52 followed by PCB138 and PCB153 were the predominant congeners measured in air. A significant reduction of the PCB concentration was only found for more volatile congeners in paint, while no significant effects were observed in the plaster or concrete. For the most effective setting (65 degrees C, 20 days), the concentration of PCB?7 in the paint was reduced by 40%. For the sandblasted samples, the less volatile congeners PCB138 and PCB153 were predominant in the air during bake-out. No effect was observed on the initially low concentrations of the sandblasted samples, possibly due to analytical limitations. PMID- 28364646 TI - The influences of Cr-tolerant rhizobacteria in phytoremediation and attenuation of Cr (VI) stress in agronomic sunflower (Helianthus annuus L.). AB - Chromium contamination of agronomic soil has to turn into a serious global problem. This research was pointed to assess the effects of three Cr-tolerant rhizobacteria (SS1, SS3, and SS6) on sunflower growth and heavy metal uptake under Cr smog i.e. 20, 30 and 40 ppm using K2Cr2O7. Root promotion assay and pot experiment were conducted to investigate and evaluate the effects of Cr tolerance rhizobacteria and Cr accumulation capacity of sunflower. From root promotion assay non-significant variation was observed in the root length between SS1 and SS3 compared with un-inoculated whereas SS6 enhanced the root length in the absence and presence of chromium. In addition, inoculation with rhizobacteria alleviated the Cr concentration and endorsed plant growth by enhancing Cr accumulation in sunflower. At different Cr levels, the Cr concentration in shoot was improved by each rhizobacterium though their difference was non-significant with each other, while the percentage increase was half as the Cr level doubled. Different rhizobacterium inoculation significantly (P < 0.05) affected the physiological and morphological characteristics of sunflower and increased the plant height, stem diameter, head diameter, grain yield, oil content of seeds, and total biomass, and among them, SS6 observed best followed by SS1 and SS3 comparing with un-inoculated. Our study illustrates an assessment about Cr tolerant bacteria and their influences and recommends that these bacteria can effectively be used for crop improvement which provides a potential approach for Cr phytoremediation. PMID- 28364647 TI - Trace elements in loggerhead turtles (Caretta caretta) stranded in mainland Portugal: Bioaccumulation and tissue distribution. AB - Pollution is among the most significant threats that endanger sea turtles worldwide. Waters off the Portuguese mainland are acknowledged as important feeding grounds for juvenile loggerheads. However, there is no data on trace element concentrations in marine turtles occurring in these waters. We present the first assessment of trace element concentrations in loggerhead turtles (Caretta caretta) occurring off the coast of mainland Portugal. Also, we compare our results with those from other areas and discuss parameters that may affect element concentrations. Trace element concentrations (As, Cd, Cu, Pb, Mn, Hg, Ni, Se, Zn) were determined in kidney, liver and muscle samples from 38 loggerheads stranded between 2011 and 2013. As was the only element with higher concentrations in muscle (14.78 MUg g-1 ww) than in liver or kidney. Considering non-essential elements, Cd presented the highest concentrations in kidney (34.67 MUg g-1) and liver (5.03 MUg g-1). Only a weak positive link was found between renal Cd and turtle size. Inter-elemental correlations were observed in both liver and kidney tissues. Hepatic Hg values (0.30 +/- 0.03 MUg g-1) were higher than values reported in loggerheads in the Canary Islands but lower than in Mediterranean loggerheads. Cd concentrations in the present study were only exceeded by values found in turtles from the Pacific. Although many endogenous and exogenous parameters related with complex life cycle changes and wide geographic range may influence trace element accumulation, the concentrations of Cd are probably related to the importance of crustaceans in loggerhead diet in the Portuguese coast. PMID- 28364648 TI - Retardation of uranium and thorium by a cementitious backfill developed for radioactive waste disposal. AB - The solubility of uranium and thorium has been measured under the conditions anticipated in a cementitious, geological disposal facility for low and intermediate level radioactive waste. Similar solubilities were obtained for thorium in all media, comprising NaOH, Ca(OH)2 and water equilibrated with a cement designed as repository backfill (NRVB, Nirex Reference Vault Backfill). In contrast, the solubility of U(VI) was one order of magnitude higher in NaOH than in the remaining solutions. The presence of cellulose degradation products (CDP) results in a comparable solubility increase for both elements. Extended X-ray Absorption Fine Structure (EXAFS) data suggest that the solubility-limiting phase for uranium corresponds to a becquerelite-type solid whereas thermodynamic modelling predicts a poorly crystalline, hydrated calcium uranate phase. The solubility-limiting phase for thorium was ThO2 of intermediate crystallinity. No breakthrough of either uranium or thorium was observed in diffusion experiments involving NRVB after three years. Nevertheless, backscattering electron microscopy and microfocus X-ray fluorescence confirmed that uranium had penetrated about 40 MUm into the cement, implying active diffusion governed by slow dissolution-precipitation kinetics. Precise identification of the uranium solid proved difficult, displaying characteristics of both calcium uranate and becquerelite. PMID- 28364649 TI - Biochar and enhanced phosphate capture: Mapping mechanisms to functional properties. AB - A multi-technique analysis was performed on a range of biochar materials derived from secondary organic resources and aimed at sustainable recovery and re-use of wastewater phosphorus (P). Our purpose was to identify mechanisms of P capture in biochar and thereby inform its future optimisation as a sustainable P fertiliser. The biochar feedstock comprised pellets of anaerobically digested sewage sludge (PAD) or pellets of the same blended in the ratio 9:1 with ochre sourced from minewater treatment (POCAD), components which have limited alternative economic value. In the present study the feedstocks were pyrolysed at two highest treatment temperatures of 450 and 550 degrees C. Each of the resulting biochars were repeatedly exposed to a 20 mg l-1 PO4-P solution, to produce a parallel set of P-exposed biochars. Biochar exterior and/or interior surfaces were quantitatively characterised using laser-ablation (LA)-ICP-MS, X-ray diffraction, X-ray photo-electron spectroscopy (XPS) and scanning electron microscopy coupled with energy dispersive X-ray. The results highlighted the general importance of Fe minerals in P capture. XPS analysis of POCAD550 indicated lower oxidation state Fe2p3 bonding compared to POCAD450, and LA-ICP-MS indicated stronger covariation of Fe and S, even after P exposure. This suggests that low-solubility Fe/S compounds are formed during pyrolysis, are affected by process parameters and impact on P capture. Other data suggested capture roles for aluminium, calcium and silicon. Overall, our analyses suggest that a range of mechanisms for P capture are concurrently active in biochar. We highlighted the potential to manipulate these through choice of form and composition of feedstock as well as pyrolysis processing, so that biochar may be increasingly tailored towards specific functionality. PMID- 28364650 TI - Developing polyetherimide/graphitic carbon nitride floating photocatalyst with good photodegradation performance of methyl orange under light irradiation. AB - Polyetherimide-graphitic carbon nitride (PEI-g-C3N4) floating photocatalyst has been synthesized by using polyetherimide (PEI) as linker to bind graphitic carbon nitride (g-C3N4) together. XRD and XPS analysis for PEI-g-C3N4 show that the interaction between PEI and g-C3N4 does not disturb the structure of g-C3N4. FTIR, TEM and theoretical results suggest that the long chain PEI binds g-C3N4 particles together to form PEI-g-C3N4 via hydrogen bonding interaction. Based on photodegradation results of methyl orange (MO), PEI can not photodegrade MO and just works as linker in PEI-g-C3N4, while the photodegradation performance of PEI g-C3N4 is from the contribution of g-C3N4. Total organic carbon (TOC) analysis show that nearly 47% organic carbon has been converted into inorganic carbon after photodegradation, suggesting that PEI-g-C3N4 can destroy both NN bond and aromatic rings in MO under light irradiation. The photodegradation efficiency (91%) of MO by g-C3N4 is higher than that (80%) by PEI-g-C3N4 with stirring. But, the photodegradation efficiency (37%) of MO by g-C3N4 is lower than that (55%) by PEI-g-C3N4 without stirring. This is the advantage of floating photocatalyst with respect to the powder photocatalyst since the former can utilize more solar energy than the latter when stirring is not available. PMID- 28364651 TI - Influence of soil characteristics on rare earth fingerprints in mosses and mushrooms: Example of a pristine temperate rainforest (Slavonia, Croatia). AB - The present study aims to investigate levels and distribution of rare earth elements (REE) in soils, mosses and mushrooms of a pristine temperate rainforest, a non-polluted natural system, in order to characterise their environmental availability and mobility. The multielement analysis of digested soil, moss and mushroom samples was performed by High Resolution Inductively Coupled Plasma Mass Spectrometry. The distribution of rare earths in mosses and mushrooms was found primarily affected by local pedological setting. Mosses displayed a consistent lithological signature with an almost insignificant REE fractionation compared to soils. Mushrooms showed differences in REE concentrations in certain parts of the fruiting body with regard to their main physiological function and indicated a significant impact of soil organic content on the overall REEs uptake. Results of our work highlight the importance of substrate characteristics on the initial levels of REEs in mosses and mushrooms. Moreover, this study provides baseline data on the rare earth element levels in mosses and mushrooms growing in a pristine forest area characterised by naturally elevated REE levels in the soil. PMID- 28364652 TI - Sequential solid entrapment and in situ electrolytic alkaline hydrolysis facilitated reagent-free bioelectrochemical treatment of particulate-rich municipal wastewater. AB - We introduce here a novel process for the treatment of particulate-rich wastewater. A two-stage combined treatment process, consisting of an electrolysis filter and a bioelectrochemical system (BES) configuration was designed and evaluated to remove particulate and soluble organic matter from municipal wastewater. The system was designed such that the electrolysis step was used as a filter, enabling physical removal and in situ alkaline hydrolysis of the entrapped particulate matter. The alkaline effluent enriched with the hydrolysed soluble compounds (soluble chemical oxygen demand, SCOD) was subsequently loaded into the BES for removal via bioanodic oxidation. The coupled system was continuously operated with a primary sedimentation tank effluent (suspended solids (SS) ~200 mg/L) for over 160 days, during which SCOD and total COD (TCOD), SS removal and current production were evaluated. With no sign of clogging the process was able to capture near 100% of the SS loaded. A high Coulombic efficiency (CE) of 93% (based on overall TCOD removed) was achieved. The results also suggest that the SCOD-laden alkaline liquor from the electrolysis step compensated for the acidification in the bioanode and a final effluent containing low COD with neutral pH was achieved. Overall, since the system can effectively entrap, in situ hydrolyse and oxidise organic matter without external dosing of chemicals for pH control, it has desirable features for practical application. PMID- 28364653 TI - Genetic characterization of fecal impacts of seagull migration on an urban scenery lake. AB - A microbial source tracking scheme was devised to differentiate fecal impacts of seagulls from that of human activities on an urban scenery lake in southern China, which is a major wintering ground for the black-headed seagull. Fecal contamination of seagulls was characterized by quantifying a novel genetic marker targeting Catellicoccus marimamalium. Quantification of this marker was combined with those of Escherichia coli, human-associated Bacteroidales, thermophilic Campylobacter and Helicobacter. Findings of a year-round study indicate that C. marimamalium levels correlated strongly, both spatially and temporally, with seagull migration. A steady increase in C. marimammalium concentrations was recorded between October 2014 and March 2015, which peaked at about 5-log copies/100 mL in January. However, a background level of about 2.1-log copies/100 mL was noticeable from April through September when seagulls were absent, probably due to other host sources or secondary habitats for C. marimammalium. Seagull migration also caused an apparent elevation of E. coli concentrations (86% and 60%, respectively for qPCR and culture method; p < 0.001) as well as Campylobacter and Helicobacter (66% and 68%, respectively; p < 0.001). Nonetheless, in contrast to the declining levels of E. coli, Campylobacter and Helicobacter, the human-specific Bacteroidales marginally increased in the seagull-absent season, indicating a limited influence of human activities, compared with seagull migration, on the seasonal variations in microbial water quality of the lake. The elevated levels of FIB, Campylobacter and Helicobacter along with C. marimammalium may imply human health risk of the lake water due to seasonal seagull migration, which requires further investigation for risk assessment. PMID- 28364654 TI - Microbial fuel cells for inexpensive continuous in-situ monitoring of groundwater quality. AB - Online monitoring of groundwater quality in shallow wells to detect faecal or organic pollution could dramatically improve understanding of health risks in unplanned peri-urban settlements. Microbial fuel cells (MFC) are devices able to generate electricity from the organic matter content in faecal pollution making them suitable as biosensors. In this work, we evaluate the suitability of four microbial fuel cell systems placed in different regions of a groundwater well for the low-cost monitoring of a faecal pollution event. Concepts created include the use of a sediment/bulk liquid MFC (SED/BL), a sediment/sediment MFC (SED/SED), a bulk liquid/air MFC (BL/Air), and a bulk liquid/bulk liquid MFC (BL/BL). MFC electrodes assembly aimed to use inexpensive, durable, materials, which would produce a signal after a contamination event without external energy or chemical inputs. All MFC configurations were responsive to a contamination event, however SED/SED and BL/Air MFC concepts failed to deliver a reproducible output within the tested period of time. BL/BL MFC and SED/BL MFCs presented an increase in the average current after contamination from -0.75 +/- 0.35 MUA to -0.66 +/- 0.41 MUA, and 0.07 +/- 0.2 mA to 0.11 +/- 0.03 mA, respectively. Currents produced by the SED/BL MFC (SMFC) were considerably higher than for the BL/BL MFCs, making them more responsive, readable and graphically visible. A factorial design of experiments (DOE) was applied to evaluate which environmental and design factors had the greatest effect on current response in a contamination event. Within the ranges of variables tested, salinity, temperature and external resistance, only temperature presented a statistically significant effect (p = 0.045). This showed that the biosensor response would be sensitive to fluctuations in temperature but not to changes in salinity, or external resistances produced from placing electrodes at different distances within a groundwater well. PMID- 28364655 TI - Real-life experience with brivaracetam in 101 patients with difficult-to-treat epilepsy-A monocenter survey. AB - PURPOSE: To assess the efficiency of brivaracetam under real-world conditions in a tertiary referral epilepsy center. METHODS: We consecutively collected patients treated at our center with brivaracetam (BRV). After a minimum observation period of six months we retrospectively analyzed the efficiency of BRV. RESULTS: Data of 101 patients (mean age 42 years, range 18-81 years, 54 females,) were analyzed. The median number of antiepileptic drugs (AEDs) used prior to BRV was 10 (range 2 18). The initial dose of BRV was at least 50mg per day, the mean maintenance dose at cut-off was 168.6mg (median 200mg, range 50-400mg). Efficacy data were assessed for the last three months or at the time of the last observation carried forward if BRV had been discontinued prematurely. Responder rate was 27.8% (n=28) with 7% seizure-free patients. Adverse events (AEs) occurred in 37 patients (37%). Most frequent AEs were dizziness (16%) and somnolence (11%). Psychiatric adverse events comprised irritability, aggression, depression and psychosis in single cases. Retention rate after six months was 51.5%. Main reason for discontinuation was a lack of efficacy. In 43 cases LEV and BRV were switched. The switch was performed abruptly without complications. In 26 cases (60%) BRV was discontinued and re-switched to LEV within weeks, mainly due to a lack of better efficacy. After the switch from LEV to BRV we even saw an aggravation both of seizure frequency and severity in 5 cases. Retention rate in patients who had not been on LEV was 57%. CONCLUSION: In our hands BRV appeared to be well tolerated and easy to handle. The retention rate was influenced by patients who were switched from LEV and re-switched because BRV was not more efficient. Switching from and re-switching to LEV was easy. PMID- 28364656 TI - Effects of antiepileptic drugs on thyroid hormone function in epilepsy patients. AB - PURPOSE: Patients with epilepsy are frequently required to take antiepileptic drugs (AEDs) for a long period of time. Many studies have shown that AEDs have a negative influence on endocrine function including the thyroid gland, however the risk factors for the development of low thyroid function in these patients are unclear. This study aimed to determine the potential risk factors of low thyroid function in patients with epilepsy. METHOD: This was a cross-sectional study including 298 patients with epilepsy. Patients with previous thyroid disease were excluded. Epidemiologic data, type of epilepsy, etiology, the age of seizure onset, duration of epilepsy, intractable epilepsy, and number and dosage of AEDs were recorded. Levels of free thyroxine (fT4) and thyroid stimulating hormone (TSH) were measured. RESULTS: Fifty-two of the 298 (17.4%) patients had low fT4. Older age (P=0.004), female sex (P=0.014), longer duration of epilepsy (P=0.001), and intractable epilepsy (P=0.009) were significantly associated with low fT4. Regarding individual AEDs, carbamazepine (30.1%), topiramate (28.6%), and levetiracetam (24.3%) were significantly associated with the presence of low fT4. After stepwise logistic regression of all significant variables, female sex, older age, three or more AEDs, and carbamazepine were independent risk factors for low fT4. CONCLUSIONS: Female patients with epilepsy and an older age, AED polytherapy, and carbamazepine treatment had a higher risk of low fT4. Thyroid function in these patients should be monitored closely. PMID- 28364657 TI - Genetic models of C9orf72: what is toxic? AB - A hexanucleotide repeat expansion in the gene C9orf72 is the most common genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Pathogenesis may occur either due to loss of function of the C9orf72 gene, or a toxic gain of function, via the production of repetitive sense and antisense RNA and/or repetitive dipeptide repeat proteins. Recently, mouse knockouts have suggested that a loss of function of C9orf72 alone is insufficient to lead to neurodegeneration, whilst overexpression of hexanucleotide DNA is sufficient in a wide range of model systems. Additionally, models have now been created to attempt to study the effects of repetitive RNA and dipeptide proteins in isolation and thus determine their relevance to disease. PMID- 28364658 TI - Novel 2-benzylthio-5-(1,3,4-oxadiazol-2-yl)benzenesulfonamides with anticancer activity: Synthesis, QSAR study, and metabolic stability. AB - A series of novel 2-benzylthio-4-chloro-5-(5-substituted 1,3,4-oxadiazol-2 yl)benzenesulfonamides (4-27) have been synthesized as potential anticancer agents. MTT assay was carried out to determine the cytotoxic activity against three human cancer cell lines: colon cancer HCT-116, breast cancer MCF-7 and cervical cancer HeLa as well as to determine the influence on human keratinocyte cell line HaCaT. Relatively high (IC50: 7-17 MUM) cytostatic activity and selectivity against HeLa cell line was found for compounds 6, 7, 9-11 and 16. While compounds 23-27 bearing styryl moieties attached to a 1,3,4-oxadiazole ring at position 5, exhibited significant activity against two and/or three cancer cell lines with IC50: 11-29 MUM. Further quantitative structure-activity relationships based on molecular descriptors calculated by DRAGON software, were investigated by Orthogonal Projections to Latent Structures (OPLS) technique and Variable Influence on Projection (VIP) analysis. Considering molecular descriptors with the highest influence on projection (highest VIP values) lipophilicity of tested compounds was pointed as main factor affecting activity towards HCT-116 cell line, while structural parameters associated with presence of styryl substituent in position 5 of 1,3,4-oxadiazole ring were identified as essential for activity towards MCF-7 breast cancer. In vitro tests for metabolic stability in the presences of pooled human liver microsomes and NADPH showed that some of the most active compounds 26 and 27 presented favorable metabolic stability with t1/2 in the range of 28.1-36.0 min. PMID- 28364659 TI - An in vitro and in vivo evaluation of new potential trans-sialidase inhibitors of Trypanosoma cruzi predicted by a computational drug repositioning method. AB - Chagas disease is one of the most important neglected parasitic diseases afflicting developed and undeveloped countries. There are currently limited options for inexpensive and secure pharmacological treatment. In this study, we employed a structure-based virtual screening protocol for 3180 FDA-approved drugs for repositioning of them as potential trans-sialidase inhibitors. In vitro and in vivo evaluations were performed for the selected drugs against trypomastigotes from the INC-5 and NINOA strains of T. cruzi. Also, inhibition of sialylation by the trans-sialidase enzyme reaction was evaluated using high-performance anion exchange chromatography with pulse amperometric detection to confirm the mechanism of action. Results from the computational study showed 38 top drugs with the best binding-energies. Four compounds with antihistaminic, anti hypertensive, and antibiotic properties showed better trypanocidal effects (LC50 range = 4.5-25.8 MUg/mL) than the reference drugs, nifurtimox and benznidazole (LC50 range = 36.1-46.8 MUg/mL) in both strains in the in vitro model. The anti inflammatory, sulfasalazine showed moderate inhibition (37.6%) of sialylation in a trans-sialidase enzyme inhibition reaction. Sulfasalazine also showed the best trypanocidal effects in short-term in vivo experiments on infected mice. This study suggests for the first time that the anti-inflammatory sulfasalazine could be used as a lead compound to develop new trans-sialidase inhibitors. PMID- 28364660 TI - Hinfinity state estimation for discrete-time neural networks with distributed delays and randomly occurring uncertainties through Fading channels. AB - In this paper, the Hinfinity state estimation problem is investigated for a class of uncertain discrete-time neural networks subject to infinitely distributed delays and fading channels. Randomly occurring uncertainties (ROUs) are introduced to reflect the random nature of the network condition fluctuations, and the channel fading phenomenon is considered to account for the possibly unreliable network medium on which the measurement signal is transmitted. A set of Bernoulli-distributed white sequences are employed to govern the ROUs and the L-th Rice fading model is utilized where channel coefficients are mutually independent random variables with certain probability density function on [0,1]. We aim to design a state estimator such that the dynamics of the estimation error is asymptotically stable while satisfying the prescribed Hinfinity performance constraint. By adopting the Lyapunov-Krasovskii functional and the stochastic analysis theory, sufficient conditions are established to ensure the existence of the desired state estimators and the explicit expression of such estimators is acquired. A simulation example is provided to verify the usefulness of the proposed approach. PMID- 28364661 TI - Fixed-time stability of dynamical systems and fixed-time synchronization of coupled discontinuous neural networks. AB - In this paper, the fixed-time stability of dynamical systems and the fixed-time synchronization of coupled discontinuous neural networks are investigated under the framework of Filippov solution. Firstly, by means of reduction to absurdity, a theorem of fixed-time stability is established and a high-precision estimation of the settling-time is given. It is shown by theoretic proof that the estimation bound of the settling time given in this paper is less conservative and more accurate compared with the classical results. Besides, as an important application, the fixed-time synchronization of coupled neural networks with discontinuous activation functions is proposed. By designing a discontinuous control law and using the theory of differential inclusions, some new criteria are derived to ensure the fixed-time synchronization of the addressed coupled networks. Finally, two numerical examples are provided to show the effectiveness and validity of the theoretical results. PMID- 28364662 TI - LogP, a yesterday's value? AB - INTRODUCTION: There is an increasing demand for high throughput methods at early stages of preclinical radioligand development, in order to predict pharmacokinetic properties (e.g., biodistribution) and blood brain barrier (BBB) penetration. One of the most important physicochemical properties is the lipophilicity, measured by means of shake-flask (logP) or HPLC methods. Yet, a plethora of experimental methods are described in the literature for the determination of logP values. These varying methods often lead to different results for one identical compound, which complicates any comparison or prediction for subsequent preclinical studies. However, a standardized and internationally applied and accepted database with logP values for a reliable comparison of the lipophilic character of radiotracers is still missing. METHOD: Lipophilicity measurements were performed with 121 molecules using a high throughput HPLC method and ClogP values were calculated using ChemBioDraw(r). Furthermore, logP measurements for six representative radiotracers were performed with the conventional shake-flask method and the results were statistically compared to the ClogP and HPLC logP results. Different logP thresholds, suggesting optimal BBB penetration according to literature, were selected and put into relation with the acquired HPLC logP and ClogP values of cerebral tracers. RESULTS: The results of the tested compounds ranged from -2.1 to 5.4 with the applied HPLC method. The acquired database comprises ClogP values of the whole set of compounds ranging from -4.11 to 6.12. LogP data from different methods were not comparable. The correlation of the obtained logP data to thresholds suggesting an optimal brain uptake resulted in a high number of false positive classifications. CONCLUSION: The logP determination for prediction of BBB penetration is obsolete. The extensive database, including clinical relevant radiotracers, can be used as comparative set of values for preclinical studies, and serves as a basis for further critical discussions concerning the eligibility of logP. PMID- 28364663 TI - Tissue growth and tumorigenesis in Drosophila: cell polarity and the Hippo pathway. AB - Cell polarity regulation is critical for defining membrane domains required for the establishment and maintenance of the apical-basal axis in epithelial cells (apico-basal polarity), asymmetric cell divisions, planar organization of tissues (planar cell polarity), and the formation of the front-rear axis in cell migration (front-rear polarity). In the vinegar fly, Drosophila melanogaster, cell polarity regulators also interact with the Hippo tissue growth control signaling pathway. In this review we survey the recent Drosophila literature linking cell polarity regulators with the Hippo pathway in epithelial tissue growth, neural stem cell asymmetric divisions and in cell migration in physiological and tumorigenic settings. PMID- 28364664 TI - Contribution of neuroinflammation to changes in [11C]flumazenil binding in the rat brain: Evaluation of the inflamed pons as reference tissue. AB - INTRODUCTION: [11C]Flumazenil is a well-known PET tracer for GABAA receptors and is mainly used as an imaging biomarker for neuronal loss. Recently, GABAA receptors on immune cells have been investigated as target for modulation of inflammation. Since neuronal loss is often accompanied by neuroinflammation, PET imaging with [11C]flumazenil is potentially affected by infiltrating immune cells. This may also compromise the validity of using the pons as reference tissue in quantitative pharmacokinetic analysis. This study aims to evaluate whether inflammatory processes in the brain can influence [11C]flumazenil uptake and affect the outcome of pharmacokinetic modeling when the pons is used as reference tissue. METHODS: The herpes simplex encephalitis (HSE) rat model is known to cause neuroinflammation in the brainstem. Dynamic [11C]flumazenil PET scans of 60-min, accompanied by arterial blood sampling and metabolite analysis, were acquired at day 6-7days post-infection of male Wistar rats (HSE, n=5 and control, n=6). Additionally, the GABAA receptor was saturated by injection of unlabeled flumazenil prior to the tracer injection in 4 rats per group. PET data were analyzed by pharmacokinetic modeling. RESULTS: No statistically significant differences were found in the volume of distribution (VT) or non-displaceable binding potential (BPND) between control and HSE rats in any of the brain regions. Pre-saturation with unlabeled flumazenil resulted in a statistically significant reduction in [11C]flumazenil VT in all brain regions. The BPND obtained from SRTM exhibited a good correlation to DVR - 1 values from the two tissue compartment model, coupled with some level of underestimation. CONCLUSION: Reliable quantification of [11C]flumazenil binding in rats can be obtained by pharmacokinetic analysis using the pons as a pseudo-reference tissue even in the presence of strong acute neuroinflammation. PMID- 28364665 TI - Doppler-limited high-resolution spectrum and VPT2 assisted assignment of the C-H stretch of CH2Br2. AB - The Doppler limited non-saturated rotationally resolved infrared spectra of the symmetric and asymmetric CH-stretch bands of CH2Br2 have been measured. A continuous wave cavity ringdown setup with a widely tunable Mid-IR-OPO laser light source yielded a single-shot minimum absorption of 4.9*10-8cm-1. In contrast to the heavily congested nu1 band, the nu6 band showed partially resolved rotational features that may serve as suitable absorption targets in future environmental detection schemes for CH2Br2. A straightforward, VPT2 (second-order vibrational perturbation theory) assisted quantum-chemical approach for assigning the rotational structure has been tested using different model chemistries. The molecular structures, anharmonic frequencies and the structural changes upon vibrational excitation of CH2Br2 have been investigated. The predicted changes of the anharmonic rotational constants have been used together with available spectroscopic ground state constants to simulate the rovibrational structures of the nu1 and nu6 bands of CH2Br2. A refined analysis of the nu6 band is presented yielding accurate values for the band origin and the rotational constants. A fit of the line positions of 312 prominent transitions of the three isotopologues revealed a low standard error of 0.00056cm-1, hence within the absolute 0.0009cm-1 wavelength accuracy of the used spectrometer setup. A combined analysis of the predicted line strengths and positions of the strong Q sub-branches of the nu6 band has been performed to test the ability of the different density functionals for VPT2 prediction of anharmonic molecular constants. The M06/6-311++G(d,p) model chemistry turned out to yield reliable state-dependent rotational constants that are accurate enough to reproduce the overall rotational structure even without fitting. PMID- 28364667 TI - SERS spectroelectrochemical study of electrode processes at copper hexacyanoferrate modified electrode. AB - Electrochemical redox processes taking place at copper hexacyanoferrate (CuHCF) modified electrode have been investigated by near-infrared laser (785nm) induced surface-enhanced Raman spectroscopy (SERS). Raman bands observed within the spectral ranges of 2200-2000cm-1 and 500-100cm-1, as well as their dependence on electrode potential, have been analysed. The most characteristic Raman bands, related to triple CN bond vibrations and centered at 2187 and 2127cm-1 were assigned to the oxidised and the reduced forms of CuHCF, respectively. Time resolved Raman spectroelectrochemical study shows that the electrochemical redox interconversions between these two forms proceed relatively slow, thus resembling the behaviour of structurally related cobalt hexacyanoferrate, and differing essentially from that of Prussian blue layer studied previously. It has been shown by the time-resolved Raman spectroelectrochemistry that the rate of some redox processes of solute species like the anodic oxidation of ascorbate or cathodic reduction of hydrogen peroxide at CuHCF modified electrode appears to be limited by the slow electrochemical redox transformations within the modifier layer itself rather than by the redox interactions of a modifier with the solute species. PMID- 28364666 TI - Biomolecular dynamics studied with IR-spectroscopy using quantum cascade lasers combined with nanosecond perturbation techniques. AB - Early events of protein folding can be studied with fast perturbation techniques triggering non-equilibrium relaxation dynamics. A nanosecond laser-excited pH jump or temperature-jump (T-jump) was applied to initiate helix folding or unfolding of poly-l-glutamic acid (PGA). PGA is a homopolypeptide with titratable carboxyl side-chains whose protonation degree determines the PGA conformation. A pH-jump was realized by the photochemical release of protons and induces PGA folding due to protonation of the side-chains. Otherwise, the helical conformation can be unfolded by a T-jump. We operated under conditions where PGA does not aggregate and temperature and pH are the regulatory properties of its conformation. The experiments were performed in such a manner that the folding/unfolding jump proceeded to the same PGA conformation. We quantified the increase/decrease in helicity induced by the pH-/T-jump and demonstrated that the T-jump results in a relatively small change in helical content in contrast to the pH-jump. This is caused by the strong pH-dependence of the PGA conformation. The conformational changes were detected by time-resolved single wavelength IR spectroscopy using quantum cascade lasers (QCL). We could independently observe the kinetics for alpha-helix folding and unfolding in PGA by using different perturbation techniques and demonstrate the high sensitivity of time-resolved IR spectroscopy to study protein folding mechanisms. PMID- 28364668 TI - Towards designing polymers for photovoltaic applications: A DFT and experimental study of polyazomethines with various chemical structures. AB - Theoretical studies of polyazomethines (PAZs) with various chemical structures designated for photovoltaic applications are presented. PAZ energy levels and optical properties were calculated within density-functional theory (DFT and TDDFT) framework for 28 oligomers (monomer, dimer and trimer) of PAZs. The correlations between chemical structure of PAZ and location of its highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy levels were examined. It turned out that the presence of triaminophenylene, dimethoxydiphenylene and fluorine group raises the orbital energies. As a consequence, it is a factor which improves the photovoltaic efficiency of solar cell built on the base of the corresponding PAZ and [6,6] phenyl C61 butyric acid methyl ester (PCBM). On the contrary, quinone, 1,3,5 triazine and perfluorophenylene groups lower orbital energies and have negative influence on the photovoltaic efficiency. Moreover, calculations for methyl, ethyl and butyl analogs of P3HT as well as polythiophenes were performed and compared with the results obtained for PAZs. In addition experimental data are presented, which cover optical, electrochemical and electrical transport properties of the studied PAZs, allowing to determine HOMO and LUMO energies of the polymers and their conductivity. Finally, comparison between calculated and experimental results were made and discussed. PMID- 28364669 TI - Suggestion of BRCA1 c.5339T>C (p.L1780P) variant confer from 'unknown significance' to 'Likely pathogenic' based on clinical evidence in Korea. AB - PURPOSE: We describe a rationale for the re-classification of the BRCA1 c.5539T>C (L1780P) variant using a clinical evidence. METHODS: A retrospective review was conducted to identify all patients with breast or ovarian cancer and the L1780P variant between 2002 and 2015 at a single institution. RESULTS: We identified the BRCA1/2 genetic mutation test results of 1223 breast cancer patients and 174 patients with ovarian cancer. Of the 160 BRCA 1/2 variant unknown significance, 16 (10.0%) patients were identified as having the L1780P variant. Among them, 10 had breast cancer, 4 had ovarian cancer, and 2 had both breast and ovarian cancer. Thirteen (81.3%) patients with this variant had family histories of breast or ovarian cancer. Two (16.7%) also had comorbid ovarian cancer. Two patients with this variant showed that co-segregation of the disease in multiple family members and family histories of breast and ovarian cancer. This variant was found to be either absent or at extremely low frequency in general population databases. CONCLUSION: The L1780P variant might confer to "Likely pathogenic" according to a clinical evidence and the ACMG standards and guidelines. A nation wide or global survey and a functional analysis are needed to confirm the pathogenicity of the L1780P variant. PMID- 28364670 TI - Alcohol consumption and risk of upper-tract urothelial cancer. AB - BACKGROUND: Upper-tract urothelial cancer (UTUC), which includes renal pelvic cancer and ureter cancer, is a rare cancer and its prognosis is poor. Smoking and high-risk occupations (e.g., printing and dyestuff working which involves exposure to aniline dyes) are well-known risk factors for UTUC. However, the risk of alcohol consumption in UTUC remains unclear. This study aimed to determine whether alcohol consumption is an independent risk factor for UTUC. METHODS: The study was a case-control study which used the nationwide clinical inpatient database of the Rosai Hospital group in Japan. We identified 1569 cases and 506,797 controls between 1984 and 2014. We estimated the odds ratio (OR) and 95% confidence interval (95%CI) of alcohol consumption for UTUC - never, up to 15g/day, >15-30g/day, or >30g/day - using unconditional logistic regression. We adjusted for the following covariates: age, sex, study period, hospital, history of smoking, and high-risk occupation. RESULTS: The risk of UTUC was significantly higher in ever-drinkers compared with never-drinkers (OR=1.23, 95%CI, 1.08-1.40; P=0.001). Compared with never-drinkers, the risk threshold for UTUC was >15g of alcohol consumption per day (equivalent to 6 ounces of Japanese sake containing 23g of alcohol). A dose-response was observed (P<0.001). CONCLUSION: Alcohol consumption may be an independent risk factor for UTUC, with a low-risk threshold of 15g of alcohol per day. PMID- 28364671 TI - Social disparities in survival after diagnosis with colorectal cancer: Contribution of race and insurance status. AB - BACKGROUND: Both minority race and lack of health insurance are risk factors for lower survival in colorectal cancer (CRC) but the interaction between the two factors has not been explored in detail. METHODS: One to 5-year survival by race/ethnic group and insurance type for patients with CRC diagnosed in 2007-13 and registered in the Surveillance Epidemiology, and End RESULTS: database were explored. Shared frailty models were computed to further explore the association between CRC specific survival and insurance status after adjustment for demographic and treatment variables. RESULTS: Age-adjusted 5-year survival estimates were 70.4% for non-Hispanic whites (nHW), 62.7% for non-Hispanic blacks (nHB), 70.2% for Hispanics, 64.7% for Native Americans, and 73.1% for Asian/Pacific Islanders (API). Survival was greater for patients with insurance other than Medicaid for all races, but the differential in survival varied with race, with the greatest difference being seen for nHW at +25.0% and +20.2%, respectively, for Medicaid and uninsured versus other insurance. Similar results were observed for stage- and age-specific analyses, with survival being consistently higher for nHW and API compared to other groups. After confounder adjustment, hazard ratios of 1.53 and 1.50 for CRC-specific survival were observed for Medicaid and uninsured. Racial/ethnic differences remained significant only for nHB compared to nHW. CONCLUSIONS: Race/ethnic group and insurance type are partially independent factors affecting survival expectations for patients diagnosed with CRC. NHB had lower than expected survival for all insurance types. PMID- 28364672 TI - Efficacy of a mouthrinse based on hydroxyapatite to reduce initial bacterial colonisation in situ. AB - OBJECTIVE: The present in situ - investigation aimed to specify the impact of pure hydroxyapatite microclusters on initial bioadhesion and bacterial colonization at the tooth surface. DESIGN: Pellicle formation was carried out in situ on bovine enamel slabs (9 subjects). After 1min of pellicle formation rinses with 8ml of hydroxyapatite (HA) microclusters (5%) in bidestilled water or chlorhexidine 0.2% were performed. As negative control no rinse was adopted. In situ biofilm formation was promoted by the intraoral slab exposure for 8h overnight. Afterwards initial bacterial adhesion was quantified by DAPI staining and bacterial viability was determined in vivo/in vitro by live/dead-staining (BacLight). SEM analysis evaluated the efficacy of the mouthrinse to accumulate hydroxyapatite microclusters at the specimens' surface and spit-out samples of the testsolution were investigated by TEM. RESULTS: Compared to the control (2.36*106+/-2.01*106bacteria/cm2), significantly reduced amounts of adherent bacteria were detected on specimens rinsed with chlorhexidine 0.2% (8.73*104+/ 1.37*105bacteria/cm2) and likewise after rinses with the hydroxyapatite testsolution (2.08*105+/-2.85*105bacteria/cm2, p<0.001). No demonstrable effect of HA-particles on Streptococcus mutans viability could be shown. SEM analysis confirmed the temporary adsorption of hydroxyapatite microclusters at the tooth surface. Adhesive interactions of HA-particles with oral bacteria were shown by TEM. CONCLUSION: Hydroxyapatite microclusters reduced initial bacterial adhesion to enamel in situ considerably and could therefore sensibly supplement current approaches in dental prophylaxis. PMID- 28364673 TI - Effect of iRoot SP and mineral trioxide aggregate (MTA) on the viability and polarization of macrophages. AB - OBJECTIVE: This study was performed to investigate the effect of iRoot SP and mineral trioxide aggregate (MTA) on the viability and polarization of macrophages. METHODS: The effect of iRoot SP and MTA on the viability of RAW 264.7 macrophages was tested using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay after 1 and 2days of culture. The gene expression levels of interleukin 1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), interleukin 10 (IL-10), interleukin 12p40 (IL-12p40) were measured by quantitative real time polymerase chain reaction (qRT-PCR) after stimulation of the RAW 264.7 macrophages with iRoot SP and MTA. The expression levels of CD11c and CD206 in RAW 264.7 macrophages were examined by immunofluorescence and flow cytometry after stimulation with iRoot SP and MTA. The data were analyzed by one-way analysis of variance and the Tukey test. RESULTS: Both iRoot SP and MTA were non-toxic to the RAW 264.7 macrophages. The use of iRoot SP and MTA increased the expression of IL-1beta, TNF-alpha, IL-10, IL-12p40 on the first day of culture and could promote macrophage M1 and M2 polarization. CONCLUSIONS: MTA and iRoot SP have good biocompatibility with macrophages, and they induced both M1 and M2 polarization of the RAW 264.7 macrophages. PMID- 28364674 TI - Static postural sway of women with and without fibromyalgia syndrome: A cross sectional study. AB - BACKGROUND: There is a frequent complaint about balance problems among fibromyalgia syndrome patients; however, there are not enough studies that have shown static postural sway of women with fibromyalgia syndrome. This study aimed to compare static postural sway of women with and without fibromyalgia syndrome. METHODS: This is a cross-sectional study in which twenty-nine women with fibromyalgia syndrome and 20 without took part. A posturography evaluation was performed in six different situations (bipedal, right tandem and left tandem, with eyes opened and closed), and questionnaires for clinical depression symptoms, clinical anxiety symptoms, sleep quality, and Visual Analogue Scales for Pain and Fatigue were applied. Mann-Whitney U test was used to check differences among groups; Wilcoxon matched-pair test was used to check differences intragroup; Cohen d coefficient was used to measure effect sizes and Pearson Correlation Coefficient was used for correlations among variables. Level of significance adopted was 5%. FINDINGS: Women with fibromyalgia syndrome have presented worse postural sway than women without fibromyalgia syndrome in all situations (P<0.05), and worse scores in all questionnaires (P<0.05). In the eyes closed situations, women with fibromyalgia syndrome presented worse postural sway than women without in the same conditions. INTERPRETATION: Women with fibromyalgia syndrome have worse performance in the static posture test, more prominent in reduced support bases with eyes closed. Pain, fatigue, depression and anxiety may have directly influenced postural sway in fibromyalgia syndrome patients. PMID- 28364675 TI - Correlation between gait analysis and clinical questionnaires in patients with spontaneous osteonecrosis of the knee. AB - BACKGROUND: Spontaneous osteonecrosis of the knee is usually verified by magnetic resonance imaging accompanied by clinical questionnaires to assess the level of pain and functional limitation. There is a lack however, in an objective functional test that will reflect the functional severity of spontaneous osteonecrosis of the knee. The purpose of the current study was to examine the correlation between spatiotemporal gait parameters and clinical questionnaires in patients with spontaneous osteonecrosis of the knee. METHODS: 28 patients (16 females and 12 males) were included in the analysis. Patients had unilateral spontaneous osteonecrosis of the knee of the medial femoral condyle confirmed by magnetic resonance imaging. All patients performed a computerized spatiotemporal gait analysis and completed the Western Ontario and McMaster University Osteoarthritis Index and the Short-Form 36. Relationships between selected spatiotemporal gait measures and self-assessment questionnaires were assessed by Spearman non-parametric correlations. FINDINGS: Significant correlations were found between selected spatiotemporal gait parameters and clinical questionnaires (r ranged between 0.28 and 0.79). Single limb support was the gait measure with the strongest correlation to pain (r=0.58), function (r=0.56) and quality of life. INTERPRETATION: Spatiotemporal gait assessment for patients with spontaneous osteonecrosis of the knee correlates with the patient's level of pain and functional limitation there by adding objective information regarding the functional condition of these patients. PMID- 28364676 TI - A time-delay neural network for solving time-dependent shortest path problem. AB - This paper concerns the time-dependent shortest path problem, which is difficult to come up with global optimal solution by means of classical shortest path approaches such as Dijkstra, and pulse-coupled neural network (PCNN). In this study, we propose a time-delay neural network (TDNN) framework that comes with the globally optimal solution when solving the time-dependent shortest path problem. The underlying idea of TDNN comes from the following mechanism: the shortest path depends on the earliest auto-wave (from start node) that arrives at the destination node. In the design of TDNN, each node on a network is considered as a neuron, which comes in the form of two units: time-window unit and auto-wave unit. Time-window unit is used to generate auto-wave in each time window, while auto-wave unit is exploited here to update the state of auto-wave. Whether or not an auto-wave leaves a node (neuron) depends on the state of auto-wave. The evaluation of the performance of the proposed approach was carried out based on online public Cordeau instances and New York Road instances. The proposed TDNN was also compared with the quality of classical approaches such as Dijkstra and PCNN. PMID- 28364677 TI - Forecasting stochastic neural network based on financial empirical mode decomposition. AB - In an attempt to improve the forecasting accuracy of stock price fluctuations, a new one-step-ahead model is developed in this paper which combines empirical mode decomposition (EMD) with stochastic time strength neural network (STNN). The EMD is a processing technique introduced to extract all the oscillatory modes embedded in a series, and the STNN model is established for considering the weight of occurrence time of the historical data. The linear regression performs the predictive availability of the proposed model, and the effectiveness of EMD STNN is revealed clearly through comparing the predicted results with the traditional models. Moreover, a new evaluated method (q-order multiscale complexity invariant distance) is applied to measure the predicted results of real stock index series, and the empirical results show that the proposed model indeed displays a good performance in forecasting stock market fluctuations. PMID- 28364679 TI - What do patients rate as most important when cared for in the ICU and how often is this met? - An empowerment questionnaire survey. PMID- 28364678 TI - Effect of neuromuscular stimulation and individualized rehabilitation on muscle strength in Intensive Care Unit survivors: A randomized trial. AB - PURPOSE: Intensive Care Unit (ICU) survivors experience muscle weakness leading to restrictions in functional ability. Neuromuscular electrical stimulation (NMES) has been an alternative to exercise in critically ill patients. The aim of our study was to investigate its effects along with individualized rehabilitation on muscle strength of ICU survivors. MATERIAL AND METHODS: Following ICU discharge, 128 patients (age: 53+/-16years) were randomly assigned to daily NMES sessions and individualized rehabilitation (NMES group) or to control group. Muscle strength was assessed by the Medical Research Council (MRC) score and hand grip at hospital discharge. Secondary outcomes were functional ability and hospital length of stay. RESULTS: MRC, handgrip, functional status and hospital length of stay did not differ at hospital discharge between groups (p>0.05). DeltaMRC% one and two weeks after ICU discharge tended to be higher in NMES group, while it was significant higher in NMES group of patients with ICU acquired weakness at two weeks (p=0.05). CONCLUSIONS: NMES and personalized physiotherapy in ICU survivors did not result in greater improvement of muscle strength and functional status at hospital discharge. However, in patients with ICU-aw NMES may be effective. The potential benefits of rehabilitation strategies should be explored in larger number of patients in future studies. CLINICAL TRIAL REGISTRATION: www.Clinicaltrials.gov: NCT01717833. PMID- 28364681 TI - Specific language impairment in a morphologically complex agglutinative Indian language-Kannada. AB - Specific Language Impairment (SLI) remains an underinvestigated disorder in morphologically complex agglutinative languages such as Kannada. Currently, only a few case reports are available on SLI in Dravidian languages. The morphological complexity inherent to Dravidian languages such as Kannada provides a potential avenue to verify one of the two prevailing accounts of SLI: the morphological richness theory and CGC (Computational Grammatical Complexity) hypothesis. While the previous theory predicts the relatively spared performance of children with SLI (CwSLI) on syntactic morphology in morphologically complex languages, the latter predicts a diametrically opposite performance. Data from a group of 15 Kannada-speaking CwSLI supported the morphological richness theory, and further revealed five distinct profiles of SLI. The results of this study reflected that CwSLI learning the agglutinative language (Kannada) as compared with language matched children without SLI, displayed some shared deficits (e.g., in phonological processing on a non-word repetition task) with CwSLI learning English. However, CwSLI learning the morphosyntactically rich language Kannada differed remarkably from English-learning CwSLI by not showing deficits in syntactic morphology relative to language-matched peers (e.g., PNG, verb, tense, case, and pronoun). PMID- 28364680 TI - Assessment of macro- and micro-oxygenation parameters during fractional fluid infusion: A pilot study. AB - PURPOSE: The main goal of this study was to assess whether maximal fluid infusion improves both oxygen delivery (DO2) and micro-circulatory parameters during hemodilution. The secondary objective was to assess the ability of baseline micro circulatory parameters to predict oxygen consumption (VO2) response following fluid infusion. MATERIALS AND METHODS: In a postoperative cardiac ICU, patients received repeated fluid infusion until stroke volume (SV) was maximized. Before and after each fluid expansion, macro- (DO2, VO2) and micro-circulatory oxygenation parameters were recorded [central venous oxygen saturation (ScVO2), blood lactate, difference in veno-arterial carbon dioxide tension (P(v-a)CO2), somatic and cerebral oxygen saturation (rSO2)]. Patients were classified as VO2 Responders or VO2-Non-Responders according to an increase in VO2 above or below 15%, respectively. RESULTS: After maximal fluid infusion, all patients showed improved macro- and micro-circulatory oxygenation parameters, but VO2-Responders had lower values (especially for ScVO2 and cerebral rSO2). Only baseline ScVO2 and cerebral rSO2 were useful to predict the VO2 response to maximal fluid infusion (ROCAUC 0.80 (95% CI: 0.54-0.95, P=0.012) and 0.83 (95% CI: 0.57-0.96, P=0.001). CONCLUSIONS: Maximal fluid infusion improves macro- and micro circulatory oxygenation parameters. For VO2-Responders, only ScVO2 and cerebral rSO2 could serve as markers of tissue hypoxia. PMID- 28364682 TI - Super-resolved 3-D imaging of live cells' organelles from bright-field photon transmission micrographs. AB - Current biological and medical research is aimed at obtaining a detailed spatiotemporal map of a live cell's interior to describe and predict cell's physiological state. We present here an algorithm for complete 3-D modelling of cellular structures from a z-stack of images obtained using label-free wide-field bright-field light-transmitted microscopy. The method visualizes 3-D objects with a volume equivalent to the area of a camera pixel multiplied by the z-height. The computation is based on finding pixels of unchanged intensities between two consecutive images of an object spread function. These pixels represent strongly light-diffracting, light-absorbing, or light-emitting objects. To accomplish this, variables derived from Renyi entropy are used to suppress camera noise. Using this algorithm, the detection limit of objects is only limited by the technical specifications of the microscope setup-we achieve the detection of objects of the size of one camera pixel. This method allows us to obtain 3-D reconstructions of cells from bright-field microscopy images that are comparable in quality to those from electron microscopy images. PMID- 28364683 TI - EMCD with an electron vortex filter: Limitations and possibilities. AB - We discuss the feasibility of detecting spin polarized electronic transitions with a vortex filter. This approach does not rely on the principal condition of the standard electron energy-loss magnetic chiral dichroism (EMCD) technique, the precise alignment of the crystal in order to use it as a beam splitter, and thus would pave the way for the application of EMCD to new classes of materials and problems, like amorphous magnetic alloys and interface magnetism. The dichroic signal strength at the L2, 3-edge of ferromagnetic Cobalt (Co) is estimated on theoretical grounds using a single atom scattering approach. To justify this approach, multi-slice simulations were carried out in order to confirm that orbital angular momentum (OAM) is conserved in amorphous materials over an extended range of sample thickness and also in very thin crystalline specimen, which is necessary for the detection of EMCD. Also artefact sources like spot size, mask tilt and astigmatism are discussed. In addition, the achievable SNR under typical experimental conditions is assessed. PMID- 28364684 TI - Biophysical and molecular docking approaches for the investigation of biomolecular interactions between amphotericin B and bovine serum albumin. AB - Exogenous drug as an antidote to treat various infections get absorbed in the blood circulatory system of a human can directly contact with transporter proteins such as serum albumin. Therefore, for rational drug discovery, understanding the biomolecular interaction between drugs and protein is highly important. In this contribution, we describe the possible interactions between an antifungal drug Amphotericin B (AmB) and Bovine Serum Albumin (BSA) using multi spectroscopic techniques and further confirmed through in-silico approaches. Binding effects of AmB on BSA conformation, surface morphology, topology, and stability were determined by Ultraviolet-visible spectroscopy (UV), Fourier transform infrared spectroscopy (FT-IR), Circular Dichroism (CD), Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS), Fluorescence Spectroscopy and Molecular dynamic simulations. The Stern-Volmer equation was used to determine the binding site (0.4) and binding constant (8.16*105M-1). The intrinsic intensity of the native BSA was quenched by AmB through static quenching mechanism. The calculated Gibbs free energy value (-8.70kcal/mol) indicated the involvement of hydrogen bonding and hydrophobic contacts in BSA-AmB interaction. The hydrodynamic radii and surface contact area of BSA-AmB molecules are decreasing which can strongly support the stabilizing action of complex particles. Moreover, the finding of this work will provide information for the drug designers to further study the AmB binding mechanism and their pharmacodynamics and pharmacokinetics features in order to achieve better therapeutic efficacy. PMID- 28364685 TI - Effectiveness of one-to-one peer support for patients with severe mental illness a randomised controlled trial. AB - BACKGROUND: One-to-one peer support is a resource-oriented approach for patients with severe mental illness. Existing trials provided inconsistent results and commonly have methodological shortcomings, such as poor training and role definition of peer supporters, small sample sizes, and lack of blinded outcome assessments. METHODS: This is a randomised controlled trial comparing one-to-one peer support with treatment as usual. Eligible were patients with severe mental illnesses: psychosis, major depression, bipolar disorder or borderline personality disorder of more than two years' duration. A total of 216 patients were recruited through in- and out-patient services from four hospitals in Hamburg, Germany, with 114 allocated to the intervention group and 102 to the control group. The intervention was one-to-one peer support, delivered by trained peers and according to a defined role specification, in addition to treatment as usual over the course of six months, as compared to treatment as usual alone. Primary outcome was self-efficacy measured on the General Self-Efficacy Scale at six-month follow-up. Secondary outcomes included quality of life, social functioning, and hospitalisations. RESULTS: Patients in the intervention group had significantly higher scores of self-efficacy at the six-month follow-up. There were no statistically significant differences on secondary outcomes in the intention to treat analyses. CONCLUSIONS: The findings suggest that one-to-one peer support delivered by trained peer supporters can improve self-efficacy of patients with severe mental disorders over a one-year period. One-to-one peer support may be regarded as an effective intervention. Future research should explore the impact of improved self-efficacy on clinical and social outcomes. PMID- 28364686 TI - Childhood trauma and psychotic experiences in a general population sample: A prospective study on the mediating role of emotion regulation. AB - BACKGROUND: The causal role of childhood trauma for psychosis is well established, but the mechanisms that link trauma to psychosis are largely unknown. Since childhood trauma is known to cause difficulties in emotion regulation (ER) and patients with psychosis show impaired ER, we hypothesize that impaired ER explains why people with a background of trauma are prone to psychotic experiences. METHODS: The study used a longitudinal cohort design based on a community sample (N=562) from Germany, Indonesia, and the United States. Childhood trauma was assessed at baseline. ER and psychotic experiences (defined as positive symptom frequency and related distress) were measured repeatedly at a 4-, 8-, and 12-month follow-up. Cross-lagged panel and longitudinal mediation analyses with structural equation modeling were used to test the predictive value of ER on psychotic experiences and its mediating role in the association of childhood trauma and psychotic experiences. RESULTS: The cross-lagged paths from impaired ER to symptom distress (but not frequency) were significant. However, there was also evidence for the reverse causation from symptom frequency and distress to impaired ER. ER partially mediated the significant prospective paths from childhood trauma to symptom distress. CONCLUSION: The findings demonstrate that ER plays a role in translating childhood trauma into distressing psychotic experiences in later life. Moreover, the findings point to a maintenance mechanism in which difficulties in ER and symptom distress exacerbate each other. Thus, ER could be a promising target for interventions aimed at prevention of psychosis. PMID- 28364687 TI - Comorbidity, family history and personality traits in pathological gamblers compared with healthy controls. AB - BACKGROUND: While DSM-5 classified pathological gambling as an addictive disorder, there is debate as to whether ICD-11 should follow suit. The debate hinges on scientific evidence such as neurobiological findings, family history of psychiatric disorders, psychiatric comorbidity, and personality variables. METHODS: In the "Baden-Wurttemberg Study of Pathological Gambling", we compared a group of 515 male pathological gamblers receiving treatment with 269 matched healthy controls. We studied differences in sociodemographic characteristics, gambling-related variables, psychiatric comorbidity (lifetime), family history of psychiatric conditions, as well as personality traits such as impulsivity (Barratt Impulsiveness Scale), sensation seeking (Zuckerman's Sensation Seeking Scale) and the NEO-FFI big five. Personality traits were validated in an age- and ethnicity-matched subsample of "pure" gamblers without any psychiatric comorbidity (including nicotine dependence). Data were analyzed using two-sample t-tests, Chi2 analyses, Fisher's exact test and Pearson correlation analysis, as appropriate. Bonferroni correction was applied to correct for multiple comparisons. RESULTS: Only 1% of the gamblers had been diagnosed with an impulse control disorder other than gambling (ICD-10). Notably, 88% of the gamblers in our sample had a comorbid diagnosis of substance dependence. The highest axis I comorbidity rate was for nicotine dependence (80%), followed by alcohol dependence (28%). Early age of first gambling experience was correlated with gambling severity. Compared to first-degree relatives of controls, first-degree relatives of pathological gamblers were more likely to suffer from alcohol dependence (27.0% vs. 7.4%), pathological gambling (8.3% vs. 0.7%) and suicide attempts (2.7% vs. 0.4%). Significant group differences were observed for the NEO FFI factors neuroticism, agreeableness and conscientiousness. Gamblers were also more impulsive than controls, but did not differ from controls in terms of sensation seeking. CONCLUSIONS: Our findings support classifying pathological gambling as a behavioural addiction in the ICD-11. This decision will have a significant impact on the approaches available for prevention (e.g. age limits) and treatment. PMID- 28364688 TI - The relationship between deinstitutionalization and quality of care in longer term psychiatric and social care facilities in Europe: A cross-sectional study. AB - BACKGROUND: The process of deinstitutionalization (community-based care) has been shown to be associated with better quality of life for those with longer-term mental health problems compared to long stay hospitals. This project aimed to investigate the relationship between national progress towards deinstitutionalization and (1) quality of longer-term mental health care (2) service users' ratings of that care in nine European countries. METHODS: Quality of care was assessed in 193 longer-term hospital- and community-based facilities in Bulgaria, Germany, Greece, Italy, the Netherlands, Poland, Portugal, Spain and the UK. Data on users' ratings of care were collected from 1579 users of these services. Country level variables were compiled from publicly available data. Multilevel models were fit to assess associations with quality of care and service user experiences of care. RESULTS: Significant positive associations were found between deinstitutionalization and (1) five of seven quality of care domains; and (2) service user autonomy. A 10% increase in expenditure was associated with projected clinically important improvements in quality of care. CONCLUSIONS: Greater deinstitutionalization of mental health mental health services is associated with higher quality of care and better service user autonomy. PMID- 28364689 TI - Label-free pharmacological profiling based on dynamic mass redistribution for characterization and authentication of hazardous natural products. AB - Natural products are becoming increasingly popular in multiple fields involving medicines, foods and beverages. However, due to the frequent occurrence of poisoning incidents, their toxicity and safety have caused a serious concern. Here we report a method of biosensor-based two-phase pharmacological profiling (BTPP) for discovery, monitor and control of receptor-targeted natural products. BTPP uses a resonant waveguide grating biosensor for label-free and non-invasive detection of intracellular dynamic mass redistribution (DMR), a phenomenon caused by protein relocalization after receptors receiving stimulation from toxicants. The method can not only facilitate the identification of hazardous materials but also quantify their bioactivity by EC50. As a proof of concept, the method was successfully applied to recognize Daturae Flos (DF), an herb that can antagonize muscarinic acetylcholine M2 receptor and further cause poisoning, from other easily confused species. BTPP combined with high performance liquid chromatography revealed that scopolamine and hyoscyamine in DF were the key marker compounds. Moreover, the method accurately picked out 2 M2 receptor antagonists from 25 natural compounds, displaying its potential in high throughput screening. This study provides a systematic illustration about the establishment, applicability and advantages of BTPP, which contributes to the safety assessment of natural products in related fields. PMID- 28364690 TI - Recanalization rate in patients with proximal vein thrombosis treated with the direct oral anticoagulants. AB - BACKGROUND: The recanalization rate in patients with deep venous thrombosis (DVT) of the legs treated with the direct oral anticoagulants (DOAC) is unknown. METHODS: In an Italian cohort, we investigated the rate of residual vein thrombosis (RVT) after three and/or six months in 352 patients with proximal DVT who had been treated with the DOACs as a stand-alone therapy or lead-in parenteral anticoagulants, and compared it to that recorded in a historical cohort of 1094 patients in which vitamin K antagonists (VKAs) had been employed. In both cohorts, RVT was defined as the ultrasound persistence of thrombotic material resulting in a diameter of at least 4mm of incompressibility of the proximal veins. RESULTS: RVT was detected in 143 patients treated with DOACs (41.2%) after three months and in 58 patients (21.1%) after six months; the corresponding figure in patients treated with conventional anticoagulation was 52.3% and 54.5%, respectively. After adjusting for the baseline characteristics, the odds ratio of RVT in patients treated with the DOACs as compared with those treated with conventional anticoagulation was 0.63 (95% CI, 0.48-0.81) after three months, and 0.17 (95% CI; 0.11-0.26) after six months. CONCLUSIONS: In patients with proximal DVT treated with the DOACs, the persistence of ultrasound detectable RVT is likely to occur less frequently than in patients treated with conventional anticoagulation. These results may have implications for the prognosis of patients with DVT. PMID- 28364691 TI - Incidence of seizures following initial ischemic stroke in a community-based cohort: The Framingham Heart Study. AB - PURPOSE: We examined the incidence of seizures following ischemic stroke in a community-based sample. METHODS: All subjects with incident ischemic strokes in the Framingham Original and Offspring cohorts between 1982 and 2003 were identified and followed for up to 20 years to determine incidence of seizures. Seizure-type was based on the 2010 International League Against Epilepsy (ILAE) classification. Disability was stratified into mild/none, moderate and severe, based on post-stroke neurological deficit documentation according to the Framingham Heart Study (FHS) protocol and functional status was determined using the Barthel Index. RESULTS: An initial ischemic stroke occurred in 469 subjects in the cohort and seizures occurred in 25 (5.3%) of these subjects. Seizure incidence was similar in both large artery atherosclerosis (LAA) (6.8%) and cardio-embolic (CE) (6.2%) strokes. No seizures occurred following lacunar strokes. The predominant seizure type was focal seizure with or without evolution to bilateral convulsive seizure. One third of participants had seizures within the first 24h from stroke onset and half of all seizures occurred within the first 30days. On multivariate analysis, moderate and severe disability following stroke was associated with increased risk of incident seizure. CONCLUSIONS: Seizures occurred in approximately 5% of subjects after an ischemic stroke. One third of these seizures occurred in the first 24h after stroke and none followed lacunar strokes. Focal seizures with or without evolution in bilateral convulsive seizures were the most common seizure type. Moderate and severe disability was predictive of incident seizures. PMID- 28364692 TI - The effect of three angiotensin-converting enzyme inhibitors on kynurenic acid production in rat kidney in vitro. AB - BACKGROUND: The renin-angiotensin system (RAS) is commonly known to regulate blood pressure, water and electrolyte homeostasis, however it also exerts paracrine and autocrine actions on the kidney. Angiotensin-converting enzyme inhibitors (ACE-Is), alongside their hypotensive properties, have been shown to decrease kidney function decline in animal models of nephropathy. Glutamate (GLU) is the main stimulatory neurotransmitter in the central nervous system, however its importance in the periphery should also be considered. Activation of renal GLU receptors has been linked to normal kidney function and also renal injury. The wide spectrum GLU receptor antagonist kynurenic acid (KYNA) possesses neuroprotective and central hypotensive effects, however its actions outside the brain are less well recognized. KYNA is a tryptophan metabolite synthesized from kynurenine by kynurenine aminotransferases (KATs). The purpose of this study was to examine the influence of three ACE-Is: lisinopril, perindopril and ramipril on KYNA production and KATs activity in rat kidney in vitro. METHODS: The effect of ACE-Is on KYNA production and KATs activity was examined in rat kidney homogenates. KYNA was detected by high-performance liquid chromatography (HPLC) and quantified fluorometrically. RESULTS: All examined ACE-Is: lisinopril, perindopril and ramipril decreased KYNA production in rat kidney in vitro. KAT I activity was decreased by lisinopril and ramipril whereas the activity of KAT II was lowered by ramipril. CONCLUSION: Our study shows that ACE-Is can decrease KYNA production in rat kidney in vitro. Further studies are required to determine the clinical importance of the inhibitory action of ACE-Is on KYNA synthesis in the kidney. PMID- 28364693 TI - The sigma1 receptor agonist (+)-pentazocine increases store-operated Ca2+ entry in MCF7sigma1 and SK-N-SH cell lines. AB - BACKGROUND: The intracellular [Ca2+] is modulated by sigma receptors. An important component of the cellular machinery governing the intracellular [Ca2+] is Store-Operated Calcium Entry (SOCE). Here we want to investigate whether ligands of sigma receptors affect SOCE. METHODS: The intracellular [Ca2+] was monitored, with the fluorescent Ca2+-sensitive probe Fura-2, in four cell lines with a different expression of sigma receptors, namely MCF7 (expressing sigma1 receptors with a low density and overexpressing sigma2 receptors), MCF7sigma1 (overexpressing sigma1 receptors), SK-N-SH, and HT-29. RESULTS: When thapsigargin was used to deplete intracellular Ca2+ stores, in a Ca2+-free incubation medium, the Ca2+ influx (following Ca2+ re-addition) was significantly increased by 1MUM (+)-pentazocine (sigma1 receptor agonist) in MCF7sigma1 (by 22.5%) and SK-N-SH (by 45.6%), but not in HT-29 and MCF7 cells. We have used, as a second approach, the "Mn2+ quenching" protocol. In MCF7sigma1 cells, after thapsigargin treatment, the fluorescence quenching induced by Mn2+ influx (evidence of Ca2+ influx) was significantly increased (by 25.8%) by 1MUM (+)-pentazocine, significantly decreased (by 18.0%) by BD1063 (sigma1 receptor antagonist), and not affected by the presence of both ligands. These effects were not observed in MCF7 cells. Finally, in MCF7 cells, 1MUM PB28 (sigma2 receptor agonist), did not affect both the Ca2+ response after Ca2+ re-addition and the fluorescence quenching induced by Mn2+ influx. CONCLUSIONS: We propose that the sigma1 receptor agonist (+) pentazocine increases SOCE in MCF7sigma1 and SK-N-SH cell lines. The sigma2 receptor agonist PB28 does not affect SOCE in MCF7 cells. PMID- 28364694 TI - The role of melatonin, neurokinin, neurotrophic tyrosine kinase and glucocorticoid receptors in antidepressant-like effect. AB - Over the last few decades, depression has become one of the major public health problems in our society. This problem is connected not only with morbidity, but also with treatment, specifically with the effectiveness of the therapy as well as the concomitant side effects of available antidepressants. Major depressive disorder is a complex clinical entity, including different molecular mechanisms and neurological processes. This complexity is a challenge for scientists seeking to discover an innovatory antidepressant drug with multiple and complementary mechanisms of action. In this review, we discuss the role of melatonin, neurokinin, neurotrophic tyrosine kinase and glucocorticoid receptors in depression and antidepressant-like effects. PMID- 28364695 TI - The influence of a single and chronic administration of venlafaxine on tramadol pharmacokinetics in a rabbit model. AB - BACKGROUND: The combined use of tramadol with selective serotonin and norepinephrine reuptake inhibitors e.g. venlafaxine may be associated with serotonin syndrome. No previous studies exist examining the influence of a weak CYP2D6 inhibitor venlafaxine on the pharmacokinetics of tramadol. Therefore, the aim of this study was to determine the effect of a single and chronic administration of venlafaxine on the pharmacokinetics of tramadol using a rabbit model. METHODS: Adult New Zealand white rabbits of both sexes (n=21) were used. Animals received 100mg of tramadol per os (one slow release tablet) and 75mg of venlafaxine (one prolonged release capsule), and were divided into four groups: control group - a single dose of tramadol alone, 1day group - a single dose of tramadol and venlafaxine, 7 and 14days groups - seven and fourteen days administration of venlafaxine once daily plus a single dose of tramadol on the last day of the study. RESULTS: Venlafaxine administration over a period of 7 and 14days resulted in faster elimination of tramadol compared to the control group: significantly higher values of k el, and lower values of t1/2kel and MRT for the 7 and 14days group were observed. Although no differences in bioavailability of tramadol were obtained. CONCLUSION: Using a rabbit model, there is no evidence that the combined administration of tramadol and venlafaxine may increase the plasma exposure of tramadol and therefore increase the risk of serotonin syndrome. PMID- 28364696 TI - Differential effects of liver steatosis on pharmacokinetic profile of two closely related hepatoselective NO-donors; V-PYRRO/NO and V-PROLI/NO. AB - PURPOSE: To analyze the effect of liver steatosis and obesity on pharmacokinetic profile of two structurally-related liver-selective NO-donors - V-PYRRO/NO and V PROLI/NO. METHODS: C57BL/6 mice were fed control or high-fat diet for 15 weeks to induced liver steatosis and obesity (HFD mice). Pharmacokinetics and renal elimination studies were conducted in vivo following iv dosing of V-PYRRO/NO and V-PROLI/NO (0.03mmol/kg). Hepatic clearance was evaluated ex vivo in the isolated perfused mice liver and in vitro with the use of liver microsomes. RESULTS: V PYRRO/NO and V-PROLI/NO, despite similar structure, displayed different pharmacokinetic properties. V-PYRRO/NO was uptaken and metabolized by the liver, while V-PROLI/NO was eliminated unchanged with urine. In HFD mice, despite increased CYP450 metabolism of V-PYRRO/NO the elimination rate was slower most likely due to the impairment of hepatic microcirculation caused by liver fat accumulation. In turn, in HFD mice renal clearence of V-PROLI/NO was accelerated and volume of distribution was increased most likely due to additional intracellular water in HFD mice. CONCLUSIONS: The pharmacokinetics of V-PROLI/NO, the novel proline-based analog of V-PYRRO/NO with additional single carboxylic acid moiety, attached to the molecule of V-PYRRO/NO to improve the water solubility, was differently affected by liver steatosis and obesity as compared with the parent compound V-PYRRO/NO. PMID- 28364697 TI - Antidepressant-like effect of 1,2,3,4-tetrahydroisoquinoline and its methyl derivative in animal models of depression. AB - BACKGROUND: Most of the currently used antidepressant drugs are monoamine-based compounds, acting by the inhibition of re-uptake or metabolism of noradrenaline (NA) and/or serotonin (5-HT), because these neurotransmitters play a key role in the pathophysiology of depression. The aim of this study was to investigate the potential antidepressant-like activity of an endogenous amine, 1,2,3,4 tetrahydroisoquinoline (TIQ) and its close derivative, 1-methyl-1,2,3,4 tetrahydroisoquinoline (1MeTIQ). METHODS: The experiments were carried out on male C57BL6J mice. The antidepressant-like activity of TIQs was evaluated in the behavioral tests: the forced swim test (FST) and tail suspension test (TST) and neurochemical analysis. TIQ and 1MeTIQ were administrated in three differences doses of 10, 25 or 50mg/kg. Imipramine (IMI; 15 or 30mg/kg) was used as a reference drug. In the neurochemical ex vivo study, the levels of NA, 5-HT and their metabolites, the rate of monoamine metabolism and their neuronal activity in different mouse brain structures were determined by HPLC with electrochemical detection. RESULTS: The results of this study have demonstrated that TIQ and 1MeTIQ produced antidepressant-like effect in the FST and TST because they significantly decreased the immobility time comparably to IMI. Biochemical data have demonstrated that administration of TIQs led to the activation of NA and 5 HT systems. CONCLUSIONS: The results reported in this paper indicate that TIQ and 1MeTIQ possess a distinct antidepressant activity. In the light of these findings, we suggest that both tested compounds may be effective for the depression therapy in a clinical setting with better tolerance of side effects. PMID- 28364698 TI - N-Heterocyclic choline analogues based on 1,2,3,4-tetrahydro(iso)quinoline scaffold with anticancer and anti-infective dual action. AB - BACKGROUND: Pharmacological effects of biologically active "small molecules" can be improved by their targeted modification, which affects drug delivery and interaction with tumor cells and microorganisms. We aimed to evaluate anticancer and antimicrobial activity of lipid-like choline derivatives modified via simultaneous introduction of tetrahydro(iso)quinoline based pharmacophore system at nitrogen atom and long chain alkyl substituent at oxygen atom. METHODS: Target compounds were synthesized under phase-transfer catalysis conditions followed by quaternization, and evaluated for cytotoxicity and NO-generation ability on HT 1080 and MG-22A tumor cell lines and NIH 3T3 normal mouse fibroblasts, and screened for antimicrobial activity against gram-positive (Staphylococcus aureus and Bacillus cereus) and gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa and Proteus mirabilis) and fungi (Candida albicans and Aspergillus niger). Inhibitory action of active compounds towards E. coli DNA gyrase was investigated. RESULTS: Target compounds exhibit high selective cytotoxicity (LC50<1MUg/mL) and NO-induction ability, and reveal strong antimicrobial activity with MIC and MBC/MFC values of 0.5-32MUg/mL, predominantly vs. gram-positive bacteria and fungi. Tested substances displayed inhibitory effect towards E. coli DNA gyrase, though less than ciprofloxacin. Tetrahydroisoquinoline derivatives and compounds possessing substituents with chain length of 10 and 11 carbon atoms have highest indices of activities. CONCLUSIONS: Lipid-like N-heterocyclic choline analogues based on 1,2,3,4-tetrahydro(iso)quinoline scaffold, possessing very high cytotoxicity with attendant strong antimicrobial activity are the leads for developing effective dual action therapeutics. PMID- 28364699 TI - Deciphering the influence of column chemistry and mass spectrometry settings for the analyses of geometrical isomers of L-chicoric acid. AB - Resolving the chemo-diversity of plant extract samples is an essential step for in-depth analyses of natural products which often exhibit promising biological activities. One of the challenges in this endeavor has been the confident differentiation of geometrical isomers. In this study, we investigated these aspects in chromatography (column chemistry and mobile phase composition) and mass spectrometry settings with regards to better differentiation of geometrical isomers. A standard of a hydroxycinnamic acid (HCA) derivative, L-chicoric acid (L-CA) - a di-acylated caffeoyltartaric acid ester found in a number of plant families - was used. Geometrical isomers of L-CA were formed by exposing the compound to ultraviolet (UV) radiation, to mimic the natural environment. The high performance liquid chromatography photo-diode array (HPLC-PDA) and ultra high performance liquid chromatography mass spectrometry (UHPLC-MS) platforms were used to analyze the trans and cis geometrical isomers of L-CA. The HPLC-PDA results confirmed the generation of two cis geometrical isomers following UV exposure of the authentic trans-L-CA standard. Furthermore, the HPLC-PDA analyses demonstrated that the changes in both column chemistry (reverse-phase: C18, biphenyl, phenyl-hexyl and pentafluorophenyl propyl) and mobile phase composition (aqueous acetonitrile and aqueous methanol) affect the chromatographic elution profiles of the L-CA isomers. The MS results, on the other hand, revealed undisputed fragmentation differences between the geometrical isomers of L-CA. Thus, this study demonstrates that the identification of the L-CA isomers can be achieved more efficiently and confidently with good chromatography coupled to well-optimized mass spectrometry conditions, a requirement which has been proven impossible with other types of HCA derivatives. Moreover, differences in the binding modes of L-CA geometrical isomers to the HIV type 1 integrase enzyme were observed, suggesting a synergistic anti-HIV-1 activity of these isomers. PMID- 28364700 TI - Pharmacokinetic study of representative anti-oxidative compounds from Denshen Chuanxiong-Honghua following oral administration in rats. AB - Almost no pharmacokinetic compounds to date have been precisely linked with the activity of their herbal or Traditional Chinese Medicine (TCM) formula. This creates challenges for pharmacokinetic significance and application of the TCM. In our study, a sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to quantitatively or qualitatively determine multiple-components (tanshinol, ferulic acid, protocatechuic acid, rosmarinic acid, salvianolic acid B, baicalin and 9'-methyl lithospermate B) in rat plasma following the oral administration of Denshen-Chuanxiong-Honghua (DCH) extract (20g/kg). Chromatographic separation was carried out on a 300SB-C18 column using a gradient elution with a mobile phase composed of acetonitrile water (containing 0.1% formic acid) at a flow rate of 1.0mL/min. Determination by mass spectrometry (MS) was conducted in multiple reaction monitoring (MRM) mode with negative electrospray ionization. The validated method exhibited good linearity, with correlation coefficients greater than 0.9949 over a wide concentration range, and the lower limits of quantification were 2.09-12.2ng/mL for the 5 analytes. This assay was successfully applied to investigate the pharmacokinetics of 5 compounds in rat plasma after the oral administration of DCH extracts. In addition, the anti-oxidant capacities of the 5 active ingredients of DCH extract in vitro and the total absorbed DCH extract in vivo were investigated at different concentrations during pharmacokinetic studies. PMID- 28364701 TI - Restoring function in major depressive disorder: A systematic review. AB - BACKGROUND: Functional impairment contributes to significant disability and economic burden in major depressive disorder (MDD). Treatment response is measured by improvement in depressive symptoms, but functional improvement often lags behind symptomatic improvement. Residual deficits are associated with relapse of depressive symptoms. METHODS: A literature search was conducted using the following terms: "major depressive disorder," "functional impairment," "functional outcomes," "recovery of function," "treatment outcome," "outcome assessment," "social functioning," "presenteeism," "absenteeism," "psychiatric status rating scales," and "quality of life." Search limits included publication date (January 1, 1995 to August 31, 2016), English language, and human clinical trials. Controlled, acute-phase, nonrecurrent MDD treatment studies in adults were included if a functional outcome was measured at baseline and endpoint. RESULTS: The qualitative analysis included 35 controlled studies. The Sheehan Disability Scale was the most commonly used functional assessment. Antidepressant treatments significantly improved functional outcomes. Early treatment response predicted functional improvement, while baseline disease severity did not. LIMITATIONS: Clinical studies utilized various methodologies and assessments for functional impairment, and were not standardized or adequately powered. CONCLUSIONS: The lack of synchronicity between symptomatic and functional improvement highlights an unmet need for MDD. Treatment guided by routine monitoring of symptoms and functionality may minimize residual functional impairments. PMID- 28364702 TI - Multiplexed nanoplasmonic biosensor for one-step simultaneous detection of Chlamydia trachomatis and Neisseria gonorrhoeae in urine. AB - Development of rapid and multiplexed diagnostic tools is a top priority to address the current epidemic problem of sexually transmitted diseases. Here we introduce a novel nanoplasmonic biosensor for simultaneous detection of the two most common bacterial infections: Chlamydia trachomatis and Neisseria gonorrhoeae. Our plasmonic microarray is composed of gold nanohole sensor arrays that exhibit the extraordinary optical transmission (EOT), providing highly sensitive analysis in a label-free configuration. The integration in a microfluidic system and the precise immobilization of specific antibodies on the individual sensor arrays allow for selective detection and quantification of the bacteria in real-time. We achieved outstanding sensitivities for direct immunoassay of urine samples, with a limit of detection of 300 colony forming units (CFU)/mL for C. trachomatis and 1500CFU/mL for N. gonorrhoeae. The multiplexing capability of our biosensor was demonstrated by analyzing different urine samples spiked with either C. trachomatis or N. gonorrhoeae, and also containing both bacteria. We could successfully detect, identify and quantify the levels of the two bacteria in a one-step assay, without the need for DNA extraction or amplification techniques. This work opens up new possibilities for the implementation of point-of-care biosensors that enable fast, simple and efficient diagnosis of sexually transmitted infections. PMID- 28364703 TI - A sensitive immunosensor via in situ enzymatically generating efficient quencher for electrochemiluminescence of iridium complexes doped SiO2 nanoparticles. AB - A sensitive electrochemiluminescent (ECL) sandwich immunosensor was proposed herein based on the tris (2-phenylpyridine) iridium [Ir(ppy)3] doped silica nanoparticles (SiO2@Ir) with improved ECL emission as signal probes and glucose oxidase (GOD)-based in situ enzymatic reaction to generate H2O2 for efficiently quenching the ECL emission of SiO2@Ir. Typically, the SiO2@Ir not only increased the loading amount of Ir(ppy)3 as ECL indicators with high ECL emission, but also improved their water-solubility, which efficiently enhanced the ECL emission. Furthermore, by the efficient quench effect of H2O2 from in situ glucose oxidase (GOD)-based enzymatic reaction on the ECL emission of SiO2@Ir, a signal-off ECL immunsensor could be established for sensitive assay. With N-terminal of the prohormone brain natriuretic peptide (BNPT) as a model, the proposed ECL assay performed high sensitivity and low detection limit. Importantly, the proposed sensitive ECL strategy was not only suitable for the detection of BNPT for acute myocardial infarction, but also revealed a new avenue for early diagnosis of various diseases via proteins, nucleotide sequence, microRNA and cells. PMID- 28364704 TI - A long-lived phosphorescence iridium(III) complex as a switch on-off-on probe for live zebrafish monitoring of endogenous sulfide generation. AB - In this work, we report a novel iridium(III)-based luminescent switch on-off-on probe, for the in vitro and in vivo detection of sulfide ion. The mechanism of this platform is based on the effective charge transfer quenching of the iridium(III) complex 1 by Fe3+, followed by the restoration of luminescence upon the addition of Na2S. The probe, hereinafter referred to as 1-Fe3+, exhibited a linear range of detection for Na2S from 0.01 to 1.5mM, with a detection limit of 2.9MUM at signal-to-noise ratio (S/N) of 3. We also demonstrate the utility of 1 Fe3+ for cell-based imaging as well as for the detection of enzymatic sulfide generation in living zebrafish. PMID- 28364705 TI - A simple stripping voltammetric method for the determination of a new anticancer prodrug in serum. AB - The determination of ethyl [4-oxo-8-(3-chlorophenyl)-4,6,7,8 tetrahydroimidazo[2,1-c][1,2,4]triazin-3-yl]acetate (ETTA), a new anticancer prodrug, using adsorptive stripping voltammetry (AdSV) was described for the first time. This method is based on adsorptive/reductive behaviour of ETTA at an in situ plated bismuth film electrode (BiFE) as a sensor. A number of experimental variables (e.g., a composition and pH of the supporting electrolyte, the conditions of bismuth film deposition, an accumulation potential and time, the scan rate, etc.) were thoroughly studied in order to achieve a high sensitivity. Experimental results under optimized conditions revealed an excellent linear correlation between the monitored voltammetric peak current and the ETTA concentration in the range of 2-50MUgL-1 following an accumulation time of 300s. The limit of detection (LOD) for ETTA following 300s of an accumulation time was 0.4MUgL-1. The proposed facile, sensitive and inexpensive method was successfully applied to the determination of ETTA in serum. The investigated prodrug was extracted from serum using SPE method. PMID- 28364706 TI - Biosensor for detection of dissolved chromium in potable water: A review. AB - The unprecedented deterioration rate of the environmental quality due to rapid urbanization and industrialization causes a severe global health concern to both ecosystem and humanity. Heavy metals are ubiquitous in nature and being used extensively in industrial processes, the exposure to excessive levels could alter the biochemical cycles of living systems. Hence the environmental monitoring through rapid and specific detection of heavy metal contamination in potable water is of paramount importance. Various standard analytical techniques and sensors are used for the detection of heavy metals include spectroscopy and chromatographic methods along with electrochemical, optical waveguide and polymer based sensors. However, the mentioned techniques lack the point of care application as it demands huge capital cost as well as the attention of expert personnel for sample preparation and operation. Recent advancements in the synergetic interaction among biotechnology and microelectronics have advocated the biosensor technology for a wide array of applications due to its characteristic features of sensitivity and selectivity. This review paper has outlined the overview of chromium toxicity, conventional analytical techniques along with a particular emphasis on electrochemical based biosensors for chromium detection in potable water. This article emphasized porous silicon as a host material for enzyme immobilization and elaborated the working principle, mechanism, kinetics of an enzyme-based biosensor for chromium detection. The significant characteristics such as pore size, thickness, and porosity make the porous silicon suitable for enzyme entrapment. Further, several schemes on porous silicon-based immobilized enzyme biosensors for the detection of chromium in potable water are proposed. PMID- 28364707 TI - Nuclease-free target recycling signal amplification for ultrasensitive multiplexing DNA biosensing. AB - Ultrasensitive biosensing technologies without gene amplification held great promise for direct detection of DNA. Herein we report a novel biosensing method, combining target recycling signal-amplification strategy and a homemade electrochemical device. Especially, the target recycling was achieved by a strand displacement process, no needing the help of any nucleases. In the presence of target DNA, the recycling system could be activated to generate a cascade of assembly steps with three hairpin DNA segments. Each recycling process were accompanied by a disassembly step that the last hairpin DNA segment displaces target DNA from the complex at the end of each circulation, freeing targets to activate the self-assembly of more trefoil DNA structures. This biosensing method could detect target DNA at aM level and can distinguish target DNA from interfering DNAs, demonstrating its high sensitivity and high selectivity. Importantly, the biosensing method could work well with serum samples. PMID- 28364708 TI - Evaluation of buffers toxicity in tobacco cells: Homopiperazine-1,4-bis (2 ethanesulfonic acid) is a suitable buffer for plant cells studies at low pH. AB - Low pH is an important environmental stressor of plant root cells. Understanding the mechanisms of stress and tolerance to acidity is critical; however, there is no widely accepted pH buffer for studies of plant cells at low pH. Such a buffer might also benefit studies of Al toxicity, in which buffering at low pH is also important. The challenge is to find a buffer with minimal cellular effects. We examined the cytotoxicity and possible metabolic disturbances of four buffers that have adequate pKa values and potential use for studies in the pH range of 4.0-5.0. These were homopipes (homopiperazine-1,4-bis (2-ethanesulfonic acid); pKa1 4.4), 3,3-dimethylglutaric acid (pKa1 3.73), beta-alanine (pKa1 3.70) and potassium biphthalate (pKa1 2.95; pKa2 5.41). First, tobacco BY-2 cells were grown in a rich medium containing 10 mM of each buffer or MES (2-(N-morpholino) ethanesulfonic acid) as a control, with the pH initially adjusted to 5.7. beta alanine was clearly toxic and dimethylgluturate and biphthalate were found to be cytostatic, in which no culture growth occurred but cell viability was either unaffected or decreased only after 5 days. Only homopipes allowed normal culture growth and cell viability. Homopipes (10 mM) was then tested in cell cultures with an initial pH of 4.3 +/- 0.17 in minimal medium to examine whether its undissociated species (H2A) displayed any cellular effects and no cytotoxic effects were observed. It is possible to conclude that among tested buffers, homopipes is the most suitable for studies at low pH, and may be especially useful for aluminum toxicity experiments. PMID- 28364709 TI - Approaches in modulating proline metabolism in plants for salt and drought stress tolerance: Phytohormones, mineral nutrients and transgenics. AB - Major abiotic stress factors such as salt and drought adversely affect important physiological processes and biochemical mechanisms and cause severe loss in crop productivity worldwide. Plants develop various strategies to stand healthy against these stress factors. The accumulation of proline (Pro) is one of the striking metabolic responses of plants to salt and drought stress. Pro biosynthesis and signalling contribute to the redox balance of cell under normal and stressful conditions. However, literature is meager on the sustainable strategies potentially fit for modulating Pro biosynthesis and production in stressed plants. Considering the recent literature, this paper in its first part overviews Pro biosynthesis and transport in plants and also briefly highlights the significance of Pro in plant responses to salt and drought stress. Secondly, this paper discusses mechanisms underlying the regulation of Pro metabolism in salt and drought-exposed plant via phytohormones, mineral nutrients and transgenic approaches. The outcome of the studies may give new opportunities in modulating Pro metabolism for improving plant tolerance to salt and drought stress and benefit sustainable agriculture. PMID- 28364710 TI - Aluminum induced physiological and proteomic responses in tea (Camellia sinensis) roots and leaves. AB - Tea (Camellia sinensis (L.) O. Kuntze), is an aluminum (Al) hyperaccumulator and grows well in acid soils. Although Al-induced growth of tea plant has been studied, the proteomic profiles of tea plants in response to Al are unclear. In the present study, the proteomic profiles in tea roots and leaves under Al stress were investigated using iTRAQ proteomics approach. In total, 755 and 1059 differentially expressed proteins were identified in tea roots and leaves, respectively. KEGG enrichment analysis showed that the differentially expressed proteins in roots were mainly involved in 11 pathways whereas those from leaves were mainly involved in 9 pathways. Abundance of most protein functions in glycolytic metabolism were enhanced in tea roots, and proteins involved in photosynthesis were stimulated in tea leaves. The protein ferulate-5-hydroxylase (F5H) in lignin biosynthetic pathway was down-regulated in both roots and leaves. Furthermore, antioxidant enzymes (ascorbate peroxidase, catalase and glutathione S-transferase) and citrate synthesis were accumulated in tea roots in response to Al. The results indicated that active photosynthesis and glycolysis as well as increased activities of antioxidant enzymes can be considered as a possible reason for the stimulatory effects of Al on the growth of tea plants. Additionally, the down-regulation of F5H and the binding of Al and phenolic acids may reduce the accumulation of lignin. PMID- 28364712 TI - Economic growth, CO2 emissions, renewable waste and FDI relation in Pakistan: New evidences from 3SLS. AB - First attempt has been made to find the effects of foreign direct investment on environmental pollution and economic growth, in addition to finding the determinants of foreign direct investment inflows in Pakistan using the annual data set for the period of 1980-2014. Simultaneous equation model has been used to find relation between the variables of concern. Results from technique and composition effects show that increase in economic growth leads towards more pollution emissions. Scale effect shows stock of capital and labor have positive effect on the economic growth of Pakistan while pollution has negative effect on growth. In case of capital accumulation effect, economic growth and foreign direct investment have positive and significant effect on stock of capital. Although increase in economic growth increases pollution, however, economic growth declines as pollution crosses a certain limit. Foreign direct investment is also found positively related with pollution. PMID- 28364711 TI - Distribution of natural and anthropogenic radionuclides in northwest Mediterranean coastal sediments. AB - The distribution of radionuclides in NW Mediterranean coastal sediments, and the processes controlling their abundance were investigated in three cores taken near the island of Porquerolles and one offshore Monaco. The sediments collected near Porquerolles were strongly anoxic due to diagenetic processes involved in the decomposition of organic matter, whereas they transitioned from oxic to anoxic at a depth of 4 cm beneath the seawater interface at Monaco. Organic carbon (OC) was more abundant in sediments at Porquerolles (by about a factor of 3-5) than at Monaco and elsewhere in the coastal NW Mediterranean. Sediment cores collected NE of Porquerolles also possessed elevated uranium concentrations that correlated with high OC content and strong reducing conditions. The 239,240Pu and 241Am activities in surficial sediments ranged from 1 to 5.7 Bq kg-1 and 0.3 to 1 Bq kg 1, respectively, while the 137Cs activity ranged from 0.3 to 6.2 Bq kg-1. The mean activity ratios of 241Am/239,240Pu and 238Pu/239,240Pu in Porquerolles and Monaco sediments were similar to the global fallout ratios. Sediment inventories of global fallout 239,240Pu (430-800 Bq m-2) and 241Am (150-285 Bq m-2) were by about a factor of 5-10 higher at Porquerolles, whereas the inventory of 137Cs (430-1000 Bq m-2) was substantially lower at the investigated stations than have been reported elsewhere at similar latitudes. Specific local conditions characterised by high OC sediment loads due to the growth and mortality of Posidonia oceanica have been responsible for deposition of large amounts of seagrass tissues at the NE corner of Porquerolles, which have had a profound effect on the distribution of radionuclides in the sediments. PMID- 28364713 TI - Variations in judgments of intentional action and moral evaluation across eight cultures. AB - Individuals tend to judge bad side effects as more intentional than good side effects (the Knobe or side-effect effect). Here, we assessed how widespread these findings are by testing eleven adult cohorts of eight highly contrasted cultures on their attributions of intentional action as well as ratings of blame and praise. We found limited generalizability of the original side-effect effect, and even a reversal of the effect in two rural, traditional cultures (Samoa and Vanuatu) where participants were more likely to judge the good side effect as intentional. Three follow-up experiments indicate that this reversal of the side effect effect is not due to semantics and may be linked to the perception of the status of the protagonist. These results highlight the importance of factoring cultural context in our understanding of moral cognition. PMID- 28364715 TI - A novel method for the quantitative determination of defects on graphene surfaces. AB - In this work, a novel method for the quantitative determination of defects on graphene surfaces has been presented in order to provide accurate, reliable and quantitative information for the defects on graphene products. It was based on the selective adsorption of a specific polar organic ion (Sodium benzenesulfonate) on the edges and defects on graphene surfaces, and the atomic force microscopy (AFM) imaging of the adsorption. By means of an image processing software, the AFM images could be analyzed and the areas as well as area percentages of the defects on the graphene surfaces could be determined. PMID- 28364714 TI - Enhancing the colloidal stability of detonation synthesized diamond particles in aqueous solutions by adsorbing organic mono-, bi- and tridentate molecules. AB - Colloidal stability of nanoparticles with particle sizes smaller than 100nm is a critical issue for various research areas, including material science, electronics and biomedicine. We propose a facile, fast and cost-efficient method to increase the colloidal stability by simply adding organic molecules as ligands, which adsorb to the nanoparticle surface subsequently. Citric acid, oxalic acid, glutamic acid and propylamine were found to stabilize the nanodiamond (ND) particles with a mean diameter of approx. 30-100nm. The charge of the particles could be controlled by the pH of the dispersions and by stabilizing with carboxylic acids or amino acids mentioned above. ND particles stabilized with citric acid and oxalic acid at a pH higher than 2.5 were negatively charged, while ND dispersions stabilized with glutamic acid were charged positively below a pH of 3.2. Furthermore, the stability of the dispersion was found to be dependent on the concentration of the stabilizing agent and the pH of the dispersion. Finally, we proposed the stabilizing mechanism of ND particles with propylamine. Glutamic acid and propylamine stabilized ND dispersions can be utilized for high seeding densities on negatively charged surfaces due to the amino-groups, which can be helpful for adsorption processes in electronics and material science. Due to the high biocompatibility, non-cytotoxicity and chemical inertness of ND particles, carboxylic acids and amino acids stabilized ND particles are envisaged to be useful in the biomedical field, i.e. bio-labels, drug delivery vehicles, and effective enterosorbent. PMID- 28364716 TI - Highly sensitive gold-decorated zinc oxide nanorods sensor for triethylamine working at near room temperature. AB - There is an increasing worldwide demand for chemiresistive sensors for specific gas working at low temperature, in particular for standalone and mobile systems, which call for small and low power devices. In this paper, we successfully assemble highly sensitive triethylamine (TEA) gas sensors working at near-room temperature with gold (Au)-decorated ZnO nanorods. ZnO nanorods grow directly on flat Al2O3 ceramic electrodes by a cost-effective hydrothermal method and Au nanoparticles are deposited onto ZnO nanorods by DC-sputtering. Au-loaded ZnO (Au/ZnO) nanorods sensor at working temperature of 40 degrees C and relative humidity of 30% exhibits high response (22-50ppm TEA), low detection concentration (~1ppm), and short response/recovery time (11s/15s), which are all much better than the pristine ZnO nanorods sensor. When the relative humidity increases, the sensor response decreases due to the water molecules adsorption. Moreover, the enhanced sensing properties of the Au/ZnO sensors are discussed in detail with the semiconductor depletion layer model introduced by the Au/ZnO Schottky contact and the catalytic effect of noble gold nanoparticles. PMID- 28364717 TI - Investigating the size effect of Au nanospheres on the photocatalytic activity of Au-modified ZnO nanorods. AB - Plasmonic nanostructures of semiconductors and noble metal nanospheres (NSs) hold great promise in the applications of solar energy conversion. Although it is known that the size of NSs plays a critical role in determining the photocatalytic performance of the resultant nanohybrids, the actual effects depend on multiple variables and needs to be elucidated for each specific scenario. Herein, ZnO nanorods (NRs) modified with AuNSs of diameters varying from 20 to 80nm have been prepared to investigate the size effect of AuNSs on the photocatalytic activity of Au-ZnO hybrids. Interestingly, the Au-ZnONRs with 40 nm AuNSs demonstrate higher photocatalytic activity than the nanohybrids with AuNSs of either smaller or larger sizes. A possible "trade-off" mechanism between efficient charge transfer for smaller NSs and stronger LSPR effect for larger ones is proposed. PMID- 28364718 TI - Determination of 4-nitrophenol in water by use of a screen-printed carbon electrode modified with chitosan-crafted ZnO nanoneedles. AB - The toxicity and environmental pollution by nitro aromatic compounds in water samples is the most recognized problem in worldwide. Hence, we have developed a simple and highly sensitive electrochemical method for the determination of 4 nitrophenol (4-NP) in water samples based on a chitosan (CHT) crafted zinc oxide nanoneedles (ZnO NDs) modified screen printed carbon electrode. The CHT/ZnO NDs were characterized by Field emission scanning electron microscope, Fourier transform infrared spectroscopy and X-ray diffraction technique. The CHT/ZnO NDs modified electrode showed an enhanced electrocatalytic activity and lower potential detection towards 4-NP, compared with other modified electrodes. Under optimum conditions, the differential pulse voltammetry (DPV) response of CHT/ZnO NDs modified electrode displayed a wide linear response range from 0.5 to 400.6MUM towards the detection of 4-NP with a detection limit (LOD) of 0.23MUM. The CHT/ZnO NDs modified electrode was used for specific and sensitive detection of 4-NP in presence of possible interfering species and common metal ions with long-term stability. In addition, the excellent analytical performance of the proposed sensor was successfully applied for determination of 4-NP in water samples. PMID- 28364719 TI - Biosynthesis and application of Ag/bone nanocomposite for the hydration of cyanamides in Myrica gale L. extract as a green solvent. AB - This study focuses on the green synthesis of the Ag/bone nanocomposite by using Myrica gale L. aqueous extract as a reducing and stabilizing agent and investigation of its catalytic activity in the hydration of cyanamides under environmentally benign reaction conditions in aqueous extract as a green solvent without use of toxic and hazardous chemicals. The green synthesized Ag/bone nanocomposite was characterized by various analytical techniques such as X-ray diffraction analysis (XRD), field emission scanning electron microscope (FESEM), transmission electron microscopy (TEM) images, energy-dispersive X-ray spectroscopy (EDS), elemental mapping, and FT-IR spectroscopy. The advantages of this system include the use of green catalyst, benign reaction conditions without use of expensive and hazardous materials, easy work up, reusability of the catalyst and excellent yield of the products. The Ag/bone nanocomposite can be recovered and recycled several times without significant loss of activity. PMID- 28364721 TI - Effects of environmental temperature on oviposition behavior in three blow fly species of forensic importance. AB - A number of factors are known to affect blow fly behavior with respect to oviposition. Current research indicates that temperature is the most significant factor. However temperature thresholds for oviposition in forensically important blow flies have not been well studied. Here, the oviposition behavior of three species of forensically important blow fly species (Calliphora vicina, Calliphora vomitoria and Lucilia sericata,) was studied under controlled laboratory conditions over a range of temperatures (10-40 degrees C). Lower temperature thresholds for oviposition of 16 degrees C and 17.5 degrees C were established for C. vomitoria and L. sericata respectively, whilst C. vicina continued to lay eggs at 10 degrees C. C. vomitoria and L. sericata both continued to lay eggs at 40 degrees C, whilst the highest temperature at which oviposition occurred in C. vicina was 35 degrees C. Within these thresholds there was considerable variation in the number of surviving pupae, with a general pattern of a single peak within the range of temperatures at which eggs were laid, but with the pattern being much less distinct for L. sericata. PMID- 28364720 TI - Metal oxide surfaces for enhanced colorimetric response in bioassays. AB - Physical stability of metal nanoparticle films on planar surfaces can be increased by employing surface modification techniques and/or type of metal nanoparticles. Subsequently, the enzymatic response of colorimetric bioassays can be increased for improved dynamic range for the detection of biomolecules. Using a model bioassay b-BSA, three planar platforms (1) poly (methyl methacrylate) (PMMA) with silver thin films (STFs), (2) silver nanowires (Ag NWs) on paper and (3) indium tin oxide (ITO) on polyethylene terephthalate (PET) were evaluated to investigate the extent of increase in the colorimetric signal. Bioassays for b BSA and Ki-67 antigen (a real-life bioassay) in buffer were performed using microwave heating (total assay time is 25-30min) and at room temperature (a control experiment, total assay time is 3h). Model bioassays showed that STFs were removed from the surface during washing steps and the extent of ITO remained unchanged. The lowest level of detection (LLOD) for b-BSA bioassays were: 10-10M for 10nm STFs on PMMA and Ag NWs on paper and 10-11M for ITO. Bioassays for Ki-67 antigen yielded a LLOD of <10-9M on ITO platforms, while STFs platforms were deemed unusable due to significant loss of STFs from the surfaces. PMID- 28364722 TI - Examining Authenticity: An Initial Exploration of the Suitability of Handwritten Electronic Signatures. AB - Considering the increasing relevance of handwritten electronically captured signatures, we evaluated the ability of forensic handwriting examiners (FHEs) to distinguish between authentic and simulated electronic signatures. Sixty-six professional FHEs examined the authenticity of electronic signatures captured with software by signotec on a smartphone Galaxy Note 4 by Samsung and signatures made with a ballpoint pen on paper (conventional signatures). In addition, we experimentally varied the name ("J. Konig" vs. "A. Zaiser") and the status (authentic vs. simulated) of the signatures in question. FHEs' conclusions about the authenticity did not show a statistically significant general difference between electronic and conventional signatures. Furthermore, no significant discrepancies between electronic and conventional signatures were found with regard to other important aspects of the authenticity examination such as questioned signatures' graphic information content, the suitability of the provided sample signatures, the necessity of further examinations and the levels of difficulty of the cases under examination. Thus, this study did not reveal any indications that electronic signatures captured with software by signotec on a Galaxy Note 4 are less well suited than conventional signatures for the examination of authenticity, precluding potential technical problems concerning the integrity of electronic signatures. PMID- 28364723 TI - Tumefactive demyelination associated with developmental venous anomaly: Report of two cases. AB - We present two cases of tumefactive demyelination (TD) occurring in close association with a developmental venous anomaly (DVA). Our purpose is to describe the association between demyelinating lesions and venous anomalies, as only one case of TD associated with a DVA has been published in the literature. Appropriate recognition of this "do not touch" lesion may avoid invasive and potentially harmful procedures such as biopsy or resection. PMID- 28364724 TI - Magnetic resonance imaging characteristics of granulomatous mastitis. AB - Granulomatous mastitis (GM) is a benign chronic inflammatory condition of the breast. This study was performed to determine the utility of magnetic resonance imaging (MRI) in differentiating GM from malignancy. MRI findings in 12 women with clinical or histopathologically-proven GM were retrospectively reviewed. Non mass enhancement on MRI was present in all 12 patients with clustered ring enhancement being the most common pattern (n=7, 58%). Architectural distortion (n=10, 83%), skin thickening (n=10, 83%) and focal skin enhancement (n=10, 83%) were also very common. MRI features of GM are often identical to features considered suspicious for malignancy on MRI. PMID- 28364725 TI - Iron assimilation and utilization in anaerobic ammonium oxidizing bacteria. AB - The most abundant transition metal in biological systems is iron. It is incorporated into protein cofactors and serves either catalytic, redox or regulatory purposes. Anaerobic ammonium oxidizing (anammox) bacteria rely heavily on iron-containing proteins - especially cytochromes - for their energy conservation, which occurs within a unique organelle, the anammoxosome. Both their anaerobic lifestyle and the presence of an additional cellular compartment challenge our understanding of iron processing. Here, we combine existing concepts of iron uptake, utilization and metabolism, and cellular fate with genomic and still limited biochemical and physiological data on anammox bacteria to propose pathways these bacteria may employ. PMID- 28364726 TI - Long-term clinical outcomes and economic evaluation of the ketogenic diet versus care as usual in children and adolescents with intractable epilepsy. AB - OBJECTIVE: To examine long-term retention rate, clinical outcomes, cost-utility and cost-effectiveness of the Ketogenic Diet (KD) compared with care as usual (CAU) in children and adolescents with intractable epilepsy from a societal perspective. METHODS: Participants were randomized into a KD or CAU group. Seizure frequency, quality adjusted life years (QALYs), side-effects, seizure severity, health care costs, production losses, patient and family costs were assessed at baseline and during 16-months of follow-up. Incremental cost effectiveness ratios (ICERs) (i.e. cost per QALY and cost per responder) and cost effectiveness acceptability curves are presented. RESULTS: 48 children were included in the analyses of this study (26 from KD group). In total, 58% of the KD group completed the follow-up of 16 months; 11 dropped-out for various reasons. At 16 months, 35% of the KD participants had a seizure reduction>=50% from baseline, compared with 18% of the CAU participants. Mean costs per patient in the CAU group were ?53,367 (extrapolated) compared to ?61,019 per patient in the KD group, resulting in an ICER of ?46,564 per responder. Cost per QALY rose well above any acceptable ceiling ratio. At 4-months' follow-up, the KD group showed significantly more gastro-intestinal problems compared to the CAU group. At 16 months, the KD group reported fewer problems compared to CAU. Furthermore, 46.2% of the KD group reported a decrease in severity of their worst seizure compared to 32% of the CAU group. CONCLUSION: The KD group resulted in more responders and showed greater improvement on seizure severity. Furthermore, the KD did not lead to worsening of side-effects other than gastro-intestinal problems (only at 4 months' follow-up). However, as only a minimal difference in QALYs was found between the KD group and the CAU group, the resulting cost per QALY ratios were inconclusive. PMID- 28364728 TI - Microbial ecology of fermentative hydrogen producing bioprocesses: useful insights for driving the ecosystem function. AB - One of the most important biotechnological challenges is to develop environment friendly technologies to produce new sources of energy. Microbial production of biohydrogen through dark fermentation, by conversion of residual biomass, is an attractive solution for short-term development of bioH2 producing processes. Efficient biohydrogen production relies on complex mixed communities working in tight interaction. Species composition and functional traits are of crucial importance to maintain the ecosystem service. The analysis of microbial community revealed a wide phylogenetic diversity that contributes in different-and still mostly unclear-ways to hydrogen production. Bridging this gap of knowledge between microbial ecology features and ecosystem functionality is essential to optimize the bioprocess and develop strategies toward a maximization of the efficiency and stability of substrate conversion. The aim of this review is to provide a comprehensive overview of the most up-to-date biodata available and discuss the main microbial community features of biohydrogen engineered ecosystems, with a special emphasis on the crucial role of interactions and the relationships between species composition and ecosystem service. The elucidation of intricate relationships between community structure and ecosystem function would make possible to drive ecosystems toward an improved functionality on the basis of microbial ecology principles. PMID- 28364727 TI - Hypothalamic-pituitary-adrenal axis genetic variation and early stress moderates amygdala function. AB - Early life stress may precipitate psychopathology, at least in part, by influencing amygdala function. Converging evidence across species suggests that links between childhood stress and amygdala function may be dependent upon hypothalamic-pituitary-adrenal (HPA) axis function. Using data from college attending non-Hispanic European-Americans (n=308) who completed the Duke Neurogenetics Study, we examined whether early life stress (ELS) and HPA axis genetic variation interact to predict threat-related amygdala function as well as psychopathology symptoms. A biologically-informed multilocus profile score (BIMPS) captured HPA axis genetic variation (FKBP5 rs1360780, CRHR1 rs110402; NR3C2 rs5522/rs4635799) previously associated with its function (higher BIMPS are reflective of higher HPA axis activity). BOLD fMRI data were acquired while participants completed an emotional face matching task. ELS and depression and anxiety symptoms were measured using the childhood trauma questionnaire and the mood and anxiety symptom questionnaire, respectively. The interaction between HPA axis BIMPS and ELS was associated with right amygdala reactivity to threat related stimuli, after accounting for multiple testing (empirical-p=0.016). Among individuals with higher BIMPS (i.e., the upper 21.4%), ELS was positively coupled with threat-related amygdala reactivity, which was absent among those with average or low BIMPS. Further, higher BIMPS were associated with greater self reported anxious arousal, though there was no evidence that amygdala function mediated this relationship. Polygenic variation linked to HPA axis function may moderate the effects of early life stress on threat-related amygdala function and confer risk for anxiety symptomatology. However, what, if any, neural mechanisms may mediate the relationship between HPA axis BIMPS and anxiety symptomatology remains unclear. PMID- 28364732 TI - Effects of antibiotic concentration and nutrient medium composition on Escherichia coli biofilm formation and green fluorescent protein expression. AB - Recombinant protein production processes have to maximise yield while minimising cost, which involves balancing plasmid maintenance with cell growth and protein expression. The aim of this study was to analyse the influence of two factors on heterologous protein production in Escherichia coli biofilm cells-the concentration of antibiotic used to maintain the selective pressure and the nutrient medium composition. Escherichia coli JM109(DE3) cells transformed with plasmid pFM23 for enhanced green fluorescent protein (eGFP) expression and containing a kanamycin resistance gene were used. They were exposed to 20 or 30 MUg mL-1 kanamycin during biofilm growth in two different culture media, a diluted medium (DM) or the lysogeny broth (LB). The higher antibiotic concentration increased the specific eGFP production in planktonic cells, whereas no increase was detected in biofilm cells. Biofilm formation was increased in DM when compared to LB. Nevertheless, bacteria grown in LB had higher eGFP production than those grown in DM in both planktonic and sessile states (20-fold and 2-fold, respectively). Therefore, among the conditions tested, LB supplemented with 20 MUg mL-1 kanamycin was the most advantageous medium to obtain the highest specific eGFP production in biofilm cells. PMID- 28364731 TI - Clonal diversity of extended-spectrum beta-lactamase producing Escherichia coli isolates in fecal samples of wild animals. AB - The clonal diversity of extended-spectrum-beta-lactamase (ESBL)-producing Escherichia coli isolates from nine different species of wild animals from distinct regions of Portugal and Spain and their content in replicon plasmids were analyzed. Among the initial 53 ESBL-producing E. coli isolates that were studied (from previous studies), 28 were selected, corresponding to different animal origins with distinct ESBL types and pulsed-field gel electrophoresis (PFGE) patterns. These 28 isolates produced different ESBLs ascribed to the following families: CTX-M, SHV and TEM. The isolates were classified into three phylogenetic groups: B1 (n = 11), A (n = 10) and D (n = 7). The seven E. coli of phylogroup D were then typed by multilocus sequence typing and ascribed to four distinct sequence types: ST117, ST115, ST2001 and ST69. The clonal diversity and relationship between isolates was studied by PFGE. Lastly, the plasmids were analyzed according to their incompatibility group using the PCR-based-replicon typing scheme. A great diversity of replicon types was identified, with up to five per isolate. Most of the CTX-M-1 and SHV-12 producing E. coli isolates carried IncI1 or IncN replicons. The diversity of ESBL-producing E. coli isolates in wild animals, which can be disseminated in the environment, emphasizes the environmental and health problems that we face nowadays. PMID- 28364730 TI - Genetics and evolution of Yersinia pseudotuberculosis O-specific polysaccharides: a novel pattern of O-antigen diversity. AB - O-antigen polysaccharide is a major immunogenic feature of the lipopolysaccharide of Gram-negative bacteria, and most species produce a large variety of forms that differ substantially from one another. There are 18 known O-antigen forms in the Yersinia pseudotuberculosis complex, which are typical in being composed of multiple copies of a short oligosaccharide called an O unit. The O-antigen gene clusters are located between the hemH and gsk genes, and are atypical as 15 of them are closely related, each having one of five downstream gene modules for alternative main-chain synthesis, and one of seven upstream modules for alternative side-branch sugar synthesis. As a result, many of the genes are in more than one gene cluster. The gene order in each module is such that, in general, the earlier a gene product functions in O-unit synthesis, the closer the gene is to the 5? end for side-branch modules or the 3? end for main-chain modules. We propose a model whereby natural selection could generate the observed pattern in gene order, a pattern that has also been observed in other species. PMID- 28364733 TI - Editorial: Why microbiologists are not barophiles. PMID- 28364729 TI - Intestinal microbiome landscaping: insight in community assemblage and implications for microbial modulation strategies. AB - High individuality, large complexity and limited understanding of the mechanisms underlying human intestinal microbiome function remain the major challenges for designing beneficial modulation strategies. Exemplified by the analysis of intestinal bacteria in a thousand Western adults, we discuss key concepts of the human intestinal microbiome landscape, i.e. the compositional and functional 'core', the presence of community types and the existence of alternative stable states. Genomic investigation of core taxa revealed functional redundancy, which is expected to stabilize the ecosystem, as well as taxa with specialized functions that have the potential to shape the microbiome landscape. The contrast between Prevotella- and Bacteroides-dominated systems has been well described. However, less known is the effect of not so abundant bacteria, for example, Dialister spp. that have been proposed to exhibit distinct bistable dynamics. Studies employing time-series analysis have highlighted the dynamical variation in the microbiome landscape with and without the effect of defined perturbations, such as the use of antibiotics or dietary changes. We incorporate ecosystem-level observations of the human intestinal microbiota and its keystone species to suggest avenues for designing microbiome modulation strategies to improve host health. PMID- 28364734 TI - Editorial: Stewardship-in praise of thankless tasks and the respecting of Wombles. PMID- 28364735 TI - CrAgDb-a database of annotated chaperone repertoire in archaeal genomes. PMID- 28364736 TI - Bleeding Complications and Management on anticoagulant therapy. AB - Patients treated with anticoagulants have an unavoidable risk of bleeding complications. There are, for all oral anticoagulants, several potential options for management of major bleeding. The first action is to assess the causative role of the anticoagulant in the current bleeding. Supportive measures have been assessed in several post hoc analyses of the phase III pivotal trials with the non-vitamin K antagonist oral anticoagulants (NOACs). Those results will be reviewed here together with emerging data on the efficacy and safety of the specific antidotes idarucizumab (for dabigatran) and andexanet-alpha (for factor Xa inhibitors). Regular or activated prothrombin complex concentrates are also evaluated and might have a role as alternatives for management of NOAC-associated major bleeding if the "specific" antidote is not available. Once hemostasis has been achieved, it is imperative to assess the possibility and timing of resumption of anticoagulation, as these patients have an inherent prothrombotic state and a non-negligible proportion of patients will have thromboembolic complications during the first month after the hemorrhage. Many factors will have to be taken into account for this decision and unfortunately the guidelines in this respect are very weak if at all available. This review will hopefully provide some assistance in the management of major bleeding and posthemorrhage care. PMID- 28364737 TI - Viscoelastic Testing in Trauma. AB - Traumatic-induced coagulopathy (TIC) is a complex condition which develops both as a response to trauma as well as to clinical care interventions. Accurate and timely diagnostics are necessary to enable therapy aimed at correction of TIC. Viscoelastic hemostatic assays (VHA) are increasingly recognized for their potential to diagnose TIC as well as for guidance of treatment. This narrative review focuses on the evidence of the use of VHAs to diagnose TIC, to monitor efficacy of treatment of TIC during bleeding and to prognosticate outcome. Pitfalls of the use of VHA are also discussed. PMID- 28364738 TI - Introduction to Focus Issue: Complex network perspectives on flow systems. AB - During the last few years, complex network approaches have demonstrated their great potentials as versatile tools for exploring the structural as well as dynamical properties of dynamical systems from a variety of different fields. Among others, recent successful examples include (i) functional (correlation) network approaches to infer hidden statistical interrelationships between macroscopic regions of the human brain or the Earth's climate system, (ii) Lagrangian flow networks allowing to trace dynamically relevant fluid-flow structures in atmosphere, ocean or, more general, the phase space of complex systems, and (iii) time series networks unveiling fundamental organization principles of dynamical systems. In this spirit, complex network approaches have proven useful for data-driven learning of dynamical processes (like those acting within and between sub-components of the Earth's climate system) that are hidden to other analysis techniques. This Focus Issue presents a collection of contributions addressing the description of flows and associated transport processes from the network point of view and its relationship to other approaches which deal with fluid transport and mixing and/or use complex network techniques. PMID- 28364739 TI - Numerical proof for chemostat chaos of Shilnikov's type. AB - A classical chemostat model is considered that models the cycling of one essential abiotic element or nutrient through a food chain of three trophic levels. The long-time behavior of the model was known to exhibit complex dynamics more than 20 years ago. It is still an open problem to prove the existence of chaos analytically. In this paper, we aim to solve the problem numerically. In our approach, we introduce an artificial singular parameter to the model and construct singular homoclinic orbits of the saddle-focus type which is known for chaos generation. From the configuration of the nullclines of the equations that generates the singular homoclinic orbits, a shooting algorithm is devised to find such Shilnikov saddle-focus homoclinic orbits numerically which in turn imply the existence of chaotic dynamics for the original chemostat model. PMID- 28364740 TI - Noise-constrained switching times for heteroclinic computing. AB - Heteroclinic computing offers a novel paradigm for universal computation by collective system dynamics. In such a paradigm, input signals are encoded as complex periodic orbits approaching specific sequences of saddle states. Without inputs, the relevant states together with the heteroclinic connections between them form a network of states-the heteroclinic network. Systems of pulse-coupled oscillators or spiking neurons naturally exhibit such heteroclinic networks of saddles, thereby providing a substrate for general analog computations. Several challenges need to be resolved before it becomes possible to effectively realize heteroclinic computing in hardware. The time scales on which computations are performed crucially depend on the switching times between saddles, which in turn are jointly controlled by the system's intrinsic dynamics and the level of external and measurement noise. The nonlinear dynamics of pulse-coupled systems often strongly deviate from that of time-continuously coupled (e.g., phase coupled) systems. The factors impacting switching times in pulse-coupled systems are still not well understood. Here we systematically investigate switching times in dependence of the levels of noise and intrinsic dissipation in the system. We specifically reveal how local responses to pulses coact with external noise. Our findings confirm that, like in time-continuous phase-coupled systems, piecewise continuous pulse-coupled systems exhibit switching times that transiently increase exponentially with the number of switches up to some order of magnitude set by the noise level. Complementarily, we show that switching times may constitute a good predictor for the computation reliability, indicating how often an input signal must be reiterated. By characterizing switching times between two saddles in conjunction with the reliability of a computation, our results provide a first step beyond the coding of input signal identities toward a complementary coding for the intensity of those signals. The results offer insights on how future heteroclinic computing systems may operate under natural, and thus noisy, conditions. PMID- 28364741 TI - Multiplex multivariate recurrence network from multi-channel signals for revealing oil-water spatial flow behavior. AB - The exploration of the spatial dynamical flow behaviors of oil-water flows has attracted increasing interests on account of its challenging complexity and great significance. We first technically design a double-layer distributed-sector conductance sensor and systematically carry out oil-water flow experiments to capture the spatial flow information. Based on the well-established recurrence network theory, we develop a novel multiplex multivariate recurrence network (MMRN) to fully and comprehensively fuse our double-layer multi-channel signals. Then we derive the projection networks from the inferred MMRNs and exploit the average clustering coefficient and the spectral radius to quantitatively characterize the nonlinear recurrent behaviors related to the distinct flow patterns. We find that these two network measures are very sensitive to the change of flow states and the distributions of network measures enable to uncover the spatial dynamical flow behaviors underlying different oil-water flow patterns. Our method paves the way for efficiently analyzing multi-channel signals from multi-layer sensor measurement system. PMID- 28364742 TI - Lower bound of assortativity coefficient in scale-free networks. AB - The degree-degree correlation is important in understanding the structural organization of a network and dynamics upon a network. Such correlation is usually measured by the assortativity coefficient r, with natural bounds r?[ 1,1]. For scale-free networks with power-law degree distribution p(k)~k-gamma, we analytically obtain the lower bound of assortativity coefficient in the limit of large network size, which is not -1 but dependent on the power-law exponent gamma. This work challenges the validation of the assortativity coefficient in heterogeneous networks, suggesting that one cannot judge whether a network is positively or negatively correlated just by looking at its assortativity coefficient alone. PMID- 28364743 TI - A complex network representation of wind flows. AB - Climate networks have proven to be a valuable method to investigate spatial connectivity patterns of the climate system. However, so far such networks have mostly been applied to scalar observables. In this study, we propose a new method for constructing networks from atmospheric wind fields on two-dimensional isobaric surfaces. By connecting nodes along a spatial environment based on the local wind flow, we derive a network representation of the low-level circulation that captures its most important characteristics. In our approach, network links are placed according to a suitable statistical null model that takes into account the direction and magnitude of the flow. We compare a simulation-based (numerically costly) and a semi-analytical (numerically cheaper) approach to determine the statistical significance of possible connections, and find that both methods yield qualitatively similar results. As an application, we choose the regional climate system of South America and focus on the monsoon season in austral summer. Monsoon systems are generally characterized by substantial changes in the large-scale wind directions, and therefore provide ideal applications for the proposed wind networks. Based on these networks, we are able to reveal the key features of the low-level circulation of the South American Monsoon System, including the South American Low-Level Jet. Networks of the dry and the wet season are compared with each other and their differences are consistent with the literature on South American climate. PMID- 28364744 TI - Climate network stability measures of El Nino variability. AB - One of the crucial aspects that is currently limiting the success of El Nino predictions is the stability of the slowly varying Pacific climate state. This property determines whether or not sea surface temperature perturbations will be amplified by coupled ocean-atmosphere feedbacks. The so-called Bjerknes stability index has been developed for this purpose, but its evaluation is severely constrained by data availability. Here, we present new network based measures of the stability of the Pacific climate state. These measures can be evaluated by using only sea surface temperature data and efficiently indicate whether positive feedbacks of perturbations to the climate state will occur. PMID- 28364745 TI - Directed weighted network structure analysis of complex impedance measurements for characterizing oil-in-water bubbly flow. AB - Characterizing the flow structure underlying the evolution of oil-in-water bubbly flow remains a contemporary challenge of great interests and complexity. In particular, the oil droplets dispersing in a water continuum with diverse size make the study of oil-in-water bubbly flow really difficult. To study this issue, we first design a novel complex impedance sensor and systematically conduct vertical oil-water flow experiments. Based on the multivariate complex impedance measurements, we define modalities associated with the spatial transient flow structures and construct modality transition-based network for each flow condition to study the evolution of flow structures. In order to reveal the unique flow structures underlying the oil-in-water bubbly flow, we filter the inferred modality transition-based network by removing the edges with small weight and resulting isolated nodes. Then, the weighted clustering coefficient entropy and weighted average path length are employed for quantitatively assessing the original network and filtered network. The differences in network measures enable to efficiently characterize the evolution of the oil-in-water bubbly flow structures. PMID- 28364746 TI - Small-world bias of correlation networks: From brain to climate. AB - Complex systems are commonly characterized by the properties of their graph representation. Dynamical complex systems are then typically represented by a graph of temporal dependencies between time series of state variables of their subunits. It has been shown recently that graphs constructed in this way tend to have relatively clustered structure, potentially leading to spurious detection of small-world properties even in the case of systems with no or randomly distributed true interactions. However, the strength of this bias depends heavily on a range of parameters and its relevance for real-world data has not yet been established. In this work, we assess the relevance of the bias using two examples of multivariate time series recorded in natural complex systems. The first is the time series of local brain activity as measured by functional magnetic resonance imaging in resting healthy human subjects, and the second is the time series of average monthly surface air temperature coming from a large reanalysis of climatological data over the period 1948-2012. In both cases, the clustering in the thresholded correlation graph is substantially higher compared with a realization of a density-matched random graph, while the shortest paths are relatively short, showing thus distinguishing features of small-world structure. However, comparable or even stronger small-world properties were reproduced in correlation graphs of model processes with randomly scrambled interconnections. This suggests that the small-world properties of the correlation matrices of these real-world systems indeed do not reflect genuinely the properties of the underlying interaction structure, but rather result from the inherent properties of correlation matrix. PMID- 28364747 TI - Hidden hyperchaos and electronic circuit application in a 5D self-exciting homopolar disc dynamo. AB - We report on the finding of hidden hyperchaos in a 5D extension to a known 3D self-exciting homopolar disc dynamo. The hidden hyperchaos is identified through three positive Lyapunov exponents under the condition that the proposed model has just two stable equilibrium states in certain regions of parameter space. The new 5D hyperchaotic self-exciting homopolar disc dynamo has multiple attractors including point attractors, limit cycles, quasi-periodic dynamics, hidden chaos or hyperchaos, as well as coexisting attractors. We use numerical integrations to create the phase plane trajectories, produce bifurcation diagram, and compute Lyapunov exponents to verify the hidden attractors. Because no unstable equilibria exist in two parameter regions, the system has a multistability and six kinds of complex dynamic behaviors. To the best of our knowledge, this feature has not been previously reported in any other high-dimensional system. Moreover, the 5D hyperchaotic system has been simulated using a specially designed electronic circuit and viewed on an oscilloscope, thereby confirming the results of the numerical integrations. Both Matlab and the oscilloscope outputs produce similar phase portraits. Such implementations in real time represent a new type of hidden attractor with important consequences for engineering applications. PMID- 28364748 TI - The two-parametric scaling and new temporal asymptotic of survival probability of diffusing particle in the medium with traps. AB - The new asymptotic behavior of the survival probability of particles in a medium with absorbing traps in an electric field has been established in two ways-by using the scaling approach and by the direct solution of the diffusion equation in the field. It has shown that at long times, this drift mechanism leads to a new temporal behavior of the survival probability of particles in a medium with absorbing traps. PMID- 28364749 TI - Percolation framework to describe El Nino conditions. AB - Complex networks have been used intensively to investigate the flow and dynamics of many natural systems including the climate system. Here, we develop a percolation based measure, the order parameter, to study and quantify climate networks. We find that abrupt transitions of the order parameter usually occur ~1 year before El Nino events, suggesting that they can be used as early warning precursors of El Nino. Using this method, we analyze several reanalysis datasets and show the potential for good forecasting of El Nino. The percolation based order parameter exhibits discontinuous features, indicating a possible relation to the first order phase transition mechanism. PMID- 28364750 TI - Records in fractal stochastic processes. AB - The record statistics in stationary and non-stationary fractal time series is studied extensively. By calculating various concepts in record dynamics, we find some interesting results. In stationary fractional Gaussian noises, we observe a universal behavior for the whole range of Hurst exponents. However, for non stationary fractional Brownian motions, the record dynamics is crucially dependent on the memory, which plays the role of a non-stationarity index, here. Indeed, the deviation from the results of the stationary case increases by increasing the Hurst exponent in fractional Brownian motions. We demonstrate that the memory governs the dynamics of the records as long as it causes non stationarity in fractal stochastic processes; otherwise, it has no impact on the record statistics. PMID- 28364751 TI - Inferring directed climatic interactions with renormalized partial directed coherence and directed partial correlation. AB - Inferring interactions between processes promises deeper insight into mechanisms underlying network phenomena. Renormalised partial directed coherence is a frequency-domain representation of the concept of Granger causality, while directed partial correlation is an alternative approach for quantifying Granger causality in the time domain. Both methodologies have been successfully applied to neurophysiological signals for detecting directed relationships. This paper introduces their application to climatological time series. We first discuss the application to El Nino-Southern Oscillation-Monsoon interaction and then apply the methodologies to the more challenging air-sea interaction in the South Atlantic Convergence Zone (SACZ). In the first case, the results obtained are fully consistent with the present knowledge in climate modeling, while in the second case, the results are, as expected, less clear, and to fully elucidate the SACZ air-sea interaction, further investigations on the specificity and sensitivity of these methodologies are needed. PMID- 28364752 TI - Smooth information flow in temperature climate network reflects mass transport. AB - A directed climate network is constructed by Granger causality analysis of air temperature time series from a regular grid covering the whole Earth. Using winner-takes-all network thresholding approach, a structure of a smooth information flow is revealed, hidden to previous studies. The relevance of this observation is confirmed by comparison with the air mass transfer defined by the wind field. Their close relation illustrates that although the information transferred due to the causal influence is not a physical quantity, the information transfer is tied to the transfer of mass and energy. PMID- 28364753 TI - Three-component Gross-Pitaevskii equations in the spin-1 Bose-Einstein condensate: Spin-rotation symmetry, matter-wave solutions, and dynamics. AB - We report new matter-wave solutions of the one-dimensional spin-1 Bose-Einstein condensate system by combining global spin-rotation states and similarity transformation. Dynamical behaviors of non-stationary global spin-rotation states derived from the SU(2) spin-rotation symmetry are discussed, which exhibit temporal periodicity. We derive generalized bright-dark mixed solitons and new rogue wave solutions and reveal the relations between Euler angles in spin rotation symmetry and parameters in ferromagnetic and polar solitons. In the modulated spin-1 Bose-Einstein condensate system, new solutions are derived and graphically illustrated for different types of modulations. Moreover, numerical simulations are performed to investigate the stability of some obtained solutions for chosen parameters. PMID- 28364754 TI - Edge anisotropy and the geometric perspective on flow networks. AB - Spatial networks have recently attracted great interest in various fields of research. While the traditional network-theoretic viewpoint is commonly restricted to their topological characteristics (often disregarding the existing spatial constraints), this work takes a geometric perspective, which considers vertices and edges as objects in a metric space and quantifies the corresponding spatial distribution and alignment. For this purpose, we introduce the concept of edge anisotropy and define a class of measures characterizing the spatial directedness of connections. Specifically, we demonstrate that the local anisotropy of edges incident to a given vertex provides useful information about the local geometry of geophysical flows based on networks constructed from spatio temporal data, which is complementary to topological characteristics of the same flow networks. Taken both structural and geometric viewpoints together can thus assist the identification of underlying flow structures from observations of scalar variables. PMID- 28364755 TI - The existence of solutions for fractional differential equations with p-Laplacian at resonance. AB - By giving proper transformation, selecting suitable Banach spaces and operators, and using Mawhin's coincident theory, we investigate the existence of solutions for fractional differential equations with p-Laplacian at resonance under two kinds of boundary conditions, respectively. Examples are given to illustrate our main results. PMID- 28364756 TI - Spatio-temporal organization of dynamics in a two-dimensional periodically driven vortex flow: A Lagrangian flow network perspective. AB - We study the Lagrangian dynamics of passive tracers in a simple model of a driven two-dimensional vortex resembling real-world geophysical flow patterns. Using a discrete approximation of the system's transfer operator, we construct a directed network that describes the exchange of mass between distinct regions of the flow domain. By studying different measures characterizing flow network connectivity at different time-scales, we are able to identify the location of dynamically invariant structures and regions of maximum dispersion. Specifically, our approach allows us to delimit co-existing flow regimes with different dynamics. To validate our findings, we compare several network characteristics to the well established finite-time Lyapunov exponents and apply a receiver operating characteristic analysis to identify network measures that are particularly useful for unveiling the skeleton of Lagrangian chaos. PMID- 28364757 TI - Regenerating time series from ordinal networks. AB - Recently proposed ordinal networks not only afford novel methods of nonlinear time series analysis but also constitute stochastic approximations of the deterministic flow time series from which the network models are constructed. In this paper, we construct ordinal networks from discrete sampled continuous chaotic time series and then regenerate new time series by taking random walks on the ordinal network. We then investigate the extent to which the dynamics of the original time series are encoded in the ordinal networks and retained through the process of regenerating new time series by using several distinct quantitative approaches. First, we use recurrence quantification analysis on traditional recurrence plots and order recurrence plots to compare the temporal structure of the original time series with random walk surrogate time series. Second, we estimate the largest Lyapunov exponent from the original time series and investigate the extent to which this invariant measure can be estimated from the surrogate time series. Finally, estimates of correlation dimension are computed to compare the topological properties of the original and surrogate time series dynamics. Our findings show that ordinal networks constructed from univariate time series data constitute stochastic models which approximate important dynamical properties of the original systems. PMID- 28364758 TI - Predictability of large-scale atmospheric motions: Lyapunov exponents and error dynamics. AB - The deterministic equations describing the dynamics of the atmosphere (and of the climate system) are known to display the property of sensitivity to initial conditions. In the ergodic theory of chaos, this property is usually quantified by computing the Lyapunov exponents. In this review, these quantifiers computed in a hierarchy of atmospheric models (coupled or not to an ocean) are analyzed, together with their local counterparts known as the local or finite-time Lyapunov exponents. It is shown in particular that the variability of the local Lyapunov exponents (corresponding to the dominant Lyapunov exponent) decreases when the model resolution increases. The dynamics of (finite-amplitude) initial condition errors in these models is also reviewed, and in general found to display a complicated growth far from the asymptotic estimates provided by the Lyapunov exponents. The implications of these results for operational (high resolution) atmospheric and climate modelling are also discussed. PMID- 28364759 TI - Clustering coefficient and periodic orbits in flow networks. AB - We show that the clustering coefficient, a standard measure in network theory, when applied to flow networks, i.e., graph representations of fluid flows in which links between nodes represent fluid transport between spatial regions, identifies approximate locations of periodic trajectories in the flow system. This is true for steady flows and for periodic ones in which the time interval tau used to construct the network is the period of the flow or a multiple of it. In other situations, the clustering coefficient still identifies cyclic motion between regions of the fluid. Besides the fluid context, these ideas apply equally well to general dynamical systems. By varying the value of tau used to construct the network, a kind of spectroscopy can be performed so that the observation of high values of mean clustering at a value of tau reveals the presence of periodic orbits of period 3tau, which impact phase space significantly. These results are illustrated with examples of increasing complexity, namely, a steady and a periodically perturbed model two-dimensional fluid flow, the three-dimensional Lorenz system, and the turbulent surface flow obtained from a numerical model of circulation in the Mediterranean sea. PMID- 28364760 TI - Chimera states and the interplay between initial conditions and non-local coupling. AB - Chimera states are complex spatio-temporal patterns that consist of coexisting domains of coherent and incoherent dynamics. We study chimera states in a network of non-locally coupled Stuart-Landau oscillators. We investigate the impact of initial conditions in combination with non-local coupling. Based on an analytical argument, we show how the coupling phase and the coupling strength are linked to the occurrence of chimera states, flipped profiles of the mean phase velocity, and the transition from a phase- to an amplitude-mediated chimera state. PMID- 28364761 TI - Stochasticity induced mixed-mode oscillations and distribution of recurrent outbreaks in an ecosystem. AB - The effect of stochasticity, in the form of Gaussian white noise, in a predator prey model with two distinct time-scales is presented. A supercritical singular Hopf bifurcation yields a Type II excitability in the deterministic model. We explore the effect of stochasticity in the excitable regime, leading to dynamics that are not anticipated by its deterministic counterpart. The stochastic model admits several kinds of noise-driven mixed-mode oscillations which capture the intermediate dynamics between two cycles of population outbreaks. Depending on the strength of noise, the prey population exhibits intermediate to high amplitude fluctuations (related to moderate or severe outbreaks respectively). We classify these fluctuations as isolated or intermittent or as clusters depending on their recurrences. We study the distribution of the random variable N, representing the number of small oscillations between successive spikes, as a function of the noise intensity and the distance to the Hopf bifurcation. The distribution of N is "asymptotically geometric" with the corresponding parameter related to the principal eigenvalue of a substochastic Markov chain. Finally, the stochastic model is transformed into its "normal form" which is used to obtain an estimate of the probability of repeated outbreaks. PMID- 28364762 TI - Levitation of heavy particles against gravity in asymptotically downward flows. AB - In the fluid transport of particles, it is generally expected that heavy particles carried by a laminar fluid flow moving downward will also move downward. We establish a theory to show, however, that particles can be dynamically levitated and lifted by interacting vortices in such flows, thereby moving against gravity and the asymptotic direction of the flow, even when they are orders of magnitude denser than the fluid. The particle levitation is rigorously demonstrated for potential flows and supported by simulations for viscous flows. We suggest that this counterintuitive effect has potential implications for the air-transport of water droplets and the lifting of sediments in water. PMID- 28364763 TI - Understanding the geometry of transport: Diffusion maps for Lagrangian trajectory data unravel coherent sets. AB - Dynamical systems often exhibit the emergence of long-lived coherent sets, which are regions in state space that keep their geometric integrity to a high extent and thus play an important role in transport. In this article, we provide a method for extracting coherent sets from possibly sparse Lagrangian trajectory data. Our method can be seen as an extension of diffusion maps to trajectory space, and it allows us to construct "dynamical coordinates," which reveal the intrinsic low-dimensional organization of the data with respect to transport. The only a priori knowledge about the dynamics that we require is a locally valid notion of distance, which renders our method highly suitable for automated data analysis. We show convergence of our method to the analytic transfer operator framework of coherence in the infinite data limit and illustrate its potential on several two- and three-dimensional examples as well as real world data. PMID- 28364764 TI - Design and implementation of dynamic logic gates and R-S flip-flop using quasiperiodically driven Murali-Lakshmanan-Chua circuit. AB - We report the propagation of a square wave signal in a quasi-periodically driven Murali-Lakshmanan-Chua (QPDMLC) circuit system. It is observed that signal propagation is possible only above a certain threshold strength of the square wave or digital signal and all the values above the threshold amplitude are termed as "region of signal propagation." Then, we extend this region of signal propagation to perform various logical operations like AND/NAND/OR/NOR and hence it is also designated as the "region of logical operation." Based on this region, we propose implementing the dynamic logic gates, namely, AND/NAND/OR/NOR, which can be decided by the asymmetrical input square waves without altering the system parameters. Further, we show that a single QPDMLC system will produce simultaneously two outputs which are complementary to each other. As a result, a single QPDMLC system yields either AND as well as NAND or OR as well as NOR gates simultaneously. Then, we combine the corresponding two QPDMLC systems in a cross coupled way and report that its dynamics mimics that of fundamental R-S flip-flop circuit. All these phenomena have been explained with analytical solutions of the circuit equations characterizing the system and finally, the results are compared with the corresponding numerical and experimental analysis. PMID- 28364765 TI - Modeling the network dynamics of pulse-coupled neurons. AB - We derive a mean-field approximation for the macroscopic dynamics of large networks of pulse-coupled theta neurons in order to study the effects of different network degree distributions and degree correlations (assortativity). Using the ansatz of Ott and Antonsen [Chaos 18, 037113 (2008)], we obtain a reduced system of ordinary differential equations describing the mean-field dynamics, with significantly lower dimensionality compared with the complete set of dynamical equations for the system. We find that, for sufficiently large networks and degrees, the dynamical behavior of the reduced system agrees well with that of the full network. This dimensional reduction allows for an efficient characterization of system phase transitions and attractors. For networks with tightly peaked degree distributions, the macroscopic behavior closely resembles that of fully connected networks previously studied by others. In contrast, networks with highly skewed degree distributions exhibit different macroscopic dynamics due to the emergence of degree dependent behavior of different oscillators. For nonassortative networks (i.e., networks without degree correlations), we observe the presence of a synchronously firing phase that can be suppressed by the presence of either assortativity or disassortativity in the network. We show that the results derived here can be used to analyze the effects of network topology on macroscopic behavior in neuronal networks in a computationally efficient fashion. PMID- 28364766 TI - Chaos emerging in soil failure patterns observed during tillage: Normalized deterministic nonlinear prediction (NDNP) and its application. AB - Real-world processes are often combinations of deterministic and stochastic processes. Soil failure observed during farm tillage is one example of this phenomenon. In this paper, we investigated the nonlinear features of soil failure patterns in a farm tillage process. We demonstrate emerging determinism in soil failure patterns from stochastic processes under specific soil conditions. We normalized the deterministic nonlinear prediction considering autocorrelation and propose it as a robust way of extracting a nonlinear dynamical system from noise contaminated motion. Soil is a typical granular material. The results obtained here are expected to be applicable to granular materials in general. From a global scale to nano scale, the granular material is featured in seismology, geotechnology, soil mechanics, and particle technology. The results and discussions presented here are applicable in these wide research areas. The proposed method and our findings are useful with respect to the application of nonlinear dynamics to investigate complex motions generated from granular materials. PMID- 28364767 TI - The 3-cycle weighted spectral distribution in evolving community-based networks. AB - One of the main organizing principles in real-world networks is that of network communities, where sets of nodes organize into densely linked clusters. Many of these community-based networks evolve over time, that is, we need some size independent metrics to capture the connection relationships embedded in these clusters. One of these metrics is the average clustering coefficient, which represents the triangle relationships between all nodes of networks. However, the vast majority of network communities is composed of low-degree nodes. Thus, we should further investigate other size-independent metrics to subtly measure the triangle relationships between low-degree nodes. In this paper, we study the 3 cycle weighted spectral distribution (WSD) defined as the weighted sum of the normalized Laplacian spectral distribution with a scaling factor n, where n is the network size (i.e., the node number). Using some diachronic community-based network models and real-world networks, we demonstrate that the ratio of the 3 cycle WSD to the network size is asymptotically independent of the network size and strictly represents the triangle relationships between low-degree nodes. Additionally, we find that the ratio is a good indicator of the average clustering coefficient in evolving community-based systems. PMID- 28364768 TI - Consistency of heterogeneous synchronization patterns in complex weighted networks. AB - Synchronization within the dynamical nodes of a complex network is usually considered homogeneous through all the nodes. Here we show, in contrast, that subsets of interacting oscillators may synchronize in different ways within a single network. This diversity of synchronization patterns is promoted by increasing the heterogeneous distribution of coupling weights and/or asymmetries in small networks. We also analyze consistency, defined as the persistence of coexistent synchronization patterns regardless of the initial conditions. Our results show that complex weighted networks display richer consistency than regular networks, suggesting why certain functional network topologies are often constructed when experimental data are analyzed. PMID- 28364769 TI - Chaotic oscillator containing memcapacitor and meminductor and its dimensionality reduction analysis. AB - In this paper, smooth curve models of meminductor and memcapacitor are designed, which are generalized from a memristor. Based on these models, a new five dimensional chaotic oscillator that contains a meminductor and memcapacitor is proposed. By dimensionality reducing, this five-dimensional system can be transformed into a three-dimensional system. The main work of this paper is to give the comparisons between the five-dimensional system and its dimensionality reduction model. To investigate dynamics behaviors of the two systems, equilibrium points and stabilities are analyzed. And the bifurcation diagrams and Lyapunov exponent spectrums are used to explore their properties. In addition, digital signal processing technologies are used to realize this chaotic oscillator, and chaotic sequences are generated by the experimental device, which can be used in encryption applications. PMID- 28364770 TI - On the control of the chaotic attractors of the 2-d Navier-Stokes equations. AB - The control problem of the chaotic attractors of the two dimensional (2-d) Navier Stokes (N-S) equations is addressed in this paper. First, the Fourier Galerkin method based on a reduced-order modelling approach developed by Chen and Price is applied to the 2-d N-S equations to construct a fifth-order system of nonlinear ordinary differential equations (ODEs). The dynamics of the fifth-order system was studied by analyzing the system's attractor for different values of Reynolds number, Re. Then, control laws are proposed to drive the states of the ODE system to a desired attractor. Finally, an adaptive controller is designed to synchronize two reduced order ODE models having different Reynolds numbers and starting from different initial conditions. Simulation results indicate that the proposed control schemes work well. PMID- 28364771 TI - Smoothing effect for spatially distributed renewable resources and its impact on power grid robustness. AB - In this paper, we show that spatial correlation of renewable energy outputs greatly influences the robustness of the power grids against large fluctuations of the effective power. First, we evaluate the spatial correlation among renewable energy outputs. We find that the spatial correlation of renewable energy outputs depends on the locations, while the influence of the spatial correlation of renewable energy outputs on power grids is not well known. Thus, second, by employing the topology of the power grid in eastern Japan, we analyze the robustness of the power grid with spatial correlation of renewable energy outputs. The analysis is performed by using a realistic differential-algebraic equations model. The results show that the spatial correlation of the energy resources strongly degrades the robustness of the power grid. Our results suggest that we should consider the spatial correlation of the renewable energy outputs when estimating the stability of power grids. PMID- 28364772 TI - A perturbation-theoretic approach to Lagrangian flow networks. AB - Complex network approaches have been successfully applied for studying transport processes in complex systems ranging from road, railway, or airline infrastructures over industrial manufacturing to fluid dynamics. Here, we utilize a generic framework for describing the dynamics of geophysical flows such as ocean currents or atmospheric wind fields in terms of Lagrangian flow networks. In this approach, information on the passive advection of particles is transformed into a Markov chain based on transition probabilities of particles between the volume elements of a given partition of space for a fixed time step. We employ perturbation-theoretic methods to investigate the effects of modifications of transport processes in the underlying flow for three different problem classes: efficient absorption (corresponding to particle trapping or leaking), constant input of particles (with additional source terms modeling, e.g., localized contamination), and shifts of the steady state under probability mass conservation (as arising if the background flow is perturbed itself). Our results demonstrate that in all three cases, changes to the steady state solution can be analytically expressed in terms of the eigensystem of the unperturbed flow and the perturbation itself. These results are potentially relevant for developing more efficient strategies for coping with contaminations of fluid or gaseous media such as ocean and atmosphere by oil spills, radioactive substances, non-reactive chemicals, or volcanic aerosols. PMID- 28364773 TI - Diffusion-driven destabilization of spatially homogeneous limit cycles in reaction-diffusion systems. AB - We study the diffusion-driven destabilization of a spatially homogeneous limit cycle with large amplitude in a reaction-diffusion system on an interval of finite size under the periodic boundary condition. Numerical bifurcation analysis and simulations show that the spatially homogeneous limit cycle becomes unstable and changes to a stable spatially nonhomogeneous limit cycle for appropriate diffusion coefficients. This is analogous to the diffusion-driven destabilization (Turing instability) of a spatially homogeneous equilibrium. Our approach is based on a reaction-diffusion system with mass conservation and its perturbed system considered as an infinite dimensional slow-fast system (relaxation oscillator). PMID- 28364774 TI - Multi-piecewise quadratic nonlinearity memristor and its 2N-scroll and 2N + 1 scroll chaotic attractors system. AB - In this paper, two kinds of novel ideal active flux-controlled smooth multi piecewise quadratic nonlinearity memristors with multi-piecewise continuous memductance function are presented. The pinched hysteresis loop characteristics of the two memristor models are verified by building a memristor emulator circuit. Using the two memristor models establish a new memristive multi-scroll Chua's circuit, which can generate 2N-scroll and 2N+1-scroll chaotic attractors without any other ordinary nonlinear function. Furthermore, coexisting multi scroll chaotic attractors are found in the proposed memristive multi-scroll Chua's circuit. Phase portraits, Lyapunov exponents, bifurcation diagrams, and equilibrium point analysis have been used to research the basic dynamics of the memristive multi-scroll Chua's circuit. The consistency of circuit implementation and numerical simulation verifies the effectiveness of the system design. PMID- 28364775 TI - Are continuum predictions of clustering chaotic? AB - Gas-solid multiphase flows are prone to develop an instability known as clustering. Two-fluid models, which treat the particulate phase as a continuum, are known to reproduce the qualitative features of this instability, producing highly-dynamic, spatiotemporal patterns. However, it is unknown whether such simulations are truly aperiodic or a type of complex periodic behavior. By showing that the system possesses a sensitive dependence on initial conditions and a positive largest Lyapunov exponent, lambda1~1/tau, we provide a tentative answer: continuum predictions of clustering are chaotic. We further demonstrate that the chaotic behavior is dimensionally dependent, a conclusion which unifies previous results and strongly suggests that the chaotic behavior is not a direct consequence of the fundamental kinematic instability, but requires a secondary (inherently multidimensional) instability. PMID- 28364776 TI - An observer for an occluded reaction-diffusion system with spatially varying parameters. AB - Spatially dependent parameters of a two-component chaotic reaction-diffusion partial differential equation (PDE) model describing ocean ecology are observed by sampling a single species. We estimate the model parameters and the other species in the system by autosynchronization, where quantities of interest are evolved according to misfit between model and observations, to only partially observed data. Our motivating example comes from oceanic ecology as viewed by remote sensing data, but where noisy occluded data are realized in the form of cloud cover. We demonstrate a method to learn a large-scale coupled synchronizing system that represents the spatio-temporal dynamics and apply a network approach to analyze manifold stability. PMID- 28364779 TI - The effects of Nobiletin, Hesperetin, and Letrozole in a combination on the activity and expression of aromatase in breast cancer cells. AB - Nobiletin (NOB) and hesperetin (HES) are the citrus polymethoxyflavone and flavonone. Aromatase or cytochrome P450 (CYP19) enzyme is a key enzyme in estrogen biosynthesis. The objective of this study was to investigate the combinational effects of HES, NOB and letrozole (LET) as aromatase inhibitors on the activity and expression of aromatase in MCF-7 cells. In this study, aromatase enzyme activity based on the conversion of androgen substrate testosterone to 17beta-Estradiol was determined. Estradiol concentrations were measured using an electrochemiluminescence immunoassay. CYP19 gene expression was determined by quantitative real-time PCR. Our findings demonstrated that none of combinations including LET+NOB, LET+HES, LET+NOB+HES, and NOB+HES had no significant effects on aromatase activity and expression. The present study showed for the first time that the combination of HES, NOB, and LET had no effects on activity and expression of aromatase in MCF-7 breast cancer cells. PMID- 28364780 TI - The link between intergenic distances and controls exerted on the transcriptional regulation; an inferential approach. AB - The position of genes along the genome is an important evolutionary factor for organizing gene regulation. Hence, transcriptional regulatory network have been studied much more extensively from gene distributions rather than other viewpoints. The systematics of intergenic distances, therefore, should be taken into account as an important source of information on the controls exerted on gene expression by various biological mechanisms. Here we study a collection of features including, intergenic and interoperonic distances, distances between isolated genes, distances between regulatory genes and distances between isolated and regulatory genes/operons in order to provide a more informative picture of gene distributions via firstly discovering the statistical model of these features. We find that all these features significantly follow the lognormal distribution. Then we test a few important biological hypotheses particularly in relation to controls exerted in the transcriptional regulatory network in a completely inferential approach using generalized p-value based on the discovered model. We find that mean distances of isolated genes significantly is less than that of regulatory genes. These findings are consistent with the previous evidences that many biological variables, especially in relation to systems biology, follow lognormal distribution. furthermore, our results inferentially support the crucial hypothesis on the two distinct logical types of control, namely digital control (i.e. control mediated by specific transcription factors) and analog control (i.e. control mediated by distribution of supercoiling energy and based on gene neighborhood) previously proposed by studying expression patterns. PMID- 28364778 TI - Clinical and molecular findings in a Moroccan family with Jervell and Lange Nielsen syndrome: a case report. AB - BACKGROUND: Jervell and Lange-Nielsen syndrome (Online Mendelian Inheritance in Man 220400) is a rare autosomal recessive cardioauditory ion channel disorder that affects 1/200,000 to 1/1,000,000 children. It is characterized by congenital profound bilateral sensorineural hearing loss, a long QT interval, ventricular tachyarrhythmias, and episodes of torsade de pointes on an electrocardiogram. Cardiac symptoms arise mostly in early childhood and consist of syncopal episodes during periods of stress, exercise, or fright and are associated with a high risk of sudden cardiac death. Jervell and Lange-Nielsen syndrome is caused by homozygous or compound heterozygous mutations in KCNQ1 on 11p15.5 or KCNE1 on 1q22.1-q22.2. CASE PRESENTATION: We report the case of a 10-year-old Moroccan boy with congenital hearing loss and severely prolonged QT interval who presented with multiple episodes of syncope. His parents are first-degree cousins. We performed Sanger sequencing and identified a homozygous variant in KCNQ1 (c.1343dupC, p.Glu449Argfs*14). CONCLUSIONS: The identification of the genetic substrate in this patient confirmed the clinical diagnosis of Jervell and Lange Nielsen syndrome and allowed us to provide him with appropriate management and genetic counseling to his family. In addition, this finding contributes to our understanding of genetic disease in the Moroccan population. PMID- 28364777 TI - In vivo MRI and ex vivo histological assessment of the cardioprotection induced by ischemic preconditioning, postconditioning and remote conditioning in a closed chest porcine model of reperfused acute myocardial infarction: importance of microvasculature. AB - BACKGROUND: Cardioprotective value of ischemic post- (IPostC), remote (RIC) conditioning in acute myocardial infarction (AMI) is unclear in clinical trials. To evaluate cardioprotection, most translational animal studies and clinical trials utilize necrotic tissue referred to the area at risk (AAR) by magnetic resonance imaging (MRI). However, determination of AAR by MRI' may not be accurate, since MRI-indices of microvascular damage, i.e., myocardial edema and microvascular obstruction (MVO), may be affected by cardioprotection independently from myocardial necrosis. Therefore, we assessed the effect of IPostC, RIC conditioning and ischemic preconditioning (IPreC; positive control) on myocardial necrosis, edema and MVO in a clinically relevant, closed-chest pig model of AMI. METHODS AND RESULTS: Acute myocardial infarction was induced by a 90-min balloon occlusion of the left anterior descending coronary artery (LAD) in domestic juvenile female pigs. IPostC (6 * 30 s ischemia/reperfusion after 90-min occlusion) and RIC (4 * 5 min hind limb ischemia/reperfusion during 90-min LAD occlusion) did not reduce myocardial necrosis as assessed by late gadolinium enhancement 3 days after reperfusion and by ex vivo triphenyltetrazolium chloride staining 3 h after reperfusion, however, the positive control, IPreC (3 * 5 min ischemia/reperfusion before 90-min LAD occlusion) did. IPostC and RIC attenuated myocardial edema as measured by cardiac T2-weighted MRI 3 days after reperfusion, however, AAR measured by Evans blue staining was not different among groups, which confirms that myocardial edema is not a measure of AAR, IPostC and IPreC but not RIC decreased MVO. CONCLUSION: We conclude that IPostC and RIC interventions may protect the coronary microvasculature even without reducing myocardial necrosis. PMID- 28364781 TI - Methyl thiophanate-induced toxicity in liver and kidney of adult rats: a biochemical, molecular and histopathological approach. AB - The aim of this study was to elucidate the redox effects of Thiophanate methyl (MT) in the rat liver and kidney. Our results showed, after 3 days of MT injection (700 mg/kg), an increase in malondialdehyde (MDA), hydrogen peroxide and advanced oxidation protein products levels. Glutathione peroxidase and superoxide dismutase activities were also remarkably increased in the liver but decrease in the kidney. Glutathione and vitamin C values were significantly reduced. The changes in biochemical parameters were substantiated by histological and molecular data. A smear without ladder formation on agarose gel was shown, indicating random DNA degradation in the liver and the kidney of MT treated rats. The increase in cyclooxygenase-2 gene expression, marker of inflammation, and an increase in genes expression of glutathione peroxidase and superoxide dismutase in liver and their decrease in the kidney were also occurred after MT exposure. These data confirmed the pro-oxidant and genotoxic effects of this fungicide. PMID- 28364782 TI - The G-protein alpha-subunit gene CGA1 is involved in regulation of resistance to heat and osmotic stress in Chlamydomonas reinhardtii. AB - In eukaryotic cells, many important functions of specific G-proteins have been identified, but microalgal G-proteins are poorly studied. In this work, we characterized a gene (CGA1) encoding the G-protein alpha-subunit in Chlamydomonas reinhardtii. Independent knockdown mutants of CGA1 were generated via RNA interference (RNAi). CGA1 expression levels were consistently and significantly reduced in both independent CGA1 mutant cell lines (cga1). Both cga1 mutants had a higher survival rate at 35 degrees C in comparison with the wild type. This stronger resistance of the cga1 mutants became more evident during simultaneous exposure to heat and osmotic stress. The stronger resistance of the CGA1 knockdown mutants to the two stressors was accompanied with significant morphological alterations-both cell size and cell wall thickness were different from those of the wild type. This finding supports the roles of CGA1 in C. reinhardtii morphology in response to stressors. To further understand biochemical mechanisms of the CGA1-mediated resistance, we thoroughly analyzed the level of reactive oxygen species (ROS) and the expression of several heat shock proteins or MAP kinase genes as possible downstream effectors of CGA1. Our data clearly indicated that CGA1 is implicated in the regulation of resistance to heat or osmotic stress in C. reinhardtii via HSP70A and MAPK6. Because the G protein alpha-subunit is highly conserved across microalgal species, our results should facilitate future biotechnological applications of microalgae under extreme environmental conditions. PMID- 28364783 TI - miRNA and mRNA expression profiling in rat brain following alcohol dependence and withdrawal. AB - Long- lasting alterations in brain gene expression in alcohol addiction have been determined although no clear mechanism has yet been elucidated. There exist many factors regulating the mechanism of gene expression. We aimed in this study to detect miRNA (microRNA) and mRNA expression profile at the specific brain regions regarding ethanol exposure and withdrawal. Rats were exposed to liquid alcohol consumption for 21 days. Oligonucleotides microarrays and bioinformatics analyses were used to identify gene expression, miRNA expression and their functions in the Prefrontal cortex, Hippocampus and Corpus striatum of wistar rats. A bioinformatics strategy with microarray analysis, quantitative real time PCR, bioinformatics and mRNA (messenger RNA) miRNA- miRNA integrative analyses revealed that expression models interact with neuroplasticity and synaptic processes. Those significantly changed after ethanol exposure and withdrawal processes included 160 mRNAs and 29 rat-miRNAs at prefrontal cortex, 142 mRNAs and 26 rat-miRNAs at hippocampus, and 143 mRNAs and 30 rat-miRNAs at corpus striatum. Gene ontology and ingenuity pathway analyses revealed that most of the altered genes were responsible for synaptic plasticity, neuron differentiation, chromatin organization and some certain important signaling pathways. In conclusion, consistent and integrated variations in miRNA expression and in their focus mRNAs in rat brain were noted after alcohol exposure and withdrawal. Besides, understanding the molecular mechanisms of alcohol abuse will no doubt guide to development of significant cure methods for addiction. We are of the opinion that our findings may shed light on classification of novel biomarkers. PMID- 28364784 TI - TTY2 genes deletions as genetic risk factor of male infertility. AB - Y chromosome has a number of genes that are expressed in testis and have a role in spermatogenesis. TTY2L12A and TTY2L2A are the members of testis transcript Y2 (TTY2) that are Y linked multi-copy gene families, located on Yp11 and Yq11 loci respectively. The aim of this study was to investigate frequency of TTY2L12A and TTY2L2A deletions in azoospermic patients compared with fertile males. This study was performed on 45 infertile males with idiopathic azoospermia without any AZF micro deletions (group A), 33 infertile males with azoospermia which do not screened for AZF micro deletions (group B) and 65 fertile males (group C), from October 2013 to April 2015 in west of Iran. Polymerase chain reaction (PCR) method was used for detection of TTY2L12A and TTY2L2A gene deletions in studied groups. No deletions were detected in normal fertile males of group C. 1 out of 45 azoospermic males of group A (2.22%) and 3 out of 33 azoospermic males of group B (9.09%) had TTY2L2A deletion (p= 0.409 and p= 0.036 respectively), also 1 out of 45 azoospermic males of group A (2.22%) and 4 out of 33 azoospermic males of group B (12.12%) had TTY2L12A deletion (p= 0.409 and p= 0.011 respectively). None of azoospermic males in Group A and B had deletions in both genes. Our data showed significant correlation between non-obstructive azoospermia and TTY2L12A and TTY2L2A deletions. Thus, it seems that TTY2L12A and TTY2L2A deletions can consider as one of the genetic risk factors for non-obstructive azoospermia. PMID- 28364785 TI - Stable silencing of IGF1R using Lentiviral-mediated shRNA in HEK293T cells. AB - Insulin-like growth factors are among the peptide mitogens that regulate cell proliferation and differentiation as well as mediator of antiapoptotic signals. The imbalance between the expression and activities of these molecules may lead to malignancy in cells. Evidences have suggested the insulin-like growth factor 1 receptor (IGF-1R) signaling pathway as a therapeutic target in the management and treatment of cancer. In this present study, we have generated silencing stable clones of HEK cells using six different pGIPZ (lentiviral vector) shRNAs targeted to human IGF-1R gene and a pGIPZ non-silencing shRNAmir lentiviral vector (as negative control). The recombinant lentiviral vectors were separately transduced into human embryonic kidney 293 T (HEK293T) cell lines. The knockdown of IGF-1R was confirmed by reverse transcription polymerase chain reaction (RT-PCR) and the relative IGF-1R mRNA levels were expressed as a ratio of IGF-1R to beta-actin by REST software. The results showed significant reduction in the expression of IGF 1R mRNAs in cells transduced with all six pGIPZ-IGF-1R recombinant lentivirals compared to non-silencing negative control. No significant difference was observed among the six cassettes. Results indicated that recombinant lentiviral vectors provided an efficient and stable knockdown of IGF-1R providing useful tool for IGF-1R pathway studies. PMID- 28364786 TI - Dandelion-enriched diet of mothers alleviates lead-induced damages in liver of newborn rats. AB - Lead (Pb) is a highly toxic metal present in the environment. It causes disturbances of several functions, including hematologic, renal, reproductive and nervous ones. Preventive or curative use of medicinal plants against these disorders may be a promising and safe therapeutic strategy. This study evaluated the hepatic toxic effects of prenatal exposure to lead in rats and the possible protective effect of dandelion (Taraxacum officinale) added to the diet. Female rats were given a normal diet (control) or a diet enriched with dandelion (treated). In addition, lead acetate was administered to half of the rats through drinking water from the 5th day of gestation until the 14th day postpartum. Lead toxicity was evaluated in their offspring by measuring body and liver weights, plasma biochemical parameters, liver damage, as well as protein content and activities of antioxidant enzymes in the liver tissues. Lead poisoning of mothers caused lead deposition in blood and stomach of their pups as well as hepatic tissue damages. Moreover, significant decreases in liver weight and protein content were found. Lead treatment caused oxidative stress and marked changes in the activity of antioxidant enzymes. However, no damages or biochemical changes were observed in puppies from the rats co-treated with lead and dandelion. These results indicate that supplementation of pregnant and lactating rats with dandelion protects their offspring against lead poisoning, likely through reduction of oxidative stress and liver damages. PMID- 28364787 TI - TGFbeta3 / SfaN1 gene variant and the risk factor of nonsyndromic cleft palate only among Indonesian patients. AB - Non-syndromic cleft palate only (NS CPO) is one of the most common congenital malformations that affect between 1 in 1000 - 2500 live births worldwide. The etiopathogenesis of clefts including NS CPO has been widely studied but is still poorly understood. NS CPO is considered to be a genetically complex, multifactorial disease. Based on several studies, mutations of TGFbeta3 gene emerged as the strong candidate gene associated with NS CPO. The purpose of this study was to analyze the relationship between the TGFbeta3 / SfaN1 gene variant and the risk of NS CPO in Indonesian patients. This study was case control design using samples from 31 NS CPO subjects and 35 control subjects. DNA was extracted from venous blood and the segment of TGFbeta3 gene/ SfaN1 were amplified by using polymerase chain reaction (PCR) technique, then digestion products by SfaN1 restriction enzyme which can detect locus of gene variant / polymorphism from restriction fragment length polymorphisms (RFLP) method were evaluated. The results indicated that the gene variant as substitution of base G into A was identified in TGFbeta3 gene and the frequency of heterozygous mutant GA genotype was 63,6% in NS CPO subjects and 36,4% in control subjects. The frequency of heterozygous mutant GA genotype was associated with increased risk of NS CPO (odds ratio (OR) = 2,260, 95% CI = 0,592 - 8,625). In conclusion, TGFbeta3 gene / SfaN1 polymorphism can be considered as the risk factor associated with NS CPO in Indonesian patients. PMID- 28364788 TI - The clinical research of Thinprep Cytology Test (TCT) combined with HPV-DNA detection in screening cervical cancer. AB - Our objective is to explore the clinical value of thinprep cytologic test (TCT) combined with HPV-DNA detection in screening cervical cancer. 420 cervical cancer patients admitted in our hospital between April, 2011-April, 2014 were selected. All patients received TCT and HPV-DNA detection, and cervical tissue biopsy was used to confirm the diagnosis. TCT screening results showed that there were 175 patients were >ASCUS and the positive rate was 41.7%, histopathological screening showed that there were 199 patients were >=cervical intraepithelial neoplasia (CIN) I and the positive rate was 47.4%. HPV-DNA detection showed 180 patients were positive which was 42.9%, and the positive rate of HPV-DNA detection was increased as the disease severity increased. The sensitivity of TCT combined with HPV-DNA detection was higher than single TCT or HPV-DNA, however the specificity was relatively low, and the positive predictive value and negative predictive value were higher which were similar to pathological results. TCT combined with HPV-DNA detection has high sensitivity and accuracy in screening cervical cancer, which is worthy of clinical application. PMID- 28364789 TI - Ghrelin did not change coronary angiogenesis in diet-induced obese mice. AB - Ghrelin is a 28 amino acids peptide that initially was recognized as an endogenous ligand for growth hormone secretagogue receptor (GHSR). Recently, a number of studies demonstrated that ghrelin is a cardiovascular hormone with a series cardiovascular effect. The main objective of this study was to investigate the effect of systemic ghrelin administration on angiogenesis in the heart and its correlation with serum leptin levels in normal and diet-induced obese mice. 24 male C57BL/6 mice were randomly divided into four groups: normal diet (ND) or control, ND+ghrelin, high-fat-diet (HFD) or obese and HFD+ghrelin (n=6/group). Obese and control groups received HFD or ND, respectively, for 14 weeks. Then, the ghrelin was injected subcutaneously 100ug/kg twice daily. After 10 days, the animals were sacrificed, blood samples were taken and the hearts were removed. The angiogenic response in the heart was assessed by immunohisochemical staining. HFD significantly increased angiogenesis in the heart expressed as the number of CD31 positive cells than standard diet. Ghrelin did not alter angiogenesis in the heart in both obese and control groups, however, it reduced serum nitric oxide (NO) and leptin levels in obese mice. There was a strong positive correlation between the number of CD31 positive cells and serum leptin concentration (r=0.74). Leptin as an angiogenic factor has a positive correlation with angiogenesis in the heart. Although systemic administration of ghrelin reduced serum leptin and NO levels in obese mice, however, it could not alter coronary angiogenesis. PMID- 28364790 TI - The effects of melatonin on oxidative stress and prevention of primordial follicle loss via activation of mTOR pathway in the rat ovary. AB - Mammalian Target of Rapamycin (mTOR) signaling pathway has important roles in the regulation of puberty onset, gonadotropin secretion, follicular development and ovulation. Melatonin (N-acetyl-5-methoxytryptamine) is a lipophilic hormone has multiple functions in regulating the fertility. Recent studies have shown that melatonin affected the number or maturation of follicles in the ovary. The aim of this study was to investigate the effects of melatonin on mTOR expression and quantity of follicle in rat ovary. In the present study, a total of 45 female rats were randomly divided into three groups. Group 1; Control (C), Group 2: Vehicle (V) and Group 3; Melatonin (M). Melatonin was administered intraperitoneally at a dose of 50 mg/kg/day for 30 days in Melatonin group. The effects of Melatonin on the expression of mTOR and downstream components were determined by Western Blot and Reverse Transcriptase PCR analysis. Upon Western Blot and RT-PCR evaluations, we detected higher expression and activation of mTOR, P70S6K, PKCalpha, PCNA and higher numbers of primordial follicles in melatonin group compared with V and C group. In addition to this results, melatonin decreased oxidative stress markers, such as MDA, on the contrary, levels of antioxidative markers, such as CAT and GPx, were increased by melatonin in rat ovary. This study indicated that melatonin may have a significant protective effect on primordial follicles and increase the expression of mTOR and downstream components in rat ovary. Melatonin treatment may have a beneficial effect on fertility. PMID- 28364791 TI - Effect of nitrogen sources on some morphological characteristics of in vitro stevia rebaudiana Bertoni. AB - Stevia rebaudiana Bertoni belongs to Asteraceae family that leaves 200-300 times sweeter than sugar. Low seed fertility is one of the most important problems in Stevia production. So, Plant tissue culture is an efficient method for mass propagation of Stevia. In this research, we studied the effect of various concentrations of nitrogen on some morphological traits of stevia under in vitro conditions. We used axillary nodes as explants and they were cultured on Murashige and Skoog (MS) medium containing inorganic nitrogen sources i.e. NH4NO3(0, 825 and 1650 mg/l), KNO3(0, 950 and 1900 mg/l) were observed. The cultures were kept for 4 weeks at a temperature of 25+/-2 degrees C with a photoperiod of 16/8 hour low light/dark each day. Maximum shoot length (89.33 mm), dry weight of plants (0.10 mg) and leaf fresh weight (0.42 mg) was observed on MS medium with 1650 mg/l NH4NO3 and 950 mg/l KNO3. Minimum shoot length (6.13 mm), root length (6.60 mm), leaf number (4.26), leaf dry weight (0.01 mg), leaf fresh weight (0.05 mg), total dry and fresh weight (0.02 and 0.15 mg) and growth rate was observed on a MS medium without nitrogen sources. Moreover, presence of nitrogen sources increases both shooting and rooting in Stevia rebaudiana Bertoni. PMID- 28364792 TI - Identification of bacteria using volatile organic compounds. AB - The rapid diagnosis of respiratory infections has always been an important goal for medical professionals, because rapid and accurate diagnosis leads to proper and timely treatment, and consequently, reduces the costs of incorrect and long term treatments, and antibiotic resistance. The present study was conducted with the aim of detecting volatile organic compounds (VOCs) in three bacteria: Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae. Headspace of the studied bacteria, after separately culturing in two types of liquid medium in three different time-periods, was extracted by solid phase microextraction and analysed by gas chromatography mass spectrometry The analysis results of the VOCs produced by the studied bacteria indicate that some VOCs are common and some are unique in each bacterium. 1-penten-3-ol, levomenthol, and 2-octyl-1-ol for P. aeruginosa, cyclohexene, 4-ethenyl, and cis-Dihydro-alpha-terpinyl acetate for A. baumannii and 1,3-butadiene, butyraldehyde, longifolene, octyl acetate, tridecanol, dodecenal, (E)-2-hexyl ester, butanoic acid, and 5,5-dodecadinyl-1 12 diol for K. pneumoniae were identified as unique VOCs for each bacterium. Finally, it can be said that an accurate and rapid bacterial detection method can be achieved by using a tool that can detect bacterial VOCs. However, more studies are needed to design a tool for which all aspects have been assessed, so that it can give us a more complete pattern for the use of these compounds as biomarkers. PMID- 28364793 TI - Signaling networks in TMPRSS2-ERG positive prostate cancers: Do we need a Pied Piper or sharpshooter to deal with "at large" fused oncoprotein. AB - Overwhelmingly increasing scientific evidence has provided near complete resolution of prostate cancer landscape and it is now more understandable that wide ranging factors underlies its development and progression. Increasingly it is being realized that genetic/epigenetic factors, Intra-tumoral and inter tumoral heterogeneity, loss of apoptosis, dysregulations of spatio-temporally controlled signaling cascades, Darwinian evolution in response to therapeutic pressures play instrumental role in prostate carcinogenesis. Moreover, multi directional patterns of spread between primary tumors and metastatic sites have also been studied extensively in prostate cancer. Research over the years has gradually and systematically revealed closer association between tumor phenotype and type of gene fusion. Latest developments in deep sequencing technologies have shown that gene fusions originate in a non-random, cell type dependent manner and are much more frequent than previously surmised. These findings enabled sub classification and categorization of seemingly identical diseases. Furthermore, research methodologies have shown that many gene fusions inform us about risk stratification and many chimeric proteins encoded by the fused genes are being studied as drug target/s. We partition this multi-component review into the molecular basis of formation of fusion transcripts, how protein network is regulated in fusion positive prostate cancer cells and therapeutic strategies which are currently being investigated to efficiently target fusion transcript and its protein product. PMID- 28364794 TI - Review of new insights into antimicrobial agents. AB - People have known the bacteria and have used various ways to deal with them, from a long time ago. Perhaps, natural antibiotics with have been the first step in fighting against pathogens. However, several factors, such as dealing with unfamiliar bacteria or emergence of drug-resistant species, have motivated us to discover new antibiotics or even change previous types. In this regard, a variety of natural and synthetic antibiotics with different origins, mechanism of action, structures and functional spectrum, have been developed and used. Some impact on the synthesis of nucleic acids and some affect protein synthesis so destroy bacteria. There is a ring in the structure of most of the antibiotics which gives them special properties. However, despite their numerous advantages, antibiotics also have drawbacks ehich limit their use in all situations. Therefore, other approaches such as photodynamic therapy (PDT) and antibacterial peptides were considered as alternatives. Photodynamic therapy (PDT) is a treatment that uses photosensitizing agents, along with light, to kill bacteria. The photosensitizing agents only work after they have been activated by certain kinds of light. Antibacterial peptides are a unique and diverse group of molecules which have between 12 and 50 amino acids in general. In this paper, will reviewt hree mentioned topics, namely antibiotics, photodynamic therapy and antibacterial peptides and will discuss the advantages and disadvantages of each approach briefly. PMID- 28364795 TI - The significance of DNA methylation profile in metastasis-related genes for the progression of colorectal cancer. AB - DNA methylation, an epigenetic modification plays a role in the pathogenesis of colorectal cancer (CRC). CRC cases, both sporadic and familial, are often characterized by abnormal pattern of the cytosine methylation in CpG dinucleotides in regulatory regions of genes important for cancer transformation. Also genes mutated in CRC can have their epigenetic pattern altered and we suggest that changes in DNA methylation array can be important for CRC metastatic potential - the main reason of CRC-associated mortality. These genes are: KRAS, genes of the Rho family of GTPases, MACC1, Met, MTA1 and RASSF1A. In addition, genes encoding miRNA important for epithelial mesenchymal transition and other metastasis-related effects, such as mir-9, miR-34 and miR-210 can be good candidates for associating their DNA methylation profiles with CRC metastasis. Analysis of DNA methylation profile in various stages of CRC along with other genetic/epigenetic changes specific for all main stages of CRC transformation could help in anti-metastatic therapy immediately after CRC diagnosis. However, targeting DNA methylation pattern in CRC therapy is a conception, which requires further work to precisely change DNA methylation array, without affecting genes, whose expression should not be changed. PMID- 28364796 TI - Comparison of two DNA extraction protocols from leave samples of Cotinus coggygria, Citrus sinensis and Genus juglans. AB - High quality DNA is essential for molecular research. Secondary metabolites can affect the quantity and quality DNA. In current research two DNA isolation methods including CTAB and Delaporta (protocols 1 & 2 respectively) were applied in three leave samples from Cotinus coggygria, Citrus sinensis and Genus juglans that their leaves are rich of secondary metabolites. We successfully isolated DNA from C. coggygria, C. sinensis and Genus Juglans using the two protocols described above. Good quality DNA was isolated from C. coggygria, C. sinensis and Genus Juglans using protocol 1, while protocol 2 failed to produce usable DNA from these sources. The highest amount of DNA (1.3-1.6) was obtained from them using protocol 1. As we discovered, procedure 1 may work better for plants with secondary metabolites. PMID- 28364797 TI - [A MOOC? A new approach for teaching pathology !] PMID- 28364798 TI - Antioxidative cellular response of lepidopteran ovarian cells to photoactivated alpha-terthienyl. AB - Photodynamic sensitizers as useful alternative agents have been used for population control against insect pests, and the response of insect ovarian cells towards the photosensitizers is gaining attention because of the next reproduction. In this paper, antioxidative responses of lepidopteran ovarian Tn5B1-4 and Sf-21 cells to photoactivated alpha-terthienyl (PAT) are investigated. PAT shows positive inhibitory cytotoxicity on the two ovarian cells, and its inhibition on cell viability is enhanced as the concentrations are increased and the irradiation time is extended. Median inhibitory concentrations (IC50) are 3.36MUg/ml to Tn5B1-4 cells, and 3.15MUg/ml to Sf-21 cells at 15min-UV A irradiation 2h-dark incubation. Under 10.0MUg/ml PAT exposure, 15min-UV-A irradiation excites higher ROS production than 5min-UV-A irradiation does in the ovarian cells, the maximum ROS content is about 7.1 times in Tn5B1-4 cells and 4.3 times in Sf-21 cells, and the maximum malondialdehyde levels in Tn5B1-4 and Sf-21 cells are about 1.47- and 1.36-fold higher than the control groups, respectively. Oxidative stress generated by PAT strongly decreases the activities of POD, SOD and CAT, and induces an accumulation of Tn5B1-4 cells in S phase and Sf-21 cells in G2/M phase in a concentration-dependent fashion. Apoptosis accumulation of Tn5B1-4 cells and the persistent post-irradiation cytotoxicity are further observed, indicating different antioxidative tolerance and arrest pattern of the two ovarian cells towards the cytotoxicity of PAT. PMID- 28364799 TI - Diuron treatment reveals the different roles of two cyclic electron transfer pathways in photosystem II in Arabidopsis thaliana. AB - Three ecotypes of Arabidopsis thaliana, ecotype Columbia (Wild type, Wt) and two mutants (pgr5 and ndf4), were used to evaluate the effects of diuron on photosynthetic activity of A. thaliana. It was found that diuron adversely affected the fresh weight and chlorophyll content of the plants. Chlorophyll fluorescence studies determined that the pgr5 mutant was more sensitive to diuron than Wt and the ndf4 mutant. Gene expression analysis revealed different roles for the two cyclic electron transfer (CET) pathways, NAD(P)H dehydrogenase (NDH) and proton gradient regulation (PGR5) pathways, in the plant after diuron treatment. For example, a gene in the NDH pathway, lhca5, was activated in the low dose (LD) group in the pgr5 mutant, but was down-regulated in the moderate dose (MD) group, along with two other NDH-related genes (ppl2 and ndhH). In the PGR5 pathway, the pgr5 gene was functional under conditions of increased stress (MD group), and was up-regulated to a greater extent in the ndf4 mutant than that in the Wt and pgr5 mutant. Our results suggest that the PGR5 pathway in plants is more important than the NDH pathway during resistance to environmental stress. Deficiencies in the PGR5 pathway could not be counteracted by the NDH pathway, but deficiencies in the NDH pathway could be overcome by stimulating PGR5. PMID- 28364800 TI - Pyrethrum-extract induced autophagy in insect cells: A new target? AB - Pyrethrum extract (PY) is a natural insecticide that is extensively used across the world, and its insecticidal activity is attributed to the presence of six active esters known as pyrethrins. PY targets the nervous systems of insects by delaying the closure of voltage-gated sodium ion channels in the nerve cells. However, limited information is available regarding the toxicity and detailed mechanisms of PY activity. This study is aimed at understanding the toxicity effect and the underlying mechanisms of PY in cellular level, which have not yet been investigated on the non-nervous system of insects. Results of the MTT assay showed that the viability of Sf9 cells was inhibited by PY in a time- and concentration-dependent manner, and observation under a microscope revealed accumulation of intracellular vacuoles. Monodansylcadaverine staining analysis and transmission electron microscope images revealed typical autophagic morphological changes in PY-treated Sf9 cells. Autophagy-related proteins such as LC3, p62, and beclin-1 were detected using by Western blotting. Protein expression levels of LC3-II and beclin-1 were upregulated while that of p62 was markedly downregulated in a dose-dependent manner upon the PY treatment in Sf9 cells. In conclusion, these results indicate that PY could induce autophagy in the non-nervous system of insects which may contribute to its insecticidal mechanism. PMID- 28364801 TI - Sulfated lentinan induced mitochondrial dysfunction leads to programmed cell death of tobacco BY-2 cells. AB - Sulphated lentinan (sLTN) is known to act as a resistance inducer by causing programmed cell death (PCD) in tobacco suspension cells. However, the underlying mechanism of this effect is largely unknown. Using tobacco BY-2 cell model, morphological and biochemical studies revealed that mitochondrial reactive oxygen species (ROS) production and mitochondrial dysfunction contribute to sLNT induced PCD. Cell viability, and HO/PI fluorescence imaging and TUNEL assays confirmed a typical cell death process caused by sLNT. Acetylsalicylic acid (an ROS scavenger), diphenylene iodonium (an inhibitor of NADPH oxidases) and protonophore carbonyl cyanide p-trifluoromethoxyphenyl hydrazone (a protonophore and an uncoupler of mitochondrial oxidative phosphorylation) inhibited sLNT induced H2O2 generation and cell death, suggesting that ROS generation linked, at least partly, to a mitochondrial dysfunction and caspase-like activation. This conclusion was further confirmed by double-stained cells with the mitochondria specific marker MitoTracker RedCMXRos and the ROS probe H2DCFDA. Moreover, the sLNT-induced PCD of BY-2 cells required cellular metabolism as up-regulation of the AOX family gene transcripts and induction of the SA biosynthesis, the TCA cycle, and miETC related genes were observed. It is concluded that mitochondria play an essential role in the signaling pathway of sLNT-induced ROS generation, which possibly provided new insight into the sLNT-mediated antiviral response, including PCD. PMID- 28364802 TI - Biocontrol potential of Halotolerant bacterial chitinase from high yielding novel Bacillus Pumilus MCB-7 autochthonous to mangrove ecosystem. AB - The multifaceted role of chitinase in medicine, agriculture, environmental remediation and various other industries greatly demands the isolation of high yielding chitinase producing microorganisms with improved properties. The current study aimed to investigate the isolation, characterization and biocontrol prospective of chitinase producing bacterial strains autochthonous to the extreme conditions of mangrove ecosystems. Among the 51 bacterial isolates screened, Bacillus pumilus MCB-7 with highest chitinase production potential was identified and confirmed by 16S rDNA typing. Chitinase enzyme of MCB-7 was purified; the chitin degradation was evaluated by SEM and LC-MS. Unlike previously reported B.pumilus isolates, MCB-7 exhibited highest chitinase activity of 3.36U/mL, active even at high salt concentrations and temperature up to 60 degrees C. The crude as well as purified enzyme showed significant antimycotic activity against agricultural pathogens such as Aspergillus flavus, Aspergillus niger, Aspergillus fumigatus, Ceratorhiza hydrophila and Fusarium oxysporum. The enzyme also exhibited biopesticidal role against larvae of Scirpophaga incertulas (Walker). [Lep.: Pyralidae], a serious agricultural pest of rice. The high chitinolytic and antimycotic potential of MCB-7 increases the prospects of the isolate as an excellent biocontrol agent. To the best of our knowledge, this is the first report of high chitinase yielding Bacillus pumilus strain from mangrove ecosystem with a biocontrol role against phytopathogenic fungi and insect larval pests. PMID- 28364803 TI - Pollen viability, physiology, and production of maize plants exposed to pyraclostrobin+epoxiconazole. AB - The use of fungicides in maize has been more frequent due to an increase in the incidence of diseases and also the possible physiological benefits that some of these products may cause. However, some of these products (e.g., strobilurins and triazoles) may interfere with physiological processes and the formation of reproductive organs. Therefore, the effect of these products on plants at different developmental stages needs to be better understood to reduce losses and maximize production. The effect of the fungicide pyraclostrobin+epoxiconazole (P+E) was evaluated at different growth stages in meiosis, pollen grain viability and germination, physiology, and production of maize plants in the absence of disease. An experiment was carried out with the hybrid DKB390 PROII and the application of pyraclostrobin+epoxiconazole at the recommended dose and an untreated control at 3 different timings (S1 - V10; S2 - V14; S3 - R1) with 5 replications. Gas exchange, chlorophyll fluorescence, pollen viability and germination, as well as the hundred-grain weight were evaluated. Anthers were collected from plants of S1 for cytogenetic analysis. The fungicide pyraclostrobin+epoxiconazole reduced the viability of pollen grains (1.4%), but this was not enough to reduce production. Moreover, no differences were observed in any of the other parameters analyzed, suggesting that P+E at the recommended dose and the tested stages does not cause toxic effects. PMID- 28364804 TI - Altered gene expression by sedaxane increases PSII efficiency, photosynthesis and growth and improves tolerance to drought in wheat seedlings. AB - Succinate dehydrogenase inhibitor (SDHI) fungicides have been shown to increase PSII efficiency and photosynthesis under drought stress in the absence of disease to enhance the biomass and yield of winter wheat. However, the molecular mechanism of improved photosynthetic efficiency observed in SDHI-treated wheat has not been previously elucidated. Here we used a combination of chlorophyll fluorescence, gas exchange and gene expression analysis, to aid our understanding of the basis of the physiological responses of wheat seedlings under drought conditions to sedaxane, a novel SDHI seed treatment. We show that sedaxane increased the efficiency of PSII photochemistry, reduced non-photochemical quenching and improved the photosynthesis and biomass in wheat correlating with systemic changes in the expression of genes involved in defense, chlorophyll synthesis and cell wall modification. We applied a coexpression network-based approach using differentially expressed genes of leaves, roots and pregerminated seeds from our wheat array datasets to identify the most important hub genes, with top ranked correlation (higher gene association value and z-score) involved in cell wall expansion and strengthening, wax and pigment biosynthesis and defense. The results indicate that sedaxane confers tolerant responses of wheat plants grown under drought conditions by redirecting metabolites from defense/stress responses towards growth and adaptive development. PMID- 28364805 TI - Transcriptomic alterations in Sitophilus zeamais in response to allyl isothiocyanate fumigation. AB - To study the fumigation mechanisms of Allyl isothiocyanate (AITC) a promising biorational alternative to present fumigants (phosphine and methyl bromide), and provide theoretical basis for its further development in the control of stored grain pests, this research presents a transcriptome analysis of Sitophilus zeamais fumigated with AITC at the concentration of LC50 (5.69MUg/mL) and control over 8h. 21,869,022 and 23,873,110 clean reads in insects fumigated with AITC and control were gained, respectively. The results of RNA-seq were confirmed by qRT PCR determination of the expression levels of NADH dehydrogenase subunit 6 and Vacuolar ATP synthase subunit B in the insects fumigated with AITC at different concentrations. After enrichment analysis of differentially expressed genes, 117 over-expressed and 271 down-regulated transcripts were gained. Following GO enrichment, these transcripts were classified into 38 GO subgroups (at level 2), and the majority enriched GO terms were "Binding" "Cell process" and "metabolic". KEGG enrichment analysis showed that the majority enriched pathway were "Folding, sorting and degradation", "Transport and catabolism", "Energy metabolism", and "Carbohydrate metabolism". Connected with previous researches on mechanisms of isothiocyanates, cytoskeleton collapse and mitochondria dysfunction are proposed to be significant lethal mechanisms of AITC. PMID- 28364806 TI - Lufenuron impact upon Anthonomus grandis Boheman (Coleoptera: Curculionidae) midgut and its reflection in gametogenesis. AB - The insecticide Match(r) (lufenuron), one of the main insect growth regulators used in pest control, has been presented as a viable alternative against the boll weevil, Anthonomus grandis (Coleoptera: Curculionidae), by inhibiting chitin synthesis. Thus, this study aimed to examine whether Match(r) interferes in the synthesis of the peritrophic matrix, leading to changes in the midgut epithelium, resulting in nutritional deficiency and reflecting, thereby, in the gametogenesis process of A. grandis. Floral cotton buds were immersed in the insecticide solution (800MUL of Match(r)+200mL of distilled water) and offered to the adult insects. The midguts of the insects were evaluated after 24 and 120h after feeding. The gonads were evaluated after 120h. The results showed that Match(r), in both evaluation periods, induced histopathological alterations such as disorganization, vacuolization and desquamation of the midgut epithelium; histochemical modifications in the distribution patterns of carbohydrates, although without quantitative changes; and a strong decrease in protein levels. No apoptosis were observed, however, there was an increase in the number of regenerative cell nests. In the testicles, a reduction in the amount of spermatozoids and reduced carbohydrate levels were observed, but no difference in protein levels. The ovarioles presented structural disorganization of follicular cells, yolk reduction and decrease in protein levels, however, no change in carbohydrates levels was noted. Therefore, it is concluded that Match(r) performs histopathologic and histochemical alterations in the midgut epithelium and the gonads of A. grandis adults, reflecting in the gametogenesis process, presenting itself as a promising tool in the management of this pest on cotton crops. PMID- 28364807 TI - Laboratory selection of chlorpyrifos resistance in an Invasive Pest, Phenacoccus solenopsis (Homoptera: Pseudococcidae): Cross-resistance, stability and fitness cost. AB - The cotton mealybug, Phenacoccus solenopsis is an important polyphagous sucking pest of ornamentals, horticultural and fiber crops worldwide. Some P. solenopsis populations have developed insecticide resistance. This study evaluated cross resistance, stability of insecticide resistance and life history traits affected by chlorpyrifos resistance in P. solenopsis. After nine generations selected with chlorpyrifos, P. solenopsis exhibited a 539.76-fold resistance level compared to an unselected population (UNSEL Pop). Chlorpyrifos selected population (Chlor-SEL Pop) displayed moderate cross-resistance to profenofos, nitenpyram and high cross resistance to lambda-cyhalothrin. Biological parameters of P. Solenopsis were affected by chlorpyrifos resistance. The Chlor-SEL Pop had a significant reduction in fitness (relative fitness=0.10), along with significant decreases in pupal weight, fecundity, egg hatching %, intrinsic rate of natural population increase, biotic potential, and mean relative growth rate. It is concluded that selection with chlorpyrifos had marked effect on resistance development in P. solenopsis and upon removal of selection pressure chlorpyrifos resistance declined significantly indicating unstable resistance. Development of resistance led to high fitness costs for the chlorpyrifos-selected strain. These findings should be helpful for better and more successful resistance management of P. solenopsis. PMID- 28364808 TI - Suppressing the activity of trehalase with validamycin disrupts the trehalose and chitin biosynthesis pathways in the rice brown planthopper, Nilaparvata lugens. AB - Trehalase (TRE) is a key enzyme in trehalose degradation and has important functions in insect growth and chitin synthesis. Though validamycin has the potential for pest control by suppressing TRE activities, it is not known whether validamycin acts on both trehalose and chitin metabolism. TRE1 and TRE2 activities and glucose and glycogen contents decreased significantly after the injection of different doses of validamycin solution compared with the control group, while the trehalose content increased significantly. Overall, it showed that about 13 to 38% insects was appeared abnormal phenotypes, and 10 to 57% of insects died 48h after injection of solutions with different concentrations of validamycin; the chitin content also decreased significantly. Validamycin altered the relative expression levels of trehalose, glycogen and chitin metabolism related genes by suppressing the activities of two TREs. We showed that the expression levels of three TRE and two trehalose-6-phosphate synthase (TPS) genes increased, while the expression levels of GP; CHS1 and its two transcripts, CHS1a, CHS1b; six chitinases, including Cht3, Cht4, Cht5, Cht6, Cht7, Cht9; and the HK, G6PI2, GFAT, GNPNA, PAGM1, UAP, VVL, CI and AP genes decreased significantly 48h after the injection of any validamycin concentration compared with the control group. These results demonstrate that by inhibiting the activities of two TREs, validamycin alters N. lugens chitin synthesis and degradation and affects trehalose and chitin metabolism-related gene expression. The development of TRE inhibitors may provide effective pest control in the future. PMID- 28364810 TI - Liver Transplantation and Bariatric Surgery: Best Approach. AB - Obesity has become increasingly prevalent, and the number of obese patients in need of liver transplant is expected to continue to increase. In addition, liver disease due to nonalcoholic fatty liver disease is expected to become the leading cause of liver transplantation in the near future. However, obesity remains a relative contraindication in liver transplant. New strategies in managing this patient population are clearly needed. To this end, the authors review the current literature on the efficacy of bariatric surgery in the setting of liver transplantation in obese patients. PMID- 28364809 TI - Influence of Ephestia kuehniella stage larvae on the potency of Bacillus thuringiensis Cry1Aa delta-endotoxin. AB - The economically important crop pest Ephestia kuehniella was tested at two stages of larval development for susceptibility to Bacillus thuringiensis Cry1Aa toxin. Bioassays showed that toxicity decreased during the development of larvae stage. In fact, Cry1Aa toxins from BNS3-Cry- (pHT-cry1Aa) showed low toxicity against the first-instar larvae (L1) with a LC50 value of about 421.02MUg/g of diet and was not toxic against the fifth-instar (L5), comparing to the BLB1 toxins used as positive control which represent a LC50 value of about 56.96 and 84.21MUg/g of diet against L1 and L5 instars larvae, respectively. Effects of Cry1Aa toxins were reflected in histopathological observations by the weak destruction of midgut epithelium, slight hypertrophy of epithelial cells, and minor alteration of brush border membrane (BBM) detected mainly in L1 larvae stage comparing to the more extensive damage caused by BLB1 toxins. Interestingly, in vitro proteolysis of Cry1Aa toxins was found to correlate with the difference of toxicity during larval stage development. In fact, the weak proteinase activity detected inside the L1 midgut has led to the persistence of the Cry1Aa active forms (65 and 58kDa) during prolonged incubations, causing the alterations described previously. Three subfamilies of aminopeptidase (APN) receptors were detected in both larvae instars with different intensities and molecular weights (150kDa and 55kDa for APN1, and 90kDa for APN2 and APN4). Remarkably, binding assay using Cry1Aa toxin seems to have no direct correlation with larval stages toxicity differences, since same putative receptors were detected. Understanding the reasons for the clear differences in the effectiveness of Cry1Aa toxins during larval development stages of E. kuehniella is very important for the design of future improvement insecticidal approaches and for the accomplishment of resistance prevention strategies. PMID- 28364811 TI - Treatment Options in Patients Awaiting Liver Transplantation with Hepatocellular Carcinoma and Cholangiocarcinoma. AB - Liver transplantation (LT) provides a good chance of cure for selected patients with hepatocellular carcinoma (HCC) and perihilar cholangiocarcinoma (pCCA). Patients with HCC on a waiting list for LT are at risk for tumor progression and dropout. Treatment of HCC with locoregional therapies may lessen dropout due to tumor progression. Strict selection and adherence to the LT criteria for patients with pCCA before and after neoadjuvant chemotherapy are critical for optimal outcome with LT. This article reviews the existing data for the various treatment strategies used for patients with HCC and pCCA awaiting LT. PMID- 28364812 TI - Coagulopathy Before and After Liver Transplantation: From the Hepatic to the Systemic Circulatory Systems. AB - The hemostatic environment in patients with cirrhosis is a delicate balance between prohemostatic and antihemostatic factors. There is a lack of effective laboratory measures of the hemostatic system in patients with cirrhosis. Many are predisposed to pulmonary embolus, deep vein thrombosis, and portal vein thrombosis in the pretransplantation setting. This pretransplantation hypercoagulable milieu seems to extend for at least several months post transplantation. Patients with nonalcoholic fatty liver disease, inherited thrombophilia, portal hypertension in the absence of cirrhosis, and hepatocellular carcinoma often require individualized approach to anticoagulation. Early reports suggest a potential role for low-molecular-weight heparins and direct-acting anticoagulants. PMID- 28364813 TI - Model for End-Stage Liver Disease-Sodium Score: The Evolution in the Prioritization of Liver Transplantation. AB - The adoption of the model of end-stage liver disease (MELD) score as surrogate marker of liver disease severity has been the greatest change in liver allocation. Since its implementation, waiting time has lost significance. The MELD score calculation was later modified to reflect the contribution of hyponatremia in the estimation of mortality risk. However, the MELD score does not capture accurately the risk of mortality of patients with hepatocellular carcinoma (HCC). Therefore the arbitrary assignment of MELD points has been used for HCC patients. The current allocation system still prioritizes transplantation in HCC patients. PMID- 28364814 TI - Extended Criteria Donors in Liver Transplantation. AB - Mortality rates on the liver transplant waiting list are increasing. The shortage of organs has resulted in higher utilization of extended criteria donors (ECDs), with centers pushing the limits of what is acceptable for transplantation. Donor quality is more appropriately represented as a continuum of risk, and careful selection and matching of ECD grafts with recipients may lead to excellent outcomes. Although there is no precise definition for what constitutes an ECD liver, this review focuses on frequently cited characteristics, including donor age, steatosis, donation after cardiac death, and donors with increased risk of disease transmission. PMID- 28364815 TI - Challenges in Renal Failure Treatment Before Liver Transplant. AB - Acute kidney injury (AKI) is common in patients with cirrhosis and ascites on the waiting list for liver transplant. Hepatorenal syndrome (HRS) is an important cause of AKI among cirrhotics. A dynamic definition of AKI in patients with cirrhosis has been introduced and changed the diagnosis criteria. Liver transplantation remains the better option but the medical management of HRS has changed. Terlipressin plus albumin is currently the gold standard. Surgery and liver or kidney support systems have been recommended. Clinical trials will assess the most appropriate approach for the treatment of HRS in light of the revised diagnostic criteria. PMID- 28364816 TI - De Novo and Recurrence of Nonalcoholic Steatohepatitis After Liver Transplantation. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in developing countries. Approximately 25% of patients with NAFLD develop nonalcoholic steatohepatitis (NASH). NASH-related cirrhosis is now a leading listing indication for liver transplantation in the United States. Although posttransplant survival for NASH-related cirrhosis is comparable with that of other liver diseases, many patients have features of metabolic syndrome, which can contribute to a recurrence of NAFLD or NASH. This article reviews the epidemiology, pathophysiology, and treatment of de novo and recurrence of NASH after liver transplantation. PMID- 28364817 TI - Management of Immunosuppression in Liver Transplantation. AB - Liver transplantation outcomes have significantly improved over the past few decades owing largely to the introduction of effective immunosuppression medications. Further comprehension of the unique immune microenvironment of the liver has led to the development of newer molecular targeted therapeutics. Understanding the mechanism of action and adverse effect profiles of these medications is crucial for appropriate management of posttransplant patients. In this review, the author describes the immunologic response elicited by liver transplantation, chronicles the various immunosuppressant drug classes, discusses the evidence behind their use, and evaluates the management of special subpopulations of posttransplantation patients. PMID- 28364818 TI - Liver Transplantation in Alpha-1 Antitrypsin Deficiency. AB - Alpha-1 antitrypsin (AAT) deficiency is a common inherited metabolic disorder caused by a point mutation in the SERPIN1A gene. A small portion of homozygous PI*ZZ individuals develop severe liver disease that requires liver transplantation. Posttransplant survival is excellent. The largest burden of advanced liver disease lies within the adult population rather than children. Evaluation of lung function in adults before transplant is essential because of the underlying risk for chronic obstructive pulmonary disease. Post-liver transplantation lung function should also be monitored for decline. Although uncommon, cases of simultaneous lung and liver transplant for AAT deficiency have been reported. PMID- 28364819 TI - Predictors of Cardiovascular Events After Liver Transplantation. AB - Indications for liver transplant have been extended, and older and sicker patients are undergoing transplantation. Infectious, malignant, and cardiovascular diseases account for the most posttransplant deaths. Cirrhotic patients can develop heart disease through systemic diseases affecting the heart and the liver, cirrhosis-specific heart disease, or common cardiovascular. No single factor can predict posttransplant cardiovascular complications. Patients with history of cardiovascular disease, and specific abnormalities on echocardiography, electrocardiography, or serum markers of heart disease seem to be at increased risk of complications. Pretransplant cardiovascular evaluation is essential to detecting these risk factors so their effects can be mitigated through appropriate intervention. PMID- 28364821 TI - Cholestatic Liver Diseases After Liver Transplant. AB - Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are the most common cholestatic liver diseases (CLD) in adults. Liver transplant (LT) is desirable for those who progress to end-stage liver disease. CLD have become an uncommon indication for LT. PSC and PBC accounted for 7.1% of all adult LT in 2015. CLD have the best post-LT outcomes compared with other indications for LT. Disease recurrence of PSC and PBC after LT is reported in up to 37% and 43% of LT recipients, respectively. Although recurrent PBC does not affect post-LT outcomes, recurrent PSC is associated with worse post-LT survival. PMID- 28364823 TI - Liver Retransplantation: How Much Is Too Much? AB - Hepatic retransplantation has been surgically challenging since the beginning of liver transplant. Outcomes have improved over time, but patient survival with retransplant continues to be significantly worse than that of primary transplant. Many studies have focused on factors to predict outcomes. Models have been developed to help predict risk, but the decision for retransplant must be a multidisciplinary transplant team decision. The question of "when is too much?" can be guided by recipient and donor factors but is an ethical decision that must be made by the liver transplant team. PMID- 28364822 TI - The New Era of Hepatitis C: Therapy in Liver Transplant Recipients. AB - Hepatitis C virus (HCV) is the leading cause of end-stage liver disease in both Europe and the United States and is the most common reason for liver transplant. In the absence of antiviral therapy, recurrent infection is the norm with subsequent graft hepatitis and impaired survival. Whether it may be better to postpone therapy in patients in whom higher risk of failure and toxicity is coupled with lower chance of liver function improvement likely depends on several factors, including waiting time, center allocation policy, presence of hepatocellular carcinoma and local prevalence of anti-HCV-positive donors. PMID- 28364824 TI - Erratum. PMID- 28364820 TI - Autoimmune Hepatitis in the Liver Transplant Graft. AB - Recurrent autoimmune hepatitis (AIH) and de novo AIH are 2 important causes of late graft failure after liver transplantation (LT). Recurrent AIH occurs in patients who undergo LT for AIH. De novo AIH occurs in patients who are transplanted for etiologies other than AIH. Although typically treated with standard treatment for AIH, including corticosteroids and azathioprine, both recurrent and de novo AIH may progress to end-stage liver disease requiring retransplantation. PMID- 28364825 TI - Liver Transplantation in the Twenty-First Century. PMID- 28364826 TI - Hand hygiene mantra: teach, monitor, improve, and celebrate. PMID- 28364827 TI - Common decisions made and actions taken during small-animal consultations at eight first-opinion practices in the United Kingdom. AB - In order for veterinary surgeons to undertake an evidence-based approach to making decisions about their patients, it is important that new evidence is generated to support the clinical decision-making process. Many of the decisions are likely to be around the actions taken to treat or manage health problems discussed during the consultation, and little is currently known about the factors which affect the type of action taken. The aim of this study was to determine the decisions made and actions taken for health problems discussed during first-opinion small-animal consultations, as well as identifying factors which may affect the decision-making process. Data were gathered during direct observation of small-animal consultations conducted by 62 veterinary surgeons in eight first-opinion practices in the United Kingdom. For each patient presented, data were gathered on all health problems discussed during the consultation. The decision made (whether an action was taken or not) and the action taken where applicable (e.g. therapeutic treatment with antibiotics) was also recorded. A three-level multivariable logistic-regression model was developed, with problem (Level 1) nested within patient (Level 2) nested within consulting veterinary surgeon (Level 3), and a binary outcome variable of action versus no action. At least one action was taken for 69% (n=2203/3192) of all problems discussed. Therapeutic treatment was the most common action taken (n=1286/3192 problems; 40.3%), followed by management advice (n=1040/3192; 32.6%) and diagnostic work-up (n=323/3192; 10.1%). The most common therapeutic treatment was antibiotics (n=386/1286; 30%), while the most common management advice given was dietary advice (n=509/1040; 48.9%). The three explanatory variables remaining in the final model were whether the problem was a presenting or non-presenting problem, the type of diagnosis made, and the body system affected. Explanatory variables which did not remain in the final model were patient signalment, problem history, consultation type, clinical examination type, and who raised the problem (veterinary surgeon or owner). For over two-thirds of problems discussed, an action was taken which suggests these problems may be seen as important by the veterinary surgeon and/or pet owner. No action was taken for almost a third of cases which could represent 'watchful waiting', which has been highlighted as important in human healthcare. Future research should focus on the common actions taken, further exploring the complex decision-making process, and examining the effect of the decisions made on long-term patient outcomes. PMID- 28364828 TI - On-farm mortality, causes and risk factors in Estonian beef cow-calf herds. AB - High on-farm mortality is associated with lower financial return of production and poor animal health and welfare. Understanding the reasons for on-farm mortality and related risk factors allows focus on specific prevention measures. This retrospective cohort study used cattle registry data from the years 2013 and 2014, collected from cattle from all Estonian cow-calf beef herds. The dataset contained 78,605 animal records from 1321 farms in total. Including unassisted deaths and euthanasia (2199 in total) the on-farm mortality rate was 2.14 per 100 animal-years. Across all age groups of both sexes the mortality rate (MR) was highest for bull calves up to three months old (MR=7.78 per 100 animal-years, 95% CI 6.97; 8.68) followed by that for heifer calves (MR=6.21 per 100 animal-years, 95% CI 5.49; 7.02). For female cattle the mortality risk declined after three months of age but increased again among animals over 18 months. The reason for death stated by the farmers was analysed for cattle under animal performance testing. Other/unknown reasons, trauma and accidents, as well as metabolic and digestive disorders, formed the three most commonly reported reasons for death in cattle of all age groups. Weibull proportional hazard models with farm frailty effects were applied in three age categories (calves up to three months, youngstock from three to 18 months and cattle aged over 18 months) to identify factors associated with the risk of mortality. Male sex was associated with increased risk of mortality in cattle up to 18 months of age. No difference between breeds was found for cattle up to 18 months of age. Beef cattle breeds rarely represented or dairy breeds (breed category 'Other') had the highest mortality hazard (HR=1.41, 95% CI 1.11; 1.78) compared to Hereford. The hazard of mortality generally increased with herd size for calves, young stock and older bulls. In female cattle over 18 months of age there was no difference in mortality hazard over herd size categories. Herd location was controlled in the models and regional differences in mortality hazard were found. Common to all age groups, calving season was associated with increased risk of mortality. PMID- 28364829 TI - Point of truth calibration for disease prioritisation-A case study of prioritisation of exotic diseases for the pig industry in Australia. AB - The objective of this study was to trial point of truth calibration (POTCal) as a novel method for disease prioritisation. To illustrate the application of this method, we used a previously described case-study of prioritisation of exotic diseases for the pig industry in Australia. Disease scenarios were constructed from criteria which described potential impact and pig-producers were asked to score the importance of each scenario. POTCal was used to model participants' estimates of disease importance as a function of the criteria, to derive a predictive model to prioritise a range of exotic diseases. The best validation of producers' estimates was achieved using a model derived from all responses. The highest weighted criteria were attack rate, case fatality rate and market loss, and the highest priority diseases were the vesicular diseases followed by swine fevers and zoonotic encephalitides. Comparison of results with a previous study in which probabilistic inversion was used to prioritise diseases for the same group of producers highlighted differences between disease prioritisation methods. Overall, this study demonstrated that POTCal can be used for disease prioritisation. An advantage of POTCal is that valid models can be developed that reflect decision-makers' heuristics. Specifically, this evaluation of the use of POTCal in animal health illustrates how the judgements of participants can be incorporated into a decision-making process. Further research is needed to investigate the influence of scenarios presented to participants during POTCal evaluations, and the robustness of this approach applied to different disease issues (e.g. exotic versus endemic) and production types (e.g. intensive versus extensive). To our knowledge, this is the first report of the use of POTCal for disease prioritisation. PMID- 28364831 TI - Using local language syndromic terminology in participatory epidemiology: Lessons for One Health practitioners among the Maasai of Ngorongoro, Tanzania. AB - Pastoralists and agro-pastoralists often occupy remote and hostile environments, which lack infrastructure and capacity in human and veterinary healthcare and disease surveillance systems. Participatory epidemiology (PE) and Participatory Disease Surveillance (PDS) are particularly useful in situations of resource scarcity, where conventional diagnostics and surveillance data of disease prevalence may be intermittent or limited. Livestock keepers, when participating in PE studies about health issues, commonly use their local language terms, which are often syndromic and descriptive in nature. Practitioners of PE recommend confirmation of their findings with triangulation including biomedical diagnostic techniques. However, the latter is not practiced in all studies, usually due to time, financial or logistical constraints. A cross sectional study was undertaken with the Maasai of Ngorongoro District, Tanzania. It aimed to identify the terms used to describe the infectious diseases of livestock and humans with the greatest perceived impact on livelihoods. Furthermore, it aimed to characterise the usefulness and limitations of relying on local terminology when conducting PE studies in which diagnoses were not confirmed. Semi-structured interviews were held with 23 small groups, totalling 117 community members within five villages across the district. In addition, informal discussions and field observations were conducted with village elders, district veterinary and medical officers, meat inspectors and livestock field officers. For human conditions including zoonoses, several biomedical terms are now part of the common language. Conversely, livestock conditions are described using local Maasai terms, usually associated with the signs observed by the livestock keeper. Several of these descriptive, syndromic terms are used inconsistently and showed temporal and spatial variations. This study highlights the complexity and ambiguity which may exist in local terminology when used in PE studies. It emphases the need for further analysis of such findings, including laboratory diagnosis where possible to improve specificity before incorporating them into PDS or disease control interventions. PMID- 28364830 TI - Impact of a 3-year pet management program on pet population and owner's perception. AB - Although pet population management programs have been established worldwide, few reports on program evaluation have been carried out to date. Accordingly, a 3 year longitudinal study has been carried out in a 4000 household neighborhood located within the metropolitan area of Curitiba, the eighth most populated city of Brazil. Visits were conducted and questionnaires completed to estimate and characterize the local pet population (animal sex, reproductive and vaccination status, street access). Care provided by owners, community perception on stray dog management and the possible changes were compared in these variables over time (2010 and 2013) were evaluated, after the establishment of a city pet population management program. In addition, associations between having children, owning dogs and cats, responsible pet ownership education and owner's perception on stray dogs were statistically tested. A total of 354/4000 (8.9%) household families were interviewed in 2010 and 70/354 (19.8%) of the same families again in 2013. No significant changes were found in overall number of dogs and cats and average pet age, animal care and owner's perception on stray dogs following the 3 year population management program. In 2010, an average of 1.6 dogs and 0.3 cats were found per family, with slightly more females (51.3% dogs and 51.1% cats), adults (4.0+/-3.5years for dogs and 2.1+/-2.4 for cats), intact (not neutered; 94.2% dogs and 84.0% cats) and lacking regular visit to veterinarian (71.6%). Although more families (53.1%) had children under 12 years old, no association was found between having children and having dogs and cats. Questionnaires revealed that owners perceived neutering/spaying to be the best pet population control method (42.4%), with "society" (50%) and "government" (49.4%) as responsible for pet population management. A significant positive association has been found between education level and the best way to control stray dogs (p=0.03), between having dogs and in favor of neutering/spaying (p=0.04) and considering neutering/spaying as the best control method (p=0.02). The chances of thinking the best way to control stray dogs by neutering/spaying and adoption were almost 2.0 fold higher than other methods. In conclusion, the present study has provided indicators (education level, having dogs) for pet population control program assessment and effectiveness evaluation. Moreover, this study may serve as a warning on the real long-term effect of such programs, which should be periodically evaluated to identify necessary adjustments and/or improvements. PMID- 28364832 TI - Investigation of in-feed organic acids as a low cost strategy to combat Salmonella in grower pigs. AB - Salmonella carriage in pigs is a significant food safety issue. Dietary supplementation with organic acids has previously been shown to reduce shedding and transmission of Salmonella. Therefore, this study aimed to examine the effect of three commercially available organic acid-based products on Salmonella levels in grower pigs, using a model of experimental infection that closely mimics natural exposure to the organism. Seven week old trial pigs (n=40) with a mean weight of 14.7kg were placed in one of four pens with 10 pigs/pen. Pens had previously been contaminated with Salmonella Typhimurium 4,[5],12;i;- via seeder pigs. Trial pigs received one of four diets for 28days: 1, control diet; 2, sodium butyrate supplemented diet; 3, benzoic acid supplemented diet and 4, formic-citric acid supplemented diet. A further 10 pigs were placed in a Salmonella-free pen receiving the control diet. Pigs were weighed and blood sampled on days 0 and 28. Faeces was collected on day 0, 2, 3, 5, 7, 14, 21 and 28 and examined for Salmonella. On day 28, 5 pigs/group were euthanised and ileocaecal lymph nodes (ILN) and caecal contents sampled for culture. The remaining 5 pigs/pen were then fed the control diet and faeces were collected on days 35 and 42. On day 42 pigs were euthanised and ILN and caecal contents tested for Salmonella levels. The trial was repeated once. Within the first two days of exposure to the contaminated environment, 96% (77/80) of pigs became infected. Most pigs shed Salmonella at levels of between 100-103 CFU/g faeces for at least 7days post-exposure. A significant reduction in Salmonella faecal concentration was observed after supplementation with sodium butyrate (p=0.001) and a formic citric acid blend (p<0.0001). Average daily weight gain (ADWG) was significantly increased in all groups fed the supplemented feed when compared to the positive control group. The use of sodium butyrate or a blend of formic and citric acid in feed could be considered a cost-effective control measure to reduce Salmonella faecal shedding and improve ADWG in Salmonella infected herds. PMID- 28364833 TI - Peripartum dynamics of Coxiella burnetii infections in intensively managed dairy goats associated with a Q fever outbreak in Australia. AB - Coxiella burnetii may cause reproduction disorders in pregnant animals but subclinical infection in other animals. Unrecognised disease may delay implementation of control interventions, resulting in transmission of infection to other livestock and to humans. Seroreactivity to C. burnetii phase-specific antigens, is routinely used to interpret the course of human Q fever. This approach could be similarly useful in identifying new and existing infections in livestock herds to help describe risk factors or production losses associated with the infections and the implementation of disease-control interventions. This study aimed to elucidate the dynamics of C. burnetii infections using seroreactivity to phase-specific antigens and to examine the impact of infection on milk yield in goats in an endemically-infected farm that was associated with a Q fever outbreak in Australia. Seroreactivity pre- and post-partum and milk yield were studied in 164 goats (86 nulliparous and 78 parous). Post-partum, the seroprevalence of antibodies to C. burnetti increased from 4.7% to 31.4% throughout goats' first kiddings and from 47.4% to 55.1% in goats kidding for the second or greater time. Of 123 goats that were seronegative pre-partum, 26.8% seroconverted over the three-month peri-partum period, highlighting the importance of controlling infection throughout this time. The risk of seroconversion was comparable in first or later kidders, suggesting constant risk irrespective of parity. No loss in milk production associated with seroconversion to phase 2 was observed within the first nine weeks of lactation. However, seroconversion to only phase 1 was associated with extra 0.276L of milk per day (95% Confidence Interval: 0.010, 0.543; P=0.042), which warrants further investigation to ascertain whether or not the association is causal. Further studies on seroreactivity and milk production over longer periods are required, as milk production loss caused by C. burnetti may be an additional reason to control the disease in goat herds. PMID- 28364835 TI - Canine tungiasis: High prevalence in a tourist region in Bahia state, Brazil. AB - Tungiasis is a parasitic skin disease neglected by authorities, health professionals, and the general population. Its occurrence is significantly associated with poverty. A cross-sectional study was conducted to describe the prevalence of tungiasis, associated clinical signs and risk factors of the canine population at a tourist site in the city of Ilheus, Bahia (northeast Brazil). All village households were visited and dogs inspected after authorization by owners. A semi-structured questionnaire was administered. Of the 114 dogs included in the study, 71 (62.3%) were infested; all of them had lesions on their pads. An ectopic lesion on the nose was observed in one dog (1.4%). The number of manipulated lesions outnumbered the number of vital and avital lesions with an average of 88.3%. Edema (95.8%) and hyperkeratosis (85.9%) were the most prevalent clinical signs. Behavioral disorders such as excessive licking (6/71; 8.5%), disobedience (1/71; 1.4%) and prostration (2/71; 2.8%) were reported. In the multi-variate analysis, semi-restricted condition of the dogs (adjusted OR=8.58; 95% CI=2.47-29.76) and the presence of sand on the compound (adjusted OR=14.23, 95% CI=2.88-70.28) were significantly associated with infestation. We concluded that, infestation with Tunga spp. is highly endemic in the canine population of the village. The low level of restrictions on dogs and the presence of sand in areas most frequented by the animals are perpetuating factors of infestation in the community, subject to integrated and multidisciplinary intervention measures. PMID- 28364834 TI - Chinese farmers' willingness to accept compensation to practice safe disposal of HPAI infected chicken. AB - Highly Pathogenic Avian Influenza (HPAI) is a high morbidity and mortality zoonotic disease, which threatens poultry and human health. An outbreak of disease in China requires strict slaughter and disposal of all chickens within a three-kilometer radius, incurring large private costs for farmers and encouraging black market transactions. A stated preference survey of 331 farmers across six provinces in China was conducted in 2015, in order to measure the responsiveness of farmers to accept various compensation prices for safely disposing of HPAI infected chicken. Findings suggest that about 25% and 40% of farmers in South and North China respectively would not adopt safe disposal at the current compensation price (10 yuan/bird) offered by the government. However, 80% of farmers would adopt safe disposal if the compensation price increased to 14.1 yuan in South China and 18.9 yuan in North China. The adoption of safe disposal by farmers was positively and significantly influenced by compensation price (p=0.000) and regular contact with epidemic prevention staff (p=0.094). However, adoption was negatively and significantly influenced by net farm income (p=0.100) and chicken production income percentage (p=0.014). Although half of (51%) of farmers were willing to receive zero compensation, a reasonable compensation scheme along with strengthened supervision, may be considered the most effective strategy to encourage safe disposal of HPAI infected chicken and reduce the risks associated with black market transactions. PMID- 28364836 TI - Molecular diagnosis and phylogeographic analysis of Trypanosoma evansi in dogs (Canis lupus familiaris) suggest an epidemiological importance of this species in Colombia. AB - Surra disease is a zoonosis caused by Trypanosoma (Trypanozoon) evansi, a salivary trypanosome, originally from Africa, which affects a wide range of mammalian worldwide. Dogs are highly susceptible to T. evansi infection and they often exhibit strong clinical signs than can lead to death, even within weeks in untreated acute cases. The present survey is the first report through clinical, parasitological and molecular approaches, of two fatal cases of T. evansi in Colombian dogs. After analysing two presumptive cases of infection with Trypanosoma spp., in dogs by parasitological methods, we confirmed by molecular techniques the presence of T. evansi, finding clinical signs such as anaemia, thrombocytopenia and hepatosplenomegaly, with fatal outcomes within a week even after the treatment. A phylogenetic and phylogeographic analysis of both isolates from T. evansi, suggest a complex evolutionary relationship with species of Trypanozoon subgenus. Moreover, the haplotype H2 was observed for the first time in Colombia, in common areas where human cases of T. evansi infection has been reported. These findings imply a relevant problem for animal health in the country, and highlight the importance of this infection in domestic animals and the possibility of human cases. PMID- 28364837 TI - The science identity and entering a science occupation. AB - The initiative to increase the number of students in STEM disciplines and train them for a science-related job is a current national focus. Using longitudinal panel data from a national study that followed underrepresented college students in STEM fields, we investigate the neglected role that social psychological processes play in influencing science activity among the young. We study the impact of identity processes related to being a science student on entering a science occupation. More broadly, we examine whether an identity formulated in one institutional setting (education) has effects that persist to another institutional setting (the economy). We find that the science identity positively impacts the likelihood of entering a science occupation. It also serves as a mediator for other factors that are related to educational success. This provides insight into how an identity can guide behavior to move persons into structural positions across institutional domains. PMID- 28364838 TI - How does the personal become political? Assessing the impact of mothers' employment on daughters' participation in political organizations. AB - The "Millennial" generation grew up in a period of changing gender roles, when labor force participation of mothers of young children was rapidly increasing. Past research has found that daughters of employed mothers are more likely to defy traditional gender scripts by seeking employment and authority positions. Building on this literature, I assess whether exposure to a full-time employed mother has an impact on Millennial women's participation in political organizations. I use prospective data on childhood context from the Panel Study of Income Dynamics, and apply propensity score weighting and a matching technique based on covariates. Evidence suggests that exposure to a full-time employed mother increases participation in political organizations for low-SES daughters. According to sensitivity tests, these findings are reasonably robust to unobserved confounders. In contrast, exposure to a full-time employed mother does not have a significant effect on the participation of sons or high-SES daughters. PMID- 28364839 TI - Disparate vantage points: Race, gender, county context, and attitudes about harsh punishments in the US. AB - In this paper, I use data from the General Social Survey, FBI Uniform Crime Reporting Statistics, and other sources to consider differences in attitudes about punishment among four groups-Black men, Black women, White men, and White women-as well as how these differences vary according to county crime rates. Centering my expectations about group-specific attitudes within conflict theory and prior empirical findings, I am guided by the presumption that race and gender are cultural categories that shape attitudes about punishment by influencing our interactions with the criminal justice system, and that the meaning of these cultural categories varies by context. Analyses provide some evidence that race, gender, and context interact to shape attitudes about punishment. Overall, this research improves our understanding of group differences in punitive attitudes and of the cultural context in which the US system of incarceration operates. PMID- 28364840 TI - Status inconsistency in groups: How discrepancies between instrumental and expressive status result in symptoms of stress. AB - This study examines whether a mismatch between the positions that individuals hold in different status hierarchies results in symptoms of stress. Prior research has focused on inconsistencies between socioeconomic status dimensions (e.g., education and income) and did not find a significant relation between status inconsistency and stress. In this paper, we build on research on role differentiation and propose to study the effect of inconsistencies between instrumental status and expressive status in group contexts. We hypothesize that people with an inconsistency between these status dimensions experience feelings of uncertainty and frustration in their interactions with others and this manifests in stress-related symptoms. We test this hypothesis with data collected in a medium-sized Dutch childcare organization (N = 93). Polynomial regression analysis, visualized in response surface plots, suggests that status inconsistent employees report higher levels of stress. PMID- 28364841 TI - American crime drops: Investigating the breaks, dips and drops in temporal homicide. AB - OBJECTIVES: While a great deal of attention has been given to the 1990s crime drop, less is known about the more recent decline in homicide rates that occurred in several large U.S. cities. This paper aims to explore whether these represent two distinct drops via statistical evidence of structural breaks in longitudinal homicide trends and explore potentially differing explanations for the two declines. METHODS: Using homicide data on a large sample of U.S. cities from 1990 to 2011, we test for structural breaks in temporal homicide rates. Combining census data and a time series approach, we also examine the role structural features, demographic shifts, and crime control strategies played in the changes in homicide rates over time. RESULTS: Statistical evidence demonstrates two structural breaks in homicide trends, with one trend reflecting the 1990s crime drop (1994-2002) and another trend capturing a second decline (2007-2011). Time series analysis confirms previous research findings about the contributions of structural conditions (e.g., disadvantage) and crime control strategies (e.g., police force size) to the crime drop of the 1990s, but these factors cannot account for the more recent drop with the exception of police presence. CONCLUSIONS: Although both structural conditions and crime control strategies are critical to the longitudinal trends in homicide rates over the entire span from 1990 to 2011, different factors account for these two distinct temporal trends. PMID- 28364843 TI - Children with disabilities and trajectories of parents' unsecured debt across the life course. AB - Prior research shows that having a child with a disability is economically burdensome for parents but we know little about whether this burden extends to unsecured debt. In this study, we examine the link between having a child with a disability that manifests between birth and age 4 and subsequent trajectories in unsecured household debt. We have three key findings. First, we find that having a child with an early-life disabling health condition is associated with a substantial increase in indebtedness in the years immediately following the child's birth, and that this association persists net of a range of potential confounders. Second, we find that parents do not quickly repay this debt, such that parents of a child with a disabling health condition have different trajectories of unsecured debt across the life course than do parents of children without a disabling health condition. Third, we find that the association between early-life child disability and debt is stronger for more severe conditions, such as those that require ongoing medical treatment. The results of this study are informative for understanding an important aspect of economic functioning indebtedness-for parents of children with disabilities, as well as the causes and correlates of rising unsecured debt in the U.S. PMID- 28364842 TI - Does death really make us equal? Educational attainment and resource compensation after paternal death in Finland. AB - Attempts to explain the persistent importance of family background for children's educational attainment typically highlight the ways in which parents pass down educational, economic and social resources to their children. However, parental resources may also play a crucial role for preventing family crises from spiraling into cumulative disadvantage. To study such compensation processes, we examine the consequences of a father's death on children's educational trajectories, using a Finnish register-based sample of children born between 1982 and 1987. The results based on multilevel linear probability models both support and contradict our compensation hypothesis. Children who lost their father were not more likely to drop out of upper secondary school, as long as their surviving mother had high levels of socioeconomic resources. Similar compensation processes were visible in the case of entering polytechnic higher education. However, with regard to university attendance, bereavement noticeably reduced the traditional advantage of children with high-resource parents. PMID- 28364844 TI - Physical-psychiatric comorbidity: Implications for health measurement and the Hispanic Epidemiological Paradox. AB - Few studies examine the co-occurrence of physical and psychiatric health problems (physical-psychiatric comorbidity), and whether these patterns differ across social groups. Using the National Comorbidity Survey-Replication and National Latino and Asian American Study, the current study asks: what are the patterns of physical-psychiatric comorbidity (PPC) between non-Hispanic Whites and Latino subgroups, further differentiated by gender and nativity? Does the PPC measurement approach reveal different patterns across groups compared to when only physical or only psychiatric health problems are the health outcomes of interest? To what extent do sociodemographic characteristics (SES, stress exposure, social support, immigration-related factors) explain PPC differences between groups? Results reveal that compared to U.S.-born non-Hispanic White men, island-born Puerto Rican men experience elevated PPC risk. Mexican and Other Latino women and men experience relatively lower risk of PPC relative to their non-Hispanic White counterparts. Social factors explain some of the health disadvantage of island-born Puerto Rican men, but do not explain the health advantage of Mexicans and Other Latinos. PMID- 28364845 TI - Using item response theory to optimize measurement of chronic stress in pregnancy. AB - OBJECTIVE: Utilize Rasch analysis to develop an optimized self-reported measure of stress in pregnancy and examine the association with patient demographics and biologic measures of stress. STUDY DESIGN: Measured self-reported stress in pregnant women using 12 existing scales. Collected blood for biologic measures of stress (Epstein Barr Virus [EBV], C-Reactive Protein [CRP], Corticotropin Reactive Hormone [pCRH], and Adenocorticotropin Hormone [ACTH]). Used multidimensional scaling and Rasch analysis to produce an item reduced self report measure. RESULTS: Enrolled 112 women. Survey items reduced to two factors: perceived stressors and buffers of stress. Women with a domestic partner had lower perceived stress (p = 0.003). Caucasian women reported higher buffers of stress (p = 0.045), as did women with private insurance (p < 0.001), a planned pregnancy (p < 0.01), and a domestic partner (p < 0.001). Women with higher buffers of stress had lower levels of pCRH (adjusted p = 0.01). CONCLUSION: Item reduced, optimized measures of stress were associated with significant differences in patient demographics and biologic measures of stress. PMID- 28364847 TI - Sexual intercourse, romantic relationship inauthenticity, and adolescent mental health. AB - Numerous studies indicate sexual intercourse, especially when it occurs early in adolescence, increases youths' risk of mental health problems. However, no research has examined whether the association between sexual intercourse and mental health varies by romantic relationship inauthenticity, or the level of incongruence between thoughts/feelings and actions within romantic relationships. Using data from a subset of romantically-involved Add Health respondents, we measured sexual involvement in romantic relationships and applied sequence analysis to reports of ideal and actual romantic relationship to measure inauthenticity within adolescent romances. Regressions of depression symptoms indicate that the magnitude of the positive associations between sexual intercourse and girls' mental health is most pronounced in relationships characterized by high levels of relationship inauthenticity and that there is no association between sexual intercourse and girls' depression at low levels of relationship inauthenticity. Having sexual intercourse is positively associated with depression symptoms among boys, but relationship inauthenticity does not alter this association. We discuss the implications of these findings for research on adolescent sexuality and programs aimed at enhancing youth sexuality development. PMID- 28364846 TI - Breastfeeding, overweight status, and inflammation. AB - Research documents a host of health benefits of breastfeeding for infants and children, including long-term health conditions arising from inflammation. Here, we provide new evidence about this association, focusing on the link between breastfeeding in infancy and inflammation in early adulthood. Our study is based on the National Longitudinal Study of Adolescent to Adult Health (Add Health) which allows us investigate a potentially important mediating pathway - overweight status from early adolescence into young adulthood. Results from pathway analyses in a structural equation modeling framework indicate that, in addition to a direct pathway linking breastfeeding and inflammation, an indirect pathway through overweight status across adolescence into young adulthood partially explains the association between breastfeeding and inflammation. Overweight status, moreover, links breastfeeding to inflammation not only through proximal timing of overweight status, but also through an indirect cascading process of overweight status over the life course that is evident in adolescence. Overall, this study highlights the importance of considering breastfeeding, overweight status and inflammation as dynamic life course processes that contribute to development of health inequalities. PMID- 28364848 TI - The adolescent family environment and cohabitation across the transition to adulthood. AB - This study draws upon a sample of men and women from Waves I and IV of Add Health to examine the linkages between the adolescent family environment and cohabitation behavior across the transition to adulthood. Using event history modeling the current paper considers the association between a variety of family factors and both the timing of first cohabiting unions and their outcomes (marriage, break up, still cohabiting). This paper also considers whether the impact of predictors for cohabitation timing and outcomes varies depending on the age of individuals. Results indicate that exposure during adolescence to family instability, parental cohabitation, lower parental SES, and low family belonging were associated with an elevated likelihood of entering into cohabiting unions, but primarily during adolescence and early adulthood. Family factors, including family belonging and parental relationship history, were also associated with the outcomes of first cohabitations. PMID- 28364849 TI - Are there neighborhood effects on young adult neighborhood attainment? Evidence from mixed-logit models. AB - Studies of racial residential attainment show an intergenerational transmission of racial contexts from youth to adulthood, but it is unclear why this transmission is so robust. It is possible that experiences in racial contexts during youth have lasting effects on neighborhood selection in adulthood, but evidence for this claim has come from research using statistical methods that suffer from problems of ecological dependence and conflation of other neighborhood characteristics. In this study, we address these limitations using mixed-logit models, a form of discrete choice analyses, allowing us to control for differences across metropolitan areas and for multiple characteristics of neighborhoods that may affect the selection of destination neighborhoods. Data for the analyses come from the National Educational Longitudinal Study, the 1990 and 2000 Censuses, and other sources. We find that most of the intergenerational process results from young adults moving to neighborhoods short distances from their origin ones, but the models also suggest a contextual effect of youth experiences in racial compositions on neighborhood selection. The latter finding indicates that policies promoting integration among youth can have long-lasting effects on residential attainment. PMID- 28364850 TI - Power and the gendered division of contraceptive use in Western European couples. AB - Recent research has approached contraceptive use, or "fertility work", as another household task that is primarily managed by women. Building on the theoretical frameworks of relative resource theory and gender perspectives, this study investigates the association between partners' power (measured as their relative education, division of housework and decision-making) and the choice of male versus female, or no contraception. Data from the Generations and Gender Survey for four Western European countries (Austria, Belgium, France and Germany; 2005 2010) are used to examine the hypotheses with multinomial logistic diagonal reference models. The results show that man's and woman's educational level are equally important predictors for a couple's contraceptive method choice. Furthermore, the findings suggest that households in which the man performs more housework or the woman has more say in decisions are more likely to rely on male methods or female sterilization, rather than on the more commonly used female reversible methods. PMID- 28364851 TI - Making gains or falling behind? Changes and stability in school readiness. PMID- 28364852 TI - Irregularly-shaped school attendance zones and racial integration. AB - This paper investigates how much the geographic shapes of school attendance zones within urban school districts are associated with levels of attendance zone racial segregation (while holding constant levels of residential segregation). Based on an analysis of 304 school districts, findings show that more irregularly shaped school attendance zones are correlated with lower levels of racial segregation in attendance zones after accounting for residential segregation. In fact, not one school district contains both highly irregularly-shaped attendance zones and unusually high levels of attendance zone racial segregation-although there are several school districts with irregularly-shaped zones and unusually high levels of racial integration. These findings undermine recent claims that irregularly-shaped attendance zones generally serve to segregate students by race. In addition to these empirical findings, this paper introduces a variation of the spatial information theory segregation index H~ that is useful for predicting segregation in school attendance zones and other types of geographic boundaries containing roughly equal populations. PMID- 28364853 TI - Affirmation effects on math scores: The importance of high school track. AB - Stereotype threat has been shown to affect academic performance of minority racial groups. Minority girls may experience the burdens of both race and gender a "double bind" theorized to affect the underrepresentation of women in STEM fields. A randomized controlled trial focused on alleviating stereotype threat in three high schools in a large U.S. metro demonstrates the effects of affirmative writing interventions, which have previously shown positive effects for minority and female students. Results indicate effects for these groups were insignificant. However, results also show that student track is highly significant at p < 0.001, and interactive analyses suggest that the intervention may help alleviate threat for higher-achieving students. PMID- 28364854 TI - Unequal views of inequality: Cross-national support for redistribution 1985-2011. AB - This research examines public views on government responsibility to reduce income inequality, support for redistribution. While individual-level correlates of support for redistribution are relatively well understood, many questions remain at the country-level. Therefore, I examine how country-level characteristics affect aggregate support for redistribution. I test explanations of aggregate support using a unique dataset combining 18 waves of the International Social Survey Programme and European Social Survey. Results from mixed-effects logistic regression and fixed-effects linear regression models show two primary and contrasting effects. States that reduce inequality through bundles of tax and transfer policies are rewarded with more supportive publics. In contrast, economic development has a seemingly equivalent and dampening effect on public support. Importantly, the effect of economic development grows at higher levels of development, potentially overwhelming the amplifying effect of state redistribution. My results therefore suggest a fundamental challenge to proponents of egalitarian politics. PMID- 28364855 TI - Bankruptcy reform and congressional action: The role of organized interests in shaping policy. AB - This paper tests the degree to which PAC contributions can influence voting outcomes on legislation that disproportionately influences the poor. Using passage of the Bankruptcy Abuse and Consumer Protection Act of 2005 in the House of Representatives, the results show an association between PAC campaign contributions from the financial industry and support for final passage of bankruptcy reform. The findings suggest that one source of underrepresentation of the poor may be donations made by interest groups during campaigns. PMID- 28364856 TI - Can the welfare state replace parents? Children's cognition in the United States and Great Britain. AB - We compare family and parental effects on child verbal facility, verbal achievement and mathematics achievement in the United States and Great Britain. We study 3,438 5-13 year-old children from the 1994 NLSY Child-Mother Data Set and 1429 same-aged children from the National Child Development Study, also known as the British Child. Multivariate analyses suggest that the processes through which families invest in child cognition are similar across societies, with factors including low birth weight, child health, maternal cognition, family size and children's home environments being consequential. We conclude that parental investments are equally important across the two societies. The more developed welfare state in Great Britain does not notably compensate for parental investments in that society, although it may play a greater role when parental resources are absent or stretched thin. PMID- 28364858 TI - Call to Action: Addressing the Challenges Facing Pediatric Nursing. PMID- 28364857 TI - In the shade of a forest status, reputation, and ambiguity in an online microcredit market. AB - Scholars have long recognized status and reputation as pervasive forces reproducing comparative advantage in social and economic systems. Yet, due in part to methodological challenges, relatively few studies have examined how status and reputation interact. We use data from an online market for peer-to peer lending to study independent and joint effects of status and reputation on borrowers' success at obtaining loans. First, we find a positive main effect of status, even when reputational signals are reliable and abundant. Second, we find that status matters the most for borrowers with moderate (rather than high or low) reputations, suggesting a curvilinear effect of status x reputation on loans. These results support the idea that status matters not only under conditions of too little information that creates information asymmetry, as typically assumed, but also under conditions of abundant information and too many choices that creates ambiguity about how to evaluate candidates. PMID- 28364859 TI - Central synapse, neural circuit, and brain function. PMID- 28364860 TI - Regulatory effects of estetrol on the endothelial plasminogen pathway and endothelial cell migration. AB - BACKGROUND: Estetrol (E4) is a natural estrogen produced solely during human pregnancy. E4 is suitable for clinical use since it acts as a selective estrogen receptor modulator. In clinical trials E4 has been seen to have little or no effect on coagulation. Hence, it is interesting to investigate whether E4 alters endothelial-dependent fibrinolysis. OBJECTIVES: We studied the effects of E4 on the fibrinolytic system and whether this could influence the ability of endothelial cells to migrate. In addition, we compared the effects of E4 with those of 17beta-estradiol (E2). STUDY DESIGN: Human umbilical vein endothelial cells (HUVEC) were obtained from healthy women. Expression of plasminogen activator inhibitor-1 (PAI-1), urokinase-type plasminogen activator (u-PA) and tissue plasminogen activator (t-PA) proteins was evaluated by Western blot analysis. Endothelial cell migration was studied by razor-scrape horizontal and multiwell insert systems assays. RESULTS: E4 increased the expression of t-PA, u PA and PAI-1 in HUVEC, but less so than did equimolar amounts of E2. The effects of E4 on t-PA, u-PA and PAI-1 were mediated by the induction of the early immediate genes c-Jun and c-Fos. E4 in combination with E2 antagonized the effects induced by pregnancy-like E2 concentrations but did not impair the effects of postmenopausal-like E2 levels. We also found that the increased synthesis of PAI-1, u-PA and t-PA induced by E2 and E4 is important for horizontal and three-dimensional migration of HUVEC. CONCLUSIONS: These results support the hypothesis that E4 acts as an endogenous selective estrogen receptor modulator (SERM), controlling the fibrinolytic system and endothelial cell migration. PMID- 28364861 TI - Laser therapy for the restoration of vaginal function. AB - Laser therapy has a therapeutic role in various medical conditions and most recently has gained interest as a non-hormonal treatment for genitourinary syndrome of menopause (GSM) and as a non-invasive option for stress urinary incontinence (SUI). Several therapies are available to alleviate GSM symptoms, including hormonal and non-hormonal products. Both microablative fractional CO2 laser and the non-ablative vaginal Er:YAG laser (VEL) induce morphological changes in the vaginal tissues, and data from non-randomized clinical trials suggest that laser therapy can alleviate vaginal dryness and dyspareunia. VEL has been reported to improve SUI as well as vaginal prolapse. Although large randomized trials have not been reported, the evidence suggests that VEL can be offered as a safe and efficacious alternative to hormone replacement therapy (HRT) for GSM, as well as a first-line treatment for mild to moderate SUI, before surgical procedures are resorted to. Randomized studies are needed to compare laser treatments with other therapies, as well as to assess the duration of the therapeutic effects and the safety of repeated applications. Research is presently evaluating both an automated robotic probe for VEL treatments and an intraurethral probe for the treatment of severe and type III SUI. PMID- 28364862 TI - Sleep patterns, sleep disorders and mammographic density in spanish women: The DDM-Spain/Var-DDM study. AB - We explored the relationship between sleep patterns and sleep disorders and mammographic density (MD), a marker of breast cancer risk. Participants in the DDM-Spain/var-DDM study, which included 2878 middle-aged Spanish women, were interviewed via telephone and asked questions on sleep characteristics. Two radiologists assessed MD in their left craneo-caudal mammogram, assisted by a validated semiautomatic-computer tool (DM-scan). We used log-transformed percentage MD as the dependent variable and fitted mixed linear regression models, including known confounding variables. Our results showed that neither sleeping patterns nor sleep disorders were associated with MD. However, women with frequent changes in their bedtime due to anxiety or depression had higher MD (ebeta:1.53;95%CI:1.04-2.26). PMID- 28364863 TI - Breast cancer in ethnic minority groups in developed nations: Case studies of the United Kingdom and Australia. AB - Recent research from the United Kingdom (UK) has highlighted some of the differences in breast cancer presentations between women of different ethnic groups. Analysis of a large database showed that Black women of African or Caribbean heritage living in England and Wales are more likely to present with stage 3 or 4 cancer than White British women and less likely to have their cancer detected through screening. In many countries around the world, migrant and cultural minority groups experience social and economic disadvantage and this is reflected in their health outcomes. With world migration at record levels, it is timely to reflect on ethnic disparities and to consider how developed nations can care for their minority groups, which are increasing in number and diversity. These issues and challenges are discussed, using the UK's migrant population and Australia's Indigenous and migrant populations as case studies. PMID- 28364864 TI - Evaluation of the efficacy and safety of Tribulus terrestris in male sexual dysfunction-A prospective, randomized, double-blind, placebo-controlled clinical trial. AB - OBJECTIVE: The primary objectives were to compare the efficacy of extracts of the plant Tribulus terrestris (TT; marketed as Tribestan), in comparison with placebo, for the treatment of men with erectile dysfunction (ED) and with or without hypoactive sexual desire disorder (HSDD), as well as to monitor the safety profile of the drug. The secondary objective was to evaluate the level of lipids in blood during treatment. PARTICIPANTS AND DESIGN: Phase IV, prospective, randomized, double-blind, placebo-controlled clinical trial in parallel groups. This study included 180 males aged between 18 and 65 years with mild or moderate ED and with or without HSDD: 90 were randomized to TT and 90 to placebo. Patients with ED and hypertension, diabetes mellitus, and metabolic syndrome were included in the study. In the trial, an herbal medicine intervention of Bulgarian origin was used (Tribestan(r), Sopharma AD). Each Tribestan film-coated tablet contains the active substance Tribulus terrestris, herba extractum siccum (35-45:1) 250mg which is standardized to furostanol saponins (not less than 112.5mg). Each patient received orally 3*2 film-coated tablets daily after meals, during the 12 week treatment period. At the end of each month, participants' sexual function, including ED, was assessed by International Index of Erectile Function (IIEF) Questionnaire and Global Efficacy Question (GEQ). Several biochemical parameters were also determined. The primary outcome measure was the change in IIEF score after 12 weeks of treatment. Complete randomization (random sorting using maximum allowable% deviation) with an equal number of patients in each sequence was used. This randomization algorithm has the restriction that unequal treatment allocation is not allowed; that is, all groups must have the same target sample size. Patients, investigational staff, and data collectors were blinded to treatment. All outcome assessors were also blinded to group allocation. RESULTS: 86 patients in each group completed the study. The IIEF score improved significantly in the TT group compared with the placebo group (R<0.0001). For intention-to-treat (ITT) there was a statistically significant difference in change from baseline of IIEF scores. The difference between TT and placebo was 2.70 (95% CI 1.40, 4.01) for the ITT population. A statistically significant difference between TT and placebo was found for Intercourse Satisfaction (p=0.0005), Orgasmic Function (p=0.0325), Sexual Desire (p=0.0038), Overall Satisfaction (p=0.0028) as well as in GEQ responses (p<0.0001), in favour of TT. There were no differences in the incidence of adverse events (AEs) between the two groups and the therapy was well tolerated. There were no drug-related serious AEs. Following the 12-week treatment period, significant improvement in sexual function was observed with TT compared with placebo in men with mild to moderate ED. TT was generally well tolerated for the treatment of ED. PMID- 28364865 TI - The effect of hormone replacement therapy and tibolone on lipoprotein (a) concentrations in postmenopausal women: A systematic review and meta-analysis. AB - OBJECTIVE: Data on the effect of hormone replacement therapy (HRT) and tibolone on lipoprotein (a) [Lp(a)], an independent risk factor for cardiovascular disease, are heterogeneous and conflicting. Studies of the effect of HRT and tibolone on Lp(a) concentrations in post-menopausal women are reviewed in this meta-analysis. DESIGN AND METHODS: MEDLINE, Scopus, EMBASE and Cochrane databases were searched (up to February 10, 2017). Two researchers identified randomized controlled studies and extracted data. Potential controversies were resolved by a third reviewer. RESULTS: In 24 eligible studies, HRT caused a significant reduction in Lp(a) concentrations compared with placebo or no treatment [mean relative difference: -20.35%, 95% Confidence Interval (CI): -25.33% to -15.37%, p<0.0001], with significant heterogeneity between studies (I2=98.5%), but without evidence of publication bias. No significant effect was found for tibolone (n=7) (mean relative difference: -23.84%, 95% CI: -63.43% to 15.74%, p=0.238) (I2=98.7%, but without publication bias). Oral estrogen caused a greater reduction in Lp(a) concentrations than transdermal estrogen (n=10) (mean relative difference: 37.66%, 95% CI: 16.84% to 58.48%, p<0.0001), with significant heterogeneity between studies (I2=99%), but no evidence of publication bias. No difference was observed when continuous was compared with cyclical HRT, conventional with low-dose estrogen, and estrogen monotherapy with estrogen combined with progestogen. No difference was observed between HRT and tibolone regarding their effect on Lp(a). CONCLUSIONS: HRT significantly decreases Lp(a) concentrations, with oral being more effective than transdermal estradiol. The type of HRT, dose of estrogen and addition of progestogen do not seem to modify the Lp(a)-lowering effect of HRT. PMID- 28364866 TI - Being overweight or obese is associated with harboring a gut microbial community not capable of metabolizing the soy isoflavone daidzein to O-desmethylangolensin in peri- and post-menopausal women. AB - OBJECTIVE: Obesity can be a considerable health concern for peri- and post menopausal women. Evidence suggests an association between the gut microbiome and obesity. The study objective was to evaluate the association between being overweight or obese and phenotypic markers of having an overall gut microbial environment not capable of metabolizing the isoflavone daidzein to equol or O desmethylangolensin (ODMA). STUDY DESIGN: Cross-sectional study of 137 peri- and 218 post-menopausal women, aged 44-55 years, who consumed at least three servings per week of soy (source of daidzein). Equol and ODMA producers and non-producers were identified based on urinary concentrations of daidzein, equol and ODMA in a 24-h urine sample. MAIN OUTCOME MEASURES: Mean body mass index (BMI) and odds of obesity. RESULTS: Fifty-one women were ODMA non-producers and 226 were equol non producers. The ODMA non-producer phenotype was positively associated with obesity (OR: 3.33, 95% CI: 1.53, 7.23), and mean BMI was significantly higher in non producers (28.9kg/m2) than in producers (26.7kg/m2), after adjusting for age, ethnicity, and menopausal status. Positive associations with being obese were observed in both peri-menopausal (OR=3.92, 95% CI: 0.90, 17.0) and post menopausal (OR=3.00, 95% CI: 1.22, 7.70) women. The equol non-producer phenotype was not associated with obesity (OR=1.13, 95% CI: 0.64, 1.98), and mean BMI was not significantly different between equol producers (27.3kg/m2) and non-producers (26.5kg/m2). CONCLUSIONS: These results suggest that the ODMA non-producer phenotype is associated with obesity in peri- and post-menopausal women. Further work is needed to confirm these observations in additional populations and to evaluate possible mechanisms. PMID- 28364867 TI - Preventing urinary tract infections after menopause without antibiotics. AB - Urinary tract infections (UTIs) are the most common bacterial infections in women, and increase in incidence after the menopause. It is important to uncover underlying abnormalities or modifiable risk factors. Several risk factors for recurrent UTIs have been identified, including the frequency of sexual intercourse, spermicide use and abnormal pelvic anatomy. In postmenopausal women UTIs often accompany the symptoms and signs of the genitourinary syndrome of menopause (GSM). Antimicrobial prophylaxis has been demonstrated to be effective in reducing the risk of recurrent UTIs in women, but this may lead to drug resistance of both the causative microorganisms and the indigenous flora. The increasing prevalence of Escherichia coli (the most prevalent uropathogen) that is resistant to antimicrobial agents has stimulated interest in novel non antibiotic methods for the prevention of UTIs. Evidence shows that topical estrogens normalize vaginal flora and greatly reduce the risk of UTIs. The use of intravaginal estrogens may be reasonable in postmenopausal women not taking oral estrogens. A number of other strategies have been used to prevent recurrent UTIs: probiotics, cranberry juice and d-mannose have been studied. Oral immunostimulants, vaginal vaccines and bladder instillations with hyaluronic acid and chondroitin sulfate are newer strategies proposed to improve urinary symptoms and quality of life. This review provides an overview of UTIs' prophylaxis without antibiotics, focusing on a practical clinical approach to women with UTIs. PMID- 28364868 TI - Sex differences in the presentation of stroke. AB - Stroke affects both men and women of all ages, although the condition is more common among the elderly. Stroke occurs at an older age among women than among men; although the incidence is lower among women than among men, as women have a longer life expectancy their lifetime risk is slightly higher. Ischemic stroke is the most common type of stroke; and reperfusion treatment is possible if the patient reaches hospital early enough. Thrombolysis and thrombectomy are time sensitive treatments - the earlier they are initiated the better is the chance of a positive outcome. It is therefore important to identify a stroke as soon as possible. Medical personnel can readily identify typical stroke symptoms but the presentation of non-traditional stroke symptoms, such as impaired consciousness and altered mental status, is often associated with a significant delay in the identification of stroke and thus delay in or inability to provide treatment. Non traditional stroke symptoms are reported to be more common in women, who are thereby at risk of delayed recognition of stroke and treatment delay. PMID- 28364869 TI - A vaginal estradiol softgel capsule, TX-004HR, has negligible to very low systemic absorption of estradiol: Efficacy and pharmacokinetic data review. AB - This paper reviews the efficacy, safety, and systemic absorption of estradiol with TX-004HR, an investigational, low-dose 17beta-estradiol vaginal softgel capsule, designed to treat vulvar and vaginal atrophy (VVA) in postmenopausal women, with an improved user experience. In phase 2 (NCT02449902) and phase 3 REJOICE (NCT02253173) studies, TX-004HR significantly improved the proportions of vaginal superficial and parabasal cells and vaginal pH, and in the phase 3 study decreased the severity of dyspareunia, vaginal dryness, and vulvar and/or vaginal itching or irritation. In two randomized, phase 1 trials, estradiol Cmax and AUC0 24 were significantly lower with 10MUg and 25MUg TX-004HR than with the same doses of an approved vaginal estradiol tablet. A substudy (n=72) of the REJOICE trial showed that estradiol Cavg and AUC0-24 with 4MUg and 10MUg TX-004HR were not different from placebo on days 1 and 14. While TX-004HR 25MUg was associated with higher Cavg and AUC0-24 versus placebo on days 1 and 14, these levels remained within the postmenopausal range. Estradiol day-84 values for all three doses were not different from placebo, demonstrating no estradiol accumulation. All TX-004HR doses were well tolerated and had an acceptable safety profile in all reviewed studies. The local vaginal efficacy of TX-004HR was significantly better than that of placebo, while the overall safety profile was similar to that of placebo. Negligible to very low systemic estradiol absorption was observed whether given at 4, 10, or 25MUg. If approved, TX-004HR may be an alternative option for women with symptomatic VVA without increasing mean systemic estradiol absorption above postmenopausal levels. PMID- 28364870 TI - Plasma orexin A levels in recently menopausal women during and 3 years following use of hormone therapy. AB - OBJECTIVE: Alterations in sleep quality and metabolism during menopause are improved by menopausal hormone therapy (MHT). The mechanisms mediating these effects remain unclear. Orexin A (OxA) is a neuro-peptide that regulates sleep/wakefulness, food intake and metabolism. This study examined changes in plasma OxA levels during and after treatment in women from the Kronos Early Estrogen Prevention Study (KEEPS). METHODS: KEEPS randomized women within three years of menopause to: oral conjugated equine estrogen (o-CEE, 0.45mg/day), transdermal 17beta estradiol (t-E2, 50MUg/day), or placebo pills and patches for four years. Plasma OxA levels were measured by enzyme immunoassays in fasting blood samples collected annually from KEEPS participants at Mayo Clinic during and three years after MHT. Changes in menopausal symptoms and plasma OxA levels were assessed for treatment differences. RESULTS: During treatment, OxA levels increased more in women randomized to o-CEE compared with the other groups. Women randomized to either form of MHT demonstrated smaller increases in BMI than those on placebo. Insomnia severity decreased similarly among treatment groups. However, neither changes in sleep nor changes in BMI correlated with changes in plasma OxA levels. Changes in waist circumference correlated positively with changes in plasma OxA levels three years after discontinuation of study treatments. CONCLUSIONS: Although OxA levels increased only in women randomized to o-CEE, these changes did not correlate with changes in sleep quality or BMI. The modest correlation of OxA levels with waist circumference once study treatments were discontinued suggests that OxA may be modulated through multiple intermediary pathways affected by metabolites of 17beta-estradiol. Clinical Trial Registration for KEEPS: NCT00154180. PMID- 28364871 TI - Oxidative stress and frailty: A systematic review and synthesis of the best evidence. AB - OBJECTIVE: Oxidative stress (OS) is associated with accelerated aging. Previous studies have suggested a possible relationship between OS and frailty but this association remains unclear. We conducted a systematic review to investigate potential interactions between OS and frailty. METHODS: A systematic literature search of original reports providing data on 'OS and antioxidant' parameters and frailty was carried out across major electronic databases from inception until May 2016. Cross-sectional/case control and longitudinal studies reporting data on the association between frailty and anti-oxidants-OS biomarkers were considered for inclusion. Results were summarized with a synthesis based on the best evidence. RESULTS: From 1856 hits, 8 studies (cross-sectional/case control) were included (N=6349; mean age of 75+/-12years; 56.4% females). Overall, there were 588 (=9.3%) frail, 3036 pre-frail (=47.8%), 40 (=0.6%) pre-frail/robust, and 2685 (=42.3%) robust subjects. Six cross-sectional/case control studies demonstrated that frailty was associated with an increase in peripheral OS biomarkers, including lipoprotein phospholipase A2 (1 study), isoprostanes (2 studies), malonaldehyde (2 studies), 8-hydroxy-20-deoxyguanosine (2 studies), derivate of reactive oxygen metabolites (2 studies), oxidized glutathione/glutathione (1 study), 4-hydroxy-2,3-nonenal (1 study), and protein carbonylation levels (1 study). In addition, preliminary evidence points to lower anti-oxidant parameters (vitamin C, E, alpha-tocopherol, biological anti-oxidant potential, total thiol levels) in frailty. CONCLUSION: Frailty and pre-frailty appear to be associated with higher OS and possibly lower anti-oxidant parameters. However, due to the cross-sectional design, it is not possible to disentangle the directionality of the relationships observed. Thus, future high-quality and in particular longitudinal research is required to confirm or refute these relationships and to further elucidate pathophysiological mechanisms. PMID- 28364872 TI - Association between pelvic organ prolapse and climacteric symptoms in postmenopausal women. AB - OBJECTIVE: To evaluate whether climacteric symptoms are related to pelvic organ prolapse (POP) in postmenopausal women. STUDY DESIGN: A cross-sectional investigation was performed on 1382 postmenopausal women attending an outpatient service for menopause at a university hospital. MAIN OUTCOME MEASURES: Data regarding climacteric symptoms, as captured by the Greene Climacteric Scale, and objective POP were retrieved from an electronic database. Additional data retrieved were age, anthropometric measures, personal and reproductive history, use of medication or drugs, coffee, smoking, state of anxiety (STAI scale score) and depression (Zung scale score). RESULTS: The score of Greene Climacteric Scale was higher (p=0.02) in women with (n=538) than in those without (n=844) POP (29.6+/-13.6 vs. 27.8+/-13.; p=0.02). In multiple logistic regression models, the score was independently related to POP as a whole (OR 1.012; 95%CI 1.003,1.022; p=0.009), and to bladder prolapse (OR 1.011; 95%CI 1.007,1.07; p=0.02) or to uterus prolapse (OR 1.003; 95%CI 0.99,1.016; p=0.63) or rectum prolapse (rectocele) (OR 1.004; 95%CI 0.988,1.02; p=0.62). CONCLUSIONS: In postmenopausal women, a higher burden of climacteric symptoms, is associated with POP. Underlying mechanisms were not assessed and deserve further investigation. PMID- 28364873 TI - Broadening our perspectives on complementary and alternative medicine for menopause: A narrative review. AB - Complementary and alternative medicine (CAM) is widely used for menopause, although not all women disclose use to their healthcare providers. This narrative review aims to expand providers' understanding of cross-cultural approaches to treating and managing menopause by providing an overarching framework and perspective on CAM treatments. Increased provider understanding and awareness may improve not only provider-patient communication but also effectiveness of treatments. The distinction between illness (what patients suffer) and disease (what physicians treat) highlights the gap between what patients seek and doctors provide, and may help clarify why many women seek CAM at menopause. For example, CAM is often sought by women for whom biomedicine has been unsuccessful or inaccessible. We review the relevance to menopause of three CAM categories: natural products, mind-body practices including meditation, and other complementary health approaches including traditional Chinese medicine (TCM) and Japanese Kampo. Assessing the effectiveness of CAM is challenging because of the individualized nature of illness patterns and associated treatments, which complicate the design of randomized controlled trials. Because many women seek CAM due to inefficacy of biomedical treatments, or cultural or economic marginalization, biomedical practitioners who make an effort to learn about CAM and ask patients about their CAM use or interest may dramatically improve the patient-provider relationship and rapport, as well as harnessing the 'meaning response' (Moerman, 2002) imbued in the clinical encounter. By working with women to integrate their CAM-related health-seeking behaviors and treatments, providers may also boost the efficacy of their own biomedical treatments. PMID- 28364874 TI - Is the hymen a suitable cut-off point for clinically relevant pelvic organ prolapse? AB - OBJECTIVES: The primary objective was to evaluate the ability of different anatomic cut-off points, as established in specialist urogynecology populations, to identify clinically relevant prolapse in a population of postmenopausal women with pelvic floor symptoms recruited from primary care. STUDY DESIGN: Cross sectional study among 890 women (>=55 years) screened for pelvic floor symptoms. MAIN OUTCOME MEASURES: The Pelvic Floor Distress Inventory 20 was used to measure symptoms, and the Pelvic Organ Prolapse Quantification (POP-Q) system was used to assess prolapse. Areas under the curves, sensitivity, and specificity were calculated for the hymen as a cut-off point for symptomatic prolapse of the anterior and posterior vaginal wall. For the apical compartment, a cut-off point of -5cm relative to the hymen was used. RESULTS: Vaginal bulging was the only symptom reported more often with increasing POP-Q stages. Areas under the curves (95% confidence intervals) to discriminate between women with and without vaginal bulging symptoms were 0.66 (0.61-0.72), 0.56 (0.50-0.63), and 0.61 (0.55-0.66) for the anterior (Ba), posterior (Bp) and apical (C) compartment, respectively. When the hymen was used as the cut-off point, Ba had a sensitivity of 38.1% and a specificity of 82.4%, and Bp had a sensitivity of 13.3% and a specificity of 96.5%. For C, the cut-off point of -5cm relative to the hymen had a sensitivity of 37.9% and a specificity of 73.1%. CONCLUSIONS: The anatomic cut-off points for clinically relevant prolapse established in the specialist urogynecology population cannot adequately identify symptomatic prolapse in a population of postmenopausal women with pelvic floor symptoms recruited from primary care. PMID- 28364875 TI - Care homes: The developing ideology of a homelike place to live. AB - This paper reports on part of a doctoral study which explored stakeholder perceptions of the importance of a homelike environment in a care home and which factors contributed to this. The changes in institutional care for older people have evolved from being a 'warehouse' type of environment for those too poor, too mad, too sick and too unloved, to a place where older people in need of care can spend their days in safety, in a 'homely' environment. Such an environment is one of the quality indicators of care home provision. Yet defining what 'homeliness' means is fraught with difficulties. This article presents a narrative literature review on the concept of 'home' and the common measures taken to address homeliness in a care home setting. The results show that although the word 'homely' is used with the presumption of a shared understanding, the concept is elusive and highly subjective. Given that long-term care now provides homes for an increasingly wide range of age groups and individuals with increasingly diverse backgrounds and personal histories, is a shared viewpoint on homeliness possible? Indeed, is it ever possible to make an institution homely? PMID- 28364877 TI - SVEPM 2016 - Current multidisciplinary advances in veterinary epidemiology and economics, Society of Veterinary Epidemiology and Preventive Medicine conference Elsinore, Denmark 16-18 March 2016. PMID- 28364876 TI - Alterations of fatty acid profiles in gestational diabetes and influence of the diet. AB - Gestational diabetes mellitus (GDM) is a pregnancy-induced complication with increased prevalence, especially in overweight women. Fatty acid (FA) composition in tissues can reflect dietary fat intake, especially essential FA intake. Moreover, it has been shown that FA profiles in blood lipid fractions are altered in diabetic patients. Consequently, women with GDM may also have a distinctive FA profile. The objective of this review is compare FA profiles in different blood lipid fractions and the influence of dietary fat intake in women with GDM or normoglycemic pregnancies. Results show that women with GDM have more saturated and less polyunsaturated FA (PUFA) in their red blood cell (RBC) membranes than normoglycemic pregnant women. Moreover, some studies reported that women with GDM have a greater energy intake from total fat and saturated FA, along with a lower energy intake from PUFA, when compared to normoglycemic pregnancies. Clinical trials showed that omega-3 PUFA levels in RBC membranes of GDM women can be restored by a dietary intervention. Further research is required to determine whether FA profiles are altered prior to the diagnosis of GDM and can be prevented by diet. PMID- 28364878 TI - Communication between doctor and patient in contemporary times. PMID- 28364879 TI - "Real-world" evaluation of AcceleDent. PMID- 28364880 TI - Child abuse prevention month. PMID- 28364881 TI - Authors' response. PMID- 28364882 TI - Necessities of documentation in canine-lateral transposition. PMID- 28364883 TI - Good science, bad science, and junk science. PMID- 28364884 TI - Authors' response. PMID- 28364886 TI - Who benefits? PMID- 28364887 TI - Does orthodontic treatment before the age of 18 years improve oral health-related quality of life? A systematic review and meta-analysis. AB - INTRODUCTION: Orthodontics aims to improve oral health-related quality of life (OHRQoL). In this systematic review, we examined the evidence for changes in OHRQoL after orthodontic treatment for patients treated before they were 18 years old. METHODS: The participants were patients aged less than 18 years. The interventions were nonorthognathic and cleft orthodontic treatment. The comparisons were before and after orthodontic treatment, or nonorthodontic control. The outcomes were validated measures of OHRQoL. The study designs were randomized controlled trials, controlled clinical trials, prospective cohort studies, and cross-sectional or case-control studies. Multiple electronic databases were searched, with no language restrictions; authors were contacted, and reference lists screened. The Newcastle-Ottawa scale was used for quality assessments. Screening, data extraction, and quality assessments were performed by 2 investigators independently. RESULTS: We found 1590 articles and included 13 studies (9 cohort, 3 cross sectional, and 1 case control), with 6 in the meta analyses. All were judged of low or moderate quality. A moderate improvement in OHRQoL was observed before and after orthodontic treatment (n = 243 participants; standardized mean difference, -0.75; 95% CI, -1.15 to -0.36) particularly in the dimensions of emotional well-being (n = 213 participants; standardized mean difference, -0.61; 95% CI, -0.80 to -0.41) and social well-being (n = 213 participants; standardized mean difference, -0.62; 95% CI, -0.82 to -0.43). CONCLUSIONS: Orthodontic treatment during childhood or adolescence leads to moderate improvements in the emotional and social well-being dimensions of OHRQoL, although the evidence is of low and moderate quality. More high quality, longitudinal, prospective studies are needed. PMID- 28364888 TI - Expert panels as a reference standard in orthodontic research: An assessment of published methods and reporting. AB - INTRODUCTION: The aim of this study was to investigate the expert panel methodology applied in orthodontics and its reporting quality. Additionally, the relationship between the reporting quality and a range of variables was explored. METHODS: PubMed was searched for orthodontic studies in which the final diagnosis or assessment was made by 2 or more experts published up to March 16, 2015. Reporting quality assessment was conducted using an established modified checklist. The relationship between potential predictors and the total score was assessed using univariable linear regression. RESULTS: We identified 237 studies with a mean score of 9.97 (SD, 1.12) out of a maximum of 15. Critical information about panel methodology was missing in all studies. The panel composition differed substantially across studies, ranging from 2 to 646 panel members, with large variations in the expertise represented. Only 17 studies (7.2%) reported sample size calculations to justify the panel size. Panel members were partly blinded in 65 (27.4%) studies. Most studies failed to report which statistic was used to compute intrarater (65.8%) and interrater (66.2%) agreements. Journal type (nonorthodontic: beta, 0.23; 95% CI, -0.07 to 0.54 compared with orthodontic), publication year (beta, 0; 95% CI, -0.02 to 0.02 for each additional year), number of authors (1-3: beta, 0.30; 95% CI, -0.13 to 0.74 compared with at least 6; 4-5: beta, 0.18; 95% CI, -0.29 to 0.33 compared with at least 6), and number of centers involved (single: beta, 0.20; 95% CI, -0.14 to 0.54 compared with multicenter) were not significant predictors of improved reporting. Studies published in Asia and Australia had significantly lower scores compared with those published in Europe (beta, -0.54; 95% CI, -0.92 to -0.17). CONCLUSIONS: Formal guidelines on methodology and reporting of studies involving expert panels are required. PMID- 28364889 TI - Streptococcus mutans forms xylitol-resistant biofilm on excess adhesive flash in novel ex-vivo orthodontic bracket model. AB - INTRODUCTION: During orthodontic bonding procedures, excess adhesive is invariably left on the tooth surface at the interface between the bracket and the enamel junction; it is called excess adhesive flash (EAF). We comparatively evaluated the biofilm formation of Streptococcus mutans on EAF produced by 2 adhesives and examined the therapeutic efficacy of xylitol on S mutans formed on EAF. METHODS: First, we investigated the biofilm formation of S mutans on 3 orthodontic bracket types: stainless steel preadjusted edgewise, ceramic preadjusted edgewise, and stainless steel self-ligating. Subsequently, tooth colored Transbond XT (3M Unitek, Monrovia, Calif) and green Grengloo (Ormco, Glendora, Calif) adhesives were used for bonding ceramic brackets to extracted teeth. S mutans biofilms on EAF produced by the adhesives were studied using the crystal violet assay and scanning electron microscopy. Surface roughness and surface energy of the EAF were examined. The therapeutic efficacies of different concentrations of xylitol were tested on S mutans biofilms. RESULTS: Significantly higher biofilms were formed on the ceramic preadjusted edgewise brackets (P = 0.003). Transbond XT had significantly higher S mutans biofilms compared with Grengloo surfaces (P = 0.007). There was no significant difference in surface roughness between Transbond XT and Grengloo surfaces (P >0.05). Surface energy of Transbond XT had a considerably smaller contact angle than did Grengloo, suggesting that Transbond XT is a more hydrophilic material. Xylitol at low concentrations had no significant effect on the reduction of S mutans biofilms on orthodontic adhesives (P = 0.016). CONCLUSIONS: Transbond XT orthodontic adhesive resulted in more S mutans biofilm compared with Grengloo adhesive on ceramic brackets. Surface energy seemed to play a more important role than surface roughness for the formation of S mutans biofilm on EAF. Xylitol does not appear to have a therapeutic effect on mature S mutans biofilm. PMID- 28364890 TI - Assessment of antibacterial and cytotoxic effects of orthodontic stainless steel brackets coated with different phases of titanium oxide: An in-vitro study. AB - INTRODUCTION: Our objective was to assess the antibacterial and cytotoxic effects of orthodontic stainless steel brackets coated with different phases of photocatalytic titanium oxide. METHODS: From a total sample of 115 brackets, 68 orthodontic stainless steel brackets were coated with titanium oxide using a radiofrequency magnetron sputtering machine. The coated brackets were then converted into 34 each of the anatase and rutile phases of titanium oxide. These brackets were subdivided into 4 groups for antibacterial study and 3 groups for cytotoxicity study. Brackets for the antibacterial study were assessed against the Streptococcus mutans species using microbiologic tests. Three groups for the cytotoxicity study were assessed using the thiazolyl tetrazolium bromide assay. RESULTS: The antibacterial study showed that both phases were effective, but the rutile phase of photocatalytic titanium oxide had a greater bactericidal effect than did the anatase phase. The cytotoxicity study showed that the rutile phase had a greater decrease in viability of cells compared with the anatase phase. CONCLUSIONS: It is recommended that orthodontic brackets be coated with the anatase phase of titanium oxide since they exhibited a significant antibacterial property and were only slightly cytotoxic. PMID- 28364892 TI - Management of overbite with the Invisalign appliance. AB - INTRODUCTION: Most of the published literature on the management of overbite with the Invisalign appliance (Align Technology, Santa Clara, Calif) consists of case reports and case series. METHODS: In this retrospective study of 120 patients, we sought to assess the nature of overbite changes with the Invisalign appliance. Records were collected from 3 practitioners, all experienced with the Invisalign technique. The patients were consecutively treated adults (>18 years old) who underwent orthodontic treatment only with the Invisalign appliance. Patients with major transverse or anteroposterior changes or extraction treatment plans were excluded. The study sample included 68 patients with normal overbites, 40 with deepbites, and 12 with open bites. Their median age was 33 years, and 70% of the patients were women. RESULTS: Cephalometric analyses indicated that the deepbite patients had a median overbite opening of 1.5 mm, whereas the open bite patients had a median deepening of 1.5 mm. The median change for the normal overbite patients was 0.3 mm. Changes in incisor position were responsible for most of the improvements in the deepbite and open bite groups. Minimal changes in molar vertical position and mandibular plane angle were noted. CONCLUSIONS: The Invisalign appliance appears to manage the vertical dimension relatively well, and the primary mechanism is via incisor movements. PMID- 28364891 TI - Improvement in Peer Assessment Rating scores after nonextraction, premolar extraction, and mandibular incisor extraction treatments in patients with Class I malocclusion. AB - INTRODUCTION: Different treatment protocols implemented for correction of Class I malocclusion aim at achieving ideal occlusal characteristics. This study was planned to evaluate the improvement in the occlusal characteristics of Class I patients treated with nonextraction (NE), all first premolar extractions (PME), and mandibular incisor extraction (MIE) as assessed by the percentage of improvement in Peer Assessment Rating (PAR) scores. METHODS: This retrospective cross-sectional study was conducted on the pretreatment and posttreatment dental casts of 108 subjects with Class I malocclusion. The total sample was divided into 3 equal groups according to the treatment protocol implemented: NE, PME, and MIE. The mean pretreatment and posttreatment PAR scores, and the percentages of improvement were compared among the 3 treatment modalities using Kruskal-Wallis and post-hoc Dunnett T3 tests. RESULTS: The mean percentages of improvement in the PAR score were 75.8% +/- 25.8% in the NE group, 73.1% +/- 19.4% in the PME group, and 70.6% +/- 24.1% in the MIE group. There was no significant difference (P = 0.351) in the percentages of improvement in PAR scores among the 3 treatment modalities. However, the mean pretreatment and posttreatment PAR scores varied significantly (P <0.001) in the 3 groups. The average pretreatment and posttreatment PAR scores were highest in the MIE group and lowest in the NE group. CONCLUSIONS: The comparable percentages of improvement in PAR scores among the 3 groups denote that equivalent occlusal corrections were achieved in Class I patients treated with the NE, PME, and MIE protocols. PMID- 28364893 TI - Genetic polymorphisms underlying the skeletal Class III phenotype. AB - INTRODUCTION: Our goal was to verify the association between candidate polymorphisms and skeletal Class III malocclusion in a well-characterized homogeneous sample set. METHODS: Thirty-five single-nucleotide polymorphisms were studied from 10 candidate loci in 54 Class III subjects and 120 controls. Skeletal Class III characteristics included ANB angle less than 0 degrees , SNB angle greater than 83 degrees (mandibular prognathism), SNA angle less than 79 degrees (maxillary deficiency), Class III molar relationship, and negative overjet. Inclusion criteria for the controls were ANB angle between 0 degrees and 4 degrees , Class I molar relationship, and normal overjet. Chi-square and Fisher exact tests and principal component (PC) analysis were used to determine overrepresentation of marker alleles with alpha of 0.05. Odds ratios and 95% confidence intervals were calculated. RESULTS: MYO1H (rs10850110 AG) (P = 0.001) with PC2 and between FGF10 (rs593307 A20 degrees ). Intraclass correlation coefficients showed strong to almost perfect agreement (mean, 0.80 mm; 95% CI, 0.75-0.85) of the two examiners. Multivariate analysis of covariance resulted in no difference in EARR between the canines and premolars of the space closure and control sides. On the contrary, there was a statistically significant difference between mesialized and nonmezialized molars (0.73 mm; 95% confidence interval, 0.19-1.27). The mean total EARR in each tooth type did not exceed 1 mm. CONCLUSIONS: Space closure through extensive tooth movement in the mandible was identified as a risk factor for EARR. However, the amount of EARR attributed to space closure and the total EARR were not considered clinically significant. PMID- 28364895 TI - Radiographic prognostic factors determining spontaneous space closure after loss of the permanent first molar. AB - INTRODUCTION: Permanent first molars (PFM) with a poor prognosis are routinely extracted in children throughout the United Kingdom. National guidelines suggest that to achieve spontaneous closure for the mandibular arch, the PFM should be extracted at 8 to 10 years of age, during bifurcation formation of the second molar. The literature is of limited quality and has suggested alternative variables that may be associated with successful space closure. Our aim was to investigate the radiographic prognostic factors associated with space closure after extraction of PFM. Two objectives of the research are reported in this article: to determine factors that might predict space closure of the second molar after extraction of the PFM, and to develop a tool kit to aid clinical decision making. METHODS: We assessed 148 maxillary and 153 mandibular PFM extracted from 81 participants retrospectively. Dental age, second molar developmental stage, second premolar and second molar angulations, and presence or absence of the third molar were assessed on the preextraction orthopantomograms. Outcome was assessed via visual examination, study models, or radiographs. RESULTS: Closure occurred in 89.9% of the maxillary and 49.0% of the mandibular quadrants. Dental age was statistically, but not clinically, significant in the maxillary arch (P <0.05). For the mandibular arch, presence or absence of the third molar and second molar angulation were statistically and clinically significant (P <0.01 and P <0.05, respectively). A tool kit was developed in relation to the mandibular arch variables. CONCLUSIONS: These findings are contradictory to the Royal College of Surgeons guidelines and suggest that the presence of the third molar and a mesially angulated second molar are favorable for space closure. The developed tool kit requires further validity testing. PMID- 28364896 TI - Sixteen-week analysis of unaltered elastomeric chain relating in-vitro force degradation with in-vivo extraction space tooth movement. AB - INTRODUCTION: The purposes of this study were to evaluate whether unaltered elastomeric chain can continue to move teeth for 16 weeks and to relate it to the amount of force remaining for the same batch of elastomeric chains. METHODS: The in-vivo portion of the study had a sample of 30 paired extraction space sites from 22 subjects who were measured for closure of the space every 28 days. The altered side elastomeric chain served as the control and was replaced at 28-day intervals whereas the experimental side remained unaltered. In the in-vitro portion of the study, 100 each of 2-unit and 3-unit segments of the same batch of elastomeric chains were placed in a water bath, and the force was measured for 20 of each segment length at the 28-day measurement points. RESULTS: Statistically significant amounts of space closure occurred at both the altered and unaltered sites at all measurement time points. The mean space closure at the altered sites was minimally greater than that observed at the paired unaltered sites. The mean differences of space closure between the altered and unaltered sites ranged from a minimum of -0.05 mm at 4 weeks to a maximum of -0.14 mm at 8 weeks. The elastomeric chain force degraded rapidly by 4 weeks but continued a gradual diminution of force to 86 g at 16 weeks. CONCLUSIONS: Unaltered elastomeric chain continued to move teeth into extraction spaces for 16 weeks in this sample from both statistically and clinically significant standpoints. There were minimal and statistically insignificant differences in the mean space closure measurements between the paired altered and unaltered sites. The elastomeric chain force at 16 weeks was less than 100 g, yet at the same time point, teeth continued to move clinically. PMID- 28364897 TI - Arch-width changes in extraction vs nonextraction treatments in matched Class I borderline malocclusions. AB - INTRODUCTION: The aims of this study were to identify a sample of borderline Class I extraction and nonextraction patients and to investigate posttreatment changes in arch-width and perimeter measurements. METHODS: A parent sample of 580 Class I patients was subjected to discriminant analysis, and a borderline subsample of 62 patients, 31 treated with extraction of 4 first premolars and 31 treated without extractions, was obtained. The patients' plaster casts were digitally scanned, and the maxillary and mandibular intercanine and intermolar widths and perimeters were assessed. RESULTS: The extraction group showed increases in maxillary and mandibular intercanine widths (P <0.001) and decreases in mandibular intermolar width and in maxillary and mandibular perimeters (P <0.001). The nonextraction group showed increases in all 4 arch-width measurements (P <=0.003), whereas the maxillary and mandibular perimeters were maintained. The posttreatment differences between the 2 groups showed significant differences in the maxillary (P <0.001) and mandibular intermolar widths (P <0.001). Also, the comparison of the arch perimeters between the 2 treatment groups showed adjusted differences of -8.51 mm (P <0.001) and -8.44 mm (P <0.001) for the maxillary and mandibular arches, respectively. The intercanine widths showed no changes between the 2 treatment groups. CONCLUSIONS: Borderline Class I patients treated with extraction of 4 first premolars had decreased maxillary and mandibular intermolar and perimeter measurements compared with nonextraction patients. The maxillary and mandibular intercanine widths showed no significant difference between the 2 treatment groups. PMID- 28364898 TI - Racial and sex differences in timing of the cervical vertebrae maturation stages. AB - INTRODUCTION: Our objective was to investigate skeletal maturation of female and male subjects from different racial groups by comparing the cervical vertebrae maturation (CVM) stages. METHODS: The study included 3 racial groups: white, African American, and Hispanic subjects. Each group was subdivided into female and male. The age range of the subjects was between 7 and 18 years. The sample included 60 lateral cephalographs for each subgroup. Skeletal maturation of the cervical vertebrae was assessed according to a method that described 6 CVM stages. RESULTS: Racial differences were evident in the mean ages of CVM stages 2, 3, 4, and 5 (P = 0.002; P = 0.003; P = 0.001; and P = 0.001, respectively) among females; among males, only stage 3 was different (P = 0.001). Sex differences in the mean ages of stages 1, 2, and 3 in Hispanic subjects (P <0.001), and in stages 2 and 3 in African American subjects (P = 0.019 and P <0.001) and white subjects (P = 0.004 and P <0.001) were detected. CONCLUSIONS: In both sexes, racial differences were not apparent between whites and African Americans, but differences were evident between Hispanics vs both whites and African Americans. Sex differences were apparent between the sexes in each of the 3 ethnic groups in CVM stages 2 and 3. No sex differences were detected in stages 4, 5, or 6 in any of the 3 racial groups. It is recommended to consider racial and sex differences when using the CVM stage as a skeletal maturation indicator. PMID- 28364899 TI - Atomic force microscopy analysis of enamel nanotopography after interproximal reduction. AB - INTRODUCTION: Interproximal reduction (IPR) removes enamel and leaves grooves and furrows on the tooth surface, which may increase the risk of caries. The aims of this study were to assess the nanotopography of enamel surfaces produced by the most commonly used IPR instruments and to evaluate the effect of polishing after IPR. METHODS: Enamel slabs were cut from the interproximal surfaces of healthy premolars and then treated with diamond burs, strips, or discs, or Sof-Lex polishing discs (3M ESPE, St Paul, Minn). All samples were cleaned by sonication in distilled water. The control group had no IPR performed and was subjected only to cleaning by sonication. The enamel surfaces were assessed using atomic force microscopy. RESULTS: The IPR instruments all produced surfaces rougher than the control sample; however, the samples that received polishing with Sof-Lex discs after enamel reduction were smoother than untreated enamel (P <0.05 for all comparisons). The larger grit medium diamond burs and medium strips generated rougher enamel surfaces than their smaller grit counterparts: fine diamond burs and fine strips (P <0.001). The difference in roughness generated by mesh and curved disks was not statistically significant (P = 0.122), nor was the difference caused by fine strips and mesh discs (P = 0.811) or by fine strips and curved discs (P = 0.076) (surface roughness values for medium bur, 702 +/- 134 nm; medium strip, 501 +/- 115 nm; mesh disc, 307 +/- 107 nm; fine bur, 407 +/- 95 nm; fine strip, 318 +/- 50 nm; curved disc, 224 +/- 65 nm). The smoothest surfaces were created by use of the entire series of Sof-Lex polishing discs after the enamel reduction (surface roughness, 37 +/- 14 nm), and these surfaces were significantly smoother than the control surfaces (surface roughness, 149 +/- 39 nm; P = 0.017). CONCLUSIONS: Different IPR instruments produced enamel surfaces with varied nanotopography and different degrees of roughness. Enamel surfaces treated with diamond-coated burs were the roughest, followed by diamond coated strips and diamond coated discs. Polishing with Sof-Lex polishing discs after IPR reduced the enamel surface roughness, and this surface was even smoother than untreated enamel. PMID- 28364900 TI - Leveling the curve of Spee with continuous archwire appliances in different vertical skeletal patterns: A retrospective study. AB - INTRODUCTION: The aim of this study was to determine the effects of the leveling of the curve of Spee in subjects treated with preadjusted appliances in different skeletal vertical patterns. METHODS: The study sample consisted of 90 white patients (39 male, 51 female; age, 19 years 4 months +/- 1 year 9 months), with a curve of Spee of 2 mm or greater before treatment. They were categorized into 3 groups: low-angle group (30 subjects; 12 male, 18 female; age, 19 years 1 month +/- 1 year 4 months), normal-angle group (30 subjects; 14 male, 16 female; age, 19 years 6 months +/- 2 years 1 month), and high-angle group (30 subjects; 13 male, 17 female; age, 19 years 7 months +/- 1 year 5 months) by their vertical facial types. Cephalometric parameters were used to evaluate the different dental movements after treatment. The curve of Spee was measured on digital dental casts. Analysis of variance was used to determine any differences between the changes in the groups with time. RESULTS: For the skeletal variables, no significant modifications were found in the 3 groups. For the dentoalveolar variables, the low-angle group showed significant buccal movements and intrusion of the mandibular incisors. The high-angle group had greater extrusion of the posterior teeth associated with uprighting of the first and second molars. CONCLUSIONS: In low-angle subjects, leveling of the curve of Spee occurs through buccal movement and intrusion of the mandibular incisors; in high-angle subjects, it occurs through extrusion and uprighting of the posterior teeth. PMID- 28364902 TI - Orthodontic and surgical management of a patient with severe skeletal Class II deformity and facial asymmetry: A case report with a 5-year follow-up. AB - In this case report, we present the orthodontic and surgical management of an 18 year-old girl who had a severe craniofacial deformity, including maxillary prognathism, vertical maxillary excess (gummy smile), mandibular retrognathism, receding chin, and facial asymmetry caused by unilateral temporomandibular joint ankylosis. For correction of the facial asymmetry, the patient's right mandibular ramus and body were lengthened via distraction osteogenesis after 5 months of preoperative orthodontic therapy. Subsequently, extraction of 4 first premolars, bimaxillary anterior segmental osteotomy, and genioplasty were simultaneously performed in the second-stage operation to correct the skeletal deformities in the sagittal and vertical planes. Postoperative orthodontic treatment completed the final occlusal adjustment. The total active treatment period lasted approximately 30 months. The clinical results show that the patient's facial esthetics were significantly improved with minimal surgical invasion and distress, and a desirable occlusion was achieved. These pleasing results were maintained during the 5-year follow-up. PMID- 28364901 TI - Analysis of dentoalveolar structures with novel corticotomy-facilitated mandibular expansion: A 3-dimensional finite element study. AB - INTRODUCTION: Surgically assisted mandibular arch expansion is an effective treatment modality for alleviating constriction and crowding. However, only mandibular symphyseal osteotomy is recommended for mandibular arch expansion. No relevant studies have compared the biomechanical responses of different corticotomy designs on mandibular expansion. Therefore, the aim of this study was to evaluate the effect of different corticotomy approaches and modes of loading on the expansion of adult mandibles using biomechanics. METHODS: Nine finite element models including 2 novel corticotomy designs were simulated. Stress, strain, and displacement of crown, root, and bone were calculated and compared under different corticotomy approaches and loading conditions. RESULTS: The biomechanical response seen in the finite element models in terms of displacement on the x-axis was consistent from anterior to posterior teeth with parasymphyseal step corticotomy and tooth-borne force application. In addition, the amount of displacement predicted by parasymphyseal step corticotomy in the tooth-borne mode was greater compared with other models. CONCLUSIONS: These results suggest that parasymphyseal step corticotomy with tooth-borne force application is a viable treatment option for true bony expansion in an adult mandible. PMID- 28364903 TI - Long-term follow-up of a patient with achondroplasia treated with an orthodontic approach. AB - We successfully treated a patient with achondroplasia with conventional orthodontic techniques. It was followed by long-term retention. The patient, a 12 year-old boy, had chief complaints of occlusal disturbance and mandibular protrusion. He had been diagnosed with achondroplasia and had growth hormone treatment in his early teenage years. His facial profile was concave with a bulging forehead and a retrognathic maxilla. It was characterized by a skeletal Class III jaw-base relationship with a retropositioned maxilla. At the age of 12 years 9 months, maxillary protraction was initiated with a reverse headgear; for 2 years 6 months, the maxillomandibular growth was controlled. After the growth spurt, at the age of 15 years 6 months, leveling and alignment of both dental arches were started with preadjusted edgewise appliances. After 83 months of multibracket treatment, an acceptable occlusion with a Class I molar relationship and an adequate interincisal relationship was achieved, despite the simultaneous marked vertical growth of the mandible. The resultant occlusion was stable during a 6-year retention period, although considerable forward-downward mandibular growth was observed. Conclusively, our results indicated the necessity of long term observation in this patient with achondroplasia, especially because of the persistent mandibular growth. PMID- 28364904 TI - Camouflage treatment of skeletal Class III malocclusion with conventional orthodontic therapy. AB - Nonextraction camouflage treatment along with Class III elastics was used to treat a 39-year-old woman with a skeletal Class III pattern and a low mandibular plane angle and short lower anterior facial height. The total active treatment time was 26 months. Her occlusion, smile esthetics, and soft tissue profile were significantly improved after treatment. PMID- 28364905 TI - Memotain: A CAD/CAM nickel-titanium lingual retainer. AB - Approximately 1/2 of maxillary and 1/5 of mandibular multi-stranded lingual retainers fail during retention in some form, either bond failure or wire breakage. Memotain is a new CAD/CAM fabricated lingual retainer wire made of custom-cut nickel-titanium, as an alternative to multi-stranded lingual retainers. It offers numerous perceived advantages to the traditional multi stranded stainless steel wire, including precision fit, avoidance of interferences, corrosion resistance and even the potential for minor tooth movement as an active lingual retainer. PMID- 28364906 TI - Use of redundant arrays of inexpensive disks in orthodontic practice. AB - In a time when orthodontists are getting away from paper charts and going digital with their patient data and imaging, practitioners need to be prepared for a potential hardware failure in their data infrastructure. Although a backup plan in accordance with the Security Rule of the Health Insurance Portability and Accountability Act (HIPAA) of 1996 may prevent data loss in case of a disaster or hard drive failure, it does little to ensure business and practice continuity. Through the implementation of a common technique used in information technology, the redundant array of inexpensive disks, a practice may continue normal operations without interruption if a hard drive fails. PMID- 28364907 TI - Do web-site postings qualify as learned treatises? PMID- 28364909 TI - APIC 2017 to feature hot topics in infection prevention. PMID- 28364910 TI - Clean your hands on May 5, 2017: Fight antibiotic resistance-it's in your hands. PMID- 28364908 TI - Logistic regression: Part 1. PMID- 28364912 TI - Safety and use of peripherally inserted central catheters versus midline catheters at a large academic medical center. PMID- 28364911 TI - Influenza vaccination among workers-21 U.S. states, 2013. AB - BACKGROUND: Influenza illnesses can result in missed days at work and societal costs, but influenza vaccination can reduce the risk of disease. Knowledge of vaccination coverage by industry and occupation can help guide prevention efforts and be useful during influenza pandemic planning. METHODS: Data from 21 states using the 2013 Behavioral Risk Factor Surveillance System industry-occupation module were analyzed. Influenza vaccination coverage was reported by select industry and occupation groups, including health care personnel (HCP) and other occupational groups who may have first priority to receive influenza vaccination during a pandemic (tier 1). The t tests were used to make comparisons between groups. RESULTS: Influenza vaccination coverage varied by industry and occupation, with high coverage among persons in health care industries and occupations. Approximately half of persons classified as tier 1 received influenza vaccination, and vaccination coverage among tier 1 and HCP groups varied widely by state. CONCLUSIONS: This report points to the particular industries and occupations where improvement in influenza vaccination coverage is needed. Prior to a pandemic event, more specificity on occupational codes to define exact industries and occupations in each tier group would be beneficial in implementing pandemic influenza vaccination programs and monitoring the success of these programs. PMID- 28364913 TI - No product, no program: The critical role of supply chains in closing the immunization gap. PMID- 28364914 TI - Immunization supply chains: Why they matter and how they are changing. PMID- 28364915 TI - The potential of next-generation supply chains to ease DRC's "Casse-tete". PMID- 28364916 TI - Transforming cold chain performance and management in lower-income countries. AB - In many countries, one of the common factors limiting full and equitable access to effective immunization is the existence of gaps in cold chain and logistics (CCL) systems. This article focuses on the critical contribution that better management of CCL performance can make in addressing these barriers, as well as some essential practices needed to achieve and sustain these gains. These include (i) an emphasis on continuous improvement in CCL performance indicators, (ii) strong coordination and accountability across multiple stakeholders, and (iii) making the most of limited financial resources. This article is informed by the Clinton Health Access Initiative's (CHAI's) experience working with National Immunization Programs (NIPs) and immunization partners to improve the effectiveness and efficiency of CCL systems (including CCE deployment and maintenance, temperature monitoring and control, stock management and distribution) across ten Gavi-supported "focus" countries. PMID- 28364917 TI - Making the leap into the next generation: A commentary on how Gavi, the Vaccine Alliance is supporting countries' supply chain transformations in 2016-2020. PMID- 28364918 TI - The origins of the vaccine cold chain and a glimpse of the future. AB - International efforts to eradicate smallpox in the 1960s and 1970s provided the foundation for efforts to expand immunization programmes, including work to develop immunization supply chains. The need to create a reliable system to keep vaccines cold during the lengthy journey from the manufacturer to the point of use, even in remote areas, was a crucial concern during the early days of the Expanded Programme on Immunization. The vaccine cold chain was deliberately separated from other medical distribution systems to assure timely access to and control of vaccines and injection materials. The story of the early development of the vaccine cold chain shows how a number of challenges were overcome with technological and human resource solutions. For example, the lack of methods to monitor exposure of vaccines to heat during transport and storage led to many innovations, including temperature-sensitive vaccine vial monitors and better methods to record and communicate temperatures in vaccine stores. The need for appropriate equipment to store and transport vaccines in tropical developing countries led to innovations in refrigeration equipment as well as the introduction and widespread adoption of novel high performance vaccine cold-boxes and carriers. New technologies also helped to make injection safer. Underlying this work on technologies and equipment was a major effort to develop the human resources required to manage and implement the immunization supply chain. This included creating foundational policies and a management infrastructure; providing training for managers, health workers, technicians, and others. The vaccine cold chain has contributed to one of the world's public health success stories and provides three priority lessons for future: the vaccine supply chain needs to be integrated with other public health supplies, re-designed for efficiency and effectiveness and work is needed in the longer term to eliminate the need for refrigeration in the supply chain. PMID- 28364920 TI - Is freezing in the vaccine cold chain an ongoing issue? A literature review. AB - Vaccine exposure to temperatures below recommended ranges in the cold chain may decrease vaccine potency of freeze-sensitive vaccines leading to a loss of vaccine investments and potentially places children at risk of contracting vaccine preventable illnesses. This literature review is an update to one previously published in 2007 (Matthias et al., 2007), analyzing the prevalence of vaccine exposure to temperatures below recommendations throughout various segments of the cold chain. Overall, 45 studies included in this review assess temperature monitoring, of which 29 specifically assess 'too cold' temperatures. The storage segments alone were evaluated in 41 articles, 15 articles examined the transport segment and 4 studied outreach sessions. The sample size of the studies varied, ranging from one to 103 shipments and from three to 440 storage units. Among reviewed articles, the percentage of vaccine exposure to temperatures below recommended ranges during storage was 33% in wealthier countries and 37.1% in lower income countries. Vaccine exposure to temperatures below recommended ranges occurred during shipments in 38% of studies from higher income countries and 19.3% in lower income countries. This review highlights continuing issues of vaccine exposure to temperatures below recommended ranges during various segments of the cold chain. Studies monitoring the number of events vaccines are exposed to 'too cold' temperatures as well as the duration of these events are needed. Many reviewed studies emphasize the lack of knowledge of health workers regarding freeze damage of vaccines and how this has an effect on temperature monitoring. It is important to address this issue by educating vaccinators and cold chain staff to improve temperature maintenance and supply chain management, which will facilitate the distribution of potent vaccines to children. PMID- 28364919 TI - Vaccine stockouts around the world: Are essential vaccines always available when needed? AB - INTRODUCTION: As countries rise to the challenge of implementing the priorities of this "Decade of Vaccine" and their commitments delineated in the Global Vaccine Action Plan (GVAP), many continue to face important challenges of securing a continuous supply of essential vaccine for their national immunization programme. This study provides evidence on the incidence of vaccine stockouts in countries, their root causes and their potential impact on service delivery. METHODS: Vaccine stockout indicators collected from the WHO-UNICEF Joint Reporting Form (JRF) and UNICEF's Vaccine Forecasting Tool were analysed for the years covering the first half of the GVAP (2011 to 2015) and using 2010 as the baseline year. While the JRF collects annual information on national and subnational stockouts by vaccine, the UNICEF Vaccine Forecasting Tool has the advantage of requesting UNICEF procuring countries to report on the reasons underpinning any stockouts. RESULTS: Every year on average, one in every three WHO Member States experiences at least one stockout of at least one vaccine for at least one month. The incidence is most pronounced in Sub-Saharan Africa where 38% of countries in this area of the world report national-level stockouts. The vaccines most affected are DTP containing vaccines (often combined with HepB and Hib) and BCG. They account for respectively 43% and 31% of stockout events reported. While national level vaccine stockouts occur in countries of all income groups, middle income countries are the most affected. In 80% of cases, national level stockouts were due to reasons internal to countries. More specifically, 39% of stockouts were attributable to government funding delays, 23% were caused by delays in the procurement processes, and poor forecasting and stock management at country level accounted for an additional 18%. When a national level stockout of vaccines occurs, there is an 89% chance that a subnational stockout will occur at district level. More concerning is that if a district level stockout occurs, this will lead to an interruption of vaccination services in 96% of cases. DISCUSSION: There continues to be important challenges of ensuring a continuous availability of essential vaccines. The global community, together with countries, urgently need to design effective interventions aimed at reducing the frequency and mitigating the impact of stockouts. PMID- 28364921 TI - The people factor: An analysis of the human resources landscape for immunization supply chain management. AB - Human resources is the backbone of any system and the key enabler for all other functions to effectively perform. This is no different with the Immunization Supply Chain, more so in todays' complex operating environment with the increasing strain caused by new vaccines and expanding immunization programmes (Source: WHO, UNICEF). In order to drive the change that is required for sustainability and continuous improvement, every immunization supply chain needs an effective leader. A dedicated and competent immunization supply chain leader with adequate numbers of skilled, accountable, motivated and empowered personnel at all levels of the health system to overcome existing and emerging immunization supply chain (ISC) challenges. Without an effective supply chain leader supported by capable and motivated staff, none of the interventions designed to strengthen the supply chain can be effective or sustainable (Source: Gavi Alliance SC Strategy 2014). This landscape analysis was preceded by an HR Evidence Review (March 2014) and has served to inform global partner strategies and country activities, as well as highlight where most support is required. The study also aimed to define the status quo in order to create some form of baseline against which to measure the impact of interventions related to HR going forward. The analysis was comprised of a comprehensive desk review, a survey of 40 respondents from 32 countries and consultations with ISC practitioners in several forums. The findings highlight key areas that should inform the pillars of a HR capacity development plan. At the same time, it revealed that there are some positive examples of where countries are actively addressing some of the issues identified and putting in place mechanisms and structures to optimize the SC function. PMID- 28364922 TI - Understanding the policy environment for immunization supply chains: Lessons learned from landscape analyses in Uganda and Senegal. AB - As immunization programs around the world undergo rapid change and expansion, supply chain and logistics systems have become strained, making it increasingly challenging for national public health systems to provide reliable, safe, and efficient access to vaccines. Governments and immunization partners have been aware of this problem for several years, and in 2010, the World Health Organization (WHO) launched the Effective Vaccine Management (EVM) process to help countries identify shortcomings in their immunization supply chains and develop plans for systematic improvement. EVM improvement plans now exist in all Gavi-eligible countries plus many middle- and upper-income countries; however, implementation has been slow and in many cases fraught with financial, managerial, structural, and political roadblocks. Recognizing that significant change of any kind requires a supportive policy environment and strong leadership, PATH began working in Uganda and Senegal to landscape the policy environment around immunization and identify relevant policies, administrative and technical roles and responsibilities, and other issues that may be affecting the supply chain for immunization. The policy landscape assessments included a desk review and a series of structured, in-depth interviews with key international, national, and local stakeholders. The findings highlighted a number of critical issues and challenges in both countries that may be preventing supply chains from functioning optimally. These challenges include a need for better coordination and planning between immunization programs and supply chain managers; the need for sufficient, timely and reliable financing for all aspects of immunization programs; the need for high-level managers trained in immunization supply chain management; and an urgent need for better, more timely data for decision-making. Overcoming these challenges will require the involvement of high-level political actors-including ministers of health and finance, parliamentarians, and other officials who have the ability to approve and influence policy, personnel, and structural changes; ensure work plans are backed with adequate resources for implementation; and hold program managers accountable for achieving agreed indicators. PMID- 28364923 TI - Equity and immunization supply chain in Madagascar. AB - : Vaccination rates have improved in many countries, yet immunization inequities persist within countries and the poorest communities often bear the largest burden of vaccine preventable disease. Madagascar has one of the world's largest equity gaps in immunization rates. Barriers to immunization include immunization supply chain, human resources, and service delivery to reflect the health system building blocks, which affect poor rural communities more than affluent communities. The Reaching Every District (RED) approach was revised to address barriers and bottlenecks. This approach focuses on the provision of regular services, including making cold chain functional. This report describes Madagascar's inequities in immunization, its programmatic causes and the country's plans to address barriers to immunization in the poorest regions in the country. METHODS: Two cross-sectional health facility surveys conducted in November and December 2013 and in March 2015 were performed in four regions of Madagascar to quantify immunization system barriers. FINDINGS: Of the four regions studied, 26-33% of the population live beyond 5km (km) of a health center. By 2015, acceptable (fridges stopped working for less than 6days) cold chains were found in 52-80% of health facilities. Only 10-57% of health centers had at least two qualified health workers. Between 65% and 95% of planned fixed vaccination sessions were conducted and 50-88% of planned outreach sessions were conducted. The proportion of planned outreach sessions that were conducted increased between the two surveys. CONCLUSION: Madagascar's immunization program faces serious challenges and those affected most are the poorest populations. Major inequities in immunization were found at the subnational level and were mainly geographic in nature. Approaches to improve immunization systems need to be equitable. This may include the replacement of supply chain equipment with those powered by sustainable energy sources, monitoring its functionality at health facility level and vaccination services in all communities. PMID- 28364925 TI - System redesign of the immunization supply chain: Experiences from Benin and Mozambique. AB - INTRODUCTION: Evidence suggests that immunization supply chains are becoming outdated and unable to deliver needed vaccines due to growing populations and new vaccine introductions. Redesigning a supply chain could result in meeting current demands. METHODS: The Ministries of Health in Benin in Mozambique recognized known barriers to the immunization supply chain and undertook a system redesign to address those barriers. Changes were made to introduce an informed push system while consolidating storage points, introducing transport loops, and increasing human resource capacity for distribution. Evaluations were completed in each country. RESULTS: Evaluation in each country indicated improved performance of the supply chain. The Effective Vaccine Management (EVM) assessment in Benin documented notable improvements in the distribution criteria of the tool, increasing from 40% to 100% at the district level. In Mozambique, results showed reduced stockouts at health facility level from 79% at baseline to less than 1% at endline. Coverage rates of DTP3 also increased from 68.9% to 92.8%. DISCUSSION: Benin and Mozambique are undertaking system redesign in order to respond to constraints identified in the vaccine supply chain. Results and learnings show improvements in supply chain performance and make a strong case for system redesign. These countries demonstrate the feasibility of system redesign for other countries considering how to address outdated supply chains. PMID- 28364924 TI - Vaccine vial monitor availability and use in low- and middle-income countries: A systematic review. AB - INTRODUCTION: The vaccine vial monitor (VVM) registers cumulative heat exposure on vaccines over time. As low- and lower-middle-income countries transition beyond support from the Global Alliance for Vaccines and Immunization (Gavi), they will assume full responsibility for vaccine financing and procurement. It is unclear to what extent countries transitioning out of Gavi support will continue to include VVMs on their vaccines. This paper aims to systematically review evidence on VVM availability and use in low- and middle-income countries to document factors behind global access to and country demand for VVMs. Such results could help identify actions needed to ensure continued use of VVMs in countries that transition out of Gavi support. METHODS: We performed a systematic review of electronic databases, reference lists, and grey literature in English and French languages with publication dates from 2005 onwards. The studies included were analyzed for the following outcomes: (1) availability and deployment of VVM-labeled vaccines; (2) VVM practices and perceptions in the immunization system; (3) vaccine introduction and decision-making processes; (4) Gavi graduation and vaccine program sustainability. RESULTS: The study found that VVM availability and use was affected by multiple sourcing of vaccines and the extent to which VVM was included in the vaccine specification in the tendering documents when procuring vaccines. Knowledge about VVM and its impact on the EPI program was found to be high among health workers as well as decision-makers. However, the study also found that weak capacity in key national institutions such as NRA and NPA might impact on demand for VVM. As countries take decisions regarding the adoption of new vaccines, factors such as disease burden and vaccine price may assume greater importance than vaccine characteristics and presentation. Finally, the study found that countries rely largely on the advice and recommendations from technical partners such as WHO and PAHO. CONCLUSION: The study concludes that global access to and country demand for VVM are dependent on policy statements and recommendations about VVM by key policy institutions such as WHO and UNICEF. The study also concludes that despite Gavi-eligible countries having access to VVM-labeled vaccines, inclusion is often below 100%. Weak institutional capacity in key national agencies such as NRA and NPA seems to be a contributing factor, while other factors include the procurement of clear national policies on the inclusion of VVM on vaccines, along with the capacity to enforce the policy. Finally, the study concludes that knowledge about VVM and its impact on vaccine program efficiency, safety, and cost is critical for transitioning countries' continuous demand for VVM. PMID- 28364926 TI - Transforming vaccines supply chains in Nigeria. AB - Nigeria is the most populous country in Africa and in 2012 was suffering some of the lowest vaccination rates in the World. A combination of factors had resulted in a dysfunctional immunization cold chain and supply chain. Recognizing that the number of unimmunized children contributed to high levels of under-5-mortality, and that health MDGs would not be attained, Minister of State for Health Mohammed Pate launched a vaccines transformation project in 2013. In partnership with BMGF, GAVI, UNICEF, WHO, other donors and implementing partners the transformation journey has so far taken three years and achieved impressive results. It has though faced challenges along the way and with the financial burden of GAVI graduation facing Nigeria, the economic downturn and the decentralized funding of health services, the results are far from sustained. This paper documents the work undertaken at the Federal level and then highlights specific work undertaken in partnership with Lagos State Government. It identifies the importance of taking an end to end approach and looking at the root causes of weak system performance. The strategy combined simple innovations in how data was captured, recorded and used to drive decision making. It included a comprehensive and systematic approach to cold chain procurement, installation and maintenance with a shift to a culture of active cold chain maintenance that is performing with higher levels of uptime. It also included supply chain redesign at both the Federal and State level. Finally, it involved an institutional transformation at the National Primary Health Care Development Agency (NPHCDA) to establish a data driven Department of Logistics and Health Commodities (DLHC) to manage the many challenges in immunizing 7.5 million children annually. While results have been impressive, there have been many challenges and lessons learned on the way. As Nigeria gets ready for its graduation from GAVI, a robust agile performing cold chain and supply chain will be essential for the good health of Nigeria's children and its economy. The necessary transformation journey has only just begun. PMID- 28364927 TI - Preliminary results from direct-to-facility vaccine deliveries in Kano, Nigeria. AB - OBJECTIVE: As part of its vaccine supply chain redesign efforts, Kano state now pushes vaccines directly from 6 state stores to primary health centers equipped with solar refrigerators. Our objective is to describe preliminary results from the first 20months of Kano's direct vaccine delivery operations. METHODS: This is a retrospective review of Kano's direct vaccine delivery program. We analyzed trends in health facility vaccine stock levels, and examined the relationship between stock-out rates and each of cascade vaccine deliveries and timeliness of deliveries. Analysis of vaccination trends was based on administrative data from 27 sentinel health facilities. Costs for both the in-sourced and out-sourced approaches were estimated using a bottoms-up model-based approach. RESULTS: Overall stock adequacy increased from 54% in the first delivery cycle to 68% by cycle 33. Conversely, stock-out rates decreased from 41% to 10% over the same period. Similar trends were observed in the out-sourced and in-sourced programs. Stock-out rates rose incrementally with increasing number of cascade facilities, and delays in vaccine deliveries correlated strongly with stock-out rates. Recognizing that stock availability is one of many factors contributing to vaccinations, we nonetheless compared pre- and post- direct deliveries vaccinations in sentinel facilities, and found statistically significant upward trends for 4 out of 6 antigens. 1 antigen (measles) showed an upward trend that was not statistically significant. Hepatitis b vaccinations declined during the period. Overall, there appeared to be a one-year lag between commencement of direct deliveries and the increase in number of vaccinations. Weighted average cost per delivery is US$29.8 and cost per child immunized is US$0.7 per year. CONCLUSION: Direct vaccine delivery to health facilities in Kano, through a streamlined architecture, has resulted in decreased stock-outs and improved stock adequacy. Concurrent operation of insourced and outsourced programs has enabled Kano build in-house logistics capabilities. PMID- 28364928 TI - Costing analysis and anthropological assessment of the vaccine supply chain system redesign in the Come District (Benin). AB - OBJECTIVE: At the end of 2013, a pilot experiment was carried out in Come health zone (HZ) in an attempt to optimize the vaccine supply chain. Four commune vaccine storage facilities were replaced by one central HZ facility. This study evaluated the incremental financial needs for the establishment of the new system; compared the economic cost of the supply chain in the Come HZ before and after the system redesign; and analyzed the changes induced by the pilot project in immunization logistics management. METHOD: The purposive sampling method was used to draw a sample from 37 health facilities in the zone for costing evaluation. Data on inputs and prices were collected retrospectively for 2013 and 2014. The analysis used an ingredient-based approach. In addition, 44 semi structured interviews with health workers for anthropological analysis were completed in 2014. RESULTS: The incremental financial costs amounted to US$55,148, including US$50,605 for upfront capital investment and US$4543 for ongoing recurrent costs. Annual economic cost per dose administered (including all vaccines distributed through the Expanded Program on Immunization (EPI)) in the Come HZ increased from US$0.09 before system redesign to US$0.15 after implementation, mainly due to a high initial investment and the operational cost of HZ mobile warehouse. Interviews with health workers suggested that the redesigned system was associated with improvements in motivation and professional awareness due to training, supportive supervision, and improved work conditions. CONCLUSIONS: The system redesign involved a considerable investment at HZ level. Benefits were found in the reduction of transportation costs to health posts (HP) and commune health center (CHC) levels, and the strengthening of health workers professional skills at all levels in Come. The redesigned system contributed to a decrease in funding needs at HP and CHC levels. The benefits of the investment need to be examined after the introduction of new vaccines and after a longer period. PMID- 28364929 TI - Professional changes induced by a redesigned immunization supply chain in the Come Health Zone, Benin. AB - At the end of 2013, the Government of Benin and Agence de Medecine Preventive (AMP) launched a demonstration project in Come Health Zone (HZ) to optimize the vaccine supply chain. A key part of the demonstration project was the creation of an "informed push model" of vaccine distribution supported by a new logistician position at the health zone (district) level. At the conclusion of the demonstration project in 2015, the authors conducted an anthropological study consisting of semi-structured interviews with 62 participants to assess how the new model changed the professional identities, roles, responsibilities, and practices of personnel involved in vaccine management during and just after the demonstration project end in Come HZ. The study found that health workers considered the logistician as a key player in enabling them to perform their public health mission, notably by improving knowledge and practices in vaccine management, providing supportive supervision, and improving the availability of vaccines and other supplies so that immunization sessions could occur more reliably and professionally within the communities they served. The demonstration project was widely accepted among study participants. The study was approved by the Cotonou Ethics Committee (CER-ISBA No. 56 dated 09/04/2015). PMID- 28364930 TI - Improving iSC performance through outsourcing - Considerations for using third party service providers to increase innovation, capacity and efficiency. AB - Development partners and donors have encouraged and incentivized governments in developing countries to explore ways of working with third-party service suppliers to reduce costs and increase service delivery capacity. The distribution of vaccines and medicines has for a long time shown demand for outsourcing but public health systems have struggled to develop the expertise and capital assets necessary to manage such ventures. Existing transport and logistics capacity within public health systems, in particular, is well documented as being insufficient to support existing, let alone future immunization needs. Today, a number of countries are contracting party logistics providers (3PLs) to supplement the in-house distribution operations of public health systems. This commentary reflects on recent, leading examples of outsourcing initiatives to address critical gaps in transport and logistics. PMID- 28364931 TI - Root cause analysis underscores the importance of understanding, addressing, and communicating cold chain equipment failures to improve equipment performance. AB - Vaccine cold chain equipment (CCE) in developing countries is often exposed to harsh environmental conditions, such as extreme temperatures and humidity, and is subject to many additional challenges, including intermittent power supply, insufficient maintenance capacity, and a scarcity of replacement parts. Together, these challenges lead to high failure rates for refrigerators, potentially damaging vaccines and adversely affecting immunization coverage. Providing a sustainable solution for improving CCE performance requires an understanding of the root causes of failure. Project teams conducted small-scale studies to determine the root causes of CCE failure in selected locations in Uganda and Mozambique. The evaluations covered 59 failed refrigerators and freezers in Uganda and 27 refrigerators in Mozambique. In Uganda, the vast majority of failures were due to a cooling unit fault in one widely used refrigerator model. In Mozambique, 11 of the 27 problems were attributable to solar refrigerators with batteries that were unable to hold a charge, and another eight problems were associated with a need to adjust thermostat settings. The studies showed that tracking and evaluation of equipment performance and failure can yield important, actionable information for a range of stakeholders, including local CCE technicians, the ministry of health, equipment manufacturers, and international partners such as the United Nations Children's Fund, World Health Organization, and Gavi, the Vaccine Alliance. Collaborative efforts to systematically collect and communicate data on CCE performance and causes of failure will help to improve the efficiency and reach of immunization programs in low- and middle income countries. PMID- 28364932 TI - Assessing stability and performance of a digitally enabled supply chain: Retrospective of a pilot in Uttar Pradesh, India. AB - BACKGROUND: Immunization supply chains in low resource settings do not always reach children with necessary vaccines. Digital information systems can enable real time visibility of inventory and improve vaccine availability. In 2014, a digital, mobile/web-based information system was implemented in two districts of Uttar Pradesh, India. This retrospective investigates improvements and stabilization of supply chain performance following introduction of the digital information system. METHODS: All data were collected via the digital information system between March 2014 and September 2015. Data included metadata and transaction logs providing information about users, facilities, and vaccines. Metrics evaluated include adoption (system access, timeliness and completeness), data quality (error rates), and performance (stock availability on immunization session days, replenishment response duration, rate of zero stock events). Stability was defined as the phase in which quality and performance metrics achieved equilibrium rates with minimal volatility. The analysis compared performance across different facilities and vaccines. RESULTS: Adoption appeared sufficiently high from the onset to commence stability measures of data quality and supply chain performance. Data quality stabilized from month 3 onwards, and supply chain performance stabilized from month 13 onwards. For data quality, error rates reduced by two thirds post stabilization. Although vaccine availability remained high throughout the pilot, the three lowest-performing facilities improved from 91.05% pre-stability to 98.70% post-stability (p<0.01; t test). Average replenishment duration (as a corrective response to stock-out events) decreased 52.3% from 4.93days to 2.35days (p<0.01; t-test). Diphtheria tetanus-pertussis vaccine was significantly less likely to be stocked out than any other material. CONCLUSION: The results suggest that given sufficient adoption, stability is sequentially achieved, beginning with data quality, and then performance. Identifying when a pilot stabilizes can enable more predictable, reliable cost estimates, and outcome forecasts in the scale-up phase. PMID- 28364933 TI - When technical achievements aren't enough: Lessons learned from efforts to catalyze policy action on supply chain in Senegal. AB - Before 2013, Senegal public health supply system was pull-based and fully public run. Lengthy and recurrent stockouts of essential health products (incl. contraceptives) were the rule, not the exception as they used to strike more than 80% of public service delivery points (SDPs). Following a successful pilot in two districts in 2012, the Senegalese Ministry of Health and Social Action (MSAS) implemented the Informed Push Model (IPM) Project (2013-2016). In its first two years, IPM bridged key gaps and expanded the distribution of contraceptives by private third party logistics operators to all public SDPs in Senegal and nearly eliminated stockouts. However, the MSAS was slow to take ownership of the project. Understanding the roots of this reluctance, executing a range of targeted communication and advocacy efforts and preparing a strong transition plan are succeeding to push Government toward full ownership to enable the National Supply Pharmacy to distribute all health products going to SDPs, including vaccines, consistently with their Strategic Plan 2014-2018. PMID- 28364934 TI - Extending supply chains and improving immunization coverage and equity through controlled temperature chain use of vaccines. PMID- 28364935 TI - When are solar refrigerators less costly than on-grid refrigerators: A simulation modeling study. AB - BACKGROUND: Gavi recommends solar refrigerators for vaccine storage in areas with less than eight hours of electricity per day, and WHO guidelines are more conservative. The question remains: Can solar refrigerators provide value where electrical outages are less frequent? METHODS: Using a HERMES-generated computational model of the Mozambique routine immunization supply chain, we simulated the use of solar versus electric mains-powered refrigerators (hereafter referred to as "electric refrigerators") at different locations in the supply chain under various circumstances. RESULTS: At their current price premium, the annual cost of each solar refrigerator is 132% more than each electric refrigerator at the district level and 241% more at health facilities. Solar refrigerators provided savings over electric refrigerators when one-day electrical outages occurred more than five times per year at either the district level or the health facilities, even when the electric refrigerator holdover time exceeded the duration of the outage. Two-day outages occurring more than three times per year at the district level or more than twice per year at the health facilities also caused solar refrigerators to be cost saving. Lowering the annual cost of a solar refrigerator to 75% more than an electric refrigerator allowed solar refrigerators to be cost saving at either level when one-day outages occurred more than once per year, or when two-day outages occurred more than once per year at the district level or even once per year at the health facilities. CONCLUSION: Our study supports WHO and Gavi guidelines. In fact, solar refrigerators may provide savings in total cost per dose administered over electrical refrigerators when electrical outages are less frequent. Our study identified the frequency and duration at which electrical outages need to occur for solar refrigerators to provide savings in total cost per dose administered over electric refrigerators at different solar refrigerator prices. PMID- 28364936 TI - Who is preparing the next generation of immunization supply chain professionals? PMID- 28364937 TI - National logistics working groups: A landscape analysis study. AB - Several countries have acknowledged the contributions made by national logistics working groups (NLWG) to ensure equitable access to the expanded program on immunization's (EPI) vaccines against preventable diseases. In order to provide key insights to the United Nations Children's Fund (UNICEF) and the World Health Organization (WHO) supply chain hub - as well as other players, including national EPI - a landscape analysis study was conducted from September 2015 to February 2016. This is a cross-sectional survey taken by 43 countries that combines qualitative and quantitative approaches. Data was collected through a desk review, consultation, interviews, and distance questioning. References and guidance were used to determine and specify the underlying mechanisms of NLWGs. The key findings are:This study has provided a general overview of the status of NLWGs for immunization in various countries. Based on the key insights of the study, technical assistance needs have been identified, and immunization partners will be required to help countries create and reinforce their NLWGs. PMID- 28364938 TI - Experiential and authentic learning approaches in vaccine management. AB - A high level of concern is placed on the storage, handling, transportation, and distribution of vaccines and other pharmaceutical products, particularly those that are time and temperature sensitive. While active and passive cooling equipment and monitoring devices are important, it is the various personnel responsible for executing and writing procedures, designing and operating systems, and investigating problems and helping prevent them who are paramount in establishing and maintaining a "cold chain" for time and temperature sensitive pharmaceutical products (TTSPPs). These professionals must possess the required competencies, knowledge, skills and abilities so they can effectively perform these activities with appropriate levels of expertise. These are complex tasks that require the development of higher cognitive skills that cannot be adequately addressed through professional development opportunities based on simple information delivery and content acquisition. This paper describes two unique learning solutions (one on a bus called the "wheels course" and the other online called "e-learning") that have been developed by WHO Global Learning Opportunities (WHO/GLO) to provide participants with opportunities not just to learn about cold chain systems or vaccine management, but, rather, to develop high levels of expertise in their respective fields through experiential and authentic learning activities. In these interactive learning environments, participants have opportunities to address real-life situations in contexts similar to what they may face in their own work environments and develop solutions and critical thinking skills they can apply when they return to their jobs. This paper further delineates the managerial and operational vaccine management functions encompassed in these two unique learning environments. The paper also describes the alignment of the objectives addressed in the "wheels course" and the e-learning version with effective vaccine management (EVM) criteria as prescribed by WHO. The paper concludes with an example of a real world product developed by course graduates (specifically a decision tree that is now used by some national programmes). These types of products, valuable in their own right, often emerge when learning environments based on authentic learning principles are designed and implemented as they were by WHO/GLO. PMID- 28364939 TI - Innovations in cold chain equipment for immunization supply chains. AB - BACKGROUND: Since 2010, numerous new technologies have entered the immunization cold chain equipment market. The World Health Organization (WHO) Immunization Devices Programme-Performance, Quality and Safety (PQS)-has played a key role in bringing these to market. In this article, the authors explore the emergence of new cold chain equipment technologies from 2004 to 2016 and the role of PQS in this evolution. METHODS: This review focuses on three major vaccine cold chain technology innovations-solar direct-drive refrigerators, long-term passive cold boxes, and equipment with user-independent freeze prevention. For the review, we used online data from WHO PQS, a literature search, and unpublished research reports. RESULTS: Timelines with key milestones in the emergence of the three focus technologies show delays of between one and three years between earliest field trials and publication of WHO specifications; procurement builds after the WHO prequalification of initial devices. DISCUSSION: The timelines show the role of PQS as both gatekeeper and enabler for cold chain equipment technologies. The use of target product profiles by PQS has increased its ability to signal preferred attributes and to engage with manufacturers during the product development stage. Procurement data show how demand for solar direct-drive refrigerators increased over time. Gavi, the Vaccine Alliance, is employing demand-generation strategies to try to drive procurement of technologies with favorable technical attributes. CONCLUSIONS: PMID- 28364940 TI - Seizing market shaping opportunities for vaccine cold chain equipment. AB - Gavi, the Vaccine Alliance, supports immunisation programmes in eligible countries to reach children with lifesaving vaccines. Dramatic improvement in the scale and performance of current cold chain systems is required to extend the reach of immunisation services - especially for children living in remote locations - to advance progress towards full vaccine coverage. Achieving these improvements will require a healthier market for cold chain equipment where the products meet user needs, are sustainably priced, and are available in sufficient quantities to meet demand. Yet evidence suggests that the cold chain market has suffered from several failures including limited demand visibility, fragmented procurement, and insufficient information exchange between manufacturers and buyers on needs and equipment performance. One of Gavi's strategic goals is to shape markets for vaccines and other immunisation products, including cold chain equipment and in 2015, Gavi created a new mechanism - the Cold Chain Equipment (CCE) Optimisation Platform - to strengthen country cold chain systems by offering financial support and incentives for higher performing CCE. The main objective of the CCE Platform is to get more equipment that is efficient, sustainable, and better performing deployed to every health facility where it is required at an affordable price. To achieve these objectives, Gavi is putting in place tested market shaping approaches and tools adapted for the CCE market: the development of market strategies or 'roadmaps'; improvement of product performance through the development of target product profiles (TPPs); strategic engagement with CCE manufacturers and countries to enhance information sharing; and tailoring procurement tactics to the CCE market. These approaches and tools will allow for increased demand and supply of higher-performing, cost-effective and quality products. By strengthening immunisation systems with improved cold chain equipment, Gavi countries can begin to address the underlying problems limiting vaccine availability and improve the coverage and equity of vaccines. PMID- 28364941 TI - Exploring new packaging and delivery options for the immunization supply chain. AB - A variety of vaccine packaging and delivery technologies may benefit the immunization supply chain. These include alternative primary packaging, such as blow-fill-seal polymer containers, and novel delivery technologies, such intradermal delivery devices, microarray patches, and sublingual formulations of vaccines, and others in development. The potential timeline to availability of these technologies varies and depends on their stage of development and the type of data necessary to achieve licensure. Some new delivery devices are anticipated to be introduced in 2017, such as intradermal devices for delivery of inactivated poliovirus vaccine to stretch vaccine supplies due to a supply limitation. Other new technologies requiring vaccine reformulation, such as microarray patches and sublingual vaccines, may become available in the long term (2021 and beyond). Development of many new technologies requires partnership between vaccine and technology manufacturers and identification of the applicable regulatory pathway. Interaction with public-sector stakeholders early on (through engagement with forums such as the World Health Organization's Immunization Practices Advisory Committee Delivery Technologies Working Group) is important to ensure suitability for immunization program use. Key considerations for programmatic suitability of a new vaccine, packaging, and delivery device include cold chain volume, costs, and health impact. PMID- 28364944 TI - In Vivo Porcine Model of Venous Air Embolism During Pars Plana Vitrectomy. PMID- 28364945 TI - Same-site Trabeculectomy Revision for Failed Trabeculectomy: Outcomes and Risk Factors for Failure. PMID- 28364942 TI - Cardiomyopathy in Patients With Hereditary Bullous Epidermolysis. AB - INTRODUCTION AND OBJECTIVE: In recent decades, an association has been reported between epidermolysis bullosa (EB) and dilated cardiomyopathy (DC). DC is typically in an advanced phase when detected, leading to a poorer prognosis. Our objective was to determine the prevalence of DC in patients with EB seen in Hospital San Joan de Deu in Barcelona, Spain, between May 1986 and April 2015. METHODS: This was a descriptive, cross-sectional chart-review study in which we recorded the type and main subtypes of EB and the presence or absence of DC. RESULTS: Fifty-seven patients with EB were found, 19 with EB simplex, 10 with junctional EB, 27 with dystrophic EB (14 dominant dystrophic and 13 recessive dystrophic), and just 1 with Kindler syndrome. DC was detected in only 2 patients with recessive dystrophic EB. Twenty-three patients had presented factors that could have had a causal relationship with the potential onset of DC. CONCLUSION: DC is a possible complication of EB, particularly in recessive dystrophic EB. Periodic follow-up should be performed to make an early diagnosis and start treatment. PMID- 28364946 TI - Relationships Between Anthropometric Measurements and Intraocular Pressure: The Korea National Health and Nutrition Examination Survey. PMID- 28364943 TI - Amygdala Lesions Reduce Anxiety-like Behavior in a Human Benzodiazepine-Sensitive Approach-Avoidance Conflict Test. AB - BACKGROUND: Rodent approach-avoidance conflict tests are common preclinical models of human anxiety disorder. Their translational validity mainly rests on the observation that anxiolytic drugs reduce rodent anxiety-like behavior. Here, we capitalized on a recently developed approach-avoidance conflict computer game to investigate the impact of benzodiazepines and of amygdala lesions on putative human anxiety-like behavior. In successive epochs of this game, participants collect monetary tokens on a spatial grid while under threat of virtual predation. METHODS: In a preregistered, randomized, double-blind, placebo controlled trial, we tested the effect of a single dose (1 mg) of lorazepam (n = 59). We then compared 2 patients with bilateral amygdala lesions due to Urbach Wiethe syndrome with age- and gender-matched control participants (n = 17). Based on a previous report, the primary outcome measure was the effect of intra-epoch time (i.e., an adaptation to increasing potential loss) on presence in the safe quadrant of the spatial grid. We hypothesized reduced loss adaptation in this measure under lorazepam and in patients with amygdala lesions. RESULTS: Lorazepam and amygdala lesions reduced loss adaptation in the primary outcome measure. We found similar results in several secondary outcome measures. The relative reduction of anxiety-like behavior in patients with amygdala lesions was qualitatively and quantitatively indistinguishable from an impact of anterior hippocampus lesions found in a previous report. CONCLUSIONS: Our results establish the translational validity of human approach-avoidance conflict tests in terms of anxiolytic drug action. We identified the amygdala, in addition to the hippocampus, as a critical structure in human anxiety-like behavior. PMID- 28364947 TI - Reply. PMID- 28364949 TI - Back to the future (supply of dentists). PMID- 28364948 TI - Adoption of dental innovations: The case of a standardized dental diagnostic terminology. AB - BACKGROUND: Standardized dental diagnostic terminologies (SDDxTs) were introduced decades ago. Their use has been on the rise, accompanying the adoption of electronic health records (EHRs). One of the most broadly used terminologies is the Dental Diagnostic System (DDS). Our aim was to assess the adoption of SDDxTs by US dental schools by using the Rogers diffusion of innovations framework, focusing on the DDS. METHODS: The authors electronically surveyed clinic deans in all US dental schools (n = 61) to determine use of an EHR and SDDxT, perceived barriers to adoption of an SDDxT, and the effect of implementing an SDDxT on clinical productivity. RESULTS: The response rate was 57%. Of the 35 responses, 91% reported using an EHR to document patient care, with 84% using axiUm; 41% used the DDS. Fifty-four percent of those who did not use an SDDxT had considered adopting the DDS, but 38% had not, citing barriers such as complexity and compatibility. CONCLUSIONS: Adoption of an SDDxT, particularly the DDS, is on the rise. Nevertheless, a large number of institutions are in the Rogers late majority and laggards categories with respect to adoption. Several factors may discourage adoption, including the inability to try out the terminology on a small scale, poor usability within the EHR, the fact that it would be a cultural shift in practice, and a perception of unclear benefits. However, the consolidation of the DDS and American Dental Association terminology efforts stands to encourage adoption. PRACTICAL IMPLICATIONS: The successful adoption of dental innovation depends not only on the intrinsic merit of the innovation, as some useful innovations do not achieve widespread traction. As such, it is important for health care providers to understand how to disseminate their ideas in order to ensure traction and widespread adoption. PMID- 28364950 TI - Unliganded and substrate bound structures of the cellooligosaccharide active lytic polysaccharide monooxygenase LsAA9A at low pH. AB - Lytic polysaccharide monooxygenases (LPMOs) have been found to be key components in microbial (bacterial and fungal) degradation of biomass. They are copper metalloenzymes that degrade polysaccharides oxidatively and act in synergy with glycoside hydrolases. Recently crystallographic studies carried out at pH 5.5 of the LPMO from Lentinus similis belonging to the fungal LPMO family AA9 have provided the first atomic resolution view of substrate-LPMO interactions. The LsAA9A structure presented here determined at pH 3.5 shows significant disorder of the active site in the absence of substrate ligand. Furthermore some differences are also observed in regards to substrate (cellohexaose) binding, although the major interaction with the N-terminal histidine remains unchanged. PMID- 28364951 TI - Between the lines: The 50th anniversary of long-term central venous catheters. AB - BACKGROUND: Tunneled central venous catheters (CVC) were developed five decades ago. Since then, several clinician-inventors have created a variety of catheters with different functions. Indeed, many catheters have been named after their inventor. Many have wondered who the inventors were of each catheter, and what specifically inspired their inventions. Many of these compelling stories have yet to be told. DATA SOURCE: A literature review of common catheters and personal communication with inventors. Only first person accounts from inventors or those close to the invention were used. CONCLUSIONS: CVCs are now essential devices that have saved countless lives. Though the inventors have earned the honor of naming their catheters, it may be reasonable to consider more consistent terminology to describe these catheters to avoid confusion. PMID- 28364952 TI - Early complications after percutaneous radiofrequency ablation for hepatocellular carcinoma: an analysis of 1,843 ablations in 1,211 patients in a single centre: experience over 10 years. AB - AIM: To evaluate the incidence of adverse events and associated factors after radiofrequency ablation (RFA) in patients with hepatocellular carcinoma within 30 days. MATERIALS AND METHODS: The early complications that occurred within 30 days after RFA at a single institution from January 2000 to July 2010 were reviewed in order to evaluate the morbidity, mortality, and risk factors associated with the complications. In total, 1,211 patients (845 men, 70.5%) with a mean age of 68 years (range, 27-88 years) underwent 1,843 RFA procedures. RESULTS: The overall incidence rate of complications was 6.8% (125 cases). Major complications (n=36, 2%) included liver abscess (n=15, 0.8%), intraperitoneal bleeding (n=8, 0.4%), liver failure (n=5, 0.3%), variceal bleeding (n=3, 0.2%), haemothorax (n=2, 0.1%), cholecystitis (n=2, 0.1%), and bowel perforation (n=1, 0.1%). Among the minor complications (n=89, 4.8%), the most common was the post RFA syndrome accompanied by pain and fever (n=75, 4.1%). Other minor complications included significant pleural effusion (n=7, 0.4%), skin wound infection (n=4, 0.2%), and thermal injuries to the skin (n=3, 0.2%). Procedural infections significantly increased with tumour size (OR=1.379; 95% confidence interval [CI], 1.191-1.579; p<0.001), and multiple overlapping ablations (OR=1.118; 95% CI, 1.019-1.227, p=0.018). Thrombocytopenia (<50,000/MUl), prothrombin time, and serum albumin level were significantly associated with post-RFA bleeding episodes (p=0.041, p=0.021, and p=0.003, respectively). The overall mortality rate was 0.3% (three cases of hepatic failure, two case of sepsis, and one case of renal failure). CONCLUSIONS: RFA is a safe and effective local treatment for hepatocellular carcinoma. Careful selection of patients and appropriate RFA planning could decrease procedural mortality and morbidity. PMID- 28364953 TI - Comparison of Morphologic Features and Flow Velocity of the Left Atrial Appendage Among Patients With Atrial Fibrillation Alone, Transient Ischemic Attack, and Cardioembolic Stroke. AB - The left atrial appendage (LAA) is a major source of emboli responsible for cardioembolic stroke (CES). We hypothesized that there could be differences in the morphologic and functional features of LAAs among patients with atrial fibrillation (AF) alone, patients with cardioembolic transient ischemic attack (CETIA), and patients with CES. Patients with AF and CETIA/CES were included in either a CETIA group or a CES group. Patients with AF without past histories of stroke were included in an AF/non-CVA (cerebrovascular accident) group. Cardiac computerized tomography and transesophageal echocardiography were employed for morphologic and functional assessments of LAAs. Cauliflower LAA morphology increased and chicken wing LAA morphology decreased in frequency in the following order: AF/non-CVA, CETIA, and CES group. LAA orifice diameters were larger in the CETIA and CES groups than in the AF/non-CVA group. LAA flow velocity was higher in the CES group than in the other groups. Multiple multinominal regression analyses showed that the cauliflower morphology was associated with CETIA and CES; however, after LAA orifice diameters and flow velocity were adjusted, LAA morphology was associated with neither of them. Receiver operating characteristic curve analysis showed that LAA orifice diameter and flow velocity accurately predicted CETIA (c-statistic 0.839) and CES (c-statistic 0.896), respectively. In conclusion, cauliflower LAA morphology is associated with an increased risk of CETIA and CES through its large LAA orifice diameters and low LAA flow velocity. There are clear differences in LAA orifice diameters and flow velocity among patients with AF alone, CES, and CETIA. PMID- 28364955 TI - 49 Years-old man with fever, malaise and pulmonary nodules. PMID- 28364954 TI - Sol-gel processing of bioactive glass nanoparticles: A review. AB - Silicate-based bioactive glass nanoparticles (BGN) are gaining increasing attention in various biomedical applications due to their unique properties. Controlled synthesis of BGN is critical to their effective use in biomedical applications since BGN characteristics, such as morphology and composition, determining the properties of BGN, are highly related to the synthesis process. In the last decade, numerous investigations focusing on BGN synthesis have been reported. BGN can mainly be produced through the conventional melt-quench approach or by sol-gel methods. The latter approaches are drawing widespread attention, considering the convenience and versatility they offer to tune the properties of BGN. In this paper, we review the strategies of sol-gel processing of BGN, including those adopting different catalysts for initiating the hydrolysis and condensation of silicate precursors as well as those combining sol gel chemistry with other techniques. The processes and mechanism of different synthesis approaches are introduced and discussed in detail. Considering the importance of the BGN morphology and composition to their biomedical applications, strategies put forward to control the size, shape, pore structure and composition of BGN are discussed. BGN are particularly interesting biomaterials for bone-related applications, however, they also have potential for other biomedical applications, e.g. in soft tissue regeneration/repair. Therefore, in the last part of this review, recently reported applications of BGN in soft tissue repair and wound healing are presented. PMID- 28364956 TI - Gendered violence: Advancing evidence-informed research, practice and policy in addressing sex, gender, and child sexual abuse. PMID- 28364958 TI - Validation of the Spanish-language version of the Montreal Cognitive Assessment test in adults older than 60 years. AB - INTRODUCTION: Few studies have validated the Spanish-language version of the Montreal Cognitive Assessment (MoCA-S) test in Latin American populations. OBJETIVE: To evaluate the psychometric properties and discriminant validity of the MoCA-S in elderly patients in Santiago de Chile. METHODS: 172 individuals were grouped according to their clinical diagnosis based on the Clinical Dementia Rating (CDR) scale as follows: amnestic mild cognitive impairment (aMCI; n+/-24), non-amnestic MCI (naMCI; n+/-24), mild dementia (n+/-20), and cognitively normal (n+/-104). Participants were evaluated with both the MoCA-S and the Mini-Mental State Examination (MMSE) to determine the discriminant validity of the MoCA-S. RESULTS: Mean age and years of schooling were 73+/-6 and 11+/-4 years, respectively, with no significant intergroup differences. The MoCA-S displayed good internal consistency (Cronbach's alpha: 0.772), high inter-rater reliability (Spearman correlation coefficient: 0.846; P<.01), and high intra-rater reliability (test-retest reliability coefficient: 0.922; P<.001). The MoCA-S was found to be an effective and valid test for detecting aMCI (AUC+/-0.903) and mild dementia (AUC+/-0.957); its effectiveness for detecting naMCI was lower (AUC+/ 0.629). The optimal cut-off points for aMCI and mild dementia were<21 and<20, respectively, with sensitivity and specificity rates of 75% and 82% for aMCI and 90% and 86% for mild dementia. The level of education had a great impact on scores: as a result, 2 points were added for patients with less than 8 years of schooling and one point for patients with 8-12 years of schooling (MoCA-S1-2). The MoCA-S1-2 showed significantly greater discriminant validity than the MMSE for differentiating aMCI from dementia. CONCLUSIONS: The MoCA-S1-2 is a short, easy-to-use, and useful test for diagnosing aMCI and mild dementia. PMID- 28364957 TI - New insights into the source of decadal increase in chemical oxygen demand associated with dissolved organic carbon in Dianchi Lake. AB - Dissolved organic carbon (DOC) can be used an alternative index of water quality instead of chemical oxygen demand (COD) to reflect the organic pollution in water. The monitoring data of water quality in a long-term (1990-2013) from Dianchi Lake confirmed the increase trend of COD concentration in the lake since 2007. The similarities and differences in the DOC components between the lake and its sources and the contribution from allochthonous and autochthonous DOC to the total DOC in this lake were determined to elucidate the reason of COD increase based on C/N atomic ratios, stable isotope abundance of carbon and nitrogen, UV visible spectroscopy, three-dimensional excitation-emission matrix (3DEEM) fluorescence spectroscopy. The terrigenous organic matter showed humic-like fluorescence, and the autochthonous organic matter showed tryptophan-like components. Agricultural runoff (9.5%), leaf litter (7.5%) and urban runoff (13.2%) were the main sources of DOC in the lake. Sewage tail was a major source of organic materials, 3DEEM for the indicates that sewage tail DOC composition did not change markedly over the biodegradation period, indicating that sewage tail contains a high load of DOC that is resistant to further biodegradation and subsequently accumulates in the lake. The change of land use in the catchment and the increase of sewage tail load into the lake are the key factors for the increase in COD concentration in Dianchi Lake. Thus, the lake should be protected by controlling the pollution from the urban nonpoint sources and refractory composition in point sources. PMID- 28364959 TI - Squamous cell carcinoma of the pinna: which histological features could be used to predict prognosis? AB - Squamous cell carcinoma (SCC) that originates in the pinna is thought to have a high risk of metastases (up to 16%) compared with under 5% for cutaneous SCC at any other site, and histological features of the primary tumour may provide evidence for further surveillance or treatment. To identify any association between histological features and the risk of metastases we made an electronic search of the histopathological records at the University Hospital Southampton NHS Foundation Trust for all patients who presented with auricular SCC from 2007 2012. Inclusion criteria included origin in the pinna, complete two-year follow up, and no history of immunosuppressive treatment. We looked for histopathological features that were thought to be relevant to metastases. We studied specimens from 192 patients, four of whom developed metastases (2%), each with involved lymph nodes. Perineural invasion and local recurrence were significantly associated with increased risk of metastases (p<0.001 and p=0.006). The overall metastatic rate was much lower than those reported in other studies, and factors other than histological features alone may explain the results. We suggest that although some histological features were significantly associated, they do not predict a high enough risk of metastatic disease to provide evidence for further surveillance or elective lymphadenopathy. PMID- 28364960 TI - The IMF and government health expenditure: A response to Sanjeev Gupta. PMID- 28364961 TI - Socio-economic life course and obesity among adults in Florianopolis, southern Brazil. AB - OBJECTIVE: To estimate the association between socio-economic life course and body mass index (BMI), waist circumference (WC) and general and abdominal obesity in adults. METHODS: A cross-sectional analysis of a population-based cohort study of 1,222 adults (aged 22-63) from Florianopolis, southern Brazil. The socio economic life course was analysed using the educational level of participants and their parents. Height, weight and WC were measured by specially trained staff. Linear and logistic regressions were used with adjustment for confounding factors, and data were stratified according to sex. RESULTS: Mean BMI and WC were about 2kg/m2 (95% CI: -3.3 to -0.7) and 6cm (95% CI: -9.7 to -2.9) lower in women with a high socio-economic position, while the association was reversed in men with a high socio-economic position, with WC being about 4cm higher (95% CI: 0.1 to 7.5). In addition, women who had always been in a high socio-economic position were less likely to have abdominal obesity (OR: 0.38; 95% CI: 0.20 to 0.76) while no such association was found in men. CONCLUSION: Socio-economic life course influences BMI, WC and obesity, with differences between males and females, thereby indicating that public policies that contemplate a socio-economic life course approach can be effective for controlling obesity. PMID- 28364962 TI - Skin-to-Skin Contact Facilitates More Equal Parenthood - A Qualitative Study From Fathers' Perspective. AB - DESIGN AND METHODS: A descriptive design was used where 20 fathers of premature infants were interviewed using a semi-structured interview-guide. The guide contained the following five topics: the fathers' feelings about and experiences of using skin-to-skin contact (SSC), the physical environment at the Neonatal Intensive Care unit, staff attitudes, and whether SSC had any impact on the relationship with their partner and other children in the family. The interviews were analyzed using directed qualitative content analysis and the results compared with those of a qualitative systematic review by Anderzen-Carlsson and colleagues. RESULTS: The result shows that the fathers' overall experience of SSC was positive and as in the aforementioned review, they described experiences that were both gratifying and challenging. They felt more included and just as important as the mother because SSC and the demands placed on them by the premature birth helped them to achieve more equal parenthood. CONCLUSION: The fathers' overall experiences of SSC were positive as they felt included in their infants' care and just as important as the mothers. To a great degree the theoretical model tested was supported, although some weaknesses and differences were identified. PRACTICAL IMPLICATIONS: It is important to include fathers in neonatal care and recognize that they feel equally important as mothers in caring for premature infants. PMID- 28364963 TI - Dopamine transporter availability in drug-naive patients with schizophrenia and later psychotic symptoms severity. PMID- 28364964 TI - Leaving Residual Varus Alignment After Total Knee Arthroplasty Does Not Improve Patient Outcomes. AB - BACKGROUND: Recent popularity of kinematic alignment and constitutional varus has caused some surgeons to leave varus limbs in residual varus after total knee arthroplasty (TKA). This study assessed whether if patients left in residual varus have improved outcomes compared with those fully corrected to neutral alignment. METHODS: A retrospective review of 361 consecutive primary TKAs was performed. Anatomic tibiofemoral alignment was measured and knees were categorized as neutral, varus, or valgus. Modern Knee Society scores and University of California Los Angeles Activity Level scores were collected at minimum 1-year follow-up. RESULTS: After exclusions for confounds and loss to follow-up, 262 knees were available for analysis, 67% (176) of which were preoperatively varus. Sixty-six percent of varus knees were corrected to neutral, 25.6% were left in residual varus, and 8.5% were corrected to valgus. Median Knee Society objective scores at latest follow-up were greater in knees corrected to neutral (97), followed by knees corrected to varus (95), and valgus (93; P = .025), but post hoc comparisons between pairs of medians were not significant. There was no difference between groups in any other outcome measure (P >= .245) or the amount of improvement from baseline (P >= .423). Sixty percent of native varus patients corrected to neutral, 64% of those corrected to varus, and 40% of those corrected to valgus reported that their knee felt normal (P = .193). CONCLUSION: Findings fail to support the notion that leaving varus knees in residual varus will improve outcomes and pain. Caution is advised when leaving limbs in residual varus after TKA. PMID- 28364965 TI - High Rate of Local Recurrence and Complications Following Total Knee Arthroplasty in the Setting of Synovial Chondromatosis. AB - BACKGROUND: Synovial chondromatosis is a rare, monoarticular arthropathy due to synovial metaplasia. There is a paucity of data examining the outcome of total knee arthroplasty (TKA) in the setting of synovial chondromatosis. The purpose of this study is to investigate the outcome and function in patients undergoing TKA for management of synovial chondromatosis. METHODS: Twenty patients who received TKA for synovial chondromatosis over a 25-year period were identified for analysis and followed for a mean of 7 years. There were 12 males and 8 females, with a mean age and body mass index of 63 years and 30.7 kg/m2. Seventeen patients had "active" disease at the time of surgery. RESULTS: The 5-year disease free survival was 73%. Five patients sustained a recurrence that was treated with synovectomy and revision TKA (n = 2), observation (n = 2), and transfemoral amputation (n = 1) due to malignant degeneration to chondrosarcoma. One of the revision TKA patients underwent a transfemoral amputation 4 months later for recurrence. The overall rate of amputation was 10%. Nine patients (45%) sustained a complication, most commonly decreased knee motion (n = 7), leading to a revision TKA in 3 patients (15%). Mean preoperative knee range of motion was 73 degrees , which improved to 97 degrees postoperatively. The Knee Society Score and functional assessment improved from 35 and 42 preoperatively to 74 and 67 following TKA. CONCLUSION: TKA in the setting of synovial chondromatosis improves patient function and knee range of motion; however, there is a high rate of local recurrence and complications. PMID- 28364966 TI - Early-onset myopathies: Entering a new age. PMID- 28364968 TI - [Sphenopalatine ganglion block for postdural puncture headache in ambulatory setting]. AB - BACKGROUND AND OBJECTIVES: Postdural puncture headache (PDPH) is a common complication following subarachnoid blockade and its incidence varies with the size of the needle used and the needle design. Supportive therapy is the usual initial approach. Epidural blood patch (EBP) is the gold-standard when supportive therapy fails but has significant risks associated. Sphenopalatine ganglion block (SPGB) may be a safer alternative. CASE REPORT: We observed a 41 year-old female patient presenting with PDPH after a subarachnoid blockade a week before. We administrated 1l of crystalloids, Dexamethasone 4mg, parecoxib 40mg, acetaminophen 1g and caffeine 500mg without significant relief after 2hours. We performed a bilateral SPGB with a cotton-tipped applicator saturated with 0.5% Levobupivacaine under standard ASA monitoring. Symptoms relief was reported 5minutes after the block. The patient was monitored for an hour after which she was discharged and prescribed acetaminophen 1g and ibuprofen 400mg every 8hours for the following 2 days. She was contacted on the next day and again after a week reporting no pain in both situations. CONCLUSIONS: SPGB may attenuate cerebral vasodilation induced by parasympathetic stimulation transmitted through neurons that have synapses in the sphenopalatine ganglion. This would be in agreement with the Monro-Kellie concept and would explain why caffeine and sumatriptan can have some effect in the treatment of PDPH. Apparently, SPGB has a faster onset than EBP with better safety profile. We suggest that patients presenting with PDPH should be considered primarily for SPGB. Patients may have a rescue EBP if needed. PMID- 28364967 TI - [Does the French Big Five Inventory evaluate facets other than the Big Five factors?] AB - INTRODUCTION: The Big Five Inventory (BFI) developed by John et al. (1991) is one of the most widely accepted tools for assessing dimensions of personality. It comprises 44 items that assess five broad dimensions of personality (the Big Five Factors): Extraversion, Agreeableness, Conscientiousness, Neuroticism and Openness to experience. Based on correlations with the facets described in the NEO Personality Inventory Revised (NEO PI-R), another Big Five assessment tool with 240 items and 6 facets per dimension, Soto and John (2009) showed that the dimensions in the BFI could be divided into two facets each (ten facets altogether). These results are in line with those of DeYoung et al. (2007), who ran factorial analyses with all the NEO PI-R facets and the International Personality Item Pool (IPIP) and identified ten intermediate factors (between facets and dimensions) which they called "aspects" (two per dimension). The goal of the present study is to investigate the ten facets described by Soto and John in a French sample, using the French version of the BFI (BFI-Fr), which has good psychometric properties, and to check whether the pattern of correlations of these facets with the NEO PI-R match those of the American version. METHOD: We created three groups. The first comprised 360 students from the Institut libre d'education physique superieure (ILEPS) and Tours University (psychology undergraduates). Participants (mean age 21.1 years+/-2.30; 58% women) completed the BFI-Fr and the NEO PI-R. The second comprised 142 psychology students from Tours University (mean age 20.6 years+/-1.78; 81% women); they completed the BFI Fr twice, two weeks apart (test and retest). The third comprised 252 psychology students from Paris-Nanterre University (mean age 23 years+/-4.2; 89% women) who described a total of 405 people they knew well (mean age 35.2+/-10.8; 49% women) using the peer-report format of the BFI-Fr. RESULTS: In the self-report format, eight of Soto and John's ten aspects had acceptable internal consistency (based on Guildford's (1954) internal consistency criteria, due to the small number of items), with Cronbach's alpha between 0.60 and 0.86 and test-retest correlations between 0.71 and 0.89, showing satisfactory temporal stability. We found a single facet for Extraversion (Assertiveness), two for Agreeableness (Altruism and Compliance), two for Conscientiousness (Self-Discipline and Order), one for Neuroticism (Anxiety), and two for Openness to Experience (Openness to aesthetics and Openness to ideas). Based on their convergence with the corresponding facets in the NEO PI-R, these eight facets showed satisfactory external validity. With regard to the peer-report format, the Activity facet of Extraversion, which did not have sufficient internal consistency in the self-report format, had acceptable properties (i.e. 9 out of 10 facets). Only the Depression facet of Neuroticism still had insufficient internal consistency. In this study, we proposed an improvement of two facets (Activity and Compliance) and added one facet specific to the French version (Emotional Instability) in place of the Depression facet. DISCUSSION: We showed that the BFI-Fr can be used to assess nine of the ten facets described by Soto and John. We also identified an Emotional Instability facet, replacing the Depression facet of Neuroticism. DeYoung et al. (2007) considered that anxiety and depression are indissociable and can be represented by a Neuroticism aspect they labeled Withdrawal. They suggested a second aspect of this dimension they called Volatility (with the N2 Angry Hostility facet of the NEO PI-R as main marker and the N5 Impulsiveness and N3 Depression as secondary markers). The Emotional Instability facet we found corresponds closely to the N2 Angry Hostility facet of the NEO PI-R and appears to be a satisfactory marker of DeYoung et al.'s (2007) Volatility aspect. Although this study has limitations, particularly related to the samples (students), the BFI-Fr facets (derived from those defined by Soto and John in the BFI or proposed as improvements on the original facets) match the corresponding NEO PI-R facets and can also be seen as main markers of the aspects defined by DeYoung et al. PMID- 28364969 TI - [Gastroschisis repair under caudal anesthesia: a series of three cases]. AB - Gastroschisis is a congenital anomaly characterized by a defect in the anterior abdominal wall with protrusion of abdominal viscera. Perioperative mortality is very high in these patients. Traditionally gastroschisis repair has been performed under general anesthesia with endotracheal intubation, requiring postoperative intensive care admission and mechanical ventilation. Caudal block is an attractive alternative to general anesthesia. We present a series of three neonates with gastroschisis, repaired solely under caudal anesthesia. PMID- 28364970 TI - Organizational structures and outcomes of newly hired and experienced nurse practitioners in New York State. AB - BACKGROUND: Given the projected increase in the nurse practitioner (NP) workforce, the number of NPs in health care organizations will grow. However, little is known about the capacity of these organizations to create conducive environments for NP practice. PURPOSE: Examine and compare the NP patient panel, job satisfaction, turnover intentions, and organizational structures of NPs with less than three (newly hired) and more than three (experienced) years of experience in their current job. METHODS: An online survey of New York State Nurse Practitioner Association members was conducted in 2012; 278 NPs completed measures of NP patient panel, job satisfaction, turnover intentions, and organizational structures. DISCUSSION: Both newly hired and experienced NPs faced organizational challenges such as poor relations with administration and lack infrastructure for care. Newly hired NPs were twice more likely to have turnover intentions. CONCLUSION: These organizational barriers should be addressed by administrators to assure optimal NP practice. PMID- 28364971 TI - The Robert Wood Johnson Foundation Nurse Faculty Scholars program. PMID- 28364972 TI - Association of atopy phenotypes with new development of asthma and bronchial hyperresponsiveness in school-aged children. AB - BACKGROUND: Although previous studies have investigated the association between atopy phenotypes and allergic diseases, atopy characterizations in association with the development of allergic diseases remain poorly understood. OBJECTIVE: To identify atopy phenotypes in school-age children and to evaluate the association between atopy phenotypes and allergic diseases. METHODS: We enrolled 616 children with atopy defined as 1 or more positive allergen responses on skin prick tests and 665 children without atopy from the Children's Health and Environmental Research (CHEER) study. All children were followed up for 4 years at 2-year intervals. Atopy phenotypes were classified using latent class analysis. RESULTS: Four atopy phenotypes were characterized: later sensitization to indoor allergens (cluster 1); multiple early sensitization (cluster 2); early sensitization to outdoor allergens, especially Alternaria, and later sensitization to indoor allergens, including Aspergillus (cluster 3); and early sensitization to indoor allergens and later sensitization to outdoor allergens (cluster 4). New cases of asthma during follow-up were increased in clusters 2 and 3 (adjusted odds ratio [aOR], 2.76 and 4.25, respectively). The risk of new-onset bronchial hyperresponsiveness was highest in cluster 3 (aOR, 5.03). Clusters 2 and 4 had an increased risk of allergic rhinitis (aOR, 7.21 and 2.37, respectively). CONCLUSION: Identification of atopy phenotypes facilitates prediction of the development of asthma and bronchial hyperresponsiveness in school-age children. Our study suggests prevention of additional sensitization is required to modify the progression of allergic diseases. PMID- 28364973 TI - Perioperative fluid therapy recommendations for major abdominal surgery. Via RICA recommendations revisited. Part I: Physiological background. PMID- 28364974 TI - Inflammation and anesthesia, is there anything new? PMID- 28364975 TI - Existing and Future Educational Needs in Graduate and Postgraduate Education. AB - INTRODUCTION: This review was designed to make recommendations on future educational needs, principles of curricular development, and how the International Society for Sexual Medicine (ISSM) should address the need to enhance and promote human sexuality education around the world. AIM: To explore the ways in which graduate and postgraduate medical education in human sexuality has evolved and is currently delivered. METHODS: We reviewed existing literature concerning sexuality education, curriculum development, learning strategies, educational formats, evaluation of programs, evaluation of students, and faculty development. We reviewed literature relating to four main areas: (i) the current status of the international regulation of training in sexual medicine; (ii) the current delivery of education and training in sexual medicine; (iii) resident and postgraduate education in sexual medicine surgery; and (iv) education and training for allied health professionals. RESULTS: The main findings in these four areas are as follows. Sexual medicine has grown considerably as a specialty during the past 20 years, with many drivers being identified. However, the regulatory aspects of training, assessment, and certification are currently in the early stages of development and are in many ways lagging behind the scientific and clinical knowledge in the field. However, there are examples of the development of curricula with accompanying assessments that have attempted to set standards of education and training that might underlie the delivery of high quality care to patients in sexual medicine. The development of competence assessment has been applied to surgical training in sexual medicine, and there is increasing interest in simulation as a means of enhancing technical skills training. Although the focus of curriculum development has largely been the medical profession, there is early interest in the development of standards for training and education of allied health professionals. CONCLUSION: Organizations of professionals in sexual health, such as the ISSM, have an opportunity, and indeed a responsibility, to provide and disseminate learning opportunities, curricula, and standards of training for doctors and allied health professionals in sexual medicine. Eardley I, Reisman Y, Goldstein S, et al. Existing and Future Educational Needs in Graduate and Postgraduate Education. J Sex Med 2017;14:475 485. PMID- 28364976 TI - Future of Penile Implant Surgery. PMID- 28364977 TI - Musings on Male Dysorgasmia. PMID- 28364979 TI - Factors Associated With Condom Use Among Sexually Active US Adults, National Survey of Family Growth, 2006-2010 and 2011-2013. AB - BACKGROUND: Condom-less sex can increase the risk of acquiring or transmitting HIV. AIM: To characterize the prevalence of condom use at the most recent sex act and identify factors associated with use of a condom at the most recent sex act in adults in the United States. METHODS: Data from the cross-sectional National Survey of Family Growth from cycles 2006 through 2010 and 2011 through 2013 were analyzed for sexually active men and women 18 to 44 years old who reported having sex (vaginal, anal, or oral) with an opposite-sex partner in the past 12 months. HIV-related sexual risk behaviors (SRBs) in the past 12 months included sex with at least four opposite-sex partners; exchanging sex for money or drugs; sex with an injection drug user; sex with an HIV-positive person; sex with a man who previously had sex with a man (women only); sex with a man (men only); or sex with a partner who had sex with other partners. OUTCOMES: The outcome for this analysis was condom use at the most recent anal or vaginal sex act. RESULTS: Overall prevalence of condom use was 24.8%; only 33.8% of adults with at least one SRB reported the use of a condom. Only 46.4% of unmarried or single men (vs 14.7% married or cohabitating men) and 32.3% unmarried or single women (vs 14.1% married or cohabitating women) with SRBs reported using a condom at the most recent sexual encounter and were less likely to use a condom at the most recent sexual encounter compared with those who did not report SRBs. We did not find a significant relation between using a condom and SRBs in married or cohabitating men and women. STRENGTHS AND LIMITATIONS: Our analysis adds to the literature on how condom use varies by marital status. We measured the use of condoms at the most recent sexual act, which might not reflect an individual's previous behavior of condom use. Nonetheless, condom use at the most recent sexual act has been documented in previous studies as a valid proxy of condom use over time. CONCLUSION: Continued efforts are needed to promote condom use in heterosexual adults in the United States, particularly those at high risk for HIV, namely individuals engaging in anal sexual acts and with multiple sex partners. Nasrullah M, Oraka E, Chavez PR, et al. Factors Associated With Condom Use Among Sexually Active US Adults, National Survey of Family Growth, 2006-2010 and 2011 2013. J Sex Med 2017;14:541-550. PMID- 28364978 TI - Associations of VEGF Gene Polymorphisms With Erectile Dysfunction and Related Risk Factors. AB - BACKGROUND: Repeated evidence from animal models suggests a strong link between vascular endothelial growth factor (VGEF) and penile vasculature and erectile function because VEGF can alter the physiologic pathways involved in the regulation of penile vasomotor tone. AIM: To investigate three VEGF polymorphisms and their link to erectile dysfunction (ED). METHODS: We enrolled 688 Taiwanese men with a mean age of 55.6 years (SD = 4.5) during a free health screening. All participants provided complete medical histories and underwent physical examinations. Fasting blood samples were obtained for biochemical analysis and hormone profiling. The allelic discrimination of three VEGF gene polymorphisms (460T/C [rs833061], 1154G/A [rs1570360], and 2578A/C [rs699947]) was performed using validated TaqMan single-nucleotide polymorphism genotyping assays. OUTCOMES: Subjects underwent assessment using the simplified five-item International Index of Erectile Function to diagnose and assess ED severity. RESULTS: The results showed that diabetes mellitus (odds ratio [OR] = 3.27, P < .01), hypertension (OR = 3.47, P < .01), and having the VEGF 2578A allele (OR = 1.54, P = .01) were the three most independent risk factors for ED. In univariate analysis, all three VEGF polymorphisms (460C, 1154A, and 2578A) were significantly associated with a higher prevalence of coronary artery disease (P < .01) and greater frequencies of hypertension were found in carriers of the 1154A allele and the 2578A allele (P = .01). Multiple logistic regression analysis showed a significant association between VEGF 2578A allele carrier status and ED (OR = 1.54, 95% CI = 1.10~2.15, P = .01). Furthermore, the prevalence and severity of ED were significantly increased with an increment of the 2578A allele number (P < .05). CLINICAL IMPLICATIONS: VEGF 2578C/A gene polymorphisms could be a genetic susceptibility factor for the development of ED. STRENGTH AND LIMITATION: This is the first study to investigate the genetic susceptibility of VEGF polymorphisms to ED. This study was cross-sectional with a lack of functional and molecular production investigations. Data on the association among conditions might not allow definitive conclusions about causal links. CONCLUSION: This study showed that VEGF 2578A allele carriers in a Taiwanese population are at greater risk for ED. Lee Y-C, Huang S-P, Tsai C-C, et al. Associations of VEGF Gene Polymorphisms With Erectile Dysfunction and Related Risk Factors. J Sex Med 2017;14:510-517. PMID- 28364980 TI - Sexual Quality of Life and Needs for Sexology Care of Cancer Patients Admitted for Radiotherapy: A 3-Month Cross-Sectional Study in a Regional Comprehensive Reference Cancer Center. AB - BACKGROUND: Providing early and better care in onco-sexuality and a better understanding of the sexual health care needs of patients before they start treatment is required. OBJECTIVE: To assess sexual quality of life and need for sexology care of patients when they are starting radiotherapy. DESIGN: We performed a cross-sectional study of adult patients with cancer admitted for radiotherapy treatment in a regional comprehensive cancer center. METHODS: We selected all consecutive adult patients scheduled to start radiotherapy within a 3-month period and excluded patients who could not complete the questionnaires. Patients were asked to complete the Sexual Quality of Life Questionnaire (SQoL) and a needs-assessment questionnaire. OUTCOMES: Total score on the SQoL and willingness (yes or no) to get help for a sexual problem. RESULTS: The study sample was composed of 77 men and 123 women. The average SQoL scores were 68.4 +/ 20.9 and 47.1 +/- 13.0 for men and women, respectively (P < .001). Of sexually active patients, 58% had decreased frequency of intercourse or had completely stopped sexual activity after their cancer diagnosis. Half the participants wanted care for their sexual concerns. The proportion desiring specific types of care varied from 28.5% (couple counseling) to 54.5% (sexual physician) with variation by sex or type of cancer. Furthermore, 11.5% of participants declared their willingness to join support groups. CLINICAL IMPLICATIONS: Early interventions before radiotherapy could improve sexual quality of life, particularly in women. STRENGTHS AND LIMITATIONS: Strengths are the SQoL validated in men and women, the original window for assessment, and the study location. Limitations are the monocentric design, the potential recall bias for data before cancer diagnosis, and the fact that some patients had treatments before radiotherapy. CONCLUSION: Our data suggest the need to examine the sexual health trajectory in a prospective fashion from diagnosis to survivorship. Almont T, Delannes M, Ducasson A, et al. Sexual Quality of Life and Needs for Sexology Care of Cancer Patients Admitted for Radiotherapy: A 3-Month Cross-Sectional Study in a Regional Comprehensive Reference Cancer Center. J Sex Med 2017;14:566 576. PMID- 28364981 TI - Heightened Pelvic Floor Muscle Tone and Altered Contractility in Women With Provoked Vestibulodynia. AB - BACKGROUND: Pelvic floor muscle (PFM) dysfunctions are reported to be involved in provoked vestibulodynia (PVD). Although heightened PFM tone has been suggested, the relative contribution of active and passive components of tone remains misunderstood. Likewise, alterations in PFM contractility have been scarcely studied. AIMS: To compare PFM tone, including the relative contribution of its active and passive components, and muscular contractility in women with PVD and asymptomatic controls. METHODS: Fifty-six asymptomatic women and 56 women with PVD participated in the study. The PVD diagnosis was confirmed by a gynecologist based on a standardized examination. OUTCOMES: PFM function was evaluated using a dynamometric speculum combined with surface electromyography (EMG). PFM general tone was evaluated in static conditions at different vaginal apertures and during repeated dynamic cyclic stretching. The active contribution of tone was characterized using the ratio between EMG in a static position and during stretching and the proportion of women presenting PFM activation during stretching. Contribution of the passive component was evaluated using resting forces, stiffness, and hysteresis in women sustaining a negligible EMG signal during stretching. PFM contractility, such as strength, speed of contraction, coordination, and endurance, also was assessed during voluntary isometric efforts. RESULTS: Greater PFM resting forces and stiffness were found in women with PVD compared with controls, indicating an increased general tone. An increased active component also was found in women with PVD because they presented a superior EMG ratio, and a larger proportion of them presented PFM activation during stretching. Higher passive properties also were found in women with PVD. Women with PVD also showed decreased strength, speed of contraction, coordination, and endurance compared with controls. CLINICAL IMPLICATIONS: Findings provide further evidence of the contribution of PFM alterations in the etiology of PVD. These alterations should be assessed to provide patient-centered targeted treatment options. STRENGTHS AND LIMITATIONS: The use of a validated tool investigating PFM alterations constitutes a strength of this study. However, the study design does not allow the determination of the sequence of events in which these muscle alterations occurred-before or after the onset of PVD. CONCLUSION: Findings support the involvement of active and passive components of PFM tone and an altered PFM contractility in women with PVD. Morin M, Binik YM, Bourbonnais D, et al. Heightened Pelvic Floor Muscle Tone and Altered Contractility in Women With Provoked Vestibulodynia. J Sex Med 2017;14:592-600. PMID- 28364982 TI - Medical Male Circumcision Is Associated With Improvements in Pain During Intercourse and Sexual Satisfaction in Kenya. AB - BACKGROUND: Two cohort studies using data from randomized controlled trials in Africa offer the best evidence to date on the effects of voluntary medical male circumcision (VMMC) on male sexual function and satisfaction, suggesting no significant impairments in sexual function or satisfaction and some improvements in sexual function after male circumcision. AIM: To assess the effects of VMMC on sexual function and satisfaction in a large population-based cohort of men circumcised as adults and uncircumcised controls in Kenya. METHODS: Sexual function and satisfaction of young (median age = 20 years) sexually active men (1,509 newly circumcised men and 1,524 age-matched uncircumcised controls after 5% loss to follow-up) were assessed at baseline and 6, 12, 18, and 24 months, with data collected in 2008 to 2012. Self-reported data on lack of sexual interest or pleasure, difficulty getting or maintaining erections, orgasm difficulties, premature ejaculation, pain during intercourse, and satisfaction with sexual intercourse were analyzed with mixed-effect models to detect differences between circumcised and uncircumcised men and changes over time. OUTCOMES: Changes over time in sexual interest, desire and pleasure, erectile and ejaculatory function, and pain during intercourse (dyspareunia) in circumcised and uncircumcised men; group differences in time trends; satisfaction with sexual performance; and enjoyment of sex before and after circumcision. RESULTS: Sexual dysfunctions decreased in the two study groups from 17% to 54% at baseline to 11% to 44% at 24 months (P < .001), except dyspareunia, which decreased only in circumcised men (P < .001). Sexual satisfaction outcomes increased in the two study groups from 34% to 82% at baseline to 66% to 93% at 24 months (P < .001), with greater improvements in circumcised men (P < .001). On average, 97% of circumcised men were satisfied with sexual intercourse and 92% rated sex as more enjoyable or no different after circumcision compared with before circumcision. CLINICAL TRANSLATION: Results are applicable to VMMC programs seeking to increase the acceptability of male circumcision as part of comprehensive HIV prevention. STRENGTHS AND LIMITATIONS: Large-scale population-based longitudinal data restricted to sexually active individuals and adjusted for differences in baseline levels of outcomes and potential confounders are used. The questionnaire used, although not a standardized survey instrument, includes all major domains of male sexual function and satisfaction used in the most common standardized tools. CONCLUSIONS: Results are consistent with large cohort studies of VMMC using data from randomized controlled trials and indicate that VMMC has no significant detrimental effect or might have beneficial effects on male sexual function and satisfaction for the great majority of men circumcised as adults. Nordstrom MPC, Westercamp N, Jaoko W, et al. Medical Male Circumcision Is Associated With Improvements in Pain During Intercourse and Sexual Satisfaction in Kenya. J Sex Med 2017;14:601-612. PMID- 28364983 TI - Re: Effect of BKCa Channel Opener LDD175 on Erectile Function in an In Vivo Diabetic Rat Model. PMID- 28364984 TI - Re: More on Predatory Journals and Illegitimate Publishing. PMID- 28364985 TI - Response and Rebuttal to Re: More on Predatory Journals and Illegitimate Publishing. PMID- 28364986 TI - Erratum. PMID- 28364987 TI - Erratum. PMID- 28364988 TI - Centers for Medicare and Medicaid Services Support for Medication Therapy Management (Enhanced Medication Therapy Management): Testing Strategies for Improving Medication Use Among Beneficiaries Enrolled in Medicare Part D. AB - In 2006, Medicare beneficiaries began receiving prescription coverage benefits through Part D of the Medicare benefit. Medicare Part D plans must provide medication therapy (MTM) services. MTM services aim to improve medication use and are targeted toward eligible beneficiaries, determined by morbidity, prescription use, and anticipated cost of prescription use. Now, 10 years after the start of Medicare Part D, several changes have been made to the program's design. This article focuses on changes related to MTM and the impact that these changes have and will continue to have on Medicare beneficiaries and medication use. PMID- 28364989 TI - The Role of Patient Preferences in Deprescribing. AB - Polypharmacy and the use of inappropriate medications has become an increasing problem globally. Deprescribing has gained attention as a means to rationalize medication use. Deprescribing interventions have been shown to be generally feasible and safe; in the few studies in which patient preferences are assessed, such interventions also seem to be acceptable to patients. Qualitative studies suggest that patients are interested in reducing medications, may need education about their medications to facilitate deprescribing, and highly value communication with their providers around deprescribing. This article focuses on patient preferences for deprescribing and highlights practical recommendations to overcome barriers to deprescribing. PMID- 28364990 TI - Polypharmacy Reduction Strategies: Tips on Incorporating American Geriatrics Society Beers and Screening Tool of Older People's Prescriptions Criteria. AB - There is no single definition of polypharmacy. Use of 5 or more medications commonly is used. An alternative, quantitative definition, such as use of more medications than clinically indicated or use of unnecessary or harmful prescribing, has been proposed. Protocols or algorithms to improve polypharmacy and prescribing in older adults have been developed. The American Geriatrics Society (AGS) Beers Criteria and Screening Tool of Older People's Prescriptions (STOPP) explicit criteria reflect elements that are common across protocols and algorithms. Concepts in AGS Beers and STOPP can be incorporated into polypharmacy reduction strategies to improve outcomes of care for older adults. PMID- 28364991 TI - Polypharmacy and Delirium in Critically Ill Older Adults: Recognition and Prevention. AB - Among older adults, polypharmacy is a sequelae of admission to the intensive care unit and is associated with increased medication-associated adverse events, drug interactions, and health care costs. Delirium is prevalent in critically ill geriatric patients and medications remain an underappreciated modifiable risk for delirium in this setting. This article reviews the literature on polypharmacy and delirium, with a focus on highlighting the relationships between polypharmacy and delirium in critically ill, older adults. Discussed are clinician strategies on how to recognize and reduce medication-associated delirium and recommendations that help prevent polypharmacy when interventions to reduce the burden of delirium in this vulnerable population are being formulated. PMID- 28364992 TI - Geriatric Polypharmacy: Pharmacist as Key Facilitator in Assessing for Falls Risk. AB - This article highlights the significant health impact of falls among older adults. An emphasis is placed on the vital role of the pharmacist, regardless of practice setting, in assessing and reducing falls risk for this growing population. In addition, the importance of a stepwise comprehensive approach to falls assessment by pharmacists in collaboration with other clinicians is elucidated. PMID- 28364993 TI - Medication Reconciliation in Long-Term Care and Assisted Living Facilities: Opportunity for Pharmacists to Minimize Risks Associated with Transitions of Care. AB - The transitions of care process involves pharmacists and other members of the health care team who are in a position to collect, review, and analyze medications lists to help improve health care outcomes. Medication reconciliation is a complex process, especially when providing care to elderly population due to increased medication use, the movement of the patient from one health care setting to another, the number of acute and chronic illnesses, and the intervention of multiple health care providers in different facilities. The use of electronic health records can provide many benefits. PMID- 28364994 TI - Can Managed Care Manage Polypharmacy? AB - Polypharmacy has come to mean the inappropriate use of multiple medications. Polypharmacy can occur as a result of a range of situations, including the excessive application of clinical guidelines, lack of coordination among multiple prescribers, treating adverse drug events, misaligned medications across transitions of care, patient self-treatment, and inappropriate overtreatment. Polypharmacy is a problem because the benefits of a specific medication at the dose and frequency that an individual patient is taking are often outweighed by the costs. These costs can be financial; however, they may place a greater burden when they lead to unrealized benefits or adverse clinical effects. PMID- 28364995 TI - Medication Risk Mitigation: Coordinating and Collaborating with Health Care Systems, Universities, and Researchers to Facilitate the Design and Execution of Practice-Based Research. AB - The high prevalence of inappropriate polypharmacy in geriatric populations is unacceptable. Traditional medication risk mitigation (MRM) strategies have proven to be effective at improving polypharmacy, but these strategies have not consistently translated into positive health outcomes. Enhanced MRM strategies, such as using pharmacogenomics information, are needed, and these strategies need to be tested. A formidable challenge is successfully integrating pharmacogenomic information into clinical practice. As the medication experts on health care teams, pharmacists have a clear role to play in developing, integrating, and assessing enhanced MRM strategies to improve therapeutic outcomes for geriatric patients. PMID- 28364996 TI - Geriatric Polypharmacy: Two Physicians' Personal Perspectives. AB - Being a clinical provider in today's health care environment has become complex with more levels of care to negotiate. Who is caught in the middle of this complexity? Senior citizens. As we evolve into the new quality model, new problems and complexities occur. Numerous protocols and guidelines necessitate the initiation of drugs for given diagnoses and aggressive treatments. This article discusses geriatric polypharmacy from two practitioners' viewpoints: Zhe Chen, MD, discusses the point of view of a physician provider, and Anthony Buonanno, MD, discusses providers' roles in their own families. PMID- 28364997 TI - Inroads into Polypharmacy: Moving Forward with Tools, Deprescribing, and Philosophical Reflection. PMID- 28364998 TI - Is a "gut full" of bad bugs driving metabolic disease in shift workers? PMID- 28364999 TI - Adaptive robust fault tolerant control design for a class of nonlinear uncertain MIMO systems with quantization. AB - In this paper, we investigate the adaptive control problem for a class of nonlinear uncertain MIMO systems with actuator faults and quantization effects. Under some mild conditions, an adaptive robust fault-tolerant control is developed to compensate the affects of uncertainties, actuator failures and errors caused by quantization, and a range of the parameters for these quantizers is established. Furthermore, a Lyapunov-like approach is adopted to demonstrate that the ultimately uniformly bounded output tracking error is guaranteed by the controller, and the signals of the closed-loop system are ensured to be bounded, even in the presence of at most m-q actuators stuck or outage. Finally, numerical simulations are provided to verify and illustrate the effectiveness of the proposed adaptive schemes. PMID- 28365000 TI - Efficacy and Feasibility of a Therapist-Guided Internet-Based Intervention for Older Persons with Childhood Traumatization: A Randomized Controlled Trial. AB - OBJECTIVE: Although cognitive-behavioral treatment approaches for post-traumatic stress disorder (PTSD) exist, only a small proportion of older adults seeks psychological treatment. Alternative treatment approaches are thus needed to fill the gap between provision and use of psychological interventions. This study aimed to investigate the efficacy and feasibility of an Internet-based, therapist guided cognitive-behavioral therapy (Internet-based CBT) for older individuals with PTSD symptoms. METHODS: Patients with clinically meaningful (i.e., subsyndromal or greater) PTSD symptoms were randomly assigned to a 6-week treatment group of therapist-guided Internet-based CBT (N = 47; treatment group) or a wait-list group (N = 47; WL). The treatment group was assessed pre- and post treatment as well as at 3-, 6- and 12-month follow-ups. RESULTS: Linear mixed effects analyses showed a significant interaction between group (treatment versus WL) and time (pre versus post) for PTSD symptoms with a moderate between-group effect size in favor of the treatment group (d = 0.42). Effects in the treatment group were maintained up to the 12-month follow-up. Findings indicate a significant interaction (group * time) for quality of life (d = 0.39) and self efficacy (d = 0.38). With regard to the feasibility, attrition rate was very low in both groups (treatment group: 12.8%, WL: 6.4%) and working alliance was very high. CONCLUSIONS: Results suggest that therapist-guided Internet-based CBT is associated with a substantial reduction in PTSD symptoms, and increase in resource-related variables in older adults with (subsyndromal) PTSD. This Internet-based intervention may offer a promising option in a stepped-care approach for older trauma-affected persons who may otherwise not pursue mental health treatment. PMID- 28365001 TI - Meprin beta and BMP-1 are differentially regulated by CaCl2. AB - The two metalloproteases meprin beta and bone morphogenetic protein 1 (BMP-1) are both members of the astacin protease family. They share specificity for negatively charged residues around the scissile bond and they are expressed in overlapping compartments of the human body. One important proteolytic substrate they share is pro-collagen I. Ablation of one of the two proteases however leads to different collagen I associated phenotypes in vivo. Over the last years calcium emerged as a regulator for the proteolytic activity of both enzymes. For meprin beta a reduction and for BMP-1 an increase in activity was reported under increasing calcium concentrations. Here we revisit different compartments that rely on pro-collagen I maturation and explore the crystal structure of both proteases to highlight possible calcium binding sites. With this we aim to emphasize a to date underestimated regulator that influences both proteases. PMID- 28365002 TI - National Survey on Pediatric Acute Agitation and Behavioral Escalation in Academic Inpatient Pediatric Care Settings. AB - BACKGROUND: Pediatric acute agitation and behavioral escalation (PAABE) is common and disruptive to pediatric inpatient health care. There is a paucity of literature on PAABE in noncritical care inpatient pediatric care settings with little consensus on its evaluation and management. METHODS: In January 2016, a 34 question survey was e-mailed to pediatric hospitalists and consultation-liaison psychiatrists through their respective professional listservs. Excluded responses included incomplete surveys, and surveys from providers in community care settings. The survey consisted of multiple-choice questions, rating scales, and free-text responses relating to the identification, education, and evaluation and management of PAABE at the respondent's respective hospital. RESULTS: Responses were obtained from 38 North American academic children's hospitals. Of the respondents, 69.3% were pediatric hospitalists and 30.7% were pediatric psychiatry consultants. Most respondents practice in urban areas (84.2%), and in hospitals with >=100 beds (89.4%). Overall, 84.2% of the respondents encountered PAABE at least once a month and as frequently as every week. Most respondents (70.0%) rated PAABE as an 8 or higher on a 10-point Likert scale. Despite being highly important and common, 53.9% of respondents do not screen for risk factors for PAABE, 63.6% reported no formal process to facilitate caregiver involvement in managing PAABE, and 59.7% indicated no physician training in PAABE evaluation and management. CONCLUSION: Many pediatric hospitals identify PAABE as a great concern, yet there is little training, screening, or standardization of care in PAABE. There is a need to consolidate existing knowledge regarding PAABE, while developing enhanced collaboration, training, and standardized practice in inpatient PAABE. PMID- 28365003 TI - Carotid intima-media thickness is associated with media rather than intima thickness. PMID- 28365004 TI - Erratum to "Multidisciplinary units in tertiary referral hospitals to improve management of Wilson disease" <[Gastroenterol Hepatol 39 (2016) 571-573]>. PMID- 28365005 TI - Neocortical and hippocampal TREM2 protein levels during the progression of Alzheimer's disease. AB - Heterozygous triggering receptor expressed on myeloid cells (TREM2) mutations are an Alzheimer's disease (AD) risk factor. Nonmutated TREM2 dysregulation occurs in AD brain. Whether TREM2 is altered in prodromal AD remains unknown. Western blotting was used to determine levels of TREM2 (~25 kDa) and Iba1 in the frontal cortex and TREM2 in the hippocampus from people who died with an ante-mortem clinical diagnosis of non- and mild-cognitive impairment, mild/moderate AD, and severe AD (sAD). Immunohistochemistry defined the relationship between amyloid and Iba1 profiles. Polymerase chain reaction analysis revealed that all subjects did not carry the most common R47H TREM2 variant. TREM2 was significantly upregulated in sAD frontal cortex but stable in hippocampus. Frontal TREM2 mRNA and protein level patterns were similar but not significantly different. Iba1 immunopositive microglia counts increased significantly in frontal cortex containing plaques in sAD. TREM2 and Iba1 levels were not associated with plaques, tangles, neuropathological criteria, or cognitive performance. Frontal cortex TREM2 upregulation is a late event and may not play a major role early in the pathogenesis of the disease. PMID- 28365006 TI - Mutations in C19orf12 and intronic repeat expansions in C9orf72 not observed in Iranian Parkinson's disease patients. AB - Various neurodegenerative disorders share some clinical features that sometimes renders differential diagnosis challenging. Genetic-based classification also has limitations as mutations in the same gene are sometimes associated with different clinically based diagnoses. In this light, we screened the C19orf12 neurodegeneration with brain iron accumulation (NBIA) causing gene and the C9orf72 intronic expansion mutation that is cause of amyotrophic lateral sclerosis in 186 Iranian Parkinson's disease (PD) patients. C19orf12 has previously been screened in PD patients in only one study, and to the best of our knowledge neither gene has ever been screened in a PD cohort from a Middle East population. The study was justified because mutations in C19orf12 had previously been shown to be common in Iranian neurodegeneration with brain iron accumulation patients and all the patients with mutations in this gene had exhibited Parkinsonism features. The C9orf72 intronic expansion mutation was screened because the mother of an Iranian amyotrophic lateral sclerosis patient with the expansion who had been diagnosed with PD also harbored the expansion. The screenings did not identify disease causing variations in either of the genes among the PD patients screened. PMID- 28365008 TI - [What are primary health care teams doing about loneliness?] PMID- 28365007 TI - Future remnant liver function as predictive factor for the hypertrophy response after portal vein embolization. AB - BACKGROUND: Preoperative portal vein embolization is widely used to increase the future remnant liver. Identification of nonresponders to portal vein embolization is essential because these patients may benefit from associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), which induces a more powerful hypertrophy response. 99mTc-mebrofenin hepatobiliary scintigraphy is a quantitative method for assessment of future remnant liver function with a calculated cutoff value for the prediction of postoperative liver failure. The aim of this study was to analyze future remnant liver function before portal vein embolization to predict sufficient functional hypertrophy response after portal vein embolization. METHODS: Sixty-three patients who underwent preoperative portal vein embolization and computed tomography imaging were included. Hepatobiliary scintigraphy was performed to determine pre-portal vein embolization and post-portal vein embolization future remnant liver function. Receiver operator characteristic analysis of pre-portal vein embolization future remnant liver function was performed to identify patients who would meet the post portal vein embolization cutoff value for sufficient function (ie, 2.7%/min/m2). RESULTS: Mean pre-portal vein embolization future remnant liver function was 1.80% +/- 0.45%/min/m2 and increased to 2.89% +/- 0.97%/min/m2 post-portal vein embolization. Receiver operator characteristic analysis in 33 patients who did not receive chemotherapy revealed that a pre-portal vein embolization future remnant liver function of >=1.72%/min/m2 was able to identify patients who would meet the safe future remnant liver function cutoff value 3 weeks after portal vein embolization (area under the curve = 0.820). The predictive value was less pronounced in 30 patients treated with neoadjuvant chemotherapy (area under the curve = 0.618). A total of 45 of 63 patients underwent liver resection, of whom 5 of 45 developed postoperative liver failure; 4 of 5 patients had a post-portal vein embolization future remnant liver function below the cutoff value for safe resection. CONCLUSION: When selecting patients for portal vein embolization, future remnant liver function assessed with hepatobiliary scintigraphy can be used as a predictor of insufficient functional hypertrophy after portal vein embolization, especially in nonchemotherapy patients. These patients are potential candidates for ALPPS. PMID- 28365009 TI - Simply the best? PMID- 28365010 TI - Antithrombin III as predictor of liver reserve: A new parameter to improve the results of mechanical circulatory support therapy. PMID- 28365011 TI - Life after training: Learning new skills as a general thoracic surgeon. PMID- 28365012 TI - Postoperative atrial fibrillation: Formulating the problem may be more challenging than the solution. PMID- 28365013 TI - Optimal timing for stage II: Waiting for Godot. PMID- 28365014 TI - Functional tricuspid pathology: To treat or not to treat? That is the question. PMID- 28365015 TI - Thymectomy for myasthenia gravis: The elephant and the blind men. PMID- 28365016 TI - 2016 The American Association for Thoracic Surgery (AATS) consensus guidelines: Surgical treatment of infective endocarditis: Executive summary. PMID- 28365017 TI - Distended or not distended? Fat or nude saphenous vein? In medio stat virtus. PMID- 28365018 TI - The combined effects of elevated pCO2 and food availability on Tigriopus japonicus Mori larval development, reproduction, and superoxide dismutase activity. AB - Previous studies have shown that ocean acidification has little effect on adult Tigriopus japonicus copepods, and mainly impairs the early development and reproduction of females. This study investigated the possible interactive effect between CO2-induced seawater acidification and food availability on larval development and reproductive output in T. japonicus. Copepods were exposed to either pH8.1 or pH7.3 under different food concentrations (0.5*104 80.0*104cells/mL). Both the development of nauplii and copepodites was delayed at pH7.3 with a greater effect at lower food concentrations. The reproductive output followed a bell-shaped curve with the highest reproductive output at food concentrations between 30*104 and 40*104cells/mL. As an indicator of oxidative stress, the activity of superoxide dismutase increased at lower pH, with a greater increase at lower food concentrations. Therefore, the effect of elevated pCO2 on T. japonicus was food dependent. PMID- 28365019 TI - Photosynthetic and transcriptional responses of the marine diatom Thalassiosira pseudonana to the combined effect of temperature stress and copper exposure. AB - A 96-h exposure experiment was conducted to elucidate the toxicity responses of the marine diatom Thalassiosira pseudonana upon exposure to different temperatures and copper (Cu) concentrations. Three Cu treatments (seawater control; 200MUg/L Cu, EC50 for the yield at 25 degrees C; and 1000MUg/L Cu, EC50 for growth inhibition at 25 degrees C) were conducted against four temperatures (10 degrees C, 15 degrees C, 25 degrees C and 30 degrees C). Growth rate and photosynthetic responses showed a significant interacting thermal-chemical effect with strong synergistic responses observed at 30 degrees C treatments. Expression of heat shock protein (hsp) was positively modulated by increasing temperatures. Hsp 90, hsp90-2 and sit1 (related to silica shell formation) were highly expressed at 30 degrees C under 1000MUg/L Cu, while the genes encoding light harvesting proteins (3HfcpA and 3HfcpB) and silaffin precursor sil3 were significantly up-regulated at 15 degrees C under 200MUg/L Cu. Our results indicated an increase Cu toxicity to T. pseudonana under high temperature and Cu dose. PMID- 28365020 TI - Distributions and contamination assessment of heavy metals in the surface sediments of western Laizhou Bay: Implications for the sources and influencing factors. AB - Heavy metals (Cu, Pb, Cr, Cd and As) contents in surface sediments from western Laizhou Bay were analysed to evaluate the spatial distribution pattern and their contamination level. As was mainly concentrated in the coastal area near the estuaries and the other metals were mainly concentrated in the central part of the study area. The heavy metals were present at unpolluted levels overall evaluated by the sediment quality guidelines and geoaccumulation index. Principal component analysis suggest that Cu, Pb and Cd were mainly sourced from natural processes and As was mainly derived from anthropogenic inputs. Meanwhile, Cr originated from both natural processes and anthropogenic contributions. Tidal currents, sediments and human activities were important factors affecting the distribution of heavy metals. The heavy metal environment was divided into four subareas to provide a reference for understanding the distribution and pollution of heavy metals in the estuary-bay system. PMID- 28365021 TI - Trophic and stoichiometric consequences of nutrification for the intertidal tropical zoanthid Zoanthus sociatus. AB - Zoanthids are conspicuous and abundant members of intertidal environments, where they are exposed to large environmental fluctuations and subject to increasing loads of anthropogenic nutrients. Here we assess the trophic ecology and stoichiometric consequences of nutrient loading for symbiotic zoanthids inhabiting different intertidal habitats. More specifically, we analysed the stable isotope signature (delta13C and delta15N), elemental composition (C, N and P) and stoichiometry (C:N, C:P, N:P) of Zoanthus sociatus differently exposed to nutrification. Results suggest that autotrophy is the main feeding mode of zoanthids and that the effect water nutrient content differently affects the elemental phenotype of zoanthids depending on tidal habitat. Additionally, habitat effects on Z. sociatus P-related stoichiometric traits highlight functional differences likely associated with variation in Symbiodinium density. These findings provide an innovative approach to assess how cnidarian dinoflagellate symbioses response to ecosystem changes in environmentally dynamic reef flats, particularly nutrient loading. PMID- 28365022 TI - An algorithm for modeling entrainment and naturally and chemically dispersed oil droplet size distribution under surface breaking wave conditions. AB - A surface oil entrainment model and droplet size model have been developed to estimate the flux of oil under surface breaking waves. Both equations are expressed in dimensionless Weber number (We) and Ohnesorge number (Oh, which explicitly accounts for the oil viscosity, density, and oil-water interfacial tension). Data from controlled lab studies, large-scale wave tank tests, and field observations have been used to calibrate the constants of the two independent equations. Predictions using the new algorithm compared well with the observed amount of oil removed from the surface and the sizes of the oil droplets entrained in the water column. Simulations with the new algorithm, implemented in a comprehensive spill model, show that entrainment rates increase more rapidly with wind speed than previously predicted based on the existing Delvigne and Sweeney's (1988) model, and a quasi-stable droplet size distribution (d<~50MUm) is developed in the near surface water. PMID- 28365023 TI - Environmental complexity of a port: Evidence from circulation of the water masses, and composition and contamination of bottom sediments. AB - Ports are complex environments due to their complicated geometry (quays, channels, and piers), the presence of human activities (vessel traffic, shipyards, industries, and discharges), and natural factors (stream and torrent inputs, sea action, and currents). Taking these factors into consideration, we have examined the marine environment of a port from the point of view of the circulation of the water masses, hydrological characteristics, distribution of the sediment grain-size, mineralogical characteristics, and metal concentrations of the bottom sediments. Our results show that, in the case of the Port of Genoa (north-western Italy), the impact of human activities (such as a coal power plant, oil depots, shipyards, dredging of the bottom sediments, etc.), natural processes (such as currents, fresh water and sediment inputs from the torrents), and the morphology of the basin, are important factors in the sediment, water, and metal distributions that have given rise to a complex environment. PMID- 28365024 TI - Reply. PMID- 28365025 TI - The Effectiveness of Prescribed Rest Depends on Initial Presentation After Concussion. AB - OBJECTIVE: To evaluate if patients with signs of injury respond differently to prescribed rest after concussion compared with patients with symptoms only. STUDY DESIGN: Secondary analysis was completed of a prospective randomized controlled trial (NCT01101724) of pediatric concussion patients aged 11-18 years. Patients completed computerized neurocognitive testing and standardized balance assessment at the emergency department within 24 hours of injury and on follow-up (3 and 10 days). Patients were randomized to rest or usual care and completed activity and symptom diaries for 10 days after injury. A series of 2?*?2 ANOVAs with grouping factors of patient group (symptoms, signs) and treatment arm (prescribed rest, standard of care) were used to examine differences on clinical measures. Univariate nonparametric test (ie, ?2 with ORs and 95% CIs) was used to examine the association between treatment arm and symptom status 1-9 days after injury. RESULTS: A 2?*?2 factorial ANOVA revealed a significant patient group * treatment arm interaction for symptom score at 3 days after injury (F?=?6.31, P?=?.01, ?2?=?0.07). Prescribed rest increased the likelihood of still being symptomatic at days 1-6 and 8 (P?1 kb in length placed outside of the expression cassette. Here, we show that transcriptional silencing can be substantially forestalled by increasing the An/Tn sequence composition in the plasmid bacterial backbone. Increasing numbers of An/Tn sequences increased sustained transcription of both backbone sequences and adjacent expression cassettes. In order to recapitulate these expression profiles in compact and portable plasmid DNA backbones, we engineered the standard kanamycin or ampicillin antibiotic resistance genes, optimizing the number of An/Tn sequence without altering the encoded amino acids. The resulting vector backbones yield sustained transgene expression from mouse liver, providing generic DNA vectors capable of sustained transgene expression without additional genes or mammalian regulatory elements. PMID- 28365031 TI - Secondary decompressive craniectomy for the management of refractory endocraneal hypertension in severe traumatic brain injury. Lights and shadows from recent studies. PMID- 28365032 TI - The Role of Mental Maps in Decision-Making. AB - A growing body of work is investigating the use of mental maps during decision making. Here we discuss how decision-making organizes experiences according to an internal model of the current task, thereby structuring memory. Likewise, we consider how the structure of mental maps contributes to decision-making. PMID- 28365033 TI - Pharmacokinetics and Tolerability of Lorcaserin in Special Populations: Elderly Patients and Patients with Renal or Hepatic Impairment. AB - PURPOSE: To determine whether dosage adjustment is likely to be necessary for effective and well-tolerated use of a pharmaceutical agent, guidance documents from the US Food and Drug Administration recommend pharmacokinetics studies in patients with impaired renal or impaired hepatic function and in the elderly population. Three studies were conducted to evaluate the pharmacokinetic properties and tolerability of lorcaserin in these populations. METHODS: Lorcaserin was evaluated in single-dose pharmacokinetics studies of 3 overweight/obese populations: (1) elderly (aged >65 years) patients; (2) patients with impaired renal function; and (3) those with impaired hepatic function. FINDINGS: In elderly patients, Cmax was lower (geometric mean ratio [GMR], 0.83; 90% CI, 0.71-0.97), but AUC was unchanged versus adult patients. In patients with renal impairment, Cmax was reduced versus that in patients with normal renal function (GMR: mild impairment, 0.99 [90% CI, 0.76-1.29]; moderate, 0.70 [90% CI, 0.54-0.90]; and severe, 0.69 [90% CI, 0.53-0.89]); no trend in AUC was observed in this group versus renal impairment. In patients with hepatic impairment, Cmax was decreased (GMR: mild impairment, 0.92 [90% CI, 0.76-1.11]; moderate, 0.86 [90% CI, 0.71-1.04]), and AUC was increased versus patients with normal hepatic function. IMPLICATIONS: Based on these findings, no lorcaserin dose adjustments are necessary in elderly patients with normal renal function or in patients with mild/moderate renal or hepatic impairment. ClinicalTrials.gov identifiers: NCT00828581, NCT00828438, and NCT00828932. PMID- 28365034 TI - Capsaicin 8% Patch Versus Oral Neuropathic Pain Medications for the Treatment of Painful Diabetic Peripheral Neuropathy: A Systematic Literature Review and Network Meta-analysis. AB - PURPOSE: A network meta-analysis (NMA) was performed, aiming to assess the relative efficacy and tolerability of the capsaicin 179-mg (8% weight for weight) cutaneous patch (capsaicin 8% patch) compared with oral, centrally acting agents (ie, pregabalin, gabapentin, duloxetine, amitriptyline) in patients with painful diabetic peripheral neuropathy (PDPN). METHODS: A systematic search of EMBASE/MEDLINE, Cochrane Library, and the National Health Service Centre for Reviews and Dissemination Database of Abstracts of Reviews of Effects was conducted to identify all randomized controlled trials. Data from eligible studies according to predefined inclusion and exclusion criteria were extracted, and analyses were based on aggregate-level data. Efficacy outcomes were the proportions of patients with >=30% and >=50% reductions in pain, and tolerability outcomes were somnolence, dizziness, nausea, diarrhea, constipation, headache, fatigue, insomnia, and rate of discontinuation due to adverse events (AEs). Data were analyzed by using a Bayesian NMA. Fixed and random effects models were estimated. Relative treatment effect was presented as odds ratios (ORs) with 95% CIs. Sources of heterogeneity were assessed. FINDINGS: The NMA included 25 randomized controlled trials. For >=30% pain reduction, the capsaicin 8% patch was significantly more effective than placebo (OR, 2.28 [95% CI, 1.19-4.03]), exhibited a numerical advantage compared with pregabalin (OR, 1.83 [95% CI, 0.91 3.34]) and gabapentin (OR, 1.66 [95% CI, 0.74-3.23]), and had similar efficacy compared with duloxetine (OR, 0.99 [95% CI, 0.5-1.79]). The evidence available was not sufficient to assess the relative efficacy of amitriptyline. In the NMA for tolerability, the capsaicin 8% patch was only included for headache because the incidence was 0% for the other outcomes. Oral, centrally acting agents had a significantly elevated risk compared with placebo for somnolence (pregabalin, gabapentin, duloxetine, and amitriptyline), dizziness (pregabalin, gabapentin, duloxetine, and amitriptyline), nausea (duloxetine), diarrhea (duloxetine), fatigue (duloxetine), and discontinuation because of AEs (pregabalin, gabapentin, and duloxetine). Compared with pregabalin and gabapentin, duloxetine had a significantly lower risk of dizziness but a significantly higher risk of nausea. IMPLICATIONS: This NMA suggests that the efficacy observed with the capsaicin 8% patch is similar to that observed with oral agents (ie, pregabalin, duloxetine, gabapentin) in patients with PDPN. The oral agents were associated with a significantly elevated risk of somnolence, dizziness, fatigue, and discontinuation because of AEs compared with placebo. The capsaicin 8% patch was as effective as oral centrally acting agents in these patients with PDPN but offers systemic tolerability benefits. PMID- 28365035 TI - Efficacy of Varenicline for Cigarette Reduction Before Quitting in Japanese Smokers: A Subpopulation Analysis of the Reduce to Quit Trial. AB - PURPOSE: This prospective analysis of the Japanese subpopulation of the varenicline reduce to quit study was conducted to evaluate whether results for Japanese participants were consistent with the full study population. METHODS: Patients received varenicline or placebo for a 24-week treatment period (12-week smoking reduction phase then a 12-week smoking abstinence phase) followed by a 28 week nontreatment, follow-up phase. Participants were to reduce the daily number of cigarettes smoked by at least 50% by week 4 and by a further 50% by week 8, with the goal of achieving complete abstinence by week 12. The primary efficacy end point was the carbon monoxide-confirmed continuous abstinence during weeks 15 to 24. FINDINGS: Overall, 210 Japanese patients were randomly assigned to 1 of the 2 study groups (varenicline, 107; placebo, 103). Continuous abstinence rates for weeks 15 to 24 were higher for participants in the varenicline group versus the placebo group (46.7% vs 12.6%; odds ratio = 14.68; 95% CI, 5.38-40.05), and the 7-day point prevalence of abstinence rates were higher for varenicline versus placebo at week 12 (odds ratio = 13.76; 95% CI, 5.28-35.86). The number of participants with a >=50% reduction in the number of daily cigarettes smoked from baseline to week 4 and a >=75% reduction by week 8 was greater in the varenicline group versus the placebo group (week 4: 59.8% vs 30.1%; week 8: 38.3% vs 12.6%). Serious adverse events were reported in 3.7% of varenicline participants and 1.0% of placebo participants. IMPLICATIONS: The efficacy and tolerability results of this analysis are consistent with those of the full varenicline reduce to quit study. Varenicline treatment and cigarette reduction before quitting may provide an alternative approach to smoking cessation in Japanese smokers who are not ready to quit immediately. ClinicalTrials.gov identifier: NCT01370356. PMID- 28365036 TI - Toward a useful standard for hospitalizing pretrial jail detainees. AB - Severely mentally ill jail detainees require an adequate spectrum of mental health services during detainment. For some this means a limited period of treatment in a mental hospital, just as some mentally ill individuals in the community occasionally require hospital treatment. Unfortunately, this appropriate level of treatment is often denied or neglected for jail detainees with adverse consequences for them. Among the reasons for this neglect, may be standards for hospital transfer that are no longer practical and can be easily skirted by policymakers and administrators with little interest in ensuring this level of care for mentally ill jail inmates. A more realistic standard and justification would recognize the need for hospitalization for the mentally disordered detainee who because of psychotic anosognosia refuses appropriate treatment including medications and/or whose severely decompensated condition is worsening or failing to improve despite attempts at treatment in the jail. PMID- 28365037 TI - Empirical treatment prescribing improvement proposal in skin and soft tissue infection. PMID- 28365038 TI - Future considerations for clinical dermatology in the setting of 21st century American policy reform: The Medicare Access and Children's Health Insurance Program Reauthorization Act and the Merit-based Incentive Payment System. AB - As the implementation of the Medicare Access and Children's Health Insurance Program Reauthorization Act begins, many dermatologists who provide Medicare Part B services will be subject to the reporting requirements of the Merit-based Incentive Payment System (MIPS). Clinicians subject to MIPS will receive a composite score based on performance across 4 categories: quality, advancing care information, improvement activities, and cost. Depending on their overall MIPS score, clinicians will be eligible for a positive or negative payment adjustment. Quality will replace the Physician Quality Reporting System and clinicians will report on 6 measures from a list of over 250 options. Advancing care information will replace meaningful use and will assess clinicians on activities related to integration of electronic health record technology into their practice. Improvement activities will require clinicians to attest to completion of activities focused on improvements in care coordination, beneficiary engagement, and patient safety. Finally, cost will be determined automatically from Medicare claims data. In this article, we will provide a detailed review of the Medicare Access and Children's Health Insurance Program Reauthorization Act with a focus on MIPS and briefly discuss the potential implications for dermatologists. PMID- 28365040 TI - Future considerations for clinical dermatology in the setting of 21st century American policy reform: The Medicare Access and Children's Health Insurance Program Reauthorization Act and Alternative Payment Models in dermatology. AB - With the introduction of the Medicare Access and Children's Health Insurance Program Reauthorization Act, clinicians who are not eligible for an exemption must choose to participate in 1 of 2 new reimbursement models: the Merit-based Incentive Payment System or Alternative Payment Models (APMs). Although most dermatologists are expected to default into the Merit-based Incentive Payment System, some may have an interest in exploring APMs, which have associated financial incentives. However, for dermatologists interested in the APM pathway, there are currently no options other than joining a qualifying Accountable Care Organization, which make up only a small subset of Accountable Care Organizations overall. As a result, additional APMs relevant to dermatologists are needed to allow those interested in the APMs to explore this pathway. Fortunately, the Medicare Access and Children's Health Insurance Program Reauthorization Act establishes a process for new APMs to be approved and the creation of bundled payments for skin diseases may represent an opportunity to increase the number of APMs available to dermatologists. In this article, we will provide a detailed review of APMs under the Medicare Access and Children's Health Insurance Program Reauthorization Act and discuss the development and introduction of APMs as they pertain to dermatology. PMID- 28365039 TI - Tumor recurrence of keratinocyte carcinomas judged appropriate for Mohs micrographic surgery using Appropriate Use Criteria. AB - BACKGROUND: The use of Mohs micrographic surgery (MMS) has increased greatly to treat basal cell and cutaneous squamous cell carcinomas (keratinocyte carcinoma [KC]), and consensus-based Appropriate Use Criteria (AUC) were developed to identify tumors for which MMS is appropriate. OBJECTIVE: We sought to compare recurrence rates after different treatments in tumors judged appropriate for MMS. METHODS: We used data from an observational prospective cohort study and retrospectively categorized consecutive tumors as appropriate for MMS according to the AUC. Among appropriate tumors, we used survival analyses to compare 5-year recurrence rates after treatments. RESULTS: Among tumors appropriate for MMS (N = 1483), adjusted 5-year recurrence rates were 2.9% (range, 1.4-4.3%) after MMS, 5.5% (range, 3.1-7.9%) after excision, 4.0% (range, 0.6-7.2%) after destruction, and 5.9% (range, 1.5-10.2%) after other treatments. In tumors treated only with MMS or excision (the most similar subgroups), the adjusted hazard ratio of 5-year recurrence after MMS was 0.6 (95% confidence interval, 0.3-1.0; P = .06). LIMITATIONS: This study is limited by its uncertain generalizability, lack of randomization, and unmeasured characteristics. CONCLUSION: The AUC identified tumors for which recurrence would be less common after MMS than after excision, but the absolute difference in recurrence rates was small. PMID- 28365041 TI - Commentary: Future considerations for clinical dermatology in the setting of 21st century American policy reform: The Medicare Access and CHIP Reauthorization Act of 2015. PMID- 28365042 TI - Racial disparities in the impact of chronic pruritus: A cross-sectional study on quality of life and resource utilization in United States veterans. AB - BACKGROUND: Chronic pruritus has a lifetime prevalence of up to 26% in the worldwide population. Research has shown that the incidence and quality of life (QoL) impact of chronic pruritus varies by race. OBJECTIVE: We sought to explore the effects of race on specific pruritus-related QoL factors and resource utilization. METHODS: We performed a cross-sectional, national telephone survey of 6000 US veterans randomly sampled from the Veterans Hospital Patient Database. We administered surveys to assess QoL impact and resource utilization of chronic pruritus. RESULTS: Nonwhites overall reported higher levels of burning and scarring with their pruritus. African Americans had a significantly greater emotional impact and use of special soaps, lotions, and clothes. African Americans were also more likely to visit their primary care provider for pruritus (P = .03), yet had similar numbers of specialty care visits. LIMITATIONS: Because our sample was drawn from a veteran population, generalizability may be limited. CONCLUSION: The data indicate a racial disparity in specific QoL impact and resource utilization from pruritus. These findings merit further exploration into explanations, such as access, communication, trust of the medical system, and biologic differences. PMID- 28365043 TI - Effects of enhanced bioturbation intensities on the toxicity assessment of legacy contaminated sediments. AB - Many benthic communities within estuarine ecosystems are highly degraded due to the close proximity of urban and industrial contamination sources. The maintenance of recolonised, healthy ecosystems following remediation is a challenge, and better techniques are required for monitoring their progressive recovery. Rates of ecosystem recovery are influenced by the changes in the concentrations and forms of contaminants, the sensitivity of recolonising organisms to bioavailable contaminants, and a range of abiotic and biotic factors influencing the exposure of organisms to the contamination. Here we investigate the influence of bioturbation by an active amphipod (Victoriopisa australiensis) on the bioavailability of metals and hydrocarbons in highly contaminated sediments. Changes in contaminant bioavailability were evaluated by assessing sublethal effects to a smaller cohabiting amphipod (Melita plumulosa). For predominantly metal-contaminated sediments, the presence of V. australiensis generally increased survival and reproduction of M. plumulosa when compared to treatments with only M. plumulosa present (from 42 to 93% survival and 3-61% reproduction). The decrease in toxic effects to M. plumulosa corresponded with lower dissolved copper and zinc concentrations in the overlying waters (14-9 MUg Cu L-1, and 14 to 6 MUg Zn L-1 for absence to presence of V. australiensis). For sediments contaminated with both hydrocarbons and metals, the increased bioturbation intensity by V. australiensis resulted in decreased reproduction of M. plumulosa, despite lower dissolved metal exposure, and indicated increased bioavailability of the hydrocarbon contaminants. Thus, the presence of a secondary active bioturbator can enhance or suppress toxicity to co-inhabiting organisms, and may depend on the contaminant class and form. The results highlight the need to consider both abiotic and biotic interactions when using laboratory studies to evaluate the ability of organisms to recolonise and reproduce within benthic environments degraded by contamination, or for more general extrapolation for sediment quality assessment purposes. PMID- 28365044 TI - Do benefits in kind or refunds affect health service utilization and health outcomes? A natural experiment from Japan. AB - Although the payment systems of public health insurance vary greatly across countries, we still have limited knowledge of their effects. To quantify the changes from a benefits in kind system to a refund system, we exploit the largest physician strike in Japan since the Second World War. During the strike in 1971 led by the Japan Medical Association (JMA), JMA physicians resigned as health insurance doctors, but continued to provide medical care and even health insurance treatment in some areas. This study uses the regional differences in resignation rates as a natural experiment to examine the effect of the payment method of health insurance on medical service utilization and health outcomes. In the main analysis, aggregated monthly prefectural data are used (N=46). Our estimation results indicate that if the participation rate of the strike had increased by 1% point and proxy claims were refused completely, the number of cases of insurance benefits and the total amount of insurance benefits would have decreased by 0.78% and 0.58%, respectively compared with the same month in the previous year. Moreover, the average amount of insurance benefits per claim increased since patients with relatively less serious diseases might have sought health care less often. Finally, our results suggest that the mass of resignations did not affect death rates. PMID- 28365045 TI - Phylogenetic Paleoecology: Tree-Thinking and Ecology in Deep Time. AB - The new and emerging field of phylogenetic paleoecology leverages the evolutionary relationships among species to explain temporal and spatial changes in species diversity, abundance, and distribution in deep time. This field is poised for rapid progress as knowledge of the evolutionary relationships among fossil species continues to expand. In particular, this approach will lend new insights to many of the longstanding questions in evolutionary biology, such as: the relationships among character change, ecology, and evolutionary rates; the processes that determine the evolutionary relationships among species within communities and along environmental gradients; and the phylogenetic signal underlying ecological selectivity in background and mass extinctions and in major evolutionary radiations. PMID- 28365046 TI - [The place of surgery in bilateral sequelae bronchiectasis]. AB - INTRODUCTION: The aim of our study is to report our surgery results in bilateral sequelae bronchiectasis and to assess its impact on the life quality of our patients. METHOD: This is a retrospective descriptive study in thoracic surgery department of Teaching Hospital Hassan II of Fez in Morocco. It involved all patients with bilateral bronchiectasis which is predominant on a few lobes or segments (localized) and who underwent surgery during the period 2010-2015. The epidemiological, clinical and paraclinical data, the surgery results, the evolution and the impact on life quality were assessed. RESULTS: From a total of 47 patients with bilateral bronchiectasis, 13 were operated, thus a frequency of 27.6%. The average age was 32years, ranging from 15 to 54years. Women were in majority (61.5%) representing a sex ratio of 1.6. The association of chronic bronchorrhea and hemoptysis was the main reason of medical consultation in 46.16%, followed by isolated chronic bronchorrhea in 38.46%. Surgical resection involved the left side in 61.5% of cases. The left lower lobectomy was the most accomplished gesture. An improvement in symptoms was found in 11 patients (84.6%) as a decrease in bronchorrhea, hemoptysis episodes and decreasing use of antibiotics. CONCLUSION: Bilateral bronchiectasis surgery can be performed with acceptable morbidity and mortality in well-selected patients with an improvement in symptoms. PMID- 28365047 TI - [Fatal bleomycin induced pneumomediastinum and bilateral pneumothorax]. PMID- 28365048 TI - [The primary pulmonary Malt lymphoma: About a case]. PMID- 28365049 TI - The authors' respond the letter: Fluid resuscitation of trauma patients: How much fluid is enough to determine the patient's response? PMID- 28365050 TI - Reply to: Fluid resuscitation of trauma patients: How much fluid is enough to determine the patient's response? PMID- 28365051 TI - Optimal front-line ALK (anaplastic lymphoma kinase) directed therapy. PMID- 28365053 TI - [Contact lens care and maintenance]. AB - All contact lenses with replacement schedules longer than daily must be maintained. At each step of their use, the lenses may be contaminated. Contact lens solutions perform the essential functions of cleaning, decontaminating and preserving the lenses to prevent infectious problems and improve wearing comfort. Contact lens contamination essentially comes from hands, cleaning solutions, cases, water and the environment. The pathogenic microorganisms are mainly Gram negative bacteria, fungi and amoebae. Contact lens deposits may or may not have an organic origin. Their presence increases the risk of infection because they serve as a nutrient matrix for microbes, and they are responsible for wearing discomfort. Contact lens solutions differ in their composition, their mechanism of action and the concentration of the various agents. To prescribe the best lens care system to each wearer and for each material, it is necessary to be very familiar with them. Maintenance is the main cause of discomfort with contact lenses, either through improper use, solution-material incompatibility, or a reaction of the wearer to the components. PMID- 28365052 TI - Snacking and Diet Quality Are Associated With the Coping Strategies Used By a Socioeconomically Diverse Urban Cohort of African-American and White Adults. AB - BACKGROUND: Stress affects health-related quality of life through several pathways, including physiological processes and health behaviors. There is always a relationship between stress (the stimulus) and coping (the response). The relationship between snacking and snackers' diet quality and stress coping is a topic overlooked in research. OBJECTIVE: The study was primarily designed to determine whether energy provided by snacks and diet quality were associated with coping behaviors to manage stress. DESIGN: We analyzed a baseline cohort of the Healthy Aging in Neighborhoods of Diversity across the Life Span study (2004 to 2009). PARTICIPANTS: The sample was composed of 2,177 socioeconomically diverse African-American and white adults who resided in Baltimore, MD. MAIN OUTCOME MEASURES: Energy from snacks was calculated from 2 days of 24-hour dietary recalls collected using the US Department of Agriculture's Automated Multiple Pass Method. Snack occasions were self-reported as distinct eating occasions. Diet quality was evaluated by the Healthy Eating Index-2010. STATISTICAL ANALYSES PERFORMED: Multiple regression analyses were used to determine whether coping factors were associated with either energy provided by snacks or Healthy Eating Index-2010, adjusting for age, sex, race, socioeconomic status, education, literacy, and perceived stress. Coping was measured by the Brief COPE Inventory with instrument variables categorized into three factors: problem-focused coping, emotion-focused coping, and use of support. Perceived stress was measured with the 4-item Perceived Stress Scale. RESULTS: Adjusting for perceived stress and selected demographic characteristics, emotion-focused coping strategies were associated with greater energy intakes from snacks (P=0.020), and use of coping strategies involving support was positively associated with better diet quality (P=0.009). CONCLUSIONS: Energy contributed by snacks and diet quality were affected by the strategy that an individual used to cope with stress. The findings suggest that health professionals working with individuals seeking guidance to modify their eating practices should assess a person's coping strategies to manage stress. PMID- 28365054 TI - Lipid Metabolism and Emerging Targets for Lipid-Lowering Therapy. AB - Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality worldwide, and dyslipidemia constitutes a major risk factor for CVD and premature atherosclerosis. Therapies to reduce the plasma levels of atherogenic lipoproteins are well established interventions that decrease CVD risk. However, treatment of dyslipidemia with the most widely used lipid-lowering drugs (ie, statins and ezetimibe) often fails to protect a significant proportion of patients from cardiovascular risk. The development of several novel therapies to treat lipid-related disorders and their associated risks is ongoing and includes the following: (1) reducing plasma levels of atherogenic lipoproteins using proprotein convertase subtilisin/kexin type 9 inhibitors, antisense inhibitors of Apolipoprotein (Apo)(a), microsomal triglyceride transfer protein inhibitors, antisense oligonucleotides of ApoB for inhibiting very low-density lipoprotein production, and inhibitors of angiopoietin-like protein 3 or ApoC-III for triglyceride-rich lipoprotein management upstream of low-density lipoprotein production as well as gene replacement therapy to improve low-density lipoprotein and triglyceride-rich lipoprotein clearance; and (2) emerging therapies that target high-density lipoprotein (HDL) and reverse cholesterol transport using cholesteryl ester transfer protein inhibitors, HDL peptide mimetics, and autologous infusion of pre-beta HDLs. Clinical trials of several of these emerging therapies are currently being conducted. Despite the potential efficacy of these new therapies in CVD prevention, their costs might limit their use because of limited reimbursement funds. Therefore, the real challenge facing the next generation of lipid-lowering agents will most likely be accessibility, reflecting a new paradigm that applies to almost all emerging therapies for any disease in the era of precision medicine. PMID- 28365055 TI - Precision Medicine for Hypertension Management in Chronic Kidney Disease: Relevance of SPRINT for Therapeutic Targets in Nondiabetic Renal Disease. AB - In this review we evaluate the literature to determine if lower blood pressure (BP) targets are beneficial for patients with nondiabetic chronic kidney disease (CKD). Modification of Diet in Renal Disease (MDRD), African American Study of Kidney Disease and Hypertension (AASK), and Ramipril Efficacy in Nephropathy-2 (REIN-2), designed to assess the benefit of lower BP on progression of nondiabetic CKD, generally came to the same negative conclusion. They were not designed and powered to assess an effect of lower BP on cardiovascular outcomes. The Systolic Blood Pressure Intervention Trial (SPRINT) was the first trial designed and powered to address this issue, and showed a clear benefit of a lower targeted and achieved BP. SPRINT did not show any renal benefits from lower BP, and it was not designed to assess this outcome, and it enrolled patients with less "renal risk" per se. A distinguishing feature of SPRINT compared with other large trials is that it highlighted the importance of precise BP measurement methods in defining targets in hypertension treatment. Accordingly, we propose that SPRINT is truly a "game-changing" clinical trial that sets the bar for management of hypertension in select patients with nondiabetic CKD. In these patients, systolic BP target depends critically on the BP measurement method: < 140 mm Hg when derived from 3 readings using a mercury sphygmomanometer after 5 minutes of rest, < 130 mm Hg when calculated from at a minimum of 3 readings using an automated oscillometric device, and < 120 mm Hg when taken using an automated oscillometric device after 5 minutes of unattended rest. PMID- 28365056 TI - Idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis is a prototype of chronic, progressive, and fibrotic lung disease. Healthy tissue is replaced by altered extracellular matrix and alveolar architecture is destroyed, which leads to decreased lung compliance, disrupted gas exchange, and ultimately respiratory failure and death. In less than a decade, understanding of the pathogenesis and management of this disease has been transformed, and two disease-modifying therapies have been approved, worldwide. In this Seminar, we summarise the presentation, pathophysiology, diagnosis, and treatment options available for patients with idiopathic pulmonary fibrosis. This disease has improved understanding of the mechanisms of lung fibrosis, and offers hope that similar approaches will transform the management of patients with other progressive fibrotic lung diseases. PMID- 28365057 TI - Early Detection and Screening for Breast Cancer. AB - OBJECTIVE: To review the history, current status, and future trends related to breast cancer screening. DATA SOURCES: Peer-reviewed articles, web sites, and textbooks. CONCLUSION: Breast cancer remains a complex, heterogeneous disease. Serial screening with mammography is the most effective method to detect early stage disease and decrease mortality. Although politics and economics may inhibit organized mammography screening programs in many countries, the judicious use of proficient clinical and self-breast examination can also identify small tumors leading to reduced morbidity. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses have exciting opportunities to lead, facilitate, and advocate for delivery of high-quality screening services targeting individuals and communities. A practical approach is needed to translate the complexities and controversies surrounding breast cancer screening into improved care outcomes. PMID- 28365058 TI - Impact of high hydrostatic pressure on bacterial proteostasis. AB - High hydrostatic pressure (HHP) is an important factor that limits microbial growth in deep-sea ecosystems to specifically adapted piezophiles. Furthermore, HHP treatment is used as a novel food preservation technique because of its ability to inactivate pathogenic and spoilage bacteria while minimizing the loss of food quality. Disruption of protein homeostasis (i.e. proteostasis) as a result of HHP-induced conformational changes in ribosomes and proteins has been considered as one of the limiting factors for both microbial growth and survival under HHP conditions. This work therefore reviews the effects of sublethal (<=100MPa) and lethal (>100MPa) pressures on protein synthesis, structure, and functionality in bacteria. Furthermore, current understanding on the mechanisms adopted by piezophiles to maintain proteostasis in HHP environments and responses developed by atmospheric-adapted bacteria to protect or restore proteostasis after HHP exposure are discussed. PMID- 28365059 TI - Commentary Re: a critical appraisal of the mild axonal peripheral neuropathy of late neurologic Lyme disease, by Wormser et al. DMID 2016. PMID- 28365060 TI - Clinical evaluation of a new single-tube multiplex reverse transcription PCR assay for simultaneous detection of 11 respiratory viruses, Mycoplasma pneumoniae and Chlamydia in hospitalized children with acute respiratory infections. AB - Respiratory Pathogen 13 Detection Kit (13* kit) is able to simultaneously detect 11 respiratory viruses, Mycoplasma pneumoniae (MP) and Chlamydia in a single reaction. Using 572 Nasopharyngeal aspirates collected from hospitalized children, the clinical performance of 13* kit for detecting 11 respiratory viruses was evaluated in comparison with a routinely used 2-tube multiplex reverse transcription PCR assay (2-tube assay) at provincial Centers for Disease Control and Prevention in China. The clinical performance of 13* kit for detecting MP and Chlamydia was evaluated by commercial real-time quantitative PCR (qPCR) kits or sequencing. For tested viruses, the assay concordance was 95.98% and the kappa coefficient was 0.89. All the MP and Chlamydia positive samples detected by 13* kit were confirmed as true positives. The utilization of the 13* kit in clinical settings will be helpful for doctors to assess clinical outcome according to virus type or multiple infections, and to limit the use of antibiotics. PMID- 28365061 TI - Gaze detection and gaze cuing in Alzheimer's disease. AB - People with Alzheimer's disease (AD) show problems with social processing in tasks which require the understanding of others' mental states. However traditional social processing tasks are cognitively complex, which may influence the effects of AD. Less is known about how AD influences more basic aspects of social perception, such as the ability to decode eye gaze direction or follow the gaze of another. The current research assessed whether those with AD showed difficulty in both explicitly decoding subtle manipulations of gaze direction (Study 1), and reflexively following another's eye gaze (Study 2). Those with AD were more impaired than a matched control group when making explicit discrimination distinctions between direct and averted gaze. In contrast people with Alzheimer's disease performed comparably to a control group when following gaze. This pattern indicates that more automatic aspects of social perception such as gaze following are unaffected by AD. In contrast, more controlled processes such as deciding whether someone is looking towards you are impaired in AD. This has implications for socially engaging with other people and interpreting their focus of interest. PMID- 28365062 TI - In situ deformation of growth plate chondrocytes in stress-controlled static vs dynamic compression. AB - Longitudinal bone growth in children/adolescents occurs through endochondral ossification at growth plates and is influenced by mechanical loading, where increased compression decreases growth (i.e., Hueter-Volkmann Law). Past in vivo studies on static vs dynamic compression of growth plates indicate that factors modulating growth rate might lie at the cellular level. Here, in situ viscoelastic deformation of hypertrophic chondrocytes in growth plate explants undergoing stress-controlled static vs dynamic loading conditions was investigated. Growth plate explants from the proximal tibia of pre-pubertal rats were subjected to static vs dynamic stress-controlled mechanical tests. Stained hypertrophic chondrocytes were tracked before and after mechanical testing with a confocal microscope to derive volumetric, axial and lateral cellular strains. Axial strain in hypertrophic chondrocytes was similar for all groups, supporting the mean applied compressive stress's correlation with bone growth rate and hypertrophic chondrocyte height in past studies. However, static conditions resulted in significantly higher lateral (p<0.001) and volumetric cellular strains (p<=0.015) than dynamic conditions, presumably due to the growth plate's viscoelastic nature. Sustained compression in stress-controlled static loading results in continued time-dependent cellular deformation; conversely, dynamic groups have less volumetric strain because the cyclically varying stress limits time-dependent deformation. Furthermore, high frequency dynamic tests showed significantly lower volumetric strain (p=0.002) than low frequency conditions. Mechanical loading protocols could be translated into treatments to correct or halt progression of bone deformities in children/adolescents. Mimicking physiological stress-controlled dynamic conditions may have beneficial effects at the cellular level as dynamic tests are associated with limited lateral and volumetric cellular deformation. PMID- 28365063 TI - Mechanical response and deformation mechanics of Type IV pili investigated using steered coarse-grained molecular dynamics simulation. AB - Type IV pili are long filamentous structures on the surface of bacteria, which can be rapidly assembled or disassembled with pilin subunits by molecular motors. They can generate force during retraction and are involved in many bacterial functions. Steered molecular dynamics simulations with coarse-grained MARTINI models are carried out to investigate the mechanical behaviors of pili under tension. Our study is the first to report a Young's modulus of 0.80+/-0.07GPa and a spring constant of 1294.6+/-116.5kJmol-1nm-2 for pilus. Our results show the mechanical responses of pili are different from those described by the worm-like chain model and the van der Waal's interactions play a critical role in the mechanical responses. Moreover, the effects of pulling rates and virtual spring constants of pilus on Young's modulus are studied and two distinct morphological stages with the conformational changes appear during the extension of pilus are observed. This work provide insight into the mechanics and the deformation mechanism of pilus assembly. PMID- 28365064 TI - Subject-specific 2D/3D image registration and kinematics-driven musculoskeletal model of the spine. AB - An essential input to the musculoskeletal (MS) trunk models that estimate muscle and spine forces is kinematics of the thorax, pelvis, and lumbar vertebrae. While thorax and pelvis kinematics are usually measured via skin motion capture devices (with inherent errors on the proper identification of the underlying bony landmarks and the relative skin-sensor-bone movements), those of the intervening lumbar vertebrae are commonly approximated at fixed proportions based on the thorax-pelvis kinematics. This study proposes an image-based kinematics measurement approach to drive subject-specific (musculature, geometry, mass, and center of masses) MS models. Kinematics of the thorax, pelvis, and individual lumbar vertebrae as well as disc inclinations, gravity loading, and musculature were all measured via different imaging techniques. The model estimated muscle and lumbar forces in various upright and flexed postures in which kinematics were obtained using upright fluoroscopy via 2D/3D image registration. Predictions of this novel image-kinematics-driven model (Img-KD) were compared with those of the traditional kinematics-driven (T-KD) model in which individual lumbar vertebral rotations were assumed based on thorax-pelvis orientations. Results indicated that while differences between Img-KD and T-KD models remained small for the force in the global muscles (attached to the thoracic cage) (<15%), L4-S1 compression (<15%), and shear (<20%) forces in average for all the simulated tasks, they were relatively larger for the force in the local muscles (attached to the lumbar vertebrae). Assuming that the skin-based measurements of thorax and pelvis kinematics are accurate enough, the T-KD model predictions of spinal forces remain reliable. PMID- 28365065 TI - Infantile hemangiopericytoma of the tongue-Efficacy of ex utero intrapartum treatment procedure and combined-modality therapy. AB - Here we present an extremely rare case of giant infantile hemangiopericytoma (HPC) of the tongue diagnosed prenatally by fetal ultrasonography and MR imaging. Due to airway stenosis, the patient was delivered by the ex utero intrapartum treatment (EXIT) procedure at 36 weeks of pregnancy. Initial diagnosis was infantile hemangioma based on physical examination, diagnostic imaging and the high incidence of hemangioma. The tumor was resistant to conservative treatments. Due to severe tumor hemorrhage, the nutrient vessel was embolized by endovascular treatment on the 73th day after birth. Two days after embolization, a hemiglossectomy was performed. Histological analysis after surgery diagnosed infantile HPC with microscopically positive stumps. After receiving adjuvant chemotherapy, the patient has had no recurrence after 53 months with normal speech and swallowing function resulting in normal growth. Our findings support that infantile HPC is one of the differential diagnosis of infantile hemangioma. The EXIT procedure could be effective for infants with upper respiratory stenosis by head and neck tumor diagnosed prenatally. Though complete resection is required for infantile HPC, our report suggests that a conservative surgical approach followed by adjuvant chemotherapy should be used for giant head and neck infantile HPC. PMID- 28365066 TI - Transcanal endoscopic approach to lesions of the suprageniculate ganglion fossa. AB - OBJECTIVE: The aim of this paper would be to describe the first case series of exclusive transcanal endoscopic approach to treat lesions with limited extension at the suprageniculate fossa. This endoscopic approach allowed a complete removal of suprageniculate disesases with low complication rates using a minimally invasive surgical route. METHODS: This is a retrospective chart analysis and a surgery video recording review of these patients were performed in August 2015. From November 2011 to November 2015, 29 patients were submitted to an endoscopic transcanal lateral skull base surgery. From those 29 subjects, in 6 patients an exclusive endoscopic transcanal suprageniculate approach was performed to remove lesions located into the geniculate fossa. Surgical indications, pre-operative assessment, results were collected and the surgical technique were described. RESULTS: The final study group was composed of 6 patients. 3 male and 3 female; median age is 25.3 years old. In all 6 subjects it was possible to remove the lesions using an exclusive endoscopic transcanal suprageniculate approach. No intraoperaoperative complications were observed in any patients. The mean follow up period was 15.16 months. CONCLUSION: Exclusive endoscopic transcanal suprageniculate approach is definitely a minimally invasive technique and should be consider an optimal solution to treat lesions located in the suprageniculate fossa in some patients. We introduce a minimally invasive approach to the geniculate ganglion region in order to allow complete removal of suprageniculate disesases with low complication rates using a minimally invasive surgical route. PMID- 28365068 TI - The effect of guided imagery on physiological and psychological outcomes of adult ICU patients: A systematic literature review and methodological implications. AB - OBJECTIVES: Guided imagery (GI) is a relaxation technique that is being increasingly explored in various patients' populations. We systematically reviewed evidence on the effects of GI on physiological and psychological outcomes of adult critically ill patients and extracted implications for future research. REVIEW METHOD USED: Systematic literature review of published studies based on the Cochrane Guidelines. DATA SOURCES: Studies were located through literature searches of CINAHL, PubMed, Embase, Cochrane Database of Systematic Reviews and Psych-Info. REVIEW METHODS: We explored effects of GI in critically illness. The outcome measures included pain, anxiety, hemodynamic measurements, stress neuropeptides, length of stay, sleep quality, inflammatory markers, patient satisfaction and cost of care. The Cochrane Collaboration's tool for assessing risk of bias was employed. Extracted data included pathophysiological framework, sample, diagnoses of participants, specifics of intervention, design, experimental groups, analyses and main outcomes. RESULTS: Based on the selection criteria, 10 studies were identified, involving N=1391 critically ill patients. The main limitations include incomplete outcome data and selective reporting, incomplete blinding and lack of experimental group allocation concealment. Due to heterogeneity and incomplete reporting, a meta-analysis was not feasible. Our findings included: (a) favourable effects of the intervention with regard to decrease of pain, anxiety and LOS; (b) many studies employing randomised controlled trial designs; (c) a predominant focus on patients with cardiac surgery; (d) large heterogeneity in measurement of outcomes. Moreover, the evidence suggests that improvements in sleep quality, patient satisfaction and cost of care merit further investigation. Methodological implications include the need to clarify the underlying physiological framework, the use of repeated measure designs and the adjustment for confounders. CONCLUSIONS: On the basis of these results, and of the absence of reported side-effects, we conclude that GI is a promising patient-centered approach for the improvement of a number of patients' outcomes that merits further investigation in critical care. PMID- 28365067 TI - The utility of a phase angle analysis in patients with severe motor and intellectual disabilities. AB - PURPOSE: The purpose of the present study was to evaluate whether evaluating the phase angle (PhA), in a bioelectrical impedance analysis (BIA) is useful for estimating the nutritional status of severe motor and intellectual disabilities (SMID) patients. SUBJECTS AND METHODS: This retrospective study included 31 SMID patients (mean age: 33.9+/-13.5years, median age: 29years (range: 18-58years), male/female: 23/8). First, each of the parameters from the total study population and the male and female SMID patients were compared with those of healthy Asian subjects. Second, correlation analyses were conducted to investigate the correlation between the PhA and the other BIA parameters (appendicular skeletal muscle mass index (ASMI), appendicular muscle mass (AMM), extracellular water (ECW)/total body water (TBW)) as well as subjective global assessment and serum nutritional markers. Finally, all patients were divided into 2 groups according to their albumin (Alb) (<3.5 or >=3.5) values and PhA of the 2 groups were compared. RESULTS: The mean PhA and ASMI were a considerably low, whereas ECW/TBW was considerably high in comparison to the healthy Asian subjects. Significant negative correlations were observed between the PhA and ECW/TBW, whereas there were significant positive correlations between PhA and AMM, ASMI, total protein and albumin levels. Furthermore, PhA of Alb >=3.5 group was significantly higher than that of Alb <3.5 group. CONCLUSIONS: The present study indicated that SMID patients demonstrate the low PhA, which were similar to sarcopenia and a certain proportion of them also potentially have nutritional disturbances. PMID- 28365069 TI - Quality of life and prognostic factors after intra-articular tibial pilon fracture. AB - BACKGROUND: Intra-articular tibial plafond fractures are a challenge for the surgeon with generally poor functional outcomes. The purpose was to assess the impact of this injury on patient quality of life (QOL), as well as analyzed the predictor factors. METHODS: Retrospective study of 47 patients with mean age of 44.4 (range 18-79) years. Patients were also invited for new clinical and radiological assessments. QOL was evaluated by the Short Form-36 questionnaire and compared to the standard in the age-matched general population. Olerud Molander ankle score (OMAS) was used to assess function. Digital radiographs were evaluated for linear and angular measurements. RESULTS: The mean follow-up at last visit was 5.3 (range, 2-10) years. Sequelae were present in 20 patients, mainly including chronic pain (8) and arthrosis (10). Articular step-off at least 2mm was present in 20 patients had, articular gap greater than 2mm in 13, and malalignment in 5. Worse reduction was obtained with external fixation. QOL was significant lower than age-matched general population (p=0.000). Main prognostic factors of worse SF36 were fracture severity, reduction quality and arthrosis. A strong significant relationship was found between SF36-physical and OMAS scores (p=0.000). CONCLUSION: Intra-articular tibial plafond fracture had a dramatic impact on QOL. Among the predictors of unsuccessful outcome, the reduction quality was the only modifiable factor by the surgeon. The OMAS had a predictive value on the prognosis of QOL. PMID- 28365070 TI - Clinical outcome of primary medial collateral ligament-posteromedial corner repair with or without staged anterior cruciate ligament reconstruction. AB - INTRODUCTION: Medial collateral ligament (MCL) is a prime valgus stabilizer of the knee, and MCL tears are currently managed conservatively. However, posteromedial corner (PMC) injury along with MCL tear is not same as isolated MCL tear and the former is more serious injury and requires operative attention. However, literature is scarce about the management and outcome of PMC-MCL tear alongside anterior cruciate ligament (ACL) tear. The purpose of this study is to report the clinical outcome of primary repair of MCL and PMC with or without staged ACL reconstruction. METHODS: A retrospective evaluation was performed on patients with MCL-PMC complex injury with ACL tear who underwent primary repair of MCL-PMC tear followed by rehabilitation. Further, several of them chose to undergo ACL reconstruction whereas rest opted conservative treatment for the ACL tear. A total of 35 patients of two groups [Group 1 (n=15): MCL-PMC repaired and ACL conserved; Group 2 (n=20): MCL-PMC repaired and ACL reconstructed] met the inclusion criteria with a minimum follow-up of two years. Clinical outcome measures included grade of valgus medial opening (0 degrees extension and 30 degrees flexion), Lysholm and International knee documentation committee (IKDC) scores, KT-1000 measurement, subjective feeling of instability, range of motion (ROM) assessment and complications. RESULTS: While comparing group 2 versus group 1, mean Lysholm (94.6 vs. 91.06; p=0.017) and IKDC scores (86.3 vs. 77.6; p=0.011) of group 2 were significantly higher than group 1. 60% patients of group 1 complained of instability against none in the group 2 (p<0.0001). All the knees of both the groups were valgus stable with none requiring late reconstruction. The mean loss of flexion ROM in group 1 and 2 was 12 degrees and 9 degrees respectively which was not statistically different (p=0.41). However while considering the loss of motion, two groups did not show any significant difference in clinical scores. CONCLUSIONS: Primary MCL-PMC repair renders the knee stable in coronal plane in both the groups and further ACL reconstruction adds on to the stability of the knee providing a superior clinical outcome. Minor knee stiffness remains a concern after primary MCL-PMC repair but without any unfavorable clinical effect. PMID- 28365071 TI - Trochanteric entry femoral nails yield better femoral version and lower revision rates-A large cohort multivariate regression analysis. AB - INTRODUCTION: Intramedullary nailing (IMN) has become the standard of care for the treatment of most femoral shaft fractures. Different IMN options include trochanteric and piriformis entry as well as retrograde nails, which may result in varying degrees of femoral rotation. The objective of this study was to analyze postoperative femoral version between three types of nails and to delineate any significant differences in femoral version (DFV) and revision rates. MATERIALS & METHODS: Over a 10-year period, 417 patients underwent IMN of a diaphyseal femur fracture (AO/OTA 32A-C). Of these patients, 316 met inclusion criteria and obtained postoperative computed tomography (CT) scanograms to calculate femoral version and were thus included in the study. In this study, our main outcome measure was the difference in femoral version (DFV) between the uninjured limb and the injured limb. The effect of the following variables on DFV and revision rates were determined via univariate, multivariate, and ordinal regression analyses: gender, age, BMI, ethnicity, mechanism of injury, operative side, open fracture, and table type/position. Statistical significance was set at p<0.05. RESULTS: A total of 316 patients were included. Piriformis entry nails made up the majority (n=141), followed by retrograde (n=108), then trochanteric entry nails (n=67). Univariate regression analysis revealed that a lower BMI was significantly associated with a lower DFV (p=0.006). Controlling for possible covariables, multivariate analysis yielded a significantly lower DFV for trochanteric entry nails than piriformis or retrograde nails (7.9+/-6.10 vs. 9.5+/-7.4 vs. 9.4+/-7.8 degrees , p<0.05). Using revision as an endpoint, trochanteric entry nails also had a significantly lower revision rate, even when controlling for all other variables (p<0.05). CONCLUSION: Comparative, objective comparisons between DFV between different nails based on entry point revealed that trochanteric nails had a significantly lower DFV and a lower revision rate, even after regression analysis. However, this is not to state that the other nail types exhibited abnormal DFV. Translation to the clinical impact of a few degrees of DFV is also unknown. Future studies to more in-depth study the intricacies of femoral version may lead to improved technology in addition to potentially improved clinical outcomes. PMID- 28365072 TI - Does femoral offset recover and affect the functional outcome of patients with displaced femoral neck fracture following hemiarthroplasty? AB - BACKGROUND: Restoring preoperative horizontal femoral offset (FO) promised good functional outcome in patients receiving total hip arthroplasty. However, relatively little was known regarding the clinical relevance of restoring the offset in patients with bipolar hemiarthroplasty to treat displaced femoral neck fracture. Therefore, the objective of this study was to evaluate postoperative FO accurately and verify its relation with functional outcome. METHODS: One hundred elderly patients who received bipolar hemiarthroplasty to treat displaced femoral neck fracture were identified. Preoperative CT scanning of contralateral hip joint and reconstruction of images led to rotation-free FO. By referencing postoperative implant specification and comparing to measured values in Picture Archive and Communication System, rotation-free postoperative FO and the amount of change were acquired. Postoperative Harris Hip Score (HHS) and Modified Barthel Index (MBI) were evaluated to measure functional outcome at 12-month after the surgery. Patients with significant FO change were identified. Multiple regression analysis was conducted to determine if the FO change might independently affect the outcome regardless of confounding factors. RESULTS: The mean preoperative offset was 37.4+/-2.5 increased by 12.7+/-9.6% after the surgery. Only 25.0% of postoperative offset after hemiarthroplasty was changed within +/-5% of preoperative offset. A total of 45.0% of postoperative offset changed within +/-10% while 77.0% of postoperative offset changed within +/-20%. 23% of patients whose FO changed more than 20% showed significantly worse outcome score than the patients whose FO change remained within +/-20% of initial value. Mean MBI and HHS were negatively correlated with FO change. After adjusting for confounding factors, significant correlation remained between modification of FO and MBI, but not between FO change and HHS (B=4.576; beta=0.235; 95% confidence interval of B: 0.534 to 8.135). CONCLUSIONS: FO was not properly restored in 23% of subjects receiving bipolar hemiarthroplasty due to femoral neck fracture. FO restoration independently predicted fair MBI after the surgery. Therefore, surgeons should pay attention to restoring FO with meticulous templating. PMID- 28365073 TI - Different Characteristics of Anterior and Posterior Branch Atheromatous Diseases with or without Early Neurologic Deterioration. AB - BACKGROUND: Among several types of ischemic stroke (IS), branch atheromatous disease (BAD) is known to be the leading cause of disability. METHODS: A total of 1919 patients with acute IS were retrospectively analyzed, and BAD patients were classified into anterior or posterior BAD, depending on the responsible vascular territories. These patients were further subcategorized with or without early neurologic deterioration (END or no-END). RESULTS: Of all IS patients, 14.3% had BAD, and 202 patients (73.7%) were further classified as anterior BAD and 72 patients (26.3%) as posterior BAD. The prevalence of diabetes mellitus and END was significantly higher in posterior than in anterior BAD (44.4% vs 26.4%, P < .01; 18.1% vs 5.4%, P < .01, respectively). Posterior BAD showed a higher proportion of female patients and an older age (69.2% vs 39.0%, P < .05; 79.1 +/- 7.7 vs 70.5 +/- 10.7, P < .01, respectively) in END than in no-END. The modified Rankin Scale was worse in posterior BAD at 90 days (2.5 +/- 1.6, P < .01) than in anterior BAD (1.6 +/- 1.4). CONCLUSIONS: Our present study shows that posterior BAD is a worse clinical outcome than anterior BAD, with more vascular risk factors. Older female patients with posterior BAD showed a higher risk of END, leading to a worse clinical outcome. PMID- 28365074 TI - Ultraviolet-B radiation mobilizes uranium from uranium-dissolved organic carbon complexes in aquatic systems, demonstrated by asymmetrical flow field-flow fractionation. AB - Humic substances have a tendency to form complexes with metal ions in aquatic medium, impacting the metal mobility, decreasing bioavailability and toxicity. Ultraviolet-B (UV-B) radiation exposure degrades the humic substance, changes their molecular weight distribution and their metal binding capacity in aquatic medium. In this study, we experimented the effect of UV-B radiation on the uranium complexed with fulvic acids and humic acids in a soft water system at different pH, uranium concentrations and radiant exposure. The concentration and distribution of uranium in a complexed form were investigated by asymmetrical flow field-flow fractionation coupled to multi detection technique (AsFlFFF-UV ICP-MS). The major concentration of uranium present in complexes was primarily associated with average and higher molecular weight fulvic and humic acids components. The concentration of uranium in a complexed form increased with increasing fulvic and humic acid concentrations as well as pH of the solution. The higher molecular weight fraction of uranium was degraded due to the UV-B exposure, transforming about 50% of the uranium-dissolved organic carbon complexes into low molecular weight uranium species in complex form with organic ligands and/or free form. The result also suggests AsFlFFF-UV-ICP-MS to be an important separation and detection technique for understanding the interaction of radionuclides with dissolved organic matter, tracking size distribution changes during degradation of organic complexes for understanding mobility, bioavailability and ecosystem transfer of radionuclides as well as metals. PMID- 28365075 TI - Determination of endocrine disrupting chemicals and antiretroviral compounds in surface water: A disposable sorptive sampler with comprehensive gas chromatography - Time-of-flight mass spectrometry and large volume injection with ultra-high performance liquid chromatography-tandem mass spectrometry. AB - Many rural dwellers and inhabitants of informal settlements in South Africa are without access to treated water and collect untreated water from rivers and dams for personal use. Endocrine disrupting chemicals (EDCs) have been detected in surface water and wildlife of South Africa. EDCs are often present in complex environmental matrices at ultra-trace levels complicating detection thereof. We report a simplified multi-residue approach for the detection and quantification of EDCs, emerging EDCs, and antiretroviral drugs in surface water. A low cost (less than one US dollar), disposable, sorptive extraction sampler was prepared in-house. The disposable samplers consisted of polydimethylsiloxane (PDMS) tubing fashioned into a loop which was then placed in water samples to concentrate EDCs and emerging pollutants. The PDMS samplers were thermally desorbed directly in the inlet of a GC, thereby eliminating the need for expensive consumable cryogenics. Comprehensive gas chromatography coupled to time-of-flight mass spectrometry (GC*GC-TOFMS) was used for compound separation and identification. Linear retention indices of EDCs and emerging pollutants were determined on a proprietary Crossbond(r) phase Rtx(r)-CLPesticides II GC capillary column. In addition, large volume injection of surface water into an ultra-performance liquid chromatograph tandem mass spectrometer (UPLC-MS/MS) was used as complementary methodology for the detection of less volatile compounds. Large volume injection reduced tedious and costly sample preparation steps. Limits of detection for the GC method ranged from 1 to 98pg/l and for the LC method from 2 to 135ng/l. Known and emerging EDCs such as pharmaceuticals, personal care products and pesticides, as well as the antiretroviral compounds, efavirenz and nevirapine, were detected in surface water from South Africa at concentration levels ranging from 0.16ng/l to 227ng/l. PMID- 28365076 TI - Analysis of linear two-dimensional general rate model for chromatographic columns of cylindrical geometry. AB - This work is concerned with the analytical solutions and moment analysis of a linear two-dimensional general rate model (2D-GRM) describing the transport of a solute through a chromatographic column of cylindrical geometry. Analytical solutions are derived through successive implementation of finite Hankel and Laplace transformations for two different sets of boundary conditions. The process is further analyzed by deriving analytical temporal moments from the Laplace domain solutions. Radial gradients are typically neglected in liquid chromatography studies which are particularly important in the case of non perfect injections. Several test problems of single-solute transport are considered. The derived analytical results are validated against the numerical solutions of a high resolution finite volume scheme. The derived analytical results can play an important role in further development of liquid chromatography. PMID- 28365077 TI - Glass bottle sampling solid phase microextraction gas chromatography mass spectrometry for breath analysis of drug metabolites. AB - Breath analysis is a non-invasive approach which may be applied to disease diagnosis and pharmacokinetic study. In the case of offline analysis, the exhaled gas needs to be collected and the sampling bag is often used as the storage vessel. However, the sampling bag usually releases some extra compounds, which may interfere with the result of the breath test. In this study, a novel breath sampling glass bottle was developed with a syringe needle sampling port for solid phase microextraction (SPME). Such a glass bottle scarcely liberates compounds and can be used to collect exhaled gas for ensuing analysis by gas chromatography mass spectrometry (GC-MS). The glass bottle sampling SPME-GC-MS analysis was carried out to investigate the breath metabolites of myrtol, a multicompound drug normally used in the treatment of bronchitis and sinusitis. Four compounds, alpha pinene, 2,3-dehydro-1,8-cineole, d-limonene and 1,8-cineole were found in the exhaled breath of all eight volunteers who had taken the myrtol. While for other ten subjects who had not used the myrtol, these compounds were undetectable. In the SPME-GC-MS analysis of the headspace of myrtol, three compounds were detected including alpha-pinene, d-limonene and 1,8-cineole. Comparing the results of breath and headspace analysis, it indicates that 2,3-dehydro-1,8-cineole in the breath is the metabolite of 1,8-cineole. It is the first time that this metabolite was identified in human breath. The study demonstrates that the glass bottle sampling SPME-GC-MS method is applicable to exhaled gas analysis including breath metabolites investigation of drugs like myrtol. PMID- 28365078 TI - Macrophage and osteoclast polarization in bisphosphonate associated necrosis and osteoradionecrosis. AB - PURPOSE: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a complication of antiresorptive therapy with nitrogen-containing bisphosphonates (BP). With various suggestions as to pathogenesis, the etiology of BRONJ is not sufficiently understood. Osteoclasts and their precursors, that is, macrophages, are the main target cells of BP. BP can repolarize regeneration- and healing associated M2 macrophages towards the tissue destructive M1-type. The current study aims to elucidate differences in macrophage and osteoclast polarization in BRONJ, osteoradionecrosis (ORN) and healthy control specimens. MATERIALS AND METHODS: A total of 39 jaw bone samples (18 BRONJ, 8 ORN and 13 healthy controls) were processed for immunohistochemistry to detect CD68-, CD11c- and CD163 positive cells. Macrophages and osteoclasts were distinguished on the basis of morphological differences. Samples were digitized, and the macrophage and osteoclast cell counts were quantitatively analyzed. RESULTS: In jaw bone affected by BRONJ, a significantly increased macrophage infiltration and M1 polarization of macrophages can be seen. The density of CD68-expressing osteoclasts is significantly increased in BRONJ specimens compared to ORN and to healthy controls. CONCLUSIONS: A bisphosphonate-derived shift of macrophage polarization towards M1-polarized macrophages might impair bone tissue homeostasis and thus contribute to the pathogenesis of BRONJ. The observed increase in osteoclast density might be caused by BP-induced prolonged osteoclast survival. PMID- 28365079 TI - A lateral cephalometry study of patients with neurofibromatosis type 1. AB - PURPOSE: Neurofibromatosis type 1 (NF1) is an autosomal dominant transmitted tumour suppressor syndrome and also a bone disease. Osseous dysplasia affecting the craniofacial region is characteristic of NF1. The aim of this study was to analyse the lateral cephalograms of NF1 patients in comparison to individuals who were not affected by this condition in order to describe the skeletal phenotype of NF1 in more detail. MATERIALS AND METHODS: The study comprises the lateral cephalograms of 172 patients with established NF1 diagnoses (female = 85, male = 87). NF1 patients were distinguished by radiological and/or histological findings of the facial region suggestive of plexiform neurofibroma (PNF) or disseminated cutaneous NF (DNF). The analysed radiographs of a collection of 29 healthy volunteers with ideal occlusion served as controls. The focus of this analysis was cephalometrically defined angles. RESULTS: Cephalometric analyses of patients with DNF did not differ from those of controls for the vast majority of parameters. However, the measurement results of patients with PNF differed significantly from those of healthy volunteers and patients with DNF. The number of trigeminal nerve branches affected in PNF patients had an effect on the measurement results. CONCLUSION: Lateral cephalograms revealed no significant alteration of the facial skeleton in NF1 patients as compared to controls. Indeed, the stigma of a so-called 'NF1 facies' cannot be derived from the cephalometric findings presented. Notably, a wide range of deviating readings were recorded for individuals with facial PNF. Clinicians who treat patients with NF1 should be aware of deviations from cephalometric standards on lateral cephalograms in NF1 patients, especially when craniofacial surgical procedures are planned. Some of these findings, particularly asymmetries of the facial skeleton, could be indicators of an associated PNF. PMID- 28365080 TI - The CoCoS trial: Caloric Control in Cardiac Surgery patients promotes survival, an interventional trial with retrospective control. AB - BACKGROUND & AIMS: Malnutrition is widespread among cardiac surgery patients and is independently related to an adverse postoperative evolution or outcome. We aimed to assess whether nutrition therapy (NT) could alter caloric deficit, morbidity, and mortality in patients scheduled for non-emergency coronary artery bypass graft (CABG) or aortic valve surgery. METHODS: 351 patients undergoing either elective CABG or aortic valve surgery were studied. Patients receiving NT were enrolled from January 2013 until December 2014. A retrospective control group (CT) consisted of 142 matched patients. The primary endpoint was to evaluate whether NT could limit caloric deficit (Intake to Need Deviation). Secondary endpoints addressed the potential effect of NT on morbidity and mortality. Patients were followed for one year after surgery. RESULTS: There was no significant difference in patient, laboratory or mortality profile between the groups. Caloric deficit could be limited in the intervention group, essentially by providing oral feeding and oral supplements. A minority of patients required enteral or parenteral nutrition during their hospital stay. Caloric deficit increased after the second postoperative day because more patients were switched to oral feeding and intravenous infusions were omitted. Combining CABG and aortic valve surgery, male patients in the NT group had significantly less arrhythmia than in the CT group (7% versus 31%; P = 0.0056), while females in the NT group had significantly less pneumonia than in the CT group (7% versus 22%; P = 0.0183). Survival was significantly higher in female NT patients compared to CT patients, both for CABG (100% versus 83%; P = 0.0015) and aortic valve surgery (97% versus 78%; P = 0.0337). CONCLUSION: The results suggest that NT beneficially affects morbidity and mortality in elective cardiac surgery patients. The impact of NT seems more pronounced in women than in men. Registration: Clinicaltrials.gov: NCT02902341. PMID- 28365081 TI - A possible role for CD26/DPPIV enzyme activity in the regulation of psoriatic pruritus. AB - BACKGROUND: Psoriasis (PSO) is one of the most common chronic inflammatory skin diseases, and pruritus affects approximately 60-90% of patients with PSO. However, the pathogenesis of pruritus in PSO remains unclear. Dipeptidyl peptidase IV (DPPIV) enzyme activity is involved in the regulation of peptide hormones, chemokines and neurotransmitters. OBJECTIVES: Our aim is to evaluate for a potential association between DPPIV and an increased risk of pruritus, and to identify possible underlying treatment targets in affected patients. METHODS: Utilizing clinical serum samples of PSO patients and in vivo experimental pruritus models, we evaluated for a potential association between DPPIV and an increased risk for pruritus, and attempted to identify possible underlying treatment targets in pruritus of PSO. RESULTS: We first showed that levels of DPPIV enzyme activity in sera of patients with PSO were significantly increased compared to those of healthy controls. We next evaluated levels of substance-P (SP), which is a neurotransmitter for pruritus and a substrate for DPPIV enzyme. Truncated form SP cleaved by DPPIV was significantly increased in sera of PSO. In an in vivo pruritus model induced by SP, scratching was decreased by treatment with a DPPIV inhibitor. Moreover, DPPIV-knockout mice showed attenuation of scratching induced by SP. Finally, scratching was decreased following the administration of a DPPIV inhibitor in an imiquimod-induced PSO model. On the other hand, scratching induced by imiquimod was increased in DPPIV overexpressing mice. CONCLUSIONS: These results suggest that inhibition of DPPIV enzyme activity regulates pruritus in PSO. PMID- 28365082 TI - Vascular Psoriasis Area Severity Index: A dermoscopic standard technique for assessing severity psoriasis and therapeutic management. PMID- 28365083 TI - Clinical transition to model-based dose calculation algorithm: A retrospective analysis of high-dose-rate tandem and ring brachytherapy of the cervix. AB - PURPOSE: To retrospectively compare clinical dosimetry of CT-based tandem-ring treatment plans using a model-based dose calculation algorithm (MBDCA) with the standard TG-43-based dose formalism. METHODS AND MATERIALS: A cohort of 10 cervical cancer cohorts treated using the tandem and ring high-dose-rate applicators were evaluated. The original treatment plans were created using the department CT-based volume optimization clinical standards. All plans originally calculated with TG-43 dose calculation formalism were recalculated using the MBDCA algorithm. The gross target volume and organs at risk (OARs) were contoured on each data set along with significant heterogeneities like air in cavity and high-density plastic tandem and ring components. The patient tissue was modeled as homogenous liquid water. D90, D95, and D100 for gross target volume, D0.1cm3, D1.0cm3, and D2.0cm3 for bladder, rectum, and sigmoid were extracted from dose volume histograms for TG-43 and MBDCA calculated plans. Mean absolute difference +/- 2sigma in the above metrics was calculated for each plan. RESULTS: Using the manual applicator contouring method, MBDCA plans (n = 10) showed 2.1 +/- 1.1% reduction in dose to Point A average, 2.6 +/- 0.9% reduction in Target D90 dose, and 2.1 +/- 0.3% dose reduction to OARs. Results from plans using vendor supplied solid applicator models (n = 5) showed 2.2 +/- 1.10% reduction in dose to Point A average, 2.7 +/- 0.2% reduction in Target D90 dose, and 2.7 +/- 1.0% dose reduction on average to OARs. CONCLUSION: For unshielded plastic gynecologic applicators, minimal dosimetric changes (<5%) were found using MBDCA relative to standard TG-43. Use of solid applicator model is more efficient than manual applicator contouring and also yielded similar MBDCA dosimetric results. Currently, TG-186 dose calculations should be reported along TG-43 until we obtain studies with larger cohorts to fully realize the potential of MBDCA dosimetry. PMID- 28365084 TI - Perianal synovial sarcoma treated postoperatively with Iodine-125 brachytherapy: Technical details. AB - PURPOSE: A 23-year-old lady had an incompletely excised perianal sarcoma. Brachytherapy as the sole treatment, rather than further surgery or external beam radiotherapy, was considered to be the best option with the least morbidity. METHODS AND MATERIALS: Although brachytherapy techniques with iridium-192 for anal and rectal carcinoma are well described using a perianal template, the size of the template was not suitable for a two-plane implant that needed to be in situ for about 4 days. An anal canal applicator was designed, which carried three templates about 15 mm apart inside it, to ensure accurate alignment of the tubes, and an inferior template that was 90 mm from the perianal skin. Three inner and three outer tubes of iodine-125 seeds were designed to treat a 2 o'clock h wedge of perianal tissue as a temporary implant. A thin metal shield was placed around a hole to protect the uninvolved anal canal. The tubes were inserted under general anesthetic and delivered a dose of 59 Gy at 0.8 Gy/h over 75 h. A spinal anesthetic was maintained for the duration of the insertion. RESULTS: The treatment was well tolerated, and the patient is well and clear of disease 6 years later with minimal morbidity. CONCLUSIONS: Iodine-125 is a low-energy isotope, readily available in our unit, that can be easily screened to reduce morbidity to surrounding normal tissues. In the form of seeds, it provides a flexible system that can be adapted to different tumor sites as required, as illustrated in this case. PMID- 28365085 TI - Authors' response. PMID- 28365086 TI - Synthesis and hyperpolarisation of eNOS substrates for quantification of NO production by 1H NMR spectroscopy. AB - Hyperpolarization enhances the intensity of the NMR signals of a molecule, whose in vivo metabolic fate can be monitored by MRI with higher sensitivity. SABRE is a hyperpolarization technique that could potentially be used to image nitric oxide (NO) production in vivo. This would be very important, because NO dysregulation is involved in several pathologies, including cardiovascular ones. The nitric oxide synthase (NOS) pathway leads to NO production via conversion of l-arginine into l-citrulline. NO is a free radical gas with a short half-life in vivo (~5s), therefore direct NO quantification is challenging. An indirect method - based on quantifying conversion of an l-Arg- to l-Cit-derivative by 1H NMR spectroscopy - is herein proposed. A small library of pyridyl containing l-Arg derivatives was designed and synthesised. In vitro tests showed that compounds 4a j and 11a-c were better or equivalent substrates for the eNOS enzyme (NO2- production=19-46MUM) than native l-Arg (NO2- production=25MUM). Enzymatic conversion of l-Arg to l-Cit derivatives could be monitored by 1H NMR. The maximum hyperpolarization achieved by SABRE reached 870-fold NMR signal enhancement, which opens up exciting future perspectives of using these molecules as hyperpolarized MRI tracers in vivo. PMID- 28365087 TI - Salivary Prostaglandin E2: Role in Tick-Induced Allergy to Red Meat. AB - Tick-induced allergy to red meat is associated with anti-alpha-Gal IgE antibody levels. We propose that tick salivary prostaglandin E2 triggers antibody class switching in mature B cells, increasing the levels of anti-alpha-Gal IgE antibodies. Immune tolerance to alpha-Gal in blood type B individuals might reduce the risk to this allergy. PMID- 28365088 TI - Heavy Drinking in Young Adulthood Increases Risk of Transitioning to Obesity. AB - INTRODUCTION: Heavy episodic alcohol use during young adulthood may contribute to excess weight gain and transition from healthy weight to overweight/obesity. This study is the first to evaluate the association between heavy episodic drinking during early adulthood and transition to overweight/obese status 5 years later using data from the U.S. National Longitudinal Study of Adolescent to Adult Health. METHODS: The study used data from Waves III and IV, when participants were aged 18-26 and 24-32 years, respectively. The final sample consisted of 7,941 participants with measured height/weight who reported ever drinking alcohol. Multinomial logistic regression models tested the association between heavy episodic drinking and risk of transitioning to an unhealthy weight class. RESULTS: Heavy episodic drinking was associated with 41% higher risk of transitioning from normal weight to overweight (relative risk ratio, 1.41; 95% CI=1.13, 1.74; p=0.002) and 36% higher risk of transitioning from overweight to obese by Wave IV (relative risk ratio, 1.36; 95% CI=1.09, 1.71; p=0.008), compared with individuals not drinking heavily, while accounting for covariates. Heavy episodic drinking was associated with 35% higher risk of maintaining obesity (relative risk ratio, 1.35; CI=1.06, 1.72; p=0.016) and gaining excess weight (OR=1.20, 95% CI=1.03, 1.39, p=0.02). CONCLUSIONS: Regular heavy episodic drinking in young adulthood is associated with higher risk of gaining excess weight and transitioning to overweight/obesity. Obesity prevention efforts should address heavy drinking as it relates to caloric content and risk of transitioning to an unhealthy weight class. PMID- 28365089 TI - Dietary and Physical Activity Counseling Trends in U.S. Children, 2002-2011. AB - INTRODUCTION: In 2007 and 2010, Expert Committee and U.S. Preventive Services Task Force guidelines were released, respectively, urging U.S. practitioners to deliver preventive obesity counseling for children. This study determined the frequency and evaluated predictors of receiving counseling for diet and physical activity among a national sample of children from 2002 to 2011. METHODS: Children aged 6-17 years were used from the 2002-2011 Medical Expenditure Panel Surveys and analyzed in 2016. Parental report of two questions assessed whether children received both dietary and exercise counseling from the provider. Children were grouped by weight category. Bivariate analyses compared the frequency of receiving counseling; logistic regression evaluated predictors of receiving counseling. RESULTS: The sample included 36,114 children; <50% of children received counseling. Across all time periods, children were more likely to receive counseling with increasing weight. Logistic regression models showed that obese children had greater odds of receiving counseling versus normal-weight children, even after adjusting for covariates. Additional significant positive correlates of receiving counseling were Hispanic ethnicity, living in an urban setting, and being in the highest income stratum. Being uninsured was associated with lower odds of counseling. Years 2007-2009 and 2010-2011 were associated with increased counseling versus the benchmark year category in the multivariable model. CONCLUSIONS: Counseling appears more likely with greater weight and increased after both guidelines in 2007 and 2010. Overall counseling rates for children remain low. Future work should focus on marginalized groups, such as racial and ethnic minorities and rural populations. PMID- 28365092 TI - Cardiac injury after convulsive status epilepticus in children. AB - OBJECTIVE: Convulsive status epilepticus (CSE) is a medical emergency with high mortality that usually occurs within 30 days following the seizure activity. One of the potential mechanisms contributing to mortality in this period following CSE is cardiac injury. The aim of the present study was to evaluate cardiac injury after CSE in children. PATIENTS AND METHODS: Sixty children presented with CSE were enrolled in this study. Thirty healthy children with matched age and sex were taken as a control. Electrocardiogram (ECG), echocardiographic examinations, plasma concentration of cardiac troponin I (cTnI) and brain-type natriuretic peptide (BNP) were done 6 h after control of seizure for patients and control groups. RESULTS: Thirty three patients were presented with CSE for the first time. ECG changes were present in 55% of patients with CSE in the form of conduction abnormalities, ischemic changes, and arrhythmias. Echocardiographic examinations revealed a significant increase in left ventricular end-diastolic dimension (LVEDD) and left ventricular end systolic dimension (LVESD) in patients with CSE than control group. Moreover, a significant decrease in LV systolic function and RV diastolic function were detected by tissue Doppler. The mean plasma concentrations of BNP and cTnI were significantly higher in patients with CSE than the control group (p value < 0.001). The overall mortality in our study was 8.3% (5/60); four of them had ECG changes. There was significant increase in duration of CSE, length of intensive care and hospital admission in CSE patients with ECG changes than those without ECG changes with p values 0.001, 0.031 and <0.001 respectively. CONCLUSION: Cardiac injury in convulsive SE is common and may be under recognized. So, cardiac assessment should be a routine step in CSE patients' management. PMID- 28365091 TI - Return to work after trauma: A survival analysis. AB - PURPOSE: To evaluate the return to work (RTW) rate, time and predictors among trauma patients using survival analysis. METHODS: This cohort study was conducted with a three-month follow-up on 300 trauma patients hospitalized in Shahid Beheshti Hospital, Kashan, Iran in 2014. The data were collected through conducting interviews and referring to patients' medical records during their hospital stay and follow-up information at one & three months after discharge from hospital. Final analysis was conducted on the data retrieved from 273 patients. Data were analyzed by chi-square test, Mann-Whitney U test and survival analysis method. RESULTS: The rate of RTW at the end of the first and the third follow-up months was respectively 21.6% and 61.2%. Survival analysis showed that the RTW time (Time between admission to first return to work) was significantly longer among patients with illiteracy, drug abuse, hospitalization history in the intensive care unit, low socioeconomic status, non-insurance coverage, longer hospital stay, multiple and severe injuries as well as severe disability. CONCLUSION: Our findings indicated that trauma has profound effects on the rate and time of RTW. Besides disability, many personal and clinical factors can affect the outcome of RTW. PMID- 28365090 TI - Smoking-Cessation Assistance: Before and After Stage 1 Meaningful Use Implementation. AB - INTRODUCTION: Brief smoking-cessation interventions in primary care settings are effective, but delivery of these services remains low. The Centers for Medicare and Medicaid Services' Meaningful Use (MU) of Electronic Health Record (EHR) Incentive Program could increase rates of smoking assessment and cessation assistance among vulnerable populations. This study examined whether smoking status assessment, cessation assistance, and odds of being a current smoker changed after Stage 1 MU implementation. METHODS: EHR data were extracted from 26 community health centers with an EHR in place by June 15, 2009. AORs were computed for each binary outcome (smoking status assessment, counseling given, smoking-cessation medications ordered/discussed, current smoking status), comparing 2010 (pre-MU), 2012 (MU preparation), and 2014 (MU fully implemented) for pregnant and non-pregnant patients. RESULTS: Non-pregnant patients had decreased odds of current smoking over time; odds for all other outcomes increased except for medication orders from 2010 to 2012. Among pregnant patients, odds of assessment and counseling increased across all years. Odds of discussing or ordering of cessation medications increased from 2010 compared with the other 2 study years; however, medication orders alone did not change over time, and current smoking only decreased from 2010 to 2012. Compared with non pregnant patients, a lower percentage of pregnant patients were provided counseling. CONCLUSIONS: Findings suggest that incentives for MU of EHRs increase the odds of smoking assessment and cessation assistance, which could lead to decreased smoking rates among vulnerable populations. Continued efforts for provision of cessation assistance among pregnant patients is warranted. PMID- 28365094 TI - High-temperature ethanol production using thermotolerant yeast newly isolated from Greater Mekong Subregion. AB - The application of high-potential thermotolerant yeasts is a key factor for successful ethanol production at high temperatures. Two hundred and thirty-four yeast isolates from Greater Mekong Subregion (GMS) countries, i.e., Thailand, The Lao People's Democratic Republic (Lao PDR) and Vietnam were obtained. Five thermotolerant yeasts, designated Saccharomyces cerevisiae KKU-VN8, KKU-VN20, and KKU-VN27, Pichia kudriavzevii KKU-TH33 and P. kudriavzevii KKU-TH43, demonstrated high temperature and ethanol tolerance levels up to 45 degrees C and 13% (v/v), respectively. All five strains produced higher ethanol concentrations and exhibited greater productivities and yields than the industrial strain S. cerevisiae TISTR5606 during high-temperature fermentation at 40 degrees C and 43 degrees C. S. cerevisiae KKU-VN8 demonstrated the best performance for ethanol production from glucose at 37 degrees C with an ethanol concentration of 72.69g/L, a productivity of 1.59g/L/h and a theoretical ethanol yield of 86.27%. The optimal conditions for ethanol production of S. cerevisiae KKU-VN8 from sweet sorghum juice (SSJ) at 40 degrees C were achieved using the Box-Behnken experimental design (BBD). The maximal ethanol concentration obtained during fermentation was 89.32g/L, with a productivity of 2.48g/L/h and a theoretical ethanol yield of 96.32%. Thus, the newly isolated thermotolerant S. cerevisiae KKU-VN8 exhibits a great potential for commercial-scale ethanol production in the future. PMID- 28365093 TI - Cardiac Fibroblast Activation Post-Myocardial Infarction: Current Knowledge Gaps. AB - In response to myocardial infarction (MI), the wound healing response of the left ventricle (LV) comprises overlapping inflammatory, proliferative, and maturation phases, and the cardiac fibroblast is a key cell type involved in each phase. It has recently been appreciated that, early post-MI, fibroblasts transform to a proinflammatory phenotype and secrete cytokines and chemokines as well as matrix metalloproteinases (MMPs). Later post-MI, fibroblasts are activated to anti inflammatory and proreparative phenotypes and generate anti-inflammatory and proangiogenic factors and extracellular matrix (ECM) components that form the infarct scar. Additional studies are needed to systematically examine how fibroblast activation shifts over the timeframe of the MI response and how modulation at different activation stages could alter wound healing and LV remodeling in distinct ways. This review summarizes current fibroblast knowledge as the foundation for a discussion of existing knowledge gaps. PMID- 28365096 TI - Preventing Bad and Expensive Things From Happening by Taking the Healthy Living Polypill: Everyone Needs This Medicine. PMID- 28365095 TI - Human leptospirosis: occurrence of serovars of Leptospira spp. in the state of Minas Gerais, Brazil, from 2008 to 2012. AB - BACKGROUND: Leptospirosis is an infectious and acute disease caused by Leptospira spp. that have high epidemic potential. This study verified the main Leptospira spp. serovars detected by MAT from serum of patients with suspicion of leptospirosis from 2008 to 2012 in Minas Gerais State. METHODS: The laboratory received sera from 4654 patients. All serum were screened by IgM-ELISA according to the manufacturer's instructions. Each sample reactive or indeterminate were tested against twenty-four serovars of Leptospira by MAT. RESULTS: In this study, 597 patients were classified as reactive on MAT. Only 301 patients were confirmed by laboratory test. It was not possible confirmation by laboratory diagnosis of 296 patients. Among the samples classified as reactive on MAT, 273 patients exhibited titers bigger than 800 for one or more serovars; seroconversion was detected in 28 cases. Percentage of 85.1% of the samples reactive on MAT corresponded to males, 39.4% corresponded to patients aged between 20 and 39 years old. The most common serovars found were Icterohaemorrhagiae, Andamana, Patoc, Tarassovi, Copenhageni, Hardjo and Australis. Concerning the samples that exhibited titers bigger than 800, serovar Icterohaemorrhagiae was also the most common, followed by Copenhageni, Andamana, Patoc, Tarassovi, Grippotyphosa and Canicola. In this study, 40% of the cases occurred to the metropolitan area, state capital and 34 neighboring towns. CONCLUSION: Our results show the possibly spreading serovars in Minas Gerais State and contribute to knowledge of human leptospirosis, aiming at improving the prevention, control of the disease, as well as the treatment of infected patients. PMID- 28365097 TI - Skilled Nursing Facility Use and Hospitalizations in Heart Failure: A Community Linkage Study. AB - OBJECTIVES: To examine the effect of skilled nursing facility (SNF) use on hospitalizations in patients with heart failure (HF) and to examine predictors of hospitalization in patients with HF admitted to a SNF. PATIENTS AND METHODS: Olmsted County, Minnesota, residents with first-ever HF from January 1, 2000, through December 31, 2010, were identified, and clinical data were linked to SNF utilization data from the Centers for Medicare and Medicaid Services. Andersen Gill models were used to determine the association between SNF use and hospitalizations and to determine predictors of hospitalization. RESULTS: Of 1498 patients with incident HF (mean +/- SD age, 75+/-14 years; 45% male), 605 (40.4%) were admitted to a SNF after HF diagnosis (median follow-up, 3.6 years; range, 0 13.0 years). Of those with a SNF admission, 225 (37%) had 2 or more admissions. After adjustment for age, sex, ejection fraction, and comorbidities, SNF use was associated with a 50% increased risk of hospitalization compared with no SNF use (adjusted hazard ratio, 1.52; 95% CI, 1.31-1.76). In SNF users, arrhythmia, asthma, chronic kidney disease, and the number of activities of daily living requiring assistance were independently associated with an increased risk of hospitalization. CONCLUSION: Approximately 40% of patients with HF were admitted to a SNF at some point after diagnosis. Compared with SNF nonusers, SNF users were more likely to be hospitalized. Characteristics associated with hospitalization in SNF users were mostly noncardiovascular, including reduced ability to perform activities of daily living. These findings underscore the effect of physical functioning on hospitalizations in patients with HF in SNFs and the importance of strategies to improve physical functioning. PMID- 28365098 TI - Relationship Between Cardiac Rehabilitation Participation and Health Service Expenditures Within a Universal Health Care System. AB - OBJECTIVES: To examine the relationship between cardiac rehabilitation participation and health service expenditures in Ontario, Canada. PATIENTS AND METHODS: A total of 6284 patients referred to cardiac rehabilitation between April 1, 2003, and December 31, 2010, were linked to 6284 matched cardiac rehabilitation eligible nonreferred controls and followed over a 3-year period across multiple linked administrative databases to identify health service utilization expenditures and mortality. All patients had previous cardiac hospitalizations within the preceding year. Four cardiac rehabilitation eligible groups of patients were balanced using propensity score weights: (1) no referral; (2) no participation; (3) low participation levels (ie, attending <67% of prescheduled classes); and (4) high participation levels (ie, attending >=67% prescheduled classes). Each group of patients was balanced in age, sex, geography, socioeconomic status, previous hospitalizations, ambulatory care conditions, cardiovascular risk factors, comorbidities, and previous health care expenditures. Generalized linear models were used to examine differences in health service expenditures (from all sources including hospitalizations, physician visits, diagnostic tests, and drugs for those older than 65 years) per "eligible day alive" over the 3-year period. RESULTS: Compared with the nonreferred population, health service expenditures followed a dose-response relationship and were lowest in patients who had the highest cardiac rehabilitation programmatic participation levels (P<.001). Cost differences across groups separated early, remained divergent, and applied to all components of health care expenditures (P<.001). Sensitivity analyses confirmed that the findings were not secondary to reverse causality. CONCLUSION: Participation in cardiac rehabilitation is associated with lower long-term health service utilization expenditures within a publicly funded health care system. PMID- 28365099 TI - Favorable Cardiovascular Health Is Associated With Lower Health Care Expenditures and Resource Utilization in a Large US Employee Population: The Baptist Health South Florida Employee Study. AB - OBJECTIVE: To examine the association of favorable cardiovascular health (CVH) status with 1-year health care expenditures and resource utilization in a large health care employee population. PARTICIPANTS AND METHODS: Employees of Baptist Health South Florida participated in a health risk assessment from January 1 through September 30, 2014. Information on dietary patterns, physical activity, blood pressure, blood glucose level, total cholesterol level, and smoking were collected. Participants were categorized into CVH profiles using the American Heart Association's ideal CVH construct as optimal (6-7 metrics), moderate (3-5 metrics), and low (0-2 metrics). Two-part econometric models were used to analyze health care expenditures. RESULTS: Of 9097 participants (mean +/- SD age, 42.7+/ 12.1 years), 1054 (11.6%) had optimal, 6945 (76.3%) had moderate, and 1098 (12.1%) had low CVH profiles. The mean annual health care expenditures among those with a low CVH profile was $10,104 (95% CI, $8633-$11,576) compared with $5824 (95% CI, $5485-$6164) and $4282 (95% CI, $3639-$4926) in employees with moderate and optimal CVH profiles, respectively. In adjusted analyses, persons with optimal and moderate CVH had a $2021 (95% CI, -$3241 to -$801) and $940 (95% CI, -$1560 to $80) lower mean expenditure, respectively, than those with low CVH. This trend remained even after adjusting for demographic characteristics and comorbid conditions as well as across all demographic subgroups. Similarly, health care resource utilization was significantly lower in those with optimal CVH profiles compared with those with moderate or low CVH profiles. CONCLUSION: Favorable CVH profile is associated with significantly lower total medical expenditures and health care utilization in a large, young, ethnically diverse, and fully insured employee population. PMID- 28365102 TI - 2016 Section on Surgery annual meeting: AAP National Conference & Exhibition. PMID- 28365101 TI - Respiratory function after esophageal replacement in children. AB - BACKGROUND: Children born with esophageal atresia require an anastomosis between the proximal and distal esophagus. When this distance is too wide (long gap esophageal atresia, LGEA) esophageal replacement strategies have to be deployed. The aim of this study was to assess long-term respiratory morbidity and lung function after esophageal replacement with either stomach (gastric pull-up, GPU) or jejunum (jejunal interposition, JI) for LGEA. METHODS: Retrospective cohort study. Patients operated with GPU and JI for LGEA (1985-2007) underwent a semi structured interview and lung function testing (LFT). RESULTS: Seven GPU-patients and eight JI-patients were included. Median age was 12years. One patient per group could not perform LFT. Respiratory symptoms were reported by 13/15 patients (7/7 GPU-patients vs 6/8 JI-patients). All LFT items were lower than reference values; 6/13 patients showed restriction and 6/13 obstruction. All six GPU patients had abnormal TLC and/or FEV1/FVC vs 3/7 after JI. Restriction was noted in 4/6 GPU-patients vs 2/7 JI-patients. CONCLUSION: After esophageal replacement for LGEA many children have impaired lung function and respiratory symptoms are common. Lung volumes seem decreased after GPU compared to JI. This may be caused by the intrathoracic stomach which may limit normal lung growth. Respiratory follow-up in adult life is important after esophageal replacement. LEVEL OF EVIDENCE: III. PMID- 28365100 TI - Cardiac Rehabilitation for Women: A Systematic Review of Barriers and Solutions. AB - Cardiac rehabilitation (CR) services improve various clinical outcomes in patients with cardiovascular disease, but such services are underutilized, particularly in women. The aim of this study was to identify evidence-based barriers and solutions for CR participation in women. A literature search was carried out using PubMed, EMBASE, Cochrane, OVID/Medline, and CINAHL to identify studies that have assessed barriers and/or solutions to CR participation. Titles and abstracts were screened, and then the full-text of articles that met study criteria were reviewed. We identified 24 studies that studied barriers to CR participation in women and 31 studies that assessed the impact of various interventions to improve CR referral, enrollment, and/or completion of CR in women. Patient-level barriers included lower education level, multiple comorbid conditions, non-English native language, lack of social support, and high burden of family responsibilities. We found support for the use of automatic referral and assisted enrollment to improve CR participation. A small number of studies suggest that incentive-based strategies, as well as home-based programs, may contribute to improving CR attendance and completion rates. A systematic approach to CR referral, including automatic CR referral, may help overcome barriers to CR referral in women and should be implemented in clinical practice. However, more studies are needed to help identify the best methods to improve CR attendance and completion of CR rates in women. PMID- 28365103 TI - Race and outcomes in gastroschisis repair: a nationwide analysis. AB - BACKGROUND: The incidence of gastroschisis has increased 30% between the periods 1995-2005 and 2006-2012, with the largest increase in Black neonates born to Black mothers younger than 20years old. OBJECTIVE: Racial disparities in peri- and post-operative outcomes have been previously identified in several types of adult and pediatric surgical patients. Is there an association between race and clinical outcomes and healthcare resource utilization in neonates with gastroschisis? METHODS: Retrospective study using national administrative data from the Kid's Inpatient Database (KID) from 2006, 2009, and 2012 for neonates (age<28days) with gastroschisis. Multivariable logistic regression was constructed to determine the association of race and socioeconomic characteristics with complications and mortality; linear regression was used for length of stay and hospital charges. RESULTS: We identified 3846 neonates with gastroschisis that underwent surgical repair, including 676 patients with complex gastroschisis. When controlling for birth weight, payer status, socioeconomic status, and hospital characteristics, Black neonates had increased odds of having complex gastroschisis and associated atresias. Mortality was higher in patients with complex gastroschisis, patients from the lowest income quartiles, and patients with Medicaid as primary payer (compared to those with private insurance). Length of stay (LOS) was increased in patients with complex gastroschisis, birth weight <2500g, and Medicaid patients. Hospital charges were higher in complex gastroschisis, Black and Hispanic neonates (as compared to Whites), males, birth weight <2500g, and Medicaid patients. CONCLUSIONS: There is an association between race and complex gastroschisis, associated intestinal atresias, and total charges in neonates with gastroschisis. In addition, income status is associated with mortality and hospital charges while payer status is associated with complications, mortality, LOS, and hospital charges. Public health and prenatal interventions should target at-risk populations to improve clinical outcomes. PROGNOSIS STUDY: Level of Evidence: II. PMID- 28365104 TI - Can we safely decrease intensive care unit admissions for children with high grade isolated solid organ injuries? Using the shock index, pediatric age adjusted and hematocrit to modify APSA admission guidelines. AB - BACKGROUND: In 2000, the American Pediatric Surgical Association (APSA) disseminated consensus practice guidelines for the management of blunt liver and splenic injury which included intensive care unit (ICU) admission for children with grade IV injuries. We sought to determine if we could better predict which children with isolated solid organ injuries (SOI) underwent an ICU-level intervention, thus necessitating ICU admission. METHODS: Children with isolated liver, spleen, or kidney injuries admitted to the ICU from November 2003 to August 2015 were identified in our trauma registry, and data were extracted from the medical record. ICU-level interventions were defined as transfusion, vasopressor use, intubation, and operative/procedural intervention. Shock index and pediatric age-adjusted (SIPA) was calculated for all patients. The sensitivity and negative predictive values (NPV) were determined. RESULTS: 133 children met inclusion criteria. 19 (14.3%) required ICU-level intervention, and 114 (85.1%) did not. 95% (n=18) of the intervention group had either an elevated SIPA or a hematocrit <30% on admission compared to 22% (n=25) of patients in the no intervention group. Sensitivity was 95%, and NPV was 99%. CONCLUSIONS: Limiting ICU admission in children with isolated SOI to those with an elevated SIPA or hematocrit <30% would reduce the ICU admission rate by two-thirds while maintaining patient safety. TYPE OF STUDY: Diagnostic study. LEVEL OF EVIDENCE: III. PMID- 28365105 TI - Helmet under-utilization by children during equestrian events is associated with increased traumatic brain injury. AB - PURPOSE: Awareness of equestrian related injury remains limited. Studies evaluating children after equestrian injury report under-utilization of safety equipment and rates of operative intervention as high as 33%. METHODS: We hypothesized that helmets are underutilized during equestrian activity and lack of use is associated with increased traumatic brain injury. We queried the trauma database of a level one pediatric trauma center for all cases of equestrian and rodeo related injury from 2005 to 2015. Analysis was conducted using SAS 9.4. RESULTS: Of 312 children identified, 142 were assessed for use of a helmet. Only 28 children (19.7%) had documented use of a helmet. Most injuries occurred while riding a horse (83%) or bull (13%) with traumatic brain injury being the most common injury (51%). Helmet use was associated with decreased ISS (7.1 vs. 11.3, p<0.01), TBI (32.4% vs. 55.3%, p=0.03), and ICU admission (10.7% vs. 29%, p=0.05). Multivariable analysis reveals lack of helmet use to be an independent predictor of TBI (OR 2.5, 95% CI 1.1-6.3). CONCLUSION: Helmets are underutilized by children during equestrian related activity. Increased awareness of TBI and education encouraging helmet use may decrease morbidity associated with equestrian activities. LEVEL OF EVIDENCE: Retrospective comparative study, Level III. PMID- 28365106 TI - Nephron-sparing surgery in the treatment of pediatric renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusions. AB - PURPOSE: To investigate the safety and efficacy of nephron-sparing surgery (NSS) in the treatment of pediatric Xp11.2 translocation renal cell carcinoma (RCC). METHODS: Clinical characteristics of 9 RCC children (7 males and 2 females) with Xp11.2 translocation who received NSS between January 1973 and December 2015 were retrospectively analyzed. The mean age was 7.8years (range: 4.5-13.5years). Xp11.2 translocation RCC was found in the left side in 4 patients and right in 5. 3 tumors were located in the upper pole of the kidney, 1 in the middle dorsal, 1 in the middle ventral and 4 in the lower pole. RCC presented with painless gross hematuria in 4 patients, abdominal mass in 1, and as an incidental finding by ultrasound examination in 4 patients. The mean course of hematuria was 3months (range: 1-7months). The mean tumor diameters were 3.7cm (range: 2.2-6.9cm). RESULTS: All the patients received NSS with open transperitoneal approach. The mean operative time and estimated blood loss were 115min and 40ml, respectively. The time of renal pedicle clamping was 19-25min (mean: 21.5min). No complications (such as leakage of urine, prolonged drainage or secondary bleeding) were noted. No patients experienced local recurrence during the mean of 50.1-month follow-up (range: 13-117months). Intravenous urography (IVU) or contrast-enhanced CT was conducted at 6months after surgery which showed favorable kidney function in all patients. CONCLUSION: Xp11.2 translocation RCC is a predominant pathological but biologically inert type of pediatric RCC. For Xp11.2 translocation RCC sized <4 7cm in diameter and located in one pole, NSS is safe and feasible. TYPE OF STUDY: Treatment Studies, LEVEL IV. PMID- 28365107 TI - Recurrent and acquired tracheoesophageal fistulae (TEF)-Minimally invasive management. AB - OBJECTIVE: Recurrent and acquired fistulae are a serious complication of congenital esophageal atresia and tracheoesophageal fistula (TEF) repair and foreign body ingestion (FBI) (e.g., button battery). We report our experience with a minimally invasive approach to recurrent and acquired TEF. METHODS: Medical records of patients referred for management of recurrent and acquired TEF between 2003 and 2015 were reviewed retrospectively. Patients underwent endoscopic procedures (de-epithelization of fistulous tract and fibrin tissue adhesive-TisseelR) under general anesthesia. RESULTS: Nine children (7 male, 2 female) with age range 3months to 3years (mean 1.5year) were managed. TEF closed spontaneously in four patients, whereas in 5 patients the TEF closed after combined endoscopic procedure. Three patients required repeat endoscopic procedures. Follow-up ranged between 7months to 10years (mean 4.2years). CONCLUSIONS: Active observation and repeat combined endoscopic procedures are safe alternatives to open surgical repair of acquired and recurrent TEF. LEVEL OF EVIDENCE: Level IV study. PMID- 28365108 TI - Hybrid interventions for catheter placement in pediatric intestinal rehabilitation patients with end-stage venous access. AB - PURPOSE: The purpose of this study is to analyze the combined approach of endovascular and open surgical procedures for insertion of permanent central venous catheters in children with intestinal failure and end-stage venous access. METHODS: Data of 14 children (16 interventions) with intestinal failure and end stage venous access, treated within the pediatric intestinal rehabilitation program at our institution between September 2011 and November 2016, were retrospectively reviewed. The patients underwent hybrid endovascular/open surgical approaches for insertion of central venous catheters. Access to central veins was established through endovascular intervention; catheter placement was achieved with combined interventional and surgical measures depending on the individual vascular conditions. RESULTS: Median age at intervention was 47months (interquartile range (IQR),29-74), median time for interventions was 66min (IQR,42-111). Catheter placement was successfully achieved in all patients. The median dose of irradiation during angiography was 0.2Gy*cm2 (IQR, 0.2-0.6), no complications occurred during or after interventions. CONCLUSIONS: Hybrid endovascular/open surgical procedures can be successfully applied for restoring or maintaining permanent central venous catheters in children with intestinal failure and end-stage venous access. These approaches are a valuable contribution in intestinal rehabilitation programs contributing to a further decrease of the need for intestinal transplantation in affected patients. TYPE OF STUDY: Treatment Study. LEVEL OF EVIDENCE: Level IV. PMID- 28365109 TI - Pushing the boundaries of ECLS: Outcomes in <34 week EGA neonates. AB - PURPOSE: Extracorporeal life support (ECLS) is usually reserved for infants >=34weeks estimated gestational age (EGA) owing to concerns about increased mortality and incidence of intracranial hemorrhage (ICH). We sought to characterize survival, rates of ICH, and complications in <34week EGA neonates placed on ECLS. METHODS: 752 neonates of EGA 29-34weeks were identified in the Extracorporeal Life Support Organization (ELSO) Registry (1976-2008). Data analyzed included birthweight, survival, pre-ECLS conditions, ventilatory parameters and complications (including ICH and other neurological outcomes). Data were compared using t-test, Chi-square and logistic regression analyses. RESULTS: When compared to survival rates of 34week EGA neonates (58%), survival was statistically different for 29-33week EGA (48%, p=0.05). No significant difference in ICH incidence was seen between the 29-33week and 34week groups (21% vs. 17%, respectively), but a significant difference was seen in the incidence of cerebral infarct between groups (22% for 29-33weeks vs. 16% for 34weeks; p=0.03). ICH and survival did not correlate with EGA during logistic regression analysis. CONCLUSIONS: Though rates of survival and cerebral infarction were worse at 29 33weeks EGA compared with 34weeks, these differences were modest and may be clinically acceptable. This suggests that EGA<34weeks may not be an absolute contraindication to use of ECLS. LEVEL OF EVIDENCE: III. PMID- 28365110 TI - Added dietary sulfur and molybdenum has a greater influence on hepatic copper concentration, intake, and performance in Holstein-Friesian dairy cows offered a grass silage-rather than corn silage-based diet. AB - To test the hypothesis that the metabolism of Cu in dairy cows is affected by basal forage and added S and Mo, 56 dairy cows that were 35 (standard error +/- 2.2) days postcalving and yielding 38.9 kg of milk/d (standard error +/- 0.91) were offered 1 of 4 diets in a 2 * 2 factorial design for a 14-wk period. The 4 diets contained approximately 20 mg of Cu/kg of dry matter (DM), and had a corn silage-to-grass silage ratio of 0.75:0.25 (C) or 0.25:0.75 (G) and were either unsupplemented (-) or supplemented (+) with an additional 2 g of S/kg of DM and 6.5 mg of Mo/kg of DM. We found an interaction between forage source and added S and Mo on DM intake, with cows offered G+ having a 2.1 kg of DM lower intake than those offered G-, but no effect on the corn silage-based diets. Mean milk yield was 38.9 kg/d and we observed an interaction between basal forage and added S and Mo, with yield being decreased in cows offered G+ but increased on C+. No effect of dietary treatment on milk composition or live weight was noted, but body condition was lower in cows fed added S and Mo irrespective of forage source. We found an interaction between forage source and added S and Mo on milk somatic cell count, which was higher in cows offered G+ compared with G-, but not in cows fed the corn silage-based diets, although all values were low (mean values of 1.72, 1.50, 1.39, and 1.67 log10/mL for C-, C+, G-, and G+, respectively). Mean plasma Cu, Fe, and Mn concentrations were 13.8, 41.3, and 0.25 umol/L, respectively, and were not affected by dietary treatment, whereas plasma Mo was 0.2 umol/L higher in cows receiving added S and Mo. The addition of dietary S and Mo decreased liver Cu balance over the study period in cows fed either basal forage, but the decrease was considerably greater in cows receiving the grass silage-based diet. Similarly, hepatic Fe decreased more in cows receiving G than C when S and Mo were included in the diet. We concluded that added S and Mo reduces hepatic Cu reserves irrespective of basal forage source, but this decrease is considerably more pronounced in cows receiving grass silage- than corn silage-based rations and is associated with a decrease in intake and milk performance and an increase in milk somatic cell count. PMID- 28365111 TI - Lower working heights decrease contraction intensity of shoulder muscles in a herringbone 30 degrees milking parlor. AB - Musculoskeletal disorders have been a main concern in milkers for many years. To improve posture, a formula was developed in a previous study to calculate ergonomically optimal working heights for various milking parlor types. However, the working height recommendations based on the formula for the herringbone 30 degrees parlor were broad. To clarify the recommendations for the optimal working height, we investigated the effect of working height on upper limb and shoulder muscle contraction intensities. We evaluated 60 milking cluster attachment procedures in a herringbone 30 degrees milking parlor in 7 men and 9 women. Specifically, we examined the effect of working height on muscle contraction intensity of 4 arm and shoulder muscles bilaterally (flexor carpi ulnaris, biceps brachii, deltoideus anterior, and upper trapezius) by using surface electromyography. The working heights (low, medium, and high), which reflect the ratio of the subject's height to the height of the udder base, were used in the milking health formula to determine and fit individual depth of pits. Data were evaluated for each muscle and arm side in the functions holding and attaching. Statistical analysis was performed using linear mixed effects models, where muscle contraction intensity served as a target variable, whereas working height coefficient, sex, subject height, and repetition were treated as fixed effects, and repetition group nested in working height nested in subject was considered a random effect. Contraction intensities decreased with decreasing working height for the deltoideus anterior and upper trapezius, but not for the flexor carpi ulnaris or the biceps brachii muscles in both holding and attaching arm functions. We found that milking at a lower working height reduced muscle contraction intensities of the shoulder muscles. Women showed higher contraction intensities than men, whereas subject height had no effect. The study demonstrated that a lower working height decreased muscular load during milking. These lower working heights should be used within the recommendations made by the milking health formula for the herringbone 30 degrees . Working heights could be adjusted effectively for milkers of varying body height. Future studies should therefore use the milking health formula as a tool to objectively compare and improve the accuracy of the working height coefficients. PMID- 28365112 TI - A mechanistic model of small intestinal starch digestion and glucose uptake in the cow. AB - The high contribution of postruminal starch digestion (up to 50%) to total-tract starch digestion on energy-dense, starch-rich diets demands that limitations to small intestinal starch digestion be identified. A mechanistic model of the small intestine was described and evaluated with regard to its ability to simulate observations from abomasal carbohydrate infusions in the dairy cow. The 7 state variables represent starch, oligosaccharide, glucose, and pancreatic amylase in the intestinal lumen, oligosaccharide and glucose in the unstirred water layer at the intestinal wall, and intracellular glucose of the enterocyte. Enzymatic hydrolysis of starch was modeled as a 2-stage process involving the activity of pancreatic amylase in the lumen and of oligosaccharidase at the brush border of the enterocyte confined within the unstirred water layer. The Na+-dependent glucose transport into the enterocyte was represented along with a facilitative glucose transporter 2 transport system on the basolateral membrane. The small intestine is subdivided into 3 main sections, representing the duodenum, jejunum, and ileum for parameterization. Further subsections are defined between which continual digesta flow is represented. The model predicted nonstructural carbohydrate disappearance in the small intestine for cattle unadapted to duodenal infusion with a coefficient of determination of 0.92 and a root mean square prediction error of 25.4%. Simulation of glucose disappearance for mature Holstein heifers adapted to various levels of duodenal glucose infusion yielded a coefficient of determination of 0.81 and a root mean square prediction error of 38.6%. Analysis of model behavior identified limitations to the efficiency of small intestinal starch digestion with high levels of duodenal starch flow. Limitations to individual processes, particularly starch digestion in the proximal section of the intestine, can create asynchrony between starch hydrolysis and glucose uptake capacity. PMID- 28365113 TI - Associations between pathogen-specific cases of subclinical mastitis and milk yield, quality, protein composition, and cheese-making traits in dairy cows. AB - The aim of this study was to investigate associations between pathogen-specific cases of subclinical mastitis and milk yield, quality, protein composition, and cheese-making traits. Forty-one multibreed herds were selected for the study, and composite milk samples were collected from 1,508 cows belonging to 3 specialized dairy breeds (Holstein Friesian, Brown Swiss, and Jersey) and 3 dual-purpose breeds of Alpine origin (Simmental, Rendena, and Grey Alpine). Milk composition [i.e., fat, protein, casein, lactose, pH, urea, and somatic cell count (SCC)] was analyzed, and separation of protein fractions was performed by reversed-phase high performance liquid chromatography. Eleven coagulation traits were measured: 5 traditional milk coagulation properties [time from rennet addition to milk gelation (RCT, min), curd-firming rate as the time to a curd firmness (CF) of 20 mm (k20, min), and CF at 30, 45, and 60 min from rennet addition (a30, a45, and a60, mm)], and 6 new curd firming and syneresis traits [potential asymptotical CF at an infinite time (CFP, mm), curd-firming instant rate constant (kCF, % * min 1), curd syneresis instant rate constant (kSR, % * min-1), modeled RCT (RCTeq, min), maximum CF value (CFmax, mm), and time at CFmax (tmax, min)]. We also measured 3 cheese yield traits, expressing the weights of total fresh curd (%CYCURD), dry matter (%CYSOLIDS), and water (%CYWATER) in the curd as percentages of the weight of the processed milk, and 4 nutrient recovery traits (RECPROTEIN, RECFAT, RECSOLIDS, and RECENERGY), representing the percentage ratio between each nutrient in the curd and milk. Milk samples with SCC > 100,000 cells/mL were subjected to bacteriological examination. All samples were divided into 7 clusters of udder health (UH) status: healthy (cows with milk SCC < 100,000 cells/mL and uncultured); culture-negative samples with low, medium, or high SCC; and culture-positive samples divided into contagious, environmental, and opportunistic intramammary infection (IMI). Data were analyzed using a linear mixed model. Significant variations in the casein to protein ratio and lactose content were observed in all culture-positive samples and in culture-negative samples with medium to high SCC compared to normal milk. No differences were observed among contagious, environmental, and opportunistic pathogens, suggesting an effect of inflammation rather than infection. The greatest impairment in milk quantity and composition, clotting ability, and cheese production was observed in the 2 UH status groups with the highest milk SCC (i.e., contagious IMI and culture-negative samples with high SCC), revealing a discrepancy between the bacteriological results and inflammatory status, and thus confirming the importance of SCC as an indicator of udder health and milk quality. PMID- 28365114 TI - A meta-analysis on the effect of dietary application of exogenous fibrolytic enzymes on the performance of dairy cows. AB - The aim of this study was to use meta-analytical methods to estimate effects of adding exogenous fibrolytic enzymes (EFE) to dairy cow diets on their performance and to determine which factors affect the response. Fifteen studies with 17 experiments and 36 observations met the study selection criteria for inclusion in the meta-analysis. The effects were compared by using random-effect models to examine the raw mean difference (RMD) and standardized mean difference between EFE and control treatments after both were weighted with the inverse of the study variances. Heterogeneity sources evaluated by meta-regression included experimental duration, EFE type and application rate, form (liquid or solid), and method (application to the forage, concentrate, or total mixed ration). Only the cellulase-xylanase (C-X) enzymes had a substantial number of observations (n = 13 studies). Application of EFE, overall, did not affect dry matter intake, feed efficiency but tended to increase total-tract dry matter digestibility and neutral detergent fiber digestibility (NDFD) by relatively small amounts (1.36 and 2.30%, respectively, or <0.31 standard deviation units). Application of EFE increased yields of milk (0.83 kg/d), 3.5% fat-corrected milk (0.55 kg/d), milk protein (0.03 kg/d), and milk lactose (0.05 kg/d) by moderate to small amounts (<0.30 standard deviation units). Low heterogeneity (I 2 statistic <25%) was present for yields and concentrations of milk fat and protein and lactose yield. Moderate heterogeneity (I 2 = 25 to 50%) was detected for dry matter intake, milk yield, 3.5% fat-corrected milk, and feed efficiency (kg of milk/kg of dry matter intake), whereas high heterogeneity (I 2 > 50%) was detected for total-tract dry matter digestibility and NDFD. Milk production responses were higher for the C-X enzymes (RMD = 1.04 kg/d; 95% confidence interval: 0.33 to 1.74), but were still only moderate, about 0.35 standardized mean difference. A 24% numerical increase in the RMD resulting from examining only C-X enzymes instead of all enzymes (RMD = 1.04 vs. 0.83 kg/d) suggests that had more studies met the inclusion criteria, the C-X enzymes would have statistically increased the milk response relative to that for all enzymes. Increasing the EFE application rate had no effect on performance measures. Application of EFE to the total mixed ration improved only milk protein concentration, and application to the forage or concentrate had no effect. Applying EFE tended to increase dry matter digestibility and NDFD and increased milk yield by relatively small amounts, reflecting the variable response among EFE types. PMID- 28365115 TI - Antibiotic treatment of metritis in dairy cows-A meta-analysis. AB - The objective of this meta-analysis was to assess the efficacy of the treatment of bovine metritis with common antibiotic and nonantibiotic treatment options. Acute puerperal metritis, a systemic and potentially painful illness with rectal temperature >39.5 degrees C and signs of toxemia due to an infection of the uterus, occurs within 21 d after parturition. Because of the infectious nature, antibiotics are considered beneficial for the treatment of acute puerperal metritis. Each use of an antimicrobial drug, however, is associated with selective pressure for eventual emergence of resistant bacteria. The 23 trials evaluated in the course of a previously conducted systematic review were the basis for meta-analytic investigations. Selected trials were screened regarding their eligibility for the following investigations: (1) comparison of different antibiotic treatments with respect to metritis prevalence at time of re examination, (2) efficacy of ceftiofur treatment with respect to metritis prevalence at time of re-examination, (3) comparison of efficacy of antibiotic versus nonantibiotic drugs with respect to metritis prevalence at time of re examination, and (4) equivalence assessment of treatment effects on reproductive performance measures. Where at least 3 trials had investigated the same outcome variable and met the inclusion criteria (inclusion of a control or reference group diagnosed with metritis; reporting means and standard deviation in case of continuous data), meta-analytic investigations were carried out. Due to a shortage of comparable studies, we could not conduct investigations (1) and (3). Ceftiofur treatment of 828 metritic cows was associated with a decrease in the prevalence of metritis following treatment in comparison to 804 untreated cows. In conclusion, meta-analytic investigations uncovered a need for more high quality studies. Furthermore, a positive effect of the most commonly used antibiotic drug, ceftiofur, for the treatment of bovine metritis could be shown. A comparison with other antibiotic or nonantibiotic treatment options could not be made. PMID- 28365116 TI - Differential somatic cell count-A novel method for routine mastitis screening in the frame of Dairy Herd Improvement testing programs. AB - Somatic cell count (SCC) is used as key indicator in mastitis screening programs typically applied in the frame of Dairy Herd Improvement (DHI) testing programs. However, mastitis is still causing tremendous economic losses to the dairy industry. Hence, new biomarkers are needed that can be used for enhanced management of mastitis on dairy farms. Besides the determination of SCC, differentiation of cells has been described to be beneficial for a more definite description of the actual udder health status of dairy cows. The aim of this study was to develop a new method for rapid and simultaneous determination of SCC and a new parameter, differential somatic cell count (DSCC), in individual cow milk samples using flow cytometry. The method is sought to be applied in central milk testing laboratories, so that existing DHI infrastructures can be used. The DSCC represents the combined proportion of polymorphonuclear leukocytes (PMN) and lymphocytes expressed in percentage. The proportion of macrophages can be calculated by subtracting DSCC from 100%. Our research revealed increasing proportions of PMN, but decreasing proportions of macrophages as SCC increased. However, lymphocytes occurred fairly constantly with low proportions across the entire SCC range. Hence, the DSCC parameter reflects the antidromic trend of PMN and macrophages. Fluorescence microscopy was used to evaluate the specificity of the new Foss DSCC method in terms of DSCC and a high correlation was found. Apart from that, the accuracy of cell differentiation using the Foss DSCC method was confirmed in a cell sorting trial. Total SCC could be determined equally well using the new method as compared with existing methods. The new method was further proven to be robust toward a range of method and milk-sample-related factors. In an initial field trial, regular DHI samples of a local dairy herd were analyzed. The DSCC values occurred in a broad range from 34 to 79% in samples with <400,000 cells/mL. Higher DSCC values (53-89%) were found in samples with >400,000 cells/mL. In conclusion, the new Foss DSCC method allows reliable, repeatable, fast, robust, and accurate determination of both DSCC and SCC at low cost. This, in turn, provides more accurate information on the actual udder health status of dairy cows. The practical application of DSCC in the frame of DHI testing programs, however, needs further investigation. PMID- 28365117 TI - Two-dimensional gas chromatography time-of-flight mass spectrometry-based serum metabolic fingerprints of neonatal calves before and after first colostrum ingestion. AB - Neonatal calves show a remarkable increase in serum IgG levels after first ingestion of colostrum. They can absorb high-molecular IgG from colostrum in the small intestine by nonspecific receptor-independent fluid pinocytosis within 24 h after birth. However, little is known about the temporal changes in serum small molecule metabolites, such as carbohydrates and AA, in neonatal calves after first colostrum ingestion. In this study, we examined temporal changes in serum metabolites of neonatal calves after first ingestion of colostrum by comprehensive 2-dimensional gas chromatography mass spectrometry (GC*GC-MS). Forty serum samples obtained from 5 calves at 8 time points between 0 and 12 h after first colostrum ingestion were analyzed in triplicate by GC*GC-MS. Multivariate analyses of 120 GC*GC-MS results revealed significant variations in the serum metabolites, primary individual differences among the calves, and secondary temporal changes within each individual calf. Several serum metabolites increased temporally after ingestion in each calf, but only a limited number of compounds were increased universally in all 5 calves. Eight compounds, including oligosaccharides such as lactose, were associated with temporal changes in IgG. Some essential AA that must be supplied from the diet increased temporally after ingestion, but differed from the temporal pattern of the oligosaccharides and IgG. These results suggest that the colostral contents may be absorbed by complex mechanisms that include intestinal pinocytosis for IgG and oligosaccharides, along with others such as specific transporters in the intestinal epithelial cells for AA in calves. PMID- 28365118 TI - Effect of increasing the proportion of dietary concentrate on gastrointestinal tract measurements and brush border enzyme activity in Holstein steers. AB - The aim of this study was to determine the time course for adaptation of the reticulo-rumen, omasum, abomasum, and small intestine in response to an abrupt increase in the proportion of grain in the diet. Adaptive responses include tissue and digesta mass, small intestinal length, and brush border enzyme activity in the duodenum, proximal jejunum, and ileum. Twenty-five Holstein steers (213 +/- 23 kg; 5 to 7 mo of age) were blocked by body weight, and within block were randomly assigned to 1 of 5 treatments: the control diet (CTRL; 92% chopped grass hay and 8% mineral and vitamin supplement on a dry matter basis) or a moderate grain diet (MGD; 50% chopped grass hay, 42% rolled barley grain, and 8% mineral and vitamin supplement) that was fed for 3 (MGD3), 7 (MGD7), 14 (MGD14), or 21 d (MGD21). Dry matter intake was limited to 2.25% of body weight to ensure that changes in dry matter intake did not confound the results. On the last day of the dietary exposure, steers were slaughtered 2 h after feeding. Reticulo-rumen tissue mass and ruminal epithelium mass in the ventral sac of the rumen were not affected by the MGD. Wet reticulo-ruminal digesta mass decreased from CTRL to MGD7 and then increased, but reticulo-ruminal digesta dry matter mass did not differ between treatments. Omasal mass, omasal tissue mass, and omasum digesta mass decreased linearly with the number of days fed MGD, but abomasal tissue mass tended to increase linearly. Duodenal tissue mass tended to increase linearly, and ileal length increased linearly with the number of days fed MGD. Lactase activity in the proximal jejunum increased linearly and maltase activity in duodenum tended to increase linearly with days fed MGD. Aminopeptidase N activity in the proximal jejunum increased cubically with days fed MGD, and dipeptidylpeptidase IV activity in ileum tended to decrease from CTRL to MGD14 and then tended to increase. Adaptation to a diet with a greater proportion of concentrate involves changes in the mass and length of regions of the gastrointestinal tract and brush border enzyme activity. These changes take place gradually over at least 3 wk. PMID- 28365119 TI - Intensive liquid feeding of dairy calves with a medium crude protein milk replacer: Effects on performance, rumen, and blood parameters. AB - The objective of this study was to evaluate the effects of different liquid feeding systems using a medium crude protein milk replacer on performance, rumen, and blood parameters. Thirty newborn Holstein calves were blocked according to birth weight and date of birth, and randomly distributed to different liquid feeding systems: conventional (4 L/d), intensive (8 L/d), or step-up/step-down (wk 1, 4 L/d; wk 2 to 6, 8 L/d; wk 7 and 8, 4 L/d). The commercial milk replacer (12.5% solids, 20.2% crude protein, 15.6% fat) was fed twice daily (0700 and 1700 h) until calves were weaned, at 8 wk of age. Calves were individually housed in wood hutches, with free access to water and starter concentrate, and to hay only after weaning. They were followed through 10 wk of age. Milk replacer and starter intake were inversely affected by feeding system. After weaning, starter intake and hay intake were similar among feeding systems. Total dry matter intake was higher during the liquid-feeding period for calves on the intensive system compared to calves on the conventional system, but conventional feeding resulted in the highest dry matter intake after weaning. Feed efficiency was similar among feeding systems before and after weaning. Average body weight and daily gain were not affected by feeding system before or after weaning. During liquid feeding, diarrhea occurrence was lower for calves on the conventional system; however, when calves on the step-up/step-down system were fed lower volumes of liquid feed, diarrhea occurrence was similar to that of calves on the conventional system. Plasma concentrations of beta-hydroxybutyrate were higher for calves on the conventional system, reflecting starter intake. Rumen pH, short-chain fatty acids, and N-NH3 were not affected by feeding system. Feeding higher volumes of milk replacer with a medium crude protein content had no beneficial effect on the performance of calves up to 10 wk of age. PMID- 28365120 TI - Estimating variance components and breeding values for number of oocytes and number of embryos in dairy cattle using a single-step genomic evaluation. AB - Reproductive technologies such as multiple ovulation and embryo transfer (MOET) and ovum pick-up (OPU) accelerate genetic improvement in dairy breeding schemes. To enhance the efficiency of embryo production, breeding values for traits such as number of oocytes (NoO) and number of MOET embryos (NoM) can help in selection of donors with high MOET or OPU efficiency. The aim of this study was therefore to estimate variance components and (genomic) breeding values for NoO and NoM based on Dutch Holstein data. Furthermore, a 10-fold cross-validation was carried out to assess the accuracy of pedigree and genomic breeding values for NoO and NoM. For NoO, 40,734 OPU sessions between 1993 and 2015 were analyzed. These OPU sessions originated from 2,543 donors, from which 1,144 were genotyped. For NoM, 35,695 sessions between 1994 and 2015 were analyzed. These MOET sessions originated from 13,868 donors, from which 3,716 were genotyped. Analyses were done using only pedigree information and using a single-step genomic BLUP (ssGBLUP) approach combining genomic information and pedigree information. Heritabilities were very similar based on pedigree information or based on ssGBLUP [i.e., 0.32 (standard error = 0.03) for NoO and 0.21 (standard error = 0.01) for NoM with pedigree, 0.31 (standard error = 0.03) for NoO, and 0.22 (standard error = 0.01) for NoM with ssGBLUP]. For animals without their own information as mimicked in the cross-validation, the accuracy of pedigree-based breeding values was 0.46 for NoO and NoM. The accuracies of genomic breeding values from ssGBLUP were 0.54 for NoO and 0.52 for NoM. These results show that including genomic information increases the accuracies. These moderate accuracies in combination with a large genetic variance show good opportunities for selection of potential bull dams. PMID- 28365121 TI - Effects of dry period length and dietary energy source on inflammatory biomarkers and oxidative stress in dairy cows. AB - Negative energy balance in dairy cows in early lactation has been associated with increased inflammation and oxidative stress in these cows. The objective of this study was to evaluate the effects of dry period (DP) length and dietary energy source on inflammatory biomarkers and oxidative stress in dairy cows. Holstein Friesian dairy cows (60 primiparous and 107 multiparous) were assigned randomly to a 3 * 2 factorial design with 3 DP length (0, 30, or 60 d) and 2 early lactation rations (glucogenic or lipogenic). Cows were fed a glucogenic or lipogenic ration from 10 d before the expected calving date. Blood was collected in wk -3, -2, -1, 1, 2, and 4 relative to calving. Dry period length affected inflammatory biomarkers and oxidative stress, especially in wk 1 and 2 after calving. Cows with a 0-d DP had higher levels of ceruloplasmin, cholesterol, and reactive oxygen metabolites, and they tended to have higher haptoglobin levels compared with cows with a 30- or 60-d DP. Cows with a 0-d DP had a lower plasma paraoxonase and bilirubin in the first 2 wk after calving and a lower liver functionality index compared with cows with a 60-d DP. Cows of parity >3 fed a glucogenic ration had higher cholesterol levels compared with cows of parity >3 fed a lipogenic ration. No interaction between DP length and ration was present for inflammatory biomarkers or oxidative stress variables. Plasma bilirubin levels for cows with a 0-d DP were negatively related to energy balance and metabolic status in these cows. Moreover, occurrence of clinical health problems (fever, mastitis, metritis, and retained placenta) was 41, 27, and 30% for cows with 0-, 30-, and 60-d DP, respectively. High levels of ceruloplasmin, cholesterol, and reactive oxygen metabolites in cows with 0-d DP were related to the occurrence of health problems in these cows. In conclusion, omitting the DP increased levels of ceruloplasmin, cholesterol, and reactive oxygen metabolites, and decreased levels of bilirubin and paraoxonase in plasma, independent of ration, compared with cows with a 60-d DP. These contrasting effects of DP length on inflammatory status could be explained in part by the improved energy balance and occurrence of health problems in these cows, but was not related to increased somatic cell count in cows with a 0-d DP. Cows with a 0-d DP had better energy balance, but also had higher levels of oxidative stress compared with cows with a 60-d DP. Moreover, occurrence of health problems did not differ between cows with different DP lengths. PMID- 28365122 TI - Derivation and genome-wide association study of a principal component-based measure of heat tolerance in dairy cattle. AB - Heat stress represents a key factor that negatively affects the productive and reproductive performance of farm animals. In the present work, a new measure of tolerance to heat stress for dairy cattle was developed using principal component analysis. Data were from 590,174 test-day records for milk yield, fat and protein percentages, and somatic cell score of 39,261 Italian Holstein cows. Test-day records adjusted for main systematic factors were grouped into 11 temperature humidity index (THI) classes. Daughter trait deviations (DTD) were calculated for 1,540 bulls as means of the adjusted test-day records for each THI class. Principal component analysis was performed on the DTD for each bull. The first 2 principal components (PC) explained 42 to 51% of the total variance of the system across the 4 traits. The first PC, a measure of the level at which the curve is located, was interpreted as a measure of the level at which the DTD curve was located. The second PC, which shows the slope of increasing or decreases DTD curves, synthesized the behavior of the DTD pattern. Heritability of the 2 component scores was moderate to high for level across all traits (range = 0.23 0.82) and low to moderate for slope (range = 0.16-0.28). For each trait, phenotypic and genetic correlations between level and slope were equal to zero. A genome-wide association analysis was carried out on a subsample of 423 bulls genotyped with the Illumina 50K bovine bead chip (Illumina, San Diego, CA). Two single nucleotide polymorphisms were significantly associated with slope for milk yield, 4 with level for fat percentage, and 2 with level and slope of protein percentage, respectively. The gene discovery was carried out considering windows of 0.5 Mb surrounding the significant markers and highlighted some interesting candidate genes. Some of them have been already associated with the mechanism of heat tolerance as the heat shock transcription factor (HSF1) and the malonyl-CoA acyl carrier protein transacylase (MCAT). The 2 PC were able to describe the overall level and the slope of response of milk production traits across increasing levels of THI index. Moreover, they exhibited genetic variability and were genetically uncorrelated. These features suggest their use as measures of thermotolerance in dairy cattle breeding schemes. PMID- 28365123 TI - Technical note: Validation of a semi-automated software tool to determine gait cycle variables in dairy cows. AB - This paper presents the validation of a software tool called Cow-Gait-Analyzer (University of Bern, Switzerland) to determine gait-cycle variables in lame and non-lame dairy cows using features derived from low-cost, stand-alone 3 dimensional accelerometers (400 Hz). The Cow-Gait-Analyzer automatically extracts the relevant gait events of foot load and toe off, which characterize gait-cycle duration, stance phase, and swing phase during walking. A nonautomatic step is visual inspection of the pedograms. If the software does not automatically choose the right peaks according to pedogram definitions, peaks can be manually chosen. We validated the algorithms by comparing the accelerometer data (pedogram) with the synchronized video data, which we used as a gold standard. We carried out the measurements at the metatarsal level of paired hind limbs during walking. We included 12 non-lame cows and 5 lame cows and expressed overall differences between the Cow-Gait-Analyzer and the gold standard as relative measurement error (RME). We analyzed 34 hind limbs with a mean of 9 gait cycles. The median RME for gait-cycle duration and stance phases were 0 and 1.69%, respectively. The peaks of gait-cycle variables showed RME of 0.67 and 0.24% for foot load and toe off, respectively. The semi-automated Cow-Gait-Analyzer can accurately determine gait cycle variables in both lame and non-lame cows, and could be used to assess gait patterns in routine clinical and research practice focusing on individual cows. PMID- 28365124 TI - Contribution of the novel sulfur-producing adjunct Lactobacillus nodensis to flavor development in Gouda cheese. AB - We assessed the efficacy of Lactobacillus nodensis CSK964 as an adjunct culture in Gouda cheese under various industrial conditions. We set up 4 different systems: a direct vat inoculum with and without adjunct using the calf rennet Kalase, and an undefined bulk starter culture with and without adjunct using the microbial rennet Milase (both rennets from CSK Food Enrichment, Ede, the Netherlands). During ripening, we subjected the cheeses to the following analyses: viability of starter and adjunct cells, composition, proteolysis, and flavor development by detection of sulfur compounds and descriptive sensory analysis. In general, the presence of Lb. nodensis increased secondary proteolysis and influenced cheese flavor, particularly in relation to volatile sulfur compounds; hydrogen sulfide and methanethiol were present in higher abundances in cheeses containing Lb. nodensis. The primary starter also influenced the range of volatile sulfur compounds produced. Methanethiol and dimethyl disulfide were more abundant in the nisin-producing direct vat inoculum cheese with adjunct; hydrogen sulfide was more prevalent when bulk starter culture was used with Lb. nodensis. Sensory analysis revealed that the direct vat inoculum cheese with adjunct scored significantly better in terms of smell and taste than the direct vat inoculum cheese without adjunct and lacked the dominant sulfur flavors of the bulk starter cheese with adjunct. Subsequent analysis using lead acetate paper and modified motility broth as indicators of hydrogen sulfide production confirmed that Lb. nodensis produced hydrogen sulfide in broth and in the cheese matrix. This study suggests that the inclusion of Lb. nodensis as an adjunct culture can significantly alter the flavor profile of the final cheese. However, the selection of a suitable primary starter is imperative to ensure a desirable product. PMID- 28365125 TI - Development of subcutaneous fat in Spanish and Latin American children and adolescents: Reference values for biceps, triceps, subscapular and suprailiac skinfolds. AB - Subcutaneous fat skinfolds represent a reliable assessment instrument of adiposity status. This study provides current percentile references for four subcutaneous skinfolds (biceps, triceps, subscapular, suprailiac) applicable to children and adolescents in Spain and in Latin American countries where data are scarce. The design consisted of a cross-sectional multicenter study performed with identical methods in 5 countries (Argentina, Cuba, Mexico, Spain and Venezuela). Total sample comprised 9163 children and youths (boys 4615 - girls 4548) aged 6-18 years, healthy and without apparent pathologies. Percentiles 3, 5, 10, 25, 50, 75, 90, 95 and 97 were calculated by the LMS method. Sexual dimorphism was assessed using the t-test and age differences with ANOVA. Normalized growth percentile references were obtained according to sex and age for each skinfold. The mean values of four skinfolds were significantly greater in girls than boys (p<0.001) and, in both sexes, all skinfolds show statistical differences through age (p<0.001) with different magnitudes. Except triceps in girls, peaks between 11 and 12 years of age are more noticeable in boys than in girls. Although the general model of growth is known, the skinfold measurements show variability among populations and differences of magnitude are presented according to the analyzed population. Therefore, these age and sex-specific reference percentile values for biceps, triceps, subscapular and suprailiac skinfolds, derived from a large sample of Spanish and Latin American children and adolescents, are a useful tool for adiposity diagnosis in this population for which no reference values were available. PMID- 28365126 TI - Prehistoric funerary complexity in northern Iberia studied by using dental morphology. AB - During the Neolithic Age and afterwards, several funerary practices coexisted in the northeast of the Iberian Peninsula from the Mediterranean to the Atlantic. According to archaeological data, there was a coexistence of sepulchral caves and megalithic monuments at the end of the Neolithic, following the dominance of open air pit burials during the Middle Neolithic. The aim of this work is to analyze the biological relationships between individuals representing those cultures, based on their dental morphology - the first such attempt. This study presents data of 156 individuals from this period, and will allow elucidate the population dynamics including the role of migrations and other factors. The results indicate that there were no significant differences between the groups living in Atlantic and Mediterranean areas. Moreover, pairwise comparisons for each trait only show two significant results. This lack of differences could be related to trade activities between the two basins, which would contribute to individual exchanges between groups. Furthermore, according to biological affinities, trade activities along the Mediterranean Sea had a more marked influence over the Catalan populations than those from the Atlantic basin. There are no biological differences between groups representing the open-air pit culture and the sepulchral caves in each area. Finally, the megalithic groups from the Atlantic basin differ the most from the surrounding populations. This could be indicative of a slightly different biological origin of the people related to this culture. PMID- 28365127 TI - Image-guided preoperative progressive pneumoperitoneum for large incisional hernia repair. PMID- 28365128 TI - Diagnosing autoimmune pancreatitis with the Unifying-Autoimmune-Pancreatitis Criteria. AB - BACKGROUND/OBJECTIVES: We had developed the Unifying-Autoimmune-Pancreatitis Criteria (U-AIP) to diagnose autoimmune pancreatitis (AiP) within the M-ANNHEIM classification of chronic pancreatitis. In 2011, International-Consensus Diagnostic-Criteria (ICDC) to diagnose AiP have been published. We had applied the U-AIP long before the ICDC were available. The aims of the study were, first, to describe patients with AiP diagnosed by the U-AIP; second, to compare diagnostic accuracies of the U-AIP and other diagnostic systems; third, to evaluate the clinical applicability of the U-AIP. METHODS: From 1998 until 2008, we identified patients with AiP using U-AIP, Japanese-, Korean-, Asian-, Mayo HISORt-, Revised-Mayo-HISORt- and Italian-criteria. We retrospectively verified the diagnosis by ICDC and Revised-Japanese-2011-criteria, compared diagnostic accuracies of all systems and evaluated all criteria in consecutive patients with pancreatitis (2009 until 2010, Pancreas-Outpatient-Clinic-Cohort, n = 84). We retrospectively validated our diagnostic approach in consecutive patients with a pancreatic lesion requiring surgery (Surgical-Cohort, n = 98). RESULTS: Overall, we identified 21 patients with AiP. Unifying-Autoimmune-Pancreatitis-Criteria and ICDC presented the highest diagnostic accuracies (each 98.8%), highest Youden indices (each 0.95238), and highest proportions of diagnosed patients (each n = 20/21, U-AIP/ICDC vs. other diagnostic systems, p < 0.05, McNemar test). In the Pancreas-Outpatient-Clinic-Cohort, seven patients were diagnosed with AiP (n = 6 by U-AIP, n = 1 by Asian-criteria). International-Consensus-Diagnostic-Criteria confirmed the diagnosis in these individuals. Based on partial fulfillment of U AIP, AiP was initially suspected in 13% (n = 10/77) of remaining patients from the Pancreas-Outpatient-Clinic-Cohort. In the Surgical-cohort, we identified one patient with AiP by U-AIP and ICDC. CONCLUSIONS: Unifying-Autoimmune-Pancreatitis Criteria revealed a satisfactory clinical applicability and offered an additional approach to diagnose AiP. PMID- 28365129 TI - Long-term results of treatment of advanced dermatofibrosarcoma protuberans (DFSP) with imatinib mesylate - The impact of fibrosarcomatous transformation. AB - BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is rare, infiltrating dermal neoplasm, characterized by indolent growth and low probability of metastases. The first effective systemic therapy in DFSP introduced into clinical practice was imatinib, demonstrating high activity in advanced cases. The aim of the study was to perform an analysis of patients with advanced DFSP treated with imatinib, with or without surgery, in routine clinical practice with long-term follow-up. PATIENTS AND METHODS: We analyzed the data of 31 Caucasian patients (14 male, 17 female; median age 56 years) with locally advanced/initially inoperable and/or metastatic DFSP who started therapy with imatinib at initial dose 800 mg daily between 12/2004 and 07/2014. All diagnoses were confirmed cytogenetically for the presence of specific COL1A1-PDGFB fusion. Median follow-up time was 5.3 years. RESULTS: Metastases were present in 15 cases (8 - lungs, 5 - soft tissue, 2 - lymph nodes). Fibrosarcomatous transformation (FS-DFSP) was confirmed in 16 patients (52%). 5-year progression-free survival (PFS) rate was 58% (median 6.8 years), 5-year overall survival (OS) rate was 64% (median time for OS was not reached). The shorter PFS and OS correlated with FS-DFSP and presence of metastatic disease. 5-year PFS rate was 93% for classic DFSP and 33% for FS-DFSP. The best overall responses were: 21 partial responses (68%, including 8 FS-DFSP, but the responses were shorter than for classic DFSP), 6 stable disease (19%) and 4 progressive diseases (13%). Thirteen patients (47%) underwent resection of residual disease and nine of them remained free of disease, although imatinib was discontinued. Median survival after progression on imatinib was 19 months, and longer survival were observed only in cases were rescue surgery/radiotherapy was possible. CONCLUSIONS: Our results indicate the long-term activity of imatinib in therapy of inoperable and/or metastatic cases of DFSP, including FS-DFSP. Some DFSP patients initially evaluated as unresectable/metastatic or necessitating mutilating surgery turned resectable after imatinib therapy and this rational approach leading to complete remission maybe potentially curative. PMID- 28365131 TI - Evolutionary Transcriptomics and Proteomics: Insight into Plant Adaptation. AB - Comparative transcriptomics and proteomics (T&P) have brought biological insight into development, gene function, and physiological stress responses. However, RNA seq and high-throughput proteomics remain underutilised in studies of plant adaptation. These methodologies have created discovery tools with the potential to significantly advance our understanding of adaptive diversification. We outline experimental recommendations for their application. We discuss analysis models and approaches that accelerate the identification of adaptive gene sets and integrate transcriptome, proteome, phenotypic, and environmental data. Finally, we encourage widespread uptake and future developments in T&P that will advance our understanding of evolution and adaptation. PMID- 28365130 TI - Predictors of growth kinetics and outcomes in small renal masses (SRM <=4 cm in size): Tayside Active Surveillance Cohort (TASC) Study. AB - OBJECTIVE: To determine outcomes of small renal masses (<=4 cm) on active surveillance and explore factors which can influence their growth. PATIENTS AND METHODS: Two hundred twenty six patients between January 2007 and December 2014 were analysed using cross-linked methodology of healthcare data and independent review. Cancer specific and non-specific survival were the primary outcomes. Growth kinetics, factors influencing growth and need for interventions were secondary outcomes. RESULTS: 101 (64.4%) solid and 4 (5.9%) cystic SRMs showed growth. 43 (19.02%) of SRMs required treatment interventions. Seven patients (7/158; 4.4%) died due to renal cancer at a median follow-up of 21.7 (SD 10.6, min 6-42) months, all in solid category. Independent review of serial radiological imaging of these seven cases showed two patients had subtle metastatic disease at the initial presentation, and 5 of the 7 did not adhere to recommended imaging regime. 33 (33/158; 20.8%) died due to other causes including non-renal cancers (14/158; 8.8%). Multivariate analyses showed that lower eGFR at baseline, co-morbidities and tumour location were independently associated with growth in size. CONCLUSIONS: A higher cancer-specific mortality was seen in the present study compared to the reported literature. Independent critical review of imaging of cases with poor outcome underscored the importance of adherence to a robust protocol including follow up. Comorbid conditions had a significant impact on growth and overall survival of patients with SRMs. PMID- 28365133 TI - In search of Insane Places. PMID- 28365132 TI - Exosomes in Cancer Nanomedicine and Immunotherapy: Prospects and Challenges. AB - Exosomes (versatile, cell-derived nanovesicles naturally endowed with exquisite target-homing specificity and the ability to surmount in vivo biological barriers) hold substantial promise for developing exciting approaches in drug delivery and cancer immunotherapy. Specifically, bioengineered exosomes are being successfully deployed to deliver potent tumoricidal drugs (siRNAs and chemotherapeutic compounds) preferentially to cancer cells, while a new generation of exosome-based therapeutic cancer vaccines has produced enticing results in early-phase clinical trials. Here, we review the state-of-the-art technologies and protocols, and discuss the prospects and challenges for the clinical development of this emerging class of therapeutics. PMID- 28365134 TI - Utility of Sonoclot in Prediction of Postoperative Bleeding in Pediatric Patients Undergoing Cardiac Surgery for Congenital Cyanotic Heart Disease: A Prospective Observational Study. AB - OBJECTIVES: To assess the utility of Sonoclot in prediction of postoperative bleeding in pediatric patients undergoing cardiac surgery with cardiopulmonary bypass for congenital cyanotic heart disease. DESIGN: Prospective, observational study. SETTING: Single university hospital. PARTICIPANTS: Eighty-seven pediatric patients undergoing cardiac surgery for congenital cyanotic heart disease. INTERVENTIONS: Laboratory coagulation parameters (prothrombin time, international normalization ratio, activated partial thromboplastin time, fibrinogen, D-dimer) as well as point-of-care Sonoclot glass bead activation time, clot rate, and platelet function (gbPF) were done before induction of anesthesia and following heparin reversal after termination of cardiopulmonary bypass (CPB) in all patients. MEASUREMENTS AND MAIN RESULTS: Postoperative blood loss was monitored by the amount of chest tube drainage. The primary outcome was to define Sonoclot parameters for prediction of postoperative bleeding. Secondary outcomes studied were amount of postoperative blood loss, transfusion requirement of various blood products, incidence of surgical re-exploration, duration of postoperative mechanical ventilation, intensive care unit and hospital stay. Among studied subjects, 37.9% (33 of 87 patients) were designated as bleeders while 62.1% (54 of 87 patients) were non-bleeders. Lower age, D-dimer, and gbPF test after termination of CPB following heparin neutralization were predictive for postoperative bleeders. Among these, post-protamine gbPF had the highest area under the curve (0.725), 95% confidence interval (0.619-0.831) for prediction of postoperative bleeders. Duration of mechanical ventilation (26.41+/-36.44 v 8.25+/-6.36 h, respectively, p = 0.001), intensive care unit stay (7.36 +/- 4.05 v 4.96 +/- 2.49, p = 0.001), and hospital stay (11.69+/-4.82 v 8.63+/-3.48 p = 0.001) were higher in bleeders; however, incidence of re-exploration was comparable between both groups. CONCLUSION: Postoperative bleeders may be predicted independently by post-CPB gbPF, postoperative D-dimer, and lower age of patients. Among these, post-CPB gbPF has maximum predictive value. PMID- 28365135 TI - Off-Label Prothrombin Complex Concentrates: Buyer Be Careful! PMID- 28365136 TI - Inappropriate Implantable Cardioverter-Defibrillator Shock Therapy During Anesthesia: How Do We Avoid This Complication? PMID- 28365137 TI - Vanishing Part of an Anterior Mitral Leaflet. PMID- 28365138 TI - Physical Incompatibility Between Protamine Sulfate and Ceftriaxone Sodium. PMID- 28365139 TI - Crohn's Colitis: Development of a multiplex gene expression assay comparing mRNA levels of susceptibility genes. AB - Crohn's disease (CD) is a multifactorial immunologically mediated disease. In this study we explored, for the first time, the efficacy of the Multiplex Gene Assay technology for detecting mRNA expression profile of 24 selected CD related genes in endoscopic biopsies and surgical specimens from CD patients with colonic localization of the disease. The polymorphisms of genes most frequently associated with CD were also analysed in DNA samples from the same patients. The analysis of endoscopic samples showed increased expression of 7 genes in inflamed mucosa compared to non-inflamed mucosa and suggests the activation of the autophagy process and of a Th17 adaptive response. The analysis of surgical specimens showed increased expression of 16 genes in inflamed tissue compared to non-inflamed internal controls and revealed the activation of immune-adaptive Th17 response in association with a Th1 response. Furthermore, an increased expression of genes involved in ionic transport and signal transduction was found in inflamed mucosa compared to non-inflamed internal controls. This study confirms the activation of Th17 and Th1 adaptive-immune response also in colonic CD. It should be stressed that these responses have been disclosed in biopsy tissue, while only Th17 differentiation is revealed in endoscopic tissue. Interestingly, the polymorphisms analysis revealed that a homozygous genotype is associated to a more complicated clinical course. PMID- 28365141 TI - Comparative Approaches to Genetic Discrimination: Chasing Shadows? AB - Genetic discrimination (GD) is one of the most pervasive issues associated with genetic research and its large-scale implementation. An increasing number of countries have adopted public policies to address this issue. Our research presents a worldwide comparative review and typology of these approaches. We conclude with suggestions for public policy development. PMID- 28365143 TI - Applying human factors and ergonomics to the misuse of nonsterile clinical gloves in acute care. AB - BACKGROUND: Health care workers (HCWs) are recommended to wear nonsterile clinical gloves (NSCG) for direct contact with blood and body fluids. However, there is evidence of extensive inappropriate NSCG use. METHODS: A mixed-methods study comprising observation of NSCG use in 2 acute hospitals and semistructured HCW interviews. Qualitative data were categorized using thematic analysis. Findings were mapped to the Systems Engineering Initiative for Patient Safety model and used to develop a strategy for improving NSCG use. RESULTS: Two hundred seventy-eight procedures performed in 178 episodes of care involved the use of NSCG. NSCG were inappropriate for 59% of procedures (165 out of 278). Risk of cross-contamination occurred in 49% (87 out of 178) episodes. Twenty-six HCWs were interviewed; emotion and socialization were key factors influencing decisions to use NSCG. Data from observation and thematic analysis were mapped to 6 interacting components of the Systems Engineering Initiative for Patient Safety work system. Interventions targeting each component informed quality improvement strategies CONCLUSIONS: Despite intense promotion of hand hygiene as the key measure to protect patients from health care-associated infection, NSCG dominate routine clinical practice and potential cross-contamination occurs in 50% of care episodes. Such practice is associated with significant environmental and financial costs and adversely affects patient safety. The application of human factors and ergonomics to the complex drivers of inappropriate NSCG behavior may be more effective than conventional approaches of education and policy in achieving the goal of preventing health care-associated infection and improving patient safety. PMID- 28365142 TI - Risk of heart disease in relation to radiotherapy and chemotherapy with anthracyclines among 19,464 breast cancer patients in Denmark, 1977-2005. AB - BACKGROUND AND PURPOSE: The risk of heart disease subsequent to breast cancer radiotherapy was examined with particular focus on women receiving anthracycline containing chemotherapy. MATERIAL AND METHODS: Women diagnosed with early-stage breast cancer in Denmark, 1977-2005, were identified from the register of the Danish Breast Cancer Cooperative Group, as was information on cancer-directed treatment. Information on heart disease was sought from the Danish National Patient and Cause of Death Registries. Incidence rate ratios were estimated comparing left-sided with right-sided cancer (IRR, LvR), stratified by calendar year, age, and time since breast cancer radiotherapy. RESULTS: Among 19,464 women receiving radiotherapy, the IRR, LvR, was 1.11 (95% CI 1.03-1.20, p=0.005) for all heart disease and among those also receiving anthracyclines the IRR, LvR, was 1.32 (95% CI 1.02-1.70, p=0.03). This risk was highest if the treatment was given before the age of 50years (IRR, LvR, 1.44, (95% CI 1.04-2.01) but there was no significant trend with age or time since treatment. CONCLUSIONS: Radiotherapy for left-sided breast cancer is associated with a higher risk of heart disease than for right-sided with the largest increases seen in women who also received anthracycline-containing chemotherapy. PMID- 28365144 TI - An economic analysis of the benefits of sterilizing medical instruments in low temperature systems instead of steam. AB - BACKGROUND: Hydrogen peroxide-based, low-temperature sterilization has been shown to do less damage to medical instruments than steam autoclaves. However, low temperature systems are more expensive to run. Higher costs need to be balanced against savings from reduced repair costs to determine value for money when choosing how to sterilize certain instruments, which are able to be reprocessed in either system. METHODS: This analysis examines the economic effects of using low-temperature sterilization systems to reprocess rigid and semi-rigid endoscopes, which are sensitive to heat and moisture, but still able to be sterilized using steam. It examines the changes to costs and frequency of repairs expected over 10 years, resulting from a choice to sterilize these instruments in a low-temperature system instead of steam. RESULTS: Overall, the results showed that increased sterilization costs are outweighed by the savings associated with less frequent repairs. Over a 10-year period, in large health care facilities, the probability of achieving an internal rate of return of at least 6% is 0.81. CONCLUSIONS: Our model shows it is likely to be a good decision for large health care facilities to invest in low-temperature sterilization systems. PMID- 28365140 TI - Deregulation of CRTCs in Aging and Age-Related Disease Risk. AB - Advances in public health in the past century have seen a sharp increase in human life expectancy. With these changes have come an increased prevalence of age related pathologies and health burdens in the elderly. Patient age is the biggest risk factor for multiple chronic conditions that often occur simultaneously within a single individual. An alternative to disease-centric therapeutic approaches is that of 'geroscience', which aims to define molecular mechanisms that link age to overall disease risk. One such mechanism is deregulation of CREB regulated transcriptional coactivators (CRTCs). Initially identified for their role in modulating CREB transcription, the past 5 years has seen an expansion in knowledge of new cellular regulators and roles of CRTCs beyond CREB. CRTCs have been shown to modulate organismal aging in Caenorhabditis elegans and to impact on age-related diseases in humans. We discuss CRTC deregulation as a new driver of aging that integrates the link between age and disease risk. PMID- 28365145 TI - The Double Thenar Flap: A Technique to Reconstruct 2 Fingertip Amputations Simultaneously. AB - Fingertip injuries are a common problem. There may be pulp loss and exposed bone. Various techniques have been described to reconstruct function as well as aesthetics; yet it is still unclear which treatment options should be chosen for each specific injury. Evidence-based treatment strategies are limited because there are no prospective randomized clinical trials evaluating one method with another. Fingertip injuries are usually variable in their presentation, and therefore treatment decisions are often dictated by the knowledge and expertise of the treating physician combined with the patient's unique injury. With exposed bone and major distal soft tissue loss, many reconstructive techniques have been well-described including local advancement flaps, thenar flaps, and cross-finger flaps. There is scarce literature discussing surgical options when multiple fingers are involved. This report details a novel technique used to reconstruct 2 simultaneously injured fingers using the double thenar flap. PMID- 28365146 TI - In Vivo Scaphoid Motion During Thumb and Forearm Motion in Casts for Scaphoid Fractures. AB - PURPOSE: In nonsurgical treatment for acute undisplaced or minimally displaced scaphoid waist fractures, immobilization of both wrist and thumb can be an option. However, in vivo scaphoid motion during forearm and thumb motion with the wrist immobilized in a cast has not been measured. Therefore, we examined the in vivo kinematics of the scaphoid during forearm and thumb motion with cast immobilization. METHODS: Ten healthy right wrists of 10 male volunteers were included. These wrists were immobilized in a short-arm spica cast with the thumb in a position of volar abduction and then were scanned with the forearm in supination, neutral rotation, and pronation using computed tomography. Next, these wrists were scanned with a forearm gauntlet cast in place with the thumb abducted radially and opposed with the forearm positioned in neutral rotation. From these data, the 3-dimensional position of the third metacarpal and scaphoid was analyzed. RESULTS: From forearm supination to pronation, the scaphoid showed 0.2 degrees radial deviation, 0.4 degrees pronation, and 8.3 degrees extension. The third metacarpal showed 14.6 degrees ulnar deviation, 6.5 degrees pronation, and 1.6 degrees flexion. During thumb opposition from radial abduction, the scaphoid showed 2.9 degrees radial deviation, 0.4 degrees supination, and 7.2 degrees extension and the third metacarpal showed 4.5 degrees ulnar deviation, 2.8 degrees pronation, and 5.5 degrees extension. CONCLUSIONS: The scaphoid was not completely immobilized by either cast. However, the scaphoid motion during forearm and thumb motion was not significant. CLINICAL RELEVANCE: Several high-quality studies have shown that undisplaced or minimally displaced scaphoid waist fractures can be successfully treated with casts. Movement of scaphoid and wrist during forearm rotation or thumb motion with a cast may not be sufficient to have a negative impact on the outcome of scaphoid fracture using a cast. PMID- 28365147 TI - The Bare Area of the Proximal Ulna: An Anatomic Study With Relevance to Chevron Osteotomy. AB - PURPOSE: A chevron osteotomy of the ulna is widely used to obtain intra-articular access to the elbow in the treatment of type C distal humerus fractures. The trochlear notch of the proximal ulna is divided into 2 articular parts by the "bare area." Ideally, the olecranon osteotomy should be centered on the bare area to minimize damage to the joint cartilage. The goals of this study were to describe the anatomy of the bare area and design an ideal chevron-shaped osteotomy. METHODS: We dissected 38 cadaver elbows and measured the width of the bare area, the distance between the tip of the triceps insertion and the area on the olecranon cortex corresponding to the bare area. We then designed a chevron osteotomy to stay within the bare area and measured the distance from the tip of the triceps insertion to the osteotomy apex as well as the angle of the osteotomy plane and the angle of the chevron cuts. RESULTS: The bare area existed in all 38 cadavers. The mean longitudinal and transverse widths were 4.0 mm (range, 1.0-8.6 mm) and 19.0 mm (range, 16.9-23.8 mm), respectively. The mean distance between the tip of the triceps insertion and the area on the olecranon cortex corresponding to the bare area was 19.0 mm (range, 16.0-23.0 mm). The mean transverse and longitudinal widths of the cortical notch were 3.0 mm (range, 1.6 4.5 mm) and 8.0 mm (range, 6.5-14.8 mm), respectively. The mean distance between the tip of the triceps insertion and the osteotomy apex was 22.0 mm (range, 18.0 24.0 mm) and the mean angle between the osteotomy surface and the vertical plane corresponding to the tangent plane was 20 degrees (range, 10 degrees to 25 degrees ). The mean angle of the V shape was 140 degrees (range, 130 degrees to 150 degrees ). CONCLUSIONS: Using the narrowest edge lacking cartilage (lateral or medial side) as a point of reference to locate the bare area, the designed chevron osteotomy entered the joint in the bare area in most specimens and decreased associated damage to the joint cartilage. CLINICAL RELEVANCE: This study describes the anatomy of the bare area and the design of the ideal chevron shaped osteotomy to treat type C distal humerus fractures. PMID- 28365148 TI - Outcomes After Flexor Tendon Repair Combined With the Application of Human Amniotic Membrane Allograft. AB - PURPOSE: Clinically proven methods to prevent adhesion formation after flexor tendon repair have not yet been established. The aim of this pilot study was to assess the feasibility of amniotic membrane allograft as a mechanical barrier to decrease adhesion formation. METHODS: Ten patients having flexor tendon injuries were planned to be recruited to the pilot study. The operative treatment consisted of tendon repair and fixation of amniotic membrane allograft around the repaired tendon. The primary outcome variable was the range of motion of the operated finger 6 months after the operation. Patients were monitored for infections and repair failures. RESULTS: The study was terminated owing to unfavorable results after treatment of 5 patients. One patient had extensive stiffness and was subjected to tenolysis and joint release. Histopathological analysis of the tendon sheath revealed focal fibrosis. Another patient had a repair failure. The other 3 patients had fair to good results. CONCLUSIONS: It seems improbable that the use of amniotic membrane allograft would yield clinically relevant improvement compared with the existing techniques. However, it remains unclear whether the unfavorable results are associated with technical factors, amniotic membrane allograft itself, or an irregular distribution of complications. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V. PMID- 28365149 TI - Absolute Quantification of Protein and mRNA Abundances Demonstrate Variability in Gene-Specific Translation Efficiency in Yeast. AB - Protein synthesis is the most energy-consuming process in a proliferating cell, and understanding what controls protein abundances represents a key question in biology and biotechnology. We quantified absolute abundances of 5,354 mRNAs and 2,198 proteins in Saccharomyces cerevisiae under ten environmental conditions and protein turnover for 1,384 proteins under a reference condition. The overall correlation between mRNA and protein abundances across all conditions was low (0.46), but for differentially expressed proteins (n = 202), the median mRNA protein correlation was 0.88. We used these data to model translation efficiencies and found that they vary more than 400-fold between genes. Non linear regression analysis detected that mRNA abundance and translation elongation were the dominant factors controlling protein synthesis, explaining 61% and 15% of its variance. Metabolic flux balance analysis further showed that only mitochondrial fluxes were positively associated with changes at the transcript level. The present dataset represents a crucial expansion to the current resources for future studies on yeast physiology. PMID- 28365150 TI - Environment Tunes Propagation of Cell-to-Cell Variation in the Human Macrophage Gene Network. AB - Cell-to-cell variation in gene expression and the propagation of such variation (PoV or "noise propagation") from one gene to another in the gene network, as reflected by gene-gene correlation across single cells, are commonly observed in single-cell transcriptomic studies and can shape the phenotypic diversity of cell populations. While gene network "rewiring" is known to accompany cellular adaptation to different environments, how PoV changes between environments and its underlying regulatory mechanisms are less understood. Here, we systematically explored context-dependent PoV among genes in human macrophages, utilizing different cytokines as natural perturbations of multiple molecular parameters that may influence PoV. Our single-cell, epigenomic, computational, and stochastic simulation analyses reveal that environmental adaptation can tune PoV to potentially shape cellular heterogeneity by changing parameters such as the degree of phosphorylation and transcription factor-chromatin interactions. This quantitative tuning of PoV may be a widespread, yet underexplored, property of cellular adaptation to distinct environments. PMID- 28365153 TI - Incidence and pattern of medication errors in a general paediatric ward in a developing nation. PMID- 28365151 TI - A Cell-Surface Membrane Protein Signature for Glioblastoma. AB - We present a systems strategy that facilitated the development of a molecular signature for glioblastoma (GBM), composed of 33 cell-surface transmembrane proteins. This molecular signature, GBMSig, was developed through the integration of cell-surface proteomics and transcriptomics from patient tumors in the REMBRANDT (n = 228) and TCGA datasets (n = 547) and can separate GBM patients from control individuals with a Matthew's correlation coefficient value of 0.87 in a lock-down test. Functionally, 17/33 GBMSig proteins are associated with transforming growth factor beta signaling pathways, including CD47, SLC16A1, HMOX1, and MRC2. Knockdown of these genes impaired GBM invasion, reflecting their role in disease-perturbed changes in GBM. ELISA assays for a subset of GBMSig (CD44, VCAM1, HMOX1, and BIGH3) on 84 plasma specimens from multiple clinical sites revealed a high degree of separation of GBM patients from healthy control individuals (area under the curve is 0.98 in receiver operating characteristic). In addition, a classifier based on these four proteins differentiated the blood of pre- and post-tumor resections, demonstrating potential clinical value as biomarkers. PMID- 28365152 TI - Dynamic Gene Regulatory Networks of Human Myeloid Differentiation. AB - The reconstruction of gene regulatory networks underlying cell differentiation from high-throughput gene expression and chromatin data remains a challenge. Here, we derive dynamic gene regulatory networks for human myeloid differentiation using a 5-day time series of RNA-seq and ATAC-seq data. We profile HL-60 promyelocytes differentiating into macrophages, neutrophils, monocytes, and monocyte-derived macrophages. We find a rapid response in the expression of key transcription factors and lineage markers that only regulate a subset of their targets at a given time, which is followed by chromatin accessibility changes that occur later along with further gene expression changes. We observe differences between promyelocyte- and monocyte-derived macrophages at both the transcriptional and chromatin landscape level, despite using the same differentiation stimulus, which suggest that the path taken by cells in the differentiation landscape defines their end cell state. More generally, our approach of combining neighboring time points and replicates to achieve greater sequencing depth can efficiently infer footprint-based regulatory networks from long series data. PMID- 28365154 TI - Activation and overexpression of Sirt1 attenuates lung fibrosis via P300. AB - Persistent fibroblast activation is a predominant feature of idiopathic pulmonary fibrosis (IPF), but the transcriptional and epigenetic mechanisms controlling this process are not well understood. Silent information regulator type-1 (Sirt1) is a member of class III histone deacetylase with important regulatory roles in a variety of pathophysiologic processes, but its role in fibrotic lung diseases is not clearly elucidated. Sirt1 expression in lung tissues of IPF patients and in a mouse model of bleomycin (BLM)-induced lung fibrosis were evaluated by immunofluorescence. The function of Sirt1 in BLM-induced lung fibrosis in the mouse model or transforming growth factor beta1 (TGF-beta1)-mediated lung fibroblast cellular model was investigated by Sirt1 activation, overexpression and knockdown of Sirt1. Finally, the involvement of p300 signaling pathways was assessed. In this study, we found up-regulation of Sirt1 in BLM-induced lung fibrosis, as well as in the lungs of IPF patients, including in the aggregated pulmonary fibroblasts of fibrotic foci. Activation or overexpression of Sirt1 attenuated TGF-beta1-mediated lung fibroblast differentiation and activation and diminished the severity of experimental lung fibrosis in mice. Whereas knockdown of Sirt1 promoted the pro-fibrogenic activity of TGF-beta1 in lung fibroblasts. A potential mechanism for the role of Sirt1 in lung fibrosis was through regulating the expression of p300. Thus, we characterized Sirt1 as an important regulator of lung fibrosis and provides a proof of principle for activation or overexpression of Sirt1 as a potential novel therapeutic strategy for IPF. PMID- 28365155 TI - A soluble recombinant form of human leucocyte antigen-G 6 (srHLA-G6). AB - Human Leucocyte Antigen-G (HLA-G) is a non classical major histocompatibility complex (MHC) molecule that through RNA splicing can encode seven isoforms which are membrane bound (-G1, -G2, -G3 and -G4) and soluble (-G5, -G6 and -G7). HLA-G is described as important immune suppressor endogenous molecule to favor maternal fetal tolerance, transplant survival and tumor immune scape. HLA-G shows low protein variability and a unique structural complexity that is related with the expression of different isoforms followed by biochemical processes, such as, proteolytic cleavage, molecular interactions, and protein ubiquitination. Studies with HLA-G have shown difficult to assess the role of the individual isoforms. Thus, the aim of this work was to obtain a HLA-G6 recombinant form. The results indicated the production of high homogeneous preparations of soluble recombinant HLA-G6 (srHLA-G6) with molecular mass 23,603.76 Da, determined by MALD-TOF/TOF. In addition, native and denatured srHLA-G6 were detected by ELISA, using commercial monoclonal antibodies. Finally, we developed a suitable methodology to express srHLA-G6 that could contribute in structural and functional studies involving specific isoforms. PMID- 28365156 TI - Mild hypothermia protects against oxygen glucose deprivation/reoxygenation induced apoptosis via the Wnt/beta-catenin signaling pathway in hippocampal neurons. AB - Mild hypothermia is thought to be one of the most effective therapies for cerebral ischemia/reperfusion injuries. Our previous research revealed that mild hypothermia inhibits the activation of caspase-3 and protects against oxygen glucose deprivation/reoxygenation (OGD/R)-induced injury in hippocampal neurons. However, the mechanisms behind the activation of caspase-3 remain unclear. The aims of this study were to determine whether the protective effects of mild hypothermia were exerted through the Wnt/beta-catenin signaling pathway. We found that, under OGD/R conditions, the pathway was down regulated, but mild hypothermia induced the reactivation of the Wnt/beta-catenin signaling pathway, which had been suppressed by OGD/R injury. Mild hypothermia also caused the down regulation of the expression of apoptosis promoting proteins (Bax cleaved caspase 3), up-regulated the expression of apoptosis inhibiting proteins (Bcl-2), and ameliorated OGD/R injury-induced apoptosis. The protective effects of mild hypothermia were blocked by DKK1 (an antagonist of the canonical Wnt signaling pathway). Taken together, these results indicate that the Wnt/beta-catenin signaling pathway mediates the protective effects of mild hypothermia against OGD/R-induced apoptosis. Our study provides evidence that mild hypothermia reactivates the Wnt/beta-catenin signaling pathway, which is suppressed by OGD/R injury, in hippocampal neurons and protects neurons from OGD/R-induced apoptosis via the reactivation of the Wnt/beta-catenin signaling pathway, ultimately suggesting that mild hypothermia could have therapeutic effects on OGD/R-induced apoptosis. PMID- 28365157 TI - Feasibility of a shorter Goal Attainment Scaling method for a pediatric spasticity clinic - The 3-milestones GAS. AB - BACKGROUND: Goal Attainment Scaling (GAS) is a method for writing personalized evaluation scales to quantify progress toward defined goals. It is useful in rehabilitation but is hampered by the experience required to adequately "predict" the possible outcomes relating to a particular goal before treatment and the time needed to describe all 5 levels of the scale. Here we aimed to investigate the feasibility of using GAS in a clinical setting of a pediatric spasticity clinic with a shorter method, the "3-milestones" GAS (goal setting with 3 levels and goal rating with the classical 5 levels). Secondary aims were to (1) analyze the types of goals children's therapists set for botulinum toxin treatment and (2) compare the score distribution (and therefore the ability to predict outcome) by goal type. METHODS: Therapists were trained in GAS writing and prepared GAS scales in the regional spasticity-management clinic they attended with their patients and families. The study included all GAS scales written during a 2-year period. GAS score distribution across the 5 GAS levels was examined to assess whether the therapist could reliably predict outcome and whether the 3-milestones GAS yielded similar distributions as the original GAS method. RESULTS: In total, 541 GAS scales were written and showed the expected score distribution. Most scales (55%) referred to movement quality goals and fewer (29%) to family goals and activity domains. CONCLUSION: The 3-milestones GAS method was feasible within the time constraints of the spasticity clinic and could be used by local therapists in cooperation with the hospital team. PMID- 28365158 TI - Ontogenetic dietary shifts and bioaccumulation of diphenhydramine in Mugil cephalus from an urban estuary. AB - Though bioaccumulation of pharmaceuticals has received attention in inland waters, studies of pharmaceutical bioaccumulation in estuarine and marine systems are limited. Further, an understanding of pharmaceutical bioaccumulation across size classes of organisms displaying ontogenetic feeding shifts is lacking. We selected the striped mullet, Mugil cephalus, a euryhaline and eurythermal species that experiences dietary shifts with age, to identify whether a model base, diphenhydramine, accumulated in a tidally influenced urban bayou. We further determined whether diphenhydramine accumulation differed among size classes of striped mullet over a two year study period. Stable isotope analysis identified that ontogenetic feeding shifts of M. cephalus occurred from juveniles to adults. However, bioaccumulation of diphenhydramine did not significantly increase across age classes of M. cephalus but corresponded to surface water levels of the pharmaceutical, which suggests inhalational uptake to diphenhydramine was more important for bioaccumulation than dietary exposure in this urban estuary. PMID- 28365161 TI - Re: Jim C. Hu, David M. Nanus, Art Sedrakyan. Increase in Prostate Cancer Metastases at Radical Prostatectomy in the United States. Eur Urol 2017;71:147-9. PMID- 28365163 TI - Comparing Clinical Outcomes for Radium-223: Do Older Patients Do Worse? AB - PURPOSE: To examine the clinical benefits and toxicities of 223Ra in 2 different age groups of patients with castrate-resistant prostate cancer. METHODS AND MATERIALS: This was a retrospective study of patients treated with 223Ra in 2 tertiary centers. Patients were divided into 2 different groups based on their age (>=72 years old and <72 years old). Treatment toxicities were graded according to Common Terminology Criteria for Adverse Events version 4.0. Comparison of characteristics and outcome was carried out with the Mann-Whitney test and analysis of overall survival with the log-rank test. RESULTS: In all, 129 patients were treated during the study period. Clinical benefit was similar in both groups. However, a statistically significant higher proportion of patients in the younger group had previously been treated with docetaxel. There was a higher rate of grade 3 anemia in younger patients. CONCLUSIONS: In line with other studies, 223Ra was well tolerated with minimum toxicities. The significantly higher rate of grade 3 anemia in younger patients may be due to more cautious patient selection in the elderly population. PMID- 28365160 TI - Bipolar Androgen Therapy: A Paradoxical Approach for the Treatment of Castration resistant Prostate Cancer. AB - Bipolar androgen therapy (BAT) is a paradoxical treatment for castrate-resistant prostate cancer whereby testosterone levels are rapidly alternated between supraphysiologic and near-castrate concentrations. Initial studies demonstrated that BAT is safe and produces clinical responses. A trial comparing enzalutamide against BAT is ongoing. PMID- 28365164 TI - Plasma interleukin-6 in remitted early bipolar I disorder and subjects at high risk for bipolar disorder. PMID- 28365165 TI - The promotion of intrauterine contraception in low- and middle-income countries: a narrative review. AB - CONTEXT: The contribution of copper-bearing intrauterine devices (IUDs) to overall contraceptive protection has declined in many countries, despite their well-known advantages. In response, initiatives to promote this method have been undertaken. OBJECTIVE: To review and interpret the experience of interventions to promote use of IUDs in low- and middle-income countries in order to provide strategic guidance for policies and programs. METHODS: We conducted a systematic search of Medline, Popline, Embase and Global Health electronic databases for relevant journal papers, reports and gray literature since 2010. Telephone interviews were held with two donors and six international family planning organizations. RESULTS: We identified a total of 31 publications. Four reported the results of randomized control trials and three were derived from quasi experiments. The majority were based on service statistics. Eight publications concerned interventions for HIV-positive women or couples, nine for postpartum or postabortion cases and 14 for general populations. Intervention approaches included vouchers, franchising of private practitioners, mobile outreach services, placement of dedicated staff in high-volume facilities and demand creation. Most publications adduced evidence of a positive impact and some reported impressively large numbers of IUD insertions. Results to date on the uptake of IUDs in postpartum interventions are modest. There is also almost no evidence of effects on IUD use at national levels. Implant uptake generally exceeded IUD uptake when both were offered. CONCLUSION: The evidence base is weak and offers few lessons on what strategies are most effective. The overall impression is that IUD use can be increased in a variety of ways but that progress is hampered by persistent adverse perceptions by both providers and potential clients. Provider enthusiasm is a key to success. The lack of a population impact stems in part from the fact that nearly all interventions are initiated by international organizations, with limited national reach except in small countries, rather than by government agencies. PMID- 28365166 TI - "I was close to death!": abortion and medical risk on American television, 2005 2016. AB - OBJECTIVES: To examine the portrayal of complications and long-term health consequences associated with abortion on television, recognizing the impact that fictional stories can have on public beliefs about abortion's safety. STUDY DESIGN: Using a systematic online search, we identified all instances of abortion on US television from 2005 to 2016. We qualitatively coded these plotlines to identify any occurrences of complications, interventions or long-term health consequences associated with abortion care, with 95% intercoder reliability. We calculated the frequencies and rates of these occurrences in Microsoft Excel. RESULTS: Our search identified 80 abortion plot lines. A percentage of 37.5 of characters who obtained an abortion experienced complications, interventions and/or negative health consequences. This rate contrasts with the 2.1% of real patients who experience complications or require intervention as a result of their abortions. Most onscreen complications were major events (e.g., hemorrhage), as opposed to real women, whose complications are mostly minor. Major medical interventions (e.g., hysterectomy) were similarly overportrayed, while the most commonly used interventions for real patients (e.g., medication) were not depicted at all. Finally, 22.5% of characters faced a long-term adverse health consequence, including mental illness, infertility or death. The onscreen abortion mortality rate was 5%, about 7000 times the actual mortality rate. CONCLUSIONS: Overall, television dramatically exaggerates the risk associated with abortion procedures, overportraying medical complications - particularly major and life-threatening complications - and long-term adverse health consequences. This pattern of misrepresentation may be partially attributable to the occurrence of stories about illegal abortions or abortions taking place outside of modern medical contexts. IMPLICATIONS: Onscreen abortion portrayals may contribute to inaccurate beliefs about abortion's risk that are common among the public, broadly, and abortion patients, specifically. Abortion advocates and providers will be more equipped to respond misinformation if they understand how and to what extent our popular culture portrays abortion as unsafe. PMID- 28365159 TI - Genetic Alterations in the Molecular Subtypes of Bladder Cancer: Illustration in the Cancer Genome Atlas Dataset. AB - CONTEXT: Recent whole genome mRNA expression profiling studies revealed that bladder cancers can be grouped into molecular subtypes, some of which share clinical properties and gene expression patterns with the intrinsic subtypes of breast cancer and the molecular subtypes found in other solid tumors. The molecular subtypes in other solid tumors are enriched with specific mutations and copy number aberrations that are thought to underlie their distinct progression patterns, and biological and clinical properties. OBJECTIVE: The availability of comprehensive genomic data from The Cancer Genome Atlas (TCGA) and other large projects made it possible to correlate the presence of DNA alterations with tumor molecular subtype membership. Our overall goal was to determine whether specific DNA mutations and/or copy number variations are enriched in specific molecular subtypes. EVIDENCE: We used the complete TCGA RNA-seq dataset and three different published classifiers developed by our groups to assign TCGA's bladder cancers to molecular subtypes, and examined the prevalence of the most common DNA alterations within them. We interpreted the results against the background of what was known from the published literature about the prevalence of these alterations in nonmuscle-invasive and muscle-invasive bladder cancers. EVIDENCE SYNTHESIS: The results confirmed that alterations involving RB1 and NFE2L2 were enriched in basal cancers, whereas alterations involving FGFR3 and KDM6A were enriched in luminal tumors. CONCLUSIONS: The results further reinforce the conclusion that the molecular subtypes of bladder cancer are distinct disease entities with specific genetic alterations. PATIENT SUMMARY: Our observation showed that some of subtype-enriched mutations and copy number aberrations are clinically actionable, which has direct implications for the clinical management of patients with bladder cancer. PMID- 28365167 TI - Outcomes of the Ilizarov frame use in elderly patients. AB - AIM: The use of circular frame is widely accepted. This is an outcome review on use of circular Ilizarov frame in elderly patients. MATERIALS & METHODS: Data from all patients treated with an Ilizarov circular frame between January 2002 and December 2014, who were 65 years of age or over at surgery was collected. Seventy Ilizarov circular frames were applied during this period in our unit at a mean age of 71.2 years. Clinical, radiological and quality of life questionnaire (SF-12) data were gathered. Mortality, complication and revision data were also collected. RESULTS: Indications of application of Ilizarov frame were fractures (53%), non-unions (19%), deformity correction (7%) and ankle fusions (21%). Mean period of time in the frame was 184.4 +/- 84.2 days. Mortality and complication rates were low (5-7%) at a mean follow-up 4.2 years. There was no case of septic arthritis or newly induced deep infection. Physical and Mental components of SF 12 questionnaire returned to normal for that age group. There was no difference between the subgroups (tibia plateau fractures, pilon fractures, ankle fusions, non-unions, deformity correction and miscellaneous trauma) concerning the physical and mental subjective (PCS and MCS SF-12 component) outcomes (p > 0.05). CONCLUSIONS: Ilizarov circular frame as a definitive treatment of many kinds of trauma and orthopaedic conditions can be safely and reliably used in the elderly with good quality of life results. PMID- 28365168 TI - Verification of the sensitivity of functional scores for treatment results - Substantial clinical benefit thresholds for the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ). AB - BACKGROUND: Validity and reliability of the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) had already been verified as the patients' self-rating assessment of low back pain and lumbar spinal disease and, the present study demonstrated the responsiveness of this measure. METHODS: 192 subjects who were determined by medical instructors of the Japanese Society for Spine Surgery and Related Research were analyzed. They had completed a series of treatment and both surveys before and after the treatment. Authors investigated rates of concordance between assessment by physicians and subjective assessment by patients. The mean, standard deviation, minimum, 25th percentile, median, 75th percentile and maximum values for pre-treatment, post-treatment, and acquired points were calculated, and then, we also investigated the trend between subjective assessment by patients and mean acquired points for each JOABPEQ domain and substantial clinical benefit thresholds for the JOABPEQ. RESULTS: Symptom changes as assessed by physicians did not coincide with those by patients, and acquired points in each JOABPEQ domain were significantly increased with improved self-rating by patients. In addition, patients who rated symptom changes as "slightly improved" showed a mean acquired points of >=20, and those reporting "improved" showed a 25th percentile points of the acquired points of >=20 approximately. CONCLUSION: A significant correlation was noted between the self-rating of patients and acquired points JOABPEQ, suggesting that >=20 acquired points can be interpreted as substantial clinical benefit thresholds for the JOABPEQ. PMID- 28365170 TI - Radio-frequency coils for ultra-high field magnetic resonance. AB - Radiofrequency (RF) coils are key components of magnetic resonance imaging (MRI) systems. The primary purpose of this review is to provide a basic theory of RF coil designs and their characterization by bench measurements, electromagnetic field simulations and MR measurements. With the continuing increase of magnetic field strength in MRI instruments, the RF wavelength in the subject under study becomes comparable to or smaller in size than the anatomical dimensions of the tissue under study, which amplifies the signal inhomogeneity. Also, RF energy increases quadratically with the Larmor frequency, which leads to increased heat deposition in the subject, especially at ultra-high field. Elegant RF coil designs are explored here to address these challenges. PMID- 28365169 TI - Clinic meatotomy under topical anesthesia. AB - OBJECTIVES: Almost 20 years after Cartwright et al. (1996) demonstrated the feasibility and effectiveness of clinic meatotomy (CM) under topical lidocaine and prilocaine (EMLA) anesthesia, 50% of meatotomies are still performed under general anesthesia (GA) (Godley et al., 2015). The cost of a meatotomy under GA is approximately 10 times the cost of CM in the present practice. This study presented the outcomes for CM under topical anesthesia, in consecutive patients who presented with meatal stenosis secondary to circumcision. MATERIALS AND METHODS: This was a retrospective descriptive study of data, which were collected prospectively for quality improvement purposes from July 2013 to September 2015, of 55 consecutive boys who underwent CM for meatal stenosis (occlusion of urethral meatus by a crust; deflected stream). Meatotomy was performed after applying EMLA and covering it with a Tegaderm(r) dressing, and then waiting 20-60 min. The recorded outcomes were pain and success rate. Pain was defined at the beginning of data collection as any sound, grimace or movement during the procedure. Success rate was recorded during follow-up in the clinic or over the phone, when the family was asked if symptoms were the same, improved or completely resolved. RESULTS: Forty-three boys (78%) had no pain and 12 (22%) had pain as defined above (Figure), but no CM had to be stopped due to pain. At a median follow-up of 1.6 months (IQR 1.3-2.7 months) 41 (75%) patients had resolution of their symptoms and a normal urinary stream, nine (16%) had improved symptoms, and three (5%) had unchanged symptoms. CONCLUSIONS: More patients reported pain than those in the Cartwright study; this was perhaps because a full hour was not waited after EMLA application with most of the present patients. The present success rate was also lower than that reported by Cartwright, and for that there is no explanation. However, all CM could be completed and >90% of patients saw resolution or improvement of their symptoms. At a cost ten times lower than a meatotomy performed under GA, and with no evidence of inferiority evident in the literature, it is believed that CM should be the standard of care when meatal stenosis is treated by a meatotomy. PMID- 28365171 TI - Midterm Clinical Outcomes and MR Imaging Changes after Transcatheter Arterial Embolization as a Treatment for Mild to Moderate Radiographic Knee Osteoarthritis Resistant to Conservative Treatment. AB - PURPOSE: To describe the safety and efficacy of transcatheter arterial embolization for mild to moderate radiographic knee osteoarthritis (OA) that is resistant to conservative treatment. MATERIALS AND METHODS: This prospective study included 72 patients (95 knees) with OA of Kellgren-Lawrence (KL) grade 1-3 and persisting moderate to severe pain that was resistant to conservative management who were treated with transcatheter arterial embolization between July 2012 and March 2016. Clinical outcomes were evaluated at 1, 4, and 6 months and then every 6 months for a maximum of 4 years. The Whole-Organ Magnetic Resonance Imaging Score (WORMS) was evaluated at baseline and at 2 years after embolization in 35 knees. RESULTS: Abnormal neovessels were identified in all cases. There were no major adverse events related to the procedures. Mean Western Ontario and McMaster Universities Osteoarthritis Index pain scores significantly decreased from baseline to 1, 4, 6, 12, and 24 months after treatment (12.1 vs 6.2, 4.4, 3.7, 3.0, and 2.6; all P < .001). The cumulative clinical success rates at 6 months and 3 years after embolization were 86.3% (95% confidence interval [CI], 78%-92%) and 79.8% (95% CI, 69%-87%), respectively. WORMS scores at 2 years after embolization in 35 knees showed significant improvement of synovitis vs baseline (P = .0016) and no osteonecrosis or other evidence indicating aggressive progression of degenerative changes. CONCLUSIONS: Transcatheter arterial embolization significantly improved pain symptoms and clinical function in patients with mild to moderate knee OA that was resistant to conservative treatment. PMID- 28365173 TI - Marijuana advertising exposure among current marijuana users in the U.S. AB - BACKGROUND: Little is known about marijuana advertising exposure among users in the U.S. We examined the prevalence of advertising exposure among young adult marijuana users through traditional and new media, and identified characteristics associated with seeking advertisements. METHODS: We conducted a cross-sectional survey of 18-34 year-old past-month marijuana users in the U.S. using a pre existing online panel (N=742). The survey queried about passively viewing and actively seeking marijuana advertisements in the past month, sources of advertisements, and marijuana use characteristics. RESULTS: Over half of participants were exposed to marijuana advertising in the past month (28% passively observed advertisements, 26% actively sought advertisements). Common sources for observing advertisements were digital media (i.e., social media, online, text/emails; 77%). Similarly, those actively seeking advertisements often used Internet search engines (65%) and social media (53%). Seeking advertisements was more common among those who used medically (41% medical only, 36% medical and recreational) than recreational users (18%), who used concentrates or edibles (44% and 43%) compared to those who did not (20% and 19%), and who used multiple times per day (33%) compared to those who did not (19%) (all p<0.01). CONCLUSIONS: Exposure to marijuana advertising among users is common, especially via digital media, and is associated with medical use, heavier use, and use of novel products with higher THC concentrations (i.e., concentrates) or longer intoxication duration (i.e., edibles). As the U.S. marijuana policy landscape changes, it will be important to examine potential causal associations between advertising exposure and continuation or frequency/quantity of use. PMID- 28365174 TI - Which alternative communication methods are effective for voiceless patients in Intensive Care Units? A systematic review. AB - OBJECTIVE: To assess the effectiveness of Augmentative and Alternative Communication (AAC) strategies to enable people who are temporarily voiceless due to medical intervention, to communicate. METHODS: A systematic review informed by a protocol published on an international register. Ten databases were searched from January 2004 to January 2017. Included studies assessed the effect of using AAC strategies on patient related outcomes and barriers to their use. All included studies were quality appraised. Due to the heterogeneity of interventions and outcome measures findings were narratively reviewed. RESULTS: Twelve studies met the inclusion criteria and were included in the review reporting outcomes from 1981 patient and 454 health professional participants. The quality of included studies were moderate to weak. AAC communication strategies increased the number of communication interactions, improved patient satisfaction with communication and reduced communication difficulties. Barriers to usage were device characteristics, the clinical condition of the patient, lack of timeliness in communication and staff constraints. CONCLUSIONS: There is preliminary, but inconsistent evidence that AAC strategies are effective in improving patient satisfaction with communication and reducing difficulties in communication. A lack of comparable studies precluded the identification of the most effective AAC strategy. PMID- 28365172 TI - Segmental Yttrium-90 Radioembolization versus Segmental Chemoembolization for Localized Hepatocellular Carcinoma: Results of a Single-Center, Retrospective, Propensity Score-Matched Study. AB - PURPOSE: To compare segmental radioembolization with segmental chemoembolization for localized, unresectable hepatocellular carcinoma (HCC) not amenable to ablation. MATERIALS AND METHODS: In a single-center, retrospective study (2010 2015), 101 patients with 132 tumors underwent segmental radioembolization, and 77 patients with 103 tumors underwent segmental doxorubicin-based drug-eluting embolic or conventional chemoembolization. Patients receiving chemoembolization had worse performance status (Eastern Cooperative Oncology Group 0, 76% vs 56%; P = .003) and Child-Pugh class (class A, 65% vs 52%; P = .053); patients receiving radioembolization had larger tumors (32 mm vs 26 mm; P < .001), more infiltrative tumors (23% vs 9%; P = .01), and more vascular invasion (18% vs 1%; P < .001). Toxicity, tumor response, tumor progression, and survival were compared. Analyses were weighted using a propensity score (PS). RESULTS: Toxicity rates were low, without significant differences. Index and overall complete response rates were 92% and 84% for radioembolization and 74% and 58% for chemoembolization (P = .001 and P < .001). Index tumor progression at 1 and 2 years was 8% and 15% in the radioembolization group and 30% and 42% in the chemoembolization group (P < .001). Median progression-free and overall survival were 564 days and 1,198 days in the radioembolization group and 271 days and 1,043 days in the chemoembolization group (PS-adjusted P = .002 and P = .35; censored by transplant PS-adjusted P < .001 and P = .064). CONCLUSIONS: Segmental radioembolization demonstrates higher complete response rates and local tumor control compared with segmental chemoembolization for HCC, with similar toxicity profiles. Superior progression-free survival was achieved. PMID- 28365175 TI - Outcomes following implantation of mechanical circulatory support in adults with congenital heart disease: An analysis of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). AB - BACKGROUND: Adults with congenital heart disease represent an expanding and unique population of patients with heart failure (HF) in whom the use of mechanical circulatory support (MCS) has not been characterized. We sought to describe overall use, patient characteristics, and outcomes of MCS in adult congenital heart disease (ACHD). METHODS: All patients entered into the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) between June 23, 2006, and December 31, 2015, were included. Patients with ACHD were identified using pre-operative data and stratified by ventricular morphology. Mortality was compared between ACHD and non-ACHD patients, and multivariate analysis was performed to identify predictors of death after device implantation. RESULTS: Of 16,182 patients, 126 with ACHD stratified as follows: systemic morphologic left ventricle (n = 63), systemic morphologic right ventricle (n = 45), and single ventricle (n = 17). ACHD patients were younger (42 years +/- 14 vs 56 years +/- 13; p < 0.0001) and were more likely to undergo device implantation as bridge to transplant (45% vs 29%; p < 0.0001). A higher proportion of ACHD patients had biventricular assist device (BiVAD)/total artificial heart (TAH) support compared with non-ACHD patients (21% vs 7%; p < 0.0001). More ACHD patients on BiVAD/TAH support were INTERMACS profile 1 compared with patients on systemic left ventricular assist device (LVAD) support (35% vs 15%; p = 0.002). ACHD and non-ACHD patients with LVADs had similar survival; survival was worse for patients on BIVAD/TAH support. BiVAD/TAH support was the only variable independently associated with mortality (early phase hazard ratio 4.4; 95% confidence interval, 1.8-11.1; p = 0.001). For ACHD patients receiving MCS, ventricular morphology was not associated with mortality. CONCLUSIONS: ACHD patients with LVADs have survival similar to non-ACHD patients. Mortality is higher for patients requiring BiVAD/TAH support, potentially owing to higher INTERMACS profile. These outcomes suggest a promising role for LVAD support in ACHD patients as part of the armamentarium of therapies for advanced HF. PMID- 28365176 TI - Into the hearts of babes: Stem cell therapy for pediatric heart failure. PMID- 28365177 TI - High-dose vitamin D after lung transplantation: A randomized trial. AB - BACKGROUND: Vitamin D may have innate immunomodulatory functions with potentially beneficial therapeutic effects in lung transplant recipients. METHODS: This was a single-center, double blind, randomized, placebo-controlled, prevention trial of once-monthly oral vitamin D (cholecalciferol; 100,000 IU, n = 44) vs placebo (n = 43) during 2 years in adult lung transplant recipients enrolled from October 2010 to August 2013. Primary outcome was prevalence of chronic lung allograft dysfunction (CLAD) 3 years after transplantation. Secondary outcomes included overall survival, prevalence of acute rejection, lymphocytic bronchiolitis and infection, lung function, pulmonary and systemic inflammation, and bone mineral density. RESULTS: All included patients underwent bilateral lung transplantation and were mostly middle-aged men with prior smoking-related emphysema. Levels of 25-hydroxy vitamin D after 1 year (p < .001) and 2 years (p < .001) were significantly higher in the vitamin D group compared with the placebo group. No difference was observed for CLAD prevalence (p = 0.7) or CLAD-free survival between both groups (p = 0.7). Secondary outcomes were overall comparable between both groups (all p > 0.05). CONCLUSIONS: Once-monthly oral vitamin D supplementation after lung transplantation fails to demonstrate a significant difference in CLAD prevalence, innate immunomodulatory, or a beneficial clinical effect compared with placebo. PMID- 28365178 TI - Pediatric Heart Donor Assessment Tool (PH-DAT): A novel donor risk scoring system to predict 1-year mortality in pediatric heart transplantation. AB - BACKGROUND: In this study we sought to quantify hazards associated with various donor factors into a cumulative risk scoring system (the Pediatric Heart Donor Assessment Tool, or PH-DAT) to predict 1-year mortality after pediatric heart transplantation (PHT). METHODS: PHT data with complete donor information (5,732) were randomly divided into a derivation cohort and a validation cohort (3:1). From the derivation cohort, donor-specific variables associated with 1-year mortality (exploratory p-value < 0.2) were incorporated into a multivariate logistic regression model. Scores were assigned to independent predictors (p < 0.05) based on relative odds ratios (ORs). RESULTS: The final model had an acceptable predictive value (c-statistic = 0.62). The significant 5 variables (ischemic time, stroke as the cause of death, donor-to-recipient height ratio, donor left ventricular ejection fraction, glomerular filtration rate) were used for the scoring system. The validation cohort demonstrated a strong correlation between the observed and expected rates of 1-year mortality (r = 0.87). The risk of 1-year mortality increases by 11% (OR 1.11 [1.08 to 1.14]; p < 0.001) in the derivation cohort and 9% (OR 1.09 [1.04 to 1.14]; p = 0.001) in the validation cohort with an increase of 1-point in score. Mortality risk increased 5 times from the lowest to the highest donor score in this cohort. Based on this model, a donor score range of 10 to 28 predicted 1-year recipient mortality of 11% to 31%. CONCLUSION: This novel pediatric-specific, donor risk scoring system appears capable of predicting post-transplant mortality. Although the PH-DAT may benefit organ allocation and assessment of recipient risk while controlling for donor risk, prospective validation of this model is warranted. PMID- 28365179 TI - Reliability and number of trials of Y Balance Test in adolescent athletes. AB - BACKGROUND: The Star Excursion Balance Test (SEBT) is commonly used to evaluate dynamic equilibrium. The Y Balance Test (Y-BT) is a shortened version of the SEBT where a Y- Balance Kit is commonly used. To date, research concerning the protocol and reliability of the SEBT and Y-BT has been conducted only for adults. OBJECTIVES: The aim of the study was to assess the protocol (the necessary number of trials to stabilize the results) and reliability of the Y-BT in adolescent athletes. DESIGN: One-way repeated-measures analysis of variance (ANOVA) and reliability study. METHOD: The sample of 38 athletes (mean age: 15.6 years) was selected from a football club. A Y-Balance test kit was applied for the evaluation of dynamic balance. The analysis used the values normalized to the relative length of the lower limbs. RESULTS: After six attempts, three consecutive ones achieved stability for all directions and both extremities (p > 0.05). The intraclass correlation coefficient (ICC3,1), standard error of measurement and minimal detectable change values for the three attempts ranged from 0.57 to 0.82, from 3 to less than 6% and from 7.68 to 13.7%, respectively. CONCLUSIONS: In the study of adolescent dynamic equilibrium using the Y-BT, it is recommended to perform nine attempts (including six trial attempts and three measurements). In order to increase reliability it is recommended that the average of the three measured attempts is analysed. PMID- 28365180 TI - Practices in management of cancer treatment-related cardiovascular toxicity: A cardio-oncology survey. AB - BACKGROUND: Cardiovascular toxicity has become a challenging issue during cancer therapy. Nonetheless, there is a lack of consensual guidelines for their management. We aimed to determine the current practices of oncologists regarding cardiovascular toxicity related to anthracyclines, trastuzumab and angiogenic inhibitors and to gather their opinions on the development of cardio-oncology programs. METHODS: A cross-sectional declarative study was submitted to French oncologists in the form of an individual, structured questionnaire. RESULTS: A total of 303 oncologists responded to the survey. Ninety-nine percent of oncologists prescribed cardiotoxic therapies, including anthracyclines (83%), trastuzumab (51%) and other angiogenic inhibitors (64%). The method adopted for managing cardiovascular toxicity was based on guidelines from expert oncology societies for only 35% of oncologists. None was aware of recommendations from expert cardiology societies. Prescription of pre-, peri- and post-therapy cardiovascular assessment was inconsistent and significantly less frequent for all classes of angiogenic inhibitors than for anthracyclines and trastuzumab (P<0.0001). Relative to pre-therapy assessment, post-therapy assessment was prescribed significantly less often for all cancer therapies (P<0.0001). Attitudes regarding the onset of left ventricular dysfunction were much more inconsistent when angiogenic inhibitors were involved. Additionally, the management of hypertension and QT prolongation was also inconsistent. Finally, 88% of oncologists supported projects of cardio-oncology programs development. CONCLUSIONS: Practices of oncologists are disparate in the field of cardiovascular toxicity. This finding underlines the complexity of managing many different situations and the need for distribution of formal guidelines from oncology and cardiology expert societies. The development of personalized cardio oncology programs seems essential. PMID- 28365181 TI - Sudden death in ischemic heart disease - 2017. AB - At this time, we find ourselves with an abundance of guidelines for management of patients with manifest ventricular tachyarrhythmias, or at risk for such arrhythmias, in patients with coronary heart disease (CHD). The guidelines are focused primarily on the "appropriate use" of the implantable cardioverter/defibrillator (ICD). Unfortunately, the bulk of the guidelines have very little basis in the underlying pathophysiology responsible for sudden cardiac death (SCD) in patients with CHD. Rather, they are based primarily on the results of randomized clinical trials that merely sought to take broad populations at elevated total mortality risk and determining whether the ICD can reduce overall mortality. The trials were not aimed at elucidating or exploiting the varying pathophysiology responsible for the ventricular arrhythmias responsible for most sudden deaths in this setting. The goal of the trials is appropriate - to improve the survival. The problem with promoting trials that solely determine whether a broad-based population (identified by one parameter such as ejection fraction that bears no direct relation to the pathogenesis of arrhythmias) derives a survival benefit from a therapy such as the ICD, is that many patients that could benefit from the ICD are missed (not covered by the guidelines), and many patients that will never benefit from the ICD are exposed to its risks and costs. How can we advance the use of potent, but expensive therapies that carry risk such as the ICD to improve survival of patients with CHD today? There are several avenues worth pursuing, both for short-term as well as long-term gain. First, there are several models shown to have the potential to identify patients currently covered by the guidelines for ICD use, that are highly unlikely to benefit, because of the existing co-morbidities. These models are likely to be valid because there is significant overlap in the parameters identified in each model, and they have been tested retrospectively in a variety of study populations. These models are not likely to be incorporated into use guidelines, until they have been tested prospectively in a randomized trial in a contemporary patient population. This can, and should be done. Use of such a model, based on noninvasive, readily available clinical markers offers the possibility of improving the efficiency with which ICDs are used to reduce the risk of SCD in CHD patients. Second, we need to recognize the fact that SCD in this population is a result of multiple potential mechanisms. And, the electrophysiologic substrates underlying these mechanisms are influenced by interactions with the autonomic nervous system and hemodynamic conditions. While most out-of-hospital cardiac arrests do not occur in persons with overt heart failure, the presence of heart failure clearly increases the risk for SCD, likely by a variety of mechanisms. There is increasing evidence that altered left ventricular geometry may not only reduce LV mechanical efficiency, but may also have direct effects on the electrophysiologic substrate. Although there is an abundance of evidence supporting the importance of autonomic interactions in the genesis of spontaneous arrhythmias, the utility of prospectively measuring autonomic indices to predict future arrhythmic events has to date not proven to be useful. Of course, that is not to discount the significant impact of beta adrenergic blockade on survival and reducing arrhythmic events. Future works must focus more on both animal models of post-infarction arrhythmias, as well as integrating findings from such studies into human physiology, with subsequent testing in the form of randomized clinical trials. PMID- 28365182 TI - Hopes and disappointments with antiarrhythmic drugs. AB - Ventricular arrhythmias such as sustained ventricular tachycardia and ventricular fibrillation account for two thirds of sudden cardiac deaths. Most ventricular tachyarrhythmias have well understood mechanisms such that it is theoretically possible to conceive of an antiarrhythmic drug-based intervention that would prevent arrhythmias that cause sudden cardiac death. Pharmaceutical agents which interfere with ion channel activity are known as antiarrhythmic drugs. Acute experiments showing antiarrhythmic effects in the basic science laboratory have often not translated into clinical effectiveness. Evidence of efficacy has been difficult to assess and appears to be sparse. However, proarrhythmia is common and complicates assessment of the potential value of antiarrhythmic drugs. Important studies such as the Cardiac Arrhythmia Suppression Trial and the Survival With ORal d-sotalol study confirmed that antiarrhythmic drugs could kill rather than cure patients at risk of sudden cardiac death, and spelled the death knell for widespread use of antiarrhythmic drugs for the primary prevention of sudden cardia death in high risk patients. However, when the implantable cardioverter defibrillator was introduced into clinical practice the situation changed - a drug that generally suppressed ventricular tachyarrhythmias was needed, but safety concerns were alleviated because the ICD could reverse proarrhythmic adverse effects. The accent changed towards the development of drugs that might reduce the prevalence or the symptomatic burden of ventricular arrhythmias. Similarly, antiarrhythmic drug development progressed towards finding an agent that might reduce symptoms associated with recurrent atrial fibrillation rather than for the treatment of ventricular arrhythmia. In recent times the goal of antiarrhythmic therapy has changed again. No longer is it thought necessary to develop blockbuster therapies, but to concentrate on the specific mechanisms of cardiac arrhythmias in individuals and to develop therapies that can be specifically engineered to help carefully defined phenotypes. Personalised or precision medicine is now guiding the development of antiarrhythmic agents that are directed to very specific targets and arrhythmia mechanisms and are without off-target effects that may compromise their efficacy. The value of antiarrhythmic medical therapy has raised great hopes which have been followed by disillusionment. Now hopes and needs are rising again, and we are better prepared to make this therapy successful. If we understand the arrhythmias we may be able to design effective and uncomplicated therapy. PMID- 28365183 TI - Sudden cardiac death in 2017: Spotlight on prediction and prevention. AB - This commentary will provide a brief synopsis of the progress made in prediction and prevention of sudden cardiac death (SCD), the challenges that remain, and the opportunities available to make a real impact in this field. The dawning of the new millennium saw the prophylactic implantable defibrillator (ICD) firmly established as the major primary prevention modality, poised to make a major impact on the burden of SCD. More than a decade and a half later, has this expectation been realized? The modest impact of the primary prevention ICD on SCD burden is largely due to the now well-recognized inadequate performance of the left ventricular ejection fraction as a risk stratification tool. Consequently, the field has transitioned from a focus on the "high-risk ejection fraction" to the broader concept of the "high-risk patient". There are currently no effective means of stratifying SCD risk in patients with preserved EF, who constitute the majority (at least 70%) of all patients who will suffer SCD. Can the field be disrupted and novel predictors of SCD identified? In addition to the ongoing quest for identification of the high-risk patient early in the nature history of SCD, a new paradigm for preventing SCD in the "near-term", within several weeks of the lethal event, has been proposed. While rapid advances in technology, data warehousing and analysis will accelerate the process of enhancing SCD prediction and prevention; regulatory, funding and clinical implementation strategies will need to keep pace if these expectations are to be realized. PMID- 28365184 TI - Annotation of plasmid genes. AB - Good annotation of plasmid genomes is essential to maximise the value of the rapidly increasing volume of plasmid sequences. This short review highlights some of the current issues and suggests some ways forward. Where a well-studied related plasmid system exists we recommend that new annotation adheres to the convention already established for that system, so long as it is based on sound principles and solid experimental evidence, even if some of the new genes are more similar to homologues in different systems. Where a well-established model does not exist we provide generic gene names that reflect likely biochemical activity rather than overall purpose particularly, for example, where genes clearly belong to a type IV secretion system but it is not known whether they function in conjugative transfer or virulence. We also recommend that annotators use a whole system naming approach to avoid ending up with an illogical mixture of names from other systems based on the highest scoring match from a BLAST search. In addition, where function has not been experimentally established we recommend using just the locus tag, rather than a function-related gene name, while recording possible functions as notes rather than in a provisional name. PMID- 28365185 TI - Curcumin and its cyclohexanone analogue inhibited human Equilibrative nucleoside transporter 1 (ENT1) in pancreatic cancer cells. AB - Our group investigated combining the phytochemical curcumin and gemcitabine in a liposome, to improve gemcitabine's activity against pancreatic tumours. While optimising the curcumin: gemcitabine ratio for co-encapsulation, we found that increasing curcumin concentrations relative to gemcitabine resulted in antagonistic interactions. As curcumin is a promiscuous transporter inhibitor; we suspected that increased resistance occurred via inhibition of Equilibrative nucleoside transporter 1 (ENT1)-mediated gemcitabine uptake. To test our hypothesis, we determined whether curcumin and a related analogue, 2,6-bis((3 methoxy-4-hydroxyphenyl)methylene)-cyclohexanone (or A13), inhibited ENT1 mediated accumulation of [3H]uridine and [3H]gemcitabine into pancreatic cancer cells. We then confirmed the inhibition of gemcitabine accumulation by investigating whether curcumin/A13 could increase gemcitabine resistance in growth inhibition assays. We found that curcumin and A13 concentration dependently inhibited the ENT1-mediated accumulation of both uridine and gemcitabine in MIA PaCa-2 and PANC-1 cells. We also found that non-toxic concentrations of curcumin and A13 significantly increased the resistance of both cell lines to gemcitabine. Increased resistance only occurred when curcumin/A13 was co-incubated with gemcitabine, and not with sequential exposure (i.e., curcumin first, followed by gemcitabine, or vice versa). We also found that the curcumin analogue (3E,5E)-3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone (or EF24) did not inhibit gemcitabine accumulation, making it more suitable in combinations than curcumin/A13. From these results, we concluded that curcumin and A13 are inhibitors of the ENT1 transporter, but only at high concentrations (2-20uM). Curcumin is unlikely to inhibit gemcitabine uptake in tumours but may interfere with the oral absorption of ENT1 substrates due to high gut concentrations readily achievable from over-the-counter tablets/capsules. PMID- 28365186 TI - Plastic bronchitis in a patient with silicosis. PMID- 28365187 TI - Percutaneous closure of coronary artery fistula before lung transplantation. PMID- 28365188 TI - Implementation and assessment of a training course for residents in neonatology and pediatric emergency medicine. AB - BACKGROUND AND AIMS: Residents must balance patient care and the ongoing acquisition of medical knowledge. With increasing clinical responsibilities and patient overload, medical training is often left aside. In 2010, we designed and implemented a training course in neonatology and pediatric emergency medicine for residents in pediatrics, in order to improve their medical education. The course was made of didactic sessions and several simulation-based seminars for each year of residency. We conducted this study to assess the impact of our program on residents' satisfaction and self-assessed clinical skills. METHODS: A survey was conducted at the end of each seminar. The students were asked to complete a form on a five-point rating scale to evaluate the courses and their impact on their satisfaction and self-assessed clinical skills, following the French National Health Institute's adapted Kirkpatrick model. RESULTS: Sixty-four (84%) of the 76 residents who attended the courses completed the form. The mean satisfaction score for the entire course was 4.78+/-0.42. Over 80% of the students felt that their clinical skills had improved. CONCLUSION: Medical education is an important part of residency training. Our training course responded to the perceived needs of the students with consistently satisfactory evaluations. Before the evaluation of the impact of the course on patient care, further studies are needed to assess the acquisition of knowledge and skills through objective evaluations. PMID- 28365189 TI - [Drugs news]. PMID- 28365190 TI - [Kikuchi-Fujimoto disease mimicking malignant lymphoma in adolescents]. AB - Kikuchi-Fujimoto disease, also known as histiocytic necrotizing lymphadenitis, is a rare cause of lymphadenopathy in children. This benign disease can mimic lymphoma and misleads doctors. It was first described in Asia, where it occurred especially in young women. Recent publications show that it can also affect teenagers and young adults in Caucasian populations. The pathophysiology remains unknown. Three hypotheses have been raised for this disease: the role of viruses (in particular HHV-8), genetic predisposition (two alleles in HLA class II genes were found more frequently in patients with Kikuchi disease), and an autoimmune cause because of the correlation with lupus erythematosus. Few cases have been reported in Europe so far. In this article, we report three cases of Kikuchi disease observed in less than 2 months in a single hospital in France. All three patients were teenagers who presented with lymphadenopathy, either isolated or combined with fever, weakness, and weight loss. In all of them, the hypermetabolic activity of the lymph node on the PET scanner misled us to suspect lymphoma. The diagnosis of Kikuchi disease was finally made, for all patients, after 2 weeks in the hospital based on lymph node biopsy. Based on this report, we highlight that early biopsy in presence of lymphadenopathy can avoid unnecessary extensive investigations. Moreover, in this rare disease, it is very surprising to come across three cases that are not family-related, in such a short period of time. This strengthens the hypothesis of the possible implication of an environmental factor in the pathophysiology of Kikuchi disease. PMID- 28365191 TI - [Thymoma and autoimmune diseases]. AB - The association between thymoma and autoimmunity is well known. Besides myasthenia gravis, which is found in 15 to 20% of patients with thymoma, other autoimmune diseases have been reported: erythroblastopenia, systemic lupus erythematosus, inflammatory myopathies, thyroid disorders, Isaac's syndrome or Good's syndrome. More anecdotally, Morvan's syndrome, limbic encephalitis, other autoimmune cytopenias, autoimmune hepatitis, and bullous skin diseases (pemphigus, lichen) have been reported. Autoimmune diseases occur most often before thymectomy, but they can be discovered at the time of surgery or later. Two situations require the systematic investigation of a thymoma: the occurrence of myasthenia gravis or autoimmune erythroblastopenia. Nevertheless, the late onset of systemic lupus erythematosus or the association of several autoimmune manifestations should lead to look for a thymoma. Neither the characteristics of the patients nor the pathological data can predict the occurrence of an autoimmune disease after thymectomy. Thus, thymectomy usefulness in the course of the autoimmune disease, except myasthenia gravis, has not been demonstrated. This seems to indicate the preponderant role of self-reactive T lymphocytes distributed in the peripheral immune system prior to surgery. Given the high infectious morbidity in patients with thymoma, immunoglobulin replacement therapy should be considered in patients with hypogammaglobulinemia who receive immunosuppressive therapy, even in the absence of prior infection. PMID- 28365192 TI - Community-level policy responses to state marijuana legalization in Washington State. AB - BACKGROUND: Washington State (WA) legalized a recreational marijuana market - including growing, processing and retail sales - through voter initiative 502 in November 2012. Legalized recreational marijuana retail sales began in July 2014. In response to state legalization of recreational marijuana, some cities and counties within the state have passed local ordinances that either further regulated marijuana markets, or banned them completely. The purpose of this study is to describe local-level marijuana regulations on recreational retail sales within the context of a state that had legalized a recreational marijuana market. METHODS: Marijuana-related ordinances were collected from all 142 cities in the state with more than 3000 residents and from all 39 counties. Policies that were in place as of June 30, 2016 - two years after the state's recreational market opening - to regulate recreational marijuana retail sales within communities were systematically coded. RESULTS: A total of 125 cities and 30 counties had passed local ordinances to address recreational marijuana retail sales. Multiple communities implemented retail market bans, including some temporary bans (moratoria) while studying whether to pursue other policy options. As of June 30, 2016, 30% of the state population lived in places that had temporarily or permanently banned retail sales. Communities most frequently enacted zoning policies explicitly regulating where marijuana businesses could be established. Other policies included in ordinances placed limits on business hours and distance requirements (buffers) between marijuana businesses and youth-related land use types or other sensitive areas. CONCLUSIONS: State legalization does not necessarily result in uniform community environments that regulate recreational marijuana markets. Local ordinances vary among communities within Washington following statewide legalization. Further study is needed to describe how such local policies affect variation in public health and social outcomes. PMID- 28365194 TI - Corrigendum to "Role of a gitogenin-type steroidal saponin (3-O-beta-d glucopyranosyl (1->2)-beta-d-glucopyranosyl (1->4)-beta-d-galactopyranoside-25R, 5alpha-spirostane-2alpha,3beta-diol), isolated from the leaves of Malvastrum coromandelianum in regulating thyrotoxicosis in rats" [Bioorg. Med. Chem. Lett. 26 (2016) 4804-4807]. PMID- 28365193 TI - Danger in the streets: exposures to bloodborne pathogens after community sharp injuries in Rio de Janeiro, Brazil. AB - OBJECTIVE: Exposures to sharps injuries occurring in the community are relatively frequent. We describe characteristics of community sharp exposures reported in the city of Rio de Janeiro from 1997 to 2010. METHODS: A cross-sectional analysis of exposure reports to sharps in the community reported to a surveillance system, designed for health care workers, of the Municipal Health Department of Rio de Janeiro. The characteristics of exposed individuals analyzed included types of exposure, the circumstances of the accident, and the prophylaxis offered. RESULTS: 582 exposures were studied. Median age was 30 years and 83 (14%) involved children with less than 10 years of age. Two hundred and seventeen (37%) occurred with sharps found in the streets. The exposure was percutaneous in 515 (89%) and needles where involved in 406 (70%) of them. The sharps were present in the trash in 227 (39%) or in the environment in 167 (29%) of the reports. Professionals who work with frequent contact with domestic or urban waste were 196 (38%). The source was known in 112 (19%) of the exposures and blood was involved in 269 (46%). Only 101 (19%) of the injured subjects reported a complete course of vaccination for hepatitis B. Antiretroviral prophylaxis was prescribed for 392 (68%) of the exposed subjects. CONCLUSIONS: Sharps injuries occurring in the community are an important health problem. A great proportion would be avoided if practices on how to dispose needles and sharps used outside health units were implemented. PMID- 28365195 TI - Zebrafish FOXP3 is required for the maintenance of immune tolerance. AB - Regulatory T (Treg) cells play a central role in the suppression of excessive immune responses against both self and non-self antigens. The development and function of Treg cells are controlled by a master regulatory gene encoding the forkhead box P3 (FOXP3) protein in mammals. However, little is known regarding the functions of Treg cells and FOXP3 in non-mammalian vertebrates. In this study, we generated mutant zebrafish lacking a functional FOXP3 ortholog, and demonstrated a significant reduction in survival accompanied by a marked increase in inflammatory gene expression, mononuclear cell infiltration, and T cell proliferation in peripheral tissues. Our findings indicate that the zebrafish FOXP3 protein may have an evolutionally conserved role in the control of immune tolerance, illuminating the potential of the zebrafish as a novel model for investigating the development and functions of Treg cells. PMID- 28365197 TI - High-sucrose diets in male rats disrupt aspects of decision making tasks, motivation and spatial memory, but not impulsivity measured by operant delay discounting. AB - Excessive consumption of sugar sweetened drinks is proposed to produce functional changes in the hippocampus and prefrontal cortex, leading to perturbations in behavioural control. Impairments in behavioural control have been observed in obese people on tasks that involve making choices, including delay-discounting, indicative of increased impulsivity. In this study we examined the impact of 2h daily access to 10% sucrose (or no sucrose in controls) in young male rats on behavioural tasks reliant on hippocampal function including delay-discounting, T maze forced choice alternation and place recognition memory, as well as progressive ratio to measure motivation. We observed deficits in place recognition memory and T-maze forced choice alternation, indicative of hippocampal deficits in rats with a history of sucrose consumption. Moreover, rats with a history of sucrose consumption were less motivated to lever press for rewards on a progressive ratio schedule. However, rats with a history of sucrose consumption performed equally to control animals during the delay-discounting task, suggesting that they discounted for reward size over a delay in a manner comparable to control animals. These findings indicate that high-sucrose diets impact on spatial and working memory processes, but do not induce impulsive-like choice behaviours in rats, suggesting that unhealthy diet choices may not influence this aspect of decision-making behaviour. PMID- 28365196 TI - Female Sprague-Dawley rats display greater appetitive and consummatory responses to alcohol. AB - The narrowing of the gender gap in alcohol drinking patterns is a concern because women are more susceptible to adverse health consequences of alcohol use. Animal models of alcohol-seeking and -consuming are useful to delineate sex differences to test for effective sex-specific pharmacological treatments. We investigated potential sex differences in appetitive and consummatory responses to alcohol. Appetitive behaviors included numbers of head entries into the dipper access area and active lever presses. Consummatory behaviors included number of reinforcers delivered and consumed. Male and female Sprague-Dawley rats were placed on an overnight alcohol (10%) drinking schedule and trained to lever press for alcohol (10% solution). Separate groups of male and female animals had access to water overnight and were trained to lever press for sucrose (3% solution). Tests were conducted under a progressive ratio schedule of reinforcement. Alcohol-responding females demonstrated higher alcohol intake overnight and showed greater appetitive and consummatory responses compared to males. Similar sex differences were seen in the sucrose group. Effect sizes indicated greater sex differences in consummatory measures in the alcohol vs. sucrose groups. Conversely, greater sex differences in appetitive behaviors were observed in the sucrose vs. alcohol groups. Overall, the magnitude of the sex differences was stronger for appetitive behaviors compared to consummatory behaviors. Findings of quantitative sex differences in appetitive and consummatory behaviors for alcohol and for the natural reinforcer, sucrose, suggest this procedure is useful to assess efficacy of sex-specific treatments aimed at reducing appetitive and consummatory responses to alcohol. PMID- 28365199 TI - Outcomes of immature oocytes collected from ovarian tissue for cryopreservation in adult and prepubertal patients. AB - The efficiency of oocyte in-vitro maturation (IVM) and vitrification procedures after ex-vivo collection from ovarian tissue were assessed according to patient age, number of retrieved oocytes and tissue transport conditions. The combined procedure was performed in 136 patients: 130 adults (mean 27.6 +/- 5.6 years) and six prepubertal girls (mean 8.7 +/- 2.3 years). A higher mean number of oocytes were collected in girls compared with adults (11.5 +/- 8.0 versus 3.8 +/- 4.2, respectively, P < 0.001) but the percentage of degenerated oocytes was significantly higher in girls (35.5% versus 17.1%, respectively, P < 0.001). IVM rates were significantly lower in prepubertal than postpubertal population (10.3% versus 28.1%, P = 0.002). In adults, a negative correlation was observed between number of retrieved oocytes and age (P = 0.002; r = -0.271); the correlation was positive between anti-Mullerian hormone (AMH) and number of collected oocytes (P = 0.002; r = 0.264). IVM rates were not correlated with AMH levels (r = 0.06) or age (r = -0.033). At present, nine oocytes and one embryo have been warmed in four patients and one biochemical pregnancy obtained. This suggests the combined procedure could be an additional option for fertility preservation. PMID- 28365198 TI - [How to act when an alpha-blocker is associated with a potent inhibitor of CYP3A4]. AB - OBJECTIVE: Combination of alpha-blockers with potent CYP3A4 inhibitors is either contra-indicated or not recommended. We searched data supporting this classification and guiding prescribers when such an interaction occurs. METHODS: We analyzed reports published by the French agency for drug safety, reference books and performed search in databases of pharmacokinetics studies and case or case series related with these interactions. RESULTS: The classification of the potential severity of these interactions defined by the French agency for drug safety evolved over time. Our literature search did not identify any cases or case series reporting serious clinical consequences of such interactions and no pharmacoepidemiological studies on the association between alpha-blockers and inhibitors of CYP3A4. The content of the summaries of product characteristics indicate that the combination of ketoconazole with alfuzosin, silodosin and tamsulosin increases the area under the curve of the alpha-blocker 3 fold. CONCLUSION: Data demonstrating the clinical consequences of an association between alpha-blocker and a potent CYP3A4 inhibitor are lacking. The 3 fold increase of the area under the curve for alfuzosin, silodosin and tamsulosin associated with ketoconazole while the association with the two first is contra indicated and is not recommended with the third raises questions. This lack of data leaves doctors and pharmacists in a situation of uncertainty on how to proceed when such an interaction occurs. PMID- 28365200 TI - Postoperative changes in neutrophil-to-lymphocyte ratio and platelet count: A simple prognostic predictor for adult-to-adult living donor liver transplantation. AB - BACKGROUND/OBJECTIVE: The neutrophil-to-lymphocyte ratio (NLR) is a simple index that represents systemic inflammatory change. The number of platelets is also known to reflect both post-transplant graft regeneration and dysfunction. Thus, we aimed to investigate the usefulness of NLR and platelet number in predicting the clinical course after adult-to-adult living donor liver transplantation (AA LDLT) in the acute postoperative period in recipients. METHODS: Between January 1999 and December 2013, 61 patients underwent their first AA-LDLT at our institute. We retrospectively analyzed their clinical data, including NLR and number of platelets, until postoperative day 14, and evaluated their ability to predict prognosis after AA-LDLT. RESULTS: The optimal cutoff values of postoperative maximum NLR and maximum platelets to predict prognosis were 50 and 80 * 103/MUL, respectively. The 1- and 5-year survival rates were 87.5% and 79.1% in the normal maximum NLR group, respectively, and 46.2% for both in the high maximum NLR group (p = 0.0033). The 1- and 5-year survival rates, respectively, were 90.9% and 84.1% in the high maximum platelets group and 47.1% and 41.2% in the low maximum platelets group (p < 0.0001). In multivariate analysis, maximum NLR >= 50 and maximum platelets < 80 * 103/MUL were independently associated with 1-year mortality. CONCLUSION: A high NLR and a low platelet count during acute postoperative period might correlate with poor prognosis after AA-LDLT. PMID- 28365201 TI - Pregnancy after Bariatric Surgery: Balancing Risks and Benefits. AB - The majority of bariatric surgeries in Canada are performed in women of reproductive age. Clinicians encounter more and more often pregnancies that occur after bariatric surgeries. The appropriate management and education of women who want to conceive after bariatric surgery is still unclear due to the lack of consistent data about maternal and neonatal outcomes following bariatric surgery. Maternal obesity during pregnancy confers a higher risk for gestational diabetes, hypertensive disorders, congenital malformations, prematurity and perinatal mortality. Generally, pregnancies in severely obese women who have undergone bariatric surgery are safe, and the women are at significantly lower risk for gestational diabetes, hypertensive disorders and large-for-gestational-age neonates, but the surgery confers a higher risk for small-for-gestational-age infants and prematurity. This review aims to provide evidence from recent publications about the risks and benefits of bariatric surgeries in the context of future pregnancies. PMID- 28365202 TI - Impact of Bariatric Surgery on White Adipose Tissue Inflammation. AB - Excess fat mass accumulation can lead to a wide range of metabolic and cardiovascular complications resulting from dysfunctional adipose tissue (AT). The latter includes immune cell infiltration and altered secretion of anti- and proinflammatory mediators, which contribute to systemic, low-grade inflammation. In this article, we review available literature documenting the impact of surgery induced weight loss on macrophage infiltration and tissue expression or circulating levels of a broad spectrum of inflammatory mediators. Reports generally show that bariatric surgery may reverse both macrophage infiltration and the altered secretory profile observed in the AT of patients with severe obesity. However, further studies are needed to confirm or elucidate the effects of specific bariatric surgery procedures on white AT inflammation and to shed light on the mechanisms involved in these effects. PMID- 28365204 TI - Individualized exergame training improves postural control in advanced degenerative spinocerebellar ataxia: A rater-blinded, intra-individually controlled trial. AB - BACKGROUND: Treatment options are rare in degenerative ataxias, especially in advanced, multisystemic disease. Exergame training might offer a novel treatment strategy, but its effectiveness has not been investigated in advanced stages. METHODS: We examined the effectiveness of a 12-week home-based training with body controlled videogames in 10 young subjects with advanced degenerative ataxia unable or barely able to stand. Training was structured in two 6-weeks phases, allowing to adapt the training according to individual training progress. Rater blinded clinical assessment (Scale for the Assessment and Rating of Ataxia; SARA), individual goal-attainment scoring (GAS), and quantitative movement analysis were performed two weeks before training, immediately prior to training, and after training phases 1 and 2 (intra-individual control design). This study is registered with ClinicalTrials.gov, NCT02874911). RESULTS: After intervention, ataxia symptoms were reduced (SARA -2.5 points, p < 0.01), with benefits correlating to the amount of training (p = 0.04). Goal attainment during daily living was higher than expected (GAS: 0.45). Movement analysis revealed reduced body sway while sitting (p < 0.01), which correlated with improvements in SARA posture and gait (p = 0.005), indicating training-induced improvements in posture control mechanisms. CONCLUSION: This study provides first evidence that, even in advanced stages, subjects with degenerative ataxia may benefit from individualized training, with effects translating into daily living and improving underlying control mechanisms. The proposed training strategy can be performed at home, is motivating and facilitates patient self-empowerment. PMID- 28365203 TI - The bidirectional longitudinal relationship between insomnia, depression and anxiety in patients with early-stage, medication-naive Parkinson's disease. AB - INTRODUCTION: While anxiety, depression and insomnia frequently (co-)occur in Parkinson's disease (PD) patients, little is known about their temporal relationship. In this study, we tested two hypotheses: i) insomnia predicts an increase in symptoms of depression or anxiety and ii) anxiety or depression at baseline predicts insomnia in PD patients six months later. METHODS: We used longitudinal data from a prospective cohort study of early-stage, medication naive PD patients. Primary outcome measures were: anxiety symptoms, measured with the State-Trait Anxiety Inventory (STAI); depressive symptoms, measured with the 15-item Geriatric Depression Scale (GDS-15); and insomnia, defined as a score >= 2 on item 1.7 of the Movement Disorder Society - Unified Parkinson's Disease Rating Scale. We performed linear and logistic regression analyses, correcting for baseline value of the respective outcome variable. RESULTS: Baseline insomnia was not associated with GDS-15 or STAI total score at follow-up. In a post hoc analysis, we found that insomnia predicted a higher STAI State score (B(SE) = 2.50 (1.07), p < 0.05), while the association with the STAI Trait score was not significant. Baseline STAI scores (B(SE) = 0.02 (0.01), p = 0.001) and GDS-15 score (B(SE) = 0.15 (0.05), p < 0.001) were significantly associated with insomnia at follow-up. CONCLUSION: Symptoms of anxiety and depression may constitute a risk factor for insomnia in PD. The relationship between insomnia and anxiety is bidirectional, which suggests that both anxiety and sleep disorders can start a negative spiral in PD patients, where one enhances the other. Independent clinical attention for these symptoms in PD patients is therefore warranted. PMID- 28365205 TI - Articular Ultrasound in Asymptomatic Volunteers: Identification of the Worst Measures of Synovial Hypertrophy, Synovial Blood Flow and Joint Damage Among Small-, Medium- and Large-Sized Joints. AB - Articular ultrasound of 6500 joint recesses was performed for the purpose of identifying which joint had the highest measurements among small-sized (SSJ), medium-sized (MSJ) and large-sized (LSJ) joints. Quantitative measurements of synovial hypertrophy (QSR) and semiquantitative measurements of synovial hypertrophy (SSH), power Doppler (SPD) and bone erosion (SBE) (score: 0-3) were made. Higher measurements (p < 0.01) of QSR were obtained in the second metatarsophalangeal joint (MTP), talonavicular joint, and hip. The highest SSH scores (2/3) were obtained in the second MTP, talonavicular joint, hip and knee; the highest SPD scores (1/2/3) in the first MTP, second MTP, dorsal second metacarpophalangeal (MCP) and radiocarpal recesses; and the highest SBE scores (2/3) in the radiocarpal, ulnocarpal and posterior recesses of the glenohumeral joint. In conclusion, higher measurements of synovial hypertrophy were found in the first and second MTPs (SSJ), talonavicular recess (MSJ) and hip (LSJ). Synovial blood flow was frequent in the first MTP and radiocarpal recess. Bone erosion stood out only in the glenohumeral joint. PMID- 28365206 TI - Prevalence and incidence density of unavoidable pressure ulcers in elderly patients admitted to medical units. AB - To describe the prevalence and incidence density of hospital-acquired unavoidable pressure sores among patients aged >=65 years admitted to acute medical units. A secondary analysis of longitudinal study data collected in 2012 and 2013 from 12 acute medical units located in 12 Italian hospitals was performed. Unavoidable pressure ulcers were defined as those that occurred in haemodynamically unstable patients, suffering from cachexia and/or terminally ill and were acquired after hospital admission. Data at patient and at pressure ulcer levels were collected on a daily basis at the bedside by trained researchers. A total of 1464 patients out of 2080 eligible (70.4%) were included. Among these, 96 patients (6.5%) hospital-acquired a pressure ulcer and, among 19 (19.7%) were judged as unavoidable. The incidence of unavoidable pressure ulcer was 8.5/100 in hospital patient days. No statistically significant differences at patient and pressure ulcers levels have emerged between those patients that acquired unavoidable and avoidable pressure sores. Although limited, evidence on unavoidable pressure ulcer is increasing. More research in the field is recommended to support clinicians, managers and policymakers in the several implications of unavoidable pressure ulcers both at the patient and at the system levels. PMID- 28365207 TI - Quality of blood pressure measurement in community health centres. AB - OBJECTIVE: To determine the quality of the blood pressure measurements performed during routine care in community health centres. METHOD: An observational, cross sectional study was conducted in 5 private and public health centres in Maldonado, Uruguay, in July-August 2015. The observations were made during the measurements performed by health personnel, using the requirements established by the American Heart Association. An analysis was made on 36 variables that were grouped in categories related to environment, equipment, interrogation, patient, and observer. Statistical analysis was performed using Chi2 test or Fisher test. Statistical significance was considered to be less than 5% (p<.05). RESULTS: The measurements were made by a registered nurse or nurse in 71% of cases, physician in 20%, and student nurse in 9%. An aneroid sphygmomanometer was used in 89%, and mercury 11%. Satisfactory results were found in variables related to environment (93%), equipment (99%), and patient attitude (82%), and intermediate in the attitudes of the operator (64%), and poor in relation to the interrogation (18%), with the mean of correct variables per measurement being 69%. CONCLUSIONS: The main flaws in the procedure were the operator. The measurement of blood pressure is a manoeuvre that healthcare professionals perform thousands of times a year. If the measurement is used for the diagnosis and/or chronic management of arterial hypertension, not systematically applying the established recommendations leads to an inappropriate care of a very significant number of patients. PMID- 28365208 TI - Postoperative hyperalgesia-A clinically applicable narrative review. AB - Postoperative hyperalgesia (POH) is a condition characterized by signs and symptoms of pain despite the provision of conventional analgesia. In most cases, anesthesiologists are called upon soon after surgery, but occasionally it may occur as a late event. Persistent uncontrolled pain may transform into chronic or neuropathic pain. Correct diagnosis of POH is essential since similar phenomenon may exacerbate if misdiagnosed, while proper treatment is frequently achievable by pharmacological remedies. This review will describe the causes for POH and its bio-neuro-pharmacological basis, and clinical symptoms and signs directing the physician towards correct diagnosis of this paradoxical condition of pain, as well as modes capable of preventing POH from occurring. The pharmacological approach upon suspecting or diagnosing POH will focus on the use of anesthetic and non-anesthetic drugs that attenuate nociceptive- and opioid-induced paradoxical pain, and non-opioid adjuvant drugs, among which are ketamine or gabapentinoids, the two notably compounds that antagonize abnormal central sensitization that is at the basis of POH. PMID- 28365210 TI - Resolution of cassava-infecting alphaflexiviruses: Molecular and biological characterization of a novel group of potexviruses lacking the TGB3 gene. AB - Several potexviruses (Family Alphaflexiviridae) have been reported infecting cassava (Manihot esculenta Crantz) in the Americas. They were isolated from severely diseased plants during the last 30-40 years and include: Cassava common mosaic virus (CsCMV), Cassava Caribbean mosaic virus (CsCaMV), Cassava Colombian symptomless virus (CsCSV) and Cassava virus X (CsVX). However, their definitive classification as distinct species remains unresolved for several reasons, including the lack of sequence data and unavailability of samples from original isolates. This complicates disease diagnostics, cassava germplasm exchange certification, evaluation of virus cleaning protocols and epidemiological studies. Furthermore, a recently detected novel alphaflexivirus, indicates that cassava-infecting potexviruses may be more diverse. To solve the identity of these viruses, we started indexing samples from different parts of Colombia using different sets of PCR primers, antisera available and inoculation to indicator plants. Results show that there are three major phylogenetic groups of potexviruses infecting cassava, and they correspond to CsCMV, CsVX and the newly identified Cassava new alphaflexivirus (CsNAV). Bioassays and sequence analysis established that isolates of CsNAV and CsVX cause latent infections in different cassava landraces, they are not efficiently transmitted to the indicator plant Nicotiana benthamiana and they lack the gene 3 of the conserved potexviral 'triple gene block' (TGB). In contrast, all isolates of CsCMV (which have a characteristic potexvirus genome arrangement) caused Cassava Common Mosaic Disease (CCMD) in single infections and were efficiently transmitted to N. benthamiana. Although phylogenetic analysis of the replicase sequence placed CsNAV and CsVX as members of the Potexvirus genus, their distinct genome arrangement and biological characteristics suggest they can be considered as members of a separate taxonomic group. PMID- 28365209 TI - Special Commentary: Early Clinical Development of Cell Replacement Therapy: Considerations for the National Eye Institute Audacious Goals Initiative. AB - The National Eye Institute launched the Audacious Goals Initiative (AGI) in 2013 with the aim "to restore vision through the regeneration of neurons and neural connections in the eye and visual system." An AGI Town Hall held at the Association for Research in Vision and Ophthalmology Annual Meeting in 2016 brought together basic, translational, and clinical scientists to address the clinical implications of the AGI, with a particular emphasis on diseases amenable to regenerative medicine and strategies to deal with barriers to progess. An example of such a barrier is that replacement of lost neurons may be insufficient because damage to other neurons and non-neuronal cells is common in retinal and optic nerve disease. Reparative processes such as gliosis and fibrosis also can make it difficult to replenish and regenerate neurons. Other issues include choice of animal models, selecting appropriate endpoints, ethics of informed consent, and regulatory issues. Another area critical to next steps in the AGI is the choice of target diseases and the stage at which early development studies should be focused. For example, an advantage of doing clinical trials in patients with early disease is that supporting cellular and structural constituents are still likely to be present. However, regenerative studies in patients with late disease make it easier to detect the effects of replacement therapy against the background of severe visual loss, whereas it may be harder to detect incremental improvement in visual function in those with early disease and considerable remaining visual function. Achieving the goals of the AGI also requires preclinical advances, new imaging techniques, and optimizing translational issues. The work of the AGI is expected to take at least 10 years but should eventually result in therapies to restore some degree of vision to the blind. PMID- 28365211 TI - A parental history of diabetes is associated with a high risk of retinopathy in patients with type 2 diabetes. PMID- 28365212 TI - Residues in the GluN1 C-terminal domain control kinetics and pharmacology of GluN1/GluN3A N-methyl-d-aspartate receptors. AB - N-methyl-d-aspartate (NMDA) receptors assembled from GluN1 and GluN3 subunits are unique in that they form glycine-gated excitatory channels that are insensitive to glutamate and NMDA. Alternative splicing of the GluN1 subunit mRNA results in eight variants with regulated expression patterns and post-translational modifications. Here we investigate the role of residues in the GluN1 C-terminal alternatively spliced cassettes in receptor gating and modulation. We measured whole-cell currents from recombinant GluN1/GluN3A receptors expressed in HEK293 cells that differed in the sequence of their GluN1 C-terminal tail. We found that these residues controlled the level of steady-state activity and the degree to which activity was facilitated by zinc and protons. Further, we found that the phosphorylation status of sites specific to certain variants can also modulate channel activity. Based on these results we suggest that GluN1 C-terminal domain splicing may confer cell-specific and activity-dependent regulation onto the level and pharmacologic sensitivity of GluN1/GluN3A currents. PMID- 28365215 TI - Mean Arterial Pressure to Central Venous Pressure Ratio: A Novel Marker for Right Ventricular Failure After Left Ventricular Assist Device Placement. AB - BACKGROUND: Early right ventricular failure (RVF) is common after left ventricular assist device (LVAD) implantation and often leads to increased morbidity and mortality. It is difficult to predict early RVF on the basis of clinical and hemodynamic parameters. We investigated the utility of mean arterial pressure (MAP) to central venous pressure (CVP) ratio in predicting early RVF. METHODS AND RESULTS: We analyzed a retrospective cohort of 212 consecutive patients who underwent hemodynamic assessment before destination-therapy LVAD implantation. Patients were followed for early RVF and mortality. Receiver operating characteristic (ROC) analysis was used to determine discriminative capacity of MAP/CVP and tested the diagnostic and prognostic value of median MAP/CVP threshold. The ROC analysis demonstrated that pre-LVAD MAP/CVP was associated with an area under the ROC curve of 0.65 (95% confidence interval 0.58 0.73; P < .001). MAP/CVP threshold <7.5 (simple nearest-to-median value) was associated with 70% sensitivity and 56% specificity for early RV failure. Patients with MAP/CVP <7.5 had a higher incidence of post-LVAD RVF than those with a ratio >=7.5 (44% vs 23%, respectively; P = .001). Right ventricular assist device requirement was higher in the MAP/CVP <7.5 group (11% vs 2%; P = .01). All cause mortality was higher in the MAP/CVP <7.5 group (annualized mortality 26% vs 16%; log-rank P = .017). MAP-CVP ratio provided incremental prognostic value for RVF and all-cause mortality beyond established Heartmate II and RVF risk scores. CONCLUSIONS: Our findings suggest that pre-LVAD MAP/CVP <7.5 is associated with early RVF and increased mortality risk. This novel parameter can be used in risk stratification of LVAD candidates. Prospective validation of our findings is needed. PMID- 28365213 TI - Alternative activation-skewed microglia/macrophages promote hematoma resolution in experimental intracerebral hemorrhage. AB - Microglia/macrophages (MMPhi) are highly plastic phagocytes that can promote both injury and repair in diseased brain through the distinct function of classically activated and alternatively activated subsets. The role of MMPhi polarization in intracerebral hemorrhage (ICH) is unknown. Herein, we comprehensively characterized MMPhi dynamics after ICH in mice and evaluated the relevance of MMPhi polarity to hematoma resolution. MMPhi accumulated within the hematoma territory until at least 14days after ICH induction. Microglia rapidly reacted to the hemorrhagic insult as early as 1-1.5h after ICH and specifically presented a "protective" alternatively activated phenotype. Substantial numbers of activated microglia and newly recruited monocytes also assumed an early alternatively activated phenotype, but the phenotype gradually shifted to a mixed spectrum over time. Ultimately, markers of MMPhi classic activation dominated at the chronic stage of ICH. We enhanced MMPhi alternative activation by administering intraperitoneal injections of rosiglitazone, and subsequently observed elevations in CD206 expression on brain-isolated CD11b+ cells and increases in IL-10 levels in serum and perihematomal tissue. Enhancement of MMPhi alternative activation correlated with hematoma volume reduction and improvement in neurologic deficits. Intraventricular injection of alternative activation signature cytokine IL-10 accelerated hematoma resolution, whereas microglial phagocytic ability was abolished by IL-10 receptor neutralization. Our results suggest that MMPhi respond dynamically to brain hemorrhage by exhibiting diverse phenotypic changes at different stages of ICH. Alternative activation-skewed MMPhi aid in hematoma resolution, and IL-10 signaling might contribute to regulation of MMPhi phagocytosis and hematoma clearance in ICH. PMID- 28365214 TI - in vivo localization of the neuronal ceroid lipofuscinosis proteins, CLN3 and CLN7, at endogenous expression levels. AB - The neuronal ceroid lipofuscinoses are a group of recessively inherited, childhood-onset neurodegenerative conditions. Several forms are caused by mutations in genes encoding putative lysosomal membrane proteins. Studies of the cell biology underpinning these disorders are hampered by the poor antigenicity of the membrane proteins, which makes visualization of the endogenous proteins difficult. We have used Drosophila to generate knock-in YFP-fusions for two of the NCL membrane proteins: CLN7 and CLN3. The YFP-fusions are expressed at endogenous levels and the proteins can be visualized live without the need for overexpression. Unexpectedly, both CLN7 and CLN3 have restricted expression in the CNS of Drosophila larva and are predominantly expressed in the glia that form the insect blood-brain-barrier. CLN7 is also expressed in neurons in the developing visual system. Analogous with murine CLN3, Drosophila CLN3 is strongly expressed in the excretory and osmoregulatory Malpighian tubules, but the knock in also reveals unexpected localization of the protein to the apical domain adjacent to the lumen. In addition, some CLN3 protein in the tubules is localized within mitochondria. Our in vivo imaging of CLN7 and CLN3 suggests new possibilities for function and promotes new ideas about the cell biology of the NCLs. PMID- 28365216 TI - Ultrasonic assisted hot metal powder compaction. AB - Hot pressing of metal powders is used in production of parts with similar properties to wrought materials. During hot pressing processes, particle rearrangement, plastic deformation, creep, and diffusion are of the most effective powder densification mechanisms. Applying ultrasonic vibration is thought to result in great rates of densification and therefore higher efficiency of the process is expected. This paper deals with the effects of power ultrasonic on the densification of AA1100 aluminum powder under constant applied stress. The effects of particle size and process temperature on the densification behavior are discussed. The results show that applying ultrasonic vibration leads to an improved homogeneity and a higher relative density. Also, it is found that the effect of ultrasonic vibration is greater for finer particles. PMID- 28365217 TI - Tropical arthritogenic alphaviruses. AB - Tropical alphaviruses have special tropism for bone and joint tissue. Patients can develop chronic rheumatic disorders similar to rheumatoid arthritis and ankylosing spondylitis. The prototype is Chikungunya virus, although other lesser known viruses in our environment such as Sindbis, Ross River, Mayaro, O'nyong nyong and Barmah Forest viruses have the potential to be sped through vectors and cause chronic rheumatic disease. International population movements have increased the numbers of patients diagnosed with these tropical viruses in areas in which they are not endemic. Since they can leave persistent symptoms and affect the quality of life of the patients, it is important that we be aware of them. Changes in ecosystems have favored the expansion of competent mosquitoes, making fears of local transmission in southern Europe a reality. The objective of this review is to provide a clinical approach to the different arthritogenic tropical alphaviruses, especially those in which chronic rheumatic disease is more frequent. PMID- 28365218 TI - Modelling of subarachnoid space width changes in apnoea resulting as a function of blood flow parameters. AB - During apnoea, the pial artery is subjected to two opposite physiological processes: vasoconstriction due to elevated blood pressure and vasorelaxation driven by rising pH in the brain parenchyma. We hypothesized that the pial artery response to apnoea may vary, depending on which process dominate. Apnoea experiments were performed in a group of 19 healthy, non-smoking volunteers (9 men and 10 women). The following parameters were obtained for further analysis: blood pressure, the cardiac (from 0.5 to 5.0Hz) and slow (<0.5Hz) components of subarachnoid space width, heart rate, mean cerebral blood flow velocity in the internal carotid artery, pulsatility and resistivity index, internal carotid artery diameter, blood oxygen saturation and end-tidal carbon dioxide. The experiment consisted of three apnoeas, sequentially: 30s, 60s and maximal apnoea. The breath-hold was separated for 5minute rest. The control process is sophisticated, involving internal cross-couplings and cross-dependences. The aim of work was to find a mathematical dependence between data. Unexpectedly, the modelling revealed two different reactions, on the same experimental procedure. As a consequence, there are two subsets of cardiac subarachnoid space width responses to breath-hold in humans. A positive cardiac subarachnoid space width change to apnoea depends on changes in heart rate and cerebral blood flow velocity. A negative cardiac subarachnoid space width change to apnoea is driven by heart rate, mean arterial pressure and pulsatility index changes. The described above two different reactions to experimental breath-hold provides new insights into our understanding of the complex mechanisms governing the adaptation to apnoea in humans. We proposed a mathematical methodology that can be used in further clinical research. PMID- 28365219 TI - Study of the efficacy of melatonin for auditory brainstem response (ABR) testing in children. AB - STUDY OBJECTIVE: To evaluate the efficacy of oral melatonin to induce sedation (natural sleep) while measuring auditory brainstem responses (ABR) in children with suspected hearing loss by calculating the ABR success rate with the use of melatonin, the percentage of children in whom sleep was induced by melatonin and the time required to perform complete ABR testing. MATERIAL AND METHODS: Twenty nine children aged 1 to 6 years were included in this prospective study. ABR testing was performed as a day-case procedure in a single room ensuring suitable sleeping conditions. Five milligrams of melatonin (or 10mg in children over the age of 6 years) were administered orally before electrode positioning. An additional 5 milligrams were administered if the child failed to sleep after 30minutes. RESULTS: ABR was performed with melatonin in 58 ears: complete ABR testing was performed in both ears in 19 children (65%), corresponding to 38 examinations; only one ear was tested in 7 children (24.2%), corresponding to 7 examinations; and ABR testing could not be performed in 3 children (10.3% failure rate). Good quality sleep was obtained in 17 children (59%), brief sleep was obtained in 4 children (14%), who nevertheless remained calm throughout the examination and 8 children (27%) did not fall asleep. The mean sleep-onset time after administration of melatonin was 41minutes with a mean sleep time of 33minutes and a mean examination time of 52minutes after the first dose of melatonin. A complete examination therefore took an average of 93minutes. CONCLUSION: The use of melatonin allowed partial or complete ABR testing in 90% of children. This method is effective, but it requires adapted facilities to receive the child and the child's parents. PMID- 28365220 TI - Adaptation of running pattern to the drop of standard cushioned shoes: A randomised controlled trial with a 6-month follow-up. AB - OBJECTIVES: While several cross-sectional studies have investigated the acute effects of shoe drop on running biomechanics, the long-term consequences are currently unknown. This study aimed to investigate if the drop of standard cushioned shoes induces specific adaptations in running technique over a six month period in leisure-time runners. DESIGN: Double-blinded randomised controlled trial. METHODS: The participants (n=59) received a pair of shoes with a heel-to-toe drop of 10mm (D10), 6mm (D6) or 0mm (D0) and were followed-up regarding running training over 6 months or 500km, whichever came first. Spatio temporal variables and kinematics (foot/ground, ankle and knee joint angles) were investigated while running at preferred speed on a treadmill before and after the follow-up. RESULTS: The participants ran 332+/-178km in the study shoes between pre- and post-tests. There was no shoe version by time interaction for any of the spatio-temporal variables nor for lower limb angles at initial ground contact. A small but significant shoe drop effect was found for knee abduction at mid-stance (p=0.032), as it decreased for the D0 version (-0.3+/-3.1 vs. -1.3+/-2.6 degrees ) while it increased for the D6 (0.3+/-2.7 vs. 1.3+/-3.1 degrees ) and D10 version (-0.2+/-3.2 vs. 0.5+/-3.1 degrees ). However, none of the pairwise comparisons was significant in the post-hoc analysis. CONCLUSIONS: Apart from knee abduction at mid-stance, no specific adaptation in spatio-temporal variables and kinematics was found between the three shoe versions during this 6-month follow-up. Thus, shoe drop of standard cushioned shoes does not seem to influence running biomechanics in the long term. PMID- 28365221 TI - Wood charcoal dust pneumoconiosis. PMID- 28365222 TI - Signaling pathways linking inflammation to insulin resistance. AB - Inflammation is closely linked to the pathogenesis of type 2 diabetes (T2D) and chronic inflammation is one of the main causes of insulin resistance. Insulin pathway is very important for the regulation of glucose, lipid, and energy homeostasis, growth and mitogenic. Proinflammatory mediators can be related to obesity and induce insulin- resistance in adipose tissue. Signaling pathways of transcription factors, particularly NF-kappaB signaling, are involved in insulin sensitivity. In addition, the crosstalk between M1-M2 macrophage polarizing plays an essential role in insulin resistance by switching from an M1 to an M2 phenotype and also activation of transcription factors such as NF-kappaB and AP1. Here, we focus on the roles of transcription factors in inflammation-induced insulin resistance and their involvement in pathogenesis of insulin resistance. PMID- 28365223 TI - Antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting: Suggested strategies tailored to an integrated evaluation of different risk profiles. PMID- 28365224 TI - Design and evaluation of a phospholipase D based drug delivery strategy of novel phosphatidyl-prodrug. AB - A strategy is proposed to design a safe and simple amphiphilic prodrug delivery system, based on the elevated expression of phospholipase D (PLD) in cancer cells. The method utilizes the transphosphatidylation ability of bacterial PLD on alcohol groups and the hydrolysis activity of overexpressed PLD on phospholipids in cancer cells. Doxorubicin (DOX) was selected as a test drug, and the phosphatidyl-doxorubicin (PX) was synthesized by bacterial PLD. The PX prodrug could be readily self-assembled to nanoparticles with uniform size and was stable during storage and circulation. The pharmacokinetics and biodistribution investigations indicated DOX could be selectively released from PX in cancer cells triggered by the local overexpressed PLD, and PX could significantly prolong the half-life of DOX in the tumors and decrease the distribution in heart and kidney. Moreover, the PX prodrug enhanced cellular uptake in MCF-7/ADR cells, demonstrating it could reverse the multi-drug resistance. Consequently, the prodrug displayed favorable anticancer efficacy in the MCF-7/ADR xenograft model without the cardiotoxicity and nephrotoxicity of DOX. The results demonstrated that phosphatidyl modification method can be used as an efficient strategy to develop a promising nanoscale drug delivery system for some drugs. PMID- 28365225 TI - Safety and immunogenicity of one versus two doses of Takeda's tetravalent dengue vaccine in children in Asia and Latin America: interim results from a phase 2, randomised, placebo-controlled study. AB - BACKGROUND: Dengue is the most common mosquito-borne viral disease in human beings, and vector control has not halted its spread worldwide. A dengue vaccine for individuals aged 9 years and older has been licensed, but there remains urgent medical need for a vaccine that is safe and effective against all four dengue virus serotypes (DENV-1-4) in recipients of all ages. Here, we present the preplanned interim analyses at 6 months of a tetravalent dengue vaccine candidate (TDV), which is comprised of an attenuated DENV-2 virus strain (TDV-2) and three chimeric viruses containing the premembrane and envelope protein genes of DENV-1, DENV-3, and DENV-4 genetically engineered into the attenuated TDV-2 genome backbone (TDV-1, TDV-3, and TDV-4). METHODS: An ongoing phase 2, randomised, double-blind, placebo-controlled trial of a TDV is being done at three sites in dengue-endemic countries (Dominican Republic, Panama, and the Philippines) to determine its safety and immunogenicity over 48 months in healthy participants aged 2-17 years who were randomly assigned (1:2:5:1) using an interactive web response system (stratified by age) to subcutaneous TDV injection (one 0.5 mL dose containing 2.5 * 104 plaque-forming units [PFU] of TDV-1; 6.3 * 103 PFU of TDV-2; 3.2 * 104 PFU of TDV-3; and 4.0 * 105 PFU of TDV-4) in different dose schedules (two-dose regimen at 0 and 3 months, one dose at 0 months, or one dose at 0 months and a booster at 12 months) or placebo. The primary endpoint of this 6 month interim analysis was geometric mean titres (GMTs) of neutralising antibodies against DENV-1-4 in the per-protocol immunogenicity subset at 1 month, 3 months, and 6 months after the first injection. Safety was assessed as a secondary outcome as percentage of participants with serious adverse events in all participants who were injected (safety set), and solicited and unsolicited adverse events (immunogenicity subset). This trial is registered with ClinicalTrials.gov, number NCT02302066. FINDINGS: 1800 participants were enrolled between Dec 5, 2014, and Feb 13, 2015. 1794 participants were given study injection as follows: 200 participants were given two-dose regimen at 0 and 3 months (group 1), 398 were given one dose at 0 months (group 2), 998 were given one dose at 0 months and will be given (trial ongoing) a booster at 12 months (group 3), and 198 were given placebo (group 4). These 1794 participants were included in the safety set; 562 participants were randomly assigned to the immunogenicity subset, of which 503 were included in the per-protocol set. TDV elicited neutralising antibodies against all DENV serotypes, which peaked at 1 month and remained elevated above baseline at 6 months. At 6 months, GMTs of neutralising antibodies against DENV-1 were 489 (95% CI 321-746) for group 1, 434 (306-615) for group 2, 532 (384-738) for group 3, and 62 (32-120) for group 4; GMTs of neutralising antibodies against DENV-2 were 1565 (1145-2140) for group 1, 1639 (1286-2088) for group 2, 1288 (1031-1610) for group 3, and 86 (44-169) for group 4; GMTs of neutralising antibodies against DENV-3 were 160 (104-248) for group 1, 151 (106-214) for group 2, 173 (124-240) for group 3, and 40 (23-71) for group 4; and GMTs of neutralising antibodies against DENV-4 were 117 (79-175) for group 1, 110 (80-149) for group 2, 93 (69-125) for group 3, and 24 (15-38) for group 4. No vaccine-related serious adverse events occurred; 15 (3%) of 562 participants in the immunogenicity subset reported vaccine-related unsolicited adverse events. The reactogenicity profile of TDV was acceptable, and similar to previous findings with TDV. INTERPRETATION: TDV is safe and immunogenic in individuals aged 2-17 years, irrespective of previous dengue exposure. A second TDV dose induced enhanced immunogenicity against DENV-3 and DENV-4 in children who were seronegative before vaccination. These data supported the initiation of phase 3 evaluation of the efficacy and safety of TDV given in a two-dose schedule 3 months apart, with analyses that take into account baseline age and dengue serostatus. FUNDING: Takeda Vaccines. PMID- 28365226 TI - Rocky Mountain spotted fever in Mexico: past, present, and future. AB - Rocky Mountain spotted fever, a tick-borne zoonosis caused by Rickettsia rickettsii, is among the most lethal of all infectious diseases in the Americas. In Mexico, the disease was first described during the early 1940s by scientists who carefully documented specific environmental determinants responsible for devastating outbreaks in several communities in the states of Sinaloa, Sonora, Durango, and Coahuila. These investigators also described the pivotal roles of domesticated dogs and Rhipicephalus sanguineus sensu lato (brown dog ticks) as drivers of epidemic levels of Rocky Mountain spotted fever. After several decades of quiescence, the disease re-emerged in Sonora and Baja California during the early 21st century, driven by the same environmental circumstances that perpetuated outbreaks in Mexico during the 1940s. This Review explores the history of Rocky Mountain spotted fever in Mexico, current epidemiology, and the multiple clinical, economic, and social challenges that must be considered in the control and prevention of this life-threatening illness. PMID- 28365227 TI - Moving forward with Takeda's live chimeric tetravalent dengue vaccine. PMID- 28365228 TI - The thoracic morphology of the wingless dune cricket Comicus calcaris (Orthoptera: Schizodactylidae): Novel apomorphic characters for the group and adaptations to sand desert environments. AB - Schizodactylidae, splay-footed or dune crickets, represents a distinct lineage among the highly diverse orthopteran subgroup Ensifera (crickets, katydids and allies). Only two extant genera belong to the Schizodactylidae: the winged Eurasian genus Schizodactylus, whose ecology and morphology is well documented, and the wingless South African Comicus, for which hardly any studies providing morphological descriptions have been conducted since its taxonomic description in 1888. Based on the first in-depth study of the skeletomuscular system of the thorax of Comicus calcaris Irish 1986, we provide information on some unique characteristics of this character complex in Schizodactylidae. They include a rigid connection of prospinasternite and mesosternum, a T-shaped mesospina, and a fused meso- and metasternum. Although Schizodactylidae is mainly characterized by group-specific anatomical traits of the thorax, its bifurcated profuca supports a closer relationship to the tettigonioid ensiferans, like katydids, wetas, and hump-winged crickets. Some specific features of the thoracic musculature of Comicus seem to be correlated to the skeletal morphology, e.g., due to the rigid connection of the tergites and pleurites in the pterothorax not a single direct flight muscle is developed. We show that many of the thoracic adaptations in these insects are directly related to their psammophilous way of life. These include a characteristic setation of thoracic sclerites that prevent sand grains from intrusion into vulnerable membranous areas, the striking decrease in size of the thoracic spiracles that reduces the respirational water loss, and a general trend towards a fusion of sclerites in the thorax. PMID- 28365229 TI - The role of interleukin 10 in human papilloma virus infection and progression to cervical carcinoma. AB - Although Human Papillomavirus (HPV) exerts a vital influence on cervical carcinogenesis, other factors influence the development of a squamous intraepithelial lesion (SIL) that may or not progress to cervical cancer. Among several cytokines, Interleukin 10 (IL-10) stands out as an important anti inflammatory factor, leading to immune system evasion through an immunosuppressive state. In the cervical microenvironment, during different stages of HPV infection, IL-10 production can be induced and maintained by different cell sources, including infected keratinocytes, some subsets of dendritic cells (DC), tumor associated macrophages (TAM), T regulatory cells (Treg) and tumor cells. Further, a wide range of effects can be exerted by IL-10 on different cell populations, such as inhibiting proinflammatory cytokine production, DCs differentiation, antigen presenting function and T-helper 1 (Th1) polarization. IL-10 is one of several cytokines involved in cancer development and sustenance, although its role in cancer is still controversial and poorly understood. However, cervical IL-10 levels tend to increase in parallel to SIL development and are even higher within cervical tumors. Accumulating data have shown that after HPV infection, IL-10 levels are enhanced as a result of HPV E2, E6 and E7 proteins action over IL-10 gene transcription, while IL-10 stimulates HPV E6 and E7 expression. Therefore, this interplay between HPV and IL-10 creates a vicious cycle that could favor an immunosuppressive microenvironment in the cervix, facilitating the progression of a simple HPV infection to SIL or cervical cancer. PMID- 28365231 TI - Embryonic yolk removal affects neither morphology nor escape performance of larval axolotls. AB - Maternal effects, the influences of maternal phenotype on the phenotypes of her offspring, mediate early ontogenetic traits through maternal investment. In amphibians, provisioning eggs with yolk is the main source of maternal investment. While larger eggs generally result in larger, higher-quality offspring, the relationship between egg size and offspring phenotype is complicated because offspring can evolve to be more or less responsive to variation in yolk provisions. Previous studies of several ambystomatid salamanders suggest that the effects of embryonic yolk reserve reduction on hatchling life history traits increase with egg size. In this study, a similar controlled experimental yolk removal technique in Ambystoma mexicanum was used to determine the effects of reduced yolk reserves on phenotypes including hatching time and stage, hatchling and larval size and performance in predation trials with fish. Surprisingly, yolk reduction revealed no effects on any traits. These findings suggest that larval morphology in A. mexicanum is highly canalized and larval phenotypes are decoupled from yolk reserve variation. This surprising lack of yolk removal effects in hatchling and larval axolotls illustrates the evolutionary flexibility of early life history traits. Traits can evolve to increase or decrease their response to resources and can even become completely unresponsive. Since we found no effects in early life history, we hypothesize that domestication of the axolotl may have altered yolk properties or allocation dynamics and that maternal investment in yolk reserves may manifest at later life stages by reducing the time to reproductive maturity or increasing fecundity. PMID- 28365230 TI - Mutational Correlates of Virological Failure in Individuals Receiving a WHO Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration. AB - Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure (VF) on a WHO-recommended TDF-containing first-line regimen. However, the full spectrum of reverse transcriptase (RT) mutations selected in individuals with VF on such a regimen is not known. To identify TDF regimen-associated mutations (TRAMs), we compared the proportion of each RT mutation in 2873 individuals with VF on a WHO recommended first-line TDF-containing regimen to its proportion in a cohort of 50,803 antiretroviral-naive individuals. To identify TRAMs specifically associated with TDF-selection pressure, we compared the proportion of each TRAM to its proportion in a cohort of 5805 individuals with VF on a first-line thymidine analog-containing regimen. We identified 83 TRAMs including 33 NRTI associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 - A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F - were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen. These 12 TDF-selected TRAMs will be important for monitoring TDF associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen. PMID- 28365232 TI - Iterative Reconstructions in Reduced-Dose CT: Which Type Ensures Diagnostic Image Quality in Young Oncology Patients? AB - RATIONALE AND OBJECTIVES: To compare adaptive statistical iterative reconstruction (ASIR) and model-based iterative reconstruction (MBIR) algorithms for reduced-dose computed tomography (CT). MATERIALS AND METHODS: Forty-four young oncology patients (mean age 30 +/- 9 years) were included. After routine thoraco-abdominal CT (dose 100%, average CTDIvol 9.1 +/- 2.4 mGy, range 4.4-16.9 mGy), follow-up CT was acquired at 50% (average CTDIvol 4.5 +/- 1.2 mGy, range 2.2-8.4 mGy) in 29 patients additionally at 20% dose (average CTDIvol 1.9 +/- 0.5 mGy, range 0.9-3.4 mGy). Each reduced-dose CT was reconstructed using both ASIR and MBIR. Four radiologists (two juniors and two seniors) blinded to dose and technique read each set of CT images regarding objective and subjective image qualities (high- or low-contrast structures), subjective noise or pixilated appearance, diagnostic confidence, and lesion detection. RESULTS: At all dose levels, objective image noise was significantly lower with MBIR than with ASIR (P < 0.001). The subjective image quality for low-contrast structures was significantly higher with MBIR than with ASIR (P < 0.001). Reduced-dose abdominal CT images of patients with higher body mass index (BMI) were read with significantly higher diagnostic confidence than images of slimmer patients (P < 0.001) and had higher subjective image quality, regardless of technique. Although MBIR images appeared significantly more pixilated than ASIR images, they were read with higher diagnostic confidence, especially by juniors (P < 0.001). CONCLUSIONS: Reduced-dose CT during the follow-up of young oncology patients should be reconstructed with MBIR to ensure diagnostic quality. Elevated body mass index does not hamper the quality of reduced-dose CT. PMID- 28365233 TI - An Interprofessional Learning Workshop for Mammography and Sonography Students Focusing on Breast Cancer Care and Management Via Simulation: A Pilot Study. AB - RATIONALE AND OBJECTIVES: The literature surrounding interprofessional education claims that students who learn with, from, and about one another in well-designed interprofessional programs will practice together collaboratively upon graduation, given the skills to do so. The objective of this study was to examine attitudes to interprofessional practice before and after an interprofessional learning (IPL) activity. MATERIALS AND METHODS: A total of 35 postgraduate medical imaging students attended a week-long mammography workshop. The sessions provided a range of didactic sessions related to diagnosis and management of breast cancer. An IPL session was incorporated on completion of the workshop to consolidate learning. Props and authentic resources were used to increase the fidelity of the simulation. Participants completed pre- and post-workshop questionnaires comprising an interprofessional education and collaboration scale and a quiz to gauge knowledge of specific content related to professional roles. Responses to each statement in the scale and quiz score, pre or post workshop, were compared, whereas responses to open-ended questions in post-workshop survey were thematically analyzed. RESULTS: Seventeen paired surveys were received. There was a significant total improvement of 10.66% (P = .036). After simulation, there was a statistically significant improvement in participants' understanding (P < .05) that IPL offers holistic care to the patient and that teamwork is useful for reducing errors in patient care. Simulation helped participants develop more awareness of their role within the profession, improve their understanding of other professionals, and gain more realistic expectations of team members. CONCLUSION: This pilot study confirmed learning within an IPL simulation improved attitudes toward shared learning, teamwork, and communication. Simulation provides opportunities for learning in a safe environment, and technology can be used in diverse ways to provide authentic learning. PMID- 28365234 TI - Chart-stimulated Recall as a Learning Tool for Improving Radiology Residents' Reports. AB - RATIONALE AND OBJECTIVES: Workplace-based assessments gauge the highest tier of clinical competence. Chart-stimulated recall (CSR) is a workplace-based assessment method that complements chart audit with an interview based on the residents' notes. It allows evaluation of the residents' knowledge and heuristics while providing opportunities for feedback and self-reflection. We evaluated the utility of CSR for improving the radiology residents' reporting skills. MATERIALS AND METHODS: Residents in each year of training were randomly assigned to an intervention group (n = 12) or a control group (n = 13). Five pre-intervention and five post-intervention reports of each resident were independently evaluated by three blinded reviewers using a modified Bristol Radiology Report Assessment Tool. The study intervention comprised a CSR interview tailored to each individual resident's learning needs based on the pre-intervention assessment. The CSR process focused on the clinical relevance of the radiology reports. Student's t test (P < .05) was used to compare pre- and post-intervention scores of each group. RESULTS: A total of 125 pre-intervention and 125 post-intervention reports were evaluated (total 750 assessments). The Cronbach's alpha for the study tool was 0.865. A significant improvement was seen in the cumulative 19 item score (66% versus 73%, P < .001) and the global rating score (59% versus 72%, P < .001) of the intervention group after the CSR. The reports of the control group did not demonstrate any significant improvement. CONCLUSION: CSR is a feasible workplace-based assessment method for improving reporting skills of the radiology residents. PMID- 28365235 TI - Diagnosing Sarcopenia on Thoracic Computed Tomography: Quantitative Assessment of Skeletal Muscle Mass in Patients Undergoing Transcatheter Aortic Valve Replacement. AB - RATIONALE AND OBJECTIVES: This study aims to assess the use of skeletal muscle mass measurements at two thoracic levels to diagnose sarcopenia on computed tomography (CT) chest examinations and to analyze the impact of these measurements on clinical outcome parameters following transcatheter aortic valve replacement. MATERIALS AND METHODS: This study retrospectively included 157 patients who underwent preoperative CT examinations. The total muscle area was measured on transverse CT images at the 3rd lumbar and 7th and 12th thoracic levels with skeletal muscle indices (SMIs) calculated at each level. SMIs were then compared to clinical outcome parameters, and thoracic cutoff values for sarcopenia at the 7th and 12th thoracic levels were calculated. RESULTS: Correlation between SMIs at the third lumbar vertebra (L3) and the 12th thoracic vertebra (T12) was stronger (r = 0.724, P < 0.001) than that between L3 and the seventh thoracic vertebra (T7) (r = 0.594, P < 0.001). SMIs at L3 and T12 significantly correlated with prolonged length of stay. Thoracic cutoff values for the 12th thoracic level were 42.6 cm2/m2 (men) and 30.6 cm2/m2 (women), and those for the 7th thoracic level were 46.5 cm2/m2 (men) and 32.3 cm2/m2 (women). CONCLUSIONS: Skeletal muscle measurements at the T12 level could permit the diagnosis of sarcopenia and could be used to correlate sarcopenia with outcome parameters in patients undergoing CT limited to the chest. PMID- 28365236 TI - The assessment of the chronic hepatotoxicity induced by Polygoni Multiflori Radix in rats: A pilot study by using untargeted metabolomics method. AB - : Polygoni Multiflori Radix is the dried root of Polygonum multiflorum Thunb officially recorded in the Chinese Pharmacopoeia as HeShouWu (HSW) in Chinese pinyin. The processed HSW are commonly used in TCM to treat liver disease and Chinese Pharmacopoeia has described the actions of it to tonify liver-kidney, replenish essence and blood, blacken beard and hair, strengthen sinew and bone, and resolve turbidity and lower lipid hence making it use not only as a herbal medicine in TCM but also as supplementary food in health care. AIM OF THE STUDY: Concerns about the hepatotoxicity in association with Polygoni Multiflori Radix and its processed products have been reported in some countries. In the present study, we aim to investigate the potential hepatotoxicity of HSW in rats with oral administration of 95% ethanol-extracts of Polygoni Multiflori Radix by using metabolomics method. MATERIALS AND METHODS: Here, male rats with 150-180g body weight were received vehicle control or Polygoni Multiflori Radix extracts (HSW Ex) orally at 19.2 (low dose), 192 (medium dose), or 1920mg/kg/day (high dose), respectively, for 28 consecutive days. Signs of HSW-induced toxicity were monitored by traditional toxicity assessments (e.g., clinical pathology and histopathology). Metabolomics investigation of serum was performed to identify potential endogenous metabolites which may be relevant to liver injury. RESULTS: Rats received High and Medium dose of HSW-Ex showed greater sign of liver injury with increased levels of ASP, ALT, and AST, as well as reduced SOD activity when compared to vehicle control. In contrast, there are no significant changes relevant to liver injury observed in rats by receiving the low dose of HSW-Ex. Metabolomics analyses have identified ten potential endogenous metabolites varied significantly among the treatment groups with varying doses of HSW-Ex, of which might be related to liver injury. CONCLUSION: Our data has further suggested that liver damage resulting from HSW-Ex consumption is dosage dependent in rats. It is possible that disruption in amino acid and energy metabolism might lead to subsequent oxidative damage in the liver of rats. Because the clinic practice often use low dose in a short time, therefore HSW usage in TCM still keep safe currently, but we present a warning to the clinical doctors and make them has some concern about high dose of HSW usage in a long term that has potential danger to damage liver. PMID- 28365237 TI - Contributions of aortic pulse wave velocity and backward wave pressure to variations in left ventricular mass are independent of each other. AB - Aortic pulse wave velocity (PWV) and backward waves, as determined from wave separation analysis, predict cardiovascular events beyond brachial blood pressure. However, the extent to which these aortic hemodynamic variables contribute independent of each other is uncertain. In 749 randomly selected participants of African ancestry, we therefore assessed the extent to which relationships between aortic PWV or backward wave pressures (Pb) (and hence central aortic pulse pressure [PPc]) and left ventricular mass index (LVMI) occur independent of each other. Aortic PWV, PPc, forward wave pressure (Pf), and Pb were determined using radial applanation tonometry and SphygmoCor software and LVMI using echocardiography; 44.5% of participants had an increased left ventricular mass indexed to height1.7. With adjustments for age, brachial systolic blood pressure or PP, and additional confounders, PPc and Pb, but not Pf, were independently related to LVMI and left ventricular hypertrophy (LVH) in both men and women. However, PWV was independently associated with LVMI in women (partial r = 0.16, P < .001), but not in men (partial r = 0.03), and PWV was independently associated with LVH in women (P < .05), but not in men (P = .07). With PWV and Pb included in the same multivariate regression models, PWV (partial r = 0.14, P < .005) and Pb (partial r = 0.10, P < .05) contributed to a similar extent to variations in LVMI in women. In addition, with PWV and Pb included in the same multivariate regression models, PWV (P < .05) and Pb (P < .02) contributed to LVH in women. In conclusion, aortic PWV and Pb (and hence pulse pressure) although both associated with LVMI and LVH produce effects which are independent of each other. PMID- 28365239 TI - Breastfeeding initiation for Aboriginal and Torres Strait Islander women in Victoria: analysis of routinely collected population-based data. AB - BACKGROUND: Increasing breastfeeding rates is one way of improving the short and long term health of Aboriginal and Torres Strait Islander children (hereafter referred to as Aboriginal). Despite the benefits of breastfeeding and recommendations for strategies to increase breastfeeding among Aboriginal people, there is a lack of available population data. AIM: To use population-based data from Victoria, Australia to compare breastfeeding initiation for Aboriginal and non-Aboriginal women and to explore factors associated with breastfeeding initiation of Aboriginal women. METHODS: Routinely collected infant feeding data obtained from the Victorian Perinatal Data Collection (VPDC) was used. The VPDC is a mandatory, population-based system where maternal and infant data on all Victorian births are collected. FINDINGS: Compared with non-Aboriginal women, Aboriginal women were less likely to attempt to breastfeed their baby (87.2% vs 95.3%; p<0.001); more likely to give formula in hospital (39.6% vs 30.6%; p<0.001) and less likely to give the last feed prior to discharge exclusively from the breast (64.4% vs 75.0% p<0.001). For Aboriginal women, factors associated with not initiating breastfeeding were being single, multiparous, smoking and length of stay. Infant factors were gestation less than 37 weeks and low birthweight (<2,500g). CONCLUSION: In Victoria, breastfeeding initiation is lower for Aboriginal women compared with non-Aboriginal women. Further research is needed to explore the effectiveness of interventions that may increase breastfeeding for Aboriginal women. PMID- 28365238 TI - An Open-Label, Randomized, Controlled Phase II Study of Paclitaxel-Carboplatin Chemotherapy With Necitumumab Versus Paclitaxel-Carboplatin Alone in First-Line Treatment of Patients With Stage IV Squamous Non-Small-Cell Lung Cancer. AB - BACKGROUND: The combination of necitumumab with gemcitabine-cisplatin significantly improved overall survival (OS) in patients with stage IV squamous non-small-cell lung cancer (NSCLC), in the phase III SQUamous NSCLC treatment with the Inhibitor of EGF REceptor (SQUIRE) trial. Paclitaxel-carboplatin was selected as an alternative standard of care in the current phase II study. PATIENTS AND METHODS: Patients were randomized (stratified according to Eastern Cooperative Oncology Group performance status and sex) 2:1 to <= six 3-week cycles (Q3W) of paclitaxel and carboplatin with or without necitumumab. Chemotherapy was paclitaxel 200 mg/m2 on day 1 Q3W and carboplatin area under the curve 6 on day 1 Q3W. Necitumumab 800 mg, on days 1 and 8, was continued until disease progression or intolerable toxicity occurred. The primary end point was objective response rate (ORR) on the basis of Response Evaluation Criteria In Solid Tumors version 1.1. RESULTS: One hundred sixty-seven patients were randomized to the necitumumab-containing arm (n = 110) or the chemotherapy-only arm (n = 57). The combination of necitumumab with chemotherapy resulted in an ORR of 48.9% versus 40.0%. Median progression-free survival and OS were 5.4 versus 5.6 months (hazard ratio [HR], 1.0) and 13.2 versus 11.2 months (HR, 0.83; P = .379) in each treatment arm, respectively. Disease control rate was 87.2% versus 84.0%. Grade >= 3 adverse events typically associated with epidermal growth factor receptor (EGFR) monoclonal antibodies showing a > 2% increase were hypomagnesemia (5.7% vs. 0) and rash (2.8% vs. 0). Any Grade thromboembolic events occurred in < 4% of patients in either arm. CONCLUSION: The results of our study support previously reported results that the combination of necitumumab with chemotherapy improves survival in patients with advanced squamous NSCLC and shows a safety profile consistent with that of EGFR monoclonal antibodies. PMID- 28365240 TI - Using Electronic Health Records to Build an Ophthalmologic Data Warehouse and Visualize Patients' Data. AB - PURPOSE: To develop a near-real-time data warehouse (DW) in an academic ophthalmologic center to gain scientific use of increasing digital data from electronic medical records (EMR) and diagnostic devices. DESIGN: Database development. METHODS: Specific macular clinic user interfaces within the institutional hospital information system were created. Orders for imaging modalities were sent by an EMR-linked picture-archiving and communications system to the respective devices. All data of 325 767 patients since 2002 were gathered in a DW running on an SQL database. A data discovery tool was developed. An exemplary search for patients with age-related macular degeneration, performed cataract surgery, and at least 10 intravitreal (excluding bevacizumab) injections was conducted. RESULTS: Data related to those patients (3 142 204 diagnoses [including diagnoses from other fields of medicine], 720 721 procedures [eg, surgery], and 45 416 intravitreal injections) were stored, including 81 274 optical coherence tomography measurements. A web-based browsing tool was successfully developed for data visualization and filtering data by several linked criteria, for example, minimum number of intravitreal injections of a specific drug and visual acuity interval. The exemplary search identified 450 patients with 516 eyes meeting all criteria. CONCLUSIONS: A DW was successfully implemented in an ophthalmologic academic environment to support and facilitate research by using increasing EMR and measurement data. The identification of eligible patients for studies was simplified. In future, software for decision support can be developed based on the DW and its structured data. The improved classification of diseases and semiautomatic validation of data via machine learning are warranted. PMID- 28365241 TI - Adjuvant Ab Interno Tumor Treatment After Proton Beam Irradiation. AB - PURPOSE: This study was performed to show long-term outcomes concerning globe preservation in uveal melanoma patients after proton beam therapy with the main focus on outcomes according to different adjuvant ab interno surgical procedures. DESIGN: Retrospective cohort study. METHODS: All patients treated with primary proton beam therapy for choroidal or ciliary body melanoma between June 1998 and June 2015 were included. RESULTS: A total of 2499 patients underwent primary proton beam therapy, with local tumor control and globe preservation rates of 95.9% and 94.8% after 5 years, respectively. A total of 110 (4.4%) patients required secondary enucleation. Unresponsive neovascular glaucoma was the leading cause of secondary enucleation in 78 of the 2499 patients (3.1%). The 5-year enucleation-free survival rate was 94.8% in the endoresection group, 94.3% in the endodrainage group, and 93.5% in the comparator group. The log-rank test showed P = .014 (comparator group vs endoresection group) and P = .06 (comparator group vs endodrainage-vitrectomy group). Patients treated with endoresection or endodrainage-vitrectomy developed less radiation retinopathy (30.5% and 37.4% after 5 years, P = .001 and P = .048 [Kaplan-Meier], respectively) and less neovascular glaucoma (11.6% and 21.3% after 5 years, P = .001 and P = .01 [Kaplan Meier], respectively) compared with the comparator group (52.3% radiation retinopathy and 57.8% neovascular glaucoma after 5 years). CONCLUSION: This study suggests that in larger tumors the enucleation and neovascular glaucoma rates might be reduced by adjuvant surgical procedures. Although endoresection is the most promising adjuvant treatment option, the endodrainage-vitrectomy is recommended in patients who are ineligible for endoresection. PMID- 28365242 TI - [Adverse events in an internal medicine: A prospective study]. PMID- 28365243 TI - CNS angiogenesis and barriergenesis occur simultaneously. AB - The blood-brain barrier (BBB) plays a vital role in the central nervous system (CNS). A comprehensive understanding of BBB development has been hampered by difficulties in observing the differentiation of brain endothelial cells (BECs) in real-time. Here, we generated two transgenic zebrafish line, Tg(glut1b:mCherry) and Tg(plvap:EGFP), to serve as in vivo reporters of BBB development. We showed that barriergenesis (i.e. the induction of BEC differentiation) occurs immediately as endothelial tips cells migrate into the brain parenchyma. Using the Tg(glut1b:mCherry) transgenic line, we performed a genetic screen and identified a zebrafish mutant with a nonsense mutation in gpr124, a gene known to play a role in CNS angiogenesis and BBB development. We also showed that our transgenic plvap:EGFP line, a reporter of immature brain endothelium, is initially expressed in newly formed brain endothelial cells, but subsides during BBB maturation. Our results demonstrate the ability to visualize the in vivo differentiation of brain endothelial cells into the BBB phenotype and establish that CNS angiogenesis and barriergenesis occur simultaneously. PMID- 28365244 TI - The CAM-ICU has now a French "official" version. The translation process of the 2014 updated Complete Training Manual of the Confusion Assessment Method for the Intensive Care Unit in French (CAM-ICU.fr). AB - INTRODUCTION: Delirium is common in Intensive-Care-Unit (ICU) patients but under recognized by bed-side clinicians when not using validated delirium-screening tools. The Confusion-Assessment-Method for the ICU (CAM-ICU) has demonstrated very good psychometric properties, and has been translated into many different languages though not into French. We undertook this opportunity to describe the translation process. MATERIAL AND METHODS: The translation was performed following recommended guidelines. The updated method published in 2014 including introduction letters, worksheet and flowsheet for bed-side use, the method itself, case-scenarios for training and Frequently-Asked-Questions (32 pages) was translated into French language by a neuropsychological researcher who was not familiar with the original method. Then, the whole method was back-translated by a native English-French bilingual speaker. The new English version was compared to the original one by the Vanderbilt University ICU-delirium-team. Discrepancies were discussed between the two teams before final approval of the French version. RESULTS: The entire process took one year. Among the 3692 words of the back translated version of the method itself, 18 discrepancies occurred. Eight (44%) lead to changes in the final version. Details of the translation process are provided. CONCLUSIONS AND RELEVANCE: The French version of CAM-ICU is now available for French-speaking ICUs. The CAM-ICU is provided with its complete training-manual that was challenging to translate following recommended process. While many such translations have been done for other clinical tools, few have published the details of the process itself. We hope that the availability of such teaching material will now facilitate a large implementation of delirium screening in French-speaking ICUs. PMID- 28365245 TI - Induced MiR-1249 expression by aberrant activation of Hedegehog signaling pathway in hepatocellular carcinoma. AB - Aberrant activations of Hedegehog (Hh) signaling were found in hepatocellular carcinoma (HCC) and some other cancer types. However, the details have not been completely understood and the underlying mechanism remains unclear. Here we reported that miR-1249 transcription in HCC cells was regulated through direct binding to the conserved sequences in miR-1249 promoter region by Gli1, which functions as a transcription factor and is a component in the Hh signaling pathway. Interestingly, expression of tumor suppressor PTCH1, which is another component of the Hh signaling pathway, was inhibited by miR-1249 through targeting its 3'-untranslated region. Down-regulation of PTCH1 further enhanced the downstream effects mediated by Gli1. In consistent with these findings, miR 1249 expression level was correlated with degree of prognosis (p=0.005) in HCC patients. Taken together, our results suggested the existence of a positive feedback loop comprised of Gli1, miR-1249 and PTCH1. During the process of HCC progression, this positive feedback loop could be continuously activated to enhance tumor cell growth, migration and invasion. PMID- 28365246 TI - The association between oxidative stress-induced galectins and differentiation of human promyelocytic HL-60 cells. AB - Galectins are multifunctional beta-galactoside-binding proteins that are involved in the regulation of cellular stress responses and differentiation. The relationship between these processes is unclear and we report here that galectins display oxidative-stress specific expression patterns in neutrophil-like differentiated HL-60 cells. Three galectins (-1, -3, and -10) are upregulated in response to either menadione or DMSO exposure whereas galectins -9 and -12 exhibited a stimulus-dependent downregulation. Changes in galectin expression are oxidant dependent based on the observations that 1) oxidative stress biomarkers HMOX1 (heme oxygenase-1) and NCF1 (neutrophil cytosolic factor 1, which is also a biomarker of neutrophil differentiation) are elevated in both cases, and 2) the antioxidant N-acetyl-L-cysteine restores basal expression of galectin-3 following oxidant exposure. In addition, our results suggest that the regulation of oxidative stress-sensitive galectins involves DNA hypomethylation mechanisms. Expression of galectin-3 and galectin-12 exhibits an opposite relationship to the expression of HMOX1/NCF1, suggesting a stimulatory and inhibitory role of these galectins in neutrophil-like differentiation of HL-60 cells. We also show that the inhibition of galectins reduces the growth rate of HL-60 cells, and facilitates their neutrophil-like differentiation. Collectively, our findings indicate that the process of cellular differentiation implicates, in part, oxidative stress-sensitive galectins, which further highlights a biological significance of galectin network remodeling in cells. PMID- 28365247 TI - Adipogenic miR-27a in adipose tissue upregulates macrophage activation via inhibiting PPARgamma of insulin resistance induced by high-fat diet-associated obesity. AB - Chronic low degree inflammation caused by macrophage activation is a crucial factor underlying insulin resistance induced by obesity. To illustrate the mechanism of regulating of macrophage activation in adipose tissue, the role of adipogenic miR-27a activating M1 macrophage polarization via blocking PPARgamma was evaluated. Obese mice model and miR-27a overexpression or knockdown mice model were established and related biochemical index were examined. Raw264.7 and 3T3-L1 were cultured and co-cultured for mimicking the microenvironment of local inflammation. Macrophage infiltration was observed. MiR-27a and cytokines levels in serum and adipose tissue were measured. Macrophage polarization markers and protein expression in insulin or inflammatory signaling pathways were observed. Impaired glucose tolerance and insulin tolerance was observed in 4w, 8w and 12w of high fat diet and miR-27a overexpression mice. Concurrently, miR-27a was increased in serum in a time-dependent manner, along with M1 cytokines and M1 macrophages increasing in adipose tissue clearly. Insulin signaling pathway was blocked, and PPARgamma was suppressed. However, NF-kappaB was activated. On the other hand, activated macrophages and hypertrophic adipocytes induced by miR-27a could increase the ratio of Raw264.7 migration, including improving cytokines generation, and blocking PPARgamma expression markedly. The present studies are conducted to clarify that miR-27a has increased along with up-regulation in the process of proinflammatory cytokines generation, macrophage influx and M1 macrophage polarization in obesity. These indicate that miR-27a gives the novel target of intervention for inflammation and insulin resistance in obesity. PMID- 28365248 TI - Parent Distress and the Decision to Have Another Child After an Infant's Death in the NICU. AB - OBJECTIVE: To examine associations among parent perceptions of infant symptoms/suffering, parent distress, and decision making about having additional children after an infant's death in the NICU. DESIGN: Mixed-methods pilot study incorporating mailed surveys and qualitative interviews. SETTING: Midwestern Level IV regional referral NICU. PARTICIPANTS: Participants were 42 mothers and 27 fathers whose infants died in the NICU. METHODS: Parents reported on infant symptoms/suffering at end of life and their own grief and posttraumatic stress symptoms. Qualitative interviews explored decision making about having additional children. RESULTS: Approximately two thirds of bereaved parents had another child after their infant's death (62% of mothers, 67% of fathers). Mothers who had another child reported fewer infant symptoms at end of life compared with mothers who did not (p = .002, d = 1.28). Although few mothers exceeded clinical levels of prolonged grief (3%) and posttraumatic stress symptoms (18%), mothers who had another child endorsed fewer symptoms of prolonged grief (p = .001, d = 1.63) and posttraumatic stress (p = .009, d = 1.16). Differences between fathers mirrored these effects but were not significant. Parent interviews generated themes related to decision making about having additional children, including Impact of Infant Death, Facilitators and Barriers, Timing and Trajectories of Decisions, and Not Wanting to Replace the Deceased Child. CONCLUSION: Having another child after infant loss may promote resilience or serve as an indicator of positive adjustment among parents bereaved by infant death in the NICU. Prospective research is necessary to distinguish directional associations and guide evidence based care. PMID- 28365249 TI - Umbilical Cord Care and Infection Rates in Turkey. AB - OBJECTIVE: To compare the efficacy of umbilical cord sponging with 70% alcohol, sponging with 10% povidone-iodine, and dry care on the time to umbilical cord separation and bacterial colonization. DESIGN: Prospective, interventional experimental study design. SETTING: Three different family health centers in Istanbul, Turkey. PARTICIPANTS: In total, 194 newborns were enrolled in one of three study groups: Group 1, 70% alcohol (n = 67); Group 2, 10% povidone-iodine (n = 62); and Group 3, dry care (n = 65). METHODS: Data were collected between January 2015 and July 2015. Umbilical separation time and umbilical cord bacterial colonization were considered as the study outcomes. RESULTS: The most commonly isolated bacteria were Staphylococcus aureus, Escherichia coli, and enterococci. There was no significant difference among the groups for umbilical cord separation times (p > .05). CONCLUSION: Dry care may be perceived as an attractive option because of cost benefits and ease of application. PMID- 28365250 TI - Corrigendum to "Preclinical studies on new proteins as carrier for glycoconjugate vaccines" [Vaccine 34 (2016) 4235-4242]. PMID- 28365251 TI - Country-level predictors of vaccination coverage and inequalities in Gavi supported countries. AB - BACKGROUND: Important inequalities in childhood vaccination coverage persist between countries and population groups. Understanding why some countries achieve higher and more equitable levels of coverage is crucial to redress these inequalities. In this study, we explored the country-level determinants of (1) coverage of the third dose of diphtheria-tetanus-pertussis- (DTP3) containing vaccine and (2) within-country inequalities in DTP3 coverage in 45 countries supported by Gavi, the Vaccine Alliance. METHODS: We used data from the most recent Demographic and Health Surveys (DHS) conducted between 2005 and 2014. We measured national DTP3 coverage and the slope index of inequality in DTP3 coverage with respect to household wealth, maternal education, and multidimensional poverty. We collated data on country health systems, health financing, governance and geographic and sociocultural contexts from published sources. We used meta-regressions to assess the relationship between these country-level factors and variations in DTP3 coverage and inequalities. To validate our findings, we repeated these analyses for coverage with measles containing vaccine (MCV). RESULTS: We found considerable heterogeneity in DTP3 coverage and in the magnitude of inequalities across countries. Results for MCV were consistent with those from DTP3. Political stability, gender equality and smaller land surface were important predictors of higher and more equitable levels of DTP3 coverage. Inequalities in DTP3 coverage were also lower in countries receiving more external resources for health, with lower rates of out of-pocket spending and with higher national coverage. Greater government spending on heath and lower linguistic fractionalization were also consistent with better vaccination outcomes. CONCLUSION: Improving vaccination coverage and reducing inequalities requires that policies and programs address critical social determinants of health including geographic and social exclusion, gender inequality and the availability of financial protection for health. Further research should investigate the mechanisms contributing to these associations. PMID- 28365252 TI - Assessment of sex-specific differences in adverse events following immunization reporting in Ontario, 2012-15. AB - We assessed sex-specific trends within passive vaccine safety surveillance in Ontario, Canada. AEFIs reported following vaccines administered between 2012 and 2015 were included. There were 2466 AEFI reports; 66.2% were female. Annualized reporting rates were 5.9 and 3.1 per 100,000 population, for females and males respectively. The female:male reporting rate ratio (RRR) was 1.9. Sex-specific differences by age group were greatest in adults 18-64years (RRR 6.3); whereas there were no differences in children <10years. Vaccine-specific RRRs were highest for vaccines recommended for routine use in adults or high risk populations. All event categories were female-predominant. The highest event specific RRRs were for oculorespiratory syndrome (5.1), anaesthesia/paraesthesia (4.6) and anaphylaxis (3.0). Serious AEFIs (n=113) were more evenly distributed (57.5% female, RRR 1.3) than non-serious (66.6% female, RRR 1.9). AEFI reporting among females was consistently elevated within the passive surveillance system in Ontario. Further study of the relationship between sex/gender and AEFI reporting is needed. PMID- 28365254 TI - Regulation of hypoxia-inducible factor-1alpha in human buccal mucosal fibroblasts stimulated with arecoline. AB - Hypoxia-inducible factor (HIF)-1alpha is consistently and dramatically upregulated in a variety of fibrotic diseases. The aim of this study was to compare HIF-1alpha expression from fibroblasts derived from human normal buccal mucosa and oral submucous fibrosis (OSF) specimens and further to explore the potential mechanisms that may lead to induce HIF-1alpha expression. OSF buccal mucosal fibroblasts (BMFs) demonstrated significantly higher HIF-1alpha mRNA expression than normal BMFs (p<0.005). Arecoline, the major areca nut alkaloid, was also found to elevate HIF-1alpha mRNA expression in a dose-dependent manner (p<0.05). Moreover, arecoline-induced HIF-1alpha expression was downregulated by mitogen-activated protein kinase inhibitor U0126, phosphatidylinositol 3-kinase inhibitor LY294002, p38 inhibitor SB203580, cyclooxygenase-2 inhibitor NS-398, and glutathione precursor N-acetyl-L-cysteine (p<0.05). Taken together, hypoxia plays an important role in the pathogenesis of areca quid chewing-associated OSF. These pharmacological agents may be further used as chemoprevention agents for OSF. PMID- 28365255 TI - Corrigendum to "Oral treatment with enrofloxacin early in life promotes Th2 mediated immune response in mice" [Pharmacol. Rep. 68 (2016) 44-50]. PMID- 28365253 TI - Semiconductor diode laser device adjuvanting intradermal vaccine. AB - A brief exposure of skin to a low-power, non-tissue damaging laser light has been demonstrated to augment immune responses to intradermal vaccination. Both preclinical and clinical studies show that this approach is simple, effective, safe and well tolerated compared to standard chemical or biological adjuvants. Until now, these laser exposures have been performed using a diode-pumped solid state laser (DPSSL) devices, which are expensive and require labor-intensive maintenance and special training. Development of an inexpensive, easy-to-use and small device would form an important step in translating this technology toward clinical application. Here we report that we have established a handheld, near infrared (NIR) laser device using semiconductor diodes emitting either 1061, 1258, or 1301nm light that costs less than $4000, and that this device replicates the adjuvant effect of a DPSSL system in a mouse model of influenza vaccination. Our results also indicate that a broader range of NIR laser wavelengths possess the ability to enhance vaccine immune responses, allowing engineering options for the device design. This small, low-cost device establishes the feasibility of using a laser adjuvant approach for mass-vaccination programs in a clinical setting, opens the door for broader testing of this technology with a variety of vaccines and forms the foundation for development of devices ready for use in the clinic. PMID- 28365256 TI - Corrigendum to "Epicutaneous immunization with protein antigen TNP-Ig and NOD2 ligand muramyl dipeptide (MDP) reverses skin-induced suppression of contact hypersensitivity" [Pharmacol. Rep. 66 (2014) 137-142]. PMID- 28365257 TI - Corrigendum to "Epicutaneous immunization with phosphorylcholine conjugated to bovine serum albumin (PC-BSA) and TLR9 ligand CpG alleviates pneumococcal pneumonia in mice" [Pharmacol. Rep. 66 (2014) 570-575]. PMID- 28365258 TI - Corrigendum to "Eplerenone promotes alternative activation in human monocyte derived macrophages" [Pharmacol. Rep. 65 (2013) 226-234]. PMID- 28365259 TI - Corrigendum to "Comparison of chosen activation markers of human monocytes/macrophages isolated from the peripheral blood of young and elderly volunteers" [Pharmacol. Rep. 66 (2014) 759-765]. PMID- 28365260 TI - CXCL12 as a Predictor of Vitiligo Activity and Disease Progression. PMID- 28365261 TI - Seven Coils in 1 Heart: Therapeutic Option for Multiple VSD. PMID- 28365262 TI - Resting Versus Hyperemic Coronary Pressure Measurements for Stenosis Evaluation: The New Kids Have Come to Stay. PMID- 28365263 TI - Percutaneous Palliation of Right Ventricular Outflow Tract Obstruction Caused by Metastatic Malignancy. PMID- 28365264 TI - Extraluminal Migration of a Drug-Eluting Stent Into a Thrombosed Coronary Aneurysm With Preserved Antegrade Flow in the Right Coronary Artery. PMID- 28365265 TI - Successful TriCinch-in-TriCinch Transcatheter Tricuspid Valve Repair. PMID- 28365266 TI - Effect of Coronary Anatomy and Hydrostatic Pressure on Intracoronary Indices of Stenosis Severity. AB - OBJECTIVES: The authors sought to analyze height differences within the coronary artery tree in patients in a supine position and to quantify the impact of hydrostatic pressure on intracoronary pressure measurements in vitro. BACKGROUND: Although pressure equalization of the pressure sensor and the systemic pressure at the catheter tip is mandatory in intracoronary pressure measurements, subsequent measurements may be influenced by hydrostatic pressure related to the coronary anatomy in the supine position. Outlining and quantifying this phenomenon is important to interpret routine and pullback pressure measurements within the coronary tree. METHODS: Coronary anatomy was analyzed in computed tomography angiographies of 70 patients to calculate height differences between the catheter tip and different coronary segments in the supine position. Using a dynamic pressure simulator, the effect of the expected hydrostatic pressure resulting from such height differences on indices stenosis severity was assessed. RESULTS: In all patients, the left anterior and right posterior descending arteries are the highest points of the coronary tree with a mean height difference of -4.9 +/- 1.6 cm and -3.8 +/- 1.0 cm; whereas the circumflex artery and right posterolateral branches are the lowest points, with mean height differences of 3.9 +/- 0.9 cm and 2.6 +/- 1.6 cm compared with the according ostium. In vitro measurements demonstrated a correlation of the absolute pressure differences with height differences (r = 0.993; p < 0.0001) and the slope was 0.77 mm Hg/cm. The Pd/Pa ratio and instantaneous wave-free ratio correlated also with the height difference (fractional flow reserve r = 0.98; p < 0.0001; instantaneous wave-free ratio r = 0.97; p < 0.0001), but both were influenced by the systemic pressure level. CONCLUSIONS: Hydrostatic pressure variations resulting from normal coronary anatomy in a supine position influence intracoronary pressure measurements and may affect their interpretation during stenosis severity assessment. PMID- 28365267 TI - Subintimal Crush of an Occluded Stent to Recanalize a Chronic Total Occlusion Due to In-Stent Restenosis: Insights From a Multimodality Imaging Approach. PMID- 28365269 TI - Does promoting resolution instead of inhibiting inflammation represent the new paradigm in treating infections? AB - Infections arise when the host response is overwhelmed by pathogens leading to organ dysfunction. In some instances patients progress to more severe conditions, including septic shock, that are associated with increased mortality. Current strategies in treating infections aim at either blocking inflammation using inhibitors to pro-inflammatory molecules and/or inhibiting bacterial growth using antibiotics. These approaches find their origins in studies conducted by Joseph Lister who demonstrated that applying carbolic acid to wounds promoted wound healing without suppuration, reducing both the necessity of amputation and mortality. While this approach is still applicable to certain infections, inhibition of the immune response is also associated with increased mortality, especially in septic patients. In many instances sepsis survivors succumb later to persistent, recurrent, nosocomial and secondary infections. This, together with a rise in resistance to many frontline antibiotics, has prompted a search for alternative ways to treat infections. Recent studies investigating processes engaged by the host response during self-resolving infections identified a novel group of mediators, termed as specialized pro-resolving mediators (SPM). These molecules, produced via the enzymatic conversion of essential fatty acids, actively reprogram the immune response to promote clearance of invading pathogens, and counter-regulate the production of inflammation-initiating molecules. Furthermore, recent studies also demonstrate that these mediators promote tissue repair and regeneration, essential processes in the re establishment of barrier and prevention of re-infection. The scope of the present review is to discuss the evidence underpinning the endogenous protective roles of these novel mediators, as well as the evidence demonstrating that dysregulation in their production and actions contribute to disease pathogenesis in infections. This review will also discuss the potential of resolution pharmacology-based approaches in developing new therapeutics for combatting infections that do not interfere with the immune response. PMID- 28365270 TI - Calcium-to-Citrate Ratio Distinguishes Solitary and Recurrent Urinary Stone Forming Children. AB - PURPOSE: The prevalence of urinary stone disease is increasing in children. We previously reported a high rate of urinary metabolic abnormalities, including hypercalciuria and hypocitraturia, in stone forming children. In this study we determined whether calcium-to-citrate ratio could help predict those at risk for recurrent stone formation. MATERIALS AND METHODS: We conducted a retrospective cohort study to assess calcium-to-citrate ratios in children with urolithiasis. Two 24-hour urine collections were performed. Urinary excretions of calcium and citrate were analyzed, and calcium-to-citrate ratio was calculated. Patients were stratified into solitary and recurrent stone formers and compared to a control group of normal children. RESULTS: We identified 73 solitary and 92 recurrent stone formers. Mean patient age was 13 years for both groups. Gender was well matched. A total of 29 normal children served as controls. Mean calcium-to citrate ratio was 0.41 in solitary stone formers and 0.64 in recurrent stone formers (p = 0.02). Mean value in normal children (0.33) was significantly less compared to recurrent stone formers (p = 0.002) and trended lower compared to solitary stone formers (p = 0.15). The ratio was abnormally high in recurrent stone formers (70%) compared to solitary stone formers (47%, p = 0.003). CONCLUSIONS: There are significant differences in urine calcium-to-citrate ratios between solitary and recurrent calcium stone forming children. Solitary stone formers trended higher compared to controls. These findings may allow more precise risk stratification and treatment to prevent recurrent stone episodes. PMID- 28365268 TI - Diagnostic Performance of Resting and Hyperemic Invasive Physiological Indices to Define Myocardial Ischemia: Validation With 13N-Ammonia Positron Emission Tomography. AB - OBJECTIVES: The authors sought to compare the diagnostic performance of fractional flow reserve (FFR), instantaneous wave-free ratio (iFR), and resting distal coronary artery pressure/aortic pressure (Pd/Pa) using 13N-ammonia positron emission tomography (PET). BACKGROUND: The diagnostic performance of invasive physiological indices was reported to be different according to the reference to define the presence of myocardial ischemia. METHODS: A total of 115 consecutive patients with left anterior descending artery stenosis who underwent both 13N-ammonia PET and invasive physiological measurement were included. Optimal cutoff values and diagnostic performance of FFR, iFR, and resting Pd/Pa were assessed using PET-derived coronary flow reserve (CFR) and relative flow reserve (RFR) as references. To compare discrimination and reclassification ability, each index was compared with integrated discrimination improvement (IDI) and category-free net reclassification index (NRI). RESULTS: All invasive physiological indices correlated with CFR and RFR (all p values <0.001). The overall diagnostic accuracies of FFR, iFR, and resting Pd/Pa were not different for CFR <2.0 (FFR 69.6%, iFR 73.9%, and resting Pd/Pa 70.4%) and RFR <0.75 (FFR 73.9%, iFR 71.3%, and resting Pd/Pa 74.8%). Discrimination and reclassification abilities of invasive physiological indices were comparable for CFR. For RFR, FFR showed better discrimination and reclassification ability than resting indices (IDI = 0.170 and category-free NRI = 0.971 for iFR; IDI = 0.183 and category-free NRI = 1.058 for resting Pd/Pa; all p values <0.001). CONCLUSIONS: The diagnostic performance of invasive physiological indices showed no differences in the prediction of myocardial ischemia defined by CFR. Using RFR as a reference, FFR showed a better discrimination and reclassification ability than resting indices. PMID- 28365271 TI - Dietary and Lifestyle Risk Factors Associated with Incident Kidney Stones in Men and Women. AB - PURPOSE: Several dietary and lifestyle factors are associated with a higher risk of kidney stones. We estimated the population attributable fraction and the number needed to prevent for modifiable risk factors, including body mass index, fluid intake, DASH (Dietary Approaches to Stop Hypertension) style diet, dietary calcium intake and sugar sweetened beverage intake. MATERIALS AND METHODS: We used data on the HPFS (Health Professionals Follow-Up Study) cohort and the NHS (Nurses' Health Study) I and II cohorts. Information was obtained from validated questionnaires. Poisson regression models adjusted for potential confounders were used to estimate the association of each risk factor with the development of incident kidney stones and calculate the population attributable fraction and the number needed to prevent. RESULTS: The study included 192,126 participants who contributed a total of 3,259,313 person-years of followup, during which an incident kidney stone developed in 6,449 participants. All modifiable risk factors were independently associated with incident stones in each cohort. The population attributable fraction ranged from 4.4% for a higher intake of sugar sweetened beverages to 26.0% for a lower fluid intake. The population attributable fraction for all 5 risk factors combined was 57.0% in HPFS, 55.2% in NHS I and 55.1% in NHS II. The number needed to prevent during 10 years ranged from 67 for lower fluid intake to 556 for lower dietary calcium intake. CONCLUSIONS: Five modifiable risk factors accounted for more than 50% of incident kidney stones in 3 large prospective cohorts. Assuming a causal relation, our estimates suggest that preventive measures aimed at reducing those factors could substantially decrease the burden of kidney stones in the general population. PMID- 28365273 TI - Experimental study of dissolution of minerals and CO2 sequestration in steel slag. AB - This study strives to achieve a substantial amount of steel slag carbonation without using any harmful chemicals. For this purpose, experiments were performed in an aqueous medium, in a semi-batch reactor, to investigate the effect of varying reaction conditions during the steel slag CO2 sequestration process. Further, studying the effect of dissolution on carbonation reactions and the mineralogical changes that subsequently occur within the slag helps provide insight into the parameters that ultimately have an impact on the carbonation rate as well the magnitude of the impact. PMID- 28365274 TI - Growth and reproductive potential of Eisenia foetida (Sav) on various zoo animal dungs after two methods of pre-composting followed by vermicomposting. AB - Disposal of animal manure without treatment can be harmful to the environment. In this study, samples of four zoo animal dungs and one horse dung were pre composted in two ways: (a) traditional composting and (b) bokashi pre-composting for 1month, followed by vermicomposting for 3months. The permanence (PEf) and reproductive potential (RP) of Eisenia foetida as well as the quality of vermicompost were evaluated. The PEf values and RP index of E. foetida were higher for samples pre-composted using the traditional composting method (98.7 88% and 31.85-16.27%, respectively) followed by vermicomposting (92.7-72.7% and 22.96-13.51%, respectively), when compared with those for bokashi pre-composted samples followed by vermicomposting, except for the horse dung sample (100% for both the parameters). The values of electrical conductivity (EC), cation exchange capacity (CEC), organic C, total N, available P, C/N ratio, and pH showed that both treatments achieved the norms of vermicompost (<4mScm-1, 40cmolkg-1, 20-50%, 1-4%, <=20, 5.5-8.5, respectively). However, the maturity indices of vermicompost, namely, organic matter loss, N loss, and CEC/organic carbon (OC) ratio indicated that bokashi pre-composting followed by vermicomposting produced the highest values (98.7-70.7%, 97.67-96.65%, and 2.7-1.97%, respectively), when compared with the other method adapted in this study. Nevertheless, further studies with plants for plant growth evaluation are needed to assess the benefits and limitations of these two pre-composting methods prior to vermicomposting. PMID- 28365272 TI - ERK1/2 signaling is required for the initiation but not progression of TGFbeta induced lens epithelial to mesenchymal transition (EMT). AB - Transforming Growth Factor Beta (TGFbeta) potently induces lens epithelial to mesenchymal transition (EMT). The resultant mesenchymal cells resemble those found in plaques of human forms of subcapsular cataract. Smad signaling has long been implicated as the sole driving force of TGFbeta-mediated activity. Rat lens epithelial explants were used to examine the role of the Smad-independent signaling, namely the MAPK/ERK1/2 signaling pathway, in the initiation and progression of TGFbeta-induced EMT. Phase contrast microscopy was used to observe the morphological changes associated with TGFbeta-induced EMT in this model, including cell elongation, cell membrane blebbing, cell loss as indicated by the area of bare capsule and capsular wrinkling. The levels of Smad2, Smad2/3 and ERK1/2 phosphorylation measured using western blotting confirmed that the addition of UO126 was sufficient in blocking all TGFbeta-induced ERK1/2 activation, as well as reducing Smad signaling at 18 h. Immunofluorescent labeling and further western blotting confirmed that TGFbeta-induced EMT was associated with an increase in alpha-smooth muscle actin (alpha-SMA) and a reduction of E-cadherin at cell borders. Pre-treatment with UO126 was effective at blocking the TGFbeta-induced EMT, as evidenced by a reduction of alpha-SMA expression and protein labeling, E-cadherin labeling at cell borders, and a reduction of cell loss, cell elongation and capsular wrinkling. Post-treatment with UO126 at 2 and 6 h after TGFbeta addition was also effective at blocking EMT while post-treatment with UO126 at 24 and 48 h was not sufficient in hampering TGFbeta-induced EMT. Our data implicates ERK1/2 signaling in the initiation but not the progression of TGFbeta-induced EMT in rat lens epithelial cells. The tight regulation of intracellular signaling pathways such as ERK1/2 are required for the maintenance of lens epithelial cell integrity and hence tissue transparency. A greater understanding of the molecular mechanisms that drive the induction and progression of EMT in the lens will provide the basis for potential therapeutics for human cataract. PMID- 28365275 TI - Recovery of lithium and cobalt from spent lithium-ion batteries using organic acids: Process optimization and kinetic aspects. AB - An environmentally-friendly route based on hydrometallurgy was investigated for the recovery of cobalt and lithium from spent lithium ion batteries (LIBs) using different organic acids (citric acid, Dl-malic acid, oxalic acid and acetic acid). In this investigation, response surface methodology (RSM) was utilized to optimize leaching parameters including solid to liquid ratio (S/L), temperature, acid concentration, type of organic acid and hydrogen peroxide concentration. Based on the results obtained from optimizing procedure, temperature was recognized as the most influential parameter. In addition, while 81% of cobalt was recovered, the maximum lithium recovery of 92% was achieved at the optimum leaching condition of 60 degrees C, S/L: 30gL-1, citric acid concentration: 2M, hydrogen peroxide concentration: 1.25Vol.% and leaching time: 2h. Furthermore, results displayed that ultrasonic agitation will enhance the recovery of lithium and cobalt. It was found that the kinetics of cobalt leaching is controlled by surface chemical reaction at temperatures lower than 45 degrees C. However, diffusion through the product layer at temperatures higher than 45 degrees C controls the rate of cobalt leaching. Rate of lithium reaction is controlled by diffusion through the product layer at all the temperatures studied. PMID- 28365276 TI - Recovery of valuable components from waste LCD panel through a dry physical method. AB - A waste liquid crystal display (LCD) panel was recycled synthetically and cleanly by using dry physical methods, namely, mechanical exfoliation, dry crushing and vibrated gas-solid fluidized bed separation. Results of elemental and phase analyses show that indium and tin contents were enriched greatly in indium tin oxide concentrate obtained from colour filter and thin-film transistor glass. The results of crushing, ash content and scanning electron microscopic analyses show that when the LCD panel was crushed into particles smaller than 0.25mm, the polarizer film is nearly completely liberated from the glass. Moreover, the results of vibrated gas-solid fluidized bed separation show that gas velocity and separation time are the main factors influencing the separation. The vibration intensity of 6.8, gas velocity of 13.6cm/s and fluidizing time of 30s are the optimum operating parameters, and the degree of separation and recovery of polarizing film reached up to 37.69 and 72.3%, respectively. Based on these results, the combination of dry enrichment, dry crushing and dry separation in a flowsheet is proposed for recycling of waste LCD panel. PMID- 28365277 TI - Practical Management of Antibiotic Hypersensitivity in 2017. AB - Antibiotics are the most common class of medications that individuals report allergy or intolerance to. Adverse reactions are reported at a predictable rate with all antibiotic use that vary by antibiotic. Antibiotic allergy incidence rates are sex dependent, higher in females than in males. Most of these events are not reproducible or immunologically mediated. Antibiotic allergy prevalence increases with increasing age and is more common in hospitalized populations and in populations that use more antibiotics. Determining potential mechanisms for the observed symptoms of the adverse reactions is the starting point for effective management of antibiotic hypersensitivity. Skin testing and direct challenges are the primary tools used to determine acute tolerance in 2017. Commercially available in vitro testing is not currently clinically useful in determining antibiotic hypersensitivity, with rare exceptions. Desensitization can be used when acute-onset immunologically mediated hypersensitivity is confirmed to safely administer a needed antibiotic. Desensitization is not possible when clinically significant T-cell-mediated delayed-type hypersensitivity is present. Effective management of antibiotic allergy is an important part of a comprehensive antibiotic stewardship program. PMID- 28365278 TI - A role for plasma aromatic amino acids in injurious pecking behavior in laying hens. AB - Injurious pecking, including feather pecking (FP), is one of the most prevalent causes of mortality for commercial laying hens. The underlying biological mechanisms of FP are not yet fully understood, but they could be related to alterations in the serotonin (5-HT) and/or dopamine (DA) circuits within the brain. In the past, the central synthesis of 5-HT and DA was found to be influenced by the availability of their precursors, aromatic amino acids (AAA) such as tryptophan (TRP), phenylalanine (PHE), and tyrosine (TYR), in blood plasma, which are transported across the blood-brain-barrier into the brain. Because knowledge about plasma levels of AAA in laying hens is very limited, the present study compared the AAA profiles of a large sample of laying hens from two genetic lines: one selected for low mortality (LM) due to injurious pecking (n=129 birds) and one high production line (HP) selected for high egg-production only (n=132 birds). Head, comb, and feather covering were scored at the end of the experiment. Blood samples were collected at weeks 24 and 29 of age and were analysed for AAA using high performance liquid chromatography. Neither FP nor feather damage was observed in the present study, but aggressive pecking directed at the head/neck area occurred in several groups with an onset of this aberrant behavior between weeks 22 and 29. Eight HP pens and seven LM pens were affected by severe head/comb injuries inflicted via aggressive pecking. Therefore, our exploratory data analysis focused upon the possible interplay between the variability of our outcome measures (absolute levels of AAA in plasma as well as the ratios PHE/TYR and TRP/(PHE+TYR)) and the aggressive head/comb pecking as an expression of social stress within the pens. We found significantly lower TRP availability relative to PHE and TYR (TRP/(PHE+TYR) ratio) and higher TYR concentrations at week 24 in pens with an early onset of injurious aggressive behavior at weeks 22-23. This was most pronounced in the LM line, but at week 29, TRP availability normalized in both lines. It was furthermore evident that in LM birds, higher aggressive pecking activity per pen was associated with higher TYR levels (n=78 birds, r=0.643, p<0.001) and lower TRP/(PHE+TYR) ratios at week 24 (r=-0.541, p<0.001). In the HP birds, these associations were of lower strength and were negatively correlated (TYR: n=73, r=-0.308, p=0.005; TRP/(PHE/TYR) ratio: r=0.314, p=0.004). Our findings indicate that in LM birds, lower TRP availability at week 24 may be attributable to higher stress levels in pens where injurious aggressive pecking developed early on. These findings may lay the important groundwork for the analysis of AAA plasma levels as a useful avenue of research to investigate underlying physiological mechanisms of behavioral problems in laying hens. PMID- 28365279 TI - Preliminary evidence of sex differences in behavioral and neural responses to palatable food reward in rats. AB - The female bias in eating disorder prevalence is the largest in all of psychiatry. Binge eating on palatable food (PF) is a core, maladaptive symptom that cuts across all major types of eating disorders and can be studied via animal models. Using an individual differences rat model of binge eating that identifies binge eating prone (BEP) and binge eating resistant (BER) phenotypes, we previously showed that, compared with males, females consume more PF and are more likely to be classified as BEP. One potential explanation for this sex difference is that PF is inherently more rewarding to females, leading to higher rates of binge eating. Here we tested the hypothesis that females have more robust behavioral and neural responses to PF reward than males. Adult male (N=18) and female (N=17) Sprague-Dawley rats were exposed to the Conditioned Place Preference paradigm using PF as the unconditioned stimulus. Select males (N=9) and females (N=9) were video-recorded during three of the PF-paired conditioning sessions to score feeding behavior. Following CPP, 13 male and 12 female rats were exposed to PF just prior to sacrifice to induce expression of the neural activation marker Fos, and Fos expression was quantified in mesocorticolimbic, hypothalamic, and amygdalar circuits. In the CPP paradigm, females displayed a more robust shift in preference for the chamber paired with PF compared with males, and behavioral analyses revealed that average duration of individual feeding bouts during pairing sessions was longer in females than in males. Fos expression was significantly higher in females vs. males in select regions of the mesocorticolimbic reward circuit, with no sex differences in hypothalamic or amygdalar regions. These results provide initial evidence that PF may be more rewarding to females than to males, possibly due to heightened responsiveness of neural substrates that mediate the hedonic and motivational responses to PF, which in part, may underlie sex differences in binge eating proneness. PMID- 28365280 TI - [Self-healing lesions in Langerhans cell histiocytosis]. PMID- 28365281 TI - [The little and large of pediatric obesity prevention]. PMID- 28365282 TI - [Risks associated with the uncontrolled use of donated breast milk]. PMID- 28365283 TI - [Epidemiological and clinical characteristics of infants admitted to hospital due to human parechovirus infections: A prospective study in Spain]. AB - INTRODUCTION: Human parechovirus (HPeV) is one of the recently described picornaviridae viruses that have been associated with fever of unknown origin (FUO), clinical sepsis, gastroenteritis, meningitis, or encephalitis in very young infants. The aim of this study is to describe the epidemiology and clinical features of these viruses. PATIENTS AND METHODS: A prospective multicentre 3-year study was conducted in 12 hospitals in Spain. Out of 850 specimens examined, 47 were positive (5.52%), with HPeV-3 being the most frequent (29 cases). Infections occurred throughout the year, but mainly in May and July, and a biennial distribution was observed. More than half (57%) were neonates, and only 2 children were older than 3 months. Fever was present in all children, with irritability in 45%, rash in 18.6%, and diarrhoea in 14%. The results of biochemical tests were all in normal range. The most common final diagnosis was FUO (61%), followed by clinical sepsis (29%). Up to 29% of infants were admitted to the intensive care unit, but only one patient had sequelae. RESULTS: Out of 850 specimens examined, 47 were positive (5.52%) for HPeV, with HPeV-3 being the most frequent (29 cases). Infections occurred throughout the year, but mainly in May and July, and a biennial distribution was observed. More than half (57%) were neonates, and only 2 children were older than 3 months. Fever was present in all children, with irritability in 45%, rash in 18.6%, and diarrhoea in 14%. The results of biochemical tests were all in normal range. The most common final diagnosis was FUO (61%), followed by clinical sepsis (29%). Up to 29% of infants were admitted to the intensive care unit, but only one patient had sequelae CONCLUSIONS: HPeV circulates in our country, mainly during spring and summer, and affects young infants with a FUO and clinical sepsis. Molecular diagnostic techniques in all hospitals could help in improving the management of patients with these infections. PMID- 28365284 TI - Synthesis and mechanical properties of double cross-linked gelatin-graphene oxide hydrogels. AB - Gelatin is an interesting biological macromolecule for biomedical applications. Here, double cross-linked gelatin nanocomposite hydrogels with incorporation of graphene oxide (GO) were synthesized in one pot using glutaraldehyde (GTA) and GTA-grafted GO as double chemical cross-linkers. The nanocomposite hydrogels, in contrast to the neat gelatin hydrogel, exhibited significant increases in mechanical properties by up to 288% in compressive strength, 195% in compressive modulus, 267% in compressive fracture energy and 160% shear storage modulus with the optimal GO concentration. Fourier transform infrared spectroscopy, scanning electron microscopy and swelling tests were implemented to characterize the nanocomposite hydrogels. PMID- 28365285 TI - Magnetic stimuli-responsive chitosan-based drug delivery biocomposite for multiple triggered release. AB - Stimuli-responsive biomaterials offer a unique advantage over traditional local drug delivery systems in that the drug elution rate can be controllably increased to combat developing symptomology or maintain high local elution levels for disease treatment. In this study, superparamagnetic Fe3O4 nanoparticles and the antibiotic vancomycin were loaded into chitosan microbeads cross-linked with varying lengths of polyethylene glycol dimethacrylate. Beads were characterized using degradation, biocompatibility, and elution studies with successive magnetic stimulations at multiple field strengths and frequencies. Thirty-minute magnetic stimulation induced a temporary increase in daily elution rate of up to 45% that was dependent on field strength, field frequency and cross-linker length. Beads degraded by up to 70% after 3 days in accelerated lysozyme degradation tests, but continued to elute antibiotic for up to 8 days. No cytotoxic effects were observed in vitro compared to controls. These promising preliminary results indicate clinical potential for use in stimuli-controlled drug delivery. PMID- 28365286 TI - Detection of glycated hemoglobin with voltammetric sensing amplified by 3D structured nanocomposites. AB - Glycated hemoglobin (HbA1c), a marker for glycine level in blood, while detecting over a long period of time (up to 2-3 months) shows consistency. Therefore, HbA1c has been mostly used and indeed an established test for monitoring the glycemic control in persons suffering from diabetes. 3D-structured reduced graphene oxide (rGO), multiwalled carbon nanotubes (MWCNT) and platinum nanoparticles (PtNPs) composite (PtNPs/rGO-MWCNT) were synthesized and used as interface for the development of an electrochemical HbA1c biosensor. The network structure of rGO MWCNT nanocomposite provides more active sites for Pt deposition and the synergistic effect of rGO, MWCNTs and PtNPs significantly improved the electrochemical performance of the working electrode. The structure of PtNPs/rGO MWCNT nanocomposite was characterized by scanning electron microscopy (SEM), cyclic voltammetry (CV) and electrochemical impedance study (EIS). This biosensor exhibited a response time of less than 3s, a wide linear concentration range of 0.05-1000MUM with detection limit of 0.1MUM, good repeatability and satisfactory reproducibility. The biosensor retained 50% of its initial response after 12 weeks at 25 degrees C. The proposed biosensor was successfully applied for the determination of HbA1c concentration in human blood samples with recoveries between 93.7 and 98.3%. PMID- 28365287 TI - Properties of gelatin-based films incorporated with chitosan-coated microparticles charged with rutin. AB - The aim of this study was development an active film based on gelatin incorporated with antioxidant, rutin carried into microparticles. The complexation between oppositely charged lecithin and chitosan was applied to prepare the chitosan-coated microparticles. The generated microparticles had an average size of 520+/-4nm and a span of 0.3 were formulated by a rotor-stator homogenize at the homogenization speed 10,000rpm. Composite films were prepared by incorporating chitosan-coated microparticles, at various concentrations (0.05, 0.1, 0.5, or 1% (based on the weight of the gelatin powder)) in the gelatin-based films. For the prepared films, the results showed that obtained physicochemical, water vapor barrier, and mechanical were compared with native gelatin film with a slight decrease for chitosan concentration higher than 0.5%. The microstructure studies done by scanning electron microscopes, revealed different micropores embedded with oil resulting from the incorporation of the microparticles into the gelatin matrix. Moreover, the calorimetric results were comparable to those of gelatin control film with Tg value 45 degrees C and increased crystallinity percentage with increasing incorporation of microparticles. This original concept of composite biodegradable films may thus be a good alternative to incorporate liposoluble active compounds to design an active packaging with good properties. PMID- 28365288 TI - Nitrate removal from aqueous solutions by ZnO nanoparticles and chitosan polystyrene-Zn nanocomposite: Kinetic, isotherm, batch and fixed-bed studies. AB - Chitosan-polystyrene-Zn nanocomposite was synthesized through precipitation procedure and well characterized by analytical instruments such as Fourier transform infrared spectroscopy, field emission scanning electron microscopy, transmission electron microscopy, X-ray diffraction, and energy-dispersive X-ray spectroscopy. After characterizations, the nanocomposite was applied as an adsorbent for removal of nitrate ions from aqueous solutions. The study parameters influencing batch adsorption show that 0.5g of chitosan-polystyrene-Zn nanocomposite removed 90% of the nitrate ions (initial concentration 10mg/L) from 25mL of water at pH=3 after 30min while, in fixed-bed column technique, and at a similar condition, it removed 82.5% of nitrate. On the other hand, ZnO nanoparticles after activation by HCl solution applied for removal of nitrate contamination at the same condition which was used for chitosan-polystyrene-Zn nanocomposite. But ZnO nanoparticles removed all nitrate in the polluted solution in both techniques. The Elovich and the Langmuir models successfully exhibited the experimental data kinetic and isotherm for the adsorption processes. PMID- 28365289 TI - Facile synthesis of bovine serum albumin conjugated low-dimensional ZnS nanocrystals. AB - We present a facile synthesis of bovine serum albumin (BSA) conjugated low dimensional ZnS nanocrystals. The experimental parameters such as effects of BSA concentration and precursor vol ratios of Zn:S on the formation of ZnS nanoparticles in BSA matrix were investigated. The ZnS crystalline sizes of 1.9, 1.8 and 1.6nm were obtained by using the BSA concentrations of 1*10-4, 5*10-4 and 10*10-4g/mL, respectively, with a fixed Zn:S vol ratio of 1:1. The ZnS samples prepared from 1:10 and 10:1 vol ratios of Zn:S at BSA concentration of 5*10-4g/mL shows the crystalline sizes of ZnS are 2.1 and 1.5nm, respectively. FT-IR analysis suggests that the prepared ZnS nanoparticles might be conjugated through the interactions of hydroxyl and amine groups present in BSA. We evaluate the cytotoxicity of the prepared ZnS nanoparticles, the THP-1 cells showed a good viability (>88%) for all the prepared ZnS samples. The plausible mechanism for the formation of ZnS-BSA composite has also been discussed. PMID- 28365290 TI - Biochemistry of fish stomach chitinase. AB - Fish are reported to exhibit chitinase activity in the stomach. Analyses of fish stomach chitinases have shown that these enzymes have the physiological function of degrading chitinous substances ingested as diets. Osteichthyes, a group that includes most of the fishes, have several chitinases in their stomachs. From a phylogenetic analysis of the chitinases of vertebrates, these particular molecules were classified into a fish-specific group and have different substrate specificities, suggesting that they can degrade ingested chitinous substances efficiently. On the other hand, it has been suggested that coelacanth (Sarcopterygii) and shark (Chondrichthyes) have a single chitinase enzyme in their stomachs, which shows multiple functions. This review focuses on recent research on the biochemistry of fish stomach chitinases. PMID- 28365291 TI - Novel chitin scaffolds derived from marine sponge Ianthella basta for tissue engineering approaches based on human mesenchymal stromal cells: Biocompatibility and cryopreservation. AB - The extraordinary biocompatibility and mechanical properties of chitinous scaffolds from marine sponges endows these structures with unique properties that render them ideal for diverse biomedical applications. In the present work, a technological route to produce "ready-to-use" tissue-engineered products based on poriferan chitin is comprehensively investigated for the first time. Three key stages included isolation of scaffolds from the marine demosponge Ianthella basta, confirmation of their biocompatibility with human mesenchymal stromal cells, and cryopreservation of the tissue-like structures grown within these scaffolds using a slow cooling protocol. Biocompatibility of the macroporous, flat chitin scaffolds has been confirmed by cell attachment, high cell viability and the ability to differentiate into the adipogenic lineage. The viability of cells cryopreserved on chitin scaffolds was reduced by about 30% as compared to cells cryopreserved in suspension. However, the surviving cells were able to retain their differentiation potential; and this is demonstrated for the adipogenic lineage. The results suggest that chitin from the marine demosponge I. basta is a promising, highly biocompatible biomaterial for stem cell-based tissue engineering applications. PMID- 28365292 TI - Evolving transpeptidase and hydrolytic variants of gamma-glutamyl transpeptidase from Bacillus licheniformis by targeted mutations of conserved residue Arg109 and their biotechnological relevance. AB - gamma-Glutamyl transpeptidase (GGT) catalyzes the transfer of the gamma-glutamyl moiety from donor compounds such as l-glutamine (Gln) and glutathione (GSH) to an acceptor. During the biosynthesis of various gamma-glutamyl-containing compounds using GGT enzyme, auto-transpeptidation reaction leads to the formation of unwanted byproducts. Therefore, in order to alter the auto-transpeptidase activity of the GGT enzyme, the binding affinity of Gln should be modified. Structural studies of the Bacillus licheniformis GGT (BlGT) complexed with the glutamic acid has shown that glutamic acid has strong ionic interactions through its alpha-carboxlic group with the guanidine moiety of Arg109. This interaction appears to be an important contributor for the binding affinity of Gln. In view of this, six mutants of Bacillus licheniformis ER15 GGT (BlGGT) viz. Arg109Lys, Arg109Ser, Arg109Met, Arg109Leu, Arg109Glu and Arg109Phe were prepared. As seen from the structure of BlGT, the mutation of Arg109 to Lys109 may reduce the affinity for Gln to some extent, whereas the other mutations are expected to lower the affinity much more. Biophysical characterization and functional studies revealed that Arg109Lys mutant has increased transpeptidation activity and catalytic efficiency than the other mutants. The Arg109Lys mutant showed high conversion rates for l-theanine synthesis as well. Moreover, the Arg109Met mutant showed increased hydrolytic activity as it completely altered the binding of Gln at the active site. Also, the salt stability of the enzyme was significantly improved on replacing Arg109 by Met109 which is required for hydrolytic applications of GGTs in food industries. PMID- 28365293 TI - A unified inter-host and in-host model of antibiotic resistance and infection spread in a hospital ward. AB - As the battle continues against hospital-acquired infections and the concurrent rise in antibiotic resistance among many of the major causative pathogens, there is a dire need to conduct controlled experiments, in order to compare proposed control strategies. However, cost, time, and ethical considerations make this evaluation strategy either impractical or impossible to implement with living patients. This paper presents a multi-scale model that offers promise as the basis for a tool to simulate these (and other) controlled experiments. This is a "unified" model in two important ways: (i) It combines inter-host and in-host dynamics into a single model, and (ii) it links two very different modeling approaches - agent-based modeling and differential equations - into a single model. The potential of this model as an instrument to combat antibiotic resistance in hospitals is demonstrated with numerical examples. PMID- 28365295 TI - In vitro and in vivo performance of monoacyl phospholipid-based self-emulsifying drug delivery systems. AB - This study investigates the effect of monoacyl phospholipid incorporation on the in vitro and in vivo performance of self-emulsifying drug delivery systems (SEDDS). Monoacyl phosphatidylcholine (Lipoid S LPC 80 (LPC)) was incorporated into four different fenofibrate (FF)-loaded long-chain SEDDS to investigate the impact of LPC on the emulsion droplet size, extent of digestion, colloidal structure evolution and drug precipitation during in vitro lipolysis simulating human conditions and drug bioavailability in a rat model. The four investigated SEDDS containing long-chain glycerides, polyoxyl 35 castor oil or polyoxyl 8 caprylocaproyl glycerides with or without LPC. In situ synchrotron small/wide angle X-ray scattering (SAXS/WAXS) was used to simultaneously real-time monitor the kinetics of lamellar phase structure development and FF crystalline precipitation. Adding LPC increased the particle size and polydispersity of the dispersed SEDDS. The two LPC-free SEDDS generated lamellar phase structures (Lalpha) with d-spacing=4.76nm during digestion. Incorporating LPC into these systems inhibited the formation of lamellar phase structures. The amount of precipitated crystalline FF from the four SEDDS was similar during the first 15min but differed during the last 45min of in vitro digestion. The kinetics of colloidal structure development and FF precipitation was related to the digestion kinetics. The in vivo bioavailability data showed no significant differences between the four SEDDS, which correlates with the in vitro FF precipitation during the first 15min of lipolysis. Thus, the presence of LPC, different emulsion droplet sizes and concentration of lamellar phase structures observed in vitro did not correlate with the FF absorption in rats. The study suggests that later time points of the in vitro lipolysis overestimated FF precipitation in rats because of the high enzyme activity, the lack of gastric and absorption steps, and the low bile salts and phospholipid concentrations of the in vitro model. PMID- 28365294 TI - Protein-lipid nanohybrids as emerging platforms for drug and gene delivery: Challenges and outcomes. AB - Nanoparticulate drug delivery systems have been long used to deliver a vast range of drugs and bioactives owing to their ability to demonstrate novel physical, chemical, and/or biological properties. An exponential growth has spurred in research and development of these nanocarriers which led to the evolution of a great number of diverse nanosystems including liposomes, nanoemulsions, solid lipid nanoparticles (SLNs), micelles, dendrimers, polymeric nanoparticles (NPs), metallic NPs, and carbon nanotubes. Among them, lipid-based nanocarriers have made the largest progress whether commercially or under development. Despite this progress, these lipid-based nanocarriers suffer from several limitations that led to the development of many protein-coated lipid nanocarriers. To less extent, protein-based nanocarriers suffer from limitations that led to the fabrication of some lipid bilayer enveloping protein nanocarriers. This review discusses in depth some limitations associated with the lipid-based or protein-based nanocarriers and the fruitful outcomes brought by protein-lipid hybridization. Also discussed are the various hybridization techniques utilized to formulate these protein-lipid nanohybrids and the mechanisms involved in the drug loading process. PMID- 28365296 TI - Running as a Key Lifestyle Medicine for Longevity. AB - Running is a popular and convenient leisure-time physical activity (PA) with a significant impact on longevity. In general, runners have a 25%-40% reduced risk of premature mortality and live approximately 3 years longer than non-runners. Recently, specific questions have emerged regarding the extent of the health benefits of running versus other types of PA, and perhaps more critically, whether there are diminishing returns on health and mortality outcomes with higher amounts of running. This review details the findings surrounding the impact of running on various health outcomes and premature mortality, highlights plausible underlying mechanisms linking running with chronic disease prevention and longevity, identifies the estimated additional life expectancy among runners and other active individuals, and discusses whether there is adequate evidence to suggest that longevity benefits are attenuated with higher doses of running. PMID- 28365297 TI - Endovascular Therapy for Acute Stroke. AB - Stroke is the most common cause of permanent disability, the second most common cause of dementia, and the fourth most common cause of death in the Western world. Recently, based on positive multicenter randomized clinical trials, endovascular therapy for acute stroke has undergone a revolution. Routine mechanical thrombectomy in addition to intravenous thrombolysis has been shown to provide excellent outcomes for patients with proximal anterior circulation occlusions. This procedure reduces disability and benefits are seen across a wide range of age and initial stroke severity. Important features that affect treatment decisions include time of presentation, the patient's clinical status, imaging characteristics, and lab tests. Under optimal conditions, it should be available to patients 24/7, similar to systems offering prompt percutaneous coronary interventions to patients with acute ST-segment elevation myocardial infarctions. PMID- 28365298 TI - Two-stage sparse coding of region covariance via Log-Euclidean kernels to detect saliency. AB - In this paper, we present a novel bottom-up saliency detection algorithm from the perspective of covariance matrices on a Riemannian manifold. Each superpixel is described by a region covariance matrix on Riemannian Manifolds. We carry out a two-stage sparse coding scheme via Log-Euclidean kernels to extract salient objects efficiently. In the first stage, given background dictionary on image borders, sparse coding of each region covariance via Log-Euclidean kernels is performed. The reconstruction error on the background dictionary is regarded as the initial saliency of each superpixel. In the second stage, an improvement of the initial result is achieved by calculating reconstruction errors of the superpixels on foreground dictionary, which is extracted from the first stage saliency map. The sparse coding in the second stage is similar to the first stage, but is able to effectively highlight the salient objects uniformly from the background. Finally, three post-processing methods-highlight-inhibition function, context-based saliency weighting, and the graph cut-are adopted to further refine the saliency map. Experiments on four public benchmark datasets show that the proposed algorithm outperforms the state-of-the-art methods in terms of precision, recall and mean absolute error, and demonstrate the robustness and efficiency of the proposed method. PMID- 28365299 TI - A minimal unified model of disease trajectories captures hallmarks of multiple sclerosis. AB - Multiple Sclerosis (MS) is an autoimmune disease targeting the central nervous system (CNS) causing demyelination and neurodegeneration leading to accumulation of neurological disability. Here we present a minimal, computational model involving the immune system and CNS that generates the principal subtypes of the disease observed in patients. The model captures several key features of MS, especially those that distinguish the chronic progressive phase from that of the relapse-remitting. In addition, a rare subtype of the disease, progressive relapsing MS naturally emerges from the model. The model posits the existence of two key thresholds, one in the immune system and the other in the CNS, that separate dynamically distinct behavior of the model. Exploring the two dimensional space of these thresholds, we obtain multiple phases of disease evolution and these shows greater variation than the clinical classification of MS, thus capturing the heterogeneity that is manifested in patients. PMID- 28365300 TI - Comparison of video analysis and simulations of a drum coating process. AB - Tablet coating is a common unit operation in the pharmaceutical industry. To improve currently established processes, it is important to understand the influence of the process parameters on the coating quality. One of the critical parameters is the tablet velocity. In this work, numerical results are compared to results obtained experimentally. Tablet movement in the drums was simulated using the Discrete Element Method (DEM). The simulation parameters were adapted to fit the simulation to the experimental data. A comparison of the experimental and simulation results showed that the simulation correctly represents the real tablet velocity. A change in the velocity over time and its dependence on the rotation rates and the baffle position in the simulation were similar to the experimental results. In summary, simulations can improve the understanding of tablet coating processes and will thus provide insights into the underlying process mechanics, which cannot be obtained via ordinary experiments. PMID- 28365301 TI - Species specificity profiling of rat and human organic cation/carnitine transporter Slc22a5/SLC22A5 (Octn2/OCTN2). AB - The purpose of this study was to characterize the uptake of carnitine, the physiological substrate, and the uptake of 3-(2,2,2 trimethylhydrazinium)propionate, a consensus substrate by rat Octn2 and human OCTN2 transporters as well as to characterize drug-mediated inhibition of l carnitine uptake by the rat and human orthologs overexpressed in CHO-K1 cells. l carnitine and 3-(2,2,2-trimethylhydrazinium)propionate were found to be a lower affinity substrate for rat Octn2 (KM = 32.66 +/- 5.11 MUM and 23.62 +/- 4.99 MUM respectively) than for human OCTN2 (KM = 3.08 +/- 0.74 MUM and 7.98 +/- 0.63 MUM). The intrinsic clearance (CLint) value for carnitine was higher for the human than for the rat transporter (22.82 +/- 5.57 ml/min*mg vs 4.008 +/- 0.675 ml/min*mg). For 3-(2,2,2-trimethylhydrazinium)propionate, in contrast, the CLint value for rat Octn2 was higher than for human OCTN2 (323.9 +/- 72.8 ml/min*mg vs 65.11 +/- 5.33 ml/min*mg). Furthermore, many pharmacologically important drugs were shown to affect l-carnitine transport by Octn2/OCTN2. The correlation between the IC50 datasets for the rat and human transporter resulted in an r value of 0.47 (p > 0.05). However, the greatest difference was less than seven fold and 13 of 15 compounds yielded a difference less than 3-fold. Thus, the transporters from these two species showed an overlapping but somewhat different substrate and inhibitor specificity. PMID- 28365302 TI - Nitroxides protect horseradish peroxidase from H2O2-induced inactivation and modulate its catalase-like activity. AB - BACKGROUND: Horseradish peroxidase (HRP) catalyzes H2O2 dismutation while undergoing heme inactivation. The mechanism underlying this process has not been fully elucidated. The effects of nitroxides, which protect metmyoglobin and methemoglobin against H2O2-induced inactivation, have been investigated. METHODS: HRP reaction with H2O2 was studied by following H2O2 depletion, O2 evolution and heme spectral changes. Nitroxide concentration was followed by EPR spectroscopy, and its reactions with the oxidized heme species were studied using stopped-flow. RESULTS: Nitroxide protects HRP against H2O2-induced inactivation. The rate of H2O2 dismutation in the presence of nitroxide obeys zero-order kinetics and increases as [nitroxide] increases. Nitroxide acts catalytically since its oxidized form is readily reduced to the nitroxide mainly by H2O2. The nitroxide efficacy follows the order 2,2,6,6-tetramethyl-piperidine-N-oxyl (TPO)>4-OH-TPO>3 carbamoyl proxyl>4-oxo-TPO, which correlates with the order of the rate constants of nitroxide reactions with compounds I, II, and III. CONCLUSIONS: Nitroxide catalytically protects HRP against inactivation induced by H2O2 while modulating its catalase-like activity. The protective role of nitroxide at MUM concentrations is attributed to its efficient oxidation by P940, which is the precursor of the inactivated form P670. Modeling the dismutation kinetics in the presence of nitroxide adequately fits the experimental data. In the absence of nitroxide the simulation fits the observed kinetics only if it does not include the formation of a Michaelis-Menten complex. GENERAL SIGNIFICANCE: Nitroxides catalytically protect heme proteins against inactivation induced by H2O2 revealing an additional role played by nitroxide antioxidants in vivo. PMID- 28365303 TI - Quasi-experimental study designs series-paper 4: uses and value. AB - Quasi-experimental studies are increasingly used to establish causal relationships in epidemiology and health systems research. Quasi-experimental studies offer important opportunities to increase and improve evidence on causal effects: (1) they can generate causal evidence when randomized controlled trials are impossible; (2) they typically generate causal evidence with a high degree of external validity; (3) they avoid the threats to internal validity that arise when participants in nonblinded experiments change their behavior in response to the experimental assignment to either intervention or control arm (such as compensatory rivalry or resentful demoralization); (4) they are often well suited to generate causal evidence on long-term health outcomes of an intervention, as well as nonhealth outcomes such as economic and social consequences; and (5) they can often generate evidence faster and at lower cost than experiments and other intervention studies. PMID- 28365304 TI - Quasi-experimental study designs series-paper 11: supporting the production and use of health systems research syntheses that draw on quasi-experimental study designs. AB - OBJECTIVES: To describe the infrastructure available to support the production of policy-relevant health systems research syntheses, particularly those incorporating quasi-experimental evidence, and the tools available to support the use of these syntheses. STUDY DESIGN AND SETTING: Literature review. RESULTS: The general challenges associated with the available infrastructure include their sporadic nature or limited coverage of issues and countries, whereas the specific ones related to policy-relevant syntheses of quasi-experimental evidence include the lack of mechanism to register synthesis titles and scoping review protocols, the limited number of groups preparing user-friendly summaries, and the difficulty of finding quasi-experimental studies for inclusion in rapid syntheses and research syntheses more generally. Although some new tools have emerged in recent years, such as guidance workbooks and citizen briefs and panels, challenges related to using available tools to support the use of policy-relevant syntheses of quasi-experimental evidence arise from such studies potentially being harder for policymakers and stakeholders to commission and understand. CONCLUSION: Policymakers, stakeholders, and researchers need to expand the coverage and institutionalize the use of the available infrastructure and tools to support the use of health system research syntheses containing quasi experimental evidence. PMID- 28365305 TI - Quasi-experimental study designs series-paper 9: collecting data from quasi experimental studies. AB - OBJECTIVE: To identify variables that must be coded when synthesizing primary studies that use quasi-experimental designs. STUDY DESIGN AND SETTING: All quasi experimental (QE) designs. RESULTS: When designing a systematic review of QE studies, potential sources of heterogeneity-both theory-based and methodological must be identified. We outline key components of inclusion criteria for syntheses of quasi-experimental studies. We provide recommendations for coding content relevant and methodological variables and outlined the distinction between bivariate effect sizes and partial (i.e., adjusted) effect sizes. Designs used and controls used are viewed as of greatest importance. Potential sources of bias and confounding are also addressed. CONCLUSION: Careful consideration must be given to inclusion criteria and the coding of theoretical and methodological variables during the design phase of a synthesis of quasi-experimental studies. The success of the meta-regression analysis relies on the data available to the meta-analyst. Omission of critical moderator variables (i.e., effect modifiers) will undermine the conclusions of a meta-analysis. PMID- 28365307 TI - Quasi-experimental study designs series-paper 2: complementary approaches to advancing global health knowledge. AB - Quasi-experiments have been infrequently used in the health sciences. Focusing on health systems implementation research, this article details key advantages of quasi-experiments and argues that they can complement (but not replace) randomized evaluations. Specifically, it may be possible to use a quasi experiment to study the causal effect of an intervention that cannot feasibly be randomized or that would be unethical (e.g., because the intervention has become the standard of care) to test in a randomized controlled trial (RCT). In addition, because they usually take advantage of routinely collected data, quasi experiments may be feasible when it is too costly (either financially or in terms of the required time) to carry out a RCT - an important advantage in research on health systems, which vary widely between settings. Nonetheless, we argue that RCTs will continue to be indispensable for implementation research because i) the assumptions needed to establish causality with a quasi-experiment are often unverifiable, ii) available data frequently do not allow for a rigorous quasi experiment, and iii) randomized designs tend to lend themselves more to informing policy makers of causal effects prior to (or during) the full-scale rollout of an intervention than quasi-experiments. PMID- 28365306 TI - Quasi-experimental study designs series-paper 7: assessing the assumptions. AB - Quasi-experimental designs are gaining popularity in epidemiology and health systems research-in particular for the evaluation of health care practice, programs, and policy-because they allow strong causal inferences without randomized controlled experiments. We describe the concepts underlying five important quasi-experimental designs: Instrumental Variables, Regression Discontinuity, Interrupted Time Series, Fixed Effects, and Difference-in Differences designs. We illustrate each of the designs with an example from health research. We then describe the assumptions required for each of the designs to ensure valid causal inference and discuss the tests available to examine the assumptions. PMID- 28365308 TI - Quasi-experimental study designs series-paper 10: synthesizing evidence for effects collected from quasi-experimental studies presents surmountable challenges. AB - OBJECTIVE: To outline issues of importance to analytic approaches to the synthesis of quasi-experiments (QEs) and to provide a statistical model for use in analysis. STUDY DESIGN AND SETTING: We drew on studies of statistics, epidemiology, and social-science methodology to outline methods for synthesis of QE studies. The design and conduct of QEs, effect sizes from QEs, and moderator variables for the analysis of those effect sizes were discussed. RESULTS: Biases, confounding, design complexities, and comparisons across designs offer serious challenges to syntheses of QEs. Key components of meta-analyses of QEs were identified, including the aspects of QE study design to be coded and analyzed. Of utmost importance are the design and statistical controls implemented in the QEs. Such controls and any potential sources of bias and confounding must be modeled in analyses, along with aspects of the interventions and populations studied. Because of such controls, effect sizes from QEs are more complex than those from randomized experiments. A statistical meta-regression model that incorporates important features of the QEs under review was presented. CONCLUSION: Meta analyses of QEs provide particular challenges, but thorough coding of intervention characteristics and study methods, along with careful analysis, should allow for sound inferences. PMID- 28365309 TI - Quasi-experimental study designs series-paper 8: identifying quasi-experimental studies to inform systematic reviews. AB - OBJECTIVE: This article reviews the available evidence and guidance on methods to identify reports of quasi-experimental (QE) studies to inform systematic reviews of health care, public health, international development, education, crime and justice, and social welfare. STUDY DESIGN AND SETTING: Research, guidance, and examples of search strategies were identified by searching a range of databases, key guidance documents, selected reviews, conference proceedings, and personal communication. Current practice and research evidence were summarized. RESULTS: Four thousand nine hundred twenty-four records were retrieved by database searches, and additional documents were obtained by other searches. QE studies are challenging to identify efficiently because they have no standardized nomenclature and may be indexed in various ways. Reliable search filters are not available. There is a lack of specific resources devoted to collecting QE studies and little evidence on where best to search. CONCLUSION: Searches to identify QE studies should search a range of resources and, until indexing improves, use strategies that focus on the topic rather than the study design. Better definitions, better indexing in databases, prospective registers, and reporting guidance are required to improve the retrieval of QE studies and promote systematic reviews of what works based on the evidence from such studies. PMID- 28365310 TI - Quasi-experimental study designs series-paper 3: systematic generation of evidence through public policy evaluation. PMID- 28365311 TI - Clinical impact and prevalence of MRSA CC398 and differences between MRSA-TetR and MRSA-TetS in an area of Spain with a high density of pig farming: a prospective cohort study. AB - OBJECTIVES: Tetracycline resistance (TetR) is a phenotypic marker of the livestock-associated methicillin-resistant Staphylococcus aureus (MRSA) CC398 clone. The aim of this study was to analyse the prevalence of MRSA CC398 in patients in contact with healthcare facilities and differences between patients with MRSA-TetR and MRSA tetracycline-susceptible (TetS) strains. METHODS: Patients diagnosed with MRSA from January 2012 to December 2015 were divided into two groups, MRSA-TetR and MRSA-TetS. Epidemiologic and clinical data were evaluated. Molecular analysis was performed (multilocus sequence typing, spa typing) on MRSA-TetR strains. RESULTS: Data from 288 MRSA patients were obtained, and 106 (36.8%) carried MRSA-TetR (93 typed as CC398 (87.7%); the remaining 13 isolates were ascribed to CC9, CC1, CC121, CC30, CC97, CC146 and CC152). The most frequent spa type was t011 (56.6%, 61/106). Detection of MRSA-TetR increased over the years (21.9%, 16/73, in 2012; 50.7%, 36/71, in 2015; p <0.001). Hospital acquisition was found in 16.7% (19/114) of MRSA-TetR patients vs. 83.3% (95/114) in MRSA-TetS patients (p <0.001). Frequency of MRSA-TetR patients in nursing homes was lower than in MRSA-TetS patients (4.7%, 5/106, vs. 27.5%, 50/182, p <0.001). MRSA-TetR as distinct from MRSA-TetS was associated with workers on pig farms (49.0%, 52/106, vs. 1.0%, 2/182; p <0.001), fewer admissions to hospital (46.2%, 49/106, vs. 68.1%, 124/182; p <0.001) and fewer comorbidities (81.1%, 86/106, vs. 59.9%, 109/182; p <0.001). Sixty cases of MRSA-CC398 infection were diagnosed, including, among others, endocarditis, septic arthritis, prosthetic joint infection, pneumonia and bacteraemia. CONCLUSIONS: Prevalence of MRSA-TetR (especially CC398) at the hospital level in a Spanish region with intensive pig farming activity is high and is responsible for severe infections. Significant differences were detected in clinical and epidemiologic characteristics among MRSA-TetR and MRSA-TetS patients. PMID- 28365312 TI - Activating transcription factor 3 is a target molecule linking hepatic steatosis to impaired glucose homeostasis. AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) contributes to impaired glucose tolerance, leading to type 2 diabetes (T2D); however, the precise mechanisms and target molecules that are involved remain unclear. Activating transcription factor 3 (ATF3) is associated with beta-cell dysfunction that is induced by severe stress signals in T2D. We aimed to explore the exact functional role of ATF3 as a mechanistic link between hepatic steatosis and T2D development. METHODS: Zucker diabetic fatty (ZDF) rats were utilized for animal experiments. An in vivo-jetPEI siRNA delivery system against ATF3 was used for loss-of-function experiments. We analyzed the baseline cross-sectional data derived from the biopsy-proven NAFLD registry (n=322). Human sera and liver tissues were obtained from 43 patients with biopsy-proven NAFLD and from seven healthy participants. RESULTS: ATF3 was highly expressed in the livers of ZDF rats and in human participants with NAFLD and/or T2D. Insulin resistance and hepatic steatosis were associated with increased ATF3 expression and decreased fatty acid oxidation via mitochondrial dysfunction and were attenuated by in vivo ATF3 silencing. Knockdown of ATF3 also ameliorated glucose intolerance, impaired insulin action, and inflammatory responses in ZDF rats. In patients with NAFLD and/or T2D, a significant positive correlation was observed between hepatic ATF3 expression and surrogate markers of T2D, mitochondrial dysfunction, and macrophage infiltration. CONCLUSIONS: Increased hepatic ATF3 expression is closely associated with hepatic steatosis and incident T2D; therefore, ATF3 may serve as a potential therapeutic target for NAFLD and hepatic steatosis-induced T2D. LAY SUMMARY: Hepatic activating transcription factor 3 (ATF3) may play an important role in oxidative stress-mediated hepatic steatosis and the development of type 2 diabetes (T2D) in a Zucker diabetic fatty (ZDF) rat model and in human patients with non-alcoholic fatty liver disease (NAFLD). Therefore, ATF3 may be a useful biomarker for predicting the progression of NAFLD and the development of T2D. Furthermore, given the significant association between hepatic ATF3 expression and both hepatic steatosis and impaired glucose homeostasis, in vivo ATF3 silencing may be a potential central strategy for preventing and managing NAFLD and T2D. PMID- 28365313 TI - Transcriptome analysis provides insights into hepatic responses to moderate heat stress in the rainbow trout (Oncorhynchus mykiss). AB - The rainbow trout is an economically important fish in the world. The limited stress tolerance of this species to high summer-like temperatures usually leads to mass mortality and great economic loss. However, there is limited information on the mechanisms underlying moderate heat responses in the liver of the rainbow trout. Here, we performed transcriptome profiling of rainbow trout liver under moderate heat stress by using the HiseqTM 4000 sequencing platform. More than 277 million clean reads were obtained from 6 libraries and aligned against the rainbow trout genome. A total of 128 unique transcripts were differentially expressed in the liver under heat-stress and control conditions, many heat shock protein genes for thermoregulation and some novel genes involved in heat stress were identified. Nine of the differently expressed genes were further validated by qRT-PCR. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that several pathways, including those for protein metabolism, energy metabolism, and immune system, were influenced by heat stress. Moreover, an important protein-processing pathway in the endoplasmic reticulum (ER) was identified, and the key role of ER-associated degradation and function of calpain as an upstream regulator of apoptosis were confirmed under heat stress. The results of this study provide a comprehensive overview of heat stress-induced transcriptional patterns in rainbow trout liver and would be particularly useful for further studies on the molecular mechanisms underlying responses to heat stress in this species. PMID- 28365314 TI - Paradoxical sleep deprivation modulates depressive-like behaviors by regulating the MAOA levels in the amygdala and hippocampus. AB - Paradoxical sleep is closely associated with depression, and brain monoamine oxidase A (MAOA) plays an important role in depression. However, the precise relationship between sleep and depression and the role of MAOA in this process remains unknown. Therefore, we established a paradoxical sleep deprivation model using the "multiple small platforms over water" protocol. Mice deprived of paradoxical sleep for 3days showed no depressive-like behaviors; however, mice deprived of paradoxical sleep deprivation for 5days (P5d) showed decreased locomotive activity in the first 3days after P5d. Additionally, the P5d mice showed depressive-like behaviors one week after P5d, with a longer immobility time and a decreased sucrose preference rate. In addition, the levels of the MAOA protein and mRNA in the amygdala and hippocampus significantly increased. Furthermore, the immobility time and sucrose preference rate of P5d mice recovered when the mice were injected with phenelzine. The P5d mice displayed depressive-like behaviors, which were likely modulated by the MAOA levels in the amygdala and hippocampus. PMID- 28365315 TI - Response inhibition or evaluation of danger? An event-related potential study regarding the origin of the motor interference effect from dangerous objects. AB - Previous studies have identified an interference effect from dangerous objects on prepared responses. However, its origin remains arguable. This study investigated the neural processes of this motor interference effect. The design adopted a motor priming paradigm mixed with a Go/NoGo task. Pictures of a left or right hand were used as primes, and green (Go signal) or red (NoGo signal) circles superimposed on dangerous or safe objects were used as targets. Participants were instructed to prepare the corresponding key press using the hand that was consistent with the handedness of the prime and not to execute until a Go signal appeared. Behavioral results indicated longer reaction times and a trend that participants made more errors for the dangerous condition than for the safe condition in the Go trials. However, the difference between the error rates for the dangerous and safe conditions did not emerge in the NoGo trials. Event related potential analysis revealed a similar effect on the P3 component, which may reflect an assignment of cognitive resources to evaluate danger. More positive parietal P3 amplitudes were identified in response to the dangerous condition in the Go trials. However, the difference in the P3 amplitudes between the dangerous and safe conditions was not significant in the NoGo trials. Together, the motor interference effect from dangerous objects may originate from the danger evaluations. Furthermore, differences between the dangerous and safe conditions also emerged in the P1, posterior N1, P2, and posterior N2 components; the possible processes that underlie these components were discussed. PMID- 28365316 TI - Bacterial arthropod-borne diseases in West Africa. AB - Arthropods such as ticks, lice, fleas and mites are excellent vectors for many pathogenic agents including bacteria, protozoa and viruses to animals. Moreover, many of these pathogens can also be accidentally transmitted to humans throughout the world. Bacterial vector-borne diseases seem to be numerous and very important in human pathology, however, they are often ignored and are not well known. Yet they are in a phase of geographic expansion and play an important role in the etiology of febrile episodes in regions of Africa. Since the introduction of molecular techniques, the presence of these pathogens has been confirmed in various samples from arthropods and animals, and more rarely from human samples in West Africa. In this review, the aim is to summarize the latest information about vector-borne bacteria, focusing on West Africa from 2000 until today in order to better understand the epidemiological risks associated with these arthropods. This will allow health and veterinary authorities to develop a strategy for surveillance of arthropods and bacterial disease in order to protect people and animals. PMID- 28365317 TI - The role of basic leucine zipper transcription factor E4BP4 in the immune system and immune-mediated diseases. AB - Basic leucine zipper transcription factor E4BP4 (also known as NFIL3) has been implicated in the molecular and cellular mechanisms of functions and activities in mammals. The interactions between E4BP4 and major regulators of cellular processes have triggered significant interest in the roles of E4BP4 in the pathogenesis of certain chronic diseases. Indeed, novel discoveries have been emerging to illustrate the involvement of E4BP4 in multiple disorders. It is recognized that E4BP4 is extensively involved in some immune-mediated diseases, but the mechanisms of E4BP4 involvement in these complex diseases remain poorly defined. Here we review the regulatory mechanisms of E4BP4 engaging in not only the biological function but also the development of immune-mediated diseases, paving the way for future therapies. PMID- 28365318 TI - Pronounced anti-proliferative activity and tumor cell selectivity of 5-alkyl-2 amino-3-methylcarboxylate thiophenes. AB - 5-(2-(4-Methoxyphenyl)ethyl)-2-amino-3-methylcarboxylate thiophene (TR560) is the prototype drug of a recently discovered novel class of tumor-selective compounds that preferentially inhibit the proliferation of specific tumor cell types (e.g. leukemia/lymphoma). Here, we further increased tumor selectivity by simplification of the molecule through replacing the 4-methoxyphenyl moiety by an alkyl chain. Several 2-amino-3-methylcarboxylate thiophene derivatives containing at C-5 an alkyl group consisting of at least 6 (hexyl) to 9 (nonyl) carbon units showed pronounced anti-proliferative activity in the mid-nanomolar range with 500 to 1000-fold tumor cell selectivity. The compounds preferentially inhibited the proliferation of T-lymphoma CEM and Molt/4, prostate PC-3, kidney Caki-1 and hepatoma Huh-7 tumor cells, but were virtually inactive against other tumor cell lines including B-lymphoma Raji and cervix carcinoma HeLa cells. The novel prototype drug 3j (containing a 5-heptyl chain) elicited a cytotoxic, rather than cytostatic activity, already after 4 h of exposure. The unusual tumor selectivity could not be explained by a differential uptake (or efflux) of the drug by sensitive versus resistant tumor cells. Exposure of a fluorescent derivative of 3j revealed pronounced uptake of the drug in the cytoplasm, no visible appearance in the nucleus, and a predominant localization in the endoplasmic reticulum. These observations may be helpful to narrow down the intracellular localization and identification of the molecular target of the 5-substituted thiophene derivatives. PMID- 28365319 TI - Anthranilamide-based 2-phenylcyclopropane-1-carboxamides, 1,1'-biphenyl-4 carboxamides and 1,1'-biphenyl-2-carboxamides: Synthesis biological evaluation and mechanism of action. AB - Several anthranilamide-based 2-phenylcyclopropane-1-carboxamides 13a-f, 1,1' biphenyl-4-carboxamides 14a-f and 1,1'-biphenyl-2-carboxamides 17a-f were obtained by a multistep procedure starting from the (1S,2S)-2-phenylcyclopropane 1-carbonyl chloride 11, the 1,1'-biphenyl-4-carbonyl chloride 12 or the 1,1' biphenyl-2-carbonyl chloride 16 with the appropriate anthranilamide derivative 10a-f. Derivatives 13a-f, 14a-f and 17a-f showed antiproliferative activity against human leukemia K562 cells. Among these derivatives 13b, 14b and 17b exerted a particular cytotoxic effect on tumor cells. Derivative 17b showed a better antitumoral effect on K562 cells than 13b and 14b. Analyses performed to explore 17b mode of action revealed that it induced an arrest in G2/M phase of cell cycle which was consequent to DNA lesions as demonstrated by the increase in phospho-ATM and gammaH2AX, two known markers of DNA repair response system. The effect of 17b was also related to ROS generation, activation of JNK and induction of caspase-3 dependent apoptosis. PMID- 28365320 TI - Use of white matter reference regions for detection of change in florbetapir positron emission tomography from completed phase 3 solanezumab trials. AB - INTRODUCTION: We compared subject-specific white matter (SSWM) and whole cerebellum (CBL) reference regions for power to detect longitudinal change in amyloid positron emission tomography signal. METHODS: Positive florbetapir positron emission tomography scans were analyzed from participants (66 placebo treated and 63 solanezumab treated) with mild dementia caused by Alzheimer's disease from the EXPEDITION and EXPEDITION2 studies. For comparison to CBL, a second normalization was performed on longitudinal data using an SSWM correction factor (SSWM normalization ratio [SSWMnr]). Analysis of covariance assessed baseline to 18-month change between treatment with solanezumab and placebo. Sample and effect size estimations provided magnitude of observed treatment changes. RESULTS: Longitudinal percent change between placebo and solanezumab using CBL was not significant (P = .536) but was significant for SSWMnr (P = .042). Compared with CBL, SSWMnr technique increased the power to detect a treatment difference, more than tripling the effect size and reducing the sample size requirements by 85% to 90%. DISCUSSION: Adjusting longitudinal standardized uptake value ratios with an SSWM reference region in these antiamyloid treatment trials increased mean change detection and decreased variance resulting in the substantial improvement in statistical power to detect change. PMID- 28365321 TI - The midlife cognitive profiles of adults at high risk of late-onset Alzheimer's disease: The PREVENT study. AB - INTRODUCTION: Although biomarker studies of late-onset Alzheimer's disease suggest pathology to be present decades before diagnosis, little is known about cognitive performance at this stage. METHODS: A sample of 210 adults (aged 40-59) of whom 103 have a parent diagnosed with dementia (family history subgroup) underwent computerized cognitive testing. Apolipoprotein E (apoE) status was determined, and 193 subjects had magnetic resonance imaging. Distance from dementia onset was estimated in relation to age of parental diagnosis, and Cardiovascular Risk Factors, Aging, and Incidence of Dementia Risk Scores were calculated. RESULTS: Lower hippocampal volumes (P = .04) were associated with poorer spatial location recall and higher Dementia Risk Scores with poorer visual recognition (P = .0005), and lower brain and hippocampal volume (P < .0001, P = .04, respectively). Family history subgroup participants closer to dementia onset had lower scores on visual working memory (P = .05), whereas those with an APOE epsilon4 allele performed better on form perception (P = .005). DISCUSSION: Middle-aged adults at risk of dementia show evidence of poorer cognitive performance, principally in visuospatial functions. PMID- 28365322 TI - Metallic nanoparticles augmented the antibacterial potency of Rhodomyrtus tomentosa acetone extract against Escherichia coli. AB - The present study was focused on the preparation of gold, silver, and gold-silver alloy nanoparticles using Rhodomyrtus tomentosa acetone extract (RAE). The synthesized nanoparticles showed the surface plasmon resonance absorption peak corresponding to gold and silver nanoparticle. However, Au-Ag-Alloy nanoparticles showed the single peak between the peaks of AuNPs and AgNPs. TEM observation ascertained the shape and size of nanoparticles. FTIR results indicated the involvement of RAE for the synthesis and capping of nanoparticles. Study on antibacterial activity demonstrated the enhanced activity of RAE capped on silver and Au-Ag-Alloy nanoparticles against Escherichia coli. PMID- 28365323 TI - Pathogenic potentials of Aeromonas species isolated from aquaculture and abattoir environments. AB - The present study elucidated the presence of antibiotics resistance, virulence genes and biofilm potentials among Aeromonas species isolated from abattoir and aquaculture environments in Benin City, Nigeria. A total of 144 wastewater samples were obtained from two independent aquaculture and abattoir environments between May and October 2016. Aeromonas species were isolated on Glutamate Starch Phenol Red (GSP) agar and confirmed using API 20NE kits. Antimicrobial susceptibility profile of the isolates was carried out using standard disc diffusion assay while biofilm potentials were detected by the microtitre plate method and PCR technique was used to detect antibiotics resistance and virulence gene markers. Overall, 32 and 26 Aeromonas species were isolated from the abattoir and aquaculture environments respectively. Isolates from both environments were completely resistant (100%) to penicillin G, ertapenem and tetracycline; whereas aquaculture isolates exhibited absolute sensitivity (100%) towards cefepime. All the virulence gene markers (aerA, hlyA, alt, ast, laf, ascF G, fla, lip, stx1, and stx2) investigated in this study (except laf) were detected in isolates from both environments. The laf genes were only detected in isolates from abattoir environments. Antibiotics resistant genes including pse, blaTEM and class 1 integron were detected in isolates from both environments. Majority of the isolates (53/58 91.4%) from both environments; demonstrated capacity for biofilm potential. The detection of antibiotic resistance and virulence gene markers as well as biofilm forming ability in Aeromonas species isolated from aquaculture and abattoir environments raise serious public health concern worthy of further investigation. PMID- 28365324 TI - Clinical features and antimicrobial resistance profiles of important Enterobacteriaceae pathogens in Guangzhou representative of Southern China, 2001 2015. AB - OBJECT: This surveillance aimed to investigate the antimicrobial resistance profiles of Enterobacteriaceae pathogens in Southern China during 2001-2015. METHODS: A total of 6858 Enterobacteriaceae isolates were collected, including 4276 E. coli, 1992 K. pneumoniae and 590 Enterobacter spp. Disk diffusion method and minimum inhibitory concentrations method were used for susceptibility testing, with results interpreted by the CLSI (2015). RESULTS: Urinary tract remained the dominant isolated site among E. coli (49.88%), whereas 53.26% K. pneumoniae and 45.25% Enterobacter spp. were from Sputum. The carbapenems maintained the highest antimicrobial activity (resistance rates <15%), followed by piperacillin-tazobactam and amikacin. Gentle increases were obtained in carbapenems-resistant K. pneumoniae and Enterobacter spp. (eg. from 4.5% to 11.2% and 3.2% to 14.5% in imipenem, repestively). The third-generation cephalosporins showed high and stable resistance among Enterobacteriaceae pathogens during the studied period, with ceftazidime as the most active third-generation cephalosporin against Enterobacteriaceae. Isolates from ICU department showed higher or similar resistance rates among Enterobacteriaceae pathogens compared to other wards. CONCLUSION: Carbapenems are the most potent antibiotic agents against Enterobacteriaceae pathogens. Due to the complicated susceptibility profiles, prescribing guidelines should be based on the knowledge of antibiogram of pathogens. PMID- 28365325 TI - Screening of novel actinobacteria and characterization of the potential isolates from mangrove sediment of south coastal India. AB - The importance of the current research is to investigate the different types of samples from the various mangrove sediments; as source of actinobacteria from the mangrove wet soil. Potential isolate screening by antimicrobial activity and identified actinobacteria was characterized based on cultural morphology, physiological and biochemical characteristics. Three different types of media were used to isolate actinobacteria from various geographical region of mangrove soil sediment and the genotype locus was recognized by 16S rDNA. Totally 144 actinobacteria isolates were recovered from 10 samples using three media. The most active culture media in the isolation of actinobacteria were ISP2 and Glycerol Yeast Extract Agar. Among 144 isolates, 38 isolates (26.38%) exhibited antimicrobial activity. Out of 38 isolates, potentially active 2 cultures were further supported for morphological and biochemical characterization analysis. Most of the isolates were produced pharmaceutically important enzymes such as protease, amylase, lipase, cellulose and also revealed antimicrobial activity against tested microorganism. The enriched salt, pH and temperature tolerance of the actinobacteria isolates to discharge commercially valuable primary and secondary bioactive metabolites. The present results functionally characterize novel mangrove actinobacteria and their metabolites for commercial interest in pharmaceutical industry. PMID- 28365326 TI - Inhibitory effects of flavonoids on biofilm formation by Staphylococcus aureus that overexpresses efflux protein genes. AB - This study evaluated the efficacy of glycone (myricitrin, hesperidin and phloridzin) and aglycone flavonoids (myricetin, hesperetin and phloretin) in inhibiting biofilm formation by Staphylococcus aureus RN4220 and S. aureus SA1199B that overexpress the msrA and norA efflux protein genes, respectively. The minimum inhibitory concentration (MIC) and minimum biofilm inhibitory concentration (MBIC50 - defined as the lowest concentration that resulted in >=50% inhibition of biofilm formation) of flavonoids were determined using microdilution in broth procedures. The flavonoids showed MIC >1024 MUg/mL against S. aureus RN4220 and S. aureus SA1199B; however, these compounds at lower concentrations (1-256 MUg/mL) showed inhibitory effects on biofilm formation by these strains. Aglycone flavonoids showed lower MBIC50 values than their respective glycone forms. The lowest MBIC50 values (1 and 4 MUg/mL) were observed against S. aureus RN4220. Myricetin, hesperetin and phloretin exhibited biofilm formation inhibition >70% for S. aureus RN4220, and lower biofilm formation inhibition against S. aureus SA1199B. These results indicate that sub-MICs of the tested flavonoids inhibit biofilm formation by S. aureus strains that overexpress efflux protein genes. These effects are more strongly established by aglycone flavonoids. PMID- 28365327 TI - Polypropylene microtitre plates modified with [Cr(OH)6]3- for enhanced ELISA sensitivity. AB - Chromium solutions have been used as wet chemical modifiers for polymer microtitre plates used in improving immunoassay performance. However, polypropylene has been excluded from the list of potentially modifiable substrates (AnteoTechnologies, 2015). Here we show that untreated polypropylene microtitre plates can indeed be modified using a [Cr(OH)6]3- complex. Compared to unmodified polypropylene, the chromium modified surfaces demonstrate an up to 4 fold improvement in both assay sensitivity and signal intensity in an antigen capture ELISA. Atomic force microscope (AFM) images indicate that the chromium complex facilitates dispersion of the antibody, reducing aggregation. PMID- 28365328 TI - Comparison of 6B11 mAb and alpha-GalCer-loaded CD1d dextramers for detection of iNKT cells by flow cytometry. AB - Invariant natural killer T (iNKT) cells are a small population of thymus-derived T cells that are restricted by non-classical MHC class I molecule CD1d and express an evolutionary conserved TCR with an invariant alpha-chain. The frequency of iNKT cells in peripheral blood is very low, thus, accurate methods to identify and enumerate iNKT cells are needed. The aim of the study was to compare 6B11 mAb or alpha-GalCer-loaded CD1d dextramers usage in iNKT cell detection. The frequency of CD3+CD56+ lymphocytes is much higher, with statistical significance (p<0,001), than real iNKT cells detected by 6B11 mAb or alpha-GalCer-loaded CD1d dextramers. The frequency of iNKT cells, recognized by 6B11 mAb or alpha-GalCer-loaded CD1d dextramers, was in a similar range. Nonetheless, when we compared whether 6B11+ and alpha-GalCer-loaded CD1d dextramers+ are the same populations, it turned out that by this approach we were able to identify three distinct subsets of iNKT cells: i) 6B11+/alpha-GalCer loaded dextramer- cells, ii) 6B11+/alpha-GalCer-loaded dextramer+ cells, and iii) 6B11-/alpha-GalCer-loaded dextramer+. Thus, although 6B11 mAb and alpha-GalCer loaded dextramers may identify not exactly the same cells, application of these methods seems to give similar results of iNKT cell frequency in peripheral blood. It seems that both approaches for iNKT detection can be used for precise identification of these cells. Moreover, our results indicate that CD3+CD56+ lymphocytes are a heterogeneous population of T cells, expressing activation markers of both NK and T lymphocytes, yet with not well characterized properties. PMID- 28365329 TI - Lot-to-lot stability of antibody reagents for flow cytometry. AB - The fluorescence detected using fluorochrome-labelled monoclonal antibodies depends not only on the abundance of the target antigen, but amongst many other factors also on the effective fluorochrome-to-antibody ratio. The diagnostic approach of the EuroFlow consortium relies on reproducible fluorescence intensities over time. A capture bead system for mouse immunoglobulin light chains was utilized to compare the mean fluorescence intensity of 1323 consecutive antibody lots to the currently used lot of the same monoclonal antibody. In total, 157 different monoclonal antibodies were assessed over seven years. Median relative difference between consecutive lots was 3.8% (range: 0.01% to 164.7%, interquartile range: 1.3% to 10.1%). The relative difference exceeded 20% in 8.8% of all comparisons. FITC labelled monoclonal antibodies (median relative difference: 2.1%) showed a significantly smaller variation between lots than antibodies conjugated to PE (3.5%), PECy7 (3.9%), PerCPCy5.5 (5.8%), APC (5.8%), APCH7 (7.4%), and APCC750 (14.5%). Reagents labelled with Pacific Blue (1.4%), Pacific Orange (2.4%), HV450 (0.7%), and HV500 (1.7%) demonstrated more consistent results compared to conjugates of BV421 (4.1%) and BV510 (16.2%). Additionally, significant differences in lot-to-lot fluorescence stability amongst antibodies labelled with the same fluorochrome were observed between manufacturers. These observations might guide future quality recommendations for the production and application of fluorescence-labelled monoclonal antibodies in multicolor flow cytometry. PMID- 28365330 TI - Differences in liver stiffness values obtained with new ultrasound elastography machines and Fibroscan: A comparative study. AB - BACKGROUND AND AIMS: Whether Fibroscan thresholds can be immediately adopted for none, some or all other shear wave elastography techniques has not been tested. The aim of the present study was to test the concordance of the findings obtained from 7 of the most recent ultrasound elastography machines with respect to Fibroscan. METHODS: Sixteen hepatitis C virus-related patients with fibrosis >=2 and having reliable results at Fibroscan were investigated in two intercostal spaces using 7 different elastography machines. Coefficients of both precision (an index of data dispersion) and accuracy (an index of bias correction factors expressing different magnitudes of changes in comparison to the reference) were calculated. RESULTS: Median stiffness values differed among the different machines as did coefficients of both precision (range 0.54-0.72) and accuracy (range 0.28-0.87). When the average of the measurements of two intercostal spaces was considered, coefficients of precision significantly increased with all machines (range 0.72-0.90) whereas of accuracy improved more scatteredly and by a smaller degree (range 0.40-0.99). CONCLUSIONS: The present results showed only moderate concordance of the majority of elastography machines with the Fibroscan results, preventing the possibility of the immediate universal adoption of Fibroscan thresholds for defining liver fibrosis staging for all new machines. PMID- 28365331 TI - On the duration of the period between exposure to HIV and detectable infection. AB - HIV infection cannot be detected immediately after exposure because plasma viral loads are too small initially. The duration of this phase of infection (the "eclipse period") is difficult to estimate because precise dates of exposure are rarely known. Therefore, the reliability of clinical HIV testing during the first few weeks of infection is unknown, creating anxiety among HIV-exposed individuals and their physicians. We address this by fitting stochastic models of early HIV infection to detailed viral load records for 78 plasma donors, taken during the period of exposure and infection. We first show that the classic stochastic birth death model does not satisfactorily describe early infection. We therefore apply a different stochastic model that includes infected cells and virions separately. Since every plasma donor in our data eventually becomes infected, we must condition the model to reflect this bias, before fitting to the data. Applying our best estimates of unknown parameter values, we estimate the mean eclipse period to be 8-10 days. We further estimate the reliability of a negative test t days after potential exposure. PMID- 28365332 TI - Effector-Decoy Pairs: Another Countermeasure Emerging during Host-Microbe Co evolutionary Arms Races? PMID- 28365333 TI - Emerging Jasmonate Transporters. PMID- 28365334 TI - Can Locoregionally Recurrent Breast Cancer Be Cured? AB - Locoregional recurrence (LRR) of breast cancer can occur after multidisciplinary treatment of a primary breast cancer. With modern multidisciplinary breast cancer treatment, the incidence of isolated LRR is decreasing. Improvements in systemic therapy are driving the decrease in LRR. LRR does still occur, however. LRR reflects biology of the cancer, as does systemic recurrence. LRR of breast cancer is frequently associated with systemic disease recurrence and poor prognosis. Given this associated poor prognosis, historically, it has been unclear whether patients with LRR would benefit from aggressive therapy with curative intent. Findings in retrospective studies suggest that prognosis for patients with LRR is not universally poor, and some patients may benefit from aggressive locoregional and systemic therapy. The challenge remains to assess prognosis and appropriately treat patients with locoregional breast cancer recurrence. PMID- 28365335 TI - Competing Risks of Mortality by PAM50 Intrinsic Subtype of British Columbia Tamoxifen-Treated Cohort of Postmenopausal Patients With Breast Cancer. AB - BACKGROUND: PAM50 intrinsic subtypes have been shown to affect breast cancer prognosis. METHODS: A British Columbia cohort of 718 postmenopausal women treated with tamoxifen, without chemotherapy, had tumors intrinsically subtyped (luminal A, luminal B, basal, HER2) and centrally reviewed by immunohistochemistry (IHC) for estrogen and progesterone receptor (ER and PgR). We tested whether intrinsic subtype and other patient and tumor characteristics were associated with type of death. RESULTS: At median 11.7 years of follow-up, 429 (60%) of 718 women died: 30% of deaths were breast cancer-specific; 30% were other type. In 425 women <70 years, 32% died of breast cancer and 19% of other type. In 293 women >= 70, 27% died of breast cancer and 45% of other type. Intrinsic subtype was associated with breast cancer (P = .001); and older age, with other type (P < .001). Additionally, stepwise cause-specific models indicated larger tumor size (P < .001), more positive lymph nodes (P < .001), and less PgR stain (P = .03) were associated with worse breast cancer survival; more positive lymph nodes (P = .002) and lymphovascular invasion (P = .02) were associated with worse other type. Adjusted breast cancer and other type survival is provided by factors at 5, 10, and 15 years. CONCLUSIONS: Intrinsic subtype was associated with breast cancer death, whereas age was associated with other type; most deaths in women >= 70 were from other type. PMID- 28365336 TI - Associations Between Patient and Anthropometric Characteristics and Aromatase Inhibitor Discontinuation. AB - BACKGROUND: Toxicity can lead to noncontinuation of adjuvant endocrine therapy. We hypothesized that endocrine therapy-induced changes in grip strength would predict for early discontinuation of therapy because of musculoskeletal toxicity and would be associated with a patient's body mass index. PATIENTS AND METHODS: Postmenopausal women with breast cancer starting a new adjuvant endocrine therapy were enrolled in the present study. The patients were monitored for 12 months to assess their symptoms, endocrine therapy adherence and change in grip strength and baseline body mass index. The association between the change in grip strength and interval to discontinuation was assessed using a joint longitudinal and survival model. RESULTS: Of the 93 aromatase inhibitor (AI)-treated and 22 tamoxifen-treated patients, 40.9% and 9% discontinued endocrine therapy within 12 months because of toxicity, respectively (P = .019). A trend was seen toward a greater decrease in grip strength in the AI-treated patients over time (P = .055); however, the decrease was not significantly associated with the interval to discontinuation (P = .96). Receipt of an AI (hazard ratio, 5.49; P = .019) and baseline pain (hazard ratio, 1.19; P = .004) significantly decreased the interval to discontinuation. CONCLUSION: In contrast with the findings from previous reports, the change in grip strength in our study was not associated with the interval to discontinuation of AI therapy. Future research should focus on proactive treatment of patients at increased risk of AI intolerance, such as those with high levels of pre-existing pain. PMID- 28365337 TI - A strategy for promoting lipid production in green microalgae Monoraphidium sp. QLY-1 by combined melatonin and photoinduction. AB - Microalgae lipids are potential candidates for the production of renewable biodiesel. The combination of plant hormones and two-step cultivation regulates lipid production in microalgae. A strategy for promoting lipid accumulation in Monoraphidium sp. QLY-1 by combining exogenous melatonin (MT) and photoinduction was developed. The effects of melatonin on the lipid content, reactive oxygen species (ROS), and activities of three key fatty acid biosynthetic enzyme in Monoraphidium sp. QLY-1 were investigated. The lipid content increased by 1.32 fold under 1MUM melatonin treatment. The maximum lipid content achieved was 49.6%. However, the protein and carbohydrate contents decreased rapidly from 57.21% to 47.96% and from 53.4% to 37.71%, respectively. Biochemical and physiological analyses suggested that the ROS and lipid biosynthesis-related enzyme activities correlated with increased lipid accumulation under photo melatonin induction conditions. PMID- 28365338 TI - On a clean power generation system with the co-gasification of biomass and coal in a quadruple fluidized bed gasifier. AB - A clean power generation system was built based on the steam co-gasification of biomass and coal in a quadruple fluidized bed gasifier. The chemical looping with oxygen uncoupling technology was used to supply oxygen for the calciner. The solid oxide fuel cell and the steam turbine were combined to generate power. The calcium looping and mineral carbonation were used for CO2 capture and sequestration. The aim of this work was to study the characteristics of this system. The effects of key operation parameters on the system total energy efficiency (nten), total exergy efficiency (ntex) and carbon sequestration rate (Rcs) were detected. The energy and exergy balance calculations were implemented and the corresponding Sankey and Grassmann diagrams were drawn. It was found that the maximum energy and exergy losses occurred in the steam turbine. The system nten and ntex could be ~50% and ~47%, and Rcs could be over unit. PMID- 28365339 TI - Impact of sulfadiazine on performance and microbial community of a sequencing batch biofilm reactor treating synthetic mariculture wastewater. AB - The impact of sulfadiazine on the performance, microbial activity and microbial community of a sequencing batch biofilm reactor (SBBR) were evaluated in treating mariculture wastewater due to the application of sulfadiazine as an antibiotic in mariculture. The COD and nitrogen removals kept stable at 0-6mg/L sulfadiazine and were inhibited at 10-35mg/L sulfadiazine. The microbial activities related to organic matter and nitrogen removals reduced with an increase in sulfadiazine concentration. The presence of sulfadiazine could affect the production and chemical composition of loosely bound extracellular polymeric substances (LB-EPS) and tightly bound EPS (TB-EPS) in the biofilm. High-throughput sequencing demonstrated that sulfadiazine could impact on the microbial richness and diversity of SBBR treating mariculture wastewater. The relative abundances of Nitrosomonas, Nitrospira, Paracoccus, Hyphomicrobium, Rhodanobacter, Thauera and Steroidobacter decreased with an increase in sulfadiazine concentration, indicating that the presence of sulfadiazine decreased the relative abundance of some nitrifying and denitrifying bacteria. PMID- 28365340 TI - Presence and transcriptional activity of anaerobic fungi in agricultural biogas plants. AB - Bioaugmentation with anaerobic fungi (AF) is promising for improved biogas generation from lignocelluloses-rich substrates. However, before implementing AF into biogas processes it is necessary to investigate their natural occurrence, community structure and transcriptional activity in agricultural biogas plants. Thus, AF were detected with three specific PCR based methods: (i) Copies of their 18S genes were found in 7 of 10 biogas plants. (ii) Transcripts of a GH5 endoglucanase gene were present at low level in two digesters, indicating transcriptional cellulolytic activity of AF. (iii) Phylogeny of the AF-community was inferred with the 28S gene. A new Piromyces species was isolated from a PCR positive digester. Evidence for AF was only found in biogas plants operated with high proportions of animal feces. Thus, AF were most likely transferred into digesters with animal derived substrates. Additionally, high process temperatures in combination with long retention times seemed to impede AF survival and activity. PMID- 28365341 TI - Engineering coenzyme A-dependent pathway from Clostridium saccharobutylicum in Escherichia coli for butanol production. AB - Clostridium saccharobutylicum has been proved to be efficient in butanol fermentation from various feedstocks. Whereas, lack of genetic manipulation system has severely hindered the engineering of C. saccharobutylicum for more extensive applications. In this study, recombinant Escherichia coli harboring heterologous coenzyme A-dependent pathway from C. saccharobutylicum DSM 13864 was constructed, which consisted of solventogenic pathway genes: acetoacetyl-CoA thiolase (thlA), aldehyde/alcohol dehydrogenase (adhE2) and bcs-operon (crt-bcd1 etfB2-fixB2-hbd). Then, a butanol titer of 67mg/L was attained. After replacing thlA with acetyl-CoA acetyltransferase (atoB) from E. coli and deleting the competitive branch genes lactate dehydrogenase (ldhA), aldehyde/alcohol dehydrogenase (adhE1) and fumarate reductase (frdBC), the butanol titer was successfully improved for 3.8-fold (254mg/L). Under the optimum fermentation conditions, the final butanol titer reached 584mg/L after 120h. This result demonstrates the feasibility of adapting CoA-dependent solventogenic pathway from C. saccharobutylicum in E. coli for butanol synthesis. PMID- 28365342 TI - A continuous system for biocatalytic hydrogenation of CO2 to formate. AB - In this work a novel bioprocess for hydrogenation of CO2 to formate was developed, using whole cell catalysis by a sulfate-reducing bacterium. Three Desulfovibrio species were tested (D. vulgaris Hildenborough, D. alaskensis G20, and D. desulfuricans ATCC 27774), of which D. desulfuricans showed the highest activity, producing 12mM of formate in batch, with a production rate of 0.09mMh 1. Gene expression analysis indicated that among the three formate dehydrogenases and five hydrogenases, the cytoplasmic FdhAB and the periplasmic [FeFe] HydAB are the main enzymes expressed in D. desulfuricans in these conditions. The new bioprocess for continuous formate production by D. desulfuricans had a maximum specific formate production rate of 14mMgdcw-1h-1, and more than 45mM of formate were obtained with a production rate of 0.40mMh-1. This is the first report of a continuous process for biocatalytic formate production. PMID- 28365343 TI - A systematic methodology to extend the applicability of a bioconversion model for the simulation of various co-digestion scenarios. AB - Detailed simulation of anaerobic digestion (AD) requires complex mathematical models and the optimization of numerous model parameters. By performing a systematic methodology and identifying parameters with the highest impact on process variables in a well-established AD model, its applicability was extended to various co-digestion scenarios. More specifically, the application of the step by-step methodology led to the estimation of a general and reduced set of parameters, for the simulation of scenarios where either manure or wastewater were co-digested with different organic substrates. Validation of the general parameter set involved the simulation of laboratory-scale data from three continuous co-digestion experiments, treating mixtures of different organic residues either at thermophilic or mesophilic conditions. Evaluation of the results showed that simulations using the general parameter set fitted experimental data quite well, indicating that it offers a reliable reference point for future simulations of anaerobic co-digestion scenarios. PMID- 28365344 TI - Azo dyes wastewater treatment and simultaneous electricity generation in a novel process of electrolysis cell combined with microbial fuel cell. AB - A new process of electrolysis cell (EC) coupled with microbial fuel cell (MFC) was developed here and its feasibility in methyl red (MR) wastewater treatment and simultaneous electricity generation was assessed. Results indicate that an excellent MR removal and electricity production performance was achieved, where the decolorization and COD removal efficiencies were 100% and 89.3%, respectively and a 0.56V of cell voltage output was generated. Electrolysis voltage showed a positive influence on decolorization rate (DR) but also cause a rapid decrease in current efficiency (CE). Although a low COD removal rate of 38.5% was found in EC system, biodegradability of MR solution was significantly enhanced, where the averaged DR was 85.6%. Importantly, COD removal rate in EC-MFC integrated process had a 50.8% improvement compared with the single EC system. The results obtained here would be beneficial to provide a prospective alternative for azo dyes wastewater treatment and power production. PMID- 28365345 TI - Potential plant growth-promoting strain Bacillus sp. SR-2-1/1 decolorized azo dyes through NADH-ubiquinone:oxidoreductase activity. AB - In this study, a bacterial strain SR-2-1/1 was isolated from textile wastewater irrigated soil for its concurrent potential of plant growth promotion and azo-dye decolorization. Analysis of 16S rRNA gene sequence confirmed its identity as Bacillus sp. The strain tolerated high concentrations (i.e. up to 1000mgL-1) of metals (Ni2+, Cd2+, Co2+, Zn2+, and Cr6+) and efficiently decolorized the azo dyes (i.e. reactive black-5, reactive red-120, direct blue-1 and congo red). It also demonstrated considerable in vitro phosphate solubilizing and 1 aminocyclopropane-1-carboxylic acid deaminase abilities at high metal and salt levels. Bioinformatics analysis of its 537bp azoreductase gene and deduced protein revealed that it decolorized azo dyes through NADH ubiquinone:oxidoreductase enzyme activity. The deduced protein was predicted structurally and functionally different to those of its closely related database proteins. Thus, the strain SR-2-1/1 is a powerful bioinoculant for bioremediation of textile wastewater contaminated soils in addition to stimulation of plant growth. PMID- 28365346 TI - Efficient removal of lead from solution by celery-derived biochars rich in alkaline minerals. AB - Biochars were produced from celery biomass by slow pyrolysis at 350 and 500 degrees C, and featured by high content of alkaline minerals namely salts of alkali and alkaline earth metals. The biochars' efficiency on removing Pb2+ from solution was investigated, and two biochars derived from celery stalk (StC350 and StC500) showed higher Pb2+ sorption capacity (288 and 304mg/g) than most biochars reported previously. The sorption mechanisms involving precipitation, cation exchange and surface complexation are related to three biochar fractions namely water-soluble matter, acid-soluble substances and insoluble organic carbon. The relative contributions of water-soluble matter and acid-soluble substances to the total Pb2+ removal were 59.8% and 36.6% for the StC350 biochar, and 62.8% and 34.9% for the StC500 biochar, respectively. The results indicate that biochars derived from vegetable wastes are potential candidates for efficient sorption of heavy metals. PMID- 28365347 TI - Kinetic studies of the strengthening effect on liquid hot water pretreatments by organic acids. AB - The liquid hot water (LHW) pretreatments would be accelerated by the organic acids produced from the process. In the study, the organic acids included not only acetic acid but also lactic acid during LHW hydrolysis of reeds, at 180-220 degrees C and for 15-135min. The lactic acid was presumably produced from xylose degradation in the pretreatment process. The different organic acids, such as acetic acid, lactic acid and acetic-lactic acids, were used to strengthen the LHW pretreatments for increasing xylose production. Moreover, the work presented kinetic models of xylose and hemicellulose at different conditions, considering the generation of lactic acid. The experimental and kinetic results both indicated that acetic-lactic acids had synergistic catalytic effect on the reaction, which could not only inhibit the degradation of xylose, but also promote the hydrolysis of hemicellulose. Besides, the highest concentration of xylose of 7.323g/L was obtained at 200 degrees C, for 45min and with 1wt% acetic lactic acids. PMID- 28365348 TI - Strengthen effects of dominant strains on aerobic digestion and stabilization of the residual sludge. AB - In order to strengthen the aerobic digestion of residual sludge, shorten the time of sludge stabilization and further reduce operating costs, 3 dominant strains identified as Pseudomonas sp. L3, Acinetobacter sp. L16 and Bacillus sp. L19 were isolated from long-term aerobic digestion sludge. Results showed that the sludge stabilization time were reduced by 3-4days compared with the control when the dominant strains were added to the process of sludge aerobic digestion. The addition of dominant strains accelerated the accumulation of TOC, nitrate nitrogen and ammonia nitrogen in the digestive solution at different levels, and it was beneficial to the dissolution of phosphorus. Controlling DO 3-5mg/L, pH 6.5, the strains of Pseudomonas sp. L3 and Bacillus sp. L19 were combined dosing with the dosage of 2% in the process of sludge aerobic digestion, compared with the control, digestion rates of TOC and MLSS were increased about 19% and 16%, respectively. PMID- 28365349 TI - Reduction of greenhouse gases emissions during anoxic wastewater treatment by strengthening nitrite-dependent anaerobic methane oxidation process. AB - Nitrite-dependent anaerobic methane oxidation (n-damo) is a recently discovered process performed by NC10 phylum, which plays an important role in greenhouse gases (GHG) reduction. In this study, co-existence of n-damo bacteria and methanogens was successfully achieved by using upflow anaerobic sludge blanket (UASB) reactor. Reactor with inorganic carbon source (CO2/H2) showed the highest abundance of n-damo bacteria and the highest n-damo potential activity, resulted in its highest nitrogen removal rate. Significant reduction in GHG was obtained after introduction of n-damo process, especially for N2O. Furthermore, GHG emissions decreased with the increase of n-damo bacteria abundance. Community structure analysis found carbon source could influence the diversity of n-damo bacteria indirectly. And phylogenetic analysis showed that all the obtained sequences were assigned to group B, mainly due to in situ production and consumption of CH4. PMID- 28365350 TI - Media arrangement impacts cell growth in anaerobic fixed-bed reactors treating sugarcane vinasse: Structured vs. randomic biomass immobilization. AB - This study reports on the application of an innovative structured-bed reactor (FVR) as an alternative to conventional packed-bed reactors (PBRs) to treat high strength solid-rich wastewaters. Using the FVR prevents solids from accumulating within the fixed-bed, while maintaining the advantages of the biomass immobilization. The long-term operation (330days) of a FVR and a PBR applied to sugarcane vinasse under increasing organic loads (2.4-18.0kgCODm-3day-1) was assessed, focusing on the impacts of the different media arrangements over the production and retention of biomass. Much higher organic matter degradation rates, as well as long-term operational stability and high conversion efficiencies (>80%) confirmed that the FVR performed better than the PBR. Despite the equivalent operating conditions, the biomass growth yield was different in both reactors, i.e., 0.095gVSSg-1COD (FVR) and 0.066gVSSg-1COD (PBR), indicating a clear control of the media arrangement over the biomass production in fixed-bed reactors. PMID- 28365351 TI - Improving anaerobic digestion with support media: Mitigation of ammonia inhibition and effect on microbial communities. AB - This study aimed at providing a better understanding of the influence of support media (10g/L of zeolites, 10g/L of activated carbons, and 1g/L of chitosan) on key phylotypes steering anaerobic digestion (AD) performance in presence of 19g/L of Total Ammonia Nitrogen (TAN) within batch digesters. Support media did not influence TAN concentration. However, both zeolites and activated carbon 1 reduced methanization lag phase by 47% and 25%, respectively. By contrast, activated carbon 2 and chitosan led to an increase of methanization lag phase by 51% and 32%, respectively. 16S rRNA gene sequencing revealed that zeolites preserved Methanosarcina and enhanced Methanobacterium. In presence of activated carbon 1, Methanoculleus, became predominant earlier than without support while chitosan and activated carbon 2 limited its implantation. This study highlighted potentialities to use supports to enhance AD stability under extreme TAN concentration and evidenced their specific influence on the microbiota composition. PMID- 28365352 TI - Wastewater recycling technology for fermentation in polyunsaturated fatty acid production. AB - To reduce fermentation-associated wastewater discharge and the cost of wastewater treatment, which further reduces the total cost of DHA and ARA production, this study first analyzed the composition of wastewater from Aurantiochytrium (DHA) and Mortierella alpina (ARA) fermentation, after which wastewater recycling technology for these fermentation processes was developed. No negative effects of DHA and ARA production were observed when the two fermentation wastewater methods were cross-recycled. DHA and ARA yields were significantly inhibited when the wastewater from the fermentation process was directly reused. In 5-L fed-batch fermentation experiments, using this cross-recycle technology, the DHA and ARA yields were 30.4 and 5.13gL-1, respectively, with no significant changes (P>0.05) compared to the control group, and the water consumption was reduced by half compared to the traditional process. Therefore, this technology has great potential in industrial fermentation for polyunsaturated fatty acid production. PMID- 28365353 TI - Metabolomic analysis and lipid accumulation in a glucose tolerant Crypthecodinium cohnii strain obtained by adaptive laboratory evolution. AB - Adaptive laboratory evolution (ALE) was commonly used for strain improvement. Crypthecodinium cohnii is known to accumulate lipids with a high fraction of docosahexaenoic acid (DHA). In order to improve DHA production under high substrate concentration, a glucose-tolerant C. cohnii strain was firstly obtained by ALE after 260 cycles for 650days with gradually increased glucose concentration. The results of lipids content showed that DHA-rich lipids accumulation in the evolved strain could increase by 15.49% at 45g/L glucose concentrations. To reveal mechanisms related to glucose tolerance of C. cohnii through ALE, metabolic profiles were then compared and the results showed that hub metabolites including glycerol, glutamic acid, malonic acid and succinic acid were positively regulated during ALE. The study demonstrated that metabolomic analysis complemented with ALE could be an effective and valuable strategy for basic mechanisms of molecular evolution and adaptive changes in C. cohnii. PMID- 28365354 TI - Production of surfactin from waste distillers' grains by co-culture fermentation of two Bacillus amyloliquefaciens strains. AB - Distillers' grains (DGS), the main waste by-products of Chinese liquor industry, were used as substrate for surfactin production. Bacillus amyloliquefaciens MT45 could grow with DGS as sole carbon source to produce 1.04g/l surfactin. However, low amylase activity of MT45 limited sugar supply and the subsequent surfactin production. Therefore, MT45 was co-cultured with Bacillus strains that exhibited remarkable hydrolases activities. Surfactin yield increased by 50% when MT45 was co-cultured with B. amyloliquefaciens X82 that showed no product inhibition effect and did not develop extracellular matrix. The inoculation ratio of X82 greatly influenced the sugar supply, cellular growth, and surfactin production of the co-culture fermentation. Maximum surfactin titration (3.4g/l) was obtained when MT45 and X82 were co-cultured with inoculation ratio at 1:0.5, using 200g/l DGS. This work highlights the feasibility of using industrial waste DGS as promising feedstocks to produce value-added surfactin by co-culture fermentation. PMID- 28365355 TI - A prospective study on the safety and effectiveness of using lauromacrogol for ablation of pancreatic cystic neoplasms with the aid of EUS. AB - BACKGROUND AND AIMS: With the development of imaging techniques, the detection rate of pancreatic cystic neoplasms (PCNs) has increased. The surgical morbidity and mortality rates of PCNs are quite high. This study is intended to evaluate the safety and effectiveness of a minimally invasive treatment, EUS-guided PCN ablation with lauromacrogol. METHODS: From April 2015 to May 2016, 120 patients with PCNs were enrolled to undergo EUS. We prospectively studied 29 of the 120 patients who underwent EUS-guided ablation with lauromacrogol. The follow-up contrast-enhanced CT or magnetic resonance image was conducted at 3 months and then 6 months after ablation. We determined the effectiveness of ablation by the changes in the volume of the cysts. RESULTS: Twenty-nine patients were enrolled in the study, and 7 of them underwent a second ablation; therefore, there were 36 treatments. The mean tumor diameter was 28.6 +/- 14.5 mm preoperation, whereas the diameter postoperation was 13.4 +/- 10.5 mm. Mild pancreatitis occurred in 2 patients and moderate fever in 1; they occurred in the cysts located in the head/uncinate. Among the 29 treatments with complete follow-up of 9 months (range, 3-15), 11 had complete response and 9 had partial response. The resolution rate was 37.9% (11/29) with 36.4% (8/22) in the cysts of the head/uncinate and 42.9% (3/7) in the body/tail (P > .05). CONCLUSIONS: EUS-guided PCN ablation with lauromacrogol is safe and efficient. Adverse event rates seem to be higher in the head/uncinate than in the body/tail, but their resolution rates are similar. Further studies involving larger populations and longer follow ups are warranted. PMID- 28365356 TI - Impact of cap-assisted colonoscopy on detection of proximal colon adenomas: systematic review and meta-analysis. AB - BACKGROUND AND AIMS: Proximal colon adenomas can be missed during routine colonoscopy. Use of a cap or hood on the tip of the colonoscope has been shown to improve overall adenoma detection with variable rates. However, it has not been systematically evaluated for detection of proximal colon or right-sided adenomas where the cap may have maximum impact on adenoma detection rate (ADR). Our aim was to perform a systematic review and meta-analysis to evaluate the impact of cap-assisted colonoscopy (CC) on right-sided ADRs (r-ADRs) compared with standard colonoscopy (SC). METHODS: PubMed, EMBASE, SCOPUS, and Cochrane databases as well as secondary sources (bibliographic review of selected articles and major GI proceedings) were searched through October 1, 2016. Primary outcome was the pooled rate of r-ADR. Detection of flat adenoma, sessile serrated adenoma/polyp (SSA/P), and number of right-sided adenomas per patient were also assessed. Pooled odds ratio (OR) and 95% confidence intervals (CIs) were calculated using random-effect models. RESULTS: We screened 686 records and analyzed data from 4 studies (CC group, 2546 patients; SC group, 2547 patients) that met criteria for determination of r-ADRs, whereas 6 studies (CC group, 3159 patients; SC group, 3137 patients) were analyzed to estimate right-sided adenomas per patient. r-ADR was significantly higher with CC compared with SC (23% vs 17%; OR, 1.49; 95% CI, 1.08-2.05; I2 = 79%; P = .01). CC also improved detection rates of flat adenoma (OR, 2.08; 95% CI, 1.35-3.20; P < .01) and SSA/P (OR, 1.33; 95% CI, 1.01-1.74; P = .04). The total number of right-sided adenomas (CC: 1428 [60%] vs SC: 1127 [58%]) and number of right-sided adenomas per patient (CC, .71 +/- .5, vs SC, .65 +/- .62 [mean +/- standard deviation]) were numerically higher for CC but were not statistically significant (P = .43). Approximately 17 CCs would be required to detect an additional patient with right-sided adenoma. CONCLUSIONS: Use of CC significantly improves the proximal colon ADR. In addition, flat adenoma and serrated colonic lesion detection rates are also significantly higher as compared with SC. PMID- 28365357 TI - Chronic Kidney Disease Is More Common in Locally Advanced Renal Cell Carcinoma. AB - OBJECTIVE: To retrospectively evaluate clinical predictors of chronic kidney disease (CKD) in renal cell carcinoma (RCC) patients to identify associations between patient- and tumor-specific factors with poorer renal function. CKD and RCC are interrelated, with 26%-44% of RCC patients having concomitant CKD at diagnosis. PATIENTS AND METHODS: Institutional registries from Spectrum Health and University of California, San Diego, were queried for preoperative glomerular filtration rate and proteinuria status before radical or partial nephrectomy. Preoperative clinical and tumor factors were recorded; proteinuria was classified as A1 (<30 mg), A2 (30-300 mg), and A3 (>300 mg). CKD was grouped by Kidney Disease Improving Global Outcomes classification (low, moderately increased, high, very high). RESULTS: We evaluated 1569 patients undergoing surgery for renal cortical tumors. CKD status was low risk in 860 (55%), moderately increased in 381 (24%), high in 194 (12%), and very high in 134 (9%) patients. Increased radius, exophytic or endophytic properties, nearness of tumor to the collecting system or sinus in millimeters, anterior or posterior, location relative to polar lines score, tumor size, and clinical tumor stage were strongly associated with increased CKD risk at baseline. Clinical stage T3/T4 disease had more at-risk patients than stages T2 and T1 disease (39.5% vs 22% and 19%, P = .0001). Clinical tumor stage and gender were the only predictors of proteinuria, lower glomerular filtration rate, and higher CKD risk group in both univariate and multivariate analyses. CONCLUSION: Forty-five percent of patients with RCC had moderate or higher CKD before treatment. A positive correlation between pretreatment CKD and locally advanced RCC (cT3/T4) was present. This likely relates to increased loss of functional parenchyma with increasing tumor size or stage, with important implications in patient management. PMID- 28365358 TI - Rapid and Short-term Extracellular Matrix-mediated In Vitro Culturing of Tumor and Nontumor Human Primary Prostate Cells From Fresh Radical Prostatectomy Tissue. AB - OBJECTIVE: To culture prostate cells from fresh biopsy core samples from radical prostatectomy (RP) tissue. Further, given the genetic heterogeneity of prostate cells, the ability to culture single cells from primary prostate tissue may be of importance toward enabling single-cell characterization of primary prostate tissue via molecular and cellular phenotypic biomarkers. METHODS: A total of 260 consecutive tissue samples from RPs were collected between October 2014 and January 2016, transported at 4 degrees C in serum-free media to an off-site central laboratory, dissociated, and cultured. A culture protocol, including a proprietary extracellular matrix formulation (ECMf), was developed that supports rapid and short-term single-cell culture of primary human prostate cells derived from fresh RP samples. RESULTS: A total of 251 samples, derived from RP samples, yielded primary human tumor and nontumor prostate cells. Cultured cells on ECMf exhibit (1) survival after transport from the operating room to the off-site centralized laboratory, (2) robust (>80%) adhesion and survival, and (3) expression of different cell-type-specific markers. Cells derived from samples of increasing Gleason score exhibited a greater number of focal adhesions and more focal adhesion activation as measured by phospho-focal adhesion kinase (Y397) immunofluorescence when patient-derived cells were cultured on ECMf. Increased Ki67 immunofluorescence levels were observed in cells derived from cancerous RP tissue when compared to noncancerous RP tissue. CONCLUSION: By utilizing a unique and defined extracellular matrix protein formulation, tumor and nontumor cells derived from primary human prostate tissue can be rapidly cultured and analyzed within 72 hours after harvesting from RP tissue. PMID- 28365361 TI - The other-race effect does not apply to infant faces: An ERP attentional study. AB - It is known that paedomorphic characteristics, called "baby schema" by Lorenz, trigger an orienting response in adults, are judged as attractive and stimulate parental care. On the other hand, it is known that ethnicity may influence face encoding, with an advantage in recognizing faces of their own ethnicity (called own-race effect). Some have argued that this effect holds also for infant faces, which conflicts with the "baby schema" phenomenon. The aim of the study was to investigate the possible presence of the own-race effect on infant vs. adult face processing. Seventeen Caucasian students participated to the study. Their EEG/ERPs were recorded as they watched 400 pictures of adult and infant faces of different ethnicity (half Caucasian, half non-Caucasian), and subsequently responded to a target orientation. The behavioral results showed that responses were faster when the target was preceded by a child face, which enhanced the arousal level, regardless of ethnicity. The electrophysiological results showed an enhanced anterior N2 response to infant than adult faces, and a lack of ORE effect only for infant faces. Overall, the data indicate that baby faces automatically attract the adult viewer's attention and that face ethnicity has no effect on this innate response. PMID- 28365360 TI - Dysfunction of mitochondrial Lon protease and identification of oxidized protein in mouse brain following exposure to MPTP: Implications for Parkinson disease. AB - Compelling evidence suggests that mitochondrial dysfunction leading to reactive oxygen species (ROS) production and protein oxidation could represent a critical event in the pathogenesis of Parkinson's disease (PD). Pioneering studies have shown that the mitochondrial matrix contains the Lon protease, which degrades oxidized, dysfunctional, and misfolded protein. Using the PD animal model of 1 methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) intoxication in mice, we showed that Lon protease expression increased in the ventral mesencephalon of intoxicated animals, concomitantly with the appearance of oxidized proteins and dopaminergic cell loss. In addition, we report that Lon is inactivated by ROS. Moreover, proteomic experiments provide evidence of carbonylation in alpha ketoglutarate dehydrogenase (KGDH), aconitase or subunits of respiratory chain complexes. Lon protease inactivation upon MPTP treatment in mice raises the possibility that Lon protease dysfunction is an early event in the pathogenesis of PD. PMID- 28365362 TI - The precuneus and hippocampus contribute to individual differences in the unfolding of spatial representations during episodic autobiographical memory. AB - Spatial information is a central aspect of episodic autobiographical memory (EAM). Space-based theories of memory, including cognitive map and scene construction models, posit that spatial reinstatement is a required process during early event recall. Spatial information can be represented from both allocentric (third-person) and egocentric (first-person) perspectives during EAM, with egocentric perspectives being important for mental imagery and supported by the precuneus. Individuals differ in their tendency to rely on allocentric or egocentric information, and in general, the subjective experience of remembering in EAM differs greatly across individuals. Here we examined individual differences in spatial aspects of EAM, how such differences influence the vividness and temporal order of recollection, and their anatomical correlates. We cued healthy young participants (n =63) with personally familiar locations and non-locations. We examined how cue type affects (i) retrieval dynamics and (ii) phenomenological aspects of remembering, and related behavioural performance to regional brain volumes (n =42). Participants tended to spontaneously recall spatial information early during recollection, even in the absence of spatial cues, and individuals with a stronger tendency to recall space first also displayed faster reaction times. Across participants, place-cued memories were re experienced more vividly and were richer in detail than those cued by objects, but not more than those cued by familiar persons. Volumetric differences were associated with behavioural performance such that egocentric remembering was positively associated with precuneus volume. Hippocampal CA2/CA3 volumes were associated with the tendency to recall place-cued memories less effortfully. Consistent with scene construction theories, this study suggests that spatial information is reinstated early and contributes to the efficiency and phenomenology of EAM. However, early recall of spatial information is not universal and other routes to recall exist, challenging some aspects of these models. Variability among participants highlights the importance of an individual differences approach to studying EAM. PMID- 28365359 TI - Leflunomide prevents ROS-induced systemic fibrosis in mice. AB - Systemic sclerosis (SSc) is a connective tissue disorder characterized by fibrosis of the skin and inner organs, vasculopathy and immunological abnormalities. Recent insights into the polarization of macrophages in scleroderma and into the implication of STAT6 and KLF4 in this process have prompted us to investigate the effects of the inhibition of STAT6 signaling pathway by leflunomide in mice. SSc was induced in BALB/c mice by daily subcutaneous injections of hypochlorous acid (HOCl) or bleomycin. Mice were treated (or not) every other day, for 4 or 6 weeks, by leflunomide. Skin and lung fibrosis as well as immunological features were studied. Mice exposed to HOCl developed a diffuse cutaneous SSc with pulmonary fibrosis and anti-DNA topoisomerase 1 auto-antibodies. STAT6 pathway was hyperactivated and KLF4 was overexpressed in the skin and the lungs of diseased mice. Their inhibition by leflunomide prevented skin and lung fibrosis. Moreover, the hyperproliferative and pro-oxidative phenotype of skin and lung fibroblasts was reversed by leflunomide. Beneficial immunological effects of leflunomide were associated with decreased activation of CD4+ and CD8+ T cells, B cell activation, decreased auto antibodies production and restored polarization of macrophages in the spleen. The improvement provided by leflunomide in both mouse models of SSc provides a rationale for the evaluation of this immunomodulating drug in the management of patients affected by this disease. PMID- 28365363 TI - Audio-visual temporal perception in children with restored hearing. AB - It is not clear how audio-visual temporal perception develops in children with restored hearing. In this study we measured temporal discrimination thresholds with an audio-visual temporal bisection task in 9 deaf children with restored audition, and 22 typically hearing children. In typically hearing children, audition was more precise than vision, with no gain in multisensory conditions (as previously reported in Gori et al. (2012b)). However, deaf children with restored audition showed similar thresholds for audio and visual thresholds and some evidence of gain in audio-visual temporal multisensory conditions. Interestingly, we found a strong correlation between auditory weighting of multisensory signals and quality of language: patients who gave more weight to audition had better language skills. Similarly, auditory thresholds for the temporal bisection task were also a good predictor of language skills. This result supports the idea that the temporal auditory processing is associated with language development. PMID- 28365365 TI - Re: Suppressed Recurrent Bladder Cancer after Androgen Suppression with Androgen Deprivation Therapy or 5alpha-Reductase Inhibitor: M. Shiota, K. Kiyoshima, A. Yokomizo, A. Takeuchi, E. Kashiwagi, T. Dejima, R. Takahashi, J. Inokuchi, K. Tatsugami and M. Eto J Urol 2017;197:308-313. PMID- 28365366 TI - Reply by Authors. PMID- 28365364 TI - Ganglioside and related-sphingolipid profiles are altered in a cellular model of Alzheimer's disease. AB - Sphingolipid-related issues are increasingly discussed to contribute to the neuropathological process of Alzheimer's disease (AD). In this study, gangliosides and related-sphingolipids (ceramides, neutral glycosphingolipids and sphingomyelins) were analyzed in neuroglioma (H4) cells expressing the Swedish mutation of the human amyloid precursor protein (H4APPsw) and compared with those of wild-type control H4 cells. These cells were chosen since H4APPsw cells were previously reported to reproduce well some essential features of AD. We found that H4APPsw cells exhibited a striking elevation of the simplest ganglioside GM3, an abnormality that was consistently reported in AD patients and animal models of AD. Concomitantly, the levels of both lactosylceramide (the immediate metabolic precursor of GM3) and ganglioside GD1a increased, suggesting a deregulation in the biosynthesis of gangliosides in the H4APPsw cells. Moreover, while the total ceramide level remained unaltered in H4APPsw cells, a shift in ceramide composition from long chain - to very long chain fatty acid-ceramide species was recorded. Because sphingolipid alterations occurring in H4APPsw cells were similar to those observed in transgenic mice and in human brains, this cellular model might be useful to further explore the complex role of sphingolipids in AD pathogenesis. PMID- 28365367 TI - Reply by Authors. PMID- 28365368 TI - Editorial Comment. PMID- 28365369 TI - Editorial Comment. PMID- 28365370 TI - Re: Efficacy and Safety of Prostatic Arterial Embolization: Systematic Review with Meta-Analysis and Meta-Regression: S. R. Shim, K. J. Kanhai, Y. M. Ko and J. H. Kim J Urol 2017;197:465-479. PMID- 28365371 TI - Trump administration budget proposals "bad for health, science, environment, and America". PMID- 28365372 TI - Endogenous Opioid Function and Responses to Morphine: The Moderating Effects of Anger Expressiveness. AB - : Long-term use of opioid analgesics may be ineffective or associated with significant negative side effects for some people. At present, there is no sound method of identifying optimal opioid candidates. Individuals with chronic low back pain (n = 89) and healthy control individuals (n = 102) underwent ischemic pain induction with placebo, opioid blockade (naloxone), and morphine in counterbalanced order. They completed the Spielberger Anger-Out subscale. Endogenous opioid function * Anger-out * Pain status (chronic pain, healthy control) interactions were tested for morphine responses to ischemic threshold, tolerance, and pain intensity (McGill Sensory and Affective subscales) and side effects. For individuals with chronic pain and healthy control participants, those with low endogenous opioid function and low anger-out scores exhibited the largest morphine analgesic responses, whereas those with high anger-out and low endogenous opioid function showed relatively weaker morphine analgesic responses. Further, individuals with chronic pain with low endogenous opioid function and low anger-out scores also reported the fewest negative effects to morphine, whereas those with low endogenous opioid function and high anger-out reported the most. Findings point toward individuals with chronic pain who may strike a favorable balance of good analgesia with few side effects, as well as those who have an unfavorable balance of poor analgesia and many side effects. PERSPECTIVE: We sought to identify optimal candidates for opioid pain management. Low back pain patients who express anger and also have deficient endogenous opioid function may be poor candidates for opioid therapy. In contrast, low back patients who tend not to express anger and who also have deficient endogenous opioid function may make optimal candidates for opioid therapy. PMID- 28365373 TI - Marijuana and acute health care contacts in Colorado. AB - Over 22 million Americans are current users of marijuana; half of US states allow medical marijuana, and several allow recreational marijuana. The objective of this study was to evaluate the impact marijuana has on hospitalizations, emergency department (ED) visits, and regional poison center (RPC) calls in Colorado, a medical and recreational marijuana state. This is a retrospective review using Colorado Hospital Association hospitalizations and ED visits with marijuana-related billing codes, and RPC marijuana exposure calls. Legalization of marijuana in Colorado has been associated with an increase in hospitalizations, ED visits, and RPC calls linked with marijuana exposure. From 2000 to 2015, hospitalization rates with marijuana-related billing codes increased from 274 to 593 per 100,000 hospitalizations in 2015. Overall, the prevalence of mental illness among ED visits with marijuana-related codes was five-fold higher (5.07, 95% CI: 5.0, 5.1) than the prevalence of mental illness without marijuana-related codes. RPC calls remained constant from 2000 through 2009. However, in 2010, after local medical marijuana policy liberalization, the number of marijuana exposure calls significantly increased from 42 to 93; in 2014, after recreational legalization, calls significantly increased by 79.7%, from 123 to 221 (p<0.0001). The age group <17years old also had an increase in calls after 2014. As more states legalize marijuana, it is important to address public education and youth prevention, and understand the impact on mental health disorders. Improvements in data collection and surveillance methods are needed to more accurately evaluate the public health impact of marijuana legalization. PMID- 28365374 TI - Harnessing neural stem cells for treating psychiatric symptoms associated with fetal alcohol spectrum disorder and epilepsy. AB - Brain insults with progressive neurodegeneration are inherent in pathological symptoms that represent many psychiatric illnesses. Neural network disruptions characterized by impaired neurogenesis have been recognized to precede, accompany, and possibly even exacerbate the evolution and progression of symptoms of psychiatric disorders. Here, we focus on the neurodegeneration and the resulting psychiatric symptoms observed in fetal alcohol spectrum disorder and epilepsy, in an effort to show that these two diseases are candidate targets for stem cell therapy. In particular, we provide preclinical evidence in the transplantation of neural stem cells (NSCs) in both conditions, highlighting the potential of this cell-based treatment for correcting the psychiatric symptoms that plague these two disorders. Additionally, we discuss the challenges of NSC transplantation and offer insights into the mechanisms that may mediate the therapeutic benefits and can be exploited to overcome the hurdles of translating this therapy from the laboratory to the clinic. Our ultimate goal is to advance stem cell therapy for the treatment of psychiatric disorders. PMID- 28365376 TI - In search of oculomotor capture during film viewing: Implications for the balance of top-down and bottom-up control in the saccadic system. AB - In the laboratory, the abrupt onset of a visual distractor can generate an involuntary orienting response: this robust oculomotor capture effect has been reported in a large number of studies (e.g. Ludwig & Gilchrist, 2002; Theeuwes, Kramer, Hahn, & Irwin, 1998) suggesting it may be a ubiquitous part of more natural visual behaviour. However the visual stimuli used in these experiments have tended to be static and had none of the complexity, and dynamism of more natural visual environments. In addition, the primary task in the laboratory (typically visual search) can be tedious for the participants with participant's losing interest and becoming stimulus driven and more easily distracted. Both of these factors may have led to an overestimation of the extent to which oculomotor capture occurs and the importance of this phenomena in everyday visual behaviour. To address this issue, in the current series of studies we presented abrupt and highly salient visual distractors away from fixation while participants watched a film. No evidence of oculomotor capture was found. However, the distractor does effect fixation duration: we find an increase in fixation duration analogous to the remote distractor effect (Walker, Deubel, Schneider, & Findlay, 1997). These results suggest that during dynamic scene perception, the oculomotor system may be under far more top-down control than traditional laboratory based-tasks have previously suggested. PMID- 28365375 TI - Preclinical molecular imaging of glutamatergic and dopaminergic neuroreceptor kinetics in obsessive compulsive disorder. AB - BACKGROUND: Molecular neuroimaging was applied in the quinpirole rat model for compulsive checking in OCD to visualize the D2- and mGluR5-receptor occupancy with Raclopride and ABP-688 microPET/CT. METHODS: Animals (n=48) were exposed to either saline (CTRL; 1mL/kg) or quinpirole (QP; dopamine D2-agonist, 0.5mg/kg) in a single injection (RAC and ABP acute groups) or twice-weekly during 7weeks (chronic group). Animals underwent PET/CT after the 1st injection (acute) or before initial exposure and following the 10th injection in week 5 (chronic). For the latter, each injection was paired with an open field test and video tracking. RESULTS: The QP animals displayed a strong increase in visiting frequency (checking) in the chronic group (+699.29%) compared to the control animals. Acute administration of the drug caused significant (p<0.01) decreases in D2R occupancy in the CP (-42.03%+/-4.01%). Chronical exposure resulted in significantly stronger decreases in the CP (-52.29%+/-3.79%). Furthermore significant increases in mGluR5 occupancy were found in the CP (10.36%+/-4.09%), anterior cingulate cortex (13.26%+/-4.01%), amygdala (24.36%+/-6.86%), entorhinal cortex (18.49%+/ 5.14%) and nucleus accumbens (13.8%+/-4.87%) of the chronic group, not present after acute exposure. CONCLUSIONS: Compared to acute exposure, sensitisation to QP as a model for OCD differs both on a dopaminergic and glutamateric level, indicating involvement of processes such as receptor internalization and changes in extracellular availability of both neurotransmitters. PMID- 28365377 TI - A Three Month Home Exercise Programme Augmented with Nordic Poles for Patients with Intermittent Claudication Enhances Quality of Life and Continues to Improve Walking Distance and Compliance After One Year. AB - OBJECTIVE/BACKGROUND: The objective of this study was to collect 1 year follow-up information on walking distance, speed, compliance, and cost in patients with intermittent claudication who took part in a previously reported 12 week randomised clinical trial of a home exercise programme augmented with Nordic pole walking versus controls who walked normally. A second objective was to look at quality of life and ankle brachial pressure indices (ABPIs) after a 12 week augmented home exercise programme. METHODS: Thirty-two of the 38 patients who completed the original trial were followed-up after 6 and 12 months. Frequency, duration, speed, and distance of walking were recorded using diaries and pedometers. A new observational cohort of 29 patients was recruited to the same augmented home exercise programme. ABPIs, walking improvement, and quality of life questionnaire were recorded at baseline and 12 weeks (end of the programme). RESULTS: Both groups in the follow-up study continued to improve their walking distance and speed over the following year. Compliance was excellent: 98% of the augmented group were still walking with poles at both 6 and 12 months, while 74% of the control group were still walking at the same point. The augmented group increased their mean walking distance to 17.5 km by 12 months, with a mean speed of 4.2 km/hour. The control group only increased their mean walking distance from 4.2 km to 5.6 km, and speed to 3.3 km/hour. Repeated ANOVA showed the results to be highly significant (p = .002). The 21/29 patients who completed the observational study showed a statistically significant increase in resting ABPIs from baseline (mean +/- SD 0.75 +/- 0.12) to week 12 (mean +/- SD 0.85 +/- 0.12) (t = (20) -8.89, p = .000 [two-tailed]). All their walking improvement and quality of life parameters improved significantly (p = .002 or less in the six categories) over the same period and their mean health scores improved by 79%. CONCLUSIONS: Following a 12 week augmented home exercise programme, most patients with intermittent claudication continued to significantly improve their walking distance and walking speed at 1 year compared with normal walking. Quality of life and ABPIs improved significantly after only 12 weeks and it is postulated that the improvement in ABPI was due to collateral development. These results justify the belief that an augmented home exercise programme will be as clinically effective as existing supervised exercise programmes, with the added benefits of lower cost and better compliance. Funding for a multicentre trial comparing an augmented home exercise programme with existing supervised exercise programme is now urgently required. PMID- 28365378 TI - Re "Analysis of the Elective Treatment Process for Critical Limb Ischaemia with Tissue Loss: Diabetic Patients Require Rapid Revascularisation". PMID- 28365379 TI - Phosphotransferase systems in Enterococcus faecalis OG1RF enhance anti-stress capacity in vitro and in vivo. AB - Phosphotransferase systems are common and essential in bacteria, which are in charge of sugar transportation and phosphorylation. However, phosphotransferase systems were found in recent years to be associated with environmental stress factors. This study investigated the role of the mannose/fructose/sorbose phosphotransferase systems in Enterococcus faecalis OG1RF in adaption to harsh environments by construction of pts mutants. More than one mannose/fructose/sorbose phosphotransferase system was found in E. faecalis OG1RF, and the elimination of pts gene at different loci generated different after-effects corresponding to different ambiences. An in vitro study showed that the presence of intact phosphotransferase systems in E. faecalis OG1RF promoted resistance to hydrogen peroxide and acid and enhanced susceptibility to pediocin. In vivo study demonstrated that the presence of intact phosphotransferase systems induced more hazardous substances like superoxide dismutase (SOD) in Caenorhabditis elegans and enhanced bacterial infection and survival in macrophages J774A.1 and BMM. In addition, phosphotransferase systems regulated transcription of antioxidant and catabolite genes such as katA, gor, lysR, hypR, rex, hprK and tpx to different extents (-6.3- to 3.5-fold). It is therefore suggested that pts genes are regulatory factors promoting adaption of E. faecalis OG1RF to stressful conditions, thereby enhancing the possibility of bacterial survival and infectivity. PMID- 28365380 TI - Unemployment and inflammatory markers in England, Wales and Scotland, 1998-2012: Meta-analysis of results from 12 studies. AB - INTRODUCTION: Unemployment represents for many affected individuals a substantial source of psychosocial stress, and is linked to both increased risk of morbidity and mortality and adverse health-related behaviours. Few studies have examined the association of unemployment with systemic inflammation, a plausible mediator of the associations of psychosocial stress and health, and results are mixed and context dependent. This study examines the association of unemployment with C reactive protein (CRP) and fibrinogen, two markers of systemic inflammation. METHODS: A random-effects meta-analysis was performed using a multilevel modelling approach, including 12 national UK surveys of working-age participants in which CRP and fibrinogen were measured between 1998 and 2012 (N=30,037 economically active participants). The moderating impact of participant age and UK country was explored. RESULTS: CRP and fibrinogen were elevated in unemployed compared to employed participants; jobseekers were also more likely (Odds Ratio: 1.39, p<0.001) to have CRP levels corresponding to high cardiovascular risk (>3mg/L), after adjustment for age, gender, education, long-term illness, smoking, and body mass index. Associations were not explained by mental health. Associations peaked in middle-age, and were stronger in Scotland and Wales than in England. CONCLUSIONS: Our study demonstrates that systemic inflammation is associated with an important but little-studied aspect of the social environment, as it is elevated in unemployed compared to employed survey participants. Modifications suggest the association of unemployment and inflammation is substantially influenced by contextual factors, and may be especially strong in Wales, where further investigation of this relationship is needed. PMID- 28365382 TI - Mapping the secretome of human chondrogenic progenitor cells with mass spectrometry. AB - Tissue engineering offers promising perspectives in the therapy of osteoarthritis. In the context of cell-based therapy, chondrogenic progenitor cells (CPCs) may be used to regenerate defects in cartilage tissue. An in-depth characterization of the secretome of CPCs is a prerequisite to this approach. In this study, a method was developed for the qualitative and quantitative analysis of the secretome of undifferentiated and differentiated CPCs. Secreted proteins from cells grown in two-dimensional as well as three-dimensional alginate cultures were extracted and analyzed by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Quantitation was achieved by internal standardization using stable isotope-labeled amino acids in cell culture (SILAC). Qualitative analysis of CPC secretomes revealed ECM-components, signal proteins and growth factors most of which were also found in healthy cartilage. A quantitative comparison revealed significantly upregulated proteins with regenerative potential during differentiation, while proteins involved in catabolic metabolism were significantly downregulated. The development of methods for qualitative and quantitative analysis of the secretome of CPCs by mass spectrometry provides a foundation for the investigation of progenitor or stem cells from other sources. PMID- 28365381 TI - The anterolateral ligament (ALL) of the knee-Part of the iliotibial tract or a truly separate structure? AB - In this Short Communication, the issue is discussed whether the recently reported anterolateral ligament of the knee is a unique structure or just part of the iliotibial tract. The presented findings from investigations in body donors support the view of a unique structure. PMID- 28365383 TI - A comparative study of the effectiveness of early and delayed loading of short tissue-level dental implants with hydrophilic surfaces placed in the posterior section of the mandible-A preliminary study. AB - The objective of the present study was to compare the primary and secondary stability of tissue-level short dental titanium implants with polished necks and hydrophilic surfaces of two different designs and manufacturers. The first implant system used (SPI(r)ELEMENT RC INICELL titanium implants, Thommen Medical AG, Grenchen, Switzerland), allowed functional loading 6 weeks after its placement, whereas the second implant system (RN SLActiv(r) tissue-level titanium implants, Straumann GmbH, Fribourg, Germany), was loaded after 15 weeks. The degree of primary and secondary stability was determined using an Osstell ISQ measuring device. Marginal bone loss (MBL) was evaluated radiographically 12 and 24 weeks after implantation and the Wachtel's healing index as well as the patient's satisfaction with the treatment was registered on a VAS scale. The intergroup comparison revealed significant differences in terms of primary stability as well as differences in MBL 3 months after the procedure, but no significant differences could be found after 6 months and for secondary stability. The primary stability was significantly higher for Thommen(r) compared to Straumann(r) implants. Insertion of short dental implants with a hydrophilic conditioned surface significantly shortens patient treatment time. PMID- 28365384 TI - Adaptive significance of precocious pupation in the bean blister beetle, Epicauta gorhami (Coleoptera: Meloidae), a hypermetamorphic insect. AB - Larvae of the bean blister beetle, Epicauta gorhami Marseul (Coleoptera: Meloidae), feed on grasshopper eggs in soil and undergo hypermetamorphosis. They normally enter diapause as a pseudopupa at the fifth instar, a form characteristic of hypermetamorphosis for meloid beetles. However, fourth-instar larvae exposed to long days and high temperature avoid pseudopupal diapause and pupate directly from the fourth instar. Fourth-instar larvae also tend to pupate precociously with a smaller body size if they are deprived of food. In these larvae, the critical day-length controlling induction of pseudopupal diapause becomes shorter than that for fully-fed larvae. In this study, we examined how the reaction norm of food-deprived E. gorhami larvae functions in nature by rearing insects from the egg stage outdoors in different seasons with manipulation of the food supply. The results indicated that most fully-fed larvae entered pseudopupal diapause, whereas food-deprived larvae tended to pupate precociously without entering diapause, especially early in the season. The resulting smaller adults reproduced early in the autumn and their progeny attained the pseudopupal stage before winter, indicating that the reaction norm may have an adaptive role in controlling seasonal development in the face of food shortages, producing a bivoltine life cycle. PMID- 28365385 TI - Molecular characterization and antibacterial activity of a phage-type lysozyme from the Manila clam, Ruditapes philippinarum. AB - A phage-type lysozyme, designed as RpPLYZ, was cloned and characterized from the clam Ruditapes philippinarum. The full-length cDNA of RpPLYZ was of 699 bp with an open reading frame (ORF) of 534 bp, encoding a polypeptide of 177-amino acid with a calculated molecular mass of 19.6 kDa and an isoelectric point of 9.05. Multiple alignments and phylogenetic analysis strongly suggested that RpPLYZ was a new member of the phage-type lysozyme family. The mRNA transcript of RpPLYZ was found to be constitutively expressed in a wide range of tissues and mainly in hemocytes and mantle. The relative expression of RpPLYZ mRNA in hemocytes was significantly up-regulated at 6, 24, 48 and 72 h after Vibrio anguillarum challenge. The recombinant RpPLYZ (rRpPLYZ) showed high activity against Entherobacter cloacae and Staphyloccocus aureus, and less effective towards Entherobacter aerogenes and V. anguillarum. Moreover, the optimal pH, temperature and ionic strength for rRpPLYZ activity was determined to be 5.5, 50 degrees C and 5 mM, respectively. These results suggested that RpPLYZ was a member of the phage-type lysozyme family and perhaps played an important role in the immune responses against bacterial invasion. PMID- 28365386 TI - Antibacterial function of herbal extracts on growth, survival and immunoprotection in the black tiger shrimp Penaeus monodon. AB - This study examined the effects of an herbal extract composed of nine herbs i.e Aloe vera, Andrographis pariculata, Annona squamosa, Azadirachta indica, Citrus aurantifolia, Coriandrum sativum, Ocimum sanctum, Ollium cepa and Psidium guajava on growth, survival rate and immunoprotection against pathogenic Vibrio harveyi in the tiger shrimp Penaeus monodon. The petroleum ether, methanol and N-hexen extracts of different herbal plants were selected, processed and thoroughly mixed in equal proportions and added to the shrimp diets at a concentration of 1.0, 2.5 and 5.0 mL kg-1. After 60 days of feeding, shrimps were challenged with V. harveyi bacteria (1 * 107 cells mL-1), which were isolated and propagated from the infected shrimps. The shrimps fed on diets with methanolic extraction of 2.5 mL kg-1 had significantly (P < 0.001) higher survival rate (76%), specific growth rate (4.26 +/- 0.11%) and better food conversion ratio (1.5) than the other groups. This study indicates that addition of methanolic herbal extracts of 2.5 mL kg-1 can positively influence the immune response of tiger shrimp against V. harveyi infection. PMID- 28365387 TI - Structural analysis and insight into Zika virus NS5 mediated interferon inhibition. AB - The Zika virus outbreak in 2015-2016 is the largest of its kind for which WHO declared a Public Health Emergency of International Concerns. No FDA approved drug is available for the treatment of the viral infection. The interaction of flavivirus NS5 protein with SIAH2 ubiquitin ligase has been previously known. NS5 of Zika virus has been implicated in the degradation of STAT2 protein, which activates interferon-stimulated antiviral activity. Based on our proposition that NS5 utilizes SIAH2-mediated proteasomal degradation of STAT2, an in-silico study was carried out to characterize the protein-protein interactions between NS5, SIAH2 and STAT2 proteins. The aim of our study was to identify the amino acid residues of NS5 involved in IFN antagonism as well as to find the association between NS5, SIAH2 and STAT2 to predict the interaction pattern of these proteins. Analysis proposed that NS5 recruits SIAH2 for the ubiquitination dependent degradation of STAT2. NS5 residues involved in interaction with SIAH2 and/or STAT2 were found to be mostly conserved across related flaviviruses. These are novel findings regarding the Zika virus and require confirmation through experimental approaches. PMID- 28365389 TI - Efficient transfection of Xenobiotic Responsive Element-biosensor plasmid using diether lipid and phosphatidylcholine liposomes in differentiated HepaRG cells. AB - In this study, we evaluated cationic liposomes prepared from diether-NH2 and egg phosphatidylcholine (EPC) for in vitro gene delivery. The impact of the lipid composition, i.e. the EPC and Diether-NH2 molar ratio, on in vitro transfection efficiency and cytotoxicity was investigated using the human HEK293T and hepatoma HepaRG cells known to be permissive and poorly permissive cells for liposome mediated gene transfer, respectively. Here, we report that EPC/Diether-NH2-based liposomes enabled a very efficient transfection with low cytotoxicity compared to commercial transfection reagents in both HEK293T and proliferating progenitor HepaRG cells. Taking advantage of these non-toxic EPC/Diether-NH2-based liposomes, we developed a method to efficiently transfect differentiated hepatocyte-like HepaRG cells and a biosensor plasmid containing a Xenobiotic Responsive Element and a minimal promoter driving the transcription of the luciferase reporter gene. We demonstrated that the luciferase activity was induced by a canonical inducer of cytochrome P450 genes, the benzo[a]pyrene, and two environmental contaminants, the fluoranthene, a polycyclic aromatic hydrocarbon, and the endosulfan, an organochlorine insecticide, known to induce toxicity and genotoxicity in differentiated HepaRG cells. In conclusion, we established a new efficient lipofection-mediated gene transfer in hepatocyte-like HepaRG cells opening new perspectives in drug evaluation relying on xenobiotic inducible biosensor plasmids. PMID- 28365390 TI - Investigation of in vitro PDT activities of zinc phthalocyanine immobilised TiO2 nanoparticles. AB - Phthalocyanines (Pcs) are commonly used as Photosensors (PSs) in Photodynamic Therapy (PDT) applications due to their intense absorption in the far red-near IR spectral region with a high extinction coefficient and high ability for generating singlet oxygen. Pcs targetspecifically tumors, and do not show any considerable toxic effects under the absence of light. In particular, their chemical versatility has allowed the introducion a number of substituent at the periferal or axial positions which provide modulating photophysical properties, increases the solubility of these compounds in organic solvents. Nanoparticles increase the bioavailability, stability, and transport of PSs to target tissue. TiO2 nanoparticles are prefered in these applications because of their non toxic, low cost and high chemical stability properties. In our study, a Zinc Phthalocyanine (ZnPc) was used as a photosensor. The design of ZnPc integrated TiO2 nanoparticles is intended to make PSs a more effective PDT agent. With the aim to examine the nuclear imaging/treatment potentials of ZnPc and ZnPc-TiO2 in hepatocellular carcinoma (HepG2), colorectal adenocarcinoma (HT29) tumor and human healthy lung (WI38) cell lines in vitro study ZnPc and TiO2-ZnPc were also labeled with 131I. It is determined that 131I-ZnPc-TiO2 nanoparticle show a potential as an agent for the imaging/treatment of hepatocellular cancer by in vitro. The toxicity studies revealed that TiO2 nanoparticle decreases the toxicity of ZnPc. In vitro PDT results show that TiO2-ZnPc has a potential as a PDT agent in colon tumor treatment. Consequently, synthesized ZnPc and ZnPc-TiO2 could be promising candidates as theranostic agents. PMID- 28365388 TI - Comparative analysis of MBD-seq and MeDIP-seq and estimation of gene expression changes in a rodent model of schizophrenia. AB - We conducted a comparative study of multiplexed affinity enrichment sequence methodologies (MBD-seq and MeDIP-seq) in a rodent model of schizophrenia, induced by in utero methylazoxymethanol acetate (MAM) exposure. We also examined related gene expression changes using a pooled sample approach. MBD-seq and MeDIP-seq identified 769 and 1771 differentially methylated regions (DMRs) between F2 offspring of MAM-exposed rats and saline control rats, respectively. The assays showed good concordance, with ~56% of MBD-seq-detected DMRs being identified by or proximal to MeDIP-seq DMRs. There was no significant overlap between DMRs and differentially expressed genes, suggesting that DNA methylation regulatory effects may act upon more distal genes, or are too subtle to detect using our approach. Methylation and gene expression gene ontology enrichment analyses identified biological processes important to schizophrenia pathophysiology, including neuron differentiation, prepulse inhibition, amphetamine response, and glutamatergic synaptic transmission regulation, reinforcing the utility of the MAM rodent model for schizophrenia research. PMID- 28365391 TI - Rational approach for design and evaluation of anti-aggregation agents for protein stabilization: A case study of trehalose phenylalaninate. AB - The present work introduces new anti-aggregation agent (AAA) derived through our new approach for design and evaluation of anti-aggregation agent as a multi purpose excipient to combat protein aggregation. Therapeutic proteins undergo aggregation due to even minor changes in environmental conditions like temperature, pH, shear and stress. Excipients play a vital role in prevention of aggregation. To stabilize a protein formulation different classes of excipients are used in combination after carefully selecting through laborious and time consuming trial and error experiments. To resolve these concerns, we have developed a rational approach based on molecular docking analysis and have designed, synthesized AAAs, and validated the approach by experimental studies. Trehalose phenylalaninate (TPA) has been synthesized and evaluated for stabilization of Bovine serum albumin (BSA). TPA was found to be non-toxic with a LC50 of >80MUg/ml. BSA solutions with and without TPA were subjected to thermal and agitation stress and aggregation was monitored using sophisticated analytical techniques. The helical structure of BSA was completely retained in stressed samples at 0.1% concentration of TPA. SEC-HPLC clearly demonstrated the absence of aggregates in presence of TPA. Although aggregation was not seen in fluorescence spectra but quenching due to TPA was evident. Moreover, molecular dynamics study on BSA-TPA complex showed lower RMSD. PMID- 28365392 TI - Effects of seaweed sterols fucosterol and desmosterol on lipid membranes. AB - Higher sterols are universally present in large amounts (20-30%) in the plasma membranes of all eukaryotes whereas they are universally absent in prokaryotes. It is remarkable that each kingdom of the eukaryotes has chosen, during the course of evolution, its preferred sterol: cholesterol in animals, ergosterol in fungi and yeast, phytosterols in higher plants, and e.g., fucosterol and desmosterol in algae. The question arises as to which specific properties do sterols impart to membranes and to which extent do these properties differ among the different sterols. Using a range of biophysical techniques, including calorimetry, fluorescence microscopy, vesicle-fluctuation analysis, and atomic force microscopy, we have found that fucosterol and desmosterol, found in red and brown macroalgae (seaweeds), similar to cholesterol support liquid-ordered membrane phases and induce coexistence between liquid-ordered and liquid disordered domains in lipid bilayers. Fucosterol and desmosterol induce acyl chain order in liquid membranes, but less effectively than cholesterol and ergosterol in the order: cholesterol>ergosterol>desmosterol>fucosterol, possibly reflecting the different molecular structure of the sterols at the hydrocarbon tail. PMID- 28365395 TI - Clinicopathological and immunohistochemical analysis of oral melanocytic nevi and review of the literature. AB - INTRODUCTION: Oral melanocytic nevi (OMNs) are uncommon benign melanocytic tumors, histologically similar to their cutaneous counterparts. The aim of this study was twofold: to contribute to the epidemiology with a literature review with the first Spanish series of OMNs, and to report on clinicopathological, immunohistochemical and demographic findings. MATERIALS AND METHODS: A retrospective analysis of cases attended over the period 1999-2010 was carried out using data drawn from the pathology unit files at two public hospitals in the Spanish region of Andalusia, serving between them a population of 823.614 inhabitants (11%). RESULTS: Ten cases of OMNs were retrieved, accounting for 0.18% of the total 5499 oral biopsies performed over the period. The female-to male ratio was 1.5:1; mean patient age was 30. The palate was the most common location (70%). Relative frequencies of histologic types were as follows: subepithelial (40%), common blue (30%), compound (20%) and junctional (10%). Immunohistochemical examination showed strong S-100 protein expression, variable reactivity to HMB-45 and high c-Kit expression by junctional melanocytes. Ki-67 was <=3 in all cases. CONCLUSIONS: Although this first clinicopathologic analysis of OMNs reported in Spain was based on a small patient series, the results are in line with those reported in larger series and additionally provide new demographic data. Since OMNs and early melanomas are usually detected at routine dental examination, detailed oral exploration should always be performed, and in case of doubt a biopsy should be taken to ensure an accurate diagnosis. PMID- 28365394 TI - Neuropathic pain in the orofacial region: The role of pain history. A retrospective study. AB - INTRODUCTION: Orofacial neuropathic pain is often difficult to treat, mostly because of still unclear underlying mechanisms. The occurrence of such neuropathic pain varies depending on different factors, of which preexisting preoperative pain seems to be of high importance. The aim of this study was thus to test the hypothesis that prior history of pain could indeed be considered a risk factor for the development of orofacial neuropathic pain in the same region. METHODS: The study was performed in the dental department of the Groupe Hospitalier Pitie-Salpetriere (GHPS) in Paris, France. We investigated the presence of prior inflammatory pain before development of orofacial neuropathic pain in 56 patients. For each patient file, the following items were collected: age, gender; medical history; diagnosis; description of the pain (at time of consultation); presence or absence of prior dental treatment; date and type of dental treatment received. RESULTS: 41 patients (73%) of orofacial neuropathic pain patients had a history of pain compatible with an inflammatory condition; 4% (n=2) did not report any prior pain and 23% (n=13) could not remember. Among the patients with documented history of pain prior to neuropathy, 88% (n=36) received surgical treatment; 61%, (n=25) endodontic treatment and 22%, (n=9) restorative treatment. All eventually received endodontic treatment or tooth extraction. These dental treatments are compatible with the hypothesis of prior inflammatory pain in these patients. CONCLUSION: These results support the hypothesis that prior inflammatory pain could favor the development of orofacial neuropathic pain. Prevention and treatment of inflammatory trigeminal pain may therefore play a key role in preventing future neuropathic pain development. PMID- 28365393 TI - Peripheral Neutrophil to Lymphocyte Ratio Improves Prognostication in Colon Cancer. AB - BACKGROUND: We studied the role of peripheral neutrophil to lymphocyte ratio (NLR) on survival outcomes in colon and rectal cancer to determine if its inclusion improved prognostication within existing staging systems. PATIENTS AND METHODS: Disease-free (DFS) and overall survival (OS) hazard ratios (HRs) of pretreatment NLR were calculated for 2536 patients with stage I to III colon or rectal cancer and adjusted for age, positive/total number of nodes, T stage, and grade. The association of NLR with clinicopathologic features and survival was evaluated and compared with the American Joint Committee on cancer (AJCC) TNM staging and Memorial Sloan Kettering Cancer Center (MSKCC) models. RESULTS: High NLR was significantly associated with worse DFS (HR, 1.36; 95% confidence interval [CI], 1.08-1.70; P = .009) and OS (HR, 1.65; 95% CI, 1.29-2.10; P < .0005) in all stages for patients with colon, but not rectal, cancer. High NLR was significantly associated with site-specific worse prognosis, which was stronger in the left versus right colon; an inverse relationship with grade was found. The impact of high NLR on DFS and OS occurred early, with the majority of deaths within 2 years following surgery. Adjusted HRs for 5-year and 2-year outcomes in colon cancer per each additional 2-unit increase in NLR were 1.15 (95% CI, 1.08-1.23) and 1.20 (95% CI, 1.10-1.30), respectively. The addition of NLR enhanced the prognostic utility of TNM (TNM alone vs. TNM + NLR: concordance index, 0.60 vs. 0.68), and MSKCC (MSKCC alone vs. MSKCC + NLR: concordance index, 0.71 vs. 0.73) models for colon cancer patients. CONCLUSION: NLR is an independent prognostic variable for nonmetastatic colon cancer that enhances existing clinical staging systems. PMID- 28365396 TI - Use of the 3D surgical modelling technique with open-source software for mandibular fibula free flap reconstruction and its surgical guides. AB - INTRODUCTION: Tridimensional (3D) surgical modelling is a necessary step to create 3D-printed surgical tools, and expensive professional software is generally needed. Open-source software are functional, reliable, updated, may be downloaded for free and used to produce 3D models. Few surgical teams have used free solutions for mastering 3D surgical modelling for reconstructive surgery with osseous free flaps. We described an Open-source software 3D surgical modelling protocol to perform a fast and nearly free mandibular reconstruction with microvascular fibula free flap and its surgical guides, with no need for engineering support. PROCEDURE: Four successive specialised Open-source software were used to perform our 3D modelling: OsiriX(r), Meshlab(r), Netfabb(r) and Blender(r). Digital Imaging and Communications in Medicine (DICOM) data on patient skull and fibula, obtained with a computerised tomography (CT) scan, were needed. The 3D modelling of the reconstructed mandible and its surgical guides were created. CONCLUSIONS: This new strategy may improve surgical management in Oral and Craniomaxillofacial surgery. Further clinical studies are needed to demonstrate the feasibility, reproducibility, transfer of know how and benefits of this technique. PMID- 28365398 TI - Are older drivers' on-road driving error rates related to functional performance and/or self-reported driving experiences? PMID- 28365397 TI - Hormonal underpinnings of status conflict: Testosterone and cortisol are related to decisions and satisfaction in the hawk-dove game. AB - A contribution to a special issue on Hormones and Human Competition.Testosterone is theorized to influence status-seeking behaviors such as social dominance and competitive behavior, but supporting evidence is mixed. The present study tested the roles of testosterone and cortisol in the hawk-dove game, a dyadic economic decision-making paradigm in which earnings depend on one's own and the other player's choices. If one person selects the hawk strategy and the other person selects the dove strategy, the player who selected hawk attains a greater financial pay-off (status differentiation). The worst financial outcome occurs when both players choose the hawk strategy (status confrontation). Ninety-eight undergraduate students (42 men) provided saliva samples and played ten rounds of the hawk-dove game with another same-sex participant. In support of the hypothesis that testosterone is related to status concern, individuals higher in basal testosterone made more hawk decisions - decisions that harmed the other player. Acute decreases in cortisol were also associated with more hawk decisions. There was some empirical support for the dual-hormone hypothesis as well: basal testosterone was positively related to satisfaction in the game among low basal-cortisol individuals but not among high basal-cortisol individuals. There were no significant sex differences in these hormonal effects. The present findings align with theories of hormones and status-seeking behavior at the individual level, but they also open up new avenues for research on hormone profiles at the collective level. Our results suggest that the presence of two or more high-testosterone members increases the likelihood of status confrontations over a limited resource that can undermine collective outcomes. PMID- 28365399 TI - Synchronised firing patterns in a random network of adaptive exponential integrate-and-fire neuron model. AB - We have studied neuronal synchronisation in a random network of adaptive exponential integrate-and-fire neurons. We study how spiking or bursting synchronous behaviour appears as a function of the coupling strength and the probability of connections, by constructing parameter spaces that identify these synchronous behaviours from measurements of the inter-spike interval and the calculation of the order parameter. Moreover, we verify the robustness of synchronisation by applying an external perturbation to each neuron. The simulations show that bursting synchronisation is more robust than spike synchronisation. PMID- 28365400 TI - MiRNA-29b suppresses tumor growth through simultaneously inhibiting angiogenesis and tumorigenesis by targeting Akt3. AB - The traditional anti-angiogenic cancer therapy could trigger hypoxia induced factor (HIF) response, leading to "reactive resistance" to chemotherapy. Simultaneously inhibiting both angiogenesis and tumorigenesis would be ideal to overcome this limitation. MicroRNAs (miRNAs) are increasingly explored as new agents for cancer therapy. In the present study, we identified a microRNA (miR 29b) with the ability of simultaneously inhibiting angiogenesis and tumorigenesis. Ectopic expression of miR-29b inhibits HUVECs formed three dimensional capillary-like tubular structures, tumor cell proliferation, migration and tumor formation. Systemic administration of miR-29b potently suppressed tumor vascularization and cancer cell activity in vivo, resulting in dramatic suppression of tumor growth without toxicity. Moreover, we demonstrated the role of miR-29b in anti-angiogenesis and anti-tumorigenesis is through targeting Akt3 and inducing VEGF and C-myc arrest in breast cancer cells. These findings indicate that this single miRNA could be used as an efficient anti cancer therapeutic agent to address a critical challenge in cancer therapy. PMID- 28365401 TI - Reverse Shoulder Arthroplasty in Patients With Amputation or Paralysis of the Contralateral Upper Extremity (One-Arm Patients). AB - BACKGROUND: Theoretically, patients with only one functional arm secondary to contralateral amputation or paralysis will subject their only functional upper extremity to increased loads. This could become an issue after reverse shoulder arthroplasty (RSA). However, there are no reported data on the implant survival or function for patients with a nonfunctional contralateral upper extremity. OBJECTIVE: To report the outcomes of RSA in patients with contralateral upper extremity amputation or paralysis. DESIGN: Retrospective case series. SETTING: Tertiary university hospital. PATIENTS: All patients who underwent RSA between January 2004 and December 2013. METHODS: Of 1335 RSA procedures performed, 5 patients had a minimum 2-year follow-up and nonfunctional contralateral upper extremity. There were 3 men and 2 women, with a mean (standard deviation) age and length of follow-up of 72.4 (7.5) years and 56.4 (24-132) months. Two of the patients had a contralateral upper extremity amputation, and the other 3 had contralateral upper extremity paralysis as a result of stroke, traumatic brain injury, and traumatic brachial plexus injury at birth. MAIN OUTCOMES: Pain, range of motion, functional scores (Simple Shoulder Test, American Shoulder and Elbow Society and Quick-Disability of the Arm, Shoulder and Hand), satisfaction, complications/reoperations, and radiographic loosening. RESULTS: RSA resulted in substantial improvement in pain (P = .008), forward flexion (P = .02), and external range of motion (P = .01). The mean (standard deviation) Simple Shoulder Test, American Shoulder and Elbow Society, and Quick-Disability of the Arm, Shoulder, and Hand scores were 9.8 (1.3), 82 (13), and 17.8 (13.4), respectively. The results were excellent in 3, satisfactory in 1, and unsatisfactory in 1 patient (due only to external rotation limited to 10 degrees ). Subjectively, all 5 patients felt greatly improved and stated they would undergo RSA again. There were no complications or reoperations. There were no shoulders with component loosening. CONCLUSIONS: RSA seems to be a safe, effective, and successful surgical procedure for patients with a nonfunctional contralateral upper extremity. Studies with larger sample sizes and longer follow-up will hopefully validate the present findings. LEVEL OF EVIDENCE: IV. PMID- 28365402 TI - Distinct fibrosis pattern in desmosomal and phospholamban mutation carriers in hereditary cardiomyopathies. AB - BACKGROUND: Desmosomal and phospholamban (PLN) mutations are associated with arrhythmogenic cardiomyopathy. Ultimately, most cardiomyopathic hearts develop significant cardiac fibrosis. OBJECTIVE: To compare the fibrosis patterns of desmosomal and p. Arg14del PLN-associated cardiomyopathies with the pattern in hearts with other hereditary cardiomyopathies. METHODS: A midventricular transversal slice was obtained from hearts of 30 patients with a cardiomyopathy with a known underlying mutation and from 8 controls. Fibrosis and fatty changes were quantitatively analyzed using digital microscopy. RESULTS: Hearts from patients with desmosomal mutations (n = 6) showed fibrosis and fibrofatty replacement in the left ventricular (LV) outer myocardium, mainly in the posterolateral wall, and in the right ventricle. A similar phenotype, but with significantly more severe fibrotic changes in the LV, was found in the PLN mutation group (n = 8). Cardiomyopathies associated with lamin A/C (n = 5), sarcomeric (n = 8), and desmin (n = 3) mutations all showed a different pattern from that of the desmosomal and PLN mutation carriers. The posterolateral LV wall appeared to be the most discriminative area with fibrosis and fatty changes predominantly at the outer compact myocardium in 13 of 14 hearts with desmosomal and PLN mutations (93%), in 0 of 13 hearts with lamin A/C and sarcomeric mutations (0%), and in 1 of 3 desminopathic hearts (33%) (P < .001). CONCLUSION: Desmosomal- and PLN-associated cardiomyopathies have a fibrosis pattern distinct from the patterns in other hereditary cardiomyopathies. The posterolateral LV wall appeared to be the most discriminative region between mutation groups. These results may provide a roadmap for cardiac imaging interpretation and may help in further unraveling disease mechanisms. PMID- 28365403 TI - Integration of heterogeneous and biochemical catalysis for production of fuels and chemicals from biomass. AB - The past decade has seen significant government and private investment in fundamental research and process development for the production of biofuels and chemicals from lignocellulosic biomass-derived sugars. This investment has helped create new metabolic engineering and synthetic biology approaches, novel homogeneous and heterogeneous catalysts, and chemical and biological routes that convert sugars, lignin, and waste products such as glycerol into hydrocarbon fuels and valuable chemicals. With the exception of ethanol, economical biofuels processes have yet to be realized. A potentially viable way forward is the integration of biological and chemical catalysis into processes that exploit the inherent advantages of each technology while circumventing their disadvantages. Microbial fermentation excels at converting sugars from low-cost raw materials streams into simple alcohols, acids, and other reactive intermediates that can be condensed into highly reduced, long and branched chain hydrocarbons and other industrially useful compounds. Chemical catalysis most often requires clean feed streams to avoid catalyst deactivation, but the chemical and petroleum industries have developed large scale processes for C-C coupling, hydrogenation, and deoxygenation that are driven by low grade heat and low-cost feeds such as hydrogen derived from natural gas. In this context, we suggest that there is a reasonably clear route to the high yield synthesis of biofuels from biomass- or otherwise derived-fermentable sugars: the microbial production of reactive intermediates that can be extracted or separated into clean feed stream for upgrading by chemical catalysis. When coupled with new metabolic engineering strategies that maximize carbon and energy yields during fermentation, biomass-to fuels processes may yet be realized. PMID- 28365404 TI - Metabolic engineering strategies to bio-adipic acid production. AB - Adipic acid is the most industrially important dicarboxylic acid as it is a key monomer in the synthesis of nylon. Today, adipic acid is obtained via a chemical process that relies on petrochemical precursors and releases large quantities of greenhouse gases. In the last two years, significant progress has been made in engineering microbes for the production of adipic acid and its immediate precursors, muconic acid and glucaric acid. Not only have the microbial substrates expanded beyond glucose and glycerol to include lignin monomers and hemicellulose components, but the number of microbial chassis now goes further than Escherichia coli and Saccharomyces cerevisiae to include microbes proficient in aromatic degradation, cellulose secretion and degradation of multiple carbon sources. Here, we review the metabolic engineering and nascent protein engineering strategies undertaken in each of these chassis to convert different feedstocks to adipic, muconic and glucaric acid. We also highlight near term prospects and challenges for each of the metabolic routes discussed. PMID- 28365405 TI - Novel insights into cardiac remodelling revealed by proteomic analysis of the trout heart during exercise training. AB - : The changes in the cardiac proteome of rainbow trout (Oncorhynchus mykiss) were quantified during the early phases (4, 7, and 14d) of a typical exercise-training regime to provide a comprehensive overview of the cellular changes responsible for developing a trained heart phenotype. Enhanced somatic growth during the 14d experiment was paralleled by cardiac growth to maintain relative ventricular mass. This was reflected in the cardiac proteome by the increased abundance of contractile proteins and cellular integrity proteins as early as Day 4, including a pronounced and sustained increase in blood vessel epicardial substance - an intercellular adhesion protein expressed in the vertebrate heart. An unexpected finding was that proteins involved in energy pathways, including glycolysis, beta oxidation, the TCA cycle, and the electron transport chain, were generally present at lower levels relative to Day 0 levels, suggesting a reduced investment in the maintenance of energy production pathways. However, as the fish demonstrated somatic and cardiac growth during the exercise-training program, this change did not appear to influence cardiac function. The in-depth analysis of temporal changes in the cardiac proteome of trout during the early stages of exercise training reveals novel insights into cardiac remodelling in an important model species. BIOLOGICAL SIGNIFICANCE: Rainbow trout hearts have a remarkable ability for molecular, structural, and functional plasticity, and the inherent athleticism of these fish makes them ideal models for studies in comparative exercise physiology. Indeed, several decades of research using exercise-trained trout has shown both conserved and unique aspects of cardiac plasticity induced by a sustained increase in the workload of the heart. Despite a strong appreciation for the outcome of exercise training, however, the temporal events that generate this phenotype are not known. This study interrogates the early stages of exercise training using in-depth proteomic analysis to understand the molecular pathways of cardiac remodelling. Two major and novel findings emerge: (1) structural remodelling is initiated very early in training, as evidenced by a general increase in proteins associated with muscle contraction and integrity at Day 4, and (2) the abundance of proteins directly involved in energy production are decreased during 14d of exercise training, which contrasts the general acceptance of an exercise-induced increase in aerobic capacity of muscle, and suggests that regulation of energy pathways occurs at a different biological level than protein abundance. PMID- 28365406 TI - A proteomic and ultrastructural characterization of Aspergillus fumigatus' conidia adaptation at different culture ages. AB - : The airborne fungus Aspergillus fumigatus is one of the most common agents of human fungal infections with a remarkable impact on public health. However, A. fumigatus conidia atmospheric resistance and longevity mechanisms are still unknown. Therefore, in this work, the processes underlying conidial adaptation were studied by a time course evaluation of the proteomics and ultrastructural changes of A. fumigatus' conidia at three time-points selected according to relevant changes previously established in conidial survival rates. The proteomics characterization revealed that conidia change from a highly active metabolic to a dormant state, culminating in cell autolysis as revealed by the increased levels of hydrolytic enzymes. Structural characterization corroborates the proteomics data, with noticeable changes observed in mitochondria, nucleus and plasma membrane ultrastructure, accompanied by the formation of autophagic vacuoles. These changes are consistent with both apoptotic and autophagic processes, and indicate that the changes in protein levels may anticipate those in cell morphology. SIGNIFICANCE: The findings presented in this work not only clarify the processes underlying conidial adaptation to nutrient limiting conditions but can also be exploited for improving infection control strategies and in the development of new therapeutical drugs. Additionally, the present study was deposited in a public database and thus, it may also be a valuable dataset to be used by the scientific community as a tool to understand and identified other potential targets associated with conidia resistance. PMID- 28365407 TI - Reaching reveals that best-versus-rest processing contributes to biased decision making. AB - The study of human decision making has revealed many contexts in which decisions are systematically biased. These biases are particularly evident in risky decisions, characterized by choice outcomes that are probabilistic. One recently explored bias is the extreme-outcome rule: the tendency for participants to overvalue both the best and worst outcome when they learn about choice probabilities through trial and error (aka experience). Here we aimed to test whether the extreme-outcome rule arises in part from a disproportionate subjective weight on extreme values. Participants reached to choose between two options in a riskless task where each choice option always produced the same result. In contrast to the idea that the overvaluing of extreme outcomes results from participants overestimating the underlying choice probabilities (e.g. treating a 50% "worst" outcome as though it occurred 60% of the time), we find overvaluation of extreme outcomes even when they are not probabilistic. Particularly, we find strong evidence for overvaluation of the best outcome relative to all other outcomes in how participants enact their decision (reaction times and reaching movements), but no evidence for such overvaluation in participants' choice accuracy. Compared to the extreme-outcome rule, these results are more simply characterized in a framework where the "best" option is given a boost in processing relative to the "rest" of other available options. PMID- 28365408 TI - Mitochondrial dysfunction underlying outer retinal diseases. AB - Dysfunction of photoreceptors, retinal pigment epithelium (RPE) or both contribute to the initiation and progression of several outer retinal disorders. Disrupted Muller glia function might additionally subsidize to these diseases. Mitochondrial malfunctioning is importantly associated with outer retina pathologies, which can be classified as primary and secondary mitochondrial disorders. This review highlights the importance of oxidative stress and mitochondrial DNA damage, underlying outer retinal disorders. Indeed, the metabolically active photoreceptors/RPE are highly prone to these hallmarks of mitochondrial dysfunction, indicating that mitochondria represent a weak link in the antioxidant defenses of outer retinal cells. PMID- 28365409 TI - New caffeic acid derivative from Tithonia diversifolia (Hemsl.) A. Gray butanolic extract and its antioxidant activity. AB - Tithonia diversifolia, Asteraceae, a promising alternative for insect control such as leaf-cutting ants, have revealed repellent and insecticidal activity against Atta cephalotes. The different biological activities of T. diversifolia, are due to the existence of sesquiterpene lactones and phenolic compounds. Some phenolic compounds have antioxidant activity and curiously also exhibited tyrosinase inhibitory activity, key enzyme in insect metamorphosis. To expand the plant phytochemical knowledge, especially for isolation and identification of secondary metabolites such as phenolic compounds not yet discovered in the polar extracts, a new caffeic acid derivative was isolated from the leaves of Tithonia diversifolia. The structure was determined as (E)-3-(((3-(3,4 dihydroxyphenyl)acryloyl)oxy)methyl)-2-methyloxyrane-2-carboxylic acid (1). Additionally, three known phenolic acids, 4,5-dicaffeoylquinic acid (2), 3,4 dicaffeoylquinic acid (3) and 3,5-dicaffeoylquinic acid (4), were also isolated; 1, 2 and 3 are the first reports for this species. The structures of compounds 1, 2 and 3 were established based on LC-MS and one- and two-dimensional (1D)- and (2D)-NMR spectroscopic analyses. Spectroscopic data of compound 1 were compared with 4-O-caffeoyl-2-C-methyl-d-threonic acid (5). Antioxidant activity evaluation in 96-well plate format, showed caffeic acid derivatives as strong 2,2-diphenyl-1 picrylhydrazyl (DPPH) radical-scavengers and moderate ferric reducing antioxidant power (FRAP). PMID- 28365410 TI - Performance evaluation of direct fluorescent antibody, Focus Diagnostics SimplexaTM Flu A/B & RSV and multi-parameter customized respiratory Taqman(r) array card in immunocompromised patients. AB - BACKGROUND: Molecular assays for diagnosis of Flu A, Flu B, and RSV with short turn-around-time (TAT) are of considerable clinical importance. In addition, rapid and accurate diagnosis of a large panel of viral and atypical pathogens can be crucial in immunocompromised patients. OBJECTIVES: First, to evaluate the performance of the SimplexaTM Direct assay system in comparison with direct fluorescent antibody (DFA) and customized Taqman(r) Array Card (TAC) testing for RSV, Flu A, and Flu B in immunocompromised patients. Second, to evaluate different algorithms for the detection of respiratory pathogens in terms of cost, turn-around-time (TAT) and diagnostic yield. STUDY DESIGN: We collected 125 nasopharyngeal swabs (NTS) and 25 BAL samples from symptomatic immunocompromised patients. Samples for which SimplexaTM and TAC results were discordant underwent verification testing. The TAC assay is based on singleplex RT-PCR, targeting 24 viruses, 8 bacteria and 2 fungi simultaneously. RESULTS: The overall sensitivity was significantly lower for DFA testing than for the two molecular methods (p<0.05). Performance characteristics of SimplexaTM testing were not significantly different compared to TAC testing (p>0.1). For BAL samples only, the sensitivity and specificity of the SimplexaTM assay was 100%. In total, 6.7, 16 and 18% of samples were positive for Flu A, Flu B or RSV by DFA, SimplexaTM and TAC testing, respectively. When considering not only these pathogens but also all results for TAC, the method identified 93 samples with one or more respiratory pathogens (62%). A co-infection rate of 15.3% was found by TAC. The estimated costs and TAT were 8.2? and 2h for DFA, 31.8? and 1.5h for SimplexaTM and 55? and 3h for TAC testing. CONCLUSIONS: Performing the SimplexaTM test 24h a day/7 days a week instead of DFA would considerably improve the overall sensitivity and time-to-result, albeit at a higher cost generated in the laboratory. Performing the TAC would increase the diagnostic yield and detection of co-infections significantly. PMID- 28365411 TI - Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials. AB - BACKGROUND: Intensive glucose control is understood to prevent complications in adults with type 2 diabetes. We aimed to more precisely estimate the effects of more intensive glucose control, compared with less intensive glucose control, on the risk of microvascular events. METHODS: In this meta-analysis, we obtained de identified individual participant data from large-scale randomised controlled trials assessing the effects of more intensive glucose control versus less intensive glucose control in adults with type 2 diabetes, with at least 1000 patient-years of follow-up in each treatment group and a minimum of 2 years average follow-up on randomised treatment. The prespecified and standardised primary outcomes were kidney events (a composite of end-stage kidney disease, renal death, development of an estimated glomerular filtration rate <30 mL/min per 1.73m2, or development of overt diabetic nephropathy), eye events (a composite of requirement for retinal photocoagulation therapy or vitrectomy, development of proliferative retinopathy, or progression of diabetic retinopathy), and nerve events (a composite of new loss of vibratory sensation, ankle reflexes, or light touch). We used a random-effects model to calculate overall estimates of effect. FINDINGS: We included four trials (ACCORD, ADVANCE, UKPDS, and VADT) with 27 049 participants. 1626 kidney events, 795 eye events, and 7598 nerve events were recorded during the follow-up period (median 5.0 years, IQR 4.5-5.0). Compared with less intensive glucose control, more intensive glucose control resulted in an absolute difference of -0.90% (95% CI -1.22 to 0.58) in mean HbA1c at completion of follow-up. The relative risk was reduced by 20% for kidney events (hazard ratio 0.80, 95% CI 0.72 to 0.88; p<0.0001) and by 13% for eye events (0.87, 0.76 to 1.00; p=0.04), but was not reduced for nerve events (0.98, 0.87 to 1.09; p=0.68). INTERPRETATION: More intensive glucose control over 5 years reduced both kidney and eye events. Glucose lowering remains important for the prevention of long-term microvascular complications in adults with type 2 diabetes. FUNDING: None. PMID- 28365412 TI - Tightening our understanding of intensive glycaemic control. PMID- 28365413 TI - Ultra-performance liquid chromatography tandem mass spectrometry for determination of Direct Acting Antiviral drugs in human liver fine needle aspirates. AB - An ultra-performance liquid chromatography with triple quadrupole mass spectrometry method was developed and validated for the determination of direct acting antiviral drug concentrations in human liver fine needle aspirates. Liver fine needle aspirate (FNA) biopsy samples were homogenized in acetonitrile to stabilize the analytes and precipitate protein. The acetonitrile supernatants were diluted with internal standards and mobile phase. Separation was achieved with a Waters Acquity BEH C18 column (50*2.1mm, 1.7um) with a gradient elution of 0.1% formic acid in water and acetonitrile. The total run time was 4.25min. Detection of analytes was achieved using electrospray ionization (positive mode) and triple quadrupole selected reaction monitoring. Standard curve concentrations ranged from 12.5 to 5000ng/mL for dasabuvir and the m1 metabolite of dasabuvir, 1.25 to 2500ng/mL for ombitasvir and ritonavir, and 5.00 to 5000ng/mL for paritaprevir. The intra- and inter-day accuracy and precision were less than 13.7% in low, medium, and high quality control samples. The validated method was applied to the analysis of a liver fine needle aspirate of a patient undergoing direct acting antiviral therapy for hepatitis C virus. PMID- 28365414 TI - Impact of sample extraction on the accurate measurement of progesterone in human serum by liquid chromatography tandem mass spectrometry. AB - In the present study, the impact of the extraction solvent on the accuracy of endogenous progesterone assay in human serum has been investigated using two selective reaction monitoring (SRM) transitions (315>97 & 315>109). Higher levels of noise and more interference were observed when more polar solvents were used for extraction, thus resulting in serious bias of the measured values of progesterone in serum. This is confirmed by monitoring the ion ratio of 315>97 315>109. This issue could not be easily resolved by changes in MS/MS transitions or chromatography conditions. More bias was observed with the SRM transition 315>109 for the polar solvent extraction. Hexane and 1-chlorobutane (polarity index of 0 and 1, respectively) did provide the cleanest samples with a lower noise level in the chromatograms. Moreover, the measured values of progesterone were not changed with different SRM transitions or longer retention time in search of an improved separation. Recovery tests of progesterone have been performed with 1-chlorobutane in matrices with phosphate buffered saline (PBS) 1x, PBS 1*3% bovine serum albumin (BSA), stripped serum/H2O (1:1) and unstripped serum. The recovery (70%~80%) consistency is observed not only at different levels but also in different matrices. The equivalent recovery between PBS 1x, PBS 1*3% BSA and unstripped serum shows that the impact of progesterone binding to serum proteins on the measurement accuracy can be avoided with this sample preparation procedure. No significant matrix effect on the determination of progesterone was observed with 1-chlorobutane. Within the range of 12.5 2000pg/mL, a good linearity is observed with R>0.99 and weighting factor 1/X. Bias and covariance efficiency of QCs are within 10%. With 1-chlorobutane as the extraction solvent, the concentration of progesterone was measured where the range for postmenopausal serum is 5.74~91.7pg/mL, which is well below the reported concentrations of 314 pg/mL~942pg/mL in postmenopausal serum by immunoassay-based techniques, while the range in premenopausal serum is 12.8 pg/mL~18.6ng/mL. PMID- 28365416 TI - Descending septal branch of right coronary artery: Rare, but important in hypertrophic cardiomyopathy. AB - A 54year old man with hypertrophic cardiomyopathy was evaluated for alcohol septal ablation. However there were no sizeable septal branches from the left anterior descending artery supplying the basal septum. He was found to have a rare variant, the descending septal branch from ostial right coronary artery and underwent ablation through the same. We describe our case and the relevant literature available for use of this anatomical variant in alcohol septal ablation. PMID- 28365415 TI - Immediate and short-term performance of a novel sirolimus-coated balloon during complex percutaneous coronary interventions. The FAtebenefratelli SIrolimus COated-balloon (FASICO) registry. AB - BACKGROUND AND PURPOSES: Drug-coated balloons (DCB) currently represent an alternative to drug-eluting stents (DES) for the treatment of in-stent restenosis and they are also variably used for small coronary vessel and bifurcation lesion management. All DCB variably elute paclitaxel as an anti-proliferative drug. The first sirolimus coated balloon (SCB) received the CE mark in 2016, but its clinical performance has not been shown yet. METHODS AND RESULTS: FASICO in an all-comer registry of the first consecutive patients with at least one lesion treated with SCB between March and July 2016 at the first European centre that used this device. All patients were prospectively enrolled in a dedicated database. Primary endpoint was procedural success; co-primary endpoint was the rate of major adverse cardiac events at short-term follow-up. The 32 patients (34 lesions) enrolled had at least 6-month clinical follow up available. Forty-five percent had diabetes and indication to PCI was ISR in 47% of the cases. Lesions were always pre-dilated and device deployment was successful in all the cases. Procedural success was achieved in 100% of patients. We observed 3 cases of TLR at follow-up. CONCLUSIONS: SCB shows high immediate technical performance and adequate short-term efficacy and safety. The ongoing EASTBOURNE registry will shed light on mid-and long-term performance of this device in an adequately powered population. PMID- 28365417 TI - Fullerenol inhibits the cross-talk between bone marrow-derived mesenchymal stem cells and tumor cells by regulating MAPK signaling. AB - The interaction between bone marrow-derived mesenchymal stem cells (BDMSCs) and tumor cells promotes tumor proliferation and metastasis. We found that 4T1 breast cancer cells induced malignant differentiation of BDMSCs and that BDMSCs also affected the growth and metastasis of 4T1 cells. However, when the interaction between BDMSCs and 4T1 cells was attenuated or blocked by C60(OH)22 nanoparticles, tumor growth and metastasis were significantly suppressed. The suppression of metastasis depended on the activation of MAPK signals in the BDMSCs, whereas the underlying pathways were related to a broad range of extracellular responses and were modulated by the secretion of multiple cytokines. Interestingly, C60(OH)22 regulated the malignantly differentiated BDMSCs via the Erk- and p38-MAPK and its downstream NF-kappaB signal pathway, but in normal BDMSCs regulation occurred only through Erk- and p38-MAPK and not by NF kappaB activation. This study may provide a novel mechanism for C60(OH)22 nanoparticles as an anti-tumor drug. PMID- 28365418 TI - Higher functionality of extracellular vesicles isolated using size-exclusion chromatography compared to ultracentrifugation. AB - Extracellular vesicles (EVs) are nano-sized, lipid bilayer-enclosed particles involved in intercellular communication. EVs are increasingly being considered as drug delivery vehicles or as cell-free approach to regenerative medicine. However, one of the major challenges for their clinical application is finding a scalable EV isolation method that yields functional EVs. Although the golden standard for EV isolation is ultracentrifugation (UC), a recent study suggested that isolation using size-exclusion chromatography (SEC) yielded EVs with more intact biophysical properties. Whether this also leads to differences in functionality remained to be investigated. Therefore, we investigated possible differences in functionality of cardiomyocyte progenitor cell-derived EVs isolated using UC and SEC. Western blot analysis showed higher pERK/ERK ratios in endothelial cells after stimulation with SEC-EVs compared to UC-EVs, indicating that SEC-EVs bear higher functionality. Therefore, we propose to use SEC-EVs for further investigation of EVs' therapeutic potential. Further optimization of isolation protocols may accelerate clinical adoption of therapeutic EVs. PMID- 28365419 TI - Mindcontrol: A web application for brain segmentation quality control. AB - Tissue classification plays a crucial role in the investigation of normal neural development, brain-behavior relationships, and the disease mechanisms of many psychiatric and neurological illnesses. Ensuring the accuracy of tissue classification is important for quality research and, in particular, the translation of imaging biomarkers to clinical practice. Assessment with the human eye is vital to correct various errors inherent to all currently available segmentation algorithms. Manual quality assurance becomes methodologically difficult at a large scale - a problem of increasing importance as the number of data sets is on the rise. To make this process more efficient, we have developed Mindcontrol, an open-source web application for the collaborative quality control of neuroimaging processing outputs. The Mindcontrol platform consists of a dashboard to organize data, descriptive visualizations to explore the data, an imaging viewer, and an in-browser annotation and editing toolbox for data curation and quality control. Mindcontrol is flexible and can be configured for the outputs of any software package in any data organization structure. Example configurations for three large, open-source datasets are presented: the 1000 Functional Connectomes Project (FCP), the Consortium for Reliability and Reproducibility (CoRR), and the Autism Brain Imaging Data Exchange (ABIDE) Collection. These demo applications link descriptive quality control metrics, regional brain volumes, and thickness scalars to a 3D imaging viewer and editing module, resulting in an easy-to-implement quality control protocol that can be scaled for any size and complexity of study. PMID- 28365420 TI - Cleaning up the fMRI time series: Mitigating noise with advanced acquisition and correction strategies. PMID- 28365421 TI - Quantitative validation of a nonlinear histology-MRI coregistration method using generalized Q-sampling imaging in complex human cortical white matter. AB - Advanced diffusion MRI methods have recently been proposed for detection of pathologies such as traumatic axonal injury and chronic traumatic encephalopathy which commonly affect complex cortical brain regions. However, radiological pathological correlations in human brain tissue that detail the relationship between the multi-component diffusion signal and underlying pathology are lacking. We present a nonlinear voxel based two dimensional coregistration method that is useful for matching diffusion signals to quantitative metrics of high resolution histological images. When validated in ex vivo human cortical tissue at a 250*250*500 MUm spatial resolution, the method proved robust in correlations between generalized q-sampling imaging and histologically based white matter fiber orientations, with r=0.94 for the primary fiber direction and r=0.88 for secondary fiber direction in each voxel. Importantly, however, the correlation was substantially worse with reduced spatial resolution or with fiber orientations derived using a diffusion tensor model. Furthermore, we have detailed a quantitative histological metric of white matter fiber integrity termed power coherence capable of distinguishing architecturally complex but intact white matter from disrupted white matter regions. These methods may allow for more sensitive and specific radiological-pathological correlations of neurodegenerative diseases affecting complex gray and white matter. PMID- 28365423 TI - Evaluation of theranostic nanocarriers for near-infrared imaging and photodynamic therapy on human prostate cancer cells. AB - This paper evaluates how effectively chloroaluminum phthalocyanine (ClAlPc) entrapped in colloidal nanocarriers, such as nanocapsule (NC) and nanoemulsion (NE), induces photodamage in human prostate cancer cells (LNCaP) during photodynamic therapy (PDT). The MTT cell viability assay showed that both ClAlPc NC and ClAlPc-NE induced phototoxicity and efficiently killed LNCaP cells at low ClAlPc-NC and ClAlPc-NE concentrations (0.3MUgmL-1) as well as under low light doses of 4Jcm-2 and 7Jcm-2, respectively, upon PDT with a 670-nm diode laser line. Confocal imaging studies indicated that ClAlPc-NC and ClAlPc-NE were preferentially localized in the perinuclear region of LNCaP cells both in the dark and upon irradiation with laser light. After PDT treatment, ClAlPc-NC treated LNCaP cells exhibited a higher green fluorescence signal, possibly due to the larger shrinkage of the actin cytoskeleton, compared to ClAlPc-NE-treated LNCaP cells. Additionally, ClAlPc-NC or ClAlPc-NE and mitochondria showed a relatively high co-localization level. The cellular morphology did not change in the dark, but confocal micrographs recorded after PDT revealed that LNCaP cells treated with ClAlPc-NC or ClAlPc-NE underwent morphological alterations. Our preliminary in vitro studies reinforced the hypothesis that biocompatible theranostic ClAlPc-loaded nanocarriers could act as an attractive photosensitizer system in PDT and could serve as an interesting molecular probe for the early diagnosis of prostate cancer and other carcinomas. PMID- 28365424 TI - Drug nanocarriers for cancer chemotherapy based on microemulsions: The case of Vemurafenib analog PLX4720. AB - Oil-in-water (O/W) microemulsions based on Tween 80 as the emulsifier and triacetin as the dispersed oil phase were formulated to be used as delivery vehicles of Vemurafenib analog PLX4720. PLX4720 is a lipophilic antitumor drug against various cancer types correlated with the BRAFV600E mutation. The limits of the single-phase region corresponding to O/W microemulsions as described by ternary phase diagrams were examined. Droplet size measurements determined by dynamic light scattering (DLS) showed mean droplet diameters equal to 10+/-0.1nm both in the presence and in absence of the drug. Cryogenic-transmission electron microscopy (Cryo-TEM) images of the microemulsions showed the existence of small structures with uniform size distribution having also average diameters of approximately 10nm. Electron paramagnetic resonance (EPR) spectroscopy applying the spin probing technique confirmed PLX4720 location in the oil cores excluding its participation in the surfactants monolayer. Furthermore, cell viability assays on colon cancer cell lines Colo-205 and HT29 showed that microemulsions did not exhibit any cytotoxicity when added in ratios between 0.005% v/v and 0.2% v/v. When the cells were treated with encapsulated PLX4720 at two different concentrations (0.063 and 0.12MUMU) the same response as when dissolved in classic DMSO was observed. PMID- 28365422 TI - Mechanisms of the cyclic nucleotide cross-talk signaling network in cardiac L type calcium channel regulation. AB - Regulation of L-type Calcium (Ca2+) Channel (LCC) gating is critical to shaping the cardiac action potential (AP) and triggering the initiation of excitation contraction (EC) coupling in cardiac myocytes. The cyclic nucleotide (cN) cross talk signaling network, which encompasses the beta-adrenergic and the Nitric Oxide (NO)/cGMP/Protein Kinase G (PKG) pathways and their interaction (cross talk) through distinctively-regulated phosphodiesterase isoenzymes (PDEs), regulates LCC current via Protein Kinase A- (PKA) and PKG-mediated phosphorylation. Due to the tightly-coupled and intertwined biochemical reactions involved, it remains to be clarified how LCC gating is regulated by the signaling network from receptor to end target. In addition, the large number of EC coupling related phosphorylation targets of PKA and PKG makes it difficult to quantify and isolate changes in L-type Ca2+ current (ICaL) responses regulated by the signaling network. We have developed a multi-scale, biophysically-detailed computational model of LCC regulation by the cN signaling network that is supported by experimental data. LCCs are modeled with functionally distinct PKA- and PKG-phosphorylation dependent gating modes. The model exhibits experimentally observed single channel characteristics, as well as whole-cell LCC currents upon activation of the cross-talk signaling network. Simulations show 1) redistribution of LCC gating modes explains changes in whole-cell current under various stimulation scenarios of the cN cross-talk network; 2) NO regulation occurs via potentiation of a gating mode characterized by prolonged closed times; and 3) due to compensatory actions of cross-talk and antagonizing functions of PKA- and PKG-mediated phosphorylation of LCCs, the effects of individual inhibitions of PDEs 2, 3, and 4 on ICaL are most pronounced at low levels of beta adrenergic stimulation. Simulations also delineate the contribution of the following two mechanisms to overall LCC regulation, which have otherwise been challenging to distinguish: 1) regulation of PKA and PKG activation via cN cross talk (Mechanism 1); and 2) LCC interaction with activated PKA and PKG (Mechanism 2). These results provide insights into how cN signals transduced via the cN cross-talk signaling network are integrated via LCC regulation in the heart. PMID- 28365425 TI - Extracellular polymeric substances dependence of surface interactions of Bacillus subtilis with Cd2+ and Pb2+: An investigation combined with surface plasmon resonance and infrared spectra. AB - Microbial extracellular polymeric substances (EPS) play an important role in resisting the shock load of toxic contaminants to microbial aggregates. In order to investigate the surface interaction process of bacteria with heavy metals, in this work, the kinetics and affinity of heavy metal (CdCl2 and PbCl2) binding on Bacillus subtilis with EPS and without EPS were determined using in situ surface plasmon resonance. The binding mechanism between bacteria (with EPS and without EPS) and heavy metals was probed using Fourier-transform infrared spectra. The effect of heavy metals on aggregations of microbial cells with EPS and without EPS was investigated. The results showed that both the binding of Pb2+ and Cd2+ to bacteria with EPS had a similar kinetics process, however Pb2+ bound to bacterial surface without EPS more firmly compared with Cd2+. From our results we theorized that heavy metals changed the protein secondary structures of bacteria without EPS protection, that EPS reduced the influence of heavy metals on microbial aggregation, and that Pb2+ inhibited cell aggregation more easily compared with Cd2+ in the absence of EPS. PMID- 28365427 TI - Classification of maltreatment-related mortality by Child Death Review teams: How reliable are they? AB - Accurate estimation of the incidence of maltreatment-related child mortality depends on reliable child fatality review. We examined the inter-rater reliability of maltreatment designation for two Alaskan Child Death Review (CDR) panels. Two different multidisciplinary CDR panels each reviewed a series of 101 infant and child deaths (ages 0-4 years) in Alaska. Both panels independently reviewed identical medical, autopsy, law enforcement, child welfare, and administrative records for each death utilizing the same maltreatment criteria. Percent agreement for maltreatment was 64.7% with a weighted Kappa of 0.61 (95% CI 0.51, 0.70). Across maltreatment subtypes, agreement was highest for abuse (69.3%) and lowest for negligence (60.4%). Discordance was higher if the mother was unmarried or a smoker, if residence was rural, or if there was a family history of child protective services report(s). Incidence estimates did not depend on which panel's data were used. There is substantial room for improvement in the reliability of CDR panel assessment of maltreatment related mortality. Standardized decision guidance for CDR panels may improve the reliability of their data. PMID- 28365426 TI - Rapid separation of bacteria from blood - Chemical aspects. AB - To rapidly diagnose infectious organisms causing blood sepsis, bacteria must be rapidly separated from blood, a very difficult process considering that concentrations of bacteria are many orders of magnitude lower than concentrations of blood cells. We have successfully separated bacteria from red and white blood cells using a sedimentation process in which the separation is driven by differences in density and size. Seven mL of whole human blood spiked with bacteria is placed in a 12-cm hollow disk and spun at 3000rpm for 1min. The red and white cells sediment more than 30-fold faster than bacteria, leaving much of the bacteria in the plasma. When the disk is slowly decelerated, the plasma flows to a collection site and the red and white cells are trapped in the disk. Analysis of the recovered plasma shows that about 36% of the bacteria is recovered in the plasma. The plasma is not perfectly clear of red blood cells, but about 94% have been removed. This paper describes the effects of various chemical aspects of this process, including the influence of anticoagulant chemistry on the separation efficiency and the use of wetting agents and platelet aggregators that may influence the bacterial recovery. In a clinical scenario, the recovered bacteria can be subsequently analyzed to determine their species and resistance to various antibiotics. PMID- 28365428 TI - Effectiveness of manualized case management on utilization of evidence-based treatments for children and adolescents after maltreatment: A randomized controlled trial. AB - : The objective of this study was to compare structured case management (CM) to usual care (UC) for helping victims of child abuse and neglect (CAN) with mental disorders access evidence-based treatment (EBT). N=121 children and adolescents aged 4-17 with a history of CAN and a current mental disorder were recruited in three German states in a multi-center parallel group trial. They were randomly assigned, stratified by study site and level of psychosocial functioning, to receive CM additionally to UC or only UC. CM was delivered by trained professionals and volunteers, most of them affiliated to local child welfare agencies or NGOs. UC comprised child welfare services typically delivered in Germany. The primary outcome was EBT utilization after 6 months. Secondary outcome was the time until commencement of EBT. Outcomes were determined by semi structured clinical interviews with assessors blinded to group allocation. Predictors of access to EBT and barriers to utilization of treatment were analyzed. The intent to treat analysis showed that after 6 months 23 of 60 participants recruited to CM (38%) and 19 of 61 participants recruited to UC (31%) were using EBT, chi2 (1, N=121)=0.689, p=.261. Female gender, out-of-home placement, and home state were significant predictors of access to EBT. Less than 40% of participants across both groups were successfully referred to EBT. Access to EBT seems to be in part due to system-level barriers, namely lack of implementation of EBT in community settings. TRIAL REGISTRATION: DRKS00003979 German Clinical Trials Register. PMID- 28365429 TI - An unusual occurrence of plasmid-mediated blaOXA-23 carbapenemase in clinical isolates of Escherichia coli from India. AB - The blaOXA-23 group was considered as the first group of OXA-type beta-lactamases conferring carbapenem resistance and has been reported worldwide in Acinetobacter baumannii, however their presence in Escherichia coli is very rare and unique. This study describes an unusual occurrence of blaOXA-23 in 14 clinical isolates of E. coli obtained from intensive care unit patients admitted to a tertiary referral hospital in India. The blaOXA-23 gene was found located within a self conjugative plasmid of IncFrepB and IncK incompatibility types and simultaneously carrying blaCTX-M-15, blaVEB-1, blaPER-1 and/or blaNDM-1. The copy number of blaOXA-23 within the IncK-type plasmid was inversely proportional to increasing concentrations of imipenem, whereas in the case of the IncFrepB-type the result was variable; and increased copy number of the IncK-type plasmid was observed with increasing concentrations of meropenem. Plasmids encoding blaOXA-23 could be successfully eliminated after single treatment and were found to be not highly stable, as complete loss of plasmids was observed within 5-10 days. This study emphasises that carbapenem stress invariably altered the copy number of two different Inc type plasmids encoding the blaOXA-23 resistance gene and also highlights a potential threat of clonal expansion of this class D carbapenemase through a heterologous host in this country, which is in second incidence globally. PMID- 28365431 TI - Non-inferiority of colistin compared with standard care for the treatment of ventilator-associated pneumonia. AB - This study examined the literature on the treatment of ventilator-associated pneumonia (VAP) using colistin or standard care (SC). Based on this clinical material, a meta-analysis was conducted and a non-inferiority test was performed. Studies were selected for inclusion based on the following criteria: (a) patients with VAP; (b) experimental arm based on intravenous or aerosolized colistin; and (c) control arm based on SC. The meta-analysis employed a fixed-effect model, and the endpoint was the rate of clinical response. No pre-specified non-inferiority threshold for the upper boundary of the 95% confidence interval was adopted; instead, the intention was to perform a retrospective evaluation of whether the threshold suggested by the results was acceptable on clinical grounds. In total, eight controlled studies were included. The pooled risk ratio was 1.019 for colistin compared with SC (95% confidence interval 0.895-1.16); this result corresponds to a non-significant 1.9% increase in cure rate with colistin compared with SC (range +16% to -10.5%). Heterogeneity was minimal (0%). The post hoc non-inferiority threshold for colistin compared with SC was -10.5% in terms of relative cure rate (pooled risk ratio = 0.895). This margin was considered to be acceptable on clinical grounds. This analysis found that colistin can play a role in the treatment of VAP, particularly when given as a combination of aerosolized and intravenous drug. PMID- 28365430 TI - Old antimicrobials and Gram-positive cocci through the example of infective endocarditis and bone and joint infections. AB - The management of some serious infections such as infective endocarditis (IE) and bone and joint infections (BJIs) caused by Gram-positive cocci (GPC) is complex and requires great responsiveness and effective antimicrobials with high bioavailability in heart valves or bone tissues. Treatment of these infections requires the use of a higher dosage that may result in increased toxicity or the use of new promising antimicrobials to control the infection. However, use of these new antimicrobials could still bring about new toxicity and resistance. Another approach may be the 'comeback' of old antimicrobials, which is evaluated in this review in the treatment of IE and BJIs caused by GPC. PMID- 28365432 TI - Long-Term Outcome of Brachial Plexus Reimplantation After Complete Brachial Plexus Avulsion Injury. AB - BACKGROUND: Complete brachial plexus avulsion injury is a severe disabling injury due to traction to the brachial plexus. Brachial plexus reimplantation is an emerging surgical technique for the management of complete brachial plexus avulsion injury. OBJECTIVE: We assessed the functional recovery in 15 patients who underwent brachial plexus reimplantation surgery after complete brachial plexus avulsion injury with clinical examination and electrophysiological testing. METHODS: We included all patients who underwent brachial plexus reimplantation in our institution between 1997 and 2010. Patients were assessed with detailed motor and sensory clinical examination and motor and sensory electrophysiological tests. RESULTS: We found that patients who had reimplantation surgery demonstrated an improvement in Medical Research Council power in the deltoid, pectoralis, and infraspinatous muscles and global Medical Research Council score. Eight patients achieved at least grade 3 MRC power in at least one muscle group of the arm. Improved reinnervation by electromyelography criteria was found in infraspinatous, biceps, and triceps muscles. There was evidence of ongoing innervation in 3 patients. Sensory testing in affected dermatomes also showed better recovery at C5, C6, and T1 dermatomes. The best recovery was seen in the C5 dermatome. CONCLUSIONS: Our results demonstrate a definite but limited improvement in motor and sensory recovery after reimplantation surgery in patients with complete brachial plexus injury. We hypothesize that further improvement may be achieved by using regenerative cell technologies at the time of repair. PMID- 28365433 TI - Percutaneous Endoscopic Cervical Discectomy (PECD): An Analysis of Outcome, Causes of Reoperation. AB - OBJECTIVE: Percutaneous endoscopic cervical discectomy (PECD) is regarded as an effective treatment modality in cervical disc herniation, including radicular pain and lateral location of disc herniation. This study aimed to evaluate the clinical and radiologic outcomes of PECD along with the causes of reoperation and the technique itself. METHODS: Between January 2007 and November 2012, 101 patients underwent PECD at the Busan Wooridul Hospital. Three patients underwent a 2-level PECD. The mean follow-up period was 34 months (range, 18-72 months). The mean age was 46.1 years; the most common operation was at the C5-C6 level (n = 45), followed by C6-C7 (n = 35), C4-C5 (n = 16), and C3-C4 (n = 8). The clinical outcomes were evaluated via the visual analog scale of the neck and arm according to the Neck Disability Index and the modified Macnab criteria. Among 101 patients, 12 underwent an additional operation at the index level. Five patients had aggravated stenosis by disc height narrowing, 4 had recurred disc, 2 had remained disc, and 1 had sustained symptoms. RESULTS: After PECD, there was a significant improvement in the visual analog scale and Neck Disability Index scores (P < 0.001). According to the modified Macnab criteria, excellent concordance was achieved in 65 patients, good in 22, fair in 2, and poor in 12. The reoperation performed on 12 patients improved their clinical outcomes. The mean duration was 4.8 months (2 days to 18 months) until reoperation. There were 3 PECD revisions, 3 artificial disc replacements, 2 corpectomies, 2 anterior cervical discectomies and fusion with cages, and 2 transfers to another hospital. The common feature was older age (P = 0.016) and male sex (P = 0.031). Preoperative radiologic findings were characterized by the foraminal disc (P = 0.04), disc degeneration at the index level (P = 0.05), combined bony spur (P = 0.001), concomitant adjacent level degeneration (P = 0.019), cervical kyphosis (P = 0.015), and segmental angle deterioration after PECD (P = 0.038). No statistical correlation was seen between the operation level and herniation size (P > 0.05). CONCLUSIONS: In total, 87% patients showed successful clinical outcome. Poor and fair outcomes at initial PECD were overcome by revision surgery, which improved outcomes. Although PECD is a promising minimally invasive procedure for cervical disc treatment, the indications for PECD should be considered carefully. PMID- 28365434 TI - Ultra-Early Angiographic Vasospasm After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: After aneurysmal subarachnoid hemorrhage (aSAH), prognosis is affected heavily by the presence of delayed cerebral ischemia (DCI). There is growing recognition of ultra-early angiographic vasospasm (UEAV) occurring within 48 hours of aSAH; however, its relationship with DCI and ultimately prognosis remains unclear. METHODS: Various databases limited to the English language through September 2016 were searched systematically. Eligible studies were those comparing UEAV with control non-UEAV outcomes and follow-up. Two independent reviewers evaluated the quality of studies and abstracted the data, with discrepancies resolved by a third. We calculated odds ratios (ORs) and 95% confidence intervals for all outcomes by using random-effects meta-analyses and performed a heterogeneity analysis. RESULTS: Four comparative studies were selected for analysis. Pooled analysis demonstrated that UEAV compared with no UEAV was associated with greater proportion of rupture aneurysms sized greater than 12 mm (38.3% vs. 24.3%, P < 0.00001). A significantly greater number of patients with UEAV had ruptured MCA aneurysms compared with patients without UEAV (29.7% vs. 19.9%, P = 0.005). Compared with no-UEAV, patients with UEAV were significantly associated with symptomatic cerebral vasospasm (OR 2.07, P = 0.05) and DCI/infarction (OR 2.52, P = 0.02). A significant association also was found between UEAV and an unfavorable outcome at follow-up (OR 1.64, P = 0.03) and greater mortality (OR 2.65, P < 0.00001). CONCLUSIONS: UEAV was significantly associated with symptomatic cerebral vasospasm, DCI/infarction, unfavorable outcome at follow-up, and greater mortality. Patients with intracerebral hematoma, intraventricular hemorrhage (Fisher Grade IV), larger ruptured aneurysms >12 mm, and an MCA location were more likely to have UEAV. PMID- 28365435 TI - A DFT/B3LYP study of the mechanisms of the O2 formation reaction catalyzed by the [(terpy)(H2O)MnIII(O)2MnIV(OH2)(terpy)](NO3)3 complex: A paradigm for photosystem II. AB - We present a theoretical study of the reaction pathway for dioxygen molecular formation catalyzed by the [(terpy)(H2O)MnIII(O)2MnIV(OH2) (terpy)](NO3)3 (terpy=2,2':6',2"-terpyridine) complex based on DFT-B3LYP calculations. In the initial state of the reaction, a partial oxido radical (0.44 spins) is formed ligated to Mn. This radical is involved in a nucleophylic attack by bulk water in the OO bond reaction formation step, in which the oxido fractional unpaired electron is delocalized toward the outermost Mn of the MU-oxo bridge, instead of the ligated Mn center. The reaction then follows with a series of proton-coupled electron transfer steps, in which the oxidation state, as well as the bond strength of the OO moiety increase, while the OOMn(1) bond gets weaker until O2 is released. In this model, basic acetate ions from the buffer solution capture protons in the proton-transfer steps. In each step there is reduction of the OOMn(1) binding strength, with concomitant increase of the OO bond strength, which culminates with the release of O2 in the last step. This last step is entropy driven, while formation of hydroperoxide and superoxide moieties is enthalpy driven. According with experiments, the rate-limiting step is the double oxidation of Mn(IV,III) or peroxymonosulfate binding, which occur prior to the OO bond formation step. This supports our findings that the barriers of all intermediate steps are below the experimental barrier of 19-21kcal/mol. The implications of these findings for understanding photosynthetic water-splitting catalysis are also discussed. PMID- 28365436 TI - Longan seed and peel as environmentally friendly corrosion inhibitor for mild steel in acid solution: Experimental and theoretical studies. AB - Longan seed and peel were extracted and used for impeding the corrosion of mild steel in hydrochloric acid solution. Experimental analyses indicate that the water extract of Longan's seed and peel, a mixed type inhibitor, can be chemically adsorbed onto the steel surface, and its inhibition effect rises with increasing extract concentration. To understand the adsorption mechanism and the contributions of the four main compounds of the extract to corrosion protection effect, quantum chemical methods and infrared spectrum were also employed. Theoretically, four main antioxidant compounds were regarded as effective components in the water extract of Longan's seed and peel. PMID- 28365437 TI - Alkyl-imidazolium based organosilica supported Fe/porphyrin complex: As novel, highly efficient and reusable catalyst for the unsymmetrical Hantzsch reaction. AB - A noble alkyl-imidazolium ionic liquid based organosilica supported Fe/meso tetrakis(4-sulfonatophenyl)porphyrin complex (ILOS@Fe/TSPP) is prepared, characterized and its catalytic efficiency is studied in the unsymmetrical Hantzsch reaction. The ILOS@Fe/TSPP was prepared by hydrolysis and co condensation of 1,3-bis(3-trimethoxysilylpropyl)imidazolium chloride under acidic conditions followed by treatment with Fe/meso-tetrakis(4 sulfonatophenyl)porphyrin complex at ambient temperature. The material was characterized with TGA, EDX, SEM, TEM, XRD and DRIFT analyses. The ILOS@Fe/TSPP was successfully applied as powerful catalyst in the Hantzsch reaction for the preparation of a set of different derivatives of polyhydroquinolines in high to excellent yields. This catalyst was recovered and reused several times without important decrease in its activity. Furthermore, compared to the classical studies, this study consistently demonstrated the advantages of low catalyst loading, free-solvent media, short reaction times and simple purification of products. PMID- 28365438 TI - Simple one-pot aqueous synthesis of AuPd alloy nanocrystals/reduced graphene oxide as highly efficient and stable electrocatalyst for oxygen reduction and hydrogen evolution reactions. AB - Herein, we develop a simple one-pot aqueous method to prepare AuPd alloy nanocrystals on reduced graphene oxide (AuPd NCs/rGO), by using 1-acetyl-4-(p hydroxyphenyl) piperazine (AHPP) as the reductant, stabilizing agent and structure-director, without any other additives (e.g., seed, surfactant or polymer). The product is mainly characterized by transmission electron microscopy, X-ray photoelectron spectroscopy, X-ray diffraction and thermogravimetric analysis. The obtained AuPd NCs/rGO displays enlarged electrochemically active surface area and superior catalytic performances toward oxygen reduction reaction (ORR) and hydrogen evolution reaction (HER) relative to Pt/C, Pd/C, Pd/rGO and Au/rGO catalysts, showing promising applications in energy storage and conversion. PMID- 28365439 TI - Nickel-cobalt hydroxide nanosheets: Synthesis, morphology and electrochemical properties. AB - This paper reports the synthesis, characterization, and electrochemical performance of nickel-cobalt hydroxide nanosheets. The hydroxide nanosheets of approximately 0.7nm thickness were prepared by delamination of layered nickel cobalt hydroxide lactate in water and formed transparent colloids that were stable for months. The nanosheets were deposited on highly oriented pyrolytic graphite by spin coating, and their electrochemical behavior was investigated by cyclic voltammetry in potassium hydroxide electrolyte. Our method of electrode preparation allows for studying the electrochemistry of nanosheets where the majority of the active centers can participate in the charge transfer reaction. The observed electrochemical response was ascribed to mutual compensation of the cobalt and nickel response via electron sharing between these metals in the hydroxide nanosheets, a process that differentiates the behavior of nickel-cobalt hydroxide nanosheets from single nickel hydroxide or cobalt hydroxide nanosheets or their physical mixture. The presence of cobalt in the nickel-cobalt hydroxide nanosheets apparently decreases the time of electrochemical activation of the nanosheet layer, which for the nickel hydroxide nanosheets alone requires more potential sweeps. PMID- 28365440 TI - Evaluate the effects of long-term valproic acid treatment on metabolic profiles in newly diagnosed or untreated female epileptic patients: A prospective study. AB - PURPOSE: Excessive weight gain associated with sodium valproate (VPA) may predispose patients with epilepsy to other health problems such as insulin resistance. We prospectively evaluated the long-term impact of VPA monotherapy compared with lamotrigine (LTG) monotherapy on anthropometric and metabolic parameters in women with epilepsy. Our primary objective is to understand the underlying mechanism responsible for VPA-induced obesity. METHODS: Sixty-six female patients with newly diagnosed or untreated epilepsy were included in the study. Thirty-four patients with VPA and thirty-two patients with LTG were treated for a period of one year in our center. Anthropometric and clinical data were collected at 5 time points: before, at 6th week, 3rd month, 6th month, 9th month and 12th month (last visit). Biochemical and hormonal data were collected 2 time points: before and last visit. RESULTS: Subjects in the VPA group had significantly higher body weight than LTG-treated subjects (64.88+/-3.25 vs. 58.28+/-2.43, P<0.001). HOMA-IR level was significantly increased (2.76 vs. 1.35, P<0.05), and adiponectin levels were significantly lower in the VPA group (3.46 vs. 6.22, P<0.05). Triglycerides levels were significantly increased (118 vs. 96, P<0.05), and HDL-C levels were significantly lower in the VPA group. Both the VPA treated group and the LTG-treated group showed no significant difference in term of total cholesterol, LDL-C, fasting blood glucose and serum leptin levels. CONCLUSIONS: Based on the findings of this study, we proposed that VPA induced hypoadiponectinemia which correlates significantly with insulin resistance. These two factors may be responsible for weight gain, possible by stimulating appetite. Valproic acid appears to be use cautionally in obese females with epilepsy. PMID- 28365441 TI - The multi-site docking protein Gab1 is constitutively phosphorylated independent from its recruitment to the plasma membrane in Jak2-V617F-positive cells and mediates proliferation of human erythroleukaemia cells. AB - The constitutively active Janus kinase 2 mutant Jak2-V617F is responsible for cytokine-independent growth of hematopoietic cells and the development of myeloproliferative neoplasms, such as polycythaemia vera and essential thrombocythaemia. Cells expressing Jak2-V617F exhibit constitutive STAT, MAPK, and PI3K signalling, and constitutive association of the multi-site docking protein Gab1 to PIP3 at the plasma membrane. Here, we demonstrate the crucial role of Gab1 for the proliferation of Jak2-V617F-positive human erythroleukaemia (HEL) cells. In Jak2-V617F-expressing cells Gab1 is constitutively phosphorylated by Erk1/2 on serine residue 552, which regulates binding to PIP3. Additionally, Gab1 is constitutively phosphorylated on tyrosine residue 627. Tyrosine 627 is a SHP2 binding site and required for Gab1-dependent Erk1/2 activation. As previously shown, Jak2-V617F-dependent Erk1/2 and PI3K activation act synergistically on the proliferation of Jak2-V617F-positive cells. Here, we examined whether constitutive membrane association of Gab1 explains cytokine independent Gab1 phosphorylation in Jak2-V617F-expressing cells. Although we could demonstrate Jak2-V617F-dependent constitutive serine 552 and tyrosine 627 phosphorylation of Gab1, interestingly, both phosphorylations do not require binding of Gab1 to PIP3 at the plasma membrane. Instead, we observed a constitutive interaction of Gab1 with the erythropoietin receptor in Jak2-V617F expressing cells, which depends on Janus kinase activity. Thus, constitutive Gab1 dependent signalling in Jak2-V617F-expressing cells does not occur due to the constitutive association of Gab1 with PIP3 at the plasma membrane. PMID- 28365442 TI - Loss of Cln3 impacts protein secretion in the social amoeba Dictyostelium. AB - Neuronal ceroid lipofuscinosis (NCL), also referred to as Batten disease, is the most common form of childhood neurodegeneration. Mutations in CLN3 cause the most prevalent subtype of the disease, which manifests during early childhood and is currently untreatable. The precise function of the CLN3 protein is still not known, which has inhibited the development of targeted therapies. In the social amoeba Dictyostelium discoideum, loss of the CLN3 homolog, Cln3, reduces adhesion during early development, which delays streaming and aggregation. The results of the present study indicate that this phenotype may be at least partly due to aberrant protein secretion in cln3- cells. It is well-established that Cln3 localizes primarily to the contractile vacuole (CV) system in Dictyostelium, and to a lesser extent, compartments of the endocytic pathway. Intriguingly, the CV system has been linked to the secretion of proteins that do not contain a signal peptide for secretion (i.e., unconventional protein secretion). Proteins that do contain a signal peptide are secreted via a conventional mechanism involving the endoplasmic reticulum, transport through the Golgi, and secretion via vesicle release. In this study, Cln3 was observed to co-localize with the Golgi marker wheat germ agglutinin suggesting that Cln3 participates in both secretion mechanisms. Chimeras of wild-type (WT) and cln3- cells displayed delayed streaming and aggregation, and interestingly, cln3- cells starved in conditioned media (CM) harvested from starving WT cells showed near normal timing of streaming and aggregation suggesting aberrant protein secretion in Cln3-deficient cells. Based on these observations, LC-MS/MS was used to reveal the protein content of CM from starved cells (mass spectrometry data are available via ProteomeXchange with identifier PXD004897). A total of 450 proteins were detected in WT and cln3- CM, of which 3 were absent in cln3- CM. Moreover, 12 proteins that were present in cln3- CM were absent in WT CM. Label-free quantification identified 42 proteins that were present in significantly higher amounts in cln3- CM compared to WT, and 3 proteins that were present in significantly reduced amounts. A GO term enrichment analysis showed that a majority of the affected proteins are linked to endocytosis, vesicle-mediated transport, proteolysis, and metabolism. In total, the results of this study indicate that Cln3 functions in both conventional and unconventional protein secretion and that loss of Cln3 results in deregulated secretion during early development. Importantly, this is the first evidence in any system linking CLN3 function to protein secretion. PMID- 28365445 TI - Antiatherogenic potential of ezetimibe in sitosterolemia: Beyond plant sterols lowering. PMID- 28365444 TI - Persistence of Nonceliac Wheat Sensitivity, Based on Long-term Follow-up. AB - We investigated how many patients with a diagnosis of nonceliac wheat sensitivity (NCWS) still experienced wheat sensitivity after a median follow-up time of 99 months. We collected data from 200 participants from a previous study of NCWS, performed between July and December 2016 in Italy; 148 of these individuals were still on a strict wheat-free diet. In total, 175 patients (88%) improved (had fewer symptoms) after a diagnosis of NCWS; 145 of 148 patients who adhered strictly to a gluten-free diet (98%) had reduced symptoms, compared with 30 of 52 patients who did not adhere to a gluten-free diet (58%) (P < .0001). Of the 22 patients who repeated the double-blind, placebo-controlled challenge, 20 reacted to wheat. We conclude that NCWS is a persistent condition. Clinicaltrials.gov registration number: NCT02823522. PMID- 28365443 TI - Genetic Alterations in Esophageal Tissues From Squamous Dysplasia to Carcinoma. AB - BACKGROUND & AIMS: Esophageal squamous cell carcinoma (ESCC) is the most common subtype of esophageal cancer. Little is known about the genetic changes that occur in esophageal cells during the development of ESCC. We performed next generation sequence analyses of esophageal nontumor, intraepithelial neoplasia (IEN), and ESCC tissues from the same patients to track genetic changes during tumor development. METHODS: We performed whole-genome, whole-exome, or targeted sequence analyses of 227 esophageal tissue samples from 70 patients with ESCC undergoing resection at Shantou University Medical College in China from 2012 through 2015 (no patients had received chemotherapy or radiation therapy); we analyzed normal tissues, tissues with simple hyperplasia, dysplastic tissues (IEN), and ESCC tissues collected from different regions of the esophagus at the same time. We also obtained 1191 nontumor esophageal biopsy specimens from the Chaoshan region (a high-risk region for ESCC) of China (a high-risk region for ESCC) and performed immunohistochemical and histologic analyses to detect inflammation. RESULTS: IEN and ESCC tissues had similar mutations and copy number alterations, at similar frequencies; these differed from mutations detected in tissues with simple hyperplasia. IEN tissues had mutations associated with apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like mediated mutagenesis (a DNA damage mutational signature). Genetic analyses indicated that most ESCCs were formed from early stage IEN clones. Trunk mutations (mutations shared by >10% of paired IEN and ESCC tissues) were in genes that regulate DNA repair and cell apoptosis, proliferation and adhesion. Mutations in TP53 and CDKN2A and copy number alterations in 11q (contains CCND1), 3q (contains SOX2), 2q (contains NFE2L2), and 9p (contains CDKN2A) were considered to be trunk variants; these were dominant mutations detected at high frequencies in clones of paired IEN and ESCC samples. In the esophageal biopsy samples from high-risk individuals (residing in the Chaoshan region), 68.9% had an evidence of chronic inflammation; the level of inflammation was correlated with atypical cell structures and markers of DNA damage. CONCLUSIONS: We analyzed mutations and gene copy number changes in nontumor, IEN, and ESCC samples, collected from 70 patients. IEN and ESCCs each had similar mutations and markers of genomic instability, including apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like. Genomic changes observed in precancerous lesions might be used to identify patients at risk for ESCC. PMID- 28365446 TI - Comorbidity trajectories in working age cancer survivors: A national study of Swedish men. AB - BACKGROUND: A large proportion of cancer survivors are of working age, and maintaining health is of interest both for their working and private life. However, patterns and determinants of comorbidity over time among adult cancer survivors are incompletely described. We aimed to identify distinct comorbidity trajectories and their potential determinants. METHODS: In a cohort study of Swedish men born between 1952 and 1956, men diagnosed with cancer between 2000 and 2003 (n=878) were matched with cancer-free men (n=4340) and followed over five years after their first year of survival. Comorbid diseases were identified using hospital diagnoses and included in the analysis using group-based trajectory modelling. The association of socioeconomic and developmental characteristics were assessed using multinomial logit models. RESULTS: Four distinct comorbidity trajectories were identified. As many as 84% of cancer survivors remained at very low levels of comorbidity, and the distribution of trajectories was similar among the cancer survivors and the cancer-free men. Increases in comorbidity were seen among those who had comorbid disease at baseline and among those with poor summary disease scores in adolescence. Socioeconomic characteristics and physical, cognitive and psychological function were associated with types of trajectory in unadjusted models but did not retain independent relationships with them after simultaneous adjustment. CONCLUSIONS: Among working-age male cancer survivors, the majority remained free or had very low levels of comorbidity. Those with poorer health in adolescence and pre existing comorbid diseases at cancer diagnosis may, however, benefit from follow up to prevent further increases in comorbidity. PMID- 28365447 TI - Suvorexant for the treatment of primary insomnia: A systematic review and meta analysis. AB - Suvorexant is a dual orexin receptor agonist and is currently approved for the treatment of insomnia in the United States and Japan. We conducted a systematic review and meta-analysis to assess the efficacy and safety of suvorexant for the treatment of primary insomnia. We searched PubMed, EMBASE, and the Cochrane central register of controlled trials, contacted a relevant pharmaceutical company, and accessed websites of the U.S. Food and Drug Administration (FDA) and Pharmaceuticals and Medical Devices Agency (PMDA) for published and unpublished data. A total of four randomized trials involving 3076 patients with primary insomnia were included in our analysis. Our analysis suggested that suvorexant was associated with significant improvements in subjective time to sleep onset, subjective total sleep time, and subjective quality of sleep at 1 mo and 3 mo. Somnolence, fatigue, and abnormal dreams were the most common adverse effects. We concluded that suvorexant was associated with improvement in some sleep parameters and some adverse effects. To determine the place of suvorexant in the treatment of insomnia, comparative effectiveness trials are needed. PMID- 28365448 TI - Synthesis and biological activities of C-glycosides of KRN 7000 with novel ceramide residues. AB - The identification of immunoactive agents for clinical and mechanistic applications is a very active area of research. In this vein, analogues of the potent immunostimulant KRN 7000 with diverse cytokine profiles have attracted considerable attention. These compounds have been shown to activate iNKT cells via presentation by CD1d. Herein, we report on the synthesis and activity for four new C-glycosides of KRN 7000, 11-phenylundecanoyl and 11-p fluorophenylundecanoyl derivatives of C-KRN 7000, 2,3-bis-epi-C-KRN 7000 and the reverse amide of C-KRN 7000. In mice, compared to C-KRN 7000, 2,3-bis-epi-C-KRN 7000 stimulated higher release of the anti-inflammatory cytokine IL-4 and lower release of the inflammatory cytokines IFN-gamma and IL-12. The phenyl terminated alkanoyl and reverse amide analogues were inactive. These data suggest that structure activity effects for KRN 7000 are not necessarily additive and their use in the design of new analogues will require an improved understanding of how subtle structural changes impact on cytokine activity. PMID- 28365449 TI - Multicenter evaluation of an enzymatic method for glycated albumin. AB - BACKGROUND: The use of glycated albumin (GA) has been proposed as an additional glycemic control marker particularly useful in intermediate-term monitoring and in situation when HbA1c test is not reliable. METHODS: We have performed the first multicenter evaluation of the analytical performance of the enzymatic method quantILab Glycated Albumin assay implemented on the most widely used clinical chemistry analyzers (i.e. Abbott Architect C8000, Beckman Coulter AU 480 and 680, Roche Cobas C6000, Siemens ADVIA 2400 and 2400 XPT). RESULTS: The repeatability of the GA measurement (expressed as CV, %) implemented in the participating centers ranged between 0.9% and 1.2%. The within-laboratory CVs ranged between 1.2% and 1.6%. A good alignment between laboratories was found, with correlation coefficients from 0.996 to 0.998. Linearity was confirmed in the range from 7.6 to 84.7%. CONCLUSION: The new enzymatic method for glycated albumin evaluated by our investigation is suitable for clinical use. PMID- 28365450 TI - A microRNA expression profile for vascular invasion can predict overall survival in hepatocellular carcinoma. AB - BACKGROUND: The presence of vascular invasion (VI) in pathology specimens is a well-known unfavorable prognostic factor of hepatocellular carcinoma (HCC) recurrence and overall survival (OS). We investigated the vascular invasion related microRNA (miRNA) expression profiles and potential of prognostic value in HCC. METHODS: MiRNA and mRNA expression data for HCC were accessed from The Cancer Genome Atlas (TCGA). LASSO logistic regression models were used to develop a miRNA-based classifier for predicting VI. The predictive capability was accessed by area under receiver operating characteristics (AUC). Concordance index (C-index) and time-dependent receiver operating characteristic (td-ROC) were used to determine its prognostic value. We validated the predictive and prognostic accuracy of this classifier in an external independent cohort of 127 patients. Functionally relevant targets of miRNAs were determined using miRNA target prediction, experimental validation and correlation of miRNA and mRNA expression data. RESULTS: A 16-miRNA-based classifier was developed which identified VI accurately, with AUC of 0.731 and 0.727 in TCGA set and validation cohort, respectively. C-index and td-ROC showed that the classifier was able to stratify patients into risk groups strongly associated with OS. When stratified by tumor characteristics, the classifier was still a clinically and statistically significant prognostic model. The predictive and prognostic accuracy of the classifier was confirmed in validation cohort. Vascular invasion related miRNA/target pairs were identified by integrating expression patterns of predicted targets, which were validated in cell lines. CONCLUSIONS: A multi-miRNA based classifier developed based on the presence of VI, which could effectively predict OS in HCC. PMID- 28365451 TI - Genetic analysis and literature review of Chinese patients with familial renal glucosuria: Identification of a novel SLC5A2 mutation. AB - BACKGROUND: Familial renal glucosuria (FRG) is an inherited renal tubular disorder characterized by persistent isolated glucosuria with normal blood glucose. SLC5A2 gene mutation was the causative of FRG. METHODS: Molecular genetic analysis of SLC5A2 gene by Sanger sequencing was conducted in two unrelated non-consanguineous Chinese families with isolated glucosuria. Extensive laboratory test and physical examination were performed. In silico algorithms were used to explore the potential effect of novel mutation on SGLT2 function. We also summarized the reported SLC5A2 mutations in the Chinese patients with FRG. RESULTS: A novel missense mutation (c.877A>T, p.Ser293Cys) in exon 3 was detected in proband 1 with weight loss accompanying by glucosuria and in her father with normal phenotype. In family 2, a previously reported compound heterozygous mutation (c.229G>C, p.Gly77Arg; c.1540C>T, p.Pro514Ser) was identified, and her healthy parents were heterozygous mutation carriers. The p.S293C mutation was predicted to be pathogenic. No hot spot mutation was found in reported Chinese patients with FRG. CONCLUSIONS: The novel pathogenic SLC5A2 mutation p.S293C was responsible for the onset of FRG. Our study further confirmed the co-dominant inheritance trait with variable penetrance and expanded the clinical and genetic spectrum of FRG. PMID- 28365453 TI - Multireference configuration interaction study of the 27 low-lying states of the PF+ cation. AB - This paper studied the spectroscopic parameters and vibrational properties of 27 Lambda-S and 60Omega states of PF+ cation. The 27 Lambda-S states were the X2Pi, A2Sigma+, B2Pi, C2Sigma-, D2Delta, a4Sigma-, b4Pi, c4Sigma+, d4Delta, 22Sigma+, 32Sigma+, 42Sigma+, 22Sigma-, 32Sigma-, 32Pi, 42Pi, 52Pi, 62Pi, 22Delta, 32Delta, 12Phi, 24Sigma-, 34Sigma-, 24Pi, 34Pi, 16Sigma-, and 16Pi, which were generated from the first four dissociation limits. The 60Omega states were produced from the 27 Lambda-S states. All the potential energy curves were calculated with the CASSCF method, which was followed by the icMRCI+Q approach. The a4Sigma-, b4Pi, and D2Delta states were inverted with the spin-orbit coupling effect accounted for. The 24Pi, 24Sigma-, 22Delta, 32Delta, 32Sigma+, 42Sigma+, 12Phi, and 22Sigma states were repulsive whether the spin-orbit coupling effect was included or not, but the 52Pi and D2Delta states became repulsive only with the spin-orbit coupling effect included. The C2Sigma- state was very weakly bound. The a4Sigma- state had one barrier. The avoided crossings existed between the a4Sigma- and 24Sigma- states, the 22Sigma+ and 32Sigma+ states as well as the D2Delta and 22Delta states. Core-valence correlation and scalar relativistic corrections were taken into account. The extrapolation to the complete basis set limit was done. The spectroscopic parameters and vibrational properties were determined. The transition dipole moments were calculated and the Franck-Condon factors of some electric dipole transitions were evaluated. The spin-orbit coupling effect on the spectroscopic and vibrational properties was discussed. PMID- 28365454 TI - Corrigendum to "Laparoscopic totally extra-peritoneal hernia repair for bilateral Spigelian hernias and coincident inguinal hernia: A case report" [Int. J. Surg. Case Rep. 28 (2016) 169-172]. PMID- 28365452 TI - Gd2O3-doped silica @ Au nanoparticles for in vitro imaging cancer biomarkers using surface-enhanced Raman scattering. AB - There has been an interest in developing multimodal approaches to combine the advantages of individual imaging modalities, as well as to compensate for respective weaknesses. We previously reported a composite nano-system composed of gadolinium-doped mesoporous silica nanoparticle and gold nanoparticle (Gd-Au NPs) as an efficient MRI contrast agent for in vivo cancer imaging. However, MRI lacks sensitivity and is unsuitable for in vitro cancer detection. Thus, here we performed a study to use the Gd-Au NPs for detection and imaging of a widely recognized human cancer biomarker, epidermal growth factor receptor (EGFR), in individual human cancer cells with surface-enhanced Raman scattering (SERS). The Gd-Au NPs were sequentially conjugated with a monoclonal antibody recognizing EGFR and a Raman reporter molecule, 4-meraptobenzoic acid (MBA), to generate a characteristic SERS signal at 1075cm-1. By spatially mapping the SERS intensity at 1075cm-1, cellular distribution of EGFR and its relocalization on the plasma membrane were measured in situ. In addition, the EGFR expression levels in three human cancer cell lines (S18, A431 and A549) were measured using this SERS probe, which were consistent with the comparable measurements using immunoblotting and immunofluorescence. Our SERS results show that functionalized Gd-Au NPs successfully targeted EGFR molecules in three human cancer cell lines and monitored changes in single cell EGFR distribution in situ, demonstrating its potential to study cell activity under physiological conditions. This SERS study, combined with our previous MRI study, suggests the Gd-Au nanocomposite is a promising candidate contrast agent for multimodal cancer imaging. PMID- 28365455 TI - Toxic effects of polyethylene terephthalate microparticles and Di(2 ethylhexyl)phthalate on the calanoid copepod, Parvocalanus crassirostris. AB - Large amounts of plastic end up in the oceans every year where they fragment into microplastics over time. During this process, microplastics and their associated plasticizers become available for ingestion by different organisms. This study assessed the effects of microplastics (Polyethylene terephthalate; PET) and one plasticizer (Di(2-ethylhexyl)phthalate; DEHP) on mortality, productivity, population sizes and gene expression of the calanoid copepod Parvocalanus crassirostris. Copepods were exposed to DEHP for 48h to assess toxicity. Adults were very healthy following chemical exposure (up to 5120ug L-1), whereas nauplii were severely affected at very low concentrations (48h LC50value of 1.04 ng L-1). Adults exposed to sub-lethal concentrations of DEHP (0.1-0.3ug L-1) or microplastics (10,000-80,000 particles mL-1) exhibited substantial reductions in egg production. Populations were exposed to either microplastics or DEHP for 6 days with 18 days of recovery or for 24 days. Populations exposed to microplastics for 24 days significantly depleted in population size (60+/-4.1%, p<0.001) relative to controls, whilst populations exposed for only 6 days (with 18 days of recovery) experienced less severe depletions (75+/-6.0% of control, p<0.05). Populations exposed to DEHP, however, exhibited no recovery and both treatments (6 and 24 days) yielded the same average population size at the termination of the experiment (59+/-4.9% and 59+/-3.4% compared to control; p<0.001). These results suggest that DEHP may induce reproductive disorders that can be inherited by subsequent generations. Histone 3 (H3) was significantly (p<0.05) upregulated in both plastic and DEHP treatments after 6 days of exposure, but not after 18 days of recovery. Hsp70-like expression showed to be unresponsive to either DEHP or microplastic exposure. Clearly, microplastics and plasticizers pose a serious threat to zooplankton and potentially to higher trophic levels. PMID- 28365456 TI - miR-21 promotes dengue virus serotype 2 replication in HepG2 cells. AB - Infection with the mosquito transmitted dengue virus (DENV) remains a significant worldwide public health problem. While the majority of infections are asymptomatic, infection can result in a range of symptoms. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression through repression or degradation of mRNAs. To understand the contribution of miRNAs to DENV 2 replication, we screened a number of candidate miRNAs for variations in expression levels during DENV 2 infection of HepG2 (liver) cells. Seven miRNAs were identified as differentially expressed, and one, miR-21, was differentially expressed at all time points examined. Interestingly, miR-21 was also differentially regulated in DENV 2 infection under conditions of antibody dependent enhancement of infection, and in direct Zika virus infection, but not in DENV 4 infection. The role of miR-21 during DENV infection was further examined by treating HepG2 cells with an anti-miR-21 (AMO-21) before DENV infection. The results showed a significant reduction in DENV 2 production, clearly suggesting that miR-21 plays a key role in DENV 2 replication. To further confirm the role of miR-21 in DENV infection, a peptide nucleic acid-21 (PNA-21) construct with a nucleotide sequence complementary to AMO-21, was co-administered with AMO-21 as an AMO-21/PNA-21 complex followed by DENV 2 infection. The results showed that AMO-21 significantly reduced DENV 2 titer, PNA-21 significantly increased DENV 2 titer and the combined AMO-21/PNA-21 showed no difference from non-treated infection controls. Taken together, the results show that miR-21 promotes DENV 2 replication, and this mechanism could serve as a possible therapeutic intervention point. PMID- 28365458 TI - Corrigendum to "Effects of ambient temperature on stroke hospital admissions: Results from a time-series analysis of 104432 strokes in Guangzhou, China" [Sci. Total Environ. 580 (2016) 307-315]. PMID- 28365459 TI - Estimation of CO2 reduction by parallel hard-type power hybridization for gasoline and diesel vehicles. AB - The purpose of this study is to investigate possible improvements in ICEVs by implementing fuzzy logic-based parallel hard-type power hybrid systems. Two types of conventional ICEVs (gasoline and diesel) and two types of HEVs (gasoline electric, diesel electric) were generated using vehicle and powertrain simulation tools and a Matlab-Simulink application programming interface. For gasoline and gasoline-electric HEV vehicles, the prediction accuracy for four types of LDV models was validated by conducting comparative analysis with the chassis dynamometer and OBD test data. The predicted results show strong correlation with the test data. The operating points of internal combustion engines and electric motors are well controlled in the high efficiency region and battery SOC was well controlled within +/-1.6%. However, for diesel vehicles, we generated virtual diesel-electric HEV vehicle because there is no available vehicles with similar engine and vehicle specifications with ICE vehicle. Using a fuzzy logic-based parallel hybrid system in conventional ICEVs demonstrated that HEVs showed superior performance in terms of fuel consumption and CO2 emission in most driving modes. PMID- 28365457 TI - The history of rabies in the Western Hemisphere. AB - Before the introduction of control programs in the 20th century, rabies in domestic dogs occurred throughout the Western Hemisphere. However, historical records and phylogenetic analysis of multiple virus isolates indicate that, before the arrival of the first European colonizers, rabies virus was likely present only in bats and skunks. Canine rabies was either rare or absent among domestic dogs of Native Americans, and first arrived when many new dog breeds were imported during the period of European colonization. The introduction of the cosmopolitan dog rabies lyssavirus variant and the marked expansion of the dog population provided ideal conditions for the flourishing of enzootic canine rabies. The shift of dog-maintained viruses into gray foxes, coyotes, skunks and other wild mesocarnivores throughout the Americas and to mongooses in the Caribbean has augmented the risk of human rabies exposures and has complicated control efforts. At the same time, the continued presence of bat rabies poses novel challenges in the absolute elimination of canine and human rabies. This article compiles existing historical and phylogenetic evidence of the origins and subsequent dynamics of rabies in the Western Hemisphere, from the era preceding the arrival of the first European colonizers through the present day. A companion article reviews the current status of canine rabies control throughout the Western Hemisphere and steps that will be required to achieve and maintain its complete elimination (Velasco-Villa et al., 2017). PMID- 28365460 TI - Aversive responses by shore crabs to acetic acid but not to capsaicin. AB - Nociception is the ability to encode and perceive harmful stimuli and allows for a rapid reflexive withdrawal. In some species, nociception might be accompanied by a pain experience, which is a negative feeling that allows for longer-term changes in behaviour. Different types of stimuli may affect nociceptors, but in crustaceans there is conflicting evidence about the ability to respond to chemical stimuli. This study attempts to resolve this situation by testing behavioural responses of the common shore crab, Carcinus maenas, to two chemical irritants frequently used in vertebrate pain studies (acetic acid and capsaicin). In our first experiment acetic acid, water, capsaicin or mineral oil were applied by brush to the mouth, and in a second experiment treatments were applied to the eyes. Application of acetic acid had a marked effect on behaviour that included vigorous movement of mouth parts, scratching at the mouth with the claws and attempts to escape from the enclosure. Acetic acid also caused holding down of the acid-treated eye in the socket. By contrast, capsaicin had no effect and was no different to the control treatment of mineral oil and water. These results demonstrate responsiveness to acetic acid and thus nociceptive capacity for at least some chemicals. Further, the responses that persist after application were consistent with the idea of pain, however, proof of pain is not possible in any animal. PMID- 28365461 TI - Age-dependent changes in sensitivity to a pesticide in tadpoles of the common toad (Bufo bufo). AB - The worldwide en masse application of pesticides and the frequently reported malign effects on several non-target organisms underpin the importance of ecotoxicological research on these anthropogenic pollutants. Previous studies showed that sensitivity to herbicides can vary widely depending on additional stress factors, on the species and even on the population investigated. However, there is little information about how sensitivity changes during ontogeny, and how the duration of exposure is linked to the magnitude of malign effects, even though this knowledge would be important for the interpretation of toxicity test results and for formulating recommendations regarding the timing of pesticide application. We exposed tadpoles of the common toad (Bufo bufo) to three concentrations (0, 2 and 4mg a.e./L) of a glyphosate-based herbicide during the 1st, 2nd, 3rd, 4th, or 5th period of larval development or during the entire experiment, and measured survival, time until metamorphosis and body mass at metamorphosis to estimate fitness-consequences. Younger tadpoles were more sensitive to the herbicide in all measured traits than older ones, and this age dependence was especially pronounced at the high herbicide concentration. Furthermore, tadpoles exposed to the herbicide during the entire experiment developed slower than tadpoles exposed only early on, but we did not observe a similar effect either on body mass or survival. The observed age-dependence of sensitivity to herbicides draws attention to the fact that results of toxicity tests obtained for one age-class are not necessarily generalizable across ontogeny. Also, the age of test animals has to be considered when planning ecotoxicological studies and interpreting their results. Finally, taking into account the temporal breeding habits of local amphibians when planning pesticide application would be highly favourable: if tadpoles would not get exposed to the herbicide during their most sensitive early development, they would sustain less anthropogenic damage from our efforts of controlling weeds. PMID- 28365462 TI - Toward understanding the role of cartilage particulates in synovial inflammation. AB - OBJECTIVE: Arthroscopy with lavage and synovectomy can remove tissue debris from the joint space and the synovial lining to provide pain relief to patients with osteoarthritis (OA). Here, we developed an in vitro model to study the interaction of cartilage wear particles with fibroblast-like synoviocytes (FLS) to better understand the interplay of cartilage particulates with cytokines on cells of the synovium. METHOD: In this study sub-10 MUm cartilage particles or 1 MUm latex particles were co-cultured with FLS +/-10 ng/mL interleukin-1alpha (IL 1alpha) or tumor necrosis factor-alpha (TNF-alpha). Samples were analyzed for DNA, glycosaminoglycan (GAG), and collagen, and media samples were analyzed for media GAG, nitric oxide (NO) and prostaglandin-E2 (PGE2). The nature of the physical interaction between the particles and FLS was determined by microscopy. RESULTS: Both latex and cartilage particles could be phagocytosed by FLS. Cartilage particles were internalized and attached to the surface of both dense monolayers and individual cells. Co-culture of FLS with cartilage particulates resulted in a significant increase in cell sheet DNA and collagen content as well as NO and PGE2 synthesis compared to control and latex treated groups. CONCLUSION: The proliferative response of FLS to cartilage wear particles resulted in an overall increase in extracellular matrix (ECM) content, analogous to the thickening of the synovial lining observed in OA patients. Understanding how cartilage particles interface with the synovium may provide insight into how this interaction contributes to OA progression and may guide the role of lavage and synovectomy for degenerative disease. PMID- 28365464 TI - The effect of mindfulness group therapy on a broad range of psychiatric symptoms: A randomised controlled trial in primary health care. AB - BACKGROUND: The need for psychotherapy in primary health care is on the increase but individual-based treatment is costly. The main aim of this randomised controlled trial (RCT) was to compare the effect of mindfulness-based group therapy (MGT) with treatment as usual (TAU), mainly individual-based cognitive behavioural therapy (CBT), on a broad range of psychiatric symptoms in primary care patients diagnosed with depressive, anxiety and/or stress and adjustment disorders. An additional aim was to compare the effect of MGT with TAU on mindful attention awareness. METHODS: This 8-week RCT took place in 2012 at 16 primary care centres in southern Sweden. The study population included both men and women, aged 20-64years (n=215). A broad range of psychiatric symptoms were evaluated at baseline and at the 8-week follow-up using the Symptom Checklist-90 (SCL-90). Mindful attention awareness was also evaluated using the Mindful Attention Awareness Scale (MAAS). RESULTS: In both groups, the scores decreased significantly for all subscales and indexes in SCL-90, while the MAAS scores increased significantly. There were no significant differences in the change in psychiatric symptoms between the two groups. The mindfulness group had a somewhat larger change in scores than the control group on the MAAS (P=0.06, non significant). CONCLUSIONS: No significant differences between MGT and TAU, mainly individual-based CBT, were found in treatment effect. Both types of therapies could be used in primary care patients with depressive, anxiety and/or stress and adjustment disorders, where MGT has a potential to save limited resources. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01476371. PMID- 28365463 TI - Internet gaming disorder in early adolescence: Associations with parental and adolescent mental health. AB - BACKGROUND: Internet gaming disorder (IGD) has been included in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Currently, associations between IGD in early adolescence and mental health are largely unexplained. In the present study, the relation of IGD with adolescent and parental mental health was investigated for the first time. METHODS: We surveyed 1095 family dyads (an adolescent aged 12-14 years and a related parent) with a standardized questionnaire for IGD as well as for adolescent and parental mental health. We conducted linear (dimensional approach) and logistic (categorical approach) regression analyses. RESULTS: Both with dimensional and categorical approaches, we observed statistically significant associations between IGD and male gender, a higher degree of adolescent antisocial behavior, anger control problems, emotional distress, self-esteem problems, hyperactivity/inattention and parental anxiety (linear regression model: corrected R2=0.41, logistic regression model: Nagelkerke's R2=0.41). CONCLUSIONS: IGD appears to be associated with internalizing and externalizing problems in adolescents. Moreover, the findings of the present study provide first evidence that not only adolescent but also parental mental health is relevant to IGD in early adolescence. Adolescent and parental mental health should be considered in prevention and intervention programs for IGD in adolescence. PMID- 28365465 TI - Recovery, relapse, or else? Treatment outcomes in gambling disorder from a multicenter follow-up study. AB - PURPOSE: Gambling disorder is associated with various adverse effects. While data on the immediate effectiveness of treatment programs are available, follow-up studies examining long-term effects are scarce and factors contributing to a stable therapy outcome versus relapse are under-researched. MATERIALS AND METHODS: Patients (n=270) finishing inpatient treatment for gambling disorder regularly participated in a prospective multicenter follow-up study (pre treatment, post-treatment, 12-month follow-up). Criteria for gambling disorder, psychopathology, functional impairment were defined as endpoints. Changes in personality were defined as an additional parameter. RESULTS: At follow-up, three groups were identified: subjects maintaining full abstinence (41.6%), patients still meeting criteria for gambling disorder (29.2%), and subjects still participating in gambling without meeting the diagnostic criteria for gambling disorder (29.2%). Every group had improvements in functional impairment, abstinent subjects showed the lowest psychopathology. Significant decreases in neuroticism and increases in both extraversion and conscientiousness were found among abstinent subjects but not in patients still meeting criteria for gambling disorder. DISCUSSION: One year after treatment, a considerable percentage of patients kept on gambling but not all of them were classified with gambling disorder leading to the question if abstinence is a necessary goal for every patient. CONCLUSIONS: The changes of personality in abstinent patients indicate that after surmounting gambling disorder a subsequent maturing of personality might be a protective factor against relapse. PMID- 28365466 TI - Early clinical predictors and correlates of long-term morbidity in bipolar disorder. AB - OBJECTIVES: Identifying factors predictive of long-term morbidity should improve clinical planning limiting disability and mortality associated with bipolar disorder (BD). METHODS: We analyzed factors associated with total, depressive and mania-related long-term morbidity and their ratio D/M, as %-time ill between a first-lifetime major affective episode and last follow-up of 207 BD subjects. Bivariate comparisons were followed by multivariable linear regression modeling. RESULTS: Total % of months ill during follow-up was greater in 96 BD-II (40.2%) than 111 BD-I subjects (28.4%; P=0.001). Time in depression averaged 26.1% in BD II and 14.3% in BD-I, whereas mania-related morbidity was similar in both, averaging 13.9%. Their ratio D/M was 3.7-fold greater in BD-II than BD-I (5.74 vs. 1.96; P<0.0001). Predictive factors independently associated with total % time ill were: [a] BD-II diagnosis, [b] longer prodrome from antecedents to first affective episode, and [c] any psychiatric comorbidity. Associated with %-time depressed were: [a] BD-II diagnosis, [b] any antecedent psychiatric syndrome, [c] psychiatric comorbidity, and [d] agitated/psychotic depressive first affective episode. Associated with %-time in mania-like illness were: [a] fewer years ill and [b] (hypo)manic first affective episode. The long-term D/M morbidity ratio was associated with: [a] anxious temperament, [b] depressive first episode, and [c] BD-II diagnosis. CONCLUSIONS: Long-term depressive greatly exceeded mania like morbidity in BD patients. BD-II subjects spent 42% more time ill overall, with a 3.7-times greater D/M morbidity ratio, than BD-I. More time depressed was predicted by agitated/psychotic initial depressive episodes, psychiatric comorbidity, and BD-II diagnosis. Longer prodrome and any antecedent psychiatric syndrome were respectively associated with total and depressive morbidity. PMID- 28365469 TI - The impact of frailty on depressive disorder in later life: Findings from the Netherlands Study of depression in older persons. AB - BACKGROUND: Physical frailty and depressive symptoms are reciprocally related in community-based studies, but its prognostic impact on depressive disorder remains unknown. METHODS: A cohort of 378 older persons (>=60 years) suffering from a depressive disorder (DSM-IV criteria) was reassessed at two-year follow-up. Depressive symptom severity was assessed every six months with the Inventory of Depressive Symptomatology, including a mood, motivational, and somatic subscale. Frailty was assessed according to the physical frailty phenotype at the baseline examination. RESULTS: For each additional frailty component, the odds of non remission was 1.24 [95% CI=1.01-1.52] (P=040). Linear mixed models showed that only improvement of the motivational (P<001) subscale and the somatic subscale (P=003) of the IDS over time were dependent on the frailty severity. CONCLUSIONS: Physical frailty negatively impacts the course of late-life depression. Since only improvement of mood symptoms was independent of frailty severity, one may hypothesize that frailty and residual depression are easily mixed-up in psychiatric treatment. PMID- 28365467 TI - The lipidome in major depressive disorder: Shared genetic influence for ether phosphatidylcholines, a plasma-based phenotype related to inflammation, and disease risk. AB - BACKGROUND: The lipidome is rapidly garnering interest in the field of psychiatry. Recent studies have implicated lipidomic changes across numerous psychiatric disorders. In particular, there is growing evidence that the concentrations of several classes of lipids are altered in those diagnosed with MDD. However, for lipidomic abnormalities to be considered potential treatment targets for MDD (rather than secondary manifestations of the disease), a shared etiology between lipid concentrations and MDD should be demonstrated. METHODS: In a sample of 567 individuals from 37 extended pedigrees (average size 13.57 people, range=3-80), we used mass spectrometry lipidomic measures to evaluate the genetic overlap between twenty-three biologically distinct lipid classes and a dimensional scale of MDD. RESULTS: We found that the lipid class with the largest endophenotype ranking value (ERV, a standardized parametric measure of pleiotropy) were ether-phosphodatidylcholines (alkylphosphatidylcholine, PC(O) and alkenylphosphatidylcholine, PC(P) subclasses). Furthermore, we examined the cluster structure of the twenty-five species within the top-ranked lipid class, and the relationship of those clusters with MDD. This analysis revealed that species containing arachidonic acid generally exhibited the greatest degree of genetic overlap with MDD. CONCLUSIONS: This study is the first to demonstrate a shared genetic etiology between MDD and ether-phosphatidylcholine species containing arachidonic acid, an omega-6 fatty acid that is a precursor to inflammatory mediators, such as prostaglandins. The study highlights the potential utility of the well-characterized linoleic/arachidonic acid inflammation pathway as a diagnostic marker and/or treatment target for MDD. PMID- 28365468 TI - Intelligence and neuroticism in relation to depression and psychological distress: Evidence from two large population cohorts. AB - BACKGROUND: Neuroticism is a risk factor for selected mental and physical illnesses and is inversely associated with intelligence. Intelligence appears to interact with neuroticism and mitigate its detrimental effects on physical health and mortality. However, the inter-relationships of neuroticism and intelligence for major depressive disorder (MDD) and psychological distress has not been well examined. METHODS: Associations and interactions between neuroticism and general intelligence (g) on MDD, self-reported depression, and psychological distress were examined in two population-based cohorts: Generation Scotland: Scottish Family Health Study (GS:SFHS, n=19,200) and UK Biobank (n=90,529). The Eysenck Personality Scale Short Form-Revised measured neuroticism and g was extracted from multiple cognitive ability tests in each cohort. Family structure was adjusted for in GS:SFHS. RESULTS: Neuroticism was strongly associated with increased risk for depression and higher psychological distress in both samples. Although intelligence conferred no consistent independent effects on depression, it did increase the risk for depression across samples once neuroticism was adjusted for. Results suggest that higher intelligence may ameliorate the association between neuroticism and self-reported depression although no significant interaction was found for clinical MDD. Intelligence was inversely associated with psychological distress across cohorts. A small interaction was found across samples such that lower psychological distress associates with higher intelligence and lower neuroticism, although effect sizes were small. CONCLUSIONS: From two large cohort studies, our findings suggest intelligence acts a protective factor in mitigating the effects of neuroticism on psychological distress. Intelligence does not confer protection against diagnosis of depression in those high in neuroticism. PMID- 28365471 TI - Biosynthetic pathways of aminoglycosides and their engineering. AB - Despite decades long clinical usage, aminoglycosides still remain a valuable pharmaceutical source for fighting Gram-negative bacterial pathogens, and their newly identified bioactivities are also renewing interest in this old class of antibiotics. As Nature's gift, some aminoglycosides possess natural defensive structural elements that can circumvent drug resistance mechanisms. Thus, a detailed understanding of aminoglycoside biosynthesis will enable us to apply Nature's biosynthetic strategy towards expanding structural diversity in order to produce novel and more robust aminoglycoside analogs. The engineered biosynthesis of novel aminoglycosides is required not only to develop effective therapeutics against the emerging 'superbugs' but also to reinvigorate antibiotic lead discovery in readiness for the emerging post-antibiotic era. PMID- 28365470 TI - Coping as a mediator of stress and psychotic-like experiences. AB - BACKGROUND: There is evidence that individuals along the whole psychosis continuum have increased responsiveness to stress; however, coping responses to stressors have not been extensively explored in subthreshold psychotic symptoms. METHODS: In 454 undergraduates, psychotic-like experiences (PLEs) were evaluated using the positive items of the Prodromal Questionnaire. Perceived stress and traumatic life events were assessed using the Life Events Checklist and Perceived Stress Scale, and coping was measured using the Brief COPE. We also examined whether different coping styles mediated the relationship between perceived stress and PLEs, as well as whether different coping styles mediated the relationship between traumatic life events and PLEs. RESULTS: Both number of traumatic life events and current level of perceived stress were significantly associated with PLEs. These relationships were both mediated by higher levels of maladaptive coping. CONCLUSIONS: Results have the potential to inform treatment strategies, as well as inform targets for exploration in longitudinal studies of those at risk for psychosis. PMID- 28365472 TI - Bioengineering towards self-assembly of particulate vaccines. AB - There is an unmet demand for safe and efficient vaccines for prevention of various infectious diseases. Subunit vaccines comprise selected pathogen specific antigens are a safe alternative to whole organism vaccines. However they often lack immunogenicity. Natural and synthetic self-assembling polymers and proteins will be reviewed in view their use to encapsulate and/or display antigens to serve as immunogenic antigen carriers for induction of protective immunity. Recent advances made in in vivo assembly of antigen-displaying polyester inclusions will be a focus. Particulate vaccines are inherently immunogenic due to enhanced uptake by antigen presenting cells which process antigens mediating adaptive immune responses. Bioengineering approaches enable the design of tailor made particulate vaccines to fine tune immune responses towards protective immunity. PMID- 28365473 TI - Pioglitazone treatment following spinal cord injury maintains acute mitochondrial integrity and increases chronic tissue sparing and functional recovery. AB - Pioglitazone is an FDA-approved PPAR-gamma agonist drug used to treat diabetes, and it has demonstrated neuroprotective effects in multiple models of central nervous system (CNS) injury. Acute treatment after spinal cord injury (SCI) in rats is reported to suppress neuroinflammation, rescue injured tissues, and improve locomotor recovery. In the current study, we additionally assessed the protective efficacy of pioglitazone treatment on acute mitochondrial respiration, as well as functional and anatomical recovery after contusion SCI in adult male C57BL/6 mice. Mice received either vehicle or pioglitazone (10mg/kg) at either 15min or 3h after injury (75kdyn at T9) followed by a booster at 24h post-injury. At 25h, mitochondria were isolated from spinal cord segments centered on the injury epicenters and assessed for their respiratory capacity. Results showed significantly compromised mitochondrial respiration 25h following SCI, but pioglitazone treatment that was initiated either at 15min or 3h post-injury significantly maintained mitochondrial respiration rates near sham levels. A second cohort of injured mice received pioglitazone at 15min post injury, then once a day for 5days post-injury to assess locomotor recovery and tissue sparing over 4weeks. Compared to vehicle, pioglitazone treatment resulted in significantly greater recovery of hind-limb function over time, as determined by serial locomotor BMS assessments and both terminal BMS subscores and gridwalk performance. Such improvements correlated with significantly increased grey and white matter tissue sparing, although pioglitazone treatment did not abrogate long-term injury-induced inflammatory microglia/macrophage responses. In sum, pioglitazone significantly increased functional neuroprotection that was associated with remarkable maintenance of acute mitochondrial bioenergetics after traumatic SCI. This sets the stage for dose-response and delayed administration studies to maximize pioglitazone's efficacy for SCI while elucidating the precise role that mitochondria play in governing its neuroprotection; the ultimate goal to develop novel therapeutics that specifically target mitochondrial dysfunction. PMID- 28365475 TI - Structural space of intramolecular peptide disulfides: Analysis of peptide toxins retrieved from venomous peptide databases. AB - Structural space of intramolecular peptide disulfides is the combination of arrangement of even number of cysteine residues in single polypeptide and the disulfide isomers resulting from differential connectivity between cysteine residues. In the current report, we are documenting theoretical analysis and derivation of general formula [2*4{(n2)-1}] to predict possible distinct cysteine patterns for given 'n' even number of cysteine residues in a sequence. Combined formula of predicting distinct cysteine patterns and different disulfide isomers can be used to deduce the truly available structural space of intramolecular peptide disulfides, which may be used in structural analysis of disulfide rich peptides and proteins. In this report, we have also analyzed cysteine patterns and disulfide connectivities of peptide toxins, which is the largest group of intramolecular peptide disulfide natural products, retrieved from publically available animal toxin databases. Observed 29 distinct cysteine patterns of toxins exhibited 61 unique intramolecular disulfide folds, with limitation of having up to eight cysteine residues in a sequence, compared to theoretically available 170 different cysteine patterns generating 13,946 distinct intramolecular disulfide folds. Database analysis of peptide toxins has also revealed the features of presence of same intramolecular disulfide motif in functionally divergent peptide toxins and adaptation of the same disulfide fold with similar functions in different venomous species. Calculations of relative accessible surface area of cystine and average value of non-cysteine residues in the representative intramolecular disulfide folds of peptide toxins has revealed the feature of poor accessibility of cystine to external agents and their dependency on number of disulfide bonds in the sequence. Implementation of new generation sequencing methods and novel disulfide mapping techniques will unravel hidden diversity of intramolecular disulfide motifs of toxins and current report points to the selection of disulfide motifs in peptide toxins. PMID- 28365474 TI - TDAG8 activation attenuates cerebral ischaemia-reperfusion injury via Akt signalling in rats. AB - BACKGROUND: T-cell death-associated gene 8 (TDAG8), a member of the proton sensitive G-protein-coupled receptor (GPCR) class with an immune-specific expression profile, was recently shown to be expressed in the rat brain; however, its role in ischaemic stroke remains unknown. METHODS: We initially confirmed the time-dependent expression of TDAG8 in rat brain tissue after ischaemic stroke and reperfusion. Further evaluations were performed to increase TDAG8 expression 6h prior to middle cerebral artery occlusion (MCAO) by injecting a specific agonist, BTB09089, into the lateral ventricle to increase TDAG8 expression. Twenty-four hours before MCAO, a specific small interfering RNA (siRNA) was introduced. The infarction volume, neurological deficit score and cleaved caspase-3 and Bcl-2 expression were used to assess the effects of TDAG8 on ischaemic stroke. Finally, the effects of TDAG8 on the development of primary cortical neurons exposed to oxygen-glucose deprivation (OGD) were investigated. RESULTS: TDAG8 expression increased both in vivo and in vitro. Pretreatment with BTB09089 up-regulated TDAG8 and Bcl-2 expression and down-regulated cleaved caspase-3 expression, while the infarction volume was reduced, and neurological deficits were ameliorated 24 and 72h after MCAO. However, the protective effects of TDAG8 were reversed when its level was reduced in TDAG8-deficient rats. More importantly, these findings are consistent with data from neurons subjected to OGD. CONCLUSIONS: TDAG8 plays an important neuroprotective role through inhibition of neuronal apoptosis and alleviation of neurological deficits by activating the Akt signalling pathway in rats. PMID- 28365477 TI - Reference natural radionuclide concentrations in Australian soils and derived terrestrial air kerma rate. AB - Sediment from drainage catchment outlets has been shown to be a useful means of sampling large land masses for soil composition. Naturally occurring radioactive material concentrations (uranium, thorium and potassium-40) in soil have been collated and converted to activity concentrations using data collected from the National Geochemistry Survey of Australia. Average terrestrial air kerma rate data are derived using the elemental concentration data, and is tabulated for Australia and states for use as baseline reference information. PMID- 28365476 TI - Secretive eating among youth with overweight or obesity. AB - PURPOSE: Secretive eating, characterized by eating privately to conceal being seen, may reflect eating- and/or body-related shame, be associated with depression, and correlate with binge eating, which predicts weight gain and eating disorder onset. Increasing understanding of secretive eating in youth may improve weight status and reduce eating disorder risk. This study evaluated the prevalence and correlates of secretive eating in youth with overweight or obesity. METHODS: Youth (N = 577) presented to five research/clinical institutions. Using a cross-sectional design, secretive eating was evaluated in relation to eating-related and general psychopathology via linear and logistic regression analyses. RESULTS: Secretive eating was endorsed by 111 youth, who were, on average, older than youth who denied secretive eating (mean age = 12.07 +/- 2.83 versus 10.97 +/- 2.31). Controlling for study site and age, youth who endorsed secretive eating had higher eating-related psychopathology and were more likely to endorse loss of control eating and purging than their counterparts who did not endorse secretive eating. Groups did not differ in excessive exercise or behavioral problems. Dietary restraint and purging were elevated among adolescents (>=13y) but not children (<13y) who endorsed secretive eating; depression was elevated among children, but not adolescents, who endorsed secretive eating. CONCLUSIONS: Secretive eating may portend heightened risk for eating disorders, and correlates of secretive eating may differ across pediatric development. Screening for secretive eating may inform identification of problematic eating behaviors, and understanding factors motivating secretive eating may improve intervention tailoring. PMID- 28365479 TI - Preconception gynecological risk factors of postpartum depression among Japanese women: The Japan Environment and Children's Study (JECS). AB - BACKGROUND: Postpartum depression is one of the major causes of disability among women who are on their childbearing years. Identifying people at risk of postpartum depression may improve its management. The objective of this study was to determine the probable association between postpartum depression and some preconception gynecological morbidities. METHODS: Data from a nationwide birth cohort study, the Japan Environment and Children's study (JECS), up to one month of postpartum were analyzed. To assess postpartum depression, the Edinburgh Postnatal Depression Scale (EPDS) was used; 11 preconception gynecological morbidities were considered as risk factors. Covariates included psychiatric illness history, psychosocial factors, some pregnancy adverse outcomes, birth outcomes, socio-demographic and health behavioral factors. RESULTS: Except for the prevalence of previous miscarriage, leiomyoma and polycystic ovarian syndrome, depressive women had more gynecological morbidities compared to non depressive ones. In logistic regression model, endometriosis (OR, 1.27; 95%CI: 1.15-1.41), dysmenorrhea (OR, 1.13; 95%CI: 1.06-1.21) and abnormal uterine bleeding (OR, 1.21; 95%CI: 1.15-1.29) were associated with postpartum depression. LIMITATIONS: CONCLUSION: Women with endometriosis and menstrual problems were at risk of developing postpartum depression. This study suggests a perinatal mental health screening for predisposed women. PMID- 28365478 TI - Clinical correlates of acute bipolar depressive episode with psychosis. AB - BACKGROUND: Psychotic bipolar depressive episodes remain remarkably understudied despite being common and having a significant impact on bipolar disorder. The aim of this study is to identify the characteristics of depressed bipolar patients with current psychosis compared to those without psychosis. METHODS: We used baseline data of a comparative effectiveness study of lithium and quetiapine for bipolar disorder (the Bipolar CHOICE study) to compare demographic, clinical, and functioning variables between those with and without psychotic symptoms. Of the 482 participants, 303 (62.9%) were eligible for the present study by meeting DSM IV criteria for an acute bipolar depressive episode. Univariate analyses were conducted first, and then included in a model controlling for symptom severity. RESULTS: The sample was composed mostly of women (60.7%) and the mean age was 39.5+/-12.1 years. Psychosis was present in 10.6% (n=32) of the depressed patients. Psychotic patients had less education, lower income, and were more frequently single and unemployed. Psychosis was also associated with a more severe depressive episode, higher suicidality, more comorbid conditions and worse functioning. Most group differences disappeared when controlling for depression severity. LIMITATIONS: Only outpatients were included and the presence of psychosis in previous episodes was not assessed. CONCLUSION: Psychosis during bipolar depressive episodes is present even in an outpatient sample. Psychotic, depressed patients have worse illness outcomes, but future research is necessary to confirm if these outcomes are only associated with the severity of the disorder or if some of them are independent of it. PMID- 28365480 TI - Rational design of charged peptides that self-assemble into robust nanofibers as immune-functional scaffolds. AB - : Self-assembling peptides programed by sequence design to form predefined nanostructures are useful for a variety of biomedical applications. However, assemblies of classic ionic self-complementary peptides are unstable in neutral pH, while charged peptide hydrogels have low mechanical strength. Here, we report on the rational design of a self-assembling peptide system with optimized charge distribution and density for bioscaffold development. Our designer peptides employs a sequence pattern that undergoes salt triggered self-assembly into beta sheet rich cationic nanofibers in the full pH range (pH 0-14). Our peptides form nanofibrils in physiological condition at a minimum concentration that is significantly lower than has been reported for self-assembly of comparable peptides. The robust fiber-forming ability of our peptides results in the rapid formation of hydrogels in physiological conditions with strong mechanical strength. Moreover, fiber structure is maintained even upon dense conjugation with a model bioactive cargo OVA257-264 peptide. Nanofibers carrying OVA257-264 significantly enhanced CD8+ T cell activation in vitro. Subcutaneous immunization of our peptide fiber vaccine also elicited robust CD8+ T cell activation and proliferation in vivo. Our self-assembling peptides are expected to provide a versatile platform to construct diverse biomaterials. STATEMENT OF SIGNIFICANCE: This work is an attempt of rational design of materials from molecular level for targeted properties and an exploration in molecular self-assembly. Current widely studied self-assembling peptides do not have stable nanofiber structures and form weak hydrogels under physiological conditions. To address this issue, we develop charged self-assembling peptides with a novel sequence pattern for strong fiber forming ability under physiological conditions. Our designer peptides can undergo salt-triggered self-assembly into nanofibers that are ultrastable in extreme pH (0-14) and dilute solutions, and into hydrogels with strong mechanical strength. Upon conjugation with a model bioactive cargo, our self-assembled peptides exhibit great potential as bioscaffolds for multiple applications. PMID- 28365483 TI - Structural transitions in torsionally constrained DNA and their dependence on solution electrostatics. AB - : Experimental studies on single molecules of DNA have reported a rich variety of structural transitions, including coexistence of three phases, in a torsionally constrained molecule. A comprehensive knowledge of these structural transitions is useful for unraveling the in vivo and in vitro behavior of DNA. Our objective is to understand the structural transitions in a torsionally constrained DNA molecule when it is pulled using optical or magnetic tweezers. We use foundational concepts from the Zimm-Bragg helix-coil transition theory and merge them with ideas from the theory of fluctuating elastic rods to model the mechanics of DNA. We also account for the electrostatic interactions between the ions and the negatively charged phosphate backbone of DNA. Using our model, we calculate the force and torque corresponding to the overstretching transition characterized by a 70% jump in the contour length of the molecule and examine the effect of salt concentration on this transition. We also deduce conditions under which the co-existence of B-, S- and P-DNA is possible. We examine how the cooperativity parameter for each transition affects the force-extension curve or torque-rotation curve. We attempt to rationalize the non-monotonic dependence of external work done on the ion concentration by connecting it to the electrostatic dependence of the interfacial energy between two phases of DNA. Our theoretical results are in agreement with multiple experiments documented in the literature and they generate falsifiable predictions that can be tested in new experiments. STATEMENT OF SIGNIFICANCE: The overarching objective of this paper is to explore the implications of variation in ion concentration on the structural transitions driven by external forces in a torsionally constrained DNA molecule. A comprehensive understanding of the phase behavior of torsionally constrained DNA is useful because DNA in cells is tightly packaged and is acted upon by molecular machines in different ionic environments. We examine the mechanics of the overstretching transition, characterized by a 70% jump in contour length, wherein a mixture of B- and S-DNA converts into a mixture of S- and P-DNA through a triple point in the phase diagram. Our results are corroborated by experimental data at every step and we make predictions that are experimentally verifiable. PMID- 28365482 TI - Distributed vasculogenesis from modular agarose-hydroxyapatite-fibrinogen microbeads. AB - : Critical limb ischemia impairs circulation to the extremities, causing pain, disrupted wound healing, and potential tissue necrosis. Therapeutic angiogenesis seeks to repair the damaged microvasculature directly to restore blood flow. In this study, we developed modular, micro-scale constructs designed to possess robust handling qualities, allow in vitro pre-culture, and promote microvasculature formation. The microbead matrix consisted of an agarose (AG) base to prevent aggregation, combined with cell-adhesive components of fibrinogen (FGN) and/or hydroxyapatite (HA). Microbeads encapsulating a co-culture of human umbilical vein endothelial cells (HUVEC) and fibroblasts were prepared and characterized. Microbeads were generally 80-100um in diameter, and the size increased with the addition of FGN and HA. Addition of HA increased the yield of microbeads, as well as the homogeneity of distribution of FGN within the matrix. Cell viability was high in all microbead types. When cell-seeded microbeads were embedded in fibrin hydrogels, HUVEC sprouting and inosculation between neighboring microbeads were observed over seven days. Pre-culture of microbeads for an additional seven days prior to embedding in fibrin resulted in significantly greater HUVEC network length in AG+HA+FGN microbeads, as compared to AG, AG+HA or AG+FGN microbeads. Importantly, composite microbeads resulted in more even and widespread endothelial network formation, relative to control microbeads consisting of pure fibrin. These results demonstrate that AG+HA+FGN microbeads support HUVEC sprouting both within and between adjacent microbeads, and can promote distributed vascularization of an external matrix. Such modular microtissues may have utility in treating ischemic tissue by rapidly re establishing a microvascular network. STATEMENT OF SIGNIFICANCE: Critical limb ischemia (CLI) is a chronic disease that can lead to tissue necrosis, amputation, and death. Cell-based therapies are being explored to restore blood flow and prevent the complications of CLI. In this study, we developed small, non aggregating agarose-hydroxyapatite-fibrinogen microbeads that contained endothelial cells and fibroblasts. Microbeads were easy to handle and culture, and endothelial sprouts formed within and between microbeads. Our data demonstrates that the composition of the microbead matrix altered the degree of endothelial sprouting, and that the addition of hydroxyapatite and fibrinogen resulted in more distributed sprouting compared to pure fibrin microbeads. The microbead format and control of the matrix formulation may therefore be useful in developing revascularization strategies for the treatment of ischemic disease. PMID- 28365481 TI - Oligomeric proanthocyanidins released from dentin induce regenerative dental pulp cell response. AB - : Proanthocyanidins (PACs) are plant-derived, multifunctional compounds that possess high interactivity with extracellular matrix (ECM) components. The documented affinity of PACs for type-I collagen is directly correlated with their structural features and degree of polymerization. In this investigation, centrifugal partition chromatography (CPC) was used to sequentially deplete less active monomeric and polymeric PACs from a crude Pinus massoniana bark extract to create refined mixtures enriched in oligomeric PACs. The ability of these oligomeric PACs to modify the mechanical properties of the dentin collagen matrix and their biocompatibility with dental pulp cells (DPCs) was evaluated in an innovative biomimetic environment. The refined mixtures displayed high interactivity with dentin collagen as demonstrated by a significant increase (>5 fold) in the modulus of elasticity of the dentin matrix. In a simplified model of the dentin-DPC complex, DPCs embedded within their native ECM in the presence of PAC-treated dentin exhibited increased proliferation. Quantitative gene expression analyses indicated that exposure to PAC-treated dentin increased the expression of key biomineralization and odontogenic differentiation regulators, including RUNX2, BMP2, OCN, and DSPP. LC-MS/MS analysis revealed that PACs two to four units long (dimers, trimers, and tetramers) were being released from dentin into media, influencing cell behavior. Overall, the results suggested that PAC dimers, trimers, and tetramers are not only biocompatible, but enhance the differentiation of DPCs towards a phenotype that favors biomineralization. PAC enriched refined mixtures can influence the field of biomaterials and regeneration by serving as renewable, non-cytotoxic agents that can increase the mechanical properties of biomaterials. STATEMENT OF SIGNIFICANCE: Pine bark extract is a renewable source of structurally diverse proanthocyanidins (PACs), multifunctional compounds whose interaction with collagen can be tailored to specific purposes by enrichment of selected PACs from the complex mixture. Oligomeric PACs were enriched from the extract and were shown here to sustain desired tissue modification and were thus assessed for cellular response in a model of the dentin-pulp interface. This model was developed to mimic leaching of potentially reactive compounds into pulp tissue. Dental pulp cells exposed to PAC treated dentin showed increased proliferation and expression of genes necessary for extracellular matrix deposition and biomineralization, processes crucial for forming new dentin. Thus, collagen-interactive PACs may also enhance tissue regeneration and have broad impact in tissue engineering. PMID- 28365484 TI - Bolus Administration of Fentanyl and Midazolam for Colonoscopy Increases Endoscopy Unit Efficiency and Safety Compared With Titrated Sedation. AB - BACKGROUND & AIMS: Guidelines recommend slow titration of sedatives for moderate sedation. Bolus sedation, in which a larger weight-based dose of medication is given upfront, has been shown in a single trial to be beneficial. We evaluated the effects of bolus sedation on procedural safety, efficiency, and patient experience. METHODS: We performed a retrospective analysis of colonoscopies performed between April 2010 and April 2011 at Duke Medical Center. Colonoscopies before October 2010 were performed with nurse-directed titration of sedative (n = 966); colonoscopies performed after October 2010 were performed with physician directed administration of bolus sedative (n = 699). We compared sedation and recovery times, medication doses, and adverse events between groups. We also compared patient satisfaction in a subset of patients from each group. Data were compared using the chi-square test for categorical variables and Wilcoxon rank sum test for continuous and ordinal categorical variables. RESULTS: Patients in the bolus group had a shorter sedation time (6.0 min) than patients in the titration group (13.0 min; P < .01) and a slightly longer colonoscopy time (25.0 min vs 24.0 min in the titration group; P < .01). Recovery time did not differ significantly between groups (53.0 min in the bolus group vs 52.1 min in the titration group; P = .07). Patients in the bolus group received lower weight adjusted doses of fentanyl (1.71 MUg/kg vs 1.89 MUg/kg in the titration group) and midazolam (0.065 mg/kg vs 0.075 mg/kg in the titration group). A smaller proportion of patients in the bolus sedative group developed hypotension (12.7% vs 17.9% in the titration group; P < .01). These findings persisted even after adjustment for baseline patient age, race, sex, smoking status, alcohol use, body mass index, and American Society of Anesthesiologists' classification. CONCLUSIONS: In a retrospective study of patients undergoing colonoscopy, we found that compared with titrated administration of sedative, bolus dosing improves endoscopy unit efficiency and safety and decreases the amount of sedative required. This benefit does not come at the expense of the patient experience. PMID- 28365485 TI - Association Between Ustekinumab Trough Concentrations and Clinical, Biomarker, and Endoscopic Outcomes in Patients With Crohn's Disease. AB - BACKGROUND & AIMS: Ustekinumab, an inhibitor of the p40 subunit of interleukins 12 and 23, is an effective treatment for patients with Crohn's disease (CD). Trough concentrations of tumor necrosis factor (TNF) antagonists and presence of anti-drug antibodies are associated with important clinical and endoscopic outcomes. We investigated associations between trough concentrations of ustekinumab and clinical, biomarker, and endoscopic outcomes of real-world patients with CD. METHODS: We recruited 62 patients with CD who were either refractory or intolerant to TNF antagonists, treated with ustekinumab from April 2014 to September 2015. Patients received 90 mg of ustekinumab subcutaneously at weeks 0, 1, and 2 during induction and 90 mg every 4 or 8 weeks during maintenance. Clinical, biomarker, and endoscopic outcomes, trough concentrations of ustekinumab, and anti-drug antibodies were assessed at both week 10 postinduction therapy and at week 26 or later during maintenance therapy in a prospective longitudinal patient cohort or at week 26 or later during maintenance therapy in a cross-sectional patient cohort. Analysis was performed on data combined from both maintenance cohorts, which had similar outcomes at week 26 or later. A primary analysis determined if ustekinumab drug trough concentrations were associated with clinical response (reduction in Harvey Bradshaw Index score of 3 or greater), clinical remission (Harvey Bradshaw Index score <5), steroid free clinical remission, biomarker (serum level of C-reactive protein [CRP] or level of fecal calprotectin) reduction, biomarker normalization (serum level of CRP below 5 mg/L or level of fecal calprotectin below 200 MUg/g), endoscopic response (simple endoscopic score for CD reduced by 50% or more), or endoscopic remission (simple endoscopic score for CD of 2 or less). RESULTS: At week 26 or beyond, 80.7% of patients had a clinical response, 66.1% were in clinical remission, 50.0% were in steroid-free clinical remission, 58.9% had an endoscopic response, and 19.6% were in endoscopic remission. The mean trough concentration of ustekinumab at this time point was higher in patients with an endoscopic response (4.7 MUg/mL) than without (3.8 ug/mL; P = .03). An optimal ustekinumab threshold trough concentration at week 26 or later was found to be 4.5 MUg/mL (area under the curve, 0.67). A greater proportion of patients with trough concentrations of ustekinumab above 4.5 MUg/mL at week 26 or later had an endoscopic response (75.9%) than did patients with trough concentrations below this level (40.7%; P = .008). Patients with trough concentrations of ustekinumab above 4.5 MUg/mL at week 26 or later also had a lower mean level of CRP (12.6 mg/L) than did patients with trough concentrations below this level (mean level of CRP, 23.9 mg/L; P = .04). We did not detect antibodies against ustekinumab in any patient. CONCLUSIONS: Ustekinumab therapy was effective in patients with CD who had not responded to or were intolerant to treatment with a TNF antagonist. Maintenance trough concentrations of ustekinumab above 4.5 MUg/mL at 26 weeks or later were associated with biomarker reduction and endoscopic response. PMID- 28365487 TI - A Flawed Meta-analysis? Similar Risk of Cardiopulmonary Adverse Events Between Propofol and Traditional Anesthesia for Gastrointestinal Endoscopy. PMID- 28365488 TI - Lymphogranuloma Venereum Proctitis. PMID- 28365486 TI - Improved Long-term Outcomes of Patients With Inflammatory Bowel Disease Receiving Proactive Compared With Reactive Monitoring of Serum Concentrations of Infliximab. AB - BACKGROUND & AIMS: Monitoring serum concentrations of tumor necrosis factor antagonists in patients receiving these drugs as treatment for inflammatory bowel disease (IBD), also called therapeutic drug monitoring, is performed either after patient loss of response (reactive drug monitoring) or in patients in clinical remission in which the drug is titrated to a target concentration (proactive drug monitoring). We compared long-term outcomes of patients with IBD undergoing proactive vs reactive monitoring of serum concentrations of infliximab. METHODS: We performed a multicenter, retrospective study of 264 consecutive patients with IBD (167 with Crohn's disease) receiving infliximab maintenance therapy. The subjects received proactive (n = 130) or reactive (n = 134) drug monitoring, based on measurements of first infliximab concentration and antibodies to infliximab, from September 2006 to January 2015; they were followed through December 2015 (median time of 2.4 years). We analyzed time to treatment failure, first IBD-related surgery or hospitalization, serious infusion reaction, and detection of antibodies to infliximab. Treatment failure was defined as drug discontinuation for loss of response or serious adverse event, or need for surgery. RESULTS: Multiple Cox regression analysis independently associated proactive drug monitoring, compared with reactive monitoring, with reduced risk for treatment failure (hazard ratio [HR], 0.16; 95% confidence interval [CI], 0.09-0.27; P < .001), IBD-related surgery (HR, 0.30; 95% CI, 0.11-0.80; P = .017), IBD-related hospitalization (HR, 0.16; 95% CI, 0.07-0.33; P < .001), antibodies to infliximab (HR, 0.25; 95% CI, 0.07-0.84; P = .025), and serious infusion reaction (HR, 0.17; 95% CI, 0.04-0.78; P = .023). CONCLUSIONS: In a retrospective analysis of patients with IBD receiving proactive vs reactive monitoring of serum concentration of infliximab, proactive monitoring was associated with better clinical outcomes, including greater drug durability, less need for IBD-related surgery or hospitalization, and lower risk of antibodies to infliximab or serious infusion reactions. PMID- 28365489 TI - Subliminal modulation of voluntary action experience: A neuropsychological investigation. AB - Human voluntary actions are often associated with a distinctive subjective experience termed 'sense of agency'. This experience could be a reconstructive inference triggered by monitoring one's actions and their outcomes, or a read-out of brain processes related to action preparation, or some hybrid of these. Participants pressed a key with the right index finger at a time of their own choice, while viewing a rotating clock. Occasionally they received a mild shock on the same finger. They were instructed to press the key as quickly as possible if they felt a shock. On some trials, trains of subliminal shocks were also delivered, to investigate whether such subliminal cues could influence the initiation of voluntary actions, or the subjective experience of such actions. Participants' keypress were always followed by a tone 250 ms later. At the end of each trial they reported the time of the keypress using the rotating clock display. Shifts in the perceived time of the action towards the following tone, compared to a baseline condition containing only a keypress but no tone, were taken as implicit measures of sense of agency. The subliminal shock train enhanced this "action binding" effect in healthy participants, relative to trials without such shocks. This difference could not be attributed to retrospective inference, since the perceptual events were identical in both trial types. Further, we tested the same paradigm in a patient with anarchic hand syndrome (AHS). Subliminal shocks again enhanced our measure of sense of agency in the unaffected hand, but had a reversed effect on the 'anarchic' hand. These findings suggest an interaction between internal volitional signals and external cues afforded by the external environment. Damage to the neural pathways that mediate interactions between internal states and the outside world may explain some of the clinical signs of AHS. PMID- 28365490 TI - Abnormal structural connectivity between the basal ganglia, thalamus, and frontal cortex in patients with disorders of consciousness. AB - Consciousness loss in patients with severe brain injuries is associated with reduced functional connectivity of the default mode network (DMN), fronto parietal network, and thalamo-cortical network. However, it is still unclear if the brain white matter connectivity between the above mentioned networks is changed in patients with disorders of consciousness (DOC). In this study, we collected diffusion tensor imaging (DTI) data from 13 patients and 17 healthy controls, constructed whole-brain white matter (WM) structural networks with probabilistic tractography. Afterward, we estimated and compared topological properties, and revealed an altered structural organization in the patients. We found a disturbance in the normal balance between segregation and integration in brain structural networks and detected significantly decreased nodal centralities primarily in the basal ganglia and thalamus in the patients. A network-based statistical analysis detected a subnetwork with uniformly significantly decreased structural connections between the basal ganglia, thalamus, and frontal cortex in the patients. Further analysis indicated that along the WM fiber tracts linking the basal ganglia, thalamus, and frontal cortex, the fractional anisotropy was decreased and the radial diffusivity was increased in the patients compared to the controls. Finally, using the receiver operating characteristic method, we found that the structural connections within the NBS-derived component that showed differences between the groups demonstrated high sensitivity and specificity (>90%). Our results suggested that major consciousness deficits in DOC patients may be related to the altered WM connections between the basal ganglia, thalamus, and frontal cortex. PMID- 28365491 TI - Solvent signal suppression for high-resolution MAS-DNP. AB - Dynamic nuclear polarization (DNP) has become a powerful tool to substantially increase the sensitivity of high-field magic angle spinning (MAS) solid-state NMR experiments. The addition of dissolved hyperpolarizing agents usually results in the presence of solvent signals that can overlap and obscure those of interest from the analyte. Here, two methods are proposed to suppress DNP solvent signals: a Forced Echo Dephasing experiment (FEDex) and TRAnsfer of Populations in DOuble Resonance Echo Dephasing (TRAPDORED) NMR. These methods reintroduce a heteronuclear dipolar interaction that is specific to the solvent, thereby forcing a dephasing of recoupled solvent spins and leaving acquired NMR spectra free of associated resonance overlap with the analyte. The potency of these methods is demonstrated on sample types common to MAS-DNP experiments, namely a frozen solution (of l-proline) and a powdered solid (progesterone), both containing deuterated glycerol as a DNP solvent. The proposed methods are efficient, simple to implement, compatible with other NMR experiments, and extendable past spectral editing for just DNP solvents. The sensitivity gains from MAS-DNP in conjunction with FEDex or TRAPDORED then permits rapid and uninterrupted sample analysis. PMID- 28365492 TI - Interaction of mycotoxin zearalenone with human serum albumin. AB - Zearalenone (ZEN) is a mycotoxin produced mainly by Fusarium species. Fungal contamination of cereals and plants can result in the formation of ZEN, leading to its presence in different foods, animal feeds, and drinks. Because ZEN is an endocrine disruptor, it causes reproductive disorders in farm animals and hyperoestrogenic syndromes in humans. Despite toxicokinetic properties of ZEN were studied in more species, we have no information regarding the interaction of ZEN with serum albumin. Since albumin commonly plays an important role in the toxicokinetics of different toxins, interaction of ZEN with albumin has of high biological importance. Therefore the interaction of ZEN with human serum albumin (HSA) was investigated using spectroscopic methods, ultrafiltration, and molecular modeling studies. Fluorescence spectroscopic studies demonstrate that ZEN forms complex with HSA. Binding constant (K) of ZEN-HSA complex was quantified with fluorescence quenching technique. The determined binding constant (logK=5.1) reflects the strong interaction of ZEN with albumin suggesting the potential biological importance of ZEN-HSA complex formation. Based on the results of the investigations with site markers as well as docking studies, ZEN occupies a non-conventional binding site on HSA. Considering the above listed observations, we should keep in mind this interaction if we would like to precisely understand the toxicokinetic behavior of ZEN. PMID- 28365493 TI - Hydrogel containing silibinin-loaded pomegranate oil based nanocapsules exhibits anti-inflammatory effects on skin damage UVB radiation-induced in mice. AB - The present study shows the development of a topical formulation (hydrogel) containing silibinin-loaded pomegranate oil based nanocapsules suspension and its evaluation as an alternative for the treatment of cutaneous UVB radiation-induced damages. For this, an animal model of skin injury induced by UVB radiation was employed. Gellan gum was used as gel forming agent by its direct addition to nanocapsules suspension. The hydrogels showed adequate pH values (5.6-5.9) and a silibinin content close to the theoretical value (1mg/g). Through vertical Franz diffusion cells it was demonstrated that nanocapsules decreased the silibinin retention in the semisolid formulation. All formulations were effective in reducing mice ear edema and leukocyte infiltration induced by UVB radiation 24h after the treatments. After 48h, only the hydrogels containing nanocapsules or silibinin associated with pomegranate oil demonstrated anti-edematogenic effect, as well as the positive control (hydrogel containing silver sulfadiazine 1%). After 72h, the hydrogel containing unloaded pomegranate oil based nanocapsules still presented a small activity. In conclusion, the results of this investigation demonstrated the feasibility to prepare a semisolid formulation presenting performance comparable to the traditional therapeutic option for skin burns (silver sulfadiazine) and with prolonged in vivo anti-inflammatory activity compared to the non-nanoencapsulated compounds. PMID- 28365494 TI - Kazachstania gamospora and Wickerhamomyces subpelliculosus: Two alternative baker's yeasts in the modern bakery. AB - Saccharomyces cerevisiae, the conventional baker's yeast, remains the most domesticated yeast monopolizing the baking industry. Its rapid consumption of sugars and production of CO2 are the most important attributes required to leaven the dough. New research attempts highlight that these attributes are not unique to S. cerevisiae, but also found in several non-conventional yeast species. A small number of these yeast species with similar properties have been described, but remain poorly studied. They present a vast untapped potential for the use as leavening agents and flavor producers due to their genetic and phylogenetic diversity. We assessed the potential of several non-conventional yeasts as leavening agents and flavor producers in dough-like conditions in the presence of high sugar concentrations and stressful environments mimicking conditions found in flour dough. We tested the capabilities of bread leavening and aroma formation in a microbread platform as well as in a bakery setup. Bread leavened with Kazachstania gamospora and Wickerhamomyces subpelliculosus had better overall results compared to control baker's yeast. In addition, both displayed higher stress tolerance and broader aroma profiles than the control baker's yeast. These attributes are important in bread and other farinaceous products, making K. gamospora and W. subpelliculosus highly applicable as alternative baker's yeasts. PMID- 28365495 TI - Relationship of the lumbar plexus branches to the lumbar spine: anatomical study with application to lateral approaches. AB - BACKGROUND CONTEXT: Injuries to the lumbar plexus during lateral approaches to the spine are not uncommon and may result in permanent deficits. However, the literature contains few studies that provide landmarks for avoiding the branches of the lumbar plexus. PURPOSE: The present anatomical study was performed to elucidate the course of these nerves in relation to lateral approaches to the lumbar spine. STUDY DESIGN: This is a quantitative anatomical cadaveric study. METHODS: The lumbar plexus and its branches were dissected on 12 cadaveric sides. Metal wires were laid on the nerves along their paths on the posterior abdominal wall. Fluoroscopy was performed in the anteroposterior and lateral positions. The relationships between regional bony landmarks and the branches of the lumbar plexus were observed. RESULTS: When viewed laterally, the greatest concentration of nerves occurred from the posteroinferior aspect of L4, inferior along the posterior one-third of the body of L5, then at the level of the sacral promontory. On the basis of our study, approaches to the anterior two-thirds of the L4 vertebra and anterior third of L5 will result in the lowest chance of lumbar plexus nerve injury. In addition, lateral muscle dissection through the psoas major should be in a superior to inferior direction in order to minimize nerve injury. Laterally, the widest corridor between branches in the abdominal wall was between the subcostal and iliohypogastric nerves. CONCLUSIONS: The findings of our cadaveric study provide surgeons who approach the lateral lumbar spine with data that could decrease injuries to the branches of the lumbar plexus, thus lessening patient morbidity. PMID- 28365497 TI - System-level perturbations of cell metabolism using CRISPR/Cas9. AB - CRISPR/Cas9 (clustered regularly interspaced palindromic repeats and the associated protein Cas9) techniques have made genome engineering and transcriptional reprogramming studies more advanced and cost-effective. For metabolic engineering purposes, the CRISPR-based tools have been applied to single and multiplex pathway modifications and transcriptional regulations. The effectiveness of these tools allows researchers to implement genome-wide perturbations, test model-guided genome editing strategies, and perform transcriptional reprogramming perturbations in a more advanced manner than previously possible. In this mini-review we highlight recent studies adopting CRISPR/Cas9 for systems-level perturbations and model-guided metabolic engineering. PMID- 28365498 TI - Microbial glycoproteomics. AB - Mass spectrometry-based "-omics" technologies are important tools for global and detailed mapping of post-translational modifications. Protein glycosylation is an abundant and important post translational modification widespread throughout all domains of life. Characterization of glycoproteins, including identification of glycan structure and components, their attachment sites and protein carriers, remains challenging. However, recent advances in glycoproteomics, a subbranch that studies and categorizes protein glycosylations, have greatly expanded the known protein glycosylation space and research in this area is rapidly accelerating. Here, we review recent developments in glycoproteomic technologies with a special focus on microbial protein glycosylation. PMID- 28365496 TI - Optimum pelvic incidence minus lumbar lordosis value after operation for patients with adult degenerative scoliosis. AB - BACKGROUND CONTEXT: Schwab classification for adult degenerative scoliosis (ADS) concluded that health-related quality of life was closely related to curve type and three sagittal modifiers. It was suggested that pelvic incidence minus lumbar lordosis value (PI-LL) should be corrected within -10 degrees ~+10 degrees . However, recent studies also indicated that ideal clinical outcomes could also be achieved in patients without the ideal PI-LL mentioned above. PURPOSE: This study evaluated the relation between the clinical outcomes and the PI-LL of Chinese patients with ADS who received long posterior internal fixation and fusion. STUDY DESIGN: This was a single-center retrospective comparative study of patients treated by long posterior internal fixation and fusion in our hospital between 2010 and 2014. PATIENT SAMPLE: Inclusion criteria were age >45 years at the time of surgery, Cobb angle of lumbar curves >=10 degrees , long posterior internal fixation and fusion >=least 3 motion segments, follow-up >=2 years, complete preoperative and postoperative radiographic data, and functional evaluation results. Exclusion criteria were history of previous lumbar spine surgery, other kinds of scoliosis, history of severe spinal trauma, spinal tumor, ankylosing spondylitis, and spinal tuberculosis. Seventy-four patients were enrolled in this study. OUTCOME MEASURES: Operative parameters included intraoperative blood loss, duration of surgery, length of hospital stay, number of fusion levels, and decompression. The radiological measurements included Cobb angle of the curves and PI-LL. Clinical outcomes were evaluated by the Japanese Orthopaedic Association score, Oswestry Disability Index (ODI), visual analog scale, and Lumbar Stiffness Disability Index (LSDI). In addition, the complications of surgery were also collected. One-way analysis of variance, Student t test, Kruskal-Wallis test, Pearson chi-square test, and curve estimation were calculated for variables. METHODS: All the patients were divided into Group 1 (long instrumentation and fusion to L5) and Group 2 (long instrumentation and fusion to S1). Operative parameters, radiological measurements, clinical outcomes, and complications of surgery were compared between two groups to confirm whether distal fusion level could influence therapeutic effect. Then patients were divided into PI-LL<10 degrees (Group A), 10 degrees <=PI-LL<=20 degrees (Group B), PI-LL>20 degrees (Group C). Operative parameters, radiological measurements, clinical outcomes, and complications of surgery were compared between each of the two groups. Curve estimation was performed to evaluate the relationship between postoperative PI-LL and clinical outcomes. RESULTS: No difference was found between Group 1 and Group 2 in all postoperative parameters (p>.05). There were significant differences in final ODI (p<.001) and final LSDI (p<.001) among Group A, Group B, and Group C. Cubic curve model fitted the relationship between PI-LL and final ODI better than other models (R2=0.379, p<.001). Cubic curve model fitted the relationship between PI-LL and final LSDI better than other models (R2=0.691, p<.001). There was a significant difference in proximal junctional kyphosis (PJK) among groups (p=.038). No significant difference was found in other parameters. CONCLUSIONS: Optimal PI-LL value may be achieved between 10 degrees and 20 degrees in Chinese patients with ADS after long posterior instrumentation and fusion surgery with excellent clinical outcomes and a lower PJK occurrence. PMID- 28365499 TI - Highly efficient simultaneous adsorption and biodegradation of a highly concentrated anionic dye by a high-surface-area carbon-based biocomposite. AB - Mesoporous high-surface-area activated carbon (MHSA-AC), which has a honeycomb structure, was produced from coconut shells by simultaneous chemical and physical activation and used for the rapid adsorption of an anionic dye, namely acid orange 10 (AO10), from water. Owing to its porosity and high Brunauer-Emmett Teller surface area (2283.91 m2g-1), MHSA-AC is a highly efficient adsorbent. It also has good biocompatibility and is a good immobilization carrier; the grooves on the MHSA-AC surface facilitate immobilization. Here, a new, highly efficient, and environmentally friendly simultaneous adsorption and biodegradation (SAB) process was developed. Highly concentrated AO10 (6000 mg L-1, 20 mL) was removed with an efficiency of 100% (pH = 7, 35 degrees C) by SAB using cells immobilized on MHSA-AC (500 mg). The immobilized cells were used directly, without pretreatment; the SAB process is therefore simple and has good potential for application in the treatment of dyes in industrial wastewater. PMID- 28365500 TI - Comprehensive assessment of heavy metal pollution in topsoil of historical urban park on an example of the Planty Park in Krakow (Poland). AB - The Historic Centre of Krakow is on the UNESCO World Heritage List and includes the Main Market Square, which is surrounded by the historical Planty Park. Soils in the Planty Park are an example of a green area in an urban environment that is particularly exposed to heavy metal-rich pollution. To assess the relative content of heavy metals and evaluate the sources of the contamination, pollution indices were used: Enrichment Factor (EF), Geoaccumulation Index (Igeo), Nemerow Pollution Index (PINemerow), Potential Ecological Risk (RI), and Contamination Security Index (CSI). Pollution indices were calculated on the base of both reference and local geochemical backgrounds. Sources of heavy metals in soils of Planty Park are related to its historic role as a metallurgy centre, as well as the more recent urban and industrial development of Krakow centre and neighbouring areas. It is concluded that increased accumulation of heavy metals is an effect of growing numbers of emission sources. The variation of each element may not unambiguously reflect the natural or anthropogenic effect on the Planty Park soil cover. In general, the present and historical emission of pollutants and heavy metal-rich contamination has led to a mixed origin of Cd, Cu, Pb, and Zn. Moreover, it can be assumed that the content of Cr and Ni is derived from natural sources. Furthermore, a comparison of the quality of the Planty Park topsoil with the heavy metal content assessment in other urban parks in the world has been presented. PMID- 28365502 TI - Groundwater quality in Ghaziabad district, Uttar Pradesh, India: Multivariate and health risk assessment. AB - This study aimed to assess the quality of groundwater and potential health risk due to ingestion of heavy metals in the peri-urban and urban-industrial clusters of Ghaziabad district, Uttar Pradesh, India. Furthermore, the study aimed to evaluate heavy metals sources and their pollution level using multivariate analysis and fuzzy comprehensive assessment (FCA), respectively. Multivariate analysis using principle component analysis (PCA) showed mixed origin for Pb, Cd, Zn, Fe, and Ni, natural source for Cu and Mn and anthropogenic source for Cr. Among all the metals, Pb, Cd, Fe and Ni were above the safe limits of Bureau of Indian Standards (BIS) and World Health Organization (WHO) except Ni. Health risk in terms of hazard quotient (HQ) showed that the HQ values for children were higher than the safe level (HQ = 1) for Pb (2.4) and Cd (2.1) in pre-monsoon while in post-monsoon the value exceeded only for Pb (HQ = 1.23). The health risks of heavy metals for the adults were well within safe limits. The finding of this study indicates potential health risks to the children due to chronic exposure to contaminated groundwater in the region. Based on FCA, groundwater pollution could be categorized as quite high in the peri-urban region, and absolutely high in the urban region of Ghaziabad district. This study showed that different approaches are required for the integrated assessment of the groundwater pollution, and provides a scientific basis for the strategic future planning and comprehensive management. PMID- 28365501 TI - Flame retardants and their metabolites in the homes and urine of pregnant women residing in California (the CHAMACOS cohort). AB - Organophosphate flame retardants (PFRs), used in consumer products since the 1970s, persist in the environment. Restrictions on penta-polybrominated diphenyl ether (PBDE) flame retardants resulted in increased use of Firemaster(r) 550 (FM(r) 550), and the organophosphate triesters: tris(1,3- dichloro-2-propyl) phosphate (TDCIPP); tris(chloropropyl) phosphate (TCIPP); tris(2-chloroethyl) phosphate (TCEP); and triphenyl phosphate (TPHP). The objectives of this study were to (1) identify determinants of flame retardants (4 PFRs, PentaBDEs and FM(r) 550) in house dust, (2) measure urinary PFR metabolites in pregnant women, and (3) estimate health risks from PFR exposure. We measured flame retardants in house dust (n = 125) and metabolites in urine (n = 310) collected in 2000-2001 from Mexican American women participating in the CHAMACOS birth cohort study in California. We detected FM(r) 550 and PFRs, including two (TCEP and TDCIPP) known to the state of California to cause cancer, in most dust samples. The maximum TCEP and TDCIPP dust levels were among the highest ever reported although the median levels were generally lower compared to other U.S. cohorts. Metabolites of TDCIPP (BDCIPP: bis(1,3-dichloro-2-propyl) phosphate) and TPHP (DPHP: diphenyl phosphate) were detected in 78% and 79% of prenatal urine samples, respectively. We found a weak but positive correlation between TPHP in dust and DPHP in 124 paired prenatal urine samples (Spearman rho = 0.17; p = 0.06). These results provide information on PFR exposure and risk in pregnant women from the early 2000's and are also valuable to assess trends in exposure and risk given changing fire safety regulations and concomitant changes in chemical flame retardant use. PMID- 28365503 TI - Complete catalytic debromination of hexabromocyclododecane using a silica supported palladium catalyst in alkaline 2-propanol. AB - Although the brominated flame retardant 1,2,5,6,9,10-hexabromocyclododecane (HBCD) has been widely used to reduce the flammability of polymeric materials, it is a toxic and persistent organic compound. In this paper, we report an efficient method for the debromination of HBCD by using a Pd-catalyzed system. HBCD was completely debrominated to the C12 cyclic compounds such as cyclododecatriene, cyclododecadiene, and cyclododecene in a solution of 2-propanol/methanol (99:1, v/v) containing dissolved NaOH in the presence of a silica-supported Pd catalyst (Pd/SiO2) at 35 degrees C. The reaction achieved product yields of 92% for the bromine-free products and 94% for the released Br ions. In the absence of Pd/SiO2, HBCD was partially debrominated to yield penta-, tetra-, and tribrominated C12 cyclic compounds. The HBCD debromination pathway seems to involve both HBr elimination by reaction with NaOH and Pd-catalyzed hydrodebromination by hydrogen transfer from 2-propanol. PMID- 28365504 TI - Metal(loid) speciation and size fractionation in sediment pore water depth profiles examined with a new meso profiling system. AB - In an exemplary incubation study with an anaerobic sediment sampled at an oxbow of the river Lahn in Germany (50 degrees 18'56.87"N; 7 degrees 37'41.25"E) and contaminated by former mining activity, a novel meso profiling and sampling system (messy) is presented. Messy enables a low invasive, automated sampling of pore water profiles across the sediment water interface (SWI), down to ~20 cm depth with a spacial resolution of 1 cm. In parallel to the pore water sampling it measures physicochemical sediment parameters such as redox potential and pH value. In an incubation experiment of 151 days the ability of the setup was proven to address several different aspects relevant for fresh water and marine sediment studies: (i) The influence of mechanical disturbance and oxygen induced acidification on the mobility of 13 metals and metalloids (Cd, Co, Cu, Fe, Mn, Mo, Ni, Sb, U, V, Zn) was quantified based on 11 profiles. The analytes were quantified by inductively coupled plasma-mass spectrometry. Three groups of elements were identified with respect to the release into the pore water and the overlying water under different experimental conditions. (ii) The capability to investigate the impacts of changing physicochemical sediment properties on arsenic and antimony (III/V) speciation is shown. (iii) An approach to obtain information on size fractionation effects and to address the colloidal pore water fractions (0.45 MUm-16 MUm) was successfully conducted for the elements Ag, As, Cu, Fe and Mn. PMID- 28365505 TI - Influence of extreme concentrations of hydrophilic pore-former on reinforced polyethersulfone ultrafiltration membranes for reduction of humic acid fouling. AB - To address the issue of membrane fouling by ubiquitous humic substances, a hydrophilic pore-former-blended polyethersulfone UF membrane was successfully synthesized via the phase inversion method. For the first time, extremely high concentrations of polyvinylpyrrolidone (PVP), up to 20 wt%, were tested as the hydrophilic pore-former in order to determine the optimum concentration for humic acid fouling. Intrinsic membrane parameters such as permeability and selectivity were evaluated using a cross-flow UF filtration setup. Interestingly, as little as 1 wt% added PVP can significantly improve membrane permeability. That tiny amount of added PVP increased membrane flux to 1107 L/m2h.bar from zero flux, with over 90% rejection of humic acid. In addition, pure water permeation increased to over 2400 L/m2h.bar without sacrificing humic acid rejection (around 90%) when 10 wt% PVP was added; pure water permeation decreased to around 1000 L/m2h.bar as added PVP was increased to 20 wt%. The order of water flux increased with the amount of added PVP up to 20 wt% during humic acid fouling while maintaining membrane selectivity. However, the membrane with 10 wt% added PVP showed the best fouling resistance in terms of flux recovery ratio (98%), total flux loss, reversible fouling ratio, and irreversible fouling ratio. Therefore, the addition of 10 wt% PVP is recommended considering cleaning efficiency and the moderately high flux during humic acid fouling for field operation in wastewater reclamation and water treatment processes. PMID- 28365507 TI - IDO1: An important immunotherapy target in cancer treatment. AB - Indoleamine 2,3-dioxigenase 1 (IDO1) acts in pathogenic inflammatory processes and engender immune tolerance to tumor antigens. IDO1 can decrease the tryptophan and produce a series of toxic kynurenine metabolites to promote the immune toleration via GCN2 pathway, mTOR pathway, toxic effect of kynurenine and favoring differentiation of Tregs. IDO1 can be induced in most human cells, especially APCs and cancer cells through canonical and non-canonical NF-kappaB and Jak/STAT pathways, as well as PKC and TGF-beta signaling pathways. A series of human cancers over-express IDO1 in a constitutive way. Thus, IDO1 is likely to be an attractive target for developing inhibitors of tumor treatments. Many preclinical and clinical trials have been underway and suggest that IDO1 inhibitor maybe an effective tool against a wide range of cancers. However, the IDO1 inhibitor alone had been verified that to be disappointment in achieving effective antitumor efficacy. Concentrating on its molecular mechanism in immune toleration and complex environments of cancer, IDO1 inhibitor could cooperate with chemotherapies and other immune target inhibitors to lessen the tumor. PMID- 28365508 TI - In vitro the differences of inflammatory and oxidative reactions due to sulfur mustard induced acute pulmonary injury underlying intraperitoneal injection and intratracheal instillation in rats. AB - This study was to investigate the differences of inflammatory reaction and oxidative stress due to sulfur mustard (SM)-induced acute pulmonary injury via two ways in rats. In intraperitoneal and tracheal SM groups, injected intraperitoneally and instilled intratracheally with 0.1mL diluted SM (0.96 LD50=8mg/kg) and SM (0.98 LD50=2mg/kg) were administered in rats. In bronchoalveolar lavage fluid, serum, and alveolar septum, lactate dehydrogenase, glutathione peroxidase, tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, C-reactive protein, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, l-selectin, r-glutamyl transpeptidase, thiobarbituric acid reactive substances levels as well as the expression of CD4, CD20, CD68, 8 hydroxy deoxyguanosine, nuclear factor-E2-related factor 2, and heme oxygenase-1 measured by ELISA, immune scatter turbidimetry and immunohistochemical method in the intraperitoneal SM group were increased at each time-point compared with the tracheal SM groups, respectively. These data demonstrated an increased inflammatory reaction and oxidative stress indices in rat via intraperitoneal injection under similar SM LD50 doses. PMID- 28365506 TI - New developments in RAN translation: insights from multiple diseases. AB - Since the discovery of repeat-associated non-ATG (RAN) translation, and more recently its association with amyotrophic lateral sclerosis/frontotemporal dementia, there has been an intense focus to understand how this process works and the downstream effects of these novel proteins. RAN translation across several different types of repeat expansions mutations (CAG, CTG, CCG, GGGGCC, GGCCCC) results in the production of proteins in all three reading frames without an ATG initiation codon. The combination of bidirectional transcription and RAN translation has been shown to result in the accumulation of up to six mutant expansion proteins in a growing number of diseases. This process is complex mechanistically and also complex from the perspective of the downstream consequences in disease. Here we review recent developments in RAN translation and their implications on our basic understanding of neurodegenerative disease and gene expression. PMID- 28365509 TI - Myristic acid-modified thymopentin for enhanced plasma stability and immune modulating activity. AB - Natural albumin ligand (fatty acids)-conjugated peptides can rapidly bind to circulating albumin and form complexes to control the release of peptides. The purpose of this study was to prolong the half-life and immune-modulating effects of thymopentin (TP5) by using the albumin binding strategy. We synthesized myristic acid-modified TP5 (TP5-MA) by conjugating a myristic acid-acylated lysine to a permissive site of TP5, which improved the albumin binding affinity of TP5-MA and dramatically enhanced its stability in human plasma. We observed well-preserved bioactivities of TP5-MA in RAW264.7 macrophages using a tumor necrosis factor (TNF)-alpha stimulation assay. Moreover, the prolonged immune modulating effect of TP5-MA was confirmed by the normalized CD4+/CD8+ ratio in immune-depressed rat models, which resulted in a reduced administration frequency (twice per week). In general, the enhanced pharmacokinetic and pharmacodynamic properties of TP5-MA make it a promising product for the treatment of immunodeficiency diseases. PMID- 28365510 TI - Drivers and applications of integrated clean-up technologies for surfactant enhanced remediation of environments contaminated with polycyclic aromatic hydrocarbons (PAHs). AB - Surfactant-enhanced remediation (SER) is considered as a promising and efficient remediation approach. This review summarizes and discusses main drivers on the application of SER in removing polycyclic aromatic hydrocarbons (PAHs) from contaminated soil and water. The effect of PAH-PAH interactions on SER efficiency is, for the first time, illustrated in an SER review. Interactions between mixed PAHs could enhance, decrease, or have no impact on surfactants' solubilization power towards PAHs, thus affecting the optimal usage of surfactants for SER. Although SER can transfer PAHs from soil/non-aqueous phase liquids to the aqueous phase, the harmful impact of PAHs still exists. To decrease the level of PAHs in SER solutions, a series of SER-based integrated cleanup technologies have been developed including surfactant-enhanced bioremediation (SEBR), surfactant enhanced phytoremediation (SEPR) and SER-advanced oxidation processes (SER-AOPs). In this review, the general considerations and corresponding applications of the integrated cleanup technologies are summarized and discussed. Compared with SER AOPs, SEBR and SEPR need less operation cost, yet require more treatment time. To successfully achieve the field application of surfactant-based technologies, massive production of the cost-effective green surfactants (i.e. biosurfactants) and comprehensive evaluation of the drivers and the global cost of SER-based cleanup technologies need to be performed in the future. PMID- 28365511 TI - Influence of graphene oxide on the transport and deposition behaviors of colloids in saturated porous media. AB - The effects of graphene oxide (GO) on the transport and deposition behaviors of colloids with different sizes in packed quartz sand were investigated in both NaCl (10 and 50 mM) and CaCl2 solutions (1 and 5 mM) at pH 6. Fluorescent carboxylate-modified polystyrene latex microspheres (CMLs) with size ranging from 0.2 to 2 MUm were utilized as model colloids. Both breakthrough curves and retained profiles of colloids in the presence and absence of GO in suspensions under all examined solution conditions were analyzed. The breakthrough curves of all three different-sized CMLs with GO were higher yet the retained profiles were lower than those without GO at both examined ionic strengths in NaCl solutions. The observation showed that GO increased the transport and decreased the deposition of all three different-sized CMLs in NaCl solutions. However, in CaCl2 solutions, opposite observation was achieved at two different ionic strength conditions. Specifically, the presence of GO increased the transport and decreased the deposition of all three different-sized CMLs in 1 mM CaCl2 solutions, whereas, it decreased the transport and increased the deposition of all three different-sized CMLs in 5 mM CaCl2 solutions. Comparison the breakthrough curves and retained profiles of CMLs versus those of GO yielded that the overall transport and deposition behaviors of all three different-sized CMLs with GO copresent in suspensions agreed well with the transport and deposition behaviors of GO under all examined conditions. The transport and deposition behaviors of CMLs in packed porous media clearly were controlled by those of GO under the conditions investigated in present study due to the adsorption of CMLs onto GO surfaces. Our study showed that once released into natural environment, GO would adsorb (interact with) different types of colloids and thus have significant influence on the fate and transport of colloids in porous media. PMID- 28365512 TI - Solute pools in Nikanotee Fen watershed in the Athabasca oil sands region. AB - Overburden and tailings materials from oil sands production were used as construction materials as part of a novel attempt to create a self-sustaining, peat accumulating fen-upland ecosystem. To evaluate the potential for elemental release from the construction materials, total elemental concentrations in the tailings sand, petroleum coke and peat used to construct a fen ecosystem were determined using microwave-assisted acid digestions and compared to a leaching experiment conducted under environmentally-relevant conditions. A comparison of solid phase to aqueous Na, Ca, S and Mg concentrations showed they were highly leachable in the materials. Given that the concentrations of these elements can affect plant community structure, it is important to understand their leachability and mobility as they migrate between materials used to construct the system. To that end, a mass balance of aqueous Na, Ca, S and Mg was conducted based on leaching experiments and materials analysis coupled with existing data from the constructed system. The data indicate that there is a large pool of leachable Na, Ca, S and Mg in the system, estimated at 27 t of Na, 14 t of Ca, 37.3 t of S and 8.8 t of Mg. Since recharge mainly drives the fen-upland system water regime, and discharge in the fen, evapo-accumulation of these solutes on the surface may occur. PMID- 28365513 TI - Relationships between soil parameters and physiological status of Miscanthus x giganteus cultivated on soil contaminated with trace elements under NPK fertilisation vs. microbial inoculation. AB - Crop growth and development can be influenced by a range of parameters, soil health, cultivation and nutrient status all play a major role. Nutrient status of plants can be enhanced both through chemical fertiliser additions (e.g. N, P, K supplementation) or microbial fixation and mobilisation of naturally occurring nutrients. With current EU priorities discouraging the production of biomass on high quality soils there is a need to investigate the potential of more marginal soils to produce these feedstocks and the impacts of soil amendments on crop yields within them. This study investigated the potential for Miscanthus x giganteus to be grown in trace element (TE)-contaminated soils, ideally offering a mechanism to (phyto)manage these contaminated lands. Comprehensive surveys are needed to understand plant-soil interactions under these conditions. Here we studied the impacts of two fertiliser treatments on soil physico-chemical properties under Miscanthus x giganteus cultivated on Pb, Cd and Zn contaminated arable land. Results covered a range of parameters, including soil rhizosphere activity, arbuscular mycorrhization (AM), as well as plant physiological parameters associated with photosynthesis, TE leaf concentrations and growth performance. Fertilization increased growth and gas exchange capacity, enhanced rhizosphere microbial activity and increased Zn, Mg and N leaf concentration. Fertilization reduced root colonisation by AMF and caused higher chlorophyll concentration in plant leaves. Microbial inoculation seems to be a promising alternative for chemical fertilizers, especially due to an insignificant influence on the mobility of toxic trace elements (particularly Cd and Zn). PMID- 28365514 TI - Automation of plasma protein binding assay using rapid equilibrium dialysis device and Tecan workstation. AB - Binding of drug molecules to plasma proteins is an important parameter in assessing drug ADME properties. Plasma protein binding (PPB) assays are routinely performed during drug discovery and development. A fully automated PPB assay was developed using rapid equilibrium dialysis (RED) device and Tecan workstation coupled to an automated incubator. The PPB assay was carried out in unsealed RED plates which allowed the assay to be fully automated. The plasma pH was maintained at 7.4 during the 6-h dialysis under 2% CO2 condition. The samples were extracted with acetonitrile and analyzed by liquid chromatography tandem mass spectrometry. The percent bound results of 10 commercial drugs in plasma protein binding were very similar between the automated and manual assays, and were comparable to literature values. The automated assay increases laboratory productivity and is applicable to high-throughput screening of drug protein binding in drug discovery. PMID- 28365515 TI - Pharmacokinetic properties of the synthetic cannabinoid JWH-018 and of its metabolites in serum after inhalation. AB - Each year, synthetic cannabinoids are occurring in high numbers in the illicit drug market, but data on their pharmacology and toxicology are scarcely available. Therefore, a pilot study was performed to assess adverse effects of JWH-018, which is one of the oldest and best known synthetic cannabinoids. Six subjects inhaled smoke from 2 and 3mg JWH-018. The drug and nine of its metabolites were analyzed in their blood samples taken during the following 12h by liquid chromatography-mass spectrometry (LC-MSMS). The maximum concentration of JWH-018 reached 2.9-9.9ng/ml after inhalation and markedly decreased during the next 1.5h, followed by a multiexponential decline (t1/2 in median 1.3h and 5.7h). The concentration of the pentanoic acid metabolite was slightly higher than that of the 3-, 4- and 5-hydroxypentyl metabolites and of the 6-hydroxyindol metabolite. The data also suggest a multiexponential decline and slow terminal elimination of JWH-018 and all metabolites. The detection of JWH-018 and of its metabolites in serum requires high analytical sensitivity. The pharmacokinetic properties of inhaled JWH-018 are similar to that of THC. A slow terminal elimination of drug and metabolites may lead to accumulation in chronic users. PMID- 28365516 TI - Charged derivatization and on-line solid phase extraction to measure extremely low cortisol and cortisone levels in human saliva with liquid chromatography tandem mass spectrometry. AB - The aim of this study was to develop a sensitive, reliable and high-throughput liquid chromatography - electrospray ionization - mass spectrometric (LC-ESI MS/MS) method for the simultaneous quantitation of cortisol and cortisone in human saliva. Derivatization with 2-hydrazino-1-methylpyridine (HMP) was one of the most challenging aspects of the method development. The reagent was reacting with cortisol and cortisone at 60 degrees C within 1h, giving mono- and bis hydrazone derivatives. Investigation of derivatization reaction and sample preparation was detailed and discussed. Improvement of method sensitivity was achieved with charged derivatization and use of on-line solid phase extraction (on-line SPE). The lower limit of quantitation (LLOQ) was 5 and 10pg/ml for cortisol and cortisone, respectively. The developed method was subsequently applied to clinical laboratory measurement of cortisol and cortisone in human saliva. PMID- 28365517 TI - Host-guest kinetic interactions between HP-beta-cyclodextrin and drugs for prediction of bitter taste masking. AB - Cyclodextrins (CD) are widely used bitter taste masking agents, for which the binding equilibrium constant (K) for the drug-CD complex is a conventional parameter for quantitating the taste masking effects. However, some exceptions have been reported to the expected relationship between K and bitterness reduction and the relationship between kinetic parameters of a drug-CD interaction, including association rate constant (Ka) and disassociation rate constant (Kd), and taste masking remains unexplored. In this study, based upon a database of kinetic parameters of drugs-HP-beta-CD generated by Surface Plasmon Resonance Imaging for 485 drugs, the host-guest kinetic interactions between drugs and HP-beta-CD for prediction of taste masking effects have been investigated. The taste masking effects of HP-beta-CD for 13 bitter drugs were quantitatively determined using an electronic gustatory system (alpha-Astree e Tongue). Statistical software was used to establish a model based on Euclidean distance measurements, Ka and Kd of the bitter drugs/HP-beta-CD-complexes (R2=0.96 and P<0.05). Optimized parameters, Ka3, Kd, KaKd, Kd3, Ka2 and Ka/Kd with notable influence, were obtained by stepwise regression from 12 parameters derived from Ka, Kd and K (Ka/Kd). 10-fold cross-validation was used to verify the reliability of the model (correlation coefficient of 0.84, P<0.05). The established model indicated a relationship between Ka, Kd, K and taste masking by HP-beta-CD and was successful in predicting the extent of taste masking by HP beta-CD of 44 bitter drugs, which was in accordance with the literature reported. In conclusion, the relationship between kinetics of drug-CD interactions and taste masking was established and providing a new strategy for predicting the cyclodextrin mediated bitter taste masking. PMID- 28365518 TI - Immunological implications of bovine leukemia virus infection. AB - This study examined neutrophil and monocyte functions and the blood lymphocyte profile of naturally BLV-infected cows with or without persistent lymphocytosis (PL). The percentage of neutrophils and monocytes that phagocytosed Staphylococcus aureus was lower in BLV-infected dairy cows, particularly those with PL. The relative percentage of CD44+ monocytes and neutrophils and CD11b expression by neutrophils was also lower in BLV-infected dairy cows with PL. A correlation between the percentage of CD11b+ neutrophils and that produced reactive oxygen species (ROS) was found. Furthermore, the percentage of CD44+ monocytes was positively correlated with the percentage of monocytes that phagocytosed S. aureus and the same phenomenon was observed for neutrophils. In BLV-infected dairy cows, particularly those with PL, inhibition of monocyte and neutrophil apoptosis was observed. Additionally, the percentage of neutrophils producing ROS was lower in BLV-infected cows with PL, in contrast to higher intensity of intracellular production of ROS by monocytes. The result from the lymphocyte immunophenotyping of BLV-infected cows with PL was an increase in B cells, mainly B CD5+ CD11b+, due to the apoptosis inhibition. In conclusion, this study provides novel insight into the implications of BLV infection for cattle, which can include the dysfunction of blood monocytes and neutrophils. PMID- 28365519 TI - Tissue-specific gene-expression patterns of genes associated with thymol/carvacrol biosynthesis in thyme (Thymus vulgaris L.) and their differential changes upon treatment with abiotic elicitors. AB - Thyme (Thymus vulgaris L.) is known to produce a variety of phenolic monoterpenes such as thymol and carvacrol. Thymol and carvacrol are health-promoting, biocide and antitoxin compounds and have been considered as the main constituents of essential oils in T. vulgaris. To improve our understanding of the regulation of monoterpene biosynthesis in thyme, the expression of genes related to thymol and carvacrol biosynthesis in different tissues and in response to abiotic elicitors was analyzed. Methyl jasmonate (MeJA), salicylic acid (SA), trans-cinnamic acid (tCA) and UV-C irradiation were applied to T. vulgare leaves and transcript levels of early (DXR) and late (TvTPS1, CYP71D178 and CYP71D180) biosynthetic genes of thymol and carvacrol were measured. The results showed that early step and late step genes in thymol/carvacrol biosynthesis are differentially regulated. DXR was not found to be exclusively expressed in glandular trichomes; in contrast, biosynthetic genes including gamma-terpinene synthase (TvTPS1) and two cytochrome P450s, CYP71D178 and CYP71D180, were preferentially expressed in glandular secretory trichomes. The high expression of late biosynthetic genes in glandular trichomes, which also contain the highest concentration of thymol and carvacrol, suggests that glandular trichomes are the structure in which thymol/carvacrol biosynthesis and accumulation occur. Our results indicate that in addition to abiotic elicitors, developmental and spatial factors also play a key role in the biosynthesis of thymol and carvacrol, most likely relating to glandular trichome density and/or activity. Hence optimization of these factors could be considered as a useful strategy to achieve high yield of valuable compounds in T. vulgare or other closely related plant species. PMID- 28365520 TI - Lack of effect of the procarcinogenic 17beta-estradiol on nutrient uptake by the MCF-7 breast cancer cell line. AB - Breast cancer is one of the most frequent cancers in the population, especially in older women. Estrogen is known to be a key hormone in the development and progression of mammary carcinogenesis. In this study, we investigated if the procarcinogenic effect of 17beta-estradiol (E2) in breast cancer MCF-7 cells is dependent on changes in glucose or folic acid cellular uptake. The effect of E2 on uptake of 3H-deoxy-d-glucose, 3H-folic acid, cell proliferation (3-thymidine incorporation assay), culture growth (sulforhodamine B assay), viability (lactate dehydrogenase activity assay), lactate production and migration capacity (injury assay) was evaluated. E2 (48h; 100nM) increased culture growth (16%), proliferation rate (24%), cellular viability (36%) and lactate production (38%). In contrast, E2 did not significantly affect the migration capacity of MCF-7 cells. The pro-proliferative, but not the cytoprotective effect of E2 was found to be ERbeta-dependent. The polyphenols rutin and caffeic acid were not able to counteract the effect of E2 upon cell proliferation and viability. Uptake of 3H deoxy-d-glucose was not affected by E2, either in the absence or presence of GLUT inhibitors (cytochalasin B plus phloridzin). Moreover, E2 did not change GLUT1 mRNA levels. Finally, 3H-folic acid uptake was also not affected by E2, both in the absence and presence of the RFC1 inhibitor, methotrexate. The pro proliferative and cytoprotective effects of E2 are not dependent neither of stimulation of glucose cellular uptake (both GLUT and non-GLUT-mediated) nor of stimulation of folic acid uptake (both RFC1-and non-RFC1-mediated). PMID- 28365521 TI - Cynanchum atratum inhibits the development of atopic dermatitis in 2,4 dinitrochlorobenzene-induced mice. AB - Cynanchum atratum Bunge (Apocynaceae) is a folk medicine to treat skin inflammatory diseases. However, the effects of C. atratum on atopic dermatitis have not been elucidated. In this study, we evaluate the effects of aqueous extract of C. atratum (CA) and its molecular mechanism on atopic dermatitis (AD). 1 and 100mg/mL CA were topically applied to 2,4-dinitrochlorobenzene (DNCB) induced AD-like skin lesions for 11 days. The number of scratching behavior was evaluated for 20min. AD-like symptoms including elevated serum IgE, skin hyperplasia and mast cell infiltration were investigated. The expressions of pro inflammatory cytokines and mediators were analyzed in AD-like skin legions. In addition, pro-inflammatory cytokine production was confirmed in human mast cells (HMC)-1 stimulated with PMA plus A23187 (PMACI). Topical application of CA attenuated total serum IgE level and scratching behavior. Skin hyperplasia including epidermis and dermis was ameliorated in CA-treated skin legions. The number of infiltrated mast cells was significantly decreased by CA treatment. In addition, CA reduced pro-inflammatory cytokines, such as IL-6, IL-1beta and TNF alpha and Th2 cytokine, IL-4, in both of AD-like skin lesions and PMACI sensitized HMC-1 cells. Furthermore, CA decreased the expressions of NF-kappaB, phospho-IkappaBalpha and MAP kinase. These results suggest the inhibitory effects of CA on the development of AD by regulating pro-inflammatory cytokines and mediators. CA could be an effective substance for the treatment of AD. PMID- 28365523 TI - Thrombin generation as a predictor of thromboembolic events in multiple myeloma patients. AB - BACKGROUND: Multiple myeloma (MM) is characterized by an increased incidence of thromboembolic events, especially when immunomodulatory drugs are used. Currently, our ability to predict these thrombotic events is limited. We hypothesized that global coagulation tests may be predictive of thrombotic events in MM patients. METHODS: Blood samples were taken from 36 MM patients before and during routine treatment. Thrombin generation (TG) tests including endogenous thrombin potential (ETP) and peak height were analyzed. RESULTS: Patients were followed for a median of 2.5years. Those who developed thrombotic events were characterized by significantly higher ETP and peak height values compared to those who did not (P=0.001). In these patients, we identified a gradual increase in TG parameters that preceded the thrombotic event. Anticoagulation therapy was associated with a significant decrease in ETP and peak height values (P<0.001). There was no statistically significant difference in TG parameters between newly diagnosed MM patients and healthy subjects, as well as between MM patients prior to and during chemotherapy. CONCLUSIONS: TG tests might predict thrombotic events in MM patients. Thus, TG tests may be incorporated into decision-making protocols of prophylactic anticoagulant therapy in MM patients. PMID- 28365522 TI - Longitudinal course and characteristics of cyclothymic disorder in youth. AB - OBJECTIVES: Epidemiological studies suggest that cyclothymic disorder is the most prevalent subtype of bipolar disorder (BD). However, it is rarely diagnosed, especially in youth. This may be because it can be difficult to ascertain whether a youth meets diagnostic criteria. Clearer, easy-to-apply criteria could reduce misdiagnosis. The objective oftable this study was to determine whether proposed research diagnostic criteria for cyclothymic disorder (RDCyc), based on DSM-5 criteria, could be quantified and validated in youth. METHODS: Participants from the Longitudinal Assessment of Manic Symptoms (LAMS) study were recruited based on symptoms of mania and followed prospectively. RDCyc criteria were: 1) At least one core symptom each of mania and depression; 2) one additional symptom of mania and of depression; 3) persistence over two consecutive six-month periods, and 4) impairment. Exclusionary criteria were having a [hypo]manic or depressive episode. Outcomes at the two-year follow-up were compared between RDCyc youth and other diagnostic groups (BD I/II, BD NOS/non-RDCyc cyclothymic disorder, disruptive behavior disorders [DBD], depression). RESULTS: Thirty-seven youth met RDCyc criteria. There were no consistent differences between the RDCyc youth and youth with other BD subtypes (ps=0.001-0.960, with all-but-one p value >0.02). RDCyc youth had higher depression (p<0.0005) and mania scores (p=0.001), lower functioning (p=0.012), and higher suicide risk than DBD youth (p=0.001). They had higher mania scores than depressed youth (p.018). LIMITATIONS: The majority of youth in the sample were recruited due to elevated symptoms of mania, which may limit the generalizability of the results. Youth were followed for two years, which may not be long enough to determine whether or not they will eventually develop a manic or depressive episode. CONCLUSIONS: Applying RDCyc criteria identified youth who were similar to others with BD and were more impaired than those with DBD. Using these criteria could reduce misdiagnosis and increase our understanding of this prevalent, but largely ignored, diagnosis. PMID- 28365524 TI - Pancreas and liver uptake of new radiolabeled incretins (GLP-1 and Exendin-4) in models of diet-induced and diet-restricted obesity. AB - INTRODUCTION: Radiolabeled GLP-1 and its analog Exendin-4, have been employed in diabetes and insulinoma. No protocol in conventional Diet-Induced Obesity (DIO), and Diet-Restricted Obesity (DRO), has been identified. Aiming to assess pancreatic beta cell uptake in DIO and DRO, a protocol was designed. METHODS: GLP 1-betaAla-HYNIC and HYNIC-betaAla-Exendin-4 were labeled with technetium-99m. Four Swiss mouse models were adopted: Controls (C), Alloxan Diabetes Controls (ADC), DIO and DRO. Biodistribution and ex-vivo planar imaging were documented. RESULTS: Radiolabeling yield was in the range of 97% and both agents were hydrophilic. Fasting Blood Glucose (FBG) was 79.2+/-8.2mg/dl in C, 590.4+/ 23.3mg/dl in ADC, 234.3+/-66.7mg/dl in DIO, and 96.6+/-9.3 in DRO (p=0.010). Biodistribution confirmed predominantly urinary excretion. DIO mice exhibited depressed uptake in liver and pancreas, for both radiomarkers, in the range of ADC. DRO only partially restored such values. 99mTc-HYNIC-betaAla-Exendin-4 demonstrated better results than GLP-1-betaAla-HYNIC-99mTc. CONCLUSIONS: 1) Diet induced obesity remarkably depressed beta cell uptake; 2) Restriction of obesity failed to normalize uptake, despite robust improvement of FBG; 3) HYNIC-betaAla Exendin-4 was the most useful marker; 4) Further studies are recommended in obesity and dieting, including bariatric surgery. PMID- 28365525 TI - Radiosynthesis of (S)-[18F]T1: The first PET radioligand for molecular imaging of alpha3beta4 nicotinic acetylcholine receptors. AB - Recent pharmacologic data revealed the implication of alpha3beta4 nicotinic acetylcholine receptors (nAChRs) in nicotine and drug addiction. To image alpha3beta4 nAChRs in vivo, we aimed to establish the synthesis of a [18F] labelled analog of the highly affine and selective alpha3beta4 ligand (S)-3-(4-(4 fluorophenyl)-1H-1,2,3-triazol-1-yl)quinuclidine ((S)-T1). (S)-[18F]T1 was synthesized from ethynyl-4-[18F]fluorobenzene ([18F]5) and (S)-azidoquinuclidine by click reaction. After a synthesis time of 130min (S)-[18F]T1 was obtained with a radiochemical yield (non-decay corrected) of 4.3+/-1.3%, a radiochemical purity of >99% and a molar activity of >158 GBq/MUmol. The brain uptake and the brain-to blood ratio of (S)-[18F]T1 in mice at 30min post injection were 2.02 (SUV) and 6.1, respectively. According to an ex-vivo analysis, the tracer remained intact (>99%) in brain. Only one major radiometabolite was detected in plasma and urine samples. In-vitro autoradiography on pig brain slices revealed binding of (S) [18F]T1 to brain regions associated with the expression of alpha3beta4 nAChRs, which could be reduced by the alpha3beta4 nAChR selective drug AT-1001. These findings make (S)-[18F]T1 a potential tool for the non-invasive imaging of alpha3beta4 nAChRs in the brain by PET. PMID- 28365526 TI - Analysis of MCNP simulated gamma spectra of CdTe detectors for boron neutron capture therapy. AB - The next step in the boron neutron capture therapy (BNCT) is the real time imaging of the boron concentration in healthy and tumor tissue. Monte Carlo simulations are employed to predict the detector response required to realize single-photon emission computed tomography in BNCT, but have failed to correctly resemble measured data for cadmium telluride detectors. In this study we have tested the gamma production cross-section data tables of commonly used libraries in the Monte Carlo code MCNP in comparison to measurements. The cross section data table TENDL-2008-ACE is reproducing measured data best, whilst the commonly used ENDL92 and other studied libraries do not include correct tables for the gamma production from the cadmium neutron capture reaction that is occurring inside the detector. Furthermore, we have discussed the size of the annihilation peaks of spectra obtained by cadmium telluride and germanium detectors. PMID- 28365527 TI - Imatinib discontinuation in chronic myeloid leukaemia patients with undetectable BCR-ABL transcript level: A systematic review and a meta-analysis. AB - PURPOSE: Tyrosine kinase inhibitors (TKIs) are the cornerstones of treatment for patients with chronic myeloid leukaemia (CML). In recent years, several studies were conducted to evaluate the safety of TKIs discontinuation. We performed a systematic review of the literature to determine the incidence of CML relapse, to identify possible factors relapse rates and to evaluate the long-term safety in CML patients with stable undetectable BCR-ABL transcript level who discontinued TKIs. DESIGN: Studies evaluating TKIs discontinuation in CML patients with undetectable BCR-ABL transcript level were identified by electronic search of MEDLINE and EMBASE database until May 2015. Weighted mean proportion and 95% confidence intervals (CIs) of CML relapse was calculated using a fixed-effects and a random-effects model. Statistical heterogeneity was evaluated using the I2 statistic. RESULTS: Fifteen cohort studies, for a total of 509 patients, were included. Nine studies were at low-risk of bias. All 15 studies included only patients on imatinib. Overall weighted mean molecular relapse rate of CML was 51% (95% CI 44-58%; I2 = 55). Weighted mean molecular relapse rate at 6-month follow up was 41% (95% CI 32-51%; I2 = 78). Eighty percent of molecular relapses occurred in the first 6 months. All 509 patients were alive at 2-year follow-up and only one patient (0.8%, 95% CI 0.2-1.8%; I2 = 0) has progressed to a blastic crisis. CONCLUSIONS: Our findings suggest that imatinib discontinuation is feasible for the majority of CML patients with stable undetectable BCR-ABL transcript level. Approximately 50% of patients remain therapy-free after imatinib discontinuation. Restarting TKIs therapy was followed by a very high rate of molecular response, with no deaths 2 years after discontinuation. PMID- 28365528 TI - European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sezary syndrome - Update 2017. AB - In order to provide a common standard for the treatment of mycosis fungoides (MF) and Sezary syndrome (SS), the European Organisation for Research and Treatment of Cancer-Cutaneous Lymphoma Task Force (EORTC-CLTF) published in 2006 its consensus recommendations for the stage-adapted selection of management options for these neoplasms. Since then, the understanding of the pathophysiology and epidemiology of MF/SS has advanced, the staging system has been revised, new outcome data have been published and novel treatment options have been introduced. The purpose of the present document is to update the original recommendations bearing in mind that there are still only a limited number of controlled studies to support treatment decisions for MF/SS and that often treatment is determined by institutional experience and availability. This consensus on treatment recommendations was established among the authors through a series of consecutive consultations in writing and a round of discussion. Recommended treatment options are presented according to disease stage, whenever possible categorised into first- and second-line options and supported with levels of evidence as devised by the Oxford Centre for Evidence-Based Medicine (OCEBM). Skin-directed therapies are still the most appropriate option for early-stage MF, and most patients can look forward to a normal life expectancy. For patients with advanced disease, prognosis is still grim, and only for a highly selected subset of patients, prolonged survival can be achieved with allogeneic stem cell transplantation (alloSCT). There is a high need for the development and investigation in controlled clinical trials of treatment options that are based on our increasing understanding of the molecular pathology of MF/SS. PMID- 28365529 TI - Giant cell tumour of bone in the denosumab era. AB - Giant cell tumour of bone (GCTB) is an intermediate locally aggressive primary bone tumour, occurring mostly at the meta-epiphysis of long bones. Overexpression of receptor activator of nuclear factor kappa-B ligand (RANKL) by mononuclear neoplastic stromal cells promotes recruitment of numerous reactive multinucleated osteoclast-like giant cells, causing lacunar bone resorption. Preferential treatment is curettage with local adjuvants such as phenol, alcohol or liquid nitrogen. The remaining cavity may be filled with bone graft or polymethylmethacrylate (PMMA) bone cement; benefits of the latter are a lower risk of recurrence, possibility of direct weight bearing and early radiographic detection of recurrences. Reported recurrence rates are comparable for the different local adjuvants (27-31%). Factors increasing the local recurrence risk include soft tissue extension and anatomically difficult localisations such as the sacrum. When joint salvage is impossible, en-bloc resection and endoprosthetic joint replacement may be performed. Local tumour control on the one hand and maintenance of a functional native joint and quality of life on the other hand are the main pillars of surgical treatment for this disease. Current knowledge and development in the fields of imaging, functional biology and systemic therapy are forcing us into a paradigm shift from a purely surgical approach towards a multidisciplinary approach. Systemic therapy with denosumab (RANKL inhibitor) or zoledronic acid (bisphosphonates) blocks, respectively inhibits, bone resorption by osteoclast-like giant cells. After use of zoledronic acid, stabilisation of local and metastatic disease has been reported, although the level of evidence is low. Denosumab is more extensively studied in two prospective trials, and appears effective for the optimisation of surgical treatment. Denosumab should be considered in the standard multidisciplinary treatment of advanced GCTB (e.g. cortical destruction, soft tissue extension, joint involvement or sacral localisation) to facilitate surgery at a later stage, and thereby aiming at immediate local control. Even though several questions concerning optimal treatment dose, duration and interval and drug safety remain unanswered, denosumab is among the most effective drug therapies in oncology. PMID- 28365531 TI - Macrophage activation syndrome: A new complication of checkpoint inhibitors. PMID- 28365530 TI - Regression of melanoma metastases and multiple non-melanoma skin cancers in xeroderma pigmentosum by the PD1-antibody pembrolizumab. PMID- 28365532 TI - Application of the fragment molecular orbital method analysis to fragment-based drug discovery of BET (bromodomain and extra-terminal proteins) inhibitors. AB - The molecular interactions of inhibitors of bromodomains (BRDs) were investigated. BRDs are protein interaction modules that recognizing epsilon-N acetyl-lysine (epsilonAc-Lys) motifs found in histone tails and are promising protein-protein interaction (PPI) targets. First, we analyzed a peptide ligand containing epsilonAc-Lys to evaluate native PPIs. We then analyzed tetrahydroquinazoline-6-yl-benzensulfonamide derivatives found by fragment-based drug design (FBDD) and examined their interactions with the protein compared with the peptide ligand in terms of the inter-fragment interaction energy. In addition, we analyzed benzodiazepine derivatives that are high-affinity ligands for BRDs and examined differences in the CH/pi interactions of the amino acid residues. We further surveyed changes in the charges of the amino acid residues among individual ligands, performed pair interaction energy decomposition analysis and estimated the water profile within the ligand binding site. Thus, useful insights for drug design were provided. Through these analyses and considerations, we show that the FMO method is a useful drug design tool to evaluate the process of FBDD and to explore PPI inhibitors. PMID- 28365533 TI - iMOLSDOCK: Induced-fit docking using mutually orthogonal Latin squares (MOLS). AB - We have earlier reported the MOLSDOCK technique to perform rigid receptor/flexible ligand docking. The method uses the MOLS method, developed in our laboratory. In this paper we report iMOLSDOCK, the 'flexible receptor' extension we have carried out to the algorithm MOLSDOCK. iMOLSDOCK uses mutually orthogonal Latin squares (MOLS) to sample the conformation and the docking pose of the ligand and also the flexible residues of the receptor protein. The method then uses a variant of the mean field technique to analyze the sample to arrive at the optimum. We have benchmarked and validated iMOLSDOCK with a dataset of 44 peptide-protein complexes with peptides. We have also compared iMOLSDOCK with other flexible receptor docking tools GOLD v5.2.1 and AutoDock Vina. The results obtained show that the method works better than these two algorithms, though it consumes more computer time. PMID- 28365534 TI - Performance or appearance? Young female sport participants' body negotiations. AB - The aim of this qualitative study was to examine young female sport participants' experiences and thoughts in terms of sport, their bodies, and social appearance norms. Six focus groups with female sport participants (N=25) from Sweden were conducted. Participants raised many positive experiences in relation to their sport participation, but they also witnessed a conflict in the intersection between the culture within their sport (emphasizing physical performance) and the culture outside their sport (emphasizing physical appearance). Through thematic analysis, four themes illustrating the balancing act between these two cultures were formed: (a) the performing body versus the objectified body, (b) food as fuel versus source of shame, (c) appreciation of body type diversity versus appearance prejudice, and (d) empowerment and agency versus disempowerment and restraints. The findings of this study indicate that young women who engage in sport have to face complex, ambiguous, and restricting norms and notions. PMID- 28365535 TI - A systematic review of the usefulness of pre-employment and pre-duty screening in predicting mental health outcomes amongst emergency workers. AB - Despite a lack of proven efficacy, pre-employment or pre-duty screening, which alleges to test for vulnerability to PTSD and other mental health disorders, remains common amongst emergency services. This systematic review aimed to determine the usefulness of different factors in predicting mental disorder amongst emergency workers and to inform practice regarding screening procedures. Systematic searches were conducted in MEDLINE, PsycINFO and EMBASE to identify cohort studies linking pre-employment or pre-duty measures in first responders with later mental health outcomes. Possible predictors of poor mental health were grouped into six categories and their overall level of evidence was assessed. Twenty-one prospective cohort studies were identified. Dynamic measures including physiological responses to simulated trauma and maladaptive coping styles (e.g. negative self-appraisal) had stronger evidence as predictors of vulnerability in first responders than more traditional static factors (e.g. pre-existing psychopathology). Personality factors (e.g. trait anger) had moderate evidence for predictive power. Based on the evidence reviewed, however, we are unable to provide emergency services with specific information to enhance their current personnel selection. The results indicate that pre-duty screening protocols that include personality assessments and dynamic measures of physiological and psychological coping strategies may be able to identify some personnel at increased risk of mental health problems. However, further longitudinal research is required in order to provide meaningful guidance to employers on the overall utility of either pre-employment or pre-duty screening. In particular, research examining the sensitivity, specificity and positive predictive values of various screening measures is urgently needed. PMID- 28365536 TI - Personality traits are associated with the valence of future imagined events in individuals with schizophrenia. AB - The relationships between the valence (positive or negative) of future imagined events and personality dimensions were examined in patients with schizophrenia. Correlational analyses showed that Extraversion was positively associated with the simulation of more positive future events whereas a statistical trend between Neuroticism and negative emotional valence was found. As in nonclinical individuals, personality is related to characteristics of mental time travel in schizophrenia patients. PMID- 28365537 TI - Suicide attempters examined in a Parisian Emergency Department: Contrasting characteristics associated with multiple suicide attempts or with the motive to die. AB - Among patients examined after a suicide attempt in a Parisian emergency department, we aimed to compare individual characteristics of i) first time and multiple suicide attempters, ii) attempters whose principal motive was "to die" and attempters who had any other motive. Information regarding sociodemographics, clinical characteristics, prior mental health care and outgoing referral was collected in 168 suicide attempters using a standardized form. Associations of these variables with suicide attempt repetition (yes or no) and with the motive underlying the attempt (to die or not) were examined using descriptive statistics and multivariable logistic regression models. Multiple attempters were more likely to have no occupation and to report previous mental health care: mental health follow-up, psychiatric medication or psychiatric hospitalization. The motive to die was not associated with the risk of multiple suicide attempts but related to past suicidal ideation and to some specific precipitating factors, including psychiatric disorder. Patients who intended to die were also more likely to be referred to inpatient than to outpatient psychiatric care. Multiple attempters and attempters who desire to die might represent two distinct high risk groups regarding clinical characteristics and care pathways. They would probably not benefit from the same intervention strategies. PMID- 28365538 TI - Co-infection with HIV associated with reduced vulnerability to symptoms of depression during antiviral treatment for hepatitis C. AB - In this prospective study, we examined new-onset major depressive disorder (MDD) and the differential expression of depressive symptoms in a sample of 132 HCV mono-infected and 40 HIV/HCV co-infected patients initiating pegylated interferon based treatment, including protease inhibitor therapy. The semi-structured clinical interview (SCID-I) was used to assess MDD. Severity of depressive symptoms was assessed using the Hamilton Depression Rating Scale. Of the total sample, 60 patients (34.9%) developed SCID-I defined MDD during antiviral treatment. The proportion of HCV mono- and HIV/HCV patients developing MDD during treatment was not significantly different (37.9% vs. 25%; p=0.185). In both groups, there was a significant increase in HAMD total score from baseline to week 4, and a significant decrease between week 24 and 6 months post-treatment cessation. The greatest increase was observed in the symptoms of the neurovegetative syndrome. HCV mono-infected patients reported higher scores than co-infected patients, particularly impaired activity and somatic symptoms, but the differences were only significant at week 12. The finding that co-infected patients appear less vulnerable to the development of depressive symptoms during HCV treatment than HCV mono-infected patients warrants further exploration, including a thorough analysis of the biological and psychosocial factors associated with this emergence. PMID- 28365539 TI - Electrospinning of continuous poly (L-lactide) yarns: Effect of twist on the morphology, thermal properties and mechanical behavior. AB - Electrospinning PLLA solutions from two oppositely charged nozzles gives a triangle of fibers, also called E-triangle, that assemble into yarns at the convergence point. The formed yarn at the E-triangle was taken up by a unit comprising a take up roller and coupled twister plate, which twist rate can be varied. At all twist rates, uniform and smooth fibers without any beads were formed. The apex angle of the deposited fibers at the E-triangle was larger at higher twist rates. By increasing the twist rate from 80rpm to 320rpm the orientation angle of fibers in the yarn changes from 18.8 degrees to 41.5 degrees . Increasing the twist rate revealed a higher polymer crystallinity likely due to the polymer orientation by the applied tension to the fibers. The ultimate strength and modulus of electrospun yarns were higher when prepared at higher twist rates. However, at the highest twist rates, the strength and modulus of electrospun yarns leveled off and even decreased slightly. The results revealed that the mechanical properties not only depend on the polymer crystallinity but also on the alignment of the fibers in the yarn and the angle at which they were deposited. These biodegradable materials are promising materials to be used in a wide range of applications where environmentally friendly products are required. PMID- 28365540 TI - Unusual effect evidenced at the investigations of the mechanical behavior of composite hydrogels under cyclic compression. AB - An unusual type of mechanical behavior was registered while studying the swollen hydrogel compositions "cellulose-polyacrylamide" in the conditions of multiple cyclic compression tests with the broad variation of the deformation speed. While increasing the deformation rate the clearly seen inversion of the positions of compression and decompression parts of the cyclic stress-strain curves was detected. While carrying out the cyclic compression tests with relatively low deformation speed (about 100-200% of the initial sample's height per minute) the well defined hysteresis of the stress-strain curve can de seen and in these conditions the decompression part of the curve is situated inferior the part corresponding to compression. But while increasing the speed of the deformation the tendency to the progressive approach of the compression and decompression curves to each other is clearly seen. This effect results in the full disappearance of the hysteresis at some value of the deformation speed: the decompression curve coincides with the compression curve. Along with the further increase of the deformation speed the hysteresis appears again but the curve corresponding to compression process is situated inferior the curve corresponding to decompression: the "inversion" of the hysteresis was detected. The precise character of this process depends upon the stiffness of the hydrogel under study. Up to date the convincing explanation o this effect can not be put forward. The authors can only present some hypotheses to explain this phenomenon. PMID- 28365541 TI - Fracture strength and probability of survival of narrow and extra-narrow dental implants after fatigue testing: In vitro and in silico analysis. AB - PURPOSE: To assess the probability of survival (reliability) and failure modes of narrow implants with different diameters. MATERIALS AND METHODS: For fatigue testing, 42 implants with the same macrogeometry and internal conical connection were divided, according to diameter, as follows: narrow (O3.3*10mm) and extra narrow (O2.9*10mm) (21 per group). Identical abutments were torqued to the implants and standardized maxillary incisor crowns were cemented and subjected to step-stress accelerated life testing (SSALT) in water. The use-level probability Weibull curves, and reliability for a mission of 50,000 and 100,000 cycles at 50N, 100, 150 and 180N were calculated. For the finite element analysis (FEA), two virtual models, simulating the samples tested in fatigue, were constructed. Loading at 50N and 100N were applied 30 degrees off-axis at the crown. The von Mises stress was calculated for implant and abutment. RESULTS: The beta (beta) values were: 0.67 for narrow and 1.32 for extra-narrow implants, indicating that failure rates did not increase with fatigue in the former, but more likely were associated with damage accumulation and wear-out failures in the latter. Both groups showed high reliability (up to 97.5%) at 50 and 100N. A decreased reliability was observed for both groups at 150 and 180N (ranging from 0 to 82.3%), but no significant difference was observed between groups. Failure predominantly involved abutment fracture for both groups. FEA at 50N-load, O3.3mm showed higher von-Mises stress for abutment (7.75%) and implant (2%) when compared to the O2.9mm. CONCLUSIONS: There was no significant difference between narrow and extra-narrow implants regarding probability of survival. The failure mode was similar for both groups, restricted to abutment fracture. PMID- 28365542 TI - A methodology for the customized design of colonic stents based on a parametric model. AB - The choice of necessary stent properties depends mainly on the length of the stenosis and degree of occlusion. So a stent design with variable radial stiffness along its longitudinal axis would be a good option. The design proposed corresponds to a tube-based stent with closed diamond-shaped cells made from a NiTi alloy. By acting independently on different geometric factors, variable geometries can be obtained with different radial force reactions. A design adjustment according to specific requirements, in order to get a better fit to ill-duct and reduces complications, is possible. A parametric analysis using finite element has been conducted to determine the influence of slot length, number of circumferential slots, tube thickness and shape-factor on stent mechanical behavior, which allow eliminating the need for extensive experimental work and knowing and quantifying the influence of those factors. The results of finite element simulations have been used, by means of least-squares fit techniques, to obtain analytical expressions for the main mechanical characteristics of the stent (Chronic Expansive Radial Force and Radial Compression Resistance) in terms of the different geometrical factors. This allows the stent geometry to be customized without launching an iterative and costly process of modeling and simulation for each case. PMID- 28365543 TI - Hyper-elastic modeling and mechanical behavior investigation of porous poly-D-L lactide/nano-hydroxyapatite scaffold material. AB - Poly-D-L-lactide/nano-hydroxyapatite (PDLLA/nano-HA) can be used as the biological scaffold material in bone tissue engineering as it can be readily made into a porous composite material with excellent performance. However, constitutive modeling for the mechanical response of porous PDLLA/nano-HA under various stress conditions has been very limited so far. In this work, four types of fundamental compressible hyper-elastic constitutive models were introduced for constitutive modeling and investigation of mechanical behaviors of porous PDLLA/nano-HA. Moreover, the unitary expressions of Cauchy stress tensor have been derived for the PDLLA/nano-HA under uniaxial compression (or stretch), biaxial compression (or stretch), pure shear and simple shear load by using the theory of continuum mechanics. The theoretical results determined from the approach based on the Ogden compressible hyper-elastic constitutive model were in good agreement with the experimental data from the uniaxial compression tests. Furthermore, this approach can also be used to predict the mechanical behaviors of the porous PDLLA/nano-HA material under the biaxial compression (or stretch), pure shear and simple shear. PMID- 28365544 TI - Outcomes from extensive training in critical care echocardiography: Identifying the optimal number of practice studies required to achieve competency. AB - PURPOSE: Optimal instruction and assessment of critical care ultrasound (CCUS) skills requires an assessment tool to measure learner competency and changes over time. In this study, a previously published tool was used to monitor the development of critical care echocardiography (CCE) competencies, the attainment of performance plateaus, and the extent to which previous experience influenced learning. MATERIALS AND METHODS: A group of experts used the Rapid Assessment of Competency in Echocardiography (RACE) scale to rate a large pool of CCE studies performed by novices in a longitudinal design. A total of 380 studies performed by twelve learners were assessed; each study was independently rated by two experts. RESULTS: Learners demonstrated improvement in mean RACE scores over time, with peak performance occurring early in training and a performance plateau thereafter. Learners with little experience received the greatest benefit from training, with an average performance plateau reached at the twentieth study. CONCLUSIONS: Supporting earlier results, the RACE scale provided a straightforward means to assess learner performance with minimal requirements for evaluator training. The results of the present study suggest that novices experience the greatest gains in competency during their first twenty practice studies, a threshold which should serve to guide training initiatives. PMID- 28365545 TI - Alpha-particle radiotherapy: For large solid tumors diffusion trumps targeting. AB - Diffusion limitations on the penetration of nanocarriers in solid tumors hamper their therapeutic use when labeled with alpha-particle emitters. This is mostly due to the alpha-particles' relatively short range (<=100 MUm) resulting in partial tumor irradiation and limited killing. To utilize the high therapeutic potential of alpha-particles against solid tumors, we designed non-targeted, non internalizing nanometer-sized tunable carriers (pH-tunable liposomes) that are triggered to release, within the slightly acidic tumor interstitium, highly diffusive forms of the encapsulated alpha-particle generator Actinium-225 (225Ac) resulting in more homogeneous distributions of the alpha-particle emitters, improving uniformity in tumor irradiation and increasing killing efficacies. On large multicellular spheroids (400 MUm-in-diameter), used as surrogates of the avascular areas of solid tumors, interstitially-releasing liposomes resulted in best growth control independent of HER2 expression followed in performance by (a) the HER2-targeting radiolabeled antibody or (b) the non-responsive liposomes. In an orthotopic human HER2-negative mouse model, interstitially-releasing 225Ac loaded liposomes resulted in the longest overall and median survival. This study demonstrates the therapeutic potential of a general strategy to bypass the diffusion-limited transport of radionuclide carriers in solid tumors enabling interstitial release from non-internalizing nanocarriers of highly-diffusing and deeper tumor-penetrating molecular forms of alpha-particle emitters, independent of cell-targeting. PMID- 28365546 TI - Joint multiple fully connected convolutional neural network with extreme learning machine for hepatocellular carcinoma nuclei grading. AB - Accurate cell grading of cancerous tissue pathological image is of great importance in medical diagnosis and treatment. This paper proposes a joint multiple fully connected convolutional neural network with extreme learning machine (MFC-CNN-ELM) architecture for hepatocellular carcinoma (HCC) nuclei grading. First, in preprocessing stage, each grayscale image patch with the fixed size is obtained using center-proliferation segmentation (CPS) method and the corresponding labels are marked under the guidance of three pathologists. Next, a multiple fully connected convolutional neural network (MFC-CNN) is designed to extract the multi-form feature vectors of each input image automatically, which considers multi-scale contextual information of deep layer maps sufficiently. After that, a convolutional neural network extreme learning machine (CNN-ELM) model is proposed to grade HCC nuclei. Finally, a back propagation (BP) algorithm, which contains a new up-sample method, is utilized to train MFC-CNN ELM architecture. The experiment comparison results demonstrate that our proposed MFC-CNN-ELM has superior performance compared with related works for HCC nuclei grading. Meanwhile, external validation using ICPR 2014 HEp-2 cell dataset shows the good generalization of our MFC-CNN-ELM architecture. PMID- 28365547 TI - Hospitalizations for ambulatory care sensitive conditions across primary care models in Ontario, Canada. AB - The study analyzes the relationship between the risk of a hospitalization for an ambulatory care sensitive condition (ACSC), and the primary care payment and the organizational model used by the patient (fee-for-service, enhanced fee-for service, blended capitation, blended capitation with interdisciplinary teams). The study used linked patient-level health administrative databases and census data housed at the Institute for Clinical Evaluative Sciences in Ontario. Since the province provides universal health care, the data capture all patients in Ontario, Canada's most populous province, with about 13 million inhabitants. All Ontario patients diagnosed with an ACSC prior to April 1, 2012, who had at least one visit with a physician between April 1, 2012, and March 31, 2013, were included in the study (n = 1,710,310). Each patient was assigned to the primary care model of his/her physician. The different models were categorized as Fee-for Service (FFS), enhanced-FFS, blended capitation, and interdisciplinary team. A logistic regression was used to model the risk of having an ACSC hospitalization during the one-year observation period. Adjustments were made for patient characteristics (age, sex, health status, and socio-economic status) and for the geographic location of the practice. Using patients belonging to FFS models as the reference group, the risk of an ACSC hospitalization was higher for patients belonging to the blended-capitation model using interdisciplinary teams (Adjusted Odds Ratio [AOR] = 1.06, 95% confidence interval [CI] = 1.00-1.12) and lower for enhanced-FFS (AOR = 0.78, CI = 0.74-0.82) and blended capitation patients (AOR = 0.91, CI = 0.86-0.96). Using patients with hypertension as the reference group, the odds of an ACSC hospitalization were much higher for patients with any other ACSC and increased with patients' morbidity. The risk was lower for patients of higher socio-economic status (AOR = 0.63, CI = 0.60-0.67) in the highest neighborhood income quintile. PMID- 28365548 TI - Water balance assessment of different substrates on potash tailings piles using non-weighable lysimeters. AB - Water balance is an important tool to evaluate water deficit or excess in crop systems. However, few studies have evaluated the water balance of vegetation grown on the residues from potash mining because the high sodium chloride levels of the residues hinder agricultural development. Therefore, this study aims to measure the water balance components in eight non-weighing lysimeters installed on a potash tailings pile in Heringen (Werra), Germany. These lysimeters were filled with different mixtures of household waste incineration slags and coal combustion residues, resulting in 4 different substrates with two repetitions. Manual seeding was performed using 65% perennial ryegrass (Lolium perenne L.), 25% red fescue (Festuca rubra L.) and 10% Kentucky bluegrass (Poa pratensis L.). Environmental conditions were monitored using an automatic weather station; ground-level and 1-m-high rain gauges. Precipitation and drainage were recorded weekly following the initial saturation of the lysimeters. Water balance components were determined for two hydrological years based on the expression: ET (mm) = P - D, where ET = evapotranspiration, P = precipitation and D = drainage. In addition, evapotranspiration was studied using the standard FAO Penman Monteith equation and Haude's method. The lysimeter water balance measured in 2014 revealed an actual evapotranspiration rate of 66.4% for substrate 1, 66.9% for substrate 2, 65.1% for substrate 3 and 64.1% for substrate 4. In 2015, evapotranspiration ranged from 65.7% for substrate 4 to 70.2% for substrate 1. We observed that the FAO Penman-Monteith and Haude's evapotranspiration models generally overestimated the water use of the green coverage by 67% and 23%, respectively. Our study suggests that an evapotranspiration cover for potash tailings piles may decrease brine drainage from these piles and reduce soil and water contamination. PMID- 28365549 TI - Greenhouse gas balance of mountain dairy farms as affected by grassland carbon sequestration. AB - Recent studies on milk production have often focused on environmental impacts analysed using the Life Cycle Assessment (LCA) approach. In grassland-based livestock systems, soil carbon sequestration might be a potential sink to mitigate greenhouse gas (GHG) balance. Nevertheless, there is no commonly shared methodology. In this work, the GHG emissions of small-scale mountain dairy farms were assessed using the LCA approach. Two functional units, kg of Fat and Protein Corrected Milk (FPCM) and Utilizable Agricultural Land (UAL), and two different emissions allocations methods, no allocation and physical allocation, which accounts for the co-product beef, were considered. Two groups of small-scale dairy farms were identified based on the Livestock Units (LU) reared: <30 LU (LLU) and >30 LU (HLU). Before considering soil carbon sequestration in LCA, performing no allocation methods, LLU farms tended to have higher GHG emission than HLU farms per kg of FPCM (1.94 vs. 1.59 kg CO2-eq/kg FPCM, P <= 0.10), whereas the situation was reversed upon considering the m2 of UAL as a functional unit (0.29 vs. 0.89 kg CO2-eq/m2, P <= 0.05). Conversely, considering physical allocation, the difference between the two groups became less noticeable. When the contribution from soil carbon sequestration was included in the LCA and no allocation method was performed, LLU farms registered higher values of GHG emission per kg of FPCM than HLU farms (1.38 vs. 1.10 kg CO2-eq/kg FPCM, P <= 0.05), and the situation was likewise reversed in this case upon considering the m2 of UAL as a functional unit (0.22 vs. 0.73 kg CO2-eq/m2, P <= 0.05). To highlight how the presence of grasslands is crucial for the carbon footprint of small-scale farms, this study also applied a simulation for increasing the forage self-sufficiency of farms to 100%. In this case, an average reduction of GHG emission per kg of FPCM of farms was estimated both with no allocation and with physical allocation, reaching 27.0% and 28.8%, respectively. PMID- 28365550 TI - Organic waste vermicomposting through the addition of rock dust inoculated with domestic sewage wastewater. AB - The aims of the present study are to assess the organic waste vermicomposting process (cattle manure mixed with tannery sludge) by using inorganic waste (rock dust) inoculated with treated domestic wastewater sewage, as well as the vermicompost application in Ruellia brittoniana seedling production. Different proportions of organic and inorganic waste moistened (or not) in wastewater were vermicomposted (by Eisenia foetida) for 120 days in the first stage of the experiment. Statistically significant earthworm density increase was observed between the 60th and 90th experimental vermicompositing days in all the assessed groups. There was decreased E. foetida population density after 90 days. The K, P, TOC, C/N ratio and Ca, Na and Mg concentrations significantly decreased at the end of the vermicompositing process in comparison to the initial concentrations identified in most treatments. On the other hand, there was pH and N, Fe, Zn and Mn concentration increase in most of the vermicomposts assessed at the end of the experiment. All plants grown in soil containing vermicomposts presented higher Dickson Quality Index (DQI) than the control group, which was cultivated in soil containing commercial topsoil. Plants grown in soil containing 100% cattle manure and tannery sludge, moistened in treated domestic wastewater sewage, showed the highest DQI. Thus, the vermicomposting waste used in the present study, which was inoculated with treated domestic wastewater sewage, is an interesting vermicompost production technology to be used in ornamental plant production. PMID- 28365551 TI - Microwave drying remediation of petroleum-contaminated drill cuttings. AB - The oil reservoir drilling phase generates contaminated cuttings with oil formation itself. These cuttings must be subjected to a decontamination process before being disposed of in the environment. Several technologies are cited in literature for the remediation of soil contaminated with oil or diesel, but none have been reported to remedy drill cuttings contaminated with oil from reservoir. The reservoir drill cuttings are a problem because its discharge is not allowed. The drying technology using microwave has shown promise in the decontamination of cuttings with non-aqueous base drilling fluid, conciliating good robustness and high removal efficiency. Considering the aspects mentioned previously, the application of heating and drying technology using microwave in the remediation of oil contaminated cuttings from well drill was studied. The influence of temperature, specific energy and initial content of water in the drying operation of the reservoir cuttings and of the drilling cuttings artificially contaminated with oil were analyzed. The results showed an influence of temperature in the drying of the cuttings, being necessary to reach the boiling temperature of heavier hydrocarbons to reach an efficient removal in the operation. The specific energy has a strong influence, reaching a total decontamination using 2.67 kWh/kg. The initial water content was effective in removing oil, reducing the residual level of oil with the increase of initial content of water. It also modifies the temperature profiles of the kinetic-warming of the contaminated cuttings. Both the technology and the equipment used proved effective for obtaining total decontamination of oil from the cuttings. PMID- 28365552 TI - Nitrate reduction in water by aluminum alloys particles. AB - Nano zero-valent iron (NZVI) particles have been extensively investigated for nitrate reduction in water. However, the reduction by NZVI requires acidic pH conditions and the final product is exclusively ammonium, leading to secondary contamination. In addition, nanomaterials have potential threats to environment and the transport and storage of nanomaterials are of safety concerns. Aluminum, the most abundant metal element in the earth's crust, is able to reduce nitrate, but the passivation of aluminum limits its application. Here we report Al alloys (85% Al) with Fe, Cu or Si for aqueous nitrate reduction. The Al alloys particles of 0.85-0.08 mm were inactivate under ambient conditions and a simple treatment with warm water (45 degrees C) quickly activated the alloy particles for rapid reduction of nitrate. The Al-Fe alloy particles at a dosage of 5 g/L rapidly reduced 50 mg-N/L nitrate at a reaction rate constant (k) of 3.2 +/- 0.1 (mg N/L)1.5/min between pH 5-6 and at 4.0 +/- 0.1 (mg-N/L)1.5/min between pH 9-11. Dopping Cu in the Al-Fe alloy enhanced the rates of reduction whereas dopping Si reduced the reactivity of the Al-Fe alloy. The Al alloys converted nitrate to 20% nitrogen and 80% ammonium. Al in the alloy particles provided electrons for the reduction and the intermetallic compounds in the alloys were likely to catalyze nitrate reduction to nitrogen. PMID- 28365553 TI - Restoration of liquid effluent from oil palm agroindustry in Malaysia using UV/TiO2 and UV/ZnO photocatalytic systems: A comparative study. AB - In this study, we have employed a photocatalytic method to restore the liquid effluent from a palm oil mill in Malaysia. Specifically, the performance of both TiO2 and ZnO was compared for the photocatalytic polishing of palm oil mill effluent (POME). The ZnO photocatalyst has irregular shape, bigger in particle size but smaller BET specific surface area (9.71 m2/g) compared to the spherical TiO2 photocatalysts (11.34 m2/g). Both scavenging study and post-reaction FTIR analysis suggest that the degradation of organic pollutant in the TiO2 system has occurred in the bulk solution. In contrast, it is necessary for organic pollutant to adsorb onto the surface of ZnO photocatalyst, before the degradation took place. In addition, the reactivity of both photocatalysts differed in terms of mechanisms, photocatalyst loading and also the density of photocatalysts. From the stability test, TiO2 was found to offer higher stability, as no significant deterioration in activity was observed after three consecutive cycles. On the other hand, ZnO lost around 30% of its activity after the 1st-cycle of photoreaction. The pH studies showed that acidic environment did not improve the photocatalytic degradation of the POME, whilst in the basic environment, the reaction media became cloudy. In addition, longevity study also showed that the TiO2 was a better photocatalyst compared to the ZnO (74.12%), with more than 80.0% organic removal after 22 h of UV irradiation. PMID- 28365554 TI - Worse than imagined: Unidentified virtual water flows in China. AB - The impact of virtual water flows on regional water scarcity in China had been deeply discussed in previous research. However, these studies only focused on water quantity, the impact of virtual water flows on water quality has been largely neglected. In this study, we incorporate the blue water footprint related with water quantity and grey water footprint related with water quality into virtual water flow analysis based on the multiregional input-output model of 2007. The results find that the interprovincial virtual flows accounts for 23.4% of China's water footprint. The virtual grey water flows are 8.65 times greater than the virtual blue water flows; the virtual blue water and grey water flows are 91.8 and 794.6 Gm3/y, respectively. The use of the indicators related with water quantity to represent virtual water flows in previous studies will underestimate their impact on water resources. In addition, the virtual water flows are mainly derived from agriculture, chemical industry and petroleum processing and the coking industry, which account for 66.8%, 7.1% and 6.2% of the total virtual water flows, respectively. Virtual water flows have intensified both quantity- and quality-induced water scarcity of export regions, where low value-added but water-intensive and high-pollution goods are produced. Our study on virtual water flows can inform effective water use policy for both water resources and water pollution in China. Our methodology about virtual water flows also can be used in global scale or other countries if data available. PMID- 28365555 TI - Reported hours of infection education received positively associated with student nurses' ability to comply with infection prevention practices: Results from a nationwide survey. PMID- 28365556 TI - A fluorescent glycosyl-imprinted polymer for pH and temperature regulated sensing of target glycopeptide antibiotic. AB - This paper demonstrates a new strategy for developing a fluorescent glycosyl imprinted polymer for pH and temperature regulated sensing of target glycopeptide antibiotic. The technique provides amino modified Mn-doped ZnS QDs as fluorescent supports, 4-vinylphenylbronic acid as a covalent monomer, N-isopropyl acrylamide as a thermo-responsive monomer in combination with acrylamide as a non-covalent monomer, and glycosyl moiety of a glycopeptide antibiotic as a template to produce fluorescent molecularly imprinted polymer (FMIP) in aqueous solution. The FMIP can alter its functional moieties and structure with pH and temperature stimulation. This allows recognition of target molecules through control of pH and temperature. The fluorescence intensity of the FMIP was enhanced gradually as the concentration of telavancin increased, and showed selective recognition toward the target glycopeptide antibiotic preferentially among other antibiotics. Using the FMIP as a sensing material, good linear correlations were obtained over the concentration range of 3.0-300.0MUg/L and with a low limit of detection of 1.0MUg/L. The analysis results of telavancin in real samples were consistent with that obtained by liquid chromatography tandem mass spectrometry. PMID- 28365557 TI - Ultrasensitive electrochemical biosensing platform based on spherical silicon dioxide/molybdenum selenide nanohybrids and triggered Hybridization Chain Reaction. AB - An ultrasensitive sandwich-type electrochemical biosensor for DNA detection is developed based on spherical silicon dioxide/molybdenum selenide (SiO2@MoSe2) and graphene oxide-gold nanoparticles (GO-AuNPs) hybrids as carrier triggered Hybridization Chain Reaction (HCR) coupling with multi-signal amplification. The proposed sensoring assay utilizes a spherical SiO2@MoSe2/AuNPs as sensing platform and GO-AuNPs hybrids as carriers to supply vast binding sites. H2O2+HQ system is used for DNA detection and HCR as the signal and selectivity enhancer. The sensor is designed in sandwich type to increase the specificity. As a result, the present biosensor exhibits a good dynamic range from 0.1fM to 100pM with a low detection limit of 0.068fM (S/N=3). This work shows a considerable potential for quantitative detection of DNA in early clinical diagnostics. PMID- 28365558 TI - Trends in prevalence and management of diabetes and related vascular risks in Japanese adults: Japan National Health and Nutrition Surveys 2003-2012. AB - AIMS: To examine temporal changes in health system performance for the control of diabetes and related risks for vascular complications in Japan over a decade. METHODS: Data of 51,128 individuals aged >=20years were obtained from the National Health and Nutrition Surveys in 2003-2012. Diabetes was defined as currently being treated by insulin or oral hypoglycaemic agents or having a glycated haemoglobin (HbA1c) level >=6.5% (>=48mmol/mol). We estimated the prevalence and proportions of people with diabetes being treated and achieving target goals of HbA1c <7.0% (<53mmol/mol), blood pressure <130/80mmHg, and non high-density lipoprotein cholesterol <130mg/dL. All estimates were age standardized using the Japanese population in 2010. RESULTS: The age-standardized prevalence of diabetes remained constant at approximately 8% and was significantly higher in men (P<0.001) and in individuals age >=65years (P<0.001) throughout the study period. The proportion of people with diabetes being treated significantly increased from 41.8% (95% confidence interval, 37.2-46.5%) in 2003 to 54.9% (51.9-57.8%) in 2012, and the proportion of those having controlled HbA1c significantly increased from 13.4% (10.3-17.3%) in 2003 to 28.8% (26.3 31.5%) in 2012. These two rates were significantly higher in age >=65years compared with younger adults in most of the survey years (P<0.05). The control rates of blood pressure and non-high-density lipoprotein cholesterol remained around 20% and 30-40%, respectively. CONCLUSIONS: Diabetes management in Japan has improved over the past decade but is still inadequate for prevention of vascular complications. PMID- 28365559 TI - Different inverse association of large high-density lipoprotein subclasses with exacerbation of insulin resistance and incidence of type 2 diabetes: The Nagahama study. AB - AIMS: In addition to its antiatherogenic action, high-density lipoprotein (HDL) may also have an antidiabetes function. Although the biological actions of small HDL (HDL3) and large HDL (HDL2) subclasses may be different, evidence in support of that hypothesis is lacking. The aim of this study was to clarify the difference in prognostic significance of HDL subclasses for exacerbation of insulin resistance and incidence of type 2 diabetes in the general population. METHODS: Study participants included 8365 community residents 52+/-13years of age not taking lipid lowering drugs. Serum HDL cholesterol subclasses and low-density lipoprotein subclasses, were measured by a homogeneous assay. Insulin resistance was assessed by homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Cross-sectional analysis adjusted for possible covariates found that HDL2 cholesterol (HDL2-C) levels were inversely associated with HOMA-IR (beta= 0.169, p<0.001), whereas HDL3-C had the opposite association (beta=0.054, p<0.001). Similar results were found in an analysis for type 2 diabetes (HDL2-C, odds ratio=0.96, p=0.001; HDL3-C, odds ratio=1.04, p=0.181). In a longitudinal analysis with 5.0years of follow-up, HDL2-C was inversely associated with exacerbation of insulin resistance (beta=-0.163, p<0.001); HDL3-C had the opposite association (beta=0.026, p=0.037). During follow-up, 205 individuals were newly diagnosed with diabetes, and HDL2-C level was associated with an inverse risk of type 2 diabetes incidence (odds ratio=0.98, p=0.006). CONCLUSIONS: HDL may have an antidiabetic function; the prognostic value of HDL2 C for diabetes and insulin resistance might be better than that of HDL3-C. PMID- 28365560 TI - Clinical significance of serum complement factor 3 in patients with type 2 diabetes mellitus. AB - AIMS: Although serum complement factor 3 (C3) is an acute phase reactant mainly synthesized in the liver, several recent studies have shown high C3 gene expression in adipose tissue (AT). However, the relationship between C3 and AT levels has not been fully clarified in type 2 diabetes mellitus (T2DM) patients. METHODS: A total of 164 T2DM patients (109men and 55 women) participated in this cross-sectional study. A computed tomography scan was performed to measure visceral, subcutaneous, and total AT. The correlation between these factors and C3 levels was examined using Pearson's correlation analysis. A multivariate regression model was used to assess an independent determinant associated with C3 levels after adjusting the explanatory variables (i.e., all ATs [visceral, subcutaneous, and total], and clinical features [sex, age, body mass index, waist circumference, glycated hemoglobin, duration of diabetes, systolic blood pressure, diastolic blood pressure, aspartate aminotransferase levels, alanine aminotransferase levels, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, log(triglyceride levels), estimated glomerular filtration rate, and log(high-sensitivity C-reactive protein levels)]). RESULTS: Serum C3 levels were correlated with visceral, subcutaneous, and total AT among both men (r=0.505, p<0.001; r=0.545, p<0.001; r=0.617, p<0.001, respectively) and women (r=0.396, p=0.003; r=0.517, p<0.001; r=0.548, p<0.001, respectively). In the multivariate regression model, the association between total AT and C3 levels remained significantly positive (beta=0.490, p<0.001). CONCLUSIONS: Serum C3 levels are associated with visceral, subcutaneous, and total AT in T2DM patients. Furthermore, C3 levels seem to be a marker for overall adiposity rather than regional adiposity. PMID- 28365561 TI - Are the results from the 2014 UK national survey on the management of diabetic ketoacidosis applicable to individual centres? AB - BACKGROUND: In 2013 the Joint British Diabetes Societies published an update to their 2010 guideline on the management of diabetic ketoacidosis (DKA). In 2014 a national survey was conducted to assess the management of DKA across the UK using the JBDS or local guidelines. Hospitals were invited to submit data on 5 people presenting with DKA. These data were published in 2016. However, whether those national results were applicable to individual hospitals remains unknown. AIM: To assess the management of people presenting with DKA at a single hospital and compare the results with the national dataset. METHODS: Using the identical data collection tool as used in the national survey we collected information on 40 subjects (a total of 52 admissions) admitted with DKA between April 2014 and July 2015. RESULTS: The data collected locally were very similar to those found in the national dataset. The management of DKA was best during the first few hours after admission, then biochemical and physical monitoring frequency decreased. The number of people who developed hypokalaemia and hypoglycaemia were very similar to the national data. Rates of biochemical improvement were slightly better locally. CONCLUSIONS: The data from the national DKA survey, even though based on a maximum of 5 people per hospital from across the UK are applicable at a hospital level. PMID- 28365562 TI - Responses of mixed methanotrophic consortia to variable Cu2+/Fe2+ ratios. AB - Methane mitigation in landfill top cover soils is mediated by methanotrophs whose optimal methane (CH4) oxidation capacity is governed by environmental and complex microbial community interactions. Optimization of CH4 remediating bio-filters need to take microbial responses into account. Divalent copper (Cu2+) and iron (Fe2+) are present in landfills at variable ratios and play a vital role in methane oxidation capacity and growth of methanotrophs. This study, as a first of its kind, therefore quantified effects of variable Cu2+ and Fe2+ (5:5, 5:25 and 5:50 MUM) ratios on mixed methanotrophic communities enriched from landfill top cover (LB) and compost soils (CB). CH4 oxidation capacity, CH4 removal efficiencies, fatty acids content/profiles and polyhydroxybutyrate (PHB; a biopolymer) contents were also analysed to quantify performance and potential co product development. Mixed methanotroph cultures were raised in 10 L continuous stirred tank reactors (CSTRs, Bioflo(r) & Celligen(r) 310 Fermentor/Bioreactor; John Morris Scientific, Chatswood, NSW, Australia). Community structure was determined by amplifying the V3-V4 region of 16s rRNA gene. Community structure and, consequently, fatty acid-profiles changed significantly with increasing Cu2+/Fe2+ ratios, and responses were different for LB and CB. Effects on methane oxidation capacities and PHB content were similar in the LB- and CB-CSTR, decreasing with increasing Cu2+/Fe2+ ratios, while biomass growth was unaffected. In general, high Fe2+ concentration favored growth of the type -II methanotroph Methylosinus in the CB-CSTR, but methanotroph abundances decreased in the LB CSTR. Increase in Cu2+/Fe2+ ratio increased the growth of Sphingopyxis in both systems, while Azospirllum was co-dominant in the LB- but absent in the CB-CSTR. After 13 days, methane oxidation capacities and PHB content decreased by ~50% and more in response to increasing Fe2+ concentrations. Although methanotroph abundance was ~2% in the LB- (compared to >50% in CB-CSTR), methane oxidation capacities were comparable in the two systems, suggesting that methane oxidation capacity was maintained by the dominant Azospirllum and Sphingopyxis in the LB CSTR. Despite similar methanotroph inoculum community composition and controlled environmental variables, increasing Cu2+/Fe2+ ratios resulted in significantly different microbial community structures in the LB- and CB-CSTR, indicative of complex microbial interactions. In summary, our results suggest that a detailed understanding of allelopathic interactions in mixed methanotrophic consortia is vital for constructing robust bio-filters for CH4 emission abatement. PMID- 28365563 TI - Pedestrian Inattention Blindness While Playing Pokemon Go as an Emerging Health Risk Behavior: A Case Report. AB - BACKGROUND: Cases of trauma resulting from the use of mobile phones while driving motor vehicles have become quite common in recent years. Road injuries incurred by people playing video games on mobile phones (or other media devices) while walking have also become a cause for concern. Pokemon Go has been the world's most popular game since it was launched in July 2016, with more than 15 million players trying to catch all Pokemon available in the game; however, the case detailed here is the first reported accident in the medical literature caused by a pedestrian distracted by the game while crossing a street. OBJECTIVE: We aim to provide additional information on the innovative nature of distractions that generate risks in road-users, and to explore the underreporting of pedestrian motor vehicle collisions due to mobile device usage. METHODS: We included in this case report a 25-year-old male who suddenly crossed a road while playing Pokemon Go and was hit by a van, reporting several injuries and being assisted by the Emergency Medical Service of our hospital (Padova, Italy). The patient's history, the circumstances in which the collision happened, imaging data, and clinical course information were recorded per our hospital's privacy policy. RESULTS: The patient hit by the van was playing Pokemon Go on his mobile phone while crossing a street, despite red traffic lights, which he did not notice due to of the distraction induced by the game. CONCLUSIONS: Mobile videogames that imply movement (ie, walking, running, cycling) to play are an effective way to improve physical activity practice, especially in adolescents and young adults. Nevertheless, cases like the one presented here point out that these games could pose a significant risk to users who play while walking, cycling, or driving in unsafe areas such as city streets, because players become distracted and may ignore surrounding hazards. Comprehensive, multilevel interventions are needed to reduce accidents caused by distraction, and to stress findings on the positive and negative effects of video games, which are becoming a source of public health concern. Health care providers should be aware of their chief role in these possible prevention strategies, based on their direct interactions with road incident victims. PMID- 28365564 TI - Statin Treatment and Clinical Outcomes of Heart Failure Among Africans: An Inverse Probability Treatment Weighted Analysis. AB - BACKGROUND: Randomized control trials of statins have not demonstrated significant benefits in outcomes of heart failure (HF). However, randomized control trials may not always be generalizable. The aim was to determine whether statin and statin type-lipophilic or -hydrophilic improve long-term outcomes in Africans with HF. METHODS AND RESULTS: This was a retrospective longitudinal study of HF patients aged >=18 years hospitalized at a tertiary healthcare center between January 1, 2009 and December 31, 2013 in Ghana. Patients were eligible if they were discharged from first admission for HF (index admission) and followed up to time of all-cause, cardiovascular, and HF mortality or end of study. Multivariable time-dependent Cox model and inverse-probability-of-treatment weighting of marginal structural model were used to estimate associations between statin treatment and outcomes. Adjusted hazard ratios were also estimated for lipophilic and hydrophilic statin compared with no statin use. The study included 1488 patients (mean age 60.3+/-14.2 years) with 9306 person-years of observation. Using the time-dependent Cox model, the 5-year adjusted hazard ratios with 95% CI for statin treatment on all-cause, cardiovascular, and HF mortality were 0.68 (0.55-0.83), 0.67 (0.54-0.82), and 0.63 (0.51-0.79), respectively. Use of inverse probability-of-treatment weighting resulted in estimates of 0.79 (0.65-0.96), 0.77 (0.63-0.96), and 0.77 (0.61-0.95) for statin treatment on all-cause, cardiovascular, and HF mortality, respectively, compared with no statin use. CONCLUSIONS: Among Africans with HF, statin treatment was associated with significant reduction in mortality. PMID- 28365565 TI - Bilirubin Prevents Atherosclerotic Lesion Formation in Low-Density Lipoprotein Receptor-Deficient Mice by Inhibiting Endothelial VCAM-1 and ICAM-1 Signaling. AB - BACKGROUND: Numerous epidemiological studies support an inverse association between serum bilirubin levels and the incidence of cardiovascular disease; however, the mechanism(s) by which bilirubin may protect against atherosclerosis is undefined. The goals of the present investigations were to assess the ability of bilirubin to prevent atherosclerotic plaque formation in low-density lipoprotein receptor-deficient (Ldlr-/- ) mice and elucidate the molecular processes underlying this effect. METHODS AND RESULTS: Bilirubin, at physiological concentrations (<=20 MUmol/L), dose-dependently inhibits THP-1 monocyte migration across tumor necrosis factor alpha-activated human umbilical vein endothelial cell monolayers without altering leukocyte binding or cytokine production. A potent antioxidant, bilirubin effectively blocks the generation of cellular reactive oxygen species induced by the cross-linking of endothelial vascular cell adhesion molecule 1 (VCAM-1) or intercellular adhesion molecule 1 (ICAM-1). These findings were validated by treating cells with blocking antibodies or with specific inhibitors of VCAM-1 and ICAM-1 signaling. When administered to Ldlr-/- mice on a Western diet, bilirubin (30 mg/kg intraperitoneally) prevents atherosclerotic plaque formation, but does not alter circulating cholesterol or chemokine levels. Aortic roots from bilirubin-treated animals exhibit reduced lipid and collagen deposition, decreased infiltration of monocytes and lymphocytes, fewer smooth muscle cells, and diminished levels of chlorotyrosine and nitrotyrosine, without changes in VCAM-1 or ICAM-1 expression. CONCLUSIONS: Bilirubin suppresses atherosclerotic plaque formation in Ldlr-/- mice by disrupting endothelial VCAM-1- and ICAM-1-mediated leukocyte migration through the scavenging of reactive oxygen species signaling intermediaries. These findings suggest a potential mechanism for the apparent cardioprotective effects of bilirubin. PMID- 28365566 TI - Prognostic Significance of Interleukin-34 (IL-34) in Patients With Chronic Heart Failure With or Without Renal Insufficiency. AB - BACKGROUND: Renal dysfunction, commonly associated with cardiac dysfunction, has predictive value for adverse long-term outcomes in heart failure (HF). We previously identified a novel renal biomarker, interleukin-34 (IL-34), elevated in HF patients and associated with kidney dysfunction and coronary artery disease during HF. However, the prognostic value of IL-34 in HF remains unclear, so that the present study aimed to determine it. METHODS AND RESULTS: This prospective, observational study included 510 consecutive HF patients with their serum IL-34 as well as other variables measured at baseline, and they were followed up for 2 years. The primary end point was a composite of cardiovascular death or a first HF hospitalization, with cardiovascular death, HF hospitalization, and all-cause mortality as secondary outcomes. There was a significant and gradual increase in risk as IL-34 increased, determined by log-rank tests with Kaplan-Meier curves. Serum IL-34 was also a significant prognostic predictor of the primary end point (1.301 [1.115-1.518]; P=0.001), cardiovascular death (1.347 [1.096-1.655]; P=0.005), HF hospitalization (1.234 [1.018-1.494]; P=0.032), and all-cause mortality (1.343 [1.115-1.618]; P=0.002) in HF as per SD increase in the log IL 34 level after adjusting for age, sex, traditional risk factors, and N-terminal pro-brain natriuretic peptide. Especially, IL-34 had a more-significant prognostic value in HF patients with kidney impairment than those without. CONCLUSIONS: IL-34 is a significant predictor of cardiovascular death, HF hospitalization, and all-cause mortality in chronic HF, especially when concomitant with renal dysfunction. Serum IL-34 measurement may provide new insights linking kidney impairment to poor HF outcomes beyond other renal markers. PMID- 28365567 TI - Use of p53-Silenced Endothelial Progenitor Cells to Treat Ischemia in Diabetic Peripheral Vascular Disease. AB - BACKGROUND: Peripheral vascular disease is a major diabetes mellitus-related complication. In this study, we noted that expressions of proapoptotic p53 gene and its downstream cascade gene such as p21 are upregulated in hyperglycemia. Therefore, we investigated whether p53- and p21-silenced endothelial progenitor cells (EPCs) were able to survive in hyperglycemic milieu, and whether transplantation of either p53 knockout (KO) or p21KO or p53- and p21-silenced EPCs could improve collateral vessel formation and blood flow in diabetic vaso occlusive peripheral vascular disease mouse models. METHODS AND RESULTS: We transplanted p53 and p21KO mouse EPCs (mEPCs) into streptozotocin-induced diabetic (type 1 diabetes mellitus model) C57BL/6J and db/db (B6.BKS(D)-Leprdb/J) (type 2 model) post-femoral artery occlusion. Similarly, Ad-p53-silenced and Ad p21-silenced human EPCs (CD34+) cells were transplanted into streptozotocin induced diabetic NOD.CB17-Prkdcscid/J mice. We measured blood flow at 3, 7, and 10 days and hindlimb muscles were obtained postsacrifice for mRNA estimation and CD31 staining. Enhanced blood flow was noted with delivery of p53 and p21KO mEPCs in streptozotocin-induced diabetic C57BL/6J mice. Similar results were obtained when human Ad-p53shEPCs(CD34+) and Ad-p21shEPCs(CD34+) were transplanted into streptozotocin-induced nonobese diabetic severe combined immunodeficiency mice. Gene expression analysis of p53 and p21KO EPCs transplanted hindlimb muscles showed increased expression of endothelial markers such as endothelial nitric oxide synthase, vascular endothelial growth factor A, and platelet endothelial cell adhesion molecule 1. Similarly, quantitative reverse transcriptase polymerase chain reaction of human Ad-p53shEPCs (CD34+)- and Ad-p21shEPCs (CD34+) transplanted hindlimb muscles also showed increased expression of endothelial markers such as vascular endothelial growth factor A, noted primarily in the p53 silenced EPCs group. However, such beneficial effect was not noted in the db/db type 2 diabetic mouse models. CONCLUSIONS: Transient silencing of p53 using adenoviral vector in EPCs may have a therapeutic role in diabetic peripheral vascular disease. PMID- 28365568 TI - Benefits of Permanent His Bundle Pacing Combined With Atrioventricular Node Ablation in Atrial Fibrillation Patients With Heart Failure With Both Preserved and Reduced Left Ventricular Ejection Fraction. AB - BACKGROUND: Clinical benefits from His bundle pacing (HBP) in heart failure patients with preserved and reduced left ventricular ejection fraction are still inconclusive. This study evaluated clinical outcomes of permanent HBP in atrial fibrillation patients with narrow QRS who underwent atrioventricular node ablation for heart failure symptoms despite rate control by medication. METHODS AND RESULTS: The study enrolled 52 consecutive heart failure patients who underwent attempted atrioventricular node ablation and HBP for symptomatic atrial fibrillation. Echocardiographic left ventricular ejection fraction and left ventricular end-diastolic dimension, New York Heart Association classification and use of diuretics for heart failure were assessed during follow-up visits after permanent HBP. Of 52 patients, 42 patients (80.8%) received permanent HBP and atrioventricular node ablation with a median 20-month follow-up. There was no significant change between native and paced QRS duration (107.1+/-25.8 versus 105.3+/-23.9 milliseconds, P=0.07). Left ventricular end-diastolic dimension decreased from the baseline (P<0.001), and left ventricular ejection fraction increased from baseline (P<0.001) in patients with a greater improvement in heart failure with reduced ejection fraction patients (N=20) than in heart failure with preserved ejection fraction patients (N=22). New York Heart Association classification improved from a baseline 2.9+/-0.6 to 1.4+/-0.4 after HBP in heart failure with reduced ejection fraction patients and from a baseline 2.7+/-0.6 to 1.4+/-0.5 after HBP in heart failure with preserved ejection fraction patients. After 1 year of HBP, the numbers of patients who used diuretics for heart failure decreased significantly (P<0.001) when compared to the baseline diuretics use. CONCLUSIONS: Permanent HBP post-atrioventricular node ablation significantly improved echocardiographic measurements and New York Heart Association classification and reduced diuretics use for heart failure management in atrial fibrillation patients with narrow QRS who suffered from heart failure with preserved or reduced ejection fraction. PMID- 28365569 TI - An Appraisal of Methods Recently Recommended for Testing Salt Sensitivity of Blood Pressure. PMID- 28365570 TI - The pathogen-related yeast protein Pry1, a member of the CAP protein superfamily, is a fatty acid-binding protein. AB - Members of the CAP superfamily (cysteine-rich secretory proteins, antigen 5, and pathogenesis-related 1 proteins), also known as SCP superfamily (sperm-coating proteins), have been implicated in many physiological processes, including immune defenses, venom toxicity, and sperm maturation. Their mode of action, however, remains poorly understood. Three proteins of the CAP superfamily, Pry1, -2, and 3 (pathogen related in yeast), are encoded in the Saccharomyces cerevisiae genome. We have shown previously that Pry1 binds cholesterol in vitro and that Pry function is required for sterol secretion in yeast cells, indicating that members of this superfamily may generally bind sterols or related small hydrophobic compounds. On the other hand, tablysin-15, a CAP protein from the horsefly Tabanus yao, has been shown to bind leukotrienes and free fatty acids in vitro Therefore, here we assessed whether the yeast Pry1 protein binds fatty acids. Computational modeling and site-directed mutagenesis indicated that the mode of fatty acid binding is conserved between tablysin-15 and Pry1. Pry1 bound fatty acids with micromolar affinity in vitro, and its function was essential for fatty acid export in cells lacking the acyl-CoA synthetases Faa1 and Faa4. Fatty acid binding of Pry1 is independent of its capacity to bind sterols, and the two sterol- and fatty acid-binding sites are nonoverlapping. These results indicate that some CAP family members, such as Pry1, can bind different lipids, particularly sterols and fatty acids, at distinct binding sites, suggesting that the CAP domain may serve as a stable, secreted protein domain that can accommodate multiple ligand-binding sites. PMID- 28365571 TI - Subclinical Cardiac Dysfunction in Polymyositis and Dermatomyositis: A Speckle tracking Case-control Study. AB - OBJECTIVE: Subclinical heart disease occurs in up to 50% of patients with idiopathic inflammatory myopathies (IIM) and is difficult to detect through conventional imaging. We investigated the usefulness of global longitudinal strain (GLS) measurement to detect a subclinical systolic ventricular dysfunction in patients with IIM. METHODS: We enrolled 28 patients with IIM and 28 matched controls in a 1:1 fashion. Standard variables for the left ventricle (LV) and right ventricle (RV) systolic and diastolic function were measured and compared between cases and controls, along with speckle-tracking GLS of the LV and RV. A possible correlation between GLS and muscle strength, disease activity, cardiovascular risk factors, and other organ systems involvement was searched. RESULTS: Standard variables of systolic and diastolic dysfunction were similar between patients and controls. GLS was significantly lower in patients when compared with controls for both LV (-18.7 +/- 4.2% vs -21.2 +/- 2.1%, p = 0.006) and RV (-19.3 +/- 6.3% vs -22.5 +/- 3.8%, p = 0.033). Patients with IIM had a 4.9 fold increased risk for impaired left GLS [relative risk (RR) 4.9, 95% CI 1.5 15.8, p = 0.006], which involved usually basal and mid-segments of the anterior, anterior-septal, and lateral wall. Patients with IIM had a 3.4-fold increased risk for impaired right GLS (RR 3.4, 95% CI 1.1-11.7, p = 0.04) with the basal segment of the free RV wall most frequently involved. Muscle strength, disease activity, damage and duration, other organ system involvement, and previous treatment were not associated with reduced GLS. CONCLUSION: Subclinical systolic impairment is common in patients with IIM without overt LV dysfunction. In this context, GLS is a potentially useful variable. PMID- 28365572 TI - Cost-effectiveness Analysis for Genotyping before Allopurinol Treatment to Prevent Severe Cutaneous Adverse Drug Reactions. AB - OBJECTIVE: Patients with an HLA-B*58:01 allele have an increased risk of developing severe cutaneous adverse drug reactions (SCAR) when treated with allopurinol. Although one-off pharmacogenetic testing may prevent life threatening adverse drug reactions, testing prior to allopurinol initiation incurs additional costs. The study objective was to evaluate the cost effectiveness of HLA-B*58:01 screening compared with using other available urate lowering agents (ULA). METHODS: A decision-analytical model was used to compare direct medical costs and effectiveness [including lifetime saved, quality adjusted life-yrs (QALY) gained] in treating new patients with the following options: (1) genetic screening followed by allopurinol prescribing for noncarriers of HLA-B*58:01, (2) prescribing benzbromarone without screening, (3) prescribing febuxostat without screening, and (4) prescribing allopurinol without screening. A 1-year time frame and third-party payer perspective were modeled for both the entire cohort (base-case) and for the subgroup of patients with chronic kidney disease (CKD). RESULTS: The incremental cost-effectiveness ratio of genetic screening prior to ULA therapy was estimated as New Taiwan (NT) $234,610 (US$7508) per QALY gained in the base-case cohort. For patients with CKD, it was estimated as NT$230,925 (US$7390) per QALY. The study results were sensitive to the probability of benzbromarone/febuxostat-related hypersensitivity, and a negative predicted value of genotyping. CONCLUSION: HLA-B*58:01 screening gave good value for money in preventing allopurinol-induced SCAR in patients indicated for ULA therapy. In addition to the costs of genotyping, it is important to monitor ULA safety closely in adopting HLA-B*58:01 screening in practice. PMID- 28365573 TI - Serum Levels of Interleukin 33 and Soluble ST2 Are Associated with the Extent of Disease Activity and Cutaneous Manifestations in Patients with Active Adult-onset Still's Disease. AB - OBJECTIVE: Interleukin 33 (IL-33), a member of the IL-1 family and a ligand of the orphan receptor ST2, plays key roles in innate and adaptive immunity. We examined the associations between IL-33/ST2 levels and clinical manifestations of patients with active adult-onset Still's disease (AOSD). METHODS: Blood samples were collected from 40 patients with active AOSD, 28 patients with rheumatoid arthritis (RA), and 27 healthy controls (HC). The serum levels of IL-33 and soluble ST2 were determined using ELISA. Expression levels of IL-33 and ST2 in biopsy specimens obtained from 34 AOSD patients with rash were immunohistochemically investigated. RESULTS: IL-33 levels of patients with AOSD were higher than those of patients with RA and HC. Soluble ST2 levels of patients with AOSD were higher than those of HC, but not of patients with RA. Serum IL-33 levels correlated with systemic score, erythrocyte sedimentation rate, ferritin levels, and aspartate transaminase levels. However, serum soluble ST2 levels correlated only with ferritin levels. The numbers of inflammatory cells expressing IL-33 and ST2 were elevated in skin lesions of patients with AOSD compared to HC, but did not differ from those of the skin lesions of eczema or psoriasis. CONCLUSION: We found significantly higher serum IL-33 and soluble ST2 levels in patients with active AOSD. Results indicate that the IL-33/ST2 signaling pathway may play a role in the pathogenesis of the acute inflammation and skin manifestations associated with AOSD. PMID- 28365574 TI - Developing a Core Set of Outcome Measures for Behcet Disease: Report from OMERACT 2016. AB - OBJECTIVE: The Outcome Measures in Rheumatology (OMERACT) Vasculitis Working Group has been working toward developing a data-driven core set of outcome measures for use in clinical trials of Behcet's syndrome [Behcet disease (BD)]. This paper summarizes the group's work through OMERACT 2016, discussions during the meeting, and the future research agenda. METHODS: Qualitative patient interviews were conducted among 20 patients with BD who have different types of organ involvement. A 3-round Delphi among BD experts and patients was initiated to identify domains, subdomains, and outcomes to be assessed in clinical trials of BD. The results of these studies were discussed during OMERACT 2016 and next steps were planned. RESULTS: Patients' perspectives and priorities were identified through qualitative interviews that identified candidate domains and subdomains for inclusion in the Delphi and characterized some shortcomings of the currently used patient-reported outcomes in BD. The first round of the Delphi was completed and several domains or subdomains were endorsed by the experts and/or the patients. Because many more items were endorsed than would be feasible to assess during a clinical trial, rating and ranking of items by physicians and patients was planned as a next critical step. The challenges of assessing specific organ system involvement was also discussed. CONCLUSION: The OMERACT Behcet Syndrome Working Group research program will identify core domains for assessment in BD with the goal of developing a core set of outcome measures for use in all trials of BD with the option to incorporate additional outcomes for specific organ involvement. PMID- 28365575 TI - A Patient-reported Outcome Measure for Effect of Glucocorticoid Therapy in Adults with Inflammatory Diseases Is Needed: Report from the OMERACT 2016 Special Interest Group. AB - OBJECTIVE: The need for a standardized instrument to measure the effect of glucocorticoid (GC) therapy has been well documented in the literature. The aim of the first GC Special Interest Group was to define a research agenda around the development of a patient-reported outcome measure (PROM) in this area. METHODS: The results of a background literature search and the preliminary results of a pilot survey and 2 qualitative studies were presented to facilitate the development of a research agenda. RESULTS: It was agreed that there was a need for a data-driven PROM that identified both positive and negative effects of GC therapy to be used across all inflammatory indications for systemic GC use in adults. A research agenda was developed, consisting of further qualitative work to assess the effect of GC across different groups including various indications for GC use, different age groups, different dosages, and duration of treatment. CONCLUSION: There was agreement on the need for a PROM in this area and a research agenda was set. PMID- 28365576 TI - Decreased Cardiovascular Mortality in Patients with Incident Rheumatoid Arthritis (RA) in Recent Years: Dawn of a New Era in Cardiovascular Disease in RA? AB - OBJECTIVE: To assess trends in cardiovascular (CV) mortality in patients with incident rheumatoid arthritis (RA) in 2000-07 versus the previous decades, compared with non-RA subjects. METHODS: The study population consisted of Olmsted County, Minnesota, USA residents with incident RA (age >= 18 yrs, 1987 American College of Rheumatology criteria was met in 1980-2007) and non-RA subjects from the same underlying population with similar age, sex, and calendar year of index. All subjects were followed until death, migration, or December 31, 2014. Followup was truncated for comparability. Aalen-Johansen methods were used to estimate CV mortality rates, adjusting for competing risk of other causes. Cox proportional hazards models were used to compare CV mortality by decade. RESULTS: The study included 813 patients with RA and 813 non-RA subjects (mean age 55.9 yrs; 68% women for both groups). Patients with incident RA in 2000-07 had markedly lower 10-year overall CV mortality (2.7%, 95% CI 0.6-4.9%) and coronary heart disease (CHD) mortality (1.1%, 95% CI 0.0-2.7%) than patients diagnosed in 1990-99 (7.1%, 95% CI 3.9-10.1% and 4.5%, 95% CI 1.9-7.1%, respectively; HR for overall CV death: 0.43, 95% CI 0.19-0.94; CHD death: HR 0.21, 95% CI 0.05-0.95). This improvement in CV mortality persisted after accounting for CV risk factors. Ten year overall CV mortality and CHD mortality in 2000-07 RA incidence cohort was similar to non-RA subjects (p = 0.95 and p = 0.79, respectively). CONCLUSION: Our findings suggest significantly improved overall CV mortality, particularly CHD mortality, in patients with RA in recent years. Further studies are needed to examine the reasons for this improvement. PMID- 28365577 TI - Submaximal Exercise Capacity in Juvenile Dermatomyositis after Longterm Disease: The Contribution of Muscle, Lung, and Heart Involvement. AB - OBJECTIVE: To compare submaximal exercise capacity in patients with juvenile dermatomyositis (JDM) with controls, and analyze contributions of muscle, heart, and lung impairment in patients. METHODS: Fifty-nine patients with JDM, with a mean 16.9 years after symptom onset, and 59 sex- and age-matched controls completed a 6-min walk test (6MWT) and a timed up and go (TUG) test. Muscle function, disease activity/damage, and health-related quality of life (HRQOL) were assessed by validated tools; heart function by echocardiography and electrocardiography; and lung function by spirometry, DLCO, and body plethysmography. A thoracic high-resolution computed tomography (HRCT) scan and magnetic resonance imaging of the thighs were completed in patients. RESULTS: The 6MWT distance (6MWD) was 592 +/- 81 m in patients versus 649 +/- 79 m in controls (p < 0.001), and 563 +/- 75 m in active versus 622 +/- 76 m in inactive JDM (p = 0.004). The TUG time was 13.1 +/- 2.1 s in patients versus 12.3 +/- 2.0 s in controls (p = 0.034), and 13.7 +/- 2.2 s in active versus 12.5 +/- 1.8 s in inactive JDM (p = 0.028). No statistically significant difference was found between inactive JDM and controls in either test. In patients, the Childhood Myositis Assessment Score influenced the 6MWD and TUG time the most, followed by a low DLCO and HRCT pathology in the 6MWT and forced vital capacity in the TUG test. Medical Outcomes Study Short Form-36 physical component summary correlated strongly with both tests. CONCLUSION: Submaximal exercise capacity was reduced in patients with JDM, particularly those with active disease. This reduction was associated with muscle and lung dysfunction and poorer HRQOL. PMID- 28365578 TI - Patients with Early Rheumatoid Arthritis in the 2000s Have Equal Disability and Pain Despite Less Disease Activity Compared with the 1990s: Data from the BARFOT Study over 8 Years. AB - OBJECTIVE: To compare outcomes over the first 8 years in patients with early rheumatoid arthritis (RA) recruited in the 1990s and the 2000s, with a special focus on functional disability and its possible predictors. METHODS: Data were acquired from 1938 patients with early RA (American College of Rheumatology 1987 criteria) included in the BARFOT study, who had completed the 8-year followup. The patients were divided into 2 cohorts: cohort 1 (n = 928, 68% women) included from 1992 to 1999 and cohort 2 (n = 1010, 70% women) included from 2000 to 2006. Health Assessment Questionnaire (HAQ), 28-joint Disease Activity Score (DAS28), visual analog scale pain, and radiographs of hands and feet scored by the van der Heijde modified Sharp method were assessed during the 8 years. Longitudinal data analyses were performed using a generalized linear model. RESULTS: Despite more active medical treatment during the 2000s, the courses of HAQ and pain showed no difference between the cohorts during followup, in either women or in men, with significantly higher levels in women compared with men. However, as expected, disease activity decreased more over time in cohort 2 compared with cohort 1, for both sexes, and women in cohort 2 had less radiographic progression compared with cohort 1. HAQ was associated with DAS28, pain, radiological scores, and sex in both cohorts, and in cohort 2 also with age and smoking. CONCLUSION: Patients included in the 2000s had lower disease activity, but not less activity limitation and pain over 8 years of followup despite more active treatment. Pain, aging, and smoking might explain why patients included in the 2000s still had the same disability levels as those included in the 1990s. PMID- 28365579 TI - The Use of Magnetic Resonance Imaging in Axial Spondyloarthritis: Time to Bridge the Gap Between Radiologists and Rheumatologists. AB - OBJECTIVE: Magnetic resonance imaging (MRI) is involved in the assessment of axial spondyloarthritis (axSpA); however, anecdotal evidence suggests diverse practice among radiologists. The objective of this study was to describe current practice in the use of MRI for assessment of axSpA by UK radiologists. METHODS: Six hundred ninety-nine UK radiologists were invited to complete an online survey. Availability of MR scanners, familiarity with axSpA disease-specific lesions, and MRI protocols and definitions of positive sacroiliac joint (SIJ) or spinal MRI were assessed. RESULTS: Two-hundred sixty-nine radiologists (38%) from 131/180 (73%) acute UK National Health Service trusts/health boards responded. MRI waiting times < 2 months were reported by 90% of radiologists. Twenty-nine radiologists (11%) used contrast as standard, 256 (91%) used T1 and short-tau inversion recovery, and 172 (64%) also used T2 sequences. Five percent scanned only SIJ, 33% scanned SIJ and lumbar spine, 29% scanned SIJ and thoracolumbar spine, and 30% scanned SIJ and the whole spine. Mean scan time was 34 min. Eighteen percent did not use the subchondral bone marrow edema of the SIJ to help diagnose axSpA and 18% did not use the inflammatory vertebral corner lesions to assist diagnosis. Awareness of axSpA was reported by 75% of radiologists, and awareness of definitions for positive MRI of SIJ and spine by 31% and 25%, respectively. CONCLUSION: These data highlight the need for better rheumatology radiology collaboration on the identification of diagnostic axSpA MRI lesions and support the need for a consensus on the most appropriate MRI protocols for the assessment of axSpA. PMID- 28365580 TI - Measuring Physical Activity in Juvenile Idiopathic Arthritis: Activity Diary Versus Accelerometer. AB - OBJECTIVE: (1) To determine convergent validity of an activity diary (AD) and accelerometer (Actical brand/Phillips-Respironics) in measuring physical activity (PA) in children with juvenile idiopathic arthritis (JIA). (2) To determine how many days give reliable results. (3) To analyze effects of correcting accelerometer data for non-wear. METHODS: Patients with JIA (8-13 yrs) were recruited from 3 Dutch pediatric rheumatology centers. PA was assessed for 7 days with an AD and accelerometer, and was expressed as mean min/day of rest, light PA (LPA), moderate to vigorous PA (MVPA), and PA level (PAL). To analyze convergent validity, intraclass correlation coefficients (ICC) were calculated and paired sample Student t tests were performed. The required number of days to achieve reliable results was calculated using the Spearman-Brown prophecy formula. RESULTS: Convergent validity between AD and accelerometer was moderate for rest and PAL (ICC 0.41). ICC for LPA and MVPA were < 0.24. AD overestimated PAL and MVPA compared with the accelerometer. Wearing the accelerometer 7-19 days gave reliable PA estimates on group and individual levels. For the AD, 13-36 days were needed. Adjusting accelerometer data for non-wear resulted in a clinically relevant higher mean number of min/day spent in LPA (effect size 1.12), but not in MVPA (effect size 0.44). CONCLUSION: Convergent validity between AD and accelerometer is moderate to poor. In children with JIA, 1-week assessment with an accelerometer is sufficient to measure PA (all levels) reliably. On an individual level and for clinical use, 3 weeks are required. Additional use of AD enables correction for non-wear of accelerometer data. PMID- 28365581 TI - Validation of a Knowledge Transfer Tool for the Knee Inflammation MRI Scoring System for Bone Marrow Lesions According to the OMERACT Filter: Data from the Osteoarthritis Initiative. AB - OBJECTIVE: To assess feasibility and reliability of scoring bone marrow lesions (BML) on knee magnetic resonance imaging (MRI) in osteoarthritis using the Outcome Measures in Rheumatology Knee Inflammation MRI Scoring System (KIMRISS), with a Web-based interface and online training with real-time iterative calibration. METHODS: Six readers new to the KIMRISS (3 radiologists, 3 rheumatologists) scored sagittal T2-weighted fat-saturated MRI in 20 subjects randomly selected from the Osteoarthritis Initiative data, at baseline and 1-year followup. In the KIMRISS, the reader moves a transparent overlay grid within a Web-based interface to fit bones, then clicks or touches each region containing BML per slice, to score 1 if BML is present. Regional and total scores are automatically calculated. Outcomes include the interreader intraclass correlation coefficients (ICC) and the smallest detectable change (SDC). RESULTS: Scoring took 3-12 min per scan and all readers rated the process as moderately to very user friendly. Despite a low BML burden (average score 2.8% of maximum possible) and small changes, interobserver reliability was moderate to high for BML status and change in the femur and tibia (ICC 0.78-0.88). Four readers also scored the patella reliably, whereas 2 readers were outliers, likely because of image artifacts. SDC of 1.5-5.6 represented 0.7% of the maximum possible score. CONCLUSION: We confirmed feasibility of knee BML scoring by new readers using interactive training and a Web-based touch-sensitive overlay system, finding high reliability and sensitivity to change. Further work will include adjustments to training materials regarding patellar scoring, and study in therapeutic trial datasets with higher burden of BML and larger changes. PMID- 28365582 TI - The Relationship Between Cardiac Conduction Times, Cardiovascular Risk Factors, and Inflammation in Patients with Early Arthritis. AB - OBJECTIVE: To investigate the prevalence of conduction disorders in patients with early arthritis and the relationship with inflammation and traditional cardiovascular (CV) risk factors. METHODS: Patients with rheumatoid arthritis (RA) have a 2-fold higher risk of sudden cardiac death, possibly owing to conduction disorders. This increased risk might already be present at the clinical onset of arthritis. Therefore, we assessed electrocardiography, blood pressure, 28-joint Disease Activity Score (DAS28), lipid profile, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) level in 480 patients with early arthritis at baseline and after 1 year. RESULTS: The prevalence of conduction disorders was 12.5%. Conduction times at baseline were not associated with DAS28, ESR, or CRP levels and did not change during antirheumatic treatment. Baseline and the improvement in DAS28 (European League Against Rheumatism response), ESR, and CRP were significantly associated with heart rate, lipid profile, and blood pressure. Elevated total cholesterol and blood pressure were associated with an increased QRS time. The change in heart rate differed 7.3 bpm between patients with the least versus largest DAS improvement. CONCLUSION: The prevalence of conduction disorders in patients with early arthritis was 12.5%, which is similar to the general population and was not associated with changes in inflammation markers. However, a high cholesterol was associated with a prolonged QRS time. Therefore, the emphasis of CV risk management in arthritis should not be only on treatment of disease activity but also on traditional CV risk factors. The relationship between the improvement in disease activity and heart rate is remarkable because this could imply a 10-year CV mortality risk difference of 24%. PMID- 28365583 TI - Predictors of Relapse after Discontinuing Systemic Treatment in Childhood Autoimmune Chronic Uveitis. AB - OBJECTIVE: To identify clinical predictors of relapse in childhood autoimmune chronic uveitis after stopping systemic treatment. METHODS: A retrospective, multicenter, cohort study. RESULTS: Ninety-four children in remission, receiving no treatments and with at least a 6-month followup, were enrolled. A higher probability of maintaining remission after discontinuing treatment was shown in idiopathic compared with juvenile idiopathic arthritis uveitis (Mantel-Cox chi square = 23.21) if inactivity had been obtained within 6 months from starting systemic treatment (Mantel-Cox chi-square = 24.17) and by antitumor necrosis factor-alpha treatment (Mantel-Cox chi-square = 6.43). CONCLUSION: Type of disease, time, and type of systemic therapy to achieve inactivity predict different duration of uveitis remission after treatment withdrawal. PMID- 28365584 TI - Antifibrillarin Antibodies Are Associated with Native North American Ethnicity and Poorer Survival in Systemic Sclerosis. AB - OBJECTIVE: To examine the clinical correlates and survival in patients with antifibrillarin antibodies (AFA) in a large international study population consisting of well-characterized systemic sclerosis (SSc) cohorts from Canada, Australia, and the United States. METHODS: Baseline clinical data from the prospective cohorts (Canadian Scleroderma Research Group, the Australian Scleroderma Cohort Study, and the American Genetics versus Environment in Scleroderma Outcome Study) were investigated. Clinical variables were harmonized and sera were tested for AFA using a commercially available SSc profile line immunoassay, regardless of the immunofluorescence staining pattern. Association of demographic and clinical features with AFA was investigated by logistic or linear regression. Further, a survival analysis was performed by Cox regression analysis. RESULTS: A total of 1506 patients with SSc with complete serological profiles were included in the study. Fifty-two patients (3.5%) had antibodies detected against fibrillarin. Patients of African descent and Native North American ethnicity were more likely to be AFA-positive compared with other ethnicities. After adjustment for demographic factors, diffuse involvement, and intestinal bacterial overgrowth requiring antibiotics, gastrointestinal reflux disease showed a trend for association with AFA. Further, AFA positivity was associated with shorter survival independently of demographic factors and disease type (HR 1.76, 95% CI 1.11-2.79, p = 0.016). CONCLUSION: In this large multinational SSc cohort, AFA was associated with Native American ethnicity and was an independent predictor of mortality. PMID- 28365585 TI - Ventilator-induced lung injury increases expression of endothelial inflammatory mediators in the kidney. AB - In critical illness, such as sepsis or the acute respiratory distress syndrome, acute kidney injury (AKI) is common and associated with increased morbidity and mortality. Mechanical ventilation in critical illnesses is also a risk factor for AKI, but it is potentially modifiable. Injurious ventilation strategies may lead to the systemic release of inflammatory mediators from the lung due to ventilator induced lung injury (VILI). The systemic consequences of VILI are difficult to differentiate clinically from other systemic inflammatory syndromes, such as sepsis. The purpose of this study was to identify unique changes in the expression of inflammatory mediators in kidney tissue in response to VILI compared with systemic sepsis to gain insight into direct effects of VILI on the kidney. Four groups of mice were compared-mice with sepsis from cecal ligation and puncture (CLP), mice subjected to injurious mechanical ventilation with high tidal volumes (VILI), mice exposed to CLP followed by VILI (CLP+VILI), and sham controls. Protein expression of common inflammatory mediators in kidneys was analyzed using a proteome array and confirmed by Western blot analysis or ELISA. VEGF and VCAM-1 were found to be significantly elevated in kidneys from VILI mice compared with sham and CLP. Angiopoietin-2 was significantly increased in CLP+VILI compared with CLP alone and was also correlated with higher levels of AKI biomarker, neutrophil gelatinase-associated lipocalin. These results suggest that VILI alters the renal expression of VEGF, VCAM-1, and angiopoietin-2, and these proteins warrant further investigation as potential biomarkers and therapeutic targets. PMID- 28365586 TI - ENaC and ROMK activity are inhibited in the DCT2/CNT of TgWnk4PHAII mice. AB - Mice transgenic for genomic segments harboring PHAII (pseudohypoaldosteronism type II) mutant Wnk4 (with-No-Lysine kinase 4) (TgWnk4PHAII) have hyperkalemia which is currently believed to be the result of high activity of Na-Cl cotransporter (NCC). This leads to decreasing Na+ delivery to the distal nephron segment including late distal convoluted tubule (DCT) and connecting tubule (CNT). Since epithelial Na+ channel (ENaC) and renal outer medullary K+ channel (ROMK or Kir4.1) are expressed in the late DCT and play an important role in mediating K+ secretion, the aim of the present study is to test whether ROMK and ENaC activity in the DCT/CNT are also compromised in the mice expressing PHAII mutant Wnk4. Western blot analysis shows that the expression of betaENaC and gammaENaC subunits but not alphaENaC subunit was lower in TgWnk4PHAII mice than that in wild-type (WT) and TgWnk4WT mice. Patch-clamp experiments detected amiloride-sensitive Na+ currents and TPNQ-sensitive K+ currents in DCT2/CNT, suggesting the activity of ENaC and ROMK. However, both Na+ and ROMK currents in DCT2/CNT of TgWnk4PHAII mice were significantly smaller than those in WT and TgWnk4WT mice. In contrast, the basolateral K+ currents in the DCT were similar among three groups, despite higher NCC expression in TgWnk4PHAII mice than those of WT and TgWnk4WTmice. An increase in dietary K+ intake significantly increased both ENaC and ROMK currents in the DCT2/CNT of all three groups. However, high-K+ (HK) intake-induced stimulation of Na+ and K+ currents was smaller in TgWnk4PHAII mice than those in WT and TgWnk4WT mice. We conclude that ENaC and ROMK channel activity in DCT2/CNT are inhibited in TgWnk4PHAII mice and that Wnk4PHAII-induced inhibition of ENaC and ROMK may contribute to the suppression of K+ secretion in the DCT2/CNT in addition to increased NCC activity. PMID- 28365587 TI - Electronic nicotine delivery system (ENDS) use during smoking cessation: a qualitative study of 40 Oklahoma quitline callers. AB - OBJECTIVES: Approximately 10% (40 000) of US quitline enrollees who smoke cigarettes report current use of electronic nicotine delivery systems (ENDS); however, little is known about callers' ENDS use. Our aim was to describe why and how quitline callers use ENDS, their beliefs about ENDS and the impact of ENDS use on callers' quit processes and use of FDA-approved cessation medications. DESIGN: Qualitative interviews conducted 1-month postregistration. Interviews were recorded, transcribed, double-coded and analysed to identify themes. SETTING: Oklahoma Tobacco Helpline. PARTICIPANTS: 40 callers aged >=18 who were seeking help to quit smoking were using ENDS at registration and completed >=1 programme calls. RESULTS: At 1-month postregistration interview, 80% of callers had smoked cigarettes in the last 7 days, almost two-thirds were using ENDS, and half were using cessation medications. Nearly all believed ENDS helped them quit or cut down on smoking; however, participants were split on whether they would recommend cessation medications, ENDS or both together for quitting. Confusion and misinformation about potential harms of ENDS and cessation medications were reported. Participants reported using ENDS in potentially adaptive ways (eg, using ENDS to cut down and nicotine replacement therapy to quit, and stepping down nicotine in ENDS to wean off ENDS after quitting) and maladaptive ways (eg, frequent automatic ENDS use, using ENDS in situations they did not previously smoke, cutting down on smoking using ENDS without a schedule or plan to quit), which could impact the likelihood of quitting smoking or continuing ENDS use. CONCLUSIONS: These qualitative findings suggest quitline callers who use ENDS experience confusion and misinformation about ENDS and FDA-approved cessation medications. Callers also use ENDS in ways that may not facilitate quitting smoking. Opportunities exist for quitlines to educate ENDS users and help them create a coordinated plan most likely to result in completely quitting combustible tobacco. PMID- 28365588 TI - Associations of anthropometry and lifestyle factors with HDL subspecies according to apolipoprotein C-III. AB - The presence of apoC-III on HDL impairs HDL's inverse association with coronary heart disease (CHD). Little is known about modifiable factors explaining variation in HDL subspecies defined according to apoC-III. The aim was to investigate cross-sectional associations of anthropometry and lifestyle with HDL subspecies in 3,631 participants from the Diet, Cancer, and Health study originally selected for a case-cohort study (36% women; age 50-65 years) who were all free of CHD. Greater adiposity and less activity were associated with higher HDL containing apoC-III and lower HDL lacking apoC-III. Per each 15 cm higher waist circumference, the level of HDL containing apoC-III was 2.8% higher (95% CI: 0.4, 5.3; P = 0.024) and the level of HDL not containing apoC-III was 4.7% lower (95% CI: -6.0, -3.4; P = <0.0001). Associations for physical activity were most robust to multivariable modeling. Each 20 metabolic equivalent task hours per week reported higher physical activity was associated with 0.9% (95% CI: 1.7, -0.1; P = 0.031) lower HDL containing apoC-III and 0.5% higher (95% CI: 0.1, 1.0; P = 0.029) HDL lacking apoC-III. Lower alcohol consumption was associated with lower HDL lacking apoC-III (percent difference per 15 g/day: 1.58 (95% CI: 0.84, 2.32; P = <0.0001). Adiposity and sedentary lifestyle were associated with a less favorable HDL subspecies profile. PMID- 28365589 TI - Survival and cause of death in multiple sclerosis: a 60-year longitudinal population study. AB - OBJECTIVE: Survival and causes of death (COD) in multiple sclerosis (MS) provide ultimate endpoints. We aimed to investigate survival and COD in a 60-year population-based MS cohort compared with the general population. METHODS: All patients with incident multiple sclerosis (MS) (N=1388) with onset during 1953 2012 in Hordaland County, Western Norway, were included. Data were obtained from patient records at Haukeland University Hospital and linked to the Norwegian COD registry. Survival adjusted for sex, age and disease course were estimated by Kaplan-Meier analyses from birth and from disease onset. Mortality and COD in MS relative to the general population were examined by standardised mortality ratio (SMR). RESULTS: Of 1388 patients, 291 had deceased, mainly of MS (56.4%). Median life expectancy was 74.7 years for MS and 81.8 years for the general population (p<0.001); 77.2 years for women with MS and 72.2 years for men with MS (p<0.001). Life expectancy for patients with relapsing remitting MS (RRMS) was 77.8 years and -71.4 years for primary progressive MS (PPMS) (p<0.001). Overall SMR was 2.7 (p>0.0001); 2.9 in women and 2.5 in men (p=0.0009). SMR was 2.4 in RRMS and 3.9 in PPMS (p<0.0001). SMR from disease onset during 1953-1974 was 3.1; 2.6 during 1975-1996 and 0.7 during 1997-2012 (p<0.0083). No difference in cause-specific deaths were found (p=0.0871). CONCLUSION: We found a 7-year shorter life expectancy and almost threefold higher mortality in MS compared with the general population. A rise in survival in MS was observed during the entire observation period. PMID- 28365590 TI - Familial primary lateral sclerosis or dementia associated with Arg573Gly TBK1 mutation. PMID- 28365591 TI - 2016 Winner: Viswanadh Madugula. PMID- 28365594 TI - Similar dynamics for ORC and Y RNAs in replication. PMID- 28365595 TI - A mechanosensory role for p130Cas FAT. PMID- 28365597 TI - How mycolactone affects Sec61 - it's complicated. PMID- 28365593 TI - Development and dynamics of cell polarity at a glance. AB - Cells exhibit morphological and molecular asymmetries that are broadly categorized as cell polarity. The cell polarity established in early embryos prefigures the macroscopic anatomical asymmetries characteristic of adult animals. For example, eggs and early embryos have polarized distributions of RNAs and proteins that generate global anterior/posterior and dorsal/ventral axes. The molecular programs that polarize embryos are subsequently reused in multiple contexts. Epithelial cells require apical/basal polarity to establish their barrier function. Migrating cells polarize in the direction of movement, creating distinct leading and trailing structures. Asymmetrically dividing stem cells partition different molecules between themselves and their daughter cells. Cell polarity can develop de novo, be maintained through rounds of cell division and be dynamically remodeled. In this Cell Science at a Glance review and poster, we describe molecular asymmetries that underlie cell polarity in several cellular contexts. We highlight multiple developmental systems that first establish cell/developmental polarity, and then maintain it. Our poster showcases repeated use of the Par, Scribble and Crumbs polarity complexes, which drive the development of cell polarity in many cell types and organisms. We then briefly discuss the diverse and dynamic changes in cell polarity that occur during cell migration, asymmetric cell division and in planar polarized tissues. PMID- 28365596 TI - Dendritic NOX2 replenishment from the lysosome. PMID- 28365598 TI - Combining serial-section EM with immunogold labelling to visualise connexosomes. PMID- 28365599 TI - The Era of Personalized Dentistry Is Upon Us: It's Time to Include It in Dental Curricula. PMID- 28365601 TI - Productivity of Senior Dental Students Engaged in Comprehensive Care: A Seven Year Follow-Up Study. AB - The aims of this study were to determine the trend of senior dental students' rate of production of clinical procedures performed in the comprehensive care clinic at one U.S. dental school and to compare that trend to what was reported immediately following inception of that clinic. In addition, total clinic revenues collected were recorded and compared. The periods used for comparisons were 2005 and 2006 combined, the last years before introduction of comprehensive care (called "pre-comp care"); 2007 and 2008 combined, the first two years of comprehensive care (called "post-comp care"); and subsequent years through 2014. The number of procedures and total charges were tracked in the electronic health record, and the total number of student-hours was calculated by multiplying the number of students in the class by the total number of available clinic hours. The rate calculated in this way was then multiplied by a factor of 1,000 for ease of interpretation. The results showed a generally upward trend and a significant increase from post-comp care to 2014 for all procedures combined and for indirect restorations. There was a generally downward trend and a significant decrease from post-comp care to 2014 for direct restorations, extractions, and root planing. There was some up and down fluctuation but no significant change from post-comp care to 2014 for exams. In terms of all procedures, the rate per student/1,000 clinic hours increased from approximately 227 to 419, an 85% increase over seven years. These results show that implementation of the comprehensive care clinic model of clinical education has increased the total clinical productivity of senior dental students at this dental school. Additional studies are indicated to determine the proper balance between a quality education and the financial capabilities of the institution. PMID- 28365600 TI - Dental Students' Clinical Experience Across Three Successive Curricula at One U.S. Dental School. AB - As dental schools continue to seek the most effective ways to provide clinical education for students, it is important to track the effects innovations have on students' clinical experience to allow for quantitative comparisons of various curricula. The aim of this study was to compare the impact of three successive clinical curricula on students' experience at one U.S. dental school. The three were a discipline-based curriculum (DBC), a comprehensive care curriculum (CCC), and a procedural requirement curriculum plus externships (PRCE). Students' clinic experience data from 1992 to 2013 were analyzed for total experience and in five discipline areas. Clinic experience metrics analyzed were patient visits (PVs), relative value units (RVUs), and equivalent amounts (EQAs). A minimum experience threshold (MET) and a high experience threshold (HET) were set at one standard deviation above and below the mean for the DBC years. Students below the MET were designated as low achievers; students above the HET were designated as high achievers. The results showed significant differences among the three curricula in almost all areas of comparison: total PVs, total EQAs, total RVUs, RVUs by discipline, and number of high and low achievers in total clinical experience and by discipline. The comprehensive care approach to clinical education did not negatively impact students' clinical experience and in many cases enhanced it. The addition of externships also enhanced student total clinical experience although more study is needed to determine their effectiveness. The insights provided by this study suggest that the methodology used including the metrics of PVs, EQAs, and RVUs may be helpful for other dental schools in assessing students' clinical experience. PMID- 28365602 TI - Benefits of Case-Based versus Traditional Lecture-Based Instruction in a Preclinical Removable Prosthodontics Course. AB - This study compared the acceptability and relative effectiveness of case-based learning (CBL) versus traditional lecture-based (LB) instruction in a preclinical removable prosthodontics course in the University of North Carolina at Chapel Hill School of Dentistry DDS curriculum. The entire second-year class (N=82) comprised this crossover study's sample. Assessments of baseline comprehension and confidence in removable partial denture (RPD) treatment planning were conducted at the beginning of the course. Near the end of the course, half of the class received CBL and LB instruction in an RPD module in alternating sequence, with students serving as their own control group. Assessments of perceived RPD treatment planning efficacy, comprehension, and instruction method preference were administered directly after students completed the RPD module and six months later. Analyses of variance accounting for period, carryover, and sequence effects were used to determine the relative effects of each approach using a p<0.05 statistical significance threshold. The results showed that the students preferred CBL (81%) over LB instruction (9%), a pattern that remained unchanged after a six-month period. Despite notable period and carryover effects, CBL was also associated with higher gains in RPD treatment planning comprehension (p=0.04) and perceived efficacy (p=0.01) compared to LB instruction. These gains diminished six months after the course-a finding based on a 49% follow-up response rate. Overall, the students overwhelmingly preferred CBL to LB instruction, and the findings suggest small albeit measurable educational benefits associated with CBL. This study's findings support the introduction and further testing of CBL in the preclinical dental curriculum, in anticipation of possible future benefits evident during clinical training. PMID- 28365603 TI - Predoctoral Dental Students' Perceptions of Dental Implant Training: Effect of Preclinical Simulation and Clinical Experience. AB - The aims of this study were to assess 1) differences in perceptions of dental implant training between dental students who received didactic training alone (control group) and those who received didactic plus simulation training (test group); 2) differences in response between students with and without clinical experience in implant dentistry; and 3) the interaction effect of simulation training and clinical experience on students' satisfaction. A survey was distributed to the control group in 2014 and to the test group in 2015; both groups were at the same U.S. dental school. Data were collected on confidence levels with various implant restorative procedures along with overall satisfaction and number of implant restorations performed by each student. The response rate was 78.7% in the control group and 81.3% in the test group. In the control group, 85.7% of students reported being satisfied with implant training compared to 90.8% of students in the test group. The interaction effect of simulation training and clinical experience on overall student satisfaction was OR=1.5 at 95% CI: 0.8, 3.0. The students who had clinical experience with implant restorative procedures had significantly greater satisfaction than those who did not (OR=4.8, 95% CI: 2.1, 11.1, p<0.01). This study found that both the simulation and clinical experience affected these students' confidence and satisfaction levels with implant education: they were almost five times more satisfied with implant training when clinical experience in implant restorative procedures was a part of their implant education. PMID- 28365604 TI - Patients' Perceptions of Dental Students' Empathic, Person-Centered Care in a Dental School Clinic in Malaysia. AB - Empathy has been identified as a crucial foundation in building an effective dentist-patient relationship. The aim of this study was to assess patients' perceptions of dental students' empathic care in the primary oral health care clinic at International Medical University in Kuala Lumpur, Malaysia in May October 2014. The study also assessed the validity and reliability of the Consultation and Relational Empathy (CARE) Measure in this setting; the association between number of encounters and students' CARE Measure scores; and the association between students' empathy (measured by the Toronto Empathy Questionnaire) and CARE Measure scores. Participants were 283 patients (aged >=18 years) who were asked to self-complete the ten-item CARE Measure immediately after their clinical encounter with students who provided care under supervision of the teaching staff. The results showed that the CARE Measure demonstrated good internal consistency (Cronbach's alpha=0.95). A single factor solution emerged, accounting for 69% of the variance. The mean CARE Measure score in the consultations was 43.55+/-6.14, and 26% of the students achieved the maximum possible score of 50. The mean number of encounters with each student was 2.33+/ 2.78. An increase of one episode was associated with an insignificant average CARE score decrease of 0.05 (-0.28, 0.38), whereas students' empathy was associated with a small increase in average CARE Measure score of 0.63 (0.08, 1.18). These results provide evidence of the measure's ability to support feedback to dental students on their empathy when interacting with patients. PMID- 28365605 TI - Perceived Dentist and Dental Hygienist Task Distribution After Dental and Dental Hygiene Students' Team Intervention. AB - Attitudes of dental students regarding the provision of treatment tend to be dentist-centered; however, facilitating mixed student group formation could change such perceptions. The aim of this study was to investigate the perceived scope of practice of dental and dental hygiene students and whether their perceptions of task distribution between dentists and dental hygienists would change following an educational intervention consisting of feedback, intergroup comparison, and competition between mixed-group teams. The study employed a pretest-posttest single group design. Third-year dental students and second-year dental hygiene students at a university in The Netherlands were randomly assigned to intraprofessional teams (four or five members) and received team-based performance feedback and comparison. The intervention was finalized with an award ceremony for the best intraprofessional team. Before and after the intervention, students completed a questionnaire measuring their perceived distribution of ten tasks between dentists and dental hygienists. A total of 38 dental students and 32 dental hygiene students participated in the intervention-all 70 of those eligible. Questionnaires were completed by a total 88.4% (n=61) of the participants: 34 dental (89.5%) and 27 dental hygiene students (84.4%). Dental and dental hygiene students had similar perceptions regarding teeth cleaning (prophylaxis) (p=0.372, p=0.404) and, after the intervention, preventive tasks (p=0.078). Following the intervention, dental students considered four out of ten tasks as less dentist-centered: radiograph for periodontal diagnosis (p=0.003), local anesthesia (p=0.037), teeth cleaning (p=0.037), and periodontal treatment (p=0.045). Dental hygiene students perceived one task as being less dentist centered after the intervention: radiograph for cariologic diagnosis (p=0.041). This study found that these dental and dental hygiene students had different opinions regarding the scope of practice for dentistry and dental hygiene. The number of redistributed tasks after the intervention was especially substantial among the dental students, although the amount of change per task was minimal. Half of all tasks were perceived as less dentist-centered as a result of the intervention. PMID- 28365606 TI - Assessment of Thiel-Embalmed Cadavers as a Teaching Tool for Oral Anatomy and Local Anesthesia. AB - The aim of this study was to determine whether Thiel-embalmed cadavers would provide a useful anatomy teaching tool for topics that cannot be approached using formalin-fixed cadavers such as oral cavity examination and maxillary anesthesia. The suitability of Thiel-embalmed bodies for performing oral examinations was assessed by asking first-year dental and dental hygiene students at a dental school in Ireland to identify oral structures on a classmate and on a Thiel embalmed body. The study was conducted in 2016. The ease of location was compared in the two settings, and their quality was assessed on the cadavers. The suitability of Thiel-embalmed cadavers to teach maxillary anesthesia was assessed by students' performing mock injections at five adjacent sites daily for five consecutive days, followed by inspection of the gingival surface by experienced anatomists and dentists. Data were obtained from 57 students, but only the 54 forms that were fully completed were analyzed, for an overall response rate of 85.7%. The results showed that most oral structures were more difficult to locate on cadavers. The texture and appearance of features in the cadavers were rated at a midpoint between realistic and unrealistic. The relative inexperience of the participants, the accumulation of fixative in the oral cavity, and discoloration were mentioned as potential confounding factors. Visual analysis of images obtained following repeated injections revealed no deterioration of the tissue. Importantly, the puncture marks appeared to reduce over time, suggesting that the gingival tissue maintains some elasticity following Thiel fixation. These findings suggest that Thiel-embalmed cadavers may be a useful tool to provide students more time to localize and study aspects of the oral cavity. Likewise, the recoiling capacity of gingival tissue suggests that Thiel-embalmed cadavers may provide an ideal tool for teaching injection technique of local anesthetics. PMID- 28365607 TI - Do Standard Bibliometric Measures Correlate with Academic Rank of Full-Time Pediatric Dentistry Faculty Members? AB - The aim of this cross-sectional study was to assess the relationship between quantitative measures of research productivity and academic rank for full-time pediatric dentistry faculty members in accredited U.S. and Canadian residency programs. For each pediatric dentist in the study group, academic rank and bibliometric factors derived from publicly available databases were recorded. Academic ranks were lecturer/instructor, assistant professor, associate professor, and professor. Bibliometric factors were mean total number of publications, mean total number of citations, maximum number of citations for a single work, and h-index (a measure of the impact of publications, determined by total number of publications h that had at least h citations each). The study sample was comprised of 267 pediatric dentists: 4% were lecturers/instructors, 44% were assistant professors, 30% were associate professors, and 22% were professors. The mean number of publications for the sample was 15.4+/-27.8. The mean number of citations was 218.4+/-482.0. The mean h-index was 4.9+/-6.6. The h index was strongly correlated with academic rank (r=0.60, p=0.001). For this sample, an h-index of >=3 was identified as a threshold for promotion to associate professor, and an h-index of >=6 was identified as a threshold for promotion to professor. The h-index was strongly correlated with the academic rank of these pediatric dental faculty members, suggesting that this index may be considered a measure for promotion, along with a faculty member's quality and quantity of research, teaching, service, and clinical activities. PMID- 28365608 TI - Challenges of Dental Assisting Students in Their Pursuit of Academic Success. AB - The aim of this study was to identify the challenges encountered by dental assisting students, especially those from underrepresented racial and ethnic groups (UREG), that affected their achieving academic success. In 2016, directors of the nine northern California dental assisting programs were contacted via email to explain the study and request an opportunity to administer the 26-item survey to their currently enrolled students. Student responses were entered into a survey research program, which tabulated the data and calculated the frequency of responses to each item. All nine programs participated, and the overall student response rate was 98%. Most (71%) of the 215 respondents agreed that they had experienced challenges in achieving academic success. Respondents reported the following challenges that made it difficult to perform well at school: financial responsibilities (41%), family responsibilities (33%), and language challenges (21%). These challenges, as well as difficulty understanding the language and vocabulary of instructional materials and cost of tuition and supplies, were statistically related to respondents' perceptions of their challenges to academic success. Most (83%) of the respondents perceived that faculty members supported their academic success. One-third of the respondents were from UREG: Hispanic, African American, and Native American. Higher percentages of UREG than non-UREG participants worked more hours/week (p=0.03) and tended to perceive financial (52%/32%) and family (42%/28%) responsibilities as challenges. Since both UREG and non-UREG respondents experienced these challenges, all students should be informed of institutional and programmatic resources that can assist them in achieving academic success. PMID- 28365609 TI - Improving Documentation, Compliance, and Approvals in an Electronic Dental Record at a U.S. Dental School. AB - The aims of this study were to improve progress note documentation by dental students, achieve accurate and timely charge capture and treatment code and note approval, and determine the effectiveness of multiple interventions in improving overall documentation of patient encounters in the clinic of one U.S. dental school. The study, conducted in 2014-15, used a logic model to create a process to address documentation issues in the clinic's electronic dental record (EDR) and to assess the effectiveness of interventions. An initial documentation review using the EDR was performed to obtain a baseline measurement. A significant correlation was noted at baseline between poor documentation and unapproved treatment codes and notes. Unapproved treatment codes and corresponding documentation were then reviewed each month. Students who had the highest number of unapproved treatment codes were identified as potentially having documentation issues. These students were contacted and met individually with the associate quality and compliance officer to review documentation and charge practices. Large group education was also provided to key learners: dental students and supervising faculty members. Education consisted of an in-service event for faculty members and a Moodle site course on documentation for students. After one year, the results showed that documentation rates improved from an overall rate of 61% to 81% of required documentation elements being present in the progress note. Although this educational intervention was successful in significantly improving documentation of treatment in the EDR, 19% of the notes at the conclusion of the study were still missing key elements. Further research is necessary to determine whether the interventions will continue to improve documentation or if additional measures need to be taken. PMID- 28365610 TI - Stereoscopy in Dental Education: An Investigation. AB - The aim of this study was to investigate whether stereoscopy can play a meaningful role in dental education. The study used an anaglyph technique in which two images were presented separately to the left and right eyes (using red/cyan filters), which, combined in the brain, give enhanced depth perception. A positional judgment task was performed to assess whether the use of stereoscopy would enhance depth perception among dental students at Osaka University in Japan. Subsequently, the optimum angle was evaluated to obtain maximum ability to discriminate among complex anatomical structures. Finally, students completed a questionnaire on a range of matters concerning their experience with stereoscopic images including their views on using stereoscopy in their future careers. The results showed that the students who used stereoscopy were better able than students who did not to appreciate spatial relationships between structures when judging relative positions. The maximum ability to discriminate among complex anatomical structures was between 2 and 6 degrees. The students' overall experience with the technique was positive, and although most did not have a clear vision for stereoscopy in their own practice, they did recognize its merits for education. These results suggest that using stereoscopic images in dental education can be quite valuable as stereoscopy greatly helped these students' understanding of the spatial relationships in complex anatomical structures. PMID- 28365611 TI - Top-Cited Articles in Problem-Based Learning: A Bibliometric Analysis and Quality of Evidence Assessment. AB - The aims of this study were to identify characteristics of the top-cited articles in problem-based learning (PBL) and assess the quality of evidence provided by these articles. The most frequently cited articles on PBL were searched in April 2015 in the Science Citation Index Expanded database (List A) and Google Scholar database (List B). Eligible articles identified were reviewed for key characteristics. The Oxford Centre for Evidence-Based Medicine guidelines were used in assessing the level of evidence. The number of citations varied (62 to 923 on List A and 218 to 2,859 on List B). Countries that contributed the majority of articles in both lists were the United States, Netherlands, United Kingdom, and Canada. No significant correlations were found between number of citations and number of years since published (p=0.451), number of authors (p=0.144), females in authorship (p=0.189), non-medical authors (p=0.869), number of institutions (p=0.452), and number of grants (p=0.143), but a strong correlation was found with number of countries involved (p=0.007). Application of the Oxford hierarchy of evidence showed that 36 articles were at levels 4 and 5 of evidence. This study found that research articles represented approximately one-third of PBL articles assessed and reported mainly on questionnaire-based studies. The most highly cited articles occupied top-ranking positions in the journals in which they were published. The lower level of evidence observed in most top-cited articles may reflect the significance of innovative ideas or content of these articles. These findings have implications for dental educators and dental researchers. PMID- 28365612 TI - Determining Recommendations for Improvement of Communication Skills Training in Dental Education: A Scoping Review. AB - Professional communication skills have a significant impact on dental patient satisfaction and health outcomes. Communication skills training has been shown to improve the communication skills of dental students. Therefore, strengthening communication skills training in dental education shows promise for improving dental patient satisfaction and outcomes. The aim of this study was to facilitate the development of dental communication skills training through a scoping review with compilation of a list of considerations, design of an example curriculum, and consideration of barriers and facilitators to adoption of such training. A search to identify studies of communication skills training interventions and programs was conducted. Search queries were run in three databases using both text strings and controlled terms (MeSH), yielding 1,833 unique articles. Of these, 35 were full-text reviewed, and 17 were included in the final synthesis. Considerations presented in the articles were compiled into 15 considerations. These considerations were grouped into four themes: the value of communication skills training, the role of instructors, the importance of accounting for diversity, and the structure of communication skills training. An example curriculum reflective of these considerations is presented, and consideration of potential barriers and facilitators to implementation are discussed. Application and evaluation of these considerations are recommended in order to support and inform future communication skills training development. PMID- 28365614 TI - 'Evolution, not revolution, at the changing of the Guard'. PMID- 28365615 TI - Practical steps in promoting synergies between clinical medicine and public health. PMID- 28365616 TI - The new UK internal medicine curriculum . AB - Reform of physician education is needed to meet the needs of patients, based on comorbidities, chronic disease management and complexity. The Joint Royal Colleges of Physicians Training Board has developed a new internal medicine curriculum for physician training that aims to not only deliver this expectation, but will simplify competency-based education, smooth the transition to the medical registrar role and hopefully fill some of the current empty funded training posts. However, the change process is complex and requires close working with the General Medical Council and other partners in curriculum delivery. PMID- 28365617 TI - The Francis Crick Institute. AB - The Francis Crick Institute Laboratory, opened in 2016, is supported by the Medical Research Council, Cancer Research UK, the Wellcome Trust, and University College London, King's College London and Imperial College London. The emphasis on research training and early independence of gifted scientists in a multidisciplinary environment provides unique opportunities for UK medical science, including clinical and translational research. PMID- 28365618 TI - Diagnosing gestational diabetes mellitus: implications of recent changes in diagnostic criteria and role of glycated haemoglobin (HbA1c). AB - Gestational diabetes mellitus (GDM; approximately 5% of pregnancies) represents the most important risk factor for development of later-onset diabetes mellitus. We examined concordance between GDM diagnosis defined using the original 1999 World Health Organization (WHO) criteria and the more recent 2013 WHO criteria and 2015 National Institute for Health and Care Excellence (NICE) criteria. We studied two groups: a case-control group of 257 GDM positive and 266 GDM negative cases, and an incident cohort 699 GDM positive and 6,231 GDM negative cases. In the incident cohort, GDM prevalence was 3.7% (WHO 1999 criteria), 11.4% (NICE 2015 criteria) and 13.7% (WHO 2013 criteria). Our results showed that a significant number of additional cases are detected using the more recent NICE and WHO criteria than the original 1999 WHO criteria, but these additional cases represent an intermediate group with 'moderate' dysglycaemia (abnormal blood glucose levels). Our results also show that use of these newer criteria misses a similar group of intermediate cases that were defined as GDM by the 1999 WHO criteria and that glycated haemoglobin in isolation is unlikely to replace the oral glucose tolerance test in GDM diagnosis. PMID- 28365619 TI - The assessment of headaches on the acute medical unit: is it adequate and how could it be improved? . AB - Neurological emergencies represent 15-25% of the medical take, second only to cardiac and respiratory cases. However, the UK's number of neurologists is lower than that of other developed nations. This quality improvement project aimed to develop a guideline to optimise acute headache management by non-specialists, informed by the findings of a survey and audit of doctors' knowledge and practice. In total, 62 doctors responded to our survey. 53/56 (94.6%) agreed a guideline would be useful. Knowledge of some important causes of headache was high, but was lower for others, including cerebral venous sinus thrombosis and cervical artery dissection. A consultant neurologist deemed 14/27 (51.9%) of acute headache presentations audited pre-guidelines to have had appropriate management. After guideline launch, a re-audit demonstrated this proportion was 18/22 (81.8%) (p=0.04). We conclude the investigation and management of acute headache requires optimisation and a guideline may help to achieve this. PMID- 28365620 TI - Current characteristics, challenges and coping strategies of young people with cystic fibrosis as they transition to adulthood. AB - This study provides detailed data on the current characteristics, perceptions and outcomes of 45 young people with cystic fibrosis (CF) as they transition into adulthood. Although many had severe disease, they generally coped well, found attendance at a transition clinic helpful and welcomed the increased independence of an adult healthcare environment. Levels of psychological distress were low with only 15.6% having anxiety and 6.7% depression. The main psychological coping strategy used was optimistic acceptance. Overall, most remained stable after transfer but 33% had some decline in lung function and 9% in nutritional status, requiring intensification of treatment. They had high levels of satisfaction with their relationships and life situations and 76% were in employment or education. These results are encouraging and as life expectancy improves, young adults with CF are coping well with transition into adulthood. PMID- 28365622 TI - Proton pump inhibitor failure in gastro-oesophageal reflux disease: a perspective aided by the Gartner hype cycle. AB - Some patients with gastro-oesophageal reflux disease (GORD) experience symptoms despite proton pump inhibitor (PPI) treatment. In the early years of their availability, these drugs were thought to be a highly effective treatment for GORD and realisation that symptom relief was often incomplete came as a disappointment. This review considers the evolution of thinking with the aid of the Gartner hype cycle - a graphical depiction of the process of innovation, evolution and adoption of new technologies. Acknowledging that over-simplistic concepts of GORD have been largely responsible for inflated expectations of PPI therapy is an important step forward in establishing how patients with persistent symptoms, despite PPIs, should be assessed and treated. PMID- 28365621 TI - Physician associates in England's hospitals: a survey of medical directors exploring current usage and factors affecting recruitment. AB - In the UK secondary care setting, the case for physician associates is based on the cover and stability they might offer to medical teams. We assessed the extent of their adoption and deployment - that is, their current usage and the factors supporting or inhibiting their inclusion in medical teams - using an electronic, self-report survey of medical directors of acute and mental health NHS trusts in England. Physician associates - employed in small numbers, in a range of specialties, in 20 of the responding trusts - were reported to have been employed to fill gaps in medical staffing and support medical specialty trainees. Inhibiting factors were commonly a shortage of physician associates to recruit and lack of authority to prescribe, as well as a lack of evidence and colleague resistance. Our data suggest there is an appetite for employment of physician associates while practical and attitudinal barriers are yet to be fully overcome. PMID- 28365623 TI - The late medical effects of cancer treatments: a growing challenge for all medical professionals. PMID- 28365624 TI - Getting to the heart of hypopituitarism. AB - A 53-year-old woman was diagnosed with hypopituitarism following an acute presentation with cardiac tamponade and hyponatraemia, having recently been investigated for a pericardial effusion. Secondary hypothyroidism is a rare cause of pericardial effusion and tamponade, but an important differential to consider. Management requires appropriate hormone replacement and, critically, a low threshold for commencing stress dose steroids. Clinical signs classically associated with cardiac tamponade are frequently absent in cases of tamponade due to primary and secondary hypothyroidism, and the relatively volume deplete state of secondary hypoadrenalism in hypopituitarism may further mask an evolving tamponade, as the rise in right atrial pressure is less marked even in the presence of large effusion. Our case demonstrates the importance of a high index of suspicion for cardiac tamponade in this patient cohort, even in the absence of clinical signs, and for measuring both thyroid-stimulating hormone and thyroxine levels when evaluating a pericardial effusion. PMID- 28365625 TI - Paradoxical reaction in the form of pleural effusion after onset of anti tuberculous medication for tubercular lymphadenitis. AB - We present the case of a 26-year-old Indian male who developed pleural effusion while undergoing treatment for tuberculous lymphadenitis. We describe the work-up for his condition and how he was managed. The possibility of development of a paradoxical reaction in the form of pleural effusion after initiation of anti tuberculous therapy has to be kept in mind while treating such patients. PMID- 28365626 TI - Update in diagnosis and management of interstitial lung disease . AB - The field of interstitial lung disease (ILD) has undergone significant evolution in recent years, with an increasing incidence and more complex, ever expanding disease classification. In their most severe forms, these diseases lead to progressive loss of lung function, respiratory failure and eventually death. Despite notable advances, progress has been challenged by a poor understanding of pathological mechanisms and patient heterogeneity, including variable progression. The diagnostic pathway is thus being continually refined, with the introduction of tools such as transbronchial cryo lung biopsy and a move towards genetically aided, precision medicine. In this review, we focus on how to approach a patient with ILD and the diagnostic process. PMID- 28365627 TI - Corrigendum: Headache in an HIV positive patient: diagnostic challenges and approach to treatment. PMID- 28365628 TI - The latest national clinical guideline for stroke. PMID- 28365629 TI - Mimics and chameleons in stroke. AB - Ischaemic stroke is a treatable medical emergency. In an era of time-dependent reperfusion techniques, it is crucial that an accurate and prompt diagnosis is made. Approximately 30% of patients admitted to hyperacute stroke units are subsequently found not to have a final diagnosis of acute stroke although some of these patients do have incidental or previously symptomatic cerebrovascular disease. These patients do not benefit from thrombolysis and may require the input of other specialists or treatments. Meanwhile, a proportion of patients with acute stroke have unusual presentations and are sometimes initially admitted to general medical admissions units prior to accessing stroke unit care. It is important that atypical presentations of stroke are recognised so that patients are not denied the benefits of stroke unit care and secondary prevention. This article describes some characteristics of common stroke mimics and chameleons, considers how to avoid diagnostic mistakes and discusses the contributory role of imaging. PMID- 28365631 TI - Management of acute intracerebral haemorrhage - an update. AB - Managing acute intracerebral haemorrhage is a challenging task for physicians. Evidence shows that outcome can be improved with admission to an acute stroke unit and active care, including urgent reversal of anticoagulant effects and, potentially, intensive blood pressure reduction. Nevertheless, many management issues remain controversial, including the use of haemostatic therapy, selection of patients for neurosurgery and neurocritical care, the extent of investigations for underlying causes and the benefit versus risk of restarting antithrombotic therapy after an episode of intracerebral haemorrhage. PMID- 28365630 TI - Thrombolysis and thrombectomy for acute ischaemic stroke. AB - The likelihood of disability-free recovery after acute ischemic stroke is significantly improved by reperfusion either by intravenous thrombolytic drug treatment or with endovascular mechanical thrombectomy in selected cases. The use of intravenous thrombolysis is limited by the short treatment window and you need to assess individual balance of benefit and risk of symptomatic intracranial haemorrhage. Benefit is greater for shorter onset-to-reperfusion time intervals, requiring optimisation of pre-hospital and in-hospital pathways. Symptomatic haemorrhage is more likely with more severe strokes, but a greater proportion of patients are left free of disability than suffer a treatment-related haemorrhage at all levels of severity. Extracranial haemorrhage and orolingual angioedema are less common complications. Endovascular mechanical thrombectomy can be used in selected patients with imaging-proven large artery occlusion. Successful therapy depends on well-organised services that can deliver treatment within a short time window at centres with adequate expertise to perform the procedure. PMID- 28365632 TI - Stroke unit care, inpatient rehabilitation and early supported discharge. AB - Stroke units reduce death and disability through the provision of specialist multidisciplinary care for diagnosis, emergency treatments, normalisation of homeostasis, prevention of complications, rehabilitation and secondary prevention. All stroke patients can benefit from provision of high-quality basic medical care and some need high impact specific treatments, such as thrombolysis, that are often time dependent. A standard patient pathway should include assessment of neurological impairment, vascular risk factors, swallowing, fluid balance and nutrition, cognitive function, communication, mood disorders, continence, activities of daily living and rehabilitation goals. Good communication and shared decision making with patients and their families are key to high-quality stroke care. Patients with mild or moderate disability, who are medically stable, can continue rehabilitation at home with early supported discharge teams rather than needing a prolonged stay in hospital. National clinical guidelines and prospective audits are integral to monitoring and developing stroke services in the UK. PMID- 28365633 TI - CME Cerebrovascular disease (108460): self-assessment questionnaire. PMID- 28365634 TI - Lesson of the month 1: Beware the atypical presentation: eosinophilic granulomatosis with polyangiitis presenting as acute coronary syndrome. AB - We describe the case of a 45-year-old woman presenting with troponin positive cardiac-sounding chest pain. An initial emergency angiogram demonstrated two vessel coronary disease, including a distal right coronary artery occlusion. No percutaneous coronary intervention was performed and the patient was treated medically. At re-presentation with further pain a few days later, coronary angiography demonstrated no significant coronary lesions. After consideration of other multisystem symptoms and raised eosinophil count, the patient was diagnosed with eosinophilic granulomatosis with polyangiitis (formerly known as Churg Strauss syndrome) presenting with coronary arteritis. This case should remind physicians to be vigilant and to consider non-atherosclerotic causes of acute coronary syndrome presentation, which should not always result in a stent. PMID- 28365635 TI - Lesson of the month 2: A choroid plexus papilloma manifesting as anorexia nervosa in an adult. AB - A Caucasian female previously diagnosed with anorexia nervosa was referred by psychiatric services to the general medical team. She presented with dehydration, vomiting, weakness, a body mass index of 13 kg/m2 and was treated with intravenous and enteral supplementation. During admission her vomiting worsened and she developed visual hallucinations and confabulation. Neurological examination demonstrated cerebellar signs and bilateral papilloedema on fundoscopy. Subsequent magnetic resonance imaging of the brain revealed a large fourth ventricular tumour causing obstructive hydrocephalus. The tumour was excised and histologically confirmed to be a choroid plexus papilloma. Postoperatively her neurological symptoms and negative feelings towards eating resolved. PMID- 28365636 TI - Image of the month: All puffed out - a case of crack lung. PMID- 28365637 TI - Setting the record straight: patient recordings of consultations. PMID- 28365638 TI - Where did the acute medical trainees go? A review of the career pathways of acute care common stem acute medical trainees in London. PMID- 28365639 TI - Where did the acute medical trainees go? A review of the career pathways of acute care common stem acute medical trainees in London. PMID- 28365640 TI - Where did the acute medical trainees go? A review of the career pathways of acute care common stem acute medical trainees in London. PMID- 28365641 TI - Stroke mimic diagnoses presenting to a hyperacute stroke unit. PMID- 28365642 TI - UK Medical Education Database: an issue of assumed consent. PMID- 28365643 TI - Response. PMID- 28365646 TI - Because Women's Lives Matter, We Need to Eliminate Gender Bias. PMID- 28365644 TI - High-Throughput Genomics and Clinical Outcome in Hard-to-Treat Advanced Cancers: Results of the MOSCATO 01 Trial. AB - High-throughput genomic analyses may improve outcomes in patients with advanced cancers. MOSCATO 01 is a prospective clinical trial evaluating the clinical benefit of this approach. Nucleic acids were extracted from fresh-frozen tumor biopsies and analyzed by array comparative genomic hybridization, next-generation sequencing, and RNA sequencing. The primary objective was to evaluate clinical benefit as measured by the percentage of patients presenting progression-free survival (PFS) on matched therapy (PFS2) 1.3-fold longer than the PFS on prior therapy (PFS1). A total of 1,035 adult patients were included, and a biopsy was performed in 948. An actionable molecular alteration was identified in 411 of 843 patients with a molecular portrait. A total of 199 patients were treated with a targeted therapy matched to a genomic alteration. The PFS2/PFS1 ratio was >1.3 in 33% of the patients (63/193). Objective responses were observed in 22 of 194 patients (11%; 95% CI, 7%-17%), and median overall survival was 11.9 months (95% CI, 9.5-14.3 months).Significance: This study suggests that high-throughput genomics could improve outcomes in a subset of patients with hard-to-treat cancers. Although these results are encouraging, only 7% of the successfully screened patients benefited from this approach. Randomized trials are needed to validate this hypothesis and to quantify the magnitude of benefit. Expanding drug access could increase the percentage of patients who benefit. Cancer Discov; 7(6); 586-95. (c)2017 AACR.See related commentary by Schram and Hyman, p. 552This article is highlighted in the In This Issue feature, p. 539. PMID- 28365647 TI - Consequences of Transfusing Blood Components in Patients With Trauma: A Conceptual Model. AB - Transfusion of blood components is often required in resuscitation of patients with major trauma. Packed red blood cells and platelets break down and undergo chemical changes during storage (known as the storage lesion) that lead to an inflammatory response once the blood components are transfused to patients. Although some evidence supports a detrimental association between transfusion and a patient's outcome, the mechanisms connecting transfusion of stored components to outcomes remain unclear. The purpose of this review is to provide critical care nurses with a conceptual model to facilitate understanding of the relationship between the storage lesion and patients' outcomes after trauma; outcomes related to trauma, hemorrhage, and blood component transfusion are grouped according to those occurring in the short-term (<=30 days) and the long term (>30 days). Complete understanding of these clinical implications is critical for practitioners in evaluating and treating patients given transfusions after traumatic injury. PMID- 28365648 TI - Passive Leg-Raising and Prediction of Fluid Responsiveness: Systematic Review. AB - Fluid boluses are often administered with the aim of improving tissue hypoperfusion in shock. However, only approximately 50% of patients respond to fluid administration with a clinically significant increase in stroke volume. Fluid overload can exacerbate pulmonary edema, precipitate respiratory failure, and prolong mechanical ventilation. Therefore, it is important to predict which hemodynamically unstable patients will increase their stroke volume in response to fluid administration, thereby avoiding deleterious effects. Passive leg raising (lowering the head and upper torso from a 45 degrees angle to lying supine [flat] while simultaneously raising the legs to a 45 degrees angle) is a transient, reversible autotransfusion that simulates a fluid bolus and is performed to predict a response to fluid administration. The article reviews the accuracy, physiological effects, and factors affecting the response to passive leg raising to predict fluid responsiveness in critically ill patients. PMID- 28365649 TI - Clinical Application of Prothrombin Complex Concentrate in Blood Management in Patients. AB - Management of patients receiving anticoagulants is a major factor in achieving better outcomes. Anticoagulant therapy may need to be discontinued or rapidly reversed before urgent surgery or invasive procedures. In these situations, treatment with concentrated vitamin K, fresh frozen plasma, and/or clotting factors can achieve more rapid anticoagulant reversal than can drug discontinuation alone. Activated prothrombin complex concentrate is used to treat hemophiliac patients with acquired factor VIII inhibitors. Nonactivated prothrombin complex concentrates are used for anticoagulant reversal. The concentrates are effective within minutes of dosing, providing a nearly immediate decrease in the international normalized ratio. The concentrates are lyophilized powders that can be quickly reconstituted, do not require ABO blood typing before use, and contain 25 times the concentration of vitamin K-dependent clotting factors compared with fresh frozen plasma. Studies suggest that the concentrates are associated with better clinical end points than is fresh frozen plasma. PMID- 28365650 TI - Advancements in Pacemaker Technology: The Leadless Device. AB - Leadless pacemakers will most likely be the future of cardiac pacing. Leadless pacing employs a single-chamber system to pace only the right ventricle and is fully self-contained, which eliminates the need for leads. These systems, implanted by using a transcatheter sheath, are indicated for patients who need right ventricular pacing only. These devices enable patients to avoid lead related complications, from lead fracture to extraction challenges, as well as pocket-related complications such as infection and disfigurement. Leadless pacemakers also are compatible with magnetic resonance imaging and do not require surgical placement, so patients avoid postoperative mobility restrictions. Because this technology will be increasingly used for cardiac internal electronic devices, commonly seen in critical care nursing, nurses must be knowledgeable about the indications for use of a wireless pacemaker, the implantation procedure, postprocedural care, device interrogation, and follow-up. This article discusses leadless pacemakers, clinical indications for their use, key similarities and differences between the current devices being used, key points for nursing care of patients with a leadless device, and the future of this technology. PMID- 28365651 TI - Access to Continuing Education for Critical Care Nurses in Rural or Remote Settings. AB - Caring for the critically ill does not occur solely in large medical centers or urban areas. Nurses practicing in rural or remote settings practice as nurse generalists, caring for a wide range of patients, including those needing critical care. As a nurse generalist, the need for a wide variety of skill sets challenges nurses in rural areas to maintain current practice through continuing education across many content areas. They also may not come in contact with critically ill patients or emergent situations as often as their urban counterparts, which can make remaining comfortable with more advanced skills difficult. Because nurses working in rural or remote areas may care for critically ill patients less often, the need to remain vigilant in pursuit of continuing education is increased; however, access to continuing education can be problematic because of geographic isolation, difficulty getting time off from work, limited financial resources, and perceived lack of applicable topics. With advances in technology, critical care nurses working in rural areas have more options for continuing education, which is crucial for maintaining a skilled nursing workforce in rural health care facilities. This article addresses challenges critical care nurses working in remote or rural areas face in pursuing continuing education and provides information about available educational opportunities. PMID- 28365652 TI - Interstage Home Monitoring After Newborn First-Stage Palliation for Hypoplastic Left Heart Syndrome: Family Education Strategies. AB - Children born with hypoplastic left heart syndrome are at high risk for serious morbidity, growth failure, and mortality during the interstage period, which is the time from discharge home after first-stage hypoplastic left heart syndrome palliation until the second-stage surgical intervention. The single-ventricle circulatory physiology is complex, fragile, and potentially unstable. Multicenter initiatives have been successfully implemented to improve outcomes and optimize growth and survival during the interstage period. A crucial focus of care is the comprehensive family training in the use of home surveillance monitoring of oxygen saturation, enteral intake, weight, and the early recognition of "red flag" symptoms indicating potential cardiopulmonary or nutritional decompensation. Beginning with admission to the intensive care unit of the newborn with hypoplastic left heart syndrome, nurses provide critical care and education to prepare the family for interstage home care. This article presents detailed nursing guidelines for educating families on the home care of their medically fragile infant with single-ventricle circulation. PMID- 28365653 TI - Platitudes and Attitudes. PMID- 28365654 TI - A Paradigm Shift for Patient/Family-Centered Care in Intensive Care Units: Bring in the Family. PMID- 28365655 TI - Nonpharmacological Interventions for Sleep Promotion in the Intensive Care Unit. PMID- 28365656 TI - Can We Talk? The Bedside Report Project. PMID- 28365663 TI - Assessment and Management of Delirium Across the Life Span. PMID- 28365664 TI - Complications of Peripheral Venous Access Devices: Prevention, Detection, and Recovery Strategies. AB - Most hospitalized patients have placement of a peripheral venous access device, either a short peripheral catheter or a peripherally inserted central catheter. Compared with central venous catheters that are not peripherally inserted, the other 2 types are generally perceived by health care providers as safer and less complicated to manage, and less emphasis is placed on the prevention and management of complications. Expertise of nurses in inserting, managing, and removing these devices may reduce the likelihood of complications, and increased recognition of complications associated with use of the devices is important to ensure continued improvements in the safety, quality, and efficiency of health care. Complications associated with short peripheral catheters and peripherally inserted central catheters include tourniquet retention, tubing and catheter misconnections, phlebitis, air embolism, device fragment embolization, and inadvertent discharge with a retained peripheral venous access device. Integration of prevention, detection, and recovery strategies into personal nursing practice promotes the quality and safety of health care delivery. PMID- 28365665 TI - Nutrition Support Protocols: Enhancing Delivery of Enteral Nutrition. AB - In critical care, malnutrition has a significant, negative impact on a patient's ability to respond to medical treatment. Enteral nutrition is known to counteract the metabolic changes associated with critical illness that increase the risk for serious complications and poor clinical outcomes. Inadequate delivery of nutrition support and underfeeding persist in intensive care units despite the availability of guidelines and current research for best practice. Recent studies have shown that nutrition support protocols are effective in promoting nutritional goals in a wide variety of intensive care patients. It is essential to find approaches that enhance early delivery of enteral nutrition that meets requirements and supports improved outcomes. Nurses are in a unique position to take an active role in promoting the best nutritional outcomes for their patients by using and evaluating nutrition support protocols. PMID- 28365666 TI - 2017 National Teaching Institute Evidence-Based Solutions Abstracts: Presented at the AACN National Teaching Institute in Houston, Texas; May 22-25, 2017. PMID- 28365667 TI - ERRATUM. PMID- 28365668 TI - ERRATUM.